subject:START_ID predicate:TYPE object:END_ID primary_knowledge_source:string knowledge_level:string agent_type:string original_subject:string original_object:string snpeff_effect:string distance_to_feature:int ligand:string protein:string affinity_parameter:string supporting_affinities:float[] publications:string[] affinity:float object_aspect_qualifier:string object_direction_qualifier:string qualified_predicate:string hetio_source:string[] tmkp_confidence_score:float sentences:string tmkp_ids:string[] detection_method:string expressed_in:string[] p_value:float[] slope:float[] species_context_qualifier:string pubchem_assay_ids:string[] patent_ids:string[] aggregator_knowledge_source:string[] id:string category:string[] provided_by:string has_evidence:string[] FAERS_llr:float disease_context_qualifier:string score:float description:string[] taxon:string has_count:string has_percentage:string has_quotient:string has_total:string frequency_qualifier:string stage_qualifier:string ASSERTION:string APPLIED_EVIDENCE_CODES_MET:string APPLIED_EVIDENCE_CODES_NOT_MET:string SUMMARY:string EXPERT_PANEL:string EVIDENCE_REPO_LINK:string APPROVAL_DATA:string PUBLISHED_DATE:string MODE_OF_INHERITANCE:string HPO_FOR_MODE_OF_INHERITANCE:string[] DIRECTION:string anatomical_context_qualifier:string phosphorylation_sites:string[] onset_qualifier:string CLINGEN_VALIDITY_CLASSIFICATION:string CLINGEN_CLASSIFICATION_DATE:string CLINGEN_CLASSIFICATION_REPORT:string CLINGEN_MODE_OF_INHERITANCE:string NORMALIZED_MODE_OF_INHERITANCE:string HPO_FOR_NORMALIZED_MODE_OF_INHERITANCE:string object_specialization_qualifier:string drugmechdb_path_id:string[] GUIDELINE:string TRIPLOSENSITIVITY_DESCRIPTION:string TRIPLOSENSITIVITY_SCORE:string negated:boolean HAPLOINSUFFICIENCY_DESCRIPTION:string HAPLOINSUFFICIENCY_SCORE:string complex_context:string[] primaryTarget:boolean endogenous:boolean sex_qualifier:string population_context_qualifier:string causal_mechanism_qualifier:string subject_context_qualifier:string object_form_or_variant_qualifier:string subject_specialization_qualifier:string object_part_qualifier:string subject_part_qualifier:string CHEBI:74947 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0575081 infores:hetionet CHEBI:6073 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0003862 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005020 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0021831 infores:hetionet CAID:CA114360 biolink:causes MONDO:0009861 infores:clingen CAID:CA114360 MONDO:0009861 PMID:2574002PMID:2574002PMID:9450897 Pathogenic PM3, PP4_Moderate, PM2, PS3 PVS1 PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF=0.00002; PP4_Moderate: Seen in PKU patients. BH4 disorders ruled out. (PMID:2574002); PS3: <3% (PMID:9450897). PM3: Detected in trans with known pathogenic variants. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PS3). Updated to reflect new PVS1 recommendations. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114360/MONDO:0009861/006 2019-03-23 2019-05-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:78543 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0007785 infores:hetionet CHEBI:9667 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0151937 infores:hetionet CHEBI:51860 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038325 infores:hetionet CHEBI:8764 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0687713 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006852 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0038362 infores:hetionet CHEBI:7798 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0012833 infores:hetionet CHEBI:23765 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C1257843 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0025061 infores:hetionet NCBIGene:2542 biolink:causes MONDO:0009288 infores:monarchinitiative not_provided not_provided HGNC:4061 MONDO:0009288 uuid:b2c69267-9be5-43a7-b905-014d188b8add biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0027497 infores:hetionet CHEBI:2038 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0012813 infores:hetionet CHEBI:63620 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0392699 infores:hetionet CHEBI:9637 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0917801 infores:hetionet CHEBI:4784 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0025222 infores:hetionet CHEBI:68579 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0013491 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0029408 infores:hetionet CHEBI:44915 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0340865 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0033777 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0012739 infores:hetionet CHEBI:46557 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0424790 infores:hetionet CHEBI:3515 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0016204 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0002622 infores:hetionet CHEBI:63617 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004093 infores:hetionet CHEBI:9566 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0042963 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0281778 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0281778 infores:hetionet CHEBI:8412 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0002888 infores:hetionet CAID:CA645369422 biolink:causes MONDO:0017623 infores:clingen CAID:CA645369422 MONDO:0017623 PMID:17526801PMID:21659347PMID:20962022PMID:21194675PMID:21956414PMID:22261759PMID:20600018PMID:25669429PMID:21190448PMID:27477328 Pathogenic PVS1, PM2, PS4_Supporting PM6, BS4, BS3, BS1, BP5, BP7, BS2, PP1, PP3, PP2, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS3, PS1 PTEN c.512dup (p.R172Efs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 17526801) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369422/MONDO:0017623/003 2019-03-05 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135935 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0042075 infores:hetionet CHEBI:8764 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C2364111 infores:hetionet CHEBI:9445 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0040822 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023067 infores:hetionet CHEBI:63611 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020453 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0547030 infores:hetionet CHEBI:7601 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0042514 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004628 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0267166 infores:hetionet CHEBI:63791 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013362 infores:hetionet CHEBI:6916 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0001824 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0267792 infores:hetionet CHEBI:27504 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C2830004 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042109 infores:hetionet CHEBI:9566 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0039231 infores:hetionet CAID:CA340929 biolink:causes MONDO:0044970 infores:clingen CAID:CA340929 MONDO:0044970 PMID:19160410PMID:19454486PMID:11119722 Likely Pathogenic PP1_Moderate, PM5, PS4_Supporting, PM2_Supporting, PS3_Moderate, PP3 The m.9176T>G (p.L217R) variant in MT-ATP6 has been reported in 9 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one case with onset in late teens). Features included Leigh syndrome, seizures, ataxia, muscle weakness, dystonia, developmental regression with illness, axonal neuropathy, optic atrophy, and retinal dystrophy. Some individuals had gradual progression including one with onset in childhood but surviving to at least 40s. Others have progressed to death within months. Brain imaging in some individuals was consistent with Leigh syndrome and others with diffuse brain atrophy. Elevated blood and CSF lactate were noted. Heteroplasmy levels were >95% in multiple tissues for those with onset in childhood, 70% for gradually-progressive phenotype, and healthy family members had 28-50% heteroplasmy (PS4_supporting; PMIDs: 11245730, 11731285; Khailany et al., 2020 with no PMID). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 11245730, 11731285; Khailany et al., 2020 with no PMID). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease; absent in gnomAD v3.1.2 and Helix databset; PM2_supporting). This variant is located at the same amino acid position as another well-known pathogenic variant, m.9176T>C (p.L217P) (PM5). Several studies in E. coli (PMID: 11119722), yeast (PMID: 19454486), and cybrids (PMID: 19160410) support the functional impact of this variant and independent studies showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1_moderate, PM2_supporting, PM5, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340929/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:119915 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0239981 infores:hetionet CHEBI:6888 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018790 infores:hetionet CHEBI:5280 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0038325 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0003123 infores:hetionet CHEBI:8214 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0264906 infores:hetionet CHEBI:7936 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0026826 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006952 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0035344 infores:hetionet CHEBI:63589 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0085932 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085096 infores:hetionet CHEBI:100246 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C1609512 infores:hetionet CHEBI:55346 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151539 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0036572 infores:hetionet CHEBI:4495 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0232462 infores:hetionet CHEBI:31624 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C2939147 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235146 infores:hetionet CHEBI:66876 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0030252 infores:hetionet CHEBI:5118 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027796 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038661 infores:hetionet NCBIGene:811 biolink:causes MONDO:0008554 infores:monarchinitiative not_provided not_provided HGNC:1455 MONDO:0008554 uuid:d8912140-237f-40ba-acab-0a74f7e15df1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3U02EL437C biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0013404 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0235032 infores:hetionet CAID:CA410147765 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147765 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1213C>G (p.Leu405Val) is a missense variant which has a REVEL score < 0.50 (0.323), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147765/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA9487931 biolink:causes MONDO:0011229 infores:clingen CAID:CA9487931 MONDO:0011229 PMID: Uncertain Significance BS1 PM5, PP3, BS2, BP4, BA1, PS1, PS3, PS4, BP5, BS3 This variant was classified as a variant of uncertain significance as there has not been sufficient evidence to support either a benign or a pathogenic classification. Specifically, this variant has not been reported in the literature in affected or unaffected patients, has no published functional data. This variant is present in population databases with an allele frequency of 0.02%, which is higher allele frequency expected for a pathogenic variant in ETHE1 (BS1). However, not enough criteria were met to support a pathogenic or benign classification. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA9487931/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5778 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0032617 infores:hetionet CHEBI:6520 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0547030 infores:hetionet CHEBI:7565 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0011606 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022081 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0003811 infores:hetionet CHEBI:64312 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0917801 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0017675 infores:hetionet CHEBI:8871 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0549249 infores:hetionet CHEBI:3419 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0917801 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0037199 infores:hetionet NCBIGene:51259 biolink:causes MONDO:0011296 infores:monarchinitiative not_provided not_provided HGNC:25018 MONDO:0011296 uuid:873ee827-ebb2-4418-88d8-34bbf7a4a1c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:5552 biolink:causes MONDO:0000306 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5552 MONDO:0000306 CAID:CA343773667 biolink:causes MONDO:0013144 infores:clingen CAID:CA343773667 MONDO:0013144 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting, PS4_Supporting The c.1057C>T variant in SERPINC1 is a missense variant predicted to cause substitution of proline by serine at amino acid 353 (p.Pro353Ser). This variant has been reported in at least two probands meeting an antithrombin activity level of < 0.8 IU/mL without a family history with reported AT activity levels or repeat testing (1 point; PS4_Supporting; PMIDs:29153735, 14754620). The total minor allele frequency in gnomAD v4.1.0 is 6.1976e-7, which is lower than the ClinGen Thrombosis VCEP threshold <0.00002 meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.983, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1058C>T (p.Pro353Leu) in the same codon has been classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4_Supporting, PP3. PM2_Supporting, PM5_Supporting Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343773667/MONDO:0013144/084 2025-10-17 2025-10-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7478 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020569 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0006826 infores:hetionet CHEBI:8481 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0039971 infores:hetionet NCBIGene:5048 biolink:causes MONDO:0011830 infores:monarchinitiative not_provided not_provided HGNC:8574 MONDO:0011830 uuid:cf691568-22a4-4d41-bcc2-fa3eb0340e07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:490877 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0234215 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020039 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0175167 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0234215 infores:hetionet NCBIGene:7428 biolink:causes MONDO:0008233 infores:monarchinitiative not_provided not_provided HGNC:12687 MONDO:0008233 uuid:85eeebc8-a214-43e2-98fa-8094f5ec7afa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0016053 infores:hetionet CAID:CA915940290 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940290 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The NM_000419.5(ITGA2B):c.2478dup (p.Gly827TrpfsTer?) variant was identified in a patient (PMID 25607928) with reported GT. This variant is absent from the gnomAD database v2.1.1 (PM2_Supporting). This variant results in the insertion of a single thymine at c.2478_2479 that results in a Gly827Trp substitution and subsequent frameshift leading to a premature stop codon at amino acid 921. This occurs >50bp from the penultimate exon/intron boundary (G variant in F8 is a missense variant predicted to cause substitution of Tyrosine by Asparagine at amino acid 738 (p.Tyr738Asp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002225 (17/7641 alleles) in the Ashkenazi Jewish population, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.000333) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568350/MONDO:0010602/071 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:5296 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C2830004 infores:hetionet CHEBI:2682 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C2047937 infores:hetionet CHEBI:16899 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0011991 infores:hetionet CHEBI:3655 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0013491 infores:hetionet CHEBI:9763 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C1527344 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0346156 infores:hetionet CHEBI:4876 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0027947 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0870082 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0860942 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0860942 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0033687 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0858346 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0858346 infores:hetionet CHEBI:7573 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0030554 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0002170 infores:hetionet CHEBI:45599 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C1720775 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0851536 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0234192 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0149931 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0027769 infores:hetionet CHEBI:474180 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151539 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0860433 infores:hetionet CAID:CA512341255 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341255 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1167G>A (p.Ser389=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.37)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341255/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7445 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C2242588 infores:hetionet CHEBI:9434 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0003467 infores:hetionet CHEBI:18332 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0948594 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0232197 infores:hetionet CHEBI:408174 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151878 infores:hetionet CHEBI:3013 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0020651 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0022650 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0162429 infores:hetionet CAID:CA121523 biolink:causes MONDO:0100039 infores:clingen CAID:CA121523 MONDO:0100039 PMID:19396824PMID:19241098PMID:25657822PMID:19396824 Pathogenic PS3_Supporting, PP3, PM6, PM5_Strong, PS4_Moderate, PM2_Supporting The p.Ile72Thr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disease (PMID 19396824, 19241098) (PM6). The p.Ile72Thr variant in CDKL5 has been reported in at least 3 other individuals with CDKL5 disease (PMID 19396824, 19241098, 25657822, ClinVar) (PS4_moderate). The p.Ile72Thr variant in CDKL5 is absent from gnomAD (PM2). Multiple likely pathogenic missense variants have been previously identified within this codon (p.Ile72Asn; p.Ile72Met) which indicates that this residue is critical to the function of the protein (PMID 28074849, 27779742, 16015284) (PM5_strong). Phosphoproteomic screening of the cellular substrates of CDKL5 (MAP1S, CEP131 and DLG5) has shown that the p.Ile72Thr variant impacts protein function (PMID 30266825) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own(PP3). In summary, the p.Ile72Thr variant in CDKL5 is classified as Pathogenic for CDKL5 disease based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121523/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:9241 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0235325 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0948036 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0948036 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0039231 infores:hetionet CHEBI:7565 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0037317 infores:hetionet CHEBI:9448 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0042963 infores:hetionet CHEBI:4562 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0043352 infores:hetionet CHEBI:17303 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0037383 infores:hetionet CHEBI:2788 biolink:causes MONDO:0002307 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0005743 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0037199 infores:hetionet CHEBI:3614 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0010200 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0007137 infores:hetionet CHEBI:80630 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0018790 infores:hetionet CHEBI:4868 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0023380 infores:hetionet CHEBI:2673 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0009806 infores:hetionet CHEBI:34967 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0020615 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0917799 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006522 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0022581 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030305 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0031350 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0009450 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0040479 infores:hetionet CHEBI:50924 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0232495 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0239385 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0031117 infores:hetionet CAID:CA347485 biolink:causes MONDO:0015152 infores:clingen CAID:CA347485 MONDO:0015152 PMID: Pathogenic PP1_Moderate, PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The NM_000070.3: c.883_886delinsCTT p.(Asp295LeufsTer57) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 8/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 4 unrelated patients with clinical signs of LGMD (PMID: 16141003, 15733273, 17994539, 16650086, 15689361, 30919934), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 1614100; PM3_Supporting). This variant has also been reported to co-segregate with autosomal recessive LGMD in 3 affected members of a single family (PMID: 16141003; PP1_Moderate). In addition, at least one of the patients with this variant and a second presumed diagnostic CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Moderate, capped with PP1_Moderate; PMID: 16650086, 15689361). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/03/2025): PVS1, PM3_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347485/MONDO:0015152/187 2025-06-03 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0035455 infores:hetionet NCBIGene:2911 biolink:causes MONDO:0013905 infores:monarchinitiative not_provided not_provided HGNC:4593 MONDO:0013905 uuid:4aeace19-c3d9-4dda-b04c-51ec648a30e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0687713 infores:hetionet CHEBI:5856 biolink:causes MONDO:0020575 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0344432 infores:hetionet CHEBI:135961 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0002170 infores:hetionet CHEBI:116278 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0232461 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0178298 infores:hetionet CHEBI:3441 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151539 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0007787 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0031350 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0162429 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0018799 infores:hetionet CAID:CA314861 biolink:causes MONDO:0012996 infores:clingen CAID:CA314861 MONDO:0012996 PMID: Likely Benign BP4, BS1 PP4, PM3 The NM_001482.3:c.1042+3A>G variant in GATM is an intronic variant affecting a nucleotide within the consensus splice region of intron 7. This variant has been detected in one individual with autism spectrum disorder and epilepsy (PMID: 35512185), who was heterozygous for the variant without a second GATM variant reported and without biochemical evidence of AGAT deficiency reported; thus, neither PM3 nor PP4 apply. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00046 (14/30616 alleles) in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.01 for donor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 205609). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314861/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0017797 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0243026 infores:hetionet CHEBI:17141 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0018524 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0020649 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0018801 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0857493 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0857493 infores:hetionet CHEBI:48538 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0009676 infores:hetionet CHEBI:84500 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1167965 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0548823 infores:hetionet NCBIGene:123263 biolink:causes MONDO:0032631 infores:monarchinitiative not_provided not_provided HGNC:29666 MONDO:0032631 uuid:1c7d9aa2-4a20-4374-982d-1af4c430bdd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018800 infores:hetionet CHEBI:63630 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042023 infores:hetionet CHEBI:63616 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0085633 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0002871 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1112353 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1112353 infores:hetionet CHEBI:64312 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018800 infores:hetionet CHEBI:40303 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0027497 infores:hetionet CHEBI:34967 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0233477 infores:hetionet CHEBI:41879 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C2242996 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013595 infores:hetionet NCBIGene:2038 biolink:causes MONDO:0012985 infores:monarchinitiative not_provided not_provided HGNC:3381 MONDO:0012985 uuid:38f2fb22-5df2-4e27-b14d-73a4e430e90a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151577 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0006840 infores:hetionet CHEBI:9566 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0023380 infores:hetionet CHEBI:64310 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C2173677 infores:hetionet CHEBI:50122 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0744727 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0541919 infores:hetionet CHEBI:4672 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0268000 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0036572 infores:hetionet CHEBI:28748 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0028961 infores:hetionet NCBIGene:51300 biolink:causes MONDO:0032634 infores:monarchinitiative not_provided not_provided HGNC:1321 MONDO:0032634 uuid:58dfe539-1ca9-4944-b575-ddfcf3c0b577 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA160105 biolink:causes MONDO:0012163 infores:clingen CAID:CA160105 MONDO:0012163 PMID: Benign BS2_Supporting, BA1 The c.731C>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 244 (p.Thr244Ile).The filtering allele frequency (the lower threshold of the 95% CI of 21695/63972 alleles) of the c.731C>T variant in IL7R is 0.2678 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 53760 homozygous adults are reported in gnomAD v.4. BS2_Supporting is Met. In summary, this variant meets the criteria to be classified as Benign for Autosomal Recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160105/MONDO:0012163/119 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA607158216 biolink:causes MONDO:0009861 infores:clingen CAID:CA607158216 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_000277.3:c.353-7_353-5dup variant in PAH is an intronic variant affecting 3 nucleotides in intron 3. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005782 (2/34590 alleles) in the Latino/Admixed American population, which is lower than the ClinGen PAH VCEP’s threshold for PM2_Supporting (<0.0002), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.28 for acceptor loss which is neither above nor below the thresholds predicting an impact (>0.5) or no impact (<0.2) on PAH splicing. There is a ClinVar entry for this variant (Variation ID: 552806, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA607158216/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:134966 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0037199 infores:hetionet CHEBI:17474 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0030554 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0948168 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0948168 infores:hetionet CHEBI:6759 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0522224 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0973461 infores:hetionet CHEBI:63611 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0240671 infores:hetionet CHEBI:64354 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0030252 infores:hetionet NCBIGene:56916 biolink:causes MONDO:0007619 infores:monarchinitiative not_provided not_provided HGNC:18398 MONDO:0007619 uuid:9208c48a-7368-4249-8fcc-72f6f06d8a60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64321 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0017178 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011570 infores:hetionet CHEBI:61049 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0031154 infores:hetionet CHEBI:2379 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0016382 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0227791 infores:hetionet CHEBI:2676 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C1443060 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0413252 infores:hetionet CHEBI:4911 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0033774 infores:hetionet CAID:CA412741589 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741589 MONDO:0100437 PMID: Likely Pathogenic PM5_Supporting, PP3_Strong, PM2_Supporting PM6, PP4, PS4 NM_001034853.2(RPGR):c.824G>T (p.Gly275Val) is a missense variant causing substitution of glycine by valine at amino acid 275. Another missense variant in the same codon, NM_001034853.2:c.823G>A (p.Gly275Ser) (PMIDs: 17480003, 31456290, 17724181, 16969763, and 8817343), has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (109) than the comparison variant (56), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a phenotype consistent with RPGR-related retinopathy (0.25 pts, PMID: 22888088), which does not score sufficient de novo points to meet PM6_Supporting. The proband's phenotypes include male onset before age 2 years (1 point), undetectable electroretinogram responses, family inheritance consistent with X-linked inheritance (2 points), and sinorespiratory infections with ciliary ultrastructural defects detected by microscopy, which together are not sufficiently specific to meet PP4 for RPGR-related retinopathy (PMID: 22888088). PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The computational predictor REVEL gives a score of 0.979, which is above the ClinGen X-linked IRD VCEP threshold of ≥0.932 and predicts a damaging effect on RPGR function (PP3_Strong). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PM5, and PP3_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741589/MONDO:0100437/106 2025-09-07 2025-09-08 X-linked inheritance HP:0001417 Supports CHEBI:6149 biolink:causes UMLS:C0456677 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0456677 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040435 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001590 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034372 infores:hetionet CHEBI:8346 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0429097 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0009450 infores:hetionet CHEBI:6444 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0020649 infores:hetionet CHEBI:31302 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0233795 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006849 infores:hetionet NCBIGene:1277 biolink:causes MONDO:0008146 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0008146 uuid:c5262296-386e-4da7-b4f7-48c212a59d2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0235896 infores:hetionet CAID:CA16020889 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020889 MONDO:0009861 PMID:25757997PMID:19292873PMID:19292873PMID:19292873 Pathogenic PP4_Moderate, PM2, PP3, PS3, PM3_Supporting The c.902A>C (p.Gln301Pro) variant in PAH has been reported in at least 1 individual with hyperphenylalaninemia, who carried a second pathogenic variant (p.Leu48Ser) (BH4 deficiency ruled out, parental analysis not performed) (PMID: 19292873, 25757997) . The p.Gln301Pro variant is absent in gnomAD and the ESP population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.987. In addition the p.Gln301Pro causes a significant reduction of enzyme activity and expression when tested in vitro (PMID: 19292873). In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_supporting, PS3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020889/MONDO:0009861/006 2019-07-14 2019-07-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50173 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030312 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020538 infores:hetionet CHEBI:27882 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0015230 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0025061 infores:hetionet CHEBI:9649 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151632 infores:hetionet GO:0090256 biolink:causes GO:0007472 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0007472 CHEBI:7575 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0012739 infores:hetionet CHEBI:61049 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019345 infores:hetionet CHEBI:3756 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0024031 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0040034 infores:hetionet CHEBI:5959 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C1291078 infores:hetionet CHEBI:16755 biolink:causes HP:0033821 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0149726 infores:hetionet CHEBI:63630 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1510410 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003123 infores:hetionet CHEBI:50922 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085631 infores:hetionet CHEBI:31536 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0520573 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0742339 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0742339 infores:hetionet GO:0032887 biolink:causes GO:0007051 infores:ubergraph knowledge_assertion manual_agent GO:0032887 GO:0007051 CHEBI:64064 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0019825 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041956 infores:hetionet CHEBI:9605 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0012833 infores:hetionet CAID:CA2499223953 biolink:causes MONDO:0011132 infores:clingen CAID:CA2499223953 MONDO:0011132 PMID:37419334PMID:34860543 Pathogenic PP1, PM2_Supporting, PS3, PVS1_Strong PP4, PS4 The NM_001369369.1(FOXN1):c.1370del (p.His457ProfsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). The variant is absent from gnomADv4.0 (PM2_supporting). The heterozygous expression of Δ505 Foxn1 in mice, the ortholog of the human mutation, results in thymic hypoplasia, a limited population of peripheral T cells, and changes in the composition of the TEC scaffold. Mice homozygous for the Δ505 mutation were hairless and lacked a thymus and peripheral T cells (PS3). Additional functional evidence is available from a luciferase reporter construct cotransfected into heterologous cells together with an expression vector containing FOXN1. This variant had 0.6% luciferase activity compared to WT (PMID: 37419334). This variant has been reported (PMID: 34860543) heterozygous in one patient with T cell lymphopenia (32% of total lymphocytes) and absence of TCR excision circles. The patients sister and father also harbor this heterozygous variant and have absent TRECs, the sister also has a missing thymus and a reduction in naive T cells (PP1). In summary, this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PS3, PM2_supporting, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499223953/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:61058 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0855242 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0040479 infores:hetionet UMLS:C0657912 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085636 infores:hetionet CHEBI:40279 biolink:causes UMLS:C2712871 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2712871 infores:hetionet CHEBI:3213 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0232766 infores:hetionet CHEBI:4975 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0039070 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0017574 infores:hetionet CHEBI:61049 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2607914 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0034186 infores:hetionet CHEBI:28001 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0042963 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0008370 infores:hetionet CHEBI:7915 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013362 infores:hetionet NCBIGene:727676 biolink:causes MONDO:0013803 infores:monarchinitiative not_provided not_provided HGNC:32952 MONDO:0013803 uuid:24d6f135-ac51-40c3-8a51-9acd4985645c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020517 infores:hetionet NCBITaxon:773 biolink:causes MONDO:0005664 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:773 MESH:D001474 DB02703_MESH_D001474_1DB01017_MESH_D001474_1DB00254_MESH_D001474_1 CHEBI:50648 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0010200 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0017601 infores:hetionet CAID:CA410203944 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203944 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.196G>A (p.Ala66Thr) is a missense variant which has a REVEL score < 0.50 (0.451), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203944/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2687 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0085612 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0855242 infores:hetionet CHEBI:15544 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0036974 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0034065 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0748726 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0748726 infores:hetionet CHEBI:15765 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0005747 infores:hetionet CHEBI:51364 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0036508 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0427108 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020649 infores:hetionet CHEBI:64312 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0014724 infores:hetionet CHEBI:66899 biolink:causes UMLS:C0877306 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0877306 infores:hetionet UNII:0RK7M7IABE biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0027765 infores:hetionet CHEBI:4657 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0043352 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0750394 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0006266 infores:hetionet CHEBI:3312 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0041582 infores:hetionet CHEBI:2618 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0009806 infores:hetionet GO:2000024 biolink:causes GO:0048367 infores:ubergraph knowledge_assertion manual_agent GO:2000024 GO:0048367 CHEBI:6413 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0948089 infores:hetionet CHEBI:5138 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0028754 infores:hetionet NCBITaxon:263 biolink:causes MONDO:0018077 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:263 MONDO:0018077 PUBCHEM.COMPOUND:122173801 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0016204 infores:hetionet CHEBI:45863 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2242996 infores:hetionet CHEBI:34764 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00663 UMLS:C0020517 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0520757 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0520757 infores:hetionet CHEBI:63630 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0338831 infores:hetionet CAID:CA404084697 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084697 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, PM5, PM4, PM1, PM3, PM6, PVS1, PP3, PP4, BS2 The NM_000527.5(LDLR):c.1210A>T (p.Thr404Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD v2.1.1 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084697/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5001 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0004093 infores:hetionet CHEBI:70735 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0036974 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0022658 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023533 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0017152 infores:hetionet CHEBI:15553 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0151798 infores:hetionet CHEBI:45409 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1145670 infores:hetionet CHEBI:204928 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0014457 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042075 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020621 infores:hetionet CHEBI:8364 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0018524 infores:hetionet NCBIGene:79005 biolink:causes MONDO:0859310 infores:monarchinitiative not_provided not_provided HGNC:23136 MONDO:0859310 uuid:27c12aea-55f2-422b-89ab-d9e3f7a529a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0006840 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0040034 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003537 infores:hetionet CAID:CA4516829 biolink:causes MONDO:0021060 infores:clingen CAID:CA4516829 MONDO:0021060 PMID: Uncertain Significance PP2 PM1, PM2, PP3, BS2, BP4 The c.1024A>G (p.Ile342Val) variant in BRAF has been identified in 0.005644% (2/35438) of Latino chromosomes in gnomAD v2.1.1. This variant has been observed in several individuals whose clinical presentations lacked clear associations with a RASopathy (Invitae internal data, SCV000820707.1; Fulgent internal data; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=8) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data, SCV000617143.2). Computational prediction tools and conservation analyses do not provide strong support for pathogenicity given the disease mechanism. In summary, the clinical significance of this variant is uncertain. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA4516829/MONDO:0021060/004 2020-03-19 2020-03-23 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:3664 biolink:causes MONDO:0007333 infores:monarchinitiative not_provided not_provided HGNC:6121 MONDO:0007333 uuid:e11136d3-9ac9-4f3c-984c-af2f4c4bd460 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28177 biolink:causes UMLS:C1140716 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C1140716 infores:hetionet CHEBI:28901 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085593 infores:hetionet CHEBI:6149 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0039231 infores:hetionet CAID:CA645288018 biolink:causes MONDO:0010305 infores:clingen CAID:CA645288018 MONDO:0010305 PMID: Likely Benign BS2, BP4 PM2 The NM_005629.4:c.913-8T>C variant in SLC6A8 is an intronic variant affecting a nucleotide in the consensus splice region of intron 5. To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population minor allele frequency is 0.00001901 (17/894100 alleles, 2 hemizygotes) in the European (non-Finnish) population. This allele frequency is just below the threshold for PM2_Supporting (<0.00002), but the criterion was not applied due to the present of hemizygotes. There are 2 hemizygotes in the European non-Finnish population (BS2). SpliceAI predicts that the variant has no impact on splicing (score <0.2) (BP4). There is a ClinVar entry for this variant (Variation ID: 702759. In summary, this variant meets criteria to be classified as likely benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645288018/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:3347 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0035455 infores:hetionet CHEBI:28593 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C1096355 infores:hetionet NCBIGene:8694 biolink:causes MONDO:0014375 infores:monarchinitiative not_provided not_provided HGNC:2843 MONDO:0014375 uuid:b6e5b75b-d019-4173-8edb-b21ea732ce0b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8665 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0006277 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009450 infores:hetionet CHEBI:8069 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0005758 infores:hetionet CHEBI:63635 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0015672 infores:hetionet CHEBI:8874 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0016658 infores:hetionet CHEBI:39867 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013604 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0746883 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0015376 infores:hetionet CHEBI:617099 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C2047937 infores:hetionet UBERON:0002394 biolink:causes MONDO:0019087 infores:ubergraph knowledge_assertion manual_agent UBERON:0002394 MONDO:0019087 CHEBI:32315 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042023 infores:hetionet CHEBI:3011 biolink:causes MONDO:0013577 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0398370 infores:hetionet CHEBI:4858 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0003467 infores:hetionet CHEBI:79699 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0423791 infores:hetionet CAID:CA10014219 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014219 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1030G>A (p.Asp344Asn) is a missense variant which has a MAF of 0.0002921 (0.0291%, 13/44506, 13 alleles) in the East Asian subpopulation of the gnomAD v4.0.0 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score < 0.50 (0.082) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014219/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50859 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0024115 infores:hetionet CHEBI:2453 biolink:causes MONDO:0000809 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0085650 infores:hetionet CHEBI:51230 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0042164 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0025061 infores:hetionet CHEBI:2379 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0264906 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018099 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0035309 infores:hetionet NCBIGene:51081 biolink:causes MONDO:0054741 infores:monarchinitiative not_provided not_provided HGNC:14499 MONDO:0054741 uuid:961e10af-ca28-4a11-939e-67635a248fab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905304 biolink:causes GO:0061061 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0061061 CHEBI:7476 biolink:causes MONDO:0850230 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0263338 infores:hetionet CHEBI:16586 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0234215 infores:hetionet CHEBI:15940 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0015967 infores:hetionet CHEBI:404903 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0043144 infores:hetionet CHEBI:50131 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020580 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0038367 infores:hetionet CHEBI:68584 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C2830004 infores:hetionet CHEBI:75722 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0344232 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042401 infores:hetionet CHEBI:6950 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1456784 infores:hetionet NCBIGene:3643 biolink:causes MONDO:0012520 infores:monarchinitiative not_provided not_provided HGNC:6091 MONDO:0012520 uuid:8e56aeb2-cd4c-4707-88c9-77a4e2641a21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:34104 biolink:causes MONDO:0001667 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:34104 MONDO:0001667 CHEBI:50567 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0012833 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0031117 infores:hetionet CAID:CA018120 biolink:causes MONDO:0005045 infores:clingen CAID:CA018120 MONDO:0005045 PMID: Uncertain Significance PP1, PP2, PP3 BP2, BA1, PS3, PS4, PS2, BS1, BS3, PM1, PM2, PM6 NM_001018005.2(TPM1):c.548C>T (p.Ala183Val). This variant has been reported in individuals with HCM (Laboratory for Molecular Medicine (LMM) data, Oxford Medical Genomics Laboratory (OMGL) data, Lopez 2015 PMID:25351510, Ross 2017 PMID: 28615295, Walsh 2017 PMID: 27532257) and has also been identified in 4 out of 113682 (FAF 95% CI > 0.004%) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). The variant is not statistically increased in individuals with HCM compared to controls (OR, lower 95% CI<5), therefore, the PS4 criterion has not been applied and the PM2_Supporting criterion has not been applied either. This variant segregated with disease in 3 affected individuals with HCM from 1 family (PP1; Ross 2017 PMID:28615295). This missense variant is in a gene that has been determined to have a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2; Walsh et al. 2019 PMID:30696458). Additionally, computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PP1, PP2 and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA018120/MONDO:0005045/100 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5613 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0027849 infores:hetionet CHEBI:8107 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013491 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027769 infores:hetionet UMLS:C0065374 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0039070 infores:hetionet CHEBI:3568 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0012691 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0038826 infores:hetionet CHEBI:135451 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0011991 infores:hetionet CHEBI:9139 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0026826 infores:hetionet CHEBI:4953 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0003862 infores:hetionet CHEBI:5103 biolink:causes MONDO:0017989 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0039235 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0851341 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0009806 infores:hetionet CAID:CA10584733 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584733 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP3, PP1 The NM_000527.5(LDLR):c.47T>C (p.Leu16Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases, as follows: 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN criteria =9 (>6) from PMID 33668494 (Sabatel-Pérez et al, 2021). So PS4_Supporting is met. PP4: Variant meets PM2. Identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4_Supporting for details). So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584733/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5118 biolink:causes MONDO:0020520 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1455705 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0002878 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0851341 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017152 infores:hetionet CAID:CA023809 biolink:causes MONDO:0007783 infores:clingen CAID:CA023809 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 3348 of the RYR1 protein, p.(Arg3348His). This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:15731587, PMID:25735680). No functional studies were identified for this variant. A REVEL score of 0.705 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023809/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true GO:0060956 biolink:causes CL:0002350 infores:ubergraph knowledge_assertion manual_agent GO:0060956 CL:0002350 CHEBI:145499 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151908 infores:hetionet CHEBI:9449 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0018524 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0034065 infores:hetionet NCBIGene:2255 biolink:causes MONDO:0859578 infores:monarchinitiative not_provided not_provided HGNC:3666 MONDO:0859578 uuid:862df0ba-a34a-4b01-bdb0-dd70349c4aba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0006142 infores:hetionet CHEBI:50275 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002994 infores:hetionet CHEBI:3568 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0333355 infores:hetionet CHEBI:4792 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0235063 infores:hetionet CHEBI:9168 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0022408 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0522055 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013922 infores:hetionet CHEBI:4027 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0028949 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0948586 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0042109 infores:hetionet CHEBI:6887 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C3248383 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0152128 infores:hetionet CHEBI:45327 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0042963 infores:hetionet CHEBI:79699 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C2364111 infores:hetionet CHEBI:101278 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0476273 infores:hetionet CHEBI:8426 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0014518 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0239150 infores:hetionet CAID:CA404093067 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093067 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP2, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PM6, PVS1, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1942T>G (p.Ser648Ala) variant is classified as Uncertain significance - insufficient evidencefor Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1), so PM2 is met.BP4 - REVEL = 0.487, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT.C) variant is exonic and there is no GT nearbyVariant is not predicted to alter splicing.--- BP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093067/MONDO:0007750/013 2023-01-27 2023-04-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA10014380 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014380 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.671G>A (p.Arg224Gln) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014380/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3213 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0032617 infores:hetionet CHEBI:5130 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042998 infores:hetionet CHEBI:9123 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027066 infores:hetionet CHEBI:39867 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042029 infores:hetionet CHEBI:50663 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0233514 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002453 infores:hetionet CHEBI:2682 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0595916 infores:hetionet CHEBI:50275 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0004093 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0021141 infores:hetionet NCBIGene:6477 biolink:causes MONDO:0859144 infores:monarchinitiative not_provided not_provided HGNC:10857 MONDO:0859144 uuid:cf607a15-7a9b-4cfb-a4f1-5e70f6157c4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA040769 biolink:causes MONDO:0007750 infores:clingen CAID:CA040769 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP1, BP4, BP2, BP3, PS1, PS4, PS2, PS3, BP5, BP7, BS1, BS4, BS3, PM5, PM1, PM3, PM4, PM6, PVS1, PP2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.2440C>T (p.Arg814Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024.The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.002229%) in East Asian exomes (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040769/MONDO:0007750/013 2024-08-30 2024-10-09 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:40279 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0021053 infores:hetionet CAID:CA008313 biolink:causes MONDO:0007356 infores:clingen CAID:CA008313 MONDO:0007356 PMID: Uncertain Significance PP4_Strong, PM2_Supporting PP3 The NM_000249.4: c.2042C>T variant in MLH1 is a missense variant predicted to cause substitution of Alanin by Valin at amino acid 681 (p.Ala681Val). This variant has been detected in at least three patient with colorectal or endometrial MSI-H / loss MLH1/PMS2 tumours (PP4_Strong). This variant is absent in gnomAD v2.1.1 using the non-cancer dataset and gnomAD v4.1 (PM2_Supporting). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PP4_STR, PM2_SUP (VCEP specifications version 1). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA008313/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C1738934 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0014591 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0037274 infores:hetionet NCBIGene:7030 biolink:causes MONDO:0859080 infores:monarchinitiative not_provided not_provided HGNC:11752 MONDO:0859080 uuid:6032f11b-a543-449d-8511-df96bd361741 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0019825 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0162429 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0005940 infores:hetionet CHEBI:18248 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0234238 infores:hetionet CHEBI:24564 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0525045 infores:hetionet CHEBI:63631 biolink:causes HP:0001995 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085569 infores:hetionet CHEBI:15544 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0016658 infores:hetionet NCBIGene:54809 biolink:causes MONDO:0012502 infores:monarchinitiative not_provided not_provided HGNC:1348 MONDO:0012502 uuid:c70ea9b9-6cc7-4fee-bee9-dd9ffca2bea4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0234913 infores:hetionet CHEBI:47499 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0015967 infores:hetionet CHEBI:63608 biolink:causes MONDO:0019136 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0026718 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0024528 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0024528 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0029089 infores:hetionet CHEBI:47898 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014724 infores:hetionet CHEBI:6640 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0035232 infores:hetionet CAID:CA10601258 biolink:causes MONDO:0700268 infores:clingen CAID:CA10601258 MONDO:0700268 PMID: Uncertain Significance PVS1_Supporting PM2 The c.442-1G>T variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 6 of the BRCA1 gene. This variant has been previously reported using legacy exon numbering as IVS7-1G>T. This variant is reported to result in aberrant mRNA splicing. RT-PCRseq demonstrated that the variant impacts splicing by disrupting the terminal dinucleotide at the intron 6 splice acceptor site and utilizing an in-frame acceptor 3 nucleotides into exon 7, resulting in an in-frame 3 nucleotide (1 amino acid) deletion, c.442_444del (p.Gln148del), with the transcript reported at 58.33% PSI (internal laboratory contributor). This deletion does not target any known domains. This alternate splicing event was also reported as a background transcript at 19.6% PSI (internal laboratory contributor; also known as ∆8p in the literature (PMID: 24569164)). Similar utilization of the cryptic acceptor site has been observed for the nearby c.442-3T>G variant (PMID: 22505045). Code strength determined by comparison of results to PVS1 decision tree and assessment of mRNA splicing data (PVS1_Supporting (RNA) met). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Supporting (RNA)). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10601258/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31302 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0004093 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0043241 infores:hetionet CHEBI:50673 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0031117 infores:hetionet NCBIGene:1482 biolink:causes MONDO:0013749 infores:monarchinitiative not_provided not_provided HGNC:2488 MONDO:0013749 uuid:1a97aa2b-f670-487d-a7b2-17b48280911e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0239150 infores:hetionet CHEBI:2904 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0003811 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0152227 infores:hetionet CHEBI:585948 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C2981158 infores:hetionet CHEBI:7931 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0497156 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009319 infores:hetionet NCBIGene:341208 biolink:causes MONDO:0009871 infores:monarchinitiative not_provided not_provided HGNC:30477 MONDO:0009871 uuid:e0dd35dc-b004-4620-9b22-d79cc774e8a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0392171 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0034882 infores:hetionet CHEBI:8028 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0022346 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0011616 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020676 infores:hetionet CHEBI:4995 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C3665347 infores:hetionet CHEBI:617099 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0015230 infores:hetionet CHEBI:8874 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020672 infores:hetionet CAID:CA315420234 biolink:causes MONDO:0015967 infores:clingen CAID:CA315420234 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, BP4, PS4 The c.1184T>C variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of methionine to threonine at codon 395 (p.(Met395Thr)) of NM_175914.5. This variant has a REVEL score of 0.242, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and absent in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1184T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA315420234/MONDO:0015967/085 2025-02-24 2025-02-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17630 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C1384666 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0302813 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0302813 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1384353 infores:hetionet NCBITaxon:746128 biolink:causes MONDO:0015243 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:746128 MESH:D001229 DB00860_MESH_D001229_1 CHEBI:5001 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027339 infores:hetionet CHEBI:94807 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0025874 infores:hetionet CHEBI:6073 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0002994 infores:hetionet UMLS:C0657912 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027424 infores:hetionet CHEBI:184555 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0948594 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0235146 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0023530 infores:hetionet CHEBI:404903 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042963 infores:hetionet CHEBI:8888 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030193 infores:hetionet CHEBI:28915 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0750394 infores:hetionet CHEBI:8502 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0206061 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0348801 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0348801 infores:hetionet CHEBI:6437 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C2363731 infores:hetionet CHEBI:40279 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0035455 infores:hetionet CHEBI:3499 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0002874 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018991 infores:hetionet CHEBI:2950 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C3257803 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0162429 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0233472 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0004936 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0038362 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0035243 infores:hetionet CHEBI:4027 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0038325 infores:hetionet CHEBI:3723 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151908 infores:hetionet CAID:CA348825220 biolink:causes MONDO:0018958 infores:clingen CAID:CA348825220 MONDO:0018958 PMID: Likely Pathogenic PM3_Strong, PP4, PM2_Supporting BA1, BP3, BP1, BP4, BP2, PS1, PS3, PS4, PS2, PM4, PM5, PM1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PP2, PP3, PP1, BS2 The NM_001164508.2 c.1493A>G (p.Asp498Gly) variant in NEB is a missense variant predicted to cause a substitution of aspartic acid by glycine at amino acid 498. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005120 (1/19532) alleles) in East Asian population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤0.0000559) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has previously been observed in probands who have had nemaline bodies on muscle biopsy (PMID:32403337; Invitae internal data SCV000659742.9) (PP4). The variant has previously been reported in trans with pathogenic variants or rare variants of uncertain significance in 4 probands with clinical features of congenital myopathy (PMID: 33333461; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PM3_Strong, PP4, PM2_Supporting; ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 3/10/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA348825220/MONDO:0018958/146 2025-03-10 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7445 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0042134 infores:hetionet CHEBI:8874 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0404521 infores:hetionet CHEBI:50663 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C2047937 infores:hetionet CHEBI:17347 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0026858 infores:hetionet CAID:CA16620251 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620251 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS3, BS4, BP7, BP5, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1587dup (p.Ala530fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). This variant has been identified in a family meeting HDGC clinical criteria (PS4_Supporting; SCV000580697.3). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620251/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:4728 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0022107 infores:hetionet CHEBI:134966 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0232461 infores:hetionet CHEBI:8707 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0041657 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0004936 infores:hetionet CHEBI:3614 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0234238 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0150450 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0004936 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0042023 infores:hetionet CHEBI:37941 biolink:causes MONDO:0000704 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0400822 infores:hetionet CHEBI:27436 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0595930 infores:hetionet CHEBI:135939 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0085631 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023533 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0235416 infores:hetionet CHEBI:9586 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0018965 infores:hetionet CHEBI:4888 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0038325 infores:hetionet CHEBI:135920 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0042029 infores:hetionet CHEBI:3568 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0242301 infores:hetionet CHEBI:10119 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0043352 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0009806 infores:hetionet CHEBI:135342 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1320474 infores:hetionet NCBIGene:1417 biolink:causes MONDO:0012336 infores:monarchinitiative not_provided not_provided HGNC:2400 MONDO:0012336 uuid:828006c4-4f57-41b8-b994-0840110c6ca9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0039240 infores:hetionet CHEBI:83804 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085688 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018799 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0002871 infores:hetionet CHEBI:102216 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0003467 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0235969 infores:hetionet CHEBI:31711 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0003467 infores:hetionet CHEBI:31348 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0235378 infores:hetionet CHEBI:10125 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235266 infores:hetionet CHEBI:7492 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0015230 infores:hetionet CHEBI:27779 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0033687 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0234215 infores:hetionet CHEBI:8597 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0013604 infores:hetionet CHEBI:100246 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C2129214 infores:hetionet CHEBI:3061 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0232461 infores:hetionet CAID:CA512318936 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318936 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP3, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.189C>G (p.Ala63=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318936/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50859 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0003862 infores:hetionet CHEBI:3001 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0031350 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0039231 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233415 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233415 infores:hetionet CHEBI:71417 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0004093 infores:hetionet CHEBI:28593 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0162830 infores:hetionet CHEBI:9674 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0043352 infores:hetionet CHEBI:3127 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0011991 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0027051 infores:hetionet CHEBI:119915 biolink:causes HP:0012532 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0150055 infores:hetionet CHEBI:5441 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020625 infores:hetionet NCBIGene:57822 biolink:causes MONDO:0011712 infores:monarchinitiative not_provided not_provided HGNC:25839 MONDO:0011712 uuid:35cbdd15-9c75-49fb-8afb-b42a0f2b6efd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0860713 infores:hetionet CHEBI:28748 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014518 infores:hetionet CHEBI:3756 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0037763 infores:hetionet CHEBI:4909 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0003862 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013295 infores:hetionet CAID:CA4239518 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239518 MONDO:0015967 PMID: Uncertain Significance PS4_Moderate, PM5_Supporting, PP2, PM2_Supporting PS3, BS1, BS3, PP3, BP4 The c.824G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 275 (p.(Arg275His)) of NM_000162.5. This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002940 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.545, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30592380). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 30592380, internal lab contributors). Another missense variant, c.823C>T p.Arg275His, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275His (PM5_Supporting). In summary, c.824G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239518/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:10650 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0155305 infores:hetionet CAID:CA292582 biolink:causes MONDO:0021060 infores:clingen CAID:CA292582 MONDO:0021060 PMID: Likely Benign BP7, BS1, BP4 PM2, BA1, PP3 The NM_002524.5:c.112-8A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 62/127294) of the c.112-8A>G variant in NRAS is 0.0003711 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4, BP7. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA292582/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3561 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1262064 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0011616 infores:hetionet CHEBI:8435 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0085631 infores:hetionet CAID:CA409106762 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106762 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting The c.593T>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to arginine at codon 198 (p.(Leu198Arg)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.593T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/22/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106762/MONDO:0015967/085 2023-12-25 2023-12-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2675 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0038454 infores:hetionet CHEBI:2453 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0030196 infores:hetionet CAID:CA410147550 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147550 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1271C>T (p.Ser424Leu) is a missense variant predicted to cause the substitution of serine by leucine at amino acid 424 (p.S424L). The highest population minor allele frequency is 0.004064% (1/24606 alleles) in Admixed Americans in gnomAD v2, 0.01310% (2/15262 alleles) in gnomAD v3, and 0.007861% (4/50884 alleles) in gnomAD v4. However, the allele balance in gnomAD is somewhat skewed, and site quality appears lower compared to some common, known pathogenic variants.This variant has been reported in a pediatric T-ALL case at a VAF of 62.5%, though its germline origin was unclear (PMID: 31721781). It has also been reported in a 20-year-old male with Hodgkin's lymphoma at a VAF of 54.65%, but with no other clinical features (Barber et al., 2019, NSGC Poster), and in three gastric cancers at VAFs of approximately 3.5-5.5% (PMID: 30239046).Functional data for this specific missense variant are not available, but in vitro studies have shown that Ser424 is a phosphorylation target of CDK/Cyclin complexes (PMID: 18003885). The computational predictor REVEL gives a score of 0.407, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, providing evidence that does not predict a damaging effect on RUNX1 function (BP4).In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147550/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9123 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1145670 infores:hetionet CHEBI:6690 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0027497 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0948089 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0009938 infores:hetionet CHEBI:367163 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0028734 infores:hetionet CHEBI:5120 biolink:causes HP:0008665 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0156394 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0314719 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151849 infores:hetionet CHEBI:51041 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0025222 infores:hetionet CHEBI:2682 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0003862 infores:hetionet CHEBI:82716 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0042963 infores:hetionet CHEBI:8412 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0013144 infores:hetionet CHEBI:231594 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0026858 infores:hetionet UMLS:C0145867 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1291077 infores:hetionet CHEBI:6541 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030252 infores:hetionet CAID:CA410204256 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204256 MONDO:0011071 PMID:18003885PMID:18003885 Uncertain Significance PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP2, BP3, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.121A>G (p.Thr41Ala) is a missense variant which is absent from gnomAD v2, v3, and v4.1 (PM2_supporting). This variant has not been reported in patients in the literature. Although it was evaluated in a construct of amino acids 28-86 in 293T cells where it did not affect phosphorylation by Cdk1 or Cdk6 (PMID: 18003885), this assay does not meet the requirements for use by the ClinGen Myeloid Malignancy VCEP. The computational predictor REVEL gives a score of 0.625, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204256/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:78543 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0242698 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027441 infores:hetionet CHEBI:72564 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0854467 infores:hetionet CHEBI:82960 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020580 infores:hetionet CHEBI:6538 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0085932 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0039446 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0149836 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0344315 infores:hetionet NCBIGene:8405 biolink:causes MONDO:0032943 infores:monarchinitiative not_provided not_provided HGNC:11254 MONDO:0032943 uuid:305ce525-61eb-4a88-a33a-cb41a91ea714 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7931 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0004604 infores:hetionet CHEBI:3723 biolink:causes HP:0003978 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0034628 infores:hetionet CAID:CA414796067 biolink:causes MONDO:0044970 infores:clingen CAID:CA414796067 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PP1_Moderate PP3, BP4, PS3 The m.8430T>C (p.L22P) variant in MT-ATP8 has not been reported in the medical literature however three unrelated families with features consistent with primary mitochondrial disease are known to members of this Expert Panel (PS4_supporting). Clinical features in affected individuals include Leigh syndrome spectrum disorder, neuropathy, mood disorder, cardiomyopathy, retinal dystrophy, and hearing loss. Heteroplasmy levels ranged from 57% to homoplasmic in blood. The variant segregated with disease manifestations in one family (PP1_moderate). This variant is present in population databases at low frequency (0.002%; one homoplasmic occurrence in MITOMAP; one homoplasmic and one heteroplasmic occurrence in gnomAD v3.1.2; three homoplasmic and three heteroplasmic occurrences in the Helix database; PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.51 however the updated APOGEE2 predicts an unknown effect on protein with a score of 0.366 (Min=0, Max=1). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 13, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414796067/MONDO:0044970/015 2025-01-13 2025-05-21 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8888 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002884 infores:hetionet CHEBI:7454 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0042023 infores:hetionet CHEBI:31348 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0036973 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0442874 infores:hetionet CHEBI:51041 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0040264 infores:hetionet CHEBI:85083 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0009450 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0409974 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0948525 infores:hetionet CHEBI:16755 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0015672 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0009450 infores:hetionet CAID:CA340740585 biolink:causes MONDO:0100368 infores:clingen CAID:CA340740585 MONDO:0100368 PMID: Pathogenic PM1, PM3, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.1580A>G is a missense variant predicted to replace histidine with arginine at position 527, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000008877, with 1 allele / 112652 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 point, PMID: 35904185, PM3). At least one proband harboring this variant exhibits a phenotype of retinitis pigmentosa with early childhood onset including progressive vision loss (1 pt), early onset nyctalopia (0.5 pts), severely depressed electroretinogram responses from rods (0.5 pts) and cones (1 pt), tritanomaly, white retinal flecks (2 pts), retinal pigment epithelium mottling (0.5 pts), attenuated retinal vessels (0.5 pts), complete loss of peripheral fundus autofluorescence (2 pts), and outer nuclear layer thickness at the low end of the normal range, which together are highly specific for RPE65-related recessive retinopathy (total 8 pts, PMID: 17525851, PP4_Moderate). The computational predictor REVEL gives a score of 0.991, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 24849605). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM1, PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340740585/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7478 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0948594 infores:hetionet CHEBI:2654 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0232462 infores:hetionet CHEBI:8245 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0009938 infores:hetionet CHEBI:7494 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1142135 infores:hetionet CL:0000738 biolink:causes GO:0002443 infores:ubergraph knowledge_assertion manual_agent CL:0000738 GO:0002443 CHEBI:84500 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0428977 infores:hetionet CHEBI:68642 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0013604 infores:hetionet CHEBI:59582 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0302295 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020557 infores:hetionet CAID:CA136140 biolink:causes MONDO:0021060 infores:clingen CAID:CA136140 MONDO:0021060 PMID: Likely Benign BP5, BS2, PP3 The c.350T>G (p.Val117Gly) variant has been identified in a patient with clinical features of a RASopathy with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2; GeneDx, Partners LMM; GTR ID's: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). Computational prediction tools and conservation analysis suggest that the p.Val117Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, BS2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136140/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:31623 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0014236 infores:hetionet CAID:CA2573131851 biolink:causes MONDO:0100437 infores:clingen CAID:CA2573131851 MONDO:0100437 PMID:21326217 Pathogenic PVS1, PP4, PM2_Supporting, PS1_Supporting PP3, PP1, PS3 NM_001034853.2(RPGR):c.1245+3A>T is an intron 10 variant located 3 nucleotides from exon 3. The splicing impact predictor SpliceAI gives a score of 0.83 for donor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, while mRNA studies from patient-derived primary fibroblasts indicate that the variant causes exon 10 skipping (PMID: 21326217). The PP3 and PS3_Supporting codes were not met as PVS1 has been applied instead (PVS1_RNA). Another variant at the same position within the splice region, NM_001034853.2(RPGR):c.1245+3A>G, has previously been classified pathogenic by the X-linked IRD VCEP (PS1_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), first or second-decade onset (1 pt), rod involvement being relatively greater than cone involvement (1 pt), night blindness (0.5 pts), pigmentary retinopathy (0.5 pts), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (5.5 points, PMID: 21326217, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS1_Supporting, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573131851/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:3219 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019372 infores:hetionet CHEBI:5383 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C2830004 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151596 infores:hetionet CHEBI:61033 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0011603 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0001824 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020456 infores:hetionet NCBIGene:167691 biolink:causes MONDO:0011473 infores:monarchinitiative not_provided not_provided HGNC:31923 MONDO:0011473 uuid:a388d3cb-559a-423c-927d-3964f17dab3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085605 infores:hetionet CHEBI:7514 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0004093 infores:hetionet CHEBI:8774 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0423791 infores:hetionet CAID:CA512341352 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341352 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM2, PM6, PVS1, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1038C>T (p.Arg346=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.0) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341352/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15367 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0031117 infores:hetionet CHEBI:55346 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0547030 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0277925 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0003123 infores:hetionet CHEBI:27470 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0085631 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0012813 infores:hetionet CHEBI:75246 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0003862 infores:hetionet CHEBI:4995 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020625 infores:hetionet CAID:CA2801095 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801095 MONDO:0001586 PMID: Pathogenic PM3, PP1_Moderate, PVS1, PP4, PM2_Supporting PM5 The NM_000203.5:c.2T>C (p.Met1?) variant in IDUA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1). Six Chinese probands and one sibling with the variant have been reported with features consistent with MPS I. This includes five probands with deficient IDUA activity, three of whom also have clinical features meeting the specifications of the LD VCEP (PMID: 21480867, 36951468, 37347427) (PP4). Another individual, identified by newborn screen with low IDUA activity, had normal GAGs (PMID: 29801497). One proband is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, including c.208C>T (p.Gln70Ter) (ClinVarID: 11909) (PMID: 21480867, phase unconfirmed, 0.5 points). Two probands are homozygous for the variant (PMID: 21480867, 37347427). Three other probands are compound heterozygous for the variant and either c.1037T>G (p.Leu346Arg) (ClinVarID: 11927) (PMID: 21480867), c.1593delG (p.Leu532CysfsTer28) (PMID: 21480867) or c.911delT (p.V304fs) (ClinVarID: 1184991) (PMID: 36951468). The allelic data from these individuals will be used in the classification of the second variant and is not included here to avoid circular logic. Total 1.5 points (PM3). An individual identified by newborn screen with low IDUA activity but normal GAGs was compound heterozygous for the variant and another variant c.343G>A (p.Asp115Asn) (PMID: 29801497). The variant has been reported to segregate with MPS-1 in 2 affected siblings. Both siblings were compound heterozygous for the variant and c.911delT. Their eldest sister, who appeared normal, was heterozygous for c.2T>C. The father was heterozygous for c.2T>C and the mother was heterozygous for c.911delT, confirmed by Sanger sequencing. These results indicate that the variants are in trans in the affected siblings. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000018 (2/1121804 alleles) in the Non-Finnish European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PP1_moderate, PM3, PP4, PM2_supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 17, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801095/MONDO:0001586/091 2025-10-17 2025-10-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2682 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0025222 infores:hetionet NCBIGene:583 biolink:causes MONDO:0014692 infores:monarchinitiative not_provided not_provided HGNC:967 MONDO:0014692 uuid:32cffe57-9f14-4f14-adaf-36c0e1c27e68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0018524 infores:hetionet CHEBI:7907 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0687133 infores:hetionet CHEBI:9566 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0002874 infores:hetionet NCBIGene:55191 biolink:causes MONDO:0030077 infores:monarchinitiative not_provided not_provided HGNC:29832 MONDO:0030077 uuid:0d66ab23-27a4-476c-9cf9-f4712dff2268 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1134 biolink:causes MONDO:0012156 infores:monarchinitiative not_provided not_provided HGNC:1955 MONDO:0012156 uuid:a6af5fc6-11ad-4083-b90f-7d22647e0d56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49713 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0011175 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0004238 infores:hetionet CHEBI:135193 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0700292 infores:hetionet CHEBI:4672 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0020625 infores:hetionet CHEBI:2668 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0600142 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0035078 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0314719 infores:hetionet CHEBI:75722 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0152031 infores:hetionet CHEBI:6456 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0162297 infores:hetionet CAID:CA6748988 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748988 MONDO:0009861 PMID:30747360PMID:28982351PMID:30459323 Uncertain Significance PP4_Moderate PM5, PM3, PM2, PP3 This c.280A>G (p.Ile94Val) variant in PAH was reported in at least three patients with PAH deficiency. BH4 deficiency was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case (PMID: 30747360, 30459323, and 28982351). This variant is present in the East Asian at a frequency of 0.00160, higher than the PAH Variant Curation Expert Panel cutoff of 0.0002. Computational evidence is conflicting in the predicted effect of this variant. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748988/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:465284 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0000731 infores:hetionet CHEBI:100147 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0031117 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0034063 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0162429 infores:hetionet CHEBI:3216 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0009421 infores:hetionet CHEBI:48947 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0020517 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0011630 infores:hetionet CHEBI:2654 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0002878 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0314719 infores:hetionet NCBIGene:25788 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:17228 MONDO:0005575 uuid:f9bbb1cb-3a0e-45ba-b514-5fe689172b42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020039 infores:hetionet CHEBI:8707 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017979 infores:hetionet NCBIGene:324 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:583 MONDO:0005575 uuid:b5eefd71-96f7-4a7b-b55b-503a93473b35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0037274 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0019158 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0265031 infores:hetionet CAID:CA210764 biolink:causes MONDO:0013144 infores:clingen CAID:CA210764 MONDO:0013144 PMID: Likely Pathogenic PM5, PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting The c.1316C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 439 (p.Pro439Leu). This variant has been reported in one proband meeting the phenotypic criteria of an antithrombin activity level of < 0.8 IU/mL and a positive family history. (PS4_Supporting; PMIDs: 6877092, 3191114). 12 segregations are counted in the Utah family where 13 members are identified as AT-deficient. 11 individuals showed electrophoretically abnormal AT; 2 individuals are obligate carriers. PMID: 3191114 performed sequence analysis on this family. Based on RFLP analysis in this paper, 12 segregations may be counted. However, criteria for PP1_Strong is not met as segregations across >1 family is required (PP1_Moderate; PMID:2983542, 3191114). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PM5, PP3, PM2, PS4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210764/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Supports CAID:CA410202503 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202503 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS4, PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.489T>A (p.Phe163Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score of 0.64 and a REVEL score of 0.914, supporting application of PP3. This missense variant is located within the Runt Homology Domain (AA 89–204), but does not occur in an established hotspot residue (PM1_Supporting). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3, PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202503/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:36795 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235969 infores:hetionet CHEBI:10101 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017565 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0086543 infores:hetionet NCBIGene:9101 biolink:causes MONDO:0009050 infores:monarchinitiative not_provided not_provided HGNC:12631 MONDO:0009050 uuid:059e1f0b-7f11-459f-9013-7f5cf0f132e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3213 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0011991 infores:hetionet CHEBI:45783 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0424790 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0549373 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151828 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0036572 infores:hetionet CHEBI:3082 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0085636 infores:hetionet NCBIGene:1535 biolink:causes MONDO:0009308 infores:monarchinitiative not_provided not_provided HGNC:2577 MONDO:0009308 uuid:3de9df92-6a1d-4be8-baa3-133c173ae548 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C3263723 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0235431 infores:hetionet CHEBI:2668 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0011603 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0032326 infores:hetionet CHEBI:6759 biolink:causes UMLS:C0240204 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0240204 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0518015 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0033860 infores:hetionet CHEBI:9130 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0039231 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0853777 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0851341 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0003123 infores:hetionet CHEBI:63610 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0085593 infores:hetionet CAID:CA215451 biolink:causes MONDO:0021060 infores:clingen CAID:CA215451 MONDO:0021060 PMID:17177198PMID:26619011PMID:29493581PMID:20237506PMID:30896080PMID:17972951 Pathogenic PS3, PM1, PM2, PP3, PP2, PS4_Supporting BS1, PM4, BP3, BP4, BP1, BA1 The c.215C>T (p.Ala72Val) variant in PTPN11 has been reported in 1 patient clinically diagnosed with both Noonan syndrome and juvenile myelomonocytic leukemia (PS4_Supporting; PMID: 30896080). It was absent from large population studies (PM2; gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1, 29493581). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 30896080). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. RASopathy-specific ACMG/AMP criteria applied: PS3, PS4_Supporting, PM1, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA215451/MONDO:0021060/004 2020-03-25 2020-03-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8863 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0016867 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0027769 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0003123 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0009450 infores:hetionet CHEBI:27779 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0024141 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0851341 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0002792 infores:hetionet GO:0061256 biolink:causes CL:0002523 infores:ubergraph knowledge_assertion manual_agent GO:0061256 CL:0002523 CHEBI:10112 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0233494 infores:hetionet CHEBI:5062 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0011124 infores:hetionet CHEBI:63611 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009782 infores:hetionet CHEBI:51364 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0018681 infores:hetionet CHEBI:8485 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0152227 infores:hetionet CHEBI:8430 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C2830004 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0522055 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0027765 infores:hetionet CHEBI:68584 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0043094 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0037274 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006826 infores:hetionet CHEBI:17347 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0021368 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0858581 infores:hetionet CHEBI:74947 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151786 infores:hetionet GO:0003339 biolink:causes GO:0072087 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0072087 CHEBI:45599 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0858598 infores:hetionet CAID:CA229548 biolink:causes MONDO:0009861 infores:clingen CAID:CA229548 MONDO:0009861 PMID:12655553PMID:28676969PMID:19015950 Uncertain Significance PM2, PP3, PP4, PM3_Supporting The c.441+4A>G variant in PAH has been reported in an individual with PAH deficiency (PP4) with likely pathogenic variant p.Val230Ile (PM3-supporting) (PMID: 12655553); and an Iranian patient with PAH deficiency ( PMID: 28676969, 2nd variant not reported). This variant is absent in population databases (PM2). Computational evidence support a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229548/MONDO:0009861/006 2019-09-29 2019-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3534 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0042267 infores:hetionet CHEBI:28787 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0428977 infores:hetionet CHEBI:17823 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C1260880 infores:hetionet CHEBI:63630 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0376358 infores:hetionet UMLS:C0065374 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151480 infores:hetionet CHEBI:8364 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0033117 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0234215 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0019158 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1384666 infores:hetionet CHEBI:107736 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0032708 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042267 infores:hetionet UMLS:C1738934 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0149745 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042514 infores:hetionet CHEBI:3640 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0030305 infores:hetionet CHEBI:9622 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0152198 infores:hetionet CHEBI:9943 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0043094 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0036572 infores:hetionet CHEBI:72564 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002994 infores:hetionet CHEBI:8713 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0033774 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0836924 infores:hetionet CHEBI:6541 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002170 infores:hetionet CAID:CA038525 biolink:causes MONDO:0007750 infores:clingen CAID:CA038525 MONDO:0007750 PMID: Uncertain Significance PP1_Strong, BS4, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP4, BS2 NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS4 - Variant does not segregate with FH phenotype in 11 informative meioses in 6 families (Laboratory of Genetics and Molecular Cardiology).PP1_strong - Variant segregates with FH phenotype in 58 informative meioses in 9 families from Laboratory of Genetics and Molecular Cardiology.PP3 - REVEL: 0,92. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038525/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31980 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0015967 infores:hetionet CAID:CA16020837 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020837 MONDO:0009861 PMID:26503515PMID:19915519 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 The c.680T>A (p.Leu227Gln) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded, PMID: 26503515, 19915519). This variant is absent in population databases. This variant was detected in trans with pathogenic variant c.611A>G (aka. EX6-96A>G, PMID:30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020837/MONDO:0009861/006 2020-08-07 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:78543 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0542571 infores:hetionet CHEBI:94609 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0235266 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0016204 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0240035 infores:hetionet CHEBI:41774 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0231528 infores:hetionet CHEBI:65349 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0232849 infores:hetionet CHEBI:94609 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0019080 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151763 infores:hetionet CHEBI:3215 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C2830004 infores:hetionet CHEBI:8871 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0032617 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027092 infores:hetionet CHEBI:4514 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0000731 infores:hetionet CHEBI:8028 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0040485 infores:hetionet CHEBI:63618 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0085633 infores:hetionet CHEBI:45409 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151904 infores:hetionet CAID:CA10583402 biolink:causes MONDO:0007648 infores:clingen CAID:CA10583402 MONDO:0007648 PMID: Likely Benign BP7, BS2, PM2_Supporting, BP4 BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.150C>A (p.Arg50=) results in a synonymous amino acid change in exon 2. This variant was found in 1 of 153,336 alleles in gnomAD (0.00001) (PM2_Supporting; http://gnomad.broadinstitute.org). However, This variant has also been observed in more than 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000665066.2; SCV000288437.6; SCV000976762.1). This variant occurs at a position that is poorly conserved and multiple computational tools predict that this variant does not impact splicing (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583402/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA014476 biolink:causes MONDO:0007947 infores:clingen CAID:CA014476 MONDO:0007947 PMID: Pathogenic PP4, PP2, PP3, PM2_Supporting, PM1, PM5, PS4, PP1_Moderate The NM_00138 c.3712G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1238 (p.Asp1238Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 12 times in ClinVar: three times as pathogenic, eight times as likely pathogenic, and once as uncertain significance (Variation ID: 200022). This variant has also been reported in multiple individuals with a clinical diagnosis of MFS, ectopia lentis and/or clinical features of MFS (PS4_Strong; PMID 32730690, 10533071, 30675029, internal lab data). This variant was found to segregate with disease in at least four affected relatives with MFS from four families (PMID 32730690, internal lab data; PP1_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3713A>G (p.Asp1238Gly), has previously been previously established as (likely) pathogenic and was reported an individual with a clinical diagnosis of MFS (PM5; PMID 11175294). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.895). This variant is located in the last nucleotide of the exon. In silico prediction programs suggest a possibly impact on splicing, however RNA analysis using patient blood showed no impact for this variant on RNA splicing (PMID 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Strong, PM1, PM5, PP1_Mod, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA014476/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6062 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0036974 infores:hetionet CHEBI:83527 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0020625 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009450 infores:hetionet CHEBI:6809 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0040517 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0234215 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0041909 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0233494 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0009938 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0403632 infores:hetionet CHEBI:4858 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0013604 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151824 infores:hetionet NCBIGene:2979 biolink:causes MONDO:0013447 infores:monarchinitiative not_provided not_provided HGNC:4679 MONDO:0013447 uuid:dfc87db2-0cdf-461c-a337-77ce8d206129 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9763 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0013384 infores:hetionet CHEBI:8435 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0023530 infores:hetionet CHEBI:66964 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0003467 infores:hetionet CHEBI:7915 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013604 infores:hetionet CHEBI:24564 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0004093 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0877306 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0877306 infores:hetionet CHEBI:8871 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0232849 infores:hetionet CHEBI:8461 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C1443060 infores:hetionet CHEBI:49713 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0235710 infores:hetionet GO:0072039 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:0072039 GO:0072001 CHEBI:8871 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0021141 infores:hetionet CHEBI:4909 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0151798 infores:hetionet CHEBI:127342 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027066 infores:hetionet CHEBI:51041 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0027497 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0332575 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0006840 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0042075 infores:hetionet CHEBI:16469 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0040460 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011570 infores:hetionet CAID:CA2802231 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802231 MONDO:0001586 PMID: Likely Benign BP7, BS1, BP4 The NM_000203.5:c.1332C>T (p.Asp444=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (all scores are <0.1). In addition, the variant is not in the first nucleotide or last three nucleotides of an exon (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0. is 0.003422 (248/72482 alleles; 4 homozygotes) in the South Asian population; GrpMax Filtering Allele Frequency 0.003071, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.0025), and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature. There is a ClinVar entry for this variant (Variation ID: 785832). In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BS1, BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802231/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3181 biolink:causes MONDO:0019933 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0001206 infores:hetionet CHEBI:134990 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0043094 infores:hetionet CHEBI:5128 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0013395 infores:hetionet GO:0021822 biolink:causes GO:0021987 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0021987 CHEBI:3568 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151827 infores:hetionet CHEBI:15640 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0043144 infores:hetionet CHEBI:3127 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2830004 infores:hetionet CHEBI:10110 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0015967 infores:hetionet CHEBI:16714 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0039070 infores:hetionet CHEBI:8871 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034155 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0856110 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0856110 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151602 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0004936 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039520 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011053 infores:hetionet CHEBI:8863 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0026826 infores:hetionet CHEBI:4027 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042963 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0006840 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037822 infores:hetionet CHEBI:4887 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0030312 infores:hetionet CHEBI:36795 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0393761 infores:hetionet CHEBI:4754 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01127 UMLS:C0033774 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0948089 infores:hetionet CHEBI:77733 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0013491 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0235431 infores:hetionet CHEBI:119915 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014591 infores:hetionet CHEBI:50692 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0017168 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0004690 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0919702 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0919702 infores:hetionet CHEBI:45783 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0235378 infores:hetionet CHEBI:32221 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0002994 infores:hetionet CHEBI:92998 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0546884 infores:hetionet CHEBI:45863 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0043144 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234930 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017152 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006277 infores:hetionet CHEBI:17303 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0023380 infores:hetionet CHEBI:3441 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002874 infores:hetionet CHEBI:50924 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C2937358 infores:hetionet CHEBI:101278 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0003813 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0015397 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0852711 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0852711 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0948089 infores:hetionet CHEBI:3732 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0424295 infores:hetionet CHEBI:125354 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0020517 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0024523 infores:hetionet CHEBI:44032 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C2830004 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853761 infores:hetionet CHEBI:2668 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0231530 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0029134 infores:hetionet CHEBI:64064 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0015967 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0017160 infores:hetionet CHEBI:3423 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0027540 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011860 infores:hetionet CHEBI:4858 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0016382 infores:hetionet CHEBI:7581 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0017178 infores:hetionet CHEBI:2788 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0231218 infores:hetionet CAID:CA2229914895 biolink:causes MONDO:0100488 infores:clingen CAID:CA2229914895 MONDO:0100488 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, PM1, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.-72T>C variant occurs in the 5'UTR at a nucleotide that is not highly conserved. This variant is absent from population databases (PM2_supporting). To our knowledge, this variant has not been observed in an individual with DGC, LBC, SRC tumours or whose family history suggests HDGC. In summary, this variant meets criteria to be classified as a variant of uncertain significance based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA2229914895/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:49375 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027339 infores:hetionet NCBIGene:158326 biolink:causes MONDO:0012165 infores:monarchinitiative not_provided not_provided HGNC:23399 MONDO:0012165 uuid:2f432102-052b-48a3-980f-926924f22473 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C0158026 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0158026 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0677500 infores:hetionet CHEBI:28787 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0011606 infores:hetionet CAID:CA396465435 biolink:causes MONDO:0100488 infores:clingen CAID:CA396465435 MONDO:0100488 PMID: Likely Pathogenic PM2_Supporting, PS3, PS4_Moderate BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS2 The c.1703C>G (p.Thr568Arg) missense variant is absent in the gnomAD v2.1.1 cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in two probands meeting HDGC phenotype criteria (PS4_Moderate; SCV000580691.5). RNA data indicates abnormal splicing resulting in an abnormal out-of-frame transcript (PS3, internal lab contributor). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PS3, PS4_Moderate, PM2_Supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396465435/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:135285 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0151766 infores:hetionet NCBIGene:701 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:1149 MONDO:0005575 uuid:38f47e52-584c-478b-aa09-7ee9b69993fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C2047937 infores:hetionet CHEBI:27834 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027497 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015230 infores:hetionet CAID:CA409103963 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103963 MONDO:0015967 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PM1_Supporting PM5 The c.195C>A variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of serine to arginine at codon 65 (p.(Ser65Arg)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also located within the DNA binding domain (codons 37-113 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.194G>A p.(Ser65Asn), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.195C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103963/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA183350 biolink:causes MONDO:0019501 infores:clingen CAID:CA183350 MONDO:0019501 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Strong PP3, BP4 The c.13808A>C (p.His4603Pro) variant in USH2A is a missense variant predicted to cause a substitution of histidine by a proline at amino acid 4603. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00000084 (4/1179986 alleles) in the european non-finnish population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.34, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in 1 proband with retinal disease and hearing loss (which was diagnosed at the age of 49 years old) in trans with a pathogenic variant by family testing (PMID: 28157192). Besides, this variant has been detected in 4 individuals with USH2A associated conditions which is highly specific for disease (PP4). All individuals were heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.2299del, p.(Glu767Serfs*21); c.5118G>A, p.(Trp1706*); c.2276G>T, p.(Cys759Phe) and c.5573-834A>G; PM3 3 points, Blueprint Genetics internal evidence SCV001239096.1) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A condition (isolated RP) based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PM3_Strong and PP4. (ClinGen Hearing Loss VCEP specifications version 2, 20.11.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA183350/MONDO:0019501/005 2024-11-20 2025-03-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:31547 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0687713 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0027947 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C1291078 infores:hetionet CHEBI:4975 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0030252 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0004652 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D018410 DB01416_MESH_D018410_1 NCBIGene:26525 biolink:causes MONDO:0013626 infores:monarchinitiative not_provided not_provided HGNC:15561 MONDO:0013626 uuid:adc8a02b-b95e-44c2-8715-f64c30215d82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47612 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0041969 infores:hetionet CHEBI:6062 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0037763 infores:hetionet CHEBI:6741 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0009676 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0853692 infores:hetionet NCBIGene:8111 biolink:causes MONDO:0014971 infores:monarchinitiative not_provided not_provided HGNC:4519 MONDO:0014971 uuid:b1831dbf-479e-4e4b-907a-3e0bd3b43e1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8428 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0018790 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0014130 infores:hetionet CHEBI:4702 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0038325 infores:hetionet CHEBI:6402 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0231528 infores:hetionet CHEBI:27306 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00165 UMLS:C0030554 infores:hetionet CHEBI:135930 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0041657 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0037274 infores:hetionet CHEBI:45599 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0027540 infores:hetionet CHEBI:63630 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0014236 infores:hetionet CHEBI:16914 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0877047 infores:hetionet CHEBI:64310 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0036974 infores:hetionet CAID:CA523749345 biolink:causes MONDO:0100368 infores:clingen CAID:CA523749345 MONDO:0100368 PMID: Likely Pathogenic PM4_Supporting, PM3, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.1443_1445del (p.Glu481del) is an in-frame deletion encoding 1 amino acid in a non-repeat region, predicted to cause a change in the length of the protein, with at least one of the deleted base pairs highly conserved with a PhyloP conservation score of 7.5 (PM4_Supporting). The variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00002287, with 35 alleles / 1,179,000 total alleles in the European (non- Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, VCEP member-provided data). This variant has also been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.989G>A (p.Cys330Tyr) variant suspected but not confirmed in trans, which has been previously classified as likely pathogenic by the ClinGen LCA/eoRD VCEP (0.25 points), or the NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) variant suspected but not confirmed in trans, which has been previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (0.5 points). This variant has been reported in at least 1 proband with retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant suspected but not confirmed in trans, which has been previously classified as pathogenic by the ClinGen LCA/eoRD VCEP, however, this final proband did not have available phenotype details to confirm the exact diagnosis and could not be included in PM3 (1.25 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), absent or severely reduced electroretinogram responses (0.5 pts), congenital night blindness (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), poor pupillary light response (0.5 pts), retinal pigment epithelium mottling (0.5 pts), macular atrophy (0.5 pts), symptomatic onset between birth and age 5 years (1 pt), optical coherence tomography preserved with respect to vision loss (1 pt), decreased peripheral vision (1 pt), abnormal color vision or evidence of cone involvement on electroretinogram (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), absence or minimal autofluorescence (2 pts), previous exome / genome / 100+ not providing an alternative explanation for disease (2 pts), and participation in a gene therapy trial with strict inclusion criteria and documented improvement of full-field stimulus threshold response after RPE65 gene therapy, including subjectively improved vision in dim light (2 pts), which together are highly specific for RPE65-related recessive retinopathy (15.5 total points, VCEP member-provided data, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PM4_Supporting, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA523749345/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8481 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0020517 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0042373 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004623 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0159028 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0159028 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0795692 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042373 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0233472 infores:hetionet UMLS:C0120107 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151825 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0231303 infores:hetionet CHEBI:28593 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0029124 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0003123 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0036454 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0160390 infores:hetionet CHEBI:9130 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020461 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0233494 infores:hetionet CHEBI:51041 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C3665347 infores:hetionet NCBITaxon:730 biolink:causes MONDO:0001797 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:730 MESH:D002602 DB00254_MESH_D002602_1DB01059_MESH_D002602_1DB02703_MESH_D002602_1DB13092_MESH_D002602_1DB01165_MESH_D002602_1DB01082_MESH_D002602_1DB01212_MESH_D002602_1DB00263_MESH_D002602_1DB00618_MESH_D002602_1DB00537_MESH_D002602_1DB01017_MESH_D002602_1DB00207_MESH_D002602_1 CHEBI:63617 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0522055 infores:hetionet CHEBI:3172 biolink:causes UMLS:C3160766 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C3160766 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013298 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0151602 infores:hetionet CAID:CA314592 biolink:causes MONDO:0100040 infores:clingen CAID:CA314592 MONDO:0100040 PMID: Benign BP5_Strong, BS2 BS1 The p.Ser425Pro variant in FOXG1 is present in one XX and one XY individual in gnomAD v2.1.1 (0.00176%) (not sufficient to meet BS1 criteria). The p.Ser425Pro variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ser425Pro variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal database) (BP5_Strong). In summary, the p.Ser425Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS2, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314592/MONDO:0100040/035 2024-04-18 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50275 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0037317 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0036983 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0030305 infores:hetionet CHEBI:8354 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0518015 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0027765 infores:hetionet CHEBI:35553 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0311394 infores:hetionet CHEBI:6706 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0004093 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0043250 infores:hetionet CHEBI:4856 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0041834 infores:hetionet CHEBI:8212 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0494475 infores:hetionet CHEBI:27504 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0013144 infores:hetionet GO:0060998 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0060998 GO:0048699 CHEBI:7959 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0015376 infores:hetionet CHEBI:50275 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0236048 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0007971 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0233796 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0233796 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1959622 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1959622 infores:hetionet CHEBI:8207 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0030252 infores:hetionet CHEBI:6375 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151754 infores:hetionet CHEBI:47519 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0002878 infores:hetionet CHEBI:41423 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151908 infores:hetionet CHEBI:3515 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0037036 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0878773 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038663 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0559031 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0025290 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0002871 infores:hetionet CHEBI:27565 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0000737 infores:hetionet CHEBI:63607 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0854467 infores:hetionet CHEBI:72564 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0043352 infores:hetionet NCBIGene:999 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:1748 MONDO:0008170 uuid:9c729e63-6034-41a2-b80d-8d18ade02f75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020621 infores:hetionet CHEBI:7466 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0156312 infores:hetionet CHEBI:63607 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0011603 infores:hetionet CHEBI:109549 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0021400 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0438215 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0001122 infores:hetionet CHEBI:9763 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0003862 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0227791 infores:hetionet CHEBI:2639 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0002962 infores:hetionet CHEBI:15367 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0000731 infores:hetionet CHEBI:52010 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0232462 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0030305 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0020517 infores:hetionet CHEBI:31705 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0002622 infores:hetionet CHEBI:17474 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C3263723 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0600327 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0000737 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0595877 infores:hetionet GO:0061168 biolink:causes GO:0042633 infores:ubergraph knowledge_assertion manual_agent GO:0061168 GO:0042633 UNII:G4PX8C4HKV biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0006826 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030807 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002884 infores:hetionet CAID:CA024171 biolink:causes MONDO:0007783 infores:clingen CAID:CA024171 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1_Supporting, PS4, PP1_Strong PP3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with isoleucine at codon 4849 of the RYR1 protein, p.(Val4849Ile). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00004, a frequency consistent with pathogenicity for MHS. This variant has been reported in 31 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 25960145, 30236257, 23558838, 24433488, 16163667, 28527222, 15731587, 19346234, 21455645). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 28403410). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). This variant segregates with MHS in 23 individuals, PP1_Strong (PMID: 25960145, 28527222). A REVEL score of 0.817 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024171/MONDO:0007783/012 2021-03-22 2022-01-04 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:5778 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0235416 infores:hetionet CHEBI:75722 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0008350 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0003467 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0017178 infores:hetionet CHEBI:6832 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0015967 infores:hetionet CHEBI:161680 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0030554 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0024205 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0014130 infores:hetionet CHEBI:52010 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0027497 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1384353 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0851341 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0031350 infores:hetionet CAID:CA512232279 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232279 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS2, PS4, PS3, BA1, BP1, BP3, BP5, BS4, BS3, BS1, PVS1, PM6, PM2, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.828C>A (p.Ser276=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 0.55 < 2.0) or the variant is the reference nucleotide in one primate (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232279/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9328 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0002878 infores:hetionet NCBIGene:83959 biolink:causes MONDO:0009019 infores:monarchinitiative not_provided not_provided HGNC:16438 MONDO:0009019 uuid:41210215-8018-4bb4-a086-73a42a367168 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027947 infores:hetionet GO:2000311 biolink:causes GO:0003333 infores:ubergraph knowledge_assertion manual_agent GO:2000311 GO:0003333 CHEBI:6076 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0149745 infores:hetionet CHEBI:5118 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0043094 infores:hetionet UMLS:C0657912 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017181 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0040034 infores:hetionet CHEBI:44915 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0030305 infores:hetionet NCBIGene:50 biolink:causes MONDO:0013802 infores:monarchinitiative not_provided not_provided HGNC:118 MONDO:0013802 uuid:da6dcf1f-1082-46e6-8ce8-865b786a8605 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1120 biolink:causes MONDO:0011246 infores:monarchinitiative not_provided not_provided HGNC:1938 MONDO:0011246 uuid:0ae4a3be-0863-4760-8bbd-77ece7ba6b53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042345 infores:hetionet CHEBI:31397 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0016655 infores:hetionet CHEBI:6030 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0015672 infores:hetionet CHEBI:3647 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0014553 infores:hetionet CHEBI:584020 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0017178 infores:hetionet CHEBI:5893 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0022346 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0221100 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085584 infores:hetionet CHEBI:4953 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0026858 infores:hetionet CHEBI:3127 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2047937 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0021400 infores:hetionet NCBIGene:10564 biolink:causes MONDO:0011966 infores:monarchinitiative not_provided not_provided HGNC:15853 MONDO:0011966 uuid:df69e153-9b33-40b6-b1d2-565e822d61d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0333355 infores:hetionet CHEBI:7494 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0424295 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0011849 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0037274 infores:hetionet CHEBI:47499 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0344232 infores:hetionet CHEBI:47499 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011206 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0043345 infores:hetionet CAID:CA10014391 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014391 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-3T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014391/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6413 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0009806 infores:hetionet CHEBI:91583 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0042963 infores:hetionet CHEBI:7824 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0043352 infores:hetionet CHEBI:5801 biolink:causes MONDO:0019056 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0027868 infores:hetionet CHEBI:7931 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0027066 infores:hetionet CHEBI:7936 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037036 infores:hetionet CHEBI:135961 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C1443060 infores:hetionet CHEBI:3515 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0038362 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0003123 infores:hetionet CHEBI:9907 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151904 infores:hetionet CHEBI:4681 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0013604 infores:hetionet NCBIGene:5157 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:8805 MONDO:0005575 uuid:4698b70d-55c6-4dfd-a2e9-c34917f84c8e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0037036 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0423773 infores:hetionet CHEBI:31624 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0039070 infores:hetionet CHEBI:116278 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0010200 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0234215 infores:hetionet CHEBI:28830 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C1320835 infores:hetionet CHEBI:8871 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0520966 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0162429 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1608945 infores:hetionet CAID:CA10014550 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014550 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP4, BP2, BS1, BS3, BS4, BP7, PM2, PM6, PVS1, PM4, PM5, PP1 NM_001754.5(RUNX1):c.332C>T (p.Thr111Ile) is a missense variant which has a REVEL score >0.88 (0.93) (PP3). Furthermore, this variant affects amino acid 111, which is one of the residues within the RHD (AA 89-204) (PM1_supporting). To our knowledge, there is no previous record of this variant, and no other pathogenic or likely pathogenic missense variants affecting the same amino acid residue or resulting in the same residue have been reported. The RUNX1 p.Thr111Ala variant has been previously classified as a VUS (PM1_supporting, PM2, PP3) by the MM-VCEP. Additionally, the RUNX1 p.Thr111Pro and p.Thr111Asn missense changes have been identified in a cohort of 13,284 patients with myelodysplastic syndrome and classified as oncogenic somatic variants (PMID: 36436542). In summary, the clinical significance of this variant is uncertain, and it meets ACMG/AMP criteria as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014550/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2682 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151905 infores:hetionet CHEBI:63584 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0149871 infores:hetionet CHEBI:49375 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0043094 infores:hetionet NCBIGene:667 biolink:causes MONDO:0013839 infores:monarchinitiative not_provided not_provided HGNC:1090 MONDO:0013839 uuid:ab75df16-f604-4251-b2c7-1ce7d6257e68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66913 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0038999 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0002453 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0032961 infores:hetionet CHEBI:46345 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C2830004 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0234913 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151313 infores:hetionet CHEBI:3387 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027497 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011053 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0160390 infores:hetionet UMLS:C0065374 biolink:causes HP:0034807 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C1956415 infores:hetionet CHEBI:144551 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0022575 infores:hetionet CHEBI:63599 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0700590 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0022660 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0009806 infores:hetionet CHEBI:2636 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0018790 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020557 infores:hetionet CHEBI:6078 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0231528 infores:hetionet CHEBI:64312 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0231218 infores:hetionet NCBIGene:88 biolink:causes MONDO:0032853 infores:monarchinitiative not_provided not_provided HGNC:164 MONDO:0032853 uuid:cc64dba7-42c5-41b1-8dec-7a1bfef082cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA5416407 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416407 MONDO:0011225 PMID: Likely Benign BP7, BS1 BS2 The c.1791C>T (NM_001033855.3) variant in the DCLRE1C gene is a synonymous variant (p.Cys597=). The filtering allele frequency (the lower threshold of the 95% CI of 49/24970) of the c.1791C>T variant in DCLRE1C is 0.001381 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold 0.00078 for BS1, and therefore meets this criterion (BS1).Additionally, According to at least two in silico tools (SpliceAI and varSEAK) this synonymous variant was predicted not to impact the splice consensus sequence nor create a new splice site (BP7 met). A comprehensive literature search has not found the variant in individuals with SCID due to DCLRE1C deficiency.In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BS1 and BP7, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416407/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0010592 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0030305 infores:hetionet CHEBI:50648 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019080 infores:hetionet CAID:CA389475782 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475782 MONDO:0100040 PMID: Likely Pathogenic PM1, PP3, PM2_Supporting, PM6_Strong PS1, PS3, PS4, PM5, PM3, BP5, BS1, BS3, BS4, PP1, PP4, BS2, BA1, BP4, BP2 The p.Gly250Ser variant in FOXG1 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with features consistent with FOXG1 disorder (Internal database - GeneDx) (PM6_Strong). The p.Gly250Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Gly250Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, the p.Gly250Ser variant in FOXG1 is classified as Likely Pathogenic based on the ACMG/AMP criteria (PM6_Strong, PM1, PP3, PM2_Supporting). (FOXG1 specification v3.0.0; approved on 12/18/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475782/MONDO:0100040/035 2024-12-18 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:18332 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0085631 infores:hetionet CHEBI:7773 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0002962 infores:hetionet CHEBI:8356 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0241060 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1258215 infores:hetionet CHEBI:59445 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0015967 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0002871 infores:hetionet CHEBI:41423 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0003862 infores:hetionet CHEBI:32184 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0019080 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020676 infores:hetionet CHEBI:8356 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085632 infores:hetionet CHEBI:27504 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C1565489 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042267 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0007222 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0002792 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018418 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0033687 infores:hetionet CHEBI:66876 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0149871 infores:hetionet CHEBI:50131 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0011175 infores:hetionet CHEBI:404903 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011603 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0037274 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151828 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085606 infores:hetionet CHEBI:240107 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0235266 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042571 infores:hetionet CHEBI:94848 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0085593 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0236071 infores:hetionet CHEBI:3636 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0033774 infores:hetionet CHEBI:2682 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018800 infores:hetionet CHEBI:9667 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0010200 infores:hetionet CHEBI:2676 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C1609512 infores:hetionet NCBIGene:2257 biolink:causes MONDO:0014949 infores:monarchinitiative not_provided not_provided HGNC:3668 MONDO:0014949 uuid:09098734-eb00-4c8c-ae3c-c74860d36935 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7488 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0020517 infores:hetionet CHEBI:9727 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0240735 infores:hetionet CHEBI:100246 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0034886 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0232459 infores:hetionet CHEBI:167638 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0042571 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0919874 infores:hetionet CHEBI:7931 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011168 infores:hetionet CHEBI:41423 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151937 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040034 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0038661 infores:hetionet CHEBI:6715 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025218 infores:hetionet CHEBI:8890 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0010200 infores:hetionet CHEBI:107736 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0041105 infores:hetionet CHEBI:6015 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0018799 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085932 infores:hetionet CHEBI:7466 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0016867 infores:hetionet CAID:CA415090882 biolink:causes MONDO:0010305 infores:clingen CAID:CA415090882 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong BS3, PS3, PS4 The NM_005629.4:c.1699T>C variant in SLC6A8 is a missense variant that is predicted to result in the substitution of serine by proline at amino acid 567 (p.Ser567Pro). This variant has been reported in one male proband with clinical features including global developmental delay, hypotonia, elevated urine creatine/creatinine, and significantly reduced creatine peak on brain magnetic resonance spectroscopy (PMID: 24953403, PMID: 23644449) (PP4_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the threshold of 0.902, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415090882/MONDO:0010305/027 2023-10-13 2023-11-08 X-linked inheritance HP:0001417 Supports CHEBI:3504 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020456 infores:hetionet CHEBI:36704 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0004093 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0038362 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0005779 infores:hetionet CHEBI:188986 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C3665386 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0036572 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0349506 infores:hetionet CHEBI:135929 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0267792 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0029443 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151763 infores:hetionet CHEBI:8435 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0085637 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0042514 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0227791 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020517 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0017178 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0870082 infores:hetionet NCBIGene:57465 biolink:causes MONDO:0013826 infores:monarchinitiative not_provided not_provided HGNC:29203 MONDO:0013826 uuid:c8d20d2a-d179-49e6-a526-a77977b6bdab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0043352 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1611162 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1611162 infores:hetionet UMLS:C0023610 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0004093 infores:hetionet CHEBI:46295 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0039231 infores:hetionet CHEBI:2636 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C2830004 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0587054 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0587054 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007114 infores:hetionet CHEBI:18358 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0085932 infores:hetionet CHEBI:44915 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0855775 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020542 infores:hetionet CHEBI:6759 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0001122 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0853813 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0851341 infores:hetionet CHEBI:9130 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0428974 infores:hetionet CHEBI:10023 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151714 infores:hetionet CAID:CA210785 biolink:causes MONDO:0013144 infores:clingen CAID:CA210785 MONDO:0013144 PMID: Uncertain Significance PM1, PP3, PM2_Supporting, PS4_Supporting The c.1271G>A variant in SERPINC1 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 424 (p.Gly424Asp). This variant has been reported in one family meeting an antithrombin activity level of < 0.8 IU/mL and a family history of reported abnormal antithrombin levels (PS4_Supporting; PMID:1547341).The computational predictor REVEL gives a score of 0.635, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2_Supporting, PS4_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210785/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8772 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0003864 infores:hetionet CHEBI:553473 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0015967 infores:hetionet CHEBI:2038 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0030193 infores:hetionet UMLS:C0065374 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0026821 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017566 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020538 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0948089 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0853895 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0853895 infores:hetionet CHEBI:3082 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0003862 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549374 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549374 infores:hetionet CAID:CA410206769 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206769 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.749G>T (p.Arg250Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206769/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68647 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020433 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0025202 infores:hetionet CAID:CA229295 biolink:causes MONDO:0009861 infores:clingen CAID:CA229295 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 The c.1038del (p.Leu347fs) variant in PAH has been reported in a Danish PKU patient, serum Phe >600 umol/L; BH4 deficiency excluded (PMID: 8406445; PP4). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 10 out of 13 coding exons (10 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229295/MONDO:0009861/006 2021-10-10 2021-12-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7852 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0233407 infores:hetionet CHEBI:5778 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0085633 infores:hetionet CAID:CA8814895 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814895 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM3, PM2_Supporting, PVS1_Strong, PS1_Moderate PP3, PS3 The NM_000152.5:c.546G>A variant alters that last nucleotide of exon 2 of GAA, but does not result in an amino acid change (p.Thr182=). Two different studies, one using real-time RT-PCR to analyze RNA from cultured fibroblasts from an patient with the variant, and another involving minigene analysis showed that the variant disrupts normal splicing, resulting in skipping of exon 2, with a low proportion of normal transcripts produced (PMID: 14695532, 31301153). Exon 2 contains the start methionine and signal sequence for GAA (amino acids 1-27; https://www.uniprot.org/uniprot/P10253). In addition, deletion of exon 2 results in complete loss of enzyme activity when expressed in heterologous cells (PMID 7881425; PMID 7717400). As this variant appears to allow a low level of normal splicing to occur, PVS1 was applied at the strong level (PVS1_Strong). Four individuals with a diagnosis of late onset Pompe disease and this variant have been reported with documented laboratory values showing GAA activity in the affected range in dried blood spots or muscle, or <30% activity in skin fibroblasts or <10% activity in muscle and lymphocytes (PMID: 14695532, 21484825, 21984055, 25037089) (PP4_Moderate). Two of these patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.525delT (PMID: 14695532), and c.655G>A (p.Gly219Arg) (PMID: 25037089), phase not confirmed (PM3). Additional patients have been reported who are compound heterozygous for the variant and either c.736delC (PMID: 30564623), c.307T>C (p.Cys103Arg) (PMID: 21984055), c.2041-1G>A (PMID: 21484825); the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Finally, allelic data for newborn screening cases was not included here due to either lack of confirmation, lack of clinical symptoms in suspected LOPD patients, or presence of pseudodeficiency variants (PMID: 33202836, 34995642). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (2/19660 alleles) in the East Asian population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants at the same nucleotide position (c.546G>T, c.546G>C), and in the same splice region (c.546+1G>T, c.546+2T>C, c.546+5G>T, and c.546del2‐5) have been reported in individuals with Pompe disease (https://www.pompevariantdatabase.nl/). All of these variants have been shown to result in skipping of exon 2 using a minigene assay (PMID: 31301153). c.546G>T has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PS1_Moderate, PMID: 37352859). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based in the specification of the ClinGen Lysosomal Diseases VCEP: PVS1_Strong, PS1_Moderate, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814895/MONDO:0009290/010 2023-07-18 2023-11-14 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA333543 biolink:causes MONDO:0007113 infores:clingen CAID:CA333543 MONDO:0007113 PMID: Likely Pathogenic PM6, PP3, PM2_Supporting, PS4_Moderate PP4, BP4 The c.1805A>G p.(Asn602Ser) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.Asn602Ser variant has been observed in at least 4 individuals with a neurodevelopmental phenotype consistent with UBE3A-related disease (University of Chicago, Ambry Genetics and GeneDx Internal databases) (PS4_moderate), and has been reported as a de novo occurrence (biological parentage unconfirmed) in 1 of these individuals (PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Asn602Ser variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PS4_moderate, PM6, PP3). (UBE3A Specifications v.5.0; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333543/MONDO:0007113/037 2025-05-07 2025-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports CHEBI:404903 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0019521 infores:hetionet CHEBI:7478 biolink:causes UMLS:C3495832 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C3495832 infores:hetionet CHEBI:10124 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042133 infores:hetionet GO:0061105 biolink:causes GO:0048565 infores:ubergraph knowledge_assertion manual_agent GO:0061105 GO:0048565 NCBITaxon:13373 biolink:causes MONDO:0005774 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:13373 MONDO:0005774 CHEBI:46081 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0025323 infores:hetionet CHEBI:6887 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085583 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0595883 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0021053 infores:hetionet CHEBI:63115 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0004364 infores:hetionet CHEBI:47780 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018520 infores:hetionet CHEBI:100246 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0030305 infores:hetionet NCBIGene:633 biolink:causes MONDO:0010248 infores:monarchinitiative not_provided not_provided HGNC:1044 MONDO:0010248 uuid:243a0906-8e3d-455f-a10f-dcbea817f7a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014193 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014193 MONDO:0011071 PMID: Benign BP4, BA1 PS4, PS2, PS1, PS3, BP1, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS1, BS4, BS3, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID: 19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID: 30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID: 17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014193/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3752 biolink:causes HP:0033400 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0000727 infores:hetionet CHEBI:15552 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0043352 infores:hetionet CHEBI:5147 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0149512 infores:hetionet GO:0060693 biolink:causes GO:0007435 infores:ubergraph knowledge_assertion manual_agent GO:0060693 GO:0007435 CHEBI:5959 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0009763 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0038999 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0595877 infores:hetionet CHEBI:31859 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018790 infores:hetionet GO:1904971 biolink:causes GO:0019080 infores:ubergraph knowledge_assertion manual_agent GO:1904971 GO:0019080 NCBIGene:26022 biolink:causes MONDO:0014426 infores:monarchinitiative not_provided not_provided HGNC:24529 MONDO:0014426 uuid:04afd4a8-31b7-4866-aa54-2d4f74a45e6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0029118 infores:hetionet CHEBI:119915 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013404 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0948525 infores:hetionet CHEBI:9434 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C3665347 infores:hetionet CAID:CA16621484 biolink:causes MONDO:0010315 infores:clingen CAID:CA16621484 MONDO:0010315 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PS4 NM_000206.3(IL2RG):c.545G>A is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 182 (p.Cys182Tyr). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.),Reduced IL2-induced phosphorylation of STAT5 (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :3.5 pts (PP4_Moderate) PMID: 18688286. This variant has been reported in 6 probands (PS4_met, 5pts)(PMIDs: 25109802,22039266,18688286,35482138, 21865537,18728247)Another missense variant Cys182Arg in the same codon has been reported (PMID: 10794430) (not classified by SCID VCEP yet) (PM5 not evaluated).In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PP4_Moderate, PS4_met(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621484/MONDO:0010315/129 2024-01-10 2024-01-10 X-linked inheritance HP:0001417 Supports CHEBI:100241 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0948807 infores:hetionet NCBITaxon:1773 biolink:causes MONDO:0005848 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1773 MESH:D014391 DB01234_MESH_D014391_1 CHEBI:28148 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0220983 infores:hetionet CHEBI:3506 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0013144 infores:hetionet CHEBI:167638 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0013144 infores:hetionet CHEBI:31711 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151636 infores:hetionet CHEBI:63617 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C2047937 infores:hetionet CHEBI:45863 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0038999 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029456 infores:hetionet NCBIGene:5826 biolink:causes MONDO:0013925 infores:monarchinitiative not_provided not_provided HGNC:68 MONDO:0013925 uuid:49b8b8f2-cc18-41d5-b7ea-98d4ce22ed05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8461 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0040822 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018799 infores:hetionet CAID:CA2580612099 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612099 MONDO:0015967 PMID: Likely Pathogenic PM4_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting PS4 The c.1169_1171del variant in the glucokinase gene, GCK, is a three-base pair deletion resulting in the in-frame deletion of isoleucine at codon 390 (p.(Ile390del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1169_1171del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a non-repeat region (PM4_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with 2H OGTT increment <3 mmol/l) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with four informative meioses in one family (PP1_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1169_1171del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_supporting, PM4_supporting, PP4_moderate, PP1_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612099/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:63598 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0241863 infores:hetionet CHEBI:135736 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0427457 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0020517 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0031117 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006266 infores:hetionet CHEBI:36791 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0000737 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0024312 infores:hetionet NCBITaxon:848 biolink:causes MONDO:0006765 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:848 MONDO:0006765 CHEBI:92998 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0037763 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0013395 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030846 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005845 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0025309 infores:hetionet CAID:CA011779 biolink:causes MONDO:0005045 infores:clingen CAID:CA011779 MONDO:0005045 PMID:24829265PMID:27532257PMID:8282798PMID:9829907PMID:12974739PMID:9822100PMID:10957787PMID:23816408PMID:19645038PMID:27532257PMID:12707239PMID:8282798PMID:22429680PMID:10957787PMID:12974739PMID:9822100 Pathogenic PP3, PS3, PM1, PM5, PM2, PP1_Strong, PS2, PS4 The c.2155C>T (p.Arg719Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; PMID:22429680; PMID:23816408; PMID:12707239; PMID:19645038; PMID:27532257; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059419.5 ), including 1 de novo occurrence (PS2; 10957787). This variant was found to segregate with disease in 8 affected family members (PP1_Strong; PMID:9829907; PMID:8282798; PMID:9822100; PMID:12974739; SHaRe consortium, PMID: 30297972). A mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:24829265). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2156G>A p.Arg719Gln - Variation ID 14107). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS2; PS3; PS4; PP1_ Strong; PM1; PM2; PM5; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011779/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6909 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2129214 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0022650 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0040409 infores:hetionet CHEBI:91583 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0014457 infores:hetionet CAID:CA367400787 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400787 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.683C>G variant in the glucokinase gene, GCK, causes an amino acid change of threonine to arginine at codon 228 (p.(Thr228Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 12955723, internal lab contributor). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). Two other missense variants, c.683C>T p.Thr228Met and c.682A>G p.Thr228Ala, have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.683C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Strong, PP1_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400787/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:4453 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C2225524 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0036220 infores:hetionet NCBIGene:55699 biolink:causes MONDO:0014455 infores:monarchinitiative not_provided not_provided HGNC:29685 MONDO:0014455 uuid:4aed46a0-d554-4ad5-9fe8-fb8880a40553 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28177 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0728899 infores:hetionet CHEBI:132233 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0042029 infores:hetionet CHEBI:59773 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0036830 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0039584 infores:hetionet CHEBI:8597 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0027497 infores:hetionet CHEBI:9943 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030318 infores:hetionet CHEBI:2955 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0013604 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0497247 infores:hetionet CHEBI:6931 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0023380 infores:hetionet CHEBI:5384 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0042109 infores:hetionet CHEBI:70735 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0043094 infores:hetionet CHEBI:63577 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0917801 infores:hetionet CHEBI:4046 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0221490 infores:hetionet CHEBI:51364 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1167965 infores:hetionet CHEBI:8888 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085628 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0005779 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0032326 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0855242 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013395 infores:hetionet CHEBI:50173 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0271321 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027339 infores:hetionet CAID:CA500651220 biolink:causes MONDO:0100326 infores:clingen CAID:CA500651220 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting BP7, PP4, PP1, BP4 The c.1431C>T variant in ITGB3 is a single nucleotide substitution that does not alter the protein sequence (p.Gly477=). RT-PCR and sequencing revealed that the variant caused a deletion of 95 base pairs (c.1430_1524del) with a frameshift, which subsequently created a premature stop codon in exon 10 of ITGB3 (p. G477Afs*30). This is predicted to cause nonsense-mediated decay. (PMID: 36704147; PVS1). This variant has been detected in a 7-yr old chinese boy with Glanzmann thrombasthenia in homozygous phase confirmed by the parental sequencing (PMID: 36704147; PM3_Supporting). This variant is absent in gnomADv4.0.0 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3_Supporting, PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500651220/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:15553 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0010200 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0015230 infores:hetionet CHEBI:50131 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0235896 infores:hetionet CHEBI:41774 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0016382 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0854146 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0854146 infores:hetionet CAID:CA512318752 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318752 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS4, PS2, PS3, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP4, PP1 This c.402T>C (p.Ala134=) synonymous variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = -2.40196 in GRCh38); it is not predicted to have any splicing impact per SpliceAI (BP7+BP4). The variant is absent from population databases, including gnomAD v2 and v3 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1 (version 2): BP4, BP7, and PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318752/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:367163 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014549 infores:hetionet CHEBI:8665 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0014591 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0040046 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005020 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0021831 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0233485 infores:hetionet CHEBI:31397 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0006266 infores:hetionet CHEBI:4728 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0042963 infores:hetionet CHEBI:28148 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0236024 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0022660 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0271650 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0003864 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033975 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020651 infores:hetionet CHEBI:39867 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0038990 infores:hetionet CHEBI:2379 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0600142 infores:hetionet CHEBI:16755 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0015967 infores:hetionet CHEBI:10124 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0011551 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0004936 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0030920 infores:hetionet CHEBI:50729 biolink:causes HP:0031970 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0438242 infores:hetionet CHEBI:8888 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151662 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0034069 infores:hetionet CHEBI:4856 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0080274 infores:hetionet CHEBI:6538 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0011991 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037199 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030305 infores:hetionet CAID:CA10529821 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529821 MONDO:0010604 PMID: Benign BA1 PS4, PP3, BP4 The NM_000133.3:c.712T>G predicts a missense variant, Phe238Val, that is reported at a high MAF of 0.0008074 (12/14862 alleles with 4 hemizygotes) in the East Asian population of gnomAD v2.1.1, meeting the BA1 cut-off of >= 0.0000556. It is reported in the literature in at least one severe Hemophilia B patient who has an additional F9 variant. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529821/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true GO:1905557 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1905557 GO:0010256 CHEBI:18332 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0003467 infores:hetionet CHEBI:51230 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0011570 infores:hetionet CHEBI:145499 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0233471 infores:hetionet CHEBI:7789 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0009676 infores:hetionet GO:0042682 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0042682 GO:0150063 CHEBI:31401 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0917798 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0017601 infores:hetionet CHEBI:16335 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0085612 infores:hetionet CHEBI:3508 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0002792 infores:hetionet CHEBI:5098 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C2363730 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0018799 infores:hetionet CHEBI:3485 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0239937 infores:hetionet CHEBI:32293 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0027497 infores:hetionet CAID:CA915940209 biolink:causes MONDO:0009861 infores:clingen CAID:CA915940209 MONDO:0009861 PMID: Uncertain Significance PP4_Moderate, PM2 PM3, PP3 This c.843-15_843-12del variant in PAH was reported in multiple Chinese patients with PAH deficiency (PMID: 26503515). The variant is referred to as ‘c.843-14_-11delCTTT’ in the paper. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. In silico models conflict on whether this variant breaks a splice donor site. In summary, this variant meets criteria to be classified as Uncertain Significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2 and PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940209/MONDO:0009861/006 2022-05-27 2022-06-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:87715 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0549433 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0522348 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0522348 infores:hetionet CHEBI:9570 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018790 infores:hetionet CHEBI:125354 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0235309 infores:hetionet CHEBI:6541 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0034152 infores:hetionet NCBIGene:79879 biolink:causes MONDO:0030714 infores:monarchinitiative not_provided not_provided HGNC:26185 MONDO:0030714 uuid:acb2caea-413a-47d7-8cf7-175fcbe0434e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0178298 infores:hetionet CHEBI:8107 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0006625 infores:hetionet CHEBI:2668 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0027497 infores:hetionet NCBIGene:1678 biolink:causes MONDO:0010578 infores:monarchinitiative not_provided not_provided HGNC:11817 MONDO:0010578 uuid:add84a0d-8d48-4005-a8a0-5972e63f3c84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6897 biolink:causes MONDO:0032806 infores:monarchinitiative not_provided not_provided HGNC:11572 MONDO:0032806 uuid:d76f638f-88b0-46cd-8285-a246590d9cdf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085593 infores:hetionet CAID:CA923726221 biolink:causes MONDO:0100326 infores:clingen CAID:CA923726221 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.756del (p.Met253CysfsTer30) in exon 5 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/15 and is predicted to lead to nonsense mediated decay (PVS1). GT1 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 1.2%, as measured by flow cytometry. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; PM3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA923726221/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:3932 biolink:causes MONDO:0014334 infores:monarchinitiative not_provided not_provided HGNC:6524 MONDO:0014334 uuid:c1534073-344c-425e-b63c-d3eaaccdc1c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0000833 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162830 infores:hetionet NCBIGene:212 biolink:causes MONDO:0010420 infores:monarchinitiative not_provided not_provided HGNC:397 MONDO:0010420 uuid:f2fa9efe-601d-4b99-8488-5d6f8c006837 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45285 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0235378 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0032584 infores:hetionet CHEBI:3387 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C3263723 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0023067 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0877232 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0863113 infores:hetionet CHEBI:45716 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0002170 infores:hetionet CHEBI:47898 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0520966 infores:hetionet CHEBI:50223 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1096035 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0221490 infores:hetionet CHEBI:5098 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0011991 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0242973 infores:hetionet CHEBI:8232 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0085593 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0009450 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011849 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011849 infores:hetionet CHEBI:10119 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0233471 infores:hetionet CHEBI:8805 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0018681 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0233472 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009938 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0595883 infores:hetionet CHEBI:5864 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0014356 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1142412 infores:hetionet CHEBI:8874 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0002962 infores:hetionet CAID:CA16020812 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020812 MONDO:0009861 PMID:26542770PMID:26503515PMID:29653233PMID:26542770PMID:28771436PMID:29316886 Pathogenic PM5, PM2, PP4_Moderate, PM3_Strong PP3, PS3 The c.532G>A (p.Glu178Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 26503515; PMID: 26542770). This variant has an extremely low allele frequency (PopMax MAF=0.00006, ENF) in gnomAD (PM2). This variant was detected in trans with F39del (PMID: 26542770) (Pathogenic/Likely Pathogenic in ClinVar by 7 submitters, see ID 188933). It has also been observed with R408W (PMID: 28771436, parental testing not performed) (Pathogenic in ClinVar (ID 577) and by ClinGen PAH VCEP) and IVS4-1G>A (PMID: 29316886, parental testing unclear) (Pathogenic in ClinVar (ID 594) and by ClinGen PAH VCEP). Computational prediction tools and conservation analysis are conflicting. This is a novel missense change at an amino acid residue where a different pathogenic missense change has been seen before (c.533A>G (p.Glu178Gly). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PM5 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020812/MONDO:0009861/006 2021-01-17 2021-02-12 Autosomal recessive inheritance HP:0000007 Supports PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027339 infores:hetionet CHEBI:127780 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0030193 infores:hetionet CHEBI:135342 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0011124 infores:hetionet CHEBI:8707 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085628 infores:hetionet CHEBI:68558 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0011991 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018991 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0851341 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0013595 infores:hetionet GO:0001549 biolink:causes CL:0000711 infores:ubergraph knowledge_assertion manual_agent GO:0001549 CL:0000711 NCBIGene:6601 biolink:causes MONDO:0032702 infores:monarchinitiative not_provided not_provided HGNC:11105 MONDO:0032702 uuid:72d647db-0fcf-4ff9-9b67-5da16f5e6fec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53766 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0041582 infores:hetionet CHEBI:50173 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0547030 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0016436 infores:hetionet CAID:CA343724686 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724686 MONDO:0020367 PMID: Uncertain Significance PP3, PP1, PM2_Supporting BS1, BS3, BP7, PM6, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.1111T>G variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Aspartic Acid at amino acid 371 (p.Tyr371Asp). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.892, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 19784393), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 19784393), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724686/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50841 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0010200 infores:hetionet CAID:CA915940263 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940263 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.1185del (p.Phe396SerfsTer26) found in a homozygous proband (PMID: 29084015; PM3_supporting) causes a premature stop codon at exon 10 and is predicted to undergo nonsense mediated decay (PVS1). The affected individual displayed abnormal bleeding and an impaired response to agonists, with a normal response to ristocetin, which is characteristic of GT. Additionally, αIIbβ3 surface expression was absent (<25%), as measured by flow cytometry (PP4_moderate). The mutation was not found in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP4_moderate, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940263/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6062 biolink:causes HP:0031657 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0577822 infores:hetionet CHEBI:2704 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0022408 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0235146 infores:hetionet CHEBI:205919 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0151908 infores:hetionet CHEBI:3814 biolink:causes HP:0005240 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0239296 infores:hetionet CHEBI:82960 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0040264 infores:hetionet CHEBI:2788 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0235270 infores:hetionet UMLS:C0011701 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C2830004 infores:hetionet CHEBI:724125 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0015672 infores:hetionet CHEBI:50922 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085632 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0038045 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0038045 infores:hetionet CAID:CA16020843 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020843 MONDO:0009861 PMID:23764561PMID:28653649PMID:23764561 Pathogenic PP4_Moderate, PM2, PP3, PS3, PM3_Strong The c.697T>A (p.Phe233Ile) variant in PAH has been reported in 2 unrelated patients with PKU (BH4 deficiency excluded) and was detected with known pathogenic variants p.R408W and p.V245A. (PP4_Moderate, PM3_Strong; PMID: 23764561). This variant is absent in population databases (PM2). This variant showed no specific activity in functional assay and no response to chaperone co-expression (PS3; PMID: 28653649). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_strong, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020843/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410147984 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147984 MONDO:0011071 PMID:32943879PMID:32943879 Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1139A>G (p.Tyr380Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147984/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0278016 infores:hetionet CAID:CA350340846 biolink:causes MONDO:0015924 infores:clingen CAID:CA350340846 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PM1 BP4, PS4 "This BMPR2 missense variant c.932G>A is predicted to change a glycine residue to a glutamic acid at position 311. This change occurs in the kinase domain, which is a well established functional domain (PM1 is met). It is absent from gnomAD v2.1.1 controls and gnomAD v4.1 (PM2_supporting is met). There are two ClinVar submissions for this variant, but the affected status of one is ""unknown"" (PS4 not met). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.979 indicating that PP3 is met based on the threshold specified by the PH-VCEP >0.75.In summary, the variant meets the criteria to be classified as variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_Supp, PP3 (VCEP specification version 1.1, 1/18/2024)." Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350340846/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:53760 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0017152 infores:hetionet CHEBI:8107 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013384 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1112214 infores:hetionet CHEBI:47898 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0575081 infores:hetionet CHEBI:145499 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019345 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0497201 infores:hetionet GO:0048927 biolink:causes CL:2000039 infores:ubergraph knowledge_assertion manual_agent GO:0048927 CL:2000039 CAID:CA626121071 biolink:causes MONDO:0100326 infores:clingen CAID:CA626121071 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5(ITGA2B):c.1946+3G>T variant is a splice region variant located in intron 19, which is absent from large population databases (gnomADv2.1.1; PM2_supporting). Two probands (GT65, GT34 of PMID:25728920) with this variant presented with significant mucocutaneous bleeding and platelet aggregometry demonstrated absence of platelet aggregation with 3 platelet agonists and normal aggregation with ristocetin. A reduced (<5%) surface expression of αIIbβ3 was demonstrated by flow cytometry (PP4_strong). Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions. The c.1946+3G>T variant on ITGA2B is present in compound heterozygous state (GT65) with another splice donor variant c.574+1G>A , which has been previously classified as pathogenic by the PD-VCEP. (PM3_supporting). This variant meets criteria for PP4_strong, PM2_supporting, and PM3_supporting , and has been classified as likely pathogenic for Glanzmann thrombasthenia based on ACMG/AMP criteria specified by the Platelet Disorders VCEP. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626121071/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9086 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0231218 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042514 infores:hetionet CHEBI:473990 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0019209 infores:hetionet CHEBI:127780 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0028734 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034063 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0013395 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019147 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0032961 infores:hetionet CHEBI:681569 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0014518 infores:hetionet CHEBI:28748 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0086439 infores:hetionet GO:1905939 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:1905939 GO:0061458 NCBIGene:54 biolink:causes MONDO:0011939 infores:monarchinitiative not_provided not_provided HGNC:124 MONDO:0011939 uuid:2add5cfd-9476-42fa-b89d-45f3de412cf3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6754 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0004093 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0042109 infores:hetionet NCBIGene:2334 biolink:causes MONDO:0010659 infores:monarchinitiative not_provided not_provided HGNC:3776 MONDO:0010659 uuid:ee4754ab-2836-4acd-8c66-725ffb23ef25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0581912 infores:hetionet NCBIGene:28956 biolink:causes MONDO:0012559 infores:monarchinitiative not_provided not_provided HGNC:29796 MONDO:0012559 uuid:70b7a99a-d001-4501-99b0-6d58c9067806 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:56606 biolink:causes MONDO:0012793 infores:monarchinitiative not_provided not_provided HGNC:13446 MONDO:0012793 uuid:b2b3feee-9de4-48bb-9267-b299333d971c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0021400 infores:hetionet CHEBI:135876 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0042401 infores:hetionet CHEBI:18332 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0016927 infores:hetionet CHEBI:17474 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0027497 infores:hetionet NCBIGene:1834 biolink:causes MONDO:0007437 infores:monarchinitiative not_provided not_provided HGNC:3054 MONDO:0007437 uuid:97c98758-ea24-4a2d-9cce-d627b84cbdd1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0013404 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019158 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0003864 infores:hetionet CHEBI:101278 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0035455 infores:hetionet CHEBI:4856 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0005758 infores:hetionet CHEBI:36791 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014553 infores:hetionet CHEBI:5100 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0151579 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0009806 infores:hetionet CHEBI:49662 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0014591 infores:hetionet CHEBI:7577 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0028734 infores:hetionet CAID:CA145749 biolink:causes MONDO:0009290 infores:clingen CAID:CA145749 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.1203G>A (p.Gln401=) in gnomAD v2.1.1 is 0.74003 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77901) and European Finnish (0.76403) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92461, two star review status), with 7 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145749/MONDO:0009290/010 2020-01-23 2020-05-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63577 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0026848 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085606 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0741921 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0741921 infores:hetionet NCBIGene:3716 biolink:causes MONDO:0033558 infores:monarchinitiative not_provided not_provided HGNC:6190 MONDO:0033558 uuid:f3f61a9a-3e32-4f59-9f58-d5681358d1c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4469 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0027497 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018802 infores:hetionet CHEBI:63115 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0344232 infores:hetionet CAID:CA397724835 biolink:causes MONDO:0008723 infores:clingen CAID:CA397724835 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PS3_Supporting NM_000018.4(ACADVL); c.1309A>G(p.Met437Val) variant in ACADVL is a missense variant predicted to cause substitution of methionine by valine at amino acid 437 (p.Met437Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). VLCAD activity and protein expression assays in transfected patient fibroblasts showed marked reductions indicating that this variant impacts protein function (PMID 11914034, PS3_Supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PS3_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724835/MONDO:0008723/021 2023-03-27 2023-03-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5790 biolink:causes MONDO:0013662 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0004763 infores:hetionet CHEBI:9014 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0020649 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0031117 infores:hetionet CHEBI:63611 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0542571 infores:hetionet CHEBI:63623 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0016199 infores:hetionet CHEBI:64355 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0025345 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011849 infores:hetionet CHEBI:64045 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0002994 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0015397 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020538 infores:hetionet NCBIGene:7020 biolink:causes MONDO:0007235 infores:monarchinitiative not_provided not_provided HGNC:11742 MONDO:0007235 uuid:0993a9f2-e3b5-4b3d-90e9-e14a17200f77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3011 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0520966 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042109 infores:hetionet CHEBI:167638 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020580 infores:hetionet CHEBI:100246 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151766 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0853692 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0005959 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0005959 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0010200 infores:hetionet CHEBI:8028 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0221152 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020517 infores:hetionet NCBIGene:5733 biolink:causes HP:0012531 infores:drugmechdb knowledge_assertion manual_agent UniProtKB:P43115 MESH:D010146 DB00814_MESH_D010146_1 CHEBI:63598 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151878 infores:hetionet CAID:CA013685 biolink:causes MONDO:0005045 infores:clingen CAID:CA013685 MONDO:0005045 PMID: Uncertain Significance PM2, PP3, PS4_Supporting PM1, PM5, PM6, PP1, BA1, PS3, BS1, BS3, BS4, BP4, PS1, PS2 The NM_000257.4(MYH7):c.341T>C (p.Ile114Thr) variant has been identified in 4 individuals with HCM (PS4_Supporting; Restrepo-Cordoba 2017 PMID:28138913; GeneDx pers. comm.; Invitae pers. comm.). This variant has also been identified in 1 individual with DCM who also carried a truncating variant in TTN and an individual with heart disease and sensory disfunction (Ambry pers. comm.; LMM pers. comm.). This variant was identified in 0.0009% (1/113612) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013685/MONDO:0005045/002 2021-03-31 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64355 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0037199 infores:hetionet CHEBI:6640 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0038358 infores:hetionet CHEBI:63791 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013428 infores:hetionet CHEBI:47780 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0039070 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020615 infores:hetionet CHEBI:7915 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0438215 infores:hetionet CHEBI:480999 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0003862 infores:hetionet CHEBI:37924 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011124 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0004936 infores:hetionet CHEBI:46557 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0016199 infores:hetionet CHEBI:15365 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0025222 infores:hetionet CAID:CA413495953 biolink:causes MONDO:0010315 infores:clingen CAID:CA413495953 MONDO:0010315 PMID: Uncertain Significance PP4, PM2_Supporting PM1, PM5, PP3, PS1 The NM_000206.3:c.694G>A variant in IL2RG is a missense variant predicted to cause substitution of glycine by arginine at amino acid 232 (p.Gly232Arg). This variant is not present in gnomAD v2.1.1 and therefore is below the minor allele frequency threshold set by the ClinGen SCID-VCEP for PM2_Supporting (<0.000124). This variant (also known as 708G>A in the literature) has been identified in a male individual with T cell lymphopenia who met WHO criteria for SCID (PMID: 9058718, 8961626) and meets the SCID VCEP's criteria for PP4 (male patient (0.5p) meeting diagnostic criteria for SCID (0.5p) = 1p, PP4 met at regular strength). This variant has also been reported in a second male individual with a reported phenotype of SCID (PMID: 28747913) but who did not meet the SCID VCEP criteria for PP4 due to lack of detailed phenotypic information. This variant does not occur in a known hotspot or well-known functional domain according to the SCID VCEP specifications for IL2RG and therefore PM1 is not met. A different nucleotide change (c.694G>C) that results in the same missense change as (p.Gly232Arg) was reported in a patient with a suspected inborn error of immunity (PMID: 35874699) who did not meet PP4 criteria for SCID. This variant has not yet been classified by the SCID VCEP and therefore PS1 is not met. Two additional variants c.695G>A and c.695G>T resulting in different missense changes at this same codon (p.Gly232Glu and p.Gly232Val, respectively) were reported in individuals with suspected primary immunodeficiencies (PMID: 28359783, 33942430) but neither meets PP4 criteria for SCID. These variants have not yet been classified by the SCID VCEP and therefore PM5 is not met. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413495953/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:4975 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0002792 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013491 infores:hetionet CHEBI:10127 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C1510410 infores:hetionet CHEBI:4995 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020621 infores:hetionet CHEBI:134966 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0232462 infores:hetionet CHEBI:77260 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0023518 infores:hetionet CHEBI:5790 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0006266 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009450 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0239978 infores:hetionet CHEBI:52717 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0005758 infores:hetionet CHEBI:63635 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0040264 infores:hetionet CHEBI:53691 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0013604 infores:hetionet GO:1905100 biolink:causes GO:0097190 infores:ubergraph knowledge_assertion manual_agent GO:1905100 GO:0097190 CHEBI:10119 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0278080 infores:hetionet CHEBI:7507 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0151692 infores:hetionet CAID:CA10577544 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577544 MONDO:0007648 PMID: Likely Benign BS2, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4 The c.1493A>C (p.Asp498Ala) variant is present at <1/100,000 alleles in the European non-Finnish subpopulation of the gnomAD cohort (1/113,758 alleles; PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been seen in at least 10 individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000279435.9, SCV000637728.4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2_Supporting, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577544/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:171719 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0857305 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003537 infores:hetionet GO:0060762 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0060762 GO:0035295 CHEBI:3176 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C2047937 infores:hetionet NCBIGene:4668 biolink:causes MONDO:0012222 infores:monarchinitiative not_provided not_provided HGNC:7631 MONDO:0012222 uuid:a65f331d-32de-431e-bce3-08f1e3da526b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3314 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0036974 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020621 infores:hetionet CAID:CA367403278 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403278 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM5, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PS4 The c.185T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 62 (p.(Val62Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.97, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.23, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 16731834). This variant has an incomputable Popmax filtering allele frequency in gnomAD v2.1.1 due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African subpopulation, below the ClinGen MDEP threshold for PM2_Supporting (Popmax FAF ≤0.000003 and ≤ 2 copies in ENF and ≤1 copy in any other subpopulation) (PM2_Supporting). It was identified in at least two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18399931, PMID: 9736233, ClinVar ID: 585917). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 18399931). This variant segregated with diabetes, with five informative meioses in one family with MODY (PP1_Strong; PMID: 9736233, internal lab contributors). Another missense variant, c.184G>A (p.Val62Met) has been interpreted as pathogenic by the ClinGen MDEP and p.Val62Ala has a greater Grantham distance (PM5). In summary, the c.185T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP1_Strong, PM5, PS3_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403278/MONDO:0015967/086 2024-07-25 2024-07-25 Semidominant inheritance HP:0032113 Supports CHEBI:59773 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0036572 infores:hetionet CHEBI:63629 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0019080 infores:hetionet NCBIGene:2099 biolink:causes MONDO:0014148 infores:monarchinitiative not_provided not_provided HGNC:3467 MONDO:0014148 uuid:d29e53b8-a5d9-42a9-ba90-6d1e59c6e0da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3403 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0004096 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0020538 infores:hetionet CHEBI:3515 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0030252 infores:hetionet CHEBI:9738 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0013395 infores:hetionet CAID:CA5922882 biolink:causes MONDO:0015152 infores:clingen CAID:CA5922882 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The NM_213599.3: c.304_308del p.(Lys102ValfsTer2) variant in ANO5 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 6/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with progressive limb girdle muscle weakness, where it was confirmed in trans with a second frameshift variant (PMID: 27862037; PP4). The filtering allele frequency of this variant is 0.000034729 (the upper threshold of the 95% CI of 28/1105382 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the VCEP threshold (0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5922882/MONDO:0015152/188 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CAID:CA367400135 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400135 MONDO:0015967 PMID: Likely Pathogenic PM1, PM5_Supporting, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PS4, PP1 The c.884G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 295 (p.(Gly295Asp)) of NM_000162.5. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 20337973, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.907, which is greater than the MDEP VCEP threshold of 0.70 (PP3). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). The Relative Activity Index (RAI) of this variant was found to be 0, which is below the MDEP cutoff (<0.5) (PMID: 28842611). Lastly, another missense variant, c.883G>A, p.Gly295Ser, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.884G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP4, PM2_Suporting, PP2, PP3, PM1, PS3_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400135/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Supports CHEBI:4710 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0687713 infores:hetionet CHEBI:7573 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0011603 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0034065 infores:hetionet CHEBI:127342 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0008031 infores:hetionet CHEBI:6792 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0020517 infores:hetionet CAID:CA412370061 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370061 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PM5_Supporting, PP3_Strong, PP4 PM1 NM_000330.4(RS1):c.656G>A (p.Cys219Tyr) is a missense variant encoding the substitution of cysteine with tyrosine at amino acid 219. Another missense variant in the same codon, NM_000330.4(RS1):c.655T>G (p.Cys219Gly) has been classified as likely pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (194) than the comparison variant (159), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5_Supporting). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype of the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 32300273, PMID: 33124204, PP4). The computational predictor REVEL gives a score of 0.979, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). PM1_Strong is not met as this code is ineligible to be used in combination with PP3_Strong. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: PM2_Supporting, PP3_Strong, PP4, and PM5_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370061/MONDO:0010725/126 2025-10-04 2025-10-05 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:8768 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0006444 infores:hetionet CHEBI:3756 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0232849 infores:hetionet CHEBI:28915 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0497156 infores:hetionet CAID:CA256608 biolink:causes MONDO:0000700 infores:clingen CAID:CA256608 MONDO:0000700 PMID:18632931PMID:18621678 Pathogenic PM2_Supporting, PS3, PP3_Moderate, PP1_Strong, PM1 BS2, PVS1, BA1, BP4, PM4, PM3, BS1, BS4, BS3 The c.4465C>A variant in SCN1A is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 1489 (p.Gln1489Lys). This variant has been reported to segregate with hemiplegic migraine in 18 affected individuals from 3 families (PMID: 16054936) (PP1_strong). This variant is absent from gnomAD (v4) (PM2_supporting). Whole-cell voltage-clamp studies were performed on human tsA201 cell model that showed increased persistent current but also enhanced entry into slow activation as well as delayed recovery from fast and slow inactivation indicating that this variant impacts protein function (PMIDs: 18621678, 18632931) (PS3). This variant resides within a Pathogenic Enriched Region that is defined as a mutational hotspot by the ClinGen Epilepsy Sodium Channel VCEP (PM1). The computational predictor (REVEL) gives a score of 0.936, evidence that correlates with impact to SCN1A function (PP3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hemiplegic migraine based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PP1_strong, PS3, PP3_moderate, PM1, PM2_supporting (v1.0; approved September 24, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA256608/MONDO:0000700/067 2024-10-01 2025-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3723 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0702166 infores:hetionet CAID:CA2801986 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801986 MONDO:0001586 PMID: Likely Pathogenic PP3_Moderate, PM3, PP4_Moderate PM5, PM2 The NM_000203.5:c.536C>T variant in IDUA is predicted to result in a missense substitution, p.Thr179Met. One patient is compound heterozyous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A or (p.Trp402Ter); the variants were identified by trio exome sequencing are are confirmed to be in trans (PMID: 32670797) (PM3). This patient has documented values showing deficient IDUA activity in two independent samples, elevated urine GAGs with high levels of heparan and dermatan sulfate which reduced to only a trace after 12 months of enzyme replacement therapy, and clinical symptoms consistent with the condition (PMID: 32670797) (PP4_Moderate). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.0002 (5/25114 alleles) in the Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion. The next highest population MAF is 0.00003 (4/128740 alleles) in the European non-Finnish population (PM2_Supporting). Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>G (p.Thr179Arg) (PMID: 21480867), and p.Thr179Lys (PMID: 28752568). The classification of c.536C>T (p.Thr179Met) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (ClinVar ID: 1455223). In summary, this variant meets the criteria to be classified as likely pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801986/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10576325 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576325 MONDO:0007750 PMID: Pathogenic PS4, PM5, PM2, PP3, PP1, PP4 BA1, BP4, BP2, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, BS2 The NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PM5, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows: PM2: PopMax MAF = 0.00003 (0.003%) in South Asian exomes (gnomAD version 2.1.1). PP3: REVEL= 0.845. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1898G>A (p.Arg633His) (ClinVar ID: 226380).PS4, PP4: Variant meets PM2 and is identified in at least 10 unrelated index cases who fulfill criteria for FH (Simon-Broome criteria or with DLCN score >=6) from different labs (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, US; Robarts Research Institute, Canada; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; PMID 17094996 (Tosi et al., 2007), UK; PMID 31491741 (Hori et al., 2019), Japan) after alternative causes of high cholesterol were excluded.PP1: Variant segregates with phenotype in at least 2 informative meiosis in 2 families from different labs (Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France): 2 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576325/MONDO:0007750/013 2023-11-07 2025-08-26 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UNII:9YCX42I8IU biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0004093 infores:hetionet CHEBI:9398 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0035455 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0023533 infores:hetionet CHEBI:136040 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0241934 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0018802 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0235416 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0020701 infores:hetionet CHEBI:44185 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0149871 infores:hetionet CAID:CA281453 biolink:causes MONDO:0007648 infores:clingen CAID:CA281453 MONDO:0007648 PMID:29511593PMID:27192129PMID:20373070PMID:22225527PMID:20824432 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1023T>G (p.Tyr341*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 27192129). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA281453/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:4325 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C2939465 infores:hetionet CHEBI:404903 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0030196 infores:hetionet CHEBI:49668 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0919924 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0008031 infores:hetionet CHEBI:585948 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0547030 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013395 infores:hetionet CHEBI:44032 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020452 infores:hetionet CHEBI:184555 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0014591 infores:hetionet CHEBI:9130 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C2830004 infores:hetionet CHEBI:49040 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C1384353 infores:hetionet CHEBI:3504 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0041657 infores:hetionet NCBIGene:10166 biolink:causes MONDO:0009393 infores:monarchinitiative not_provided not_provided HGNC:10985 MONDO:0009393 uuid:00d0e3ee-1c8f-4484-bb34-a268132f5e66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes UMLS:C0391996 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0391996 infores:hetionet CHEBI:61049 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0877303 infores:hetionet CAID:CA137541 biolink:causes MONDO:0019501 infores:clingen CAID:CA137541 MONDO:0019501 PMID: Uncertain Significance PP1, PM3, PM2_Supporting PP3 The variant c.6614C>T (NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)) in CDH23 is a missense variant predicted to cause substitution of proline by leucine at amino acid 2205 (p.Pro2205Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000002920 (8/1179896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.342, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. This variant has been detected in at least 8 individuals with autosomal recessive hearing loss. All of these individuals were homozygous for the variant (1.0 pts; PMIDs: 28501645, 32747562 & LMM Internal Data (SCV000062934.5); PM3). There was a common haplotype found between five affected individuals from three families, one of which had three affected siblings, including a set of twins. Personal communication confirmed the three siblings were sequenced; however, it was not apparent whether the twins were dizygotic or monozygotic and therefore only one twin was counted toward segregation (PP1_Supporting; 28501645). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3, PP1_Supporting; Version 2; 11/15/23). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA137541/MONDO:0019501/005 2023-11-15 2024-01-10 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:9943 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018378 infores:hetionet CAID:CA134665 biolink:causes MONDO:0021060 infores:clingen CAID:CA134665 MONDO:0021060 PMID:24728327 Likely Benign BP5, BS1 PP2, BS2 The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Université Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134665/MONDO:0021060/004 2019-08-19 2019-12-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8069 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0000768 infores:hetionet NCBIGene:212 biolink:causes MONDO:0020721 infores:monarchinitiative not_provided not_provided HGNC:397 MONDO:0020721 uuid:07aae18c-669f-4655-9990-686d8ad3fc26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0022568 infores:hetionet CAID:CA229803 biolink:causes MONDO:0009861 infores:clingen CAID:CA229803 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong, PS3_Supporting The c.833C>T (p.Thr278Ile) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency ruled out), detected with pathogenic variants: R241C (PMID: 21307867); R241C, A259T (2 patients), R413P, Y356X (PMID: 15503242). Functional studies show a PAH enzyme activity of 1% compared to wild type (PMID: 9860305). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229803/MONDO:0009861/006 2022-03-05 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6067 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018802 infores:hetionet CHEBI:52717 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004144 infores:hetionet CHEBI:42797 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004604 infores:hetionet CHEBI:9738 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0234133 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0744403 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0744403 infores:hetionet CHEBI:83527 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0018681 infores:hetionet CHEBI:72690 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0080274 infores:hetionet CHEBI:4657 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0027947 infores:hetionet NCBIGene:84936 biolink:causes MONDO:0030800 infores:monarchinitiative not_provided not_provided HGNC:20758 MONDO:0030800 uuid:5317eebb-ce15-4e55-a318-220d1948c1c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0039070 infores:hetionet CHEBI:8346 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0240327 infores:hetionet CHEBI:15367 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0010038 infores:hetionet CHEBI:135930 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0700225 infores:hetionet CHEBI:3082 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0232849 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0023530 infores:hetionet CHEBI:182080 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0020538 infores:hetionet CHEBI:63580 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0231835 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0687707 infores:hetionet CHEBI:50924 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020546 infores:hetionet CHEBI:46081 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0036104 infores:hetionet CHEBI:40279 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0242429 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0004936 infores:hetionet CHEBI:3723 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013404 infores:hetionet CHEBI:15940 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020458 infores:hetionet CHEBI:7798 biolink:causes MONDO:0003648 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0041825 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0393444 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0393444 infores:hetionet CHEBI:9667 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0030486 infores:hetionet CAID:CA415087494 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087494 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4: c.1428C>G (p.Tyr476Ter) variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 10/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported a male with intellectual disability, autistic features, seizures and absent creatine peak on brain MRS (PMID: 29435807) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1802549). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on February 22, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087494/MONDO:0010305/027 2024-02-22 2024-03-29 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports UNII:15G12L5X8K biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085610 infores:hetionet CHEBI:63605 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0011603 infores:hetionet CHEBI:33130 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0009450 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0948070 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0948070 infores:hetionet CAID:CA229317 biolink:causes MONDO:0009861 infores:clingen CAID:CA229317 MONDO:0009861 PMID: Uncertain Significance PM3, PP4_Moderate, BP4 PM2, BA1, BS1 This variant has been detected in one individual with PAH deficiency (PMID: 36104584). This individual was a compound heterozygote for the variant and a pathogenic variant, p.Arg408Gln, in trans (phase confirmed by parental testing) (PMID: 36104584). This individual had plasma phenylalanine >120 μmol/L with the exclusion of a defect of BH4 cofactor metabolism (PP4_Moderate) (PMID: 36104584). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001 (20/19766 alleles) in the East Asian population (none of the population data codes are met). The computational splicing predictor SpliceAI gives a score of 0.05 for donor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 102503, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance, one submitter classifying the variant as likely benign, and one submitter classifying the variant as benign. Due to conflicting evidence, this variant is classified as a variant of unknown significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4, BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229317/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135961 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0030794 infores:hetionet NCBIGene:3827 biolink:causes MONDO:0023660 infores:monarchinitiative not_provided not_provided HGNC:6383 MONDO:0023660 uuid:abdd987f-f710-42a3-9f50-60002ed11373 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17698 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0020517 infores:hetionet CHEBI:3213 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0020625 infores:hetionet CHEBI:2904 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0016382 infores:hetionet CHEBI:10125 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020903 infores:hetionet CHEBI:474180 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004364 infores:hetionet CHEBI:15940 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0019209 infores:hetionet CHEBI:3312 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0004093 infores:hetionet CHEBI:3561 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0344232 infores:hetionet CHEBI:63637 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C1519353 infores:hetionet CHEBI:27974 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C2979982 infores:hetionet CHEBI:6149 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C2939147 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0021053 infores:hetionet CHEBI:50742 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0004093 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0235431 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0151559 infores:hetionet UNII:R43D2573WO biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013456 infores:hetionet CHEBI:6129 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0497156 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0003123 infores:hetionet CHEBI:63631 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0024902 infores:hetionet CHEBI:3441 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042963 infores:hetionet CAID:CA410207109 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207109 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.637C>G (p.Gln213Glu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207109/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68478 biolink:causes HP:0030171 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0473124 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0019158 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0027651 infores:hetionet CAID:CA533254006 biolink:causes MONDO:0015152 infores:clingen CAID:CA533254006 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting PP4 The NM_003494.4: c.863dup p.(Asp288GlufsTer40) variant in DYSF, which is also known as NM_001130987.2: c.959dup p.(Asp320GlufsTer40), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two individuals with dysferlinopathy (PMID: 36983702, 33715265, 14673575; LOVD DYSF_000186), including in unknown phase with a pathogenic variant (NM_003494.4: c.3031+2T>C, 0.5 pts, PMID: 36983702; PM3_Supporting). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.000008232 (the upper threshold of the 95% CI of 4/1111996 European (non-Finnish) chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3_Supporting, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA533254006/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020672 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0020649 infores:hetionet CHEBI:7915 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0231530 infores:hetionet CHEBI:9907 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0014591 infores:hetionet CHEBI:4511 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0023380 infores:hetionet CAID:CA377781931 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781931 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PS3_Moderate, PM2_Supporting, PS2 NM_000314.8(PTEN):c.44G>C (p.Arg15Thr) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. [internal laboratory contributor(s)]PS3_M: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.2.PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: in silico REVEL score of 0.87 (>0.7) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781931/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40279 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2973529 infores:hetionet CHEBI:9086 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018843 infores:hetionet CHEBI:134991 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0015967 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0031350 infores:hetionet CHEBI:39867 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085641 infores:hetionet CHEBI:28001 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0002792 infores:hetionet CHEBI:63613 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0013604 infores:hetionet CHEBI:7915 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040460 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0019158 infores:hetionet NCBIGene:60468 biolink:causes MONDO:0032723 infores:monarchinitiative not_provided not_provided HGNC:14078 MONDO:0032723 uuid:63457747-2382-4eef-a6fe-3caad57d588d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386965729 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965729 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PP1_Strong, PP3 The c.715G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 239 (p.(Ala239Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.902, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). Furthermore, this variant segregated with diabetes with at least 4 informative meioses in four families (PP1_Strong; internal lab contributors). In summary, c.707G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PS4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965729/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3207 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042769 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004096 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0151726 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151726 infores:hetionet CHEBI:8888 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151907 infores:hetionet NCBIGene:56259 biolink:causes MONDO:0030798 infores:monarchinitiative not_provided not_provided HGNC:15879 MONDO:0030798 uuid:4d9426d5-432f-4bac-886f-8e94bea06230 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020456 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0031350 infores:hetionet CHEBI:2666 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0151480 infores:hetionet CAID:CA2802173 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802173 MONDO:0001586 PMID: Likely Pathogenic PP3_Moderate, PM1, PM3, PM5_Supporting, PP4_Moderate, PM2_Supporting The NM_000203.5:c.1046A>G (p.Asp349Gly) variant in IDUA results in missense substitution of aspartate to glycine at amino acid 349. This variant alters amino acid Asp349, a residue that has been shown to be important in substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 23959878, 24036510) (PM1). Two Vietnamese probands are compound heterozygous for the variant and another variant in IDUA that has been classified as likely pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP, c.1190-10C>A; for one of those patients, the variants were confirmed to be in trans by parental testing (PMID: 34833038) (1.25 points) (PMID: 34833038). These individuals had deficient IDUA activity, elevated urine heparan and dermatan sulfates, and multiple systems involved with clinical features consistent with MPS I (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00013 (10/7,542 alleles) in the African / African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.899 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PMID: 36413997) (PP3_Moderate). Several other amino acid substitutions at the same position have been reported, including c.1045G>A (p.Asp349Asn) (ClinVar Variation ID: 92623), c.1045G>T (p.Asp349Tyr) (ClinVar Variation ID: 638075), and c.1045G>C(p.Asp349His) (ClinVar Variation ID: 2585078). One variant, c.1045G>A (p.Asp349Asn), has been classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 950889). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM1, PM3, PP4_Moderate, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802173/MONDO:0001586/091 2024-12-06 2025-06-08 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0065374 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0029882 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0023067 infores:hetionet CAID:CA8337761 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337761 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4_Moderate PM3, PM5 The c.577G>C variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 193 (p.Gly193Arg). This variant has been described in several reportedly affected individuals, and at least one individual displayed VLCAD enzyme levels <20% of controls which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 25834949, 25737446). The variant has been described not confirmed in trans to distinct uncertain variants and has also been described in the homozygous state in an individual who did not meet PP4 criteria and was therefore unable to be counted toward PM3 data (PMIDs: 25834949, 25737446, 17999356, 16950999, 25737446, 24305961,16435213, 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337761/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:4952 biolink:causes MONDO:0010645 infores:monarchinitiative not_provided not_provided HGNC:8108 MONDO:0010645 uuid:dad27ba8-a41e-4486-8510-7f97e74a7507 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50730 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0027765 infores:hetionet CHEBI:50692 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0027441 infores:hetionet CHEBI:2379 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0041657 infores:hetionet NCBIGene:200162 biolink:causes MONDO:0030307 infores:monarchinitiative not_provided not_provided HGNC:26620 MONDO:0030307 uuid:1d718d25-efae-40bd-90cb-1697ee3bdf44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0424295 infores:hetionet CHEBI:85078 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0027441 infores:hetionet CHEBI:63635 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0022346 infores:hetionet CHEBI:3647 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0022354 infores:hetionet CHEBI:8107 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0012569 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0023533 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006826 infores:hetionet CHEBI:28593 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042963 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0042963 infores:hetionet CHEBI:4909 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0020458 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0031542 infores:hetionet CHEBI:28748 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018965 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0232492 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0038362 infores:hetionet CHEBI:50173 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017565 infores:hetionet NCBIGene:3980 biolink:causes MONDO:0030696 infores:monarchinitiative not_provided not_provided HGNC:6600 MONDO:0030696 uuid:4b60ed1f-1a82-4cbe-92e3-ee6a96d70d08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16664 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0151740 infores:hetionet CHEBI:15367 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035317 infores:hetionet CHEBI:188986 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013404 infores:hetionet CHEBI:116278 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0016204 infores:hetionet CHEBI:5855 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0234632 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0042373 infores:hetionet CHEBI:4681 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0917801 infores:hetionet CHEBI:2950 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0011991 infores:hetionet CHEBI:84500 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0015672 infores:hetionet CHEBI:9288 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0003460 infores:hetionet CHEBI:38940 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0034886 infores:hetionet CHEBI:64310 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151603 infores:hetionet CHEBI:16755 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151517 infores:hetionet GO:0051988 biolink:causes GO:0051310 infores:ubergraph knowledge_assertion manual_agent GO:0051988 GO:0051310 CHEBI:8107 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0036974 infores:hetionet CHEBI:4636 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0027424 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0041912 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0013395 infores:hetionet CHEBI:4910 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0424296 infores:hetionet CHEBI:39867 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151786 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011616 infores:hetionet CHEBI:8207 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0003537 infores:hetionet CHEBI:2567 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C2697368 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0178298 infores:hetionet CHEBI:101278 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0015967 infores:hetionet CHEBI:5280 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1260880 infores:hetionet CHEBI:27834 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0019348 infores:hetionet CAID:CA374974153 biolink:causes MONDO:0008535 infores:clingen CAID:CA374974153 MONDO:0008535 PMID: Likely Pathogenic PP3, PM5, PM1, PM2_Supporting, PS4_Moderate The NM_001114753.3: c.1645T>G variant in ENG is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 549 (p.Cys549Gly). This variant has been reported in 3 probands with a phenotype consistent with Hereditary Hemorrhagic Telangiectasia (PS4_Moderate, Internal lab contributors, Invitae, Victorian Clinical Genetics Service). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.644, evidence that correlates with impact to ENG function (PP3). Another missense variant c.1646G>A, p.Cys549Tyr (PMIDs: 38828001, 20414677, 21158752; ClinVar Variation ID: 407135) in the same codon has been classified as pathogenic for Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). This variant resides within a region, amino acid C549, of ENG that is defined as a mutational hotspot or critical functional domain by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PMIDs: 28564608, 25312062) (PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4_Moderate, PM2_Supporting, PP3, PM5, PM1 (specifications version 1.1.0; 09/11/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374974153/MONDO:0008535/136 2024-09-11 2024-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:114785 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0000737 infores:hetionet GO:0032826 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0032826 GO:0006955 CHEBI:7903 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0034063 infores:hetionet CHEBI:71940 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0002965 infores:hetionet CHEBI:40009 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0233407 infores:hetionet GO:1902872 biolink:causes GO:0060041 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0060041 CHEBI:3756 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0439857 infores:hetionet CHEBI:31397 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C1384353 infores:hetionet CAID:CA085712 biolink:causes MONDO:0007750 infores:clingen CAID:CA085712 MONDO:0007750 PMID: Likely Benign BP4, BP7, PM2, PP4 The NM_000527.5 (LDLR):c.48C>A (p.Leu16=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00006 in Latino population in gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from PMID 7635461 (Ekstrom et al., 1995), Sweden. BP4: Variant is synonymous and splicing evaluation is required. Functional data on splicing is not available. MES: A) Not on limits. B) Not on limits. Variant is not predicted to alter splicing. SpliceAI did not predict alternative splicing (Δ score=0).BP7 met: Variant is synonymous and meets BP4.This variant has 2 supporting evidence codes (BP4, BP7) towards Benign, enough to classify as Likely Benign, and only PM2 and PP4 evidence codes towards Pathogenic, not enough for Likely Pathogenic, so we are confident in classifying this variant as Likely Benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA085712/MONDO:0007750/013 2023-11-07 2024-10-03 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9288 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C1443060 infores:hetionet CHEBI:32315 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0687713 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0152128 infores:hetionet GO:0020013 biolink:causes GO:0034117 infores:ubergraph knowledge_assertion manual_agent GO:0020013 GO:0034117 CHEBI:59560 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0162429 infores:hetionet CHEBI:64355 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0026858 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0019196 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0029456 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0855242 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0162429 infores:hetionet CHEBI:8356 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2939147 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0019054 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0424000 infores:hetionet GO:0090095 biolink:causes GO:0009887 infores:ubergraph knowledge_assertion manual_agent GO:0090095 GO:0009887 CHEBI:63631 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0392699 infores:hetionet CHEBI:3176 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C2938875 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0267596 infores:hetionet CHEBI:17650 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0232461 infores:hetionet CHEBI:31236 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019825 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0221773 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0349506 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0877322 infores:hetionet CHEBI:6754 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0036974 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011991 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0458109 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0458109 infores:hetionet CHEBI:65173 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0020452 infores:hetionet CAID:CA120581 biolink:causes MONDO:0044970 infores:clingen CAID:CA120581 MONDO:0044970 PMID:21194154PMID:33128823PMID:19720722 Likely Pathogenic PP3, PS4, PS3_Supporting PP1, BP4, PS2, PM2, PM6 The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly associated with reversible infantile respiratory chain deficiency (RIRCD), and has an estimated penetrance of 30% in reported families. The variant has been reported in the homoplasmic state in both affected and unaffected family members. There is one report of a heteroplasmic occurrence (90%) in a healthy mother. Age of onset in affected individuals generally ranged from birth to six weeks old, however there have been reports of weak fetal movements and one report with onset at four years old. Features include severe myopathy, feeding difficulty, and hypotonia that gradually improve over time, however mild myopathic features persist in many reported cases. Muscle biopsy findings in affected individuals include ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities in early biopsies that normalize on subsequent biopsies (PS4; PMIDs: 8155739, 19720722, 21194154, 21931168, 31333056, 33832841, 34732400, 34806237). There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases which is to be expected given the known reduced penetrance of this variant (Mitomap: 56,910 sequences, AF=0.018%; Helix: 195,983 sequences, AF=0.006%; gnomAD v3.1.2: 56,429 sequences, AF=0.004% - homoplasmic in two individuals and heteroplasmic in three individuals). The computational predictor MitoTIP suggests this variant is pathogenic (29.4 percentile but confirmed pathogenicity) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120581/MONDO:0044970/015 2023-01-23 2023-03-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6149 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1443060 infores:hetionet CHEBI:85161 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0016204 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0018834 infores:hetionet CHEBI:4511 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C1291078 infores:hetionet CHEBI:6076 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0917801 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034069 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0023418 infores:hetionet CHEBI:17303 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0242184 infores:hetionet CHEBI:9586 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0037036 infores:hetionet CHEBI:31644 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0037036 infores:hetionet CAID:CA902151 biolink:causes MONDO:0100368 infores:clingen CAID:CA902151 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS1_Moderate, PP1_Moderate, PP4, PM2_Supporting PM5 NM_000329.3(RPE65):c.1451G>T (p.Gly484Val) is a putative missense variant located in the first nucleotide of exon 14 that is predicted to cause the replacement of glycine with valine at codon 484. The computational predictor REVEL gives a score of 0.991, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.56, which is above the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3_Moderate). Another missense variant at the same nucleotide, NM_000329.3(RPE65):c.1451G>A (p.Gly484Asp), has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP and has a SpliceAI score of 0.23 for acceptor loss, indicating that both variants are predicted to have a damaging impact on splicing (PMID: 30025081, PMID: 34492281, PS1_Moderate). This variant is present in gnomAD v2.1.1 at a GrpMax allele frequency of 0.000002990, with 2 alleles / 111,040 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who are homozygous for the variant (1 pt, PMID: 33308271, PMID: 32531858, PMID: 33472769). The variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variant confirmed in trans (1 pt, PMID: 38002999), which was previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (2 total pts, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PMID: 33308271, PP1_Moderate). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), symptomatic onset at age 3 months (1 pt), extinguished ERG responses from rods (0.5 pts) and cones, optic nerve pallor (0.5 pts), macular atrophy (0.5 pts), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (total 7 pts, PMID: 33308271, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS1_moderate, PM2_supporting, PM3_strong, PP1_moderate, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902151/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41977 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1306341 infores:hetionet CHEBI:135005 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0003467 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0001339 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0156312 infores:hetionet CAID:CA000663 biolink:causes MONDO:0017623 infores:clingen CAID:CA000663 MONDO:0017623 PMID: Benign BA1 PTEN c.-9C>G (NC_000010.10:g.89624218C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.048 (4.8%, 903/18,870 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000663/MONDO:0017623/003 2016-11-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:201163 biolink:causes MONDO:0800445 infores:monarchinitiative not_provided not_provided HGNC:27310 MONDO:0800445 uuid:b8e1b7cf-87bb-40c5-a26f-785578cb7283 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes UMLS:C0679048 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0679048 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151479 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020517 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0009450 infores:hetionet CHEBI:49040 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0002170 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0032285 infores:hetionet CHEBI:63629 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0002962 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0149931 infores:hetionet CAID:CA404082758 biolink:causes MONDO:0007750 infores:clingen CAID:CA404082758 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3 PS4, PS3, PP4 The NM_000527.5 (LDLR):c.1028G>T (p.Gly343Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.983, it is above 0.75.PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met.PP4, PS4 not met: Variant meets PM2, and is reported in 1 index case, but the FH diagnosis and clinical information for the patient is not clear, reported by Miyake et al, 2009, National Cardiovascular Center Research Institute, Osaka, Japan, PMID18718593.PS3 not met: Functional data is not available. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404082758/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:53691 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0476273 infores:hetionet CAID:CA020046 biolink:causes MONDO:0008667 infores:clingen CAID:CA020046 MONDO:0008667 PMID: Benign BA1 The variant NM_000551.4(VHL):c.119C>T (p.Pro40Leu) is a missense variant predicted to cause substitution of Proline by Leucine. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0006831 (71/ 84504 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020046/MONDO:0008667/078 2024-06-25 2024-07-17 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9139 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0947912 infores:hetionet CHEBI:45327 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C2830004 infores:hetionet NCBIGene:24 biolink:causes MONDO:0011137 infores:monarchinitiative not_provided not_provided HGNC:34 MONDO:0011137 uuid:9fc344f0-6658-41d9-b2de-05b71046ea12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4657 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0011603 infores:hetionet NCBITaxon:5763 biolink:causes MONDO:0000290 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5763 MONDO:0000290 CHEBI:15551 biolink:causes UMLS:C0269806 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0269806 infores:hetionet CHEBI:55346 biolink:causes MONDO:0042233 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0153252 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042109 infores:hetionet CHEBI:4814 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020621 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0549343 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549343 infores:hetionet CHEBI:15365 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0009676 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0020517 infores:hetionet CHEBI:5296 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0033774 infores:hetionet CHEBI:83527 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0030252 infores:hetionet CHEBI:9586 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0518988 infores:hetionet CHEBI:9613 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0042109 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0021843 infores:hetionet CHEBI:125354 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0015230 infores:hetionet CHEBI:63620 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011206 infores:hetionet CAID:CA915940889 biolink:causes MONDO:0010602 infores:clingen CAID:CA915940889 MONDO:0010602 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PS4_Supporting BP7, PP3, BP4 The intronic variant, NM_000132.3:c.144-26A>C, is not reported in gnomAD v2.1 or v3.1.2 meeting PM2_Supporting criteria. SpliceAI predicts an acceptor loss of 0.07, which is above the BP4 threshold of 0.05 and below the PP3 threshold of 0.5, so neither code was applied. The nucleotide at this position is also conserved. This variant has been reported in one patient in the literature with severe hemophilia A (PMID: 37285902) and in one male from internal laboratory data with mild hemophilia A with a family history consistent with X-linked inheritance. These probands meet F8 phenotype criteria specified by the CFD VCEP: PS4_Mod. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940889/MONDO:0010602/071 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:39867 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0686347 infores:hetionet CHEBI:5128 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0233407 infores:hetionet NCBIGene:1857 biolink:causes MONDO:0014819 infores:monarchinitiative not_provided not_provided HGNC:3087 MONDO:0014819 uuid:11997119-9f55-46ca-904c-be405bfdf195 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50859 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0002884 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0235818 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020621 infores:hetionet CHEBI:31184 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0162835 infores:hetionet CAID:CA220197 biolink:causes MONDO:0008723 infores:clingen CAID:CA220197 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PM1, PP4_Moderate, PM5_Supporting The c.1406G>A variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 469 (p.Arg469Trp). This variant has been detected in 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency; of the 3 homozygous individuals, 2 were monozygotic twins; in one heterozygous individual, a second distinct pathogenic variant in ACADVL was not observed. (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). At least one patient with this variant displayed ACADVL enzyme activity of <20% of normal which is highly specific for VLCADD (PP4_Moderate, PMID: 25834949). Another missense variant c.1405C>T (p.Arg469Trp) [VCV000021017.19, PMIDs: 9973285, 17374501, 17999356] in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285) (PM1). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM5, PM1, PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-16-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220197/MONDO:0008723/021 2022-10-12 2022-10-12 Autosomal recessive inheritance HP:0000007 Supports NCBITaxon:32008 biolink:causes MONDO:0043953 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:32008 MONDO:0043953 CHEBI:68478 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020598 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002418 infores:hetionet CHEBI:52172 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0017181 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0332534 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0025061 infores:hetionet CHEBI:6950 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0021177 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0162429 infores:hetionet CHEBI:28748 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006625 infores:hetionet CAID:CA397397066 biolink:causes MONDO:0100438 infores:clingen CAID:CA397397066 MONDO:0100438 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PP3_Moderate, PS3_Supporting NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg) is a missense variant predicted to replace cysteine with arginine at amino acid p.89. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000018, with 3 alleles / 1605620 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in 2 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 total point, PMID: 27208204, PMID: 30366342). This variant has also been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.618_619dup (p.Cys207SerfsTer3) variant confirmed in trans (1 point, PMIDs: 39986747), which was previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by a next-generation sequencing panel of 163 known inherited retinal disease-associated genes (2 pts), severe visual disturbances in infancy or early childhood (1 pt), visual acuity limited to light perception (1 pt), moderate hypermetropia, kinetic visual field extent not detectable (1 pt), keratoconus (0.5 pts), nystagmus (1 pt), posterior subcapsular cataract (0.5 pts), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are highly specific for AIPL1-related retinopathy (total 9 points, PMID: 20702822, PMID: 23847139, PP4_Moderate). Co-expression of the variant with PDE6C and Pγ resulted in less than 10% of cGMP hydrolysis activity relative to the wild-type AIPL1 control (PMID: 27268253, PS3_Supporting). Yeast 2-hybrid and ELISA experiments identified abolished or dramatically decreased interaction of the variant protein with HSP90alpha and HSP90beta (PMID: 28973376). The computational predictor REVEL gives a score of 0.841, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP4_Moderate, PS3_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397397066/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5855 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085641 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006840 infores:hetionet NCBIGene:7038 biolink:causes MONDO:0010135 infores:monarchinitiative not_provided not_provided HGNC:11764 MONDO:0010135 uuid:b9ba7da5-7eb7-403e-849f-2734a8431fb9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0026205 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0162429 infores:hetionet CAID:CA386959458 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959458 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM1, PP1_Strong, PP4_Moderate, PP3 PS4 The c.394G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 132 (p.(Glu132Lys)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 17407387, 11272211, internal lab contributors). This variant was segregated with diabetes/hyperglycemia, with 6 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.394G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_supporting, PM1, PP3, PP1_strong, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959458/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3011 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0013404 infores:hetionet CHEBI:15407 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0234369 infores:hetionet CHEBI:3654 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0041349 infores:hetionet GO:0110137 biolink:causes GO:0048707 infores:ubergraph knowledge_assertion manual_agent GO:0110137 GO:0048707 CHEBI:47780 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030920 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0518015 infores:hetionet CAID:CA410203507 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203507 MONDO:0011071 PMID:25840971 Likely Pathogenic PM1_Supporting, PS1_Moderate, PM2_Supporting, PS3_Moderate, PP3 PS4, PS2, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS4, BS1, BS3, PM6, PVS1, PM3, PM5, PM4, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.316T>C (p.Trp106Arg) is found within the runt homology domain (RHD) in a residue which is not an established hotspot (PM1_supporting). The c.316T>C variant is the same amino acid change (p.Trp106Arg) as a previously established likely pathogenic variant (ClinVar ID 436617) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). This missense variant has a REVEL score ≥ 0.88 (0.976) (PP3) and transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q)(PS3_moderate, PMID: 25840971). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS1_moderate, PS3_moderate, PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203507/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63580 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0917801 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0424740 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0424740 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0009763 infores:hetionet CHEBI:7443 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0011991 infores:hetionet CHEBI:147675 biolink:causes UMLS:C0221384 infores:sider not_provided not_provided DRUGBANK:DB00249 UMLS:C0221384 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0005940 infores:hetionet CHEBI:3207 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0010200 infores:hetionet CHEBI:3561 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0030232 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0016977 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0018799 infores:hetionet CHEBI:4911 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0011168 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0858589 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0858589 infores:hetionet CHEBI:9667 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C2586050 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1306341 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1443060 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009782 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004239 infores:hetionet CHEBI:6367 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013428 infores:hetionet CHEBI:63631 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030805 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030305 infores:hetionet CHEBI:23765 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0242301 infores:hetionet NCBIGene:9790 biolink:causes MONDO:0007145 infores:monarchinitiative not_provided not_provided HGNC:23505 MONDO:0007145 uuid:391d0df9-5908-424d-81e7-29876bc23fc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0000737 infores:hetionet CHEBI:36704 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0037299 infores:hetionet CAID:CA255418 biolink:causes MONDO:0010604 infores:clingen CAID:CA255418 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4_Very Strong, PP3 PM5, PP4 The c.1324G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 442 (p.Gly442Arg). This variant has been reported in at least 8 probands with severe or moderate hemophilia B (PS4_Very Strong; PMID: 24656159, 27109384, 22544209, 29296726, 8055323, 10739381, 2714791). This variant is absent from gnomAD v2.1, v3.1.2. The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255418/MONDO:0010604/080 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Supports NCBIGene:7074 biolink:causes MONDO:0859256 infores:monarchinitiative not_provided not_provided HGNC:11805 MONDO:0859256 uuid:9c740e9d-91b5-42c0-a574-2af87a6d0751 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0019829 infores:hetionet CHEBI:50223 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0018681 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0235639 infores:hetionet UMLS:C0209366 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0853813 infores:hetionet CHEBI:5165 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0036454 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002418 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0009676 infores:hetionet CHEBI:231425 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C2979982 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151951 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151951 infores:hetionet CHEBI:261649 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0014591 infores:hetionet CHEBI:50924 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0014591 infores:hetionet CHEBI:9137 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0233471 infores:hetionet CAID:CA2497030194 biolink:causes MONDO:0100368 infores:clingen CAID:CA2497030194 MONDO:0100368 PMID: Pathogenic PP1_Strong, PVS1, PM2_Supporting PM3, PP4 NM_000329.3(RPE65):c.1205_1206insCCTG (p.Trp402CysfsTer6) is a frameshift variant that introduces a premature stop codon into exon 6 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 3 similarly affected relatives, with the variant present in the compound heterozygous state with the p.Leu341Ser variant in trans (PP1_strong; PMID: 9501220). At least 1 proband with early-onset severe retinal dystrophy harbored the variant in the compound heterozygous state with the p.Leu341Ser variant confirmed in trans (PMID: 9501220), however, the PM3 code was not considered to avoid circularity. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PP1_Strong. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497030194/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:82981 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0014518 infores:hetionet CHEBI:17334 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0344232 infores:hetionet NCBIGene:26173 biolink:causes MONDO:0032817 infores:monarchinitiative not_provided not_provided HGNC:24555 MONDO:0032817 uuid:845bec37-eb46-49bd-bc0c-c164343bd2f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0948525 infores:hetionet CHEBI:5855 biolink:causes HP:0012213 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0853068 infores:hetionet CAID:CA320249723 biolink:causes MONDO:0011071 infores:clingen CAID:CA320249723 MONDO:0011071 PMID: Likely Benign BS1 PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP2, BP3, PM2, PM6, PVS1, BS3, BS4, BP5, BP7, PM3, PM4, PM1, PM5, BS2, PP1, PP2, PP3, PP4 NM_001754.5(RUNX1):c.*2201T>G is a 3’UTR variant. This variant has a MAF of 0.0008115 (0.08115%, 12/14788 alleles) in the European (non-Finnish) subpopulation of the gnomAD v2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320249723/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3732 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0001339 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0852810 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0037274 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0012833 infores:hetionet CAID:CA2580612112 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612112 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.497dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein leading to premature termination at codon 166 (p.Tyr166Ter) of NM_000545.8. This variant, located in biologically relevant exon 2 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary c.497dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PVS1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612112/MONDO:0015967/017 2025-01-24 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31205 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0018681 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0035078 infores:hetionet CHEBI:27777 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0003467 infores:hetionet CHEBI:404903 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027540 infores:hetionet CHEBI:31401 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0017152 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151736 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0860967 infores:hetionet CHEBI:63635 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0700225 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0021053 infores:hetionet CHEBI:8764 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151827 infores:hetionet CAID:CA515477887 biolink:causes MONDO:0010725 infores:clingen CAID:CA515477887 MONDO:0010725 PMID: Likely Benign BP7, BP4 BS1, PM2 NM_000330.4(RS1):c.177T>C (p.Cys59=) is a synonymous variant at amino acid 59, within exon 3, and does not have predicted splicing impact (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v4.1.0 at a frequency of 0.000007745 among hemizygous individuals, with 3 variant alleles / 387,371 total alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.000002 and BS1 threshold of >0.00002 and fails to meet these criteria. In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BP4 and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA515477887/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Contradicts true CHEBI:6715 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151942 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0019158 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0026848 infores:hetionet CHEBI:75722 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011175 infores:hetionet CHEBI:5441 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0231528 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0152027 infores:hetionet CHEBI:36791 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234535 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0151849 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0018799 infores:hetionet CHEBI:3181 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011206 infores:hetionet CHEBI:182080 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0022107 infores:hetionet CHEBI:6888 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151905 infores:hetionet CAID:CA229885 biolink:causes MONDO:0009861 infores:clingen CAID:CA229885 MONDO:0009861 PMID:18985011PMID:18985011 Pathogenic PM2, PP4_Moderate, PVS1, PM3_Very Strong The c.975C>G (p.Tyr325Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least 13 PKU probands, at least 5 of whom BH4 deficiency was formally excluded (PP4_Moderate), including in trans with pathogenic or likely pathogenic variants in 9 cases, in trans with VUS in two cases, and homozygous in two cases (PM3_VeryStrong). It was first identified in a Korean patient with classic PKU (as confirmed by blood Phe levels) in trans with the N207D variant (pathogenic per PAH VCEP) (PMID: 9452061; PMID: 15503242); BH4 deficiency was excluded by urinary pterin analysis and DPHR assay. It was also found in another four patients with PKU, BH4 deficiency was excluded by urinary pterin analysis and DPHR assay (PMID: 15503242): one in trans with the known pathogenic (per PAH VCEP and in Clinvar) p.R413P variant (patient’s PKU phenotype not specified); one with classic PKU in trans with the known pathogenic (per PAH VCEP) p.V388M variant; one with mild hyperphenylalanemia in trans with the ClinVar pathogenic p.Y204C variant; and one in trans with the known pathogenic (per PAH VCEP) p. R243Q variant (PKU phenotype not specified). It has also been found in a Hispanic patient with classic PKU and BH4 deficiency excluded in trans with the pathogenic (per PAH VCEP) p.R261X variant (PMID: 23430918). It has also been found in 9 Chinese PKU cases (PMID: 26503515; PMID: 30050108), BH4 deficiency does not appear to have been ruled out: 2 homozygotes (classic PKU); one classic PKU case in trans with p.EX6-96A>G variant (pathogenic per PAH VCEP); one classic PKU case in trans with c.843-14_-11delCTTT (no PAH VCEP classification); one mild PKU case in trans with p.A434D (pathogenic per PAH VCEP); one mild hyperphenylalanemia case in trans with p.R241C (ClinVar pathogenic, PAH VCEP pathogenic); one classic PKU case in trans with p.Y206C (Likely pathogenic per PAH VCEP); and one mild hyperphenylalanemia case in trans with p.T418P (VUS per PAH VCEP). It is also listed Pathogenic in ClinVar by two labs (variant ID 102921). Classification: PathogenicSupporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229885/MONDO:0009861/006 2020-04-13 2020-04-13 Autosomal recessive inheritance HP:0000007 Supports CAID:CA266215 biolink:causes MONDO:0100437 infores:clingen CAID:CA266215 MONDO:0100437 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PS4, PP1_Strong PM6, PP2, PP3, PM4, PM1, PM3, PS3, PS2, BA1, BP1, BP4, BP2, BP7, BP5, BS1, BS3 NM_001034853.2(RPGR):c.2405_2406del (p.Glu802GlyfsTer?) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years and/or decreased or absent cone and/or rod electroretinogram responses (PMID: 34745198, 29453956, PS4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from at least 2 families (PP1_strong, PMID: 34745198, 21857984). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4, PM2_supporting, and PP1_strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA266215/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Supports CHEBI:50648 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0035078 infores:hetionet CHEBI:144093 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018790 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151888 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041969 infores:hetionet CHEBI:135888 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0030193 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0009806 infores:hetionet CHEBI:63627 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0231218 infores:hetionet CHEBI:3312 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C1443060 infores:hetionet CHEBI:3515 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0008031 infores:hetionet CHEBI:66901 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0024894 infores:hetionet CHEBI:63622 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0549622 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0013395 infores:hetionet NCBITaxon:803 biolink:causes MONDO:0005991 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:803 MONDO:0005991 CHEBI:61049 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0948586 infores:hetionet CHEBI:50777 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0025323 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0012833 infores:hetionet NCBIGene:4625 biolink:causes MONDO:0008409 infores:monarchinitiative not_provided not_provided HGNC:7577 MONDO:0008409 uuid:8859cfef-d8ed-4a65-bdd0-16dc0b649d9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:VL0L558GCB biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0518015 infores:hetionet CHEBI:28148 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0015230 infores:hetionet CAID:CA16020824 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020824 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PVS1 PM3 The c.594T>G (p.Tyr198Ter) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in a patient with PAH deficiency with second allele not reported (PMID: 21307867). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP4_moderate, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020824/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46195 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0220870 infores:hetionet NCBIGene:2767 biolink:causes MONDO:0014146 infores:monarchinitiative not_provided not_provided HGNC:4379 MONDO:0014146 uuid:6bb0faa0-2f28-4a39-badb-db6549b83d3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50729 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C2047937 infores:hetionet GO:0050935 biolink:causes CL:0000431 infores:ubergraph knowledge_assertion manual_agent GO:0050935 CL:0000431 UNII:Y2V2R4W9TQ biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0011603 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0042571 infores:hetionet CHEBI:87715 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0006826 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0042373 infores:hetionet CHEBI:68478 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0206062 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0037274 infores:hetionet CHEBI:110423 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0020437 infores:hetionet CAID:CA397848094 biolink:causes MONDO:0018875 infores:clingen CAID:CA397848094 MONDO:0018875 PMID: Pathogenic PP4_Moderate, PVS1, PS4_Supporting, PM2_Supporting BP4, BA1, PS2, PS3, PS1, PM5, PM1, BS1, BS3, BS4, PP3, PP1, BS2 The NM_000546.6 c.97-1G>A is a TP53 variant within the canonical acceptor site of exon 4. (PVS1 (RNA); PMIDs :9792154, 11420676). This variant has been reported in 1 proband meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID 9242456, Internal lab contributors: SCV001181068.4). At least one individual with this variant was found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, Internal lab contributors: SCV001181068.4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).. In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4_moderate, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397848094/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31932 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0220870 infores:hetionet CHEBI:135005 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0085593 infores:hetionet CHEBI:31980 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0151744 infores:hetionet CHEBI:48669 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0231218 infores:hetionet CHEBI:3508 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0085631 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0040046 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0029124 infores:hetionet CHEBI:32315 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0278106 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0152020 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0314719 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0024137 infores:hetionet CHEBI:127342 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0080274 infores:hetionet CHEBI:50156 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0546817 infores:hetionet CHEBI:45863 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2607914 infores:hetionet CHEBI:79699 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0013404 infores:hetionet CHEBI:135791 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0020555 infores:hetionet CHEBI:42797 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0024902 infores:hetionet CHEBI:2676 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0042963 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0700345 infores:hetionet CHEBI:4798 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0231218 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0015230 infores:hetionet CHEBI:168396 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0001925 infores:hetionet CHEBI:66964 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0085593 infores:hetionet CHEBI:7465 biolink:causes MONDO:0003067 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0149642 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0027051 infores:hetionet CHEBI:47780 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151798 infores:hetionet CAID:CA8815250 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815250 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.1286A>G (p.Gln429Arg) in gnomAD v2.1.1 is 0.01028 in the East Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 284497; 2 star review status) with three submitters classifying the variant as benign and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815250/MONDO:0009290/010 2020-01-22 2020-05-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:100241 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0010692 infores:hetionet CHEBI:2682 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0014518 infores:hetionet CHEBI:31625 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0022281 infores:hetionet CHEBI:9907 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0542571 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0859577 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0859577 uuid:be239078-4d3c-4cb6-b233-69a2f4057630 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0746883 infores:hetionet CHEBI:6539 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0037317 infores:hetionet CHEBI:63619 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0600142 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235146 infores:hetionet CHEBI:253342 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0026821 infores:hetionet CHEBI:4995 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018524 infores:hetionet CHEBI:63621 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018932 infores:hetionet CHEBI:175901 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1262141 infores:hetionet CHEBI:50648 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0344232 infores:hetionet CHEBI:10110 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0043144 infores:hetionet CHEBI:5801 biolink:causes HP:0012155 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0859996 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0687133 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0002871 infores:hetionet CHEBI:42797 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0332563 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0012833 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0033860 infores:hetionet CHEBI:135736 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0236075 infores:hetionet CHEBI:3127 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0010200 infores:hetionet CHEBI:4911 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0038999 infores:hetionet CHEBI:465284 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042384 infores:hetionet CHEBI:49575 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233514 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151609 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0020651 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0851341 infores:hetionet CHEBI:3127 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0016658 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0031117 infores:hetionet CHEBI:8107 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085641 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009319 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013395 infores:hetionet CHEBI:15544 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2939147 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0919625 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0919625 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0025061 infores:hetionet CAID:CA377781789 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781789 MONDO:0017623 PMID:29706350 Uncertain Significance PP2, PM2_Supporting, BS3_Supporting, BP4, PS2 PP3, PM5, PM1, PS1 NM_000314.8(PTEN):c.10A>G (p.Ile4Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history (SCV002569820.2).PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_Supporting: Well-established functional studies show no deleterious effect: Phosphatase activity ≤ -1.11 (score = 1.00) per Mighell et al. 2018 (PMID: 29706350).BP4: REVEL score < 0.5 (score=0.294)Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 pathogenic strong, 2 pathogenic supporting and 2 benign supporting codes get 4 + (1*2) +(- 1*2) points = total is 4 (VUS). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781789/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8382 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0271738 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009806 infores:hetionet GO:0060651 biolink:causes GO:0060648 infores:ubergraph knowledge_assertion manual_agent GO:0060651 GO:0060648 CHEBI:7488 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0948595 infores:hetionet CHEBI:135342 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0014591 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0022354 infores:hetionet CHEBI:94686 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0015672 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0027769 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0234987 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014868 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0233494 infores:hetionet CHEBI:2788 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C1384353 infores:hetionet CHEBI:52172 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020546 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423232 infores:hetionet CHEBI:63618 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0040586 infores:hetionet CHEBI:77260 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0236075 infores:hetionet CHEBI:3127 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042029 infores:hetionet CAID:CA8366103 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366103 MONDO:0100453 PMID: Likely Pathogenic PM3, PP3_Moderate, PP1_Moderate, PP4_Moderate, PM2_Supporting NM_000180.4(GUCY2D):c.2384G>A (p.Arg795Gln) is a missense variant that replaces arginine with glutamine at position p.795. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000009916, with 16 alleles / 1,613,582 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 total point, PMIDs: 17724218, 31630094, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 26352687). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts) with onset at age 7 months (1 pt), genotyping by targeted exome sequencing without identification of another cause of retinal disease (2 pts), extinguished electroretinogram responses from both rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), photophobia (1 pt), and no visual acuity (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 31630094, PP4_Moderate). The computational predictor REVEL gives a score of 0.83, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC1 protein function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366103/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CAID:CA9871628 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871628 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4:c.569G>A is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at amino acid 190 (p.Gly190Glu).The filtering allele frequency (the upper threshold of the 95% CI of 9/44886) of the c.569G>A variant in ADA is 0.00009929 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as Variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871628/MONDO:0007064/114 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA392331872 biolink:causes MONDO:0007947 infores:clingen CAID:CA392331872 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1_Strong BS2 NM_00138 c.6866G>C is a missense variant in FBN1 predicted to cause a substitution of cysteine by serine at amino acid 2289 (p.Cys2289Ser). This variant is not reported in the literature in any individuals with Marfan syndrome (MFS). This variant has been reported once in ClinVar as Likely pathogenic and once as uncertain significance (Variation ID: 632813). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.0.0). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.992, PP3). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup,PP3, PP2. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392331872/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8874 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1368065 infores:hetionet CAID:CA658655962 biolink:causes MONDO:0015967 infores:clingen CAID:CA658655962 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.1133_1149del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 378 (NM_000162.5), adding 75 novel amino acids before encountering a stop codon (p.(Ala378GlyfsTer75)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.1133_1149del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655962/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:7773 biolink:causes UMLS:C1141863 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C1141863 infores:hetionet CHEBI:31401 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0038325 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030353 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0020456 infores:hetionet CHEBI:5100 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0042963 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233472 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0314719 infores:hetionet CHEBI:50275 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020598 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0021053 infores:hetionet CHEBI:3638 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0014518 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0042109 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0423736 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0423736 infores:hetionet NCBIGene:16 biolink:causes MONDO:0030517 infores:monarchinitiative not_provided not_provided HGNC:20 MONDO:0030517 uuid:e734513e-89db-4f73-a43d-dd84a25807c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004134 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0456909 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0011570 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0857121 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085762 infores:hetionet CHEBI:72297 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0020458 infores:hetionet CHEBI:68478 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020555 infores:hetionet CHEBI:49575 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042029 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0027765 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0151763 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0851341 infores:hetionet CHEBI:63629 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C1321686 infores:hetionet CHEBI:8028 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0242422 infores:hetionet CHEBI:31932 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0409974 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0241166 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0241166 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0542052 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0542052 infores:hetionet CHEBI:6375 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085632 infores:hetionet CAID:CA410208068 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208068 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.551C>T (p.Pro184Leu) is a missense variant which has a REVEL score ≥ 0.88 (0.944) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208068/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31401 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0403632 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0520459 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0152025 infores:hetionet CAID:CA414905992 biolink:causes MONDO:0010602 infores:clingen CAID:CA414905992 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4_Very Strong PM5 The c.6622C>G (p.Gln2208Glu) variant is absent in gnomAD v2.1.1 and 3.1.2 meeting PM2_Supporting. The variant has a REVEL score of 0.799 meeting PP3. There have been more than 10 probands reported with mild hemophilia A, and at least one proband with FVIII:C 24% had VWD type 2N ruled out (PMID: 29296726, 21645180, 16769589 & EAHAD Database), meeting PP4_Moderate and PS4_Very strong. There is another variant at the codon, c.6622C>G, p.Gln2208Arg, and has been classified as pathogenic by CFD VCEP. However, PM5 will not be applied to avoid circularity. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PM2_Supporting, PP3, PP4_Moderate, PS4_Very strong. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414905992/MONDO:0010602/071 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Supports CHEBI:63598 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0522224 infores:hetionet GO:0061035 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:0061035 GO:0001501 CHEBI:17334 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018802 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007971 infores:hetionet CHEBI:472657 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0009319 infores:hetionet CHEBI:8060 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0020458 infores:hetionet CAID:CA16041413 biolink:causes MONDO:0700270 infores:clingen CAID:CA16041413 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PM3 The c.5005+1G>T variant in ATM occurs within the canonical splice donor site (+1,2) of intron 33. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. (PVS1_Strong, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041413/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3568 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020453 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0019158 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027932 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0031350 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0030312 infores:hetionet CHEBI:68558 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0002994 infores:hetionet CHEBI:3403 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0018926 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0030200 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030200 infores:hetionet CAID:CA8459619 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459619 MONDO:0011132 PMID: Likely Benign BS1 PP3, BP4 The missense variant NM_001369369.1(FOXN1):c.1757G>A (p.Cys586Tyr) has a gnomADv3.1.2 popmax filtering allele frequency of 0.003485 based upon the African/African American population (165/41444 alleles), which is above the BS1 threshold of >0.00141 but below the BA1 threshold of >0.00447 and thus meets BS1. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459619/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true UMLS:C0025241 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151942 infores:hetionet CHEBI:28148 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0018681 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042267 infores:hetionet CHEBI:9086 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004134 infores:hetionet CHEBI:16755 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0032227 infores:hetionet CAID:CA151481 biolink:causes MONDO:0017623 infores:clingen CAID:CA151481 MONDO:0017623 PMID: Likely Benign BP5, BS1_Supporting BP7, BS3, BS4, PM2, PM6, BS2, PP1, PP2, PP3, PP4, PM3, PM4, PM1, PM5, BP1, BP4, BP2, BP3, BA1, PS3, PS4, PS1, PS2 PTEN c.-1170C>T (NC_000010.10:g. 89623056C>T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1_P: Allele frequency of 0.0002477 (0.02477%, 16/64,586 alleles) in the European subpopulation of the gnomAD cohort. (PMID 27535533)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000149466.6, SCV000184146.1) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA151481/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7915 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042401 infores:hetionet NCBIGene:1644 biolink:causes MONDO:0012084 infores:monarchinitiative not_provided not_provided HGNC:2719 MONDO:0012084 uuid:175a1a9b-d9bb-4945-88b4-20975e01ba67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA343869 biolink:causes MONDO:0010602 infores:clingen CAID:CA343869 MONDO:0010602 PMID: Benign BP4, BA1 The missense variant, NM_000132.3(F8):c.6769A>G (p.Met2257Val), is reported at an MAF of 0.2418 (4578/18936 with 1245 hemizygotes) in the African population in gnomAD v2.1.1. A REVEL score of 0.292 and SpliceAI score of 0 meets BP4 cut-off (respective thresholds <0.3 and <0.05). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency variant curation expert panel for F8: BA1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA343869/MONDO:0010602/071 2024-02-01 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:5062 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0002994 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0015397 infores:hetionet CHEBI:3077 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0162834 infores:hetionet NCBIGene:134353 biolink:causes MONDO:0030361 infores:monarchinitiative not_provided not_provided HGNC:30860 MONDO:0030361 uuid:b8e5ec2b-bb88-42e1-8678-7b937d7e78ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27666 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0003123 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151734 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030567 infores:hetionet NCBIGene:3939 biolink:causes MONDO:0013047 infores:monarchinitiative not_provided not_provided HGNC:6535 MONDO:0013047 uuid:4fe76b35-fc1a-4f33-91c1-e364235f144c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0232462 infores:hetionet CHEBI:50841 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0012833 infores:hetionet CHEBI:7492 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0677500 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0152029 infores:hetionet CHEBI:9649 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0027066 infores:hetionet CHEBI:6950 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0033774 infores:hetionet CHEBI:135285 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0037274 infores:hetionet CHEBI:4653 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0019080 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003850 infores:hetionet CAID:CA386959990 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959990 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PM1, PP1_Strong, PP3 PM5, PP4 The c.434C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 145 (p.(Ser145Phe)) of NM_000545.8. This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 28701371, internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; PMID: 28701371, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.433T>C (p.(Ser145Pro)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in at least six individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, and PP4 cannot be applied (PMID:28701371, internal lab contributors). In summary, c.434C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PP3, PM1, PM2_Supporting, PS4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959990/MONDO:0015967/017 2022-04-08 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64028 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0004093 infores:hetionet CHEBI:77260 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013428 infores:hetionet CHEBI:68554 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0027497 infores:hetionet NCBIGene:7428 biolink:causes MONDO:0009892 infores:monarchinitiative not_provided not_provided HGNC:12687 MONDO:0009892 uuid:8e6b017c-7c07-407f-9431-f9b3c3aa9182 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50673 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0013604 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0239062 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0239062 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007137 infores:hetionet CHEBI:4530 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0011991 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0039503 infores:hetionet CHEBI:42355 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0033774 infores:hetionet CAID:CA222191 biolink:causes MONDO:0015152 infores:clingen CAID:CA222191 MONDO:0015152 PMID: Benign BA1 PM3, BP2, BP4 The NM_003494.4: c.5626G>A variant in DYSF, which is also known as NM_001130987.2: c.5743G>A p.(Asp1915Asn), is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1876, p.(Asp1876Asn). The filtering allele frequency of the variant is 0.007927 for South Asian chromosomes in gnomAD v4.1.0 (the lower threshold of the 95% CI of 767/91080), which is higher than the VCEP threshold of 0.003 (BA1). The c.5626G>A p.(Asp1876Asn) variant has been detected in a homozygous state in two individuals with LGMD or Miyoshi myopathy (PMID: 21522182, 29970176). One of these individuals was also homozygous for a pathogenic variant (NM_003494.4: c.5181delA p.(Glu1727AspfsTer7)), indicating the two variants were on the same chromosome (PMID: 29970176). Given there are 27 homozygotes in gnomAD v4.1.0, PM3 not met. The SpliceAI score for this variant is 0.02, suggesting it does not impact splicing. The computational predictor REVEL gives a score of 0.38, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/30/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222191/MONDO:0015152/180 2025-10-30 2025-11-11 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:71255 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0013395 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0015397 infores:hetionet CAID:CA294004 biolink:causes MONDO:0700270 infores:clingen CAID:CA294004 MONDO:0700270 PMID: Likely Benign BP7 BA1, BP4, BS1, PM2, PP3 The c.496+4T>C variant in ATM is an intronic variant that is not predicted by SpliceAI to impact splicing. RNA data revealed no observed effect on splicing (Spanish ATM Cancer Susceptibility Variant Interpretation Working Group). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001652 in the Middle Eastern population (PM2_Supporting, BS1, and BA1 are not met). In summary this variant meets the criteria to be classified as likely benign for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP7_Moderate(RNA)) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA294004/MONDO:0700270/020 2025-09-25 2025-10-20 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8382 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0001623 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0040034 infores:hetionet CHEBI:7494 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0404521 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1258215 infores:hetionet CAID:CA114371 biolink:causes MONDO:0009861 infores:clingen CAID:CA114371 MONDO:0009861 PMID:27121329PMID:29288420PMID:9634518PMID:17924342PMID:30037505 Pathogenic PP4_Moderate, PM3_Very Strong, PS3 PM5, PM2, PP3 This c.527G>T (p.Arg176Leu) variant in PAH was reported in multiple patients with hyperphenylalaninemia and detected with 11 pathogenic variants (PMID: 27121329, 9634518, and 29288420). Experimental studies from two publications have demonstrated this variant to have a deleterious effect (PMID: 17924342 and 30037505). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PS3, and PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114371/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32315 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002957 infores:hetionet CAID:CA145184 biolink:causes MONDO:0800472 infores:clingen CAID:CA145184 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PP1_Strong, PVS1 PP3, BA1, BP4, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, BP7 The c.868dup variant in CYP1B1 is a duplication of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 37 of the frameshift, or amino acid 326 (p.Arg290ProfsTer37). The highest minor allele frequency of this variant was in the Middle Eastern genetic ancestry group of gnomAD (v4.1) = 0.0001647 (1 allele out of 6072), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This frameshift variant was predicted to undergo NMD (PVS1 met). There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 25018621), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in seven individuals with a CYP1B1-related phenotype. Three individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) for the variant. Four individuals are homozygous (consanguineous) for the variant (PMIDs: 30820150, 25018621, 33745036, 17893647, 35170016, 21815720, 38990107). Total points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 21 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Very strong, PP1_Strong, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145184/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:70735 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0013362 infores:hetionet CHEBI:5165 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0010520 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0037284 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0151313 infores:hetionet CHEBI:68610 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0009806 infores:hetionet CHEBI:109549 biolink:causes UMLS:C0852792 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0852792 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042373 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0038362 infores:hetionet NCBIGene:84162 biolink:causes MONDO:0060631 infores:monarchinitiative not_provided not_provided HGNC:26953 MONDO:0060631 uuid:bc554a77-c7fd-4a18-9387-046d23625850 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:617099 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0023530 infores:hetionet CHEBI:75045 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0004093 infores:hetionet CHEBI:9435 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0042963 infores:hetionet GO:2000826 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:2000826 GO:0007507 GO:0010725 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0010725 GO:0009790 CHEBI:8768 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003811 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0877365 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0877365 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0178298 infores:hetionet CAID:CA913189266 biolink:causes MONDO:0011071 infores:clingen CAID:CA913189266 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.601dup (p.Arg201ProfsTer12) is a frameshift variant. The transcript product is predicted to undergo NMD (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has been reported in 1 proband with family history meeting RUNX-1 phenotypic criteria (thrombocytopenia) (PMID 26175287) (PS4_supporting). This variant was also reported in Clinvar in 2021 by Invitae but the affected status of the proband is unknown (Variation ID 1073884). There are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) without use of PM5_Supporting (PMID: 35764482) (PM5_supporting).In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_supporting, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189266/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64355 biolink:causes UMLS:C0853974 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0853974 infores:hetionet CHEBI:7954 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0041912 infores:hetionet CHEBI:408174 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0040586 infores:hetionet CHEBI:5383 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0014457 infores:hetionet CHEBI:63635 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0239134 infores:hetionet CHEBI:100241 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0271298 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0041912 infores:hetionet CHEBI:37333 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0235996 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0037274 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151919 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151919 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151479 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020517 infores:hetionet UNII:UMD7G2653W biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C1519353 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0033975 infores:hetionet CHEBI:3441 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C1456784 infores:hetionet CHEBI:145499 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0232849 infores:hetionet CAID:CA414435714 biolink:causes MONDO:0010604 infores:clingen CAID:CA414435714 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3 PM1 The F9 c.155T>C; p.Leu52Ser missense variant is completely absent from gnomADv2.1.1 and v3.1.1 meeting PM2_supporting. This missense variant has a REVEL score of 0.931 (>0.6) meeting PP3. Three probands with moderate (Turkish) and severe (Italian) and unknown severity (Chinese) hemophilia B are reported in the literature (PMID: 12588353, PMID: 15921378, PMID: 32875744) and two probands were reported from a VCEP member, meeting F9 phenotype criteria. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414435714/MONDO:0010604/080 2025-04-04 2025-08-24 X-linked inheritance HP:0001417 Supports CHEBI:3207 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0948594 infores:hetionet CHEBI:4953 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0002962 infores:hetionet CHEBI:63617 biolink:causes HP:0001482 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151811 infores:hetionet CHEBI:6532 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0033774 infores:hetionet CHEBI:40279 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0011606 infores:hetionet CHEBI:9288 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0235378 infores:hetionet UMLS:C0005740 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0042963 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0086543 infores:hetionet CHEBI:50378 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0005741 infores:hetionet CHEBI:72296 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0015230 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018799 infores:hetionet CHEBI:70735 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0151576 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0043250 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0178298 infores:hetionet CHEBI:10110 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0038362 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0948594 infores:hetionet CHEBI:63629 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020625 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0427160 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0427160 infores:hetionet CHEBI:9763 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020625 infores:hetionet CHEBI:5790 biolink:causes EFO:0020923 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151821 infores:hetionet CHEBI:5959 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0017178 infores:hetionet CHEBI:6916 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C2047937 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0035302 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0027765 infores:hetionet GO:1903072 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:1903072 GO:0051716 CHEBI:5558 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0041657 infores:hetionet CHEBI:3011 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0917801 infores:hetionet CHEBI:71219 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0948008 infores:hetionet CHEBI:63607 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0006846 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0332534 infores:hetionet CAID:CA658658873 biolink:causes MONDO:0015967 infores:clingen CAID:CA658658873 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting BA1, BS1 The c.968del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 323 in NM_175914.5, adding 7 novel amino acids before encountering a stop codon (p.(Gln323Argfs*7)). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.968del meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0 approved 10/11/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658873/MONDO:0015967/085 2024-04-07 2024-04-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:79699 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0013491 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0521170 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0521170 infores:hetionet CHEBI:6339 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0042963 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151828 infores:hetionet NCBIGene:7915 biolink:causes MONDO:0010083 infores:monarchinitiative not_provided not_provided HGNC:408 MONDO:0010083 uuid:a827448c-437e-4af5-989c-c9f611a4ec88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0233494 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0002957 infores:hetionet CHEBI:63622 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C2363730 infores:hetionet CHEBI:9943 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015371 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0036572 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0021053 infores:hetionet CHEBI:7824 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013404 infores:hetionet CHEBI:6931 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0234518 infores:hetionet NCBIGene:23064 biolink:causes MONDO:0011223 infores:monarchinitiative not_provided not_provided HGNC:445 MONDO:0011223 uuid:a1510346-5a89-430b-94ed-58e3eb4a23cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5106 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C2363731 infores:hetionet CAID:CA16621285 biolink:causes MONDO:0100039 infores:clingen CAID:CA16621285 MONDO:0100039 PMID: Benign BS1, BS2 PP3, BA1, BP4 The allele frequency of the p.Ser849Leu variant in CDKL5 is 0.009217% in European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ser849Leu variant is observed in at least 2 unaffected individuals (internal database-GeneDX) (BS2). In summary, the p.Ser849Leu variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621285/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:2639 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0010200 infores:hetionet CAID:CA220343 biolink:causes MONDO:0015152 infores:clingen CAID:CA220343 MONDO:0015152 PMID: Pathogenic PP1_Moderate, PP4_Moderate, PM3_Very Strong, PVS1_Moderate PP3, BS1 The NM_000070.3: c.1746-20C>G variant occurs in intron 13 of the CAPN3 gene. The filtering allele frequency for this variant is 0.006051 in gnomAD v2.1.1 European (non-Finnish) genomes (the lower threshold of the 95% CI of 172/31388), which is higher than the LGMD VCEP threshold of 0.001 for BS1; in total, three homozygous individuals are also observed. However, this variant may act as a hypomorphic allele, and the VCEP opted not to apply this code (BS1 exception). RNAseq/cDNA analysis of muscle from patients carrying one copy of the variant suggests that it results in aberrant splicing, the inclusion of various portions of intron 13, and premature truncation (PMID: 20635405, 35731190). An earlier study concluded the variant does not affect splicing (PMID: 17979987); however, later investigations showed that the aberrantly spliced transcripts are variably expressed and not always detectable even when splicing-specific PCR is used, possibly due to nonsense-mediated mRNA decay (PMID: 20635405) (PVS1_RNA_Moderate). The c.1746-20C>G variant has been detected with a second CAPN3 variant in at least 34 individuals with LGMD (PMID: 37589857, 20635405, 17979987, 17157502, 35731190), including confirmed in trans with a pathogenic variant in five cases (c.550delA p.(Thr184ArgfsTer36), 4.0 pts, PMID: 20635405, 35731190; c.643_663del p.(Ser215_Gly221del): 1.0 pt, PMID: 35731190) (PM3_Very Strong). The variant was also reported to co-segregate with autosomal recessive disease in four affected family members from three families (PP1_Moderate; PMID: 37589857, 20635405, 35731190). Several patients with the c.1746-20C>G variant and a second CAPN3 variant displayed progressive limb girdle muscle weakness or clinical suspicion of limb-girdle muscular dystrophy as well as significantly reduced or absent expression of calpain-3, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 20635405). While two homozygous patients with a mild phenotype have been reported (PMID: 35731190), the number of apparently unaffected homozygous individuals described and present in population databases suggests this variant may show reduced penetrance in the homozygous state. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 10/28/2025): PVS1_RNA_Moderate, PM3_Very Strong, PP1_Moderate, PP4_Moderate. The LGMD VCEP recommends careful correlation with patient phenotype and family history as well as consideration of the combined functional impact of both CAPN3 alleles when the c.1746-20C>G variant is detected in an individual with signs of limb girdle muscular dystrophy. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220343/MONDO:0015152/187 2025-10-28 2025-11-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31711 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0034063 infores:hetionet CHEBI:7931 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0017178 infores:hetionet CHEBI:7865 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0041969 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0920166 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0920166 infores:hetionet CAID:CA255082 biolink:causes MONDO:0010602 infores:clingen CAID:CA255082 MONDO:0010602 PMID: Pathogenic PM2, PP3, PP1, PS4, PS2 The c.923C>T (NM_000132.3) variant in F8 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 308 (p.Ser308Leu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This variant has been reported in at least 21 probands meeting the hemophilia A phenotype criteria specified by the Coagulation Factor Deficiency VCEP. Several probands are reported with mild hemophilia A (>4) and VWD 2N exclusion was reported in at least 2 probands (PS4_VeryStrong; PMID: 10338101, 8759905, 19448530, 8449505, 18691168, 15921397, 19719828, 16972227, 18371166, 28674365, 30046696, 31026269, 21645180, 24845853, 22958177, 17445092). This variant has been identified as a de novo occurrence with confirmed maternal relationship (X-linked condition) in 1 male patient with severe hemophilia A (2 points per the ClinGen SVI PS2/PM6 table; PS2; PMID: 1837116). The variant has been reported to segregate with mild hemophilia A in 2 affected siblings from 1 family (PP1; PMID: 19448530). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.800, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has also been associated with discrepant factor VIII activity levels, with lower chromogenic factor VIII lab values (PMID: 32232366). In summary, this variant meets the criteria to be classified as pathogenic for X-linked recessive hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PS2, PP1, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255082/MONDO:0010602/071 2024-06-19 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:64355 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0009676 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027765 infores:hetionet CHEBI:27666 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0015672 infores:hetionet NCBIGene:1317 biolink:causes MONDO:0957211 infores:monarchinitiative not_provided not_provided HGNC:11016 MONDO:0957211 uuid:75f3d28b-f921-432c-ac18-33bdcebb2653 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3614 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0948594 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0241426 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0022104 infores:hetionet CHEBI:6367 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018520 infores:hetionet CHEBI:63580 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0518988 infores:hetionet CHEBI:9448 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0043352 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0242784 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0242784 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020514 infores:hetionet CHEBI:3515 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0033774 infores:hetionet CHEBI:4027 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027796 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1287298 infores:hetionet CHEBI:29007 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C1320835 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0019087 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0518015 infores:hetionet CHEBI:15553 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0011603 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0033975 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0235746 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235746 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0522063 infores:hetionet CHEBI:6887 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0428977 infores:hetionet GO:0060224 biolink:causes GO:0060221 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0060221 CHEBI:28593 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0013491 infores:hetionet CHEBI:7581 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0004134 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0021400 infores:hetionet CHEBI:9137 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002792 infores:hetionet CHEBI:49575 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042790 infores:hetionet CHEBI:2379 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C2830004 infores:hetionet CHEBI:31236 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151905 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0035078 infores:hetionet CHEBI:92769 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0015230 infores:hetionet CHEBI:6690 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0003811 infores:hetionet CHEBI:4466 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0541782 infores:hetionet CHEBI:9086 biolink:causes HP:0007378 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017185 infores:hetionet CHEBI:63581 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0027947 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0015376 infores:hetionet CHEBI:91541 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0009763 infores:hetionet GO:0006954 biolink:causes MONDO:0006554 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D016460 DB01130_MESH_D016460_1DB00547_MESH_D016460_1 CHEBI:194135 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0311468 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0403723 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0403723 infores:hetionet NCBIGene:2571 biolink:causes MONDO:0030856 infores:monarchinitiative not_provided not_provided HGNC:4092 MONDO:0030856 uuid:88c796e5-0d7b-4857-bb40-c933b1ccf413 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040460 infores:hetionet CHEBI:28593 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0014518 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031046 infores:hetionet CHEBI:5280 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0003467 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0917798 infores:hetionet CHEBI:7444 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0234238 infores:hetionet CHEBI:3699 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C1443060 infores:hetionet CHEBI:71415 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0855329 infores:hetionet CHEBI:3242 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0575081 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0018799 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0235431 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232492 infores:hetionet CHEBI:61390 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0027765 infores:hetionet CHEBI:5098 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0002994 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0040034 infores:hetionet CHEBI:7798 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0019348 infores:hetionet GO:0045616 biolink:causes GO:0043588 infores:ubergraph knowledge_assertion manual_agent GO:0045616 GO:0043588 NCBIGene:10381 biolink:causes MONDO:0013541 infores:monarchinitiative not_provided not_provided HGNC:20772 MONDO:0013541 uuid:4b4bc133-10ec-41fe-ac0e-19fdb4019d9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0267792 infores:hetionet CHEBI:50841 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C2830004 infores:hetionet GO:0090006 biolink:causes GO:0007129 infores:ubergraph knowledge_assertion manual_agent GO:0090006 GO:0007129 CHEBI:10650 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0152030 infores:hetionet CHEBI:5004 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0344232 infores:hetionet CHEBI:9168 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1384353 infores:hetionet CHEBI:31236 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2937350 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0025061 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0948089 infores:hetionet CHEBI:182080 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0235082 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0038454 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042267 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014742 infores:hetionet CHEBI:9362 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0332575 infores:hetionet CHEBI:63580 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0010200 infores:hetionet CHEBI:2637 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0030554 infores:hetionet CHEBI:135451 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0042487 infores:hetionet CHEBI:75922 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0022568 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0333641 infores:hetionet CHEBI:5280 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0085593 infores:hetionet CHEBI:144551 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0041969 infores:hetionet CHEBI:2663 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0344232 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0034150 infores:hetionet NCBIGene:29072 biolink:causes MONDO:0859331 infores:monarchinitiative not_provided not_provided HGNC:18420 MONDO:0859331 uuid:84e5897c-96b9-47da-b3cc-4b77bcf38fcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0020517 infores:hetionet GO:1904847 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:1904847 GO:0070887 CHEBI:7852 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0025061 infores:hetionet CAID:CA915940949 biolink:causes MONDO:0007947 infores:clingen CAID:CA915940949 MONDO:0007947 PMID: Pathogenic PP4, PM2_Supporting, PS2, PM4, PM1 PVS1, PM6, BS2, PP2, PP3, BP3, BP1, BP4, BA1, PS4, PS3, PM3, BS1, BS3 NM00138 c.4149_4154del is a deletion predicted to remove the methionine and glycine at amino acid positions 1384 and 1385, respectively, but is not expected to impact the reading frame (PM4). This variant was found to be confirmed as de novo in a young child with a clinical diagnosis of Marfan syndrome (PP4 and PS2; Universitair Ziekenhuis Antwerpen). This variant is not present in gnomAD v2.1.1 (PM2_supporting). p.Gly1385 is known to be involved in interdomain packaging of the protein, and its deletion may disrupt protein structure and/or function (PM1). This variant has not been reported in the published literature or public databases. In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS2, PM1, PM4, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940949/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ NCBIGene:3920 biolink:causes MONDO:0010281 infores:monarchinitiative not_provided not_provided HGNC:6501 MONDO:0010281 uuid:65c9144c-0142-4dd9-bdf5-bbe708d5bc67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15407 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0011206 infores:hetionet CHEBI:66901 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0311468 infores:hetionet CHEBI:92769 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0012833 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0746883 infores:hetionet CAID:CA10585106 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585106 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP1, PP4, BS2 The NM_000527.5(LDLR):c.737G>A (p.Gly246Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1)PP3: REVEL score is 0.877, this is greater than 0.75. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585106/MONDO:0007750/013 2023-01-27 2025-03-21 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:84883 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0017152 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0017675 infores:hetionet NCBIGene:26277 biolink:causes MONDO:0013522 infores:monarchinitiative not_provided not_provided HGNC:11824 MONDO:0013522 uuid:8a709f89-9603-47ef-a616-17cc4fae5286 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030232 infores:hetionet CAID:CA10585839 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585839 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PVS1_Strong, PP1_Moderate, PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PM6, BS2, PP2, PP3 The NM_000527.5(LDLR):c.2389+2T>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1_Strong, PP1_moderate, PM2, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - variant is at +2 donor splice site, and is predicted to lead to exon 16 skipping. Exon 16 is in frame, so PVS1_Strong is met.PP1_moderate - variant segregates with FH phenotype in 5 relatives from Robarts Research Institute, so PP1_Moderate is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PS4_Supporting - variant meets PM2 and is identified in 3 unrelated index cases, after alternative causes of hypercholesterolemia were excluded, from different labs (1 with DLCN >=6 from Robarts Research Institute, 1 with possible FH according to Simon-Broome criteria from PMID 17539906 (UK) and 1 with DLCN >=6 from PMID 33418990 (Russia)), so PS4_Supporting is met.PP4 - variant meets PM2 and is identified in 3 unrelated index cases from different labs (see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585839/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:691037 biolink:causes UMLS:C0406317 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0406317 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0015230 infores:hetionet CHEBI:6797 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0033774 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0861149 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0861149 infores:hetionet CHEBI:8356 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015672 infores:hetionet CHEBI:101085 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C1443060 infores:hetionet CHEBI:63791 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0428974 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0403632 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0009806 infores:hetionet CHEBI:9086 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0014457 infores:hetionet CHEBI:70707 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0232461 infores:hetionet CHEBI:4909 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0030193 infores:hetionet CHEBI:49713 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0040822 infores:hetionet CHEBI:64317 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0020458 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0038826 infores:hetionet NCBIGene:64857 biolink:causes MONDO:0014766 infores:monarchinitiative not_provided not_provided HGNC:29515 MONDO:0014766 uuid:e3cff249-02ef-495d-86f8-f15af26e497e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0018681 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0027947 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0018799 infores:hetionet CHEBI:4024 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0022073 infores:hetionet CHEBI:29013 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0030312 infores:hetionet CAID:CA404089805 biolink:causes MONDO:0007750 infores:clingen CAID:CA404089805 MONDO:0007750 PMID: Uncertain Significance PM2 BP3, BP2, BP1, BP4, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP1, PP4, PP2, PP3 The NM_000527.5(LDLR):c.1800G>C (p.Glu600Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specifications version 1.2) on 4 May 2023. The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404089805/MONDO:0007750/013 2023-05-04 2025-02-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:119573 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151904 infores:hetionet CHEBI:7865 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0036974 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0011849 infores:hetionet CHEBI:3568 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018681 infores:hetionet CHEBI:94609 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0035455 infores:hetionet CHEBI:8024 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018790 infores:hetionet CHEBI:94501 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0042571 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0948594 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0858797 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0086543 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0233485 infores:hetionet CAID:CA367397285 biolink:causes MONDO:0007453 infores:clingen CAID:CA367397285 MONDO:0007453 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4, PP1 The c.1261G>T variant in the glucokinase gene, GCK, results in a premature termination at codon 421 (p.(Glu421Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and fasting glucose between 5.5-8 mmol/L) (PP4; internal lab contributors). In summary, c.1261G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397285/MONDO:0007453/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:66899 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0162285 infores:hetionet NCBIGene:55599 biolink:causes MONDO:0032569 infores:monarchinitiative not_provided not_provided HGNC:18666 MONDO:0032569 uuid:3787c915-2cb5-4149-b1c2-f0abd479e89a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042109 infores:hetionet CHEBI:45863 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0039231 infores:hetionet UMLS:C0010592 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0015967 infores:hetionet CHEBI:2687 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C1384353 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0006849 infores:hetionet CHEBI:7824 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020580 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0151736 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0800029 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C1800706 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0855242 infores:hetionet CHEBI:5100 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0162297 infores:hetionet UNII:3K045XR58X biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01303 UMLS:C0151735 infores:hetionet CHEBI:8028 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0023052 infores:hetionet CHEBI:6456 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0040822 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020557 infores:hetionet CHEBI:64355 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1443060 infores:hetionet CHEBI:6339 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1291078 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0029878 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0460048 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0460048 infores:hetionet CAID:CA386971876 biolink:causes MONDO:0015967 infores:clingen CAID:CA386971876 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PP3 The c.1556C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 519 (p.(Pro519Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.828, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with diabetes, with at least 9 informative meioses in 7 families with MODY (PP1_Strong; PMID: 30293189, internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 32238361, 29758564, 30293189, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-sensitive) (PP4_Moderate; internal lab contributors). In summary, c.1556C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting, PP3, PS4, PP4, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386971876/MONDO:0015967/017 2024-10-25 2024-10-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10125 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0520589 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0237326 infores:hetionet CHEBI:6444 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0424295 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029882 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0267033 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0267033 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0004623 infores:hetionet CHEBI:52172 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0234632 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085584 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0234458 infores:hetionet CAID:CA229660 biolink:causes MONDO:0009861 infores:clingen CAID:CA229660 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PM3, PP3 The NM_000277.3(PAH):c.617A>G (p.Tyr206Cys) missense variant has been reported in 1 patient with mild phenylketonuria (Phe = 914 umol/liter, BH4 deficiency excluded) (PP4_moderate; PMID: 29499199). This variant is absent from population databases (PM2), and is predicted deleterious by SIFT, Polyphen2, Mutation Taster. REVEL= 0.96 (PP3). This variant has been detected with pathogenic variants: p.Y204C (PMID: 16256386) and R241C (PMID: 26322415) (PM3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229660/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2569 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0178298 infores:hetionet CHEBI:7865 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0013146 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0022650 infores:hetionet CHEBI:135930 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0235896 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1274594 infores:hetionet NCBITaxon:234 biolink:causes MONDO:0005683 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:234 MONDO:0005683 CHEBI:82960 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0239571 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0347721 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0347721 infores:hetionet NCBIGene:1188 biolink:causes MONDO:0000909 infores:monarchinitiative not_provided not_provided HGNC:2027 MONDO:0000909 uuid:0758883b-f7e4-4d83-a349-899f6f53795a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA213727 biolink:causes MONDO:0015967 infores:clingen CAID:CA213727 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1160C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 387 (p. (Ala387Val)) of NM_000162.5. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to no copies in the European non-Finnish subpopulation and one copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.871 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1159G>A p.(Ala387Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala387Glu has a greater Grantham distance (PM5). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 34421822, Internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 34421822). This variant segregated with hyperglycemia, with five informative meioses in three families (PP1_Strong; PMID: 34421822, Internal lab contributor). In summary, c.1160C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5, PS4_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213727/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports NCBIGene:6331 biolink:causes MONDO:0011003 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0011003 uuid:c596bc43-4c90-4da1-a580-d26d4dcd8eac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0031350 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0020538 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0233485 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0042373 infores:hetionet CHEBI:3312 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0013604 infores:hetionet CHEBI:9725 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0022346 infores:hetionet CHEBI:45327 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0011603 infores:hetionet CL:0001063 biolink:causes MONDO:0005086 infores:drugmechdb knowledge_assertion manual_agent CL:0001063 MESH:D002292 DB06824_MESH_D002292_2DB06626_MESH_D002292_1DB06287_MESH_D002292_1DB06824_MESH_D002292_3DB06824_MESH_D002292_1 CHEBI:31981 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0234428 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0677500 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0042963 infores:hetionet CHEBI:31236 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0312420 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0149931 infores:hetionet CAID:CA376062237 biolink:causes MONDO:0011225 infores:clingen CAID:CA376062237 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting, BP7 BS2, PS1, PM5 The c.291T>C (NM_001033855.3) variant in the DCLRE1C gene is a synonymous variant (p.Asp97=). The filtering allele frequency (the upper threshold of the 95% CI of 2/44736 alleles) of the c.291T>C variant in DCLRE1C is 0.000007410 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.According to at least two in silico tools (SpliceAI and varSEAK), this synonymous variant was not predicted to impact the consensus sequence or create a new site (BP7).To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, due to conflict evidence, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and BP7(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376062237/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6375 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019360 infores:hetionet CAID:CA891842591 biolink:causes MONDO:0021056 infores:clingen CAID:CA891842591 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PS3_Moderate, PM2_Supporting The NM_000038.6(APC):c.531+6T>C variant in APC is an intronic variant which is located at the 6th nucleotide in intron 5. This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, Ambry Genetics, internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). Capture-based RNA sequencing demonstrated that the variant impacts splicing by skipping of exon 5 resulting in a premature stop codon, r.423_531del109 (p.R141Sfs*8) (PS3_Moderate, Ambry internal data). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: criteria PS3_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA891842591/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CAID:CA382518439 biolink:causes MONDO:0700270 infores:clingen CAID:CA382518439 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PS3_Moderate, PM3, PP3 BA1, BP4, BS1 The ATM c.8546G>C (p.Arg2849Pro) variant has been observed in a compound heterozygous state (presumed) in an individual with biallelic disease and in heterozygosity in an individual with biallelic disease with a second variant unidentified (PM3, PMID: 23667852, PMID: 9887333). This variant is non-functional in multiple different protein assays (PS3_Moderate, PMID: 11805335). In silico protein predictors (ALIGN GVGD: Class C65; REVEL: 0.919; SIFT: damaging; PolyPhen2: probably damaging) predict that this alteration is deleterious (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382518439/MONDO:0700270/020 2022-03-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63619 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030554 infores:hetionet CAID:CA1022028089 biolink:causes MONDO:0011071 infores:clingen CAID:CA1022028089 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.805+14G>A is an upstream variant of RUNX1. SpliceAI showed a very low chance that the variant affects splicing (SpliceAI ∆ scores < 0.02) (BP4). The 100 Vertebrates Basewise Conservation score for the position of this variant was 0.11, indicating that this position is not highly conserved (phyloP score <2.0) (BP7). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1022028089/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50275 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013456 infores:hetionet CAID:CA2573132571 biolink:causes MONDO:0100368 infores:clingen CAID:CA2573132571 MONDO:0100368 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting PM3 NM_000329.3(RPE65):c.1360del (p.Thr454LeufsTer?) is a frameshift variant that introduces a premature stop codon into exon 13 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including severely decreased ERG responses (0.5 pts), optic disc pallor (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 28130426, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 28130426, PP1). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573132571/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2904 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0037052 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0004936 infores:hetionet CHEBI:4784 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151632 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013395 infores:hetionet CHEBI:38940 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0040128 infores:hetionet CHEBI:9649 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151905 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0233494 infores:hetionet CHEBI:168396 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0015402 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0863084 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0023895 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037315 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0017152 infores:hetionet CAID:CA397723367 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723367 MONDO:0008723 PMID:26385305 Uncertain Significance PM2_Supporting, PP3, PM1 The NM_000018.4: c.640T>G (p.Phe214Val) in ACADVL is a missense variant predicted to cause substitution of phenylalanine by valine at amino acid 214 (p.Phe214Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in the literature in five individuals with an abnormal newborn screen who are apparently heterozygous carriers for the variant (PMID: 26385305), but this information is insufficient to use toward classification. This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723367/MONDO:0008723/021 2024-04-26 2024-04-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2453 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0030554 infores:hetionet CHEBI:9139 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2937350 infores:hetionet CHEBI:4672 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0206062 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0015393 infores:hetionet CHEBI:5138 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0008350 infores:hetionet UNII:R43D2573WO biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085612 infores:hetionet CHEBI:32221 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0008031 infores:hetionet CHEBI:53760 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011168 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0035455 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009760 infores:hetionet CHEBI:101853 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0015967 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0003123 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009450 infores:hetionet CHEBI:116278 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0085702 infores:hetionet CHEBI:50861 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C1443060 infores:hetionet CHEBI:68841 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0235639 infores:hetionet CHEBI:3696 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0019521 infores:hetionet CHEBI:4798 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0030807 infores:hetionet CHEBI:51450 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0030554 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029928 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042267 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0015256 infores:hetionet CHEBI:3738 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0022107 infores:hetionet CHEBI:8107 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0038325 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085096 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0018681 infores:hetionet CAID:CA116953176 biolink:causes MONDO:0012163 infores:clingen CAID:CA116953176 MONDO:0012163 PMID: Uncertain Significance PM2_Supporting, BP7 BS2 The c.82+14A>T (NM_002185.5) variant in IL7R is an intronic variant which locates in the deep intronic region in intron 1. It is not predicted to impact splicing by SpliceAI, varSEAK, and NNSplice. BP7 is met.This variant is absent from gnomAD v2.1.1 (PM2_Supporting).In summary, this variant is classified as uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting and BP7. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA116953176/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9622 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C3665347 infores:hetionet CHEBI:15367 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0043144 infores:hetionet CHEBI:8802 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0027424 infores:hetionet CHEBI:9635 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0023530 infores:hetionet NCBITaxon:194 biolink:causes MONDO:0005688 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:194 MONDO:0005688 CHEBI:7476 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020649 infores:hetionet NCBIGene:5297 biolink:causes MONDO:0030482 infores:monarchinitiative not_provided not_provided HGNC:8983 MONDO:0030482 uuid:59422f53-ce9a-49ca-b191-d9541cbd89c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:T58MSI464G biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0302809 infores:hetionet CHEBI:9927 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0030252 infores:hetionet CHEBI:28901 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151905 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0012394 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0012394 uuid:bf39dc6d-48e3-4967-b9ff-8e0cf14b8f86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0032285 infores:hetionet CHEBI:27470 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0009676 infores:hetionet CHEBI:75722 biolink:causes MONDO:0024352 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0877203 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0002871 infores:hetionet CHEBI:3441 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0004238 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151854 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0344315 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0022568 infores:hetionet CHEBI:49375 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0026858 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0333641 infores:hetionet UMLS:C0011701 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0424295 infores:hetionet CHEBI:3534 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0852911 infores:hetionet CHEBI:8107 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0030848 infores:hetionet CHEBI:6761 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0013144 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020456 infores:hetionet CHEBI:77032 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0011991 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0018834 infores:hetionet CAID:CA170191 biolink:causes MONDO:0010726 infores:clingen CAID:CA170191 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BP5, BS1 The allele frequency of the p.Pro388_Pro393del (NM_004992.3) variant in MECP2 is 0.01% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro388_Pro393del variant is observed in at least 1 unaffected individual (PMID 21160487)(BS2_supporting). The p.Pro388_Pro393del variant is found in a patient with an alternate molecular basis of disease (PMID 21160487)(BP5). In summary, the p.Pro388_Pro393del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BS2_supporting, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170191/MONDO:0010726/016 2021-12-22 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:5613 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0025345 infores:hetionet CAID:CA10360445 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360445 MONDO:0100039 PMID: Likely Benign BP5, BP4 BS1, BS2 The c.2046+3A>G variant in CDKL5 is present in 1 female and 1 male individual(s) in gnomAD (0.001097) (not sufficient to meet BS1 criteria). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.2046+3A>G variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the c.2046+3A>G variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360445/MONDO:0100039/034 2023-08-23 2023-09-14 X-linked inheritance HP:0001417 Contradicts true CHEBI:5100 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0033247 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0012833 infores:hetionet CHEBI:31413 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0042029 infores:hetionet CAID:CA6798648 biolink:causes MONDO:0021060 infores:clingen CAID:CA6798648 MONDO:0021060 PMID:28074573PMID:22253195PMID:28074573PMID:23756559 Likely Pathogenic PS4, PM1, PP2 PS3, PM5, PM2, PP3 The c.782T>A (p.Leu261His) variant in PTPN11 is present in 1/6064 “other” alleles in gnomAD v2.1.1; however, it is absent from gnomAD v3 (PM2 not met). It has been identified in 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 28074573, 22253195, 23756559). A functional assay performed on this variant does not meet approved RASopathy VCEP guidelines for criteria application (PS3 not met; PMID: 28074573). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of PTPN11 (PM1; PMID 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM1, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6798648/MONDO:0021060/004 2020-03-16 2020-03-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3723 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020514 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0232492 infores:hetionet CHEBI:63599 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0085692 infores:hetionet CHEBI:7931 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0000737 infores:hetionet CHEBI:6715 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0039070 infores:hetionet CHEBI:6801 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0018681 infores:hetionet CHEBI:3371 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0023895 infores:hetionet NCBIGene:146057 biolink:causes MONDO:0011464 infores:monarchinitiative not_provided not_provided HGNC:19141 MONDO:0011464 uuid:2e4a305b-f211-4467-beed-e674b47e88d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:43968 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C1145670 infores:hetionet CHEBI:63617 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0404521 infores:hetionet CHEBI:4885 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0027497 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0497327 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0021390 infores:hetionet CHEBI:50777 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0015672 infores:hetionet CHEBI:100241 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020453 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0522245 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0522245 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0542165 infores:hetionet NCBIGene:1075 biolink:causes MONDO:0008226 infores:monarchinitiative not_provided not_provided HGNC:2528 MONDO:0008226 uuid:fae1f9d6-67ac-480f-b22a-23a053b97f02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410207972 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207972 MONDO:0011071 PMID:17485549PMID:17650443PMID:27479822 Likely Pathogenic PS4_Moderate, PM5_Supporting, PM1, PM2_Supporting, PP3 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.4:c.593A>T (p.Asp198Val) is a missense variant which affects a hotspot residue within the RHD (PM1). Two probands meeting RUNX1-phenotypic criteria were reported to have this variant (PMID: 27479822; Internal laboratory data) (PS4_moderate). This variant has a REVEL score of 0.959 > 0.75 (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). Additionally, this variant is a missense change at the same residue (p.D198) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 561251, 2665098) based on MM-VCEP rules for RUNX1 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PS4_moderate, PP3, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207972/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:231594 biolink:causes UMLS:C0729552 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0729552 infores:hetionet CHEBI:8597 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C1368065 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042401 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0019151 infores:hetionet CHEBI:52172 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013404 infores:hetionet CAID:CA2573320718 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573320718 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PS2_Supporting, PM2_Supporting, PS4_Supporting PS3, PS1, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1, PP4 The NM_001754.5:c.968del (p.Thr323ArgfsTer5) variant in RUNX1 is a frameshift variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region is critical for protein function (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant was identified in a patient meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal data). The de novo status has been confirmed (PS2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PS2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573320718/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:82960 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019196 infores:hetionet CHEBI:2950 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0542571 infores:hetionet CHEBI:35778 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1510410 infores:hetionet CHEBI:68841 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0236075 infores:hetionet CHEBI:3082 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013404 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0687133 infores:hetionet CHEBI:8461 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0013144 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0030196 infores:hetionet CHEBI:28001 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0151578 infores:hetionet CHEBI:9086 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0033774 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0700345 infores:hetionet CHEBI:27470 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0003123 infores:hetionet GO:1903581 biolink:causes GO:0002560 infores:ubergraph knowledge_assertion manual_agent GO:1903581 GO:0002560 CHEBI:63637 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0085649 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013395 infores:hetionet NCBIGene:4141 biolink:causes MONDO:0014566 infores:monarchinitiative not_provided not_provided HGNC:6898 MONDO:0014566 uuid:02250a1b-43a9-483e-a993-a5df05b2b809 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0235416 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0854382 infores:hetionet CHEBI:5002 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0020621 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0036572 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040586 infores:hetionet CHEBI:453011 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0237849 infores:hetionet CHEBI:6741 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0026858 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0522063 infores:hetionet CHEBI:3534 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0086565 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0233571 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0013404 infores:hetionet CHEBI:7459 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0234369 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0018799 infores:hetionet CAID:CA228494 biolink:causes MONDO:0015629 infores:clingen CAID:CA228494 MONDO:0015629 PMID: Likely Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PS4_Moderate PS3, PM5 The NM_000552.4(VWF):c.3929C>T (p.Ser1310Phe) missense variant has been identified in at least three unrelated patients, with phenotypes specific to VWD type 2B (PS4_moderate; PMIDs: 27978591, 8815591). At least 2 patients with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of loss of high molecular weight multimers and a GP1b assay with enhanced low-dose RIPA showing gain of function, which together are highly specific for VWD type 2B (PP4_moderate; PMID: 27978591). The variant has been reported to segregate with VWD type 2M through 3 affected siblings from 1 family (PP1; PMID: 27978591). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.937, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP1, PP3, PP4_moderate, PM2_supporting, and PS4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228494/MONDO:0015629/081 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Supports CAID:CA412740071 biolink:causes MONDO:0100437 infores:clingen CAID:CA412740071 MONDO:0100437 PMID: Likely Pathogenic PP3_Strong, PP4, PP1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.1070G>A (p.Gly357Asp) is a missense variant encoding the substitution of glycine with aspartic acid at amino acid 357. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), first decade onset (1 pt), night blindness (0.5 pt), pigmentary retinopathy (0.5 pt), decreased central vision acuity (0.5 pt), and visual field constriction (0.5 pt), which together are specific for RPGR-related retinopathy (5 points, PMID: 31645972, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 36832217, PMID: 31645972; PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through an affected mother and son (PP1; PMID: 31645972). The computational predictor REVEL gives a score of 0.982, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.04 for donor gain, which is below the ClinGen Xlinked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP3_Strong, PP4, PS4_Supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412740071/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports GO:2000557 biolink:causes GO:0002385 infores:ubergraph knowledge_assertion manual_agent GO:2000557 GO:0002385 CHEBI:31638 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0600142 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0853692 infores:hetionet CHEBI:135935 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0030554 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0687133 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0574067 infores:hetionet CHEBI:8871 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085632 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0242073 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0243026 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0015230 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0235093 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0235093 infores:hetionet CHEBI:135876 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0231528 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0595877 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0267792 infores:hetionet CHEBI:59773 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0024141 infores:hetionet CHEBI:8768 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0006384 infores:hetionet CHEBI:18357 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0001807 infores:hetionet CHEBI:5778 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0004093 infores:hetionet CAID:CA274455 biolink:causes MONDO:0009290 infores:clingen CAID:CA274455 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Supporting PM5 The NM_000152.5: c.1979G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 660 (p.Arg660His). More than nine individuals with features consistent with Pompe disease have been reported with this variant. Of these patients 3 probands (and two siblings) have documented laboratory values indicating GAA deficiency in the affected range in dried blood spot, or muscle, or <1% activity in cultured skin fibroblasts (PMID: 21484825, 25037089, 27649523), and three probands are reported to have low GAA activity and to be on enzyme replacement therapy (PP4_Moderate). Six patients are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP. For two patients, the second variant was confirmed in trans by parental testing - c.525delT (PMID: 30559630, possibly same case in PMID: 30214072), and c.670C>T (p.Arg224Trp) (PMID: 14643388) – and in four patients the phase of the second variant is unconfirmed - c.655G>A (p.Gly219Arg) (PMID: 29122469), c.1082C>T (p.Pro361Leu) (PMID: 21484825), c.1998C>T (p.Arg600Cys) (PMID: 14643388), and c.2560C>T (p.Arg854Ter) (PMID: 30214072). Two homozygous siblings have also been reported (PMID: 27649523) (PM3_Very Strong). Two probands have been reported who are compound heterozygous for the variant and either c.-32-17_-32-10del8ins30 (PMID: 25037089; two affected siblings), or c.1114C>T (p.His372Tyr) (PMID: 30214072). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (6/23566) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In two independent studies, in which the variant was expressed in COS cells, the GAA activity was <2% wild type, indicating that the variant has a damaging effect on GAA function (PS3_Supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant, c.1978C>T (p.Arg660Cys), has been reported at this position. p.Arg660His will be used to support the classification of p.Arg660Cys and thus PM5 is not applied here, in order to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 189172; 2 star review status) with nine submitters classifying the variant as pathogenic, and three as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274455/MONDO:0009290/010 2022-03-01 2022-07-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:47898 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0162830 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0011991 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0851341 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0235639 infores:hetionet CAID:CA132253 biolink:causes MONDO:0019501 infores:clingen CAID:CA132253 MONDO:0019501 PMID: Uncertain Significance BS1, PP3, PM3, BP2, BP4 The c.2527G>A variant in MYO7A is a missense variant predicted to cause substitution of valine by methionine at amino acid 843. The variant is present in 0.0006965 (23/22568) of South Asian alleles with a confidence interval of 95% in gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.25, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. The variant has been reported in 6 probands, all of whom did not have clinical/phenotypic data, had other potentially pathogenic variants, or did not present with hearing loss (PMID:30755392, GeneDx, EGL Eurofins, Illumina). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the absence of ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132253/MONDO:0019501/005 2022-08-03 2022-08-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:140621 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0151786 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0037274 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0948594 infores:hetionet CHEBI:59773 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0011168 infores:hetionet CAID:CA387746086 biolink:causes MONDO:0700269 infores:clingen CAID:CA387746086 MONDO:0700269 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3, PM3 BP7 The c.7796A>G variant in BRCA2 is a missense variant predicted to cause substitution of Glutamic Acid by Glycine at amino acid 2599 (p.(Glu2599Gly)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.36, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.06 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (PMID: 24123850), but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). This variant has been detected in one individual with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least one clinical feature of FA (physical features AND pathology findings) and confirmed chromosome breakage are seen in this individual. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (BRCA2:c.1813dup) which was confirmed to be in trans. Total points equated to 2 (PM3 met; PMIDs: 34504103, 33984160). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3, PM3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA387746086/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7773 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0043250 infores:hetionet CHEBI:48538 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0043387 infores:hetionet NCBIGene:6315 biolink:causes MONDO:0012116 infores:monarchinitiative not_provided not_provided HGNC:10561 MONDO:0012116 uuid:0890e2fa-2817-4bcd-894d-25215834a7f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7822 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C1443060 infores:hetionet CHEBI:44241 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0018681 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014742 infores:hetionet CHEBI:34829 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C1761613 infores:hetionet CHEBI:7773 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0014518 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0038454 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0948594 infores:hetionet CHEBI:66876 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0231807 infores:hetionet CHEBI:4858 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085633 infores:hetionet CHEBI:63622 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0002962 infores:hetionet CHEBI:9445 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0011603 infores:hetionet CHEBI:10102 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0162830 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0035078 infores:hetionet CHEBI:44185 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0242301 infores:hetionet CHEBI:3423 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0019080 infores:hetionet CHEBI:7581 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233407 infores:hetionet NCBIGene:348 biolink:causes MONDO:0007089 infores:monarchinitiative not_provided not_provided HGNC:613 MONDO:0007089 uuid:8e24beb0-9a37-4176-92b6-af9106f5af90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0041834 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0010346 infores:hetionet CHEBI:27974 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0156404 infores:hetionet CHEBI:15765 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0086439 infores:hetionet NCBITaxon:967 biolink:causes MONDO:0020532 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:967 MONDO:0020532 CHEBI:47381 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0028734 infores:hetionet GO:0052027 biolink:causes GO:0007165 infores:ubergraph knowledge_assertion manual_agent GO:0052027 GO:0007165 CHEBI:63613 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0019158 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0558348 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0558348 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017601 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037274 infores:hetionet CHEBI:63598 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018794 infores:hetionet CHEBI:15544 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0023380 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0852733 infores:hetionet CHEBI:63619 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0041834 infores:hetionet CHEBI:5855 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C2047937 infores:hetionet CHEBI:8764 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151905 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0000737 infores:hetionet CHEBI:74947 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011175 infores:hetionet CHEBI:63617 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0041657 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0236065 infores:hetionet CHEBI:6950 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1328337 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042514 infores:hetionet CAID:CA2695237640 biolink:causes MONDO:0010726 infores:clingen CAID:CA2695237640 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, PVS1 BA1, BP2, PS3, PS2, PS4, PM1, PM3, BP5, BS1, BS3, BS4, PM6, PP1, PP4, BS2 The p.His368LeufsTer18 variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.His368LeufsTer18 variant in MECP2 is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was observed in a previously healthy 30-40yo woman with neurodegeneration (no criteria met, Internal communication). In summary, the p.His368Leufs variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PVS1, PM2_Supporting). (MECP2 specification v3.0.0; approved on 12/18/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695237640/MONDO:0010726/036 2024-12-18 2025-03-26 X-linked inheritance HP:0001417 Inconclusive true CHEBI:31980 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0013604 infores:hetionet CHEBI:3219 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0522251 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0234215 infores:hetionet CHEBI:27300 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0032617 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0028738 infores:hetionet CAID:CA367398309 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398309 MONDO:0015967 PMID: Pathogenic PM1, PM5, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4 The c.1229G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartate at codon 410 (p.(Gly410Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Another missense variant, c.1228G>A p.Gly410Ser, has been interpreted as pathogenic by the ClinGen MDEP, and p.Gly410Asp has a greater Grantham distance (PM5). In summary, c.1229G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5, PP1, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398309/MONDO:0015967/086 2024-06-22 2024-06-22 Semidominant inheritance HP:0032113 Supports CHEBI:31622 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0085631 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013609 infores:hetionet NCBIGene:171023 biolink:causes MONDO:0011510 infores:monarchinitiative not_provided not_provided HGNC:18318 MONDO:0011510 uuid:2a23ee76-5441-4649-acdf-9947f52044e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:6029 biolink:causes MONDO:0005846 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6029 MONDO:0005846 CHEBI:63605 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020649 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0239978 infores:hetionet CHEBI:63612 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0023380 infores:hetionet CHEBI:44185 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C2047937 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0235416 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038358 infores:hetionet CHEBI:18248 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C1443060 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0029882 infores:hetionet CHEBI:404903 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013428 infores:hetionet CHEBI:116278 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0014457 infores:hetionet CHEBI:2038 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0039231 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0022660 infores:hetionet CHEBI:100241 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0235266 infores:hetionet CAID:CA399790399 biolink:causes MONDO:0100326 infores:clingen CAID:CA399790399 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PP1, PM2_Supporting, PS3, PVS1_Moderate PM3 The c.2941C>T (p.Gln981Ter) variant in exon 28 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 28 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Additionally, In two siblings, it has been shown that this mutation results in exon 28 being spliced out of the final protein product (PMID: 8111043, PVS1_Moderate). Surface expression of αIIb measured by Western blot in COS-1 cells transiently co-transfected with c.2941C>T (p.Gln981Ter) αIIb and wild type αIIb showed decreased expression at 0% of WT levels, indicating that this variant impacts protein function (PMID: 1932748)(PS3). At least two patients (Patient 1 and Patient 2 from PMID:8111043) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate). This variant has also been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus the proband's affected sister. The c.2941C>T (p.Gln981Ter) variant is inherited from the patients' father and an unspecified ITGA2B variant is inherited from their mother (PP1_Supporting, PMID: 8111043). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PS3, PP4_Moderate, PP1 and PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399790399/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4672 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0023895 infores:hetionet CHEBI:50381 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0009782 infores:hetionet CHEBI:2675 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0152198 infores:hetionet CHEBI:5130 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0003811 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0476089 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0243026 infores:hetionet GO:0006954 biolink:causes MONDO:0006547 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D005076 DB00547_MESH_D005076_1DB01130_MESH_D005076_1DB09321_MESH_D005076_1 CHEBI:4887 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0178298 infores:hetionet CAID:CA026335 biolink:causes MONDO:0012933 infores:clingen CAID:CA026335 MONDO:0012933 PMID: Uncertain Significance PM2_Supporting PVS1, BS3, PS3 The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 3309 (p.Glu3309Ter). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met).In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA026335/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7494 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0023530 infores:hetionet CHEBI:9654 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0221345 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0162287 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0877322 infores:hetionet NCBIGene:2742 biolink:causes MONDO:0024772 infores:monarchinitiative not_provided not_provided HGNC:4327 MONDO:0024772 uuid:e18fb5ae-2475-4feb-8a3f-70504ac7e64e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0687713 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0152447 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152447 infores:hetionet CHEBI:9599 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C2747891 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151888 infores:hetionet CHEBI:5864 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002878 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0007642 infores:hetionet CAID:CA124484 biolink:causes MONDO:0015967 infores:clingen CAID:CA124484 MONDO:0015967 PMID: Uncertain Significance BS4 PS4, BS1, PM2, PP3 The c.1592G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 531 (p.(Ser531Thr)) of NM_000545.8. This variant does not segregate with diabetes in four families (BS4; internal lab contributors). In summary, c.1592G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): BS4 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124484/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3371 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0014457 infores:hetionet CHEBI:465284 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151786 infores:hetionet CAID:CA004651 biolink:causes MONDO:0005045 infores:clingen CAID:CA004651 MONDO:0005045 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM6_Supporting, PS3_Supporting, PM4, PM2_Supporting BA1, PS2, BS1, BS3 NM_001276345.2(TNNT2):c.517_519del (p.Glu173del) - This variant has been reported in individuals with HCM and other cardiomyopathies (LMM data, PMIDs: 7898523, 11606294, 12707239, 20624503, 22144547, 22260945, 24792744, 27532257, 27662471, 28771489) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criterion has been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). This variant segregated with disease in multiple affected individuals across multiple families (PP1_Strong; OMGL Data, LMM Data, PMID: 7898523). This variant has been confirmed as de novo (PM6_Supporting; OMGL Data). Functional studies have been reported and are sufficient to apply PS3_Supporting (PMID: 10497196, 10731693, 14636924, 22579624, 24480310, 27036851). This variant is a deletion 1 amino acid and is not predicted to alter the protein reading-frame (PM4). In summary, this variant has been classified as Pathogenic for HCM in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PP1_Strong, PM6_Supporting, PS3_Supporting, and PM4. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA004651/MONDO:0005045/099 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31176 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0016382 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0041912 infores:hetionet CHEBI:465284 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0239134 infores:hetionet CHEBI:53760 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C2225524 infores:hetionet GO:0090199 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:0090199 GO:0006915 CHEBI:100241 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0029878 infores:hetionet CHEBI:167638 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0151766 infores:hetionet CHEBI:8888 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C3665347 infores:hetionet GO:0098673 biolink:causes GO:0006261 infores:ubergraph knowledge_assertion manual_agent GO:0098673 GO:0006261 CHEBI:23765 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0497156 infores:hetionet CHEBI:15367 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020672 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0042075 infores:hetionet CHEBI:9649 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0008031 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0233472 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0017178 infores:hetionet CAID:CA2499225875 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225875 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BS2 The NM_001754.5(RUNX1):c.528_531dup (p.Thr178fs) variant is a frameshift variant predicted to introduce a premature stop codon, resulting in nonsense-mediated mRNA decay (PVS1). Additionally, it is located in c.528_531, which is downstream of c.98 (in transcript NM_001754.4) (PM5_Supporting). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). . In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225875/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135005 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0242350 infores:hetionet CHEBI:135342 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0018520 infores:hetionet CAID:CA293967 biolink:causes MONDO:0700270 infores:clingen CAID:CA293967 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PS3_Supporting The c.8565_8566delinsAA variant in ATM is an in-frame deletion insertion predicted to cause substitution of serine and valine by arginine and isoleucine at amino acids 2855-2856 This variant has been detected in multiple unrelated individuals with Ataxia-Telangiectasia (PMIDs: 9872980, 10817650, 12673797, 26896183, 37438524). This variant is absent from gnomAD v4.1.0. Western blotting in ATM null cells transfected with cDNA carrying this variant showed inactive phosphorylation of ATM downstream targets as compared to wild-type controls indicating that this variant impacts protein function (PMID: 19431188). The computational predictor Provean gives a score of -4.871, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Very Strong, PM2_Supporting, PS3_Supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA293967/MONDO:0700270/020 2025-11-11 2025-11-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5128 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0038587 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0027765 infores:hetionet CAID:CA414773403 biolink:causes MONDO:0044970 infores:clingen CAID:CA414773403 MONDO:0044970 PMID:38582886 Uncertain Significance PP3, PM2_Supporting, PS4_Supporting PS2, PS3, PM6 The m.3734A>G (p.E143G) variant in MT-ND1 has been reported in two probands with primary mitochondrial disease (PS4_supporting; PMIDs: 35892476, 38582886). The first reported proband had Leber Hereditary Optic Neuropathy (LHON) and the variant present at homoplasmy. This case was reported as part of a cohort study so limited clinical information was provided (PMID: 35892476). The second proband reported was part of a large family with several family members with LHON. The variant was homoplasmic in blood in 18 affected and 40 unaffected maternal family members (PMID: 38582886). There are no de novo occurrences of this variant to our knowledge. There are several occurrences in population databases (one occurrence in MITOMAP GenBank sequences, two homoplasmic occurrences in gnomAD v3.1.2, two homoplasmic occurrences in the Helix dataset), however the frequency is still low (PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (APOGEE2: 0.603, APOGEE1: 0.63; PP3). Cybrid studies were performed but not significantly different from controls (PMID: 38582886). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS4_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414773403/MONDO:0044970/015 2025-02-04 2025-05-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:38562 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0027765 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0152027 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011609 infores:hetionet CHEBI:6904 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018794 infores:hetionet CAID:CA16020897 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020897 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 The frameshift variant NM_000277.3(PAH):c.919del (p.Gly307AlafsTer34) occurs in exon 9 of 13 and is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One patient has been reported (PMID: 23430918) with this variant. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020897/MONDO:0009861/006 2020-12-08 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63791 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020625 infores:hetionet CHEBI:8764 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0001127 infores:hetionet CAID:CA5950542 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950542 MONDO:0000573 PMID: Pathogenic PP1, PP4, PS3_Moderate, PM2_Supporting, PM3_Strong, PM1_Supporting BS2, PM5 The c.685C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Arginine by Tryptophan at amino acid 229 (p.Arg229Trp).The filtering allele frequency (the upper threshold of the 95% CI of (11/1180024 alleles) is 0.000005000 in gnomad v4 for the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous has been described.This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 10.5% (SEM 0.5), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).The variant has been reported to segregate in two affected family members (Proband + 1) (PP1); (Proband 30a and 30b, PMID: 11133745).At least 9 probands were reported in the literature carrying this variant. 8 of them were homozygous, reaching the maximum of 1 point for homozygous occurrence. Also, 1 proband is compound heterozygous for paternal Arg229Trp and maternal Gly95Arg, which is likely pathogenic according to SCID VCEP specifications, as phase is confirmed; 1 point—a total of 2 points, PM3_Strong.Proband 24 presents: *Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + *T-B-NK+ lymphocyte subset profile 0.5pts; total 1pt, PP4 is met (PMID: 11133745).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Supporting, PS3_Moderate, PP1, PM3_Strong, and PP4 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950542/MONDO:0000573/124 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8404 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0233485 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0030312 infores:hetionet CHEBI:82960 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0001175 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003123 infores:hetionet CHEBI:9448 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0004093 infores:hetionet CHEBI:7565 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0030554 infores:hetionet CAID:CA249117 biolink:causes MONDO:0021060 infores:clingen CAID:CA249117 MONDO:0021060 PMID: Likely Benign BP3, BP4, BP7 PM2, PP3, PM4, PM3, BA1, PS4, BS1 The NM_006767.4:c.651+10_651+46del variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The c.651+10_651+46del variant is predicted to cause an in-frame deletion of 37 nucleotides in an intronic repetitive region of no known function, as determined by the ClinGen RASopathy VCEP (BP3). In summary, this variant meets the criteria to be classified as likely benign for RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP3, BP4, BP7. (ClinGen RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA249117/MONDO:0021060/094 2024-09-17 2024-11-04 Undetermined mode of inheritance Contradicts true CHEBI:16796 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C1384353 infores:hetionet CAID:CA915940608 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940608 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.1986dup (p.Asp663Ter) found in a homozygous proband (PMID: 29084015; PM3_supporting) causes a premature stop codon at exon 12 and is predicted to undergo nonsense mediated decay (PVS1). The affected individual displayed abnormal bleeding and an impaired response to agonists, with a normal response to ristocetin, which is characteristic of GT. Additionally, αIIbβ3 surface expression was absent (<25%), as measured by flow cytometry (PP4_strong). The variant was not found in gnomAD v2.1.1 (PM2_supporting). In summary the criteria PSV1, PP4_strong, PM2_supporting, and PM3_supporting, were applied to reach a classification of pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940608/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA10585693 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585693 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP3, PP4 BA1, BP4, BP3, BP2, PS1, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1951G>T (p.Asp651Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3: Level 1 assays: PMID 32937241: Heterologous cells (CHO) - results - 53% LDLR expression, 50% binding, and 80% uptake. Expression and binding are below 70% of wild-type, so functional study is consistent with damaging effect. PS3 is met.PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3: REVEL = 0.933. It is above 0.75, so PP3 is met. PP4: Variant meet PM2. PMID: 16389549 (Humphries et al., 2005) - 1 case who fulfills Simon-Broome criteria for FH. So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585693/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:49662 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0009319 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0086543 infores:hetionet CHEBI:6444 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0011603 infores:hetionet GO:1904103 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1904103 GO:0009790 CHEBI:8890 biolink:causes UMLS:C0235839 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235839 infores:hetionet CHEBI:3387 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0003862 infores:hetionet CHEBI:28593 biolink:causes HP:0001133 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0235095 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1868752 infores:hetionet CHEBI:31644 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0030794 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027932 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0029456 infores:hetionet CHEBI:178699 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0004610 infores:hetionet CAID:CA229443 biolink:causes MONDO:0009861 infores:clingen CAID:CA229443 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM3, PP3, PS3_Supporting The c.155T>C (p.Leu52Ser) variant in PAH is reported in 2 patients with PAH deficiency, detected with pathogenic variants: Exon 5_6 deletion and p.R243Q (BH4 deficiency excluded, PMID: 15319459, 30050108). PAH activity in COS cells was 27% (PMID: 9860305). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PM2, PM3, PS3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229443/MONDO:0009861/006 2022-03-05 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28001 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0026946 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0031117 infores:hetionet CHEBI:45863 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0948008 infores:hetionet CHEBI:41879 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C2047937 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0917799 infores:hetionet CAID:CA10585429 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585429 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4, PP1 PS3, PM5 The NM_000527.5 (LDLR):c.1367T>A (p.Leu456His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PP1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: Variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.856.PP4: Variant meets PM2 and is identified in 1 index case who fulfills criteria for FH after alternative causes of high cholesterol were excluded (PMID 16542394, Brusgaard et al., 2006, Denmark).PP1: Variant segregates with FH phenotype in at least 2 informative meioses from 1 family (PMID 16542394, Brusgaard et al., 2006, Denmark): 2 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585429/MONDO:0007750/013 2023-06-23 2024-10-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:36704 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0010709 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0178298 infores:hetionet CHEBI:68584 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0575081 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033860 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0853908 infores:hetionet CHEBI:2788 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0020452 infores:hetionet CHEBI:7789 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0018524 infores:hetionet CHEBI:51860 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018790 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151752 infores:hetionet CHEBI:8871 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0025323 infores:hetionet CHEBI:46081 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0687713 infores:hetionet CHEBI:50122 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0011991 infores:hetionet CAID:CA303506 biolink:causes MONDO:0018214 infores:clingen CAID:CA303506 MONDO:0018214 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PM6, PP3_Moderate PM1, PM5 The c.1259C>T variant in SCN1A is a missense variant predicted to cause substitution of alanine by valine at amino acid 420 (p.Ala420Val). The variant has been identified as a de novo occurrence with unconfirmed parental relationships in two individuals with a consistent phenotype in the published literature (PMIDs:35696452, 26096185) (PM6_Moderate), and in one individual with seizures and intellectual disability with unknown inheritance (PMID: 22944210) (PS4_Supporting). The variant is absent from the population database, gnomAD v4.0 (PM2_Supporting). A novel missense variant at the corresponding position in the paralogous gene, SCN8A (p.Ala408Thr), has been previously reported (PMID: 26993267), however, >1 novel variant in a paralogous gene is required for PM5 (not met). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant SCN1A-related disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6_Moderate, PS4_Supporting, PM2_Supporting, PP3_Moderate. (version 1.0; July 23, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA303506/MONDO:0018214/067 2024-07-30 2025-10-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9907 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0029882 infores:hetionet CHEBI:6640 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0014868 infores:hetionet CHEBI:9927 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0085932 infores:hetionet CHEBI:85078 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0546884 infores:hetionet CHEBI:3077 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0016242 infores:hetionet UMLS:C0004609 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151836 infores:hetionet CHEBI:8888 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037672 infores:hetionet CHEBI:7773 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0007222 infores:hetionet CHEBI:63581 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0028643 infores:hetionet CHEBI:3568 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0041657 infores:hetionet CHEBI:6904 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0015230 infores:hetionet NCBIGene:51317 biolink:causes MONDO:0032883 infores:monarchinitiative not_provided not_provided HGNC:24156 MONDO:0032883 uuid:e27e37e2-f2fe-43b9-8cb3-026946c98b75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0152032 infores:hetionet CHEBI:4514 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0235031 infores:hetionet CHEBI:5441 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020433 infores:hetionet CHEBI:119915 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013144 infores:hetionet CHEBI:3699 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0009676 infores:hetionet CHEBI:17347 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0392525 infores:hetionet CHEBI:40009 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0029408 infores:hetionet CHEBI:8232 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0027947 infores:hetionet CHEBI:4877 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0027947 infores:hetionet CAID:CA838788768 biolink:causes MONDO:0015967 infores:clingen CAID:CA838788768 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PVS1, PP4, PM2_Supporting The c.1340_1368del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 2 novel amino acids before encountering a stop codon (p.(Arg447LeufsTer2)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID 19790256) This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 16 unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia with 8 informative meioses in one family with MODY (PP1_Strong; internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA838788768/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Supports CHEBI:6402 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013595 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0030446 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020651 infores:hetionet CHEBI:5775 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0948594 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234930 infores:hetionet CHEBI:6888 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0019572 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020538 infores:hetionet CAID:CA023969 biolink:causes MONDO:0007783 infores:clingen CAID:CA023969 MONDO:0007783 PMID: Uncertain Significance BP4 PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 4041 of the RYR1 protein, p.(Arg4041Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000026, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual without a clear personal or family history of an MH episode, the individual had a positive in vitro contracture test (IVCT) result, this does not meet PS4 (PMID:16835904). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.435) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023969/MONDO:0007783/012 2021-05-27 2021-05-27 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:30659 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0022107 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151826 infores:hetionet CHEBI:50663 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0231528 infores:hetionet CHEBI:10125 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151205 infores:hetionet CHEBI:45863 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027424 infores:hetionet CHEBI:3568 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018808 infores:hetionet CHEBI:4469 biolink:causes MONDO:0002420 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0040188 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0022408 infores:hetionet CHEBI:35677 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C2830004 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019345 infores:hetionet CHEBI:9566 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0030312 infores:hetionet CAID:CA248706 biolink:causes MONDO:0044970 infores:clingen CAID:CA248706 MONDO:0044970 PMID: Benign BS2, BA1 The c.3428 A>G (p.E1143G) variant in POLG has been reported 2.881 % in gnomAD (BA1). It is also seen in the homozygous state in 175 individuals in gnomAD and 65 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA248706/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA042515 biolink:causes MONDO:0007750 infores:clingen CAID:CA042515 MONDO:0007750 PMID: Uncertain Significance PS3_Moderate, PP3 BA1, BP4, BP3, BP2, PS1, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, BS2, PP4, PP1 The NM_000527.5(LDLR):c.226G>C (p.Gly76Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS3_Moderate and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Moderate: Level 2 assays: PMID 34970301: Heterologous cells (HEK-293), WB and CLSM assays- result: 63% uptake. Result it below 70% of wild-type, so PS3_Moderate is met.PP3: REVEL=0.83. It is above 0.75. So, PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042515/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:49668 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0011991 infores:hetionet NCBIGene:29998 biolink:causes MONDO:0025699 infores:monarchinitiative not_provided not_provided HGNC:4332 MONDO:0025699 uuid:31c461dd-5020-4d54-97cc-564acbde6ca3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0072106 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0060993 CHEBI:8874 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037822 infores:hetionet CHEBI:6950 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002962 infores:hetionet CHEBI:119573 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0042963 infores:hetionet CHEBI:46557 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0349790 infores:hetionet CHEBI:63581 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0009763 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0021053 infores:hetionet CHEBI:7852 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0010520 infores:hetionet NCBIGene:9187 biolink:causes MONDO:0013450 infores:monarchinitiative not_provided not_provided HGNC:10975 MONDO:0013450 uuid:63d0cb0d-5876-422c-8ae8-b277b70d93a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16335 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0234215 infores:hetionet CHEBI:567361 biolink:causes HP:0002273 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0270790 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0948089 infores:hetionet CHEBI:110423 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0017178 infores:hetionet CHEBI:5441 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0151746 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006325 infores:hetionet CHEBI:55346 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0023518 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0031350 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0037195 infores:hetionet CHEBI:8499 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C2830004 infores:hetionet CHEBI:135679 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0043352 infores:hetionet CHEBI:94440 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0233414 infores:hetionet CHEBI:70718 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0238106 infores:hetionet CHEBI:41879 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0240735 infores:hetionet CHEBI:63627 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0687713 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013395 infores:hetionet CHEBI:31199 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0271738 infores:hetionet CHEBI:5103 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0030252 infores:hetionet CHEBI:36791 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0231530 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0010709 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0233494 infores:hetionet CHEBI:8884 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0007222 infores:hetionet CHEBI:101278 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0002994 infores:hetionet CHEBI:41879 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0262431 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235756 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235756 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0027651 infores:hetionet CHEBI:3478 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013390 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0162281 infores:hetionet CAID:CA308128959 biolink:causes MONDO:0018493 infores:clingen CAID:CA308128959 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with proline at codon 3217 of the RYR1 protein, p.(Ser3217Pro). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual also had a second variant of uncertain significance in RYR1 (p.Arg367Leu) and was not counted for PS4 (PMID:19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308128959/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:2675 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C1443060 infores:hetionet CHEBI:8869 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0002962 infores:hetionet CHEBI:17347 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0013378 infores:hetionet GO:0008283 biolink:causes MONDO:0004967 infores:drugmechdb knowledge_assertion manual_agent GO:0008283 MESH:D054198 DB00059_MESH_D054198_1 CHEBI:47381 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022081 infores:hetionet CHEBI:100246 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0152227 infores:hetionet CHEBI:93305 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0015230 infores:hetionet CHEBI:41423 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C2242737 infores:hetionet CAID:CA645293837 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293837 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, BP4, PS1 PP3, BA1, BS1 The BMPR2 c.1277-9A>C variant is a non-canonical splice site (-9) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with PAH (PMID: 19555857). In silico prediction (SpliceAI) indicates no impact on splicing (BP4). However, the variant is located in the same splice region as previously established pathogenic variants, NM_001204.7(BMPR2) c.1277-8A>G and c.1277-9A>G, classified by the PH VCEP (PS1). No familial segregation data were available, and no functional analysis has been reported for this variant. In summary, the variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1, PM2_supporting, BP4 (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293837/MONDO:0015924/125 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:815 biolink:causes MONDO:0030919 infores:monarchinitiative not_provided not_provided HGNC:1460 MONDO:0030919 uuid:60204bc5-9cfc-4021-99b8-2b29c61b027c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0234518 infores:hetionet CHEBI:119486 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0003578 infores:hetionet CHEBI:5383 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0086525 infores:hetionet CHEBI:36795 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0015672 infores:hetionet CHEBI:6950 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0014724 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0017601 infores:hetionet CHEBI:64355 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0005778 infores:hetionet GO:0140646 biolink:causes GO:0030097 infores:ubergraph knowledge_assertion manual_agent GO:0140646 GO:0030097 CHEBI:681569 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0237849 infores:hetionet CHEBI:2673 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C1306341 infores:hetionet CHEBI:63610 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0000768 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0037274 infores:hetionet CHEBI:6801 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0027947 infores:hetionet CHEBI:10023 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027796 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0239211 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0239211 infores:hetionet CHEBI:8890 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0428977 infores:hetionet CHEBI:50663 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0035243 infores:hetionet CHEBI:6822 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0349506 infores:hetionet CHEBI:17141 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0085633 infores:hetionet CHEBI:31709 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0002994 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040435 infores:hetionet CHEBI:64321 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0038325 infores:hetionet CHEBI:17347 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0240671 infores:hetionet CAID:CA120552 biolink:causes MONDO:0044970 infores:clingen CAID:CA120552 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate PS2, PS3, PM6 The m.616T>C variant in MT-TF has been reported in at least 12 individuals from six families with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life with delays or seizures at 10 months old to late teenage years with renal disease or epilepsy). Several individuals had chronic kidney disease or renal failure; some even had transplants with non-recurrence of disease post-transplant. Other symptoms reported include developmental delay, epilepsy, status epilepticus (EPC), and myoclonus. Muscle biopsy revealed COX negative fibers. Heteroplasmy levels were the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Of note, some healthy family members had the variant at lower heteroplasmy levels but in at least one healthy family member, the variant was present at a heteroplasmy level as high as 92% (PS4_moderate; PMIDs: 31722346, 28267784, 20142618). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower or undetectable levels of the variant (PP1_moderate; PMIDs: 31722346, 28267784, 20142618). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There is one cybrid study for this variant however the cybrid also had another mtDNA variant precluding scoring for PS3. There are no single fiber studies or other functional assays reported for this variant. The computational predictor MitoTIP suggests this variant is pathogenic (83.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120552/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:135342 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0018524 infores:hetionet CHEBI:8805 biolink:causes HP:0001325 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0020617 infores:hetionet CHEBI:16755 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0232849 infores:hetionet CHEBI:6076 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0003811 infores:hetionet CHEBI:8428 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0011570 infores:hetionet CHEBI:28787 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C2830004 infores:hetionet NCBIGene:6340 biolink:causes MONDO:0859318 infores:monarchinitiative not_provided not_provided HGNC:10602 MONDO:0859318 uuid:e78a1f79-d39e-4b31-b41b-8c5df8d3877c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0036572 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0006325 infores:hetionet CHEBI:142290 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0002962 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0232492 infores:hetionet CHEBI:32315 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011206 infores:hetionet CHEBI:29007 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0002878 infores:hetionet CHEBI:7573 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C3665347 infores:hetionet CHEBI:3242 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0015967 infores:hetionet NCBIGene:49 biolink:causes MONDO:0957594 infores:monarchinitiative not_provided not_provided HGNC:126 MONDO:0957594 uuid:fca01ab7-7b7d-4f5a-ad38-4dddd920c559 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83531 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0013362 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0031350 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0038814 infores:hetionet CHEBI:63621 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0036973 infores:hetionet CHEBI:6904 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0004245 infores:hetionet CAID:CA389474839 biolink:causes MONDO:0100040 infores:clingen CAID:CA389474839 MONDO:0100040 PMID: Uncertain Significance PM2_Supporting, BP4 PP4 The p.Leu104Phe variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.057, which is below the threshold of 0.29, evidence that p.Leu104Phe does not predict a damaging effect on FOXG1 function (BP4). The p.Leu104Phe variant in FOXG1 has been observed in an affected individual, however, the clinical phenotype was not specific enough to meet PP4 criteria (GeneDx Internal Database) (PP4_not met). The p.Leu104Phe variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Leu104Phe variant in FOXG1 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, BP4). (FOXG1 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389474839/MONDO:0100040/035 2025-05-07 2025-06-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4708 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042029 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0031046 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0032300 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032300 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0027813 infores:hetionet NCBIGene:9365 biolink:causes MONDO:0060715 infores:monarchinitiative not_provided not_provided HGNC:6344 MONDO:0060715 uuid:e27688df-8120-439e-9780-9b2cc3261ac5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0037268 infores:hetionet NCBIGene:53904 biolink:causes MONDO:0958232 infores:monarchinitiative not_provided not_provided HGNC:7601 MONDO:0958232 uuid:812d735d-52b2-4a42-ae41-205603ecdcb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0242429 infores:hetionet CAID:CA10385291 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385291 MONDO:0100437 PMID: Benign BS2, BP4, BA1 NM_001034853.2(RPGR):c.2341G>A (p.Ala781Thr) is a missense variant encoding the substitution of alanine with threonine at amino acid 781. This variant is present in gnomAD v.4.1.0 at a frequency of 0.1538 among hemizygous individuals, with 54,741 variant alleles / 356,024 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been identified in 13 healthy individuals meeting the BS2 requirement of no electroretinogram defects by the age of 30 years (PMIDs: 12657579, 18552978, 18552978, 32679846, BS2). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BS2, and BP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385291/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:2676 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0151596 infores:hetionet NCBIGene:64065 biolink:causes MONDO:0030941 infores:monarchinitiative not_provided not_provided HGNC:17637 MONDO:0030941 uuid:23cb20fb-43f6-4ded-93a4-ab06521c2a91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51032 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0041912 infores:hetionet NCBIGene:22954 biolink:causes MONDO:0009683 infores:monarchinitiative not_provided not_provided HGNC:16380 MONDO:0009683 uuid:924139be-872f-4ffa-8352-afb4e94977df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3757 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0013404 infores:hetionet CHEBI:48844 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0018524 infores:hetionet CHEBI:144551 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0027497 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0521495 infores:hetionet CHEBI:85083 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0004604 infores:hetionet CHEBI:8768 biolink:causes HP:0032024 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0520564 infores:hetionet CAID:CA013375 biolink:causes MONDO:0005045 infores:clingen CAID:CA013375 MONDO:0005045 PMID: Likely Pathogenic PM2, PP3, PS4_Moderate, PP1_Moderate PP4, BS2, PM3, BA1, PM5, PM4, PM1, PS3, PM6, BP3, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP5, BP2, PVS1 The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013375/MONDO:0005045/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports UNII:G4PX8C4HKV biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0019112 infores:hetionet CHEBI:5847 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0010200 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151767 infores:hetionet CAID:CA024901 biolink:causes MONDO:0018493 infores:clingen CAID:CA024901 MONDO:0018493 PMID: Uncertain Significance PS4_Moderate, PP3_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with aspartic acid at codon 2733 of the RYR1 protein, p.(Gly2733Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:15731587, PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.923) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024901/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3077 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0518015 infores:hetionet CHEBI:10102 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0008031 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0042109 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0205204 infores:hetionet NCBIGene:3720 biolink:causes MONDO:0859306 infores:monarchinitiative not_provided not_provided HGNC:6196 MONDO:0859306 uuid:f3995f68-6179-4961-a4c5-836b6a771bc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386964227 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964227 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM5_Strong, PM1, PP4_Moderate, PP3 The c.607C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 203 (p.(Arg203Ser)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.607C>T (p.Arg203Cys) and c.608G>A (p.Arg203His),have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg203Ser has a greater Grantham distance than p.Arg203His (PM5_Strong). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.876, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.607C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1, PM2_Supporting, PP3, PM5_Strong, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964227/MONDO:0015967/017 2022-04-11 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CAID:CA120536 biolink:causes MONDO:0044970 infores:clingen CAID:CA120536 MONDO:0044970 PMID:9450773 Uncertain Significance PP3, PM2_Supporting, PM6_Supporting, PS3_Supporting PP1, PS4 The m.1606G>A variant in MT-TV has been reported in two affected individuals in two families (PMIDs: 9450773, 2056939), however haplogroups were not provided as necessary to apply PS4_supporting. These two individuals had strikingly similar courses, as both were males who were relatively healthy until their 20s/30s when they developed progressive cognitive impairment. Other features seen in both men include bilateral cataracts, bilateral SNHL, imbalance/ataxia, and basal ganglia classifications, with both men harboring the variant at 67-70% heteroplasmy. This variant occurred de novo in one individual (absent in blood and urine from mother and brother; PM6_supporting, PMID: 12056939). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at <10% in muscle, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (85%) than in COX positive fibers (57%), p<0.0001 (PS3_supporting, PMID: 9450773). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 73.6%, as does HmtVar with a score of 0.9 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120536/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:37333 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0039070 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004596 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034072 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006444 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0015734 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0152029 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0018799 infores:hetionet NCBIGene:55120 biolink:causes MONDO:0013566 infores:monarchinitiative not_provided not_provided HGNC:20748 MONDO:0013566 uuid:3c2803d6-1f0e-4670-8a28-671aafea954c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020870 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020870 MONDO:0009861 PMID:21147011PMID:21147011 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PAH-specific ACMG/AMP criteria applied: PP3: HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4_Moderate: IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP. (PMID:21147011); PM3: Detected in trans with A300S, pathogenic in ClinVar (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM2, PP4_Moderate, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020870/MONDO:0009861/006 2018-08-12 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6775 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1384353 infores:hetionet CHEBI:45081 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0033774 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020615 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0342579 infores:hetionet CHEBI:10650 biolink:causes UMLS:C2750515 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2750515 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0002871 infores:hetionet CHEBI:3219 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040822 infores:hetionet CHEBI:6128 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0025290 infores:hetionet CHEBI:94848 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0011991 infores:hetionet CHEBI:63629 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0035317 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030920 infores:hetionet CAID:CA410206682 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206682 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS4, PS1, PS3, PS2, BP3, BP2, BP1, BP4, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.791A>G (p.Gln264Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206682/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9939 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0042373 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003864 infores:hetionet CHEBI:31236 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085624 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0542203 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0854303 infores:hetionet CHEBI:4708 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0028961 infores:hetionet CHEBI:6690 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0014457 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0042267 infores:hetionet CHEBI:101085 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C1306571 infores:hetionet CHEBI:3752 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0042023 infores:hetionet NCBIGene:4841 biolink:causes MONDO:0010501 infores:monarchinitiative not_provided not_provided HGNC:7871 MONDO:0010501 uuid:84c9eeca-52a5-41be-9fa2-a149ec954175 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2161 biolink:causes MONDO:0012526 infores:monarchinitiative not_provided not_provided HGNC:3530 MONDO:0012526 uuid:f13b2d2b-5187-413e-872b-c10539bac01d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0086769 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0234458 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0948594 infores:hetionet NCBIGene:5831 biolink:causes MONDO:0013051 infores:monarchinitiative not_provided not_provided HGNC:9721 MONDO:0013051 uuid:04a559d0-a679-4c45-9e27-47845b9a998a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0021177 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042018 infores:hetionet CHEBI:119486 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020443 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0424605 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0243026 infores:hetionet CHEBI:135888 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C1325847 infores:hetionet CHEBI:3011 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0018681 infores:hetionet CHEBI:9123 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0231218 infores:hetionet CHEBI:127342 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0233514 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0025160 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0029445 infores:hetionet CHEBI:63845 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0001824 infores:hetionet CHEBI:2637 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0235032 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005452 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C2267227 infores:hetionet CHEBI:10650 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015672 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013595 infores:hetionet CHEBI:8764 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0231528 infores:hetionet CHEBI:3077 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0338831 infores:hetionet CHEBI:8884 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0340865 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0233632 infores:hetionet CHEBI:42355 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0687713 infores:hetionet CHEBI:31711 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0020453 infores:hetionet CHEBI:71219 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0236075 infores:hetionet CHEBI:367163 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0038325 infores:hetionet CHEBI:9434 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0010200 infores:hetionet CHEBI:3223 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0005758 infores:hetionet CHEBI:9588 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0040264 infores:hetionet CHEBI:10023 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0080274 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0032285 infores:hetionet NCBIGene:64121 biolink:causes MONDO:0957960 infores:monarchinitiative not_provided not_provided HGNC:19902 MONDO:0957960 uuid:fb3d1f01-1544-4700-b4b0-195980c05f08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0002453 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0234894 infores:hetionet CHEBI:50648 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2830004 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0426576 infores:hetionet CHEBI:135939 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0014457 infores:hetionet CAID:CA2259833 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259833 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.124G>A (p.Ala42Thr) variant in the RAF1 gene is 0.026% (25/66738) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259833/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:49960 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0403632 infores:hetionet CHEBI:16469 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0021368 infores:hetionet CHEBI:7445 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0017152 infores:hetionet CHEBI:7931 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0231218 infores:hetionet CHEBI:136040 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0039231 infores:hetionet CAID:CA023886 biolink:causes MONDO:0007783 infores:clingen CAID:CA023886 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 3707 of the RYR1 protein, p.(Arg3707Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual described as having malignant hyperthermia (MH) without clear details on personal or family history of an MH episode or in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results (PMID:16917943). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.906) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023886/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:167309 biolink:causes UMLS:C1167785 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C1167785 infores:hetionet CHEBI:135342 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0917801 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0235234 infores:hetionet CHEBI:7798 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0015967 infores:hetionet HP:0031377 biolink:causes MONDO:0005586 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D006258 DB01005_MESH_D006258_1 CHEBI:75984 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018965 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0948594 infores:hetionet CHEBI:71940 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0002994 infores:hetionet CAID:CA16020786 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020786 MONDO:0009861 PMID:23932990PMID:26503515PMID:19915519 Pathogenic PVS1, PM2, PP4_Moderate, PM3_Supporting This c.441+2T>A (aka IVS4+2T>A) variant in PAH has been observed in at least two patients with PAH deficiency (PMID: 26503515, 23932990, and 19915519). The variant was observed with pathogenic variant p.Y356X; phase unknown. This variant is absent from controls in population databases. This variant in the +2 splice donor site of intron 4 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay. This variant breaks the splice site in intron 4 according to computational models. In summary, this variant meets criteria to be classified as pathogenic in PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting and PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020786/MONDO:0009861/006 2020-10-23 2020-10-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7915 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014848 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0040034 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0086543 infores:hetionet CHEBI:3175 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0030232 infores:hetionet CHEBI:4315 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0002453 infores:hetionet CHEBI:4717 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0027849 infores:hetionet CHEBI:8871 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026858 infores:hetionet CHEBI:4325 biolink:causes MONDO:0016474 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0263591 infores:hetionet CHEBI:8768 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0026826 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0851341 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0340726 infores:hetionet CHEBI:28864 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0858635 infores:hetionet CAID:CA287435425 biolink:causes MONDO:0008723 infores:clingen CAID:CA287435425 MONDO:0008723 PMID:27209629 Uncertain Significance PM2_Supporting, PP3, PP4, PM3_Supporting PM1, PM5, PS1 The c.439C>T (p.Pro147Ser) variant in ACADVL is a missense in exon 6. This variant has been reported once in the literature in a proband with very-long chain acyl-CoA dehydrogenase deficiency, and elevated C14:1 in NBS (PP4, PMID27209629). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.88, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). However, there is insufficient experimental or case data identified in the literature for this variant and is therefore classified as a VUS. (ACADVL-specific ACMG/AMP criteria applied: PP4; PM2_supporting; PP3). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287435425/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:16469 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0162566 infores:hetionet UNII:UMD7G2653W biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0021368 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0019158 infores:hetionet UMLS:C0010592 biolink:causes HP:0003146 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151718 infores:hetionet CAID:CA16020726 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020726 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The c.75del (p.Ile25MetfsTer13) variant in PAH results in a frameshift in exon 2, with NMD predicted. It was reported in a Chinese patient with hyperphenylalaninemia, with pathogenic variant p.Gln419Arg (PMID: 25456745). It is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2_supporting, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020726/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135888 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0000737 infores:hetionet CHEBI:75998 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0011175 infores:hetionet CAID:CA386304179 biolink:causes MONDO:0009861 infores:clingen CAID:CA386304179 MONDO:0009861 PMID:28982351PMID:29499199 Likely Pathogenic PM3, PP4_Moderate, PM2 PM5, PP3 This c.223G>C (p.Asp75His) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 29499199, 28982351) detected with the pathogenic variant p.Val399= (PMID: 28982351). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 29499199). This variant is absent in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386304179/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27504 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0030193 infores:hetionet CHEBI:82981 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0006266 infores:hetionet CHEBI:41774 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151691 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0040479 infores:hetionet CHEBI:194135 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151610 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006852 infores:hetionet CHEBI:50122 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0038325 infores:hetionet CHEBI:17141 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C1306341 infores:hetionet CHEBI:4670 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0027497 infores:hetionet NCBIGene:57545 biolink:causes MONDO:0030859 infores:monarchinitiative not_provided not_provided HGNC:29253 MONDO:0030859 uuid:ad78a7f4-b494-42b1-bfb3-b93cc0577a58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70707 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C1443060 infores:hetionet CHEBI:94686 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0030252 infores:hetionet UNII:0RK7M7IABE biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0332575 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085692 infores:hetionet CHEBI:63608 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0702166 infores:hetionet CHEBI:16469 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013378 infores:hetionet CHEBI:4717 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0036973 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0919643 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0919643 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0877401 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0877401 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0426959 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0426959 infores:hetionet CHEBI:127780 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0036508 infores:hetionet UNII:5V9KLZ54CY biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0854467 infores:hetionet UNII:D27V6190PM biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C2830004 infores:hetionet CAID:CA134647 biolink:causes MONDO:0021060 infores:clingen CAID:CA134647 MONDO:0021060 PMID:15987685 Likely Benign BP5, BS3 The c.1678C>T (p.Leu560Phe) variant in PTPN11 (NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)) has been identified in individuals with some features of a RASopathy but none were diagnosed with a RASopathy (PS4 not met; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data; GTR ID's: 28338, 26957, 21766; SCV000061285.5; SCV000208999.2; SCV000207690.1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data: GTR ID: 26957; SCV000208999.2). In vitro functional studies provide some evidence that the p.Leu560Phe variant does not impact protein function (BS3; PMID: 15987685). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied: BS3, BP5 (Version 2.1; 09/17/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134647/MONDO:0021060/043 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50223 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0009782 infores:hetionet CHEBI:38940 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0008031 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0497365 infores:hetionet CHEBI:50922 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151825 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0853761 infores:hetionet CHEBI:6128 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0014591 infores:hetionet CHEBI:473990 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0162429 infores:hetionet CHEBI:45979 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C1443060 infores:hetionet CAID:CA377482264 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482264 MONDO:0017623 PMID: Uncertain Significance PP2, PP3, PS3_Moderate, PM2_Supporting BS1, BS3, PM5, PM1, BA1, PS1, PS4 NM_000314.8(PTEN):c.359C>A (p.Ala120Glu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.09 (<= -1.11) on a high throughput phosphatase assay (PMID:29706350).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.901).PM2_P: Absent in gnomAD. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482264/MONDO:0017623/003 2024-04-05 2024-04-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6887 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0004604 infores:hetionet CHEBI:8871 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006625 infores:hetionet NCBIGene:400916 biolink:causes MONDO:0014025 infores:monarchinitiative not_provided not_provided HGNC:15559 MONDO:0014025 uuid:91136ca0-4368-4d9f-bec7-b1e9b3d1968e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011603 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0038362 infores:hetionet CHEBI:5128 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0232462 infores:hetionet CAID:CA16020980 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020980 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3_Supporting, PM5_Supporting The c.1246C>A (p.Pro416Thr) variant in PAH has been reported in 1 patient with mild non-PKU HPA with Phe = 246-420umol/L (BH4 deficiency not excluded) (PP4; PMID: 9380432). It has been reported in unknown phase with the pathogenic p.R408Q variant (ClinVar ID: 577) (PM3_Supporting). This variant is absent from the population database gnomAD v2.1.1. (PM2_Supporting). This variant is predicted to be deleterious by REVEL (score 0.965) (PP3_Strong). A different missense variant at the same site, p.Pro416Gln, has been classified as likely pathogenic in ClinVar by the PAH VCEP (ID: 558091, PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3_Supporting, PP3_Strong, PP4, PM5_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020980/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:567361 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004604 infores:hetionet CHEBI:6715 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1291077 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151734 infores:hetionet CHEBI:135622 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06771 UMLS:C0344232 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0031542 infores:hetionet CHEBI:27974 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0404521 infores:hetionet NCBIGene:6608 biolink:causes MONDO:0009436 infores:monarchinitiative not_provided not_provided HGNC:11119 MONDO:0009436 uuid:2fccd8ba-af0e-4d56-9858-baa447e14bca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020615 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0178298 infores:hetionet CHEBI:31236 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019521 infores:hetionet CHEBI:5864 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0009763 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0476414 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0476414 infores:hetionet CHEBI:9674 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0017675 infores:hetionet CHEBI:31236 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0005758 infores:hetionet CHEBI:9566 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0009806 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C127841 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0476427 infores:hetionet CHEBI:6149 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0746961 infores:hetionet CHEBI:94440 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0000737 infores:hetionet CHEBI:5790 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0030196 infores:hetionet CAID:CA409104377 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104377 MONDO:0015967 PMID: Likely Pathogenic PP3, PM2_Supporting, PM1_Supporting, PP1_Strong The c.304G>A p.(Gly102Ser) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the DNA binding domain of NM_175914.5 which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with at least 5 informative meiosis in 1 family with MODY (PP1_Strong, PMID: 10227563). This variant is predicted to be deleterious by computational evidence, with a REVEL score or 0.989, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.304G>A p.(Gly102Ser) meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PM1_Supporting, PM2_Supporting, PP1_Strong, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104377/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:104011 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0016382 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1321686 infores:hetionet CHEBI:45081 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0030193 infores:hetionet CAID:CA5689680 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689680 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.894A>C (p.Ala298=) variant in the SHOC2 gene is 0.054% (9/8648) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689680/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:3467 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0003862 infores:hetionet NCBIGene:745 biolink:causes MONDO:0010836 infores:monarchinitiative not_provided not_provided HGNC:1181 MONDO:0010836 uuid:5df0935b-a73a-41e8-b25d-c7bdba97fb51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35854 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0021051 infores:hetionet NCBITaxon:38323 biolink:causes MONDO:0005692 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:38323 MONDO:0005692 CHEBI:82960 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0033774 infores:hetionet CHEBI:9907 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013182 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0086543 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0595877 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0271899 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0271899 infores:hetionet CHEBI:31348 biolink:causes EFO:1001771 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013608 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0151767 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0403632 infores:hetionet CAID:CA414919140 biolink:causes MONDO:0010602 infores:clingen CAID:CA414919140 MONDO:0010602 PMID: Pathogenic PVS1, PS2_Moderate, PM2_Supporting, PS4_Supporting PM1, PS1 The NM_000132.3:c.686C>A variant predicts a nonsense change, Ser229Ter, in exon 6 of the F8 gene and the resulting transcript is predicted to undergo NMD, which meets PVS1 criteria. The variant is absent from gnomAD v2.1.1 and v3, which meets PM2_Suppporting. It is not reported in male patients with hemophilia A in the literature; however, another nucleotide change that results in the same nonsense variant is reported in two patients (PMID: 18217193, 22958177). At least one male with severe hemophilia A was found to be de novo for the variant, without confirmation of maternity, from internal laboratory data, which meets the PS2_Moderate and PS4_Supporting criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency variant curation expert panel: PVS1, PS2_Moderate, PS4_Supporting, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414919140/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C1739363 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0037199 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0015967 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0019372 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003873 infores:hetionet CHEBI:9674 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0033774 infores:hetionet CHEBI:15552 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0035455 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022660 infores:hetionet NCBIGene:7068 biolink:causes MONDO:0010131 infores:monarchinitiative not_provided not_provided HGNC:11799 MONDO:0010131 uuid:cd217f9a-9fd4-46b9-ba39-86878adb3bda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28001 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0009806 infores:hetionet CHEBI:3732 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085593 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0032285 infores:hetionet CHEBI:49040 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0085649 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235431 infores:hetionet CHEBI:6887 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085632 infores:hetionet CHEBI:75988 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0243026 infores:hetionet CHEBI:63115 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0030252 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151883 infores:hetionet CHEBI:32315 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0009676 infores:hetionet GO:1903703 biolink:causes CL:0000584 infores:ubergraph knowledge_assertion manual_agent GO:1903703 CL:0000584 CHEBI:49040 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151662 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0025061 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0015397 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1306341 infores:hetionet CHEBI:71219 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0013378 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1608945 infores:hetionet CHEBI:3216 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0030252 infores:hetionet CHEBI:9123 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0028961 infores:hetionet CHEBI:27834 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0018681 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0541820 infores:hetionet CHEBI:2704 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C2979982 infores:hetionet CHEBI:16899 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0030193 infores:hetionet NCBITaxon:88456 biolink:causes MONDO:0005725 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:88456 MONDO:0005725 UMLS:C0903898 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0015672 infores:hetionet CAID:CA367398695 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398695 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1159G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 387 (p.(Ala387Thr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2) This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.908, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with hyperglycemia, with at least 4 meioses in four families (PP1_Strong; PMID: 36257325). One of these probands (described PMID: 14517956) has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 2-hour increment on OGTT < 3mmol/L) (PP4_Moderate). In summary, c.1159G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP1_Strong, PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398695/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:72296 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0019079 infores:hetionet CHEBI:4495 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0016382 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0152227 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235639 infores:hetionet CHEBI:9763 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0002792 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0012833 infores:hetionet CAID:CA015952 biolink:causes MONDO:0005045 infores:clingen CAID:CA015952 MONDO:0005045 PMID: Uncertain Significance BS2, PP2, PS3, BA1, PM2, PM5, PM1, PM6, PM3, PM4, PP3, PP1, BP1, BP3, BS1, BS4, BS3, BP4, BP2, BP5, BP7, PS4, PS1, PS2, PVS1 The NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr) variant has been identified in at least 14 individuals with HCM, 2 of whom had an additional variant in another gene that may contribute to their disease, 1 individual with RCM with another pathogenic MYH7 variant, and 5 individuals with DCM including 2 that also had disease-causing variants (Richard 2003 PMID:12707239; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Walsh 2017 PMID: 27532257; Ho 2018 PMID:30297972; Ambry pers. comm.; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm). This variant has also been identified in 1 individual with LVNC requiring transplant who also had 2 pathogenic MYBPC3 variants, 1 individual with Brugada syndrome, and 2 individuals with myopathy - 1 with myofibrillar myopathy and 1 with distal and axial myopathy (Hertz 2014 PMID:25467552; Evilä 2016 PMID:26627873; Chanson 2016 PMID:26969127; Liu 2020 PMID:31918855). This variant has been observed to segregate with DCM in 1 relative of a proband with DCM as well as not segregate with HCM in an affected sibling of a proband with HCM (OMGL per. comm.). Because of the variability in phenotypes observed in individuals with this variant and because PS4 is only applicable when the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Additionally, the segregation data is currently insufficient to establish segregation or non-segregation with disease and therefore neither PP1 nor BS4 were applied. This variant has been identified in 0.008% (FAF 95% CI; 17/129,190) of European chromosomes in gnomAD v.2.1.1 (http://gnomad.broadinstitute.org) and is above the threshold of 0.004%, therefore PM2 cannot be applied. Computational prediction tools and conservation do not provide evidence for or against an impact to the protein. In summary, due to conflicting evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015952/MONDO:0005045/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63598 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020453 infores:hetionet CHEBI:144551 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0152032 infores:hetionet CHEBI:6437 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0575081 infores:hetionet CHEBI:92923 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0404521 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005039 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0178829 infores:hetionet CHEBI:145499 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085932 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006840 infores:hetionet GO:1904933 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:1904933 GO:0007420 CHEBI:47519 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0002792 infores:hetionet CHEBI:5165 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0030794 infores:hetionet CHEBI:5134 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C1384353 infores:hetionet CHEBI:6538 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0027765 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0015397 infores:hetionet CHEBI:5118 biolink:causes NCIT:C78280 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0221727 infores:hetionet CHEBI:44423 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1384353 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042075 infores:hetionet CHEBI:367163 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0009782 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0025061 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0027051 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1258215 infores:hetionet CHEBI:3219 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016204 infores:hetionet CHEBI:31401 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0030920 infores:hetionet CHEBI:584020 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0008031 infores:hetionet NCBITaxon:29459 biolink:causes MONDO:0005683 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:29459 MESH:D002006 DB00759_MESH_D002006_1 CHEBI:9943 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009760 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011616 infores:hetionet NCBIGene:54968 biolink:causes MONDO:0013546 infores:monarchinitiative not_provided not_provided HGNC:26050 MONDO:0013546 uuid:bc310c39-380b-49a3-8cf4-50b481c92c10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6437 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009806 infores:hetionet CHEBI:2682 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0015967 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0023895 infores:hetionet CHEBI:31643 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0010200 infores:hetionet CHEBI:9434 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0026826 infores:hetionet CHEBI:4784 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030196 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0878544 infores:hetionet CHEBI:7444 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0701811 infores:hetionet CHEBI:68584 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0344232 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011570 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0009450 infores:hetionet CHEBI:9635 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0085633 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235283 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235283 infores:hetionet CHEBI:39112 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0086565 infores:hetionet CHEBI:6472 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0042963 infores:hetionet UMLS:C0879264 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0009676 infores:hetionet CHEBI:32588 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0031542 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004987 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005695 infores:hetionet CHEBI:8768 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0012569 infores:hetionet CHEBI:7496 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0027121 infores:hetionet NCBIGene:1756 biolink:causes MONDO:0010311 infores:monarchinitiative not_provided not_provided HGNC:2928 MONDO:0010311 uuid:c22d6264-941e-4d72-8d3a-52465661bab7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8455 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0027765 infores:hetionet NCBIGene:1729 biolink:causes MONDO:0014714 infores:monarchinitiative not_provided not_provided HGNC:2876 MONDO:0014714 uuid:acabeadc-fda9-4f52-8ba4-425e8859e271 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9927 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0002994 infores:hetionet CHEBI:46557 biolink:causes NCIT:C98911 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0877225 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018801 infores:hetionet CHEBI:100147 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0220981 infores:hetionet CHEBI:7852 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C2830004 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020651 infores:hetionet CAID:CA915940222 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940222 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PM6, PP3, PP4, PP1, PS2 The c.401del (p.Glu134GlyfsTer10) variant in exon 4 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 1 proband with Glanzmann thrombasthenia. This proband was homozygous for the variant (PMID: 3102915; PM3_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3_Supporting, PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940222/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:45409 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017160 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0033975 infores:hetionet CHEBI:10127 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0232462 infores:hetionet CHEBI:391960 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0404521 infores:hetionet CAID:CA261728 biolink:causes MONDO:0018997 infores:clingen CAID:CA261728 MONDO:0018997 PMID:21387466PMID:19352411 Pathogenic PS4_Moderate, PM1_Strong, PM2, PM6, PP2, PP3 PS3, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM3, PM4, PM5, PVS1, PP1, PP4, BS2, BA1, BP1, BP4, BP2, BP3 The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID: 21387466, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The p.Arg552 residue has been defined as a hotspot by the RAS EP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg552Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PM2, PM6, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261728/MONDO:0018997/004 2019-04-23 2024-08-23 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7488 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0020452 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042373 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0038454 infores:hetionet CHEBI:64355 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0086565 infores:hetionet CHEBI:82960 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0040822 infores:hetionet CHEBI:3698 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0035243 infores:hetionet CAID:CA2802392 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802392 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.1743C>G (p.Tyr581Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13 out of 14. While the premature stop codon is predicted to occur in the penultimate exon of the gene, it is 5' to the last 50 nucleotides of the exon and, therefore, this variant is expected to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 5 patients with this variant and a diagnosis of MPS I, confirmed by reduced IDUA activity, have been reported. This included patients with documented laboratory values indicating undetectable IDUA activity along with clinical features such as intellectual disability, dysmorphic facial features, multiple dysostosis, joint stiffness, hepatosplenomegaly, umbilical hernia, chronic rhinorrhea, and hydrocephalus (PMID: 22074387, 27196898) (PP4). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908, PMID: 3351789); the phase is unknown (0.5 points). Two Tunisian patients are homozygous for the variant (PMID: 22074387) (2 x 0.5 points). A further two patients are compound heterozygous for the variant and p.Pro533Arg (PMID: 12796790, 27196898); the allelic data from these patients will be used in the classification of p.Pro533Arg and are not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00008921 (4/44840 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802392/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2611 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0011991 infores:hetionet CHEBI:63589 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0011991 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0022568 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151664 infores:hetionet CAID:CA414801969 biolink:causes MONDO:0044970 infores:clingen CAID:CA414801969 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS2, PS3, PM2, PM6 The m.9038T>C variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 17, 2023. There are no individuals or families with this variant reported in the medical literature to our knowledge. There are several occurrences in population databases. This variant is present in 0.025% of individuals in GenBank MITOMAP sequences, in 0.012% of individuals in gnomAD v3.1.2 (homoplasmic in 22 individuals and heteroplasmic in five), and in 0.011% of individuals in the Helix dataset. The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.45 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414801969/MONDO:0044970/015 2023-04-17 2023-05-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6931 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0855775 infores:hetionet NCBIGene:219285 biolink:causes MONDO:0030805 infores:monarchinitiative not_provided not_provided HGNC:1349 MONDO:0030805 uuid:abbb3293-87d6-43a7-901b-5727e1403492 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72564 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0917798 infores:hetionet CHEBI:8707 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018926 infores:hetionet CHEBI:9434 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0040264 infores:hetionet CHEBI:7936 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042029 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0152010 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0152010 infores:hetionet UMLS:C0004609 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0026827 infores:hetionet CHEBI:5103 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0235939 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0031350 infores:hetionet CHEBI:7478 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0019080 infores:hetionet CHEBI:5893 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1318520 infores:hetionet CHEBI:38562 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0085605 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0039971 infores:hetionet CHEBI:35854 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0019348 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151779 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0018801 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0037822 infores:hetionet CHEBI:9727 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0085636 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0032584 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0034065 infores:hetionet NCBIGene:10283 biolink:causes MONDO:0009598 infores:monarchinitiative not_provided not_provided HGNC:10664 MONDO:0009598 uuid:dc8850d6-83cc-41d3-825a-bd23de33c5b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0003862 infores:hetionet CHEBI:6904 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0020615 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085584 infores:hetionet CHEBI:10119 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0017979 infores:hetionet CHEBI:499361 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1145670 infores:hetionet CHEBI:92712 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0026826 infores:hetionet CHEBI:36704 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0008031 infores:hetionet CHEBI:10101 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0522251 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0015423 infores:hetionet CHEBI:8802 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0009676 infores:hetionet CHEBI:3223 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0014457 infores:hetionet CHEBI:4469 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0004093 infores:hetionet CHEBI:5613 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0013404 infores:hetionet UBERON:0003075 biolink:causes UBERON:0002328 infores:ubergraph knowledge_assertion manual_agent UBERON:0003075 UBERON:0002328 CHEBI:31236 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234133 infores:hetionet CHEBI:9460 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0002170 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0022081 infores:hetionet CHEBI:7956 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0033774 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0038358 infores:hetionet CHEBI:6933 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0022107 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0040046 infores:hetionet GO:1901210 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1901210 GO:0007507 CHEBI:44032 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0231218 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013395 infores:hetionet CHEBI:9332 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C1320835 infores:hetionet CHEBI:10650 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0233471 infores:hetionet UMLS:C0004609 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0017181 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1112469 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1112469 infores:hetionet CHEBI:3638 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0878544 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0015967 infores:hetionet CHEBI:68558 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0008031 infores:hetionet CAID:CA119417 biolink:causes MONDO:0021060 infores:clingen CAID:CA119417 MONDO:0021060 PMID: Pathogenic PP3, PM2_Supporting, PM6_Strong, PS4, PM1, PS3_Supporting BA1, BP4, PM5, BS1 The c.400T>C variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 134 (p.Tyr134His). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.917, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 128-138). Furthermore, a different pathogenic variant at this residue (Tyr134Cys) has been identified in several patients with RASopathies (PM5). This variant has been identified in at least 6 patients with a RASopathy, of which 2 were unconfirmed de novo cases (PS4, PM6_Strong; Partners LMM, Labcorp internal data, ClinVar: SCV000063166.5, SCV002210187.3; PMID: 18042262, 18456719, 27763634). Western blot assay in Ba/F3 cells showed that the variant activated ERK signaling while the wildtype did not (PS3_Supporting, PMID: 30867592). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4, PM6_Strong, PM1, PM5, PS3_Supprting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA119417/MONDO:0021060/048 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:1296 biolink:causes MONDO:0012199 infores:monarchinitiative not_provided not_provided HGNC:2216 MONDO:0012199 uuid:f7ef6f0e-abcc-46bc-87cb-c953860daf5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0700225 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0027424 infores:hetionet CHEBI:3044 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0338614 infores:hetionet CHEBI:28901 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0017181 infores:hetionet CHEBI:119915 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0041657 infores:hetionet CHEBI:8665 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030554 infores:hetionet CHEBI:44185 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1142499 infores:hetionet CHEBI:68575 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0015230 infores:hetionet CHEBI:31348 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042029 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020437 infores:hetionet CHEBI:36795 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0021141 infores:hetionet CHEBI:45081 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0018979 infores:hetionet CHEBI:6121 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0014544 infores:hetionet CAID:CA8815358 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815358 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3 The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID: 24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompedisease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815358/MONDO:0009290/010 2024-02-11 2024-02-11 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CAID:CA287437693 biolink:causes MONDO:0008723 infores:clingen CAID:CA287437693 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1077+1G>A variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PMID: 26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287437693/MONDO:0008723/021 2022-07-12 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:39867 biolink:causes HP:0002926 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0857576 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0030196 infores:hetionet CHEBI:9123 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020578 infores:hetionet CHEBI:68579 biolink:causes HP:0031625 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C1510412 infores:hetionet CHEBI:3441 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0043144 infores:hetionet CHEBI:39867 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0043352 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1565489 infores:hetionet CHEBI:9727 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0040034 infores:hetionet CAID:CA8337548 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337548 MONDO:0008723 PMID: Likely Benign PM2_Supporting, BP4, BP7 The c.114G>C (p.Arg38=) (NM_000018.4) is a synonymous (silent) variant that is not predicted by NNSplice, SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser Multiz Aligments of 100 Vertebrates (BP4, BP7). To our knowledge, this variant has not been reported in the literature in any individuals with autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001224 (8/65370 alleles) in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337548/MONDO:0008723/021 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:144551 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018799 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0040034 infores:hetionet CHEBI:421707 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0853034 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0030305 infores:hetionet NCBIGene:55532 biolink:causes MONDO:0013208 infores:monarchinitiative not_provided not_provided HGNC:25355 MONDO:0013208 uuid:cccb85ca-1345-4fe8-8cda-26338fe45342 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6438 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0022568 infores:hetionet CHEBI:7903 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0024312 infores:hetionet CHEBI:194135 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020458 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0349506 infores:hetionet CHEBI:8228 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0013404 infores:hetionet CHEBI:3534 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0002792 infores:hetionet CAID:CA10602282 biolink:causes MONDO:0044970 infores:clingen CAID:CA10602282 MONDO:0044970 PMID: Likely Pathogenic PP3, PM3_Strong, PM2 BS2 The c.3573 G>T (K1191N) variant in POLG is absent in population databases (PM2 met). Computational prediction tool Revel score 0.876 (PP3 met Revel score > 0.75). This variant has been seen in 3 cases as compound heterozygotes. Two cases with Ala467Thr presenting with Alpers syndrome and one with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM3_strong met; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, this variant is characterized as a likely pathogenic variant for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602282/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:7915 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151826 infores:hetionet CHEBI:71417 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0018681 infores:hetionet CAID:CA399802559 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802559 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000419.5(ITGA2B):c.1555C>T (p.Gln519Ter) found in a homozygous proband (PMID:31029159) causes a premature stop codon at exon 16 and is predicted to undergo nonsense mediated decay (PVS1). The variant was not found in gnomAD v2.1.1 (PM2_supporting). It has been detected homozygous in at least 1 proband reported to have Glanzmann thrombasthenia (PM3_supporting; PMID:31029159). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802559/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:32315 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0027497 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0037199 infores:hetionet CHEBI:6640 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0043094 infores:hetionet NCBIGene:9969 biolink:causes MONDO:0032485 infores:monarchinitiative not_provided not_provided HGNC:22474 MONDO:0032485 uuid:8cc6aeb0-e011-41d1-b182-4613e5023fba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0036830 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043349 infores:hetionet CHEBI:8863 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034886 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023418 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0009450 infores:hetionet CHEBI:31859 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0039231 infores:hetionet CHEBI:50692 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0037763 infores:hetionet CHEBI:31413 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0235063 infores:hetionet CHEBI:15765 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0042963 infores:hetionet NCBITaxon:727 biolink:causes MONDO:0005842 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:727 MESH:D015523 DB01211_MESH_D015523_1 CHEBI:6916 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0701811 infores:hetionet CHEBI:94392 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0549249 infores:hetionet CHEBI:50275 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0231528 infores:hetionet CHEBI:119573 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020625 infores:hetionet CHEBI:17334 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C1321898 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011991 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0034882 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020649 infores:hetionet CHEBI:2788 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0015423 infores:hetionet GO:1901339 biolink:causes GO:0070588 infores:ubergraph knowledge_assertion manual_agent GO:1901339 GO:0070588 CHEBI:5784 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0022346 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0027651 infores:hetionet CAID:CA410147444 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147444 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, PM4, PM3, PM5, PM1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.1303G>T (p.Ala435Ser) is a missense variant which has a REVEL score < 0.50 (0.148) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147444/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5790 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0700590 infores:hetionet CHEBI:76607 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0031350 infores:hetionet CHEBI:28748 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0520887 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0040479 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0029882 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027441 infores:hetionet CHEBI:5778 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0231749 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020557 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007097 infores:hetionet CHEBI:68478 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0024305 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233632 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027339 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0521506 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0521506 infores:hetionet CHEBI:17303 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0426390 infores:hetionet CHEBI:119486 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151747 infores:hetionet CHEBI:3441 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0005778 infores:hetionet CHEBI:9139 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0271710 infores:hetionet NCBIGene:29925 biolink:causes MONDO:0014141 infores:monarchinitiative not_provided not_provided HGNC:22932 MONDO:0014141 uuid:15df171f-1bd6-49dc-83da-ccdb1816df9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011168 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013146 infores:hetionet CHEBI:49668 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C1579838 infores:hetionet NCBIGene:6329 biolink:causes MONDO:0013234 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0013234 uuid:7479b4e1-1b33-4d7b-8249-8f31e84d0baa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0040822 infores:hetionet CHEBI:2654 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0027947 infores:hetionet CAID:CA16020983 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020983 MONDO:0009861 PMID:22300847 Likely Pathogenic PP4_Moderate, PM2, PM5, PP3, PM3_Supporting PS3 The c.1250A>G (p.Tyr417Cys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). It was detected with the pathogenic variant IVS10-11G>A (PMID: 28593914). Computational evidence support a deleterious effect. Another missense change at the same amino acid (p.Tyr417His) is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020983/MONDO:0009861/006 2020-08-13 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:79699 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0004623 infores:hetionet CHEBI:47381 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C2979982 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020676 infores:hetionet UBERON:0011202 biolink:causes MONDO:0003715 infores:ubergraph knowledge_assertion manual_agent UBERON:0011202 MONDO:0003715 CHEBI:6149 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030232 infores:hetionet NCBIGene:7453 biolink:causes MONDO:0957218 infores:monarchinitiative not_provided not_provided HGNC:12729 MONDO:0957218 uuid:eb2fce96-a2b6-46ae-8d7b-7c5f399ba519 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037274 infores:hetionet CHEBI:29013 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0018681 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0035258 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0235198 infores:hetionet NCBIGene:1186 biolink:causes MONDO:0032805 infores:monarchinitiative not_provided not_provided HGNC:2025 MONDO:0032805 uuid:16347cb1-1382-42a5-b41e-7569c5b71822 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5191 biolink:causes MONDO:0013945 infores:monarchinitiative not_provided not_provided HGNC:8860 MONDO:0013945 uuid:e4cf00bc-a056-49b2-99b3-04f0deb68cb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040038 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0426747 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0426747 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0029408 infores:hetionet CHEBI:3696 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0032617 infores:hetionet CHEBI:101853 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0600142 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0003460 infores:hetionet CHEBI:5106 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C3257803 infores:hetionet CAID:CA120194 biolink:causes MONDO:0015967 infores:clingen CAID:CA120194 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PS4, PP1_Strong The c.421C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 141 (p.(Arg141Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9294105, internal lab contributors). Three individuals had a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes, with at least seven informative meioses in two families (PP1_Strong; PMID: 9294105, internal lab contributor). In summary, c.421C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA120194/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:94609 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0020517 infores:hetionet UBERON:0001295 biolink:causes MONDO:0006196 infores:ubergraph knowledge_assertion manual_agent UBERON:0001295 MONDO:0006196 CHEBI:6472 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0011603 infores:hetionet CHEBI:47519 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0162830 infores:hetionet CHEBI:36795 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0027497 infores:hetionet CHEBI:3561 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151603 infores:hetionet CHEBI:135005 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0042963 infores:hetionet CHEBI:9168 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0497156 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0021400 infores:hetionet CHEBI:82960 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0231528 infores:hetionet CHEBI:31643 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0221201 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0574067 infores:hetionet CHEBI:8024 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018808 infores:hetionet CHEBI:135888 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0043144 infores:hetionet CHEBI:51209 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0020538 infores:hetionet CHEBI:93635 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0031117 infores:hetionet CHEBI:28901 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0000731 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0270994 infores:hetionet CHEBI:60761 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0234215 infores:hetionet CHEBI:100246 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0030554 infores:hetionet CHEBI:9448 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0086565 infores:hetionet NCBITaxon:1773 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1773 GO:0006954 DB01234_MESH_D014391_1 CHEBI:31236 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151838 infores:hetionet GO:0030318 biolink:causes CL:0000148 infores:ubergraph knowledge_assertion manual_agent GO:0030318 CL:0000148 CAID:CA000183 biolink:causes MONDO:0017623 infores:clingen CAID:CA000183 MONDO:0017623 PMID:30039884 Uncertain Significance PP2, PM2_Supporting, BS3_Supporting BP7, BP5, BS1, BS4, PM6, PVS1, PP3, PP1, BS2, PM4, PM1, PM3, PM5, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 NM_000314.8(PTEN):c.700C>T (p.Arg234Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: Functional studies showing no damaging effect on protein function. Score of this variant = 0.106334511 (>0, WT-like range) on high throughput phosphatase assay (PMID:29706350).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + (1*2) points; total is 1 (Uncertain significance). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000183/MONDO:0017623/003 2023-10-11 2023-10-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0267596 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0022660 infores:hetionet NCBIGene:7341 biolink:causes MONDO:0013378 infores:monarchinitiative not_provided not_provided HGNC:12502 MONDO:0013378 uuid:da6c9e36-ee6f-47cd-aa84-2fec7f803db3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9622 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0013604 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235416 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0019147 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042514 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0242422 infores:hetionet CHEBI:8502 biolink:causes MONDO:0017236 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0221239 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0235416 infores:hetionet NCBIGene:4621 biolink:causes MONDO:0032751 infores:monarchinitiative not_provided not_provided HGNC:7573 MONDO:0032751 uuid:b520cb89-5aa9-46b5-b9d5-d4f84e6b8681 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0040261 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0948594 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0013404 infores:hetionet NCBIGene:23175 biolink:causes MONDO:0009992 infores:monarchinitiative not_provided not_provided HGNC:13345 MONDO:0009992 uuid:b38f4094-eb32-48d4-82f7-920d06e1e9d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020555 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0240564 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0240564 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0232431 infores:hetionet CHEBI:44915 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0030193 infores:hetionet CHEBI:27777 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0231218 infores:hetionet CHEBI:48947 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0042109 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0037274 infores:hetionet CHEBI:4885 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0162830 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0031046 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0015397 infores:hetionet NCBIGene:729920 biolink:causes MONDO:0013835 infores:monarchinitiative not_provided not_provided HGNC:37276 MONDO:0013835 uuid:c69d1101-d816-44f5-bb54-8b5f0392182a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151905 infores:hetionet CHEBI:36704 biolink:causes HP:0002373 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0009952 infores:hetionet CHEBI:31859 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0019348 infores:hetionet CHEBI:2682 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0024031 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0151736 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235146 infores:hetionet NCBIGene:23522 biolink:causes MONDO:0011640 infores:monarchinitiative not_provided not_provided HGNC:17582 MONDO:0011640 uuid:945c464f-c9c2-4354-9d25-0dc531fa4fbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0019572 infores:hetionet CHEBI:8597 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0043352 infores:hetionet NCBIGene:80320 biolink:causes MONDO:0031084 infores:monarchinitiative not_provided not_provided HGNC:14530 MONDO:0031084 uuid:07114f9b-4d83-40e1-884a-52d393b09339 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0029134 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0006145 infores:hetionet CHEBI:4469 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0042029 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0004623 infores:hetionet CHEBI:5893 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0026826 infores:hetionet NCBIGene:92002 biolink:causes MONDO:0010408 infores:monarchinitiative not_provided not_provided HGNC:28434 MONDO:0010408 uuid:40b36bd6-67ae-44d8-8db2-0ee658ae4f8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50730 biolink:causes HP:0001892 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C1458140 infores:hetionet CAID:CA367403041 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403041 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PM1, PP2, PP3, PM2_Supporting PS4 The c.233A>G variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to glycine at codon 78 (p.(Asp78Gly)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.996, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, internal lab contributors). Two other missense variants, c.234C>G (p.Asp78Glu) and c.232G>C (p.Asp78His) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.233A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403041/MONDO:0015967/086 2024-10-28 2024-12-02 Semidominant inheritance HP:0032113 Supports CAID:CA1139771343 biolink:causes MONDO:0007453 infores:clingen CAID:CA1139771343 MONDO:0007453 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1297_1300dup variant in the glucokinase gene, GCK, results in a premature termination at codon 434 (p.(Cys434Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1297_1300dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771343/MONDO:0007453/086 2023-11-03 2023-11-03 Semidominant inheritance HP:0032113 Supports UNII:U6XF9NP8HM biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0042487 infores:hetionet CHEBI:50922 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0002963 infores:hetionet CHEBI:10125 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0549249 infores:hetionet CHEBI:68478 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0267028 infores:hetionet CHEBI:182080 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C1510472 infores:hetionet CHEBI:6456 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0030193 infores:hetionet CHEBI:10101 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2129214 infores:hetionet GO:0045477 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0045477 GO:0019953 CHEBI:17474 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0340726 infores:hetionet CHEBI:35854 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0040435 infores:hetionet CAID:CA397722617 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722617 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PM3, PP4_Moderate PP3, PM1 The c.339C>A variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 113 (p.(Phe113Leu)). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID: 21932095; c.848T>C, p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). This individual had NBS C14:1 levels (1.10 uM) above the threshold of ≥ 1.0 μM as specified by the ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID: 21932095) (PP4_Moderate). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP. In summary, this variant meets the criteria to be classified as UNCERTAIN SIGNIFICANCE for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting (ClinGen ACADVL VCEP specifications version #1.0; approved 2022-12-13) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722617/MONDO:0008723/021 2022-12-13 2022-12-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7565 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C2363731 infores:hetionet CHEBI:4903 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0020580 infores:hetionet CAID:CA387747060 biolink:causes MONDO:0700269 infores:clingen CAID:CA387747060 MONDO:0700269 PMID:32444794PMID:33609447 Likely Pathogenic PP3, PM2_Supporting, PS3 BP5, PP4 The variant c.7857G>C in BRCA2 is a missense variant predicted to cause substitution of Tryptophan by Cysteine at amino acid 2619 (p.Trp2619Cys). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.49, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.17 indicates an unclear predicted impact on splicing (score threshold 0.10-0.20) (PP3 met). Reported by four calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 38417439, 32444794, 39779857, 39779848) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.81 (based on Family History LR=1.81), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMIDs 31853058). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PM2_Supporting, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA387747060/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6775 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0427008 infores:hetionet CHEBI:8245 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0013144 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0948586 infores:hetionet CHEBI:16469 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0234233 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0011991 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0574067 infores:hetionet CHEBI:168396 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020598 infores:hetionet CHEBI:8485 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0023895 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0233472 infores:hetionet CHEBI:8802 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0035508 infores:hetionet GO:0072301 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:0072301 GO:0001656 CHEBI:5132 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0242350 infores:hetionet CHEBI:10023 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0004134 infores:hetionet CHEBI:47780 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0086439 infores:hetionet CHEBI:5778 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0023530 infores:hetionet CHEBI:3387 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0025290 infores:hetionet CHEBI:92998 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C2364111 infores:hetionet CHEBI:10127 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0003862 infores:hetionet NCBIGene:79705 biolink:causes MONDO:0014080 infores:monarchinitiative not_provided not_provided HGNC:18608 MONDO:0014080 uuid:be47f59a-1c86-46ef-9944-5ae9d4af092b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31709 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0011603 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013922 infores:hetionet CHEBI:68579 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151662 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0002170 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0035305 infores:hetionet CHEBI:51364 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0085637 infores:hetionet CHEBI:6916 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0013404 infores:hetionet CHEBI:3534 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0018681 infores:hetionet CHEBI:135929 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0011124 infores:hetionet CHEBI:6715 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013428 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0162281 infores:hetionet CHEBI:8481 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0043352 infores:hetionet CHEBI:27999 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0041834 infores:hetionet CHEBI:44423 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0162834 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040147 infores:hetionet CHEBI:7627 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0042963 infores:hetionet CHEBI:63629 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0085605 infores:hetionet CHEBI:171719 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0030252 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013395 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0003469 infores:hetionet NCBIGene:5580 biolink:causes MONDO:8000024 infores:monarchinitiative not_provided not_provided HGNC:9399 MONDO:8000024 uuid:40e648e4-b0ff-4a18-953e-8017ade81ae7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0239739 infores:hetionet GO:0030217 biolink:causes CL:0000084 infores:ubergraph knowledge_assertion manual_agent GO:0030217 CL:0000084 CHEBI:3082 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0162429 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009319 infores:hetionet CAID:CA023482 biolink:causes MONDO:0007750 infores:clingen CAID:CA023482 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 The NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2: PopMax MAF = 0.00001764 in European non-Finnish exomes (gnomAD v2.1.1)PP3: REVEL = 0.82 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023482/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8207 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151786 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0948594 infores:hetionet CHEBI:8863 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027066 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0474381 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023418 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015230 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018939 infores:hetionet CHEBI:8863 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0023518 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0948089 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0876973 infores:hetionet CHEBI:5100 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0022346 infores:hetionet CHEBI:4670 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0039231 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006840 infores:hetionet CHEBI:50922 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0231218 infores:hetionet CHEBI:83527 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0344232 infores:hetionet CHEBI:45863 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0232462 infores:hetionet CAID:CA638054529 biolink:causes MONDO:0011071 infores:clingen CAID:CA638054529 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-20C>G is an intronic variant. This variant has a SpliceAI score ≤ 0.20 (0.00) (BP4) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.377)(BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054529/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45863 biolink:causes UMLS:C0263008 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0263008 infores:hetionet CHEBI:63617 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0000731 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0020542 infores:hetionet CHEBI:48273 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0009676 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0009319 infores:hetionet CHEBI:28901 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0338908 infores:hetionet CHEBI:6775 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0003862 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0008311 infores:hetionet NCBIGene:8312 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:903 MONDO:0007256 uuid:d3c2bbb5-1749-4f06-b0d9-f1df380a7c2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000457 biolink:causes MONDO:0018875 infores:clingen CAID:CA000457 MONDO:0018875 PMID: Likely Benign BS3, PM5_Supporting, PP3, BS2 BP4, BP2, BA1, PS3, PS4, PS1, PS2, PM1, PM3, BS1, BP5, PM2, PVS1, PP1, PP4 The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000457/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3423 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0015469 infores:hetionet CHEBI:83527 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0022107 infores:hetionet CHEBI:47780 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0686347 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020538 infores:hetionet UMLS:C0120107 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0037763 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0235416 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0037274 infores:hetionet CAID:CA410150061 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150061 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS4, PS3, BP1, BP3, BP2, BA1, BS1, BS4, BS3, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.877T>C (p.Ser293Pro) is a missense variant which is completely absent from gnomAD 2.0 with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.212) and a SpliceAI score ≤0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150061/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6909 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0000729 infores:hetionet CAID:CA222934 biolink:causes MONDO:0010278 infores:clingen CAID:CA222934 MONDO:0010278 PMID: Pathogenic PP1, PP4, PVS1, PM2_Supporting The p.Gln326Ter variant in SLC9A6 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln326Ter variant in SLC9A6 is absent from gnomAD (PM2_supporting). The variant has been reported in an individual with clinical features consistent with Christianson syndrome (EGL internal data) (PP4). The variant has been reported to segregate in two informative meioses (EGL internal data) (PP1). In summary, the p.Gln326Ter variant in SLC9A6 is classified as Pathogenic for Christianson syndrome based on the ACMG/AMP criteria (PVS1, PM2_supporting, PP1, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222934/MONDO:0010278/016 2021-02-10 2021-05-05 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA267642 biolink:causes MONDO:0009861 infores:clingen CAID:CA267642 MONDO:0009861 PMID:26666653 Pathogenic PVS1, PM2, PP4 The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is present at extremely low frequencies in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00014 in Other subpopulation in gnomAD, below the 0.0002 allele frequency cutoff for PAH variants (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267642/MONDO:0009861/006 2019-09-29 2019-10-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2704 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0009450 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0023530 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0150450 infores:hetionet CHEBI:6359 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0016204 infores:hetionet CHEBI:9130 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0085593 infores:hetionet CHEBI:63632 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0043094 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0040479 infores:hetionet CHEBI:421707 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0009763 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0018799 infores:hetionet CHEBI:49662 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1368065 infores:hetionet CAID:CA251540 biolink:causes MONDO:0009861 infores:clingen CAID:CA251540 MONDO:0009861 PMID:1682235PMID:23500595 Pathogenic PM2, PVS1, PP4 The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID: 1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251540/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45783 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020639 infores:hetionet CHEBI:9635 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0038990 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151626 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235431 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0027651 infores:hetionet CHEBI:61049 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151936 infores:hetionet CHEBI:63619 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085610 infores:hetionet CAID:CA3054201764 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201764 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.191_192insA (p.Ala65fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98–c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201764/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5118 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027651 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0236068 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0854532 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0854532 infores:hetionet GO:0010058 biolink:causes GO:0090558 infores:ubergraph knowledge_assertion manual_agent GO:0010058 GO:0090558 CHEBI:9168 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020649 infores:hetionet CHEBI:3286 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0236075 infores:hetionet GO:1905715 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:1905715 GO:0060429 CHEBI:8077 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0015672 infores:hetionet CHEBI:131512 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0232462 infores:hetionet CHEBI:9448 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0239571 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0005940 infores:hetionet CHEBI:39867 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0520966 infores:hetionet CHEBI:3696 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020672 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0037274 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0853692 infores:hetionet GO:0097279 biolink:causes HP:0000989 infores:drugmechdb knowledge_assertion manual_agent GO:0097279 MESH:D011537 DB00871_MESH_D011537_2DB00871_MESH_D011537_1 CHEBI:42068 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0030312 infores:hetionet CHEBI:63629 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0085628 infores:hetionet CHEBI:194135 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002390 infores:hetionet CAID:CA010796 biolink:causes MONDO:0004994 infores:clingen CAID:CA010796 MONDO:0004994 PMID: Uncertain Significance PM2 PM5, PM4, PM1, PM6, BA1, PP1, PS3, BS2, BS1, BS3, BS4, BP3, PS4, PS1, PS2, BP7, BP5, PVS1 The NM_000257.3(MYH7):c.1477_1478delAT (p.Met493Valfs) variant has been identified in 1 individual with features of both HCM and DCM (Zimmerman 2010 PMID:20474083; Walsh 2017 PMID: 27532257, LMM pers. comm.) however, this is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; http:// gnomad.broadinstitute.org, v.2.1.1). This variant is predicted to cause a frameshift leading to a truncated or absent protein. The contribution of loss of function (LOF) variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood therefore PVS1 was not applied. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010796/MONDO:0004994/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9667 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0011616 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0019061 infores:hetionet CHEBI:5778 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151786 infores:hetionet CHEBI:59773 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0040264 infores:hetionet CHEBI:63580 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085636 infores:hetionet CHEBI:63638 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0232462 infores:hetionet CHEBI:404903 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042384 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0013395 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0004690 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042109 infores:hetionet CHEBI:5864 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0242184 infores:hetionet CHEBI:2637 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0151723 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027765 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0006849 infores:hetionet CAID:CA251522 biolink:causes MONDO:0009861 infores:clingen CAID:CA251522 MONDO:0009861 PMID:24941924PMID:23500595PMID:17935162PMID:3615198 Pathogenic PM3, PP4_Moderate, PVS1, PS3 PAH-specific ACMG/AMP criteria applied: PS3: abolishes PAH activity due to protein instability (PMID:17935162; PMID:3615198); PM3: (PMID:24941924); PP4_Moderate: Reported in Galician PAH deficiency population. BH4 deficiency ruled out. (PMID:23500595); PVS1: Canonical +1 splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM3, PP4_Moderate, PVS1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251522/MONDO:0009861/006 2018-08-05 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:724125 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0241136 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0853700 infores:hetionet CHEBI:7476 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151786 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042075 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0027769 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235660 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0497247 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019348 infores:hetionet CHEBI:100241 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013390 infores:hetionet CHEBI:585948 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0026821 infores:hetionet CHEBI:5118 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029944 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0019112 infores:hetionet CHEBI:4784 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027424 infores:hetionet CHEBI:5004 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0001824 infores:hetionet CHEBI:66899 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0027765 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013595 infores:hetionet CHEBI:5103 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C2047937 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0392386 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235706 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235706 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0011991 infores:hetionet CHEBI:9586 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013456 infores:hetionet NCBITaxon:372083 biolink:causes MONDO:0015260 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:372083 MONDO:0015260 CHEBI:63791 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002453 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0029882 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1384353 infores:hetionet CAID:CA6831857 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831857 MONDO:0015967 PMID: Uncertain Significance PP1_Moderate, PP4_Moderate BP4, PS3, PS4, PM1, PM5, BS1, BS3, PM2, PP3 The c.871C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 291 (p.(Pro291Thr)) of NM_000545.8. The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold and the variant has a MAF in gnomAD that is above the PM2_Supporting cutoff (PMIDs: 18003757, 30455330; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (>50% MODY probability calculator result and negative HNF4A testing; negative diabetes autoantibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with three informative meioses in two families (PP1_Moderate; PMID: 22432108; internal lab contributors). This variant has a REVEL score of 0.587, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. Functional studies of this variant are also inconclusive, as the variant results in transactivation activity 59.2% of WT, which falls between the cutoffs for PS3 and BS3. However, DNA binding activity and protein expression are not significantly different from WT (PMID: 18003757, Gloyn group)​. In summary, c.871C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP1_moderate, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831857/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6339 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0042373 infores:hetionet CHEBI:64318 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0231303 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0014544 infores:hetionet CHEBI:27436 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0019572 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0948594 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0549386 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0031099 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0034063 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041747 infores:hetionet CHEBI:10127 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0043352 infores:hetionet UNII:R15UI3245N biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C1258215 infores:hetionet CHEBI:8772 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0010200 infores:hetionet CHEBI:3647 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0004044 infores:hetionet CHEBI:65346 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0011849 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029927 infores:hetionet CHEBI:15551 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0700590 infores:hetionet CHEBI:6916 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0027497 infores:hetionet CHEBI:45285 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0030920 infores:hetionet CHEBI:3568 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042024 infores:hetionet CHEBI:50648 biolink:causes UMLS:C1611174 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1611174 infores:hetionet CHEBI:5864 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002994 infores:hetionet CHEBI:3175 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0016242 infores:hetionet CHEBI:3568 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0520966 infores:hetionet GO:2000181 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:2000181 GO:0001568 CHEBI:44032 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0031117 infores:hetionet CHEBI:521033 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0376358 infores:hetionet CAID:CA397396361 biolink:causes MONDO:0100438 infores:clingen CAID:CA397396361 MONDO:0100438 PMID:33067476 Likely Pathogenic PP4, PM2_Supporting, PP3_Moderate, PM3, PS3_Supporting NM_014336.5(AIPL1):c.364G>A (p.Gly122Arg) is a missense variant predicted to replace glycine with arginine at amino acid 122. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000006197, with 10 / 1613572 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the p.Trp278Ter variant suspected in trans (1 point, PMIDs: 20702822, 21474771), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including reduced visual acuity (1 pt), nyctalopia (0.5 pts), abnormal peripheral vision (1 pt) from the first decade of life (1 pt), pigmentary retinal degeneration with atrophy (1 pt), optic nerve drusen (0.5 pts), abnormal electroretinogram responses from both rods (0.5 pts) and cones (1 pt), and maculopathy (0.5 pts), which together are specific for AIPL1-related retinopathy (total 7 points, PMID: 20702822, PP4). The computational predictor REVEL gives a score of 0.851, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). Additionally, the splicing impact predictor SpliceAI gives a score of 0.11, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant was associated with 60-70% PDE6 enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, which was comparable to the negative control lacking AIPL1, indicating that it triggers a severe defect in protein function (PMID: 33067476, PS3_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_supporting, PP3_moderate, PP4_supporting, PM3_moderate, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397396361/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3698 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0558489 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0010709 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0235807 infores:hetionet CHEBI:31302 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0015230 infores:hetionet CHEBI:42068 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0014356 infores:hetionet CAID:CA16020872 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020872 MONDO:0009861 PMID:10429004PMID:10429004 Uncertain Significance PM2, PP4, PP3 PM3 The c.842+6T>A PAH variant has been identified in at least one patient with hyperphenylalaninemia (PMID: 10429004). Serum phenylalanine was considered severe in this patient (>28mg/dl), however without indication of a second PAH variant. This variant is absent from 1000G, ESP, and gnomAD databases. It is intronic in a highly conserved nucleotide, and computation analysis predict a reduction in splicing at the donor site of intron 7. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020872/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:251408 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0000737 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0178298 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151888 infores:hetionet CAID:CA280058 biolink:causes MONDO:0021060 infores:clingen CAID:CA280058 MONDO:0021060 PMID:29493581PMID:16439621PMID:19206169PMID:8042262 Pathogenic PM1, PM2, PP2, PP3, PS4_Supporting, PM6_Strong The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280058/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10650 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0948089 infores:hetionet CHEBI:100241 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0162297 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0149931 infores:hetionet CHEBI:490877 biolink:causes UMLS:C1142357 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C1142357 infores:hetionet CAID:CA006347 biolink:causes MONDO:0100316 infores:clingen CAID:CA006347 MONDO:0100316 PMID:15528464PMID:25344363PMID:11799244 Pathogenic PM2_Supporting, PS4, PS3, PM3_Supporting, PP3 BS1, PM5, PP1, PP4 NM_000218.3(KCNQ1):c.1766G>A is a missense variant in KCNQ1 that substitutes glycine with aspartic acid at codon 589. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0000008.474, with 1 allele / 1,180,024 total alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). Please note that the variant has a higher frequency of 0.0005504 (35 alleles / 63,586 total alleles) in the European Finnish population. which is not one of the 5 continental populations eligible to meet a population code. The variant has been reported in 34 apparently unrelated probands affected with long QT syndrome 1 (PS4; PMID: 11216980). The variant has also been detected in at least 2 apparently unrelated probands with Jervell and Lange-Nielsen syndrome who had both a long QTc interval and congenital deafness. 1 proband was compound heterozygous for this variant and the p.Tyr171Ter variant, which has not yet been classified by the VCEP, confirmed in trans by family testing, while the other proband was homozygous for the variant (0.5 pts, PM3_Supporting, PMID: 11216980). The variant has been reported to segregate with long QT syndrome 1 through the proband and at least 1 confirmed affected family member with QTc >480 ms, however, this does not meet the requirement of at least 2 segregations to meet PP1 (PMID: 11216980). This variant has been reported in at least one affected proband exhibiting QTc prolongation and an exercise-related syncopal spell, however the QTc is not available to evaluate in relation to the required threshold of >480 ms, so PP4 is not met (PMID: 10483966). The computational predictor REVEL gives a score of 0.863, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). This variant has been shown to disrupt KCNQ1 function in experimental assays from at least 5 independent research groups, including manual patch-clamp (PMID: 11216980, PMID: 25344363, PMID: 22095730, PMID: 11799244), electrophysiology studies in iPSC-derived cardiomyocytes (PMID: 15528464), and cell surface localization (PMID: 25344363). The combination of 5 electrophysiology studies with 1 protein metabolism study satisfies the VCEP requirement for the strong level of the experimental code (PS3). Another missense variant in the same codon, c.1765G>A (p.Gly589Ser) has been reported in association with long QT syndrome 1 (PMID: 31565860), however, PM5 has not been considered in order to avoid circularity. In summary, this variant meets the criteria to be classified as pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3, PS4, PM2_Supporting, PM3_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006347/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63613 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0021368 infores:hetionet CHEBI:3504 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0017152 infores:hetionet CHEBI:10127 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0039070 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018099 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0017601 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0001824 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0948521 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0948521 infores:hetionet CHEBI:4974 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0015967 infores:hetionet CHEBI:8378 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0018800 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003537 infores:hetionet CHEBI:50885 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0085633 infores:hetionet CHEBI:6375 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0233762 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0234215 infores:hetionet CHEBI:83804 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0007859 infores:hetionet CHEBI:6847 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0020651 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0687133 infores:hetionet CAID:CA2697547488 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547488 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1321_1322delinsTG (p.Leu441Trp) is a variant which results in a missense change. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547488/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2950 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0235234 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0013404 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0855242 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0041976 infores:hetionet CHEBI:2453 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C1510431 infores:hetionet CHEBI:9667 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0039070 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020517 infores:hetionet CHEBI:91834 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013144 infores:hetionet CHEBI:5141 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0018834 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011570 infores:hetionet CHEBI:4784 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151539 infores:hetionet CHEBI:31980 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C2047937 infores:hetionet CHEBI:6532 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C1291077 infores:hetionet CHEBI:4466 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151904 infores:hetionet CHEBI:5132 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0004093 infores:hetionet CHEBI:32221 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0022281 infores:hetionet CHEBI:36791 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085632 infores:hetionet CHEBI:135736 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0149512 infores:hetionet CAID:CA9871538 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871538 MONDO:0007064 PMID: Uncertain Significance PM2 NM_000022.4(ADA):c.757C>T is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 253 (p.Arg253Trp).The filtering allele frequency (the upper threshold of the 95% CI of 101/1180020) of the c.757C>T variant in ADA is 0.00007452 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting.However, 1 homozygote was reported (PM2 not met). There are no publications for this variant in the literature. Another missense variant R253P in the same codon has been reported (PMIDs : 8258146,9758612) (not classified by SCID VCEP yet):PM5 not evaluated.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: No criteria met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871538/MONDO:0007064/114 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7915 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0860803 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78501 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0240464 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0037199 infores:hetionet CHEBI:10124 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0019521 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0032285 infores:hetionet CHEBI:75984 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0013384 infores:hetionet CHEBI:2675 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C2584688 infores:hetionet CHEBI:18357 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0013404 infores:hetionet CHEBI:9086 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0026827 infores:hetionet CAID:CA645293839 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293839 MONDO:0015924 PMID: Uncertain Significance PVS1, PM2_Supporting BA1, PS4, BS1 The BMPR2 c.1277-8A>G is a non-canonical splice site (-8) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single individual with PAH (PMID: 26387786); a single entry in ClinVar documents the same individual. In silico prediction indicated likely splice site acceptor gain (SpliceAI = 0.90, acceptor loss = 0.27) and cDNA analysis demonstrated an aberrant splice product leading to premature truncation (p.Gly426Valfs*424) with predicted nonsense mediated decay (PMID: 26387786) (PVS1 (RNA)). The variant is located in the same splice region as a previously established pathogenic variant, NM_001204.7(BMPR2):c.1277-9A>G, classified by the PH VCEP (PS1). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1(RNA), PS1, PM2_supporting (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293839/MONDO:0015924/125 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10110 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0001125 infores:hetionet CHEBI:28864 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C2047937 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C2363730 infores:hetionet CHEBI:2654 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0042109 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011849 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0020649 infores:hetionet GO:1904118 biolink:causes GO:0071599 infores:ubergraph knowledge_assertion manual_agent GO:1904118 GO:0071599 CHEBI:144551 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042401 infores:hetionet CAID:CA915940333 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940333 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting PM3, BP7 The NM_000419.5(ITGA2B):c.408+11C>A intronic variant has been reported in at least one patient (GT22 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). The highest population minor allele frequency in gnomAD v4.1 is 8.508e-7 (1/1175406 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary this variant meets criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940333/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9086 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013390 infores:hetionet CHEBI:35553 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0030353 infores:hetionet CHEBI:63621 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0006625 infores:hetionet CHEBI:63635 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013604 infores:hetionet CHEBI:4710 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0231218 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0409497 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0042075 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0027651 infores:hetionet CAID:CA151920 biolink:causes MONDO:0700270 infores:clingen CAID:CA151920 MONDO:0700270 PMID: Benign BP4, BA1, BP2_Strong BS1, PM2 The ATM c.3118A>G (p.Met1040Val) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.2% (AFR) which is above the ATM BA1 threshold of 0.5% (BA1). This variant has been observed in a homozygous state in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). In silico protein predictors (BayesDel, score:-0.45, AGVGD, Class C0) predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA151920/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5134 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0041834 infores:hetionet CHEBI:2639 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0151786 infores:hetionet CAID:CA214311 biolink:causes MONDO:0015967 infores:clingen CAID:CA214311 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM5, PP1_Strong, PP4_Moderate, PP3 The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID: 32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214311/MONDO:0015967/017 2022-04-10 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50673 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0018681 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0003123 infores:hetionet CHEBI:31981 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0020456 infores:hetionet UMLS:C0004609 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0037036 infores:hetionet CHEBI:15367 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0542571 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0518015 infores:hetionet CAID:CA8603479 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603479 MONDO:0100326 PMID: Uncertain Significance BP7, BS1 The c.408+16C>T variant in ITGA2B is an intronic variant which is located in intron 3. The highest population minor allele frequency in gnomAD v4 is 0.001457 (92/63124 alleles) in the European (Finnish) population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational splicing predictor SpliceAI gives a score of 0.25 for donor site loss, predicting that the variant may disrupt the splice site of intron 3 of ITGA2B (BP7_NotMet). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603479/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:100241 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042384 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0000833 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151849 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0162429 infores:hetionet CHEBI:4735 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0040822 infores:hetionet CHEBI:51380 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0018524 infores:hetionet CHEBI:17303 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0009763 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0743680 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0853193 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0549335 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0549335 infores:hetionet NCBIGene:26999 biolink:causes MONDO:0033374 infores:monarchinitiative not_provided not_provided HGNC:13760 MONDO:0033374 uuid:557f35f0-122c-4668-afa6-d80c0929984e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013609 infores:hetionet CHEBI:50131 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151699 infores:hetionet NCBIGene:331 biolink:causes MONDO:0010385 infores:monarchinitiative not_provided not_provided HGNC:592 MONDO:0010385 uuid:22687633-e45b-4bbe-9d63-f1da8e01dc31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68554 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0004936 infores:hetionet CHEBI:3371 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0040034 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0854375 infores:hetionet UMLS:C0879264 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0028961 infores:hetionet CHEBI:45716 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0041657 infores:hetionet CHEBI:63631 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085624 infores:hetionet CHEBI:47519 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0016204 infores:hetionet CHEBI:8888 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030554 infores:hetionet NCBIGene:63924 biolink:causes MONDO:0014098 infores:monarchinitiative not_provided not_provided HGNC:24229 MONDO:0014098 uuid:d0dcf22a-06a9-4212-9153-a7fcf49d0165 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31624 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0021775 infores:hetionet CHEBI:7773 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0013384 infores:hetionet CHEBI:3568 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0019079 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0575090 infores:hetionet CHEBI:63610 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0234238 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0017152 infores:hetionet CHEBI:9720 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0011603 infores:hetionet CAID:CA222133 biolink:causes MONDO:0015152 infores:clingen CAID:CA222133 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PS3_Moderate PM2 The NM_003494.4: c.1663C>T variant in DYSF, which is also known as NM_001130987.2: c.1717C>T p.(Arg573Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 555 (p.Arg555Trp). This variant has been detected in at least nine unrelated individuals with limb girdle muscular dystrophy (PMID: 16010686, 17698709, 18853459, 25591676, 25143362, 19015158), including in a homozygous state in two patients (0.75 pts, PMID: 25143362,16010686) and in trans with a pathogenic variant in at least two patients (c.3708delA p.(Asp1237ThrfsTer24), 1.0 pt, PMID: 19015158; c.3220_3221delCT p.(Leu1074PheTer39), 1.0 pt, PMID: 25591676) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16010686, 25143362, 19015158, 18853459). The variant has also been reported to segregate with LGMD in two affected family members from one family (PP1; PMID: 25143362). The filtering allele frequency of the variant is 0.0002685 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/28874), which is greater than the LGMD VCEP threshold (<0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222133/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:23765 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0424295 infores:hetionet NCBIGene:4089 biolink:causes MONDO:0017380 infores:monarchinitiative not_provided not_provided HGNC:6770 MONDO:0017380 uuid:586e8036-f8c9-447b-a723-49f86d240b03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101085 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0085679 infores:hetionet CHEBI:40303 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0086565 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0243026 infores:hetionet CHEBI:10125 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0558489 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0853761 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0021053 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0392025 infores:hetionet CHEBI:72564 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1145670 infores:hetionet CHEBI:5132 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0027651 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0004936 infores:hetionet NCBIGene:9197 biolink:causes MONDO:0013772 infores:monarchinitiative not_provided not_provided HGNC:95 MONDO:0013772 uuid:6f752b69-85eb-4b3c-87b3-0b3e1ee8274a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0231528 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0039103 infores:hetionet CHEBI:10101 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0026826 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0948586 infores:hetionet CHEBI:63791 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0035243 infores:hetionet CHEBI:82866 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0151908 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0025202 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0037199 infores:hetionet CHEBI:63584 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042023 infores:hetionet CAID:CA226144 biolink:causes MONDO:0100453 infores:clingen CAID:CA226144 MONDO:0100453 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000180.4(GUCY2D):c.3G>A variant is predicted to change the initiation codon (p.Met1) to a stop codon, with no known alternative start codons present (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_supporting). This variant has been reported in 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (0.5 points each), PMIDs: 37327959, 10951519). (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), severe visual loss present at birth (1 pt), congenital nystagmus (1 pt), photophobia (1 pt), dyschromatopsia (1 pt), and nonrecordable ERG (0.5 pts) which together are specific for GUCY2D-related recessive retinopathy (total of 5 points, PMID: 37327959, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, PP4, PM3. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226144/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50648 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004604 infores:hetionet CHEBI:92998 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0424295 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0232462 infores:hetionet CHEBI:70746 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0002994 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042487 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0023798 infores:hetionet CHEBI:47898 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020453 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018099 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0001430 infores:hetionet CHEBI:30830 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027424 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0042075 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0086132 infores:hetionet CHEBI:4907 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0016655 infores:hetionet CHEBI:4792 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0015967 infores:hetionet CHEBI:74947 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0037763 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0149904 infores:hetionet CHEBI:63631 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0001925 infores:hetionet CHEBI:4975 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0013456 infores:hetionet CHEBI:5384 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0015230 infores:hetionet CHEBI:5296 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0022354 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026848 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0919625 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0919625 infores:hetionet CHEBI:4530 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C2830004 infores:hetionet CHEBI:5280 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0024902 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011991 infores:hetionet CHEBI:6367 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0520966 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0042109 infores:hetionet CHEBI:3479 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0687713 infores:hetionet CHEBI:45783 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0149725 infores:hetionet CHEBI:41977 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0162834 infores:hetionet CHEBI:8232 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0030312 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0948525 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0948594 infores:hetionet CHEBI:5383 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0030554 infores:hetionet CHEBI:135876 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0018965 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007286 infores:hetionet CHEBI:47519 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0030554 infores:hetionet CHEBI:8764 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020453 infores:hetionet CHEBI:261649 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0004096 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0020649 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0851341 infores:hetionet CHEBI:2208 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0002871 infores:hetionet CHEBI:77733 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0035455 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0853700 infores:hetionet CHEBI:9168 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0033774 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0162119 infores:hetionet CHEBI:71219 biolink:causes HP:0012117 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1142113 infores:hetionet CHEBI:8888 biolink:causes HP:0002059 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235946 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0030554 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0151998 infores:hetionet CHEBI:7577 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0033774 infores:hetionet CHEBI:64321 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0041969 infores:hetionet CHEBI:49662 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0038990 infores:hetionet CHEBI:391960 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0035455 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0423273 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0423273 infores:hetionet CHEBI:2618 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0013604 infores:hetionet CHEBI:45951 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0011606 infores:hetionet CHEBI:6078 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0036508 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0015230 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011053 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0220870 infores:hetionet CHEBI:83804 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040460 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0520532 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0520532 infores:hetionet CHEBI:253342 biolink:causes UMLS:C1142015 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1142015 infores:hetionet NCBIGene:7139 biolink:causes MONDO:0007266 infores:monarchinitiative not_provided not_provided HGNC:11949 MONDO:0007266 uuid:dceb2c3b-d044-42c8-bfc2-bed640958742 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0100345 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022951 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020621 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0338614 infores:hetionet CHEBI:8863 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085632 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0020651 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0041912 infores:hetionet CHEBI:51173 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0019209 infores:hetionet NCBIGene:57102 biolink:causes MONDO:0032605 infores:monarchinitiative not_provided not_provided HGNC:1184 MONDO:0032605 uuid:03618563-bdd0-475d-8a5e-36df217a4b76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085649 infores:hetionet CHEBI:61049 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018681 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0677500 infores:hetionet CHEBI:3044 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0878544 infores:hetionet CHEBI:55346 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020458 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0239725 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0239725 infores:hetionet CHEBI:63589 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0038362 infores:hetionet CHEBI:51141 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0041657 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013295 infores:hetionet CHEBI:5775 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0020580 infores:hetionet CHEBI:10023 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0016204 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0020651 infores:hetionet CHEBI:42944 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151836 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0877211 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0877211 infores:hetionet NCBIGene:6469 biolink:causes MONDO:0007733 infores:monarchinitiative not_provided not_provided HGNC:10848 MONDO:0007733 uuid:ea66d3d6-134b-4632-8e19-a7b8fb9587a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3032 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0302295 infores:hetionet CHEBI:84050 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0004604 infores:hetionet CHEBI:7798 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0014742 infores:hetionet CHEBI:63580 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017565 infores:hetionet CHEBI:31174 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0042109 infores:hetionet CHEBI:194135 biolink:causes HP:0003158 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0232831 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019163 infores:hetionet GO:2000025 biolink:causes GO:0010016 infores:ubergraph knowledge_assertion manual_agent GO:2000025 GO:0010016 CHEBI:50648 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0021368 infores:hetionet CHEBI:31705 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151539 infores:hetionet NCBIGene:54790 biolink:causes MONDO:0030858 infores:monarchinitiative not_provided not_provided HGNC:25941 MONDO:0030858 uuid:cdd527a6-e605-4e8e-8092-cf6ca4893434 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:521033 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0018801 infores:hetionet CHEBI:16469 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1291077 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0160390 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0564768 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0564768 infores:hetionet CHEBI:2618 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0026961 infores:hetionet CHEBI:3508 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C1565489 infores:hetionet CHEBI:6640 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0009806 infores:hetionet CHEBI:63621 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030794 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0852733 infores:hetionet CHEBI:2618 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0013362 infores:hetionet CAID:CA283310260 biolink:causes MONDO:0007648 infores:clingen CAID:CA283310260 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Moderate, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.1566-1G>C variant is a canonical splice variant predicted to result in the use of a cryptic splice site which preserves the reading frame (PVS1_moderate). This variant is absent in the gnomAD v2.1.1 cohort. In the gnomAD v3 it has a frequency of 0.000006978 (1 of 143,302) with a maximum non-founder allele frequency of 0.00001549 (1 of 64,570) in the European non-Finnish subpopulation (PM2_supporting; http://gnomad.broadinstitute.org). The variant has been reported in two families meeting clinical criteria for HDGC (PS4_moderate, SCV000666335.2, internal laboratory contributor). In summary, the clinical significance of this variant is classified as of uncertain significance based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_moderate, PS4_moderate, PM2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA283310260/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3696 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042024 infores:hetionet CHEBI:37941 biolink:causes UMLS:C1112632 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1112632 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005693 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0392548 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0013378 infores:hetionet CHEBI:31644 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0037383 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0344315 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0267792 infores:hetionet CAID:CA229427 biolink:causes MONDO:0009861 infores:clingen CAID:CA229427 MONDO:0009861 PMID:21147011PMID:16256386PMID:16256386PMID:18247293 Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3_Supporting PM5 The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229427/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes UMLS:C0549391 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549391 infores:hetionet CAID:CA157971 biolink:causes MONDO:0007648 infores:clingen CAID:CA157971 MONDO:0007648 PMID: Likely Benign BS2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4 The c.113C>T (p.Thr38Met) variant results in a non-synonymous amino acid substitution in exon 2 of CDH1. The variant allele occurs in 1 of 156,704 alleles in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in 1 of 1,362 alleles among individuals undergoing genome sequencing who are not known to meet IGCLC criteria for HDGC (PMID: 24728327). In addition, this variant has been observed in at least 10 individuals without DGC, LBC or SRC tumors and whose families do not suggest HDGC (BS2; SCV000666274.3, SCV000567622.4, SCV000954584.2). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, PM2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157971/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true UNII:VL0L558GCB biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0011615 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014868 infores:hetionet CHEBI:42068 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0549410 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0007222 infores:hetionet CAID:CA350341378 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341378 MONDO:0015924 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting, PM1 BP4 The NM_001204.7(BMPR2) c.1016T>A (p.Val339Asp) variant is harboured in exon 8 of the gene, encoding the functionally relevant catalytic kinase domain (PM1_met). The variant has been twice reported in the Japanese population in one IPAH and one HPAH subject (PMID: 23579436 and PMID: 23675998), (PS4_supporting). This variant is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The REVEL prediction algorithm score is 0.967, AlphaMissense is 0.9992 indicating pathogenicity (PP3_met). PP1 and PS2 were not assessed due to absence of co-segregation data and parental data respectively. No other amino acid change at the same position has been reported for PAH (PS1 and PM5 not assessed). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as VUS for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting, PP3, PS4_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341378/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:7662KG2R6K biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0018681 infores:hetionet CHEBI:31413 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0023380 infores:hetionet CHEBI:28901 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0022346 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0027051 infores:hetionet CHEBI:142290 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0162830 infores:hetionet UMLS:C1738934 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0016382 infores:hetionet GO:0160217 biolink:causes GO:0006366 infores:ubergraph knowledge_assertion manual_agent GO:0160217 GO:0006366 CHEBI:92998 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0042384 infores:hetionet CAID:CA16021003 biolink:causes MONDO:0009861 infores:clingen CAID:CA16021003 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Supporting The c.925G>A (p.Ala309Thr) variant in PAH has been reported a Danish patient with mild PKU (PMID: 26542770) and a Chinese patient with moderate PKU (BH4 deficiency excluded PMID: 30747360) (PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant c.1241A>G, p.Y414C (PM3_supporting). Computational evidence supports a deleterious effect. A different pathogenic missense change has been seen at the same amino acid residue (A309M). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16021003/MONDO:0009861/006 2019-12-14 2021-09-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA038968 biolink:causes MONDO:0021056 infores:clingen CAID:CA038968 MONDO:0021056 PMID: Benign BS2, BS3_Supporting, BP1, BP5, BS1 PP3, BP4, PS3 The c.4399C>T variant in APC is a missense variant predicted to cause the substitution of Proline by Serine at amino acid position 1467 (p.Pro1467Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in a heterozygous state in 75 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data). In addition, it has also been observed in 1 patient with an alternate molecular basis for disease – a pathogenic MSH6 germline variant (BP5; Melbourne Internal data). Functional study of β-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as the wild type (BS3_Supporting; PMID: 18199528). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BS3_Supporting, BP1 and BP5 (VCEP Specification version 1, date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA038968/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45863 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151786 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0948594 infores:hetionet CHEBI:4710 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0017178 infores:hetionet CHEBI:37333 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0020458 infores:hetionet CAID:CA245268 biolink:causes MONDO:0010726 infores:clingen CAID:CA245268 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BS1 PS4 The allele frequency of the p.Pro176His variant in MECP2 (NM_004992.3) is 0.022% in Other sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro176His variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Pro176His variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BA1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA245268/MONDO:0010726/016 2022-12-09 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3752 biolink:causes UMLS:C1696704 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1696704 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0025061 infores:hetionet CAID:CA10644644 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644644 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS1, PS3, PS4, PS2, BP3, BP2, BP1, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.-59-10C>T is an intronic variant with a MAF of 0.00149 (0.149%, 7/4830,) in the South Asian subpopulation of gnomAD 3.1.2 cohort is ≥ 0.0015 (0.15%)(BA1).This synonymous/intronic variant has a SpliceAI score ≥ 0.20 (0.05) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.40 < 2.0) (BP7). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644644/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:37924 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0558489 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0162830 infores:hetionet NCBIGene:83871 biolink:causes MONDO:0958230 infores:monarchinitiative not_provided not_provided HGNC:16519 MONDO:0958230 uuid:f9e14505-aa05-4961-a1ea-7f94e18d4f35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84883 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0034886 infores:hetionet CHEBI:3723 biolink:causes MONDO:0044986 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0024228 infores:hetionet CAID:CA367397326 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397326 MONDO:0015967 PMID: Pathogenic PS4, PVS1_Strong, PP1_Moderate, PP4_Moderate, PM2_Supporting The c.1254-1G>C variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000162.5. While this variant is predicted to cause skipping of exon 10 and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 27256595, 32375122, internal lab contributors). Additionally, this variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). Lastly, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595). In summary, c.1254-1G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PS4, PP1_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397326/MONDO:0015967/086 2023-07-29 2023-07-29 Semidominant inheritance HP:0032113 Supports GO:0140166 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0140166 GO:0010467 CHEBI:6062 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0281981 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0029408 infores:hetionet CHEBI:3380 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0151480 infores:hetionet CHEBI:8871 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0016204 infores:hetionet CHEBI:474180 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0231856 infores:hetionet CHEBI:9654 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C2225524 infores:hetionet CHEBI:3757 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0039070 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013595 infores:hetionet CHEBI:135005 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0699828 infores:hetionet CHEBI:617099 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0026848 infores:hetionet CHEBI:63619 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0231528 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009806 infores:hetionet CHEBI:63619 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0015672 infores:hetionet CAID:CA16041906 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041906 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting PP3 The NM_000152.5:c.2331+2T>A variant in GAA occurs within the canonical splice donor site of intron 16. RT-PCR of RNA from cultured fibroblasts from a patient who is compound heterozygous for this variant revealed that c.2331+2T>A leads to use of an alternative splice donor at c.2315, resulting in a frameshift, premature stop codon and nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 33168984). Western blot of protein from cultured fibroblasts from another patient with this variant found absence of cross-reactive immunological material for GAA supporting that this variant results in lack of gene product (PMID 22252923)(PVS1). At least 5 patients with Pompe disease have been reported with this variant including 4 patients with documented GAA deficiency (PMID 26693141, 27189384, 32071926)(PP4_Moderate). Of these patients, three are compound heterozygous for the variant and c.-32-13T>G, with one confirmed in trans (PMIDs 27189384, 30922962, 29149851), one is compound heterozygous for the variant and c.1327-61_1437+171del, phase unknown (PMID 32071926), and one patient is homozygous (PMID 26693141)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European non-Finnish population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.97 for donor loss, predicting that the variant disrupts the donor splice site of intron 16 of GAA. But since PVS1 is applied, PP3 cannot be applied at the same time. There is a ClinVar entry for this variant (Variation ID: 371281, 2 star review status) with seven submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (ACMG/AMP specifications version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041906/MONDO:0009290/010 2024-12-19 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2682 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0010200 infores:hetionet CHEBI:92998 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0041834 infores:hetionet CHEBI:9445 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0033117 infores:hetionet CAID:CA120549 biolink:causes MONDO:0044970 infores:clingen CAID:CA120549 MONDO:0044970 PMID:32305257PMID:7689388 Likely Pathogenic PM2_Supporting, PS4_Supporting, PS3_Supporting, PM6 PP3, PP1 The m.15990C>T variant in MT-TP gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). The age of onset ranged from the first decade of life to adulthood. Features seen in these individuals include chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance (PMIDs: 32305257, 7689388, 8190311). The variant occurred de novo in both individuals (PM6; PMIDs: 7689388, 8190311, 32305257). There are no other large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (51.7 percentile) but HmtVAR predicts it to be neutral with a score of 0.1. Single fiber testing in both reported individuals support the functional impact of this variant (PS3_supporting). In one study, there were higher levels of the variant in COX-negative fibers (91-97%) than in COX-positive fibers (63-86%, p= < 0.001; PMID: 7689388). In the other study, there were again higher levels of the variant in COX-negative fibers (89.75 ± 6.84%, n = 20) than in COX-positive fibers (14.00 ± 6.84 %, n = 17; p < 0.001; PMID: 32305257). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotype and functional testing performed in each reported individual. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PM6, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120549/MONDO:0044970/015 2023-02-13 2023-04-03 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria NCBIGene:6647 biolink:causes MONDO:0032828 infores:monarchinitiative not_provided not_provided HGNC:11179 MONDO:0032828 uuid:04c35d07-a70d-4a72-b041-1f535792d126 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0234987 infores:hetionet CHEBI:31622 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0018524 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040435 infores:hetionet GO:0001928 biolink:causes GO:0006887 infores:ubergraph knowledge_assertion manual_agent GO:0001928 GO:0006887 CHEBI:6887 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0004936 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0023530 infores:hetionet CAID:CA2573157370 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157370 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.59-20C>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.05) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.05) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.26) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157370/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3176 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0010037 infores:hetionet CAID:CA229824 biolink:causes MONDO:0009861 infores:clingen CAID:CA229824 MONDO:0009861 PMID:26503515PMID:29499199PMID:9634518PMID:17924342 Uncertain Significance PP4_Moderate, PM2, PP3 PM5 The c.853C>T (p.His285Tyr) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency excluded) (PMID: 9634518, 26503515) This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229824/MONDO:0009861/006 2020-04-03 2020-04-03 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0120107 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0600142 infores:hetionet NCBIGene:55779 biolink:causes MONDO:0054724 infores:monarchinitiative not_provided not_provided HGNC:25631 MONDO:0054724 uuid:9e8111ea-1b2b-44ca-bcff-7621a12fe476 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037763 infores:hetionet CAID:CA9306657 biolink:causes MONDO:0100283 infores:clingen CAID:CA9306657 MONDO:0100283 PMID: Benign BA1 PP2 The c.160G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Val54Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004092 in the European (non Finnish) population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BA1; -8 points (VCEP specifications version 1; Approved: 1/31/2021) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA9306657/MONDO:0100283/018 2022-02-11 2022-02-11 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Contradicts https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:4027 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0016059 infores:hetionet CHEBI:167638 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0007398 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0027769 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0149931 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0948525 infores:hetionet CHEBI:2676 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0025289 infores:hetionet CHEBI:68642 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0024312 infores:hetionet CHEBI:9727 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0019521 infores:hetionet CHEBI:5088 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0018681 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0677500 infores:hetionet CHEBI:9605 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0013604 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0025061 infores:hetionet CAID:CA915940727 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940727 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The ITGA2B frameshift variant NM_000419.5:c.727del (p.Leu243PhefsTer136) introduces a frameshift in exon 7 of 30 total exons and premature termination codon in exon 12. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT41, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM3_Supporting, PP4_Moderate, and PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940727/MONDO:0100326/011 2021-07-14 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5123 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0002994 infores:hetionet CHEBI:63631 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0033774 infores:hetionet CHEBI:36791 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020458 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0042109 infores:hetionet GO:0060787 biolink:causes GO:0001840 infores:ubergraph knowledge_assertion manual_agent GO:0060787 GO:0001840 CHEBI:36795 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232498 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0475765 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0475765 infores:hetionet CAID:CA227886 biolink:causes MONDO:0100438 infores:clingen CAID:CA227886 MONDO:0100438 PMID: Pathogenic PP3_Strong, PP4, PM2_Supporting, PP1_Strong, PM3 NM_014336.5(AIPL1):c.589G>C (p.Ala197Pro) is a missense variant replacing the alanine at position p.197 with proline. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.93 and predicts a damaging effect on AIPL1 function (PP3_Strong). This variant has been reported in 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (PMIDs 10873396, 15024725). (1 point, PM3). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with severe visual impairment from birth or during early infancy (1 pt) accompanied by nystagmus (1 pt), absent or very sluggish pupillary responses (0.5 pts), and absent or markedly reduced electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 4.5 points, PMID: 10873396, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 3 similarly affected relatives, with the variant present in the homozygous state (PP1_Strong; PMID: 10873396). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Strong, PM3, PP4, and PP1_Strong. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227886/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6030 biolink:causes UMLS:C0858814 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0858814 infores:hetionet CHEBI:8869 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0014724 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018790 infores:hetionet CHEBI:38940 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014591 infores:hetionet NCBIGene:103 biolink:causes MONDO:0014007 infores:monarchinitiative not_provided not_provided HGNC:225 MONDO:0014007 uuid:991b466a-28f9-4f1e-a554-beb95df1b1ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0232766 infores:hetionet GO:0072043 biolink:causes GO:0001822 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0001822 CHEBI:36704 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030193 infores:hetionet CHEBI:2682 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019079 infores:hetionet CHEBI:474180 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0038999 infores:hetionet CHEBI:51450 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0700200 infores:hetionet CHEBI:7627 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0033774 infores:hetionet CHEBI:49713 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0151740 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0031350 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0015376 infores:hetionet CHEBI:5103 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0011206 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0235431 infores:hetionet CAID:CA8622840 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622840 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.72C>T (p.Gly24=), no individuals with Glanzmann thrombasthenia were reported with the variant and has only been observed in a ostensibly healthy population. The variant has a minor allele frequency of 0.00110 (18/16424 alleles) in the South Asian population in gnomAD, which does not meet our threshold criteria for PM2_supporting or BS1. In silico predictor SpliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -0.28 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622840/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:3219 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233762 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0948089 infores:hetionet CHEBI:74947 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0028643 infores:hetionet CHEBI:253342 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0040822 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030305 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0435002 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0020649 infores:hetionet CHEBI:8207 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0040264 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0234215 infores:hetionet CHEBI:167638 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C2981158 infores:hetionet CHEBI:8871 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0242339 infores:hetionet CHEBI:50859 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0028734 infores:hetionet CHEBI:27666 biolink:causes HP:0001896 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0858867 infores:hetionet CAID:CA913184971 biolink:causes MONDO:0009861 infores:clingen CAID:CA913184971 MONDO:0009861 PMID:26503515 Pathogenic PVS1, PM2, PP4 The c.184_187insCTGA variant in PAH has been previously reported as a single (heterozygous) mutation in 1 Chinese PKU case (PMID: 26503515; PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184971/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3696 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020639 infores:hetionet CHEBI:32315 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C1458155 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0948594 infores:hetionet CHEBI:6402 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020546 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042571 infores:hetionet CHEBI:48273 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0600142 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041969 infores:hetionet CHEBI:136040 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0232849 infores:hetionet CHEBI:175901 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0017086 infores:hetionet CHEBI:63580 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0025323 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0021053 infores:hetionet CHEBI:3515 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0085631 infores:hetionet CHEBI:18332 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0040822 infores:hetionet CHEBI:7627 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0011603 infores:hetionet CHEBI:50673 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0231528 infores:hetionet CHEBI:8871 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011206 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0035078 infores:hetionet CHEBI:45783 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085649 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0035309 infores:hetionet NCBIGene:63899 biolink:causes MONDO:0033566 infores:monarchinitiative not_provided not_provided HGNC:26208 MONDO:0033566 uuid:34b84544-1c7a-47a9-a965-d6cec960d615 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes UMLS:C0373705 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0373705 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0022660 infores:hetionet CHEBI:63631 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002064 infores:hetionet CHEBI:7465 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0232495 infores:hetionet GO:0072052 biolink:causes CL:1000618 infores:ubergraph knowledge_assertion manual_agent GO:0072052 CL:1000618 CHEBI:28830 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0024312 infores:hetionet CHEBI:16899 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C2363730 infores:hetionet CAID:CA5252712 biolink:causes MONDO:0008535 infores:clingen CAID:CA5252712 MONDO:0008535 PMID: Likely Benign BS1_Supporting, BP2, BP5 The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID: 18498373) which is classified as likely pathogenic (PMID: 18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5252712/MONDO:0008535/136 2024-09-11 2024-09-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31705 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0040053 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1565489 infores:hetionet NCBIGene:8379 biolink:causes MONDO:0859346 infores:monarchinitiative not_provided not_provided HGNC:6762 MONDO:0859346 uuid:18bf0987-635f-4abe-ab09-bd11092e87e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2948 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0151773 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0006277 infores:hetionet CAID:CA390867498 biolink:causes MONDO:0100216 infores:clingen CAID:CA390867498 MONDO:0100216 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PS4_Supporting BP4, BP2, BA1, PP1, BS2, PM5, PM1, PS1, PS3, PS2, BS1, BS3, BS4 The NM_177438.2:c.4697T>C variant in DICER1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 1566 (p.Leu1566Pro). This variant received a total of 1 phenotype point in 1 proband, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal contributor). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 syndrome (PP4, Internal contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.915) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PP3. (Bayesian Points: 4; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390867498/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4798 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0028643 infores:hetionet CHEBI:100241 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0005758 infores:hetionet CHEBI:180905 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C1167965 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036572 infores:hetionet CHEBI:45409 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151594 infores:hetionet NCBIGene:79783 biolink:causes MONDO:0009283 infores:monarchinitiative not_provided not_provided HGNC:16001 MONDO:0009283 uuid:55bb2878-0a9c-4356-bbd1-27cc70928459 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70746 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0041912 infores:hetionet CHEBI:42797 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037384 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0425945 infores:hetionet CHEBI:6916 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0151970 infores:hetionet CHEBI:9086 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0025323 infores:hetionet CHEBI:6888 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0340865 infores:hetionet CHEBI:50922 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0011603 infores:hetionet CHEBI:17347 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0600142 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0031117 infores:hetionet CHEBI:53691 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0042963 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0002170 infores:hetionet CHEBI:6367 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003537 infores:hetionet CHEBI:3219 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013384 infores:hetionet CHEBI:3561 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0232461 infores:hetionet CHEBI:47381 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C2047937 infores:hetionet CAID:CA273573 biolink:causes MONDO:0044970 infores:clingen CAID:CA273573 MONDO:0044970 PMID: Uncertain Significance PP1, PP3, BP4, PS3, PS4, PS2, PM6 The m.1027A>G variant in MT-RNR1 has been reported in six unrelated individuals with primary mitochondrial disease. All had hearing loss (4/6 had aminoglycoside exposure; PMIDs: 21205314, 20100600). The variant was present at homoplasmy in both affected and unaffected individuals from these families. There are no de novo occurrences of this variant to our knowledge. This variant is present in population databases (MITOMAP: 0.028%; gnomAD v3.1.2: 0.025%; Helix: 0.037%). There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): None. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273573/MONDO:0044970/015 2024-08-12 2025-04-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:84500 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0016977 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0027769 infores:hetionet CAID:CA127307 biolink:causes MONDO:0015152 infores:clingen CAID:CA127307 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP1, PM2_Supporting, PM3_Strong, PVS1_Moderate The NM_000070.3: c.2362_2363delinsTCATCT p.(Arg788SerfsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 23/24 that may cause loss of function of the protein, however, it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been detected in at least 30 individuals with limb girdle muscular dystrophy, including in a homozygous state in one patient (0.5 pts, PMID: 18337726), in trans with a pathogenic variant in at least one patient (c.643_663del p.(Ser215_Gly221del), 1.0 pt, PMID: 9150160), and in unknown phase with a pathogenic variant (c.223dup p.(Tyr75LeufsTer5), 0.5 pts, PMID: 30564623, LOVD Individual #00220184) (PM3_Strong). At least one patient with this variant displayed a clinical suspicion of limb girdle muscular dystrophy and absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18337726). The variant has also been reported to segregate with LGMD in one affected family member (PP1; PMID: 9150160). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA127307/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CAID:CA297240 biolink:causes MONDO:0021060 infores:clingen CAID:CA297240 MONDO:0021060 PMID:27236105 Likely Benign BS1, BP5, BP4 PS1, PS2, PS3, PS4, PM5, PM4, PM1, BS3, BS4, BP7, PM6, PM2, BS2, PP1, PP3, PP2, BP3, BP2, BP1, BA1 The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297240/MONDO:0021060/004 2019-06-27 2019-06-28 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5138 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234518 infores:hetionet NCBITaxon:487 biolink:causes MONDO:0018059 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:487 MESH:D008585 DB00263_MESH_D008585_1DB00446_MESH_D008585_1DB00438_MESH_D008585_1DB01212_MESH_D008585_1DB00493_MESH_D008585_1DB01053_MESH_D008585_1DB00415_MESH_D008585_1 CHEBI:7936 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151611 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0006145 infores:hetionet CHEBI:5106 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0234708 infores:hetionet CHEBI:116278 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0011606 infores:hetionet NCBIGene:29929 biolink:causes MONDO:0011291 infores:monarchinitiative not_provided not_provided HGNC:23157 MONDO:0011291 uuid:26eb382a-17f2-49eb-a52f-5122624c210e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6846 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0023530 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0007222 infores:hetionet CHEBI:5959 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013604 infores:hetionet CHEBI:9599 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0030196 infores:hetionet CAID:CA589652 biolink:causes MONDO:0100283 infores:clingen CAID:CA589652 MONDO:0100283 PMID: Uncertain Significance PP2, PM1_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM3, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.4382T>C (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of valine by alanine at residue 1461 (p.Val1461Ala). In gnomAD v4.1.0, this variant has a filtering allele frequency of 0.001962% in the European (non-Finnish) population (PM2_Supporting and BS1 not met). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BM VCEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PP2, PM1_Supporting; 2 points (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA589652/MONDO:0100283/018 2025-07-01 2025-07-01 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:75988 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0033774 infores:hetionet CHEBI:127780 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0003537 infores:hetionet CHEBI:50861 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C1096343 infores:hetionet CHEBI:6715 biolink:causes HP:0005305 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151945 infores:hetionet CHEBI:63617 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013390 infores:hetionet CHEBI:94392 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0013395 infores:hetionet CHEBI:7496 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0021655 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0020517 infores:hetionet CHEBI:3082 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0002962 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233472 infores:hetionet NCBIGene:80144 biolink:causes MONDO:0054737 infores:monarchinitiative not_provided not_provided HGNC:19185 MONDO:0054737 uuid:74af4a66-a8f6-4298-9e87-be98b581e041 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48844 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0033774 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0013395 infores:hetionet CHEBI:27690 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C1443060 infores:hetionet CHEBI:188986 biolink:causes HP:0034808 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1142349 infores:hetionet CHEBI:107736 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0241442 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0948296 infores:hetionet NCBIGene:6616 biolink:causes MONDO:0014590 infores:monarchinitiative not_provided not_provided HGNC:11132 MONDO:0014590 uuid:79c3ab93-e1dd-4373-98a2-3ce87df873b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0920171 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0011053 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0332575 infores:hetionet CHEBI:37333 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0009421 infores:hetionet CHEBI:567361 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0002874 infores:hetionet CAID:CA281968 biolink:causes MONDO:0021060 infores:clingen CAID:CA281968 MONDO:0021060 PMID:25348715PMID:30937965PMID:22495831 Pathogenic PS3, PM1, PM6, PM2, PP3, PP2, PS4_Supporting PM5 The c.1411G>T (p.Val471Phe) variant in BRAF was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in at least 2 individuals diagnosed with RASopathies (PS4_Supporting; PMID: 22495831, 30937965). One of these cases was shown to be a de novo occurrence without maternity or paternity confirmed (PM6). In vitro functional studies provide some evidence that the p.Val471Phe variant may impact protein function (PS3; PMID: 25348715). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; 29493581). Computational prediction tools and conservation analysis suggest that the p.Val471Phe variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA281968/MONDO:0021060/004 2020-06-25 2020-07-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:41879 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0424000 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0575090 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042571 infores:hetionet CHEBI:7627 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0000786 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0019360 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005246 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D010019 DB00479_MESH_D010019_1 CHEBI:6367 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004238 infores:hetionet CHEBI:51173 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0003811 infores:hetionet CHEBI:31643 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0043352 infores:hetionet NCBIGene:3295 biolink:causes MONDO:0009300 infores:monarchinitiative not_provided not_provided HGNC:5213 MONDO:0009300 uuid:7f6d14b3-1aa9-417f-b0c4-2c14e3874da0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C3263723 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0029456 infores:hetionet CHEBI:3423 biolink:causes HP:0030049 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0006105 infores:hetionet CHEBI:5280 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0041657 infores:hetionet CHEBI:3286 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0027497 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026603 infores:hetionet CAID:CA5416772 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416772 MONDO:0011225 PMID: Uncertain Significance BA1, PM2, BS1, PM5 The c.590G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 197 (p.Ser197Asn).The filtering allele frequency (the upper threshold of the 95% CI of 95/1180058 alleles) of the c.590G>A variant in DCLRE1C is 0.00006723 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.Another missense variant [c.589A>G (p.Ser197Gly)] in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not met). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416772/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7445 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0232462 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033975 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0162820 infores:hetionet CHEBI:94848 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0015230 infores:hetionet CHEBI:63617 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0025320 infores:hetionet CAID:CA16604447 biolink:causes MONDO:0021060 infores:clingen CAID:CA16604447 MONDO:0021060 PMID: Uncertain Significance PM1, PM2, PP2 BS2, PP3 The c.1871C>G (p.Ser624Cys) variant in RAF1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been identified in at least 1 unaffected parent of a proband with features of a RASopathy; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000534967.4). RAF1 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16604447/MONDO:0021060/004 2020-07-23 2020-07-27 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6704 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0001824 infores:hetionet CHEBI:9943 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022346 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0948089 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0042075 infores:hetionet CHEBI:7478 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2004489 infores:hetionet CAID:CA340742376 biolink:causes MONDO:0100368 infores:clingen CAID:CA340742376 MONDO:0100368 PMID: Likely Pathogenic PM3_Supporting, PP3_Moderate, PP4_Moderate, PP1, PM2_Supporting NM_000329.3:c.1328T>C(p.Val443Ala) is a predicted missense variant that replaces valine with alanine at position 443 in RPE65. The computational predictor REVEL gives a score of 0.877, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.27 for acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, VCEP member-provided data, PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including onset in early childhood (1 pt), night blindness (required, 0.5 pts), undetectable rod ERG (required, 0.5 pts), decreased peripheral vision (1 pt), poor color vision (1 pt), severely reduced cone ERG responses, reduced visual acuity (1 pt), waxy optic disc (0.5 pts) with optic disc drusen (0.5 pts), and mildly attenuated retinal vessels (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6.5 points, PP4, PMID: 20811047). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative (PMID: 20811047, PP1). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Supporting, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340742376/MONDO:0100368/120 2024-05-10 2024-05-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9566 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0002871 infores:hetionet CHEBI:421707 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0013404 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009760 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0520589 infores:hetionet CAID:CA398324489 biolink:causes MONDO:0011132 infores:clingen CAID:CA398324489 MONDO:0011132 PMID:37419334 Likely Pathogenic PP3, PP4, PM2_Supporting, PS3_Moderate, PM1, PM5_Supporting The NM_001369369.1(FOXN1):c.961C>A (p.His321Asn) missense variant is located within the well-established DNA binding forkhead domain (amino acids 270-367) at amino acid position 321 (PM1). This variant occurs at the same codon as His321Arg which has been classified as Likely Pathogenic by the SCID VCEP (PM5_supporting). Targeted analysis of SCID-associated genes identified this variant in heterozygous state in a newborn (PMID: 31447097) with low TREC level and T cell lymphopenia (14 CD3+ cells/μL) (PP4_Supporting). The variant has a REVEL score of 0.926 which is above the SCID VCEP specified threshold of ≥0.644 for PP3_Supporting to support a deleterious effect of the variant (PP3_Supporting). The variant H321N engineered into the TAT-Foxn1 wildtype protein resulted in a loss of function effect based on the luciferase reported assay (5%) (PS3_Moderate) and led to variable suppressive effects on thymus growth in reaggregate thymus organ cultures (PMID: 37419334). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PM5_Supporting, PP4_Supporting, PP3_Supporting, PS3_Moderate, PM2_Supporting. (VCEP specifications version 1.0.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398324489/MONDO:0011132/113 2025-07-18 2025-07-18 Semidominant inheritance HP:0032113 Supports CHEBI:36791 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0541798 infores:hetionet CAID:CA6909790 biolink:causes MONDO:0015152 infores:clingen CAID:CA6909790 MONDO:0015152 PMID: Likely Benign BS1 BP7, BP4 The NM_000231.3: c.579-17T>G variant in SGCG is an intronic variant that occurs in a splice region (+7/-21). The filtering allele frequency for this variant is 0.001937 for the South Asian population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 172/77950 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.0009 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.18, which is greater than the LGMD threshold of 0.05 (BP4, BP7 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6909790/MONDO:0015152/185 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:127780 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0008031 infores:hetionet CHEBI:3032 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0009676 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0233494 infores:hetionet GO:0099041 biolink:causes GO:0048193 infores:ubergraph knowledge_assertion manual_agent GO:0099041 GO:0048193 CHEBI:8713 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0010200 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0553704 infores:hetionet CHEBI:46195 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0028084 infores:hetionet CHEBI:35677 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0004096 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038367 infores:hetionet UNII:8NZ41MIK1O biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0018944 infores:hetionet CHEBI:64355 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027497 infores:hetionet CHEBI:61033 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0236024 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004096 infores:hetionet CHEBI:204928 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0002994 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0748536 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0748536 infores:hetionet CHEBI:63617 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0012569 infores:hetionet CHEBI:17650 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0267940 infores:hetionet CHEBI:17698 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0000731 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0018939 infores:hetionet CHEBI:2611 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0344232 infores:hetionet CHEBI:421707 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0035243 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0021053 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009763 infores:hetionet CHEBI:6801 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0040460 infores:hetionet CHEBI:83804 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020578 infores:hetionet CHEBI:135930 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0917801 infores:hetionet CHEBI:3764 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0042109 infores:hetionet CHEBI:4909 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0001824 infores:hetionet CHEBI:28177 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0002792 infores:hetionet CHEBI:94501 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151904 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017152 infores:hetionet NCBIGene:10758 biolink:causes MONDO:0014230 infores:monarchinitiative not_provided not_provided HGNC:1343 MONDO:0014230 uuid:34edc357-b2ff-4b0a-adb1-b9c56939134b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0030193 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0347390 infores:hetionet NCBIGene:22 biolink:causes MONDO:0010524 infores:monarchinitiative not_provided not_provided HGNC:48 MONDO:0010524 uuid:ac33b675-936f-4473-bcc2-3a0a21764a22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0233494 infores:hetionet CHEBI:74947 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0001925 infores:hetionet CHEBI:9362 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0019087 infores:hetionet CHEBI:145499 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0030193 infores:hetionet CHEBI:50692 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0002994 infores:hetionet CHEBI:32020 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0003862 infores:hetionet CHEBI:6062 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013404 infores:hetionet CHEBI:6375 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014848 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0002871 infores:hetionet CHEBI:63619 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018808 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0278080 infores:hetionet CHEBI:2682 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002390 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002453 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0033117 infores:hetionet NCBIGene:79876 biolink:causes MONDO:0014934 infores:monarchinitiative not_provided not_provided HGNC:23230 MONDO:0014934 uuid:81c8d0e0-a281-47e9-a312-6211e9beaf3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C1328337 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0022658 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085096 infores:hetionet CHEBI:101085 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0086525 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0032461 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0227791 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0024115 infores:hetionet UMLS:C0657912 biolink:causes HP:0034773 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0422980 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042035 infores:hetionet CHEBI:291342 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0033774 infores:hetionet CHEBI:4027 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0344232 infores:hetionet CHEBI:51164 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0042963 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0948525 infores:hetionet GO:0061930 biolink:causes GO:0048822 infores:ubergraph knowledge_assertion manual_agent GO:0061930 GO:0048822 UNII:VL0L558GCB biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151799 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0518015 infores:hetionet CHEBI:4657 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0042023 infores:hetionet GO:1900154 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:1900154 GO:0048513 CAID:CA367398281 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398281 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM1, PP4, PP2, PP3, PM2_Supporting PS4 The c.1235T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 412 (p.(Val412Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1235T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398281/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:7936 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017675 infores:hetionet CHEBI:4702 biolink:causes HP:0012155 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0859996 infores:hetionet GO:1901301 biolink:causes GO:0090114 infores:ubergraph knowledge_assertion manual_agent GO:1901301 GO:0090114 CAID:CA1619847 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619847 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PM5_Strong, PP1_Strong, PP3_Strong BA1, BP4, PM1, PM4, PS1, PS2, PS3, BP7, BS1, BS4, PVS1 The c.1168C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 390 (p.Arg390Cys). The highest minor allele frequency of this variant was in the Remaining genetic ancestry group of gnomAD (v4.1.0) = 0.00006402 (4 alleles out of 62,484), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.965, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on CYP1B1 function. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 21081970), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in five individuals with a CYP1B1-related phenotype. Three of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) (PMIDs: 23218701, 38755526, 21081970). Two individuals are homozygous (non-consanguineous) for the variant (PMID: 14507861). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. Two other missense variants (p.Arg390His, Grantham score = 29, ClinVar ID: 592512 and p.Arg390Ser, Grantham score = 110, ClinVar ID: 2203048) in the same codon have been classified as pathogenic for a CYP1B1-related phenotype by the ClinGen Glaucoma VCEP. CYP1B1:p.Arg390Cys has a higher Grantham score (= 180) than the previously classified amino acid changes, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Strong to apply. In summary, this variant met the criteria to receive a score of 18 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very Strong, PM5_Strong, PP1_Strong, PP3_Strong, PM2_Supporting (combination of PP3 and PM5 is capped at 5 points). Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619847/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6801 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0009938 infores:hetionet CHEBI:16755 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0497156 infores:hetionet CHEBI:52172 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151786 infores:hetionet CHEBI:28177 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0033774 infores:hetionet CAID:CA412744917 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744917 MONDO:0100437 PMID: Pathogenic PP3_Strong, PM2_Supporting, PS4_Moderate, PP1_Strong PM6, PP4, PM5 NM_001034853.2(RPGR):c.494G>A (p.Gly165Asp) is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 165. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one male proband harboring this variant has onset before age 30 years (required), macular integrity assessment of 0, optic nerve pallor (0.5 pts), pigmentary retinopathy (0.5 pts), nyctalopia (0.5 pts), decreased central vision acuity (0.5 pts), and high myopia (1 pt), combined with panel-based genotyping that excludes alternative causes in other relevant loci (2 pts), but cannot meet PP4 due to the absence of the reduced electroretinogram requirement (5 pts total, PMID: 27596865). This variant has been identified as a de novo occurrence in this proband, with an assumed but unconfirmed maternal relationship (0.25 pts, PMID: 27596865), however, de novo points were not sufficient to meet PS2_Supporting. This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, with decreased or absent cone and/or rod electroretinogram responses (PMIDs: 31456290, 27596865, 30887160, PS4_Moderate).The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses total from at least 2 families (PP1_Strong; PMIDs: 30887160, 31456290). Another missense variant in the same codon, NM_001034853.2(RPGR):c.494G>T (p.Gly165Val), has a higher Grantham score than this variant, so PM5 has not been considered. The computational predictor REVEL gives a score of 0.968, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_strong). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP1_strong, PS4_moderate, and PP3_strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744917/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Supports UNII:R43D2573WO biolink:causes NCIT:C112180 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0239343 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0003123 infores:hetionet CHEBI:101853 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0030305 infores:hetionet CHEBI:4562 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0000737 infores:hetionet CHEBI:68478 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0242528 infores:hetionet CHEBI:567361 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1565489 infores:hetionet CHEBI:4027 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085605 infores:hetionet CAID:CA327012012 biolink:causes MONDO:0100039 infores:clingen CAID:CA327012012 MONDO:0100039 PMID: Likely Benign BS1, BS2_Supporting, BP4 PM1 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2783C>T (p.Thr928Met) variant in CDKL5 transcript (NM_003159.2) (RS1 c.326+1115G>A) is 0.0188% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Thr928Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). Additionally, the p.Thr928Met variant is observed in at least 1 unaffected individual (PMID: 31209962) (BS2_supporting). In summary, the p.Thr928Met variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA327012012/MONDO:0100039/034 2023-02-20 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:52717 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019079 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0018802 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0221490 infores:hetionet CHEBI:6909 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0028643 infores:hetionet CAID:CA248618 biolink:causes MONDO:0011071 infores:clingen CAID:CA248618 MONDO:0011071 PMID:11830488PMID:11830488PMID:11830488PMID:11830488 Pathogenic PS3, PP1_Strong, PS4_Supporting, PM2_Supporting, PP3 PS1, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, BP7, BP5, BS3, BS1, BS4, PM6, PM4, PM1, PM5, PM3, PP2, PP4, BS2 There is RT-PCR assay evidence demonstrating that the NM_001754.4:c.508+3delA variant creates a cryptic splice donor site that is used and results in a frameshift and introduction of premature termination codon (PS3; PMID: 11830488). This variant was found to co-segregate with disease in multiple affected family members, with eight meioses observed in one family (PP1_Strong; PMID: 11830488). It is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant (in intron 5) is located in reference to the exon at positions +3 for donor splice site and has a predicted decrease in the score of the canonical splice site by at least 75% (measured by both MES and SSF). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM2_supporting, PP3, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248618/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16469 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020488 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0002453 infores:hetionet NCBIGene:3604 biolink:causes MONDO:0859526 infores:monarchinitiative not_provided not_provided HGNC:11924 MONDO:0859526 uuid:bc5cb97a-b5eb-4264-b934-f29f6d78842c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:253017 biolink:causes MONDO:0013529 infores:monarchinitiative not_provided not_provided HGNC:27365 MONDO:0013529 uuid:cb01e908-aac9-4b7e-8d5e-c393e6c67359 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0030193 infores:hetionet CHEBI:8764 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085679 infores:hetionet CHEBI:92923 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0152227 infores:hetionet CAID:CA8603055 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603055 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting BP4 The NM_000419.5:c.1537G>A (p.Val513Met) variant in ITGA2B is a missense variant which is predicted to cause substitution of Valine by Methionine at amino acid 513. This variant has been reported to ClinVar in association with Glanzmann thrombasthenia (affected status unknown (Accession: VCV000888902.6). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008912 (4/44882 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.50 for donor site loss, predicting that the variant disrupts the splice site of intron 15 of ITGA2B (PP3).In summary, this variant meets the criteria to be classified as a variant of unknown significance due to insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603055/MONDO:0100326/011 2024-11-07 2024-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63791 biolink:causes MONDO:0006507 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018995 infores:hetionet CHEBI:45327 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0033036 infores:hetionet CHEBI:3485 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0151594 infores:hetionet CHEBI:5613 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011168 infores:hetionet CHEBI:10127 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017565 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027813 infores:hetionet GO:0010717 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:0010717 GO:0048513 CHEBI:92923 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0009450 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013298 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020517 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0022660 infores:hetionet CHEBI:63598 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013362 infores:hetionet CHEBI:49375 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C2830004 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0042109 infores:hetionet CHEBI:8802 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0547030 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0234913 infores:hetionet CAID:CA399803524 biolink:causes MONDO:0100326 infores:clingen CAID:CA399803524 MONDO:0100326 PMID:34275420 Likely Pathogenic PP4_Strong, PS3_Supporting, PP3, PM2_Supporting, PM3_Supporting "The NM_000419.5(ITGA2B):c.1361G>A (p.Gly454Asp) variant has been reported, in the homozygous state, in at least one GT proband (P3 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). Surface expression of αIIbβ3 measured by flow cytometry in COS-7 cells transiently co-transfected with Gly454Asp variant αIIb and wild type β3 showed impaired expression levels. There is a clear decrease in percent positive cells with near absence interpreted as <25% (PMID: 34275420; PS3_supporting). The variant is predicted deleterious (REVEL score 0.812). This variant is absent from gnomAD v2.1.1 and present in gnomADv4.1 on 1 allele in the ""Remaining"" genetic ancestry group (PM2_supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporting, PP4_strong, PS3_supporting, and PP3." Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399803524/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6472 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0002994 infores:hetionet CHEBI:75722 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232849 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0041912 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018799 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0026946 infores:hetionet CHEBI:8024 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0085631 infores:hetionet NCBIGene:5147 biolink:causes MONDO:0014297 infores:monarchinitiative not_provided not_provided HGNC:8788 MONDO:0014297 uuid:9693c666-6c3c-42c8-9252-e8196f97d551 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3738 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0349506 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151479 infores:hetionet GO:0021936 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0021936 GO:0007417 CAID:CA10014224 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014224 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.998C>T (p.Pro333Leu) is a missense variant with a MAF of 0.0001937 (0.01937%, 1/5162, 1 allele) in the East Asian subpopulation of the gnomAD v3.1.2 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score < 0.50 (0.346) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014224/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5855 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0852810 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027430 infores:hetionet CHEBI:6076 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042384 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0003123 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0021167 infores:hetionet NCBIGene:10015 biolink:causes MONDO:0031060 infores:monarchinitiative not_provided not_provided HGNC:8766 MONDO:0031060 uuid:26a9638d-b923-4bd3-b71d-4d20da35ba9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367402194 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402194 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1, PP1 The c.374A>G variant in the glucokinase gene, GCK, causes an amino acid change of tyrosine to cysteine at codon 125 (p.(Tyr125Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19790256, ClinVar: 1705456, internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies as well as a three generation dominant family history of diabetes) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.374A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402194/MONDO:0015967/086 2025-04-07 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:31547 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0033774 infores:hetionet CAID:CA16020760 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020760 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The c.277_280del (p.Asn93SerfsTer5) variant in PAH results in a frameshift in exon 3, with NMD predicted. It was reported in a Polish patient with classic PKU, with pathogenic variant p.R408W (PMID: 24350308). It is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2_supporting, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020760/MONDO:0009861/006 2023-10-13 2023-10-29 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:8575 biolink:causes MONDO:0012789 infores:monarchinitiative not_provided not_provided HGNC:9438 MONDO:0012789 uuid:f4f44b98-57a6-40d3-bfd2-ea3093dfe0d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6456 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0332563 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0024902 infores:hetionet CHEBI:8888 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0541798 infores:hetionet CAID:CA913163107 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163107 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS4, PS3 The m.10406G>A variant in MT-TR has been reported in two individuals with primary mitochondrial disease (PMIDs: 17588757, 31965079). Clinical features in affected individuals include myopathy, autism spectrum disorder, and exercise intolerance. The first reported individual had reduced activities of complexes I and IV in skeletal muscle had the variant present at 96% heteroplasmy in muscle, 94% in urine, 36% in buccal mucosa, 29% in blood, and 0-7% in hair follicles (PMID: 17588757). The variant was undetectable in the mother and siblings (PMID: 17588757; PM6_supporting). The variant was present at 17% heteroplasmy in blood in the second reported individual and information on family members was not provided (PMID: 31965079). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). MitoTIP predicts the variant is possibly pathogenic (72.3 percentile) and HmtVAR predicts the variant is pathogenic (score of 0.45; PP3). There are no single fiber studies or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163107/MONDO:0044970/015 2024-12-03 2025-11-07 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8356 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006852 infores:hetionet CHEBI:4868 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0600142 infores:hetionet CHEBI:49575 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C2981158 infores:hetionet CHEBI:68642 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0020621 infores:hetionet CHEBI:4814 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0039231 infores:hetionet CHEBI:41774 biolink:causes MONDO:0000088 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0034013 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0006266 infores:hetionet CHEBI:16480 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0036572 infores:hetionet UMLS:C0065374 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0012569 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0232431 infores:hetionet CHEBI:17303 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0600104 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0031350 infores:hetionet CHEBI:7936 biolink:causes HP:0004332 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0427546 infores:hetionet CHEBI:63622 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0033774 infores:hetionet CHEBI:4953 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0013604 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0233494 infores:hetionet CHEBI:10101 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020433 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234458 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0003123 infores:hetionet CHEBI:3001 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0086543 infores:hetionet CHEBI:39669 biolink:causes MONDO:0004835 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0238124 infores:hetionet NCBIGene:3766 biolink:causes MONDO:0013005 infores:monarchinitiative not_provided not_provided HGNC:6256 MONDO:0013005 uuid:68de155e-5ce1-4f73-844d-a51f70d4512b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0086132 infores:hetionet CHEBI:6367 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085631 infores:hetionet CHEBI:38562 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0042963 infores:hetionet CHEBI:3756 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0023380 infores:hetionet CHEBI:168396 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085633 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0587054 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0587054 infores:hetionet CHEBI:3213 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0085680 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002622 infores:hetionet CHEBI:35778 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0162297 infores:hetionet CHEBI:46557 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0037317 infores:hetionet NCBIGene:9531 biolink:causes MONDO:0976226 infores:monarchinitiative not_provided not_provided HGNC:939 MONDO:0976226 uuid:d1bf60d3-998d-4481-8623-12789dda805e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039070 infores:hetionet CAID:CA066877 biolink:causes MONDO:0007783 infores:clingen CAID:CA066877 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Proline with Serine at codon 1773 of the RYR1 protein, p.(Pro1773Ser). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0147, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA066877/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:5138 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151825 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0233794 infores:hetionet CAID:CA10591069 biolink:causes MONDO:0700268 infores:clingen CAID:CA10591069 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.5236C>G variant in BRCA1 is a missense variant predicted to cause substitution of Histidine by Aspartic Acid at amino acid 1746 (p.(His1746Asp)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10591069/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports GO:0141158 biolink:causes GO:0090382 infores:ubergraph knowledge_assertion manual_agent GO:0141158 GO:0090382 CHEBI:51380 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0030312 infores:hetionet CHEBI:8871 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151905 infores:hetionet CHEBI:3380 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C1443060 infores:hetionet CHEBI:94385 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0009806 infores:hetionet CHEBI:52172 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020598 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0021400 infores:hetionet CHEBI:64310 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0009806 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0242350 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015300 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020458 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0035078 infores:hetionet CHEBI:63608 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0877192 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0029456 infores:hetionet CHEBI:6804 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0041657 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0858589 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0858589 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0002994 infores:hetionet CHEBI:68606 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C1522133 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0005779 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0235431 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0000833 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0021053 infores:hetionet CHEBI:63620 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0012569 infores:hetionet CHEBI:39867 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0242422 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0520589 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0855704 infores:hetionet CHEBI:31932 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0851578 infores:hetionet CAID:CA512232222 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232222 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.903C>T (p.Pro301=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.05) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232222/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45285 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0005778 infores:hetionet CAID:CA915952142 biolink:causes MONDO:0010305 infores:clingen CAID:CA915952142 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_005629.4:c.457dup (p.Ala153GlyfsTer36) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 out of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. and v.4.1.0. ((PM2_Supporting). To out knowledge, this variant has not been reported in the literature in individuals with creatine transporter deficiency. There is a ClinVar entry for this variant (Variation ID: 651752). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen Cerebral creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM2_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 9, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952142/MONDO:0010305/027 2025-01-09 2025-01-09 X-linked inheritance HP:0001417 Supports CHEBI:3175 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C2830004 infores:hetionet CHEBI:4511 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0040046 infores:hetionet CAID:CA023959 biolink:causes MONDO:0007783 infores:clingen CAID:CA023959 MONDO:0007783 PMID: Pathogenic PP1, PS3_Moderate, PM1, PS4, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with histidine at codon 401 of the RYR1 protein, p.(Arg401His). The maximum allele frequency for this variant in the Finish population in gnomAD was 0.000046 with one alternate allele. This variant was not identified in any of the six continental populations in gnomAD. This is consistent with pathogenicity. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:12059893, PMID:16163667, PMID:30236257, PMID:23460944, PMID:24433488). This variant segregates with MHS in three individuals, PP1_Supporting ( PMID:12059893). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:26115329, PMID:31841587). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:12059893). A REVEL score >0.85 (0.903) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Supporting, PP3_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023959/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ NCBIGene:30813 biolink:causes MONDO:0013618 infores:monarchinitiative not_provided not_provided HGNC:12723 MONDO:0013618 uuid:399131fa-c728-485f-8f1c-fd2c77ba556b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6710 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0042109 infores:hetionet UBERON:0001016 biolink:causes GO:0007610 infores:ubergraph knowledge_assertion manual_agent UBERON:0001016 GO:0007610 CHEBI:8024 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0021775 infores:hetionet CHEBI:4708 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013428 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0948586 infores:hetionet NCBIGene:6340 biolink:causes MONDO:0013112 infores:monarchinitiative not_provided not_provided HGNC:10602 MONDO:0013112 uuid:728e3ecc-8015-4eeb-87d8-830220c79ece biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48131 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0151908 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0037274 infores:hetionet CHEBI:6456 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0020453 infores:hetionet UMLS:C0004609 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0235439 infores:hetionet CHEBI:31348 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0016059 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0009760 infores:hetionet CHEBI:28830 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0027813 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042267 infores:hetionet CHEBI:2038 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0031256 infores:hetionet CHEBI:16714 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0017178 infores:hetionet CHEBI:9086 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0041657 infores:hetionet CAID:CA135584 biolink:causes MONDO:0021060 infores:clingen CAID:CA135584 MONDO:0021060 PMID: Benign BA1, BP5 BS1, PM2 The c.531_533delGAA variant in the KRAS gene is an in-frame deletion of the amino acid lysine (Lys) at position 180 (p.Lys180del). The gnomAD v.4.1.0 filtering allele frequency of this variant is 0.1339% for European (non-Finnish) chromosomes (1637/1177578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 21766, 26957; ClinVar SCV000061947, SCV000207865). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135584/MONDO:0021060/044 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64312 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0232462 infores:hetionet CHEBI:478164 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0700345 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027932 infores:hetionet NCBIGene:10844 biolink:causes MONDO:0032893 infores:monarchinitiative not_provided not_provided HGNC:18599 MONDO:0032893 uuid:9385b767-498b-42dc-af55-992e6daa03b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549373 infores:hetionet GO:1904086 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1904086 GO:0009790 CHEBI:167309 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0428977 infores:hetionet CAID:CA10585649 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585649 MONDO:0007750 PMID: Uncertain Significance PM3, PM2 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1845+15C>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PM3 - Variant meets PM2 and is identified in an index case published in PMID: 30269829 with homozygous FH phenotype (LDL-C = 14.5 mmol/l) and also duplication of whole PCSK9 gene, classified as Pathogenic by the general ACMG guidelines. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585649/MONDO:0007750/013 2022-07-22 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31711 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0004604 infores:hetionet CHEBI:6715 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0035222 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0034063 infores:hetionet CHEBI:47657 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0001339 infores:hetionet GO:0080113 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0080113 GO:0061458 CHEBI:135930 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0042109 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042075 infores:hetionet CHEBI:31981 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0023052 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0004239 infores:hetionet CHEBI:5801 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0022107 infores:hetionet CHEBI:10650 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037036 infores:hetionet CHEBI:28901 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0546817 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0442874 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040053 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0595883 infores:hetionet NCBIGene:22861 biolink:causes MONDO:0060457 infores:monarchinitiative not_provided not_provided HGNC:14374 MONDO:0060457 uuid:2357378a-de4e-4292-b55a-8ec892bba983 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0392525 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0442874 infores:hetionet CHEBI:50922 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0947912 infores:hetionet NCBIGene:7436 biolink:causes MONDO:0024542 infores:monarchinitiative not_provided not_provided HGNC:12698 MONDO:0024542 uuid:32c13437-caf1-40c7-a078-4fd858673b79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3845 biolink:causes MONDO:0001187 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0001187 uuid:2c6dfd4f-e9aa-42b8-9bc6-449fafa0a406 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA396458013 biolink:causes MONDO:0007648 infores:clingen CAID:CA396458013 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP3, PP2, PP4, PP1, BP4, BP1, BP3, BP2, BA1, PS3, PS1, PS2 The c.614T>C (p. Phe205Ser) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; internal laboratory contributor). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396458013/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6067 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0542571 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018801 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0270810 infores:hetionet CHEBI:7447 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0151799 infores:hetionet CHEBI:83804 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0234022 infores:hetionet CAID:CA392326412 biolink:causes MONDO:0007947 infores:clingen CAID:CA392326412 MONDO:0007947 PMID: Uncertain Significance PP2, PM1, PM5 PM2, PP3 The NM_00138 c.3409C>T is a missense variant in FBN1 predicted to cause a substitution of a an arginine by cysteine at amino acid 1137 (p. Arg1137Cys) within a calcium binding EGF-like domain of the protein. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant has been reported four times in ClinVar: twice as likely pathogenic and twice as uncertain significance (Variation ID: 928903). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is present in 3/74922 (0.004%) of alleles tested from the African/African American population gnomAD (https://gnomad.broadinstitute.org/ v4.0.0). A different missense variant affecting the same residue, p.Arg1137Pro, has been previously reported in individuals with Marfan syndrome and was observed to de novo (PMID 1852208, PM5). Computational prediction tools and conservation analysis are inconclusive data with regards to a possible impact on this variant protein function and structure (REVEL: 0.736). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PP2 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392326412/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3032 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C2697368 infores:hetionet NCBIGene:55670 biolink:causes MONDO:0013939 infores:monarchinitiative not_provided not_provided HGNC:22965 MONDO:0013939 uuid:26c28412-7f09-4677-9280-23dd382f0973 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0022354 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020517 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0151735 infores:hetionet CHEBI:367163 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0002962 infores:hetionet CHEBI:135342 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0080274 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001505 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019187 infores:hetionet NCBIGene:23592 biolink:causes MONDO:0008157 infores:monarchinitiative not_provided not_provided HGNC:28887 MONDO:0008157 uuid:489d1afd-3ba9-429c-96e5-ab98670569d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5269 biolink:causes MONDO:0013269 infores:monarchinitiative not_provided not_provided HGNC:8950 MONDO:0013269 uuid:d0ed8f09-3267-422b-8c2b-837b787d2354 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0155626 infores:hetionet GO:1903023 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0030154 CHEBI:9352 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0012739 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0919874 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007114 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014742 infores:hetionet CHEBI:48273 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0231528 infores:hetionet CHEBI:64355 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0028081 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0016382 infores:hetionet CHEBI:4735 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0231218 infores:hetionet CHEBI:50131 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0518988 infores:hetionet CAID:CA2695202180 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695202180 MONDO:0100437 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PS4_Supporting BS2, BA1, BS1 NM_001034853.2(RPGR):c.3394_3395del (p.Asn1132ArgfsTer11) is a frameshift variant due to 2-nucleotide deletion that introduces a premature stop codon in exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including cone dystrophy with macular atrophy (1 pt) with onset in the first decade (1 pt), electroretinogram recordings showing severely reduced cone amplitudes with normal rod amplitudes (1 pt), abnormal color vision (0.5 pts), decreased central visual acuity (0.5 pts), photophobia (1 pts), and family history consistent with X-linked inheritance (2 pts) with delayed or milder phenotype in female family members (1 pts), which together are highly specific for RPGR-related retinopathy (8 points, PMID: 16969763, PP4_Moderate). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male harboring a truncating variant after c.2128 with a diagnosis of cone or cone-rod dystrophy, in addition to the apparently unrelated proband previously used for the PP4 code (PMIDs: 25283059, 16969763, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_supporting, PM2_supporting, and PP4_moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202180/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:8888 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024305 infores:hetionet CHEBI:31859 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0424295 infores:hetionet CHEBI:45951 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0002792 infores:hetionet CHEBI:31624 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0033774 infores:hetionet CHEBI:5280 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0085932 infores:hetionet NCBIGene:4040 biolink:causes MONDO:0014749 infores:monarchinitiative not_provided not_provided HGNC:6698 MONDO:0014749 uuid:db4c8cf5-b67b-4fb7-a094-c693da037e66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0267596 infores:hetionet CHEBI:144093 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0028734 infores:hetionet CHEBI:473990 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0011991 infores:hetionet CHEBI:6690 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0236075 infores:hetionet CHEBI:119915 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015967 infores:hetionet CHEBI:8768 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027796 infores:hetionet CHEBI:15407 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0009676 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151559 infores:hetionet CHEBI:681569 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0423791 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027769 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0699893 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0349506 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0857257 infores:hetionet CHEBI:9566 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0023530 infores:hetionet CHEBI:7640 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0020458 infores:hetionet CHEBI:39585 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0019080 infores:hetionet CHEBI:40237 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C1443060 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151571 infores:hetionet CHEBI:2948 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0002886 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0021053 infores:hetionet CHEBI:4514 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C2242996 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0004936 infores:hetionet CHEBI:7822 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0344232 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0919874 infores:hetionet CAID:CA405666261 biolink:causes MONDO:0007783 infores:clingen CAID:CA405666261 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of cysteine with tyrosine at codon 2237 of the RYR1 protein, p.Cys2237Tyr. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:24433488). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.939) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405666261/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:27565 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0019158 infores:hetionet CAID:CA410206888 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206888 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.689A>G (p.Gln230Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206888/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8888 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0403632 infores:hetionet CHEBI:9139 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0013447 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0012833 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0235416 infores:hetionet CHEBI:50223 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0033774 infores:hetionet CHEBI:7798 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C1257843 infores:hetionet CHEBI:50777 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0600142 infores:hetionet CHEBI:71941 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0042109 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0042401 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0233414 infores:hetionet CHEBI:31236 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037036 infores:hetionet CHEBI:3387 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162830 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0009450 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020649 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0014518 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0011551 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000931 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151622 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042035 infores:hetionet CAID:CA288016 biolink:causes MONDO:0007648 infores:clingen CAID:CA288016 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP3, PP2, PP1, PP4, BS2, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.1018A>G (p.Thr340Ala) variant has an allele frequency of 0.00360 (0.36%, 68/18,866 alleles) in the East Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288016/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5801 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0028077 infores:hetionet CHEBI:16796 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0042075 infores:hetionet NCBIGene:2162 biolink:causes MONDO:0013187 infores:monarchinitiative not_provided not_provided HGNC:3531 MONDO:0013187 uuid:c3f9bd3b-2f83-4b93-82fc-fe66e2c2072a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020651 infores:hetionet CHEBI:36791 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235490 infores:hetionet CHEBI:63631 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020458 infores:hetionet CHEBI:3312 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0015967 infores:hetionet CAID:CA3060570859 biolink:causes MONDO:0011071 infores:clingen CAID:CA3060570859 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.260del (p.Gly87fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). This frameshift variant is downstream of c.98 (PM5_supporting) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3060570859/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8207 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C1443060 infores:hetionet CHEBI:3310 biolink:causes UMLS:C3267206 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C3267206 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0855242 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0006826 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0001824 infores:hetionet CHEBI:144093 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0004690 infores:hetionet CHEBI:2666 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0344232 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0017178 infores:hetionet GO:0008359 biolink:causes GO:0009994 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0009994 CHEBI:2668 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0231218 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009763 infores:hetionet CHEBI:28148 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0027709 infores:hetionet CHEBI:71415 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0017178 infores:hetionet CHEBI:127780 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085641 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020550 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085584 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003864 infores:hetionet CHEBI:240107 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0010037 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0948089 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020615 infores:hetionet CHEBI:52010 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0085631 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C2938875 infores:hetionet NCBIGene:958 biolink:causes MONDO:0011735 infores:monarchinitiative not_provided not_provided HGNC:11919 MONDO:0011735 uuid:f950e693-61f8-48cf-9a5d-e405c35268de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3437 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0041657 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0917801 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0041969 infores:hetionet CHEBI:209807 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0001824 infores:hetionet CHEBI:63584 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0018681 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1384666 infores:hetionet CHEBI:6062 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0002962 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0948089 infores:hetionet CHEBI:9725 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0027424 infores:hetionet NCBIGene:5573 biolink:causes MONDO:0009719 infores:monarchinitiative not_provided not_provided HGNC:9388 MONDO:0009719 uuid:0512ce60-4206-4959-b9d9-bbf58d887066 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0040822 infores:hetionet CHEBI:47780 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0015967 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0033581 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0853692 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014130 infores:hetionet CHEBI:168396 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0016204 infores:hetionet CHEBI:2914 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0033774 infores:hetionet GO:1904156 biolink:causes CL:0000807 infores:ubergraph knowledge_assertion manual_agent GO:1904156 CL:0000807 CHEBI:43968 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0027769 infores:hetionet CHEBI:41423 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0700590 infores:hetionet CHEBI:63580 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011175 infores:hetionet CHEBI:6402 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C2242588 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0340865 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0012833 infores:hetionet CHEBI:3061 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0040822 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027769 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0011615 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042373 infores:hetionet NCBIGene:5019 biolink:causes MONDO:0009492 infores:monarchinitiative not_provided not_provided HGNC:8527 MONDO:0009492 uuid:0a48e1ce-7603-4f24-abb1-d9b9a71b43f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2788 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0392163 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0221047 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0221047 infores:hetionet NCBIGene:79703 biolink:causes MONDO:0032747 infores:monarchinitiative not_provided not_provided HGNC:26197 MONDO:0032747 uuid:e91487c2-b945-4e24-9c9b-372d374492d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0039231 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019360 infores:hetionet CAID:CA2802458 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802458 MONDO:0001586 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PM5, BS1, BA1, PP4 The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PM2 Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802458/MONDO:0001586/091 2024-12-06 2025-07-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:49575 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0028738 infores:hetionet CHEBI:68575 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0018681 infores:hetionet CHEBI:49040 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151576 infores:hetionet CHEBI:4995 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018979 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0001824 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042035 infores:hetionet UMLS:C0120107 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0043094 infores:hetionet CHEBI:3219 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085636 infores:hetionet CHEBI:134991 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0000737 infores:hetionet CHEBI:27899 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1443060 infores:hetionet CHEBI:15765 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0023222 infores:hetionet CHEBI:4888 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0011991 infores:hetionet CHEBI:101278 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C2830004 infores:hetionet CHEBI:180905 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0085649 infores:hetionet CHEBI:75988 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0220981 infores:hetionet CHEBI:75045 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C1167791 infores:hetionet CHEBI:63577 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0035455 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0234458 infores:hetionet CHEBI:77260 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0025222 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0855242 infores:hetionet CHEBI:3082 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0234238 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027051 infores:hetionet CHEBI:7476 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013491 infores:hetionet CHEBI:53760 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0235195 infores:hetionet CHEBI:17141 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0009782 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0010692 infores:hetionet CHEBI:63618 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0851578 infores:hetionet CHEBI:28787 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0002994 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022081 infores:hetionet CHEBI:465284 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013378 infores:hetionet CHEBI:7640 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0030554 infores:hetionet CHEBI:17263 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0000729 infores:hetionet CAID:CA399795907 biolink:causes MONDO:0100326 infores:clingen CAID:CA399795907 MONDO:0100326 PMID:17488698 Likely Pathogenic PM3, PP4_Strong, PM2_Supporting PP3, BP4, PS3 The missense variant NM_000419.5(ITGA2B):c.2437C>A (p.His813Asn) has been reported in at least one patient (PMID: 17488698) with mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 4.5%, as measured by flow cytometry (PP4_strong). The patient is compound heterozygous for in trans variants c.1771dup (classified Pathogenic by the PD-EP) and His813Asn (PM3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399795907/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6633 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0002878 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030332 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0031350 infores:hetionet UMLS:C0657912 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151905 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014549 infores:hetionet CAID:CA402995274 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995274 MONDO:0012999 PMID: Likely Pathogenic PVS1, PM2_Supporting BA1 The NM_000156.6:c.419C>A (p.Ser140Ter) variant in GAMT is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant exon 4 out of 6 exons that leads to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v4.1.0. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with GAMT deficiency. There is a ClinVar entry for this variant (Variation ID: 225369). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 25, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995274/MONDO:0012999/026 2025-04-25 2025-04-25 Autosomal recessive inheritance HP:0000007 Supports CAID:CA351756706 biolink:causes MONDO:0008667 infores:clingen CAID:CA351756706 MONDO:0008667 PMID: Uncertain Significance PVS1_Moderate PS4, BS1 The variant NM_000551.4(VHL):c.634G>T (p.Gly212Ter) is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein. It is within 2 amino acids from the last in VHL, and AA 205-213 have unknown or uncertain function in the protein (PVS1_Moderate). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00001063 (3/74922 from African/African American Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of >=0.0000156 (0.00156%) for BS1, and therefore does not meet any criterion (BS1, BA1, PM2_Supporting are not met). A total of 12 cases are reported from 3 commercial laboratories, and none of the cases harbor VHL spectrum tumors (PS4_NotMet). There are no additional cases reported in published literature. In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA351756706/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6015 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0015230 infores:hetionet CHEBI:17026 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1291077 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020649 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020456 infores:hetionet NCBIGene:2202 biolink:causes MONDO:0958335 infores:monarchinitiative not_provided not_provided HGNC:3218 MONDO:0958335 uuid:e62a67ea-1a87-413c-b411-a9b4105124f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0030193 infores:hetionet CAID:CA136074 biolink:causes MONDO:0021060 infores:clingen CAID:CA136074 MONDO:0021060 PMID: Likely Benign BP5, BS4, BP4 The c.109A>G (p.Thr37Ala) variant did not segregate with disease in affected family members (BS4; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062187.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062187.5). Computational prediction tools and conservation analysis suggest that the p.Thr37Ala variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136074/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8774 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0030805 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1368065 infores:hetionet CHEBI:7824 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042023 infores:hetionet CHEBI:63612 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C1443060 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0027947 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0002871 infores:hetionet NCBIGene:2000 biolink:causes MONDO:0024770 infores:monarchinitiative not_provided not_provided HGNC:3319 MONDO:0024770 uuid:bff4b524-9e46-4cec-9c61-52f8616ef3df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0852911 infores:hetionet CHEBI:7640 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0151798 infores:hetionet CHEBI:490877 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0015967 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0032461 infores:hetionet CHEBI:135961 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0025362 infores:hetionet GO:1903776 biolink:causes GO:0045002 infores:ubergraph knowledge_assertion manual_agent GO:1903776 GO:0045002 CHEBI:49375 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0349506 infores:hetionet CHEBI:6339 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0025222 infores:hetionet CHEBI:41774 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0149871 infores:hetionet CHEBI:100246 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0013390 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013595 infores:hetionet CHEBI:68841 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0006147 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1565489 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0027051 infores:hetionet NCBIGene:57003 biolink:causes MONDO:0032645 infores:monarchinitiative not_provided not_provided HGNC:24856 MONDO:0032645 uuid:a5c66c75-d275-4ead-91c2-a6d8598e12c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94609 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0030193 infores:hetionet CHEBI:8888 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0043387 infores:hetionet CHEBI:44423 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0041582 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0037274 infores:hetionet CHEBI:3441 biolink:causes EFO:0001425 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0349782 infores:hetionet CHEBI:9738 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0003467 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0426498 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0426498 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0035455 infores:hetionet CHEBI:4702 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0019209 infores:hetionet CHEBI:9123 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0428974 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0520962 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033581 infores:hetionet CAID:CA2577483375 biolink:causes MONDO:0011071 infores:clingen CAID:CA2577483375 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*83G>A is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2577483375/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39867 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002792 infores:hetionet CHEBI:3219 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011253 infores:hetionet CHEBI:4974 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0038325 infores:hetionet CHEBI:5138 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0702166 infores:hetionet CHEBI:3696 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0271710 infores:hetionet NCBIGene:9725 biolink:causes MONDO:0032871 infores:monarchinitiative not_provided not_provided HGNC:29118 MONDO:0032871 uuid:c3402b2b-44a8-46dc-995e-63238c67b076 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0151786 infores:hetionet CHEBI:8713 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0017178 infores:hetionet CHEBI:37333 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0547030 infores:hetionet CHEBI:35778 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0009763 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0041912 infores:hetionet CHEBI:45409 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0023218 infores:hetionet CHEBI:18248 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0041657 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0476089 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0006849 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0243026 infores:hetionet CHEBI:4702 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0040264 infores:hetionet CHEBI:119915 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0856054 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0021053 infores:hetionet UMLS:C0657912 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151594 infores:hetionet CHEBI:6129 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015371 infores:hetionet CHEBI:9086 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0015967 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0852733 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C1861172 infores:hetionet CHEBI:29688 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0018681 infores:hetionet CHEBI:3347 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0018965 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020649 infores:hetionet CHEBI:8212 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C1262064 infores:hetionet CHEBI:585948 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0035243 infores:hetionet CHEBI:8863 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0035455 infores:hetionet CHEBI:9168 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034063 infores:hetionet CHEBI:6437 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1443060 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0025061 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0015927 infores:hetionet CHEBI:8228 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0016658 infores:hetionet CHEBI:31348 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0851578 infores:hetionet CHEBI:6931 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0035229 infores:hetionet CHEBI:8888 biolink:causes EFO:0011023 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006107 infores:hetionet CHEBI:6887 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013390 infores:hetionet CHEBI:8356 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0016199 infores:hetionet CHEBI:64064 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0085631 infores:hetionet CHEBI:3723 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013384 infores:hetionet CHEBI:101853 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0027497 infores:hetionet CAID:CA405694193 biolink:causes MONDO:0018493 infores:clingen CAID:CA405694193 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tryptophan with serine at codon 5020 of the RYR1 protein, p.(Trp5020Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant was reported in any individuals with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:24433488), PS4 not met. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405694193/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:5103 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0002957 infores:hetionet CHEBI:2955 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151827 infores:hetionet CHEBI:5050 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0012833 infores:hetionet NCBITaxon:34487 biolink:causes MONDO:0000303 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:34487 MONDO:0000303 CAID:CA5779334 biolink:causes MONDO:0021060 infores:clingen CAID:CA5779334 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.309G>A (p.Val103=) variant in the HRAS gene is 0.063% (10/8640) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5779334/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true UMLS:C0657912 biolink:causes UMLS:C0151955 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151955 infores:hetionet NCBIGene:83550 biolink:causes MONDO:0010492 infores:monarchinitiative not_provided not_provided HGNC:14963 MONDO:0010492 uuid:0503d167-facd-458a-aa83-f4b9ac611bd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3061 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0085614 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0021053 infores:hetionet CHEBI:8028 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0015967 infores:hetionet CHEBI:66919 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0854467 infores:hetionet CHEBI:9588 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0231528 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0242350 infores:hetionet CAID:CA10014504 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014504 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.492C>G (p.Val164=) is a synonymous variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014504/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50692 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0025874 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0004936 infores:hetionet NCBIGene:5698 biolink:causes MONDO:0968983 infores:monarchinitiative not_provided not_provided HGNC:9546 MONDO:0968983 uuid:1df1d62d-fca7-4e47-9c7d-8be5604a2cd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7822 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0876973 infores:hetionet CAID:CA640956478 biolink:causes MONDO:0100437 infores:clingen CAID:CA640956478 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Supporting, PP1_Strong NM_001034853.2(RPGR):c.2543del (p.Glu848GlyfsTer?) is a frameshift variant due to deletion of 1 nucleotide that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including first/second-decade onset (1 pt), rod involvement relatively greater than cone involvement (1 pt), delayed or milder phenotype in females (1 pt), patient report of night blindness (0.5 pts), optic nerve pallor (0.5 pts), pigmentary retinopathy (0.5 pts), myopia (0.5 pts) and genotyping by next-generation sequencing that showed no alternative basis for disease (2 pts) which together are specific for RPGR-related retinopathy (7 points, PMID: 36882936, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, in addition to the apparently unrelated proband previously used for the PP4 code (PMID: 25352739, PMID: 36882936, PMID: 28863407, PMID: 12402343, PMID: 32531858. PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses total from at least 2 families (PP1_Strong; PMID: PMID: 25352739, PMID: 36882936). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, PM2_ Supporting, PP4, PP1_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA640956478/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:50131 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0011603 infores:hetionet GO:1904238 biolink:causes CL:0000669 infores:ubergraph knowledge_assertion manual_agent GO:1904238 CL:0000669 CHEBI:4887 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0001824 infores:hetionet CHEBI:63630 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013604 infores:hetionet CHEBI:3996 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C1443060 infores:hetionet CHEBI:37333 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0231218 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0020651 infores:hetionet CHEBI:8107 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151603 infores:hetionet CHEBI:31348 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018681 infores:hetionet NCBIGene:9639 biolink:causes MONDO:0011998 infores:monarchinitiative not_provided not_provided HGNC:14103 MONDO:0011998 uuid:7036c498-0574-4162-b200-26f2dfdf8c86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0037274 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0687707 infores:hetionet CHEBI:51450 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0004509 infores:hetionet CHEBI:5893 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0036974 infores:hetionet CHEBI:84050 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0003862 infores:hetionet CHEBI:16914 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0232493 infores:hetionet CHEBI:3723 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013362 infores:hetionet CHEBI:83804 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0009782 infores:hetionet CHEBI:31401 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0010692 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0242073 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0232459 infores:hetionet CHEBI:63637 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0043037 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0041912 infores:hetionet CHEBI:5959 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0037317 infores:hetionet CHEBI:6904 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0260662 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0037822 infores:hetionet CHEBI:27432 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0151905 infores:hetionet NCBIGene:57156 biolink:causes MONDO:0031019 infores:monarchinitiative not_provided not_provided HGNC:23787 MONDO:0031019 uuid:95177ba6-41ce-45a0-a36b-da6d0a8314d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA5416545 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416545 MONDO:0011225 PMID: Pathogenic PM2_Supporting, PVS1_Strong, PM3_Strong, PP4_Moderate PS3 The c.1147C>T (p.Arg383Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant that is predicted to escape nonsense-mediated decay; however, removes >10% of the protein with known P/LP variants downstream (PVS1_Strong).The filtering allele frequency (the upper threshold of the 95% CI of 2/39692 alleles) of the c.1147C>T variant in DCLRE1C is 0.000008350 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.This variant has been detected in at least three probands: two are homozygous for this variant PMIDs: 25917813 and 35482138, 1 pt. The third proband is compound heterozygous with c.109 + 2T>C (Paternal - At least Likely Pathogenic, PVS1, and PM2_Supporting) and c.1147C>T;p.R383X (Maternal). 1 pt (PMID: 37901335). Total is 2 pts, PM3_Strong.At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + TmatB−NK+ (0.5 pts), increased cellular radiosensitivity (0.5 pts), and decreased V(D)J recombination (0.5 pts), totaling 2 points, PP4_Moderate (PMIDs: 25917813 and 19953608). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Strong, PM2_Supporting, PM3_Strong, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416545/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2549 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0043352 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0015397 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019112 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0743680 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0221752 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0392025 infores:hetionet CHEBI:49662 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0041948 infores:hetionet CHEBI:63630 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0080274 infores:hetionet CAID:CA404088487 biolink:causes MONDO:0007750 infores:clingen CAID:CA404088487 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP4, PM5 The NM_000527.5(LDLR):c.1590C>A (p.Phe530Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL = 0.768. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404088487/MONDO:0007750/013 2025-02-20 2025-06-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:42355 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0085612 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042571 infores:hetionet CHEBI:63115 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0549463 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042373 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0027769 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0004936 infores:hetionet CHEBI:8869 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0036396 infores:hetionet GO:0110116 biolink:causes GO:0048749 infores:ubergraph knowledge_assertion manual_agent GO:0110116 GO:0048749 CAID:CA913175547 biolink:causes MONDO:0044970 infores:clingen CAID:CA913175547 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting PP1, PP3, PS2, PS3, PM6 The m.591C>T variant in MT-TF has been reported in individuals from five families with primary mitochondrial disease (PS4_moderate; PMID: 34607911). Affected individuals had Gitelman-like syndrome, characterized by hypokalemia and hypomagnesemia related to renal magnesium wasting and elevated renin. Additional features seen in affected individuals include paresthesia and fatigue. The variant was present at homoplasmy in affected individuals and limited unaffected individuals were tested. There are no reported de novo occurrences of this variant. This variant is absent in the MITOMAP GenBank dataset and gnomAD v3.1.2, and there are three heteroplasmic occurrences in the Helix dataset (PM2_supporting). In silico prediction tools are conflicting as MitoTIP suggests this variant is benign (7.2 percentile) however manual review has resulted in an upgraded prediction to pathogenic. Patient fibroblasts showed decreased maximal mitochondrial respiration and complex IV activity was reduced in fibroblasts from one family (PMID: 34607911). Inhibition of mitochondrial respiratory chain complex IV in HEK293 cells resulted in reduced sodium chloride cotransporter (NCC)-mediated sodium reabsorption. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotype seen across affected individuals from different haplogroups and compelling functional validation. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913175547/MONDO:0044970/015 2024-07-22 2025-07-16 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:9086 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0036508 infores:hetionet CHEBI:9241 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0017178 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0236071 infores:hetionet CHEBI:6822 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0011603 infores:hetionet CHEBI:40050 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0033774 infores:hetionet CHEBI:5784 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0042963 infores:hetionet CHEBI:404903 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009676 infores:hetionet CHEBI:9434 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C2047937 infores:hetionet CHEBI:5147 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0009782 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151717 infores:hetionet CHEBI:3732 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0037317 infores:hetionet CAID:CA902225 biolink:causes MONDO:0100368 infores:clingen CAID:CA902225 MONDO:0100368 PMID: Likely Benign BS1, PP3 NM_000329.3(RPE65):c.1244-5C>T is a non-coding variant in intron 11 near the junction with exon 12. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.002561, with 70 alleles / 24966 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives scores of 0.26 for acceptor gain and 0.20 for donor gain, which are above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing (PP3). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1 and PP3 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902225/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2453 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0349506 infores:hetionet CHEBI:75722 biolink:causes HP:0012710 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027343 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0349506 infores:hetionet CHEBI:31644 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1510410 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0919980 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042514 infores:hetionet CHEBI:6030 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0030554 infores:hetionet CHEBI:51209 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0085631 infores:hetionet CHEBI:3216 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0085641 infores:hetionet CHEBI:4907 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C2711248 infores:hetionet CHEBI:7915 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017672 infores:hetionet NCBIGene:8858 biolink:causes MONDO:0013532 infores:monarchinitiative not_provided not_provided HGNC:9460 MONDO:0013532 uuid:89ca5243-fac1-4bc7-9bf2-2fea9d640b87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8597 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0015672 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0855242 infores:hetionet CHEBI:63621 biolink:causes MONDO:0018646 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0008313 infores:hetionet GO:1903221 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:1903221 GO:0000278 CHEBI:10102 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0549249 infores:hetionet CHEBI:6541 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C1291078 infores:hetionet CHEBI:15854 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0027540 infores:hetionet CHEBI:5123 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0270611 infores:hetionet CHEBI:63619 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013404 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027769 infores:hetionet CAID:CA204563 biolink:causes MONDO:0001586 infores:clingen CAID:CA204563 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4 BS1, PM2 The NM_000203.5:c.208C>T (p.Gln70Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of a total of 14 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. An immunochemical assay performed in fibroblast lines from two individuals homozygous for the variant and three individuals compound heterozygous for the variant and p.Trp402Ter found no detectable IDUA protein (PMID: 1301941) (PVS1). This variant is the second most common variant identified in patients with mucopolysacchararidosis type 1 (MPS1), and is present mainly in Northern Europe, including Norway (54% of MPS1 alleles), Russia (42% of MPS1 alleles), Poland (30% of MPS1 alleles), and Austria (31% of MPS1 alleles) (Reviewed in PMID: 29393969). At least 14 homozygotes (max 0.5 x 2 points = 1 point) and at least 45 individuals who are compound heterozygous for the variant and a second variant in IDUA, including another well-known pathogenic variant, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908), have been reported (PMID: 1301941, 7951228, 11735025, 28752568). The allelic data for many of these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, only 1 point was awarded here, the maximum points for homozygotes (PM3). Patients meeting two of the requirements for PP4, IDUA deficiency and elevated urine GAG levels have been reported (PMID: 1301941) (PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.002123 in the Finnish population, followed by 0.0005348 in the European non-Finnish population. This is higher than the Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.00025) and lower than the threshold for BS1 (>0.0025). Therefore, no population codes are met. More data is available in the literature but the classification of pathogenic has already been reached. There is a ClinVar entry for this variant (Variation ID: 11909). In summary, c.208C>T (p.Gln70Ter) is the second most frequent variant identified in patients with MPS1 and meets the criteria to be classified as pathogenic for this condition. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA204563/MONDO:0001586/091 2025-01-02 2025-01-02 Autosomal recessive inheritance HP:0000007 Supports GO:0060693 biolink:causes GO:0035272 infores:ubergraph knowledge_assertion manual_agent GO:0060693 GO:0035272 CHEBI:2704 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0026857 infores:hetionet CHEBI:50922 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0011606 infores:hetionet CAID:CA2580098678 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098678 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.723_729dup (p.Ala244ProfsTer19) is a frameshift variant in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098678/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16335 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0018790 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C3263723 infores:hetionet CHEBI:10101 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0424790 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0011849 infores:hetionet NCBIGene:10935 biolink:causes MONDO:0859248 infores:monarchinitiative not_provided not_provided HGNC:9354 MONDO:0859248 uuid:da064584-7f11-4432-ac85-a0a8130bab22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014260 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014260 MONDO:0011071 PMID: Uncertain Significance BP4 PS4, PS2, PS3, PS1, BA1, BP3, BP1, BP2, BS1, BS3, BP7, PM2, PM6, PM4, PM1, PM5, PM3, PP2, PP3, PP4 NM_001754.5(RUNX1):c.959G>A (p.Arg320Gln) is a missense variant which has a highest population minor allele frequency in gnomAD v2 of 0.00003516 (4/113756 alleles) in the non-Finnish European population. This variant has not been reported in relevant cases in the literature. The computational predictor REVEL gives a score of 0.450, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014260/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4953 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0013922 infores:hetionet CHEBI:31397 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0009763 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0006277 infores:hetionet CHEBI:10101 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0039070 infores:hetionet CHEBI:144093 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0024902 infores:hetionet CAID:CA136108 biolink:causes MONDO:0021060 infores:clingen CAID:CA136108 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2760G>A (p.Arg920=) variant in the SOS1 gene is 0.098% (79/66592) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136108/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:49960 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020615 infores:hetionet CHEBI:64354 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0003467 infores:hetionet CAID:CA415174142 biolink:causes MONDO:0010726 infores:clingen CAID:CA415174142 MONDO:0010726 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PM5 BP4, PS1, PM1, PP3 The p.Arg167Pro variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). A pathogenic missense variant (p.Arg167Trp) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar) (PM5). The p.Arg167Pro variant has been observed in at least 2 individuals with Rett syndrome (PMID 34457282, internal database - Labcorp (formerly Invitae)) (PS4_Supporting). In summary, the p.Arg167Pro variant in MECP2 is classified as uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, PM5, PS4_Supporting). (MECP2 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415174142/MONDO:0010726/036 2025-08-27 2025-10-01 X-linked inheritance HP:0001417 Inconclusive true CHEBI:10119 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0686347 infores:hetionet CAID:CA16020822 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020822 MONDO:0009861 PMID: Uncertain Significance PM3, PM2, PP4, BP4 PM5 The c.586T>A (p.Ser196Thr) variant in PAH has been reported in at least one individual with mild hyperphenylalanemia, where it was observed in trans to c.1055del (p.Gly352fs), which is classified as pathogenic by the PAH VCEP (Variation ID: 102498). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence do not support a deleterious effect. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, BP4, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020822/MONDO:0009861/006 2023-03-24 2023-03-24 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA10549199 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549199 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, PP3, BP4 The NM_005629.4:c.463G>A variant in SLC6A8 is a missense variant predicted to result in the substitution of glycerin by serine at amino acid 155 (p.Gly155Ser). In gnomAD v2.1.1, the highest population minor allele frequency is 0.00002 (2/80546 alleles) in the European non-Finnish population, which is equal to the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), and lower and the allele frequency threshold for BS1. Therefore, no population data codes were applied. There are no hemizygotes in gnomAD v2.1.1.The computational predictor REVEL gives a score of 0.245 which is neither above the threshold predicting a damaging (>0.75) impact on SLC6A8 function, or below the threshold predicting a benign impact (<0.2). Therefore, neither code is met. To our knowledge, this variant has not been reported in the literature in any patient with creatine transporter deficiency. There is a ClinVar entry for this variant (Variation ID: 652028). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 1.1.0): No criteria were met.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549199/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CHEBI:45783 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0235266 infores:hetionet CHEBI:7494 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0043387 infores:hetionet CHEBI:64310 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0013378 infores:hetionet CHEBI:47426 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0003811 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0020649 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0041912 infores:hetionet NCBIGene:2556 biolink:causes MONDO:0859564 infores:monarchinitiative not_provided not_provided HGNC:4077 MONDO:0859564 uuid:7f42bea2-34f4-4597-885f-5f2270636390 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0850149 infores:hetionet CHEBI:3398 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0011991 infores:hetionet CHEBI:6472 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0033777 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0339916 infores:hetionet CHEBI:27786 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C2939147 infores:hetionet CHEBI:9435 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0424296 infores:hetionet NCBIGene:1294 biolink:causes MONDO:0007557 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0007557 uuid:1a385815-dd9b-42bc-93b8-e4fdc9c57fb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6538 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0027769 infores:hetionet CAID:CA748900873 biolink:causes MONDO:0011071 infores:clingen CAID:CA748900873 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*801A>C is a 3' UTR variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA748900873/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:421707 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0020557 infores:hetionet CHEBI:61390 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0232462 infores:hetionet CHEBI:63611 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014518 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0032461 infores:hetionet CAID:CA229727 biolink:causes MONDO:0009861 infores:clingen CAID:CA229727 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PP3_Moderate PM5 The c.737C>T (p.Ala246Val) variant in PAH is a missense variant that is predicted damaging by REVEL (REVEL score 0.932) (PP3_Moderate). has been reported in multiple patients with PAH deficiency (BH4 deficiency excluded in one patient) (PMID: 9634518, 10394930, 12655553, 30747360, 32668217), including in one patient in unknown phase with the known pathogenic variant p.Arg408Trp (ClinVar ID: 577) (PM3_Supporting). The maximum population allele frequency in gnomAD v2.1.1 is 0.000008808, under the 0.0002 cutoff for use of PM2 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3_Supporting, PP3_Moderate, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229727/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4710 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0015967 infores:hetionet CHEBI:135613 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0002792 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0234458 infores:hetionet CHEBI:31485 biolink:causes UMLS:C1112366 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C1112366 infores:hetionet CHEBI:2904 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C2004489 infores:hetionet CHEBI:5138 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0016204 infores:hetionet CAID:CA16621657 biolink:causes MONDO:0100040 infores:clingen CAID:CA16621657 MONDO:0100040 PMID: Likely Pathogenic PM1, PP3, PM6, PM2_Supporting The p.Ile229Leu variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). The p.Ile229Leu variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with intellectual disability and seizures (Genetic Services Laboratory, University of Chicago internal data)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance (PP3). The p.Ile229Leu variant in FOXG1 is absent in gnomAD (PM2_supporting). In summary, the p.Ile229Leu variant in FOXG1 is classified as likely pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PM1, PM6, PP3, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621657/MONDO:0100040/016 2022-02-18 2022-06-30 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:724125 biolink:causes UMLS:C0574741 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0574741 infores:hetionet CHEBI:4779 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0030193 infores:hetionet CHEBI:9137 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0338831 infores:hetionet CHEBI:474180 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0018681 infores:hetionet CHEBI:135925 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0043094 infores:hetionet CHEBI:52717 biolink:causes MONDO:0042976 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042850 infores:hetionet CHEBI:47381 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0039070 infores:hetionet CHEBI:18248 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0151662 infores:hetionet CHEBI:2704 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C2047937 infores:hetionet CAID:CA15842843 biolink:causes MONDO:0044970 infores:clingen CAID:CA15842843 MONDO:0044970 PMID: Benign BS2, BA1 The c.3483-164 A>C variant in POLG is present in population databases gnomAD at 5.9% and seen in 12 homozygotes (BA1; observed > 1% frequency and BS2). In summary, this variant is characterized as a benign variant for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1, BS2 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA15842843/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0687713 infores:hetionet CAID:CA2061546 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061546 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting PP3, BP4, PM5, PM1, PS1, BS1 The BMPR2 c.1882A>G variant is a missense variant predicted to result in an arginine to serine substitution at amino acid position 842 (p.Arg842Ser). The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.000070 in the European (non-Finnish) population thus meeting the threshold for PM2_supporting, resultantly neither BS1 nor BA1 were met. Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.468 indicating that neither BP4 nor PP3 were met. Additionally, the SpliceAI algorithm predicts no deleterious impact on putative acceptor or donor splice sites. The BMPR2 C-terminus is of unclear functional and/or structural relevance, hence PM1 is not met. Due to no evidence of familial segregation PP1, PM6 and PS2 were not assessed. BS3 and PS3 were not evaluated as functional data is unavailable for this variant. In summary, the variant meets the criteria to be classified as a variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061546/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9649 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C1384353 infores:hetionet CHEBI:82941 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0029118 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020517 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0019087 infores:hetionet CHEBI:6456 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0042024 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0025061 infores:hetionet CHEBI:9137 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C2830004 infores:hetionet CHEBI:63638 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0235198 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0036572 infores:hetionet CHEBI:48273 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0038999 infores:hetionet CHEBI:71415 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0002792 infores:hetionet CHEBI:7824 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0206062 infores:hetionet CHEBI:135930 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0004364 infores:hetionet CAID:CA130516 biolink:causes MONDO:0015152 infores:clingen CAID:CA130516 MONDO:0015152 PMID: Pathogenic PP1_Strong, PP3, PP4, PM3_Very Strong PS1, PS2, PS3, PS4, BP7, BP5, BS4, BS1, BS3, PVS1, PM2, PM6, PM4, PM5, PM1, PP2, BS2, BA1, BP1, BP4, BP2, BP3 The NM_213599.3: c.2272C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 758 (p.Arg758Cys). This variant has been detected in at least 7 individuals with LGMD, five of whom had a second ANO5 variant classified as pathogenic or likely pathogenic, with one confirmed in trans by parental testing (c.191dup x5, 3.0 pts, PMID: 25135358, 24803842, 21739273, 21186264). Two patients were homozygous for the variant (1.0 pt, PMID: 20096397) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMD: 31395899). The variant has been reported to segregate with LGMD in six affected family members from three families (PP1_Strong; PMID: 20096397, 27911336). The maximum minor allele frequency for this variant is 0.0003116 (40/128354 chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which exceeds the VCEP threshold of 0.0001 for PM2 (criterion not met). The computational predictor REVEL gives a score of 0.82, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Very Strong, PP4, PP1_Strong, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA130516/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes MONDO:0001265 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0036358 infores:hetionet CHEBI:6538 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0014591 infores:hetionet CHEBI:68478 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018681 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0004096 infores:hetionet CHEBI:51364 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0232462 infores:hetionet CHEBI:10127 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0008350 infores:hetionet CAID:CA023445 biolink:causes MONDO:0007750 infores:clingen CAID:CA023445 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM3, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - Level 1 FS: Chang et al., 2003 (PMID 12837857): Heterologous cells (COS), FACS and WB assays - results: 22% LDLR expression, 20% LDL-LDLR binding and internalization, LDLR retained in endosomal/lysosomal regions. Activity is below 70% of wild-type, so PS3 is met. PS4 - variant meets PM2 and was identified in - 7 unrelated index cases (1 index case with Simon Broome possible FH and 6 index cases with DLCN >=6) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 1 index case with Simon Broome possible FH (high chol in child w/ family hx) from Ambry Genetics, USA;- 1 index case with Simon Broome possible FH (LDL-C high, family history of high cholesterol) from GeneDx Inc, USA;- 47 unrelated index cases w/ Simon Broome possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 1 index case with Simon Broome possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), reported in Tichy et al. 2012 PMID: 22698793, Czech Republic;at least 57 unrelated cases, so PS4 is met.PP1_strong - variant segregates with FH phenotype in 72 informative meiosis from 28 families:- 10 informative meiosis from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): F1: 6 relatives with the variant have LDL >75th percentile, F2: 3 relatives with the variant have LDL >75th percentile, F3: 1 relative with the variant has LDL >75th percentile.- 28 informative meiosis from 14 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: in total, 21 relatives with the variant have LDL-C >75th percentile, and 7 relatives without the variant have LDL-C <50th percentile. The greatest # segregations occurring within a family is 5;- 34 informative meiosis from 11 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: in total, 20 relatives with the variant have LDL-C >75th percentile, and 14 relatives without the variant have LDL-C <50th percentile. The greatest number of segregations occurring in a family was 9 (6 relatives positive for variant w/ phenotype, and 3 relatives negative for variant w/o phenotype).--- 72 informative meiosis support co-segregation, so PP1_Strong is metPM2 - PopMax MAF = 0.00005439 (0.005%) in East Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM3 - Variant meets PM2 and was identified in - 1 index case homozygous for the variant under curation and untreated LDL = 512mg/dL from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.----- it is an homozygous patient with an homozygous phenotype, so PM3 is met.PP3 - REVEL = 0.914. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 57 unrelated cases (see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023445/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6717 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0032617 infores:hetionet CHEBI:9599 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018524 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948089 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0392390 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0392390 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0152029 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0026848 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023067 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0399459 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003460 infores:hetionet CHEBI:40009 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C2830004 infores:hetionet CHEBI:64312 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015967 infores:hetionet CHEBI:31644 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0438142 infores:hetionet CAID:CA410204228 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204228 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.127C>T (p.Pro43Ser) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204228/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA155062 biolink:causes MONDO:0100038 infores:clingen CAID:CA155062 MONDO:0100038 PMID: Benign BA1 PS1, PS2, PS3, BS3, PM6, PM1, PM5, PP3, PP4, BP4 The c.56G>A variant in SCN2A is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.Arg19Lys). This variant is present at an allele frequency of 8% of the total population in gnomAD (v2.1.1), with the highest sub-population allele frequency in the East Asian population with an AF of 15%, which exceeds the threshold of 0.01% to meet the stand-alone criterion for Benign (BA1). This variant has not been reported in the literature to date in an individual with a complex neurodevelopmental disorder (PS2_not met, PM6_not met, PS4_not met). The variant has not been functionally characterized, and is not located in a pathogenic enriched region defined as a mutational hotspot (PM1_not met). In summary, this variant meets the criteria to be classified as BENIGN for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 (Epilepsy Sodium Channel VCEP specifications, version 1.0; approved 6/13/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA155062/MONDO:0100038/068 2024-05-07 2024-05-08 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA376065933 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065933 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.50A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Aspartic Acid by Glycine at amino acid 17 (p.Asp17Gly).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065933/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA410205692 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205692 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.85A>G (p.Arg29Gly) is a missense variant which has a REVEL score of 0.377 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205692/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA258138 biolink:causes MONDO:0100084 infores:clingen CAID:CA258138 MONDO:0100084 PMID:11333380PMID:15226407 Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PP4_Moderate, PS2 BP4, PS4 The NM_001100.4:c.1075A>C variant in ACTA1 is a missense variant predicted to cause substitution of isoleucine by leucine at amino acid 359. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.865, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with autosomal dominant alpha-actinopathy (PS2; PMID: 11333380). At least one patient with this variant displayed nemaline bodies and intranuclear rods, which is highly specific for autosomal dominant alpha-actinopathy (PP4_Moderate, PMID: 11333380). Actin localization in patient muscle biopsies showed abnormal localization of actin indicating that this variant impacts protein function (PMID: 11333380). Actin polymerization in expressed α-skeletal-muscle actins (wild-type and mutants) as 35S-labeled proteins by in vitro transcription translation reactions in reticulocyte lysate showed impaired co-polymerization of I357L actin with wild-type rabbit α-skeletal-muscle actin indicating that this variant impacts protein function (PMID:15226407) (PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; July 8th, 2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA258138/MONDO:0100084/147 2024-07-08 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:43968 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0392386 infores:hetionet CHEBI:2955 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042963 infores:hetionet CAID:CA10014558 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014558 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.264G>C (p.Glu88Asp) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014558/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2659 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0237849 infores:hetionet CHEBI:9671 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0041349 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0853857 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0853857 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0026848 infores:hetionet NCBIGene:1406 biolink:causes MONDO:0013449 infores:monarchinitiative not_provided not_provided HGNC:2383 MONDO:0013449 uuid:c6707dcb-15c0-4456-aab1-b5d64f44557c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585779 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585779 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP3, PP4 BP1, BP4, BP3, BA1, PS4, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.2119G>T (p.Asp707Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.973. PS3: Level 1 functional studies performed using heterologous cells (CHO) with Western blot and flow cytometry, showed <2% cell surface expression, 2% binding and 6% uptake, reported in PMID 32015373 (Galicia-Garcia et al., 2020). Activity is below 70% of wild-type, consistent with damaging effect. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6 after alternative causes of high cholesterol were excluded, reported in PMID 19318025 (Alonso et al., 2009). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585779/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5296 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0030312 infores:hetionet CHEBI:3242 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013362 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0037274 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0014544 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0205204 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0007222 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0011991 infores:hetionet CHEBI:8093 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0026961 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011991 infores:hetionet CHEBI:32139 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0151578 infores:hetionet CHEBI:63580 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018524 infores:hetionet CHEBI:32184 biolink:causes MONDO:0006564 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0162823 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0876973 infores:hetionet CHEBI:63635 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1535939 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0518015 infores:hetionet CHEBI:77733 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0042963 infores:hetionet CHEBI:5128 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0009806 infores:hetionet CHEBI:9738 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2047937 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003615 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1269683 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020437 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042075 infores:hetionet CHEBI:28177 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0085612 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0042109 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040046 infores:hetionet CAID:CA281998 biolink:causes MONDO:0021060 infores:clingen CAID:CA281998 MONDO:0021060 PMID:20735442PMID:20735442 Pathogenic PS3, PM1, PM6, PM2, PP3, PP2, PS4_Supporting The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA281998/MONDO:0021060/004 2020-06-25 2020-06-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:17263 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0016204 infores:hetionet CHEBI:8802 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0031350 infores:hetionet CHEBI:8768 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0016204 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014130 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0022408 infores:hetionet GO:1901509 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:1901509 GO:0035295 GO:2000702 biolink:causes GO:0060676 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0060676 CHEBI:8888 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1269683 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0029928 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006145 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0038663 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0010692 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0014742 infores:hetionet CHEBI:15765 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0023530 infores:hetionet CHEBI:4858 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0231218 infores:hetionet CAID:CA412379043 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379043 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000330.4(RS1):c.38T>A (p.Leu13His) is a missense variant encoding the substitution of leucine with histidine at position 13. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.625, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of <0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379043/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:145499 biolink:causes UMLS:C0004063 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004063 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037199 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0160390 infores:hetionet CHEBI:10125 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C2830004 infores:hetionet CHEBI:53691 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0028961 infores:hetionet CHEBI:7565 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C3665386 infores:hetionet CHEBI:7444 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0010200 infores:hetionet CHEBI:50729 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0340865 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549622 infores:hetionet CHEBI:5864 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085631 infores:hetionet CHEBI:6438 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0008031 infores:hetionet CHEBI:134991 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0085593 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0004936 infores:hetionet CAID:CA343727103 biolink:causes MONDO:0005338 infores:clingen CAID:CA343727103 MONDO:0005338 PMID:36267417 Uncertain Significance PM2_Supporting, BP4, BS3_Supporting BP7, BS1, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.626C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Asparagine at amino acid 209 (p.Thr209Asn). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.188, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. The Thr209Asn protein had similar secretion levels compared to wild type myocilin protein in this study (PMID: 36267417). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 22933836), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS3_Moderate, BP4, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343727103/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA256580 biolink:causes MONDO:0021060 infores:clingen CAID:CA256580 MONDO:0021060 PMID:22190897PMID:28378436PMID:21784453PMID:22465605PMID:26297936PMID:29625050PMID:21387466PMID:29696744PMID:22488759PMID:23885229PMID:25862627PMID:17143282PMID:19352411PMID:18925667PMID:19020799PMID:23885229PMID:27304678PMID:17143282PMID:17143282PMID:23885229 Pathogenic PM5_Strong, PS4, PS3_Supporting, PS2_Very Strong, PP3, PM2_Supporting BA1, BP2, BP1, BP4, BP3, PS1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM3, PM4, PM1, BS2, PP2, PP1, PP4 The NM_005633.4:c.1656G>C variant in SOS1 is a missense variant predicted to cause substitution of arginine by serine at amino acid 552 (p.Arg552Ser). This variant was absent from gnomAD v2.1.1 (PM2_Supporting). The computational prediction tool REVEL gives a score of 0.863, suggesting that the p.Arg552Ser variant may impact protein function (PP3). Five different (likely) pathogenic variants at this residue (Arg552Gly, Arg552Lys, Arg552Met, Arg552Thr, Arg552Trp) have been identified in several patients with RASopathies (PM5_Strong). This variant has been reported in at least 8 patients with clinical features of a RASopathy, of which 2 were reported as confirmed de novo occurrences and 1 was assumed to be de novo (PS4, PS2_VeryStrong; PMIDs:17143282, 19352411, 18651097, 18925667, 1902079). In vitro functional studies showed that the p.Arg552Ser variant led to increased ERK1/2 phosphorylation (PS3_Supporting; PMID: 27304678). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM5_Strong, PS3_Supporting PM2_Supporting, PP3 (Specification Version 2.3, 1/10/2025) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256580/MONDO:0021060/041 2025-01-10 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CAID:CA248819 biolink:causes MONDO:0011071 infores:clingen CAID:CA248819 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS3, BS1, BS4, PM4, PM5, PM3, BS2, PP2, PP1, PP4 NM_001754.4(RUNX1):c.557T>A (p.Val186Asp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.953 (> 0.75), supporting PP3. This variant is located within the Runt Homology Domain (RHD), affecting one of the residues (AA 105-204) but not an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248819/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:32139 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0009450 infores:hetionet CHEBI:55346 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0042029 infores:hetionet CHEBI:6539 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0012569 infores:hetionet CAID:CA015454 biolink:causes MONDO:0004994 infores:clingen CAID:CA015454 MONDO:0004994 PMID: Likely Benign BS1, BP4 PM2, PS4 The c.4909G>A (p.Ala1637Thr) variant in MYH7 has been observed in 0.060% (FAF 95% CI; 22/24960) of African chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Additionally, computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, BP4 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015454/MONDO:0004994/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030920 infores:hetionet CHEBI:51141 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0039231 infores:hetionet CHEBI:144093 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011603 infores:hetionet CHEBI:7936 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0016658 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0010692 infores:hetionet CHEBI:33325 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0234233 infores:hetionet CHEBI:46295 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C2830004 infores:hetionet GO:0070920 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:0070920 GO:0032774 CHEBI:45951 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0152115 infores:hetionet CHEBI:5441 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0022354 infores:hetionet CHEBI:32221 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0043094 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0853813 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0013395 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549356 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0267792 infores:hetionet CHEBI:7903 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0021368 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0518015 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0435001 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0435001 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C1145628 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027769 infores:hetionet CHEBI:50924 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0037763 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0013395 infores:hetionet CAID:CA10587783 biolink:causes MONDO:0007947 infores:clingen CAID:CA10587783 MONDO:0007947 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PS4 The NM_00138 c.8488C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 42 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PMID 29875124, PP4). This variant has been reported twice in ClinVar, once as pathogenic and once as uncertain significance (Variation ID: 263414). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PM2_Sup, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587783/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CAID:CA000591 biolink:causes MONDO:0017623 infores:clingen CAID:CA000591 MONDO:0017623 PMID: Pathogenic PVS1, PM2, PS4_Supporting PTEN c.802-2A>T (IVS7-2A>T) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s), SCV000222230.9) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000591/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135939 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0020522 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0267792 infores:hetionet CHEBI:5775 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0948586 infores:hetionet CHEBI:28918 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0233407 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0018799 infores:hetionet CHEBI:6887 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009782 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0040136 infores:hetionet CHEBI:6067 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0241729 infores:hetionet CAID:CA410203483 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203483 MONDO:0011071 PMID: Likely Pathogenic PM1, PS4_Supporting, PM2_Supporting, PP3, PP1 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM5, BS2, PP2, PP4 NM_001754.5(RUNX1):c.320G>A (p.Arg107His) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (R107) (PM1). This missense variant has a REVEL score >0.88 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27112265). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PP1, PP3, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203483/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Supports CAID:CA236229 biolink:causes MONDO:0012163 infores:clingen CAID:CA236229 MONDO:0012163 PMID: Pathogenic PM2_Supporting, PM5, PVS1 BS1, BA1 The c.636T>G (p.Tyr212Ter) (NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in gene IL7R in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v4.1.0 (PM2_supporting). Currently, there are two premature truncation variants annotated likely pathogenic/pathogenic by the SCID VCEP downstream of this variant (W217Ter; S235Ter). There are also two variants that have not yet been annotated (p.Y225Ter; p.C330Ter). Therefore, this variant meets PM5_Moderate. To our knowledge, this variant has not been reported in individuals affected with IL7R-related conditions. In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM5 (VCEP specifications version 2.1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA236229/MONDO:0012163/119 2025-10-31 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94609 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0015672 infores:hetionet CHEBI:63791 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0949059 infores:hetionet CHEBI:43968 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0036974 infores:hetionet CHEBI:8764 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085616 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0020649 infores:hetionet CHEBI:16586 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0040264 infores:hetionet CHEBI:3485 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0085631 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0015230 infores:hetionet CHEBI:68478 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0015672 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030305 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027441 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0034069 infores:hetionet CHEBI:2955 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027424 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0236071 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0855242 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0518015 infores:hetionet CHEBI:9139 biolink:causes MONDO:0021681 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0036916 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0018799 infores:hetionet CHEBI:50742 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0017675 infores:hetionet CHEBI:10023 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151904 infores:hetionet CHEBI:8212 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0151878 infores:hetionet UMLS:C1738934 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042023 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009806 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0042109 infores:hetionet NCBIGene:29071 biolink:causes MONDO:0010381 infores:monarchinitiative not_provided not_provided HGNC:24338 MONDO:0010381 uuid:950c2dc1-be4a-4893-896f-c2e9a6475464 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9566 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0002994 infores:hetionet CAID:CA744720831 biolink:causes MONDO:0015967 infores:clingen CAID:CA744720831 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PM1_Supporting PS4 The c.-135A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 7.7e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant is located within the HNF6/OC2 binding site of the promoter (c.-132 to c.-141) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.-135A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA744720831/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:34967 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0004936 infores:hetionet CHEBI:144093 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0043094 infores:hetionet CHEBI:4024 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0033975 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0001122 infores:hetionet NCBIGene:100506658 biolink:causes MONDO:0020789 infores:monarchinitiative not_provided not_provided HGNC:8104 MONDO:0020789 uuid:d31e9e55-dd5f-4ab4-9b4b-da57a8559f6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0034186 infores:hetionet CHEBI:45863 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0270612 infores:hetionet CHEBI:6741 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042023 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0032326 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0034069 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0014549 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0005714 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:D013590 DB09320_MESH_D013590_1 PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0162830 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0028960 infores:hetionet CHEBI:51209 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0004093 infores:hetionet CHEBI:3175 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0162285 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0009450 infores:hetionet CHEBI:61049 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0687713 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0012833 infores:hetionet CHEBI:5134 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0037763 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0020517 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020517 infores:hetionet CHEBI:472657 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C1257843 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0011175 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1142158 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1142158 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0040034 infores:hetionet CHEBI:2675 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0011253 infores:hetionet CHEBI:10110 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0013404 infores:hetionet CHEBI:46557 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151825 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0018418 infores:hetionet CHEBI:31932 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0235996 infores:hetionet CHEBI:76010 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0035078 infores:hetionet CHEBI:7809 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0017178 infores:hetionet CHEBI:93635 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0013144 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019061 infores:hetionet CHEBI:6067 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0014591 infores:hetionet CHEBI:46081 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C2129214 infores:hetionet NCBIGene:16 biolink:causes MONDO:0013212 infores:monarchinitiative not_provided not_provided HGNC:20 MONDO:0013212 uuid:8704906e-ed53-4d14-a805-ceb0a57215d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011860 infores:hetionet CHEBI:8080 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0018681 infores:hetionet CHEBI:135005 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0009782 infores:hetionet CHEBI:47780 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0035410 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0340464 infores:hetionet CHEBI:28148 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0005779 infores:hetionet CHEBI:8214 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0851578 infores:hetionet CHEBI:40279 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0017979 infores:hetionet CHEBI:7820 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0033117 infores:hetionet CAID:CA8623176 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623176 MONDO:0100326 PMID: Benign BP7, BP4, BA1 The c.1143A>T (p.Val381=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.329 (BP7). The computational predictor REVEL predicts no damaging effect on ITGB3 function (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006167 (123/19946 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP7, BP4 and BA1 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623176/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:92712 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0234518 infores:hetionet CHEBI:63717 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0038990 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009782 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233472 infores:hetionet CHEBI:27974 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0014743 infores:hetionet CHEBI:28593 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0034063 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0426576 infores:hetionet CHEBI:63580 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027121 infores:hetionet CHEBI:3061 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0040264 infores:hetionet CHEBI:9123 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0016204 infores:hetionet CHEBI:74947 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014457 infores:hetionet CHEBI:47898 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018926 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0234543 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0234543 infores:hetionet CHEBI:63631 biolink:causes HP:0003146 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151718 infores:hetionet CHEBI:63580 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0877192 infores:hetionet CHEBI:10119 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085702 infores:hetionet CHEBI:261649 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C3665596 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0919715 infores:hetionet CHEBI:45924 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0020625 infores:hetionet NCBIGene:90161 biolink:causes MONDO:0026724 infores:monarchinitiative not_provided not_provided HGNC:19133 MONDO:0026724 uuid:09a9a6c1-55c7-43d4-a9e5-ed4cda1d53e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037199 infores:hetionet CAID:CA1244094 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244094 MONDO:0020367 PMID: Likely Benign BP7, BP4 BS1, BS3, PM2, PM6, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.1020G>A variant in MYOC is a synonymous variant (p.Glu340=). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.0001603 (4 alleles out of 24,954), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.124 which met the ≤ 10 threshold for BP4, and the GERP score = -2.03 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244094/MONDO:0020367/019 2023-04-04 2023-04-04 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0017797 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0015230 infores:hetionet CHEBI:6754 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0233477 infores:hetionet CHEBI:64045 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0041105 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0011991 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030446 infores:hetionet CHEBI:136040 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0687713 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233794 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0007097 infores:hetionet CHEBI:499361 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0038325 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0006840 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0003123 infores:hetionet CHEBI:6715 biolink:causes MONDO:0000755 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0032987 infores:hetionet CHEBI:51450 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0013404 infores:hetionet CHEBI:5098 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0013378 infores:hetionet CHEBI:3698 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0030305 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0043094 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0518015 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0853619 infores:hetionet CHEBI:10102 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0231528 infores:hetionet CAID:CA10360833 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360833 MONDO:0010725 PMID: Uncertain Significance BS1, BS3, PS3, PS4, PM2, BP4, PM5, PP3 NM_000330.4(RS1):c.37C>T (p.Leu13Phe) is a missense variant encoding the substitution of leucine with phenylalanine at amino acid 13. Another missense variant in the same codon, NM_000330.4(RS1):c.38T>C (p.Leu13Pro), has been reported in association with X-linked retinoschisis (PMID: 10533068, PMID: 20809529, PMID: 30652005), but has a higher Grantham score (98) than the present variant (22), so PM5 is not met. This variant is present in gnomAD v4.1.0 at a frequency of 0.00001010 among hemizygous individuals, with 4 variant alleles / 396,100 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.000002 but lower than the BS1 threshold of >0.00002, so neither population code is met. This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 20809529), however, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The computational predictor REVEL gives a score of 0.444, which is lower than the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and higher than the BP4 threshold of<0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. COS7 cells exogenously expressing the variant exhibit RS1 expression and secretion into the medium at levels similar to the wild-type control (PMID: 20809529). However, the BS3_Supporting code is considered not applicable for RS1 variants due to the absence of sufficient benign control variants from established assays of RS1 function. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: None. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360833/MONDO:0010725/126 2025-09-22 2025-09-22 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true NCBIGene:56652 biolink:causes MONDO:0010060 infores:monarchinitiative not_provided not_provided HGNC:1160 MONDO:0010060 uuid:3bcbfcee-0e84-462c-b8bd-5a7ec2ca1df9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32139 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020649 infores:hetionet CHEBI:4953 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0151825 infores:hetionet CHEBI:50173 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0010520 infores:hetionet CHEBI:5778 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020621 infores:hetionet CHEBI:100246 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151904 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006849 infores:hetionet CHEBI:184555 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0017565 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042075 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0018681 infores:hetionet CHEBI:29013 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0038999 infores:hetionet CAID:CA137903 biolink:causes MONDO:0021060 infores:clingen CAID:CA137903 MONDO:0021060 PMID: Likely Benign BP7, BP5 BA1, PS4, BS1, PM2 The c.*8C>T variant in the MAP2K2 gene is located in the untranslated mRNA region downstream of the termination codon. The filtering allele frequency in gnomAD v4.1.0 is 0.01257%(172/1145270 alleles) in non-Finnish European population (PM2_Supporting/BS1/BA1 are not met). This variant is at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The c.*8C>T variant has been observed in at least 6 individuals who underwent testing for RASopathies (PS4 not met; GeneDx, LMM internal data; GTR ID's: 26957, 21766; SCV000063150.4, SCV000170190.9). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, SCV000170190.9). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP5, BP7 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137903/MONDO:0021060/048 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51450 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0151907 infores:hetionet CHEBI:691037 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0011603 infores:hetionet CHEBI:127780 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0013428 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0521471 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0521471 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0149931 infores:hetionet CHEBI:8499 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0018524 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0033774 infores:hetionet CHEBI:6847 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0017979 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0029408 infores:hetionet CHEBI:10650 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042384 infores:hetionet CHEBI:27432 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0002792 infores:hetionet CHEBI:76010 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0004364 infores:hetionet CHEBI:2659 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0012833 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0013395 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235234 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0021053 infores:hetionet CHEBI:4856 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0151636 infores:hetionet CHEBI:110423 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0023467 infores:hetionet CHEBI:52717 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C3665347 infores:hetionet CAID:CA367401332 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401332 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PM1, PP4 The c.619G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 207 (p.(Val207Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.922, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of monogenic diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 34826540). Another missense variant, c.619G>T p.Val207Leu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.619G>A meets the criteria to be classified as a variant of uncertain significane for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401332/MONDO:0015967/086 2025-01-29 2025-01-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:8382 biolink:causes UMLS:C0151510 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151510 infores:hetionet CHEBI:39867 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0947912 infores:hetionet CHEBI:63580 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2830004 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0006145 infores:hetionet CHEBI:4784 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0239377 infores:hetionet CHEBI:167309 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0042510 infores:hetionet CHEBI:9168 biolink:causes HP:0004872 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0267716 infores:hetionet CAID:CA254862 biolink:causes MONDO:0044970 infores:clingen CAID:CA254862 MONDO:0044970 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Moderate, PS3_Supporting PP1, BA1, BP4, PS1, BS1, PM5, PM6 The m.3946G>A (p.E214K) variant in MT-ND1 has been reported in at least five unrelated individuals with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life to mid-teenage years). Features were variable but consistent with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), complex seizure disorder, or Leigh syndrome. Heteroplasmy ranged from 45% to 66% in fibroblasts or muscle (PS4_moderate; PMIDs: 26741492, 15466014, 31996177, 24105702). The variant was not detected in the blood or urine sediment of the mother in one case, however these tissues differed from that tested in the proband (PMID: 24105702). Electron transport chain (ETC) enzyme activities were assessed in multiple unrelated affected individuals with non-diagnostic exome sequencing and chromosomal microarray. Two individuals had major combined complex deficiency (Pt619 and Pt640; PMID: 26741492). An additional individual had approximately 20% residual activity in fibroblasts compared to controls, a 40%–60% decrease in mature complex I levels, reduced levels of MT-ND1 protein, and normal MT-ND1 mRNA levels (PP4; PMID: 24105702). Studies in E. coli (PMID: 16849371) and cybrids (PMID: 15466014) support the functional impact of this variant, and independent studies showed independent deleterious effects of the variant (PS3_supporting). The m.3946G>A variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup L0f). This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.66 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP4, PS3_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254862/MONDO:0044970/015 2023-08-22 2024-11-25 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA229836 biolink:causes MONDO:0009861 infores:clingen CAID:CA229836 MONDO:0009861 PMID:8807331PMID:27121329PMID:8807331PMID:21307867 Likely Pathogenic PM5, PM3, PP4_Moderate, PM2, PP3 The c.889C>T (p.R297C) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded: PMID: 8807331, 21307867). It was detected in trans with the pathogenic variant IVS12nt1 (VarID576; PMID 8807331). This variant has an extremely low allele frequency in gnomAD (7/245782). Two other missense variants at the same codon are pathogenic. (92750). Computational prediction tools and conservation analysis suggest that the c.889C>T variant may impact the protein. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3, PM5, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229836/MONDO:0009861/006 2019-07-14 2019-07-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94392 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C3665347 infores:hetionet GO:0090016 biolink:causes GO:0060794 infores:ubergraph knowledge_assertion manual_agent GO:0090016 GO:0060794 CHEBI:3723 biolink:causes UMLS:C0549391 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549391 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0242461 infores:hetionet CHEBI:63607 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0017178 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0009241 infores:hetionet CHEBI:63617 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042384 infores:hetionet CHEBI:3216 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0007859 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0033774 infores:hetionet CHEBI:3508 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0020433 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0349506 infores:hetionet CHEBI:45924 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0034152 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0232492 infores:hetionet CHEBI:3082 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0007859 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038363 infores:hetionet CAID:CA415086679 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086679 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting PP3, PM5, BP4 The NM_005629.4:c.1262G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a glycine for an aspartate at amino acid position 421 (p.Gly421Asp). To our knowledge, this variant has not been reported in the literature and no functional studies are available. This variant is absent in gnomAD v4.0.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.585, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 427187). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 9, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086679/MONDO:0010305/027 2025-01-09 2025-01-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:28918 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0518015 infores:hetionet CHEBI:39669 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0162830 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013687 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0025061 infores:hetionet CAID:CA10653550 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653550 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*3229C>T is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653550/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64019 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0037274 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0020649 infores:hetionet CHEBI:16899 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0476280 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0027765 infores:hetionet CHEBI:17630 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0030193 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0497327 infores:hetionet CHEBI:44423 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1142520 infores:hetionet CHEBI:63610 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0036974 infores:hetionet CHEBI:9586 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020580 infores:hetionet CAID:CA355961124 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961124 MONDO:0001586 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PP4 The NM_000203.5:c.343G>A variant in IDUA is a missense variant predicted to cause substitution of aspartate by asparagine at amino acid 115 (p.Asp115Asn). An infant was identified on newborn screening with the variant and has reduced enzyme activity but normal GAGs all within range (PMID: 29801497) Insufficient evidence to apply PP4. This infant is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.2T>C (p.M1?) (ClinVarID: 639529) (PMID: 29801497, phase unconfirmed). Since disease status is unknown in this infant, PM3 is not met. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.764 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (PMID: 36413997) (PP3). SpliceAI predicts that the variant has no impact on splicing (all scores <0.1). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for MPS I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_supporting, PP3_met(Classification approved by the ClinGen Lysosomal Storage Diseases Variant Curation Expert Panel on October 6, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961124/MONDO:0001586/091 2025-10-06 2025-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:94501 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0040822 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0021141 infores:hetionet NCBIGene:1436 biolink:causes MONDO:0800027 infores:monarchinitiative not_provided not_provided HGNC:2433 MONDO:0800027 uuid:d91e3411-3bb0-4ce6-88b1-5f6bf2ac9340 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes UMLS:C1096106 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1096106 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0004936 infores:hetionet CHEBI:35778 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151827 infores:hetionet CHEBI:3032 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0151559 infores:hetionet CHEBI:3082 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0424790 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0005779 infores:hetionet CHEBI:8802 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0023518 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0011570 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0037274 infores:hetionet CHEBI:9570 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0856054 infores:hetionet CHEBI:7601 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0040034 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0032285 infores:hetionet CHEBI:16899 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0026858 infores:hetionet CAID:CA16020918 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020918 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.1002C>A (p.Cys334Ter) variant in PAH is a nonsense variant in exon 10 of 13 predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a PKU patient from Shaanxi with blood Phe concentration over 2.0 mg/dL (PMID: 24510568; PP4). This variant is absent from gnomAD. In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020918/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410204054 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204054 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.164C>A (p.Ala55Glu) is a missense variant which has a REVEL score < 0.50 (0.385), and a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204054/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:38940 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0037278 infores:hetionet CAID:CA340744926 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744926 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_000329.3(RPE65):c.912C>A (p.Tyr304Ter) variant is a nonsense variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), symptomatic onset between birth and age 5 (1 pt), and previous exome sequencing that did not provide an alternative explanation for visual impairment (2 pt), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 34830511, 25356976, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744926/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0162830 infores:hetionet CHEBI:6887 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013456 infores:hetionet CHEBI:40279 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0232292 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0037199 infores:hetionet CHEBI:10110 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0424790 infores:hetionet CHEBI:9288 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0040034 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0233494 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0349506 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0858678 infores:hetionet CHEBI:6970 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0030554 infores:hetionet NCBIGene:8398 biolink:causes MONDO:0012444 infores:monarchinitiative not_provided not_provided HGNC:9039 MONDO:0012444 uuid:9c73ce61-39ca-40ba-8b8c-a3cda0fb1fdd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C2242588 infores:hetionet CHEBI:75722 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0427457 infores:hetionet CHEBI:45367 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0024312 infores:hetionet CHEBI:36795 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0003862 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0038661 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0040034 infores:hetionet CHEBI:4995 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151836 infores:hetionet CHEBI:40050 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0020433 infores:hetionet CHEBI:63598 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0278134 infores:hetionet CHEBI:50275 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014866 infores:hetionet CHEBI:50730 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0030554 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0015397 infores:hetionet CHEBI:9613 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0002874 infores:hetionet CHEBI:92998 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085649 infores:hetionet CHEBI:63681 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0015967 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0018799 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0541832 infores:hetionet CHEBI:50275 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0026826 infores:hetionet CAID:CA386952411 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952411 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PS3_Supporting, PP3 PS4 The c.34T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to histidine at codon 12 (p.(Leu12His)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).  This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:24905847, PMID:10078571, PMID:9287053). Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.34C>T (p.Leu12Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Lastly, functional studies demonstrated the p.Leu12His protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 10581189, 10491332, 10966642). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3, PM5_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952411/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6520 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0242429 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003690 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0587246 infores:hetionet CHEBI:4445 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0019158 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0027947 infores:hetionet CHEBI:8107 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0028961 infores:hetionet CHEBI:92998 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0003467 infores:hetionet CHEBI:5864 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0003811 infores:hetionet CHEBI:46557 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0013404 infores:hetionet CHEBI:32315 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013456 infores:hetionet CHEBI:63610 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0027497 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0003864 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0729552 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0729552 infores:hetionet CHEBI:31709 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0022104 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0151705 infores:hetionet CHEBI:47780 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013456 infores:hetionet CHEBI:92712 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0038990 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0022073 infores:hetionet CHEBI:5098 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0687713 infores:hetionet CHEBI:8890 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0025289 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0474381 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0009450 infores:hetionet CHEBI:9086 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023530 infores:hetionet CHEBI:7983 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0020517 infores:hetionet CHEBI:8871 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0000731 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006716 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0010072 infores:hetionet CHEBI:51364 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C3665347 infores:hetionet CHEBI:63616 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151905 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0027769 infores:hetionet CHEBI:6062 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0428977 infores:hetionet CHEBI:7824 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0043349 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0029882 infores:hetionet NCBIGene:23165 biolink:causes MONDO:0014818 infores:monarchinitiative not_provided not_provided HGNC:18658 MONDO:0014818 uuid:83de0637-37ad-46d4-abf0-e25fa199acb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10648801 biolink:causes MONDO:0007648 infores:clingen CAID:CA10648801 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM5, PM4, PVS1, PM2, PM6, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS3, PS2, PS4, PS1 The NM_004360.5(CDH1):c.*1176T>G variant has an allele frequency of 0.04739 (4.739%, 413/8714 alleles, 12 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10648801/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5138 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0086565 infores:hetionet CHEBI:50859 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011606 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0232492 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0236171 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0236171 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0032131 infores:hetionet CHEBI:63681 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C1260922 infores:hetionet CHEBI:44032 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0026858 infores:hetionet CHEBI:4975 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0206062 infores:hetionet CHEBI:7476 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0232493 infores:hetionet CHEBI:7954 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0012833 infores:hetionet CHEBI:10112 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0015967 infores:hetionet CAID:CA333406 biolink:causes MONDO:0007113 infores:clingen CAID:CA333406 MONDO:0007113 PMID:26255772 Uncertain Significance PP4, PS4_Moderate, PM2_Supporting PP3, BP4, PS3 The c.349T>C p.(Cys117Arg) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.(Cys117Arg) variant has been observed in at least 3 individuals with a clinical phenotype suggestive of Angelman syndrome (PMID 25212744, ClinVar SCV000570280.3) (PS4_moderate, PP4). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.349T>C p.(Cys117Arg) variant in UBE3A is classified as a Variant of Unknown Significance based on the ACMG/AMP criteria (PS4_moderate, PP4, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333406/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UNII:F64QU97QCR biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0015376 infores:hetionet CHEBI:7640 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0042963 infores:hetionet NCBIGene:1041 biolink:causes MONDO:0024548 infores:monarchinitiative not_provided not_provided HGNC:1802 MONDO:0024548 uuid:bfd418d2-1a1f-4825-a25d-89859f0a77be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151692 infores:hetionet CHEBI:41423 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0232461 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0278079 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151734 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0006266 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0002871 infores:hetionet CHEBI:2950 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0858635 infores:hetionet CHEBI:6367 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0026827 infores:hetionet NCBIGene:3832 biolink:causes MONDO:0007918 infores:monarchinitiative not_provided not_provided HGNC:6388 MONDO:0007918 uuid:b23ff333-3e73-43af-83c3-3844446da4ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9613 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0541900 infores:hetionet CHEBI:71940 biolink:causes MONDO:0001617 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0338591 infores:hetionet CHEBI:2567 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0151970 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0277925 infores:hetionet CAID:CA343725818 biolink:causes MONDO:0020367 infores:clingen CAID:CA343725818 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PS3_Moderate BP7, BS1, BS3, PM6, PP1, PM4, PM5, PS1, PS2, BP4, BA1 The c.856T>C variant in MYOC is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 286 (p.Trp286Arg). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00005811 (2 alleles out of 34,418), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.917, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Trp286Arg protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. Only 2 segregations had been reported for primary open angle glaucoma (E. Souzeau pers. comm.), not meeting the ≥ 3 segregations required for PP1. 5 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 23453510, 22879734, 9535666, E. Souzeau pers. comm.), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725818/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50922 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151744 infores:hetionet NCBIGene:8622 biolink:causes MONDO:0012205 infores:monarchinitiative not_provided not_provided HGNC:8794 MONDO:0012205 uuid:89e34386-0c8b-428f-b64a-21f8190b8706 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0022568 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0018799 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0410919 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0410919 infores:hetionet CHEBI:6950 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1320474 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0043012 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0043012 infores:hetionet CHEBI:4876 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0015672 infores:hetionet CAID:CA2695202957 biolink:causes MONDO:0015967 infores:clingen CAID:CA2695202957 MONDO:0015967 PMID: Pathogenic PS4, PM4_Supporting, PP1_Strong, PM1, PP4_Moderate, PM2_Supporting The c.452_454del variant in the glucokinase gene, GCK, is a 3 base pair deletion resulting in the in-frame deletion of serine at codon 151 (p.(Ser151del)) within exon 4 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.452_454del variant is predicted to change the length of the protein due an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Furthermore, this variant affects an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in twelve unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 19790256, 22493702, 29510678, 31028668, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 4 families (PP1_Strong; PMIDs: 17573900, 29510678, internal lab contributors). In summary, c.452_454del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PS4, PP1_Strong, PP4_Moderate, PM1, PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202957/MONDO:0015967/086 2025-01-29 2025-01-29 Semidominant inheritance HP:0032113 Supports CHEBI:45783 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0268000 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027441 infores:hetionet CHEBI:16714 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C3665347 infores:hetionet CHEBI:8428 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0012833 infores:hetionet CHEBI:3219 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085623 infores:hetionet CHEBI:2567 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0018681 infores:hetionet CHEBI:8081 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0151602 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0948349 infores:hetionet CHEBI:681569 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0231528 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235996 infores:hetionet CHEBI:46295 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0036974 infores:hetionet CHEBI:4798 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0424295 infores:hetionet CHEBI:17549 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0011603 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0948525 infores:hetionet CHEBI:31401 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C2047937 infores:hetionet CHEBI:76607 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0042373 infores:hetionet CAID:CA10644627 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644627 MONDO:0011071 PMID: Benign BA1 PS3, PS1, PS4, BP2, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*2193del variant in the 3' UTR has an MAF of 0.007918 (0.79%, 69/8714 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644627/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9215 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0595916 infores:hetionet CHEBI:10125 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0026827 infores:hetionet CAID:CA254843 biolink:causes MONDO:0044970 infores:clingen CAID:CA254843 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PS4 The m.9997T>C variant in MT-TG has been reported in one large family to date (PMID: 8079988). The most common clinical feature in affected family members was cardiomyopathy, however additional clinical features seen include renal failure, muscle cramps, muscle weakness, exercise intolerance, and gastrointestinal dysmotility. Heteroplasmy levels were variable in affected family members and appeared to segregate with cardiomyopathy but not the other clinical features (PMID: 8079988). This variant is present in population databases (absent in gnomAD v3.1.2; one heteroplasmic in the Helix dataset; one homoplasmic occurrence in the Mitomap GenBank sequences; PM2_supporting). Cybrid studies support the deleterious effect of this variant (PMID: 10090480; PS3_supporting). The computational predictor MitoTIP suggests this variant is deleterious (80.3 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254843/MONDO:0044970/015 2024-07-22 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3561 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0014724 infores:hetionet CHEBI:8028 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0085636 infores:hetionet CHEBI:4995 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0232461 infores:hetionet CHEBI:3738 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0232292 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0234916 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0855242 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020456 infores:hetionet CHEBI:74947 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0242422 infores:hetionet CHEBI:65346 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0029408 infores:hetionet UMLS:C1709429 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020580 infores:hetionet CHEBI:50223 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0162119 infores:hetionet CAID:CA891844091 biolink:causes MONDO:0010726 infores:clingen CAID:CA891844091 MONDO:0010726 PMID: Likely Benign BS2 PM4, BS1 The p.Leu386_Pro387del variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Ambry, internal database - Invitae) (BS2). The highest population minor allele frequency of the p.Leu386_Pro387del variant in MECP2 in gnomAD v4.1 is 0.000001123 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Leu386_Pro387del variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844091/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:3752 biolink:causes MONDO:0004631 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0153349 infores:hetionet GO:0060420 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:0060420 GO:0007507 CHEBI:3387 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0015672 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0018790 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020701 infores:hetionet NCBIGene:203859 biolink:causes MONDO:0012652 infores:monarchinitiative not_provided not_provided HGNC:27337 MONDO:0012652 uuid:290a406d-af44-4a2e-a553-3b667b97f01f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399792054 biolink:causes MONDO:0100326 infores:clingen CAID:CA399792054 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.2770C>T (p.Gln924Ter) nonsense variant in exon 27/30 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (GT15 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIb surface expression was absent, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399792054/MONDO:0100326/011 2022-04-18 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:31623 biolink:causes UMLS:C0858708 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0858708 infores:hetionet CHEBI:9362 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0041834 infores:hetionet CHEBI:3077 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0030193 infores:hetionet CHEBI:17334 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0039231 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1167870 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1167870 infores:hetionet CHEBI:66876 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0042029 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0235431 infores:hetionet CHEBI:78543 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0015230 infores:hetionet CHEBI:3223 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0014394 infores:hetionet CHEBI:31949 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0000737 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0917799 infores:hetionet CHEBI:7492 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0004093 infores:hetionet CHEBI:51041 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042023 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0239385 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032461 infores:hetionet CHEBI:7931 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0039070 infores:hetionet CHEBI:8869 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0000731 infores:hetionet GO:0072248 biolink:causes CL:0002525 infores:ubergraph knowledge_assertion manual_agent GO:0072248 CL:0002525 CHEBI:63791 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0152025 infores:hetionet NCBITaxon:5811 biolink:causes MONDO:0005989 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5811 MESH:D014123 DB00359_MESH_D014123_1DB00205_MESH_D014123_1DB01015_MESH_D014123_1 CHEBI:8214 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0428977 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0836924 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0004936 infores:hetionet CHEBI:36791 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151836 infores:hetionet NCBIGene:2671 biolink:causes MONDO:0013116 infores:monarchinitiative not_provided not_provided HGNC:4236 MONDO:0013116 uuid:cb566d6f-c196-4175-8603-9fce03e0d492 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7809 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C2697368 infores:hetionet CHEBI:68478 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0085593 infores:hetionet CHEBI:36791 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004093 infores:hetionet CHEBI:47780 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0039231 infores:hetionet CHEBI:10023 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0000737 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020473 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0851341 infores:hetionet CAID:CA179513 biolink:causes MONDO:0019501 infores:clingen CAID:CA179513 MONDO:0019501 PMID: Likely Benign BS1 BS2, PP3, PP4, PM3, BP4, BA1 The c.12505A>G variant in USH2A is a missense variant predicted to cause substitution of threonine by alanine at amino acid 4169. The highest population minor allele frequency in gnomAD v4.1 is 0.003637 (273/75052 alleles) in the African/African-American population, which is higher than the ClinGen HL VCEP threshold (>0.003]) for BS1, and therefore meets this criterion (BS1 met).The computational predictor REVEL gives a score of 0.207, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. (PP3 and BP4 not met). This variant has been observed in the homozygous state in at least six apparently healthy adults (GeneDx internal data, SCV000583079.4). This variant has also been observed with a co-occurring pathogenic variant, phase unknown, in three patients with retinitis pigmentosa/other retinal disease (Labcorp Genetics (formerly Invitae) SCV001039753.7). However, given its high allele frequency in the population and unknown phase with the co-occurring variant, PM3 was not applied. In summary, this variant has been classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA179513/MONDO:0019501/005 2025-05-21 2025-06-30 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:63589 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0003123 infores:hetionet CHEBI:63635 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0497156 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0011616 infores:hetionet CHEBI:101853 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0039231 infores:hetionet CHEBI:31644 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013456 infores:hetionet CAID:CA288034 biolink:causes MONDO:0100488 infores:clingen CAID:CA288034 MONDO:0100488 PMID: Likely Benign BS2 BP5, BS4, BS1, BS3, PM5, PM6, PM2, PP1, PP3, BP2, BA1, PS4, PS2, PS3 The c.1360G>A (p.Val454Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 4 in 152,164 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288034/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:28748 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036508 infores:hetionet CHEBI:6402 biolink:causes HP:0001482 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151811 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151849 infores:hetionet CHEBI:6912 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0013428 infores:hetionet UMLS:C0657912 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0043094 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0853193 infores:hetionet CHEBI:7915 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0030196 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0011570 infores:hetionet CHEBI:92712 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0026961 infores:hetionet CHEBI:17026 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0026826 infores:hetionet NCBITaxon:485 biolink:causes MONDO:0004277 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:485 MONDO:0004277 CHEBI:135613 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0039231 infores:hetionet CHEBI:64355 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003862 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0022408 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0035309 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017601 infores:hetionet CHEBI:3223 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013604 infores:hetionet CHEBI:4024 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0423153 infores:hetionet NCBIGene:8802 biolink:causes MONDO:0009504 infores:monarchinitiative not_provided not_provided HGNC:11449 MONDO:0009504 uuid:b599d8de-dd99-42cc-898d-bb6aa424b792 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0235198 infores:hetionet CHEBI:5790 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0002994 infores:hetionet CHEBI:45081 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0021141 infores:hetionet CHEBI:4708 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C2830004 infores:hetionet CHEBI:520985 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0004093 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151559 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0011991 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0521592 infores:hetionet CHEBI:9943 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014724 infores:hetionet CHEBI:31705 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0015967 infores:hetionet NCBIGene:6392 biolink:causes MONDO:0008192 infores:monarchinitiative not_provided not_provided HGNC:10683 MONDO:0008192 uuid:984c0c5d-694a-4455-92f4-27a1adf40dd5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C1704272 infores:hetionet CHEBI:45951 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0344232 infores:hetionet CAID:CA414801916 biolink:causes MONDO:0044970 infores:clingen CAID:CA414801916 MONDO:0044970 PMID: Uncertain Significance PP3, PP1, PP4 PM5, PM4, BP4, PS4, PS1, PS2, PS3, PVS1, PM2, PM6 The m.9026G>A (p.G167D) variant in MT-ATP6 has been reported in one family to date and features in this family included exercise intolerance, vomiting, and a maternal family history of similar spectrum concerns (PMID: 30763462). Oxidative phosphorylation testing in fibroblasts from the proband were consistent with CV deficiency and all other potential etiologies were reasonably excluded (PP4). Per our literature review and a recently published review, there are no reported de novo occurrences of this variant (PMID: 30763462). This variant segregated with disease in the single reported family as the proband’s healthy brother had undetectable levels of variant in blood and his less severely affected mother (fatigue, migraines, neuropathy) had lower heteroplasmy (4% blood, 8% urine) than the proband (PP1, PMID: 30763462). In silico tools predict this variant to be pathogenic (PP3). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP4, PP1, PP3). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414801916/MONDO:0044970/014 2021-05-07 2021-10-22 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7824 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0033860 infores:hetionet CHEBI:6067 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036974 infores:hetionet CHEBI:27300 biolink:causes UMLS:C1533591 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C1533591 infores:hetionet CHEBI:681569 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0014356 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0853891 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0853891 infores:hetionet CHEBI:87715 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0428977 infores:hetionet CHEBI:51164 biolink:causes UMLS:C0853895 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0853895 infores:hetionet CHEBI:9435 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0012569 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042109 infores:hetionet CAID:CA134743 biolink:causes MONDO:0021060 infores:clingen CAID:CA134743 MONDO:0021060 PMID: Benign BP5, BP7, BP4, BA1 The c.639T>C (p.Thr213Thr) variant in RAF1 is classified as benign because it has been identified in 0.05616% (lower bound of the 95% CI of 28/35434) of Latino alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). It was observed in an individual with an alternate molecular basis for disease (BP5; SCV000061357.6). It does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact to splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134743/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9168 biolink:causes MONDO:0015265 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0006272 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0022650 infores:hetionet CHEBI:28487 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0002962 infores:hetionet CHEBI:28241 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0027497 infores:hetionet CHEBI:116278 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0017181 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0851341 infores:hetionet CHEBI:84500 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0151766 infores:hetionet CHEBI:5138 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0455204 infores:hetionet CHEBI:63621 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0242301 infores:hetionet CAID:CA114164 biolink:causes MONDO:0015630 infores:clingen CAID:CA114164 MONDO:0015630 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3 PP1, PS4, PM5 The NM_000552.5(VWF):c.3854C>T variant in VWF is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 1285. This variant is absent from gnomAD v4.1 (PM2_supporting). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (<0.5), and markedly reduced ristocetin-induced VWF binding to GPIb, which together are highly specific for VWD type 2M. (PP4_moderate, PMID: 12588351). The computational predictor REVEL gives a score of 0.946, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The A1 domain from this variant exhibited complete loss of shear-flow-dependent platelet adhesion (PMID: 25185554, PS3).This variant is classified as Likely Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_Moderate, PP3, PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114164/MONDO:0015630/081 2024-12-03 2024-12-03 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:2767 biolink:causes MONDO:0007792 infores:monarchinitiative not_provided not_provided HGNC:4379 MONDO:0007792 uuid:da02b2c3-152a-4fbe-b27a-c2e89806a6cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020598 infores:hetionet CHEBI:2611 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042024 infores:hetionet CHEBI:5558 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0030252 infores:hetionet CHEBI:51041 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011603 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042109 infores:hetionet CHEBI:204734 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0151514 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0004652 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D018410 DB00319_MESH_D018410_1DB00218_MESH_D018410_1DB00766_MESH_D018410_1DB00537_MESH_D018410_1DB01172_MESH_D018410_1DB00415_MESH_D018410_1DB01413_MESH_D018410_1DB01607_MESH_D018410_1DB01059_MESH_D018410_1DB01066_MESH_D018410_3DB02703_MESH_D018410_1DB01155_MESH_D018410_2DB00438_MESH_D018410_1DB01155_MESH_D018410_1DB01165_MESH_D018410_1 CHEBI:17303 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0917801 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0521305 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0521305 infores:hetionet NCBIGene:57551 biolink:causes MONDO:0859199 infores:monarchinitiative not_provided not_provided HGNC:29259 MONDO:0859199 uuid:9305f066-b8f3-4d2e-89b0-a89f6b26872a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8802 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020672 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0029408 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0019158 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0014701 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0014701 uuid:747a3b94-90f1-4bf3-b644-f0dbf9ed906c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3098 biolink:causes MONDO:0009340 infores:monarchinitiative not_provided not_provided HGNC:4922 MONDO:0009340 uuid:94d460c3-238b-4985-b1d8-d32c59ca1c67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44423 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0239488 infores:hetionet CHEBI:50924 biolink:causes NCIT:C78280 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0221727 infores:hetionet NCBITaxon:613 biolink:causes EFO:1001421 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:613 MESH:D016868 DB02703_MESH_D016868_1DB00948_MESH_D016868_1DB00319_MESH_D016868_1DB01212_MESH_D016868_1DB00684_MESH_D016868_1DB00355_MESH_D016868_1DB00493_MESH_D016868_1DB01607_MESH_D016868_1 CHEBI:8874 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0040053 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0155550 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0155550 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0852909 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0852909 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0596170 infores:hetionet CHEBI:2788 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0005747 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0030305 infores:hetionet CAID:CA2573153469 biolink:causes MONDO:0011132 infores:clingen CAID:CA2573153469 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong The NM_001369369.1(FOXN1):c.1010del (p.Gly337GlufsTer?) frameshift variant in exon 6 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong).Variant has a Grpmax allele frequency of 0 in gnomADv4.1.0 with a single allele present in the European non-Finnish population. It was detected in P5 (PMID: 31447097), who displayed phenotypes such as T lymphopenia, CD3 571 cells/ul [nv:2500-5500], low TRECs, but did not display nail dystrophy. The patient was also sequenced for other SCID related genes (PP4). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573153469/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:135929 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0012833 infores:hetionet NCBIGene:8890 biolink:causes MONDO:0957872 infores:monarchinitiative not_provided not_provided HGNC:3260 MONDO:0957872 uuid:63435a3e-1704-4d32-9ac5-c5a0501f3d7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:26276 biolink:causes MONDO:0859278 infores:monarchinitiative not_provided not_provided HGNC:12712 MONDO:0859278 uuid:bd5101f4-6273-456b-ba0a-911a79677d75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28445 biolink:causes UMLS:C0581883 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0581883 infores:hetionet CHEBI:6367 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0149745 infores:hetionet CHEBI:4887 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0019572 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0007642 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0013395 infores:hetionet CHEBI:4466 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0392676 infores:hetionet CHEBI:36791 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0000729 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0559546 infores:hetionet CHEBI:520985 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0085631 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0038454 infores:hetionet CHEBI:35854 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0235031 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0006852 infores:hetionet CHEBI:10101 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085633 infores:hetionet CHEBI:4672 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C2363730 infores:hetionet NCBIGene:8643 biolink:causes MONDO:0011556 infores:monarchinitiative not_provided not_provided HGNC:9586 MONDO:0011556 uuid:5f439697-cac0-427a-9302-782eb389999a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235266 infores:hetionet CHEBI:9328 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0003862 infores:hetionet UNII:R43D2573WO biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011603 infores:hetionet CHEBI:3994 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0085593 infores:hetionet CHEBI:71417 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0009421 infores:hetionet CHEBI:71229 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0234233 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0221201 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0740330 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0740330 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020538 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151479 infores:hetionet GO:1900133 biolink:causes GO:0001991 infores:ubergraph knowledge_assertion manual_agent GO:1900133 GO:0001991 CHEBI:79699 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011168 infores:hetionet CHEBI:61049 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018133 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0236024 infores:hetionet CHEBI:48390 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0017178 infores:hetionet CHEBI:45783 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0917801 infores:hetionet CHEBI:15553 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020578 infores:hetionet CHEBI:7865 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0236075 infores:hetionet CHEBI:45979 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0085593 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006285 infores:hetionet CHEBI:4798 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0023222 infores:hetionet CHEBI:50859 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C3495920 infores:hetionet CHEBI:141474 biolink:causes UMLS:C0332687 infores:sider not_provided not_provided DRUGBANK:DB00772 UMLS:C0332687 infores:hetionet CHEBI:367163 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0024305 infores:hetionet CHEBI:8485 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0162820 infores:hetionet CHEBI:27834 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C1258215 infores:hetionet CHEBI:6073 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0042023 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002775 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0003128 infores:hetionet CAID:CA8815496 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815496 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM5, PM3, PM2_Supporting The NM_000152.5:c.1841C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 614 (p.Thr614Met). At least 2 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PP4_Moderate). This variant has been detected in at least 3 individuals with Pompe disease. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant (PMID: 33741225). At least 2 individuals were homozygous for the variant (PMID: 33301762, 33741225, 33250842) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004184 (1/23902 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.769 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5). Splicing prediction using Splice AI revealed no expected effects on splicing due to either of these variants. There is a ClinVar entry for this variant (Variation ID: 286469, 1 star review status) with 3 submitters classifying the variant as uncertain significance, 2 submitters as likely pathogenic, and 1 submitter as pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_Moderate, PP3, PM3, PM5, PM2_Supporting Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815496/MONDO:0009290/010 2022-09-19 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:46295 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0021053 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0042109 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0702266 infores:hetionet CHEBI:2379 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0027497 infores:hetionet CHEBI:63577 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0035243 infores:hetionet CHEBI:77733 biolink:causes HP:0012733 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0332573 infores:hetionet CAID:CA012747 biolink:causes MONDO:0004994 infores:clingen CAID:CA012747 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.261C>T (p.Ile87=) variant in the MYH7 gene is 0.18% (26/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012747/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2038 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0038160 infores:hetionet CHEBI:100246 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0012833 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0948815 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0948815 infores:hetionet CHEBI:5103 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0004134 infores:hetionet CHEBI:145499 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0035317 infores:hetionet CHEBI:5062 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0178415 infores:hetionet CHEBI:31302 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0750394 infores:hetionet CHEBI:9635 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0002962 infores:hetionet CHEBI:63791 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030252 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0030920 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0948594 infores:hetionet CHEBI:6706 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0003123 infores:hetionet CHEBI:3403 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0020458 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0031117 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0037199 infores:hetionet CAID:CA013849 biolink:causes MONDO:0005045 infores:clingen CAID:CA013849 MONDO:0005045 PMID: Uncertain Significance PP3, PS4_Supporting PP2, PP1, PM2, PM6, PM5, PM1, BA1, BP4, BP2, PS1, PS3, PS2, BP5, BS1, BS3, BS4 NM_000258.3(MYL3):c.460C>T (p.Arg154Cys). This variant has been reported in individuals with HCM and other cardiomyopathies (ClinVar Variation ID 43124) and has also been identified in 4 out of 282804 (0.025% FAF 95% CI) of pan-ethnic chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v2.1). The variant is statistically increased in individuals with HCM compared to controls (OR, lower 95% CI>5), therefore, the PS4 criterion has been applied at supporting strength (PS4_Supporting) and the PM2_Supporting criterion has not been applied. Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYL2-specific ACMG/AMP criteria applied: PS4_Supporting, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013849/MONDO:0005045/103 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6804 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0018681 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0005972 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D011018 DB00567_MESH_D011018_1DB13179_MESH_D011018_1DB01053_MESH_D011018_1DB01066_MESH_D011018_3DB01139_MESH_D011018_1DB01328_MESH_D011018_1DB01155_MESH_D011018_1DB01165_MESH_D011018_1DB00447_MESH_D011018_1DB00415_MESH_D011018_1DB06590_MESH_D011018_1DB01327_MESH_D011018_1DB01416_MESH_D011018_1DB00833_MESH_D011018_1DB01112_MESH_D011018_1DB00365_MESH_D011018_1DB00218_MESH_D011018_1DB01208_MESH_D011018_1DB00303_MESH_D011018_1DB00766_MESH_D011018_1DB01326_MESH_D011018_1DB01053_MESH_D011018_2DB09320_MESH_D011018_1DB00976_MESH_D011018_1DB00537_MESH_D011018_1DB00207_MESH_D011018_1DB01137_MESH_D011018_1DB01059_MESH_D011018_1DB01330_MESH_D011018_1DB01597_MESH_D011018_1DB01333_MESH_D011018_1DB00954_MESH_D011018_1DB00438_MESH_D011018_1DB00493_MESH_D011018_1DB01190_MESH_D011018_1DB01212_MESH_D011018_1DB01332_MESH_D011018_1DB09335_MESH_D011018_1DB01060_MESH_D011018_1DB00199_MESH_D011018_1DB01331_MESH_D011018_1DB00685_MESH_D011018_1 CHEBI:45863 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C3665347 infores:hetionet CHEBI:75722 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0497156 infores:hetionet NCBIGene:51741 biolink:causes MONDO:0007576 infores:monarchinitiative not_provided not_provided HGNC:12799 MONDO:0007576 uuid:4fdb6cf5-a3af-4a12-9e64-986e2ecb0e67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5123 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0037036 infores:hetionet CHEBI:50692 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0011991 infores:hetionet CHEBI:5855 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027497 infores:hetionet CHEBI:681850 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020615 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0243026 infores:hetionet CHEBI:82960 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0018524 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0038362 infores:hetionet CHEBI:3176 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0232462 infores:hetionet CHEBI:47499 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0027497 infores:hetionet CHEBI:8869 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0041582 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0027947 infores:hetionet CAID:CA6197622 biolink:causes MONDO:0019497 infores:clingen CAID:CA6197622 MONDO:0019497 PMID: Uncertain Significance PP3, PM3 BP7, BP5, BS1, BS3, BS4, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM2, PM6, PVS1, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.1817 G>A (NM_000260.4(MYO7A):c.1817G>A (p.Arg606His)) variant in MYO7A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 606. The highest major allele frequency in gnomAD v2.1.1 is 0.00035 (0.035 % or 8/23092 alleles) in the South Asian population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.832, (which is above the threshold of 0.7), evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least one individual with autosomal recessive nonsyndromic genetic hearing loss. This proband was compound heterozygous for the variant and a pathogenic variant, confirmed in trans by parental testing (PM3; 1.0 point; LMM Internal Data). The patient with this variant displayed moderate to severe sensorineural hearing loss, although no vision anomalies or difficulty seeing at night were noted (PP4 not met; LMM Internal Data). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic deafness, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PP3, PM3; Version 2, 7.19.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6197622/MONDO:0019497/005 2023-07-19 2023-10-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:8768 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0040034 infores:hetionet CHEBI:64355 biolink:causes HP:0005542 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151563 infores:hetionet CHEBI:75246 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C1384353 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0011991 infores:hetionet NCBIGene:406960 biolink:causes MONDO:0013678 infores:monarchinitiative not_provided not_provided HGNC:31555 MONDO:0013678 uuid:503b3ceb-c947-4036-b95c-3356721ab585 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027441 infores:hetionet CHEBI:145499 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0025222 infores:hetionet CAID:CA255124 biolink:causes MONDO:0010602 infores:clingen CAID:CA255124 MONDO:0010602 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PS4 The c.1804C>T (p.Arg602Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 12 and expected to result in nonsense-mediated mRNA decay. This variant is absent from males in gnomAD v2.1.1 and v3.1.1, which meets criteria for PM2_Supporting. More than 25 patients with moderate-severe hemophilia A are reported in the literature and internal laboratory data, meeting criteria for PS4_Very Strong and PP4_Moderate (PMID: 29296726, 18387975, 18691168, 16769589, 8639447, 20331761). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255124/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5118 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029191 infores:hetionet CHEBI:34829 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0022568 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0040046 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0853750 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0853750 infores:hetionet CHEBI:5280 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0027497 infores:hetionet CHEBI:204734 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0020456 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0030552 infores:hetionet CAID:CA645614063 biolink:causes MONDO:0011071 infores:clingen CAID:CA645614063 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1214_1217dup (p.Tyr407ValfsTer?) is a duplication variant that results in a frameshift in the last exon. This variant is located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting), is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which is critical for protein function (PVS1_Strong). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645614063/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3696 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0947912 infores:hetionet CHEBI:119915 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003537 infores:hetionet CHEBI:45951 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0018681 infores:hetionet CHEBI:91541 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C1112320 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0039971 infores:hetionet CHEBI:6375 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018926 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0036572 infores:hetionet CHEBI:50742 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0022354 infores:hetionet CHEBI:7931 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085932 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0017160 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0267792 infores:hetionet NCBIGene:3643 biolink:causes MONDO:0012381 infores:monarchinitiative not_provided not_provided HGNC:6091 MONDO:0012381 uuid:416981bd-f80f-4e21-bca4-36b05e6ea977 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0034150 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0221745 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0221745 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0277585 infores:hetionet CHEBI:168396 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003862 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0034882 infores:hetionet CAID:CA210756 biolink:causes MONDO:0013144 infores:clingen CAID:CA210756 MONDO:0013144 PMID: Pathogenic PS4, PM1, PP1_Strong, PP3, PP4 PS3, PM2 The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210756/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135342 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0037199 infores:hetionet CHEBI:31980 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0013395 infores:hetionet CHEBI:4858 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0232461 infores:hetionet CAID:CA409103974 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103974 MONDO:0015967 PMID: Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4, PP1_Strong The c.200G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 67 (p.(Arg67Gln)) of NM_175914.5. This variant has poor data quality in gnomAD v2.1.1 exomes but is absent in gnomAD genomes v3.0 and therefore at the discretion of the ClinGen MDEP PM2_Supporting will be applied (PM2_Supporting). This variant was identified in 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31523701, 20705777, 21353246, 29493090, internal lab contributors). At least 3 of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:20705777, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 10 informative meioses in five families (PP1_Strong; PMID:20705777, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Another missense variant, c.199C>T (p.(Arg67Trp)), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg67Gln)​ (PM5_Supporting). In summary, the c.200G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103974/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:11014 biolink:causes MONDO:0030861 infores:monarchinitiative not_provided not_provided HGNC:6305 MONDO:0030861 uuid:fe88f585-9384-4306-83da-81f389ef610e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94449 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0042029 infores:hetionet CHEBI:180905 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0009806 infores:hetionet CHEBI:5141 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0003467 infores:hetionet NCBIGene:643226 biolink:causes MONDO:0014363 infores:monarchinitiative not_provided not_provided HGNC:33862 MONDO:0014363 uuid:e2271b54-0c6c-45a0-86ad-be8c13259df3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C1443060 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0040409 infores:hetionet CHEBI:63631 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234632 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0162429 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0042109 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0003123 infores:hetionet NCBIGene:2222 biolink:causes MONDO:0032566 infores:monarchinitiative not_provided not_provided HGNC:3629 MONDO:0032566 uuid:6e3d49b6-1c7c-423c-9cd3-bc460e5b904f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28445 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0026858 infores:hetionet CAID:CA2580098625 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098625 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.351+3A>G is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This intronic variant has a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098625/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135736 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0876973 infores:hetionet CHEBI:75998 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0027497 infores:hetionet CAID:CA386971639 biolink:causes MONDO:0015967 infores:clingen CAID:CA386971639 MONDO:0015967 PMID: Likely Benign BP4, BP7 PS4, BS1, PM2, PP4 The c.1521C>A variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 507 (p.Pro507=) of NM_000545.8. The Grpmax filtering allele frequency of the c.1521C>A variant in gnomAD v4.1.0 is 0.00000953, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This synonymous variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0.03, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -4.291), which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, therefore PP4 cannot be applied and PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1521C>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386971639/MONDO:0015967/017 2025-08-29 2025-08-29 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA255318 biolink:causes MONDO:0010604 infores:clingen CAID:CA255318 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4_Very Strong, PP3, PP4_Moderate PM1 NM_000133.4(F9):c.224G>A (p.Arg75Gln) missense variant has a REVEL score of 0.904, which meets criteria for PP3. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). Approximately 24 patients are reported in the literature with mild hemophilia B and this variant, meeting F9 phenotype criteria for PS4_Very strong (PMID: 31064749, PMID: 2066105, PMID: 8314564, PMID: 29296726, PMID: 27213901, PMID: 2773937). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PP4_Moderate, PP3, PM2_supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255318/MONDO:0010604/080 2024-10-11 2025-01-07 X-linked inheritance HP:0001417 Supports CHEBI:3215 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1619712 infores:hetionet NCBIGene:79415 biolink:causes MONDO:0030066 infores:monarchinitiative not_provided not_provided HGNC:28672 MONDO:0030066 uuid:59bd6a56-65f9-4c6e-ad50-db3743baf195 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6329 biolink:causes MONDO:0018959 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0018959 uuid:d635a7c0-fc94-4623-bdbd-7b11a03b6c4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA037094 biolink:causes MONDO:0007750 infores:clingen CAID:CA037094 MONDO:0007750 PMID: Likely Benign BP4, BP2, PM2 BA1, BP1, BP3, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, PP4, BS2 NM_000527.5(LDLR):c.1846-10G>T variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00009643 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1).BP2 - Variant identified in an index case with heterozygous FH phenotype (LDLc = 6.5 mmol/l) and APOB variant p.(Arg3527Gln), classified as Pathogenic by the general ACMG guidelines from Robarts Research Institute.BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -20 to +3 bases of canonical acceptor splicing site MES scores: de novo acceptor = 11.36, authentic acceptor = 9.58. Ratio variant/wt = 1.18. It is above 1.0. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met.Variant has 2 BP evidence codes towards Benign, enough to classify as Likely benign, and only 1 PM evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037094/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:142290 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0020542 infores:hetionet CHEBI:9123 biolink:causes UMLS:C1142239 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1142239 infores:hetionet CHEBI:31536 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0042029 infores:hetionet CHEBI:291342 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0004093 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877661 infores:hetionet CAID:CA16020746 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020746 MONDO:0009861 PMID:23430918PMID:23430918 Pathogenic PM3, PVS1, PM2, PP4 The c.206dupC variant in PAH has been previously reported as a heterozygous variant detected in trans with the known pathogenic c.1066-11G>A variant in a single Caucasian proband with classic PKU; BH4 deficiency was not formally excluded (PMID: 23430918) (PM3, PP4). The variant is a 1bp insertion leading to a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020746/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7627 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0029134 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1167965 infores:hetionet CHEBI:10124 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085631 infores:hetionet CHEBI:8888 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2981158 infores:hetionet CHEBI:31547 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0232807 infores:hetionet CHEBI:10650 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0231218 infores:hetionet CHEBI:10650 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0012569 infores:hetionet CHEBI:7565 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0947912 infores:hetionet CHEBI:48390 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0040053 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0836924 infores:hetionet CHEBI:100147 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0015230 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0002994 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0687133 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151505 infores:hetionet CHEBI:3207 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0549622 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0031542 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011581 infores:hetionet CHEBI:8356 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0239134 infores:hetionet CHEBI:3508 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0151872 infores:hetionet CAID:CA376062485 biolink:causes MONDO:0011225 infores:clingen CAID:CA376062485 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BA1, BS1, PM5 The c.247A>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Isoleucine by Leucine at amino acid 83 (p.Ile83Leu).The filtering allele frequency (the upper threshold of the 95% CI of 2/1092968) of the c.247A>C variant in DCLRE1C is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).No homozygotes have been observed in gnomAD.Another missense variant NM_001033855.3(DCLRE1C):c.247A>G (p.Ile83Val) in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 is not met).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376062485/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:68642 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0015672 infores:hetionet NCBIGene:9439 biolink:causes MONDO:0013651 infores:monarchinitiative not_provided not_provided HGNC:2372 MONDO:0013651 uuid:85473410-f7c2-4a3d-897a-c80c45287f30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27565 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0011615 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011053 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0002792 infores:hetionet CHEBI:7915 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0001925 infores:hetionet CAID:CA013144 biolink:causes MONDO:0005045 infores:clingen CAID:CA013144 MONDO:0005045 PMID: Likely Pathogenic PM2, PM6, PP3, PS4_Moderate PM5, PM1, PM4, PP1, BA1, PS3, BS1, BS3, BS4, PS1, PS2, BP4, BP5, BP7, BP2, PVS1 The c.2845G>A (p.Glu949Lys) variant in MYH7 has been reported in 12 individuals with HCM (PS4_Moderate; Watkins 1992 PMID:1552912; Walsh 2017 PMID:27532257; Zigova 2018 PMID:28815794; CHEO pers comm.). This variant segregated with disease in 1 affected relative with HCM (Watkins 1992 PMID:1552912); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has been reported as a de novo occurence in 1 child with RCM (PM6; Kapoor 2017 http://repository.ias.ac.in/114592/1/JPractCardiovascSci33143-8313497_230534.pdf). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM6; PM2; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013144/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:520985 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0024902 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C1384666 infores:hetionet CHEBI:6073 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0011615 infores:hetionet CHEBI:17026 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0032708 infores:hetionet CHEBI:231594 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0019572 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0020517 infores:hetionet CAID:CA386966029 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966029 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate BP4, PS4, PP3 The c.770A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 257 (p.(Asn257Ser)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a REVEL score of 0.598, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in one unrelated individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, which is below the ClinGen MDEP threshold for PS4_Moderate to be applied (internal lab contributors). However, this indiviudal did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Another variant at this location, c.770A>C p.(Asn257Thr), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.770A>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP4_Moderate, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966029/MONDO:0015967/017 2024-11-27 2024-11-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64312 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007820 infores:hetionet CAID:CA8622902 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622902 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.261C>G (p.Ala87=), no individuals with Glanzmann thrombasthenia were reported with the variant and has only been observed in a ostensibly healthy population. The variant has a minor allele frequency of 0.00006 (1/16256 alleles) in the African/African American population in gnomAD, which meets the threshold criteria for PM2_supporting. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of 1.32 shows that the nucleotide position is not highly conserved (BP4, BP7). Due to conflicting evidence, this variant is classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, BP4, BP7. (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622902/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true UMLS:C0025241 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0006826 infores:hetionet CHEBI:4708 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0004604 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0025061 infores:hetionet CHEBI:72690 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0149871 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0234913 infores:hetionet CHEBI:6437 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0520966 infores:hetionet CHEBI:9586 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013491 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0024115 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0042373 infores:hetionet CAID:CA10650450 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650450 MONDO:0011071 PMID: Benign BA1, BP2, BP4 PS1, PS4, PS2, BP3, BP1, BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM5, PM4, PM3, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.-135G>T is an intronic variant with a MAF of 0.01272 (1.3%, 66/5190,) in the East Asian subpopulation of gnomAD 3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 2 indviduals in gnomAD 3.1.2 East Asian cohort (BP2). This intronic variant has a SpliceAI score ≤ 0.20 (Donor Loss 0.12) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650450/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2948 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0015967 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0497327 infores:hetionet CHEBI:76010 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0029118 infores:hetionet CHEBI:9586 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042963 infores:hetionet CHEBI:9943 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0010520 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0015230 infores:hetionet CHEBI:4710 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0007859 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0038826 infores:hetionet GO:0110073 biolink:causes GO:0003381 infores:ubergraph knowledge_assertion manual_agent GO:0110073 GO:0003381 CHEBI:9586 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085932 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020676 infores:hetionet CAID:CA3232036 biolink:causes MONDO:0012163 infores:clingen CAID:CA3232036 MONDO:0012163 PMID: Likely Benign BS1 NM_002185.5(IL7R):c.602A>G is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 201 (p.Tyr201Cys). The highest population minor allele frequency in gnomAD v4 is 0.004560 (135/29604) in Ashkenazi Jewish population which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. As per SCID VCEP specifications, 1 Strong criteria is enough to reach Likely Benign classification. In summary, this variant meets the criteria to be classified as a Likely Benign variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3232036/MONDO:0012163/119 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8890 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0026837 infores:hetionet NCBIGene:10342 biolink:causes MONDO:0014295 infores:monarchinitiative not_provided not_provided HGNC:11758 MONDO:0014295 uuid:1b73873d-64ec-486d-8e2e-36cc0c6eadbb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes UMLS:C0403639 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0403639 infores:hetionet CHEBI:8707 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0015672 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0243026 infores:hetionet CHEBI:63605 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0015230 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042075 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0005940 infores:hetionet CHEBI:15367 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0033774 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0029456 infores:hetionet CHEBI:17650 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0423791 infores:hetionet CAID:CA229499 biolink:causes MONDO:0009861 infores:clingen CAID:CA229499 MONDO:0009861 PMID:24401910PMID:14722928 Pathogenic PM3, PP4_Moderate, PM2, PVS1 This c.241_256del (p.Thr81fs) variant in PAH has been reported in two patients with PKU, observed with two pathogenic variants: p.R241C, phase unknown (PMID: 14722928) and with p.V399V, phase unknown (PMID: 24401910). This variant is absent from controls is population databases. This is a frameshift variant in exon 3 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate, and PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229499/MONDO:0009861/006 2020-10-22 2020-10-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49960 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0042029 infores:hetionet CAID:CA250589 biolink:causes MONDO:0044970 infores:clingen CAID:CA250589 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, BA1, BP4, PS4, BS1 The m.10563T>C (p.C32R) variant in MT-ND4L has not been reported in individuals with primary mitochondrial disease to our knowledge. The computational predictors APOGEE1 and APOGEE2 produce conflicting evidence regarding the predicted functional impact of this variant with raw scores of 0.42 (neutral) and 0.840 (likely pathogenic), respectively (Min=0, Max=1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA250589/MONDO:0044970/015 2023-10-23 2024-11-25 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:101278 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0038999 infores:hetionet CHEBI:27958 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0085631 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0235293 infores:hetionet NCBIGene:3431 biolink:causes MONDO:0009338 infores:monarchinitiative not_provided not_provided HGNC:5401 MONDO:0009338 uuid:463b36b3-978a-4ab1-9e3c-f3dd76a1fc85 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3858 biolink:causes MONDO:0007809 infores:monarchinitiative not_provided not_provided HGNC:6413 MONDO:0007809 uuid:42e43db3-799c-4302-aef2-c304839f2143 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0025323 infores:hetionet CHEBI:6367 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0231530 infores:hetionet CHEBI:7822 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0025222 infores:hetionet CHEBI:4530 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0023530 infores:hetionet CHEBI:53760 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020621 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0025061 infores:hetionet CAID:CA213719 biolink:causes MONDO:0015967 infores:clingen CAID:CA213719 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1142T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 381 (p.(Met381Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9629, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 22060211 (likely same cases as PMID 29927023, PMID 32375122, PMID 2555642, and PMID 24804978 (Kawakita et al 2014)), PMID 24804978, internal lab contributors). At least one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Arg has a greater Grantham distance (PM5). In summary, the c.1142T>G variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PM5, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213719/MONDO:0015967/086 2023-07-17 2023-07-17 Semidominant inheritance HP:0032113 Supports CHEBI:78320 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0031542 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0020517 infores:hetionet CHEBI:17026 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0033046 infores:hetionet CAID:CA341526 biolink:causes MONDO:0008723 infores:clingen CAID:CA341526 MONDO:0008723 PMID:9973285PMID:17374501 Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate, PS3_Supporting The NM_000018.4(ACADVL): c.779C>T (p.Thr260Met) variant is a missense variant predicted to cause substitution of threonine by methionine at amino acid 260. This variant has been detected in individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 8845838, 17374501, 32518924). This variant was found homozygous in two individuals with VLCAD deficiency (PM3, 1.0 point, PMIDs: 9327992, 32518924). Two enzyme activity assays in Cos-7 cells and E.coli showed residual enzyme activity between 3-5% of wildtype indicating that this variant impacts protein function (PMIDs: indicating that this variant impacts protein function (PMID: 9973285, 9973285; PS3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.875, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3_moderate, PP3, PP4_Moderate, PS3_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA341526/MONDO:0008723/021 2024-05-16 2024-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47898 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0025061 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042401 infores:hetionet CHEBI:145499 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0022107 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0009676 infores:hetionet CHEBI:4466 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0009676 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235431 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0314719 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0025290 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042998 infores:hetionet CHEBI:53691 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0010520 infores:hetionet CHEBI:6931 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0231837 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0858678 infores:hetionet CHEBI:63632 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0027796 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0004936 infores:hetionet CHEBI:7514 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0036572 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0011609 infores:hetionet CHEBI:8382 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011206 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0424000 infores:hetionet CHEBI:101853 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0003537 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1527311 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0037315 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0031350 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0270994 infores:hetionet CHEBI:101278 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0012569 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0235146 infores:hetionet CHEBI:4784 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C2363730 infores:hetionet CHEBI:52717 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0016655 infores:hetionet CHEBI:64355 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1527344 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0853034 infores:hetionet CHEBI:36791 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0392156 infores:hetionet CHEBI:63599 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0011603 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0041912 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011551 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0151828 infores:hetionet CAID:CA354447740 biolink:causes MONDO:0009276 infores:clingen CAID:CA354447740 MONDO:0009276 PMID: Uncertain Significance PM3_Supporting, PP3, PP4, PM2_Supporting The c.259T>C variant in GP9 is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 87. At least one patient (BSS-1 in PMID: 25539746) with this variant had macrothrombocytopenia and less than 10% expression of GPIba and GP9 measured by flow cytometry which together are highly specific for Bernard-Soulier syndrome (PP4). This proband was homozygous for the variant (PM3_supporting, PMID: 25539746). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.716, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as VUS- insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3, PP4, PM3_Supporting. (VCEP specifications version 1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA354447740/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:101278 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042401 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0027651 infores:hetionet NCBIGene:197258 biolink:causes MONDO:0020777 infores:monarchinitiative not_provided not_provided HGNC:29500 MONDO:0020777 uuid:414b8b44-004d-41f8-8757-c5ce890808e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75045 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0042963 infores:hetionet CHEBI:47780 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037763 infores:hetionet CAID:CA2580612100 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612100 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4 The c.1144del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 382 in NM_000162.4), adding 20 novel amino acids before encountering a stop codon (p.(Cys382Alafs*20)). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1144del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0 approved 7/23/2025): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612100/MONDO:0015967/086 2025-07-28 2025-07-28 Semidominant inheritance HP:0032113 Supports CHEBI:63115 biolink:causes MONDO:0012521 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0276226 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1096717 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1096717 infores:hetionet CHEBI:38940 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0042029 infores:hetionet CHEBI:5384 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0021141 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0040034 infores:hetionet CHEBI:6149 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020672 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006809 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007780 infores:hetionet CHEBI:9566 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0242422 infores:hetionet GO:0002816 biolink:causes GO:0050830 infores:ubergraph knowledge_assertion manual_agent GO:0002816 GO:0050830 CHEBI:585948 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0036974 infores:hetionet CAID:CA1393328 biolink:causes MONDO:0019501 infores:clingen CAID:CA1393328 MONDO:0019501 PMID: Uncertain Significance PP4, PM3 PM2 The c.13217T>C variant in USH2A is a missense variant predicted to cause substitution of leucine by proline at amino acid 4406 (p.Leu4406Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.02% (15/74934) in the African / African American population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.338, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been identified in one individual with Usher syndrome who was compound heterozygous with a pathogenic variant phase unknown (PP4, 0.5 point PM3; PMID: 36011402). This individual also had a third variant that was reviewed by the Hearing Loss VCEP and was determined to be likely benign. This variant was also identified in an individual with retinitis pigmentosa who was compound heterozygous with a pathogenic variant, though phase was unknown (0.5 point PM3, PMID: 37217489). The variant was also reported in other individuals with Usher syndrome; however, these individuals were not awarded any evidence as zygosity / phasing was unknown, the second variant was likely benign, or the individual had a possible alternate explanation for disease (PMID: 26927203, 24944099, 36011402). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1393328/MONDO:0019501/005 2024-11-20 2025-03-27 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6438 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0018681 infores:hetionet CHEBI:63619 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0427457 infores:hetionet CHEBI:5134 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0001622 infores:hetionet CHEBI:7822 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0014868 infores:hetionet CHEBI:46557 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0344232 infores:hetionet CHEBI:7936 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2364111 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0235032 infores:hetionet CHEBI:45285 biolink:causes HP:0012132 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0014800 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0041912 infores:hetionet CHEBI:5050 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C3263723 infores:hetionet CHEBI:42068 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0876994 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0038367 infores:hetionet CHEBI:7447 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C1257843 infores:hetionet CHEBI:10125 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0231528 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0085136 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0007222 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0332691 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0332691 infores:hetionet CHEBI:404903 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0085610 infores:hetionet CHEBI:47519 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0030193 infores:hetionet CHEBI:194135 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0231528 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0043345 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0006145 infores:hetionet NCBIGene:22930 biolink:causes MONDO:0010822 infores:monarchinitiative not_provided not_provided HGNC:17063 MONDO:0010822 uuid:0b20022d-ee30-438c-9362-788b4800f527 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63607 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0853149 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C98911 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0877225 infores:hetionet CHEBI:63630 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0231530 infores:hetionet CHEBI:10119 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0237314 infores:hetionet CHEBI:204928 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0006840 infores:hetionet CHEBI:28364 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0151904 infores:hetionet CHEBI:7824 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0006277 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0151735 infores:hetionet GO:1905298 biolink:causes GO:0048565 infores:ubergraph knowledge_assertion manual_agent GO:1905298 GO:0048565 CHEBI:32588 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C1443060 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0085584 infores:hetionet CHEBI:50693 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0042510 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020517 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0851341 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0855242 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0023530 infores:hetionet GO:0039645 biolink:causes GO:0000082 infores:ubergraph knowledge_assertion manual_agent GO:0039645 GO:0000082 CAID:CA91169370 biolink:causes MONDO:0001586 infores:clingen CAID:CA91169370 MONDO:0001586 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4, PM2_Supporting PM1, PM5 The NM_000203.5:c.1163C>G variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 388 (p.Thr388Arg). Two patients with this variant had IDUA deficiency within the affected range in leukocytes (specific values not provided) and clinical features specific to MPS I including corneal clouding (PMID: 17606547, 30120129). This variant has been detected in at least 10 individuals with MPS I who were heterozygous for the variant and a pathogenic or likely pathogenic variant classified by the ClinGen Lysosomal Diseases VCEP (variants: c.1139A>G, c.1205G>A, c.1855C>T, c.1861C>T); however, phase was not confirmed in any case (PMID: 14516901, 17606547, 21253827, 21963080, 28752568, 30120129) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006003 (69/1149360 alleles) in the NFE population (gnomAD v2.1.1 is 0.00001342 with 1/74540 alleles in the NFE population), which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.824 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PM2_Supporting, PP3_Moderate, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA91169370/MONDO:0001586/091 2024-12-06 2025-06-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32599 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0085620 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0265031 infores:hetionet CHEBI:9599 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0024440 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0178298 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0241863 infores:hetionet CHEBI:3061 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0687713 infores:hetionet CHEBI:6715 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0236075 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0836924 infores:hetionet CHEBI:49040 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0004093 infores:hetionet CHEBI:3223 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0036104 infores:hetionet CHEBI:17823 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0020438 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0877014 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0877014 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0040584 infores:hetionet NCBIGene:1584 biolink:causes MONDO:0008729 infores:monarchinitiative not_provided not_provided HGNC:2591 MONDO:0008729 uuid:2d5ede1f-4e1f-4401-925d-4b433be8c93f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4735 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0011606 infores:hetionet CHEBI:94848 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0233494 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0039242 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0039242 infores:hetionet CHEBI:9649 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151908 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0038454 infores:hetionet CAID:CA410204352 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204352 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.98-13C>T is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score < 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as VUS. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204352/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1167965 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0011991 infores:hetionet CHEBI:61049 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0033036 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0267596 infores:hetionet CHEBI:63612 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0026826 infores:hetionet CHEBI:77260 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0009676 infores:hetionet CHEBI:8207 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011253 infores:hetionet CHEBI:16469 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0149871 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0542184 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0033246 infores:hetionet CHEBI:50131 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0006277 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001339 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0155773 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0855242 infores:hetionet CHEBI:8430 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0011603 infores:hetionet CHEBI:9907 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0085593 infores:hetionet CHEBI:75045 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020598 infores:hetionet CHEBI:205919 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0085649 infores:hetionet CAID:CA10014518 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014518 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.426T>C (p.Ala142=) is a synonymous variant therefore REVEL score is not applicable and SpliceAI is ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -2.86813 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014518/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17026 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C3665386 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019112 infores:hetionet CHEBI:18358 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0237849 infores:hetionet CHEBI:72564 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151905 infores:hetionet NCBIGene:55131 biolink:causes MONDO:0012794 infores:monarchinitiative not_provided not_provided HGNC:21863 MONDO:0012794 uuid:ec511908-805c-40e3-8434-cf05dfa5a7aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0012833 infores:hetionet CHEBI:2676 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0014518 infores:hetionet CHEBI:6375 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0005818 infores:hetionet CHEBI:4027 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0040264 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0037822 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014534 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0849913 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0849913 infores:hetionet NCBIGene:10585 biolink:causes MONDO:0009364 infores:monarchinitiative not_provided not_provided HGNC:9202 MONDO:0009364 uuid:e399e8e2-708b-4999-b81c-cc89e01145ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C2047937 infores:hetionet CHEBI:36791 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017181 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001942 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0270549 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0019348 infores:hetionet CAID:CA10588378 biolink:causes MONDO:0021056 infores:clingen CAID:CA10588378 MONDO:0021056 PMID: Likely Pathogenic PP3, PS1_Moderate, PS4_Moderate, PM2_Supporting The NM_000038.6(APC):c.1312+5G>C variant in APC is an intronic variant which is located at the 5th nucleotide in intron 10. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 2.5 points (PS4_Moderate, Ambry Genetics, GeneDx, Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from two in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 10 of APC (PP3). Moreover, this variant has similar in silico predictions compared to another non-canonical splicing variant at that same nucleotide position (c.1312+5G>A) which is classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PP3, PS1_Moderate, PS4_Moderate, PM2_Supporting (VCEP specifications version 2.1.0; date of approval: 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588378/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50131 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0008325 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0234192 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0002871 infores:hetionet UMLS:C0065374 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0040822 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853348 infores:hetionet CHEBI:8774 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0004093 infores:hetionet NCBIGene:10102 biolink:causes MONDO:0012512 infores:monarchinitiative not_provided not_provided HGNC:12367 MONDO:0012512 uuid:23f0b1d2-daed-4ea9-b3f3-dfcbd95c948f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6539 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0232849 infores:hetionet CHEBI:72690 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0030196 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0267792 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020538 infores:hetionet NCBIGene:1630 biolink:causes MONDO:0008002 infores:monarchinitiative not_provided not_provided HGNC:2701 MONDO:0008002 uuid:8792269e-134e-4484-9276-c1ef3e6eee3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA312287 biolink:causes MONDO:0008723 infores:clingen CAID:CA312287 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1316dup (p.Met440fs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 13/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant has been reported once as a result of a positive newborn screening for VLCADD (PMID:26385305). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312287/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8435 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0541919 infores:hetionet NCBIGene:1301 biolink:causes MONDO:0007949 infores:monarchinitiative not_provided not_provided HGNC:2186 MONDO:0007949 uuid:ec77c9a5-b0b2-4959-ada9-6fde3aee3e29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28971 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0001824 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002871 infores:hetionet CHEBI:50693 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0006266 infores:hetionet CHEBI:28925 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0037274 infores:hetionet CHEBI:2687 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0017565 infores:hetionet CHEBI:3207 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0917801 infores:hetionet CHEBI:3650 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0012833 infores:hetionet CHEBI:68606 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0851578 infores:hetionet CHEBI:6792 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0020621 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020649 infores:hetionet GO:0045453 biolink:causes MONDO:0008159 infores:drugmechdb knowledge_assertion manual_agent GO:0045453 MESH:D015663 DB00630_MESH_D015663_1DB00977_MESH_D015663_1DB06202_MESH_D015663_1DB00783_MESH_D015663_1 CHEBI:7476 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0005940 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0521839 infores:hetionet CHEBI:44915 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0522055 infores:hetionet CHEBI:93635 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0080274 infores:hetionet CHEBI:3723 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013378 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0009450 infores:hetionet CHEBI:10127 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0231218 infores:hetionet CHEBI:9328 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0014742 infores:hetionet CAID:CA202865 biolink:causes MONDO:0015152 infores:clingen CAID:CA202865 MONDO:0015152 PMID: Pathogenic PP1, PP4, PM3_Very Strong BS1, PM2, PM5, PP3 The NM_213599.3: c.172C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 58 (p.Arg58Trp). This variant has been detected in at least seven individuals with limb girdle muscular dystrophy or persistent hyperCKemia, including in unknown phase with a pathogenic variant (c.191dup x2, 1.0 pts, PMID: 22499103, 30564623, LOVD Individual #00220701) and confirmed in trans with a pathogenic variant (c.2018A>G p.(Tyr673Cys), 1.0 pt, PMID: 23055322; c.148C>T p.(Arg50Ter), 1.0 pt, PMID: 30564623, LOVD Individual #00078872). Three individuals were homozygous for the variant, all of whom experienced progressive muscle weakness or showed myopathic or dystrophic signs on muscle biopsy (1.0 pt, PMID: 31353849, 27854218) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in one affected family member (PP1; PMID: 23055322). The Grpmax filtering allele frequency for this variant is 0.002728 in gnomAD v4.1.0 exomes (the lower bound of the 95% confidence interval of 23/5762 Middle Eastern chromosomes), which is higher than the threshold of 0.001 for BS1. The Middle Eastern genetic ancestry group also includes three homozygous individuals. However, in light of the overall evidence for this variant and the potential for late onset and subclinical presentation, the LGMD VCEP considers this variant a BS1 exception. The computational predictor REVEL gives a score of 0.572 (PP3, BP4 not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PM3_Very Strong, PP4, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA202865/MONDO:0015152/188 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9622 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0043352 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0877635 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0877635 infores:hetionet CHEBI:6538 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0043352 infores:hetionet CAID:CA314862 biolink:causes MONDO:0012996 infores:clingen CAID:CA314862 MONDO:0012996 PMID: Likely Benign BP4, BS1 PM5, PS3, BS3 The NM_001482.3:c.277A>G variant in GATM is a missense variant that is predicted to cause the substitution of an isoleucine by a valine at amino acid position 93 (p.Ile93Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (2/16256 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.143 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). Expression of the variant in HeLa cells resulted in 18% of wild type AGAT activity, over than the cutoff for PS3_Supporting (<15%) and less than the cutoff for BS3_Supporting (≥30%), such that no experimental evidence codes are met. There is a ClinVar entry for this variant (Variation ID: 205610). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314862/MONDO:0012996/025 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4681 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0151763 infores:hetionet CHEBI:61049 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0024305 infores:hetionet CHEBI:4653 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0240717 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0037199 infores:hetionet CHEBI:7915 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013456 infores:hetionet CHEBI:63622 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0023530 infores:hetionet CHEBI:71255 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0231218 infores:hetionet CHEBI:83804 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151907 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0012833 infores:hetionet CHEBI:31348 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0162834 infores:hetionet CAID:CA024753 biolink:causes MONDO:0007783 infores:clingen CAID:CA024753 MONDO:0007783 PMID: Likely Pathogenic PM5, PS4_Moderate, PM1_Supporting, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 2435 of the RYR1 protein, p.(Arg2435Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:10051009, PMID:23558838, PMID:30236257, The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2435His), PM5. A REVEL score >0.85 (0.948) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024753/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ GO:0106020 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:0106020 GO:0016192 CHEBI:6775 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042023 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235234 infores:hetionet GO:0044476 biolink:causes GO:0008332 infores:ubergraph knowledge_assertion manual_agent GO:0044476 GO:0008332 CAID:CA012723 biolink:causes MONDO:0005045 infores:clingen CAID:CA012723 MONDO:0005045 PMID: Likely Pathogenic PM1, PM2_Supporting, PS4, PP1_Moderate PP2, BS2, PM5, PM4, PM6, PP3, PS3, BA1, BP1, BP3, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 The NM_000257.4(MYH7):c.2606G>A (p.Arg869His) variant has been identified in >30 individuals with HCM, including at least 2 individuals with an additional variant in another gene that may contribute to their disease (PS4; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Cecchi 2006 PMID: 17180650; Olivotto 2008 PMID: 18533079; Girolami 2010 PMID: 20359594; Olivotto 2011 PMID: 21835430; Witjas-Paalberends 2013 PMID: 23674513; Marsiglia 2013 PMID: 24093860; Bos 2014 PMID: 24793961; Coppini 2014 PMID: 25524337; Adalsteinsdottir 2014 PMID: 25078086; Homburger 2016 PMID: 27247418; Viswanathan 2017 PMID: 29121657; Walsh 2017 PMID: 2753225; Ho 2018 PMID: 30297972; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 6 affected relatives with HCM from at least two families (PP1_Moderate; Girolami 2010 PMID: 20359594; GeneDx pers. comm.). Additionally, this variant has also been reported in 1 individual with DCM with an additional variant in another gene that may contribute to their disease, 1 individual with LVH and suspected HCM, 1 individual with LVNC, 1 individual with septal hypertrophy with AV conduction defect, and 4 individuals with unspecified heart disease (Ambry pers. comm.; GenDx pers. comm.). This variant was identified in 0.002% (FAF 95% CI; 2/16254) of African chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but has also been identified in a greater number of African chromosomes in gnomAD v.3.1. Therefore, the PM2 criterion was downgraded to PM2_supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM2_Supporting, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012723/MONDO:0005045/002 2021-09-28 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63608 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019348 infores:hetionet CHEBI:64355 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232766 infores:hetionet CHEBI:40009 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0001807 infores:hetionet CHEBI:8228 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0035243 infores:hetionet CHEBI:79699 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0008031 infores:hetionet CHEBI:10023 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020598 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0948594 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0007508 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0007508 uuid:8662b321-5951-4643-9076-1ed207d3cf88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0014591 infores:hetionet NCBIGene:7140 biolink:causes MONDO:0032750 infores:monarchinitiative not_provided not_provided HGNC:11950 MONDO:0032750 uuid:95c8d610-5e2a-40bf-8f00-f9a33efd4430 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0424295 infores:hetionet NCBIGene:3291 biolink:causes MONDO:0009025 infores:monarchinitiative not_provided not_provided HGNC:5209 MONDO:0009025 uuid:7dd8cade-6e32-4c8a-84c5-07d3670ba267 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0235032 infores:hetionet CHEBI:8871 biolink:causes HP:0002305 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004158 infores:hetionet CAID:CA341479 biolink:causes MONDO:0015152 infores:clingen CAID:CA341479 MONDO:0015152 PMID: Pathogenic PM5, PP3, PP4, PM3_Very Strong PM2 The NM_000070.3: c.1469G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 490 (p.Arg440Gln). This variant has been detected in at least 16 individuals with limb girdle muscular dystrophy (PMID: 26404900, 18055493, 10330340, 22378277, 22443334, 18854869), including in a homozygous state in at least four cases (1.0 pt; PMID: 18055493, 10330340, 22443334) and confirmed in trans with a pathogenic variant in three cases (c.550del p.(Thr184ArgfsTer36), 3.0 pts, PMID: 26404900, 18854869, 22378277) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.0001846 (3/16248 exome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1468C>T p.(Arg490Trp), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4, PP3, PM5. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA341479/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:145499 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085096 infores:hetionet CHEBI:3240 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0037763 infores:hetionet CAID:CA16020858 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020858 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate, PP3 PM5, PM3 The c.793T>C (p.Cys265Arg) variant in PAH is reported in at least 1 Chinese patient with PAH deficiency (BH4 deficiency ruled out, PMID: 23932990). It was detected in trans with a variant of unknown significance, p.Arg53His (PMID: 30050108). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020858/MONDO:0009861/006 2022-03-13 2022-04-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5118 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0227791 infores:hetionet GO:1900193 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:1900193 GO:0048477 GO:0051940 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0051940 GO:0051641 CHEBI:9328 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0038325 infores:hetionet CHEBI:2704 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0024902 infores:hetionet CHEBI:135005 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0028081 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1263846 infores:hetionet CAID:CA454608279 biolink:causes MONDO:0015967 infores:clingen CAID:CA454608279 MONDO:0015967 PMID: Uncertain Significance BP7, PP4_Moderate, PM2_Supporting, BP4 PP3, PP1 The c.864G>C variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 288 (p.(p.Leu288 =)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). This synonymous variant is not predicted to impact splicing (SpliceAI score of 0.04 for donor loss, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.771, which is below the MDEP cutoff of 2.0) (BP4, BP7). In summary, c.864G>C meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 2/17/2025): PP4_Moderate, BP4, BP7, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA454608279/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:23765 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0022346 infores:hetionet CHEBI:5004 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0043352 infores:hetionet CHEBI:6775 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0039239 infores:hetionet CHEBI:64355 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0231528 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0521839 infores:hetionet CHEBI:83527 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0600142 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027769 infores:hetionet CHEBI:17549 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0017178 infores:hetionet CHEBI:5001 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0026826 infores:hetionet CHEBI:4562 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0030193 infores:hetionet CHEBI:64355 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013378 infores:hetionet CHEBI:8364 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0014591 infores:hetionet CAID:CA16041888 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041888 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1099del (p.Trp367GlyfsTer25) variant in GAA is a nonsense variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. ( PM2_Supporting). To our knowledge, this variant has not been reported in patients with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 370810). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041888/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3176 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0020580 infores:hetionet CHEBI:63619 biolink:causes HP:4000214 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0238844 infores:hetionet CHEBI:61033 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020488 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0234458 infores:hetionet CAID:CA367401296 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401296 MONDO:0015967 PMID: Pathogenic PM5_Strong, PS4_Moderate, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.630G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 210 (p.(Met210Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and/or persistent fasting hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.630G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Strong, PP1_Moderate, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401296/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:10119 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0041834 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027769 infores:hetionet CHEBI:6741 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0024031 infores:hetionet CHEBI:691037 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0033774 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0020538 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0019112 infores:hetionet CHEBI:8356 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037384 infores:hetionet CHEBI:474180 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0022346 infores:hetionet CHEBI:6717 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0232462 infores:hetionet CHEBI:473990 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0016382 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0025061 infores:hetionet CHEBI:4356 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0234632 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0012817 infores:hetionet CHEBI:8888 biolink:causes MONDO:0017373 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0032371 infores:hetionet CHEBI:75984 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0240211 infores:hetionet CHEBI:63580 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2363731 infores:hetionet CHEBI:41977 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0004245 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0042373 infores:hetionet CHEBI:6935 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0015230 infores:hetionet CHEBI:4798 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0026827 infores:hetionet CHEBI:2611 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0221170 infores:hetionet GO:1903301 biolink:causes GO:0046835 infores:ubergraph knowledge_assertion manual_agent GO:1903301 GO:0046835 CHEBI:8093 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0021053 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0038454 infores:hetionet NCBIGene:2201 biolink:causes MONDO:0014501 infores:monarchinitiative not_provided not_provided HGNC:3604 MONDO:0014501 uuid:bdd5b994-ab8a-45d0-a922-010e04ccfd57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004604 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018801 infores:hetionet CHEBI:44185 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018989 infores:hetionet NCBIGene:727857 biolink:causes MONDO:0012271 infores:monarchinitiative not_provided not_provided HGNC:35126 MONDO:0012271 uuid:2ababdc9-4182-4bc6-8ae8-bb490c4b54b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003962 infores:hetionet CHEBI:9654 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0018681 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0040409 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0035258 infores:hetionet CHEBI:63630 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0030318 infores:hetionet CHEBI:63635 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0030201 infores:hetionet CHEBI:49713 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0002994 infores:hetionet CHEBI:9398 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0026826 infores:hetionet CAID:CA320741233 biolink:causes MONDO:0100083 infores:clingen CAID:CA320741233 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.-59-5C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741233/MONDO:0100083/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:11011 biolink:causes MONDO:0054837 infores:monarchinitiative not_provided not_provided HGNC:11842 MONDO:0054837 uuid:dc012733-739c-4113-9ada-592d177edeb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229732 biolink:causes MONDO:0009861 infores:clingen CAID:CA229732 MONDO:0009861 PMID:21307867PMID:18985011PMID:16256386PMID:18985011PMID:16256386 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.739G>C (p.Gly247Arg) variant in PAH has been reported in 3 patients with PAH deficiency, with BH4 deficiency assessed in 2 patients. PMID: 21307867, 18985011, 16256386. It was detected with known pathogenic variants R413P (PMID: 16256386) and V388M (PMID: 18985011). It was absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.981. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229732/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3387 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0232766 infores:hetionet CAID:CA132729 biolink:causes MONDO:0010134 infores:clingen CAID:CA132729 MONDO:0010134 PMID: Benign BP7, BA1, BP4 PM3 The filtering allele frequency of the c.416-7T>C variant in SLC29A4 is 0.59% (169/24960) in African chromosomes in gnomAD (BA1). Additionally, computational prediction tools and conservation analysis suggest that the c.416-7T>C variant may not impact the protein (BP4, BP7). In summary, this variant meets criteria to be classified as benign for autosomal recessive Pendred syndrome. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP7, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132729/MONDO:0010134/005 2019-10-02 2019-10-02 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6801 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0518988 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0020517 infores:hetionet CHEBI:49662 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0003467 infores:hetionet CHEBI:16469 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1510431 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0015397 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151735 infores:hetionet CHEBI:50173 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013604 infores:hetionet NCBIGene:129563 biolink:causes MONDO:0009965 infores:monarchinitiative not_provided not_provided HGNC:28648 MONDO:0009965 uuid:1df266f6-a9fb-49da-9a17-8e919d43d770 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0030193 infores:hetionet CHEBI:8802 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0040822 infores:hetionet GO:0061035 biolink:causes GO:0061448 infores:ubergraph knowledge_assertion manual_agent GO:0061035 GO:0061448 CHEBI:49375 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0743680 infores:hetionet UMLS:C1738934 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233514 infores:hetionet CHEBI:50885 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0018681 infores:hetionet CHEBI:6375 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0043352 infores:hetionet CHEBI:9588 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C1368065 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0032584 infores:hetionet CHEBI:3499 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0023530 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0852990 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0852990 infores:hetionet CHEBI:167309 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0043352 infores:hetionet CAID:CA060404 biolink:causes MONDO:0017623 infores:clingen CAID:CA060404 MONDO:0017623 PMID:29706350PMID:27147599 Uncertain Significance PP2, PM2_Supporting, BS3_Supporting BP7, BP5, BS1, BS4, PM6, PVS1, PP3, PP1, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.698G>A (p.R233Q) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.11604447) per Mighell et al. 2018 (PMID: 29706350).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + 1*2 points; total is 1 (Uncertain significance). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA060404/MONDO:0017623/003 2023-10-11 2023-10-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2466435899 biolink:causes MONDO:0010305 infores:clingen CAID:CA2466435899 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PM4, PP4_Strong  The NM_005629.4(SLC6A8):c.191_193del variant is a deletion of three nucleotides within exon 1/13 of the SLC6A8 gene, and is predicted to lead to the in-frame deletion of a single amino acid, (p.Ser64del). This variant is absent from gnomAD v4.0.0, (PM2_Supporting), and is predicted to cause a change in the length of the protein (p.Ser64del) (PM4). The NM_005629.4(SLC6A8):c.191_193del (p.Ser64del) variant is scored 0.82895 by MutPred-Indel, which meets the range for PP3_Met by Pejaver et al. 2022. The variant was identified in a 20-month-old boy with worsening failure to thrive and global developmental delays. Urine analysis showed elevated creatine:creatinine ratios, and a diminished creatine peak via brain MRS (PMID:36752093) (PP4_Strong). In summary, the NM_005629.4(SLC6A8):c.191_193del (p.Ser64del) variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0). PM2_Supporting, PM4, PP4_Strong, PP3.(Classification approved by the ClinGen CCDS VCEP on December 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2466435899/MONDO:0010305/027 2023-12-14 2023-12-14 X-linked inheritance HP:0001417 Supports CHEBI:9332 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0221242 infores:hetionet CHEBI:8764 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0740394 infores:hetionet CHEBI:2955 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0025222 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235746 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235746 infores:hetionet CHEBI:49960 biolink:causes UMLS:C1704381 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1704381 infores:hetionet CHEBI:3732 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013384 infores:hetionet CHEBI:64318 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0022116 infores:hetionet CHEBI:6690 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011206 infores:hetionet CHEBI:465284 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085612 infores:hetionet CHEBI:18332 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0020550 infores:hetionet CHEBI:31397 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0013378 infores:hetionet GO:0061294 biolink:causes GO:0061206 infores:ubergraph knowledge_assertion manual_agent GO:0061294 GO:0061206 CHEBI:7476 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013428 infores:hetionet CAID:CA10584836 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584836 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, PS4, PS3, BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.305A>C (p.Gln102Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584836/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:2611 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0232461 infores:hetionet CHEBI:127780 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0231528 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030846 infores:hetionet CAID:CA10549335 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549335 MONDO:0010305 PMID: Benign BS1, BS2, BP4 BP7 The NM_005629.4:c.826C>T variant in SLC6A8 is a synonymous (silent) variant (p.Leu276=). The computational predictors SpliceAI and varSEAK predict that the variant has no impact on splicing (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00037 in the African/African-American population, which is higher than the ClinGen CCDS VCEP’s allele frequency threshold for BS1 (>0.0002) (BS1). Two hemizygotes are present in gnomAD v2.1.1 (BS2). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 388608). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549335/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:63638 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0022107 infores:hetionet CHEBI:9667 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0030193 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0086543 infores:hetionet CHEBI:31348 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1321898 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002265 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0038273 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004239 infores:hetionet CHEBI:2663 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0428977 infores:hetionet CAID:CA412376925 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376925 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PP1_Moderate, PVS1 PS4 NM_000330.4(RS1):c.53-1G>A is a canonical splice site variant in intron 1, located 1 nucleotide before exon 2, and is predicted to disrupt splicing and induce skipping of exon 2, which is expected to disrupt a critical functional domain in RS1 (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with X-linked retinoschisis through 2 meioses in one family (PP1_Moderate; PMID: 36212125). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PVS1, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376925/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance HP:0001417 Supports CHEBI:175901 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0041969 infores:hetionet CHEBI:3478 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0038325 infores:hetionet CHEBI:4798 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0018524 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0031117 infores:hetionet CHEBI:5558 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0013378 infores:hetionet NCBIGene:3694 biolink:causes MONDO:0014540 infores:monarchinitiative not_provided not_provided HGNC:6161 MONDO:0014540 uuid:82a791ad-7d2d-446c-9d60-adac3c587ed0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63622 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0235266 infores:hetionet CHEBI:6402 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042029 infores:hetionet CHEBI:82960 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0853225 infores:hetionet CHEBI:3723 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003862 infores:hetionet CHEBI:49662 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020461 infores:hetionet NCBIGene:80208 biolink:causes MONDO:0011196 infores:monarchinitiative not_provided not_provided HGNC:11226 MONDO:0011196 uuid:baeed365-3490-4b7c-b0fe-1a5dc714e99b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0456909 infores:hetionet CHEBI:136040 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0008031 infores:hetionet CHEBI:41977 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0002962 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0037290 infores:hetionet CHEBI:51380 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0040822 infores:hetionet CHEBI:52717 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0263386 infores:hetionet CHEBI:6887 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011071 infores:hetionet CHEBI:7494 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0016382 infores:hetionet CHEBI:107736 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0016382 infores:hetionet CHEBI:82960 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151691 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0232849 infores:hetionet CHEBI:16664 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0040034 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0011630 infores:hetionet CHEBI:3423 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0004604 infores:hetionet CHEBI:4909 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C3665347 infores:hetionet CAID:CA410204067 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204067 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.161A>G (p.Glu54Gly) is a missense variant which has not been reported in any populations featured in any version of gnomAD, allowing for application of PM2_Supporting. This variant has a SpliceAI score of 0 and a REVEL score of 0.738, which does not meet thresholds for computational evidence codes. In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204067/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135736 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018944 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0017160 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0001824 infores:hetionet NCBIGene:1144 biolink:causes MONDO:0014584 infores:monarchinitiative not_provided not_provided HGNC:1965 MONDO:0014584 uuid:75566b96-cd1f-49ee-b863-804a2028b379 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135929 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0011603 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0549475 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0221185 infores:hetionet CHEBI:28748 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0311468 infores:hetionet CHEBI:3175 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0423153 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0175167 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0162429 infores:hetionet CAID:CA913163293 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163293 MONDO:0044970 PMID:19252805PMID:21540128 Uncertain Significance PS3_Supporting, PM2_Supporting, PS4_Supporting, PP3, PP4 PP1, PM6 The m.1630A>G variant in MT-TV has been reported in two unrelated individuals. One individual had features consistent with mitochondrial neurogastrointestinal encephalopathy (MNGIE) with additional features of hearing loss, mild psychomotor delay, headache, and small stature (PMID: 19252805). Another individual had features consistent with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in addition to bilateral sensorineural hearing loss, myopia, short stature requiring growth hormone supplementation, and delayed onset of puberty (PMID: 21540128; PS4_supporting). The variant was heteroplasmic in the individual with MNGIE-like features at 90% in muscle and 70% in blood, with 60% heteroplasmy being seen in the asymptomatic mother’s blood (PMID: 19252805). In the individual with MELAS, the variant was present at 75% heteroplasmy in blood, 95% in urine, and 90% in fibroblasts; the variant was present in the mother at 93% in blood, 98% in urine, and 95% in fibroblasts (PMIDs: 21540128, 30709774). No correlating segregations or de novo occurrences of this variant were found in our review of the literature. The computational predictor MitoTIP suggests this variant is pathogenic (65th percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). The m.1630A>G variant is absent in the GenBank dataset, the Helix dataset (although there are four heteroplasmic occurrences), and gnomAD3.1.2 (PM2_supporting). Single-fiber testing (PMID: 19252805) showed 90% heteroplasmy in COX-negative fibers and 50% in COX-positive fibers. Cybrids showed marked decrease in cytochrome-c oxidase activity. Oxygen consumption/respiration activity was also greatly reduced in both homoplasmic and heteroplasmic cybrid lines. Northern blotting showed a pronounced loss of MTTV in mutant cybrids when compared to controls (PMID: 21540128; PS3_supporting). Electron transport enzyme activities were assessed in one of the individuals and her healthy mother, and showed a significant difference between the proband and the mother and a healthy control individual. Exome sequencing was performed in the proband and her mother, ruling out other known genetic etiologies (PMID: 30709774; PP4). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP3, PM2_supporting, PS3_supporting, PP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163293/MONDO:0044970/014 2022-11-14 2023-03-13 Mitochondrial inheritance (primarily or exclusively heteroplasmic) HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:102216 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0042109 infores:hetionet UMLS:C1738934 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020458 infores:hetionet CAID:CA399802478 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802478 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000419.5(ITGA2B):c.1591C>T (p.Gln531Ter) nonsense variant in exon 16/30 is predicted to to cause a premature stop codon in a biologically-relevant-exon and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). GT type 1 patient NA (PMID: 11798398) is homozygous for this variant (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802478/MONDO:0100326/011 2022-10-06 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50275 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0006840 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0019348 infores:hetionet CAID:CA210752 biolink:causes MONDO:0013144 infores:clingen CAID:CA210752 MONDO:0013144 PMID: Likely Pathogenic PM5, PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting The c.1274G>C variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by proline at amino acid 425 (p.Arg425Pro). This variant has been reported in one proband meeting an antithrombin activity level of < 0.8 IU/mL with a family history of antithrombin activity levels of < 0.8 IU/mL (PS4_Supporting; PMID:3828226, 2722864). The variant has been reported to segregate with hereditary antithrombin deficiency in seven affected meioses from the proband's family (PP1_Moderate; PMID: 3828226). The computational predictor REVEL gives a score of 0.878, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM2_Supporting, PS4_Supporting, PP3, PM5, PP1_Moderate. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210752/MONDO:0013144/084 2024-07-03 2024-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8713 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0042401 infores:hetionet CHEBI:135888 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0006826 infores:hetionet CHEBI:39867 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232462 infores:hetionet CHEBI:31236 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2240374 infores:hetionet CHEBI:134990 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0344232 infores:hetionet CAID:CA024693 biolink:causes MONDO:0007783 infores:clingen CAID:CA024693 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 2355 of the RYR1 protein, p.(Arg2355Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000036, a frequency consistent with pathogenicity for MHS. This variant has been reported in 18 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 17 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 23558838, 24361844, 12123492, 15210166, 23460944, 25256590, 22473935). This variant segregates with MHS in at least 12 individuals, PP1_Strong (PMID: 30236257, 24361844). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). Additionally, two ex vivo studies using myotubes and B-lymphocytes, showed increased sensitivity to RYR1 agonists in multiple unrelated individuals (PMID: 15210166, 24361844). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.861) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024693/MONDO:0007783/012 2021-03-19 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6640 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0019158 infores:hetionet CHEBI:8461 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0917801 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0020517 infores:hetionet CAID:CA2759533408 biolink:causes MONDO:0100326 infores:clingen CAID:CA2759533408 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 "The NM_000419.5(ITGA2B):c.1654del (p.Val552CysfsTer13) (also referred as ""c.1686delG"") variant in ITGA2B is a deletion in exon 17, resulting in a shift of the reading frame and a premature stop signal (p.Val552Cysfs*13). This variant is predicted to cause a premature stop codon in biologically relevant exon (exon 17) leading to nonsense mediated decay (PVS1). This variant has been detected in trans with a pathogenic variant NM_000419.4:c.480del (mentioned as ""c.512delC"" in the article) in an individual with Glanzmann thrombasthenia. The patient (PMID: 27416581) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry. This variant is absent from gnomAD v4.1.0 population databases (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting." Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2759533408/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:17303 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0948594 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0475858 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019360 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0151736 infores:hetionet CHEBI:3423 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085624 infores:hetionet CHEBI:4784 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0232462 infores:hetionet CHEBI:8024 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013404 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0263978 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0263978 infores:hetionet CHEBI:84500 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0338831 infores:hetionet GO:1904415 biolink:causes GO:0098542 infores:ubergraph knowledge_assertion manual_agent GO:1904415 GO:0098542 CHEBI:194135 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027441 infores:hetionet CHEBI:4027 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0009917 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0027765 infores:hetionet CHEBI:71940 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0038999 infores:hetionet CHEBI:4702 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0033774 infores:hetionet CHEBI:40303 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0011991 infores:hetionet CHEBI:84500 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011253 infores:hetionet CHEBI:6076 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020433 infores:hetionet CHEBI:5109 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0234894 infores:hetionet CHEBI:5855 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019294 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020678 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014868 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020538 infores:hetionet CHEBI:16586 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0428977 infores:hetionet CHEBI:3403 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0232292 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0018674 infores:hetionet UNII:R43D2573WO biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0018520 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0151736 infores:hetionet CAID:CA229303 biolink:causes MONDO:0009861 infores:clingen CAID:CA229303 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 PP4 The c.1044_1047dup (p.Ser350fs) variant in PAH is absent from population databases (PM2). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 10 out of 13 coding exons (10 out of total exons) (PVS1). This variant is absent from the literature. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229303/MONDO:0009861/006 2020-08-31 2021-12-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9445 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0231528 infores:hetionet CHEBI:145499 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027849 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0012833 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0019158 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0019348 infores:hetionet CHEBI:144551 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0022408 infores:hetionet CHEBI:2469 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0027765 infores:hetionet NCBIGene:3769 biolink:causes MONDO:0008663 infores:monarchinitiative not_provided not_provided HGNC:6259 MONDO:0008663 uuid:69f2d7b9-3142-4801-bb64-949ec6293bba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0080274 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0948715 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006852 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0151602 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0002453 infores:hetionet GO:0061330 biolink:causes CL:1000155 infores:ubergraph knowledge_assertion manual_agent GO:0061330 CL:1000155 CHEBI:28748 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0236075 infores:hetionet CHEBI:3485 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0011603 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1579838 infores:hetionet CAID:CA255116 biolink:causes MONDO:0010602 infores:clingen CAID:CA255116 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PP3, PP1_Strong, PS4 PM2 The c.1660A>G (p.Ser554Gly) missense variant has a REVEL score of 0.938 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and therefore, does not meet criteria for rarity in the population. Fifty-three patients are reported in Johnsen, et. al. 2107 with mild/moderate hemophilia A and the Gly554Ser variant, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726). The variant has been found to segregate with hemophilia A across 6 meioses among 4 different families, the PP1 criteria at the strong weight (Internal VCEP contributor). This variant has been reported in individuals who developed an inhibitor to factor replacement therapy and discrepant chromogenic and one-stage factor VIII activity levels (CDC CHAMPS database/Internal VCEP contributor). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PP1_Strong, PP4_Moderate, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255116/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:63621 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151699 infores:hetionet CHEBI:15940 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0086439 infores:hetionet CHEBI:50693 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0011603 infores:hetionet CHEBI:520985 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C2047937 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017152 infores:hetionet NCBIGene:65992 biolink:causes MONDO:0011252 infores:monarchinitiative not_provided not_provided HGNC:16110 MONDO:0011252 uuid:ff07917e-51d5-4a2f-80ac-4b26bdd0552a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15854 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0235369 infores:hetionet GO:1902276 biolink:causes GO:0030157 infores:ubergraph knowledge_assertion manual_agent GO:1902276 GO:0030157 CHEBI:6541 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011603 infores:hetionet NCBIGene:55212 biolink:causes MONDO:0014435 infores:monarchinitiative not_provided not_provided HGNC:18758 MONDO:0014435 uuid:01ff6538-5a9f-4396-9106-65c12405c5db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412745623 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745623 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PS4 NM_001034853.2(RPGR):c.191G>A (p.Trp64Ter) is a nonsense variant that substitutes a premature stop for amino acid 64 within exon 3 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 34745198). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The variant has been reported to segregate with retinal dystrophy through a female proband and her affected father from 1 family, however, at least 2 segregations are required for PP1, so this code was not met (PMID: 34745198). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745623/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:41774 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0007222 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0010346 infores:hetionet CHEBI:63791 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002962 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0948692 infores:hetionet CHEBI:6909 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151766 infores:hetionet CHEBI:63610 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0030232 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020456 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0277925 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0043094 infores:hetionet CHEBI:42797 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0242301 infores:hetionet CHEBI:50692 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0020615 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0859229 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0859229 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0205204 infores:hetionet CHEBI:7445 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0232849 infores:hetionet CHEBI:4995 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0497156 infores:hetionet CHEBI:4659 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0175167 infores:hetionet CHEBI:119486 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0520573 infores:hetionet CHEBI:77032 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0021053 infores:hetionet CHEBI:5109 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0152459 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0476089 infores:hetionet CHEBI:4909 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0015967 infores:hetionet CHEBI:5165 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0015371 infores:hetionet CAID:CA6402552 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402552 MONDO:0019565 PMID: Benign BA1, BP5 PP3, BS2, BP4 The NM_000552.5:c.4304A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 1435. TThe Grpmax filtering allele frequency in gnomAD v4.1 is 0.1104 (based on 8427/74964 alleles in the African American population[, including 498 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic by the ClinGen VWD Type 2 VCEP (BP5; PMID: 30817071). At least 16 healthy adult individuals harboring the p.Asn1435Ser variant were found to be unaffected, with no diagnosis of a bleeding disorder and normal lab values, including bleeding scores lower than 4, VWF:RCo/VWF:Ag ratios >0.6, and no increased response to low-dose ristocetin (PMID: 20231421). The mean VWF:RCo/VWF:Ag ratio of 0.71-0.77 within this group was significantly reduced compared to 0.91-0.97 for WT, but above the threshold of <0.6. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP5. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402552/MONDO:0019565/090 2024-11-05 2024-11-06 Undetermined mode of inheritance Contradicts true CHEBI:3048 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0020580 infores:hetionet CHEBI:6532 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0549249 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0852810 infores:hetionet CHEBI:8768 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013456 infores:hetionet CHEBI:31401 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151744 infores:hetionet NCBIGene:5921 biolink:causes MONDO:0011556 infores:monarchinitiative not_provided not_provided HGNC:9871 MONDO:0011556 uuid:ab8cb2f2-54b8-45c5-95e8-6b8ed5a6cdac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0021099 infores:hetionet CHEBI:23765 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0011603 infores:hetionet UMLS:C1872203 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151479 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0017178 infores:hetionet CHEBI:71219 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0029163 infores:hetionet CHEBI:63577 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1142412 infores:hetionet CHEBI:5959 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0015672 infores:hetionet NCBIGene:4677 biolink:causes MONDO:0030837 infores:monarchinitiative not_provided not_provided HGNC:7643 MONDO:0030837 uuid:4833bd6d-10cf-4fed-b913-9cbfe7fea279 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9763 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0014335 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0004936 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018790 infores:hetionet CHEBI:47426 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0014457 infores:hetionet CHEBI:2955 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0005758 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004238 infores:hetionet CHEBI:2038 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0004144 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0948594 infores:hetionet CHEBI:6741 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C2697368 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0034882 infores:hetionet CHEBI:49662 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0009676 infores:hetionet CHEBI:94385 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151744 infores:hetionet CHEBI:31515 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0011603 infores:hetionet NCBIGene:5610 biolink:causes MONDO:0030035 infores:monarchinitiative not_provided not_provided HGNC:9437 MONDO:0030035 uuid:8b1da207-694d-4fa0-ba29-eb825a40866d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0006840 infores:hetionet CHEBI:8499 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0086525 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0023530 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0039971 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0006145 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0025160 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0152198 infores:hetionet CHEBI:31980 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0039070 infores:hetionet CAID:CA2573050986 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573050986 MONDO:0015967 PMID: Likely Pathogenic PM4, PP4_Moderate, PM2_Supporting, PS3_Moderate PS4, PM1 The c.509_517dup variant in the glucokinase gene, GCK, is a 9 base pair insertion resulting in the in-frame addition of 3 amino acid(s) at codon 173 (p.(Lys172_Ala173insGlyPheLys)) within exon 5 of NM_000162.5. The c.509_517dup variant is predicted to change the length of the protein due an in-frame insertion of 3 amino acids in a nonrepeat region (PM4). This variant is absent in gnomAD v4.1 (PM2_Supporting), and was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals did have a phenotype specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and autoantibody negative) . The Relative Activity Index (RAI) of this variant was found to be 0, which is below the MDEP cutoff (<0.5) (PS3_Moderate; Internal lab contributor). In summary, the c.509_517dup variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PM4, PM2_Supporting, PP4_Moderate, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573050986/MONDO:0015967/086 2025-04-04 2025-04-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9139 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1384353 infores:hetionet CHEBI:63577 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0042384 infores:hetionet UMLS:C0120107 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0000737 infores:hetionet CHEBI:94609 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0011603 infores:hetionet CHEBI:8382 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0240735 infores:hetionet CHEBI:6073 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0043094 infores:hetionet CHEBI:63605 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0018681 infores:hetionet CHEBI:4466 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0546817 infores:hetionet CHEBI:8024 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002878 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0687133 infores:hetionet CHEBI:6129 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0392163 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0221100 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0178298 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0851578 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009450 infores:hetionet GO:0009506 biolink:causes GO:0010497 infores:ubergraph knowledge_assertion manual_agent GO:0009506 GO:0010497 CHEBI:8107 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018802 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0037274 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0033975 infores:hetionet CAID:CA367398625 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398625 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PM2, PP2, PP3 PP4 The c.1174C>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 392 (p.(Arg392Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Gly (PM5_Supporting). In summary, c.1174C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398625/MONDO:0015967/086 2023-08-26 2023-08-26 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:4710 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1384353 infores:hetionet CHEBI:68642 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0015230 infores:hetionet CHEBI:9435 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0021141 infores:hetionet CHEBI:7822 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0232849 infores:hetionet CHEBI:404903 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018946 infores:hetionet CHEBI:5855 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1167709 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0233414 infores:hetionet CHEBI:29688 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0041657 infores:hetionet CHEBI:28971 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C1579838 infores:hetionet CHEBI:3738 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0015672 infores:hetionet CAID:CA915940309 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940309 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The c.613_614+2del variant on ITGB3 gene is a splice donor variant located on intron4 which is predicted to result in skipping of exon 4. It is absent from all large population cohorts (gnomAD). This variant has been reported to occur in homozygous state in one proband who meets the PD-VCEP criteria for the GT phenotype (PMID: 25728920). This variant meets GT specific criteria for PVS1, PP4_Strong, PM2_supporting, and PM3_supporting and is therefore classified as Pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940309/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:10650 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003862 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0032617 infores:hetionet CHEBI:10101 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0004604 infores:hetionet NCBIGene:22866 biolink:causes MONDO:0030909 infores:monarchinitiative not_provided not_provided HGNC:19701 MONDO:0030909 uuid:e3c01fbb-5cc7-44ed-9bf7-b2034fb2a1b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0040409 infores:hetionet CHEBI:63611 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0032227 infores:hetionet CHEBI:7465 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0026837 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0002871 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027947 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151849 infores:hetionet CHEBI:9667 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0019521 infores:hetionet CHEBI:47780 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0429097 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0877183 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0877183 infores:hetionet NCBIGene:55812 biolink:causes MONDO:0011415 infores:monarchinitiative not_provided not_provided HGNC:20423 MONDO:0011415 uuid:55102f71-bc87-42ba-a6f2-1bd5f4bac7ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0009450 infores:hetionet CHEBI:50922 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013456 infores:hetionet CHEBI:63617 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0917801 infores:hetionet CHEBI:82716 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0017181 infores:hetionet CAID:CA410147964 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147964 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP4, BP2, PVS1, PM6, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PP1 NM_001754.5(RUNX1):c.1145C>G (p.Pro382Arg) is a missense variant which is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, both of which provide coverage of at least 20x for the RUNX1 gene at this genomic position (PM2_supporting). This missense variant has a REVEL score >0.88 (0.942) (PP3). To our knowledge, this variant has not been reported before, and there are no other pathogenic or likely pathogenic amino acid changes affecting the same residue. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147964/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0048088 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0048088 GO:0007275 CHEBI:60761 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0232462 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0152128 infores:hetionet GO:0002155 biolink:causes GO:0032870 infores:ubergraph knowledge_assertion manual_agent GO:0002155 GO:0032870 CHEBI:63611 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C2240374 infores:hetionet CHEBI:49713 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0027497 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0520539 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0520539 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0687133 infores:hetionet CAID:CA16608696 biolink:causes MONDO:0010278 infores:clingen CAID:CA16608696 MONDO:0010278 PMID: Uncertain Significance PVS1_Supporting, PM2_Supporting The p.Met1? variant in SLC9A6 may cause a truncated or absent protein by altering the start codon of the coding sequence, however, to date, there is no additional evidence to support that the loss of this methionine is associated with disease (PVS1_supporting). The p.Met1? variant in SLC9A6 is absent from gnomAD (PM2_supporting). In summary, the p.Met1? variant in SLC9A6 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PVS1_supporting, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608696/MONDO:0010278/016 2021-03-24 2021-05-10 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:49375 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0039070 infores:hetionet UMLS:C0025241 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0013604 infores:hetionet CHEBI:42797 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0242184 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0020615 infores:hetionet CHEBI:63638 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0542571 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034065 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042373 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023418 infores:hetionet CHEBI:63618 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0085593 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020538 infores:hetionet CAID:CA916081957 biolink:causes MONDO:0011071 infores:clingen CAID:CA916081957 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1367_1426dup (p.Ala475_Val476insGluGlySerHisSerAsnSerProThrAsnMetAlaProSerAlaArgLeuGluGluAla) is an in-frame duplication variant that does not occur within the RHD (PM4 not applicable). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081957/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5384 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0013428 infores:hetionet CHEBI:7986 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0042109 infores:hetionet NCBIGene:54805 biolink:causes MONDO:0020787 infores:monarchinitiative not_provided not_provided HGNC:103 MONDO:0020787 uuid:f9a28e90-1888-46b3-9d0d-1b078955d51b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0015967 infores:hetionet CHEBI:8597 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0031256 infores:hetionet CHEBI:51450 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0085593 infores:hetionet CAID:CA386960737 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960737 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PP3 The c.517G>A variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 173 (p.(Val173Met)) of NM_000545.8. This variant is located within the DNA binding domains (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant segregated with diabetes, with at least ten informative meioses in one family (PP1_Strong; internal lab contributors). In summary, c.517G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960737/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8805 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0009806 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0041912 infores:hetionet CHEBI:101853 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0039240 infores:hetionet CHEBI:47898 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006625 infores:hetionet CHEBI:408174 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0000737 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0038363 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042401 infores:hetionet CHEBI:100241 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0600228 infores:hetionet CHEBI:2567 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0038358 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014869 infores:hetionet CHEBI:27504 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0009676 infores:hetionet CHEBI:8713 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0003862 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0033975 infores:hetionet CHEBI:82960 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085605 infores:hetionet NCBIGene:2308 biolink:causes MONDO:0009994 infores:monarchinitiative not_provided not_provided HGNC:3819 MONDO:0009994 uuid:e07ac931-af8a-4d68-8f8c-34cef5e873bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:161680 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0042109 infores:hetionet CHEBI:3994 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0009782 infores:hetionet CHEBI:3310 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0030554 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0342579 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853348 infores:hetionet CHEBI:3568 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085633 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0853960 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0853960 infores:hetionet CHEBI:50378 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0006118 infores:hetionet CHEBI:135530 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0031350 infores:hetionet CHEBI:63584 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0018790 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002871 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0020517 infores:hetionet CHEBI:31705 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0040046 infores:hetionet CHEBI:135005 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0151766 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0851341 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0004096 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0392176 infores:hetionet CHEBI:7565 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0851578 infores:hetionet CAID:CA397722484 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722484 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3, PVS1 PP4, PM4 The c.277+2T>G variant in ACADVL occurs within the canonical splice donor (+2) of intron 4. It is predicted to cause skipping of biologically-relevant-exon 4/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a distinct pathogenic or likely pathogenic variant; confirmed in trans by parental testing (c.388_390del; VCV000001626.12; PM3 points = 1.0, PMID:22847164) (PM3). To our knowledge, functional assays have not been reported for this variant. PM2_Supporting is met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM3, PM2_Supporting; VCEP specifications v2.0; approved 12-09-21. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722484/MONDO:0008723/021 2022-03-08 2022-04-06 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:5076 biolink:causes MONDO:0014451 infores:monarchinitiative not_provided not_provided HGNC:8616 MONDO:0014451 uuid:299a2716-9be7-47f0-a640-26ef6d6ab218 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018681 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0040479 infores:hetionet CAID:CA10360804 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360804 MONDO:0010725 PMID: Likely Benign BS1 BP4, PP3 The NM_000330.4(RS1):c.150G>T variant is a missense variant encoding the substitution of Tryptophan with Cysteine at amino acid 50. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001765 among hemizygous individuals, with 70 variant alleles / 396581 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >>0.00002 (BS1). The computational predictor REVEL gives a score of 0.625, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 and <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.05, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes do not apply. In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BS1. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360804/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:63925 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0948594 infores:hetionet NCBIGene:3053 biolink:causes MONDO:0012876 infores:monarchinitiative not_provided not_provided HGNC:4838 MONDO:0012876 uuid:eaf1cce9-0f70-483e-92ee-a13cdb231f73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10265 biolink:causes MONDO:0012634 infores:monarchinitiative not_provided not_provided HGNC:14361 MONDO:0012634 uuid:a952c3ad-f72c-4b62-99bb-79f3f7b660d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C2830004 infores:hetionet CHEBI:9139 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020621 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040409 infores:hetionet CHEBI:3640 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0011991 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0027769 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014858 infores:hetionet GO:0052080 biolink:causes GO:0000165 infores:ubergraph knowledge_assertion manual_agent GO:0052080 GO:0000165 CHEBI:9448 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0008031 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0948594 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0403632 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0149931 infores:hetionet CHEBI:10127 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0024141 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151511 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151511 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0021843 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0042373 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026848 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005672 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0005716 infores:hetionet CHEBI:472657 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0022346 infores:hetionet CHEBI:5384 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0020538 infores:hetionet UMLS:C1872203 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0085610 infores:hetionet CHEBI:6539 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0042024 infores:hetionet CHEBI:31397 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0036689 infores:hetionet CHEBI:404903 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0040460 infores:hetionet CHEBI:9130 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0009763 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0037199 infores:hetionet GO:1901249 biolink:causes GO:0060482 infores:ubergraph knowledge_assertion manual_agent GO:1901249 GO:0060482 CHEBI:9613 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0015672 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0029191 infores:hetionet UMLS:C0017797 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0011603 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042571 infores:hetionet CAID:CA286815 biolink:causes MONDO:0700270 infores:clingen CAID:CA286815 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1 BA1, BS1, PM2 The c.3802del (p.Val1268*) variant in ATM is a nonsense variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in several individuals with Ataxia-Telangiectasia (PMID: 9463314, 12815592, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008473 in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Very Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA286815/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63635 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0231218 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0011551 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0234215 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0009806 infores:hetionet CAID:CA410147163 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147163 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1357G>A (p.Val453Met) is a missense variant which has not been observed in any population according to gnomAD (PM2_Supporting). The nucleotide substitution is not predicted to disrupt splicing (SpliceAI score = 0.00), and the amino acid change is not predicted to be disruptive to protein function (REVEL score 0.186, < 0.5) (BP4). Functional evidence is not available in the literature, and there are no published cases with this variant. Overall, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147163/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:5V9KLZ54CY biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0042963 infores:hetionet CAID:CA10652912 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652912 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2780A>G is a UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652912/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:474180 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853760 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0522224 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0018802 infores:hetionet CAID:CA277552 biolink:causes MONDO:0007648 infores:clingen CAID:CA277552 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.2295+166C>T variant has an allele frequency of 0.00653 (205 in 31,398) in gnomAD, with a maximum subpopulation frequency of 0.00966 (149 in 15,424) in European (Non-Finnish) subpopulation (BA1; http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets criteria to be classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA277552/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5855 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017152 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004610 infores:hetionet CHEBI:209807 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0332534 infores:hetionet CHEBI:50859 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0152009 infores:hetionet GO:0060622 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0060622 GO:0009653 CHEBI:4027 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0031039 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0042109 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0349506 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0948089 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C2748540 infores:hetionet CHEBI:2666 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0699828 infores:hetionet CHEBI:5106 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0699744 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019917 infores:hetionet CHEBI:50729 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0002453 infores:hetionet UMLS:C1738934 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0231528 infores:hetionet CHEBI:10650 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0040264 infores:hetionet CAID:CA658760619 biolink:causes MONDO:0021056 infores:clingen CAID:CA658760619 MONDO:0021056 PMID:22431159 Uncertain Significance PS3_Moderate, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.1408+735A>T variant in APC is an intronic variant which is located in intron 11. Sequencing of cDNA demonstrated that the variant impacts splicing by insertion of an out of frame pseudoexon between exon 11 and 12 which was not present in 3 controls (PS3_Moderate as we have no data on leakage, PMID: 22431159). The variant c.1408+735A>T is located six nucleotides downstream of the pseudoexon and seems to improve the consensus sequence motif at the less-conserved +6 position of a cryptic splice donor site (for details see PMID: 22431159, this donor gain is also predicted by SpliceAI, score 0.62). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, PMID: 22431159). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Based on the limited data in a single case, this variant is evaluated as a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS3_Moderate, PS4_Supporting, PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760619/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47657 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0013378 infores:hetionet CHEBI:37924 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1260880 infores:hetionet CHEBI:64321 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0018944 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0233414 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006549 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0345903 infores:hetionet CHEBI:31515 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0004093 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0227791 infores:hetionet CHEBI:31515 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0235660 infores:hetionet CHEBI:10112 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0497156 infores:hetionet CHEBI:50305 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0917801 infores:hetionet CHEBI:5775 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0027947 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0015397 infores:hetionet CHEBI:9649 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0015230 infores:hetionet CHEBI:3216 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013404 infores:hetionet CHEBI:3347 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020625 infores:hetionet CHEBI:39669 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0042571 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0849918 infores:hetionet CHEBI:28939 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0043144 infores:hetionet CHEBI:17650 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0702166 infores:hetionet CHEBI:17347 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085631 infores:hetionet CAID:CA8459424 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459424 MONDO:0011132 PMID: Likely Pathogenic PP4, PP3, PM2_Supporting, PM1, PM3_Supporting PS3 NM_001369369.1(FOXN1):c.1049C>T (p.Pro350Leu) is a missense variant predicted to cause a proline to leucine substitution at amino acid residue 350. The variant has been found, by whole exome sequencing, in at least one compound heterozygous patient with FOXN1 deficiency (P9, PMID: 33464451). The patient displayed alopecia and low t-cell numbers (less than 1,000,000 cells/L) (PP4). They also had poor proliferative response to phytohemagglutinin on total cells, though normal when evaluated on separated T cells, flow cytometric analysis showed near complete absence of CD45RA+ CD4 T cells, and they had very low TRECs. They received a thymus transplant but T cell levels were not reported post transplant. Interestingly the patients alopecia spontaneously reversed at age 3. The patient (P9 of PMID: 33464451) is compound heterozygous with pathogenic variant NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter), confirmation of trans phase not reported (PM3_supporting). The variant has a gnomADv4.1 Grpmax filtering allele frequency of 0.000003590, which is based upon the European (non-Finnish) population (9/1180006 alleles), which is lower than the ClinGen SCID VCEP threshold (≤0.00002412) for PM2_Supporting. The computational predictor REVEL gives a score of 0.893, which is above the threshold of ≥0.644, evidence that correlates with impact to FOXN1 function (PP3). Additionally, this variant is found within the DNA binding forkhead domain, a well established functional domain (PM1). In vitro assays demonstrated conflicting results, the p.Pro350Leu variant showed significantly reduced activity in a luciferase assay (<50%) from PMID: 33464451, though the variant showed only partial loss of function (88%) in another luciferase assay as part of a validated assay with pathogenic and benign controls (PMID: 37419334, PS3 not met). This may be a mild hypomorphic variant, contributing to the patients phenotype in the context of a second pathogenic variant. In summary this variant meets criteria to be classified as Likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PP4, PP3, PM2_supporting, PM3_supporting, PM1 as specified by the ClinGen SCID VCEP FOXN1 subgroup (Pilot, date of approval 03/01/2024). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459424/MONDO:0011132/113 2024-09-27 2024-09-27 Semidominant inheritance HP:0032113 Supports CHEBI:5818 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0036572 infores:hetionet NCBIGene:116442 biolink:causes MONDO:0010709 infores:monarchinitiative not_provided not_provided HGNC:16499 MONDO:0010709 uuid:0cb5d015-3cbb-4a1b-ab3f-dab84038c799 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0877153 infores:hetionet CAID:CA10014381 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014381 MONDO:0011071 PMID:23817177 Likely Benign BP2, BS3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BS1, BS4, PVS1, PM2, PM6, BP5, BP7, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.668A>G (p.Glu223Gly) is a missense variant predicted to cause the substitution of glutamic acid by glycine at amino acid 223 (p.E223G). The highest population minor allele frequency in gnomAD v2 is 0.0001146 (13/113452 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This variant has also been observed in gnomAD v3/v4 in one homozygous individual of Finnish descent, and there are no known reports of affected patients with homozygous RUNX1 variants, plus RUNX1-null mice do not survive (BP2). The germline variant has been published in 2-3 children with B-ALL (PMID: 26580448; PMID: 34166225) and in a 22-year-old female with thrombocytopenia (low platelet count) and mild bleeding (menorrhagia), congenital aortic valve abnormality, and periventricular nodular heterotopia of the cerebrum but a negative family history of thrombocytopenia and hematologic malignancy (DOI: 10.1155/2023/4738660). However, the variant's presence in the general population (gnomAD) precludes the application of PS4 at any strength level. The computational predictor REVEL gives a score of 0.799, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. However, in vitro functional data indicate that the mutant protein exhibits normal transcriptional activity in a luciferase reporter assay using U937 cells (~105-115% of WT activity, Fig. 4), normal DNA-binding and β-subunit interaction in an EMSA assay using Cos7 cells (Fig. 2), appropriate nuclear localization in NIH3T3 cells, and normal ubiquitination (Fig. 5) (PMID: 23817177) (BS3). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP2 and BS3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014381/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16899 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0015672 infores:hetionet CHEBI:3380 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0027497 infores:hetionet CHEBI:5959 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020625 infores:hetionet CHEBI:31981 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0011603 infores:hetionet CHEBI:101278 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0033575 infores:hetionet CHEBI:3723 biolink:causes HP:0012710 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027343 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030305 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011991 infores:hetionet CHEBI:7466 biolink:causes HP:0010588 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0151628 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019348 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0232492 infores:hetionet CHEBI:5134 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0340865 infores:hetionet CHEBI:50378 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0014591 infores:hetionet CHEBI:5613 biolink:causes GO:0030432 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0031133 infores:hetionet CHEBI:84500 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0017168 infores:hetionet NCBIGene:261734 biolink:causes MONDO:0011756 infores:monarchinitiative not_provided not_provided HGNC:19104 MONDO:0011756 uuid:0516a23e-114a-4107-ac55-c9e3e6dfb51f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020175 infores:hetionet CHEBI:75988 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0015967 infores:hetionet CHEBI:9328 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0014518 infores:hetionet CHEBI:2904 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0039070 infores:hetionet CHEBI:5002 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0020458 infores:hetionet GO:0048209 biolink:causes GO:0051650 infores:ubergraph knowledge_assertion manual_agent GO:0048209 GO:0051650 CHEBI:171719 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011609 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0080274 infores:hetionet CAID:CA512319085 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319085 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.585C>T (p.Ile195=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.02) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319085/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6413 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0018801 infores:hetionet CHEBI:36795 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0012569 infores:hetionet CHEBI:691037 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0151514 infores:hetionet NCBIGene:6875 biolink:causes MONDO:0014365 infores:monarchinitiative not_provided not_provided HGNC:11538 MONDO:0014365 uuid:72d79b2f-bef1-4a76-8afd-2a8d8d92dcfc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10110 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0037290 infores:hetionet CHEBI:2668 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0151907 infores:hetionet CHEBI:42797 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0080274 infores:hetionet CHEBI:2704 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0340865 infores:hetionet CHEBI:4562 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0232462 infores:hetionet CHEBI:31623 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0858617 infores:hetionet CHEBI:94848 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0001824 infores:hetionet CHEBI:4728 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0917801 infores:hetionet CHEBI:2904 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0428977 infores:hetionet CHEBI:64028 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0013362 infores:hetionet CHEBI:94385 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0040053 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0011849 infores:hetionet CHEBI:9649 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0026821 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0021843 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0853959 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0853959 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0948873 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0853746 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0853746 infores:hetionet NCBIGene:5428 biolink:causes MONDO:0011835 infores:monarchinitiative not_provided not_provided HGNC:9179 MONDO:0011835 uuid:cc00192e-068c-47b0-a5f1-01f189d11fa3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75045 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0033774 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0006145 infores:hetionet CHEBI:585948 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0151436 infores:hetionet CHEBI:45863 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0024440 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0037274 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0014534 infores:hetionet CHEBI:50859 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151786 infores:hetionet CHEBI:51450 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C2129214 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549284 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549284 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1956346 infores:hetionet CHEBI:8768 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0022346 infores:hetionet NCBIGene:1534 biolink:causes MONDO:0020751 infores:monarchinitiative not_provided not_provided HGNC:2571 MONDO:0020751 uuid:fb3f498c-49d5-43ec-849d-0aa29be532e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0234708 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0271650 infores:hetionet CHEBI:15544 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0000737 infores:hetionet CAID:CA294776 biolink:causes MONDO:0100040 infores:clingen CAID:CA294776 MONDO:0100040 PMID: Benign BS2, BP4, BA1 The highest population minor allele frequency of the p.Gln70Pro variant in FOXG1 in gnomAD v4.1 is 0.00033 in the Admixed American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Gln70Pro variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Gln70Pro variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gln70Pro variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294776/MONDO:0100040/035 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:474053 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C2242737 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0521592 infores:hetionet CHEBI:17474 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0006152 infores:hetionet CHEBI:85083 biolink:causes UMLS:C1698259 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C1698259 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0009450 infores:hetionet CHEBI:94449 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0151908 infores:hetionet CHEBI:4469 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0039231 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009443 infores:hetionet CHEBI:4657 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0003811 infores:hetionet CHEBI:9328 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0032617 infores:hetionet CHEBI:6954 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C3263723 infores:hetionet CHEBI:15365 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0018926 infores:hetionet CAID:CA10014508 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014508 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.463G>C (p.Val155Leu) is a missense variant which is located in the Runt Homology Domain, but does not occur at an established hotspot residue (PM1_supporting). Multiple lines of computational evidence supports a deleterious effect on the gene (REVEL: 0.904, phyloP100way: 7.568) (PP3). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014508/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3175 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0151827 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233472 infores:hetionet CAID:CA2579985607 biolink:causes MONDO:0010305 infores:clingen CAID:CA2579985607 MONDO:0010305 PMID: Pathogenic PM6, PVS1, PP4, PM2_Supporting The NM_005629.4:c.1146_1150dup (p.Leu384ArgfsTer14) (a.k.a. NC_000023.11:g.153693909_153693913dup) in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 8 of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A male patient with clinical features consistent with creatine transporter deficiency, hemizygous for the variant, was reported to have had elevated urine creatine levels on two occasions (PMID: 27096572) (PP4). His mother did not appear to carry the variant; maternity was not confirmed (PM6). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM6, PP4, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 8, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579985607/MONDO:0010305/027 2023-08-08 2024-03-29 X-linked inheritance HP:0001417 Supports CHEBI:68478 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019196 infores:hetionet CHEBI:7823 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0002622 infores:hetionet GO:0048089 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0048089 GO:0007275 CHEBI:51380 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C1260880 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0919980 infores:hetionet CHEBI:3207 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0041582 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0231218 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0235146 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0349506 infores:hetionet GO:1905699 biolink:causes GO:0009636 infores:ubergraph knowledge_assertion manual_agent GO:1905699 GO:0009636 CHEBI:63616 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0003123 infores:hetionet CHEBI:31236 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0043144 infores:hetionet CHEBI:27690 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0349506 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0521592 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0025061 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037315 infores:hetionet GO:2000139 biolink:causes GO:0032094 infores:ubergraph knowledge_assertion manual_agent GO:2000139 GO:0032094 CAID:CA285292 biolink:causes MONDO:0008723 infores:clingen CAID:CA285292 MONDO:0008723 PMID: Benign BS3_Supporting, BA1, BP4 BP2, PS3 The c.194C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 65 (p.Pro65Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1129 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Palmitoyl-CoA dehydrogenase activity in VLCAD-null fibroblasts transfected with c.194C>T cDNA showed activity comparable to the cells transfected with wild-type cDNA indicating that this variant does not impact protein function (PMID: 10790204, BS3_supporting). The computational predictor REVEL gives a score of 0.276, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BS3_supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA285292/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7494 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0019521 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027932 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0004096 infores:hetionet CHEBI:7454 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C1443060 infores:hetionet CHEBI:521033 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0012833 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014118 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1305875 infores:hetionet CHEBI:34967 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0022107 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0234215 infores:hetionet CHEBI:3756 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019572 infores:hetionet CHEBI:28177 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0011616 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042075 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0234913 infores:hetionet CHEBI:3441 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0206061 infores:hetionet CHEBI:48538 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C2830004 infores:hetionet CAID:CA5416967 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416967 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.245T>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Isoleucine by Threonine at amino acid 82 (p.Ile82Thr).The filtering allele frequency (the upper threshold of the 95% CI of 3/69074 alleles) of the c.245T>C variant in DCLRE1C is 0.00001153 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Despite a warning showing that this variant is covered in fewer than 50% of individuals in gnomAD v4.0.0 exomes, the frequency on gnomAD v2.1.1 was already lower than the PM2 threshold (0.00001090 in the same population).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416967/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15544 biolink:causes UMLS:C0241558 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0241558 infores:hetionet CHEBI:36791 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002994 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0008325 infores:hetionet CHEBI:5100 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0043352 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001315 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1535893 infores:hetionet CHEBI:6775 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0231528 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002904 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0013528 infores:hetionet CHEBI:5778 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0009763 infores:hetionet CHEBI:63598 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042384 infores:hetionet CHEBI:145499 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013378 infores:hetionet CAID:CA350341785 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341785 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, PM1 PVS1, PP3, BA1, BP4, PS4, PM4, BS1 The c.1178A>G (p.Asn393Ser) variant is a missense variant harboured inexon 9 of the BMPR2 gene, predicted to cause substitution of asparagine toserine encoding the functionally relevant catalytic kinase domain but withoutfunctional evidence indicating critical or non-critical (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1(PM2_supporting). The REVEL prediction algorithm score is 0.68,AlphaMissense is 0.79, both below our thresholds for pathogenicity (PP3_not met) but above our thresholds for benignity (BP4 not met). The variant has been reported only once in a PAH subject (PMID: 32581362) (PS4 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341785/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6741 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0015397 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0339916 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0031117 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0041747 infores:hetionet CAID:CA414439515 biolink:causes MONDO:0010604 infores:clingen CAID:CA414439515 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM1, PS4, PP3 The NM_000133.4(F9):c.520G>A (p.Val174Met) missense variant is completely absent from gnomAD v2.1.1 and v3.1.2 meeting criteria for PM2_Supporting. The variant has a REVEL score of 0.811 (>0.6) meeting criteria for PP3. The variant changes the last nucleotide of exon 5 and SpliceAI predicts a donor loss of intron 5 (delta score of 0.66) meeting criteria for PM1. At least four probands with moderate or severe hemophilia B are reported in the literature and internal laboratory data (PMID: 1680287; doi: 10.5336/medsci.2020-75066), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PM1, PS4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414439515/MONDO:0010604/080 2024-11-05 2025-01-07 X-linked inheritance HP:0001417 Supports CHEBI:53760 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020473 infores:hetionet CHEBI:50156 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0004093 infores:hetionet CHEBI:4562 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0424295 infores:hetionet CHEBI:39669 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0027726 infores:hetionet CHEBI:15544 biolink:causes UMLS:C2242621 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2242621 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0746883 infores:hetionet CHEBI:53760 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0012569 infores:hetionet CHEBI:3176 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0018681 infores:hetionet CHEBI:8485 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0026961 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0427008 infores:hetionet CHEBI:46345 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0002792 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0853777 infores:hetionet CAID:CA273686 biolink:causes MONDO:0009290 infores:clingen CAID:CA273686 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PS3 PM5 The NM_000152.5:c.896T>C variant in GAA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 299 (p.Leu299Pro). At least 4 individuals have been reported with this variant and either diagnosis of Pompe disease with ERT treatment or GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/unknown tissue (PMIDs 26622091, 26873529, 25626711,29422078). Another patient was homozygous for this variant and identified by newborn screening for Pompe disease (PMID: 22133539). This meets the criteria for PP4_Moderate. This variant has been detected in at least 7 individuals with Pompe disease or identified by newborn screening for Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G (PMID:18757064, 26622091, 26873529). At least 1 individual was homozygous for the variant (PMID: 22133539,25626711). Criteria for PM3 were met. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal synthesis and processing on Western blots leading the variant to be described as Class B (“potentially less severe”, indicating that this variant may impact protein function (PMID:18425781)(PS3). REVEL Score = 0.952 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 180144, 2 star review status) with 5 submitters classifying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PS3, PP4_Moderate, PM3, PM2_Supporting, PP3 Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273686/MONDO:0009290/010 2022-05-11 2022-05-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9637 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0020625 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0403632 infores:hetionet CHEBI:7514 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0016204 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0748725 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0748725 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0015230 infores:hetionet CAID:CA037264 biolink:causes MONDO:0007750 infores:clingen CAID:CA037264 MONDO:0007750 PMID: Uncertain Significance BP2, PM2, PP4 BA1, BP4, BP3, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, BS2, PP3, PP1 The NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, and BP2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PP4: Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met. BP2: 1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037264/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9943 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0277925 infores:hetionet CAID:CA10014405 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014405 MONDO:0011071 PMID: Benign BA1, BP4, BP2 PS3, PS1, PS4, PVS1, PM2, PM6, BS3, BS1, BS4, BP7, PM4, PM1, PM5, PP3, PP1 The NM_001754.4:c.614-34C>T variant has a MAF of 1 (100%) in gnomAD cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014405/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4784 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0041834 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0162830 infores:hetionet CHEBI:46557 biolink:causes HP:0031846 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0015802 infores:hetionet NCBIGene:91949 biolink:causes MONDO:0012118 infores:monarchinitiative not_provided not_provided HGNC:18622 MONDO:0012118 uuid:f653c5e4-89f6-4d56-84a4-245d88146a80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64028 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0011168 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006716 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0010072 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040261 infores:hetionet CHEBI:3387 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0016382 infores:hetionet CHEBI:8802 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1321898 infores:hetionet CHEBI:28918 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0034642 infores:hetionet CHEBI:7476 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014457 infores:hetionet NCBIGene:9573 biolink:causes MONDO:0013375 infores:monarchinitiative not_provided not_provided HGNC:4218 MONDO:0013375 uuid:79a96dac-8577-4d80-84a8-f14dea6a258c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0233472 infores:hetionet CHEBI:8356 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152030 infores:hetionet CHEBI:49375 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0423791 infores:hetionet CHEBI:135736 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0031256 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041364 infores:hetionet CHEBI:63619 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018790 infores:hetionet CHEBI:4445 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0022568 infores:hetionet CHEBI:7903 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0035222 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0239375 infores:hetionet CHEBI:3314 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0041657 infores:hetionet CHEBI:135005 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0152198 infores:hetionet CHEBI:8871 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003813 infores:hetionet UMLS:C0025241 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0027497 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0015230 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0031117 infores:hetionet CHEBI:31397 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0043144 infores:hetionet CHEBI:68595 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0014518 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0014742 infores:hetionet CHEBI:2663 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0010200 infores:hetionet CHEBI:30830 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0025874 infores:hetionet CHEBI:49040 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0231218 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151998 infores:hetionet CHEBI:31705 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0041969 infores:hetionet CHEBI:3387 biolink:causes MONDO:0016463 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0086438 infores:hetionet CHEBI:31397 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0006277 infores:hetionet CHEBI:9943 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003813 infores:hetionet CHEBI:64019 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0085649 infores:hetionet CHEBI:31401 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0013404 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0853754 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0853754 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004239 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0015230 infores:hetionet GO:0072095 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0072006 CAID:CA267656 biolink:causes MONDO:0009861 infores:clingen CAID:CA267656 MONDO:0009861 PMID:26666653PMID:26666653 Pathogenic PM2, PVS1, PP4, PM3_Supporting The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (PMID: 26666653; PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH VCEP, see ClinVar ID 92751) c.898G>T (p.Ala300Ser); however, the phase of the variants was not confirmed via parental testing (PM3_supporting).The sequence change results in a nonsense variant which occurs in exon 5 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267656/MONDO:0009861/006 2019-05-26 2019-05-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31348 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948586 infores:hetionet CHEBI:6413 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0030196 infores:hetionet CAID:CA401369436 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369436 MONDO:0009290 PMID:21687968 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1802C>A (p.Ser601Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that a patient with this variant has no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 21687968). The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with c.525del in one patient with Pompe disease meeting the specifications for PP4. The phase is unknown (PMID 26497565). This data meets PM3_Supporting. A patient with the same genotype has been reported (PMID 21687968) and might be the same patient but this could not be verified. There is a ClinVar entry for this variant (Variation ID: 593486, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Suporting, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369436/MONDO:0009290/010 2020-06-03 2020-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2038 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0004604 infores:hetionet CAID:CA400024922 biolink:causes MONDO:0100326 infores:clingen CAID:CA400024922 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM3, PS1_Moderate, PP3, PM2_Supporting The NM_000212.3(ITGB3):c.856G>A (p.Gly286Arg) missense variant has been reported in at least two unrelated Glanzmann thrombasthenia patients (PMIDs: 32237906, 21113249). Patient TE displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <1%, as measured by flow cytometry, and there was loss of binding to PAC-1. (PP4_strong). Patient TE is compound heterozygous for the paternal Gly286Arg and maternal c.1129dup (classified Pathogenic by the PD-VCEP) variants; GT3 of PMID: 32237906 is compound heterozygous for this variant and a pathogenic variant (c.361+1G>A) (PM3). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91070 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.967 (PP3). The same amino acid change, resulting from a different nucleotide change c.856G>C, has been reported in a patient with Glanzmann thrombasthenia (PMID: 31064749). It has been classified likely pathogenic by the ClinGen PD VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM3, PM2_supporting, PP3, PS1_Moderate. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400024922/MONDO:0100326/011 2025-06-19 2025-06-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6437 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0687713 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0031117 infores:hetionet CHEBI:63613 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0011606 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0152267 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0521498 infores:hetionet CHEBI:100246 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0852911 infores:hetionet CHEBI:205919 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0026113 infores:hetionet CHEBI:17141 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0577559 infores:hetionet CHEBI:63617 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0392156 infores:hetionet CHEBI:63610 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C2979982 infores:hetionet CHEBI:41774 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151825 infores:hetionet CHEBI:45863 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013378 infores:hetionet NCBIGene:23133 biolink:causes MONDO:0010286 infores:monarchinitiative not_provided not_provided HGNC:20672 MONDO:0010286 uuid:4f91fe7a-c0d5-46f6-ae46-3e88f575f318 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68579 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0029408 infores:hetionet NCBIGene:55278 biolink:causes MONDO:0030006 infores:monarchinitiative not_provided not_provided HGNC:21020 MONDO:0030006 uuid:a785629c-dd19-4823-b1e5-18f667b99417 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018802 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0025061 infores:hetionet CHEBI:9150 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0038999 infores:hetionet CHEBI:4653 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0428977 infores:hetionet CHEBI:5147 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0040822 infores:hetionet CAID:CA7435393 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435393 MONDO:0007113 PMID: Likely Benign BP4, BS1 The highest population minor allele frequency of the c.2221-20A>G variant in UBE3A (NM_130838.2) in gnomAD v4.1 is 0.0002158 in African/African American sub population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). Splice prediction analysis (Splice AI), does not suggest an impact to splicing (BP4). In summary, the c.2221-20A>G variant in UBE3A is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). (UBE3A Specifications v.5.0; curation approved on 4/18/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435393/MONDO:0007113/037 2024-04-18 2025-03-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:100241 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0521491 infores:hetionet NCBIGene:8314 biolink:causes MONDO:0013692 infores:monarchinitiative not_provided not_provided HGNC:950 MONDO:0013692 uuid:4d0d337a-e9aa-4c81-be44-08f1e078534e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68575 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0178298 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0221185 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0005684 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014742 infores:hetionet CHEBI:49662 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0700361 infores:hetionet CHEBI:7601 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0036572 infores:hetionet CHEBI:31000 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0033774 infores:hetionet CHEBI:75984 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0028738 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002878 infores:hetionet CHEBI:15428 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0024115 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0302858 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0302858 infores:hetionet CHEBI:32588 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0000833 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0948089 infores:hetionet NCBIGene:51185 biolink:causes MONDO:0011828 infores:monarchinitiative not_provided not_provided HGNC:30185 MONDO:0011828 uuid:1e877528-c3be-4904-aef1-d1f42c0b7bf2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0581912 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0574067 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0013395 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0002957 infores:hetionet CHEBI:4798 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151836 infores:hetionet CHEBI:8382 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0033845 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0585186 infores:hetionet CHEBI:101278 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0235266 infores:hetionet CHEBI:473990 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0438717 infores:hetionet CHEBI:2379 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0030252 infores:hetionet CHEBI:50131 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0030312 infores:hetionet CHEBI:7465 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0023380 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0041912 infores:hetionet CHEBI:4975 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0022346 infores:hetionet CHEBI:31932 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002878 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0004936 infores:hetionet CHEBI:63608 biolink:causes MONDO:0006031 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0149516 infores:hetionet CHEBI:75722 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0024902 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002911 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0677865 infores:hetionet CHEBI:101278 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151744 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0015230 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0027769 infores:hetionet CAID:CA519374734 biolink:causes MONDO:0010602 infores:clingen CAID:CA519374734 MONDO:0010602 PMID: Likely Pathogenic PM2_Supporting, PP1, PS4 PP3 The NM_000132.3(F8):c.5217C>T (p.Asn1739=) synonymous variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3.1.1). SpliceAI predicts a score of 0.31 for the loss of the canonical donor of intron 14; however the threshold (>0.5) for SpliceAI is not met and does not meet criteria for PP3. At least 4 probands with mild hemophilia A from the literature and internal laboratory data meet F8-phenotype criteria. This variant was found to co-segregate with disease in affected family members, with two meioses observed in a family (Internal Laboratory Data), meeting criteria for PP1. In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4, PP1, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA519374734/MONDO:0010602/071 2024-10-11 2025-01-07 X-linked inheritance HP:0001417 Supports CHEBI:63618 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0009676 infores:hetionet CHEBI:28901 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1384353 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011053 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0031350 infores:hetionet CAID:CA305287338 biolink:causes MONDO:0007750 infores:clingen CAID:CA305287338 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 PP1 The NM_000527.4(LDLR):c.-97G>A is a LDLR-AS1 Non Coding Transcript Variant and is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow:PM2_Met : absent from controls in GnomAD (gnomAD v2.1.1).PP4_Met : 1 index case with Dutch lipid clinic network >=6PS4_supporting: variant met PM2 and was found in 1 index case with Dutch lipid clinic network >=6 (sequenced by progenica) from M.Arca Lab and 1 patient from Lille University & CHRU Lille (ClinVar entry) with Dutch Lipid Clinic Scoring of Probable FH Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305287338/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7907 biolink:causes NCIT:C54056 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0521987 infores:hetionet CHEBI:617099 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0149745 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0028173 infores:hetionet CHEBI:6909 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0014457 infores:hetionet CHEBI:50648 biolink:causes MONDO:0022096 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085653 infores:hetionet CAID:CA213763 biolink:causes MONDO:0015967 infores:clingen CAID:CA213763 MONDO:0015967 PMID: Likely Benign BP5, PP2, BS2 PS4, BS1, PM2, PP3, PP4, BP4 The c.1386G>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 462 (p.(Met462Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.45, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant was identified in at least 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). This variant was identified in at least two individuals with a normal fasting glucose (BS2) (PMID: 24097065). The Popmax filtering allele frequency of the c.1386G>T variant in gnomAD v2.1.1 is 0.00001159, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1386G>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, BP5, BS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213763/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Contradicts true CHEBI:6375 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0232498 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0237849 infores:hetionet CHEBI:3756 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019080 infores:hetionet CHEBI:8874 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151699 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0017574 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0015397 infores:hetionet CHEBI:8212 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0042023 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235431 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0162429 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029456 infores:hetionet CHEBI:25703 biolink:causes MONDO:0800386 infores:ubergraph knowledge_assertion manual_agent CHEBI:25703 MONDO:0800386 CHEBI:42797 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003862 infores:hetionet CHEBI:92712 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0031256 infores:hetionet NCBIGene:60386 biolink:causes MONDO:0013382 infores:monarchinitiative not_provided not_provided HGNC:14409 MONDO:0013382 uuid:2601fa1c-c974-49b4-bc83-c9e7b4d97f7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA119936 biolink:causes MONDO:0015924 infores:clingen CAID:CA119936 MONDO:0015924 PMID:18321866 Likely Benign PP3, BS3 PM2, PM5, PS1, BS1 The NM_0001204.7(BMPR2) c.545G>A variant is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 182 (p.Gly182Asp). The highest subpopulation minor allele frequency in gnomAD v2.1.1 (controls) is 0.0003507 in the European (non-Finnish) population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The REVEL computational prediction analysis tool produced a score of 0.8069, which is above the threshold (>0.75) for pathogenicity (PP3). Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID: 18321866). The PH Expert Panel reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case. In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3, PP3. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA119936/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA265898350 biolink:causes MONDO:0100216 infores:clingen CAID:CA265898350 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, PM6, BP2, BA1, PP3, PP1, PM5, PM1, PS1, PS2, PS4, BS1, BS4 The NM_177438.2:c.4376G>A variant in DICER1 is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 1459 (p.Gly1459Glu). The total allele frequency in gnomAD v4.1.0 is 0.000004789 (7/1461620 alleles) with a highest population minor allele frequency of 0.00008955 (4/44670alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.476; SpliceAI and MaxEnt no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 04/23/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA265898350/MONDO:0100216/024 2024-04-23 2024-05-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3011 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0031350 infores:hetionet CHEBI:63624 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0027441 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0028173 infores:hetionet CHEBI:32139 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C1291077 infores:hetionet CHEBI:28901 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0162566 infores:hetionet CHEBI:5118 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0001807 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0274435 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0274435 infores:hetionet CHEBI:6909 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1609512 infores:hetionet CHEBI:47781 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0030554 infores:hetionet NCBIGene:3659 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:6116 MONDO:0001056 uuid:257b3d3d-58ed-471a-a144-22304895c2b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:5476 biolink:causes MONDO:0004795 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D010032 DB09552_MESH_D010032_1 CHEBI:50381 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0042847 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037315 infores:hetionet CAID:CA902275 biolink:causes MONDO:0100368 infores:clingen CAID:CA902275 MONDO:0100368 PMID: Likely Benign BP4, BS1 BP7 NM_000329.3(RPE65):c.1129-14A>G is a non-coding variant located in intron 10. This variant is present in gnomAD v.4.1.1 at a GrpMax allele frequency of 0.003418, with 254 alleles / 74804 total alleles in the African / African American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor loss and donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This intronic variant is located between -1 and -21 relative to exon 11, and so is not considered eligible for BP7. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1 and BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902275/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:474053 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0026826 infores:hetionet CHEBI:16586 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0036974 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020569 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0233472 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0162429 infores:hetionet CHEBI:9586 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0043094 infores:hetionet CHEBI:82960 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0393761 infores:hetionet CHEBI:9763 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0575081 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017601 infores:hetionet CHEBI:31236 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233762 infores:hetionet CHEBI:68478 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0221395 infores:hetionet CAID:CA10586117 biolink:causes MONDO:0700268 infores:clingen CAID:CA10586117 MONDO:0700268 PMID: Uncertain Significance PM2_Supporting PP3, PM5 The c.628C>T variant in BRCA1 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamine at amino acid 210 (p.(Gln210Ter)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This variant has a SpliceAI score of 0.51, predicting an impact on splicing (score threshold ≥0.2). It is predicted to cause skipping of exon 9(10), however this exon is absent from the biologically relevant transcript (PP3 not met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that no evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 9(10) (PVS1_N/A, PM5_N/A (PTC)). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586117/MONDO:0700268/092 2025-08-20 2025-08-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3223 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0232461 infores:hetionet CAID:CA413496514 biolink:causes MONDO:0010315 infores:clingen CAID:CA413496514 MONDO:0010315 PMID: Pathogenic PVS1, PM2_Supporting, PS1 The NM_000206.3:c.455-2A>C variant in IL2RG occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4 (SpliceAI score 0.59), resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2.1.1 and gnomAD v4.0 (PM2_Supporting). The variant has not been reported in the literature in individuals with SCID. However, it is located in the splice consensus sequence at the same nucleotide position as a pathogenic variant classified by SCID VCEP specification, NM_000206.3:c.455-2A>T (PS1). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PS1. (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413496514/MONDO:0010315/129 2024-03-08 2024-03-08 X-linked inheritance HP:0001417 Supports CHEBI:8707 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0004936 infores:hetionet CHEBI:8597 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0021141 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0012206 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0012206 uuid:c6592c81-cd6e-47cf-90d2-b27e4af87f56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA267689 biolink:causes MONDO:0009861 infores:clingen CAID:CA267689 MONDO:0009861 PMID:26666653PMID:26666653 Pathogenic PVS1, PM2, PP4, PM3_Supporting The c.931_932del frameshift variant has been identified in at least 1 proband with mild PKU, BH4 deficiency not excluded (PMID: 26666653). It has been detected in trans with the pathogenic variant R241C (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. c.931_932delCT generates a frameshift predicted to result in a premature stop codon 4 residues downstream in exon 9 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3_Supporting, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267689/MONDO:0009861/006 2019-07-14 2019-07-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52717 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0035229 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C2225524 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0029560 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0029560 infores:hetionet CHEBI:72564 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0014518 infores:hetionet CHEBI:3393 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0015230 infores:hetionet CHEBI:45863 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085631 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0152154 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0152154 infores:hetionet CAID:CA294896907 biolink:causes MONDO:0009290 infores:clingen CAID:CA294896907 MONDO:0009290 PMID:22791670PMID:22791670PMID:22711147PMID:18425781 Pathogenic PM2, PP3, PP4, PM3, PM4_Supporting, PS3 This variant, c.1962_1964delAGA, is predicted to result in an inframe deletion of one amino acid in GAA, p.Glu656del, meeting PM4_Supporting. This variant is not present in gnomAD v2.1.1, meeting PM2. From unpublished clinical laboratory data, three patients with this variant meet the ClinGen LSD VCEP’s specifications for PP4. One of these individuals is homozygous for the variant and the parents are confirmed to be heterozygous; one individual is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter); and one individual is compound heterozygous for the variant and c.883C>A (p.His295Asn). Based on this data, PM3 is met. At least one Indian patient with this variant has been described but full details, such as reference range for GAA activity, were not provided and therefore the data was not included (PMIDs 22711147, 22791670). When expressed in COS-7 cells, the variant has 2% wild type GAA activity and exhibits abnormal GAA processing on Western blot (PMID 18425781), meeting PS3. PROVEAN and Mutation Taster predict that the variant has a deleterious impact on protein function, meeting PP3. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3, PM4_Supporting, PP3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294896907/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:59773 biolink:causes UMLS:C0863079 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0863079 infores:hetionet GO:1904907 biolink:causes GO:0099404 infores:ubergraph knowledge_assertion manual_agent GO:1904907 GO:0099404 CHEBI:47898 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151734 infores:hetionet CHEBI:75722 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0038325 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0851536 infores:hetionet CHEBI:2618 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0235198 infores:hetionet CHEBI:51860 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0231530 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013220 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0030446 infores:hetionet UMLS:C0017797 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0016204 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019340 infores:hetionet GO:0005246 biolink:causes GO:0070588 infores:ubergraph knowledge_assertion manual_agent GO:0005246 GO:0070588 CHEBI:6741 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1971624 infores:hetionet CHEBI:4562 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235086 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0009450 infores:hetionet CHEBI:63631 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0015967 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0851341 infores:hetionet CAID:CA245543 biolink:causes MONDO:0019501 infores:clingen CAID:CA245543 MONDO:0019501 PMID: Likely Benign BS1, BP4 The c.5131 (p.Val1711Ile) variant has been identified in 0.3% (51/19534 CI 95%) of East Asian alleles in gnomAD (BS1). This variant was observed in 1 patient with Usher syndrome, without a second variant in CDH23 (PMID: 25333064). Computational prediction analysis using the metapredictor tool REVEL produced a score of .17; this combined with the presence of the isoleucine amino acid at position 1711 in 5 organisms including 3 mammals in UCSC suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA245543/MONDO:0019501/005 2019-10-29 2019-10-29 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:7903 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0013395 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151736 infores:hetionet CHEBI:9352 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0392525 infores:hetionet CHEBI:32139 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0039231 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0232459 infores:hetionet CHEBI:3568 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030196 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040053 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0032290 infores:hetionet CAID:CA386965866 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965866 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5, BP5, PP3 PS4, PP4, PP1 The c.737T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to alanine at codon 246 (p.(Val246Ala)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.736G>T (p.Val246Leu) has been interpreted as pathogenic by the ClinGen MDEP, and p.Val246Ala has a greater Grantham distance (PM5). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In one of these individuals, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor). In summary, c.737T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM5, BP5, PP3, PM1_supporting, PM2_supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965866/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63584 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0016199 infores:hetionet CHEBI:4911 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0333355 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0333258 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0333258 infores:hetionet CHEBI:45716 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0017178 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0022658 infores:hetionet CHEBI:8428 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0011991 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0178298 infores:hetionet NCBIGene:80208 biolink:causes MONDO:0011445 infores:monarchinitiative not_provided not_provided HGNC:11226 MONDO:0011445 uuid:c4978258-6838-4325-9e96-1af4f1380233 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0017565 infores:hetionet CHEBI:10124 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020453 infores:hetionet CHEBI:8327 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0037763 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0022660 infores:hetionet CAID:CA16043073 biolink:causes MONDO:0007750 infores:clingen CAID:CA16043073 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP4, PP1 The NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.768. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043073/MONDO:0007750/013 2021-12-16 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3441 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020538 infores:hetionet CHEBI:50922 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042023 infores:hetionet CHEBI:17347 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0009676 infores:hetionet CHEBI:36791 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0231218 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003864 infores:hetionet CHEBI:47780 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027796 infores:hetionet CHEBI:6741 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1384353 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018621 infores:hetionet CHEBI:71272 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0029118 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0700572 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0700572 infores:hetionet CHEBI:8378 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0221423 infores:hetionet CAID:CA226605 biolink:causes MONDO:0010725 infores:clingen CAID:CA226605 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PS3, PM1_Strong PS1, PP3, PP4, PP1 NM_000330.4(RS1):c.175T>A (p.Cys59Ser) is a missense variant encoding the substitution of cysteine with serine at amino acid 59, which is a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). A missense variant encoding the same amino acid substitution, NM_000330.4(RS1):c.176G>C (p.Cys59Ser), (PMIDs: 12746437,19849666, 23288992, 35456481, 34645606) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing. The PS1 code was not considered to avoid circularity. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with XLRS (PMIDs: 10450864, 17987333, 9618178, 35982512, PS4_Supporting). Knock-in mice harboring the variant exhibited reduced electroretinogram b-wave amplitudes and developed schisis (PMID: 31174210, PS3). The computational predictor REVEL gives a score of 0.916, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function. PP3 is not met as this code is ineligible to be combined with the PM1_Strong code. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, PS3, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226605/MONDO:0010725/126 2025-10-03 2025-10-03 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:135351 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0027424 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0392702 infores:hetionet CHEBI:3387 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009421 infores:hetionet UNII:VL0L558GCB biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0018944 infores:hetionet CHEBI:2904 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0011606 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0007222 infores:hetionet CHEBI:3650 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0023530 infores:hetionet CHEBI:49575 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C3665347 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0006266 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027441 infores:hetionet CHEBI:72690 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C1384353 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0038362 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0016419 uuid:3d5af87a-2841-4b7e-8f47-2248cc3aba7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0011168 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0027769 infores:hetionet CHEBI:5138 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042029 infores:hetionet CHEBI:37941 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020580 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0234458 infores:hetionet CHEBI:3286 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0000768 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006145 infores:hetionet CHEBI:2904 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0009676 infores:hetionet CHEBI:28177 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0030252 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0032285 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151734 infores:hetionet NCBIGene:5611 biolink:causes MONDO:0014523 infores:monarchinitiative not_provided not_provided HGNC:9439 MONDO:0014523 uuid:2346b177-faa1-4be7-a369-a236f3e53fc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91834 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0004604 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0038367 infores:hetionet CHEBI:10650 biolink:causes MONDO:0007972 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0025281 infores:hetionet CHEBI:3219 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040264 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0234458 infores:hetionet CHEBI:47381 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042029 infores:hetionet CHEBI:135736 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0011175 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002356 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030286 infores:hetionet CHEBI:7444 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0004245 infores:hetionet CHEBI:17303 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C2937350 infores:hetionet CHEBI:31623 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0152030 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0011849 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0020649 infores:hetionet CHEBI:64312 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151904 infores:hetionet CHEBI:2038 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0013404 infores:hetionet CHEBI:9599 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0917801 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020538 infores:hetionet CHEBI:61049 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011168 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0032285 infores:hetionet CHEBI:17347 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0017168 infores:hetionet CHEBI:50131 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0017168 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0948586 infores:hetionet CHEBI:63581 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0018965 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0235315 infores:hetionet CHEBI:2687 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0011603 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0004936 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027651 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0948089 infores:hetionet CHEBI:50173 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0027497 infores:hetionet CHEBI:64321 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0041657 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0858678 infores:hetionet CHEBI:28901 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020578 infores:hetionet CHEBI:32315 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013428 infores:hetionet CAID:CA226540 biolink:causes MONDO:0100368 infores:clingen CAID:CA226540 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PP1, PP4, PM2_Supporting NM_000329.3(RPE65):c.304G>T (p.Glu102Ter) is a nonsense variant that introduces a premature stop codon into exon 4 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00004117, with 9 alleles / 113674 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including childhood onset, nystagmus (1 pt), nyctalopia, reduced visual acuity (1 pt), undetectable electroretinogram responses from rods (0.5 pts) and cones (1 pt), and decreased peripheral vision (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 11095629, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 15512997, PM3_Supporting). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PMID: 15512997, PP1). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226540/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17026 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0234233 infores:hetionet CHEBI:8404 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0012569 infores:hetionet CHEBI:39867 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0004245 infores:hetionet CHEBI:3044 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0033975 infores:hetionet CHEBI:404903 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0008350 infores:hetionet CHEBI:9123 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0311468 infores:hetionet CHEBI:8768 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011124 infores:hetionet CAID:CA414916097 biolink:causes MONDO:0010602 infores:clingen CAID:CA414916097 MONDO:0010602 PMID: Uncertain Significance PM5_Supporting, PM2_Supporting, PP3, PS4_Moderate PM1 The variant, NM_000132.3:c.1213A>T predicts a missense change, Ile405Phe, that is absent from gnomAD v2.1.1 and v3 (PM2_Supporting). This variant has been reported in at least two patients with moderate Hemophilia A in the literature (PS4_Moderate, PMID: 10404764 and 18691168). The variant has a REVEL score of 0.927 (PP3, threshold >0.6). Another variant at the same codon, Ile405Thr, is curated by the Coagulation Factor Deficiency Variant Curation Expert Panel as likely pathogenic (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414916097/MONDO:0010602/071 2024-06-19 2024-07-11 X-linked inheritance HP:0001417 Inconclusive true CHEBI:42797 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0232462 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0031350 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0008031 infores:hetionet CHEBI:101085 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0342579 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0234930 infores:hetionet CHEBI:135738 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0020517 infores:hetionet CHEBI:8871 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0080274 infores:hetionet CHEBI:41977 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011168 infores:hetionet CHEBI:6897 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0231528 infores:hetionet CHEBI:47426 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0340865 infores:hetionet NCBIGene:1308 biolink:causes MONDO:0030750 infores:monarchinitiative not_provided not_provided HGNC:2194 MONDO:0030750 uuid:262b2d65-25f2-4d75-a501-55e73cb459a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002878 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020517 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037199 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0521495 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0948594 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0040479 infores:hetionet CHEBI:5002 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0520888 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0020557 infores:hetionet GO:0141135 biolink:causes GO:1990869 infores:ubergraph knowledge_assertion manual_agent GO:0141135 GO:1990869 NCBIGene:1175 biolink:causes MONDO:0010926 infores:monarchinitiative not_provided not_provided HGNC:565 MONDO:0010926 uuid:7fa9522f-aa85-472e-b098-696ff03e9c59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0043094 infores:hetionet CHEBI:63637 biolink:causes MONDO:0002529 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0553723 infores:hetionet CAID:CA386965290 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965290 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS3_Supporting, PP1_Moderate, PP4_Moderate, PP3 PS4 The c.695T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 232 (p.(Leu232Pro)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, functional studies demonstrated the p.Leu232Pro protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, internal lab contributor). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29875428, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, treated with low-dose sulfonylureas, and persistent C-peptide) (PP4_Moderate; internal lab contributor). This variant also segregated with diabetes/hepatic adenomas, with three informative meioses in two families (PP1_Moderate; PMID: 29875428, internal lab contributors). In summary, the c.695T>C variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Moderate, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965290/MONDO:0015967/017 2023-08-14 2023-08-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72690 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0424605 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0241266 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0241266 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0178298 infores:hetionet CAID:CA367402230 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402230 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting PP4 The c.364C>T variant in the glucokinase gene, GCK, causes an amino acid change of leucine to phenylalanine at codon 122 (p.(Leu122Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 29927023, 31905448, internal lab contributors). However, PP4 is unable to be evaluated due to insufficient clinical information. This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 3 families (PP1_Strong; PMID: 31905448, internal lab contributors). In summary, c.364C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402230/MONDO:0015967/086 2024-08-01 2024-08-01 Semidominant inheritance HP:0032113 Supports CHEBI:16335 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0948089 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0235496 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0235496 infores:hetionet CHEBI:9123 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085932 infores:hetionet CHEBI:63631 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0022107 infores:hetionet CHEBI:16469 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0040038 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1274594 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235234 infores:hetionet CHEBI:7565 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151205 infores:hetionet CHEBI:7983 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0028084 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0019163 infores:hetionet CHEBI:5855 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0034152 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0847033 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0234215 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0232487 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0014130 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0042109 infores:hetionet CHEBI:9927 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0003862 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0006826 infores:hetionet CHEBI:16914 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0520893 infores:hetionet CHEBI:28901 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0232849 infores:hetionet CHEBI:64198 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0036104 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1305875 infores:hetionet GO:0072034 biolink:causes GO:0072009 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0072009 CHEBI:63608 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0031350 infores:hetionet CHEBI:36791 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0920289 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0021359 infores:hetionet CHEBI:8024 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0036974 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0014549 infores:hetionet CHEBI:61033 biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C2747793 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0221100 infores:hetionet CHEBI:68478 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0024314 infores:hetionet CHEBI:2687 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0015967 infores:hetionet GO:1904152 biolink:causes GO:0036503 infores:ubergraph knowledge_assertion manual_agent GO:1904152 GO:0036503 CHEBI:50742 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0041657 infores:hetionet CHEBI:61049 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042023 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0020514 infores:hetionet CHEBI:48273 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0030193 infores:hetionet CHEBI:60761 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0019080 infores:hetionet CHEBI:3723 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014553 infores:hetionet CHEBI:3176 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0234632 infores:hetionet CAID:CA229486 biolink:causes MONDO:0009861 infores:clingen CAID:CA229486 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PM3 PM5, PM1, PP3, PS1, PS3 The c.205C>T (p.Pro69Ser) variant in PAH has been reported in at least two individuals with PKU without specified Phe levels, including at least one for whom BH4 deficiency has been excluded (PMID: 15503242, PMID: 32668217, PMID: 26503515). p.Pro69Ser has been detected at least twice with p.Arg261Gln, which is classified pathogenic by PAH VCEP, but without documentation of parental testing to establish phase. In-vitro studies show reduced enzyme activity, but not below the PAH VCEP cutoff of 50% (PMID: 16253218). p.Pro69Ser is absent from population databases. Multiple lines of computational evidence yield inconsistent predictions regarding the impact of this substitution. In summary, this variant meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229486/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4466 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0018799 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009806 infores:hetionet CAID:CA120602 biolink:causes MONDO:0044970 infores:clingen CAID:CA120602 MONDO:0044970 PMID:11063732PMID:14597761 Likely Pathogenic PM2_Supporting, PVS1_Strong, PS3_Supporting PP3, PS4 The m.9537dupC variant in MT-CO3 has been reported in one individual with primary mitochondrial disease to date (PMID: 11063732), in an 11-year-old girl with Leigh syndrome spectrum disorder. Progressive spastic paraparesis, ophthalmoplegia, and moderate intellectual disability were noted at age four years, as was severe lactic acidosis and lesions in the putamina on brain imaging. The variant was reported as being “virtually homoplasmic” in skeletal muscle, fibroblasts, and lymphocytes. The variant was not detected in lymphocytes from her unaffected brother and maternal grandmother, and was similarly absent in lymphocytes, hair, and oral epithelial cells in her mother. However, technology at the time was limited in detecting low heteroplasmy levels. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This frameshift variant at amino position 111 creates a stop codon three positions downstream, resulting in a significant (57%) truncation of the MT-CO3 protein (PVS1_strong). Cybrid studies supported the functional impact of this variant (PMID: 11063732), as did studies in colonic crypt stem cells (PMID: 14597761; PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120602/MONDO:0044970/015 2024-04-22 2024-12-11 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:64355 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0007222 infores:hetionet CHEBI:3077 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1761613 infores:hetionet CHEBI:32315 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0392525 infores:hetionet CHEBI:5165 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C3263723 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0006145 infores:hetionet CAID:CA410147541 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147541 MONDO:0011071 PMID:25840971 Likely Benign BP4, BS3, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1274C>T (p.Pro425Leu) is a missense variant in which transactivation assays demonstrating normal transactivation (80-115% of wt) and data from a secondary DNA and CBFβ dimerization assay demonstrating normal binding and dimerization (BS3; PMID: 25840971). This missense variant has a REVEL score < 0.50 (0.485) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3, BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147541/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9434 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0006266 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0314719 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027813 infores:hetionet CAID:CA337098144 biolink:causes MONDO:0044970 infores:clingen CAID:CA337098144 MONDO:0044970 PMID: Uncertain Significance PS4_Supporting PP3, PS3, PM2 The m.9025G>A (p.G167S) variant in MT-ATP6 has been reported in three individuals with primary mitochondrial disease (PS4_supporting, PMID: 24986921, note P1 in PMID: 24986921 is also listed in PMID: 30763462). Of note, other genetic etiologies were not excluded in these cases. One individual had Leigh syndrome spectrum (LSS) disorder, 3-methylglutonic aciduria, and the variant present at homoplasmy in muscle, liver, and blood. The variant was also homoplasmic in blood from her healthy mother and sister. Another individual also had LSS but heteroplasmy levels were not provided. The last reported case had motor neuropathy but no other details or heteroplasmy levels were provided. This variant is present in population databases (MITOMAP: 0.067%, 41/61,134 however at least two sequences are from individuals reported with primary mitochondrial disease; gnomAD v3.1.2: 0.080%, 45/56,418 homoplasmic occurrences, 15 heteroplasmic occurrences; Helix: 0.090%, 177/195,983 homoplasmic occurrences, 38 heteroplasmic occurrences). Computational predictors are conflicting (APOGEE1: 0.300, APOGEE2: 0.726; range 0-1). Studies in yeast showed a deficit in ATP production (PMID: 37083953). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337098144/MONDO:0044970/015 2025-02-04 2025-05-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:44185 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0029118 infores:hetionet CAID:CA014353 biolink:causes MONDO:0004994 infores:clingen CAID:CA014353 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4005G>A (p.Ser1335=) variant in the MYH7 gene is 0.19% (140/64766) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014353/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5801 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0235818 infores:hetionet CHEBI:42797 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085605 infores:hetionet CHEBI:50742 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0039231 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0235299 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235299 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0039971 infores:hetionet CHEBI:9667 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C1443060 infores:hetionet CHEBI:28148 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0042963 infores:hetionet NCBIGene:6295 biolink:causes MONDO:0009775 infores:monarchinitiative not_provided not_provided HGNC:10521 MONDO:0009775 uuid:dcca94d6-1506-4e07-b4c5-1850f0af4517 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0025241 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151773 infores:hetionet CHEBI:51230 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0349790 infores:hetionet CHEBI:7454 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C2242996 infores:hetionet CHEBI:50156 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0015230 infores:hetionet CHEBI:5130 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0231218 infores:hetionet CHEBI:23765 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042384 infores:hetionet CHEBI:6706 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0020651 infores:hetionet CHEBI:74947 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0344232 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0010043 infores:hetionet CHEBI:101085 biolink:causes UMLS:C1096658 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C1096658 infores:hetionet CAID:CA891843979 biolink:causes MONDO:0010305 infores:clingen CAID:CA891843979 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_005629.4:c.946dup (p.Ser316PhefsTer149)variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 586615). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843979/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Supports CHEBI:61390 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0013404 infores:hetionet CHEBI:8776 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0151636 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0851341 infores:hetionet CAID:CA10014555 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014555 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, PM2, PM6, PVS1, BP5, BP7, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.287A>G (p.Asn96Ser) is a missense variant which has a REVEL score ≥ 0.88 (0.769) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014555/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:184555 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0013491 infores:hetionet CHEBI:50648 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020580 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0026946 infores:hetionet CHEBI:5130 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0026826 infores:hetionet CHEBI:3756 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C2047937 infores:hetionet CHEBI:5001 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0008350 infores:hetionet GO:2000725 biolink:causes GO:0048738 infores:ubergraph knowledge_assertion manual_agent GO:2000725 GO:0048738 CHEBI:2676 biolink:causes UMLS:C0577115 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0577115 infores:hetionet CHEBI:8707 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235996 infores:hetionet CAID:CA10652913 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652913 MONDO:0011071 PMID: Benign BP4, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2532G>A is a variant within the 3'UTR. Its minor allele frequency (MAF) of 0.003724 (0.3724%, 32/8594 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD v4.0.0 cohort is ≥ 0.0015 (0.15%) (BA1). This variant has a SpliceAI score ≤ 0.20 (0.0) and does not have an impact on the protein (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.16)) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652913/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes MONDO:0002567 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040580 infores:hetionet CHEBI:8874 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0010200 infores:hetionet CHEBI:94848 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0235710 infores:hetionet CHEBI:9073 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0242184 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0002940 infores:hetionet CHEBI:63791 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017168 infores:hetionet CHEBI:5130 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014724 infores:hetionet GO:0010083 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0010083 GO:0007275 CHEBI:6715 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042109 infores:hetionet CHEBI:16467 biolink:causes UMLS:C1168149 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C1168149 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0234215 infores:hetionet CHEBI:3698 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0151744 infores:hetionet CHEBI:5103 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0003467 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0009938 infores:hetionet CHEBI:17514 biolink:causes MONDO:0017640 infores:ubergraph knowledge_assertion manual_agent CHEBI:17514 MONDO:0017640 CHEBI:45924 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0151798 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0021308 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0687707 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151885 infores:hetionet CHEBI:47426 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C3544060 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0497327 infores:hetionet CHEBI:6832 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0033774 infores:hetionet CL:0002494 biolink:causes MONDO:0000591 infores:ubergraph knowledge_assertion manual_agent CL:0002494 MONDO:0000591 CHEBI:63616 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0011175 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1608945 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0919980 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0018099 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0006266 infores:hetionet CHEBI:9570 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0010692 infores:hetionet CAID:CA347215735 biolink:causes MONDO:0015152 infores:clingen CAID:CA347215735 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1_Moderate, PP1, PM2_Supporting The NM_003494.4: c.1354-1G>A variant in DYSF, which is also known as NM_001130987.2: c.1450-1G>A, occurs within the canonical splice acceptor site of intron 14. It is predicted to cause skipping of biologically relevant exon 15/55, resulting in an in-frame deletion of 15 amino acids (PVS1_Moderate). This variant has been identified in trans with a pathogenic variant in at least one individual with limb girdle muscular dystrophy (c.5835_5838delCCAG p.(Gln1946TrpfsTer19), 1.0 pt, PMID: 19528035). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 19528035). The variant was also reported to co-segregate with the disease in 1 affected family member (PMID: 19528035; PP1). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1_Moderate, PM3, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347215735/MONDO:0015152/180 2025-01-09 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8713 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0036974 infores:hetionet CAID:CA386966227 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966227 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PS4, PS3, PM5 The c.797A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 266 (p.(Asn266Ser)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.856, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the admixed American population and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 24097065, PMID: 23348805, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive (PP4_Moderate; internal lab contributors). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 35257744). Another missense variant at the same codon, c.798C>G p.(Asn266Lys),​ has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.797A>G as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP3, PM1_Supporting, PM2_Supporting, PP4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966227/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:141474 biolink:causes UMLS:C0441713 infores:sider not_provided not_provided DRUGBANK:DB00772 UMLS:C0441713 infores:hetionet CAID:CA399806223 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806223 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.337C>T (p.Gln113Ter) variant in exon 3/30 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (reported via personal communication with Dr. Jose Rivera, Servicio de Hematologıa y Oncologıa Medica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacion, Universidad de Murcia) with this variant (in combination with c.2150T>C (p.Leu717Pro)) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry and Western blot, and ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Strong, PM2_Supporting. (VCEP specifications version 2; date of approval 03/15/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806223/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8888 biolink:causes MONDO:0005311 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004153 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0015624 infores:hetionet CHEBI:7915 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0231218 infores:hetionet CHEBI:3996 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0341047 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0160390 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0596170 infores:hetionet CAID:CA10385168 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385168 MONDO:0100437 PMID: Benign BP4_Strong, BA1, BS2_Supporting NM_001034853.2(RPGR):c.3231T>A (p.Asn1077Lys) is a missense variant encoding the substitution of asparagine with lysine at position 1077. This variant is present in gnomAD v.4.1.0 at a frequency of 0.02339 among hemizygous individuals, with 9,240 variant alleles / 395,050 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.05, which is below the ClinGen X-linked IRD VCEP threshold of <0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_strong). This variant has been reported in at least 2 apparently unrelated control individuals meeting the BS2 requirement of no functional visual impairment by age 30 years (PMIDs: 12657579, BS2_supporting). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4_strong, and BS2_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385168/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:51364 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0241442 infores:hetionet CHEBI:7454 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C2830004 infores:hetionet CHEBI:5959 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0542571 infores:hetionet CHEBI:101085 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0013395 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0018799 infores:hetionet CHEBI:6741 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0600142 infores:hetionet CHEBI:6801 biolink:causes UMLS:C1260871 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1260871 infores:hetionet CHEBI:3696 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0232462 infores:hetionet CHEBI:465284 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0232462 infores:hetionet CAID:CA512318994 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318994 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS2, PS4, PS3, BP1, BP2, BP3, BA1, PM6, PVS1, BP5, BS1, BS4, BS3, PM3, PM4, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.114C>T (p.Arg38=) is a synonymous variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.53< 2.0 or the variant is the reference nucleotide in one primate and three mammal species) (BP7). This synonymous variant has a SpliceAI score ≤ 0.20 (0.02). The variant is absent from gnomAD with mean of 20X coverage (gnomAD v2.1 or v3.1.2) (PM2_supporting). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP7, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318994/MONDO:0011071/008 2022-08-23 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:32315 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C2242996 infores:hetionet CHEBI:82981 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0013390 infores:hetionet CHEBI:6532 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0011603 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0858797 infores:hetionet CHEBI:15640 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0041657 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020651 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0002871 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0162429 infores:hetionet CHEBI:51041 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0424295 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0687133 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0006840 infores:hetionet CHEBI:6541 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020580 infores:hetionet CHEBI:4909 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0025222 infores:hetionet CHEBI:10101 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0015672 infores:hetionet CHEBI:100147 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0002792 infores:hetionet CHEBI:2948 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0042963 infores:hetionet CHEBI:100241 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013378 infores:hetionet CAID:CA120585 biolink:causes MONDO:0044970 infores:clingen CAID:CA120585 MONDO:0044970 PMID:16908752 Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PS3_Supporting, PM6 PP1 The m.5728T>C variant in MT-TN has been reported in three unrelated individuals with primary mitochondrial disease (PS4_supporting). Onset was in infancy or childhood, and features seen in these individuals included myopathy, ataxia, developmental delay, multiorgan failure, ptosis, and ophthalmoplegia. The variant was seen at varying heteroplasmy levels in affected individuals, including undetectable to 50% in blood and 41-97% in muscle (PMIDs: 16908752, 23847141, 31026515). The variant was confirmed to have occurred de novo in one of the reported cases, as the variant was undetectable in the mother’s blood and muscle by next-generation sequencing (PMID: 31026515, PM6). In another case, the variant appeared to have arisen de novo as it was not detected in blood from the healthy mother, two siblings, and maternal grandmother, however technology used at the time would not have detected low levels of the variant and additional tissues were not assessed (PMID: 16908752). No details of family member testing were provided in the third case. There are no other large families reported in the medical literature with this variant to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 71st percentile and HmtVAR also predicts it to be pathogenic, scoring 0.75 (PP3). Cybrid studies support the functional impact of this variant as a combined defect of complexes I and IV was seen (PS3_supporting; PMID: 6908752). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS3_supporting, PM2_supporting, PP3, PM6. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120585/MONDO:0044970/015 2023-02-13 2023-03-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:45863 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0575081 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0549433 infores:hetionet CHEBI:83804 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0476273 infores:hetionet CHEBI:8802 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018932 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0042373 infores:hetionet CAID:CA134607 biolink:causes MONDO:0021060 infores:clingen CAID:CA134607 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.648C>T (p.Ile216=) variant in the MAP2K1 gene is 0.274% (38/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134607/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:84500 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0000737 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0011570 infores:hetionet NCBITaxon:471472 biolink:causes MONDO:0005834 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:471472 MONDO:0005834 CHEBI:61049 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0010200 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0855242 infores:hetionet CHEBI:135613 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0011991 infores:hetionet CAID:CA410146813 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146813 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1399G>A (p.Ala467Thr) is a missense variant which has a REVEL score < 0.50 (0.108), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146813/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0033771 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009763 infores:hetionet NCBIGene:6872 biolink:causes MONDO:0010500 infores:monarchinitiative not_provided not_provided HGNC:11535 MONDO:0010500 uuid:45b36193-59be-4fe2-a417-aead266227b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27999 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0853026 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0025061 infores:hetionet CHEBI:3423 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0013404 infores:hetionet CHEBI:5118 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085637 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0549249 infores:hetionet CHEBI:134936 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0018681 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001882 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0004659 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0855242 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0011991 infores:hetionet CHEBI:16467 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0027540 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235431 infores:hetionet CHEBI:31711 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0028643 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022904 infores:hetionet CHEBI:5558 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0014394 infores:hetionet CAID:CA347205929 biolink:causes MONDO:0015152 infores:clingen CAID:CA347205929 MONDO:0015152 PMID: Uncertain Significance PM3_Supporting, PP4, PM2_Supporting PM5, PS3, BP4, PP3 The NM_003494.4: c.17T>A variant in DYSF is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 6, p.(Ile6Asn). This variant has been identified in unknown phase with a pathogenic DYSF variant (NM_003494.4: c.4794G>T p.(Lys1598Asn), 0.5 pts) in an individual with progressive muscle weakness (PMID: 36983702; PM3_Supporting, PP4). Dysferlin expression in blood monocytes in this individual was considered outside the disease range. The filtering allele frequency for this variant in gnomAD v4.1.0 exomes is 0.000026135 (the upper threshold of the 95% CI of 20/1112000 European (non-Finnish) chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.489, which is above the VCEP threshold for BP4 but below the threshold for PP3 (neither code met). The variant is not located in a splice region and has a SpliceAI score of 0. In summary, due to the limited evidence available, this variant is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347205929/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8869 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0018681 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0012833 infores:hetionet CHEBI:27300 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0232462 infores:hetionet CAID:CA355963971 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963971 MONDO:0001586 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000203.5(IDUA):c.1323C>A (p.Tyr441Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 9 (IDUA has 14 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2704858). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). T\In summary, this variant also meets the criteria to be classified as likely pathogenic for MPS 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0: PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963971/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8768 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0017574 infores:hetionet CHEBI:6933 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0033774 infores:hetionet CHEBI:3647 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0027769 infores:hetionet CHEBI:3393 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0014457 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006849 infores:hetionet CHEBI:18332 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0043144 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0003123 infores:hetionet UMLS:C0657912 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151799 infores:hetionet UMLS:C0005740 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C1167791 infores:hetionet CHEBI:8764 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085682 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0236072 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151736 infores:hetionet CHEBI:4995 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0007820 infores:hetionet CHEBI:3723 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C3665386 infores:hetionet CAID:CA10583413 biolink:causes MONDO:0100488 infores:clingen CAID:CA10583413 MONDO:0100488 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3, PS4_Moderate BP7, BS1, BS3, PM1, PM3, PVS1, PP2, PP4, BS2, BP1, BP4, BP3, BA1, PS1 The NM_004360.5(CDH1):c.833-9C>G variant is an intronic variant in the vicinity of the 3' splice site of intron 6. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). Additionally, this variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; internal laboratory contributor). Furthermore, RNA analysis has demonstrated a novel eight base pair insertion (TCTTCCAG) resulting in a premature stop codon (p.G278Vfs*7) (PS3, internal data). In summary, this variant is classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PS3, PS4_supporting, PM2_supporting, PP3. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583413/MONDO:0100488/007 2023-08-28 2023-09-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA255344 biolink:causes MONDO:0010604 infores:clingen CAID:CA255344 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PVS1_Strong, PP4_Moderate The F9 c.880C>T (Arg294Ter) variant occurs in exon 8/8 of the F9 gene, and NMD is not predicted. PVS1_Strong is applied based on truncation of the Peptidase S1 domain. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting criteria. Over 90 patients have been reported in the literature and the EAHAD database with hemophilia B in the moderate-severe range and history of inhibitors to factor replacement products are reported, meeting PP4_Moderate and PS4_Very strong (selected PMIDs: 29296726, 8217825, 8314564). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_VeryStrong, PVS1_Strong, PP4_Moderate, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255344/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports NCBITaxon:70999 biolink:causes MONDO:0001444 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:70999 MONDO:0001444 CHEBI:29688 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0003811 infores:hetionet CAID:CA10014588 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014588 MONDO:0011071 PMID: Uncertain Significance PS3, PS2, PS1, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.140T>A (p.Leu47Gln) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014588/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:142290 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0040034 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0232492 infores:hetionet CHEBI:3127 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0231530 infores:hetionet CHEBI:48273 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0012833 infores:hetionet CHEBI:8378 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0151786 infores:hetionet CHEBI:6067 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030196 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0006145 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0036454 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017160 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0009806 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007972 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0025281 infores:hetionet CAID:CA404081041 biolink:causes MONDO:0007750 infores:clingen CAID:CA404081041 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP1, PP4, BS2 The NM_000527.5(LDLR):c.911A>T (p.Asp304Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PM5 - 4 other missense variants in the same codon:- NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.910G>C (p.Asp304His) (ClinVar ID 440612) - VUS by these guidelines- NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.PP3 - REVEL = 0.985.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404081041/MONDO:0007750/013 2022-03-18 2022-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4710 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0003578 infores:hetionet CAID:CA337319439 biolink:causes MONDO:0010602 infores:clingen CAID:CA337319439 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4_Very Strong PM1, PM5 The c.6932C>A (NM_000132.3) variant in F8 is a missense variant predicted to cause substitution of proline by histidine at amino acid 2311 (p.Pro2311His). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. More than 9 probands with mild hemophilia A, with von Willebrand disease type 2N ruled out in at least 3 patients, meeting PP4_Moderate and PS4_Very strong phenotypic criteria for F8 (PMIDs:16972227, 29388750, 23711237, 29296726, 21883705, 16601852, internal laboratory communications). The variant has a REVEL score of 0.639 (threshold >0.6) meeting PP3 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very Strong, PP4_Moderate, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA337319439/MONDO:0010602/071 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Supports CHEBI:47381 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023530 infores:hetionet CHEBI:48390 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0178298 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0349506 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002871 infores:hetionet CHEBI:6402 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0043352 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0001824 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0242656 infores:hetionet CHEBI:40279 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0041948 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0542008 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0740482 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0740482 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0025061 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0021359 infores:hetionet CHEBI:64321 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0015967 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036416 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0021308 infores:hetionet CHEBI:4636 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0027497 infores:hetionet CHEBI:63631 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151205 infores:hetionet NCBIGene:6558 biolink:causes MONDO:0033664 infores:monarchinitiative not_provided not_provided HGNC:10911 MONDO:0033664 uuid:05248d07-5f69-4b5e-ae32-769214091e1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011603 infores:hetionet CHEBI:41879 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151786 infores:hetionet CHEBI:6359 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0011991 infores:hetionet CHEBI:31980 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0038999 infores:hetionet CAID:CA8815746 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815746 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3 PM5 The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID: 33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID: 22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815746/MONDO:0009290/010 2023-12-20 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63631 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0041747 infores:hetionet CHEBI:10102 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151610 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0042109 infores:hetionet CHEBI:45652 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0020461 infores:hetionet CHEBI:3176 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0026826 infores:hetionet CHEBI:6078 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0039103 infores:hetionet CHEBI:17698 biolink:causes HP:0001908 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0178416 infores:hetionet CAID:CA034662 biolink:causes MONDO:0007750 infores:clingen CAID:CA034662 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5 (LDLR): c.1529C>T (p.Thr510Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002228 (0.002228%) in East Asian exomes (gnomAD v4.1.0). PP3 - REVEL = 0.85. PS4_supporting, PP4: Variant meets PM2 and was identified in 4 unrelated index cases (1 case with DLCN score >=6 from Robarts Research Institute, Canada; 1 case meeting Simon Broome criteria from PMID 10947889 (Tonstad et al., 2000), Norway; 1 case with possible FH by MedPed criteria from PMID 22698793 (Tichý et al., 2012), Czech Republic; 1 case with clinical diagnosis of definite FH, probable FH or severe hypercholesterolemia according to the Canadian definition of FH from PMID 37607748 (Guerin et al., 2023), Canada]. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034662/MONDO:0007750/013 2024-08-30 2024-10-03 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9448 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0002994 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0019112 infores:hetionet CHEBI:50673 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0042571 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0038454 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0152128 infores:hetionet CHEBI:5775 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0033774 infores:hetionet CAID:CA270580 biolink:causes MONDO:0010726 infores:clingen CAID:CA270580 MONDO:0010726 PMID: Likely Pathogenic PS3_Supporting, PP3, PM5_Strong, PM2_Supporting, PS4_Supporting The p.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong). The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Lys304Glu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PS3_supporting, PS4_supporting, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270580/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:31348 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0033777 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0235146 infores:hetionet CHEBI:8435 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C2363730 infores:hetionet CHEBI:3756 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0522153 infores:hetionet NCBIGene:55605 biolink:causes MONDO:0021083 infores:monarchinitiative not_provided not_provided HGNC:19349 MONDO:0021083 uuid:d6f9fa21-8827-42df-a346-cbc5fe8556c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013604 infores:hetionet CHEBI:9398 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0031350 infores:hetionet CHEBI:74947 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040822 infores:hetionet GO:0180039 biolink:causes GO:0000750 infores:ubergraph knowledge_assertion manual_agent GO:0180039 GO:0000750 UMLS:C0025241 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0085669 infores:hetionet CHEBI:31199 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0026113 infores:hetionet CHEBI:63925 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0041834 infores:hetionet CHEBI:63630 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0424295 infores:hetionet CHEBI:10124 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0917801 infores:hetionet CL:0000233 biolink:causes GO:0070560 infores:ubergraph knowledge_assertion manual_agent CL:0000233 GO:0070560 CHEBI:36791 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0000786 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0240515 infores:hetionet CL:0000097 biolink:causes GO:0002448 infores:ubergraph knowledge_assertion manual_agent CL:0000097 GO:0002448 CHEBI:66913 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0041834 infores:hetionet CHEBI:6887 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0231530 infores:hetionet CHEBI:6775 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0344232 infores:hetionet CHEBI:94449 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0010692 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0036454 infores:hetionet CHEBI:47657 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0002994 infores:hetionet CHEBI:6797 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C2697368 infores:hetionet CAID:CA2580098650 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098650 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1208_1214del (p.Tyr403CysfsTer?) is a deletion frameshift variant which occurs in the last exon. This variant is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_Strong). This deletion is not found in gnomAD v2.1.1 or gnomAD v3.1.2 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098650/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50777 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C3665347 infores:hetionet CHEBI:2038 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0033771 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0234215 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0233494 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0595877 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0025061 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0009806 infores:hetionet CHEBI:5790 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0043352 infores:hetionet GO:0033139 biolink:causes GO:0046425 infores:ubergraph knowledge_assertion manual_agent GO:0033139 GO:0046425 CHEBI:6909 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0008031 infores:hetionet CHEBI:5864 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027540 infores:hetionet CHEBI:16347 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0039231 infores:hetionet CHEBI:41977 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0221201 infores:hetionet NCBIGene:2516 biolink:causes MONDO:0013504 infores:monarchinitiative not_provided not_provided HGNC:7983 MONDO:0013504 uuid:9ffaae3d-7b49-4894-b195-6581bb988b74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0009450 infores:hetionet CHEBI:8774 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0014457 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0014591 infores:hetionet GO:0072043 biolink:causes GO:0072077 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072077 CHEBI:63621 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0000833 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0234458 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0243026 infores:hetionet NCBIGene:10117 biolink:causes MONDO:0008770 infores:monarchinitiative not_provided not_provided HGNC:3344 MONDO:0008770 uuid:5a47f27a-b160-4fe4-bcdd-e572d47926ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0036973 infores:hetionet CHEBI:64312 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0424790 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233472 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001266 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014733 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0347950 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0347950 infores:hetionet CHEBI:7444 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0009763 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0392171 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017152 infores:hetionet CAID:CA915940806 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940806 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.330_336del (p.Ser110ArgfsTer32)frameshift variant in exon 3 is predicted to cause a premature stop codon in biologically-relevant-exon 4/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (UPN 10 in PMID: 16879215) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 3%, as measured by flow cytometry. UPN 10 is homozygous for this variant (PM3_supporting; PMID: 16879215). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940806/MONDO:0100326/011 2022-10-06 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:28748 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0025061 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1112369 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1112369 infores:hetionet CHEBI:4445 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151744 infores:hetionet CHEBI:2659 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0009421 infores:hetionet CAID:CA213928 biolink:causes MONDO:0015967 infores:clingen CAID:CA213928 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.281_282delinsC variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes a frameshift in the protein at codon 94 (NM_175914.5), adding 10 novel amino acids before encountering a stop codon (p.(Arg94Thrfs*10)). This variant, located in exon 3 of 10 in a biologically-relevant transcript, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.281_282delinsC meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213928/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6538 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0030554 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0002170 infores:hetionet GO:2000004 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000004 GO:0072001 NCBIGene:4669 biolink:causes MONDO:0009656 infores:monarchinitiative not_provided not_provided HGNC:7632 MONDO:0009656 uuid:2973eb2b-4553-443a-81bd-5d6daef16c62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28148 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C1291078 infores:hetionet CAID:CA147631 biolink:causes MONDO:0100039 infores:clingen CAID:CA147631 MONDO:0100039 PMID: Benign BS2, BA1 The allele frequency of the p.His1001= variant in CDKL5 is 2.6% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.His1001= variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.His1001= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA147631/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UNII:R43D2573WO biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0687713 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0012833 infores:hetionet CAID:CA404071097 biolink:causes MONDO:0007750 infores:clingen CAID:CA404071097 MONDO:0007750 PMID: Likely Pathogenic PVS1_Moderate, PM5, PM2 BA1, PS1, PS3, BP7, BS1, BS3, PM4, PP4 The NM_000527.5(LDLR):c.3G>A (p.Met1Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5- Three other missense variants at this same codon have been reported, and one is Pathogenic:1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines.2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines.3) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines.Note: One other variant resulting in the same amino acid change at this codon has been reported:1) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PS1 not applicable as such variants must be Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404071097/MONDO:0007750/013 2022-01-22 2022-04-22 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:2000004 biolink:causes GO:0072273 infores:ubergraph knowledge_assertion manual_agent GO:2000004 GO:0072273 CHEBI:8356 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0547030 infores:hetionet NCBIGene:686 biolink:causes MONDO:0009665 infores:monarchinitiative not_provided not_provided HGNC:1122 MONDO:0009665 uuid:063a4e10-51ae-4d27-8bb4-592091b5440b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2937350 infores:hetionet CHEBI:231594 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1305875 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0006147 infores:hetionet CAID:CA2580612107 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612107 MONDO:0015967 PMID: Pathogenic PS4, PM4_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting The c.449_451del variant in the glucokinase gene, GCK, is a one-base pair deletion resulting in the in-frame deletion of phenylalanine codon 150 (p.Phe150del) within exon 4 of NM_000162.5. The c.449_451del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a non-repeat region (PM4_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMID: 19564454, 31576961, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibody) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in two families (PP1_Moderate, internal lab contributors). In summary, c.449_451del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PM2_Supporting, PM4_Supporting, PP4_Moderate, PP1_Moderate, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612107/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Supports CHEBI:10023 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0917798 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0025362 infores:hetionet CHEBI:68642 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0151905 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0740425 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0155550 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0155550 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0006147 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0340726 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0746883 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0518015 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0031350 infores:hetionet CHEBI:5130 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0016204 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0011849 infores:hetionet CHEBI:46195 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0013428 infores:hetionet CHEBI:4798 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0002994 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C2363730 infores:hetionet CHEBI:9566 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0041105 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0032584 infores:hetionet CHEBI:3314 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0042401 infores:hetionet CHEBI:63599 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0027947 infores:hetionet CHEBI:9599 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0010200 infores:hetionet NCBIGene:4076 biolink:causes MONDO:0957985 infores:monarchinitiative not_provided not_provided HGNC:6743 MONDO:0957985 uuid:d6a41029-06a1-4336-afa6-976374991720 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA168961 biolink:causes MONDO:0007648 infores:clingen CAID:CA168961 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM1, PM3, PM5, PM4, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS3, PS4, PS2, PS1 The NM_004360.5(CDH1):c.2634C>T (p.Gly878=) variant has an allele frequency of 0.03601 (3.6%, 899/24962 alleles, 20 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA168961/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:30830 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0017178 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0149931 infores:hetionet CAID:CA624861220 biolink:causes MONDO:0008723 infores:clingen CAID:CA624861220 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3, PVS1, PP4_Moderate PM5, PM4, PS1, BP7 The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID: 25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624861220/MONDO:0008723/021 2022-04-06 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA182505 biolink:causes MONDO:0019497 infores:clingen CAID:CA182505 MONDO:0019497 PMID: Likely Benign BS1 PP3, PM4, PM2, PVS1, BP2, BP3, BP4 The filtering allele frequency of the c.701A>G (p.Gln234Arg) variant in the TECTA gene is 0.37% (104/23994) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA182505/MONDO:0019497/005 2018-09-28 2019-07-17 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:7824 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0029456 infores:hetionet CHEBI:83531 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0236075 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0233472 infores:hetionet CHEBI:9738 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0030446 infores:hetionet CHEBI:194135 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0035410 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0036572 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0740425 infores:hetionet CHEBI:584020 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0020453 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0006145 infores:hetionet CAID:CA6748680 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748680 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong PM3 This c.1316-2A>G variant in PAH was reported in 1 Han Chinese patient with PAH deficiency (PMID: 28982351). This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF=0.00001), and ExAC (MAF=0.00002). This variant in the -2 splice acceptor site of intron 12, disrupts the reading frame and is not predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1 strong, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748680/MONDO:0009861/006 2022-12-09 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63611 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009676 infores:hetionet GO:0097028 biolink:causes CL:0000451 infores:ubergraph knowledge_assertion manual_agent GO:0097028 CL:0000451 CHEBI:5165 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020456 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0015397 infores:hetionet CHEBI:17026 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0041834 infores:hetionet CHEBI:188986 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0027424 infores:hetionet CHEBI:31981 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0162830 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0039971 infores:hetionet CHEBI:5118 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014743 infores:hetionet CHEBI:100241 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0476273 infores:hetionet CHEBI:5138 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0231530 infores:hetionet CHEBI:101085 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C2830004 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0006840 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0027765 infores:hetionet CHEBI:45951 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0151564 infores:hetionet CHEBI:31624 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0687713 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0022408 infores:hetionet CHEBI:31859 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151744 infores:hetionet CHEBI:9362 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0019080 infores:hetionet CHEBI:7986 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0008370 infores:hetionet NCBIGene:3753 biolink:causes MONDO:0013372 infores:monarchinitiative not_provided not_provided HGNC:6240 MONDO:0013372 uuid:db32415c-e7a7-483f-8b39-e2e3b613a388 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7459 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0151735 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0043251 infores:hetionet CHEBI:27690 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0002874 infores:hetionet CHEBI:3506 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0404521 infores:hetionet CAID:CA1367611013 biolink:causes MONDO:0015967 infores:clingen CAID:CA1367611013 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM1_Supporting, PM4_Supporting PS4 The c.945_946insGTC variant in the hepatic nuclear factor 4-alpha, HNF4A, is a three base pair insertion resulting in the in-frame addition of one amino acid at codon 315 (p.(Leu315_Leu316)) within exon 8 of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The total protein length changes as a result of this single amino acid insertion (PM4_Supporting). This variant is located within the ligand binding of HNF4A, which is critical for the protein’s function (PM1_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; PMID:10447526, internal lab contributors). In summary, c.945_946insGTC meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PM1_Supporting, PM4_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1367611013/MONDO:0015967/085 2025-04-23 2025-04-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94449 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0020517 infores:hetionet CHEBI:8356 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0008350 infores:hetionet CHEBI:9086 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0234238 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0024115 infores:hetionet CAID:CA7542902 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542902 MONDO:0012996 PMID:27233232 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, BP4 The NM_001482.3:c.541G>A variant in GATM is a missense variant that is predicted to result in the substitution of glutamine by lysine at amino acid 181 (p.Glu181Lys). The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00001864 (22/1180012 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity (PMID: 27233232). The computational predictor REVEL gives a score of 0.608, which neither predicts a damaging nor a benign impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. There is a ClinVar entry for this variant (Variation ID: 225914). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542902/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7494 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0031085 infores:hetionet GO:0060768 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060768 GO:0007275 NCBIGene:2263 biolink:causes MONDO:0007042 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0007042 uuid:78a7eccf-cdf1-4371-8b87-6debcffc6d85 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0855775 infores:hetionet CHEBI:17263 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0233494 infores:hetionet CHEBI:8802 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018794 infores:hetionet CHEBI:5778 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C1291078 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0152227 infores:hetionet CHEBI:3181 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0085649 infores:hetionet CHEBI:85083 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0003862 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0856984 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0856984 infores:hetionet CHEBI:8802 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1443060 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042401 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0035258 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002453 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002884 infores:hetionet CHEBI:34911 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0028643 infores:hetionet GO:0031283 biolink:causes GO:0006182 infores:ubergraph knowledge_assertion manual_agent GO:0031283 GO:0006182 CHEBI:4657 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0232493 infores:hetionet CHEBI:2639 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0000737 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0518015 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0340726 infores:hetionet CHEBI:2636 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0340865 infores:hetionet CHEBI:367163 biolink:causes MONDO:0019056 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027868 infores:hetionet CHEBI:7454 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0028643 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0025061 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0017566 infores:hetionet CHEBI:7931 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0015672 infores:hetionet CHEBI:135930 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0003467 infores:hetionet CHEBI:46557 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0015230 infores:hetionet CHEBI:9086 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0549622 infores:hetionet CHEBI:31348 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151766 infores:hetionet CHEBI:82960 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0033771 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0549336 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0021400 infores:hetionet CHEBI:167638 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0027497 infores:hetionet CAID:CA241302 biolink:causes MONDO:0100453 infores:clingen CAID:CA241302 MONDO:0100453 PMID: Benign BP4, BP7, BS1, BS2_Supporting The NM_000180.4(GUCY2D):c.369C>T (p.Gly123=) variant is silent and occurs outside of the donor and acceptor splice regions. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.001777, with 2088 alleles / 1133038 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 4 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥3 (gnomAD v4.1.0; BS2_Supporting). The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2_Supporting, BP4, BP7.(VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA241302/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15367 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235146 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0036572 infores:hetionet CHEBI:85078 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0006826 infores:hetionet CHEBI:127342 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0011206 infores:hetionet CHEBI:28593 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0036454 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0857093 infores:hetionet CAID:CA012355 biolink:causes MONDO:0007947 infores:clingen CAID:CA012355 MONDO:0007947 PMID: Uncertain Significance PP2, PP3 PM2, PS4, PM1 The NM_00138 c.1634G>A is a missense variant in FBN1 predicted to cause a substitution of an arginine by histidine at amino acid 545 (p.Arg545His) located within a cbEGF-like domain of the protein. This variant has been reported seven times in ClinVar: once as likely pathogenic, and six times as uncertain significance (Variation ID: 36034). This variant was found in a proband with an aortic root aneurysm and a family history of Marfan syndrome (MFS) (Internal lab data). This variant has been identified in 1/15428 (0.006%) individuals of European (non-Finnish) origin (https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.1634G>C (p.Arg545Pro), has previously been reported in an individual with ectopia lentis and in an individual with thoracic aortic aneurysm (PMID 31730815, internal lab data). A cysteine-creating variant at this position, c.1633C>T (p.Arg545Cys), has been previously established as pathogenic and was reported in several individuals with MFS or ectopia lentis (PMID 25053872, 15241795, 27611364, 27353645, 19159394 , 12446365, 17679947, 20564469, internal lab data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.764, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA012355/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:15940 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0404521 infores:hetionet CHEBI:47780 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0019521 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023530 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0027947 infores:hetionet CHEBI:40009 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0151889 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0009806 infores:hetionet CHEBI:8869 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0009782 infores:hetionet CHEBI:3175 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0010200 infores:hetionet CAID:CA199071 biolink:causes MONDO:0015152 infores:clingen CAID:CA199071 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3, PM2_Supporting, PP3 PM5 The NM_000023.4: c.101G>A variant in SGCA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 34 (p.Arg34His). This variant has been detected in at least two individuals with autosomal recessive limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Arg77Cys, 1.0 pt, PMID: 18285821) (PM3). At least one patient with this variant and a second presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness as well as significantly reduced or absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 1828582). The filtering allele frequency of this variant is 0.000023 (the upper threshold of the 95% CI of 6/113724 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is lower than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.708, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PP4_Strong, PM2_Supporting, PM3, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA199071/MONDO:0015152/189 2025-01-09 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4530 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0038454 infores:hetionet CHEBI:6797 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0232487 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0542203 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0026848 infores:hetionet CAID:CA399805506 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805506 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.647C>T (p.Ala216Val) missense variant has been previously reported in the context of Glanzmann thrombasthenia. One individual (GT55) with the p.Ala216Val missense variant in homozygous state (PM3_supporting) presented with significant mucocutaneous bleeding. Platelet aggregometry demonstrated absence of platelet aggregation with 3 platelet agonists and normal aggregation with ristocetin. Surface expression of αIIbβ3 was demonstrated to be reduced (11-22%) by flowcytometry. Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions (PMID:25728920; PP4_strong). This variant is absent from all continental populations in gnomAD v4.1.0 (PM2_Supporting). Multiple in silico tools predict this variant to be deleterious (REVEL score = 0.85; PP3). This variant meets criteria for PP4_strong, PM2_supporting, PM3_supporting and PP3 and is classified as Likely pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805506/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:36791 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0041747 infores:hetionet CHEBI:4911 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C2242737 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0281856 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042514 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0006840 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034359 infores:hetionet CHEBI:5778 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0027707 infores:hetionet CAID:CA414914388 biolink:causes MONDO:0010602 infores:clingen CAID:CA414914388 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PP3, PS4_Very Strong PM1, PP4 The variant, NM_000132.3(F8):c.1421G>A predicts a missense change, Gly474Glu, which is not reported in gnomAD v2.1 or v3.1.1, meeting PM2_Supporting. This variant has been reported in at least 8 patients with severe hemophilia A (at least one patient with an inhibitor to factor replacement therapy - PMID: 16601827) in the literature (PMID: 31134694, 10404764, and 29296726) and from internal VCEP data; meeting the F8 phenotype criteria at PS4_Very Strong. The variant has a REVEL score of 0.973 (threshold >0.6) meeting PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very Strong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414914388/MONDO:0010602/071 2025-01-14 2025-03-28 X-linked inheritance HP:0001417 Supports CHEBI:68554 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0034065 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0035455 infores:hetionet CHEBI:8863 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013491 infores:hetionet CHEBI:114785 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0022568 infores:hetionet CHEBI:10650 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026837 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085129 infores:hetionet CHEBI:74947 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0006277 infores:hetionet CHEBI:45863 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085635 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0344375 infores:hetionet CHEBI:63623 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C1519353 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041912 infores:hetionet CHEBI:29688 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0027947 infores:hetionet CHEBI:47519 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0022575 infores:hetionet CHEBI:3242 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0039231 infores:hetionet CHEBI:50922 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0007398 infores:hetionet CAID:CA124475 biolink:causes MONDO:0015967 infores:clingen CAID:CA124475 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS3, PS4_Moderate, PM1, PP1_Strong, PP4_Moderate, PP3 The c.335C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 112 (p.(Pro112Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro112Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMID: 32910913). Lastly, this variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). In summary, c.335C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PP3, PM1_Supporting, PM2_Supporting, PP4_Moderate, PS4_Moderate,PS3_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124475/MONDO:0015967/017 2022-04-08 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:64864 biolink:causes MONDO:0957228 infores:monarchinitiative not_provided not_provided HGNC:25777 MONDO:0957228 uuid:f20a293e-84eb-4818-a624-3f06700a6e97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229322 biolink:causes MONDO:0009861 infores:clingen CAID:CA229322 MONDO:0009861 PMID:26503515PMID:26322415 Pathogenic PVS1, PP4_Moderate, PM2 The PAH variant c.1066-1G>A (IVS10-1G>A) is a null variant (acceptor site) located in exon number 11 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Fifteen pathogenic null variants in exon 11 of the PAH gene have been reported. This variant is predicted to disrupt the reading frame by skipping exon 11, altering a region that is critical to protein function (27 pathogenic non-nonsense variants in exon 11 have been reported). The mRNA transcript is predicted to undergo NMD. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.559). HSF (-35.29 variation) and MaxEnt (-276.58 variation) agree that this alteration of the WT acceptor site most probably affects splicing by breaking the splicing site. The PAH variant c.1066-1G>A (IVS10-1G>A) was found in a Chinese patient with classical PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in another Chinese patient with undetermined PKU/MHP phenotype (PMID: 26503515). This variant is absent from the gnomAD, ExAC, 1000 Genomes, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, and PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229322/MONDO:0009861/006 2020-05-09 2020-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37941 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018099 infores:hetionet CHEBI:50648 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0035317 infores:hetionet CHEBI:6339 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151905 infores:hetionet CHEBI:3506 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C2830004 infores:hetionet CAID:CA915948961 biolink:causes MONDO:0015967 infores:clingen CAID:CA915948961 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1255_1264delTTCAAGGAGC variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 419 (NM_000162.5), adding 9 novel amino acids before encountering a stop codon (p.(F419GfsX9)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1255_1264delTTCAAGGAGC meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915948961/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Supports NCBIGene:2706 biolink:causes MONDO:0007866 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0007866 uuid:4a06768e-a83e-4a83-a743-56f2a7877c15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0178298 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0033246 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0259799 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0004936 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0021053 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0040034 infores:hetionet CHEBI:3219 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0393761 infores:hetionet CHEBI:8863 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0023530 infores:hetionet CHEBI:46081 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0015672 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020651 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040435 infores:hetionet CHEBI:135193 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0003578 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0037199 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0948807 infores:hetionet GO:0098528 biolink:causes CL:0008002 infores:ubergraph knowledge_assertion manual_agent GO:0098528 CL:0008002 CAID:CA658824420 biolink:causes MONDO:0100083 infores:clingen CAID:CA658824420 MONDO:0100083 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NC_000021.9:g.34880712_34880714del is an in-frame deletion which affects residues within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM4_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824420/MONDO:0100083/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9599 biolink:causes UMLS:C0857073 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0857073 infores:hetionet CHEBI:5132 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0034065 infores:hetionet CHEBI:2611 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0037317 infores:hetionet CHEBI:59773 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0002792 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151883 infores:hetionet CHEBI:8694 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0038587 infores:hetionet CHEBI:10127 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0014394 infores:hetionet CHEBI:63619 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151878 infores:hetionet CHEBI:27690 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C2830004 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004830 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015645 infores:hetionet CHEBI:9757 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0002792 infores:hetionet CAID:CA390864683 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864683 MONDO:0100216 PMID: Pathogenic PP3, PM2_Supporting, PS4_Supporting, PM1, PS2, PS3_Supporting PM6, BP4, BP2, BA1, PP1, PP4, BS2, PS1, BS1, BS3, BS4 The NM_177438.2:c.5425G>A variant in DICER1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1809 (p.Gly1809Arg). This variant has been identified as a de novo occurrence with constitutional mosaicism in 1 individual with lung cysts, pleuropulmonary blastoma, and multinodular goiter (PS2, PS4_Supporting; PMID: 26475046, 34544839). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In vitro cleavage assay showed that this variant reduces the capacity of the protein to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting, PMID: 25190313, 26033159). The computational predictor REVEL gives a score of 0.852, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides in the p.G1809 metal ion-binding residues located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1, PMID: 31342592). In summary, this variant meets the criteria to be classified as Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS2, PS4_Supporting, PM2_Supporting, PS3_Supporting, PP3, PM1. (Bayesian Points: 10; VCEP specifications version 1.2.0; 8/22/23) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864683/MONDO:0100216/024 2023-08-22 2023-09-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:100241 biolink:causes MONDO:0004369 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0021313 infores:hetionet CHEBI:30830 biolink:causes HP:0025233 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0456511 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0040046 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018801 infores:hetionet CHEBI:9137 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0019080 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027947 infores:hetionet NCBIGene:9147 biolink:causes MONDO:0030849 infores:monarchinitiative not_provided not_provided HGNC:10663 MONDO:0030849 uuid:ff10089a-0aca-4316-b214-96bdea821076 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151539 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0234215 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0014130 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0036572 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0018801 infores:hetionet CHEBI:17334 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0151539 infores:hetionet CHEBI:6954 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1167791 infores:hetionet CHEBI:9649 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0547030 infores:hetionet CHEBI:28593 biolink:causes MONDO:0013361 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C3203356 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007097 infores:hetionet CHEBI:9763 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C1306341 infores:hetionet CHEBI:64198 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0027441 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019917 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018799 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151740 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1609512 infores:hetionet CHEBI:68554 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0014038 infores:hetionet CHEBI:9352 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0002874 infores:hetionet CHEBI:6413 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0026858 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006626 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011882 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0022354 infores:hetionet CHEBI:28748 biolink:causes HP:0045014 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0342892 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0162429 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1720775 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0020517 infores:hetionet CHEBI:39867 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009782 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0241379 infores:hetionet CHEBI:63681 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0039070 infores:hetionet CHEBI:7915 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0700590 infores:hetionet CHEBI:68595 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0015672 infores:hetionet CHEBI:5165 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013384 infores:hetionet NCBIGene:1161 biolink:causes MONDO:0013829 infores:monarchinitiative not_provided not_provided HGNC:3439 MONDO:0013829 uuid:779c3c5b-8c34-4473-8c98-8c4a33f27ddb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040425 infores:hetionet CHEBI:35677 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0011603 infores:hetionet CHEBI:465284 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151907 infores:hetionet CHEBI:37924 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027497 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1527407 infores:hetionet CHEBI:15765 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0003467 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0027765 infores:hetionet CHEBI:17549 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0020580 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0687133 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0036572 infores:hetionet CHEBI:5558 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0018794 infores:hetionet CHEBI:47657 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0242379 infores:hetionet CHEBI:32599 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0032343 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034063 infores:hetionet CHEBI:9570 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009763 infores:hetionet CHEBI:3215 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0424790 infores:hetionet CHEBI:144093 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0026826 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002173 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027858 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0002508 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D005891 DB00878_MESH_D005891_1 CHEBI:61033 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1321686 infores:hetionet CAID:CA023815 biolink:causes MONDO:0007783 infores:clingen CAID:CA023815 MONDO:0007783 PMID: Likely Benign BS3_Supporting PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of lysine with arginine at codon 3367 of the RYR1 protein, p.(Lys3367Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:32535660). A REVEL score of 0.632 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS3_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023815/MONDO:0007783/012 2021-05-27 2021-05-27 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:36791 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023518 infores:hetionet CHEBI:27974 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0040046 infores:hetionet CHEBI:31623 biolink:causes MONDO:0002776 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0155388 infores:hetionet UMLS:C0657912 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015371 infores:hetionet CHEBI:49662 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013144 infores:hetionet CHEBI:2687 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0042510 infores:hetionet NCBIGene:9126 biolink:causes MONDO:0012555 infores:monarchinitiative not_provided not_provided HGNC:2468 MONDO:0012555 uuid:ce20a49e-6f1a-4df3-8b97-5ab75fe7716c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0009676 infores:hetionet CHEBI:51364 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0231528 infores:hetionet CHEBI:135736 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0949059 infores:hetionet CHEBI:4681 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0020458 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0259768 infores:hetionet CAID:CA412379329 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379329 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4 PS3, PS4, PM5, PP3 The NM_000330.4(RS1):c.1A>T variant is a start loss variant encoding the substitution of Methionine with Leucine at amino acid 1. The variant may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. Use of the next in-frame start codon would omit 147 amino acids (66% of the sequence (PVS1; PMIDs, ClinVar SCVs implicating pathogenic variants between this and 1st possible start codon). Moreover, this variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). COS-7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 20809529). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family 4 brothers, one sister, and her daughter w/o their mother's genotype. (PP1_strong; PMID: 17031297). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 17031297, PP4). This variant has been reported in multiple other publications (PMIDs: 30551202, 28559085, 30025115, 22039241, 20809529, 37396901), however, it was not clear that the probands were different individuals, so PS4_Supporting was not met. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PM2_supporting, PP1_strong, and PP4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379329/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Supports CAID:CA258396564 biolink:causes MONDO:0100040 infores:clingen CAID:CA258396564 MONDO:0100040 PMID: Likely Benign BP5, BS2 BS1, PM2, BP4, BA1 The p.Gly128Cys variant is observed in at least 2 unaffected individuals (internal databases - GeneDx and Invitae) (BS2). The p.Gly128Cys variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Gly128Cys variant in FOXG1 in gnomAD v4.1 is 0.00001400 in African/African American population (not sufficient to meet BS1 criteria). In summary, the p.Gly128Cys variant variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). (FOXG1 specification v.3; approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA258396564/MONDO:0100040/035 2024-08-30 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101853 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C1384353 infores:hetionet CHEBI:47519 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C2830004 infores:hetionet CHEBI:48844 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0234215 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0003123 infores:hetionet CHEBI:71941 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0014518 infores:hetionet CHEBI:4453 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0233472 infores:hetionet CHEBI:5123 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0015371 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0518015 infores:hetionet CHEBI:134991 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0011991 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005638 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0001816 infores:hetionet NCBITaxon:12814 biolink:causes MONDO:0001577 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12814 MESH:D018357 DB00110_MESH_D018357_1DB00811_MESH_D018357_1 UMLS:C0120107 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0002418 infores:hetionet GO:0045063 biolink:causes CL:0000545 infores:ubergraph knowledge_assertion manual_agent GO:0045063 CL:0000545 CHEBI:17334 biolink:causes HP:0000011 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0005697 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011570 infores:hetionet CHEBI:8356 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0021177 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0232492 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0037199 infores:hetionet CAID:CA270435 biolink:causes MONDO:0010726 infores:clingen CAID:CA270435 MONDO:0010726 PMID: Pathogenic PM5, PM1, PP3, PP4, PS4_Moderate, PS1, PM2_Supporting The c.471C>G (p.Phe157Leu) variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15675358) (PP4). The p.Phe157Leu variant in MECP2 has been observed in 2 additional individuals with MECP2-related conditions (PMID 30536762, RettBASE) (PS4_moderate). The p.Phe157Leu variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Phe169Leu variant in MECP2 is absent from gnomAD (PM2_supporting). The c.471C>A variant in the MECP2 gene results in a p.Phe157Leu change that is a previously established pathogenic variant (ClinVar, Invitae - internal database) (PS1). A pathogenic missense variant (p.Phe157Ile) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16832102, 27929079, RettBASE) (PM5). In summary, the c.471C>G (p.Phe157Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1 + PM1 + PM5 + PS4_moderate + PM2_supporting + PP3 + PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270435/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:3699 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0003467 infores:hetionet CAID:CA410147365 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147365 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.1324C>T (p.Leu442Phe) is a missense variant which has a REVEL score < 0.50 (0.18) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147365/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50692 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0011603 infores:hetionet CHEBI:5134 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0040460 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0011334 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0011334 uuid:0f894b8f-706b-47e5-a10b-b2612ca2d3cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0024894 infores:hetionet CHEBI:27732 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0020456 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0438173 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0438173 infores:hetionet CHEBI:2549 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0037763 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009763 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014175 infores:hetionet GO:0010061 biolink:causes GO:0010054 infores:ubergraph knowledge_assertion manual_agent GO:0010061 GO:0010054 CHEBI:3387 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0043352 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0033774 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0149892 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0149892 infores:hetionet CHEBI:49668 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0010692 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0020517 infores:hetionet CHEBI:47381 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151594 infores:hetionet CHEBI:8024 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0232462 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0015300 infores:hetionet CHEBI:92712 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0018524 infores:hetionet CHEBI:28445 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151825 infores:hetionet CHEBI:17650 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0917801 infores:hetionet CHEBI:3996 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0232462 infores:hetionet CHEBI:9123 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232461 infores:hetionet CHEBI:52172 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0028081 infores:hetionet CHEBI:32599 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0016382 infores:hetionet CHEBI:63623 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C2363731 infores:hetionet CHEBI:47780 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0036974 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0027769 infores:hetionet CHEBI:47426 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020621 infores:hetionet CHEBI:7465 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0016204 infores:hetionet CHEBI:47780 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027121 infores:hetionet CHEBI:4754 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01127 UMLS:C0677500 infores:hetionet CHEBI:71255 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0002871 infores:hetionet CHEBI:28925 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0027497 infores:hetionet CHEBI:31236 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026640 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002567 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040580 infores:hetionet CHEBI:47898 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C3665347 infores:hetionet CHEBI:6715 biolink:causes HP:0002378 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0239842 infores:hetionet CHEBI:63620 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0030662 infores:hetionet UBERON:0004810 biolink:causes MONDO:0003011 infores:ubergraph knowledge_assertion manual_agent UBERON:0004810 MONDO:0003011 CHEBI:43968 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0009450 infores:hetionet CHEBI:8107 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0268000 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0855304 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0855304 infores:hetionet CAID:CA377482801 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482801 MONDO:0017623 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PM6_Strong, PS4_Moderate BS2, PM5 PTEN c.476G>A (p.Arg159Lys) meets criteria to be classified as Pathogenic for PTEN hamartoma tumor syndrome in a autossomal dominant manner under ACMG criteria for PTEN gene v3 (PMID:30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Phosphatase activity <-1.11 per Mighell et al. 2018 (PMID: 29706350). PP2: PTEN classified as a gene with missense variants that have low rate of benign missense variation and where missense variants are common mechanisms of disease. PP3: REVEL score (0.961) greater than 0.7. PM2_P: Variant absent on gnomad (v4). PM6_S: Assumed de novo case with strong PTEN-specific phenotype in patient (reported with extreme macrocephaly, autism and developmental delay, and seizures (Pediatric score +5) (internal laboratory contributor). PS4_M: Pediatric patient reported in Tuli et al. (PMID: 34184188) to have neonatal overgrowth, macrocephaly (+5.6 SD), developmental delay and periventricular leukomalacia.(Pediatric score +5. +1 proband point). Pediatric patient reported with developmental delay, macrocephaly and polymicrogyria. (Pediatric score +6, +1 proband point) (Internal laboratory contributor). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482801/MONDO:0017623/003 2025-10-03 2025-10-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41879 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0013491 infores:hetionet CHEBI:51164 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0312420 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0024115 infores:hetionet CHEBI:75045 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0023530 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0235639 infores:hetionet CHEBI:4027 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0011603 infores:hetionet CHEBI:8665 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0151908 infores:hetionet CHEBI:8884 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0027497 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020456 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0010692 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0036572 infores:hetionet NCBIGene:79813 biolink:causes MONDO:0027407 infores:monarchinitiative not_provided not_provided HGNC:24650 MONDO:0027407 uuid:34cf57d4-1e30-44eb-9dc5-67680762f90f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3175 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0152030 infores:hetionet CHEBI:92712 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0038999 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0042373 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0027769 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015397 infores:hetionet CAID:CA774734051 biolink:causes MONDO:0008723 infores:clingen CAID:CA774734051 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1611_1627dup (p.Phe543Tyrfs*15) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 17/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA774734051/MONDO:0008723/021 2022-09-20 2022-09-20 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:6522 biolink:causes MONDO:0957262 infores:monarchinitiative not_provided not_provided HGNC:11028 MONDO:0957262 uuid:dfe9e6f5-f0c9-4b84-a442-2cd084582bd2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027947 infores:hetionet CHEBI:40279 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151610 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0028643 infores:hetionet NCBITaxon:6282 biolink:causes MONDO:0017137 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6282 MONDO:0017137 CHEBI:4975 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0030196 infores:hetionet CHEBI:51141 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0015672 infores:hetionet CHEBI:8382 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011603 infores:hetionet UMLS:C1872203 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0000737 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0011991 infores:hetionet CAID:CA658683948 biolink:causes MONDO:0007648 infores:clingen CAID:CA658683948 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS4, BS3, BP5, BP7, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.656del p.(Pro219fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000760825.3). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683948/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:101278 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0040435 infores:hetionet CHEBI:32293 biolink:causes MONDO:0004037 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0242420 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0235082 infores:hetionet CHEBI:31981 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0392156 infores:hetionet CHEBI:31709 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0018790 infores:hetionet CHEBI:5118 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011206 infores:hetionet NCBITaxon:5820 biolink:causes MONDO:0005136 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5820 MONDO:0005136 CHEBI:17026 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0014724 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0027765 infores:hetionet CHEBI:49960 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0042023 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0029882 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030305 infores:hetionet CAID:CA013227 biolink:causes MONDO:0004994 infores:clingen CAID:CA013227 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.2945T>C (p.Met982Thr) variant in the MYH7 gene is 0.11% (88/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013227/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true GO:1900217 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:1900217 GO:0072006 CHEBI:44185 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0028961 infores:hetionet CAID:CA10585596 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585596 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS1, BP5, BP7, BS1, BS3, BS4, PM1, PM4, PM3, PVS1, BS2, PP2, PP1 NM_000527.5(LDLR):c.1749C>A (p.His583Gln) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.805. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921).PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6, after alternative causes of high cholesterol were excluded, from PMID 19318025 (Alonso et al., 2009). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585596/MONDO:0007750/013 2023-11-07 2024-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8356 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030232 infores:hetionet CHEBI:567361 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0231528 infores:hetionet CHEBI:3077 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0039070 infores:hetionet CHEBI:5847 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0013395 infores:hetionet CHEBI:36791 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022281 infores:hetionet CHEBI:8874 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0233565 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0025061 infores:hetionet CHEBI:2569 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0020458 infores:hetionet NCBIGene:54903 biolink:causes MONDO:0014441 infores:monarchinitiative not_provided not_provided HGNC:7121 MONDO:0014441 uuid:88836e22-9060-4a33-a626-c401f752ccf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3061 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0030193 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0242785 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0242785 infores:hetionet CHEBI:3242 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0233477 infores:hetionet CHEBI:6030 biolink:causes MONDO:0019975 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0030783 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0033860 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0033975 infores:hetionet NCBIGene:23417 biolink:causes MONDO:0009556 infores:monarchinitiative not_provided not_provided HGNC:7150 MONDO:0009556 uuid:5c06e967-bdee-4b95-ad30-ffa927f28b62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0035078 infores:hetionet CHEBI:63589 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0018418 infores:hetionet CHEBI:6437 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0042024 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0018801 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0232492 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0085617 infores:hetionet CHEBI:44423 biolink:causes NCIT:C121623 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0221470 infores:hetionet CHEBI:72690 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0006277 infores:hetionet CHEBI:50777 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0027497 infores:hetionet CAID:CA000509 biolink:causes MONDO:0017623 infores:clingen CAID:CA000509 MONDO:0017623 PMID: Pathogenic PVS1, PM2, PS4_Supporting PTEN c.534_535delTAinsAT (p.Y178X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 9832032, PMID 23335809) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000509/MONDO:0017623/003 2018-04-06 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7494 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0424000 infores:hetionet CAID:CA188674 biolink:causes MONDO:0007648 infores:clingen CAID:CA188674 MONDO:0007648 PMID:15322508 Likely Benign BS1, BP4 BP7, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP3, PP2, PP1, PP4, BS2, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1138-3C>T variant has an allele frequency of 0.00121 (0.121%, 29/24,036 alleles) in the African subpopulation of the gnomAD cohort (BS1). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BP4 (Variant Interpretation Guidelines Version 3.1). CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA188674/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:38940 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0155320 infores:hetionet CHEBI:8059 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0038990 infores:hetionet CHEBI:7824 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C2937358 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0005940 infores:hetionet NCBIGene:28982 biolink:causes MONDO:0976126 infores:monarchinitiative not_provided not_provided HGNC:24682 MONDO:0976126 uuid:1753e27e-4b63-4f6c-9020-d0ca9ee89088 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135920 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0013428 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0087169 infores:hetionet CHEBI:80630 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1443060 infores:hetionet CHEBI:41977 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0035455 infores:hetionet CHEBI:6073 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C2363730 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009324 infores:hetionet CHEBI:28241 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0016382 infores:hetionet CAID:CA10585349 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585349 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, BA1, PS1, BS1, PM5, PP3 The NM_000527.5(LDLR):c.1189T>A (p.Ser397Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v20210610).PP4: Variant meets PM2 and is identified in at least 1 index case with clinical Dutch Lipid Clinic Network Criteria score ≥ 6 in PMID 11810272 (Fouchier et al., 2001), The Netherlands, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585349/MONDO:0007750/013 2023-06-23 2025-09-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8707 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018681 infores:hetionet CHEBI:9398 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0009782 infores:hetionet CHEBI:9649 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0438717 infores:hetionet CHEBI:3561 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013456 infores:hetionet CHEBI:52172 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151904 infores:hetionet CHEBI:100241 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025287 infores:hetionet CHEBI:3723 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149871 infores:hetionet GO:1902890 biolink:causes GO:0048765 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0048765 CHEBI:17688 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0010692 infores:hetionet CAID:CA345144073 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144073 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS2, PM5 BS2, PP1, PP4, PVS1, PM6, BP1, BP4, BP3, BP2, BA1, PS4, PS3, PS1, BP5, BP7, BS1, BS3, BS4, PM4, PM1, PM3 The variant NM_001100.4:c.1127G>T in ACTA1 is a missense variant predicted to cause substitution of cysteine by phenylalanine at amino acid 376 (p.Cys376Phe) in exon 7/7. The variant is absent from gnomAD v4.1.1 with adequate coverage (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.955, which is above the threshold necessary to apply PP3. In addition, ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported as a de novo observation with confirmed parental relationships in one proband with features associated with congenital myopathy which meets the criteria for PS2 (Invitae, SCV002228646.2). Another missense variant c.1127G>C (p.Cys376Ser) in the same codon is classified as pathogenic for autosomal dominant alpha-actinopathy (PM5, PMIDs:25890230, 19562689). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM5, PP2, PP3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144073/MONDO:0100084/147 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8093 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0018799 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0160390 infores:hetionet CHEBI:3219 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0424790 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085584 infores:hetionet CHEBI:68642 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0042963 infores:hetionet CHEBI:72564 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020621 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0239488 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0015397 infores:hetionet CHEBI:4445 biolink:causes UMLS:C1141938 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1141938 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0037199 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0017601 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0038454 infores:hetionet CHEBI:4798 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0242422 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0403632 infores:hetionet CHEBI:6444 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0020458 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0015397 infores:hetionet CHEBI:5118 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0278134 infores:hetionet CHEBI:39112 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0015230 infores:hetionet CHEBI:28830 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0232849 infores:hetionet NCBIGene:59 biolink:causes MONDO:0013452 infores:monarchinitiative not_provided not_provided HGNC:130 MONDO:0013452 uuid:ca8bcbc4-be42-41cd-9a45-327603cf40b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6532 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0018681 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005684 infores:hetionet CHEBI:167638 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0037763 infores:hetionet CHEBI:5103 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0085628 infores:hetionet CHEBI:36791 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085628 infores:hetionet CHEBI:37333 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0040264 infores:hetionet CHEBI:2663 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0037317 infores:hetionet CHEBI:127342 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0011991 infores:hetionet NCBIGene:4507 biolink:causes MONDO:0007205 infores:monarchinitiative not_provided not_provided HGNC:7413 MONDO:0007205 uuid:4b4d6e77-e78f-4526-84b5-602e1ae00d8e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0855242 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0037274 infores:hetionet CAID:CA410148699 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148699 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.997C>T (p.Pro333Ser) is a missense variant which has a REVEL score < 0.50 (0.291), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148699/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3749 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0234632 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0234215 infores:hetionet NCBIGene:1301 biolink:causes MONDO:0032802 infores:monarchinitiative not_provided not_provided HGNC:2186 MONDO:0032802 uuid:3224a9d5-2b4a-429f-9f3a-bc72715b43c4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003123 infores:hetionet CHEBI:3082 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0026826 infores:hetionet CHEBI:3398 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0002878 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0033123 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0033123 uuid:612682d6-87a1-4171-93fe-9291cae2d29c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3013 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0020649 infores:hetionet GO:0060617 biolink:causes GO:0060592 infores:ubergraph knowledge_assertion manual_agent GO:0060617 GO:0060592 CHEBI:474053 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0343863 infores:hetionet CHEBI:36795 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085631 infores:hetionet CHEBI:35778 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0018790 infores:hetionet CHEBI:8327 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0262988 infores:hetionet CHEBI:63630 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0009676 infores:hetionet CHEBI:72564 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042024 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0013395 infores:hetionet CHEBI:63613 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0017178 infores:hetionet CHEBI:145499 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013404 infores:hetionet CAID:CA774742300 biolink:causes MONDO:0008723 infores:clingen CAID:CA774742300 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 PM3 The c.642_643del (p.Phe214LeufsTer38) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed increased acylcarnitine levels, which ishighly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 31620161). Additionally, two individuals carried a distinct likely pathogenic variant not confirmed to be in trans, but one of these individuals was not confirmed by biochemical testing to be affected with VLCAD deficiency (PMID: 35400565). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00001470 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Moderate, PP4 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA774742300/MONDO:0008723/021 2022-12-14 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15854 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0019080 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0349231 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0948089 infores:hetionet CHEBI:175901 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0235896 infores:hetionet NCBIGene:388662 biolink:causes MONDO:0014559 infores:monarchinitiative not_provided not_provided HGNC:31399 MONDO:0014559 uuid:632a09c3-4613-45d9-867c-789b50a71239 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes UMLS:C2349423 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C2349423 infores:hetionet CHEBI:49575 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013428 infores:hetionet GO:2000825 biolink:causes GO:0006357 infores:ubergraph knowledge_assertion manual_agent GO:2000825 GO:0006357 CHEBI:43968 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0038325 infores:hetionet GO:0039524 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:0039524 GO:0032774 CHEBI:38562 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0600142 infores:hetionet CHEBI:63632 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0013456 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013595 infores:hetionet CHEBI:3371 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0235639 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0392162 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027813 infores:hetionet CHEBI:27504 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0015672 infores:hetionet CAID:CA398320910 biolink:causes MONDO:0011132 infores:clingen CAID:CA398320910 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PVS1 PM3 NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter) is a nonsense variant predicted to cause a premature stop codon (3/9) and lead to nonsense mediated decay in a disease that is loss of function (PVS1). The variant has been found in at least one compound heterozygous patient with FOXN1 deficiency (P9, PMID: 33464451). The patient displayed alopecia and low t-cell numbers (less than 1,000,000 cells/L) (PP4). They also had poor proliferative response to phytohemagglutinin on total cells, though normal when evaluated on separated T cells, flow cytometric analysis showed near complete absence of CD45RA+ CD4 T cells, and they had very low TRECs. They received a thymus transplant but T cell levels were not reported post transplant. Interestingly the patients alopecia spontaneously reversed at age 3. The variant is absent from gnomADv4.1 (PM2_supporting). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup (Pilot, date of approval xx/xx/2024). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398320910/MONDO:0011132/113 2024-09-27 2025-02-20 Semidominant inheritance HP:0032113 Supports CHEBI:9943 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0162835 infores:hetionet CAID:CA226588 biolink:causes MONDO:0100368 infores:clingen CAID:CA226588 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 NM_000329.3(RPE65):c.89dup (p.Thr31fs) is a frameshift variant that introduces a premature stop codon into exon 2 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of cone-rod dystrophy, nyctalopia, RPE mottling (0.5 pts), abnormal color vision (1 pt), absence of fundus autofluorescence (2 pts), and infantile onset (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 17525851, PMID: 15288992, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226588/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6375 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2047937 infores:hetionet CHEBI:8874 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037763 infores:hetionet CHEBI:681848 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C1145670 infores:hetionet CHEBI:499361 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0011603 infores:hetionet UMLS:C0657912 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011168 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0002622 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0178298 infores:hetionet CHEBI:43968 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0027947 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1269683 infores:hetionet CHEBI:80630 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0003811 infores:hetionet CHEBI:127780 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151611 infores:hetionet CHEBI:9599 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0015967 infores:hetionet CHEBI:9727 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0027720 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0948594 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018802 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0019054 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020437 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0854114 infores:hetionet NCBIGene:7503 biolink:causes MONDO:0026404 infores:monarchinitiative not_provided not_provided HGNC:12810 MONDO:0026404 uuid:50dd2839-212e-4572-9d01-a1417f04ae78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0037763 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0006145 infores:hetionet CHEBI:5147 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0023218 infores:hetionet CHEBI:3647 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0340865 infores:hetionet CHEBI:10023 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151878 infores:hetionet CAID:CA367403047 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403047 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.232G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 78 (p.(Asp78Asn)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.947, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, internal lab contributors). One of the individuals harboring this variant had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antiboides) (PP4_Moderate; internal lab contributors). Two other missense variants, c.234C>G (p.Asp78Glu) and c.232G>C (p.Asp78His) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.232G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PP4_Moderate, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403047/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:6067 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0037199 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038454 infores:hetionet CHEBI:8768 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151594 infores:hetionet CHEBI:5141 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0541799 infores:hetionet NCBIGene:9898 biolink:causes MONDO:0957588 infores:monarchinitiative not_provided not_provided HGNC:29877 MONDO:0957588 uuid:bee3ece7-2f5f-4309-b6fc-170a215723f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1142135 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0240035 infores:hetionet CAID:CA367402547 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402547 MONDO:0015967 PMID: Pathogenic PVS1, PP1, PM2_Supporting PP4 The c.363+1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 3 of NM_000162.5. This variant is predicted to cause skipping of biologically relevant exon 3 of 10, resulting in a frameshift, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with hyperglycemia, with three informative meioses in one family (PP1; PMID:10447526). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID:10447526). In summary, c.363+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402547/MONDO:0015967/086 2024-03-15 2024-03-15 Semidominant inheritance HP:0032113 Supports CHEBI:9168 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020598 infores:hetionet CHEBI:68558 biolink:causes HP:0002584 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0267373 infores:hetionet CHEBI:5001 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0231528 infores:hetionet NCBITaxon:523103 biolink:causes MONDO:0001698 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:523103 MONDO:0001698 UMLS:C0065374 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020625 infores:hetionet CAID:CA6832196 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832196 MONDO:0015967 PMID: Benign BA1, PM5_Supporting The c.1780A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to glycine at codon 594 (p.(Ser594Gly)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD v2.1.1 of 0.0002499, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Another missense variant, c.1781G>T, p.Ser594Ile, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser594Gly (PM5_Supporting). In summary, c.1780A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BA1, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832196/MONDO:0015967/017 2022-07-01 2022-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5778 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0242350 infores:hetionet CHEBI:3478 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0853034 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0876998 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0876998 infores:hetionet CHEBI:51364 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0026827 infores:hetionet NCBIGene:617 biolink:causes MONDO:0007415 infores:monarchinitiative not_provided not_provided HGNC:1020 MONDO:0007415 uuid:863429d7-3f42-44c6-9114-9e12a56e7b77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0035455 infores:hetionet CHEBI:50173 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013428 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018801 infores:hetionet NCBIGene:8913 biolink:causes MONDO:0014776 infores:monarchinitiative not_provided not_provided HGNC:1394 MONDO:0014776 uuid:e935bea4-ce41-49a7-a8c7-0ef3209c3363 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0009315 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0239134 infores:hetionet CHEBI:31176 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0036104 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0022568 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0549209 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0235290 infores:hetionet CAID:CA226041 biolink:causes MONDO:0100453 infores:clingen CAID:CA226041 MONDO:0100453 PMID: Likely Benign BP4, BP7 BS1, PM2 NM_000180.4(GUCY2D):c.1236C>T (p.Asp412=) is a synonymous variant in exon 4 of 20. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.001028 with 1659 alleles / 1,613,498 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. This variant has a Grpmax allele frequency of 0.001233, with 1519 alleles / 1180008 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion as well. The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226041/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:134991 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0151825 infores:hetionet NCBIGene:1288 biolink:causes MONDO:0010484 infores:monarchinitiative not_provided not_provided HGNC:2208 MONDO:0010484 uuid:61bcf529-72b6-479a-8941-340a1e08f534 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0878544 infores:hetionet CHEBI:119573 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017181 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0234913 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0032285 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0855242 infores:hetionet CHEBI:63611 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030196 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0231875 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0231875 infores:hetionet CAID:CA157986 biolink:causes MONDO:0007648 infores:clingen CAID:CA157986 MONDO:0007648 PMID: Benign BS2, BP2_Strong BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BA1, PS1, PS3, PS4, PS2 The c.1162G>A (p.Glu388Lys) variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; SCV000254804.3). The variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BP2_Strong, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157986/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:49375 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0007787 infores:hetionet NCBIGene:4439 biolink:causes MONDO:0044317 infores:monarchinitiative not_provided not_provided HGNC:7328 MONDO:0044317 uuid:6812c9ac-3243-4615-a4af-43ff94b6970e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65173 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0744727 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0015230 infores:hetionet CHEBI:92511 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0011991 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0233472 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0392176 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0012833 infores:hetionet CHEBI:4466 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0039231 infores:hetionet CHEBI:63611 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022575 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0009450 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0948525 infores:hetionet CAID:CA410207042 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207042 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.650G>C (p.Gly217Ala) variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. This missense variant has a REVEL score of 0.562 and does not meet criteria for PP3 (≥0.88) or BP4 (≤0.50). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207042/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68554 biolink:causes EFO:0020909 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0877167 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0037274 infores:hetionet CHEBI:7575 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0020458 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0426576 infores:hetionet CAID:CA16618077 biolink:causes MONDO:0021056 infores:clingen CAID:CA16618077 MONDO:0021056 PMID: Likely Pathogenic PS3, PM2_Supporting, PS4_Supporting The c.1956C>T variant in APC is predicted to be a synonymous (silent) variant (p.His652=). It is located at the third-last nucleotide of exon 15. Two RNA based RT-PCR assays demonstrate out-of-frame skipping of exon 15, with evidence that the variant allele produces <10% of the full-length transcript (PS3; PMID: 15459959, 22987206). This variant has been reported in 3 probands meeting least 1.5 phenotype points (PS4_Supporting; PMID: 15459959, 22987206). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3, PS4_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618077/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63580 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030232 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0851578 infores:hetionet CHEBI:64064 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0239377 infores:hetionet CHEBI:101853 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0239935 infores:hetionet CAID:CA367403044 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403044 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PP1 The c.232G>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to tyrosine at codon 78 (p.(Asp78Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of the individuals harboring this variant had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antiboides) (PP4_Moderate; internal lab contributors). While this variant segregated with diabetes with two informative meioses in a single family; this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.234C>G (p.Asp78Glu) and c.232G>C (p.Asp78His) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.232G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PP4_Moderate, PM5_Strong). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403044/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CAID:CA2654380174 biolink:causes MONDO:0011071 infores:clingen CAID:CA2654380174 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.352-19T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.74) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2654380174/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA288037 biolink:causes MONDO:0100488 infores:clingen CAID:CA288037 MONDO:0100488 PMID: Likely Benign BS2 BP5, BS1, BS3, BS4, PM2, PM6, PP3, PP1, BP2, BA1, PS4, PS3, PS2 The c.1417G>A (p.Val473Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 5 of 152,172 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288037/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6887 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0221201 infores:hetionet CAID:CA386965984 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965984 MONDO:0015967 PMID:27229139 Uncertain Significance PM2_Supporting, BS3_Supporting, PM1_Supporting, PP3 PS4, PP4, PP1 The c.763G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to serine at codon 255 (p.(Gly255Ser)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP. Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.951, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in one individual with diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate. The clinical history of this individual is suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and so PP4 cannot be applied (internal lab contributor). This variant segregated with diabetes with one informative meiosis in this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). Functional studies demonstrated the p.Gly255Ser protein has DNA binding above 75% of wild type (PMID: 27229139; BS3_Supporting). In summary, c.763G>A meets the criteria to be classified as variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PM1_Supporting, PP3, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965984/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94385 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0018965 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022568 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0009450 infores:hetionet CHEBI:3723 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020546 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0037284 infores:hetionet CHEBI:9445 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0015672 infores:hetionet CHEBI:6532 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0016204 infores:hetionet CL:0000624 biolink:causes GO:0035743 infores:ubergraph knowledge_assertion manual_agent CL:0000624 GO:0035743 CHEBI:4562 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0043251 infores:hetionet CHEBI:3207 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0085631 infores:hetionet CHEBI:9150 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0004238 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0235818 infores:hetionet CAID:CA410147021 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147021 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM1, PM3, PM5, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.1378A>G (p.Ser460Gly) is a missense variant which is absent from gnomAD v2, v3, and v4 (PM2_Supporting) and has not been reported in the literature. The computational predictor REVEL gives a score of 0.277, below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, providing evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147021/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410148061 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148061 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1117T>G (p.Ser373Ala) is a missense variant which has a REVEL score < 0.50 (0.262), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148061/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:134990 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0424000 infores:hetionet CHEBI:31705 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0004093 infores:hetionet CHEBI:7478 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0162275 infores:hetionet CHEBI:7915 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013404 infores:hetionet CHEBI:50275 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0015967 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0151765 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151765 infores:hetionet CHEBI:31348 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C3665347 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0948594 infores:hetionet CAID:CA376059912 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059912 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.509A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Aspartic Acid by Glycine at amino acid 170 (p.Asp170Gly).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059912/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:VL0L558GCB biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151883 infores:hetionet CHEBI:5959 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020580 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0037274 infores:hetionet CHEBI:4798 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0040822 infores:hetionet CHEBI:2379 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0013428 infores:hetionet CHEBI:135935 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0233407 infores:hetionet CHEBI:70707 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0011124 infores:hetionet CHEBI:63622 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0006266 infores:hetionet CHEBI:77733 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0009676 infores:hetionet CHEBI:68841 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0085606 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0687133 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0851341 infores:hetionet CHEBI:9130 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0036973 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0027765 infores:hetionet CHEBI:101853 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0019080 infores:hetionet CHEBI:31236 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016199 infores:hetionet CHEBI:10119 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151539 infores:hetionet CAID:CA016662 biolink:causes MONDO:0005021 infores:clingen CAID:CA016662 MONDO:0005021 PMID:29867217PMID:29666183PMID:29867217PMID:29666183 Likely Pathogenic PM2, PP3, PP1, PS4_Moderate, PM6_Supporting BA1, PM5, PM1, PS3, BS2, BS1, BS3, BS4, PS1, PS2, BP2, BP5 The NM_000257.4(MYH7):c.709C>T (p.Arg237Trp) variant has been identified in at least 10 individuals with DCM, 3 of whom also carried other disease-causing variants (PS4_Moderate; Hershberger 2008 PMID:19412328; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; Franaszczyk 2017 PMID:28045975; Dal Ferro 2017 PMID:28416588; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant has also been identified in 2 individuals with unspecified cardiomyopathy, 1 individual with LVNC, and 1 with ventricular tachycardia (GeneDx pers. comm.; Invitae pers. comm.). This variant has been reported as de novo in 1 individual with sudden death and suspected HCM based on autopsy (PM6_supporting; Ambry pers. comm.); however, because the reported phenotype is not specific enough, the PM6 criterion was downgraded to PM6_supporting. This variant segregated with disease in 3 affected individuals with DCM in 1 family (LMM pers. comm.). In vitro functional studies provide some evidence that this variant impacts protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Ujfalusi 2018 PMID:29666183; Liu 2018 PMID:29867217). This variant was identified in 0.0023% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM6_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016662/MONDO:0005021/002 2022-07-30 2022-07-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6149 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235086 infores:hetionet CHEBI:4466 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0220981 infores:hetionet CHEBI:55346 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0011127 infores:hetionet NCBIGene:7468 biolink:causes MONDO:0859219 infores:monarchinitiative not_provided not_provided HGNC:12766 MONDO:0859219 uuid:b15d69bb-a90e-45a0-b334-85de7a81d96d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0042373 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0242073 infores:hetionet CAID:CA16020892 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020892 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The c.910C>T (p.Gln304Ter) variant in PAH has been reported in at least 1 individual with PKU however without indication of the genotype (BH4 deficiency not ruled out) (PMID: 23357515) . This variant occurs in exon 8 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to result in a truncated protein (with truncation of >10% of the encoded protein) or mRNA subject to nonsense-mediated decay. The c.910C>T variant is absent from gnomAD and the ESP population databases. Based on available information, this variant is considered to be pathogenic. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020892/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports UNII:VL0L558GCB biolink:causes UMLS:C3160769 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C3160769 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0518015 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0403632 infores:hetionet CAID:CA337263250 biolink:causes MONDO:0010726 infores:clingen CAID:CA337263250 MONDO:0010726 PMID: Likely Benign BS2 BP4, BS1 The p.His372Tyr variant in MECP2 (NM_004992.3) is present in 2 female individuals in gnomAD (0.001%) (not sufficient to meet BS1 criteria). The p.His372Tyr variant is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.His372Tyr variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA337263250/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:82941 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0035410 infores:hetionet CHEBI:76010 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0232492 infores:hetionet CHEBI:188986 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0021368 infores:hetionet CHEBI:8382 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0002994 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0013395 infores:hetionet CHEBI:28593 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0232462 infores:hetionet CHEBI:9613 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0020625 infores:hetionet CHEBI:9241 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0002792 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0027765 infores:hetionet CHEBI:8888 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1527344 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0010692 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0002871 infores:hetionet CHEBI:135876 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0015967 infores:hetionet CAID:CA7542887 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542887 MONDO:0012996 PMID:27233232 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, BP4 The NM_001482.3:c.622G>A variant in GATM is a missense variant that is predicted to result in the substitution of alanine by threonine at amino acid 208 (p.Ala208Thr). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00002228 (1/44874 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% of wild-type AGAT enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.48 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 225916). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0.): PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542887/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5130 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0023533 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0037822 infores:hetionet CHEBI:17650 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0013604 infores:hetionet CAID:CA10650412 biolink:causes MONDO:0100083 infores:clingen CAID:CA10650412 MONDO:0100083 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP7, BP5, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.*3580T>G is a 3' UTR variant which has a MAF of 0.00057 (0.057%, 5/8716, alleles) in the African subpopulation of the 20210610 (gnomAD) cohort which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650412/MONDO:0100083/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68606 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0235378 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0236068 infores:hetionet CHEBI:63621 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020458 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0036572 infores:hetionet CHEBI:10119 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011168 infores:hetionet CAID:CA645369685 biolink:causes MONDO:0018875 infores:clingen CAID:CA645369685 MONDO:0018875 PMID: Likely Pathogenic PVS1_Strong, PP1, PM2_Supporting, PS4_Supporting BP4, BP3, BP2, BA1, PS2, PS3, PS1, PM4, PM1, PM3, PM5, BP7, BP5, BS1, BS4, BS3, PM6, BS2, PP3, PP4 The NM_000546.6:c.993+1del is a deletion of a single G nucleotide within the canonical donor site of exon 9 of TP53. Through exon 9 skipping, the variant is observed in an RT-PCR assay to produce multiple aberrant transcripts encoding frameshift alterations predicted to induce nonsense-mediated decay. Since the assay does not fully account for leakiness, code weight downgraded to Strong (PVS1_Strong (RNA); PMID: 10980596). This variant has been reported in 1 proband meeting Classic LFS criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 10980596). This variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 10980596). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).. In summary, this variant meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1_Strong(RNA), PS4_Supporting, PP1, PM2_Supporting (Bayesian Points: 7; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369685/MONDO:0018875/009 2025-06-24 2025-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7496 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0021053 infores:hetionet CHEBI:8764 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151662 infores:hetionet CHEBI:8707 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C3665347 infores:hetionet CHEBI:9445 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0042029 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0038454 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009782 infores:hetionet CHEBI:28364 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0009806 infores:hetionet GO:0048686 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0048686 GO:0007399 CHEBI:10119 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0041912 infores:hetionet CHEBI:46557 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151539 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0877322 infores:hetionet CHEBI:82960 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0311468 infores:hetionet CHEBI:7903 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0085593 infores:hetionet CHEBI:7581 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0012569 infores:hetionet CHEBI:8764 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151818 infores:hetionet HP:0030126 biolink:causes HP:0100608 infores:drugmechdb knowledge_assertion manual_agent HP:0030126 MESH:D008796 DB00717_MESH_D008796_1DB00396_MESH_D008796_1DB00603_MESH_D008796_1 CHEBI:84883 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0043352 infores:hetionet CHEBI:45409 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151827 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0025637 infores:hetionet CHEBI:23765 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0010520 infores:hetionet CHEBI:46081 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0027947 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0009806 infores:hetionet CHEBI:72297 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0018965 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1739418 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1739418 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0162429 infores:hetionet CHEBI:135888 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0038999 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0004936 infores:hetionet CHEBI:8461 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0855775 infores:hetionet CHEBI:6640 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0009676 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0948089 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0162429 infores:hetionet NCBIGene:5077 biolink:causes MONDO:0009994 infores:monarchinitiative not_provided not_provided HGNC:8617 MONDO:0009994 uuid:df1282f8-8909-442c-b5e7-c2366821669e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0041912 infores:hetionet CHEBI:9434 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0007820 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005075 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0238463 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013395 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948525 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235351 infores:hetionet CHEBI:50729 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0004604 infores:hetionet NCBIGene:51021 biolink:causes MONDO:0012510 infores:monarchinitiative not_provided not_provided HGNC:14048 MONDO:0012510 uuid:86e28ec3-7af9-4689-a690-93b3d498e0f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3172 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0042963 infores:hetionet NCBIGene:8823 biolink:causes MONDO:0010669 infores:monarchinitiative not_provided not_provided HGNC:3672 MONDO:0010669 uuid:e8245ee1-1148-449b-93ff-a86a427d5757 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0002317 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0231686 infores:hetionet CHEBI:5138 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023066 infores:hetionet CHEBI:50275 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2830004 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017658 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1504343 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1504343 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0747979 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0747979 infores:hetionet CHEBI:3699 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0021051 infores:hetionet CAID:CA415085022 biolink:causes MONDO:0010305 infores:clingen CAID:CA415085022 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 "The NM_005629.4:c.1016+2T>C variant occurs within the canonical splice donor of intron 6 of SLC6A8. It is predicted to cause skipping of biologically-relevant-exon 6/13, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two male patients have been reported who are hemizygous for the variant (presumed to be different cases). One of these patients has profound intellectual disability, seizures, and elevated urine creatine/creatinine ratio (PMID 16738945) (PP4). There was ""clinical suspicion"" for a CCDS for the other patient., but results of follow up biochemical testing or brain magnetic resonance spectrscopy are not available (PMID 23660394). There is a ClinVar entry for this variant (Variation ID: 520792). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Verions 1.1.0): PVS1, PP4, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on February 23, 2023)." Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415085022/MONDO:0010305/027 2023-02-23 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:465284 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042514 infores:hetionet CHEBI:63631 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0476280 infores:hetionet CHEBI:9086 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1739363 infores:hetionet NCBIGene:9742 biolink:causes MONDO:0009964 infores:monarchinitiative not_provided not_provided HGNC:29077 MONDO:0009964 uuid:e139a10d-6489-4127-b5a5-6183866682bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes UMLS:C0239591 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0239591 infores:hetionet CHEBI:4027 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0037383 infores:hetionet CHEBI:4779 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0155169 infores:hetionet CHEBI:71255 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0149745 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0008325 infores:hetionet CHEBI:47519 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085649 infores:hetionet CHEBI:6062 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C1443060 infores:hetionet CHEBI:2663 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0004604 infores:hetionet CHEBI:6129 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0033247 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0427008 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0002170 infores:hetionet CHEBI:32221 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0009763 infores:hetionet CHEBI:44241 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0012833 infores:hetionet CHEBI:50381 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0042963 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042131 infores:hetionet CHEBI:28787 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0002962 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0948824 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0948824 infores:hetionet CHEBI:5855 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0149745 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0852913 infores:hetionet CAID:CA4239519 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239519 MONDO:0015967 PMID: Pathogenic PS4, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS3 The c.823C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 275 (p.(Arg275Cys)) of NM_000162.5. This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 24001579, internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 3 informative meioses in 1 family (PP1; PMID: 24001579). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While a study exploring the effect of this variant on protein function has been performed and suggests a possible impact on stability and dimerization, the study does not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 24001579). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 1 copy in the European non-Finnish subpopulation, 1 copy in the African/African American subpopulation, and 1 copy in the South Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, 823C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239519/MONDO:0015967/086 2023-09-20 2023-09-20 Semidominant inheritance HP:0032113 Supports CHEBI:119573 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0030554 infores:hetionet CHEBI:8107 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002063 infores:hetionet CHEBI:7852 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085649 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0031117 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0037274 infores:hetionet CHEBI:47780 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235198 infores:hetionet CHEBI:15544 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0030196 infores:hetionet NCBIGene:3575 biolink:causes MONDO:0012163 infores:monarchinitiative not_provided not_provided HGNC:6024 MONDO:0012163 uuid:88176676-2be5-411d-8ce3-8f5381191f99 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4911 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0015230 infores:hetionet CHEBI:8058 biolink:causes MONDO:0005912 infores:ubergraph knowledge_assertion manual_agent CHEBI:8058 MONDO:0005912 CHEBI:6067 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042963 infores:hetionet CAID:CA10603548 biolink:causes MONDO:0007648 infores:clingen CAID:CA10603548 MONDO:0007648 PMID:12800196 Pathogenic PM5_Supporting, PM2_Supporting, PS4_Moderate, PS3, PVS1_Strong BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS2 The c.1711+1G>C is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). RNA studies have demonstrated that this alteration results in abnormal out of frame splicing (PS3). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in three families meeting HDGC clinical criteria (PS4_Moderate; SCV000329230.6). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS3, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603548/MONDO:0007648/007 2023-10-23 2023-11-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:71255 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0085631 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0036454 infores:hetionet CHEBI:53760 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0235660 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151883 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0039971 infores:hetionet CHEBI:31711 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026821 infores:hetionet CAID:CA8815546 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815546 MONDO:0009290 PMID: Likely Benign BP4, BP7 PM2, PP4 The NM_000152.5:c.1920T>G variant in GAA is a synonymous (silent) variant that does not change the encoded amino acid (p.Pro640=) and is not predicted to impact splicing. This variant has not been reported as disease-causing in an individual with Pompe disease. It has been described as a polymorphism in a cohort of patients with infantile or juvenile-onset Pompe disease from Taiwan (PMID:18458862). It was also reported in two patients in a European cohort with limb-girdle muscle weakness without a second variant (PMID: 29149851). Thus, there is insufficient data to apply PP4. The highest population minor allele frequency in gnomAD v3.1.2 is [0.001534] (8/5184 alleles) in East Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), and lower than the threshold for BS1 (>0.005). Therefore none of the population data codes are met. This variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100 (-2.182) and PhastCons (0.000) (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 255358; 1-star review status) with 10 submitters classifying the variant as uncertain significance (4) or likely benign (6). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815546/MONDO:0009290/010 2024-05-07 2024-12-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:51860 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0547030 infores:hetionet CHEBI:53760 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042024 infores:hetionet CHEBI:9763 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0009676 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0013395 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009806 infores:hetionet NCBIGene:80036 biolink:causes MONDO:0859382 infores:monarchinitiative not_provided not_provided HGNC:17992 MONDO:0859382 uuid:cd25ac30-d201-4191-b84f-9e0de85732de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0039520 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151735 infores:hetionet CHEBI:6532 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0080274 infores:hetionet CHEBI:9086 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0021177 infores:hetionet CAID:CA367397316 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397316 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PS4, PP4 The c.1255T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 419 (p.(Phe419Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 17204055, 20337973, 16602010, internal lab contributors). One of these individuals had a clinical history consistent with GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 17204055, 20337973, 16602010). Another missense variant, c.1256T>C p.Phe419Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397316/MONDO:0015967/086 2023-08-26 2023-08-26 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:42797 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151699 infores:hetionet CHEBI:23765 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0086439 infores:hetionet CHEBI:10119 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018926 infores:hetionet CHEBI:94440 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0007820 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0031117 infores:hetionet CHEBI:9654 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0013144 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0948089 infores:hetionet CHEBI:474180 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0860864 infores:hetionet CHEBI:253342 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0042963 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0029408 infores:hetionet CHEBI:567361 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1384353 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026650 infores:hetionet GO:0017156 biolink:causes GO:0007204 infores:ubergraph knowledge_assertion manual_agent GO:0017156 GO:0007204 CHEBI:7476 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009782 infores:hetionet CHEBI:681569 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0030305 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151626 infores:hetionet CHEBI:3310 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0020649 infores:hetionet CHEBI:31348 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0023380 infores:hetionet CHEBI:92998 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0010200 infores:hetionet CHEBI:8428 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0019209 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042373 infores:hetionet CHEBI:16755 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0232462 infores:hetionet UMLS:C1872203 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0549475 infores:hetionet CHEBI:40237 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0020615 infores:hetionet CAID:CA188969 biolink:causes MONDO:0100488 infores:clingen CAID:CA188969 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting, BP4 BP7, BP5, BS1, BS3, BS4, PM5, PM3, PM4, PM1, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP2, BP3, BA1, PS1, PS4, PS3, PS2 The c.300C>G variant (NM_004360.5) is a synonymous (silent) variant (p.Val100=) that is not predicted by SpliceAI, varSEAK, to impact splicing (BP4). Although this variant is absent in gnomAD v2.1.1 and v3.1 (PM2_Supporting), it has been observed in more than 10 heterozygous individuals with no DCG, SRC tumours, or LBC and whose families do not suggest HDGC (BS2; Ambry Genetics, Invitae, University of Washington). In summary, although there are both pathogenic and benign types of evidence for this variant, the CDH1 VCEP classified the variant as likely benign for DGLBCS based on BS2 alone. (CDH1 VCEP specifications version 3.1; 05/06/2022) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA188969/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3723 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017675 infores:hetionet CHEBI:27779 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0042109 infores:hetionet CHEBI:3207 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C2830004 infores:hetionet CHEBI:79699 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0017181 infores:hetionet CHEBI:68558 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0015967 infores:hetionet CHEBI:27974 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1609512 infores:hetionet CHEBI:44185 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0009676 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0392197 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0013395 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0034063 infores:hetionet CHEBI:3175 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0027441 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0234192 infores:hetionet CHEBI:3223 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0242422 infores:hetionet CAID:CA259740 biolink:causes MONDO:0044970 infores:clingen CAID:CA259740 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4_Supporting, PP1_Moderate PS2, PM6 The m.12201T>C variant in MT-TH has been reported in three families with features of primary mitochondrial disease (PS4_supporting). The first family reported was 5-generation Han Chinese family with late-onset non-syndromic deafness (PMIDs: 21931169, 24920829, 31819004, 32169613). A second case was reported in a Vietnamese cohort of children with non-syndromic hearing loss (https://www.ojhas.org/issue65/2018-1-6.html). The third case was reported in a cohort of individuals with dilated cardiomyopathy (PMID: 34991096). Seventeen of 35 matrilineal relatives in the first reported family exhibited variable severity and age at onset of sensorineural hearing loss and blood heteroplasmy levels correlated with both onset age and symptom severity (PP1_moderate). There are no reported de novo occurrences of this variant to our knowledge. Although there are several occurrences in population databases, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (67th percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). Cybrid studies show different classes of function defects including a decrease in the steady-state level of tRNAHis, diminished respiratory capacity, marked decreases in mtATP levels and membrane potential, increased reactive oxygen species (ROS) production, decreased melting temperature, conformational changes, and instability of the mutated tRNA, and HARS2 overexpression corrected the mitochondrial dysfunction (PS3_moderate; PMIDs: 24920829, 31819004). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA259740/MONDO:0044970/015 2023-04-17 2023-05-19 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:75988 biolink:causes MONDO:0002334 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0376545 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0039971 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0948594 infores:hetionet CHEBI:35778 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0006266 infores:hetionet CHEBI:71219 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0019521 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151849 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0863070 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0863070 infores:hetionet CAID:CA229473 biolink:causes MONDO:0009861 infores:clingen CAID:CA229473 MONDO:0009861 PMID:8406445 Uncertain Significance PP4_Moderate, PM2 PM5, PP3 The c.187A>C (p.Thr63Pro) variant in PAH was detected in 1 Danish PKU patient (Phenylalanine > 600 umol/L). Other causes of hyperphenylalaninemia had been ruled out. (PMID: 8406445). It was in cis with a p.H64N variant (No assertion provided, ClinVar). The c.187A>C variant is absent from ExAC, gnomAD, 1000G, and ESP. There are conflicting predictions of pathogenicity: SIFT:T,D; Polyphen2:D,P; MutationTaster:Disease causing; REVEL:0.768. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229473/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:85161 biolink:causes UMLS:C0429059 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0429059 infores:hetionet CAID:CA512318677 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318677 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.480C>T (p.Asp160=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318677/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:55346 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0027497 infores:hetionet CHEBI:18248 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0037763 infores:hetionet CHEBI:8356 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0031256 infores:hetionet CHEBI:63115 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0344315 infores:hetionet CAID:CA010508 biolink:causes MONDO:0005045 infores:clingen CAID:CA010508 MONDO:0005045 PMID: Pathogenic PP1_Strong, PM5, PS4, PM2_Supporting PP3, PS1 NM_000256.3(MYBPC3):c.1505G>A (p.Arg502Gln) - This variant has been reported in numerous individuals with HCM (statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >20]), and shown to segregate with disease in numerous individuals across multiple families (PMIDs: 9562578, 16566405, 16858239, 18403758, 18533079, 18803133, 18957093, 20433692, 21239446, 22112859, 22857948, 23074333, 24093860, 27532257, 27561770, 27930701, LMM data, OMGL data). Therefore, the PS4 and PP1_Strong criteria have been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Another variant involving this codon (p.Arg502Trp) has been identified in individuals with HCM and is classified as pathogenic by this VCEP (PM5). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated with HCM (PMID: 30696458), but this cannot be combined with PM5. Computational prediction tools are inconclusive about the potential impact of this variant (REVEL score <0.7). In summary, this variant is classified as Pathogenic for HCM in an autosomal dominant manner based on PS4, PP1_Strong, PM5, and PM2_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010508/MONDO:0005045/095 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CAID:CA226523 biolink:causes MONDO:0100368 infores:clingen CAID:CA226523 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.202C>T (p.His68Tyr) is a missense variant that replaces histidine with tyrosine at amino acid 68. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 3.0 x10-7, with 2 alleles /1180040 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.883A>T (p.Lys295Ter) variant or the NM_000329.3(RPE65):c.65T>C (p.Leu22Pro) variant confirmed in trans, which were previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PMID: 32556084, PMID: 11264131, PMID: 9801879, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), salt-and-pepper mottling of the fundus (2 pts), absence of fundus autofluorescence (2 pts), OCT showing retina and RPE atrophy with preservation of the fovea (1 pt), decreased visual acuity( 1 pt), nystagmus (1 pt), and patient participation in a gene therapy trial with subjective improvement as well as improvement in BCVA and increased fundus autofluorescence (2 pts), which together are highly specific for RPE65-related recessive retinopathy [total 9.5 points, PMID: 32556084, PP4_Moderate). The computational predictor REVEL gives a score of 0.839, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited <2 % enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16150724). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226523/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3756 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0043387 infores:hetionet CAID:CA10385264 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385264 MONDO:0100437 PMID: Likely Benign BP4, BP7 PM2, BA1 NM_001034853.2(RPGR):c.2589A>G (p.Glu863=) is a synonymous variant in exon 15 of 15 at codon 863 with no predicted impact on splicing (BP7). The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is absent among hemizygous individuals in gnomAD v4.1.0 but is present in 52 heterozygotes and has been flagged as a low quality site, so no population code is met. In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BP4 and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385264/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:50922 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0011551 infores:hetionet CHEBI:85083 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0311468 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0008370 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0007114 infores:hetionet CAID:CA211250 biolink:causes MONDO:0010726 infores:clingen CAID:CA211250 MONDO:0010726 PMID: Pathogenic PM1, PP3, PS2_Very Strong, PS4, PM2_Supporting The p.Arg133Cys (NM_004992) variant in MECP2 has been reported as an assumed de novo occurrence in at least 4 individuals with Rett Syndrome (PMID: 10814718, PMID: 10991688, PMID: 12707946) (PS2_very-strong). The p.Arg133Cys variant has been observed in at least 4 other individuals with Rett Syndrome (PMID: 10814718, PMID: 10991688, PMID: 12707946, PMID: 17387578, PMID: 16473305) (PS4). The p.Arg133Cys variant occurs in the well-characterized (Methyl-DNA binding [MDB]: aa 90-162) functional domain of the MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg133Cys variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary the p.Arg133Cys variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS2_very-strong, PS4, PM1, PP3, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA211250/MONDO:0010726/016 2022-05-10 2022-07-25 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:73274 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0036572 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0027051 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0684249 infores:hetionet UMLS:C0209366 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0018681 infores:hetionet CHEBI:94848 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0027769 infores:hetionet CHEBI:9086 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1112442 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020538 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0413252 infores:hetionet CHEBI:8772 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0151936 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0002792 infores:hetionet CHEBI:51364 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0040485 infores:hetionet CHEBI:3371 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0023518 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002453 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0037199 infores:hetionet CAID:CA1139667843 biolink:causes MONDO:0010305 infores:clingen CAID:CA1139667843 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PM4, PP4_Strong PM6, PS4 The NM_005629.4:c.942_944del variant in SLC6A8 is predicted to cause a change in the length of the protein (p.Phe315del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4). The variant has been identified in two individuals with clinical symptoms consistent with creatine transporter deficiency. One of them, a male, is reported with elevated urine creatine/creatiine ratio on three occassions, absent creatine peak on brain H-MRS, and reduced creatine uptake in fibroblasts (PMIDs: 17825809, 18925426, 19706062) (PP4_Strong). There is one more independent proband, a female with urine creatine/creatinine ratio 2.3-fold greater than the upper control limit. She presented a severe phenotype similar to affected male patients (PMID: 23234264) (PS4_Supporting). The variant is predicted to be damaging by in silico predictors (PP3), and it is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 983532). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM4, PP3, PS4_Supporting, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 11, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139667843/MONDO:0010305/027 2023-05-11 2024-04-18 X-linked inheritance HP:0001417 Supports CHEBI:100241 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0234215 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038358 infores:hetionet CHEBI:50648 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0162835 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0235234 infores:hetionet CHEBI:167638 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0037317 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0037274 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037822 infores:hetionet NCBIGene:6712 biolink:causes MONDO:0010848 infores:monarchinitiative not_provided not_provided HGNC:11276 MONDO:0010848 uuid:20378bf6-39cf-4179-81c6-c81fc1d04802 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0424790 infores:hetionet CHEBI:2038 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0000731 infores:hetionet CHEBI:480999 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0010200 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0857332 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0857332 infores:hetionet CHEBI:8764 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0029118 infores:hetionet CAID:CA658798979 biolink:causes MONDO:0009290 infores:clingen CAID:CA658798979 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1692del (p.Leu565SerfsTer13) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature, and the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 520974). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798979/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:15367 biolink:causes UMLS:C0151955 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151955 infores:hetionet CHEBI:6909 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0040822 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0518015 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0750466 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0750466 infores:hetionet CHEBI:72297 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0015967 infores:hetionet CHEBI:4445 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0039231 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0857468 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0857468 infores:hetionet CAID:CA320637836 biolink:causes MONDO:0011071 infores:clingen CAID:CA320637836 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS4, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.493G>A (p.Gly165Ser) is a missense variant which has a REVEL score ≥ 0.88 (0.949) (PP3). This variant is located within the Runt Homology Domain (RHD; AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320637836/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45924 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0040822 infores:hetionet CHEBI:6970 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0011603 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0012833 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0027726 infores:hetionet CHEBI:9168 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0014724 infores:hetionet CAID:CA10549558 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549558 MONDO:0010305 PMID: Likely Benign BS2 BS1, PM2, PP3, BP4, PM5 The NM_005629.4:c.1525T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of a cysteine by an arginine at amino acid position 509 (p.Cys509Arg). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population allele frequency is 0.00008761 (4/45655 alleles) in the Admixed American population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 2 hemizygotes in gnomAD v4.1.0.; one in the South Asian population and one in the European non-Finnish population (BS2). The computational predictor REVEL gives a score of 0.376, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 654456). Due to the presence of 2 hemizygotes in gnomAD v4.1.0. in the absence of any evidence for pathogenicity, the consensus of the ClinGen CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549558/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:50305 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0151908 infores:hetionet CHEBI:16335 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0003578 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151479 infores:hetionet CHEBI:63681 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0023518 infores:hetionet CHEBI:3757 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0009676 infores:hetionet CHEBI:6759 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0035232 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0003469 infores:hetionet CHEBI:4735 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0002871 infores:hetionet CAID:CA10558543 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558543 MONDO:0010726 PMID: Benign BA1, BS2 BP4 The allele frequency of the p.Ala281Thr variant in MECP2 (NM_004992.3) is 0.037% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala281Thr variant is observed in at least 8 unaffected individuals (internal database - Invitae) (BS2). In summary, the p.Ala281Thr variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558543/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:4470 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0021053 infores:hetionet CAID:CA7331484 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331484 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, BP2, BA1, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.3:c.1410G>C variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 470 (p.Glu470Asp). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000004957 (8/1613840 alleles) with a highest population minor allele frequency of 0.00009345 (7/74906alleles) in the African/African American population and with multiple alleles present in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.311; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331484/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63631 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0028961 infores:hetionet CAID:CA114369 biolink:causes MONDO:0009861 infores:clingen CAID:CA114369 MONDO:0009861 PMID:8268925PMID:7981714PMID:27620137 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PS3 PM5, PM2 The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% enzyme activity (PS3; PMID: 27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID: 7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Very-strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114369/MONDO:0009861/006 2018-10-01 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:72564 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0600142 infores:hetionet CHEBI:52010 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0013395 infores:hetionet CHEBI:7936 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0086769 infores:hetionet CHEBI:2569 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0015230 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0521839 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0948089 infores:hetionet CHEBI:71272 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0017160 infores:hetionet NCBIGene:51763 biolink:causes MONDO:0024607 infores:monarchinitiative not_provided not_provided HGNC:33882 MONDO:0024607 uuid:2aeb0cc1-5d62-4a34-a511-91eeb5a22989 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0332601 infores:hetionet CHEBI:82960 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085633 infores:hetionet NCBIGene:10406 biolink:causes MONDO:0975835 infores:monarchinitiative not_provided not_provided HGNC:15939 MONDO:0975835 uuid:74a352ac-15d5-48c6-a0f8-a5e0ff7c8503 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40237 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0043094 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0234913 infores:hetionet CHEBI:8378 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0019080 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0853761 infores:hetionet CAID:CA3054201753 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201753 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1 NM_001754.5(RUNX1):c.805+12A>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4) and is predicted by evolutionary conservation algorithms to occur at a site that is not conserved (PhyloP score ≤ 2.0 (-0.23)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201753/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:92923 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0042109 infores:hetionet CHEBI:68558 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0428977 infores:hetionet UMLS:C0657912 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019572 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0018667 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D016724 DB01190_MESH_D016724_1 CAID:CA410150175 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150175 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.848A>C (p.Gln283Pro) is a missense variant in exon 8 of 9, not located in a hotspot or the RHD domain. It is not predicted to affect splicing or protein function ( REVEL score 0.355, SplicaAI score 0.01 ). The variant is absent from population databases. There is no available literature.In summary, the clinical significance of this variant remains uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150175/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:48273 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0042373 infores:hetionet NCBIGene:999 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:1748 MONDO:0016419 uuid:3821de79-01cd-4bc8-bac9-aa011797eaf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17076 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0023530 infores:hetionet CHEBI:3387 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0344232 infores:hetionet CHEBI:15940 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0017181 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0518015 infores:hetionet CHEBI:63622 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0040586 infores:hetionet CHEBI:724125 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0162820 infores:hetionet CHEBI:15367 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035410 infores:hetionet CHEBI:39867 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0037317 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0007642 infores:hetionet NCBIGene:5283 biolink:causes MONDO:0060724 infores:monarchinitiative not_provided not_provided HGNC:8964 MONDO:0060724 uuid:0efb6a58-acb9-4930-91ba-fe4ff7a072f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2688 biolink:causes MONDO:0009876 infores:monarchinitiative not_provided not_provided HGNC:4261 MONDO:0009876 uuid:e4f8adfe-a972-4b75-83ba-64f81384fb12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0017168 infores:hetionet CAID:CA2580098627 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098627 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+18C>T is a splicing variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). No splicing impact or creation of cryptic splice sites is predicted by SSF and MES. Splice AI predicts no impact on splicing (score: 0.01) (BP4). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2146436). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098627/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68595 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0033775 infores:hetionet NCBIGene:10049 biolink:causes MONDO:0021018 infores:monarchinitiative not_provided not_provided HGNC:14888 MONDO:0021018 uuid:f7fa4c8f-24c5-4c85-ade1-b7460ca6ab17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0002878 infores:hetionet CHEBI:194135 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014518 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0162830 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0019158 infores:hetionet CAID:CA294642 biolink:causes MONDO:0007113 infores:clingen CAID:CA294642 MONDO:0007113 PMID: Uncertain Significance BP4 BS2, BP5, BS1 The p.Arg118Gly variant in UBE3A (NM_130838.2) is present in 11 XX and 7 XY individual(s) in gnomAD v4.0 (0.001%) (not sufficient to meet BS1 criteria). The p.Arg118Gly variant is observed and was maternally inherited in 1 unaffected individual (GeneDx internal database) (BS2 not met). Computational analysis prediction tools suggest that the p.Arg118Gly variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Arg118Gly variant was observed in a male patient with seizures, hypotonia, ataxia, and language and motor delays (which improved with seizure control). However, the patient also harbored a reportedly pathogenic SCN1A variant (PMID: 22494076) (BP5 not met). In summary, the p.Arg118Gly variant in UBE3A is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294642/MONDO:0007113/037 2024-04-18 2024-10-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5441 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0021141 infores:hetionet CHEBI:7931 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0032343 infores:hetionet CHEBI:71417 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0003811 infores:hetionet CHEBI:55346 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0042963 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017574 infores:hetionet CHEBI:31485 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0235266 infores:hetionet CHEBI:6375 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014335 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0333641 infores:hetionet CHEBI:27690 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0086565 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0009450 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0021053 infores:hetionet GO:1905304 biolink:causes GO:0048738 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0048738 CHEBI:421707 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0012833 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0005779 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0152227 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005386 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1306889 infores:hetionet CHEBI:39585 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0008031 infores:hetionet CHEBI:100246 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0020615 infores:hetionet CHEBI:134990 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0020458 infores:hetionet CAID:CA017499 biolink:causes MONDO:0007947 infores:clingen CAID:CA017499 MONDO:0007947 PMID: Benign BA1, BP4 BP2 The NM_000138.5 c.79G>A, is a missense variant in FBN1 predicted to cause a substitution of a alanine acid by threonine at amino acid 27 (p.Ala27Thr). This variant has been previously reported in ClinVar as likely benign and benign (Variation ID: 163486). This variant has been identified in 129/19954 (0.65%) of individuals of East Asian origin (MAF: 0.65%) (BA1; https://gnomad.broadinstitute.org/ version 2.1.1). It has been reported in individuals with thoracic aortic aneurysm and/or dissection, and in individuals with clinical features of Marfan syndrome, however it was considered to be a polymorphism (PMID 26272055, 19839986, 16835936). Computational prediction tools and conservation analysis suggests no impact on the protein (REVEL: 0.097) (BP4). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGenFBN1 VCEP: BA1, BP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017499/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:10023 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030312 infores:hetionet CHEBI:28748 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0043352 infores:hetionet CHEBI:100147 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0033774 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0001824 infores:hetionet CHEBI:40303 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0234238 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019360 infores:hetionet CHEBI:92712 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0027424 infores:hetionet CHEBI:50861 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0236000 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011991 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0027947 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0595883 infores:hetionet CHEBI:48947 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0027497 infores:hetionet CHEBI:3996 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0043352 infores:hetionet CHEBI:10023 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0262662 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0027765 infores:hetionet CAID:CA412370012 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370012 MONDO:0010725 PMID:12746437 Likely Pathogenic PM2_Supporting, PS3_Supporting, PP3_Strong PS1, PM5, PM1 NM_000330.4(RS1):c.667T>A (p.Cys223Ser) is a missense variant encoding the substitution of cysteine with serine at amino acid 223. Another missense variant encoding the same amino acid substitution, NM_000330.4(RS1):c.668G>C (p.Cys223Ser) has been classified as likely pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, however, the PS1 code was not used to avoid circularity. Another missense variant in the same codon, NM_000330.4(RS1):c.667T>C (p.Cys223Arg), (PMIDs: 34645606, 10533068, 30652005, 33460243, 16361673) has been classified as pathogenic. However, the present variant has a lower Grantham’s distance (112) than the comparison variant (180), so PM5 is not met. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.958, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control, as well as aberrant immunofluorescent localization of RS1 to the ER/Golgi relative to the wild-type control (PMID: 12746437, PS3_Supporting). This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). However, the PP3_Strong code has been met, which is ineligible to be used in combination with the PM1 code at any strength, so the PM1 code was not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, and PS3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370012/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:3723 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038160 infores:hetionet CHEBI:74947 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023473 infores:hetionet CHEBI:161680 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0010200 infores:hetionet CAID:CA410208054 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208054 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.557T>C (p.Val186Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score ≥ 0.88 (0.954) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208054/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9586 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0086439 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0014868 infores:hetionet CHEBI:6690 biolink:causes UMLS:C1290864 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C1290864 infores:hetionet MONDO:0800180 biolink:causes NCBIGene:1371 infores:ubergraph knowledge_assertion manual_agent MONDO:0800180 HGNC:2321 CHEBI:6897 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0006277 infores:hetionet CHEBI:83527 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0009806 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0011991 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0017160 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0025061 infores:hetionet CHEBI:45081 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0030252 infores:hetionet UNII:7F465U79Q1 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0013604 infores:hetionet CAID:CA401327377 biolink:causes MONDO:0009290 infores:clingen CAID:CA401327377 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3 PP3, PM5, BP4 The NM_000152.5:c.2783A>G in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 928 (p.Tyr928Cys). The variant has been identified in at least four individuals (all Indian where the country of origin is known). One of these patients has symptoms consistent with late onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID: 33741225) (PP4_Moderate). Three individuals are homozygous for the variant (PMID: 33301762, clinical diagnostic laboratory, max 2 x 0.5 points). One individual is compound heterozygous for the variant and c.2015G>T (p.Arg672Leu) (PMID: 29122469, 33741225). The allelic data for this patient will be used in the classification of p.Arg672Leu and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003294 (3/91080 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.664 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 1048589). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 30, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401327377/MONDO:0009290/010 2025-07-30 2025-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true UNII:R43D2573WO biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0221185 infores:hetionet CHEBI:10023 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0947912 infores:hetionet CHEBI:10100 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0085932 infores:hetionet CHEBI:135285 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0086565 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020517 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0232431 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0025061 infores:hetionet CHEBI:2687 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0522153 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0152227 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004892 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0034951 infores:hetionet CHEBI:23359 biolink:causes MONDO:0017859 infores:ubergraph knowledge_assertion manual_agent CHEBI:23359 MONDO:0017859 CHEBI:404903 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0040034 infores:hetionet UNII:R15UI3245N biolink:causes HP:6000264 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0410918 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0026946 infores:hetionet CHEBI:7492 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0017160 infores:hetionet CHEBI:404903 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0015967 infores:hetionet CHEBI:5128 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0344232 infores:hetionet CAID:CA367399685 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399685 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PS3, PP1_Strong, PP4_Moderate, PP3, PM2_Supporting The c.1019G>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to threonine at codon 340 (p.(Ser340Thr)) of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 24804978, 28012402, 34440516, 36257325, internal lab contributors). Furthermore, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% in an incidentally identified pediatric individual during routine screening) (PP4_Moderate; PMID: 24804978). This variant segregated with hyperglycemia with four informative meioses in three families (PP1_Strong; PMID: 28012402, 29927023, 34440516). While this variant has a REVEL score of 0.662, which does not meet ClinGen MDEP cutoffs for PP3 or BP4, the computational splicing predictor SpliceAI gives a score of 0.93 for donor loss, predicting that the variant disrupts the donor site of intron 8 (PP3). Additionally, there is evidence from RNA studies that this non-canonical splicing variant results in aberrant splicing, indicating that this variant impacts protein function (PS3; PMID: 40225161). In summary, c.1019G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS3, PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399685/MONDO:0015967/086 2025-11-18 2025-11-18 Semidominant inheritance HP:0032113 Supports CHEBI:119915 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015734 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0392025 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0034150 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0021053 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0162429 infores:hetionet NCBIGene:3785 biolink:causes MONDO:0013387 infores:monarchinitiative not_provided not_provided HGNC:6296 MONDO:0013387 uuid:6f779ad9-2df2-4f2e-bdb5-0a483cb7015d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46295 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0178298 infores:hetionet CHEBI:8871 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1320474 infores:hetionet CHEBI:681850 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020621 infores:hetionet CHEBI:63598 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151578 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0040435 infores:hetionet CAID:CA382525484 biolink:causes MONDO:0700270 infores:clingen CAID:CA382525484 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PM5_Supporting, PVS1 BP4, PP3 The c.467G>A (p.Trp156*) variant in ATM gene is a nonsense variant predicted to cause premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (p.Arg3047*), as classified by the HBOP VCEP, and it is expected to be more deleterious. This variant has been detected in at least three unrelated individuals with Ataxia-Telangiectasia (PMIDs: 26896183, 34771661, 24954719). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382525484/MONDO:0700270/020 2025-09-25 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports GO:0072095 biolink:causes GO:0060677 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0060677 CHEBI:9086 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes MONDO:0018310 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019621 infores:hetionet CHEBI:28177 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0003123 infores:hetionet CHEBI:72690 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0549249 infores:hetionet CHEBI:5123 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0023518 infores:hetionet CHEBI:75246 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0600142 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0234215 infores:hetionet CHEBI:2788 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0005745 infores:hetionet CHEBI:51860 biolink:causes HP:5200231 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0235013 infores:hetionet CHEBI:77260 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0037763 infores:hetionet CHEBI:28787 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0030252 infores:hetionet CHEBI:2948 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0424790 infores:hetionet CHEBI:144093 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0232462 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020651 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085096 infores:hetionet CHEBI:5138 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C2047937 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0040409 infores:hetionet CAID:CA410202677 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202677 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.408T>A (p.Asn136Lys) is a missense variant which has a REVEL score ≥ 0.88 (0.883) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_Supporting, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202677/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5106 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0234215 infores:hetionet GO:0014041 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:0014041 GO:0048666 CHEBI:2639 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0020651 infores:hetionet CHEBI:2668 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0003467 infores:hetionet CHEBI:50859 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0023380 infores:hetionet CHEBI:231594 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0002884 infores:hetionet CHEBI:68478 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020458 infores:hetionet CHEBI:27504 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0039070 infores:hetionet NCBIGene:80207 biolink:causes MONDO:0009787 infores:monarchinitiative not_provided not_provided HGNC:8142 MONDO:0009787 uuid:0dfafa85-3c01-44cd-9663-586bc10c7bb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0428977 infores:hetionet CHEBI:9139 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0522055 infores:hetionet CHEBI:3213 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0008370 infores:hetionet CHEBI:2675 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0233407 infores:hetionet NCBIGene:3852 biolink:causes MONDO:0024534 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0024534 uuid:ba04ec08-6477-4706-b749-bca05600e0f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0012833 infores:hetionet NCBIGene:6720 biolink:causes MONDO:0100221 infores:monarchinitiative not_provided not_provided HGNC:11289 MONDO:0100221 uuid:27a285f7-ad09-46ee-aba6-06c595ba0977 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31623 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0151692 infores:hetionet CHEBI:63622 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0030554 infores:hetionet CHEBI:94807 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0033774 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0231528 infores:hetionet CAID:CA367398699 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398699 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP2, PP3, PM2_Supporting PS4 The c. variant in the glucokinase gene, GCK, causes an amino acid change of leucine to arginine at codon 386 (p.(Leu386Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Two other missense variants, c.1156C>G p.Leu386Val and c.1157T>C p.Leu386Pro, have been interpreted as pathogenic by the ClinGen MDEP, and p.Leu386Arg has a greater Grantham distance than p.Leu386Val and p.Leu386Pro (PM5_Strong). In summary, c.1157T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Strong, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398699/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:9674 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0022107 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0234215 infores:hetionet CHEBI:135530 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0015672 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853246 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853246 infores:hetionet CHEBI:46557 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0009676 infores:hetionet GO:0042755 biolink:causes MONDO:0015645 infores:ubergraph knowledge_assertion manual_agent GO:0042755 MONDO:0015645 CHEBI:3761 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0027769 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0022650 infores:hetionet CHEBI:64321 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C2363731 infores:hetionet CHEBI:9763 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085649 infores:hetionet CHEBI:78543 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0009782 infores:hetionet CHEBI:9014 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0019158 infores:hetionet NCBIGene:6925 biolink:causes MONDO:0013203 infores:monarchinitiative not_provided not_provided HGNC:11634 MONDO:0013203 uuid:4b3e3036-4fc5-46cb-8c3d-40eb944e8dff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9927 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C1565489 infores:hetionet CHEBI:100147 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0085932 infores:hetionet CHEBI:75246 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020461 infores:hetionet CHEBI:3647 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0043352 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020676 infores:hetionet CHEBI:63635 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013428 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0860801 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0860801 infores:hetionet CHEBI:38940 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020580 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0332534 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0003123 infores:hetionet CHEBI:135930 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0002994 infores:hetionet GO:0060510 biolink:causes CL:0002063 infores:ubergraph knowledge_assertion manual_agent GO:0060510 CL:0002063 CHEBI:83531 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0149931 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0948594 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0392171 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0032285 infores:hetionet CHEBI:46557 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0009763 infores:hetionet CHEBI:31622 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0043352 infores:hetionet CHEBI:9445 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0022346 infores:hetionet GO:0021914 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0021914 GO:0007275 CHEBI:31236 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0455769 infores:hetionet CHEBI:63617 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0039231 infores:hetionet CHEBI:44032 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0043352 infores:hetionet NCBIGene:716 biolink:causes MONDO:0014954 infores:monarchinitiative not_provided not_provided HGNC:1247 MONDO:0014954 uuid:54dd977a-8c2b-46c6-995a-376627267a9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0029408 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C2830004 infores:hetionet CHEBI:167309 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0151723 infores:hetionet CHEBI:520985 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0151744 infores:hetionet CHEBI:231594 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1609512 infores:hetionet CHEBI:8214 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0018834 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0427108 infores:hetionet CHEBI:63630 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0700590 infores:hetionet CAID:CA016969 biolink:causes MONDO:0004994 infores:clingen CAID:CA016969 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.930T>C (p.Tyr310=) variant in the MYH7 gene is 0.23% (33/10334) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016969/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94392 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C2047937 infores:hetionet CHEBI:3732 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151539 infores:hetionet CHEBI:4681 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0018681 infores:hetionet NCBIGene:9230 biolink:causes MONDO:0060624 infores:monarchinitiative not_provided not_provided HGNC:9761 MONDO:0060624 uuid:4d40559f-0a70-46d8-bb73-d59b408fefdf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8346 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0010709 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1112573 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1112573 infores:hetionet CHEBI:27882 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0042963 infores:hetionet CHEBI:18358 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C1619702 infores:hetionet NCBIGene:3420 biolink:causes MONDO:0012943 infores:monarchinitiative not_provided not_provided HGNC:5385 MONDO:0012943 uuid:66593f39-e19c-42b6-ae76-050d862ddf45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2937358 infores:hetionet CHEBI:63580 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1145670 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0013395 infores:hetionet CHEBI:46557 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C1384353 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0038454 infores:hetionet CHEBI:6375 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0034886 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0497247 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0036572 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0242073 infores:hetionet CHEBI:8499 biolink:causes HP:0002486 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0027125 infores:hetionet CHEBI:71417 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0232462 infores:hetionet CHEBI:28593 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0002994 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0006266 infores:hetionet CHEBI:3223 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0019521 infores:hetionet NCBIGene:7546 biolink:causes MONDO:0012322 infores:monarchinitiative not_provided not_provided HGNC:12873 MONDO:0012322 uuid:69e95ad1-9958-4a31-b6c2-9d4c21afcb7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512318955 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318955 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS3, BS4, BS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.165G>A (p.Ala55=) is a synonymous variant predicted by SSF and MES to lead to either an increase or decrease in the canonical splice site score by no more than 10%, with no putative cryptic splice sites created (BP4). Evolutionary conservation algorithms predict the site as being weakly conserved (PhyloP score: 0.77), and the variant is not the reference nucleotide in one primate and/or three mammal species. This variant is also completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318955/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45409 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0232726 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0518015 infores:hetionet CHEBI:84883 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0085633 infores:hetionet NCBIGene:11136 biolink:causes MONDO:0009067 infores:monarchinitiative not_provided not_provided HGNC:11067 MONDO:0009067 uuid:f73d2584-c997-41f0-ad2a-5e20f623d324 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0236065 infores:hetionet CHEBI:10112 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0016204 infores:hetionet CHEBI:7798 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C1260880 infores:hetionet CHEBI:64317 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0002962 infores:hetionet CHEBI:94609 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0036830 infores:hetionet CHEBI:52172 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003862 infores:hetionet UMLS:C0879264 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0013378 infores:hetionet CHEBI:134991 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C1443060 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1306341 infores:hetionet CHEBI:5864 biolink:causes MONDO:0012883 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023487 infores:hetionet CHEBI:84500 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0028084 infores:hetionet CHEBI:7986 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0011991 infores:hetionet CHEBI:4514 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0231218 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013298 infores:hetionet NCBIGene:84168 biolink:causes MONDO:0009263 infores:monarchinitiative not_provided not_provided HGNC:21014 MONDO:0009263 uuid:5678ce81-ebf8-4475-8094-4f67d2501c7a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8430 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0085612 infores:hetionet CHEBI:5558 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0231528 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0023067 infores:hetionet NCBIGene:9897 biolink:causes MONDO:0009073 infores:monarchinitiative not_provided not_provided HGNC:28984 MONDO:0009073 uuid:0b44ab18-f930-45b2-9e0b-430758ee4fde biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0008311 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0085614 infores:hetionet CHEBI:41879 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0041296 infores:hetionet NCBIGene:5158 biolink:causes MONDO:0008099 infores:monarchinitiative not_provided not_provided HGNC:8786 MONDO:0008099 uuid:414d71f1-7099-47b1-befb-61066cc82fe7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167638 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0151798 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0025061 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0001824 infores:hetionet CHEBI:175901 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0024305 infores:hetionet NCBIGene:2627 biolink:causes MONDO:0013770 infores:monarchinitiative not_provided not_provided HGNC:4174 MONDO:0013770 uuid:064ed8f4-05a4-40d8-bf4f-1b8bd0340691 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA261730 biolink:causes MONDO:0021060 infores:clingen CAID:CA261730 MONDO:0021060 PMID:18854871PMID:17586837PMID:29625050PMID:17586837PMID:17586837PMID:17586837PMID:17586837 Pathogenic PS4_Moderate, PS1, PS2, PM1_Strong, PM2, PP3, PP2 PS3, BP5, BP7, BS3, BS4, BS1, PM4, PM5, PM6, PP1, BS2, BP3, BP2, BP4, BP1, BA1 The c.1656G>T (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in one patient and 2 other probands with clinical features of a RASopathy (PS2, PS4_Moderate; PMID 17586837, 18854871). Of note, one of these cases was an affected mother-child duo (PP1 not met; PMID: 17586837). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). This amino acid residue has been designated as a hotspot. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). Of note, the p.Arg552Ser variant in SOS1 has also been a consequence of the c.1656G>C nucleotide change which has been classified as pathogenic (PS1; ClinVar ID 12872). Computational prediction tools and conservation analysis suggest that the p.Arg552Ser variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS1, PM1_Strong, PM2, PS4_Moderate, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261730/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ NCBIGene:3149 biolink:causes MONDO:0010485 infores:monarchinitiative not_provided not_provided HGNC:5004 MONDO:0010485 uuid:1ef4864b-a9d2-420f-a789-51325e84fe9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0206061 infores:hetionet CHEBI:53760 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0004604 infores:hetionet CAID:CA399805123 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805123 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting PP3, BP4 Missense variant NM_000419.5(ITGA2B):c.812C>G (p.Ala271Gly) has been identified in at least 2 probands, including GT6 of PMID: 29675921 meeting the criteria for PP4_strong criteria. Patient GT6 of PMID: 29675921 is compound heterozygous for Ala271Gly and Met724Ile (classified Likely Pathogenic) by the PD VCEP) and Patient 436 of the GT database is compound heterozygous for Ala271Gly and Tyr220Cys (classified Likely Pathogenic by the PD VCEP) (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3_supporting, PM2_supporting, PP4_strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805123/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:38562 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0687713 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0403632 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0037274 infores:hetionet UMLS:C0010592 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013378 infores:hetionet CHEBI:31348 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0032227 infores:hetionet GO:0048349 biolink:causes GO:0048340 infores:ubergraph knowledge_assertion manual_agent GO:0048349 GO:0048340 CHEBI:5847 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0038990 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004610 infores:hetionet CHEBI:47381 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023052 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0857353 infores:hetionet CHEBI:71272 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0002792 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0877047 infores:hetionet CHEBI:101085 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0009806 infores:hetionet CHEBI:51173 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0547030 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0013595 infores:hetionet CHEBI:3996 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0021177 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0042373 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0020538 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0004093 infores:hetionet CHEBI:4909 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0232487 infores:hetionet CHEBI:3534 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0030312 infores:hetionet CHEBI:6916 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0151908 infores:hetionet CHEBI:9123 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002792 infores:hetionet CHEBI:50275 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0018965 infores:hetionet CHEBI:5147 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0220981 infores:hetionet CHEBI:3738 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0012569 infores:hetionet CHEBI:7565 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0235198 infores:hetionet CHEBI:61049 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0010481 infores:hetionet CHEBI:5109 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0151514 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0036508 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0039971 infores:hetionet CHEBI:3732 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0041657 infores:hetionet CAID:CA10586686 biolink:causes MONDO:0021060 infores:clingen CAID:CA10586686 MONDO:0021060 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PP2, PS2 The c.820G>A (p.Glu274Lys) variant in PP1CB is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 274. This variant is absent from gnomAD v2 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP2). This variant was observed in 2 probands with phenotypes consistent with RASopathy (PS4_Supporting; PMID:27681385, GeneDx). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27681385). In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586686/MONDO:0021060/128 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32192 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0017152 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022573 infores:hetionet CHEBI:7478 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0015402 infores:hetionet NCBIGene:9620 biolink:causes MONDO:0030270 infores:monarchinitiative not_provided not_provided HGNC:1850 MONDO:0030270 uuid:32589406-400d-4ef4-86ca-3e4669bd8a36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C2830004 infores:hetionet CHEBI:17303 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0575081 infores:hetionet CAID:CA350399510 biolink:causes MONDO:0015924 infores:clingen CAID:CA350399510 MONDO:0015924 PMID: Pathogenic PP3, PM2_Supporting, PM5, PS4_Moderate, PM1_Strong PP2, BP1, BA1 NM_001204.7 (BMPR2):c.251G>A (p.Cys84Tyr)The BMPR2 c.251G>A variant is a missense variant predicted to cause a cysteine to tyrosine substitution at amino acid 84 (p.Cys84Tyr).The variant is absent from gnomAD controls v.2.1.1 and gnomAD v4.0.0 (PM2_supporting). Four unrelated pulmonary arterial hypertension probands were identified with this variant (PMID: 31727138, PMID: 29650961 and 2 identified in the internal ClinGen Pulmonary Hypertension VCEP database) (PS4_moderate). BMPR2 p.Cys84Tyr is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID: 16429395, PMID: 9886286) (PM1_strong). A different amino acid change at the same position (p.Cys84Phe) was classified as pathogenic (PMID: 21737554, PMID: 28507310) (PM5). Two more amino acid changes, p.Cys84Arg and p.Cys84Gly, were reported to be pathogenic (PMID: 19555857). In silico prediction (REVEL =0.951) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_sup, PS4_mod, PM1_strong, PM5, PP3 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350399510/MONDO:0015924/125 2024-05-01 2024-05-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50223 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151605 infores:hetionet CHEBI:4856 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0043352 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1142412 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0017152 infores:hetionet CHEBI:4495 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0043094 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027947 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042029 infores:hetionet CAID:CA011785 biolink:causes MONDO:0005045 infores:clingen CAID:CA011785 MONDO:0005045 PMID:27532257PMID:7848441PMID:18411228PMID:16199542PMID:15358028PMID:7848441PMID:15858117 Pathogenic PP3, PM1, PM5, PM2, PP1_Strong, PS4 The c.2156G>A (p.Arg719Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:7848441; PMID:16199542; PMID:15358028; PMID:18411228; Partners LMM ClinVar SCV000059421.5; AGCMC Sydney ClinVar SCV000212634.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:7848441; Partners LMM ClinVar SCV000059421.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2155C>T p.Arg719Trp ClinVar Variation ID 14104). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011785/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75722 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0744727 infores:hetionet CHEBI:8863 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0007859 infores:hetionet CHEBI:82960 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0026858 infores:hetionet CHEBI:84883 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0021843 infores:hetionet CHEBI:4708 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0438142 infores:hetionet CHEBI:31711 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C3665347 infores:hetionet CHEBI:6904 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C2830004 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0012254 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0012254 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018991 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004139 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085577 infores:hetionet CHEBI:520985 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0002962 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027765 infores:hetionet CHEBI:28748 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0003467 infores:hetionet CHEBI:9352 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0549249 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0019061 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0428167 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0428167 infores:hetionet CHEBI:9943 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151889 infores:hetionet CHEBI:68478 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151723 infores:hetionet CHEBI:71272 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0271710 infores:hetionet CAID:CA402997146 biolink:causes MONDO:0012999 infores:clingen CAID:CA402997146 MONDO:0012999 PMID: Likely Pathogenic PP4_Strong, PM3, PM2_Supporting, PP3_Moderate The NM_000156.6:c.212T>G variant in GAMT is predicted to result in the substitution of methionine by arginine at amino acid 71 (p.Met71Arg). A Chinese male with clinical features consistent with GAMT deficiency has been reported who has elevated urine guanidinoacetate, low urine creatine, and decreased creatine on brain MRS. This patient is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.418_419del. The variants were confirmed to be in trans by parental testing (Journal of Clinical Pediatrics, 2024 Vol.42 No.12 1039-1046 (article in Chinese), link to article - https://jcp.xinhuamed.com.cn/EN/10.12372/jcp.2024.24e0300) (PP4_Strong, PM3). The computational predictor REVEL gives a score of 0.931 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PM3, PP4_Moderate, PM2_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402997146/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3504 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0042023 infores:hetionet UBERON:0000991 biolink:causes MONDO:0006233 infores:ubergraph knowledge_assertion manual_agent UBERON:0000991 MONDO:0006233 CHEBI:3061 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0018681 infores:hetionet CAID:CA009798 biolink:causes MONDO:0021056 infores:clingen CAID:CA009798 MONDO:0021056 PMID: Likely Benign BS2, BP2, BP1, PM2_Supporting BP4 The c.4906G>T variant in APC is a missense variant predicted to cause the substitution of aspartate by tyrosine at amino acid position 1636 (p.Asp1636Tyr). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in trans with the variant c.3100G>T (p.Glu1034*) (Bonn internal data) which is classified as Pathogenic by the HCCP VCEP in an individual with FAP (BP2). This variant has been observed in heterozygous state in 11 unrelated healthy adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, although there are both pathogenic and benign types of evidence for this variant, the pathogenic/benign evidence is not considered inconsistent with the final Likely Benign classification for FAP. ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, and BP2 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA009798/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5383 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0030196 infores:hetionet CHEBI:4887 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0023530 infores:hetionet NCBIGene:645104 biolink:causes MONDO:0030905 infores:monarchinitiative not_provided not_provided HGNC:33939 MONDO:0030905 uuid:c9c562d6-ad34-4a6d-be77-41f42597bfd8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C1504435 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1504435 infores:hetionet CHEBI:51032 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0152227 infores:hetionet CAID:CA290951 biolink:causes MONDO:0100040 infores:clingen CAID:CA290951 MONDO:0100040 PMID: Benign BA1 BP7 The p.Ser441= variant in FOXG1 has an allele frequency of 0.049% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Ser441= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA290951/MONDO:0100040/016 2022-02-18 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:5165 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0340865 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005152 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020635 infores:hetionet CHEBI:28487 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C2830004 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0427108 infores:hetionet CAID:CA314620 biolink:causes MONDO:0100040 infores:clingen CAID:CA314620 MONDO:0100040 PMID: Pathogenic PS4_Moderate, PS2_Very Strong, PP3, PM2_Supporting The p.Ser234Phe variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in at least 3 individuals with FOXG1-disorder (Internal database – Ambry, PMID 37308910) (PS2_Very Strong). The p.Ser234Phe variant has been observed in at least 3 individuals with FOXG1-disorder (Internal database – Invitae, PMID 26633542, 38539105) (PS4_Moderate). The p.Ser234Phe variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ser234Phe variant in FOXG1 is classified as Pathogenic for FOXG1-disorder based on the ACMG/AMP criteria (PS2_Very Strong, PS4_Moderate, PM2_Supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314620/MONDO:0100040/035 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6931 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C1527344 infores:hetionet CHEBI:63577 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0037763 infores:hetionet CHEBI:465284 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042963 infores:hetionet CHEBI:3125 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0017178 infores:hetionet CHEBI:7823 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0018524 infores:hetionet CHEBI:6759 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0344232 infores:hetionet CAID:CA2580098654 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098654 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.97+10dup is an intronic variant which has a SpliceAI score ≤ 0.20 (0.05) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0; -0.04, 0.18) (BP7). This variant is not present in any population database (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098654/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8107 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0037199 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022893 infores:hetionet CHEBI:4798 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0027849 infores:hetionet CHEBI:4445 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0235063 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0036508 infores:hetionet CHEBI:8890 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0004093 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0013395 infores:hetionet CHEBI:39867 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009421 infores:hetionet CHEBI:50378 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0085631 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0349506 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0242379 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0031212 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0020461 infores:hetionet CHEBI:45863 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019209 infores:hetionet CHEBI:9927 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0008031 infores:hetionet CHEBI:50305 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0021368 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1456865 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1456865 infores:hetionet CHEBI:8069 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0003467 infores:hetionet CHEBI:10023 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0497156 infores:hetionet CHEBI:32315 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085628 infores:hetionet CHEBI:31413 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C1760428 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0002453 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0549635 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549635 infores:hetionet CHEBI:408174 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0003467 infores:hetionet CHEBI:4027 biolink:causes HP:0011227 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0742906 infores:hetionet CHEBI:63630 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0012569 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0041582 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0235416 infores:hetionet CHEBI:8024 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013144 infores:hetionet CHEBI:3044 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0020458 infores:hetionet CHEBI:367163 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0013404 infores:hetionet CAID:CA228433 biolink:causes MONDO:0019565 infores:clingen CAID:CA228433 MONDO:0019565 PMID: Likely Benign BP4, BP5, BS1 BS2, PP4, PP1, BP2, BA1, PS4, BS3 NM_000552.5(VWF):c.3686T>G is a missense variant encoding a substitution of valine by glycine at position 1229. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID: 8134377, PMID: 17190853, PMID: 31064749, PMID: 16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID: 8134377, PMID: 2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least three control individuals (PMID: 22197721). The computational predictor REVEL gives a score of 0.149, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID: 16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01529 (based on 1200/74796 alleles, with 10 homozygotes) in the African/African-American population, which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228433/MONDO:0019565/090 2024-08-12 2024-08-12 Undetermined mode of inheritance Contradicts true NCBIGene:2549 biolink:causes MONDO:0011553 infores:monarchinitiative not_provided not_provided HGNC:4066 MONDO:0011553 uuid:bdff391c-476f-4d43-8432-a62140ca487d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0019209 infores:hetionet CHEBI:8327 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0235416 infores:hetionet CHEBI:61049 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013428 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0020651 infores:hetionet CAID:CA2499307108 biolink:causes MONDO:0012999 infores:clingen CAID:CA2499307108 MONDO:0012999 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PVS1_Moderate, PM3_Supporting The NM_000156.6:c.610_611delAGinsGAA (p.Arg204Glufs*63) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). This variant has been detected in one individual with elevated plasma GAA with low serum creatine, and decreased creatine peak with slight elevation of GAA peak on brain MRS, with full GAMT gene sequencing performed (PMID: 19027335) (PP4_Strong). This patient is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.402C>G (p.Tyr134Ter) (ClinVar Variation ID: 947458); phase not confirmed (PMID: 19027335) (0.5pts) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 8.475e-7 (1/1179880 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2570640). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Moderate, PM2_Supporting, PM3_Supporting, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499307108/MONDO:0012999/026 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119486 biolink:causes HP:0000528 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0003119 infores:hetionet CHEBI:184555 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0404521 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0004623 infores:hetionet CHEBI:44915 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0080274 infores:hetionet NCBIGene:116931 biolink:causes MONDO:0030030 infores:monarchinitiative not_provided not_provided HGNC:16050 MONDO:0030030 uuid:1b6b1023-d2d8-4316-ad69-6d89eeca1205 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0019348 infores:hetionet CHEBI:31711 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0040264 infores:hetionet CHEBI:9613 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0027497 infores:hetionet CHEBI:41879 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0036974 infores:hetionet CHEBI:7581 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0020649 infores:hetionet CHEBI:42068 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0016382 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0036572 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0006444 infores:hetionet CHEBI:3757 biolink:causes UMLS:C1696574 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1696574 infores:hetionet CHEBI:5959 biolink:causes UMLS:C1142277 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C1142277 infores:hetionet NCBIGene:1272 biolink:causes MONDO:0012929 infores:monarchinitiative not_provided not_provided HGNC:2171 MONDO:0012929 uuid:b05e0a3a-a5a9-47f0-9d0b-677e39e264e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019079 infores:hetionet CHEBI:135613 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0043144 infores:hetionet CHEBI:253342 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0232487 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235416 infores:hetionet CHEBI:5106 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0015672 infores:hetionet CHEBI:3077 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0023518 infores:hetionet CHEBI:50922 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0000731 infores:hetionet CHEBI:10124 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0040264 infores:hetionet CHEBI:291342 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0424295 infores:hetionet CHEBI:4514 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0278134 infores:hetionet CHEBI:6715 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0242422 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0009946 infores:hetionet GO:0090173 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0090173 GO:0019953 CHEBI:7983 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0085631 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232431 infores:hetionet CHEBI:3441 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C2047937 infores:hetionet CHEBI:3757 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0041657 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0948089 infores:hetionet CHEBI:42068 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0041582 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003864 infores:hetionet CHEBI:4798 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0231530 infores:hetionet GO:1902897 biolink:causes GO:0001941 infores:ubergraph knowledge_assertion manual_agent GO:1902897 GO:0001941 CHEBI:15640 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0011991 infores:hetionet CHEBI:16469 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0404521 infores:hetionet CHEBI:127342 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0017178 infores:hetionet CHEBI:8024 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0033774 infores:hetionet CHEBI:31236 biolink:causes HP:0012651 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877217 infores:hetionet CHEBI:9757 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0042963 infores:hetionet CAID:CA10584720 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584720 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PS3, PS1, PVS1_Moderate, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS2, BS1, BS3, BS4, BP5, BP7, PM5, PM1, PM4, PM3, PM6, BS2, PP1, PP2, PP3 The NM_000527.5(LDLR):c.1A>T (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS1, PS3, PM2, PVS1_Moderate, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PS1 - One more missense variant that leads to the same amino acid change: (1)NM_000527.5(LDLR):c.1A>C (p.Met1Leu) (ClinVar ID 250966) - Pathogenic by these guidelines--- variant is classified as Pathogenic, so PS1 is Met.PS3 - Level 1 (and other levels) FS: Graça et al., 2021 (PMID 34572405) Heterologous cells (CHO), FACS, luciferase and microscopy assays: FACS: 10% cell surface LDLR, 3% binding and 8% uptake; luciferase : 1% luciferase construct activity; microscopy: 5-10% LDLR expression and 5-10% LDLR activity.--- functional study in heterologous cells results in expression, binding and uptake less than 70% of wild-type, so PS3 is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PVS1_moderate - Variant is in initiation codon, so PVS1_Moderate is Met.PS4_supporting - Variant meets PM2 and was identified in:- 1 index case with DLCN score above 6 from University of British Columbia, Canada;- 1 index case with Simon-Broome criteria of possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 1 index case with Simon-Broome criteria of possible FH (Inclusion: LDL-C level>95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, and a family history of hypercholesterolemia and cardiovascular disease) from PMID: 21382890 (van der Graaf et al., 2011), The Netherlands;- 1 index case with Simon-Broome criteria of at least possible FH from PMID: 17094996 (Tosi et al., 2007), UK.--- 4 cases, so PS4_Supporting is MetPP4 - Variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584720/MONDO:0007750/013 2022-03-17 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:127780 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0015672 infores:hetionet CHEBI:40050 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0002994 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0497327 infores:hetionet CHEBI:3207 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0026821 infores:hetionet CHEBI:7581 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0015672 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0035085 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0035085 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0948594 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1619712 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0234913 infores:hetionet CHEBI:8888 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033845 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0027765 infores:hetionet CHEBI:142290 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0011603 infores:hetionet GO:0061001 biolink:causes GO:0048667 infores:ubergraph knowledge_assertion manual_agent GO:0061001 GO:0048667 CHEBI:75722 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0700184 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0948089 infores:hetionet CAID:CA1619909 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619909 MONDO:0800472 PMID:17363580PMID:27243976 Uncertain Significance PP3, PM2_Supporting, PM3 PP1, BP4, BA1, PM5, PM1, PM4, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.985G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 329 (p.Gly329Ser). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00008918 (4 alleles out of 44,852), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.682, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) (PMIDs: 17363580, 27243976) or the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27243976). This variant has been identified in 2 individuals with a CYP1B1-related phenotype. One individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) and the other is homozygous (non-consanguineous) (PMID: 21850185). Total proband points = 1, meeting PM3. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619909/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45783 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0236124 infores:hetionet CHEBI:70746 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0004604 infores:hetionet CAID:CA410202721 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202721 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.388G>A (p.Val130Ile) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202721/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3752 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0233494 infores:hetionet CHEBI:37924 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0085641 infores:hetionet CHEBI:7494 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1443060 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0853117 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0037274 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0027769 infores:hetionet CHEBI:77733 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0002170 infores:hetionet CHEBI:5959 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0040586 infores:hetionet CHEBI:85161 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0013384 infores:hetionet CHEBI:5165 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0520966 infores:hetionet CHEBI:6437 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0042029 infores:hetionet CHEBI:36791 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0231528 infores:hetionet NCBIGene:83479 biolink:causes MONDO:0008267 infores:monarchinitiative not_provided not_provided HGNC:25360 MONDO:0008267 uuid:389acbea-f5e7-45a9-92ae-745c986f1a8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0456909 infores:hetionet CHEBI:391960 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C2830004 infores:hetionet CHEBI:9605 biolink:causes MONDO:0041656 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C1536220 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0424813 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0424813 infores:hetionet CHEBI:75922 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0003873 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0013395 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030305 infores:hetionet CHEBI:5864 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0038220 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0854121 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0854121 infores:hetionet CAID:CA16602456 biolink:causes MONDO:0021060 infores:clingen CAID:CA16602456 MONDO:0021060 PMID: Pathogenic PP2, PP3, PS3_Supporting, PS2_Very Strong, PM2_Supporting, PM1, PM5, PS4_Moderate BA1, BS1 The NM_002755.4:c.370C>T variant in MAP2K1 is a missense variant predicted to cause substitution of proline by serine at amino acid 124 (p.Pro124Ser). This variant was absent from gnomAD v2.1.1 (PM2_Supporting). The computational prediction tool REVEL gives a score of 0.855, suggesting that this variant may impact the protein (PP3). The p.Pro124Ser variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical domain of MAP2K1 (AA 124-134, PM1). Furthermore, 4 different (likely) pathogenic variants at this residue (Pro124Leu, Pro124Arg, Pro124Ala, Pro124Gln) have been identified in several patients with RASopathies (PM5). This variant has been observed in at least 7 probands with a RASopathy, of which 3 were reported as a de novo occurrence with confirmed parental relationships and 1 was assumed to be de novo (PS2_VeryStrong, PS4_Moderate; PMIDs: 36777711, 32978145, GeneDx, LabCorp, ClinVar SCV000572401.6, SCV003316958.3). In vitro functional studies showed that the p.Pro124Ser variant led to ERK1/2 phosphorylation indicating that the mutant was constitutively active (PS3_Supporting; PMID: 22197931). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PM1, PM5, PS3_Supporting PM2_Supporting, PP2, PP3 (Specification Version 2.3, 1/10/2025) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602456/MONDO:0021060/045 2025-01-10 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CAID:CA748913376 biolink:causes MONDO:0011071 infores:clingen CAID:CA748913376 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-7A>C is a synonymous variant with a SpliceAI score of 0.01, which is ≤ 0.20 (BP4). Additionally, evolutionary conservation algorithms predict the site as being not conserved, with a PhyloP score of -0.14, which is ≤ 2.0 (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA748913376/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45409 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0853692 infores:hetionet CHEBI:50648 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0043352 infores:hetionet CHEBI:8461 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0232462 infores:hetionet CHEBI:7476 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038325 infores:hetionet CHEBI:10101 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011603 infores:hetionet CHEBI:32315 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0004930 infores:hetionet CHEBI:8888 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085639 infores:hetionet CHEBI:17474 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042256 infores:hetionet CHEBI:231594 biolink:causes MONDO:0000918 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0014179 infores:hetionet CHEBI:7494 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0043094 infores:hetionet CHEBI:63599 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0029118 infores:hetionet CHEBI:75045 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0037763 infores:hetionet CHEBI:32221 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0235267 infores:hetionet CHEBI:7444 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0007398 infores:hetionet CHEBI:47519 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151474 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0021053 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0267792 infores:hetionet CHEBI:7773 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0023066 infores:hetionet CHEBI:17303 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0015672 infores:hetionet CHEBI:6888 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0027497 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0233494 infores:hetionet CHEBI:63611 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003126 infores:hetionet CHEBI:5004 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0232462 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0349506 infores:hetionet CHEBI:6710 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0038325 infores:hetionet CHEBI:63611 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0043352 infores:hetionet NCBIGene:85452 biolink:causes MONDO:0859353 infores:monarchinitiative not_provided not_provided HGNC:29368 MONDO:0859353 uuid:1d27a5bf-094c-4a37-a98f-120b1c8dd6ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9587 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C1257843 infores:hetionet CHEBI:47780 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0392156 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0021400 infores:hetionet CHEBI:16335 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0003811 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0003864 infores:hetionet CHEBI:47780 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0236024 infores:hetionet CHEBI:5165 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0037763 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0038362 infores:hetionet NCBIGene:2201 biolink:causes MONDO:0007363 infores:monarchinitiative not_provided not_provided HGNC:3604 MONDO:0007363 uuid:ecd38aa0-5b27-4085-a48e-3ae4c8ae47d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0221423 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0026113 infores:hetionet CHEBI:7514 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0037763 infores:hetionet CHEBI:8871 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0858635 infores:hetionet CHEBI:127342 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0393760 infores:hetionet CHEBI:453011 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0002170 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0027441 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0014745 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014745 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0027769 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0456909 infores:hetionet CHEBI:6888 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0237849 infores:hetionet CHEBI:3181 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0036974 infores:hetionet CHEBI:7640 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0011615 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0031039 infores:hetionet CHEBI:28148 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0030554 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020557 infores:hetionet CAID:CA10014289 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014289 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP3, BP1, BP2, BS1, BS3, BS4, BP5, PM2, PVS1, PM6, PM4, PM5, PM1, PM3, BS2, PP4, PP2, PP3, PP1 This synonymous variant (no REVEL score applicable) has SpliceAI scores ≤0.20 (0.01) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score < 2.0 (0.522) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014289/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0065374 biolink:causes UMLS:C0877664 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0877664 infores:hetionet CHEBI:63611 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0005818 infores:hetionet CHEBI:10650 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030232 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0018799 infores:hetionet CHEBI:3568 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011644 infores:hetionet CHEBI:77260 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0016658 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151849 infores:hetionet CHEBI:51860 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0039231 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0497247 infores:hetionet CHEBI:167638 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0428977 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0017160 infores:hetionet CHEBI:3723 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036973 infores:hetionet GO:0141155 biolink:causes GO:0006414 infores:ubergraph knowledge_assertion manual_agent GO:0141155 GO:0006414 CHEBI:17688 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0027765 infores:hetionet CHEBI:94807 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0009450 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0035455 infores:hetionet CHEBI:68647 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020546 infores:hetionet CHEBI:39669 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0003123 infores:hetionet CHEBI:16586 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0151786 infores:hetionet CHEBI:31547 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0041657 infores:hetionet CHEBI:63599 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0018681 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005091 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1175175 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017178 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0011334 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0025202 infores:hetionet NCBIGene:546 biolink:causes MONDO:0010663 infores:monarchinitiative not_provided not_provided HGNC:886 MONDO:0010663 uuid:01d0a6ee-66c8-4f6c-adb2-45d6b5bdb633 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63599 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0029132 infores:hetionet CAID:CA007168 biolink:causes MONDO:0100316 infores:clingen CAID:CA007168 MONDO:0100316 PMID:16987820 Likely Pathogenic PVS1, PP4 BA1, PS3, PS4, BS1, PM2, PM3 NM_000218.3(KCNQ1):c.477+1G>A is a splicing variant predicted to cause out-of-frame skipping of exon 2, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds, congenital deafness and a swimming-associated event, which together are highly specific for long QT syndrome 1 (PP4; PMID:16987820). This variant has been reported in homozygosity in one proband with Jervell and Lange-Nielsen syndrome that was reported to have both a long QT interval and congenital deafness (PMID: 16987820), however PM3_Supporting is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting). This variant has been shown to disrupt KCNQ1 function in two required experimental assays, including RNA Metabolism and automated patch clamp (PMID: 16987820), however, PS3_Supporting is not met since the variant has already met PVS1. In summary, this variant has been classified as likely pathogenic for long QT syndrome 1 according to the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel: PVS1 and PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007168/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6715 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0156404 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0028949 infores:hetionet GO:0072039 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:0072039 GO:0072028 CHEBI:6078 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0013404 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0339916 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0027651 infores:hetionet CHEBI:2904 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0476273 infores:hetionet CHEBI:5790 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0039070 infores:hetionet UMLS:C1144403 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0042963 infores:hetionet NCBIGene:23533 biolink:causes MONDO:0014084 infores:monarchinitiative not_provided not_provided HGNC:30035 MONDO:0014084 uuid:59028aae-d53c-48c3-a6b1-03f89044ed10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0013922 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0032584 infores:hetionet CHEBI:47898 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026827 infores:hetionet CHEBI:3996 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0028643 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018790 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0233494 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0403632 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0152029 infores:hetionet CHEBI:9137 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085649 infores:hetionet GO:1900825 biolink:causes GO:0086001 infores:ubergraph knowledge_assertion manual_agent GO:1900825 GO:0086001 CHEBI:48390 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0039621 infores:hetionet CHEBI:135925 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0001807 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0038362 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0152517 infores:hetionet NCBIGene:6521 biolink:causes MONDO:0008494 infores:monarchinitiative not_provided not_provided HGNC:11027 MONDO:0008494 uuid:90f1acc4-c63e-4c06-aaad-145a83b73c27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042373 infores:hetionet NCBIGene:54583 biolink:causes MONDO:0012353 infores:monarchinitiative not_provided not_provided HGNC:1232 MONDO:0012353 uuid:fc399914-62bd-4fea-9e9f-f24eb33f406d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3084 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0423153 infores:hetionet CHEBI:63717 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0011991 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0018801 infores:hetionet CHEBI:7936 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0547030 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0344304 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0344304 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003123 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0085605 infores:hetionet CHEBI:8499 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0234238 infores:hetionet CHEBI:63638 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026826 infores:hetionet CHEBI:4530 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013404 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0232459 infores:hetionet CHEBI:9622 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0004093 infores:hetionet CHEBI:44032 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0013428 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0009319 infores:hetionet CHEBI:6076 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0231528 infores:hetionet GO:0072043 biolink:causes GO:0072087 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072087 GO:0060319 biolink:causes CL:0002355 infores:ubergraph knowledge_assertion manual_agent GO:0060319 CL:0002355 CHEBI:9635 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0003811 infores:hetionet NCBIGene:57589 biolink:causes MONDO:0032901 infores:monarchinitiative not_provided not_provided HGNC:17686 MONDO:0032901 uuid:32c88c23-d75d-4765-a5ea-858fa92b29d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0151773 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0041912 infores:hetionet CHEBI:3423 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1142499 infores:hetionet CHEBI:194135 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0220870 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0857199 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0857199 infores:hetionet CHEBI:404903 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0476273 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020615 infores:hetionet CHEBI:3506 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0040425 infores:hetionet CHEBI:50859 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0852911 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0233414 infores:hetionet CHEBI:161680 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0151904 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0233571 infores:hetionet CAID:CA415087081 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087081 MONDO:0010305 PMID: Uncertain Significance PS3_Supporting, PM2_Supporting PP3, BP4 The NM_005629.4:c.1381A>G variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a methionine for a valine at amino acid position 461 (p.Met461Val). This variant has not been reported in the published literature in individuals with creatine transporter deficiency. This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.713 which is neither above the threshold of 0.75 for PP3 nor below the threshold of 0.2 (BP4), such that neither PP3 nor BP4 applies. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087081/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:74947 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0017563 infores:hetionet CHEBI:9137 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0034152 infores:hetionet CHEBI:94501 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0041657 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0009806 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0684249 infores:hetionet CHEBI:70718 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0020621 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0042571 infores:hetionet CHEBI:31644 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0014742 infores:hetionet CHEBI:5613 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011991 infores:hetionet CHEBI:6339 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0917801 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0161679 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0392620 infores:hetionet CHEBI:92998 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151205 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019163 infores:hetionet CHEBI:63791 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085649 infores:hetionet CAID:CA410203328 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203328 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 The c.351+2T>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and is expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203328/MONDO:0011071/008 2022-03-24 2022-07-05 Autosomal dominant inheritance HP:0000006 Supports UNII:D27V6190PM biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0037274 infores:hetionet CHEBI:48131 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0020555 infores:hetionet CAID:CA6831829 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831829 MONDO:0015967 PMID: Likely Benign BS3_Supporting, PM1_Supporting, BS1, PP3 PS4, PM2, PP4 The c.766T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 256 (p.Ser256Thr) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003551, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.782, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Ser256Thr protein has DNA binding above 50% of wild type and normal nuclear localization and transactivation, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 12574234). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 12574234, internal lab contributors). One of these individuals had a calculated MODY probability <50%, and the MODY probability could not be calculated in the other two due to limited clinical information, and PP4 could not be applied. In summary, c.766T>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, BS1, PP3, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831829/MONDO:0015967/017 2022-04-13 2022-07-12 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:G4PX8C4HKV biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020557 infores:hetionet CHEBI:9588 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0013491 infores:hetionet CHEBI:45081 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0014457 infores:hetionet CHEBI:8207 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0016204 infores:hetionet CHEBI:3216 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020578 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0149931 infores:hetionet CHEBI:3752 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0234233 infores:hetionet CHEBI:71219 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0041657 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149904 infores:hetionet CHEBI:50730 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0014742 infores:hetionet CHEBI:68841 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0030252 infores:hetionet CHEBI:31236 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0744727 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0233494 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1443060 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0439857 infores:hetionet CHEBI:31199 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0039446 infores:hetionet CHEBI:36791 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039070 infores:hetionet CHEBI:6062 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0040264 infores:hetionet CHEBI:29688 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0015230 infores:hetionet CHEBI:6367 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011603 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0239375 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035258 infores:hetionet CHEBI:94385 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0011991 infores:hetionet CHEBI:16335 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C1096250 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0018213 infores:hetionet CAID:CA367398930 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398930 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting The c.1113C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 371 (p.(Cys371Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9/10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398930/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:42355 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0022107 infores:hetionet CHEBI:10125 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235996 infores:hetionet CHEBI:3732 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014591 infores:hetionet CHEBI:8764 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018800 infores:hetionet CHEBI:9150 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0151798 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038814 infores:hetionet CHEBI:3994 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0037763 infores:hetionet CHEBI:114785 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0008031 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0036572 infores:hetionet UMLS:C0010592 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0003862 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013395 infores:hetionet CHEBI:7577 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0018418 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0574067 infores:hetionet CHEBI:5130 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027796 infores:hetionet CHEBI:2567 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0011991 infores:hetionet CHEBI:7573 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151578 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0853813 infores:hetionet CHEBI:39585 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0023222 infores:hetionet CAID:CA16020799 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020799 MONDO:0009861 PMID:26322415PMID:26322415 Pathogenic PM3, PP4_Moderate, PVS1, PM2_Supporting The c.478C>T (p.Gln160*) variant in PAH has been reported in an individual with mild hyperphenylalaninemia (BH4 deficiency excluded) in trans with a known pathogenic variant (p.R241C; PMID:26322415). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, ESP. It is a nonsense variant predicted to undergo NMD (exon 5 of 13, amino acid 160 of 453). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020799/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:7037 biolink:causes MONDO:0014760 infores:monarchinitiative not_provided not_provided HGNC:11763 MONDO:0014760 uuid:7b7266b6-9f0b-4d51-a87e-b9d78964858f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0002962 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020517 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0178298 infores:hetionet CHEBI:3223 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C2363730 infores:hetionet CHEBI:4708 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0236075 infores:hetionet CHEBI:168396 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020443 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0037278 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0001622 infores:hetionet CHEBI:45863 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018965 infores:hetionet CHEBI:3403 biolink:causes MONDO:0006996 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0040127 infores:hetionet NCBIGene:338 biolink:causes MONDO:0007751 infores:monarchinitiative not_provided not_provided HGNC:603 MONDO:0007751 uuid:1b431cdf-b1cc-409a-aed2-31ef5e0cb5e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0233472 infores:hetionet CHEBI:38940 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0852911 infores:hetionet NCBIGene:4137 biolink:causes MONDO:0010857 infores:monarchinitiative not_provided not_provided HGNC:6893 MONDO:0010857 uuid:cf05e203-2bd4-4673-bd98-fb21397cf09c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8461 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0011991 infores:hetionet CHEBI:5165 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013456 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151735 infores:hetionet CHEBI:100246 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0744727 infores:hetionet CHEBI:5778 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0027424 infores:hetionet UMLS:C0011701 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0687713 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0041969 infores:hetionet CHEBI:36795 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0278106 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0178298 infores:hetionet CHEBI:77260 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0232493 infores:hetionet GO:0044470 biolink:causes GO:0007596 infores:ubergraph knowledge_assertion manual_agent GO:0044470 GO:0007596 CHEBI:135530 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0010692 infores:hetionet CHEBI:9598 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0231528 infores:hetionet NCBIGene:785 biolink:causes MONDO:0013464 infores:monarchinitiative not_provided not_provided HGNC:1404 MONDO:0013464 uuid:18d5e7f0-a391-405d-847d-b59e707e9bc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0041969 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0004936 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020649 infores:hetionet CHEBI:68841 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0233471 infores:hetionet CHEBI:83804 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0005747 infores:hetionet CHEBI:3181 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0018824 infores:hetionet CHEBI:6847 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0042109 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0007642 infores:hetionet GO:0008359 biolink:causes GO:0007314 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0007314 CHEBI:8707 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0003864 infores:hetionet NCBIGene:93233 biolink:causes MONDO:0014030 infores:monarchinitiative not_provided not_provided HGNC:26560 MONDO:0014030 uuid:66789a4e-fd0b-442f-a189-571db5cfda22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0428977 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0013395 infores:hetionet GO:0021863 biolink:causes CL:1000042 infores:ubergraph knowledge_assertion manual_agent GO:0021863 CL:1000042 NCBIGene:7252 biolink:causes MONDO:0010139 infores:monarchinitiative not_provided not_provided HGNC:12372 MONDO:0010139 uuid:7ca7f03d-611e-43b2-b7b0-ba57ad8ec6b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0235315 infores:hetionet CHEBI:8378 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0267940 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0018802 infores:hetionet NCBIGene:3572 biolink:causes MONDO:0030681 infores:monarchinitiative not_provided not_provided HGNC:6021 MONDO:0030681 uuid:0baeeca5-68b9-4e0c-aa62-968553d1e201 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0040822 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0585186 infores:hetionet CHEBI:37941 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0015230 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0236068 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0003123 infores:hetionet CHEBI:135351 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C3665386 infores:hetionet CHEBI:9587 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0011603 infores:hetionet CHEBI:28001 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0238106 infores:hetionet CHEBI:79699 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C3495920 infores:hetionet CAID:CA915940267 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940267 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.2374del (p.Val792TrpfsTer34) frameshift variant leads to to a premature stop codon in biologically-relevant-exon 25/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient GT1 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severly reduced, as measured by flow cytometry while αIIb was absent on Western blot and β3 was decreased. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). GT1 of PMID: 25373348 is homozygous for c.2374del (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 01/18/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940267/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UBERON:0002346 biolink:causes MONDO:0005462 infores:ubergraph knowledge_assertion manual_agent UBERON:0002346 MONDO:0005462 CAID:CA399805605 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805605 MONDO:0100326 PMID:15219201 Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS3 The c.605T>G variant in ITGA2B is a missense variant predicted to cause substitution of phenylalanine by cystine at amino acid 202. At least one patient (Proband in PMID:15219201) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). The variant has been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus two affected family members, all with the homozygous genotype with the c.605T>G variant. (PP1_moderate; PMID:15219201). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Surface expression of αIIbβ3 measured by flow cytometry in CHO cells transiently co-transfected with p.Phe202Cys αIIb and wild type β3 showed absent expression (<5%) WT levels, indicating that this variant impacts protein function (PMID:15219201)(PS3). The computational predictor REVEL gives a score of 0.781, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PP1_moderate, PP4_moderate, PP3, PM2_supporting. (VCEP specifications version 2; date of approval 03/07/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805605/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5127 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0011616 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0036572 infores:hetionet CHEBI:101278 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C2747891 infores:hetionet CHEBI:9667 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0242429 infores:hetionet CHEBI:5106 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0027441 infores:hetionet CAID:CA397722888 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722888 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4 PM5, PM1, PM4, PS1, PVS1, BP7 The c.430C>G variant in ACADVL is a missense variant predicted to cause substitution of leucine by valine at amino acid 144 (p.Leu144Val). One patient with this variant had a 10% residual enzyme activity of wildtype measured from lymphocytes, which is highly specific for VLCAD deficiency (PP4_supporting, PMID:30194637). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: (PM2_Supporting,PP3, PP4_supporting) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722888/MONDO:0008723/021 2022-09-23 2022-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6067 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009806 infores:hetionet CHEBI:2636 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0019521 infores:hetionet CAID:CA046762 biolink:causes MONDO:0005045 infores:clingen CAID:CA046762 MONDO:0005045 PMID:28255936PMID:24093860PMID:27247418 Uncertain Significance PM2, PM4, PM5, PM1, PP3, PS3, BA1, BP3, BS1, BS3, PS4, PS1, BP4, BP7, PVS1 The c.5422G>A (p.Gly1808Ser) variant in MYH7 has been reported in 3 individuals with HCM (Marsiglia 2013 PMID:24093860; Homburger 2016 PMID:27247418; Invitae pers. comm.), 1 individual with unspecified cardiomyopathy (Invitae pers. comm.) and in 1 individual with sudden cardiac death (Campuzano 2017 PMID:28255936). This variant has also been identified in 0.0045% (FAF 95% CI, 4/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to a lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA046762/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020615 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0233494 infores:hetionet CHEBI:6375 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0231218 infores:hetionet CHEBI:37941 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0009676 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0270458 infores:hetionet GO:0042478 biolink:causes GO:0001754 infores:ubergraph knowledge_assertion manual_agent GO:0042478 GO:0001754 CHEBI:3207 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0232461 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0009450 infores:hetionet CHEBI:4708 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0003811 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0232498 infores:hetionet CHEBI:44185 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042963 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004987 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0005695 infores:hetionet CHEBI:3510 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0006840 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151636 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020649 infores:hetionet CHEBI:135451 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0015376 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0036572 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235639 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0413252 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948586 infores:hetionet CHEBI:171719 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0233407 infores:hetionet NCBIGene:4607 biolink:causes MONDO:0007268 infores:monarchinitiative not_provided not_provided HGNC:7551 MONDO:0007268 uuid:1f8935af-96c8-4070-b0ec-996d1af811e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0917801 infores:hetionet CHEBI:175901 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0006142 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040147 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027651 infores:hetionet CHEBI:46295 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0235266 infores:hetionet CAID:CA226418 biolink:causes MONDO:0100437 infores:clingen CAID:CA226418 MONDO:0100437 PMID: Uncertain Significance PS3_Supporting, PP4, PP3, PP1, PM2_Supporting PM5, PS4 NM_001034853.2(RPGR):c.389T>G (p.Phe130Cys) is a missense variant predicted to cause substitution of phenylalanine by cysteine at amino acid 130. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives the variant a score of 0.764, which is between the ClinGen X-linked IRD VCEP threshold of 0.644 to 0.773 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.05 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. The variant protein has shown severely decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID: 10958648, PMID: 23213406), as well as complete mislocalization to the cytoplasm rather than to the primary cilium (PMID: 30622176) and disrupted interactions with PDE6D, RPGRIP1L, and INPP5E (PMID: 30622176, PS3_supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1), family history consistent with X-linked inheritance (2) with a milder phenotype in females (1), pigmentary retinopathy (0.5), optic nerve pallor (0.5), and decreased central visual acuity (0.5), which together are specific for RPGR-related retinopathy (5.5 points, PP4, personal communication with clinician regarding an unpublished proband). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis (an affected mother and her son) from 1 family. (PP1, personal communication with author). In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PS3_Supporting, PM2_Supporting, PP3, PP4, and PP1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226418/MONDO:0100437/106 2025-05-20 2025-05-23 X-linked inheritance HP:0001417 Inconclusive true CAID:CA658658176 biolink:causes MONDO:0015967 infores:clingen CAID:CA658658176 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS1_Moderate, PP4_Moderate, PP3 PS4 The c.526+2dup variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). Other variants at this splice donor site, c.526+1G>C, c.526+1G>T, c.526+1G>A, and c.526+2del, have all been classified as pathogenic by the ClinGen Monogenic Diabetes VCEP (PS1_Moderate). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.526+2dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS1_Moderate, PM2_Supporting, PP4_Moderate, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658176/MONDO:0015967/017 2025-10-28 2025-10-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:145499 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017979 infores:hetionet CHEBI:490877 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0043352 infores:hetionet CAID:CA49780605 biolink:causes MONDO:0015152 infores:clingen CAID:CA49780605 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.4360G>T p.(Glu1454Ter) variant in DYSF, which is also known as NM_001130987.2: c.4414G>T p.(Glu1472Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 40/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in one individual with late-onset dysferlinopathy, where it was identified in unknown phase with a pathogenic variant (NM_003494.4: c.4756C>T p.(Arg1586Ter), 0.5 pts, PMID: 27602406, 33610434, 33715265, 36983702; PM3_Supporting). In addition to a clinical diagnosis of LGMD, this patient had absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 33715265, 36983702, 33610434; PP4_Strong). The highest minor allele frequency of this variant in gnomAD v4.1.0 is 0.00003334 (2/59984 Admixed American alleles), which is less than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PVS1, PM3_Supporting, PM2_Supporting, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA49780605/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3638 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0018784 infores:hetionet CHEBI:7865 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0428977 infores:hetionet CAID:CA240224 biolink:causes MONDO:0008723 infores:clingen CAID:CA240224 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3_Strong, PP4_Moderate The c.1367G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 456 (p.Arg456His). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 30194637, 17206456). Of those individuals, one individual was presumed homozygous for the variant and two were confirmed compound heterozygous for the variant and a distinct variant, one of which is approved by the ACADVL VCEP as pathogenic (PM3, 1.5 points, PMIDs: 30194637, 17206456). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001709 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA240224/MONDO:0008723/021 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68610 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0178298 infores:hetionet NCBIGene:79791 biolink:causes MONDO:0014430 infores:monarchinitiative not_provided not_provided HGNC:16510 MONDO:0014430 uuid:93de3b10-7e26-4220-be0f-a2f3c33a18be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006840 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0851341 infores:hetionet CAID:CA8603151 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603151 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 The NM_000419.5(ITGA2B):c.1389C>T (p.Tyr463=) synonymous variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population. After a comprehensive literature search, the synonymous variant has not identified with any individuals with Glanzmann Thrombasthenia. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001230 (2/16254 alleles) in the African/African American population but the gnomAD v3.2.1 African/African American population has an additional 28728 alleles (non-overlapping with v2.1.1) with no occurrences of this variant. Overall, there is a frequency of 2/44,982 = 0.000044 which is lower than the ClinGen PD VCEP threshold <0.0001 for PM2_Supporting. In silico predictor SpliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of 0.46 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603151/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7907 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0002792 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0242350 infores:hetionet CHEBI:7514 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0042024 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0009319 infores:hetionet CHEBI:119486 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0030252 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0012833 infores:hetionet CHEBI:46295 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0542571 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006798 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020579 infores:hetionet GO:0061140 biolink:causes CL:1000272 infores:ubergraph knowledge_assertion manual_agent GO:0061140 CL:1000272 CHEBI:5165 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0029408 infores:hetionet CHEBI:63577 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0042023 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0007971 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0023895 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040046 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013687 infores:hetionet CHEBI:64312 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085631 infores:hetionet CHEBI:4784 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011603 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235344 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235344 infores:hetionet CHEBI:9654 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1456784 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042373 infores:hetionet CHEBI:36791 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015967 infores:hetionet CHEBI:6149 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0003811 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0852711 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0852711 infores:hetionet GO:0090189 biolink:causes GO:0072080 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0072080 UMLS:C0025241 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0740394 infores:hetionet CAID:CA9043617 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043617 MONDO:0012999 PMID: Likely Pathogenic PM4, PM3, PP4_Strong, PM2_Supporting PP3 The NM_000156.6:c.507_521dup (p.Cys169_Ser173dup) variant in GAMT is a protein length-changing variant (in-frame insertion) in a non-repeat region (PM4). This variant has been previously reported in at least two unrelated individuals with clinical symptoms consistent with GAMT deficiency. One individual had elevated plasma GAA and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.327G>A (p.Lys109=, ClinVar ID: 21065), with the variants confirmed in trans by parental testing (PMID: 23583224, 29506905; personal communication) (PM3). The other individual had elevated plasma GAA and reduced cerebral creatine by MRS, pretreatment (PP4_Strong), and was compound heterozygous for the variant and c.403G>T (p.Asp135Tyr) (PMID: 19027335, 23660394); however, the allelic data for the latter patient will be used in the classification of p.Asp135Tyr and was not included here to avoid circular logic and thus this individual was not counted towards PM3 evidence. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001525 (14/1180016 alleles; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor PROVEAN predicts a damaging effect on GAMT function, but MutationTaster suggested no impact, such that PP3 is not met. There is a ClinVar entry for this variant (Variation ID: 431959). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PM3, PM4, PM2_supporting.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043617/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3181 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0034069 infores:hetionet CHEBI:119915 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018681 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007820 infores:hetionet NCBIGene:23229 biolink:causes MONDO:0010375 infores:monarchinitiative not_provided not_provided HGNC:14561 MONDO:0010375 uuid:c24b9d21-b8e8-44d4-95cd-ca91e4594283 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0028734 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0270458 infores:hetionet CHEBI:46557 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0023380 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0015393 infores:hetionet CAID:CA386969139 biolink:causes MONDO:0015967 infores:clingen CAID:CA386969139 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4 BP4, PS4, PP3 The c.1168G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to glutamine at codon 390 (p.(Glu390Gln)) of NM_000545.8. This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold. Additionally, this variant has a REVEL score of 0.4729, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, the c.1168G>C variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386969139/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9168 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0235378 infores:hetionet GO:1901490 biolink:causes GO:0001945 infores:ubergraph knowledge_assertion manual_agent GO:1901490 GO:0001945 CHEBI:6804 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0039070 infores:hetionet GO:1904390 biolink:causes CL:0000752 infores:ubergraph knowledge_assertion manual_agent GO:1904390 CL:0000752 CHEBI:8404 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0030554 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0948594 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042594 infores:hetionet CHEBI:9139 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0030193 infores:hetionet CHEBI:65346 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0040460 infores:hetionet CHEBI:28445 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0028643 infores:hetionet CHEBI:45409 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0520966 infores:hetionet CHEBI:6073 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0008031 infores:hetionet CAID:CA337098672 biolink:causes MONDO:0044970 infores:clingen CAID:CA337098672 MONDO:0044970 PMID: Benign BA1, BP4 The m.10034T>C variant in MT-TG was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is associated with haplogroup I (almost 100% of individuals in this haplogroup have this variant) and the overall allele frequency in the GenBank database is 1.553% (BA1). Additionally, the computational predictor MitoTIP suggests this variant is benign (6.7th percentile) and HmtVAR predicts it to be polymorphic (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337098672/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:10650 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015469 infores:hetionet CAID:CA228506 biolink:causes MONDO:0013304 infores:clingen CAID:CA228506 MONDO:0013304 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate The p.Arg1315Leu variant has a REVEL score of 0.854, which is above the VWD VCEP threshold of > 0.644 and therefore, the variant predicts a damaging effect on VWF function (PP3). There is at least one proband with excessive bleeding as well as low activity/VWF:Ag ratio, which together are specific for VWD type 2A (PMID: 28971901). It should be noted that this variant has been associated with both VWD type 2A (PMID: 16985174) as well as type 2M (PMID: 22329792); therefore, it has been published in the literature as VWD type “2M/2A” as it has been demonstrated to exhibit characteristics of both type 2A and 2M (PMID: 35452508). The variant is absent from gnomADv4, thus, meeting PM2_supporting criteria. The p.Arg1315His variant located in the same codon has been classified as likely pathogenic for VWD type 2M by the VWD VCEP (PM5_Supporting). Additional variants, p.Arg1315Gly and p.Arg1315Cys were found at the same codon but have not been curated by the VWD VCEP and therefore were not used in the assessment of PM5. Functional data, including simulation data is present for the variant but does not meet our specifications to be counted towards PS3. The p.Arg1315Leu variant has been reported in at least 3 additional probands meeting PP4 criteria (PS4_moderate). Taken together, the variant has been classified as likely pathogenic for VWD type 2 by the Von Willebrand Disease variant curation expert panel. PP3, PP4_moderate, PM2_suppporting, PM5_supporting, PS4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228506/MONDO:0013304/081 2025-04-01 2025-04-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63598 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041657 infores:hetionet CHEBI:44185 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151315 infores:hetionet CHEBI:480999 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0011168 infores:hetionet CHEBI:2955 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0002994 infores:hetionet CHEBI:7915 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151904 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0340726 infores:hetionet CHEBI:100246 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0013404 infores:hetionet CHEBI:94501 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0013395 infores:hetionet CHEBI:39585 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0041105 infores:hetionet CHEBI:135961 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0028734 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0021053 infores:hetionet CHEBI:9907 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C3665347 infores:hetionet CHEBI:85078 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0700345 infores:hetionet NCBIGene:10528 biolink:causes MONDO:0013594 infores:monarchinitiative not_provided not_provided HGNC:15911 MONDO:0013594 uuid:47f7c664-49a0-411b-98f1-b1b34e648c61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0002622 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042571 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0687133 infores:hetionet NCBIGene:29072 biolink:causes MONDO:0014791 infores:monarchinitiative not_provided not_provided HGNC:18420 MONDO:0014791 uuid:f9c6f8d8-5a71-4a0b-bfe0-b6347b2b9073 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68610 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0018681 infores:hetionet CHEBI:30830 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0010692 infores:hetionet CHEBI:45652 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0015967 infores:hetionet CHEBI:27732 biolink:causes NCIT:C107587 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0015544 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002529 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0553723 infores:hetionet CHEBI:7494 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0030232 infores:hetionet CHEBI:7476 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1167965 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0030312 infores:hetionet NCBITaxon:570 biolink:causes MONDO:0030603 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:570 MESH:D007710 DB01059_MESH_D007710_1DB00218_MESH_D007710_1 CHEBI:2663 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0013395 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042571 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0442874 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0549373 infores:hetionet CHEBI:188986 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0277890 infores:hetionet CHEBI:71417 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0024282 infores:hetionet CHEBI:6128 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0043094 infores:hetionet CHEBI:7822 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0033774 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0006840 infores:hetionet CHEBI:3228 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C3203358 infores:hetionet CHEBI:28939 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0002792 infores:hetionet CHEBI:2788 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0920171 infores:hetionet CHEBI:127342 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0700590 infores:hetionet CHEBI:3387 biolink:causes HP:0008669 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0520933 infores:hetionet CAID:CA16618473 biolink:causes MONDO:0015967 infores:clingen CAID:CA16618473 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PS2, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting The c.171G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 57 (p.(Met57Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 24323243, internal lab contributors). In one of these individuals this variant was identified as a de novo occurrence with confirmed parental relationships and a clinical picture higly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L, HbA1c 5.6-7.6 and negative autoantibodies) (PS2, PP4_Moderate; PMID: 24323243). This variant segregated with hyperglycemia, with 2 informative meioses in two families (PP1; internal lab contributors). In summary, c.170T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP1, PP2, PP3, PP4_Moderate, PS2). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618473/MONDO:0015967/086 2025-02-28 2025-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:4858 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0042109 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0005940 infores:hetionet NCBIGene:3251 biolink:causes MONDO:0010299 infores:monarchinitiative not_provided not_provided HGNC:5157 MONDO:0010299 uuid:789c6d68-87f5-46f3-a367-6180c703d262 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6801 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0151766 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0005779 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020649 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0948525 infores:hetionet CHEBI:3478 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0340865 infores:hetionet CHEBI:100241 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0162285 infores:hetionet CHEBI:4653 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C1527344 infores:hetionet CHEBI:36791 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2981158 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0022660 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0042373 infores:hetionet CHEBI:50275 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2364111 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0221745 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0221745 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0423232 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014549 infores:hetionet CHEBI:3568 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017979 infores:hetionet CHEBI:2453 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0041834 infores:hetionet CHEBI:17026 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0024902 infores:hetionet CHEBI:72564 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0206062 infores:hetionet UMLS:C0657912 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0428974 infores:hetionet CHEBI:46557 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020580 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020542 infores:hetionet CHEBI:9588 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0022408 infores:hetionet CHEBI:6775 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0037763 infores:hetionet CAID:CA229778 biolink:causes MONDO:0009861 infores:clingen CAID:CA229778 MONDO:0009861 PMID:9012412 Pathogenic PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. gnomAD MAF=0.00007.; PP4: Detected in a PKU patient. BH4 deficiency not assessed. (PMID:9012412). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229778/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4798 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0018834 infores:hetionet CHEBI:32315 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0004134 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0015397 infores:hetionet CAID:CA247031 biolink:causes MONDO:0009290 infores:clingen CAID:CA247031 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3 PP3 The NM_000152.5:c.1194+3G>C variant in GAA is located in the donor splice site consensus region of intron 7. The variant has been identified in four individuals, three with documented laboratory values showing GAA activity in the affected range in dried blood spots (Clinical Diagnostic Laboratories, PMID: 33073003). One of these individuals is reported to be symptomatic, with GAA activity in the affected range in dried blood spots, and absence of known pseudodeficiency variants (PP4_Moderate); this individual is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP - c.1210G>A (p.Asp404Asn), ClinVar Variation ID: 657348, SCV002817441.1, confirmed in trans (Clinical Laboratory) (PM3). The other individuals were identified on newborn screen will not be included because it is unknown if they are clinically symptomatic or if the enzyme deficiency could be the result of pseudodeficiency. These individuals are compound heterozygous for the variant and either c.1781G>A (p.Arg594His) (in trans based on testing of one parent), ClinVar Variation ID: 972747; SCV002817431.1; c.1841C>A (p.Thr614Lys), ClinVar Variation ID: 167113, SCV001371751.1, phase unknown (Clinical Laboratory); or c.1827del (ClinVar Variation ID: 188936, SCV001371738.1) (Clinical Laboratory). The highest population minor allele frequency in gnomAD v2.1.1. is 0.0003149 (40/127034 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor SpliceAI gives a score of 0.17 for loss of the intron 7 donor splice site, and a score of 0.31 for loss of the intron 6 acceptor splice site suggesting possible effect on splicing but not meeting the current SpliceAI threshold (>0.5) of the ClinGen Lysosomal Diseases VCEP (PP3 not met). There is a ClinVar entry for this variant (Variation ID: 198393). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA247031/MONDO:0009290/010 2024-05-21 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:9352 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0018965 infores:hetionet CHEBI:3478 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0542571 infores:hetionet CAID:CA399804710 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804710 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The c.989A>T variant in ITGA2B is a missense variant predicted tocause substitution of Asparagine by Isoleucine at amino acid 330 (p.Asn330Ile). At least one patient (Patient 6 in PMID:36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIb and β3 surface expression were reduced to 4% and 9%, respectively, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). The computational predictor REVEL gives a score of 0.796, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Strong, PM3_Supporting, PM2_Supporting and PP3 (VCEP specifications version 2; date of approval 12/17/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804710/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:15367 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151888 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0001824 infores:hetionet CHEBI:28445 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0234428 infores:hetionet CHEBI:28925 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0020517 infores:hetionet CHEBI:17688 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0221423 infores:hetionet CHEBI:3314 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0027540 infores:hetionet CAID:CA279958 biolink:causes MONDO:0021060 infores:clingen CAID:CA279958 MONDO:0021060 PMID:17981815PMID:16439621 Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM5, PM1, PS3_Supporting, PM6 BA1, BP4, BS3, BS1 The c.170T>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of phenylalanine by cysteine at amino acid 57 (p.Phe57Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.959, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 47-65). Furthermore, other pathogenic missense variants has been previously identified at this codon of MAP2K2 (Phe57Val, Phe57Ile, Phe57Leu) and in nearby residues in association with CFC syndrome, which may indicate that this residue is critical to the function of the protein (PM5). This variant has been identified in at least 4 patients with RASopathy, of which 1 was an unconfirmed de novo occurrence (PS4_Moderate, PM6; GenomeConnect, ClinVar: SCV002047662.1; PMID: 16439621, 18039235, 21062266). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID: 16439621, 17981815). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM5, PM6, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279958/MONDO:0021060/048 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0403632 infores:hetionet CHEBI:31236 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030794 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001276 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0236826 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0239093 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0239093 infores:hetionet CAID:CA412370587 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370587 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PP3_Strong, PM5 NM_000330.4(RS1):c.533G>T (p.Gly178Val) is a missense variant encoding the substitution of glycine with valine at amino acid 178. Another missense variant in the same codon, NM_000330.4(RS1):c.533G>A (p.Gly178Asp), (PMID: 31087526, 12928282, 31149861, 11738458, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (109) than the comparison variant (94), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.981, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_strong, and PM5_supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370587/MONDO:0010725/126 2025-09-18 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CAID:CA203312 biolink:causes MONDO:0100438 infores:clingen CAID:CA203312 MONDO:0100438 PMID:33067476 Benign BS2, BP4, BA1 BS3 NM_014336.5(AIPL1):c.1126C>T (p.Pro376Ser) is a missense variant in exon 6 of 6 that is predicted to replace proline with serine at amino acid p.376. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.06125, with 4,695 alleles / 74,822 total alleles and 166 homozygotes in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). The variant has been found in the homozygous state in 170 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.129, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on AIPL1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA203312/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46557 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0026764 infores:hetionet CHEBI:16714 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0162297 infores:hetionet CHEBI:584020 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0023222 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0012359 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013595 infores:hetionet GO:0120235 biolink:causes GO:0006620 infores:ubergraph knowledge_assertion manual_agent GO:0120235 GO:0006620 CHEBI:75722 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235146 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0035304 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0042373 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0012833 infores:hetionet CHEBI:6690 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0000737 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0011570 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0521158 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0521158 infores:hetionet CHEBI:63620 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0007859 infores:hetionet CHEBI:135939 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0015967 infores:hetionet CAID:CA410147594 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147594 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS4, PS1, PS2, PS3, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS4, BS3, PM1, PM4, PM5, PM3, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.1264G>T (p.Glu422Ter) is a nonsense variant that is not predicted to undergo NMD (PVS1_strong, SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147594/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61033 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020458 infores:hetionet CHEBI:16796 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0085631 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0038454 infores:hetionet CHEBI:40050 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0035410 infores:hetionet CHEBI:38562 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0438717 infores:hetionet CHEBI:7443 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0038325 infores:hetionet CHEBI:92923 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0152030 infores:hetionet CHEBI:4858 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0039070 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0003621 infores:hetionet CHEBI:63622 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0004604 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0005779 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0038362 infores:hetionet CHEBI:404903 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151786 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0042514 infores:hetionet CHEBI:9123 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0080274 infores:hetionet CHEBI:47519 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0020473 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039971 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0017178 infores:hetionet CHEBI:7907 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0037036 infores:hetionet CAID:CA402997207 biolink:causes MONDO:0012999 infores:clingen CAID:CA402997207 MONDO:0012999 PMID:24415674 Likely Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Supporting, PS3_Supporting The NM_000156.6:c.202G>T variant in GAMT is predicted to result in the missense substitution of glycine by cysteine at amino acid 68 (p.Gly68Cys). The variant has been reported in homozygosity in a proband and sibling with clinical symptoms consistent with GAMT deficiency (PM3_Supporting). The proband has absent creatine peak and guanidinoacetate peak on brain MRS. Urine guanidinoacetate levels were elevated in all patients and were between 1.1 and 12 times above the upper limit of reference range, but specific values for each patient were not provided (PP4_Moderate) (PMID: 24415674). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.994 which is above the threshold of 0.932, evidence that correlates with impact to GAMT function at the strong level (PMID: 36413997) (PP3_Strong). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 2446456). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 2.0.0): PP3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 15, 2025 Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402997207/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75179 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0235270 infores:hetionet CHEBI:3215 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0042024 infores:hetionet CHEBI:3314 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0012833 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020615 infores:hetionet CHEBI:3757 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0019158 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0042075 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1619733 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1619733 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027651 infores:hetionet CHEBI:92712 biolink:causes HP:0005348 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0677600 infores:hetionet CHEBI:4027 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0700590 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020517 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042109 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0475858 infores:hetionet CHEBI:44423 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0016059 infores:hetionet CHEBI:100246 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0037317 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019348 infores:hetionet CHEBI:51380 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0857305 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0020517 infores:hetionet CHEBI:9448 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C1260880 infores:hetionet CHEBI:194135 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0237849 infores:hetionet CHEBI:7444 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0011603 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0497247 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0036572 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0037274 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0740409 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0740409 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0042109 infores:hetionet CHEBI:74947 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0031256 infores:hetionet NCBIGene:112939 biolink:causes MONDO:0044306 infores:monarchinitiative not_provided not_provided HGNC:20967 MONDO:0044306 uuid:f5e4a8b2-19cd-4bd2-a036-bd045f303238 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8430 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0011551 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0026946 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0858635 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0002418 infores:hetionet CHEBI:2038 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0023380 infores:hetionet CHEBI:45716 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0003123 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0010709 infores:hetionet CHEBI:94848 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0040264 infores:hetionet CHEBI:47426 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0023530 infores:hetionet CHEBI:75722 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0086769 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002418 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0233472 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0332575 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0268732 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0268732 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0852911 infores:hetionet CHEBI:63611 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085641 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0151763 infores:hetionet CHEBI:51041 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0028734 infores:hetionet GO:0010695 biolink:causes GO:0090307 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0090307 CHEBI:135736 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0029163 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0858797 infores:hetionet CHEBI:77733 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0013604 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042401 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0022660 infores:hetionet NCBIGene:1639 biolink:causes MONDO:0008201 infores:monarchinitiative not_provided not_provided HGNC:2711 MONDO:0008201 uuid:c82bcec2-f6f1-43d0-af79-756dd9fc3f4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085631 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020649 infores:hetionet CHEBI:63611 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235266 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0008301 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0392025 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1262144 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0015624 infores:hetionet CHEBI:92607 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0040046 infores:hetionet CHEBI:5847 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0232462 infores:hetionet CHEBI:9586 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0014724 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002884 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001910 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0028817 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0236068 infores:hetionet CAID:CA16616277 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616277 MONDO:0011071 PMID:33692461PMID:32943879 Uncertain Significance PM1_Supporting, PS3_Moderate, PM2_Supporting, PP3 PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.433A>G (p.Arg145Gly) is a missense variant which has a REVEL score ≥ 0.88 (0.925) (PP3). Data from two or more secondary assays (FRET assay and SEUSS) demonstrate altered function, including decreased phosphorylation of RUNX1 and decreased gene expression (PS3_moderate; PMID: 33692461, 32943879). This variant is located within the Runt Homology Domain (RHD; AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_moderate, PP3, PM1_supporting, and PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616277/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27834 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0017178 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0035302 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0017160 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0031542 infores:hetionet CHEBI:68606 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0001623 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020538 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0549373 infores:hetionet CHEBI:6438 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0004093 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0241863 infores:hetionet CHEBI:135930 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0232462 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0281774 infores:hetionet CAID:CA5545996 biolink:causes MONDO:0019497 infores:clingen CAID:CA5545996 MONDO:0019497 PMID: Pathogenic PP3, PP1, PM3_Very Strong PM2 The c.6085C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2029 (p.Arg2029Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.02% (3/17816 alleles) in the East Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in many individuals with hearing loss or deafness, without any reported vision loss or evidence of retinopathy. Of those individuals, over 10 were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic and many of those were confirmed in trans (6.75 PM3_Very Strong points, PMID: 35020051, 25963016, 22899989, 17850630). The variant has been reported to segregate with hearing loss in 1 affected family member from 1 family (PP1_Supporting; PMID: 22899989, 17850630). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3, PP1. (VCEP specifications version 2; 06.26.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA5545996/MONDO:0019497/005 2023-06-26 2023-06-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:59773 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0003862 infores:hetionet CHEBI:70735 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0428977 infores:hetionet CHEBI:9566 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0040034 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0014130 infores:hetionet CHEBI:92998 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085932 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0006145 infores:hetionet CHEBI:3757 biolink:causes NCIT:C112176 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0948786 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0004096 infores:hetionet CHEBI:49375 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0740394 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0040425 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0018524 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0012833 infores:hetionet CAID:CA414904027 biolink:causes MONDO:0010602 infores:clingen CAID:CA414904027 MONDO:0010602 PMID:12428094 Likely Pathogenic PP1_Moderate, PM2_Supporting, PS4_Supporting, PP3, PS3 The c.2138A>T; p.Asn713Ile variant is completely absent from gnomAD v2.1.1 and v3.1.1. This missense variant has a REVEL score of 0.803 and meets PP3 criteria (threshold >0.6). One large Danish family with mild hemophilia A, with well over 3 meioses of variant segregation, is reported in the literature, meeting F8 phenotype criteria for PS4_Supporting and PP1_Moderate (PMID: 10886198). Monkey COS-1 cells with variant demonstrated decreased factor VIII antigen and activity levels discrepant between 1- and 2-stage assays, which meets PS3 criteria. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS3, PS4_Supporting, PP1_Moderate, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414904027/MONDO:0010602/071 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Supports CHEBI:37924 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0032617 infores:hetionet CHEBI:5002 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0042029 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042035 infores:hetionet CHEBI:9445 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0039070 infores:hetionet CAID:CA024282 biolink:causes MONDO:0007783 infores:clingen CAID:CA024282 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Threonine with Asparagine at codon 51 of the RYR1 protein, p.(Thr51Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00012 (15 alleles), a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:18564801 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).This variant segregates with MHS in 1 individual (PMID:18564801). A REVEL score of 0.769 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024282/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3752 biolink:causes HP:0000929 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0235942 infores:hetionet NCBIGene:65267 biolink:causes MONDO:0010667 infores:monarchinitiative not_provided not_provided HGNC:14543 MONDO:0010667 uuid:0d4d0ce0-84dc-484b-a509-283419426ff6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0014591 infores:hetionet CHEBI:6954 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0011615 infores:hetionet CHEBI:6121 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0028738 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0542203 infores:hetionet CHEBI:6847 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0020437 infores:hetionet CHEBI:5384 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0231528 infores:hetionet CHEBI:9150 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0017178 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1565489 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0700184 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0019158 infores:hetionet UMLS:C1872203 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0231528 infores:hetionet CHEBI:2208 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0023530 infores:hetionet CHEBI:127342 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0018524 infores:hetionet CHEBI:8435 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0015371 infores:hetionet CHEBI:10102 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0006384 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0039070 infores:hetionet CHEBI:83804 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042963 infores:hetionet CHEBI:45081 biolink:causes MONDO:0006009 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0243010 infores:hetionet CHEBI:4856 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0235490 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020649 infores:hetionet UNII:3QJA87N40S biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C2242996 infores:hetionet CHEBI:9332 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C1257843 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0549475 infores:hetionet CAID:CA367397199 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397199 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4, BS1, PP4, BA1, BP4 The c.1280T>G variant in the glucokinase gene, GCK, causes an amino acid change of valine to glycine at codon 427 (p.(Val427Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1280T>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397199/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:404903 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0006266 infores:hetionet CAID:CA410147171 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147171 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1354G>C (p.Val452Leu) is a missense variant which has a REVEL score < 0.50 (0.044), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147171/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45081 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0234930 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0029445 infores:hetionet CHEBI:3485 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0023530 infores:hetionet CHEBI:63629 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0000768 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0034186 infores:hetionet CHEBI:32599 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0855775 infores:hetionet CHEBI:45409 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0424295 infores:hetionet CHEBI:51450 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C2830004 infores:hetionet CAID:CA638054528 biolink:causes MONDO:0011071 infores:clingen CAID:CA638054528 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-18C>T is an intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.16) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054528/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:71 biolink:causes MONDO:0013812 infores:monarchinitiative not_provided not_provided HGNC:144 MONDO:0013812 uuid:64099cf7-abc0-49eb-8380-771cc2091857 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410148028 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148028 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, BP7, BP5, BS1, BS3, BS4, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1127G>A (p.Arg376His) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148028/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:80336 biolink:causes MONDO:0976137 infores:monarchinitiative not_provided not_provided HGNC:15797 MONDO:0976137 uuid:53160313-5674-4f15-a59c-5bbbcf8e2cc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0007476 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013312 infores:hetionet NCBIGene:55159 biolink:causes MONDO:0044325 infores:monarchinitiative not_provided not_provided HGNC:25539 MONDO:0044325 uuid:af92db3b-2af1-4587-b0fd-7fd2714539d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0043352 infores:hetionet CHEBI:40279 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0235710 infores:hetionet CHEBI:64355 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020488 infores:hetionet CAID:CA8365708 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365708 MONDO:0100453 PMID: Likely Benign BS1, BS2_Supporting PP3 The NM_000180.4(GUCY2D):c.1315G>A (p.Gly439Arg) variant is predicted to replace the glycine at position p.439 with arginine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.001850 with 190 alleles / 90756 total alleles in the South Asian population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 4 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥ 3 (gnomAD version 4.1.0; BS2_supporting). In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2_supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365708/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31302 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0235169 infores:hetionet CHEBI:724125 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0041834 infores:hetionet CHEBI:480999 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0438717 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0521839 infores:hetionet CHEBI:75998 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0035410 infores:hetionet CHEBI:51860 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0236075 infores:hetionet GO:0042675 biolink:causes CL:0000718 infores:ubergraph knowledge_assertion manual_agent GO:0042675 CL:0000718 CHEBI:3242 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0039971 infores:hetionet CHEBI:46195 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0546817 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005900 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030583 infores:hetionet CHEBI:44032 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0235086 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0021400 infores:hetionet CHEBI:83531 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0041657 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0001824 infores:hetionet CHEBI:100246 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0220870 infores:hetionet CHEBI:47381 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014518 infores:hetionet CAID:CA000138 biolink:causes MONDO:0018875 infores:clingen CAID:CA000138 MONDO:0018875 PMID: Likely Benign PP3_Moderate, BS3 BP4, BP2, BA1, PS3, PS4, PM5, PM1, BS1, BS4, PM2, BS2, PP1 The NM_000546.6: c.370T>A variant in TP53 is a missense variant predicted to cause substitution of Cysteine by Serine at amino acid 124 (p.Cys124Ser). This variant received a total of 0.5 points across 1 proband. (PS4 not met; Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.258 ; Align GVGD = Class C65 are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, PP3_Moderate (Bayesian Points: -2; VCEP specifications version 2.2; 2/6/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000138/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4909 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013491 infores:hetionet CAID:CA367401330 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401330 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS1, PM1, PP4 The c.619G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 207 (p.(Val207Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.939, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). The nucleotide change c.619G>T, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.619G>T variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.619G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401330/MONDO:0015967/086 2025-01-29 2025-01-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:83804 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0004604 infores:hetionet CHEBI:47426 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C2830004 infores:hetionet CHEBI:9086 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0376358 infores:hetionet CHEBI:209807 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0038826 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0836924 infores:hetionet CHEBI:135736 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0004134 infores:hetionet CHEBI:51380 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0015230 infores:hetionet CHEBI:2682 biolink:causes HP:0003158 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232831 infores:hetionet UMLS:C0004609 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0085649 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0017178 infores:hetionet NCBIGene:219285 biolink:causes MONDO:0009646 infores:monarchinitiative not_provided not_provided HGNC:1349 MONDO:0009646 uuid:d0e2e701-4cc9-48b4-8494-5789da218bd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0039070 infores:hetionet CAID:CA6326508 biolink:causes MONDO:0019497 infores:clingen CAID:CA6326508 MONDO:0019497 PMID: Likely Benign BP7, BP4 BS1, BP5, BA1, PS4 The c.487-7C>G intronic variant in TECTA was present in 0.05081% (18/35428) of Latino alleles in gnomAD; however, because this gene has been associated with both AR and AD hearing loss, no criteria were applied based on population data. This variant was identified in 1 white patient with nonsyndromic hearing loss (PS4 not met; Laboratory for Molecular Medicine internal data, SCV000272492.3). The c.487-7C>G variant is classified as likely benign because a C>G change at this position does not diverge from the splice consensus sequence, making it unlikely to impact splicing, and computational splice prediction tools do not predict an impact on splicing. ACMG/AMP Criteria applied, as specified by the Hearing Loss Expert Panel: BP4, BP7. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6326508/MONDO:0019497/005 2019-10-02 2019-10-02 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:16469 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042267 infores:hetionet CHEBI:15551 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0011053 infores:hetionet CHEBI:41977 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0018790 infores:hetionet CHEBI:63717 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0018681 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0013604 infores:hetionet CAID:CA399806497 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806497 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.212C>G (p.Pro71Arg) missense variant has been reported in at least one Glanzmann thrombasthenia patient (PMID: 21113249). Patient GE displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia . Additionally, αIIbβ3 surface expression was reduced to <1%, as measured by flow cytometry, and there was<1% binding to PAC-1. (PP4_strong). The full genotype of Patient GE was reported later in Pilgrimm-Thorp (2012) Haemophilia 18S3 157 and a PhD dissertation from D. Pillitteri, the patient is compound heterozygous for this variant and Leu684Arg (classified VUS by the PD VCEP; PM3_NotMet). The Pro71Arg variant is absent from gnomAD v2.1.1 (PM2_Supporting) and the computational predictor REVEL gives a score of 0.809, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporitng, PP3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806497/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3223 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0042963 infores:hetionet CHEBI:2675 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0156404 infores:hetionet CHEBI:3077 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0003467 infores:hetionet CHEBI:9738 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0030252 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0178298 infores:hetionet CAID:CA1139665604 biolink:causes MONDO:0700268 infores:clingen CAID:CA1139665604 MONDO:0700268 PMID: Uncertain Significance PVS1_Moderate PM2 The c.3991_4096+10delinsAT variant is an intronic variant spanning the native donor 1,2 splice site occurring in exon and intron 10(11) of the BRCA1 gene. This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). This variant is predicted to cause loss of splice site resulting in in-frame, suspected (partially) functional transcript (PVS1_Moderate met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Moderate). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665604/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:70735 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0340726 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0005940 infores:hetionet CHEBI:6402 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0016204 infores:hetionet CHEBI:66964 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0231218 infores:hetionet CHEBI:45783 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027497 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0392176 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0003811 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0240322 infores:hetionet CHEBI:691037 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0549567 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0442874 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0033774 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1868752 infores:hetionet GO:0010803 biolink:causes GO:0071356 infores:ubergraph knowledge_assertion manual_agent GO:0010803 GO:0071356 CHEBI:2955 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020517 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018099 infores:hetionet CHEBI:3310 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0011206 infores:hetionet CHEBI:31401 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0017565 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0858259 infores:hetionet CHEBI:16469 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0036974 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0034065 infores:hetionet CHEBI:31536 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0027497 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1608953 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1608953 infores:hetionet CHEBI:63618 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0011991 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002170 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020550 infores:hetionet NCBIGene:23250 biolink:causes MONDO:0859242 infores:monarchinitiative not_provided not_provided HGNC:13552 MONDO:0859242 uuid:e98a72cf-1dd0-4c47-bdb5-31dd0df702ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085593 infores:hetionet CHEBI:404903 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013384 infores:hetionet CHEBI:4702 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0038990 infores:hetionet NCBIGene:4854 biolink:causes MONDO:0014122 infores:monarchinitiative not_provided not_provided HGNC:7883 MONDO:0014122 uuid:e24d971f-f4b8-4070-b5a1-5f4b7ad62fb8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94807 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0231528 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0027765 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0849796 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0849796 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020580 infores:hetionet CHEBI:64064 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0004604 infores:hetionet CHEBI:5123 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0242422 infores:hetionet CHEBI:32192 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0030920 infores:hetionet GO:1905939 biolink:causes GO:0007548 infores:ubergraph knowledge_assertion manual_agent GO:1905939 GO:0007548 CHEBI:6030 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0241863 infores:hetionet CHEBI:31236 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1145670 infores:hetionet CHEBI:63638 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0040435 infores:hetionet CHEBI:27690 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C1504494 infores:hetionet CHEBI:49375 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0035222 infores:hetionet CHEBI:35778 biolink:causes HP:0003452 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151900 infores:hetionet CHEBI:46195 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C1443060 infores:hetionet CHEBI:8107 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020555 infores:hetionet CHEBI:53760 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0035455 infores:hetionet CHEBI:61058 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0037023 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015397 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0030305 infores:hetionet CHEBI:101278 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0011991 infores:hetionet CHEBI:6710 biolink:causes UMLS:C0694575 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0694575 infores:hetionet CHEBI:7454 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0013378 infores:hetionet CHEBI:44185 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013404 infores:hetionet CAID:CA6831684 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831684 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3 PS4, PM5, PP4 The c.202C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 68 (p.(Arg68Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.827, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant was Identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of information about time to insulin use; therefore, PP4 could not be applied (internal lab contributor). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and therefore, PP4 could not be applied (internal lab contributor). Another missense variant, c.203G>A (p.(Arg68Gln)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.202C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831684/MONDO:0015967/017 2022-04-04 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63115 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0033774 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151605 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0242350 infores:hetionet CHEBI:38545 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0042029 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0034065 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0853692 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037278 infores:hetionet CHEBI:7514 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0037274 infores:hetionet CHEBI:27779 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0042963 infores:hetionet CHEBI:38940 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151205 infores:hetionet NCBIGene:51168 biolink:causes MONDO:0010860 infores:monarchinitiative not_provided not_provided HGNC:7594 MONDO:0010860 uuid:a9e311c0-f06d-4119-8b46-213a8e427138 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0019158 infores:hetionet CHEBI:7640 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0237314 infores:hetionet CHEBI:63616 biolink:causes EFO:0005632 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C2243080 infores:hetionet CHEBI:168396 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0702166 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C1565489 infores:hetionet CAID:CA274436 biolink:causes MONDO:0008723 infores:clingen CAID:CA274436 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PP3, PM1, PM3, PM5, PM4, BP2, BP1, BP3, PS1, BP7 The c.433C>T (p.Gln145Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.11 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA274436/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5893 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0015672 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0948594 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027441 infores:hetionet NCBIGene:57798 biolink:causes MONDO:0013848 infores:monarchinitiative not_provided not_provided HGNC:29941 MONDO:0013848 uuid:875c6e9f-f1cd-4907-9575-3d167ea48671 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0042963 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1961112 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1961112 infores:hetionet CAID:CA10580940 biolink:causes MONDO:0018875 infores:clingen CAID:CA10580940 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PP3_Moderate, BS2_Supporting, PM2_Supporting BA1, BP4, PS3, PS2, PS1, PS4, PM1, BS1, BS4, PM6, PP1 The NM_000546.6:c.541C>A variant in TP53 is a missense variant predicted to cause substitution of arginine by serine at amino acid 181 (p.Arg181Ser). This variant has been observed in 3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Ambry SCV000274425.4). This variant received a total of 0.5 points across 1 family meeting Chompret criteria and does not meet criteria for PS4 (PS4 not met; IARC database). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.204; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, PM2_supporting, BS3_supporting, PP3_moderate (Bayesian Points: 1; VCEP specifications version 2.3). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580940/MONDO:0018875/009 2025-03-04 2025-06-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:35778 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0004604 infores:hetionet CAID:CA1705344 biolink:causes MONDO:0015152 infores:clingen CAID:CA1705344 MONDO:0015152 PMID: Likely Benign BP2 PM3, BP4, BS3, PM2, PP4 The NM_003494.4: c.401C>T variant in DYSF, which is also known as NM_001130987.2: c.404C>T p.(Pro135Leu), is a missense variant predicted to cause substitution of proline by leucine at amino acid 134, p.(Pro134Leu). This variant has been observed in two individuals with features consistent with LGMD (PMID: 36983702; 23406536; 30564623; LOVD Individual #00222735); however, in both cases it was identified in cis with a null variant, including one classified as pathogenic by the ClinGen LGMD VCEP (NM_003494.4: c.5022del p.(Phe1674LeufsTer48), PMID: 36983702) (BP2; PP4 and PM3 not applicable). The filtering allele frequency of this variant is 0.0001865 in gnomAD v4.1.0 genomes (the upper threshold of the 95% CI of 3/41580 African/African American chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (PM2 not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Pro134Leu protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met). The computational predictor REVEL gives a score of 0.15, which is above the LGMD VCEP threshold of ≤0.1 for BP4 (criterion not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/17/2025): BP2. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1705344/MONDO:0015152/180 2025-06-17 2025-07-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:472657 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0036974 infores:hetionet CHEBI:28925 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0019080 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011849 infores:hetionet CHEBI:9139 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0547030 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0006145 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0152227 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0087169 infores:hetionet CHEBI:3082 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0740394 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0233477 infores:hetionet GO:1904301 biolink:causes GO:0007567 infores:ubergraph knowledge_assertion manual_agent GO:1904301 GO:0007567 CHEBI:44915 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0015376 infores:hetionet CHEBI:8405 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0002878 infores:hetionet CHEBI:94392 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0004604 infores:hetionet CHEBI:32139 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0005778 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0025061 infores:hetionet CHEBI:8502 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0019080 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0559031 infores:hetionet CHEBI:6933 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0037274 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0012241 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0012241 infores:hetionet CHEBI:50122 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020443 infores:hetionet CHEBI:40303 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0023530 infores:hetionet CHEBI:7865 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C1306341 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0020538 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0521839 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0036572 infores:hetionet CAID:CA386964506 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964506 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP3, PP4 PP1 The c.626C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glutamic acid at codon 209 (p.(Ala209Glu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.822, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.626C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PS4_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964506/MONDO:0015967/017 2022-07-01 2022-07-01 Autosomal dominant inheritance HP:0000006 Supports CAID:CA1139666828 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666828 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.*3642C>T is a 3'UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666828/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7903 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0019348 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151826 infores:hetionet CHEBI:490877 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0042963 infores:hetionet CAID:CA253889 biolink:causes MONDO:0019497 infores:clingen CAID:CA253889 MONDO:0019497 PMID:24662630PMID:9931344PMID:16151338PMID:24662630PMID:9931344PMID:16151338PMID:11332404PMID:12928864PMID:25230692PMID:26256111PMID:16481359PMID:20228067PMID:28733840PMID:16151338PMID:11332404 Pathogenic PP1_Strong, PP3, PM2, PS4 BS4, BS1, BP5, BP7, BS2, PP4, PM3, PM1, PM4, PM5, PVS1, PM6, BP2, BP3, BP4, BA1, PS2, PS3, PS1 The c.151C>T (p.Pro51Ser) variant in COCH has been reported to segregate with late onset progressive hearing loss and vestibular dysfunction in > 25 family members (PP1_S; PMID: 9931344, 11332404). The variant meets PM2 and has been observed in at least 15 affected probands (PS4, PMID: 28733840, 16151338, 11332404). The allele frequency of the p.Pro51Ser variant is 0.001% (1/111716) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Pro51Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_S, PS4, PM2, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA253889/MONDO:0019497/005 2018-09-19 2019-07-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:78543 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0006826 infores:hetionet CHEBI:71415 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0026846 infores:hetionet CHEBI:100246 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0220981 infores:hetionet CHEBI:6030 biolink:causes MONDO:0004574 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C1527330 infores:hetionet CHEBI:100241 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023380 infores:hetionet CHEBI:4975 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0025345 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002884 infores:hetionet CHEBI:3061 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0043352 infores:hetionet CHEBI:63622 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0023380 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0518015 infores:hetionet NCBIGene:2972 biolink:causes MONDO:0014529 infores:monarchinitiative not_provided not_provided HGNC:11551 MONDO:0014529 uuid:6839edd5-a927-4c89-bda1-b0f74978f6b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0152227 infores:hetionet CAID:CA2061522 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061522 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 BA1, PS4, PM1, BS1 The NM_001204.7(BMPR2) c.2352C>T variant is a synonymous (silent) variant (p.Val784=). This variant is present in gnomADv2.1.1 controls at a frequency of 0.00002 and gnomADv4.1 at 0.00006 (PM2_supporting). In silico prediction algorithms indicate that the nucleotide is not highly conserved (REVEL score not available; CADD = 1.4; phyloP = 0.207) (BP4) and has no impact on splicing (SpliceAI = 0) (BP7). In summary, this variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BP4, BP7, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061522/MONDO:0015924/125 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135679 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0011603 infores:hetionet CHEBI:6761 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0014742 infores:hetionet CHEBI:4822 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0948089 infores:hetionet CHEBI:64355 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0021368 infores:hetionet CHEBI:188986 biolink:causes HP:0025560 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423282 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0040034 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030920 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0263888 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0263888 infores:hetionet CHEBI:3561 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0404521 infores:hetionet CHEBI:36791 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018965 infores:hetionet CHEBI:63115 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0085614 infores:hetionet CAID:CA320648518 biolink:causes MONDO:0011071 infores:clingen CAID:CA320648518 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP3, BP2, BP1, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP1 NM_001754.5(RUNX1): c.59-12C>G is an intronic variant that is located at a nucleotide that is not highly conserved per the PhyloP evolutionary conservation algorithm (BP7). The result from SpliceAI, an in silico splicing predictor, supports that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320648518/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0065374 biolink:causes MONDO:0018680 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0311220 infores:hetionet UNII:K2J09EMJ52 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0033774 infores:hetionet CHEBI:8077 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0232487 infores:hetionet CHEBI:4822 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0020649 infores:hetionet UMLS:C0010592 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0016655 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0006840 infores:hetionet CHEBI:3181 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0013378 infores:hetionet CHEBI:44915 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0002994 infores:hetionet CHEBI:68478 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0231218 infores:hetionet CHEBI:4562 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235490 infores:hetionet CAID:CA257062 biolink:causes MONDO:0018997 infores:clingen CAID:CA257062 MONDO:0018997 PMID:17603482PMID:20683980PMID:17603482 Pathogenic PS3, PM1, PM2, PP2, PM6_Strong The c.781C>T (p.Pro261Ser) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17603482, 20683980). In vitro functional studies provide some evidence that the p.Pro261Leu variant may impact protein function (PS3; PMID 17603483, 17603482). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA257062/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:5864 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030305 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023067 infores:hetionet CHEBI:9566 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0027424 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0040034 infores:hetionet CHEBI:127342 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0009763 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0006285 infores:hetionet CHEBI:75988 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0333355 infores:hetionet CHEBI:8890 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0149871 infores:hetionet NCBIGene:3897 biolink:causes MONDO:0010611 infores:monarchinitiative not_provided not_provided HGNC:6470 MONDO:0010611 uuid:310259ec-9e9c-4f96-9357-05a55e3c121d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45924 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C1320835 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0015397 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013609 infores:hetionet CAID:CA2499225874 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225874 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 This synonymous/intronic/UTR/frameshift variant has a SpliceAI score ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.12< 2.0) (BP7). Variant is not present in population databases (gnomAD v2.1 or v3.1.2) (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225874/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6715 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020517 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0585186 infores:hetionet CHEBI:473990 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0015672 infores:hetionet CHEBI:474180 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0014742 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0265031 infores:hetionet CAID:CA305300066 biolink:causes MONDO:0007750 infores:clingen CAID:CA305300066 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP1, BP3, BP2, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.1224G>C (p.Glu408Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.BP4 - REVEL = 0.414. It is below 0.50, splicing evaluation required.Functional data on splicing not available.A) not on limitsB) does not create AGVariant is not predicted to alter splicing, so BP4 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305300066/MONDO:0007750/013 2021-12-16 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3696 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0027765 infores:hetionet CHEBI:291342 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0017178 infores:hetionet CHEBI:7476 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0032617 infores:hetionet CHEBI:3752 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0012569 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0003123 infores:hetionet CHEBI:49040 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0000737 infores:hetionet CHEBI:31638 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0008031 infores:hetionet CHEBI:8774 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0033774 infores:hetionet CHEBI:8499 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0020615 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0033777 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0236072 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011609 infores:hetionet CHEBI:4887 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0024141 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040034 infores:hetionet CHEBI:42944 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0392525 infores:hetionet CHEBI:9086 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0024031 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0032285 infores:hetionet CHEBI:5959 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C2047937 infores:hetionet CAID:CA360617465 biolink:causes MONDO:0021056 infores:clingen CAID:CA360617465 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.220+1G>A variant in APC occurs within the canonical splice donor site (+1) of intron 3. It is predicted to cause skipping of exon 3, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1). This prediction is confirmed by RNA analysis (internal data from Ambry Genetics and Invitae). This variant has been reported in one family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, [internal data from Ambry Genetics]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA360617465/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:553473 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0221742 infores:hetionet CHEBI:100246 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0152169 infores:hetionet CAID:CA410202586 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202586 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.449C>A (p.Ala150Asp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202586/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233414 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018418 infores:hetionet CHEBI:2611 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0028084 infores:hetionet CHEBI:585948 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0030252 infores:hetionet CHEBI:4027 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0850149 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0031046 infores:hetionet GO:0031285 biolink:causes GO:0031150 infores:ubergraph knowledge_assertion manual_agent GO:0031285 GO:0031150 CHEBI:6847 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0349506 infores:hetionet CHEBI:82716 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0027540 infores:hetionet CHEBI:7915 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0007859 infores:hetionet CHEBI:4046 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0002878 infores:hetionet CHEBI:584020 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0030193 infores:hetionet CHEBI:6149 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0006266 infores:hetionet CAID:CA10603725 biolink:causes MONDO:0100437 infores:clingen CAID:CA10603725 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Moderate, PP1_Strong NM_001034853.2(RPGR):c.3317dup (p.Ser1107ValfsTer4) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 2 families (PP1_strong; PMIDs: [21866333, 19429592]). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, with decreased or absent cone and/or rod electroretinogram responses (PMIDs: 29528978, 15734019, 32860923, PS4_moderate). At least one additional proband harboring this variant exhibits a phenotype including onset before age 20 years (1 pt), mild myopia, reduced visual acuity (0.5 pts), family history consistent with X-linked inheritance (2 pts), and poor color vision (0.5 pts), which together are specific for RPGR-related retinopathy (4 points, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_moderate. PM2_supporting, PP1_strong, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603725/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:465284 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0031350 infores:hetionet CHEBI:3647 biolink:causes UMLS:C1112182 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C1112182 infores:hetionet CHEBI:32020 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0009241 infores:hetionet CHEBI:8356 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011175 infores:hetionet CHEBI:5864 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0004093 infores:hetionet NCBIGene:8204 biolink:causes MONDO:0032646 infores:monarchinitiative not_provided not_provided HGNC:8001 MONDO:0032646 uuid:23d30ea3-8900-4d11-b5b2-d89e9ce3ba04 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020456 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0032285 infores:hetionet CHEBI:3175 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0392163 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0032285 infores:hetionet CHEBI:31709 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0085636 infores:hetionet NCBIGene:6789 biolink:causes MONDO:0013934 infores:monarchinitiative not_provided not_provided HGNC:11408 MONDO:0013934 uuid:7da52c8d-65df-4447-9adb-b14f1434cb07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013428 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0021569 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0021569 uuid:3e735d9e-60d9-460e-9531-0c6898e661ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399803733 biolink:causes MONDO:0100326 infores:clingen CAID:CA399803733 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.1259T>C (p.Val420Ala) missense variant has been reported in at least one patient (GT22 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PP3. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399803733/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5123 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0011615 infores:hetionet CAID:CA011361 biolink:causes MONDO:0007356 infores:clingen CAID:CA011361 MONDO:0007356 PMID:32849802 Benign BS3, BS1, BP5 The NM_000249.4(MLH1):c.649C>T (p.Arg217Cys) variant is a missense variant predicted to cause substitution of Arginine by Cystein at amino acid 217 (p.Arg217Cys). The allele frequency of the variant c.649C>T is 0.3% (PopMax Filtering AF 0.0037 in East Asian Population) for the total non-cancer dataset from gnomAD (v2.1.1), and gnomAD v4.1 Grpmax AF is 0.003970 which is higher than the ClinGen InSiGHT MMR VCEP threshold (≥ 0.001 or 0,1%) for BS1, and therefore meets this criterion (BS1).The CIMRA Functional Odds for Pathogenicity is 0.01 which is below the VCEP threshold of ≤ 0.052 (BS3 met).Also the variant has been detected in 2 or 3 tumours: CRC/Endometrial tumours with MSS and/or no loss of MMR protein expression and/or LS spectrum tumoursf with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation (BP5 met).In summary, this variant meets the criteria to be classified as benign for autosomal-dominant inherited Lynch syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP : criteria BS2, BS3 and BP5 applied. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA011361/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6067 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015256 infores:hetionet CHEBI:92607 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0008031 infores:hetionet CHEBI:72564 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002792 infores:hetionet CHEBI:68584 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C3665347 infores:hetionet CHEBI:3640 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0342579 infores:hetionet CHEBI:28864 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0013378 infores:hetionet CHEBI:94686 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0042029 infores:hetionet CHEBI:119915 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151754 infores:hetionet CHEBI:82960 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151905 infores:hetionet GO:0140321 biolink:causes GO:0006914 infores:ubergraph knowledge_assertion manual_agent GO:0140321 GO:0006914 NCBIGene:246176 biolink:causes MONDO:0032757 infores:monarchinitiative not_provided not_provided HGNC:24846 MONDO:0032757 uuid:f58ceece-6199-4489-a40a-51332dfad498 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94609 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C2363730 infores:hetionet CHEBI:4046 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0020701 infores:hetionet CHEBI:28748 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0549410 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0948089 infores:hetionet CHEBI:50859 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0041657 infores:hetionet CHEBI:8874 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0221170 infores:hetionet CHEBI:6437 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0014742 infores:hetionet GO:2000006 biolink:causes GO:0003338 infores:ubergraph knowledge_assertion manual_agent GO:2000006 GO:0003338 CHEBI:100241 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1609512 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020456 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0035455 infores:hetionet CAID:CA1139771800 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139771800 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1278_1279del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 427 (NM_000162.5), adding 31 novel amino acids before encountering a stop codon (p.(Val427AlafsTer31)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (internal lab contributor). In summary, the c.1278_1279del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771800/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Supports CHEBI:31932 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0149514 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0239295 infores:hetionet CHEBI:16480 biolink:causes MONDO:0015742 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0023529 infores:hetionet CHEBI:7824 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0702166 infores:hetionet CHEBI:5296 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0023530 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0235416 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0520893 infores:hetionet CHEBI:6754 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0522224 infores:hetionet CHEBI:7443 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0687713 infores:hetionet CHEBI:63611 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0080274 infores:hetionet CHEBI:78320 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0677500 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0029408 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0008489 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042109 infores:hetionet CHEBI:100241 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004134 infores:hetionet CAID:CA232898 biolink:causes MONDO:0010726 infores:clingen CAID:CA232898 MONDO:0010726 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting The p.Val380fs variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Val380fs variant has been observed in at least 2 individuals with neurodevelopmental phenotypes (GeneDx internal cases) (PS4_Supporting). The p.Val380fs variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary the p.Val380fs variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PVS1, PS4_Supporting, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA232898/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf GO:0010058 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0010058 GO:0007275 CHEBI:6128 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0009676 infores:hetionet CHEBI:8776 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0012833 infores:hetionet CHEBI:4911 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0039231 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1565489 infores:hetionet CHEBI:2914 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0016382 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020456 infores:hetionet CHEBI:180905 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0013604 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0857353 infores:hetionet CHEBI:3647 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0011168 infores:hetionet CHEBI:3561 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0025874 infores:hetionet NCBIGene:6342 biolink:causes MONDO:0013391 infores:monarchinitiative not_provided not_provided HGNC:10606 MONDO:0013391 uuid:3755a189-c07b-4f47-a0f8-1daace58b34c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46345 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0003811 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0548823 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0018099 infores:hetionet CHEBI:16469 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235086 infores:hetionet CHEBI:135679 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0030193 infores:hetionet CHEBI:8356 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018965 infores:hetionet CHEBI:45979 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0234632 infores:hetionet CHEBI:64064 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0020523 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0085584 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0020649 infores:hetionet CHEBI:408174 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0039240 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0267792 infores:hetionet CHEBI:2654 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C2830004 infores:hetionet CHEBI:3752 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0025323 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0010032 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0010032 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020565 infores:hetionet CHEBI:3286 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0702166 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0002418 infores:hetionet CHEBI:46557 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0008031 infores:hetionet CHEBI:50730 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0018524 infores:hetionet CHEBI:8059 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0013428 infores:hetionet CHEBI:64312 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017168 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0549373 infores:hetionet CHEBI:4710 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0085631 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006325 infores:hetionet CHEBI:28748 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002874 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0027765 infores:hetionet CHEBI:64312 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013384 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0018674 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0003123 infores:hetionet CHEBI:29007 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0011606 infores:hetionet CHEBI:9599 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0013404 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0012833 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004096 infores:hetionet CHEBI:136040 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0009782 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0684249 infores:hetionet CHEBI:2788 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0542571 infores:hetionet CHEBI:5138 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027066 infores:hetionet CHEBI:253342 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C2047937 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022660 infores:hetionet CHEBI:63791 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0221201 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019348 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0700345 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0041969 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002886 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0007785 infores:hetionet CHEBI:63115 biolink:causes MONDO:0004095 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0079731 infores:hetionet CHEBI:3568 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0687713 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0002871 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030305 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0854382 infores:hetionet CHEBI:7494 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0027849 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0009450 infores:hetionet CHEBI:50659 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0235431 infores:hetionet CHEBI:28487 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0043094 infores:hetionet CHEBI:8069 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C2830004 infores:hetionet CHEBI:5138 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0030794 infores:hetionet CHEBI:2666 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0520966 infores:hetionet CHEBI:3215 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0034880 infores:hetionet CHEBI:7983 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0011606 infores:hetionet CHEBI:231594 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0040460 infores:hetionet CHEBI:47499 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0018681 infores:hetionet CHEBI:15367 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085077 infores:hetionet NCBIGene:644096 biolink:causes MONDO:0030935 infores:monarchinitiative not_provided not_provided HGNC:33867 MONDO:0030935 uuid:5c8f8ad3-3d3f-4ca9-97ab-3d5aaf7314d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0031039 infores:hetionet NCBIGene:116115 biolink:causes MONDO:0859251 infores:monarchinitiative not_provided not_provided HGNC:29415 MONDO:0859251 uuid:67775143-3903-495a-b456-0a30d09df063 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226728 biolink:causes MONDO:0010725 infores:clingen CAID:CA226728 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS3, PS4, PP3_Moderate, PP1_Strong, PP4 NM_000330.4(RS1):c.421C>T (p.Arg141Cys) is a missense variant encoding the substitution of arginine with cysteine at amino acid 141. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 5 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMID: 34828422, PMID: 34822951, PMID: 33124204, PMID: 30025115, PMID: 39435478, PS4). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 19093009, PP4). The variant has been reported to segregate with X-linked retinoschisis through at least 3 meioses in two families (PP1_Strong; PMID: 19093009). Additional publications report on other families diagnosed with retinitis pigmentosa, however, the genotyped family members were limited to an unaffected mother and the proband, which were not included in the PP1 crtierion (PMID: 34828422, PMID: 33124204). The computational predictor REVEL gives a score of 0.817, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.01 for donor gain and 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. Knock-in mice harboring the variant exhibited reduced electroretinogram b-wave amplitudes and developed schisis (PMID: 31174210, PS3). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Moderate, PS3, PS4, PP4, and PP1_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226728/MONDO:0010725/126 2025-09-22 2025-09-22 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:46081 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0008370 infores:hetionet CHEBI:17141 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0852911 infores:hetionet CAID:CA135028 biolink:causes MONDO:0021060 infores:clingen CAID:CA135028 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1068A>G (p.Gln356=) variant in the BRAF gene is 0.115% (27/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135028/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:231594 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1458155 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002622 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0522172 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0234215 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0162830 infores:hetionet CHEBI:5801 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0162557 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0178298 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151763 infores:hetionet CHEBI:84883 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0085593 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0518015 infores:hetionet CHEBI:2208 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0008370 infores:hetionet CHEBI:63631 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020488 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0009806 infores:hetionet CHEBI:10650 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0016382 infores:hetionet CHEBI:5106 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0042029 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233459 infores:hetionet CHEBI:36795 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009763 infores:hetionet CHEBI:65349 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0011603 infores:hetionet CHEBI:125354 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0027497 infores:hetionet CHEBI:74947 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013404 infores:hetionet GO:1903302 biolink:causes GO:0009060 infores:ubergraph knowledge_assertion manual_agent GO:1903302 GO:0009060 CHEBI:6129 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0017675 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151736 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0025061 infores:hetionet CAID:CA8328525 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328525 MONDO:0100438 PMID: Uncertain Significance PP3, PM2_Supporting NM_014336.5(AIPL1):c.383C>T (p.Ala128Val) is a missense variant in exon 3 of 6 that is predicted to change alanine to valine at amino acid p.128. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0002108, with 340 alleles / 1,613,238 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004. Additionally, there are no homozygotes recorded in gnomAD (PM2_Supporting). The computational predictor REVEL gives a score of 0.689, which is slightly above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing (PP3). No published probands harboring the variant have been identified. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328525/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:47780 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0429098 infores:hetionet GO:0003427 biolink:causes GO:0060348 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0060348 CHEBI:64028 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0041969 infores:hetionet CHEBI:7514 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0549373 infores:hetionet CAID:CA16620249 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620249 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1565+1delG variant is a canonical splice variant predicted to result in an altered or absent protein (PVS1_strong). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant is at +1 donor site variant with other pathogenic canonical splicing variants curated at the same splice site (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620249/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:59773 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0152031 infores:hetionet UMLS:C0010592 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020453 infores:hetionet CHEBI:188986 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0085636 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0033975 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0013395 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0152227 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0234458 infores:hetionet CAID:CA45506319 biolink:causes MONDO:0800472 infores:clingen CAID:CA45506319 MONDO:0800472 PMID:17363580PMID:10910054PMID:11854439 Benign BA1 PP3, PP1, BP4, PS3, PS1, PS2, PM3, PM1, PM4, PM5, BP7, BS1, BS4, PM2, PVS1 The c.1294C>G variant in CYP1B1 is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 432 (p.Leu432Val). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.7774, which met the ≥ 0.05 threshold set for BA1 (58,263 alleles out of 74,942, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant is not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), but a REVEL score was unavailable for this variant, thus BP4 was not applied. PS3_Supporting was not applied as the assays reported in PMIDs: 11854439, 17363580, 10910054 did not meet the OddsPath threshold (> 2.1). In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA45506319/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3387 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0429097 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151744 infores:hetionet CHEBI:2379 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0231218 infores:hetionet CHEBI:47381 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002994 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0007642 infores:hetionet CHEBI:4911 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0018790 infores:hetionet CHEBI:3561 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0030252 infores:hetionet CAID:CA414796749 biolink:causes MONDO:0044970 infores:clingen CAID:CA414796749 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PP1, PS2, PS4, PS3, PM6 The m.8570T>C variant (p.L15P in MT-ATP6; p.Term669Q in MT-ATP8) has not been reported in individuals with primary mitochondrial disease to date. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414796749/MONDO:0044970/015 2024-12-09 2025-05-16 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3176 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0025061 infores:hetionet CHEBI:80630 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0002792 infores:hetionet CHEBI:47898 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013604 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0015230 infores:hetionet CHEBI:9763 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0037763 infores:hetionet CHEBI:3175 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0010520 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004936 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042109 infores:hetionet CAID:CA392257504 biolink:causes MONDO:0012996 infores:clingen CAID:CA392257504 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_001482.3:c.958C>T variant in GATM is a missense variant that is predicted to result in the substitution of proline by serine at amino acid 320 (p.Pro320Ser). It is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.356 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. To our knowledge, this variant has not been reported in an individual with phenotypic features of AGAT deficiency. It has been reported as a single heterozygous variant segregating in a family autosomal dominant renal Fanconi syndrome and kidney failure (PMID: 29654216). However, classification with respect to this alternative disorder is outside the scope of this curation. There is a ClinVar entry for this variant (Variation ID: 917493). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392257504/MONDO:0012996/025 2023-01-24 2023-01-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15854 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C1384666 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0026650 infores:hetionet CHEBI:8713 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0004604 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0574067 infores:hetionet CHEBI:3181 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042420 infores:hetionet CHEBI:8435 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0030446 infores:hetionet CHEBI:63620 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018524 infores:hetionet CHEBI:6958 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0018799 infores:hetionet CHEBI:100241 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151872 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1458155 infores:hetionet CHEBI:64310 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151786 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027765 infores:hetionet CHEBI:2955 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1457883 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001625 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0010093 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0541831 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0541831 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0011570 infores:hetionet CHEBI:3310 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0428977 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0948525 infores:hetionet CHEBI:41423 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011071 infores:hetionet CHEBI:83531 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0013378 infores:hetionet CAID:CA637749751 biolink:causes MONDO:0011071 infores:clingen CAID:CA637749751 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.58+10T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.20) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637749751/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9943 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0740425 infores:hetionet CHEBI:17549 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0162835 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151705 infores:hetionet GO:0070808 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0070808 GO:0007275 CHEBI:28748 biolink:causes UMLS:C0856053 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0856053 infores:hetionet GO:0001649 biolink:causes CL:0000062 infores:ubergraph knowledge_assertion manual_agent GO:0001649 CL:0000062 CHEBI:64355 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0948525 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027651 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0018991 infores:hetionet CHEBI:71940 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0542571 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0541923 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0541923 infores:hetionet CHEBI:5384 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C1443060 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1384666 infores:hetionet CAID:CA367398780 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398780 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1139A>C variant in the glucokinase gene, GCK, causes an amino acid change of histidine to proline at codon 380 (p.(His380Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.789, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in nine unrelated individuals with hyperglycemia (PS4; PMIDs: 34440516, 19790256, internal lab contributors). At least two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 2 hour OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate, PMID: 34440516, internal lab contributor). This variant segregated with hyperglycemia, with at least eight informative meioses in six families (PP1_Strong; PMID: 34440516, internal lab contributor). In summary, c.1139A>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PS4, PP2, PP3, PM2_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398780/MONDO:0015967/086 2023-09-19 2023-09-19 Semidominant inheritance HP:0032113 Supports CHEBI:5959 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0043352 infores:hetionet NCBIGene:1743 biolink:causes MONDO:0032771 infores:monarchinitiative not_provided not_provided HGNC:2911 MONDO:0032771 uuid:d670637a-9c91-4f27-a106-8cec35896915 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151578 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0011849 infores:hetionet CHEBI:48273 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0003467 infores:hetionet CHEBI:490877 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0004364 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042075 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0037274 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0948349 infores:hetionet NCBIGene:23031 biolink:causes MONDO:0859314 infores:monarchinitiative not_provided not_provided HGNC:19036 MONDO:0859314 uuid:2d5c175e-abc8-4bd1-848c-24b7bfc4c29c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46345 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0016059 infores:hetionet NCBIGene:130951 biolink:causes MONDO:0030846 infores:monarchinitiative not_provided not_provided HGNC:25183 MONDO:0030846 uuid:de884a29-83c2-4fcf-8ace-a6498058083a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0023610 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0013390 infores:hetionet CHEBI:10127 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0016204 infores:hetionet CHEBI:9555 biolink:causes EFO:0005632 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C2243080 infores:hetionet CHEBI:3732 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0009763 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0042769 infores:hetionet CAID:CA280052 biolink:causes MONDO:0021060 infores:clingen CAID:CA280052 MONDO:0021060 PMID:20395089PMID:21871821PMID:18039235PMID:16474404 Likely Pathogenic PS4_Moderate, PM5, PM2, PP3, PP2 PS3 The c.1454T>C (p.Leu485Ser) variant in BRAF is absent from gnomAD (PM2). It has been identified in at least 4 patients clinically diagnosed with Cardiofaciocutaneous syndrome (CFC) (PS4_Moderate; 18039235, 21871821, 20395089, SCV000197150.4). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Additionally, computational prediction tools and conservation analysis suggest that p.Leu485Ser may affect the protein (PP3). Two different pathogenic missense variants have been previously identified at this codon of BRAF, each resulting in p.Leu485Phe, which supports that this residue may be critical to the function of the protein (PM5; ClinVar 177844, 13975). A functional assay has been performed on this variant, but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:16474404). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PP2, PP3, PM5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280052/MONDO:0021060/004 2020-02-27 2020-02-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3723 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0277925 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0476089 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0031350 infores:hetionet CHEBI:94848 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0232292 infores:hetionet CHEBI:567361 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0085593 infores:hetionet CAID:CA382551078 biolink:causes MONDO:0700270 infores:clingen CAID:CA382551078 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.6212T>A (p.Leu2071*) variant in ATM gene is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382551078/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:205919 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0035854 infores:hetionet CHEBI:5778 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030920 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0746883 infores:hetionet CHEBI:10119 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0003862 infores:hetionet CHEBI:49375 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0156404 infores:hetionet NCBIGene:84529 biolink:causes MONDO:0014285 infores:monarchinitiative not_provided not_provided HGNC:26929 MONDO:0014285 uuid:cc5f9801-bbf1-4e98-9451-d12cada3fa16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA242074 biolink:causes MONDO:0015152 infores:clingen CAID:CA242074 MONDO:0015152 PMID: Likely Benign BS1, PP3 PM3, PP4 The NM_003494.4: c.1966A>G variant in DYSF, which is also known as NM_001130987.2: c.2020A>G p.(Lys674Glu), is a missense variant predicted to cause substitution of lysine to glutamic acid at amino acid 656, p.(Lys656Glu). The Grpmax filtering allele frequency of this variant is 0.001638 (the lower threshold of the 95% CI of 169/90468 chromosomes) in the South Asian population of gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold >0.001 for BS1, meeting this criterion (BS1). There are also four homozygotes in gnomAD v4.1.0. This variant has been reported in at least two individuals with suspected LGMD with no second DYSF variant identified (PMID: 36983702, 30564623). It has also been reported in one patient with Miyoshi myopathy who was also heterozygous for a pathogenic DYSF variant (NM_003494.4: c.2200-2205delinsT p.(Thr734SerfsTer18); PMID: 26088049) but without convincing evidence for pathogenicity (PM3_Supporting not met since BS1 is met). The computational predictor REVEL gives a score of 0.795, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/30/2025): BS1, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA242074/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15854 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0004245 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0149931 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0162429 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0235146 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013395 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0040034 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0015376 infores:hetionet CHEBI:15553 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0013404 infores:hetionet CHEBI:4657 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0428977 infores:hetionet CL:0000166 biolink:causes MONDO:0021072 infores:ubergraph knowledge_assertion manual_agent CL:0000166 MONDO:0021072 CHEBI:4909 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0038325 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0006849 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0340464 infores:hetionet CAID:CA287434293 biolink:causes MONDO:0008723 infores:clingen CAID:CA287434293 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c199A>T (p.Lys67Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency without an additional ACADVL variant identified or assertion of follow-up plasma acylcarnitines (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. VCEP specifications v2.0; Approved on 08/12/2021. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287434293/MONDO:0008723/021 2022-02-22 2022-02-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6539 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0338831 infores:hetionet CHEBI:8764 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0028961 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0740399 infores:hetionet UMLS:C0025241 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0476273 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014518 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0009241 infores:hetionet CAID:CA915940805 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940805 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000212.3(ITGB3):c.161_165+1delinsCTGATT occurs within the canonical splice donor site of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2, resulting in a frameshift with a premature stop codon in exon 3/15, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Confirmation of exon 2 deletion was made by RT-PCR in patient cells (PVS1; PMID: 8471765). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). One homozygous patient has been reported with Glanzmann thrombasthenia (PMID: 8471765; PM3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 01/18/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940805/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50730 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0014457 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0233494 infores:hetionet NCBITaxon:42231 biolink:causes MONDO:0005731 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:42231 MONDO:0005731 CAID:CA226342 biolink:causes MONDO:0100437 infores:clingen CAID:CA226342 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.1092dup (p.Ala365CysfsTer12) is a 1-bp duplication variant in exon 10 of 15, which results in a frameshift and premature stop codon after 12 amino acids and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 10937588, 21857984, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226342/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:8869 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0032584 infores:hetionet CHEBI:10119 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0522224 infores:hetionet CHEBI:8764 biolink:causes HP:0020071 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042749 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0349506 infores:hetionet CHEBI:8081 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0033774 infores:hetionet CHEBI:50859 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0037287 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0259799 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1610049 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1610049 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0542313 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0542313 infores:hetionet CHEBI:8772 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0020458 infores:hetionet CHEBI:50648 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004364 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0403632 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0012833 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0013395 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0155003 infores:hetionet CHEBI:100241 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151937 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0241705 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001498 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042341 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0033975 infores:hetionet CHEBI:681850 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0032617 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020676 infores:hetionet CAID:CA410150264 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150264 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BA1, BS1, BS3, BS4, BP7, PM6, PVS1, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.829C>T (p.Pro277Ser) s a missense variant which is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, which provide coverage of at least 20x for the RUNX1 gene at this genomic position (PM2_supporting). Additionally, this missense variant has a REVEL score <0.50 (0.447) (BP4) and affects a residue located outside of the RHD or amino acids 89-204. To our knowledge, this variant has not been reported before in patients with RUNX1-related disorders, and functional studies are not available. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150264/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63577 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0000731 infores:hetionet CHEBI:5959 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0086565 infores:hetionet CAID:CA409106289 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106289 MONDO:0015967 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong The c.582+1G>C variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of transcript NM_175914.5. This variant is predicted to cause an in-frame deletion of the biologically-relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide with negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). In summary, c.582+1G>C, meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PVS1_Strong, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106289/MONDO:0015967/085 2023-03-26 2023-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5801 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0015672 infores:hetionet CHEBI:5138 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0034880 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0038454 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0521591 infores:hetionet CHEBI:28001 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0018784 infores:hetionet CHEBI:7447 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0042109 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0004238 infores:hetionet CHEBI:45716 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0011991 infores:hetionet CHEBI:8774 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0008031 infores:hetionet CHEBI:68606 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0392525 infores:hetionet CAID:CA8328551 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328551 MONDO:0100438 PMID: Uncertain Significance PP3, PM2_Supporting NM_014336.5(AIPL1):c.281C>T (p.Thr94Met) is a missense variant replacing the threonine at position p.94 with methionine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000030, with 50 alleles / 1613732 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.687, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function (PP3). There are 3 submissions to ClinVar but no publications. In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328551/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3723 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232208 infores:hetionet NCBIGene:2626 biolink:causes MONDO:0013746 infores:monarchinitiative not_provided not_provided HGNC:4173 MONDO:0013746 uuid:7eda1cd7-987f-471c-9790-2fc437ebc74c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0004936 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0019158 infores:hetionet CHEBI:4511 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0542184 infores:hetionet CHEBI:175901 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0003862 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C3665347 infores:hetionet CHEBI:16664 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0020517 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0234458 infores:hetionet CHEBI:4877 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C3665347 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0031846 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0015802 infores:hetionet CHEBI:71219 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0242698 infores:hetionet CHEBI:42797 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0231530 infores:hetionet CHEBI:32315 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0035243 infores:hetionet CHEBI:47381 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0392163 infores:hetionet CAID:CA1139667436 biolink:causes MONDO:0100437 infores:clingen CAID:CA1139667436 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.1872_1873del (p.Glu624AspfsTer5) is a frameshift variant due to a two-nucleotide deletion that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper function of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), night blindness (0.5 pts), electroretinogram responses consistent with retinitis pigmentosa, and reduced visual fields (0.5 pts), with genotyping by next-generation sequencing identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4 points, ClinVar Accession: SCV001427266.1, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/pr decreased or absent electroretinogram responses (PMID: 34745198), in addition to the proband previously used to meet the PP4 code (ClinVar Accession: SCV001427266.1) (PS4_Supporting). This variant has been reported in at least 6 other apparently unrelated probands (PMID: 34985506, PMID: 37217489, PMID: 12657579, PMID: 12402343, PMID: 32531858, PMID: 30902645, ClinVar Accession: SCV001427266.1) who were not described in sufficient detail for inclusion in PS4. The variant has been reported to segregate with retinal dystrophy through an affected mother and son (PP1; PMID: 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP4, PS4_Supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139667436/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:10650 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0039231 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0036572 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0019080 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0017160 infores:hetionet CHEBI:70735 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0004245 infores:hetionet GO:0044559 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:0044559 GO:0071805 CAID:CA415078874 biolink:causes MONDO:0010305 infores:clingen CAID:CA415078874 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The NM_005629.4:c.507G>A p.(Trp169Ter) variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 3/13, and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent in gnomADv2.1.1, meeting criteria for PM2_Supporting, and has not been previously reported in ClinVar. The p.Trp169Ter variant in the SLC6A8 gene has been reported in 1 male individual with Autism, Intellectual disability, afebrile seizures, and proximal motor weakness and was identified to be inherited from his mother with mild intellectual disability [PMID:34974949]. While this individual was clinically diagnosed with Creatine Transporter Deficiency, specific biochemical testing results for this patient were not provided, therefore PP4 criteria is not applicable. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1, PM2_Supporting. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ).(Classification approved by the ClinGen CCDS VCEP:, August 24, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415078874/MONDO:0010305/027 2023-08-24 2024-04-10 X-linked inheritance HP:0001417 Supports NCBIGene:5831 biolink:causes MONDO:0013755 infores:monarchinitiative not_provided not_provided HGNC:9721 MONDO:0013755 uuid:ab499976-f626-42fc-ba7a-4c2f4f7c5d59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085593 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018939 infores:hetionet CHEBI:51860 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0857305 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0149931 infores:hetionet CHEBI:3515 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0002792 infores:hetionet CHEBI:50885 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0917801 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011849 infores:hetionet NCBITaxon:775 biolink:causes MONDO:0006927 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:775 MONDO:0006927 CHEBI:63608 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0852911 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0240066 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0240066 infores:hetionet CHEBI:8461 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0027540 infores:hetionet CHEBI:3423 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0235378 infores:hetionet CHEBI:17823 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0030196 infores:hetionet CHEBI:48273 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0022281 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1328337 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0242656 infores:hetionet NCBIGene:7439 biolink:causes MONDO:0012733 infores:monarchinitiative not_provided not_provided HGNC:12703 MONDO:0012733 uuid:9c68fbbc-35b2-4caf-bdda-ecb1d0098802 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16586 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0005779 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0011991 infores:hetionet CHEBI:6062 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020598 infores:hetionet CAID:CA2573320295 biolink:causes MONDO:0100216 infores:clingen CAID:CA2573320295 MONDO:0100216 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting PVS1, BA1, BP4, BP2, BS2, PP1, PP4, PM5, PM1, PM4, PS1, PS2, PS3, BP7, BS1, BS4, BS3 The NM_177438.3:c.2650+5_2650+7del variant in DICER1 is an intronic variant in intron 16. This variant received a total of 1 phenotype point across 1 unrelated proband/family, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PM2_Supporting, PP3. (Bayesian Points: 3; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573320295/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3504 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0042571 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0017160 infores:hetionet CHEBI:6761 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0036974 infores:hetionet GO:0039595 biolink:causes GO:0006402 infores:ubergraph knowledge_assertion manual_agent GO:0039595 GO:0006402 CHEBI:49375 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018418 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0004238 infores:hetionet CHEBI:63607 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0013491 infores:hetionet CHEBI:23765 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0025874 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0004096 infores:hetionet CHEBI:8024 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151636 infores:hetionet CAID:CA120616 biolink:causes MONDO:0044970 infores:clingen CAID:CA120616 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PS3, PM6 The m.15615G>A (p.Gly290Asp) variant in MT-CYB has been reported in one individual with primary mitochondrial disease (PMID: 8910895). This individual had exercise intolerance, elevated blood lactate, and ragged red fibers on muscle biopsy. Complex III deficiency was noted in muscle. The variant was present at 80% heteroplasmy in muscle and was undetectable in blood. The variant was also undetectable in blood from the unaffected mother and two unaffected sisters. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.82 (Min=0, Max=1, PP3). There are no single fiber studies or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120616/MONDO:0044970/015 2025-02-04 2025-11-11 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:100246 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151827 infores:hetionet CAID:CA244520152 biolink:causes MONDO:0015967 infores:clingen CAID:CA244520152 MONDO:0015967 PMID: Uncertain Significance PM1_Supporting, PP4 PS4, PM2, PP1 The c.-258A>G variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This variant is located in the promoter of NM_000545.8. This variant is located at the HNF1A binding site (c.-238 to c.-259) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.-258A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244520152/MONDO:0015967/017 2024-01-18 2024-01-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:38940 biolink:causes UMLS:C1704381 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1704381 infores:hetionet CHEBI:7445 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0151827 infores:hetionet CHEBI:16469 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151905 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0027765 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0033687 infores:hetionet CHEBI:27899 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0267792 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0010709 infores:hetionet GO:0072106 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0072028 CHEBI:8107 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0235567 infores:hetionet CHEBI:51209 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0233494 infores:hetionet CHEBI:48273 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0022107 infores:hetionet CAID:CA229620 biolink:causes MONDO:0009861 infores:clingen CAID:CA229620 MONDO:0009861 PMID:23357515 Pathogenic PVS1, PM2, PP4, PM3_Supporting This c.556del (p.Thr186fs) variant in PAH has been observed in two patients with non-PKU hyperphenylalaninemia, with pathogenic variant p.Arg408Trp, phase unknown (PMID: 23357515). This variant is absent from controls in population databases. This is a predicted null frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229620/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38940 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0474378 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020550 infores:hetionet CHEBI:4784 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0547030 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0235234 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042401 infores:hetionet CAID:CA377784477 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784477 MONDO:0017623 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PS4_Supporting, PS2 NM_000314.8(PTEN):c.107G>A (p.Gly36Glu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor: SCV001781083.1)PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.797438259 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor: SCV001781083.1)PM2_P: Absent in gnomAD.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.98). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784477/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7823 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0039070 infores:hetionet CHEBI:3216 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0018524 infores:hetionet NCBIGene:10667 biolink:causes MONDO:0013986 infores:monarchinitiative not_provided not_provided HGNC:21062 MONDO:0013986 uuid:ae9ff55d-1fc9-4882-8900-2bce5b56e2c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0038454 infores:hetionet CHEBI:8435 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0022354 infores:hetionet GO:1901261 biolink:causes GO:0048837 infores:ubergraph knowledge_assertion manual_agent GO:1901261 GO:0048837 CAID:CA410204142 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204142 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.144C>A (p.Ser48Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204142/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3515 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0427008 infores:hetionet CHEBI:6801 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0235430 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0041912 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0003123 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0012833 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002622 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0235296 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235296 infores:hetionet CAID:CA404083996 biolink:causes MONDO:0007750 infores:clingen CAID:CA404083996 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 PS3, PM5 The NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for definite/possible FH after alternative causes of high cholesterol were excluded. Reported by Miroshnikova et al, National Research Center ”Kurchatov Institute”, Gatchina, Russian Federation, PMID 33269076. PP3: REVEL= 0.702, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. The variant is predicted affecting splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23 Variant canonical donor motif: TGCGTGAGC, MES: 3.45. Var/Wt ratio = 0.48, (< 0.8), met PP3.PS3 not met: Functional data not available.PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404083996/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA1139532270 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139532270 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PP4, PM3 The c.1801del variant in ACADVL, also published as 1798del1, is a frameshift variant that may cause loss of function of the protein; however, it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been reported presumed in trans to a likely pathogenic variant, but this individual does not meet the ACADVL VCEP criteria to be counted as affected with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, so this information is not considered evidence of pathogenicity. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532270/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10127 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0014868 infores:hetionet CHEBI:31236 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0001973 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042769 infores:hetionet CAID:CA10584253 biolink:causes MONDO:0021056 infores:clingen CAID:CA10584253 MONDO:0021056 PMID:18199528 Uncertain Significance PS3_Supporting, BP1, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.4735A>T variant in APC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid position 1579 (p.Ile1579Phe). β-catenin regulated transcription activity assay in SW480 cells showed increased β-catenin regulated transcription activity indicating that this variant impacts protein function (PS3_Supporting, PMID: 18199528). This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 points (PS4_Supporting [Ambry Genetics, Invitae, GeneDx]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_Supporting, PS4_Supporting, PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584253/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49375 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018800 infores:hetionet CHEBI:6715 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0018681 infores:hetionet CHEBI:7627 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0340865 infores:hetionet CHEBI:9763 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151610 infores:hetionet CHEBI:119915 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235761 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0010037 infores:hetionet CHEBI:5558 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C2830004 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018799 infores:hetionet CHEBI:17650 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0231528 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0497365 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0017574 infores:hetionet CHEBI:38562 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0014518 infores:hetionet CHEBI:8869 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0015967 infores:hetionet CHEBI:41423 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0019080 infores:hetionet CAID:CA10608378 biolink:causes MONDO:0005338 infores:clingen CAID:CA10608378 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BS1, BS3, BP7, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.335A>G variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Glycine at amino acid 112 (p.Glu112Gly). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000002543 (3 alleles out of 1,179,584), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.082, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA10608378/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5775 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0037763 infores:hetionet CHEBI:3437 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0344232 infores:hetionet GO:0060782 biolink:causes GO:0001655 infores:ubergraph knowledge_assertion manual_agent GO:0060782 GO:0001655 CHEBI:61049 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006840 infores:hetionet CHEBI:4657 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0028643 infores:hetionet CHEBI:6715 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042790 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041912 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0948594 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0031117 infores:hetionet CHEBI:17334 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0231530 infores:hetionet CAID:CA000618 biolink:causes MONDO:0017623 infores:clingen CAID:CA000618 MONDO:0017623 PMID: Likely Benign BS1, PP2, BP4 PM2, PM6, PVS1, BS3, BS4, BP5, BP7, BS2, PP3, PP1, PP4, PM5, PM3, PM4, PM1, BA1, BP1, BP2, BP3, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.882T>G (p.Ser294Arg) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1: Filtering allele frequency of 0.0002887 (0.02887%, 13/24922 African/African American alleles) in gnomAD. BP4: REVEL score = 0.365. PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID: 29300386): BS1 (-4 pts), BP4 (-1 pt), PP2 (+1 pt) = -4 pts total (Likely Benign). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000618/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009676 infores:hetionet CHEBI:5138 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0012569 infores:hetionet CHEBI:2611 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0018681 infores:hetionet CHEBI:63617 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151766 infores:hetionet CHEBI:92998 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020621 infores:hetionet CHEBI:119573 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037287 infores:hetionet CAID:CA414906836 biolink:causes MONDO:0010602 infores:clingen CAID:CA414906836 MONDO:0010602 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PP3 PS4 The c.5815G>C variant in F8 is a missense variant predicted to cause substitution of Alanine by Proline at amino acid 1939 in the last codon in exon 17, affecting the A3 domain of Factor VIII. It is reported affecting one individual in EAHAD with FVIII:C 1-stage =<1% with full gene sequencing and deletion/duplication analysis done, therefore it meets the phenotypic criteria for PP4_Moderate to be applied (PMID: 29296726). This variant has been reported in 1 proband with severe hemophilia A. However, PS4_Supporting cannot be applied because the individual also has a c.5493C>G i.e., p.(Thr1831Thr) variant (PMID: 30793713). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.6, and Splice AI gives a score of 0.94 for donor loss, which is above the threshold of 0.5 set by the CFD VCEP and is evidence that correlates with impact to F8 function (PP3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F8 (version 1.0.0, released 10/5/2023): PP4_Moderate, PP3_Supporting, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414906836/MONDO:0010602/071 2024-10-11 2024-10-11 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63629 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0034065 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011551 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0005741 infores:hetionet CHEBI:27300 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0427008 infores:hetionet CAID:CA346365698 biolink:causes MONDO:0021060 infores:clingen CAID:CA346365698 MONDO:0021060 PMID: Uncertain Significance PM2, PP2 PS4, PM5, PM1, PP3 The c.1645A>G (p.Thr549Ala) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346365698/MONDO:0021060/004 2020-03-19 2020-03-23 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:82960 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0149931 infores:hetionet CHEBI:46195 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0235063 infores:hetionet CHEBI:50861 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0151825 infores:hetionet CHEBI:175901 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0008031 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0344315 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0039971 infores:hetionet CHEBI:50922 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0162529 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004623 infores:hetionet CHEBI:83531 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0001807 infores:hetionet CHEBI:10110 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1325847 infores:hetionet UMLS:C0025241 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0231528 infores:hetionet CHEBI:7581 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233514 infores:hetionet CHEBI:50692 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0085649 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0037199 infores:hetionet CHEBI:45081 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0023380 infores:hetionet CHEBI:48273 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0002963 infores:hetionet CHEBI:9738 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0026961 infores:hetionet CHEBI:45783 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0000731 infores:hetionet NCBIGene:2626 biolink:causes MONDO:0008542 infores:monarchinitiative not_provided not_provided HGNC:4173 MONDO:0008542 uuid:75ef67e7-07ff-40fc-a684-b546f10b19f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0013378 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0278080 infores:hetionet CHEBI:119573 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0015967 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002263 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0017411 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0150450 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020615 infores:hetionet CHEBI:145499 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0035455 infores:hetionet GO:2000764 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:2000764 GO:0007507 CHEBI:8871 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1320835 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234215 infores:hetionet CHEBI:9943 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151907 infores:hetionet CHEBI:8232 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0018944 infores:hetionet CHEBI:63599 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0019079 infores:hetionet CHEBI:132233 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0013395 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0857448 infores:hetionet CHEBI:3504 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0026636 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0267596 infores:hetionet CHEBI:82960 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0006277 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0017658 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042109 infores:hetionet NCBIGene:166378 biolink:causes MONDO:0014698 infores:monarchinitiative not_provided not_provided HGNC:18119 MONDO:0014698 uuid:617f2a5c-84e7-4a82-b457-8d4e6eb3a3c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2363731 infores:hetionet CHEBI:3223 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0242429 infores:hetionet CHEBI:8207 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011603 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0034065 infores:hetionet CHEBI:76010 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0019196 infores:hetionet CHEBI:9727 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0027947 infores:hetionet CHEBI:8107 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151827 infores:hetionet CHEBI:92923 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C3263723 infores:hetionet CHEBI:32293 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0547030 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0475765 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0475765 infores:hetionet CHEBI:92712 biolink:causes HP:0002312 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0233844 infores:hetionet CHEBI:63115 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0004604 infores:hetionet CHEBI:42797 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011603 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0521476 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0521476 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0574002 infores:hetionet CHEBI:63925 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0151827 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0007642 infores:hetionet CHEBI:50659 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0013395 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0026946 infores:hetionet CAID:CA16616503 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616503 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1387C>T (p.Pro463Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616503/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8694 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0043352 infores:hetionet CHEBI:10101 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020625 infores:hetionet CHEBI:16469 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0016204 infores:hetionet CHEBI:2549 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0026821 infores:hetionet CHEBI:18332 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0003862 infores:hetionet CHEBI:3061 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0013395 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0235146 infores:hetionet CHEBI:27565 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0024523 infores:hetionet NCBITaxon:1763 biolink:causes MONDO:0020590 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1763 MONDO:0020590 CHEBI:3387 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0029408 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0004936 infores:hetionet CHEBI:567361 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0030554 infores:hetionet CHEBI:31236 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2830004 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002170 infores:hetionet CHEBI:6887 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0311468 infores:hetionet CAID:CA16616259 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616259 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1266G>C (p.Glu422Asp) is a missense variant which has a REVEL score < 0.50 (0.11) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616259/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5775 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0027497 infores:hetionet CHEBI:9086 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151836 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1384606 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0403632 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0030193 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0239978 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0038454 infores:hetionet GO:0032888 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0032888 GO:0140014 NCBIGene:9739 biolink:causes MONDO:0030005 infores:monarchinitiative not_provided not_provided HGNC:29010 MONDO:0030005 uuid:cd4316e2-2e5d-4c69-8ddc-627ccbe512a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3814 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0008325 infores:hetionet CHEBI:8228 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0020615 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0036572 infores:hetionet CHEBI:84883 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0011071 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152027 infores:hetionet CHEBI:47519 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0027497 infores:hetionet CHEBI:31236 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0231528 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1167686 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1167686 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0149904 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0151505 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0014868 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0853619 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013985 infores:hetionet CAID:CA256478 biolink:causes MONDO:0021060 infores:clingen CAID:CA256478 MONDO:0021060 PMID:17875937 Pathogenic PP3, PP2, PM2_Supporting, PS3_Moderate, PS4, PS2_Very Strong BA1, BP4, BS1, BS3 The c.458A>T variant in the KRAS gene is a missense variant predicted to cause substitution of asparagine by valine at amino acid 153 (p.Asp153Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.791 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in at least 6 individuals with four confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies showed that this variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 17875937, 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256478/MONDO:0021060/044 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31932 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002994 infores:hetionet CHEBI:2208 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0013604 infores:hetionet CHEBI:45924 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0013404 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011991 infores:hetionet GO:0044827 biolink:causes GO:0019058 infores:ubergraph knowledge_assertion manual_agent GO:0044827 GO:0019058 NCBIGene:5932 biolink:causes MONDO:0011715 infores:monarchinitiative not_provided not_provided HGNC:9891 MONDO:0011715 uuid:bc2eb043-5bee-49ed-b11a-7c24e0ce86dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0042963 infores:hetionet CHEBI:77733 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0041657 infores:hetionet CHEBI:9637 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0020649 infores:hetionet CHEBI:10101 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0004093 infores:hetionet CAID:CA367398313 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398313 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1228G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 410 (p.(Gly410Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Two other missense variants, c.1229G>A p.Gly410Asp and c.1228G>A p.Gly410Ser, have been interpreted as pathogenic by the ClinGen MDEP, and p.Gly410Arg has a greater Grantham distance than p.Gly410Asp and p.Gly410Ser (PM5_Strong). In summary, c.1228G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398313/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:499361 biolink:causes UMLS:C0740401 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0740401 infores:hetionet CHEBI:31644 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0019348 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0919874 infores:hetionet CHEBI:6970 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C1527344 infores:hetionet CAID:CA10576905 biolink:causes MONDO:0019501 infores:clingen CAID:CA10576905 MONDO:0019501 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3 The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID: 21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022).1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576905/MONDO:0019501/005 2023-01-18 2023-02-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:44185 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0037822 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0018802 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0011414 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0011414 uuid:42fb79ef-ec99-41b4-bf68-6b52744a9551 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000491 biolink:causes MONDO:0018875 infores:clingen CAID:CA000491 MONDO:0018875 PMID:29979965 Likely Benign BP4, BS3, PM2_Supporting BP1, BP2, BP3, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM4, BP7, BP5, BS1, BS4, PVS1, PM6, PP2, PP3, PP1, PP4, BS2 The NM_000546.6: c.907A>G variant in TP53 is a missense variant predicted to cause substitution of serine by glycine at amino acid 303 (p.Ser303Gly). This variant has an allele frequency of 0.000002542 (3/1180040 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0726; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000491/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8080 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0018524 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0024437 infores:hetionet CHEBI:36791 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0520966 infores:hetionet CHEBI:2948 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0231218 infores:hetionet CHEBI:55346 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C1096035 infores:hetionet CHEBI:47381 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151315 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0035455 infores:hetionet CHEBI:391960 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0018524 infores:hetionet NCBIGene:23043 biolink:causes MONDO:0014876 infores:monarchinitiative not_provided not_provided HGNC:30765 MONDO:0014876 uuid:09cf65ab-b037-4fe1-8048-0adeaca1f1aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0860713 infores:hetionet CHEBI:30830 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0009782 infores:hetionet NCBIGene:51604 biolink:causes MONDO:0014166 infores:monarchinitiative not_provided not_provided HGNC:14938 MONDO:0014166 uuid:d4d21209-6c12-426a-b479-87073624bbd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4974 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0042109 infores:hetionet CHEBI:3398 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0001824 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232492 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235431 infores:hetionet GO:0031630 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:0031630 GO:0099504 CHEBI:2549 biolink:causes MONDO:0005081 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0032914 infores:hetionet CHEBI:3756 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020580 infores:hetionet NCBIGene:55012 biolink:causes MONDO:0032739 infores:monarchinitiative not_provided not_provided HGNC:17485 MONDO:0032739 uuid:a83f2ef3-8b6e-49da-91f6-793db150bf38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0262431 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0042373 infores:hetionet CHEBI:4672 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0235378 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030305 infores:hetionet CHEBI:465284 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C2129214 infores:hetionet CAID:CA228510 biolink:causes MONDO:0015629 infores:clingen CAID:CA228510 MONDO:0015629 PMID: Likely Pathogenic PP4, PM2_Supporting, PS4_Supporting, PS3 PP3 The NM_000552.5:c.4010C>T variant in VWF is a missense variant predicted to cause substitution of proline by leucine at amino acid 1377 (p.Pro1377Leu). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of enhanced RIPA and loss of HMWM, which is specific for VWD type 2B. (PP4, PMID 1373334). This variant has been reported in 1 additional proband meeting VWD 2B PP4 laboratory phenotype of enhanced RIPA (PS4_Supporting; Gold Variant Database).The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00000183 (based on 6/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for type 2B (PM2_Supporting). Platelet binding assay performed with the p.Pro1377Leu recombinant mutant vWF expressed by COS-7 showed increased binding at low doses of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID 1373334)(PS3_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4, PS4_Supporting, PM2_Supporting, PS3 (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228510/MONDO:0015629/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47898 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0858678 infores:hetionet CHEBI:6775 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0234238 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151436 infores:hetionet NCBIGene:11224 biolink:causes MONDO:0032669 infores:monarchinitiative not_provided not_provided HGNC:10344 MONDO:0032669 uuid:395c1ecc-0cd8-4125-8fb8-c7997a6801fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0021053 infores:hetionet CHEBI:478164 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0019080 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0033860 infores:hetionet CHEBI:100246 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0022354 infores:hetionet CHEBI:66919 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0032131 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011991 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0851341 infores:hetionet CAID:CA16043067 biolink:causes MONDO:0012589 infores:clingen CAID:CA16043067 MONDO:0012589 PMID: Likely Benign BP4, BS2 PS4, BS1, PM2 The highest population minor allele frequency of the p.Pro236Ala variant in TCF4 in gnomAD v4.1 is 0.00000062 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro236Ala variant is observed in at least 2 unaffected individuals (Internal database - GeneDx, Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Pro236Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro236Ala variant in TCF4 is classified as a likely benign variant based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043067/MONDO:0012589/032 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17823 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0438215 infores:hetionet CHEBI:28915 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0233494 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151736 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028077 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0086543 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0265057 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0042109 infores:hetionet CHEBI:3561 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011603 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0037284 infores:hetionet CHEBI:167638 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C2363731 infores:hetionet CHEBI:31199 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0442886 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0242350 infores:hetionet CAID:CA2580612109 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612109 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4 The c.363del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 122 in NM_000545.8, adding an uncertain number of novel amino acids before encountering a stop codon (p.(Tyr122ThrfsTer?)). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 9392505, 16759564, 35673428). In summary, c.363del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612109/MONDO:0015967/017 2024-12-09 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA10014598 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014598 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.98-30A>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.03) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.09)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014598/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64028 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0428977 infores:hetionet CHEBI:3699 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0233407 infores:hetionet CHEBI:3286 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0031039 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022904 infores:hetionet CAID:CA405677313 biolink:causes MONDO:0100150 infores:clingen CAID:CA405677313 MONDO:0100150 PMID: Pathogenic PVS1, PP4, PM3_Strong BS1, PM2, BA1 The c.8310+1G>T (NM_000540.3(RYR1):c.8310+1G>T) variant in RYR1 occurs within the canonical splice donor site (+1) of intron 52. It is predicted to cause skipping of biologically-relevant exon 52, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1 is 0.00001336 (1/74870 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 2 individuals with autosomal recessive RYR1-related myopathy. For both of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant and both of those were confirmed in trans by parental testing (PM3_strong; SCV002012482; GeneDx and HudsonAlpha Institute for Biotechnology Internal Data; PMID: 34930662). At least one patient with this variant displayed neonatal hypotonia, and reduced mobility of facial muscles and extremities, which is highly specific for autosomal recessive RYR1-related myopathies (PP4; SCV002012482; GeneDx and HudsonAlpha Institute for Biotechnology Internal Data; PMID: 34930662). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM3_Strong, PP4 (Congenital Myopathies VCEP specifications Version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA405677313/MONDO:0100150/179 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0434437 infores:hetionet CHEBI:101853 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0043352 infores:hetionet CAID:CA915952602 biolink:causes MONDO:0011071 infores:clingen CAID:CA915952602 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1164del (p.Ser389ArgfsTer?) is a frameshift variant which terminates 205 residues later, is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952602/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8060 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0013604 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0403632 infores:hetionet CHEBI:63611 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151937 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1328308 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1328308 infores:hetionet CHEBI:127780 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0035410 infores:hetionet CHEBI:32192 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0002994 infores:hetionet CHEBI:8890 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0032227 infores:hetionet CHEBI:6437 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0014518 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0008325 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020514 infores:hetionet CHEBI:83527 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0152032 infores:hetionet CHEBI:6909 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2830004 infores:hetionet CHEBI:75246 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011603 infores:hetionet CHEBI:7986 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0027497 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0006145 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0259749 infores:hetionet CHEBI:63617 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0392525 infores:hetionet NCBIGene:9154 biolink:causes MONDO:0032773 infores:monarchinitiative not_provided not_provided HGNC:11001 MONDO:0032773 uuid:cf56a030-36c8-46e6-ace2-5439ec1ca8a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:3467 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0340865 infores:hetionet CHEBI:45783 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0231528 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0033797 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0033797 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020649 infores:hetionet CAID:CA120542 biolink:causes MONDO:0044970 infores:clingen CAID:CA120542 MONDO:0044970 PMID:15054399 Uncertain Significance PP1, PM2_Supporting, PS3_Supporting PP3, PS4 The m.5532G>A variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 15054399), in a 16-year-old girl with failure to thrive, short stature, recurrent vomiting, developmental delay and regression, ophthalmoplegia, ptosis, pigmentary retinopathy, sensorineural hearing loss, and myopathy. Brain imaging showed generalized atrophy and periventricular white matter changes. Elevated lactate was seen in blood and cerebrospinal fluid. Muscle biopsy showed ragged red fibers and mitochondrial respiratory chain complex I and IV deficiency. The variant was present at 92% heteroplasmy in muscle, 37% in fibroblasts, and 21% in blood. The variant was present at lower heteroplasmy levels in blood from her healthy mother (7%) and brother (9%; PP1; PMID: 15054399). There are no other individuals or families reported in the medical literature. Although there is one occurrence of this variant in population databases (1/61,134 in MITOMAP, absent in Helix and gnomad v3.1.2), the frequency is still low (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is likely benign (19.4 percentile) but HmtVAR predicts it to be deleterious with a score of 0.7. Single fiber testing showed higher levels of the variant in COX-negative fibers (>90%) than in COX-positive fibers (6-85%, p<0.0001, PS3_supporting, PMID: 15054399). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120542/MONDO:0044970/015 2024-05-13 2024-12-06 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:15367 biolink:causes UMLS:C0268948 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0268948 infores:hetionet CHEBI:7445 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0231919 infores:hetionet CHEBI:28241 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0497247 infores:hetionet CHEBI:34829 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0015403 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020649 infores:hetionet CHEBI:63624 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0476281 infores:hetionet CHEBI:9757 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0855704 infores:hetionet CHEBI:45081 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151539 infores:hetionet CHEBI:478164 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0002792 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0043251 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151736 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0007860 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0262576 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0262576 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0233414 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020538 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0036341 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0022408 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0267792 infores:hetionet CHEBI:64321 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020672 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0403632 infores:hetionet CHEBI:32192 biolink:causes MONDO:0021124 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0021361 infores:hetionet CHEBI:391960 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0006277 infores:hetionet CHEBI:3814 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0917801 infores:hetionet CHEBI:47898 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085624 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0004936 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027121 infores:hetionet CHEBI:9667 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0040038 infores:hetionet CHEBI:63681 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0917801 infores:hetionet GO:0035203 biolink:causes GO:0048542 infores:ubergraph knowledge_assertion manual_agent GO:0035203 GO:0048542 CHEBI:85161 biolink:causes UMLS:C0948779 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0948779 infores:hetionet CAID:CA229304 biolink:causes MONDO:0009861 infores:clingen CAID:CA229304 MONDO:0009861 PMID:9634518 Likely Pathogenic PM2, PP4_Moderate, PM5, PP3 The c.1048T>A (p.Ser350Thr) variant in PAH has been reported in 1 individual with classic PKU and BH4 deficiency excluded (PMID: 9634518). This variant is absent in population databases. Computational evidence supports a deleterious effect. A different pathogenic missense change (p.Ser350Tyr) has been seen at the same amino acid. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229304/MONDO:0009861/006 2021-02-16 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63613 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0029118 infores:hetionet CHEBI:16796 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C1963818 infores:hetionet CHEBI:585948 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0152031 infores:hetionet CHEBI:6375 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0080274 infores:hetionet UNII:D27V6190PM biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0042963 infores:hetionet CHEBI:7823 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0001807 infores:hetionet CHEBI:50305 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0013604 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0234215 infores:hetionet CHEBI:7581 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0030554 infores:hetionet CHEBI:40303 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0037011 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0034882 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0031350 infores:hetionet CHEBI:167638 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0015672 infores:hetionet CAID:CA386960413 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960413 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PP4_Moderate, PP3, PP1 The c.476G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 159 (p.Arg159Gln) of NM_000545.8. This variant was identified in more than 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 10078571, 12488961, 15928245, 20132997, 9097962, 10754480, internal lab contributors). Also, this variant segregated with diabetes, with at least 11 informative meioses in 17 families with MODY (PP1_Strong; PMIDs: 9097962, 10754480, internal lab contributors). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, functional studies demonstrated the p.Arg159Gln protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 10585442). In summary, c.476G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PS4, PP1_Strong, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP3, PS3_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960413/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63621 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0024031 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0036572 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085096 infores:hetionet CHEBI:44032 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0021655 infores:hetionet CHEBI:50859 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011168 infores:hetionet CAID:CA412489767 biolink:causes MONDO:0100039 infores:clingen CAID:CA412489767 MONDO:0100039 PMID: Likely Pathogenic PM1, PM5, PP3, PM2_Supporting The p.Gly22Glu variant occurs in the well-characterized ATP binding region functional domain of the CDKL5 gene (PM1). A pathogenic missense variant (p.Gly22Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein ( GeneDx internal database) (PM5). The p.Gly22Glu variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gly22Glu variant in CDKL5 is classified as likely pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PM1, PM5, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412489767/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Supports CHEBI:6801 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0232492 infores:hetionet CHEBI:16335 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0011603 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0033777 infores:hetionet CHEBI:71941 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0548823 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014868 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042109 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948296 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011849 infores:hetionet CHEBI:64355 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0031256 infores:hetionet CHEBI:7494 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0012569 infores:hetionet CHEBI:17334 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0023530 infores:hetionet CHEBI:50648 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042384 infores:hetionet CHEBI:82981 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0004093 infores:hetionet CHEBI:3655 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0012833 infores:hetionet CHEBI:5959 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0038999 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0041912 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0002622 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0036572 infores:hetionet CHEBI:45409 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0155365 infores:hetionet CHEBI:7514 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0235086 infores:hetionet CHEBI:39585 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0085637 infores:hetionet CHEBI:40303 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0085593 infores:hetionet CHEBI:6965 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0235146 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0233494 infores:hetionet CHEBI:6541 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0040460 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0178298 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0042769 infores:hetionet CHEBI:44032 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0029118 infores:hetionet CHEBI:5441 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0221395 infores:hetionet CHEBI:3698 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0085636 infores:hetionet CHEBI:27786 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0032227 infores:hetionet CHEBI:32588 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0085620 infores:hetionet CHEBI:6076 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0001925 infores:hetionet CHEBI:5784 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0023530 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0023895 infores:hetionet CAID:CA404085845 biolink:causes MONDO:0007750 infores:clingen CAID:CA404085845 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BA1, BP2, PS1, PS3, PS2, PS4, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM3, PVS1, PM6, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1412G>A (p.Arg471Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).BP4: REVEL = 0.412, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) does not create AG or GTC) variant is exonic and there are 2 AG nearby;#1 MES scores: variant cryptic = -4.92, wt cryptic = -10.07, canonical acceptor= 6.76;#2 MES scores: variant cryptic = -7.95, wt cryptic = -13.41, canonical acceptor= 6.76.Scores are negative, so variant is not predicted to alter splicing.PP4: Variant meets PM2 and is identified in at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583828.1), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404085845/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:45783 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042109 infores:hetionet CHEBI:5118 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002994 infores:hetionet CHEBI:91541 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0037822 infores:hetionet CHEBI:6413 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0015672 infores:hetionet CHEBI:3441 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011175 infores:hetionet CAID:CA120599 biolink:causes MONDO:0044970 infores:clingen CAID:CA120599 MONDO:0044970 PMID: Likely Pathogenic PM4, PM2_Supporting, PS4_Supporting, PM6_Supporting PP4, PP1, PS2, PS3 The m.9205_9206delTA (p.Ter227M) variant in MT-ATP6 has been reported in two unrelated probands with features of primary mitochondrial disease (neonatal lactic acidosis, failure to thrive, spasticity, microcephaly, developmental delay; PS4_supporting; PMIDs: 8739943, 15265003). The variant was de novo in one of these individuals (absent in mother and maternal grandmother's lymphocytes via PCR-SSCP; PM6_supporting; PMID: 8739943). In the other family, this variant segregated with disease in two unaffected family members as they had lower levels of the variant, however the unaffected mother’s heteroplasmy level was still fairly high at >90% (PMID: 15265003). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids or single fiber studies reported on this variant. The loss residue removes the termination codon for MT-ATP6 and sets MT-CO3 immediately in frame. This results in decreased steady state level of RNA14, the ATPase 8- and 6-encoding bi-cistronic mRNA unit, causing dysregulation of mRNA stability (PM4, PMID: 12915481). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the functional evidence showing destabilization of the RNA. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PM4, PS4_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120599/MONDO:0044970/014 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:46195 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0302809 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0036572 infores:hetionet CHEBI:7954 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0233407 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003523 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017150 infores:hetionet CHEBI:2611 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0022346 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0042075 infores:hetionet CHEBI:134991 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0019521 infores:hetionet CHEBI:8214 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0030193 infores:hetionet CHEBI:2038 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0476273 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0855242 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0004096 infores:hetionet CHEBI:3347 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0151539 infores:hetionet CHEBI:7936 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0232849 infores:hetionet CHEBI:135736 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0033036 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020514 infores:hetionet CHEBI:75722 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0043387 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0855223 infores:hetionet CHEBI:9332 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0018681 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1384353 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0393759 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0393759 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235876 infores:hetionet CHEBI:6456 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0011168 infores:hetionet CHEBI:188986 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0178415 infores:hetionet GO:0046632 biolink:causes CL:0000789 infores:ubergraph knowledge_assertion manual_agent GO:0046632 CL:0000789 CHEBI:3485 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0006840 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0349506 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0853714 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C2242582 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C2242582 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0403632 infores:hetionet CAID:CA2499224908 biolink:causes MONDO:0008723 infores:clingen CAID:CA2499224908 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The c.1808del (p.Cys603fs) variant in ACADVL, also known as p.Cys603LeufsTer77, is a frameshift variant that may cause loss of function of the protein; however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499224908/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:125354 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0011991 infores:hetionet GO:1903593 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1903593 GO:0051641 CHEBI:2682 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020473 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0085584 infores:hetionet CAID:CA023654 biolink:causes MONDO:0007750 infores:clingen CAID:CA023654 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, BS2 NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1).PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case published in PMID: 16250003 (Fouchier et al., 2005), Netherlands; 1 case published in PMID: 16159606 (Graham et al., 2005), United Kingdom).PP4 - Variant meets PM2. PMID: 16159606 - 1 case who fulfills Simon-Broome criteria for FH. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023654/MONDO:0007750/013 2022-05-30 2022-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:74947 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0025320 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0005779 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0694536 infores:hetionet CHEBI:16347 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0031350 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020550 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0016419 uuid:22105d6e-1bd1-4da0-ba4e-b2c8c40b051b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2569 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0235063 infores:hetionet CHEBI:27565 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C1368065 infores:hetionet UMLS:C0005740 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0001807 infores:hetionet CHEBI:188986 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C3263723 infores:hetionet CHEBI:50924 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0018681 infores:hetionet CHEBI:3175 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0039231 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0011570 infores:hetionet CHEBI:49603 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0151908 infores:hetionet CHEBI:55346 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0027947 infores:hetionet CAID:CA386958695 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958695 MONDO:0015967 PMID: Pathogenic PS1_Supporting, PM2_Supporting, PVS1 The c.327-1G>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within intron 1 of NM_000545.8. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). This variant is predicted to cause skipping of biologically-relevant exon 1 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). The c.327-1G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.327-1G>T has a similar predicted impact on splice acceptor loss by Splice AI (0.99) as c.327-1G>A (1.00) (PS1_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PS1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958695/MONDO:0015967/017 2022-04-18 2022-04-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10650 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026961 infores:hetionet CHEBI:6129 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151578 infores:hetionet CHEBI:15367 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151692 infores:hetionet CHEBI:10110 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0017178 infores:hetionet CHEBI:27882 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0003862 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0007787 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0151735 infores:hetionet GO:1905936 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1905936 GO:0019953 UNII:DJJ95FJP1H biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0033774 infores:hetionet CHEBI:50659 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0004093 infores:hetionet CAID:CA2499217419 biolink:causes MONDO:0021056 infores:clingen CAID:CA2499217419 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PS3_Moderate, PM2_Supporting The NM_000038.6:c.423-8A>G variant in APC is an intronic variant which is located in intron 4. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate, internal data Ambry genetics, Myriad genetics; PMID: 32067438). The variant has been reported in 2 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (internal data Ambry and Labcorp Genetics (formerly Invitae)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 4 and creating a cryptic acceptor splice site (PP3). RNA analysis demonstrated that the variant impacts splicing by insertion of the last 7 bp of intron 4 resulting in a premature stop codon, but the presence of < 10% of full-length transcript could not be demonstrated (PS3_Moderate, PMID: 32067438, Ambry Genetics internal data). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PM2_Supporting; PS4_Moderate; PP3; PS3_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499217419/MONDO:0021056/089 2025-05-14 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36795 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0231528 infores:hetionet CHEBI:7601 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0040435 infores:hetionet CAID:CA412731500 biolink:causes MONDO:0100437 infores:clingen CAID:CA412731500 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2080A>T (p.Lys694Ter) is a nonsense variant introducing a premature stop in codon 694 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands (PMID: 31953110, PMID: 14564670), however, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent cone and/or rod electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412731500/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:9598 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0521839 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0031542 infores:hetionet CHEBI:9570 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0013428 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0042109 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1861172 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0007971 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0012833 infores:hetionet NCBIGene:90416 biolink:causes MONDO:0030873 infores:monarchinitiative not_provided not_provided HGNC:28295 MONDO:0030873 uuid:86bdf9e2-d0ce-4b43-b553-55d0619d667c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0343863 infores:hetionet CHEBI:100241 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151786 infores:hetionet CHEBI:135736 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0017181 infores:hetionet CHEBI:2663 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0600142 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0007860 infores:hetionet CHEBI:42820 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0012833 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0001925 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020678 infores:hetionet CHEBI:32221 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0002792 infores:hetionet NCBIGene:5692 biolink:causes MONDO:0054699 infores:monarchinitiative not_provided not_provided HGNC:9541 MONDO:0054699 uuid:e7e00392-5917-498d-b0b2-0bc7f8e8dcb5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003123 infores:hetionet NCBITaxon:1817 biolink:causes MONDO:0017776 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1817 MESH:D009617 DB00263_MESH_D009617_1 CAID:CA354063 biolink:causes MONDO:0019501 infores:clingen CAID:CA354063 MONDO:0019501 PMID: Uncertain Significance PP4, PM3, PM2_Supporting BS1, PP3, PM5, BP4, BA1, PS1 The NM_206933.4:c.6446C>A variant in the USH2A gene is a missense variant predicted to cause the substitution of proline by glutamine at amino acid 2149 (p.Pro2149Gln). The minor allele frequency of this variant in gnomAD v.4.1.0 was 0.00059% (7/1179718 alleles) in the European (non-Finnish) population meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.355, which doesn’t meet either of the thresholds necessary to apply PP3/BP4. It has been detected with another suspected pathogenic variant in two patients with Usher syndrome type 2, of which one patient displayed hearing loss with an onset in the first decade and retinitis pigmentosa with an onset at 22y.o, which is specific for Usher syndrome (PM3, PP4; PMIDs: 26872967, 29074561, 32176120, 31836858). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PM3, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 4/16/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA354063/MONDO:0019501/005 2025-04-16 2025-06-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:38940 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0007787 infores:hetionet GO:1900217 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:1900217 GO:0001656 CHEBI:65173 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0021122 infores:hetionet CHEBI:68478 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2047937 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0029134 infores:hetionet CHEBI:7465 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0424295 infores:hetionet CHEBI:6062 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151904 infores:hetionet CAID:CA10385235 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385235 MONDO:0100437 PMID: Likely Benign BP3 PM4, BS1 NM_001034853.2(RPGR):c.2901_2903del (p.Glu968del) is an in-frame deletion variant. This variant is a short in-frame deletion of 3 base pairs that encodes amino acid 968, and is located within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v4.1.0 at a frequency of 0.000009574 among hemizygous individuals, with 1 variant allele / 104,450 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005. However, the VCEP recommended not to apply the BS1 code based on the gnomAD quality control data indicating low coverage and sequencing quality at this site. In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385235/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:83804 biolink:causes UMLS:C0234952 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0234952 infores:hetionet CHEBI:16755 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0014724 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0162429 infores:hetionet CHEBI:17026 biolink:causes GO:0009566 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0015914 infores:hetionet NCBIGene:83715 biolink:causes MONDO:0012170 infores:monarchinitiative not_provided not_provided HGNC:13281 MONDO:0012170 uuid:5a70adfa-b1e8-44a6-846f-2432a89daa31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63607 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0013404 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0007986 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0007986 uuid:e66efef9-2eef-452e-a12f-0c4c3ba57d22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0235293 infores:hetionet CHEBI:474053 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0232462 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011570 infores:hetionet CHEBI:41977 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0013456 infores:hetionet CHEBI:9588 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0042384 infores:hetionet CHEBI:79699 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0085682 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0687707 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0041912 infores:hetionet CHEBI:63619 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030232 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0032787 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0032787 infores:hetionet CHEBI:9014 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0002994 infores:hetionet CHEBI:135686 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0080274 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0027497 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0233494 infores:hetionet CHEBI:73275 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0006145 infores:hetionet CHEBI:6717 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002878 infores:hetionet CHEBI:6954 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0013362 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0344357 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0344357 infores:hetionet CHEBI:7852 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235195 infores:hetionet CHEBI:2379 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0020458 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0040046 infores:hetionet CHEBI:66876 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0013395 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0031350 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0027651 infores:hetionet CHEBI:3696 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0007859 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0221185 infores:hetionet CHEBI:9570 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0011206 infores:hetionet CHEBI:31236 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013362 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042510 infores:hetionet CHEBI:478164 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0011603 infores:hetionet GO:0031664 biolink:causes GO:0071222 infores:ubergraph knowledge_assertion manual_agent GO:0031664 GO:0071222 NCBIGene:1203 biolink:causes MONDO:0009745 infores:monarchinitiative not_provided not_provided HGNC:2076 MONDO:0009745 uuid:a30ca8ce-a8bb-40ff-82db-00fcc5c166b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:729359 biolink:causes MONDO:0011155 infores:monarchinitiative not_provided not_provided HGNC:29393 MONDO:0011155 uuid:ffac02a2-d366-4030-99b9-8b4cb2d6e861 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0040822 infores:hetionet CHEBI:2379 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0547030 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0002170 infores:hetionet CHEBI:49960 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0009763 infores:hetionet CHEBI:85161 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0085610 infores:hetionet CHEBI:7465 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0019825 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0233494 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0009319 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151479 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0041969 infores:hetionet NCBIGene:7703 biolink:causes MONDO:0032707 infores:monarchinitiative not_provided not_provided HGNC:12929 MONDO:0032707 uuid:ec5dc9c7-48a8-491b-b827-6f24675831fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014868 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0018799 infores:hetionet CHEBI:8874 biolink:causes HP:0031657 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0577822 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0025637 infores:hetionet CHEBI:8028 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0857305 infores:hetionet CHEBI:5847 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0027947 infores:hetionet CHEBI:71941 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0004093 infores:hetionet CHEBI:27666 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0003962 infores:hetionet NCBIGene:6899 biolink:causes MONDO:0016581 infores:monarchinitiative not_provided not_provided HGNC:11592 MONDO:0016581 uuid:b30e4f3f-3fad-4376-afdb-7f4f10a96a41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085641 infores:hetionet CHEBI:8107 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151830 infores:hetionet CAID:CA405686237 biolink:causes MONDO:0018493 infores:clingen CAID:CA405686237 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, BP4 PP3, PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of alanine with threonine at codon 3090 of the RYR1 protein, p.(Ala3090Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.454) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405686237/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:83527 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0020517 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0018418 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017160 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011991 infores:hetionet NCBIGene:9509 biolink:causes MONDO:0009161 infores:monarchinitiative not_provided not_provided HGNC:218 MONDO:0009161 uuid:d2e5219b-ded0-44c0-8c7e-ba6cb667f462 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5801 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0085636 infores:hetionet CHEBI:5856 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0085610 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0042373 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0042514 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0948594 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029443 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235416 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0012833 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0007785 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020615 infores:hetionet CHEBI:32315 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0027796 infores:hetionet CHEBI:2549 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042963 infores:hetionet CHEBI:8874 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0575081 infores:hetionet CAID:CA269921 biolink:causes MONDO:0009861 infores:clingen CAID:CA269921 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 The c.781C>G (p.Arg261Gly) variant in PAH has not been reported in the literature (to our knowledge). This variant is at extremely low frequency in gnomAD (MAF=0.00006, PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.962. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA269921/MONDO:0009861/006 2019-05-04 2019-05-04 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45951 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0010200 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0549234 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0549234 infores:hetionet CHEBI:9943 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0025874 infores:hetionet CAID:CA10644617 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644617 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2822C>T is a UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644617/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51230 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0162834 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0000833 infores:hetionet NCBITaxon:810 biolink:causes MONDO:0021697 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:810 MONDO:0021697 CHEBI:7824 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020625 infores:hetionet CHEBI:175901 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0019156 infores:hetionet CHEBI:135005 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0033893 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006846 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020540 infores:hetionet CHEBI:135351 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0555120 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0151735 infores:hetionet UMLS:C0145185 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0476273 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0029408 infores:hetionet CHEBI:10124 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1443060 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0017178 infores:hetionet CHEBI:4710 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042029 infores:hetionet CHEBI:52717 biolink:causes HP:0012764 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085619 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0852733 infores:hetionet CHEBI:5118 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009421 infores:hetionet CAID:CA293619 biolink:causes MONDO:0010278 infores:clingen CAID:CA293619 MONDO:0010278 PMID: Benign BA1 The allele frequency of the c.*8A>T variant in SLC9A6 is 0.1% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.*8A>T variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA293619/MONDO:0010278/016 2022-02-18 2022-06-30 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3508 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0042373 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0027765 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0027765 infores:hetionet CHEBI:6792 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0043352 infores:hetionet CHEBI:16469 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020580 infores:hetionet CHEBI:31624 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0017178 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0042109 infores:hetionet CHEBI:6801 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0002888 infores:hetionet CAID:CA226468 biolink:causes MONDO:0100437 infores:clingen CAID:CA226468 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.980T>G (p.Leu327Ter) is a nonsense variant introducing a premature stop in codon 327 within exon 9 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 17325176, 32531858, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226468/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:9927 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0025061 infores:hetionet NCBIGene:10526 biolink:causes MONDO:0859177 infores:monarchinitiative not_provided not_provided HGNC:9853 MONDO:0859177 uuid:5cf3bfda-faf8-4000-826e-f41fe3b22525 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0023222 infores:hetionet CHEBI:7454 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0700590 infores:hetionet CAID:CA410204236 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204236 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.125C>T (p.Pro42Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204236/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes UMLS:C0233519 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233519 infores:hetionet CHEBI:91834 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0041105 infores:hetionet CHEBI:3387 biolink:causes NCIT:C98911 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0877225 infores:hetionet CHEBI:77733 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0020580 infores:hetionet CHEBI:28925 biolink:causes UMLS:C0015408 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0015408 infores:hetionet NCBIGene:1834 biolink:causes MONDO:0011571 infores:monarchinitiative not_provided not_provided HGNC:3054 MONDO:0011571 uuid:62c12825-be4d-4fcb-a59c-f9ba43976935 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0032227 infores:hetionet NCBITaxon:11084 biolink:causes MONDO:0017572 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11084 MONDO:0017572 CHEBI:3761 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0013362 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0745153 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0745153 infores:hetionet CHEBI:5147 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151636 infores:hetionet NCBIGene:2717 biolink:causes MONDO:0010526 infores:monarchinitiative not_provided not_provided HGNC:4296 MONDO:0010526 uuid:1fb401aa-8967-4567-89b0-06078554b534 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94609 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0037274 infores:hetionet NCBIGene:58472 biolink:causes MONDO:0030982 infores:monarchinitiative not_provided not_provided HGNC:20390 MONDO:0030982 uuid:72480389-bac3-40e9-a3b2-8ebb059c51f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032326 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0427008 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033771 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0026919 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0026919 infores:hetionet GO:0150011 biolink:causes GO:0031175 infores:ubergraph knowledge_assertion manual_agent GO:0150011 GO:0031175 UMLS:C0657912 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018520 infores:hetionet CHEBI:16714 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0018524 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007642 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0235710 infores:hetionet CHEBI:2788 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0004096 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0521839 infores:hetionet CHEBI:205919 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C2242996 infores:hetionet CHEBI:52172 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0242339 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0021400 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001294 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0019937 infores:hetionet CHEBI:6438 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0004134 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0003864 infores:hetionet CHEBI:45863 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C3665386 infores:hetionet CHEBI:5441 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0086565 infores:hetionet CHEBI:48273 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0042963 infores:hetionet CHEBI:3175 biolink:causes NCIT:C112176 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0948786 infores:hetionet CHEBI:6067 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018800 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0022658 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0006826 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0037199 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0034150 infores:hetionet NCBIGene:345 biolink:causes MONDO:0013534 infores:monarchinitiative not_provided not_provided HGNC:610 MONDO:0013534 uuid:984f3d19-dced-40e9-a6d6-b4b4073ae5f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31397 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0151692 infores:hetionet CHEBI:4784 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0023530 infores:hetionet CHEBI:6149 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C3160741 infores:hetionet CHEBI:49960 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020598 infores:hetionet GO:0060236 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0060236 GO:0000278 CHEBI:3219 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0035243 infores:hetionet CHEBI:16714 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0022107 infores:hetionet CHEBI:66903 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0011603 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0031085 infores:hetionet CHEBI:8228 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0040435 infores:hetionet NCBIGene:7170 biolink:causes MONDO:0012239 infores:monarchinitiative not_provided not_provided HGNC:12012 MONDO:0012239 uuid:4903011a-096b-40d1-a536-8cdacd7dc7f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17698 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0677500 infores:hetionet NCBITaxon:724 biolink:causes MONDO:0006926 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:724 MONDO:0006926 CHEBI:8863 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0700345 infores:hetionet CAID:CA638504295 biolink:causes MONDO:0009276 infores:clingen CAID:CA638504295 MONDO:0009276 PMID: Likely Pathogenic PS3_Supporting, PP4, PM2_Supporting, PVS1_Strong PS4, PM3 The variant NM_000407.5(GP1BB):c.448del (p.Ala150ArgfsTer?) has been reported in at least one individual with Bernard Soulier Syndrome. At least one patient compound heterozygous for this variant had macrothrombocytopenia and aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, surface expression of GP1ba, GP1bb, and GP9 measured by flow cytometry in 293T cells transiently co-transfected with the c.448del variant and wild type GP1ba and GP9 showed decreased expression at 0% (<25%) WT levels, indicating that this variant impacts protein function (PMID:16978236) (PS3_supporting). Finally, the variant is a frameshift variant which may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein, affecting the critical transmembrane domain (PVS1_strong). The Grpmax filtering allele frequency in gnomaDv4.1 is 0.00001079 (based on 2/30690 alleles) in the East Asian population, which is below the <0.0000651678 threshold for PM2_supporting. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PM2_supporting, PP4, PS3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA638504295/MONDO:0009276/082 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3207 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0035455 infores:hetionet CHEBI:63611 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0037299 infores:hetionet CHEBI:28864 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235266 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0035204 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151626 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0151559 infores:hetionet CHEBI:8069 biolink:causes HP:0100507 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0016412 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018418 infores:hetionet CHEBI:7915 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0852911 infores:hetionet CHEBI:5296 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0008031 infores:hetionet CHEBI:35778 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0043352 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0853760 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0234233 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0151436 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0013595 infores:hetionet CHEBI:6775 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013456 infores:hetionet CAID:CA171639 biolink:causes MONDO:0100039 infores:clingen CAID:CA171639 MONDO:0100039 PMID: Benign BA1 The allele frequency of the c.283-13 A>G variant in CDKL5 is 0.036% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.283-13 A>G variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171639/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Contradicts true CHEBI:4975 biolink:causes UMLS:C0424813 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0424813 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0018021 infores:hetionet CHEBI:136040 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0600142 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0042267 infores:hetionet CHEBI:63580 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235266 infores:hetionet NCBIGene:79572 biolink:causes MONDO:0009935 infores:monarchinitiative not_provided not_provided HGNC:24113 MONDO:0009935 uuid:10212fd7-27f1-4bcd-a8b5-7b9f36b25683 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135888 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0006277 infores:hetionet NCBIGene:1663 biolink:causes MONDO:0013252 infores:monarchinitiative not_provided not_provided HGNC:2736 MONDO:0013252 uuid:2cd23203-34bd-4945-af9e-37246020bd8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0030794 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0018802 infores:hetionet GO:0002308 biolink:causes CL:0000794 infores:ubergraph knowledge_assertion manual_agent GO:0002308 CL:0000794 CAID:CA228423 biolink:causes MONDO:0015628 infores:clingen CAID:CA228423 MONDO:0015628 PMID: Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS4_Very Strong The NM_000552.5:c.3568T>C variant in VWF is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 1190. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:Collagen binding assay, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 34532631). An additional consistent phenotype was also reported in the patient specifically, a normal platelet count. This variant has been reported in 12 additional probands meeting PP4 laboratory phenotype criteria (PS4_Moderate; WiN Study - Personal Communication). The variant has been reported to segregate with VWD type 2A through >2 affected meioses in 2 families (PP1_moderate; WiN Study Database personal communication). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.982, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS4_VeryStrong, PP1_Moderate, PM2_Supporting, PP3. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228423/MONDO:0015628/081 2025-05-06 2025-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5855 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018801 infores:hetionet CHEBI:27974 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0547030 infores:hetionet NCBITaxon:28901 biolink:causes MONDO:0005619 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:28901 MONDO:0005619 CAID:CA270779 biolink:causes MONDO:0044970 infores:clingen CAID:CA270779 MONDO:0044970 PMID: Uncertain Significance PP4, PM2_Supporting PP1, PP3, BP4, PS4, PS3 The m.10134C>A (p.Q26K) variant in MT-ND3 has been reported in one individual to date, in a girl with Leigh syndrome spectrum disorder (PMID: 25118196). She was reportedly slower than her siblings in reaching motor milestones and at 4-years-old lost the ability to jump, developed an abnormal gait, and had speech difficulty. At 4.5-years-old, she developed worsening speech, mobility, balance, and behaviors after undergoing anesthesia. Brain MRI performed at this time showed extensive signal abnormality involving putamen, globus pallidus bilaterally, and the cerebral peduncles, and brain MRS showed elevated lactate in the basal ganglia. Blood and cerebrospinal fluid (CSF) lactates were normal. Muscle biopsy showed fat accumulation and slightly increased subsarcolemmal mitochondrial aggregates. Liver biopsy showed increased glycogen content and mild biliary ductular proliferation, and electron microscopy showed occasional moderately enlarged mitochondria with paracrystalline and crystalline inclusions. The variant was present at homoplasmy in blood, fibroblasts, liver, and muscle. As this is the only case reported to date, PS4 could not be applied. Complex I deficiency was noted in muscle, and exome sequencing was performed in the proband, her parents, and three healthy siblings ruling out other known genetic etiologies (PMID: 25118196; PP4). This variant segregated with disease features in this family as her healthy mother had the variant present 1% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.19 (Min=0, Max=1), which predicts no damaging effect on gene function, however an updated version of this predictor (APOGEE2) predicts a deleterious effect with a score of 0.752. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA270779/MONDO:0044970/015 2023-11-28 2024-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:84500 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0040213 infores:hetionet CHEBI:44032 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0018520 infores:hetionet CHEBI:31302 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0012833 infores:hetionet GO:0014004 biolink:causes CL:0000129 infores:ubergraph knowledge_assertion manual_agent GO:0014004 CL:0000129 CHEBI:131512 biolink:causes UMLS:C0221154 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0221154 infores:hetionet CHEBI:3181 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C1443060 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027765 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0001824 infores:hetionet CHEBI:8214 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0232487 infores:hetionet CAID:CA023402 biolink:causes MONDO:0007750 infores:clingen CAID:CA023402 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00005431 (0.005431%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.843. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in:- 3 unrelated index cases who fulfill Dutch lipid clinic network >=6 from Robarts Research Institute, Canada;- at least 1 index case with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583773.1), France;- 1 index case with DLNC > or = 6 from Bañares et al. 2017 (PMID: 28502510), Argentina;at least 5 unrelated index cases with clinical FH criteria, so PP4 is met.PP4 - variant meets PM2 and was identified in at least 5 unrelated index cases with clinical FH criteria (see PS4_Supporting for details), so PP4 is met.PS3_supporting - Level 3 FS: Hobbs et al. 1992 (PMID: 1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity.--- activity is below 85% of wild-type, so PS3_Supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023402/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:4445 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0860713 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0233494 infores:hetionet CHEBI:17347 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0149744 infores:hetionet CHEBI:6909 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013390 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027765 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0010692 infores:hetionet CHEBI:23765 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0012569 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0041834 infores:hetionet CHEBI:6775 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151798 infores:hetionet GO:0002305 biolink:causes CL:0000802 infores:ubergraph knowledge_assertion manual_agent GO:0002305 CL:0000802 NCBIGene:440275 biolink:causes MONDO:0009329 infores:monarchinitiative not_provided not_provided HGNC:19687 MONDO:0009329 uuid:857498ce-775c-46c6-be20-85d55186a9a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85161 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0600142 infores:hetionet CAID:CA011552 biolink:causes MONDO:0005045 infores:clingen CAID:CA011552 MONDO:0005045 PMID:27532257PMID:10750581PMID:27532257PMID:16199542PMID:15358028PMID:11133230PMID:10750581PMID:12707239PMID:15563892 Pathogenic PM1, PM2, PP1_Strong, PS4 The c.1988G>A (p.Arg663His) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:10750581; PMID:11133230; PMID:12707239; PMID:15563892; PMID:16199542; PMID:15358028; AGCMC Sydney ClinVar SCV000212629.1; Invitae ClinVar SCV000219103.7; Partners LMM ClinVar SCV000059409.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >15 affected individuals (PP1_Strong; PMID:10750581; Partners LMM ClinVar SCV000059409.5; SHaRe consortium, PMID: 30297972). This variant was identified in 2/66718 European chromosomes (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011552/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:194135 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0232807 infores:hetionet CHEBI:584020 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0030848 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0007114 infores:hetionet CHEBI:47898 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0003811 infores:hetionet CHEBI:7476 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0019080 infores:hetionet CHEBI:68647 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0740394 infores:hetionet CHEBI:27834 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0018524 infores:hetionet CHEBI:4657 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0043094 infores:hetionet CAID:CA194301 biolink:causes MONDO:0007648 infores:clingen CAID:CA194301 MONDO:0007648 PMID:31642931PMID:15831593PMID:31642931PMID:15831593 Likely Pathogenic PM5_Supporting, PS4_Supporting, PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 This c.1137+2T>C variant occurs at the canonical donor splice site of exon 8 (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org) and has been observed in at least one individual meeting IGCLC criteria for HDGC (PS4_supporting; internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting (Variant Interpretation Guidelines Version 3.1). CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA194301/MONDO:0007648/007 2023-10-23 2023-11-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7915 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002962 infores:hetionet CAID:CA16020723 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020723 MONDO:0009861 PMID:10394930 Pathogenic PM2, PP4, PP3 PM5 The c.60+5G>C variant in PAH has been reported in a cohort of Germany PKU/HPA patients (PMID: 10394930) This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020723/MONDO:0009861/006 2020-06-04 2020-06-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7915 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0236075 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0028077 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0259749 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0042233 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:C536777 DB00582_MESH_C536777_1 CHEBI:135939 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0015397 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0002622 infores:hetionet CHEBI:73275 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0020458 infores:hetionet CHEBI:42820 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0041948 infores:hetionet CHEBI:50648 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011606 infores:hetionet CHEBI:3723 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033247 infores:hetionet CHEBI:64312 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0035317 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0234458 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0034065 infores:hetionet UMLS:C0145867 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0344232 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0036983 infores:hetionet CHEBI:101853 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0232462 infores:hetionet CHEBI:3286 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C1443060 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0522224 infores:hetionet CHEBI:4495 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0008031 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0041912 infores:hetionet NCBIGene:9681 biolink:causes MONDO:0024556 infores:monarchinitiative not_provided not_provided HGNC:18423 MONDO:0024556 uuid:eac35b6e-d3de-4ec7-92a8-c940d61c1440 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:136040 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0232462 infores:hetionet CHEBI:63608 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0035243 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0003850 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0002170 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0023067 infores:hetionet NCBIGene:84839 biolink:causes MONDO:0013406 infores:monarchinitiative not_provided not_provided HGNC:18286 MONDO:0013406 uuid:0707dc6c-e578-43a3-b974-d50c03227df4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085602 infores:hetionet CHEBI:2038 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0039070 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0040034 infores:hetionet CHEBI:8028 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0235660 infores:hetionet CAID:CA8337751 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337751 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 The NM_000018.4: c.521T>C (p.Val174Ala) in ACADVL is a missense variant predicted to cause substitution of valine by alanine at amino acid 174 (p.Val174Ala). The highest population minor allele frequency in GnomAD v4.0.0 is 0.0001 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in the literature in an individual with an abnormal newborn screen who is an apparently heterozygous carrier for the variant (PMID: 24503138), but this information is insufficient to use toward classification. The computational predictor REVEL gives a score of 0.926, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337751/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:77260 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014724 infores:hetionet CHEBI:3125 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0002994 infores:hetionet CHEBI:77260 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C2830004 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018902 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0206669 infores:hetionet CHEBI:135736 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0002962 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0020517 infores:hetionet CHEBI:31711 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C2047937 infores:hetionet CHEBI:63619 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0024902 infores:hetionet CAID:CA10585475 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585475 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4 PS3 The NM_000527.5 (LDLR):c.1475A>G (p.Asp492Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows:PM2: Variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.994.PM5: Two other missense variants in the same codon: NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn), ClinVar 161285, classified as Pathogenic by these guidelines; NM_000527.5(LDLR):c.1474G>C (p.Asp492His), ClinVar 251846, classified as Likely Pathogenic by these guidelines. Therefore PM5 is met.PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated cases who fulfil DLCN criteria for FH clinical diagnosis: 1 case from PMID 16250003 (Fouchier et al., 2005), the Netherlands; 1 case from PMID 30270055 (Corral et al., 2018), Argentina. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585475/MONDO:0007750/013 2023-11-07 2024-10-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA412737625 biolink:causes MONDO:0100437 infores:clingen CAID:CA412737625 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1541C>G (p.Ser514Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 514 within exon 13 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), night blindness (0.5 pts), reduction in visual acuity (0.5 pts), pigment deposits (0.5 pts), and genotyping by next-generation sequencing panel of 483 genes finding no alternative explanation for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 pts, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412737625/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Supports GO:0008359 biolink:causes GO:0007308 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0007308 CHEBI:31623 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0015230 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0855704 infores:hetionet CHEBI:127780 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0011603 infores:hetionet CHEBI:3403 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0600142 infores:hetionet CHEBI:16755 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0023052 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1263846 infores:hetionet CHEBI:63599 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0017178 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0024115 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0034063 infores:hetionet CHEBI:7492 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0010200 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0037274 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024236 infores:hetionet CHEBI:142290 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0018681 infores:hetionet CHEBI:63608 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151904 infores:hetionet CHEBI:6715 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0017979 infores:hetionet CHEBI:5109 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0018681 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027813 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0027765 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0037199 infores:hetionet CHEBI:68584 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0028738 infores:hetionet CHEBI:6846 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0151205 infores:hetionet CHEBI:75045 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0030196 infores:hetionet CAID:CA257066 biolink:causes MONDO:0021060 infores:clingen CAID:CA257066 MONDO:0021060 PMID:17603483PMID:17603482PMID:22826437 Pathogenic PM2_Supporting, PS3_Moderate, PS2_Very Strong, PS4 The c.1837C>G (p.Leu613Val) variant in the RAF1 gene is a missense variant predicted to cause substitution of leucine by valine at amino acid 613. This variant is absent from gnomAD v2 (PM2_Supporting). The variant has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2_VeryStrong; PMID:17603483), and its prevalence in affecteds is statistically increased over controls (PS4). In vitro functional studies also provide some evidence that the p.Leu613Val variant may impact protein function (PS3; PMID: 7603482, 17603483, 22826437). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting. (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA257066/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:55346 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0011570 infores:hetionet CAID:CA16020795 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020795 MONDO:0009861 PMID:31332730PMID:24368688 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Supporting The c.461A>T (p.Tyr154Phe) variant in PAH has been reported in 3 individuals with PKU (BH4 deficiency excluded). (PMID: 24368688, 31332730). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant c.1315+1G>A (IVS12+1G>A) (PMID: 24368688). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020795/MONDO:0009861/006 2020-01-26 2020-01-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75722 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0687707 infores:hetionet CHEBI:6339 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C3263723 infores:hetionet CHEBI:64310 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0234632 infores:hetionet CHEBI:3175 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0004093 infores:hetionet CHEBI:6761 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0033774 infores:hetionet CHEBI:5138 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0037036 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009319 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1096034 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1096034 infores:hetionet CHEBI:4646 biolink:causes UMLS:C0221384 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0221384 infores:hetionet CHEBI:2549 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013144 infores:hetionet CHEBI:3216 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0015967 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032961 infores:hetionet CHEBI:4672 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0876994 infores:hetionet CHEBI:63577 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0151905 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0014742 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0015397 infores:hetionet CHEBI:94392 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0030252 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0016385 infores:hetionet CAID:CA16020794 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020794 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting This c.461A>G (p.Tyr154Cys) variant in PAH was reported in trans with pathogenic variant c.728G>A (p. Arg243Gln) in a patient with PAH deficiency (>120 μmol/L Phe) (PMID: 19915519, 23932990, 28754886). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 1000 Genomes, ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020794/MONDO:0009861/006 2021-01-15 2021-07-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4672 biolink:causes EFO:1001816 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0343387 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020676 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0855246 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0855246 infores:hetionet CHEBI:50729 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0878544 infores:hetionet CHEBI:10127 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018965 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010043 infores:hetionet CAID:CA000318 biolink:causes MONDO:0017623 infores:clingen CAID:CA000318 MONDO:0017623 PMID: Likely Benign BS2_Supporting, BS1, BP7, BP5 PTEN c.132C>T (p.G44=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.167 (1.67%, 463/276,792 alleles) in the gnomAD cohort. (PMID 27535533)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000212700.3)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000212700.3)BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000318/MONDO:0017623/003 2016-11-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4495 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0033774 infores:hetionet CHEBI:9599 biolink:causes MONDO:0010030 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0086981 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0027051 infores:hetionet CHEBI:6129 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013378 infores:hetionet CAID:CA913177107 biolink:causes MONDO:0044970 infores:clingen CAID:CA913177107 MONDO:0044970 PMID: Uncertain Significance PS4_Supporting, BP4 PP3, PP1, PS3, PM2, PM6 The m.7462C>T variant in MT-TS1 has been reported in three unrelated individuals with hearing loss (PS4_supporting, PMID: 20722495). Age of onset ranged from six to 26 years old. The variant was present at homoplasmy in all reported individuals. Testing was limited in their family members. There are no reported de novo occurrences. This variant is present in population databases (MITOMAP's 61,134 sequences: AF=0.008%; Helix's 195,983 sequences: AF=0.004%; and gnomAD v3.1.2: absent). MitoTIP suggests this variant is benign (11.2 percentile) and HmtVAR predicts it to be polymorphic (0.1) (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913177107/MONDO:0044970/015 2024-07-08 2025-04-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:119915 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0036572 infores:hetionet GO:0060932 biolink:causes CL:0010007 infores:ubergraph knowledge_assertion manual_agent GO:0060932 CL:0010007 CHEBI:50729 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0232462 infores:hetionet CHEBI:63581 biolink:causes UMLS:C1096176 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1096176 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027769 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0948525 infores:hetionet CHEBI:63638 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0017181 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151596 infores:hetionet CHEBI:5103 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0027497 infores:hetionet CHEBI:261649 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0043094 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0017178 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0851341 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0004623 infores:hetionet CHEBI:51209 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0232286 infores:hetionet CHEBI:9943 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040264 infores:hetionet CHEBI:64355 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020598 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0474381 infores:hetionet CAID:CA6832161 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832161 MONDO:0015967 PMID: Benign BA1, PP1 BP4, PS4, PP3 The c.1529C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to asparagine at codon 577 (p.(His577Asp)) of NM_000545.8. This variant has a REVEL score of 0.531, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001310, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). This variant was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31968686, internal lab contributors). Additionally, this variant segregated with diabetes, with 3 informative meioses in 1 family (PP1; PMID:31968686). In summary, c.1729C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2024): BA1, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832161/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63581 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0022346 infores:hetionet CHEBI:63618 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0027441 infores:hetionet CHEBI:41774 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C3544060 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0152227 infores:hetionet CHEBI:4814 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0042024 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0035204 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162119 infores:hetionet CAID:CA120582 biolink:causes MONDO:0044970 infores:clingen CAID:CA120582 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS3, PS2 The m.7526A>G variant in MT-TD has been reported in one individual with primary mitochondrial disease to date (PMID: 16059939), in a 21-year-old woman with onset at 9-years-old of exercise intolerance (exercise testing over time showed reduction in the anaerobic threshold to undetectable values and severely reduced maximal oxygen uptake), elevated creatine kinase and lactate, hypotonia, limb girdle weakness, and minimal terminal limitation of abduction on eye movements. Muscle biopsy showed ragged red fibers and subsarcolemmal accumulations of mitochondria with paracrystalline inclusions. Mitochondrial respiratory chain enzyme analysis showed reduced activities of complexes I and IV. The variant was present at homoplasmy in muscle in the proband and was barely detectable (<3%) in blood and fibroblasts. The variant was undetectable in muscle from the mother (PM6_supporting). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (50.4 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.6 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120582/MONDO:0044970/015 2024-07-22 2025-08-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63631 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0150450 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0003123 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0011991 infores:hetionet CHEBI:31236 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0031256 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0035304 infores:hetionet CHEBI:6067 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019080 infores:hetionet CAID:CA401365436 biolink:causes MONDO:0009290 infores:clingen CAID:CA401365436 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000152.5:c.1326+1G>A variant in GAA is a canonical splice site variant in the donor splice site of intron 8. RT-PCR evidence suggests that the variant results in nonsense-mediated decay (PMID: 10189220) (PVS1). Two African-American patients with infantile-onset Pompe disease have been reported with this variant. GAA activity is available for one of these patients and was 0.35% in fibroblasts (PMID: 10189220) (PP4_Moderate). These patients are compound heterozygous for the variant and either c.1441T>C (p.Trp481Arg) or c.1555A>G (p.Met519Val) (PMID: 10189220, 25256446). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000114 (1/8708 alleles) in the African/ African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is ClinVar entry to this variant (Variant ID: 597944). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_moderate, PM2_supporting.(Classification approved by the ClinGen LSD VCEP on October 17, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401365436/MONDO:0009290/010 2022-10-17 2022-12-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:42797 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0237849 infores:hetionet CHEBI:44032 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0007820 infores:hetionet CHEBI:421707 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0013182 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0267596 infores:hetionet CHEBI:6402 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151937 infores:hetionet CHEBI:68554 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0026827 infores:hetionet UNII:T58MSI464G biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0239571 infores:hetionet CHEBI:9130 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0015230 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0004936 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006798 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020579 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0233494 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0549202 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0549202 infores:hetionet CHEBI:100246 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C1257843 infores:hetionet CHEBI:52717 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002962 infores:hetionet NCBIGene:6718 biolink:causes MONDO:0009339 infores:monarchinitiative not_provided not_provided HGNC:388 MONDO:0009339 uuid:fa2446f8-c66f-45f8-9b6b-1aae568211df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0086439 infores:hetionet CHEBI:4784 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0010200 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0006277 infores:hetionet CHEBI:167309 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0547030 infores:hetionet CHEBI:36791 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2242737 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0037274 infores:hetionet NCBIGene:581 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:959 MONDO:0005575 uuid:563a3300-8d4a-424d-9515-a74fb2dce137 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0233414 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0027947 infores:hetionet CHEBI:521033 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0020517 infores:hetionet CHEBI:50777 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0016204 infores:hetionet CHEBI:92712 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0234708 infores:hetionet CAID:CA400029121 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029121 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The ITGB3 nonsense variant NM_000212.3:c.1402G>T (p.Glu468Ter) introduces a premature termination codon in exon 10 of 15 total exons and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT34, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029121/MONDO:0100326/011 2021-07-14 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:28748 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0033860 infores:hetionet CHEBI:45599 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0268000 infores:hetionet CHEBI:93363 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0012833 infores:hetionet CHEBI:4710 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0156404 infores:hetionet CHEBI:2682 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0043094 infores:hetionet CAID:CA6748836 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748836 MONDO:0009861 PMID: Likely Benign BP7, BS1 The c.837C>T (p.Pro279=) variant in PAH has a MAF of 0.00201 in gnomAD (BS1). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP7). In summary, this variant meets criteria to be classified as likely benign. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748836/MONDO:0009861/006 2020-01-26 2020-01-31 Autosomal recessive inheritance HP:0000007 Contradicts true GO:0006954 biolink:causes MONDO:0002471 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D002062 DB01397_MESH_D002062_1 CHEBI:35778 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0015967 infores:hetionet CAID:CA10529891 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529891 MONDO:0010604 PMID: Uncertain Significance PS4 PM5, PP3, PM2, BA1 The c.1346G>A, p.Arg449Gln variant is reported with a Grpmax of 0.0001042 in gnomAD v2.1.1 with 7 hemizygotes meets the BA1 threshold of 0.0000556. However, this code was not applied due to the number of reported very mild hemophilia B cases being similar to the number of hemizygotes in gnomAD. There are at least 6 published cases in the literature and >1 unpublished case in the EAHAD Database with this variant and very mild hemophilia B meeting PS4 (PMID: 31267011, 31272859, 8091381, 10739381, 8076946, 8320491). Typically, the PS4 code would not be applied when criteria for BA1 is met, but an exception was made for this variant given the number of known cases of very mild hemophilia B, which could lead to affected or undiagnosed individuals in control populations. In summary, this variant meets criteria to be classified as variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529891/MONDO:0010604/080 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Inconclusive true CAID:CA341206 biolink:causes MONDO:0021060 infores:clingen CAID:CA341206 MONDO:0021060 PMID: Pathogenic PS2, PS1, PS4_Moderate, PM1, PP3, PP2, PM2_Supporting BS1, BA1, BP4, BP1 The c.173C>T variant in the HRAS gene is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 58 (p.Thr58Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.777, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicity of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 1 was reported as a de novo occurrence (PS2, PS4_Moderate; CeGaT Center for Human Genetics, ClinVar SCV003916655.13; PMIDs: 22488832, 18247425, 23321623, 26888048). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS1, PS2, PS4_Moderate, PM1, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA341206/MONDO:0021060/046 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3207 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C1141861 infores:hetionet CHEBI:5004 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0039231 infores:hetionet CHEBI:39112 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0011175 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011053 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0012833 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0456909 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0549373 infores:hetionet CAID:CA222195 biolink:causes MONDO:0015152 infores:clingen CAID:CA222195 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1 PM2 The NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14) variant in DYSF, which is also known as NM_001130987.2: c.5815_5816del (p.Ser1939GlnfsTer14), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 51/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected with a second DYSF variant in at least six individuals with suspected LGMD (PMID: 27602406; 32400077; 35135626; 36983702), including in unknown phase with a pathogenic variant in two individuals (NM_003494.4: c.1392dupA p.(Asp465ArgfsTer9), 0.5 pts, PMID: 27602406; NM_003494.4: c.3805dupG p.(Glu1269GlyfsTer7), 0.5 pts, PMID: 27602406) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical suspicion of LGMD or progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 36983702; 35135626; 27602406; PP4_Strong). The filtering allele frequency of this variant is 0.0001765 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 173/1112006 European (non-Finnish) chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/11/2025): PVS1, PM3, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222195/MONDO:0015152/180 2025-04-11 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:114785 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0234233 infores:hetionet CAID:CA123256 biolink:causes MONDO:0100326 infores:clingen CAID:CA123256 MONDO:0100326 PMID:20020534 Uncertain Significance PS3_Supporting, PP3, PM2_Supporting PM3, PP4 The ITGB3 missense variant NM_000212.3:c.740G>A replaces the glycine residue with an aspartate residue (p.Gly247Asp) and is absent from control population databases, including gonmADv4.1.0 (PM2_supporting). The variant is predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.963; PP3). The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-19% compared to wild type; PMID: 20020534; PS3_supporting). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123256/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8764 biolink:causes UMLS:C0877690 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0877690 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0015376 infores:hetionet CHEBI:8356 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015371 infores:hetionet CHEBI:16469 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0518988 infores:hetionet NCBIGene:283 biolink:causes MONDO:0012753 infores:monarchinitiative not_provided not_provided HGNC:483 MONDO:0012753 uuid:59714d82-b5fa-4128-8c89-6364aa0ccf69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17141 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0011991 infores:hetionet CHEBI:10650 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018926 infores:hetionet CHEBI:83804 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0231528 infores:hetionet CHEBI:8382 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0156404 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0042373 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042134 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0863113 infores:hetionet CHEBI:3478 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0041657 infores:hetionet CHEBI:45327 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0002994 infores:hetionet CHEBI:3380 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0028961 infores:hetionet CHEBI:9448 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0016204 infores:hetionet CHEBI:4784 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0022346 infores:hetionet CHEBI:8080 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0011991 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0948595 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0018799 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0018799 infores:hetionet NCBIGene:8867 biolink:causes MONDO:0014233 infores:monarchinitiative not_provided not_provided HGNC:11503 MONDO:0014233 uuid:2048e722-0c74-4218-917e-8e8cb61beb68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0151786 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0038362 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0152517 infores:hetionet CAID:CA512341135 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341135 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1278G>C (p.Pro426=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.50)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341135/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48273 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0015672 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0015397 infores:hetionet GO:1905356 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:1905356 GO:0010467 CHEBI:9123 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0034880 infores:hetionet CHEBI:50730 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0027441 infores:hetionet CHEBI:37941 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C3665347 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0042075 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042571 infores:hetionet CHEBI:8404 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0340865 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0013609 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0009806 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0541799 infores:hetionet CHEBI:3077 biolink:causes UMLS:C1963897 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1963897 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0040046 infores:hetionet CHEBI:29013 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0151205 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018991 infores:hetionet CAID:CA320603662 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603662 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.734C>T (p.Pro245Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603662/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4672 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0024236 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0161479 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0030252 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0403632 infores:hetionet CHEBI:9137 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0023218 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0149931 infores:hetionet CHEBI:8212 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0011603 infores:hetionet GO:0030516 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0048699 CAID:CA410208245 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208245 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.31C>A (p.Pro11Thr) is a missense variant which has a REVEL score < 0.50 (0.467) and a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208245/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135530 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0042075 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0037286 infores:hetionet CHEBI:64312 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018965 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0018939 infores:hetionet CHEBI:5138 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0686347 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1142412 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0001824 infores:hetionet CHEBI:31644 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085649 infores:hetionet GO:2000015 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000015 GO:0007275 CHEBI:9086 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004998 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0233472 infores:hetionet CHEBI:6339 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0003862 infores:hetionet CAID:CA222200 biolink:causes MONDO:0015152 infores:clingen CAID:CA222200 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1 PM2 The NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3) variant in DYSF, which is also known as NM_001130987.2: c.6096dup p.(Glu2033ArgfsTer3), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 53/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least seven unrelated individuals with features consistent with LGMD (PMID: 26404900, 14678801, 36983702, 18853459), including in a homozygous state (0.25 pts, PMID: 18853459) and in unknown phase with a variant classified as at least likely pathogenic (NM_003494.4: c.5057+5G>A, 0.25 pts, PMID: 36983702) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 14678801, 36983702, 18853459). The filtering allele frequency of this variant is 0.0003511 (the upper threshold of the 95% CI of 9/44724 Admixed American exome chromosomes) in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1, PM3_Supporting, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222200/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7573 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0004093 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042109 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0025061 infores:hetionet CHEBI:52172 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0476281 infores:hetionet CHEBI:31643 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0008031 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0267792 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0009319 infores:hetionet CHEBI:68579 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0017178 infores:hetionet UMLS:C0010592 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0009421 infores:hetionet CHEBI:119573 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0241060 infores:hetionet CHEBI:50223 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0030193 infores:hetionet CHEBI:194135 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085641 infores:hetionet CHEBI:4562 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0015230 infores:hetionet CAID:CA2695203127 biolink:causes MONDO:0015967 infores:clingen CAID:CA2695203127 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.663_673dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 225 (NM_000162.5), adding 4 novel amino acids before encountering a stop codon (p.(Ile225ArgfsTer4). This variant, located in biologically-relevant exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant was identified in one individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and not enough clinical information was provided to apply PP4 (PMID: 16965331). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, c.663_673dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695203127/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports CHEBI:2673 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0015230 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0274702 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0274702 infores:hetionet CHEBI:9622 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0037199 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0595877 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0006266 infores:hetionet NCBIGene:2178 biolink:causes MONDO:0010953 infores:monarchinitiative not_provided not_provided HGNC:3586 MONDO:0010953 uuid:e904a41e-6040-4092-bcd0-fa7f4bc3c85e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0392025 infores:hetionet CHEBI:4798 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0012569 infores:hetionet CHEBI:47780 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042024 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0236071 infores:hetionet CHEBI:8024 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037763 infores:hetionet CAID:CA390867215 biolink:causes MONDO:0100216 infores:clingen CAID:CA390867215 MONDO:0100216 PMID: Uncertain Significance PM2_Supporting PVS1, PM6, BA1, BP4, BP3, BP2, BS2, PP3, PP1, PP4, PM5, PM4, PM1, PM3, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7 NM_177438.3(DICER1):c.4775C>T variant in DICER1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 1592 (p.P1592L). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The computational predictor REVEL gives a score of 0.693, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting. (Bayesian Points: 1; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390867215/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA114127 biolink:causes MONDO:0015629 infores:clingen CAID:CA114127 MONDO:0015629 PMID:27212476 Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PS3, PS4_Very Strong, PS2_Moderate PM6 The NM_000552.5(VWF):c.3946G>A variant in VWF is a missense variant predicted to cause substitution of valine by methionine at amino acid 1316. This variant is absent from gnomADv4.1 (PM2_Supporting). This variant has been reported in at least 9 probands showing excessive mucocutaneous bleeding as well as a laboratory phenotype of loss of high molecular weight multimers and/or enhanced platelet aggregation at low doses of ristocetin (PS4_VeryStrong, PMID: 19060241, PMID: 27885890, PMID: 28640903). At least 1 patient showed excessive mucocutaneous bleeding, loss of high molecular weight multimers, and enhanced platelet aggregation at low doses of ristocetin, which together are specific for VWD type 2B, along with consistent features of thrombocytopenia and low VWF antigen/activity ratio (PP4_Moderate, PMID: 28640903). Two additional affected patients harbored the variant in an apparent de novo heterozygous state (PS2_Moderate, PMID: 7909449, PMID: 2010538). The variant has been reported to segregate with VWD type 2B through 3 affected meioses from 1 family (PP1; PMID: 19060241). The computational predictor REVEL gives a score of 0.74, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A knock-in mouse model expressing VWF p.Val1316Met has shown prolonged bleeding time, absence of high-MW multimers, large platelet aggregates, decreased in vitro platelet adhesion to thrombin or collagen, and enhanced in vivo VWF/platelet string formation, indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PS4_VeryStrong, PP4_Moderate, PS2_Moderate, PP1, PP3, PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114127/MONDO:0015629/081 2024-08-13 2024-08-19 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:1984 biolink:causes MONDO:0859163 infores:monarchinitiative not_provided not_provided HGNC:3300 MONDO:0859163 uuid:e70fdae3-cecc-47ec-825d-406a71a09033 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70707 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0344232 infores:hetionet CHEBI:31348 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0028734 infores:hetionet CHEBI:50648 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151970 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0152227 infores:hetionet CHEBI:34764 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00663 UMLS:C1325847 infores:hetionet CHEBI:8428 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0029443 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0746883 infores:hetionet CHEBI:8435 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0014553 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0029134 infores:hetionet CAID:CA10385539 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385539 MONDO:0100437 PMID: Likely Benign BS2, PP3, PP4, BS1 PP1, BP4 NM_001034853.2(RPGR):c.1105C>T (p.Arg369Cys) is a missense variant causing substitution of arginine by cysteine at amino acid 369. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00003776 among hemizygous individuals, with 15 variant alleles / 397,273 total hemizygous alleles (12 European non-Finnish, 2 Admixed American, and 1 South Asian], which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinitis pigmentosa with night blindness (0.5 pts), visual field constriction (0.5 pts), reduced best-corrected visual acuity in both eyes (0.5 pts), high myopia (1 pt), family history consistent with X-linked inheritance (2 pts), and reduced electroretinogram responses, which together are specific for RPGR-related retinopathy (4.5 points, PMID: 27768226, PP4). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family, however, the variant was reported in at least 1 additional unaffected family member meeting one of the BS2 requirements of a male with no functional vision impairment by age 30 years, so PP1 was not met (PMID: 27768226, BS2). The computational predictor REVEL gives a score of 0.182, which is below the ClinGen X-linked IRD VCEP threshold of ≥ 0.644 and does not predict a damaging effect on RPGR function. The splicing impact predictor SpliceAI gives delta scores of 0.26 for acceptor loss and 0.23 for donor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a deleterious impact on splicing (PP3). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1, BS2, PP3, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385539/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:2618 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0030662 infores:hetionet CHEBI:5138 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003873 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027769 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0853813 infores:hetionet CHEBI:83531 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0017574 infores:hetionet CHEBI:50859 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042963 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0080274 infores:hetionet CHEBI:8890 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0687713 infores:hetionet CHEBI:127780 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0038325 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006826 infores:hetionet CHEBI:7565 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014591 infores:hetionet CHEBI:7575 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0853149 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019158 infores:hetionet CAID:CA145869 biolink:causes MONDO:0001586 infores:clingen CAID:CA145869 MONDO:0001586 PMID: Benign BA1 NM_000203.5:c.1190-10dupC variant is in the acceptor splice site region of intron 8 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2350 (16758/71322 alleles; 1409 homozygotes; Grpmax Filtering AF 95% confidence = 0.2320) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92626). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145869/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5165 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0948594 infores:hetionet CAID:CA354671596 biolink:causes MONDO:0021060 infores:clingen CAID:CA354671596 MONDO:0021060 PMID:28289718 Likely Pathogenic PS2, PM1, PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting The c.68G>T (p.Gly23Val) variant in MRAS is a missense variant predicted to cause substitution of glycine by valine at amino acid 23. This variant has a minor allele frequency of 0.00008624% (1/1159522) in the European (non-Finnish) population in gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.923, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). This variant resides within the P-loop (amino acids 20 – 27) of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been identified in 1 individual with features of RASopathy (PS4_Supporting; PMID:28289718). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:28289718). RAS and ERK activation assays in HEK293T/17 showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:28289718) (PS3_Moderate). Given the Moderate strength of gene-disease relationship between MRAS and autosomal dominant RASopathy, ClinGen’s sequence variant interpretation working group does not recommend the classification of variants in this gene beyond likely pathogenic. Based on ACMG/AMP criteria alone, this variant has enough supporting evidence to be classified as pathogenic; however, the RASopathy VCEP has downgraded this classification to likely pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS3_M, PM1, PS4_P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA354671596/MONDO:0021060/087 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5864 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085692 infores:hetionet NCBIGene:55814 biolink:causes MONDO:0032639 infores:monarchinitiative not_provided not_provided HGNC:13652 MONDO:0032639 uuid:9e6e6bf8-16a9-4711-a58f-ce006522e1dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0232487 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023067 infores:hetionet CHEBI:79699 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0010692 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040034 infores:hetionet CHEBI:3515 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0085593 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0240671 infores:hetionet CHEBI:29688 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0037763 infores:hetionet GO:2000248 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000248 GO:0007275 CHEBI:474180 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151662 infores:hetionet CHEBI:71940 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0013604 infores:hetionet CHEBI:4798 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0006384 infores:hetionet CHEBI:2666 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0878544 infores:hetionet CHEBI:63608 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0038325 infores:hetionet CHEBI:194135 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085932 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0041349 infores:hetionet CHEBI:42068 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0036983 infores:hetionet CHEBI:6690 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0027066 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0234215 infores:hetionet CHEBI:4717 biolink:causes UMLS:C0475746 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0475746 infores:hetionet CAID:CA386965858 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965858 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PP1_Strong, PP4_Moderate, PP3 The c.736G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 246 (p.(V246L)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.781, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). At least 3 of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes, with at least seven informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Taken together, this evidence supports the classification of c.736G>T as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_strong, PP4_moderate, PS4_moderate, PP3, PM1_supporting, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965858/MONDO:0015967/017 2021-08-18 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8805 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0522055 infores:hetionet CHEBI:3506 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0033774 infores:hetionet CHEBI:44915 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0039231 infores:hetionet CAID:CA409110369 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110369 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PP1, PM2_Supporting, PS2_Moderate PS4 The c.1256C>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, results in a premature termination at codon 419 (p.(Ser419Ter)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 10 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose SU (extreme response-hypoglycemia) ) (PP4_Moderate; PMID: 31096182). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with diabetes, but whose clinical picture is not highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Moderate; PMID: 24323243). This variant was segregated with diabetes, with three informative meioses in one family (PP1; PMID:31096182). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:24323243, 31096182). In summary, c.1256C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PS2_moderate, PP4_moderate, PP1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110369/MONDO:0015967/085 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:74947 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042963 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027051 infores:hetionet GO:0035542 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:0035542 GO:0016192 CHEBI:119915 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0919671 infores:hetionet CHEBI:74947 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0547030 infores:hetionet CHEBI:6367 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1142412 infores:hetionet CHEBI:2663 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C2242588 infores:hetionet CHEBI:2567 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0151908 infores:hetionet CHEBI:175901 biolink:causes HP:0001923 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0206160 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0014534 infores:hetionet CHEBI:7575 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0017181 infores:hetionet CHEBI:15553 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0039070 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0009806 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0392386 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0011570 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0595877 infores:hetionet CHEBI:5959 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0002878 infores:hetionet CHEBI:63717 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0039231 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0042109 infores:hetionet CHEBI:5147 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020438 infores:hetionet CAID:CA413497595 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497595 MONDO:0010315 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.100G>T (p.Glu34Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497595/MONDO:0010315/129 2024-06-14 2024-06-14 X-linked inheritance HP:0001417 Supports CHEBI:32192 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0037317 infores:hetionet CHEBI:52717 biolink:causes HP:0031274 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020683 infores:hetionet UNII:R15UI3245N biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0015230 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004936 infores:hetionet CHEBI:63681 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0085633 infores:hetionet CHEBI:8107 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151766 infores:hetionet CHEBI:3219 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040460 infores:hetionet CHEBI:66903 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0025320 infores:hetionet CAID:CA10585401 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585401 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BP4, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP1, PP4 The NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PM5) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.769.It is above 0.75, so PP3 is Met.PM5 - 2 other missense variants in the same codon:- NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID: 251782) - VUS by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585401/MONDO:0007750/013 2022-01-17 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UMLS:C0657912 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017566 infores:hetionet CHEBI:47781 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C1443060 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0000729 infores:hetionet CHEBI:83804 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C2240374 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011053 infores:hetionet CAID:CA2918371 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918371 MONDO:0015152 PMID: Likely Benign BP7, BP4 BS1 The NM_000232.5: c.519G>A p.(Pro173=) variant in SGCB is a synonymous (silent) variant that is not predicted to influence splicing by SpliceAI (score 0.03) (BP4, BP7). The filtering allele frequency of the variant is 0.0005025 for East Asian genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 6/5192), which is lower than the VCEP threshold of 0.001 (BS1 not met; PM2_Supporting also not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918371/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:36704 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0086565 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0233414 infores:hetionet CAID:CA213740 biolink:causes MONDO:0015967 infores:clingen CAID:CA213740 MONDO:0015967 PMID: Pathogenic PS4, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting BS1, BA1, BP1, BP4 The c.1268T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 423 (p.(Phe423Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.801, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 23843579, 31968686, internal lab contributors). This variant segregated with hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 28012402, 23843579). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6% and OGTT with minimal increment <3 mmol/l) (PP4_Moderate; PMID: 23843579). In summary, c.1268T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PM2_supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213740/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:8356 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0264906 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0233494 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0853692 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0007793 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0007793 uuid:b375993e-603d-44b9-aa5f-9ac7f620e616 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:87681 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0012569 infores:hetionet CHEBI:2948 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0235378 infores:hetionet GO:1904393 biolink:causes GO:0007528 infores:ubergraph knowledge_assertion manual_agent GO:1904393 GO:0007528 CHEBI:49575 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020458 infores:hetionet CAID:CA014743 biolink:causes MONDO:0005021 infores:clingen CAID:CA014743 MONDO:0005021 PMID: Uncertain Significance PM2, PP3, PS4_Supporting PM5, PM1, PM6, PP1, BA1, PS3, BS1, BS3, PS1 The NM_000257.4 (MYH7): c.4276G>A (p.Glu1426Lys) variant has been identified in 5 individuals with DCM (PS4_Supporting; Villard 2005 PMID: 1576978; Shipman 2011 PMID: 21482996; Vikhorev 2017 PMID: 29093449; GeneDx pers. comm.; LMM pers. comm.), including as a de novo occurrence in 1 infant with an additional variant in a cardiomyopathy-associated gene (GeneDx pers. comm.) and in 1 individual with HCM (Walsh 2017 PMID: 27532257; OMGL pers. comm.). Because of the additional variant observed in the individual with the de novo occurrence, the PM6 criterion was not applied. This variant has also been reported in 1 individual with LVNC and reduced ejection fraction and in 1 individual with familial nondilated cardiomyopathy and their child with LVNC (Ambry pers. comm.; Invitae pers. comm). This variant segregated with disease in 2 affected relatives with DCM from 1 family (Villard 2005 PMID: 1576978); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014743/MONDO:0005021/002 2021-09-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9654 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0015672 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019340 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020651 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0232461 infores:hetionet CAID:CA512341386 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341386 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.996C>T (p.Asp332=) is a synonymous variant. The spliceAI score is less than 0.2 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341386/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0879264 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0162429 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0003864 infores:hetionet CHEBI:3207 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0015672 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0231441 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019158 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151846 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151846 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0155169 infores:hetionet CHEBI:7494 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042133 infores:hetionet CHEBI:8768 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0040264 infores:hetionet CAID:CA410204199 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204199 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.136G>A (p.Ala46Thr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.387) and a SpliceAI score ≤0.20 (0) (BP4). ClinVar has one entry (Invitae, variation ID 1003215) for this variant, but the affected status is unknown. To our knowledge, this variant has not been reported in the literature in individuals affected with RUNX1-related conditions. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204199/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46345 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0344232 infores:hetionet CHEBI:167638 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0162529 infores:hetionet MONDO:0800181 biolink:causes NCBIGene:4976 infores:ubergraph knowledge_assertion manual_agent MONDO:0800181 HGNC:8140 CAID:CA915940789 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940789 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting PP4, PP3 The NM_000419.5(ITGA2B):c.1616_1620delinsGGCAC (p.Leu539_Gln540delinsArgHis) indel variant results in the in-frame replacement of Leu539 and Gln540 with Arg and His respectively. This variant has been detected in at least 1 proband reported to have Glanzmann thrombasthenia (GT_43 in PMID: 30792900), who was homozygous for the variant (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3_Supporting and PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940789/MONDO:0100326/011 2023-09-07 2023-09-08 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:10102 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0022638 infores:hetionet CHEBI:17549 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0162830 infores:hetionet UMLS:C0010592 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235198 infores:hetionet CHEBI:5893 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151878 infores:hetionet CHEBI:9139 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011168 infores:hetionet GO:0034776 biolink:causes MONDO:0011786 infores:drugmechdb knowledge_assertion manual_agent GO:0034776 MESH:D065631 DB00455_MESH_D065631_1DB00366_MESH_D065631_1DB01246_MESH_D065631_1 CHEBI:9757 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0015672 infores:hetionet NCBIGene:9968 biolink:causes MONDO:0010655 infores:monarchinitiative not_provided not_provided HGNC:11957 MONDO:0010655 uuid:a4a13d45-6702-495f-83f5-acfa51f7d154 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0338831 infores:hetionet CHEBI:16899 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0014724 infores:hetionet NCBIGene:80781 biolink:causes MONDO:0800167 infores:monarchinitiative not_provided not_provided HGNC:2195 MONDO:0800167 uuid:a154ecd3-9c7f-47a5-b09e-5501d91b3a8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5566 biolink:causes MONDO:0030876 infores:monarchinitiative not_provided not_provided HGNC:9380 MONDO:0030876 uuid:9a8445d7-78b6-47df-a6ec-a20b6d7cf5e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0231528 infores:hetionet CHEBI:75988 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0013404 infores:hetionet NCBIGene:7345 biolink:causes MONDO:0014209 infores:monarchinitiative not_provided not_provided HGNC:12513 MONDO:0014209 uuid:8b15912d-5018-4958-bd69-1b7a39fda167 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0009315 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0231856 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042075 infores:hetionet CHEBI:3219 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0392156 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0041912 infores:hetionet CHEBI:45599 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C1291078 infores:hetionet CHEBI:3504 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0032227 infores:hetionet CHEBI:8060 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0151772 infores:hetionet CHEBI:135613 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0009782 infores:hetionet CHEBI:17987 biolink:causes MONDO:0002922 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0034212 infores:hetionet CHEBI:4995 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014591 infores:hetionet CHEBI:5138 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014518 infores:hetionet CHEBI:7459 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0015967 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0025160 infores:hetionet CHEBI:4995 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0428977 infores:hetionet GO:0099044 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:0099044 GO:0010256 CHEBI:42068 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0023418 infores:hetionet CHEBI:5775 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0231218 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0235329 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235329 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151899 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151899 infores:hetionet CHEBI:27834 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C3495920 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030920 infores:hetionet CHEBI:27777 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0549386 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025202 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151826 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0853692 infores:hetionet CHEBI:31705 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0034063 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0520587 infores:hetionet CHEBI:47780 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0028734 infores:hetionet CAID:CA10584817 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584817 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM3, PM2, PP3, PP1, PP4 BP4, BP2, BA1, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM6, PVS1, BS2 The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1 - Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID: 9974426), so PM3 is Met.PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID: 16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID: 16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID: 20145306), so PS4_Supporting is Met.PP1 - Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met.PP3 - REVEL = 0.973. It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 5 unrelated index cases fulfilling clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584817/MONDO:0007750/013 2022-03-25 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:10101 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151934 infores:hetionet NCBITaxon:4751 biolink:causes MONDO:0044070 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D058387 DB01141_MESH_D058387_1 CHEBI:5818 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0020649 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0948586 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0949059 infores:hetionet CHEBI:5147 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0002994 infores:hetionet NCBIGene:4353 biolink:causes MONDO:0009694 infores:monarchinitiative not_provided not_provided HGNC:7218 MONDO:0009694 uuid:f0222c05-21c6-4391-ad8f-46ad727e0b4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0231218 infores:hetionet CHEBI:2663 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0700361 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0232197 infores:hetionet CHEBI:41774 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0003811 infores:hetionet CHEBI:41423 biolink:causes MONDO:0021661 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0010054 infores:hetionet CHEBI:52172 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151539 infores:hetionet NCBIGene:157922 biolink:causes MONDO:0957217 infores:monarchinitiative not_provided not_provided HGNC:19946 MONDO:0957217 uuid:0af5f545-7562-48ee-954d-dba23b01cc84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:389827 biolink:causes MONDO:0800437 infores:monarchinitiative not_provided not_provided HGNC:33778 MONDO:0800437 uuid:c269888c-5f55-407f-a423-d3d3de78d95e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018524 infores:hetionet CHEBI:17347 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0549448 infores:hetionet CHEBI:9587 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0518015 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0003123 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020550 infores:hetionet CHEBI:82981 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C1112214 infores:hetionet CHEBI:3011 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0033687 infores:hetionet CHEBI:8768 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0085631 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0041969 infores:hetionet CHEBI:7954 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0015672 infores:hetionet CHEBI:50861 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0037763 infores:hetionet CHEBI:3219 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0010200 infores:hetionet CAID:CA213810 biolink:causes MONDO:0015967 infores:clingen CAID:CA213810 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.605C>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 202 (p.(Met202Thr)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in 4 families (PP1_Strong; internal lab contributors). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; PMID: 17573000, internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.917, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and 2 copies observed in the European non-Finnish population and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). In summary, c.605C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213810/MONDO:0015967/086 2023-12-01 2023-12-01 Semidominant inheritance HP:0032113 Supports CHEBI:42944 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020517 infores:hetionet CHEBI:6931 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0038450 infores:hetionet CHEBI:4466 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0011603 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0426576 infores:hetionet CHEBI:5001 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0702166 infores:hetionet CHEBI:92998 biolink:causes MONDO:0024633 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0848548 infores:hetionet CHEBI:168396 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0040053 infores:hetionet CAID:CA10604030 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604030 MONDO:0015152 PMID: Uncertain Significance PM3, PP3, PP4, PM2_Supporting PS3, PS1, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM1, PM5, BS2, PP2, PP1, BP1, BP4, BP2, BP3, BA1 The NM_213599.3: c.648+5G>C variant in ANO5 is an intronic variant located in the donor splice region in intron 7. This variant has been detected in at least two individuals with LGMD, including confirmed in trans with a pathogenic or likely pathogenic variant (c.2503_2505del p.(Phe835del), 1.0 pt, ClinVar SCV002196824.2 internal data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor SpliceAI gives a score of 0.87 for donor loss, which is greater than the VCEP threshold of 0.5, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant cannot be classified as pathogenic nor benign at this time and remains a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3, PP4, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604030/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2663 biolink:causes MONDO:0019203 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1279945 infores:hetionet CAID:CA320255686 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255686 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.806-13del is an intronic variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. It has a SpliceAI score of 0.03 and a PhyloP score of 1.9, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255686/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3732 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0030305 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0032131 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0029134 infores:hetionet CHEBI:47381 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0178415 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0021390 infores:hetionet CHEBI:51164 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0009676 infores:hetionet CHEBI:71417 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0030193 infores:hetionet CHEBI:41774 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0011991 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0162316 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0473117 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0473117 infores:hetionet CAID:CA143316 biolink:causes MONDO:0019501 infores:clingen CAID:CA143316 MONDO:0019501 PMID: Uncertain Significance PM3_Supporting, BP4 BP7, BP5, BS1, BS4, BS3, BS2, PP2, PP3, PP1, PP4, PM5, PM4, PM1, PVS1, PM2, PM6, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143316/MONDO:0019501/005 2022-11-22 2023-02-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true UMLS:C0145867 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0027709 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151705 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0006145 infores:hetionet CHEBI:39867 biolink:causes HP:0002059 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0235946 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0152128 infores:hetionet CHEBI:567361 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0085649 infores:hetionet CHEBI:7478 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0041582 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0152029 infores:hetionet CHEBI:71941 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0014591 infores:hetionet CHEBI:10023 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0162557 infores:hetionet CHEBI:15940 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0271051 infores:hetionet CHEBI:3723 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002994 infores:hetionet GO:0048385 biolink:causes GO:0032870 infores:ubergraph knowledge_assertion manual_agent GO:0048385 GO:0032870 CHEBI:79699 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0041834 infores:hetionet CHEBI:3207 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042029 infores:hetionet CHEBI:31859 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0080274 infores:hetionet CHEBI:6067 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C3665346 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0040046 infores:hetionet NCBIGene:6390 biolink:causes MONDO:0007273 infores:monarchinitiative not_provided not_provided HGNC:10681 MONDO:0007273 uuid:607c48dc-8c3b-4896-b1f2-91cea5105e06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004096 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0423602 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0434437 infores:hetionet GO:2001109 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:2001109 GO:0150063 GO:1904444 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0007275 CHEBI:3172 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0012833 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0235416 infores:hetionet CHEBI:3698 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0007820 infores:hetionet CHEBI:6062 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020458 infores:hetionet CHEBI:8435 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0234428 infores:hetionet CHEBI:119486 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085628 infores:hetionet CHEBI:231594 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0039070 infores:hetionet CHEBI:63617 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0040485 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007286 infores:hetionet CHEBI:8354 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0018681 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1112353 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1112353 infores:hetionet CHEBI:3761 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0004093 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0041969 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0687133 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0009806 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042401 infores:hetionet CHEBI:8764 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0015967 infores:hetionet CHEBI:9943 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030554 infores:hetionet GO:0061190 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0061190 GO:0009790 CHEBI:51141 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0392171 infores:hetionet CHEBI:83804 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0035410 infores:hetionet CHEBI:18248 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0687713 infores:hetionet CHEBI:39585 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0010200 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0013589 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013589 infores:hetionet CHEBI:5138 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0392156 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0030252 infores:hetionet CAID:CA915952200 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952200 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PS4, PS3 The m.4611del (or m.4605del, p.M48Ter) variant in MT-ND2 has been reported in one individual with primary mitochondrial disease to date however clinical details are not provided (PMID: 32652755). There is also a ClinVar submission from the same lab who published the cohort study that included the only case report however it is not clear if this is a second unrelated case or the same case as reported in the medical literature. This variant has also been reported in 10 unrelated Chinese individuals from a large cohort with maternally inherited essential hypertension (PMID: 32414374). However, after examining the sequencing data presented for this region, this Expert Panel agreed that the deletion call was not convincing and care needs to be taken when evaluating variants in this A polytract. Furthermore, hypertension is not a highly concerning feature for primary mitochondrial disease and therefore these cases were not included in this curation. There are no additional individuals or families reported with de novo occurrences of this variant or with this variant segregating with clinical manifestations to our knowledge. If this variant was not the result of a sequencing error, it would create stop codon at amino acid 48 (p.M48Ter), removing 86.5% of the protein (PVS1_strong). There is one heteroplasmic occurrence of this variant in gnomAD v3.1.2 and it is otherwise absent from population databases (GenBank dataset, Helix dataset; PM2_supporting). There are no computational predictors for this variant type in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 14, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952200/MONDO:0044970/015 2024-10-14 2024-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4903 biolink:causes UMLS:C0235678 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0235678 infores:hetionet CHEBI:3561 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151610 infores:hetionet CHEBI:2704 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0034152 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0015230 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1443060 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0016436 infores:hetionet CHEBI:61390 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0042029 infores:hetionet CHEBI:39585 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0031542 infores:hetionet CAID:CA354672403 biolink:causes MONDO:0021060 infores:clingen CAID:CA354672403 MONDO:0021060 PMID: Likely Pathogenic PS1, PS4, PS3_Supporting, PS2_Very Strong, PM1, PP3, PM2_Supporting The NM_001085049.3: c.203C>T variant in MRAS is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 68 (p.Thr68Ile). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with Noonan syndrome and 1 with congenital heart disease (PS2_VeryStrong; PMID: 28289718, 31108500, 32368696). The same amino acid change (p.Thr58Ile), resulting from a different nucleotide change c.173C>T in HRAS and KRAS ClinVar ID: 12610 and 12588, is classified as pathogenic for Costello syndrome and Noonan syndrome respectively by the ClinGen RASopathy VCEP (PS1). ERK and AKT activation assays in HEK 293 T cells showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:31108500) (PS3). This variant has been reported in 5 probands, 3 with NS and two with congenital heart disease and conotruncal heart defects with extracardiac anomalies with neurodevelopmental disorder (PS4; PMID:28289718, 28991257, 31108500, 32368696, 33318624). This variant resides within the Switch II domain (amino acids 67 – 74), of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). This variant is absent from gnomAD v4 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant Noonan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VS, PS1, PS3, PS4, PM1, PP3, PM2_P. (RASopathy VCEP Specifications V1.1; 9/17/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA354672403/MONDO:0021060/087 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5118 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0852733 infores:hetionet CHEBI:27786 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0002792 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0033777 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041976 infores:hetionet UMLS:C0879264 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0011603 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0243026 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0023067 infores:hetionet CHEBI:6888 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0852911 infores:hetionet CHEBI:2955 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0702166 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0021364 infores:hetionet CHEBI:8707 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1522133 infores:hetionet NCBIGene:718 biolink:causes MONDO:0013417 infores:monarchinitiative not_provided not_provided HGNC:1318 MONDO:0013417 uuid:61cb0540-421b-4543-8d71-050951dc323f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019196 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0232492 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027765 infores:hetionet CHEBI:9586 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0033774 infores:hetionet CHEBI:7936 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0877359 infores:hetionet CHEBI:42797 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022107 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0037199 infores:hetionet CHEBI:84050 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0852911 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0836924 infores:hetionet CAID:CA913190077 biolink:causes MONDO:0015152 infores:clingen CAID:CA913190077 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_003494.4: c.1535_1538dup p.(Phe514GlyfsTer57) variant in DYSF, which is also known as NM_001130987.2: c.1589_1592dup p.(Phe532GlyfsTer57), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 19/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in one individual with suspected LGMD in unknown phase with a pathogenic variant (NM_003494.4: c.3051dup p.(Ile1018HisfsTer14), 0.5 pts, GRASP-LGMD consortium internal data communication) (PM3_Supporting; PP4). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/28/2025): PVS1, PM2_Supporting, PM3_Supporting, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190077/MONDO:0015152/180 2025-05-28 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42355 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0041834 infores:hetionet CHEBI:78543 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0030305 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042769 infores:hetionet GO:1904933 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:1904933 GO:0060322 NCBIGene:1302 biolink:causes MONDO:0013795 infores:monarchinitiative not_provided not_provided HGNC:2187 MONDO:0013795 uuid:900fbabb-f230-42c9-9771-26875e939048 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0434437 infores:hetionet CHEBI:47499 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0018418 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0518015 infores:hetionet CHEBI:5384 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0151474 infores:hetionet CHEBI:585948 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0041657 infores:hetionet CHEBI:9598 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0035455 infores:hetionet CHEBI:188986 biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009759 infores:hetionet CHEBI:10119 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2363731 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009450 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0687133 infores:hetionet CHEBI:5098 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0022346 infores:hetionet CHEBI:9168 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0037763 infores:hetionet NCBIGene:153201 biolink:causes MONDO:0009448 infores:monarchinitiative not_provided not_provided HGNC:18762 MONDO:0009448 uuid:e4ba59e0-3be9-4930-a882-dde384abc992 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3716 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0042109 infores:hetionet CHEBI:7915 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0542571 infores:hetionet CHEBI:31236 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085628 infores:hetionet CHEBI:7443 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0242528 infores:hetionet CHEBI:45783 biolink:causes UMLS:C1699324 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1699324 infores:hetionet CHEBI:5106 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0013604 infores:hetionet CHEBI:75246 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0019294 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014534 infores:hetionet CHEBI:6741 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0036396 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235639 infores:hetionet NCBIGene:56922 biolink:causes MONDO:0008861 infores:monarchinitiative not_provided not_provided HGNC:6936 MONDO:0008861 uuid:63ef2b50-e646-475a-83e2-17abbcebb2d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes UMLS:C1739422 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1739422 infores:hetionet CHEBI:51860 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009676 infores:hetionet UMLS:C0004609 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0231837 infores:hetionet CHEBI:6775 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013428 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0003123 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030312 infores:hetionet CHEBI:9571 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0027849 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0151541 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151541 infores:hetionet CHEBI:253342 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0000731 infores:hetionet CHEBI:16796 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0003862 infores:hetionet CHEBI:6538 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0020538 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0021053 infores:hetionet CHEBI:9674 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013404 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0877153 infores:hetionet CHEBI:9763 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0041657 infores:hetionet CHEBI:6402 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C2047937 infores:hetionet CAID:CA204612 biolink:causes MONDO:0100039 infores:clingen CAID:CA204612 MONDO:0100039 PMID: Uncertain Significance PM2_Supporting, PM6 BP4 The p.Val172Ile variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with early onset epileptic encephalopathy (PMID 25356970) (PM6). The p.Val172Ile variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Val172Ile variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM6, PM2_supporting). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA204612/MONDO:0100039/034 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Inconclusive true NCBITaxon:562 biolink:causes MONDO:0004652 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D018410 DB01606_MESH_D018410_1DB00303_MESH_D018410_2DB01330_MESH_D018410_1 CHEBI:45863 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0000731 infores:hetionet CHEBI:51137 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0001824 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034069 infores:hetionet GO:2000595 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000595 GO:0007275 CHEBI:63621 biolink:causes UMLS:C0043046 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043046 infores:hetionet CHEBI:6532 biolink:causes MONDO:0000257 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0740441 infores:hetionet CAID:CA16617183 biolink:causes MONDO:0100368 infores:clingen CAID:CA16617183 MONDO:0100368 PMID: Likely Pathogenic PM3_Supporting, PP3_Moderate, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.1244C>T is a missense variant causing substitution of alanine with valine at position 415. This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.0001638, with 1 allele / 6104 total alleles in the Remaining individuals population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.886dup (p.Arg296fs) variant suspected in trans (PMID: 27102010, PMID: 30268864, PMID: 37660736), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting). At least one proband harboring this variant has exhibited a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), onset before age 5 years (1 pt), flat ERG responses for rods (0.5 pts) and cones (1 pt), and improvement of night vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (11 total pts, PMID: 37660736, PP4_Moderate). The computational predictor REVEL gives a score of 0.775, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Supporting, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16617183/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Supports CAID:CA000535 biolink:causes MONDO:0017623 infores:clingen CAID:CA000535 MONDO:0017623 PMID:29785012PMID:29706350 Pathogenic PP2, PP3, PM6_Strong, PS3_Moderate, PM2_Supporting, PS4_Supporting PVS1, BP7, BP5, BS1, BS4, BS3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS2 PTEN c.610C>G (p.Pro204Ala) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (internal laboratory contributor SCV000222125.7)PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.675 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000222125.7)PM2_P: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.881) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000535/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45783 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0003962 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0037274 infores:hetionet NCBIGene:6927 biolink:causes MONDO:0007718 infores:monarchinitiative not_provided not_provided HGNC:11621 MONDO:0007718 uuid:51d490fa-61a4-403e-a8b8-ac8ef8704854 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0035455 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027051 infores:hetionet CHEBI:17026 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0026858 infores:hetionet CHEBI:5147 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0018681 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006977 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0037859 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0442886 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0031350 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038661 infores:hetionet CHEBI:39585 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0278134 infores:hetionet CHEBI:2904 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0030196 infores:hetionet CHEBI:3380 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C2830004 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020538 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0025061 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0042109 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0042075 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0034065 infores:hetionet CHEBI:17474 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1112214 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017178 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0948089 infores:hetionet CHEBI:9599 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0004096 infores:hetionet CHEBI:3077 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0030554 infores:hetionet CAID:CA624861283 biolink:causes MONDO:0008723 infores:clingen CAID:CA624861283 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM1, PVS1 The NM_000018.4(ACADVL):c.1145del (p.Lys382Serfs*11) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11 leading to nonsense mediate decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (< 0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL Variant Curation Expert Panel (PM1; PMID: 20060901). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624861283/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA340130 biolink:causes MONDO:0009290 infores:clingen CAID:CA340130 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM3_Very Strong PM2 This variant, c.2560C>T (p.Arg854Ter) is a nonsense variant that is predicted to result in a premature stop codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross-reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613). This variant is the most commonly reported variant in individuals with infantile onset Pompe disease, especially in those of African descent (PMIDs 9529346, 22253258, 31342611). The highest population minor allele frequency is gnomAD v2.1.1 is 0.00189 in the African population. This variant been reported in numerous individuals with Pompe disease who meet the specifications of the ClinGen LSD VCEP for PP4. This includes homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315), c.525delT (PMID 23825616), c.1165delG (PMID 22252923), c.1654delC (PMID 25741864), c.1933G>A (p.Asp645Asn) (PMID 31193175), c.1655T>C (p.Leu552Pro)(PMID 31193175). This data meets PM3_Very Strong. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Very Strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340130/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:497661 biolink:causes MONDO:0859271 infores:monarchinitiative not_provided not_provided HGNC:31690 MONDO:0859271 uuid:bc35b4de-a656-49b1-b64a-bb29ed4bfde6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020538 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0003123 infores:hetionet CHEBI:10124 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020580 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0038661 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0001339 infores:hetionet CHEBI:180905 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0004093 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0403632 infores:hetionet CAID:CA512341113 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341113 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1287G>A (p.Leu429=) is a synonymous variant. This variant has been seen once in gnomADv3.1.2 at a MAF of 0.0002895 (0.02895%, 1/3454 in the Ashkenazi Jewish sub-population). It does not meet any population criteria. Evolutionary conservation prediction algorithms predict the site is not-conserved (phyloP100 way score 0.170 < 2.0 ) and there is no splice impact SpliceAI<0.2 (0)(BP7, BP4). The variant has not been reported in patients with the RUNX1-defined phenotype. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1:BP7, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341113/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA16616748 biolink:causes MONDO:0020367 infores:clingen CAID:CA16616748 MONDO:0020367 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting BS1, BS3, BP7, PM6, PP1, PM5, PM4, PS1, PS3, PS2, BA1, BP4 The c.1441C>A variant in MYOC is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 481 (p.Pro481Thr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.839 , which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for juvenile open angle glaucoma (E. Souzeau pers. comm.), not meeting the ≥ 3 segregations required for PP1. 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 23453510, 10196380), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616748/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:29007 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0023052 infores:hetionet CHEBI:100246 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0547030 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0014130 infores:hetionet CHEBI:7936 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0024282 infores:hetionet CHEBI:8673 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0040034 infores:hetionet CHEBI:17688 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0036974 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151735 infores:hetionet CHEBI:4784 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0040460 infores:hetionet CHEBI:32221 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0027497 infores:hetionet GO:1902863 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1902863 GO:0009790 CHEBI:135342 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0235146 infores:hetionet CAID:CA658824833 biolink:causes MONDO:0008723 infores:clingen CAID:CA658824833 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4:c.105_109dup (p.Arg37LeufsTer26) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from GnomAD v2.1.1 (PM2_Supporting). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). In summary, this variant meets the criteria to be classified as Likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824833/MONDO:0008723/021 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31709 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0018944 infores:hetionet CHEBI:175901 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0235378 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0349506 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020517 infores:hetionet CHEBI:3996 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0004245 infores:hetionet CHEBI:5384 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0002878 infores:hetionet CHEBI:63637 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0235378 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1510472 infores:hetionet NCBIGene:392255 biolink:causes MONDO:0013376 infores:monarchinitiative not_provided not_provided HGNC:4221 MONDO:0013376 uuid:72af7182-bbd4-4cfc-a03b-1b5fc4389e6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0232849 infores:hetionet NCBIGene:4601 biolink:causes MONDO:0700275 infores:monarchinitiative not_provided not_provided HGNC:7534 MONDO:0700275 uuid:0ac81e34-d9ee-4ad1-8d8b-3742451dbd41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035302 infores:hetionet CHEBI:8802 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1868855 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0021053 infores:hetionet CHEBI:15552 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020458 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0235299 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0235299 infores:hetionet CHEBI:41237 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00676 UMLS:C0030193 infores:hetionet CHEBI:7494 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0037763 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0004936 infores:hetionet CHEBI:49575 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020578 infores:hetionet NCBIGene:1621 biolink:causes MONDO:0009123 infores:monarchinitiative not_provided not_provided HGNC:2689 MONDO:0009123 uuid:07c092f3-6348-4e4c-958a-794b354713aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2573102977 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573102977 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PP1 The c.1391_1392delGC variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 464 (NM_000162.5), adding 69 novel amino acids before encountering a stop codon (p.(p.Gly464AlafsTer69)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant was reported in an individual with MODY, autosomal dominant family history of diabetes, antibody negativity, non-insulin dependence, and segregation with diabetes, but there was insufficient information given to apply PP4 or PP1 (PMID: 29056535). In summary, c.1391_1392delGC meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 3/23/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573102977/MONDO:0015967/086 2023-03-24 2023-05-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6128 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0006266 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0332534 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0021400 infores:hetionet CHEBI:63619 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0231218 infores:hetionet CHEBI:6444 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0035078 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013295 infores:hetionet CHEBI:109549 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0011991 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0022408 infores:hetionet CHEBI:63620 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0010200 infores:hetionet NCBIGene:948 biolink:causes MONDO:0012031 infores:monarchinitiative not_provided not_provided HGNC:1663 MONDO:0012031 uuid:f5df7929-b042-4b87-8abc-1816bd693ea5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0002962 infores:hetionet CHEBI:6690 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0004134 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0027765 infores:hetionet GO:0010984 biolink:causes GO:0097006 infores:ubergraph knowledge_assertion manual_agent GO:0010984 GO:0097006 CHEBI:4754 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01127 UMLS:C0030193 infores:hetionet CHEBI:64045 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0687713 infores:hetionet CHEBI:2948 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0023467 infores:hetionet CHEBI:8890 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0003708 infores:hetionet CHEBI:6775 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0040053 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0013595 infores:hetionet CHEBI:9434 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020458 infores:hetionet CHEBI:7573 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0852911 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0010346 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0035455 infores:hetionet CHEBI:4798 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0428977 infores:hetionet CHEBI:8802 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0013395 infores:hetionet CHEBI:6690 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C1384353 infores:hetionet CHEBI:49668 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0025222 infores:hetionet CHEBI:6437 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085605 infores:hetionet UMLS:C0657912 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015732 infores:hetionet CHEBI:116278 biolink:causes HP:0012117 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0740469 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0012833 infores:hetionet CAID:CA10585255 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585255 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS3, PS1, PS2, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM6, PP1, PP2, PP3, BS2 The NM_000527.5(LDLR):c.1024G>T (p.Asp342Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (citation pending). The supporting evidence is as follows: PM2 - Not found in gnomAD (accessed 5th June 2020). FAF is under 0.02%, so PM2 is Met; PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria (high LDL value, family history of CVD = possible FH). ---- PP4 is Met; PS4_supporting - Variant meets PM2. Variant identified in 2 index cases from Center of molecular biology and gene therapy with Simon-Broome criteria for FH. ---- PS4_Supporting is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585255/MONDO:0007750/013 2020-08-11 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:47780 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2979982 infores:hetionet CHEBI:50378 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C2830004 infores:hetionet CAID:CA320618189 biolink:causes MONDO:0011071 infores:clingen CAID:CA320618189 MONDO:0011071 PMID: Likely Benign BP4, BP2, BP7, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BA1, PVS1, PM2, PM6, BP5, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.509-197T>C is an intronic variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. The MAF of 0.01296 n the European (Non-Finnish) subpopulation of the gnomAD v2 cohort allows for application of BS1; the observation of this variant in a homozygous state in the same population allows for the application BP2. This variant has a SpliceAI score of 0, and a PhyloP score of -0.58, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320618189/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5383 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0000731 infores:hetionet CHEBI:3614 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0392171 infores:hetionet CHEBI:71415 biolink:causes HP:6000647 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0235014 infores:hetionet NCBIGene:27249 biolink:causes MONDO:0700297 infores:monarchinitiative not_provided not_provided HGNC:25221 MONDO:0700297 uuid:0e770ac2-8349-4780-b239-d55f6596ec93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151786 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0023530 infores:hetionet CHEBI:8805 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0027497 infores:hetionet CHEBI:101278 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0031542 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011053 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0852908 infores:hetionet CHEBI:15940 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0023067 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0026848 infores:hetionet CHEBI:136040 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0011206 infores:hetionet CHEBI:71417 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0027697 infores:hetionet CHEBI:8871 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020555 infores:hetionet CHEBI:92511 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0039070 infores:hetionet CHEBI:85078 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0028734 infores:hetionet CHEBI:7915 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0030554 infores:hetionet CHEBI:7936 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015732 infores:hetionet CHEBI:70746 biolink:causes UMLS:C3160769 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C3160769 infores:hetionet CHEBI:8461 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0686347 infores:hetionet CHEBI:9352 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0017675 infores:hetionet CHEBI:4514 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0151786 infores:hetionet CHEBI:171719 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0549249 infores:hetionet CHEBI:5001 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027441 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0040409 infores:hetionet CHEBI:44423 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0332563 infores:hetionet CHEBI:4514 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0041834 infores:hetionet CHEBI:5779 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0009806 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0002622 infores:hetionet CHEBI:63638 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0027424 infores:hetionet CHEBI:8107 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0016658 infores:hetionet CHEBI:5778 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030554 infores:hetionet NCBIGene:5138 biolink:causes MONDO:0030900 infores:monarchinitiative not_provided not_provided HGNC:8777 MONDO:0030900 uuid:f88bd6a6-69ce-47f6-91b2-ed6dca040ca8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C1142135 infores:hetionet CAID:CA16020853 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020853 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 The frameshift variant NM_000277.3(PAH):c.753del (p.Arg252GlyfsTer89) occurs in exon 7 of 13 and is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One patient has been reported (PMID: 21307867) with this variant. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020853/MONDO:0009861/006 2020-12-08 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:9918 biolink:causes MONDO:0054804 infores:monarchinitiative not_provided not_provided HGNC:24305 MONDO:0054804 uuid:f8011b27-921d-4f15-8dd9-26dcb1cb085e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1565489 infores:hetionet CHEBI:6061 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0002878 infores:hetionet CHEBI:93363 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0022568 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020517 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0009319 infores:hetionet CHEBI:8764 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0028734 infores:hetionet CHEBI:76010 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0221201 infores:hetionet CHEBI:6367 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011206 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0009938 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0178298 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0234215 infores:hetionet CHEBI:5106 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0010200 infores:hetionet CHEBI:51450 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0004604 infores:hetionet NCBIGene:4669 biolink:causes MONDO:0014665 infores:monarchinitiative not_provided not_provided HGNC:7632 MONDO:0014665 uuid:ec9b1fe1-8a10-4670-b338-2f257fa6bbd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014868 infores:hetionet CHEBI:83531 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0040264 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042109 infores:hetionet CHEBI:51364 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0015967 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0002871 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0002871 infores:hetionet CHEBI:27666 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0030193 infores:hetionet CHEBI:23765 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0028643 infores:hetionet CHEBI:2038 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0026821 infores:hetionet CHEBI:45652 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0042510 infores:hetionet CAID:CA10585467 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585467 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Moderate, PS3_Supporting, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2 The NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr) name variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP1_Moderate, PS4_Supporting, PS3_Supporting, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.888.PS3_Supporting - Level 3 assay: PMID: 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays - 20-39% LDLR expression and 45-63% LDLR activity---- results are below 85% of wild-type activity, so PS3_Supporting is met.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 unrelated FH cases (3 index cases with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; 1 index case with definite FH from PMID 11810272 (Fouchier et al., 2001), The Netherlands), after alternative causes of high cholesterol were excluded.PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis from 4 families from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal: 4 affected family members have the variant and 1 non-affected family member does not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585467/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UMLS:C0657912 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011570 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017601 infores:hetionet CHEBI:2567 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0349506 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0009938 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0233414 infores:hetionet CHEBI:31174 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0036508 infores:hetionet CHEBI:75722 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037299 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0264939 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0264939 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0852733 infores:hetionet GO:0008359 biolink:causes GO:0007350 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0007350 CHEBI:3508 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0008370 infores:hetionet CHEBI:31932 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0027497 infores:hetionet GO:0039522 biolink:causes GO:0006403 infores:ubergraph knowledge_assertion manual_agent GO:0039522 GO:0006403 CHEBI:6128 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C3665347 infores:hetionet NCBIGene:51601 biolink:causes MONDO:0014576 infores:monarchinitiative not_provided not_provided HGNC:29569 MONDO:0014576 uuid:15204c1d-2b40-4006-a9aa-756c5bb75269 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0236051 infores:hetionet CAID:CA000190 biolink:causes MONDO:0018875 infores:clingen CAID:CA000190 MONDO:0018875 PMID: Uncertain Significance BP4, PS3, PM2_Supporting, PS4_Supporting BA1, PS1, PS2, PM5, PM1, BS1, BS3, BS4, BS2, PP3, PP4, PP1 The NM_000546.6: c.436T>G variant in TP53 is a missense variant predicted to cause substitution of tryptophan by glycine at amino acid 146 (p.Trp146Gly). This variant has been reported in 2 families, one meeting Classic and one Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = 0.0351; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PM2_Supporting, PS3, BP4. (Bayesian Points: 5; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000190/MONDO:0018875/009 2025-03-04 2025-06-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410207059 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207059 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.646C>T (p.Pro216Ser) is a missense variant which has a REVEL score < 0.50 (0.381) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207059/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47781 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0013395 infores:hetionet CHEBI:3172 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0019521 infores:hetionet CHEBI:31236 biolink:causes EFO:0009614 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0159658 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0151828 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0743680 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0743680 infores:hetionet CHEBI:168396 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017168 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0518015 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007156 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0574960 infores:hetionet CAID:CA226586 biolink:causes MONDO:0100368 infores:clingen CAID:CA226586 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting BA1, BS1 NM_000329.3(RPE65):c.893delA (p.Lys298fs) is a frameshift variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002294, with 7 alleles / 129102 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least two probands harboring this variant exhibit a phenotype including undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), retinal pigment epithelial mottling (0.5 pts), and reduced visual acuity (1 pt), which together are specific for RPE65-related recessive retinopathy (4 total points, PMID: 35129589, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226586/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030920 infores:hetionet CHEBI:2922 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0001824 infores:hetionet CHEBI:94807 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0004604 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151883 infores:hetionet CHEBI:2950 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0043349 infores:hetionet CHEBI:39867 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0025874 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0853813 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242350 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0149931 infores:hetionet CHEBI:64064 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0023066 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0240035 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0017178 infores:hetionet CHEBI:7565 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0220870 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0002170 infores:hetionet CHEBI:32020 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0085605 infores:hetionet CHEBI:6541 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0003467 infores:hetionet CHEBI:9654 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0004604 infores:hetionet CAID:CA8603212 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603212 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting PS3 The NM_000419.5(ITGA2B):c.1162G>A (p.Gly388Ser) missense variant has been reported in at least one patient (UPN 4 in PMID: 16879215) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). UPN 4 is homozygous for this variant (PM3_supporting; PMID: 16879215). The highest population minor allele frequency in gnomAD v4.1 is 0.00001101 (1/90832 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.855, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting, PP4_moderate, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603212/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9288 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0027540 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0152227 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0235146 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0004592 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1314 MONDO:0004592 CHEBI:3387 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0033774 infores:hetionet CHEBI:27786 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0085593 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027796 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0687707 infores:hetionet CHEBI:83804 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0006277 infores:hetionet CHEBI:50885 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0151786 infores:hetionet CHEBI:135736 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009376 infores:hetionet CHEBI:50777 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0024103 infores:hetionet CHEBI:6950 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0546884 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009319 infores:hetionet CHEBI:3310 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0018790 infores:hetionet CHEBI:9445 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0042024 infores:hetionet CHEBI:7986 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0036104 infores:hetionet CHEBI:4784 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0016512 infores:hetionet CAID:CA199495 biolink:causes MONDO:0010726 infores:clingen CAID:CA199495 MONDO:0010726 PMID: Likely Benign BP5, BS1 The allele frequency of the c.377+6_377+9del variant in MECP2 (NM_004992.3) is 0.014% in the East Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The c.377+6_377+9del variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the c.377+6_377+9del variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199495/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:135935 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0236075 infores:hetionet GO:0044830 biolink:causes GO:0019058 infores:ubergraph knowledge_assertion manual_agent GO:0044830 GO:0019058 CHEBI:17303 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0031542 infores:hetionet CHEBI:4995 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0039231 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0002957 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011849 infores:hetionet CHEBI:77260 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027497 infores:hetionet CHEBI:63632 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0009806 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0027769 infores:hetionet CHEBI:45409 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0853034 infores:hetionet CAID:CA454592033 biolink:causes MONDO:0015967 infores:clingen CAID:CA454592033 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting The c.45G>A variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 15 (p.(Lys15=)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.51 for donor gain and 0.34 for donor loss, which are greater than the MDEP cutoff of 0.2) (PP3). This variant was identified in two unrelated individuals with mildly elevated HbA1c that did not require treatment, however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19564454, 18248649, internal contributor). One of these individuals has stable impaired fasting glucose, which meets MDEP criteria for PP4, and had negative diabetes autoantibodies (PP4_Moderate; internal contributor) In summary, c.45G>A meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 3/23/23): PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA454592033/MONDO:0015967/086 2023-05-26 2023-05-26 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:46345 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C1443060 infores:hetionet CHEBI:5088 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0392676 infores:hetionet CHEBI:41774 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0026858 infores:hetionet CHEBI:4995 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085593 infores:hetionet CHEBI:101853 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0741494 infores:hetionet CHEBI:9571 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0027424 infores:hetionet CHEBI:6933 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0038362 infores:hetionet CHEBI:5138 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0028961 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0004238 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0006826 infores:hetionet CHEBI:3723 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151904 infores:hetionet CHEBI:53766 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0042109 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0027765 infores:hetionet NCBIGene:26227 biolink:causes MONDO:0011152 infores:monarchinitiative not_provided not_provided HGNC:8923 MONDO:0011152 uuid:2048f5c6-0b1f-4077-bacf-0ae69f4d11ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0028734 infores:hetionet CAID:CA226499 biolink:causes MONDO:0100368 infores:clingen CAID:CA226499 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting BP4, BA1, BS1 NM_000329.3(RPE65):c.1249G>C is a predicted missense variant substituting glutamic acid with glutamine at position 417. The computational predictor REVEL gives a score of 0.954, which is above the ClinGen LCA / eoRD VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In addition, the splicing impact predictor SpliceAI gives a score of 0.24 for acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a minor allele frequency of 0.000008825, with 1 allele / 113312 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 11462243, PMID: 20079931). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.11+5G>A variant confirmed in trans (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype that is highly specific for PE65-related recessive retinopathy (9 total points, VCEP member-provided data, PP4_Moderate). The variant exhibited 1-2% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 26427455, PMID: 16150724). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226499/MONDO:0100368/120 2024-02-01 2024-02-01 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:4322 biolink:causes MONDO:0011198 infores:monarchinitiative not_provided not_provided HGNC:7159 MONDO:0011198 uuid:64147fe3-76c7-41c1-8511-82e7cdc01b54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45327 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C2242996 infores:hetionet CHEBI:9763 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0040435 infores:hetionet CHEBI:9168 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004998 infores:hetionet CHEBI:16586 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0033774 infores:hetionet CHEBI:28177 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0151636 infores:hetionet CAID:CA298940 biolink:causes MONDO:0007648 infores:clingen CAID:CA298940 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.1979dup p.(Asp662Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 26681312). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA298940/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:408174 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0013395 infores:hetionet CAID:CA145181 biolink:causes MONDO:0800472 infores:clingen CAID:CA145181 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PP1_Strong, PS2_Supporting, PVS1 PP3, BP4, BA1, PS3, PS1, PM1, PM4, PM5, BP7, BS1, BS4, PM2 The c.1200_1209dup variant in CYP1B1 is a deletion of 10 consecutive nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 30 of the frameshift (p.Thr404SerfsTer30). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1) = 0.0005832 (35 alleles out of 60,014), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). This frameshift variant was not predicted to undergo NMD but removes the haem-binding domain (PVS1 met). There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 12567107, 14729846), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in five individuals with a CYP1B1-related phenotype. Three of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) for the variant and two individuals are homozygous (non-consanguineous) for the variant (PMIDs: 14729846, 17893647, 23218183, 11558822, 23922489). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. One assumed de novo proband with PCG phenotype has been identified (PMID: 23218701). Total proband points = 0.5, meeting PS2_Supporting. In summary, this variant met the criteria to receive a score of 21 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Very strong, PP1_Strong, PS2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145181/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6538 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0012833 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0027947 infores:hetionet CHEBI:49575 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0162297 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0027051 infores:hetionet CAID:CA16602341 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602341 MONDO:0007750 PMID: Uncertain Significance PP1_Moderate, PM2 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP4 The NM_000527.5(LDLR):c.1982C>T (p.Pro661Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP1_Moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 2 families from Laboratory of Genetics and Molecular Cardiology, Brazil. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602341/MONDO:0007750/013 2023-06-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:51141 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0151763 infores:hetionet CHEBI:6078 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0042963 infores:hetionet NCBIGene:83548 biolink:causes MONDO:0957820 infores:monarchinitiative not_provided not_provided HGNC:18619 MONDO:0957820 uuid:66a61d56-f00a-4c99-a8e9-380342583ade biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0917801 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042514 infores:hetionet CHEBI:4445 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0428977 infores:hetionet CHEBI:75998 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0018965 infores:hetionet CHEBI:71415 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0015967 infores:hetionet CHEBI:61049 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151539 infores:hetionet CHEBI:15765 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0028643 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0549475 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151596 infores:hetionet CHEBI:3387 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018681 infores:hetionet CHEBI:9139 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0003811 infores:hetionet CHEBI:27690 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0004093 infores:hetionet CHEBI:50648 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0035243 infores:hetionet CHEBI:2676 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C1320835 infores:hetionet GO:0052081 biolink:causes GO:0009863 infores:ubergraph knowledge_assertion manual_agent GO:0052081 GO:0009863 CHEBI:7575 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0015230 infores:hetionet CHEBI:5855 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0004093 infores:hetionet GO:0030218 biolink:causes CL:0000232 infores:ubergraph knowledge_assertion manual_agent GO:0030218 CL:0000232 CHEBI:167638 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0242429 infores:hetionet CAID:CA902401 biolink:causes MONDO:0100368 infores:clingen CAID:CA902401 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting The NM_000329.3(RPE65):c.762G>T (p.Glu254Asp) variant is a missense variant in RPE65 causing a substitution of glutamic acid with aspartic acid at position 254. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.774, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PM3, PMID: 35129589). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of LCA (0.5 pt) and significant, documented improvement of FST or other measure of dark-adapted vision after treatment with Luxturna or other RPE65 gene therapy. (8.5 points, PMID: 38295874, PP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PP4_Moderate, PM3 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902401/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA346327976 biolink:causes MONDO:0800472 infores:clingen CAID:CA346327976 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 PP3, BP4, BA1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4 The c.1044-1G>C variant in CYP1B1 is a single nucleotide splice site variant (p.?). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This splice site variant was predicted to lead to exon skipping, intron inclusion or use of a cryptic splice site, disrupting the reading frame. It was not predicted to undergo NMD but removes the haem-binding domain (PVS1 met). There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 30270463), which fulfilled PP1_Strong. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is homozygous (consanguineous) for the variant (PMID: 30270463), with total proband points = 0.25, not meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 13 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PP1_Strong, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346327976/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2788 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0205204 infores:hetionet CHEBI:2673 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0018524 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042075 infores:hetionet CHEBI:5138 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0233471 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0235901 infores:hetionet CAID:CA915940225 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940225 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000419.5(ITGA2B):c.1071dup (p.Arg358AlafsTer47) found in a homozygous proband (PMID:31029159; PM3_supporting) causes a premature stop codon at exon 13 and is predicted to undergo nonsense mediated decay (PVS1). The variant was not found in gnomAD v2.1.1 (PM2_supporting). In conclusion the criteria PSV1, PM2_supporting, and PM3_supporting, were applied to reach a classification of pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940225/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51364 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0085612 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0008325 infores:hetionet CHEBI:5959 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013404 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002170 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0277577 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0277577 infores:hetionet NCBIGene:4693 biolink:causes MONDO:0010691 infores:monarchinitiative not_provided not_provided HGNC:7678 MONDO:0010691 uuid:f0772005-15e5-4c34-a1da-275bf6d57751 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0025061 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0178298 infores:hetionet GO:0032213 biolink:causes GO:0033260 infores:ubergraph knowledge_assertion manual_agent GO:0032213 GO:0033260 CHEBI:5778 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0014742 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0012833 infores:hetionet CHEBI:63617 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0038002 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020039 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009806 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0029882 infores:hetionet CAID:CA2580060377 biolink:causes MONDO:0009276 infores:clingen CAID:CA2580060377 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting BP7 The c.10+33_10+39delinsGAGTCCGGTCG variant is an intronic variant that is not predicted by SpliceAI to impact splicing (delta scores 0.00-0.02) and conservation PhyloP scores range from -1.6 to 1.8, indicating parts of the deletion may be highly conserved. This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant was not found in any BSS patients in ClinVar or published literature but has been observed heterozygous in two patients for which BSS was not indicated. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580060377/MONDO:0009276/082 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5004 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0011991 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0233494 infores:hetionet CHEBI:253342 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0042023 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0017601 infores:hetionet CHEBI:8426 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0002792 infores:hetionet CHEBI:39112 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0085649 infores:hetionet CHEBI:4953 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C3665347 infores:hetionet CHEBI:31624 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0020458 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0036454 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0018802 infores:hetionet CHEBI:9649 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0263386 infores:hetionet CHEBI:70746 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0017168 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C1861172 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027707 infores:hetionet CL:0000076 biolink:causes MONDO:0005096 infores:ubergraph knowledge_assertion manual_agent CL:0000076 MONDO:0005096 NCBIGene:345895 biolink:causes MONDO:0012978 infores:monarchinitiative not_provided not_provided HGNC:21558 MONDO:0012978 uuid:e90d6dcf-9b62-40b1-ac58-aa528bc3390c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232431 infores:hetionet CHEBI:63629 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0080274 infores:hetionet CHEBI:6690 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0030446 infores:hetionet CAID:CA409104130 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104130 MONDO:0015967 PMID: Uncertain Significance PP4, PP3, PM2_Supporting, PM1 PP1, BA1, BP4, PS4, BS1 The c.240C>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of cysteine to tryptophan at codon 80 (p.(Cys80Trp)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.882​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is in one of the amino acids that directly binds DNA and is necessary for Zinc-finger formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; PMID: 16917892). In summary, c.240C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104130/MONDO:0015967/085 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6741 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0917801 infores:hetionet CHEBI:75722 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2129214 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0853326 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0853326 infores:hetionet CHEBI:6792 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0006266 infores:hetionet CHEBI:64028 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0156404 infores:hetionet CHEBI:3061 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0013404 infores:hetionet CHEBI:68841 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0027497 infores:hetionet CHEBI:8871 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018681 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0030312 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0004238 infores:hetionet CHEBI:9328 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0085593 infores:hetionet CAID:CA8602501 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602501 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The c.2946G>A (p.Val982=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing and the nucleotide is only moderately conserved, as shown by phyloP score of 0.703 (BP4, BP7). The highest population minor allele frequency in gnomAD v3.1.2 is 0.0001448 (6/41436 alleles) in the African/African American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting, so no allele frequency criteria were met. In addition, no cases of the variant segregating with Glanzmann thrombasthenia were found in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia with the following ACMG/AMP applied, as specified by the ClinGen PD VCEP: BP4, BP7 (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602501/MONDO:0100326/011 2023-12-19 2023-12-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6888 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C3665347 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0040034 infores:hetionet CAID:CA913179026 biolink:causes MONDO:0044970 infores:clingen CAID:CA913179026 MONDO:0044970 PMID:28729369 Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting, PM6 The m.8340G>A variant in MT-TK has been reported in five unrelated individuals with features of primary mitochondrial disease (PS4_moderate; PMIDs: 24161205, 29501485, 28729369, 36999085, 34969639). Affected individuals were variably affected and had myopathy, exercise intolerance, muscle weakness, and chronic progressive external ophthalmoplegia (CPEO). Additional features seen include sensorineural hearing loss, retinal dystrophy, cataracts, migraines, epilepsy, microcephaly, and poor growth, and one individual was reported to have congenital heart disease and urinary tract anomalies. There are at least three de novo occurrences reported in the literature (PM6; PMIDs: 29501485, 28729369, 24161205). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (65th percentile) and HmtVAR predicts it to be pathogenic score of 0.4 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (93.1% ± 0.26%, N=17) than in COX-positive fibers (29.5% ± 8.97, N=16), p<0.0001 (PS3_supporting, PMID: 28729369). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913179026/MONDO:0044970/015 2023-05-22 2024-07-23 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:32139 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0003467 infores:hetionet CHEBI:32020 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0751295 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0009806 infores:hetionet GO:0140199 biolink:causes GO:0003015 infores:ubergraph knowledge_assertion manual_agent GO:0140199 GO:0003015 NCBIGene:4867 biolink:causes MONDO:0009728 infores:monarchinitiative not_provided not_provided HGNC:7905 MONDO:0009728 uuid:6cb71b8a-a5d6-4e89-8c37-4f41b643b7bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0162429 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020538 infores:hetionet CHEBI:8871 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151818 infores:hetionet CHEBI:8764 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0043094 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0855242 infores:hetionet CHEBI:6775 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0026826 infores:hetionet UMLS:C0065374 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0231749 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C1384666 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151849 infores:hetionet CHEBI:5384 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0022346 infores:hetionet CHEBI:4909 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0235896 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0234215 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0015397 infores:hetionet CHEBI:3176 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0041834 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0023474 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0023474 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0376297 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0376297 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0232115 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0232115 infores:hetionet CHEBI:31623 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0030196 infores:hetionet CHEBI:71941 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0013604 infores:hetionet CHEBI:8802 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0080274 infores:hetionet CHEBI:17650 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0018800 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0018418 infores:hetionet CHEBI:39585 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0687713 infores:hetionet CHEBI:8888 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018926 infores:hetionet CHEBI:135888 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0014591 infores:hetionet CAID:CA382539488 biolink:causes MONDO:0700270 infores:clingen CAID:CA382539488 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PVS1 The c.2251-2A>T variant in ATM occurs within the canonical splice acceptor site (+/- 1,2) of intron 14. It is predicted to cause disrupted splicing of a biologically-relevant-exon resulting in an out-frame deletion that is predicted to escape nonsense mediated decay. This variant has been detected in at least two unrelated individuals with Ataxia-Telangiectasia (PMIDs: 26896183, 34859152). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3_Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382539488/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CAID:CA915952143 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952143 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP3, PP1, PS4, PS3, PS2, PM6 The m.11621_11622del (p.Y288LfsX59) variant in MT-ND4 has been reported in one individual with primary mitochondrial disease to date, in a 21-year-old man with chronic progressive external ophthalmoplegia (CPEO) and exercise intolerance. Ragged red fibers were seen on muscle biopsy. The variant was present in muscle at heteroplasmy (level not reported) and was undetectable in blood (PMID: 23463613). Family member affected status and inheritance of the variant was not reported. Another individual with primary mitochondrial disease and this variant has been reported in the medical literature however this report was part of a large cohort and clinical details were not provided precluding consideration of this case for this curation (PMID: 32652755). This variant results in >10% of the protein being truncated (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952143/MONDO:0044970/015 2024-12-09 2025-05-16 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7959 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0149704 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027059 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020649 infores:hetionet CHEBI:4708 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0010200 infores:hetionet CHEBI:31515 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0600142 infores:hetionet CHEBI:5959 biolink:causes HP:0003690 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0587246 infores:hetionet CHEBI:3380 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0042384 infores:hetionet CHEBI:6149 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0027497 infores:hetionet CHEBI:45409 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009421 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0003123 infores:hetionet CHEBI:135736 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0022281 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0042109 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0027769 infores:hetionet CHEBI:584020 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0009806 infores:hetionet GO:2000004 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:2000004 GO:0001656 CHEBI:132233 biolink:causes HP:0100034 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0751900 infores:hetionet CHEBI:391960 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0033774 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0018099 infores:hetionet CHEBI:40050 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0015672 infores:hetionet CHEBI:6149 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0026205 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0151828 infores:hetionet CHEBI:3561 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0018524 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0040034 infores:hetionet CHEBI:77260 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027540 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0032584 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0013395 infores:hetionet CHEBI:6067 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0231835 infores:hetionet CHEBI:3423 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0042963 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0553702 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C3665347 infores:hetionet CHEBI:63624 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0001125 infores:hetionet CHEBI:10127 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C3263723 infores:hetionet CAID:CA4239602 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239602 MONDO:0015967 PMID: Uncertain Significance BS1, PM5_Supporting, PP4_Moderate, PP2, PP1 PS4, PM1, PM2, PP3 The c.565A>G variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to valine at codon 189 (p.Ile189Val) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Another missense variant, c.566T>C, p.Ille189Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile189Val (PM5_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006302, which is greater than the MDEP threshold for BS1 (0.00004) (BS1). This variant was identified in 11 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 32533685, PMID: 33565752, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with two informative meioses in two families (PP1; internal lab contributors). This variant has a REVEL score of 0.6499, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. In summary, c.565A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PM5_Supporting, PP4_Moderate, PP1, BS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239602/MONDO:0015967/086 2023-11-22 2023-11-22 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:87715 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0020538 infores:hetionet NCBIGene:22806 biolink:causes MONDO:0030333 infores:monarchinitiative not_provided not_provided HGNC:13178 MONDO:0030333 uuid:add2ba36-2c37-48d7-bf07-29248b97a2c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0018802 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0086132 infores:hetionet CHEBI:91834 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0039070 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0013395 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235893 infores:hetionet NCBIGene:729991 biolink:causes MONDO:0975837 infores:monarchinitiative not_provided not_provided HGNC:37247 MONDO:0975837 uuid:0ba3a176-03c4-4eec-abaa-1f6533f18e92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040046 infores:hetionet CHEBI:8863 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085636 infores:hetionet CHEBI:17334 biolink:causes HP:0004844 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0520736 infores:hetionet CHEBI:7444 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0001339 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0022893 infores:hetionet NCBIGene:9772 biolink:causes MONDO:0032672 infores:monarchinitiative not_provided not_provided HGNC:28983 MONDO:0032672 uuid:8bde5dfe-2e65-49ff-a26d-8065c291da90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151773 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0340464 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0036572 infores:hetionet CHEBI:4728 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0085612 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0521592 infores:hetionet CHEBI:5004 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0016204 infores:hetionet NCBIGene:4627 biolink:causes MONDO:0015912 infores:monarchinitiative not_provided not_provided HGNC:7579 MONDO:0015912 uuid:7769e30b-d8ca-4900-98c4-85b274ba6c80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6717 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0042109 infores:hetionet CHEBI:135736 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0237314 infores:hetionet CHEBI:4470 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0042963 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0858259 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0027813 infores:hetionet CHEBI:194135 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0029944 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027051 infores:hetionet CHEBI:63580 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0850149 infores:hetionet CHEBI:4717 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0013144 infores:hetionet CHEBI:45599 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0022660 infores:hetionet CHEBI:44915 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0043352 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1291078 infores:hetionet CHEBI:2704 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0018681 infores:hetionet CHEBI:7459 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0027441 infores:hetionet CHEBI:8768 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0038325 infores:hetionet CHEBI:61049 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020625 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017152 infores:hetionet CHEBI:8356 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0575081 infores:hetionet CHEBI:204734 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C1384353 infores:hetionet CHEBI:6532 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0042109 infores:hetionet CHEBI:8673 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0038325 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0002957 infores:hetionet GO:0030516 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0007275 CHEBI:84883 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0014534 infores:hetionet CHEBI:7824 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0043094 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0521491 infores:hetionet CAID:CA2697547489 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547489 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP4, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1210del (p.His404ThrfsTer?) is a frameshift variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (frameshift (-) c.759–c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547489/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:114785 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0027765 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0029927 infores:hetionet NCBIGene:51132 biolink:causes MONDO:0010506 infores:monarchinitiative not_provided not_provided HGNC:13429 MONDO:0010506 uuid:b1b20b6c-705e-473a-a3af-3f69de4b1f49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2774 biolink:causes MONDO:0014033 infores:monarchinitiative not_provided not_provided HGNC:4388 MONDO:0014033 uuid:1574a84c-2674-484f-8534-45c9bd9fe7ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1763 biolink:causes MONDO:0014350 infores:monarchinitiative not_provided not_provided HGNC:2939 MONDO:0014350 uuid:9c1d312b-4151-4324-a690-cfaf4c65134d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135342 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0041657 infores:hetionet CHEBI:3723 biolink:causes HP:0005165 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0520878 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0232462 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1112214 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0265031 infores:hetionet CHEBI:2569 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0162297 infores:hetionet CHEBI:31199 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0020555 infores:hetionet NCBIGene:326 biolink:causes MONDO:0009411 infores:monarchinitiative not_provided not_provided HGNC:360 MONDO:0009411 uuid:5446dab1-27e1-4d36-94a4-d0bacab47f49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8232 biolink:causes GO:0090075 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0026836 infores:hetionet UMLS:C0657912 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085649 infores:hetionet CAID:CA16608317 biolink:causes MONDO:0010726 infores:clingen CAID:CA16608317 MONDO:0010726 PMID: Likely Benign BP4, BP7, BP5, BS2_Supporting BS1, PP3 The highest population minor allele frequency of the p.Ser229= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000028 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ser229= variant is observed in at least 1 unaffected individual (Internal database - Invitae) (BS2_Supporting). The p.Ser229= variant is found in a patient with an alternate molecular basis of disease (Internal database - Invitae) (BP5). The silent p.Ser229= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the p.Ser229= variant in MECP2 is classified as a likely benign variant based on the ACMG/AMP criteria (BS2_Supporting, BP5, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608317/MONDO:0010726/036 2024-06-25 2025-03-13 X-linked inheritance HP:0001417 Contradicts true CHEBI:4907 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0011603 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0851341 infores:hetionet CHEBI:231594 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0006277 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042373 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0037199 infores:hetionet CHEBI:17474 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0030305 infores:hetionet CHEBI:64310 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0344232 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0034065 infores:hetionet CAID:CA270167214 biolink:causes MONDO:0012996 infores:clingen CAID:CA270167214 MONDO:0012996 PMID:27233232 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, BP4 The NM_001482.3:c.845G>A variant in GATM is a missense variant that is predicted to result in the substitution of arginine by histidine at amino acid 282 (p.Arg282His). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00003334 (2/59984 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <10% of wild-type GATM enzyme activity (PMID: 27233232), meeting the CCDS VCEP's threshold (which is <15% wild type activity) for PS3_Supporting. The computational predictor REVEL gives a score of 0.382 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 225918). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting; PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 10, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA270167214/MONDO:0012996/025 2025-04-10 2025-04-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31536 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0029442 infores:hetionet CAID:CA7331742 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331742 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, PM6, PVS1, BA1, BP3, BP2, PP3, PP1, PM5, PM4, PM1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.128C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 43 (p.Thr43Met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.429; MaxEntScan and SpliceAI: no effect on splicing) (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0002667 (16/59982 alleles) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 06/25/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331742/MONDO:0100216/024 2024-06-25 2024-07-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7476 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151936 infores:hetionet CHEBI:27882 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0003460 infores:hetionet CHEBI:6413 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0020443 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003123 infores:hetionet NCBIGene:861 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:10471 MONDO:0018874 uuid:cd2d61e8-508c-41a8-a44f-b494d2570a3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7459 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0018524 infores:hetionet CHEBI:9448 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0035410 infores:hetionet CHEBI:63627 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0027947 infores:hetionet CHEBI:8327 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0003123 infores:hetionet CHEBI:2469 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0026848 infores:hetionet CHEBI:31236 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151564 infores:hetionet NCBIGene:8239 biolink:causes MONDO:0010487 infores:monarchinitiative not_provided not_provided HGNC:12632 MONDO:0010487 uuid:240896a8-0122-4893-bffc-2bfd1a110eae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134966 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C1167965 infores:hetionet GO:0030710 biolink:causes GO:0030707 infores:ubergraph knowledge_assertion manual_agent GO:0030710 GO:0030707 CHEBI:47898 biolink:causes MONDO:0018646 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0008313 infores:hetionet CHEBI:51230 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0016242 infores:hetionet NCBITaxon:5839 biolink:causes MONDO:0005136 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5839 MESH:D008288 DB00205_MESH_D008288_1 CHEBI:17347 biolink:causes UMLS:C0006434 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0006434 infores:hetionet CHEBI:10101 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0038999 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1443060 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0041912 infores:hetionet CAID:CA214330 biolink:causes MONDO:0015967 infores:clingen CAID:CA214330 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PS2_Moderate, PP3 PM5, PP4, PP1 The c.803T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to serine at codon 268 (p.(Phe268Ser)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.986 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 15305805). One of these individuals did have a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, so PP4 cannot be applied (internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). Two other missense variants, c.802T>A p.(Phe268Ile)​ and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.803T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PS2_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214330/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:29688 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0520587 infores:hetionet CHEBI:3061 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C2981158 infores:hetionet CHEBI:10119 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085602 infores:hetionet CHEBI:94501 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0003467 infores:hetionet CAID:CA327915386 biolink:causes MONDO:0100437 infores:clingen CAID:CA327915386 MONDO:0100437 PMID: Benign BA1, BP3 NM_001034853.2(RPGR):c.2847_2852del (p.Glu951_Glu952del) is a short in-frame deletion of 6 base pairs that encode amino acids 951 and 952, located within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v4.1.0 at a frequency of 0.00006948 among hemizygous individuals, with 8 variant alleles / 115,145 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3 X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327915386/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:27834 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0041912 infores:hetionet CHEBI:17347 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0043352 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027051 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0877306 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0877306 infores:hetionet CHEBI:2663 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0043352 infores:hetionet CHEBI:9241 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0022660 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0149931 infores:hetionet CHEBI:33325 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0041582 infores:hetionet CHEBI:63618 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0085605 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0036454 infores:hetionet CAID:CA512318949 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318949 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP3, BP2, BP1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM5, PM3, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.172C>T (p.Leu58=) is a synonymous variant predicted by SpliceAI not to impact splicing (BP4). However, an evolutionary conservation algorithm predicts the site as conserved (PhyloP score = 5.77813 in GRCh38), and the variant is not the reference nucleotide in one primate and/or three mammal species (BP7 not met). It is absent from gnomAD v2 and v3 (PM2_Supporting) and has not been reported in cases or the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318949/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51860 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0852911 infores:hetionet GO:0010928 biolink:causes GO:0071365 infores:ubergraph knowledge_assertion manual_agent GO:0010928 GO:0071365 CHEBI:175901 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0002792 infores:hetionet CHEBI:6532 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0013144 infores:hetionet CHEBI:63617 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0010520 infores:hetionet CHEBI:7476 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0040822 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0948089 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020651 infores:hetionet CHEBI:8874 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004134 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0034063 infores:hetionet CHEBI:9598 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0027497 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0041912 infores:hetionet NCBIGene:57679 biolink:causes MONDO:0008780 infores:monarchinitiative not_provided not_provided HGNC:443 MONDO:0008780 uuid:42440299-d14a-4464-83ae-1820e823ce32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10681 biolink:causes MONDO:0014957 infores:monarchinitiative not_provided not_provided HGNC:4401 MONDO:0014957 uuid:bbf824a2-d6e0-4731-8c1c-a62497296cc7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151826 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0013595 infores:hetionet CAID:CA16609265 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609265 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Moderate, PVS1, PP4_Moderate, PM2_Supporting The c.1344del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 165 novel amino acids before encountering a stop codon (p.(p.Ala449ArgfsTer165)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; ClinVar ID 393448, internal lab contributors). This variant segregated with disease, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(PP4_Moderate, internal lab contributor). In summary, the c.1344del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP1_Moderate, PP4_Moderate, PS4_Moderate, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609265/MONDO:0015967/086 2023-06-24 2023-06-24 Semidominant inheritance HP:0032113 Supports CHEBI:61049 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027796 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0235340 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235340 infores:hetionet CHEBI:4910 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0039231 infores:hetionet GO:1904058 biolink:causes MONDO:0008599 infores:drugmechdb knowledge_assertion manual_agent GO:1904058 MESH:D014277 DB00564_MESH_D014277_1 CHEBI:7852 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0152227 infores:hetionet CHEBI:4814 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0242301 infores:hetionet CHEBI:31401 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0019080 infores:hetionet NCBIGene:10382 biolink:causes MONDO:0012905 infores:monarchinitiative not_provided not_provided HGNC:20774 MONDO:0012905 uuid:7c737d81-10a3-4366-abb7-26270bf22de1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0037763 infores:hetionet CHEBI:50841 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0026837 infores:hetionet CHEBI:59582 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0151514 infores:hetionet CHEBI:50223 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0854467 infores:hetionet CHEBI:16480 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0017181 infores:hetionet CHEBI:135876 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0015230 infores:hetionet CHEBI:4702 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C2363731 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0011630 infores:hetionet CHEBI:27834 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0004093 infores:hetionet CHEBI:100241 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0008031 infores:hetionet UMLS:C1709429 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0037763 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013238 infores:hetionet CHEBI:63631 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011124 infores:hetionet CAID:CA343723835 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723835 MONDO:0020367 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS3, PS1, PS2, BP4, BA1 The c.1313C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 438 (p.Thr438Ile). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.734, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 27 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12789574, 12872267, 25582056, 34923728), which fulfilled PP1_Strong (≥7 meioses in >1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12789574, 12872267, 25582056, 34923728), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 7 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723835/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2569 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0018681 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020649 infores:hetionet CHEBI:8774 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0040822 infores:hetionet CHEBI:49375 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0040053 infores:hetionet CHEBI:116278 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0424295 infores:hetionet CHEBI:45081 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020598 infores:hetionet NCBIGene:8516 biolink:causes MONDO:0024519 infores:monarchinitiative not_provided not_provided HGNC:6144 MONDO:0024519 uuid:2e17b3cc-458e-49bf-b5db-cc88a7f7a999 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0036983 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042769 infores:hetionet CHEBI:2950 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C2830004 infores:hetionet NCBIGene:3675 biolink:causes MONDO:0013881 infores:monarchinitiative not_provided not_provided HGNC:6139 MONDO:0013881 uuid:c1b3b3b4-a692-4f97-9795-853267069997 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27796 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0012833 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151734 infores:hetionet CHEBI:116278 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0023530 infores:hetionet CHEBI:6909 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0009676 infores:hetionet PR:000001245 biolink:causes GO:0016056 infores:ubergraph knowledge_assertion manual_agent PR:000001245 GO:0016056 CHEBI:7852 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0162429 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0235874 infores:hetionet CHEBI:9150 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0409974 infores:hetionet CHEBI:3723 biolink:causes HP:0030788 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0021092 infores:hetionet CHEBI:75722 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0080274 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233632 infores:hetionet CHEBI:4858 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0009676 infores:hetionet CHEBI:7809 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C1325847 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038367 infores:hetionet UNII:3U02EL437C biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0028961 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0236068 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017178 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0015256 infores:hetionet NCBIGene:50 biolink:causes MONDO:0014571 infores:monarchinitiative not_provided not_provided HGNC:118 MONDO:0014571 uuid:2fd0978d-270b-4445-b4b9-923ec79e9024 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0520893 infores:hetionet CHEBI:2549 biolink:causes UMLS:C1328540 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1328540 infores:hetionet CHEBI:8768 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023218 infores:hetionet CHEBI:63624 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0004604 infores:hetionet CHEBI:46081 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0011603 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0852733 infores:hetionet CHEBI:7931 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0003811 infores:hetionet CHEBI:6375 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C3665386 infores:hetionet CHEBI:681848 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0085631 infores:hetionet CAID:CA135149 biolink:causes MONDO:0021060 infores:clingen CAID:CA135149 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.968C>T (p.Ser323Leu) variant in the BRAF gene is 0.06% for South Asian chromosomes by the Exome Aggregation Consortium (17/16512 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135149/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:74947 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002884 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0003123 infores:hetionet CHEBI:49375 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018965 infores:hetionet CHEBI:6775 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085649 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0025202 infores:hetionet CHEBI:74947 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018965 infores:hetionet CHEBI:4995 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1145670 infores:hetionet CHEBI:18358 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0041834 infores:hetionet CHEBI:80630 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0027947 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0036572 infores:hetionet CHEBI:31980 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0340865 infores:hetionet GO:0048742 biolink:causes GO:0007519 infores:ubergraph knowledge_assertion manual_agent GO:0048742 GO:0007519 UNII:G4PX8C4HKV biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020538 infores:hetionet CHEBI:18258 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0015967 infores:hetionet CHEBI:16467 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0018681 infores:hetionet CHEBI:9073 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0027497 infores:hetionet CHEBI:51364 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027849 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0006266 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005543 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0520463 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0002170 infores:hetionet CHEBI:3561 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C3665347 infores:hetionet CHEBI:6761 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0015967 infores:hetionet CHEBI:42355 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C1257843 infores:hetionet CHEBI:7494 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0000731 infores:hetionet CAID:CA226699 biolink:causes MONDO:0010725 infores:clingen CAID:CA226699 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PP1_Moderate, PVS1, PP4 The NM_000330.4(RS1):c.33_36del variant is a frameshift variant due to four nucleotide deletion introducing a premature stop codon after 114 amino acids and causing a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper function of RS1 (PVS1, PMID: 19849666). The variant has been reported to segregate with retinal dystrophy through at least 2 meioses in the one family families (PP1_moderate; PMID: 34828422). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 34828422, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis, as well as a second apparently unrelated proband previously used for the PP4 code (PMIDs: 32531858, 9618178, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PM2_supporting, PP4, PS4_supporting, and PP1_strong (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226699/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:5001 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0003862 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0003123 infores:hetionet CHEBI:5855 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009763 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0342579 infores:hetionet CHEBI:39669 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0233407 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038814 infores:hetionet CHEBI:4814 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0039070 infores:hetionet CHEBI:3398 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0003123 infores:hetionet CHEBI:6897 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0015230 infores:hetionet CHEBI:9139 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0038450 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0948300 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0948300 infores:hetionet CHEBI:42944 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151539 infores:hetionet NCBIGene:16 biolink:causes MONDO:0014593 infores:monarchinitiative not_provided not_provided HGNC:20 MONDO:0014593 uuid:64b4a285-6375-4b65-8836-52e7a5756ac4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151736 infores:hetionet NCBIGene:7136 biolink:causes MONDO:0020820 infores:monarchinitiative not_provided not_provided HGNC:11946 MONDO:0020820 uuid:ffb27ee3-93c8-4175-a9ce-9e1d6f47be96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:2350 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0033774 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003864 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009938 infores:hetionet CHEBI:4953 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0026766 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0877154 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0877154 infores:hetionet CHEBI:18332 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0027497 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042075 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0011991 infores:hetionet CHEBI:40237 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0262988 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033860 infores:hetionet CHEBI:5280 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0011603 infores:hetionet CHEBI:8888 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0237849 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0456909 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0042109 infores:hetionet CHEBI:28830 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0333355 infores:hetionet CHEBI:84050 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C1384353 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0160390 infores:hetionet CHEBI:724125 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C1325847 infores:hetionet CHEBI:6715 biolink:causes MONDO:0016642 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025286 infores:hetionet CAID:CA367399229 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399229 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PP1 The c.1055T>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to arginine at codon 352 (p.(Leu352Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 genomes (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a 3 generation dominant family history of hyperglycemia) (PP4_Moderate; PMID: 24804978). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 24804978). Another missense variant at the same residue, c.1055T>C (p.Leu352Pro), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1055T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399229/MONDO:0015967/086 2025-07-18 2025-07-25 Semidominant inheritance HP:0032113 Supports CHEBI:63577 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0042109 infores:hetionet UMLS:C0879264 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020625 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0003811 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0857322 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0857322 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0302295 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0221185 infores:hetionet CHEBI:3380 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030232 infores:hetionet CHEBI:64312 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011168 infores:hetionet CHEBI:7823 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0020649 infores:hetionet CHEBI:135361 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0012833 infores:hetionet CHEBI:107736 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0038450 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0007642 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0020615 infores:hetionet CAID:CA412350143 biolink:causes MONDO:0100039 infores:clingen CAID:CA412350143 MONDO:0100039 PMID: Uncertain Significance BP5, BS1, PM1, PM5, PP3, PM2, BP4, BA1, PS2, PS1 The p.Tyr117Cys variant in CDKL5 has not been reported in individuals with a clinical phenotype suggestive of CDKL5 disorder. The allele frequency of the p.Tyr117Cys variant in CDKL5 is 0.009% in European (non-Finnish) sub population in gnomAD. No pathogenic missense variants have been previously identified within this codon. The p.Tyr117Cys variant does not occur in either well-characterized functional domain of the CDKL5. The p.Tyr117Cys variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with features inconsistent with CDKL5 disorder (internal database). In summary, the p.Tyr117Cys variant in CDKL5 is classified as a variant of unknown significance based on the lack of ACMG/AMP criteria. Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412350143/MONDO:0100039/016 2022-09-01 2022-09-06 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA226749 biolink:causes MONDO:0010725 infores:clingen CAID:CA226749 MONDO:0010725 PMID: Likely Benign BS2 BS1, BS3, PM2, BP4, PP3 The NM_000330.4(RS1):c.472G>A variant is a missense variant encoding the substitution of Aspartic acid with Asparagine at amino acid 158. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000005012 among hemizygous individuals, with 2 variant alleles / 399058 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.395, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 and <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes do not apply. EBNA293 cells exogenously expressing the variant exhibit no loss of RS1 secretion into the medium relative to the wild-type control (PMID: 17525175). Additionally, molecular modeling studies have predicted this change to have a mild effect (DOI: 10.5772/24453). However, the BS3 code is not considered applicable for RS1, so BS3_Supporting is not met. This variant has also been reported as a polymorphism present in a healthy control individual (PMID: 9618178, PMID: 10703138, BS2). In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BS2 (date of approval 01/024/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226749/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:116278 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0020538 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0022904 infores:hetionet CHEBI:52717 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151825 infores:hetionet CHEBI:6472 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0036974 infores:hetionet CHEBI:36795 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0022346 infores:hetionet CHEBI:3698 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0232462 infores:hetionet CHEBI:4495 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0015371 infores:hetionet CHEBI:3478 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0030312 infores:hetionet NCBIGene:2934 biolink:causes MONDO:0007097 infores:monarchinitiative not_provided not_provided HGNC:4620 MONDO:0007097 uuid:527e81ca-9aa1-4f2b-b22e-3a1b4e7fdad3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042345 infores:hetionet CHEBI:175901 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0542571 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0005745 infores:hetionet CHEBI:17141 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0042075 infores:hetionet GO:0080152 biolink:causes GO:0015977 infores:ubergraph knowledge_assertion manual_agent GO:0080152 GO:0015977 CHEBI:47898 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0000737 infores:hetionet NCBITaxon:5759 biolink:causes UMLS:C0023886 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5759 MESH:D008101 DB00911_MESH_D008101_1DB00916_MESH_D008101_1 CHEBI:7445 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0021177 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235893 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1384666 infores:hetionet CHEBI:10124 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013491 infores:hetionet GO:0110082 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:0110082 GO:0044085 CHEBI:63598 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085129 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0700031 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0700031 infores:hetionet CHEBI:5959 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0004093 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0026946 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1258215 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0860703 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0860703 infores:hetionet CAID:CA4432373 biolink:causes MONDO:0010134 infores:clingen CAID:CA4432373 MONDO:0010134 PMID:31599023 Likely Benign BS1_Supporting, BP4, BS3_Supporting BS4, BS2, PP3, PP1, PM5, PM1, PM3, PM2, PS1, PS3, PS4 The NM_000441.2(SLC26A4):c.147C>G (p.Ser49Arg) variant has been identified in a heterozygous state in two Chinese individuals with congenital non-syndromic hearing loss (PMID: 25149764). No information about segregation of the variant or whether it was in trans with another SLC26A4 variant was given. The filtering allele frequency of the c.147C>G variant in the SLC26A4 gene is 0.27% for East Asian chromosomes by gnomADv4 with 95% CI, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein and splice prediction analysis using MaxEntScan does not suggest an impact to splicing (BP4). Fluorescence HCO3−/Cl− and I−/Cl− antiport functional assay show no difference compared to wild type protein (PMID : 31599023 ; BS3_P). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting, BS3_Supporting, BP4 (ClinGen Hearing Loss VCEP specifications version 2; 7/16/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA4432373/MONDO:0010134/005 2025-07-16 2025-09-23 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:4466 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0025061 infores:hetionet CHEBI:8774 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0037036 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027441 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0029456 infores:hetionet CHEBI:53760 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0344232 infores:hetionet CHEBI:9123 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0028084 infores:hetionet CHEBI:41879 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C3263723 infores:hetionet CHEBI:3568 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037763 infores:hetionet CHEBI:6741 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0033774 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0002170 infores:hetionet CHEBI:63624 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0151576 infores:hetionet CHEBI:75984 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018524 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0151883 infores:hetionet CHEBI:5138 biolink:causes NCIT:C96935 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0149707 infores:hetionet CHEBI:2948 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0024314 infores:hetionet CAID:CA7331374 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331374 MONDO:0100216 PMID: Uncertain Significance PP3 PM2, BP4, BP2, BA1, BS2, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by serine at amino acid 635 (p.Asp635Ser). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMIDs: 33718253, Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 (non-cancer) is 0.00001 (1/91082 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). While in silico tools do not predict damaging impact of the variant on protein function (REVEL: 0.398), the splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331374/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA151480 biolink:causes MONDO:0017623 infores:clingen CAID:CA151480 MONDO:0017623 PMID: Likely Benign BS1, BP2 PTEN c.-1142C>T (NC_000010.10:g.89623084C>T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0049 (0.49%, 8/1622 alleles) in the East Asian subpopulation of the gnomAD cohort. (PMID 27535533) BP2: Observed in trans with a pathogenic or likely pathogenic PTEN variant, at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (Internal laboratory contributors SCV000187279.1, SCV000149465.6) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA151480/MONDO:0017623/003 2018-04-06 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8863 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0476273 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0235146 infores:hetionet CHEBI:6541 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C3263723 infores:hetionet CHEBI:6706 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0027497 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0302295 infores:hetionet CHEBI:6775 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033774 infores:hetionet NCBIGene:26576 biolink:causes MONDO:0975828 infores:monarchinitiative not_provided not_provided HGNC:11402 MONDO:0975828 uuid:58afe352-5039-4e2c-9aab-a3ab6e981b98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6846 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0239937 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0032285 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0004239 infores:hetionet CHEBI:49375 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0854467 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014130 infores:hetionet CHEBI:27958 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0233571 infores:hetionet CHEBI:3654 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0018681 infores:hetionet NCBIGene:81545 biolink:causes MONDO:0014259 infores:monarchinitiative not_provided not_provided HGNC:28844 MONDO:0014259 uuid:e247b63a-8a0c-4dca-b77e-0db65d08fab3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0085635 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151752 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013220 infores:hetionet CHEBI:51860 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0393760 infores:hetionet CHEBI:9588 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0409974 infores:hetionet CHEBI:50730 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0040822 infores:hetionet CAID:CA251523 biolink:causes MONDO:0009861 infores:clingen CAID:CA251523 MONDO:0009861 PMID:9634518PMID:25596310PMID:25596310PMID:17935162PMID:1971147PMID:9634518PMID:1609797 Pathogenic PP4_Moderate, PP3, PS3, PM3_Strong PM2 PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: PMID 17935162: Table 1: p.Arg408Trp 1.85% WT activity PMID 25596310: 1.3% activity of WT (Table S4) (PMID:25596310; PMID:17935162); PP4_Moderate: most common PAH mutation in cohort; exclude BH4 deficiency. (PMID:25596310; PMID:9634518); PM3_Strong: Detected with IVS12+1G>A, M1V (Pathogenic/LP) (PMID:9634518; PMID:1971147; PMID:1609797). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251523/MONDO:0009861/006 2018-08-06 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6775 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0019193 infores:hetionet CHEBI:28864 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151827 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030305 infores:hetionet CAID:CA10585459 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585459 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP1, BS2 The NM_000527.5(LDLR):c.1449G>T (p.Trp483Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.951.It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 1 index case with Simon Broome criteria from Poland (PMID 26892515), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585459/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50173 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151717 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0234458 infores:hetionet CHEBI:50742 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0234233 infores:hetionet CAID:CA350341975 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341975 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, PM1 PP3, BA1, BP4, BS1 BMPR2 c.1257A>T is a missense variant predicted to cause substitution of arginine to serine at amino acid position 419 (p.Arg419Ser). The variant is absent from gnomAD v2.1.1 controls and found at a maximum allele frequency of 0.000022 in gnomAD v4.1.0 in the East Asian ancestry group, meeting PM2_supporting criterion of <0.01% (BA1 and BS1 not met). The REVEL score of 0.59 does not meet BP4 (<=0.25) or PP3 (>=0.75) criteria. This variant resides within the critical kinase domain (PM1_moderate met). Co-segregation/case, experimental criteria, and alternative missense variants at the same location were not evaluated due to lack of reported evidence. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1_moderate (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341975/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8028 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0344232 infores:hetionet CHEBI:5118 biolink:causes HP:0040242 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151702 infores:hetionet CHEBI:168396 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030554 infores:hetionet CHEBI:32588 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0085632 infores:hetionet CHEBI:2038 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151825 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0080276 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0854679 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0854679 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0332534 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0227791 infores:hetionet CHEBI:63612 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0011175 infores:hetionet CHEBI:47780 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011071 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151795 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0025061 infores:hetionet NCBIGene:2074 biolink:causes MONDO:0010909 infores:monarchinitiative not_provided not_provided HGNC:3438 MONDO:0010909 uuid:c8dcf50d-9af3-4cbf-8dfc-231bb5742d21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6078 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0022568 infores:hetionet CHEBI:80630 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0016204 infores:hetionet CHEBI:9139 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0043352 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0429029 infores:hetionet CHEBI:142290 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0004604 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0017152 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151888 infores:hetionet CHEBI:5775 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0018524 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0428409 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0428409 infores:hetionet CHEBI:61058 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0011603 infores:hetionet CHEBI:3240 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0000737 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017152 infores:hetionet CHEBI:45863 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0037763 infores:hetionet CHEBI:9435 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0028084 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0241863 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0221745 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0221745 infores:hetionet CHEBI:7601 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0232462 infores:hetionet CHEBI:39112 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0041969 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003452 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151900 infores:hetionet CHEBI:53766 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0151799 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0001824 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0006277 infores:hetionet CAID:CA386966081 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966081 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS4 The c.779C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to lysine at codon 260 (p.(Thr260Lys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result nearly 50%, negative genetic testing for HNF4A, and negative antibodies). While the MODY probability score was slightly below 50%, the patient was on insulin with a C-peptide in the normal range and thus the score was likely an underestimate, and clinical judgment was used to apply PP4_Moderate (internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Lys (PM5_Supporting). In summary, c.779C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966081/MONDO:0015967/085 2023-09-19 2023-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63630 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151907 infores:hetionet CHEBI:72564 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0005778 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0015397 infores:hetionet CHEBI:52717 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015402 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0948594 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0234930 infores:hetionet NCBIGene:10695 biolink:causes MONDO:0033369 infores:monarchinitiative not_provided not_provided HGNC:11968 MONDO:0033369 uuid:ccdbba8c-751e-4ff4-b69a-fe152714a142 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0005741 infores:hetionet NCBITaxon:297308 biolink:causes MONDO:0005980 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:297308 MONDO:0005980 CHEBI:63638 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0011206 infores:hetionet CHEBI:7798 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0015230 infores:hetionet CAID:CA10607101 biolink:causes MONDO:0007783 infores:clingen CAID:CA10607101 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Serine at codon 533 of the RYR1 protein, p.(Arg533Ser). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. No publications were identified that reported this variant in individuals with a personal or family history of MH. The variant is present in ClinVar. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.86) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA10607101/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:36704 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0392386 infores:hetionet CHEBI:94501 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0016204 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0855242 infores:hetionet CHEBI:71255 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0005758 infores:hetionet CHEBI:5855 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0039070 infores:hetionet CHEBI:31624 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0037383 infores:hetionet CHEBI:4887 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0151610 infores:hetionet CHEBI:28901 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0028961 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030552 infores:hetionet CHEBI:63630 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0016204 infores:hetionet CAID:CA229583 biolink:causes MONDO:0009861 infores:clingen CAID:CA229583 MONDO:0009861 PMID:16256386PMID:16256386 Pathogenic PM3, PVS1, PM2, PP4 The c.498C>A (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in individuals with Classic PKU in German and Chinese cohorts. (PP4, PMID:16256386; 10394930). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). This variant was detected with multiple known pathogenic variants (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229583/MONDO:0009861/006 2019-04-08 2019-04-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0025320 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0002928 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0002928 infores:hetionet CHEBI:3286 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0220870 infores:hetionet NCBIGene:4915 biolink:causes MONDO:0013483 infores:monarchinitiative not_provided not_provided HGNC:8032 MONDO:0013483 uuid:9d1018fe-6541-465d-b23b-653415bce629 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84050 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0034065 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0876973 infores:hetionet NCBIGene:9820 biolink:causes MONDO:0010117 infores:monarchinitiative not_provided not_provided HGNC:21024 MONDO:0010117 uuid:8bd58602-3b36-43ec-9277-b066ce11d82c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10385730 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385730 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.153C>T (p.Thr51=) is a synonymous variant located in the penultimate nucleotide of exon 2, which is a position not eligible to meet the BP7 code. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0003871 among hemizygous individuals, with 151 variant alleles / 390,063 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385730/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:10023 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0239571 infores:hetionet CAID:CA343726016 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726016 MONDO:0020367 PMID:11004290 Uncertain Significance PP1_Moderate, PS3_Supporting, PP3, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS4, PS1, PS2, BP4, BA1 The c.814C>G variant in MYOC is a missense variant predicted to cause substitution of Arginine by Glycine at amino acid 272 (p.Arg272Gly). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.743, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 11004290) demonstrated that the Arg272Gly protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 5 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 11004290), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 11004290), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PS3_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726016/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:65993 biolink:causes MONDO:0054654 infores:monarchinitiative not_provided not_provided HGNC:16618 MONDO:0054654 uuid:57d0a6b8-9324-4070-8620-24561eba614f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8623491 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623491 MONDO:0100326 PMID: Benign BP7, BA1, BP4 After a comprehensive literature search of the intronic variant NM_000212.3(ITGB3):c.2301+9C>T, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.4805 (11916/24800 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets BA1. In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of -.336 shows that the nucleotide position is not highly conserved (BP4,BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623491/MONDO:0100326/011 2023-04-06 2023-04-07 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA320642592 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642592 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.351+10C>G is an intronic variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. It has a SpliceAI score of 0 and a PhyloP score of -0.6, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642592/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5441 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0030312 infores:hetionet CHEBI:4027 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0014518 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0520589 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0003123 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0021400 infores:hetionet CHEBI:5001 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0040038 infores:hetionet NCBITaxon:5501 biolink:causes MONDO:0005706 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5501 MONDO:0005706 CHEBI:9434 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0009806 infores:hetionet CHEBI:5132 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C2981158 infores:hetionet CHEBI:2549 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0687713 infores:hetionet CHEBI:44915 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0041834 infores:hetionet CAID:CA386959363 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959363 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, BS4, PP1, PP4 The c.383T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to asparagine at codon 128 (p.(Ile128Asn)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v4.1.0 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 9075819; PMID:15928245). It is unclear whether this variant segregates with diabetes in this individual's family; the variant is not found in the proband's diabetic mother and brother; however, it is found in the proband's diabetic son, and the proband's diabetic father and paternal family members were not tested (PMID 9075819). Additionally, another missense variant, c.382A>G (p.Ile128Val) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.383T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959363/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7936 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034882 infores:hetionet CHEBI:28830 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0004093 infores:hetionet CHEBI:17263 biolink:causes UMLS:C0235511 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0235511 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0702266 infores:hetionet CHEBI:7476 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0008031 infores:hetionet CHEBI:3696 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0041657 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033581 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235876 infores:hetionet CHEBI:478164 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C1609512 infores:hetionet CHEBI:40279 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1142135 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009806 infores:hetionet CHEBI:38562 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0231528 infores:hetionet CHEBI:63617 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0080274 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037195 infores:hetionet CAID:CA121220 biolink:causes MONDO:0019169 infores:clingen CAID:CA121220 MONDO:0019169 PMID: Benign BS2, BA1 PM5, PM1, PP3, BP4, PM2 The allele frequency of the c.844A>C; p. M282L variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA121220/MONDO:0019169/014 2021-04-02 2021-05-06 X-linked inheritance HP:0001417 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA414796680 biolink:causes MONDO:0044970 infores:clingen CAID:CA414796680 MONDO:0044970 PMID: Benign BS1_Stand Alone BP4 The m.8857G>A (p.A11T) variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen at high frequencies across multiple haplogroups in the GenBank dataset (BS1_stand alone) including in haplogroup R7b (100% of individuals however only 9 sequences), H32 (89% of individuals however only 8/9 sequences), M30f (80% of individuals), M11d (67% of individuals), J1B (46% of individuals out of 390 sequences), X1c (40% of individuals), M52b (21% of individuals), D1g (10% of individuals), H7c (8% of individuals), and I2 (7% of individuals). If an affected individual is not a member of one of these haplogroups, further evaluation of the variant in that particular individual should be considered. In summary, this variant meets criteria to be classified as benign given high frequency in the general population across multiple haplogroups. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1_stand alone. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414796680/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:45716 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0010200 infores:hetionet CL:0000786 biolink:causes MONDO:0004959 infores:ubergraph knowledge_assertion manual_agent CL:0000786 MONDO:0004959 CHEBI:84050 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0151735 infores:hetionet NCBIGene:57688 biolink:causes MONDO:0011359 infores:monarchinitiative not_provided not_provided HGNC:29316 MONDO:0011359 uuid:554c72d6-3466-4fd0-abbf-68606f2ad57c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9288 biolink:causes UMLS:C1527401 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C1527401 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0042514 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0849918 infores:hetionet CHEBI:100241 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C3665386 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0243026 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017160 infores:hetionet CHEBI:61033 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0004604 infores:hetionet CHEBI:2950 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0042963 infores:hetionet CHEBI:27834 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0085636 infores:hetionet CHEBI:10101 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0007859 infores:hetionet CHEBI:63620 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0043352 infores:hetionet CHEBI:6715 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019572 infores:hetionet CAID:CA9870226 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870226 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5, PM1, PS4, PP1_Strong The c.334C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 112 (p.Arg112Trp)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to zero copies in the European non-Finnish subpopulation and one copy in the Latino subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). It was identified in 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:29207974, 12627330, internal lab contributors). At least two of these individuals have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and responsive to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). Additionally, this variant segregated with diabetes, with 7 informative meioses in two families (PP1_Strong; PMID:12627330, internal lab contributor). This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.95, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.335G>A (p.Arg112Gln) has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg112Trp has a greater Grantham distance (PM5). In summary, c.334C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PP1_strong, PS4, PP4_Moderate, PM1, PM5, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870226/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5103 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0151828 infores:hetionet CHEBI:75722 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030794 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020615 infores:hetionet CHEBI:17141 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0041834 infores:hetionet CHEBI:41774 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0004093 infores:hetionet GO:0098828 biolink:causes GO:0099565 infores:ubergraph knowledge_assertion manual_agent GO:0098828 GO:0099565 CHEBI:2704 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C2364111 infores:hetionet CHEBI:3761 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0013144 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0037199 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0009806 infores:hetionet GO:0060782 biolink:causes GO:0030850 infores:ubergraph knowledge_assertion manual_agent GO:0060782 GO:0030850 CHEBI:45327 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0340464 infores:hetionet CHEBI:50173 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0877359 infores:hetionet CAID:CA180077 biolink:causes MONDO:0009290 infores:clingen CAID:CA180077 MONDO:0009290 PMID: Benign BA1 PM2 The NM_000152.5:c.2400C>T variant in GAA is a synonymous (silent) variant (p.Ser800=) that is not predicted to impact splicing. The highest population minor allele frequency in gnomAD v2.1.1. is 0.02504 (617/24640 alleles; 9 homozygotes) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 167115. In summary, this variant meets the criteria to be classified as Benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA180077/MONDO:0009290/010 2024-08-06 2024-09-03 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:9586 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0233494 infores:hetionet CHEBI:3561 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042023 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0027051 infores:hetionet CHEBI:8028 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0032617 infores:hetionet CHEBI:5296 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0311468 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0574067 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0836924 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0013922 infores:hetionet CHEBI:51173 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0011603 infores:hetionet CHEBI:6970 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0006277 infores:hetionet CHEBI:28487 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0232462 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0027726 infores:hetionet CHEBI:17026 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042256 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038363 infores:hetionet CHEBI:9927 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0016204 infores:hetionet CHEBI:7476 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1720775 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0575090 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0314719 infores:hetionet CHEBI:7809 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0042109 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0036572 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0031117 infores:hetionet CHEBI:48273 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0043387 infores:hetionet CHEBI:52717 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032227 infores:hetionet CAID:CA213725 biolink:causes MONDO:0015967 infores:clingen CAID:CA213725 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP2, PP3, PP4, PM2_Supporting PS4, PM1 The c.1160C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glutamic acid at codon 387 (p. (Ala387Glu)) of NM_000162.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and no copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.958 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Two other missense variants, c.1159G>A p.(Ala387Thr) and c.1160C>T p.(Ala387Val) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). In summary, c.1160C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213725/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:9434 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042109 infores:hetionet CHEBI:31709 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0006266 infores:hetionet CHEBI:63589 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0275524 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0022660 infores:hetionet CHEBI:15765 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0043094 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0917801 infores:hetionet CHEBI:9086 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085633 infores:hetionet CHEBI:8356 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0041657 infores:hetionet CHEBI:9445 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0011124 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0006147 infores:hetionet CHEBI:144093 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0022346 infores:hetionet CHEBI:9434 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0030554 infores:hetionet NCBIGene:10978 biolink:causes MONDO:0014349 infores:monarchinitiative not_provided not_provided HGNC:16999 MONDO:0014349 uuid:1f2c9efd-520d-44ac-88b9-2eaff3a08b54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042134 infores:hetionet CHEBI:8707 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0028081 infores:hetionet CHEBI:17698 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0002792 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0028259 infores:hetionet CHEBI:3219 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151836 infores:hetionet UMLS:C0145185 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0178298 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0233494 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0151472 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151472 infores:hetionet CHEBI:161680 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C2047937 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0015256 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549209 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017601 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0002871 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005192 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0235974 infores:hetionet CHEBI:3347 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C1565489 infores:hetionet GO:0010520 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0010520 GO:0019953 CHEBI:119915 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009782 infores:hetionet CHEBI:7465 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0013404 infores:hetionet CHEBI:3175 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0042907 infores:hetionet CHEBI:7852 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0917801 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C1956346 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0413252 infores:hetionet CHEBI:16469 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1140680 infores:hetionet CHEBI:4710 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0232461 infores:hetionet CHEBI:50924 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0003811 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0036508 infores:hetionet CHEBI:567361 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0009782 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0001339 infores:hetionet CHEBI:6916 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0030193 infores:hetionet CAID:CA354446617 biolink:causes MONDO:0009276 infores:clingen CAID:CA354446617 MONDO:0009276 PMID: Uncertain Significance PM3_Supporting, PM5_Supporting, PP1, PP4, PM2_Supporting BP4, PP3 The NM_000174.5(GP9):c.72T>G (p.Cys24Trp) missense variant is absent from gnomAD v4.1 (PM2_Supporting). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome [c.70T>C (p.Cys24Arg)] (PMID:21173099) and classified Likely Pathogenic by the PD-VCEP (PM5_supporting). At least one patient (Patient P7 in PMID:21173099) with this variant had less than 10% expression of GPIba and GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. This individual was homozygous for the variant (PM3_supporting) and one affected first degree relative was also homozygous (PP1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM5_supporting, PP4, PM3_supporting, PP1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA354446617/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:116278 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151798 infores:hetionet UMLS:C0011701 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0009676 infores:hetionet CHEBI:3082 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0028961 infores:hetionet CHEBI:30830 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0852911 infores:hetionet CHEBI:6121 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0030193 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042075 infores:hetionet CHEBI:15765 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0017178 infores:hetionet CHEBI:63629 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0549249 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0032961 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0267792 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018939 infores:hetionet CHEBI:3127 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0018790 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0009806 infores:hetionet CHEBI:6950 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085611 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0178298 infores:hetionet CHEBI:63605 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0878544 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018418 infores:hetionet CHEBI:66901 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0020453 infores:hetionet CHEBI:3077 biolink:causes MONDO:0019801 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151467 infores:hetionet CHEBI:10102 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0006277 infores:hetionet CHEBI:119486 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0236075 infores:hetionet CHEBI:167309 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0423153 infores:hetionet CHEBI:5118 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0232462 infores:hetionet CHEBI:44185 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030193 infores:hetionet CHEBI:10119 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013362 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0020649 infores:hetionet CHEBI:10125 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0034063 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0849907 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0849907 infores:hetionet NCBIGene:361 biolink:causes MONDO:0957534 infores:monarchinitiative not_provided not_provided HGNC:637 MONDO:0957534 uuid:06945151-4840-4887-8cab-92f3dd2e0596 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0035317 infores:hetionet CHEBI:75246 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0231528 infores:hetionet CHEBI:3732 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085641 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0853692 infores:hetionet CHEBI:2038 biolink:causes MONDO:0030602 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0519030 infores:hetionet CHEBI:15854 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0009676 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0017160 infores:hetionet CHEBI:16796 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0023380 infores:hetionet CHEBI:42797 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C3263723 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017675 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0018621 infores:hetionet CHEBI:8435 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0427086 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002635 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0031090 infores:hetionet CHEBI:70735 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0011168 infores:hetionet CHEBI:178699 biolink:causes UMLS:C1112349 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C1112349 infores:hetionet NCBIGene:23005 biolink:causes MONDO:0014997 infores:monarchinitiative not_provided not_provided HGNC:29536 MONDO:0014997 uuid:45f78e9d-44df-40d3-bacc-ac223a021162 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA7542986 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542986 MONDO:0012996 PMID: Likely Benign BP4, BS1 BP7 The NM_001482.3:c.156T>A variant in GATM is a synonymous (silent) variant (p.Ala52=). The computational predictor, SpliceAI, predicts that the variant does not impact splicing (BP4). BP7 was not applied because the nucleotide is moderately conserved, as shown by phyloP (score 2.27). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00016 (4/24964 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). There is a ClinVar entry for this variant (Variation ID: 469137). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BP4.Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542986/MONDO:0012996/025 2024-11-08 2024-11-13 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63681 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C2939465 infores:hetionet CHEBI:45716 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0085593 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0024115 infores:hetionet CHEBI:64355 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019209 infores:hetionet CHEBI:93305 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0011603 infores:hetionet CHEBI:5050 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0231528 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023533 infores:hetionet CHEBI:31643 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0020538 infores:hetionet CHEBI:142290 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0020580 infores:hetionet CHEBI:41977 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0023530 infores:hetionet CHEBI:5864 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0233407 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0024115 infores:hetionet CHEBI:39585 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042487 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0015397 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0425481 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0425481 infores:hetionet CHEBI:64312 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0855333 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0038663 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009806 infores:hetionet CAID:CA2580098652 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098652 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.352-13G>T is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score of 0.01 (≤ 0.20), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 1.09 ≤ 2.0), supporting BP7. Multiple lines of computational evidence suggest no impact on the gene or gene product, with a SpliceAI score of 0.01, supporting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098652/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27834 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0038362 infores:hetionet CHEBI:4653 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0026858 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004450 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0265101 infores:hetionet CHEBI:51860 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0728899 infores:hetionet NCBIGene:7818 biolink:causes MONDO:0976232 infores:monarchinitiative not_provided not_provided HGNC:2673 MONDO:0976232 uuid:c211f016-fef6-498a-9bfe-3bf552492c14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0002994 infores:hetionet CHEBI:2549 biolink:causes HP:6000264 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0410918 infores:hetionet NCBIGene:51322 biolink:causes MONDO:0014741 infores:monarchinitiative not_provided not_provided HGNC:17327 MONDO:0014741 uuid:4112abe1-a420-4622-a3fa-e8ffae85310b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0033774 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0476327 infores:hetionet CAID:CA902589 biolink:causes MONDO:0100368 infores:clingen CAID:CA902589 MONDO:0100368 PMID: Likely Benign BP4, BP7, PM2_Supporting NM_000329.3(RPE65):c.126C>T is a synonymous variant in codon 42, near the center of exon 3. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00006012, with 13/129178 in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The splicing impact predictor SpliceAI gives a delta score of 0.03 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902589/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4708 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0008350 infores:hetionet CHEBI:45409 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013404 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0029882 infores:hetionet CHEBI:32184 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0030193 infores:hetionet CHEBI:5778 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0085649 infores:hetionet CHEBI:63610 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0030193 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1328308 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1328308 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151849 infores:hetionet CHEBI:92998 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0003962 infores:hetionet CAID:CA007174 biolink:causes MONDO:0100316 infores:clingen CAID:CA007174 MONDO:0100316 PMID: Likely Pathogenic PS4, PP3, PP4 BA1, BP1, BP4, BP2, BP3, PS3, PS1, PS2, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM1, PM4, PM5, PP1, PP2, BS2 NM_000218.3(KCNQ1):c.477+5G>A is a variant in intron 2. The computational splicing predictor SpliceAI gives a score of 0.64 for donor gain (Threshold is > 0.5), predicting that the variant disrupts the donor splice site of intron 2 of KCNQ1 (PP3). A minigene assay showed that the variant disrupts splicing resulting in stop codon, indicating that this variant impacts protein function (PMID: 36197721), however at least two functional studies are needed for PS3_Supporting, so this criterion is not met. Another variant disrupting this splice site, NM_000218.3(KCNQ1):c.477+1G>A, has been classified as pathogenic for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, however, PS1 is not considered applicable for intronic variants. This variant has been reported in at least 13 probands with long QT syndrome (PS4; PMID: 19716085, PMID: 21350584, PMID: 23995044, PMID: 15840476, PMID: 10973849, PMID: 10728423). At least one affected proband exhibited QTc prolongation above 480 milliseconds and swimming-associated events, which together are highly specific for long QT syndrome 1 (PP4, PMID: 10560595). This variant has been reported to segregate with LQTS in 2 mother/child relationships, as well as one proband with JLNS and aunt affected with LQTS with QTc>480, which are not sufficient to meet the PP1 code (PMID: 23124029, PMID: 10728423). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001337, with 1/74812 in the African / African-American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant has been detected in at least 2 individuals with a diagnosis of Jervell and Lange-Nielsen syndrome, one of whom harbored the variant confirmed in trans with the NM_000218.3(KCNQ1):c.1741A>T (p.Lys581Ter) variant, which was previously classified pathogenic by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 32508908), however PM3 is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting). The other patient harbored the variant confirmed in trans with the p.Tyr171Ter variant, which was not specifically described at the DNA level and has not been previously classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 23392653). In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007174/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5050 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0027441 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0232492 infores:hetionet CHEBI:77733 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0015230 infores:hetionet NCBIGene:6311 biolink:causes MONDO:0008458 infores:monarchinitiative not_provided not_provided HGNC:10555 MONDO:0008458 uuid:4b8aa376-7406-470b-b52d-386e4b5bcb7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0271650 infores:hetionet CHEBI:3647 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C1527311 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0040210 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0040210 infores:hetionet CHEBI:520985 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020443 infores:hetionet CHEBI:42068 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0015230 infores:hetionet CHEBI:61390 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0151908 infores:hetionet CHEBI:4027 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0549567 infores:hetionet CHEBI:87681 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0017178 infores:hetionet CAID:CA2802205 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802205 MONDO:0001586 PMID: Pathogenic PP3_Moderate, PS3_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting, PM3_Very Strong PM1 The NM_000203.5:c.1148G>A variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 383 (p.Arg383His). At least five patients with this variant had documented IDUA deficiency within the affected range in leukocytes, enzyme replacement therapy resulting in a significant reduction in total urine GAGs, and/or clinical features specific to MPS I including corneal and joint involvement (PMID: 23786846, 23837464, 31090850) (PP4_Moderate). This variant has been detected in at least 1 individual with MPS I who was homozygous for the variant (PMID: 7550242, 0.5 points). It has also been detected in at least 8 individuals who were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; variants: c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909)(PMID: 23837464, 0.5 points); c.266G>A (p.Arg89Gln) ( (PMID: 31194252, 0.5 points), c.386-2A>G (ClinVar Variation ID: 222994) (PMID: 23837464, 2 unrelated patients, 2 x 0.5 points), c.266G>A (p.Arg89Gln) (ClinVar Variation ID: 11922) (PMID: 31194252, 0.5 points), c.979G>C (p.Ala327Pro) (Variation ID: 167190) (PMID: 12559846, 23837464, 0.5 points), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 12559846, 23837464, 0.5 points), c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910) (PMID: 30419879, 0.5 points); however, phase was not confirmed in any case (Total >4 points) (PM3_Very Strong). One pair of sibling with MPS I and compound heterozygous for the variant and p.Gln70Ter, and another pairs of siblings compound heterozygous for the variant and c.386-2A>G (aka c.474-2A>G) ( PMID: 23837464) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001653 (14/84692 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When expressed in CHO cells, the activity of the variant was <2% wild type activity (PS3_Supporting). The computational predictor REVEL gives a score of 0.874 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for the variant (Variation ID: 558189). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802205/MONDO:0001586/091 2024-12-05 2025-03-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7025 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0877661 infores:hetionet CHEBI:34967 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0036396 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038663 infores:hetionet NCBIGene:10436 biolink:causes MONDO:0008879 infores:monarchinitiative not_provided not_provided HGNC:16912 MONDO:0008879 uuid:6e69ed16-4acb-484a-98aa-f33e3d45dcdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0005779 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151849 infores:hetionet CAID:CA401369874 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369874 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM5, PM3_Strong The NM_000152.5:c.1913G>T variant in GAA is predicted to result in the substitution of glycine by valine at amino acid 638 (p.Gly638Val). At least 4 patients diagnosed with Pompe disease have been reported with this variant. This includes three patients with symptoms consistent with infantile onset Pompe disease (including cardiac hypertrophy and hypotonia), and treated with enzyme replacement therapy, two of whom also had documented values showing very low GAA activity (PMID: 15121988, 19588081, 24715333, 29573408, 30049495, 32888769, 38524130), (PP4_Moderate). Four patients have been reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP including c.307T>G (p.Cys103Gly) (ClinVar Variation ID: 92483, SCV002817442.1) (PMID: 38524130, phase unknown, 0.5 points), c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 19588081, phase unknown, 0.5 points)), c.1548G>A (p.Trp516Ter) (ClinVar Variation ID: 189025, SCV001371740.1 (PMIDs: 15121988, 24715333, 29573408, 30049495, 32888769, phase unknown, 0.5 points), and c.1912G>T (p.Gly638Trp) (PMID: 19588081, confirmed in trans, 1 point). Total 2.5 points (PM3_Strong). When expressed in HEK293 cells, the variant result in no GAA activity, and was incorrectly processed remaining as the precursor 100kD band on Western blot of cellular protein (PMID: 24715333) (PS3_Moderate). The computational predictor REVEL gives a score of 0.986 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change at the same amino acid position, c.1912G>T (p.Gly638Trp) has been classified as pathogenic by the ClinGen LD VCEP (PM5). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In gnomAD v4.1, the highest population minor allele frequency is 0.000003394 (4/1178708 alleles) in the European non-Finnish population population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), also meeting this criterion. Another missense change at the same amino acid position, c.1912G>T (p.Gly638Trp) has been classified as pathogenic by the ClinGen LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 928930). In summary, this variant meets the criteria to be classified as a pathogenic variant for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PM5, PS3_Moderate, PP3, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369874/MONDO:0009290/010 2024-06-06 2024-06-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:585948 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0009938 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005693 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0392548 infores:hetionet CHEBI:15940 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0011630 infores:hetionet UMLS:C1738934 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085633 infores:hetionet CHEBI:31711 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0278134 infores:hetionet NCBIGene:4920 biolink:causes MONDO:0007220 infores:monarchinitiative not_provided not_provided HGNC:10257 MONDO:0007220 uuid:5aab4b32-247b-4fee-af07-99a216c738d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0048399 biolink:causes GO:0048389 infores:ubergraph knowledge_assertion manual_agent GO:0048399 GO:0048389 CHEBI:6129 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015397 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0178298 infores:hetionet CHEBI:7492 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C1262144 infores:hetionet UMLS:C0011701 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0235996 infores:hetionet CHEBI:18385 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0020458 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0857093 infores:hetionet CHEBI:63631 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085602 infores:hetionet CHEBI:9130 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0043144 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020651 infores:hetionet CHEBI:68579 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0011615 infores:hetionet CHEBI:50742 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0019572 infores:hetionet CHEBI:9288 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0085679 infores:hetionet CHEBI:28915 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0035455 infores:hetionet CHEBI:6538 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0017178 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0232459 infores:hetionet CHEBI:5778 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0547030 infores:hetionet CHEBI:10124 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042023 infores:hetionet CHEBI:2788 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0018681 infores:hetionet CHEBI:8869 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C3263723 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0086543 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0278008 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027441 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0029408 infores:hetionet CHEBI:6912 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0018681 infores:hetionet CHEBI:38940 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0239739 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0001339 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0036572 infores:hetionet CHEBI:71940 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0015230 infores:hetionet CHEBI:3441 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002962 infores:hetionet CHEBI:8888 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011168 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0242350 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0012797 infores:hetionet CHEBI:63622 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0007222 infores:hetionet CHEBI:68584 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0040034 infores:hetionet CHEBI:6935 biolink:causes HP:0002584 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0267373 infores:hetionet CHEBI:28748 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085633 infores:hetionet CHEBI:6754 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0039070 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0877661 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0000814 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0000814 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020538 infores:hetionet NCBIGene:6857 biolink:causes MONDO:0033864 infores:monarchinitiative not_provided not_provided HGNC:11509 MONDO:0033864 uuid:2ba4e85d-57a0-4387-ba3b-d3e0ebf5fc2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:4751 biolink:causes MONDO:0001628 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D014009 DB00400_MESH_D014009_1DB01188_MESH_D014009_1 CAID:CA229274 biolink:causes MONDO:0009861 infores:clingen CAID:CA229274 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM5_Supporting The c.1022A>C (p.Lys341Thr) variant in PAH has been reported in a patient with PKU (BH4 deficiency not assessed, PMID: 9012412). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.945. A different likely pathogenic missense change at the same amino acid (p.Lys341Arg) has been seen before. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PM5_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229274/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63622 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0000737 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0003123 infores:hetionet CHEBI:47657 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0917801 infores:hetionet CHEBI:9637 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0035455 infores:hetionet CHEBI:6715 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0033774 infores:hetionet CHEBI:45863 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0032617 infores:hetionet CAID:CA410147797 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147797 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS4, PS2, PS3, PS1, BP1, BP3, BA1, BP7, BP5, BS1, BS4, BS3, PVS1, PM6, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1199C>T (p.Ser400Leu) is a missense variant which is absent from gnomAD v2, v3, and v4 (PM2_Supporting) and has not been reported as a germline variant in the literature. The computational predictor REVEL gives a score of 0.36, below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, providing evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147797/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31711 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0013378 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0541799 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0424605 infores:hetionet CHEBI:4653 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0031350 infores:hetionet CHEBI:6888 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0029118 infores:hetionet CHEBI:135935 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0042029 infores:hetionet CHEBI:45951 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0085649 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030552 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1141893 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1141893 infores:hetionet CHEBI:3347 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0853034 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0856049 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0856049 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0235620 infores:hetionet CHEBI:9613 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0234215 infores:hetionet CHEBI:3504 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0231528 infores:hetionet CHEBI:63638 biolink:causes MONDO:0006499 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0018552 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0403632 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0040034 infores:hetionet CHEBI:6367 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040053 infores:hetionet CAID:CA409118270 biolink:causes MONDO:0007064 infores:clingen CAID:CA409118270 MONDO:0007064 PMID: Likely Pathogenic PVS1_Moderate, PP4_Moderate, PM3, PM2_Supporting BS2 The c.1078+2T>A (NM_000022.4) variant in ADA occurs within the canonical splice donor site (+2) of intron 11. It is predicted to cause skipping of biologically relevant exon by SpliceAI (Δ score = Donor Loss = 0.97); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; PVS1_Moderate.This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient present: Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), reaching 3 points, PP4_Moderate.This variant has been detected in 02 individuals with ADA SCID. One of them is compound heterozygous with c.955-958delGAAG, p.E320RfsX6, a frameshift termination, which is at least LP according to SCID VCEP. Phase is unknown, so 0.5 pt; The second one is compound heterozygous, for c.482G > A, p.W161X (Also at least LP according to SCID VCEP). Phase is not shown. 0.5pts. Total is 1 pt, PM3_Moderate (PMIDs: 32307643 and 26255240).In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PVS1_Strong, PP4_Moderate, and PM3_Moderate. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409118270/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51364 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0233471 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001134 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085580 infores:hetionet CHEBI:2567 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0015967 infores:hetionet CHEBI:78543 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0085593 infores:hetionet CHEBI:85078 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0002792 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1443060 infores:hetionet CAID:CA367403317 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403317 MONDO:0015967 PMID: Likely Pathogenic PM5, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4 The c.170T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 57 (p.(Met57Lys)) of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 39859454, ClinVar ID: 2684202, internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (multiple instances of fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with at least 3 meioses in a single family (PP1; internal lab contributors). Another missense variant at the same codon, c.171G>A, p.(Met57Ile), has been interpreted as pathogenic by the ClinGen MDEP, and p.(Met57Lys) has a greater Grantham distance (PM5). In summary, c.170T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PM2_Supporting, PP1, PP2, PP3, PP4_Moderate, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403317/MONDO:0015967/086 2025-06-17 2025-06-17 Semidominant inheritance HP:0032113 Supports CHEBI:17347 biolink:causes MONDO:0010198 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0349464 infores:hetionet CHEBI:4027 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0032227 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0392386 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0919874 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0029456 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0232492 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0036572 infores:hetionet NCBIGene:6571 biolink:causes MONDO:0018130 infores:monarchinitiative not_provided not_provided HGNC:10935 MONDO:0018130 uuid:5eac6fbb-d538-49be-bbe4-38b66765c98b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0015230 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0037578 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037578 infores:hetionet NCBIGene:23761 biolink:causes MONDO:0030045 infores:monarchinitiative not_provided not_provided HGNC:8999 MONDO:0030045 uuid:cd491a30-4bfc-45fa-b1da-44c7d5ee74f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0020458 infores:hetionet CHEBI:42797 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0021177 infores:hetionet CHEBI:8481 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0042109 infores:hetionet CHEBI:50648 biolink:causes HP:0001595 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0157733 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0227791 infores:hetionet CHEBI:6775 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235896 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0027765 infores:hetionet CHEBI:50885 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0340865 infores:hetionet CHEBI:75988 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C1443060 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0948425 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0948425 infores:hetionet CHEBI:15428 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0036104 infores:hetionet CHEBI:38562 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C3665386 infores:hetionet CHEBI:7627 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0004093 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0521839 infores:hetionet CAID:CA5689601 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689601 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.613A>G (p.Thr205Ala) variant in the SHOC2 gene is 0.0328% (10/16502) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689601/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:48538 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0042029 infores:hetionet CHEBI:36791 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016927 infores:hetionet CHEBI:5855 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0080274 infores:hetionet CHEBI:72296 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0018932 infores:hetionet CHEBI:40279 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0014518 infores:hetionet CAID:CA913175191 biolink:causes MONDO:0044970 infores:clingen CAID:CA913175191 MONDO:0044970 PMID:29648639 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PM6 The m.15915G>A variant in MT-TT has been reported in one individual with primary mitochondrial disease (PMID: 8769114). This individual had myopathy, muscle wasting, seizures, myoclonus, headaches, vomiting, progressive hearing loss, cataracts, hypogonadism, and short stature. He had elevated blood and cerebrospinal fluid lactate levels. Brain imaging showed diffuse cerebellar and cerebral atrophy and calcifications in putamen, globus pallidus, caudate head, and dentate nucleus. Muscle biopsy showed moderate variation in fiber size, marked type 2B fiber atrophy, few ragged red fibers, focal COX deficiency, and some SDH-reactive blood vessels. The variant was present at 74% heteroplasmy in muscle, 32% in fibroblasts, and 18% in blood. The variant was not detected in blood from the mother and brother, however technology at the time was limited in detecting low heteroplasmy levels. This variant is absent in the MITOMAP GenBank sequences and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). MitoTIP predicts the variant is possible pathogenic (73.7 percentile) and HmtVAR predicts the variant is pathogenic (0.55, PP3). Functional characterization of the mutant tRNA suggest the variant changes the tRNA conformation, reduces the stability of the tRNA, reduces charging capacity of the tRNA, and affects modification of the tRNA (PMID: 29648639, PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913175191/MONDO:0044970/015 2024-03-26 2025-10-29 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:36795 biolink:causes UMLS:C2242583 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2242583 infores:hetionet CHEBI:63620 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027066 infores:hetionet CHEBI:6402 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0014518 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0008311 infores:hetionet CHEBI:15940 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0011603 infores:hetionet CHEBI:6775 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151907 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0017160 infores:hetionet NCBIGene:5696 biolink:causes MONDO:0054698 infores:monarchinitiative not_provided not_provided HGNC:9545 MONDO:0054698 uuid:d3f32ef4-8435-4fbd-ab72-81e6ae1f1cfe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0013781 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0241863 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0030193 infores:hetionet CHEBI:50648 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0014236 infores:hetionet CHEBI:421707 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0021655 infores:hetionet CHEBI:17026 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0231218 infores:hetionet CHEBI:63617 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085688 infores:hetionet CHEBI:7573 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0085636 infores:hetionet CHEBI:68584 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0030554 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0267792 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0150450 infores:hetionet UMLS:C0657912 biolink:causes HP:0010702 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151669 infores:hetionet CAID:CA355964387 biolink:causes MONDO:0001586 infores:clingen CAID:CA355964387 MONDO:0001586 PMID: Likely Pathogenic PVS1_Strong, PM3, PP4, PM2_Supporting PS1 The NM_000203.5: c.1402+1G>T variant in IDUA occurs within the canonical splice donor site of intron 9. It is predicted to cause skipping of biologically-relevant-exon 9 (there are 14 exons in IDUA), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been identified in three patients with clinical features of severe MPS 1 including including cognitive delay, visual impairment, joint disease, hepatosplenomegaly, hernia, cardiac disease, and/or respiratory disease. Two of these patients also had documented IDUA deficiency within the affected range in leukocytes (PMID: 21480867, 27896125). An additional patient was identified by newborn screening with confirmatory deficient IDUA, elevated urine GAGs, and was treated with ERT and HSCT (PMID: 37516270) (PP4). Of these individuals, two were homozygous for the variant (PMID: 21480867, 27896125), and one individual was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter), phase unknown (ClinVar Variation ID: 11908) (PMID: 37516270). Another individual is compound heterozygous for the variant and p.Ala79Val; the allelic data for this individual will be used in the classification of p.Ala79Val and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003924 (1/25482; 0 homozygotes) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Additional variants at this splice donor site have been identified in individuals with features of MPS 1, including c.1402+1G>A (PMID: 27146977). There is a ClinVar entry for this variant (Variation ID: 1323099. In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_Strong, PP4, PM3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355964387/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports NCBITaxon:36826 biolink:causes MONDO:0015803 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36826 MONDO:0015803 CHEBI:6970 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0016867 infores:hetionet CHEBI:27436 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0042373 infores:hetionet CHEBI:3723 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235996 infores:hetionet CHEBI:3176 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C2830004 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004238 infores:hetionet CHEBI:5118 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019080 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0033687 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0221743 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221743 infores:hetionet CHEBI:64310 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151313 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0021167 infores:hetionet CHEBI:3996 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0917801 infores:hetionet CHEBI:4653 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C1443060 infores:hetionet CHEBI:3082 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0008031 infores:hetionet NCBIGene:1441 biolink:causes MONDO:0008092 infores:monarchinitiative not_provided not_provided HGNC:2439 MONDO:0008092 uuid:5bb7aa2b-8011-4a54-ba7b-b874af31ac55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0033687 infores:hetionet CHEBI:5801 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0027497 infores:hetionet CHEBI:681848 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0008031 infores:hetionet GO:0003339 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0072210 CHEBI:2922 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0206061 infores:hetionet CHEBI:45367 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0151907 infores:hetionet CHEBI:5134 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0021099 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0028173 infores:hetionet CHEBI:5141 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0221100 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0948525 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549234 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549234 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0435002 infores:hetionet CAID:CA254379 biolink:causes MONDO:0012999 infores:clingen CAID:CA254379 MONDO:0012999 PMID: Likely Pathogenic PP3, PP4_Strong, PM3, PM2_Supporting, PS3_Supporting PM5 The NM_000156.6:c.505T>A variant in GAMT is a missense variant predicted to cause substitution of a cysteine by tyrosine at amino acid 169 (p.Cys169Tyr). At least 4 unrelated probands and one sibling were found to be homozygous for the variant (PMID: 15651030, 2323426424415674, 24268530, 32606525) (max 2 x 0.5, PM3). Three individuals with the variant had elevated guanidinoacetate in plasma and/or urine); in addition, one individual showed absent creatine peak on brain MRS; another had deficient (<5% wild-type) GAMT activity in lymphoblasts ( PMID: 15651030, 24268530, 24415674). Two sibs had absent creatine peak on brain MRS (PMID: 32606525) (PP4_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000333 (2/60014 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.754 which is in the range of 0.644-0.773, evidence that correlates with impact to GAMT function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 8304). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 16, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA254379/MONDO:0012999/026 2025-10-16 2025-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64310 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0860207 infores:hetionet CHEBI:18248 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0039070 infores:hetionet CHEBI:6030 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C1443060 infores:hetionet CHEBI:6904 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0232286 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020676 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1510472 infores:hetionet CHEBI:17474 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0020488 infores:hetionet CHEBI:9637 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0018099 infores:hetionet CHEBI:119915 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030232 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027769 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042109 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0041912 infores:hetionet CHEBI:23765 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0016867 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0518015 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0234215 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019348 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0026946 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0155003 infores:hetionet CHEBI:5050 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0016382 infores:hetionet CHEBI:63580 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0014591 infores:hetionet CHEBI:3242 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C3665347 infores:hetionet CAID:CA353680 biolink:causes MONDO:0007947 infores:clingen CAID:CA353680 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PM2_Supporting, PM1, PS4_Moderate PP3 The NM_00138 c.338C>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 113 (p. Ser113Cys) within an EGF-like domain of the protein. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (Internal data, PP4). This variant has been reported twice in ClinVar: once as likely pathogenic and once as uncertain significance (Variation ID: 222600). It has been reported in the literature in individuals with a clinical diagnosis or clinical features of Marfan syndrome (PMID 34281902, Invitae Clinvar entry, Blueprint Genetics ClinVar entry, internal data, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant protein function and structure (REVEL: 0.384). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM1, PM2_Sup, PP2, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA353680/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8869 biolink:causes UMLS:C0853023 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0853023 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151849 infores:hetionet CAID:CA2573157343 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157343 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+16A>G is an intronic variant which is not predicted to impact splicing and the nucleotide is not highly conserved (BP4, BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157343/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8404 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0161479 infores:hetionet CHEBI:3698 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0023218 infores:hetionet CAID:CA340922 biolink:causes MONDO:0044970 infores:clingen CAID:CA340922 MONDO:0044970 PMID:10371545PMID:14960712 Likely Pathogenic PP3, PS3_Moderate, PS4_Moderate PP1, PM6, PM2 The m.7511T>C variant in MT-TS1 has been reported in ten unrelated probands from ten kindreds of varying ethnic background with nonsyndromic sensorineural hearing loss (PS4_moderate; PMIDs: 10371545, 12461693, 15670746, 18340555, 26279247, 25968158, 28320335, 29257206). In these families, the variant is present in family members with and without hearing loss. Hearing loss was variable overall when present, ranging from mild to profound. Age of onset of hearing loss varied from childhood to adulthood. Hearing loss was stable in some individuals and progressive in others. Some individuals also reported tinnitus and vertigo. There has been no other organ system involvement reported to date (although it is not clear if other organ systems were assessed in affected individuals). Muscle biopsy was not routinely performed in affected individuals however one individual did have COX-deficient fibers and complex IV deficiency (PMID: 10371545). The variant was generally present at homoplasmy (in maternal family members with and without hearing loss), however there were some heteroplasmic occurrences (PMIDs: 10371545, 12461693, 15670746, 26279247, 29257206). Penetrance differed across reported families, and several modifying factors were discussed, including variants in the genes PCDH15 (PMID: 26279247) and YARS2 (PMID: 25968158). Affected and unaffected individuals in these families had the variant and there was no correlation between severity and heteroplasmy level, thus preventing consideration for PP1. There are no de novo occurrences of this variant reported to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (78.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Single fiber testing (PMID: 10371545) and cybrid analysis (PMID: 14960712) support the pathogenicity of this variant (PS3_moderate), as do other functional assays performed (PMIDs: 31685661, 16361254). This variant meets criteria to be classified as of uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340922/MONDO:0044970/015 2022-11-30 2023-01-10 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:9139 biolink:causes MONDO:0000499 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1852242 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0851341 infores:hetionet CHEBI:4672 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C2830004 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0232910 infores:hetionet NCBIGene:65217 biolink:causes MONDO:0010984 infores:monarchinitiative not_provided not_provided HGNC:14674 MONDO:0010984 uuid:d260d920-6b6b-4571-9f79-810efa6ef727 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15640 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0232498 infores:hetionet CHEBI:42820 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0004134 infores:hetionet CHEBI:10650 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2939147 infores:hetionet CHEBI:6715 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085593 infores:hetionet CHEBI:8364 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0041657 infores:hetionet CHEBI:82941 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0004364 infores:hetionet CHEBI:8356 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233471 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0001126 infores:hetionet CHEBI:584020 biolink:causes MONDO:0020674 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0232352 infores:hetionet CHEBI:4657 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0917801 infores:hetionet CHEBI:17650 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0039070 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0018799 infores:hetionet CHEBI:15544 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0019294 infores:hetionet CHEBI:44032 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0033774 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005940 infores:hetionet CHEBI:127342 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0858635 infores:hetionet CHEBI:3732 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C2047937 infores:hetionet NCBIGene:64374 biolink:causes MONDO:0009567 infores:monarchinitiative not_provided not_provided HGNC:24624 MONDO:0009567 uuid:2d0f5bec-5c10-43b3-b74e-61a572ce8e18 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134966 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0042963 infores:hetionet CHEBI:28915 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0011991 infores:hetionet CHEBI:50223 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0012833 infores:hetionet CHEBI:6717 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0043352 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0011609 infores:hetionet CHEBI:52172 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0027497 infores:hetionet CHEBI:8212 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0030312 infores:hetionet CHEBI:72564 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C2937358 infores:hetionet CHEBI:499361 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0036983 infores:hetionet CHEBI:63620 biolink:causes HP:0000072 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0521620 infores:hetionet NCBIGene:8139 biolink:causes MONDO:0009749 infores:monarchinitiative not_provided not_provided HGNC:4137 MONDO:0009749 uuid:2c668ec2-436d-4b86-81c9-7535ca98da0b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45979 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0015230 infores:hetionet CHEBI:102216 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0019521 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0948586 infores:hetionet CHEBI:9137 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020473 infores:hetionet NCBIGene:5649 biolink:causes MONDO:0009760 infores:monarchinitiative not_provided not_provided HGNC:9957 MONDO:0009760 uuid:e8a9cf71-ffca-4534-921d-943d091179d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235546 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0021141 infores:hetionet CHEBI:5118 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1510410 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042267 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042075 infores:hetionet UMLS:C0657912 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018800 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151705 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017160 infores:hetionet CHEBI:5801 biolink:causes HP:0000603 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0152191 infores:hetionet CAID:CA8328666 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328666 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting, BP4 BP7 NM_014336.5(AIPL1):c.96+7G>T is a nucleotide substitution in intron 1, at position +7 of the donor sequence. The splicing impact predictor SpliceAI gives a delta score of 0.08, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). BP7 has not been applied due to the variant's position at +7 of the donor sequence, which is an excluded position. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 6.196e-7, with 1 allele / 1614040 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP4 and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328666/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2955 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020625 infores:hetionet CAID:CA386972734 biolink:causes MONDO:0015967 infores:clingen CAID:CA386972734 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1624-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of information about when insulin was started, and HNF4A was not tested (internal lab contributors). In summary, c.1624-G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0 approved 8/11/2023): PVS1, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386972734/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6539 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0009676 infores:hetionet CHEBI:46195 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0877055 infores:hetionet CHEBI:168396 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C3263723 infores:hetionet NCBIGene:79651 biolink:causes MONDO:0007856 infores:monarchinitiative not_provided not_provided HGNC:20788 MONDO:0007856 uuid:5b66a9fb-ab9d-4ca7-859a-f067f03ee45b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0006277 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0740482 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0740482 infores:hetionet CHEBI:8502 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0019158 infores:hetionet CHEBI:180905 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0520887 infores:hetionet CHEBI:72323 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0042109 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0019158 infores:hetionet NCBIGene:9241 biolink:causes MONDO:0008521 infores:monarchinitiative not_provided not_provided HGNC:7866 MONDO:0008521 uuid:bb17c3e8-aa73-40a4-a296-166556ff794e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4495 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020649 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1269683 infores:hetionet CHEBI:194135 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0233407 infores:hetionet CHEBI:5004 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0085649 infores:hetionet CHEBI:6897 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0003467 infores:hetionet NCBIGene:9775 biolink:causes MONDO:0009998 infores:monarchinitiative not_provided not_provided HGNC:18683 MONDO:0009998 uuid:69c037e1-d323-47fe-9d27-6f6de33ce1ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0278134 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0017178 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0009450 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0034063 infores:hetionet NCBIGene:84839 biolink:causes MONDO:0012483 infores:monarchinitiative not_provided not_provided HGNC:18286 MONDO:0012483 uuid:ee8d26e8-a24f-4ae8-a871-575733c2d166 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0017152 infores:hetionet CHEBI:10101 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017672 infores:hetionet CHEBI:391960 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0041657 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0006014 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D002181 DB00196_MESH_D002181_1DB00259_MESH_D002181_1DB00639_MESH_D002181_1DB01007_MESH_D002181_1 CHEBI:4858 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C1443060 infores:hetionet CAID:CA410147847 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147847 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1181G>A (p.Gly394Asp) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.161) and a spliceAI score <0.2 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147847/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28445 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0027497 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0239295 infores:hetionet CAID:CA151833 biolink:causes MONDO:0015152 infores:clingen CAID:CA151833 MONDO:0015152 PMID: Benign BA1 PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP3, BP1, BP4, BP2 The NM_213599.3: c.616A>G variant in ANO5 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 206 (p.Thr206Ala). The filtering allele frequency of this variant is 0.02707 (the lower threshold of the 95% CI of 562/250584 African/African American chromosomes in gnomAD v2.1.1), which is higher than the ClinGen LGMD VCEP threshold (>0.003) for BA1 and therefore meets this criterion (BA1). At least one patient who displayed progressive weakness and a possible congenital myopathy has been reported to have this variant (PMID: 25891276); however, PP4 is not applied when BA1 is met. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA151833/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6640 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0014591 infores:hetionet CHEBI:8874 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042023 infores:hetionet CAID:CA293052 biolink:causes MONDO:0000572 infores:clingen CAID:CA293052 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The NM_000448.3:c.2638G>A variant in RAG1 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 880 (p.Glu880Lys). The filtering allele frequency (the lower threshold of the 95% CI of 3496/75044) of the c.2638G>A variant in RAG1 is 0.04730 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 84 homozygous adults are reported on gnomAD v.4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA293052/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8890 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0231835 infores:hetionet CHEBI:2453 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0237849 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0162830 infores:hetionet CHEBI:4888 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0700361 infores:hetionet CAID:CA414446711 biolink:causes MONDO:0010604 infores:clingen CAID:CA414446711 MONDO:0010604 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PM5, PP3 The c.1235G>C (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Alanine at amino acid 412 (p.Gly412Ala). This variant has been reported in at least 1 proband meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Supporting; PMID: 11013449). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.984, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PM5, PP3, PS4_Supporting, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414446711/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Inconclusive true CHEBI:59560 biolink:causes NCIT:C78280 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0221727 infores:hetionet CHEBI:3485 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0013384 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0003123 infores:hetionet CHEBI:9150 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0152025 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0855644 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0855644 infores:hetionet CHEBI:2636 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0812387 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042131 infores:hetionet CHEBI:9168 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0853034 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0041969 infores:hetionet CHEBI:83804 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0037763 infores:hetionet CHEBI:8426 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0015967 infores:hetionet CHEBI:32599 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0413252 infores:hetionet CAID:CA16020781 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020781 MONDO:0009861 PMID:26503515 Uncertain Significance PP4_Moderate, PM2, PP3 The c.379G>A (p.Glu127Lys) variant in PAH has been reported in a patient with PAH deficiency (BH4 deficiency excluded) (PP4_Moderate; PMID: 26503515) This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2 HVAR, MutationTaster, and REVEL=0.781. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020781/MONDO:0009861/006 2019-11-10 2019-11-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5778 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002874 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0013395 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151571 infores:hetionet CHEBI:92607 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0043049 infores:hetionet CAID:CA8815309 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815309 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 PP3, PP4, PM3 The NM_000152.5:c.1409A>C variant in GAA is a missense variant predicted to cause substitution of Asn by Thr at amino acid 470 (p.Asn470Thr). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0001068 (8/74918 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.468 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It has been reported in two cases identified as affected by newborn screening (PMID 23430949, 37087815). There is insufficient data to apply PP4. There is a ClinVar entry for this variant (Variation ID: 526525, 2 star review status) with 3 submitters classifying the variant as Uncertain significance. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815309/MONDO:0009290/010 2024-02-11 2024-02-11 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:7959 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0015967 infores:hetionet CHEBI:40009 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0033975 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0948586 infores:hetionet CAID:CA114151 biolink:causes MONDO:0015629 infores:clingen CAID:CA114151 MONDO:0015629 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS3, PS4_Moderate, PS2_Moderate PP3, BP4, PM5 The NM_000552.5(VWF):c.3940G>C (p.Val1314Leu) missense variant has been reported in at least 3 probands with VWD 2B phenotypes (PS4_moderate; PMIDs: 1419803, 27215777, ISTH 2015 Congress Poster). At least one proband displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and an increased response to LD-RIPA showing gain of function, which together are highly specific for VWD type 2B (PP4_moderate; PMID: 1419803). The variant was identified as a de novo occurrence in this patient (PS2_Moderate; PMIDs: 1419803). This variant is absent from gnomAD v4.1 (PM2_Supporting). A Platelet binding assay performed with the Val1314Leu recombinant mutant vWF expressed by COS-7 showed increased binding in the absence of, or at low doses, of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID: 8630394; PS3). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS4_moderate, PS2_Moderate, PP4_moderate, and PM2_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114151/MONDO:0015629/081 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8707 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027765 infores:hetionet CHEBI:10119 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0028084 infores:hetionet CHEBI:3175 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0005741 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0009450 infores:hetionet CHEBI:3061 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0016204 infores:hetionet CHEBI:36795 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0003467 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004096 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0006145 infores:hetionet CHEBI:3181 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0004093 infores:hetionet CHEBI:5855 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1368065 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1704202 infores:hetionet CHEBI:2704 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0019557 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0017152 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0038587 infores:hetionet CHEBI:17924 biolink:causes GO:0006970 infores:drugmechdb knowledge_assertion manual_agent MESH:D013012 GO:0006970 DB02383_MESH_D048909_1 CHEBI:50885 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0034150 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038663 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034069 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017152 infores:hetionet CHEBI:64198 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0423153 infores:hetionet CAID:CA7176917 biolink:causes MONDO:0021060 infores:clingen CAID:CA7176917 MONDO:0021060 PMID: Uncertain Significance BP4 BA1, BS1, PM2 The c.2957G>A (NM_006939.4(SOS2):c.2957G>A (p.Arg986Lys)) variant in SOS2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 986. The highest MAF in gnomAD v2.1.1 is 0.004629 % in the African/African American population (no population codes met). The computational predictor REVEL gives a score of 0.051, which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7176917/MONDO:0021060/042 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6775 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151849 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005181 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162292 infores:hetionet CHEBI:16914 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0232487 infores:hetionet CHEBI:3380 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C2981158 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0281982 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0281982 infores:hetionet CHEBI:75922 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0043352 infores:hetionet UNII:DJJ95FJP1H biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0520893 infores:hetionet UNII:T58MSI464G biolink:causes UMLS:C0032320 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0032320 infores:hetionet CHEBI:8378 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0858617 infores:hetionet CHEBI:6897 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0234215 infores:hetionet CHEBI:47898 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0015672 infores:hetionet NCBIGene:2898 biolink:causes MONDO:0859201 infores:monarchinitiative not_provided not_provided HGNC:4580 MONDO:0859201 uuid:c9c81ea1-d7ce-47ad-bfba-993e8e75bc5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0012359 infores:hetionet CHEBI:6958 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0031542 infores:hetionet CHEBI:68606 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0234458 infores:hetionet CHEBI:49375 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018681 infores:hetionet CHEBI:6541 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0013404 infores:hetionet CAID:CA294544 biolink:causes MONDO:0010726 infores:clingen CAID:CA294544 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, PM1, PP3, BS2 PM6, PP4 The p.Arg115Cys (NM_004992.4) in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome; however, this individual was also heterozygous for a de novo truncating variant in MECP2 (PMID 18652533). The p.Arg115Cys variant (NM_004992.4) occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg115Cys variant (NM_004992.4) in MECP2 is absent from gnomAD (PM2_supporting). The p.Arg115Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (internal databases) (BS2). In summary, the p.Arg115Cys variant in MECP2 (NM_004992.4) is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294544/MONDO:0010726/036 2023-08-28 2023-09-15 X-linked inheritance HP:0001417 Inconclusive true CHEBI:27504 biolink:causes UMLS:C0919590 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0919590 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0001824 infores:hetionet CAID:CA270037 biolink:causes MONDO:0100437 infores:clingen CAID:CA270037 MONDO:0100437 PMID:32958805 Likely Pathogenic PP1_Moderate, PP4, PM2_Supporting, PP3_Moderate PS4, PS3 NM_001034853.2(RPGR):c.922G>C (p.Ala308Pro) is a missense variant encoding substitution of alanine with proline at amino acid 308. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.904, which is between the ClinGen X-linked IRD VCEP thresholds of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. At least one proband harboring this variant exhibits a phenotype including early onset (1 pt) of night blindness (0.5 pts), decreased central visual acuity (0.5 pts), visual field constriction (0.5 pts), family history consistent with X-linked inheritance (2 pts), delayed or milder phenotype in females (1 pt), and next-generation sequencing-based genotyping identifying no alternative causes of retinal disease (2 pts), which together are specific for RPGR-related retinopathy (7.5 pts, PP4, PMID: 25324289). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1; PMID: 26316687, PMID: 25324289). The variant has been included in multiple publications (PMIDs: 25324289, 26316687, and 26427425), however these have reported the same family, so PS4_Supporting was not met. In summary, this variant meets the criteria to be classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PP1_moderate, PP3_moderate, and PP4_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA270037/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:28748 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009421 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0278008 infores:hetionet CHEBI:7798 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0002962 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233472 infores:hetionet CHEBI:9570 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0080274 infores:hetionet CHEBI:3181 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0005747 infores:hetionet CAID:CA023485 biolink:causes MONDO:0007750 infores:clingen CAID:CA023485 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BS3 The NM_000527.5(LDLR):c.1402G>A (p.Val468Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001146 (0.012%) in non-Finnish European exomes/genomes (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in at least 1 index case (Robarts Research Institute - 1 index case w/ DLCN>=6), after alternative causes of high cholesterol have been excluded.BP4 - REVEL = 0.239. It is below 0.50. splicing evaluation required. Functional data not availableA) not on limitsB) does not create AGVariant is not predicted to alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023485/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UMLS:C0005740 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0027051 infores:hetionet CHEBI:474053 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0015672 infores:hetionet CHEBI:6950 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0015371 infores:hetionet CL:0000185 biolink:causes MONDO:0002380 infores:ubergraph knowledge_assertion manual_agent CL:0000185 MONDO:0002380 CHEBI:2704 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0549399 infores:hetionet CHEBI:17347 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0004509 infores:hetionet CHEBI:209807 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0011603 infores:hetionet UMLS:C0065374 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0041834 infores:hetionet CHEBI:28748 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038325 infores:hetionet CAID:CA412725852 biolink:causes MONDO:0100437 infores:clingen CAID:CA412725852 MONDO:0100437 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PM4_Strong PS4 NM_001034853.2(RPGR):c.3458A>C (p.Ter1153Ser) is a stop-loss variant that disrupts the stop codon at the end of exon 15 and is predicted to result in extension of the RPGR C-terminus by 38 additional amino acids before the occurrence of the next stop codon (PM4_strong). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). Another variant in the same codon, NM_001034853.2:c.3458A>C (p.Ter1153Serext*38), has previously been classified as likely pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP. Both variants are predicted to extend the C-terminus of RPGR by 38 residues in the same frame, however, they replace the start codon with serine and lysine, respectively (PM5_supporting). At least one proband harboring this variant has a diagnosis of cone dystrophy and exhibits the reduced scotopic and photopic electroretinogram responses required for inclusion in the PS4 code (PMID: 29555955), however, PS4_supporting requires at least 2 probands and therefore is not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM4_strong, PM5_supporting, and PM2_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412725852/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Supports CHEBI:3061 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0009806 infores:hetionet NCBIGene:7414 biolink:causes MONDO:0012667 infores:monarchinitiative not_provided not_provided HGNC:12665 MONDO:0012667 uuid:022282b8-b434-4606-9115-32ce1719b940 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0009934 biolink:causes GO:0048507 infores:ubergraph knowledge_assertion manual_agent GO:0009934 GO:0048507 CHEBI:35677 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0017178 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005657 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004030 infores:hetionet CHEBI:23765 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0030554 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151763 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020651 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151773 infores:hetionet CHEBI:10101 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0232462 infores:hetionet CHEBI:35854 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0852911 infores:hetionet CHEBI:3286 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0040460 infores:hetionet CHEBI:36791 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232292 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0006266 infores:hetionet CHEBI:3387 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0023518 infores:hetionet CHEBI:119915 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0033774 infores:hetionet CHEBI:68478 biolink:causes HP:0200123 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019189 infores:hetionet GO:0060800 biolink:causes GO:0001890 infores:ubergraph knowledge_assertion manual_agent GO:0060800 GO:0001890 CHEBI:9137 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235431 infores:hetionet CHEBI:4356 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0014457 infores:hetionet CHEBI:50841 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0235660 infores:hetionet CHEBI:6128 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0018418 infores:hetionet CHEBI:50156 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C2129214 infores:hetionet NCBIGene:5395 biolink:causes MONDO:0013699 infores:monarchinitiative not_provided not_provided HGNC:9122 MONDO:0013699 uuid:23b0d3ee-6068-4af0-bda8-16ee2d603154 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0392676 infores:hetionet CHEBI:9943 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0149745 infores:hetionet CHEBI:31401 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151766 infores:hetionet CHEBI:6904 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C2363731 infores:hetionet CHEBI:6775 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085641 infores:hetionet CHEBI:68558 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0004604 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0019054 infores:hetionet CHEBI:135961 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0042029 infores:hetionet CHEBI:15544 biolink:causes UMLS:C2938972 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2938972 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0041912 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0002871 infores:hetionet CHEBI:6128 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0030305 infores:hetionet CHEBI:6541 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0035455 infores:hetionet UMLS:C0004609 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0700590 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0040034 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0341439 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0341439 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0020651 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0014130 infores:hetionet CHEBI:68579 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0002792 infores:hetionet CHEBI:7496 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0029118 infores:hetionet CAID:CA000018 biolink:causes MONDO:0018875 infores:clingen CAID:CA000018 MONDO:0018875 PMID: Likely Benign BP4, BS3, BS2_Supporting, PS4_Supporting BA1, PS1, PS3, PS2, PM1, BS1, BS4, PM2, PP3, PP1, PP4 The NM_000546.6: c.1015G>C variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by glutamine at amino acid 339 (p.Glu339Gln). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been observed in 2 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Ambry lab). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3, BP4. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000018/MONDO:0018875/009 2024-09-06 2024-09-06 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:84883 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0030305 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006277 infores:hetionet CHEBI:2704 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0002170 infores:hetionet CHEBI:168396 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C3160741 infores:hetionet CAID:CA414447216 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447216 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3 PM1 The F9 c.1303T>G; p.Cys435Gly variant is completely absent from gnomAD v2.1.1 and v3.1.1. This missense variant has a REVEL score of 0.964 and meets PP3 criteria (threshold >0.6). One proband is reported in the literature with moderate hemophilia B and this variant and a second proband was reported with severe hemophilia B, meeting F9 phenotype criteria for PS4_Moderate. Cys35Tyr is another pathogenic variant at the same residue (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Moderate, PM5, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447216/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Supports NCBIGene:5281 biolink:causes MONDO:0859161 infores:monarchinitiative not_provided not_provided HGNC:8962 MONDO:0859161 uuid:94820c27-a963-4158-a78f-4d9a51717aa4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0003467 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0040034 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0542184 infores:hetionet CHEBI:100241 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0392699 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0042109 infores:hetionet GO:0061453 biolink:causes CL:0002088 infores:ubergraph knowledge_assertion manual_agent GO:0061453 CL:0002088 CHEBI:3219 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0025320 infores:hetionet NCBIGene:9200 biolink:causes MONDO:0859264 infores:monarchinitiative not_provided not_provided HGNC:9639 MONDO:0859264 uuid:b87ecdb9-5da6-4afd-9e75-f3d07b4c806f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1510497 infores:hetionet CHEBI:36704 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0003862 infores:hetionet CHEBI:8107 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020453 infores:hetionet NCBIGene:118491 biolink:causes MONDO:0032863 infores:monarchinitiative not_provided not_provided HGNC:30726 MONDO:0032863 uuid:c19267fc-9baa-4596-b0a8-14515bf2fb75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:209807 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0002994 infores:hetionet CHEBI:100246 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0233407 infores:hetionet CHEBI:49040 biolink:causes MONDO:0007750 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0745103 infores:hetionet CAID:CA16615930 biolink:causes MONDO:0018875 infores:clingen CAID:CA16615930 MONDO:0018875 PMID:12826609PMID:30224644 Benign BP4, BS2_Supporting, BS3 BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, PP3, PP1, PP4 The NM_000546.6: c.1151T>C variant in TP53 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 384 (p.Met384Thr). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.121169; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.0; 1/15/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615930/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135888 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0027765 infores:hetionet CHEBI:15940 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151942 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0021390 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0011428 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0011428 uuid:d6f640fb-ede1-4782-a652-43b2736cdcae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8815886 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815886 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM3_Very Strong, PM2_Supporting, PVS1_Moderate The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate). At least 10 probands with this variant who have been diagnosed with Pompe disease have been described including 4 probands for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (PMID: 37542277, https://doi.org/10.3390/metabo11070446). Two of these probands and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate). Patients reported with this variant include compound heterozygotes for the variant and another pathogenic/likely pathogenic variant in GAA, phase unknown, including for c.118C>T (p.Arg40Ter) (ClinVar SCV001371737.1) (PMID 24269976, 0.5 points), c.1935C>A (p.Asp645Glu) (ClinVar SCV002032138.1) (PMIDs 22538254, 28394184, 32373469, at least two patients, 2 x 0.5 points), c.2238G>C (p.Trp746Cys) (ClinVar SCV002032122.1) (PMIDs: 25316892, 34647686, 0.5 points), c.1082C>T (p.Pro361Leu) (ClinVar SCV002540670.1) (PMID: 37542277, 0.5 points), and c.1843G>A (p.Gly615Arg) (ClinVar SCV002583372.1) (PMID: 37542277, 0.25 points) and c.2585delG (PMID 28394184, 0.25 points); and confirmed in trans with c.2238G>C (p.Trp746Cys) https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf, 1 point). Total 4 points for PM3 (PM3_VeryStrong). Another patient has been reported as compound heterozygous for the variant and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from this patient will be used for the assessment of p.Arg89Leu and is not included here in order to avoid circular logic. For another patient described with Pompe disease and the variant, a second variant was not identified (PMID 10338092). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 (3/18388; no homozygotes), and in gnomAD v4.1.0. it is 0.00006684 (3/44884; no homozygotes) in the East Asian population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371481). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PM3_VeryStrong, PVS1_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815886/MONDO:0009290/010 2024-11-22 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9599 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0242461 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0018939 infores:hetionet CHEBI:6472 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0025160 infores:hetionet CHEBI:9720 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0009676 infores:hetionet CHEBI:5130 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013144 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0853777 infores:hetionet CHEBI:63605 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0042963 infores:hetionet CHEBI:10101 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0004134 infores:hetionet CHEBI:9086 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C2937350 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0031099 infores:hetionet CHEBI:41423 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C2937358 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0036572 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0858678 infores:hetionet NCBIGene:10845 biolink:causes MONDO:0060729 infores:monarchinitiative not_provided not_provided HGNC:2088 MONDO:0060729 uuid:dc01c41c-a43b-4c6f-ba01-d98c9467017b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3515 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0239113 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0027765 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0005940 infores:hetionet CHEBI:4653 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0008031 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020538 infores:hetionet CHEBI:6339 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040460 infores:hetionet CHEBI:8435 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0014457 infores:hetionet CHEBI:6792 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0002792 infores:hetionet CHEBI:5130 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0030554 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0009450 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0009763 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0004936 infores:hetionet CHEBI:15552 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0015967 infores:hetionet CHEBI:31348 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0030554 infores:hetionet CAID:CA229450 biolink:causes MONDO:0009861 infores:clingen CAID:CA229450 MONDO:0009861 PMID: Likely Pathogenic PM4, PM3, PM2, PP4 BP3 This c.163_165del (p.Phe55del) variant in PAH was detected in trans with the c.168+5G>C and p.Phe39Leu pathogenic variants in multiple individuals with PKU (PMID:28676969, 17513426). This variant is absent in population databases. This in-frame variant is not found in a repetitive region and does not cause a stop-loss. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PM4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229450/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5280 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0404521 infores:hetionet CHEBI:8707 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0003862 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0029878 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0152198 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005020 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0021831 infores:hetionet CHEBI:7640 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0017574 infores:hetionet CAID:CA16020801 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020801 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4_Moderate, PM3_Supporting The c.498C>G (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay. It has been reported in multiple individuals, including in homozygosity in a classic PKU patient in the Uyger population. (PM3, PP4, PMID:31355225). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020801/MONDO:0009861/006 2022-01-22 2022-06-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:40303 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0014518 infores:hetionet CHEBI:490877 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0235031 infores:hetionet CHEBI:6775 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0039070 infores:hetionet NCBIGene:146183 biolink:causes MONDO:0011762 infores:monarchinitiative not_provided not_provided HGNC:16378 MONDO:0011762 uuid:93a9c5c9-07f4-4bf0-a8ef-ce5b92606144 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0270458 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0541832 infores:hetionet GO:1904933 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:1904933 GO:0007417 CHEBI:83804 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C2225524 infores:hetionet CHEBI:63717 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0015672 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235876 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151744 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036454 infores:hetionet NCBIGene:144165 biolink:causes MONDO:0012904 infores:monarchinitiative not_provided not_provided HGNC:17019 MONDO:0012904 uuid:57a421d9-78ad-4327-b242-e5aeebf9126e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0019080 infores:hetionet CHEBI:101278 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0031256 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0025061 infores:hetionet CAID:CA229632 biolink:causes MONDO:0009861 infores:clingen CAID:CA229632 MONDO:0009861 PMID:26666653 Pathogenic PVS1, PM2, PP4, PM3_Supporting The c.578_579del PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Leu348Val (ClinVar 92727). This variant is absent from 1000G, ESP, and gnomAD databases. This variant leads to the frameshift Leu194GlufsTer5, creating a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229632/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:747 biolink:causes MONDO:0008206 infores:monarchinitiative not_provided not_provided HGNC:1165 MONDO:0008206 uuid:e1f50bbe-fa70-4af9-9f97-5de7e44bbbf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA010249 biolink:causes MONDO:0005045 infores:clingen CAID:CA010249 MONDO:0005045 PMID: Benign BA1 NM_000256.3(MYBPC3):c.13G>C (p.Gly5Arg) - This variant has been identified in 0.00102 FAF (1,251/1,171,934) of Non-Finnish European chromosomes by gnomAD v4.1.0 (http://gnomad.broadinstitute.org). In summary, this variant is classified as benign based on BA1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010249/MONDO:0005045/095 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17303 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026837 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0041912 infores:hetionet CHEBI:17334 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0030232 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0020557 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0000737 infores:hetionet CHEBI:91583 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0015967 infores:hetionet CHEBI:8461 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0241442 infores:hetionet CHEBI:10125 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085593 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0008170 uuid:fd2be6b5-be8b-45e8-9e01-b59b5df04c62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0009421 infores:hetionet CHEBI:5001 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151636 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0152227 infores:hetionet UMLS:C0005740 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0030193 infores:hetionet CAID:CA2582121298 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582121298 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.1318dup variant in SLC6A8 is frameshift variant predicted to cause a premature stop codon in biologically relevant exon 9/13 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (p.Arg440ProfsTer25) (PVS1). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582121298/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:47780 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013144 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0178298 infores:hetionet CHEBI:6912 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0011991 infores:hetionet NCBIGene:23400 biolink:causes MONDO:0014975 infores:monarchinitiative not_provided not_provided HGNC:30213 MONDO:0014975 uuid:62d8e896-d8ed-4637-91a3-5ebabd087c43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:472657 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0038826 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004623 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151736 infores:hetionet CHEBI:36791 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235437 infores:hetionet CHEBI:3181 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0035357 infores:hetionet CAID:CA410203798 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203798 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.253C>T (p.His85Tyr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203798/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151594 infores:hetionet CHEBI:3732 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0232462 infores:hetionet CHEBI:31524 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0039070 infores:hetionet CAID:CA10014628 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014628 MONDO:0011071 PMID: Uncertain Significance PS4_Moderate PS3, PS1, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.97+1G>A is a splice donor variant which is only predicted to affect isoform c. This variant is present in three alleles (European Non-Finnish), 0.002656% in gnomAD v2.1.1, and is absent in gnomAD v3.1.2 (mean depth coverage 30x). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 33075818). In summary, this variant meets the criteria to be classified as a variant of unknown significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_Moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014628/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41977 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0036572 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0037199 infores:hetionet CHEBI:66901 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0687713 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0013395 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0013295 infores:hetionet CAID:CA240817 biolink:causes MONDO:0100453 infores:clingen CAID:CA240817 MONDO:0100453 PMID: Likely Benign BP4, BS1 The NM_000180.4(GUCY2D):c.3098C>T (p.Ser1033Leu) variant is predicted to replace the serine at position p.1033 with leucine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.003423, with 284 alleles / 75032 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1). The computational predictor REVEL gives a score of 0.203, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA240817/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63638 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0002871 infores:hetionet CHEBI:50922 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0235710 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0006266 infores:hetionet CHEBI:4995 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0855775 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0018799 infores:hetionet CAID:CA10606720 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606720 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.1517C>G p.(Ser506Ter) variant in DYSF is also known as NM_001130987.2: c.1577-1655C>G. While this variant is intronic in the canonical transcript, it introduces a stop codon in the transcript expressed in skeletal muscle and is predicted to cause a premature stop codon in biologically relevant exon 17/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in one individual with suspected LGMD, where it was reported in unconfirmed phase with a pathogenic variant (NM_003494.4: c.4408C>T p.(Gln1470Ter), 0.5 pts, PMID: 36983702; PM3_Supporting). This individual displayed slowly progressive lower extremity and hand muscle weakness and had absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong). Dysferlin expression by blood monocyte assay was out of the disease range, but the dominant dysferlin isoform in the blood naturally skips exon 17, the location of this variant, allowing for expression of dysferlin in the blood. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/30/2025): PVS1, PM3_Supporting, PM2_Supporting, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606720/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28445 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0235032 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151849 infores:hetionet CHEBI:110423 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0151578 infores:hetionet CHEBI:8093 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0003811 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0004936 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027651 infores:hetionet CHEBI:45367 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0015967 infores:hetionet CHEBI:63115 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0428977 infores:hetionet CHEBI:6061 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042029 infores:hetionet CHEBI:31524 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0042029 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0849918 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0008310 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0008310 uuid:02cdc3ca-4a14-43c6-88b2-e87dc03cf401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135342 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042373 infores:hetionet NCBIGene:1584 biolink:causes MONDO:0007080 infores:monarchinitiative not_provided not_provided HGNC:2591 MONDO:0007080 uuid:b3a8c1ae-98e5-4072-887b-755653554b5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1412 biolink:causes MONDO:0007283 infores:monarchinitiative not_provided not_provided HGNC:2395 MONDO:0007283 uuid:4956f3a0-a0a6-4765-b8db-7f05935c5065 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0009763 infores:hetionet CHEBI:39867 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151315 infores:hetionet CHEBI:6375 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2363731 infores:hetionet CHEBI:46081 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0016382 infores:hetionet CHEBI:8707 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011071 infores:hetionet CHEBI:8435 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0235270 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0010709 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0948594 infores:hetionet CHEBI:34385 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0858635 infores:hetionet CHEBI:5118 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038325 infores:hetionet CHEBI:8707 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020625 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0017160 infores:hetionet CHEBI:41774 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0162566 infores:hetionet CHEBI:68478 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860864 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0232492 infores:hetionet CHEBI:68610 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0853692 infores:hetionet CHEBI:28939 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0010200 infores:hetionet CHEBI:8214 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0040264 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0340464 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020651 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0857370 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0857370 infores:hetionet CHEBI:102216 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0600228 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0234458 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0036572 infores:hetionet CHEBI:9352 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0011606 infores:hetionet NCBIGene:6928 biolink:causes MONDO:0007669 infores:monarchinitiative not_provided not_provided HGNC:11630 MONDO:0007669 uuid:f4b527da-7dc8-487a-ae31-7e49e5c8bed2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0031350 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0150077 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0150077 infores:hetionet CHEBI:4708 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0080274 infores:hetionet CHEBI:8874 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0233471 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0038363 infores:hetionet CHEBI:7577 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0002622 infores:hetionet CHEBI:6741 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0002994 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0002871 infores:hetionet CHEBI:71940 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0002622 infores:hetionet CHEBI:3077 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0013491 infores:hetionet CHEBI:63638 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0018681 infores:hetionet CHEBI:4562 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0242172 infores:hetionet CHEBI:3312 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0003123 infores:hetionet CHEBI:135686 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0002871 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0011991 infores:hetionet CHEBI:7936 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020429 infores:hetionet CHEBI:16755 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C1458155 infores:hetionet CHEBI:23765 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0040264 infores:hetionet CHEBI:6950 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0043352 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0549209 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0017178 infores:hetionet CHEBI:45863 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0035243 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006852 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0342579 infores:hetionet NCBIGene:1589 biolink:causes MONDO:0008728 infores:monarchinitiative not_provided not_provided HGNC:2600 MONDO:0008728 uuid:c5d4611b-cb72-4ee7-84bb-8003ad8f6fc7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0149871 infores:hetionet CHEBI:77260 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014591 infores:hetionet CAID:CA376065915 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065915 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.53G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Histidine at amino acid 18 (p.Arg18His).The filtering allele frequency (the upper threshold of the 95% CI of 2/761900 alleles) of the c.53G>A variant in DCLRE1C is 0.00000044 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1c-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065915/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3485 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0030920 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0020538 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0003123 infores:hetionet CHEBI:5106 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0038362 infores:hetionet CHEBI:8107 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0340865 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0011991 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009450 infores:hetionet GO:0043363 biolink:causes CL:0000562 infores:ubergraph knowledge_assertion manual_agent GO:0043363 CL:0000562 CHEBI:480999 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0231218 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0031046 infores:hetionet GO:2001109 biolink:causes GO:0002088 infores:ubergraph knowledge_assertion manual_agent GO:2001109 GO:0002088 CHEBI:474053 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0007971 infores:hetionet CHEBI:63791 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004604 infores:hetionet CHEBI:31401 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151701 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0026946 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0239978 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0162429 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027051 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037199 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0006277 infores:hetionet CHEBI:4779 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0014236 infores:hetionet CHEBI:135961 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0042023 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030312 infores:hetionet CAID:CA1563284 biolink:causes MONDO:0019497 infores:clingen CAID:CA1563284 MONDO:0019497 PMID: Likely Benign BS1 PP3, BP4, BA1 The filtering allele frequency (the lower threshold of the 95% CI of 128/24484) of the c.4091G>T (p.Gly1364Val) variant in the OTOF gene is 0.449% for African/African-American chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1563284/MONDO:0019497/005 2022-05-13 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:4858 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0013404 infores:hetionet CHEBI:31236 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235996 infores:hetionet CHEBI:50924 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0011175 infores:hetionet NCBIGene:81858 biolink:causes MONDO:0968982 infores:monarchinitiative not_provided not_provided HGNC:25321 MONDO:0968982 uuid:8a8dc2c3-ddf5-4a5f-9540-cdf4fe166961 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7931 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C1260880 infores:hetionet CHEBI:2675 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0014457 infores:hetionet CHEBI:3504 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0023530 infores:hetionet CHEBI:6532 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0020517 infores:hetionet CHEBI:9570 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0231528 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0278080 infores:hetionet CHEBI:127780 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0687713 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151698 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0027497 infores:hetionet CHEBI:65346 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0236072 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0858765 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0858765 infores:hetionet CHEBI:63632 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0040034 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0013395 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0392176 infores:hetionet CHEBI:119486 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1456784 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042373 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020433 infores:hetionet CHEBI:5132 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0011603 infores:hetionet UNII:7F465U79Q1 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0042487 infores:hetionet CHEBI:5893 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020580 infores:hetionet CHEBI:421707 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0038362 infores:hetionet CHEBI:63627 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0004134 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0409974 infores:hetionet CHEBI:4562 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0019521 infores:hetionet UBERON:0004645 biolink:causes MONDO:0005605 infores:ubergraph knowledge_assertion manual_agent UBERON:0004645 MONDO:0005605 CHEBI:465284 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002874 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011570 infores:hetionet CHEBI:171719 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C3665347 infores:hetionet CHEBI:63613 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0002792 infores:hetionet UMLS:C0005740 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0854467 infores:hetionet CHEBI:3636 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0085612 infores:hetionet UMLS:C0005740 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0234909 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0027051 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853697 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0344315 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005693 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0392548 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0857121 infores:hetionet NCBIGene:9785 biolink:causes MONDO:0032604 infores:monarchinitiative not_provided not_provided HGNC:17211 MONDO:0032604 uuid:cc6d95fb-b5a0-4def-96da-c51f98cf6a03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0028961 infores:hetionet CHEBI:2469 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0037274 infores:hetionet CHEBI:7478 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0015672 infores:hetionet CAID:CA512341298 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341298 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, BP1, BP3, BP2, BA1, PM2, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1116C>T (p.Gly372=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341298/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50381 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0011991 infores:hetionet CHEBI:6128 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0003467 infores:hetionet CHEBI:7822 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0025289 infores:hetionet GO:0006954 biolink:causes MONDO:0004822 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D001987 DB00901_MESH_D001987_1 CAID:CA10014178 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014178 MONDO:0011071 PMID:27106701 Benign BP4, BP2, BA1, BP7 PS1, PS3, PS2, PS4, BP1, BP3, PVS1, PM6, PM2, BP5, BS3, BS4, BS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) is a synonymous variant which has a minor allele frequency of 0.1206 (1976/16382 alleles) in the African subpopulation of the gnomAD cohort, meeting the threshold for BA1. It is detected in a homozygous state in 202 individuals in gnomAD (BP2). Splicing predictors SSF and MES indicate no significant impact on the canonical splice site, and no cryptic splice sites are created (BP4). Evolutionary conservation algorithms predict the site as not being conserved (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014178/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA024535 biolink:causes MONDO:0012933 infores:clingen CAID:CA024535 MONDO:0012933 PMID: Benign BP5, BS3, BP7_Strong, BS1_Supporting, BP4 The c.68-7del variant is an intronic variant occurring in intron 2 of the BRCA2 gene. The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00002293 in the Latino/Admixed American population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.04 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMIDs: 10534775, 21673748, 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 35979650) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.32 (based on Pathology LR=0.32), within the thresholds for Supporting benign evidence (LR 0.23-0.48) (BP5 met; PMID: 35979650).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP4, BP7_Strong (RNA), BS3, BP5). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA024535/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31705 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0027497 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0518015 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0270458 infores:hetionet CHEBI:63620 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0009782 infores:hetionet CHEBI:52717 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235896 infores:hetionet CHEBI:51380 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0038325 infores:hetionet CAID:CA16620648 biolink:causes MONDO:0009290 infores:clingen CAID:CA16620648 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.2061del (p.Phe687LeufsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 423932). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620648/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31236 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0947999 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027726 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002622 infores:hetionet NCBIGene:640 biolink:causes MONDO:0013242 infores:monarchinitiative not_provided not_provided HGNC:1057 MONDO:0013242 uuid:2c39c81f-cf6f-48e1-ac22-baa1b1baa435 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:267010 biolink:causes MONDO:0859360 infores:monarchinitiative not_provided not_provided HGNC:19380 MONDO:0859360 uuid:9144c6c5-b275-4931-b00b-b7ab2a3edc28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027769 infores:hetionet CHEBI:46345 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0234909 infores:hetionet CHEBI:30830 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0043352 infores:hetionet CHEBI:2668 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0030252 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0042075 infores:hetionet CHEBI:6775 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235996 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0236068 infores:hetionet CHEBI:10110 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0018965 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020456 infores:hetionet NCBIGene:5339 biolink:causes MONDO:0014661 infores:monarchinitiative not_provided not_provided HGNC:9069 MONDO:0014661 uuid:eee05d25-006e-46c2-9f14-80f83affa580 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3738 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0012833 infores:hetionet CHEBI:9674 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0038362 infores:hetionet CHEBI:8228 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0004093 infores:hetionet CHEBI:27432 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0042963 infores:hetionet CHEBI:85161 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0017178 infores:hetionet GO:0006954 biolink:causes MONDO:0020283 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D014605 DB00253_MESH_D014605_1DB00896_MESH_D014605_1 NCBIGene:64601 biolink:causes MONDO:0025691 infores:monarchinitiative not_provided not_provided HGNC:14584 MONDO:0025691 uuid:4614208a-2ba4-4bbd-958a-d5edbc6b1af1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042075 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0233494 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0033777 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0033777 infores:hetionet NCBIGene:1326 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:6860 MONDO:0008903 uuid:2047e2a4-d25e-4c87-9b3b-05283eaaea56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0018799 infores:hetionet CHEBI:7936 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0001807 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0027765 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151904 infores:hetionet CHEBI:44423 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0237938 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0855242 infores:hetionet CHEBI:6754 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0547030 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002871 infores:hetionet CHEBI:2682 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0021368 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020456 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0009450 infores:hetionet CHEBI:7798 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0085605 infores:hetionet CHEBI:9727 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0004093 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020517 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0005779 infores:hetionet CAID:CA2499225880 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225880 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-5A>G is an intronic variant which is not predicted to affect gene splicing. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (gnomAD v2.1.1 and v3). This variant has not been reported in an individual meeting at least one of the RUNX1-phenotypic criteria. Multiple lines of computational evidence suggest no impact on the gene/gene product (BP4, SpliceAI ≤ 0.20). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225880/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2950 biolink:causes UMLS:C1112369 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C1112369 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0025362 infores:hetionet CHEBI:6933 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0042373 infores:hetionet CHEBI:134991 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0522055 infores:hetionet CHEBI:17688 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1145670 infores:hetionet CHEBI:681569 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0018926 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0595877 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0178298 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0851578 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0521490 infores:hetionet CHEBI:135925 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0018681 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0851341 infores:hetionet CHEBI:6690 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0030252 infores:hetionet CHEBI:73274 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C1112214 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0877046 infores:hetionet NCBIGene:8815 biolink:causes MONDO:0013523 infores:monarchinitiative not_provided not_provided HGNC:17397 MONDO:0013523 uuid:9f09083a-c390-45dd-b79c-483d9adb3d52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0851341 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013395 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0017178 infores:hetionet CHEBI:7025 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0042109 infores:hetionet CHEBI:17474 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0235660 infores:hetionet CHEBI:3347 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0002994 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0392171 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C1761613 infores:hetionet CHEBI:31980 biolink:causes HP:0032310 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C1282609 infores:hetionet CHEBI:64064 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0011991 infores:hetionet CHEBI:9086 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0344232 infores:hetionet NCBIGene:83861 biolink:causes MONDO:0014657 infores:monarchinitiative not_provided not_provided HGNC:21054 MONDO:0014657 uuid:f9aba47e-6a51-4263-b766-e3c9881830ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3175 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1519353 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0795692 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037315 infores:hetionet CAID:CA412733107 biolink:causes MONDO:0100437 infores:clingen CAID:CA412733107 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PP3, PP1, PS3, PS4 NM_001034853.2(RPGR):c.1754-3C>G is an intron 14 variant located 3 nucleotides from exon 15. The splicing impact predictor SpliceAI gives a score of 0.37 for acceptor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, while cells transected with the variant intron showed almost no mCherry signal relative to the wild-type intron control, indicating severely defective splicing (PMID: 36276946). The PP3 and PS3_Supporting codes were not met as the evidence has been combined to meet PVS1 instead (PVS1_RNA). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), optic disc pallor (0.5 pts), pigment deposits (0.5 pts), markedly reduced rod electroretinogram responses (1 pt), and genotyping by a next-generation sequencing panel of 483 genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (6 points, PP4). The variant has been reported to segregate with retinal dystrophy through at least 2 meioses from 1 family (PMID: 36276946), however, the PP1 code is not met as the carrier mother is unaffected. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412733107/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:135451 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0031542 infores:hetionet CAID:CA10568332 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568332 MONDO:0010602 PMID: Benign BA1 PS4 The c.2383A>G (p.Arg795Gly) variant has a Grpmax frequency of 0.004164 in exomes in v2.1.1 and MAF = 0.004124 in v3.1.2, meeting BA1 (>=0.000333). This variant is classified as benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568332/MONDO:0010602/071 2025-10-03 2025-10-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:45783 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0015967 infores:hetionet CHEBI:50131 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013604 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0234913 infores:hetionet CHEBI:3732 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013447 infores:hetionet CHEBI:135929 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0178298 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0948089 infores:hetionet CHEBI:8874 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0021368 infores:hetionet CAID:CA512318662 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318662 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.670C>A (p.Arg224=) is a synonymous variant. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318662/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:474180 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0042384 infores:hetionet CHEBI:5384 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0086565 infores:hetionet CHEBI:31547 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0015230 infores:hetionet CHEBI:35677 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0585186 infores:hetionet NCBIGene:5336 biolink:causes MONDO:0013944 infores:monarchinitiative not_provided not_provided HGNC:9066 MONDO:0013944 uuid:d187e6c5-5b5e-4a61-89cd-8dce326b59c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0235416 infores:hetionet CHEBI:7823 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0011609 infores:hetionet CHEBI:6078 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C2363730 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020649 infores:hetionet CHEBI:63618 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0030193 infores:hetionet CHEBI:9352 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C3665347 infores:hetionet CHEBI:119573 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0015672 infores:hetionet CHEBI:9241 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0242350 infores:hetionet CHEBI:3001 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0020522 infores:hetionet CAID:CA512341302 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341302 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1107G>A (p.Ser369=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.62) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341302/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5893 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0547030 infores:hetionet CHEBI:6640 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0013491 infores:hetionet CHEBI:5103 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0036454 infores:hetionet CHEBI:8346 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0039231 infores:hetionet NCBIGene:4204 biolink:causes MONDO:0010283 infores:monarchinitiative not_provided not_provided HGNC:6990 MONDO:0010283 uuid:db01f15c-740c-4f15-8a9d-b790f16a7036 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0027051 infores:hetionet CHEBI:4027 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019209 infores:hetionet GO:0030337 biolink:causes GO:0071897 infores:ubergraph knowledge_assertion manual_agent GO:0030337 GO:0071897 CHEBI:29007 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0086565 infores:hetionet CHEBI:64355 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151905 infores:hetionet CHEBI:6520 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0013362 infores:hetionet NCBIGene:1136 biolink:causes MONDO:0008630 infores:monarchinitiative not_provided not_provided HGNC:1957 MONDO:0008630 uuid:5a910ca2-db29-461e-a0d1-5cedd551d1f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:3467 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0019209 infores:hetionet NCBITaxon:552467 biolink:causes MONDO:0005724 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:552467 MONDO:0005724 NCBITaxon:10407 biolink:causes MONDO:0005789 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10407 MONDO:0005789 CHEBI:7931 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0004093 infores:hetionet CHEBI:3213 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0042109 infores:hetionet CHEBI:3757 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1619702 infores:hetionet CHEBI:85078 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C1268766 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0085620 infores:hetionet CHEBI:8802 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0026837 infores:hetionet CHEBI:8888 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0231218 infores:hetionet CHEBI:9434 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020580 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0007405 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0007405 uuid:ff26734d-fa38-4ba5-9bbc-eaa41192ce2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042376 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011168 infores:hetionet CAID:CA024116 biolink:causes MONDO:0018493 infores:clingen CAID:CA024116 MONDO:0018493 PMID: Likely Pathogenic PP1, PS4_Moderate, PM1_Supporting, PP3_Moderate, PM5_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 4737 of the RYR1 protein, p.(Arg4737Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 16163667, 26631338, 30236257, VCEP participating clinical laboratory). This variant segregates with MHS in 4 individuals, PP1 (PMID:26631338, 12208234). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (.882) supports a pathogenic status for this variant, PP3_Moderate. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg4737Gln), PM5_Supporting (PMID: 23460944). This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024116/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3314 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0085616 infores:hetionet CHEBI:5959 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C1318520 infores:hetionet CHEBI:135939 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0002994 infores:hetionet CHEBI:51041 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151578 infores:hetionet CHEBI:9667 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C2363730 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0002792 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0042769 infores:hetionet CHEBI:6062 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0031345 infores:hetionet CHEBI:43968 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0015967 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020039 infores:hetionet CHEBI:9168 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151754 infores:hetionet CHEBI:18067 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0010520 infores:hetionet CHEBI:63599 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0220981 infores:hetionet CHEBI:4356 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0344232 infores:hetionet CHEBI:28748 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013428 infores:hetionet CAID:CA377784575 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784575 MONDO:0017623 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PM6_Strong, PS4_Supporting NM_000314.8(PTEN):c.149T>C (p.Ile50Thr) meets criteria to be classified as Pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_S: Two proband with presumed de novo occurrence (maternity/paternity not confirmed, PMID:24375884, internal laboratory contributor).PS3_M: FFunctional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.37953835.PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID:24375884).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.979)PM2_P: Absent in the gnomAD cohort. (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784575/MONDO:0017623/003 2024-02-09 2024-03-02 Autosomal dominant inheritance HP:0000006 Supports CAID:CA512318700 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318700 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.465T>G (p.Val155=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-4.27)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318700/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7494 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018099 infores:hetionet NCBIGene:7249 biolink:causes MONDO:0011818 infores:monarchinitiative not_provided not_provided HGNC:12363 MONDO:0011818 uuid:74999a77-09de-40a2-843d-4f722465f622 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905310 biolink:causes GO:0060485 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0060485 CHEBI:3077 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0043251 infores:hetionet CHEBI:9674 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0080274 infores:hetionet CHEBI:168396 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018524 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020517 infores:hetionet CHEBI:32588 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C2697368 infores:hetionet CHEBI:34825 biolink:causes MONDO:0001405 infores:sider not_provided not_provided DRUGBANK:DB08933 UMLS:C1384589 infores:hetionet CHEBI:4903 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0027497 infores:hetionet CHEBI:119573 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085641 infores:hetionet CHEBI:94686 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0027497 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042769 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0234913 infores:hetionet CHEBI:36704 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0040264 infores:hetionet CHEBI:5103 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0004093 infores:hetionet CHEBI:6062 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151905 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0006840 infores:hetionet CHEBI:3181 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0344232 infores:hetionet CHEBI:8802 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020621 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013595 infores:hetionet CHEBI:6887 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0041582 infores:hetionet CHEBI:4903 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0268000 infores:hetionet CHEBI:520985 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0035455 infores:hetionet CHEBI:8024 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151480 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151824 infores:hetionet CHEBI:31932 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002874 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0948873 infores:hetionet CHEBI:31547 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0025345 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0232492 infores:hetionet CHEBI:135929 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0043352 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0152128 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0221725 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0221725 infores:hetionet CHEBI:2922 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0033774 infores:hetionet CHEBI:31932 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0151905 infores:hetionet CHEBI:3077 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0014236 infores:hetionet CHEBI:9398 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0039231 infores:hetionet NCBIGene:57465 biolink:causes MONDO:0011506 infores:monarchinitiative not_provided not_provided HGNC:29203 MONDO:0011506 uuid:f9af9012-6610-4f47-9cd3-3f8ff2a8ad3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0852911 infores:hetionet CHEBI:2704 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0027497 infores:hetionet CHEBI:87715 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0014591 infores:hetionet CHEBI:119915 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0428977 infores:hetionet CHEBI:63717 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0027441 infores:hetionet CHEBI:5141 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0428977 infores:hetionet CHEBI:17141 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0013298 infores:hetionet CHEBI:17303 biolink:causes HP:0032149 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1135120 infores:hetionet CHEBI:63577 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0026858 infores:hetionet CAID:CA392265208 biolink:causes MONDO:0012996 infores:clingen CAID:CA392265208 MONDO:0012996 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_001482.3:c.216G>A (p.Trp72Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 out of a total of 9 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002542 (3/1180018 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in a patient with AGAT deficiency.The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ).In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392265208/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:184555 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0152227 infores:hetionet CHEBI:8232 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0043352 infores:hetionet CHEBI:3216 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0085593 infores:hetionet CHEBI:64312 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0344232 infores:hetionet CAID:CA000077 biolink:causes MONDO:0018875 infores:clingen CAID:CA000077 MONDO:0018875 PMID:30224644PMID:12826609PMID:29979965 Likely Benign BP4, BS2_Supporting, BS3, PM2_Supporting BA1, BP3, BP2, PS1, PS3, PS4, PS2, PM5, PM4, PM1, BP7, BS1, BS4, PM6, PVS1, PP3, PP1, PP4 The NM_000546.6: c.221C>T variant in TP53 is a missense variant predicted to cause substitution of alanine by valine at amino acid 74 (p.Ala74Val). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). This variant has an allele frequency of 0.000006782 (8/1179650 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.2135; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -6; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000077/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:46345 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0027051 infores:hetionet CHEBI:6809 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0012833 infores:hetionet UBERON:0003911 biolink:causes MONDO:0016717 infores:ubergraph knowledge_assertion manual_agent UBERON:0003911 MONDO:0016717 CAID:CA57635829 biolink:causes MONDO:0018958 infores:clingen CAID:CA57635829 MONDO:0018958 PMID: Likely Pathogenic PVS1_Strong, PM3, PM2_Supporting BA1, BS1 The NM_001164508.2:c.11910+1G>A variant in NEB occurs in the canonical splice site (+1) of intron 79. It is predicted to result in an in-frame loss of the adjacent exon (PVS1_Strong). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. At least one proband with congenital myopathy and congenital fiber type disproportion has been identified with this variant and another pathogenic NEB variant in trans (PM3; GeneDx, ClinVar: SCV005328220.1). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal recessive nemaline myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA57635829/MONDO:0018958/146 2025-01-13 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47781 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0043352 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0031350 infores:hetionet CAID:CA16616520 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616520 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805G>C (p.Asp269His) is a missense variant which has a REVEL score < 0.50 (0.318) and a SpliceAI score ≤ 0.20 (0.09) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616520/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4710 biolink:causes EFO:0009472 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0206504 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0281981 infores:hetionet CHEBI:261649 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0041834 infores:hetionet CHEBI:38940 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0231919 infores:hetionet CHEBI:6715 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0231528 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0948586 infores:hetionet CHEBI:41423 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151905 infores:hetionet CAID:CA240473 biolink:causes MONDO:0012589 infores:clingen CAID:CA240473 MONDO:0012589 PMID: Likely Benign BP4, BP7, BP5, BS1 The highest population minor allele frequency of the c.1245T>C (p.His415His) variant in TCF4 in gnomAD v2.1 is 0.00028 in the African population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The c.1245T>C (p.His415His) variant is found in a patient with an alternate molecular basis of disease (Internal database - Invitae) (BP5). The silent c.1245T>C (p.His415His) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary the c.1245T>C (p.His415His) variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP5, BP4, BP7). (TCF4 Specifications v.3; approval date 6/25/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA240473/MONDO:0012589/032 2024-06-25 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8405 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0221490 infores:hetionet CHEBI:168396 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C3495920 infores:hetionet CHEBI:9150 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0851578 infores:hetionet CHEBI:8435 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0002792 infores:hetionet CHEBI:52172 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0858635 infores:hetionet GO:2000977 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:2000977 GO:0007417 CHEBI:42944 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C1302752 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042769 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0037274 infores:hetionet CHEBI:2666 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0002170 infores:hetionet CHEBI:84883 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0002962 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0231528 infores:hetionet NCBIGene:10785 biolink:causes MONDO:0032690 infores:monarchinitiative not_provided not_provided HGNC:12756 MONDO:0032690 uuid:ae5a89d9-550c-4db7-b04c-89b827dd42e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2607914 infores:hetionet CHEBI:161680 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0033774 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013182 infores:hetionet CHEBI:5130 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1112525 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0012739 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0034902 infores:hetionet NCBIGene:29110 biolink:causes MONDO:0014641 infores:monarchinitiative not_provided not_provided HGNC:11584 MONDO:0014641 uuid:140643c9-63e5-40b4-93ef-8502337fc367 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0042023 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0035455 infores:hetionet CHEBI:47381 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018926 infores:hetionet NCBIGene:93210 biolink:causes MONDO:0014318 infores:monarchinitiative not_provided not_provided HGNC:23719 MONDO:0014318 uuid:90d87153-ea93-4434-89e4-c835ddb4941b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1442826 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0233459 infores:hetionet CHEBI:3286 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0018979 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040409 infores:hetionet CHEBI:5001 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0037299 infores:hetionet CHEBI:16347 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0234930 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1321686 infores:hetionet CAID:CA512318579 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318579 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.759G>A (p.Leu253=) is a synonymous variant that is not predicted to impact splicing. This variant is a synonymous variant; therefore, REVEL score cannot be applied, and SpliceAI is ≤ 0.20 (Donor Loss 0.13 and Donor Gain 0.07) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP 1.97177 is < 2.0) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318579/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51450 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0232492 infores:hetionet CAID:CA8337582 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337582 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 BP7 The c.201G>A (p.Lys67=) variant (NM_000018.4) is a synonymous (silent) variant. BP7 was not applied because the nucleotide is conserved, as shown by PhastCons. However, the results from three in silico splicing predictors (SpliceAI, NNsplice, MaxEntScan) support that this variant does not affect splicing (BP4). The highest population minor allele frequency in gnomAD v3.1.2 is 0.000008793 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337582/MONDO:0008723/021 2023-12-12 2023-12-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:27666 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0948594 infores:hetionet CAID:CA32685677 biolink:causes MONDO:0020367 infores:clingen CAID:CA32685677 MONDO:0020367 PMID: Uncertain Significance PP3, PP1, PM2_Supporting BS1, BS3, BP7, PM6, PM4, PM5, PS3, PS1, PS2, PS4, BP4, BA1 The c.1153G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 385 (p.Glu385Lys). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.948, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 31653660), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 31653660), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA32685677/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2687 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0001824 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0032285 infores:hetionet CHEBI:5959 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0264886 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0029445 infores:hetionet CHEBI:92712 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0004238 infores:hetionet CHEBI:9139 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042963 infores:hetionet CHEBI:7025 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0016867 infores:hetionet CHEBI:3568 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235939 infores:hetionet CHEBI:7444 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0015967 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0027769 infores:hetionet CHEBI:84500 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037036 infores:hetionet CHEBI:3441 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0812387 infores:hetionet NCBIGene:81 biolink:causes MONDO:0011303 infores:monarchinitiative not_provided not_provided HGNC:166 MONDO:0011303 uuid:1fb193b5-e93f-43c8-9ab8-9598fef7cd9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4995 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151786 infores:hetionet CHEBI:46195 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0037763 infores:hetionet CAID:CA410147834 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147834 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1186T>A (p.Phe396Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a REVEL score < 0.50 (0.293) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147834/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8212 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0232461 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0007137 infores:hetionet CHEBI:50156 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0032343 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151736 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0032961 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0021053 infores:hetionet NCBIGene:10342 biolink:causes MONDO:0011468 infores:monarchinitiative not_provided not_provided HGNC:11758 MONDO:0011468 uuid:c437170e-e904-47b6-904b-f2bb2e436a2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0015230 infores:hetionet GO:1902667 biolink:causes GO:0061564 infores:ubergraph knowledge_assertion manual_agent GO:1902667 GO:0061564 CHEBI:2038 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C1368065 infores:hetionet CHEBI:9352 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0020461 infores:hetionet CHEBI:8378 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0000731 infores:hetionet CAID:CA226358 biolink:causes MONDO:0100437 infores:clingen CAID:CA226358 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PS4_Supporting PM2, BS1 NM_001034853.2(RPGR):c.1377_1378del (p.Leu460IlefsTer2) is a frameshift variant due to a two-nucleotide deletion that introduces a premature stop codon in exon 11 of 15 that is predicted to trigger nonsense-mediated decay (PVS1). This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002234 among hemizygous individuals, with 1 variant allele / 895,258 total alleles, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 and fails to meet PM2_Supporting. This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 34985506, PMID: 31953110, PMID: 10480356, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 31953110). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PP4, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226358/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:75722 biolink:causes UMLS:C0015408 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015408 infores:hetionet CHEBI:231594 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151825 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0040034 infores:hetionet CAID:CA405672067 biolink:causes MONDO:0018493 infores:clingen CAID:CA405672067 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glycine at codon 2593 of the RYR1 protein, p.(Arg2593Gly). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000079, a frequency consistent with pathogenicity for MHS. To our knowledge, this variant has not been reported in any individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.769 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405672067/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8502 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0002170 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002418 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0233472 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011991 infores:hetionet CHEBI:92712 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0549249 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0019158 infores:hetionet CHEBI:3698 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0027947 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0022650 infores:hetionet CHEBI:4784 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0019825 infores:hetionet CHEBI:3403 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0002994 infores:hetionet UBERON:0000344 biolink:causes MONDO:0000544 infores:ubergraph knowledge_assertion manual_agent UBERON:0000344 MONDO:0000544 CHEBI:8426 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0018681 infores:hetionet CHEBI:17650 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0231218 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0019158 infores:hetionet CHEBI:61049 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0423791 infores:hetionet CHEBI:584020 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0040034 infores:hetionet CHEBI:52717 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2938875 infores:hetionet CHEBI:8346 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020580 infores:hetionet CHEBI:3242 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0027497 infores:hetionet CHEBI:5141 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0019521 infores:hetionet CHEBI:3996 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0002994 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0009806 infores:hetionet NCBIGene:5956 biolink:causes MONDO:0010565 infores:monarchinitiative not_provided not_provided HGNC:9936 MONDO:0010565 uuid:540c56c6-4635-492e-95e2-1e6d34fc76da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8060 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0026826 infores:hetionet NCBIGene:1282 biolink:causes MONDO:0012726 infores:monarchinitiative not_provided not_provided HGNC:2202 MONDO:0012726 uuid:aec2e9a4-7e3f-4811-a92a-94f0c4f83ae1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011603 infores:hetionet CHEBI:31401 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0011603 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0020649 infores:hetionet CAID:CA226528 biolink:causes MONDO:0100368 infores:clingen CAID:CA226528 MONDO:0100368 PMID: Likely Pathogenic PP3_Moderate, PM3_Supporting, PS3_Supporting, PP4, PM2_Supporting The NM_000329.3(RPE65):c.235T>C (p.Tyr79His) variant is a missense variant in RPE65 causing a substitution of tyrosine with histidine at position 79. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 6.800e-7, with 3 alleles / 1180040 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the ClinGen LCA/ oRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 2.5% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 18599565). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (0.5 total points, VCEP member-provided data, PM3_Supporting). The Pro25Leu and Tyr79His variants have also been reported in the compound heterozygous state in probands in multiple publications, but were not counted as additional cases as these may represent the same individual as above (PMIDs: 22807296, 30268864). The Pro25Leu variant has also been reported in the compound heterozygous state with the Glu95Gln and the Asp482Gly variants, but these cases were not counted due to insufficient phenotype and/or to avoid circularity in curation (PMID: 22807296, 11095629, 30268864, 17525851). At least one proband harboring this variant exhibits a phenotype including diagnosis of rod-cone dystrophy with congenital onset (1 pt), reduced central visual acuity (1 pt) multifocal ERG below threshold, no fundus autofluorescence (2 pts), nyctalopia, fine dots in the fundus, OCT preserved with respect to vision loss (1 pt), and paramacular photoreceptor thinning (5 total points, VCEP-member provided data, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PP4, PM3_Supporting, PS3_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226528/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8772 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0426576 infores:hetionet NCBIGene:89869 biolink:causes MONDO:0014970 infores:monarchinitiative not_provided not_provided HGNC:19218 MONDO:0014970 uuid:69609716-fc73-4942-aeda-0aca235ba360 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0221242 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0267596 infores:hetionet CHEBI:71219 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0017181 infores:hetionet CHEBI:61049 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151692 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0853692 infores:hetionet CHEBI:8888 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0234632 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0015397 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0018799 infores:hetionet CHEBI:140621 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0002792 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042373 infores:hetionet CHEBI:31236 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234233 infores:hetionet CHEBI:134745 biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0220994 infores:hetionet CHEBI:50648 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0028643 infores:hetionet CHEBI:27306 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00165 UMLS:C0031117 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0009806 infores:hetionet CHEBI:64321 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0233407 infores:hetionet CHEBI:79699 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C2830004 infores:hetionet CHEBI:240107 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0423006 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0267596 infores:hetionet CHEBI:3398 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0085593 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0006145 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0042401 infores:hetionet UMLS:C1738934 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0152031 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0038358 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0919715 infores:hetionet NCBIGene:10765 biolink:causes MONDO:0020850 infores:monarchinitiative not_provided not_provided HGNC:18039 MONDO:0020850 uuid:e0958a03-860d-4430-9a49-5f58eb04a61d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915940690 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940690 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong PM3 The c.2217del (p.Ile740SerfsTer89) variant in ITGB3 is a frameshift variant that is predicted to cause a stop loss leading to elongation of the protein by 39 amino acids until a new stop codon is reached. The frameshift is expected to disrupt a functionally important region (affecting the cytoplasmic domain of ITGB3 spanning amino acids 742-788) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). This variant has been detected in at least one proband with Glanzmann thrombasthenia. However, it is unclear if the reported proband (GT11, PMID: 19691478) was homozygous for this variant or if a second ITGA2B variant was identified. At least one patient (Patient GT11 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PM2_Supporting, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940690/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:36791 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016382 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0012833 infores:hetionet CHEBI:9352 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0009763 infores:hetionet GO:0110026 biolink:causes GO:0006261 infores:ubergraph knowledge_assertion manual_agent GO:0110026 GO:0006261 NCBIGene:51704 biolink:causes MONDO:0957533 infores:monarchinitiative not_provided not_provided HGNC:13308 MONDO:0957533 uuid:746b3289-2e7b-4206-9d66-afb6d97c7789 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042018 infores:hetionet CHEBI:7601 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0740394 infores:hetionet NCBIGene:8021 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:8064 MONDO:0013108 uuid:b243179d-53c6-44a8-9630-a54a587c3b08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009763 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0029408 infores:hetionet CHEBI:9137 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151904 infores:hetionet CHEBI:59773 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C1443060 infores:hetionet CHEBI:17334 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018965 infores:hetionet CHEBI:8764 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C3665386 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0948594 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0002994 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0037199 infores:hetionet CHEBI:3077 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0019209 infores:hetionet NCBIGene:9529 biolink:causes MONDO:0030680 infores:monarchinitiative not_provided not_provided HGNC:941 MONDO:0030680 uuid:eba09352-60eb-4549-a15a-5ba0a2f71bd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:7662KG2R6K biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0021400 infores:hetionet CHEBI:367163 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020488 infores:hetionet CHEBI:4511 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0235378 infores:hetionet CHEBI:9943 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151905 infores:hetionet NCBIGene:8942 biolink:causes MONDO:0009372 infores:monarchinitiative not_provided not_provided HGNC:6469 MONDO:0009372 uuid:57e4dbba-6064-433c-a68c-7fc6ff2813bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17026 biolink:causes UMLS:C0152010 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0152010 infores:hetionet CHEBI:63791 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013491 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0858598 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004239 infores:hetionet CHEBI:472657 biolink:causes UMLS:C0348801 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0348801 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0343863 infores:hetionet CHEBI:44185 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0549463 infores:hetionet CHEBI:10125 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0017168 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0152227 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0033246 infores:hetionet CHEBI:8890 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0041969 infores:hetionet CHEBI:4670 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0031542 infores:hetionet CHEBI:36791 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0005747 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0037195 infores:hetionet CHEBI:23765 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013378 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020649 infores:hetionet CHEBI:94609 biolink:causes MONDO:0006996 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0040127 infores:hetionet CHEBI:63631 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151825 infores:hetionet CHEBI:9943 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085641 infores:hetionet CHEBI:16755 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151907 infores:hetionet CHEBI:64318 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0017086 infores:hetionet CAID:CA116593 biolink:causes MONDO:0009290 infores:clingen CAID:CA116593 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Very Strong PM5 The NM_000152.5:c.1561G>A variant in GAA is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 521 (p.Glu521Lys). This substitution of a negatively charged, polar amino acid with a neutral, non-polar amino acid is predicted to functionally impact the GAA precursor protein (PMID: 1898413). This variant was first reported in homozygosity in a case report of siblings with IOPD and no detectable GAA activity in fibroblasts (PMID: 1898413), meeting criteria for PP4_moderate. This variant has been detected in at least four additional individuals with IOPD. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMIDs: 17723315, 37542277) and two were homozygous for the variant (PMIDs: 19862843,33301762). This variant has also been reported in at least nine individuals with LOPD. Of those, six were compound heterozygous for the common IVS splice site pathogenic variant c.-32-13T>G (PMIDs: 22676651, 20308911, 2270448, 20033296, 25673129, 30312517,34852371 and 39045638), and one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID:21605996 and 22676651) (PM3_Very Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003334 (2/59992 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In the first report of this variant, transient expression in COS cells was performed and revealed no detectable activity, and immunocytochemistry results suggested the mutant precursor is not transported to the lysosome (PMID: 1898413). Subsequent expression studies in COS cells revealed <2% wild type GAA activity, indicating that this variant may impact protein function (PMID: 19862843). Thus, PS3_Supporting can be applied. The computational predictor REVEL gives a score of 0.932 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change at the same amino acid position (p.Glu521Gln) has been reported in IOPD (PMID: 22658377, 19588081), but this variant has not been reviewed by the ClinGen Lysosomal Diseases Variant Curation Expert panel and thus PM5 will not be applied. There is a ClinVar entry for this variant (Variation ID: 4022, 2-star review status) with 8 submitters classifying the variant as pathogenic (7 submitters) or likely pathogenic (1 submitters). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM3_Very Strong, PP4_moderate, PM2_supporting, PP3, PS3_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 3, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116593/MONDO:0009290/010 2024-12-03 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63619 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0000737 infores:hetionet CHEBI:4858 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0036974 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0439857 infores:hetionet CHEBI:9288 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0023380 infores:hetionet CHEBI:7494 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C2830004 infores:hetionet CAID:CA000640 biolink:causes MONDO:0017623 infores:clingen CAID:CA000640 MONDO:0017623 PMID: Uncertain Significance PM2 BS1, PM5, BA1, PS1 PTEN c.-930G>A (NC_000010.10:g.89623296G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000640/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:714 biolink:causes MONDO:0005076 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:714 MESH:D010518 DB01017_MESH_D010518_1 CHEBI:145499 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0149871 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0233494 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0475858 infores:hetionet CHEBI:68534 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0016658 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042963 infores:hetionet CHEBI:3723 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0547030 infores:hetionet CHEBI:63681 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0239571 infores:hetionet CHEBI:94501 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C3665386 infores:hetionet CHEBI:3698 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0043352 infores:hetionet CAID:CA314824 biolink:causes MONDO:0012999 infores:clingen CAID:CA314824 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000156.6:c.608G>A variant in GAMT is a missense variant predicted to result in the substitution of arginine for glutamine at amino acid 203 (p.Arg203Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001333 (8/60002 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.196 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). To our knowledge, this variant has not been previously reported in the published literature, but has been noted in ClinVar (Variation ID: 205590). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314824/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0021523 biolink:causes CL:0005024 infores:ubergraph knowledge_assertion manual_agent GO:0021523 CL:0005024 CHEBI:28593 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0006266 infores:hetionet CHEBI:15940 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0085641 infores:hetionet CHEBI:8426 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0002878 infores:hetionet NCBIGene:7175 biolink:causes MONDO:0957288 infores:monarchinitiative not_provided not_provided HGNC:12017 MONDO:0957288 uuid:15890c77-f409-4c3d-9bb0-49c7e454b85a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042029 infores:hetionet CHEBI:4511 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0042373 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0010073 infores:hetionet CHEBI:6076 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011168 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0023533 infores:hetionet CHEBI:135736 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0232461 infores:hetionet NCBIGene:7991 biolink:causes MONDO:0012615 infores:monarchinitiative not_provided not_provided HGNC:30242 MONDO:0012615 uuid:63400afb-8f60-4181-82df-020762865976 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0027765 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0000833 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0003123 infores:hetionet GO:0080113 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0080113 GO:0007275 CHEBI:5384 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C1321898 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0574067 infores:hetionet CHEBI:100246 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0011991 infores:hetionet CHEBI:4856 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0220870 infores:hetionet CHEBI:7492 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0037199 infores:hetionet CHEBI:9445 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0042963 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0234215 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0600142 infores:hetionet CAID:CA400028645 biolink:causes MONDO:0100326 infores:clingen CAID:CA400028645 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000212.3(ITGB3):c.1303G>T (p.Glu435Ter) found in a homozygous proband (PMID:31029159; PM3_supporting) causes a premature stop codon at exon 10/15 and is predicted to undergo nonsense mediated decay (PVS1). The mutation was not found in gnomAD v2.1.1 (PM2_supporting). In conclusion the criteria PVS1, PM2_supporting, and PM3_supporting were applied to reach a classification of pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400028645/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8871 biolink:causes UMLS:C0234953 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234953 infores:hetionet CHEBI:37941 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0017181 infores:hetionet CHEBI:3181 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011168 infores:hetionet CHEBI:6128 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0018524 infores:hetionet CHEBI:15765 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0030193 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0023530 infores:hetionet CHEBI:6801 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C2830004 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0019163 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0036572 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0020538 infores:hetionet NCBIGene:22852 biolink:causes MONDO:0008555 infores:monarchinitiative not_provided not_provided HGNC:29186 MONDO:0008555 uuid:c30ec41f-f276-4186-abbb-f419bc0fb1f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2635578680 biolink:causes MONDO:0009276 infores:clingen CAID:CA2635578680 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.275del (p.Leu92ArgfsTer20) variant in GP1BA is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove (>10%) of the protein (PVS1_Strong). At least one patient (Proband in PMID: 7855797 or internal with this variant had aggregation absent for ristocetin and present for all other agonists and absent expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is absent (based on 1/1179908 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1.0.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2635578680/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135930 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020557 infores:hetionet CHEBI:50729 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0041364 infores:hetionet CHEBI:32020 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0027080 infores:hetionet CHEBI:144093 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042023 infores:hetionet CAID:CA172597 biolink:causes MONDO:0018947 infores:clingen CAID:CA172597 MONDO:0018947 PMID: Benign BA1 PP3, BP4, BS1, PM2 The c.1702A>G variant in MTM1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 568. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.00002629 (33/895101 alleles, 9 hemizygotes) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.212, which is neither above nor below the thresholds predicting a damaging or benign impact on MTM1 function. In summary, this variant meets the criteria to be classified as benign for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA172597/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:8356 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151610 infores:hetionet CHEBI:44185 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0008031 infores:hetionet CHEBI:8481 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0011168 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0041969 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0221717 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0037274 infores:hetionet CAID:CA16020844 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020844 MONDO:0009861 PMID:25894915PMID:25894915 Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Strong PS1 The c.699C>G (p.Phe233Leu) variant in PAH has been reported in multiple individuals with moderate/mild PKU (BH4 deficiency excluded). (PMID: 25894915, 26322415). This variant is absent in population databases. This variant was detected with multiple pathogenic/likely pathogenic variants: p.R243Q (PMID: 25894915); p.G247V (PMID: 26322415); c.442-1G>A; p.A434D (PMID: 30050108). Another pathogenic variant at the same amino acid (p.Phe233Ile) is reported (by PAH VCEP). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020844/MONDO:0009861/006 2020-08-07 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15765 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0522153 infores:hetionet CHEBI:4784 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151636 infores:hetionet GO:0033025 biolink:causes GO:0033023 infores:ubergraph knowledge_assertion manual_agent GO:0033025 GO:0033023 CHEBI:4514 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0041657 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0017160 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0155320 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0041912 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0005747 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0011175 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0031350 infores:hetionet CHEBI:8455 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0017178 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0009450 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0040034 infores:hetionet CHEBI:10650 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003811 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042373 infores:hetionet CHEBI:3650 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0162533 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0149904 infores:hetionet CHEBI:17650 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0018681 infores:hetionet CHEBI:44241 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0002170 infores:hetionet CHEBI:51380 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0002994 infores:hetionet CHEBI:80630 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0035455 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0001824 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0877042 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0877042 infores:hetionet CAID:CA915952247 biolink:causes MONDO:0009290 infores:clingen CAID:CA915952247 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.806_830del (p.Leu269ProfsTer37) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in a patient with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 656144). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952247/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:44915 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0026821 infores:hetionet CHEBI:135939 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0016204 infores:hetionet UMLS:C0657912 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040822 infores:hetionet CHEBI:101278 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0039070 infores:hetionet CHEBI:91583 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0178298 infores:hetionet CHEBI:7907 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0151786 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0033687 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0021843 infores:hetionet NCBITaxon:624 biolink:causes MONDO:0019345 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:624 MESH:D004405 DB00415_MESH_D004405_1DB01165_MESH_D004405_1DB00440_MESH_D004405_1 CHEBI:39585 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0017152 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029882 infores:hetionet UNII:S78SFW950O biolink:causes GO:0008219 infores:drugmechdb knowledge_assertion manual_agent MESH:D001085 GO:0008219 DB00987_MESH_D015473_1DB00987_MESH_D015470_1 CHEBI:68647 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0043352 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011615 infores:hetionet CHEBI:2914 biolink:causes UMLS:C0857370 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0857370 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0302295 infores:hetionet CHEBI:77260 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013404 infores:hetionet CHEBI:45863 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042963 infores:hetionet CHEBI:5790 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0003467 infores:hetionet CHEBI:47898 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085932 infores:hetionet CHEBI:8764 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0522055 infores:hetionet CHEBI:8024 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0231218 infores:hetionet CHEBI:42355 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0019158 infores:hetionet CHEBI:119486 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C2830004 infores:hetionet NCBIGene:9256 biolink:causes MONDO:0957539 infores:monarchinitiative not_provided not_provided HGNC:16831 MONDO:0957539 uuid:5456a6b4-b86b-4aef-8397-7688c58cb03c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116735 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0042109 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042571 infores:hetionet CHEBI:367163 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0231218 infores:hetionet CAID:CA1139665155 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665155 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1534_1535del (p.Arg512GlyfsTer49) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. . In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1.0; approved 12-29-22). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665155/MONDO:0008723/021 2023-06-29 2023-06-29 Autosomal recessive inheritance HP:0000007 Supports CAID:CA409108272 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108272 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM5_Strong, PM1_Supporting The c.932G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to leucine at codon 311 (p.(Arg311Leu)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.932G>A p.Arg311His and c.931C>T p.Arg311Cys, have been interpreted as pathogenic by the ClinGen MDEP and p.Arg311Leu has a greater Grantham distance than p.Arg311His (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.932G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108272/MONDO:0015967/085 2024-07-31 2024-07-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6456 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0020580 infores:hetionet CHEBI:66876 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0030846 infores:hetionet CHEBI:15854 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0235378 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0948594 infores:hetionet CHEBI:7565 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0392525 infores:hetionet CHEBI:4995 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0027540 infores:hetionet NCBIGene:149461 biolink:causes MONDO:0009548 infores:monarchinitiative not_provided not_provided HGNC:2040 MONDO:0009548 uuid:2bb249bd-88c9-4cb0-b68a-3a834d2a5d3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6970 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0242301 infores:hetionet CHEBI:119915 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C3665347 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0011991 infores:hetionet CHEBI:3216 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013378 infores:hetionet CHEBI:7954 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0234238 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0740482 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0740482 infores:hetionet CHEBI:8890 biolink:causes EFO:1001863 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042135 infores:hetionet CHEBI:32139 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0028961 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1302752 infores:hetionet CHEBI:127342 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0020580 infores:hetionet CAID:CA017692 biolink:causes MONDO:0007947 infores:clingen CAID:CA017692 MONDO:0007947 PMID:24982166 Pathogenic PP4, PM2_Supporting, PS3, PS4, PP1_Strong, PVS1_Strong PM6, BS2, BA1, PS1, PM1, BS1, BS3, BS4 The NM_00138 c.8326C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 96 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). In an in-vitro microfibril assay, this variant was reported to result in intracellular retention of the protein (PMID 24982166; PS3). This variant was found in a proband with aortic aneurysm and dissection, ectopia lentis, and skeletal features, who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported 10 times in ClinVar, nine as pathogenic and once as likely pathogenic (Variation ID: 16439). Several other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (internal lab data, PMID 9338581, 31098894, 31730815, 33059708, 25907466, 19293843, 34916231; PS4). In one individual with aortic dissection and myopia, this variant was reported to be de novo without confirmation of parental relationships (PMID 31098894; 0.25 points). In two families with MFS, this variant was found to segregate with disease in five affected family members (internal lab data; PP1_Strong). This variant is present in in 10/24982 (0.04%) of alleles tested from the Finnish population in gnomAD and did not pass the quality control criteria in the genome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PS4, PS3, PP1_Strong, PM2_Sup, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017692/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:171719 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011616 infores:hetionet GO:0046928 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0046928 GO:0051641 CHEBI:10110 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0041657 infores:hetionet CHEBI:119573 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1262113 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0027497 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0242073 infores:hetionet CHEBI:691037 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0020456 infores:hetionet CHEBI:64198 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0004093 infores:hetionet CHEBI:3647 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0004096 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0751535 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0751535 infores:hetionet CHEBI:188986 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0010200 infores:hetionet CHEBI:73275 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0009782 infores:hetionet NCBIGene:25913 biolink:causes MONDO:0014368 infores:monarchinitiative not_provided not_provided HGNC:17284 MONDO:0014368 uuid:c2b9bd9a-4ec5-4d9c-950c-d2b3dde89f1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68534 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0023530 infores:hetionet CHEBI:6950 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0004044 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0024236 infores:hetionet CAID:CA190759 biolink:causes MONDO:0100488 infores:clingen CAID:CA190759 MONDO:0100488 PMID: Likely Pathogenic PP3, PP1, PS4_Supporting, PM2_Supporting, PS3 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS2 The c.1565+5G>A variant occurs in the splice donor region of intron 10. This variant is absent from population databases (PM2_supporting). The variant is predicted to result in loss of the canonical donor splice site and gain of a cryptic donor site at the +7 position by SpliceAI and VarSeak (PP3). RNA analysis has demonstrated a novel six base pair insertion (GTAAAT) resulting in a premature stop codon (p.Tyr523*) in carriers (PS3, internal data, SCV000214990.7). The c.1565+5G>A variant segregates with diffuse gastric cancer in one family meeting IGCLC criteria for HDGC (PS4_supporting and PP1, unpublished). In summary, this variant is classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, PS3, PS4_supporting, PP3 and PP1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA190759/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:171719 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0027947 infores:hetionet CHEBI:6690 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0013144 infores:hetionet CHEBI:61033 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0023222 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0020517 infores:hetionet CL:0001063 biolink:causes MONDO:0008170 infores:drugmechdb knowledge_assertion manual_agent CL:0001063 MESH:D010051 DB00488_MESH_D010051_2DB00488_MESH_D010051_1 CHEBI:51137 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C1443060 infores:hetionet CAID:CA023495 biolink:causes MONDO:0007750 infores:clingen CAID:CA023495 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs:- Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile;- Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant.so PP1_Strong is metPS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs:- 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory),so PS4 is metPM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023495/MONDO:0007750/013 2021-12-14 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:63619 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0002622 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0152198 infores:hetionet CAID:CA10580956 biolink:causes MONDO:0018875 infores:clingen CAID:CA10580956 MONDO:0018875 PMID: Uncertain Significance BP4, PM2_Supporting BA1, PS3, PS1, PS4, PS2, PM5, PM1, BS1, BS3, BS4, PP1, PP4, BS2 The NM_000546.6 :c.206C>G variant in TP53 is a missense variant predicted to cause substitution of alanine by glycine at amino acid 69 (p.Ala69Gly). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.1612; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version v2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580956/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6954 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0002871 infores:hetionet CHEBI:82960 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0028734 infores:hetionet CHEBI:9398 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0038990 infores:hetionet CAID:CA229348 biolink:causes MONDO:0009861 infores:clingen CAID:CA229348 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate, PM3_Supporting PM5, PP3 The c.1112A>G (p.Lys371Arg) variant in PAH has been reported in a patient with PKU (BH4 deficiency excluded) (PMID: 23430918, 9169088) detected with pathogenic variant IVS10-11G>A, parental analysis not reported PMID: 9169088. This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PP3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229348/MONDO:0009861/006 2021-04-23 2021-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6887 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0041657 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0011616 infores:hetionet CAID:CA003291 biolink:causes MONDO:0700268 infores:clingen CAID:CA003291 MONDO:0700268 PMID: Pathogenic PVS1, PM2_Supporting, PS3 PP3, PP4, BP5 The c.5152+6T>C variant is an intronic variant occurring in intron 17(18) of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.7, predicting an impact on splicing (score threshold >0.20) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 32123317, 32761968). The percent reference (full-length) and aberrant transcripts produced from the variant allele is not stated, however assessment of gel electrophoresis shows apparent (near) complete splicing effect. The complete splicing effect has been confirmed in an allele-specific RT-PCR assay by an Internal lab contributor. Final code strength determined by the rubric: PVS1 (RNA). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.65 (based on Co-occurrence LR=1.07; Family History LR=0.61), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PVS1 (RNA)). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003291/MONDO:0700268/092 2025-08-21 2025-08-21 Autosomal dominant inheritance HP:0000006 Supports CHEBI:43968 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0852911 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002888 infores:hetionet CHEBI:42068 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0018681 infores:hetionet CHEBI:61390 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0015397 infores:hetionet CAID:CA410149617 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149617 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.940T>C (p.Ser314Pro) is a missense variant which has a REVEL score < 0.50 (0.244), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149617/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49668 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0085641 infores:hetionet CAID:CA913169888 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169888 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PM5_Supporting PP1, PS2, PS3, PM6 The m.12258C>T variant in MT-TS2 has been reported in one individual with primary mitochondrial disease to date however clinical details were not provided (PMID: 31965079). There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. Another variant at this position was classified by this Expert Panel as likely pathogenic (m.12258C>A; PM5_supporting). There is one heteroplasmic occurrence of this variant in the Helix dataset and this variant is absent in the MITOMAP GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (81.5 percentile) but HmtVAR predicts it to be neutral with a score of 0.05. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 7, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169888/MONDO:0044970/015 2025-01-07 2025-05-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3207 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0034359 infores:hetionet UMLS:C0023610 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0024902 infores:hetionet CHEBI:6456 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0009421 infores:hetionet NCBIGene:3299 biolink:causes MONDO:0007290 infores:monarchinitiative not_provided not_provided HGNC:5227 MONDO:0007290 uuid:3a7d3e42-6cc0-4585-b68b-785c74a12e06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UBERON:0002481 biolink:causes MONDO:0003945 infores:ubergraph knowledge_assertion manual_agent UBERON:0002481 MONDO:0003945 CAID:CA4239569 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239569 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.623C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 208 (p.(Ala208Val)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with 9 informative meioses in 6 families (PP1_Strong; internal lab contributors). This variant was identified in 16 unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a 5 generation family history of diabetes) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.851, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, c.623C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239569/MONDO:0015967/086 2024-01-18 2024-01-18 Semidominant inheritance HP:0032113 Supports CAID:CA367400540 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400540 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PM1, PP4 The c.797T>A variant in the glucokinase gene, GCK, causes an amino acid change of leucine to glutamine at codon 266 (p.(Leu266Gln)) of NM_000162.5.GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID:19790256). In summary, c.797T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400540/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:31949 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0040034 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0235980 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235980 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0009450 infores:hetionet CHEBI:10102 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0023518 infores:hetionet UMLS:C0120107 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0022346 infores:hetionet CHEBI:63631 biolink:causes NCIT:C122529 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0857494 infores:hetionet CHEBI:145499 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011175 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013295 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0233494 infores:hetionet CHEBI:8455 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0018681 infores:hetionet CHEBI:8874 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042384 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0857448 infores:hetionet CHEBI:28748 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1535939 infores:hetionet CHEBI:9943 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029261 infores:hetionet CHEBI:68534 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0012833 infores:hetionet CHEBI:6438 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0026896 infores:hetionet CHEBI:28901 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085631 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0010692 infores:hetionet CAID:CA220146 biolink:causes MONDO:0018997 infores:clingen CAID:CA220146 MONDO:0018997 PMID:22711529PMID:24219368PMID:12634870PMID:12325025PMID:11704759PMID:12634870PMID:16498234PMID:12325025 Pathogenic PS3, PS4, PP1_Strong, PM1, PP2, PP3 PM2 The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; PMID: 16498234, 12634870, 12325025, 11704759). In-vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220146/MONDO:0018997/004 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ UNII:2N4O9L084N biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0270996 infores:hetionet NCBITaxon:90370 biolink:causes MONDO:0005619 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:90370 MESH:D014435 DB00537_MESH_D014435_1DB00446_MESH_D014435_1DB01059_MESH_D014435_1DB07565_MESH_D014435_1DB01165_MESH_D014435_1DB07565_MESH_D014435_2 CHEBI:8874 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013447 infores:hetionet CHEBI:44032 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0013378 infores:hetionet CHEBI:6444 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0009421 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020538 infores:hetionet CHEBI:50275 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0234632 infores:hetionet CHEBI:50692 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0003862 infores:hetionet CHEBI:94501 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0004245 infores:hetionet CHEBI:135791 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0030554 infores:hetionet CHEBI:8499 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0006266 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0178298 infores:hetionet NCBIGene:5830 biolink:causes MONDO:0008736 infores:monarchinitiative not_provided not_provided HGNC:9719 MONDO:0008736 uuid:43c33100-9b07-4bfd-94c1-7162b05dca46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020649 infores:hetionet CHEBI:3207 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013428 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0267792 infores:hetionet CHEBI:2453 biolink:causes MONDO:0011644 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0030593 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002170 infores:hetionet CHEBI:44032 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0034642 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027765 infores:hetionet CHEBI:2549 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0917801 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0743680 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0595879 infores:hetionet CHEBI:10119 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0026826 infores:hetionet UMLS:C0657912 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2937350 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1698400 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1698400 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0152029 infores:hetionet CHEBI:184555 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0003862 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0009806 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0854097 infores:hetionet CHEBI:3044 biolink:causes MONDO:0006526 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0149526 infores:hetionet UMLS:C0120107 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0014591 infores:hetionet NCBIGene:25959 biolink:causes MONDO:0014492 infores:monarchinitiative not_provided not_provided HGNC:29300 MONDO:0014492 uuid:61e82c5f-526d-4d98-9ecc-bc7f10492381 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0004604 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011991 infores:hetionet CAID:CA392342185 biolink:causes MONDO:0007947 infores:clingen CAID:CA392342185 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP1, PM2_Supporting, PS4, PM1, PS2_Supporting PM6, PVS1, PP4, BS2, BP4, BP2, BP3, BA1, PS1, PS3, PM5, PM3, PM4, BP7, BP5, BS1, BS3 The NM_00138 c.1556A>G, is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 519 (p.Tyr519Cys). This variant was found in at least 7 probands with features consistent with or suggestive of Marfan syndrome including the following: one proband who met the original Ghent criteria with cardiovascular, skeletal, and skin involvement; one proband with bilateral ectopia lentis (EL) and systemic features; one proband with thoracic aortic aneurysm and dissection (TAAD); one proband with EL and systemic features; one proband with isolated EL; one proband with TAAD and systemic features; and once as de novo with confirmed maternity/paternity with bilateral EL, TAAD, and systemic features, a phenotype highly specific for Marfan syndrome (PS2_supporting, PS4; PMID: 15241795; University of Tokyo, UZG, Invitae, & Ambry internal data; ClinVar Variation ID: 5490254). The variant also segregates with features of Marfan syndrome in at least two affected family members (PP1; Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PS2_supporting, PM2_supporting, PP1, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392342185/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6067 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0001122 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151955 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151955 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0853891 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0853891 infores:hetionet CHEBI:15640 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0013395 infores:hetionet CHEBI:5959 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0039231 infores:hetionet CHEBI:31199 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0677500 infores:hetionet CHEBI:15367 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0917801 infores:hetionet CHEBI:40237 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0017178 infores:hetionet CHEBI:7640 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0027497 infores:hetionet CHEBI:474180 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0018133 infores:hetionet NCBIGene:2245 biolink:causes MONDO:0010589 infores:monarchinitiative not_provided not_provided HGNC:3663 MONDO:0010589 uuid:badff7f7-b4e7-49a6-856a-379ed4cd472e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027947 infores:hetionet CHEBI:4975 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0002170 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0006826 infores:hetionet CHEBI:4024 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0042571 infores:hetionet NCBITaxon:2 biolink:causes UMLS:C1112209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D059413 DB00493_MESH_D059413_1DB00355_MESH_D059413_1DB01190_MESH_D059413_1DB00916_MESH_D059413_1DB00479_MESH_D059413_1DB01326_MESH_D059413_1DB01332_MESH_D059413_1DB00199_MESH_D059413_1DB01598_MESH_D059413_1DB01331_MESH_D059413_1DB01597_MESH_D059413_1DB02703_MESH_D059413_1DB00798_MESH_D059413_1DB00274_MESH_D059413_1DB06211_MESH_D059413_1DB01212_MESH_D059413_1 CHEBI:77260 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0948594 infores:hetionet CHEBI:2666 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0018418 infores:hetionet CAID:CA2580612113 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612113 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM4 The c.521_526del variant in the HNF1 homeobox A gene, HNF1A, is a six base pair deletion resulting in the in-frame deletion of three amino acids at codons 174 to 176 followed by the insertion of glutamic acid (p.(Ala174_Gln176delinsGlu)) within exon 2 of NM_000545.8. The c.521_526del variant is an in-frame deletion predicted to result in the deletion of two amino acids (Gln175 and Gln176) (as well as the replacement of Ala174 with Glu174) (PM4). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.521_526del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612113/MONDO:0015967/017 2025-02-14 2025-04-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64310 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0018799 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0018799 infores:hetionet CHEBI:194135 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151825 infores:hetionet CHEBI:63599 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0014591 infores:hetionet CHEBI:7865 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0013404 infores:hetionet CHEBI:75998 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0009782 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235876 infores:hetionet CHEBI:8327 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0004093 infores:hetionet CHEBI:50924 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1720798 infores:hetionet CHEBI:8404 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0242184 infores:hetionet CHEBI:28177 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0039231 infores:hetionet CHEBI:72297 biolink:causes HP:0030878 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0476405 infores:hetionet CHEBI:7936 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015672 infores:hetionet CAID:CA115285 biolink:causes MONDO:0007064 infores:clingen CAID:CA115285 MONDO:0007064 PMID: Likely Pathogenic PP1_Moderate, PM5, PM3 PM2 NM_000022.4:c.631C>T is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 211 (p. Arg211Cys). The highest population minor allele frequency in gnomAD v4 is 0.0005167 (31/60000) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The variant has been reported to segregate with SCID in 2 affected family members from 1 family (PP1_moderate; PMID :8051429). Patient was found heterozygous for R211C & L107P which is classified as likely pathogenic by SCID VCEP (1 pt.) (PM3) (PMID: 2166947).Another missense variant [c.632G>A, p.Arg211His)] in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5).In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate,PM3,PM5(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA115285/MONDO:0007064/114 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8774 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0011603 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151609 infores:hetionet CHEBI:125354 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0424810 infores:hetionet CHEBI:9168 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030794 infores:hetionet CHEBI:5280 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0234632 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0262397 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0029408 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0005940 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0042109 infores:hetionet CHEBI:2682 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151754 infores:hetionet CHEBI:15940 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0011991 infores:hetionet CHEBI:3242 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0232462 infores:hetionet CAID:CA229490 biolink:causes MONDO:0009861 infores:clingen CAID:CA229490 MONDO:0009861 PMID:25456745PMID:25456745 Pathogenic PM4, PM3, PM2, PP4, PS3 PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, PM3, PS3, PM2, PM4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229490/MONDO:0009861/006 2018-08-05 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:1001 biolink:causes MONDO:0011107 infores:monarchinitiative not_provided not_provided HGNC:1762 MONDO:0011107 uuid:9e3ad4ad-c980-4fc7-9ae9-4444f7f3a8ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2788 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0009806 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0023067 infores:hetionet CHEBI:48669 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C1096250 infores:hetionet CHEBI:36795 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018932 infores:hetionet CHEBI:5855 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0002874 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0027697 infores:hetionet CHEBI:3638 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0036454 infores:hetionet NCBIGene:6905 biolink:causes MONDO:0009426 infores:monarchinitiative not_provided not_provided HGNC:11582 MONDO:0009426 uuid:614751ae-2618-46ad-8c91-beb64a66b902 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0234458 infores:hetionet CHEBI:8874 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018524 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017601 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0240322 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0235431 infores:hetionet CHEBI:6804 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0042963 infores:hetionet CHEBI:2637 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0522224 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0267055 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0267055 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0853760 infores:hetionet CHEBI:31638 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0015230 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0151773 infores:hetionet CHEBI:7476 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0438142 infores:hetionet NCBIGene:6654 biolink:causes MONDO:0012547 infores:monarchinitiative not_provided not_provided HGNC:11187 MONDO:0012547 uuid:ae4f7670-9ba0-4a51-8c76-3b95e38a79f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA143392 biolink:causes MONDO:0019501 infores:clingen CAID:CA143392 MONDO:0019501 PMID: Benign BA1 BP5, BP7, BS4, BS1, BS2, PP4, PP1, PP3, PM3, PM1, PM4, PM5, PM6, PM2, PVS1, BP2, BP3, BP4, PS3, PS2, PS4, PS1 The filtering allele frequency of the c.15297+3A>G variant in the USH2A gene is 0.99% (265/24032) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143392/MONDO:0019501/005 2018-09-14 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:63598 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013604 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0034882 infores:hetionet CHEBI:6067 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015672 infores:hetionet CHEBI:53760 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0009763 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0015672 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0039520 infores:hetionet CHEBI:5613 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0162557 infores:hetionet CHEBI:691037 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0235259 infores:hetionet CHEBI:421707 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0006277 infores:hetionet CHEBI:6715 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0577559 infores:hetionet CHEBI:3082 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0030554 infores:hetionet CHEBI:6472 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0027497 infores:hetionet CHEBI:41977 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0600142 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0205204 infores:hetionet CHEBI:17698 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0030312 infores:hetionet CHEBI:93363 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0259817 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0701836 infores:hetionet CHEBI:8802 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0024312 infores:hetionet CHEBI:10110 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0002878 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0271412 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0271412 infores:hetionet NCBIGene:90952 biolink:causes MONDO:0957267 infores:monarchinitiative not_provided not_provided HGNC:17474 MONDO:0957267 uuid:747f06e7-368c-4d4c-bb9c-b264434a16d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0013404 infores:hetionet CHEBI:9288 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0085682 infores:hetionet UMLS:C0004609 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0231530 infores:hetionet CHEBI:31348 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011606 infores:hetionet CHEBI:15544 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0012739 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0751249 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0751249 infores:hetionet CHEBI:4445 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0019080 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0227791 infores:hetionet CAID:CA341499 biolink:causes MONDO:0100084 infores:clingen CAID:CA341499 MONDO:0100084 PMID:19206168 Pathogenic PP2, PP3, PP4, PM2_Supporting, PS3, PM5 The c.1000C>T (NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by serine at amino acid 334 (p.Pro334Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). 2 different missense variants, [p.Pro334Leu, (VCV000532770); p.Pro334Arg, (VCV001031829)], in the same codon have been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). One patient with the p.Pro334Ser variant displayed fiber type disproportion, which is highly specific for alpha-actinopathy (PP4, PMID: 15468086 & University of Western Australia internal data). Localization analysis of the mutant in myotubes showed no incorporation into nascent sarcomeres. Analysis in fibroblasts showed diffuse cytoplasmic myc-actin staining (PMID: 19206168; PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_supporting, PP2, PP3, PM5, PP4, PS3 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 10/25/24). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA341499/MONDO:0100084/147 2024-10-25 2025-04-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15367 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0424000 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0728725 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0728725 infores:hetionet CHEBI:2379 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0002622 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149931 infores:hetionet CHEBI:6067 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151825 infores:hetionet CHEBI:8871 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037299 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030353 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0037274 infores:hetionet CHEBI:61049 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009421 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0234215 infores:hetionet CAID:CA405673698 biolink:causes MONDO:0007783 infores:clingen CAID:CA405673698 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with tyrosine at codon 60 of the RYR1 protein p.(Asp60Tyr). This variant was not present in a large population database (gnomAD). This variant has been reported in an individual with a personal history of an MH episode and a positive in vitro contracture test (IVCT) result, PS4_Supporting (PMID:24433488). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1. A REVEL score >0.85 (0.961) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405673698/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA229341 biolink:causes MONDO:0009861 infores:clingen CAID:CA229341 MONDO:0009861 PMID:8268925PMID:8830172PMID:21147011PMID:22841515 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1097C>A (p.Pro366His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8268925). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.R158Q (PMID: 8830172); c.165delT (p.F55fs, PMID: 19292873); c.1066-11G>A (PMID: 22841515); p.P281L (PMID: 21147011). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229341/MONDO:0009861/006 2020-08-14 2021-07-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10110 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0234913 infores:hetionet CHEBI:3082 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0003811 infores:hetionet CHEBI:7476 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0221242 infores:hetionet CHEBI:585948 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0032617 infores:hetionet CHEBI:42797 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022281 infores:hetionet CHEBI:3698 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C1167965 infores:hetionet CHEBI:9622 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C1443060 infores:hetionet CHEBI:3757 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0042963 infores:hetionet CHEBI:3696 biolink:causes HP:0003537 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0221333 infores:hetionet CHEBI:66913 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0162285 infores:hetionet CAID:CA589193 biolink:causes MONDO:0100283 infores:clingen CAID:CA589193 MONDO:0100283 PMID: Uncertain Significance PP2 BS1 The c.5978A>G (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Lys1993Arg). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PP2; 1 point (VCEP specifications version 1; Approved: 1/31/2021) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA589193/MONDO:0100283/018 2022-02-11 2022-02-11 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:51137 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0018799 infores:hetionet CHEBI:7852 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0019209 infores:hetionet CHEBI:9943 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0039231 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0549383 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0549383 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0549475 infores:hetionet CHEBI:63631 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0016199 infores:hetionet CHEBI:6520 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0919924 infores:hetionet CHEBI:50131 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0004604 infores:hetionet CHEBI:4995 biolink:causes MONDO:0044037 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085642 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0031117 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004238 infores:hetionet CHEBI:42797 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151786 infores:hetionet CHEBI:28748 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2979982 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0021053 infores:hetionet CAID:CA000501 biolink:causes MONDO:0017623 infores:clingen CAID:CA000501 MONDO:0017623 PMID:29706350 Likely Pathogenic PP3, PP2, PM5, PS3_Moderate, PM2_Supporting PP1, PS4 PTEN c.520T>A (p.Tyr174Asn) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria v3.1.0 (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM5: Missense change at the same amino acid position and equal BLOSUM62 score (Henikoff et al. 1992 (PMID: 1438297)). c.521A>G (p.Tyr174Cys), has been identified and characterized by PTEN VCEP as likely pathogenic. PS3_M: Truncation-like score of -2.92 in Massively parallel functional assay interrogating phosphatase activity Mighell et al. 2018 (PMID: 29706350). Additionally, mutated protein found to have greater than 50% reduction in phosphatase activity in Han et al. 2000 (PMID: 10866302). PP2: PTEN classified as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score (.946) greater than 0.7. PM2_P: Variant absent from gnomad v4. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000501/MONDO:0017623/003 2025-10-03 2025-10-27 Autosomal dominant inheritance HP:0000006 Supports CAID:CA210766 biolink:causes MONDO:0013144 infores:clingen CAID:CA210766 MONDO:0013144 PMID: Pathogenic PS4, PP1_Moderate, PP3, PP4, PM2_Supporting PM5, PVS1 The c.1274G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 425 (p.Arg425His; legacy nomenclature p.R393H aka Antithrombin Glasgow). The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF <2.0 X 10-5). This variant has been reported in at least 16 probands in the literature with AT deficiency meeting PP4 and PS4_VeryStrong (PMID: 26134363; 27766527; 28607330; 28300866; 3179448). Additionally, this variant has been report in at least 4 meioses across 14 families meeting PP1_Moderate. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Moderate, PP3, PP4, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210766/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10023 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151577 infores:hetionet CAID:CA034973 biolink:causes MONDO:0007750 infores:clingen CAID:CA034973 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP2, PS1, PS3, PS2, PS4, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1586+15C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 May 2025.The supporting evidence is as follows:PM2: PopMax MAF = 0.0001991 (0.01991%) in South Asian exomes+genomes (gnomAD v4.1.0).BP4: No REVEL, splicing evaluation needed.Functional data on splicing not available.A) variant not on limits.B) variant is not exonic.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034973/MONDO:0007750/013 2025-05-09 2025-10-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8863 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003123 infores:hetionet CHEBI:63616 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151578 infores:hetionet CHEBI:3077 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0240735 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009324 infores:hetionet NCBIGene:125150 biolink:causes MONDO:0030736 infores:monarchinitiative not_provided not_provided HGNC:26993 MONDO:0030736 uuid:d7d7978b-b121-4a3e-a912-c5fac619b017 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3757 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0002994 infores:hetionet CHEBI:2618 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0015672 infores:hetionet CHEBI:6887 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018681 infores:hetionet CHEBI:50275 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0016658 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0948594 infores:hetionet CHEBI:70735 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0085631 infores:hetionet GO:0044487 biolink:causes GO:0019226 infores:ubergraph knowledge_assertion manual_agent GO:0044487 GO:0019226 CHEBI:84050 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0023530 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0034065 infores:hetionet CHEBI:6717 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1167709 infores:hetionet CHEBI:8871 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0039239 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0347390 infores:hetionet CHEBI:75722 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0021368 infores:hetionet CHEBI:3752 biolink:causes HP:0100694 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0426900 infores:hetionet CHEBI:7931 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0033774 infores:hetionet CHEBI:28748 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019080 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0041912 infores:hetionet CHEBI:63620 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0002962 infores:hetionet CHEBI:63681 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0520966 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0029882 infores:hetionet CHEBI:7915 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019521 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0205204 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0233494 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151625 infores:hetionet CHEBI:8764 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019270 infores:hetionet CHEBI:63631 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017672 infores:hetionet CHEBI:47499 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0030554 infores:hetionet CAID:CA6402595 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402595 MONDO:0019565 PMID: Benign BA1, BP4, BP5 BS2 The NM_000552.5:c.4138A>G variant in VWF is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1380. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1164 (based on 8878/74958 alleles in the African/African American population, including 541 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 VWD Type 2B patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic for VWD Type 2B by the ClinGen VWD Type 2 VCEP (BP5; PMID: 30817071). At least 16 healthy adult individuals harboring the p.Asn1435Ser variant were found to be unaffected, with no diagnosis of a bleeding disorder and normal lab values, including bleeding scores lower than 4, VWF:RCo/VWF:Ag ratios >0.6, and no increased response to low-dose ristocetin (PMID: 20231421). The mean VWF:RCo/VWF:Ag ratio of 0.71-0.77 within this group was significantly reduced compared to 0.91-0.97 for WT, but within the normal range. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. The computational predictor REVEL gives a score of 0.098, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant is classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4, BP5. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402595/MONDO:0019565/090 2024-11-05 2024-11-06 Undetermined mode of inheritance Contradicts true CHEBI:18248 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0233494 infores:hetionet CHEBI:135351 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0033774 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0035078 infores:hetionet CHEBI:5855 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0004144 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0003834 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0948594 infores:hetionet CHEBI:63622 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0019080 infores:hetionet CHEBI:2950 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0024902 infores:hetionet CHEBI:61049 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0231528 infores:hetionet CHEBI:50131 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0015230 infores:hetionet CHEBI:63717 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0002994 infores:hetionet CHEBI:465284 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0149745 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0018801 infores:hetionet CHEBI:101278 biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0520886 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0042401 infores:hetionet CHEBI:2618 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0522224 infores:hetionet CHEBI:5613 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0018843 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0027651 infores:hetionet CHEBI:3752 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020555 infores:hetionet CHEBI:8060 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C2047937 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017566 infores:hetionet CHEBI:31397 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0271738 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0233494 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0041969 infores:hetionet CHEBI:7931 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0023530 infores:hetionet CHEBI:107736 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0233565 infores:hetionet CHEBI:8435 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0241442 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0004096 infores:hetionet CHEBI:2788 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0030554 infores:hetionet CHEBI:7915 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0035410 infores:hetionet CHEBI:119915 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006625 infores:hetionet CHEBI:68579 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0085932 infores:hetionet CHEBI:5558 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0022107 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0003123 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037284 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0042109 infores:hetionet CHEBI:50729 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0013144 infores:hetionet GO:0072094 biolink:causes GO:0072273 infores:ubergraph knowledge_assertion manual_agent GO:0072094 GO:0072273 CHEBI:64321 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0392618 infores:hetionet CHEBI:135451 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0016204 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042514 infores:hetionet CAID:CA043225 biolink:causes MONDO:0007750 infores:clingen CAID:CA043225 MONDO:0007750 PMID: Likely Pathogenic PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS3, PS1, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4.PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA043225/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:79699 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0009806 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020517 infores:hetionet CAID:CA197176 biolink:causes MONDO:0700272 infores:clingen CAID:CA197176 MONDO:0700272 PMID:31757951PMID:31636395 Uncertain Significance PM2_Supporting, BP1 PS3 The c.2831T>A variant in PALB2 is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 944 (p.Ile944Asn). This variant is absent from gnomAD v2.1.1. This variant is non-functional in multiple different protein assays (PMID: 31757951, 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM2_Supporting, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA197176/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47381 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0043144 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0022658 infores:hetionet CAID:CA226506 biolink:causes MONDO:0100368 infores:clingen CAID:CA226506 MONDO:0100368 PMID:16150724 Pathogenic PM3, PP3_Moderate, PP1_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.131G>A (p.Arg44Gln) is a missense variant predicted to replace arginine with glutamine at amino acid p.44. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00008443, with 13 alleles / 91,066 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 20079931, PMID: 20683928, PMID: 25775262, PMID: 31960602). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant suspected in trans (0.5 points, PMID: 20079931), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), onset before the age of 5 years (1 pt), strong night blindness, light-seeking behavior (1 pt), absent electroretinogram responses from both rods (0.5 pts) and cones (1 pt), abnormal color vision, reduced central visual acuity (1 pt), hyperopia, esotropia, discrete retinal vessel attenuation in the context of a normal fundus, very small white intraretinal flecks in mid- and far periphery (2 pts), visual field constriction (1 pt), obesity, mild mental retardation, and autism, which together are highly specific for RPE65-related recessive retinopathy (total 8 points, PMID: 20683928, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 25775262). The computational predictor REVEL gives a score of 0.971, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0-2% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 16150724, PMID: 19431183, PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3, PP1_Moderate, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226506/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3504 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0002792 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002378 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011649 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017168 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0011849 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0859871 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0859871 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0948594 infores:hetionet CHEBI:3996 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0020580 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0005940 infores:hetionet CAID:CA392254551 biolink:causes MONDO:0012996 infores:clingen CAID:CA392254551 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_001482.3: c.1269C>G variant in GATM is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 423 (p.Asp423Glu). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.092 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function, and SpliceAI does not predict any impact in splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 58991). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392254551/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4466 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151744 infores:hetionet CAID:CA367400799 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400799 MONDO:0015967 PMID: Pathogenic PS4, PVS1, PM2_Supporting PP4 The c.680-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 6 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 7 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4: PMIDs: 19790256, 31704690, 36257325, 34362814, ClinVar ID:585924). At least 2 of these individuals had a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 31704690). In summary, c.680-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PVS1, PS4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400799/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:61390 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0013395 infores:hetionet CHEBI:391960 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0004604 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0235639 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0023418 infores:hetionet CHEBI:9130 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0026826 infores:hetionet CHEBI:7444 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0851578 infores:hetionet CHEBI:9622 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0042029 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0012833 infores:hetionet CAID:CA10576310 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576310 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP4, PM5 The NM_000527.5(LDLR):c.1588T>G (p.Phe530Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001891 (0.001891%) in European (non-Finnish) exomes/genomes (gnomAD v4.1.0). PP3: REVEL = 0.868. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases (1 case with DLCN>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; 1 case fulfilling Japan Atherosclerosis Society criteria for FH reported in PMID 36229376 (Tada et al., 2022)), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576310/MONDO:0007750/013 2025-02-20 2025-06-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9168 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018965 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0002170 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034882 infores:hetionet CHEBI:101278 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0234133 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0851341 infores:hetionet NCBIGene:4174 biolink:causes MONDO:0033046 infores:monarchinitiative not_provided not_provided HGNC:6948 MONDO:0033046 uuid:e43ce052-27e5-48bc-8a73-2e355967b677 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:240107 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0497201 infores:hetionet CHEBI:36791 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018524 infores:hetionet CHEBI:7581 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0028084 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0006266 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0018418 infores:hetionet CHEBI:31547 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0007820 infores:hetionet CAID:CA913169128 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169128 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PP1_Moderate BP4, PS4, PS2, PM6 The m.3288A>G variant in MT-TL1 has been reported in one family to date, and several family members were affected with primary mitochondrial disease (PMID: 10402027). Clinical features seen in affected individuals included mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), respiratory failure requiring tracheostomy, myopathy, neuropathy, migraines, gastroparesis, lipoma, ptosis, and mood disorder. COX-negative and ragged red fibers were seen on muscle biopsy. The variant was present in skeletal muscle from the proband at 97% and present in blood from other affected family members ranging from 61-78%. The variant has further segregated with disease manifestations in this family (PP1_moderate). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is benign (36.1 percentile) but HmtVAR predicts it to be pathogenic with a score of 0.35. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP1_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169128/MONDO:0044970/015 2024-12-09 2025-05-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA274538167 biolink:causes MONDO:0044970 infores:clingen CAID:CA274538167 MONDO:0044970 PMID: Uncertain Significance PM2 The c.*100G>A variant in POLG was see in gnomAD at 0.013% allele frequency and not present in any homozygotes (PM2). There are no cases reported in the literature. In summary, this variant meets criteria to be classified as a variant of uncertain significance for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PM2 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274538167/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:64355 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235198 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0030305 infores:hetionet CHEBI:33130 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0546817 infores:hetionet CHEBI:45599 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0041657 infores:hetionet CHEBI:45652 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0020649 infores:hetionet CAID:CA8970178 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970178 MONDO:0012589 PMID: Benign BA1, PP3, BS2 The highest population minor allele frequency of the c.1487-5G>A variant in TCF4 in gnomAD v4.1 is 0.0016 in the Ashkenazi Jewish population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The c.1487-5G>A variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). The computational splicing predictor SpliceAI gives a score of 1 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 16 of TCF4 (PP3). However, the resulting protein impact is minimal (one amino acid insertion) and therefore does not conflict with other benign lines of evidence. Therefore, in summary, the c.1487-5G>A variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970178/MONDO:0012589/032 2024-06-25 2025-03-07 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:79188 biolink:causes MONDO:0011459 infores:monarchinitiative not_provided not_provided HGNC:28472 MONDO:0011459 uuid:801ecdba-846d-4ae1-97ee-9050cc9d1940 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3508 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0267792 infores:hetionet CHEBI:71219 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151934 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0236071 infores:hetionet CHEBI:135876 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0004604 infores:hetionet CHEBI:15765 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0085637 infores:hetionet CHEBI:2904 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0547030 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027051 infores:hetionet CAID:CA3044620384 biolink:causes MONDO:0100216 infores:clingen CAID:CA3044620384 MONDO:0100216 PMID:39976125 Uncertain Significance PP4, PM2_Supporting, PM4_Supporting BP2, BA1, PP1, BS2, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS4 The NM_177438.2:c.4560_4562del variant is predicted to cause a change in the length of the protein (p.Glu1520del) due to an in-frame deletion of 1 amino acid in a non-repeat region outside of the RNase IIIb domain (PM4_Supporting). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with phenotypes of DICER1-related tumor predisposition warranting points application (PS4 not met; PMIDs: 39976125, Internal lab contributors). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMIDs: 39976125). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Functional data supporting impaired function of the mutant protein has been published; however, the assays reported are not supported under the current DICER1 VCEP v1.4 variant classification criteria specifications (PS3 not met; PMID: 39976125). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 3; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA3044620384/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5004 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0040264 infores:hetionet CHEBI:6073 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0010200 infores:hetionet CHEBI:47381 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C2830004 infores:hetionet CHEBI:9123 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020564 infores:hetionet CHEBI:7983 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0242184 infores:hetionet CAID:CA401361913 biolink:causes MONDO:0009290 infores:clingen CAID:CA401361913 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting The NM_000152.5:c.546+1G>T variant in GAA occurs within the canonical splice donor site of intron 2. Two studies involving minigene analysis have showed that the variant disrupts normal splicing, resulting in skipping of exon 2 (PMID: 31301153, 39905333). Exon 2 contains the start methionine and signal sequence for GAA (amino acids 1-27; https://www.uniprot.org/uniprot/P10253). Deletion of exon 2 causes complete loss of enzyme activity when expressed in heterologous cells (Huie et al, 1994, PMID 7881425; Boerkoel et al, 1995, PMID 7717400) (PVS1). At least 5 probands with symptoms consistent with late-onset Pompe disease have been reported with this variant (PMID: 18285536, 25396301, 25712382, 28838325), one with documented GAA deficiency with <10% of normal mean control level of GAA activity in a muscle sample (PP4_Moderate). Of those individuals, 4 were compound heterozygous for this variant and another variant in GAA, c.-32-13T>G (ClinVar Variation ID: 4027), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. The phase is unconfirmed in all cases (PMID: 18285536, 25396301, 25712382, 28838325) (PM3). Additionally, this variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 3241650). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PM2_Supporting, PM3, PP4_Moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 1, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401361913/MONDO:0009290/010 2025-07-01 2025-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7959 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0027497 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0234215 infores:hetionet CHEBI:8802 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0855775 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009319 infores:hetionet CHEBI:68606 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C1262113 infores:hetionet CHEBI:28864 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0231218 infores:hetionet CHEBI:7809 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0948594 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0027765 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009450 infores:hetionet CHEBI:8024 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0033687 infores:hetionet CHEBI:16914 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0042963 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0178298 infores:hetionet CHEBI:6367 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013390 infores:hetionet CHEBI:64028 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0013144 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0740832 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0740832 infores:hetionet CHEBI:4910 biolink:causes UMLS:C0520904 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0520904 infores:hetionet CAID:CA229383 biolink:causes MONDO:0009861 infores:clingen CAID:CA229383 MONDO:0009861 PMID: Pathogenic PM2, PP4, PM3_Strong, PVS1_Strong The c.1198del (p.Arg400fs) variant in PAH has been detected in 1 patient from the Northeastern US, serum Phe > 240umol/L; BH4 deficiency not excluded (PMID: 8659548; PP4). This variant was detected with c.168+1G>A and I65T, both reported as pathogenic in ClinVar and confirmed in trans (2.0points; PM3_Strong). This frameshift variant is not predicted to undergo NMD, located in intron 11-12 out of 13 total exons (11 out of total exons) (PVS1_Strong), and this variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_Strong, PM2, PP4, PM3_Strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229383/MONDO:0009861/006 2021-05-29 2021-05-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:144093 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0085649 infores:hetionet CHEBI:8107 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0043352 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1510497 infores:hetionet CHEBI:8874 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151205 infores:hetionet CHEBI:17474 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0003467 infores:hetionet CHEBI:10023 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020580 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0162429 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0836924 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0005575 uuid:b1172542-f50c-44ea-9596-bb61450efb68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017160 infores:hetionet CHEBI:4907 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0001824 infores:hetionet CHEBI:63622 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0042963 infores:hetionet CHEBI:44915 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0011570 infores:hetionet CHEBI:42944 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C2047937 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0235280 infores:hetionet CHEBI:4784 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0038325 infores:hetionet CHEBI:66876 biolink:causes NCIT:C96935 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0149707 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0025061 infores:hetionet CAID:CA015727 biolink:causes MONDO:0005045 infores:clingen CAID:CA015727 MONDO:0005045 PMID: Pathogenic PP1_Strong, PM2, PS4 PM1, PM4, PM6, PM5, PP3, BA1, PS3, BS1, BS4, BS3, BP3, BP4, BP7, BP2, BP5, PS2, PS1, PVS1 The NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln) variant has been reported in >30 individuals with HCM (PS4; Miller 2013 PMID: 23054336; Mook 2013 PMID: 23785128; Glotov 2015 PMID: 25892673; Lopes 2015 PMID: 25351510; Helms 2016 PMID: 27688314; Mademont-Soler 2017 PMID: 28771489; Weissler-Snir 2017 PMID: 28193612; van Velzen 2017 PMID: 2879411; van Lint 2019 PMID: 30847666; Tran Vu 2019 PMID: 31308319; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected relatives with HCM in at least 9 families (PP1_strong; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.002% (FAF 95% CI; 6/128842) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PP1_strong, PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015727/MONDO:0005045/002 2021-12-09 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4909 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0392525 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0948594 infores:hetionet CHEBI:31413 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0004134 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151735 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020514 infores:hetionet CAID:CA023404 biolink:causes MONDO:0007750 infores:clingen CAID:CA023404 MONDO:0007750 PMID: Benign BP4, BA1 BP1, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met.BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023404/MONDO:0007750/013 2021-12-13 2022-01-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:9326 biolink:causes MONDO:0009841 infores:monarchinitiative not_provided not_provided HGNC:12309 MONDO:0009841 uuid:7e3b2f57-7d38-43c5-b5e9-96c76161b925 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0008370 infores:hetionet CHEBI:3510 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0022346 infores:hetionet CHEBI:5558 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0028084 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0242151 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0743300 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0743300 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0041349 infores:hetionet CHEBI:5118 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0026961 infores:hetionet CHEBI:93305 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0018681 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0003864 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0003123 infores:hetionet CHEBI:194135 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085628 infores:hetionet CHEBI:45783 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020598 infores:hetionet CHEBI:6715 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151671 infores:hetionet CHEBI:5147 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0018965 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0041969 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151736 infores:hetionet CHEBI:44915 biolink:causes HP:0031967 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0278034 infores:hetionet CAID:CA396457352 biolink:causes MONDO:0007648 infores:clingen CAID:CA396457352 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.308G>A p.(Trp103*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000669020.2). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396457352/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:135451 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0009450 infores:hetionet CHEBI:8207 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0019521 infores:hetionet CHEBI:63598 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235086 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0036572 infores:hetionet CHEBI:6438 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0009763 infores:hetionet NCBITaxon:1392 biolink:causes MONDO:0001701 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1392 MESH:C571911 DB02703_MESH_C571911_1DB01053_MESH_C571911_1DB00254_MESH_C571911_1 CHEBI:119486 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0015663 infores:hetionet CHEBI:6792 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0030193 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0877517 infores:hetionet CHEBI:8802 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018965 infores:hetionet CHEBI:6532 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0015230 infores:hetionet CAID:CA397317955 biolink:causes MONDO:0009276 infores:clingen CAID:CA397317955 MONDO:0009276 PMID: Uncertain Significance PP4, PM2_Supporting, BP4, PM3_Supporting The c.663C>A variant in GP1BA is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 221 (p.Asn221Lys). At least one patient (Patient 3 in PMID:33217855) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.259, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BA function and the SpliceAI score is zero (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PP4, PM3_Supporting, PM2_Supporting and BP4 (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397317955/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45951 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0392156 infores:hetionet CHEBI:3215 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0278134 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0013395 infores:hetionet CHEBI:2922 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0038362 infores:hetionet CHEBI:52172 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0023211 infores:hetionet CHEBI:9150 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0438717 infores:hetionet CHEBI:15544 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0392171 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042769 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0152029 infores:hetionet CHEBI:472657 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0002792 infores:hetionet CHEBI:74947 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003862 infores:hetionet CAID:CA367397324 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397324 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS1_Supporting PS4, PP1 The c.1254-1G>T variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000162.5. While this variant is predicted to cause skipping of exon 10 and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 24735133). The c.1254-1G>C variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1254-1G>T has a similar predicted impact by Splice AI (0.95 and 0.95) (PS1_Supporting). In summary, c.1254-1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4, PS1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397324/MONDO:0015967/086 2023-06-26 2023-06-26 Semidominant inheritance HP:0032113 Supports CHEBI:3698 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0349506 infores:hetionet CHEBI:63619 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0028734 infores:hetionet CHEBI:3380 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030805 infores:hetionet CHEBI:68554 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0033774 infores:hetionet CHEBI:16914 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0040264 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0027765 infores:hetionet NCBIGene:9211 biolink:causes MONDO:0700090 infores:monarchinitiative not_provided not_provided HGNC:6572 MONDO:0700090 uuid:7c46a843-02bc-4362-9899-3f57c2fae232 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0021400 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0178298 infores:hetionet NCBIGene:57465 biolink:causes MONDO:0014133 infores:monarchinitiative not_provided not_provided HGNC:29203 MONDO:0014133 uuid:b91be101-522f-4c6d-8aae-cecd78edd909 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68595 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0035309 infores:hetionet CHEBI:28748 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085649 infores:hetionet CHEBI:63791 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0016382 infores:hetionet CHEBI:3749 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0151825 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0235146 infores:hetionet CHEBI:42944 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0008031 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0267537 infores:hetionet CHEBI:71415 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0232462 infores:hetionet CHEBI:5138 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0004604 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0233794 infores:hetionet CHEBI:92607 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0018681 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009938 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0521839 infores:hetionet CHEBI:92511 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0042963 infores:hetionet CHEBI:4672 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0236075 infores:hetionet CHEBI:7773 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0494475 infores:hetionet CHEBI:49575 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0004134 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018799 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0027339 infores:hetionet NCBIGene:9128 biolink:causes MONDO:0014400 infores:monarchinitiative not_provided not_provided HGNC:17349 MONDO:0014400 uuid:2516ff90-df34-4962-a024-f201dcd2b693 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0232292 infores:hetionet CHEBI:3216 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0003578 infores:hetionet CHEBI:8863 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085649 infores:hetionet CHEBI:7936 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027066 infores:hetionet CHEBI:31236 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0852911 infores:hetionet CHEBI:2654 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0235378 infores:hetionet CHEBI:31236 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026826 infores:hetionet CHEBI:64312 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1456822 infores:hetionet CAID:CA16020838 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020838 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4 PM3 The nonsense variant c.682G>T (p.Glu228Ter) generates a stop codon in exon 6 of 13 and is predicted to undergo NMD. The variant is absent from population databases, including gnomAD. It has been reported in at least one compound heterozygous patient with classical PKU (PMID: 24401910), in trans with VUS variant Val190Gly. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020838/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037317 infores:hetionet CHEBI:72564 biolink:causes HP:0007359 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0751495 infores:hetionet CHEBI:4784 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0042029 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0029408 infores:hetionet CHEBI:116278 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0340865 infores:hetionet CHEBI:23765 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0423791 infores:hetionet UMLS:C0009315 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0011603 infores:hetionet CHEBI:63619 biolink:causes NCIT:C168039 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0007280 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0948595 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020473 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0041912 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0012833 infores:hetionet CHEBI:17688 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0042963 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0036572 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0851341 infores:hetionet CHEBI:51860 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018965 infores:hetionet CHEBI:6402 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0018944 infores:hetionet CHEBI:2668 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0017178 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877232 infores:hetionet CHEBI:6067 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0750394 infores:hetionet CHEBI:10023 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019209 infores:hetionet CHEBI:9586 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019209 infores:hetionet CHEBI:3437 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0030252 infores:hetionet NCBITaxon:12080 biolink:causes MONDO:0005684 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12080 MONDO:0005684 CHEBI:68478 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0311468 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0149931 infores:hetionet CHEBI:71223 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0549373 infores:hetionet CHEBI:63623 biolink:causes UMLS:C0574068 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0574068 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0009759 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002305 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0398623 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002529 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0553723 infores:hetionet CHEBI:8888 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002962 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0162429 infores:hetionet CHEBI:63619 biolink:causes MONDO:1030011 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235480 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009806 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042075 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D001991 DB01150_MESH_D001991_1 CHEBI:40279 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0028961 infores:hetionet CHEBI:28971 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0023066 infores:hetionet CHEBI:3082 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0027497 infores:hetionet CHEBI:3223 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0025874 infores:hetionet CHEBI:63617 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019209 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0023895 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0015397 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040046 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0004936 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0860866 infores:hetionet CAID:CA2573051050 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051050 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM4 PP4 The c.1864_1890dup variant in the HNF1 homeobox A gene, HNF1A, is a 27 base pair insertion resulting in the in-frame addition of 9 amino acids at codon 622 (p.Ile622_Ser630dup) within exon 10 of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The c.1864_1890dup variant is also predicted to change the length of the protein due an in-frame insertion of 9 amino acids in a nonrepeat region (PM4). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and HNF4A was not tested; therefore, PP4 could not be applied (internal lab contributors). In summary, c.1864_1890dup meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0 approved 6/30/2025): PM2_Supporting, PM4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051050/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75722 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0392525 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042594 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0151763 infores:hetionet CAID:CA10585740 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585740 MONDO:0007750 PMID: Likely Pathogenic PM1, PM2, PP3, PP4 BA1, BP4, PS1, BS1, PM5 The NM_000527.5(LDLR):c.2041T>G (p.Cys681Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v.4.1.0). PM1: Variant meets PM2 and alters Cys681, one of the cysteine residues listed.PP3: REVEL = 0.957.PP4: Variant meets PM2 and is identified in 1 case with DLCN score >=6 in PMID 18648394 (Snozek et al., 2009), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585740/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:40237 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0043352 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0009450 infores:hetionet CHEBI:63631 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027424 infores:hetionet CHEBI:134745 biolink:causes UMLS:C0541772 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0541772 infores:hetionet CHEBI:50859 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0014591 infores:hetionet NCBIGene:10060 biolink:causes MONDO:0859224 infores:monarchinitiative not_provided not_provided HGNC:60 MONDO:0859224 uuid:602570a2-6f76-42e2-9524-f1facd4e68a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0879264 biolink:causes MONDO:0005657 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004030 infores:hetionet CHEBI:70735 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0013384 infores:hetionet CHEBI:5383 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0428977 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0162429 infores:hetionet CHEBI:7822 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0030920 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0030312 infores:hetionet CHEBI:4708 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0008031 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0025061 infores:hetionet CHEBI:5280 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151825 infores:hetionet CHEBI:4657 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0231919 infores:hetionet CHEBI:261649 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0013491 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233632 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C1269683 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0038661 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0012833 infores:hetionet CHEBI:5165 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0014038 infores:hetionet CAID:CA000555 biolink:causes MONDO:0017623 infores:clingen CAID:CA000555 MONDO:0017623 PMID:15805158PMID:21194675PMID:21828076PMID:25527629PMID:29785012PMID:25937288PMID:29373119PMID:29706350PMID:26579216PMID:15805158 Likely Pathogenic PP3, PP2, PS3_Moderate, PS4_Supporting, PM2_Supporting BP5, BP7, BS4, BS3, BS1, PM6, PVS1, PP1, PP4, BS2, PM3, PM1, PM4, PM5, BP2, BP4, BP1, BP3, BA1, PS2, PS1 NM_000314.8(PTEN):c.722T>C (p.Phe241Ser) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:15805158).PM2_P: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score=0.858). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000555/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83527 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0037274 infores:hetionet CHEBI:80630 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0020625 infores:hetionet CHEBI:47898 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151908 infores:hetionet CHEBI:6904 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0700361 infores:hetionet CHEBI:4735 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0027540 infores:hetionet CHEBI:4953 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0877055 infores:hetionet CHEBI:6888 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0036974 infores:hetionet CHEBI:2955 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0030193 infores:hetionet CHEBI:5001 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0015967 infores:hetionet CHEBI:3749 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C3665347 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0021099 infores:hetionet NCBIGene:3858 biolink:causes MONDO:0700248 infores:monarchinitiative not_provided not_provided HGNC:6413 MONDO:0700248 uuid:297be3e6-9a0c-47ba-a842-d161879ed4e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:K2J09EMJ52 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0019158 infores:hetionet CHEBI:5790 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235996 infores:hetionet CHEBI:31236 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0547030 infores:hetionet CHEBI:131512 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0085631 infores:hetionet CHEBI:46195 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0030805 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0162296 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0162296 infores:hetionet CHEBI:3242 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0020458 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027051 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0518015 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0032285 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235146 infores:hetionet CAID:CA404083112 biolink:causes MONDO:0007750 infores:clingen CAID:CA404083112 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4 The variant NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.903PS4_Supporting: Variant meets PM2, and is identified in 2 unrelated cases: 1 case with DLCN>6 from PMID: 30745730; 1 case with Simon-Broome criteria of possible FH from Color Health. So, PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded.PM5 - 4 other missense variants in the same codon:1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines.2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines.3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines.4) NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) (ClinVar ID 251645) - Likely Pathogenic by these guidelines.There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404083112/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:2453 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0549249 infores:hetionet CHEBI:28487 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0028084 infores:hetionet CHEBI:10119 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085636 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0040034 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0234192 infores:hetionet CHEBI:38940 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027424 infores:hetionet CHEBI:45863 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0016382 infores:hetionet CAID:CA1244333 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244333 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PVS1, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.56_72dup variant in MYOC is predicted to cause a change in the length of the protein due to a duplication of 17 nucleotides which leads to a frameshift and termination of the protein at amino acid 89 (p.Cys25SerfsTer65). Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with primary open angle glaucoma is not loss-of-function. The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00002669 (2 alleles out of 74,934), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 10196380), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244333/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4653 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0019158 infores:hetionet CHEBI:17334 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0037299 infores:hetionet CHEBI:3223 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0152032 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0037274 infores:hetionet CHEBI:8874 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1306341 infores:hetionet CHEBI:7824 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0035455 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0852913 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0234708 infores:hetionet CHEBI:63631 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0750857 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0037199 infores:hetionet CHEBI:17303 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0030232 infores:hetionet CHEBI:5123 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C2830004 infores:hetionet CHEBI:6015 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0020649 infores:hetionet CHEBI:100241 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0015967 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017675 infores:hetionet CHEBI:49668 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C1145670 infores:hetionet CAID:CA386304171 biolink:causes MONDO:0009861 infores:clingen CAID:CA386304171 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4 PM3 The c.229T>C (p.Tyr77His) variant in PAH is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 77. It has been detected in 1 patient with mild PKU with second variant not reported (PMID: 27469133). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant is classified as uncertain significance due to insufficient evidence for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386304171/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8805 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0023530 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020295 infores:hetionet CHEBI:94440 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0233494 infores:hetionet CHEBI:27436 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0340726 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0860713 infores:hetionet CHEBI:3175 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1761613 infores:hetionet CAID:CA214321 biolink:causes MONDO:0015967 infores:clingen CAID:CA214321 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PM5, PP4 The c.731G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to isoleucine at codon 244 (p.Arg244Ile) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.939, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 21224407); therefore, PP4 cannot be applied. Another missense variant, c.732A>T (p.Arg244Ser) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 cannot be applied. In summary, c.731G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214321/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7577 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C3665347 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0004936 infores:hetionet CAID:CA2573142156 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573142156 MONDO:0015967 PMID: Uncertain Significance PM4_Supporting, PP4_Moderate, PM2_Supporting PS4, PP1 The c.48_50del variant in the glucokinase gene, GCK, is a 3 base pair deletion resulting in the in-frame deletion of glutamic acid at codon 17 (p.(Glu17del)) within exon 2 of NM_000162.5. The c.48_50del variant is predicted to change the length of the protein due an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36178555, ClinVar). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; PMID: 36178555). This variant segregated with diabetes with a single informative meiosis in one family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 36178555). In summary, c.48_50del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PP4_Moderate, PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573142156/MONDO:0015967/086 2025-01-03 2025-01-03 Semidominant inheritance HP:0032113 Inconclusive true NCBIGene:6786 biolink:causes MONDO:0008497 infores:monarchinitiative not_provided not_provided HGNC:11386 MONDO:0008497 uuid:a4e838c0-f9da-453a-b816-c5a9592c776b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235431 infores:hetionet CHEBI:135930 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151904 infores:hetionet CHEBI:68606 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0549475 infores:hetionet NCBIGene:7837 biolink:causes MONDO:0010015 infores:monarchinitiative not_provided not_provided HGNC:14966 MONDO:0010015 uuid:f85f74c2-b6c1-4fe6-a989-4ae478128277 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:43968 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0004096 infores:hetionet CHEBI:404903 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0033687 infores:hetionet CHEBI:31536 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0017178 infores:hetionet UMLS:C0657912 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015967 infores:hetionet CHEBI:4657 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0027497 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0231218 infores:hetionet CHEBI:135920 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0039231 infores:hetionet CHEBI:131512 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0344232 infores:hetionet CHEBI:75722 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040460 infores:hetionet CHEBI:16469 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006152 infores:hetionet NCBIGene:157570 biolink:causes MONDO:0008992 infores:monarchinitiative not_provided not_provided HGNC:27230 MONDO:0008992 uuid:325f8edb-a181-4826-b1c0-932b136f8e6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9738 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0235660 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0036572 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151773 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0162429 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023530 infores:hetionet CHEBI:6067 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0043352 infores:hetionet CHEBI:83804 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0043352 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0333641 infores:hetionet CHEBI:28901 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085641 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0151827 infores:hetionet CHEBI:3723 biolink:causes UMLS:C3203531 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C3203531 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0853813 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0009806 infores:hetionet CHEBI:4672 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151594 infores:hetionet CHEBI:10650 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0232849 infores:hetionet NCBIGene:1967 biolink:causes MONDO:0020507 infores:monarchinitiative not_provided not_provided HGNC:3257 MONDO:0020507 uuid:00629410-c642-4255-97ca-862b1057d498 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0033774 infores:hetionet CHEBI:16335 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0085631 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027651 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0035258 infores:hetionet CHEBI:8888 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038435 infores:hetionet CAID:CA1251475 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251475 MONDO:0013144 PMID: Likely Benign BS1, BP4 The c.47T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of valine by alanine at amino acid residue 16 (p.Val16Ala). The variant is reported at a Grpmax allele frequency of 0.0005418 in gnomAD v4.1 meeting BS1 (>0.0002). The computational predictor REVEL gives a score of 0.146, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251475/MONDO:0013144/084 2024-08-16 2024-08-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4822 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0017086 infores:hetionet CHEBI:8768 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0043094 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0032584 infores:hetionet CHEBI:8888 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1443060 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0948693 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0948693 infores:hetionet NCBIGene:9896 biolink:causes MONDO:0012986 infores:monarchinitiative not_provided not_provided HGNC:16873 MONDO:0012986 uuid:8dbcbb72-9511-4b3d-9cf6-64a9ae6424c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0231303 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0948594 infores:hetionet CHEBI:63599 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0547030 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0151479 infores:hetionet CHEBI:38545 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0853034 infores:hetionet CHEBI:36791 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015806 infores:hetionet CHEBI:5790 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0549622 infores:hetionet CL:0000057 biolink:causes MONDO:0006209 infores:ubergraph knowledge_assertion manual_agent CL:0000057 MONDO:0006209 NCBIGene:23221 biolink:causes MONDO:0033373 infores:monarchinitiative not_provided not_provided HGNC:18756 MONDO:0033373 uuid:1b879a43-70fa-4bf9-a7b5-71d0d23d2c70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes UMLS:C0588128 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0588128 infores:hetionet CAID:CA7542750 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542750 MONDO:0012996 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_001482.3:c.1257G>A (p.Gln419=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30612 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 509542). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen CCDS VCEP based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GATM-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542750/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8869 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0019080 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0041912 infores:hetionet CAID:CA658657370 biolink:causes MONDO:0001586 infores:clingen CAID:CA658657370 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PP4_Moderate, PM2_Supporting The NM_000203.5:c.876del (p.Asp292GlufsTer25) variant in IDUA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in two individuals with clinical features consistent with MPS I, one of whom also had documented laboratory values showing deficiency leukocyte IDUA activity and elevated urine GAGs prior to initiation of treatment with enzyme replacement therapy (PMID: 35848209) (PP4). One of these individuals is compound heterozygous for the variant (labeled as 964del in the publication, using older numbering) and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908); the phase was not confirmed (PMID: 7951228, 0.5 points). Another patient is compound heterozygous for the variant and c.1499A>G (p.Gln500Arg) (PMID: 35848209). The allelic data from this patient will be used in the classification of p.Gln500Arg and is not included here to avoid circular logic. Total 0.5 points (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001280 (15/1172250 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 456720). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PVS1, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658657370/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:474180 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0006266 infores:hetionet CHEBI:4315 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0036508 infores:hetionet GO:0141070 biolink:causes GO:0000165 infores:ubergraph knowledge_assertion manual_agent GO:0141070 GO:0000165 CHEBI:7601 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0018099 infores:hetionet CHEBI:135451 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0027540 infores:hetionet CHEBI:63621 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151908 infores:hetionet CHEBI:31401 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0242301 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0406317 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0406317 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0518015 infores:hetionet CHEBI:8502 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0948594 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0029882 infores:hetionet CHEBI:6954 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1142499 infores:hetionet CHEBI:8346 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0162285 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020550 infores:hetionet CAID:CA414443531 biolink:causes MONDO:0010604 infores:clingen CAID:CA414443531 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3, PP4_Moderate PM1 The F9 c.802T>A (p.Cys268Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.1 meeting PM2_Supporting. This missense variant has a REVEL score of 0.969 and meets PP3 criteria (threshold >0.6 - PP3). Three probands are reported in the literature with moderate and severe hemophilia B meeting F9 criteria (PMID: 31064749, PMID: 8091381, PMID: 21263151 - PS4_Moderate & PP4_Moderate). The c.802T>A (p.Cys268Ser) variant is a missense change at the same residue (p.Cys268) where at least 3 different missense changes have been previously established as pathogenic/likely pathogenic variants (p.Cys268Gly, p.Cys268Arg, p.Cys268Tyr) using CFD-VCEP rules for F9 and SpliceAI shows no splicing impact (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Moderate, PP4_Moderate, PM5, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414443531/MONDO:0010604/080 2024-12-06 2024-12-06 X-linked inheritance HP:0001417 Supports CHEBI:119915 biolink:causes MONDO:0004868 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0005424 infores:hetionet CHEBI:3504 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0151908 infores:hetionet CHEBI:4995 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014335 infores:hetionet NCBIGene:57514 biolink:causes MONDO:0024506 infores:monarchinitiative not_provided not_provided HGNC:29216 MONDO:0024506 uuid:a29cfe9c-3198-4e5e-a588-82d4c57ff1a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027424 infores:hetionet CHEBI:4445 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0018790 infores:hetionet CHEBI:144093 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0015672 infores:hetionet CHEBI:6129 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0085605 infores:hetionet NCBIGene:85300 biolink:causes MONDO:0011025 infores:monarchinitiative not_provided not_provided HGNC:779 MONDO:0011025 uuid:390cf100-8027-47ee-bbc8-6566befa8b58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51380 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0012833 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018790 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0160390 infores:hetionet CHEBI:9599 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0151766 infores:hetionet CHEBI:48273 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0038990 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0162429 infores:hetionet CAID:CA8815664 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815664 MONDO:0009290 PMID:24158270PMID:16917947PMID:22237443PMID:21484825PMID:17056254PMID:12923862PMID:24158270PMID:18429042PMID:16917947PMID:26497565PMID:22237443PMID:21484825PMID:17056254PMID:24269976PMID:12923862 Pathogenic PM2, PVS1, PP4, PM3_Very Strong This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 22252923). The highest population minor allele frequency in gnomAD for this variant is 0.000008834 in the European non-Finnish population, meeting PM2 (<0.001). This variant has been reported in at least 15 patients who also meet the LSD VCEP’s PP4 criterion (PMIDs 12923862, 16917947, 17056254, 18285536, 21484825, 22237443, 24158270, 26497565). The c.2237G>A variant was found in compound heterozygosity with c.-32-13T>G in 9 of 40 Italian patients studied; six of these patients meet PP4 and in 4 of those patients the phase was confirmed in trans (PMID 16917947) (4.5 points). Additional patients meeting PP4 have been reported to be compound heterozygous for the variant and c.-32-13T>G, c.2481+110_2646+39del, c.1128_1129delinsC, c.670C>T (p.Arg224Trp), c.853C>T (p.Pro285Ser) (PMIDs 12923862, 17056254, 18285536, 21484825, 22237443); the phase was not confirmed in any of these cases. Four patients meeting PP4 criteria are reported to be homozygous for the variant (PMID 26497565). Four additional patients have been reported with this variant but residual GAA activity was not reported, and therefore PP4 cannot be assessed (PMID 18429042, 24269976). Based on this data, PP4 and PM3_Very Strong are met. There is a ClinVar entry for this variant (Variation ID: 280063; 2 star review status) with 5 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Very strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815664/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:51860 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0302295 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021451 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0496899 infores:hetionet CHEBI:64354 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0013378 infores:hetionet CHEBI:63577 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0085595 infores:hetionet CHEBI:8207 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020672 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032584 infores:hetionet CHEBI:16469 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0008350 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0178298 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1258215 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0948594 infores:hetionet CHEBI:3485 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C1257843 infores:hetionet CHEBI:15552 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0000731 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005253 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0221045 infores:hetionet CHEBI:9448 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0221423 infores:hetionet CAID:CA229315 biolink:causes MONDO:0009861 infores:clingen CAID:CA229315 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong, PM3_Supporting The PAH variant c.1065+1G>A (IVS10+1G>A) affects the canonical splice site (donor site). Loss of function in the PAH gene is a known mechanism of disease. Exon skipping is predicted to not disrupt the reading frame. This variant is predicted to alter a region that is critical to protein function. The PAH variant c.1065+1G>A (IVS10+1G>A) was identified in two French patients with mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L) with the likely pathogenic variant c.261C>A (p.Ser87Arg) and with the pathogenic variant c.1169A>G (p.Glu390Gly)(PMID: 26666653). The PAH variant c.1065+1G>A was also reported in an European patient with PAH deficiency (PMID: 10679941). According to gnomAD, the PAH variant c.1065+1G>A (IVS10+1G>A) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Finnish) population (0.00005). In summary, this variant meets the criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4, and PVS1_Strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229315/MONDO:0009861/006 2021-03-21 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports CAID:CA134762 biolink:causes MONDO:0021060 infores:clingen CAID:CA134762 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.923C>T (p.Pro308Leu) variant in the RAF1 gene is 1.516% (179/10394) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134762/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:49668 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0206061 infores:hetionet CHEBI:10112 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0015230 infores:hetionet CHEBI:5613 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0021177 infores:hetionet CHEBI:145499 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2747891 infores:hetionet CHEBI:3504 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0014724 infores:hetionet CHEBI:8768 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0522055 infores:hetionet NCBIGene:1788 biolink:causes MONDO:0014382 infores:monarchinitiative not_provided not_provided HGNC:2978 MONDO:0014382 uuid:b0a2c4dd-bc1f-4b0c-a1f8-1dc4b307d4c4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135005 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0232462 infores:hetionet CHEBI:8772 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0024902 infores:hetionet CHEBI:50648 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0014743 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0037274 infores:hetionet CHEBI:7573 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0042963 infores:hetionet CHEBI:8207 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0035455 infores:hetionet CHEBI:17474 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0002792 infores:hetionet CHEBI:135736 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0232487 infores:hetionet CHEBI:4995 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0042384 infores:hetionet NCBIGene:4621 biolink:causes MONDO:0020746 infores:monarchinitiative not_provided not_provided HGNC:7573 MONDO:0020746 uuid:c25ac66c-58e4-4d38-9191-11f765ddbbf0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA405696626 biolink:causes MONDO:0007783 infores:clingen CAID:CA405696626 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with glutamine at codon 3410 of the RYR1 protein, p.(Pro3410Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in an individual with a personal or family history of an MH episode. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.934) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405696626/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:52717 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0267028 infores:hetionet CHEBI:4953 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0085649 infores:hetionet CHEBI:17688 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0851578 infores:hetionet CHEBI:9907 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151662 infores:hetionet CHEBI:43968 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0013604 infores:hetionet CHEBI:6916 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0151480 infores:hetionet CHEBI:31705 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042075 infores:hetionet CHEBI:16796 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0438215 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151664 infores:hetionet CAID:CA214043 biolink:causes MONDO:0012163 infores:clingen CAID:CA214043 MONDO:0012163 PMID: Pathogenic PP1, PM3_Very Strong, PM2_Supporting, PP4_Moderate The missense variant NM_002185.5(IL7R):c.353G>A (p.Cys118Tyr) occurs at a low filtering allele frequency of 0.000009610 in gnomAD v2.1.1 (<0.00004129; PM2_Supporting). At least 14 SCID or Omenn syndrome patients have been reported with this variant in 10 publications (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025, 34153518, 17827065, 24578017, 27833609). Several have highly specific phenotypes which meet criteria for PP4 (PMIDs: 35503492, 24759676) and one patient (PMID: 27833609) had sufficient information to meet PP4_moderate; this patient fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID), with at T-B+NK+ subtype, absence of CD127 expression, and reduced f IL-7 induced pSTAT5 (Y694) in T-cells, which together are highly specific for IL7R-related SCID (PP4_moderate). Additionally, the variant has been reported to segregate with SCID in 2 affected family members from family 2 in PMID: 15661025 (PP1). Of the 14 patients, eight patients have been reported homozygous for this variant (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025; PM3) and six compound heterozygous; second variants were reported in P19 (PMID: 35503492) and the SCID patient reported in Zago CA et al. (PMID: 24759676) both harboring c.361dup without confirmation of trans phase (classified Pathogenic by the SCID VCEP; 0.5+0.5pt), the patients reported by Tsilifis C et al. (PMID: 34153518) and Butte MJ et al. (PMID: 17827065) both harbor c.379+288G>A confirmed in trans (provisionally classified by the SCID VCEP as VUS; 0.25+0.25pt), Case 1 (PMID: 24578017) has c.83-2A>T without confirmation of trans phase (provisionally classified as Pathogenic by the SCID VCEP; 0.5pt), and the patient reported by Gallego-Bustos F et al. (PMID: 27833609) has c.333T>A confirmed in trans (provisionally classified Likely Pathogenic by the SCID VCEP; 1pt), Total=4pts (PM3_VeryStrong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3_VeryStrong, PP1, PP4_moderate. (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214043/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6897 biolink:causes UMLS:C0457798 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0457798 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020649 infores:hetionet CAID:CA658795267 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795267 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000152.5c.1848dup in GAA is a frameshift variant predicted to cause a premature stop codon (p.Val617ArgfsTer19), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with the variant has been reported who has infantile onset Pompe disease, <1% GAA activity in skin fibroblasts, and is on enzyme replacement therapy (PMID: 22252923, personal communication with first author) (PP4_Moderate). This patient is compound heterozygous, phase unknown, for c.1832G>A (p.Gly611Asp) (PMID: 22252923, personal communication with first author). The allelic data from this patient was used in the evaluation of c.1832G>A (p.Gly611Asp) and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795267/MONDO:0009290/010 2022-09-06 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5778 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013609 infores:hetionet CHEBI:8485 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0019080 infores:hetionet NCBIGene:8106 biolink:causes MONDO:0958176 infores:monarchinitiative not_provided not_provided HGNC:8565 MONDO:0958176 uuid:95a0010c-6f98-47d3-889d-00eb6c2d54fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA011440 biolink:causes MONDO:0004994 infores:clingen CAID:CA011440 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.189C>T (p.Thr63=) variant in the MYH7 gene is 61.57% (6532/10394) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011440/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0156404 infores:hetionet CHEBI:3568 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023518 infores:hetionet CHEBI:47780 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0002390 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1142520 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0006849 infores:hetionet UNII:T58MSI464G biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0011603 infores:hetionet GO:0044487 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0044487 GO:0007154 CHEBI:2663 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0027947 infores:hetionet NCBIGene:2700 biolink:causes MONDO:0011162 infores:monarchinitiative not_provided not_provided HGNC:4277 MONDO:0011162 uuid:84c8c8cf-a039-4f18-9bc6-30492d58cbc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4495 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0018965 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1321686 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0018802 infores:hetionet CHEBI:46557 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0029453 infores:hetionet CHEBI:17334 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0033117 infores:hetionet CHEBI:50648 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036690 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0029134 infores:hetionet CAID:CA9200848 biolink:causes MONDO:0018947 infores:clingen CAID:CA9200848 MONDO:0018947 PMID: Benign BA1 BP1, BP4, BP3, PS3, PS1, PS4, PM1, PM4, PM5, BP7, BS1, BS3, PM2, PVS1, PP2, PP3, PP4, BS2 The variant NM_001005361.3:c.643G>A in DNM2 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 215 (p.Asp215Asn). The filtering allele frequency (the lower threshold of the 95% CI of 10/6060) of the c.643G>A variant in DNM2 is 0.0009407 for Middle Eastern chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL predicts a score of 0.479 which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function (PP3, BP4 not met). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2, not applied for this variant due to high allele frequency). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA9200848/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10110 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0948594 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020651 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0021400 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0161479 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0021053 infores:hetionet NCBIGene:6390 biolink:causes MONDO:0030974 infores:monarchinitiative not_provided not_provided HGNC:10681 MONDO:0030974 uuid:b4bb2786-8474-4d0f-8b47-e93578270d22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0030305 infores:hetionet CHEBI:421707 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0002792 infores:hetionet CHEBI:27999 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0021141 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0019372 infores:hetionet CHEBI:4708 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013604 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042571 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0162429 infores:hetionet CHEBI:49375 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0023212 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0241075 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0241075 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0549444 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0549444 infores:hetionet CHEBI:6076 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151603 infores:hetionet CHEBI:7931 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0038999 infores:hetionet CHEBI:71940 biolink:causes MONDO:0000499 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C1852242 infores:hetionet CHEBI:50663 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0853908 infores:hetionet CHEBI:17688 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0003862 infores:hetionet CHEBI:82981 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0018681 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0027769 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004936 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0015376 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0857332 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0857332 infores:hetionet CHEBI:3216 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C2830004 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0233401 infores:hetionet CHEBI:63627 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0151904 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1392046 infores:hetionet CHEBI:5098 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0027707 infores:hetionet CHEBI:50859 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1519353 infores:hetionet CHEBI:46557 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0038999 infores:hetionet NCBIGene:4762 biolink:causes MONDO:0957563 infores:monarchinitiative not_provided not_provided HGNC:7764 MONDO:0957563 uuid:7f930b29-8c75-4c55-b2b6-300ae6fcc289 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes UMLS:C0858589 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0858589 infores:hetionet NCBIGene:84230 biolink:causes MONDO:0975957 infores:monarchinitiative not_provided not_provided HGNC:25075 MONDO:0975957 uuid:23bded4a-e78e-439c-a7a3-26db13ffc213 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013404 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0149931 infores:hetionet CHEBI:3996 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0027849 infores:hetionet CHEBI:8378 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C1443060 infores:hetionet CHEBI:36795 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018520 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0041912 infores:hetionet CHEBI:4466 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0003811 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0037199 infores:hetionet NCBIGene:6652 biolink:causes MONDO:0030055 infores:monarchinitiative not_provided not_provided HGNC:11184 MONDO:0030055 uuid:a282a477-a8a1-4e4d-bfed-4b1f43f53ae0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915940689 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940689 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3:c.674del (p.Gln225ArgfsTer2) variant in ITGB3 exon 5 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one proband with Glanzmann thrombasthenia. The reported proband (GT30, PMID: 19691478) was homozygous for the variant (PM3_Supporting). At least one patient (Patient GT30 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. (VCEP specifications version 2; date of approval 05/17/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940689/MONDO:0100326/011 2022-05-17 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UBERON:0000365 biolink:causes MONDO:0024337 infores:ubergraph knowledge_assertion manual_agent UBERON:0000365 MONDO:0024337 CHEBI:8356 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2979982 infores:hetionet CHEBI:2914 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0270611 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019112 infores:hetionet CHEBI:8461 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0040046 infores:hetionet CHEBI:2611 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0003467 infores:hetionet CHEBI:3510 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0001824 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0028738 infores:hetionet CAID:CA410147389 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147389 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1318G>A (p.Ala440Thr) is a missense variant which has a REVEL score < 0.50 (0.058), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147389/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0004609 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0017178 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0549433 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151763 infores:hetionet CHEBI:15552 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0017152 infores:hetionet CHEBI:5062 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0855242 infores:hetionet CAID:CA145739 biolink:causes MONDO:0800472 infores:clingen CAID:CA145739 MONDO:0800472 PMID:10910054 Benign BP4, BA1 PP3, PP1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4, PVS1, PM2 The c.142C>G variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Glycine at amino acid 48 (p.Arg48Gly). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1) = 0.5206, which met the ≥ 0.05 threshold set for BA1 (38983 alleles out of 74878, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.029, which was within the 0.017-0.183 range for BP4_Moderate and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), suggesting that the variant does not impact CYP1B1 function. PS3_Supporting was not applied as the assay reported in PMID: 10910054 did not meet the OddsPath threshold (> 2.1). In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1, BP4_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145739/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46557 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0038362 infores:hetionet CHEBI:52172 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009676 infores:hetionet CHEBI:100246 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151578 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0152227 infores:hetionet CHEBI:45081 biolink:causes HP:0002317 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0231686 infores:hetionet CHEBI:3216 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0085649 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020295 infores:hetionet CHEBI:41879 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0018813 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0013609 infores:hetionet CHEBI:9570 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0162297 infores:hetionet NCBIGene:54551 biolink:causes MONDO:0014243 infores:monarchinitiative not_provided not_provided HGNC:6814 MONDO:0014243 uuid:d8bd179a-31c5-4823-85b3-1a961a857bda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0039231 infores:hetionet NCBIGene:84896 biolink:causes MONDO:0044330 infores:monarchinitiative not_provided not_provided HGNC:25903 MONDO:0044330 uuid:b241dcf1-9cec-4d18-9ebe-bbf4492824fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0031117 infores:hetionet CHEBI:50381 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0015672 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235639 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0497364 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0497364 infores:hetionet CHEBI:9622 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0151908 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009782 infores:hetionet CHEBI:68478 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0035243 infores:hetionet CHEBI:66876 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0311468 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0037822 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0027765 infores:hetionet CAID:CA387462302 biolink:causes MONDO:0019497 infores:clingen CAID:CA387462302 MONDO:0019497 PMID: Pathogenic PM3_Supporting, PM2_Supporting, PVS1 The c.3G>A (p.Met1Ile) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 550716, 551915, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It was identified in 1 patient with nonsyndromic hearing loss and was assumed compound heterozygous with the pathogenic variant c.235delC, p.Leu79fs (0.5 PM3_Supporting points; ClinVar ID: 17014, PMID: 29605365). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting (VCEP specifications version 2; 10.18.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387462302/MONDO:0019497/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:8805 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0151744 infores:hetionet NCBIGene:9742 biolink:causes MONDO:0054708 infores:monarchinitiative not_provided not_provided HGNC:29077 MONDO:0054708 uuid:479fdcb5-acc8-46dc-aab5-542f25e9154c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0002321 biolink:causes CL:0000825 infores:ubergraph knowledge_assertion manual_agent GO:0002321 CL:0000825 CHEBI:2687 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0002874 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0012833 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0020920 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D004927 DB01212_MESH_D004927_1DB01326_MESH_D004927_1DB00684_MESH_D004927_1DB01060_MESH_D004927_1DB06590_MESH_D004927_1DB09324_MESH_D004927_1DB01059_MESH_D004927_1DB00415_MESH_D004927_1DB00537_MESH_D004927_1DB00438_MESH_D004927_1DB01332_MESH_D004927_1DB01111_MESH_D004927_1DB01607_MESH_D004927_1DB01112_MESH_D004927_1DB00766_MESH_D004927_1DB00479_MESH_D004927_1DB02703_MESH_D004927_1DB00803_MESH_D004927_1DB01165_MESH_D004927_1DB00319_MESH_D004927_1DB00355_MESH_D004927_1DB01139_MESH_D004927_1DB01330_MESH_D004927_1DB00798_MESH_D004927_1DB01331_MESH_D004927_1 CHEBI:40237 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0149514 infores:hetionet CHEBI:4657 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0013428 infores:hetionet CHEBI:8404 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0013362 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0007642 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0009806 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0022660 infores:hetionet CHEBI:8874 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085298 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C3495440 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020538 infores:hetionet NCBITaxon:10245 biolink:causes MONDO:0002595 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10245 MONDO:0002595 CHEBI:8024 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013491 infores:hetionet CAID:CA208615 biolink:causes MONDO:0010726 infores:clingen CAID:CA208615 MONDO:0010726 PMID: Likely Benign BS2 BP4, PS4, PM1, BS1, PP3 The highest population minor allele frequency of the NM_004992.4:c.1328C>T p.Ala443Val variant in gnomAD v4.1 is 0.00007 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ala443Val variant is observed in at least 2 unaffected individuals (internal data, Labcorp Genetics Inc.) (BS2). The p.Ala443Val variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.492). In the absence of conflicting evidence, this is sufficient evidence to classify the p.Ala443Val variant as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208615/MONDO:0010726/036 2025-02-28 2025-03-26 X-linked inheritance HP:0001417 Contradicts true CHEBI:9654 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0030193 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0027765 infores:hetionet NCBIGene:545 biolink:causes MONDO:0008869 infores:monarchinitiative not_provided not_provided HGNC:882 MONDO:0008869 uuid:9560165d-17c3-4365-99aa-3bc5cba33625 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15854 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042401 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0521839 infores:hetionet CHEBI:9943 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233715 infores:hetionet UMLS:C0657912 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018965 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0877144 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0877144 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040046 infores:hetionet CHEBI:3510 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0015672 infores:hetionet CHEBI:7903 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0231218 infores:hetionet CHEBI:46557 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0021368 infores:hetionet CHEBI:36791 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0497156 infores:hetionet CHEBI:10023 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0344232 infores:hetionet GO:0006954 biolink:causes MONDO:0005093 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D012871 DB06786_MESH_D012871_1 CHEBI:6904 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0027497 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0011991 infores:hetionet CHEBI:161680 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0031542 infores:hetionet CHEBI:5384 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0001824 infores:hetionet CAID:CA915940480 biolink:causes MONDO:0010305 infores:clingen CAID:CA915940480 MONDO:0010305 PMID: Pathogenic PM2_Supporting, PP4_Strong, PVS1_Strong The NM_005629.4:c.1690_1703del variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene (p.Phe564HisfsTer21) and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 18443316) (PP4_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_Strong, PM2_Supporting, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940480/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:46081 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0600142 infores:hetionet CHEBI:68556 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0151735 infores:hetionet CAID:CA229547 biolink:causes MONDO:0009861 infores:clingen CAID:CA229547 MONDO:0009861 PMID: Benign BA1, BP7 PM2, PM3, PP4 This c.441+47C>T variant in PAH is widely found in population databases at a frequency of 0.372401 in ExAC. This intronic variant is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229547/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9168 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151763 infores:hetionet CHEBI:18385 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0020517 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0015397 infores:hetionet CHEBI:63622 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0000731 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018099 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0150450 infores:hetionet CHEBI:8378 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0043094 infores:hetionet CAID:CA6798615 biolink:causes MONDO:0021060 infores:clingen CAID:CA6798615 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.643-6dupG variant in the PTPN11 gene is 0.0461% (9/10166) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6798615/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6073 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0028734 infores:hetionet CHEBI:8772 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0018681 infores:hetionet CHEBI:53691 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C1142412 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027051 infores:hetionet NCBIGene:79719 biolink:causes MONDO:0007858 infores:monarchinitiative not_provided not_provided HGNC:25662 MONDO:0007858 uuid:a0bd7c69-194b-4945-94ce-f77d4fbfe707 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3930 biolink:causes MONDO:0018663 infores:monarchinitiative not_provided not_provided HGNC:6518 MONDO:0018663 uuid:479dac10-4a65-4b80-861c-a0031b48307f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0232493 infores:hetionet CHEBI:3441 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C1260922 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0021359 infores:hetionet CHEBI:2788 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C1260880 infores:hetionet CHEBI:6950 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013404 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009450 infores:hetionet CHEBI:63845 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0014742 infores:hetionet CHEBI:9123 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0043352 infores:hetionet CHEBI:8888 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024282 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0232459 infores:hetionet CHEBI:31624 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0011603 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0040409 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0007117 infores:hetionet CAID:CA024705 biolink:causes MONDO:0007783 infores:clingen CAID:CA024705 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with arginine at codon 2366 of the RYR1 protein, p.(Pro2366Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction without positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4_Supporting (PMID: 16732084, PMID:31559918). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.88) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024705/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:47898 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0231807 infores:hetionet CHEBI:28148 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0012833 infores:hetionet CHEBI:63619 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0032617 infores:hetionet CHEBI:465284 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0015402 infores:hetionet CHEBI:37941 biolink:causes MONDO:0006004 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0035460 infores:hetionet CHEBI:6888 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0021368 infores:hetionet CHEBI:3380 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0027540 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1262064 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0340464 infores:hetionet CAID:CA293940 biolink:causes MONDO:0007648 infores:clingen CAID:CA293940 MONDO:0007648 PMID: Benign BP2_Strong, BS2 BS1, PM2 The c.2336G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 779 (p.Arg779Gln). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; internal clinical data). This variant has been observed in more than 10 (134) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC. (BS2; PMID: 29522266, 36436516; ClinVar SCVs: SCV000172951.7, SCV000288462.10, SCV000210875.16; internal lab contributors). In summary, this variant meets the criteria to be classified as benign for hereditary diffuse gastric cancer based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 variant curation expert panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_S. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA293940/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63598 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0423602 infores:hetionet CHEBI:73274 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0039070 infores:hetionet CHEBI:68478 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0022346 infores:hetionet CAID:CA8603526 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603526 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 The c.188+7C>T (NM_000419.5) variant in ITGA2B is an intronic variant which is in intron 1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003268 (1/30600 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The c.188+7C>T variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.008496 (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2, BP4, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603526/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0006147 infores:hetionet CHEBI:47898 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026766 infores:hetionet CHEBI:4469 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0018681 infores:hetionet NCBITaxon:333922 biolink:causes MONDO:0005173 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:333922 MESH:D055623 DB00724_MESH_D055623_1 CAID:CA024414 biolink:causes MONDO:0007783 infores:clingen CAID:CA024414 MONDO:0007783 PMID: Likely Pathogenic PP1, PS3_Moderate, PM1, PS4_Moderate PP3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of leucine with arginine at codon 13 of the RYR1 protein, p.(Leu13Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:19191329; PMID:30236257; PMID:16732084). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 341427251). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals ,PP1 (PMID:19191329, personal communication, RYR1/MHS_VCEP). A REVEL score of 0.828 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024414/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6367 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0600142 infores:hetionet CHEBI:8776 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0002871 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0877153 infores:hetionet CHEBI:50841 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0043144 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002529 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0553723 infores:hetionet CHEBI:68584 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0877359 infores:hetionet CHEBI:7936 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0428974 infores:hetionet CHEBI:31711 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0035455 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0679403 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0679403 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151849 infores:hetionet CHEBI:51380 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0085633 infores:hetionet CHEBI:64312 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040460 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0015230 infores:hetionet CHEBI:17688 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0149745 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0233485 infores:hetionet CHEBI:41423 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027497 infores:hetionet CHEBI:63598 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151937 infores:hetionet CHEBI:5778 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0022346 infores:hetionet CHEBI:68584 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0013428 infores:hetionet CHEBI:101085 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0232462 infores:hetionet CHEBI:51860 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027430 infores:hetionet UNII:7F465U79Q1 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0015967 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0020517 infores:hetionet CHEBI:28787 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0025637 infores:hetionet CHEBI:39669 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0040264 infores:hetionet CAID:CA8603524 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603524 MONDO:0100326 PMID: Benign BP7, BA1 The c.188+8G>A (NM_000419.5) variant in ITGA2B is an intronic variant which is in intron 1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009779 (195/19940 alleles) in East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1). The c.188+8G>A variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -2.9895 (BP7). In summary, this variant meets the criteria to be classified as benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603524/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA229319 biolink:causes MONDO:0009861 infores:clingen CAID:CA229319 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, BP4 (PAH):c.1065+7C>A is an intronic variant that is predicted to be have no effect on splicing by multiple lines of computational evidence. This variant was identified in a patient with mild HPA. Patient genotype was not specified homozygous or compound heterozygous (PMID 10947211). This variant is absent in population databases. In summary, this variant has insufficient evidence and is classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, BP4, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229319/MONDO:0009861/006 2020-07-25 2020-07-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28177 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0020517 infores:hetionet CHEBI:6775 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0039231 infores:hetionet CHEBI:4325 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0031350 infores:hetionet CHEBI:15367 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0278134 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0029882 infores:hetionet CHEBI:8764 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013456 infores:hetionet CHEBI:4717 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0233477 infores:hetionet CHEBI:63611 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0039070 infores:hetionet CAID:CA294197 biolink:causes MONDO:0007648 infores:clingen CAID:CA294197 MONDO:0007648 PMID:23435907PMID:20921021PMID:23435907PMID:20921021 Benign BS2, BP2_Strong BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM3, PM4, PM1, PP3, PP2, PP4, PP1, BP4, BP1, BP3, BA1, PS1, PS3, PS4, PS2 The c.1298A>G (p.Asp433Gly) variant was observed at least twice in the homozygous state in individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; SCV000253407.6). This variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BP2_Strong, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294197/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true NCBIGene:26092 biolink:causes MONDO:0014900 infores:monarchinitiative not_provided not_provided HGNC:29456 MONDO:0014900 uuid:4667eb99-d95c-489a-b601-4c0a8894f489 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9927 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0039070 infores:hetionet NCBIGene:2623 biolink:causes MONDO:0010308 infores:monarchinitiative not_provided not_provided HGNC:4170 MONDO:0010308 uuid:3d5c2366-53e5-441f-9aa5-c14d8c49f689 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0085631 infores:hetionet CHEBI:3996 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C1306341 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0234913 infores:hetionet CHEBI:63607 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0030193 infores:hetionet CHEBI:63622 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0030196 infores:hetionet CHEBI:7824 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038325 infores:hetionet CAID:CA8970510 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970510 MONDO:0012589 PMID: Likely Benign BP4, BS2 BS1 The highest population minor allele frequency of the p.Pro156Thr variant in TCF4 in gnomAD v4.1 is 0.000067 in the Admixed American population (not sufficient to meet BS1 criteria). The p.Pro156Thr variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Pro156Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro156Thr variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970510/MONDO:0012589/032 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7798 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0040034 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0743680 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018798 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0948586 infores:hetionet CHEBI:480999 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0039231 infores:hetionet CAID:CA367398715 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398715 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1153G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to tryptophan at codon 385 (p.(Gly385Trp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD 4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and persistent impaired fasting glucose) (PP4_Moderate; PMID: 20337973). Another missense variant at the same codon, c.1153G>A (p.Gly385Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1153G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_supporting, PP4_Moderate, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398715/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Supports UNII:15G12L5X8K biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0232487 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0423602 infores:hetionet CHEBI:8707 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0007859 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0085682 infores:hetionet CHEBI:63791 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085682 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0030312 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0574067 infores:hetionet CHEBI:63631 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0024282 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0853019 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877508 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877508 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0015230 infores:hetionet CHEBI:49040 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0016204 infores:hetionet CHEBI:77260 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0016382 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0017675 infores:hetionet CHEBI:9649 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042345 infores:hetionet CHEBI:6887 biolink:causes UMLS:C3536794 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C3536794 infores:hetionet CHEBI:17823 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0027497 infores:hetionet CAID:CA010677 biolink:causes MONDO:0004994 infores:clingen CAID:CA010677 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1395C>T (p.Phe465=) variant in the MYH7 gene is 0.18% (27/10402) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010677/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3219 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233472 infores:hetionet CHEBI:168396 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0002962 infores:hetionet CHEBI:8772 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C1510431 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0014130 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023067 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0041976 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0040046 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021308 infores:hetionet CHEBI:9943 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026603 infores:hetionet CHEBI:5779 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0040822 infores:hetionet CHEBI:171719 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0036454 infores:hetionet CHEBI:3996 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0030252 infores:hetionet UMLS:C1738934 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037299 infores:hetionet NCBIGene:10205 biolink:causes MONDO:0029142 infores:monarchinitiative not_provided not_provided HGNC:3496 MONDO:0029142 uuid:929cac41-21c9-4e13-8749-461de2457c08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0858581 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151578 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0031117 infores:hetionet CAID:CA180441 biolink:causes MONDO:0010278 infores:clingen CAID:CA180441 MONDO:0010278 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting The c.508-1G>A variant in SLC9A6 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.508-1G>A variant in SLC9A6 has been reported to segregate in three informative meioses (internal database) (PP1_moderate). This variant is absent from gnomAD (PM2_supporting). In summary, the c.508-1G>A variant in GENE is classified as Pathogenic for Christianson syndrome based on the ACMG/AMP criteria (PVS1, PP1_moderate, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA180441/MONDO:0010278/016 2021-03-02 2021-05-07 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf UNII:3U02EL437C biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0033774 infores:hetionet CHEBI:9570 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085631 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0429059 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0429059 infores:hetionet CHEBI:9332 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0917801 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1861172 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0023218 infores:hetionet NCBITaxon:945 biolink:causes MONDO:0000225 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:945 MONDO:0000225 CHEBI:7915 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020625 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0242350 infores:hetionet CHEBI:168396 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013456 infores:hetionet CAID:CA401360532 biolink:causes MONDO:0009290 infores:clingen CAID:CA401360532 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000152.5:c.246C>A (p.Cys82Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PMID: 33741225) (PP4_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PVS1, PM2_Supporting, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401360532/MONDO:0009290/010 2022-01-04 2022-01-04 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:135888 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0015230 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0011991 infores:hetionet CAID:CA012913 biolink:causes MONDO:0005021 infores:clingen CAID:CA012913 MONDO:0005021 PMID: Pathogenic PM2, PP3, PP1_Strong, PM6_Strong, PS4 PM5, PM1, PS3, PP2, BS4, BS3, BP1, PS2, PS1, BP4 The NM_000257.4(MYH7):c.2711G>A (p.Arg904His) variant has been identified in at least 14 individuals with DCM in the literature (PS4; Waldmüller 2011 PMID:21750094; Lakdawala 2012 PMID:22464770; Pugh 2014 PMID:24503780; Chami 2014 PMID:25448463; Walsh 2017 PMID:27532257; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.). In 3 of theses cases, the variant was identified as an unconfirmed de novo occurrence (PM6_Strong; Lakdawala 2012 PMID:22464770; GeneDx pers. comm.; OMGL pers. comm.). This variant also segregated with disease in 7 affected individuals with DCM across 4 families (PP1_Strong; Chami 2014 PMID:25448463; GeneDx pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. Finally, computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy (DCM) in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PM6_Strong, PP1_Strong, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012913/MONDO:0005021/002 2021-09-27 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2549 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0017168 infores:hetionet NCBIGene:51611 biolink:causes MONDO:0859295 infores:monarchinitiative not_provided not_provided HGNC:24270 MONDO:0859295 uuid:83182f4f-7f21-4b60-b239-26b2ac811ba1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0231218 infores:hetionet CHEBI:8207 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0231530 infores:hetionet CHEBI:499361 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0037383 infores:hetionet CAID:CA10613575 biolink:causes MONDO:0015924 infores:clingen CAID:CA10613575 MONDO:0015924 PMID: Likely Benign BP4, BS1 PM2, PP3, BA1 The BMPR2 NM_001204.7(BMPR2):c.-93A>G variant is a 5' UTR variant. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.006608 (6/908 alleles) in the East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >0.1% for BS1, and therefore meets this criterion (BS1). No functional data was available for review and multiple lines of computational evidence suggest no impact on the gene (BP4). No other criteria were met. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, BP4 [VCEP specification version 1.1, 1/18/2024]. Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA10613575/MONDO:0015924/125 2024-04-30 2024-04-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6801 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0041657 infores:hetionet CHEBI:5138 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0039070 infores:hetionet NCBIGene:1134 biolink:causes MONDO:0011088 infores:monarchinitiative not_provided not_provided HGNC:1955 MONDO:0011088 uuid:db54b5f1-964c-4fcd-8ca2-83be31b914d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0006849 infores:hetionet CHEBI:63638 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0033774 infores:hetionet CHEBI:145499 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020639 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0032285 infores:hetionet CHEBI:31638 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0033774 infores:hetionet CHEBI:28748 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1142499 infores:hetionet CHEBI:6935 biolink:causes MONDO:0006912 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0032266 infores:hetionet CHEBI:8707 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0023218 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030469 infores:hetionet CHEBI:3176 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0010200 infores:hetionet UMLS:C0879264 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020598 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0031099 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0040046 infores:hetionet CHEBI:3478 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0086565 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0009806 infores:hetionet CHEBI:5558 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0018524 infores:hetionet CHEBI:64355 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040822 infores:hetionet CHEBI:107736 biolink:causes HP:0002781 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0740852 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0854448 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0854448 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002614 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0029400 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0004623 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0863113 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0003862 infores:hetionet CHEBI:135736 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0011603 infores:hetionet CHEBI:40050 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0020443 infores:hetionet CHEBI:3286 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0024902 infores:hetionet CHEBI:7824 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1167965 infores:hetionet CHEBI:5280 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0042963 infores:hetionet CHEBI:27974 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0042963 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0948089 infores:hetionet UMLS:C0065374 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0086565 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0032545 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0159066 infores:hetionet CHEBI:28241 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0234215 infores:hetionet CHEBI:31348 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0043094 infores:hetionet CHEBI:101278 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018794 infores:hetionet CHEBI:3756 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0547030 infores:hetionet CHEBI:114785 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0018681 infores:hetionet GO:0006954 biolink:causes MONDO:0003085 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D007634 DB01380_MESH_D007634_1 CHEBI:42820 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0151766 infores:hetionet CHEBI:465284 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0010200 infores:hetionet CHEBI:8502 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0022346 infores:hetionet CHEBI:2659 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0085612 infores:hetionet CAID:CA500624478 biolink:causes MONDO:0100326 infores:clingen CAID:CA500624478 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 After a comprehensive literature search of the synonymous variant NM_000419.5(ITGA2B):c.322C>A (p.Arg108=), no individuals with Glanzmann thrombasthenia were reported with the variant. The variant is absent from gnomADv2.1.1 (PM2_supporting). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -.065 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500624478/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:2567 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0004096 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0008350 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0010692 infores:hetionet CHEBI:8869 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0029453 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042514 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019360 infores:hetionet CHEBI:6067 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0234233 infores:hetionet NCBIGene:51364 biolink:causes MONDO:0014192 infores:monarchinitiative not_provided not_provided HGNC:19412 MONDO:0014192 uuid:e3ca035f-74c3-43f2-9c0d-02a4584cde3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0003811 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235234 infores:hetionet CHEBI:6532 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0014742 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0012797 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0018802 infores:hetionet CHEBI:60761 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0018681 infores:hetionet CHEBI:5383 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0009421 infores:hetionet CHEBI:49662 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0242422 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0020649 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0677500 infores:hetionet CAID:CA10360187 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360187 MONDO:0100039 PMID: Uncertain Significance BP4 PM2 The c.65-4A>G variant in CDKL5 is present in 1 XX individual in gnomAD (does not meet BS1 based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.65-4A>G in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360187/MONDO:0100039/034 2023-10-13 2023-12-11 X-linked inheritance HP:0001417 Inconclusive true CHEBI:72564 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0025061 infores:hetionet CHEBI:27974 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1384353 infores:hetionet NCBITaxon:35790 biolink:causes MONDO:0000233 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:35790 MONDO:0000233 CHEBI:8871 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023533 infores:hetionet CHEBI:8863 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C3203358 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0038814 infores:hetionet CHEBI:35778 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0220870 infores:hetionet CHEBI:10124 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0404521 infores:hetionet CHEBI:71255 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0015230 infores:hetionet CHEBI:5118 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022346 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0041969 infores:hetionet CHEBI:9637 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0018681 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0853619 infores:hetionet CAID:CA352065368 biolink:causes MONDO:0007356 infores:clingen CAID:CA352065368 MONDO:0007356 PMID: Uncertain Significance PP3_Moderate, PP1, PP4, PM2_Supporting The NM_000249.4(MLH1):c.1889T>A (p.Ile630Asn) variant is a missense variant predicted to cause substitution of Isoleucin by Asparagin at amino acid 630 (p.Ile630Asn). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_Supporting).The variant meets the MMR-VCEP specific modifications for PP1, since the co-segregation with disease in pedigree(s) with a combined Bayes Likelihood Ratio is 2,23 (>2.08 & ≤4.32). The variant meets the MMR-VCEP specific modifications for PP4, since it has been detected in One CRC MSI-H tumour using a standard panel of 5-10 markersg and/or loss of MMR protein expression consistent with the variant location. The missense variant has a prior probability for pathogenicity >0.81 (PP3_Mod met). In summary there is insufficient evidence (VUS) (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA352065368/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46557 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020461 infores:hetionet CHEBI:168396 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003962 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0042109 infores:hetionet CHEBI:85161 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151603 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0029408 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0149931 infores:hetionet CHEBI:50859 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C2939447 infores:hetionet UMLS:C0004599 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0027497 infores:hetionet CHEBI:101085 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0009676 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0221752 infores:hetionet CHEBI:31536 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0022672 infores:hetionet CHEBI:5165 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0006384 infores:hetionet CHEBI:100241 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0086565 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020542 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0853750 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853750 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1504383 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1504383 infores:hetionet CHEBI:63620 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085641 infores:hetionet CHEBI:63584 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0151904 infores:hetionet CHEBI:40050 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0267792 infores:hetionet GO:2000025 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000025 GO:0007275 CHEBI:47426 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0853813 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007593 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0278151 infores:hetionet CHEBI:49040 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151904 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007222 infores:hetionet CHEBI:5134 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0011603 infores:hetionet GO:0007317 biolink:causes GO:0007314 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0007314 CHEBI:85078 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0031542 infores:hetionet CAID:CA367398660 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398660 MONDO:0015967 PMID: Likely Pathogenic PP2, PP3, PP4, PS3_Moderate, PM2_Supporting PS4, PP1 The c.1166T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to aspartic acid at codon 389 (p.(Val389Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be <0.1, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 2145522). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia, however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 23771925, 32741144, internal lab contributors). This variant segregated with hyperglycemia with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.1166T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PS3_Moderate, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398660/MONDO:0015967/086 2024-06-22 2024-06-22 Semidominant inheritance HP:0032113 Supports CHEBI:49662 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0014518 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0314719 infores:hetionet CHEBI:4735 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0027424 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0232431 infores:hetionet CHEBI:8863 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0014866 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020295 infores:hetionet CHEBI:5959 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0002874 infores:hetionet CHEBI:119915 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0024902 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235416 infores:hetionet CHEBI:61033 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0004238 infores:hetionet CHEBI:28939 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0542571 infores:hetionet CHEBI:107736 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0042024 infores:hetionet CHEBI:49668 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0022568 infores:hetionet CHEBI:3181 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0020580 infores:hetionet CHEBI:127342 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0231528 infores:hetionet CHEBI:17347 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042907 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018801 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004095 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0079731 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0040034 infores:hetionet CHEBI:8382 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0018681 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0086543 infores:hetionet NCBIGene:51726 biolink:causes MONDO:0054842 infores:monarchinitiative not_provided not_provided HGNC:14889 MONDO:0054842 uuid:7bd99f22-4694-4fbe-ab77-a79cb1071be2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015732 infores:hetionet CHEBI:63580 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0851578 infores:hetionet CAID:CA274067 biolink:causes MONDO:0009290 infores:clingen CAID:CA274067 MONDO:0009290 PMID:25466677PMID:29122469PMID:10338092PMID:19948615PMID:20080426PMID:8604985PMID:21232767PMID:31510962PMID:27692865PMID:18458862PMID:27183828PMID:24243590PMID:28394184PMID:23632029 Pathogenic PM2, PVS1, PP4 PM3 This variant, c.1411_1414del (p.Glu471ProfsTer5), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002513 in the East Asian population, meeting PM2. This variant has been reported multiple times in Asian patients with Pompe disease presenting clinically and identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu) (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). There is a ClinVar entry for this variant (Variation ID: 188874, 2 star review status) with three submitters classifying the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274067/MONDO:0009290/010 2020-10-08 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA390865107 biolink:causes MONDO:0100216 infores:clingen CAID:CA390865107 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting, BS2_Supporting PVS1, PM6, BA1, BP1, BP2, BP3, PP2, PP3, PP1, PP4, PM3, PM4, PM5, PS2, PS3, PS4, PS1, BP5, BP7, BS1, BS3, BS4 The NM_177438.2:c.5257G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1753 (p.Asp1753Asn). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390865107/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:79699 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0034069 infores:hetionet NCBIGene:164 biolink:causes MONDO:0859174 infores:monarchinitiative not_provided not_provided HGNC:555 MONDO:0859174 uuid:71f08f87-b434-4629-b4d9-f218707803e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0234215 infores:hetionet CAID:CA637689285 biolink:causes MONDO:0011071 infores:clingen CAID:CA637689285 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*195C>T is a 3' UTR variant which has a MAF of 0.0003387 (0.03387%, 23/67904, 23 alleles) in the European (non-finnish) subpopulation of the gnomAD 3.1.2 cohort which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637689285/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:35854 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0027441 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042514 infores:hetionet CHEBI:63624 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0009782 infores:hetionet CHEBI:31705 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0039070 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0007642 infores:hetionet CHEBI:23765 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085610 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011570 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027651 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0011991 infores:hetionet GO:0044058 biolink:causes GO:0007586 infores:ubergraph knowledge_assertion manual_agent GO:0044058 GO:0007586 CHEBI:41879 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0030193 infores:hetionet CHEBI:16899 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0042963 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0233494 infores:hetionet CAID:CA414822605 biolink:causes MONDO:0044970 infores:clingen CAID:CA414822605 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate PS3, PM6 The m.14465G>A (p.T70I) variant in MT-ND6 has been reported in five unrelated individuals with primary mitochondrial disease to date (PS4_moderate; PMIDs: 32652755, 34536563, 34264415, 37628761). Affected individuals had clinical features consistent with Leber Hereditary Optic Neuropathy (LHON) and Leigh syndrome spectrum (LSS) disorder as well as ataxia, microcephaly, gastrointestinal dysmotility, and lactic acidosis. Heteroplasmy levels in affected individuals ranged from 76% to homoplasmy in varying tissues. The variant segregated with clinical manifestations in two families (PP1_moderate), as one proband with multisystem involvement had the variant present at homoplasmy in blood while his less severely affected sister had the variant present at 74% and asymptomatic mother had the variant present at 50% (PMID: 32652755). In one of the other reported families, the proband with LHON had the variant present at 76% whereas his asymptomatic mother had the variant present at 11% and two asymptomatic brothers had the variant present between 9-13% (PMID: 34264415). There is one reported de novo occurrence of this variant (PMID: 32652755). This variant is absent in in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (0.665, range 0-1; PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 13, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414822605/MONDO:0044970/015 2025-01-13 2025-05-28 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:7824 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C2830004 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0034150 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0232492 infores:hetionet CHEBI:50275 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0040822 infores:hetionet CHEBI:42944 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0235996 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0687707 infores:hetionet CHEBI:5138 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013144 infores:hetionet CHEBI:9086 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085932 infores:hetionet CHEBI:15854 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0011606 infores:hetionet CHEBI:8107 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0015371 infores:hetionet CHEBI:36795 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017181 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0032285 infores:hetionet CHEBI:31859 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C1142412 infores:hetionet CAID:CA641945097 biolink:causes MONDO:0010315 infores:clingen CAID:CA641945097 MONDO:0010315 PMID: Uncertain Significance BP7, PM2_Supporting BS2 The NM_000206.3:c.924+9G>T is a deep intron variant affecting nucleotides beyond the +7 (donor) position. The variant is not predicted by SpliceAI, varSEAK, and NNsplice to impact splicing (BP7). In gnomAD v2.1.1, this variant is not observed in any hemizygous adult individual. The highest subpopulation minor allele frequency in gnomAD v2.1.1 is 0.00001223 (1/81766 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000124) for PM2_Supporting (PM2_Supporting). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BP7, PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA641945097/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true NCBIGene:203068 biolink:causes MONDO:0020738 infores:monarchinitiative not_provided not_provided HGNC:20778 MONDO:0020738 uuid:c6644c0c-77d1-42ff-99d5-18043ef50c98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0851341 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0235639 infores:hetionet UMLS:C0879264 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0149871 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0009450 infores:hetionet CHEBI:7936 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0264893 infores:hetionet CHEBI:3077 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0016655 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0314719 infores:hetionet CHEBI:4953 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0026821 infores:hetionet NCBIGene:6584 biolink:causes MONDO:0008919 infores:monarchinitiative not_provided not_provided HGNC:10969 MONDO:0008919 uuid:facb89b5-8be3-4cc5-b94a-dc8210f58863 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151746 infores:hetionet CHEBI:28787 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0027497 infores:hetionet NCBIGene:2492 biolink:causes MONDO:0024463 infores:monarchinitiative not_provided not_provided HGNC:3969 MONDO:0024463 uuid:4707ab60-e286-4d15-8430-3c0ec21dde72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:DJJ95FJP1H biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0014591 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0013378 infores:hetionet CHEBI:7852 biolink:causes MONDO:1040026 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0220650 infores:hetionet CHEBI:3568 biolink:causes MONDO:0054550 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0410480 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0009450 infores:hetionet CHEBI:9123 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0036104 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0011616 infores:hetionet NCBITaxon:1392 biolink:causes MONDO:0004652 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1392 MESH:D018410 DB01416_MESH_D018410_1DB01137_MESH_D018410_1 GO:2001109 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2001109 GO:0007275 CHEBI:68478 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0021400 infores:hetionet CHEBI:63631 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0004604 infores:hetionet CAID:CA16602559 biolink:causes MONDO:0012163 infores:clingen CAID:CA16602559 MONDO:0012163 PMID: Uncertain Significance PM2_Supporting NM_002185.5(IL7R):c.553A>T is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 185 (p.Ser185Cys). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602559/MONDO:0012163/119 2024-03-20 2024-03-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63610 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0003811 infores:hetionet CHEBI:2379 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0009763 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020517 infores:hetionet CHEBI:3403 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0039070 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0021053 infores:hetionet CHEBI:8707 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0428977 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0019348 infores:hetionet CAID:CA916083885 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083885 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.2714_2715del (p.Glu905GlyfsTer?) is a frameshift variant due to a 2-nucleotide deletion that introduces a premature stop codon in exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 23681342, PMID: 14564670, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083885/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CAID:CA204984 biolink:causes MONDO:0021060 infores:clingen CAID:CA204984 MONDO:0021060 PMID: Likely Pathogenic PP3, PM2_Supporting, PS2, PS4_Moderate The c.800T>A variant in SOS2 (NM_006939.4(SOS2):c.800T>A (p.Met267Lys)) is a missense variant predicted to cause substitution of methionine by lysine at amino acid 267. It has been identified in at least 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV001426180.1, PMIDs: 25795793, 30707178). Two of these cases were reported as de novo occurrences, one with maternity and paternity confirmation and the other without (PS2, PM6; SCV001426180.1, PMID: 25795793). The computational predictor REVEL gives a score of 0.802, which is above the threshold of 0.7, evidence that correlates with impact to SOS2 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied: PS2, PS4_Moderate, PM2_Supporting, PP3 (Version 2.1; 9/7/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA204984/MONDO:0021060/042 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4909 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0018834 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018799 infores:hetionet CHEBI:5779 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0023380 infores:hetionet CHEBI:6062 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151786 infores:hetionet CAID:CA8328409 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328409 MONDO:0100438 PMID: Likely Benign BP7, BS2, BP4 BS1, PM2 NM_014336.5(AIPL1):c.756C>T (p.His252=) is a synonymous variant predicted to be a silent nucleotide change in codon 252. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000027, with 43 alleles / 1180026 total alleles in the non-Finnish European population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.00057 and fails to meet this criterion. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00058, with 938 alleles / 1614156 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion as well. This variant has been found in the homozygous state in 7 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The splicing impact predictor SpliceAI gives a delta score of 0.10, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≤0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP:BS2, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328409/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7443 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0740394 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0031350 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0162429 infores:hetionet CHEBI:51380 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0011175 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0221758 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0221758 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0149931 infores:hetionet CHEBI:5801 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C3665347 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0002063 infores:hetionet CHEBI:6067 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085593 infores:hetionet CHEBI:28830 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0041956 infores:hetionet CHEBI:50223 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0231218 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0027051 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0014742 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0025061 infores:hetionet CAID:CA8622917 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622917 MONDO:0100326 PMID: Uncertain Significance PP3 BS1, PM2, BP2, BA1 The c.346C>T variant in ITGB3 is a missense variant predicted to cause substitution of Leucine by Phenylalanine at amino acid 116 (p.Leu116Phe). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0003737 (28/74930 alleles) in the African/African American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.773, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. This variant is also reported in ClinVar in a heterozygous, Portuguese female, presenting with autosomal dominant macrothrombocytopenia (Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto; SCV002540771.1). The only case of this variant occurring in autosomal recessive Glanzmann thrombasthenia (PMID: 27469266) was in a patient with an alternate explanation for disease, compound heterozygous for c.861del and c.1456del (both classified Pathogenic by the PD-VCEP). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622917/MONDO:0100326/011 2023-12-19 2023-12-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA875126160 biolink:causes MONDO:0100437 infores:clingen CAID:CA875126160 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.2517_2518del (p.Glu841GlyfsTer?) is a frameshift variant due to deletion of 2 nucleotides and introduces a premature stop codon after 237 amino acids that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 21857984). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), childhood-onset (1 pt), rod involvement relatively greater than cone (1 pt), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 21857984, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 36017691, PS4_Supporting). This variant has been reported in other apparently unrelated probands (PMID: 23372056, PMID: 34985506, and PMID: 14564670), however, the individuals did not meet one of the PS4 requirements. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, PM2_Supporting, PP1_Moderate, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA875126160/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:30830 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0000731 infores:hetionet CHEBI:6761 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0221242 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151705 infores:hetionet CHEBI:17141 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0027497 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0459435 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0459435 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0149904 infores:hetionet CHEBI:520985 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0028738 infores:hetionet CHEBI:5132 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0015672 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0857386 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0857386 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0038826 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0429029 infores:hetionet CHEBI:3764 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0016204 infores:hetionet CHEBI:4653 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0024902 infores:hetionet CHEBI:17474 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0232487 infores:hetionet GO:1903859 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0007399 CHEBI:82960 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0032584 infores:hetionet CHEBI:49375 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151603 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0853692 infores:hetionet CAID:CA2573051039 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051039 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4 The c.282dup variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 95 (p.(Glu95Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors); therefore, PP4 cannot be applied. In summary, c.282dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051039/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9448 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0041834 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020615 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0006145 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027765 infores:hetionet CHEBI:134990 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0017178 infores:hetionet CHEBI:40009 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0018802 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0851341 infores:hetionet CHEBI:253342 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0231528 infores:hetionet CHEBI:5127 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0015230 infores:hetionet CHEBI:131512 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C2830004 infores:hetionet CHEBI:50275 biolink:causes MONDO:0013662 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0004763 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020517 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042109 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0042373 infores:hetionet CHEBI:63791 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038002 infores:hetionet CHEBI:3561 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0023218 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019348 infores:hetionet CHEBI:7465 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1527344 infores:hetionet CAID:CA410202466 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202466 MONDO:0011071 PMID: Uncertain Significance PM1, PM2_Supporting, PP3 PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.508G>C (p.Gly170Arg) is a missense variant which affects one of the hotspot residues established by the MM-VCEP for RUNX1 (AA G170) (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score > 0.88 (0.947) (PP3). This variant has been reported in ClinVar; however, no phenotypic data was provided. Two individuals with a NM_001754.5(RUNX1).508G>A variant resulting in the same amino acid change have been described (PMID: 22430633). This is a novel missense change at AA Gly170, where a pathogenic insertion causing a frameshift has been identified previously (CA410205628, NM_001754.5(RUNX1).506dupG, p.(Gly170ArgfsTer43), PMID: 26316320). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202466/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3393 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0221490 infores:hetionet CAID:CA8315002 biolink:causes MONDO:0009276 infores:clingen CAID:CA8315002 MONDO:0009276 PMID: Pathogenic PP1, PP4, PM2_Supporting, PM3_Strong, PVS1_Strong, PS3_Supporting NM_000173.7(GP1BA):c.1454dup is a frameshift variant (p.Ser486IlefsTer12), which has been reported in multiple probands with Bernard-Soulier syndrome (PMIDs:11776304, 16916536, 23402648, 24934643, 9241731). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000004440 (based on 2/74766) in the African/African American population, which does not meet PM2_supporting or BS1. The frameshift variant may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove 24% of the protein (PVS1_Strong). Case 2 of PMID: 9241731 is compound heterozygous with c.1480del (classified Pathogenic by the PD-VCEP) confirmed in trans and at least two additional patients are homozygous for the variant (PM3_strong). At least one patient (Proband in PMID:11776304) with this variant had aggregation absent for ristocetin but present for all other agonists and flow cytometry with less than 10% expression of GPIBa (PP4). The variant segregated with Bernard-Soulier syndrome in this patient plus an affected sibling, both compound heterozygous for this variant and Cys225Ser (PP1). Finally, surface expression of GP1Balpha measured by flow cytometry from transient transfection of the c.1454dup variant in CHO cells stably co-expressing the GPIbbeta and GPIX subunits showed decreased expression at 0% (<25%) WT levels, indicating that this variant impacts protein function (PMID:11776304; PS3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM3_strong, PS3_supporting, PVS1_strong, PP4, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8315002/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9434 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0000833 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0038362 infores:hetionet CHEBI:78543 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0236075 infores:hetionet CHEBI:31348 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0041105 infores:hetionet CHEBI:31547 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0009782 infores:hetionet CHEBI:6078 biolink:causes MONDO:0004674 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0008513 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0009450 infores:hetionet CHEBI:10023 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003862 infores:hetionet CAID:CA330970071 biolink:causes MONDO:0010315 infores:clingen CAID:CA330970071 MONDO:0010315 PMID: Likely Benign BS2 PM2 The c.406C>T (NM_000206.3) variant in IL2RG is a missense variant predicted to cause the substitution of Arginine by Tryptophan at amino acid 136 (p.Arg136Trp).The filtering allele frequency (the upper threshold of the 95% CI of 5/57157 alleles) of the c.406C>T variant in IL2RG is 0.00003386 for African/African American chromosomes by gnomAD v4.1.0, which is lower than the ClinGen SCID VCEP threshold (<0.000124) for PM2_Supporting. However, 04 hemizygotes were observed in gnomAD; thus, PM2 was not met, and BS2 is applicable.In summary, this variant meets the criteria to be classified as Likely Benign for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS2 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA330970071/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Contradicts true CHEBI:9907 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151517 infores:hetionet CAID:CA229312 biolink:causes MONDO:0009861 infores:clingen CAID:CA229312 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2, PM3_Very Strong, PVS1_Strong The c.1056del (p.Glu353AsnfsTer47) frameshift variant in PAH is predicted to terminate at codon 400 in exon 12, and would not undergo nonsense mediated-decay. This variant was reported in 4 patients within a Spanish cohort with mild and classic PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329). The variant was identified in trans with 4 pathogenic variants: p.Ala403Val, p.Ile306Val, c.1066-11G>A and p.Glu280Lys (PMID 27121329). This variant is absent from gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PM3 very strong, and PP4 moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229312/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6970 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0031350 infores:hetionet CAID:CA377784465 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784465 MONDO:0017623 PMID: Uncertain Significance PP2, PP3, PM5, PM2_Supporting NM_000314.8(PTEN):c.105G>A (p.Met35Ile) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID: 231916).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.947).PM2_P: Absent in gnomAD. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784465/MONDO:0017623/003 2023-10-11 2023-10-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3207 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0043352 infores:hetionet CHEBI:42820 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0016382 infores:hetionet CHEBI:6923 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0027765 infores:hetionet GO:0030183 biolink:causes CL:0000236 infores:ubergraph knowledge_assertion manual_agent GO:0030183 CL:0000236 CHEBI:3499 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0038325 infores:hetionet CHEBI:3723 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0242301 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0002888 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0015376 infores:hetionet CHEBI:16899 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0017168 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020649 infores:hetionet CHEBI:6704 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0425945 infores:hetionet CHEBI:8024 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151632 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0853619 infores:hetionet CHEBI:75984 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C2047937 infores:hetionet CHEBI:85161 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0000731 infores:hetionet CHEBI:15553 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C1145670 infores:hetionet CAID:CA024112 biolink:causes MONDO:0018493 infores:clingen CAID:CA024112 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with glutamic acid at codon 4734 of the RYR1 protein, p.(Gly4734Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). A functional study using [3H]ryanodine in HEK293 cells showed altered activity of this variant compared to wild-type but this study did not meet the VCEP criteria for a well-established functional study (PMID:27558158). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.871) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024112/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45409 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151736 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0043352 infores:hetionet CHEBI:2637 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0014457 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0031350 infores:hetionet UMLS:C0657912 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020639 infores:hetionet CAID:CA401364951 biolink:causes MONDO:0009290 infores:clingen CAID:CA401364951 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PS3_Supporting PVS1, BS2, PM1, PM5, BP4, BP2, BA1, PS1, BS3, BS1 The NM_000152.5: c.1099T>C (p.Trp367Arg) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.0000013 (1/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant has been reported in at least 3 patients with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and/or on enzyme replacement therapy (ERT) (PMID: 17056254‚ 22658377, 23787031, 25139343, 31510962); it was also reported in one patient of late-onset Pompe disease (LOPD) (PMID: 22958975) (PP4_Moderate). This variant was found to be homozygous in one Spanish-Italian patient with IOPD and was confirmed to be inherited from both parents (PMID: 17056254). At least one Hispanic patient with IOPD under ERT (PMID: 22658377, 23787031, 25139343) was found to be compound heterozygous (phase unknown) for this variant and c.1802C>T (p.Ser601Leu), a GAA variant classified as pathogenic by the ClinGen LD VCEP. This variant was confirmed to be in trans with c.1942G>A (p.Gly648Ser), a GAA variant classified as pathogenic by the ClinGen LD VCEP, in a Thailand patient with IOPD (PMID: 31510962). One Italian patient with LOPD was reported to be compound heterozygous (phase unknown) for the variant and c.-32-13T>G, the most common pathogenic GAA variant associated with LOPD (PMID: 22958975) (PM3_Strong). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity without mature processed GAA protein on immunoblots, indicating a negative impact on GAA function (PMID: 19862843) (PS3_Supporting). The computational meta-predictor REVEL has a score of 0.944 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). Another missense variant, c.1099T>G (p.Trp367Gly), in the same codon has been reported in a patient with LOPD (PMID: 29124014). However, the data for p.Trp367Arg will be used in the assessment of p.Trp367Gly and therefore PM5 is not met here in order to avoid circular argument. There is a ClinVar entry for this variant (Variation ID: 555820). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LD VCEP, on December 5, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401364951/MONDO:0009290/010 2023-12-05 2023-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5004 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0028961 infores:hetionet CHEBI:9150 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0038325 infores:hetionet UMLS:C0657912 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024282 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0029408 infores:hetionet GO:2000733 biolink:causes GO:0001657 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0001657 CHEBI:8888 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0948586 infores:hetionet GO:1904030 biolink:causes GO:0051726 infores:ubergraph knowledge_assertion manual_agent GO:1904030 GO:0051726 CHEBI:2668 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0233494 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042571 infores:hetionet CHEBI:5384 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0017178 infores:hetionet CHEBI:9168 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004144 infores:hetionet CHEBI:4672 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0162834 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002637 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019618 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0162119 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0152227 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0520758 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0520758 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042035 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020615 infores:hetionet CHEBI:2676 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0700345 infores:hetionet CHEBI:7954 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0015967 infores:hetionet CHEBI:6847 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0232462 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0041912 infores:hetionet CHEBI:31705 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0424790 infores:hetionet CHEBI:28177 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0011991 infores:hetionet CHEBI:4514 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0013384 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0520589 infores:hetionet CHEBI:8871 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017979 infores:hetionet NCBIGene:1690 biolink:causes MONDO:0054860 infores:monarchinitiative not_provided not_provided HGNC:2180 MONDO:0054860 uuid:fec30a93-88cb-4828-ae9f-8669f8f318c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7954 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0010200 infores:hetionet CHEBI:63610 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C2981158 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0424230 infores:hetionet CHEBI:7824 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151889 infores:hetionet CHEBI:6129 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018681 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0041969 infores:hetionet CHEBI:2639 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0000731 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0162848 infores:hetionet CHEBI:3654 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0232462 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0002871 infores:hetionet CHEBI:51860 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0029944 infores:hetionet NCBIGene:10586 biolink:causes MONDO:0014380 infores:monarchinitiative not_provided not_provided HGNC:6758 MONDO:0014380 uuid:97ac9f84-93d2-4f12-b7ad-016bd692835f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:590 biolink:causes MONDO:0000827 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:590 MESH:D012480 DB07565_MESH_D012480_1 CHEBI:63580 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0855242 infores:hetionet CHEBI:63619 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0034642 infores:hetionet GO:0021708 biolink:causes CL:0011006 infores:ubergraph knowledge_assertion manual_agent GO:0021708 CL:0011006 CHEBI:63635 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011168 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002453 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0700201 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0700201 infores:hetionet NCBIGene:118924 biolink:causes MONDO:0859312 infores:monarchinitiative not_provided not_provided HGNC:1162 MONDO:0859312 uuid:51b96a69-c010-4c09-86ea-b22158cd60f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042769 infores:hetionet CHEBI:3127 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0151942 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0178298 infores:hetionet CHEBI:28593 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0038325 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0037199 infores:hetionet CHEBI:127780 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151904 infores:hetionet CHEBI:28939 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0013395 infores:hetionet CAID:CA377784441 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784441 MONDO:0017623 PMID: Uncertain Significance PP2, PP3, PM2_Supporting NM_000314.8(PTEN):c.98T>C (p.Ile33Thr) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.972)PM2_P: Absent in gnomAD database PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784441/MONDO:0017623/003 2023-10-11 2023-10-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7824 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0520966 infores:hetionet CAID:CA416041964 biolink:causes MONDO:0100283 infores:clingen CAID:CA416041964 MONDO:0100283 PMID: Uncertain Significance BP4 BP7, BS1, PM2, BA1 The NM_004958.4:c.997C>T (p.Leu333=) variant in MTOR is a synonymous (silent) variant. In gnomAD v4.1.0, this variant has a minor allele frequency of 0.00008474% (1/1180028) in the European (non-Finnish) population and a filtering allele frequency is not provided (PM2_Supporting, BS1, and BA1 not met). The computational predictor SpliceAI gives a score of 0.02 and the computational predictors MaxEntScan and varSEAK indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on MTOR function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BP4 (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA416041964/MONDO:0100283/018 2025-07-01 2025-07-01 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:114785 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0035410 infores:hetionet CHEBI:79699 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0032227 infores:hetionet NCBIGene:641 biolink:causes MONDO:0008876 infores:monarchinitiative not_provided not_provided HGNC:1058 MONDO:0008876 uuid:939d7d4c-6a1e-4f4b-bab9-fccdc52f73c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011991 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0004096 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0002792 infores:hetionet CAID:CA410148231 biolink:causes MONDO:0100083 infores:clingen CAID:CA410148231 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, BP4, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP1, PP4, PP2, PP3, BS2 NM_001754.5(RUNX1):c.1072A>C (p.Thr358Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148231/MONDO:0100083/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:474053 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0149745 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0009450 infores:hetionet CHEBI:71223 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0041912 infores:hetionet CHEBI:9571 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0030446 infores:hetionet CHEBI:6128 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0036690 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0021053 infores:hetionet CHEBI:6717 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0041657 infores:hetionet CHEBI:3814 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0002962 infores:hetionet CAID:CA000332 biolink:causes MONDO:0017623 infores:clingen CAID:CA000332 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PS4_Supporting PP1, PM5, PM1 PTEN c.182A>G (p.His61Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Massively parallel functional assay interrogating phosphatase activity demonstrating a statistically significant difference from wild type (PMID: 29706350).PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID: 28526761). PM2_P: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score = 0.981. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000332/MONDO:0017623/003 2023-12-01 2023-12-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7476 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0033774 infores:hetionet CHEBI:7798 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C2363730 infores:hetionet CL:0000129 biolink:causes GO:0090634 infores:ubergraph knowledge_assertion manual_agent CL:0000129 GO:0090634 CHEBI:51041 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011053 infores:hetionet CHEBI:17263 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0006852 infores:hetionet CAID:CA170485 biolink:causes MONDO:0100039 infores:clingen CAID:CA170485 MONDO:0100039 PMID: Benign BS1, BS2 PP4, PM2 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.2908C>T (p.Arg970Ter) variant in CDKL5 transcript (NM_003159.2) is 0.02285% in the Middle Eastern sub population in gnomAD v4, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Arg970Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID 19428276), however this criterion cannot be applied due the allele frequency of the variant in gnomAD (PP4 not met). The p.Arg970Ter is observed in at least 5 unaffected individuals (internal database - GeneDx). In summary, the p.Arg970Ter variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170485/MONDO:0100039/034 2023-12-06 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:8863 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1142135 infores:hetionet CHEBI:16714 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0027441 infores:hetionet CHEBI:64317 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0013404 infores:hetionet CHEBI:45409 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0040264 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0919662 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0919662 infores:hetionet CHEBI:2659 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0011606 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0037274 infores:hetionet CHEBI:7573 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0011570 infores:hetionet CHEBI:31348 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151786 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0151824 infores:hetionet CHEBI:75988 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0027497 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0020517 infores:hetionet CHEBI:36704 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0002170 infores:hetionet CHEBI:9763 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0015967 infores:hetionet CHEBI:4657 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0018418 infores:hetionet CHEBI:10124 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085633 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036572 infores:hetionet CHEBI:4858 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0028961 infores:hetionet CHEBI:5120 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0855242 infores:hetionet CHEBI:119915 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085633 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0026857 infores:hetionet CAID:CA8814829 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814829 MONDO:0009290 PMID: Likely Benign BP4, BS1, BP7 PM2, BS2, BA1, PS3, BS3 The NM_000152.5: c.258C>A (p.Pro86=) variant in GAA is a synonymous variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.00509 (382/75054 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for BS1 (>0.005), meeting this criterion (BS1). The variant is not predicted to impact splicing; the nucleotide is not conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 282138). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7. (Classification approved by the ClinGen Lysosomal Diseases VCEP on December 5, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814829/MONDO:0009290/010 2023-12-05 2023-12-07 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:9599 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0011570 infores:hetionet UMLS:C0023610 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0030794 infores:hetionet CHEBI:63599 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0030193 infores:hetionet CHEBI:5855 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151529 infores:hetionet CHEBI:68642 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0041969 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0004936 infores:hetionet CHEBI:6375 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0152009 infores:hetionet CAID:CA1706197 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706197 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.2496_2499del p.(Thr833SerfsTer3) variant in DYSF, which is also known as NM_001130987.2: c.2550_2553del p.(Thr851SerfsTer3), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 24/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least three patients with signs of LGMD, including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 21522182) and in unknown phase with a pathogenic variant (NM_003494.4: c.5668-7G>A, 0.5 pts, PMID: 36983702) (PM3). At least one patient with this variant had a second presumed diagnostic variant in DYSF and displayed progressive limb girdle muscle weakness and significantly reduced dysferlin expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong). The filtering allele frequency for this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1112012 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706197/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31348 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0541832 infores:hetionet CHEBI:5775 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0002878 infores:hetionet CHEBI:80630 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0011071 infores:hetionet CHEBI:9943 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233514 infores:hetionet CAID:CA000474 biolink:causes MONDO:0018875 infores:clingen CAID:CA000474 MONDO:0018875 PMID: Likely Benign BP4, BS3, PM2_Supporting BP2, BA1, PS3, PS4, PS1, PM1, PM5, BP5, BS1, BS4, BS2, PP1, PP3 The NM_000546.6: c.886C>T variant in TP53 is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 296 (p.His296Tyr). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has an allele frequency of 0.000001695 (2/1180034 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Computational predictor scores (BayesDel = -0.12; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, PM2_Supporting, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000474/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31644 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0018799 infores:hetionet CHEBI:7581 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0012833 infores:hetionet CHEBI:38940 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0017565 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0004936 infores:hetionet CHEBI:28939 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0233477 infores:hetionet CHEBI:8232 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0001824 infores:hetionet CHEBI:681850 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0041969 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0021053 infores:hetionet CHEBI:17650 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0030554 infores:hetionet CHEBI:6061 biolink:causes UMLS:C0857468 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0857468 infores:hetionet CHEBI:44032 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0085595 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0518015 infores:hetionet CHEBI:3485 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0595916 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0019112 infores:hetionet NCBIGene:127833 biolink:causes MONDO:0014468 infores:monarchinitiative not_provided not_provided HGNC:11510 MONDO:0014468 uuid:1543b577-01d1-4da8-a684-c3afd10c69ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0003864 infores:hetionet NCBIGene:1075 biolink:causes MONDO:0009490 infores:monarchinitiative not_provided not_provided HGNC:2528 MONDO:0009490 uuid:000e0298-54ba-4efd-844f-2feb209f6934 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6832 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0030193 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0521491 infores:hetionet CHEBI:63681 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0011991 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0162830 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0029408 infores:hetionet CHEBI:42068 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0031542 infores:hetionet CHEBI:40050 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0151904 infores:hetionet CAID:CA658683961 biolink:causes MONDO:0007648 infores:clingen CAID:CA658683961 MONDO:0007648 PMID:26182300 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.2100del p.(Val701Serfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 26182300). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683961/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA214200 biolink:causes MONDO:0000572 infores:clingen CAID:CA214200 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000448.3(RAG1):c.2904C>A is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 968 (p.Asn968Lys). This missense variant is located in the core domain (amino acids 387-1011)(PM1_Supporting). The highest population minor allele frequency in gnomAD v4 is 8.993e-7 (1/1112012 alleles) in European Non-Finnish population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient with Omenn syndrome was found heterozygous for c.3016C>G, p.N968K & c.2387C>T, p.R759C (not classified by SCID VCEP yet) (PMID: 15908971):PM3 not evaluated.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_Supporting, PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214200/MONDO:0000572/123 2024-05-07 2024-05-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8499 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0232462 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003850 infores:hetionet CHEBI:3478 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0011991 infores:hetionet CHEBI:5383 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0042790 infores:hetionet CHEBI:6950 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0014518 infores:hetionet CHEBI:47898 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020473 infores:hetionet CHEBI:127780 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0009763 infores:hetionet CHEBI:9588 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0002792 infores:hetionet NCBIGene:9215 biolink:causes MONDO:0012138 infores:monarchinitiative not_provided not_provided HGNC:6511 MONDO:0012138 uuid:b23c0045-6102-4b2b-9ed8-14de9e6e9442 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44032 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0267792 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0267792 infores:hetionet CHEBI:41423 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018965 infores:hetionet NCBIGene:65266 biolink:causes MONDO:0013777 infores:monarchinitiative not_provided not_provided HGNC:14544 MONDO:0013777 uuid:d8f323ff-f1af-4606-a3ad-4dc099cb59ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0022660 infores:hetionet CHEBI:45863 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0237849 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0162429 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0948586 infores:hetionet CHEBI:6887 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0028778 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0234215 infores:hetionet NCBIGene:10367 biolink:causes MONDO:0014300 infores:monarchinitiative not_provided not_provided HGNC:1530 MONDO:0014300 uuid:a1840296-da00-43fa-bc7b-a785b7346d67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1619712 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151717 infores:hetionet CHEBI:3696 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0036974 infores:hetionet CHEBI:2611 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0455204 infores:hetionet CHEBI:2788 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0042963 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013595 infores:hetionet CHEBI:68478 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0023380 infores:hetionet CHEBI:63580 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0026826 infores:hetionet CAID:CA6831794 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831794 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3, PP4 PM5 The c.682G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 228 (p.(Glu228Lys)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is predicted to be deleterious by computational evidence, with a REVEL score of 0.8799, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant has a minor allele frequency of 0.0000088 in the gnomAD v2.1.1 European non-Finnish population and zero copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). The c.682G>A variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). Another missense variant, c.683A>G p.Glu228Gly, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.682G>A meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PM2_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831794/MONDO:0015967/017 2022-08-05 2022-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6367 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C2047937 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0031350 infores:hetionet CAID:CA392332017 biolink:causes MONDO:0007947 infores:clingen CAID:CA392332017 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PM1, PM5 PS4 The NM_00138 c.2660G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 887 (p.Cys887Tyr). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (PMID 23684891) (PP4). This variant has been reported three times in ClinVar: twice as pathogenic and once as uncertain significance (Variation ID: 915814). This variant has been reported in the literature in an individual with a suspected diagnosis of Marfan syndrome (PMID 29907982). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Other missense variants affecting the same residue, including p.Cys887Tyr and p.Cys887Arg have been previously reported in individuals with clinical features of Marfan syndrome (PMID 27906200, 34281902, internal data; PM5). This variant affects a cysteine residue in a hybrid domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.926, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392332017/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:45409 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0031350 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0021775 infores:hetionet CHEBI:31859 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0015672 infores:hetionet CHEBI:10101 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0013428 infores:hetionet CHEBI:51041 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020580 infores:hetionet CHEBI:9241 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0002170 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0004096 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0349506 infores:hetionet UMLS:C1738934 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C3665347 infores:hetionet NCBIGene:5921 biolink:causes MONDO:0020783 infores:monarchinitiative not_provided not_provided HGNC:9871 MONDO:0020783 uuid:db7ca2b8-24d1-4f3a-b6f2-421367c026c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0919659 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0919659 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0178298 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0232498 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151479 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0340464 infores:hetionet CHEBI:16714 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C1392046 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0020538 infores:hetionet CHEBI:6715 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0005778 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0018799 infores:hetionet CHEBI:49668 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0036974 infores:hetionet CHEBI:478164 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0015230 infores:hetionet CHEBI:7577 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0043094 infores:hetionet CHEBI:8028 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0004134 infores:hetionet CHEBI:68579 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018946 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0948594 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0008566 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0008566 uuid:0f4a4d23-db75-4758-b4ab-c4ed303e2231 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0003397 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017567 infores:hetionet NCBITaxon:10566 biolink:causes MONDO:0001209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10566 MESH:D014860 DB08809_MESH_D014860_1DB00724_MESH_D014860_1 CHEBI:136040 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0085593 infores:hetionet CAID:CA405636001 biolink:causes MONDO:0007783 infores:clingen CAID:CA405636001 MONDO:0007783 PMID: Uncertain Significance PS4_Moderate PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 1058 of the RYR1 protein, p.Glu1058Lys. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:19346234, PMID:30236257). Three additional cases have been identified in clinical laboratories associated with the MHS-RYR1 VCEP, all three cases had a personal or family history of a malignant hyperthermia reaction but only two had contracture testing, PS4_Moderate (MH Investigation Unit (MHIU), UHN, Toronto (2 cases), The UK (Leeds) MH Unit (1 case)). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.78 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405636001/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA7331564 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331564 MONDO:0100216 PMID: Uncertain Significance BP4, PP4, PS4_Supporting, PS2 PM2, BP2, BA1, PP3, PP1, BS2, PM5, PM1, PS1, PS3, BS1, BS4, BS3 The NM_177438.3:c.832C>T variant in DICER1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 278 (p.Leu278Phe). This variant received a total of 1 phenotype point in 1 proband, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 26925222). In the same individual, this variant was identified as a de novo occurrence with constitutional mosaicism (PS2; PMID: 26925222). This individual was also found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 26925222). The total allele frequency in gnomAD v4.1.0 is 0.000003799 (6/1579166 alleles) with a highest population minor allele frequency of 0.00006640 (6/90360 alleles) in the South Asian population and with multiple alleles present in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.326); MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PP4, BP4. (Bayesian Points: 5; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331564/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5383 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0271710 infores:hetionet CHEBI:8871 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0278061 infores:hetionet CHEBI:4672 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027497 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020456 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042373 infores:hetionet CHEBI:4858 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0004096 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0039520 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0037199 infores:hetionet CHEBI:61033 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0027497 infores:hetionet CHEBI:10119 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0019079 infores:hetionet CHEBI:3387 biolink:causes HP:0100507 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0016412 infores:hetionet CHEBI:8863 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0037763 infores:hetionet CHEBI:50838 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0040053 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0178298 infores:hetionet CHEBI:5100 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0015672 infores:hetionet CHEBI:8430 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C1142412 infores:hetionet CHEBI:8378 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0003708 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0162119 infores:hetionet CHEBI:75722 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235490 infores:hetionet CHEBI:261649 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0030193 infores:hetionet CHEBI:404903 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011168 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0392162 infores:hetionet CHEBI:63624 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0151904 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0549209 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006849 infores:hetionet CHEBI:50859 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151904 infores:hetionet NCBIGene:23001 biolink:causes MONDO:0054593 infores:monarchinitiative not_provided not_provided HGNC:20751 MONDO:0054593 uuid:90a75a85-9138-4c8d-9a2a-f0980ff0b252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5050 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0042769 infores:hetionet NCBITaxon:5811 biolink:causes MONDO:0004674 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5811 MESH:D002825 DB00359_MESH_D002825_1 NCBIGene:55835 biolink:causes MONDO:0012029 infores:monarchinitiative not_provided not_provided HGNC:17272 MONDO:0012029 uuid:a7c63226-7ac8-4fb0-9090-1f6fac3da8c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233472 infores:hetionet CHEBI:3756 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C2364111 infores:hetionet CAID:CA199325 biolink:causes MONDO:0010726 infores:clingen CAID:CA199325 MONDO:0010726 PMID: Pathogenic PP4, PS2_Very Strong, PS4, PM2_Supporting PM1, PP3, BP4 The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199325/MONDO:0010726/016 2022-07-28 2022-09-06 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:3723 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0344232 infores:hetionet CHEBI:3504 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0014518 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042075 infores:hetionet CHEBI:44185 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018378 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019348 infores:hetionet CHEBI:6887 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0039240 infores:hetionet CAID:CA10652922 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652922 MONDO:0011071 PMID: Benign BA1 PS1, PS4, PS3, BP2, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM5, PM1, PM4, PP1, PP3 The RUNX1 c.*2005A>G variant in the 3' UTR has an MAF of 0.001606 (0.16%, 14/8716 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652922/MONDO:0011071/008 2020-08-24 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:44185 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0021053 infores:hetionet CAID:CA386970379 biolink:causes MONDO:0015967 infores:clingen CAID:CA386970379 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 The c.1489C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 497 (p.(Gln497Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 7 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% (45.5%), but negative genetic testing for HNF4A and an extreme response to low dose sulfonylurea) (PP4; internal lab contributors). In summary, c.1489C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PM2_Supporting, PP4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386970379/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3077 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0241863 infores:hetionet CHEBI:553473 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0030312 infores:hetionet CHEBI:87681 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0600142 infores:hetionet CHEBI:4636 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0040264 infores:hetionet CHEBI:8207 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0040822 infores:hetionet CHEBI:3127 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0004604 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233494 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0017178 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0020538 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038454 infores:hetionet CHEBI:7915 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042029 infores:hetionet CHEBI:70707 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0151636 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1262144 infores:hetionet CAID:CA213733 biolink:causes MONDO:0015967 infores:clingen CAID:CA213733 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM5_Supporting, PP4_Moderate, PP2, PM2_Supporting PP3 The c.1175G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 392 (p.(Arg392Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.568, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. Another missense variant, c.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Leu (PM5_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a three generation family history) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1175G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PM5_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213733/MONDO:0015967/086 2024-10-17 2024-10-17 Semidominant inheritance HP:0032113 Supports CHEBI:8888 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1167965 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042109 infores:hetionet CHEBI:3504 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020461 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0040479 infores:hetionet NCBIGene:9373 biolink:causes MONDO:0060502 infores:monarchinitiative not_provided not_provided HGNC:9043 MONDO:0060502 uuid:ee5e0062-d5a9-4e90-81e3-ecd6ea38aacc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:D27V6190PM biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0270996 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020550 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013395 infores:hetionet CAID:CA9870224 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870224 MONDO:0015967 PMID: Likely Benign BP4, BP7 PM2, BS1 The c.321C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 107 (p.(Ala107=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.636, which is below the MDEP cutoff of 2.0) (BP4, BP7). ). The Popmax frequency of the c.321C>T variant in gnomAD v2.1.1 is 0.000007040, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.321C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870224/MONDO:0015967/085 2023-01-12 2023-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3568 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011991 infores:hetionet CHEBI:6062 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151662 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0574067 infores:hetionet CHEBI:17549 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0033774 infores:hetionet CHEBI:15940 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0542571 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007097 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0006849 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0036572 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0853692 infores:hetionet CAID:CA015116 biolink:causes MONDO:0004994 infores:clingen CAID:CA015116 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4566T>C (p.Thr1522=) variant in the MYH7 gene is 2.98% (376/11574) of Latino chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015116/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:82960 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0006625 infores:hetionet CHEBI:31859 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018681 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027947 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0013922 infores:hetionet CHEBI:47781 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0011570 infores:hetionet CHEBI:101085 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0040264 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1142412 infores:hetionet CAID:CA116619 biolink:causes MONDO:0009290 infores:clingen CAID:CA116619 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3, BP4, PS3 "The NM_000152.5:c.710C>T variant in GAA is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 237 (p.Ala237Val). A patient with late onset Pompe disease and this variant has been described with a severely reduced GAA activity (<10% normal) and an increase of total glycogen in muscle (PMID: 15668445, 17573812, 17643989) (PP4_Moderate). This patient is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.877G>A (p.Gly293Arg) (PMID: 15668445, 17573812, 17643989) (PM3_Supporting). Another patient has been reported who is compound heterozygous for the variant and p.Met173del (PMID: 28196920). However, the cDNA changes for these variants were not provided and therefore the data was not included. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00013 (4/30616 alleles) in the South Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had ""greater than 2% wild-type GAA activity"", but the activity was not provided (PS3 not met). The computational predictor REVEL gives a score of 0.693 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen LSD VCEP on November 2, 2022)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116619/MONDO:0009290/010 2022-11-02 2022-12-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CAID:CA003230 biolink:causes MONDO:0700268 infores:clingen CAID:CA003230 MONDO:0700268 PMID:30209399PMID:30765603 Likely Pathogenic PP3, PM2_Supporting, PS3 BP5 The c.5090G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 1697 (p.Cys1697Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.386, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.02 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 38709234) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.48 (based on Family History LR=0.48), within the thresholds for supporting benign evidence (LR >0.23 & ≥0.48) (PMID: 31853058). The VCEP decided to not yet include BP5_Supporting as the LR is very close to the threshold of no evidence, and the Family history model is currently being updated. The VCEP is interested in additional data that could be incorporated in the classification of this variant, please contact the submitter. In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003230/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CAID:CA401368767 biolink:causes MONDO:0009290 infores:clingen CAID:CA401368767 MONDO:0009290 PMID: Likely Pathogenic PP3, PP4, PM3, PS3_Moderate, PM2_Supporting PM5, PS1 The NM_000152.5:c.1645G>C variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 549 (p.Gly549Arg). At least 1 proband with this variant has been reported to be on enzyme replacement therapy for Pompe disease and was noted to have deficient GAA activity but results were not provided (PMID: 16917947, 28433478, 33426149) (PP4). This proband was compound heterozygous for the variant and c.692+1G>C (ClinVar Variation ID: 972793), which is classified as pathogenic by the ClinGen LD VCEP, confirmed in trans by DNA analysis of parents and/or other relatives (PMID: 16917947, 28433478, 33426149) (PM3). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). In at least three different studies, expression of the variant in HEK cells, Ad5-SV40 immortalized human GAA-deficient fibroblast cells, or COS cells resulted in less than 10% of wild-type GAA activity and showed evidence of abnormal GAA processing. Western blot revealed presence of the active 76kDa GAA band, but at a lower level than wild type (PMID: 17213836, 17915575, 19862843). Given the number of functional studies performed in a variety of cell types, PS3 will be applied at the moderate level of strength (PS3_Moderate). Additionally, the computational predictor REVEL gives a score of 0.878, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The same amino acid change, resulting from a different nucleotide change c.1645G>A (PMID: 14695532, ClinVar Variation ID: 2202283), has been reported in a patient with Pompe disease. In addition, different missense changes at the same amino acid are reported including c.1646G>A (p.Gly549Glu), ClinVar Variation ID: 2091465 ), and c.1646G>C (p.Gly549Ala) (ClinVar Variation ID: 951481). None of these variants have been classified yet by the ClinGen LD VCEP and therefore neither PS1 nor PM5 was applied. There is a ClinVar entry for this variant (Variation ID: 3769497). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PS3_Moderate, PM2_Supporting, PM3, PP3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 1, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401368767/MONDO:0009290/010 2025-07-01 2025-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6887 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0017601 infores:hetionet CHEBI:17347 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042023 infores:hetionet CAID:CA913180249 biolink:causes MONDO:0044970 infores:clingen CAID:CA913180249 MONDO:0044970 PMID:23696415 Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting PP1, PS2, PM6 The m.5690A>G variant in MT-TN has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). One individual was a male with features consistent with Kearns Sayre syndrome including ptosis, ophthalmoplegia, cardiac conduction defects, myopathy, and ragged red fibers (PMID: 23847141, additional clinical details obtained from correspondence with author team). This individual had the variant present at 47% in muscle and no mitochondrial DNA single large scale deletions were identified. The second individual was a female with chronic progressive external ophthalmoplegia (CPEO) and myopathy (PMID: 23696415). The variant was present at 35% in muscle and was undetectable in her urine and blood. Testing in family members was not reported or not assessed for these two individuals, therefore it is unclear if the variant arose de novo or was present at lower levels in healthy family members. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (75.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (86.8 ± 18.3%) than in COX-positive fibers (27.9 ± 31.3%, p<0.0001, PMID: 23696415; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given similar features were seen in the two reported individuals with this variant and the strong single fiber study that was performed. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913180249/MONDO:0044970/015 2023-01-09 2023-03-31 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:32221 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0030252 infores:hetionet CHEBI:7514 biolink:causes UMLS:C0877617 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0877617 infores:hetionet CAID:CA143283 biolink:causes MONDO:0019501 infores:clingen CAID:CA143283 MONDO:0019501 PMID:22135276PMID:25649381PMID:25649381PMID:25910913PMID:22135276 Pathogenic PVS1_Strong, PP4, PM2_Supporting, PM3_Strong BP7, PS3 The c.12295-3T>A variant in USH2A is an intronic variant located within the acceptor splice consensus sequence of intron 62. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000039 (5/127918 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant has been identified in 4 individuals with clinical features or diagnosis of Usher syndrome with hearing loss (PMID: 25649381, 22135276; PP4). Three of these individuals were compound heterozygous, phase unknown, with the pathogenic p.Glu767Serfs*21 USH2A variant. The fourth individual harbored the Tyr4031* variant in USH2A, which was likely in trans as shown through RT-PCR sequencing (PM3_Strong). While this variant does not occur within the canonical splice site (±1,2), it has been shown to cause out-of-frame exon skipping in patient-derived cells and pathogenic variants in this exon have been reported in ClinVar (PVS1_Strong, PMID:25649381). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PVS1_Strong, PM3_Strong, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143283/MONDO:0019501/005 2022-10-31 2023-02-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:7824 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018991 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0178298 infores:hetionet CHEBI:5106 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0004604 infores:hetionet CHEBI:9943 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002994 infores:hetionet CHEBI:28971 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0034150 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005301 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0026769 infores:hetionet CHEBI:9667 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0151692 infores:hetionet NCBIGene:5251 biolink:causes MONDO:0010619 infores:monarchinitiative not_provided not_provided HGNC:8918 MONDO:0010619 uuid:fd58aa78-85f8-412a-bee1-72dedd46c29d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038587 infores:hetionet CHEBI:3419 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0042963 infores:hetionet CHEBI:8024 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0041834 infores:hetionet CAID:CA386954942 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954942 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PP4, PP1 The c.323T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 108 (p.(Leu108Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.968, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (DOI: 10.3760/cma.j.cn121383-20200729-07076, internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (DOI: 10.3760/cma.j.cn121383-20200729-07076). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). Therefore, PP4 cannot be applied. In summary, c.323T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954942/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2955 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0003862 infores:hetionet CHEBI:84500 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0025345 infores:hetionet CHEBI:48390 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0002994 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0011570 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0917801 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0013604 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0162820 infores:hetionet NCBIGene:50717 biolink:causes MONDO:0012411 infores:monarchinitiative not_provided not_provided HGNC:24891 MONDO:0012411 uuid:12be7217-1372-4199-8df6-57642af4860a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0034359 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0085129 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042133 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0033581 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0028259 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0037274 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235030 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0040822 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085584 infores:hetionet CHEBI:6129 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0038325 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0233494 infores:hetionet CHEBI:5165 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0025289 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018799 infores:hetionet CHEBI:499361 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020458 infores:hetionet CAID:CA645293833 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293833 MONDO:0015924 PMID: Likely Pathogenic PP3, PS1_Supporting, PM2_Supporting, PM1_Strong BA1, BP4, BS1 The BMPR2 c.1276+3A>G variant is a non-canonical splice site (+3) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with heritable PAH (PMID: 16429395). In silico prediction (SpliceAI = 0.59) indicates a likely impact on splicing with loss of the canonical donor site in intron 9 (PP3). This predicted splicing event matches a known likely pathogenic variant (c.1276+4A>G) within the same donor site (PS1_supporting) (PMID: 37352859). Exon skipping or use of a cryptic splice site would disrupt the region encoding the conserved intracellular kinase domain (PM1_strong). No familial segregation data were available, and no functional analysis has been reported for this variant. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PS1_supporting, PM2_supporting, PP3 (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293833/MONDO:0015924/125 2025-04-29 2025-04-29 Autosomal dominant inheritance HP:0000006 Supports GO:1904429 biolink:causes GO:0090737 infores:ubergraph knowledge_assertion manual_agent GO:1904429 GO:0090737 UMLS:C0010592 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C3160741 infores:hetionet CHEBI:50729 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0041582 infores:hetionet NCBIGene:375748 biolink:causes MONDO:0014317 infores:monarchinitiative not_provided not_provided HGNC:26922 MONDO:0014317 uuid:8e2c5caf-b3a2-4b23-804d-60e894471fd2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0037763 infores:hetionet CHEBI:194135 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0476273 infores:hetionet CHEBI:6950 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151636 infores:hetionet CHEBI:3752 biolink:causes MONDO:0009047 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0010417 infores:hetionet CAID:CA210746 biolink:causes MONDO:0013144 infores:clingen CAID:CA210746 MONDO:0013144 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PP3, PM2_Supporting PM1 The c.1306G>A (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 436 (p.Ala436Thr). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL with either a family history of antithrombin activity levels of < 0.8 IU/mL or an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. One more proband is reported with antithrombin activity levels of < 0.8 IU/mL but no repeat testing or family history is specified so 0.5 point is awarded (PS4_Moderate; PMID:3055413, 1469094). The variant has been reported to segregate with autosomal dominant antithrombin deficiency in 11 affected meioses from one family (PP1_Moderate; PMIDs:1469094, 3055413). The computational predictor REVEL gives a score of 0.778, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1_Moderate, PM2_Supporting, PS4_Moderate, PP3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210746/MONDO:0013144/084 2024-08-16 2024-08-21 Autosomal dominant inheritance HP:0000006 Supports PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0042571 infores:hetionet CHEBI:63637 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0004238 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0243026 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0178298 infores:hetionet CHEBI:47381 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085649 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0267792 infores:hetionet CHEBI:9927 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C1384353 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020437 infores:hetionet CHEBI:8502 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0027497 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0042109 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0035455 infores:hetionet CAID:CA119184 biolink:causes MONDO:0020367 infores:clingen CAID:CA119184 MONDO:0020367 PMID:19234343PMID:27092720PMID:19234343PMID:27092720 Uncertain Significance PP3, PP1, PM2_Supporting BS1, BS3, BP7, PM6, PM4, PM5, PS3, PS4, PS1, PS2, BA1, BP4 The c.734G>A variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 245 (p.Cys245Tyr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The studies reporting functional evidence (PMIDs: 19234343, 27092720) demonstrated that the Cys245Tyr protein had reduced secretion and solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. 3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 16401791), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 16401791), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM2_Supporting, PP1, PP3 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119184/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3127 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0030252 infores:hetionet CHEBI:39112 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0004093 infores:hetionet CHEBI:94686 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0232495 infores:hetionet CHEBI:50275 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C3665386 infores:hetionet CHEBI:4975 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0038999 infores:hetionet CHEBI:5613 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0023530 infores:hetionet CHEBI:50131 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0600228 infores:hetionet CHEBI:9137 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0021177 infores:hetionet CHEBI:231594 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0004604 infores:hetionet CHEBI:28901 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0003467 infores:hetionet UMLS:C1738934 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0018808 infores:hetionet CHEBI:7514 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0015230 infores:hetionet CHEBI:9654 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0151878 infores:hetionet CHEBI:8863 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151904 infores:hetionet CHEBI:29007 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0013378 infores:hetionet CHEBI:8024 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0015672 infores:hetionet CHEBI:6402 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0008031 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037274 infores:hetionet CHEBI:51380 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0037383 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0876973 infores:hetionet CAID:CA064575 biolink:causes MONDO:0018493 infores:clingen CAID:CA064575 MONDO:0018493 PMID: Likely Benign PS4_Supporting, BS2_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 1075 of the RYR1 protein, p.(Arg1075Gln). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). One relative was shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented (PMID: 19454545). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.846 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PS4_Supporting, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA064575/MONDO:0018493/012 2022-03-14 2022-03-14 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10112 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0012833 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018418 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0856554 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0856554 infores:hetionet CHEBI:74947 biolink:causes EFO:0010671 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0549124 infores:hetionet CHEBI:71415 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0013395 infores:hetionet NCBITaxon:52283 biolink:causes MONDO:0004525 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:52283 MONDO:0004525 CHEBI:6888 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0525045 infores:hetionet CHEBI:94848 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0040034 infores:hetionet CHEBI:83804 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0156404 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0031350 infores:hetionet CHEBI:87681 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0027497 infores:hetionet CHEBI:50173 biolink:causes HP:0100716 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085271 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0021141 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0007222 infores:hetionet CHEBI:8774 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0009676 infores:hetionet CHEBI:94848 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0022893 infores:hetionet CHEBI:10119 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0037672 infores:hetionet CHEBI:28864 biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0009759 infores:hetionet CHEBI:9073 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C1443060 infores:hetionet CHEBI:3216 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0026205 infores:hetionet CHEBI:3082 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0231218 infores:hetionet CHEBI:135888 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0003862 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0740380 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0740380 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0027051 infores:hetionet CHEBI:5778 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0152031 infores:hetionet CHEBI:82716 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C1112525 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0023067 infores:hetionet CAID:CA124466 biolink:causes MONDO:0015967 infores:clingen CAID:CA124466 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BS3_Supporting, PP1_Strong, BS2, PP4 PS4 The c.1859C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to isoleucine at codon 620 (p.Thr620Ile) of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 9075818, 25414397, 10482964, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). Furthermore, this variant segregated with diabetes, with 7 informative meioses in a single family (PP1_Strong; PMID: 10482964). Functional studies demonstrated the p.Thr620Ile protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 12530534) (BS3_Supporting). This variant was also identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (PMID: 10482964) (BS2). In summary, c.1859C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0 approved 6/30/2025): PM2_Supporting, PP1_Strong, BS3_Supporting, BS2, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124466/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA023443 biolink:causes MONDO:0007750 infores:clingen CAID:CA023443 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR):c.1285G>A (p.Val429Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.00003266 (0.003%) in South Asian exomes (gnomAD v2.1.1). PP3: REVEL = 0.809. PS3_Moderate: Level 2 assay – PMID 2569482 (Leitersdorf et al., 1989) - Immunoprecipitation assay on heterozygous CHO cells where the receptor was degraded more rapidly. After 6 h, only 13% of the LDL receptor protein remained. Level 2 assay – PMID 3202825 (Fourie et al., 1988) - 125I-labelled LDL assay on homozygous patient's fibroblasts with overall LDL receptor activity of ~2% of wildtype. PS4, PP4: Variant meets PM2 and is identified in at least 55 unrelated index cases who fulfill criteria for FH- 1 case with DLCN score >=6 from Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain;- 4 cases with DLCN score >=6 from Robarts Research Institute, Canada;- 9 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia;- 2 cases with DLCN score >=6 and 1 case with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France;- 2 cases with possible FH by Simon Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 36 cases fulfilling MEDPED criteria from PMID 8399083 (Kotze et al., 1993), South Africa. PP1_Strong: Variant segregates with FH phenotype in 27 informative meiosis from at least 10 families from different labs (Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain; Robarts Research Institute, Canada; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; Laboratory of Genetics and Molecular Cardiology, Brazil; PMID 26036859 (Brænne et al., 2016), Germany; PMID 21925660 (Versmissen et al., 2011), the Netherlands): 19 affected family members have the variant and 8 unaffected family members do not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023443/MONDO:0007750/013 2023-03-27 2024-10-04 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7852 biolink:causes HP:0032149 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1135120 infores:hetionet CHEBI:7789 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0039231 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1268766 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0549257 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549257 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018099 infores:hetionet CHEBI:107736 biolink:causes MONDO:0006988 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0038732 infores:hetionet CHEBI:168396 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0947912 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0700184 infores:hetionet CHEBI:31711 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C1443060 infores:hetionet CHEBI:3561 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0424790 infores:hetionet CAID:CA229339 biolink:causes MONDO:0009861 infores:clingen CAID:CA229339 MONDO:0009861 PMID:1363837PMID:18538294PMID:1363837 Likely Pathogenic PM4, PM3, PM2, PP4 PM1 The c.1092_1106del (p.Leu365_Leu369del) variant in PAH has been reported in 1 individual with PKU (PP4; PMID: 1363837) in trans with pathogenic variant p.R408W (PM3). This variant is absent in population databases (PM2). This variant is a 15 bp in-frame deletion in exon 11 (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PM4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229339/MONDO:0009861/006 2019-05-04 2021-02-26 Autosomal recessive inheritance HP:0000007 Supports PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0003054 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0281784 infores:hetionet CHEBI:8356 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011124 infores:hetionet CAID:CA135558 biolink:causes MONDO:0021060 infores:clingen CAID:CA135558 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.24A>G (p.Val8=) variant in the KRAS gene is 0.0499% (35/51828) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135558/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50885 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0518015 infores:hetionet CHEBI:42355 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0038325 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0020517 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0041969 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0149741 infores:hetionet CHEBI:31547 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0023212 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009782 infores:hetionet CHEBI:44423 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0854467 infores:hetionet CHEBI:50648 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009421 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0518015 infores:hetionet CHEBI:6822 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0025222 infores:hetionet CHEBI:68642 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0015967 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0029927 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0849918 infores:hetionet CAID:CA2579914604 biolink:causes MONDO:0011071 infores:clingen CAID:CA2579914604 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS4, PS2, PS3, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 The c.489dup (p.Val164Cysfs*49) variant in RUNX1 is a frameshift duplication predicted to cause a premature stop codon in biologically-relevant exon 7/9 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2 and v3 with a mean coverage of at least 20X (PM2_Supporting). It has also been described in a 67yo male with AML who had a daughter with AML at age 21 (HSCT at age 26), and an additional daughter and 2 sons with thrombocytopenia, but germline origin was not confirmed (PMID: 32804409, cited by PMID: 35884491) (PS4_Supporting does not apply). Regardless, there are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) with sufficient molecular and specific clinical data (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_Supporting, and PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579914604/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6923 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0232492 infores:hetionet NCBIGene:59336 biolink:causes MONDO:0030890 infores:monarchinitiative not_provided not_provided HGNC:13998 MONDO:0030890 uuid:2c877dde-6f5a-4abf-9544-9d4c794e207f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0022346 infores:hetionet GO:0009787 biolink:causes GO:0071215 infores:ubergraph knowledge_assertion manual_agent GO:0009787 GO:0071215 CHEBI:2663 biolink:causes MONDO:0020575 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0344432 infores:hetionet CHEBI:6715 biolink:causes HP:0001883 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1301937 infores:hetionet CAID:CA512341201 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341201 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS3, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1236C>T (p.Gly412=) is a synonymous variant therefore no REVEL score is applicable and SpliceAI is ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.61874 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341201/MONDO:0011071/008 2022-03-08 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA337099716 biolink:causes MONDO:0044970 infores:clingen CAID:CA337099716 MONDO:0044970 PMID: Likely Benign BP4, BP5 BA1, PS4, PS3, BS1, PM2 The m.13528A>G (p.T398A) variant in MT-ND5 gene has been reported in six unrelated families to date. The proband in one of these families was subsequently found to have a homozygous pathogenic variant in POLG (PMID: 17940288, BP5). Four other probands had features consistent with primary mitochondrial disease however comprehensive analysis of other genetic etiologies was not performed. Three of these individuals had with features consistent with Leber Hereditary Optic Neuropathy (LHON; PMIDs: 11102991, 22589247). The fourth proband had features consistent with Leigh syndrome spectrum disorder (PMID: 19103152). There is also a report of a family with several siblings with autism spectrum disorder having this variant (PMID: 28419775). However, while this variant is present in these families, it is present at fairly high frequency in the general population. The frequency in the MITOMAP GenBank sequences is 75/61,168 (0.123%). The frequency in the Helix dataset is 516/195,983 (0.263%) homoplasmic occurrences in addition to four heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 118/56,421 (0.209%) homoplasmic occurrences in addition to three heteroplasmic occurrences. In all three population databases, this variant is seen in individuals from different haplogroups. Cybrid studies support a deleterious effect however it is not clear if this effect is related to the variant or other factors such as mitochondrial DNA content and/or haplogroup effects (PMIDs: 17940288, 22589247). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.45 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt uncertain significance was a more appropriate classification given the cybrid studies however the majority (four) agreed with likely benign. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4, BP5. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337099716/MONDO:0044970/015 2023-08-22 2024-03-20 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4911 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0332534 infores:hetionet CHEBI:134991 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0028734 infores:hetionet CHEBI:80630 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0041657 infores:hetionet CHEBI:6367 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0392156 infores:hetionet CHEBI:5165 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011848 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1145628 infores:hetionet CHEBI:9168 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0232461 infores:hetionet CHEBI:50729 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0035078 infores:hetionet CHEBI:3423 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0206062 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0041969 infores:hetionet CAID:CA136126 biolink:causes MONDO:0021060 infores:clingen CAID:CA136126 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2997T>C (p.Asn999=) variant in the SOS1 gene is 1.009% (120/10162) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136126/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:64355 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085633 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0234215 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0541832 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0277925 infores:hetionet CHEBI:8774 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0851578 infores:hetionet CAID:CA296157 biolink:causes MONDO:0021060 infores:clingen CAID:CA296157 MONDO:0021060 PMID:27763634 Uncertain Significance BP5, PP2 PS4, PS1, PM1, PM5, BS4, BS1, PM2, BP4, BA1 The p.Arg371Gln variant in MAP2K2 has been identified in 0.00401% (lower bound of the 95% CI of 7/81796) of non-Finnish European chromosomes in gnomAD (https://gnomad.broadinstitute.org) (BS1 not met). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants, and pathogenic missense variants are common (PP2; PMID: 29493581). This variant has been observed in many individuals with varying clnical presentations that lack clear associations with a RASopathy. This variant was identified in 1 individual with syncope and atrial fibrillation, who carried an additional pathogenic variant in a cardiomyopathy gene sufficient to explain their clinical presentation (BP5; Invitae internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP2, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296157/MONDO:0021060/004 2019-08-26 2019-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63608 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0041582 infores:hetionet CHEBI:167309 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0036974 infores:hetionet CHEBI:44915 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0036973 infores:hetionet CHEBI:31705 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0030193 infores:hetionet CHEBI:64045 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0086439 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0025061 infores:hetionet CHEBI:4466 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0011206 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0002957 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0021400 infores:hetionet CHEBI:31547 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0007222 infores:hetionet GO:0007096 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0007096 GO:0140014 CHEBI:3994 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0004093 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0423232 infores:hetionet CHEBI:49375 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151786 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151729 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151729 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235848 infores:hetionet GO:2000310 biolink:causes GO:1905039 infores:ubergraph knowledge_assertion manual_agent GO:2000310 GO:1905039 CHEBI:63580 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0024902 infores:hetionet CHEBI:7936 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002962 infores:hetionet CHEBI:65173 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0270996 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0021053 infores:hetionet CHEBI:8327 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0018681 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0005940 infores:hetionet CHEBI:17688 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0027497 infores:hetionet CHEBI:205919 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0016436 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0948089 infores:hetionet CHEBI:51041 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C2047937 infores:hetionet CHEBI:6935 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0016204 infores:hetionet CHEBI:9139 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0028081 infores:hetionet CHEBI:5103 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0041834 infores:hetionet CHEBI:9566 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0424295 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0009450 infores:hetionet CHEBI:291342 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0039231 infores:hetionet CHEBI:83531 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C1291078 infores:hetionet CHEBI:50692 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0600142 infores:hetionet CHEBI:93363 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C3544060 infores:hetionet CHEBI:100241 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014743 infores:hetionet CHEBI:42068 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0024305 infores:hetionet CHEBI:7640 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0012833 infores:hetionet CHEBI:7936 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C3263723 infores:hetionet CHEBI:49375 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0041657 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0948525 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019048 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0235969 infores:hetionet CHEBI:3393 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0033774 infores:hetionet CHEBI:63845 biolink:causes UMLS:C0239093 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0239093 infores:hetionet CAID:CA320603756 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603756 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.614-15T>C is an intronic variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. It has a SpliceAI score of 0 and a PhyloP score of 1.47, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603756/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49040 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0239377 infores:hetionet CHEBI:63611 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0034880 infores:hetionet GO:0002328 biolink:causes CL:0000826 infores:ubergraph knowledge_assertion manual_agent GO:0002328 CL:0000826 NCBIGene:4131 biolink:causes MONDO:0030061 infores:monarchinitiative not_provided not_provided HGNC:6836 MONDO:0030061 uuid:9783a5ac-7543-4a8b-82b1-32e2105cec85 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2196 biolink:causes MONDO:0033480 infores:monarchinitiative not_provided not_provided HGNC:3596 MONDO:0033480 uuid:8b5a10c5-0369-46fe-a4ff-09765c8c1caf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0023530 infores:hetionet CHEBI:182080 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0009806 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0027769 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013781 infores:hetionet CHEBI:136040 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0043352 infores:hetionet CHEBI:182080 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0043352 infores:hetionet CAID:CA410202461 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202461 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.508+1G>T is a splicing variant which is predicted to alter splicing. This variant affects intron 5 at the canonical Donor site c.508 (SpliceAI value = Donor Loss 1.00) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202461/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4670 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0277884 infores:hetionet CHEBI:6847 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0015230 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0020514 infores:hetionet CHEBI:2955 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0030305 infores:hetionet CHEBI:63620 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011606 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0392025 infores:hetionet CHEBI:77032 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0037274 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0021141 infores:hetionet CHEBI:50381 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0005684 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0029456 infores:hetionet CHEBI:9130 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0035410 infores:hetionet CHEBI:6950 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0016204 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0040479 infores:hetionet CHEBI:31980 biolink:causes UMLS:C1096267 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C1096267 infores:hetionet CHEBI:7476 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022346 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151736 infores:hetionet CHEBI:3216 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0004096 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0009319 infores:hetionet CHEBI:8888 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013384 infores:hetionet NCBITaxon:685953 biolink:causes MONDO:0000292 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:685953 MONDO:0000292 CHEBI:3696 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C1443060 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0341012 infores:hetionet CAID:CA645294060 biolink:causes MONDO:0017623 infores:clingen CAID:CA645294060 MONDO:0017623 PMID: Likely Pathogenic PP3, PM6_Strong, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PVS1, PP2, PP4, PP1, BS2, PM3, PM4, PM1, PM5, BP1, BP4, BP2, BP3, BA1, PS2, PS3, PS1 NM_000314.8(PTEN):c.635-3C>G (IVS6-3C>G) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Absent in large sequenced populations (PMID:27535533).PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMID:19265751)PP3: SpliceAI predicts a splicing impact.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:35278038) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645294060/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes HP:0030848 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0520861 infores:hetionet CHEBI:31536 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0013404 infores:hetionet CHEBI:84500 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0043094 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0005940 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0853336 infores:hetionet NCBITaxon:1773 biolink:causes MONDO:0006052 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1773 MESH:D014397 DB01082_MESH_D014397_1DB08993_MESH_D014397_1DB00339_MESH_D014397_1DB00951_MESH_D014397_1DB00609_MESH_D014397_1DB01201_MESH_D014397_2DB12829_MESH_D014397_1DB00260_MESH_D014397_1DB00233_MESH_D014397_1DB00314_MESH_D014397_1DB01201_MESH_D014397_1DB01045_MESH_D014397_1DB08903_MESH_D014397_1DB00330_MESH_D014397_1 CHEBI:31413 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0427008 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0687707 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0006266 infores:hetionet CHEBI:63580 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085631 infores:hetionet CHEBI:7627 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0085633 infores:hetionet CHEBI:61049 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3665347 infores:hetionet NCBIGene:114548 biolink:causes MONDO:0007349 infores:monarchinitiative not_provided not_provided HGNC:16400 MONDO:0007349 uuid:115044e8-6214-4456-994e-f81f8cd83c76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0595916 infores:hetionet CHEBI:10101 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0030196 infores:hetionet CHEBI:63618 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0042029 infores:hetionet CHEBI:6539 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0018681 infores:hetionet CHEBI:8378 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0428977 infores:hetionet CHEBI:50648 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0016204 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011609 infores:hetionet CHEBI:9123 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0549622 infores:hetionet CHEBI:8378 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0011603 infores:hetionet CHEBI:4445 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1145670 infores:hetionet CHEBI:404903 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0016199 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0235146 infores:hetionet CHEBI:3219 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235086 infores:hetionet CHEBI:3568 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0043387 infores:hetionet CHEBI:9635 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0042963 infores:hetionet CHEBI:63598 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018944 infores:hetionet CHEBI:4911 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1720798 infores:hetionet CHEBI:49960 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0015672 infores:hetionet CHEBI:194135 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0162297 infores:hetionet NCBIGene:3689 biolink:causes MONDO:0007293 infores:monarchinitiative not_provided not_provided HGNC:6155 MONDO:0007293 uuid:69e7b19d-922c-4f47-bd7f-24dfc0a9f65c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0023530 infores:hetionet CHEBI:6958 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0015230 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0030312 infores:hetionet CHEBI:8890 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0023066 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0233494 infores:hetionet CHEBI:70707 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0015672 infores:hetionet CHEBI:30659 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C1112320 infores:hetionet CHEBI:64312 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0149871 infores:hetionet CHEBI:231425 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C1145670 infores:hetionet CHEBI:50841 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0018418 infores:hetionet NCBIGene:3938 biolink:causes MONDO:0009115 infores:monarchinitiative not_provided not_provided HGNC:6530 MONDO:0009115 uuid:c7b599f0-f7d7-4555-91aa-01e57c5354c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4657 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0003578 infores:hetionet CHEBI:8214 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0013144 infores:hetionet CHEBI:7581 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C2830004 infores:hetionet CHEBI:3638 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0018524 infores:hetionet CAID:CA229453 biolink:causes MONDO:0009861 infores:clingen CAID:CA229453 MONDO:0009861 PMID:26413448PMID:9429153PMID:27121329PMID:26413448PMID:9429153PMID:27121329 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID: 26413448) as well as in trans with pathogenic variants R297H (PMID: 9429153), I65T, and S349P (PMID: 27121329). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229453/MONDO:0009861/006 2019-05-26 2019-05-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0001807 infores:hetionet CHEBI:31980 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0424790 infores:hetionet CHEBI:142290 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0010200 infores:hetionet CHEBI:63621 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042029 infores:hetionet CHEBI:6015 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0042963 infores:hetionet CHEBI:61049 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235378 infores:hetionet CHEBI:40279 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018681 infores:hetionet CHEBI:50742 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0085633 infores:hetionet CHEBI:31547 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0017168 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0497247 infores:hetionet CHEBI:101085 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0027769 infores:hetionet GO:1900618 biolink:causes GO:0048367 infores:ubergraph knowledge_assertion manual_agent GO:1900618 GO:0048367 CAID:CA658824773 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824773 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.376del (p.Trp126GlyfsTer16) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 556716). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824773/MONDO:0009290/010 2024-04-05 2024-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63791 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162834 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0151763 infores:hetionet CAID:CA410202604 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202604 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.440C>G (p.Ala147Gly) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202604/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410207960 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207960 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM3, PM4, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.599C>A (p.Pro200His) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.947 (REVEL score ≥ 0.88), meeting PP3. This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, and PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207960/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA638054608 biolink:causes MONDO:0011071 infores:clingen CAID:CA638054608 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.98-5C>G is an intronic variant which has a SpliceAI score ≥ 0.38 (Acceptor Loss 0.44) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054608/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9398 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0235969 infores:hetionet CHEBI:520985 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0011603 infores:hetionet CHEBI:38545 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0338656 infores:hetionet CHEBI:66876 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0042075 infores:hetionet NCBIGene:2165 biolink:causes MONDO:0013190 infores:monarchinitiative not_provided not_provided HGNC:3534 MONDO:0013190 uuid:cd817280-aef9-4ed1-af27-3df78902cf77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes MONDO:0002187 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042994 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0541941 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0267596 infores:hetionet CHEBI:8874 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013378 infores:hetionet GO:0060657 biolink:causes GO:0060444 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0060444 CHEBI:85078 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0005684 infores:hetionet CHEBI:7514 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0027497 infores:hetionet CHEBI:6067 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0344232 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0032285 infores:hetionet CHEBI:2379 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0030848 infores:hetionet CHEBI:9123 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0039231 infores:hetionet CAID:CA384906013 biolink:causes MONDO:0010880 infores:clingen CAID:CA384906013 MONDO:0010880 PMID: Pathogenic PS4, PVS1_Strong, PP1_Strong, PM2_Supporting The NM_000020.3: c.1468C>T (p.Gln490Ter) variant in ACVRL1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense medicated decay, however it is a truncation of a functionally important region (removes amino acids 490-503) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 15879500, 16829353, 20301525). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 16829353, 16540754, 32573726, 11484689, Internal lab contributors). The variant has been reported to segregate with HHT in several affected family members from two large families (PP1_Strong; PMID: 16829353, 11484689). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PS4, PP1_Strong (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA384906013/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63621 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020461 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020615 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1328337 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0011570 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0019158 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0001824 infores:hetionet CHEBI:8713 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0151766 infores:hetionet CHEBI:37941 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0340865 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0242350 infores:hetionet CAID:CA1624690 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624690 MONDO:0021060 PMID: Likely Benign BP5, BP4 BS1 The c.899G>A (p.Arg300Gln) variant in SOS1 is present in 0.01% (3/30610) South Asian alleles in gnomAD. Computational prediction tools and conservation analysis suggest that this variant does not impact the protein (BP4). This variant has been identified in 5 probands with an alternate molecular basis for disease (BP5: SCV000430444.2; SCV000430443.2; SCV000730061.1; SCV000939867.1). In summary, the clinical significance of the p.Arg300Gln variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624690/MONDO:0021060/004 2019-12-05 2019-12-05 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:31348 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0341012 infores:hetionet CHEBI:31625 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0677500 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0013395 infores:hetionet CHEBI:50648 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151908 infores:hetionet UMLS:C0903898 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0011603 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0344315 infores:hetionet CHEBI:9086 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0262662 infores:hetionet CAID:CA286503 biolink:causes MONDO:0009861 infores:clingen CAID:CA286503 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.385G>T (p.Asp129Tyr) variant in PAH has not been reported in the literature to our knowledge. This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). There are 2 other missense variants at this residue in ClinVar; p.Asp129Gly is Likely Pathogenic by 1 submitter and PAH EP (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286503/MONDO:0009861/006 2019-04-07 2019-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:41879 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0041834 infores:hetionet CHEBI:7773 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0267792 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0234193 infores:hetionet CHEBI:3310 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0027540 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0151729 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151729 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0016436 infores:hetionet CHEBI:94392 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0424790 infores:hetionet CHEBI:61033 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0003811 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020039 infores:hetionet CHEBI:681569 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0010200 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0014130 infores:hetionet CHEBI:51173 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0018524 infores:hetionet CHEBI:3752 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0014742 infores:hetionet CHEBI:64355 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0206061 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0948594 infores:hetionet CHEBI:63632 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0151904 infores:hetionet CHEBI:3441 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0004093 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0043251 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0233414 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0007642 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151596 infores:hetionet CHEBI:50173 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011644 infores:hetionet CHEBI:6367 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0424295 infores:hetionet CHEBI:5855 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0032617 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0235290 infores:hetionet CHEBI:31711 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026827 infores:hetionet CHEBI:64045 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0020458 infores:hetionet CHEBI:6741 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C2047937 infores:hetionet CHEBI:6149 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0917801 infores:hetionet CHEBI:31236 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033774 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038363 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0034065 infores:hetionet CHEBI:8069 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0231528 infores:hetionet CHEBI:41423 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0917801 infores:hetionet CAID:CA016653 biolink:causes MONDO:0005045 infores:clingen CAID:CA016653 MONDO:0005045 PMID: Uncertain Significance PM2, PM1, PS4_Supporting PM5, PM6, PP3, PP1, PS3, BA1, BS1, BS4, BS3, PS2, BP4 The c.707T>C (p.Val236Ala) variant in MYH7 has been identified in 2 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers comm; LMM pers comm). This variant has also been observed in relatives with non-compaction cardiomyopathy, though this is considered insufficient to apply PP1. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016653/MONDO:0005045/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7443 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0020456 infores:hetionet CHEBI:7025 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0149745 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0877338 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0314719 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020621 infores:hetionet CHEBI:8346 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C1258215 infores:hetionet CHEBI:34967 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0851578 infores:hetionet CHEBI:2948 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0086565 infores:hetionet CHEBI:4995 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020488 infores:hetionet CHEBI:100147 biolink:causes UMLS:C0877854 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0877854 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0860239 infores:hetionet CHEBI:45863 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027796 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0080194 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0518015 infores:hetionet CHEBI:3749 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0019158 infores:hetionet CHEBI:61049 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038990 infores:hetionet CHEBI:404903 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0085593 infores:hetionet CHEBI:47381 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020453 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0017152 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013146 infores:hetionet CHEBI:51380 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0011570 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151609 infores:hetionet CHEBI:3423 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0038362 infores:hetionet CHEBI:3757 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0554976 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0020651 infores:hetionet CHEBI:6541 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0476273 infores:hetionet CHEBI:40237 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0018681 infores:hetionet CAID:CA367403889 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403889 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.46-1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 2 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.46-1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403889/MONDO:0015967/086 2025-01-03 2025-01-03 Semidominant inheritance HP:0032113 Supports CHEBI:39867 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0027651 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0750194 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0750194 infores:hetionet CHEBI:10124 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0023903 infores:hetionet CHEBI:31623 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0162835 infores:hetionet CHEBI:63613 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0021655 infores:hetionet CHEBI:31643 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0030193 infores:hetionet CHEBI:17650 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0085570 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0020458 infores:hetionet CHEBI:135530 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C1565489 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0033975 infores:hetionet CHEBI:78543 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0026858 infores:hetionet CHEBI:27666 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0032285 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0234930 infores:hetionet CHEBI:45081 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0542571 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0162287 infores:hetionet CHEBI:17026 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0035455 infores:hetionet CHEBI:10119 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0001925 infores:hetionet CHEBI:79699 biolink:causes UMLS:C1096106 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1096106 infores:hetionet CHEBI:49960 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0010200 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0233472 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0017152 infores:hetionet CHEBI:47519 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0877055 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0234215 infores:hetionet CHEBI:4798 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013428 infores:hetionet CHEBI:3499 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0011991 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0948089 infores:hetionet CAID:CA16020970 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020970 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PP3_Strong, PM2_Supporting PM5 The c.1205 (p.Phe402Cys) variant in PAH has been detected in 1 Japanese patient with mild HPA and BH4 deficiency excluded (PMID: 21307867; PP4_Moderate). This variant is absent from population databases (PM2_Supporting), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.94 (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PP3_Strong, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020970/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CAID:CA279176 biolink:causes MONDO:0007113 infores:clingen CAID:CA279176 MONDO:0007113 PMID: Uncertain Significance PP4, PS2 BS1, PP3, PM2, BP4, PS4 The c.947T>C p.(Met316Thr) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.003% in the Latino/Admixed sub population (no criteria met). The p.(Met316Thr) variant in UBE3A has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Angelman syndrome (PMID 27864847) (PS2, PP4), however the gnomAD frequency of this variant means that the PS4 criterion cannot be applied. Computational prediction analysis tools are inconclusive for this variant. In summary, the c.947T>C p.(Met316Thr) variant in UBE3A is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PS2, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA279176/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:6741 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030252 infores:hetionet CHEBI:6640 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0232487 infores:hetionet CHEBI:6539 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0424296 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233632 infores:hetionet CHEBI:17303 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0036973 infores:hetionet CHEBI:6633 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0542571 infores:hetionet CHEBI:40279 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2363730 infores:hetionet CHEBI:3752 biolink:causes UMLS:C1535975 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1535975 infores:hetionet CHEBI:27436 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0042755 infores:hetionet CHEBI:2611 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0027441 infores:hetionet CHEBI:9445 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0014591 infores:hetionet CHEBI:6775 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0004604 infores:hetionet CHEBI:63612 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0017178 infores:hetionet CHEBI:3077 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020555 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0852810 infores:hetionet CAID:CA9043767 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043767 MONDO:0012999 PMID: Likely Benign BP4, BP7 PM2, BS1 The NM_000156.6:c.189G>C (p.Arg63=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -1.308) (BP4, BP7). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004955 (3/6054) in the Middle Eastern population. This is higher than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), and lower than the threshold for BS1 (>0.001). Therefore, no population criteria are met. There is a ClinVar entry for this variant (Variation ID: 288963). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043767/MONDO:0012999/026 2025-05-20 2025-05-20 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0657912 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0152128 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003123 infores:hetionet CHEBI:8772 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0010692 infores:hetionet CHEBI:499361 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0037763 infores:hetionet CHEBI:4469 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0013384 infores:hetionet CAID:CA270328 biolink:causes MONDO:0010726 infores:clingen CAID:CA270328 MONDO:0010726 PMID: Pathogenic PM1, PP4, PP3, PM5_Strong, PS4, PM2_Supporting The p.Pro101Ser variant has been observed in at least 4 other individuals with Rett syndrome (RettBASE, internal database) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10767337, 31439979) (PM5_Strong). The p.Pro101Ser variant in MECP2 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Pro101Ser variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 11269512) (PP4). In summary, the p.Pro101Ser variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM5_strong, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270328/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:8499 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0014742 infores:hetionet CHEBI:4710 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0855775 infores:hetionet CHEBI:27834 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0162830 infores:hetionet CHEBI:50648 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0241057 infores:hetionet CHEBI:5855 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1167965 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0221752 infores:hetionet CHEBI:68595 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0041657 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0036572 infores:hetionet CHEBI:5441 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0018834 infores:hetionet CHEBI:9073 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0028084 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0020621 infores:hetionet CHEBI:7573 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0013604 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0009450 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0878544 infores:hetionet CHEBI:135791 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0039446 infores:hetionet CHEBI:4975 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0033036 infores:hetionet CHEBI:4653 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0020578 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0043246 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017675 infores:hetionet CHEBI:36704 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0151825 infores:hetionet CHEBI:3314 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0033774 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0574067 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0042373 infores:hetionet CHEBI:5441 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020458 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0042075 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0042514 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0426747 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0426747 infores:hetionet CHEBI:5118 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1142011 infores:hetionet CHEBI:35677 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0015230 infores:hetionet CHEBI:135276 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0015230 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009938 infores:hetionet CAID:CA2573051030 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051030 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM4, PP4_Moderate PS4 The c.24_35dup variant in the HNF1 homeobox A gene, HNF1A, is a 12 base pair insertion resulting in the in-frame addition of 3 amino acid(s) at codon 9 (p.(Gln9_Leu12dup)) within exon 1 of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, the c.24_35dup variant is predicted to change the length of the protein due an in-frame insertion of three amino acids in a non-repeat region (PM4). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 19169489, 25174781; internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; PMID: 25174781). In summary, c.24_35dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM1_Supporting, PM2_Supporting, PM4, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051030/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:408174 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0231218 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020619 infores:hetionet CHEBI:10101 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0232292 infores:hetionet CHEBI:9123 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1142412 infores:hetionet CHEBI:2687 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0085605 infores:hetionet CHEBI:31547 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0151539 infores:hetionet CHEBI:52717 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2937358 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0009326 infores:hetionet CHEBI:16899 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0239134 infores:hetionet CHEBI:4027 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0549410 infores:hetionet CHEBI:499361 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0750426 infores:hetionet CHEBI:6741 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013144 infores:hetionet CHEBI:38562 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0037763 infores:hetionet CHEBI:3228 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0151559 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0012797 infores:hetionet CHEBI:4798 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0025323 infores:hetionet CHEBI:144551 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0858635 infores:hetionet CHEBI:2663 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0239571 infores:hetionet CHEBI:15551 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0003811 infores:hetionet CHEBI:135935 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0344232 infores:hetionet CHEBI:4653 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0017178 infores:hetionet CHEBI:63623 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0033774 infores:hetionet CHEBI:91583 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0018681 infores:hetionet CHEBI:31236 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018965 infores:hetionet CHEBI:6640 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0018834 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0020517 infores:hetionet CHEBI:40303 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0013404 infores:hetionet CHEBI:10650 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0041657 infores:hetionet CHEBI:48273 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0917801 infores:hetionet CHEBI:9671 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0002792 infores:hetionet NCBIGene:10516 biolink:causes MONDO:0009052 infores:monarchinitiative not_provided not_provided HGNC:3602 MONDO:0009052 uuid:103f00b4-bcbd-486b-a1fb-d5dc741105cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0026961 infores:hetionet CHEBI:17303 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0152032 infores:hetionet CHEBI:7936 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085593 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0009760 infores:hetionet CHEBI:553473 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0031542 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0031117 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151735 infores:hetionet CHEBI:171719 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011606 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0948089 infores:hetionet CHEBI:3696 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011175 infores:hetionet CHEBI:9123 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0026961 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0006285 infores:hetionet NCBIGene:5727 biolink:causes MONDO:0958174 infores:monarchinitiative not_provided not_provided HGNC:9585 MONDO:0958174 uuid:9d21aea1-744a-4eea-a51b-71549af12e8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:27010 biolink:causes MONDO:0013761 infores:monarchinitiative not_provided not_provided HGNC:17358 MONDO:0013761 uuid:a70d4b3c-3f04-44e2-ab28-b52c5911f5c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0013491 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0541832 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018799 infores:hetionet CHEBI:6887 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0232462 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0015423 infores:hetionet CHEBI:8024 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1368065 infores:hetionet CHEBI:63638 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0009676 infores:hetionet CHEBI:231594 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C2979982 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0003864 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0233472 infores:hetionet CHEBI:9667 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0041834 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042075 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041912 infores:hetionet CHEBI:135351 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0003862 infores:hetionet CHEBI:50648 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1325847 infores:hetionet CHEBI:6539 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0004245 infores:hetionet CHEBI:92712 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0018681 infores:hetionet CHEBI:27899 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C2047937 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0042109 infores:hetionet CHEBI:46345 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0005758 infores:hetionet CHEBI:2663 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151907 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042345 infores:hetionet CAID:CA267785992 biolink:causes MONDO:0007113 infores:clingen CAID:CA267785992 MONDO:0007113 PMID: Uncertain Significance BP4 BS1 The c.532G>T p.Ala178Ser variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0023% in the European (non-Finnish) sub population (no criteria met). Computational analysis prediction tools suggest that the p.Ala178Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own. In summary, the c.926A>G p.Asn309Ser variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA267785992/MONDO:0007113/032 2023-06-15 2023-06-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63619 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0162119 infores:hetionet CAID:CA414914394 biolink:causes MONDO:0010602 infores:clingen CAID:CA414914394 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM5, PM2_Supporting, PP3 PM1, PS4 The variant, NM_000132.3(F8):c.1420G>T, predicts a missense change, Gly474Trp, which is not reported in gnomAD v2.1.1 or v3. This variant has been reported in at least one male patient with severe hemophilia A in the literature meeting PP4_Moderate criteria (PMID: 19473408). Another nucleotide change at the same codon, c.1421G>A; p.Gly474Glu is classified as pathogenic by CFD-VCEP meeting the PM5 criteria. The variant has a REVEL score of 0.952 (threshold >0.6) meeting PP3 criteria. In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PP4_Moderate, PP3, PM2_Supporting, PM5. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414914394/MONDO:0010602/071 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Supports CHEBI:8378 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0239488 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0595877 infores:hetionet CHEBI:134991 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0027497 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0948594 infores:hetionet GO:0045446 biolink:causes CL:0000115 infores:ubergraph knowledge_assertion manual_agent GO:0045446 CL:0000115 CHEBI:77260 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0392025 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0027769 infores:hetionet CHEBI:28830 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0017178 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0948594 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0025061 infores:hetionet CHEBI:63631 biolink:causes HP:0010822 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235068 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0003123 infores:hetionet CHEBI:3441 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0740394 infores:hetionet CHEBI:404903 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018681 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0019360 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037274 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0549209 infores:hetionet CHEBI:41423 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0015672 infores:hetionet CHEBI:8884 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0522055 infores:hetionet CHEBI:27777 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0040046 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0002622 infores:hetionet CHEBI:5138 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0547030 infores:hetionet CHEBI:6741 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0162830 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0041969 infores:hetionet CHEBI:2636 biolink:causes UMLS:C0595882 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0595882 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1167868 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1167868 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0020651 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011849 infores:hetionet CHEBI:168396 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018790 infores:hetionet CHEBI:31705 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0004604 infores:hetionet CHEBI:4953 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0020580 infores:hetionet UMLS:C0120107 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0030193 infores:hetionet CHEBI:2208 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C1320835 infores:hetionet CHEBI:8888 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0312420 infores:hetionet UNII:9YCX42I8IU biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0948594 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027769 infores:hetionet CHEBI:10125 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002994 infores:hetionet CHEBI:68478 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151904 infores:hetionet NCBIGene:84818 biolink:causes MONDO:0014642 infores:monarchinitiative not_provided not_provided HGNC:18358 MONDO:0014642 uuid:0a866056-851d-4865-a55a-ef779f0c2cc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0232462 infores:hetionet CHEBI:8665 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0231528 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013395 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0019163 infores:hetionet CHEBI:2704 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151744 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0522055 infores:hetionet CHEBI:6912 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0038999 infores:hetionet NCBIGene:25790 biolink:causes MONDO:0030475 infores:monarchinitiative not_provided not_provided HGNC:17229 MONDO:0030475 uuid:a467ae5a-49fe-43f8-af94-69bd66ecce7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0575081 infores:hetionet CHEBI:3215 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0007859 infores:hetionet NCBIGene:6533 biolink:causes MONDO:0007777 infores:monarchinitiative not_provided not_provided HGNC:11052 MONDO:0007777 uuid:6e217e4d-fec0-4278-8a89-93467edadbb5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1565489 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0003621 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0011603 infores:hetionet CHEBI:2453 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013378 infores:hetionet CHEBI:47780 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0032617 infores:hetionet CHEBI:9123 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0022346 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0039231 infores:hetionet CHEBI:27470 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0041834 infores:hetionet CHEBI:73274 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0151539 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0232197 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0234215 infores:hetionet CHEBI:15367 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151908 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0033860 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020456 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0017178 infores:hetionet CHEBI:8713 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0002170 infores:hetionet CHEBI:3219 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0455769 infores:hetionet CAID:CA1139533037 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139533037 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate The c.997_998insT (p.Ala333ValfsTer26) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed ꞵ-Oxidation Flux <20% of normal, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMID:17999356). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM2_supporting (ACADVL VCEP specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139533037/MONDO:0008723/021 2023-03-28 2023-03-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8024 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151786 infores:hetionet CHEBI:47781 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0027849 infores:hetionet CHEBI:145499 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0232493 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0030312 infores:hetionet CAID:CA412371856 biolink:causes MONDO:0010725 infores:clingen CAID:CA412371856 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PP3_Strong, PM5, PP4 NM_000330.4(RS1):c.422G>C (p.Arg141Pro) is a missense variant encoding the substitution of arginine with proline at amino acid 141. Another missense variant in the same codon, NM_000330.4(RS1):c.422G>A (p.Arg141His), (PMID: 29851975, PMID: 34645606, PMID: 30450322, PMID: 29739629, PMID: 35984651, PMID: 30652005, PMID: 19093009, PMID: 30630865, PMID: 30040949, PMID: 17525175, PMID: 30630865, PMID: 30040949) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (103) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits phenotypes including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 33460243, PP4). The computational predictor REVEL gives a score of 0.955, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.02 for acceptor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked Retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PM5, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412371856/MONDO:0010725/126 2025-09-22 2025-09-22 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports NCBIGene:91574 biolink:causes MONDO:0013306 infores:monarchinitiative not_provided not_provided HGNC:26784 MONDO:0013306 uuid:b95c20d9-bbb1-4d2c-b7e4-564fa4c8f154 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915952057 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952057 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PS1, PM6_Supporting The m.8993_8994delinsCA (p.Leu156Pro) variant in MT-ATP6 has been reported in one individual with primary mitochondrial disease (PMID: 32652755). This individual had myopathy and developmental delay. The variant was present at near homoplasmy in blood and was not detected in the asymptomatic mother (PMID: 32652755, PM6_supporting). This variant results in the same amino acid change, p.Leu156Pro, as the pathogenic variant m.8993T>C (PS1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS1, PM6_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952057/MONDO:0044970/015 2024-08-27 2025-11-03 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:4708 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0039971 infores:hetionet GO:0099148 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0099148 GO:0051641 CHEBI:3393 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0000737 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0018799 infores:hetionet CHEBI:71229 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0011603 infores:hetionet CHEBI:50567 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0151744 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042075 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0035078 infores:hetionet CHEBI:53760 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0947912 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0413252 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0574067 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020456 infores:hetionet CAID:CA10014205 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014205 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1093G>A (p.Gly365Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014205/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31981 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0149871 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0234930 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020456 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0029408 infores:hetionet CHEBI:35677 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0013395 infores:hetionet CHEBI:74947 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151754 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0855242 infores:hetionet CHEBI:9362 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0030193 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0026650 infores:hetionet CHEBI:51041 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0040822 infores:hetionet CHEBI:144093 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0002994 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0150450 infores:hetionet CAID:CA147734 biolink:causes MONDO:0015152 infores:clingen CAID:CA147734 MONDO:0015152 PMID: Benign BP4, BA1 The NM_003494.4: c.2500A>G variant in DYSF, which is also known as NM_001130987.2: c.2554A>G p.(Ile852Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 834 (p.Ile834Val). The filtering allele frequency of the variant is 0.08367 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1541/31380), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0, which suggests it does not impact splicing and is below the LGMD VCEP threshold of ≤0.05. The computational predictor REVEL gives a score of 0.08, which is below the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1) (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147734/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:50223 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0518015 infores:hetionet CAID:CA001212 biolink:causes MONDO:0018875 infores:clingen CAID:CA001212 MONDO:0018875 PMID:30224644PMID:12826609PMID:30224644PMID:12826609 Likely Benign BP4, BS2_Supporting, PM2_Supporting BA1, PS1, PS2, PS3, PS4, PM5, PM1, BS1, BS4, BS3, PM6, PP3, PP1 The NM_000546.6:c.946C>A variant in TP53 is a missense variant predicted to cause substitution of proline by threonine at amino acid 316 (p.Pro316Thr). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor). This variant has an allele frequency of 0.000003098 (5/1614040 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0226052; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001212/MONDO:0018875/009 2025-03-04 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2469 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0019158 infores:hetionet CHEBI:63584 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0011175 infores:hetionet CHEBI:72292 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0019079 infores:hetionet GO:1905024 biolink:causes GO:0086005 infores:ubergraph knowledge_assertion manual_agent GO:1905024 GO:0086005 CHEBI:87681 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0030196 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005883 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0019364 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151936 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0029134 infores:hetionet CHEBI:9725 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0020621 infores:hetionet CAID:CA6904233 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904233 MONDO:0019497 PMID:26749107 Pathogenic PP3, PS3_Moderate, PM3_Very Strong PM2 The c.583A>G is a missense variant predicted to cause a substitution of methionine by valine at amino acid 195 (p.Met195Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.022% (16/44880, CI 95%) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 4 individuals with hearing loss with another pathogenic or suspected-pathogenic variant found in trans (4 PM3 points PMIDs: 24013081, 20497192, 30146550,33597575) (PM3_VeryStrong). It has also been identified in several probands with hearing loss in whom a second variant was not identified (PMIDs: 23555729, 19366456, 19125024, 27627659, 24507663). The computational predictor REVEL gives a score of 0.962 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Analysis in Hela cells demonstrated that the CX26-p.Met195Val protein was not transported to the cell membrane since there is an accumulation of the protein in the endoplasmic reticulum, indicating that this variant impacts protein function (PMID:26749107; PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM3_VeryStrong, PS3_Moderate; Version 2; 5/15/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904233/MONDO:0019497/005 2024-05-15 2024-07-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:4356 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C3665347 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0233571 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0011609 infores:hetionet CHEBI:10119 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020473 infores:hetionet CHEBI:8077 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0020651 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0236073 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0236073 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0038663 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0262397 infores:hetionet CHEBI:17347 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0039591 infores:hetionet NCBIGene:26160 biolink:causes MONDO:0023670 infores:monarchinitiative not_provided not_provided HGNC:30391 MONDO:0023670 uuid:4b1e4a7a-9000-40a9-aa02-81e3940fd4d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0013182 infores:hetionet CHEBI:45409 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0010200 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0948594 infores:hetionet CHEBI:5134 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C2047937 infores:hetionet CHEBI:71255 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0015672 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0023510 infores:hetionet CAID:CA519186681 biolink:causes MONDO:0010305 infores:clingen CAID:CA519186681 MONDO:0010305 PMID: Likely Benign BP7, PM2_Supporting, BP4 The NM_005629.4:c.681G>A (p.Val227=) variant in SLC6A8 is a synonymous (silent) variant that is not predicted to impact splicing and the nucleotide is not well conserved (BP4, BP7). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 669127). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA519186681/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:31981 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0032285 infores:hetionet CHEBI:92712 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0233715 infores:hetionet CAID:CA281921 biolink:causes MONDO:0021060 infores:clingen CAID:CA281921 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.36G>A (p.Ala12=) variant in the BRAF gene is 0.116% (14/7290) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA281921/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63629 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0000833 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002622 infores:hetionet CHEBI:567361 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0036690 infores:hetionet CHEBI:31302 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0030252 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0021400 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0314719 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0233571 infores:hetionet CHEBI:3216 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C3665347 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0006840 infores:hetionet CHEBI:48390 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0006826 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0178298 infores:hetionet CHEBI:4315 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0004604 infores:hetionet CHEBI:6923 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0010200 infores:hetionet CHEBI:5893 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1443060 infores:hetionet CHEBI:29688 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0017672 infores:hetionet CHEBI:63608 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0233762 infores:hetionet UMLS:C0065374 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037036 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042373 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235146 infores:hetionet CHEBI:261649 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0042487 infores:hetionet CHEBI:5106 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0232292 infores:hetionet CAID:CA114364 biolink:causes MONDO:0009861 infores:clingen CAID:CA114364 MONDO:0009861 PMID:1358789PMID:1358789PMID:18299955PMID:12501224PMID:11161839 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PM5, PP3, PS3 The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; http://gnomad.broadinstitute.org). This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID: 1358789; PMID: 12501224; PMID: 18299955). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114364/MONDO:0009861/006 2018-08-12 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50381 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0016204 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0017160 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0267792 infores:hetionet CHEBI:7514 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0235063 infores:hetionet CHEBI:4551 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0012833 infores:hetionet CHEBI:144551 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0015672 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017178 infores:hetionet CHEBI:3380 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0231218 infores:hetionet CHEBI:16467 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0237849 infores:hetionet CAID:CA410207987 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207987 MONDO:0011071 PMID: Likely Pathogenic PS4_Moderate, PM1, PM2_Supporting, PP3 PS1, PS3, PS2, BP2, BP1, BP4, BP3, BA1, BP5, BP7, BS1, BS4, BS3, PVS1, PM6, PM3, PM5, PM4, BS2, PP4, PP2, PP1 The NM_001754.4: c.586A>G (p.Thr196Ala) variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (AA T196) (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It. This missense variant has a REVEL score >0.88(0.957) (PP3). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ Moderate; PMID: 27479822, SCV001450794.1, PMID: 31698193). This variant is a missense change at the same residue (p.Thr196) where a different missense change has been previously reported as a pathogenic variant (PMID: 34233450, p.(Thr196Ile), p.(Thr196Arg)) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects. PM5 cannot be applied at this stage as these variants still need to be recognized as pathogenic by MM-VCEP. In summary, this variant meets criteria to be classified as a Likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PS4_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207987/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71417 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0023530 infores:hetionet CHEBI:4858 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0002622 infores:hetionet CHEBI:8774 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151632 infores:hetionet CHEBI:9086 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085669 infores:hetionet CAID:CA410148133 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148133 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP4, BP2, BA1, BP7, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1099G>C (p.Gly367Arg) is a missense variant which is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.707, which does not allow applying either PP3 (>0.88) or BP4 (<0.50). Additionally, there is no previous report of this variant. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148133/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39867 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233794 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020542 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042510 infores:hetionet CHEBI:231425 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020615 infores:hetionet CAID:CA367401222 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401222 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4, PS1 The c.651C>G variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to glutamic acid at codon 217 (p.(Asp217Glu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.805, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in a single individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19790256). The nucleotide change c.651C>A, which causes the same amino acid change, has been reported in an individual with monogenic diabetes; however, the c.651C>A variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.651C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401222/MONDO:0015967/086 2024-11-16 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:127342 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0036572 infores:hetionet CHEBI:45081 biolink:causes MONDO:0018312 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019655 infores:hetionet CHEBI:63791 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162285 infores:hetionet CHEBI:41423 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042510 infores:hetionet CHEBI:17474 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0025218 infores:hetionet CHEBI:168396 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004998 infores:hetionet CHEBI:49575 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151872 infores:hetionet GO:0039722 biolink:causes GO:0002224 infores:ubergraph knowledge_assertion manual_agent GO:0039722 GO:0002224 CHEBI:10102 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0917798 infores:hetionet CHEBI:5790 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0000737 infores:hetionet CHEBI:3172 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0687713 infores:hetionet CHEBI:6931 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0018681 infores:hetionet CHEBI:5855 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151539 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0031046 infores:hetionet NCBIGene:2775 biolink:causes MONDO:0060491 infores:monarchinitiative not_provided not_provided HGNC:4389 MONDO:0060491 uuid:55f59d15-a862-4596-8f0a-7ffb4184c770 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C2047937 infores:hetionet CHEBI:63791 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0039070 infores:hetionet CHEBI:44185 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0033687 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020517 infores:hetionet CHEBI:41423 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0005778 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027813 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0595878 infores:hetionet CHEBI:66876 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0016382 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1443060 infores:hetionet CHEBI:4708 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0040435 infores:hetionet CHEBI:8024 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0239377 infores:hetionet CHEBI:41977 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0234909 infores:hetionet CHEBI:79699 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0038325 infores:hetionet CHEBI:2687 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0852911 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0233571 infores:hetionet CHEBI:39112 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0033774 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0235639 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042571 infores:hetionet GO:1903684 biolink:causes GO:0030707 infores:ubergraph knowledge_assertion manual_agent GO:1903684 GO:0030707 CHEBI:50859 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0022346 infores:hetionet CAID:CA410208040 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208040 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.565T>C (p.Tyr189His) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a REVEL score ≥ 0.88 (0.965) (PP3) and the variant is within the Runt Homology Domain between the residues (AA 89-204) (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3, and PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208040/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410149578 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149578 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.959G>T (p.Arg320Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149578/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45783 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151479 infores:hetionet CHEBI:63612 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0040822 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0687133 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0575090 infores:hetionet CHEBI:83804 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0014591 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0687133 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0149931 infores:hetionet CHEBI:75722 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085605 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235025 infores:hetionet CHEBI:15940 biolink:causes MONDO:0000816 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0524620 infores:hetionet CHEBI:408174 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0042963 infores:hetionet CHEBI:8888 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0392676 infores:hetionet CAID:CA8622990 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622990 MONDO:0100326 PMID: Uncertain Significance BS3, PM2_Supporting PM3, PP3, PP4, BP4, PS3 The c.598G>A variant in ITGB3 is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 200 (p.Glu200Lys). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00006684 (3/44884 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). A homozygous patient was reported with Glanzmann thrombasthenia in a thesis from The University of Sheffield (Sabi, 2016; https://etheses.whiterose.ac.uk/13584/). The patient has mucocutaneous bleeding symptoms, including epistaxis, however they also have macrothrombocytopenia (not consistent with GT) and no aggregation or surface expression data were reported to confirm the diagnosis. Additionally, the thesis reported functional studies; CHO cells were cotransfected with wild-type ITGA2B cDNA and variant ITGB3 cDNA, demonstrating similar surface expression, activation, and ligand binding, of αIIbβ3 to that observed in cells expressing the wild-type receptor (BS3). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS3, PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622990/MONDO:0100326/011 2023-12-19 2023-12-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7494 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011175 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1096250 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027769 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0243026 infores:hetionet CHEBI:6931 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0027497 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0011991 infores:hetionet CAID:CA10558689 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558689 MONDO:0010726 PMID: Benign BP5_Strong, BS2 BS1 The c.-106G>A variant in MECP2 (NM_004992.3) is present in 27 XX and 9 XY individual(s) in gnomAD v4.1 (0.003%) (not sufficient to meet BS1 criteria). The c.-106G>A variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The c.-106G>A variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal database) (BP5_strong). In summary, the c.-106G>A variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS2, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558689/MONDO:0010726/036 2024-06-25 2024-07-01 X-linked inheritance HP:0001417 Contradicts true CAID:CA10648814 biolink:causes MONDO:0007648 infores:clingen CAID:CA10648814 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM5, PVS1, PM2, PM6, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.*1873G>A variant has an allele frequency of 0.04673 (4.673%, 407/8710 alleles, 11 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10648814/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:15553 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C3203358 infores:hetionet CHEBI:100241 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0920171 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0162429 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0027531 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027531 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0020458 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0041909 infores:hetionet CHEBI:31643 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0000729 infores:hetionet CHEBI:9434 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0027497 infores:hetionet CHEBI:474180 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0018790 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0021843 infores:hetionet CHEBI:8364 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0042024 infores:hetionet CHEBI:63613 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0009763 infores:hetionet CHEBI:4974 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0015230 infores:hetionet CHEBI:92998 biolink:causes HP:0001325 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020617 infores:hetionet CHEBI:76010 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0423791 infores:hetionet CHEBI:42355 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0009676 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0022650 infores:hetionet CHEBI:36704 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0162285 infores:hetionet CHEBI:63791 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0041364 infores:hetionet CHEBI:10650 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037763 infores:hetionet GO:0021755 biolink:causes CL:0000253 infores:ubergraph knowledge_assertion manual_agent GO:0021755 CL:0000253 CHEBI:31980 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C1384666 infores:hetionet CHEBI:50663 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0340865 infores:hetionet CHEBI:8707 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0021177 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0151505 infores:hetionet CHEBI:78543 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0476280 infores:hetionet CHEBI:8707 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0920289 infores:hetionet CHEBI:127342 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1384353 infores:hetionet CHEBI:31547 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0002994 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0004936 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0026946 infores:hetionet CHEBI:39112 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0014742 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0851341 infores:hetionet CHEBI:63618 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0008031 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0022660 infores:hetionet CAID:CA367399915 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399915 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PP2, PP3 PS4, BS1, PM1, PM2 The c.951C>G variant in the glucokinase gene, GCK, causes an amino acid change of histidine to glutamine at codon 317 (p.(His317Gln)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.191, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. However, the computational splicing predictor SpliceAI gives a score of 0.34 for acceptor gain, indicating that this variant may disrupt GCK splicing (PP3). The Grpmax filtering allele frequency of the c.951C>G variant in gnomAD v4.1.0 is 0.00000803, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has been identified in at leat 15 individuals with hyperglycemia; however, PS4 cannot be applied because the variant Grpmax in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31063852, 36257325, internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (persistent hyperglycemia with multiple documented values (≥ 2) of fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with three informative meioses in three families (PP1_Moderate; PMID: 31063852; internal lab contributors). In summary, c.951C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PP4_Moderate, PP1_Moderate, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399915/MONDO:0015967/086 2025-08-29 2025-08-29 Semidominant inheritance HP:0032113 Supports CHEBI:8888 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0242422 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0020517 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0027813 infores:hetionet CHEBI:6775 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0024902 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033575 infores:hetionet CAID:CA8337873 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337873 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate, PS3_Supporting The c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID: 14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID: 14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337873/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94609 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0002994 infores:hetionet CHEBI:135342 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020473 infores:hetionet CHEBI:23765 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0011606 infores:hetionet CHEBI:70746 biolink:causes HP:0001727 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C1112433 infores:hetionet CHEBI:7494 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017181 infores:hetionet CHEBI:107736 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018794 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0017178 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0036572 infores:hetionet CHEBI:9622 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0340865 infores:hetionet CAID:CA10014590 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014590 MONDO:0011071 PMID: Uncertain Significance PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM4, PM1, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.122C>T (p.Thr41Met) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014590/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31348 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0039240 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0019158 infores:hetionet CHEBI:4530 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C1167965 infores:hetionet CAID:CA8623284 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623284 MONDO:0100326 PMID: Benign BP7, BA1, BP4 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1545G>A (p.Arg515=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19946 alleles) in gnomAD, found in the East Asian population, which is considerably higher than the expected frequency of the disease(BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of 0.285 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623284/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:92712 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0701811 infores:hetionet CHEBI:75984 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0549249 infores:hetionet CHEBI:367163 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020598 infores:hetionet CHEBI:63617 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027849 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0413252 infores:hetionet CHEBI:7865 biolink:causes EFO:0801084 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0596240 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0413252 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0553698 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0553698 infores:hetionet CAID:CA8970233 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970233 MONDO:0012589 PMID: Benign BA1 The highest population minor allele frequency of the p.Gly440Ser variant in TCF4 in gnomAD v4.1 is 0.0004063 in the South Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). In the absence of conflicting evidence, this is sufficient evidence to classify as benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (TCF4 Specifications v.4.0; curation approved on [5/7/2025]). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970233/MONDO:0012589/032 2025-05-07 2025-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:2512 biolink:causes MONDO:0010952 infores:monarchinitiative not_provided not_provided HGNC:3999 MONDO:0010952 uuid:ea64c24d-e6ad-44b7-b394-38e41d03445c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes NCIT:C90501 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0553668 infores:hetionet CHEBI:8228 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0015672 infores:hetionet CAID:CA338371453 biolink:causes MONDO:0100283 infores:clingen CAID:CA338371453 MONDO:0100283 PMID: Likely Pathogenic PS2_Moderate, PP2, PM2_Supporting, PM1_Supporting, PS4_Moderate BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3 The NM_004958.4:c.4468T>C variant in MTOR is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 1490 (p.Trp1490Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BM VCEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). This variant has been identified as a de novo occurrence with parental relationships confirmed in one individual with macrocephaly ( >=2 SD) and developmental delay or intellectual disability without cortical malformations (PS2_M, PS4_M; PMID: 27830187). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_supporting, PP2, PM1_supporting, PS4_moderate, PS2_moderate; 7 points (VCEP specifications version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA338371453/MONDO:0100283/018 2025-07-01 2025-07-01 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Supports https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ CHEBI:17474 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0037274 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0744403 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0744403 infores:hetionet CHEBI:8461 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0036974 infores:hetionet CHEBI:2666 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0001824 infores:hetionet NCBIGene:284086 biolink:causes MONDO:0013444 infores:monarchinitiative not_provided not_provided HGNC:13387 MONDO:0013444 uuid:37b02d3c-4acf-45f6-b497-b2b7da142776 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0028961 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151744 infores:hetionet CHEBI:66964 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0016382 infores:hetionet CHEBI:17347 biolink:causes UMLS:C2721578 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C2721578 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0030920 infores:hetionet CHEBI:7454 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0026821 infores:hetionet CAID:CA10605471 biolink:causes MONDO:0009290 infores:clingen CAID:CA10605471 MONDO:0009290 PMID: Pathogenic PVS1, PM2, PP4, PM3 The c.1754+1G>A variant alters the canonical donor splice site of intron 12 and is predicted to cause skipping of exon 12, which would result in a frameshift, creation of a premature stop codon, and nonsense-mediated decay. This is supported by the finding of no cross reactive immunological material in fibroblasts from a patient with this variant (PMID: 22252923). Therefore PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in a patient with infantile onset Pompe disease in trans with a frameshift variant, c.722_723delTT (PMID 19775921), meeting PM3. There is a ClinVar entry for this variant (Variant ID: 286458; one star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605471/MONDO:0009290/010 2020-02-05 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:135939 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0018939 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018939 infores:hetionet CAID:CA2588340081 biolink:causes MONDO:0100437 infores:clingen CAID:CA2588340081 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2701del (p.Glu901LysfsTer?) is a frameshift variant due to 1-nucleotide deletion in codon 901 introducing a premature stop codon in exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 10 years (1 pt), reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with pigment deposits (0.5 pts), optic disc pallor (0.5 pts), cataract, severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2588340081/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:61049 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0014868 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0037274 infores:hetionet CAID:CA273357 biolink:causes MONDO:0009861 infores:clingen CAID:CA273357 MONDO:0009861 PMID:11142755PMID:8222245PMID:15319459PMID:7915167PMID:11142755 Pathogenic PM2, PP4_Moderate, PP3, PS3, PM3_Strong PM5 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong, PS3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273357/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10102 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0235378 infores:hetionet CHEBI:31236 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085635 infores:hetionet NCBIGene:5447 biolink:causes MONDO:0008726 infores:monarchinitiative not_provided not_provided HGNC:9208 MONDO:0008726 uuid:14705e25-231f-4cec-9efa-ef47f69dae76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6785 biolink:causes MONDO:0013760 infores:monarchinitiative not_provided not_provided HGNC:14415 MONDO:0013760 uuid:acc53518-8ad0-4d3e-9795-9f16dab553e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0702166 infores:hetionet CHEBI:3310 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0085628 infores:hetionet CHEBI:9137 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002994 infores:hetionet CAID:CA229784 biolink:causes MONDO:0009861 infores:clingen CAID:CA229784 MONDO:0009861 PMID:9012412 Uncertain Significance PM2, PP4, PP3 PM5 The c.811C>T (p.His271Tyr) variant in PAH has been reported in 2 unrelated PKU patients. BH4 deficiencies not assessed. (PMID: 9012412) A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.978. This variant has an extremely low frequency in ExAC, 1000G, ESP, and gnomAD (MAF=0.00001). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229784/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:82960 biolink:causes MONDO:0024280 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0162323 infores:hetionet CHEBI:5613 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0424448 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005779 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1442903 infores:hetionet CHEBI:17303 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028734 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0860703 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0860703 infores:hetionet NCBIGene:35 biolink:causes MONDO:0008722 infores:monarchinitiative not_provided not_provided HGNC:90 MONDO:0008722 uuid:fa15e497-c08e-4f52-b951-86f7bee17ce1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0025874 infores:hetionet CHEBI:2914 biolink:causes UMLS:C0849916 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0849916 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0012833 infores:hetionet CHEBI:6904 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0022281 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005495 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0001621 infores:hetionet CAID:CA122867 biolink:causes MONDO:0000573 infores:clingen CAID:CA122867 MONDO:0000573 PMID:11313270 Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM3_Strong, PM1_Supporting, PP1_Moderate NM_000536.4(RAG2):c.115A>G is a missense variant predicted to cause substitution of Arginine by Glycine at amino acid 39 (p.Arg39Gly).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The variant is absent in gnomAD v4 (PM2_supporting). Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) :Total :1.5 pts. PP4 met (PMID: 11313270). This variant was found to segregate in 2 affected siblings from one family (PP1_moderate) (PMID: 11313270).Two patients (PMID: 11313270) were found compound heterozygous for R39G and R229Q (pathogenic variant) ;total : 2pts. (PM3_strong).This variant showed <25 % of wild type activity in In vitro V(D)J recombination assay (PS3_moderate) (PMID: 11313270).In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_supporting,PP4 met,PP1_moderate,PM3_strong,PS3_moderate(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA122867/MONDO:0000573/124 2024-02-26 2024-02-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0677500 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0023533 infores:hetionet CHEBI:6775 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0003467 infores:hetionet CHEBI:41423 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042023 infores:hetionet CHEBI:63629 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0035410 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040584 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0160390 infores:hetionet CHEBI:408174 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C2607914 infores:hetionet NCBIGene:2290 biolink:causes MONDO:0100040 infores:monarchinitiative not_provided not_provided HGNC:3811 MONDO:0100040 uuid:d073bf2e-0263-4f03-864d-46b00dbfaf26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA902128 biolink:causes MONDO:0100368 infores:clingen CAID:CA902128 MONDO:0100368 PMID: Pathogenic PM1, PM3, PM5, PP3_Moderate, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.1579C>T (p.His527Tyr) is a missense variant predicted to replace histidine with tyrosine at position p.527, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). Another missense variant in the same codon, NM_000329.3(RPE65):c.1580A>G (p.His527Arg), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5, PMID: 17525851). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. This variant is present in gnomAD v.4.1.0 at an allele frequency of 0.0000008476, with 1 allele / 1,179,738 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 35129589, PM3_Supporting). A second unpublished proband carries the variant confirmed in trans with the NM_000329.3(RPE65):c.246-11A>G variant, which has been previously classified by the ClinGen LCA/eoRD VCEP as likely pathogenic (1 point, VCEP member-provided data, PM3). At least one proband harboring this variant exhibits a phenotype including a diagnosis of early onset severe retinal dystrophy (0.5 pts), nystagmus (1 pt), fundus appearance characteristic of retinitis pigmentosa (0.5 pts), and best corrected visual acuity limited to hand motion (1 pt), which are not sufficiently specific for RPE65-related recessive retinopathy to meet the PP4 code (total 3 points, PMID: 35129589). A second unpublished proband had more detailed phenotypes reported, which together were highly specific for RPE65-related recessive retinopathy (12 total points, VCEP member-provided data, PP4_Moderate). The computational predictor REVEL gives a score of 0.965, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM3, PM5, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902128/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:23363 biolink:causes MONDO:0013039 infores:monarchinitiative not_provided not_provided HGNC:29092 MONDO:0013039 uuid:52942029-6c88-4e8c-bd04-42adab40ddbb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA214327 biolink:causes MONDO:0015967 infores:clingen CAID:CA214327 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PP4_Moderate, PP3 PS4, PP1 The c.790G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to phenylalanine at codon 264 (p.(Val264Phe)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, 36257325, internal lab contributors). At least 2 of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and one had a low renal glucose threshold) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 36257325). In summary, c.790G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214327/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:92607 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0030252 infores:hetionet CHEBI:5778 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0851578 infores:hetionet CHEBI:47898 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151754 infores:hetionet CHEBI:63622 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0151878 infores:hetionet CHEBI:135736 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0221201 infores:hetionet CHEBI:9566 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0232333 infores:hetionet CHEBI:68478 biolink:causes MONDO:0019722 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0268731 infores:hetionet CHEBI:63618 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0409974 infores:hetionet GO:2000280 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000280 GO:0007275 CHEBI:4530 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0242350 infores:hetionet CHEBI:37924 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0040460 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0005940 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0235567 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0025061 infores:hetionet CHEBI:36704 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0039240 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0018099 infores:hetionet CAID:CA2582131482 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582131482 MONDO:0010305 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PP1 The NM_005629.4(SLC6A8):c.219del (p.Asn74ThrfsTer23) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A 5 year old male, hemizygous for the variant, with clinical symptoms consistent with creatine transporter deficiency has been reported with very low creatine on brain MRS and elevated urine creatine (values not provided) (PMID: 18726626) (PP4_Moderate). His 7 year old sister is heterozygous for the variant, with mild intellectual disability and reduced creatine on brain MRS. Their mother is reported to be asymptomatic (insufficient evidence to apply PP1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582131482/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Supports CHEBI:9123 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0025323 infores:hetionet CHEBI:4027 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0221152 infores:hetionet CHEBI:65346 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0600228 infores:hetionet CHEBI:8327 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0001824 infores:hetionet CHEBI:63630 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0235710 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0343886 infores:hetionet NCBIGene:65055 biolink:causes MONDO:0013884 infores:monarchinitiative not_provided not_provided HGNC:25786 MONDO:0013884 uuid:ba91188a-b01f-4aff-977f-816c56858080 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905706 biolink:causes GO:0006119 infores:ubergraph knowledge_assertion manual_agent GO:1905706 GO:0006119 CHEBI:171719 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1096355 infores:hetionet CAID:CA410148583 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148583 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS4, PS1, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1016T>G (p.Leu339Arg) is a missense variant which is absent in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). The REVEL score is 0.311 (<0.50), indicating that the variant is likely to be tolerated, and the SpliceAI score is 0 (<0.20), meaning that the variant is highly unlikely to impact splicing (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148583/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15367 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0239340 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0152128 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0037274 infores:hetionet CHEBI:64045 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0018681 infores:hetionet CHEBI:4653 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0003467 infores:hetionet CHEBI:35854 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0015230 infores:hetionet CHEBI:84050 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0015230 infores:hetionet CHEBI:4907 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0002170 infores:hetionet CHEBI:47381 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0016242 infores:hetionet CHEBI:465284 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0235266 infores:hetionet CHEBI:3723 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0920289 infores:hetionet CHEBI:7931 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0013604 infores:hetionet CHEBI:8890 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0917801 infores:hetionet CHEBI:134991 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235198 infores:hetionet NCBIGene:2778 biolink:causes MONDO:0011301 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0011301 uuid:21ea011c-c352-442a-8248-ae7f57635e08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042571 infores:hetionet CHEBI:47781 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0278134 infores:hetionet CHEBI:3013 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0040034 infores:hetionet CHEBI:43968 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0311468 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0151313 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027765 infores:hetionet CHEBI:15367 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0152459 infores:hetionet CHEBI:180905 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0026826 infores:hetionet CHEBI:4653 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0023066 infores:hetionet CHEBI:5050 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0037199 infores:hetionet CHEBI:9943 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022107 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0018129 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018129 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0001824 infores:hetionet GO:1902412 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:1902412 GO:0000278 CHEBI:27565 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0011606 infores:hetionet CHEBI:101085 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0233407 infores:hetionet CAID:CA16603044 biolink:causes MONDO:0018875 infores:clingen CAID:CA16603044 MONDO:0018875 PMID:29979965PMID:30224644PMID:12826609PMID:16861262 Likely Pathogenic PS3, PP3_Moderate, PM1, PM2_Supporting BA1, BP4, BP2, PS1, PS4, PS2, PM5, BS1, BS3, BS4, PM6, PP1, BS2 Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, TP53 c.396G>C (p.Lys132Asn) meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS3, PP3_Moderate, PM1, PM2_Supporting. TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603044/MONDO:0018875/009 2022-03-18 2022-03-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5296 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0013378 infores:hetionet CHEBI:6413 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0023222 infores:hetionet CHEBI:64198 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0039231 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0004936 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0152198 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151735 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0038358 infores:hetionet CHEBI:135351 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0021177 infores:hetionet CHEBI:72297 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C1443060 infores:hetionet CHEBI:127342 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0424790 infores:hetionet CHEBI:75722 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019080 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0038362 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0038362 infores:hetionet CHEBI:44915 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151818 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006716 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0010072 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0009450 infores:hetionet CHEBI:39112 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0221201 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011991 infores:hetionet CHEBI:63621 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2830004 infores:hetionet CHEBI:3437 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0004093 infores:hetionet CHEBI:47381 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009421 infores:hetionet CHEBI:101853 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0687713 infores:hetionet CHEBI:74947 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0034642 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0036572 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0424000 infores:hetionet NCBIGene:9968 biolink:causes MONDO:0010590 infores:monarchinitiative not_provided not_provided HGNC:11957 MONDO:0010590 uuid:e05c0ea3-8301-43db-a25e-cc0e5296e589 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes MONDO:0008294 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162565 infores:hetionet NCBIGene:182 biolink:causes MONDO:0060713 infores:monarchinitiative not_provided not_provided HGNC:6188 MONDO:0060713 uuid:a323c08d-2cd9-47e5-9e4b-83989df9710d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27470 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0042847 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151773 infores:hetionet CHEBI:10650 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013404 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0012833 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0518015 infores:hetionet CHEBI:27786 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0085649 infores:hetionet CHEBI:28593 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0034155 infores:hetionet CHEBI:72297 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0016204 infores:hetionet GO:1901163 biolink:causes GO:0007566 infores:ubergraph knowledge_assertion manual_agent GO:1901163 GO:0007566 CHEBI:5001 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0017178 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0036983 infores:hetionet CAID:CA5950009 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950009 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The c.577G>A (NM_000448.3) variant in RAG1 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 193 (p.Glu193Lys).The filtering allele frequency (the lower threshold of the 95% CI of 772/30614) of the c.577G>A variant in RAG1 is 0.02374 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). 12 adult homozygous reported on GnomAD v2.1.1, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950009/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:17141 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0017160 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020456 infores:hetionet NCBIGene:4935 biolink:causes MONDO:0010435 infores:monarchinitiative not_provided not_provided HGNC:20145 MONDO:0010435 uuid:beaf8073-fff3-4a51-b1ce-d69b213ccc9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0242301 infores:hetionet CHEBI:291342 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0013404 infores:hetionet CHEBI:2682 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0333355 infores:hetionet CHEBI:6128 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0014724 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0012833 infores:hetionet CHEBI:3561 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013390 infores:hetionet CHEBI:34385 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0575090 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0011972 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0085083 infores:hetionet CHEBI:63620 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0000737 infores:hetionet CHEBI:8382 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0152459 infores:hetionet CHEBI:31644 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0002792 infores:hetionet CHEBI:161680 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0018681 infores:hetionet CHEBI:64321 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0039070 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549209 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0877048 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0877048 infores:hetionet CHEBI:63611 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0024282 infores:hetionet NCBITaxon:384509 biolink:causes MONDO:0005812 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:384509 MESH:D007251 DB06614_MESH_D007251_1 NCBIGene:4175 biolink:causes MONDO:0006065 infores:monarchinitiative not_provided not_provided HGNC:6949 MONDO:0006065 uuid:564350c9-1eac-40b6-ae8e-f243a3001666 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6904 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0011603 infores:hetionet CHEBI:3510 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0016204 infores:hetionet CHEBI:35854 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0018524 infores:hetionet GO:0062042 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0062042 GO:0007275 CHEBI:9667 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0031350 infores:hetionet NCBIGene:59336 biolink:causes MONDO:0859229 infores:monarchinitiative not_provided not_provided HGNC:13998 MONDO:0859229 uuid:d524ca8d-5a1f-4b04-8aad-aeb5133fd00c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1141930 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0520962 infores:hetionet CHEBI:64355 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0043352 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0162316 infores:hetionet CAID:CA135984 biolink:causes MONDO:0021060 infores:clingen CAID:CA135984 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.378A>G (p.Glu126=) variant in the HRAS gene is 0.095% (23/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135984/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:28001 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C1384353 infores:hetionet CHEBI:9398 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0237849 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0009450 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0019340 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006325 infores:hetionet CHEBI:29688 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0022354 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0151763 infores:hetionet CHEBI:51230 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0022081 infores:hetionet CHEBI:142290 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0016204 infores:hetionet CHEBI:101278 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0232487 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0701836 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235169 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020615 infores:hetionet CHEBI:3371 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C1384666 infores:hetionet CHEBI:8768 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013447 infores:hetionet GO:0141080 biolink:causes GO:0140888 infores:ubergraph knowledge_assertion manual_agent GO:0141080 GO:0140888 CHEBI:7454 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0233715 infores:hetionet CAID:CA2588340092 biolink:causes MONDO:0100437 infores:clingen CAID:CA2588340092 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PP1 NM_001034853.2(RPGR):c.530dup (p.Ser178LysfsTer2) is a frameshift variant due to 1-nucleotide duplication resulting in a premature stop codon after 2 amino acids within exon 6 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), family history consistent with X-linked inheritance (2 pts), night blindness (0.5 pts), reduced visual acuity (0.5 pts), attenuated retinal arteries, pigment deposits (0.5 pts), and extinguished electroretinogram responses, which together are specific for RPGR-related retinopathy (4.5 points, PMID: 24938718, PP4). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis from 1 family, which was not sufficient to meet the PP1 code (PMID: 24938718). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2588340092/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:3048 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C1258215 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0340464 infores:hetionet CHEBI:63589 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0085605 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020651 infores:hetionet CHEBI:51041 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0023066 infores:hetionet CHEBI:6741 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0085633 infores:hetionet CHEBI:7565 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0028084 infores:hetionet CHEBI:7444 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0003123 infores:hetionet CHEBI:7478 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085593 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0260662 infores:hetionet CHEBI:3082 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0014518 infores:hetionet CHEBI:10102 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0027497 infores:hetionet CHEBI:27504 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0850149 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0009450 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0234458 infores:hetionet CHEBI:50305 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0038999 infores:hetionet CHEBI:75045 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020433 infores:hetionet CAID:CA410148429 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148429 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1040T>G (p.Met347Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148429/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41774 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0002871 infores:hetionet CHEBI:42068 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0042963 infores:hetionet CHEBI:5384 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0018932 infores:hetionet CHEBI:9123 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027849 infores:hetionet CHEBI:17823 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0011124 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0234215 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0015230 infores:hetionet CHEBI:77032 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0002994 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0038587 infores:hetionet CHEBI:2654 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0948594 infores:hetionet CHEBI:80630 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0004093 infores:hetionet NCBIGene:56623 biolink:causes MONDO:0008944 infores:monarchinitiative not_provided not_provided HGNC:21474 MONDO:0008944 uuid:e1c21f68-23d0-484b-81dd-b14814f300ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes UMLS:C0948991 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0948991 infores:hetionet NCBITaxon:6187 biolink:causes MONDO:0044351 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6187 MONDO:0044351 CHEBI:4024 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0020452 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0234215 infores:hetionet CHEBI:46295 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0020458 infores:hetionet CHEBI:6706 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0855242 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0581912 infores:hetionet CHEBI:3077 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0010481 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0746883 infores:hetionet CHEBI:27732 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0035078 infores:hetionet CHEBI:6359 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0026821 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0233494 infores:hetionet CAID:CA067890 biolink:causes MONDO:0100150 infores:clingen CAID:CA067890 MONDO:0100150 PMID: Uncertain Significance PP3, BP4, BA1, BS1, PM2 The c.619C>T variant in RYR1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 207 (p.Arg207Cys). The highest population minor allele frequency in gnomAD v4.1 is 0.00001017 (12/1179596 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.459, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. In summary, this variant meets the criteria to be classified as uncertain significance for AD/AR RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: None. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA067890/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:84500 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233414 infores:hetionet CHEBI:6801 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1384353 infores:hetionet CHEBI:45409 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0025323 infores:hetionet CHEBI:367163 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0235378 infores:hetionet CHEBI:17650 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0020555 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0948594 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0234215 infores:hetionet CHEBI:367163 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0004364 infores:hetionet CHEBI:9086 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0231530 infores:hetionet CAID:CA404089700 biolink:causes MONDO:0007750 infores:clingen CAID:CA404089700 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1739C>G (p.Ser580Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.88. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404089700/MONDO:0007750/013 2023-11-07 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3478 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0085593 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0002871 infores:hetionet CHEBI:10119 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013404 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011551 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085932 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020456 infores:hetionet CHEBI:6472 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0009319 infores:hetionet GO:0039672 biolink:causes GO:0002323 infores:ubergraph knowledge_assertion manual_agent GO:0039672 GO:0002323 CHEBI:52717 biolink:causes MONDO:0000748 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024904 infores:hetionet CHEBI:391960 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C1443060 infores:hetionet CHEBI:27777 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C2939147 infores:hetionet CHEBI:3723 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011175 infores:hetionet CHEBI:5002 biolink:causes NCIT:C34517 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0010263 infores:hetionet CHEBI:23765 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042963 infores:hetionet NCBIGene:8493 biolink:causes MONDO:0044318 infores:monarchinitiative not_provided not_provided HGNC:9277 MONDO:0044318 uuid:40990284-2275-4ffc-a642-f924d27d90e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018991 infores:hetionet CHEBI:52717 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0043144 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235431 infores:hetionet CHEBI:5134 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0858635 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0022568 infores:hetionet CHEBI:61049 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232849 infores:hetionet CHEBI:15367 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019825 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0151888 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0340464 infores:hetionet CHEBI:48538 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0002962 infores:hetionet CHEBI:119915 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085637 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C1527407 infores:hetionet UMLS:C1709429 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0085593 infores:hetionet CHEBI:59560 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0032617 infores:hetionet CHEBI:9130 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0037036 infores:hetionet CHEBI:52717 biolink:causes HP:0001933 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0854107 infores:hetionet CHEBI:87681 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0043352 infores:hetionet GO:0141080 biolink:causes GO:0071345 infores:ubergraph knowledge_assertion manual_agent GO:0141080 GO:0071345 CHEBI:3387 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020625 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0234215 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0234215 infores:hetionet CHEBI:6775 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0005758 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0032617 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0852911 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0034150 infores:hetionet CHEBI:44185 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0919924 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0011616 infores:hetionet CHEBI:31623 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0002170 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011053 infores:hetionet CHEBI:61049 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0149745 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040435 infores:hetionet CHEBI:63629 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0003467 infores:hetionet CHEBI:3515 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0086565 infores:hetionet CHEBI:6970 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0009376 infores:hetionet CHEBI:5384 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0004093 infores:hetionet CHEBI:7865 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0011615 infores:hetionet CHEBI:50156 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0013362 infores:hetionet CHEBI:6923 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0014742 infores:hetionet CHEBI:135736 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0232462 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020649 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0034150 infores:hetionet NCBIGene:5324 biolink:causes MONDO:0008401 infores:monarchinitiative not_provided not_provided HGNC:9045 MONDO:0008401 uuid:d8d0bb24-2aa9-4770-aae5-ba53dac74610 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018794 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005752 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0270629 infores:hetionet CAID:CA410148042 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148042 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1123A>C (p.Thr375Pro) is a missense variant which does not meet any ACMG/AMP codes. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148042/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:421707 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0009450 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0041969 infores:hetionet CHEBI:45409 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020580 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0033845 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0032285 infores:hetionet CHEBI:61049 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007859 infores:hetionet CAID:CA5949891 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949891 MONDO:0000572 PMID: Uncertain Significance PM2 NM_000448.3(RAG1):c.37T>G is a missense variant predicted to cause substitution of Serine by Alanine at amino acid 13 (p.Ser13Ala).The highest population minor allele frequency in gnomAD v4 is 0.0007334 (44/59996) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met).There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: No criteria met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949891/MONDO:0000572/123 2024-01-24 2024-01-24 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135930 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0149931 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0003123 infores:hetionet CHEBI:31236 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014724 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151602 infores:hetionet CAID:CA915951016 biolink:causes MONDO:0100437 infores:clingen CAID:CA915951016 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1243_1244del (p.Arg415GlyfsTer?) is a frameshift variant due to 2-nucleotide deletion within exon 10 of 15 that introduces a premature stop codon and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through 16 affected meioses from 1 family (PP1_Moderate; PMID: 14516808). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts) with delayed or milder phenotype in females (1 pt), early onset (1 pt), rod involvement greater than cone (1 pt), high myopia (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), visual field constriction (0.5), and pigmentary retinopathy (0.5 pts), which together are specific for RPGR-related retinopathy (8 points, PMID: 14516808, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1_Moderate, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915951016/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports UMLS:C0657912 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151636 infores:hetionet CHEBI:7476 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0152009 infores:hetionet CHEBI:4653 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0039070 infores:hetionet CHEBI:63631 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235267 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0007785 infores:hetionet CHEBI:39867 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151905 infores:hetionet CHEBI:135736 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0241729 infores:hetionet CHEBI:2469 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0011991 infores:hetionet CHEBI:45409 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0149745 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0019158 infores:hetionet CHEBI:41774 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0547030 infores:hetionet CHEBI:39585 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C1443060 infores:hetionet CAID:CA220233 biolink:causes MONDO:0015152 infores:clingen CAID:CA220233 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4_Strong, PM2_Supporting, PP3, PP1 The NM_000023.4: c.241C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 81 (p.Arg81Cys). This variant has been detected in at least three individuals with symptoms of limb girdle muscular dystrophy, including confirmed in trans with a pathogenic or likely pathogenic variant (c.850C>T p.(Arg284Cys), 1.0 pt, PMID: 17994539) and in a homozygous state in two patients (0.75 pts, PMID: 31069529, 30345904) (PM3). At least one patient with this variant and a second presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness and significantly reduced or absent alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 17994539, 26404900; LOVD Individual #00133411). In addition, the variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 17994539). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30576 alleles) in the South Asian population, which is lower than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.934, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PP4_Strong, PM3, PP1, PP3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220233/MONDO:0015152/189 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7640 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0009806 infores:hetionet CAID:CA340742114 biolink:causes MONDO:0100368 infores:clingen CAID:CA340742114 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1380G>A (p.Trp460Ter) is a nonsense variant that introduces a premature stop codon into exon 13 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A variant suspected in trans (0.5 points, PMID: 19117922) or the c.886del (p.Arg296fs) variant confirmed in trans (1 point, PMID: 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), infantile onset (1 pt), nystagmus (1 pt), no detectable rod ERG responses (0.5 pts), reduced cone ERG responses (1 pt), reduced visual acuity (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5.5 total points, PMID: 19117922, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340742114/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71223 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0858635 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0857353 infores:hetionet CHEBI:9328 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0009917 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0850420 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0267941 infores:hetionet CHEBI:4702 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0392163 infores:hetionet CHEBI:8871 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151610 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0855242 infores:hetionet CHEBI:28901 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0023380 infores:hetionet CHEBI:63631 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0032617 infores:hetionet CHEBI:31643 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0013404 infores:hetionet CHEBI:8232 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0035078 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0025061 infores:hetionet CHEBI:94449 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0000731 infores:hetionet CHEBI:4708 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0027497 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033777 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0033975 infores:hetionet CHEBI:8890 biolink:causes MONDO:0001294 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0019937 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151735 infores:hetionet CHEBI:8764 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151786 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0040034 infores:hetionet CHEBI:42068 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0546817 infores:hetionet CHEBI:39112 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0013404 infores:hetionet CHEBI:8228 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0000768 infores:hetionet CHEBI:8069 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0020649 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0027651 infores:hetionet CHEBI:3479 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0002874 infores:hetionet CHEBI:16796 biolink:causes HP:0200097 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0853945 infores:hetionet CHEBI:5384 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0041657 infores:hetionet CHEBI:27786 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0030193 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0035222 infores:hetionet CHEBI:64321 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0037763 infores:hetionet CHEBI:27666 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0085605 infores:hetionet CHEBI:3423 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C2937358 infores:hetionet CHEBI:8871 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026827 infores:hetionet NCBIGene:2260 biolink:causes MONDO:0014196 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0014196 uuid:9765ab02-a6bf-4b99-b23a-1ef142b4a6fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0009782 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0340464 infores:hetionet CHEBI:63584 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0600142 infores:hetionet CHEBI:5004 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0030312 infores:hetionet NCBIGene:10653 biolink:causes MONDO:0010036 infores:monarchinitiative not_provided not_provided HGNC:11247 MONDO:0010036 uuid:6c435c0e-3cef-4046-8e64-78cea98e693c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1266194 infores:hetionet CHEBI:7476 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042029 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151735 infores:hetionet CHEBI:6909 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0015672 infores:hetionet CHEBI:17987 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0030193 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0021053 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0020517 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0018802 infores:hetionet CHEBI:10102 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0340865 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006826 infores:hetionet CAID:CA229262 biolink:causes MONDO:0009861 infores:clingen CAID:CA229262 MONDO:0009861 PMID: Benign BA1 The c.-71A>Cvariant in PAH has a MAF of 0.16686 in the gnomAD African population. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229262/MONDO:0009861/006 2020-03-27 2020-03-27 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:38562 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C1368065 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042267 infores:hetionet CHEBI:32221 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0013404 infores:hetionet CAID:CA226730 biolink:causes MONDO:0010725 infores:clingen CAID:CA226730 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4, PP3_Moderate, PP1_Strong, PS3_Supporting, PP4 NM_000330.4(RS1):c.422G>A (p.Arg141His) is a missense variant encoding the substitution of arginine with histidine at amino acid 141. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 34645606, 30450322, 29739629, 35984651, 30652005, 19093009, PS4). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 29851975, PP4). The variant has been reported to segregate with retinal dystrophy through at least 9 meioses in three families- one male proband tested with his uncle and the two 1st cousins once removed, 2 brothers in one family, and a mother carrier and her affected son in the other (PP1_Strong; PMIDs: 29851975, 30450322, 19093009). The computational predictor REVEL gives a score of 0.909, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predicted splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 membrane binding, and the variant is unable to attenuate photoreceptor degeneration in retinal explants (PMID: 30040949, PS3_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Moderate, PS3_Supporting, PP1_Strong, PP4, and PS4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226730/MONDO:0010725/126 2025-09-21 2025-09-21 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:92998 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0042963 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0162429 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0003123 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006277 infores:hetionet CHEBI:3176 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0043352 infores:hetionet NCBIGene:55505 biolink:causes MONDO:0957294 infores:monarchinitiative not_provided not_provided HGNC:14378 MONDO:0957294 uuid:65d2a67e-4572-478c-93df-c3d52759d89e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31355 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0015376 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005366 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0524909 infores:hetionet CHEBI:5118 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151632 infores:hetionet CHEBI:473990 biolink:causes UMLS:C1619727 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C1619727 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0521626 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0521626 infores:hetionet CHEBI:51141 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0392525 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0027765 infores:hetionet CHEBI:16755 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0000729 infores:hetionet CHEBI:49375 biolink:causes HP:0030402 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0541767 infores:hetionet NCBIGene:23019 biolink:causes MONDO:0033618 infores:monarchinitiative not_provided not_provided HGNC:7877 MONDO:0033618 uuid:e6f9712c-3310-403f-bfb3-f0b7335250e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94440 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0012833 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020651 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0033860 infores:hetionet CAID:CA410208132 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208132 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.520A>G (p.Thr174Ala) is a missense variant which has a REVEL score ≥ 0.88 (0.951) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208132/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:37727 biolink:causes MONDO:0000304 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:37727 MONDO:0000304 CHEBI:63630 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0010200 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0014534 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0242350 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0239093 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0239093 infores:hetionet CHEBI:5864 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002792 infores:hetionet CHEBI:9570 biolink:causes MONDO:0021124 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0021361 infores:hetionet CHEBI:85083 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0037274 infores:hetionet CHEBI:75984 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0085610 infores:hetionet NCBIGene:24140 biolink:causes MONDO:0010660 infores:monarchinitiative not_provided not_provided HGNC:13254 MONDO:0010660 uuid:e6b504f0-cbc5-4b39-a87d-394e2f884fcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039231 infores:hetionet CHEBI:6062 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0016382 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0267792 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0021053 infores:hetionet CHEBI:38940 biolink:causes EFO:1001753 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0243001 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151898 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151898 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0019158 infores:hetionet CHEBI:3698 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0017181 infores:hetionet CAID:CA010543 biolink:causes MONDO:0004994 infores:clingen CAID:CA010543 MONDO:0004994 PMID:17548557PMID:17548557 Benign PM1, BA1 BS2, PP2, PP4, PM3, PM2, PM5, PM4, PS3, PM6, PP3, PP1, BP1, BP3, BS1, BS3, BS4, PS1, PS4, PS2, BP4, BP7, BP2, BP5, PVS1 The c.1322C>T (p.Thr441Met) in MYH7 has been identified in 0.2% (FAF 95% CI; 47/18394) of East Asian chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257), this is not considered to be in conflict with BA1 since benign variation within this region was considered during that analysis. In summary, this variant meets criteria to be is classified as benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010543/MONDO:0004994/002 2021-06-16 2021-06-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0264906 infores:hetionet CHEBI:7640 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2981158 infores:hetionet CHEBI:6775 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0497156 infores:hetionet CHEBI:5001 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027796 infores:hetionet CHEBI:7986 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0023418 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0032285 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0234547 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0234547 infores:hetionet CHEBI:3504 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0231218 infores:hetionet CHEBI:5296 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0687713 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0392176 infores:hetionet CHEBI:63638 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0278134 infores:hetionet CHEBI:63608 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019079 infores:hetionet CHEBI:70735 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0086439 infores:hetionet CHEBI:31236 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948008 infores:hetionet CAID:CA172240 biolink:causes MONDO:0019497 infores:clingen CAID:CA172240 MONDO:0019497 PMID:18941476PMID:9139825PMID:15070423PMID:24123366PMID:18941476PMID:9139825PMID:15070423PMID:24123366PMID:18941476 Pathogenic BS1, PM3_Very Strong, PVS1, PS3 BS4, BP5, BP7, PP4, PP1, PP3, BS2, PM1, PM4, PM5, PM6, PM2, BP3, BP4, BP2, BA1, PS2, PS4, PS1 The filtering allele frequency of the p.Trp24X variant in the GJB2 gene is 0.38% (137/ 30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1 code will not contribute to the overall classification. The p.Trp24X variant in GJB2 is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15070423, 24123366, 18941476, 9139825). A knock-in mouse model demonstrates that the p.Trp24X variant leads to the phenotype (PS3; PMID:18941476). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS3, BS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA172240/MONDO:0019497/005 2018-09-17 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:4027 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0425945 infores:hetionet CHEBI:50223 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0876994 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0232492 infores:hetionet CHEBI:3216 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151908 infores:hetionet CHEBI:9927 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0014591 infores:hetionet CAID:CA10652910 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652910 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*3060T>C variant in the 3' UTR has an MAF of 0.02835 (2.8%, 387/13650 alleles) in the Latino subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 12 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652910/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6067 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0010346 infores:hetionet CHEBI:59773 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0004093 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011570 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0042035 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0010692 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023787 infores:hetionet CHEBI:8776 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0013384 infores:hetionet CHEBI:3752 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013404 infores:hetionet CHEBI:34967 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0917801 infores:hetionet CAID:CA267628 biolink:causes MONDO:0009861 infores:clingen CAID:CA267628 MONDO:0009861 PMID:26666653 Likely Pathogenic PM5, PM2, PP4, PP3 PM3 The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The variant results in the substitution of a moderately conserved Valine residue with Alanine, a physiochemically similar amino acid. However, the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.919) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Other missense changes at this Valine residue (Val388) have been previously reported Pathogenic or Likely Pathogenic in ClinVar, e.g., p.Val388Met (Pathogenic per internal PAH ClinGen Working Group classification, ClinVar ID 619), as well as p.Val388Leu (PM5). The c.181A>G (p.Asn61Asp) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 12501224). This variant is absent in population databases (PM2). This variant was detected with p.R261Q (Pathogenic/likely pathogenic in ClinVar) (PM3; PMID: 12501224). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267628/MONDO:0009861/006 2019-05-05 2019-07-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:480999 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0014130 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0002871 infores:hetionet CHEBI:47381 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0220870 infores:hetionet CHEBI:48844 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0160390 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0007760 infores:hetionet CHEBI:40009 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C1443060 infores:hetionet CHEBI:6897 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0012833 infores:hetionet CHEBI:63589 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0041969 infores:hetionet CHEBI:23765 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C1609512 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0009450 infores:hetionet CHEBI:9943 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042345 infores:hetionet NCBIGene:5959 biolink:causes MONDO:0007639 infores:monarchinitiative not_provided not_provided HGNC:9940 MONDO:0007639 uuid:86d60448-e3da-4186-8047-2138f8740036 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0018813 infores:hetionet CHEBI:71940 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0037763 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0015376 infores:hetionet NCBIGene:221078 biolink:causes MONDO:0968944 infores:monarchinitiative not_provided not_provided HGNC:23529 MONDO:0968944 uuid:f063e38d-2efe-4aa8-b169-1aff324f7a6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3423 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0013687 infores:hetionet CHEBI:50275 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0392699 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0007642 infores:hetionet CAID:CA386954880 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954880 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM5_Strong, PM1_Supporting, PS2_Moderate, PP3 PP4 The c.320T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 107 (p.(Leu107Pro)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v.4.1.0 (PM2_Supporting), and was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor). This variant was identified as a de novo occurrence with confirmed/parental relationships in this individual, but their clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). Two other missense variants at the same residue, c.319C>G (p.Leu107Val) and c.319C>A (p.Leu107Ile), have been interpreted as pathogenic by the ClinGen MDEP, and p.Leu107Arg has greater Grantham distance than p.Leu107Val and p.Leu107Ile (PM5_Strong). In summary, c.320T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM5_Strong, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954880/MONDO:0015967/017 2025-07-16 2025-07-25 Autosomal dominant inheritance HP:0000006 Supports CAID:CA396452267 biolink:causes MONDO:0100488 infores:clingen CAID:CA396452267 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.145G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Gly by Arg at amino acid 49 (p.Gly49Arg). This allele is absent from populations in gnomAD v2.1.1 and v3 (PM2_Supporting). This variant has been observed in ≥3 individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396452267/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:47898 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1510410 infores:hetionet CHEBI:45783 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0036396 infores:hetionet CHEBI:50693 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0040034 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0160390 infores:hetionet CHEBI:45599 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0040586 infores:hetionet CHEBI:73274 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0033774 infores:hetionet CHEBI:15367 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004095 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0542184 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0031350 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0017601 infores:hetionet CHEBI:47657 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0018418 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0027769 infores:hetionet CHEBI:724125 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0085641 infores:hetionet CHEBI:34385 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0030554 infores:hetionet CHEBI:9398 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0014742 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0233494 infores:hetionet CHEBI:6437 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0003862 infores:hetionet CAID:CA340933 biolink:causes MONDO:0044970 infores:clingen CAID:CA340933 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PP1_Moderate PS2, PS3, PM6 The m.14495A>G (p.L60S) variant in MT-ND6 has been reported in five individuals from three families, all of whom had LHON (PS4_supporting; PMIDs: 2287992, 11133798). There are no reports of de novo occurrences to our knowledge. This variant segregated with disease in one family with LHON (all testing was performed in blood; affected individuals: proband/mother with variant present at 51% heteroplasmy, sons with variant at 93% and 92%; unaffected individuals: sister with variant at 23%, maternal niece with variant at 53%, and maternal nephew with variant at 37%; PP1_moderate; PMID: 11133798). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.87 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the strong segregation evidence and consistent phenotype in affected individuals. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340933/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:465284 biolink:causes UMLS:C0151629 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151629 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0021167 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0014742 infores:hetionet CHEBI:17263 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0349790 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020542 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0013395 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0549609 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0549609 infores:hetionet NCBIGene:10280 biolink:causes MONDO:0013715 infores:monarchinitiative not_provided not_provided HGNC:8157 MONDO:0013715 uuid:56ca3191-360b-4b0d-84d3-45ebf62d32e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151763 infores:hetionet CHEBI:42797 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011253 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0018134 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018134 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0004936 infores:hetionet CHEBI:474180 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0014591 infores:hetionet CHEBI:6149 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0037383 infores:hetionet CHEBI:9014 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0852810 infores:hetionet CHEBI:40303 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0231218 infores:hetionet CHEBI:75179 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0020517 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0040034 infores:hetionet CHEBI:8426 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0033774 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042510 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0035455 infores:hetionet CHEBI:7824 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0002874 infores:hetionet CHEBI:66899 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0009443 infores:hetionet CHEBI:50885 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0234894 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025209 infores:hetionet CAID:CA314806 biolink:causes MONDO:0012999 infores:clingen CAID:CA314806 MONDO:0012999 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PP3_Moderate, PM3_Supporting, PS3_Supporting The NM_000156.6:c.328G>T variant in GAMT is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 110 (p.Val110Phe). Two patient(s) with this variant had elevated guanidinoacetate in urine and decreased creatine peak on MRS (PMID: 24415674; CreatineInfo Registry) (PP4_Strong). Both individuals with GAMT deficiency were heterozygous for the variant and another variant in GAMT that has been classified as pathogenic (c.327G>A, PMID: 24415674) or likely pathogenic (CreatineInfo Registry data) by the ClinGen CCDS VCEP. The phase was unconfirmed in both cases (PM3_Supporting). The variant has also been reported in an individual with neurodevelopmental disorder/epilepsy but further details are unavailable, and it is unknown if this case may overlap with either of the other 2 cases (PMID: 29655203). Expression of the variant in GAMT-deficient fibroblasts resulted in extremely low GAMT activity, and no detectable expression of the protein (Figure 1, PMID 24415674) indicating that this variant may impact protein function (PS3_Supporting). The computational predictor REVEL gives a score of 0.928 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level. Furthermore, SpliceAI predicts that this variant, which alters the first nucleotide of exon 3, impacts normal splicing (score = 0.4 for acceptor loss) (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000009326 (11/1179478 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205580. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_strong, PP3_Moderate, PS3_Supporting, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 18, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314806/MONDO:0012999/026 2025-04-18 2025-04-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3077 biolink:causes UMLS:C0859229 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0859229 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0221203 infores:hetionet CHEBI:7454 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0018681 infores:hetionet CHEBI:4672 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0011168 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0333516 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0333516 infores:hetionet UBERON:0000965 biolink:causes UBERON:0003902 infores:ubergraph knowledge_assertion manual_agent UBERON:0000965 UBERON:0003902 CHEBI:521033 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0011603 infores:hetionet CHEBI:188986 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0011991 infores:hetionet CHEBI:180905 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C1142412 infores:hetionet CHEBI:4636 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0022107 infores:hetionet CHEBI:2569 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0085593 infores:hetionet CHEBI:31236 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233754 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0221384 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0221384 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0276141 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0276141 infores:hetionet CHEBI:29688 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0917801 infores:hetionet CHEBI:3176 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0162285 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0006277 infores:hetionet CHEBI:9649 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0162830 infores:hetionet CHEBI:31302 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0028084 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0549399 infores:hetionet NCBIGene:79577 biolink:causes MONDO:0012004 infores:monarchinitiative not_provided not_provided HGNC:16783 MONDO:0012004 uuid:67c5ef6a-e8b1-48dc-b1dc-bea6ce70b67e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234215 infores:hetionet CHEBI:51230 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0008031 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0948369 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0948369 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005855 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0026393 infores:hetionet CHEBI:8346 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C2363731 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0027769 infores:hetionet CAID:CA409106173 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106173 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PM2_Supporting, PM1_Supporting PP3, PS4 The c.553G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to threonine at codon 185 (p.(Ala185Thr)) of NM_175914.5. This variant is located in the ligand binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant has a REVEL score of 0.605, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative antibodies, and family history of neonatal hypoglycemia and LGA infants in absence of maternal hyperglycemia) (PP4_Moderate; internal lab contributor). Additionally, this variant segregated with diabetes, with at four informative meioses in one family (PP1_Moderate; internal lab contributor). In summary, c.553G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Moderate, PP4_Moderate, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106173/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3219 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015230 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0232492 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006852 infores:hetionet CHEBI:3479 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151905 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027765 infores:hetionet CAID:CA020089 biolink:causes MONDO:0008667 infores:clingen CAID:CA020089 MONDO:0008667 PMID:16452184PMID:11331612PMID:15611064 Pathogenic PS4, PM2_Supporting, PM6_Supporting, PM1, PP3, PS3_Supporting PP1 The NM_000551.3(VHL):c.191G>C (p.Arg64Pro) variant in the VHL gene is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides within a region, amino acids 63 - 155 (Beta domain), of VHL that is defined as a mutational hotspot and critical functional domain by the ClinGen VHL VCEP (PM1). The computational predictor REVEL gives a score of 0.938, which is above the threshold of 0.664, evidence that correlates with impact to VHL function (PP3). This variant has been reported in 11 probands with features of Von-Hippel-Lindau syndrome/ meeting Danish criteria (9.25 points, PS4; PMID: 19336503, 9663592, 17661816, 30455982, 28646318, 31383958, 19576851, 17639058, 28944243, 17102083, 21463266). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with bilateral pheochromocytoma (PM6_Supporting; PMID: 24555745). In vitro assays show conflicting results but suggest this variant impacts protein function as shown by reduced binding and ubiquitination of HIF-alpha (PMID: 16452184, 15611064, 11331612) (PS3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020089/MONDO:0008667/078 2024-06-25 2024-07-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71219 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0027441 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042571 infores:hetionet CHEBI:63605 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0017168 infores:hetionet CHEBI:16469 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0085688 infores:hetionet CHEBI:9398 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0033117 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037284 infores:hetionet CHEBI:31622 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0004093 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0029408 infores:hetionet CHEBI:5118 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018965 infores:hetionet CAID:CA120587 biolink:causes MONDO:0044970 infores:clingen CAID:CA120587 MONDO:0044970 PMID: Likely Pathogenic PP1, PP3, PM2_Supporting, PS3_Moderate, PS4_Supporting PM6 The m.5650G>A variant in MT-TA has been reported in three unrelated individuals with primary mitochondrial disease. The predominant feature in these individuals was myopathy (muscle weakness, exercise intolerance), and other features were seen in one individual each (lipomas, ptosis, migraines, sensorineural hearing loss, impaired glucose tolerance). Age of onset varied from teens to young adulthood and all individuals were alive at the time of report. Brain imaging was variable in the three individuals and muscle biopsies showed ragged red fibers, COX-negative fibers, and respiratory chain enzyme deficiencies. Lab values were significant for variably elevated lactate and CK. There was a range of variant heteroplasmy levels in tissues from each individual although the heteroplasmy level was consistently highest in muscle (PS4_supporting, PMIDs: 14569122, 17825557, 11715067). Of note, one individual also had a NOTCH3 pathogenic variant (PMID: 11715067), however this expert panel elected to include this case given NOTCH3 pathogenic variants are associated with CADASIL (cerebral arteriopathy with subcortical infarcts and leukoencephalopathy), and this individual had additional features that were consistent with a primary mitochondrial disease. This variant segregated with disease in two families: one family with an unaffected sister having the variant present at lower heteroplasmy levels than the proband (PMID: 14569122) and one family with an affected mother with similarly high levels of the variant to the proband and a less severely affected maternal grandmother with lower heteroplasmy levels (PMID: 17825557; PP1_supporting). There are no reports of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (77th percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3). This variant is absent in the Helix dataset and gnomAD v3.1.2, and the single occurrence in the GenBank dataset is from an affected individual (PM2_supporting). Single fiber testing was performed in two of the three reported individuals. In one individual, the variant was essentially present at homoplasmy in ragged red fibers (n=11) and at 62% in normal fibers (n=11, p<0.01; PMID: 14569122). In the other individual, the variant was present at 99.0 ± 0.29% (n = 9) in COX-deficient fibers compared to 87.6 ± 2.26% (n = 15) in COX-positive fibers (p<0.0008, PMID: 17825557). Additionally, there is a mouse model of this variant with features consistent with primary mitochondrial disease (PMID: 27626666) that shows improvement when heteroplasmy is shifted (PMIDs: 30250142, 34050192). The combination of strong single fiber testing and mouse model led this expert panel to increase the weight of this criterion to moderate (PS3_moderate). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_supporting, PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120587/MONDO:0044970/015 2022-10-24 2023-01-09 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:31236 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018524 infores:hetionet CHEBI:32588 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0041582 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151626 infores:hetionet CHEBI:7954 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0013404 infores:hetionet NCBIGene:8729 biolink:causes MONDO:0011675 infores:monarchinitiative not_provided not_provided HGNC:4181 MONDO:0011675 uuid:2ae2f4d9-a2d8-4750-b087-8c12ca6367a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151754 infores:hetionet CHEBI:51380 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0023530 infores:hetionet CHEBI:77260 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0000731 infores:hetionet CHEBI:9570 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0854467 infores:hetionet CAID:CA367401116 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401116 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PS3, PM5, PP4_Moderate, PP3, PP1, PM2_Supporting The c.679G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 227 (p.(Gly227Arg)) of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been identified in four individuals with hyperglycemia (PS4_Moderate; PMID: 36257325, ClinVar SCV004037051.2, internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with 2 informative meioses in two families (PP1; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.60 for donor loss, predicting that the variant disrupts the donor site of intron 6 (PP3). Furthermore, there is evidence from RNA studies that this variant results in aberrant splicing with minigene assay showing a complex alteration of residual full-length transcripts and 2 alternative transcripts (deletion of the last 4 bp of exon 6 (r.676_679del, p.Val226Alafs*67) and deletion of the last 16 bp of exon 6 (r.663_679del, p.Val222Alafs*67) (PS3; PMID 40225161). Another missense variant at the same residue that has also been shown to disrupt splicing at the same donor site, c.679G>A (p.Gly227Ser), has been interpreted as pathogenic by the ClinGen MDEP (PM5). In summary, c.679G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS3, PS4_Moderate, PM5, PP4_Moderate, PM2_Supporting, PP1, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401116/MONDO:0015967/086 2025-09-26 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:465284 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151664 infores:hetionet CHEBI:7824 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0039621 infores:hetionet CHEBI:74947 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0019270 infores:hetionet CAID:CA121994 biolink:causes MONDO:0007648 infores:clingen CAID:CA121994 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2512A>G (p.Ser838Gly) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA121994/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6904 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0012833 infores:hetionet CHEBI:553473 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0036572 infores:hetionet CHEBI:10119 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020443 infores:hetionet GO:1903224 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1903224 GO:0009790 CHEBI:17688 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0332575 infores:hetionet CHEBI:9445 biolink:causes MONDO:0041775 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C1688637 infores:hetionet CHEBI:65173 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C1168034 infores:hetionet CHEBI:46081 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C3665386 infores:hetionet CHEBI:8874 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151786 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0235069 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0235069 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027651 infores:hetionet CHEBI:63620 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0549249 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014549 infores:hetionet CHEBI:5134 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0037278 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0002871 infores:hetionet CHEBI:6717 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0040822 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0010346 infores:hetionet CHEBI:3764 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0027497 infores:hetionet CHEBI:50275 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0404521 infores:hetionet CHEBI:75998 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0878544 infores:hetionet CHEBI:77260 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151908 infores:hetionet CHEBI:8093 biolink:causes HP:0011499 infores:drugmechdb knowledge_assertion manual_agent MESH:D010656 MESH:D015878 DB00388_MESH_D015878_1 CHEBI:8871 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011603 infores:hetionet CHEBI:75998 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0013604 infores:hetionet CHEBI:45716 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0008325 infores:hetionet CHEBI:50275 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014591 infores:hetionet CHEBI:5959 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0000731 infores:hetionet CHEBI:51230 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0917801 infores:hetionet NCBIGene:286151 biolink:causes MONDO:0030523 infores:monarchinitiative not_provided not_provided HGNC:28521 MONDO:0030523 uuid:e2038ba5-8aa1-4cdc-a241-659df6f12560 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0233494 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0232492 infores:hetionet CHEBI:3996 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0004134 infores:hetionet CHEBI:3240 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0026821 infores:hetionet CHEBI:28864 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0700225 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0029878 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0948089 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027769 infores:hetionet CHEBI:92923 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0085932 infores:hetionet CAID:CA278089 biolink:causes MONDO:0015924 infores:clingen CAID:CA278089 MONDO:0015924 PMID:31797984PMID:34400635 Pathogenic PS3_Supporting, PP1, PP3, PM2_Supporting, PM5, PS4, PS2, PM1_Strong PP2, BA1, BP1, BP4, BP3, PM4, PS1, BP7, BS3, BS1 The NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln) variant is a missense variant predicted to cause an arginine to glutamine substitution at amino acid position 491. The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant co-segregated with PAH in a large Iberian family with at least four confirmed meioses (PP1; PMID: 30894412), is recurrent in more than four unrelated PAH patients (PS4; PMID: 20534176 and PMID: 29023671) and confirmed de novo in at least two probands with unaffected parents (PS2; PMID: 10903931 and PMID: 23298310). c.1472G>A resides in the conserved kinase domain of BMPR-II and changes an invariant and critical arginine residue at position 491 (PM1_Strong; PMID: 7768349, PMID: 34400635), likely impairing interaction with other BMP receptors. The functional assay evidence for a role in BMP receptor interactions was based on a PH VCEP approved luciferase activity assay but lacked known pathogenic and benign variant controls, so PS3 was scored at the supporting level (PS3_supporting; PMID: 18321866). A different amino acid change at the same position (p.Arg491Trp) was classified as pathogenic (PM5). PP3 was met based on a REVEL score of 0.962. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS2, PS3_supporting, PS4, PM1_strong, PM2_supporting, PM5, PP1, PP3 (VCEP specification version v 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA278089/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7577 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0018681 infores:hetionet CAID:CA029634 biolink:causes MONDO:0007750 infores:clingen CAID:CA029634 MONDO:0007750 PMID: Likely Benign BP4, BS1 PS4, PP4 The NM_000527.5(LDLR):c.817+9T>C variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025.The supporting evidence is as follows: BS1: PopMax FAF=0.2689% in population exomes/genomes (gnomAD v4.1.0).BP4: Not in splicing limits, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA029634/MONDO:0007750/013 2025-02-20 2025-06-17 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31401 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0267596 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151565 infores:hetionet CAID:CA212859 biolink:causes MONDO:0015152 infores:clingen CAID:CA212859 MONDO:0015152 PMID: Pathogenic PM3, PP1_Moderate, PVS1, PP4_Moderate, PM2_Supporting The NM_003494.4: c.5594del p.(Gly1865AlafsTer101) variant in DYSF, which is also known as NM_001130987.2: c.5711del (p.Gly1904fsTer101), is a frameshift variant expected to introduce a premature stop codon in exon 52/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). In the literature, this variant has also been described as p.(Gly1865AlafsTer100). Across a selection of the available literature, this variant has been reported in at least seven patients with features consistent with LGMD (PMID: 17698709, 22194990, 18853459), including in a homozygous state in two unrelated individuals without reported familial consanguinity and in two unrelated patients with known consanguinity (1.0 pt, PMID: 17698709, 22194990, 18853459; PM3). This variant was shown to segregate with autosomal recessive LGMD in at least two affected family members from a single family (PMID: 18853459; PP1_Moderate). In addition, at least one of the patients with this variant and a second presumed diagnostic DYSF allele had absent dysferlin in blood monocytes and skeletal muscle as well as a clinical diagnosis of LGMD (PMID: 22194990; PP4_Moderate, capped with PP1_Moderate). The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.00001667 (1/60000 Admixed American chromosomes), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/17/2025): PVS1, PM3, PP1_Moderate, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA212859/MONDO:0015152/180 2025-09-17 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2038 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0019112 infores:hetionet CHEBI:63598 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0037763 infores:hetionet CAID:CA024029 biolink:causes MONDO:0100150 infores:clingen CAID:CA024029 MONDO:0100150 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000540.3:c.13013_13032del p.(Ala4338Glyfs*238) variant in RYR1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 91/106 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1 is 0.000004965 (5/1006982 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤ 0.00000697) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant was found in trans with an RYR1 VUS NM_000540.3:c.1559T>C p.(Leu520Pro), in an adult woman affected with centronuclear myopathy which is highly compatible with recessive RYR1-related myopathy (PM3_Supporting, PP4, Internal VCEP contributors). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PM3_Supporting, PP4 (Congenital Myopathies VCEP specifications Version 1: 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024029/MONDO:0100150/179 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:30659 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0021359 infores:hetionet CAID:CA10602385 biolink:causes MONDO:0017623 infores:clingen CAID:CA10602385 MONDO:0017623 PMID: Likely Benign BS1 BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PP2, PP3, PP4, PP1, BS2, PM3, PM4, PM1, PM5, BP1, BP4, BP2, BP3, BA1, PS3, PS4, PS2, PS1 NM_000314.8(PTEN):c.-735G>A meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF in gnomAD for South Asians: 0.01758%.Per ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3, 1 Benign Strong = Likely Benign. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602385/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3504 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0040034 infores:hetionet CHEBI:61049 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0039231 infores:hetionet CAID:CA5416821 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416821 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.484G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Valine by Isoleucine at amino acid 162 (p.Val162Ile).The filtering allele frequency (the upper threshold of the 95% CI of 5/74888 alleles) of the c.484G>A variant in DCLRE1C is 0.00002550 for African/African American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416821/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2788 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0005741 infores:hetionet CHEBI:50173 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0392171 infores:hetionet CHEBI:63638 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0151889 infores:hetionet CHEBI:16335 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0006266 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085762 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0151825 infores:hetionet CHEBI:77260 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013456 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005790 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0019159 infores:hetionet CHEBI:6887 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009421 infores:hetionet CAID:CA415076044 biolink:causes MONDO:0010305 infores:clingen CAID:CA415076044 MONDO:0010305 PMID: Uncertain Significance BP4 BS1, PM2 The NM_005629.4:c.54G>C variant in SLC6A8 is a missense variant predicted to cause the substitution of a lysine by an asparagine at amino acid position (p.Lys18Asn). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1., the highest population allele frequency is 0.00005 (1/21835 alleles, 1 hemizygote) in the European (Non-Finnish) population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). There is a ClinVar entry for this variant (Variation ID: 655315). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen CCDS VCEP on September 23, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415076044/MONDO:0010305/027 2024-09-23 2024-09-23 X-linked inheritance HP:0001417 Inconclusive true CHEBI:28748 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020453 infores:hetionet GO:2000136 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:2000136 GO:0007507 CHEBI:50922 biolink:causes MONDO:0005032 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151468 infores:hetionet CHEBI:50173 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0162275 infores:hetionet CHEBI:17650 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0027497 infores:hetionet CAID:CA013436 biolink:causes MONDO:0005045 infores:clingen CAID:CA013436 MONDO:0005045 PMID: Likely Pathogenic PM2, PP3, PS4 PM5, PM4, PM1, PM6, PP1, PS3, BA1, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013436/MONDO:0005045/002 2021-12-09 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8665 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0002170 infores:hetionet CHEBI:5893 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013404 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0270795 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0270795 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0039971 infores:hetionet CHEBI:9086 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0278134 infores:hetionet CHEBI:75984 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0235896 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0018799 infores:hetionet CHEBI:63627 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0030554 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0456909 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0029927 infores:hetionet CAID:CA915940237 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940237 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PP1, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.1525del variant results in a frameshift (p.Gln509ArgfsTer160) with a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT15a of PMID: 29675921 meets the criteria for PP4_strong. Siblings GT15a and GT15b are both compound heterozygous for Cys400Tyr and c.1525del (PP1; PMID: 29675921). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP1, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940237/MONDO:0100326/011 2021-06-30 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UNII:15G12L5X8K biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018681 infores:hetionet CAID:CA128832 biolink:causes MONDO:0044970 infores:clingen CAID:CA128832 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PS2, PS3, PM6 The m.608A>G variant in MT-TF has been reported in one family with primary mitochondrial disease to date (PMID: 11231339). The older brother in this family had failure to thrive, chronic renal insufficiency, developmental delay, decreased limb muscle tone, muscle atrophy, myopathy, and ataxia. The younger brother had similar but milder manifestations. The variant was present at homoplasmy in both children in renal tissue and leukocytes. The variant was also homoplasmic in leukocytes from the healthy mother. This variant is absent in the GenBank dataset, there are four heteroplasmic occurrences in gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (65th percentile) but HmtVAR predicts it to be neutral with a score of 0.3. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA128832/MONDO:0044970/015 2024-07-22 2025-08-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:79699 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0004936 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0021053 infores:hetionet UMLS:C0017797 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0700590 infores:hetionet CHEBI:50131 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0009782 infores:hetionet CHEBI:49713 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0011991 infores:hetionet CHEBI:31348 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0028081 infores:hetionet CHEBI:3393 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0015967 infores:hetionet CHEBI:73274 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0011603 infores:hetionet CHEBI:3216 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1142412 infores:hetionet CHEBI:6413 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0020437 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0031046 infores:hetionet CHEBI:5130 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0039231 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0578455 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0578455 infores:hetionet CHEBI:135920 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0858635 infores:hetionet CHEBI:231594 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0002170 infores:hetionet CHEBI:5002 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0438717 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0029878 infores:hetionet CHEBI:6965 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0033117 infores:hetionet CHEBI:70746 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0042963 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001596 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020604 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0595930 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0012833 infores:hetionet CHEBI:68579 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018965 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0027051 infores:hetionet CHEBI:64321 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0311468 infores:hetionet CHEBI:6909 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0022107 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0042109 infores:hetionet CHEBI:5801 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C2363731 infores:hetionet CHEBI:63589 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020458 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0278080 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0011570 infores:hetionet CAID:CA367397245 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397245 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1270C>T variant in the glucokinase gene, GCK, causes an amino acid change of histidine to tyrosine at codon 424 (p.(His424Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.897, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 1709730, PMIDs: 27726111, 22035297, 31595705 internal lab contributors), including 3 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% as well as OGTT increment < 3 mmol/L and/or negative antibodies in untreated pediatric case) (PP4_Moderate; PMIDs: 19410318, 28726111, internal lab contributors). This variant segregated with hyperglycemia, with 4 informative meioses in 1 family (PP1_Moderate; PMIDs: 22035297). In summary, c.1270C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP1_Moderate, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397245/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Supports CHEBI:119486 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0026848 infores:hetionet NCBIGene:343450 biolink:causes MONDO:0033366 infores:monarchinitiative not_provided not_provided HGNC:18866 MONDO:0033366 uuid:ffdddbb2-ea71-4b85-9bf9-8983b8829199 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:79699 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0038999 infores:hetionet CAID:CA6832109 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832109 MONDO:0015967 PMID: Uncertain Significance PM5, BP5, PP3 PM1, BS1, PM2, PP4 The c.1556C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 519 (p.(Pro519Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.881, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Grpmax filtering allele frequency of the c.1556C>G variant in gnomAD v2.1.1 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). This variant has been observed in unknown phase in three other individuals in with variants in GCK classified as pathogenic or likely pathogenic (BP5; internal lab contributors). Another missense variant, c.1556C>T p.Pro519Leu, has been interpreted as pathogenic by the ClinGen MDEP, and p.Pro519Arg has a greater Grantham distance (PM5). In summary, c.1556C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1 approved 8/11/2023): PM5, BP5, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832109/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2850445536 biolink:causes MONDO:0015967 infores:clingen CAID:CA2850445536 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PS1, PP4 The c.864-7T>G variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 7 of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor gain, predicting that the variant disrupts the acceptor site of intron 7 of GCK (PP3). PS1_Supporting cannot be applied, as the nucleotide change c.864-7T>A, which is predicted to disrupt the intron 7 splice acceptor site to a lesser extent than c.864-7T>G, has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. While this variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.864-7T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2850445536/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:3013 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0232462 infores:hetionet CHEBI:171719 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0017178 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151883 infores:hetionet CHEBI:4856 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0522055 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0314719 infores:hetionet CHEBI:50859 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0702166 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0243026 infores:hetionet CHEBI:17303 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235195 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018939 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0017160 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0332575 infores:hetionet CHEBI:490877 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0019209 infores:hetionet CHEBI:6640 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0020598 infores:hetionet CHEBI:9241 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0234215 infores:hetionet CHEBI:15428 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C3665347 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0036974 infores:hetionet NCBIGene:7355 biolink:causes MONDO:0010478 infores:monarchinitiative not_provided not_provided HGNC:11022 MONDO:0010478 uuid:a363a28b-d8d7-4f28-88de-e5de0dfc4c50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085631 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0018129 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0018129 infores:hetionet CHEBI:8888 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2010560 infores:hetionet CAID:CA16042438 biolink:causes MONDO:0018214 infores:clingen CAID:CA16042438 MONDO:0018214 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PP1, PP4, PP2, BS2, PM6, PVS1, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1, PM3, PM4, PM1, PM5, BS1, BS4, BS3, BP5, BP7 The c.2941C>A variant in SCN1A is a missense variant predicted to cause substitution of leucine by isoleucine at amino acid 981 (p.Leu981Ile). This variant has not been reported in the published literature to date. The variant is absent in gnomAD (v2.1.1) (PM2_supporting). The computational predictor REVEL gives a score of 0.843 (PP3). Another missense variant (c.2942T>C (p.Leu981Pro) in the same codon of the same gene has been reported in a patient with Dravet syndrome (PMIDs: 28012175). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by ClinGen (Epilepsy Sodium Channel VCEP). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_supporting, PP3 (version 1.0, approved July 23, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042438/MONDO:0018214/067 2024-07-30 2024-11-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3441 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0233632 infores:hetionet CHEBI:3568 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039240 infores:hetionet CHEBI:8774 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151744 infores:hetionet CHEBI:135930 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0030252 infores:hetionet CHEBI:6888 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0030305 infores:hetionet CHEBI:119915 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0575081 infores:hetionet CHEBI:63791 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0026821 infores:hetionet CHEBI:3756 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0008031 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085584 infores:hetionet GO:0060218 biolink:causes CL:0000037 infores:ubergraph knowledge_assertion manual_agent GO:0060218 CL:0000037 CHEBI:5132 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0267596 infores:hetionet CHEBI:31711 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151786 infores:hetionet NCBIGene:51 biolink:causes MONDO:0009919 infores:monarchinitiative not_provided not_provided HGNC:119 MONDO:0009919 uuid:6a6a9b85-98b7-4985-b048-18bae5174ae3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C2830004 infores:hetionet CHEBI:36795 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020625 infores:hetionet CAID:CA042408 biolink:causes MONDO:0007750 infores:clingen CAID:CA042408 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.211G>A (p.Gly71Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001230 (0.0123%) in African/African American exomes (gnomAD v2.1.1).BP4: REVEL= 0.45, splicing evaluation required.A) variant not on limitsB) variant is exonic and at least 50bp upstream/downstream from canonical donor/acceptor site and creates AG.Score in MES: denovo_variant = 4.34. WT = 7.07. Ratio = 4.34/7.07 = 0.61 (less than 0.8). Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042408/MONDO:0007750/013 2023-03-24 2024-12-18 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15407 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0013395 infores:hetionet CHEBI:63925 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0042029 infores:hetionet CHEBI:4445 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0031350 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0005741 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0233794 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0021400 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0013295 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C1096460 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C1096460 infores:hetionet CHEBI:10650 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0014591 infores:hetionet GO:2000359 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:2000359 GO:0019953 CHEBI:175901 biolink:causes UMLS:C0853289 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0853289 infores:hetionet UNII:R15UI3245N biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0020615 infores:hetionet NCBIGene:144132 biolink:causes MONDO:0030531 infores:monarchinitiative not_provided not_provided HGNC:26532 MONDO:0030531 uuid:0eaaf847-6e20-4cae-be86-bcdd08bf188c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9316 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0033774 infores:hetionet CHEBI:6775 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002994 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151689 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005989 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0040558 infores:hetionet CHEBI:4907 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C1443060 infores:hetionet CHEBI:10127 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085641 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151888 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0032326 infores:hetionet CHEBI:51364 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0003467 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162316 infores:hetionet CHEBI:3219 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2939147 infores:hetionet CHEBI:3242 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C1443060 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0016169 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0016169 infores:hetionet CHEBI:9566 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0043094 infores:hetionet CHEBI:6801 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0242528 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022408 infores:hetionet CHEBI:66899 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0344232 infores:hetionet CHEBI:5847 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0234215 infores:hetionet CHEBI:8069 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0023380 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151477 infores:hetionet CHEBI:7581 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0041657 infores:hetionet CHEBI:30659 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0002170 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151559 infores:hetionet CHEBI:135361 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0039231 infores:hetionet CHEBI:5383 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0009676 infores:hetionet CHEBI:8888 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019079 infores:hetionet CHEBI:53760 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011175 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0541799 infores:hetionet CAID:CA285287 biolink:causes MONDO:0008723 infores:clingen CAID:CA285287 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4 PM5, PM3, BA1, BS1 The c.1001T>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of methionine by arginine at amino acid 334 (p.Met334Arg). At least one patient with this variant displayed abnormal newborn screen and follow-up acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, which is highly specific for VLCAD (PP4_supporting, PMID: 27209629) Additionally, at least six individuals with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003874 for the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.945, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA285287/MONDO:0008723/021 2024-08-13 2025-01-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6367 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151889 infores:hetionet NCBIGene:57338 biolink:causes MONDO:0011671 infores:monarchinitiative not_provided not_provided HGNC:14203 MONDO:0011671 uuid:7e7b0eb8-37be-439b-9ac2-a9addd9a46dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66919 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0919874 infores:hetionet CHEBI:135613 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0040264 infores:hetionet NCBIGene:92344 biolink:causes MONDO:0009271 infores:monarchinitiative not_provided not_provided HGNC:25676 MONDO:0009271 uuid:3a0cb1c2-a1d3-45c1-a9fd-916f20b06ad3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0438142 infores:hetionet CHEBI:9654 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0235198 infores:hetionet GO:0033635 biolink:causes GO:0009628 infores:ubergraph knowledge_assertion manual_agent GO:0033635 GO:0009628 CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0022660 infores:hetionet CHEBI:135939 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0001824 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042029 infores:hetionet CAID:CA410146757 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146757 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1405T>C (p.Ser469Pro) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score <0.5 (0.028)(BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146757/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100246 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0917801 infores:hetionet CHEBI:50924 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0039070 infores:hetionet CHEBI:3506 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0595916 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0162529 infores:hetionet CHEBI:7573 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0009806 infores:hetionet CHEBI:567361 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0006826 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013922 infores:hetionet NCBIGene:1413 biolink:causes MONDO:0012489 infores:monarchinitiative not_provided not_provided HGNC:2396 MONDO:0012489 uuid:8119ed3b-894c-4865-b5aa-d79f1ddc109a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72564 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002871 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0009450 infores:hetionet CHEBI:49960 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0030554 infores:hetionet CHEBI:114785 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0042164 infores:hetionet CHEBI:50885 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0020488 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C1956346 infores:hetionet CAID:CA10014636 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014636 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BP2, BP1, BP3, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM1, PM3, PM4, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.59-12_59-11del is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a spliceAI score under 0.20 (0.04) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 1.24 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014636/MONDO:0011071/008 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6970 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0013404 infores:hetionet CHEBI:490877 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C1262113 infores:hetionet CAID:CA220134 biolink:causes MONDO:0007893 infores:clingen CAID:CA220134 MONDO:0007893 PMID:24935154PMID:18849586PMID:18372317PMID:16638574PMID:24767283PMID:17935252PMID:12058348PMID:20883402PMID:15520399PMID:24767283PMID:17935252PMID:15520399PMID:20883402PMID:29493581PMID:19864201PMID:25884655 Pathogenic PS3, PS4, PP1_Strong, PM1, PP2, PP3, PM6_Strong PM2 The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220134/MONDO:0007893/004 2017-04-03 2019-07-15 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4953 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0029118 infores:hetionet CHEBI:5138 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040485 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0522224 infores:hetionet CHEBI:8502 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0033774 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0240417 infores:hetionet CHEBI:6149 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0428977 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0238311 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0238311 infores:hetionet CHEBI:50742 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C1443060 infores:hetionet CHEBI:66876 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0017152 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0559031 infores:hetionet CAID:CA500025 biolink:causes MONDO:0007750 infores:clingen CAID:CA500025 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP4, BP3, PS3, BS1, BS3, PM4, PVS1 The NM_000527.5(LDLR):c.1845G>A (p.Glu615=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2: The only >10,000 subpopulation is European (Non-Finnish), in which the variant is absent. So PM2 is met. PP3: No REVEL, splicing evaluation required.Functional data on splicing not available.A) variant located -3 to +6 from canonical donor siteMES scores: canonical site variant = -1.8; canonical donor wt = 4.48.Ratio: -1.8/4.48 = -0.4 ---- It is below 0.8.Variant is predicted to alter splicing. So PP3 is met. PP4: Variant meets PM2 and is identified in 1 case fulfilling Simon-Broome criteria for possible FH published in PMID: 17539906 (Taylor et al., 2007). So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA500025/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:68841 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0917801 infores:hetionet CAID:CA235336 biolink:causes MONDO:0021060 infores:clingen CAID:CA235336 MONDO:0021060 PMID: Uncertain Significance PP3, PM2_Supporting PS4 The c.1193G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by leucine at amino acid 398 (p.Arg398Leu). This variant is absent from gnomAD v2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function. The variant is also entirely conserved in the UCSC database, and Alamut does not predict an impact to splicing (PP3). This variant has been identified in at least 5 probands with variable phenotypic features, with two of them having a clinical suspicion of Noonan syndrome (PS4 not met; Rady Children's Institute for Genomic Medicine internal communications, Invitae; SCV000209025.5; SCV000207671.1; SCV000552095.2, SCV000552095.6). In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM2_Supporting, PP3. (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235336/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0019209 infores:hetionet CHEBI:52172 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030196 infores:hetionet CHEBI:52717 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0546884 infores:hetionet CHEBI:6931 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0234535 infores:hetionet CHEBI:4710 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0033774 infores:hetionet CHEBI:6775 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0014743 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0036454 infores:hetionet CAID:CA011770 biolink:causes MONDO:0005045 infores:clingen CAID:CA011770 MONDO:0005045 PMID:20641121PMID:8282798PMID:18953637PMID:27532257PMID:12084606PMID:23074333PMID:12975413PMID:20641121PMID:15358028PMID:12707239PMID:18953637PMID:8282798 Pathogenic PP1_Strong, PP3, PM6, PM1, PM2, PS4 The c.2146G>A (p.Gly716Arg) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:23074333; PMID:20641121; PMID:12084606; PMID:8282798; PMID:18953637; PMID:12707239; PMID:15358028; PMID:12975413; Partners LMM ClinVar SCV000059418.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 2 probands with hypertrophic cardiomyopathy (PM6; PMID:18953637; Partners LMM ClinVar SCV000059418.5). This variant segregated with disease in 11 affected individuals (PP1_Strong; PMID:8282798; PMID:20641121; Partners LMM ClinVar SCV000059418.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM6; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011770/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9570 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0019080 infores:hetionet CHEBI:45863 biolink:causes MONDO:0008661 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042900 infores:hetionet CHEBI:4814 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0151904 infores:hetionet CHEBI:63619 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0019209 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0854058 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0854058 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004977 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020981 infores:hetionet CHEBI:63717 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0013404 infores:hetionet CHEBI:135736 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085614 infores:hetionet CHEBI:2663 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0037036 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011551 infores:hetionet CAID:CA410147882 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147882 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1171G>A (p.Ala391Thr) is a missense variant which has a REVEL score < 0.50 (0.08), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147882/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5130 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042029 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0027769 infores:hetionet CHEBI:71941 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0011991 infores:hetionet UNII:R15UI3245N biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0020649 infores:hetionet CHEBI:70707 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0028081 infores:hetionet CAID:CA10638249 biolink:causes MONDO:0007648 infores:clingen CAID:CA10638249 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM4, PM5, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS2, PS4, PS3, PS1 The NM_004360.5(CDH1):c.*988G>A variant has an allele frequency of 0.02078 (2%, 181/8712 alleles, 1 homozygote) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10638249/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6067 biolink:causes UMLS:C0235283 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235283 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0007642 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0015423 infores:hetionet CHEBI:5818 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0085628 infores:hetionet CHEBI:75922 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0151827 infores:hetionet CHEBI:119915 biolink:causes HP:0001807 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0423820 infores:hetionet CHEBI:10023 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0039240 infores:hetionet CHEBI:2950 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0151905 infores:hetionet CHEBI:7581 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0344232 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0241705 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027651 infores:hetionet CHEBI:27690 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0085602 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042907 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0001824 infores:hetionet CAID:CA410207199 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207199 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS2, PS4, BA1, BP2, BP3, BP1, BP4, PM2, PM6, PVS1, BP7, BS1, BS3, BS4, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.620G>A (p.Arg207Gln) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207199/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71028 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0011991 infores:hetionet CHEBI:41879 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151692 infores:hetionet CHEBI:3485 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0206061 infores:hetionet CHEBI:8346 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0010200 infores:hetionet CHEBI:29007 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0008350 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0086543 infores:hetionet CAID:CA410149662 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149662 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.917G>C (p.Arg306Pro) is a missense variant which does not meet any ACMG/AMP criteria. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149662/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45951 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0033117 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0026946 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0853117 infores:hetionet CHEBI:94686 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0699744 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0919980 infores:hetionet CHEBI:7936 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015644 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0948594 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0878544 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0002871 infores:hetionet CAID:CA2602691 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602691 MONDO:0009276 PMID: Uncertain Significance BP4, PS4, BS1, PM2 The c.334C>T variant in GP9 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 112 (p.Arg112Cys). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0002283 (based on 29/90864 alleles) in the South Asian population, which is above the ClinGen PD VCEP PM2_supporting threshold (<0.0000329) but below the BS1 threshold (>0.0007). The computational predictor REVEL gives a score of 0.263, which is below the ClinGen PD VCEP PP3 threshold of <0.290 and the computational splicing predictor SpliceAI reported a delta score 0.01 for acceptor loss. This variant has been observed heterozygous in at least two macrothrombocytopenia cases but no BSS patients have been reported. In summary this variant is classified as uncertain significance for autosomal recessive Bernard Soulier syndrome, with PD VCEP specified criteria applied: NA. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602691/MONDO:0009276/083 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:72296 biolink:causes UMLS:C0919591 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0919591 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0234458 infores:hetionet CHEBI:63621 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040264 infores:hetionet CAID:CA409107443 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107443 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting PP3, BP4, PS4 The c.731T>C variant in the Hepatocyte nuclear factor 4 alpha, HNF4A, causes an amino acid change of isoleucine to threonine at codon 244 (p.(Ile244Thr)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant has a REVEL score of 0.324, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.731T>C meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107443/MONDO:0015967/085 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10100 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0917801 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0542149 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0002170 infores:hetionet CHEBI:473990 biolink:causes HP:0020071 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0042749 infores:hetionet CHEBI:10023 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014591 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1565489 infores:hetionet CAID:CA166617 biolink:causes MONDO:0100488 infores:clingen CAID:CA166617 MONDO:0100488 PMID: Likely Benign BS2 BS1, PM2, BA1 The NM_004360.5(CDH1):c.1684A>G (p.Thr562Ala) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166617/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA320255487 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255487 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.936C>T (p.Thr312=) is a synonymous variant. REVEL score not calculable, as this is a synonymous variant. SpliceAI predicts: Acceptor Loss: 0.00, Donor Loss: 0.00, Acceptor Gain: 0.00, Donor Gain: 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.171551 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255487/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47381 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014591 infores:hetionet CHEBI:161680 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0004093 infores:hetionet CAID:CA10653560 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653560 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*2320T>G is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653560/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0029261 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0010692 infores:hetionet CHEBI:50841 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C1443060 infores:hetionet NCBIGene:1278 biolink:causes MONDO:0009159 infores:monarchinitiative not_provided not_provided HGNC:2198 MONDO:0009159 uuid:b1518e59-9fa1-4486-9348-1f2ebcd4b186 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002792 infores:hetionet CHEBI:28593 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0344232 infores:hetionet CAID:CA10363173 biolink:causes MONDO:0019169 infores:clingen CAID:CA10363173 MONDO:0019169 PMID: Benign BS2, BS1 PM1, PM5, PP3, BA1, BP4, PS1, PVS1, PM2 The allele frequency of the c.999A>C variant in the PDHA1 gene is 0.044% in gnomAD, including 25 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.0092%- BS1; gnomAD >16 hemizygotes- BS2). In silico predictors provide a conflicting score (REVEL score 0.509). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BS1, BS2). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10363173/MONDO:0019169/014 2021-05-06 2021-05-06 X-linked inheritance HP:0001417 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:47780 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0010520 infores:hetionet CAID:CA191059 biolink:causes MONDO:0700272 infores:clingen CAID:CA191059 MONDO:0700272 PMID:31636395 Uncertain Significance BP1 BS1, BS3, PM2, BA1 The c.109C>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by serine at amino acid 37 (p.Arg37Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the African population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in multiple different protein assays (PMID: 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA191059/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1244050 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244050 MONDO:0005338 PMID:25524706PMID:21612213PMID:23129764PMID:36579626PMID:24333014PMID:16466712 Uncertain Significance PP3_Moderate, BS3_Supporting BP7, BS1, PM2, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.1279G>A variant in MYOC is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 427 (p.Ala427Thr). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.0001427 (13 alleles out of 91,084), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.87, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Ala427Thr protein had similar secretion levels compared to wild type myocilin protein in this study (PMID: 16466712). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. This protein has also been assessed in another solubility/secretion assay (PMID: 36579626) as well as in thermostability assays (PMIDs: 24333014, 25524706, 23129764, 21612213, 36579626). Due to indeterminate and inconsistent results, the results from the other assays have not been included as functional evidence. Only 1 segregation had been reported for primary open angle glaucoma (PMID: 12189160), not meeting the ≥ 3 segregations required for PP1. Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3_Moderate, BS3_Moderate Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244050/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:87715 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0017565 infores:hetionet NCBIGene:5351 biolink:causes MONDO:0016002 infores:monarchinitiative not_provided not_provided HGNC:9081 MONDO:0016002 uuid:0fd992f5-4b35-4f6d-8451-7592cdd39b03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013604 infores:hetionet CHEBI:404903 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0043352 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029134 infores:hetionet CHEBI:10650 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0000737 infores:hetionet CHEBI:134991 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0085633 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0851341 infores:hetionet CHEBI:453011 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0030193 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0234215 infores:hetionet CHEBI:4728 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0232493 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1609512 infores:hetionet CHEBI:16469 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0041834 infores:hetionet CHEBI:10125 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0034186 infores:hetionet CHEBI:71417 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0023467 infores:hetionet CHEBI:9086 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085641 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0015672 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235416 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0002622 infores:hetionet CHEBI:17026 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0002994 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0178298 infores:hetionet CHEBI:7577 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0017181 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0036572 infores:hetionet CHEBI:31236 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015468 infores:hetionet CHEBI:3387 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0014742 infores:hetionet CHEBI:175901 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1145670 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0750394 infores:hetionet CAID:CA400031690 biolink:causes MONDO:0100326 infores:clingen CAID:CA400031690 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting PP1 The NM_000212.3(ITGB3):c.121C>T (p.Gln41Ter) variant in exon 2/15 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It has been reported homozygous (PM3_supporting) in at least one GT proband (patient 3 in PMID: 32089034) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400031690/MONDO:0100326/011 2022-09-20 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:45783 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1167791 infores:hetionet CHEBI:17630 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0001925 infores:hetionet CAID:CA2577490157 biolink:causes MONDO:0011071 infores:clingen CAID:CA2577490157 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.806-16_806-13del is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2577490157/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410148136 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148136 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BS1, BS3, BS4, BP7, PM6, PVS1, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1098C>G (p.Ile366Met) is a missense variant which is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score <0.50 (0.451) (BP4). Additionally, there is no previous report of this variant. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148136/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52172 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030305 infores:hetionet CAID:CA011799 biolink:causes MONDO:0004994 infores:clingen CAID:CA011799 MONDO:0004994 PMID: Benign BA1, BP4 The filtering allele frequency of the c.2162+4G>A variant in the MYH7 gene is 0.75% (93/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Additionally, computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011799/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8768 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020625 infores:hetionet CAID:CA014751 biolink:causes MONDO:0005045 infores:clingen CAID:CA014751 MONDO:0005045 PMID: Pathogenic PP3, PP1_Strong, PM2_Supporting, PS4, PM5_Supporting PS3, BA1, PM4, PM1, PM6, BP3, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP5, PVS1 NM_000257.4(MYH7):c.427C>T (p.Arg143Trp) - This variant has been reported in numerous individuals with HCM, including 1 individual in which it was observed in the homozygous state (LMM data, OMGL data, PMIDs: 12820698, 12974739, 21839045, 22455086, 23711808, 24510615, 25086479, 28193612, 28771489, 30588760, 32344918) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >20]. This variant segregated with disease in >9 affected relatives from three families (PMID: 28771489, GeneDx pers. comm., OMGL pers. comm.). Therefore, the PS4_Strong and PP1_Strong criteria have been applied. It was also identified in 2 infants with DCM that had loss of function variants in MYH7 and both variants segregated with DCM in one affected infant sibling (Ambry pers. comm; LMM pers. comm.). This variant is present in gnomAD (v4.1.0), but did meet the threshold for PM2_Supporting. Another variant at this codon (p.Arg143Gln) has been identified in individuals with HCM and is classified as likely pathogenic by this VCEP (PM5_Supporting). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Pathogenic for HCM in an autosomal dominant manner based on PS4, PP1_Strong, PM2_Supporting, PM5_Supporting, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014751/MONDO:0005045/002 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63621 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0237938 infores:hetionet CHEBI:40279 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0004093 infores:hetionet CHEBI:63620 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0008031 infores:hetionet CHEBI:31949 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0030252 infores:hetionet CHEBI:16347 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0037763 infores:hetionet CHEBI:32020 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0027441 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042267 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0948595 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151883 infores:hetionet CHEBI:2636 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0015967 infores:hetionet CHEBI:80630 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151904 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0040034 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018799 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0031350 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023530 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009938 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0013687 infores:hetionet CHEBI:3176 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0037383 infores:hetionet CHEBI:45409 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0016382 infores:hetionet CHEBI:3696 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C3665386 infores:hetionet CHEBI:6413 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0033774 infores:hetionet CAID:CA414915809 biolink:causes MONDO:0010602 infores:clingen CAID:CA414915809 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM5, PM2_Supporting, PP3, PS4_Moderate The c.1244C>A (p.Ala415Asp) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3/gnomAD v4). The missense variant has a REVEL score of 0.922 (PP3, >0.6). This variant has been reported in three probands with mild and moderate hemophilia A, meeting phenotypic criteria for F8 (PP4, PS4_Moderate, PMID: 16786531). Ala415Val is a pathogenic variant at the same residue (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM5, PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414915809/MONDO:0010602/071 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:4466 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0948089 infores:hetionet CHEBI:60761 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0151798 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013146 infores:hetionet CHEBI:50648 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0234233 infores:hetionet CHEBI:2038 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0015672 infores:hetionet CAID:CA405678835 biolink:causes MONDO:0007783 infores:clingen CAID:CA405678835 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with valine at codon 4568 of the RYR1 protein, p.(Leu4568Val). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.775 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405678835/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:119915 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027066 infores:hetionet CAID:CA400024958 biolink:causes MONDO:0100326 infores:clingen CAID:CA400024958 MONDO:0100326 PMID:10891446 Pathogenic PP4_Strong, PM3, PP3, PM2_Supporting, PS3 The NM_000212.3(ITGB3):c.863T>C (p.Leu288Pro) missense variant has been identified in one compound heterozygous individual (Patient LD in PMID:10891446 which reported the variant as c.883T>C using an alternate nucleotide numbering system, confirmed in Figure 4). This patient had mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann Thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 10% (<25%), as measured by Western blot (PP4_strong). This variant was confirmed in trans with c.847_848del (classified Pathogenic by the PD VCEP; PM3) in Patient LD in PMID:10891446. A functional impact of this variant was reported in PMID: 10891446; Leu288Proβ3 cDNA was constructed and cotransfected with wild-type αIIb into COS-7 cells. Biotin surface labeling of these transiently transfected cells showed that the complex-specific antibody AP2 immunoprecipitated only trace amounts of αIIbLeu262Proβ3. Furthermore, Leu288Pro cDNA was transfected into 293 cells and showed 40-50% expression of αv-Leu288Proβ3 compared to wild type as measured by flow cytometry and transfected 293 cells with the variant were unable to interact with immobilized fibrinogen, unlike WT transfected cells which demonstrated significant adhesion and spreading to immobilized fibrinogen (PMID: 10891446: PS3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In silico predictor revealed a REVEL score of 0.99, predicting a deleterious effect (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP3, PM2_supporting, PM3, and PS3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400024958/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6909 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0002792 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1971624 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006664 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018817 infores:hetionet CAID:CA229887 biolink:causes MONDO:0009861 infores:clingen CAID:CA229887 MONDO:0009861 PMID:24705691PMID:25456745PMID:25456745 Pathogenic PM2, PP4_Moderate, PVS1, PM3_Very Strong The c.977G>A (p.Trp326Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). Classification: PathogenicSupporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229887/MONDO:0009861/006 2020-04-13 2020-04-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3223 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0040822 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0520806 infores:hetionet CHEBI:2637 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0021308 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1384353 infores:hetionet CHEBI:9168 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0039231 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0158369 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0158369 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0853149 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0042376 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0205204 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0007222 infores:hetionet CHEBI:63610 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C2830004 infores:hetionet CHEBI:82716 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0015376 infores:hetionet NCBIGene:57057 biolink:causes MONDO:0012654 infores:monarchinitiative not_provided not_provided HGNC:11598 MONDO:0012654 uuid:8737df76-c60e-41ea-9f8a-7707716110a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018188 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232492 infores:hetionet CHEBI:6539 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0235195 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0003123 infores:hetionet CAID:CA037254 biolink:causes MONDO:0007750 infores:clingen CAID:CA037254 MONDO:0007750 PMID: Uncertain Significance BS1, PP1 BA1, BP4, BP3, BP2, PS3, PS2, PS1, BS3, BS4, PM4, PM1, PM3, PM5, PM2, PM6, PVS1, PP4, BS2 The NM_000527.5(LDLR):c.1867A>G (p.Ile623Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1 and PP1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: The supporting evidence is as follows: BS1: PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1). PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037254/MONDO:0007750/013 2023-01-27 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9123 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C2225524 infores:hetionet CHEBI:52717 biolink:causes HP:0011227 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0742906 infores:hetionet GO:1904177 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:1904177 GO:0048513 CHEBI:94686 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0013395 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0392386 infores:hetionet CHEBI:4814 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0009763 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0340464 infores:hetionet CHEBI:3994 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0917801 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0038454 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006277 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0041912 infores:hetionet CAID:CA410208022 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208022 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.572G>A (p.Arg191Lys) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208022/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50841 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0013604 infores:hetionet GO:1901668 biolink:causes GO:0019430 infores:ubergraph knowledge_assertion manual_agent GO:1901668 GO:0019430 UNII:Z5N076G8YQ biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0012833 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0012833 infores:hetionet CHEBI:7476 biolink:causes HP:0001482 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151811 infores:hetionet CHEBI:7903 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0036974 infores:hetionet CHEBI:49040 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0011603 infores:hetionet CHEBI:261649 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0013395 infores:hetionet CHEBI:3638 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0020649 infores:hetionet CHEBI:17823 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0700225 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0040034 infores:hetionet CHEBI:8871 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011253 infores:hetionet CHEBI:9654 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0018794 infores:hetionet CHEBI:4995 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0017168 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232197 infores:hetionet CAID:CA410146582 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146582 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1431G>C (p.Trp477Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146582/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5856 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0004245 infores:hetionet CAID:CA8815726 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815726 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, BP4, PM3_Supporting The NM_000152.5:c.2395C>T variant in GAA is a missense variant predicted to cause substitution of His by Tyr at amino acid 799 (p.His799Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00038 (6/15954 alleles) in the African population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.443 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It only has been reported in one case as LOPD, in which has unknown phase concurrence in compound heterozygous with c.-32-13T>G (PMID: 22958975). Thus met PM3_supporting. The LOPD case has been reported to have GAA residue level 0.25 (normal cutoff unknown. But average of 20 LOPD patients is 8.35, so <10% of normal mean control level). Thus PP4_moderate is applied. There is a ClinVar entry for this variant (Variation ID: 284886, 2 star review status) with 8 submitters classifying the variant as Uncertain significance with no conflicts. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_moderate, PM3_supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP, September 5, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815726/MONDO:0009290/010 2023-09-05 2023-10-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:15765 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0017152 infores:hetionet CHEBI:3638 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0036572 infores:hetionet CHEBI:18357 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0017086 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235818 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1565489 infores:hetionet CAID:CA410208288 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208288 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.13A>G (p.Ser5Gly) is a missense variant. Multiple lines of computational evidence suggest no impact on gene /gene product (BP4). In addition, this variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208288/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10585103 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585103 MONDO:0007750 PMID: Pathogenic PVS1, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PM6, PP1, PP2, PP3, BS2 The NM_000527.5(LDLR):c.718G>T (p.Glu240Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a stop in codon 240. It is upstream of amino acid 830, so PVS1 is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2. Variant identified in 1 index case with definite heterozygous hypercholesterolemia by DLCN score from PMID: 16250003. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585103/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6367 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0025061 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0042075 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0034882 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0856088 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0856088 infores:hetionet CHEBI:64355 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018989 infores:hetionet CHEBI:85078 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0013428 infores:hetionet CHEBI:231425 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0033771 infores:hetionet NCBIGene:4646 biolink:causes MONDO:0011660 infores:monarchinitiative not_provided not_provided HGNC:7605 MONDO:0011660 uuid:a283d7dd-c542-4b45-a0eb-f5129411cb08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:184555 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0030554 infores:hetionet CHEBI:50749 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0162834 infores:hetionet CHEBI:9586 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0002962 infores:hetionet NCBIGene:10210 biolink:causes MONDO:0012367 infores:monarchinitiative not_provided not_provided HGNC:21653 MONDO:0012367 uuid:443ae6f2-9e8c-47bc-b155-0cf74af97cad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3738 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0027813 infores:hetionet CHEBI:18067 biolink:causes UMLS:C0863083 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0863083 infores:hetionet CHEBI:71223 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0042963 infores:hetionet CHEBI:404903 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0001807 infores:hetionet NCBIGene:23345 biolink:causes MONDO:0013071 infores:monarchinitiative not_provided not_provided HGNC:17089 MONDO:0013071 uuid:4ce3db49-6733-4898-a7df-73f11ed3c27e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4128 biolink:causes MONDO:0010379 infores:monarchinitiative not_provided not_provided HGNC:6833 MONDO:0010379 uuid:36fdb8d2-7c5c-4309-913a-de2d028f23f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0021368 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0426576 infores:hetionet CHEBI:70746 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0033774 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0037274 infores:hetionet CHEBI:63717 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0700225 infores:hetionet CHEBI:63605 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0041105 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0032584 infores:hetionet CHEBI:47780 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0026961 infores:hetionet CHEBI:4027 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0013604 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1696942 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1696942 infores:hetionet CHEBI:47898 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2939420 infores:hetionet CHEBI:6067 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027497 infores:hetionet CAID:CA2573157360 biolink:causes MONDO:0100083 infores:clingen CAID:CA2573157360 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.7del (p.Ser3GlnfsTer16) is a frameshift variant located in an exon that is absent from RUNX1 isoforms a and b (c.1-c.97 as per VCEP specifications) (PVS1_NA). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157360/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003467 infores:hetionet GO:2000595 biolink:causes GO:0021631 infores:ubergraph knowledge_assertion manual_agent GO:2000595 GO:0021631 CAID:CA512318934 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318934 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, PVS1, PM6, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.189C>A (p.Ala63=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318934/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7476 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0016204 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0030920 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020538 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0152025 infores:hetionet CHEBI:10125 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0025323 infores:hetionet CAID:CA410147459 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147459 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1298C>G (p.Thr433Ser) is a missense variant which has a REVEL score < 0.50 (0.16) and a SpliceAI score ≤ 0.20 (0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147459/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4909 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0011606 infores:hetionet CHEBI:4672 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151744 infores:hetionet NCBIGene:23414 biolink:causes MONDO:0014480 infores:monarchinitiative not_provided not_provided HGNC:16700 MONDO:0014480 uuid:3633b702-d5e2-41ac-9043-7b2e8bb3c7b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63581 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0023895 infores:hetionet CAID:CA359431210 biolink:causes MONDO:0012163 infores:clingen CAID:CA359431210 MONDO:0012163 PMID: Likely Pathogenic PM2_Supporting, PVS1 BS2 The c.704C>G (p.Ser235Ter)(NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has not been identified in the literature to our knowledge. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359431210/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4974 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0085593 infores:hetionet CHEBI:49662 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C2242737 infores:hetionet NCBITaxon:121752 biolink:causes MONDO:0001616 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:121752 MONDO:0001616 CHEBI:8888 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037199 infores:hetionet CAID:CA386941334 biolink:causes MONDO:0015967 infores:clingen CAID:CA386941334 MONDO:0015967 PMID: Uncertain Significance PVS1_Supporting, PM2, BS2 The c.1873C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 625 (p.(Gln625Ter)) of NM_000545.8. This nonsense variant, located 3’ of codon 601 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript nor to significantly disrupt the transactivation domain of the protein (PVS1_Supporting). There is insufficient clinical evidence that variants in this region lead to a monogenic diabetes phenotype. Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in a normoglycemic individual 70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2; internal lab contributors). In summary, c.1873C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1_Supporting, PM2_Supporting, BS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386941334/MONDO:0015967/017 2022-04-17 2022-04-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45863 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0024312 infores:hetionet CHEBI:51860 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0858635 infores:hetionet CHEBI:27565 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0042075 infores:hetionet CHEBI:63617 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C2979982 infores:hetionet CHEBI:51380 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0232462 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0001622 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235030 infores:hetionet CHEBI:10124 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0012569 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0002170 infores:hetionet CHEBI:63791 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2364111 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0028643 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0039971 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003864 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0020538 infores:hetionet CHEBI:5790 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0034063 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0020649 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0233414 infores:hetionet CHEBI:7494 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1167965 infores:hetionet CHEBI:63617 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0009676 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0043246 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033117 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027051 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0037199 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0746883 infores:hetionet CHEBI:61049 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0206062 infores:hetionet CHEBI:3423 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0007859 infores:hetionet CHEBI:79699 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0542571 infores:hetionet CHEBI:92998 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0043352 infores:hetionet CHEBI:36795 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0016382 infores:hetionet CHEBI:5002 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0016382 infores:hetionet CHEBI:50275 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0043094 infores:hetionet CHEBI:71941 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0027497 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0011991 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0003123 infores:hetionet CHEBI:3698 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0231528 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0027769 infores:hetionet CHEBI:63620 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0338831 infores:hetionet CHEBI:63580 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151636 infores:hetionet CHEBI:94392 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0030554 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C1510472 infores:hetionet CAID:CA10385244 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385244 MONDO:0100437 PMID: Benign BP3, BA1 PM2, BS1 NM_001034853.2(RPGR):c.2820_2840dup (p.Asp943_Glu949dup) is a short in-frame insertion of 21 base pairs that encode additional residues between amino acids 947 and 948 within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v.4.1.0 at a frequency of 0.04787 among hemizygous individuals, with 23,809 variant alleles / 596,268 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385244/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:9907 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0000729 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0014130 infores:hetionet CHEBI:9139 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0000737 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0015397 infores:hetionet NCBIGene:79147 biolink:causes MONDO:0011787 infores:monarchinitiative not_provided not_provided HGNC:17997 MONDO:0011787 uuid:5fdc6d4a-98d1-45d9-a3e2-c568d7ab440e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1142135 infores:hetionet CHEBI:45783 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0041657 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0012833 infores:hetionet NCBIGene:2997 biolink:causes MONDO:0012693 infores:monarchinitiative not_provided not_provided HGNC:4706 MONDO:0012693 uuid:993d7940-1b86-422a-ad22-5fb78a7377d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0030554 infores:hetionet CHEBI:209807 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C1257843 infores:hetionet NCBIGene:51684 biolink:causes MONDO:0033309 infores:monarchinitiative not_provided not_provided HGNC:16466 MONDO:0033309 uuid:5bbb0505-7f1d-4da9-b3d8-5b06d915bb6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0037199 infores:hetionet CHEBI:2611 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0011551 infores:hetionet NCBIGene:112476 biolink:causes MONDO:0100352 infores:monarchinitiative not_provided not_provided HGNC:30500 MONDO:0100352 uuid:3a25cebb-200a-451c-802a-e3c009fe4500 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8232 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0018681 infores:hetionet CHEBI:6970 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0006266 infores:hetionet CHEBI:63612 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0520966 infores:hetionet CHEBI:64312 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017181 infores:hetionet CHEBI:36704 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C2242737 infores:hetionet CHEBI:36704 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0022603 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0919980 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0029408 infores:hetionet CHEBI:3403 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0011991 infores:hetionet CHEBI:15940 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0043352 infores:hetionet GO:0008359 biolink:causes GO:0048599 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0048599 CHEBI:63598 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0036454 infores:hetionet CHEBI:7798 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0340865 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0030305 infores:hetionet CHEBI:9757 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0344232 infores:hetionet CHEBI:3568 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003811 infores:hetionet CHEBI:63631 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0038220 infores:hetionet CAID:CA515708874 biolink:causes MONDO:0100437 infores:clingen CAID:CA515708874 MONDO:0100437 PMID: Likely Benign PM2_Supporting, BP4, BP7 NM_001034853.2(RPGR):c.3451T>C (p.Leu1151=) is a synonymous variant at codon 1151 within exon 15 of 15, with no predicted impact on splicing (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, BP4 and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA515708874/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:10124 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151849 infores:hetionet CHEBI:9943 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151636 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0038367 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030353 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0243026 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0234215 infores:hetionet CHEBI:499361 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0003467 infores:hetionet CHEBI:4530 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C1443060 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010650 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010650 uuid:2ed70f6b-bb5e-4839-92ec-9caec4c8dd45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C1443060 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0948586 infores:hetionet CHEBI:63598 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0086565 infores:hetionet NCBIGene:3909 biolink:causes MONDO:0030746 infores:monarchinitiative not_provided not_provided HGNC:6483 MONDO:0030746 uuid:fd0aac8b-9835-402f-95a0-7c8308127260 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231594 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0549310 infores:hetionet CHEBI:75984 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0220870 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0037274 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0020538 infores:hetionet CHEBI:80630 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0017181 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0009450 infores:hetionet CHEBI:77260 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0036974 infores:hetionet GO:0007596 biolink:causes MONDO:0005279 infores:drugmechdb knowledge_assertion manual_agent GO:0007596 MESH:D011655 DB00682_MESH_D011655_1 CHEBI:9943 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011168 infores:hetionet NCBIGene:5917 biolink:causes MONDO:0014506 infores:monarchinitiative not_provided not_provided HGNC:9870 MONDO:0014506 uuid:c6be7a0e-f6a7-4630-a375-c5feb0b63e67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0039621 infores:hetionet CHEBI:8107 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2242588 infores:hetionet CHEBI:18248 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0015230 infores:hetionet CHEBI:102216 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0085631 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0342579 infores:hetionet CHEBI:6887 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0001807 infores:hetionet CHEBI:48131 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0004096 infores:hetionet CHEBI:64317 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0004093 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233472 infores:hetionet CHEBI:6970 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0231528 infores:hetionet CHEBI:94807 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0039231 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0027765 infores:hetionet CHEBI:44185 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004604 infores:hetionet CHEBI:3650 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0853026 infores:hetionet CHEBI:6909 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0036974 infores:hetionet CHEBI:94501 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0015371 infores:hetionet CHEBI:27899 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0231528 infores:hetionet CHEBI:5128 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0003467 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0041912 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0016167 infores:hetionet CHEBI:31623 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0019348 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0234215 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0017178 infores:hetionet NCBIGene:10195 biolink:causes MONDO:0010998 infores:monarchinitiative not_provided not_provided HGNC:23056 MONDO:0010998 uuid:f34719b1-3588-4e3b-8326-ed260c783f2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0474378 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0012833 infores:hetionet CHEBI:91541 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0043352 infores:hetionet CAID:CA9870497 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870497 MONDO:0015967 PMID: Likely Benign BP4, BS1, BP5 PP4, PS4 The c.1199G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 400 (p.(Arg400Gln)) of NM_175914.5. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009487, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar Variation ID: 1411449, internal lab contributors). Several of these individuals have antibody-negative diabetes; however, the calculated MODY probability is <50% (internal lab contributors). Additionally, this variant is predicted to be benign by computational evidence, with a REVEL score of 0.06199, which is less than the MDEP threshold of 0.15 (BP4). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor). In summary, this variant meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BP4, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870497/MONDO:0015967/085 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63630 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1956346 infores:hetionet NCBIGene:168507 biolink:causes MONDO:0014967 infores:monarchinitiative not_provided not_provided HGNC:18053 MONDO:0014967 uuid:004d12d8-5c95-49f8-9dcc-b80fe4db3584 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151763 infores:hetionet CHEBI:51041 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0040485 infores:hetionet CHEBI:7640 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0023530 infores:hetionet CHEBI:31536 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0853034 infores:hetionet CHEBI:71941 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0012833 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0235431 infores:hetionet CHEBI:100246 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C2973529 infores:hetionet CHEBI:3077 biolink:causes HP:0025560 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0423282 infores:hetionet CHEBI:92712 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0011175 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042373 infores:hetionet CHEBI:3216 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0016204 infores:hetionet CHEBI:7465 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0000729 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0392386 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0863090 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0863090 infores:hetionet CAID:CA386964629 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964629 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3, PP1 PS4, PP2 The c.637A>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to phenylalanine at codon 213 (p.(Ile213Phe)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.87, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified an an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant was identified in one family with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors, PMID:36257325, PMID:23348805). In summary, c.637A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PP4_Moderate, PP1, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964629/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36704 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0232462 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0036572 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027441 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0011570 infores:hetionet CHEBI:42797 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015967 infores:hetionet CHEBI:28787 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0162820 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037023 infores:hetionet CHEBI:135939 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0004093 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0235750 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0278008 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0281803 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0281803 infores:hetionet CHEBI:60761 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0017675 infores:hetionet CHEBI:3061 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0152030 infores:hetionet CHEBI:114785 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0018926 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0011603 infores:hetionet CHEBI:9649 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0014518 infores:hetionet CHEBI:145499 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151907 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003123 infores:hetionet CHEBI:71940 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0344232 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0010709 infores:hetionet CHEBI:681848 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0042510 infores:hetionet CHEBI:9288 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0017979 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020649 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018799 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038814 infores:hetionet CAID:CA410206704 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206704 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.780C>A (p.Asn260Lys) is a missense variant. Multiple lines of computational evidence (REVEL: 0.401. SpliceAI: Δ score 0.01) suggest no impact on gene /gene product (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206704/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes HP:0041055 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020162 infores:hetionet CHEBI:94440 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0424295 infores:hetionet CHEBI:7447 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0011603 infores:hetionet CHEBI:119486 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020580 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009806 infores:hetionet CHEBI:4659 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0029134 infores:hetionet CHEBI:31625 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0015397 infores:hetionet CHEBI:4876 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0034152 infores:hetionet CHEBI:84500 biolink:causes HP:0011227 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0742906 infores:hetionet NCBITaxon:6334 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6334 GO:0006954 DB01234_MESH_D014235_1 CHEBI:46557 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0011570 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0235431 infores:hetionet CHEBI:63619 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0026821 infores:hetionet CHEBI:7865 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0746961 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0016385 infores:hetionet CAID:CA410202694 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202694 MONDO:0011071 PMID: Likely Pathogenic PM1, PM5, PM2_Supporting, PP3 PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP7, PM4, PM3, PP4, PP2, PP1 NM_001754.5(RUNX1):c.400G>A (p.Ala134Thr) is a missense variant which affects a hotspot residue within the Runt Homology Domain (RHD): A134 (PM1). This variant is a missense change at the same residue where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468), with RNA data or agreement in splicing predictors (SSF and MES) showing no splicing effects (PM5). It has a REVEL score ≥ 0.88 (0.961) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5, PP3, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202694/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CAID:CA397397285 biolink:causes MONDO:0100438 infores:clingen CAID:CA397397285 MONDO:0100438 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_014336.5(AIPL1):c.216G>A (p.Trp72Ter) is a nonsense variant that introduces a premature stop codon into exon 2 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), severely reduced central visual acuity (1 pt), kinetic visual field extent (V-4e) undetectable (1 pt), nystagmus (1 pt), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 5 points, PMID: 20702822, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397397285/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:180905 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0043352 infores:hetionet CHEBI:31625 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0036454 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0159039 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0159039 infores:hetionet GO:0030860 biolink:causes GO:0001738 infores:ubergraph knowledge_assertion manual_agent GO:0030860 GO:0001738 CAID:CA345150874 biolink:causes MONDO:0100084 infores:clingen CAID:CA345150874 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS2 PS4 The c.172G>A variant in ACTA 1 is a missense variant predicted to cause a substitution of aspartic acid by asparagine at amino acid position 58. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.7 set by the CM VCEP (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant was observed to occur de novo in a proband with congenital hypotonia, muscle weakness, failure to thrive, poor feeding, developmental delay and normal creatine kinase levels (PS2, SCV000934090.3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345150874/MONDO:0100084/147 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41423 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0022893 infores:hetionet CAID:CA10014213 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014213 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1062C>G (p.Thr354=) is a synonymous variant that does not have a REVEL score and SpliceAI score is ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain meeting BP4 ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014213/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8356 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0008489 infores:hetionet CAID:CA413497183 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497183 MONDO:0010315 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.175G>T (p.Glu59Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497183/MONDO:0010315/129 2024-06-12 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:125354 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0332534 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006952 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0035344 infores:hetionet CHEBI:68642 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0027441 infores:hetionet CHEBI:5864 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0392699 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235969 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0019158 infores:hetionet CHEBI:16469 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0700590 infores:hetionet CHEBI:8888 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2129214 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042109 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0038454 infores:hetionet NCBIGene:27341 biolink:causes MONDO:0030339 infores:monarchinitiative not_provided not_provided HGNC:24286 MONDO:0030339 uuid:4a5254d6-1064-4071-9989-8433ba8d2140 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes MONDO:0011972 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0085083 infores:hetionet CHEBI:45924 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0018965 infores:hetionet CHEBI:52172 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0006277 infores:hetionet CHEBI:8207 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0003811 infores:hetionet CHEBI:53691 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0541782 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0221752 infores:hetionet UMLS:C0145867 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C2242996 infores:hetionet CHEBI:87715 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0004093 infores:hetionet CHEBI:7581 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0033774 infores:hetionet CHEBI:31711 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0007859 infores:hetionet CHEBI:71940 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0035243 infores:hetionet UMLS:C0903898 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0687713 infores:hetionet CHEBI:15553 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0012569 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0853619 infores:hetionet CHEBI:2379 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0085633 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0231170 infores:hetionet CHEBI:35677 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0011615 infores:hetionet CHEBI:28901 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0026896 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0018802 infores:hetionet CHEBI:63621 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0232488 infores:hetionet CHEBI:31536 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0030554 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001134 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0085580 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151971 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0274702 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0274702 infores:hetionet CHEBI:47426 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0011603 infores:hetionet CHEBI:5134 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0039240 infores:hetionet CHEBI:3216 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0600142 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0423008 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0423008 infores:hetionet CHEBI:6775 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013447 infores:hetionet CHEBI:175901 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0015672 infores:hetionet CHEBI:48669 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0002792 infores:hetionet CHEBI:74947 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0019209 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235290 infores:hetionet CHEBI:5134 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C2363731 infores:hetionet CHEBI:9434 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013404 infores:hetionet NCBIGene:4613 biolink:causes MONDO:0008115 infores:monarchinitiative not_provided not_provided HGNC:7559 MONDO:0008115 uuid:eba6173f-e9b4-4199-89d4-e31375864b78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0404521 infores:hetionet CHEBI:51860 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0311468 infores:hetionet CHEBI:50742 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0231218 infores:hetionet NCBIGene:23479 biolink:causes MONDO:0009706 infores:monarchinitiative not_provided not_provided HGNC:29882 MONDO:0009706 uuid:3285b2b7-0022-47f5-bfd0-70a0e1cb31f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0004604 infores:hetionet CHEBI:5130 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002994 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019360 infores:hetionet CHEBI:47426 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0040053 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0022408 infores:hetionet CHEBI:35778 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0008031 infores:hetionet CHEBI:6437 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0018681 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0006848 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0006848 infores:hetionet CHEBI:10119 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0086439 infores:hetionet CHEBI:63115 biolink:causes MONDO:0019383 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0014059 infores:hetionet CHEBI:6437 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0017178 infores:hetionet CHEBI:31859 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0041969 infores:hetionet CHEBI:45409 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C3263723 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0403632 infores:hetionet CHEBI:2682 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0038002 infores:hetionet UMLS:C0657912 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242301 infores:hetionet CHEBI:135930 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151480 infores:hetionet CHEBI:47898 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027796 infores:hetionet GO:0030710 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0030710 GO:0019953 CHEBI:63637 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C1384353 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0040034 infores:hetionet CAID:CA114133 biolink:causes MONDO:0019565 infores:clingen CAID:CA114133 MONDO:0019565 PMID: Uncertain Significance PP3, PP4, PS3, BP5, BS1, PM5_Supporting PM6, PS4 The NM_000552.5:c.4196G>A variant in VWF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1399. The Arg1399His variant has a relatively high Grpmax filtering allele frequency in gnomAD v4.1 of 0.01289 (based on 15410/1179858 alleles in the European non-Finnish population), which is higher than the ClinGen VWD VCEP threshold (>0.01; BS1). At least 4 patients with this variant displayed excessive mucocutaneous bleeding as well as the laboratory phenotype of an abnormal collagen binding assay, which together are consistent with VWD Type 2M (PP4, PS4_Moderate), however, all patients exhibited a VWF:RCo/VWF:Ag ratio between 0.7 and 1.5 (PMID: 22507569, PMID: 28083987, PMID: 28971901). This variant has also been observed in at least 2 patients with an alternate molecular basis for disease, one of whom exhibited VWD Type 2B phenotypes and harbored the c.3916C>T (p.Arg1306Trp) variant in cis (PMID: 1672694), which is classified as pathogenic for VWD Type 2B by the ClinGen VWD VCEP. The second patient exhibited a VWD Type 2M phenotype and harbored this variant as well as the c.4225G>T (p.Val1409Phe) variant, which is classified as likely pathogenic for VWD Type 2M by the ClinGen VWD VCEP (PMID: 28971901). The computational predictor REVEL gives a score of 0.698, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Another missense variant in the same codon, NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys), has been reported in multiple patients with VWD Type 2M (PMID: 17000885, PMID: 26988807, PMID: 28083987). This variant has been classified as likely pathogenic by the ClinGen VWD VCEP (PM5_supporting). Multiple functional studies show a deleterious effect on protein function, including a hydrodynamic mouse model showing >75% loss of both collagen 4 binding and platelet adhesion PMID: 25662333) and a knock-in mouse model showing decreased VWF binding to collagen IV but not collagen III, decreased platelet adhesion, and increased bleeding, indicating a hypomorphic effect (PMID: 30565388). Exogenous expression of the p.Arg1399His mutant in 293 cells identified undetectable binding to type VI (PMID: 22507569) and type IV collagen (PMID: 25662333) (PS3). In summary, this variant meets the criteria to be classified as a Variant of Unknown Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PM5_supporting, PP3, PP4, BP5, BS1. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114133/MONDO:0019565/090 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA8602464 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602464 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PP4 The c.3061-4C>T variant in ITGA2B is an intronic variant located in intron 29. The variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of 1.44101 (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006687 (3/44864 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating in GT patients were found in the literature. Due to conflicting evidence, this variant is classified as likely benign for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BP4, BP7 and PM2_Supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602464/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:42944 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0041969 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0234913 infores:hetionet CHEBI:8430 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0037383 infores:hetionet CHEBI:6950 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0235198 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0002871 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0032584 infores:hetionet CHEBI:63627 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0037036 infores:hetionet CHEBI:35854 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0917801 infores:hetionet CAID:CA915940251 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940251 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PP1_Strong PP3 The ITGA2B intronic variant NM_000419.5:c.1210+5G>A is located proximal to a splice donor site, however in silico tools do not agree on the predicted effect on splicing. This variant has been observed in homozygosity (PM3_supporting) in an individual with Glanzmann's thrombasthenia (GT) (GT-01 in PMID: 30792900), as well as at least six affected family members (PP1_strong). At least one proband (https://doi.org/10.1182/blood-2023-182694) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent or reduced, as measured by flow cytometry. The highest population minor allele frequency in gnomAD v4.1.0 is 8.482e-7 (1/1179018 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PP1_strong, PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940251/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:37924 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0029118 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020615 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0233632 infores:hetionet CHEBI:171719 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013404 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020437 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013395 infores:hetionet CAID:CA251537 biolink:causes MONDO:0009861 infores:clingen CAID:CA251537 MONDO:0009861 PMID: Pathogenic PM2, PP4, PP1, PM3_Very Strong PS3 The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID: 23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID: 8659548), F55fsdelT (2 patients, PMID: 15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID: 23430918). There is cosegregation with disease in affected siblings in 2 families PMID: 2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251537/MONDO:0009861/006 2020-03-27 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6444 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0003578 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017160 infores:hetionet CHEBI:6129 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235996 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0235431 infores:hetionet CHEBI:50885 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0700590 infores:hetionet CHEBI:6950 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0235437 infores:hetionet CHEBI:9907 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0206062 infores:hetionet CHEBI:28748 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0043094 infores:hetionet NCBIGene:23262 biolink:causes MONDO:0032740 infores:monarchinitiative not_provided not_provided HGNC:29035 MONDO:0032740 uuid:666a86de-f24a-432e-ad5a-b72cee584dce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes UMLS:C3160770 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C3160770 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0853697 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0262385 infores:hetionet CHEBI:4024 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0018524 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001538 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0162291 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042109 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0521839 infores:hetionet NCBIGene:2121 biolink:causes MONDO:0009162 infores:monarchinitiative not_provided not_provided HGNC:3497 MONDO:0009162 uuid:72694c45-4844-4e14-a9dc-6a93a4af40f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0004093 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0853813 infores:hetionet GO:0006954 biolink:causes MONDO:0004855 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D013717 DB01234_MESH_D013717_1 CAID:CA2580100844 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100844 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, BP3 NM_001034853.2(RPGR):c.2820_2840del (p.Gly941_Glu947del) is a short in-frame deletion of 21 base pairs encoding amino acids 941 through 947 and is located within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is absent from hemizygotes in gnomAD v4.1.0. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and BP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100844/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Inconclusive true CHEBI:50729 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0041956 infores:hetionet CAID:CA413497314 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497314 MONDO:0010315 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.116-2A>G (NM_000206.3) variant in IL2RG occurs within the canonical acceptor splice site (-2) of intron 1. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 2, resulting in a frameshift (p.Asp39Glyfs*57) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497314/MONDO:0010315/129 2024-06-13 2024-06-14 X-linked inheritance HP:0001417 Supports NCBIGene:64087 biolink:causes MONDO:0008862 infores:monarchinitiative not_provided not_provided HGNC:6937 MONDO:0008862 uuid:757b5e8f-34f7-4311-8c60-75b3f1d6b9e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31949 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0018681 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004690 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0027932 infores:hetionet CHEBI:127342 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027849 infores:hetionet NCBITaxon:848 biolink:causes MONDO:0006865 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:848 MESH:D005892 DB00257_MESH_D005892_1 CHEBI:2666 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0036974 infores:hetionet NCBIGene:84081 biolink:causes MONDO:0859275 infores:monarchinitiative not_provided not_provided HGNC:25305 MONDO:0859275 uuid:b85da033-fa53-487a-8aa6-247fad6fa799 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5100 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0151798 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0948089 infores:hetionet CHEBI:231594 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0018681 infores:hetionet CHEBI:9667 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0240735 infores:hetionet CHEBI:31711 biolink:causes MONDO:0021553 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026976 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0240322 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0004936 infores:hetionet CHEBI:8499 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0022107 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0403632 infores:hetionet CHEBI:6367 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004604 infores:hetionet CHEBI:71223 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0006826 infores:hetionet CHEBI:28748 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0015672 infores:hetionet CHEBI:9571 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0041657 infores:hetionet CHEBI:17347 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151904 infores:hetionet CAID:CA405664296 biolink:causes MONDO:0018493 infores:clingen CAID:CA405664296 MONDO:0018493 PMID: Likely Pathogenic PS4_Supporting, PM5, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 2163 of the RYR1 protein, p.(Arg2163Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two individuals with personal or family history of an MH episode without positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4_Sup (PMID: 32919876, personal communication). No functional studies were identified for this variant. Another variant assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.926) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Sup, PM1_Sup, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405664296/MONDO:0018493/012 2023-12-15 2023-12-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:5134 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0162835 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0234215 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018418 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0019054 infores:hetionet CAID:CA400030376 biolink:causes MONDO:0100326 infores:clingen CAID:CA400030376 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1690G>C (p.Gly564Arg) missense variant has been reported in one patient, GT3 (of PMID: 32237906) with mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.61%, as measured by flow cytometry. GT3 of PMID: 32237906 is compound heterozygous for this variant and a pathogenic variant (c.361+1G>A) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1 is 8.475e-7 (1/1179884 alleles) in the European Non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.749, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_moderate, PM3_supporting, PM2_supporitng, PP3. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400030376/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6954 biolink:causes UMLS:C0858226 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0858226 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013395 infores:hetionet CHEBI:68579 biolink:causes MONDO:0004822 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0006267 infores:hetionet GO:1901163 biolink:causes GO:0007565 infores:ubergraph knowledge_assertion manual_agent GO:1901163 GO:0007565 CHEBI:2569 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0151828 infores:hetionet CHEBI:49713 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0018524 infores:hetionet CHEBI:47381 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0853034 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0020649 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0037199 infores:hetionet GO:0021914 biolink:causes GO:0021511 infores:ubergraph knowledge_assertion manual_agent GO:0021914 GO:0021511 UNII:G4PX8C4HKV biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0030196 infores:hetionet CHEBI:7494 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020453 infores:hetionet CHEBI:7025 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0033774 infores:hetionet CHEBI:50730 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0040586 infores:hetionet CHEBI:9907 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0235896 infores:hetionet CHEBI:6532 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0004093 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0009450 infores:hetionet CHEBI:145499 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0558401 infores:hetionet CHEBI:37941 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0014591 infores:hetionet CHEBI:10124 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0002994 infores:hetionet CHEBI:5127 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0442886 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0004936 infores:hetionet CHEBI:10650 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085602 infores:hetionet CAID:CA060268 biolink:causes MONDO:0017623 infores:clingen CAID:CA060268 MONDO:0017623 PMID: Likely Benign PM2, BP7, BP4 PTEN c.577C>T (p.Leu193=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent) and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA060268/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0120107 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0011603 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0043250 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1384353 infores:hetionet NCBIGene:6201 biolink:causes MONDO:0012939 infores:monarchinitiative not_provided not_provided HGNC:10440 MONDO:0012939 uuid:f333e271-254d-44f7-9407-d3c0919081d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA344821 biolink:causes MONDO:0044970 infores:clingen CAID:CA344821 MONDO:0044970 PMID: Benign BA1, BP4 PP3, PS2, PS3, PS4, PM2, PM6 The m.12811T>C (p. Y159H) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 17, 2023. This variant has not been reported in the medical literature as an individual cause of primary mitochondrial disease to our knowledge. However, there are nine cases reported that have this variant and the common Leber Hereditary Optic Neuropathy (LHON) variant, m.11778G>A, and one case with this variant and the m.3460G>A common LHON variant (PMIDs: 17406640, 17434142, 19026397). While this variant has been reported to be a modifier or secondary variant for LHON, assessment of such variants is outside the scope of this curation. The computational predictor APOGEE gives a consensus rating of 0.32 (Min=0, Max=1), supporting a neutral effect of this variant on function (BP4). This variant is present in population databases including MITOMAP’s GenBank sequences (674/59,389; 1.135%), in the Helix dataset (1,274/195,983; 0.650%; includes 1274 homoplasmic occurrences and 14 heteroplasmic occurrences and seen in haplogroups H, M, A, K, W, D, L2, T), and in gnomAD v3.1.2 (328/56,429; 0.581%; includes 328 homoplasmic occurrences across individuals of East Asian, European (non-Finnish), Latino, and South Asian descent; BA1). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4, BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA344821/MONDO:0044970/015 2023-04-17 2023-05-19 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8871 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0032290 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0018802 infores:hetionet NCBIGene:79092 biolink:causes MONDO:0011269 infores:monarchinitiative not_provided not_provided HGNC:16446 MONDO:0011269 uuid:4c507131-2947-48e8-a30e-290e7aed3c7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0023530 infores:hetionet CHEBI:66919 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0027947 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042075 infores:hetionet CHEBI:27470 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C1325847 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0020517 infores:hetionet CHEBI:30830 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027441 infores:hetionet CHEBI:8028 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0085649 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0035078 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0018801 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0009806 infores:hetionet CHEBI:9123 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1456784 infores:hetionet CHEBI:63632 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0020580 infores:hetionet CHEBI:134966 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C1384353 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004830 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015645 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0039971 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0234215 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0041969 infores:hetionet CHEBI:28830 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0038362 infores:hetionet CAID:CA367398819 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398819 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting PS4, PP4 The c.1129C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 377 (p.(Arg377Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in a family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors). Another missense variant, c.1129C>T p.Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377Ser) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398819/MONDO:0015967/086 2023-09-20 2023-09-20 Semidominant inheritance HP:0032113 Supports CHEBI:5165 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151559 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0042514 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0017566 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0034150 infores:hetionet CAID:CA512318790 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318790 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BP1, BP3, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.361C>T (p.Leu121=) is synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318790/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6754 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0002792 infores:hetionet CHEBI:3077 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0231218 infores:hetionet CHEBI:6822 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C2830004 infores:hetionet CHEBI:16347 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0030554 infores:hetionet CHEBI:73274 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0036974 infores:hetionet CHEBI:3393 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0042267 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0521839 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0023533 infores:hetionet CHEBI:78543 biolink:causes UMLS:C3495797 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C3495797 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0038826 infores:hetionet CHEBI:7956 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0178298 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0034065 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0227791 infores:hetionet CAID:CA229374 biolink:causes MONDO:0009861 infores:clingen CAID:CA229374 MONDO:0009861 PMID:16256386 Likely Pathogenic PM2, PM5, PP3, PP4 This c.1184C>A (p.Ala395Asp) variant in PAH was reported in 1 patient with PAH deficiency (>1200 μmol/L Phe) (PMID 16256386). This variant was found at an amino acid residue where p.Ala395Pro, a pathogenic missense variant has been seen before. Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3, PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229374/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63611 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038363 infores:hetionet CHEBI:36791 biolink:causes HP:0041220 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0159321 infores:hetionet CAID:CA410206789 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206789 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.739C>T (p.Pro247Ser) is a missense variant which has a REVEL score < 0.50 (0.341), and a SpliceAI score ≤ 0.20 (0.02) (BP4).This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206789/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:8NZ41MIK1O biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C1443060 infores:hetionet CHEBI:134991 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0031350 infores:hetionet GO:0099106 biolink:causes GO:0034220 infores:ubergraph knowledge_assertion manual_agent GO:0099106 GO:0034220 CHEBI:119573 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0023380 infores:hetionet CAID:CA512341080 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341080 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 Synonymous variant (no REVEL score applicable), and SpliceAI score is ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.878 (< 2.0)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341080/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4702 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0042029 infores:hetionet CHEBI:5103 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0008031 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0015397 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0858797 infores:hetionet CHEBI:36795 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0014591 infores:hetionet CHEBI:5893 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0016655 infores:hetionet CHEBI:2611 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0023380 infores:hetionet CHEBI:16714 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0020458 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020456 infores:hetionet CHEBI:7824 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0003862 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0424823 infores:hetionet CHEBI:5106 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0032231 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011616 infores:hetionet CHEBI:6832 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0027424 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020538 infores:hetionet CHEBI:3568 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042029 infores:hetionet NCBITaxon:1639 biolink:causes MONDO:0006836 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1639 MESH:D008584 DB01053_MESH_D008584_1 GO:0160068 biolink:causes GO:0009856 infores:ubergraph knowledge_assertion manual_agent GO:0160068 GO:0009856 CHEBI:6965 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0241442 infores:hetionet CHEBI:681569 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0085593 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0003123 infores:hetionet CHEBI:3814 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0004604 infores:hetionet CHEBI:8382 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0000731 infores:hetionet NCBIGene:81848 biolink:causes MONDO:0014102 infores:monarchinitiative not_provided not_provided HGNC:15533 MONDO:0014102 uuid:5c86e4cf-bd61-42f9-9be1-76ab28bda355 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48538 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0018524 infores:hetionet CHEBI:3752 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0040128 infores:hetionet CHEBI:72564 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0023530 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0026946 infores:hetionet CHEBI:93635 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0039446 infores:hetionet CHEBI:59560 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0011603 infores:hetionet CHEBI:16755 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0404521 infores:hetionet CHEBI:7936 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018944 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013295 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0162429 infores:hetionet CHEBI:52717 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0424790 infores:hetionet CHEBI:28915 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0948594 infores:hetionet CHEBI:17026 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0600142 infores:hetionet CHEBI:64312 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020433 infores:hetionet CHEBI:3387 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013362 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006585 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027822 infores:hetionet CHEBI:70735 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0232461 infores:hetionet CHEBI:16796 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0036974 infores:hetionet CHEBI:6916 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0040264 infores:hetionet CHEBI:63611 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151936 infores:hetionet CHEBI:75246 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232462 infores:hetionet CHEBI:78543 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0311468 infores:hetionet CHEBI:6801 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0033774 infores:hetionet CHEBI:6954 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0001925 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0041969 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038454 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151838 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009938 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0276252 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0276252 infores:hetionet CHEBI:17026 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1140680 infores:hetionet CAID:CA405685492 biolink:causes MONDO:0018493 infores:clingen CAID:CA405685492 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of guanine with thymine at position 14364+1 of the RYR1 cDNA, c.14364+1G>T. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 25960145). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant is predicted to disrupt splicing, however, loss of function of RYR1 is not a common molecular etiology for MHS. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405685492/MONDO:0018493/012 2022-01-03 2022-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10124 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0014591 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0034882 infores:hetionet CHEBI:50275 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0031256 infores:hetionet CAID:CA16616934 biolink:causes MONDO:0008723 infores:clingen CAID:CA16616934 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c.1593dup (p.Ser532GlufsTer30) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 09-05-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616934/MONDO:0008723/021 2022-09-05 2022-12-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3127 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0268000 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027726 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0243065 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0006147 infores:hetionet CHEBI:119486 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0008031 infores:hetionet CHEBI:36791 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014724 infores:hetionet CHEBI:2682 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020639 infores:hetionet CAID:CA273936 biolink:causes MONDO:0009861 infores:clingen CAID:CA273936 MONDO:0009861 PMID:1301942PMID:1301942PMID:8825928 Likely Pathogenic PM2, PP4, PM3_Strong, PVS1_Moderate The c.168_168+1delGGinsAA variant has been identified in at least 6 probands with classic PKU (PMIDs: 1301942, 8825928). It has been detected in the homozygous form (PMID: 1301942) as well as in trans with the pathogenic variant R408W (PMID: 8825928). This variant is absent from 1000G, ESP, and gnomAD databases. This variant results in a broken donor splice site, expected to result in the in-frame deletion of exon 2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PVS1_Moderate, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273936/MONDO:0009861/006 2019-08-25 2019-08-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9566 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0085631 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033777 infores:hetionet CHEBI:4356 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0018784 infores:hetionet CHEBI:94501 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0231218 infores:hetionet NCBIGene:4780 biolink:causes MONDO:0060591 infores:monarchinitiative not_provided not_provided HGNC:7782 MONDO:0060591 uuid:35f128cf-bebb-4cf7-bfc5-e6070412d570 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9150 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0035410 infores:hetionet CHEBI:71219 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0542571 infores:hetionet CHEBI:74947 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085610 infores:hetionet CHEBI:31205 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0038362 infores:hetionet CHEBI:51860 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002874 infores:hetionet CHEBI:6121 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0023066 infores:hetionet CAID:CA915940438 biolink:causes MONDO:0015967 infores:clingen CAID:CA915940438 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong PP4 The c.811del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 271 NM_000545.8, adding 71 novel amino acids before encountering a stop codon (p.(Arg271GlyfsTer71). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 will not be applied (PMID: 16917892, internal lab contributors). In summary, c.811delC meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940438/MONDO:0015967/017 2022-04-13 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4469 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0232459 infores:hetionet CHEBI:7476 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030252 infores:hetionet CHEBI:63621 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0000731 infores:hetionet CAID:CA6831834 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831834 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PM5, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 The c.787C>T variant in the HNF1 homeobox A] gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 263 (p.Arg263Cys) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent in the gnomAD v2.1.1 European non-Finnish population, and there is one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 30155490, 12574234, 25414397, 9287053; internal lab contributors). Additionally, another missense variant, c.788G>A (p.Arg263His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg263Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg263Cys protein has DNA binding and transactivation activity below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 12574234). Also, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). Lastly, this variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID: 12574234, internal lab contributors). In summary, c.787C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PM5, PS3_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831834/MONDO:0015967/017 2022-04-14 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8382 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0026848 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0853813 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0425945 infores:hetionet CAID:CA1139771342 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139771342 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4, PP1 The c.1265_1273delinsTGCGAGCCACCTTCAT variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 422 (NM_000162.5), adding 39 novel amino acids before encountering a stop codon (p.(Arg422LeufsTer39)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1265_1273delinsTGCGAGCCACCTTCAT meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771342/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Supports CHEBI:6775 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0030554 infores:hetionet CHEBI:32192 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C3665347 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0016658 infores:hetionet CHEBI:64045 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0917801 infores:hetionet NCBIGene:1749 biolink:causes MONDO:0009080 infores:monarchinitiative not_provided not_provided HGNC:2918 MONDO:0009080 uuid:3f408340-2c32-4f00-bd52-d7d67772f69b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes HP:0001920 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0035067 infores:hetionet CHEBI:8869 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0039503 infores:hetionet CHEBI:27470 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0011570 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0518015 infores:hetionet CHEBI:8874 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003873 infores:hetionet CAID:CA409106287 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106287 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PVS1_Strong The c.582+1G>A variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of NM_175914.5. This variant is predicted to cause an in-frame deletion of biologically relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong). This variant failed QC in gnomAD v2.1.1 , is found in only one individual in BRAVO and absent from the Geisinger and UK Biobanks (PM2_Supporting). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, history of large for gestational age, and family history of persistent neonatal hypoglycemia) (PP4_Moderate; PMID: 17407387, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in this family with MODY (PP1; PMID: 17407387). In summary, c.582+1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PVS1_strong, PM2_supporting, PP4_moderate, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106287/MONDO:0015967/085 2023-09-15 2023-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0041582 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0426584 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0426584 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0037199 infores:hetionet CHEBI:6149 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0009676 infores:hetionet CHEBI:3756 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0234518 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020517 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020649 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020649 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0015230 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0032285 infores:hetionet CHEBI:8060 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0040822 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0034065 infores:hetionet CHEBI:64355 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003467 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001110 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085697 infores:hetionet CAID:CA396451249 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451249 MONDO:0007648 PMID:26901067PMID:26022348 Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP4, PP1, PP2, PP3, BS2, BP3, BP2, BP1, BP4, BA1, PS4, PS1, PS3, PS2 The c.12G>A (p.Trp4Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451249/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:5790 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020651 infores:hetionet CHEBI:5118 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0476273 infores:hetionet CHEBI:49603 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0030196 infores:hetionet CHEBI:3125 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0162429 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0009450 infores:hetionet CAID:CA10584722 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584722 MONDO:0007750 PMID: Uncertain Significance PM2 NM_000527.5(LDLR):c.4G>A (p.Gly2Arg) variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - Variant is absent from gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584722/MONDO:0007750/013 2022-03-08 2022-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:46195 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0001339 infores:hetionet CHEBI:6909 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0009782 infores:hetionet CHEBI:63621 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0232462 infores:hetionet CAID:CA390863280 biolink:causes MONDO:0100216 infores:clingen CAID:CA390863280 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PVS1, PM6, BA1, BP1, BP2, BP3, PP2, PP3, PP4, PP1, BS2, PM5, PM1, PM3, PM4, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP5, BP7 The NM_177438.3:c.5678T>C variant in DICER1 is a missense variant predicted to cause substitution of valine by alanine at amino acid 1893 (p.Val1893Ala). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.266; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390863280/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16347 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0948594 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018500 infores:hetionet CHEBI:63613 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0423791 infores:hetionet CAID:CA251910 biolink:causes MONDO:0008723 infores:clingen CAID:CA251910 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PP4, PM3_Strong BP4 The c.1349G>A (p.Arg450His) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 450. At least one individual with this variant displayed reduced VLCAD activity, which is specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 11158518). This variant has been confirmed in trans to at least one likely pathogenic variant, not confirmed in trans to distinct likely pathogenic variants, and has been identified in the homozygous state in 2 individuals (PM3_Strong, PMID: 29519241, 15210884, 11158518, 9546340). The highest population minor allele frequency in gnomAD v2.0 is 0.00025 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA251910/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17347 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0162820 infores:hetionet CHEBI:474180 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151872 infores:hetionet CHEBI:7565 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0917801 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0235735 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235735 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029408 infores:hetionet CAID:CA122549 biolink:causes MONDO:0009026 infores:clingen CAID:CA122549 MONDO:0009026 PMID:17412879PMID:19206176PMID:19371735PMID:16329078PMID:16372351PMID:16969868PMID:16835863PMID:20660566PMID:18039947PMID:29493581PMID:17054105PMID:16443854PMID:19669404PMID:16170316PMID:16881968PMID:16835863 Pathogenic PS3, PS4, PM1, PM2, PS2_Very Strong, PP2, PP3 The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA122549/MONDO:0009026/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3515 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042029 infores:hetionet CHEBI:64064 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0009763 infores:hetionet CHEBI:15640 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0015230 infores:hetionet CHEBI:46081 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0404521 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0029882 infores:hetionet CHEBI:36795 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085606 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0267596 infores:hetionet CHEBI:63925 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0162285 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0024115 infores:hetionet CHEBI:31932 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0009782 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005131 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0302592 infores:hetionet CHEBI:27732 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0034063 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0035309 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0403632 infores:hetionet CAID:CA409103833 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103833 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS4 The c.139G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to serine at codon 47 (p.(Gly47Ser)) of NM_175914.5. This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and 3 generation family history of diabetes or personal history of neonatal hypoglycemia) (PP4_Moderate; internal lab contributors). In summary, c.139G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103833/MONDO:0015967/085 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:253342 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1260922 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0684249 infores:hetionet CHEBI:8707 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0600142 infores:hetionet CHEBI:6775 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0010200 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0031350 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0027697 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0242350 infores:hetionet CAID:CA512318889 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318889 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.249C>T (p.Ala83=) is a synonymous variant. REVEL score not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. (BP4) Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.324528 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). PM2_supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318889/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0015230 infores:hetionet CHEBI:15765 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0700225 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0034063 infores:hetionet NCBIGene:356 biolink:causes MONDO:0011158 infores:monarchinitiative not_provided not_provided HGNC:11936 MONDO:0011158 uuid:dc59ec5c-8b03-40a4-b6a9-f3d06321361d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0018965 infores:hetionet CHEBI:85161 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0011615 infores:hetionet CHEBI:3534 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0017178 infores:hetionet CHEBI:8764 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020578 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0003862 infores:hetionet CHEBI:7459 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0004093 infores:hetionet CHEBI:681850 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0004238 infores:hetionet CHEBI:7565 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002792 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0699893 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0006849 infores:hetionet CHEBI:50924 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0022346 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0231365 infores:hetionet UMLS:C0657912 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017086 infores:hetionet CHEBI:135193 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0042373 infores:hetionet CHEBI:45409 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0231530 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0041912 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0018799 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0031046 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0151736 infores:hetionet CHEBI:31536 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0019209 infores:hetionet CHEBI:6121 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0002792 infores:hetionet CHEBI:35778 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0027441 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233794 infores:hetionet CHEBI:9586 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0004998 infores:hetionet CHEBI:47426 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0032617 infores:hetionet CHEBI:3207 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C1262113 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0149904 infores:hetionet CHEBI:50275 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0428977 infores:hetionet GO:1902119 biolink:causes GO:0140013 infores:ubergraph knowledge_assertion manual_agent GO:1902119 GO:0140013 CHEBI:8890 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0392025 infores:hetionet CHEBI:74947 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042023 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0233494 infores:hetionet CHEBI:9763 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C3665386 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0011570 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0497247 infores:hetionet CHEBI:27470 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0232462 infores:hetionet CHEBI:3181 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0009676 infores:hetionet CHEBI:39669 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0022346 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0549385 infores:hetionet CHEBI:68575 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0030554 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0006849 infores:hetionet CHEBI:45783 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151825 infores:hetionet CHEBI:45081 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0015967 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005536 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0868908 infores:hetionet CHEBI:51364 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1142135 infores:hetionet CHEBI:31980 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005741 infores:hetionet CHEBI:63631 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151904 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0007682 infores:hetionet CHEBI:6149 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0086439 infores:hetionet CHEBI:100241 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232462 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0853813 infores:hetionet CHEBI:6887 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233407 infores:hetionet CHEBI:52172 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085636 infores:hetionet CHEBI:63620 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003578 infores:hetionet CHEBI:3215 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0003862 infores:hetionet CHEBI:2453 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0438142 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005191 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0278883 infores:hetionet CHEBI:5893 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0015967 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0243026 infores:hetionet CHEBI:107736 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0015371 infores:hetionet CHEBI:31236 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152032 infores:hetionet CAID:CA8314893 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314893 MONDO:0009276 PMID: Benign BP4, BA1, BP7 BP2 The synonymous variant NM_000173.7(GP1BA):c.1074A>G (p.Arg358=) is not predicted by SpliceAI to impact splicing (score 0.00; BP4). In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of 0.134386 (BP7). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.2116 (based on 9653/44866 alleles, including 1018 homozygotes) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.001; BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4, BP7 (ClinGen Platelet Disorders VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314893/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8364 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C2047937 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0023798 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0008370 infores:hetionet CHEBI:3756 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009421 infores:hetionet CHEBI:51450 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0021177 infores:hetionet CHEBI:48390 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0011991 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0497201 infores:hetionet CHEBI:4909 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0030252 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0020538 infores:hetionet CHEBI:71229 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0027540 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0006840 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0860901 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0860901 infores:hetionet CHEBI:8772 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0005684 infores:hetionet CHEBI:46557 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C2830004 infores:hetionet NCBIGene:3419 biolink:causes MONDO:0033563 infores:monarchinitiative not_provided not_provided HGNC:5384 MONDO:0033563 uuid:75137a99-06a3-4003-97f6-832d2265260b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA343772365 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772365 MONDO:0013144 PMID: Uncertain Significance PM5, PP3, PM2_Supporting PS4 The c.1315C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by serine at amino acid 439 (p.Pro439Ser). This variant is completely absent from gnomAD v2.1.1, v3.1.2 and v4.0.0 (PM2_Supporting). One proband with this variant is reported in the literature but cannot be counted towards PS4 as the AT levels of this patient are not published. The computational predictor REVEL gives a score of 0.901, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM5, PP3, PM2_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772365/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9139 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0023530 infores:hetionet CAID:CA10385163 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385163 MONDO:0100437 PMID: Benign BP4_Strong, BS1 NM_001034853.2(RPGR):c.3293G>A (p.Gly1098Asp) is a missense variant causing substitution of glycine by aspartic acid at amino acid 1098. This variant is present in gnomAD v4.1.0 at a frequency of 0.00002270 among hemizygous individuals, with 9 variant alleles / 396,549 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.012, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1 and BP4_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385163/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:27436 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0030781 infores:hetionet CHEBI:6472 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0033687 infores:hetionet CHEBI:135920 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0235996 infores:hetionet NCBIGene:1277 biolink:causes MONDO:0009804 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0009804 uuid:5589d119-3f8b-4dac-9fe8-342ff2a2268a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0233632 infores:hetionet CHEBI:68558 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018965 infores:hetionet CHEBI:63613 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0235378 infores:hetionet CHEBI:6402 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0002994 infores:hetionet CHEBI:171719 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151766 infores:hetionet CHEBI:3723 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0575081 infores:hetionet CHEBI:49713 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0038999 infores:hetionet CHEBI:47381 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010038 infores:hetionet GO:0042665 biolink:causes GO:0001712 infores:ubergraph knowledge_assertion manual_agent GO:0042665 GO:0001712 CAID:CA000623 biolink:causes MONDO:0017623 infores:clingen CAID:CA000623 MONDO:0017623 PMID:25980754PMID:29706350PMID:29785012 Likely Benign PP2, BS1_Supporting, BS3_Supporting, BP4 PM2, PM6, PVS1, BP7, BP5, BS4, PP3, PP1, BS2, PM5, PM4, PM1, PM3, BP1, BP3, BP2, BA1, PS1, PS4, PS2, PS3 NM_000314.8(PTEN):c.892C>G (p.Gln298Glu) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1_Supporting: Filtering allele frequency of 0.00002132 (0.002132%, 4/24900 African/African American alleles) in gnomAD. BS3_Supporting: Massively parallel functional assay interrogating phosphatase activity demonstrating no statistically significant difference from wild type (PMID: 29706350). BP4: REVEL score = 0.229. PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID: 29300386): BS1_P (-1 pt1), BS3_P (-1 pt), BP4 (-1 pt), PP2 (+1 pt) = -2 pts total (Likely Benign). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000623/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5441 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0003862 infores:hetionet CHEBI:35778 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085631 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0162119 infores:hetionet CAID:CA16020950 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020950 MONDO:0009861 PMID:26803807 Uncertain Significance PM2, PP3 PP4, PS3 The c.1150C>T (p.Pro384Ser) PAH variant has been reported in at least one “phenylketonuria” or “hyperphenylalaninemia” proband (PMID: 31332730). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant predicted deleterious by Polyphen (probably damaging), MutationTaster (disease causing), and has a REVEL score of 0.902. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020950/MONDO:0009861/006 2021-04-23 2021-09-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:30830 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0855775 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0270458 infores:hetionet CHEBI:2955 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0333355 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0033687 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0281981 infores:hetionet CHEBI:23765 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0001824 infores:hetionet CHEBI:61049 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0043352 infores:hetionet CHEBI:8245 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0278134 infores:hetionet CHEBI:9435 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0036974 infores:hetionet CHEBI:42797 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0149745 infores:hetionet CHEBI:16469 biolink:causes UMLS:C2609183 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2609183 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0021053 infores:hetionet GO:0044509 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0044509 GO:0007154 CHEBI:8863 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027651 infores:hetionet CHEBI:30830 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0037384 infores:hetionet CHEBI:4672 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0476281 infores:hetionet NCBIGene:10054 biolink:causes MONDO:0859262 infores:monarchinitiative not_provided not_provided HGNC:30661 MONDO:0859262 uuid:394a07ff-168c-4695-9c44-bdfda1210034 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA273990 biolink:causes MONDO:0700270 infores:clingen CAID:CA273990 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1 BA1, BS1, PM2 The c.1564_1565del (p.Glu522Ilefs*43) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in numerous unrelated individuals with Ataxia-Telangiectasia (PMIDs: 26896183, 10330348, 9792409, 12497634, 15880721, 31407689, 30549301, 30772474, 9887333, 28126470, 23566627, 22213089, 21792198, 17985259, 8755918, 16266405, 21965147, 10817650, 8789452, 9463314, 19535770). The highest population minor allele frequency in gnomAD v4.1.0 0.00007373 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive ataxia-telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA273990/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0004609 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0026961 infores:hetionet CHEBI:6067 biolink:causes HP:0011032 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2364164 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0423773 infores:hetionet CHEBI:3732 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0338831 infores:hetionet CHEBI:41774 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0011168 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0549418 infores:hetionet NCBIGene:2335 biolink:causes MONDO:0008479 infores:monarchinitiative not_provided not_provided HGNC:3778 MONDO:0008479 uuid:1d2e85a8-915b-4ae2-b9bc-80a4838bd1c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0332575 infores:hetionet CHEBI:31711 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0036396 infores:hetionet CHEBI:8481 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0030252 infores:hetionet CHEBI:135361 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0030252 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0424000 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011551 infores:hetionet CHEBI:391960 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0013404 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0236022 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0236022 infores:hetionet CAID:CA10558596 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558596 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BS1 BP4, BA1, PS4, PM1, PM2 The highest population minor allele frequency of the NM_004992.4:c.533C>G (p.Ser178Cys) variant in MECP2 in gnomAD v4.1 is 0.00009 in the South Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Ser178Cys variant is observed in at least 1 unaffected individual (internal data, Labcorp Genetics Inc.) (BS2_Supporting). The p.Ser178Cys variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Ser178Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BS2_Supporting) (MECP2 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558596/MONDO:0010726/036 2025-02-28 2025-03-26 X-linked inheritance HP:0001417 Contradicts true CHEBI:28748 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006852 infores:hetionet CAID:CA512341248 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341248 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 The variant NM_001754.5(RUNX1):c.1176G>A (p.Gln392=) is a synonymous variant. As this is a synonymous variant, there is no REVEL score however SpliceAI is ≤0.20 (0.00) (BP4). The PhyloP score is <2.0 (0.869) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341248/MONDO:0011071/008 2022-01-20 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6402 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0041969 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0023895 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151849 infores:hetionet CHEBI:72292 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0231528 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0002026 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D002177 DB01263_MESH_D002177_1 CHEBI:8107 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0010520 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0016385 infores:hetionet CHEBI:5147 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0035455 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0013595 infores:hetionet GO:0070163 biolink:causes GO:0050886 infores:ubergraph knowledge_assertion manual_agent GO:0070163 GO:0050886 CHEBI:27974 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0267792 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0034065 infores:hetionet NCBIGene:2998 biolink:causes MONDO:0009414 infores:monarchinitiative not_provided not_provided HGNC:4707 MONDO:0009414 uuid:6b9aae39-8155-4b72-a103-a592219e1f4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes UMLS:C0403723 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0403723 infores:hetionet CHEBI:8107 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0404521 infores:hetionet CHEBI:9362 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0151601 infores:hetionet CHEBI:74947 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1142011 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0151723 infores:hetionet CHEBI:7444 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0001824 infores:hetionet CHEBI:94686 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0013604 infores:hetionet CAID:CA7511222 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511222 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000070.3: c.1027G>T (p.Glu343Ter) variant in CAPN3, which is also known as p.(Glu343del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of limb girdle muscular dystrophy (PMID: 34628793, 30564623; LOVD CAPN3_000602; ClinVar SCV000953543.3 internal data communication), including in unknown phase with a pathogenic variant in two cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 30564623; LOVD Individual #00222348; ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The highest population minor allele frequency of the variant is 0.00005787 (2/34560 exome chromosomes) in the Admixed American population of gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511222/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:18248 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0428977 infores:hetionet CHEBI:178699 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0012739 infores:hetionet NCBIGene:1119 biolink:causes MONDO:0859282 infores:monarchinitiative not_provided not_provided HGNC:1937 MONDO:0859282 uuid:d8f30ad1-7785-4515-a177-873ab0f74738 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0853692 infores:hetionet CHEBI:31705 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085628 infores:hetionet NCBIGene:8546 biolink:causes MONDO:0011997 infores:monarchinitiative not_provided not_provided HGNC:566 MONDO:0011997 uuid:b74afdf5-0cf7-45bd-a1a1-e1fb9577543c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9352 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0039231 infores:hetionet CHEBI:5132 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0236075 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020615 infores:hetionet CHEBI:6367 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1142135 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0086543 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0038363 infores:hetionet CHEBI:30830 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011603 infores:hetionet CHEBI:8093 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0007859 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0234215 infores:hetionet CHEBI:2639 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0015672 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0948089 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0031350 infores:hetionet CHEBI:144551 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0026826 infores:hetionet CHEBI:52172 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1384353 infores:hetionet CHEBI:681569 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1145670 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0235431 infores:hetionet CHEBI:6149 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030193 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0427008 infores:hetionet CHEBI:63598 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040822 infores:hetionet CHEBI:3219 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0518988 infores:hetionet NCBIGene:8091 biolink:causes MONDO:0020795 infores:monarchinitiative not_provided not_provided HGNC:5009 MONDO:0020795 uuid:aef5f511-c14e-43db-ade7-3c69cb6a82d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C1142412 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0017574 infores:hetionet CHEBI:49668 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0002994 infores:hetionet CHEBI:29007 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0042963 infores:hetionet CAID:CA410203589 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203589 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP7, BS1, BS3, BS4, PM6, PM5, PM4, PP4, PP2, PP1 NM_001754.5(RUNX1):c.301G>C (p.Val101Leu) is a missense variant within the Runt Homology domain (AA 89-204), but does not affect an established hotspot variant (PM1_supporting). This missense variant has a REVEL score ≥ 0.88 (0.921) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203589/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:66899 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0013404 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030920 infores:hetionet CHEBI:15765 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0231218 infores:hetionet CHEBI:3696 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0040822 infores:hetionet CHEBI:367163 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0003862 infores:hetionet CAID:CA16020903 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020903 MONDO:0009861 PMID: Uncertain Significance PM2 PP3 The NM_000277.3:c.949T>C (p.Tyr317His) variant is a missense variant in exon 9/13 of PAH. The variant does not appear to have been reported in the published literature (as of 07/02/2020).The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.983), but tolerated by SIFT, such that PP3 is not met.Classification: VUS – insufficient evidenceSupporting Criteria: PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020903/MONDO:0009861/006 2020-07-25 2020-07-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63607 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0699828 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0235416 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0855242 infores:hetionet CHEBI:3764 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0000731 infores:hetionet GO:1905421 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905421 GO:0007275 CHEBI:63611 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0575081 infores:hetionet CHEBI:8461 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0022107 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0272753 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0272753 infores:hetionet CHEBI:2914 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0340865 infores:hetionet CHEBI:9763 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0039070 infores:hetionet CHEBI:2704 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0038999 infores:hetionet CHEBI:5138 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0836924 infores:hetionet CHEBI:3994 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0267792 infores:hetionet CHEBI:6950 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0012569 infores:hetionet CHEBI:3176 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0231528 infores:hetionet CAID:CA16609462 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609462 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PM5 The c.640T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to threonine at codon 214 (p.Ser214Thr)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). A number of other missense variants at this codon (c.640T>G, p.Ser214Ala; c.641C>T, p.Ser214Phe; c.641C>A, p.Ser214Tyr) have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.640T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609462/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:125354 biolink:causes UMLS:C3160759 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C3160759 infores:hetionet CHEBI:28864 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0476280 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027121 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0948089 infores:hetionet CHEBI:8378 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0085570 infores:hetionet CHEBI:3723 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2937350 infores:hetionet CHEBI:68478 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0032227 infores:hetionet CAID:CA386952410 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952410 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP1_Moderate, PP4, PP3 The c.34C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 12 (p.(Leu12Phe)) of NM_000545.8. This variant failed quality control metrics in gnomAD v2.1.1, but is absent in gnomAD v3.1.2 and v4.1 (PM2_Supporting).  Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors, PMID:15928245). Furthermore, one of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors).  This variant segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3, PP4, PP1_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952410/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA286882 biolink:causes MONDO:0700270 infores:clingen CAID:CA286882 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PS3_Supporting, PP3 BA1, BP4, BS1, PM2 The c.5228C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1743 (p.Thr1743Ile). This variant has been detected in numerous unrelated individuals with Ataxia-Telangiectasia (PMIDs: 19147735, 21792198, 26896183, 31921190). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008476 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). Western blotting in ATM null cells transfected with cDNA carrying this variant showed a reduction in phosphorylation of ATM downstream targets as compared to wild-type controls, indicating that this variant impacts protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.835 which is above the threshold of 0.7333, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_VeryStrong, PS3_Supporting, PP3). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA286882/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63608 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011570 infores:hetionet CHEBI:8060 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0023530 infores:hetionet CHEBI:421707 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0020443 infores:hetionet CHEBI:15544 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020433 infores:hetionet CHEBI:480999 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0015230 infores:hetionet CHEBI:7824 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0030196 infores:hetionet NCBIGene:124583 biolink:causes MONDO:0009629 infores:monarchinitiative not_provided not_provided HGNC:19721 MONDO:0009629 uuid:3b53e2d6-6e0b-4c84-949c-093d361a5fe6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA340748044 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748044 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP1, PP4, PM2_Supporting NM_000329.3(RPE65):c.354-2A>G is a canonical splice site variant in intron 4 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in a proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PMID: 33952291, PM3). This proband exhibits a phenotype including onset at birth (1 pt), extinguished electroretinogram responses from both rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), and bone spicules/clumped pigment (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 4 points, PMID: 33952291, PP4). This variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 33952291, PP1). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PM3, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748044/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0011701 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0521839 infores:hetionet CHEBI:2567 biolink:causes HP:0031846 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0015802 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009760 infores:hetionet NCBIGene:1356 biolink:causes MONDO:0011426 infores:monarchinitiative not_provided not_provided HGNC:2295 MONDO:0011426 uuid:6e024967-4f50-4c61-9b17-8b0da66da7ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75922 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C1761613 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0026848 infores:hetionet CHEBI:5120 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0018681 infores:hetionet CAID:CA273937 biolink:causes MONDO:0008723 infores:clingen CAID:CA273937 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM3_Supporting, PVS1_Moderate, PP4_Moderate The c.1182+1G>A variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 11. It is predicted to cause skipping of biologically-relevant-exon 11/20, resulting in an in-frame deletion (removes amino acids 360-394) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The prediction of exon 11 skipping was confirmed by RT-PCR of fibroblasts from an individual homozygous for this variant; however, no VLCAD protein was detected (PMID:7479827). At least one patient with this variant displayed increased C14:1 acylcarnitines and reduced VLCAD activity in fibroblasts, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 23480858). This variant has been described in individuals identified by newborn screen, but this information is insufficient to use toward classification (PMID:26385305, 21932095). This variant has been described in affected individuals in the homozygous state and not confirmed in trans to a distinct variant of uncertain significance (PM3_Supporting; PMID: 7479827, 27209629, 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006154 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PP4_Moderate, PM3_Supporting, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA273937/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CL:0000187 biolink:causes MONDO:0021545 infores:ubergraph knowledge_assertion manual_agent CL:0000187 MONDO:0021545 CHEBI:35854 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0235431 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085096 infores:hetionet CHEBI:5106 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C2364111 infores:hetionet CHEBI:31643 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0020458 infores:hetionet CHEBI:10023 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002874 infores:hetionet CHEBI:474180 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0741494 infores:hetionet CHEBI:135686 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0162429 infores:hetionet NCBIGene:80270 biolink:causes MONDO:0011906 infores:monarchinitiative not_provided not_provided HGNC:18324 MONDO:0011906 uuid:b5a3c52d-c281-4838-ae91-a798c3c84c5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63717 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0162283 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0549225 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0549225 infores:hetionet CHEBI:15640 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0013378 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0041912 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029408 infores:hetionet CHEBI:3723 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232461 infores:hetionet CAID:CA410148684 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148684 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1000C>T (p.Arg334Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148684/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:48273 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0016204 infores:hetionet CHEBI:3441 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020443 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0700184 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0085606 infores:hetionet CHEBI:101853 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C2830004 infores:hetionet CHEBI:63624 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0013378 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0233494 infores:hetionet CHEBI:16796 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0027497 infores:hetionet CHEBI:135736 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0033687 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0677500 infores:hetionet CHEBI:30742 biolink:causes MONDO:0017861 infores:ubergraph knowledge_assertion manual_agent CHEBI:30742 MONDO:0017861 CAID:CA345911 biolink:causes MONDO:0044970 infores:clingen CAID:CA345911 MONDO:0044970 PMID:23246842 Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PS3_Supporting PP4, PS2, PM6 The m.3890G>A (p.R195Q) variant in MT-ND1 has been reported in at least nine individuals from nine families in the literature, who had features falling within the Leber Hereditary Optic Neuropathy (LHON) or Leigh syndrome spectrums (PS4_moderate; PMIDs: 34390870, 33337510, 27798429, 18504678, 30095618, 23246842, 23847141). There are no reports of de novo occurrence of this variant to our knowledge. Although this variant most often is seen in the homoplasmic state, in one multi-generational family, there were five unaffected relatives with low heteroplasmy levels in urine and blood, compared to much higher levels in the proband (PP1_moderate; PMID 2324842). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease – PMID: 23246842; variant absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID: 23246842). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS4_moderate, PP3, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345911/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:63629 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0004093 infores:hetionet CHEBI:63616 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0013378 infores:hetionet NCBIGene:4720 biolink:causes MONDO:0958197 infores:monarchinitiative not_provided not_provided HGNC:7708 MONDO:0958197 uuid:d2e01b5a-61c4-47c8-87a9-4e8ad378254b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4822 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0011991 infores:hetionet CHEBI:53760 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233514 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0038587 infores:hetionet CHEBI:16714 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0030252 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042373 infores:hetionet CHEBI:231594 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1384353 infores:hetionet GO:0060211 biolink:causes GO:0000288 infores:ubergraph knowledge_assertion manual_agent GO:0060211 GO:0000288 CHEBI:63631 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0035455 infores:hetionet NCBIGene:59335 biolink:causes MONDO:0014662 infores:monarchinitiative not_provided not_provided HGNC:13997 MONDO:0014662 uuid:779005e8-2af4-4f06-9110-0534334f5dab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0020517 infores:hetionet CHEBI:93363 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0015397 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0178298 infores:hetionet NCBIGene:5205 biolink:causes MONDO:0007829 infores:monarchinitiative not_provided not_provided HGNC:3706 MONDO:0007829 uuid:9b27f1b1-71cb-4fec-a523-0ebee2931760 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0332534 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0038454 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0021053 infores:hetionet UMLS:C0004609 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042023 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0038587 infores:hetionet CHEBI:63580 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0037763 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0233494 infores:hetionet CHEBI:71223 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0039231 infores:hetionet CHEBI:45081 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0018932 infores:hetionet CHEBI:8871 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0424790 infores:hetionet CHEBI:46195 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C2047937 infores:hetionet CHEBI:41977 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0019079 infores:hetionet CHEBI:18248 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0042029 infores:hetionet CHEBI:50861 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C2047937 infores:hetionet CHEBI:5775 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0014457 infores:hetionet CHEBI:7915 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1328337 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0027765 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0038999 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151849 infores:hetionet CHEBI:7852 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085633 infores:hetionet CHEBI:63637 biolink:causes MONDO:0002527 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0022572 infores:hetionet CHEBI:231594 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0085602 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0015376 infores:hetionet CHEBI:50922 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0035243 infores:hetionet CHEBI:9570 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151905 infores:hetionet CHEBI:47426 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0017178 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0036974 infores:hetionet CHEBI:3172 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C1443060 infores:hetionet CHEBI:2038 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0027497 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0031117 infores:hetionet CHEBI:2704 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0003467 infores:hetionet CHEBI:27504 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0023530 infores:hetionet CHEBI:3647 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0392676 infores:hetionet CHEBI:31184 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0234894 infores:hetionet CHEBI:52717 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030794 infores:hetionet CHEBI:4888 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0004134 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0853908 infores:hetionet CHEBI:46081 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0025874 infores:hetionet NCBIGene:6536 biolink:causes MONDO:0015010 infores:monarchinitiative not_provided not_provided HGNC:11056 MONDO:0015010 uuid:278ca09a-e140-4ade-aa59-b1377649c8fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3499 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0001824 infores:hetionet CHEBI:68855 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0020517 infores:hetionet CHEBI:2663 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0013384 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0018949 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018949 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0442874 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020538 infores:hetionet CHEBI:41879 biolink:causes HP:0031616 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0423281 infores:hetionet CAID:CA115479 biolink:causes MONDO:0011229 infores:clingen CAID:CA115479 MONDO:0011229 PMID: Pathogenic PS3_Supporting, PM5, PP3, PP1_Strong, PM3_Strong, PP4_Moderate BS2, PP2, BA1, BP2, BP1, BP4, PS4, PS1, PM2, BS4, BS1 The ETHE1 c.487C>T mutation is a missense mutation at the 163 amino acid position where one other pathogenic mutation has been reported (c.488G>A) indicating that this residue is critical to the function of the protein (PM5_moderate). There are multiple lines of computational evidence supporting a deleterious effect (PP3_supporting). Functional studies performed in ETHE1 isolated from E-coli cells demonstrated 10 fold reduced ETHE1 catalytic activity when compared to controls (PS3_supporting; PMID:25198162). The c.487C>T mutation has been reported in four unrelated affected individuals including three who were homozygous for the mutation (PMID:16183799; PMID:16828325; PMID:28698729) and one proband where the c. 487C>T was found in trans with another reportedly pathogenic ETHE1 mutation (PMID:18593870) (PM3_strong). One of these patients demonstrated a clinical phenotype specific to ethylmalonic encephalopathy including chronic diarrhea, petechiae, acrocyanosis, and developmental delay in addition to the biochemical findings urinary ethylmalonic acid and elevated blood C4-acylcarnitine esters and blood C5-acylcarnitines (PP4_moderate; PMID: 16828325). A larger family including 7 children has been reported where homozygous c.487C>T mutation was identified in the three affected siblings and segregated with disease in the unaffected siblings (PP1_strong; PMID:14732903). In summary, this variant meets criteria to be classified as pathogenic for ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied PM5_moderate; PP3_supporting; PS3_supporting; PM3_strong; PP4_moderate; PP1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA115479/MONDO:0011229/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:5864 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0013362 infores:hetionet CHEBI:8356 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0312420 infores:hetionet CHEBI:71272 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0022661 infores:hetionet CHEBI:50305 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0030193 infores:hetionet CHEBI:6775 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0858635 infores:hetionet CAID:CA410204280 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204280 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.115C>T (p.Arg39Cys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204280/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA033384 biolink:causes MONDO:0007750 infores:clingen CAID:CA033384 MONDO:0007750 PMID: Likely Benign BP2, BP4, BP7, PM2, PP4 BP3, BP1, BA1, PS4, PS3, PS2, PS1, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PVS1, PM6, BS2, PP1, PP2, PP3 The NM_000527.5(LDLR):c.1279A>C (p.Arg427=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP2, BP4, BP7, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.00006976 (0.006976%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).BP4: No REVEL, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) does not create AG/GTC) variant is exonic and there is no AG/GT nearby Variant is not predicted to alter splicing.--- BP4 is met.BP7: Variant is synonymous and meets BP4.BP2: Variant identified in an index case with heterozygous FH phenotype (LDL-C=170mg/dL on statins) and LDLR c.530C>T (p.Ser177Leu) (confirmed in trans), classified as Pathogenic by these guidelines, from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal.PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal.Variant has 3 Supporting evidence codes towards Benign, enough to classify as Likely Benign and only 1 Moderate plus 1 Supporting evidence codes towards Pathogenic, so we are confident in classifying this variant as Likely Benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033384/MONDO:0007750/013 2023-01-27 2024-12-15 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63627 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0151596 infores:hetionet CHEBI:45327 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0232487 infores:hetionet CHEBI:94440 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0043352 infores:hetionet CHEBI:50838 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0019080 infores:hetionet CHEBI:9927 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C2981158 infores:hetionet NCBIGene:2260 biolink:causes MONDO:0008603 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0008603 uuid:70673dc7-9b7a-4f18-b3df-12f93a8a6e83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44032 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0392699 infores:hetionet CHEBI:5001 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013428 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0237326 infores:hetionet GO:0050684 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0050684 GO:0010467 CHEBI:3181 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0009450 infores:hetionet CHEBI:61049 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0234428 infores:hetionet CHEBI:8890 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0022346 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0030305 infores:hetionet CHEBI:8871 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0423006 infores:hetionet CAID:CA160213 biolink:causes MONDO:0010938 infores:clingen CAID:CA160213 MONDO:0010938 PMID: Benign BA1, BS2_Supporting NM_000215.4(JAK3):c.1843C>T (p.Arg615Cys) is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 615.The filtering allele frequency (the upper threshold of the 95% CI of 534/91086) of the c.1843C>T variant in JAK3 is 0.005451 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1 and therefore meets this criterion (BA1). Additionally, 5 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting).In summary, this variant meets the criteria to be classified as a Benign variant for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160213/MONDO:0010938/121 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:93363 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0152227 infores:hetionet CHEBI:6887 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151905 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1328332 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1328332 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0518015 infores:hetionet CHEBI:64355 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020625 infores:hetionet CHEBI:64354 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0220870 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0032584 infores:hetionet NCBIGene:87178 biolink:causes MONDO:0013978 infores:monarchinitiative not_provided not_provided HGNC:23166 MONDO:0013978 uuid:91e7a56d-1c0a-44fb-9bc4-286c467d45ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0005940 infores:hetionet CHEBI:9328 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0409974 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0221706 infores:hetionet CHEBI:41774 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020443 infores:hetionet CAID:CA357078 biolink:causes MONDO:0008667 infores:clingen CAID:CA357078 MONDO:0008667 PMID:35475554PMID:21715564 Likely Pathogenic PS4_Moderate, PM2_Supporting, PP3, PM1, PS3_Supporting The variant NM_000551.4(VHL):c.264G>T (p.Trp88Cys) is a missense variant predicted to cause substitution of Cysteine for Tryptophan at position 88. There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (PM2_Supporting). Three commercial laboratories report at total of 6 cases harboring this variant, and sum to a total of 4 points (Moderate). Ambry: Case1 (0.5 points): 15-20yo with retinal hemangioblastomas; Case 2(0.5 points) 15-20yo with bilateral retinal hemangioblastomas; Gene DX: Case1(1 point) bilateral clear cell renal cell carcinoma and hemangioblastoma as a minor. Invitae: Case 1(0.5 points) Hemangioblastoma of thoracic spine and retinal angioma in 20s. Case 2 (1 point) Hemangioblastoma in CNS x2, pancreatic cysts, venal cyst in 30s. Case 3 (0.5 points) multiple bilateral enhancing cystic and solid renal masses and multiple pancreatic cystic lesions, highly suspicious for VHL in 30s. (PS4_Moderate). HIF degradation assays in mouse embryonic fibroblasts showed W88C was unable to degrade HIF1a or HIF2a compared to wild type VHL, indicting that this variant impacts protein functions (PMID:21715564)(PS3_Supporting). This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including: NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1). The computational predictor REVEL gives a score of 0.945, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA357078/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64354 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020456 infores:hetionet CHEBI:63611 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0039231 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C1258215 infores:hetionet CHEBI:6061 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0002965 infores:hetionet CHEBI:17026 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0039231 infores:hetionet CHEBI:84883 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0014591 infores:hetionet CHEBI:40303 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0016204 infores:hetionet CHEBI:17650 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0036974 infores:hetionet CHEBI:5778 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0040264 infores:hetionet CHEBI:10119 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0012569 infores:hetionet CHEBI:8378 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0018813 infores:hetionet CAID:CA2580098629 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098629 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.613+16T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098629/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64310 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085682 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0234215 infores:hetionet NCBIGene:348 biolink:causes MONDO:0018473 infores:monarchinitiative not_provided not_provided HGNC:613 MONDO:0018473 uuid:6c1855ea-931a-4153-bb88-b9436a8cdc2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35553 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0042963 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0948594 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0027813 infores:hetionet NCBIGene:919 biolink:causes MONDO:0012426 infores:monarchinitiative not_provided not_provided HGNC:1677 MONDO:0012426 uuid:f24ae47c-20ab-448b-bc39-599d4e9d40ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0231835 infores:hetionet NCBIGene:1453 biolink:causes MONDO:0014088 infores:monarchinitiative not_provided not_provided HGNC:2452 MONDO:0014088 uuid:55780d9a-a101-4ba0-b282-fd761edb436c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50122 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0009806 infores:hetionet CHEBI:3013 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0042963 infores:hetionet CHEBI:63608 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0020433 infores:hetionet CHEBI:35677 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0039231 infores:hetionet CHEBI:84500 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0541798 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0235146 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011570 infores:hetionet CHEBI:63791 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2047937 infores:hetionet CAID:CA389475496 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475496 MONDO:0100040 PMID: Likely Pathogenic PP3, PM1, PM2_Supporting, PS2 The p.Ile207Thr variant in FOXG1 occurs in the de novo state (biological parentage confirmed) in an individual with a neurological disorder (Ambry internal database) (PS2). The p.Ile207Thr variant occurs in the well-characterized Forkhead functional domain of the FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Ile207Thr variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Ile207Thr variant in FOXG1 is classified as a likely pathogenic variant based on the ACMG/AMP criteria (PS2, PM1, PP3, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475496/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:65346 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0025061 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0520806 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0038587 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0041969 infores:hetionet CHEBI:6149 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0012569 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1141861 infores:hetionet CHEBI:7494 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0036974 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0555120 infores:hetionet CHEBI:6715 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0000731 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0235030 infores:hetionet CHEBI:7581 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0001824 infores:hetionet CHEBI:3696 biolink:causes UMLS:C1168174 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C1168174 infores:hetionet CHEBI:45863 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0917801 infores:hetionet CAID:CA512318762 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318762 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 Synonymous variant (no REVEL score applicable), and SpliceAI score is ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.628 (< 2.0)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318762/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8871 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038663 infores:hetionet CHEBI:4636 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0031117 infores:hetionet CHEBI:4027 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0235490 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0018939 infores:hetionet CHEBI:8378 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0036974 infores:hetionet CHEBI:75722 biolink:causes HP:6001020 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0343166 infores:hetionet CHEBI:8060 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0003467 infores:hetionet CHEBI:63611 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0438215 infores:hetionet CHEBI:9137 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0014457 infores:hetionet CHEBI:63584 biolink:causes EFO:1001816 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0343387 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003123 infores:hetionet GO:0040036 biolink:causes GO:0044344 infores:ubergraph knowledge_assertion manual_agent GO:0040036 GO:0044344 CAID:CA512341177 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341177 MONDO:0011071 PMID: Likely Benign BP4, BP7, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1257G>A (p.Val419=) is a synonymous variant which meets criteria for likely benign classification. The MAF is 0.0001369 (0.01369%, 7/51146 alleles) in the Admixed American subpopulation of the gnomAD v4.1.0 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). It has a SpliceAI score ≤ 0.20 (Donor gain Δ score 0.01) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.370)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341177/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:87681 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0025061 infores:hetionet CHEBI:180905 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0040264 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0024225 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0040409 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0022408 infores:hetionet CHEBI:82941 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C1262113 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0549475 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0332575 infores:hetionet CHEBI:6437 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151836 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0000833 infores:hetionet CAID:CA409108074 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108074 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PM5_Strong BA1, BP4, BS1 The c.869G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to leucine at codon 290 (p.(Arg290Leu)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and responsive to sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 1 family (PP1; internal lab contributors). Two other missense variants, c.868C>T p.Arg290Cys and c.869G>A p.Arg290His, have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.869G>T meets the criteria to be classified as Likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP4_Moderate, PP1, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108074/MONDO:0015967/085 2024-04-07 2024-04-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:134966 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0162316 infores:hetionet CHEBI:6402 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0019270 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0549373 infores:hetionet CHEBI:101278 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0007859 infores:hetionet CHEBI:50742 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0699885 infores:hetionet CHEBI:131512 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0917801 infores:hetionet NCBIGene:5621 biolink:causes MONDO:0007656 infores:monarchinitiative not_provided not_provided HGNC:9449 MONDO:0007656 uuid:55a26db5-ef2e-40a1-9d73-ef8625ac3077 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0232462 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0015256 infores:hetionet CHEBI:4779 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0027765 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085584 infores:hetionet CAID:CA915940312 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940312 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.2095-19T>A intronic variant is predicted to cause loss of the intron 20 canonical acceptor site by computational splicing predictor SpliceAI with a score of 0.98 for acceptor loss, it further predicts an acceptor site gain at c.2095-17, with a score of 1.00 (PP3). At least one patient (GT15 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIb surface expression was absent, as measured by flow cytometry (PP4_strong). GT15 (PMID: 25728920) is compound heterozygous for Gln924Ter (classified Pathogenic by the PD-EP) and c.2095-19T>A (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940312/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4551 biolink:causes MONDO:0020675 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C2004435 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0022660 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0009806 infores:hetionet CHEBI:2567 biolink:causes UMLS:C3495700 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C3495700 infores:hetionet GO:0060800 biolink:causes GO:0001701 infores:ubergraph knowledge_assertion manual_agent GO:0060800 GO:0001701 CHEBI:9927 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0231528 infores:hetionet CAID:CA024086 biolink:causes MONDO:0018493 infores:clingen CAID:CA024086 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 4645 of the RYR1 protein, p.(Arg4645Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00038, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, neither of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. Additionally, one of these individuals had a second variant in RYR1, p.(Arg2435His) that is classified as pathogenic, PS4 was not implemented (PMID: 16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.567 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024086/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:31236 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0428977 infores:hetionet CHEBI:63791 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149871 infores:hetionet CHEBI:2038 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0041364 infores:hetionet CHEBI:8694 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0013144 infores:hetionet CHEBI:3228 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0011603 infores:hetionet CHEBI:3286 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0035455 infores:hetionet CAID:CA410203676 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203676 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, PVS1, PM5, PM4, PM3, PP4, PP2, PP3, BS2 NM_001754.5(RUNX1):c.284C>T (p.Pro95Leu) is a missense variant within the Runt Homology domain (AA 89-204), but does not affect an established hotspot variant (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203676/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31176 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0035078 infores:hetionet CHEBI:194135 biolink:causes UMLS:C3665444 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C3665444 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0040034 infores:hetionet CHEBI:4514 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0028643 infores:hetionet CHEBI:9316 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0023066 infores:hetionet CHEBI:63629 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013384 infores:hetionet CHEBI:6067 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042384 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0005940 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0860711 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0860711 infores:hetionet CHEBI:28787 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0031350 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0036983 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0475858 infores:hetionet CHEBI:31348 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085593 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013182 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030794 infores:hetionet NCBIGene:79633 biolink:causes MONDO:0014454 infores:monarchinitiative not_provided not_provided HGNC:23109 MONDO:0014454 uuid:c3fcfc64-415e-4788-a452-9e1b218478cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28445 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0030312 infores:hetionet CHEBI:51230 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0036454 infores:hetionet GO:1902627 biolink:causes GO:0042273 infores:ubergraph knowledge_assertion manual_agent GO:1902627 GO:0042273 CHEBI:50275 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0038325 infores:hetionet CHEBI:9086 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151786 infores:hetionet CHEBI:63624 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0030193 infores:hetionet CHEBI:3011 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0003862 infores:hetionet CHEBI:17141 biolink:causes HP:0002857 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0576093 infores:hetionet CHEBI:9352 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0038362 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0029878 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1384353 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020517 infores:hetionet NCBIGene:128 biolink:causes MONDO:0030894 infores:monarchinitiative not_provided not_provided HGNC:253 MONDO:0030894 uuid:c734d253-7288-42a1-9c24-605a35cecaf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0438142 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0240417 infores:hetionet CHEBI:64064 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0035455 infores:hetionet CHEBI:10023 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0004604 infores:hetionet CHEBI:5778 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0085631 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1698400 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1698400 infores:hetionet CHEBI:4877 biolink:causes MONDO:0024335 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0085582 infores:hetionet CHEBI:63638 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026766 infores:hetionet CHEBI:36791 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039239 infores:hetionet CHEBI:63630 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0023380 infores:hetionet CHEBI:7514 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0042023 infores:hetionet NCBIGene:10999 biolink:causes MONDO:0012089 infores:monarchinitiative not_provided not_provided HGNC:10998 MONDO:0012089 uuid:b84fef36-6832-49d1-9a48-63cca660f50f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0028077 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0006145 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011630 infores:hetionet CHEBI:63635 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C3665386 infores:hetionet CHEBI:52717 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0497156 infores:hetionet CHEBI:2453 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0023530 infores:hetionet CHEBI:50122 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020433 infores:hetionet CAID:CA297202 biolink:causes MONDO:0021060 infores:clingen CAID:CA297202 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.2156G>C (p.Gly719Ala) variant in the SOS1 gene is 0.0414% (37/66598) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297202/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6402 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0037287 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0027051 infores:hetionet CHEBI:7476 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0037763 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0032326 infores:hetionet CHEBI:3213 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0042963 infores:hetionet CAID:CA195965 biolink:causes MONDO:0700272 infores:clingen CAID:CA195965 MONDO:0700272 PMID: Uncertain Significance PVS1_Moderate, PM2_Supporting BS1, PP1, BA1 The c.49-2A>T variant in PALB2 occurs within the canonical splice acceptor site (-1,2) of intron 1. The computational splicing predictor SpliceAI gives a score of 0.97 for acceptor loss and 0.71 score for an acceptor gain, predicting that the variant disrupts the acceptor splice site. This alteration is predicted to result in an in-frame loss impacting two amino acids from of exon 2 in the coiled-coiled domain with unknown functional impact (PMID: 30890586, 30289697, 31159747, Ambry Genetics). This variant is absent in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Moderate, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA195965/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51450 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0041912 infores:hetionet CHEBI:17347 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0240211 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011849 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0003123 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0241863 infores:hetionet NCBIGene:860 biolink:causes MONDO:0007984 infores:monarchinitiative not_provided not_provided HGNC:10472 MONDO:0007984 uuid:a226863b-26b3-400c-9cde-9bff62d41735 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0002170 infores:hetionet CHEBI:5280 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0235267 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0521501 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0521501 infores:hetionet CHEBI:7936 biolink:causes HP:0040307 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1112443 infores:hetionet CHEBI:5138 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040460 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002418 infores:hetionet CAID:CA412742873 biolink:causes MONDO:0100437 infores:clingen CAID:CA412742873 MONDO:0100437 PMID: Likely Pathogenic PVS1, PS4_Supporting PM2, PM6, BS2, PP1, PP3, PP4, PM4, PM5, PS3, PS1, PS2, BP4, BA1, BP7, BP5, BS1, BS4 NM_001034853.2(RPGR):c.679C>T (p.Gln227Ter) is a nonsense variant that introduces a premature stop in codon 227 within exon 7 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is present in gnomAD v4.1.0 at a frequency of 0.00000251 among hemizygous individuals, with 1 variant allele / 397,826 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 and fails to meet this criterion. This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years (PMID: 32047640; SCV001240417.1, personal communication, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinitis pigmentosa with pediatric onset (1 pt), night blindness (0.5 pts), decreased central visual acuity (0.5 pts), annular scotoma, and paracentral retinal atrophy, however, the PP4 code was not met as the proband did not have full-field elecroretinogram or fundus autofluorescence results available (PMID: 32047640). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412742873/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:3696 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0004096 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0267792 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0038663 infores:hetionet CHEBI:59750 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0020555 infores:hetionet GO:2000659 biolink:causes GO:0071347 infores:ubergraph knowledge_assertion manual_agent GO:2000659 GO:0071347 UMLS:C0879264 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0014130 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0009319 infores:hetionet NCBIGene:8398 biolink:causes MONDO:0024457 infores:monarchinitiative not_provided not_provided HGNC:9039 MONDO:0024457 uuid:05bfb141-7748-48bc-a9f7-eefe5669c71d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0005818 infores:hetionet CHEBI:51230 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0232849 infores:hetionet CAID:CA10014267 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014267 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least 5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although the variant is predicted by SSF and MES to create a putative cryptic donor splice site at c.925 (insignificant prediction by SpliceAI), evolutionary conservation prediction algorithms predict the site as being weakly conserved (PhyloP score: 1.25 > 0.1 [-14.1;6.4]), and the variant is not the reference nucleotide in one primate and/or three mammal species, SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10%. In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014267/MONDO:0011071/008 2021-01-12 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6541 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0740394 infores:hetionet CAID:CA267693 biolink:causes MONDO:0009861 infores:clingen CAID:CA267693 MONDO:0009861 PMID:30050108PMID:30747360PMID:28771436PMID:30050108 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PP3 The c.505C>T (p.Arg169Cys) PAH variant has been identified in at least 3 compound heterozygous probands with mild HPA to classic PKU, with at least 1 proband excluding BH4 deficiency (PMIDs: 28771436, 30050108, 30747360). It has been detected in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). This variant occurs and a very low frequency of 0.00001194 in gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267693/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3127 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0948594 infores:hetionet CHEBI:9086 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013456 infores:hetionet CHEBI:4445 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0231218 infores:hetionet NCBIGene:120227 biolink:causes MONDO:0010810 infores:monarchinitiative not_provided not_provided HGNC:20580 MONDO:0010810 uuid:0b267484-ad91-4916-82ff-6937a3b94110 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0010200 infores:hetionet CHEBI:6970 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0232462 infores:hetionet CHEBI:75998 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0011603 infores:hetionet CHEBI:10119 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C3665347 infores:hetionet CHEBI:5864 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0013404 infores:hetionet CHEBI:6129 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C2363730 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006898 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0031037 infores:hetionet CHEBI:71219 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0011175 infores:hetionet CHEBI:3723 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1260880 infores:hetionet CHEBI:31980 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0011991 infores:hetionet UMLS:C1738934 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0033774 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0426649 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0426649 infores:hetionet CHEBI:9571 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0392156 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0029927 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0022107 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151602 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0033775 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0012739 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C3665347 infores:hetionet CAID:CA003783 biolink:causes MONDO:0011450 infores:clingen CAID:CA003783 MONDO:0011450 PMID: Pathogenic PVS1, PM5_Strong, PS3 PM2, BA1, BS1 The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met).In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003783/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50730 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0023067 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0521505 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0521505 infores:hetionet CHEBI:45863 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1145670 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0853958 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853958 infores:hetionet CHEBI:61033 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151904 infores:hetionet CHEBI:9137 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003578 infores:hetionet CHEBI:8430 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0085593 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0015927 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0003864 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1322281 infores:hetionet CHEBI:31348 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0010200 infores:hetionet CHEBI:127780 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0549249 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020542 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0002871 infores:hetionet CHEBI:3082 biolink:causes MONDO:0024291 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0158570 infores:hetionet CHEBI:3393 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0042109 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0854082 infores:hetionet CHEBI:63638 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0549249 infores:hetionet CHEBI:5790 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0746961 infores:hetionet CHEBI:4530 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0017178 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0022408 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0040034 infores:hetionet CHEBI:15854 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0041834 infores:hetionet CHEBI:3655 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0234215 infores:hetionet CHEBI:92923 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0006277 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0011053 infores:hetionet CHEBI:3756 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0026821 infores:hetionet CHEBI:116278 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0027497 infores:hetionet CHEBI:3534 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151754 infores:hetionet CHEBI:465284 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1619712 infores:hetionet CHEBI:50693 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0428974 infores:hetionet NCBIGene:1490 biolink:causes MONDO:0976230 infores:monarchinitiative not_provided not_provided HGNC:2500 MONDO:0976230 uuid:ad0f6ca6-2af2-4dbf-ad19-89717e5dc03d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5165 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0019079 infores:hetionet CAID:CA398326368 biolink:causes MONDO:0011132 infores:clingen CAID:CA398326368 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PVS1 NM_001369369.1(FOXN1):c.1420C>T (p.Gln474Ter) is a nonsense variant in exon 8, of 9, which is predicted to undergo NMD (PVS1). This variant was reported in P20 (PMID: 31447097) with nail dystrophy, low TRECs, and low CD8 cell counts 488 cells/ul [nv:560-1700], which together is highly specific for FOXN1 related disease (PP4). This variant is absent from gnomADv2.1.1 (PM2_supporting). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398326368/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:4027 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0086565 infores:hetionet CHEBI:64312 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011175 infores:hetionet NCBIGene:10128 biolink:causes MONDO:0009069 infores:monarchinitiative not_provided not_provided HGNC:15714 MONDO:0009069 uuid:5f860c2a-98ef-4d18-bfcd-4968db025b54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2001154 biolink:causes GO:0006113 infores:ubergraph knowledge_assertion manual_agent GO:2001154 GO:0006113 CHEBI:2682 biolink:causes MONDO:0004139 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085577 infores:hetionet CHEBI:8028 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0392156 infores:hetionet CHEBI:8869 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0003467 infores:hetionet CHEBI:5558 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0004096 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042769 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151838 infores:hetionet CHEBI:31705 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0006277 infores:hetionet CHEBI:9599 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0234238 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0042373 infores:hetionet CAID:CA270179 biolink:causes MONDO:0010726 infores:clingen CAID:CA270179 MONDO:0010726 PMID: Benign BS1, BS2 PP4, PM2, PS4 The allele frequency of the p.R344W variant in MECP2 is 0.01% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.R344W variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.R344W variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270179/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:10112 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0008031 infores:hetionet CHEBI:8768 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C3495920 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042023 infores:hetionet CHEBI:71023 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0021400 infores:hetionet CHEBI:8888 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0036396 infores:hetionet CHEBI:3001 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0235259 infores:hetionet CHEBI:45951 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0026961 infores:hetionet CHEBI:41423 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011603 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0042510 infores:hetionet CHEBI:61049 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002792 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020649 infores:hetionet CHEBI:17334 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0009421 infores:hetionet CHEBI:6741 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0043094 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0029456 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0087169 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0497247 infores:hetionet NCBIGene:55503 biolink:causes MONDO:0032591 infores:monarchinitiative not_provided not_provided HGNC:14006 MONDO:0032591 uuid:b4372136-c615-4d96-9042-5f65f1972a95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151313 infores:hetionet CHEBI:6933 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0043352 infores:hetionet CHEBI:6754 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0030252 infores:hetionet CAID:CA253913 biolink:causes MONDO:0015152 infores:clingen CAID:CA253913 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PP1, PM2_Supporting PS3, PP3 The NM_003494.4: c.1555G>A variant in DYSF, which is also known as NM_001130987.2: c.1609G>A p.(Gly537Arg), is a missense variant expected to cause substitution of glycine at position 519 for arginine, p.(Gly519Arg). While this variant is not located in a splice region, SpliceAI gives a score of 0.48 for disruption of the splice acceptor site for exon 18 and 0.990 for the creation of a cryptic acceptor within the exon. Both cDNA and mini-gene analyses have demonstrated that this variant induces use of the cryptic acceptor splice site, causing deletion of 34 bp from the 5' side of exon 18, r.1523_1556del. This deletion is expected to result in a frameshift and premature truncation, p.Leu508CysfsTer108, with nonsense mediated decay predicted (PMID: 25312915, 17070050; PVS1_RNA). This variant has been reported in two unrelated individuals with features consistent with LGMD (PMID: 17070050, 17287450, 30107846), including in a homozygous state in a patient without reported familial consanguinity (0.5 pts, PMID: 17070050, 17287450; PM3_Supporting). At least one patient homozygous for this variant had a clinical diagnosis of LGMD/Miyoshi myopathy and absent dysferlin protein expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PMID: 17287450, 17070050; PP4_Strong). In addition, this variant co-segregated with the disease in one affected family member (PMID: 17287450, 17070050; PP1). The filtering allele frequency for this variant is 0.000011824 in gnomAD v4.1.0 exomes (the upper bound of the 95% CI of 7/1111986 European (non-Finnish) alleles), which is lower than the LGMD VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). The REVEL score for this variant is 0.9, suggesting a deleterious effect of the predicted amino acid change. Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells also showed the Gly519Arg protein did not reach the cell membrane, indicating a negative impact on protein function (PMID: 35028538). However, given the experimental data indicating this variant affects splicing, PP3 and PS3_Moderate were not applied. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/15/2025): PVS1_RNA, PM3_Supporting, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA253913/MONDO:0015152/180 2025-07-15 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:724066 biolink:causes MONDO:0012116 infores:monarchinitiative not_provided not_provided HGNC:32925 MONDO:0012116 uuid:00d37d45-8d24-4c5a-ad08-a90c802dbecc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2830004 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1565489 infores:hetionet CHEBI:499361 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0750394 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1322281 infores:hetionet CHEBI:4995 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085669 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020517 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0426576 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0027651 infores:hetionet CHEBI:17026 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013362 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0037274 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0014868 infores:hetionet CHEBI:9352 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0033687 infores:hetionet CHEBI:3716 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0011603 infores:hetionet CHEBI:8024 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0023530 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151810 infores:hetionet CHEBI:10127 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0554976 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0012833 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011609 infores:hetionet CHEBI:9570 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151686 infores:hetionet NCBIGene:8842 biolink:causes MONDO:0011370 infores:monarchinitiative not_provided not_provided HGNC:9454 MONDO:0011370 uuid:8366b167-0ca4-4638-a604-031cefbcba5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C3665386 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0178298 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0039971 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0000737 infores:hetionet CHEBI:9328 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0027497 infores:hetionet CHEBI:5147 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C1302752 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0152965 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0152965 infores:hetionet CHEBI:51380 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0042075 infores:hetionet CHEBI:65173 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0004093 infores:hetionet CAID:CA000492 biolink:causes MONDO:0017623 infores:clingen CAID:CA000492 MONDO:0017623 PMID: Pathogenic PM2, PP1, PP2, PS3, PS4_Moderate PTEN c.510T>A (p.Ser170Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 17942903, PMID 10866302, PMID 9256433, PMID 21828076PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 17526800, PMID 23335809, PMID 30528446)PM2: Absent in large sequenced populations (PMID 27535533)PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 17526800, PMID 9241266)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000492/MONDO:0017623/003 2021-10-29 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51230 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0151601 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042571 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0392386 infores:hetionet CHEBI:3310 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0001122 infores:hetionet CHEBI:3223 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0151908 infores:hetionet CHEBI:28148 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0003811 infores:hetionet CHEBI:184555 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0042023 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0042109 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0162429 infores:hetionet CHEBI:38940 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0085932 infores:hetionet CAID:CA405691206 biolink:causes MONDO:0018493 infores:clingen CAID:CA405691206 MONDO:0018493 PMID: Likely Pathogenic PS4_Moderate, PM1_Supporting, PP1_Strong, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with serine at codon 4935 of the RYR1 protein, p.(Gly4935Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:19918671, PMID:21455645). This variant segregates with MHS in >10 individuals, PP1_Strong (PMID:19918671). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.962) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405691206/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CAID:CA226667 biolink:causes MONDO:0010725 infores:clingen CAID:CA226667 MONDO:0010725 PMID: Pathogenic PS4, PP1_Strong, PP3_Strong, PP4 BS1, PM2 The NM_000330.4(RS1):c.304C>T variant is a missense variant encoding the substitution of Arginine with Tryptophan at amino acid 102. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000008256 among hemizygous individuals, with 3 variant alleles / 363368 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.958, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.01 Acceptor Gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through 3 meioses in a family including two affected brothers and 5 other affected members (PP1_strong; PMID: 36695495, 9326935, 16901436, 24634885). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (5 points, PMID: 24634885, PP4). This variant has been reported in at least 5 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 33124204, 9326935, 22245991, 36695495, 28348004, 35456481, PS4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PP3_strong, PP1_strong, PS4, and PP4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226667/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:31709 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0015397 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0009450 infores:hetionet CHEBI:16335 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0016382 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0595885 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0595885 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006919 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0032827 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0948594 infores:hetionet NCBITaxon:815 biolink:causes MONDO:0006705 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:815 MONDO:0006705 CHEBI:63638 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0231218 infores:hetionet CAID:CA409108770 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108770 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS2 The c.1045C>T variant in the HNF4 homeobox A gene, HNF4A, results in a premature termination at codon 349 (p.(Gln349Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified as a de novo occurrence with confirmed parental relationships in 1 individual whose clinical picture is highly specific for HNF4A-MODY (diazoxide-repsonsive hyperinsulinemic hypoglycemia and negative testing for KCNJ11 and ABCC8)(PS2; PP4; PMID: 20164212). In summary, c.1045C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PS2, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108770/MONDO:0015967/085 2024-10-24 2024-10-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:92998 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0558489 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0234215 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0687133 infores:hetionet CHEBI:71219 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151908 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0033777 infores:hetionet CHEBI:72323 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0018681 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0038663 infores:hetionet CHEBI:4885 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0232462 infores:hetionet CHEBI:5130 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0010038 infores:hetionet CHEBI:7936 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011124 infores:hetionet CHEBI:8356 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030193 infores:hetionet CHEBI:63580 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0028081 infores:hetionet CHEBI:2618 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C3665347 infores:hetionet CHEBI:10101 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2173677 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0234458 infores:hetionet CHEBI:9448 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C3665347 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0518015 infores:hetionet CHEBI:4974 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0002994 infores:hetionet CHEBI:15765 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0031542 infores:hetionet CHEBI:27834 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0039231 infores:hetionet CHEBI:16796 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0041834 infores:hetionet CHEBI:47898 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004093 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0162429 infores:hetionet GO:1902908 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1902908 GO:0051641 CHEBI:38562 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0234215 infores:hetionet CHEBI:16586 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0151539 infores:hetionet CAID:CA023571 biolink:causes MONDO:0007750 infores:clingen CAID:CA023571 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BS3, PM5, PP3 The NM_000527.5(LDLR):c.1765G>C (p.Asp589His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.000008790 (0.0009%) in Non-Finnish European exomes+genomes (gnomAD v2.1.1)BP4 - REVEL = 0.424. It is below 0.5, splicing evaluation needed. Functional data on splicing not available.A) variant not on limits.B) does not create AG or GTVariant is not predicted to alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023571/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:35778 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042963 infores:hetionet CHEBI:78543 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151905 infores:hetionet CHEBI:28748 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0031256 infores:hetionet CHEBI:142290 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0015230 infores:hetionet CHEBI:44185 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0014591 infores:hetionet CHEBI:45285 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0232462 infores:hetionet CHEBI:9599 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0023066 infores:hetionet CHEBI:75922 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0005741 infores:hetionet CHEBI:17650 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C2242996 infores:hetionet CHEBI:6933 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0020538 infores:hetionet NCBIGene:7287 biolink:causes MONDO:0013457 infores:monarchinitiative not_provided not_provided HGNC:12423 MONDO:0013457 uuid:0d40ed40-4fa3-4b9e-90b9-ded2b104f720 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011168 infores:hetionet CHEBI:31348 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0014742 infores:hetionet CAID:CA2480594443 biolink:causes MONDO:0015967 infores:clingen CAID:CA2480594443 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4 PS4 The c.-187C>A variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). In summary, c.-187C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP4, PM1_Supporting, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2480594443/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0002792 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002342 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0007302 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1963790 infores:hetionet CHEBI:37333 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0008031 infores:hetionet CHEBI:9123 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0032617 infores:hetionet CHEBI:4858 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0027497 infores:hetionet CAID:CA2580063208 biolink:causes MONDO:0100368 infores:clingen CAID:CA2580063208 MONDO:0100368 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3 NM_000329.3(RPE65):c.1282_1303del (p.Gly428MetfsTer5) is a frameshift variant that introduces a premature stop codon into exon 12 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant confirmed in trans (PMID: 19431183). However, the proband was not counted for PM3 in order to avoid circularity. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1 and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580063208/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:567361 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1368065 infores:hetionet CHEBI:7443 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0030920 infores:hetionet CHEBI:5138 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151908 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0267406 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0267406 infores:hetionet CHEBI:28830 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0009676 infores:hetionet CHEBI:45863 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0239981 infores:hetionet CHEBI:72297 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0004093 infores:hetionet CHEBI:116278 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0011603 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0032326 infores:hetionet CHEBI:94411 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0235238 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0009443 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038454 infores:hetionet CHEBI:77733 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0011991 infores:hetionet CHEBI:15552 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0032227 infores:hetionet CHEBI:74947 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0852911 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0234913 infores:hetionet CHEBI:15940 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151671 infores:hetionet CHEBI:167309 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0231530 infores:hetionet CHEBI:101853 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0017178 infores:hetionet CHEBI:3048 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0018843 infores:hetionet CAID:CA229385 biolink:causes MONDO:0009861 infores:clingen CAID:CA229385 MONDO:0009861 PMID:23357515 Pathogenic PVS1, PM2, PP4 This c.1199+1G>A variant in PAH was reported in 1 Czech patient with PAH deficiency (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF: 0.00001). This variant in the +1 splice donor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229385/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2611 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0030196 infores:hetionet CHEBI:40303 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0409974 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011570 infores:hetionet CHEBI:92923 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0042267 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0019158 infores:hetionet NCBIGene:4921 biolink:causes MONDO:0032579 infores:monarchinitiative not_provided not_provided HGNC:2731 MONDO:0032579 uuid:98da9fe3-cc55-4e85-a00e-da4fb77be0a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C2047937 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0520893 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0037274 infores:hetionet CHEBI:31625 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0011603 infores:hetionet CHEBI:9123 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0231530 infores:hetionet CHEBI:3654 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0151723 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235763 infores:hetionet GO:0030098 biolink:causes CL:0000542 infores:ubergraph knowledge_assertion manual_agent GO:0030098 CL:0000542 CHEBI:10650 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235266 infores:hetionet CAID:CA292876 biolink:causes MONDO:0044970 infores:clingen CAID:CA292876 MONDO:0044970 PMID: Benign BA1 BP4 The c.1637C>T (p.Arg546Cys) variant in POLG has been reported with an allele frequency in the African American population at 1.88% in gnomAD. (BA1). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA292876/MONDO:0044970/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:15428 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0080274 infores:hetionet CHEBI:474053 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0151904 infores:hetionet CHEBI:63622 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0018681 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0015397 infores:hetionet GO:1901249 biolink:causes GO:0060541 infores:ubergraph knowledge_assertion manual_agent GO:1901249 GO:0060541 CHEBI:3223 biolink:causes HP:6000855 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0009269 infores:hetionet CHEBI:4975 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0015672 infores:hetionet CHEBI:499361 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0232462 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011570 infores:hetionet CHEBI:10023 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151610 infores:hetionet CHEBI:9570 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151904 infores:hetionet CHEBI:8890 biolink:causes HP:0011891 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0032797 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0948594 infores:hetionet CAID:CA16607872 biolink:causes MONDO:0008723 infores:clingen CAID:CA16607872 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PP4, PM1, PM3, PM5_Supporting The c.1146G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 382 (p.Lys382Asn). Information provided to the ACADVL VCEP provided by an external clinical laboratory shows an elevated plasma C14:1 in an individual that that had c.848T>C (p.Val283Ala) confirmed in trans (PP4, PM3). Another missense variant c.1144A>C (p.Lys382Gln) (Variation ID: 1628) in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.91, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as [CLASSIFICATION] for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM3, PM5_Supporting, PP3 PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607872/MONDO:0008723/021 2024-09-24 2024-09-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4708 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0033117 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0040046 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020651 infores:hetionet CHEBI:52010 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0018681 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002792 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0032961 infores:hetionet CHEBI:194135 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0267797 infores:hetionet CHEBI:499361 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0014518 infores:hetionet NCBITaxon:318479 biolink:causes MONDO:0016472 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:318479 MONDO:0016472 CHEBI:47499 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0236075 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0015376 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0235431 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0015075 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0549473 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021843 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0033774 infores:hetionet CHEBI:3286 biolink:causes UMLS:C2720436 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C2720436 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0007642 infores:hetionet CHEBI:16469 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0162285 infores:hetionet CHEBI:3568 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1458155 infores:hetionet CHEBI:63612 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C3665624 infores:hetionet CHEBI:10023 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0038002 infores:hetionet NCBIGene:2693 biolink:causes MONDO:0014403 infores:monarchinitiative not_provided not_provided HGNC:4267 MONDO:0014403 uuid:6be7ed9b-f3dd-46cc-bf78-eb9a351ec214 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3650 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0014457 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0403632 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042373 infores:hetionet CAID:CA10644631 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644631 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*933T>C is a 3' UTR variant which has a MAF of 0.0007054 (0.07054%, 48/68048, 48 alleles) in the European (non-finnish) subpopulation of the gnomAD 3.1.2 cohort which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644631/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3310 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0677500 infores:hetionet NCBIGene:340533 biolink:causes MONDO:0010483 infores:monarchinitiative not_provided not_provided HGNC:29433 MONDO:0010483 uuid:d9dd681c-a1a2-4218-b3c1-b36e47f9118c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16714 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0012569 infores:hetionet CHEBI:41977 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0015672 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0595877 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0037274 infores:hetionet CHEBI:63630 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0036974 infores:hetionet CHEBI:3654 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0026821 infores:hetionet CHEBI:66903 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0026858 infores:hetionet CHEBI:6438 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C3665347 infores:hetionet CHEBI:3441 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0018681 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0020538 infores:hetionet CHEBI:63613 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0041834 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0040034 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0014358 infores:hetionet CHEBI:3077 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0040038 infores:hetionet CHEBI:724125 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C1527358 infores:hetionet CHEBI:50131 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0039231 infores:hetionet CHEBI:51209 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0037763 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0006145 infores:hetionet CHEBI:8404 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C2939147 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0018799 infores:hetionet CHEBI:3077 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0237849 infores:hetionet CHEBI:50922 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0232292 infores:hetionet CHEBI:45924 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C1368065 infores:hetionet NCBIGene:1917 biolink:causes MONDO:0014617 infores:monarchinitiative not_provided not_provided HGNC:3192 MONDO:0014617 uuid:092d7031-8e80-4f3f-8fa2-cc10ffe90eeb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0011991 infores:hetionet CAID:CA410207932 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207932 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.613+1G>A is a canonical splice site variant affecting the splice donor site at c.613 in intron 6, leading to exon 6 skipping. This results in an in-frame deletion of amino acids 171-205, including G170, within the Runt Homology Domain (RHD) (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207932/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0029408 infores:hetionet CHEBI:15551 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0080274 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015397 infores:hetionet CHEBI:100241 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0424790 infores:hetionet CAID:CA16044278 biolink:causes MONDO:0019497 infores:clingen CAID:CA16044278 MONDO:0019497 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PM3 The NM_022124.6:c.478G>A variant in the CDH23 gene is a missense variant predicted to cause substitution of aspartic acid to asparagine at amino acid 160 (p.Asp160Asn). The computational predictor REVEL gives a score of 0.8, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/112644 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. This variant has been identified in one individual homozygous for the variant with Usher syndrome (PMID: 2746042, 0.5 PM3 points, PP4). Another individual with hearing loss and cochlear implants at age 1 year harbored this variant and another pathogenic variant, though phase was unknown (PMID: 35020051, 0.5 PM3 points). A third individual with Usher syndrome had a variant of uncertain significance phase unknown (Invitae internal data, SCV001516999.2, 0 PM3 points). It has been reported in additional individuals with hearing loss who either did not have an age of onset noted or did not have a second variant reported (PMID: 35020051, 22899989). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting, PM3, PP3, PP4. (VCEP specifications version 2.0.0; Dec 21, 2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA16044278/MONDO:0019497/005 2022-12-21 2023-02-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3614 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0151610 infores:hetionet NCBIGene:23007 biolink:causes MONDO:0030886 infores:monarchinitiative not_provided not_provided HGNC:29185 MONDO:0030886 uuid:e1956482-3b01-45e3-a645-9261b270d641 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0030193 infores:hetionet CAID:CA170157 biolink:causes MONDO:0010726 infores:clingen CAID:CA170157 MONDO:0010726 PMID: Benign BS1, BS2 The p.Arg354Leu variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The highest population minor allele frequency of the p.Arg354Leu variant in MECP2 in gnomAD v4.1 is 0.0001252 in the European (non-Finnish) population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1 and therefore meets this criterion (BS1). In summary, the p.Arg354Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170157/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Contradicts true CHEBI:7936 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0558489 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0024299 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0162279 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0162279 infores:hetionet CAID:CA1396372 biolink:causes MONDO:0019501 infores:clingen CAID:CA1396372 MONDO:0019501 PMID: Pathogenic PP3, PP4, PP1, PM3_Very Strong, PM2_Supporting PS3 The c.1859G>T in USH2A is a missense variant predicted to cause a substitution of cysteine to phenylalanine at amino acid 620 (p.Cys620Phe) . The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (5/129062) in the European(non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.974 (PP3). This variant has been detected in at least four probands with other pathogenic or suspected-pathogenic variants confirmed in trans (4.0 PM3_Very Strong points; PMID: 22135276, 33089500, 36011334). The probands harbored these variants in USH2A: p.Trp1607*, p.Glu767Serfs*21, p.Cys759Phe, p.Gly3195*. At least one patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 22135276). The variant has been reported to segregate with AR Usher syndrome in one affected family member from one family (PP1; PMID: 36011334). In summary, this variant meets the criteria to be classified as pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Very Strong, PP4, PP1. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1396372/MONDO:0019501/005 2023-10-24 2023-10-25 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:7447 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0018965 infores:hetionet CHEBI:63621 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0036974 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0033845 infores:hetionet CHEBI:7581 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0549249 infores:hetionet CHEBI:119915 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0035455 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C1861172 infores:hetionet CHEBI:5847 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0009450 infores:hetionet CHEBI:8060 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0015230 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0857073 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0857073 infores:hetionet CAID:CA401366685 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366685 MONDO:0009290 PMID: Pathogenic PM2_Supporting, PM3_Strong, PVS1_Strong PP4, PS1 The NM_000152.5:c.1437+2T>C variant alters the donor consensus splice site of intron 9 of GAA. Sequencing of fibroblast cDNA from a patient who is compound heterozygous for the variant revealed skipping of exon 9. Exon 9 skipping is predicted to result in loss of amino acids 443-479; this region of the protein forms part of the GAA catalytic barrel)(amino acids 347-727) (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837) (PVS1_Strong). At least 3 patients with symptoms consistent with Pompe disease have been reported with this variant. Two of them are reported to have deficient GAA activity. However, the values were not provided (PMID: 11343339, 18429042, 29122469, 31392188) (insufficient evidence to apply PP4). At least 3 patients with symptoms consistent with Pompe disease have been reported with this variant. Two of them are reported to have deficient GAA activity. However, the values were not provided (PMID: 11343339, 18429042, 29122469, 31392188) (insufficient evidence to apply PP4). All three patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. This includes c.-32-13T>G (ClinVar variation ID: 4027) (phase unconfirmed, 0.5 points) (PMID: 29122469, 31392188), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (phase unconfirmed, 0.5 points) (PMID: 18429042), and c.1551+1G>C (ClinVar Variation ID: 554983) (confirmed in trans by parental testing, 1 point) (PMID: 11343339). Total 2 points (PM3_Strong). The variant is absent in gnomAD v2.1.1. The highest population minor allele frequency in gnomAD v4.1.0. is 8.489e-7 (1/1177976 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants in the consensus sequence of this donor splice site have been reported in patients with Pompe disease including c.1437+1G>A (PMID: 22252923) and c.1437G>A (PMID: 26160551). These variant have not yet been classified by the ClinGen LD VCEP. There is a ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 4, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366685/MONDO:0009290/010 2024-10-04 2024-10-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8364 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0234215 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018790 infores:hetionet CHEBI:100246 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151754 infores:hetionet CHEBI:7476 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0037299 infores:hetionet CHEBI:63791 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235896 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1260922 infores:hetionet CAID:CA2573051035 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051035 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4_Moderate The c.185delA variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 62 (NM_000545.8), adding 93 novel amino acids before encountering a stop codon (p.(Asn62MetfsTer93)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant segregated with diabetes, with 8 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, response to low dose sulfonylurea, and low renal threshold) (PP4_Moderate; PMID: 28701371, internal lab contributors). In summary, c.185delA meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051035/MONDO:0015967/017 2022-04-03 2022-04-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:168396 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0232492 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0234913 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0424000 infores:hetionet CHEBI:17347 biolink:causes MONDO:0021259 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0033578 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0392025 infores:hetionet CHEBI:50922 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0032617 infores:hetionet CHEBI:5959 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0547030 infores:hetionet CHEBI:291342 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C2830004 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0518015 infores:hetionet NCBIGene:374654 biolink:causes MONDO:0011778 infores:monarchinitiative not_provided not_provided HGNC:30497 MONDO:0011778 uuid:ab8a0ac2-ecf3-43ea-8957-d10b0f8074f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020517 infores:hetionet CHEBI:175901 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0014742 infores:hetionet CHEBI:8059 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0027497 infores:hetionet CAID:CA402998096 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998096 MONDO:0012999 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3 BA1, BS1 The NM_000156.6:c.134G>A (p.Trp45Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 1/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least two probands with GAMT deficiency. Of those probands, both were homozygous for the variant (PMIDs 31222513, 33996490) (PM3). At least one proband (two siblings) with this variant had elevated GAA and low creatine in plasma (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2419155). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct 12, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998096/MONDO:0012999/026 2023-10-12 2023-11-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52717 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020542 infores:hetionet CAID:CA152665 biolink:causes MONDO:0015152 infores:clingen CAID:CA152665 MONDO:0015152 PMID: Benign BA1 PM3, BP4, BP7 The NM_003494.4: c.3534C>T p.(Ile1178=) variant in DYSF, which is also known as NM_001130987.2: c.3588C>T (p.Ile1196=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008874 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 10642/1180038 European (non-Finnish) chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant was detected in a heterozygous state in one individual with suspected LGMD and absent dysferlin expression by blood monocyte assay. No second variant in DYSF was identified, and this individual also had two variants in DNAJB6 (PMID: 25493284, 36983702). The SpliceAI prediction score for this variant is 0.27, which is greater than the VCEP threshold of <0.05 (BP4 not met). However, RNASeq data showed this variant does not affect splicing (PMID: 36983702). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/19/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA152665/MONDO:0015152/180 2025-05-19 2025-06-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4728 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0030252 infores:hetionet CHEBI:194135 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0232462 infores:hetionet CHEBI:8768 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0149745 infores:hetionet CHEBI:50648 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0041657 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0853697 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042373 infores:hetionet GO:0043353 biolink:causes CL:0000595 infores:ubergraph knowledge_assertion manual_agent GO:0043353 CL:0000595 CHEBI:63635 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0041969 infores:hetionet CHEBI:119573 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0030232 infores:hetionet CHEBI:63622 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0020458 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0242350 infores:hetionet CHEBI:68584 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0233407 infores:hetionet CHEBI:50859 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0024902 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0031350 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0521169 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0521169 infores:hetionet CHEBI:15551 biolink:causes UMLS:C1868769 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C1868769 infores:hetionet CHEBI:84500 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085593 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0019112 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0015230 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0948089 infores:hetionet CAID:CA315433936 biolink:causes MONDO:0007064 infores:clingen CAID:CA315433936 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting PM5 The c.940G>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Aspartic Acid by Tyrosine at amino acid 314 (p.Asp314Tyr). The filtering allele frequency (the upper threshold of the 95% CI of 3/74910 alleles) of the c.940G>T variant in ADA is 0.00001063 for African/African American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Another missense variant [c.941A>G, p.Asp314Gly] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA315433936/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA10014174 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014174 MONDO:0011071 PMID: Benign BA1, BP4 PS3, PS1, PS2, PS4, BP2, BP3, BP1, BS1, BS3, BS4, BP5, BP7, PM2, PVS1, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1415T>C (p.Leu472Pro) is a missense variant in the final exon of the protein. MAF of 0.002289 (0.2289%, 23/10046 alleles, gnomad v2.11) in South East Asian population: cohort is ≥ 0.0015 (0.15%) (BA1). The REVEL score= 0.414 (≤0.50) and SpliceAI is ≤0.20 (0.00) (BP4). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014174/MONDO:0011071/008 2022-04-08 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3082 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0041912 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0042109 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005086 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0007134 infores:hetionet CAID:CA10443808 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443808 MONDO:0010315 PMID: Uncertain Significance PM1_Strong, PM2_Supporting The NM_000206.3(IL2RG):c.821T>C (p.Ile274Thr) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. This variant introduces a polar residue within the transmembrane region (amino acids 263-283) of IL2RG, which is defined as a critical functional domain by the ClinGen SCID VCEP (PM1_Strong).The filtering allele frequency (the upper threshold of the 95% CI of 2/70896) of the c.821T>C variant in IL2RG is 0.000004680 for European (non- Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000124; PM2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: PM1_strong and PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443808/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:5138 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C3495920 infores:hetionet UMLS:C0879264 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020461 infores:hetionet CHEBI:2659 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0001925 infores:hetionet CHEBI:6129 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0149745 infores:hetionet CHEBI:3312 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0011991 infores:hetionet CAID:CA645616656 biolink:causes MONDO:0100437 infores:clingen CAID:CA645616656 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PP4 NM_001034853.2(RPGR):c.3317del (p.Lys1106SerfsTer25) is a frameshift variant due to 1-nucleotide deletion resulting in a premature stop codon after 25 amino acids in exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA645616656/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CAID:CA410148157 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148157 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS4, PS2, BA1, BP4, BP2, BS3, BS4, PM6, PVS1, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1092C>G (p.Ile364Met) is a missense variant which is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). To the best of our knowledge, this variant has not been reported in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148157/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7640 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0151827 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0853117 infores:hetionet CHEBI:51380 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0030305 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0027092 infores:hetionet UBERON:0002539 biolink:causes UBERON:0007690 infores:ubergraph knowledge_assertion manual_agent UBERON:0002539 UBERON:0007690 CHEBI:6775 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009421 infores:hetionet CHEBI:8805 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0011603 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0040053 infores:hetionet CHEBI:82960 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0024305 infores:hetionet CHEBI:5558 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0039584 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0024299 infores:hetionet CAID:CA1139532300 biolink:causes MONDO:0000572 infores:clingen CAID:CA1139532300 MONDO:0000572 PMID: Pathogenic PP4, PM2_Supporting, PM3, PVS1 PM1, BA1, PS3, BS1, BS3 The NM_000448.3:c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer) variant in RAG1 is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay but is predicted to cause a premature stop codon that leads to the truncation of part of the core region (aa 387-1011) critical to protein function (PVS1; PMID 26996199). This variant is absent from gnomAD v2.1.1. (PM2_Supporting). This variant has been detected in four individuals with SCID. Of those individuals, one individual was homozygous for the variant (0.5pt, PMID 25869295, 30307608). One individual was compound heterozygous (p.K621E, VUS by the SCID VCEP, in trans) (0pt, PMID 30307608). One individual was with this variant and a variant Pathogenic according to the SCID VCEP (p.K86VfsX33), but the phase was not confirmed (0.5pt, PMID 32311393). One individual was reported in a ClinVar entry, but the information on the other allele is not available (0pt, Baylor Genetics, SCV001530390.1). TOTAL: 1.0pt, PM3.PMID 25869295: Patient #4 with this variant was diagnosed with SCID (0.5pt) and displayed a T-B-NK+ profile (0.5pt). Total: 1.0 pt, PP4 is met.In summary, this variant meets the criteria to be classified as Pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PM3, and PP4. (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532300/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5790 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0035455 infores:hetionet CHEBI:3757 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0851578 infores:hetionet CAID:CA501005 biolink:causes MONDO:0009290 infores:clingen CAID:CA501005 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PS3_Moderate, PM2_Supporting PM5 The NM_000152.5:c.1003G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 335 (p.Gly335Arg). At least 4 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples or were reported to be on enzyme replacement therapy for Pompe disease (PP4_Moderate) (PMIDs 31510962, 26497565, 31193175, 24685124). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.876C>G p.Tyr292X (PMID 31510962); the variants were confirmed in trans by familial testing (PM3). The highest population minor allele frequency in gnomAD v4.1.0 for this variant is 0.000011 (1/91090) alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 0.8% GAA activity in cells and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1004G>A (p.Gly335Glu), in the same codon has been reported in a patient with Pompe disease (PMIDs 22644586, 32711049). This variant has been classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP. Since c.1003G>A (p.Gly335Arg) was used to apply PM5 in the classification of c.1004G>A (p.Gly335Glu), PM5 is not included here to avoid circular logic (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 972790; 3 star review status) with six submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0.0): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the Lysosomal Diseases VCEP, June 17, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA501005/MONDO:0009290/010 2025-06-17 2025-07-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3216 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151505 infores:hetionet CHEBI:4710 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0043094 infores:hetionet CHEBI:7443 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C2979982 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C2225524 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0033774 infores:hetionet CHEBI:51230 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0013404 infores:hetionet NCBITaxon:1311 biolink:causes MONDO:0700217 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1311 MESH:D000071074 DB00512_MESH_D000071074_1 CHEBI:3647 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0024141 infores:hetionet CHEBI:3419 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0221490 infores:hetionet CHEBI:8212 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0232333 infores:hetionet CHEBI:47519 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085641 infores:hetionet CHEBI:4511 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0023530 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0017675 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0020517 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0233414 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0004936 infores:hetionet CHEBI:9448 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0015672 infores:hetionet UMLS:C0005740 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0233407 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0006852 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001221 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0014867 infores:hetionet CHEBI:135935 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0549622 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0152227 infores:hetionet GO:0061168 biolink:causes GO:0071696 infores:ubergraph knowledge_assertion manual_agent GO:0061168 GO:0071696 CAID:CA10014514 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014514 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BS3, BS1, BS4, PM4, PM1, PM5, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.444C>T (p.Thr148=) is a synonymous variant which has a SpliceAI score of 0.00 and a PhyloP score of -6.58, indicating no predicted impact on splicing and lack of conservation (BP4, BP7). This variant is present in gnomAD but not at an elevated frequency, so no population codes were applied. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014514/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true NCBITaxon:1301 biolink:causes MONDO:0021680 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1301 MESH:D013290 DB02703_MESH_D013290_1DB01112_MESH_D013290_1DB00447_MESH_D013290_1DB01416_MESH_D013290_1DB00199_MESH_D013290_1DB01053_MESH_D013290_2DB01140_MESH_D013290_1DB01415_MESH_D013290_1DB01150_MESH_D013290_1DB00671_MESH_D013290_1 CHEBI:2549 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0497156 infores:hetionet CHEBI:6375 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0235378 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011616 infores:hetionet CHEBI:7852 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0037383 infores:hetionet CHEBI:4653 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C2242737 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0009319 infores:hetionet CHEBI:10650 biolink:causes MONDO:0044339 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0158252 infores:hetionet CHEBI:2663 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0043144 infores:hetionet CAID:CA226437 biolink:causes MONDO:0100437 infores:clingen CAID:CA226437 MONDO:0100437 PMID:10958648 Pathogenic PVS1, PP4, PM2_Supporting PS3 NM_001034853.2(RPGR):c.706C>T (p.Gln236Ter) is a nonsense variant that introduces a premature stop in codon 236 within exon 7 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). Exogenously expressed RPGR harboring the variant exhibits reduced interaction with RPGRIP1 in a yeast-2-hybrid experiment (PMID: 10958648). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts) with a female relative showing fundus signs only (1 pt), early onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), moderate myopia (0.5 pts), optic disc pallor (0.5 pts), attenuated vessels, bone spicule pigmentation (0.5 pts), macular atrophy, visual field constriction (0.5 pts), and abnormal fundus autofluorescence, which together are specific for RPGR-related retinopathy (PMID: 32012938, 7 points, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226437/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:478164 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C3665624 infores:hetionet CHEBI:171719 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013491 infores:hetionet CHEBI:47381 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085624 infores:hetionet CHEBI:8871 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023211 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001517 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013369 infores:hetionet UMLS:C0005740 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0232462 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0595877 infores:hetionet CHEBI:5100 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0001824 infores:hetionet CAID:CA214221 biolink:causes MONDO:0000573 infores:clingen CAID:CA214221 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PP4, PM5, PS3 The c.328A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Methionine by Leucine at amino acid 110 (p.Met110Leu). The filtering allele frequency (the upper threshold of the 95% CI of 7/1180032alleles) of the c.328A>C variant in RAG2 is 0.000001940 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.The variant has a mean recombination activity of 74.6% (SEM 1.8) compared to WT hRAG2, which is higher than 60% of wild-type activity (to be considered at least a supporting level). So, PS3 is not applied at any strength level. (PMID: 29772310).At least one patient in the literature seems to be a carrier of this variant (PMID: 29772310); however, the complete genetic and clinical information for the patient is not available. PP4 is not met.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PM1_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214221/MONDO:0000573/124 2024-05-13 2024-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:51860 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0042075 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1565489 infores:hetionet CHEBI:10023 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0006384 infores:hetionet CAID:CA121717 biolink:causes MONDO:0010726 infores:clingen CAID:CA121717 MONDO:0010726 PMID: Likely Pathogenic PP1_Moderate, PS3_Supporting, PM1, PM5, PP3 PM2 Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701) (PS3_supporting). The variant has been reported to segregate in three informative meioses (PMID 18989701, internal database) (PP1_Moderate). The p.Pro152Ala variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (10767337) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro152Ala variant in MECP2 is classified as likely pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS3_supporting, PP1_moderate, PM1, PM5, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121717/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:253342 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0023067 infores:hetionet CHEBI:4909 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0030554 infores:hetionet CHEBI:41423 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151576 infores:hetionet CHEBI:50841 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0037036 infores:hetionet CHEBI:5004 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0011606 infores:hetionet NCBIGene:4190 biolink:causes MONDO:0030072 infores:monarchinitiative not_provided not_provided HGNC:6970 MONDO:0030072 uuid:c7aa5ad7-b4e9-4122-8c02-4aa5ee2280a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0003467 infores:hetionet CHEBI:31622 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0015230 infores:hetionet CHEBI:50922 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020580 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0013404 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042571 infores:hetionet CHEBI:175901 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0085593 infores:hetionet CHEBI:51364 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0041969 infores:hetionet CHEBI:32139 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0232462 infores:hetionet CHEBI:39867 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0007859 infores:hetionet CHEBI:8214 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0042023 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020649 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0233494 infores:hetionet CHEBI:6775 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0023218 infores:hetionet CHEBI:15854 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0242528 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0948594 infores:hetionet CHEBI:64355 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0015967 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0041912 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0853847 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011991 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0151883 infores:hetionet CHEBI:28901 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0428974 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0241558 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0241558 infores:hetionet CHEBI:7443 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002994 infores:hetionet CHEBI:5165 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0542571 infores:hetionet CHEBI:28787 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0022660 infores:hetionet CHEBI:31397 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C1527344 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0409962 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0409962 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0009938 infores:hetionet NCBIGene:5518 biolink:causes MONDO:0014605 infores:monarchinitiative not_provided not_provided HGNC:9302 MONDO:0014605 uuid:0fd06f65-f446-4032-a7f0-8414e49c1fe1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50841 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0013144 infores:hetionet CHEBI:47780 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017565 infores:hetionet CHEBI:3749 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0010692 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0009241 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0006266 infores:hetionet CAID:CA209272 biolink:causes MONDO:0015967 infores:clingen CAID:CA209272 MONDO:0015967 PMID: Likely Benign BP4, BS1 The c.427-5C>T variant in the hepatocyte nuclear factor-4-alpha gene, HNF4A, is located in the non-canonical splice acceptor region five base pairs upstream of the intron 4/ exon 4 splice junction of NM_175914.5. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006366, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). The computational splicing predictor SpliceAI gives a score of 0.00 for acceptor loss/gain, suggesting that the variant has no impact on splicing. In summary, c.427-5C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDENmP (specification version 1.0.0, approved 11/16/2022): BP4, BS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA209272/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3437 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0423232 infores:hetionet CHEBI:6931 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0009676 infores:hetionet CHEBI:38940 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0009782 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006846 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020540 infores:hetionet CHEBI:194135 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042510 infores:hetionet CAID:CA220587 biolink:causes MONDO:0009861 infores:clingen CAID:CA220587 MONDO:0009861 PMID:15589814PMID:26666653PMID:27121329 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong PM5 PAH-specific ACMG/AMP criteria applied: PM2: 1 allele in ExAC ; PP3: tools predict damaging ; PP4_Moderate: P281S Identified in at least one patient with classic PKU. BH4 deficiency excluded. (PMID:15589814); PM3_Strong: Detected with c.1315+1G>A & p.Arg243Ter, pathogenic in ClinVar (PMID:26666653; PMID:27121329). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220587/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38940 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0006840 infores:hetionet CHEBI:116278 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0917801 infores:hetionet CHEBI:4636 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0042963 infores:hetionet CHEBI:16899 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0237849 infores:hetionet CHEBI:7959 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0151786 infores:hetionet CHEBI:28864 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0043144 infores:hetionet CHEBI:71940 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0017168 infores:hetionet CHEBI:4659 biolink:causes UMLS:C0231230 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0231230 infores:hetionet CHEBI:142290 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042963 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0039971 infores:hetionet UMLS:C0009315 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0858635 infores:hetionet NCBIGene:23224 biolink:causes MONDO:0013072 infores:monarchinitiative not_provided not_provided HGNC:17084 MONDO:0013072 uuid:f5a878dd-c200-4afc-a278-ccd707a3a86d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46295 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0948089 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0948296 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235969 infores:hetionet CHEBI:584020 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0040046 infores:hetionet CHEBI:7936 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0005758 infores:hetionet NCBIGene:23495 biolink:causes MONDO:0012291 infores:monarchinitiative not_provided not_provided HGNC:18153 MONDO:0012291 uuid:517a2c03-77bc-4783-aca9-310d1069ebb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:145226 biolink:causes MONDO:0012990 infores:monarchinitiative not_provided not_provided HGNC:19977 MONDO:0012990 uuid:8bb2b34e-cd91-4cde-8670-3f9d158a4f1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0013295 infores:hetionet CHEBI:7496 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0013404 infores:hetionet CHEBI:9570 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018965 infores:hetionet CHEBI:135935 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0013395 infores:hetionet CHEBI:48844 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0006266 infores:hetionet CHEBI:3994 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0085932 infores:hetionet CHEBI:68575 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0740304 infores:hetionet CAID:CA915943525 biolink:causes MONDO:0021056 infores:clingen CAID:CA915943525 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 The NM_000038.6(APC):c.7803_7807del (p.Ser2601ArgfsTer17) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 1 proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PS4 not met; internal data Labcorp Genetics [formerly Invitae]). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1 and PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA915943525/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports UNII:DJJ95FJP1H biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0085620 infores:hetionet NCBIGene:80347 biolink:causes MONDO:0032643 infores:monarchinitiative not_provided not_provided HGNC:29932 MONDO:0032643 uuid:0b24ac7e-454b-47f2-b542-2d01e91fca27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:65055 biolink:causes MONDO:0012453 infores:monarchinitiative not_provided not_provided HGNC:25786 MONDO:0012453 uuid:0e7e8609-62bb-40e2-a00f-e8230f8f8bfc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9725 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0232197 infores:hetionet CHEBI:16469 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0040822 infores:hetionet CHEBI:51380 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0151740 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0919715 infores:hetionet CHEBI:5001 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C2047937 infores:hetionet CHEBI:5062 biolink:causes MONDO:0021259 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0033578 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0009806 infores:hetionet CHEBI:42797 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085593 infores:hetionet CHEBI:4877 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0030554 infores:hetionet CAID:CA10647460 biolink:causes MONDO:0044970 infores:clingen CAID:CA10647460 MONDO:0044970 PMID: Uncertain Significance PM2, BP5 BS2, BP4, PS4, BS4 The c.122G>A (p.Arg42) variant in POLG has been observed in population database gnomAD at 0.03% (PM2). This variant has been observed in 1 casewith another molecular cause a large scale mitochondrial DNA deletion with clinical features of Kearns Sayre Syndrome (BP5; PMID: 21378381). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, BP5. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10647460/MONDO:0044970/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6062 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0233494 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1442903 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0234215 infores:hetionet CHEBI:63632 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0035222 infores:hetionet CHEBI:3994 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0085631 infores:hetionet CHEBI:7789 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0037274 infores:hetionet CHEBI:194135 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013404 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013295 infores:hetionet CHEBI:3403 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0013144 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0178298 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0037274 infores:hetionet CHEBI:48273 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0011551 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0033975 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037278 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0018099 infores:hetionet UBERON:0010531 biolink:causes UBERON:0000084 infores:ubergraph knowledge_assertion manual_agent UBERON:0010531 UBERON:0000084 GO:0090128 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0090128 GO:0007399 CHEBI:5118 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0033774 infores:hetionet NCBIGene:117144 biolink:causes MONDO:0013070 infores:monarchinitiative not_provided not_provided HGNC:17116 MONDO:0013070 uuid:419ae025-3991-4e5d-a8fa-d12cc22733bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040586 infores:hetionet CHEBI:63629 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151905 infores:hetionet CHEBI:8871 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085932 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020649 infores:hetionet CHEBI:4784 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0032617 infores:hetionet CHEBI:5855 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0239981 infores:hetionet CHEBI:7798 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0002792 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0014549 infores:hetionet CHEBI:63598 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0039231 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0040435 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0235818 infores:hetionet CHEBI:119486 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235996 infores:hetionet CHEBI:52010 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0003123 infores:hetionet CHEBI:6909 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0085605 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013922 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011991 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0262578 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0262578 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0004096 infores:hetionet CHEBI:50922 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151786 infores:hetionet CHEBI:45327 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0004093 infores:hetionet CHEBI:28748 biolink:causes HP:0033113 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0232200 infores:hetionet CHEBI:6539 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020578 infores:hetionet CHEBI:94609 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0020580 infores:hetionet CHEBI:8435 biolink:causes HP:0025387 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0751564 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0853692 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0024312 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0038363 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0020649 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0002878 infores:hetionet CHEBI:50131 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C2938875 infores:hetionet CHEBI:37924 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0004364 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0162429 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151436 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0031350 infores:hetionet CHEBI:4784 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0039231 infores:hetionet CHEBI:9654 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0011991 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0027651 infores:hetionet CHEBI:119486 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0016199 infores:hetionet CHEBI:28925 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0699893 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0040147 infores:hetionet CHEBI:51164 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0018524 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0042373 infores:hetionet CAID:CA2582115078 biolink:causes MONDO:0012999 infores:clingen CAID:CA2582115078 MONDO:0012999 PMID: Uncertain Significance PP3, PM2_Supporting, PM3_Supporting PP4 The NM_000156.6(GAMT):c.391+5G>C variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 3. This variant has been previously reported in one individual with suggestive features of GAMT deficiency, including developmental delay and seizures; however, no biochemical testing and/or brain MRS was performed, such that PP4 is not met (PMID: 37228909). This individual was homozygous for the variant (PMID: 37228909) (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.87 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 of GAMT (PP3). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, PM3_Supporting, PP3. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 26, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582115078/MONDO:0012999/026 2024-04-26 2024-07-02 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:171719 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0040264 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018418 infores:hetionet GO:0048345 biolink:causes GO:0048339 infores:ubergraph knowledge_assertion manual_agent GO:0048345 GO:0048339 CHEBI:47781 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0028643 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027651 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0009450 infores:hetionet CHEBI:100241 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0751494 infores:hetionet CHEBI:8435 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C1260926 infores:hetionet CHEBI:28445 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0018524 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0038454 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0740482 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0740482 infores:hetionet NCBIGene:4149 biolink:causes MONDO:0958227 infores:monarchinitiative not_provided not_provided HGNC:6913 MONDO:0958227 uuid:e007a136-3bd8-4799-bf5b-41265edf19bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0178298 infores:hetionet CHEBI:63621 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235857 infores:hetionet CHEBI:3756 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0039231 infores:hetionet GO:0052553 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0052553 GO:0006955 PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0040409 infores:hetionet CHEBI:4876 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0232462 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0032285 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042075 infores:hetionet CHEBI:10100 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0014457 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0009938 infores:hetionet NCBIGene:2617 biolink:causes MONDO:0011091 infores:monarchinitiative not_provided not_provided HGNC:4162 MONDO:0011091 uuid:5b83e8f0-f5b9-4b01-8166-c93879400275 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:209807 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0006840 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0948594 infores:hetionet CHEBI:53760 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0039231 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038661 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0019054 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0239816 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0239816 infores:hetionet CHEBI:64354 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0008031 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0857448 infores:hetionet CHEBI:31625 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0010043 infores:hetionet UMLS:C0145867 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0000729 infores:hetionet CHEBI:84500 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0027121 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0036572 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0037284 infores:hetionet CAID:CA320249350 biolink:causes MONDO:0011071 infores:clingen CAID:CA320249350 MONDO:0011071 PMID: Likely Benign BP4, BP7, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2531C>T is an intronic variant with a MAF of 0.0005566 (0.05566%, 3/5390, 3 alleles) in the South Asian subpopulation of the gnomAD v4.0.0 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This synonymous or intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.1)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320249350/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8404 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0040264 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027813 infores:hetionet CAID:CA5950243 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950243 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000448.3(RAG1):c.2291G>A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 764 (p.Arg764His). This missense variant is located in the core domain (amino acids 387-1011) (PM1_supporting). The filtering allele frequency (the upper threshold of the 95% CI of 22/1180042) of the c.2291G>A variant in RAG1 is 0.00001213 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Two missense variants c. 2291G>C, p.R764P (PMID: 24290284); c.2290C>T , p.Arg764Cys (PMID: 25104208) (not classified by SCID VCEP yet) in the same codon have been reported. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950243/MONDO:0000572/123 2024-02-26 2024-02-26 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:162514 biolink:causes MONDO:0014622 infores:monarchinitiative not_provided not_provided HGNC:18084 MONDO:0014622 uuid:86d3aac4-aed5-4fa3-9f85-2780119369a3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0234215 infores:hetionet CHEBI:53760 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0575081 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1269683 infores:hetionet CHEBI:182080 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C2830004 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0002871 infores:hetionet CHEBI:7575 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0043144 infores:hetionet CHEBI:84500 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0041657 infores:hetionet CHEBI:10650 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003467 infores:hetionet CHEBI:75722 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037383 infores:hetionet CHEBI:31401 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018681 infores:hetionet UMLS:C1738934 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020453 infores:hetionet CHEBI:4903 biolink:causes MONDO:0019623 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0019243 infores:hetionet CHEBI:63619 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013144 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0021053 infores:hetionet CHEBI:144551 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0016204 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0017657 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017657 infores:hetionet CHEBI:42820 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0015230 infores:hetionet CHEBI:31485 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0033774 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0518015 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0034150 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0037274 infores:hetionet CHEBI:77733 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0038325 infores:hetionet CHEBI:71255 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0009782 infores:hetionet CHEBI:5790 biolink:causes HP:0012196 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0008039 infores:hetionet CHEBI:3176 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C1443060 infores:hetionet CAID:CA003191 biolink:causes MONDO:0011450 infores:clingen CAID:CA003191 MONDO:0011450 PMID: Uncertain Significance PP3, PM2_Supporting PS3, BS3 The c.5073A>G variant in BRCA1 is a synonymous variant (p.Thr1691=). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met). Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID: 30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003191/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46345 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0858259 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0151763 infores:hetionet CHEBI:36704 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030196 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0030319 infores:hetionet CHEBI:4702 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0020456 infores:hetionet CHEBI:5778 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C2047937 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002170 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0015397 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006444 infores:hetionet NCBIGene:25886 biolink:causes MONDO:0013894 infores:monarchinitiative not_provided not_provided HGNC:24488 MONDO:0013894 uuid:6374c31f-7b51-4b50-9c69-320341cb3a9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7447 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0014457 infores:hetionet CHEBI:63610 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013144 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0041969 infores:hetionet CHEBI:2904 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0001824 infores:hetionet CHEBI:94686 biolink:causes MONDO:0001517 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0013369 infores:hetionet CHEBI:9907 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151825 infores:hetionet CAID:CA170260 biolink:causes MONDO:0010726 infores:clingen CAID:CA170260 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, BS2_Supporting BP4 The p.His51Gln variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). However, the p.His51Gln variant is observed in at least 1 unaffected individual (PMID 21300488) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.His51Gln variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170260/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3082 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0027796 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037199 infores:hetionet CHEBI:64028 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0018681 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0018799 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0234215 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0424823 infores:hetionet CHEBI:27690 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0027497 infores:hetionet CHEBI:64312 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0242422 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0011616 infores:hetionet CHEBI:4495 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C1368065 infores:hetionet CHEBI:61049 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0917801 infores:hetionet NCBIGene:122961 biolink:causes MONDO:0014611 infores:monarchinitiative not_provided not_provided HGNC:19857 MONDO:0014611 uuid:df71ab42-1dee-4bc8-82d7-5df059384a28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:56006 biolink:causes MONDO:0859274 infores:monarchinitiative not_provided not_provided HGNC:25763 MONDO:0859274 uuid:47bd4100-a731-4403-aea2-4bd92b9d1e28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011849 infores:hetionet CHEBI:87681 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0080274 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0001824 infores:hetionet CHEBI:8888 biolink:causes HP:0001605 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042928 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0007222 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0277925 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0007037 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0007037 uuid:5c01a29e-b0c2-4e99-8470-20d0c45495dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31709 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0015376 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002622 infores:hetionet CHEBI:72296 biolink:causes UMLS:C1328411 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C1328411 infores:hetionet HP:0031377 biolink:causes MONDO:0012817 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D012512 DB00970_MESH_D012512_1 CHEBI:28864 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C1527344 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0149931 infores:hetionet UMLS:C0004609 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020578 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0002871 infores:hetionet CHEBI:6801 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0004093 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020538 infores:hetionet NCBIGene:4342 biolink:causes MONDO:0957278 infores:monarchinitiative not_provided not_provided HGNC:7199 MONDO:0957278 uuid:41afdb1e-d1b7-48e1-b306-d4ddd9fb5d95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8694 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0233632 infores:hetionet CHEBI:8772 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0009782 infores:hetionet CHEBI:2639 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0042963 infores:hetionet CHEBI:71941 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0018965 infores:hetionet CHEBI:490877 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0035304 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027769 infores:hetionet CHEBI:3506 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0009319 infores:hetionet CHEBI:6367 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0019521 infores:hetionet CHEBI:31981 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0030446 infores:hetionet GO:1900214 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900214 GO:0007275 CHEBI:9123 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020507 infores:hetionet CHEBI:5893 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0231218 infores:hetionet CHEBI:3175 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0026827 infores:hetionet CHEBI:7565 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0344232 infores:hetionet CHEBI:465284 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151315 infores:hetionet CHEBI:36795 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0043352 infores:hetionet CHEBI:68478 biolink:causes MONDO:0011705 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0751674 infores:hetionet CHEBI:27882 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0235025 infores:hetionet GO:0060723 biolink:causes GO:0001701 infores:ubergraph knowledge_assertion manual_agent GO:0060723 GO:0001701 CHEBI:4784 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C1167965 infores:hetionet NCBIGene:915 biolink:causes MONDO:0014280 infores:monarchinitiative not_provided not_provided HGNC:1673 MONDO:0014280 uuid:af1cfe22-bd43-4766-aa87-4f7c4d805e0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367398717 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398717 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PS1_Moderate, PP2, PP3, PM2_Supporting PP4 The c.1153G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 385 (p.(Gly385Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Another missense variant at the same codon, c.1153G>T (p.Gly385Trp), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Additionally, another missense variant resulting in the same amino acid substitution, c.1153G>A (p.Gly385Arg), has been classified as likely pathogenic by the ClinGen MDEP (PS1_Moderate). In summary, c.1153G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PP2, PP3, PM2_supporting, PM5_supporting, PS1_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398717/MONDO:0015967/086 2025-09-29 2025-09-29 Semidominant inheritance HP:0032113 Supports CHEBI:31302 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0018799 infores:hetionet CHEBI:10119 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0019209 infores:hetionet CHEBI:50859 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0221269 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0040046 infores:hetionet CHEBI:7443 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0039070 infores:hetionet CHEBI:46081 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0040822 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0002170 infores:hetionet CHEBI:6741 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0039070 infores:hetionet CHEBI:8871 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234022 infores:hetionet NCBIGene:100131801 biolink:causes MONDO:0033646 infores:monarchinitiative not_provided not_provided HGNC:40038 MONDO:0033646 uuid:30cefb37-2b88-4131-99e6-c92ffdf6a230 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0042075 infores:hetionet CHEBI:7824 biolink:causes NCIT:C83493 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0423701 infores:hetionet CHEBI:41977 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0027339 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0036572 infores:hetionet CHEBI:52717 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020488 infores:hetionet GO:0060639 biolink:causes GO:0007431 infores:ubergraph knowledge_assertion manual_agent GO:0060639 GO:0007431 CHEBI:15940 biolink:causes MONDO:0002177 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020459 infores:hetionet CHEBI:6076 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0027497 infores:hetionet CHEBI:70735 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0015672 infores:hetionet CHEBI:4466 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085593 infores:hetionet CHEBI:7577 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0017675 infores:hetionet CAID:CA913189537 biolink:causes MONDO:0015152 infores:clingen CAID:CA913189537 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.2706dup p.(Lys903GlnfsTer4) variant in DYSF, which is also known as NM_001130987.2: c.2760dup p.(Lys921GlnfsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 26/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been observed in at least eight individuals with features consistent with LGMD (PMID: 21522182, 22616201; Jain Foundation Dysferlin Registry internal data communication), including in a homozygous state in one patient without familial consanguinity (0.5 pts) and one Iranian individual with known familial consanguinity (0.25 pts) (Jain Foundation Dysferlin Registry internal data communication). In another patient, it was observed in trans with a likely pathogenic or pathogenic DYSF variant (NM_003494.4: c.4024C>T p.(Arg1342Trp), 1.0 pt, PMID: 21522182, 22616201) (PM3). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness as well as absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 22616201, 21522182; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/19/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189537/MONDO:0015152/180 2025-03-19 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7627 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0020517 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0002940 infores:hetionet UMLS:C0120107 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0030794 infores:hetionet CHEBI:4453 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0344315 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0242350 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0521500 infores:hetionet CHEBI:453011 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0151908 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0038661 infores:hetionet CHEBI:6710 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C2047937 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085682 infores:hetionet CHEBI:40303 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0018681 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0036974 infores:hetionet CHEBI:39867 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042023 infores:hetionet CHEBI:9943 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023518 infores:hetionet CHEBI:8884 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0151786 infores:hetionet CHEBI:63581 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0013428 infores:hetionet CHEBI:240107 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0022281 infores:hetionet CHEBI:72564 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0040264 infores:hetionet CHEBI:8665 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0231530 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0521170 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0521170 infores:hetionet CHEBI:63631 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0424790 infores:hetionet CHEBI:18248 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0031154 infores:hetionet CHEBI:31174 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0162830 infores:hetionet CHEBI:51450 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0236000 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0031350 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0410198 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0410198 infores:hetionet CHEBI:4814 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0236075 infores:hetionet CHEBI:5118 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0016867 infores:hetionet NCBIGene:27068 biolink:causes MONDO:0014974 infores:monarchinitiative not_provided not_provided HGNC:28883 MONDO:0014974 uuid:77ba9c3a-dacb-49d6-b036-2744d97fa7be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027497 infores:hetionet CAID:CA10585774 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585774 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, BP2, BA1, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM5, PVS1, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.2100C>G (p.Asp700Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill SB criteria for FH from Malaysia (PMID: 21418584), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585774/MONDO:0007750/013 2022-03-25 2022-04-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7445 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0008031 infores:hetionet CHEBI:4659 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0152025 infores:hetionet CHEBI:28445 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0155320 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085606 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0232570 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0232570 infores:hetionet CHEBI:135961 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0018418 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0037383 infores:hetionet CHEBI:93635 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0036974 infores:hetionet CHEBI:5383 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0004093 infores:hetionet CHEBI:4710 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1306341 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0004238 infores:hetionet CHEBI:17141 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0017178 infores:hetionet CHEBI:3723 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011168 infores:hetionet CHEBI:6339 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0033774 infores:hetionet CHEBI:3752 biolink:causes MONDO:0011827 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013274 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0948586 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151436 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0002871 infores:hetionet CHEBI:7494 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085649 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019829 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0434437 infores:hetionet CHEBI:9927 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0035410 infores:hetionet CHEBI:240107 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0010043 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0018801 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022104 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0020649 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0562057 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0562057 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0520589 infores:hetionet CHEBI:31536 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0015230 infores:hetionet CHEBI:465284 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0852911 infores:hetionet CHEBI:7478 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0040822 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0029882 infores:hetionet NCBIGene:50615 biolink:causes MONDO:0014082 infores:monarchinitiative not_provided not_provided HGNC:6006 MONDO:0014082 uuid:5174d3cf-15f2-4f47-8b8d-3df24b993a22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019214 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0013491 infores:hetionet CHEBI:4562 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C1306341 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C3665386 infores:hetionet CHEBI:35854 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0035455 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0232492 infores:hetionet CHEBI:194135 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0852911 infores:hetionet UMLS:C0004609 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0039070 infores:hetionet CHEBI:31623 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0162834 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0687133 infores:hetionet CAID:CA10014215 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014215 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1044C>T (p.His348=) is a synonymous variant. This synonymous variant has a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014215/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0031350 infores:hetionet GO:0005921 biolink:causes GO:1990349 infores:ubergraph knowledge_assertion manual_agent GO:0005921 GO:1990349 CHEBI:9588 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0012833 infores:hetionet CHEBI:8356 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0858635 infores:hetionet CHEBI:75179 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0677500 infores:hetionet CHEBI:10119 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0520966 infores:hetionet CHEBI:3441 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0037763 infores:hetionet CHEBI:3508 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0012833 infores:hetionet CHEBI:63612 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0151786 infores:hetionet CHEBI:4909 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0344232 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0227791 infores:hetionet CHEBI:3207 biolink:causes HP:0011227 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0742906 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0151601 infores:hetionet GO:1905140 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905140 GO:0007275 CHEBI:10102 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0004134 infores:hetionet CHEBI:5165 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0012569 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0035078 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0423729 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0423729 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0574067 infores:hetionet CHEBI:8874 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0024902 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0015967 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0687133 infores:hetionet CHEBI:6916 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0235896 infores:hetionet CHEBI:8080 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0004093 infores:hetionet CHEBI:131512 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0023530 infores:hetionet CHEBI:17303 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0003578 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0004093 infores:hetionet CHEBI:17650 biolink:causes UMLS:C1735864 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C1735864 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0948594 infores:hetionet CHEBI:144551 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0232462 infores:hetionet CHEBI:27432 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0033774 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0020621 infores:hetionet CHEBI:3732 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0017565 infores:hetionet CHEBI:63616 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0038362 infores:hetionet CAID:CA180267 biolink:causes MONDO:0009861 infores:clingen CAID:CA180267 MONDO:0009861 PMID: Benign BP4, BA1 PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA180267/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:37941 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0004096 infores:hetionet CHEBI:32293 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0004604 infores:hetionet CHEBI:119573 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013604 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0034065 infores:hetionet CHEBI:63631 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0028734 infores:hetionet CHEBI:6775 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0014591 infores:hetionet CHEBI:6909 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0020458 infores:hetionet CHEBI:3478 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0018965 infores:hetionet NCBIGene:4311 biolink:causes MONDO:0014866 infores:monarchinitiative not_provided not_provided HGNC:7154 MONDO:0014866 uuid:4fd53d52-e467-44ca-bd04-4cfffccd1f87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0027051 infores:hetionet CHEBI:48390 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0011603 infores:hetionet CHEBI:100147 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0018681 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C1258215 infores:hetionet CHEBI:8461 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0012833 infores:hetionet CHEBI:251408 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0152227 infores:hetionet CHEBI:6456 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0040264 infores:hetionet CAID:CA410202473 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202473 MONDO:0011071 PMID: Uncertain Significance PM5_Supporting, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.505A>G (p.Arg169Gly) is a missense mutation found within the RHD. This variant affects at least one of the following hotspot residues within the RHD: (R169) (PM1). This missense variant has a REVEL score ≥ 0.88 (0.921) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a missense change at the same residue (p.Arg169) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 869207) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202473/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8499 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0028084 infores:hetionet CHEBI:31236 biolink:causes HP:0200085 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235081 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0150450 infores:hetionet CHEBI:8776 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0700361 infores:hetionet CHEBI:17303 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233407 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0521491 infores:hetionet CHEBI:5856 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0020538 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0235431 infores:hetionet CHEBI:7822 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0036830 infores:hetionet CHEBI:6437 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0007859 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0006266 infores:hetionet CHEBI:5134 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0042963 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0009806 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042035 infores:hetionet CHEBI:37333 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C2364111 infores:hetionet CHEBI:3219 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042024 infores:hetionet NCBIGene:51109 biolink:causes MONDO:0014495 infores:monarchinitiative not_provided not_provided HGNC:17964 MONDO:0014495 uuid:27ea54fb-61aa-4c68-9d00-d0716b5249c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7931 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0015967 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1510472 infores:hetionet CHEBI:64321 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0013395 infores:hetionet NCBIGene:148867 biolink:causes MONDO:0957595 infores:monarchinitiative not_provided not_provided HGNC:19306 MONDO:0957595 uuid:31eed6fb-5a26-447b-8555-828c6bf49538 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0003123 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0231218 infores:hetionet CHEBI:49662 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0232726 infores:hetionet CHEBI:51137 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0948594 infores:hetionet CHEBI:47499 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0004134 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0035455 infores:hetionet CHEBI:27504 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0041582 infores:hetionet CHEBI:5118 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0024305 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151826 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0574067 infores:hetionet CHEBI:3698 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0016204 infores:hetionet CHEBI:28901 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0013604 infores:hetionet CHEBI:83531 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0851578 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0549225 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0549225 infores:hetionet CHEBI:28864 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0023518 infores:hetionet CAID:CA6197402 biolink:causes MONDO:0019497 infores:clingen CAID:CA6197402 MONDO:0019497 PMID: Likely Pathogenic PP1_Strong, PP3, PM3 BS1, PP4, PM2, BA1, BP4 The c.1183C>T variant in MYO7A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 395. The highest population minor allele frequency in gnomAD v4.1 is 0.00008472 (2/23608 alleles) in the South Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 6 individuals with nonsyndromic genetic hearing loss. Out of 3 of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant for Usher syndrome and none of those were confirmed in trans (c.401T>A (p.Ile134Asn), 0 PM3 points, SCV: SCV001232108.5, Invitae). The other 2 were compound heterozygous for the variant and a variant of uncertain significance for nonsyndromic genetic hearing loss, 1 of them was confirmed in trans by family testing (0.25 PM3 points, c.1496T>C (p.Ile499Thr); c.1496T>C(p.Ile499Thr), PMIDs: 34416374, 34979615). 3 individuals were homozygous for the variant (1 PM3 point, PMIDs: 23770805, 27573290, ClinVar SCV: SCV001232108.5, Invitae) (PM3). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 8 affected family members from 3 families (PP1_Strong; PMIDs: 23770805, 27573290, 34979615). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PM3, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 7/23/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6197402/MONDO:0019497/005 2024-09-24 2024-09-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CAID:CA000197 biolink:causes MONDO:0017623 infores:clingen CAID:CA000197 MONDO:0017623 PMID: Likely Benign BP7, BS3, PM2_Supporting PM6, PVS1, BP5, BS1, BS4, PP2, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.75G>A (p.Leu25=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS3: Synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (internal laboratory contributor)BP7: Variant is synonymous and no splicing impact is predicted.PM2_P: Absent in gnomAD.Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign strong, 1 benign supporting and 1 pathogenic supporting codes get -4 + (-1) + 1 points; total is – 4 (likely benign). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000197/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:37941 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0032285 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0518015 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0012833 infores:hetionet CHEBI:10127 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151904 infores:hetionet CHEBI:6909 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0014518 infores:hetionet CHEBI:50173 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C2242737 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0041912 infores:hetionet CHEBI:8707 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013491 infores:hetionet CHEBI:87681 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0014591 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0162429 infores:hetionet CHEBI:3242 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0547030 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0595878 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151736 infores:hetionet CHEBI:167638 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0030193 infores:hetionet CHEBI:63631 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0021177 infores:hetionet CHEBI:63584 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0232462 infores:hetionet CAID:CA414914682 biolink:causes MONDO:0010602 infores:clingen CAID:CA414914682 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PP3, PP1, PS4 PP4 The c.1372C>T (p.Arg458Cys) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.839 (>0.6), meeting criteria for PP3. At least 8 mild hemophilia A patients meeting F8-phenotype criteria are reported in the literature (PMID: 25628142, PMID: 18387975, PMID: 16173970, PMID: 17610549) and internal VCEP data. This variant was noted to segregate in a maternal uncle and nephew pair with hemophilia A (PMID: 25628142), which meets criteria for PP1. Additionally, this variant has been associated with a history of an inhibitor in at least one individual (PMID: 17610549). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very strong, PP1, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414914682/MONDO:0010602/071 2024-06-20 2024-07-11 X-linked inheritance HP:0001417 Supports UNII:3U02EL437C biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0281856 infores:hetionet CHEBI:127342 biolink:causes NCIT:C54056 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0521987 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0036454 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0004238 infores:hetionet CHEBI:64312 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0036974 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033046 infores:hetionet CHEBI:7577 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0085593 infores:hetionet NCBIGene:51098 biolink:causes MONDO:0014915 infores:monarchinitiative not_provided not_provided HGNC:15901 MONDO:0014915 uuid:8cb93504-44ee-4565-bc9f-0c670730c7ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151723 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0011991 infores:hetionet CHEBI:10125 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085632 infores:hetionet CHEBI:28593 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0151766 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0178298 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0160390 infores:hetionet CHEBI:63613 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0023787 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0521508 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0521508 infores:hetionet CHEBI:60761 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0030312 infores:hetionet CHEBI:49375 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0033774 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0232208 infores:hetionet CHEBI:87681 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0030312 infores:hetionet CHEBI:28925 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0028961 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0340726 infores:hetionet CHEBI:32293 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0020443 infores:hetionet CHEBI:64355 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2979982 infores:hetionet CHEBI:5004 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0002994 infores:hetionet CHEBI:50859 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0549249 infores:hetionet CHEBI:51141 biolink:causes HP:0002611 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0860204 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0233459 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006670 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085437 infores:hetionet GO:2000087 biolink:causes GO:0061215 infores:ubergraph knowledge_assertion manual_agent GO:2000087 GO:0061215 CHEBI:6456 biolink:causes UMLS:C1096225 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C1096225 infores:hetionet CHEBI:8212 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C2830004 infores:hetionet CHEBI:51209 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0008031 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0009450 infores:hetionet CHEBI:6916 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0011991 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0021775 infores:hetionet NCBIGene:3767 biolink:causes MONDO:0011153 infores:monarchinitiative not_provided not_provided HGNC:6257 MONDO:0011153 uuid:3423af37-c94c-4f43-bc58-356fcabf3fe6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7581 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0020903 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0020649 infores:hetionet CHEBI:421707 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0232487 infores:hetionet CHEBI:8060 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0018681 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0036572 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002775 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0003128 infores:hetionet CHEBI:45863 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0024236 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0162429 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0948349 infores:hetionet CAID:CA410146940 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146940 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1388C>T (p.Pro463Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146940/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47519 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0013395 infores:hetionet CHEBI:4670 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0002962 infores:hetionet CHEBI:17303 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085593 infores:hetionet CHEBI:5384 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C2830004 infores:hetionet CHEBI:4027 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0035455 infores:hetionet CHEBI:63598 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0036974 infores:hetionet CHEBI:135888 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0002792 infores:hetionet CHEBI:64355 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151754 infores:hetionet CHEBI:7852 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C3263723 infores:hetionet CHEBI:3568 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0019521 infores:hetionet CHEBI:50131 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0687713 infores:hetionet CHEBI:168396 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0344232 infores:hetionet CHEBI:50275 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0030196 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0549209 infores:hetionet CHEBI:6149 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0000731 infores:hetionet GO:0110137 biolink:causes GO:0048737 infores:ubergraph knowledge_assertion manual_agent GO:0110137 GO:0048737 CHEBI:4027 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085612 infores:hetionet CHEBI:15640 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C1565489 infores:hetionet CHEBI:83527 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0917801 infores:hetionet CHEBI:51380 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0041834 infores:hetionet CHEBI:4903 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0013390 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0032285 infores:hetionet CHEBI:45409 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085633 infores:hetionet CHEBI:16714 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0006145 infores:hetionet CHEBI:135342 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0011603 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0497327 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0270458 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0025061 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0001430 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C1565489 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002878 infores:hetionet CHEBI:2549 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0014591 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0021167 infores:hetionet CHEBI:51137 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0018418 infores:hetionet CHEBI:168396 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0031256 infores:hetionet CHEBI:135566 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0392163 infores:hetionet CHEBI:3181 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0547030 infores:hetionet CAID:CA401368744 biolink:causes MONDO:0009290 infores:clingen CAID:CA401368744 MONDO:0009290 PMID: Likely Benign PM2_Supporting, BS3_Supporting, BP4, BP2 PP3, PP4 The NM_000152.5:c.1642G>T variant in GAA is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 548 (p.Val548Phe). This variant has been observed in cis with the variant c.1880C>T (p.Ser627Phe) (PMID 28763149, ClinVar #000597382.19), which is classified as pathogenic by ClinGen LD VCEP, in two individuals with Pompe disease. The phase of variant was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.269, which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). This variant is absent in gnomAD v4.1.0, meeting this criterion (PM2_Supporting). Expression of the variant in HEK293 cells resulted in normal activity and processing, indicating that variant does not impact protein function ((unpublished data from the laboratory that published PMID: 36246652) (BS3_supporting). There is a ClinVar entry for this variant (Variation ID: 597381). Although PM2_Supporting is met, this is the only pathogenic criterion that was met. Overall, the evidence indicates that this variant is likely benign (BS3_Supporting, BP2, BP4) and thus the ClinGen LD VCEP classified this variant as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS3_supporting, BP2, BP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 3, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401368744/MONDO:0009290/010 2025-06-03 2025-09-16 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:31644 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151205 infores:hetionet CHEBI:7492 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0021400 infores:hetionet CHEBI:182080 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0040264 infores:hetionet NCBITaxon:1639 biolink:causes MONDO:0005828 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1639 MESH:D008088 DB01017_MESH_D008088_1 CHEBI:10650 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0019372 infores:hetionet CHEBI:5130 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0012569 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0011849 infores:hetionet CHEBI:7798 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0002965 infores:hetionet GO:0075193 biolink:causes GO:0044409 infores:ubergraph knowledge_assertion manual_agent GO:0075193 GO:0044409 CHEBI:119573 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037036 infores:hetionet CHEBI:64354 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0231218 infores:hetionet CHEBI:39585 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0034152 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0232492 infores:hetionet CHEBI:9352 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0234233 infores:hetionet NCBIGene:5295 biolink:causes MONDO:0014453 infores:monarchinitiative not_provided not_provided HGNC:8979 MONDO:0014453 uuid:abb56c87-1065-4ed1-ac47-e96d4fd9c712 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0033845 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853692 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0853813 infores:hetionet CAID:CA404075130 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075130 MONDO:0007750 PMID: Uncertain Significance PM1, PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM3, PVS1, PM6, BS2, PP2, PP4, PP1 The NM_000527.5(LDLR):c.188G>T (p.Cys63Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.921.PM1: Variant is missense, meets PM2, and alters Cys63, one of the 60 highly conserved cysteine residues. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075130/MONDO:0007750/013 2023-03-27 2024-10-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10125 biolink:causes UMLS:C0235847 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235847 infores:hetionet CHEBI:681850 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0031542 infores:hetionet CHEBI:7824 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011603 infores:hetionet CHEBI:64019 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0042571 infores:hetionet CHEBI:3077 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0018813 infores:hetionet CHEBI:8207 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042963 infores:hetionet NCBIGene:8822 biolink:causes MONDO:0014106 infores:monarchinitiative not_provided not_provided HGNC:3673 MONDO:0014106 uuid:38541314-482c-41a7-b105-3fdadf361955 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0023510 infores:hetionet CHEBI:567361 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0854467 infores:hetionet CHEBI:50648 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027497 infores:hetionet CHEBI:9139 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0037299 infores:hetionet CHEBI:48669 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0151744 infores:hetionet CHEBI:8774 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0000737 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0006840 infores:hetionet CHEBI:47898 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0232849 infores:hetionet CHEBI:8890 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0018681 infores:hetionet CHEBI:64318 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0700361 infores:hetionet NCBIGene:11284 biolink:causes MONDO:0014557 infores:monarchinitiative not_provided not_provided HGNC:9154 MONDO:0014557 uuid:23a5399d-8da2-49ab-9eaf-fb5ef4ae2850 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6792 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0232487 infores:hetionet CHEBI:31397 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0234708 infores:hetionet CHEBI:50648 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004095 infores:hetionet CHEBI:6539 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0042963 infores:hetionet CHEBI:6887 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0026961 infores:hetionet CHEBI:78543 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0917801 infores:hetionet CHEBI:681850 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0018965 infores:hetionet CHEBI:7931 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0241057 infores:hetionet CHEBI:43968 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0404521 infores:hetionet GO:0110073 biolink:causes GO:0007370 infores:ubergraph knowledge_assertion manual_agent GO:0110073 GO:0007370 CHEBI:36791 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009763 infores:hetionet CHEBI:94686 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1963818 infores:hetionet CHEBI:8776 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0038990 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0235431 infores:hetionet CHEBI:47612 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0021400 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0948586 infores:hetionet CAID:CA16020971 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020971 MONDO:0009861 PMID:26322415 Pathogenic PM3, PVS1, PP4_Moderate, PM2 Variant c.1215_1219del (p.Ile406SerfsTer15) in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). This is a frameshift variant in exon 12 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). Variant was found in trans with pathogenic variant p.P147L (PMID: 26322415) (PM3). Parental DNA was sequenced via NGS. The variant is absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PP4-Moderate, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020971/MONDO:0009861/006 2020-05-14 2020-05-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7443 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0040264 infores:hetionet CHEBI:8802 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0476280 infores:hetionet CHEBI:63717 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0009782 infores:hetionet CAID:CA6327326 biolink:causes MONDO:0019497 infores:clingen CAID:CA6327326 MONDO:0019497 PMID: Likely Benign BS1 PP3, BP4 The c.4004G>A variant in TECTA is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 1335. The filtering allele frequency of this variant in gnomAD v4.1 is 0.2865% in the African/African American population, and there was agreement to apply BS1, which has a threshold of 0.3% for the ClinGen Hearing Loss group. The computational predictor REVEL gives a score of 0.35, which is neither above nor below the thresholds predicting a damaging or benign impact on TECTA function (BP4 and PP3 not met). The variant has been detected in heterozygosity in 1 individual with sloping moderately-severe sensorineural hearing loss, but no variant on the other allele was identified (Partners LMM internal data, SCV000711207.2). This variant has been observed in the heterozygous state and in combination with a second variant (phase unknown) in individuals undergoing testing for hearing loss (GeneDx internal data, SCV001770060.3). The variant has also been detected with another TECTA variant of uncertain significance in phase unknown in a patient with bilateral sensorineural hearing loss, and in the homozygous state in a patient with sensorineural hearing loss (Labcorp internal data, SCV001051355.5). In summary, this variant meets criteria to be classified as likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6327326/MONDO:0019497/005 2025-05-21 2025-06-30 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:136040 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0043387 infores:hetionet CHEBI:49713 biolink:causes NCIT:C180702 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0312422 infores:hetionet NCBITaxon:6252 biolink:causes MONDO:0005654 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6252 MONDO:0005654 CAID:CA404074850 biolink:causes MONDO:0007750 infores:clingen CAID:CA404074850 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM5, PM3, PM4, PM1, PM6, PVS1, BS2, PP2, PP1, PP4 The NM_000527.5(LDLR):c.139G>C (p.Asp47His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755 The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.977. It is above 0.75, so met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404074850/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10110 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0035410 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0015376 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003123 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0233472 infores:hetionet CHEBI:9587 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0042963 infores:hetionet CHEBI:6067 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1720775 infores:hetionet NCBIGene:7030 biolink:causes MONDO:0010456 infores:monarchinitiative not_provided not_provided HGNC:11752 MONDO:0010456 uuid:0533f9e4-f778-4bd5-8389-571ca870d8a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0004604 infores:hetionet CAID:CA957287 biolink:causes MONDO:0800406 infores:clingen CAID:CA957287 MONDO:0800406 PMID: Uncertain Significance PM2_Supporting BP7, PP4, BP4, PS4 The NM_000350.3(ABCA4):c.5406C>T is a synonymous variant (p.Ile1802=). The total minor allele frequency in gnomAD v4.1.0 is 0.000039652 (64/1614042 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The SpliceAI predictor score for this variant is 0.13, which is greater than 0.1, the ABCA4 VCEP's threshold for BP7 or BP4 criterion. To our knowledge, this variant has not been reported in the literature in any individuals with ABCA4-related retinopathy. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PM2_Supporting. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA957287/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17334 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0003862 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0014742 infores:hetionet CHEBI:4024 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0233407 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019360 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151838 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0037274 infores:hetionet CHEBI:6073 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0232462 infores:hetionet CHEBI:15854 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0024141 infores:hetionet CAID:CA229270 biolink:causes MONDO:0009861 infores:clingen CAID:CA229270 MONDO:0009861 PMID: Uncertain Significance PM2 PM5, PP3 The c.1019T>C (p.Ile340Thr) variant in PAH has been not been reported in a patient with PAH deficiency (to our knowledge). It was reported to the PAHdb (McGill) by Tyfield in 2003. This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. There are conflicting predictions of pathogenicity: SIFT (T); PolyPhen2 (B); REVEL=0.731; MutationTaster (D). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229270/MONDO:0009861/006 2019-12-15 2021-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8207 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020569 infores:hetionet CHEBI:63610 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0016204 infores:hetionet GO:1900154 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:1900154 GO:0001501 CHEBI:16714 biolink:causes UMLS:C0151560 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0151560 infores:hetionet CAID:CA410148810 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148810 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS2, BA1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, PM4, PM1, PM3, PP4, PP1 NM_001754.5(RUNX1):c.979C>G (p.Leu327Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148810/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004144 infores:hetionet CHEBI:7959 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0018378 infores:hetionet CHEBI:8107 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020598 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1384353 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018801 infores:hetionet UMLS:C0065374 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0027497 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013395 infores:hetionet CHEBI:145499 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004134 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0233494 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0014868 infores:hetionet CHEBI:5280 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009763 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0232841 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0302295 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011616 infores:hetionet CHEBI:3568 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0149745 infores:hetionet CHEBI:39867 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0026826 infores:hetionet CHEBI:33130 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0031542 infores:hetionet CAID:CA14892082 biolink:causes MONDO:0011071 infores:clingen CAID:CA14892082 MONDO:0011071 PMID: Benign BA1, BP2, BP4, BP7 PS3, PS1, PS2, PS4, BP3, BP1, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 The NM_001754.5(RUNX1):c.805+12836A>G variant is a deep intronic variant that is not predicted by SpliceAI to impact splicing (BP4). The variant's highest minor allele frequency (MAF) of 0.9987(99.87%, 1156/1558 alleles) in the East Asian subpopulation of the gnomADv2.1.1 cohort is ≥ 0.0015 (0.15%) (BP1). Additionally this variant is detected in a homozygous state in 777 individuals in a population database (gnomADv2.1.1) (BP2). This deep intronic variant is not well conserved with a phyloP100way score of -0.014 (BP7 ≤2.0). It has not been reported in individuals meeting at least one of the RUNX1 phenotypic criteria. In summary, the clinical significance of this variant is Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14892082/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9637 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0038325 infores:hetionet CHEBI:17823 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0009763 infores:hetionet CHEBI:7565 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085612 infores:hetionet CAID:CA036457 biolink:causes MONDO:0007750 infores:clingen CAID:CA036457 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BA1, PS3, PS4, BS1, BS3, BS4, BS2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.00001356 (0.0014%) in European (non-Finnish) (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036457/MONDO:0007750/013 2025-03-28 2025-06-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63611 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0580413 infores:hetionet CHEBI:63620 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0022346 infores:hetionet CHEBI:7494 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0162830 infores:hetionet CHEBI:9123 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0036830 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0231303 infores:hetionet CHEBI:2682 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085681 infores:hetionet CHEBI:4798 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0028734 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020615 infores:hetionet CHEBI:7640 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C1320835 infores:hetionet CHEBI:15553 biolink:causes NCIT:C92716 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0018811 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0029132 infores:hetionet CAID:CA114367 biolink:causes MONDO:0009861 infores:clingen CAID:CA114367 MONDO:0009861 PMID:8088845PMID:21147011PMID:10479481PMID:8088845PMID:21147011PMID:10479481PMID:21147011 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong PS3 The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID: 8088845; PMID: 21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID: 10479481; PMID: 21147011; PMID: 8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114367/MONDO:0009861/006 2018-10-01 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3485 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0004096 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0004096 infores:hetionet CHEBI:64355 biolink:causes UMLS:C1536070 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1536070 infores:hetionet CHEBI:7852 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0027497 infores:hetionet UMLS:C0120107 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0030252 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0042109 infores:hetionet CHEBI:2611 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085605 infores:hetionet CHEBI:8356 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024902 infores:hetionet CHEBI:100147 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0340865 infores:hetionet CHEBI:5775 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0023530 infores:hetionet CHEBI:6472 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0028961 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0233794 infores:hetionet CHEBI:4911 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0031542 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235763 infores:hetionet CHEBI:38940 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C2711248 infores:hetionet CHEBI:135679 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0155169 infores:hetionet CAID:CA2424844266 biolink:causes MONDO:0100437 infores:clingen CAID:CA2424844266 MONDO:0100437 PMID:36445968 Likely Pathogenic PVS1, PM2_Supporting PS4, PS3 NM_001034853.2(RPGR):c.3034del (p.Glu1012LysfsTer?) is a frameshift variant due to a 1-nucleotide deletion introducing a premature stop codon in exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant was confirmed to result in a 40% decrease in glutamylation of RPGR when co-transfected into HEK293 cells with the glutamylase TTLL5 (PMID: 36445968), however, PS3_Supporting was not scored as PVS1 has already been met. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands (PMIDs: 36445968, 30543658). However, the number of individuals meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2424844266/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:63611 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0744727 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0086543 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016397 infores:hetionet CHEBI:42797 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0232461 infores:hetionet CHEBI:10127 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018926 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235416 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0018799 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0038362 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003850 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040409 infores:hetionet CHEBI:6472 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0014742 infores:hetionet CHEBI:6904 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0013404 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020175 infores:hetionet CAID:CA267785638 biolink:causes MONDO:0007113 infores:clingen CAID:CA267785638 MONDO:0007113 PMID: Benign BA1, BP7 PM2 The highest population minor allele frequency of the p.Lys312= variant in UBE3A in gnomAD v4.1 is 0.0003300 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The silent c.876G>A (p.Lys292=) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Lys312= variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP7). (UBE3A Specifications v.5.0; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA267785638/MONDO:0007113/037 2025-06-25 2025-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts true CAID:CA16615707 biolink:causes MONDO:0018875 infores:clingen CAID:CA16615707 MONDO:0018875 PMID:29979965PMID:12826609PMID:30224644 Likely Benign BP4, BS3, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BP7, BS1, BS4, PVS1, BS2, PP3, PP1, PP4 The NM_000546.6: c.556G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 186 (p.Asp186Asn). This variant has an allele frequency of 0.00003332 (2/60018 alleles) in the Admixed American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0517; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615707/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6954 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0015967 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0031542 infores:hetionet CHEBI:32221 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0011603 infores:hetionet UMLS:C0657912 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023212 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0497327 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0521592 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0022104 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0233494 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0235004 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235004 infores:hetionet CHEBI:8435 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0040034 infores:hetionet CHEBI:40279 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085605 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0037199 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0013395 infores:hetionet CHEBI:61033 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0019080 infores:hetionet CHEBI:84500 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0040822 infores:hetionet CHEBI:4672 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0423153 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0037195 infores:hetionet CHEBI:63589 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0022660 infores:hetionet GO:2001204 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:2001204 GO:0001501 CHEBI:4798 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0011570 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0009806 infores:hetionet CHEBI:74947 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014743 infores:hetionet CHEBI:2955 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0039070 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013395 infores:hetionet CAID:CA320251215 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251215 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1407C>T (p.Ser469=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.25)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251215/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6437 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151763 infores:hetionet CHEBI:29688 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0004093 infores:hetionet CHEBI:45081 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0232462 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1306341 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042075 infores:hetionet CAID:CA10580076 biolink:causes MONDO:0100488 infores:clingen CAID:CA10580076 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.161G>A (p.Arg54Lys) missense variant is absent in the gnomAD 2.1.1 cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000274257.4, SCV000637737.4, unpublished data). In summary, although a conflicting code PM2_supporting is met, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580076/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA410207157 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207157 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.629T>C (p.Leu210Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Clinical and functional information for this variant has not been reported in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207157/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15428 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0342579 infores:hetionet CHEBI:8245 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0038362 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001684 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030293 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0006145 infores:hetionet CHEBI:135935 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0003862 infores:hetionet CHEBI:194135 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003126 infores:hetionet CHEBI:9588 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0033774 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0004936 infores:hetionet CHEBI:4910 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0027066 infores:hetionet CHEBI:91541 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0080274 infores:hetionet CHEBI:8024 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0040822 infores:hetionet CHEBI:7822 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013491 infores:hetionet CHEBI:7640 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0030318 infores:hetionet CHEBI:63607 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0037763 infores:hetionet CHEBI:9571 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0030312 infores:hetionet CHEBI:44423 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0004509 infores:hetionet NCBIGene:7941 biolink:causes MONDO:0013663 infores:monarchinitiative not_provided not_provided HGNC:9040 MONDO:0013663 uuid:ceca99ee-6227-4640-8605-4ec0ed4c05e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16608763 biolink:causes MONDO:0010726 infores:clingen CAID:CA16608763 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, BA1, PM2, BS1, PP3 The p.Ala378Thr variant in MECP2 (NM_004992.4) is present in 1 female individual in gnomAD (0.00057%) (not sufficient to meet BS1 criteria). The p.Ala378Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ala378Thr variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Ala378Thr variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608763/MONDO:0010726/036 2023-08-28 2023-09-15 X-linked inheritance HP:0001417 Contradicts true CHEBI:45951 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0040485 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0948594 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018099 infores:hetionet CHEBI:6888 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0268000 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0747979 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0747979 infores:hetionet CHEBI:28148 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0006266 infores:hetionet CHEBI:63623 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0004604 infores:hetionet UNII:2N4O9L084N biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020903 infores:hetionet CHEBI:42944 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0019080 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151849 infores:hetionet CHEBI:4495 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0015230 infores:hetionet CHEBI:8356 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C3263723 infores:hetionet NCBITaxon:1485 biolink:causes MONDO:0004789 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1485 MESH:D002761 DB09324_MESH_D002761_1DB00415_MESH_D002761_1DB01172_MESH_D002761_1 CHEBI:41774 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0006277 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0178298 infores:hetionet CAID:CA213775 biolink:causes MONDO:0015967 infores:clingen CAID:CA213775 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.304A>T variant in the glucokinase gene, GCK, results in a premature termination at codon 102 (p.(Lys102Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene for which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.304A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213775/MONDO:0015967/086 2025-01-03 2025-01-03 Semidominant inheritance HP:0032113 Supports UNII:G4PX8C4HKV biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0037036 infores:hetionet CHEBI:71417 biolink:causes HP:0011273 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0221278 infores:hetionet CHEBI:4681 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0004093 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027769 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0018021 infores:hetionet NCBIGene:3728 biolink:causes MONDO:0011017 infores:monarchinitiative not_provided not_provided HGNC:6207 MONDO:0011017 uuid:4fdaf27d-0b5f-4469-adda-696fdab45749 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0231835 infores:hetionet CHEBI:6741 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0231218 infores:hetionet CHEBI:9137 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037287 infores:hetionet CHEBI:6520 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0023530 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0020538 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0031350 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0263437 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0263437 infores:hetionet CHEBI:68841 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0042963 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0011053 infores:hetionet CAID:CA344827 biolink:causes MONDO:0044970 infores:clingen CAID:CA344827 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4, PS3_Supporting PP4, PP1, PS2, BS4, PM6 The m.3635G>A (p.S110N) variant in MT-ND1 has been reported in >16 individuals with primary mitochondrial disease, and more specifically Leber's hereditary optic neuropathy (LHON). This variant has been observed in affected individuals primarily in the homoplasmic state to date (20/21 cases) (PS4; PMIDs: 25194554, 21074518, 23304069,19527690, 19497304, 11479733, 33417421). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in Helix and the GenBank dataset. It is present in gnomAD 3.1 in 1/56428 individuals (0.002%). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 25194554, 11479733). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PP3, PS4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA344827/MONDO:0044970/015 2022-08-23 2022-09-02 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria UMLS:C0011701 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0085649 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0043387 infores:hetionet CHEBI:6965 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0231441 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0542313 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0542313 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0019112 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1302752 infores:hetionet CHEBI:5165 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151610 infores:hetionet NCBIGene:7855 biolink:causes MONDO:0958239 infores:monarchinitiative not_provided not_provided HGNC:4043 MONDO:0958239 uuid:4d4498eb-8181-4dae-8281-4abd27e5d83b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0003460 infores:hetionet NCBIGene:843 biolink:causes MONDO:0011508 infores:monarchinitiative not_provided not_provided HGNC:1500 MONDO:0011508 uuid:cf3e51f0-82db-4718-b2f2-9cde9c5a4c73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042024 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013595 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0010709 infores:hetionet CHEBI:585948 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0041834 infores:hetionet CHEBI:75722 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233471 infores:hetionet CHEBI:64321 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0151786 infores:hetionet CHEBI:5893 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0404521 infores:hetionet CHEBI:100147 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0042963 infores:hetionet UMLS:C0010592 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0014591 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0020651 infores:hetionet CHEBI:3485 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C1609512 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0040479 infores:hetionet CAID:CA14745070 biolink:causes MONDO:0011229 infores:clingen CAID:CA14745070 MONDO:0011229 PMID: Benign BS2, BA1 PM2 The c.505+264T>G (NM_014297.5) variant in ETHE1 is an intronic variant which is located in intron 4 (intron 4/6). The highest population minor allele frequency for the c.505+264T>G variant in gnomAD v2.1.1 is 0.077 (2,431/31,374 alleles) in the general population, which is higher than the ClinGen ETHE1 threshold >0.001 for BA1, and therefore meets this criterion (BA1). This variant has been observed in at least 169 homozygous individuals (gnomAD v2.1.1) with no features of ethylmalonic aciduria, petechiae, chronic diarrhea, acrocyanosis, nor developmental delay. In summary, this variant meets the criteria to be classified as benign, and therefore not causative of Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): BA1, BS2. Approved 7/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA14745070/MONDO:0011229/014 2021-07-27 2021-07-27 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9570 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0028961 infores:hetionet CHEBI:7496 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0027947 infores:hetionet CHEBI:4911 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0231218 infores:hetionet CHEBI:474180 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0017178 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0549373 infores:hetionet CHEBI:44185 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0270612 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0036454 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011991 infores:hetionet CHEBI:3723 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037763 infores:hetionet CHEBI:8874 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0917801 infores:hetionet CHEBI:100241 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0026821 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020295 infores:hetionet NCBIGene:8013 biolink:causes MONDO:0012825 infores:monarchinitiative not_provided not_provided HGNC:7982 MONDO:0012825 uuid:7d923ffc-cc89-402b-bdd9-5645b5c25a6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3749 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0002871 infores:hetionet CHEBI:59582 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0162820 infores:hetionet CHEBI:6062 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0034886 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0040435 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0028077 infores:hetionet CHEBI:6715 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020461 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0520904 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0520904 infores:hetionet NCBIGene:3284 biolink:causes MONDO:0008727 infores:monarchinitiative not_provided not_provided HGNC:5218 MONDO:0008727 uuid:5909aa17-03a9-43cc-964e-4facf7f5f2a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0231218 infores:hetionet NCBIGene:9692 biolink:causes MONDO:0030543 infores:monarchinitiative not_provided not_provided HGNC:19958 MONDO:0030543 uuid:3968b880-1a88-41e2-8222-95b25e04108c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65349 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0042029 infores:hetionet CHEBI:10650 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0006152 infores:hetionet NCBITaxon:10239 biolink:causes MONDO:0005108 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10239 MONDO:0005108 UMLS:C0145867 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0016382 infores:hetionet CHEBI:4027 biolink:causes MONDO:0015265 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0006272 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0919661 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0919661 infores:hetionet CHEBI:2682 biolink:causes MONDO:0020533 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0152063 infores:hetionet CHEBI:2675 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0011124 infores:hetionet NCBIGene:10084 biolink:causes MONDO:0010653 infores:monarchinitiative not_provided not_provided HGNC:9330 MONDO:0010653 uuid:dd007e3a-39d0-4d3f-89c9-713c3901d41d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399798192 biolink:causes MONDO:0100326 infores:clingen CAID:CA399798192 MONDO:0100326 PMID:19175981 Pathogenic PP4_Strong, PM3, PM2_Supporting, PS3 PM5, PP3 The NM_000419.5:c.2255T>G variant in ITGA2B is a missense variant predicted to cause substitution of leucine by arginine at amino acid 752 (p.Leu752Arg). At least one patient (PMID: 19175981, also reported as Patient 180 reported in the Glanzmann Thrombasthenia Database, https://glanzmann.mcw.edu) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIb and β3 surface expression was reduced to <5% as measured by flow cytometry (PP4_Strong). The variant was observed in this individual in compound heterozygosity with the ITGA2B c.2671C>T variant (p.Gln891Ter, classified as pathogenic by the Platelet Disorders VCEP) (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Surface expression of αIIb measured by flow cytometry in 293T cells transiently co-transfected with c.2255T>G variant αIIb and wild type β3 showed decreased expression at 2.1%, indicating that this variant impacts protein function (PMID: 19175981) (PS3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PS3, PM2_supporting, PM3, PP4_Strong. (VCEP specifications version 2; date of approval 2/3/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399798192/MONDO:0100326/011 2022-03-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:63631 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0920289 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235146 infores:hetionet CHEBI:6950 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0242429 infores:hetionet CHEBI:8764 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0242379 infores:hetionet CHEBI:6690 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0038362 infores:hetionet CHEBI:63621 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0016867 infores:hetionet CHEBI:2675 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0018418 infores:hetionet NCBIGene:151516 biolink:causes MONDO:0007812 infores:monarchinitiative not_provided not_provided HGNC:26321 MONDO:0007812 uuid:e9f56623-3799-44ba-9433-742528dbd0ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C2047937 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0020517 infores:hetionet NCBIGene:64518 biolink:causes MONDO:0859522 infores:monarchinitiative not_provided not_provided HGNC:14293 MONDO:0859522 uuid:a73dccab-bdaa-4398-bd70-36480e73120a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0428977 infores:hetionet GO:0061105 biolink:causes GO:0055123 infores:ubergraph knowledge_assertion manual_agent GO:0061105 GO:0055123 CHEBI:50885 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0004093 infores:hetionet CHEBI:8871 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0041582 infores:hetionet CHEBI:17076 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0030312 infores:hetionet CHEBI:681569 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0014742 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0029878 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0852810 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2979982 infores:hetionet CHEBI:135925 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0022107 infores:hetionet CHEBI:68478 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0002994 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011991 infores:hetionet CHEBI:10125 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0018681 infores:hetionet CHEBI:5138 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0026961 infores:hetionet CHEBI:9448 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C2364111 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0009326 infores:hetionet CHEBI:101853 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0004604 infores:hetionet NCBIGene:6647 biolink:causes MONDO:0007103 infores:monarchinitiative not_provided not_provided HGNC:11179 MONDO:0007103 uuid:79a83748-5465-430c-8509-b7f48b0900ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0019338 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0036202 infores:hetionet CHEBI:17303 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0080274 infores:hetionet CAID:CA10585186 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585186 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.905G>A (p.Cys302Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP3: REVEL= 0.98.PM1: Variant meets PM2 and alters Cys302, one of the cysteine residues listed.PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 index cases who fulfill criteria for FH (Japan Atherosclerosis Society) from PMID 33461934 (Tada et al., 2021), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585186/MONDO:0007750/013 2023-06-23 2025-08-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:77260 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020580 infores:hetionet UNII:DJJ95FJP1H biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0266813 infores:hetionet CAID:CA226856 biolink:causes MONDO:0010725 infores:clingen CAID:CA226856 MONDO:0010725 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PVS1, PP4 The NM_000330.4(RS1):c.78+1G>A variant is a canonical splice site variant in intron 2, located 1 nucleotide after exon 2. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant occurs at a canonical splice site in intron 2 and is predicted to disrupt splicing and induce skipping of exon 3, which is expected to introduce a premature stop codon in RS1 (PVS1). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 12383832, PP4). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis, as well as a second apparently unrelated proband previously used for the PP4 code (PMIDs: 33946315, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PP4, PS4_supporting, and PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226856/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:3423 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0010709 infores:hetionet CHEBI:136040 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0235660 infores:hetionet CHEBI:83531 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C1971624 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0025202 infores:hetionet CHEBI:94609 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C3160741 infores:hetionet CHEBI:6520 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0019080 infores:hetionet CAID:CA512341390 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341390 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.987G>C (p.Ala329=) is a synonymous variant. REVEL score not calculable as this is a synonymous variant. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.503315 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341390/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3561 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0016204 infores:hetionet CAID:CA10014546 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014546 MONDO:0100083 PMID: Likely Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS3, BS4, BP5, PM2, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 This variant has a MAF of 0.0002513 (0.02513%, 5/19896 alleles) in the East Asian subpopulation of the gnomAD V2 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This intronic variant has a SpliceAI ∆ score ≤ 0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.49) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014546/MONDO:0100083/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:77260 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0043094 infores:hetionet CHEBI:10124 biolink:causes HP:0007379 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042065 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0852733 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0302295 infores:hetionet CHEBI:6970 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0020522 infores:hetionet CHEBI:5613 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011606 infores:hetionet CHEBI:8028 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0041834 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0041364 infores:hetionet CHEBI:47612 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0033774 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151584 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151584 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0018099 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0006266 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011991 infores:hetionet CHEBI:7494 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0026827 infores:hetionet CHEBI:64019 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0004245 infores:hetionet CHEBI:167309 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C1610069 infores:hetionet CHEBI:8382 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011253 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0017178 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022408 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020550 infores:hetionet CHEBI:50173 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0041834 infores:hetionet CAID:CA229509 biolink:causes MONDO:0009861 infores:clingen CAID:CA229509 MONDO:0009861 PMID:10679941PMID:10679941 Pathogenic PM3, PP4_Moderate, PM2, PVS1 PM5, PP3 The PAH:p.M1R variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106). There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the pathogenic variant p.R408W (PMID: 10679941; PM3); BH4 deficiency was excluded (PP4_Moderate). The variant is sufficiently rare in control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP4_moderate, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229509/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0392171 infores:hetionet GO:0010901 biolink:causes GO:0097006 infores:ubergraph knowledge_assertion manual_agent GO:0010901 GO:0097006 GO:0030249 biolink:causes GO:0006182 infores:ubergraph knowledge_assertion manual_agent GO:0030249 GO:0006182 NCBIGene:1278 biolink:causes MONDO:0040501 infores:monarchinitiative not_provided not_provided HGNC:2198 MONDO:0040501 uuid:5054bbd2-0ec5-4d01-80b1-be0481c987f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64310 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0009450 infores:hetionet CAID:CA409120756 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120756 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4:c.596A>G is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 199 (p.Gln199Arg). The highest population minor allele frequency in gnomAD v4 is 0.00001440 (1/69426 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120756/MONDO:0007064/114 2024-06-10 2024-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6909 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0521839 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0853939 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0853939 infores:hetionet CHEBI:135736 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003962 infores:hetionet CHEBI:17303 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0220870 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0019385 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0019385 infores:hetionet CHEBI:59560 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0011991 infores:hetionet CAID:CA6904231 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904231 MONDO:0019497 PMID: Uncertain Significance PP3, PM5 PM2 The c.585G>C is a missense variant predicted to cause a substitution of methionine by isoleucine at amino acid 195 (p.Met195Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.048% (56/91086, CI 95%) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). The c.585G>C (p.Met195Ile) variant has been detected in two patients with hearing loss but without a second variant (PMID: 20601923; 18941476). The computational predictor REVEL gives a score of 0.928 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Another missense variant c.583G>C (p.Met195Val; ClinVar Variation ID: 22537) in the same codon has been classified as pathogenic for hearing loss by the ClinGen Hearing Loss VCEP (PM5). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM5; Version 2; 5/15/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904231/MONDO:0019497/005 2024-05-15 2024-07-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3723 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0152032 infores:hetionet UMLS:C0017797 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0042963 infores:hetionet CHEBI:4659 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0012833 infores:hetionet CHEBI:83531 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0004093 infores:hetionet CHEBI:72564 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042790 infores:hetionet CHEBI:6775 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0017672 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013595 infores:hetionet CHEBI:51860 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018808 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011849 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151505 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0233632 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0002170 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0003123 infores:hetionet CHEBI:3756 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0085593 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0003123 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027765 infores:hetionet CHEBI:45951 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0037763 infores:hetionet GO:1904847 biolink:causes GO:0044344 infores:ubergraph knowledge_assertion manual_agent GO:1904847 GO:0044344 NCBIGene:351 biolink:causes MONDO:0007088 infores:monarchinitiative not_provided not_provided HGNC:620 MONDO:0007088 uuid:d7fb8ced-6be3-4d36-8f1e-e8fed9472739 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512318720 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318720 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.447A>C (p.Ala149=) is a synonymous variant. No REVEL score because a synonymous variant and SpliceAI is ≤0.20 (BP4). The c.447A>C (p.Ala149=) variant is a synonymous (silent) variant. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20). Evolutionary algorithms predict the site is not conserved, phyloP100 way score is -4.26. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318720/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7915 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0033247 infores:hetionet CAID:CA10653547 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653547 MONDO:0011071 PMID: Likely Benign BP2, BS1 PS1, PS3, PS4, PS2, BA1, BP3, BP1, BP4, BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM3, PM4, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.*3444A>G is an intronic variant. MAF of 0.001 (0.1%, 18/15,276 alleles) in the Latino/Admixed American subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.00015 (0.015%) (BS1). This variant is reported in 4 homozygotes in gnomAD v2.1.1 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1 and BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653547/MONDO:0011071/008 2022-07-08 2022-07-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:44185 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151626 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0235818 infores:hetionet CAID:CA410203905 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203905 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.206G>C (p.Gly69Ala) is a missense variant which has a REVEL score < 0.50 (0.472) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203905/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4659 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0013144 infores:hetionet CHEBI:9316 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0080274 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1963818 infores:hetionet CHEBI:31515 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0039971 infores:hetionet CHEBI:2788 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0014236 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002888 infores:hetionet CHEBI:4657 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0001824 infores:hetionet CHEBI:44915 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0003467 infores:hetionet CAID:CA2499225757 biolink:causes MONDO:0015967 infores:clingen CAID:CA2499225757 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PVS1_Strong The c.1del variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PMID: 23348805).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea responsive) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with three informative meioses in one family (PP1; Internal lab contributors). In summary, c.1del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/1024): PVS1_Strong, PP4_Moderate, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225757/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4672 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0031039 infores:hetionet CHEBI:7936 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027497 infores:hetionet CHEBI:38545 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0438142 infores:hetionet CHEBI:73274 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C1167965 infores:hetionet NCBIGene:5077 biolink:causes MONDO:0008670 infores:monarchinitiative not_provided not_provided HGNC:8617 MONDO:0008670 uuid:f0aa7b68-dda6-472e-a4a9-d097aab079e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0042963 infores:hetionet CHEBI:18357 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0085636 infores:hetionet CHEBI:31236 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085636 infores:hetionet CHEBI:32184 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0015230 infores:hetionet CHEBI:8212 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0085637 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151736 infores:hetionet CHEBI:45924 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0002874 infores:hetionet CHEBI:28864 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C3665347 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0003864 infores:hetionet CHEBI:82960 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C2239176 infores:hetionet NCBIGene:2737 biolink:causes MONDO:0007804 infores:monarchinitiative not_provided not_provided HGNC:4319 MONDO:0007804 uuid:8a88db4b-6352-4c8b-92d1-5061e7181ca1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63581 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0021368 infores:hetionet CHEBI:3216 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011991 infores:hetionet UMLS:C0004609 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0043352 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0008035 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001517 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013369 infores:hetionet CHEBI:30830 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0344232 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0042109 infores:hetionet CHEBI:2639 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0011570 infores:hetionet CHEBI:16796 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0018681 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0033774 infores:hetionet CHEBI:27796 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0009421 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0233632 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0178298 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0150450 infores:hetionet CHEBI:31348 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0344232 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0014175 infores:hetionet CAID:CA404083801 biolink:causes MONDO:0007750 infores:clingen CAID:CA404083801 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1154T>C (p.Leu385Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.787. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404083801/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:39867 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0548823 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020517 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0349506 infores:hetionet CHEBI:16914 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0030193 infores:hetionet CHEBI:50859 biolink:causes HP:0045014 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0342892 infores:hetionet CAID:CA409118978 biolink:causes MONDO:0007064 infores:clingen CAID:CA409118978 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting PM5 The c.902A>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Lysine by Methionine at amino acid 301 (p.Lys301Met).This variant is absent from gnomAD v4 (PM2_Supporting). Another missense variant [c.902A>G (p.Lys301Arg)] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409118978/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6775 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0149904 infores:hetionet CHEBI:4814 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0018965 infores:hetionet CHEBI:9014 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0239150 infores:hetionet CHEBI:7494 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1456784 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038661 infores:hetionet CHEBI:3181 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0013395 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0009676 infores:hetionet CHEBI:8382 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151937 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0857983 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0857983 infores:hetionet CHEBI:70735 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0041969 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0029089 infores:hetionet CAID:CA631301060 biolink:causes MONDO:0012999 infores:clingen CAID:CA631301060 MONDO:0012999 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000156.6:c.145del (p.Tyr49Ilefs*65) variant in GAMT is a frameshift variant that is predicted to cause a premature stop codon in biologically-relevant-exon 3/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A Spanish patient, who is homozygous for the variant, has been reported with clinical symptoms consistent with GAMT deficiency, elevated guanidinoacetate in urine and plasma, and deficient GAMT activity in fibroblasts (PMID: 19892372, 21140503) (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000373 (1/26808 alleles) in the Lation/Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 695019). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631301060/MONDO:0012999/026 2023-09-14 2023-11-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45327 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0042023 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0026636 infores:hetionet CAID:CA210768 biolink:causes MONDO:0013144 infores:clingen CAID:CA210768 MONDO:0013144 PMID: Likely Pathogenic PS4_Moderate, PM1, PP3, PP4, PP1, PM2_Supporting The c.1240G>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 414 (p.Ala414Thr). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:36764659). This variant has been reported in 4 more probands meeting an antithrombin activity level of < 0.8 IU/mL on repeated independent tests or a family history of disease with reported antithrombin levels (PS4_Moderate, 3.5pts; PMID:25466846, 24684277, 3179438, 28300866). One proband did not meet the full requirements and thus half a point is awarded. The variant has been reported to segregate with hereditary antithrombin deficiency in at least 2 additional affected family members from one family (PP1; PMID:3179438).This variant resides within a residue, Ala414, of SERPINC1 that is defined as a reactive site residue by the ClinGen Thrombosis VCEP (PMID:2615648, PM1). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1180010 alleles) in European (non-Finnish) population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (PM2_Supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM1, PS4_moderate, PP1, PP3, PP4, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210768/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16606474 biolink:causes MONDO:0015967 infores:clingen CAID:CA16606474 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 PM5 The c.599G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 200 (p.(Arg200Gln)) of transcript, e.g. NM_000545.8. This variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.926, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in nine unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 23517481; internal lab contributors). Functional studies demonstrated the p.Arg200Gln protein has transactivation 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 15522234). Lastly, this variant was identified in at least three individuals from one family with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.599G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PP3, PM2_Supporting, PS3_Supporting, PS4, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606474/MONDO:0015967/017 2022-04-10 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6076 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0034063 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0032285 infores:hetionet CHEBI:5864 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0032227 infores:hetionet CHEBI:50305 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0021053 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0014549 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0035302 infores:hetionet CHEBI:51230 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0027497 infores:hetionet CHEBI:3312 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0232487 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0233494 infores:hetionet CHEBI:4646 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0020517 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0948525 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0028738 infores:hetionet CHEBI:490877 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0278134 infores:hetionet CHEBI:100147 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0151311 infores:hetionet NCBIGene:25821 biolink:causes MONDO:0013865 infores:monarchinitiative not_provided not_provided HGNC:19261 MONDO:0013865 uuid:09b292ba-fa47-4f27-836f-f1805f46fd45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1903587 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0001568 CHEBI:63620 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0424295 infores:hetionet CHEBI:39867 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0010200 infores:hetionet CHEBI:6970 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0018681 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0011849 infores:hetionet CHEBI:41423 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0037763 infores:hetionet CHEBI:474053 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C2830004 infores:hetionet CAID:CA16020737 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020737 MONDO:0009861 PMID:18346471PMID:17096675 Pathogenic PM3, PVS1, PM2, PP4 The c.184delC variant in PAH has been previously reported as a heterozygous single variant in one Italian proband with mild HPA (PMID: 17096675) and in trans with the known pathogenic p.A403V allele in an Italian proband (PMID: 18346471). Of note, the two papers share the primary authors, so it is unclear whether this represents one versus two distinct patients. The variant is a 1bp deletion leading to a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020737/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0010592 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0032584 infores:hetionet CHEBI:50742 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0235660 infores:hetionet CHEBI:28748 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0016204 infores:hetionet CHEBI:3561 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0022107 infores:hetionet NCBIGene:5575 biolink:causes MONDO:0859214 infores:monarchinitiative not_provided not_provided HGNC:9390 MONDO:0859214 uuid:5f7f7357-c78b-4353-9e14-29bc4656a378 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA390865129 biolink:causes MONDO:0100216 infores:clingen CAID:CA390865129 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting BP2, BA1, BS2, PP3, PP1, PP4, PM5, PS2, PS4, PS3, PS1, BS1, BS4, BS3 The NM_177438.3:c.5248G>A variant in DICER1 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 1750 (p.Val1750Ile). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000001239 (2/1614128 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.304; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting. (Bayesian Points: 1; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390865129/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5384 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0037763 infores:hetionet CHEBI:68606 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0917801 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1142135 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233472 infores:hetionet CHEBI:71255 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0221423 infores:hetionet CHEBI:28148 biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C2748540 infores:hetionet CHEBI:72564 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0003537 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0241863 infores:hetionet NCBITaxon:31704 biolink:causes MONDO:0005791 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:31704 MONDO:0005791 UMLS:C0657912 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0428977 infores:hetionet CAID:CA915940375 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940375 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The p.Arg287Serfs variant in exon 6 of ITGB3 gene is predicted to introduce a premature stop codon 34 amino acids downstream to it and result in NMD. This variant is absent from large population databases including gnomAD. It has been reported previously in compound heterozygous state in one proband who meets the ClinGen PD-VCEP criteria for the GT phenotype. The variant meets criteria for PVS1, PP4_moderate and PM2_supporting and is classified as pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940375/MONDO:0100326/011 2021-08-17 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:48131 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0332575 infores:hetionet CHEBI:6847 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0553548 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001539 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0035321 infores:hetionet CHEBI:5784 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0235416 infores:hetionet NCBIGene:6100 biolink:causes MONDO:0008378 infores:monarchinitiative not_provided not_provided HGNC:10288 MONDO:0008378 uuid:4d3fdf63-2f20-41c4-beaf-d28ac3c2cd0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145185 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0018799 infores:hetionet CHEBI:3216 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0858635 infores:hetionet CHEBI:40303 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0030305 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0030976 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030976 infores:hetionet CHEBI:9168 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151539 infores:hetionet CHEBI:8694 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0018681 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0020517 infores:hetionet CHEBI:23765 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085932 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0855242 infores:hetionet CHEBI:66964 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0033774 infores:hetionet GO:2001212 biolink:causes GO:0048514 infores:ubergraph knowledge_assertion manual_agent GO:2001212 GO:0048514 CHEBI:2668 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C2830004 infores:hetionet NCBIGene:25839 biolink:causes MONDO:0019407 infores:monarchinitiative not_provided not_provided HGNC:18620 MONDO:0019407 uuid:bfd3b954-18a7-46b9-ac53-7257e554290e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7823 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0030554 infores:hetionet CHEBI:7476 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042384 infores:hetionet CHEBI:31980 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0018681 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0851341 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020550 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0009450 infores:hetionet CHEBI:5280 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0013404 infores:hetionet CHEBI:10023 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0340865 infores:hetionet CHEBI:5790 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0003578 infores:hetionet NCBIGene:11235 biolink:causes MONDO:0011305 infores:monarchinitiative not_provided not_provided HGNC:8761 MONDO:0011305 uuid:64511774-437a-4dcc-91fc-32a10baae4a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7447 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0002792 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0855242 infores:hetionet CHEBI:5132 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0041582 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020538 infores:hetionet CHEBI:10650 biolink:causes HP:0032552 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235472 infores:hetionet CAID:CA277507 biolink:causes MONDO:0010604 infores:clingen CAID:CA277507 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4_Very Strong, PP3, PP4_Moderate PP1 The NM_000133.3:c.835G>A variant that results in the Ala279Thr missense change is absent from gnomAD v2.1.1 and v3, meeting PM2_Supporting. More than 59 male patients with mild hemophilia B are reported hemizygous for this variant in the literature, meeting PS4_Very strong and PP4_Moderate criteria (PMID: 29296726, 29656491). It is noted as a founder variant but may also have arisen de novo as a recurrent variant and is found in multiple ethnicities. The variant has a REVEL score of 0.765 (>0.6) which meets the thresholds recommended for PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very Strong, PP3, PP4_Moderate, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA277507/MONDO:0010604/080 2025-02-19 2025-02-19 X-linked inheritance HP:0001417 Supports CHEBI:4356 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0003537 infores:hetionet CHEBI:8774 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1368065 infores:hetionet CHEBI:7954 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0428977 infores:hetionet CAID:CA390887078 biolink:causes MONDO:0100216 infores:clingen CAID:CA390887078 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting BA1, PP3, PP1, PP4, BS2, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.3:c.1047C>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 349 (p.Asp349Glu). This variant has an allele frequency of 0.000001239 (2/1613918 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.151; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 04/23/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390887078/MONDO:0100216/024 2024-04-23 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151571 infores:hetionet CHEBI:63599 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0013395 infores:hetionet CHEBI:3508 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0027066 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0022354 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0031085 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027051 infores:hetionet CAID:CA10014282 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014282 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS3, BS4, BS1, PM6, PM2, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.844G>A (p.Asp282Asn) is a missense variant. This missense variant has a REVEL score <0.50 (0.329) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014282/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C2938875 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020517 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0041912 infores:hetionet CHEBI:5118 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0549622 infores:hetionet CAID:CA512318837 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318837 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.309T>C (p.Pro103=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.64) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318837/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4495 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0015967 infores:hetionet CHEBI:39669 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0016382 infores:hetionet CHEBI:34829 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0030193 infores:hetionet CHEBI:17076 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0040034 infores:hetionet GO:1900225 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:1900225 GO:0007154 CHEBI:63115 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0600125 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0019360 infores:hetionet CHEBI:8382 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0018790 infores:hetionet CHEBI:9139 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018965 infores:hetionet NCBIGene:55148 biolink:causes MONDO:0030963 infores:monarchinitiative not_provided not_provided HGNC:20344 MONDO:0030963 uuid:76a48b3d-13b0-41be-8e53-174b3cbd5fd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0016204 infores:hetionet CAID:CA043398 biolink:causes MONDO:0007947 infores:clingen CAID:CA043398 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PS4_Moderate, PM1 PM2, PVS1, PM6, PP4, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, PM4, PM5, PM3, BP7, BP5, BS1, BS3, BS4 NM_00138 c.1030C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 344 (p.Arg344Cys). This variant was found in one published proband with unspecified ocular and skeletal features, one internal proband with ectopia lentis and a systemic score of 3, and two probands with isolated thoracic aortic aneurysm and dissection, none of whom met the revised Ghent criteria for Marfan syndrome (PS4_moderate; PMID: 25652356; UZG & Invitae internal data, ClinVar Variation ID: 548999). This variant is present in gnomAD v2.1.1 (3/113642 [0.0026%] European alleles; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact protein structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_moderate, PM1, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA043398/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7465 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0852733 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0162830 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042109 infores:hetionet CHEBI:499361 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0036974 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0002170 infores:hetionet CHEBI:3219 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0033046 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025202 infores:hetionet CHEBI:4858 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C2047937 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0232431 infores:hetionet CHEBI:474180 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0231218 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0948594 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0016053 infores:hetionet CHEBI:10102 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013378 infores:hetionet CHEBI:9086 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018944 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042769 infores:hetionet CHEBI:8768 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030554 infores:hetionet NCBIGene:83605 biolink:causes MONDO:0011304 infores:monarchinitiative not_provided not_provided HGNC:21708 MONDO:0011304 uuid:5f8fa44a-fd9f-4e41-9495-3ff89b464735 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71023 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0027441 infores:hetionet CAID:CA2580650463 biolink:causes MONDO:0010725 infores:clingen CAID:CA2580650463 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1, PP4 The NM_000330.4(RS1):c.96dup variant is a frameshift variant due to one nucleotide duplication introducing a premature stop codon after 53 amino acids and causing a truncated protein. This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 30450322, PP4). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 35456481, 29739629, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PP4, PS4_supporting, and PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580650463/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:135679 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C3665347 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009766 infores:hetionet CAID:CA8337855 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337855 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3, PP4_Moderate, PVS1 The NM_000018.4(ACADVL):c.799_802del (p.Val267GlnfsTer8) variant in ACADVL is a frameshift variant predicted cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000003978 in general population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, of whom both were homozygous for the variant (PM3 score = 1.0, PM3, PMIDs: 27995075, 9973285). Patients with this variant displayed abnormal NBS and follow-up acylcarnitine profiles, and/or non-detectable ACADVL transcript by northern blot analysis, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMIDs: 27995075, 9973285). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting, PM3, PP4_moderate. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337855/MONDO:0008723/021 2025-03-31 2025-03-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:72296 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0002792 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0853813 infores:hetionet CHEBI:92998 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0009676 infores:hetionet CHEBI:261649 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0012833 infores:hetionet CHEBI:6359 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0027497 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0035078 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0233414 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0243026 infores:hetionet CHEBI:194135 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0086565 infores:hetionet CAID:CA10604820 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604820 MONDO:0015152 PMID: Uncertain Significance PP4, PM2_Supporting, PM4 PVS1, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP3, PP1, BP2, BP3, BP1, BP4, BA1, PS1, PS3, PS4, PS2, PM3, PM5, PM1 The NM_000232.5: c.199_210del variant in SGCB is predicted to cause a change in the length of the protein due to an in-frame deletion of four amino acids in a non-repeat region, p.(Cys67_Ile70del) (PM4). At least one individual with this variant and a second SGCB variant was clinically suspected to have limb girdle muscular dystrophy (LOVD Individual #00220457, PMID: 30564623; PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant cannot be classified as pathogenic nor benign at this time and remains a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM4, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604820/MONDO:0015152/184 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:64312 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151849 infores:hetionet CHEBI:50729 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0015967 infores:hetionet CAID:CA410148819 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148819 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.976G>A (p.Asp326Asn) is a missense variant with a population frequency of 0.000005094 in gnomAD v2.1.1. This was found in heterozygosis in one European (non-Finnish) female individual in a region with at least 20x coverage (42x). This missense variant does not affect either one of the 13 AA established residues or other AA residues 89-204 within the Runt Homology Domain (RHD). This missense variant has a REVEL score <0.50 (0.183) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148819/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3561 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C2047937 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0033581 infores:hetionet CHEBI:77733 biolink:causes MONDO:0008647 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0700053 infores:hetionet CHEBI:46081 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0231218 infores:hetionet CHEBI:15553 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0428977 infores:hetionet CHEBI:94609 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C2242996 infores:hetionet CAID:CA10014559 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014559 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS3, BS1, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP1, PP4 NM_001754.4(RUNX1):c.259G>T (p.Gly87Cys) is a missense variant which has a REVEL score ≥ 0.88 (0.918) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014559/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:59773 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0037383 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0027769 infores:hetionet CAID:CA2838185707 biolink:causes MONDO:0015967 infores:clingen CAID:CA2838185707 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM1_Supporting The c.-173_-172del variant in the hepatocyte nuclear factor 4-alpha, HNF4A, is a two base pair deletion within the promoter of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within the HNF1A/HNF1B binding domain (c.-170 to c.-173 and c.-178 to c.-181) of the HNF4A P2 promoter region, which is defined as critical for the protein’s function by the ClinGen MDEP. Given this is a deletion instead of a single nucleotide variant, and no experimental data are available, PM1_Supporting will be applied. This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.-173_-172del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 4.0.0, approved 10/10/2025): PM1_Supporting, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2838185707/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15367 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0575081 infores:hetionet CHEBI:617099 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C2363731 infores:hetionet CHEBI:144093 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0080274 infores:hetionet CAID:CA6264597 biolink:causes MONDO:0700270 infores:clingen CAID:CA6264597 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.387del (p.Asp130IlefsTer23) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in two individuals with Ataxia-Telangiectasia (PMID: 26896183, 30549301), and is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM3, PM5_Supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6264597/MONDO:0700270/020 2023-10-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31932 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0017160 infores:hetionet CHEBI:66876 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0085631 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034902 infores:hetionet CHEBI:6832 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0041657 infores:hetionet CHEBI:9137 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0231218 infores:hetionet CHEBI:50841 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0006266 infores:hetionet CHEBI:28864 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0003578 infores:hetionet CHEBI:168396 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0015672 infores:hetionet CHEBI:4868 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C1527344 infores:hetionet NCBIGene:10463 biolink:causes MONDO:0044726 infores:monarchinitiative not_provided not_provided HGNC:1329 MONDO:0044726 uuid:8dbd63e1-4a36-4508-8a47-e57419ca7078 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151636 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0232203 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0232203 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0400823 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0013604 infores:hetionet CHEBI:5004 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0027720 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0233494 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0008370 infores:hetionet CHEBI:64064 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0040586 infores:hetionet CHEBI:135566 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0019348 infores:hetionet CHEBI:5959 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0234233 infores:hetionet CHEBI:135613 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0004096 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0041969 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0853692 infores:hetionet CHEBI:9622 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0003862 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0948586 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013395 infores:hetionet CHEBI:15367 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0037299 infores:hetionet CHEBI:2948 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0003811 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0004096 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0853263 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0853263 infores:hetionet CHEBI:85083 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0037763 infores:hetionet CHEBI:9586 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1142412 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0413252 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0035309 infores:hetionet NCBITaxon:317865 biolink:causes MONDO:0000229 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:317865 MONDO:0000229 CHEBI:63629 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0239571 infores:hetionet CHEBI:9599 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C3665347 infores:hetionet CHEBI:135285 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0020458 infores:hetionet CHEBI:6367 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0032617 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0413252 infores:hetionet CHEBI:4710 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0162820 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0041747 infores:hetionet CHEBI:691037 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0010481 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007972 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025281 infores:hetionet CHEBI:617099 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0042109 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0948594 infores:hetionet CHEBI:119573 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0002994 infores:hetionet CHEBI:474180 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0009782 infores:hetionet CHEBI:28918 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0018524 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0267792 infores:hetionet NCBIGene:117581 biolink:causes MONDO:0009203 infores:monarchinitiative not_provided not_provided HGNC:20670 MONDO:0009203 uuid:21991b3e-c71c-42a3-9d54-33fc58cd7c9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0033777 infores:hetionet CHEBI:63791 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1145670 infores:hetionet CHEBI:7025 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0013378 infores:hetionet NCBIGene:3899 biolink:causes MONDO:0851095 infores:monarchinitiative not_provided not_provided HGNC:6473 MONDO:0851095 uuid:74538ad6-bd26-448d-99d8-f399e5b4a551 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0242350 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0518015 infores:hetionet CAID:CA275277 biolink:causes MONDO:0019501 infores:clingen CAID:CA275277 MONDO:0019501 PMID:27318125PMID:18273898PMID:27318125PMID:25425308PMID:28944237PMID:23591405PMID:27318125PMID:25425308PMID:28944237PMID:23591405 Pathogenic PP3, PP4, PM2_Supporting, PM3_Very Strong BS4, BS1, BP5, BP7, BS2, PP1, PM4, PM1, PVS1, PM6, BP3, BP4, BP2, BA1, PS3, PS2, PS4 The c.8682-9A>G variant in USH2A has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 27318125, 25425308, 28944237, 23591405). The allele frequency of the c.8682-9A>G variant in the USH2A gene is 0.04% (5/10112) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). At least one patient with this variant displayed features of retinitis pigmentosa and hearing loss which is consistent with Usher syndrome (PP4; PMID: 27318125, 25425308, 28944237, 23591405). Computational prediction tools and conservation analysis suggest that the c.8682-9A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PM2_Supporting, PP4, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA275277/MONDO:0019501/005 2018-09-24 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:465284 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151698 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0856050 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0856050 infores:hetionet CHEBI:85078 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0271710 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0015929 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015929 infores:hetionet CAID:CA350341886 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341886 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PM1 BS2, BP4, BA1, PS4, BS1 The c.1220A>C (p. Tyr407Ser) variant is a missense variant located in exon 9 of the BMPR2 gene, predicted to cause substitution of tyrosine to serine at amino acid position 407. The variant is present in the conserved catalytic kinase domain but without functional evidence indicating a critical or non-critical amino acid residue (PM1_moderate). The variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.981 and AlphaMissense is 0.9904 indicating pathogenicity (PP3_met). The variant has been reported in only one individual with PAH (PMID: 26387786) (PS4 not met). PS2 was not assessed due to lack of paternity data. No functional studies have been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341886/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0023530 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1368065 infores:hetionet CHEBI:49668 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0042963 infores:hetionet CHEBI:9943 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0241633 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0041969 infores:hetionet CHEBI:119915 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0852911 infores:hetionet CAID:CA1906766 biolink:causes MONDO:0018958 infores:clingen CAID:CA1906766 MONDO:0018958 PMID:25110572 Pathogenic PM3_Strong, PP1_Strong, PP4 BA1, BP4, PS3, BS1, PM2, PP3 The c.22144A>C p.(Thr7382Pro) variant in NEB is a missense variant predicted to cause substitution of Threonine by Proline at amino acid 7382. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001406 (9/64028 alleles) in the Finnish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a SCORE of 0.286 which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. This variant has been detected in 4 individuals with typical nemaline myopathy. Two of those individuals were compound heterozygous with an LP/P variant, phase confirmed and two were homozygous (PMID:16917880, 17525139) (PM3_Strong). At least two individuals with this variant displayed nemaline bodies (confirmed by electron microscopy), which is highly specific for nemaline myopathy (PP4, PMID:17525139). The variant has been reported to segregate with nemaline myopathy in 3 individuals with biallelic occurrence and 5 unaffected family members did not have biallelic occurrence in 2 families (PP1_Strong; PMID:17525139). Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_Strong, PP1_Strong, PP4. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1906766/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63580 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0260662 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0011274 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0011274 uuid:fcb89985-c373-4b32-924c-9630299ea298 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011603 infores:hetionet CAID:CA229401 biolink:causes MONDO:0009861 infores:clingen CAID:CA229401 MONDO:0009861 PMID:8268925PMID:21147011PMID:8268925PMID:21147011PMID:21953985 Pathogenic PM3, PP4_Moderate, PM2, PS3 PM5, PP3 The c.121C>T (p.Leu41Phe) variant in PAH has been reported in 2 individuals with mild PKU (BH4 deficiency excluded). (PMID: 21147011, 8268925). This variant is absent in population databases. This variant has 10% enzyme activity PMID: 21953985. This variant was detected with IVS10-11G>A (PMID: 21147011) and R261Q (PMID: 8268925)). Computational prediction tools are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229401/MONDO:0009861/006 2020-06-01 2020-06-01 Autosomal recessive inheritance HP:0000007 Supports UNII:UMD7G2653W biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0242429 infores:hetionet CAID:CA199315 biolink:causes MONDO:0010726 infores:clingen CAID:CA199315 MONDO:0010726 PMID: Benign BS2, BA1 The allele frequency of the p.Ala280= variant in MECP2 (NM_004992) is 0.034% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala280= variant is observed in at least 2 unaffected individuals (PMID 11469283, PMID 20479760) (BS2). In summary the p.Ala280= variant in MECP2 is classified as Benign for Rett syndrome disorder based on the ACMG/AMP criteria (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199315/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:68558 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0011603 infores:hetionet CHEBI:6078 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0018965 infores:hetionet NCBIGene:4194 biolink:causes MONDO:0030015 infores:monarchinitiative not_provided not_provided HGNC:6974 MONDO:0030015 uuid:eb79ab21-6516-4368-9705-816c16bb1d71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0237849 infores:hetionet CHEBI:5118 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0039070 infores:hetionet CHEBI:84883 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0004096 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0030781 infores:hetionet CHEBI:2950 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0043094 infores:hetionet CHEBI:8890 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0002622 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006840 infores:hetionet CHEBI:6067 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1527344 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0553548 infores:hetionet CHEBI:28001 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0031542 infores:hetionet CHEBI:28177 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0015230 infores:hetionet CHEBI:50275 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151904 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0677500 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0027765 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0242350 infores:hetionet CHEBI:474180 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0003862 infores:hetionet CHEBI:8412 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C2830004 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0233494 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002170 infores:hetionet UMLS:C0011701 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0042963 infores:hetionet CHEBI:50730 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0042963 infores:hetionet CHEBI:8080 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0000737 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0020538 infores:hetionet CHEBI:70735 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0004093 infores:hetionet CHEBI:7986 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0013456 infores:hetionet CHEBI:5801 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0085633 infores:hetionet CHEBI:31236 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0600142 infores:hetionet UMLS:C0009315 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0028961 infores:hetionet CHEBI:5280 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0004096 infores:hetionet CAID:CA000047 biolink:causes MONDO:0018875 infores:clingen CAID:CA000047 MONDO:0018875 PMID:30224644PMID:21900752PMID:12826609 Likely Benign BP4, BS2_Supporting, BS3 BA1, BP2, PS1, PS3, PS2, PM5, PM1, BS1, BS4, PVS1, PM2, PM6, PP3, PP1 Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.1163A>C (p.Glu388Ala) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting. TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000047/MONDO:0018875/009 2022-01-10 2022-01-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101853 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0018681 infores:hetionet CHEBI:10101 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0013604 infores:hetionet CHEBI:50841 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0035078 infores:hetionet CHEBI:8327 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C1368065 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042571 infores:hetionet CHEBI:7852 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0000731 infores:hetionet CHEBI:6367 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038220 infores:hetionet CHEBI:17334 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C2047937 infores:hetionet CHEBI:9674 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0030554 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0031350 infores:hetionet CHEBI:64198 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0020458 infores:hetionet CHEBI:63845 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0009450 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0039971 infores:hetionet CHEBI:63613 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0085932 infores:hetionet NCBIGene:10973 biolink:causes MONDO:0958204 infores:monarchinitiative not_provided not_provided HGNC:18697 MONDO:0958204 uuid:d02f6c7e-f07d-4cec-b570-f127c42eecb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29688 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0014742 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009782 infores:hetionet CHEBI:23765 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0016204 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0424332 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0424332 infores:hetionet NCBITaxon:52564 biolink:causes MONDO:0005880 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:52564 MONDO:0005880 CHEBI:61049 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020461 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0004936 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0917798 infores:hetionet CAID:CA2677125568 biolink:causes MONDO:0100437 infores:clingen CAID:CA2677125568 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PS4 NM_001034853.2(RPGR):c.2272del (p.Glu758LysfsTer?) is a frameshift variant due to a 1-nucleotide deletion that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 34745198). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The variant has been reported to segregate with retinal dystrophy through an affected mother and daughter from 1 family, however, at least 2 affected meioses are required for PP1, so this code is not met (PMID: 34745198). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2677125568/MONDO:0100437/106 2025-08-28 2025-08-29 X-linked inheritance HP:0001417 Supports CHEBI:480999 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151904 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0041349 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017152 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0746883 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020649 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035854 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020456 infores:hetionet CHEBI:8871 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007859 infores:hetionet GO:2001026 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:2001026 GO:0070887 CAID:CA278724 biolink:causes MONDO:0019501 infores:clingen CAID:CA278724 MONDO:0019501 PMID: Likely Pathogenic PP1_Moderate, PP3, PP4, PM2_Supporting, PM3_Strong The variant NM_000260.4:c.6326C>T in MYO7A is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 2109 (p.Thr2109Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (8/128408 alleles, 0 homozygotes) for the European (Non-Finnish) population, which meets PM2_supporting criteria. The REVEL computational prediction analysis tool produced a score of 0.821, meeting PP3 criteria. This variant has been reported in two unrelated probands, both with Usher syndrome (PP4; SCV000199631.4). In addition, both probands had an additional MYO7A pathogenic or likely pathogenic variant in trans, meeting PM3_Strong criteria. Finally, the variant was shown to segregate with two affected family members (PP1_Moderate). In summary, the variant meets criteria to be classified as likely pathogenic for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PP4, PM3_Strong, PP1_Moderate (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278724/MONDO:0019501/005 2023-01-18 2023-02-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:8888 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0878773 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0149931 infores:hetionet CHEBI:8461 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0428977 infores:hetionet CHEBI:135929 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0278106 infores:hetionet CHEBI:94501 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0017178 infores:hetionet CHEBI:45863 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0037299 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022650 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0002170 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020649 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0034882 infores:hetionet CHEBI:45599 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0022107 infores:hetionet CHEBI:50924 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C2973529 infores:hetionet CHEBI:6916 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0013604 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0021141 infores:hetionet CHEBI:9137 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011253 infores:hetionet CHEBI:16796 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0004093 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0019054 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0015230 infores:hetionet CHEBI:8228 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0009782 infores:hetionet CHEBI:31236 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011880 infores:hetionet CHEBI:52172 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0241060 infores:hetionet CHEBI:71255 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020625 infores:hetionet CHEBI:34829 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C3665347 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0017178 infores:hetionet CHEBI:6541 biolink:causes HP:0011032 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C2364164 infores:hetionet CHEBI:6801 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0231218 infores:hetionet CAID:CA116663 biolink:causes MONDO:0009276 infores:clingen CAID:CA116663 MONDO:0009276 PMID: Pathogenic PP4, PM2_Supporting, PP1_Strong, PVS1_Strong, PM3, PS3_Supporting The c.1620G>A (p.Trp540Ter) variant in GP1BA is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However the truncation includes the functionally important transmembrane domain (removes amino acids 540-553) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMID:9639514). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 0.000009540 (based on 18/1179684 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). Surface expression of GP1a measured by flow cytometry in CHO cells transiently co-transfected with the p.Trp540Ter variant in GP1a and wild type GP1b, and GP9 was barely detectable compared to controls, indicating that this variant impacts protein function (PMID:9639514)(PS3_supporting). This variant has been detected in at least 6 individuals with Bernard-Soulier syndrome. At least one individual had excessive mucocutaneous bleeding and macrothrombocytopenia and absent expression of GPIba measured by flow cytometry (PP4 - PMID:25370924). Two of those individuals were homozygous for this variant (PMID:25370924, 9233564). Two individuals were compound homozygous for this variant and the p.Cys81Arg variant and confirmed in trans by family testing, but was used for that curation (PMID:25370924). Another proband (different publication and authorship) was compound homozygous for this variant and the p.Cys81Arg variant and confirmed in trans by family testing, but was used for this curation (PMID: 9639514) for a total of 2 points (PM3). The variant has been reported to segregate in a homozygous proband plus 2 compound heterozygotes (PMID:25370924) and a proband plus 1 additional compound heterozygous affected sibling (PMID: 9639514) meeting PP1_strong. In summary, this variant meets the criteria to be classified as pathogenic for Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PM3, PP4, PP1_moderate, PM2_supporting, PS3_supporting (Platelet VCEP GP1BA specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA116663/MONDO:0009276/079 2025-09-04 2025-09-04 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0065374 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0021308 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0494165 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0494165 infores:hetionet CHEBI:7986 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C2363730 infores:hetionet CHEBI:8499 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0027497 infores:hetionet CHEBI:135929 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0027441 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0027947 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0476327 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0018799 infores:hetionet UMLS:C0065374 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151603 infores:hetionet CHEBI:168396 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0023524 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0242350 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0236083 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0236083 infores:hetionet CHEBI:135686 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0041969 infores:hetionet UMLS:C1144403 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0151905 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0162429 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0039520 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0877338 infores:hetionet CHEBI:4653 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0700361 infores:hetionet CHEBI:520985 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0002994 infores:hetionet NCBIGene:5468 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:9236 MONDO:0005148 uuid:3e0cdec2-9b50-4fba-89fb-3bfaa2480fb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50859 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030232 infores:hetionet CAID:CA010449 biolink:causes MONDO:0005045 infores:clingen CAID:CA010449 MONDO:0005045 PMID: Likely Pathogenic PP1_Strong, PM1, PS4_Moderate, PM2_Supporting BS1, BS3, BS4, PP2, PP3, PM5, BA1, BP4, PS1, PS3 NM_000256.3(MYBPC3):c.1483C>G (p.Arg495Gly) - This variant has been reported in individuals with HCM (ClinVar Variation ID: 42537) and has also been identified in 1 out of 112990 (0.004% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). This variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>10), therefore, the PS4 criterion has been applied at moderate strength (PS4_Moderate) and the PM2_Supporting criterion has been applied (PM2_Supporting). This variant segregated with disease in more than 7 affected relatives with HCM from at least 4 families [PP1_Strong: Teirlinck 2012 PMID: 23140321, Page 2012 PMID: 22267749, Oxford Medical Genetics Laboratory (OMGP; pers. comm.), Laboratory for Molecular Medicine (LMM; pers. comm.)]. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (REVEL score <0.7). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Strength; Walsh 2019 PMID: 30696458). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PP1_Strong, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010449/MONDO:0005045/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47381 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0043094 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0031039 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0004936 infores:hetionet CAID:CA000015 biolink:causes MONDO:0018875 infores:clingen CAID:CA000015 MONDO:0018875 PMID: Likely Pathogenic BP4, PS3, PM1, PM2_Supporting, PS4_Supporting BA1, PM5, BS3, BS4, BS2, PP3, PP1, PP4 The NM_000546.6(TP53):c.1010G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 337 (p.Arg337Leu). This variant has been reported in 2 families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.067; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). This variant has 20 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, BP4, PM2_Supporting, PS4_Supporting. (Bayesian Points: 7; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000015/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5790 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042075 infores:hetionet CHEBI:7956 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0149931 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0233494 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018099 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0012833 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0019158 infores:hetionet CHEBI:134991 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020580 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0037274 infores:hetionet CHEBI:6801 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C2047937 infores:hetionet CHEBI:6030 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0700361 infores:hetionet CHEBI:261649 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0220870 infores:hetionet CAID:CA383506185 biolink:causes MONDO:0015629 infores:clingen CAID:CA383506185 MONDO:0015629 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5 The NM_000552.5(VWF):c.3926T>A (p.Ile1309Asn) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.886, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Another type 2B missense change (p.I1309V) has been reported at this amino acid residue and has been classified Pathogenic for type 2B VWD by the VWD VCEP (PM5). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of thrombocytopenia and an assay showing gain of function (flow cytometry showed markedly increased baseline activity), which together are highly specific for VWD type 2B. (PP4_moderate, SCV002515788.1). The patient was also reported to a VWF antigen/activity ratio (0.2) consistent with type 2B. In summary, this variant has been classified as likely pathogenic for type 2B Von Willebrand Disease based on the ACMG/AMP criteria applied as specified by the von Willebrand Disease Variant Curation Expert Panel. PM2_supporting, PP3, PM5, PP4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383506185/MONDO:0015629/081 2025-05-06 2025-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64064 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0020517 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0426576 infores:hetionet CAID:CA410146980 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146980 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1382A>C (p.Asn461Thr) is a missense variant which has a REVEL score < 0.50 (0.133), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146980/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038363 infores:hetionet CHEBI:107736 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0156404 infores:hetionet CHEBI:39669 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0011603 infores:hetionet CHEBI:10650 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0038999 infores:hetionet CHEBI:50648 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030196 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0029445 infores:hetionet CHEBI:3508 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0018681 infores:hetionet CHEBI:17347 biolink:causes HP:0040411 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0497481 infores:hetionet CHEBI:5790 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151786 infores:hetionet CHEBI:5864 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0037036 infores:hetionet UMLS:C0010592 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0233407 infores:hetionet CHEBI:8346 biolink:causes MONDO:0006996 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0040127 infores:hetionet CHEBI:2675 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0001824 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0497247 infores:hetionet CHEBI:64321 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0151904 infores:hetionet CHEBI:72296 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0025874 infores:hetionet CHEBI:32293 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0022408 infores:hetionet CHEBI:40237 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0085649 infores:hetionet CHEBI:6717 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0017181 infores:hetionet CHEBI:6717 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0018681 infores:hetionet CHEBI:10127 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0917801 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004026 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0037293 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0003123 infores:hetionet GO:1902762 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:1902762 GO:0043009 CAID:CA000595 biolink:causes MONDO:0017623 infores:clingen CAID:CA000595 MONDO:0017623 PMID:11238682PMID:11238682PMID:11238682PMID:11238682PMID:11238682PMID:11238682 Likely Pathogenic PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.802del (p.Asp268ThrfsTer8) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort (PMID:27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000595/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9566 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0015967 infores:hetionet CHEBI:404903 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0025222 infores:hetionet CHEBI:4702 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0011606 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0343263 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0343263 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0853714 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0014742 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0005779 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0003123 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020517 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038363 infores:hetionet CHEBI:45783 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011168 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C3665624 infores:hetionet CHEBI:10125 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233407 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042109 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013922 infores:hetionet CHEBI:49960 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151908 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0233472 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0001039 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D014069 DB00954_MESH_D014069_1 CHEBI:92712 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0677500 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0031542 infores:hetionet CAID:CA000187 biolink:causes MONDO:0017623 infores:clingen CAID:CA000187 MONDO:0017623 PMID: Pathogenic PM6, PP2, PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting, PS2 PTEN c.70G>C (p.Asp24His) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) SCV005686053.1).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 34374989).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.602 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350).PP3: REVEL score > 0.7 (score of this variant = 0.98).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID 23764071).PM2_P: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000187/MONDO:0017623/003 2025-04-04 2025-10-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:34967 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0002622 infores:hetionet NCBITaxon:5476 biolink:causes UMLS:C1112209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D059413 DB00681_MESH_D059413_1 CHEBI:6078 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0009763 infores:hetionet NCBIGene:9928 biolink:causes MONDO:0054761 infores:monarchinitiative not_provided not_provided HGNC:19181 MONDO:0054761 uuid:78c8147d-3f0a-420c-8d3a-e267c87d82ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17549 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0311468 infores:hetionet CHEBI:51041 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0014724 infores:hetionet GO:2000354 biolink:causes GO:0046660 infores:ubergraph knowledge_assertion manual_agent GO:2000354 GO:0046660 CHEBI:50173 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0015967 infores:hetionet CHEBI:6149 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0039070 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0948594 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0012504 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0012504 uuid:321331f9-ef17-46a1-8a16-eccf377a51fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0010200 infores:hetionet CHEBI:9123 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0852911 infores:hetionet CAID:CA120551 biolink:causes MONDO:0044970 infores:clingen CAID:CA120551 MONDO:0044970 PMID: Uncertain Significance PS3_Supporting PP3, PS4, PM2 The m.622G>A variant in MT-TF has been reported in one individual to date, in a woman with adult-onset myopathy and neuropathy. She was healthy until her early 60s when she developed exercise intolerance, fatigue, paresthesia, muscle cramps, and mild hearing impairment. Muscle biopsy showed several atrophic fibers, COX-deficient fibers, subsarcolemmal mitochondrial accumulation, and enlarged mitochondria with paracrystalline inclusions. She had reductions in complex I (50% controls), complex III (68% controls), and complex IV (55% controls) activities. The variant was present at 88% heteroplasmy in muscle, 70% in hair, 66% in urine, 63% in buccal sample, and 36% in blood (PMID: 16769874). Her mother was reported to have similar walking difficulties but did not undergo testing for this variant. Her healthy daughter had the variant present at lower heteroplasmy levels however her daughter was younger than the proband was at symptom onset. This variant is present in population databases (absent in Mitomap's GenBank sequences; one heteroplasmic and one homoplasmic occurrence in gnomAD v3.1.2; eight heteroplasmic occurrences in the Helix dataset). Single fiber testing showed higher levels of the variant in COX-negative fibers (93%±1.0; N = 11) than in COX-positive fibers (82%±8.5; N = 14), p<0.001 (PS3_supporting, PMID: 16769874). Aminoacylation defects and tRNA structural changes were also reported (PMID: 17878308). The computational predictor MitoTIP suggests this variant is neutral (41.5 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120551/MONDO:0044970/015 2024-06-24 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8869 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0010692 infores:hetionet CHEBI:7809 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0022658 infores:hetionet CHEBI:8107 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0042510 infores:hetionet NCBIGene:25977 biolink:causes MONDO:0014360 infores:monarchinitiative not_provided not_provided HGNC:24539 MONDO:0014360 uuid:3a776e15-fed2-45f9-a422-e11c3be117fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367400539 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400539 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1 The c.797T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 266 (p.(Leu266Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.975, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:275059371. 24918535, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.797T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP2, PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400539/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:5864 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002170 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002871 infores:hetionet CHEBI:17334 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0233407 infores:hetionet CAID:CA410208110 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208110 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS3, BS1, BS4, PM5, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.4:c.532A>C (p.Thr178Pro) is a missense variant which affects one of the residues within the Runt Homology Domain (AA 105-204) (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.971) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000807789.1). In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PS4_ supporting, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208110/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68579 biolink:causes MONDO:0004431 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018924 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0040034 infores:hetionet CAID:CA041995 biolink:causes MONDO:0007750 infores:clingen CAID:CA041995 MONDO:0007750 PMID: Uncertain Significance BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.148G>A (p.Ala50Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041995/MONDO:0007750/013 2024-10-28 2025-01-20 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:75722 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015672 infores:hetionet CHEBI:45285 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0013395 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0007785 infores:hetionet CHEBI:3082 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0021368 infores:hetionet CAID:CA1022023103 biolink:causes MONDO:0011071 infores:clingen CAID:CA1022023103 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.967+10T>C is an intronic variant. This variant has a SpliceAI score ≤ 0.20 (0.01) (BP4) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.171)(BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1022023103/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3175 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0863084 infores:hetionet CHEBI:31302 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0013144 infores:hetionet CHEBI:61049 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011603 infores:hetionet CHEBI:3347 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0014591 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0342579 infores:hetionet CHEBI:28748 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027121 infores:hetionet CHEBI:49603 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0009782 infores:hetionet CHEBI:101853 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0009782 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0004238 infores:hetionet CAID:CA410148782 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148782 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.986C>T (p.Ala329Val) is a missense variant which has a REVEL score < 0.50 (0.131), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148782/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7581 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0085631 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0162119 infores:hetionet CHEBI:4910 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0019521 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011991 infores:hetionet CHEBI:9667 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0019080 infores:hetionet CHEBI:50131 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0036983 infores:hetionet CHEBI:4909 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0041657 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0948089 infores:hetionet CAID:CA193402 biolink:causes MONDO:0100488 infores:clingen CAID:CA193402 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, PS4 The c.173A>T (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of Glu by Val at amino acid 58 (p. Glu58Val). This variant has been observed in more than 10 heterozygous individuals with no DGC, SRC tumours or LBC and and whose families do not suggest HDGC of HDGC (BS2; Invitae, GeneDx, Ambry). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Although there are both pathogenic and benign types of evidence for this variant, the CDH1 VCEP classified the variant as likely benign for DGLBCS based on BS2 alone. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA193402/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:2659 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0020517 infores:hetionet CHEBI:53760 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0917801 infores:hetionet CHEBI:6413 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0040038 infores:hetionet CAID:CA6748996 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748996 MONDO:0009861 PMID: Uncertain Significance PM2, BS1, BP7 The NM_000277.3:c.222A>G variant in PAH is a synonymous (silent) variant (p.Lys74=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003204 (8/24966 alleles) in the African/African American population (none of the population data codes are met). There is a ClinVar entry for this variant (Variation ID: 991624, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): no criteria are met. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748996/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36795 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011849 infores:hetionet CHEBI:52717 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0438142 infores:hetionet CAID:CA039797 biolink:causes MONDO:0007750 infores:clingen CAID:CA039797 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.2324T>C (p.Val775Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is follows: PM2: PopMax MAF = 0.00002627 (0.0026%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0). BP4: REVEL=0.244. It is below 0.5, so splicing evaluation is required.A) not on limitsB) does not create AGC) there is an AG nearby.MES scores: variant cryptic = 1.45, wt cryptic = 2.52, canonical acceptor = 11.36.Ratio variant cryptic/wt cryptic: 0.57 --- it is below 1.1.Ratio variant cryptic/canonical acceptor: 0.12--- it is below 0.9.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA039797/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:7401 biolink:causes MONDO:0010170 infores:monarchinitiative not_provided not_provided HGNC:12605 MONDO:0010170 uuid:b7406031-fa31-46d0-b5ee-78f600afbd7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75246 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0042023 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0037199 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0004623 infores:hetionet CHEBI:4702 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0151539 infores:hetionet CAID:CA367398617 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398617 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.1175G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 392 (p.(Arg392Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.909, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Two other missense variants at the same amino acid position, c.1174C>T p.(Arg392Cys) and c.1175G>T p.(Arg392Leu), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, OGTT increment < 3 mmol/L, and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID: 23624530, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 7/23/2025): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398617/MONDO:0015967/086 2025-09-29 2025-09-29 Semidominant inheritance HP:0032113 Supports CHEBI:31705 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042029 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0151574 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151574 infores:hetionet CHEBI:37941 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020443 infores:hetionet CHEBI:70746 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0085649 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019054 infores:hetionet CHEBI:68647 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0333355 infores:hetionet CHEBI:145499 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0041657 infores:hetionet CHEBI:2659 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0027497 infores:hetionet CHEBI:8405 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0025637 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085606 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0038454 infores:hetionet CHEBI:5103 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C3665386 infores:hetionet CAID:CA8315085 biolink:causes MONDO:0009276 infores:clingen CAID:CA8315085 MONDO:0009276 PMID: Likely Benign PVS1_Moderate, BS1 PP4, PM3 The variant NM_000173.7(GP1BA):c.1845_1849del is a frameshift variant predicted to cause a premature stop codon and remove <2% of the protein (PVS1_moderate). This variant is reported in two patients with abnormal bleeding (PMID: 28748566 and internal data) but insufficient information was available to determine if the phenotype was specific to Bernard Soulier syndrome. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0008013 (997/1179914 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0005 for GP1BA), and therefore meets this criterion (BS1). In summary, the variant can be classified as Likely Benign, based off the ACMG criteria applied: BS1 and PVS1_moderate; conflicting evidence was evaluated using the point system described by Tavtigian, et al. 2020 (PMID: 32720330). (PD VCEP GP1BA specifications v1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8315085/MONDO:0009276/079 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3515 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0002878 infores:hetionet CHEBI:29688 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0030305 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042075 infores:hetionet CAID:CA3054201762 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201762 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, PM4, PM1, PM3, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.524del (p.Leu175fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (–) c.98–c.758 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201762/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:77733 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0007194 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0018099 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0005972 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D011018 DB00535_MESH_D011018_2 CHEBI:7986 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C1443060 infores:hetionet CHEBI:63631 biolink:causes HP:0002345 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234376 infores:hetionet NCBIGene:23314 biolink:causes MONDO:0012864 infores:monarchinitiative not_provided not_provided HGNC:21637 MONDO:0012864 uuid:59d60741-ba5c-43ef-a6d3-b00c171924dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0235266 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009450 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0035854 infores:hetionet CHEBI:31623 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0035455 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0232459 infores:hetionet GO:1904942 biolink:causes GO:0003231 infores:ubergraph knowledge_assertion manual_agent GO:1904942 GO:0003231 UNII:8NZ41MIK1O biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0036974 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0019348 infores:hetionet CAID:CA410202496 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202496 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS1, PS3, PS2, BA1, BP3, BP1, BP4, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM4, PM5, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.493G>C (p.Gly165Arg) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score greater than 0.88 (0.952) and a SpliceAI score less than 0.20 (0.01, 8bp, Donor Loss) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant has been reported in one proband meeting at least one of the RUNX1 phenotypic criteria (PS4_supporting; PMID: 29797310, Table 2). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202496/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6472 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0020649 infores:hetionet CHEBI:3508 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0236075 infores:hetionet NCBIGene:55679 biolink:causes MONDO:0014788 infores:monarchinitiative not_provided not_provided HGNC:16084 MONDO:0014788 uuid:97d5e70e-fc5f-41a1-89ca-d46894a2f4d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038661 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0011849 infores:hetionet CHEBI:145499 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015672 infores:hetionet CHEBI:30659 biolink:causes MONDO:0015469 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0010278 infores:hetionet CAID:CA10585480 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585480 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PM2, PP4, PP3 BA1, BP1, BP4, BP2, PS3, PS1, PS2, BP5, BS1, BS3, BS4, PM1, PM5, PM3, PM6, PP2, BS2 The NM_000527.5(LDLR):c.1495T>C (p.Ser499Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP1_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.0.0).PP3: REVEL = 0.758. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (4 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France). PP1_Moderate - Variant segregates with FH phenotype in 4 informative meiosis in 4 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France): 4 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585480/MONDO:0007750/013 2024-02-23 2024-10-07 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8776 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0015967 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0023380 infores:hetionet CHEBI:253342 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0018944 infores:hetionet CHEBI:52717 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085649 infores:hetionet CHEBI:50648 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0040264 infores:hetionet NCBIGene:1630 biolink:causes MONDO:0054602 infores:monarchinitiative not_provided not_provided HGNC:2701 MONDO:0054602 uuid:cb09e8fd-bb0d-45e9-80cd-aafac35fa70b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6904 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0030554 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0027765 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0087169 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0002871 infores:hetionet GO:0075184 biolink:causes GO:0044409 infores:ubergraph knowledge_assertion manual_agent GO:0075184 GO:0044409 CHEBI:16469 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042109 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0021400 infores:hetionet CHEBI:3478 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0002878 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0038587 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0007222 infores:hetionet CHEBI:209807 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0011991 infores:hetionet CHEBI:5138 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C2242737 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0005741 infores:hetionet CHEBI:9435 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0023518 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0008370 infores:hetionet CHEBI:7443 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0015230 infores:hetionet CHEBI:74947 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0000731 infores:hetionet CHEBI:421707 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0520573 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0036572 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0919702 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0919702 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0497247 infores:hetionet NCBIGene:10273 biolink:causes MONDO:0032526 infores:monarchinitiative not_provided not_provided HGNC:11427 MONDO:0032526 uuid:37c7c9ec-95c2-414b-b278-f156552b3f1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0037199 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003850 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0234913 infores:hetionet CHEBI:168396 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0497156 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0851341 infores:hetionet CHEBI:17650 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0162834 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0042514 infores:hetionet CHEBI:184555 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0018965 infores:hetionet CHEBI:168396 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0014591 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0235919 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235919 infores:hetionet CHEBI:3084 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0011991 infores:hetionet CHEBI:63619 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0700590 infores:hetionet CHEBI:51364 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0152198 infores:hetionet CHEBI:52717 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0022107 infores:hetionet CHEBI:31401 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151517 infores:hetionet CHEBI:3215 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0085593 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0021843 infores:hetionet CHEBI:40279 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0009421 infores:hetionet CHEBI:8430 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0014457 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0339916 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0022354 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0011053 infores:hetionet UMLS:C0145867 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0546817 infores:hetionet CHEBI:47499 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0917801 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0007787 infores:hetionet CHEBI:9637 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C2363730 infores:hetionet CHEBI:119573 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151825 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0042571 infores:hetionet CAID:CA226472 biolink:causes MONDO:0100368 infores:clingen CAID:CA226472 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP1_Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting The NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) missense variant replaces the leucine at position 341 with serine and has been reported in several patients. At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing (2 pt) in PMID: 23847139) who displayed a non-detectable ERG (2 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate). One patient was compound heterozygous for this variant and a pathogenic pathogenic variant (c.1205_1206insCCTG classified Pathogenic by the LCA/eoRD VCEP) confirmed in trans by parental testing (PMID: 9501220) and two probands were homozygous for the variant (PMID: 9501220, PMID: 15837919) (PM3_strong). The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent or severely decreased rod electroretinogram response) in the proband plus 3 affected family members, all with the compound heterozygous genotype of Leu341Ser and c.1205_1206insCCTG variants. (PP1_strong; PMID: 9501220). The computational predictor REVEL gives a score of 0.988 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 and has a Grpmax Filtering AF of 0.00005290 in gnomAD v.3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP1_strong, PM3_strong, PP3_Moderate, PP4_Moderate, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226472/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:180905 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0039231 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027051 infores:hetionet CAID:CA346327851 biolink:causes MONDO:0800472 infores:clingen CAID:CA346327851 MONDO:0800472 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PP3_Moderate PP1, BA1, BP4, PM5, PM4, PM1, PS1, PS3, PS2, BP7, BS1, PVS1 The c.1103G>T variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Leucine at amino acid 368 (p.Arg368Leu). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.797, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is homozygous (assumed non-consanguineous) for this variant (PMID: 18852424). Total proband points = 0.5, meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PP3_Moderate, PM3_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346327851/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:94449 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0017178 infores:hetionet CAID:CA1624221 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624221 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.3330G>C (p.Ser1110=) variant in the SOS1 gene is 0.0382% (8/10406) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624221/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA410202733 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202733 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP2, BP3, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM5, PM3, PM4, PP2, PP1, PP4 NM_001754.5(RUNX1):c.380G>T (p.Gly127Val) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (coverage >= 20) (PM2_supporting). This missense variant has a REVEL score ≥ 0.88 (0.97) (PP3). This variant affects an amino acid residue within the RHD domain [amino acids 89-204] that is defined as a critical functional domain by the ClinGen MM-VCEP (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202733/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6950 biolink:causes UMLS:C0151589 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151589 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235639 infores:hetionet CHEBI:8435 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0017979 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0037274 infores:hetionet CHEBI:6715 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0008031 infores:hetionet CHEBI:7478 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0577559 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042134 infores:hetionet CHEBI:45716 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0040038 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0227791 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0243026 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0021400 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0031350 infores:hetionet CHEBI:68478 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0028081 infores:hetionet CHEBI:584020 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0002170 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0004936 infores:hetionet CAID:CA409104379 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104379 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP3, PP4, PM2_Supporting, PM1_Supporting BS1 The c.305G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of glycine to aspartic acid at codon 102 (p.(Gly102Asp)) of NM_175914.5. This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant failed QC in gnomAD exomes and is absent in gnomAD genomes, BRAVO genomes, Geisinger exomes, and UKBB exomes (PM2_Supporting). Another missense variant, c.304G>A p.(Gly102Ser), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9689, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4). In summary, c.305G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104379/MONDO:0015967/085 2023-09-01 2023-09-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1579838 infores:hetionet CHEBI:3011 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0542571 infores:hetionet CHEBI:9907 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0004093 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0234987 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151763 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001325 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020617 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017658 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0857448 infores:hetionet CHEBI:8863 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1145670 infores:hetionet CHEBI:8214 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0043144 infores:hetionet CHEBI:7445 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C2225524 infores:hetionet CHEBI:9671 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0042963 infores:hetionet NCBIGene:5604 biolink:causes MONDO:0007970 infores:monarchinitiative not_provided not_provided HGNC:6840 MONDO:0007970 uuid:93d4515e-6a25-4a43-baf7-ce60a3d59bce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0035309 infores:hetionet CHEBI:78543 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020621 infores:hetionet CHEBI:51450 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0428977 infores:hetionet CHEBI:5384 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0231218 infores:hetionet CHEBI:63618 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151662 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036454 infores:hetionet CHEBI:85161 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0004093 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0020651 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0585186 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0007642 infores:hetionet CHEBI:31711 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0522055 infores:hetionet CHEBI:68556 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0015967 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0521491 infores:hetionet NCBIGene:10008 biolink:causes MONDO:0013145 infores:monarchinitiative not_provided not_provided HGNC:6243 MONDO:0013145 uuid:a51376cd-94d9-4029-8826-faacaaf2ac73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:8NZ41MIK1O biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0040034 infores:hetionet CAID:CA412349776 biolink:causes MONDO:0100039 infores:clingen CAID:CA412349776 MONDO:0100039 PMID: Likely Pathogenic PP3, PM2_Supporting, PS2 The p.Leu97Pro variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in an individual (GeneDx Internal Database) (PS2). The p.Leu97Pro variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu97Pro variant in CDKL5 is classified as likely pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412349776/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Supports CHEBI:31623 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0013595 infores:hetionet CHEBI:6954 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0027947 infores:hetionet CAID:CA8815666 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815666 MONDO:0009290 PMID: Pathogenic PM2, PVS1, PP4, PM3, PS3 This variant, c.2238G>A (p.Trp746Ter), is a nonsense variant, predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923), as well as functional studies in which there was no measurable GAA activity when the variant was expressed in HEK-293 cells (PMID 23430493). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, meeting PM2. This variant has been reported in 3 patients who meet the ClinGen LSD VCEP’s specifications for PP4. Two of these patients are compound heterozygous for pathogenic variants, either c.-32-13T>G or c.1826dupA (PMIDs 16860134, 22613277, 25741864). The phase is unknown. This data meets PM3. Another patient is compound heterozygous for the variant and c.1843G>A (p.Gly615Arg). This in trans data was used in the assessment of p.Gly615Arg and therefore was not included here in order to avoid circular logic. There is a ClinVar entry for this variant (ClinVar variation ID: 270904, 2 star review status) with 3 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4 Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815666/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:36795 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042023 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0035455 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0036508 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0340464 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0152198 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0011570 infores:hetionet CHEBI:5864 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0854467 infores:hetionet CHEBI:465284 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0026766 infores:hetionet CHEBI:3716 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0013144 infores:hetionet CAID:CA7435364 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435364 MONDO:0007113 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PP3 PS3 The c.2359A>G p.Thr787Ala variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_Supporting). The p.Thr787Ala variant has been observed in multiple individuals with seizures, where at least 2 of these cases are known to be maternally inherited (Invitae internal data) (PS4_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Functional studies suggest p.Thr787Ala is a gain of function variant that increases UBE3A ubiquitin ligase activity (PMID: 34815418). However, as loss of function is the known mechanism of UBE3A-associated disease, this evidence has not been applied. In summary, the p.Thr787Ala variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_Supporting, PS4_Supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435364/MONDO:0007113/032 2023-06-20 2023-06-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7773 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0234215 infores:hetionet CHEBI:6950 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0009421 infores:hetionet CHEBI:7956 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0041834 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0025061 infores:hetionet CHEBI:8890 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0023052 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0043251 infores:hetionet CHEBI:3732 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0040434 infores:hetionet NCBIGene:10916 biolink:causes MONDO:0010503 infores:monarchinitiative not_provided not_provided HGNC:16353 MONDO:0010503 uuid:b84a20b6-72a2-4f69-93dc-802a72ea4c61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0037284 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0004936 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0178298 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0541832 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003621 infores:hetionet CHEBI:100147 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0023530 infores:hetionet CHEBI:50777 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0037763 infores:hetionet CHEBI:567361 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1287298 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0009319 infores:hetionet CHEBI:6076 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0162557 infores:hetionet CAID:CA000532 biolink:causes MONDO:0017623 infores:clingen CAID:CA000532 MONDO:0017623 PMID:29706350PMID:29706350PMID:21659347 Uncertain Significance PM2, PP2, PS4_Moderate PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PP3, PP1, BS2, PM5, PM4, PM1, BA1, BP4, BP2, PS1, PS3, PS2 PTEN c.599T>C (p.Phe200Ser) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor SCV000222124.11)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000532/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50777 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0024902 infores:hetionet CHEBI:2682 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019156 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0003123 infores:hetionet CHEBI:9130 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0085631 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0541832 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151824 infores:hetionet CAID:CA229795 biolink:causes MONDO:0009861 infores:clingen CAID:CA229795 MONDO:0009861 PMID:25894915PMID:25894915 Likely Pathogenic PM5, PM3, PM2, PP4_Moderate PP3 The c.827T>A (p.Met276Lys) variant in PAH is absent from population databases, and found in the same codon as a previously reported pathogenic variant (p.Met276Val). It has been identified in trans with a known pathogenic variant (I95del), in which a defect of BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 25894915). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229795/MONDO:0009861/006 2018-12-09 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0520589 infores:hetionet CHEBI:15552 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C1384353 infores:hetionet CHEBI:134966 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0042023 infores:hetionet NCBIGene:27031 biolink:causes MONDO:0009966 infores:monarchinitiative not_provided not_provided HGNC:7907 MONDO:0009966 uuid:8a4a83b4-e1f1-46c2-8c34-66335f7cffb9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853761 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0020538 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022568 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020651 infores:hetionet UNII:8NZ41MIK1O biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0340865 infores:hetionet CHEBI:53691 biolink:causes MONDO:0021553 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0026976 infores:hetionet CHEBI:17823 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0019080 infores:hetionet CHEBI:3419 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0019521 infores:hetionet CHEBI:66903 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0476280 infores:hetionet CHEBI:75998 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0003811 infores:hetionet CHEBI:63611 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151908 infores:hetionet CAID:CA410147574 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147574 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS4, PS2, PS3, PS1, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS4, BS3, PM6, PVS1, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1267C>T (p.Arg423Cys) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). It has only been reported in myeloproliferative neoplasm-associated myelofibrosis (PMID: 32770086) and a stomach adenocarcinoma (PMID: 30239046), but the variant origin is unclear. The computational predictor REVEL gives a score of 0.547, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, but the splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147574/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1139771058 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139771058 MONDO:0011071 PMID:34166225PMID:34166225 Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, PM6, BS1, BS3, BS4, BP5, BP7, PM3, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.637_638del (p.Gln213AspfsTer14) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771058/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports UNII:UMD7G2653W biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0521591 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0178298 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0003864 infores:hetionet CHEBI:94411 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0080274 infores:hetionet CHEBI:9139 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0232461 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0267792 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027697 infores:hetionet CHEBI:27565 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0585186 infores:hetionet CHEBI:8776 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0006266 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0015397 infores:hetionet CHEBI:10101 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0005758 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0033581 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042109 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0877153 infores:hetionet CHEBI:31705 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042963 infores:hetionet CHEBI:31980 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0085612 infores:hetionet CHEBI:7640 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0015230 infores:hetionet CHEBI:41423 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0041657 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0011849 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033775 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0003864 infores:hetionet CHEBI:4784 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0041657 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1167965 infores:hetionet CHEBI:77260 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0220870 infores:hetionet CHEBI:31401 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0917801 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0040479 infores:hetionet CHEBI:3996 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0028084 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0013595 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0851341 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0031117 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019061 infores:hetionet CHEBI:8481 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0344232 infores:hetionet CHEBI:8461 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0233407 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0403632 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0040034 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0041969 infores:hetionet CHEBI:127780 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0042029 infores:hetionet CHEBI:188986 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0344232 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0010399 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0024115 infores:hetionet CHEBI:204928 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0085584 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085681 infores:hetionet CHEBI:7459 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0085593 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0022660 infores:hetionet CAID:CA273790 biolink:causes MONDO:0100437 infores:clingen CAID:CA273790 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2426_2427del (p.Glu809GlyfsTer25) is a frameshift variant due to deletion of 2 nucleotides that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 3 years (1 pt), reduced visual acuity (0.5 pts), reduced rod electroretinogram responses, fundus appearance showing widespread retinal pigment epithelium degeneration with mid-periphery pigment deposits (0.5 pts), optic disc pallor (0.5 pts), severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a panel of 483 genes identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA273790/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CAID:CA213749 biolink:causes MONDO:0015967 infores:clingen CAID:CA213749 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4, PM1, BS1, PP4, BP4, BA1 The c.1289T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 430 (p.(Leu430Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 30191644, internal lab contributors). In summary, c.1289T>C meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213749/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:6539 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0424000 infores:hetionet CHEBI:63629 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0026826 infores:hetionet CHEBI:5801 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0002994 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0035078 infores:hetionet CHEBI:8069 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0035078 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038454 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0021053 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0019112 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032231 infores:hetionet CHEBI:6888 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0235259 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042401 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0948226 infores:hetionet CHEBI:15551 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0151315 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0853026 infores:hetionet CHEBI:6715 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040822 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151689 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036983 infores:hetionet CHEBI:4562 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C1519353 infores:hetionet CHEBI:71219 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0019079 infores:hetionet CHEBI:2948 biolink:causes MONDO:0019474 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1333984 infores:hetionet CHEBI:521033 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0004936 infores:hetionet CHEBI:46295 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0235267 infores:hetionet CHEBI:48390 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0017181 infores:hetionet CHEBI:5106 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0232462 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0008301 infores:hetionet CHEBI:135929 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0015230 infores:hetionet CHEBI:8707 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C3251821 infores:hetionet CHEBI:77733 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0012569 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020542 infores:hetionet CHEBI:29013 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0002994 infores:hetionet CHEBI:63627 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0009676 infores:hetionet CHEBI:31859 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0022408 infores:hetionet CHEBI:6761 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0020649 infores:hetionet CHEBI:65173 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0014394 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0021843 infores:hetionet CHEBI:36791 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042023 infores:hetionet CHEBI:49960 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0037763 infores:hetionet CHEBI:2682 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0004144 infores:hetionet CHEBI:31980 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0043352 infores:hetionet CHEBI:17347 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0023903 infores:hetionet CAID:CA229411 biolink:causes MONDO:0009861 infores:clingen CAID:CA229411 MONDO:0009861 PMID:10479481 Pathogenic PP4_Moderate, PP3_Strong, PM5, PM2_Supporting, PS3_Supporting The c.1237C>A (p.Arg413Ser) variant in PAH has been reported in 1 patient with mild hyperphenylalenemia (BH4 deficiency excluded). This variant has been reported in at least 2 in vitro studies showing <50% PAH activity as compared to wild type. This variant is absent from population databases, and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, REVEL = 0.934. This variant is at the same codon as c.1238G>C (p.Arg413Pro) which has been curated as pathogenic by the ClinGen PAH VCEP (ClinVarID:592). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM5, PP4_Moderate, PP3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229411/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5558 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0233494 infores:hetionet CHEBI:7443 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0085932 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0026650 infores:hetionet CHEBI:71255 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0041582 infores:hetionet CHEBI:6897 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0020538 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0349506 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0027651 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151736 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002263 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0017411 infores:hetionet CHEBI:63607 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0027947 infores:hetionet CHEBI:63577 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0152032 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0162429 infores:hetionet CHEBI:27974 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0009782 infores:hetionet CHEBI:4469 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0030252 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0029882 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0347390 infores:hetionet CHEBI:8024 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0019825 infores:hetionet CHEBI:5130 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0016059 infores:hetionet CHEBI:2788 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0231919 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0011570 infores:hetionet CHEBI:6129 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015967 infores:hetionet NCBIGene:8733 biolink:causes MONDO:0060627 infores:monarchinitiative not_provided not_provided HGNC:4446 MONDO:0060627 uuid:b77b9310-63c2-4321-ac95-66c094e00c66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51230 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0012569 infores:hetionet CHEBI:85161 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0264906 infores:hetionet CHEBI:61058 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0016204 infores:hetionet CHEBI:3478 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0035455 infores:hetionet CHEBI:8774 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0023066 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0687707 infores:hetionet GO:0008283 biolink:causes MONDO:0005233 infores:drugmechdb knowledge_assertion manual_agent GO:0008283 MESH:D002289 DB00530_MESH_D002289_1DB11737_MESH_D002289_1DB13164_MESH_D002289_1DB09559_MESH_D002289_1DB00317_MESH_D002289_1 CHEBI:3757 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1258215 infores:hetionet CAID:CA2573102979 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573102979 MONDO:0015967 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting The c.1373_1376del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 458 (NM_000162.5), adding 155 novel amino acids before encountering a stop codon (p.(Lys458ArgfsTer155)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256), This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with disease with 3 informative meioses in 1 family with MODY (PP1; internal lab contributors). In summary, the c.1373_1376del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573102979/MONDO:0015967/086 2023-07-29 2023-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:52172 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0015397 infores:hetionet CHEBI:7959 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0392676 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0035455 infores:hetionet CHEBI:691037 biolink:causes UMLS:C1323189 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C1323189 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0022354 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0035078 infores:hetionet CHEBI:4975 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0042963 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027609 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0008325 infores:hetionet CHEBI:50173 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0012569 infores:hetionet UMLS:C0657912 biolink:causes HP:0007894 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151891 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0235431 infores:hetionet CHEBI:8764 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0232849 infores:hetionet CHEBI:63637 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0002170 infores:hetionet CHEBI:17347 biolink:causes HP:0008665 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0156394 infores:hetionet CHEBI:3207 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0852911 infores:hetionet CHEBI:9907 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0015230 infores:hetionet CHEBI:28939 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0038990 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013220 infores:hetionet CHEBI:49713 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0085602 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0178415 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0221490 infores:hetionet CHEBI:119573 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0018681 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0040034 infores:hetionet CHEBI:75722 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0750426 infores:hetionet CHEBI:51860 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038999 infores:hetionet CHEBI:2955 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151754 infores:hetionet CHEBI:119915 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020578 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0020538 infores:hetionet CHEBI:119915 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231856 infores:hetionet CAID:CA293951 biolink:causes MONDO:0007648 infores:clingen CAID:CA293951 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.160A>G (p.Arg54Gly) missense variant has a frequency of 0.00002737 (5 of 182,668) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00004080 (3 of 73,538) in the non-Finnish European subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >50 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000183777.5, SCV000545364.6, SCV000210888.14). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA293951/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7956 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0015672 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0001824 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0011849 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0031350 infores:hetionet CHEBI:7936 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006625 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027051 infores:hetionet GO:0060837 biolink:causes CL:0000071 infores:ubergraph knowledge_assertion manual_agent GO:0060837 CL:0000071 CHEBI:3312 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0085618 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0001824 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0267792 infores:hetionet NCBIGene:773 biolink:causes MONDO:0008457 infores:monarchinitiative not_provided not_provided HGNC:1388 MONDO:0008457 uuid:33cf0adb-3f58-40e5-a9db-3cc328ba182a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0549249 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0856088 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0856088 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0853019 infores:hetionet CHEBI:45652 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0235567 infores:hetionet CAID:CA367403546 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403546 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting PP4 The c.110T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 37 (p.(Met37Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9549, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.110T>G p.Met37Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met37Lys has a greater Grantham distance (PM5). In summary, c.110T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403546/MONDO:0015967/086 2024-02-02 2024-02-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:9570 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085636 infores:hetionet CAID:CA261612 biolink:causes MONDO:0021060 infores:clingen CAID:CA261612 MONDO:0021060 PMID:29493581PMID:20679480 Pathogenic PM1, PP3, PM2_Supporting, PS3_Moderate, PS2, PS4 The c.1472C>T (p.Thr491Ile variant in the RAF1 gene is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 491. This variant is absent from gnomAD v2 (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the p.Thr491Ile variant may impact the RAF1 protein (PP3). In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3_Moderate; PMID:20679480). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). The variant has also been identified as a de novo occurrence with confirmed parental relationships in an individual with features of RASopathy (PS2), and the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PS4, PM1, PS3_Moderate, PP3, PM2_Supporting. (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261612/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CAID:CA228410 biolink:causes MONDO:0015628 infores:clingen CAID:CA228410 MONDO:0015628 PMID: Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS3, PS4 BA1, PM5, BS1 The NM_000552.5(VWF):c.3445T>C variant in VWF is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 1149 in the D3 (multimerization) domain. This variant has been reported in at least 8 apparently unrelated families exhibiting a VWD Type 2A phenotype (PMID: 19286880, PMID: 8839833, PMID: 28971901, PS4). At least 7 patients with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:RCo, activity/VWF:Ag ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A (PP4_moderate, PMID: 19286880, PMID: 28971901). The variant has been reported to segregate with VWD type 2A through at least 2 affected meioses from 3 different families (PP1_Moderate; PMID: 8839833, PMID: 19286880, PMID: 28971901). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/316464 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Multimerization assays performed with the p.Cys1149Arg recombinant mutant and wild-type vWF expressed by 293T cells showed an overall decrease in secreted multimers, with particular loss of high-molecular weight multimers), indicating that this variant has a damaging effect on protein function (PMID: 839833 Fig. 3, PMID: 14995987)(PS3). Additional functional characterization studies have found that the variant protein exhibits characteristics of a quantitative VWF defect as well, as it is retained in the endoplasmic reticulum, exerts a partially dominant negative effect on VWF secretion, and is more rapidly cleared from circulation (PMID: 11698279, PMID: 8839833, PMID: 21596755, PMID: 16194200). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS4, PP4_Moderate, PP1_Moderate, PS3, PP3, PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228410/MONDO:0015628/081 2024-07-09 2024-08-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2687 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0039231 infores:hetionet NCBIGene:91137 biolink:causes MONDO:0014671 infores:monarchinitiative not_provided not_provided HGNC:25198 MONDO:0014671 uuid:833ce9a0-d47c-45fa-a860-ca218bb615c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027765 infores:hetionet CHEBI:16586 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0235490 infores:hetionet CHEBI:6954 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0233715 infores:hetionet CHEBI:63580 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151662 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0243026 infores:hetionet CHEBI:5138 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020473 infores:hetionet CHEBI:7773 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C1443060 infores:hetionet CHEBI:5130 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0232462 infores:hetionet CHEBI:3215 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0025287 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0020517 infores:hetionet CHEBI:6887 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0424109 infores:hetionet CHEBI:3314 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0011991 infores:hetionet NCBIGene:7078 biolink:causes MONDO:0007640 infores:monarchinitiative not_provided not_provided HGNC:11822 MONDO:0007640 uuid:731c1125-069e-4461-b335-90de65de78a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:73274 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0039971 infores:hetionet CHEBI:17303 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0270810 infores:hetionet CHEBI:45716 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0948008 infores:hetionet CAID:CA376061171 biolink:causes MONDO:0011225 infores:clingen CAID:CA376061171 MONDO:0011225 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PM3 PP3 "The NM_001033855.3:c.436T>C variant in DCLRE1C is a missense variant predicted to cause the substitution of cysteine by arginine at amino acid 116 (p.Cys116Arg). This variant is absent from gnomAD and therefore has a population max filtering allele frequency that is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for DCLRE1C (<0.00003266). This variant has been reported in an individual with SCID (PMID: 36546626). ART012: As per inclusion criteria in supplement files in PMID: 36546626, diagnostic criteria for SCID/leaky SCID is met (0.5 points), and phenotype was corrected by lentiviral gene therapy (CNV test performed, unpublish data) (7 points). Additional information from Dr. Cowan (unpublished): radiation sensitivity testing in the patient's fibroblasts and demonstrated that the Artemis vector (AProArt) corrected the radiation sensitivity both in terms of proliferation and gH2AX production - therefore 2 additional points added as per specification ""Vector-based complementation corrected increased cellular radiosensitivity and/or decreased VDJ recombination."" Therefore the total from this patient, by PMID plus unpublished data, is = 9.5 points = PP4_Strong. In this individual, the variant co-occurred in trans with a second variant c.161+2T>G, which would be classified as Likely Pathogenic by the ClinGen SCID VCEP; therefore, PM3 is met (1p). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM2_Supporting, PP4_Strong, and PM3 as specified by the ClinGen SCID VCEP (VCEP specifications version 1)." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376061171/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:6508 biolink:causes MONDO:0859368 infores:monarchinitiative not_provided not_provided HGNC:11029 MONDO:0859368 uuid:a55a5c77-a3ae-49a5-84a4-8dc2023dd2ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151763 infores:hetionet CHEBI:63610 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0009763 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0039446 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020517 infores:hetionet CHEBI:64354 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0000731 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011551 infores:hetionet CHEBI:42068 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0019080 infores:hetionet CAID:CA8338099 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338099 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP4_Moderate PP3, PM1 The c.1434G>A variant in ACADVL is a missense variant predicted to cause substitution of Methionine by Isoleucine at amino acid 478 (p.Met478Ile). The highest population minor allele frequency in gnomAD v4.1 is 0.0009 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.457, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. This variant does not reside within a region of ACADVL that is defined as a mutational hotspot or critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel. At least 14 patients with this variant displayed abnormal enzyme levels and NBS, which is highly specific for very long chain acyl-CoA dehydrogenase deficiency (PMID: 38390979, 32710939). This variant has been detected in 14 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 6 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variants (PM3: 2.0 points, PMIDs:38390979, 32710939, PM3_strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Strong, PP4_moderate, PM2_supporting (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338099/MONDO:0008723/021 2025-08-12 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31348 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0428974 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0234215 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0003864 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0036572 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0018798 infores:hetionet NCBIGene:11284 biolink:causes MONDO:0011570 infores:monarchinitiative not_provided not_provided HGNC:9154 MONDO:0011570 uuid:b2a3cddc-5a14-44b9-8e80-69179a056c49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27974 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0497327 infores:hetionet CHEBI:28001 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0085649 infores:hetionet CHEBI:8212 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0030252 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011991 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0006840 infores:hetionet CHEBI:3698 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0038325 infores:hetionet CHEBI:36791 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151905 infores:hetionet CHEBI:63618 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0037763 infores:hetionet CHEBI:15367 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0026858 infores:hetionet CHEBI:64355 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0392171 infores:hetionet CHEBI:63638 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0043094 infores:hetionet CAID:CA413495835 biolink:causes MONDO:0010315 infores:clingen CAID:CA413495835 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.738G>A (p.Trp246Ter) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts), total is 1 point, PP4 is met.In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413495835/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Supports CHEBI:2611 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0021177 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0235560 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0235560 infores:hetionet CHEBI:2659 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0235063 infores:hetionet CHEBI:50275 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0000737 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0162429 infores:hetionet CHEBI:23765 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0035410 infores:hetionet CHEBI:3082 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0851578 infores:hetionet CHEBI:63791 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0549249 infores:hetionet CAID:CA229452 biolink:causes MONDO:0009861 infores:clingen CAID:CA229452 MONDO:0009861 PMID:24368688PMID:18294361PMID:8807331PMID:24368688 Pathogenic PM3, PVS1, PP4_Moderate, PM2 The c.168+1G>A variant in PAH is at a canonical splice site at intron 3, and is absent in all population databases. It has been identified in trans with a pathogenic variant (Ho, 2014), and as a homozygous variant (PMID: 18294361) in patients with phenylketonuria. Defects in BH4 metabolism were excluded as a cause of elevated phenylalanine in two patients (PMID: 24368688, 8807331). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229452/MONDO:0009861/006 2018-12-09 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3387 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020517 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151311 infores:hetionet CHEBI:6541 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0013604 infores:hetionet CHEBI:31932 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0008031 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0162429 infores:hetionet CHEBI:5864 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0028778 infores:hetionet CAID:CA10014286 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014286 MONDO:0011071 PMID:34166225 Likely Benign BS3_Supporting, BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS4, BP5, BP7, PM2, PVS1, PM6, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.832C>T (p.Pro278Ser) is a missense variant with transactivation assays demonstrating normal transactivation (80-115% of wt) (BS3_Supporting; PMID: 34166225). This missense variant has a REVEL score < 0.50 (0.275) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014286/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA8815660 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815660 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2221G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 741 (p.Asp741Asn). One proband with symptoms consistent with infantile-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (PMID: 29122469). This proband is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys) (PMID: 29122469) (PM3_supporting). Another proband with symptoms consistent with late-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (Duke University; PMID: 31904026, 32518148, 39983297). Additionally, both patients were treated with enzyme replacement therapy (PP4_Moderate). This proband is compound heterozygous for the variant, a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys), and a variant classified as liekly pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1477C>T (p.Pro493Ser). The c.2221G>A (p.Asp741Asn) and c.1477C>T (p.Pro493Ser) variants were confirmed in trans with the c.1978C>T (p.Arg660Cys) variant. The variants are confirmed in trans for this patient (Duke University). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009603 (6/62480 alleles) in the Remaining population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.828 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3_met). Two other missense variants, c.2222A>T (p.Asp741Val) (ClinVar Variation ID: 291139) and c.2223C>G (p.Asp741Glu) (ClinVar Variation ID: 526539), in the same codon have been reported. However, these variants have not been classified by the ClinGen Lysosomal Diseases VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 571521). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_supporting, PP4_moderate, PM2_supporting, PP3_met). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815660/MONDO:0009290/010 2025-05-06 2025-05-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:6375 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0227791 infores:hetionet CHEBI:6710 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0022354 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0227791 infores:hetionet CHEBI:3077 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151908 infores:hetionet CHEBI:10101 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0239783 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0919883 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0919883 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0014549 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027339 infores:hetionet NCBIGene:25814 biolink:causes MONDO:0011330 infores:monarchinitiative not_provided not_provided HGNC:10549 MONDO:0011330 uuid:cc0a8d82-5964-40b1-84c5-442f4c21bdc4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1565489 infores:hetionet NCBIGene:9531 biolink:causes MONDO:0976227 infores:monarchinitiative not_provided not_provided HGNC:939 MONDO:0976227 uuid:80a77fc0-2bc4-46e0-aee9-c7573c5f06c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0002792 infores:hetionet CHEBI:10119 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0004245 infores:hetionet CHEBI:49375 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0031256 infores:hetionet CHEBI:6759 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0033774 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0578455 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0578455 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0549418 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0863113 infores:hetionet CHEBI:119573 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0001175 infores:hetionet CHEBI:9137 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151603 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005844 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0007933 infores:hetionet CHEBI:47381 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002874 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0019112 infores:hetionet NCBIGene:79868 biolink:causes MONDO:0010472 infores:monarchinitiative not_provided not_provided HGNC:30881 MONDO:0010472 uuid:3454aad7-910d-4e70-9652-7e5721f2d930 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:10508 biolink:causes MONDO:0005911 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10508 MONDO:0005911 NCBIGene:6337 biolink:causes MONDO:0013087 infores:monarchinitiative not_provided not_provided HGNC:10599 MONDO:0013087 uuid:42a8bf49-215f-47f9-8cdd-a650a60882e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0311468 infores:hetionet CHEBI:50861 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0039231 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0020538 infores:hetionet CHEBI:65173 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0149745 infores:hetionet CHEBI:724125 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0542571 infores:hetionet CHEBI:63589 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C1443060 infores:hetionet CHEBI:3638 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0011606 infores:hetionet NCBIGene:7102 biolink:causes MONDO:0010266 infores:monarchinitiative not_provided not_provided HGNC:11854 MONDO:0010266 uuid:9e51ce46-ba55-4b8b-83f9-2325d62c446a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2580096763 biolink:causes MONDO:0010938 infores:clingen CAID:CA2580096763 MONDO:0010938 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PM2_Supporting, PM3_Supporting, PP3 The variant NM_000215.4(JAK3):c.2680+89G>A has been found in three individuals with T-B+NK- SCID. In three related consanguineous families, the disease phenotype segregated with the homozygous deep intronic variant in the proband, P3, and two affected relatives (PP1_moderate, PM3_supporting). In at least one of those patients, P3, with T-B+NK- SCID, whole exome sequencing was performed and STAT3 and STAT5 phosphorylation were found to be absent in B cells after stimulation with IL-21 (PMID:26769277, 3 points, PP4_moderate). The variant is absent from gnomAD (PM2_Supporting). Finally, the in silico predictor SpliceAI predicts that the deep intronic variant may impact splicing with a delta score of 0.30 (PP3). In summary, this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate, PM3_supporting, PP4_moderate, PP3, PM2_supporting (SCID VCEP Specifications Version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580096763/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3387 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027769 infores:hetionet CHEBI:7627 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0040053 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0267596 infores:hetionet CHEBI:50156 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0035232 infores:hetionet GO:0062229 biolink:causes GO:0002164 infores:ubergraph knowledge_assertion manual_agent GO:0062229 GO:0002164 CHEBI:135342 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020651 infores:hetionet CHEBI:175901 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0017178 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0017178 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0017675 infores:hetionet CHEBI:4798 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0085637 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151849 infores:hetionet CHEBI:142290 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013491 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0549405 infores:hetionet CHEBI:63619 biolink:causes MONDO:0008848 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004331 infores:hetionet CHEBI:6832 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0012833 infores:hetionet NCBIGene:1848 biolink:causes MONDO:0014105 infores:monarchinitiative not_provided not_provided HGNC:3072 MONDO:0014105 uuid:a2c28096-39b9-4a54-a519-f507719436dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8093 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0037274 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0020651 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027726 infores:hetionet CHEBI:16347 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0011991 infores:hetionet CHEBI:82960 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C2242737 infores:hetionet CHEBI:8485 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C1761613 infores:hetionet CHEBI:41774 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020580 infores:hetionet CHEBI:7478 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0002962 infores:hetionet NCBITaxon:46580 biolink:causes MONDO:0005963 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:46580 MONDO:0005963 CHEBI:63632 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0162429 infores:hetionet CHEBI:8435 biolink:causes UMLS:C1112182 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C1112182 infores:hetionet NCBIGene:488 biolink:causes MONDO:0007417 infores:monarchinitiative not_provided not_provided HGNC:812 MONDO:0007417 uuid:08392bbd-aaf4-4e00-8ed6-f61c10ac05c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0521839 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0042109 infores:hetionet CHEBI:6715 biolink:causes MONDO:0008586 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040588 infores:hetionet CHEBI:17698 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0018681 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0007177 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1142135 infores:hetionet CHEBI:27777 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C2697368 infores:hetionet CHEBI:82960 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0023380 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151737 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151737 infores:hetionet CHEBI:2469 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0011603 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013595 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018500 infores:hetionet CHEBI:2038 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0085649 infores:hetionet CHEBI:6640 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C3665596 infores:hetionet CHEBI:66876 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0011991 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0006444 infores:hetionet CHEBI:2676 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0151579 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020676 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0233494 infores:hetionet CHEBI:51364 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0000737 infores:hetionet CHEBI:3387 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042023 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0040046 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0041912 infores:hetionet CHEBI:63580 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0455204 infores:hetionet CHEBI:71028 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0040425 infores:hetionet CHEBI:145499 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085602 infores:hetionet CHEBI:2611 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0027497 infores:hetionet CHEBI:9763 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0237849 infores:hetionet CHEBI:42797 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015402 infores:hetionet CHEBI:3614 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C3263723 infores:hetionet CHEBI:3732 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0522153 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0281774 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0015397 infores:hetionet CHEBI:5138 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0026827 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0520962 infores:hetionet CHEBI:50648 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0039231 infores:hetionet CHEBI:77260 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0039591 infores:hetionet CHEBI:28593 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0009421 infores:hetionet NCBIGene:4693 biolink:causes MONDO:0010588 infores:monarchinitiative not_provided not_provided HGNC:7678 MONDO:0010588 uuid:5d3e0957-1608-4f6b-a4e9-88a8f09f1053 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2687 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0018926 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0149931 infores:hetionet CHEBI:31236 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0311394 infores:hetionet GO:0090178 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0007399 CHEBI:8093 biolink:causes HP:0100583 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0339293 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0521498 infores:hetionet CAID:CA399789759 biolink:causes MONDO:0100326 infores:clingen CAID:CA399789759 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3, PS3 The c.2994G>A (p.Trp998Ter) variant in exon 29 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 29 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The resulting stop codon is upsteam of the last 50 bp of the penultimate exon in the ITGA2B gene (PVS1). At least one patient (Patient GT-1 in PMIDs 22837472 and 30934104) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% (<25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate and PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399789759/MONDO:0100326/011 2023-04-07 2023-04-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:17650 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0009241 infores:hetionet CHEBI:39112 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0423791 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0151848 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151848 infores:hetionet NCBIGene:833 biolink:causes MONDO:0030047 infores:monarchinitiative not_provided not_provided HGNC:1493 MONDO:0030047 uuid:19d85cde-7a0a-4233-b536-263e74069698 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367398289 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398289 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1234G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 412 (p.(Val412Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.82, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). Three other missense variants, c.1235T>A p.Val412Glu, c.1235T>C Val412Ala, and c.1235T>G Val412Gly have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.1234G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023: PM5_Strong, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398289/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:144551 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0917801 infores:hetionet CHEBI:4798 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0021177 infores:hetionet CHEBI:27834 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0151636 infores:hetionet CHEBI:4562 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0011168 infores:hetionet CHEBI:3127 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0003126 infores:hetionet GO:0075030 biolink:causes GO:0075025 infores:ubergraph knowledge_assertion manual_agent GO:0075030 GO:0075025 CHEBI:31236 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017160 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020649 infores:hetionet CHEBI:2682 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0014742 infores:hetionet CAID:CA024711 biolink:causes MONDO:0007783 infores:clingen CAID:CA024711 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with threonine at codon 2367 of the RYR1 protein, p.(Ala2367Thr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000559, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:11575529, The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.899) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024711/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7936 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0522055 infores:hetionet CHEBI:7931 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0009782 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0022568 infores:hetionet CHEBI:107736 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0686347 infores:hetionet CHEBI:100241 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C2242996 infores:hetionet CHEBI:9943 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233565 infores:hetionet CHEBI:43968 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0002878 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0021400 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0333650 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0333650 infores:hetionet CHEBI:9907 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0026113 infores:hetionet CHEBI:3723 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0553721 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003709 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0001818 infores:hetionet CAID:CA916083908 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083908 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.2257_2260del (p.Gly753LysfsTer?) is a frameshift variant due to a 4-nucleotide deletion that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 23681342, PMID: 33576794, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), childhood onset (1 pt), myopia (0.5 pts), night blindness (0.5 pts), reduced visual acuity (0.5 pts), visual field constriction (0.5 pts), bone spicule pigmentation (0.5 pts), and pale optic discs (0.5 pts), which together are specific for RPGR-related retinopathy (6 points, PP4, PMID: 28157192). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PS4_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083908/MONDO:0100437/106 2025-08-27 2025-08-27 X-linked inheritance HP:0001417 Supports CAID:CA410207961 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207961 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.598C>T (p.Pro200Ser) is a missense variant which has a REVEL score ≥ 0.88 (0.941) (PP3). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207961/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4636 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0036572 infores:hetionet CHEBI:8890 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0018794 infores:hetionet CHEBI:48947 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0014742 infores:hetionet CHEBI:5134 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0240557 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027441 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0694549 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0694549 infores:hetionet CAID:CA294710 biolink:causes MONDO:0010726 infores:clingen CAID:CA294710 MONDO:0010726 PMID: Uncertain Significance PS3_Supporting, BS2 PS2, PS4, PM5, PM1, BS1, PP3 The NM_004992.4:c.568C>T (p.Arg190Cys) variant in MECP2 is observed in at least 2 unaffected individuals (GeneDx internal database, LabCorp Genetics Inc. internal database) (BS2). Quantitative immunofluorescence localization assays have shown that this variant impacts protein function (PMID: 29431277) (PS3_Supporting). The highest population frequency in gnomAD v4.1 is 0.00002 in the European (Finnish) population (BS1_Not Met). The p.Arg190Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with schizophrenia (PMID: 24776741) (PS2 - not met as patient was not described to have features of Rett syndrome). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.626). A missense variant (p.Arg190His) has been previously identified within this codon which may indicate that this residue is critical to the function of the protein; however, this variant is not currently classified as pathogenic by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (PM5- not met). In summary, the p.Arg190Cys variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS3_Supporting) (MECP2 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294710/MONDO:0010726/036 2025-02-28 2025-03-26 X-linked inheritance HP:0001417 Inconclusive true CHEBI:4315 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0017160 infores:hetionet CHEBI:3312 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0085616 infores:hetionet CHEBI:50659 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0015672 infores:hetionet CAID:CA16620645 biolink:causes MONDO:0009290 infores:clingen CAID:CA16620645 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000152.5:c.1062C>A (p.Tyr354Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with infantile onset Pompe disease, identified by newborn screen and treated with enzyme replacement therapy, has been reported (PMID: 32373469) (PP4). This patient is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (PMID: 32373469) (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 423925). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications version 2.0): PVS1, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620645/MONDO:0009290/010 2023-04-19 2023-04-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:32293 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0948715 infores:hetionet CHEBI:3534 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0038325 infores:hetionet CHEBI:161680 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0234238 infores:hetionet CAID:CA377485551 biolink:causes MONDO:0017623 infores:clingen CAID:CA377485551 MONDO:0017623 PMID: Uncertain Significance PM2, BS3, PP2 PVS1, PM6, BP7, BP5, BS1, BS4, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.838A>G (p.Ile280Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29706350, PMID 29785012) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377485551/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135935 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0013146 infores:hetionet CHEBI:8327 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0553548 infores:hetionet CHEBI:68478 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0149871 infores:hetionet CHEBI:2659 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0546817 infores:hetionet CAID:CA229810 biolink:causes MONDO:0009861 infores:clingen CAID:CA229810 MONDO:0009861 PMID:15300621 Pathogenic PVS1, PP4, PM2_Supporting The c.839_840insT (p.Glu280Aspfs) variant in PAH has been reported in an individual with PKU (PP4; 15300621). This variant has is absent from ExAC and gnomAD (PM2_supporting). It is a null variant (frameshift) in exon 7/13 with NMD predicted (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229810/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7507 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0009450 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038587 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0022660 infores:hetionet CAID:CA10585793 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585793 MONDO:0007750 PMID: Uncertain Significance BS3, PM2 PM5, PP3, PP4 The NM_000527.5(LDLR):c.2150C>G (p.Ala717Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February-28-2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).BS3: Level 1 assays: PMID 12837857 (Chang et al., 2003); Heterologous cells (COS-7), flow cytometry and Western blot assays showed normal (>90%) expression and LDL particle clearance ---- functional study is consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585793/MONDO:0007750/013 2025-02-28 2025-04-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7915 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013298 infores:hetionet CHEBI:499361 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020625 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026650 infores:hetionet CHEBI:404903 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0030193 infores:hetionet CHEBI:175901 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0311468 infores:hetionet CHEBI:9086 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0518988 infores:hetionet NCBIGene:282809 biolink:causes MONDO:0014427 infores:monarchinitiative not_provided not_provided HGNC:30836 MONDO:0014427 uuid:55f83618-cad2-4f14-8694-49bf4a0da3bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92607 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0042963 infores:hetionet CHEBI:72690 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0043094 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0267792 infores:hetionet CHEBI:9763 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0520966 infores:hetionet CHEBI:4445 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0014236 infores:hetionet CHEBI:7466 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0011124 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037315 infores:hetionet CHEBI:7444 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0242350 infores:hetionet CHEBI:6909 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0018681 infores:hetionet NCBIGene:1583 biolink:causes MONDO:0013400 infores:monarchinitiative not_provided not_provided HGNC:2590 MONDO:0013400 uuid:422ac7b0-3fc6-43d2-8981-5dec28fb3361 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0037383 infores:hetionet CHEBI:5280 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151474 infores:hetionet CHEBI:6916 biolink:causes MONDO:0044903 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0026987 infores:hetionet CAID:CA8602740 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602740 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate PM3, BS1, PM2, PP3, BP4 The NM_000419.5(ITGA2B):c.2315C>G (p.Pro772Arg) missense variant has been reported in at least one patient (Patient 7 in PMID:19172520/GT database record 164) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <10%, as measured by flow cytometry. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602740/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0003862 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0002622 infores:hetionet CAID:CA410150219 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150219 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.837G>T (p.Trp279Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150219/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3082 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0085628 infores:hetionet CHEBI:82960 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0014457 infores:hetionet CHEBI:5088 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0042571 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0520821 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0520821 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0040034 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005159 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0600139 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0178298 infores:hetionet CHEBI:42820 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0004238 infores:hetionet CHEBI:64019 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C1456822 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085606 infores:hetionet CAID:CA136083 biolink:causes MONDO:0021060 infores:clingen CAID:CA136083 MONDO:0021060 PMID:20683980PMID:20683980 Likely Benign BS3, BP5 PS4, PM1, PM2, PP3, PP2 The c.1490G>A (p.Arg497Gln) variant in SOS1 was present in 0.0113% (4/35392) of Latino chromosomes in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been observed in 1 proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980). Of note, it has also been observed in other probands with disparate phenotypes and their reportedly unaffected parents; however, these individuals were not well-phenotyped and, therefore, do not meet current requirements for BS2 (BS2 not met; PMID:21387466, Otto von Guericke University Magdeburg, GeneDx, Partners Laboratory for Molecular Medicine, Integrated Genetics, and Baylor Genetics internal data; ClinVar SCV000209114.12, SCV000062197.7, SCV001361139.1). In vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980). Although this variant occurs in a location defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1, expert judgement was used to classify this variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): BS3, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136083/MONDO:0021060/004 2020-07-02 2020-07-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8874 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085633 infores:hetionet CHEBI:64355 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2242588 infores:hetionet CAID:CA405692341 biolink:causes MONDO:0018493 infores:clingen CAID:CA405692341 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tryptophan with arginine at codon 3284 of the RYR1 protein, p.(Trp3284Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual without a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT), PS4 was not implemented (PMID:21455645). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.873) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405692341/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:48844 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0018681 infores:hetionet CHEBI:61049 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003467 infores:hetionet CHEBI:60761 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0423153 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0020510 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0020510 infores:hetionet CHEBI:6532 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0009806 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0018799 infores:hetionet CHEBI:231594 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0151908 infores:hetionet NCBIGene:5376 biolink:causes MONDO:0007691 infores:monarchinitiative not_provided not_provided HGNC:9118 MONDO:0007691 uuid:5eaa554d-7753-4e35-b73c-50a8f1063d4f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7865 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0080274 infores:hetionet CHEBI:3614 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0020580 infores:hetionet CHEBI:3125 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0039070 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0151595 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151595 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0151828 infores:hetionet CHEBI:6076 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0002994 infores:hetionet CHEBI:184555 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C2047937 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0002962 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0162429 infores:hetionet CHEBI:3380 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0013404 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0041969 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0021390 infores:hetionet CHEBI:9622 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0009676 infores:hetionet CHEBI:31401 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0206061 infores:hetionet GO:0030099 biolink:causes CL:0000763 infores:ubergraph knowledge_assertion manual_agent GO:0030099 CL:0000763 UMLS:C0657912 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0041976 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151828 infores:hetionet CHEBI:8364 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0011991 infores:hetionet CHEBI:100246 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C2242737 infores:hetionet CHEBI:2659 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0003811 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0032285 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0339961 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0339961 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0549389 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0549389 infores:hetionet CHEBI:404903 biolink:causes NCIT:C50739 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0262627 infores:hetionet CHEBI:63580 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042024 infores:hetionet CAID:CA414438824 biolink:causes MONDO:0010604 infores:clingen CAID:CA414438824 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM1, PS4, PP3 NM_000133.4(F9):c.407T>C (p.Ile136Thr) missense variant has a REVEL score of 0.634, which meets criteria for PP3. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The variant occurs within exon 5, a region deemed critical for the encoded FIX protein by the CFD-VCEP, and meets criteria for PM1. The c.407T>C (p.Ile136Thr) variant is reported in at least two individuals with mild hemophilia B and two individuals with hemophilia B of unspecified severity (PMID: 8680410, 8091381, 31064749), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PS4, PM1, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414438824/MONDO:0010604/080 2024-11-01 2024-11-01 X-linked inheritance HP:0001417 Supports CHEBI:45783 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0014724 infores:hetionet CAID:CA290573 biolink:causes MONDO:0011225 infores:clingen CAID:CA290573 MONDO:0011225 PMID: Benign BA1, BS2_Supporting The NM_001033855.3:c.959C>G variant in DCLRE1C is a missense variant predicted to cause substitution of serine by cysteine at amino acid 320 (p.Ser320Cys). This variant has an allele frequency of 0.03553 in the African / African American population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for DCLRE1C (>0.00346). In addition, 16 adult homozygous individuals with this variant are present in gnomAD v2.1.1 (in African/African American population)(BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA290573/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63638 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0029134 infores:hetionet CHEBI:63791 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0152031 infores:hetionet CHEBI:3752 biolink:causes MONDO:0019781 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0004114 infores:hetionet CHEBI:30659 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0917801 infores:hetionet CHEBI:3001 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0234708 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0001824 infores:hetionet NCBIGene:6521 biolink:causes MONDO:0012981 infores:monarchinitiative not_provided not_provided HGNC:11027 MONDO:0012981 uuid:3608269d-6014-4da7-b4f6-e799255d6e04 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011570 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020538 infores:hetionet CHEBI:37924 biolink:causes HP:0032106 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0240962 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0948089 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003811 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0700590 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0239978 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027051 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0028738 infores:hetionet CHEBI:7466 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0018418 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1565489 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0347390 infores:hetionet CHEBI:9605 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0019080 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0043246 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1258215 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0917801 infores:hetionet CHEBI:38940 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018681 infores:hetionet CHEBI:9398 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0003862 infores:hetionet CHEBI:8707 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042023 infores:hetionet CHEBI:8673 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0232462 infores:hetionet UMLS:C0065374 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0014591 infores:hetionet CAID:CA16040953 biolink:causes MONDO:0015152 infores:clingen CAID:CA16040953 MONDO:0015152 PMID: Likely Pathogenic PP1, PP4, PM2_Supporting, PVS1_Strong, PM3 PM6, BP7, BP5, BS4, BS1, BS3, PP2, PP3, BS2, BP2, BP3, BP1, BP4, BA1, PS3, PS4, PS2, PS1, PM4, PM1, PM5 The NM_000232.5: c.699_702del p.(Phe233LeufsTer16) variant in SGCB is a frameshift variant that may cause loss of function of the protein; the resulting transcript is predicted to escape nonsense mediated decay but remove >10% of the protein (PVS1_Strong). This variant has been detected in at least two unrelated individuals with autosomal recessive limb girdle muscular dystrophy, including confirmed in trans with a likely pathogenic or pathogenic variant (c.377_384dup, 1 pt, PMID: 25862795) and in a homozygous state (0.25 pts, PMID: 25862795) (PM3). At least one patient with this variant and a second SGCB variant displayed progressive limb girdle muscle weakness as well as absent expression of beta-sarcoglycan protein, which is highly specific for SGCB-related LGMD; however, the presence of potentially diagnostic variants in all of the other sarcoglycan genes was not ruled out (PP4; PMID: 12868499, 25862795, 9032047). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 25862795) and is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Strong, PM3, PP4, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16040953/MONDO:0015152/184 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0120107 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0031350 infores:hetionet CHEBI:367163 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014457 infores:hetionet CAID:CA412354904 biolink:causes MONDO:0100039 infores:clingen CAID:CA412354904 MONDO:0100039 PMID: Benign BP5_Strong, BS2 BS1, PM1, PP3, BP4 The c.761A>G p.His254Arg variant in CDKL5 (NM_001323289.2) is present in 1 XX and 2 XY individuals in gnomAD (0.0036% in the Latino/Admixed American sub population) (not sufficient to meet BS1 criteria). The p.His254Arg variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.His254Arg variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal data) (BP5_Strong). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In summary, the c.761A>G p.His254Arg variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BS2, BP5_Strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412354904/MONDO:0100039/034 2023-06-20 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:63791 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0008370 infores:hetionet CHEBI:31622 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0001807 infores:hetionet CHEBI:6950 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1167965 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0575090 infores:hetionet CHEBI:7824 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014724 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0013922 infores:hetionet CHEBI:5280 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0030305 infores:hetionet CHEBI:2654 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0012833 infores:hetionet CHEBI:17263 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0002792 infores:hetionet CAID:CA15179711 biolink:causes MONDO:0015152 infores:clingen CAID:CA15179711 MONDO:0015152 PMID: Benign BP4, BA1, BP7 PM4, PM1, PM3, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, BS2, PP2, PP3, PP1, PP4 The NM_003494.4: c.88+12589T>C variant in DYSF is an intronic variant that is not located in a splice region. The filtering allele frequency of the variant is 0.4326 for South Asian genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 2314/5168), which is higher than the VCEP threshold of 0.003 (BA1). The computational splicing predictor SpliceAI gives a score of 0, suggesting that the variant has no impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA15179711/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:80173 biolink:causes MONDO:0014926 infores:monarchinitiative not_provided not_provided HGNC:21424 MONDO:0014926 uuid:c439455f-5b61-4633-a9bf-f1d27fa8f4f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0002390 infores:hetionet CHEBI:3640 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0002792 infores:hetionet NCBIGene:2617 biolink:causes MONDO:0033621 infores:monarchinitiative not_provided not_provided HGNC:4162 MONDO:0033621 uuid:b9228d6e-52f6-4c08-b188-f5190481a107 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410203349 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203349 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.349A>G (p.Lys117Glu) is a missense variant which has a REVEL score ≥ 0.88 (0.95) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203349/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:2273 biolink:causes MONDO:0010292 infores:monarchinitiative not_provided not_provided HGNC:3702 MONDO:0010292 uuid:ff518a37-441a-4712-855c-c61726a66b06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0019080 infores:hetionet CAID:CA343776467 biolink:causes MONDO:0013144 infores:clingen CAID:CA343776467 MONDO:0013144 PMID: Uncertain Significance PP3, PM2_Supporting PM5 The c.536T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 179 (p.Phe179Ser). The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.946, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PP3, PM2_Supporting Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343776467/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47780 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0034150 infores:hetionet CHEBI:41423 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0542571 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0232910 infores:hetionet CHEBI:8077 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C2697368 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151908 infores:hetionet CHEBI:50742 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151579 infores:hetionet CHEBI:31236 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035410 infores:hetionet CHEBI:45863 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0031154 infores:hetionet CHEBI:4784 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0236075 infores:hetionet CHEBI:31709 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0231218 infores:hetionet CHEBI:7488 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0152227 infores:hetionet CAID:CA341522 biolink:causes MONDO:0008723 infores:clingen CAID:CA341522 MONDO:0008723 PMID: Benign BA1, BP4 PP4, BS2, PM1 The c.49C>T variant in ACADVL has been reported as part of premature screening panels, however no probands have shown increased VLCAD activity or newborn screening (PMID: 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06989 in the African population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.236, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP4 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA341522/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6030 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0020517 infores:hetionet CHEBI:4856 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0085593 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0042514 infores:hetionet CHEBI:8888 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0497156 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0036572 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0007642 infores:hetionet CHEBI:4822 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0020538 infores:hetionet CHEBI:63631 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011253 infores:hetionet CHEBI:5103 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0010200 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0033775 infores:hetionet CHEBI:64321 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0002994 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235901 infores:hetionet CHEBI:9720 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0033975 infores:hetionet CHEBI:3699 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0221423 infores:hetionet CHEBI:145499 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013604 infores:hetionet CHEBI:71417 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0039231 infores:hetionet CAID:CA229889 biolink:causes MONDO:0009861 infores:clingen CAID:CA229889 MONDO:0009861 PMID:10394930PMID:9634518 Uncertain Significance PP4_Moderate, PM2, PP3 PM5 The c.981T>G (p.Phe327Leu) variant in PAH has been reported in a German patient with classic PKU (BH4 deficiency excluded) (PMID: 9634518, 10394930) This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229889/MONDO:0009861/006 2020-04-03 2020-04-03 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31859 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011603 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1384666 infores:hetionet CHEBI:85078 biolink:causes HP:0002719 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0239998 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0021053 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042075 infores:hetionet CHEBI:17650 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0234708 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040479 infores:hetionet CHEBI:520985 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0017178 infores:hetionet CHEBI:3061 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0030554 infores:hetionet CHEBI:45652 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0235063 infores:hetionet CHEBI:63598 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151610 infores:hetionet CAID:CA331121466 biolink:causes MONDO:0010315 infores:clingen CAID:CA331121466 MONDO:0010315 PMID: Uncertain Significance PM2 NM_000206.3(IL2RG):c.1076C>T is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 359 (p.Ala359Val). The highest population minor allele frequency in gnomAD v4 is 0.0001453 (126/867358) in European Non-Finnish population (PM2_Supporting, BS1, and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with IL2RG related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: None (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA331121466/MONDO:0010315/129 2024-01-10 2024-01-10 X-linked inheritance HP:0001417 Inconclusive true CHEBI:101085 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0302295 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0036508 infores:hetionet CHEBI:75246 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0019080 infores:hetionet CHEBI:75984 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0231530 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0004238 infores:hetionet CHEBI:68855 biolink:causes UMLS:C0016579 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0016579 infores:hetionet CHEBI:49960 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0011168 infores:hetionet CHEBI:63638 biolink:causes MONDO:0100577 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0014550 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007745 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017551 infores:hetionet CHEBI:2038 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0002792 infores:hetionet CHEBI:404903 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0039070 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017675 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0042109 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0424000 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0149931 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027765 infores:hetionet CHEBI:119915 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026205 infores:hetionet CHEBI:17698 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0015230 infores:hetionet CHEBI:3175 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020452 infores:hetionet CHEBI:4858 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0011603 infores:hetionet CHEBI:6520 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0085669 infores:hetionet CHEBI:16469 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0702166 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0549493 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0344315 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0009938 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0344232 infores:hetionet CHEBI:2676 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0015967 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030305 infores:hetionet CAID:CA229696 biolink:causes MONDO:0009861 infores:clingen CAID:CA229696 MONDO:0009861 PMID:30050108PMID:10408782PMID:30050108 Pathogenic PM3, PVS1, PM2, PP4 The c.694C>T (p.Gln232Ter) variant in PAH has been reported in multiple individuals with PKU (PP4; PMID: 30050108). This variant has an extremely low allele frequency (MAF=0.00003; PM2). This variant was detected with known pathogenic variant c.442-1G>A (PM3; PMID: 30050108). This is a null variant (nonsense) in exon 6 of 13 (NMD predicted) of PAH, a gene where loss of function is a known mechanism of disease (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229696/MONDO:0009861/006 2020-05-31 2020-05-31 Autosomal recessive inheritance HP:0000007 Supports CAID:CA327922574 biolink:causes MONDO:0100437 infores:clingen CAID:CA327922574 MONDO:0100437 PMID: Benign BA1, BP4, BP7 NM_001034853.2(RPGR):c.1414+1450C>G is an intron 11 variant located 1450 nucleotides from exon 11. This variant is present in gnomAD v.4.1.0 at a frequency of 0.03626 among hemizygous individuals, with 1,213 variant alleles / 33,454 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). The variant is located outside of the splice donor region (BP7). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327922574/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:68606 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0029118 infores:hetionet CHEBI:7445 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C2981158 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0009766 infores:hetionet CHEBI:50859 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030554 infores:hetionet CHEBI:100241 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0233407 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0027769 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0019158 infores:hetionet CAID:CA9870503 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870503 MONDO:0015967 PMID: Uncertain Significance PP3 PM2, PP4 The c.1216+6C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 9 of NM_175914.5. The Grpmax filtering allele frequency of the c.1216+6C>A variant in gnomAD v2.1.1 is 0.0007090%, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. The computational splicing predictor SpliceAI gives a score of 0.24 for donor Loss, predicting that the variant disrupts the donor site of intron 9 of HNF4A (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (internal lab contributors). In summary, c.1216+6C>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870503/MONDO:0015967/085 2024-12-12 2024-12-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5801 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0012833 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235639 infores:hetionet CHEBI:16755 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151766 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0021053 infores:hetionet CHEBI:7773 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0008031 infores:hetionet CHEBI:63638 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0699744 infores:hetionet CHEBI:75998 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C1384353 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0497327 infores:hetionet CHEBI:49713 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020456 infores:hetionet CHEBI:3175 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0242184 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020538 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151479 infores:hetionet CHEBI:6444 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0042109 infores:hetionet CHEBI:7494 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011991 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0227791 infores:hetionet CHEBI:5118 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C3203358 infores:hetionet CAID:CA367403551 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403551 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PP1 The c.109A>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to valine at codon 37 (p.(Met37Val)) of NM_000162.5.This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8759, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.110T>G (p.Met37Arg)​ has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met37Val (PM5_Supporting). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributor). In summary, c.109A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403551/MONDO:0015967/086 2023-11-22 2023-11-22 Semidominant inheritance HP:0032113 Supports CHEBI:50275 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0003864 infores:hetionet NCBIGene:2188 biolink:causes MONDO:0011325 infores:monarchinitiative not_provided not_provided HGNC:3587 MONDO:0011325 uuid:eed4344c-1d42-4c67-9b32-16680ca1c41f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0018801 infores:hetionet CHEBI:6538 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0018681 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009763 infores:hetionet CHEBI:47780 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037036 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011334 infores:hetionet CHEBI:4653 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0020580 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0027497 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0015967 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009324 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040409 infores:hetionet CHEBI:9137 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0030193 infores:hetionet CHEBI:44032 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0038990 infores:hetionet UMLS:C0010592 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0011603 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0042373 infores:hetionet CHEBI:92712 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0039239 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1443060 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020649 infores:hetionet CAID:CA2286774128 biolink:causes MONDO:0015967 infores:clingen CAID:CA2286774128 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PP1_Strong, PS3_Supporting, PP4_Moderate The c.-283A>C in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant in the promoter of NM_000545.8. This variant is located within the HNF4A binding domain (c.-276 to c.-288) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Functional studies demonstrated the c.-283A>C protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:10649494). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:9313764; internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant also segregated with diabetes, with 7 informative meioses in two families with MODY (PP1_Strong; PMID: 9313764; internal lab contributor). Taken together, this evidence suggests the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP1_Strong, PP4_Moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2286774128/MONDO:0015967/017 2025-07-25 2025-07-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75722 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232292 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0026975 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0023895 infores:hetionet CHEBI:7478 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0231530 infores:hetionet GO:1903593 biolink:causes GO:0002349 infores:ubergraph knowledge_assertion manual_agent GO:1903593 GO:0002349 CHEBI:63630 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0160390 infores:hetionet CHEBI:31236 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011071 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0239521 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0239521 infores:hetionet CAID:CA090925 biolink:causes MONDO:0100488 infores:clingen CAID:CA090925 MONDO:0100488 PMID: Benign BS1, BS2, BP2_Strong PM2, BA1 The filtering allele frequency of the c.1568A>G (p.Tyr523Cys) variant in the CDH1 gene is 0.15% for Latino/Admixed American chromosomes in gnomAD (95% CI of 23/15282), which meets the allele frequency threshold defined by the ClinGen CDH1 Variant Curation Expert Panel for considering strong evidence against pathogenicity for autosomal dominant hereditary diffuse gastric cancer variants (BS1). This variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA090925/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:28864 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0038999 infores:hetionet CHEBI:134745 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0011603 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0032285 infores:hetionet CHEBI:5004 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0011570 infores:hetionet CHEBI:15854 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0039231 infores:hetionet CAID:CA16606475 biolink:causes MONDO:0015967 infores:clingen CAID:CA16606475 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 PM5 The c.788G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 263 (p.Arg263His) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater thanthe MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 19336507, 26853433, 28012402, 29927023, 31166087, internal lab contributors). Additionally, functional studies demonstrated the p.Arg263His protein has DNA binding and nuclear localization below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 26853433). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). Finally, this variant segregated with diabetes, with 9 informative meioses in multiple families with MODY (PP1_Strong; 19336507, internal lab contributors). While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263Cys and PM5_Strong to Arg263Leu and thus PM5 is not applied to p.Arg263His. In summary, c.788G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PS3_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606475/MONDO:0015967/017 2022-04-14 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6775 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0270996 infores:hetionet CHEBI:2663 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0037188 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0234458 infores:hetionet CHEBI:6472 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0027947 infores:hetionet CHEBI:6775 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0744727 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042109 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0008370 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1323189 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1323189 infores:hetionet CHEBI:8874 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018790 infores:hetionet NCBIGene:5244 biolink:causes MONDO:0011214 infores:monarchinitiative not_provided not_provided HGNC:45 MONDO:0011214 uuid:ed933827-2fed-4506-a918-f59575649b57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0031117 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0302295 infores:hetionet CHEBI:34385 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0009676 infores:hetionet CHEBI:28487 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0234238 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0034902 infores:hetionet CHEBI:8863 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0376358 infores:hetionet CHEBI:8404 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0027497 infores:hetionet NCBIGene:6834 biolink:causes MONDO:0700250 infores:monarchinitiative not_provided not_provided HGNC:11474 MONDO:0700250 uuid:86456660-88b1-480b-91bf-39130ead42a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0021177 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006852 infores:hetionet CHEBI:3423 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0016382 infores:hetionet CHEBI:63610 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0031542 infores:hetionet CAID:CA229529 biolink:causes MONDO:0009861 infores:clingen CAID:CA229529 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.386A>T (p.Asp129Val) variant in PAH has not been reported in the literature to our knowledge. This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.986 (PM3). The (p.Asp129Gly) variant is likely pathogenic by 1 submitter and PAH VCEP (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229529/MONDO:0009861/006 2020-01-26 2020-01-31 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8776 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0041349 infores:hetionet CHEBI:41774 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0236075 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0234215 infores:hetionet CHEBI:5132 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0151904 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0233472 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0861157 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0861157 infores:hetionet CHEBI:7852 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013404 infores:hetionet CAID:CA10014548 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014548 MONDO:0011071 PMID: Benign BP2, BP4, BA1 PS4, PS2, PS3, PS1, BP1, BP3, PM2, PM6, PVS1, BS1, BS4, BS3, BP5, BP7, PM3, PM4, PM1, PM5, PP1, PP4, PP2, PP3, BS2 NM_001754.5(RUNX1):c.342C>A (p.Ile114=) is a synonymous variant. This variant has a MAF of 0.00256 (0.256%, 47/18362, 47 alleles) in the East Asian gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). Variant observed in homozygous state (1) in gnomAD v2.1.1 and v3.1.2. (BP2). This variant is not a missense variant therefore REVEL score is not applicable and SpliceAI is ≤0.50 (0.00) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014548/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:5889 biolink:causes MONDO:0013248 infores:monarchinitiative not_provided not_provided HGNC:9820 MONDO:0013248 uuid:0cb0f81b-0cce-4c4b-acdc-56419beb2f8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0234215 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0003460 infores:hetionet CHEBI:84500 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0016204 infores:hetionet CHEBI:31348 biolink:causes MONDO:0021340 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0021807 infores:hetionet CHEBI:3242 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0026827 infores:hetionet CHEBI:3223 biolink:causes MONDO:0001160 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0012746 infores:hetionet CHEBI:10119 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0037763 infores:hetionet CHEBI:2904 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0010200 infores:hetionet NCBIGene:7249 biolink:causes MONDO:0013199 infores:monarchinitiative not_provided not_provided HGNC:12363 MONDO:0013199 uuid:f0d71eb8-f9a4-420a-a9bf-f4b972d7025d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013404 infores:hetionet CHEBI:7444 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0151942 infores:hetionet CHEBI:31932 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0013604 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0019151 infores:hetionet CHEBI:41423 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0036974 infores:hetionet CHEBI:3485 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0042963 infores:hetionet CHEBI:7822 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013182 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0031046 infores:hetionet CHEBI:36795 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0004134 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235890 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024415 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0341245 infores:hetionet CHEBI:116278 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0038325 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017160 infores:hetionet CAID:CA320251893 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251893 MONDO:0011071 PMID: Benign BP2, BP4, BA1, BP7 PS3, PS2, PS1, PS4, BP3, BP1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM3, PM4, PM1, PM5, PP4, PP2, PP3, PP1, BS2 The NM_001754.5(RUNX1):c.968-269G>A variant is a deep intronic variant that is not predicted by SpliceAI to impact splicing (BP4). The variant's highest minor allele frequency (MAF) of 0.08447(8.447%, 731/8654 alleles) in the African/African American subpopulation of the gnomADv2.1.1 cohort is ≥ 0.0015 (0.15%) (BP1). Additionally, this variant is detected in a homozygous state in 28 individuals in a population database (gnomADv2.1.1) (BP2). This deep intronic variant is not well conserved with a phyloP100way score of -0.476 (BP7 ≤2.0). It has not been reported in individuals meeting at least one of the RUNX1 phenotypic criteria. In summary, the clinical significance of this variant is Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251893/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA273107 biolink:causes MONDO:0009861 infores:clingen CAID:CA273107 MONDO:0009861 PMID:25894915PMID:25894915 Pathogenic PP4_Moderate, PM2, PVS1, PM3_Strong PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: gnomAD MAF 0.00017; PP4_Moderate: Detected in PKU patients (PMID:25894915); PM3_Strong: in trans with p.W326X (Pathogenic), and IVS4-1G>A (Pathogenic). (PMID:25894915). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273107/MONDO:0009861/006 2018-08-13 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37941 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1608945 infores:hetionet CHEBI:51041 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0549622 infores:hetionet CHEBI:3499 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0002792 infores:hetionet CHEBI:68478 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0025874 infores:hetionet CHEBI:63631 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0221201 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0233494 infores:hetionet CHEBI:6754 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C1456784 infores:hetionet CAID:CA348941 biolink:causes MONDO:0007648 infores:clingen CAID:CA348941 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.504delA p.(Gly169Alafs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; DOI: 10.1200/PO.16.00021). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA348941/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:3380 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0948594 infores:hetionet CHEBI:8081 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0151828 infores:hetionet CHEBI:50841 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0017178 infores:hetionet CHEBI:3723 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042029 infores:hetionet CHEBI:66903 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0271321 infores:hetionet CHEBI:50749 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0677500 infores:hetionet CAID:CA16619040 biolink:causes MONDO:0017623 infores:clingen CAID:CA16619040 MONDO:0017623 PMID: Uncertain Significance PM2 BP7, BP5, BP4 PTEN c.42G>A (p.Arg14=) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619040/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:567361 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0740394 infores:hetionet CHEBI:27504 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0040046 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0009450 infores:hetionet CHEBI:6717 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0009763 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085584 infores:hetionet CHEBI:6775 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013604 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042029 infores:hetionet CHEBI:8764 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006846 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0870082 infores:hetionet UMLS:C0145867 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0027540 infores:hetionet CHEBI:8888 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004093 infores:hetionet CAID:CA229460 biolink:causes MONDO:0009861 infores:clingen CAID:CA229460 MONDO:0009861 PMID:9521426PMID:21147011PMID:9521426 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PS3 The c.169-13T>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 9521426, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with pathogenic variants: IVS10-11G>A (PMID: 21147011); p.L213P (PMID: 9521426); p.R158Q (PMID: 12640344); p.Y356X (c.1068C > G in 1 patient and c.1068C > A in 1 patient, PMID: 30389586). Computational evidence support a deleterious effect on splicing. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229460/MONDO:0009861/006 2020-08-17 2021-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009806 infores:hetionet CHEBI:2038 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0003862 infores:hetionet CHEBI:61390 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0011175 infores:hetionet CHEBI:9435 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0002622 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0029456 infores:hetionet CHEBI:4798 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0085932 infores:hetionet CHEBI:17141 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0151766 infores:hetionet CHEBI:7465 biolink:causes MONDO:0006581 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0162423 infores:hetionet CHEBI:50841 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0002453 infores:hetionet CAID:CA772541579 biolink:causes MONDO:0100326 infores:clingen CAID:CA772541579 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The p.Gln508SerfsTer161 variant on ITGB3 gene is a frameshift variant in exon 10 which is predicted to introduce a premature stop codon 161 amino acids downstream and result in NMD. It is absent from all large population cohorts (gnomAD). This variant has been reported to occur in compound heterozygous state in one proband who meets the PD-VCEP criteria for the GT phenotype (PMID: 25728920). This variant meets GT specific criteria for PVS1, PP4_Strong and PM2_supporting and is therefore classified as Pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA772541579/MONDO:0100326/011 2021-08-17 2021-08-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:28748 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0237849 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0234215 infores:hetionet CHEBI:194135 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235996 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042571 infores:hetionet CHEBI:6030 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0027497 infores:hetionet CHEBI:9150 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0015230 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009946 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0013404 infores:hetionet CHEBI:2569 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0004093 infores:hetionet GO:0140166 biolink:causes GO:0002002 infores:ubergraph knowledge_assertion manual_agent GO:0140166 GO:0002002 CHEBI:18358 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0162830 infores:hetionet CHEBI:5134 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0004604 infores:hetionet CAID:CA058118 biolink:causes MONDO:0007783 infores:clingen CAID:CA058118 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 4010 of the RYR1 protein, p.(Glu4010Lys). The maximum allele frequency for this variant among the six major gnomAD populations is AFR:0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.178) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA058118/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45327 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0038990 infores:hetionet CHEBI:16469 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0039231 infores:hetionet GO:0034106 biolink:causes GO:0034101 infores:ubergraph knowledge_assertion manual_agent GO:0034106 GO:0034101 NCBIGene:57187 biolink:causes MONDO:0010496 infores:monarchinitiative not_provided not_provided HGNC:19073 MONDO:0010496 uuid:cfb03f36-fc17-4126-9762-de0269c52dd6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0018799 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0016436 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018418 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0162316 infores:hetionet CHEBI:71223 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0041364 infores:hetionet UMLS:C0025241 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151692 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0853149 infores:hetionet UMLS:C0657912 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027497 infores:hetionet CHEBI:28148 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C2242996 infores:hetionet CHEBI:6888 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0015672 infores:hetionet CHEBI:84883 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C2047937 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042109 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0233494 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027765 infores:hetionet CHEBI:63584 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0030196 infores:hetionet CHEBI:45081 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0428977 infores:hetionet CHEBI:9139 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C3263723 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0013378 infores:hetionet NCBIGene:6785 biolink:causes MONDO:0010819 infores:monarchinitiative not_provided not_provided HGNC:14415 MONDO:0010819 uuid:10303286-f1e7-4a35-909d-4464f09737bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0040264 infores:hetionet CHEBI:28241 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0042571 infores:hetionet CAID:CA512318940 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318940 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.180C>A (p.Ala60=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318940/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA386296662 biolink:causes MONDO:0009861 infores:clingen CAID:CA386296662 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.637C>T (p.Leu213Phe) variant in PAH is the same amino acid change as an established pathogenic variant, c.638T>C (p.Leu213Pro) VarID:92747. (PM5). This variant is absent in population databases (PM2). This variant has not been reported in the literature to our knowledge. Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386296662/MONDO:0009861/006 2019-09-27 2019-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8776 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0917801 infores:hetionet CHEBI:74947 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011603 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0332534 infores:hetionet CHEBI:6437 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0006277 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042109 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0020517 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0021400 infores:hetionet CHEBI:3207 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0038999 infores:hetionet GO:0060126 biolink:causes CL:0000295 infores:ubergraph knowledge_assertion manual_agent GO:0060126 CL:0000295 CHEBI:3207 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0018799 infores:hetionet CHEBI:5132 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0022354 infores:hetionet CHEBI:5779 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0024031 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0235431 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0155169 infores:hetionet NCBIGene:9409 biolink:causes MONDO:0013943 infores:monarchinitiative not_provided not_provided HGNC:8857 MONDO:0013943 uuid:8841c7a3-3dad-4a09-a2f6-b1f3e0340b03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0031117 infores:hetionet CHEBI:45951 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0011168 infores:hetionet CHEBI:5001 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0011124 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0497201 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015397 infores:hetionet CHEBI:3419 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0023530 infores:hetionet CHEBI:68478 biolink:causes HP:0030804 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0546956 infores:hetionet CHEBI:38940 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0085605 infores:hetionet CAID:CA367400478 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400478 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.824G>C variant in the glucokinase gene, GCK, causes an amino acid change of arginine to proline at codon 275 (p.(Arg275Pro)) of NM_000162.5. This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmolL) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.811, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants at this residue, c.823C>T p.(Arg275Cys) and c.823C>G (p.Arg275Gly), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.824G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400478/MONDO:0015967/086 2025-01-10 2025-01-10 Semidominant inheritance HP:0032113 Supports CHEBI:68554 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0085593 infores:hetionet CHEBI:16586 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0039070 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0007867 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0162281 infores:hetionet GO:0070808 biolink:causes GO:0070791 infores:ubergraph knowledge_assertion manual_agent GO:0070808 GO:0070791 CHEBI:6715 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041834 infores:hetionet CHEBI:4909 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013428 infores:hetionet CHEBI:28177 biolink:causes MONDO:0017988 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0221158 infores:hetionet CAID:CA410206735 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206735 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.766T>C (p.Ser256Pro) is a missense variant which has a REVEL score < 0.50 (0.242) and a SpliceAI score ≤ 0.20 (0.05) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206735/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C3665624 infores:hetionet CHEBI:64045 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0149871 infores:hetionet CHEBI:55346 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0423791 infores:hetionet CHEBI:63925 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085628 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0948586 infores:hetionet CHEBI:47898 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0404521 infores:hetionet CHEBI:9939 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0006266 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151735 infores:hetionet NCBIGene:2072 biolink:causes MONDO:0010215 infores:monarchinitiative not_provided not_provided HGNC:3436 MONDO:0010215 uuid:81e575ab-4618-4635-9f07-ed17a1e4bd2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0022116 infores:hetionet UNII:VL0L558GCB biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0221423 infores:hetionet CHEBI:7465 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0424790 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0836924 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033575 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0235855 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0235855 infores:hetionet CHEBI:63791 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0232849 infores:hetionet CHEBI:8871 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1260880 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0948089 infores:hetionet CHEBI:5784 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0553548 infores:hetionet CHEBI:32020 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0030196 infores:hetionet NCBIGene:57688 biolink:causes MONDO:0060642 infores:monarchinitiative not_provided not_provided HGNC:29316 MONDO:0060642 uuid:31a1f396-f62f-422a-81e3-cd91681dc8af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0006829 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023501 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0008473 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0008473 uuid:547b337f-f6d5-4f6a-ae23-acbfb592d13c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes MONDO:0006835 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027721 infores:hetionet CHEBI:168396 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0740394 infores:hetionet CHEBI:6375 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013428 infores:hetionet CHEBI:8776 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0042384 infores:hetionet CHEBI:75998 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0024236 infores:hetionet CHEBI:28177 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0021141 infores:hetionet CHEBI:8869 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0002994 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0036572 infores:hetionet CHEBI:6775 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0014724 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0851341 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0235416 infores:hetionet CHEBI:7773 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0040822 infores:hetionet CHEBI:83804 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1519353 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0009241 infores:hetionet CHEBI:4445 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1142412 infores:hetionet CHEBI:63629 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0017181 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0010709 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0021053 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0015663 infores:hetionet CHEBI:101085 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0232459 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0259768 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0152027 infores:hetionet CHEBI:45951 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0015230 infores:hetionet CHEBI:50730 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0003862 infores:hetionet CHEBI:3032 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0006266 infores:hetionet CHEBI:63589 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0851578 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0178298 infores:hetionet CAID:CA229391 biolink:causes MONDO:0009861 infores:clingen CAID:CA229391 MONDO:0009861 PMID:19915519PMID:23932990PMID:16256386PMID:16256386 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PM5, PP3 The c.1199G>C (p.Arg400Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 16256386, 19915519, 23932990). This variant is absent in population databases. It has been detected with pathogenic variants: IVS7+2T>A, p.R243Q, p.G346R (PMID: 16256386); and in trans with IVS4+3G＞C, p.His107Arg, EX6-96A＞G, p.Arg243Gln, IVS4-1G＞A (PMID: 29316886). Computational prediction tools and conservation analysis are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229391/MONDO:0009861/006 2020-06-05 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:9051 biolink:causes MONDO:0011462 infores:monarchinitiative not_provided not_provided HGNC:9580 MONDO:0011462 uuid:abc57a1a-a07f-4352-80a7-e60a291076e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45599 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0031542 infores:hetionet UMLS:C0004609 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0392156 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0549346 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0549346 infores:hetionet CHEBI:3207 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0025345 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0242350 infores:hetionet CHEBI:465284 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0009421 infores:hetionet CHEBI:31302 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0012569 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0162429 infores:hetionet CAID:CA170169 biolink:causes MONDO:0010726 infores:clingen CAID:CA170169 MONDO:0010726 PMID: Benign BP5, BS1, BS2 BA1, BP4 The highest population minor allele frequency of the p.Pro361Ala variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.0001029 in the Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Pro361Ala variant is observed in at least 2 unaffected individuals (Internal database - Ambry Genetics) (BS2). The p.Pro361Ala variant is found in a patient with an alternate molecular basis of disease (internal database - Labcorp Genetics) (BP5). In summary, the p.Pro361Ala variant in MECP2 (NM_004992.4) is classified as benign based on ACMG/AMP criteria (BS1, BS2, BP5). (MECP2 Specifications v.4.1; curation approved on 06/25/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170169/MONDO:0010726/036 2025-06-25 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:5959 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0220870 infores:hetionet CHEBI:9622 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0009450 infores:hetionet CHEBI:6538 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0008031 infores:hetionet CHEBI:6931 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0600260 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0026857 infores:hetionet CHEBI:41774 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0010200 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020649 infores:hetionet NCBIGene:57017 biolink:causes MONDO:0013840 infores:monarchinitiative not_provided not_provided HGNC:25302 MONDO:0013840 uuid:7fe74335-9243-4548-acd6-867a6dd2bc02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0014868 infores:hetionet CHEBI:135930 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020443 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0031350 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0019348 infores:hetionet CHEBI:49713 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0015644 infores:hetionet CHEBI:3215 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0010200 infores:hetionet CHEBI:6539 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0043352 infores:hetionet CAID:CA410207999 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207999 MONDO:0011071 PMID: Uncertain Significance PM5_Supporting, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.581A>T (p.Lys194Ile) is a missense variant which affects the following hotspot residues within the Runt Homology domain: K194 (PM1). This variant has a REVEL score ≥ 0.88 (0.945) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a missense change at the same residue (p.Lys194) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 561250) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207999/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16796 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0013595 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030312 infores:hetionet CHEBI:4445 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0086565 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1321686 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0034065 infores:hetionet CHEBI:63620 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018965 infores:hetionet CHEBI:5123 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0232462 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0595877 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0037274 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027651 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0003864 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0027769 infores:hetionet UMLS:C0657912 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0012569 infores:hetionet CHEBI:3485 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0424295 infores:hetionet CHEBI:10112 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0033774 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002450 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0520477 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0001969 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0001969 infores:hetionet NCBIGene:1825 biolink:causes MONDO:0013136 infores:monarchinitiative not_provided not_provided HGNC:3037 MONDO:0013136 uuid:b9fa91f0-f665-4521-8808-56d3395aa19d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0006840 infores:hetionet CHEBI:127780 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0009421 infores:hetionet CHEBI:63623 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0029882 infores:hetionet GO:0006954 biolink:causes NCIT:C27003 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D059787 DB08976_MESH_D059787_1 CHEBI:167638 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0006266 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0027765 infores:hetionet GO:0072034 biolink:causes GO:0072077 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0072077 CHEBI:41879 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042963 infores:hetionet CHEBI:2950 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0027497 infores:hetionet CHEBI:70746 biolink:causes MONDO:0004001 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0009492 infores:hetionet CHEBI:50648 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0025345 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009782 infores:hetionet CHEBI:3127 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0009421 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0541923 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0541923 infores:hetionet NCBIGene:255758 biolink:causes MONDO:0054565 infores:monarchinitiative not_provided not_provided HGNC:28482 MONDO:0054565 uuid:fb67273e-2ee2-4cd0-8191-9660ffc945f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8404 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0442874 infores:hetionet CHEBI:6709 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0015672 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0021843 infores:hetionet CHEBI:3510 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C2129214 infores:hetionet CHEBI:4672 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0149725 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0314719 infores:hetionet CHEBI:4495 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0040034 infores:hetionet CHEBI:42944 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0036974 infores:hetionet CHEBI:30830 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0004604 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022568 infores:hetionet CHEBI:4495 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0034150 infores:hetionet NCBIGene:53630 biolink:causes MONDO:0007272 infores:monarchinitiative not_provided not_provided HGNC:13815 MONDO:0007272 uuid:510a2150-7d2a-4f1c-86c6-296f10d25a0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0518988 infores:hetionet CHEBI:7903 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0013604 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1262144 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235890 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0497247 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085614 infores:hetionet CHEBI:92923 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0006444 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0033246 infores:hetionet CAID:CA179713 biolink:causes MONDO:0100438 infores:clingen CAID:CA179713 MONDO:0100438 PMID:27268253 Benign BS2, BP4, BA1 BS3 NM_014336.5(AIPL1):c.286G>A (p.Val96Ile) is a missense variant in exon 3 of 6 predicted to replace valine with isoleucine at amino acid p.96. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.02348, with 27,980 alleles / 1,179,700 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057. (BA1). Additionally, the variant has been found in the homozygous state in 382 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.255, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.290 and predicts a non-damaging effect on AIPL1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, and BP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA179713/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2666 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0235293 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0025517 infores:hetionet CHEBI:9727 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0409974 infores:hetionet CHEBI:8461 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0037763 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0038362 infores:hetionet CHEBI:27504 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0595916 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0042373 infores:hetionet CHEBI:31174 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0151908 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0162830 infores:hetionet CAID:CA172183 biolink:causes MONDO:0100040 infores:clingen CAID:CA172183 MONDO:0100040 PMID: Benign BA1 The allele frequency of the p.Gly152= variant in FOXG1 is 0.04% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Gly152= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172183/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63621 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0854382 infores:hetionet HP:0031377 biolink:causes MONDO:0009273 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D031901 DB00970_MESH_D031901_1 CHEBI:28748 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151539 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151705 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0332575 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0031117 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0234913 infores:hetionet CHEBI:6887 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009763 infores:hetionet CAID:CA409107472 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107472 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.745G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 249 (p.(Glu249Ter)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and located in biologically relevant exon 7 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). In summary, c.745G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107472/MONDO:0015967/085 2024-08-30 2024-08-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9571 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0427086 infores:hetionet CAID:CA273984 biolink:causes MONDO:0009290 infores:clingen CAID:CA273984 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong PM5 This variant, NM_000152.5(GAA):c.784G>A, is predicted to result in the substitution of glutamate to lysine at amino acid 262 (p.Glu262Lys). This variant represented 6.8% of alleles in an Italian case series of 29 infants with Pompe disease (PMID: 18429042). This variant has been reported in at least 20 individuals with Pompe disease, including at least 12 individuals with documented laboratory data showing deficiency of GAA activity and/or clinical symptoms consistent with infantile onset Pompe disease (cardiomegaly and muscle weakness), and/or on treated with enzyme replacement therapy (ERT) meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 11738358, 18285536, 19588081, 19948615, 25455803, 26497565, 27344650, 29181627, 29422078, 30023291, 31193175 31915562, 33228748)(PP4_Moderate). The variant has been reported in compound heterozygosity with a pathogenic variant in at least 8 patients, phase unconfirmed (PMID: 11738358, 18285536, 19948615, 24269976, 25455803, 29181627, 29422078, 29880332), and in at least 5 homozygous patients diagnosed with Pompe disease (PMIDs: 18429042, 26497565, 29422078, 33228748, 33325062) (PM3_Very Strong). More data is available in the literature but the maximum evidence for PM3_Very Strong has been reached. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, allowing this criterion to be applied (PM2_Supporting). The computational predictor REVEL gives a score of 0.888 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies have not been reported for this variant. There is a ClinVar entry for this variant (ClinVar variation ID: 188806) with 3 submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PM2_Supporting. (Classification approved: August 17, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273984/MONDO:0009290/010 2021-08-25 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:109549 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0233632 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0027765 infores:hetionet CAID:CA024497 biolink:causes MONDO:0007783 infores:clingen CAID:CA024497 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with arginine at codon 1729 of the RYR1 protein, p.Met1729Arg. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.712 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024497/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:194135 biolink:causes UMLS:C1096387 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1096387 infores:hetionet CHEBI:64028 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0242422 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009319 infores:hetionet CHEBI:3061 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0013604 infores:hetionet CHEBI:63627 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0015967 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0033975 infores:hetionet CHEBI:116278 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0080274 infores:hetionet CHEBI:3001 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0858259 infores:hetionet CHEBI:8707 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0237314 infores:hetionet CHEBI:37333 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0231528 infores:hetionet CHEBI:45716 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0040034 infores:hetionet UMLS:C0010592 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1260926 infores:hetionet CHEBI:6950 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0014591 infores:hetionet CHEBI:135961 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0039591 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0042109 infores:hetionet CHEBI:8863 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0010520 infores:hetionet CHEBI:18358 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0234233 infores:hetionet CHEBI:94501 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0010200 infores:hetionet CHEBI:45716 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0023380 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0851341 infores:hetionet CHEBI:50729 biolink:causes MONDO:0000918 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0014179 infores:hetionet CHEBI:100246 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0022346 infores:hetionet CHEBI:4562 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0013604 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027947 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0853692 infores:hetionet CHEBI:17303 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0156404 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0034882 infores:hetionet CHEBI:7577 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0085614 infores:hetionet CAID:CA2579830394 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830394 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM1 The c.-172T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is located within the HNF1A/HNF1B binding region (c.-170 to c.-173 and c.-178 to c.-181) of the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.-172T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PP4_Moderate, PM1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830394/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31413 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0028738 infores:hetionet CHEBI:6539 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0027497 infores:hetionet CHEBI:47781 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0028734 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0002170 infores:hetionet CHEBI:9168 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013491 infores:hetionet CHEBI:9943 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040822 infores:hetionet CHEBI:5779 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0040034 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027059 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0948376 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0948376 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0917798 infores:hetionet NCBIGene:8504 biolink:causes MONDO:0054549 infores:monarchinitiative not_provided not_provided HGNC:8858 MONDO:0054549 uuid:c03e05d0-677c-484e-afb9-84ac3ea79861 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32192 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0237938 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151826 infores:hetionet CHEBI:100147 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0012833 infores:hetionet NCBIGene:3909 biolink:causes MONDO:0009513 infores:monarchinitiative not_provided not_provided HGNC:6483 MONDO:0009513 uuid:dd810a55-d16b-4496-a8eb-ef04d67b8e0b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0149931 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0011991 infores:hetionet NCBIGene:5664 biolink:causes MONDO:0013373 infores:monarchinitiative not_provided not_provided HGNC:9509 MONDO:0013373 uuid:c22af4e4-9583-48c5-b164-5faa985ebe9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009676 infores:hetionet CHEBI:116278 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0231530 infores:hetionet CHEBI:18248 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C1384353 infores:hetionet CHEBI:8499 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0242429 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0011991 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0036572 infores:hetionet CHEBI:36704 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0021368 infores:hetionet CHEBI:17688 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0236000 infores:hetionet CHEBI:7581 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0009676 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006256 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853879 infores:hetionet CHEBI:4708 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0392171 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0024312 infores:hetionet CAID:CA000580 biolink:causes MONDO:0017623 infores:clingen CAID:CA000580 MONDO:0017623 PMID:28677221PMID:28677221PMID:25669429PMID:21659347 Likely Benign BS3 PM2, PM6, PVS1, BS1, BS4, BP7, BP5, BS2, PP3, PP2, PP4, PP1, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2, PS4 NM_000314.8(PTEN):c.79+7A>G variant meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID: 28677221) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000580/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4995 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020649 infores:hetionet CHEBI:9927 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0013604 infores:hetionet CAID:CA351512423 biolink:causes MONDO:0021060 infores:clingen CAID:CA351512423 MONDO:0021060 PMID:23391722 Pathogenic PM5_Strong, PS2_Very Strong, PM2, PP2, PS4_Supporting PS3 The c.775T>G (p.Ser259Ala) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported as a confirmed de novo occurrence in 2 probands (PS2_VeryStrong; SCV000808501.1). The variant has been identified in 1 proband with Noonan syndrome (PS4_Supporting; SCV000710868.2). At least 2 other pathogenic missense variants have been previously identified at the Ser259 codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40601, 44633). A functional assay has been performed on c.775T>G (p.Ser259Ala), but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:23391722). Finally, the variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4_Supporting, PM5_Strong, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA351512423/MONDO:0021060/004 2020-06-25 2020-06-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:84500 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038358 infores:hetionet CHEBI:36704 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0010200 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027651 infores:hetionet CHEBI:5864 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085605 infores:hetionet CHEBI:8805 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0267792 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042594 infores:hetionet CHEBI:6761 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0028961 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0476089 infores:hetionet CHEBI:55346 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0853034 infores:hetionet CHEBI:45783 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0014457 infores:hetionet CHEBI:77260 biolink:causes EFO:0008501 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0334044 infores:hetionet CHEBI:3510 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0917801 infores:hetionet CAID:CA340740587 biolink:causes MONDO:0100368 infores:clingen CAID:CA340740587 MONDO:0100368 PMID: Likely Pathogenic PM1, PM5, PP3_Moderate, PM2_Supporting PM3 NM_000329.3(RPE65):c.1580A>C (p.His527Pro) is a missense variant predicted to replace histidine with proline at amino acid p.527, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). Another missense variant in the same codon, NM_000329.3(RPE65):c.1580A>G (p.His527Arg), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5, PMID: 17525851). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of inherited retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 30268864) with the NM_000329.3(RPE65):c.651del (p.Asp218IlefsTer3) variant suspected but not confirmed in trans. However, the proband was not counted for PM3_Supporting because sufficient phenotype details were unavailable to confirm the compatibility of the diagnosis with RPE65 as the cause. The computational predictor REVEL gives a score of 0.991, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01 for acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM5, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340740587/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3175 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0151601 infores:hetionet CAID:CA392341228 biolink:causes MONDO:0007947 infores:clingen CAID:CA392341228 MONDO:0007947 PMID: Pathogenic PP2, PP3, PM2_Supporting, PM5, PM1, PS1 PS4 The NM_00138 c.1630G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by arginine at amino acid 544 (p.Gly544Arg). This variant impacts a critical glycine between Cys2 and Cys3 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant has been reported twice in ClinVar: once as pathogenic, and once as uncertain significance (Variation ID: 495558). This variant has been previously reported in at least 1 individual with clinical features of Marfan syndrome (MFS) (Invitae lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different nucleotide change resulting in the same amino acid substitution, missense variant at this position, c.1630G>C p.Gly544Arg, has previously been previously established as pathogenic, and was found to segregate with MFS with or without thoracic aortic aneurysm in eight affected individuals from one family (PS1; PMID 30087447, internal lab data). A different missense variant at this position, c.1630G>C p.Gly544Arg, has been found in an individual with a clinical diagnosis of MFS, and has been established as likely pathogenic (PM5; internal lab data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.918). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS1, PM1, PM5, PM2_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392341228/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:119915 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0476273 infores:hetionet CHEBI:472657 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0595916 infores:hetionet CHEBI:5864 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027796 infores:hetionet CHEBI:7577 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0014591 infores:hetionet CHEBI:5280 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0025874 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0015230 infores:hetionet CHEBI:82941 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0877192 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020437 infores:hetionet NCBIGene:203190 biolink:causes MONDO:0859277 infores:monarchinitiative not_provided not_provided HGNC:18711 MONDO:0859277 uuid:79de0b2a-1d9a-4dc9-a88e-04fd20abd491 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0029944 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0026650 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0853813 infores:hetionet CHEBI:3423 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0040053 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0178298 infores:hetionet CHEBI:7573 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0015967 infores:hetionet CHEBI:3437 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0028077 infores:hetionet GO:0086092 biolink:causes GO:0002026 infores:ubergraph knowledge_assertion manual_agent GO:0086092 GO:0002026 CHEBI:64354 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0002871 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0021400 infores:hetionet CHEBI:4469 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0085631 infores:hetionet CHEBI:7577 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011124 infores:hetionet CHEBI:8356 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019079 infores:hetionet CHEBI:107736 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0003467 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0235680 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235680 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009450 infores:hetionet CHEBI:6715 biolink:causes HP:0001195 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1384670 infores:hetionet CAID:CA203395653 biolink:causes MONDO:0011225 infores:clingen CAID:CA203395653 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PM3 BS2, PP3, PM1 The c.632G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Alanine at amino acid 211 (p.Gly211Ala).The filtering allele frequency (the upper threshold of the 95% CI) of the c.632G>C variant in DCLRE1C is 0.00001921 African/African American Genomes, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD v4.One patient is reported in the literature (PMID: 34420125) present: *Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pt + *SCID gene panel or exome/genome sequencing conducted 0.5pt + *T-B-NK+ lymphocyte subset profile 0.5 pt, total is 1.5pts. PP4_Supporting.This proband is compound heterozygous for mutations in DCLRE1C, with a maternally inherited pathogenic deletion in exons 1–3 (at least LP according to SCID VCEP specifications) and a paternally variant (NM 001033855.2; c.632G > C, p.Gly211Ala). 1 point, PM3 is met.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4_Supporting, and PM3_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA203395653/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:71255 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0015397 infores:hetionet CHEBI:2682 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0026821 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0234215 infores:hetionet CHEBI:63621 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0032343 infores:hetionet CHEBI:50673 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0027697 infores:hetionet CAID:CA10014157 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014157 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS3, PS2, PS4, BP1, BP4, BP3, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*121G>C is a 3' UTR variant. This variant has a MAF of 0.013 (1.32%, 468/35294 alleles) in the European (Non-Finnish) subpopulation of the gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 6 homozygotes in gnomAD v2.1.1 (BP2). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014157/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003467 infores:hetionet CHEBI:3698 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0013604 infores:hetionet CHEBI:64312 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0002962 infores:hetionet CHEBI:17303 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0002878 infores:hetionet CAID:CA915952202 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952202 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP1, PP4, PP3, PS4, PS3, PM6 The m.5001dupA variant in MT-ND2 has been reported in one individual with primary mitochondrial disease to date, in a child with developmental delay, seizures, and cardiomyopathy (PMIDs: 32652755, 23288206, 23463613). The variant was present at 99.5% in muscle and 15.9% in blood. The variant was not detected in the blood of the unaffected mother however additional details were not provided confirm de novo status. Decreased activities of complex I (46% controls) and complex I + III (47% controls), mitochondrial proliferation with increased citrate synthase activity, and elevated mitochondrial DNA content (153% of control) were reported, however additional clinical details such as tissue this was performed in and exclusion of other genetic etiologies was not provided (PMID: 32652755). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The duplication at base position m.5001 causes a frameshift at codon 178, creating a stop only 22 positions downstream. This causes a significant truncation (43%) of the ND2 protein (PVS1_strong). There are no cybrids, single fiber studies, or other key functional assays reported for this variant to date. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PVS1_strong). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952202/MONDO:0044970/015 2023-10-09 2024-08-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA248627 biolink:causes MONDO:0011071 infores:clingen CAID:CA248627 MONDO:0011071 PMID:27112265PMID:27112265PMID:27112265 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS3, BS1, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.4(RUNX1):c.442_449delACCGCAGC (p.Thr148Hisfs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27112265). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248627/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31348 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0035078 infores:hetionet CHEBI:8707 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0242422 infores:hetionet GO:2001212 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2001212 GO:0007275 CHEBI:17263 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0013390 infores:hetionet CHEBI:27565 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0151579 infores:hetionet CAID:CA410148448 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148448 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS2, PS4, BA1, BP1, BP4, BP5, BP7, BS1, PM6, PM1, PM5, PP2, PP3 NM_001754.5(RUNX1):c.1037G>C (p.Arg346Pro) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.666, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, but the splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148448/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:116278 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C3665386 infores:hetionet CHEBI:8435 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0041834 infores:hetionet CAID:CA296130 biolink:causes MONDO:0021060 infores:clingen CAID:CA296130 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.535C>T (p.Arg179Trp) variant in the MAP2K2 gene is 0.0362% (3/2258) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296130/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA269532860 biolink:causes MONDO:0007947 infores:clingen CAID:CA269532860 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PP1, PM2_Supporting, PS4_Supporting, PM6_Supporting The NM_00138 c.5826C>A, is a nonsense variant in FBN1 expected to cause a premature stop codon and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with infantile Marfan syndrome (MFS) and was found to be de novo without confirmation of parental relationships (internal data, PP4, PM6_Supporting). This variant has been reported 7 times in ClinVar, twice as pathogenic and five times as uncertain significance (Variantion ID: 547334). At least three other probands with clinical features of MFS carry the same variant (PMID 12068374, 22772377, Centre for Human Genetics ClinVar entry, PS4_Sup). In one family with features of MFS, including mitral valve prolapse, striae, pectus carinatum, scoliosis, striae, joint hypermobility, and wrist and thumb sign, this variant was found to segregate with disease in four affected family members (PMID 12068374, PP1). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4_Sup, PM2_Sup, PM6_Sup, PP1, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA269532860/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7809 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0151773 infores:hetionet CHEBI:18248 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0235886 infores:hetionet CHEBI:53760 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085593 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002334 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0376545 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0521634 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0521634 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0037274 infores:hetionet CHEBI:6950 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1522133 infores:hetionet CAID:CA2801887 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801887 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4_Moderate, PM2_Supporting, PS1_Supporting "The NM_000203.5:c.385+1G>C variant in IDUA occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3 out of 14 exons, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients from a Mexican cohort have been reported with ""low or no activity of α-L-iduronidase"" and treated with enzyme replacement therapy. One patient from Spain was reported with clinical features consistent with MPS1, elevated urine GAGs, and deficient IDUA activity, meeting three criteria for PP4 (PP4_Moderate). Both of the individuals from Mexico are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP - c.46_57del ((p.Ser16_Ala19del) (ClinVar variation ID: 92643) in one patient and c.1598C>G (p.Pro533Arg) (ClinVar variation ID: 11910) in the other patient. Phase was not confirmed in either patient (PMID: 25098213) (2 x 0.5 points = 1 point) (PM3). The patient from Spain is compound heterozygous for the variant and c.655G>C (p.Gy219Arg). The allelic data from this patient will be used in the classification of p.Gly219 Arg and is not included here to avoid circular logic. The variant is absent in gnomAD v4.1.0. (PM2_Supporting). Another variant at the same position, c.385+1G>A (ClinGen Allele Registry ID: CA355961228), has been classified as pathogenic by the ClinGen LD VCEP (PS1_Supporting, PMID: 37352859). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0: PVS1, PM3, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801887/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31485 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0858617 infores:hetionet CHEBI:51450 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0040586 infores:hetionet CHEBI:127342 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0424109 infores:hetionet CHEBI:18243 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0027540 infores:hetionet CHEBI:8863 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013456 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0009450 infores:hetionet CHEBI:3387 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0019214 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0853714 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235431 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0178298 infores:hetionet CHEBI:10101 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020598 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C3665347 infores:hetionet NCBIGene:23495 biolink:causes MONDO:0009413 infores:monarchinitiative not_provided not_provided HGNC:18153 MONDO:0009413 uuid:be46341b-5473-4ff9-b987-b73579cc06c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0086565 infores:hetionet CAID:CA8815492 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815492 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PP3, PP4, PM5, PM3, BP4 The NM_000152.5:GAA:c.1828G>A variant in GAA is a missense variant predicted to cause substitution of Ala by Thr at amino acid 610 (p.Ala610Thr). Two patients with this variant have been reported in the literature (PMID: 32504392, 35775064). However, because the diagnosis of Pompe disease was unclear for both patients, neither PP4 nor PM3 was applied. One of these patients, a 4-year-old girl with IOPD identified as homozygous for GAA:c.1828G>A, was also diagnosed with congenital myasthenia syndrome type 5. Because her symptoms, which included bradycardia, poor suckling, respiratory distress, respiratory failure, subglottic stenosis, and tachypnea, could be related to congenital myasthenia syndrome and not Pompe disease, and GAA activity was unavailable, this data was not used as evidence to support pathogenicity of the variant. Another individual was reported to be compound heterozygous for c.1828G>A and c.1966-1968del, but clinical information regarding the presence or absence of clinical symptoms of Pompe disease, and GAA activity was unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000439 (4/91034 alleles) in the South Asian population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.641 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met), and the computational splicing predictor SpliceAI gives a score of 0.00 for donor/acceptor loss suggesting that the variant has no impact on splicing. Another missense variant c.1829C>T (p.Ala610Val) in the same codon has been reported (PMID: 21484825, 17643989). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 282242). In summary, this variant meets the criteria to be classified as uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0.0): PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 26, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815492/MONDO:0009290/010 2025-06-26 2025-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true NCBIGene:1277 biolink:causes MONDO:0007244 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0007244 uuid:87f0c72b-0dee-4288-a5f0-19080e7b1f79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0037274 infores:hetionet CHEBI:61049 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011175 infores:hetionet CHEBI:367163 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0232462 infores:hetionet CHEBI:3215 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0007222 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0007097 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0041969 infores:hetionet CHEBI:3082 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0024141 infores:hetionet CHEBI:4356 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0013404 infores:hetionet CHEBI:37924 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0013404 infores:hetionet NCBIGene:8309 biolink:causes MONDO:0015015 infores:monarchinitiative not_provided not_provided HGNC:120 MONDO:0015015 uuid:e5694535-192b-43c8-87a2-4bb008484306 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C2129214 infores:hetionet CHEBI:48131 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0030193 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0259799 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0233494 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030312 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0948594 infores:hetionet GO:0098689 biolink:causes GO:0019042 infores:ubergraph knowledge_assertion manual_agent GO:0098689 GO:0019042 CAID:CA2837995559 biolink:causes MONDO:0015152 infores:clingen CAID:CA2837995559 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1_Moderate, PP1, PM2_Supporting The NC_000002.12: g.71599650_71600993del (GRCh38) variant is a deletion that encompasses exon 34 of the DYSF gene, r.3703_3843del based on NM_003494.4. RNAseq analysis in an individual with this variant demonstrated skipping of exon 34 and an inframe deletion, p.Gly1235_Lys1281del (PMID: 36983702; PVS1_Moderate_RNA). This variant has been identified in trans with a likely pathogenic or pathogenic variant in an individual with LGMD (NM_003494.4: c.3051dup p.(Ile1018HisfsTer14), 1.0 pt, PMID: 36983702) (PM3). This patient displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle and by blood monocyte assay, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant was also reported to co-segregate with the LGMD phenotype in one affected family member, the affected sister of the proband (PP1; PMID: 36983702). Similar deletions of this exon are not observed in gnomAD SVs or CNVs v4.1.0 or in the Database of Genomic Variants (PMID: 24174537) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/30/2025): PVS1_Moderate_RNA, PM3, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2837995559/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45409 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0016436 infores:hetionet GO:1902276 biolink:causes GO:0007586 infores:ubergraph knowledge_assertion manual_agent GO:1902276 GO:0007586 CHEBI:145499 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2047937 infores:hetionet CHEBI:50730 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0233763 infores:hetionet CHEBI:104011 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0002792 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0017178 infores:hetionet CHEBI:10101 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0019345 infores:hetionet CAID:CA658657473 biolink:causes MONDO:0021056 infores:clingen CAID:CA658657473 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PS3_Moderate, PM2_Supporting The NM_000038.6(APC):c.423-9A>G variant in APC is an intronic variant which is localized in intron 4. This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, internal data Labcorp Genetics (formerly Invitae)). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (internal data Labcorp Genetics (formerly Invitae)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by creating a new acceptor splice site and disrupting the native acceptor splice site of intron 4 of APC, resulting in the insertion of the 8 last bp of intron 4 (PP3). RT-PCR and mini-gene demonstrated that the variant impacts splicing by insertion of the last 8 bp of intron 4 resulting in a premature stop codon (PS3_Moderate, PMID: 24599579). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS3_Moderate, PS4_Moderate, PM2_Supporting, PP3 (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658657473/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63580 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042029 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030305 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0027651 infores:hetionet CHEBI:4974 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0027441 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0003123 infores:hetionet CAID:CA367398808 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398808 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP2, PP3, PM2_Supporting PS4, PM1, PP1, PP4 The c.1132G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 378 (p.(Ala378Pro)) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, there is only 1 filtered allele present (≤ 1 copy in any subpopulation), thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting) GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The c.1133C>T, p.(Ala378Val) and c.1132G>A, p.(Ala378Thr) variants have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 22035297, 24918535, internal lab contributor). One of these individuals had HbA1c 5.6 - 7.6%; however, the fasting glucose exceeded mmol/L, and PP4 could not be applied, and there was insufficient clinical data provided for the other individual to evaluate for PP4 (PMIDs: 22035297, 24918535; internal lab contributor). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 22035297). In summary, c.1132G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398808/MONDO:0015967/086 2023-10-03 2023-10-03 Semidominant inheritance HP:0032113 Supports CHEBI:6472 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0042571 infores:hetionet CHEBI:3175 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0041834 infores:hetionet CHEBI:6887 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0241934 infores:hetionet CHEBI:84883 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0035455 infores:hetionet CHEBI:44423 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C2939420 infores:hetionet CHEBI:16755 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0043094 infores:hetionet CHEBI:8863 biolink:causes MONDO:0016588 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0001198 infores:hetionet CAID:CA147047 biolink:causes MONDO:0100084 infores:clingen CAID:CA147047 MONDO:0100084 PMID: Benign BP4, BA1, BP7 The NM_001100.4(ACTA1):c.809-13dup variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.2123 (1318/5930) in the Middle Eastern population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The c.809-13dup is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA147047/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:119573 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020453 infores:hetionet CHEBI:8356 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0236024 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0948349 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0037274 infores:hetionet CHEBI:17303 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0012569 infores:hetionet CHEBI:135285 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0027765 infores:hetionet CHEBI:2569 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C2830004 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0035078 infores:hetionet CHEBI:8214 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C1443060 infores:hetionet CHEBI:7454 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0038999 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027651 infores:hetionet CHEBI:119915 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013362 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0235290 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036572 infores:hetionet CHEBI:31643 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0036572 infores:hetionet CHEBI:94807 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0031350 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0344320 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0278107 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0278107 infores:hetionet CHEBI:8430 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0011991 infores:hetionet NCBIGene:23499 biolink:causes MONDO:0032677 infores:monarchinitiative not_provided not_provided HGNC:13664 MONDO:0032677 uuid:9f8e4ad5-e3f2-48ae-a0c6-3146d381aed3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0023530 infores:hetionet CHEBI:7465 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0455769 infores:hetionet NCBIGene:55704 biolink:causes MONDO:0020495 infores:monarchinitiative not_provided not_provided HGNC:25523 MONDO:0020495 uuid:97bad2ab-2e71-4761-b552-8f49c6b92539 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0151671 infores:hetionet CAID:CA16602490 biolink:causes MONDO:0011071 infores:clingen CAID:CA16602490 MONDO:0011071 PMID: Uncertain Significance PM1, PM2_Supporting, PP3 PS3, PS4, PS2, PS1, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.485G>A (p.Arg162Lys) is a missense variant which affects one of the following hotspot residues within the RHD: R162 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score of 0.949 (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602490/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5106 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0033774 infores:hetionet CHEBI:4027 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0239937 infores:hetionet CHEBI:2569 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0012833 infores:hetionet CAID:CA396471960 biolink:causes MONDO:0007648 infores:clingen CAID:CA396471960 MONDO:0007648 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PVS1_Strong BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM5, PM4, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.2446A>T (p.Lys816Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein within the NMD-resistant zone and located upstream the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in one family meeting clinical criteria for HDGC (PS4_Supporting; PMID: 29798843). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel(Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396471960/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:17334 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0009676 infores:hetionet CHEBI:107736 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0151564 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0031542 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027769 infores:hetionet CHEBI:10119 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022568 infores:hetionet CHEBI:135939 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0233794 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C2979982 infores:hetionet CHEBI:63584 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0003467 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0917798 infores:hetionet CHEBI:3207 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0017675 infores:hetionet CAID:CA1393780 biolink:causes MONDO:0019501 infores:clingen CAID:CA1393780 MONDO:0019501 PMID: Pathogenic PM3_Supporting, PM2_Supporting, PVS1 BP5, BP7, BS4, BS1, PP4, PP1, PP3, BS2, PM1, PM4, PM5, PM6, BP2, BP3, BP4, BA1, PS2, PS4, PS3, PS1 The p.Tyr3747X variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 58/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Tyr3747X variant in the Ush2A gene is 0.017% (4/24020) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss ( PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a suspected pathogenic variant (PM3_Supporting, Partners LMM internal data SCV000713838.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Supporting. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1393780/MONDO:0019501/005 2018-09-17 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:52717 biolink:causes UMLS:C0877325 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0877325 infores:hetionet CHEBI:3215 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0344232 infores:hetionet CHEBI:2569 biolink:causes UMLS:C1319200 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C1319200 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0426576 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0332575 infores:hetionet CHEBI:5847 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0038362 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0007137 infores:hetionet CHEBI:27690 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0042963 infores:hetionet CAID:CA320255462 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255462 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.952T>C (p.Ser318Pro) is a missense variant which has a REVEL score < 0.50 (0.188) and a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255462/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0879264 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0040822 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0857093 infores:hetionet CHEBI:74947 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003467 infores:hetionet CHEBI:63624 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0027497 infores:hetionet CHEBI:168396 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030232 infores:hetionet NCBIGene:30062 biolink:causes MONDO:0012604 infores:monarchinitiative not_provided not_provided HGNC:18662 MONDO:0012604 uuid:0594c627-c32f-4de7-aab7-6c20578815c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31644 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013604 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0232492 infores:hetionet CHEBI:28487 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C1368065 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0042373 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0038454 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0221100 infores:hetionet CHEBI:63581 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0018681 infores:hetionet CHEBI:94807 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0018681 infores:hetionet CHEBI:64355 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018944 infores:hetionet CHEBI:6076 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0039070 infores:hetionet CAID:CA367403604 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403604 MONDO:0015967 PMID: Likely Pathogenic PS4, PP4_Moderate, PP2, PP3, PM2_Supporting PS3, PM1, PM5 The c.98T>C variant in the glucokinase gene, GCK, causes an amnio acid change of valine to alanine at codon 33 (p.(Val33Ala)) of NM_000162.5. This variant was identified in at least 17 unrelated individuals with hyperglycemia (PS4; PMID: 22332836, 26641800, 36257325 internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative (PP4_Moderate; internal lab contributors). The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and thermostability was not evaluated; therefore PS3 was not applied (PMID: 28842611). Additional missense variants at the same codon, c.98T>A p.(Val33Glu) and c.98T>G p.(Val33Gly) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.98T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PM2_Supporting, PP2, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403604/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports CHEBI:6456 biolink:causes MONDO:0006650 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0221069 infores:hetionet CHEBI:9130 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0004238 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0032285 infores:hetionet CHEBI:31348 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013428 infores:hetionet CHEBI:27504 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0042963 infores:hetionet CHEBI:7476 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0234233 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0006826 infores:hetionet CHEBI:5893 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1260880 infores:hetionet CHEBI:9328 biolink:causes MONDO:0019170 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0031036 infores:hetionet CHEBI:5001 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0011991 infores:hetionet CHEBI:45367 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0014724 infores:hetionet CHEBI:9927 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0027497 infores:hetionet NCBIGene:23203 biolink:causes MONDO:0008943 infores:monarchinitiative not_provided not_provided HGNC:18667 MONDO:0008943 uuid:aca47b16-ffde-48fe-89a4-2dd52064b654 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5784 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0020456 infores:hetionet CHEBI:3696 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151539 infores:hetionet CHEBI:7465 biolink:causes MONDO:0021661 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0010054 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002170 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0000735 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0000735 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0152128 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0235969 infores:hetionet CHEBI:94449 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0027441 infores:hetionet CAID:CA314834 biolink:causes MONDO:0012999 infores:clingen CAID:CA314834 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_000156.6:c.689C>T variant in GAMT is a missense variant in exon 6, predicted to result in the substitution of threonine for methionine at amino acid 230 (p.Thr230Met). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00008784 (8/91070 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.48 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function. SpliceAI predicts that the variant has no impact on splicing. To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205595). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting(Classification approved by the ClinGen CCDS VCEP on April 25, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314834/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:38940 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0149871 infores:hetionet CHEBI:61033 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1384353 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0020458 infores:hetionet CHEBI:59773 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0020523 infores:hetionet CHEBI:2950 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C1510410 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0021308 infores:hetionet CHEBI:4681 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0011991 infores:hetionet CHEBI:553473 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0007642 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0235416 infores:hetionet CHEBI:2663 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0021368 infores:hetionet NCBIGene:55130 biolink:causes MONDO:0014193 infores:monarchinitiative not_provided not_provided HGNC:25583 MONDO:0014193 uuid:344a22a9-1d5c-400a-88ab-2022d999b282 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3314 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0030554 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0344232 infores:hetionet CHEBI:473990 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0917801 infores:hetionet CHEBI:63681 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0000737 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0032285 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0030554 infores:hetionet CAID:CA255098 biolink:causes MONDO:0010602 infores:clingen CAID:CA255098 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM5_Supporting, PM2_Supporting, PP3, PS4_Moderate PM1 The variant, NM_000132.3(F8):c.1214T>G causes a missense change, Ile405Ser, which is not reported in gnomAD v2.1.1 or v3 or v4. This variant has been reported in at least three patients with Hemophilia A in the literature (PS4_Moderate, PP4_Moderate, PMIDs: 8307558). The variant has a REVEL score of 0.985 (PP3 threshold >0.6). Another variant at the same codon, Ile405Thr, is curated by the Coagulation Factor Deficiency Variant Curation Expert Panel as likely pathogenic (PM5_Supporting). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255098/MONDO:0010602/071 2024-06-19 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5001 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0687133 infores:hetionet CHEBI:68558 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0019079 infores:hetionet CHEBI:8232 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0015672 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0031350 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0017658 infores:hetionet CHEBI:61033 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0220983 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0700345 infores:hetionet CHEBI:7852 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0423153 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0003123 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040425 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0085082 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085082 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0028259 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0007222 infores:hetionet CHEBI:64355 biolink:causes HP:0002152 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0267988 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0014549 infores:hetionet CHEBI:6067 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151907 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0008717 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0008717 uuid:c58d2155-d579-4008-b01f-85b2b504e2a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA261445 biolink:causes MONDO:0010134 infores:clingen CAID:CA261445 MONDO:0010134 PMID:10874637PMID:10874637PMID:23151025PMID:23151025 Pathogenic PP1_Strong, BS1, PM3_Very Strong, PVS1 BS4, BP5, BP7, BS2, PP4, PP3, PM1, PM5, PM4, PM6, PM2, BP2, BP3, BP4, BA1, PS2, PS4, PS3, PS1 The filtering allele frequency of the c.919-2A>G variant in the SLC26A4 gene is 0.4% for East Asian chromosomes in the Genome Aggregation Database (91/18860 with 95% CI) , which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, the c.919-2A>G variant in SLC26A4 is predicted to cause the skipping of a biologically-relevant out-of-frame exon 8. This is then expected to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). Additionally, this variant has been detected in 16 patients with hearing loss in trans with more than 4 pathogenic variants (PM3_VeryStrong; PMID: 23151025). The c.919-2A>G variant in SLC26A4 has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; 10874637). Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PP1_Strong, PM3_VeryStrong, BS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261445/MONDO:0010134/005 2018-09-20 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:209807 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0086565 infores:hetionet CHEBI:6633 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0857807 infores:hetionet CHEBI:7915 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0016655 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0007222 infores:hetionet CHEBI:101853 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0040822 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235146 infores:hetionet CAID:CA024065 biolink:causes MONDO:0007783 infores:clingen CAID:CA024065 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Glutamine at codon 4558 of the RYR1 protein, p.(Arg4558Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0001, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with a personal or family history of congenital myopathy. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.957) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024065/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45783 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0220870 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0004238 infores:hetionet CHEBI:8346 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0728899 infores:hetionet NCBIGene:256471 biolink:causes MONDO:0012588 infores:monarchinitiative not_provided not_provided HGNC:28486 MONDO:0012588 uuid:a728ea4f-2371-4eaf-88bf-ca36fc9cd5cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042024 infores:hetionet CHEBI:48273 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0025345 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0152128 infores:hetionet CHEBI:15367 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013428 infores:hetionet CHEBI:10023 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0221242 infores:hetionet CAID:CA221485 biolink:causes MONDO:0100084 infores:clingen CAID:CA221485 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PM6 The variant NM_001100.4:c.442G>A in ACTA1 is a missense variant predicted to cause substitution of glycine by serine at amino acid 148 (p.Gly148Ser). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.935, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Two different missense variants, p.Gly148Arg and p.Gly148Val (Variation IDs: 280732 and 2582809), in the same codon have been classified as likely pathogenic for alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5 applied to p.Gly148Val). This variant has been reported in 3 probands with alpha-actinopathy, and one of these probands had a de novo occurrence of the variant with parental relationships unconfirmed (PS4_Supporting, PM6; PMIDs: 19562689, 32222963. SCV000680134.1). In summary, this variant meets the criteria to be classified as likely pathogenic for AD alpha-actinopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP (Specification Version 2.0.0): PM2_Supporting, PP3, PP2, PS4_Supporting, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 3/10/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA221485/MONDO:0100084/147 2025-03-10 2025-04-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119915 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0344232 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0034069 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0233414 infores:hetionet CHEBI:7824 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0231528 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011991 infores:hetionet CHEBI:135613 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0151827 infores:hetionet CHEBI:32293 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0009806 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0007222 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0008035 infores:hetionet CHEBI:6887 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0036974 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0017178 infores:hetionet CHEBI:49960 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0014591 infores:hetionet NCBIGene:54928 biolink:causes MONDO:0013561 infores:monarchinitiative not_provided not_provided HGNC:26019 MONDO:0013561 uuid:c2ca7e6d-0895-4264-829a-d58f5e7e9606 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes UMLS:C0000735 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0000735 infores:hetionet CHEBI:9927 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0232462 infores:hetionet CHEBI:8707 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020458 infores:hetionet CAID:CA10585455 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585455 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, BS2, PP1, PP4 The NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June, 2023. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.99. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines; - NM_000527.5(LDLR):c.1444G>C (p.Asp482His) (ClinVar ID 251844) - Likely Pathogenic by these guidelines; - NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) (ClinVar ID 251846) - Likely Pathogenic by these guidelines;There is 1 variant in the same codon classified as Pathogenic by these guidelines. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585455/MONDO:0007750/013 2023-06-23 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:84883 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0010200 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0002170 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018801 infores:hetionet CHEBI:49575 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0438717 infores:hetionet CHEBI:45409 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042023 infores:hetionet CHEBI:42797 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085632 infores:hetionet CHEBI:15544 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0855775 infores:hetionet CHEBI:9086 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013144 infores:hetionet CHEBI:8869 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0025320 infores:hetionet CHEBI:17334 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0030193 infores:hetionet CHEBI:8430 biolink:causes NCIT:C50643 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0270697 infores:hetionet CHEBI:2618 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0022660 infores:hetionet CHEBI:194135 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C2830004 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0007117 infores:hetionet CHEBI:49662 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013384 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0021053 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0040584 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0220981 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005526 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0039614 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0020649 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013595 infores:hetionet CHEBI:681569 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0029163 infores:hetionet CHEBI:10100 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0001824 infores:hetionet CHEBI:87681 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0020580 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0497365 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0032131 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006444 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0018799 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0031350 infores:hetionet CHEBI:10119 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0043094 infores:hetionet CHEBI:3207 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0424295 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0151908 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0547000 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0547000 infores:hetionet CHEBI:145499 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0870082 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0042963 infores:hetionet CAID:CA16020729 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020729 MONDO:0009861 PMID:26503515 Pathogenic PVS1, PM2, PP4 The c.127G>T (p.Glu43*) variant is a nonsense variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 2 individuals with PKU (BH4 deficiency not excluded). (PP4; PMID: 26503515). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020729/MONDO:0009861/006 2019-04-03 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5165 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0036974 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0008489 infores:hetionet CHEBI:28830 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0014518 infores:hetionet NCBIGene:539 biolink:causes MONDO:0957255 infores:monarchinitiative not_provided not_provided HGNC:850 MONDO:0957255 uuid:11f6bcf4-47f4-4776-84b2-2d57ab9f14cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0041909 infores:hetionet NCBIGene:351 biolink:causes MONDO:0011583 infores:monarchinitiative not_provided not_provided HGNC:620 MONDO:0011583 uuid:63343bc4-71bc-4a61-8b02-365093871835 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013595 infores:hetionet CHEBI:35854 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0034882 infores:hetionet CHEBI:63621 biolink:causes HP:0004386 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1535950 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0039584 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0242350 infores:hetionet UMLS:C0657912 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020625 infores:hetionet GO:0050920 biolink:causes GO:0042221 infores:ubergraph knowledge_assertion manual_agent GO:0050920 GO:0042221 CHEBI:2569 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0013384 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0234894 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0549386 infores:hetionet CHEBI:85078 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042075 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0269189 infores:hetionet CHEBI:50729 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0010200 infores:hetionet CHEBI:16714 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0043352 infores:hetionet CHEBI:9605 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0027497 infores:hetionet CHEBI:9328 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0020615 infores:hetionet UMLS:C0145867 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0027497 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0006325 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0347941 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0347941 infores:hetionet CHEBI:3419 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0042769 infores:hetionet CHEBI:17698 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0235266 infores:hetionet CHEBI:5558 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0086439 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0342579 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0231303 infores:hetionet CAID:CA7724139 biolink:causes MONDO:0044970 infores:clingen CAID:CA7724139 MONDO:0044970 PMID: Uncertain Significance BP7 BA1, PM2, BS1 The c.3451C>T (p.L1151L) variant in POLG is present in population databases ExAC at 0.11% frequency and not observed in homozygotes (no criteria is met). There is limited computational predictions and the tool Revel unavailable given limited data. This variant is a coding synonymous change (BP7). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BP7 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA7724139/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:85161 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0012833 infores:hetionet CHEBI:5132 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C2830004 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235620 infores:hetionet CHEBI:3423 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0040822 infores:hetionet CHEBI:3398 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0349506 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0403632 infores:hetionet CHEBI:46557 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0231528 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0039971 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0037928 infores:hetionet CHEBI:4798 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0018681 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0162429 infores:hetionet NCBIGene:1200 biolink:causes MONDO:0012235 infores:monarchinitiative not_provided not_provided HGNC:2073 MONDO:0012235 uuid:bbaff26f-1fb6-42ae-a023-6df84ac425ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59773 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0009806 infores:hetionet CHEBI:9139 biolink:causes MONDO:0042495 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0339478 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017168 infores:hetionet NCBIGene:55361 biolink:causes MONDO:0958240 infores:monarchinitiative not_provided not_provided HGNC:30031 MONDO:0958240 uuid:29fd57d2-390a-447d-aac6-c08f74d8a6b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0000737 infores:hetionet CHEBI:5790 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0011991 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002187 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042994 infores:hetionet CHEBI:94609 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0003862 infores:hetionet CHEBI:6129 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042023 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0009806 infores:hetionet CHEBI:209807 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0033774 infores:hetionet CHEBI:7627 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0030196 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0948089 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0007114 infores:hetionet CAID:CA000526 biolink:causes MONDO:0017623 infores:clingen CAID:CA000526 MONDO:0017623 PMID:9832032 Pathogenic PVS1, PM2, PS4_Supporting PM6, BP5, BP7, BS4, BS3, BS1, PP4, PP1, PP2, PP3, BS2, PM1, PM4, PM5, BA1, BP2, BP4, PS2, PS3, PS1 PTEN c.586delC (p.H196Tfs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 9832032) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000526/MONDO:0017623/003 2018-04-06 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:5624 biolink:causes MONDO:0012860 infores:monarchinitiative not_provided not_provided HGNC:9451 MONDO:0012860 uuid:23e4a86b-cdc9-4618-9dea-86cdb52166a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0019158 infores:hetionet CHEBI:27882 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0040034 infores:hetionet CHEBI:7959 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0018965 infores:hetionet CHEBI:8802 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1096343 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0238201 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0238201 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0019158 infores:hetionet CHEBI:27300 biolink:causes MONDO:0009876 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0013336 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0009806 infores:hetionet CHEBI:9649 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0015967 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0877517 infores:hetionet CAID:CA7435533 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435533 MONDO:0007113 PMID: Likely Benign BP4, BP7 BS1 The c.1422T>C p.Asn474= variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0062% in the European (non-Finnish) sub population (no criteria met). The silent p.Asn474= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1422T>C p.Asn474= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435533/MONDO:0007113/032 2023-06-16 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA10014396 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014396 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-11C>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.27)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014396/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0341012 infores:hetionet CHEBI:4708 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0041657 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0178298 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0022658 infores:hetionet CAID:CA8815855 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815855 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting PS1 The NM_000152.5:c.2799+4A>G is located in the donor splice site region of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.62 for donor loss, predicting that the variant disrupts the donor splice site of this intron (PP3). Two individuals with Pompe disease have been reported to have this variant; one has documentation of deficient GAA activity and is on enzyme replacement therapy (PMID: 26873529) (PP4_Moderate), and the second patient has limb girdle muscular dystrophy (PMID: 30564623). Both individuals are compound heterozygous for this variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.1548G>A (p.Trp516Ter) (PMID: 26873529) or c.2501_2502delCA (PMID: 30564623); the phase is unknown in each case (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005338 (4/74932 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Additional variants in this splice region have been identified, including c.2799+2C>T, c.2799+2C>A, and c.2799+5G>A (PMID: 28265479); all currently classified by the ClinGen LD VCEP as variants of uncertain significance. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, Sept. 16, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815855/MONDO:0009290/010 2025-09-16 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA350399236 biolink:causes MONDO:0015924 infores:clingen CAID:CA350399236 MONDO:0015924 PMID: Uncertain Significance PM2, PM1 PP3, BP4, BA1, PM5, PS4, PS1, BS1 The NM_001204.7(BMPR2):c.140G>A (p.Gly47Asp) variant is a missense variant located within exon 2 of BMPR2, predicted to cause substitution of glycine to an aspartic acid. This variant is located within the conserved extracellular domain of the protein but does not affect a known critical residue (PM1_moderate). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.55, which is below our threshold of >=0.75 for pathogenicity (PP3_not met) and above our threshold for benignity (BP4 not met). The variant has been reported in an individual with PAH associated with congenital heart disease (PMID: 15358693) but not in patients with hereditary or idiopathic PAH (PS4 not met). Alternative alleles at the same nucleotide or amino acid have not been reported (PS1 and PM5 not met). Functional studies have not been reported (PS3, not evaluated). Neither segregation or maternity/paternity studies have not been reported (PS2, PP1, BS4 not evaluated). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350399236/MONDO:0015924/125 2025-01-22 2025-01-22 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31644 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0030193 infores:hetionet CHEBI:9398 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0085649 infores:hetionet NCBIGene:1576 biolink:causes MONDO:0033640 infores:monarchinitiative not_provided not_provided HGNC:2637 MONDO:0033640 uuid:477ea006-5b76-4ab5-90ac-0f9b95bd53af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes NCIT:C54356 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151598 infores:hetionet CAID:CA16020933 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020933 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2, PVS1, PM3_Strong This variant c.1071C>A (p.Cys357Ter) in PAH was reported with pathogenic variants p.Val399=, p.Arg243Gln and c.721C>T in 3 patients with PAH deficiency. BH4 deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay for 1 patient. (PMID: 28754886, 28982351, 31445982). This is a nonsense variant in exon 11 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay. The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 strong, PM2, PP4 moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020933/MONDO:0009861/006 2020-12-07 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5959 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0476280 infores:hetionet CHEBI:6904 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0086565 infores:hetionet CAID:CA2499225755 biolink:causes MONDO:0015967 infores:clingen CAID:CA2499225755 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PM1 The c.-181G>C p.(?) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the promoter region of NM_175914.5. This variant is located within the HNF1A/HNF1B binding region (c.-170 to c.-173 and c.-178 to c.-181) of the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.-181G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PP4, PM1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225755/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:116278 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0086565 infores:hetionet NCBIGene:6389 biolink:causes MONDO:0031006 infores:monarchinitiative not_provided not_provided HGNC:10680 MONDO:0031006 uuid:944d5f04-ecf7-4957-9c39-c85e3bb0e6a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013395 infores:hetionet CHEBI:41977 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0006384 infores:hetionet CHEBI:80630 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C2830004 infores:hetionet CHEBI:7820 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0702166 infores:hetionet CAID:CA390864653 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864653 MONDO:0100216 PMID: Uncertain Significance PP3, PM2_Supporting, PM1, PS3_Supporting PM6, BA1, BP1, BP4, BP2, BP3, PP2, PP1, PP4, BS2, PM5, PM3, PM4, PS1, PS4, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.5438A>C variant in DICER1 is a missense variant predicted to cause substitution of Glutamic acid by Alanine at amino acid 1813 (p.Glu1813Ala). Although this variant has been observed in low variant allele fraction cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Glu1813Ala showed that this variant reduces the capacity of the protein to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; PMID: 15242644, 17920623, 23132766). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.949) (PP3). This variant resides in the p.E1813 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1; PMID: 31342592). This variant is a hotspot variant reported as a somatic finding in many individuals both with and without a separate germline DICER1 variant. This variant has been observed at low allele fraction in two probands with cancer diagnoses outside the recognized DICER1 spectrum (Internal laboratory contributors). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS3_Supporting, PM2_Supporting, PP3, PM1. (Bayesian Points: 5; VCEP specifications version 1.3.0; 01/07/2025). Although available evidence supports germline pathogenicity of recurrent DICER1 somatic hotspot variants (PMID: 26925222), the clinical significance of this variant in the germline remains uncertain at this time since it has not yet been observed in the germline of an individual with a recognized DICER1 phenotype. DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864653/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63624 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0017152 infores:hetionet CHEBI:36791 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0012569 infores:hetionet CHEBI:135342 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0040822 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0003864 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0160390 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0031117 infores:hetionet CHEBI:47426 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0232849 infores:hetionet NCBIGene:56983 biolink:causes MONDO:0014977 infores:monarchinitiative not_provided not_provided HGNC:22954 MONDO:0014977 uuid:a6c80c78-4dfd-40a7-9f5a-a983d28e4a29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA6832105 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832105 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate PS4, PM2, PP3 The c.1544C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 515 (p.(Thr515Met)) of NM_000545.8. This variant has a REVEL score of 0.673, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. The Grpmax filtering allele frequency of the c.1544C>T variant in gnomAD v4.1.0 is 0.00001627, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 29666556, PMID: 29207974, internal lab contributor). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, antibody negative, and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributor). In summary, the c.1544C>T variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0, approved 6/30/2025): PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832105/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63621 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0853692 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023533 infores:hetionet CHEBI:8774 biolink:causes HP:0004386 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1535950 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002874 infores:hetionet CHEBI:5165 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0034886 infores:hetionet CAID:CA410148738 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148738 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.992G>C (p.Ser331Thr) is a missense variant which has a REVEL score < 0.50 (0.079) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148738/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45863 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0547030 infores:hetionet CHEBI:7581 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0037763 infores:hetionet CHEBI:7465 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0015230 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0017152 infores:hetionet CHEBI:83804 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0080274 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0241426 infores:hetionet CHEBI:9566 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0003811 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0948349 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0849925 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0849925 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0013395 infores:hetionet CHEBI:7496 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C1443060 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0221100 infores:hetionet NCBIGene:1213 biolink:causes MONDO:0030922 infores:monarchinitiative not_provided not_provided HGNC:2092 MONDO:0030922 uuid:1aa66e81-479b-47bb-a035-b8c876fec1cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0080274 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0015672 infores:hetionet CHEBI:6931 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0006266 infores:hetionet CHEBI:6809 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0600228 infores:hetionet CHEBI:135961 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0015672 infores:hetionet CHEBI:63632 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0085593 infores:hetionet CHEBI:4888 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0012833 infores:hetionet CAID:CA038621 biolink:causes MONDO:0007750 infores:clingen CAID:CA038621 MONDO:0007750 PMID: Uncertain Significance PM2 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.2106G>C (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003294 (0.0033%) in South Asian exomes (gnomAD v4.1.0). It is below 0.02%, so PM2 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038621/MONDO:0007750/013 2024-08-30 2024-10-03 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UNII:R43D2573WO biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0232493 infores:hetionet GO:1901207 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0072359 CHEBI:63581 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0595939 infores:hetionet GO:1900055 biolink:causes GO:0048367 infores:ubergraph knowledge_assertion manual_agent GO:1900055 GO:0048367 CAID:CA916563969 biolink:causes MONDO:0015152 infores:clingen CAID:CA916563969 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3, PP1 The NM_003494.4: c.125dup p.(Asn43GlufsTer6) variant in DYSF, which is also known as NM_001130987.2: c.128dup (p.Asn44GlufsTer6), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in one individual with a diagnosis of Miyoshi myopathy, where it was identified in unknown phase with a second DYSF variant that can be classified as likely pathogenic independent of its observation in this patient (NM_003494.4: c.5159del p.(Arg1720LeufsTer2), 0.25 pts, PMID: 36983702; PM3_Supporting not met). This patient showed both progressive limb girdle muscle weakness and disease range dysferlin expression in blood monocytes (PMID: 36983702, Jain Foundation Registry internal data communication; PP4_Strong). The affected sibling of this patient carried the same two DYSF variants and also had disease range dysferlin protein expression in blood monocytes, but segregation could not be scored since the phase of the variants was not confirmed (PP1 not met). This variant is absent from gnomAD v2.1.1 and v4.1.0, although a different variant resulting in the same frameshift is present on one allele (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916563969/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3077 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1510472 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0038941 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0038941 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0038362 infores:hetionet CAID:CA399802403 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802403 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting PM3, PP3 The NM_000419.5(ITGA2B):c.1622T>A (p.Leu541Gln) missense variant has been reported at least once, GT19 (PMID: 32237906) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIb surface expression was reduced to 0.371%, as measured by flow cytometry. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_moderate, PM2_supporitng. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802403/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9288 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0011991 infores:hetionet CHEBI:7865 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0233477 infores:hetionet CHEBI:116278 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0034063 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0014868 infores:hetionet CHEBI:44915 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0019080 infores:hetionet CAID:CA413496915 biolink:causes MONDO:0010315 infores:clingen CAID:CA413496915 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.281C>A (p.Ser94Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).The variant is absent in gnomAD v4 (PM2_supporting). Male Patient (0.5 pt.) with SCID (0.5 pt.) (Total : 1 pt. , PP4 met, PMID: 23250629).In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1,PM2_supporting,PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413496915/MONDO:0010315/129 2024-06-12 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:63631 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009806 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0234215 infores:hetionet CHEBI:119486 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0032617 infores:hetionet CHEBI:3013 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0030305 infores:hetionet CHEBI:9635 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0043094 infores:hetionet CHEBI:17688 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C3257803 infores:hetionet CHEBI:6822 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0042571 infores:hetionet CHEBI:71219 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0333355 infores:hetionet CHEBI:31643 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0948525 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0239488 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0233632 infores:hetionet CHEBI:5558 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0042024 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0870082 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0011570 infores:hetionet CHEBI:2637 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0011603 infores:hetionet CHEBI:6715 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027497 infores:hetionet CHEBI:44915 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151539 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0497209 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0497209 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151588 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151588 infores:hetionet CAID:CA254380 biolink:causes MONDO:0012999 infores:clingen CAID:CA254380 MONDO:0012999 PMID:24415674 Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting, PP3_Moderate, PS3_Supporting PM5 The NM_000156.6:c.148A>C variant in GAMT is predicted to result in the substitution of methionine by leucine at amino acid 50 (p.Met50Leu). One individual has been reported who was homozygous for the variant and had a low creatine peak on brain MRS, elevated urinary GAA, low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PMID: 17101918, 24415674) (PM3_Supporting, PP4_Strong). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.923 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications Version 2.0.0): PP4_Strong, PP3_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA254380/MONDO:0012999/025 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15640 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0231218 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042769 infores:hetionet CHEBI:101853 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0020433 infores:hetionet CAID:CA229585 biolink:causes MONDO:0009861 infores:clingen CAID:CA229585 MONDO:0009861 PMID:11385716 Uncertain Significance PP4, BS1 PP3 PAH-specific ACMG/AMP criteria applied: PP4: N167S was observed in 1 case (genotype N167S/-) with benign persistent hyperphenylalaninemia (200-600 uM). (PMID:11385716); BS1: gnomAD MAF: 0.01461. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, BS1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229585/MONDO:0009861/006 2018-08-13 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8764 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019572 infores:hetionet CHEBI:9086 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030193 infores:hetionet CHEBI:52172 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0043144 infores:hetionet CAID:CA8129836 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129836 MONDO:0007648 PMID: Likely Benign BS2 BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM1, PM3, PM4, PM5, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS3, PS2, PS1 The c.370C>T (p.Arg124Cys) missense variant has a frequency of 0.039% in South Asians (12/30610 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in ≥10 (62) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; PMID: 30287823, SCV000288481.8, SCV000661624.3). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129836/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:10023 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013378 infores:hetionet CHEBI:3387 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0039231 infores:hetionet CHEBI:102216 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0035455 infores:hetionet CHEBI:6402 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0232849 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001741 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020502 infores:hetionet CAID:CA269784 biolink:causes MONDO:0018214 infores:clingen CAID:CA269784 MONDO:0018214 PMID: Uncertain Significance PM2 PVS1, PS4 The c.5797del variant in SCN1A is a single nucleotide deletion predicted to cause a frameshift at amino acid position 1933 leading to a premature stop codon (p.Arg1933Glufs*3). The variant is located within the last exon and thus predicted to escape nonsense mediated decay. The truncated region is not known to be important for protein function, as missense variants reported in the region do not meet PLP per these criteria. Furthermore, LOF variants within this exon are relatively common in gnomAD v4.1. As such, this variant does not meet criteria to apply PVS1. This variant has been identified in a family in which 2 affected siblings with developmental and epileptic encephalopathy (DEE) harbored the variant, in addition to an unaffected parent and 2 unaffected siblings (LabCorp Genetics, Inc. internal data). Given the severity of the phenotype and presence in multiple unaffected family members, this case was not included as evidence for PS4. The variant is absent from the population database, gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting. (version 1.0, approved September 24, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA269784/MONDO:0018214/067 2024-10-01 2024-11-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7494 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C3665347 infores:hetionet CHEBI:135961 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0043094 infores:hetionet CHEBI:135530 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0267792 infores:hetionet CHEBI:3216 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0002418 infores:hetionet CHEBI:7852 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0026961 infores:hetionet NCBIGene:11005 biolink:causes MONDO:0009735 infores:monarchinitiative not_provided not_provided HGNC:15464 MONDO:0009735 uuid:f85e5775-1e6b-4269-a2ad-fd0acd823369 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9622 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0018524 infores:hetionet CHEBI:134743 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0025061 infores:hetionet CHEBI:2469 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0231528 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0349506 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019163 infores:hetionet CAID:CA10014198 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014198 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS2, PS3, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS4, BS3, BP5, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 The variant NM_001754.5(RUNX1): c.1119G>C (p.Ser373=) is a synonymous variant. As this is a synonymous variant, there is no REVEL score however SpliceAI is ≤0.20 (0.00) (BP4). The PhyloP score is <2.0 (-0.771) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014198/MONDO:0011071/008 2022-02-11 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:184555 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0232462 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0575090 infores:hetionet CHEBI:567361 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0034642 infores:hetionet CHEBI:8707 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020578 infores:hetionet CHEBI:78543 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0030193 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029443 infores:hetionet CHEBI:3223 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0231528 infores:hetionet CHEBI:28445 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0015672 infores:hetionet CHEBI:4887 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0042963 infores:hetionet CAID:CA390867526 biolink:causes MONDO:0100216 infores:clingen CAID:CA390867526 MONDO:0100216 PMID: Uncertain Significance BS3_Supporting, PP3, PP4, PM2_Supporting PM6, BA1, BP4, BP2, BS2, PP1, PM5, PM1, PS1, PS3, PS2, PS4, BS1, BS4 The NM_177438.2:c.4685G>A variant in DICER1 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 1562 (p.Cys1562Tyr). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant p.Cys1562Tyr showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (BS3_Supporting; Internal contributor: Foulkes). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.752) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP4, PM2_supporting, PP3, BS3_Supporting. (Bayesian Points: 2; VCEP specifications version1.3.0; 02/27/24). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390867526/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:209807 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0518015 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0006147 infores:hetionet CHEBI:28487 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0041657 infores:hetionet CAID:CA2497029997 biolink:causes MONDO:0700270 infores:clingen CAID:CA2497029997 MONDO:0700270 PMID: Pathogenic PM3, PM5_Supporting, PVS1, PM2 The c.1782del (p.Val595Cysfs*19) variant in ATM gene is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.2.1.1. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497029997/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83804 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0035258 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2239176 infores:hetionet NCBIGene:5199 biolink:causes MONDO:0010713 infores:monarchinitiative not_provided not_provided HGNC:8864 MONDO:0010713 uuid:a9b01a54-bbc7-4a58-8610-4a69ee2bed5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0277925 infores:hetionet CHEBI:64317 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0018681 infores:hetionet CHEBI:3219 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0014394 infores:hetionet NCBIGene:3630 biolink:causes MONDO:0007454 infores:monarchinitiative not_provided not_provided HGNC:6081 MONDO:0007454 uuid:04c0e403-ea3c-489a-af71-ec8a79cfa76a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4702 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0151827 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0026848 infores:hetionet NCBIGene:8929 biolink:causes MONDO:0700041 infores:monarchinitiative not_provided not_provided HGNC:9143 MONDO:0700041 uuid:4d2e3afa-44ec-4fdd-b698-3dad40a8fba3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000263 biolink:causes GO:0072378 infores:ubergraph knowledge_assertion manual_agent GO:2000263 GO:0072378 CHEBI:6741 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042373 infores:hetionet CHEBI:9943 biolink:causes MONDO:0043494 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003860 infores:hetionet CHEBI:3387 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042384 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038454 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0020651 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0948594 infores:hetionet CHEBI:9649 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0027497 infores:hetionet CHEBI:16796 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0030193 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0009319 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011849 infores:hetionet CAID:CA410149655 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149655 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM6, PVS1, BP7, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.920C>T (p.Ala307Val) is a missense variant which has a REVEL score < 0.50 (0.098) and a SpliceAI score ≤ 0.20 (Δ score 0.00) (BP4). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149655/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3561 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0227791 infores:hetionet CHEBI:63623 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0013144 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0027051 infores:hetionet CHEBI:4046 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0030252 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020456 infores:hetionet CHEBI:31711 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151942 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0003460 infores:hetionet CHEBI:4814 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0520888 infores:hetionet CAID:CA251535 biolink:causes MONDO:0009861 infores:clingen CAID:CA251535 MONDO:0009861 PMID:29560316PMID:30747360PMID:18985011PMID:30050108PMID:26503515PMID:29316886PMID:19292873PMID:25894915PMID:26666653PMID:24368688 Pathogenic PM4, PM2, PP4_Moderate, PM3_Strong This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316, 18985011). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 2 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant is present at a frequency below 0.0002 in the population databases ExAC and gnomAD. This variant changes protein length from an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM4, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251535/MONDO:0009861/006 2019-10-18 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42797 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0024299 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0002170 infores:hetionet CHEBI:9448 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0409974 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0021053 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020456 infores:hetionet CHEBI:5004 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0012833 infores:hetionet CHEBI:51164 biolink:causes MONDO:0016028 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0014804 infores:hetionet CHEBI:9667 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0030554 infores:hetionet CHEBI:45409 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151907 infores:hetionet CAID:CA658798683 biolink:causes MONDO:0008723 infores:clingen CAID:CA658798683 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3, BP7 The c.103_112del (p.(Pro35Glyfs*23)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. In summary, this variant has been classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 11/10/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798683/MONDO:0008723/021 2022-04-06 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42797 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002962 infores:hetionet CHEBI:4798 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0031924 infores:hetionet CHEBI:2567 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0020517 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0013395 infores:hetionet CHEBI:291342 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0009782 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0919882 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0919882 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0234458 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1145670 infores:hetionet CHEBI:116278 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0003537 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0234215 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0016034 infores:hetionet CAID:CA024185 biolink:causes MONDO:0018493 infores:clingen CAID:CA024185 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate, PM5_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 4861 of the RYR1 protein, p.(Arg4861Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). This variant has also been reported in many individuals with myopathy without reported MH events, these individuals were not considered for PS4 as this assessment is specific to MH inherited in an autosomal dominant pattern (PMID:12565913, PMID:16621918, PMID:17226826 and others). Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg4861His), PM5_Supporting (PMID: 23558838). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024185/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63619 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042023 infores:hetionet CHEBI:7798 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0013595 infores:hetionet CHEBI:9720 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0013144 infores:hetionet CAID:CA229307 biolink:causes MONDO:0009861 infores:clingen CAID:CA229307 MONDO:0009861 PMID:9634518 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 PM5 The c.1054G>C (p.Gly352Arg) variant in PAH has been reported in multiple individuals with classical and mild PKU (BH4 deficiency excluded) (PMID 9634518, 29316886, 30747360). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. Another missense variant at the same amino acid, p.Gly352Cys, has no assertion in ClinVar. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229307/MONDO:0009861/006 2021-02-14 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94411 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0004093 infores:hetionet CHEBI:63580 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0014394 infores:hetionet CHEBI:2549 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0014724 infores:hetionet CHEBI:6801 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0235309 infores:hetionet CHEBI:47499 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042510 infores:hetionet CHEBI:10127 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009676 infores:hetionet CHEBI:63618 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0013428 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0020538 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1760428 infores:hetionet CHEBI:3757 biolink:causes HP:5200424 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0424024 infores:hetionet CHEBI:7903 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0018681 infores:hetionet NCBIGene:51259 biolink:causes MONDO:0975840 infores:monarchinitiative not_provided not_provided HGNC:25018 MONDO:0975840 uuid:60b84939-50fc-4868-bbb8-77ac077c5568 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes UMLS:C0235353 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235353 infores:hetionet CHEBI:48538 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C1260880 infores:hetionet CHEBI:53691 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0040822 infores:hetionet CHEBI:36704 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0019270 infores:hetionet CHEBI:3084 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0018681 infores:hetionet CHEBI:9674 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013428 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0002170 infores:hetionet GO:0010807 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:0010807 GO:0099504 CHEBI:63611 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0476280 infores:hetionet GO:1902119 biolink:causes GO:0045132 infores:ubergraph knowledge_assertion manual_agent GO:1902119 GO:0045132 CHEBI:30659 biolink:causes UMLS:C0235395 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0235395 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0039621 infores:hetionet CHEBI:73274 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0006145 infores:hetionet CAID:CA032236 biolink:causes MONDO:0007750 infores:clingen CAID:CA032236 MONDO:0007750 PMID: Benign BA1 BP4, PS4, BS1, PM2, PP3, PP4, BS2 The NM_000527.5(LDLR):c.*13A>G variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BA1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:BA1: FAF = 0.007871(0.7871%) in African/African American exomes (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA032236/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:49713 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0017979 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011616 infores:hetionet CHEBI:6950 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0041657 infores:hetionet CHEBI:7959 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0023530 infores:hetionet CAID:CA410203993 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203993 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.181C>A (p.Pro61Thr) is a missense variant which has a REVEL score <0.50 (0.338) and a SpliceAI score ≤0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203993/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31623 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0017160 infores:hetionet CHEBI:5098 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C2047937 infores:hetionet CHEBI:4909 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0014724 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037315 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1112303 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1112303 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0021390 infores:hetionet CHEBI:5128 biolink:causes HP:0030187 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0701824 infores:hetionet NCBIGene:11078 biolink:causes MONDO:0012355 infores:monarchinitiative not_provided not_provided HGNC:17009 MONDO:0012355 uuid:2a62fd57-8c5a-4cec-9955-34b05b261699 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042571 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0020517 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0015397 infores:hetionet CHEBI:46295 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0600142 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0040046 infores:hetionet CHEBI:31980 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0085636 infores:hetionet CHEBI:9352 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0013604 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151849 infores:hetionet CHEBI:15367 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0263449 infores:hetionet CHEBI:31401 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0232462 infores:hetionet CHEBI:135361 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0013144 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0036508 infores:hetionet CHEBI:28748 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085932 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037199 infores:hetionet CHEBI:6888 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0027540 infores:hetionet CHEBI:3723 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033036 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0235818 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027769 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0595930 infores:hetionet CHEBI:4027 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0232487 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002187 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042994 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0016397 infores:hetionet CHEBI:7478 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0221170 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037199 infores:hetionet NCBIGene:4036 biolink:causes MONDO:0009104 infores:monarchinitiative not_provided not_provided HGNC:6694 MONDO:0009104 uuid:0d1f404c-5488-4dab-bca1-6ed4ca119005 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0033036 infores:hetionet CHEBI:41774 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030554 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0233632 infores:hetionet CHEBI:50275 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0011168 infores:hetionet CHEBI:65346 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0344232 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0037274 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0012833 infores:hetionet CHEBI:101278 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0015402 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0235416 infores:hetionet CHEBI:7627 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C3495440 infores:hetionet CHEBI:5100 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0023530 infores:hetionet CHEBI:46295 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0013395 infores:hetionet CHEBI:63589 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0242339 infores:hetionet CHEBI:7956 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0038325 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085606 infores:hetionet CHEBI:8107 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018800 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0020517 infores:hetionet CHEBI:134936 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0027424 infores:hetionet CHEBI:9448 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0027947 infores:hetionet CHEBI:82941 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0020473 infores:hetionet NCBIGene:4487 biolink:causes MONDO:0012142 infores:monarchinitiative not_provided not_provided HGNC:7391 MONDO:0012142 uuid:42efc076-7e3d-4b58-8ee0-df331d8e33b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40303 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0042109 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003864 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011849 infores:hetionet CHEBI:8107 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0030252 infores:hetionet CHEBI:9649 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0033774 infores:hetionet CHEBI:2549 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0017979 infores:hetionet NCBIGene:54834 biolink:causes MONDO:0032706 infores:monarchinitiative not_provided not_provided HGNC:18010 MONDO:0032706 uuid:a9eb1d4f-7c8f-4bc3-93de-f66cbedcd42d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0037199 infores:hetionet CHEBI:64318 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0027497 infores:hetionet CHEBI:70735 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0041105 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018500 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0015376 infores:hetionet CHEBI:465284 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0853034 infores:hetionet CHEBI:27882 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0004509 infores:hetionet CHEBI:47519 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151798 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0003864 infores:hetionet CHEBI:4814 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0030193 infores:hetionet CHEBI:119573 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011168 infores:hetionet CHEBI:45327 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0036454 infores:hetionet CHEBI:3127 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235490 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0006849 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0000833 infores:hetionet CHEBI:64312 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085611 infores:hetionet CHEBI:8346 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0016204 infores:hetionet CHEBI:28830 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0011991 infores:hetionet CAID:CA142888 biolink:causes MONDO:0019497 infores:clingen CAID:CA142888 MONDO:0019497 PMID: Uncertain Significance PP3, BS1_Supporting The filtering allele frequency (the lower threshold of the 95% of 73/60,014) of the c.4463A>T (p.Asp1488Val) variant in OTOF is 0.122% for Latino/Admixed American alleles in gnomAD v4, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The REVEL computational prediction tool produced a score of 0.805, which is above the threshold necessary to apply PP3. While this variant has been observed in at least 6 probands with hearing loss, none of these individuals had a second variant identified in OTOF (Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000065239.6). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 01.15.2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA142888/MONDO:0019497/023 2025-01-15 2025-03-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf true CHEBI:6741 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0009450 infores:hetionet CHEBI:6759 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0018790 infores:hetionet CHEBI:16664 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0011603 infores:hetionet CHEBI:8356 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020505 infores:hetionet CHEBI:7466 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0242350 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0855704 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0035455 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0339916 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0035078 infores:hetionet CHEBI:3215 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030252 infores:hetionet CHEBI:27899 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0232487 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0039971 infores:hetionet CAID:CA902499 biolink:causes MONDO:0100368 infores:clingen CAID:CA902499 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting BP5 The NM_000329.3(RPE65):c.484A>C (p.Thr162Pro) variant is a missense variant in RPE65 causing a substitution of threonine with proline at position 162. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000002470, with 7 / 1180020 in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the Arg91Trp variant suspected in trans, the c.370C>T (p.Arg124Ter) variant confirmed in trans, or the p.Thr306Ile variant suspected in trans, which were previously classified pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (1.75 total points, PM3, PMID: 20079931, laboratory-provided internal data). This variant has also been reported in a summary of genotypes for a cohort of patients with Leber Congenital Amaurosis, but no detailed phenotype information or data about a second allele was provided (PMID: 17964524). At least one patient with retinal degeneration harboring this variant in the heterozygous state has been identified with an alternative disease-causing variant in the IMPDH1 gene (VCEP member-provided data). However, the BP5 code is not applicable due to the high genetic heterogeneity and limited phenotypic specificities of retinal dystrophies, as well as the presence of this variant simply representing carrier status. At least one proband harboring this variant exhibits a phenotype including suspected diagnosis of RP/LCA (0.5 pt), decreased peripheral vision (1 pt), decreased central visual acuity (1 pt), bone spicules/RPE mottling/abnormal fundus (0.5 pt), and and 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts), which together are specific for RPE65-related recessive retinopathy (5 points, Invitae-provided internal data, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902499/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31000 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0011603 infores:hetionet CAID:CA392335588 biolink:causes MONDO:0007947 infores:clingen CAID:CA392335588 MONDO:0007947 PMID: Pathogenic PM6, PP4, PP2, PP3, PM2_Supporting, PS4_Supporting, PM1_Strong The NM_00138 c.2287T>G is a missense variant in FBN1 predicted to cause a substitution of a cysteine by glycine at amino acid 763 (p.Cys763Gly). This variant was found in two probands with a clinical diagnosis of Marfan syndrome (internal data, PP4, PS4_Supporting). In one of these probands the variant was found de novo with assumed paternity and maternity (PM6). This variant has been reported 3 times in ClinVar, once as pathogenic, once as likely pathogenic and once as uncertain significance (Variation ID: 549070). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.98) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM6, PS4_Supporting, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392335588/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:15367 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042075 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0005779 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0270795 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0270795 infores:hetionet CHEBI:8356 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0010520 infores:hetionet CHEBI:53691 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0018944 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0040053 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0005758 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0028259 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0018802 infores:hetionet CHEBI:50122 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0009782 infores:hetionet NCBIGene:100996717 biolink:causes MONDO:0011327 infores:monarchinitiative not_provided not_provided HGNC:53924 MONDO:0011327 uuid:d08703cc-4ebc-4200-812e-53db0a0bf47b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C2939147 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0020649 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042373 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0426732 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0853662 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0853662 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0026848 infores:hetionet CHEBI:23765 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151908 infores:hetionet CHEBI:28177 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0039239 infores:hetionet CHEBI:63631 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0035243 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030846 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0003123 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0014457 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042571 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0235641 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0235641 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0029925 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0029925 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0017160 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042109 infores:hetionet CAID:CA229503 biolink:causes MONDO:0009861 infores:clingen CAID:CA229503 MONDO:0009861 PMID:21147011PMID:21147011 Pathogenic PM3, PP4_Moderate, PVS1, PM2 Variant classified as Pathogenic using the following criteria: PVS1; PM2; PM3; PP4_Moderate. PVS1: frameshift variant in exon 2 of 13, predicted to result in PTC with removal of >10% of the protein and NMD; PM2: absent from ExAC, gnomAD, 1000G, ESP. PP4_Moderate; PM3: c.266_267insC seen on 2 PKU alleles, with BH4 deficiency ruled out (PMID: 21147011). Detected with pathogenic variants IVS12+1G>A and p.I65T (PMID: 9452062); and p.Pro281Leu (Likely Pathogenic per ClinGen PAH VCEP, PMID: 26666653). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229503/MONDO:0009861/006 2020-05-08 2020-05-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8874 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0162830 infores:hetionet CHEBI:3371 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0332534 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0235146 infores:hetionet CHEBI:6129 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C2830004 infores:hetionet CHEBI:68647 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0002170 infores:hetionet CHEBI:39585 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0030252 infores:hetionet NCBIGene:55275 biolink:causes MONDO:0014370 infores:monarchinitiative not_provided not_provided HGNC:25608 MONDO:0014370 uuid:3415beb8-fa82-4712-9861-7915e8f9073f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0018674 infores:hetionet CHEBI:51137 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0151773 infores:hetionet CHEBI:46195 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0855775 infores:hetionet CHEBI:5147 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020461 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0003123 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0162429 infores:hetionet CHEBI:77260 biolink:causes MONDO:0019610 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0043515 infores:hetionet CHEBI:63581 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0004364 infores:hetionet CHEBI:134991 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0008031 infores:hetionet CHEBI:5383 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0086565 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009450 infores:hetionet CHEBI:70735 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0007222 infores:hetionet CHEBI:68534 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0178298 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0032461 infores:hetionet CHEBI:63620 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085636 infores:hetionet CHEBI:64019 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0027497 infores:hetionet CHEBI:44915 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1142135 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0234215 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0178421 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0013146 infores:hetionet CHEBI:31401 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0037763 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027051 infores:hetionet CAID:CA410150304 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150304 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.823C>T (p.Pro275Ser) is a missense variant that is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting). The REVEL score is 0.057 (<0.50), indicating that the variant is likely to be tolerated (BP4). Additionally, a SpliceAI score of 0 (<0.20) suggests that the variant is unlikely to impact splicing. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150304/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CL:1001428 biolink:causes MONDO:0005605 infores:ubergraph knowledge_assertion manual_agent CL:1001428 MONDO:0005605 CHEBI:107736 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0013404 infores:hetionet CHEBI:6339 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0022346 infores:hetionet CHEBI:45327 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0006266 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0234215 infores:hetionet CHEBI:63627 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0438142 infores:hetionet CHEBI:135736 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018965 infores:hetionet CHEBI:8764 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010520 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0234215 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1258215 infores:hetionet CHEBI:6775 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0040822 infores:hetionet CHEBI:15367 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020453 infores:hetionet CHEBI:100241 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0001925 infores:hetionet CHEBI:100147 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0005758 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0541799 infores:hetionet CHEBI:74947 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0549622 infores:hetionet CHEBI:7478 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0149741 infores:hetionet CHEBI:29007 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0018681 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017178 infores:hetionet CHEBI:5128 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0234518 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0010692 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0033771 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0017601 infores:hetionet CHEBI:7575 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C1258215 infores:hetionet GO:2000790 biolink:causes GO:0060541 infores:ubergraph knowledge_assertion manual_agent GO:2000790 GO:0060541 CAID:CA229402 biolink:causes MONDO:0009861 infores:clingen CAID:CA229402 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PM3_Strong PM5, PP3 The c.1220C>T (p.Pro407Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9950317, 23357515, 23792259). This variant is absent in population databases. This variant was detected with pathogenic variants: p.F55fs (PMID: 9950317); p.Tyr414Cys (PMID: 23357515); p.Ala403Val (PMID: 23792259); and p.R408W (PMID: 24350308). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229402/MONDO:0009861/006 2020-08-28 2021-02-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3380 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0033687 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0162429 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0332534 infores:hetionet CHEBI:15365 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C1291078 infores:hetionet CHEBI:7581 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0278134 infores:hetionet CHEBI:18332 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0002994 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0009763 infores:hetionet CHEBI:3723 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030794 infores:hetionet CHEBI:41879 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015967 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0948594 infores:hetionet CHEBI:64312 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0034933 infores:hetionet CAID:CA16020852 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020852 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4, PM3_Supporting The frameshift variant NM_000277.3(PAH):c.750_751del (p.Arg252GlyfsTer30) occurs in exon 7 of 13 and is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One PKU patient has been reported (PMID: 32106880) compound heterozygous for Arg252GlyfsTer30 and Arg158Trp (ClinVar 102693, Pathogenic). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020852/MONDO:0009861/006 2020-12-08 2022-03-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36704 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0013404 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042755 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0149741 infores:hetionet CHEBI:7931 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0232462 infores:hetionet CHEBI:72564 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0009676 infores:hetionet CHEBI:30830 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027796 infores:hetionet CHEBI:70746 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0030196 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0948525 infores:hetionet CHEBI:50859 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085631 infores:hetionet CHEBI:2950 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0020580 infores:hetionet CHEBI:9907 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0008031 infores:hetionet CHEBI:64312 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151905 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0302295 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0332575 infores:hetionet CHEBI:5004 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0004093 infores:hetionet CHEBI:45863 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0040822 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042267 infores:hetionet CHEBI:29688 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0043352 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0025061 infores:hetionet CHEBI:79699 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0085932 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0497247 infores:hetionet CHEBI:52717 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0016658 infores:hetionet GO:1901546 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1901546 GO:0051641 CHEBI:5004 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0027441 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037199 infores:hetionet UNII:K2J09EMJ52 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0018681 infores:hetionet CHEBI:49575 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013378 infores:hetionet CHEBI:3534 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0002874 infores:hetionet CAID:CA410148214 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148214 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1075C>T (p.Pro359Ser) is a missense variant which has a REVEL score of 0.423 (< 0.50) and a SpliceAI score of 0.00 (≤ 0.20), allowing for the application of BP4. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148214/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:Y2V2R4W9TQ biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C1443060 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020437 infores:hetionet CHEBI:52010 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0009806 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0029134 infores:hetionet CHEBI:9130 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0028961 infores:hetionet NCBIGene:6235 biolink:causes MONDO:0014394 infores:monarchinitiative not_provided not_provided HGNC:10419 MONDO:0014394 uuid:54ef17d7-e2d9-4b2b-b7d9-4783601d51bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0039231 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0234215 infores:hetionet CAID:CA401369055 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369055 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PS3_Moderate, PM2_Supporting PS1 "The NM_000152.5(GAA):c.1716C>G variant in GAA is a missense variant predicted cause the substitution of histidine by clutamine at amino acid 572 (p.His572Gln). At least 3 patients with this variant had had documented GAA deficiency with activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot (PMID: 3112512) or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 25455803, 29122469), meeting PP4_Moderate. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic variant, phase unknown. One patient was compound heterozygous for the variant and c.-32-13T>G ( PMID: 31125121). One patient was compound heterozygous for c.1716C>G (p.His572Gln) and c.1293_1312del20 (p.Gln433Aspfs*66) (PMID: 29122469), meeting the specifications for PM3. This variant is absent in gnomAD, meeting PM2_Supporting. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B (""potentially less severe"") by Kroos et al, 2012 (PMID:22644586). This includes 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.793 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP (Specifications Verion 2.0): PP4_Moderate, PM3, PS3_Moderate, PM2_Supporting, PP3." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369055/MONDO:0009290/010 2022-05-11 2022-05-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:480999 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1142412 infores:hetionet CHEBI:71255 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0037036 infores:hetionet CAID:CA10585197 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585197 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.921T>G (p.Asp307Glu) variant is classified as VUS for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.85. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite FH after alternative causes of high cholesterol were excluded (PMID: 12436241). PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill SB definite FH/DLCN>=6 for FH (PMID: 12436241, Lille University SCV000583761.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585197/MONDO:0007750/013 2023-06-23 2023-07-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:53691 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0677500 infores:hetionet CHEBI:27666 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0151904 infores:hetionet NCBIGene:124842 biolink:causes MONDO:0032776 infores:monarchinitiative not_provided not_provided HGNC:26991 MONDO:0032776 uuid:517bf50f-7970-45d5-8a10-25e673cddc3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017152 infores:hetionet CHEBI:50729 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151825 infores:hetionet CHEBI:29007 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0000737 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0038358 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032231 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0162429 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0877144 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877144 infores:hetionet CAID:CA367400043 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400043 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP2, PP3, PP4, PM2_Supporting, PS3_Moderate The c.911T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 304 (p.(Leu304Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.874, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 13 unrelated individuals with hyperglycemia (PS4; PMID 29207974, 11942313, internal lab contributors). This variant segregated with diabetes with 4 informative meioses in 3 families with diabetes/hyperglycemia (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Leu304Pro variant has RAI=0.19, which is less than the MDEP VCEP threshold of 0.50. (PMIDs: 29704611, 26208450). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP3, PP2, PP4, PS4, PP1_Strong, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400043/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:4445 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151798 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0392702 infores:hetionet CHEBI:52717 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036974 infores:hetionet CHEBI:6444 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0036974 infores:hetionet CHEBI:408174 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0008031 infores:hetionet CHEBI:68558 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0151699 infores:hetionet CHEBI:31859 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0034880 infores:hetionet CHEBI:5784 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0232462 infores:hetionet CHEBI:5138 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0015732 infores:hetionet CHEBI:63599 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0018965 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0026946 infores:hetionet CHEBI:6076 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0004604 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0595930 infores:hetionet CHEBI:16714 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0028084 infores:hetionet CHEBI:39867 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0030554 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0234458 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0239385 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0005741 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037822 infores:hetionet CHEBI:5818 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0040822 infores:hetionet CAID:CA902346 biolink:causes MONDO:0100368 infores:clingen CAID:CA902346 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting BP4, PM3, PP3, PP4 NM_000329.3(RPE65):c.902A>G is a missense variant causing substitution of asparagine with serine at position 301. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00008810, with 17/129134 in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa 87 with choroidal involvement, which is a dominant condition and implies harboring the variant in the heterozygous state (SCV002580301.1). However, the proband was not counted for PM3 because a second variant was not reported in trans. The computational predictor REVEL gives a score of 0.304, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902346/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0048841 biolink:causes GO:0007411 infores:ubergraph knowledge_assertion manual_agent GO:0048841 GO:0007411 CHEBI:66964 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0039231 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0151736 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0038454 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0041912 infores:hetionet CHEBI:8346 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0027441 infores:hetionet CHEBI:567361 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0018681 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042267 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017152 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0042109 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0001817 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0154946 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0020538 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0002994 infores:hetionet CHEBI:6909 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0038362 infores:hetionet CHEBI:28487 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0039070 infores:hetionet CHEBI:46295 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0042798 infores:hetionet CAID:CA014098 biolink:causes MONDO:0007947 infores:clingen CAID:CA014098 MONDO:0007947 PMID: Benign BS1, BS4 PM2, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BP5, BS3 NM_00138 c.3422C>T is a missense variant in FBN1 predicted to cause a substitution of a Proline by Leucine at amino acid 1141 (p.Pro1141Leu). This variant has been reported in the literature in at least 3 individuals in association with thoracic aortic aneurysm and dissection (TAAD), MASS syndrome, and features possibly consistent with Marfan syndrome (PMID: 10533071; PMID: 24740214; PMID: 26188975). This variant was also identified in an internal proband with isolated TAAD with a family history highly specific for Marfan syndrome, however it does not segregate with disease in an affected family member (BS4) and therefore PP4 cannot be used. This variant has been previously reported in ClinVar as benign, likely benign, and uncertain significance (Variation ID: 42334). This variant has been identified in 0.026% of individuals of European origin (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BS4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA014098/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3082 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0018794 infores:hetionet CHEBI:6950 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020580 infores:hetionet CHEBI:3387 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013604 infores:hetionet CAID:CA199475 biolink:causes MONDO:0010726 infores:clingen CAID:CA199475 MONDO:0010726 PMID: Pathogenic PS2_Very Strong, PVS1, PM2_Supporting The p.Gly269Alafs*20 variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199475/MONDO:0010726/016 2021-03-09 2021-05-07 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:63632 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0424790 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019112 infores:hetionet CHEBI:42797 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0232807 infores:hetionet CHEBI:9445 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0344232 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0920114 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0920114 infores:hetionet CHEBI:2668 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0004134 infores:hetionet CHEBI:15640 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0232462 infores:hetionet CHEBI:50859 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0027497 infores:hetionet NCBIGene:55739 biolink:causes MONDO:0034121 infores:monarchinitiative not_provided not_provided HGNC:25576 MONDO:0034121 uuid:ef031d67-01cf-4212-a7a5-524bbc69fd83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:80630 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0700590 infores:hetionet CHEBI:681848 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0233485 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0021053 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0037274 infores:hetionet GO:0044559 biolink:causes GO:0005249 infores:ubergraph knowledge_assertion manual_agent GO:0044559 GO:0005249 GO:0120194 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0120194 GO:0007275 CHEBI:9086 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233565 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042075 infores:hetionet CHEBI:8430 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0002878 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0236053 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0236053 infores:hetionet CHEBI:10112 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0750394 infores:hetionet CAID:CA2573157359 biolink:causes MONDO:0100083 infores:clingen CAID:CA2573157359 MONDO:0100083 PMID: Uncertain Significance PM1_Supporting, PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.428_439dup (p.Asn146_Ala147insGluLeuArgAsn) is an in-frame deletion/insertion variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM4_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157359/MONDO:0100083/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3082 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0038362 infores:hetionet CHEBI:5098 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0015230 infores:hetionet NCBIGene:4771 biolink:causes MONDO:0007039 infores:monarchinitiative not_provided not_provided HGNC:7773 MONDO:0007039 uuid:950b496a-df4e-4ffe-a685-566317ee2bb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0017574 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0040046 infores:hetionet CAID:CA410147976 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147976 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1142T>C (p.Leu381Pro) is a missense variant which has not been reported in any populations featured in any version of gnomAD, allowing for application of PM2_Supporting. This variant has a SpliceAI score of 0 and a REVEL score of 0.929, but neither BP4 nor PP3 were applied. In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147976/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17026 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0005779 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0043251 infores:hetionet CHEBI:10102 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C3665347 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0006826 infores:hetionet CHEBI:49575 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0015230 infores:hetionet CHEBI:41423 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0085679 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0025061 infores:hetionet CHEBI:31625 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0270996 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0001122 infores:hetionet CAID:CA10014496 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014496 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.508+20T>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.05) (BP7). Multiple lines of computational evidence suggest no impact on gene /gene product (SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014496/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA294235 biolink:causes MONDO:0007648 infores:clingen CAID:CA294235 MONDO:0007648 PMID:27582386PMID:27582386 Benign BS2, BA1 BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM1, PM3, PM4, PM5, PP2, PP3, PP4, PP1, BP1, BP4, BP2, BP3, PS1, PS4, PS3, PS2 The c.808T>G (p.Ser270Ala) variant has a maximum subpopulation frequency of 0.002269 (0.2269%, 57 of 25124 alleles) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1). This variant has also has been observed in more than 10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000185687.6, SCV000254832.8). In summary, this variant meets criteria to be classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294235/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:367163 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020676 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151514 infores:hetionet CAID:CA412355889 biolink:causes MONDO:0100039 infores:clingen CAID:CA412355889 MONDO:0100039 PMID: Uncertain Significance PP4, PM2_Supporting, PS4_Supporting, PM6 PM5 The p.Cys291Arg variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Cys291Arg variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with clinical features consistent with CDKL5 disorder (PMID 31313283) (PM6). The p.Cys291Arg variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PP4). The p.Cys291Arg variant has been observed in 2 individuals with CDKL5 disorder (PMID 31313283, internal database) (PS4_Supporting). In summary, the p.Cys291Arg variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, PM6, PP4, PS4_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412355889/MONDO:0100039/034 2023-08-28 2023-09-14 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6129 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0002874 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0009806 infores:hetionet CHEBI:2618 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0231835 infores:hetionet CHEBI:84883 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0151936 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0009450 infores:hetionet CHEBI:47898 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151904 infores:hetionet CHEBI:2453 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0037763 infores:hetionet CAID:CA891842378 biolink:causes MONDO:0011071 infores:clingen CAID:CA891842378 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.277dup (p.Asp93fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98–c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 39772771). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA891842378/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9352 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0014518 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0162429 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020538 infores:hetionet CHEBI:31623 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0332563 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027720 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0007114 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0233401 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0015397 infores:hetionet CAID:CA024453 biolink:causes MONDO:0007783 infores:clingen CAID:CA024453 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with lysine at codon 156 of the RYR1 protein, p.(Arg156Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in individuals with a personal or family history of an MH episode or central core disease but without sufficient information to consider the reports for informing PS4 (PMID:16835904). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.886) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024453/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3441 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151746 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0010692 infores:hetionet CHEBI:6067 biolink:causes HP:0001595 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0157733 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0919715 infores:hetionet CHEBI:82960 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0038325 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0027765 infores:hetionet CHEBI:9137 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0008350 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0852628 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0852628 infores:hetionet CHEBI:6715 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085595 infores:hetionet CHEBI:16664 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0021053 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0024205 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0029456 infores:hetionet CHEBI:4445 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0522055 infores:hetionet CHEBI:7496 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0151905 infores:hetionet CHEBI:119573 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014457 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013928 infores:hetionet CHEBI:63791 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0036980 infores:hetionet CHEBI:45863 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030252 infores:hetionet CHEBI:7492 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0040822 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006147 infores:hetionet CHEBI:6775 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C3495920 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0575805 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0575805 infores:hetionet CAID:CA199447 biolink:causes MONDO:0100040 infores:clingen CAID:CA199447 MONDO:0100040 PMID: Uncertain Significance PM1, PP3, PM2_Supporting PP4 The p.Asn227Lys variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asn227Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). The p.Asn227Lys variant was observed in an individual with microcephaly, rocking movements, absent speech, epilepsy, bruxism, severe scoliosis, and who is non-ambulatory. However, this individual's parents were not available for segregation analysis and this individual was evaluated once at the age of 13 years old (PMID 19578037) (PP4_not met). In summary, the p.Asn227Lys variant in FOXG1 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM1, PP3, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199447/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:77260 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0029124 infores:hetionet CHEBI:9943 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151766 infores:hetionet CHEBI:135876 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0016204 infores:hetionet CHEBI:135005 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0027947 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0030312 infores:hetionet CHEBI:10102 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C3665386 infores:hetionet NCBIGene:402569 biolink:causes MONDO:0957220 infores:monarchinitiative not_provided not_provided HGNC:21839 MONDO:0957220 uuid:7927cb19-d8e8-4fa4-9861-e111a4f99361 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3703 biolink:causes MONDO:0859223 infores:monarchinitiative not_provided not_provided HGNC:6172 MONDO:0859223 uuid:6d9ebc67-822b-4b22-9e39-580429ab221e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes NCIT:C27003 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0184567 infores:hetionet CHEBI:5165 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0016204 infores:hetionet CHEBI:17347 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0234708 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022073 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521490 infores:hetionet CHEBI:167309 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0020621 infores:hetionet CHEBI:44032 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0451641 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0271650 infores:hetionet CAID:CA114147 biolink:causes MONDO:0015630 infores:clingen CAID:CA114147 MONDO:0015630 PMID: Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PS3, PS4_Moderate PM5 The NM_000552.4(VWF):c.3970G>A (p.Gly1324Ser) variant is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 1324. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and a decreased GP1b binding assay, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 30084138). The variant has been reported to segregate with VWD type 2M through 2 affected meioses from 1 family (PP1; PMID: 29341351). At least 3 additional VWD type 2M probands have been reported with this variant (PMIDs: 29341351, 22102201, 1409710; PS4_moderate). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000003650 (based on 2/91074 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.718, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A platelet binding assay in COS-7 cells expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function. In a direct binding assay, the ristocetin-induced binding of rvWF(G1324S) to platelets was markedly reduced compared with rvWF(wt). (PMID: 1409710) (PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP1, PP3, PP4_moderate, PS4_moderate. (VCEP specifications version Pilot; date of approval). von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114147/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31348 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020621 infores:hetionet CHEBI:39867 biolink:causes HP:0000869 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232940 infores:hetionet CAID:CA024503 biolink:causes MONDO:0007783 infores:clingen CAID:CA024503 MONDO:0007783 PMID: Pathogenic PM1, PS2_Moderate, PS4, PP1_Strong, PP3_Moderate, BS2_Supporting BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 177 of the RYR1 protein, p.(Arg177Cys). This variant was not present in the six major gnomAD populations at the time this variant was interpreted. This variant has been reported in 11 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 11 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:16163667). This variant has been identified an individual with a negative IVCT/CHCT result BS2_Moderate. In one individuals the variant was determined to be de novo with confirmed parentage PS2_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 7 individuals PP1_Strong (PMID:19648156). A REVEL score >0.85 (0.931) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS2_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024503/MONDO:0007783/012 2021-03-16 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:75722 biolink:causes HP:0034431 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0231592 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0027765 infores:hetionet CHEBI:37941 biolink:causes UMLS:C1961112 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1961112 infores:hetionet CAID:CA405684225 biolink:causes MONDO:0018493 infores:clingen CAID:CA405684225 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting PP3, PS4, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of histidine with proline at codon 4729 of the RYR1 protein, p.(His4729Pro). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction, this individual had a second variant in RYR1, p.(Arg3167*). This individual did not have a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID: 26951757). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.758 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405684225/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3506 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0014518 infores:hetionet CHEBI:4708 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042024 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0002170 infores:hetionet CHEBI:6958 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0043144 infores:hetionet CHEBI:521033 biolink:causes UMLS:C0948856 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0948856 infores:hetionet CAID:CA10653558 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653558 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.*2474T>C variant in the 3' UTR has an MAF of 0.119 (12%, 5001/41950 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 276 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653558/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135939 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0020517 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040034 infores:hetionet CHEBI:63617 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0024902 infores:hetionet CHEBI:8774 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0038325 infores:hetionet NCBITaxon:10368 biolink:causes MONDO:0000337 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10368 MONDO:0000337 GO:1904956 biolink:causes GO:0030901 infores:ubergraph knowledge_assertion manual_agent GO:1904956 GO:0030901 CHEBI:63621 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0520966 infores:hetionet CHEBI:7581 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0036572 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0021843 infores:hetionet CHEBI:64321 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0162830 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0541881 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0541881 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0000833 infores:hetionet CHEBI:6456 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0001122 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0006266 infores:hetionet CHEBI:50156 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0085632 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0860866 infores:hetionet CHEBI:71415 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0006384 infores:hetionet CAID:CA006607 biolink:causes MONDO:0007356 infores:clingen CAID:CA006607 MONDO:0007356 PMID:27629256 Benign BA1, BS3 BP1, BP4, BP3, BP2, PS1, PS4, PS2, PS3, PM5, PM4, PM3, PM1, BP7, BP5, BS1, BS4, PVS1, PM2, PM6, PP2, PP3, PP4, PP1, BS2 NM_000249.4(MLH1):c.1732-19T>A is an intronic variant for which the gnomAD filtering allele frequency (African/African American) is 2.8% and gnomAD v4.1 Grpmax AF is 2.898%, meeting BA1 criteria according to the Maximum Credible Allele Frequency (MCAF) cutoffs for MLH1. There was also no impact on splicing in laboratory assays using nonsense-mediated decay inhibition (PMID: 27629256). In summary, this variant meets the criteria to be classified as benign for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: BA1 and BS3 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA006607/MONDO:0007356/115 2024-09-19 2024-10-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:404903 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0852911 infores:hetionet CHEBI:8430 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0277794 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0027051 infores:hetionet GO:0120313 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0120313 GO:0051321 CHEBI:5138 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0237938 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0919590 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0919590 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0001824 infores:hetionet CHEBI:3499 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0036572 infores:hetionet CHEBI:77260 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151798 infores:hetionet CHEBI:2038 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0015967 infores:hetionet CHEBI:4798 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0852911 infores:hetionet CHEBI:7443 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0085631 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1384666 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020517 infores:hetionet CHEBI:68478 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0040053 infores:hetionet CHEBI:3013 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0027497 infores:hetionet CHEBI:7954 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0857305 infores:hetionet CHEBI:47612 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0948594 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151596 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0000833 infores:hetionet CHEBI:6149 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0311468 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0227791 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0392386 infores:hetionet CAID:CA8602670 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602670 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 PP4 The c.2471C>G variant in ITGA2B is a missense variant predicted to cause substitution of Threonine by Serine at amino acid 824 (p.Thr824Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001552 (2/128896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.127, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602670/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8356 biolink:causes UMLS:C1096185 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1096185 infores:hetionet CHEBI:3716 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0013604 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0948594 infores:hetionet CHEBI:63613 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C2242588 infores:hetionet CHEBI:3176 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0015423 infores:hetionet CHEBI:18258 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0018802 infores:hetionet CHEBI:9168 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0015967 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0008035 infores:hetionet CAID:CA386296754 biolink:causes MONDO:0009861 infores:clingen CAID:CA386296754 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4_Moderate PM3 The c.590T>A (p.Leu197Ter) variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in an Ugyur proband (PMID: 31355225) with mild PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). The patient was compound heterozygous for the variant (confirmed by parental testing) and carried it in trans with the p.R53H variant (VUS per ClinGen PAH working group) (0.25 points per SVI criteria for PM3, and thus insufficient to use PM3 at any strength). It is also reported pathogenic in Clinvar (ID 625288) variant by one lab, in a case with PKU; no further information is given. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386296754/MONDO:0009861/006 2020-04-16 2020-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27446 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0011991 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0012833 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007137 infores:hetionet GO:1902659 biolink:causes GO:0071333 infores:ubergraph knowledge_assertion manual_agent GO:1902659 GO:0071333 CHEBI:4562 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0010073 infores:hetionet CHEBI:2682 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019521 infores:hetionet CAID:CA10576302 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576302 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4, PP1 BP4, BP2, BA1, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, BS2 The NM_000527.5(LDLR):c1217G>C (p.Arg406Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5, PS4_Supporting, PP1, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.89, which is above the threshold of 0.75.PM5 - 2 other missense variants in the same codon:1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines.2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Trp) – Pathogenic by these guidelines.There is 1 variant in the same codon classified as Pathogenic by these guidelines. – therefore PM5 is met.PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (1 case with SB criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation– FH VCEP member lab; 1 case with DLCN criteria from PMID: 16250003)PP1 - Variant segregates with phenotype in 2 informative meioses from 2 families in data provided by FH VCEP member labs (Laboratory of Genetics and Molecular Cardiology – 1 family: 1 affected family member with the variant; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation – 1 family: 1 affected family member with the variant).PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576302/MONDO:0007750/013 2022-04-22 2022-04-22 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:75045 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0015397 infores:hetionet CHEBI:8060 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0022346 infores:hetionet CHEBI:50692 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0014743 infores:hetionet CHEBI:51364 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0011603 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085606 infores:hetionet CHEBI:63610 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013390 infores:hetionet CHEBI:8499 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0000729 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0006147 infores:hetionet CHEBI:44032 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0003467 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011570 infores:hetionet CHEBI:75984 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0020555 infores:hetionet CHEBI:9637 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0014518 infores:hetionet CHEBI:30830 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0040822 infores:hetionet CHEBI:72297 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0018681 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0233494 infores:hetionet CHEBI:94501 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0042963 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029443 infores:hetionet CHEBI:135530 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0027497 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0004096 infores:hetionet CHEBI:50692 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0004604 infores:hetionet CHEBI:63635 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0026821 infores:hetionet CHEBI:4858 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0851578 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0919600 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0919600 infores:hetionet GO:0002332 biolink:causes CL:0000818 infores:ubergraph knowledge_assertion manual_agent GO:0002332 CL:0000818 CHEBI:82960 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020458 infores:hetionet CHEBI:17823 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0003811 infores:hetionet CHEBI:61390 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0009763 infores:hetionet CHEBI:17650 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0011253 infores:hetionet CHEBI:6367 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0007859 infores:hetionet CHEBI:32020 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0231218 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0314719 infores:hetionet CHEBI:63612 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0853034 infores:hetionet CAID:CA392354488 biolink:causes MONDO:0007947 infores:clingen CAID:CA392354488 MONDO:0007947 PMID: Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong PVS1, PM6, PP1, BS2, BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS2, PM5, PM3, PM4, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4409G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1470 (p.Cys1470Tyr). This variant has been identified in at least three individuals with clinical diagnoses of Marfan syndrome (PS4_moderate, PP4; PMIDs: 35058154, 11933199; Bichat, & CHEO internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.976). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392354488/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63580 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034882 infores:hetionet CHEBI:85161 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0220981 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0024115 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235966 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013595 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0877153 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0853761 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1368065 infores:hetionet GO:0110137 biolink:causes GO:0007552 infores:ubergraph knowledge_assertion manual_agent GO:0110137 GO:0007552 CHEBI:7915 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0036572 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0948594 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0020538 infores:hetionet CHEBI:31711 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026975 infores:hetionet CAID:CA410149605 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149605 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS4, PS1, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PVS1, PM6, BP5, BP7, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.946G>A (p.Glu316Lys) is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 316 (p.Glu316Lys). This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting), and the germline variant has not been reported in cases or in the literature. The computational predictor REVEL gives a score of 0.094, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149605/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0037274 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0852733 infores:hetionet CAID:CA374978246 biolink:causes MONDO:0008535 infores:clingen CAID:CA374978246 MONDO:0008535 PMID: Likely Pathogenic PM2_Supporting, PP4_Moderate, PS4 The NM_001114753.3: c.1268A>G variant in ENG is a missense variant predicted to cause substitution of asparagine by serine at amino acid 423 (p.Asn423Ser). This variant has been reported in more than 4 probands with a phenotype consistent with HHT (PS4; PMID: 32573726, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 34872578). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.490, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374978246/MONDO:0008535/136 2024-11-12 2025-03-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6129 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0008031 infores:hetionet CHEBI:15428 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0032617 infores:hetionet CHEBI:8871 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020578 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0553732 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0003123 infores:hetionet CHEBI:45327 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0494475 infores:hetionet CHEBI:6149 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0016204 infores:hetionet CHEBI:17026 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0025323 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020538 infores:hetionet CHEBI:5134 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0424295 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0014130 infores:hetionet CHEBI:8764 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014591 infores:hetionet CHEBI:63612 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0085649 infores:hetionet CHEBI:3082 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0030193 infores:hetionet CHEBI:9014 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0000737 infores:hetionet CHEBI:6792 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0015967 infores:hetionet CHEBI:6067 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151576 infores:hetionet CHEBI:5098 biolink:causes HP:0032004 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0033778 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017675 infores:hetionet CAID:CA2061448 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061448 MONDO:0015924 PMID: Likely Benign BS1 PM2, PP3, BP4, PM1 The BMPR2 c.1766A>G variant is a missense variant predicted to result in a tyrosine to cysteine substitution at amino acid 589 (p.Tyr589Cys). The minor allele frequency in gnomAD v2.1.1 controls at a frequency of 0.001511 (22/14,556 alleles) which is above the cut-off of 0.1% for PAH (BS1 met). The variant is located outside of the critical extracellular and kinase domains of BMPR2 (PM1 not met). The REVEL score is 0.577, not exceeding the threshold of >=0.75 (PP3 not met) or <=0.25 (BP4 not met). No functional data was available and SpliceAI does not predict an effect on splicing. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061448/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15552 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020453 infores:hetionet CHEBI:8707 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027796 infores:hetionet CHEBI:3723 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0231218 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0027051 infores:hetionet CHEBI:7565 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002994 infores:hetionet NCBIGene:3265 biolink:causes MONDO:0009026 infores:monarchinitiative not_provided not_provided HGNC:5173 MONDO:0009026 uuid:aa299698-ccc3-4599-b52a-ac51431b5dfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1443060 infores:hetionet CHEBI:17347 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235710 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020517 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042401 infores:hetionet CAID:CA9043611 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043611 MONDO:0012999 PMID: Likely Benign BP4, BS1 The NM_000156.6:c.570+4C>T variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 5. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population frequency in gnomAD v4.1.0. is 0.001148 (86/74912 alleles; no homozygotes) in the African / African American population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.01 for donor loss and suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 582572). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): BS1, BP4.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on April 16, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043611/MONDO:0012999/026 2025-04-16 2025-04-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:68558 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0042963 infores:hetionet CHEBI:167638 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0233407 infores:hetionet CHEBI:9168 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C3665386 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042514 infores:hetionet CHEBI:6931 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0237849 infores:hetionet CHEBI:28748 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0438215 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0031117 infores:hetionet NCBIGene:6714 biolink:causes MONDO:0014837 infores:monarchinitiative not_provided not_provided HGNC:11283 MONDO:0014837 uuid:3c1f7284-ecda-4423-9a2b-6777faab1b55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0011603 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0022408 infores:hetionet NCBIGene:4214 biolink:causes MONDO:0013410 infores:monarchinitiative not_provided not_provided HGNC:6848 MONDO:0013410 uuid:e6c2f51e-7dcd-4640-88e0-13c940691ddf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:184555 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0151766 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0235980 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235980 infores:hetionet CHEBI:3127 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0001824 infores:hetionet CHEBI:7476 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0947912 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018799 infores:hetionet CHEBI:9943 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033771 infores:hetionet CAID:CA355961928 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961928 MONDO:0001586 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PP3_Moderate, PS3_Supporting PM5, PS1 The NM_000203.5:c.614G>A variant in IDUA is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 205 (p.Cys205Tyr). Two patients with a diagnosis of MPS I are reported to be compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen LD VCEP. The phase is unconfirmed in both cases. The second variant is c.501C>A (p.Tyr167Ter) in one patient (pathogenic, 0.5 points, PMID: 11735025) and c.1240delA in the second patient (likely pathogenic, PMID: 28752568, 0.25 points). Total points = 0.75 (PM3_Supporting). One of these individuals was described as having symptoms typical of attenuated MPS I (Scheie syndrome) with documentation of low IDUA activity values (PMID: 11735025) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002202 (2/90842 alleles) in the South Asian population which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in COS-7 resulted in <1% wild-type IDUA activity indicating that this variant may impact protein function (Table 8, PMID: 11735025) (PS3_Supporting). The computational predictor REVEL gives a score of 0.951, which is above the threshold of 0.773, evidence, that correlates with impact to IDUA function at the moderate level, based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). Three other missense variants have been reported at the same amino acid position: c.613T>G (p.Cys205Gly) (ClinVar Variation ID: 2184620, LP in ClinVar), c.613T>A (p.Cys205Ser) (ClinVar Variation ID: 2145829, VUS in ClinVar), and c.615C>G (p.Cys205Trp) (ClinVar Variation ID: 3613351, LP in ClinVar). The classification of the current variant, c.614G>A (p.Cys205Tyr), will be used in the assessment of the other variants at Cys205. Therefore, PM5 is not applied in order to avoid circular logic. In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I. IDUA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PP3_Moderate, PP4, PS3_Supporting. PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961928/MONDO:0001586/010 2024-12-06 2025-06-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63631 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0031117 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0011053 infores:hetionet CHEBI:10110 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0013378 infores:hetionet CHEBI:28915 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0232462 infores:hetionet CHEBI:6437 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085633 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0235416 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0234458 infores:hetionet CHEBI:68610 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0002792 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1167965 infores:hetionet CHEBI:52717 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0206062 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0035455 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0010692 infores:hetionet CHEBI:7454 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0013395 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0852967 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0852967 infores:hetionet CAID:CA9870225 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870225 MONDO:0015967 PMID: Pathogenic PP3, PP4, PM2_Supporting, PM1_Supporting, PS4, PP1_Strong The c.322G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 108 (p.(Val108Ile)) of NM_175914.5. This variant is located within the DNA binding domain (codons 80-110) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 1 copy in the East Asian subpopoulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.804, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 16 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID 12203996, PMID 12627330, PMID 28701371, internal lab contributors). This variant segregated with diabetes with 18 informative meioses in 3 families (PP1_Strong; PMID 12203996, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, this evidence supports the classification of this variant as pathogenic for HNF4A-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PS4, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870225/MONDO:0015967/085 2023-08-13 2023-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6717 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0004096 infores:hetionet CHEBI:50381 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0030196 infores:hetionet CHEBI:75246 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0043094 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005306 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0038013 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0007787 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0852733 infores:hetionet CHEBI:7789 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0033774 infores:hetionet CHEBI:6715 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0038990 infores:hetionet CHEBI:16469 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007820 infores:hetionet GO:1905298 biolink:causes GO:0060575 infores:ubergraph knowledge_assertion manual_agent GO:1905298 GO:0060575 CHEBI:3723 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036974 infores:hetionet CHEBI:73274 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042023 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0037274 infores:hetionet CHEBI:5441 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0002994 infores:hetionet CHEBI:71219 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0000737 infores:hetionet CHEBI:70735 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0027497 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0162429 infores:hetionet CHEBI:28918 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0019080 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0006145 infores:hetionet NCBIGene:57217 biolink:causes MONDO:0800030 infores:monarchinitiative not_provided not_provided HGNC:19750 MONDO:0800030 uuid:c9488a9b-893f-4a75-a657-15eea1670bd6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5004 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0234215 infores:hetionet GO:1905132 biolink:causes GO:0045132 infores:ubergraph knowledge_assertion manual_agent GO:1905132 GO:0045132 CHEBI:63605 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0004936 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0344232 infores:hetionet CHEBI:10102 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011253 infores:hetionet CHEBI:6633 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0041834 infores:hetionet CHEBI:68554 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0151904 infores:hetionet CHEBI:10119 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002994 infores:hetionet CHEBI:5855 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151701 infores:hetionet CHEBI:17698 biolink:causes HP:0012195 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0425492 infores:hetionet CHEBI:3723 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151936 infores:hetionet CHEBI:116278 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0004093 infores:hetionet CHEBI:63619 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0700200 infores:hetionet CHEBI:16796 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0085633 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004471 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1692886 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0022568 infores:hetionet CHEBI:101853 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151683 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0853008 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853008 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0025061 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027765 infores:hetionet CHEBI:8107 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0004134 infores:hetionet UMLS:C1709429 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0018681 infores:hetionet CAID:CA10014221 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014221 MONDO:0011071 PMID: Uncertain Significance BS1, PP3 PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BS3, BS4, BP7, BP5, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP1, PP4 NM_001754.4:c.1007T>C is a missense variant which has an MAF of 0.0002133 (0.02%, 7/32818 alleles) in the Latino subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.791) (PP3). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014221/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31547 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C1956346 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022650 infores:hetionet CHEBI:194135 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0080274 infores:hetionet CHEBI:6539 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0023380 infores:hetionet CHEBI:119915 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026837 infores:hetionet CHEBI:2663 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C2747891 infores:hetionet NCBIGene:11267 biolink:causes MONDO:0968947 infores:monarchinitiative not_provided not_provided HGNC:17028 MONDO:0968947 uuid:8339eb17-9e4e-4163-87cd-baec380977c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085636 infores:hetionet CHEBI:9434 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235086 infores:hetionet NCBIGene:153562 biolink:causes MONDO:0012420 infores:monarchinitiative not_provided not_provided HGNC:26401 MONDO:0012420 uuid:18ccb592-da44-4872-83c4-44f18afe9c9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3757 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011206 infores:hetionet CHEBI:92923 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0037278 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0234215 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0877092 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877092 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0027765 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0235906 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0235906 infores:hetionet CHEBI:65173 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0015732 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027769 infores:hetionet CAID:CA2322775423 biolink:causes MONDO:0007750 infores:clingen CAID:CA2322775423 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, PS3, PS4, PM5, PP3, PP4 The NM_000527.5 (LDLR):c.1958_1959delinsCC (p.Val653Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows:PM2: The multi-nucleotide variant 19-1230880-TT-CC is observed once in at least 251454 total alleles from gnomAD (gnomAD v2.1.1). PopMax MAF for 19-11230880-T-C (NM_000527.5 (LDLR):c.1958T>C (p.Val653Ala) (CA305302665) is 0.00009921 (1/10080 alleles) in Ashkenazi Jewish population (gnomAD v2.1.1), whereas 19-11230881-T-C (NM_000527.5 (LDLR):c.1959T>C (p.Val653=) (ClinVar ID 252131) is a common variant with Grpmax FAF of 0.5225 (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA2322775423/MONDO:0007750/013 2024-02-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63598 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0022650 infores:hetionet CHEBI:46195 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0003467 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0080276 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0009938 infores:hetionet CHEBI:27834 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0085649 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0031117 infores:hetionet CHEBI:5088 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0042109 infores:hetionet CHEBI:2567 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0392171 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0017178 infores:hetionet CHEBI:63638 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0406834 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0011570 infores:hetionet CHEBI:8093 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0026205 infores:hetionet CHEBI:7476 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0518988 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0235146 infores:hetionet CHEBI:7915 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0522055 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0948807 infores:hetionet CHEBI:68534 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0011991 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0006142 infores:hetionet CHEBI:79699 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0311468 infores:hetionet CHEBI:9943 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0008031 infores:hetionet GO:0061001 biolink:causes GO:0048813 infores:ubergraph knowledge_assertion manual_agent GO:0061001 GO:0048813 CHEBI:47381 biolink:causes UMLS:C0863090 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0863090 infores:hetionet CHEBI:15940 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0008370 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017601 infores:hetionet CHEBI:15544 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0522055 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0006266 infores:hetionet CHEBI:9086 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0026961 infores:hetionet CHEBI:8888 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085631 infores:hetionet NCBIGene:3376 biolink:causes MONDO:0014911 infores:monarchinitiative not_provided not_provided HGNC:5330 MONDO:0014911 uuid:fad535b8-2dfe-435e-9e59-2c11dde19706 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3504 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0017178 infores:hetionet CHEBI:30830 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0497156 infores:hetionet CHEBI:45599 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0004093 infores:hetionet NCBIGene:9076 biolink:causes MONDO:0011874 infores:monarchinitiative not_provided not_provided HGNC:2032 MONDO:0011874 uuid:76366b42-b369-49ad-a186-384ee9d0510f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0001430 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0013395 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0233472 infores:hetionet GO:0003420 biolink:causes GO:0048705 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0048705 CHEBI:6640 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0023380 infores:hetionet CHEBI:50378 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0036572 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0007642 infores:hetionet CHEBI:3082 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0231530 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0017152 infores:hetionet CHEBI:5893 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085605 infores:hetionet CHEBI:7936 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0016204 infores:hetionet CHEBI:37924 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0009782 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023530 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0424605 infores:hetionet CHEBI:46195 biolink:causes NCIT:C34938 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0032788 infores:hetionet CHEBI:79699 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151904 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0877314 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877314 infores:hetionet CHEBI:17698 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0085624 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0242350 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0853760 infores:hetionet CHEBI:5296 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0013604 infores:hetionet CHEBI:44032 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0001175 infores:hetionet NCBIGene:859 biolink:causes MONDO:0019947 infores:monarchinitiative not_provided not_provided HGNC:1529 MONDO:0019947 uuid:62357823-2905-48f6-85e5-e58eec3d516c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0948586 infores:hetionet CHEBI:29688 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0085611 infores:hetionet CHEBI:135961 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0038999 infores:hetionet CHEBI:9434 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0030252 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0017160 infores:hetionet CHEBI:78543 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020625 infores:hetionet CHEBI:8382 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C2047937 infores:hetionet CHEBI:8713 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0013604 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006840 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015695 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015300 infores:hetionet CHEBI:9137 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0014724 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0031350 infores:hetionet CHEBI:10119 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0035455 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0243026 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0424000 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151849 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0427108 infores:hetionet CHEBI:2676 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0917799 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0553548 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0021775 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0027726 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0815316 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2004521 infores:hetionet CAID:CA8815547 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815547 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000152.5:c.1930_1936dup (p.Val646GlyfsTer93) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 2 probands with IOPD and documented GAA activity in the affected range in dried blood spot have been reported with this variant (Duke Molecular Diagnostic Laboratory; PMIDs: 19966354, 22252923, 31606152) (PP4_Moderate). Of those individuals, one was homozygous for the variant (PMID: 19966354). The other individual was compound heterozygous for the variant and c.2189+3G>C (ClinVar Variation ID: 1409309); phase unconfirmed (Duke Molecular Diagnostic Laboratory; PMIDs: 22252923, 31606152). The allelic data for this patient will be used to support the classification of c.2189+3G>C and is not included here in order to avoid circular logic. (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006640 (6/90366 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Of note, this variant has been described in the literature using historical nomenclature, including c.1929_1935dup (PMID: 19966354) and c.1936_1937insGCCGACG (PMIDs: 22252923, 31606152); for the purpose of this summary, current HGVS nomenclature was used. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 2, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815547/MONDO:0009290/010 2025-09-02 2025-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:44915 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0010200 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0042514 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1145628 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0232591 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C1455782 infores:hetionet CAID:CA229882 biolink:causes MONDO:0009861 infores:clingen CAID:CA229882 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PM3_Supporting, PVS1_Strong The c.970-2A>C variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 10 (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported in ClinVar (variant ID 102918), without a classification. It has been previously reported (PMID: 7866411) in one Polish proband with classic PKU (as ascertained by abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), who was homozygous for the variant (0.5 points; PM3_Supporting). Classification: Likely PathogenicSupporting Criteria: PVS1_Strong; PM2; PM3_Supporting; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229882/MONDO:0009861/006 2020-08-27 2020-08-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51041 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0022650 infores:hetionet CAID:CA192745675 biolink:causes MONDO:0009595 infores:clingen CAID:CA192745675 MONDO:0009595 PMID: Uncertain Significance PM2_Supporting This variant has been identified in 4 individuals among 700288 (0.000005712) in gnomAD v4.1.0. It has an AF of 0.00001999 in admixed Americans and a Grpmax Filtering AF of 0.000002080, which is below the threshold established by the SCID VCEP (<0.0000447). Therefore this criterion is met: PM2_Supporting. The variant has not been described in patients with cartilage-hair hypoplasia or in trans with any other RMRP variant. In summary, this variant is classified as Uncertain Significance for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA192745675/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:37924 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1112320 infores:hetionet CHEBI:8772 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0023218 infores:hetionet CHEBI:134991 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0236000 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0235431 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0521495 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0019158 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C2830004 infores:hetionet CHEBI:45863 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011168 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0403632 infores:hetionet CHEBI:17026 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0030252 infores:hetionet CHEBI:135613 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0231218 infores:hetionet CHEBI:161680 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0239113 infores:hetionet CHEBI:6916 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0278134 infores:hetionet UNII:T58MSI464G biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0042963 infores:hetionet CHEBI:490877 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0235378 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151578 infores:hetionet CAID:CA386959690 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959690 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PP4 The c.412G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to serine at codon 138 (p.(Gly138Ser)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9539, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757; internal lab contributors). Additionally, the calculated MODY probability in these individuals is <50% and HNF4A was not tested (internal lab contributor). In summary, this variant meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied as specified by the GlinGen MDEP VCEP (specification version 3.0, approved 6/30/2025): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959690/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27786 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0016436 infores:hetionet CHEBI:3996 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C2584688 infores:hetionet CHEBI:101853 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0853697 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151605 infores:hetionet CHEBI:47381 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151529 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0021775 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0877605 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0877605 infores:hetionet CHEBI:9123 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0242184 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0038362 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0006840 infores:hetionet CHEBI:9332 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0002792 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0027441 infores:hetionet CAID:CA16608280 biolink:causes MONDO:0010278 infores:clingen CAID:CA16608280 MONDO:0010278 PMID: Likely Benign BS2, BP4, BP5 BS1 The c.698-5A>G variant in SLC9A6 (NM_006359.2) is present in 26 XX and 8 XY individuals in gnomAD v4 (0.004%) (not sufficient to meet BS1 criteria). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.698-5A>G variant is observed in the hemizyous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The c.698-5A>G variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the c.698-5A>G variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BP4, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608280/MONDO:0010278/033 2024-02-23 2024-03-31 X-linked inheritance HP:0001417 Contradicts true CAID:CA7331523 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331523 MONDO:0100216 PMID: Likely Benign BP4, BP7 PM2, BA1, BP2, PP3, PP1, PP4, BS2, PM1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.1140G>C (p.Leu380=) variant is a synonymous (silent) variant that is not predicted to impact splicing by MaxEntScan or SpliceAI (BP4, BP7). The total allele frequency in gnomAD v4.1.0 is 0.000006195 (10/1614118alleles) with a highest population minor allele frequency of 0.00008783 (8/91086alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, BP7. (Bayesian Points: -2; VCEP specifications version 1.3.0; 06/28/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331523/MONDO:0100216/024 2024-06-25 2024-07-30 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA5544361 biolink:causes MONDO:0020678 infores:clingen CAID:CA5544361 MONDO:0020678 PMID: Pathogenic PP3, PM5, PM3_Very Strong PM2, BP4 The p.Glu956Lys variant in CDH23 is a missense variant predicted to cause substitution of glutamic acid to lysine at amino acid 956. The highest population minor allele frequency in gnomAD v3.1.2 is 0.02895% (12/41444) in African/African American population which is greater than the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) and less than the BS1_supporting MAF of ≥0.0007 (0.07%) for autosomal recessive disorders (no codes met). The computational predictor REVEL produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine homology. This variant has been detected in at least six probands with hearing loss without evidence of retinal disease (5 PM3_Very Strong points, PMID: 26763877,25963016, 22899989, Invitae Internal Data (SCV001228538.3)). Of those individuals, four harbored the p.Pro240Leu pathogenic variant in CDH23 with three individuals confirmed in trans (PMID 25963016, 22899989). The fifth individual harbored the p.Asp645Gly variant in CDH23, but phasing was not performed (PMID 25963016). The sixth proband carried a second pathogenic CDH23 variant in trans (Invitae Internal Data). 1 different missense variant, c.2867A>G (p.Glu956Gly) ClinVar Variation ID:1180655, in the same codon has been classified as likely pathogenic for AR sensorineural hearing loss by two submitters in ClinVar (PM5). In summary, this variant meets the criteria to be classified as pathogenic for AR hearing loss based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PP3, PM3_Very Strong, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA5544361/MONDO:0020678/005 2023-06-27 2023-10-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CAID:CA409108146 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108146 MONDO:0015967 PMID: Likely Pathogenic PS3_Supporting, PP3, PP4, PM2_Supporting, PM1_Supporting, PS2 PP1, PS4 The c.901A>T variant in the Hepatocyte nuclear factor 4 alpha, HNF4A, causes an amino acid change of isoleucine to phenylalanine at codon 301 (p.(Ile301Phe)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located within the ligand binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified as a de novo occurrence with confirmed parental relationships in 1 individual with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2; PMID:15830177). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Ile301Phe protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID:23485969). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 15830177). In summary, c.901A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PS2, PS3_Supporting, PM2_Supporting, PM1_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108146/MONDO:0015967/085 2023-07-30 2023-07-31 Autosomal dominant inheritance HP:0000006 Supports CAID:CA415078334 biolink:causes MONDO:0010305 infores:clingen CAID:CA415078334 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting PM5 The NM_005629.4(SLC6A8):c.407C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Valine at amino acid 136 p.(Ala136Val). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.873 which is above the threshold of 0.75 established for in silico predictions, therefore PP3 criteria is applicable. This variant has not been previously reported in ClinVar, and a different amino acid change at the same amino acid is reported there as a Variant of Uncertain Significance (c.406G>A (p.Ala136Thr); VarID:1285463). At the time of this curation, this variant has not been reported in individuals with suspected Creatine Transporter Deficiency in the literature. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PM2_Supporting, PP3.(Classification approved by the ClinGen CCDS VCEP, March 23, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415078334/MONDO:0010305/027 2023-03-23 2024-02-11 X-linked inheritance HP:0001417 Inconclusive true CAID:CA5543878 biolink:causes MONDO:0019501 infores:clingen CAID:CA5543878 MONDO:0019501 PMID: Uncertain Significance PP3, PP4, PM3 PM2 The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA5543878/MONDO:0019501/005 2023-10-18 2024-07-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:465284 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0038325 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0458104 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0458104 infores:hetionet CHEBI:4636 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0020458 infores:hetionet CHEBI:3752 biolink:causes HP:0003811 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0410916 infores:hetionet CHEBI:8435 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0012833 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0043251 infores:hetionet CHEBI:6690 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0151786 infores:hetionet CHEBI:3757 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0004245 infores:hetionet CHEBI:32315 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020903 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151565 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027947 infores:hetionet CAID:CA14902396 biolink:causes MONDO:0011071 infores:clingen CAID:CA14902396 MONDO:0011071 PMID: Benign BA1, BP4, BP2, BP7 PS4, PS3, PS2, PS1, BP1, BP3, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM1, PM5, PM4, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.98-1560C>T is an intronic variant. MAF of 0.0.05199 (5.19%, 251/1328, 4828 alleles) in the South Asian subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). There are 12 homozygotes present in gnomAD v3.1.2 (BP2). This variant is not a missense variant therefore will not have a REVEL score and SpliceAI score <0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.82 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14902396/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:70746 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0406834 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0549433 infores:hetionet CHEBI:63619 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0039070 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027765 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034186 infores:hetionet NCBIGene:3315 biolink:causes MONDO:0011687 infores:monarchinitiative not_provided not_provided HGNC:5246 MONDO:0011687 uuid:9123eef1-63a4-45eb-b5a0-80d74357cf5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6916 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0600142 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0029408 infores:hetionet CHEBI:8461 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0080274 infores:hetionet CHEBI:94392 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0042109 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0233494 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0025061 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0027051 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0302295 infores:hetionet CHEBI:10102 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002962 infores:hetionet CHEBI:4903 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0021177 infores:hetionet CHEBI:91541 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0000729 infores:hetionet CHEBI:2904 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0917801 infores:hetionet NCBIGene:256472 biolink:causes MONDO:0859380 infores:monarchinitiative not_provided not_provided HGNC:28497 MONDO:0859380 uuid:cc345793-71a9-49de-b0bf-b677b3490ad2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5098 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0002878 infores:hetionet CHEBI:100246 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0014518 infores:hetionet CHEBI:50223 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0040822 infores:hetionet CHEBI:4511 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0030193 infores:hetionet CHEBI:9586 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011603 infores:hetionet CHEBI:6970 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C2607914 infores:hetionet CHEBI:9555 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0151798 infores:hetionet CHEBI:7581 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0020580 infores:hetionet CHEBI:7915 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013491 infores:hetionet CHEBI:51137 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0018681 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0031350 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013298 infores:hetionet CHEBI:7936 biolink:causes MONDO:0041526 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0156543 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0024050 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0024050 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0860967 infores:hetionet CHEBI:135935 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0028084 infores:hetionet CHEBI:6520 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0595916 infores:hetionet CHEBI:6717 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0004093 infores:hetionet CHEBI:10101 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235710 infores:hetionet CHEBI:17347 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0027424 infores:hetionet CHEBI:3752 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0016382 infores:hetionet CAID:CA658658870 biolink:causes MONDO:0015967 infores:clingen CAID:CA658658870 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.724del variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 242 in NM_175914.5, adding 39 novel amino acids before encountering a stop codon (p.(Val242Cysfs*39)). This variant, located in biologically-relevant exon 7 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.724del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658870/MONDO:0015967/085 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports GO:0110057 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:0110057 GO:0001944 GO:0008359 biolink:causes GO:0008358 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0008358 CHEBI:480999 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0237849 infores:hetionet GO:0072301 biolink:causes GO:0072224 infores:ubergraph knowledge_assertion manual_agent GO:0072301 GO:0072224 CHEBI:480999 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151888 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0033246 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151971 infores:hetionet NCBIGene:5592 biolink:causes MONDO:0014187 infores:monarchinitiative not_provided not_provided HGNC:9414 MONDO:0014187 uuid:f435c8e8-82a7-4ab2-8691-32f518979336 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4876 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0003467 infores:hetionet CHEBI:4708 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1735601 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0948586 infores:hetionet CHEBI:3499 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0042267 infores:hetionet CAID:CA272702 biolink:causes MONDO:0012589 infores:clingen CAID:CA272702 MONDO:0012589 PMID: Likely Pathogenic PM1, PP3, PM6, PS4_Supporting, PM2_Supporting The p.Val581Phe variant in TCF4 is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). This variant is absent from gnomAD (PM2_supporting). The p.Val581Phe variant in TCF4 occurs in the de novo state (biological parentage unconfirmed) in an individual with delays, hypotonia, not walking, dysmorphic features (University of Chicago internal database) (PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Invitae internal database) (PS4_supporting). In summary, the p.Val581Phe variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM1, PM2_supporting, PM6, PP3, PS4_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA272702/MONDO:0012589/016 2022-02-18 2022-06-30 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:16899 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0018801 infores:hetionet NCBIGene:95 biolink:causes MONDO:0012368 infores:monarchinitiative not_provided not_provided HGNC:177 MONDO:0012368 uuid:f72aeb18-76d3-4846-adc1-f946025eacee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes HP:0004409 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C2364082 infores:hetionet CHEBI:4562 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235198 infores:hetionet CHEBI:6775 biolink:causes HP:0012701 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0426636 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017152 infores:hetionet CHEBI:4495 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0017979 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036130 infores:hetionet CHEBI:18332 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0002962 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0006849 infores:hetionet NCBIGene:1654 biolink:causes MONDO:0010497 infores:monarchinitiative not_provided not_provided HGNC:2745 MONDO:0010497 uuid:c372b9da-a7a0-47a7-9e49-cd2caebd05a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0018794 infores:hetionet CHEBI:50777 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042345 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0017601 infores:hetionet CAID:CA170175 biolink:causes MONDO:0010726 infores:clingen CAID:CA170175 MONDO:0010726 PMID: Benign BS1, BS2 BP4 The allele frequency of the p.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170175/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:47898 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042029 infores:hetionet CHEBI:408174 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020461 infores:hetionet CAID:CA274531 biolink:causes MONDO:0044970 infores:clingen CAID:CA274531 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PP1, BP4, PS2, PS4, PM6 The m.5631G>A in MT-TA has been reported in one individual to date, in a woman with adult-onset myopathy (PMID: 25873012). Her muscle biopsy showed numerous COX-deficient fibers and ragged red fibers. Decreased activities of mitochondrial respiratory chain enzymes complexes I, II/III, and IV were noted although values were not provided. The variant was present in the proband at 92% in muscle, 77% in blood, 77% in hair shafts, 69% in urinary epithelial cells, and 44% in buccal sample. As this is the only case reported to date, PS4 could not be applied. Her healthy mother had the variant present at lower heteroplasmy levels (8% blood, 4% urine, 6% buccal sample) however, given no additional family members were tested, segregation evidence (PP1) could not be applied. There are no reported de novo occurrences of this variant to our knowledge. Computational predictors are conflicting precluding consideration of PP3 or BP4 (MitoTIP: 43.4%; HmtVAR: 0.45). There is one occurrence of this variant in Mitomap's 61, 134 sequences (AF=0.002%; Hg L0a); one heteroplasmic occurrence in Helix's 195,983 sequences (AF=0.001%; 10-20% heteroplasmy, Hg W); and one heteroplasmic occurrence in gnomAD v3.1.2 (0.002%; Hg V, PM2_supporting). Single fiber testing showed higher levels of the variant in COX deficient fibers (n=18; 95.1% +/- 0.45) than in COX positive fibers (n=22; 83.8% +/- 3.38; PS3_supporting, PMID: 25873012). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274531/MONDO:0044970/015 2024-02-26 2024-03-14 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:38545 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0027765 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0522224 infores:hetionet CHEBI:94501 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0025222 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151888 infores:hetionet CHEBI:50922 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0043387 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0574067 infores:hetionet CHEBI:68478 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0149725 infores:hetionet CHEBI:8863 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011603 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C3489393 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0003123 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001259 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0342405 infores:hetionet CAID:CA229851 biolink:causes MONDO:0009861 infores:clingen CAID:CA229851 MONDO:0009861 PMID:14726806PMID:18590700 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting PS3 The NM_000277.1(PAH):c.922C>T (p.Leu308Phe) variant is a missense variant in exon 9/13 of PAH. The variant has been found to lead to 47% of wild-type enzyme activity in an intron-included (Intinc) system (PMID: 18590700) and is listed as having 49% of wild-type enzyme activity in BioPKU (ID PAH0362), consistent with a published report in a prokaryotic system (PMID: 16091306; PMID: 15557004). It has been found in at least seven PKU patients, including in trans with other Pathogenic or Likely Pathogenic variants and among patients with BH4 deficiency excluded (PM3_VeryStrong (6 points total); PP4_Moderate). It has been found in trans with the p.R261Q variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) in a patient with classic PKU (plasma Phe >1200 umol/L) with BH4 deficiency excluded by urine pterin profile and blood dihydropteridine reductase (DHPR) activity (PMID: 15557004; PMID: 14726806). It has been found in a Chinese patient with plasma Phe 467 umol/L and BH4 deficiency excluded by urinary pterin analysis and DHPR activity assay, in trans with a deletion of exon 1 (unclassified variant) (PMID: 29499199). It has also been noted in at least 3 Swedish PKU patients detected by NBS (PMID: 27469133). The variant has been previously reported in 3 Chinese PKU patients with BH4 deficiency excluded by dihydropteridine reductase activity, urinary biopterin and neopterin ratio: one with mild hyperphenylalanemia in trans with p.S70del (Pathogenic in ClinVar and by ClinGen PAH VCEP); one with mild PKU in trans with p.Q232* (Pathogenic in ClinVar); and one with mild PKU in trans with with c.442-1G>A (Pathogenic in ClinVar and by ClinGen PAH VCEP) (PMID: 30050108). It has been noted in 2 Czech patients with mild PKU, one with p.R252W and one with p.P281L; neither parental testing or exclusion of BH4 deficiency were noted (PMID: 23357515). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.892) (PP3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229851/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8382 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0243026 infores:hetionet CHEBI:7865 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0232462 infores:hetionet CHEBI:8888 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0392171 infores:hetionet NCBIGene:2056 biolink:causes MONDO:0060662 infores:monarchinitiative not_provided not_provided HGNC:3415 MONDO:0060662 uuid:4ad1ac1b-8ed6-4f13-8cf3-2617e32f7c42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1901210 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1901210 GO:0007275 CHEBI:47780 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0600142 infores:hetionet CAID:CA10014503 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014503 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.492C>T (p.Val164=) is a synonymous variant. No REVEL score because a synonymous variant and SpliceAI is ≤0.20( 0.01 Donor Loss -16bp and 0.11 Donor Gain 7bp) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP 1.91014 ≤ 2.0) meeting BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014503/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3568 biolink:causes UMLS:C0235972 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235972 infores:hetionet CHEBI:145499 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017181 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0011609 infores:hetionet CHEBI:30830 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0003467 infores:hetionet CHEBI:209807 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0015230 infores:hetionet CHEBI:4325 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0162830 infores:hetionet CHEBI:29688 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0020461 infores:hetionet CHEBI:3756 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0035455 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232492 infores:hetionet CHEBI:3061 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0015230 infores:hetionet CHEBI:49375 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151908 infores:hetionet NCBIGene:3315 biolink:causes MONDO:0012080 infores:monarchinitiative not_provided not_provided HGNC:5246 MONDO:0012080 uuid:0c3d8068-5b69-49af-9cf9-1c3760151537 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2687 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0009450 infores:hetionet NCBIGene:10021 biolink:causes MONDO:0008102 infores:monarchinitiative not_provided not_provided HGNC:16882 MONDO:0008102 uuid:1ba84c1a-78d9-4fff-b386-947be0e19765 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6438 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0036974 infores:hetionet CHEBI:63791 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0423006 infores:hetionet CHEBI:101085 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0040822 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009938 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020621 infores:hetionet CAID:CA410207044 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207044 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.650G>A (p.Gly217Glu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207044/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64355 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085636 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002311 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0154833 infores:hetionet CHEBI:5118 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151539 infores:hetionet NCBIGene:8565 biolink:causes MONDO:0012012 infores:monarchinitiative not_provided not_provided HGNC:12840 MONDO:0012012 uuid:d75d2cb5-9355-4f2e-8e24-7281ff291447 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134990 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0027441 infores:hetionet CHEBI:9137 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018520 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0341742 infores:hetionet CHEBI:8764 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151830 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0267792 infores:hetionet CHEBI:6741 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0340865 infores:hetionet CHEBI:47381 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042384 infores:hetionet CAID:CA414447212 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447212 MONDO:0010604 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PM5, PP3 The NM_000133.4:c.1304G> variant in F9 is a missense variant predicted to cause substitution of Cys by Phe at amino acid 435 (p.Cys435Phe). This variant has been reported in 1 proband meeting F9 phenotype criteria (PS4_Supporting; PMID: 22544209). This variant is absent from gnomAD v2, v3 and v4 (PM2_Supporting). Another missense variant c.1304G>A (p.Cys435Tyr) in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). The computational predictor REVEL gives a score of 0.969, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_Supporting, PM2_Supporting, PP3, PM5. (Version 1.0.0, 10/05/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447212/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63631 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020456 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0031117 infores:hetionet UMLS:C0023610 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0687713 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0497327 infores:hetionet CHEBI:50122 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0027441 infores:hetionet CHEBI:9586 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085649 infores:hetionet CHEBI:63617 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0338831 infores:hetionet CHEBI:4814 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0043349 infores:hetionet CHEBI:42797 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1145670 infores:hetionet CHEBI:10100 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0232487 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001265 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0036358 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018021 infores:hetionet CAID:CA024625 biolink:causes MONDO:0007783 infores:clingen CAID:CA024625 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with phenylalanine at codon 2210 of the RYR1 protein, p.Val2210Phe. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:15731587, The UK (Leeds) MH Unit, Prevention Genetics). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.961) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024625/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ NCBIGene:6305 biolink:causes MONDO:0014117 infores:monarchinitiative not_provided not_provided HGNC:10542 MONDO:0014117 uuid:30059ead-553a-4e1e-a776-46b4a5f4b47a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA343726308 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726308 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PM6, PP3, PP1, PM5, PM4, PS4, PS1, PS3, PS2, BA1, BP4 The c.731G>C variant in MYOC is a missense variant predicted to cause substitution of Glycine by Alanine at amino acid 244 (p.Gly244Ala). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.629, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with JOAG had been reported (PMID: 12442283), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726308/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:18248 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0333641 infores:hetionet CHEBI:75246 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0041969 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015927 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0039070 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0040409 infores:hetionet CHEBI:7986 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C2047937 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018799 infores:hetionet CHEBI:28925 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0040053 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0021845 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0522336 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0522336 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042063 infores:hetionet CHEBI:101278 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027441 infores:hetionet CHEBI:50841 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0392676 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027932 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0151826 infores:hetionet CHEBI:63598 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030193 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0037195 infores:hetionet CHEBI:17303 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0019521 infores:hetionet CHEBI:75998 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0015402 infores:hetionet CHEBI:3561 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0041657 infores:hetionet CHEBI:5280 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0023218 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1384666 infores:hetionet CHEBI:8768 biolink:causes MONDO:0020642 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0311245 infores:hetionet CAID:CA041346 biolink:causes MONDO:0007750 infores:clingen CAID:CA041346 MONDO:0007750 PMID:25386756 Likely Benign PS4_Supporting, BP4, BS3, PM2, PP4 BA1, BP1, BP2, BP3, PS1, PS3, PS2, BP5, BP7, BS1, BS4, PM5, PM1, PM3, PM4, PM6, PVS1, PP2, PP3, PP1, BS2 NM_000527.5(LDLR):c.2575G>A (p.Val859Met) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS3, BP4, and PM2, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS3 - PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%.BP4 - REVEL: 0,209. Score is below 0,5. Splicing predictors - negative. so BP4 is met.PM2 - PopMa MAF = 0.0001629 (0.01629%) in 'Other' (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill Simon-Broome criteria for FH (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria for FH.Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate and 1 Supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041346/MONDO:0007750/013 2021-06-24 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:478164 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0549249 infores:hetionet CHEBI:3371 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes HP:0030788 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0021092 infores:hetionet CHEBI:68558 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0027497 infores:hetionet CAID:CA367401967 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401967 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PP4, PM2_Supporting The c.442T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to isoleucine at codon 148 (p.(Phe148Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6%) (PP4; internal lab contributor). In summary, c.442T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401967/MONDO:0015967/086 2023-10-02 2023-10-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:36791 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042024 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0037274 infores:hetionet CHEBI:10650 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151744 infores:hetionet CHEBI:42068 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0023530 infores:hetionet CHEBI:44241 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0014130 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233494 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235431 infores:hetionet CHEBI:10119 biolink:causes HP:0040307 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1112443 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0008311 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0549209 infores:hetionet CHEBI:49713 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0030353 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037284 infores:hetionet CHEBI:16796 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0233407 infores:hetionet CAID:CA913177906 biolink:causes MONDO:0044970 infores:clingen CAID:CA913177906 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PM6_Supporting PP1, PP3, BP4, PS4, PS2, PS3 The m.4372C>T variant in MT-TQ has been reported in one individual with primary mitochondrial disease to date however clinical details are not provided (PMIDs: 23463613, 31965079). The variant was present in blood of the proband at 22.8% heteroplasmy and was reportedly absent in an unspecified tissue from the mother (PM6_supporting; PMIDs: 23463613, 31965079). There are no other families reported in the medical literature to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 71.3%; HmtVAR: 0.25). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913177906/MONDO:0044970/015 2024-09-24 2024-11-21 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA024091 biolink:causes MONDO:0100150 infores:clingen CAID:CA024091 MONDO:0100150 PMID: Uncertain Significance PP3, PP4, PM3, PM2_Supporting PM5, PM1, BP4, BA1, PS1, PS3, BS1 The c.13949T>C variant in RYR1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 4650 (p.Leu4650Pro). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.805, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been detected in two individuals with central core disease (CCD). Of those individuals, both were compound heterozygous for the variant and a VUS and both of those were confirmed in trans by parental testing (RYR1 p.Lys4724Gln, PMID: 12937085, PMID: 30611313, ClinVar Variation ID: 65957) (PM3). At least one patient with this variant displayed Type I fiber predominance, unique large eccentric cores, few necrotic/regenerative fibers, and connective tissue increase, which is highly specific for RYR1-related myopathy (PP4, PMID: 12937085). In summary, the variant meets the criteria to be classified as uncertain significance for autosomal recessive RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3, PM3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024091/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0085610 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0004096 infores:hetionet CAID:CA7511659 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511659 MONDO:0015152 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PM2_Supporting The NM_000070.3: c.1993-1G>A variant in CAPN3 occurs within the -1/2 dinucleotide splice acceptor site of intron 17. This variant is predicted to abolish the consensus splice acceptor site, with a SpliceAI score of 0.99, and strengthen an alternative site 1 bp away, with a SpliceAI score of 1.0. Use of the alternative acceptor site or skipping of exon 18, which is out of frame, would be expected to disrupt the reading frame, leading to nonsense mediated decay in a gene in which loss of function is an established mechanism of disease (PVS1). This variant has been reported in at least six patients with clinical features consistent with LGMD (PMID: 30564623, 26404900, 18055493; LOVD CAPN3_000288), including in a homozygous state in one proband from a family without reported consanguinity (0.5 pts, PMID: 30564623, LOVD Individual #00220357) and in unknown phase with a pathogenic variant in one individual (c.550del, 0.5 pts, PMID: 30564623, LOVD Individual #00219523) (PM3). At least one individual with this variant and a second presumed diagnostic variant in CAPN3 had a clinical suspicion of LGMD and significantly reduced calpain-3 protein expression on western blot, which is specific for CAPN3-related LGMD (PMID: 18055493; PP4_Moderate). The filtering allele frequency of this variant is 0.000030594 in the European (non-Finnish) population in gnomAD v4.1.0 (24/1103246 exomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/03/2025): PVS1, PM3, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511659/MONDO:0015152/187 2025-05-03 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7640 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0151596 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0015376 infores:hetionet CHEBI:63791 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149512 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0521839 infores:hetionet CHEBI:77733 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0235378 infores:hetionet CAID:CA349020645 biolink:causes MONDO:0100038 infores:clingen CAID:CA349020645 MONDO:0100038 PMID: Likely Pathogenic PP3_Moderate, PM6_Supporting, PM5_Supporting, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP5, BS1, BS3, PM1, PP1, BA1, BP2, BP4 The NM_001040142.2:c.1094C>T variant in SCN2A is a missense variant predicted to cause substitution of threonine by methionine at amino acid 365 (p.Thr365Met). This variant has been reported in 1 proband meeting criteria for complex neurodevelopmental disorder and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a complex neurodevelopmental disorder (PM6_Supporting, PS4_Supporting; PMID 27824329). This variant is absent from gnomAD v[4.1.0] (PM2_Supporting). The computational predictor REVEL gives a score of 0.885, which is above the threshold of 0.773, evidence that correlates with impact to SCN2A function (PP3_Moderate). 2 different missense variants, SCN1A c.1088C>T, p.Thr363Ile and SCN1A c.1088C>G, p.Thr363Arg, (PMIDs 36034301, 31864146, 24679980, 32613771) in the paralogous codon of SCN1A have been classified as likely pathogenic for Dravet syndrome (MONDO:0100135) by the ClinGen Epilepsy Sodium Channel VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PP3_Moderate, PM2_Supporting, PM6_Supporting, PS4_Supporting, PM5_Supporting. (Variant Interpretation Guidelines for SCN2A Version 2.0.0, 3/25/2025). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349020645/MONDO:0100038/068 2025-03-25 2025-04-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA915940463 biolink:causes MONDO:0700270 infores:clingen CAID:CA915940463 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5_Supporting, PVS1 BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM6, BS2, PP2, PP3, PP1, PP4 The c.6958del (p.Asp2320Metfs*11) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive ataxia-telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_supporting, PM2_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940463/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3219 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1609512 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0234458 infores:hetionet CHEBI:4495 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C2939147 infores:hetionet CHEBI:94686 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0035078 infores:hetionet CHEBI:31174 biolink:causes UMLS:C1112366 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C1112366 infores:hetionet CHEBI:8802 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C3665347 infores:hetionet NCBIGene:8074 biolink:causes MONDO:0060714 infores:monarchinitiative not_provided not_provided HGNC:3680 MONDO:0060714 uuid:b1edd72e-cc2d-4ea8-9b3a-30c4de7090f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0240211 infores:hetionet CHEBI:6030 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0004093 infores:hetionet CHEBI:9123 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151610 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013595 infores:hetionet CHEBI:36791 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0700361 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0042109 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0026946 infores:hetionet CHEBI:5384 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0012569 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0031350 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0026946 infores:hetionet CHEBI:134990 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C2830004 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0014868 infores:hetionet CHEBI:38562 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0015230 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0451641 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001245 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085576 infores:hetionet CHEBI:2955 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1096343 infores:hetionet CHEBI:5138 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013491 infores:hetionet CHEBI:7640 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0043352 infores:hetionet CHEBI:16899 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0030196 infores:hetionet CHEBI:6950 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085612 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013595 infores:hetionet NCBIGene:3712 biolink:causes MONDO:0009475 infores:monarchinitiative not_provided not_provided HGNC:6186 MONDO:0009475 uuid:7d990dad-cf59-4b84-8687-c8b593be432a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042075 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0036416 infores:hetionet CHEBI:10125 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0016382 infores:hetionet CHEBI:194135 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0851578 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0853149 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0857245 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0857245 infores:hetionet CHEBI:32588 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0011603 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0023530 infores:hetionet CHEBI:3506 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0002874 infores:hetionet CHEBI:31644 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0027424 infores:hetionet CHEBI:8890 biolink:causes MONDO:0006737 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013418 infores:hetionet CHEBI:63627 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0038362 infores:hetionet CHEBI:9137 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0023518 infores:hetionet CHEBI:8802 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0017168 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017675 infores:hetionet CHEBI:4702 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0162529 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0853035 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0853035 infores:hetionet CHEBI:6437 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0030554 infores:hetionet CHEBI:5790 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0234238 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0475765 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0475765 infores:hetionet CHEBI:7852 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0026837 infores:hetionet CHEBI:28177 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0012833 infores:hetionet CHEBI:5109 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0021053 infores:hetionet CHEBI:2569 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0002792 infores:hetionet CHEBI:35778 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0036974 infores:hetionet CHEBI:31547 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0013404 infores:hetionet CHEBI:4798 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1456784 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0039971 infores:hetionet CHEBI:52717 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015967 infores:hetionet CHEBI:41423 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0344232 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006044 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027719 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0040034 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0009450 infores:hetionet NCBIGene:2332 biolink:causes MONDO:0010382 infores:monarchinitiative not_provided not_provided HGNC:3775 MONDO:0010382 uuid:01d24dff-818a-4295-8dd3-f60c2745f114 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:140621 biolink:causes MONDO:0006009 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0243010 infores:hetionet CAID:CA401369658 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369658 MONDO:0009290 PMID:19862843 Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3_Supporting The NM_000152.5:c.1857C>G variant in GAA is predicted to result in the substitution of serine by arginine at amino acid 619 (p.Ser619Arg).This variant has been reported in at least 10 patients with features consistent with Pompe disease including individuals with clinical symptoms of Pompe disease and documented laboratory data showing GAA activity below the normal reference range or <10% in relevant tissues (PMID: 14643388, 17092519, 29124014, 21984055, 23884227), and additional patients without GAA activity reported but on enzyme replacement therapy (PMID: 25213570, 29869463) (PP4_Moderate). Five patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.1579_1580del (p.Arg527GlyfsTer3), confirmed in trans (PMID: 29869463); c.1156C>T (p.Gln386Ter), phase unknown (PMID: 23884227); c.1309C>T (p.Arg437Cys), phase unknown (PMID: 29124014); c.1798C>T (p.Arg600Cys), phase unknown (PMID: 29124014); and c.1735G>A (p.Glu579Lys), phase unknown (PMID: 29124014); and at least three are homozygous for the variant (PMID: 14643388, 29124014) (maximum allowed = 2 x 0.5 points = 1 point). Additional patients have been reported who are compound heterozygous for the variant and either c.875A>G (p.Tyr292Cys) (PMID: 23884227, 25213570), or c.2015G>A (p.Arg672Gln) (PMID: 17092519). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Finally, additional patients may also carry the variant but were not included because the cDNA change for the variant was not reported (PMID: 17805474, 18495398, 21676566) (PM3_Very Strong). When expressed in COS cells in two seprate function, studies, the variant results in <2% GAA activity compared to wild type (PMIDs: 14643388, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.795 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 550825). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP on December 6, 2022) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369658/MONDO:0009290/010 2022-12-06 2022-12-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:50381 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0235031 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0236072 infores:hetionet CHEBI:63925 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0152227 infores:hetionet CHEBI:77260 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0033774 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0018099 infores:hetionet CHEBI:7825 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0030193 infores:hetionet CHEBI:41977 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0876994 infores:hetionet CHEBI:28939 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C2939147 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0018099 infores:hetionet CAID:CA040016 biolink:causes MONDO:0007750 infores:clingen CAID:CA040016 MONDO:0007750 PMID: Uncertain Significance PP3 PS3, PM5, PM2 The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PP3: REVEL = 0.773.PM2 not met: PopMax MAF = 0.00056 in Latino population in gnomAD (gnomAD version: 2.1.1).PP4, PS4 not applicable: Variant did not meet PM2.PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2374A>T (p.Ile792Phe) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040016/MONDO:0007750/013 2022-08-26 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:52717 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0262988 infores:hetionet CHEBI:7454 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0009676 infores:hetionet CHEBI:3647 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0221152 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0037274 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0034065 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006325 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0860434 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0860434 infores:hetionet CHEBI:4514 biolink:causes MONDO:0001617 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0338591 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0042109 infores:hetionet CHEBI:64355 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0438142 infores:hetionet NCBIGene:51520 biolink:causes MONDO:0024568 infores:monarchinitiative not_provided not_provided HGNC:6512 MONDO:0024568 uuid:1b85c31f-00b2-46bd-a812-ceff19645f53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA658798616 biolink:causes MONDO:0007648 infores:clingen CAID:CA658798616 MONDO:0007648 PMID: Likely Benign BS2_Supporting, PM2_Supporting, BP4 BP5, BP7, BS4, BS1, BS3, PM3, PM5, PM4, PM1, PVS1, PM6, PP4, PP1, PP2, PP3, BP2, BP1, BP3, BA1, PS2, PS4, PS1, PS3 The c.49-9C>A is an intronic variant in the splice acceptor region of intron 1. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; SCV000729557.1, SCV000760811.1). This variant is predicted to have no impact on splicing by multiple in silico splice site predictors. HumanSpliceFinder predicts that this variant may alter an exonic ESE site, but this effect has not been demonstrated experimentally to our knowledge (BP4). In summary, due to the use of the Bayesian point system for this variant with conflicting evidence, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2_Supporting, BP4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798616/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3084 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0027497 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0012833 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0032961 infores:hetionet NCBIGene:875 biolink:causes MONDO:0009352 infores:monarchinitiative not_provided not_provided HGNC:1550 MONDO:0009352 uuid:faaaacab-04f5-44c1-b760-ab6347251fae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0027051 infores:hetionet CHEBI:3515 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0404521 infores:hetionet CHEBI:261649 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0018834 infores:hetionet NCBITaxon:5878 biolink:causes MONDO:0005704 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5878 MONDO:0005704 CHEBI:9398 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0152029 infores:hetionet CHEBI:4514 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C2047937 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0234458 infores:hetionet CAID:CA229799 biolink:causes MONDO:0009861 infores:clingen CAID:CA229799 MONDO:0009861 PMID:2063869 Uncertain Significance PM2 PM5, PP3, PP4, PS1 The c.828G>T (p.Met276Ile) variant in PAH has been reported detected in a control clone from a subject who did not have PKU (PMID: 8364546, 9634518) This variant is absent from gnomAD, 1000G, ESP, and PAGE. Computational evidence is conflicting (Disease causing in MutationTaster, tolerated in SIFT, benign in PolyPhen2). There are 3 other missense changes at this amino acid: M276R (interpretation not provided in ClinVar, ID 102858); M276K (Likely Pathogenic in ClinVar, ID 102857); M276V (Likely Pathogenic in ClinVar, ID 102856). A different codon change leading to the same amino acid change, c.828G>A, has been interpreted as a variant of uncertain significance in ClinVar (ID 551519). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229799/MONDO:0009861/006 2021-01-17 2021-04-09 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31644 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0037199 infores:hetionet CHEBI:10023 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0086565 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0014742 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0038325 infores:hetionet CHEBI:3756 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013404 infores:hetionet CAID:CA9871470 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871470 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting BS2, PM5, BS3, PS1, PS3 The c.899T>G (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Phenylalanine by Cysteine at amino acid 300 (p.Phe300Cys).The filtering allele frequency (the upper threshold of the 95% CI of 64/1180048) of the c.899T>G variant in ADA is 0.00004346 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871470/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:27666 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0002170 infores:hetionet CHEBI:63599 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0019080 infores:hetionet CHEBI:8081 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0030554 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030517 infores:hetionet CHEBI:51380 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0014518 infores:hetionet NCBITaxon:1513 biolink:causes MONDO:0005526 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1513 MONDO:0005526 CHEBI:478164 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0036690 infores:hetionet GO:0140884 biolink:causes GO:0045087 infores:ubergraph knowledge_assertion manual_agent GO:0140884 GO:0045087 CHEBI:7915 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011630 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0392106 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0392106 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0035085 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0035085 infores:hetionet CHEBI:28939 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes MONDO:0007500 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0266589 infores:hetionet UNII:3U02EL437C biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0015672 infores:hetionet CHEBI:3479 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0311468 infores:hetionet NCBIGene:80746 biolink:causes MONDO:0012890 infores:monarchinitiative not_provided not_provided HGNC:28422 MONDO:0012890 uuid:a2deb9f3-0d21-4ef8-9517-10314f56a1a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8597 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0152128 infores:hetionet CHEBI:31711 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0015967 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0271051 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0162429 infores:hetionet CHEBI:50173 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C1527344 infores:hetionet CAID:CA173814 biolink:causes MONDO:0007113 infores:clingen CAID:CA173814 MONDO:0007113 PMID: Uncertain Significance BP4 BS1, PM2, PS4 The c.2284G>A p.(Val762Ile) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.004% in the African/African-American sub population (no criteria met). The p.(Val762Ile) variant has been observed in at least 1 individual with a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 25212744), however the PS4 criteria cannot be applied due to the gnomAD frequency of this variant. Computational analysis prediction tools suggest that the p.(Val762Ile) variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2284G>A p.(Val762Ile) variant in UBE3A is classified as a Variant of Uncertain Signficance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA173814/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:6775 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027726 infores:hetionet GO:0045685 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0045685 GO:0007399 CHEBI:9649 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0021053 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0426747 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0426747 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0234458 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002519 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0003462 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0012833 infores:hetionet CHEBI:36795 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0236075 infores:hetionet CHEBI:31184 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0152459 infores:hetionet CHEBI:83531 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0235996 infores:hetionet CHEBI:3757 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0035455 infores:hetionet CHEBI:5818 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0020517 infores:hetionet CHEBI:8327 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0023530 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0011609 infores:hetionet CAID:CA645369482 biolink:causes MONDO:0017623 infores:clingen CAID:CA645369482 MONDO:0017623 PMID:10400993PMID:22261759PMID:27477328PMID:25669429 Likely Pathogenic PVS1, PM2_Supporting PM6, BS1, BS3, BS4, BP7, BP5, BS2, PP3, PP2, PP1, PP4, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.441_442delinsA (p.Ala148HisfsTer5) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PM2_P: Absent in large sequenced populations in the gnomAD cohort (PMID:27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369482/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50131 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0003123 infores:hetionet CAID:CA7331519 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331519 MONDO:0100216 PMID: Likely Benign BP4, BP2, BS2_Supporting PM2, PM6, PVS1, BA1, BP1, BP3, PP2, PP3, PP1, PP4, PM4, PM3, PM1, PM5, PS2, PS3, PS4, PS1, BS1, BS3, BS4, BP7, BP5 The NM_177438.3:c.1157A>G variant in DICER1 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 386 (p.Lys386Arg). This variant has been observed in trans with the variant c.3091C>T, p.Gln1031Ter (Internal lab contributors) which would be classified as pathogenic/likely pathogenic by the ClinGen DICER1 VCEP specifications (BP2). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001053 (17/1614068 alleles) with a highest population minor allele frequency of 0.00001356 (16/1180004 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.123; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_supporting, BP2, BP4. (Bayesian Points: -3; VCEP specifications version 1.3.0; 08/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331519/MONDO:0100216/024 2024-08-27 2024-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7986 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0178298 infores:hetionet CHEBI:44915 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0028961 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0029445 infores:hetionet CHEBI:31949 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0812387 infores:hetionet NCBIGene:10370 biolink:causes MONDO:0013750 infores:monarchinitiative not_provided not_provided HGNC:1987 MONDO:0013750 uuid:5cd476f0-a00e-4cec-aebc-65479be49f78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0030554 infores:hetionet CHEBI:8378 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0041834 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151735 infores:hetionet CHEBI:10101 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0242301 infores:hetionet CHEBI:68478 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0156404 infores:hetionet CAID:CA386296833 biolink:causes MONDO:0009861 infores:clingen CAID:CA386296833 MONDO:0009861 PMID: Likely Pathogenic PM3, PM2, PP4, PP3 This c.563G>T (p.Gly188Val) variant in PAH was reported in trans with pathogenic variant p.Val399= in 1 patient with PAH deficiency (>120 μmol/L Phe) (PMID: 28982351). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386296833/MONDO:0009861/006 2020-11-16 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:74947 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027947 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0235453 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0235453 infores:hetionet CAID:CA343724606 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724606 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3, PM2_Supporting, PS4_Supporting BS1, BS3, BP7, PM6, PM5, PM4, PS1, PS3, PS2, BA1, BP4 The c.1130C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Lysine at amino acid 377 (p.Thr377Lys). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.908, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 5 segregations in 1 family, with juvenile open angle glaucoma, have been reported (PMID: 11774072), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 11774072, 31302906), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724606/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2676 biolink:causes UMLS:C1736172 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C1736172 infores:hetionet CHEBI:521033 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0234047 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0518015 infores:hetionet CHEBI:5959 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0520966 infores:hetionet CHEBI:36791 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0086439 infores:hetionet CHEBI:49713 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0043352 infores:hetionet CAID:CA5546544 biolink:causes MONDO:0019497 infores:clingen CAID:CA5546544 MONDO:0019497 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PM3 The c.8083G>A variant in CDH23 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 2695 (p.Asp2695Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005% (4/74190) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007]) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.789, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in a total of three individuals with phenotypes consistent with CDH23-related disorders. One individual with hearing loss was compound heterozygous for the variant and a pathogenic variant, however phase was unknown (c.6085C>T p.Arg2029Trp , 0.5 PM3 points, PMID: 35020051). The second individual was a one-year-old female with hearing loss who harbored the c.6866A>G p.Asn2289Ser variant of uncertain significance in trans (0.25 PM3 points, ARUP internal data SCV000602953.1). The third individual had hearing loss and retinopathy, which is highly specific for Usher syndrome,, and harbored the c.7225-1G>A variant of uncertain significance in trans (0.25 PM3 points, PP4, PMID: 30081015). This individual also had seizures, developmental delay, and ADHD and a de novo ANKRD11 variant thought to cause these additional features. In summary, this variant has been classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PP4, PM3. (VCEP specifications version 2; 06.26.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA5546544/MONDO:0019497/005 2023-06-26 2023-10-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:68478 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1619712 infores:hetionet CHEBI:94848 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0022107 infores:hetionet CHEBI:9123 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019065 infores:hetionet CHEBI:4798 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0019080 infores:hetionet NCBIGene:2271 biolink:causes MONDO:0007888 infores:monarchinitiative not_provided not_provided HGNC:3700 MONDO:0007888 uuid:7be334e7-726b-47cc-95b4-c0e4387ee24c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4888 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0015672 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0349506 infores:hetionet CHEBI:7465 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C2047937 infores:hetionet CHEBI:6129 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0025222 infores:hetionet CAID:CA245628 biolink:causes MONDO:0015152 infores:clingen CAID:CA245628 MONDO:0015152 PMID: Likely Benign BP4, BS1 BP7, BP5 The NM_003494.4: c.4512C>G p.(Val1504=) variant in DYSF, which is also known as NM_001130987.2: c.4629C>G p.(Val1543=), is a synonymous (silent) variant that is not expected to change the amino acid sequence. The filtering allele frequency for this variant is 0.001985 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2286/1111986 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). While this variant affects the first amino acid of exon 42 and so is located in a splice region (BP7 not met), the SpliceAI score is 0, which is less than the LGMD VCEP threshold of 0.05 (BP4). This variant has been identified in a patient with a clinical suspicion of LGMD but as a single hit in an individual with an alternative molecular diagnosis (LOVD Individual #00220067). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA245628/MONDO:0015152/180 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:48273 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0011991 infores:hetionet CHEBI:27666 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0015967 infores:hetionet CHEBI:84500 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235490 infores:hetionet CHEBI:53760 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233795 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0162429 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0021053 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0017178 infores:hetionet CHEBI:135935 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0023380 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0020517 infores:hetionet CHEBI:29007 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0011615 infores:hetionet CHEBI:7773 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0006266 infores:hetionet CHEBI:2663 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0003578 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0034155 infores:hetionet NCBIGene:84946 biolink:causes MONDO:0859355 infores:monarchinitiative not_provided not_provided HGNC:21173 MONDO:0859355 uuid:dbc1878f-760b-4cf4-8418-1e62747d5e49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0242429 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0027765 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0855242 infores:hetionet CHEBI:52717 biolink:causes HP:6000364 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085648 infores:hetionet CHEBI:4885 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0012833 infores:hetionet CHEBI:31980 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0005778 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0023530 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151436 infores:hetionet NCBIGene:51626 biolink:causes MONDO:0014907 infores:monarchinitiative not_provided not_provided HGNC:24595 MONDO:0014907 uuid:fabfd266-2094-450a-9d34-945f19b37abf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0033975 infores:hetionet CHEBI:84883 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0000731 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0009450 infores:hetionet CHEBI:8707 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027497 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009676 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0242350 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0030920 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0235431 infores:hetionet CHEBI:92712 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0522224 infores:hetionet CHEBI:37924 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030232 infores:hetionet CHEBI:77733 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0031350 infores:hetionet CHEBI:64317 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0016382 infores:hetionet CHEBI:3757 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0085610 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006147 infores:hetionet CHEBI:75998 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0017565 infores:hetionet NCBITaxon:5811 biolink:causes MONDO:0005715 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5811 MESH:D014125 DB00359_MESH_D014125_1 CHEBI:61049 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007114 infores:hetionet NCBIGene:27316 biolink:causes MONDO:0010277 infores:monarchinitiative not_provided not_provided HGNC:9910 MONDO:0010277 uuid:edba6512-f154-4ffc-844f-a20df6b741cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0879264 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0018790 infores:hetionet CHEBI:92998 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0021843 infores:hetionet CHEBI:7823 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0036974 infores:hetionet CHEBI:52717 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004134 infores:hetionet CHEBI:27690 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0042109 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0008370 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0031350 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0038661 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0041912 infores:hetionet CAID:CA023403 biolink:causes MONDO:0012933 infores:clingen CAID:CA023403 MONDO:0012933 PMID: Pathogenic PVS1, PM3_Strong, PM5_Strong PM2 The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA023403/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3175 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0027424 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006852 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009806 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0948594 infores:hetionet CHEBI:52717 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020580 infores:hetionet CHEBI:7852 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0162297 infores:hetionet GO:0110137 biolink:causes GO:0007478 infores:ubergraph knowledge_assertion manual_agent GO:0110137 GO:0007478 CAID:CA658658931 biolink:causes MONDO:0010725 infores:clingen CAID:CA658658931 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4 The NM_000330.4(RS1):c.221_237delinsTCCCCTGACCGGGTTAGAGT variant is a frameshift variant due to a deletion of 17 nucleotides and an insertion of 20 nucleotides, introducing a premature stop codon after 3 amino acids and causing a truncated protein. This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family (PP1_strong; PMID: 9699564). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 9699564, PP4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PM2_supporting, PP1_strong, and PP4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658931/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports NCBIGene:346007 biolink:causes MONDO:0011272 infores:monarchinitiative not_provided not_provided HGNC:21555 MONDO:0011272 uuid:7ab8eed8-3411-4e10-9cb0-9bb57f27fdf1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085610 infores:hetionet CHEBI:7865 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0006266 infores:hetionet CHEBI:127780 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C1145670 infores:hetionet CHEBI:15544 biolink:causes MONDO:0016056 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0025958 infores:hetionet CHEBI:6456 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0035232 infores:hetionet CHEBI:9738 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0040822 infores:hetionet CHEBI:68584 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0012833 infores:hetionet CAID:CA377481238 biolink:causes MONDO:0017623 infores:clingen CAID:CA377481238 MONDO:0017623 PMID: Pathogenic PS2_Very Strong, PP2, PP3, PM2_Supporting, PS3_Moderate NM_000314.8(PTEN):c.212G>A (p.Cys71Tyr) meets criteria to be classified as Pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: One proven plus two assumed de novo observations in a patient with the disease and no family history. (internal laboratory contributors: SCV003918479.1, SCV001376634.5)PS3_M: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.57581.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.957)PM2_P: Absent in the gnomAD cohort. (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377481238/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6970 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0021400 infores:hetionet CHEBI:3716 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0000729 infores:hetionet CHEBI:9738 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0232462 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0860967 infores:hetionet CHEBI:64064 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0149725 infores:hetionet CHEBI:23765 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003862 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1384353 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0034186 infores:hetionet CAID:CA414793083 biolink:causes MONDO:0044970 infores:clingen CAID:CA414793083 MONDO:0044970 PMID: Uncertain Significance PP3 PP1, BA1, PS4, PS2, PS3, BS1, PM6, PM2 The m.7637G>A (p.E18K) variant in MT-CO2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual with Parkinson disease with haplogroup Uk1 (PMID: 19076426). There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 2/59,389 (0.003%). The frequency in gnomAD v3.1.2 is 6/56,427 (0.011%). This includes three homoplasmic occurrences (two European, one African/African American, haplogroups T, J, L2) and three heteroplasmic occurrences (two European, one African/African American; haplogroups K, L3, U; one with 10-20% heteroplasmy, one with 30-40% heteroplasmy, one with 60-70% heteroplasmy; two individuals in 70-75-year-old range with details not provided on other individuals). The frequency in the Helix dataset is 16/195,983 (0.008%) including 12 homoplasmic occurrences (haplogroups T=6, H=3, A=1, C=1, L2=1) and four heteroplasmic occurrences (haplogroup J=1, K=1, L3=1, T=1). Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). There are no cybrids, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.91 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414793083/MONDO:0044970/015 2023-06-26 2023-08-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:17347 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C2239176 infores:hetionet CAID:CA512341039 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341039 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1326C>T (p.Leu442=) is a synonymous variant that has a SpliceAI score ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.86 < 2.0) (BP7). The variant is not present in population databases (gnomAD v2.1 or v3.1.2) (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341039/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45716 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0000833 infores:hetionet CHEBI:134745 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0004093 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0232492 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0029882 infores:hetionet CHEBI:7445 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0236075 infores:hetionet CHEBI:8713 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0151539 infores:hetionet CHEBI:8024 biolink:causes HP:0040307 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1112443 infores:hetionet CHEBI:39669 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0019158 infores:hetionet CHEBI:10101 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151786 infores:hetionet CHEBI:135736 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151579 infores:hetionet CHEBI:72564 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0004604 infores:hetionet CHEBI:5100 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0033774 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0037274 infores:hetionet CHEBI:4717 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0018790 infores:hetionet CHEBI:7931 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0237314 infores:hetionet CHEBI:8461 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C2830004 infores:hetionet CHEBI:9907 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0043352 infores:hetionet CHEBI:8107 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0003578 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001245 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085576 infores:hetionet CHEBI:8869 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0003862 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0021400 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042571 infores:hetionet CHEBI:49375 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0917801 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0037928 infores:hetionet CHEBI:63605 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0036974 infores:hetionet CHEBI:9649 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C2830004 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0019112 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017160 infores:hetionet CHEBI:131512 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0030554 infores:hetionet CAID:CA255668 biolink:causes MONDO:0018947 infores:clingen CAID:CA255668 MONDO:0018947 PMID: Pathogenic PP4, PP1, PM2_Supporting, PS4, PVS1, PM6 BA1, BS1 The c.141_144del (p.Glu48LeufsTer24) variant in MTM1 is a deletion variant predicted to cause a premature stop codon in biologically-relevant-exon 4/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The c.141_144del variant has been identified in at least 6 male probands with severe centronuclear myopathy, one of which was de novo with unconfirmed parental relationships, and one severely affected female (PMIDs: 9285787, 30241883, 33062893, 33164942, 10063835) (PS4, PM6). Additionally, the variant segregated with disease in an uncle and a male sibling from two separate families (PMID: 9285787) (PP1). At least one patient with this variant displayed a muscle biopsy consistent with centronuclear myopathy (PMID:33164942) (PP4). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PS4, PM6, PM2_Supporting, PP1, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA255668/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Supports CHEBI:4798 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0027765 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0016479 infores:hetionet CHEBI:2569 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0233407 infores:hetionet CHEBI:6950 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0001807 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0836924 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0034069 infores:hetionet CHEBI:6888 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0162835 infores:hetionet CHEBI:63630 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0030193 infores:hetionet CHEBI:3814 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0151905 infores:hetionet CHEBI:6437 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1145670 infores:hetionet CHEBI:231425 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0036974 infores:hetionet CHEBI:167638 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0002962 infores:hetionet CHEBI:15407 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0003123 infores:hetionet CHEBI:63577 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1096250 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0007642 infores:hetionet CHEBI:28939 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0239488 infores:hetionet CHEBI:6754 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0016382 infores:hetionet CAID:CA1244011 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244011 MONDO:0005338 PMID:36579626PMID:36579626 Likely Benign BS1 BP7, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.1499A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 500 (p.Lys500Arg). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.005811, which met the ≥ 0.001 threshold set for BS1 (436 alleles out of 75,032, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.502, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Lys500Arg protein was assessed in an assay (PMID: 36579626), however, the results of this study were inconsistent and functional evidence was not included. Although probands with primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -4 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244011/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0270458 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0032961 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0949070 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0949070 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0020517 infores:hetionet NCBIGene:84892 biolink:causes MONDO:0029135 infores:monarchinitiative not_provided not_provided HGNC:25902 MONDO:0029135 uuid:fef85e30-8ba9-4b88-9d87-f8ecc8bddda0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410208309 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208309 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.3G>C (p.Met1Ile) is a start-loss variant which is not predicted to undergo nonsense-mediated decay. RUNX1 has multiple biologically relevant isoforms, and this variant only affects isoform C. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208309/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2208 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0030312 infores:hetionet CAID:CA1619871 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619871 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PVS1 PP1, PP3, BP4, BA1, PM1, PM4, PM5, PS2, PS3, PS1, BP7, BS1, BS4, BS3 The c.1063C>T variant in CYP1B1 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Arginine at amino acid 355 (p.Arg355Ter). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00008008 (6 alleles out of 74,922), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This nonsense variant was not predicted to undergo NMD but removes the haem-binding domain (PVS1 met). There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in 6 individuals with a CYP1B1-related phenotype. 4 of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (2 confirmed in trans = 2 points and 2 phase unknown = 1 point). 2 probands are homozygous for the variant (non-consanguineous = 1 point) (PMIDs: 20057908, 23218701,35085548, 21815720). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. Although a possible de novo occurrence has been reported (PMID: 20827438), the specifications for this criterion were not met and PS2 was not applied. In summary, this variant met the criteria to receive a score of 17 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Very-strong, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619871/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4974 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C2830004 infores:hetionet CHEBI:63608 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0010200 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0205204 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0027769 infores:hetionet CHEBI:85083 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0033774 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0948525 infores:hetionet CHEBI:8499 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0037299 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0035078 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0037199 infores:hetionet CHEBI:75988 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0031542 infores:hetionet CHEBI:52172 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0025323 infores:hetionet CHEBI:6832 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0023530 infores:hetionet CHEBI:63616 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0004093 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0578455 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0578455 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020651 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0042075 infores:hetionet CHEBI:51380 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0152227 infores:hetionet CHEBI:5855 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0040822 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0086543 infores:hetionet CHEBI:50922 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0002994 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0030554 infores:hetionet CHEBI:51364 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0080274 infores:hetionet CHEBI:9586 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0522224 infores:hetionet CHEBI:71255 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0043144 infores:hetionet CHEBI:63635 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0149745 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027765 infores:hetionet CHEBI:5001 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0700345 infores:hetionet CHEBI:9150 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C2239176 infores:hetionet CHEBI:6754 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0520966 infores:hetionet NCBIGene:64094 biolink:causes MONDO:0007436 infores:monarchinitiative not_provided not_provided HGNC:20323 MONDO:0007436 uuid:4a1af9f4-5b06-46cd-bada-632b8b81aec7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0036572 infores:hetionet CHEBI:50648 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038999 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0009450 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0006840 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0151773 infores:hetionet CHEBI:71255 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0549622 infores:hetionet NCBIGene:341640 biolink:causes MONDO:0054738 infores:monarchinitiative not_provided not_provided HGNC:25396 MONDO:0054738 uuid:19425d8f-02c8-43c2-ad40-00f3b96bdcc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA352048631 biolink:causes MONDO:0012249 infores:clingen CAID:CA352048631 MONDO:0012249 PMID: Pathogenic PS3, PP3_Moderate, PP1_Strong, PM2_Supporting The NM_000249.4(MLH1):c.923A>C (p.His308Pro) variant in MLH1 has a CIMRA Functional Odds for Pathogenicity of 69.27 (PS3). The variant has been reported to segregate with Lynch-syndrome and reaches 25.20 total segregation odds. The variant is not reported in gnomAD v4.1 (PM2_supporting). The variant has a prior probability of 0.974 (PP3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal-dominant inherited Lynch syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS3, PP1_Strong, PP3_Moderate and PM2_supporting applied. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA352048631/MONDO:0012249/115 2024-10-11 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0031039 infores:hetionet CHEBI:63620 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0264906 infores:hetionet CHEBI:107736 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0234428 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022081 infores:hetionet CHEBI:3181 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0009782 infores:hetionet CHEBI:8707 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006118 infores:hetionet CHEBI:51450 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0085633 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042571 infores:hetionet CHEBI:102216 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0151766 infores:hetionet CHEBI:63598 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1456784 infores:hetionet CHEBI:50729 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0031256 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0853760 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014868 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0025061 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0236071 infores:hetionet UMLS:C0120107 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C2830004 infores:hetionet CHEBI:94807 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0003123 infores:hetionet CHEBI:3125 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0027497 infores:hetionet CHEBI:3048 biolink:causes UMLS:C0587054 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0587054 infores:hetionet NCBITaxon:1647 biolink:causes MONDO:0006751 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1647 MONDO:0006751 CAID:CA10568042 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568042 MONDO:0010602 PMID:24108539PMID:21645226 Likely Benign BS3, PM2_Supporting, PP3 BS1, PS4 The NM_000132.4(F8):c.5063C>T variant in F8 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 1688 (p.Ser1688Leu). This variant has been reported in 1 proband with moderate Hemophilia A. However, PS4 cannot be applied because VWD 2N was not ruled out (PMID: 18387975, PMID: 18217193). The variant is absent in males in gnomAD v2.1.1 (PM2_supporting). One-stage clotting assay and antigen specific ELISAs in CHO Chinese Hamster cell line and HEK293 human cells showed normal FVIII activity and antigen levels indicating that this variant does not impact protein function (PMID: 21645226, PMID: 24108539)(BS3). The computational predictor REVEL gives a score of 0.616, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). Due to conflicting evidence, this variant is classified as a variant likely benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BS3, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568042/MONDO:0010602/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:47780 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009782 infores:hetionet CHEBI:8871 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0015672 infores:hetionet NCBIGene:3300 biolink:causes MONDO:0013947 infores:monarchinitiative not_provided not_provided HGNC:5228 MONDO:0013947 uuid:4aed598e-78ef-46a2-8ba4-67a4a1174c6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA414802316 biolink:causes MONDO:0044970 infores:clingen CAID:CA414802316 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6 PP1, PS2, PS3 The m.9155A>G (p.Q210R) variant in MT-ATP6 has been reported in three unrelated individuals in the literature (PMIDs: 34961688, 27966441, 27450679) and has been reported to have been seen by experts on this panel in an additional three unrelated individuals. Heteroplasmy levels were variable in affected individuals as were mitochondrial disease features, although diabetes and deafness were reported in several individuals (PS4_moderate; PMIDs: 34961688, 27966441, 27450679). The variant occurred in de novo in one of the cases reported by an expert on this panel and in one of the cases reported in the literature (PS2_moderate; PMID: 27450679). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS2_moderate, PS4_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414802316/MONDO:0044970/015 2022-07-25 2022-10-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:2549 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0700345 infores:hetionet CHEBI:68534 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0233414 infores:hetionet CHEBI:4995 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0340865 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1384353 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0041969 infores:hetionet CHEBI:44185 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0002390 infores:hetionet CHEBI:7445 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0013456 infores:hetionet CHEBI:8890 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0085612 infores:hetionet CHEBI:168396 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0014724 infores:hetionet CHEBI:37941 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151942 infores:hetionet CHEBI:167638 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0022354 infores:hetionet CHEBI:5558 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0237849 infores:hetionet CHEBI:93635 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0039070 infores:hetionet CHEBI:10119 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0032617 infores:hetionet CHEBI:520985 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0011991 infores:hetionet CHEBI:31644 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042963 infores:hetionet CAID:CA405669616 biolink:causes MONDO:0018493 infores:clingen CAID:CA405669616 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405669616/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:75988 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0020458 infores:hetionet CHEBI:6367 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0035410 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011616 infores:hetionet NCBIGene:3889 biolink:causes MONDO:0700342 infores:monarchinitiative not_provided not_provided HGNC:6460 MONDO:0700342 uuid:8cd78260-1150-4201-a8c0-152dcbcc915c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0011570 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0034065 infores:hetionet CHEBI:182080 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0011603 infores:hetionet CHEBI:9139 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0037011 infores:hetionet CHEBI:2950 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C2364111 infores:hetionet CHEBI:47898 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0040264 infores:hetionet NCBIGene:7148 biolink:causes MONDO:0014422 infores:monarchinitiative not_provided not_provided HGNC:11976 MONDO:0014422 uuid:07a27295-e2b6-48ff-9525-02eba3d6adcc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0042029 infores:hetionet CHEBI:7823 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0234518 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035309 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0027769 infores:hetionet CHEBI:6741 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0008033 infores:hetionet NCBITaxon:5759 biolink:causes MONDO:0005644 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5759 MESH:D000562 DB12780_MESH_D000562_1 CHEBI:168396 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030193 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0542101 infores:hetionet CAID:CA134989 biolink:causes MONDO:0019497 infores:clingen CAID:CA134989 MONDO:0019497 PMID:15700112PMID:26749107PMID:25388846PMID:23967136PMID:15479191PMID:19043807PMID:16840571PMID:26178431PMID:12792423PMID:20497192PMID:23826813PMID:24256046PMID:19043807PMID:12560944PMID:27247933PMID:27627659PMID:27792752PMID:15700112PMID:19366456PMID:15790391PMID:16840571 Uncertain Significance PM3_Supporting, PS3_Supporting, PP3, BS2, BS1_Supporting PS4 The c.571T>C (p.Phe191Leu) variant in GJB2 has been reported in over 19 Asian probands in the literature. However, a case control comparison using Chi-squared analysis did not show a statistical significance between cases and controls in the published studies, or between cases and East Asians in gnomAD (case chromosomes= 19/16415, control chromosomes = 6/8626, 36/18870 East Asian chromosomes in gnomAD; PMIDs 19366456, 15700112, 23826813, 27247933, 27792752, 12792423, 12560944, 19043807, 27627659, 20497192 and https://doi.org/10.1016/S1672-2930(07)50004-8). The filtering allele frequency of the p.Phe191Leu variant in the GJB2 gene is 0.14% for East Asian chromosomes in gnomAD (36/18870 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected in 1 individual with hearing loss who was homozygous for the variant, and in 4 compound heterozygous individuals who had a second pathogenic GJB2 variant identified (3 with p.Val37Ile and 1 with c.235delC) (Oguchi 2005 PMID: 15700112; ARUP SCV000603821; Partners Lab for Molecular Medicine SCV000061527). Phase was not confirmed for any of these individuals. It is possible that these homozygous and compound heterozygous observations are due to the relatively high allele frequencies of these variants in gnomAD and therefore PM3 was downgraded (PM3_Supporting). In addition, this variant was reported in the homozygous state in a normal hearing parent (BS2, Wattanasirichiagoon 2004, PMID 15479191). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). Two in vitro functional studies demonstrates that this variant resulted in abnormal protein trafficking and retention of the protein in the endoplasmic reticulum; however, further electrical coupling studies were not performed (PS3_Supporting; PMID: 23967136, 26749107). In summary, due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2, PM3_Supporting, PS3_Supporting, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA134989/MONDO:0019497/005 2018-09-24 2019-07-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:45863 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027497 infores:hetionet CHEBI:4856 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0015672 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085096 infores:hetionet CHEBI:6456 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0035455 infores:hetionet CHEBI:3534 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0017152 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0034065 infores:hetionet CHEBI:8364 biolink:causes MONDO:0041775 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C1688637 infores:hetionet CHEBI:681850 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0085611 infores:hetionet CHEBI:5296 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0039070 infores:hetionet CHEBI:77260 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0233471 infores:hetionet CHEBI:49713 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0037036 infores:hetionet CHEBI:31348 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019521 infores:hetionet CHEBI:23765 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0149745 infores:hetionet CHEBI:119915 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003962 infores:hetionet CHEBI:63115 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0234632 infores:hetionet GO:0003427 biolink:causes GO:0003423 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0003423 GO:0042669 biolink:causes GO:0009912 infores:ubergraph knowledge_assertion manual_agent GO:0042669 GO:0009912 CHEBI:3127 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0007859 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0027051 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020517 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0239093 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0239093 infores:hetionet CHEBI:63631 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0152031 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1258215 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0008325 infores:hetionet NCBIGene:1410 biolink:causes MONDO:0012130 infores:monarchinitiative not_provided not_provided HGNC:2389 MONDO:0012130 uuid:3f90f2b1-fb49-4a7e-8255-e2e8c2eb1685 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0016382 infores:hetionet CAID:CA1940318 biolink:causes MONDO:0100038 infores:clingen CAID:CA1940318 MONDO:0100038 PMID: Uncertain Significance PS1, PS4, BS1, PM5, PM1, PM2, PP3, BA1 The NM_001040142.2 c.4775T>C variant in SCN2A is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 1592 (p.Ile1592Thr). To our knowledge, this variant has not been reported in the literature in any individuals with Complex Neurodevelopmental Disorder. This variant does not reside within a region of SCN2A that is defined as a mutational hotspot or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP. The highest population minor allele frequency in gnomAD v4 is [0.00008001] (5/62490 alleles) in uncharacterized populations. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.745, which is neither above nor below the thresholds predicting a damaging or benign impact on SCN2A function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: No criteria met. (VCEP specifications version 1.0.0; approved 11/26/2024) Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1940318/MONDO:0100038/068 2024-11-26 2025-04-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61390 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C1384353 infores:hetionet CHEBI:48273 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0010200 infores:hetionet CHEBI:6339 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017181 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011551 infores:hetionet CHEBI:18358 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0037763 infores:hetionet CHEBI:135939 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0008031 infores:hetionet CHEBI:180905 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0042023 infores:hetionet CHEBI:4708 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C3665386 infores:hetionet CHEBI:3176 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0344232 infores:hetionet NCBIGene:2302 biolink:causes MONDO:0032874 infores:monarchinitiative not_provided not_provided HGNC:3816 MONDO:0032874 uuid:cb1d7a89-2ac5-406e-a902-9da1dd323433 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042373 infores:hetionet CHEBI:50659 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0033774 infores:hetionet CHEBI:6690 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0020580 infores:hetionet CAID:CA343725980 biolink:causes MONDO:0020367 infores:clingen CAID:CA343725980 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.821C>G variant in MYOC is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 274 (p.Pro274Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.949, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 15255110), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 15255110), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725980/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144093 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0027947 infores:hetionet CHEBI:63608 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151594 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0221100 infores:hetionet CHEBI:8356 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013390 infores:hetionet CHEBI:4445 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0010200 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0314719 infores:hetionet NCBIGene:51259 biolink:causes MONDO:0011963 infores:monarchinitiative not_provided not_provided HGNC:25018 MONDO:0011963 uuid:bca979d2-1a2e-41f3-8d07-e092b28cb91c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0852733 infores:hetionet CHEBI:15551 biolink:causes MONDO:0850046 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0013927 infores:hetionet CHEBI:5138 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0152198 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0029408 infores:hetionet NCBITaxon:773 biolink:causes MONDO:0005664 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:773 MONDO:0005664 CAID:CA132691 biolink:causes MONDO:0010134 infores:clingen CAID:CA132691 MONDO:0010134 PMID: Likely Benign BP4, BP2 PP3, PP1, PP4, PM3, PM2 The c.200C>G (p.Thr67Ser) variant in SLC26A4 is a missense variant predicted to cause substitution of threonine by serine at amino acid 67. The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population (PM2_supporting, BS1, and BA1 not met). The results from two predictors/lines of evidence, MaxEntScan and conservation analysis, with serine present at this residue in ten vertebrates, suggest that the variant does not impact SLC26A4 function (BP4). This variant has been observed in cis with the variant p.Leu236Val (c.706C>G) [PMIDs: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6], which is classified as likely pathogenic by the ClinGen Hearing Loss VCEP, in at least six affected individuals (BP2). The variant has been seen in the homozygous and compound heterozygous (in trans, phase confirmed) state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Pendred Syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BP4, BP2; Version 2; 3/20/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132691/MONDO:0010134/005 2024-03-20 2024-04-01 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:68478 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027765 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0017168 infores:hetionet NCBITaxon:813 biolink:causes MONDO:0005834 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:813 MESH:D008219 DB00759_MESH_D008219_1DB01017_MESH_D008219_1DB02703_MESH_D008219_1DB00618_MESH_D008219_1DB00254_MESH_D008219_1DB00595_MESH_D008219_1DB13092_MESH_D008219_1 CAID:CA16039798 biolink:causes MONDO:0021056 infores:clingen CAID:CA16039798 MONDO:0021056 PMID: Uncertain Significance PS4_Moderate, PM2_Supporting PVS1 The c.8514C>A variant in APC is a variant predicted to cause a premature stop codon at position 2838 (p.Tyr2838*) in exon 16, downstream of codon 2645. As a result, the PVS1 rule is not applicable. This variant has been reported in 2 probands meeting phenotype criteria, resulting in a total phenotype score of 2 (PS4_moderate, Ambry and Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this is a Variant of Unknown Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_moderate and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16039798/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7465 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0021400 infores:hetionet CHEBI:3228 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0151763 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0027765 infores:hetionet CHEBI:7514 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0006266 infores:hetionet NCBIGene:4803 biolink:causes MONDO:0012092 infores:monarchinitiative not_provided not_provided HGNC:7808 MONDO:0012092 uuid:878426bb-aa42-4696-8372-076f5a62ea9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0405479 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0405479 infores:hetionet CHEBI:75045 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151878 infores:hetionet CHEBI:31236 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015672 infores:hetionet CAID:CA645596587 biolink:causes MONDO:0007648 infores:clingen CAID:CA645596587 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM6, PP1, PP2, PP3, PP4, BS2, BP1, BP4, BP2, BP3, BA1, PS3, PS1, PS2 The c.208dup p.(Ser70Phefs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two family meeting HDGC clinical criteria (PS4_Moderate; SCV000637771.2, SCV000779081.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645596587/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:3223 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0018681 infores:hetionet CAID:CA240506 biolink:causes MONDO:0100039 infores:clingen CAID:CA240506 MONDO:0100039 PMID: Benign BS2_Supporting, BA1 The allele frequency of the p.Asn748Ser variant in CDKL5 is 0.03683% in African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Asn748Ser variant is observed in at least 1 unaffected individual (PMID: 29264392) (BS2_supporting). In summary, the p.Asn748Ser variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA240506/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:15551 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0948089 infores:hetionet GO:0038108 biolink:causes GO:0032099 infores:ubergraph knowledge_assertion manual_agent GO:0038108 GO:0032099 CHEBI:3419 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0018681 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0036572 infores:hetionet CHEBI:10023 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0016867 infores:hetionet CHEBI:3219 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030196 infores:hetionet CHEBI:6532 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0013395 infores:hetionet CHEBI:4710 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0015672 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027651 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0233494 infores:hetionet CAID:CA386960129 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960129 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5 The c.448A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamic acid at codon 150 (p.(Lys150Glu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additonally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.951, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325). Another missense variant at this residue, p.(Lys150Asn) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.448A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960129/MONDO:0015967/017 2024-10-13 2024-10-24 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:183 biolink:causes MONDO:0009970 infores:monarchinitiative not_provided not_provided HGNC:333 MONDO:0009970 uuid:2c1d2a74-66b4-486b-a2a7-42b46a2adbb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037384 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0039971 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030846 infores:hetionet CHEBI:31643 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0232208 infores:hetionet CHEBI:47781 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0011253 infores:hetionet CHEBI:8107 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0235546 infores:hetionet GO:0033047 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0033047 GO:0000278 CHEBI:8212 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C1096355 infores:hetionet CHEBI:100241 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0080274 infores:hetionet CHEBI:3387 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0549622 infores:hetionet CHEBI:4046 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0162830 infores:hetionet CHEBI:9445 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0002994 infores:hetionet CAID:CA9043587 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043587 MONDO:0012999 PMID: Likely Benign BP4, BS1 The NM_000156.6:c.570+161T>A variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 5. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population frequency in gnomAD v4.1.0. is 0.001162 (85/73150 alleles; no homozygotes) in the African / African American population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss and suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 625952). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): BS1, BP4.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043587/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:127780 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0852911 infores:hetionet CAID:CA410208010 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208010 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, BS1, BS3, BS4, BP5, BP7, PVS1, PM2, PM6, PM5, PM3, PM4, PP2, PP3, PP1, PP4, BS2 NM_001754.5:c.577A>G (p.Ile193Val) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208010/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0009782 infores:hetionet CHEBI:7903 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0039231 infores:hetionet CHEBI:10650 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0004093 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0543467 infores:hetionet CHEBI:49960 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0043352 infores:hetionet CHEBI:61390 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0007971 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0020651 infores:hetionet GO:0070445 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0070445 GO:0007399 CHEBI:63620 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0600104 infores:hetionet CHEBI:2469 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0031350 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0037199 infores:hetionet CHEBI:5103 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0040046 infores:hetionet CHEBI:127342 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0015967 infores:hetionet CHEBI:71941 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C2830004 infores:hetionet CHEBI:4466 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0018790 infores:hetionet CHEBI:7443 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002962 infores:hetionet CHEBI:2038 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0037763 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038663 infores:hetionet CAID:CA410203938 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203938 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.197C>A (p.Ala66Asp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203938/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63629 biolink:causes HP:0001395 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0239946 infores:hetionet GO:0048324 biolink:causes GO:0048322 infores:ubergraph knowledge_assertion manual_agent GO:0048324 GO:0048322 CHEBI:6775 biolink:causes MONDO:0006711 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0031048 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0036974 infores:hetionet CHEBI:6970 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0043144 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0021390 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0917801 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0549399 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0017178 infores:hetionet CHEBI:167638 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0004245 infores:hetionet NCBIGene:5158 biolink:causes MONDO:0013429 infores:monarchinitiative not_provided not_provided HGNC:8786 MONDO:0013429 uuid:1a8e5999-59cf-4ebe-893b-6f8155c6fc83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0152227 infores:hetionet CHEBI:391960 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0542571 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040435 infores:hetionet CHEBI:46295 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0267792 infores:hetionet CHEBI:3216 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013604 infores:hetionet CHEBI:5165 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0428977 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1384353 infores:hetionet CHEBI:2950 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0687713 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877098 infores:hetionet CHEBI:64312 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0039231 infores:hetionet CHEBI:17650 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0013491 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0876973 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0027651 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027947 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0040264 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020538 infores:hetionet CAID:CA10529834 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529834 MONDO:0010604 PMID: Benign BA1 PP3, BP4 The c.769G>A variant in F9 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 257 (p.Val257Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001548 (23/14862 alleles) in the East Asian population a grpmax FAF for exomes = 0.001015 and genomes = 0.0003535, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.0000556) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for Hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F9 (version 1.0.0, released 10/5/2023): BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529834/MONDO:0010604/080 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:8435 biolink:causes UMLS:C0267516 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0267516 infores:hetionet CHEBI:4027 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0011644 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006145 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1321686 infores:hetionet CHEBI:6541 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0085631 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0031542 infores:hetionet CHEBI:7444 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0023066 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014868 infores:hetionet CHEBI:28915 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0030554 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0234916 infores:hetionet CHEBI:3534 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0014518 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0013295 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0278079 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0282074 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0282074 infores:hetionet CHEBI:29688 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0022346 infores:hetionet CHEBI:109549 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0004093 infores:hetionet CHEBI:8764 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0040053 infores:hetionet CHEBI:584020 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0028961 infores:hetionet CHEBI:5062 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0234233 infores:hetionet CHEBI:6933 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0009676 infores:hetionet CAID:CA024333 biolink:causes MONDO:0007783 infores:clingen CAID:CA024333 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with tyrosine at codon 71 of the RYR1 protein, p.(Ser71Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in the literature in individuals with autosomal recessive myopathies. It has also been described in individuals that were noted to be MHS but without a clear history of an MH reaction. These cases did not meet the criteria for PS4 according to the ClinGen RYR1 VCEP for MHS, (PMID:16835904, PMID:16940308, PMID:17365175). Functional studies published for this variant test the variant in trans with other variants and these studies were not considered for PS3/BS3, (PMID:16940308). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score >0.85 (0.937) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024333/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:4858 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0014356 infores:hetionet CHEBI:15940 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0023218 infores:hetionet NCBITaxon:11676 biolink:causes MONDO:0005109 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11676 MONDO:0005109 CHEBI:15551 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0011175 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0038363 infores:hetionet CHEBI:127342 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0242429 infores:hetionet CHEBI:5004 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0017181 infores:hetionet CHEBI:18358 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0003811 infores:hetionet CHEBI:36791 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0856054 infores:hetionet CHEBI:5109 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0011616 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0085082 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0085082 infores:hetionet CHEBI:6067 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003962 infores:hetionet CHEBI:63581 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0149745 infores:hetionet CHEBI:135351 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0001807 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0221203 infores:hetionet CHEBI:3696 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0027066 infores:hetionet CAID:CA149405 biolink:causes MONDO:0007113 infores:clingen CAID:CA149405 MONDO:0007113 PMID: Benign BA1, BP4 The allele frequency of the c.2064+9T>C variant in UBE3A is 0.4% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions. Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.2064+9T>C variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA149405/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3215 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0011991 infores:hetionet CAID:CA023688 biolink:causes MONDO:0007750 infores:clingen CAID:CA023688 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PVS1_Strong, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS1, PS2, BP5, BP7, BS4, BS1, BS3, PM5, PM1, PM4, PM3, PM6, BS2, PP2, PP3 The NM_000527.4(LDLR):c.313+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1_Strong, PS4, PP1_Strong, PM2, PS3_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - Variant is in canonical GT +1 splice site, predicted to lead to exon 3 skipping (in frame).PS4 - Variant meets PM2. Identified in at least 14 unrelated index cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCS equal or above 6. PP1_strong - variant segregates with FH phenotype in 6 informative meiosis in 5 families from different laboratories. PM2 - PopMax MAF = 0.00006156 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1).PS3_moderateLevel 2 assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3; amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and above 25% of total transcript, and uptake is below 70% of wild-type, so PS3_moderate is Met.PP4 - Variant meets PM2. Identified in 3 FH cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria and in 13 FH cases from University of British Columbia (UBC, Canada) and 14 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023688/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7936 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0008031 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002173 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0273482 infores:hetionet CHEBI:65173 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0234022 infores:hetionet CHEBI:8597 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0034150 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018213 infores:hetionet CHEBI:3181 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0002170 infores:hetionet CHEBI:17303 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0006625 infores:hetionet CHEBI:3176 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C1260880 infores:hetionet CHEBI:5801 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0344232 infores:hetionet CHEBI:37333 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0013404 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0574067 infores:hetionet CHEBI:6801 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0235710 infores:hetionet CHEBI:63629 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013456 infores:hetionet NCBITaxon:1280 biolink:causes EFO:1001753 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D018784 DB00218_MESH_D018784_1 CHEBI:8707 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1142011 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0346156 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0026650 infores:hetionet CAID:CA024615 biolink:causes MONDO:0007783 infores:clingen CAID:CA024615 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP1_Moderate PP3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with valine at codon 2200 of the RYR1 protein, p.Ala2200Val. The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00015, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), apply PS4_Supporting due to EAS MAF of 0.00015 (PMID:15731587, PMID:21455645, PMID:30236257 ). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 6 individuals (PMID:21455645, PMID:16835904, personal communication). A REVEL score of 0.564 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP1_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024615/MONDO:0007783/012 2023-04-10 2023-04-10 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:16664 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0037274 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0040034 infores:hetionet UMLS:C0879264 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0000731 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0015397 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0595930 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1456863 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1456863 infores:hetionet CHEBI:63635 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0702166 infores:hetionet CHEBI:7447 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0151766 infores:hetionet CHEBI:8863 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004044 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0151763 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0518015 infores:hetionet CAID:CA412741596 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741596 MONDO:0100437 PMID: Likely Pathogenic PM5_Supporting, PP3_Strong, PM2_Supporting PP4 NM_001034853.2(RPGR):c.823G>C (p.Gly275Arg) is a missense variant causing substitution of glycine by arginine at amino acid 275. Another missense variant in the same codon, NM_001034853.2:c.823G>A (p.Gly275Ser), (PMIDs: 17480003, 31456290, 17724181, 16969763, and 8817343) has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (125) than the comparison variant (56), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype of retinal dystrophy, which is consistent with RPGR-related retinopathy but does not include sufficient details to meet PP4 (ClinVar submission SCV001240404.1). The computational predictor REVEL gives a score of 0.979, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.923 and predicts a damaging effect on RPGR function (PP3_Strong). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PM5_Supporting, and PP3_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741596/MONDO:0100437/106 2025-09-07 2025-09-08 X-linked inheritance HP:0001417 Supports CHEBI:3699 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0004245 infores:hetionet CHEBI:10100 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0015672 infores:hetionet CHEBI:49668 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0019080 infores:hetionet CHEBI:83527 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0042963 infores:hetionet CHEBI:51450 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0149725 infores:hetionet CAID:CA410208257 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208257 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.26C>A (p.Ser9Ter) is a nonsense variant in an exon that is absent from RUNX1 isoform a and b (c.1-c.97 as per VCEP specifications) (PVS1_NA). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208257/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:194135 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041582 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0085605 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0027651 infores:hetionet GO:0170060 biolink:causes GO:0007019 infores:ubergraph knowledge_assertion manual_agent GO:0170060 GO:0007019 CHEBI:63611 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0010692 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0040046 infores:hetionet CHEBI:51860 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011606 infores:hetionet NCBIGene:84987 biolink:causes MONDO:0033639 infores:monarchinitiative not_provided not_provided HGNC:28216 MONDO:0033639 uuid:db7741a7-49e1-4cf3-80b2-1c090cd91e02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C1384353 infores:hetionet CHEBI:31625 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0423602 infores:hetionet CHEBI:40279 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042384 infores:hetionet CHEBI:4708 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0003862 infores:hetionet CHEBI:4858 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085636 infores:hetionet CAID:CA410202462 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202462 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+1G>C is a dinucleotide splicing variant which results in the skipping of exon 5 (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PVS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202462/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4784 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0023052 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0037317 infores:hetionet CAID:CA2802338 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802338 MONDO:0001586 PMID: Likely Benign BS1, BP4 The NM_000203.5:c.1651-10C>T variant is located close to the acceptor splice region of intron 11 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.002868 (261/91014 alleles, 1 homozygote; GrpMax Filtering Allele Frequency (95% confidence) = 0.002582) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.0025), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (BP4). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802338/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:51230 biolink:causes UMLS:C1096668 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1096668 infores:hetionet CAID:CA202190 biolink:causes MONDO:0700270 infores:clingen CAID:CA202190 MONDO:0700270 PMID: Benign BA1, BP2_Strong BP4, PP3 The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA202190/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8356 biolink:causes UMLS:C0542313 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0542313 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0029882 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0020649 infores:hetionet NCBIGene:8291 biolink:causes MONDO:0011721 infores:monarchinitiative not_provided not_provided HGNC:3097 MONDO:0011721 uuid:d4ab6f6c-2767-448e-97ca-6aa31f0e884b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011991 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0241166 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0241166 infores:hetionet CHEBI:8212 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0013144 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011991 infores:hetionet CHEBI:53766 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0025222 infores:hetionet CHEBI:175901 biolink:causes MONDO:0020533 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0152063 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0030446 infores:hetionet CHEBI:4885 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0034150 infores:hetionet CHEBI:45409 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011124 infores:hetionet CHEBI:9907 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0232462 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235901 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0521839 infores:hetionet GO:0060487 biolink:causes CL:0000082 infores:ubergraph knowledge_assertion manual_agent GO:0060487 CL:0000082 CHEBI:5613 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0877338 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0031039 infores:hetionet CHEBI:3723 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0423791 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233414 infores:hetionet CHEBI:50648 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013604 infores:hetionet CHEBI:36791 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1112442 infores:hetionet NCBIGene:24142 biolink:causes MONDO:0970998 infores:monarchinitiative not_provided not_provided HGNC:30252 MONDO:0970998 uuid:2dbbccd0-1d49-4c9d-91e9-d0d1fcfe44e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5654 biolink:causes MONDO:0010829 infores:monarchinitiative not_provided not_provided HGNC:9476 MONDO:0010829 uuid:bca400ad-b0b4-4ae7-94ee-1497e4fa4a7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0052170 biolink:causes GO:0045087 infores:ubergraph knowledge_assertion manual_agent GO:0052170 GO:0045087 CHEBI:10650 biolink:causes UMLS:C0877096 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0877096 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0521508 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0521508 infores:hetionet CHEBI:51230 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0010200 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0002622 infores:hetionet CHEBI:5147 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0010200 infores:hetionet CHEBI:16755 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0438215 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0920102 infores:hetionet CHEBI:6067 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003537 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0027769 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0920166 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0920166 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0036572 infores:hetionet CHEBI:8024 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0003811 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0033687 infores:hetionet CHEBI:64064 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0007859 infores:hetionet GO:1903538 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:1903538 GO:0048477 CHEBI:46557 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0521839 infores:hetionet CHEBI:41977 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0027947 infores:hetionet CAID:CA198786 biolink:causes MONDO:0009290 infores:clingen CAID:CA198786 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3 PP3, BP4 The NM_000152.5:c.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 4 patients have been identified with this variant. Two had documented GAA deficiency, one with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID: 21757382; 18458862) and one within affected range in dried blood spot (Clinical diagnostic laboratory). (PP4_Moderate). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3). Additional patients had evidence of pseudodeficiency variants with (PMID: 21484825, 28302345). The computational predictor REVEL gives a score of 0.531 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 188480). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_Moderate, PM3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA198786/MONDO:0009290/010 2024-03-05 2024-03-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:8874 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1456784 infores:hetionet CHEBI:161680 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0700225 infores:hetionet CHEBI:5558 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0232462 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0013395 infores:hetionet CHEBI:3647 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0011071 infores:hetionet NCBIGene:6391 biolink:causes MONDO:0011544 infores:monarchinitiative not_provided not_provided HGNC:10682 MONDO:0011544 uuid:5a4f2508-fe2e-435e-a558-55b9d3f7e73b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000564 biolink:causes MONDO:0017623 infores:clingen CAID:CA000564 MONDO:0017623 PMID:23335809PMID:15805158PMID:21194675PMID:21659347PMID:17286265PMID:21828076PMID:29373119PMID:29706350PMID:29706633PMID:25527629 Pathogenic PP3, PP2, PS4_Supporting, PS3_Moderate, PM2_Supporting, PM6_Strong BP7, BP5, BS1, BS3, BS4, PVS1, PP4, PP1, BS2, PM5, PM4, PM1, PM3, BP4, BP1, BP3, BP2, BA1, PS1, PS2 NM_000314.8(PTEN):c.755A>G (p.Asp252Gly) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMID: 23335809).PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score=0.971)PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 23335809). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000564/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3786 biolink:causes MONDO:0007366 infores:monarchinitiative not_provided not_provided HGNC:6297 MONDO:0007366 uuid:c44c08b1-4a13-4b35-87db-767ab147b111 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3650 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0268000 infores:hetionet CHEBI:10110 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0011603 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0221269 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0002622 infores:hetionet CHEBI:7936 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C3160741 infores:hetionet CHEBI:7496 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0231528 infores:hetionet CHEBI:31547 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0015672 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0006840 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0017181 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0042109 infores:hetionet CAID:CA279970 biolink:causes MONDO:0015280 infores:clingen CAID:CA279970 MONDO:0015280 PMID: Pathogenic PS3_Supporting, PS2_Very Strong, PM1, PP3, PP2, PM2_Supporting, PS4 The c.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant is absent from gnomAD v4 (PM2_Supporting). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). The REVEL computational prediction analysis tool produced a score of 0.921, which is above the threshold necessary to apply PP3 (PP3). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel functional domain of BRAF (PM1). This variant has been reported in the literature in at least 12 patients with clinical features of RASopathy (PS4, PMIDs: 18042262, 16474404, 30141192, 29907801, 35418823), out of which 3 patients were reported as a confirmed de novo occurrence (PS2_VeryStrong; PMIDs: 18042262, 16474404). Luciferase assays showed that p.Gly469Glu did not enhance ELK-dependent transcription indicating that this variant impacts protein function (PS3_Supporting; 16474404). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM1, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279970/MONDO:0015280/049 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:76607 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0027441 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042373 infores:hetionet CHEBI:7936 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0232461 infores:hetionet CHEBI:9332 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0085632 infores:hetionet CHEBI:50838 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0017178 infores:hetionet CAID:CA410208219 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208219 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, PVS1, PM6, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.44A>G (p.Gln15Arg) is a missense variant which is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, both providing at least 20x coverage for the RUNX1 gene at this genomic position (PM2_supporting). This variant has a REVEL score of 0.236 (< 0.50), allowing for the application of BP4. To our knowledge, this variant has not been previously reported, nor are there any pathogenic or likely pathogenic amino acid changes affecting the same residue. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208219/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:9896 biolink:causes MONDO:0012945 infores:monarchinitiative not_provided not_provided HGNC:16873 MONDO:0012945 uuid:6a4c4f43-424d-4805-9ce1-bdaf45cd8ea4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0033687 infores:hetionet CHEBI:135930 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0239571 infores:hetionet CHEBI:145499 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0000731 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0034065 infores:hetionet CHEBI:474180 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0011603 infores:hetionet CHEBI:7465 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C2830004 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0011053 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011127 infores:hetionet CHEBI:9599 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0034063 infores:hetionet CHEBI:4876 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0022346 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0852908 infores:hetionet CHEBI:7903 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C3263723 infores:hetionet CHEBI:82941 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0020443 infores:hetionet CHEBI:50663 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C1443060 infores:hetionet CHEBI:39112 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0006277 infores:hetionet CHEBI:50122 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0231528 infores:hetionet CHEBI:50729 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0311468 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020615 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0017178 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0948288 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0948288 infores:hetionet CHEBI:75246 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C2047937 infores:hetionet CHEBI:31401 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0030794 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0023510 infores:hetionet NCBIGene:10681 biolink:causes MONDO:0014953 infores:monarchinitiative not_provided not_provided HGNC:4401 MONDO:0014953 uuid:b61d1dee-e6a7-4cac-b698-5d1f6360a419 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7045 biolink:causes MONDO:0012044 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0012044 uuid:17a2dc5f-b890-453d-b095-043a091bed5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0687713 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0010692 infores:hetionet CHEBI:65173 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0027497 infores:hetionet CHEBI:478164 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0006840 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0031117 infores:hetionet CHEBI:3127 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C1443060 infores:hetionet CHEBI:94449 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0152032 infores:hetionet CHEBI:8378 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0917801 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0042109 infores:hetionet CHEBI:145499 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0039240 infores:hetionet CHEBI:51860 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0232462 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0020651 infores:hetionet CHEBI:205919 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0018681 infores:hetionet CHEBI:7986 biolink:causes NCIT:C78300 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C1295715 infores:hetionet NCBIGene:3209 biolink:causes MONDO:0007698 infores:monarchinitiative not_provided not_provided HGNC:5102 MONDO:0007698 uuid:6e3b68cc-ad8e-414a-8fbb-897b1704f691 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0085622 infores:hetionet CHEBI:63616 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0009763 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002527 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0022572 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0542571 infores:hetionet CHEBI:3696 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0086565 infores:hetionet NCBIGene:10734 biolink:causes MONDO:0014321 infores:monarchinitiative not_provided not_provided HGNC:11356 MONDO:0014321 uuid:8475feb0-6bef-427d-b72d-41a9a778a6d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0020458 infores:hetionet CAID:CA658824782 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824782 MONDO:0009290 PMID: Uncertain Significance PM4, PM2_Supporting PP3, BP4 The NM_000152.5:c.1336_1356dup variant in GAA is predicted to cause a change in the length of the protein (p.Ile446_Ala452dup) due to an in-frame duplication of 7 amino acids in a non-repeat region (PM4). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. Computational evidence is conflicting; PROVEAN predicts that the variant will impact the function of GAA, while Mutation Taster predicts no impact. As a result, neither PP4 nor BP4 can be applied. There is a ClinVar entry for this variant (Variation ID: 556985). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824782/MONDO:0009290/010 2024-06-17 2024-06-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:31236 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018989 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0235431 infores:hetionet CHEBI:7798 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0014038 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0042109 infores:hetionet CHEBI:100241 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0392525 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0001824 infores:hetionet CHEBI:5130 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042384 infores:hetionet CHEBI:28864 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0920171 infores:hetionet CHEBI:5801 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0085932 infores:hetionet CHEBI:6076 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C2363731 infores:hetionet CHEBI:490877 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0030193 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0037199 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042109 infores:hetionet CHEBI:49960 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0018681 infores:hetionet NCBIGene:25793 biolink:causes MONDO:0009830 infores:monarchinitiative not_provided not_provided HGNC:13586 MONDO:0009830 uuid:dfce4879-3258-48ff-a69c-15e89929d4e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:34967 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0027769 infores:hetionet CHEBI:147675 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00249 UMLS:C0009763 infores:hetionet NCBIGene:64065 biolink:causes MONDO:0030961 infores:monarchinitiative not_provided not_provided HGNC:17637 MONDO:0030961 uuid:5c92370f-5265-43cf-ad11-153afcbb7c92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1902866 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:1902866 GO:0043010 CHEBI:17026 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0235198 infores:hetionet CHEBI:42797 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C2364111 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0000833 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0033775 infores:hetionet CHEBI:5147 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0018794 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017675 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0029134 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1443060 infores:hetionet CHEBI:5128 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0013404 infores:hetionet CHEBI:421707 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0038002 infores:hetionet CHEBI:94686 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C2047937 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0015967 infores:hetionet CHEBI:53760 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151907 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004833 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149756 infores:hetionet CHEBI:66903 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0011991 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0027765 infores:hetionet CHEBI:10101 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0015468 infores:hetionet NCBIGene:8883 biolink:causes MONDO:0859361 infores:monarchinitiative not_provided not_provided HGNC:621 MONDO:0859361 uuid:4b7575ff-fb5b-4a62-8667-935a17056d0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:142290 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042023 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0259749 infores:hetionet CHEBI:63608 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0003467 infores:hetionet CHEBI:7025 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0019080 infores:hetionet CHEBI:38940 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151786 infores:hetionet CHEBI:29688 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0007222 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0235416 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0008325 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0578687 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0578687 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1458155 infores:hetionet CHEBI:63577 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0085636 infores:hetionet UBERON:0003074 biolink:causes MONDO:0004255 infores:ubergraph knowledge_assertion manual_agent UBERON:0003074 MONDO:0004255 GO:0072039 biolink:causes GO:0001822 infores:ubergraph knowledge_assertion manual_agent GO:0072039 GO:0001822 CHEBI:3213 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0008031 infores:hetionet CHEBI:8863 biolink:causes HP:0001537 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1306503 infores:hetionet CHEBI:47898 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0025222 infores:hetionet CHEBI:5613 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011124 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0876973 infores:hetionet CHEBI:5138 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042963 infores:hetionet CHEBI:9448 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0220870 infores:hetionet CHEBI:47381 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011606 infores:hetionet CHEBI:59773 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0041834 infores:hetionet CHEBI:27777 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0002170 infores:hetionet CAID:CA232483 biolink:causes MONDO:0100040 infores:clingen CAID:CA232483 MONDO:0100040 PMID: Benign BP7, BA1 The allele frequency of the p.Ala149= variant in FOXG1 is 0.227% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Ala149= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala149= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA232483/MONDO:0100040/016 2022-08-25 2022-09-06 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA287473 biolink:causes MONDO:0017623 infores:clingen CAID:CA287473 MONDO:0017623 PMID: Benign BA1 PVS1, PM2, PM6, BP7, BP5, BS3, BS4, BS2, PP2, PP3, PP1, PP4, PM5, PM4, PM1, PM3, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.-1190G>A (NC_000010.10:g.89623036) is currently classified as a benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Filtering allele frequency of 0.1089% in the African subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA287473/MONDO:0017623/003 2025-06-06 2025-10-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9168 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0795692 infores:hetionet CHEBI:119915 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0920289 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0021053 infores:hetionet NCBIGene:776 biolink:causes MONDO:0013960 infores:monarchinitiative not_provided not_provided HGNC:1391 MONDO:0013960 uuid:45bde2e5-ef3e-4fc4-984d-126f2f2fbe17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:392255 biolink:causes MONDO:0014145 infores:monarchinitiative not_provided not_provided HGNC:4221 MONDO:0014145 uuid:2a61fed8-991f-40fc-875f-d3c243b62863 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32020 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0242350 infores:hetionet CHEBI:474053 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C1112214 infores:hetionet CHEBI:7824 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1443060 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0162830 infores:hetionet CHEBI:8364 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0023646 infores:hetionet CHEBI:63610 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013604 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0018802 infores:hetionet CHEBI:6402 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0085593 infores:hetionet CHEBI:77733 biolink:causes HP:0002273 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0270790 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0233494 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0860866 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027441 infores:hetionet CHEBI:5383 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0042023 infores:hetionet CHEBI:28787 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0042963 infores:hetionet GO:2000280 biolink:causes GO:0022622 infores:ubergraph knowledge_assertion manual_agent GO:2000280 GO:0022622 CHEBI:7465 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0028754 infores:hetionet CHEBI:6804 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0476273 infores:hetionet CHEBI:38940 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0035410 infores:hetionet CAID:CA024634 biolink:causes MONDO:0007783 infores:clingen CAID:CA024634 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with isoleucine at codon 2214 of the RYR1 protein, p.Val2214Ile. The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00016, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, the high MAF in the AFR population in gnomAD precludes the use of PS4 (PMID:11575529). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.798 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024634/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:68579 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0004093 infores:hetionet CHEBI:30830 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0030193 infores:hetionet CHEBI:31644 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0023066 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0162429 infores:hetionet CHEBI:31623 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0004604 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042109 infores:hetionet CHEBI:145499 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003467 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0235964 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0235964 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0023067 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0002871 infores:hetionet CHEBI:10023 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003962 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0855242 infores:hetionet GO:1904073 biolink:causes GO:0001701 infores:ubergraph knowledge_assertion manual_agent GO:1904073 GO:0001701 UNII:9430ZR8ZAN biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1510410 infores:hetionet CHEBI:4784 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020458 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0020744 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0264907 infores:hetionet CHEBI:7954 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0018681 infores:hetionet CAID:CA2582119824 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582119824 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_005629.4:c.1432dup variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/13 in a gene in which loss of function is an established disease mechanism (p.Ala478GlyfsTer24) (PVS1). This variant has not been reported in the published literature in individuals with creatine transporter deficiency. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582119824/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Supports CHEBI:64354 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0011603 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2711227 infores:hetionet GO:0060224 biolink:causes GO:0048593 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0048593 NCBITaxon:10407 biolink:causes MONDO:0005366 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10407 MESH:D019694 DB00300_MESH_D019694_1DB00718_MESH_D019694_1DB00105_MESH_D019694_1DB01265_MESH_D019694_1DB00709_MESH_D019694_1 CHEBI:28901 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0687713 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0019360 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0000256 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0553576 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014848 infores:hetionet NCBITaxon:210 biolink:causes MONDO:0001126 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:210 MESH:D013276 DB05197_MESH_D013276_1 CHEBI:64064 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0700184 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0233632 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027092 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0858259 infores:hetionet CHEBI:5147 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0037317 infores:hetionet NCBIGene:2911 biolink:causes MONDO:0033479 infores:monarchinitiative not_provided not_provided HGNC:4593 MONDO:0033479 uuid:d55f0d8c-4a8e-47eb-8aa3-cb4d2ea0f805 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31515 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0000737 infores:hetionet CHEBI:6690 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0039070 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0700345 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151740 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0239295 infores:hetionet CHEBI:9398 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0344232 infores:hetionet CAID:CA5949936 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949936 MONDO:0000572 PMID: Pathogenic PP4, PM3, PS3_Moderate, PM2, PVS1 The c.256_257del (p.Lys86ValfsTer33) variant in RAG1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. The variant causes a truncation of a functionally important region (removes amino acids 86-1011) of the RAG1 protein. The variants also cause the usage of an alternative in-frame start codon (Met183), but the alternatively transcribed protein has decreased recombination activity and mislocalization in cells (PMIDs 11121059, 27301863). So the variant may cause protein loss-of-function (PVS1; PMIDs 11121059, 27301863).The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 6/128846 observed alleles) is 0.000007030 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.000102) and therefore meets this criterion (PM2_Supporting).The in vitro recombination assay shows that the p.Lys86ValfsTer33 variant in RAG1 causes a decrease of recombination activity to below 25%, indicating that the variant impacts the protein function. (PS3_Moderate; PMID 24290284).One homozygous individual with OS. One homozygous individual with SCID. 1pt for PM3. (PMID 11121059, patient OS8; PMID 32655540, patient #32). PM3 met.One patient with this variant was diagnosed with SCID (0.5pt). The patient showed T-B-NK+ lymphocyte profile (0.5pt). 1pt in total, PP4 met. (PMID 32655540, proband #32)In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PM3_moderate, PS3_moderate, and PP4_supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949936/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9435 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0232462 infores:hetionet CAID:CA10960823 biolink:causes MONDO:0013144 infores:clingen CAID:CA10960823 MONDO:0013144 PMID: Benign BS2, BA1 The NM_000488.4:c.1154-53G>A variant is reported at a popmax FAF of 0.3028 and the highest MAF of 0.3263 (32%; 507/1554 alleles with 81 homozygotes) in the East Asian population in gnomAD v2.1.1, meeting criteria for BA1 (MAF >0.002). The variant is reported in 8 individuals with normal antithrombin levels. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BS2. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10960823/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63635 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0016242 infores:hetionet CHEBI:2676 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0003467 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0595877 infores:hetionet CHEBI:10127 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0026827 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0021308 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0549369 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0549369 infores:hetionet CHEBI:6062 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0024902 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042769 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0011991 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0853692 infores:hetionet CHEBI:63616 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0011603 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0232492 infores:hetionet CHEBI:44423 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1287298 infores:hetionet CHEBI:8378 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0026961 infores:hetionet CHEBI:5001 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C1609512 infores:hetionet CHEBI:3127 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042510 infores:hetionet CHEBI:63580 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002994 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0020538 infores:hetionet CHEBI:119915 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042963 infores:hetionet CHEBI:253342 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0010200 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0262985 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0702266 infores:hetionet CHEBI:144093 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0947912 infores:hetionet CAID:CA915940616 biolink:causes MONDO:0015967 infores:clingen CAID:CA915940616 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate PP1 The c.-287G>A variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This region is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). Additionally, the c.-287G>A variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low doses of sulfonylurea) (PP4_Moderate; PMID: 23348805).  This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributors). In summary, c.-287G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM1_Supporting, PM2_Supporting, PP4_Moderate.   Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940616/MONDO:0015967/017 2025-04-11 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0120107 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013390 infores:hetionet CHEBI:3504 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0023518 infores:hetionet CHEBI:6437 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0003467 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0151735 infores:hetionet CHEBI:74947 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0017181 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011570 infores:hetionet CHEBI:240107 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0010200 infores:hetionet CHEBI:2673 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0015967 infores:hetionet CHEBI:47612 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0242350 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017178 infores:hetionet CHEBI:63925 biolink:causes NCIT:C50547 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C1704212 infores:hetionet CHEBI:71219 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0237849 infores:hetionet CHEBI:167309 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0878544 infores:hetionet CHEBI:7565 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0438215 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020649 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0018939 infores:hetionet CHEBI:82941 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0041969 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0013295 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0038362 infores:hetionet GO:1903186 biolink:causes GO:0007292 infores:ubergraph knowledge_assertion manual_agent GO:1903186 GO:0007292 CHEBI:15544 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0012691 infores:hetionet CHEBI:5855 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0030252 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0020649 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0522172 infores:hetionet CHEBI:15854 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0013491 infores:hetionet CHEBI:6538 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0039231 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017152 infores:hetionet CHEBI:16469 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0542571 infores:hetionet CHEBI:404903 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0033774 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2717961 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0037199 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027059 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1141949 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1141949 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0033975 infores:hetionet GO:1900206 biolink:causes GO:0048793 infores:ubergraph knowledge_assertion manual_agent GO:1900206 GO:0048793 CHEBI:47381 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0947912 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1322281 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0521591 infores:hetionet CHEBI:8028 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0039070 infores:hetionet CHEBI:38562 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C2239176 infores:hetionet CHEBI:3228 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0242184 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0037274 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0003467 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0948594 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042373 infores:hetionet GO:2000061 biolink:causes GO:0072189 infores:ubergraph knowledge_assertion manual_agent GO:2000061 GO:0072189 CHEBI:6887 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0039231 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0034150 infores:hetionet CHEBI:32315 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0015672 infores:hetionet CHEBI:9332 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0023530 infores:hetionet CHEBI:31174 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0011606 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0002871 infores:hetionet CHEBI:45652 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0006266 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1258215 infores:hetionet GO:0001779 biolink:causes CL:0000623 infores:ubergraph knowledge_assertion manual_agent GO:0001779 CL:0000623 CHEBI:9137 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0009806 infores:hetionet CHEBI:3723 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037011 infores:hetionet CAID:CA414772609 biolink:causes MONDO:0044970 infores:clingen CAID:CA414772609 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS3, PM2 The m.3357G>C (p.M17I) variant in MT-ND1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There are two occurrences in the GenBank sequences queried through MITOMAP on 6/29/2020 (1 individual from haplogroup M5a and 1 from T2b). In silico tools (APOGEE) predict this variant to be neutral (score of 0.46, BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414772609/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:47780 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0404521 infores:hetionet NCBIGene:50940 biolink:causes MONDO:0012505 infores:monarchinitiative not_provided not_provided HGNC:8773 MONDO:0012505 uuid:90bea5e8-6a62-4f70-bd78-7dd583561671 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0003811 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0149931 infores:hetionet CHEBI:82941 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0014742 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0027769 infores:hetionet CHEBI:63631 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020453 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0235234 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0007642 infores:hetionet CHEBI:6801 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0030305 infores:hetionet NCBIGene:4868 biolink:causes MONDO:0009732 infores:monarchinitiative not_provided not_provided HGNC:7908 MONDO:0009732 uuid:af6c5c15-3daf-4138-b968-a638ef6f53aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5141 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0024031 infores:hetionet CAID:CA6831858 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831858 MONDO:0015967 PMID: Benign BS3_Supporting, BS1, BS2 PS4, PM2, PP3 The c.872C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to glutamine at codon 291 (p.(Pro291Gln)) of NM_000545.8. This variant has a Grpmax Filtering allele frequency in gnomAD 4.1.0 of 0.00009220, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant has a REVEL score of 0.4469, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. However, functional studies demonstrated the p.Pro291Gln protein has transactivation activity and DNA binding that is above 75% of WT, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 32910913). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2; internal lab contributors). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 23771925, internal lab contributors). In summary, c.872C>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1, BS2 BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831858/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47381 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009766 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0014549 infores:hetionet CHEBI:2663 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0013378 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0178298 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0855242 infores:hetionet CHEBI:5062 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0043251 infores:hetionet CHEBI:6539 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0522224 infores:hetionet CHEBI:9586 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0043352 infores:hetionet CHEBI:10119 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018681 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0948586 infores:hetionet CHEBI:37941 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0035317 infores:hetionet CHEBI:18357 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0428977 infores:hetionet CHEBI:480999 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0033774 infores:hetionet CAID:CA421939061 biolink:causes MONDO:0005338 infores:clingen CAID:CA421939061 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.798G>A variant in MYOC is a synonymous variant (p.Lys266=). The highest minor allele frequency of this variant was in the Remaining genetic ancestry group of gnomAD (v4.1.0) = 0.00001600 (1 allele out of 62,492), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, BP7, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421939061/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31625 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0020517 infores:hetionet CAID:CA229408 biolink:causes MONDO:0009861 infores:clingen CAID:CA229408 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4, PM2_Supporting, PP3_Moderate The PAH variant c.122T>C (p.Leu41Pro) was found in one patient with mild PKU (serum phenylalanine levels between 600 and 1,200 μmol/liter) (PP4) with the pathogenic variant c.728G>A (p.Arg243Gln) (CinVar ID: 591) (PMID: 10679941), and in a patient with moderate/mild PKU with the pathogenic variant c.838G>A (p.Glu280Lys) (CinVar ID: 580) (PMID: 22841515) PM3 (Points total = 1).This variant is absent in the gnomAD, ExAC, and PAGE population databases (PM2_Supporting). The variant is predicted to be damaging by REVEL (REVEL score 0.868) (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for PAH deficiency. PAH-specific ACMG/AMP criteria applied: PM2_Supporting, PM3, PP3_Moderate, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229408/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50648 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015256 infores:hetionet CHEBI:135939 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0020580 infores:hetionet CHEBI:3568 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0025345 infores:hetionet CHEBI:6078 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0085649 infores:hetionet CHEBI:2682 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0031256 infores:hetionet CHEBI:6775 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C2830004 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027726 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0036572 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0267033 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0267033 infores:hetionet CHEBI:8707 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0004604 infores:hetionet CHEBI:82981 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C1443060 infores:hetionet CHEBI:9649 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018926 infores:hetionet CAID:CA030891 biolink:causes MONDO:0007750 infores:clingen CAID:CA030891 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, PS1, BP7, BS1, PM5, PM4, PM1, PVS1, PP2, PP1 The NM_000527.5(LDLR):c.949G>A (p.Glu317Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 March 2025.The supporting evidence is as follows:PM2: PopMax MAF = 0.0001867 (0.01867%) in European (non-Finnish) (gnomAD v4.1.0). PP3: REVEL = 0.899. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 index cases with DLCN score >=6, after alternative causes of high cholesterol were excluded: 1 case from Robarts Research Institute, Canada; 1 case from PMID 33418990 (Meshkov et al., 2021), Russia; 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA030891/MONDO:0007750/013 2025-03-25 2025-03-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:119573 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151883 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0010692 infores:hetionet CHEBI:8426 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0023530 infores:hetionet CAID:CA512232229 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232229 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.897A>G (p.Ala299=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.29) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232229/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006384 infores:hetionet CHEBI:119573 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0016927 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0740304 infores:hetionet CHEBI:52717 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026858 infores:hetionet CHEBI:10101 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0043144 infores:hetionet CHEBI:6761 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0039231 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0020517 infores:hetionet CHEBI:2682 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0013491 infores:hetionet CHEBI:60761 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0037763 infores:hetionet CHEBI:16796 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0030554 infores:hetionet CHEBI:45409 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0404521 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0701836 infores:hetionet CHEBI:8869 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0016655 infores:hetionet CHEBI:71415 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0000737 infores:hetionet GO:0008359 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0048477 CHEBI:135736 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015672 infores:hetionet NCBIGene:121391 biolink:causes MONDO:0020717 infores:monarchinitiative not_provided not_provided HGNC:28929 MONDO:0020717 uuid:bb112ece-cee3-4f73-95d3-2c7b028d3e89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63717 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0031117 infores:hetionet GO:0090189 biolink:causes GO:0060675 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0060675 CHEBI:9434 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0003123 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0025061 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020517 infores:hetionet CAID:CA229324 biolink:causes MONDO:0009861 infores:clingen CAID:CA229324 MONDO:0009861 PMID:8098245 Pathogenic PP4_Moderate, PM3_Very Strong, PM2_Supporting PP3, PS3 The c.1066-3C>T variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 9634518, 27121329). It has been detected with multiple pathogenic variants: c.1222C>T (p.Arg408Trp) (in trans, PMID: 27121329); c.1315+1G>A (PMID: 17502162); p.G272X, p.S310F (PMID: 23430918); c.194T>C (p.I65T), c.1208C>T (p.A403V), c.398_401del (p.N133fs), c.1222C>T (p.R408W) 2 patients, c.165delT (p.F55fs), c.168+5G>C (IVS2+5G>C) (PMID: 22526846). This variant has an extremely low allele frequency in ExAC and gnomAD (MAF=0.00014). This variant has 0% enzyme activity. This variant resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (PMID: 8098245). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PM2_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229324/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0314719 infores:hetionet CHEBI:83804 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0025345 infores:hetionet NCBIGene:3990 biolink:causes MONDO:0013533 infores:monarchinitiative not_provided not_provided HGNC:6619 MONDO:0013533 uuid:fe34f370-6b00-433b-987b-adf618478734 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63616 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0013922 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018772 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0037274 infores:hetionet CHEBI:47499 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0043094 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020517 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0233494 infores:hetionet CHEBI:724125 biolink:causes UMLS:C1274926 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C1274926 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0017160 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0020517 infores:hetionet CHEBI:6067 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004095 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0233632 infores:hetionet CHEBI:367163 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0010200 infores:hetionet CHEBI:50859 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151825 infores:hetionet CHEBI:3504 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0015230 infores:hetionet CHEBI:8774 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151578 infores:hetionet CHEBI:63613 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0497156 infores:hetionet CAID:CA000071 biolink:causes MONDO:0018875 infores:clingen CAID:CA000071 MONDO:0018875 PMID: Benign BP4, BS3, BS2, PM2_Supporting BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, PP3, PP1, PP4 The NM_000546.6: c.215C>A variant in TP53 is a missense variant predicted to cause substitution of proline by histidine at amino acid 72 (p.Pro72His). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: LabCorp Genetics). This variant has an allele frequency of 0.00002197 (2/91052 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.1017; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000071/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8768 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0392025 infores:hetionet CHEBI:63598 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0011603 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0020538 infores:hetionet CHEBI:15428 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0013604 infores:hetionet NCBIGene:64849 biolink:causes MONDO:0032716 infores:monarchinitiative not_provided not_provided HGNC:14430 MONDO:0032716 uuid:73253042-790b-41ba-88e4-93cd07befd7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:34967 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0002957 infores:hetionet CHEBI:3219 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0242422 infores:hetionet CHEBI:8060 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0011603 infores:hetionet NCBIGene:6658 biolink:causes MONDO:0010712 infores:monarchinitiative not_provided not_provided HGNC:11199 MONDO:0010712 uuid:30b9a2f9-b623-4c01-b3c7-e0d448ef5ba3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0031542 infores:hetionet CHEBI:34385 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0027441 infores:hetionet CHEBI:9566 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0234967 infores:hetionet CHEBI:7581 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0000768 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0234215 infores:hetionet NCBIGene:23451 biolink:causes MONDO:0018881 infores:monarchinitiative not_provided not_provided HGNC:10768 MONDO:0018881 uuid:b1208534-a54f-46a7-af51-4c45629cc840 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA318518 biolink:causes MONDO:0010278 infores:clingen CAID:CA318518 MONDO:0010278 PMID: Uncertain Significance PM2_Supporting, BS2_Supporting, BP5 BP4 The p.Ala215Thr variant in SLC9A6 is absent from gnomAD (PM2_supporting). The p.Ala163Thr variant is observed in at least 1 unaffected individual (internal database) (BS2_Supporting). The p.Ala215Thr variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Ala215Thr variant in the SLC9A6 gene is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BS2_Supporting, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA318518/MONDO:0010278/033 2023-08-28 2023-09-15 X-linked inheritance HP:0001417 Inconclusive true UNII:Z5N076G8YQ biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0011609 infores:hetionet CHEBI:5790 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0036973 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1306341 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017574 infores:hetionet CHEBI:31980 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0162297 infores:hetionet NCBIGene:3757 biolink:causes MONDO:0012312 infores:monarchinitiative not_provided not_provided HGNC:6251 MONDO:0012312 uuid:fddcf084-9a6c-4aae-8577-cee1eef52e49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:184555 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0043094 infores:hetionet CAID:CA386955008 biolink:causes MONDO:0015967 infores:clingen CAID:CA386955008 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PM5 The c.326+2T>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 2 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.326+2T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386955008/MONDO:0015967/017 2022-04-07 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9725 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0022354 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0017160 infores:hetionet CHEBI:84500 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085602 infores:hetionet CAID:CA7331526 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331526 MONDO:0100216 PMID: Benign BS2, BS1 PM2, PVS1, PM6, BP2, BP3, BP4, BA1, PP3, PP4, PM1, PM4, PM5, PS3, PS2, PS4, PS1, BP7, BP5, BS3 The NM_177438.2:c.1124C>G variant in DICER1 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 375 (p.Pro375Arg). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors, PMIDs 29641532, 33630087). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004911 (58/118098 alleles) in the European (non-Finnish) population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met). The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2. (Bayesian Points: -8; VCEP specifications version 1.2.0; 08/22/23). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331526/MONDO:0100216/024 2023-08-22 2023-09-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:52717 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0948296 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0152029 infores:hetionet CAID:CA120608 biolink:causes MONDO:0044970 infores:clingen CAID:CA120608 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS4, PS2, PS3, PM6 The m.6742T>C (p.I280T) variant in MT-CO1 has been reported in one individual to date, in a man with sideroblastic anemia (PMID: 9389715). The variant was present at 52% in bone marrow, 59% in peripheral blood, 71% in platelets, and was undetectable in buccal and fibroblasts. As this is the only case reported to date, PS4 could not be applied. There was no mention of family member testing precluding consideration for de novo status or segregation. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.63 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (0.001%, haplogroup I; PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120608/MONDO:0044970/015 2023-12-21 2024-03-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:31236 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234215 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042401 infores:hetionet CHEBI:421707 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0015967 infores:hetionet CHEBI:9168 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011168 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030920 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020649 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0403723 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0403723 infores:hetionet CAID:CA10549369 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549369 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting BS3, PP4, BS2, PS4, PS3 The NM_005629.4:c.952G>A variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of an alanine for a threonine at amino acid position 318 (p.Ala318Thr). This variant has been previously reported in one heterozygous female from the Exome Variant Server database (PMID: 25861866), without additional phenotypic information available; thus, PS4, PP4, and BS2 are all not met. This variant was reported to result in 78% of wild-type activity when transfected into HeLa cells (PMID: 25861866); as this assay is not among the assays approved for PS3/BS3 by the CCDS VCEP, neither PS3 nor BS3 is met. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.788 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549369/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:9907 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0014868 infores:hetionet NCBIGene:4938 biolink:causes MONDO:0020840 infores:monarchinitiative not_provided not_provided HGNC:8086 MONDO:0020840 uuid:66479496-0e8d-4cf8-b7fd-7f364b57efc5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0520966 infores:hetionet CHEBI:85161 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0003467 infores:hetionet NCBIGene:10220 biolink:causes MONDO:0030871 infores:monarchinitiative not_provided not_provided HGNC:4216 MONDO:0030871 uuid:09308bb7-5ac6-48b6-a512-48f2c5e42fdd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235198 infores:hetionet CHEBI:75922 biolink:causes HP:0010750 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0423124 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014868 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004095 infores:hetionet CHEBI:8888 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0428977 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0549399 infores:hetionet CAID:CA367400084 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400084 MONDO:0015967 PMID: Likely Pathogenic PM5, PS3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.898G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 300 (p.(Glu300Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 8433729, 22035297, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.898G>C p.(Glu300Gln), has been classified as pathogenic by the ClinGen MDEP VCEP and has a lower Grantham distance than p.(Glu300Lys) (PM5). While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the variant was shown through a cellular assay to be unstable (PS3_Supporting; PMIDs: 10455021, 10525657, https://doi.org/10.1159/000079009). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400084/MONDO:0015967/086 2024-10-13 2024-10-13 Semidominant inheritance HP:0032113 Supports CHEBI:101853 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0011860 infores:hetionet CHEBI:75998 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0025222 infores:hetionet CHEBI:63616 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0236124 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C1565489 infores:hetionet CHEBI:47898 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011603 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0857983 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0857983 infores:hetionet CHEBI:4909 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0039231 infores:hetionet GO:0060390 biolink:causes GO:0007178 infores:ubergraph knowledge_assertion manual_agent GO:0060390 GO:0007178 CHEBI:49375 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0019158 infores:hetionet CHEBI:4888 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0278134 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0005741 infores:hetionet CHEBI:8207 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0341047 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0016204 infores:hetionet CHEBI:3423 biolink:causes MONDO:0012089 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1504431 infores:hetionet CHEBI:64312 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030554 infores:hetionet CHEBI:499361 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0036104 infores:hetionet CAID:CA512318678 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318678 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.657G>A (p.Leu219=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318678/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:92712 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0004093 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0854381 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0854381 infores:hetionet NCBIGene:84504 biolink:causes MONDO:0033043 infores:monarchinitiative not_provided not_provided HGNC:19321 MONDO:0033043 uuid:ff3308f2-9970-439d-a745-338491f113b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151905 infores:hetionet UMLS:C0011701 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0008031 infores:hetionet CAID:CA376059715 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059715 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2 The c.539A>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Valine at amino acid 180 (p.Glu180Val).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059715/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3561 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013604 infores:hetionet CAID:CA024018 biolink:causes MONDO:0007783 infores:clingen CAID:CA024018 MONDO:0007783 PMID: Benign BS2_Supporting, BS1, BP4, BP2 PP3, PM1, PS4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Alanine with Valine at codon 4295 of the RYR1 protein, p.(Ala4295Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0019, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate, (PMID:25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant was observed in cis with a variant assessed as pathogenic, p.(Arg2435His), BP2 (PMID:19513315). A REVEL score <0.5 (0.152) supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, BP2, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024018/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9168 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0029445 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018802 infores:hetionet CHEBI:17347 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1510410 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0036508 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042109 infores:hetionet NCBIGene:1278 biolink:causes MONDO:0030855 infores:monarchinitiative not_provided not_provided HGNC:2198 MONDO:0030855 uuid:003239e1-21d1-4fde-9e0c-fd3c7f6fdb9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:391960 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0021400 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0853011 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853011 infores:hetionet CHEBI:145499 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013362 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0851341 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020517 infores:hetionet CHEBI:15552 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C1141861 infores:hetionet CHEBI:9434 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0003811 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0018801 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151735 infores:hetionet CHEBI:9086 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0032227 infores:hetionet NCBIGene:2660 biolink:causes MONDO:0013598 infores:monarchinitiative not_provided not_provided HGNC:4223 MONDO:0013598 uuid:0f4dee50-7d64-4658-b12a-39e346c3c14c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0020677 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011057 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0233472 infores:hetionet CHEBI:31205 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0038363 infores:hetionet CHEBI:52172 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042029 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0041912 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018099 infores:hetionet CHEBI:6375 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0026826 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0022660 infores:hetionet CHEBI:71417 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0018418 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0520723 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0520723 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0009806 infores:hetionet GO:1901190 biolink:causes GO:0006413 infores:ubergraph knowledge_assertion manual_agent GO:1901190 GO:0006413 UMLS:C0017797 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0013604 infores:hetionet CHEBI:9637 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0013604 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0038661 infores:hetionet CHEBI:7445 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0033774 infores:hetionet CHEBI:2549 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013390 infores:hetionet CHEBI:75722 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233715 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0006325 infores:hetionet CHEBI:6761 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0002792 infores:hetionet CHEBI:50173 biolink:causes HP:0030788 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0021092 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0035309 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0011616 infores:hetionet CHEBI:6887 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151686 infores:hetionet CHEBI:94385 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0007820 infores:hetionet CHEBI:31184 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0041834 infores:hetionet CHEBI:5613 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0156404 infores:hetionet CAID:CA367398732 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398732 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PP1 The c.1150G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 384 (p.(Ala384Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.865, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and autoantibody negative) (PP4_Moderate; PMID: 24735133). Another missense variant at the same codon, c.1151C>A (p.Ala384Glu), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala384Thr (PM5_Supporting). In summary, c.1150G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP4_Moderate, PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398732/MONDO:0015967/086 2025-06-06 2025-06-06 Semidominant inheritance HP:0032113 Supports CHEBI:66876 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0043094 infores:hetionet CHEBI:4027 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0231528 infores:hetionet CHEBI:29688 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0852911 infores:hetionet CHEBI:6149 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1320474 infores:hetionet CHEBI:63791 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0239134 infores:hetionet CHEBI:49960 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0041657 infores:hetionet NCBIGene:5075 biolink:causes MONDO:0014254 infores:monarchinitiative not_provided not_provided HGNC:8615 MONDO:0014254 uuid:84bb0fe2-cd76-4ab5-ab9a-f6df45f639ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0011991 infores:hetionet CHEBI:68558 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0006145 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0017178 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0220981 infores:hetionet CHEBI:70707 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0018524 infores:hetionet CHEBI:47780 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C3203358 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042571 infores:hetionet CAID:CA275937 biolink:causes MONDO:0009861 infores:clingen CAID:CA275937 MONDO:0009861 PMID:23942198PMID:23942198 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 The c.242C>A (p.Thr81Asn) variant in PAH is reported in 1 PKU patient. PAH and BH4DH genes were sequenced. It was detected with p.V230I which is interpreted as Pathogenic/Likely Pathogenic in ClinVar. (PMID: 23942198) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, MutationTaster, and Polyphen-2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA275937/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7476 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0235198 infores:hetionet CHEBI:5130 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0018926 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0851341 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0025061 infores:hetionet CHEBI:8802 biolink:causes UMLS:C1736186 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1736186 infores:hetionet CHEBI:8776 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0008031 infores:hetionet CHEBI:5790 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151889 infores:hetionet CHEBI:204928 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C1443060 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0233494 infores:hetionet CHEBI:5855 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013378 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0009938 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0002453 infores:hetionet CHEBI:44185 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0547030 infores:hetionet CHEBI:63638 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233407 infores:hetionet CHEBI:41774 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151904 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1527407 infores:hetionet CHEBI:465284 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151578 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0018099 infores:hetionet CHEBI:168396 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0000737 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0039971 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0851341 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0027765 infores:hetionet CHEBI:63635 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020598 infores:hetionet CHEBI:4910 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0428977 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0497327 infores:hetionet GO:1903487 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:1903487 GO:0030879 CHEBI:64019 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0162429 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0221147 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0221147 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0025061 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0235351 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020569 infores:hetionet CHEBI:6904 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0009782 infores:hetionet CHEBI:6888 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0043094 infores:hetionet NCBIGene:7137 biolink:causes MONDO:0013211 infores:monarchinitiative not_provided not_provided HGNC:11947 MONDO:0013211 uuid:964dd9ba-7085-4dc8-88aa-50a7fb4a57f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0036974 infores:hetionet GO:1900187 biolink:causes GO:0090609 infores:ubergraph knowledge_assertion manual_agent GO:1900187 GO:0090609 CHEBI:6690 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0017178 infores:hetionet NCBIGene:1130 biolink:causes MONDO:0008963 infores:monarchinitiative not_provided not_provided HGNC:1968 MONDO:0008963 uuid:b65a6265-8620-4793-9b39-be53cae17201 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75045 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C1262036 infores:hetionet CHEBI:6339 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0014591 infores:hetionet CHEBI:45924 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0009676 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018939 infores:hetionet CHEBI:8207 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0041657 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0010692 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006142 infores:hetionet UNII:D27V6190PM biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0392163 infores:hetionet CHEBI:50841 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0085637 infores:hetionet CHEBI:135888 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0027424 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0005940 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0080274 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020676 infores:hetionet CHEBI:16796 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0038362 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151692 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151596 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0853692 infores:hetionet CHEBI:9943 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1145670 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0340726 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0010078 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0010078 uuid:8db29447-4fd5-476a-bab6-0779e548c7b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410148478 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148478 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1033C>T (p.Pro345Ser) is a missense variant which has a REVEL score <0.50 (0.35) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148478/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63619 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0231856 infores:hetionet NCBIGene:2623 biolink:causes MONDO:0020458 infores:monarchinitiative not_provided not_provided HGNC:4170 MONDO:0020458 uuid:182dc30f-5841-40e6-aa8b-1830fb6e0edc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018932 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0010692 infores:hetionet CHEBI:50648 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030554 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022354 infores:hetionet CHEBI:50275 biolink:causes UMLS:C1096311 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1096311 infores:hetionet CHEBI:8874 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009763 infores:hetionet CHEBI:3082 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020555 infores:hetionet CHEBI:45081 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0036974 infores:hetionet CHEBI:5790 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C2830004 infores:hetionet CHEBI:5893 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C3665347 infores:hetionet CHEBI:63612 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020580 infores:hetionet GO:0021936 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:0021936 GO:0007420 CHEBI:51860 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0023380 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0343863 infores:hetionet CHEBI:64312 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151786 infores:hetionet CHEBI:8382 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020488 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009319 infores:hetionet CHEBI:68534 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0600142 infores:hetionet CHEBI:101853 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C3665347 infores:hetionet CHEBI:101853 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0014724 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0034063 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0948594 infores:hetionet NCBIGene:29968 biolink:causes MONDO:0014466 infores:monarchinitiative not_provided not_provided HGNC:19129 MONDO:0014466 uuid:614645bc-1f79-4cbc-a47f-eacd874c76f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0239978 infores:hetionet CHEBI:8772 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0020580 infores:hetionet CHEBI:47426 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0220983 infores:hetionet CAID:CA410202511 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202511 MONDO:0011071 PMID: Likely Pathogenic PM5, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BS1, BS3, BS4, PM4, PM3, PP4, PP2, PP1 NM_001754.5(RUNX1):c.485G>C (p.Arg162Thr) is a missense variant which affects a hotspot residue within the Runt Homology Domain (RHD): R162 (PM1). This variant is a missense change at the same residue where a different missense change has been previously established as a pathogenic variant (ClinVar ID 376022), with RNA data or agreement in splicing predictors (SSF and MES) showing no splicing effects (PM5). It has a REVEL score ≥ 0.88 (0.957) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5, PP3, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202511/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3698 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0030554 infores:hetionet CHEBI:8874 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0234369 infores:hetionet CHEBI:135930 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C1260880 infores:hetionet CHEBI:9086 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0338831 infores:hetionet CAID:CA136088 biolink:causes MONDO:0021060 infores:clingen CAID:CA136088 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1964C>T (p.Pro655Leu) variant in the SOS1 gene is 1.153% (803/65674) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136088/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:520985 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0013390 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042075 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0037274 infores:hetionet CHEBI:10110 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0152032 infores:hetionet CHEBI:2569 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0036973 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0013395 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013395 infores:hetionet CHEBI:85083 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0010200 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0521592 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020456 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038362 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0025061 infores:hetionet CHEBI:30830 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0013491 infores:hetionet CHEBI:7459 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0036973 infores:hetionet NCBIGene:219854 biolink:causes MONDO:0030454 infores:monarchinitiative not_provided not_provided HGNC:27344 MONDO:0030454 uuid:124b1541-cc08-49bc-91f4-8210c7e50bd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0009763 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0033777 infores:hetionet CHEBI:32020 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0917801 infores:hetionet CHEBI:31236 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014457 infores:hetionet CHEBI:77260 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0030196 infores:hetionet CHEBI:16469 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0043094 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0027051 infores:hetionet CHEBI:3219 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0231218 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0347390 infores:hetionet CHEBI:3757 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0028084 infores:hetionet CHEBI:3215 biolink:causes MONDO:0006650 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0221069 infores:hetionet GO:2000226 biolink:causes GO:0031016 infores:ubergraph knowledge_assertion manual_agent GO:2000226 GO:0031016 UNII:Y2V2R4W9TQ biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0085649 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0549386 infores:hetionet CHEBI:10023 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020625 infores:hetionet CHEBI:68534 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0042075 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0242073 infores:hetionet CHEBI:4876 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0040034 infores:hetionet CHEBI:9150 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0029089 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0019158 infores:hetionet CHEBI:8888 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024236 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020621 infores:hetionet NCBIGene:60509 biolink:causes MONDO:0014871 infores:monarchinitiative not_provided not_provided HGNC:26147 MONDO:0014871 uuid:6a81e1f2-dd7f-4886-a0c5-21418143b131 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0948089 infores:hetionet CHEBI:3242 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C2364111 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0024115 infores:hetionet NCBIGene:11128 biolink:causes MONDO:0009910 infores:monarchinitiative not_provided not_provided HGNC:30074 MONDO:0009910 uuid:ab3ef105-da5b-4c03-9d5a-6c6f8e588e02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0025874 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0020651 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0542351 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0542351 infores:hetionet CHEBI:6444 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C3203358 infores:hetionet CHEBI:7820 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0242350 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0006444 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0403632 infores:hetionet CHEBI:617099 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0023895 infores:hetionet CHEBI:71272 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0018681 infores:hetionet CHEBI:70707 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0042023 infores:hetionet CHEBI:63621 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0028081 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0025061 infores:hetionet CHEBI:39585 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0005779 infores:hetionet NCBIGene:126695 biolink:causes MONDO:0015024 infores:monarchinitiative not_provided not_provided HGNC:26624 MONDO:0015024 uuid:985b8b78-418d-4eaf-aa50-f848e8145258 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA327916152 biolink:causes MONDO:0100437 infores:clingen CAID:CA327916152 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PP4, PS4 NM_001034853.2(RPGR):c.2248G>T (p.Glu750Ter) is a nonsense variant that substitutes a premature stop in codon for amino acid 750 within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of an affected male relative (PMID: 34745198). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The variant has been reported in a family in which 3 members are affected with retinal dystrophy, however, only the proband has been genotyped, so the PP1 code is not met (PMID: 34745198). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), early onset (1 pts), night blindness (0.5 pts), reduced visual acuity (0.5 pts), and genetic testing with exome sequencing finding no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (6 points, PMID: 34745198). However, the proband described is a female and PP4 requires a male, so the code is not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327916152/MONDO:0100437/106 2025-08-04 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:84500 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235259 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0035078 infores:hetionet CHEBI:51380 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0917801 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007097 infores:hetionet CHEBI:84500 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0151827 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0234913 infores:hetionet CAID:CA182451 biolink:causes MONDO:0019497 infores:clingen CAID:CA182451 MONDO:0019497 PMID: Likely Pathogenic PM5, PM3, PP3, PP4, PM2_Supporting PM1, PM4, PS1, PS2, PS3, PS4, BS1, BS4, BP5, BP7, PM6, PVS1, PP1, BS2, BP4, BP2, BP3, BA1 The c.5374C>T variant in OTOF is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1792. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16256 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). 1 different missense variant, c.5375G>A (p.R1792H) (PMID: 29048421, ClinVar Variation ID: 48259), in the same codon has been classified as likely pathogenic for nonsyndromic hearing loss by multiple submitters in ClinVar (PM5). This variant has been detected in at least 3 individuals with AR deafness. For two of those individuals, both were compound heterozygous for the variant and a VUS meeting PM2_Supporting, and both of those were confirmed in trans by family testing (c.2676G>A (p.K892K) which occurs at the last nucleotide in exon (22) of OTOF and c.4748G>A (p.R1583H), 1.5 PM3 points, PMID: 34416374, Universitätsmedizin Göttingen, Institute of Human Genetics/Institute of Auditory Neuroscience & InnerEarLab) (PM3). ​​At least one patient was compound heterozygous for this variant and the p.K892K variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for autosomal recessive deafness (PP4, PMID: 34416374). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3, PM5 (ClinGen Hearing Loss VCEP specifications version 2; 6/27/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA182451/MONDO:0019497/023 2023-06-29 2023-06-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:5165 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0009421 infores:hetionet CHEBI:9907 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0086565 infores:hetionet CHEBI:65349 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0033774 infores:hetionet CHEBI:32139 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0687713 infores:hetionet CHEBI:15407 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0037763 infores:hetionet NCBIGene:4117 biolink:causes MONDO:0013611 infores:monarchinitiative not_provided not_provided HGNC:6816 MONDO:0013611 uuid:0abb79d0-b8df-4f7f-883e-4d2b78717e83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020039 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038363 infores:hetionet CHEBI:9570 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020433 infores:hetionet CHEBI:6954 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0152025 infores:hetionet CHEBI:50173 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0008031 infores:hetionet CHEBI:9907 biolink:causes MONDO:0019065 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002726 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853089 infores:hetionet CHEBI:3215 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0003578 infores:hetionet CAID:CA49761605 biolink:causes MONDO:0015152 infores:clingen CAID:CA49761605 MONDO:0015152 PMID: Pathogenic PM3_Strong, PS1, PP4, PP3, PS3_Moderate, PM2_Supporting The NM_003494.4: c.895G>C variant in DYSF, which is also known as NM_001130987.2: c.991G>C (p.Gly331Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 299, p.(Gly299Arg). This variant has been reported in at least two individuals with LGMD, where it was confirmed in trans with a pathogenic variant (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pt, PMID: 17994539; NM_003494.4: c.2077del p.(His693ThrfsTer4), 1.0 pt; PMID: 34559919, 28403181, 27647186) (PM3_Strong). At least one of these patients displayed progressive limb girdle muscle weakness (PMID: 34559919; PP4). The highest frequency for this variant in gnomAD v4.1.0 is 0.00001666 in the Admixed American population (1/60024 chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly299Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). The computational predictor REVEL gives a score of 0.968, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Another nucleotide change resulting in the same amino acid change, NM_003494.4: c.895G>A p.(Gly299Arg), is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Strong, PP4, PM2_Supporting, PS3_Moderate, PP3, PS1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA49761605/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6078 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0456909 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1368065 infores:hetionet CHEBI:40279 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0033774 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0018802 infores:hetionet CHEBI:42797 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0025323 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002871 infores:hetionet CHEBI:9435 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0037317 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006835 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027721 infores:hetionet CHEBI:17347 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0013604 infores:hetionet CHEBI:2611 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0235660 infores:hetionet CHEBI:140621 biolink:causes UMLS:C0520758 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0520758 infores:hetionet CHEBI:145499 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1384353 infores:hetionet CHEBI:3568 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013378 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020649 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0040034 infores:hetionet CHEBI:3215 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0040822 infores:hetionet CHEBI:2659 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0042963 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0234913 infores:hetionet CHEBI:27786 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0232487 infores:hetionet NCBIGene:54820 biolink:causes MONDO:0011504 infores:monarchinitiative not_provided not_provided HGNC:17619 MONDO:0011504 uuid:045a9b08-fa43-4a8f-a814-04b2e23949e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1510471 infores:hetionet CHEBI:42797 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030252 infores:hetionet NCBIGene:388531 biolink:causes MONDO:0958190 infores:monarchinitiative not_provided not_provided HGNC:30304 MONDO:0958190 uuid:b83837e8-c92a-4606-847e-28d18692bd94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1105 biolink:causes MONDO:0060568 infores:monarchinitiative not_provided not_provided HGNC:1915 MONDO:0060568 uuid:30c1e7ae-c3ce-4f60-a08f-972d382379ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0040409 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0235146 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0042109 infores:hetionet CHEBI:68478 biolink:causes MONDO:0019369 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0458219 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0020456 infores:hetionet CHEBI:63598 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0016204 infores:hetionet CHEBI:5855 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042029 infores:hetionet CHEBI:8499 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0014518 infores:hetionet CHEBI:5147 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151908 infores:hetionet CHEBI:6904 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0015672 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002886 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0232570 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0232570 infores:hetionet CHEBI:51860 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0600142 infores:hetionet CHEBI:6076 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232849 infores:hetionet CAID:CA1139532534 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139532534 MONDO:0009861 PMID:28982351 Likely Pathogenic PM3, PM2, PP4, PP3 This c.1200-3T>G (aka IVS11-3T>G) intronic variant in PAH was reported in one patient with classic PKU, in trans with pathogenic variant p.Tyr204Cys. Patients with BH4 cofactor deficiency were excluded but only urinary pterin analysis was mentioned as a method of exclusion (PMID:28982351). According to in silico splicing predictions, this variant is probably damaging. The variant is absent from controls in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532534/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3510 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0027497 infores:hetionet CHEBI:8499 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0340865 infores:hetionet CHEBI:4046 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0018681 infores:hetionet CHEBI:4466 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0027796 infores:hetionet CHEBI:63630 biolink:causes EFO:1001863 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042135 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0024312 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0007787 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0521161 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0521161 infores:hetionet CHEBI:50131 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0234233 infores:hetionet CHEBI:83804 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0699744 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022650 infores:hetionet CHEBI:17303 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0700590 infores:hetionet CHEBI:63620 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042024 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0855242 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0232492 infores:hetionet CHEBI:71417 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C1527344 infores:hetionet CAID:CA012578 biolink:causes MONDO:0005045 infores:clingen CAID:CA012578 MONDO:0005045 PMID: Pathogenic PM2, PM1, PP1_Strong, PS4 PS3, BA1, PM6, PM3, PM5, PP3, BS1, BP4, BP2, BP5, PS2, PS1 The NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu) variant has been identified in >50 individuals with HCM (PS4; Atiga 2000 PMID:10725281; Kaski 2009 PMID:20031618; Aletras 2011 PMID:21576279; Leung 2013 PMID:23271734; Nunez 2013 PMID:23782526; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ross 2017 PMID:28615295; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute pers. comm.). This variant segregated with disease in 7 affected individuals with HCM in 5 families (PP1_Strong; Ross 2017 PMID:28615295; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide evidence for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012578/MONDO:0005045/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0009806 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0836924 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0041349 infores:hetionet CHEBI:4868 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0018802 infores:hetionet CHEBI:40237 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0009782 infores:hetionet CHEBI:6438 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0011570 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0521839 infores:hetionet CHEBI:31236 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018944 infores:hetionet CHEBI:144093 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011991 infores:hetionet CHEBI:8871 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011168 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0006145 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0149931 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0023530 infores:hetionet CHEBI:41977 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0009806 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0025061 infores:hetionet CHEBI:119486 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151772 infores:hetionet CHEBI:50122 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0023530 infores:hetionet CHEBI:63616 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0035229 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019112 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151736 infores:hetionet NCBIGene:81689 biolink:causes MONDO:0033282 infores:monarchinitiative not_provided not_provided HGNC:28660 MONDO:0033282 uuid:2acb41a4-36cc-42c5-a6d2-89a8d8f8c8b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0013144 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0023218 infores:hetionet CHEBI:8107 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011603 infores:hetionet CHEBI:5147 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0011175 infores:hetionet CAID:CA574226173 biolink:causes MONDO:0015967 infores:clingen CAID:CA574226173 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PP4_Moderate, PP1, PM2_Supporting The c.1155del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 386 in NM_000162.5, adding 15 novel amino acids before encountering a stop codon (p.(Leu386TrpfsTer16)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to the presence of only 1 copy in any subpopulation, thereby meeting ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with two informative meioses in two families (PP1; internal lab contributors). In summary, c.1155del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PVS1, PM2_supporting, PS4_moderate, PP4_moderate, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA574226173/MONDO:0015967/086 2025-09-26 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:15428 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0020517 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0042963 infores:hetionet NCBIGene:5605 biolink:causes MONDO:0014114 infores:monarchinitiative not_provided not_provided HGNC:6842 MONDO:0014114 uuid:2dbb172f-7716-4923-97bf-d45083b58ce2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15552 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0085593 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0034150 infores:hetionet CAID:CA16042157 biolink:causes MONDO:0007648 infores:clingen CAID:CA16042157 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PS4_Moderate, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.2296-1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least three families meeting HDGC clinical criteria (PS4_moderate; SCV000580714.3). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PS4_moderate, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042157/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:17688 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0403632 infores:hetionet CHEBI:8232 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C1384353 infores:hetionet NCBIGene:58 biolink:causes MONDO:0008070 infores:monarchinitiative not_provided not_provided HGNC:129 MONDO:0008070 uuid:119761ab-77a8-42e7-9cff-602c1a3c6762 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0026858 infores:hetionet CHEBI:10100 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0030193 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017160 infores:hetionet CHEBI:8502 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C2973529 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0002871 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0006145 infores:hetionet CHEBI:9352 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0023518 infores:hetionet CHEBI:6847 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0009806 infores:hetionet CHEBI:2469 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0700225 infores:hetionet NCBIGene:26128 biolink:causes MONDO:0012280 infores:monarchinitiative not_provided not_provided HGNC:23419 MONDO:0012280 uuid:93b9e2ab-6e0e-4328-a9ed-dd0977ef43e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3403 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0020538 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0031117 infores:hetionet GO:0042661 biolink:causes GO:0001710 infores:ubergraph knowledge_assertion manual_agent GO:0042661 GO:0001710 CHEBI:8382 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0034063 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151736 infores:hetionet CHEBI:3732 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0009782 infores:hetionet CHEBI:6909 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0232462 infores:hetionet CHEBI:253342 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0234233 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042109 infores:hetionet CHEBI:474180 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0032227 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0151559 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0549239 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0549239 infores:hetionet CHEBI:63608 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151662 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151596 infores:hetionet CHEBI:5123 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0036104 infores:hetionet UMLS:C1738934 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1510410 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013447 infores:hetionet CHEBI:31302 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0016655 infores:hetionet CHEBI:50275 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235996 infores:hetionet CHEBI:76010 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0232487 infores:hetionet CHEBI:5165 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013428 infores:hetionet CHEBI:9667 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0085932 infores:hetionet CHEBI:51364 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0231218 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0022893 infores:hetionet CHEBI:39585 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0233407 infores:hetionet CHEBI:93305 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0030193 infores:hetionet CHEBI:63580 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1527344 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0860434 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0860434 infores:hetionet CHEBI:45652 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0948594 infores:hetionet CHEBI:6741 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151905 infores:hetionet CHEBI:3756 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0001807 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0235874 infores:hetionet CAID:CA247034 biolink:causes MONDO:0015967 infores:clingen CAID:CA247034 MONDO:0015967 PMID: Likely Pathogenic PM1, PM5_Supporting, PP2, PP3, PM2_Supporting PS4, PP4 The c.688T>C variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to arginine at codon 230 (p.(Cys230Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with hyperglycemia; however, this does not meet the threshold set by the ClinGen MDEP for the application of PS4 (internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, the fasting blood sugar was slightly below the threshold for PP4 (5.5 mmol/L) (internal lab contributors). Another missense variant, c.689G>A p.Cys230Tyr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Cys230Arg (PM5_Supporting). In summary, c.688T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA247034/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:45652 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0234708 infores:hetionet CHEBI:68579 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0042029 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026946 infores:hetionet CHEBI:18332 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0008301 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0034067 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1619712 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0851341 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034069 infores:hetionet CHEBI:119573 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014335 infores:hetionet CHEBI:28445 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0029124 infores:hetionet CHEBI:8024 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0338656 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0029134 infores:hetionet CHEBI:7915 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0851578 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0152128 infores:hetionet CHEBI:7476 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018965 infores:hetionet CHEBI:9943 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030252 infores:hetionet GO:1901028 biolink:causes GO:0006839 infores:ubergraph knowledge_assertion manual_agent GO:1901028 GO:0006839 CHEBI:2639 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0917801 infores:hetionet CAID:CA10576326 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576326 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Strong, PM2, PP4 BP4, PS1, PS3, PM5, PP3 The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2: PopMax = 0.00005 in East Asians (gnomAD v2.1.1).PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfil clinical criteria for FH: 1 patient with DLCN >6 from the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI); 1 patient with Simon Broome = Definite FH (PMID: 20236128).PP1_Strong: Variant segregates with the FH phenotype in 8 informative meioses from 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI): 5 affected family members have the variant and 3 non-affected family members do not have the variant.PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH (Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA, Australia; VCI), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576326/MONDO:0007750/013 2023-10-25 2023-10-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:71219 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0856882 infores:hetionet CHEBI:9086 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233471 infores:hetionet CHEBI:7492 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0014457 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0151505 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0948586 infores:hetionet NCBIGene:1910 biolink:causes MONDO:0010895 infores:monarchinitiative not_provided not_provided HGNC:3180 MONDO:0010895 uuid:f4ac0dcc-809c-4d23-9e6b-73f126441776 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3647 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0751494 infores:hetionet CHEBI:4653 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0010200 infores:hetionet CHEBI:681850 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0042963 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0025061 infores:hetionet CHEBI:5296 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0011124 infores:hetionet CHEBI:6538 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0004093 infores:hetionet CHEBI:6015 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0010200 infores:hetionet CHEBI:28487 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0030193 infores:hetionet NCBIGene:150 biolink:causes MONDO:0958022 infores:monarchinitiative not_provided not_provided HGNC:281 MONDO:0958022 uuid:4ebd4d1f-1d07-4a18-8a09-314e2136c42e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9763 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0424295 infores:hetionet CHEBI:6367 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1458155 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0349506 infores:hetionet CHEBI:8499 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0002792 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0235097 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0235097 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0026848 infores:hetionet CHEBI:17650 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0015672 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002622 infores:hetionet UMLS:C0145867 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0039621 infores:hetionet CHEBI:61390 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0004093 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0152128 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0232492 infores:hetionet CHEBI:3732 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0547030 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0000833 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0233472 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0027051 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0036454 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0518015 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0021053 infores:hetionet CHEBI:36791 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003862 infores:hetionet CHEBI:72690 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0009782 infores:hetionet CHEBI:2922 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0018965 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0004936 infores:hetionet GO:1901632 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1901632 GO:0010256 CHEBI:15365 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0018834 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0027651 infores:hetionet CHEBI:50729 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0031542 infores:hetionet CAID:CA390864547 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864547 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting PVS1, PM6, BP2, BA1, BS2, PP3, PP1, PP4, PM4, PM5, PM3, PS2, PS3, PS1, PS4, BP7, BP5, BS1, BS4, BS3 The NM_177438.3:c.5486C>G variant in DICER1 is a missense variant predicted to cause substitution of threonine by arginine at amino acid 1829 (p.Thr1829Arg). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met). This variant has an allele frequency of 0.000000619 (1/1614150 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.347, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_supporting, PM2_supporting, BP4. (Bayesian points 1; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864547/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28901 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0006826 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020580 infores:hetionet GO:2001284 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:2001284 GO:0007267 CHEBI:28177 biolink:causes UMLS:C0948268 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0948268 infores:hetionet CHEBI:4702 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0037188 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009763 infores:hetionet CHEBI:3485 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0002792 infores:hetionet CHEBI:2038 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0239134 infores:hetionet CAID:CA10014181 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014181 MONDO:0011071 PMID:25840971 Benign BP4, BA1, BS3 PS4, PS3, PS1, BP2, PM6, PM2, PVS1, BP7, BS4, BS1, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.1355T>G (p.Val452Gly) variant has a MAF of 0.00177 (0.177%, 22/12,406 alleles) in the East Asian subpopulation of the gnomAD cohort that is ≥ 0.0015 (0.15%) (BA1). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding and CBFβ binding (BS3; PMID: 25840971). This missense variant has a REVEL score <0.15 (0.046) and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014181/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10101 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1112214 infores:hetionet CHEBI:7822 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0232493 infores:hetionet CHEBI:3082 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0015402 infores:hetionet CHEBI:41774 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0002994 infores:hetionet CHEBI:5050 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0013390 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0038362 infores:hetionet CHEBI:8768 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0009421 infores:hetionet CHEBI:31236 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035508 infores:hetionet CHEBI:49668 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0011603 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0262417 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0262417 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0040034 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0043349 infores:hetionet CHEBI:43968 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0085593 infores:hetionet GO:1904058 biolink:causes MONDO:0002639 infores:drugmechdb knowledge_assertion manual_agent GO:1904058 MESH:D020435 DB00564_MESH_D020435_1 CHEBI:2639 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0030920 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0151763 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0021053 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0277941 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0277941 infores:hetionet CHEBI:3654 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0162830 infores:hetionet NCBIGene:4166 biolink:causes MONDO:0009020 infores:monarchinitiative not_provided not_provided HGNC:6938 MONDO:0009020 uuid:6e1b869b-af81-4aa2-964c-9d20f60d711d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6538 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0003811 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0006852 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0851043 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0851043 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0003862 infores:hetionet CHEBI:3561 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0003811 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0267792 infores:hetionet CHEBI:3032 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0023066 infores:hetionet CHEBI:7465 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0033774 infores:hetionet CHEBI:3654 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0034150 infores:hetionet CHEBI:36791 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042029 infores:hetionet CHEBI:3561 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0917801 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0002170 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0403632 infores:hetionet CHEBI:5118 biolink:causes HP:0400007 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0032519 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0392160 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0392160 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0021053 infores:hetionet CHEBI:78543 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0018681 infores:hetionet GO:1903519 biolink:causes GO:0060443 infores:ubergraph knowledge_assertion manual_agent GO:1903519 GO:0060443 CHEBI:17823 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C1167965 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0004936 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0521839 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0003123 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0151785 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0232197 infores:hetionet CHEBI:17141 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0232462 infores:hetionet CHEBI:51380 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0026837 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0022904 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0009319 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0235431 infores:hetionet CAID:CA2499225873 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225873 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP2, BP3, PM6, BS1, BS3, BS4, BP7, BP5, PM3, PM1, PM4, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.813del (p.Arg271fs)is a frameshift variant that is not predicted to result in nonsense-mediated mRNA decay but the truncated region is critical to protein function (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225873/MONDO:0011071/008 2022-04-25 2022-06-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5441 biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0234222 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0022660 infores:hetionet CHEBI:3423 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0017181 infores:hetionet GO:0003348 biolink:causes CL:0010008 infores:ubergraph knowledge_assertion manual_agent GO:0003348 CL:0010008 CHEBI:7865 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0476273 infores:hetionet CHEBI:6950 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0007820 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007593 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0278151 infores:hetionet CHEBI:3077 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0702166 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0037278 infores:hetionet CHEBI:71941 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0497247 infores:hetionet CAID:CA386953857 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953857 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PS1 The c.225C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to glutamate at codon 75 (p.(Asp75Glu)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The nucleotide change c.225C>G, which causes the same amino acid change, was classified as a VUS by by the ClinGen MDEP; therefore, PS1 will not be applied. In summary, c.225C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953857/MONDO:0015967/017 2022-04-08 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0035203 biolink:causes GO:0002520 infores:ubergraph knowledge_assertion manual_agent GO:0035203 GO:0002520 CHEBI:2549 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042109 infores:hetionet CHEBI:8069 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0004134 infores:hetionet CHEBI:3647 biolink:causes HP:0025387 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0751564 infores:hetionet UMLS:C0657912 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235063 infores:hetionet NCBIGene:2697 biolink:causes MONDO:0008514 infores:monarchinitiative not_provided not_provided HGNC:4274 MONDO:0008514 uuid:c46c6979-0fa6-4b83-a04b-19fffcfc2226 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9430ZR8ZAN biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C2747793 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027051 infores:hetionet CHEBI:63638 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026827 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0314719 infores:hetionet CHEBI:47499 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042963 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011849 infores:hetionet CHEBI:6078 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0542571 infores:hetionet CHEBI:63599 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0038325 infores:hetionet CHEBI:3001 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0012833 infores:hetionet CAID:CA512341228 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341228 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1203C>T (p.Pro401=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-4.10) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341228/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8890 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0031542 infores:hetionet CHEBI:135736 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019209 infores:hetionet CHEBI:6931 biolink:causes NCIT:C50850 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0542127 infores:hetionet CHEBI:6375 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0851578 infores:hetionet CHEBI:59773 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0014591 infores:hetionet CHEBI:4562 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0424790 infores:hetionet CHEBI:63631 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151610 infores:hetionet CHEBI:92998 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0232487 infores:hetionet NCBITaxon:11908 biolink:causes MONDO:0005801 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11908 MONDO:0005801 CHEBI:8774 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0009806 infores:hetionet CHEBI:8245 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0002170 infores:hetionet CHEBI:35854 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0085649 infores:hetionet CHEBI:50648 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0232462 infores:hetionet NCBIGene:1294 biolink:causes MONDO:0007552 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0007552 uuid:a054d605-7fd3-4fce-aa32-c07a459d7fba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0086439 infores:hetionet NCBIGene:100303755 biolink:causes MONDO:0033654 infores:monarchinitiative not_provided not_provided HGNC:40045 MONDO:0033654 uuid:b079b758-d4df-416f-ba97-f9ed9c7229d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0595877 infores:hetionet CHEBI:4495 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0004093 infores:hetionet CHEBI:171719 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0232333 infores:hetionet CHEBI:8356 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003578 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0032290 infores:hetionet CHEBI:46081 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C1368065 infores:hetionet CHEBI:36791 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030554 infores:hetionet CHEBI:61049 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027066 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0237326 infores:hetionet CHEBI:16347 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0023218 infores:hetionet CAID:CA16020967 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020967 MONDO:0009861 PMID:23932990 Likely Pathogenic PM5, PP4_Moderate, PM2, PP3 The c.1200G>T (p.Arg400Ser) variant in PAH has been reported in 2 Chinese patients, type of PKU not determined, serum Phe at least 120umol/L; BH4 deficiency excluded (PMID: 23932990; PP4_Moderate). This variant is at the same codon as c.1199G>C (p.R400T) - curated as Pathogenic by ClinGen PAH VCEP; c.1198del (p.Arg400fs) - reported as Pathogenic in ClinVar (VarID:102554); and c.1198A>C (p.Arg400=) - curated as VUS by ClinGen PAH VCEP (PM5). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, Mutation Taster, and REVEL = 0.901 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020967/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6067 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0037299 infores:hetionet CAID:CA512341128 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341128 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1281C>A (p.Arg427=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.25)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341128/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:G4PX8C4HKV biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0008031 infores:hetionet CHEBI:28971 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0023530 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0009806 infores:hetionet CHEBI:6717 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C2830004 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0006912 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0032266 infores:hetionet CHEBI:31711 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085624 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0010073 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042514 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0002170 infores:hetionet CHEBI:46295 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0231218 infores:hetionet CHEBI:9434 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0547030 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0006852 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0035455 infores:hetionet CHEBI:53760 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1328337 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0017675 infores:hetionet CHEBI:3716 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0030554 infores:hetionet UMLS:C0004609 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0520966 infores:hetionet CAID:CA10014358 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014358 MONDO:0011071 PMID: Uncertain Significance BP4 PS4, PS2, PS3, PS1, BP1, BP2, BP3, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM5, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.787C>T (p.Pro263Ser) is a missense variant which has a REVEL score of 0.286 and a SpliceAI score ≤ 0.20, meeting the threshold for BP4. It is reported at a frequency of 0.0002620 (4/15268 alleles) in the Admixed American population in gnomAD v2.1.1, which does not meet population-based criteria. Although reported in a patient with chronic myelomonocytic leukemia (PMID: 24764152), germline status is not confirmed and other reports concern acquired variants. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014358/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027051 infores:hetionet CHEBI:50131 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0002792 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0013125 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0013125 uuid:ff739a98-057d-48ab-8711-3762b8a20e61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030196 infores:hetionet CHEBI:6887 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0036830 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0009450 infores:hetionet CHEBI:45951 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0026205 infores:hetionet CHEBI:7476 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0017181 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0028077 infores:hetionet CAID:CA220579698 biolink:causes MONDO:0000573 infores:clingen CAID:CA220579698 MONDO:0000573 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4 The NM_000536.4:c.955G>T variant in RAG2 is a nonsense variant predicted to result in a truncated protein (p.Gly319*). Although this variant is expected to escape nonsense-mediated decay (NMD), it would be expected to disrupt approximately 40% of the RAG2 protein. In addition, this variant would be expected to disrupt/remove the entire PHD domain (amino acids 414-487), which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 15964836). PVS1 met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).To our knowledge, the variant has not been identified in the literature in patients/case reports or functional studies.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2 and PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA220579698/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9168 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004093 infores:hetionet CHEBI:4636 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0001824 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0151479 infores:hetionet CL:0000669 biolink:causes MONDO:0002604 infores:ubergraph knowledge_assertion manual_agent CL:0000669 MONDO:0002604 CHEBI:63580 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0021053 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0002871 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0155320 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0010709 infores:hetionet CHEBI:2663 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0027497 infores:hetionet CHEBI:85161 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0236075 infores:hetionet CAID:CA82551874 biolink:causes MONDO:0009276 infores:clingen CAID:CA82551874 MONDO:0009276 PMID: Benign BA1, BP7 The c.-124C>T variant in GP9 is a non-coding variant which located upstream of the 5' UTR. It was identified through an ICLS predisposition screen in an ostensibly healthy population. To date, this variant has not been reported in any patients with BSS. The c.-124C>T variant is an intronic variant that is not predicted by SpliceAI to impact splicing (acceptor gain score of 0.1 which is less than the VCEP threshold of <0.2). In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of 0.314583 (<1.5) (BP7). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.004120 (248/54052 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA82551874/MONDO:0009276/083 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:53691 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0020538 infores:hetionet CHEBI:37941 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151529 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0235369 infores:hetionet CHEBI:31711 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151799 infores:hetionet CHEBI:37924 biolink:causes HP:0012041 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151640 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017152 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1096035 infores:hetionet CAID:CA2697554180 biolink:causes MONDO:0100216 infores:clingen CAID:CA2697554180 MONDO:0100216 PMID: Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PS3 PVS1, BP4, BP2, BA1, PP1, PP4, BS2, PM5, PM4, PM1, PS1, PS2, BP7, BS1, BS3, BS4 The NM_177438.3:c.734+3A>T variant in DICER1 is an intronic variant resulting in an A to T substitution 3 nucleotides downstream from coding exon 5. This variant received a total of 1 phenotype point(s) across 1 proband, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributors). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PM2_Supporting, PS3, PP3. (Bayesian Points: 7; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697554180/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63599 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0015967 infores:hetionet NCBIGene:7036 biolink:causes MONDO:0011417 infores:monarchinitiative not_provided not_provided HGNC:11762 MONDO:0011417 uuid:b474397d-a069-4046-acc7-9195ebf7793f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0016204 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0042109 infores:hetionet NCBIGene:5781 biolink:causes MONDO:0008104 infores:monarchinitiative not_provided not_provided HGNC:9644 MONDO:0008104 uuid:63bc7032-29a5-42b4-848b-f27802aa1ffe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085611 infores:hetionet CHEBI:3732 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C2830004 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0549373 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027051 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0020649 infores:hetionet CHEBI:8764 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1456784 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020538 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0020517 infores:hetionet CHEBI:3286 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0003811 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0919909 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0919909 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0024115 infores:hetionet CHEBI:6367 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0010481 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0031212 infores:hetionet CHEBI:59750 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0152459 infores:hetionet CHEBI:47898 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020625 infores:hetionet CHEBI:7465 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0001973 infores:hetionet CHEBI:9332 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C1368065 infores:hetionet CHEBI:8364 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0700590 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0522224 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0855242 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029132 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0542203 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1096701 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1096701 infores:hetionet CHEBI:3534 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0041969 infores:hetionet CHEBI:7773 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0015967 infores:hetionet GO:0141079 biolink:causes GO:0141084 infores:ubergraph knowledge_assertion manual_agent GO:0141079 GO:0141084 CHEBI:3696 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0037299 infores:hetionet CHEBI:6402 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0015672 infores:hetionet CHEBI:6128 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0040264 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0795692 infores:hetionet CHEBI:2682 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1368065 infores:hetionet CHEBI:28901 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0033774 infores:hetionet GO:1903653 biolink:causes GO:0048870 infores:ubergraph knowledge_assertion manual_agent GO:1903653 GO:0048870 CHEBI:50729 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0011991 infores:hetionet CHEBI:6775 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0026858 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0003864 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005394 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0751955 infores:hetionet CHEBI:63627 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C1291078 infores:hetionet CHEBI:42797 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013456 infores:hetionet CHEBI:63612 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0013604 infores:hetionet CHEBI:43968 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0015230 infores:hetionet CHEBI:9571 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0026961 infores:hetionet CHEBI:51380 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0015672 infores:hetionet NCBIGene:859 biolink:causes MONDO:0008647 infores:monarchinitiative not_provided not_provided HGNC:1529 MONDO:0008647 uuid:1c4d387d-50e5-4848-bafd-2ec70b72b75c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0233414 infores:hetionet CAID:CA14879301 biolink:causes MONDO:0011071 infores:clingen CAID:CA14879301 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS3, PS1, PS4, PS2, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.508+232A>G is an intronic variant with a MAF of 0.31559 (31.559%, 2745/8698, 11,443 alleles) in the African subpopulation of the gnomAD v.2 cohort is ≥ 0.0015 (0.15%) (BA1). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.537268 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) and splicing is not predicted to be impacted (BP4, BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14879301/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6078 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0948594 infores:hetionet CHEBI:3756 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0239739 infores:hetionet CHEBI:144551 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0022081 infores:hetionet CAID:CA248623 biolink:causes MONDO:0011071 infores:clingen CAID:CA248623 MONDO:0011071 PMID:23848403PMID:12060124PMID:12060124PMID:12060124 Pathogenic PS3, PM5_Supporting, PM1, PM2_Supporting, PS4_Supporting, PP3, PP1 PS1, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS3, BS1, BS4, BP7, BP5, PM4, PM3, PP2, PP4, BS2 Transactivation assays demonstrate altered transactivation (<20% of wt) for the missense variant, NM_001754.4:c.400G>C (p.Ala134Pro) and data from secondary assays demonstrate altered CBFβ binding and sub-cellular localization.(PS3; PMID: 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.945) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 12060124). It was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 12060124). This variant is a missense change at the same residue (p.A134) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1484777) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PM2_supporting, PP1, PP3, PS4_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248623/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9763 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0004093 infores:hetionet CHEBI:9448 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0040460 infores:hetionet UMLS:C0657912 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025320 infores:hetionet CHEBI:83527 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0026961 infores:hetionet CHEBI:10101 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0010200 infores:hetionet CHEBI:31401 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0006277 infores:hetionet CHEBI:53760 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0025323 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0235431 infores:hetionet CAID:CA399801154 biolink:causes MONDO:0100326 infores:clingen CAID:CA399801154 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PM3, PP3, PP4 The NM_000419.5(ITGA2B):c.1922C>T (p.Pro641Leu) missense variant was identified in a patient (PMID 25607928) with reported GT. This variant is absent from the gnomAD database v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399801154/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:135935 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0581912 infores:hetionet CHEBI:231594 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0699744 infores:hetionet GO:0048395 biolink:causes GO:0048390 infores:ubergraph knowledge_assertion manual_agent GO:0048395 GO:0048390 CHEBI:31236 biolink:causes HP:0030812 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0272386 infores:hetionet CHEBI:65346 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0010200 infores:hetionet NCBIGene:6650 biolink:causes MONDO:0036189 infores:monarchinitiative not_provided not_provided HGNC:11182 MONDO:0036189 uuid:00a2c69f-e71b-446e-8ebf-a903cb36baa9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63632 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0013395 infores:hetionet CHEBI:5280 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0042164 infores:hetionet CHEBI:64064 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0015230 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0009806 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037052 infores:hetionet CHEBI:8774 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0231218 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0023067 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0030567 infores:hetionet CHEBI:63631 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025874 infores:hetionet CHEBI:44423 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0231218 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0497327 infores:hetionet CHEBI:3347 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0030554 infores:hetionet CAID:CA1244346 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244346 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.20G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 7 (p.Arg7His). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00008331 (5 alleles out of 60,014), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.099, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 20668460), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244346/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31413 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0023530 infores:hetionet CHEBI:17303 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0004134 infores:hetionet CHEBI:5141 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C3665347 infores:hetionet CHEBI:2569 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C1443060 infores:hetionet CHEBI:3696 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0015967 infores:hetionet CHEBI:63619 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0237314 infores:hetionet CHEBI:5141 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0042571 infores:hetionet CHEBI:63608 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151744 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0026848 infores:hetionet CHEBI:49603 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0333355 infores:hetionet CAID:CA915943466 biolink:causes MONDO:0021056 infores:clingen CAID:CA915943466 MONDO:0021056 PMID:9669663 Uncertain Significance PS3_Supporting, PM2_Supporting BS2, BP4, PS4 "The NM_000038.6(APC):c.835-17A>G variant in APC is an intronic variant in intron 8. This variant has been reported in 1 proband with phenotype consistent with APC but not highly specific, resulting in a total phenotype score of 0.5 (PS4 not met) (PMID: 9669663). This variant has been observed in a heterozygous state in three individuals without a colorectal cancer/polyposis associated phenotype worth 1 healthy individual point in total (BS2_Supporting not met; [Invitae and Ambry Genetics]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RT-PCR sequencing of cDNA demonstrated that the variant impacts splicing by insertion of the last sixteen nucleotides of intron 7 between exon 7 and 8, adding two novel amino acids and a stop codon at position 281. Even though not quantitative, it is described that ""RT-PCR analysis suggested that the abnormal APC RNA molecules are present at low levels as compared to normal APC RNA molecules,"" the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) decided to use this result as PS3_Supporting (PMID: 9669663). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) are not conclusive. In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PM2_Supporting, PS3_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023)." InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA915943466/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41423 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0086565 infores:hetionet CHEBI:4814 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0151825 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0012813 infores:hetionet CHEBI:9738 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0000737 infores:hetionet UMLS:C0025241 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151766 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0162830 infores:hetionet CHEBI:7459 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0020458 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0022116 infores:hetionet CHEBI:74947 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0015672 infores:hetionet CHEBI:2668 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C3665347 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0235723 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235723 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0012833 infores:hetionet NCBIGene:5589 biolink:causes MONDO:0008265 infores:monarchinitiative not_provided not_provided HGNC:9411 MONDO:0008265 uuid:75d29b03-56d6-47b6-ba9b-aeea7f707b8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4903 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0002453 infores:hetionet CHEBI:50648 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235896 infores:hetionet CHEBI:119915 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151662 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015230 infores:hetionet CHEBI:4562 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0085631 infores:hetionet CHEBI:9727 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0022107 infores:hetionet CHEBI:7959 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0024141 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0003123 infores:hetionet CHEBI:8207 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0030193 infores:hetionet CHEBI:251408 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0036572 infores:hetionet CHEBI:7936 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0699828 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009326 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0030920 infores:hetionet CAID:CA367398622 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398622 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP2, PP3, PP4, PM2_Supporting The c.1174C>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Cys at codon 392 (p.(Arg392Cys)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.911 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:29758564 , internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least 19 informative meioses in 10 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1174C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4, PS4, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398622/MONDO:0015967/086 2023-07-16 2023-07-16 Semidominant inheritance HP:0032113 Supports CHEBI:32221 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0025290 infores:hetionet CHEBI:42068 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0600142 infores:hetionet NCBIGene:4010 biolink:causes MONDO:0009724 infores:monarchinitiative not_provided not_provided HGNC:6654 MONDO:0009724 uuid:30704092-c7cf-40d0-bbef-8628eb5c9ff7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0235369 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0860210 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0035455 infores:hetionet NCBIGene:2013 biolink:causes MONDO:0014373 infores:monarchinitiative not_provided not_provided HGNC:3334 MONDO:0014373 uuid:00bf3cc7-2d10-4f29-9e4b-7a2392681e08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44032 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0011603 infores:hetionet CHEBI:46195 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0028961 infores:hetionet UNII:R43D2573WO biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0428974 infores:hetionet CHEBI:6838 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0520459 infores:hetionet CHEBI:37924 biolink:causes MONDO:0018181 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0038165 infores:hetionet NCBITaxon:171 biolink:causes MONDO:0005825 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:171 MONDO:0005825 CHEBI:64355 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2242737 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001221 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014867 infores:hetionet CHEBI:5138 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1167965 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005160 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003486 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0008325 infores:hetionet CHEBI:61049 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038325 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027769 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0021400 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0005779 infores:hetionet CHEBI:46345 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0013404 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020550 infores:hetionet CHEBI:6539 biolink:causes MONDO:0007147 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0520679 infores:hetionet NCBIGene:54845 biolink:causes MONDO:0033202 infores:monarchinitiative not_provided not_provided HGNC:25966 MONDO:0033202 uuid:1ff6eec3-75e3-49e5-97d9-6f9c79f7bf0c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0032285 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020621 infores:hetionet CHEBI:4325 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0237849 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0038362 infores:hetionet CHEBI:6402 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C2363731 infores:hetionet CHEBI:136040 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0278106 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0011849 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C2225524 infores:hetionet UMLS:C0004609 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C3665347 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0011630 infores:hetionet NCBIGene:100151683 biolink:causes MONDO:0009191 infores:monarchinitiative not_provided not_provided HGNC:34016 MONDO:0009191 uuid:4d8addd2-3f80-42f3-83eb-db0ae91b974e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:123872 biolink:causes MONDO:0013174 infores:monarchinitiative not_provided not_provided HGNC:30539 MONDO:0013174 uuid:4cd2ea09-0cb7-401a-8567-afd7cdc1c39f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0020580 infores:hetionet CHEBI:15544 biolink:causes HP:0040411 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0497481 infores:hetionet CHEBI:63845 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0033774 infores:hetionet CAID:CA7542789 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542789 MONDO:0012996 PMID: Likely Benign BP4, BS1 PP3 The NM_001482.3:c.1043-3T>C variant in GATM is an intronic variant affecting a nucleotide within the consensus splice region of intron 7. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (4/34572 alleles) in the Latino population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.04 for acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 587965). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542789/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:68478 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0341012 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027651 infores:hetionet CHEBI:100241 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0423153 infores:hetionet CHEBI:94449 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0042075 infores:hetionet CAID:CA012568 biolink:causes MONDO:0005045 infores:clingen CAID:CA012568 MONDO:0005045 PMID: Likely Pathogenic PM2, PP1, PM4_Supporting, PS4 PM6, BA1, PS3, BP3, BS1, BS3, PS2, BP2, BP5 The NM_000257.4: c.2539_2541del (p.Lys847del) variant in MYH7 has been reported in >15 individuals with HCM (PS4; Van Driest 2004 PMID:15358028; Santos 2012 PMID:22429680; Kassem 2013 PMID:23233322; Marsiglia 2013 PMID:24093860; Waldmuller 2008 PMID:18258667; Walsh 2017 PMID: 27532257; Ho 2018 PMID: 30297972; Jaaskelainen 2019 PMID: 30775854; LMM pers. comm.; Invitae pers. comm.). This variant segregated with disease in 3 affected individuals with HCM from 2 families(PP1; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v.2.1.1, http://exac.broadinstitute.org,). This variant is a deletion of 1 amino acid at position 847 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1; PM2; PM4_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012568/MONDO:0005045/002 2021-10-05 2021-10-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3216 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0278134 infores:hetionet GO:0045700 biolink:causes GO:0007283 infores:ubergraph knowledge_assertion manual_agent GO:0045700 GO:0007283 CHEBI:49713 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0003813 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0162287 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0233494 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0271211 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0271211 infores:hetionet CHEBI:63791 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085641 infores:hetionet CHEBI:8764 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085680 infores:hetionet NCBIGene:4041 biolink:causes MONDO:0044327 infores:monarchinitiative not_provided not_provided HGNC:6697 MONDO:0044327 uuid:220f334c-60a1-4648-8e67-27b481c965fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:107736 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0242350 infores:hetionet CHEBI:39585 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0080274 infores:hetionet NCBIGene:144577 biolink:causes MONDO:0976231 infores:monarchinitiative not_provided not_provided HGNC:26517 MONDO:0976231 uuid:2641203a-fcc3-4e2b-8255-21a5edba5321 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0426390 infores:hetionet CHEBI:45783 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0003862 infores:hetionet CHEBI:10650 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0231530 infores:hetionet CHEBI:4907 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0234215 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0017160 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0013395 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0853714 infores:hetionet CHEBI:46295 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0033774 infores:hetionet CAID:CA8970372 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970372 MONDO:0012589 PMID: Benign BP4, BP7, BP5, BS1, BS2 The allele frequency of the p.Asn301= variant in TCF4 is 0.011% in East Asian sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Asn301= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Asn301= variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Asn301= variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Asn301= variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970372/MONDO:0012589/032 2024-02-23 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10101 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1167965 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0423273 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0423273 infores:hetionet CHEBI:6015 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0151798 infores:hetionet CHEBI:64064 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0030196 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0040046 infores:hetionet CHEBI:8890 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0015230 infores:hetionet CAID:CA8338308 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338308 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 PP3, PP4, PM3 The NM_000018.4(ACADVL): c.1894C>T; (p.Arg632Cys) variant is a missense variant predicted to cause substitution of arginine by cystine at amino acid 632. The highest population minor allele frequency in gnomAD v4.1 is 0.0003 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.407, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 27209629, PMID: 35281659). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, PM2_supporting (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338308/MONDO:0008723/021 2025-07-22 2025-10-03 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50885 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0011849 infores:hetionet CHEBI:5893 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0004134 infores:hetionet CHEBI:135961 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0042963 infores:hetionet CHEBI:480999 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0002874 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0031039 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0035455 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0015230 infores:hetionet CAID:CA386297078 biolink:causes MONDO:0009861 infores:clingen CAID:CA386297078 MONDO:0009861 PMID: Pathogenic PM3, PM2, PVS1, PP4 This c.510-1G>C variant in PAH was detected in a patient with PKU with the pathogenic variant p.Arg111Ter (PMID: 28982351). This variant was absent in population databases. This is a canonical variant in the -1 splice acceptor of intron 5. Exon skipping or use of a cryptic splice site would disrupt reading frame with nonsense mediated decay predicted. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386297078/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63619 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151905 infores:hetionet CHEBI:8888 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0750876 infores:hetionet CHEBI:4466 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151662 infores:hetionet CHEBI:42944 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0009782 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042769 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0160390 infores:hetionet CHEBI:5280 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0235266 infores:hetionet CHEBI:6775 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0242429 infores:hetionet CHEBI:50729 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0085661 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0018213 infores:hetionet CHEBI:63925 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0042909 infores:hetionet CHEBI:135342 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1268766 infores:hetionet CHEBI:4027 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0043049 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0403632 infores:hetionet CAID:CA405646836 biolink:causes MONDO:0007783 infores:clingen CAID:CA405646836 MONDO:0007783 PMID: Uncertain Significance PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glutamine at codon 3584 of the RYR1 protein, p.(Glu3584Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual noted to have malignant hyperthermia (MH) without details on a clear personal or family history of an MH episode and without a clear in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16917943). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.798 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405646836/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:46195 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0011615 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0852733 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0178298 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1384353 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0851341 infores:hetionet CHEBI:68558 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0007177 infores:hetionet CAID:CA10650438 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650438 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*436G>C is a 3' UTR variant which has a MAF of 0.0005771 (0.05771%, 3/5198, 3 alleles) in the East Asian subpopulation of the gnomAD 3.1.2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650438/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3756 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019825 infores:hetionet CHEBI:2666 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0233407 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0235431 infores:hetionet CHEBI:47898 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014743 infores:hetionet UNII:R43D2573WO biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0036974 infores:hetionet CHEBI:3238 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01091 UMLS:C0030193 infores:hetionet CHEBI:8059 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0030252 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0151730 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0151730 infores:hetionet CHEBI:36795 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013491 infores:hetionet CHEBI:4024 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0234708 infores:hetionet CHEBI:16714 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C2981158 infores:hetionet CHEBI:3312 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0018790 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011615 infores:hetionet CHEBI:4453 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0268000 infores:hetionet CHEBI:135285 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0030305 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0919714 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0919714 infores:hetionet CHEBI:40237 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0002792 infores:hetionet CHEBI:2663 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0022346 infores:hetionet CAID:CA768463754 biolink:causes MONDO:0800472 infores:clingen CAID:CA768463754 MONDO:0800472 PMID:18470941 Likely Pathogenic PM2_Supporting, PM3_Strong, PM1_Supporting, PM4, PS3_Supporting PP3, PP1, BP4, BA1, PS1, PS2, PM5, BP7, BS1, BS4, PVS1 The c.1033_1035del variant in CYP1B1 is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Leu345del), meeting PM4. This in-frame indel variant is located in the I-helix, meeting PM1_Supporting. The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000002542 (3 alleles out of 1,179,956), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. A previous study (PMID: 18470941) demonstrated that the Leu345del protein had reduced 17B Estradiol Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. This variant has been identified in 2 individuals with a CYP1B1-related phenotype. These individuals are compound heterozygous for the variant and pathogenic or likely pathogenic variants (confirmed in trans) (PMIDs: 19195637, 16735994). Total proband points = 2, meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PM4, PS3_Supporting, PM1_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA768463754/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0025241 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0018790 infores:hetionet CHEBI:7931 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0002994 infores:hetionet CHEBI:17076 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0595916 infores:hetionet UMLS:C0145185 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0013404 infores:hetionet CHEBI:17688 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0033774 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0877094 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0877094 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0042373 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020039 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0027051 infores:hetionet CAID:CA397840049 biolink:causes MONDO:0018875 infores:clingen CAID:CA397840049 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PM5, PP3, PP4, PM2_Supporting BA1, BP4, BP2, PS1, PS3, PS2, PS4, PM1, BS1, BS4, PP1, BS2 The NM_000546.6: c.640C>T variant in TP53 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 214 (p.His214Tyr). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMID: 36091175, Internal lab contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.188725; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Computational predictor scores (BayesDel = 0.188725; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant(c.641A>G, p.His214Arg) (ClinVar Variation ID: 376615), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP3, PP4, PM2_Supporting, PM5, BS3_Supporting. (Bayesian Points: 4; VCEP specifications version 2.3; date of approval) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397840049/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA8623016 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623016 MONDO:0100326 PMID:11722423PMID:11722423 Likely Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting BS3, PS3 The NM_000212.3(ITGB3):c.655G>A (p.Val219Met) missense variant has been reported in at least one patient (Patient GTa, PMID:11722423) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). GTa is compound heterozygous for this variant and pathogenic variant c.602del (PM3). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91078 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.874, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3, PP4_moderate, and PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623016/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6067 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0023380 infores:hetionet CHEBI:31981 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0001807 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0030193 infores:hetionet CHEBI:6367 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014591 infores:hetionet CHEBI:2637 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0015230 infores:hetionet NCBIGene:5081 biolink:causes MONDO:0032821 infores:monarchinitiative not_provided not_provided HGNC:8621 MONDO:0032821 uuid:20a6f1ea-75fc-49a3-bc18-1d03732e7641 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018834 infores:hetionet CHEBI:8028 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0751494 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0017160 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0022354 infores:hetionet CHEBI:10101 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0015402 infores:hetionet CHEBI:82960 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0236075 infores:hetionet CHEBI:50924 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0086565 infores:hetionet CHEBI:135285 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0009806 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0851341 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0002871 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0239521 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0239521 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0035455 infores:hetionet CHEBI:408174 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0009763 infores:hetionet CAID:CA229579 biolink:causes MONDO:0009861 infores:clingen CAID:CA229579 MONDO:0009861 PMID:19786003PMID:10598814PMID:8981952PMID:26666653 Likely Pathogenic PM3, PP4_Moderate, PM2, PP1, PP3 The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID: 8981952; PP1, PMID: 26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID: 10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229579/MONDO:0009861/006 2019-04-07 2019-04-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:681569 biolink:causes EFO:1001478 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0242966 infores:hetionet CHEBI:6909 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0022346 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018801 infores:hetionet CHEBI:9649 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0040264 infores:hetionet CHEBI:50859 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0000731 infores:hetionet CHEBI:7852 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235710 infores:hetionet CHEBI:465284 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085636 infores:hetionet CHEBI:3640 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0030554 infores:hetionet CHEBI:63622 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0234238 infores:hetionet CHEBI:3723 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0423798 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0006941 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D011906 DB01053_MESH_D011906_1 NCBIGene:6820 biolink:causes MONDO:0033091 infores:monarchinitiative not_provided not_provided HGNC:11459 MONDO:0033091 uuid:cbc4cd0f-8f0a-47f6-85c3-bbb26b61d81e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060058 biolink:causes GO:0060056 infores:ubergraph knowledge_assertion manual_agent GO:0060058 GO:0060056 CHEBI:3756 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009806 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1145628 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027430 infores:hetionet CHEBI:6954 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0001623 infores:hetionet CHEBI:39585 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0015967 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096106 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096106 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005165 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0086692 infores:hetionet CHEBI:28445 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0476273 infores:hetionet CHEBI:9588 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0004093 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0002622 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0042075 infores:hetionet CHEBI:135736 biolink:causes HP:0007359 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0751495 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0243026 infores:hetionet CAID:CA10652914 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652914 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.2529_2530dup is an intronic variant which meets criteria for benign classification. It has a MAF of 0.07635 (7.6%, 2892/37880 alleles) in the African/African American subpopulation of the gnomAD vX cohort, which is ≥ 0.0015 (0.15%) (BA1). This variant has been observed in 90 homozygotes in gnomAD v3 (BP2). It also has a SpliceAI score ≤ 0.20 (0.01) (BP4) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.16, 0.53)) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652914/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3219 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038663 infores:hetionet CHEBI:8499 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0002170 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0948525 infores:hetionet CHEBI:52172 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0860864 infores:hetionet CHEBI:3310 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0012833 infores:hetionet CHEBI:6367 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038990 infores:hetionet CAID:CA000467 biolink:causes MONDO:0017623 infores:clingen CAID:CA000467 MONDO:0017623 PMID: Pathogenic PM2, PVS1, PS4_Supporting PTEN c.469G>T (p.E157X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 8071972) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000467/MONDO:0017623/003 2018-10-30 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6073 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0017178 infores:hetionet NCBIGene:344167 biolink:causes MONDO:0958194 infores:monarchinitiative not_provided not_provided HGNC:35123 MONDO:0958194 uuid:a72fb86d-bd71-48c1-9cb6-e971406724c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:53371 biolink:causes MONDO:0957385 infores:monarchinitiative not_provided not_provided HGNC:17359 MONDO:0957385 uuid:be26d757-e565-44da-9503-a35c9e4cb8af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0005758 infores:hetionet CHEBI:10023 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2979982 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0024115 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1142011 infores:hetionet NCBIGene:55167 biolink:causes MONDO:0975836 infores:monarchinitiative not_provided not_provided HGNC:25544 MONDO:0975836 uuid:7be645c6-9778-4bfe-be98-a4af88e329d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0010520 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0036572 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0042514 infores:hetionet CHEBI:63599 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0020598 infores:hetionet CHEBI:52172 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0014743 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0853697 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0027627 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0027627 infores:hetionet CHEBI:136040 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0010692 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002884 infores:hetionet CHEBI:6413 biolink:causes MONDO:0008600 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0158328 infores:hetionet CAID:CA8815081 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815081 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting The NM_000152.5:c.883C>A variant in GAA is a missense variant predicted to cause substitution of His by Asn at amino acid 295 (p.His295Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (3/24448 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.716 which is above the thresholds predicting a damaging (>0.7) impact on GAA function (PP3. This variant has been detected in 1 individual with Pompe disease, who was compound heterozygous for the variant and variant c.2560C>T (VCEP Pathogenic) with unknown phase (PMID: 37087815). It has also been detected in 1 individual with low GAA enzyme activity with compound heterozygous for the variant and variant c.1962_1964delAGA; p.Glu655del (VCEP Pathogenic) with unknown phase (Clinical lab data), thus met PM3. At least 2 patient with this variant had documented GAA activity in blood (PMID: 37087815; clinical lab), meeting PP4_Moderate. There is a ClinVar entry for this variant (Variation ID: 953728). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, PP3, PM3, PP4_moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815081/MONDO:0009290/010 2024-12-19 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UMLS:C0010592 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0003873 infores:hetionet CHEBI:3814 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0037763 infores:hetionet CHEBI:10119 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042963 infores:hetionet GO:0010083 biolink:causes GO:0048367 infores:ubergraph knowledge_assertion manual_agent GO:0010083 GO:0048367 NCBIGene:91624 biolink:causes MONDO:0013477 infores:monarchinitiative not_provided not_provided HGNC:29557 MONDO:0013477 uuid:bc8ee40a-814b-4277-ab35-c9af9953b32e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0022658 infores:hetionet GO:1903379 biolink:causes GO:0000070 infores:ubergraph knowledge_assertion manual_agent GO:1903379 GO:0000070 CHEBI:474053 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0042963 infores:hetionet NCBIGene:8481 biolink:causes MONDO:0010265 infores:monarchinitiative not_provided not_provided HGNC:2567 MONDO:0010265 uuid:f749e7a1-4011-4abc-8483-32117bf78f20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16616526 biolink:causes MONDO:0100083 infores:clingen CAID:CA16616526 MONDO:0100083 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.530_532dup (p.Ile177_Thr178insIle) is an in-frame insertion which affects a residue within the Runt Homology domain (AA 89-294) but does not impact a residue which has been established as a hotspot (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616526/MONDO:0100083/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17303 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C3263723 infores:hetionet CHEBI:6067 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085633 infores:hetionet CHEBI:39867 biolink:causes MONDO:0024291 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0158570 infores:hetionet UMLS:C0657912 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0232462 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235146 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0013395 infores:hetionet NCBITaxon:34384 biolink:causes MONDO:0001628 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:34384 MESH:D014009 DB00857_MESH_D014009_1 CAID:CA8366083 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366083 MONDO:0100453 PMID:23035049 Pathogenic PM5, PM3_Strong, PS3_Supporting, PP3, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.2303G>A (p.Arg768Gln) is a missense variant predicted to replace arginine with glutamine at position p.768 in the RetGC-1 protein. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000008057, with 13 alleles / 1,613,428 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.734 which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function (PP3). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 28224992, 2604750). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous. The first has the p.Ser626Phe variant confirmed in trans but this variant has not been curated by the LCA/eoRD VCEP (not counted, PMID:26626312). The second has the c.82dup, p.Arg28Profs*291 variant confirmed in trans, which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP(1 pt, PMID: 26047050) (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with presentation at birth (1 pt), extinct electroretinogram responses from both rods (0.5 pts) and cones (1 pt), attenuated vessels and muddy retinal pigmentation (0.5 pts), and nystagmus (1 pt), which together are specific for GUCY2D-related recessive retinopathy (total 4.5 points, PMID: 26626312, PP4). Another missense variant in the same codon, NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp), has previously been classified as pathogenic for GUCY2D-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5). The variant exhibited ~0% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of ≤10% activity, indicating that it triggers a severe defect in protein function (PMID: 23035049, PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3, PM3_Strong, PP4, PM5, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366083/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7565 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151766 infores:hetionet CHEBI:6912 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0917801 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151596 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235431 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235369 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0018799 infores:hetionet CHEBI:31622 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0022107 infores:hetionet CHEBI:472657 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0036830 infores:hetionet NCBIGene:51117 biolink:causes MONDO:0014562 infores:monarchinitiative not_provided not_provided HGNC:19693 MONDO:0014562 uuid:d2a0bf3d-caf5-4a9d-acd0-2a280c0c76b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6801 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0021053 infores:hetionet CHEBI:3380 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0002962 infores:hetionet CHEBI:6847 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C1291078 infores:hetionet CHEBI:144551 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C3263723 infores:hetionet CAID:CA199303 biolink:causes MONDO:0010726 infores:clingen CAID:CA199303 MONDO:0010726 PMID: Likely Benign BP7, BP5, BP4 The silent p.Arg468= variant in MECP2 (NM_004992) is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). The p.Arg468= variant is found in two patients with an alternate molecular basis of disease (INVITAE internal cases) (BP5). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary the p.Arg468= variant in MECP2 is classified as Likely Benign for Rett syndrome disorder based on the ACMG/AMP criteria (BP7, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199303/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA333369 biolink:causes MONDO:0007113 infores:clingen CAID:CA333369 MONDO:0007113 PMID:25212744PMID:25212744 Likely Pathogenic PP4, PS4_Supporting, PM6_Strong, PM2_Supporting The p.Ser582del variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Ser582del variant in UBE3A has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Angelman syndrome (PMID 25212744, internal database) (PM6_Strong). The p.Ser582del variant has been observed in at least 1 other individual with Angelman syndrome (PMID 25212744) (PS4_Supporting). The p.Ser582del variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 25212744) (PP4). In summary, the p.Ser582del variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PM6_strong, PS4_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333369/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA016398 biolink:causes MONDO:0004994 infores:clingen CAID:CA016398 MONDO:0004994 PMID:27532257PMID:25086479 Likely Benign BS1 BA1, PM2, PM5, PM1, PS3, PM6, PP3, PP1, BS3, BS4, PS4, PS1, PS2, BP4 The c.5704G>C (p.Glu1902Gln) variant in MYH7 has been identified in 0.096% (FAF 95% CI; 27/19954) of East Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016398/MONDO:0004994/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0031630 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0031630 GO:0051641 CHEBI:10101 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0149931 infores:hetionet CHEBI:10125 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0700590 infores:hetionet NCBIGene:1956 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:3236 MONDO:0008903 uuid:a7f9f663-088d-445e-8fd2-2cea8f6da49c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA175333 biolink:causes MONDO:0021060 infores:clingen CAID:CA175333 MONDO:0021060 PMID: Likely Benign BP7, BP4 PM2, PP2 The c.*7T>C variant in the 3' UTR of BRAF is classified as likely benign because it occurs in a noncoding region, computational splice analyses do not predict an impact on splicing, and Alamut indicates that this nucleotide is not highly conserved (BP4, BP7). It has been identified in 0.0008791% (1/113754) of non-Finnish European chromosomes in gnomAD v2. RASopathy-specific ACMG/AMP Criteria applied (PMID:29493581): BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA175333/MONDO:0021060/004 2020-01-31 2020-01-31 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:15854 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0344232 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0239978 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0233632 infores:hetionet NCBIGene:9401 biolink:causes MONDO:0009039 infores:monarchinitiative not_provided not_provided HGNC:9949 MONDO:0009039 uuid:2f5a2321-b301-4357-86ee-251ed28f5bf9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5384 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0234215 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0149931 infores:hetionet CHEBI:39867 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085605 infores:hetionet CHEBI:31302 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0235063 infores:hetionet CAID:CA1393629 biolink:causes MONDO:0019501 infores:clingen CAID:CA1393629 MONDO:0019501 PMID: Pathogenic PP3, PP4, PM2_Supporting, PM3_Very Strong PM5 The c.11713C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3905 (p.Arg3905Cys). The highest population minor allele frequency in gnomAD v4 is 0.007% (6/75036) in the African / African American population, which meets the ClinGen Hearing Loss VCEP threshold (≤0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been detected in at least 6 individuals with Usher syndrome and at least 4 individuals with inherited retinal dystrophy. Of those individuals, 1 was homozygous and 7 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. At least 1 of those were confirmed in trans by family testing (PM3_VeryStrong, PMID: 31877679, 25333064, 28559085, 24944099, 34781295, 36011402, 32531858, 36909829, 27208204, 37217489). At least one patient with this variant was diagnosed with Usher syndrome, which is highly specific for USH2A-related disorders (PP4, PMID: 31877679). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1393629/MONDO:0019501/005 2024-10-16 2025-01-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:75179 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0234708 infores:hetionet CHEBI:585948 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0004093 infores:hetionet CHEBI:7443 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0042384 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002418 infores:hetionet GO:1905715 biolink:causes GO:0030216 infores:ubergraph knowledge_assertion manual_agent GO:1905715 GO:0030216 UNII:9430ZR8ZAN biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0497201 infores:hetionet CHEBI:7445 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0010692 infores:hetionet CHEBI:31643 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0151603 infores:hetionet CAID:CA396462787 biolink:causes MONDO:0100488 infores:clingen CAID:CA396462787 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM1, PM4, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1363G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Ala by Thr at amino acid 455 (p.Ala455Thr). This variant was observed in more than three heterozygous individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae, Ambry, GeneDx). This variant is absent from gnomAD 2.1.1 (PM2_Spporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396462787/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3561 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0041969 infores:hetionet CHEBI:42068 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0041969 infores:hetionet CHEBI:204928 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0404521 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0003467 infores:hetionet CHEBI:52717 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030193 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0853813 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0162830 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0151476 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0151476 infores:hetionet GO:2000022 biolink:causes GO:0071395 infores:ubergraph knowledge_assertion manual_agent GO:2000022 GO:0071395 CHEBI:7581 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0235966 infores:hetionet CHEBI:28918 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0020580 infores:hetionet CHEBI:681569 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0151578 infores:hetionet CHEBI:7959 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0003862 infores:hetionet CHEBI:4027 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085593 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014549 infores:hetionet CHEBI:49713 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0026896 infores:hetionet CHEBI:6375 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019209 infores:hetionet CHEBI:63580 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0438142 infores:hetionet CHEBI:5100 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0018524 infores:hetionet CHEBI:9943 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0001807 infores:hetionet CHEBI:64064 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0004238 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0016169 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0016169 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0014394 infores:hetionet NCBIGene:11155 biolink:causes MONDO:0012277 infores:monarchinitiative not_provided not_provided HGNC:15710 MONDO:0012277 uuid:a6a06352-1980-41c8-bf93-9daf14942c77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA017250 biolink:causes MONDO:0007947 infores:clingen CAID:CA017250 MONDO:0007947 PMID: Pathogenic PP4, PP2, PM2_Supporting, PS4, PP1_Strong PP3 The NM_000138.5 c.7540G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine acid by arginine at amino acid 2514 (p.Gly2514Arg), located within a calcium binding EGF-like (cbEGF) domain of the protein. This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (internal data-Bichat) (PP4). This variant has been reported in at least 4 individuals with thoracic aortic aneurysm and/or clinical features of Marfan syndrome (PMID 26272055, 19720936, 11875032, Laboratory for Molecular Medicine ClinVarentry), and in at least 3 individuals clinically diagnosed with Marfan syndrome (PMID 33483584, 28468757, Rurali et al. 2019) (PS4). It was also found to segregate with the disease in at least 5 affected family members from multiple families (Rurali et al. 2019, Laboratory for Molecular Medicine ClinVar entry, internal data) (PP1_Strong). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.945) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_Strong, PM2_Sup, PP2, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017250/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ NCBIGene:79669 biolink:causes MONDO:0859341 infores:monarchinitiative not_provided not_provided HGNC:26255 MONDO:0859341 uuid:f6810e15-b57b-4009-bf50-999824488016 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1257843 infores:hetionet CHEBI:3738 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0344232 infores:hetionet CHEBI:63608 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019829 infores:hetionet CHEBI:168396 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018965 infores:hetionet CHEBI:36791 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149514 infores:hetionet CHEBI:50173 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0242379 infores:hetionet CHEBI:75988 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0002871 infores:hetionet GO:1905079 biolink:causes GO:0021953 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0021953 CHEBI:3312 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0031542 infores:hetionet NCBIGene:374354 biolink:causes MONDO:0032651 infores:monarchinitiative not_provided not_provided HGNC:24731 MONDO:0032651 uuid:7fda0b47-b045-4d0e-93fb-f6c07ae169b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9352 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0917801 infores:hetionet CHEBI:32192 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0014518 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0542165 infores:hetionet CHEBI:6367 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085641 infores:hetionet CHEBI:63608 biolink:causes MONDO:0019087 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0206698 infores:hetionet CHEBI:18385 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0034063 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0038454 infores:hetionet CAID:CA396451431 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451431 MONDO:0007648 PMID:20719348PMID:24366306PMID:20719348PMID:24366306 Pathogenic PP1_Moderate, PM5_Supporting, PM2_Supporting, PS4_Moderate, PVS1_Strong BP5, BP7, BS1, BS4, BS3, PM1, PM3, PM4, PM6, PP3, PP2, PP4, BS2, BP4, BP1, BP2, BP3, BA1, PS3, PS1, PS2 The c.48+1G>A is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 20719348, 24366306). The variant was also found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; SCV000617359.1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Moderate and PP1_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451431/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:135276 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0038587 infores:hetionet GO:1900214 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:1900214 GO:0001656 CHEBI:9328 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0038362 infores:hetionet CHEBI:36791 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025874 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0034150 infores:hetionet NCBIGene:388939 biolink:causes MONDO:0013263 infores:monarchinitiative not_provided not_provided HGNC:34383 MONDO:0013263 uuid:9e9a2b33-1240-4cb6-8a1f-1deca815e3ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32139 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0015967 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0003123 infores:hetionet CHEBI:83527 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0041969 infores:hetionet CAID:CA658798256 biolink:causes MONDO:0100216 infores:clingen CAID:CA658798256 MONDO:0100216 PMID: Uncertain Significance PP3, PP1, PS4_Supporting, PM2_Supporting PVS1, BA1, BP4, BP2, PP4, BS2, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.2256+6T>A variant in DICER1 is an intronic variant which located in intron 14. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Invitae, Ambry). The variant has been reported to segregate with PPB in 3 affected family members (4 meioses) from 1 family (PP1; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP1, PM2_Supporting, PP3. (Bayesian Points: 4; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798256/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0595939 infores:hetionet CAID:CA386952195 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952195 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PP1_Strong, PP4_Moderate BP4, PM5, PP3 The c.17G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to asparagine at codon 6 (p.(Ser6Cys)) of NM_000545.8. This variant is located within the DNA binding of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a REVEL score of 0.625, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative, and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). Lastly, this variant segregated with diabetes, with at least four informative meioses in three families with MODY (PP1_Strong; PMID: 18513305, internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952195/MONDO:0015967/017 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15940 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0006444 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0020437 infores:hetionet CHEBI:8707 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0233471 infores:hetionet CHEBI:40303 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0002622 infores:hetionet CHEBI:44032 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0008031 infores:hetionet CHEBI:8869 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C2711248 infores:hetionet CHEBI:4856 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0042510 infores:hetionet CHEBI:50924 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020621 infores:hetionet CAID:CA409109840 biolink:causes MONDO:0015967 infores:clingen CAID:CA409109840 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PVS1_Strong PP4 The c.2T>C variant in the hepatic nuclear factor-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). This variant is only present in one copy in the Latino/Admixed American subpopulation in gnomAD v2.1.1 and therefore a Popmax FAF is unavailable. Still, the variant meets the ClinGen MDEP threshold for PM2_Supporting (gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population) (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.2T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Strong, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409109840/MONDO:0015967/085 2024-01-02 2024-01-02 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3559 biolink:causes MONDO:0011664 infores:monarchinitiative not_provided not_provided HGNC:6008 MONDO:0011664 uuid:2b611e3e-ec4d-47ab-a910-8a6d8c8b5a4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50381 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C1291077 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0233472 infores:hetionet NCBIGene:6424 biolink:causes MONDO:0009943 infores:monarchinitiative not_provided not_provided HGNC:10778 MONDO:0009943 uuid:50852807-7fb6-4fc6-a5c1-d4cb2d3b1729 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17376 biolink:causes MONDO:0008171 infores:drugmechdb knowledge_assertion manual_agent CHEBI:17376 HP:0000787 DB06823_MESH_D003555_1 CHEBI:2682 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0009806 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042373 infores:hetionet CHEBI:63605 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0042384 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0006852 infores:hetionet NCBIGene:83452 biolink:causes MONDO:0014087 infores:monarchinitiative not_provided not_provided HGNC:16075 MONDO:0014087 uuid:ae1c49fe-bb90-4168-b37b-5f98240a9d3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8623295 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623295 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 BS1, PP4, BA1 The c.1605C>T (p.His535=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 0.424748 (BP7 and BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008483 (100/1178874 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating in GT patients were found in the literature. Due to conflicting evidence, this variant is classified as likely benign for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BP4, BP7 and PM2_Supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623295/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:68478 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2830004 infores:hetionet CAID:CA2259832 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259832 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.125C>T (p.Ala42Val) variant in the RAF1 gene is 0.026% (25/66738) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259832/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6339 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040264 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022408 infores:hetionet CHEBI:5856 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0264893 infores:hetionet CHEBI:10110 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0010692 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0877634 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0877634 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0231365 infores:hetionet CHEBI:35677 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0231218 infores:hetionet CHEBI:75984 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0003467 infores:hetionet CHEBI:7852 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0002994 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0006145 infores:hetionet CHEBI:50861 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0008031 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0028738 infores:hetionet CHEBI:64355 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151872 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020517 infores:hetionet CHEBI:7956 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0234913 infores:hetionet CHEBI:38545 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0851578 infores:hetionet CHEBI:4562 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0009763 infores:hetionet CHEBI:47381 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013604 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0023067 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020649 infores:hetionet CHEBI:465284 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0018965 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0018021 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0010823 infores:hetionet CHEBI:6640 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0347390 infores:hetionet CHEBI:681569 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0034886 infores:hetionet CHEBI:63791 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019080 infores:hetionet CHEBI:5801 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0162281 infores:hetionet CHEBI:4953 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0010200 infores:hetionet CHEBI:8024 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0233715 infores:hetionet CAID:CA1706424 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706424 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1, PP1, PM2_Supporting PM3 The NM_003494.4: c.3051dup p.(Ile1018HisfsTer14) variant in DYSF, which is also known as NM_001130987.2: c.3105dup p.(Ile1036HisfsTer14), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 29/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in trans with a second presumed diagnostic DYSF variant in a patient who displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PMID: 36983702; PP4_Strong). This variant has also been reported to segregate with autosomal recessive LGMD in one affected family member (PP1; PMID: 36983702). The filtering allele frequency of this variant is 0.000028252 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 22/1111934 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/28/2025): PVS1, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706424/MONDO:0015152/180 2025-05-28 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports GO:0022626 biolink:causes GO:0002181 infores:ubergraph knowledge_assertion manual_agent GO:0022626 GO:0002181 CAID:CA10014222 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014222 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1006T>A (p.Phe336Ile) is a missense variant which does not meet any ACMG/AMP criteria. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014222/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50173 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030193 infores:hetionet CHEBI:31485 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0152227 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0162429 infores:hetionet CHEBI:5130 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0025222 infores:hetionet CHEBI:6067 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030232 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019372 infores:hetionet CHEBI:61049 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151798 infores:hetionet CHEBI:31932 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0085649 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0036220 infores:hetionet CHEBI:4814 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0030554 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0020517 infores:hetionet CHEBI:3441 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0023218 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0233494 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0424000 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0013595 infores:hetionet CHEBI:72292 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0235996 infores:hetionet CAID:CA066494 biolink:causes MONDO:0007783 infores:clingen CAID:CA066494 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with histidine at codon 163 of the RYR1 protein, p.(Arg163His). This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.864) supports a pathogenic status for this variant, PP3_Moderate. While another variant has been assessed as pathogenic at this codon, p.(Arg163Cys), PM5 is not implemented as the Grantham difference between arginine and histidine is not greater than the difference between arginine and cysteine. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA066494/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:39585 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0018524 infores:hetionet CHEBI:28864 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0040264 infores:hetionet CAID:CA000575 biolink:causes MONDO:0017623 infores:clingen CAID:CA000575 MONDO:0017623 PMID: Uncertain Significance BP7, PM2_Supporting PVS1, PM6, BP5, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.79+20C>G (IVS1+20C>G) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_Supporting: Absent in large sequenced populations (PMID 27535533).BP7: Variant is intronic and at or beyond +7/-21, nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000575/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2549 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0027765 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151605 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0242656 infores:hetionet CHEBI:5864 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0428974 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009806 infores:hetionet CHEBI:16347 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0232462 infores:hetionet CHEBI:119915 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0028734 infores:hetionet CHEBI:6062 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C1167965 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0855242 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027769 infores:hetionet CAID:CA913187448 biolink:causes MONDO:0015967 infores:clingen CAID:CA913187448 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM1 c.583-2delA p.(?)The c.583-2delA variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A alters a consensus splice site and is predicted to cause out-of-frame skipping of exon 6 of 10 of NM_175914.5. This variant is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2 supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; PMID: 12050210). In summary, c.583-2delA meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913187448/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports UNII:15G12L5X8K biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020437 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0022116 infores:hetionet CHEBI:63577 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0877192 infores:hetionet GO:2000477 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0007275 CHEBI:8346 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0221423 infores:hetionet CHEBI:64354 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0022281 infores:hetionet CHEBI:474180 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0015230 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0274312 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0274312 infores:hetionet CHEBI:2654 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0020649 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0010709 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027441 infores:hetionet CHEBI:68606 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0003467 infores:hetionet CHEBI:4453 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0011991 infores:hetionet CHEBI:7476 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002792 infores:hetionet CHEBI:3499 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0015230 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009806 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0235431 infores:hetionet CHEBI:51364 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0039231 infores:hetionet CAID:CA149398 biolink:causes MONDO:0007113 infores:clingen CAID:CA149398 MONDO:0007113 PMID: Benign BP7, BA1 The allele frequency of the p.Asp423= variant in UBE3A is 0.18% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Asp423= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Asp423= variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA149398/MONDO:0007113/016 2022-09-01 2022-09-06 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true NCBIGene:4222 biolink:causes MONDO:0008958 infores:monarchinitiative not_provided not_provided HGNC:7013 MONDO:0008958 uuid:190da2a3-2df3-4d64-894e-524de534b0b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0017181 infores:hetionet CHEBI:2666 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0917801 infores:hetionet CHEBI:136040 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0038325 infores:hetionet CHEBI:45367 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0232462 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521839 infores:hetionet UMLS:C0657912 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020488 infores:hetionet CHEBI:7565 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1167965 infores:hetionet CHEBI:8871 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043352 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0852990 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0852990 infores:hetionet CHEBI:168396 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011168 infores:hetionet CHEBI:584020 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0231528 infores:hetionet CHEBI:31981 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0039231 infores:hetionet CHEBI:5779 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0027497 infores:hetionet CHEBI:15365 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0013404 infores:hetionet CAID:CA8815136 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815136 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong PM5, PS1 The NM_000152.5:c.1064T>C variant in GAA is a missense variant predicted to cause substitution of leucine to proline at amino acid 355 (p.Leu355Pro). This variant has been reported in over 20 individuals with Pompe disease including at least 9 individuals with documented laboratory values showing GAA deficiency (PP4_Moderate) (PMIDs 14972326, 17213836, 17723315, 17213836, 23632174, 24016645, 30595407)(PP4_Moderate). The variant is homozygous in multiple patients (PMIDs 14972326, 16917947, 17213836, 17573812, 17723315, 18429042, 22658377, 23787031, 24016645, 30023291, 33325062). Three individuals are compound heterozygous for the variant and another variant that has been assessed as pathogenic by the ClinGen LSD VCEP; c.-32-13T>G in two patients (PMIDs 17643989, 21803581), and confirmed in trans with c.670C>T (p.Arg224Trp) in another patient (PMID 23632174; (PM3_Strong). p.Leu355Pro has also been reported in individuals with Pompe disease who are compound heterozygous for c.2041-2A>C (PMID 33325062), c.2303C>G (p.Pro768Arg) (PMID 17027861), c.1210G>A (p.Asp404Asn) (PMID 22658377, 23787031), c.1120T>C (p.Cys374Arg) (PMID 14695532), c.1927G>A (p.Gly643Arg) (PMID 18429042), c.1106T >C (p.Leu369Pro) (PMID 23430493), and c.380G>T (p.Cys127Phe) (PMID 24016645). The in trans data from these patients will be used in the assessment of the other variant and was not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34580) in the Latino population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in absent GAA activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 284093, 2 star review status) with four submitters each classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved August 17, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815136/MONDO:0009290/010 2021-09-07 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9943 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003811 infores:hetionet CHEBI:205919 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0020580 infores:hetionet CHEBI:3756 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1260880 infores:hetionet CHEBI:28748 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151825 infores:hetionet CHEBI:9674 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0011603 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027051 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0423232 infores:hetionet NCBIGene:83483 biolink:causes MONDO:0032586 infores:monarchinitiative not_provided not_provided HGNC:13635 MONDO:0032586 uuid:e92edd4e-278f-4659-ba2a-a7457cfaf77e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0333355 infores:hetionet CHEBI:8874 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013428 infores:hetionet CHEBI:4653 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0013395 infores:hetionet CHEBI:48947 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0033774 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0015397 infores:hetionet CHEBI:63621 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C3160741 infores:hetionet CHEBI:50859 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0497156 infores:hetionet CAID:CA386965032 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965032 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PP4_Moderate, PP3 PS4 The c.676A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamic acid at codon 226 (p.(Lys226Glu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.815, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:18003757, internal lab contributors). One individual has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with at least four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). In summary, c.676A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965032/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15553 biolink:causes EFO:1001863 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042135 infores:hetionet CHEBI:188986 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042024 infores:hetionet UMLS:C0120107 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0016204 infores:hetionet CHEBI:91583 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0151594 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0004936 infores:hetionet CHEBI:74947 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030196 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0032285 infores:hetionet CHEBI:30659 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0085631 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0025061 infores:hetionet CAID:CA402994686 biolink:causes MONDO:0012999 infores:clingen CAID:CA402994686 MONDO:0012999 PMID:24415674 Likely Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Supporting, PS3_Supporting The NM_000156.6:c.476T>C variant in GAMT is predicted to result in the substitution of leucine by proline at amino acid 159 (p.Leu159Pro). This variant has been identified in one homozygous individual with an absent creatine peak on brain MRS and elevated urine guanidinoacetate (value not provided) (PM3_Supporting, PP4_Moderate) (PMID: 24415674). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.947 which is above the threshold of 0.932, evidence that correlates with impact to GAMT function at the strong level (PMID: 36413997) (PP3_Strong). This variant was shown to result in undetectable GAMT enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 2.0.0): PP3_Strong, PP4_Strong, PS3_Supporting, PM2_Supporting, PM3_Supporting(Classification approved by the ClinGen CCDS VCEP on October 8, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402994686/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4551 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0687133 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853149 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0037199 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0041912 infores:hetionet CHEBI:68606 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0011603 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0014742 infores:hetionet NCBIGene:51314 biolink:causes MONDO:0012571 infores:monarchinitiative not_provided not_provided HGNC:16473 MONDO:0012571 uuid:9df09c39-6d04-4c5e-b065-1c115386c5a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0023067 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0153676 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0153676 infores:hetionet CHEBI:5002 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0003467 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0018799 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034063 infores:hetionet CHEBI:68610 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0027441 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040046 infores:hetionet CHEBI:8107 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0086439 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234458 infores:hetionet CAID:CA10558493 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558493 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BP5 BP4, BS1, PP3 The highest population minor allele frequency of the p.Pro385Ser variant in MECP2 in gnomAD v4.1 is 0.00003532 in South Asian population (not sufficient to meet BS1 criteria). The p.Pro385Ser variant in MECP2 (NM_004992.4) is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). The p.Pro385Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Ambry) (BP5). In summary, the p.Pro385Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2_supporting, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558493/MONDO:0010726/036 2024-10-30 2024-12-23 X-linked inheritance HP:0001417 Contradicts true CHEBI:2904 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0028084 infores:hetionet NCBIGene:1281 biolink:causes MONDO:0032688 infores:monarchinitiative not_provided not_provided HGNC:2201 MONDO:0032688 uuid:1ff11484-e93b-4044-b525-c1d8b43afa83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16796 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0009450 infores:hetionet CAID:CA16614686 biolink:causes MONDO:0007947 infores:clingen CAID:CA16614686 MONDO:0007947 PMID: Likely Pathogenic PVS1, PM2 PM6, PP1, PP4, BP2, BP1, BA1, PS2, PS4, PS1, PS3, PM5, PM1, BP5, BS1, BS4, BS3 The NM_00138 c.799_805del, is a frameshift variant in FBN1 and is predicted to result in a premature stop codon at position 327. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was reported a pathogenic once in ClinVar (Variation ID: 406374). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614686/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6437 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013395 infores:hetionet CHEBI:63631 biolink:causes HP:0001103 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0730362 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0020538 infores:hetionet CHEBI:136040 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0039070 infores:hetionet CHEBI:9727 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0019080 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0026946 infores:hetionet CHEBI:100241 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0033845 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0001883 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011053 infores:hetionet CHEBI:6761 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0004134 infores:hetionet CHEBI:6402 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0041296 infores:hetionet NCBIGene:288 biolink:causes MONDO:0014210 infores:monarchinitiative not_provided not_provided HGNC:494 MONDO:0014210 uuid:559dd9a3-bdb9-4a70-892e-064e53c1b5d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83531 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0008031 infores:hetionet CHEBI:75988 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0023467 infores:hetionet CHEBI:72690 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0011175 infores:hetionet CHEBI:180905 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0039240 infores:hetionet CHEBI:6950 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151766 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0018799 infores:hetionet CHEBI:3228 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0003578 infores:hetionet CHEBI:9316 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0026837 infores:hetionet CHEBI:6438 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0020615 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0005741 infores:hetionet CAID:CA10585344 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585344 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4_Moderate, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1186+5G>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PS3_moderate - Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing.PS4_moderate - Variant meets PM2 and was found in 8 unrelated FH cases.PP4 - Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585344/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3568 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0028084 infores:hetionet CHEBI:51164 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0855242 infores:hetionet CHEBI:3654 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0015230 infores:hetionet CHEBI:3757 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0015230 infores:hetionet CHEBI:4798 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0043352 infores:hetionet CHEBI:28918 biolink:causes UMLS:C3267019 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C3267019 infores:hetionet CHEBI:44423 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0023530 infores:hetionet CAID:CA400032666 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032666 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP2 PM3, PP3, PP4, BP4 The NM_000212.3(ITGB3):c.1843A>G (p.Ile615Val) missense variant has been reported in cis, with the variant NM_000212.3(ITGB3):c.1815C>T (p.Gly605=), which is classified as pathogenic by the ClinGen PD VCEP, in an individual with Glanzmann thrombasthenia. The phase of the variants was confirmed by parental testing (BP2). The highest MAF in gnomADv4.0.0 is 8.993e-7 (1/1112012) alleles in the European (non-Finnish) population, below the threshold of <0.0001 for PM2_supporting. In summary, the variant is classified as uncertain significance for autosomal recessive Glanzmann thrombasthenia according to the ACMG/AMP criteria as specified by the PD VCEP: PM2_supporting and BP2. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032666/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9168 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0025202 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006946 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1527410 infores:hetionet CHEBI:6822 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C1443060 infores:hetionet CHEBI:6792 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0011991 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0521516 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0521516 infores:hetionet CHEBI:64355 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013456 infores:hetionet CHEBI:31236 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030232 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0021053 infores:hetionet CHEBI:3419 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0018939 infores:hetionet CHEBI:63621 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0232461 infores:hetionet CHEBI:472657 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0036572 infores:hetionet CHEBI:47780 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003467 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0235431 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0575090 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1262013 infores:hetionet CHEBI:10127 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0016199 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0948594 infores:hetionet NCBIGene:79631 biolink:causes MONDO:0044205 infores:monarchinitiative not_provided not_provided HGNC:25789 MONDO:0044205 uuid:76da850e-145b-452b-b6e6-c6b743b1d0ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0233494 infores:hetionet CHEBI:50859 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020461 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020676 infores:hetionet NCBIGene:8048 biolink:causes MONDO:0011840 infores:monarchinitiative not_provided not_provided HGNC:2472 MONDO:0011840 uuid:e3b1cab3-7d85-494a-8d67-0ff9585597f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1320835 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0332575 infores:hetionet CHEBI:7640 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0040034 infores:hetionet CHEBI:2955 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0014742 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C0700509 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0700509 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0178298 infores:hetionet CHEBI:7565 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0031256 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038661 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0001125 infores:hetionet CHEBI:490877 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0086565 infores:hetionet CAID:CA037227 biolink:causes MONDO:0007750 infores:clingen CAID:CA037227 MONDO:0007750 PMID:9409298 Likely Pathogenic PS4_Supporting, PS3_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00003266 (0.003266%) in East Asian (gnomAD v2.1.1). PP3 - REVEL: 0,857. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling validated clinical criteria for FH from different labs.PS3_supporting - PMID: 9409298 - Level 3 assay - study on htz patient's cultured lymphoblasts, immunoblotting + I125-LDL assay, no precursor detectable, degradation of 125I-LDL 63%. ---- functional study is consistent with damaging effect.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case with Simon-Broome from Color laboratory; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037227/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UMLS:C0011701 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0039070 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151571 infores:hetionet CHEBI:63638 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1760428 infores:hetionet CHEBI:63619 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0026205 infores:hetionet CHEBI:64064 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0030554 infores:hetionet CHEBI:41977 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0221423 infores:hetionet CHEBI:6887 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0032343 infores:hetionet CHEBI:2955 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0002792 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1142523 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1142523 infores:hetionet CHEBI:3723 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004093 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0425945 infores:hetionet CHEBI:3814 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0011603 infores:hetionet CHEBI:39112 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0017181 infores:hetionet CHEBI:5050 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0039231 infores:hetionet CHEBI:681848 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0026961 infores:hetionet CHEBI:36791 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017565 infores:hetionet CHEBI:7488 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0743680 infores:hetionet CAID:CA356991 biolink:causes MONDO:0001586 infores:clingen CAID:CA356991 MONDO:0001586 PMID: Pathogenic PVS1_Moderate, PP4, PM2_Supporting, PM3_Very Strong The NM_000203.5:c.386-2A>G variant in IDUA, reported in older literature as 474-2A>G, occurs within the canonical splice acceptor site of intron 3. RT-PCR studies revealed that this variant results in skipping of exon 4 (PMID: 8019563). This is expected to result in an in-frame deletion of 36 amino acids which represents <10% of the protein. The in silico predictor SpliceAI does not predict the use of a cryptic splice site nearby (PVS1_Moderate). The variant has been identified in more than 20 individuals who have been diagnosed with MPS1, including 3 individuals with documented laboratory values showing deficiency of IDUA activity, two of who also have elevated urine GAGs (PMIDs: 23430808, 23837464) (PP4). Of these individuals at least 17 are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP including c.1205G>A, p.Trp402Ter (at least 10 individuals) (PMIDs: 8019563, 28752568), c.1855C>T (p.Arg619Ter) (PMID: 11735025), p.Pro533Arg (PMID: 8019563), c.208C>T (p.Gln70Ter) (at least 2 individuals) (PMIDs: 23430808, 28752568), and c.540_544delGAATG (p.Trp180Ter) (PMID: 28752568), and at least two are homozygous for the variant homozygotes (PMID: 28752568, 31194252) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and either c.236C>T (p.Ala79Val) (PMID: 28752568), c.653T>C (p.Leu218Pro) (PMID: 28752568), c.41T>G (p.Leu14Arg) (PMID: 28752568), p.Arg383His (PMID: 23837464) or p.Leu238Gln (PMID: 24368159); The allelic data from these patients will be used in the classifications of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0.is 0.0002086 (249/1179062 alleles; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).There is a ClinVar entry for this variant (Variation ID: 222994). In summary, this variant meets the criteria to be classified as pathogenic for MPS1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PVS1_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA356991/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63608 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1384353 infores:hetionet CHEBI:76010 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0026857 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0004936 infores:hetionet CHEBI:63599 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0003862 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0948594 infores:hetionet CHEBI:49575 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0031542 infores:hetionet GO:0050770 biolink:causes GO:0048667 infores:ubergraph knowledge_assertion manual_agent GO:0050770 GO:0048667 CHEBI:7852 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0234458 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0002622 infores:hetionet CHEBI:478164 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0027497 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0035078 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005845 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0025309 infores:hetionet CHEBI:45081 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019079 infores:hetionet CHEBI:2666 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C2242996 infores:hetionet CHEBI:41977 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011175 infores:hetionet CHEBI:5959 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0028643 infores:hetionet CHEBI:7476 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009676 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0023222 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0546817 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0002871 infores:hetionet NCBIGene:54977 biolink:causes MONDO:0008785 infores:monarchinitiative not_provided not_provided HGNC:26054 MONDO:0008785 uuid:93c889d4-665c-4e55-9f2b-50103cbc3811 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0026946 infores:hetionet CHEBI:41977 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0040822 infores:hetionet CHEBI:3011 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0162830 infores:hetionet CHEBI:39867 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151889 infores:hetionet CHEBI:31622 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0013362 infores:hetionet CHEBI:253342 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0042029 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022660 infores:hetionet CHEBI:681569 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0151904 infores:hetionet CHEBI:8768 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2239176 infores:hetionet CHEBI:3640 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0042571 infores:hetionet CHEBI:51164 biolink:causes UMLS:C0919582 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0919582 infores:hetionet CHEBI:9150 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0017152 infores:hetionet CAID:CA340749039 biolink:causes MONDO:0100368 infores:clingen CAID:CA340749039 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PP4_Moderate, PVS1, PM2_Supporting NM_000329.3(RPE65):c.190C>T (p.Gln64Ter) is a nonsense variant that introduces a premature stop codon into exon 3 of 14, and is predicted to lead to nonsense-mediated decay in a gene (RPE65) in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) but has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 10090910, PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts) with symptomatic onset between birth and age five years (1 pt). Additional phenotype features included nystagmus (1 pt), inability to follow light or objects, initially normal fundus, which gradually displayed a salt-and-pepper appearance (2 pts) with a reduction in blood-vessel diameter and often the typical appearance of retinitis pigmentosa (0.5 pts). Rod and cone ERG response were totally extinguished (1.5 pts). Proband also exhibited night blindness (0.5 pts), reduced visual acuity and decreased peripheral vision (1 pt). Together these are highly specific for RPE65-related recessive retinopathy (total 8 points, PMID:10090910, PP4_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, PM3_Supporting, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340749039/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:134990 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0852911 infores:hetionet CAID:CA1620014 biolink:causes MONDO:0800472 infores:clingen CAID:CA1620014 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PS2_Moderate, PP1_Strong, PVS1 PP3, BA1, BP4, PM4, PM1, PM5, PS3, PS1, BP7, BS1, BS4, BS3 The c.535del variant in CYP1B1 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 18 of the frameshift (p.Ala179ArgfsTer18). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.0001895 (10 alleles out of 52,762), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This frameshift variant was predicted to undergo NMD, meeting PVS1. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. ≥3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 25826643), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in 5 individuals with a CYP1B1-related phenotype. 3 individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) and 2 are homozygous (non-consanguineous) for the variant (PMIDs: 19528825, 32832252, 25826643). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. 1 confirmed de novo proband with a CYP1B1-related phenotype has been identified (PMID: 32832252). Total proband points = 1, meeting PS2_Moderate. In summary, this variant met the criteria to receive a score of 23 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Very-strong, PP1_Strong, PS2_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1620014/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4702 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0002994 infores:hetionet CHEBI:3387 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0751494 infores:hetionet CAID:CA401360590 biolink:causes MONDO:0009290 infores:clingen CAID:CA401360590 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.276C>A (p.Cys92Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). To our knowledge, this variant has not been reported in individuals with Pompe disease in the literature and functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 654482). The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 29, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401360590/MONDO:0009290/010 2024-10-29 2024-10-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9757 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0003811 infores:hetionet CHEBI:5106 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0009763 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0243026 infores:hetionet CHEBI:46295 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0036454 infores:hetionet CHEBI:63589 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0016204 infores:hetionet CHEBI:3723 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2047937 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C2173677 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0015376 infores:hetionet NCBIGene:55154 biolink:causes MONDO:0044714 infores:monarchinitiative not_provided not_provided HGNC:29678 MONDO:0044714 uuid:fc557207-77ff-4a7b-8dba-21df9701c396 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042024 infores:hetionet CHEBI:3032 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0027497 infores:hetionet CHEBI:50131 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0877303 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0152198 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027932 infores:hetionet CHEBI:47657 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0004604 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002957 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0851341 infores:hetionet CHEBI:4858 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0232462 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0021053 infores:hetionet CAID:CA415087229 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087229 MONDO:0010305 PMID: Likely Pathogenic PP1_Moderate, PP3, PM2_Supporting, PS4_Supporting, PP4_Strong PS3 The NM_005629.4:c.1396G>A variant in SLC6A8 is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 466 (p.Gly466Arg). The variant was shown to segregate in a family from a heterozygous grandmother with mild intellectual disability to one affected daughter who had one affected daughter and one affected son; a clinically unaffected granddaughter did not harbor the variant (PMID: 24190795) (PP1_Moderate). In this family (PMID: 24190795), the (hemizygous) male had elevated urinary creatine/creatinine and significantly decreased creatine peak on brain MRS with full SLC6A8 gene sequencing (PP4_Strong). This variant has also been reported in another unrelated affected male (PMID: 21140503) (PS4_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). When expressed in HEK-293T cells, this variant was found to reduce cellular creatine transport activity (PMID: 32207963), but this study does not meet the specifications of the CCDS VCEP for assessment of cellular creatine transporter activity (must be done in SLC6A8-deficient fibroblasts with <125 mM creatine); hence, this cannot be used as evidence for PS3. The computational predictor REVEL gives a score of 0.95 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 804101). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP1_Moderate, PP4_Strong, PP3, PM2_Supporting, PS4_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on September 14, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087229/MONDO:0010305/027 2023-09-14 2024-03-29 X-linked inheritance HP:0001417 Supports GO:0090199 biolink:causes GO:0097190 infores:ubergraph knowledge_assertion manual_agent GO:0090199 GO:0097190 CHEBI:4672 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0038999 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0036508 infores:hetionet CHEBI:7852 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0086439 infores:hetionet CHEBI:92511 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0013144 infores:hetionet CHEBI:10102 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1142135 infores:hetionet CHEBI:28864 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151908 infores:hetionet CHEBI:28864 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0022281 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0022116 infores:hetionet CHEBI:63598 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003962 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233494 infores:hetionet CHEBI:84883 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0004604 infores:hetionet CHEBI:10102 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0043352 infores:hetionet CHEBI:6339 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0235378 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0009450 infores:hetionet CAID:CA2582130583 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582130583 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.884_885del variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 9/13 (p.Pro295ArgfsTer169) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been previously reported in one male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582130583/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:10119 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0000737 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0003615 infores:hetionet CHEBI:28148 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0013404 infores:hetionet CHEBI:8871 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027497 infores:hetionet CHEBI:2549 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0024902 infores:hetionet CHEBI:64317 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0003811 infores:hetionet CHEBI:77032 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0020517 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021680 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038395 infores:hetionet CAID:CA410149602 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149602 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.947A>G (p.Glu316Gly) is a missense variant which has not been reported in any populations featured in any version of gnomAD, allowing for the application of PM2_supporting. This variant has a SpliceAI score of 0 and a REVEL score of 0.138, allowing for the application of BP4. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149602/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2695201441 biolink:causes MONDO:0011071 infores:clingen CAID:CA2695201441 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1173_1174del (p.Gln392GlyfsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong). This frameshift variant that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695201441/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7478 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2607914 infores:hetionet CHEBI:4659 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0015672 infores:hetionet CHEBI:16467 biolink:causes MONDO:0011382 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0002895 infores:hetionet NCBIGene:8029 biolink:causes MONDO:0030042 infores:monarchinitiative not_provided not_provided HGNC:2548 MONDO:0030042 uuid:421ae069-dfdb-4653-8e75-70f6e31dc812 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6933 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0038325 infores:hetionet CAID:CA256758 biolink:causes MONDO:0007893 infores:clingen CAID:CA256758 MONDO:0007893 PMID:20578946PMID:15520399 Pathogenic PP1_Moderate, PS2_Very Strong, PM2, PP2, PP3, PS4_Supporting The c.1529A>C (p.Gln510Pro) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). The p.Gln510Pro variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 4 family members (PP1_Moderate; APHP-Robert Debré Hospital: GTR Lab ID: 28338). The variant has also been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in PTPN11, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1_Moderate, PM2, PP2, PP3, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256758/MONDO:0007893/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9168 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017178 infores:hetionet CHEBI:31348 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0231218 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0233571 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0011991 infores:hetionet CHEBI:16469 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027066 infores:hetionet CHEBI:9150 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0014518 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0153251 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0153251 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0030920 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020517 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0542165 infores:hetionet CHEBI:499361 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0000731 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0014394 infores:hetionet NCBIGene:125988 biolink:causes MONDO:0032679 infores:monarchinitiative not_provided not_provided HGNC:33702 MONDO:0032679 uuid:c107ccc7-374e-4dce-bdac-3046d76adbf5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0022346 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018802 infores:hetionet CHEBI:28864 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151904 infores:hetionet CHEBI:15765 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0018681 infores:hetionet UMLS:C0010592 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040822 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0042109 infores:hetionet CHEBI:63621 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0017181 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0015397 infores:hetionet CHEBI:63589 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0019158 infores:hetionet CHEBI:3423 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020625 infores:hetionet CHEBI:16914 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0237849 infores:hetionet CHEBI:49375 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0743400 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0011616 infores:hetionet CHEBI:16469 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235660 infores:hetionet CHEBI:3423 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0010481 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C1510410 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0008325 infores:hetionet CHEBI:5118 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020473 infores:hetionet CHEBI:63619 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0007859 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042023 infores:hetionet CHEBI:9599 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0701811 infores:hetionet CHEBI:41774 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0085633 infores:hetionet CHEBI:76010 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0011991 infores:hetionet CHEBI:3387 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042963 infores:hetionet GO:0046669 biolink:causes GO:0001745 infores:ubergraph knowledge_assertion manual_agent GO:0046669 GO:0001745 CHEBI:63611 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0343886 infores:hetionet NCBIGene:1278 biolink:causes MONDO:0008148 infores:monarchinitiative not_provided not_provided HGNC:2198 MONDO:0008148 uuid:635ee6d5-08dc-4661-be6b-d2fded29419a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0004936 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151625 infores:hetionet CHEBI:17334 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018524 infores:hetionet CHEBI:8412 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0232462 infores:hetionet CHEBI:119915 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020621 infores:hetionet CHEBI:5128 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0016382 infores:hetionet UNII:R43D2573WO biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0025345 infores:hetionet CHEBI:5775 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0026821 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235822 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235822 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0596601 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0596601 infores:hetionet CHEBI:9362 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0020517 infores:hetionet CHEBI:3506 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0031350 infores:hetionet CHEBI:9738 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2242996 infores:hetionet CHEBI:4953 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0007222 infores:hetionet NCBIGene:145173 biolink:causes MONDO:0009856 infores:monarchinitiative not_provided not_provided HGNC:20207 MONDO:0009856 uuid:57ab307a-a18c-46a4-9d27-6b4b63be769b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27777 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C3263723 infores:hetionet CHEBI:9570 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0010200 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0687707 infores:hetionet CAID:CA290947 biolink:causes MONDO:0100040 infores:clingen CAID:CA290947 MONDO:0100040 PMID: Benign BP7, BA1 The allele frequency of the p.Pro67= variant in FOXG1 is 0.055% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Pro67= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Pro67= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA290947/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UNII:F64QU97QCR biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0027540 infores:hetionet UMLS:C0657912 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0016204 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0863113 infores:hetionet CHEBI:79699 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0015967 infores:hetionet CHEBI:6532 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0687713 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0746883 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0041747 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0262385 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0028259 infores:hetionet CHEBI:78320 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0015376 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0205204 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0085129 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013595 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0027765 infores:hetionet CHEBI:66899 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0018681 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0221100 infores:hetionet NCBITaxon:1747 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1747 GO:0006954 DB02701_MESH_D000152_1DB00257_MESH_D000152_2 CHEBI:5847 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0392171 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0024205 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0392176 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0036572 infores:hetionet CHEBI:116278 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0037299 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013395 infores:hetionet CHEBI:50742 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0003962 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020557 infores:hetionet CHEBI:44032 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027796 infores:hetionet CHEBI:724125 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0033774 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0037274 infores:hetionet CHEBI:92923 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0162834 infores:hetionet CHEBI:134936 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0037199 infores:hetionet CAID:CA4239565 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239565 MONDO:0015967 PMID: Uncertain Significance PP2, PP3 BS1, PM2 The c.646G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 216 (p.Glu216Lys) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.711, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The Popmax filtering allele frequency of the c.646G>A variant in gnomAD v2.1.1 is 0.00001897 (East Asian), which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. In summary, c.646G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP3, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239565/MONDO:0015967/086 2023-07-30 2023-07-30 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:27958 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0042963 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020456 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0152029 infores:hetionet CHEBI:42068 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0027947 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0853193 infores:hetionet CHEBI:7492 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0541799 infores:hetionet CHEBI:10110 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0231528 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0025061 infores:hetionet CHEBI:4672 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0003962 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0162533 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0035333 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0242350 infores:hetionet CAID:CA132738 biolink:causes MONDO:0010134 infores:clingen CAID:CA132738 MONDO:0010134 PMID:25991456 Pathogenic PP1_Moderate, PP4, PM5, PM3_Very Strong PP3, PM2 The c.706C>G variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by valine at amino acid 236 (p.Leu236Val). The variant was identified in 0.01833% (11/59998) of admixed American alleles, which is the highest population minor allele frequency in gnomAD v4.1.0 (PM2_Supporting and BS1 are not met). This variant has been detected in 3 probands in trans with a pathogenic variant, in 5 probands in phase unknown with a pathogenic variant, and in the homozygous state in 3 probands, all of whom had hearing loss and/or inner ear malformations consistent with Pendred syndrome. The variant was also identified with a pathogenic splice site variant in 2 probands (PM3_VeryStrong; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5, ARUP internal data ClinVar SCV000605149.1, Chinese PLA General Hospital internal data, Molecular Otolaryngology and Renal Research Laboratories internal data, Revvity ClinVar SCV002023538.3GeneDx internal data ClinVar SCV001783711.3, Invitae internal data ClinVar SCV002234501.3). This variant was seen in two probands with no second variant identified whose phenotypes were consistent with Pendred syndrome (PMID: 34410491, 34515852), as well as in one proband with enlarged vestibular aqueduct who was compound heterozygous with a likely pathogenic variant in phase unknown (PP4; PMID: 36703223). A different pathogenic missense variant (p.Leu236Pro) has been previously identified at this codon of SLC26A4, which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 4817). Additionally, the variant was seen in an adult with deafness who had two pathogenic GJB2 variants in trans (Revvity internal data ClinVar SCV002023538.3). The variant has been reported to segregate with hearing loss in two affected family members (PP1_Moderate; Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PM5, PP1_Moderate, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132738/MONDO:0010134/005 2024-10-16 2025-01-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:3504 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0281856 infores:hetionet CHEBI:8713 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0036980 infores:hetionet CHEBI:38940 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151578 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085681 infores:hetionet CHEBI:61049 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042024 infores:hetionet CHEBI:3696 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0009676 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0017178 infores:hetionet CHEBI:9086 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0003862 infores:hetionet CHEBI:7465 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0002792 infores:hetionet CHEBI:3228 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0002994 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005411 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0153452 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0149931 infores:hetionet CHEBI:3419 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0020651 infores:hetionet CHEBI:42944 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042790 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017675 infores:hetionet CHEBI:27300 biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0860433 infores:hetionet CHEBI:27779 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0030554 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031046 infores:hetionet CHEBI:9168 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1142135 infores:hetionet CHEBI:8404 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0162297 infores:hetionet CHEBI:4911 biolink:causes UMLS:C1735348 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1735348 infores:hetionet CHEBI:63791 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085669 infores:hetionet CHEBI:31413 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C2830004 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038358 infores:hetionet CHEBI:6339 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0043094 infores:hetionet CHEBI:50859 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0740394 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0235146 infores:hetionet CHEBI:9622 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0002792 infores:hetionet CAID:CA126154 biolink:causes MONDO:0009276 infores:clingen CAID:CA126154 MONDO:0009276 PMID: Likely Pathogenic PS4_Moderate, PS3_Supporting, PP1_Moderate, PP3, PP4, PM2_Supporting, PM3_Supporting PM5 The NM_000407.5(GP1BB):c.338A>G (p.Tyr113Cys) is a rare missense variant with a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00004600 (based on 4/29100 alleles in the East Asian population), which is lower than the ClinGen PD VCEP threshold (<0.00006517; PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). Plasmids encoding GPIb, GPIb and GPIX were transiently transfected into 293T cells, and this variant suppressed the expression of GPIb/IX complexes (PMID: 11816714; PS3_supporting). This variant has been reported in one homozygous BSS patient (PMID: 11816714; PM3_supporting) and one compound heterozygous BSS patient (PMID: 24051937) with in trans variant Arg82Cys (classified VUS by the PD VCEP). At least one patient (PMID: 11816714) with this variant had aggregation absent for ristocetin and present for all other agonists and GPIb was detectable in reduced amounts on platelet surfaces by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Seven individuals heterozygous for the variant are considered informative due to measurable, quantitative abnormalities relevant to the disease (i.e. significantly reduced platelet surface expression of GP1b, giant platelets, and macrothrombocytopenia) in PMIDs: 11816714 and 28064200 (PS4_moderate). Plus there was segregation of this variant in 5 additional informative heterozygous family members (PMID: 28064200 and PMID: 11816714; PP1). In summary this variant is classified as Likely Pathogenic using the ACMG criteria specified by the PD VCEP: PS4_Moderate, PS3_supporting, PM2_supporting, PM3_supporting, PP1, PP3, and PP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA126154/MONDO:0009276/082 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31709 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0003864 infores:hetionet CAID:CA10580921 biolink:causes MONDO:0018875 infores:clingen CAID:CA10580921 MONDO:0018875 PMID: Likely Benign BS2_Supporting, BS3, PM2_Supporting BA1, BP4, BP2, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, PP3, PP1 The NM_000546.6: c.779C>A variant in TP53 is a missense variant predicted to cause substitution of serine by tyrosine at amino acid 260 (p.Ser260Tyr). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; ClinVar SCV000830817.4, Internal lab contributors). This variant has an allele frequency of 0.000001864 (3/1609760 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3. (Bayesian Points: -4; VCEP specifications version 2.2; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580921/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47780 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0023066 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0032285 infores:hetionet CHEBI:231594 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0025323 infores:hetionet CHEBI:7824 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0012569 infores:hetionet CHEBI:10101 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0036974 infores:hetionet CHEBI:3636 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0003578 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0012797 infores:hetionet CHEBI:8024 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0085633 infores:hetionet NCBIGene:79944 biolink:causes MONDO:0009370 infores:monarchinitiative not_provided not_provided HGNC:20499 MONDO:0009370 uuid:f3a95ee9-3fb3-4402-bf97-f99b6da64ac4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235431 infores:hetionet CHEBI:9139 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151604 infores:hetionet CAID:CA377784976 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784976 MONDO:0017623 PMID: Pathogenic PVS1, PM2, PS4_Supporting PM6, BS4, BS1, BS3, BP5, BP7, BS2, PP1, PP3, PP2, PM5, PM4, PM1, BP2, BP4, BA1, PS1, PS2, PS3 PTEN c.165-1G>C (IVS2-1G>C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populationsPS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784976/MONDO:0017623/003 2020-03-23 2020-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0036396 infores:hetionet CHEBI:28748 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0003811 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0029134 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0003123 infores:hetionet CHEBI:140621 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0428977 infores:hetionet CHEBI:61049 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1291077 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0281981 infores:hetionet CHEBI:79699 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042963 infores:hetionet NCBIGene:1896 biolink:causes MONDO:0010585 infores:monarchinitiative not_provided not_provided HGNC:3157 MONDO:0010585 uuid:9d20c39c-6bb7-404d-a3ea-6f6cc50a4cb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0007971 infores:hetionet CHEBI:10127 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0019572 infores:hetionet CAID:CA8602782 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602782 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000419.5:c.2198C>T (p.Ala733Val) variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 733. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006709 (5/74528 alleles) in the African/African American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.089, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4).In summary, this variant meets the criteria to be classified as a variant of unknown significance due to insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602782/MONDO:0100326/011 2024-11-07 2024-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:39867 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085602 infores:hetionet CHEBI:8888 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011175 infores:hetionet UMLS:C1872203 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151872 infores:hetionet CHEBI:135285 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0267792 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0027051 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0575090 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0858797 infores:hetionet GO:0030710 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:0030710 GO:0048477 CHEBI:7443 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0003811 infores:hetionet CHEBI:3761 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0015672 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0423773 infores:hetionet CHEBI:3698 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0162830 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0037274 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0234215 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0018128 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018128 infores:hetionet CHEBI:9586 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085606 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0151763 infores:hetionet CHEBI:68558 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0036974 infores:hetionet CHEBI:5801 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0040264 infores:hetionet CHEBI:36791 biolink:causes NCIT:C54356 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151598 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0042401 infores:hetionet CHEBI:4511 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0036830 infores:hetionet CHEBI:63627 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0042963 infores:hetionet CHEBI:194135 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0019080 infores:hetionet CHEBI:39585 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0028084 infores:hetionet CHEBI:6149 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0231530 infores:hetionet CHEBI:68595 biolink:causes UMLS:C1167654 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C1167654 infores:hetionet CHEBI:3242 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0006277 infores:hetionet CHEBI:5123 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0001824 infores:hetionet CHEBI:31711 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0037383 infores:hetionet CHEBI:5134 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0542571 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0948594 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0011616 infores:hetionet CHEBI:6931 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235063 infores:hetionet NCBIGene:284654 biolink:causes MONDO:0012530 infores:monarchinitiative not_provided not_provided HGNC:21679 MONDO:0012530 uuid:0594b789-1869-4443-a15d-84c8f2b59b11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C2748540 infores:hetionet CHEBI:63577 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0014591 infores:hetionet CHEBI:4027 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0600142 infores:hetionet CHEBI:7627 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0035078 infores:hetionet CHEBI:71415 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0151798 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0558148 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0558148 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0010709 infores:hetionet CHEBI:52010 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0013144 infores:hetionet CHEBI:4885 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C1368065 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0178298 infores:hetionet CAID:CA229545 biolink:causes MONDO:0009861 infores:clingen CAID:CA229545 MONDO:0009861 PMID:22112818PMID:22112818PMID:26503515PMID:1998345PMID:8535445 Pathogenic PM3, PVS1, PM2, PP4, PS3_Supporting The c.441+1G>A variant in PAH is a canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). In addition, the variant has been previously shown by RT-PCR analysis to alter RNA splicing (PS3_Supporting; PMID: 8535445). It is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002 (PM2). It has been found in multiple probands with classic PKU (e.g., PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308, 23430918, 23764561, 8535445), although BH4 deficiency does not appear to have been formally excluded (PP4), including in trans with the Clinvar-Pathogenic R408W allele (PMID: 22112818) (PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229545/MONDO:0009861/006 2018-12-22 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9139 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2939147 infores:hetionet CHEBI:94392 biolink:causes UMLS:C0235575 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0235575 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0518015 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0009450 infores:hetionet CHEBI:45951 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0085637 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0006266 infores:hetionet CHEBI:3814 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0018932 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0037274 infores:hetionet CHEBI:8768 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0004604 infores:hetionet CHEBI:17076 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0002878 infores:hetionet CHEBI:161680 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0038999 infores:hetionet CHEBI:144551 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0017675 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0043246 infores:hetionet CHEBI:84500 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0917801 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0424823 infores:hetionet CHEBI:15940 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0085932 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0240417 infores:hetionet CHEBI:9316 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0041969 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0267596 infores:hetionet CAID:CA124393 biolink:causes MONDO:0012163 infores:clingen CAID:CA124393 MONDO:0012163 PMID: Benign BA1 NM_002185.5(IL7R):c.412G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 138 (p.Val138Ile). The filtering allele frequency (the lower threshold of the 95% CI of 65661/74940 alleles) of the c.412G>A variant in IL7R is 0.8743 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1 and therefore meets this criterion (BA1). Additionally, 367924 homozygous have been described.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA124393/MONDO:0012163/119 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true UNII:3QJA87N40S biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0542571 infores:hetionet CHEBI:51164 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0039070 infores:hetionet CHEBI:8107 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0947912 infores:hetionet UMLS:C0209366 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0010200 infores:hetionet CHEBI:6715 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0030794 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038363 infores:hetionet CAID:CA024260 biolink:causes MONDO:0018493 infores:clingen CAID:CA024260 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with methionine at codon 4938 of the RYR1 protein, p.(Ile4938Met). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction, it has been reported associated with CCD (PMID:14985404, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.855) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024260/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7824 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0233494 infores:hetionet CHEBI:136040 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0917801 infores:hetionet CHEBI:40279 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0003578 infores:hetionet CHEBI:10650 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1527344 infores:hetionet CHEBI:51141 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0011603 infores:hetionet CHEBI:135935 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0020458 infores:hetionet GO:0062236 biolink:causes CL:0005006 infores:ubergraph knowledge_assertion manual_agent GO:0062236 CL:0005006 CHEBI:2682 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C3665347 infores:hetionet CHEBI:64198 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0018681 infores:hetionet CHEBI:4822 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0000737 infores:hetionet CHEBI:6970 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0020555 infores:hetionet CAID:CA402998003 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998003 MONDO:0012999 PMID: Uncertain Significance PP3, PM2_Supporting PM5 The NM_000156.6:c.170C>A variant in GAMT is predicted to result in the missense substitution of alanine by aspartate at amino acid 57 (p.Ala57Asp). To our knowledge, this variant has not been previously published in individuals with guanidinoacetate methyltransferase deficiency or in ClinVar. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.759 which is in the range of 0.644-0.773, evidence that correlates with impact to GAMT function at the supporting level (PP3). SpliceAI predicts that the variant has no significant impact on splicing. In summary, the clinical significance of the p.Ala57Asp variant is uncertain. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 2.0.0): PM2_Supporting, PP3.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998003/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA003567 biolink:causes MONDO:0700268 infores:clingen CAID:CA003567 MONDO:0700268 PMID:30209399PMID:35167739PMID:31143303 Likely Pathogenic PVS1, PM2_Supporting PS3 The c.5407-10G>A variant is an intronic variant occurring in intron 21 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This variant is reported to result in aberrant mRNA splicing. RTPCR data demonstrated that the variant impacts splicing by retaining 8 basepairs of the adjacent intron resulting in a frameshift. (PMIDs 31143303, 35167739). Appropriate code strength determined by comparison of results to PVS1 decision tree and assessment of mRNA splicing data (PVS1 (RNA) met).This variant is reported by one calibrated study to exhibit intermediate protein function between benign and pathogenic control variants (PMIDs 30209399) (PS3 and BS3 not met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003567/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5001 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0267596 infores:hetionet CHEBI:85161 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0855333 infores:hetionet CHEBI:180905 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0030554 infores:hetionet CHEBI:51209 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0003811 infores:hetionet CHEBI:37333 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0042790 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0853692 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0859290 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0859290 infores:hetionet CHEBI:8382 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1318520 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011570 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0030305 infores:hetionet CHEBI:3534 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0009676 infores:hetionet CHEBI:49668 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0030305 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0158687 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0158687 infores:hetionet CHEBI:135876 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0033774 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0235639 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0042373 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0024117 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0031212 infores:hetionet NCBIGene:3717 biolink:causes MONDO:0009692 infores:monarchinitiative not_provided not_provided HGNC:6192 MONDO:0009692 uuid:962ee1b5-4129-427c-a6e8-e3fc39793096 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0259749 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0042109 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020649 infores:hetionet CHEBI:8768 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1142011 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0038454 infores:hetionet CHEBI:31236 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007859 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0521501 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0521501 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0858678 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0020651 infores:hetionet CHEBI:17303 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0021141 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0522351 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0522351 infores:hetionet CHEBI:47381 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0518988 infores:hetionet CHEBI:76010 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0027497 infores:hetionet CHEBI:41977 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0018681 infores:hetionet CHEBI:584020 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0004604 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0087169 infores:hetionet CHEBI:3423 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0025289 infores:hetionet CHEBI:28748 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004604 infores:hetionet CHEBI:37941 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0010692 infores:hetionet CAID:CA270371 biolink:causes MONDO:0010726 infores:clingen CAID:CA270371 MONDO:0010726 PMID: Pathogenic PM1, PS2, PS1, PM2_Supporting PP3, PP4, PS3 The c.372G>T (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the mosaic state in a male patient with a neurodevelopmental phenotype consistent with the MECP2 gene (internal database - Invitae) and therefore confirmed to be de novo (PS2). The c.372G>T (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>T (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). The c.372G>C variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (PMID 10991688, 12843318) (PS1). In summary, the c.372G>T (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PS2, PM1, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270371/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:72564 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151786 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0948594 infores:hetionet UMLS:C0010592 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0022346 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0232492 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0014868 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0042373 infores:hetionet CHEBI:6904 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0220870 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0036572 infores:hetionet CHEBI:45409 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009782 infores:hetionet CHEBI:6933 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0015230 infores:hetionet CHEBI:421707 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0021368 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0027013 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027013 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0029882 infores:hetionet NCBIGene:55164 biolink:causes MONDO:0859258 infores:monarchinitiative not_provided not_provided HGNC:25543 MONDO:0859258 uuid:a210d46a-e204-416d-b5a5-e19b300e0f67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50841 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0575081 infores:hetionet CHEBI:9674 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0085631 infores:hetionet CHEBI:135005 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0002962 infores:hetionet CHEBI:10100 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0151766 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042075 infores:hetionet CHEBI:6438 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0038325 infores:hetionet CHEBI:64312 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042963 infores:hetionet CHEBI:8707 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0028754 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042907 infores:hetionet NCBIGene:54888 biolink:causes MONDO:0012613 infores:monarchinitiative not_provided not_provided HGNC:25994 MONDO:0012613 uuid:a4563136-6c0e-4a40-8186-e02462584e40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0018802 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0019158 infores:hetionet CHEBI:72297 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C1384353 infores:hetionet CHEBI:5118 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0497156 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0006840 infores:hetionet CHEBI:2687 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0027497 infores:hetionet CHEBI:9445 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0009806 infores:hetionet CAID:CA035154 biolink:causes MONDO:0007750 infores:clingen CAID:CA035154 MONDO:0007750 PMID: Uncertain Significance PS3_Moderate BA1, BP1, BP4, BP3, PS4, PS2, PS1, BP7, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1586+5G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PS3_Moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PS3_Moderate:-Level 2, PMID 10668928 (Jensen et al., 1999), heterologous cells (COS-7), FACS and CLSM assays, mutant protein retained at ER; <2% LDLR at surface, 2-5% LDL uptake. Overall LDLR activity is below 70% of wild-type activity.-Level 3, PMID 19208450 (Holla et al., 2009), heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays showed skipping of exon 10 (p.Thr454_Gly529del). -Level 3, PMID 10668928 (Jensen et al., 1999), heterozygous patients' Epstein Barr virus transformed lymphocytes, quantitative RT-PCR assays. Mutated transcripts were 47% of total transcripts; from mutated allele: 50% correctly spliced RNA, skipping of exon 10 (p.Thr454_Gly529del) in 25% of RNAs and retention of the first 66 nucleotides from intron 10 (p.Gly529_Phe530insCysValSerThrThrLeuArgAlaAlaGluGlyMetGluGlyAlaGlyArgSerPheArgAsnCys) in 25% of RNAs. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA035154/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3723 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151599 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0040053 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0009450 infores:hetionet CAID:CA337802 biolink:causes MONDO:0018875 infores:clingen CAID:CA337802 MONDO:0018875 PMID: Pathogenic PM1_Supporting, PS4_Moderate, PS3, PP1_Strong, PP3, PM2_Supporting BP4, BA1, PS2, PS1, PM5, PM4, BS1, BS3, BS4, PVS1, BS2, PP4 The NM_000546.6: c.1025G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 342 (p.Arg342Pro). This variant has been reported in 3 unrelated families meeting Classic criteria. Based on this evidence, this variant scores 3 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs 25981898, 25226867, 19714490). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 3 families (PP1_Strong; PMIDs 25981898, 25226867, 19714490). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation, loss of growth suppression activity, and impaired tetramer formation indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 16007150). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.24; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 8 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1_Strong, PS3, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 9/6/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA337802/MONDO:0018875/009 2024-09-06 2024-09-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0033775 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020538 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0042075 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0012833 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0854456 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0854456 infores:hetionet CHEBI:70707 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0004093 infores:hetionet CHEBI:63605 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0149725 infores:hetionet CHEBI:50648 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235266 infores:hetionet CAID:CA040801 biolink:causes MONDO:0007750 infores:clingen CAID:CA040801 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM2, PP3, PP4 PS1, PM5 The NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF= 0.00001 in European (Non-Finnish) population (gnomAD v2.1.1).PP3: REVEL = 0.802.PS3: Level 1 experiment using heterologous cells (CHO), the experiments shown 50-60% LDL uptake, and normal LDL-LDLR binding (95%) and normal cell surface LDLR (95%), Etxebarria et al, 2015, Unidad de Biofísica (CSIC, UPV/EHU), Departamento de Bioquímica, Universidad del País Vasco, Spain, PMID25378237.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4: Variant meets PM2 and is identified in 22 unrelated index cases who fulfil FH diagnostic criteria. Four index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), three of them had DLCN score ≥6, one met Simon Broome possible for FH. Three index cases with DLCN score ≥6, from Robarts Research Institute, Canada. One case fulfil criteria of TC and LDLc higher than the 95th percentile, with presence of tendon xanthomata, CAD in the proband or in a first degree relative, Chaves et al, 2001, Institute of cytological research and service of endocrinology and nutrition, University of Valencia, Spain, PMID 11600564. Fourteen index cases fulfil 2 of 3 criteria of: 1) TC>8mmol/l, LDL>6mmol/l, TG<2.5mmol/l, 2) CAD before 60yr or family history of CAD, 3) presence of tendon xanthoma, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394.PP1_Strong: Variant segregates with FH phenotype in 16 informative meiosis from more than 3 families. Two affected relatives, one each from 2 families tested positive for the variant from Robarts Research Institute, Canada. Fourteen affected relatives from unknown number of families tested positive for the variant, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394.PS1 not met: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic by these guidelines, therefore PS1 is not met. PM5 not met: One other missense variants in the same codon: NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp), (ClinVarID 252340) is classified as Likely Pathogenic by these guidelines, therefore PM5 not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040801/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:50648 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151505 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0011849 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0948594 infores:hetionet CHEBI:94392 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0009806 infores:hetionet CHEBI:32293 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0231218 infores:hetionet GO:0002643 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0002643 GO:0007275 GO:1903636 biolink:causes GO:0070585 infores:ubergraph knowledge_assertion manual_agent GO:1903636 GO:0070585 CHEBI:35854 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0035078 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040034 infores:hetionet GO:0010080 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0010080 GO:0061458 CAID:CA229802 biolink:causes MONDO:0009861 infores:clingen CAID:CA229802 MONDO:0009861 PMID:23764561PMID:8268925PMID:23764561 Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Strong The c.833C>A (p.Thr278Asn) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded; PMID: 23764561, 16198137). This variant was detected with multiple pathogenic variants: p.R408W (PMID: 23764561); p.P281L (2 patients), and c.1315+1G>A (PMID: 23430918). This variant is absent in population databases Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Thr278Ile) is pathogenic by 2 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229802/MONDO:0009861/006 2020-10-29 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CAID:CA274666 biolink:causes MONDO:0010726 infores:clingen CAID:CA274666 MONDO:0010726 PMID: Likely Pathogenic PM6_Strong, PM2_Supporting, PS4_Moderate, PP4 The p.Met1Leu variant in MECP2 (NM_004992.4) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID: 16225173, GeneDx Internal Database) (PM6_strong, PP4). The p.Met1Leu variant has been observed in 4 individuals with clinical features of Rett syndrome (PMID: 16225173, 19365833, GeneDx Internal Database) (PS4_moderate). The p.Met1Leu variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Met1Leu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PP4, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274666/MONDO:0010726/036 2024-10-30 2024-12-20 X-linked inheritance HP:0001417 Supports CHEBI:8028 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0017601 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0235032 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0001824 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0033975 infores:hetionet CHEBI:41423 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0004093 infores:hetionet CHEBI:135876 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0030794 infores:hetionet GO:2000277 biolink:causes GO:1902600 infores:ubergraph knowledge_assertion manual_agent GO:2000277 GO:1902600 UMLS:C0011701 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0033774 infores:hetionet CAID:CA412376875 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376875 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3 NM_000330.4(RS1):c.62G>T (p.Gly21Val) is a missense variant encoding the substitution of glycine with valine at amino acid 21. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.622, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of <0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives scores of 0.44 for acceptor loss and 0.39 for donor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on RS1 splicing (PP3). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting and PP3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376875/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:6710 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0231218 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0860866 infores:hetionet CHEBI:9943 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1456784 infores:hetionet CHEBI:5118 biolink:causes MONDO:0021645 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0155789 infores:hetionet CHEBI:135530 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0017168 infores:hetionet GO:0048324 biolink:causes GO:0048321 infores:ubergraph knowledge_assertion manual_agent GO:0048324 GO:0048321 CHEBI:8485 biolink:causes UMLS:C0235263 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0235263 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1291077 infores:hetionet CHEBI:7903 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0546817 infores:hetionet CHEBI:6456 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0085593 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0234215 infores:hetionet CHEBI:6822 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0151579 infores:hetionet CHEBI:68554 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0004604 infores:hetionet CAID:CA120642 biolink:causes MONDO:0044970 infores:clingen CAID:CA120642 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS3_Supporting PP1, PP3, PS4, PM6 The m.4810G>A (p.W114*) variant in MT-ND2 has been reported in three individuals with primary mitochondrial disease to date. One individual was reported to have severe exercise intolerance, muscle weakness, myalgia, ophthalmoplegia, ptosis, elevated blood lactate, elevated CK, electromyography consistent with myopathy, and ragged red fibers on muscle biopsy (PMID: 15781840). Complex I activity was reduced in muscle. The variant was present at 94% heteroplasmy in muscle and was undetectable in blood. The two additional individuals reported had ophthalmoplegia and ptosis, however no additional details were provided (Roisin 2022, Newcastle University, https://theses.ncl.ac.uk/jspui/bitstream/10443/5737/1/Stout%20R%20B%202022.pdf). There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The transition at base position m.4810 causes a W114Ter change. This causes a significant truncation (67%) of the ND2 protein (PVS1_strong). Single fiber testing showed numerous ragged-red fibers with the variant present at a mean of 84.27% (n=15) compared to the variant being present at a mean heteroplasmy of 7.15% in the normal fibers (n=14, PS3_supporting, PMID: 15781840). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt uncertain significance was the more appropriate classification given only one case with clinical details has been reported and extensive functional validation is lacking. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120642/MONDO:0044970/015 2023-10-09 2024-08-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:4469 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C2830004 infores:hetionet CHEBI:9130 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151740 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151767 infores:hetionet CHEBI:50729 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020625 infores:hetionet CHEBI:18358 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0005758 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0948089 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0006852 infores:hetionet CHEBI:3478 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013456 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0086543 infores:hetionet CHEBI:28748 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011603 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040425 infores:hetionet CAID:CA397396413 biolink:causes MONDO:0100438 infores:clingen CAID:CA397396413 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting PP3, BP4 NM_014336.5(AIPL1):c.352G>A (p.Val118Met) is a missense variant replacing the valine at position p.118 with methionine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000086, with 14 alleles / 1613666 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.356, which is above the ClinGen LCA/eoRD VCEP threshold of <0.290 for BP4 and below the threshold of ≥0.644 for PP3 so neither code is applicable. No published probands harboring the variant have been identified. In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397396413/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135736 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014335 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025061 infores:hetionet CHEBI:28445 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C2937358 infores:hetionet CHEBI:31348 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0232487 infores:hetionet CHEBI:8024 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0340865 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0151559 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0009450 infores:hetionet CHEBI:681569 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0015967 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0006145 infores:hetionet CHEBI:240107 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0004096 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0857353 infores:hetionet CHEBI:28001 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0015967 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0948525 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0234913 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001268 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0017572 infores:hetionet CHEBI:6541 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C1565489 infores:hetionet CHEBI:49662 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0003811 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0178298 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0008370 infores:hetionet CHEBI:32184 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0162830 infores:hetionet CHEBI:49662 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C2830004 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013595 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0085096 infores:hetionet CHEBI:31236 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0241060 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0014868 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027059 infores:hetionet GO:0003420 biolink:causes GO:0060350 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0060350 CHEBI:46295 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0917801 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0161479 infores:hetionet NCBIGene:60481 biolink:causes MONDO:0014417 infores:monarchinitiative not_provided not_provided HGNC:21308 MONDO:0014417 uuid:3ebf7c80-55e9-45d9-81e5-761b0608649f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3228 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0160390 infores:hetionet CHEBI:75246 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0033774 infores:hetionet CHEBI:38940 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018926 infores:hetionet CAID:CA915952347 biolink:causes MONDO:0010604 infores:clingen CAID:CA915952347 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4_Very Strong, PP3 The c.520+13A>G in F9 is an intronic variant which located in intron 5. This variant has been reported in 38 probands with abnormal factor IX activity levels meeting the phenotypic criteria for PS4_Very Strong (threshold >=8 probands); PMID: 14675097, PMID: 32155688, PMID: 27213901, PMID: 15921378, PMID: 10090477 and PMID: 2198809. The computational predictor Splice AI gives a delta score of 0.92 for donor gain (threshold >=0.5), evidence that correlates with impact to F9 function (PP3_supporting).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PP3, PM2_Supporting (version 1.0.0, released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952347/MONDO:0010604/080 2024-10-11 2024-10-11 X-linked inheritance HP:0001417 Supports NCBIGene:8622 biolink:causes MONDO:0013616 infores:monarchinitiative not_provided not_provided HGNC:8794 MONDO:0013616 uuid:ca272621-eb6c-4a39-b22a-e1d751190a5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014280 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014280 MONDO:0011071 PMID: Likely Benign BP4, BS3_Supporting PS3, PS1, PS4, PS2, BP3, BP1, BP2, BA1, BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM4, PM1, PM5, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys) is a missense variant which is predicted to cause substitution of glutamine by lysine at amino acid 286. The highest population minor allele frequency in gnomAD v2 is 0.00003096 (4/129198 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). The germline variant has been reported in a patient with JMML but without features consistent with the RUNX1 phenotypic criteria (PMID: 20955399), and the variant of unclear origin was reported in a patient with cytopenia (PMID: 32241844). In vitro functional studies using HEK293T and HEL cells confirmed the expression of the mutant protein, and the variant demonstrated 80-115% transactivation activity for the CSF1R and MYL9 promoters (PMID: 35026845) (BS3_Supporting). This aligns with the computational predictor, REVEL, which gives a score of 0.152 that is below the threshold of 0.50 and, thus, evidence that does not predict a damaging effect on RUNX1 function; the splice site predictor, SpliceAI, which gives a score of <0.20, also indicates that the variant has no impact on splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014280/MONDO:0011071/008 2024-09-11 2024-09-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030554 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0020538 infores:hetionet CHEBI:49713 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C3160741 infores:hetionet CHEBI:7959 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0232493 infores:hetionet CHEBI:18248 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0233407 infores:hetionet CHEBI:61049 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013456 infores:hetionet GO:1902866 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1902866 GO:0007275 CHEBI:8764 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017181 infores:hetionet GO:0046668 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:0046668 GO:0030154 CHEBI:31236 biolink:causes HP:0000742 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036601 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0023895 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151828 infores:hetionet CHEBI:27899 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0542571 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0025061 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0034150 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0232431 infores:hetionet NCBIGene:55215 biolink:causes MONDO:0012186 infores:monarchinitiative not_provided not_provided HGNC:25568 MONDO:0012186 uuid:40338cf6-a83c-47a7-8dbf-029b81be0b32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10059 biolink:causes MONDO:0012543 infores:monarchinitiative not_provided not_provided HGNC:2973 MONDO:0012543 uuid:4eb08f8b-336f-461c-814d-9edd9856da26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0009450 infores:hetionet CHEBI:2666 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0004245 infores:hetionet CAID:CA382562092 biolink:causes MONDO:0700270 infores:clingen CAID:CA382562092 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PS3_Supporting, PP3 The c.8096C>T variant in ATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 2699 (p.Pro2699Leu). This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 22649200). This variant is absent from gnomAD v4.1.0. ATM kinase activity assay in ATM-null lymphoblastoid cell line showed reduced ATM kinase activity on its downstream targets indicating that this variant impacts protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.952, which is above the threshold of 0.7333, evidence that correlates to impact to ATM function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Supporting, PM2_Supporting, PS3_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382562092/MONDO:0700270/020 2025-09-25 2025-10-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA320255675 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255675 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.806-3C>T is an intronic variant that has a SpliceAI score ≤ 0.20 (0.0) (BP4). Its minor allele frequency of 0.0002229 (0.02229%, 10/44872, 10 alleles) in the East Asian subpopulation of the gnomAD v4.1.0 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255675/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135613 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0041657 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0851341 infores:hetionet CHEBI:9763 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0013428 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0009938 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0497365 infores:hetionet CHEBI:45951 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0235660 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005089 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1261473 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0027651 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019163 infores:hetionet CHEBI:52172 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009782 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0232492 infores:hetionet CHEBI:6402 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0002792 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0341742 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0028738 infores:hetionet CHEBI:119915 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151825 infores:hetionet CHEBI:9738 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0011603 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0026848 infores:hetionet CAID:CA10603688 biolink:causes MONDO:0010315 infores:clingen CAID:CA10603688 MONDO:0010315 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4, PS1 The NM_000206.3(IL2RG):c.924+1G>A variant disrupts of the canonical splice donor site in intron 7, which is predicted to cause skipping of exon 7 and a frameshift in exon 8 (the final exon) with a stop loss and elongation of the protein by 31 amino acids (p.Thr286Profs*57). While the critical cytoplasmic domain is not truncated (as per IL2RG PVS1 specifications) it is entirely altered and considered to be functionally lost, therefore loss of the critical cytoplasmic domain was considered to apply PVS1. Additionally, the splice effect was confirmed in PMID: 9058718 which reported that in patient derived cells trace amounts of an abnormally large IL2RG mRNA was found with sequence continuing into the introns. The male Patient 1 of PMID: 35812426 was identified to have this variant by WES and has a T-B+NK- lymphocyte subset profile ( 3x10^9/L CD3 T cells, 111x10^9/L CD19 B cells, 3x10^9/L CD56 NK cells). This is highly specific for SCID due to gamma chain deficiency (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PP4_moderate. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603688/MONDO:0010315/129 2024-01-17 2024-09-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CAID:CA410204095 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204095 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.156G>A (p.Met52Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204095/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:91541 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0521491 infores:hetionet CHEBI:194135 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013390 infores:hetionet CHEBI:119486 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0001807 infores:hetionet CHEBI:10102 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0232462 infores:hetionet CHEBI:4636 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0232462 infores:hetionet CHEBI:71223 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0030196 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020456 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040034 infores:hetionet CHEBI:135939 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0004134 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0152227 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019158 infores:hetionet CHEBI:9168 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020433 infores:hetionet NCBIGene:2561 biolink:causes MONDO:0020631 infores:monarchinitiative not_provided not_provided HGNC:4082 MONDO:0020631 uuid:48156ce5-8a55-4da1-8f29-9d5e52bdfbc0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0546817 infores:hetionet CHEBI:10023 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0035317 infores:hetionet CHEBI:3696 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0018965 infores:hetionet CHEBI:16347 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0042963 infores:hetionet CAID:CA356968 biolink:causes MONDO:0021060 infores:clingen CAID:CA356968 MONDO:0021060 PMID: Likely Pathogenic PM2_Supporting, PM6_Strong, PS4_Moderate, PS3_Supporting, PP3 BP4, PM1, PP2, PP1 The c.71T>A (p.Ile24Asn) variant in NRAS is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 24. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.863, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 4 probands with features of RASopathy (PS4_Moderate; PMIDs:21263000, 22855653, 28594414, GeneDx). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with features of RASopathy (PM6_Strong; PMIDs: 21263000, 22855653). RAS activation assays in 293T cells showed a mild increase in GTP-bound RAS and enhanced MAPK phosphorylation indicating that this variant impacts protein function. A zebrafish model using injected RNA showed developmental and craniofacial defects. The phenotype was completely rescued by MEK inhibition (PMID:21263000)(PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM6_Strong, PS4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 2.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA356968/MONDO:0021060/039 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6129 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030312 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0150450 infores:hetionet CHEBI:7565 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0034063 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0037199 infores:hetionet CHEBI:43968 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0003467 infores:hetionet CHEBI:64064 biolink:causes UMLS:C1096257 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1096257 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0543467 infores:hetionet CHEBI:194135 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235063 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0037274 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1258215 infores:hetionet CHEBI:7476 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0036974 infores:hetionet CHEBI:9586 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0030554 infores:hetionet CHEBI:52717 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1260880 infores:hetionet CHEBI:42944 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0085632 infores:hetionet CHEBI:3699 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0085631 infores:hetionet CHEBI:7773 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0041657 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027651 infores:hetionet NCBIGene:4053 biolink:causes MONDO:0013122 infores:monarchinitiative not_provided not_provided HGNC:6715 MONDO:0013122 uuid:2fa09c21-85ce-4008-b976-0b5db42a9d18 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0010200 infores:hetionet CHEBI:681569 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0014591 infores:hetionet UBERON:0004638 biolink:causes MONDO:0021080 infores:ubergraph knowledge_assertion manual_agent UBERON:0004638 MONDO:0021080 CAID:CA243707917 biolink:causes MONDO:0021060 infores:clingen CAID:CA243707917 MONDO:0021060 PMID: Likely Pathogenic PM5, PM2, PP3, PP2, PS4_Supporting PS3, PS2, PS1, BS3, BS4, BS1, BP5, BP7, PM1, PM4, PM6, BS2, PP1, BP3, BP2, BP4, BP1, BA1 The c.167T>C (p.Ile56Thr) variant in PTPN11 has been identified in 2 related patients with clinical features of a RASopathy (PS4_Supporting, PP1; Invitae internal data; GTR Lab ID 500031; ClinVar SCV000659038.1). A different pathogenic missense variant (p.Ile56Val) has been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40485). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ile56Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PP1, PM2, PM5, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA243707917/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:404903 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0948586 infores:hetionet CHEBI:17549 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0041582 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0041912 infores:hetionet CAID:CA913184733 biolink:causes MONDO:0009290 infores:clingen CAID:CA913184733 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PM3 "The NM_000152.5:c.1602_1605delinsAGG (p.Asn535GlyfsTer43) variant in GAA is a frameshift variant predicted to cause a premature stop codon in exon 12 out of 20 total exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). It has been reported in one patient who was diagnosed with infantile onset Pompe disease ""based on clinical presentations and GAA enzyme activity assay"" and who is compound heterozygous for the variant and c.796C>T (p.Pro266Ser) (PMID 28394184, 35747179). The allelic data from this patient was used in the classification of the missense change and is not included here to avoid circular logic. There is insufficient data to apply PP4. There is a ClinVar entry for this variant (Variation ID: 1693551). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Nov. 17, 2025)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184733/MONDO:0009290/010 2025-11-17 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4909 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0035078 infores:hetionet UNII:DJJ95FJP1H biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0232492 infores:hetionet CHEBI:28487 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0034150 infores:hetionet NCBIGene:8818 biolink:causes MONDO:0014023 infores:monarchinitiative not_provided not_provided HGNC:3006 MONDO:0014023 uuid:c0b8efa0-be9d-4fc3-b4f1-cd6408f0dfec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2047937 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011616 infores:hetionet CHEBI:72296 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0311468 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0233794 infores:hetionet CHEBI:64354 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0001824 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0019158 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0019158 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0013595 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0019158 infores:hetionet CHEBI:167638 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0043144 infores:hetionet CHEBI:32184 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0011616 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0243026 infores:hetionet NCBIGene:5173 biolink:causes MONDO:0012449 infores:monarchinitiative not_provided not_provided HGNC:8820 MONDO:0012449 uuid:194e93ec-b7bf-4c47-9790-33cabeb4a61b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2695202183 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695202183 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.297_306del (p.Leu100GlnfsTer?) is a frameshift variant due to a 10-nucleotide deletion that introduces a premature stop codon after 30 amino acids within exon 4 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa (PMID: 23372056), however, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in an affected male by age 30 years, and/or decreased or absent cone and/or rod electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202183/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:5165 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0026961 infores:hetionet CHEBI:7936 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037317 infores:hetionet GO:1900457 biolink:causes GO:0071383 infores:ubergraph knowledge_assertion manual_agent GO:1900457 GO:0071383 UMLS:C0879264 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0019209 infores:hetionet CAID:CA308120058 biolink:causes MONDO:0100150 infores:clingen CAID:CA308120058 MONDO:0100150 PMID: Uncertain Significance PM2_Supporting PP3, BP4, BA1, BS1 The c.14173G>C variant in RYR1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 4725. The highest population minor allele frequency in gnomAD v4.1 is 0.00001667 (1/59980 alleles) in the Admixed American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent, 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.661, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. In summary, the variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA308120058/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94501 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0036974 infores:hetionet CHEBI:2668 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0547030 infores:hetionet CHEBI:7443 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0340865 infores:hetionet CHEBI:119573 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0338656 infores:hetionet CHEBI:29007 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0015967 infores:hetionet CHEBI:31643 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0040409 infores:hetionet CHEBI:63621 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011168 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020651 infores:hetionet CHEBI:6775 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151723 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018418 infores:hetionet CHEBI:74947 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011124 infores:hetionet NCBIGene:2301 biolink:causes MONDO:0013067 infores:monarchinitiative not_provided not_provided HGNC:3808 MONDO:0013067 uuid:c3a238a9-ad6a-4765-bb56-0d6080648019 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70746 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0162429 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0030552 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0033975 infores:hetionet CHEBI:28364 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0002792 infores:hetionet CHEBI:35778 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C2363730 infores:hetionet CHEBI:3614 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0031350 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0151892 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151892 infores:hetionet CHEBI:9586 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0000737 infores:hetionet CHEBI:6149 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013362 infores:hetionet CHEBI:4315 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0156312 infores:hetionet CAID:CA137955 biolink:causes MONDO:0021060 infores:clingen CAID:CA137955 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.580+6G>A variant in the MAP2K2 gene is 0.311% (91/24374) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137955/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50648 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0241005 infores:hetionet CHEBI:9622 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0039231 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002622 infores:hetionet CHEBI:31348 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013491 infores:hetionet CHEBI:5004 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0020458 infores:hetionet CHEBI:31932 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020443 infores:hetionet CHEBI:135961 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0018681 infores:hetionet CHEBI:135920 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0231919 infores:hetionet NCBIGene:25778 biolink:causes MONDO:0012561 infores:monarchinitiative not_provided not_provided HGNC:29043 MONDO:0012561 uuid:56cbfc4b-ba30-4cb0-86d8-9af6775972b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020615 infores:hetionet CHEBI:480999 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0018681 infores:hetionet CHEBI:83804 biolink:causes MONDO:0006609 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0221244 infores:hetionet CHEBI:72564 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0027424 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0426576 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0314719 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015393 infores:hetionet CHEBI:4974 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C1443060 infores:hetionet CAID:CA170308 biolink:causes MONDO:0010726 infores:clingen CAID:CA170308 MONDO:0010726 PMID: Pathogenic PP1_Strong, PS2_Very Strong, PM2_Supporting The p.Arg167Trp variant (NM_004992.3) in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with MECP2-related disorders through testing completed at GeneDx (PS2_very strong). The variant has been reported to segregate in at least five informative meioses in published literature (Couvert et al., 2001) (PP1_strong). The p.Arg167Trp variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg167Trp variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PP1_strong, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170308/MONDO:0010726/016 2021-12-13 2023-02-24 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:5165 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085593 infores:hetionet CHEBI:3723 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020443 infores:hetionet CHEBI:100241 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085632 infores:hetionet CHEBI:4514 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0018524 infores:hetionet CHEBI:4975 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0018524 infores:hetionet CHEBI:75988 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0016382 infores:hetionet CHEBI:4910 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0036572 infores:hetionet CHEBI:8435 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0018790 infores:hetionet CHEBI:16899 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0003862 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0034150 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1720798 infores:hetionet CHEBI:7454 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0037822 infores:hetionet CHEBI:8863 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151662 infores:hetionet CHEBI:204928 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0014356 infores:hetionet NCBIGene:5077 biolink:causes MONDO:0007395 infores:monarchinitiative not_provided not_provided HGNC:8617 MONDO:0007395 uuid:f0da92ac-82bb-488d-a5af-54de77a9dd54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0542571 infores:hetionet CHEBI:3752 biolink:causes HP:0011359 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0277960 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0856882 infores:hetionet CHEBI:84500 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0014591 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020649 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0235431 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0027765 infores:hetionet CAID:CA168964 biolink:causes MONDO:0007648 infores:clingen CAID:CA168964 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.933C>G variant has an allele frequency of 0.03128 (3.1%, 781/24,968 alleles) in the African subpopulation of the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA168964/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7936 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235969 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0004471 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D001170 DB01212_MESH_D001170_1DB00493_MESH_D001170_1 CHEBI:5893 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0040128 infores:hetionet CHEBI:3441 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0700200 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0032326 infores:hetionet CHEBI:4657 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0016204 infores:hetionet CHEBI:3478 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0011603 infores:hetionet CHEBI:2611 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0001807 infores:hetionet CHEBI:4702 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0018524 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011053 infores:hetionet CHEBI:42820 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0020458 infores:hetionet CAID:CA409108257 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108257 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting The c.928G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to serine at codon 310 (p.(Gly310Ser)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.785, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.928G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0 approved 10/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108257/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40237 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0027497 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234987 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0549249 infores:hetionet CAID:CA16621485 biolink:causes MONDO:0010315 infores:clingen CAID:CA16621485 MONDO:0010315 PMID: Uncertain Significance PM2_Supporting NM_000206.3(IL2RG):c.460C>T is a missense variant predicted to cause substitution of Proline by Serine at amino acid 154 (p.Pro154Ser).The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with IL2RG related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621485/MONDO:0010315/129 2024-01-10 2024-01-10 X-linked inheritance HP:0001417 Inconclusive true CHEBI:135888 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0024305 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0018939 infores:hetionet NCBIGene:7515 biolink:causes MONDO:0033116 infores:monarchinitiative not_provided not_provided HGNC:12828 MONDO:0033116 uuid:8c0ee717-8da9-4557-bb4d-8545d08fc003 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27666 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0011168 infores:hetionet CHEBI:82941 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0027497 infores:hetionet UNII:D27V6190PM biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0020452 infores:hetionet CHEBI:5001 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0162830 infores:hetionet CHEBI:5296 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0015672 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0019212 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0521839 infores:hetionet CHEBI:6797 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0042963 infores:hetionet CHEBI:45599 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0021843 infores:hetionet CHEBI:6367 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017565 infores:hetionet CHEBI:38545 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0917801 infores:hetionet CHEBI:4779 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0022568 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C2225524 infores:hetionet CHEBI:41977 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0232462 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235416 infores:hetionet CHEBI:49575 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013362 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0020538 infores:hetionet CHEBI:17347 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0156404 infores:hetionet CHEBI:68478 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011071 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020615 infores:hetionet CHEBI:188986 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0026961 infores:hetionet CAID:CA273848 biolink:causes MONDO:0010726 infores:clingen CAID:CA273848 MONDO:0010726 PMID: Pathogenic PP4, PVS1, PS4_Moderate, PM6_Strong, PM2_Supporting The p.Val485fs (NM_004992) variant in MECP2 is predicted to cause a frameshift that results in a read-through of the stop codon (PVS1). The p.Val485fs variant in MECP2 has been reported as de novo occurrence in at least two individuals (biological parentage unconfirmed) with Rett Syndrome (PMID 11402105, Clinvar Variation ID: 143485) (PM6_strong). The p.Val485fs variant has been observed in at least 3 other individuals with Rett Syndrome (PMID 11402105, PMID 16473305, ClinVar) (PS4_moderate). The p.Val485fs variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Val485fs variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett Syndrome (PMID 11402105) (PP4). In summary the p.Val485fs variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA273848/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:47898 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0221269 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0341012 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019112 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0854100 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030552 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0221185 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0030794 infores:hetionet CHEBI:4708 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0030252 infores:hetionet CHEBI:5790 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042963 infores:hetionet CHEBI:45599 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0015967 infores:hetionet CHEBI:51141 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0002962 infores:hetionet UNII:7F465U79Q1 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0019054 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0242350 infores:hetionet CHEBI:16469 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0699744 infores:hetionet CHEBI:50730 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0149514 infores:hetionet CHEBI:83804 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0041834 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151785 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0042769 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0549373 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0032584 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0037199 infores:hetionet CAID:CA229811 biolink:causes MONDO:0009861 infores:clingen CAID:CA229811 MONDO:0009861 PMID:24941924PMID:20188615PMID:23764561PMID:10394930PMID:1671810 Pathogenic PM3, PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PVS1: Canonical +1 splice site; PM2: gnomAD MAF 0.00008; PP4: Reported in 3 PKU populations: Slovak, Germany, Italy (PMID:1671810; PMID:10394930; PMID:23764561); PM3: (PMID:20188615; PMID:24941924). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229811/MONDO:0009861/006 2018-08-13 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94686 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0037763 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0948594 infores:hetionet CAID:CA119849 biolink:causes MONDO:0015152 infores:clingen CAID:CA119849 MONDO:0015152 PMID:37317968 Pathogenic PP1_Moderate, PP3, PP4, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000232.5: c.452C>G variant in SGCB is a missense variant predicted to cause substitution of threonine by arginine at amino acid 151 p.(Thr151Arg). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy, including in a homozygous state (1.0 pt; PMID: 30564623, 21480868, 7581448) and confirmed in trans with a pathogenic variant (c.271C>T p.(Arg91Cys), 1.0 pt, PMID: 9565988) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The variant has also been shown to segregate with autosomal recessive LGMD in at least 5 affected family members in families from the Plain community in southern Indiana and has been proposed as a founder variant for this population (PP1_Moderate; PMID: 7581448, 9565988, 28615891, 3083835). The minor allele frequency of this variant is 0.00006498 for European (non-Finnish) chromosomes in gnomAD v2.1.1 (1/15390), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays of membrane localization in HEK293 and HER-911 cells showed that expression of p.Thr151Arg in β-sarcoglycan disrupted localization of both the β-sarcoglycan subunit and the sarcoglycan complex to the plasma membrane, indicating an impact of the variant on protein function (PMID: 37317968, 22095924) (PS3_Moderate). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to SGCB function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PP1_Moderate, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA119849/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9763 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0242350 infores:hetionet CHEBI:74947 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020625 infores:hetionet CHEBI:4453 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0019572 infores:hetionet GO:1901963 biolink:causes GO:0003151 infores:ubergraph knowledge_assertion manual_agent GO:1901963 GO:0003151 CHEBI:63620 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0231365 infores:hetionet CHEBI:9943 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0016658 infores:hetionet CHEBI:63619 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0036396 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0009319 infores:hetionet CAID:CA410203530 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203530 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.311C>T (p.Thr104Met) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203530/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63618 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0242350 infores:hetionet CAID:CA16020826 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020826 MONDO:0009861 PMID: Likely Pathogenic PM3, PM2, PP3, PP4 PM5 The c.603T>G (p.His201Gln) variant in PAH has been reported in at least one individual with classic PKU (PMID: 20920871), where it was observed in trans with p.Arg243Ter (Variation ID: 588, classified as Pathogenic by the PAH VCEP). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020826/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3077 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0085570 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1963789 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1963789 infores:hetionet CHEBI:3479 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0002994 infores:hetionet CHEBI:8364 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0036974 infores:hetionet CHEBI:50859 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018965 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0687133 infores:hetionet CHEBI:6717 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0917801 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005867 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0032302 infores:hetionet CHEBI:2950 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0242301 infores:hetionet CAID:CA151230 biolink:causes MONDO:0700272 infores:clingen CAID:CA151230 MONDO:0700272 PMID:31757951PMID:31636395PMID:33964450 Benign BA1, BP1 BS1, BS3, PM2, PP3, BP4 The c.2014G>C variant in PALB2 is a missense variant predicted to cause a substitution of a glutamic acid by glutamine at amino acid 672 (p.Glu672Gln). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.02846 in non-Finnish European population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays (PMID: 31636395, PMID: 31757951, PMID: 33964450); however, due to a lack of known positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA151230/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135888 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C1260880 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0022650 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020557 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235431 infores:hetionet NCBIGene:7879 biolink:causes MONDO:0010949 infores:monarchinitiative not_provided not_provided HGNC:9788 MONDO:0010949 uuid:6517e04f-1321-44db-93d3-b6144bdb8de9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027339 infores:hetionet CHEBI:31348 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022107 infores:hetionet CHEBI:79699 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0206061 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0018799 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0795692 infores:hetionet CHEBI:46081 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0030193 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0014745 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0014745 infores:hetionet CHEBI:5165 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C2242737 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034902 infores:hetionet CHEBI:44915 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0043144 infores:hetionet CHEBI:8107 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0026827 infores:hetionet CHEBI:92998 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0033771 infores:hetionet CHEBI:8871 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027849 infores:hetionet CAID:CA218972 biolink:causes MONDO:0010725 infores:clingen CAID:CA218972 MONDO:0010725 PMID:29851975 Uncertain Significance PM2_Supporting, PS3_Supporting, PM4, PP4 The NM_000330.4(RS1):c.583_585dup variant is an in-frame duplication variant in amino acid 195 not predicted to result in premature protein termination. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant is a short in-frame insertion of 3 base pairs that encode additional residues between amino acids 195-196 within a non-repetitive region of RS1 (PM4). COS-7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 29851975, PS3_Supporting). At least one proband harboring this variant exhibits a phenotype including the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 29851975, PP4). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PM4, PS3_supporting, and PP4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA218972/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:251408 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0235086 infores:hetionet CHEBI:65173 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0392156 infores:hetionet CAID:CA658824658 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824658 MONDO:0011071 PMID:25840971PMID:14615365PMID:19808697PMID:25840971PMID:14615365PMID:19808697 Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 This late duplication which results in a frameshift is not expected to result in nonsense mediated mRNA decay, but will alter the transactivation domain/inhibitory domain/VWRPY motif and elongate the protein (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). It has been described in a patient with thrombocytopenia (personal communication with last author) and short telomeres (<1st percentile), but the variant could not be confirmed in the germline (PMID: 29463756). However, other C-terminal frameshift variants have been reported with some showing loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong and PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824658/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75722 biolink:causes UMLS:C0520547 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0520547 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018991 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0853714 infores:hetionet NCBIGene:10551 biolink:causes MONDO:0859370 infores:monarchinitiative not_provided not_provided HGNC:328 MONDO:0859370 uuid:486b439f-e4f3-492e-8e30-c455fca4ed34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042907 infores:hetionet CHEBI:4702 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0151942 infores:hetionet CHEBI:5383 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0023530 infores:hetionet NCBIGene:1080 biolink:causes MONDO:0010178 infores:monarchinitiative not_provided not_provided HGNC:1884 MONDO:0010178 uuid:0543cd20-c61a-4b48-8739-2b14f0b2fbb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47612 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0948089 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233494 infores:hetionet CHEBI:6437 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0022107 infores:hetionet CHEBI:8499 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0002622 infores:hetionet CHEBI:28748 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0497156 infores:hetionet CHEBI:5118 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1320474 infores:hetionet NCBITaxon:51028 biolink:causes MONDO:0005746 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:51028 MONDO:0005746 CAID:CA404093077 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093077 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP2, PS4, PS1, PS3, PS2, BS1, BS4, BS3, BP7, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP4, PP1, PP3 The NM_000527.5(LDLR):c.1943C>T (p.Ser648Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.BP4 - REVEL = 0.487, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT.C) variant is exonic and there is an GT nearby MES scores: variant cryptic = -20.85, wt cryptic = -15.66, canonical donor = 10.28. Ratio variant cryptic/wt cryptic: -20.85/-15.66 = 1,33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -20.85/10.28 --- it is not above 0.9 Variant is not predicted to alter splicing--- BP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093077/MONDO:0007750/013 2023-01-27 2023-04-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3387 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0017979 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0009782 infores:hetionet CHEBI:45599 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0149514 infores:hetionet CHEBI:3732 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014457 infores:hetionet CAID:CA658795236 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795236 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting The NM_000152.5:c.742del (p.Leu248CysfsTer20) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 4/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 3 probands with this variant have been reported with Pompe disease (2 with IOPD, and 1 with LOPD). One of the probands with IOPD was reported to have hypertrophic cardiomyopathy, muscle weakness, was on enzyme replacement therapy for Pompe disease, and was noted to have deficient GAA activity but results were not provided (PMID: 29422078). GAA activity and clinical details were not provided for the other proband reported to have IOPD (PMID: 18429042) or the proband reported to have LOPD (PMID: 29122469) (PP4_Moderate). Two of these probands are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.-32-13T>G (PMID: 29122469) or c.896T>C (p.Leu299Pro) (PMID: 29422078) (PM3). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2683630). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0.0): PVS1, PM2_Supporting, PM3, PP4_Moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795236/MONDO:0009290/010 2025-06-17 2025-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6067 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004936 infores:hetionet CHEBI:46345 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0028643 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0233472 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0392106 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0392106 infores:hetionet CAID:CA145888 biolink:causes MONDO:0001586 infores:clingen CAID:CA145888 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.60G>A variant in IDUA is a synonymous (silent) variant (p.Ala20=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.5266 (17787/33780 alleles; 4836 homozygotes; Grpmax Filtering AF 95% confidence = 0.5201) in the Admixed American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145888/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4469 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0033975 infores:hetionet CHEBI:31397 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0030196 infores:hetionet CHEBI:6822 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0015672 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0518015 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0403632 infores:hetionet CHEBI:3756 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1306341 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0015230 infores:hetionet CHEBI:68841 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0020517 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151795 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020550 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1305875 infores:hetionet CHEBI:4514 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0152032 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0151736 infores:hetionet CHEBI:5383 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0013395 infores:hetionet CHEBI:59773 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0011606 infores:hetionet NCBIGene:29914 biolink:causes MONDO:0007374 infores:monarchinitiative not_provided not_provided HGNC:30791 MONDO:0007374 uuid:c8a3908a-bd7a-4018-a630-3e0083272ca9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6261 biolink:causes MONDO:0007294 infores:monarchinitiative not_provided not_provided HGNC:10483 MONDO:0007294 uuid:07162543-7cd5-4b34-ad06-5ce3b727f4fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:142290 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0021167 infores:hetionet CHEBI:7852 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0026827 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0858678 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0232097 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0232097 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0021308 infores:hetionet CHEBI:40279 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151723 infores:hetionet NCBIGene:8085 biolink:causes MONDO:0007843 infores:monarchinitiative not_provided not_provided HGNC:7133 MONDO:0007843 uuid:1400025e-8944-4eca-bd66-75b13a4f78a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94686 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0917801 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233632 infores:hetionet CHEBI:145499 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0233477 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0497365 infores:hetionet CHEBI:8707 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0025222 infores:hetionet CHEBI:3568 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151786 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020678 infores:hetionet CHEBI:3723 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151878 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023530 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0267792 infores:hetionet CHEBI:8028 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0085637 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0021053 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0521510 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0521510 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013595 infores:hetionet CHEBI:31547 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0018965 infores:hetionet CAID:CA382516339 biolink:causes MONDO:0700270 infores:clingen CAID:CA382516339 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP3 The c.8300T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 2767 (p.Leu2767Pro). This variant has been detected at least in two unrelated individuals with Ataxia-Telangiectasia (PMIDs: 22649200, 26896183). This variant is absent from gnomAD v4.1.0. The computational predictor REVEL gives a score of 0.94, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Strong, PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382516339/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3515 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C1609512 infores:hetionet CHEBI:8499 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0020461 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0162287 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0029408 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021680 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038395 infores:hetionet CHEBI:567361 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0014518 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0019158 infores:hetionet CHEBI:16899 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0042487 infores:hetionet CHEBI:50742 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0031542 infores:hetionet CHEBI:9725 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0085623 infores:hetionet CHEBI:27777 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0017178 infores:hetionet CHEBI:3515 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0558489 infores:hetionet UMLS:C0903898 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0232461 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0178298 infores:hetionet CHEBI:9168 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011606 infores:hetionet CHEBI:119573 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0039070 infores:hetionet CHEBI:3077 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0016658 infores:hetionet CHEBI:3756 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009782 infores:hetionet CHEBI:9123 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0021177 infores:hetionet CHEBI:7445 biolink:causes EFO:0010671 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0549124 infores:hetionet CHEBI:10119 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0006384 infores:hetionet NCBIGene:54828 biolink:causes MONDO:0859208 infores:monarchinitiative not_provided not_provided HGNC:14347 MONDO:0859208 uuid:30f8baed-717c-4849-9197-f7e945b3d939 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0018520 infores:hetionet CHEBI:8871 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085583 infores:hetionet CHEBI:3636 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0036572 infores:hetionet CHEBI:231594 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0023218 infores:hetionet CHEBI:474180 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0002792 infores:hetionet CHEBI:9605 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0042109 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014534 infores:hetionet CHEBI:32315 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0030252 infores:hetionet CHEBI:15365 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0002792 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0015397 infores:hetionet CHEBI:49603 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0003862 infores:hetionet CAID:CA229842 biolink:causes MONDO:0009861 infores:clingen CAID:CA229842 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.907T>G (p.Ser303Ala) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 23430859, 23500595, 24941924, 27121329). This variant is absent in population databases (PM2). This variant was detected in 2 patients in trans with p.G46S (PMID: 27121329) (this variant is Pathogenic in ClinVar by 5 submitters, ID G46S) and with c.673C>A p.(Pro225Thr) (PMID: 24941924, parental analysis not described) (this variant is Pathogenic in ClinVar by 4 submitters, ID 102779). Computational evidence predicts a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229842/MONDO:0009861/006 2021-01-18 2021-04-09 Autosomal recessive inheritance HP:0000007 Supports GO:1904130 biolink:causes GO:0001840 infores:ubergraph knowledge_assertion manual_agent GO:1904130 GO:0001840 CHEBI:144093 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0948594 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0475858 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020456 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0948089 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040259 infores:hetionet CHEBI:9654 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1306341 infores:hetionet CHEBI:8212 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0025345 infores:hetionet CHEBI:94848 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0013144 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0012833 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0020538 infores:hetionet CHEBI:6539 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0085631 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0037199 infores:hetionet CHEBI:2676 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0424295 infores:hetionet CHEBI:84050 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0036974 infores:hetionet CHEBI:6375 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0149871 infores:hetionet CAID:CA354422 biolink:causes MONDO:0007750 infores:clingen CAID:CA354422 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM2, PP1, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3 The NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Moderate, PM2, PP1, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4_Moderate: Variant meets PM2 and is identified in 8 unrelated index cases (1 case with Simon-Broome criteria of possible FH and 1 case with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 2 cases with Simon-Broome criteria of possible FH and 1 case with DLCN>6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, and 3 cases in PMID 15241806 (Mozas P et al., 2004)). So PS4_Moderate is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So PM2 is met. PP1: Variant segregates with FH phenotype in 3 informative meioses identified by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So PP1 is met. PP4: Variant meets PM2 and is identified in2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA354422/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0006954 biolink:causes MONDO:0005642 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003233 DB01176_MESH_D003233_1DB01069_MESH_D003233_1DB00885_MESH_D003233_1DB00719_MESH_D003233_1DB00341_MESH_D003233_1DB08936_MESH_D003233_1DB00972_MESH_D003233_1DB00637_MESH_D003233_1DB00253_MESH_D003233_1DB01246_MESH_D003233_1DB00967_MESH_D003233_1DB06794_MESH_D003233_1DB00768_MESH_D003233_1DB00557_MESH_D003233_1 CHEBI:4027 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0014356 infores:hetionet CHEBI:5098 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0015967 infores:hetionet CHEBI:15367 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0702166 infores:hetionet CHEBI:8707 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0231528 infores:hetionet CHEBI:5384 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0917801 infores:hetionet CHEBI:75984 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0010200 infores:hetionet CHEBI:6950 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018681 infores:hetionet CHEBI:7824 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0235886 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0151734 infores:hetionet NCBIGene:4790 biolink:causes MONDO:0014697 infores:monarchinitiative not_provided not_provided HGNC:7794 MONDO:0014697 uuid:6412e7b2-0297-47cd-80d8-c7bb7a482110 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0031350 infores:hetionet CHEBI:51041 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0000731 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036454 infores:hetionet CHEBI:53691 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0600228 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0019158 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0277925 infores:hetionet CHEBI:8435 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0014742 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016385 infores:hetionet CHEBI:52717 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085631 infores:hetionet CHEBI:8502 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0017658 infores:hetionet CHEBI:63620 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0033774 infores:hetionet CHEBI:7025 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0677500 infores:hetionet NCBIGene:158 biolink:causes MONDO:0007068 infores:monarchinitiative not_provided not_provided HGNC:291 MONDO:0007068 uuid:3f4cd502-e473-443e-b3ec-720bf07a87eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006325 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0030305 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1145670 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042109 infores:hetionet NCBIGene:9829 biolink:causes MONDO:0014231 infores:monarchinitiative not_provided not_provided HGNC:15469 MONDO:0014231 uuid:36f3642a-b017-4354-bf6c-3ecdab51178d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235195 infores:hetionet CHEBI:15552 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0030252 infores:hetionet CHEBI:84050 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0017178 infores:hetionet CHEBI:4779 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0018799 infores:hetionet CHEBI:5004 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0041349 infores:hetionet UNII:R15UI3245N biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0020598 infores:hetionet CHEBI:82960 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0043094 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0030446 infores:hetionet CHEBI:87715 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0857305 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0029408 infores:hetionet CHEBI:32192 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0038325 infores:hetionet CHEBI:100246 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0013144 infores:hetionet CHEBI:3032 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C1443060 infores:hetionet CAID:CA399805900 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805900 MONDO:0100326 PMID:34275420 Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting PS3 The missense variant NM_000419.5(ITGA2B):c.476G>T (p.Gly159Val) has been reported in at least one patient (P2 in PMID: 34275420) with mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). The patient is homozygous for Gly159Val (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.751, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3) and is is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant c.475G>A (p.Gly159Ser) [PMID: 16359515] in the same codon has been classified Likely Pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5_supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PP4_moderate, PM2_supporting, PM3_supporting, PM5_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805900/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:29920 biolink:causes MONDO:0014632 infores:monarchinitiative not_provided not_provided HGNC:30262 MONDO:0014632 uuid:36809747-5f81-4670-be91-92371703e434 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0549249 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151838 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0015397 infores:hetionet CHEBI:50648 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009676 infores:hetionet CHEBI:94848 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C1443060 infores:hetionet CHEBI:61390 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0038363 infores:hetionet CHEBI:6897 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0005741 infores:hetionet NCBIGene:5310 biolink:causes MONDO:0008263 infores:monarchinitiative not_provided not_provided HGNC:9008 MONDO:0008263 uuid:7ba34d6e-cb58-4d6a-b30f-ed3c202ac9ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0600142 infores:hetionet GO:1903847 biolink:causes GO:0035904 infores:ubergraph knowledge_assertion manual_agent GO:1903847 GO:0035904 CHEBI:75984 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0428977 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0015376 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0027765 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0006277 infores:hetionet CHEBI:3636 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0428977 infores:hetionet CHEBI:27899 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1260880 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0233414 infores:hetionet CHEBI:8430 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0025287 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0677500 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0031350 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0037199 infores:hetionet CHEBI:28748 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0542571 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0018939 infores:hetionet CHEBI:4653 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0232726 infores:hetionet CAID:CA412731062 biolink:causes MONDO:0100437 infores:clingen CAID:CA412731062 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2260G>T (p.Glu754Ter) is a nonsense variant that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) at age 7 (1 pt), pigment deposits (0.5 pts), optic disc pallor (0.5 pts), and genotyping by next-generation sequencing with a 483-gene panel finding no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412731062/MONDO:0100437/106 2025-08-28 2025-08-28 X-linked inheritance HP:0001417 Supports PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2981158 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0032584 infores:hetionet CHEBI:480999 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0149871 infores:hetionet CHEBI:2618 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0042024 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013298 infores:hetionet CHEBI:2948 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0038325 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0029408 infores:hetionet CHEBI:3716 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0020517 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151717 infores:hetionet CHEBI:37924 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020580 infores:hetionet CHEBI:135351 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0015230 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0004936 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0022660 infores:hetionet CHEBI:63617 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020443 infores:hetionet CHEBI:5778 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0234708 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0034065 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0037274 infores:hetionet CHEBI:8776 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0004245 infores:hetionet CHEBI:63605 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1145670 infores:hetionet CAID:CA10584575 biolink:causes MONDO:0011450 infores:clingen CAID:CA10584575 MONDO:0011450 PMID: Pathogenic PP4_Moderate, PVS1_Strong, PP1_Strong PM2 The c.442-22_442-13del variant is an intronic variant occurring in intron 6 of the BRCA1 gene. This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and qPCR assays demonstrated that the variant impacts splicing by activation of a cryptic acceptor site, resulting in a 59nt intron retention of intron 6. Combination of non-allele specific assay results (PMIDs: 10323242, 32745242) and assessment of full-length transcript quantification by real-time PCR in carriers (personal communication) suggests a near complete splicing effect. Appropriate code strength determined by comparison of results to PVS1 decision tree and assessment of mRNA splicing data (PVS1_Strong (RNA) met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 48.83, within the thresholds for strong pathogenic evidence (LR >18.7 & ≤350) (PP1_Strong met; PMID: 32745242, Internal lab contributors). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 4.83 (based on Pathology LR=4.83), within the thresholds for Moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; 32745242, Internal lab contributors). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Strong (RNA), PP1_Strong, PP4_Moderate). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584575/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28864 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0034642 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0031154 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0234215 infores:hetionet CAID:CA220509 biolink:causes MONDO:0001586 infores:clingen CAID:CA220509 MONDO:0001586 PMID: Pathogenic PM4, PS3_Supporting, PP4, PM3_Very Strong, PM2_Supporting "The NM_000203.5:c.46_57del variant results in an inframe deletion of 4 amino acids (p.Ser16_Ala19del) within the lysosomal signal sequence of IDUA (PM4). This variant is named ""134del12"" in older literature. At least twelve patients with with variant and a diagnosis of mucopolysaccharidosis type 1 have been reported in the literature. This includes four patients with documented laboratory values showing deficiency of IDUA activity in fibroblasts or leukocytes (PMID: 15300847, 21394825, 23786846) one of whom also had documented clinical features consistent with the diagnosis including corneal clouding, joint stiffness, digital contractures, cardiac valve disease, airway obstruction, and developmental delay (PMID: 15300847) (PP4). Four individuals have been reported who are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including two confirmed in trans - c.1750C>T (p.Gln584Ter) (PMID: 12189649) and p.Trp402Ter (PMID: 11735025); and two phase unknown - c.208C>T (p.Gln70Ter) (PMID: 21394825) and c.386-2A>G (PMID: 11735025). In addition, at least two homozygotes have been reported PMID: 7951228, 21394825) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and c.603C>G (p.Tyr201Ter) (PMID: 21394825), c.1189+5G>A (PMID: 21394825); c.1960T>C (p.Ter654ArgextTer*62) (PMID: 21394825), c.1049A>T (p.Asn350Ile) (PMID: 12559846) and c.1598C>G (p.Pro533Arg) (PMID: 15300847). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. When expressed in COS-7 cells, the variant (labeled as ""134del12"") resulted in 124.6% of normal activity. A 77-kDa precursor protein was observed on Western blot, compared with a major mature 63-kDa form and a minor 77-kDa precursor in cells transfected with wild-type cDNA. These results suggested that the variant prevents correct posttranslational processing and transport to the lysosome (PMID: 12189649) (PS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006251 (69/1103836 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92643). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PM4, PP4, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220509/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10385722 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385722 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.154+43A>G is an intron 2 variant located 43 nucleotides from exon 2. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0008354 among hemizygous individuals, with 279 variant alleles / 333,989 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). The variant is located outside of the splice donor region (BP7). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385722/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:4814 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0029408 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151602 infores:hetionet CHEBI:135351 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0021368 infores:hetionet CHEBI:6741 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C3665386 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0022904 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0234215 infores:hetionet CHEBI:3387 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0001925 infores:hetionet CHEBI:27974 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0006145 infores:hetionet CHEBI:9599 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0003467 infores:hetionet CAID:CA389344542 biolink:causes MONDO:0011058 infores:clingen CAID:CA389344542 MONDO:0011058 PMID: Likely Pathogenic PP3, PM2_Supporting, PM5_Strong The c.260G>A variant in COCH is a missense variant predicted to cause substitution of glycine by glutamate at amino acid 87 (p.Gly87Glu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The amino acid residue is well conserved and the REVEL computational prediction analysis tool produced a score of 0.885, which is above the threshold necessary to apply PP3 (PP3). Three different missense variants, c.259G>T; p.Gly87Trp [PMID:16835921, ClinVar Variation ID: 1297642], c.260G>C; p.Gly87Ala [ClinVar Variation ID: 517362, with variant segregation in 3 affected family members per lab communication], and c.260G>T; p.Gly87Val [PMIDs:23767834, 23993205], have been classified as pathogenic or likely pathogenic for autosomal dominant, adult-onset hearing loss with vestibular symptoms (PM5_Strong). The p.Gly87Glu variant was detected via a hearing loss gene panel for a patient with a 3-generation history of progressive adult-onset hearing loss in the 5th or 6th decade with vestibular symptoms. In summary, this variant has been classified as likely pathogenic for autosomal dominant, adult-onset, nonsyndromic, sensorineural genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM5_Strong, PM2_Supporting, PP3 (ClinGen Hearing Loss VCEP specifications version 1; 3/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA389344542/MONDO:0011058/005 2025-03-12 2025-06-30 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CAID:CA115281 biolink:causes MONDO:0007064 infores:clingen CAID:CA115281 MONDO:0007064 PMID: Uncertain Significance PM5_Supporting, BS3_Supporting PP1, PP4, PM2, PM6, PM3, PS1, PS3, PS2 The NM_000022.4(ADA):c.446G>A (p.Arg149Gln) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 149 (p.Arg149Gln). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/107374 observed alleles) is 0.000003610 on gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742). However, we can not use this evidence because it has a filter warning (RF).Expressed ADA activity in Escherichia coli strain SO3834 (ADA-deleted) showed 13.0 +- 13.1% of Wild Type ADA activity, belonging to group IV (range: 4.8–28.2). These results indicate that this variant does not impact the protein function (PMID: 9758612, BS3_moderate).At least one additional missense variant was observed as LP according to SCID VCEP specifications version (PM5_supporting).Due to conflicting evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS3_Supporting, and PM5_Suppoting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA115281/MONDO:0007064/114 2024-01-16 2024-01-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7798 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0022346 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0233494 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030353 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0948089 infores:hetionet CHEBI:71415 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0018681 infores:hetionet CHEBI:49713 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0015230 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0581912 infores:hetionet GO:0060222 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0048699 CHEBI:36791 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015256 infores:hetionet CHEBI:5855 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085932 infores:hetionet CHEBI:10127 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0428977 infores:hetionet CAID:CA172208 biolink:causes MONDO:0019497 infores:clingen CAID:CA172208 MONDO:0019497 PMID:17666888PMID:16125251PMID:26043044PMID:17666888PMID:16125251PMID:26043044 Likely Pathogenic PP3, PM3_Very Strong BS1, BS3, BP7, BP5, PP2, PP4, BS2, PM5, PM4, PM1, PVS1, PM2, BA1, BP1, BP4, BP2, BP3, PS1, PS3 The NM_004004.6:c.107T>C variant in the GJB2 gene is a missense variant predicted to cause substitution of leucine by proline at amino acid 36 (p.Leu36Pro). The highest population minor allele frequency of the variant is 0.01% (2/19954) in the East Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). The REVEL computational prediction analysis tool produced a score of 0.945, which is above the threshold necessary to apply PP3. This variant has been detected in trans with a pathogenic variant in three patients with hearing loss (4 points, PM3_VeryStrong; PMID:16125251, 16467727, 29605365, 31246659, Invitae internal date (SCV002241983.2)). The variant has also been reported in five individuals with no pathogenic variant reported in trans (PMIDs:17666888, 26043044, 31581539, 31992338). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA172208/MONDO:0019497/005 2022-01-18 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63624 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0026766 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014544 infores:hetionet CHEBI:10101 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0242429 infores:hetionet CHEBI:7936 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0033774 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0035078 infores:hetionet CHEBI:3561 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C2830004 infores:hetionet CHEBI:16714 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C1260880 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0006266 infores:hetionet CHEBI:6067 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011606 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0027765 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0009763 infores:hetionet CHEBI:50275 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042029 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042075 infores:hetionet CHEBI:32293 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C1761613 infores:hetionet NCBIGene:4659 biolink:causes MONDO:0032934 infores:monarchinitiative not_provided not_provided HGNC:7618 MONDO:0032934 uuid:798e3bab-563b-4905-a557-8743d90a42f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0518015 infores:hetionet CHEBI:72564 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0149871 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001164 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003431 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151849 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0037199 infores:hetionet CHEBI:46081 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0043352 infores:hetionet CHEBI:3423 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0011168 infores:hetionet CHEBI:63635 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0023518 infores:hetionet NCBIGene:6567 biolink:causes MONDO:0010354 infores:monarchinitiative not_provided not_provided HGNC:10923 MONDO:0010354 uuid:643dfdb4-35b4-4162-aa80-d672176d7a77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018099 infores:hetionet CHEBI:45081 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0043352 infores:hetionet CHEBI:50275 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0232461 infores:hetionet CHEBI:3561 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235198 infores:hetionet CHEBI:16347 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0026826 infores:hetionet CAID:CA10014230 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014230 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS1, PS3, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.4(RUNX1):c.973C>T (p.Pro325Ser) is a missense variant which is absent from gnomAD v2, but has a highest population minor allele frequency of 0.006543% (1/15284 alleles) in the African American/African population from gnomAD v3. This variant is not published, and out of 19 carriers reported in clinical laboratories, only one was diagnosed with MDS in their 40s and is a confirmed germline carrier (PS4_supporting). The computational predictor REVEL gives a score of 0.05, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PS4_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014230/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51137 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0020538 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0042373 infores:hetionet CHEBI:39585 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0008489 infores:hetionet NCBIGene:6340 biolink:causes MONDO:0020854 infores:monarchinitiative not_provided not_provided HGNC:10602 MONDO:0020854 uuid:cfd61e7d-661f-4ede-b5bd-1904507ca49d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes UMLS:C0266648 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0266648 infores:hetionet CHEBI:9398 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0392171 infores:hetionet CHEBI:3013 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0004093 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0037199 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0015397 infores:hetionet CHEBI:5165 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020580 infores:hetionet CHEBI:47898 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013378 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006147 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0236071 infores:hetionet CHEBI:42355 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0030193 infores:hetionet CHEBI:49575 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0036974 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0002170 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011603 infores:hetionet CHEBI:4868 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0234233 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0151888 infores:hetionet CAID:CA066926 biolink:causes MONDO:0018493 infores:clingen CAID:CA066926 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, BP4 PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of cysteine with arginine at codon 1781 of the RYR1 protein, p.(Cys1781Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000018, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.298) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA066926/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8888 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020453 infores:hetionet CAID:CA010216 biolink:causes MONDO:0013699 infores:clingen CAID:CA010216 MONDO:0013699 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000535.7: c.1753C>A variant in PMS2 is a missense variant predicted to cause substitution of Leucin by Isoleucin at amino acid 585 (p. Leu585Ile). This alteration has been identified in cis with a pathogenic PMS2 mutation in an HNPCC/Lynch syndrome family and was shown to be mismatch-repair proficient in vitro (PMID: 16472587; 24027009). This alteration has been classified as a variant of unknown significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15;) The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is (3/268266 alleles) in the European (non-Finish) population, and the GnomAD v4.1 Grpmax AF is 0.000007310 which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore meets this criterion (PM2_Supporting). This missense variant meets the criteria for BP4 (Missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity <0.11).Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM2_SUP, BP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA010216/MONDO:0013699/139 2024-09-18 2025-08-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8764 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0001122 infores:hetionet CHEBI:8310 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0242528 infores:hetionet CHEBI:7627 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0024902 infores:hetionet GO:0098905 biolink:causes GO:0061337 infores:ubergraph knowledge_assertion manual_agent GO:0098905 GO:0061337 CHEBI:3504 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C2830004 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0005741 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0023895 infores:hetionet CHEBI:66903 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0017178 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0025061 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014534 infores:hetionet CHEBI:135613 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0151744 infores:hetionet CAID:CA410206745 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206745 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP3, BP2, BP1, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, PP4, PP1, PP2, PP3, BS2 NM_001754.5(RUNX1):c.762C>G (p.Asn254Lys) is a missense variant which is absent from gnomAD v2, v3, and v4 (PM2_Supporting) and has not been reported in the literature. The computational predictor REVEL gives a score of 0.484, below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, providing evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206745/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6754 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0039231 infores:hetionet CHEBI:9727 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0019158 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0235032 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0038454 infores:hetionet CHEBI:8888 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0026821 infores:hetionet CAID:CA21112664 biolink:causes MONDO:0019497 infores:clingen CAID:CA21112664 MONDO:0019497 PMID: Likely Pathogenic PP3, PM5, PM1, PM2_Supporting BS1, BS3, BS4, BP5, BP7, BS2, PP1, PP4, PP2, PM3, PM4, PM6, PVS1, BA1, BP4, BP1, BP2, BP3, PS4, PS3, PS2, PS1 The c.825G>C variant in KCNQ4 is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 275 (p.Trp275Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928, which is above the threshold of 0.7, evidence that correlates with impact to KCNQ4 function (PP3). This variant has been reported in one individual with hearing loss and segregated in an affected first degree relative (SCV000712456.1). This variant is located within the pore-forming intramembrane region (amino acids 271-292) where many variants that cause autosomal dominant hearing loss are located and is defined as a critical functional domain by the ClinGen Hearing Loss VCEP (PM1; PMID: 23717403). A different missense variant at the same codon (p.Trp275Arg) has been classified as Pathogenic by the ClinGen Hearing Loss VCEP (PM5; ClinVar Variation ID 204597, PMID: 25116015). In summary, this variant is classified as Likely Pathogenic for autosomal dominant sensorineural hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PM1, PM5. (VCEP specifications version 2; 10.18.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA21112664/MONDO:0019497/005 2023-10-18 2024-07-02 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:16469 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0424790 infores:hetionet CHEBI:68647 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0042075 infores:hetionet NCBIGene:54332 biolink:causes MONDO:0011898 infores:monarchinitiative not_provided not_provided HGNC:15968 MONDO:0011898 uuid:794149d8-81b4-4b72-991b-d815e24b3923 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011175 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0021053 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0948594 infores:hetionet CHEBI:4445 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0003811 infores:hetionet CHEBI:8871 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0028949 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002871 infores:hetionet CHEBI:5855 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0338656 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1527311 infores:hetionet CHEBI:49375 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0234632 infores:hetionet CHEBI:63638 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0040822 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0314719 infores:hetionet CHEBI:6690 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0043094 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0009450 infores:hetionet CHEBI:64312 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011071 infores:hetionet CHEBI:31980 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0042510 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151889 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0037199 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0522224 infores:hetionet CHEBI:135276 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0011603 infores:hetionet CHEBI:4562 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0014591 infores:hetionet CHEBI:63681 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0041657 infores:hetionet CHEBI:50924 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0221776 infores:hetionet NCBIGene:3097 biolink:causes MONDO:0014858 infores:monarchinitiative not_provided not_provided HGNC:4921 MONDO:0014858 uuid:c3c776db-2076-455d-9fad-7656fd2e0d81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8245 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0242429 infores:hetionet CHEBI:7822 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0018524 infores:hetionet CHEBI:7514 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0042963 infores:hetionet UMLS:C0145867 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0038999 infores:hetionet CHEBI:47781 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0034150 infores:hetionet CHEBI:48273 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0151610 infores:hetionet CHEBI:50648 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030232 infores:hetionet CHEBI:16335 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0010200 infores:hetionet CHEBI:135888 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0040460 infores:hetionet CHEBI:116278 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0011168 infores:hetionet CHEBI:44185 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013428 infores:hetionet NCBIGene:5243 biolink:causes MONDO:0975801 infores:monarchinitiative not_provided not_provided HGNC:40 MONDO:0975801 uuid:0ff038b9-1711-449c-80ae-1d0a11355533 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014522 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014522 MONDO:0011071 PMID: Likely Benign BP2, BP4, BS1, BP7 PS4, PS2, PS1, PS3, BA1, BP1, BP3, PM2, PM6, PVS1, BS4, BS3, BP5, PM3, PM4, PM5, PM1, PP4, PP1, PP2, PP3, BS2 The c.393T>C predicts a synonymous change, Thr131= variant and has an MAF of 0.001013 (0.1%, 31/30616 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.00015 (0.015%) (BS1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 population database (BP2). This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -4.47871 < 0.1) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014522/MONDO:0011071/008 2021-06-22 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true NCBITaxon:813 biolink:causes MONDO:0005808 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:813 MESH:D003235 DB00634_MESH_D003235_1DB00618_MESH_D003235_1DB00254_MESH_D003235_1DB13092_MESH_D003235_1DB00595_MESH_D003235_1DB01017_MESH_D003235_1DB00199_MESH_D003235_1DB00759_MESH_D003235_1DB01015_MESH_D003235_1 CHEBI:66964 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0042401 infores:hetionet CHEBI:5134 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0392171 infores:hetionet NCBIGene:50484 biolink:causes MONDO:0012792 infores:monarchinitiative not_provided not_provided HGNC:17296 MONDO:0012792 uuid:b17ed594-af15-4c9e-9474-718451a529df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0162429 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0162429 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0235639 infores:hetionet CHEBI:10119 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013384 infores:hetionet CHEBI:49375 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0023473 infores:hetionet CAID:CA294895841 biolink:causes MONDO:0009290 infores:clingen CAID:CA294895841 MONDO:0009290 PMID:19862843 Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000152.:c.1735G>A variant in GAA is a missense variant predicted to result in the substitution of glutamate by lysine at amino acid 579 (p.Glu579Lys). Five patients with a diagnosis of Pompe disease and the variant have been reported, three with documented laboratory values showing deficiency of GAA activity (PMID: 21676566, 23601496, 29124014, 34357340), one with reported features consistent with infantile-onset Pompe disease (PMID: 24269976), and another reported to have Pompe disease (PMID: 14695532) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, all phase unknown, including c.-32-13T>G (PMID: 34357340) (0.5 points), c.525delT (PMID: 14695532) (0.5 points), c.2237G>A (p.Trp746Ter) (PMID: 24269976) (0.5 points), and c.655G>A (p.Gly219Arg) (PMIDs: 23601496, 31086307,31193175) (0.5 points). Total 2 points (PM3_Strong). Another patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg) (PMIDs: 21676566, 29124014) The allelic data from this patient will be used in the classification of p.Ser619Arg and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/129092) in the European Non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% GAA activity in cells and <2% in medium, evidence of abnormal synthesis and processing on Western blot, and did not localize to the lysosomes (PMID: 14695532, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.878 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 495664). In summary this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the Clingen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP on December 6, 2022) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294895841/MONDO:0009290/010 2022-12-06 2022-12-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA10585297 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585297 MONDO:0007750 PMID: Uncertain Significance BS3_Supporting, BP4, PM2, PP4 BA1, PS1, PS3, PS4, BS1, BS4, PM5, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BS3_Supporting and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).BP4: REVEL=0.345, it is below 0.50, splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby:First AG -- MES score: variant cryptic site= 1.75, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 1.75/2.69=0.65 --- not above 1.1. Ratio Var cryptic/Wt canonical=1.75/13.90=0.92 --- it is above 0.9. Second AG -- MES score: variant cryptic site= -5.84, wt cryptic site= -3.45, canonical WT site=13.90.Variant not predicted to alter splicing.BS3_Supporting: Level 3 assay, PMID 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays. Result: 90-100% LDLR expression and 95-98% LDLR activity. Functional study is consistent with no damaging effect.PP4: Variant meets PM2 and is identified in 1 case with Possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585297/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31623 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0241157 infores:hetionet CHEBI:91834 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0027497 infores:hetionet CHEBI:3077 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0030486 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0013395 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0162429 infores:hetionet CHEBI:63638 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0042963 infores:hetionet CHEBI:9139 biolink:causes NCIT:C96935 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0149707 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0234215 infores:hetionet CHEBI:5855 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0030554 infores:hetionet CHEBI:7447 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0021368 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0232197 infores:hetionet CHEBI:53691 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0237849 infores:hetionet CHEBI:5130 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0024902 infores:hetionet CHEBI:4315 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C3665347 infores:hetionet CHEBI:68845 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0042373 infores:hetionet CHEBI:9448 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0030193 infores:hetionet CHEBI:8232 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0002878 infores:hetionet CAID:CA401324918 biolink:causes MONDO:0009290 infores:clingen CAID:CA401324918 MONDO:0009290 PMID: Likely Pathogenic PP3, PP4, PS3_Moderate, PM2_Supporting, PM3_Supporting PM5 The NM_000152.5:c.2314T>C variant in GAA is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 772 (p.Trp772Arg). This variant has been detected in at least 1 individual with Pompe disease that was compound heterozygous for the variant and a pathogenic variant (PMID: 31619483, 18757064) (PM3_Supporting). At least 1 patient with this variant had documented GAA deficiency in leukocytes or fibroblasts was noted to have deficient GAA activity but results were not provided and was reported to be eligible for enzyme replacement therapy for Pompe disease (PMID: 31619483, 18757064) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS cells resulted in 5% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.93 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 552527; 1 star review status) with 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PS3_Moderate, PM2_Supporting, PP3, PP4, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401324918/MONDO:0009290/010 2022-09-19 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UMLS:C1738934 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042571 infores:hetionet CAID:CA267660 biolink:causes MONDO:0009861 infores:clingen CAID:CA267660 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.568G>A (p.Val190Met) variant in PAH has not been reported in the literature to our knowledge. The reference from BioPKU (Namour B, Jeannesson E, Chery C, Gueant JL, Feillet F, 2013) cannot be located. This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.836. Another variant at this amino acid (p.V190G) is interpreted as pathogenic by the PAH VCEP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267660/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3223 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0028084 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151888 infores:hetionet CAID:CA1706954 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706954 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PVS1, PP1, PP4 PM2 The NM_003494.4: c.4228C>T p.(Gln1410Ter) variant in DYSF, which is also known as NM_001130987.2: c.4282C>T (p.Gln1428Ter), is a nonsense variant predicted to introduce a premature stop codon in exon 39/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been observed in four individuals with features of LGMD from two families (PMID: 35047756, 34624274). In a consanguineous family from Jordan, it was identified in a homozygous state in two affected siblings (PMID: 35047756; PP1). In the affected child of one of the homozygous individuals, it was also identified in unconfirmed phase with a pathogenic variant (NM_003494.4: c.4022T>C p.(Leu1341Pro), 0.5 pts; PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF allele displayed progressive proximal muscle weakness or had a clinical diagnosis of LGMD (PMID: 35047756, 34624274; PP4). The filtering allele frequency for this variant is 0.0001752 in gnomAD v4.1.0 (the upper bound of the 95% confidence interval of 5/60012 Admixed American alleles), which is higher than the VCEP threshold of 0.0001 for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/30/2025): PVS1, PP1, PM3_Supporting, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706954/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030554 infores:hetionet CHEBI:6909 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1096250 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018418 infores:hetionet CHEBI:41423 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0008350 infores:hetionet CHEBI:9566 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0018790 infores:hetionet CHEBI:3215 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0017178 infores:hetionet CHEBI:2950 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0009676 infores:hetionet GO:0044479 biolink:causes GO:0002279 infores:ubergraph knowledge_assertion manual_agent GO:0044479 GO:0002279 CHEBI:31980 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0019080 infores:hetionet CHEBI:51860 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0026603 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0009450 infores:hetionet CHEBI:31623 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0152227 infores:hetionet CAID:CA16020976 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020976 MONDO:0009861 PMID:21154324 Uncertain Significance PM5, PM2, PP3 PP4 The c.1237C>G (p.Arg413Gly) variant in PAH has been reported in the literature according to BioPKU in PMID: 21154324 (Wang et al., 2010), however article is written in Chinese, and there is no access to the full translated article. This variant is absent from population databases (PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.958 (PP3). This variant is at same codon as c.1237C>A (p.R413S) curated as Pathogenic by ClinGen PAH VCEP (ClinVarID:102575) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020976/MONDO:0009861/006 2020-07-23 2020-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3499 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0015967 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0005741 infores:hetionet CHEBI:5118 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036830 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0521161 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0521161 infores:hetionet CAID:CA010125 biolink:causes MONDO:0004994 infores:clingen CAID:CA010125 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1062C>T (p.Gly354=) variant in the MYH7 gene is 9.56% (1644/16510) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010125/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17263 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0011603 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0085605 infores:hetionet CHEBI:10102 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0037036 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0877094 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0877094 infores:hetionet CHEBI:4470 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0011991 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027051 infores:hetionet CAID:CA10014273 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014273 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.899C>T (p.Thr300Met) is a missense variant which has a REVEL score < 0.50 (0.423) and a SpliceAI score of 0 (BP4). This variant has been observed in gnomAD v2.1 at a MAF of 0.00005274 (0.005274%, 6/113766) in the European (non-Finnish) sub-population, but does not meet any population criteria. It has not been reported in individuals with a RUNX1-defined phenotype. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014273/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31705 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C2830004 infores:hetionet CAID:CA398323326 biolink:causes MONDO:0011132 infores:clingen CAID:CA398323326 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PM1, PP3_Moderate, PM3_Supporting The NM_001369369.1:c.814C>A variant in FOXN1 is a missense variant predicted to cause substitution of proline by threonine at amino acid 74 (p.Pro272Thr). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant was observed in one patient who was homozygous for this variant (PMID 35064468) (PM3_Supporting). The patient presented with alopecia universalis, nail dystrophy, and T-B-NK+ lymphocyte counts (CD3+, 489 cells/μL; CD4+, 295 cells/μL; CD8+, 164 cells/μL; CD19+, 373 cells/μL; CD16+56+, 3978 cells/μL). No other variant of interest was reported from a PID gene panel of 407 genes (PP4). The variant resides within the DNA binding forkhead domain (amino acids 270-367) that is defined as a critical functional domain of FOXN1 with low tolerance for benign variation (PM1_Moderate). The REVEL score for this variant is 0.939, also supporting a deleterious effect on the protein function (PP3_Moderate). In summary, this variant is classified as a likely pathogenic variant for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Supporting, PP4, PM1, PP3_Moderate. (VCEP specifications version 1.0.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398323326/MONDO:0011132/113 2025-04-25 2025-04-25 Semidominant inheritance HP:0032113 Supports NCBIGene:8216 biolink:causes MONDO:0011531 infores:monarchinitiative not_provided not_provided HGNC:6742 MONDO:0011531 uuid:edcbe51a-6c7b-4db6-a946-f15433eb96e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0687713 infores:hetionet NCBIGene:5095 biolink:causes MONDO:0011628 infores:monarchinitiative not_provided not_provided HGNC:8653 MONDO:0011628 uuid:eaabec54-1ee7-481a-ba23-9af320c47ceb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1306341 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0236068 infores:hetionet CHEBI:135791 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0011616 infores:hetionet CHEBI:6128 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0027540 infores:hetionet CHEBI:135736 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016242 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042514 infores:hetionet CHEBI:5062 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0004093 infores:hetionet CHEBI:78543 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0017168 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1384666 infores:hetionet CHEBI:92511 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0851578 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0497365 infores:hetionet CHEBI:64028 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0011570 infores:hetionet CHEBI:3207 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013491 infores:hetionet CHEBI:10119 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022354 infores:hetionet CHEBI:39867 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013378 infores:hetionet CHEBI:82941 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0687713 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0234215 infores:hetionet CHEBI:63635 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0017181 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0027765 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0037274 infores:hetionet CHEBI:478164 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0040034 infores:hetionet CHEBI:5383 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0041834 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0232124 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0232124 infores:hetionet CHEBI:18248 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C2047937 infores:hetionet CHEBI:80630 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0547030 infores:hetionet CHEBI:8207 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042024 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0018801 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0036572 infores:hetionet CHEBI:127780 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C1457883 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0032584 infores:hetionet CHEBI:64355 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232602 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0036572 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0917799 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0234458 infores:hetionet CHEBI:46557 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0009782 infores:hetionet GO:0044468 biolink:causes GO:0042060 infores:ubergraph knowledge_assertion manual_agent GO:0044468 GO:0042060 CHEBI:6904 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0042514 infores:hetionet CHEBI:6775 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042963 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0152021 infores:hetionet CAID:CA10014517 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014517 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.433A>C (p.Arg145=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.44)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014517/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4708 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1167965 infores:hetionet CHEBI:3757 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0264893 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0032584 infores:hetionet CHEBI:188986 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0231218 infores:hetionet CHEBI:8665 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0035232 infores:hetionet CAID:CA386960156 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960156 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PS1, PM5, PP1 The c.450G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to asparagine at codon 150 (p.(Lys150Asn)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additonally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.883, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 16917892, 22432108)). In one of these families, this variant segregated with diabetes with two informative meioses; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 22432108). Another missense variant at this residue, p.(Lys150Glu) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Additionally, another nucleotide change at this location resulting in the same amino acid change, c.450G>C p.(Lys150Asn), has been classified as a VUS by the ClinGen MDEP; therefore, PS1 will not be applied. In summary, c.450G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960156/MONDO:0015967/017 2024-10-13 2024-10-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:59445 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0011603 infores:hetionet CHEBI:4995 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0035410 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020517 infores:hetionet CHEBI:135276 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0042571 infores:hetionet CHEBI:77260 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0003862 infores:hetionet CHEBI:6339 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1384353 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0042075 infores:hetionet NCBIGene:27077 biolink:causes MONDO:0014927 infores:monarchinitiative not_provided not_provided HGNC:24123 MONDO:0014927 uuid:c73c4e4a-3420-4d6e-9b83-52d038e01363 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0423153 infores:hetionet CHEBI:64064 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0013390 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0748538 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0748538 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0037199 infores:hetionet CHEBI:478164 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0020598 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0151828 infores:hetionet CHEBI:3077 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151686 infores:hetionet CHEBI:5384 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0003467 infores:hetionet CHEBI:64019 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0042963 infores:hetionet CHEBI:6078 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0497201 infores:hetionet CHEBI:499361 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0231528 infores:hetionet CHEBI:41977 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0010200 infores:hetionet CAID:CA226367 biolink:causes MONDO:0100437 infores:clingen CAID:CA226367 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1512_1513del (p.Ile505HisfsTer7) is a 2-bp deletion variant in exon 13 of 15, which results in a frameshift and premature stop codon after 7 amino acids and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family. (PP1_Moderate; PMID: 9488274). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), childhood-onset (1 pt), mild myopia, pale optic discs (0.5 pts), visual field constriction (0.5 pts), and reduced visual acuity (0.5 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 9488274, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1_Moderate, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226367/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Supports CHEBI:168396 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0392025 infores:hetionet CHEBI:72564 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085669 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040485 infores:hetionet NCBITaxon:5206 biolink:causes MONDO:0005724 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5206 MESH:D003453 DB00681_MESH_D003453_1 UNII:2N4O9L084N biolink:causes MONDO:0006527 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0003028 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0153676 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0153676 infores:hetionet CHEBI:41423 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0600142 infores:hetionet CAID:CA410202761 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202761 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, BP4, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP4, PP2, PP1, BS2 NM_001754.5(RUNX1):c.368A>G (p.Asp123Gly) is a missense variant which is completely absent from gnomAD 2.1.1 with at least 20x coverage for RUNX1 (PM2_supporting). This variant is located within the Runt Homology domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). Additionally, this variant has a REVEL score of 0.92, which is above the 0.88 threshold (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202761/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5613 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0006266 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0079043 infores:hetionet CHEBI:5147 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0034359 infores:hetionet CHEBI:94501 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0042024 infores:hetionet CHEBI:7936 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015371 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0011849 infores:hetionet CHEBI:65173 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0020621 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0497247 infores:hetionet CHEBI:92712 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0002792 infores:hetionet CHEBI:17347 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0028734 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0242656 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0553713 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0031085 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0003864 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0178298 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1322281 infores:hetionet CHEBI:9168 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042024 infores:hetionet CHEBI:6706 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0040822 infores:hetionet CHEBI:100241 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0947912 infores:hetionet CHEBI:119573 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0232602 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096035 infores:hetionet CHEBI:100241 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003126 infores:hetionet CHEBI:4953 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0020443 infores:hetionet CHEBI:7865 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C1258215 infores:hetionet CHEBI:10101 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085932 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0836924 infores:hetionet CHEBI:83804 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0030193 infores:hetionet CAID:CA391351072 biolink:causes MONDO:0007113 infores:clingen CAID:CA391351072 MONDO:0007113 PMID: Likely Pathogenic PP3, PM2_Supporting, PS2 BP4, PS4 The c.2444G>A (p.Gly815Glu) variant in UBE3A has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with clinical features of Angelman syndrome (PS2; GeneDx: internal data). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.705, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3). In summary, the p.Gly815Glu variant in UBE3A is classified as Likely Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS2, PP3, PM2_supporting) (UBE3A specifications version 5.0; 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA391351072/MONDO:0007113/037 2025-02-28 2025-03-27 Autosomal dominant inheritance HP:0000006 Supports CAID:CA314836 biolink:causes MONDO:0012999 infores:clingen CAID:CA314836 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_000156.6:c.707G>C (p.Gly236Ala) variant in GAMT is a missense variant predicted to cause substitution of glycine by alanine at amino acid 236 (p.Gly236Ala). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001679 (198/1179492 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.323 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function. SpliceAI predicts that the variant has no impact on splicing. To our knowledge, this variant has not been reported in the published literature. This variant is noted in ClinVar (ID 205596). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314836/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4798 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0700361 infores:hetionet CHEBI:7465 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0344232 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0021400 infores:hetionet CHEBI:63598 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020461 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019360 infores:hetionet CHEBI:9907 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0231218 infores:hetionet CHEBI:135939 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0520966 infores:hetionet CAID:CA386965917 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965917 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PVS1, PP4_Moderate The c.748C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 250 (p.(Gln250Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate, internal lab contributors). Lastly, this variant was identified in unrelated individuals from four different families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 1244228, internal lab contributors). In summary, c.748C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PM2_Supporting, PP4_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965917/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31932 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0035455 infores:hetionet CHEBI:6129 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0232461 infores:hetionet CHEBI:71940 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0014591 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0687707 infores:hetionet CHEBI:171719 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0039070 infores:hetionet CHEBI:9763 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085636 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0027769 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0004623 infores:hetionet CHEBI:45367 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0002871 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005192 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235974 infores:hetionet CHEBI:76010 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0033771 infores:hetionet CHEBI:6067 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003862 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0028961 infores:hetionet CHEBI:3207 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0015967 infores:hetionet CAID:CA024311 biolink:causes MONDO:0007783 infores:clingen CAID:CA024311 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM5, PS4, PP1_Strong, PP3_Moderate, BS2_Supporting PM1, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Cysteine at codon 614 of the RYR1 protein, p.(Arg614Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00019, a frequency consistent with pathogenicity for MHS. This variant has been reported in over 100 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 100 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:24433488, PMID:16163667, PMID:30236257, and others). This variant has been identified in an individual with negative IVCT/CHCT results, BS2_Moderate (PMID:10484775). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg614Leu), PM5 (PMID:16917943). p.(Arg614Cys) segregates with MHS in 38 individuals PP1_Strong, (PMID:25960145, PMID:7586638, PMID:11493496 and others). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Criteria implemented: PS3_Moderate, PS4, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024311/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6067 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004093 infores:hetionet CHEBI:10023 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0041657 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0518015 infores:hetionet NCBIGene:26115 biolink:causes MONDO:0030051 infores:monarchinitiative not_provided not_provided HGNC:30212 MONDO:0030051 uuid:d1f9a9b3-ad94-4acf-b802-eef5e028f627 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2453 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0011206 infores:hetionet CHEBI:63612 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0008031 infores:hetionet CHEBI:6532 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0027765 infores:hetionet CAID:CA512318973 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318973 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.135C>T (p.Thr45=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318973/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9137 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235876 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014549 infores:hetionet CHEBI:50777 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0009782 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235431 infores:hetionet CHEBI:114785 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0041834 infores:hetionet CHEBI:60761 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C1443060 infores:hetionet CHEBI:31302 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0022107 infores:hetionet CHEBI:2611 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085633 infores:hetionet CHEBI:7476 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0025323 infores:hetionet NCBIGene:220296 biolink:causes MONDO:0013490 infores:monarchinitiative not_provided not_provided HGNC:26361 MONDO:0013490 uuid:00b3d0f0-3237-4a18-80b5-585e2d3903b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C1443060 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0085607 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0085607 infores:hetionet CHEBI:51173 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0086565 infores:hetionet CHEBI:6761 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C1368065 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0233472 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0162287 infores:hetionet CHEBI:31624 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0004093 infores:hetionet CHEBI:68579 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0038325 infores:hetionet CHEBI:8024 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013456 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0948595 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0267596 infores:hetionet NCBIGene:255928 biolink:causes MONDO:0013645 infores:monarchinitiative not_provided not_provided HGNC:23143 MONDO:0013645 uuid:b39cffb0-0b8d-4f42-991f-49a3575c7ce7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018681 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027051 infores:hetionet CHEBI:32139 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0039070 infores:hetionet CHEBI:5855 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0043144 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0948692 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0234215 infores:hetionet CHEBI:31980 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0023530 infores:hetionet CHEBI:8327 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0020456 infores:hetionet CAID:CA10014371 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014371 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.706A>G (p.Met236Val) is a missense variant that occurs at AA position 236 in RUNX1 (outside the conserved runt-homology domain, AA 89-204), producing a p.Met236Val protein change. There are no other reported pathogenic variants at this same site, or with this same protein product. The other single-nucleotide variant at this position (p.M236I) is predicted as a variant of uncertain significance. In silico prediction does not suggest a damaging protein effect, with a REVEL score of 0.558 (less than 0.88). There is no evidence of splicing alteration. This variant is present at low MAF in non-Finnish populations in gnomAD v3 (maximum MAF 0.00006587 %). In summary, the clinical significance of this variant is uncertain. No ACMG/AMP criteria could be applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014371/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:32293 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0015376 infores:hetionet CHEBI:63632 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0151905 infores:hetionet CHEBI:17688 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0011603 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0032285 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0403632 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0030305 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0857027 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0857027 infores:hetionet CHEBI:7820 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0004509 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0853034 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C1527344 infores:hetionet NCBIGene:11117 biolink:causes MONDO:0859300 infores:monarchinitiative not_provided not_provided HGNC:19880 MONDO:0859300 uuid:96d0e69a-e0c9-48be-9cbe-510e24a5070d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1096274 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0006277 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0280100 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0280100 infores:hetionet GO:1902427 biolink:causes GO:0006833 infores:ubergraph knowledge_assertion manual_agent GO:1902427 GO:0006833 CHEBI:31236 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015732 infores:hetionet GO:0030997 biolink:causes GO:0000226 infores:ubergraph knowledge_assertion manual_agent GO:0030997 GO:0000226 CHEBI:5801 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0234632 infores:hetionet CHEBI:17026 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0019080 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042514 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151547 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853777 infores:hetionet CHEBI:3215 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0231530 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0014868 infores:hetionet NCBIGene:977 biolink:causes MONDO:0012190 infores:monarchinitiative not_provided not_provided HGNC:1630 MONDO:0012190 uuid:aa2174bc-bbd8-468c-98cd-e56c430ca6f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0162429 infores:hetionet CAID:CA157963 biolink:causes MONDO:0007648 infores:clingen CAID:CA157963 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The c.2329G>A (p.Asp777Asn) missense variant has a frequency of 0.0001202 (34 of 282,830) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.0002400 (31 of 129,162) in the non-Finnish European subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149760.14, SCV000261509.8, PMIDs: 29522266, 26534844, 26976419, 25142776, 24728327). In summary, the clinical significance of this variant is classified as Likely Benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157963/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:17688 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0085932 infores:hetionet CHEBI:3423 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C2830004 infores:hetionet CHEBI:5001 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042345 infores:hetionet CHEBI:6887 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151636 infores:hetionet CHEBI:3764 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0000729 infores:hetionet CHEBI:6076 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0009782 infores:hetionet CAID:CA2017997779 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997779 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1368del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 457 (NM_000545.6), adding 157 novel amino acids before encountering a stop codon (p.(Cys457Valfs157)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, c.1368del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997779/MONDO:0015967/086 2023-06-19 2023-06-19 Semidominant inheritance HP:0032113 Supports CHEBI:6954 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0042963 infores:hetionet CHEBI:5165 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0018681 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0227791 infores:hetionet CHEBI:9943 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085631 infores:hetionet CHEBI:2788 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0917801 infores:hetionet CHEBI:408174 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004093 infores:hetionet CHEBI:92923 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0231528 infores:hetionet CAID:CA340939 biolink:causes MONDO:0044970 infores:clingen CAID:CA340939 MONDO:0044970 PMID:7763260PMID:10976107 Pathogenic PP3, PS4, PP1_Moderate, PS3_Supporting PS2, PM5, PM6, PM2 The m.11778G>A (p.R340H) variant in MT-ND4 has been reported in >16 unrelated individuals with primary mitochondrial disease. While this variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353), affected individuals can also have other features. Indeed, affected individuals have been reported with features including LHON, Leigh syndrome, cerebellar ataxia, migraines, regression, leukoencephalopathy, myoclonus, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, and ophthalmoplegia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 3201231, 2575667, 2566021, 2390098, 1635296, 17724295, 18848389, 25917160, 18216301, 17254817, 8902729, 27119776). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 27119776, 2390098). There are no confirmed de novo occurrences of this variant to our knowledge. This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10976107, 7763260). This variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4, PP1_moderate, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340939/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria GO:1900217 biolink:causes GO:0072234 infores:ubergraph knowledge_assertion manual_agent GO:1900217 GO:0072234 CHEBI:51364 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020517 infores:hetionet CHEBI:64312 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0023380 infores:hetionet CHEBI:3219 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026821 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0242656 infores:hetionet CHEBI:94501 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0017181 infores:hetionet CHEBI:3228 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0004134 infores:hetionet CHEBI:8430 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0233407 infores:hetionet CHEBI:64310 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0206062 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0041657 infores:hetionet GO:0032071 biolink:causes GO:0006259 infores:ubergraph knowledge_assertion manual_agent GO:0032071 GO:0006259 CHEBI:7824 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0019158 infores:hetionet CHEBI:53760 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0026821 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0017160 infores:hetionet CHEBI:8888 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0036974 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042401 infores:hetionet NCBIGene:4644 biolink:causes MONDO:0008962 infores:monarchinitiative not_provided not_provided HGNC:7602 MONDO:0008962 uuid:19d1233f-2c59-4544-affa-d1b4992d3cfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72297 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0858635 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004096 infores:hetionet CHEBI:15640 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0151746 infores:hetionet CHEBI:9130 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0042510 infores:hetionet CHEBI:51230 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0019572 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0856053 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0856053 infores:hetionet GO:0061078 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0061078 GO:0006955 CHEBI:24564 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0235031 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0012833 infores:hetionet GO:0010975 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:0010975 GO:0030182 CHEBI:63631 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042963 infores:hetionet NCBIGene:1311 biolink:causes MONDO:0030883 infores:monarchinitiative not_provided not_provided HGNC:2227 MONDO:0030883 uuid:979659e8-4806-4879-8732-9083e5efe957 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0042075 infores:hetionet UNII:R43D2573WO biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0028961 infores:hetionet CAID:CA410202690 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202690 MONDO:0011071 PMID: Likely Pathogenic PM5, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.401C>T (p.Ala134Val) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is a missense change at the same residue (p.Ala134) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468) based on MM-VCEP rules for RUNX1, and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5). This missense variant has a REVEL score ≥ 0.88 (0.949) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202690/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:194135 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004245 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0242350 infores:hetionet CHEBI:135005 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0080274 infores:hetionet CHEBI:75722 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020443 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0034150 infores:hetionet NCBIGene:164045 biolink:causes MONDO:0014322 infores:monarchinitiative not_provided not_provided HGNC:20193 MONDO:0014322 uuid:3de54689-590d-401f-988a-9ea3693b4bba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0038362 infores:hetionet CHEBI:36791 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007820 infores:hetionet UMLS:C0657912 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085631 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0009450 infores:hetionet CHEBI:8364 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0040264 infores:hetionet CHEBI:10650 biolink:causes HP:0003750 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0242979 infores:hetionet CAID:CA8815133 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815133 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP4, PM3 The NM_000152.5(GAA):c.1048G>A variant in GAA is a missense variant predicted to cause substitution of valine by methionine at amino acid 350 (p.Val350Met). This variant has been detected in at least 12 individuals, and at least 11 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (Clinical Laboratory data, PMIDs: 25451853, 36310651, 36246652). However, due to the absence of clinical symptoms supporting a diagnosis of Pompe disease, PP4 was not applied. Of those individuals, 1 was homozygous for the variant, and 11 were compound heterozygous for the variant and another variant in GAA including c.-32-13T>G (ClinVar Variation ID: 4027, pathogenic based on classification by the ClinGen LD VCEP, 9 patients, Clinical laboratory data, PMID:25451853, 1 patient confirmed in trans), c.2051C>T (p.Pro684Leu) (1 patient, PMID:36310651, phase unknown), c.1589del (p.Glu530GlyfsTer48) (1 patient, PMID: 36246652, phase unknown), and c.2238G>C (p.Trp746Cys) (2 patients, one confirmed in trans and one with a pseudodeficiency allele, Clinical Laboratory data). The allelic data from these patients was not included at this time due to the caveats noted for PP4 (PM3_not met). When expressed in HEK293 cells, GAA enzyme activity was 1.5% of the positive control, and Western blot revealed a faint precursor (110 k Da) and mature (76 kDa) protein bands with lower intensity compared to the positive control, indicating this variant may be impacting GAA protein stability and processing ( PMID: 36246652) (PS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008305 (90/1180054 alleles) in the European non-Finnish population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.878 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 555998). In summary, while individuals with this variant have been reported with deficient GAA activity, and the variant has been found in compound heterozygosity with pathogenic and likely pathogenic variants in GAA, the Lysosomal Diseases VCEP concluded that there is insufficient phenotypic evidence to indicate that this variant causes Pompe disease at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PS3_Supporting, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 5, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815133/MONDO:0009290/010 2025-08-05 2025-08-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3219 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011615 infores:hetionet CAID:CA2580616986 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580616986 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting PP4 NM_001034853.2(RPGR):c.2270_2271del (p.Glu757GlyfsTer12) is a frameshift variant due to a 2-nucleotide deletion that introduces a premature stop codon after 12 amino acids within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 18552978, PMID: 38586746, PMID: 17325176, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including first/second-decade onset (1 pt), diagnosis of cone or cone-rod dystrophy (1 pt), decreased central visual acuity (0.5 pts), and visual field constriction (0.5 pts), however, the 3 total points were below the required 4 points for the PP4 code. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616986/MONDO:0100437/106 2025-08-28 2025-08-28 X-linked inheritance HP:0001417 Supports CHEBI:50861 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0085649 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1956346 infores:hetionet CHEBI:6965 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0021177 infores:hetionet CHEBI:4046 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0085605 infores:hetionet CHEBI:5118 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C3665386 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042384 infores:hetionet CHEBI:127780 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020598 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042571 infores:hetionet CHEBI:2704 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0015672 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011570 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020517 infores:hetionet CAID:CA226338 biolink:causes MONDO:0100437 infores:clingen CAID:CA226338 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.1033A>G (p.Asn345Asp) is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 345. This variant is present in gnomAD v4.1.0 at a frequency of 0.009588 among hemizygous individuals, with 3,751 variant alleles / 391,205 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.241, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226338/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:63925 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0085636 infores:hetionet CHEBI:3441 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0231218 infores:hetionet CAID:CA409106789 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106789 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4, PP1 The c.601C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of histidine to tyrosine at codon 201 (p.(His201Tyr)) of NM_175914.5. This variant is located within the ligand binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.899, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 19929997). The variant segregated with diabetes, with one informative meiosis in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 19929997). In summary, c.601C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106789/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C1738934 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011603 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0948594 infores:hetionet CHEBI:3048 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0026961 infores:hetionet NCBITaxon:10358 biolink:causes MONDO:0005132 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10358 MESH:D003586 DB01610_MESH_D003586_1 CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0042510 infores:hetionet NCBIGene:123263 biolink:causes MONDO:0013987 infores:monarchinitiative not_provided not_provided HGNC:29666 MONDO:0013987 uuid:de869eb4-2007-42ec-be96-7da882c87b1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127342 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0162429 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0037290 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0042109 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0233494 infores:hetionet CHEBI:83531 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0015230 infores:hetionet CHEBI:64354 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0037763 infores:hetionet CHEBI:9649 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020458 infores:hetionet GO:0044794 biolink:causes GO:0016032 infores:ubergraph knowledge_assertion manual_agent GO:0044794 GO:0016032 CHEBI:64310 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0024312 infores:hetionet CHEBI:46195 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0009782 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0853149 infores:hetionet CHEBI:66876 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0043352 infores:hetionet CHEBI:10127 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0027849 infores:hetionet NCBIGene:3162 biolink:causes MONDO:0013536 infores:monarchinitiative not_provided not_provided HGNC:5013 MONDO:0013536 uuid:731dbfe1-be02-462c-a6f4-4fd0074372cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50841 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0234518 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0042373 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1112371 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1112371 infores:hetionet CHEBI:9635 biolink:causes MONDO:0004701 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0156369 infores:hetionet CHEBI:31859 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C1306341 infores:hetionet CHEBI:5855 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0547030 infores:hetionet CHEBI:134966 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0497156 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0178298 infores:hetionet NCBIGene:5159 biolink:causes MONDO:0009227 infores:monarchinitiative not_provided not_provided HGNC:8804 MONDO:0009227 uuid:69926560-c19e-440d-a3f0-8d47d6bd6ed0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0016167 infores:hetionet CHEBI:17026 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0019572 infores:hetionet CHEBI:92923 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0162830 infores:hetionet CHEBI:85161 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0268000 infores:hetionet CHEBI:31413 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0038325 infores:hetionet CHEBI:3127 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0022408 infores:hetionet CHEBI:6375 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0032617 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0853149 infores:hetionet CHEBI:7852 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0687713 infores:hetionet CHEBI:63620 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0917801 infores:hetionet NCBIGene:91875 biolink:causes MONDO:0030999 infores:monarchinitiative not_provided not_provided HGNC:19274 MONDO:0030999 uuid:28aa49ea-775b-4066-9ff7-a753305d7369 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0041657 infores:hetionet CHEBI:4877 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0031117 infores:hetionet NCBIGene:6326 biolink:causes MONDO:0013388 infores:monarchinitiative not_provided not_provided HGNC:10588 MONDO:0013388 uuid:d1c47124-748f-4d4b-8f1c-67ccf2792a75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0687707 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0024437 infores:hetionet CHEBI:3568 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0750876 infores:hetionet CAID:CA512318611 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318611 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.717C>T (p.Ser239=) is a synonymous variant therefore no REVEL score and SpliceAI score donor gain 0.52 which is ≥0.38 (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318611/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5120 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0011124 infores:hetionet CHEBI:107736 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C1145670 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0236171 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0236171 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0392025 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0022116 infores:hetionet CHEBI:7822 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0023380 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0424000 infores:hetionet CHEBI:3508 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0022346 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0017675 infores:hetionet CAID:CA229643 biolink:causes MONDO:0009861 infores:clingen CAID:CA229643 MONDO:0009861 PMID:9521426PMID:16198137PMID:9521426PMID:16198137 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PM5, PP3 The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229643/MONDO:0009861/006 2019-11-10 2020-01-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0000786 infores:hetionet CHEBI:6822 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0220981 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0009946 infores:hetionet CHEBI:2955 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020458 infores:hetionet CAID:CA314580 biolink:causes MONDO:0100040 infores:clingen CAID:CA314580 MONDO:0100040 PMID: Benign BP5, BS2, BP4, BA1 The allele frequency of the p.Ala115Val variant in FOXG1 is 0.061% in South Asian sub population in gnomAD v2, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Computational analysis prediction tools suggest that the p.Ala115Val variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala115Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Ala115Val variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Ala115Val variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP4, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314580/MONDO:0100040/035 2024-02-23 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:367163 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0547030 infores:hetionet CHEBI:39112 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0008031 infores:hetionet CAID:CA210084 biolink:causes MONDO:0015152 infores:clingen CAID:CA210084 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3_Supporting, PM5_Supporting, PM2_Supporting, PP3, PP1 The NM_000023.4: c.100C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 34 (p.Arg34Cys). This variant has been reported in at least three patients with symptoms of limb girdle muscular dystrophy (PMID: 7663524, 21031578; Washington University internal clinic data communication), including in a homozygous state in one patient from a consanguineous family (0.25 pts) and confirmed in trans with a SGCA variant not yet curated by the VCEP and considered VUS (0.25 pts) (PM3_Supporting). At least one patient with this variant displayed progressive muscle weakness and significantly reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 7663524, 21031578, Washington University internal clinic data communication). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 7663524). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113724 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant at the same codon, c.101G>A (p.Arg34His), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Supporting, PP4_Strong, PM5_Supporting, PP3, PM2_Supporting, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA210084/MONDO:0015152/189 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8707 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151474 infores:hetionet CHEBI:15428 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0009421 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042109 infores:hetionet NCBIGene:4035 biolink:causes MONDO:0018855 infores:monarchinitiative not_provided not_provided HGNC:6692 MONDO:0018855 uuid:6b4618ef-061a-4e6d-a7fe-880f6e1e0f61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA312247 biolink:causes MONDO:0008723 infores:clingen CAID:CA312247 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4, PM3_Supporting PM5, PM1, PS1, PS3 The c.260T>C variant in ACADVL has been reported in one individual with very long chain acyl-CoA dehydrogenase deficiency in the literature with reduced VLCAD activity (PP4; PMID: 30194637). In this same proband, the variant was detected one time not confirmed in-trans with the pathogenic variant c.848T>C (PM3_supporting; PMID: 30194637). The highest population minor allele frequency in gnomAD is 0.000003977 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.76, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant currently has uncertain pathogenic significance for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4; PM3_supporting; PM2_Supporting; PP3. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312247/MONDO:0008723/021 2022-09-23 2022-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:474053 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0023895 infores:hetionet CHEBI:45783 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0023380 infores:hetionet CHEBI:10023 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0026961 infores:hetionet CHEBI:9943 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C3203358 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0948586 infores:hetionet CHEBI:8707 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0520966 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020517 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0037199 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022081 infores:hetionet CHEBI:2453 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0004134 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0853761 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0178298 infores:hetionet CHEBI:3508 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0031542 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0035455 infores:hetionet CHEBI:5959 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0740394 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0345904 infores:hetionet UMLS:C0017797 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0018681 infores:hetionet CHEBI:180905 biolink:causes MONDO:0000469 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0428908 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0037274 infores:hetionet CHEBI:5383 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0002878 infores:hetionet CHEBI:79699 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151692 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0042373 infores:hetionet CHEBI:71940 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020580 infores:hetionet CAID:CA412371862 biolink:causes MONDO:0010725 infores:clingen CAID:CA412371862 MONDO:0010725 PMID:18690710 Likely Pathogenic PS4_Supporting, PM2_Supporting, PS3_Supporting, PM5, PP3, PP4 NM_000330.4(RS1):c.421C>A (p.Arg141Ser) is a missense variant encoding the substitution of arginine with serine at amino acid 141. Another missense variant in the same codon, NM_000330.4(RS1):c.422G>A (p.Arg141His), (PMID: 29851975, PMID: 34645606, PMID: 30450322, PMID: 29739629, PMID: 35984651, PMID: 30652005, PMID: 19093009, PMID: 30630865, PMID: 30040949, PMID: 17525175, PMID: 30630865, PMID: 30040949) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (110) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype of the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 29851975, PP4). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 34645606, PS4_Supporting). The computational predictor REVEL gives a score of 0.765, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.02 for acceptor loss, which is below the ClinGen X linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. Carbohydrate-agarose affinity chromatography assays of wild-type and variant RS1 secreted from Weri-Rb1 cells showed reduced binding to galactose-agarose by RS1 harboring the variant relative to the wild-type control (PS3_Supporting, PMID: 18690710). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3, PS3_Supporting, PP4, PS4_Supporting, and PM5. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412371862/MONDO:0010725/126 2025-09-22 2025-09-22 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:2950 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0013404 infores:hetionet CHEBI:8707 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0039070 infores:hetionet CHEBI:82960 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027497 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1384666 infores:hetionet CHEBI:10102 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017565 infores:hetionet CHEBI:9727 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0000737 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0013922 infores:hetionet CHEBI:27899 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0002792 infores:hetionet CHEBI:47898 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0003467 infores:hetionet GO:0035990 biolink:causes CL:0000388 infores:ubergraph knowledge_assertion manual_agent GO:0035990 CL:0000388 CHEBI:91541 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0233763 infores:hetionet NCBITaxon:6318 biolink:causes MONDO:0005995 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6318 MONDO:0005995 CHEBI:17347 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0152169 infores:hetionet CHEBI:15544 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020458 infores:hetionet CHEBI:6954 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0009676 infores:hetionet CHEBI:92998 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0008031 infores:hetionet CHEBI:2549 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0522055 infores:hetionet CHEBI:7565 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C2939147 infores:hetionet CHEBI:4717 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0042514 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0233494 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0001364 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0836924 infores:hetionet CHEBI:41423 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0852911 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0857353 infores:hetionet CHEBI:68554 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0015230 infores:hetionet CHEBI:17347 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0239739 infores:hetionet CHEBI:41977 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0019112 infores:hetionet CHEBI:50924 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0237849 infores:hetionet CHEBI:8356 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0043352 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0342579 infores:hetionet CHEBI:3403 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0016927 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0233472 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0009806 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0079035 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0079035 infores:hetionet CHEBI:7903 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0233763 infores:hetionet CHEBI:8356 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026858 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0038454 infores:hetionet CAID:CA308125799 biolink:causes MONDO:0007783 infores:clingen CAID:CA308125799 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 684 of the RYR1 protein, p.(Gly684Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308125799/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:49575 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042024 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0015376 infores:hetionet CHEBI:3011 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0016204 infores:hetionet CHEBI:3175 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0547030 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0007787 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0426732 infores:hetionet GO:0021702 biolink:causes CL:0000121 infores:ubergraph knowledge_assertion manual_agent GO:0021702 CL:0000121 CHEBI:4885 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0344232 infores:hetionet CHEBI:3207 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0030193 infores:hetionet CHEBI:49375 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0028949 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0020456 infores:hetionet CHEBI:3437 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0013404 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0271650 infores:hetionet CHEBI:29007 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0019080 infores:hetionet CHEBI:3176 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0009763 infores:hetionet CAID:CA207213 biolink:causes MONDO:0100039 infores:clingen CAID:CA207213 MONDO:0100039 PMID: Benign BP7, BS2_Supporting, BA1 The allele frequency of the p.Ala334= variant in CDKL5 is 0.07448% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala334= variant is observed in at least 1 unaffected individual (Clinvar 210642) (BS2_supporting). The silent p.Ala334= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala334= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA207213/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA040197 biolink:causes MONDO:0007750 infores:clingen CAID:CA040197 MONDO:0007750 PMID: Benign BA1, BP4 BP2, PS4, BS1, PM3, PM2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.2389+41C>A variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: BA1: FAF = 0.01376 (1.376%) in African/African American exomes (gnomAD v4.1.0).BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) Does not create a GT. C) No nearby GT. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040197/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:681569 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0003862 infores:hetionet CHEBI:7465 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0851578 infores:hetionet CHEBI:68841 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0042023 infores:hetionet CHEBI:94449 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0013604 infores:hetionet CHEBI:107736 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0039240 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0860645 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0860645 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0521490 infores:hetionet CHEBI:94686 biolink:causes HP:0030804 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0546956 infores:hetionet CHEBI:28830 biolink:causes MONDO:0002334 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0376545 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0027947 infores:hetionet CHEBI:6916 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0151636 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0008035 infores:hetionet CHEBI:135613 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C2939147 infores:hetionet CHEBI:75045 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0015402 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0004604 infores:hetionet GO:0061141 biolink:causes CL:1000271 infores:ubergraph knowledge_assertion manual_agent GO:0061141 CL:1000271 CHEBI:37924 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0036974 infores:hetionet UMLS:C1144403 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0085649 infores:hetionet CHEBI:50777 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0235660 infores:hetionet CHEBI:8597 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0016382 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0403632 infores:hetionet CHEBI:46295 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0392699 infores:hetionet CHEBI:61033 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0011168 infores:hetionet CHEBI:144551 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0004093 infores:hetionet NCBIGene:51151 biolink:causes MONDO:0011683 infores:monarchinitiative not_provided not_provided HGNC:16472 MONDO:0011683 uuid:2e9ed784-4c21-4230-824d-4491135d45f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66903 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0004604 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0020517 infores:hetionet CHEBI:135939 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0012569 infores:hetionet CHEBI:50861 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0015967 infores:hetionet CHEBI:47612 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0700225 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0002453 infores:hetionet CHEBI:3181 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0018524 infores:hetionet CHEBI:6801 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1443060 infores:hetionet CHEBI:5118 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0242301 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0021053 infores:hetionet CHEBI:61058 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0151766 infores:hetionet CHEBI:31515 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0037763 infores:hetionet CHEBI:50742 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0236178 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0555120 infores:hetionet NCBIGene:348938 biolink:causes MONDO:0012847 infores:monarchinitiative not_provided not_provided HGNC:28018 MONDO:0012847 uuid:ff17df4d-85dd-47f5-a043-a338be3a9a2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71028 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0851341 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027765 infores:hetionet CHEBI:7445 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0151691 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0015230 infores:hetionet CHEBI:5130 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0740394 infores:hetionet CAID:CA5949893 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949893 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting PS3 The NM_000448.3:c.40G>A variant in RAG1 is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 14 (p.Ala14Thr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008797 (1/113676 alleles) in the European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.000102) for PM2_Supporting. No homozygous individual has been observed in the gnomAD v2.1.1(PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV002113580.2). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949893/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA915949143 biolink:causes MONDO:0700272 infores:clingen CAID:CA915949143 MONDO:0700272 PMID: Likely Pathogenic PVS1, PM2_Supporting BS1, PP3, BS2, BP4, BA1 The c.108+1_108+2insC variant in PALB2 occurs within the canonical splice donor site (+/- 1,2) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2, resulting in an in-frame deletion (removes amino acids 17-36) that is predicted to escape nonsense mediated decay but is predicted to adversely disrupt the coiled-coiled domain. This variant is absent from gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949143/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3077 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0041582 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0855242 infores:hetionet CHEBI:6541 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C1368065 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0037274 infores:hetionet CHEBI:65349 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0242379 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0017178 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0009806 infores:hetionet GO:1905304 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0007275 CHEBI:47780 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085616 infores:hetionet CHEBI:70735 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0600142 infores:hetionet CHEBI:135736 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0043144 infores:hetionet CHEBI:50729 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0014335 infores:hetionet CHEBI:63619 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C1145670 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0038454 infores:hetionet CHEBI:5134 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0008031 infores:hetionet CHEBI:5123 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0030446 infores:hetionet CAID:CA409107565 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107565 MONDO:0015967 PMID: Likely Pathogenic PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting, PP1_Strong PM1, PM5, PS4 The c.787G>C variant in the HNF4A gene causes an amino acid change of glutamic acid to glutamine at codon 263 (p.Glu263Gln) of NM_175914.5. Functional studies demonstrated the p.Glu276Gln protein has transactivation below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 30325586, 30191603). This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.789G>C p.Glu263Asp has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant segregated with diabetes, with at least 5 informative meioses in 1 family with MODY (PP1_Strong). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and a family history of neonatal hyperglycemia and response to sulphonylurea) (PP4_Moderate; internal lab collaborator). In summary, c.787G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PS3_Supporting PM2_Supporting, PP1_Strong, PP3_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107565/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3127 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0015230 infores:hetionet CHEBI:9763 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0002874 infores:hetionet CHEBI:50861 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0011570 infores:hetionet CHEBI:49662 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1443060 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0009450 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1142135 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0497327 infores:hetionet CHEBI:7444 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0016204 infores:hetionet CHEBI:17549 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0006118 infores:hetionet CHEBI:45367 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0438716 infores:hetionet CHEBI:8871 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038325 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0006277 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0026113 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0852908 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017160 infores:hetionet CHEBI:2904 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018681 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0031117 infores:hetionet CHEBI:9727 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0014591 infores:hetionet CHEBI:51041 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011071 infores:hetionet CHEBI:2663 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0011606 infores:hetionet CHEBI:134991 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0036974 infores:hetionet CHEBI:5134 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0020580 infores:hetionet CHEBI:7492 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0085636 infores:hetionet CHEBI:7824 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011168 infores:hetionet CHEBI:145499 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0006277 infores:hetionet CHEBI:9737 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0151849 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0038454 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0233494 infores:hetionet CHEBI:7494 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0040435 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151514 infores:hetionet CHEBI:134991 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C2242996 infores:hetionet CHEBI:2682 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0392171 infores:hetionet NCBIGene:55329 biolink:causes MONDO:0030070 infores:monarchinitiative not_provided not_provided HGNC:29636 MONDO:0030070 uuid:07e3ebab-8c21-492a-bd96-d7f58b6cbe7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA196286 biolink:causes MONDO:0100488 infores:clingen CAID:CA196286 MONDO:0100488 PMID: Likely Benign BS2 BS1, PM2 NM_004360.5(CDH1):c.1296C>G (p.Asn432Lys) variant has been observed in more than 10 (29) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; ClinVar SCVs: SCV000217409.6, SCV000545471.7, internal lab contributors). The CDH1-VCEP recommended a variant to reach a likely benign classification based on BS2 alone. In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA196286/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5100 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0014457 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0233472 infores:hetionet CHEBI:8888 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020461 infores:hetionet CHEBI:50730 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C2830004 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0234215 infores:hetionet CHEBI:2922 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0027947 infores:hetionet CHEBI:53760 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018843 infores:hetionet CHEBI:31638 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0003862 infores:hetionet CHEBI:63598 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018965 infores:hetionet NCBIGene:4976 biolink:causes MONDO:0007429 infores:monarchinitiative not_provided not_provided HGNC:8140 MONDO:0007429 uuid:d3c46661-971e-4c1b-8b5c-049de28e7daa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0004238 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0008370 infores:hetionet CHEBI:127780 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0025289 infores:hetionet CHEBI:135736 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0392699 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0152021 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0024115 infores:hetionet CAID:CA228284 biolink:causes MONDO:0019565 infores:clingen CAID:CA228284 MONDO:0019565 PMID: Likely Benign BP4, BS1 PP4, PS4 NM_000552.5:c.1728G>T is a missense variant in VWF that replaces methionine with isoleucine at position 576. The The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02820 (based on 1745/59454 alleles in the Admixed American population, with 41 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in the heterozygous state in at least 6 patients with a diagnosed blood disorder, with several exhibiting mild or moderate reduction of VWF:Ag (PMID: 17190853, PMID: 25780857, PMID: 33556167). However, diagnoses are not consistent and the variant is ineligible for consideration for PS4 due to its high frequency in the control population. The computational predictor REVEL gives a score of 0.038, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228284/MONDO:0019565/090 2024-07-09 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:4562 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0040264 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0029408 infores:hetionet CHEBI:47781 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0021141 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0178298 infores:hetionet CHEBI:18067 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0020433 infores:hetionet CHEBI:119915 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151904 infores:hetionet CAID:CA8815831 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815831 MONDO:0009290 PMID: Benign BA1 The NM_000152.5:c.2668G>C variant in GAA is predicted to result in the missense substitution of valine by leucine at amino acid position 890. The highest population minor allele frequency in gnomAD v2.1.1 is 0.02652 (812/30616 alleles with 13 homozygotes) in the South Asian population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 255361). In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BA1.(Classified approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815831/MONDO:0009290/010 2023-10-01 2024-03-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:41423 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0002994 infores:hetionet CHEBI:6076 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0003467 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0006852 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0855242 infores:hetionet CHEBI:8356 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0542571 infores:hetionet CHEBI:28148 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0041657 infores:hetionet CHEBI:135736 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0022575 infores:hetionet NCBIGene:9094 biolink:causes MONDO:0014226 infores:monarchinitiative not_provided not_provided HGNC:12565 MONDO:0014226 uuid:5dd738f1-ddf3-4f07-9d51-fdc47930965f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0746883 infores:hetionet GO:0010520 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:0010520 GO:0007127 CHEBI:135342 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0027769 infores:hetionet CHEBI:134991 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0151827 infores:hetionet CHEBI:64064 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0231218 infores:hetionet CHEBI:3310 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0549249 infores:hetionet CHEBI:17347 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235267 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0030846 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0040034 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151736 infores:hetionet CAID:CA337098731 biolink:causes MONDO:0044970 infores:clingen CAID:CA337098731 MONDO:0044970 PMID: Likely Benign BP7, BS1 BA1 The m.10172G>A (p.E38E) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in over 0.8% of individuals in the GenBank dataset (BS1), including in haplogroups J2b (97.91% of individuals), U6a (7.44% of individuals), Q1f (10/17 individuals), and M13b (7/13 individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 0.58% including in haplogroup J at 6.7%. If an affected individual is not a member of one of these haplogroups, further evaluation of the variant in that particular individual should be considered. This is a synonymous variant (BP7). In summary, this variant meets criteria to be classified as likely benign given its synonymous nature and high frequency in the general population. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP7. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337098731/MONDO:0044970/014 2021-10-26 2021-10-26 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0232462 infores:hetionet CHEBI:184555 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0022346 infores:hetionet CHEBI:50156 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0019080 infores:hetionet CHEBI:3437 biolink:causes UMLS:C0861157 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0861157 infores:hetionet CHEBI:178699 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0151970 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0267596 infores:hetionet CAID:CA2061247 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061247 MONDO:0015924 PMID:25688877 Likely Pathogenic PS3, PM1 PM2, PP3, BP4, BA1, PS4, BS1 The BMPR2 c.908G>A variant is a missense variant in exon 7 predicted to result in substitution of arginine to histidine at amino acid position 303 (p. Arg303His). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.00043 (1/2334 alleles) in subpopulation “remaining individuals” which exceeds the ClinGen PH VCEP threshold (<0.01%) for PM2 (PM2 not met). Neither BS1 (≥0.1%) nor BA1 (1%) met. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. The variant is located in the kinase domain (PM1 met). Genetic evidence showed the presence of the variant in only one IPAH patient (PMID:16429395) (PS4 not met). Immunofluorescence staining of Hela cells transfected with an R303H mutant construct showed mislocalization of BMPR2 protein to the endoplasmic reticulum (PMID:25688877) and included positive and negative controls (PS3 met). In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PM1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061247/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6438 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0917798 infores:hetionet CHEBI:2682 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0039231 infores:hetionet GO:0070103 biolink:causes GO:0071354 infores:ubergraph knowledge_assertion manual_agent GO:0070103 GO:0071354 NCBIGene:6850 biolink:causes MONDO:0030308 infores:monarchinitiative not_provided not_provided HGNC:11491 MONDO:0030308 uuid:586c68e8-f419-49f5-91b4-803fba8b74de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152128 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085129 infores:hetionet CHEBI:64045 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0037036 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002871 infores:hetionet CHEBI:3207 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C2607914 infores:hetionet CHEBI:49375 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0162285 infores:hetionet CHEBI:47426 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0000737 infores:hetionet CHEBI:2682 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0009763 infores:hetionet CHEBI:3638 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0002874 infores:hetionet CHEBI:4858 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0014591 infores:hetionet CHEBI:9649 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0000737 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0442874 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235082 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232492 infores:hetionet CAID:CA915940776 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940776 MONDO:0100326 PMID: Uncertain Significance BP7, BS1, PM3, PM2, PP3, PP4 The intronic variant NM_000419.5(ITGA2B):c.188+5G>T has been reported in one individual with a disorder of platelet function (TGP0048 in PMID:31064749). Communication with the authors confirmed a diagnosis of Glanzmann thrombasthenia. The patient had impaired platelet aggregation and prolonged bleeding after dental extraction. This individual, TGP0048, is compound heterozygous for this variant and a likely pathogenic frameshift variant (NM_000419.5(ITGA2B):c.1973del), phasing unspecified. The variant is absent from gnomAD (PM2_supporting). The computational splicing predictor SpliceAI gives a score of 0.14 for donor site loss, which indicates the variant has no affect on splicing (PP3 not met). Meanwhile, the variant occurs at a nucleotide position that is highly conserved, as shown by phyloP score of 3.27 (BP7 not met). In summary, this variant meets the criteria to be classified as variant of uncertain significance- insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on no ACMG/AMP criteria applied.(VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940776/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63635 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0242350 infores:hetionet CHEBI:9566 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0030232 infores:hetionet CHEBI:9123 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151603 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1608397 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1608397 infores:hetionet CHEBI:2666 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0011991 infores:hetionet CHEBI:8093 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0034063 infores:hetionet NCBIGene:81794 biolink:causes MONDO:0010194 infores:monarchinitiative not_provided not_provided HGNC:13201 MONDO:0010194 uuid:355bade0-7778-4bda-8fa2-5021a31b848c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91834 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0149745 infores:hetionet CHEBI:49662 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0017979 infores:hetionet CHEBI:3172 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0428977 infores:hetionet GO:0045066 biolink:causes CL:0000815 infores:ubergraph knowledge_assertion manual_agent GO:0045066 CL:0000815 CHEBI:31485 biolink:causes UMLS:C1444680 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C1444680 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0553704 infores:hetionet CHEBI:6846 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C1443060 infores:hetionet CHEBI:7496 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0017181 infores:hetionet CHEBI:4888 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0497156 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016436 infores:hetionet CHEBI:10127 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0040822 infores:hetionet CHEBI:94440 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0011570 infores:hetionet CHEBI:114785 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0235896 infores:hetionet CHEBI:5118 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018794 infores:hetionet CHEBI:231594 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0917801 infores:hetionet CAID:CA343724072 biolink:causes MONDO:0005338 infores:clingen CAID:CA343724072 MONDO:0005338 PMID:21612213PMID:25524706PMID:11004290PMID:23129764 Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3_Moderate, PP1_Strong BP7, BS1, BS3, PM4, PM5, PS1, PS2, BA1, BP4 The c.1276G>T variant in MYOC is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 426 (p.Val426Phe). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.764, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Val426Phe protein had instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. This protein has also been assessed in these other studies (PMIDs: 10545602, 11004290, 16297911), however, the same level of evidence was not met. 26 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9521427, 9772276, 12671462), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23922489, 9521427, 9772276, 12671462), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP1_Strong, PS3_Moderate, PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724072/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3175 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0038999 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0001122 infores:hetionet CHEBI:144551 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0010200 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0024115 infores:hetionet NCBIGene:3617 biolink:causes MONDO:0007934 infores:monarchinitiative not_provided not_provided HGNC:6055 MONDO:0007934 uuid:4ce73df8-dd9b-4b48-bc1a-8a00f97e32b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9588 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0014457 infores:hetionet CHEBI:63599 biolink:causes HP:0032964 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0151582 infores:hetionet CHEBI:6067 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0546817 infores:hetionet CHEBI:83804 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151662 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0497327 infores:hetionet CHEBI:31547 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020433 infores:hetionet CHEBI:2636 biolink:causes MONDO:0001220 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0020626 infores:hetionet CAID:CA410202479 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202479 MONDO:0011071 PMID: Likely Pathogenic PS4_Moderate, PM1_Supporting, PM2_Supporting, PP3, PP1 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS3, BS1, BS4, BP7, BP5, PM5, PM4, PM3, BS2, PP2, PP4 NM_001754.4:c.502G>A (p.Gly168Arg) is a missense variant which affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.947) (PP3). This variant has been identified in two families with thrombocytopenia, abnormal bleeding and bruising (PS4_moderate) and has been observed in 3 meioses across 2 families (PP1) (PMID:39375928, NIH RUNX1 Natural History Study unpublished). In summary, the clinical significance of this variant is Likely Pathogenic (LP). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_moderate, PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202479/MONDO:0011071/008 2025-01-27 2025-01-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:87681 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0037763 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0004238 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027769 infores:hetionet CHEBI:135920 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0008031 infores:hetionet CAID:CA10584691 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584691 MONDO:0007750 PMID: Benign BA1, BS3_Supporting BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS4, PM5, PM4, PM1, PM3, PM2, PVS1, PM6, BS2, PP3, PP4, PP1 The NM_000527.4(LDLR):c.-217C>T variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: BA1: FAF=0.01016 (1.016%) in African/African American Genomes (gnomAD v4.0.0).BS3_Supporting: Level 3 assay: PMID 10484771 (Scholtz CL et al., 1999): Heterologous cells (HepG2). Luciferase assays demonstrated 160% gene expression ---- functional study is consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584691/MONDO:0007750/013 2023-11-07 2024-09-25 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5280 biolink:causes UMLS:C0948085 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0948085 infores:hetionet CAID:CA404080996 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080996 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PM1, PM5, PP3 The variant NM_000527.5(LDLR):c.899G>A (p.Arg300Lys) is classified as a variant of uncertain significance for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2_Met : This variant is absent from controls in gnomAD (V2.1.1)BP4_Met : REVEL = 0.366. It is below 0.50.Functional data on splicing not availableA) Not on limitsB) Does not create AG nor GTC) nearby GT Variant is not predicted to alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080996/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15552 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0013595 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0267596 infores:hetionet CHEBI:51141 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0003862 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011991 infores:hetionet CAID:CA2499214555 biolink:causes MONDO:0100084 infores:clingen CAID:CA2499214555 MONDO:0100084 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PP1_Moderate The c.617-5C>A variant in ACTA1 is an intronic variant in the 3’ non-canonical splice site of intron 4. This variant is predicted to create a cryptic splice site, and add one amino acid (Ala) translated from intron 4 to the mature protein, but the exact impact is unknown because no functional studies have been performed. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor SpliceAI gives a score of 1 predicting an acceptor gain, which is above the threshold of 0.5, evidence that correlates with impact to ACTA1 function (PP3). This variant has been reported in two families with myopathy without muscle biopsies and three adults with features of muscle weakness (PS4_Supporting; PMID: 19562689, Invitae, SCV001556001.2, GeneDx, SCV001986137.1). The variant has been reported to segregate with myopathy in 2 affected family members from 1 family (PP1_Moderate, Invitae, SCV001556001.2). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PP1_Moderate, PM2_Supporting, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499214555/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50841 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0160390 infores:hetionet NCBIGene:84701 biolink:causes MONDO:0012992 infores:monarchinitiative not_provided not_provided HGNC:16232 MONDO:0012992 uuid:7cc495c8-c6ca-4aa1-a529-cc3aed7c5435 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0595878 infores:hetionet CHEBI:71940 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0011991 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C2973529 infores:hetionet CHEBI:18243 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0010520 infores:hetionet CHEBI:8207 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0235266 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011551 infores:hetionet CHEBI:231594 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0392171 infores:hetionet CHEBI:72292 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0267792 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0028734 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042721 infores:hetionet CHEBI:4046 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0012569 infores:hetionet CHEBI:50922 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0015230 infores:hetionet CHEBI:49603 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0011603 infores:hetionet CHEBI:3561 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0015967 infores:hetionet CHEBI:8871 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151836 infores:hetionet CHEBI:17263 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0030305 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0973461 infores:hetionet CHEBI:116278 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151907 infores:hetionet CHEBI:5123 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0549567 infores:hetionet GO:1901261 biolink:causes GO:0031154 infores:ubergraph knowledge_assertion manual_agent GO:1901261 GO:0031154 CHEBI:10112 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0030193 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006468 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0238461 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0574770 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0574770 infores:hetionet CAID:CA5252673 biolink:causes MONDO:0008535 infores:clingen CAID:CA5252673 MONDO:0008535 PMID: Uncertain Significance PP3, PM2, BS1 The NM_001114753.3: c.1711C>T variant in ENG is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 571 (p.Arg571Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004233 (15/35434 alleles) in the Admixed American population. The computational predictor REVEL gives a score of 0.31, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: None (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5252673/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135736 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014457 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0150450 infores:hetionet CHEBI:3048 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0009676 infores:hetionet CAID:CA1624554 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624554 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1772A>G (p.Asn591Ser) variant in the SOS1 gene is 0.054% (11/11524) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624554/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:16469 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0023380 infores:hetionet GO:0090249 biolink:causes GO:0001756 infores:ubergraph knowledge_assertion manual_agent GO:0090249 GO:0001756 CHEBI:7959 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0497156 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0027765 infores:hetionet CHEBI:64310 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0852911 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002237 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007078 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0746883 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0011991 infores:hetionet CHEBI:9168 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1167965 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1443060 infores:hetionet CAID:CA10585331 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585331 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1154T>G (p.Leu385Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meet PM2. PMID: 10422804 (Loubser et al., 1999), South Africa - 1 case who fulfills Simon-Broome criteria for FH. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585331/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0438717 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0011053 infores:hetionet CAID:CA10014732 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014732 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.27A>G (p.Ser9=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014732/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030312 infores:hetionet CHEBI:136040 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0016204 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0009806 infores:hetionet CHEBI:3082 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0023066 infores:hetionet NCBIGene:5354 biolink:causes MONDO:0010733 infores:monarchinitiative not_provided not_provided HGNC:9086 MONDO:0010733 uuid:62ad1bc2-a7ef-4c55-81c8-3338c46e5a86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127342 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0233477 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018801 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002622 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009763 infores:hetionet CHEBI:59750 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0234894 infores:hetionet CHEBI:6339 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0344232 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0006147 infores:hetionet CHEBI:52717 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013132 infores:hetionet CHEBI:31401 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0039240 infores:hetionet CHEBI:92923 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0042029 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0413252 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0037274 infores:hetionet CHEBI:107736 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0338831 infores:hetionet CAID:CA192745556 biolink:causes MONDO:0009595 infores:clingen CAID:CA192745556 MONDO:0009595 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP4_Moderate The NC_000009.12:g.35657788G>A variant is present in a frequency of 0.000006567 Grpmax filtering AF with only 1 allele in 152284, which is below the PM2_Supporting threshold that the SCID VCEP has established. Therefore PM2_Supporting is met.At least one patient (PMID: 21146796) presented with metaphyseal dysplasia (+1.0 points), T cell lymphopenia (+0.5 points), hypotrichosis (+0.5 points), and microcytic anemia (+0.25 points) reaching a total of 2.25 points. Therefore PP4_Moderate is met. This variant has been found in trans with the variants (g.−26 to −13 dupTACTACTCTGTGAA located in the promoter region (+0.5 points) (PMID: 21146796), n.211C>G/n.212C>G (PMID: 12107819, +0.25 points), and [Internal communication - Invitae/Labcorp]: n.-15_-8dup (+0.25 points), n.71A>G (+1.0 points), n.5_6ins27 (+0.25 points), and n.-19_-13dup in two probands (+0.25 points each), reaching a total of 2.75 points. Therefore PM3_Strong is met.In summary, this variant is classified as Likely Pathogenic for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4_Moderate, PM3_Strong, (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA192745556/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135276 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0002994 infores:hetionet CHEBI:4975 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0151636 infores:hetionet GO:0031991 biolink:causes GO:0061640 infores:ubergraph knowledge_assertion manual_agent GO:0031991 GO:0061640 CHEBI:7986 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0015967 infores:hetionet CHEBI:74947 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C3665347 infores:hetionet CHEBI:3001 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0027497 infores:hetionet CHEBI:31711 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0009676 infores:hetionet CHEBI:63598 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0917801 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0002871 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0018802 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0948395 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948395 infores:hetionet CAID:CA658823287 biolink:causes MONDO:0001586 infores:clingen CAID:CA658823287 MONDO:0001586 PMID: Likely Pathogenic PM4, PM3, PM1, PM2_Supporting PP4 The NM_000203.5:c.886_894dupTACAACGAC variant is predicted to cause a change in the length of the protein (p.Tyr296_Asp298dup) due to an in-frame duplication of 3 amino acids in a non-repeat region (PM4). The duplication inserts 3 amino acids (Tyr, Asn, Asp) between Asp298 and Glu299, one of the active site nucleophiles in IDUA. Glu299 has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 11735025, 21480867) (PM1). This variant has been detected in one individual with MPS I, who was homozygous for the variant (PMID: 35005816) (PM3_Supporting).There is a ClinVar entry for this variant (Variation ID: 558316) In summary, this variant meets the criteria to be classified as a likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PM1, PM4, PM2_Supporting, PM3_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658823287/MONDO:0001586/010 2024-12-06 2024-12-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3756 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0687713 infores:hetionet GO:0120313 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0120313 GO:0019953 CHEBI:6888 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0428977 infores:hetionet CHEBI:8597 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0020580 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0151828 infores:hetionet NCBIGene:5345 biolink:causes MONDO:0009883 infores:monarchinitiative not_provided not_provided HGNC:9075 MONDO:0009883 uuid:2822e85a-0344-4874-9886-dc6cad097c35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0033036 infores:hetionet CHEBI:4466 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0231837 infores:hetionet CHEBI:194135 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085633 infores:hetionet CHEBI:10119 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2240374 infores:hetionet CHEBI:52172 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0036974 infores:hetionet CHEBI:4953 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0037763 infores:hetionet CHEBI:63115 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0010200 infores:hetionet CHEBI:5147 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C1443060 infores:hetionet CHEBI:61049 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0392171 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0040046 infores:hetionet CHEBI:520985 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020578 infores:hetionet NCBIGene:55129 biolink:causes MONDO:0013392 infores:monarchinitiative not_provided not_provided HGNC:25519 MONDO:0013392 uuid:9fa3a662-fd76-41e4-a356-405a5b17af4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes UMLS:C2747853 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C2747853 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0029445 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0022660 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0009319 infores:hetionet CHEBI:9570 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0333355 infores:hetionet CHEBI:7824 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0004093 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0039971 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162429 infores:hetionet CHEBI:3814 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0025061 infores:hetionet CHEBI:136040 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0033774 infores:hetionet CHEBI:7865 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0000737 infores:hetionet CHEBI:10119 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0920289 infores:hetionet CHEBI:4953 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0018681 infores:hetionet CHEBI:47499 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0041969 infores:hetionet CHEBI:474053 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0023530 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0037284 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0008093 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0008093 uuid:eb06e134-7a63-4ed0-8bd7-ba26637af2c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66919 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0178298 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0027726 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0853692 infores:hetionet CHEBI:36795 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009782 infores:hetionet CAID:CA280027 biolink:causes MONDO:0021060 infores:clingen CAID:CA280027 MONDO:0021060 PMID: Pathogenic PM1, PS2_Very Strong, PM2, PP3, PP2, PS4_Supporting PS1, PS3, PM4, PM5, BS3, BS4, BS1, BP5, BP7, PM6, BS2, PP1, BP3, BP2, BP4, BP1, BA1 The c.735A>C (p.Leu245Phe) variant in BRAF has been reported as a a de novo occurrence, one of which was confirmed in at least 4 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx University Magdeburg GTR Lab ID's 21766, 26957, 506381; ClinVar SCV000061622.5, SCV000057188.16 PMID 19416762). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PM2, PM1, PP2, PP3, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280027/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:36791 biolink:causes UMLS:C0003044 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003044 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1096243 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1096243 infores:hetionet CHEBI:132233 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0015967 infores:hetionet UMLS:C0903898 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0004093 infores:hetionet CHEBI:6339 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017168 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1959622 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1959622 infores:hetionet CAID:CA270202 biolink:causes MONDO:0010726 infores:clingen CAID:CA270202 MONDO:0010726 PMID: Uncertain Significance PS4_Moderate, BS2 BP4, PM1, BS1, PP4 The p.Ala378Gly variant has been observed in 3 individuals with Rett syndrome (PMID 16473305, 20031356, 11960578) (PS4_moderate). The p.Ala378Gly variant is observed in at least 7 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Ala378Gly variant in MECP2 is present in 3 female and 1 male individual(s) in gnomAD (0.002%) (not sufficient to meet BS1 criteria). In summary, the p.Ala378Gly variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS4_moderate). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270202/MONDO:0010726/036 2022-10-11 2024-11-29 X-linked inheritance HP:0001417 Inconclusive true CHEBI:5959 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013456 infores:hetionet CHEBI:31709 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0013378 infores:hetionet CHEBI:3181 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0232462 infores:hetionet CHEBI:465284 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0235490 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1306341 infores:hetionet CHEBI:7915 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C2129214 infores:hetionet CHEBI:27666 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0009917 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0235416 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0009450 infores:hetionet CHEBI:5959 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0037023 infores:hetionet CHEBI:8024 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C2938875 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0518015 infores:hetionet CHEBI:15940 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0086565 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0349398 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0349398 infores:hetionet CHEBI:8888 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232286 infores:hetionet CAID:CA2573052265 biolink:causes MONDO:0001586 infores:clingen CAID:CA2573052265 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.911del (p.Val304GlyfsTer13) in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A proband and sibling with the variant and clinical symptoms meeting criteria of the LD VCEP and positive urine test for GAGs have been reported (PMID: 36951468) (PP4). These individuals are compound heterozygous, confirmed in trans by parental testing, for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.2T>C (ClinVar Variation ID: 639529) (PMID: 36951468, 1 point). Another individual, who was identified by newborn screen, with reduced IDUA activity but normal GAGs is compound heterozygous for the variant and c.76G>A (p.Ala26Thr) (Variation ID: 712785, VUS based on classification by the ClinGen LD VCEP) (PMID: 29801497). This variant, c.911del, is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for the variant (Variation ID: 1184991). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 6, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573052265/MONDO:0001586/091 2025-10-06 2025-10-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9352 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0687713 infores:hetionet CHEBI:66903 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0015230 infores:hetionet CHEBI:7025 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0011603 infores:hetionet CAID:CA042227 biolink:causes MONDO:0007750 infores:clingen CAID:CA042227 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1 NM_000527.5(LDLR):c.190+4A>T variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4 and PS3_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.00020 (0.02%) in East Asian exomes+genomes (gnomAD v2.1.1).PP4 - Variant meets PM2. Variant identified in 11 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 21418584; 3 cases fulfilling Simon-Broome criteria published in PMID: 20236128; 5 cases with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with Dutch lipid clinic network >=6 from Robarts Research Institute; 1 case with MedPed definite from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory.PS3_Moderate - Level 2 assays: PMID 19208450:Heterozygous patient cells, FACS/RT-PCR/Nothern blotting assays - result - 47% low-density lipoprotein particle receptor activity (LDLR activity reported as a mean value of cell-surface LDLR and LDL internalization measurements); aberrant transcript is not confirmed by sequencing (NMD expected) and is 40% of total transcripts.PS4 - Variant meets PM2. Variant identified in 11 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 21418584; 3 cases fulfilling Simon-Broome criteria published in PMID: 20236128; 5 cases with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with Dutch lipid clinic network >=6 from Robarts Research Institute; 1 case with MedPed definite from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042227/MONDO:0007750/013 2022-02-09 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:63589 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0520573 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027051 infores:hetionet CHEBI:4551 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0018799 infores:hetionet CHEBI:3650 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0020615 infores:hetionet CHEBI:63611 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0025345 infores:hetionet CHEBI:17347 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0040053 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0023895 infores:hetionet CHEBI:17026 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040264 infores:hetionet CHEBI:3638 biolink:causes MONDO:0021718 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0032541 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0009450 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0042769 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0920184 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0920184 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0700184 infores:hetionet CHEBI:28001 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0700225 infores:hetionet CAID:CA291224635 biolink:causes MONDO:0100326 infores:clingen CAID:CA291224635 MONDO:0100326 PMID:21896032 Uncertain Significance PM2_Supporting BS3, PP3, BP4 After a comprehensive literature search, the missense variant NM_000212.3:c.385C>A (p.Gln129Lys) was not identified in any individuals with Glanzmann thrombasthenia. The variant is not present in any continental genetic ancestry group in gnomADv4.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.408, which is intermediate between PP3 and BP4. The variant was identified in relation to severe neonatal alloimmune thrombocytopenia, where the variant was found to have normal surface expression in HEK-293 cells, though this assay use did not meet our criteria for BS3 specification (PMID: 21896032). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291224635/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5050 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0016204 infores:hetionet CHEBI:10101 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0042256 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1971624 infores:hetionet CHEBI:6916 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0013378 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0004936 infores:hetionet CHEBI:8356 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233477 infores:hetionet CHEBI:36791 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0494475 infores:hetionet CHEBI:4975 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0018681 infores:hetionet CHEBI:5134 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0016436 infores:hetionet CHEBI:3207 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0231528 infores:hetionet CAID:CA412745786 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745786 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PS4 NM_001034853.2(RPGR):c.125G>T (p.Cys42Phe) is a missense variant predicted to cause substitution of cysteine by phenylalanine at amino acid 42. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.851, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all types of changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. This variant has been reported in ClinVar in at least 1 affected proband who does not meet one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (ClinVar Accession: SCV003195626.3), so PS4_Supporting is not met. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and PP3_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745786/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Inconclusive true CHEBI:40237 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0700225 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0343863 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0009938 infores:hetionet CHEBI:82960 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0000737 infores:hetionet CHEBI:5784 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0262988 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0042401 infores:hetionet CAID:CA1251245 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251245 MONDO:0013144 PMID: Benign BP7, BP4, BA1 PS4 The NM_000488.4:c.1218+27G>C variant is reported at an Popmax FAF MAF of 0.2409 (4979/19948 alleles) in the East Asian population in the genomes in gnomAD v2.1.1 with a total of 2550 homozygotes, meeting BA1 criteria of FAF >= 0.002. The variant is not predicted to cause a splicing impact by by SpliceAI and VARSEAK, and the nucleotide is not conserved with a PhyloP score of -1.65 and a PhastCons score of ~0. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BP4, BP7. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251245/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10023 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013491 infores:hetionet NCBIGene:1421 biolink:causes MONDO:0007281 infores:monarchinitiative not_provided not_provided HGNC:2411 MONDO:0007281 uuid:daf4a328-f108-4156-ab93-7f32e80abbd6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151699 infores:hetionet CAID:CA400026292 biolink:causes MONDO:0100326 infores:clingen CAID:CA400026292 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The p.Asn365Ser missense variant on ITGB3 gene has been previously reported in the context of Glanzmann thrombasthenia. The highest population minor allele frequency in gnomAD v4.1 is 0.000001695 (2/1179950 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant has been reported to occur in compound heterozygous state with a pathogenic frameshift variant (p.Gln508Serfs*) in one proband (PM3_supporting) who meets the PD-VCEP criteria for the GT phenotype (PMID: 25728920). The patient presented with significant mucocutaneous bleeding. Platelet aggregometry demonstrated absence of platelet aggregation with 3 platelet agonists and normal aggregation with ristocetin. Surface expression of αIIbβ3 was demonstrated to be reduced (<5%) by flowcytometry (PMID: 25728920); PP4_strong). Multiple in silico tools predict this variant to be deleterious (REVEL score = 0.94). This variant meets GT specific criteria for PP4_Strong, PM3_supporting, PP3 and PM2_supporting and is therefore classified as Likely Pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400026292/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9352 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0027947 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0027765 infores:hetionet CHEBI:3756 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019209 infores:hetionet CAID:CA179947 biolink:causes MONDO:0800472 infores:clingen CAID:CA179947 MONDO:0800472 PMID: Benign BA1, BP4, BP7 PP3, PP1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, PM2, PVS1 The c.1347T>C variant in CYP1B1 is a synonymous variant (p.Asp449=). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.8767, which met the ≥ 0.05 threshold set for BA1 (39,343 alleles out of 44,878, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact CYP1B1 function. This synonymous variant is located outside of the first and the last 3 bases of the exon and BP4 is met, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1, BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA179947/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135876 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0403632 infores:hetionet CHEBI:681569 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0151908 infores:hetionet NCBITaxon:766 biolink:causes MONDO:0006956 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:766 MONDO:0006956 CHEBI:478164 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0234428 infores:hetionet CHEBI:37924 biolink:causes UMLS:C1141938 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1141938 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022568 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0025061 infores:hetionet CHEBI:110423 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0041969 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0014868 infores:hetionet CHEBI:6472 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0000729 infores:hetionet CHEBI:4646 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0677500 infores:hetionet CHEBI:8069 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C1443060 infores:hetionet GO:0046668 biolink:causes GO:0001654 infores:ubergraph knowledge_assertion manual_agent GO:0046668 GO:0001654 CHEBI:51230 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0042373 infores:hetionet CHEBI:70718 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0027947 infores:hetionet CAID:CA16043042 biolink:causes MONDO:0008723 infores:clingen CAID:CA16043042 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.316_325del (p.Val106Cysfs*8) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. In summary, this variant has been classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ACADVL Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#2.0; approved 05-09-22). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043042/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports UMLS:C1738934 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0853692 infores:hetionet CHEBI:17474 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0015967 infores:hetionet GO:0070099 biolink:causes GO:1990869 infores:ubergraph knowledge_assertion manual_agent GO:0070099 GO:1990869 CHEBI:10650 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017160 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0037274 infores:hetionet CHEBI:6062 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0086439 infores:hetionet CHEBI:2914 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0025061 infores:hetionet CHEBI:6775 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0233407 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0162429 infores:hetionet NCBIGene:22856 biolink:causes MONDO:0011533 infores:monarchinitiative not_provided not_provided HGNC:17198 MONDO:0011533 uuid:c0909128-6f61-4734-bb33-603fff02d46a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0853813 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0031117 infores:hetionet NCBIGene:732 biolink:causes MONDO:0013421 infores:monarchinitiative not_provided not_provided HGNC:1353 MONDO:0013421 uuid:af95a3c0-c677-45f0-9a03-e3901a07d645 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40303 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0687713 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005551 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0852875 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0012833 infores:hetionet CHEBI:94686 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0033774 infores:hetionet CHEBI:38940 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0702166 infores:hetionet CHEBI:35778 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0231835 infores:hetionet CAID:CA013482 biolink:causes MONDO:0005021 infores:clingen CAID:CA013482 MONDO:0005021 PMID: Uncertain Significance PM2, PP3 PM5, PM1, PM6, PP1, BA1, PS3, BS1, BS3, BS4, BP4, BP2, BP5, PS1, PS4, PS2 The NM_000257.4(MYH7):c.323G>A (p.Arg108His) variant has been identified in 2 individuals with DCM, including 1 that also had LVNC and another that had a truncating variant in TTN (GeneDx pers. comm.; OMGL pers. comm.), as well as in 1 individual with LVNC (Ambry pers. comm.). However, collectively this data is insufficient to apply PS4. Additionally, this variant segregated with disease in 1 affected individual with DCM and LVNC from 1 families (OMGL pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013482/MONDO:0005021/002 2021-11-19 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016199 infores:hetionet CHEBI:4530 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0043352 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0038362 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0178298 infores:hetionet CHEBI:46345 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0011168 infores:hetionet CHEBI:7494 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1306341 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0006849 infores:hetionet CHEBI:46295 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0037763 infores:hetionet CHEBI:51860 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002994 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0006277 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030353 infores:hetionet CHEBI:47898 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0039239 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040261 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0007642 infores:hetionet CHEBI:71940 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0004604 infores:hetionet CHEBI:3485 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0036830 infores:hetionet CHEBI:92712 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0344232 infores:hetionet CHEBI:16914 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0013491 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0234894 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0233479 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0233479 infores:hetionet CHEBI:72296 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0025222 infores:hetionet CHEBI:66903 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0151904 infores:hetionet CHEBI:6931 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0009782 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0541820 infores:hetionet CHEBI:47499 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0030446 infores:hetionet CAID:CA9043657 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043657 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000156.6:c.459+9_459+12del variant in GAMT is an intronic variant in intron 4 and leads to a deletion of 4 base pairs. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005330 (4/75046 alleles; no homozygotes) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor SpliceAI suggests that this variant has no impact on the gene/gene product (score <0.1) (BP4). There is a ClinVar entry for the variant (Variation ID: 513151). Due to conflicting evidence, this variant is classified as a variant of unknown significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, PM2_Supporting.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043657/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:182080 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0085631 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030319 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0948168 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0948168 infores:hetionet CAID:CA915943443 biolink:causes MONDO:0021056 infores:clingen CAID:CA915943443 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PM2_Supporting, PS3_Moderate PM5 The c.423-11A>G variant in APC is an intronic variant which substitutes adenine with guanine at position -11 in intron 4. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, Ambry Genetics, Bonn internal data). RT-PCR of this APC variant in patients with FAP showed that it impacted splicing by leading to insertion of the last 10 bp of intron 4 (r.422_423ins423-10_423-1)(p.Ser142Lysfs*3)(PS3_Moderate; PMID21779980, Ambry Genetics, Bonn internal data). The results from 2 in silico splicing predictors indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 4 of APC (PP3). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PP3 and PM2_supporting (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA915943443/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:131377 biolink:causes MONDO:0014138 infores:monarchinitiative not_provided not_provided HGNC:30372 MONDO:0014138 uuid:63b7178f-d93e-4121-92f2-e0d647198a53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes HP:0001809 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0263530 infores:hetionet CAID:CA020051 biolink:causes MONDO:0008667 infores:clingen CAID:CA020051 MONDO:0008667 PMID: Benign BA1 The variant NM_000551.4(VHL):c.150C>G (p.Ala50=) is a synonymous (silent) variant that is not predicted by SpliceAI or VarSeak to impact splicing. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.0.0 is 0.001000 (1222/1163922 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020051/MONDO:0008667/078 2024-06-25 2024-07-17 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3757 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0009806 infores:hetionet CHEBI:100246 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0011603 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0242350 infores:hetionet CHEBI:9150 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0232462 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0018939 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0022107 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0700345 infores:hetionet CHEBI:64355 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004604 infores:hetionet CHEBI:3387 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0231528 infores:hetionet CHEBI:7959 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0002878 infores:hetionet CHEBI:8874 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0039231 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0041582 infores:hetionet CHEBI:3568 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0010200 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235416 infores:hetionet CHEBI:6129 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013491 infores:hetionet CHEBI:8212 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0234133 infores:hetionet CHEBI:49575 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0028643 infores:hetionet CHEBI:5296 biolink:causes HP:0012041 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0151640 infores:hetionet CHEBI:63845 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0024141 infores:hetionet UNII:3U02EL437C biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0018520 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0162429 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0010709 infores:hetionet CHEBI:15544 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C1963790 infores:hetionet CHEBI:6541 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0004604 infores:hetionet CHEBI:63635 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0424790 infores:hetionet CHEBI:5784 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0162830 infores:hetionet CAID:CA2580610940 biolink:causes MONDO:0009276 infores:clingen CAID:CA2580610940 MONDO:0009276 PMID:9326230PMID:9326229 Pathogenic PP4, PM2_Supporting, PM3_Strong, PVS1_Strong, PS3_Supporting The c.1562_1563del (p.Leu521ProfsTer81) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however the truncation includes the functionally important transmembrane domain in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BSS-1 in PMID:23300803) with this variant had aggregation absent for ristocetin and present for all other agonists as well as less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This variant has been detected in at least three probands with Bernard-Soulier syndrome. One proband was compound heterozygous for this variant and the likely pathogenic c.952del (p.Ala318ProfsTer17) variant (PMID: 23300803) and two additional probands (PMIDs: 9326230 and 9326229) were homozygous for the variant (PM3_Strong). Surface expression of GP1a measured by flow cytometry and western blot in CHO cells transiently co-transfected with c.1562_1563del variant GP1a and wild type GP1a showed decreased expression at <25% WT levels, indicating that this variant impacts protein function (PMID: 9326230)(PS3_supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Strong, PS3_Supporting, and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610940/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3654 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0017979 infores:hetionet CHEBI:2567 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0392525 infores:hetionet CAID:CA6831762 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831762 MONDO:0015967 PMID: Likely Benign BP2, PM1_Supporting, PS4_Moderate, BP5, PP3, BS2 PM5, BS1, PM2 The c.503G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 168 (p.(Arg168His)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Grpmax filtering allele frequency of the c.503G>A variant in gnomAD v2.1.1 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in a total of eight unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors). However, in one case this variant was detected in trans with another variant in HNF1A that is classified as likely pathogenic by the ClinGen MDEP (BP2, internal lab contributors). In another case, this variant was detected in an individual with diabetes, who also harbored a whole gene deletion of HNF1B (BP5, internal lab contributors). Therefore, that leaves six individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes and this variant (PS4_Moderate, internal lab contributors). This variant was also identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2, internal lab contributors). Another missense variant at the same codon, c.503G>C p.Arg168Pro, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.503G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS2, BP2, BP5, PS4_Moderate, PP3, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831762/MONDO:0015967/017 2024-10-24 2024-10-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17650 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0027051 infores:hetionet CHEBI:6402 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0004093 infores:hetionet CHEBI:8346 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C2242996 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040128 infores:hetionet CHEBI:64355 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549249 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151602 infores:hetionet CHEBI:45081 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0037036 infores:hetionet CHEBI:35778 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0812387 infores:hetionet CAID:CA410148731 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148731 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.993C>A (p.Ser331Arg) is a missense variant which has a REVEL score < 0.50 (0.144), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148731/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8874 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009806 infores:hetionet CHEBI:50730 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0041969 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0877232 infores:hetionet CHEBI:6367 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0542571 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0162830 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0151735 infores:hetionet CHEBI:101853 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0149745 infores:hetionet CHEBI:3499 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0086565 infores:hetionet CHEBI:6847 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0476273 infores:hetionet CHEBI:4858 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0040822 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0011616 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013395 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0851341 infores:hetionet CHEBI:261649 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0015376 infores:hetionet CHEBI:8774 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0917801 infores:hetionet CHEBI:94609 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0014457 infores:hetionet CHEBI:5855 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0022346 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042571 infores:hetionet CHEBI:4710 biolink:causes HP:0033566 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1112436 infores:hetionet CAID:CA213913 biolink:causes MONDO:0015967 infores:clingen CAID:CA213913 MONDO:0015967 PMID: Benign PP4_Moderate, BS3_Supporting, BA1, BP5, BS4 PP3, PM1, BP4, PS4 The c.1321A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of isoleucine to valine at codon 441 (p.(Ile441Val)) of NM_175914.4. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). This variant has a REVEL score of 0.354, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213913/MONDO:0015967/085 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:18332 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0036572 infores:hetionet GO:2000367 biolink:causes GO:0007340 infores:ubergraph knowledge_assertion manual_agent GO:2000367 GO:0007340 CHEBI:474180 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0600142 infores:hetionet CHEBI:27504 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0018926 infores:hetionet CHEBI:31623 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0017178 infores:hetionet CHEBI:473990 biolink:causes MONDO:0100345 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0022951 infores:hetionet CHEBI:71272 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0013395 infores:hetionet CHEBI:3001 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0009450 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0021167 infores:hetionet CHEBI:63638 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0037036 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0023533 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1386135 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1386135 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0020649 infores:hetionet CHEBI:38940 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0004604 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0026946 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151479 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003864 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0011991 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0040034 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0017178 infores:hetionet CHEBI:4653 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0034063 infores:hetionet CHEBI:7494 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0699828 infores:hetionet CHEBI:59445 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0042487 infores:hetionet CHEBI:4911 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0340865 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0162830 infores:hetionet CHEBI:42820 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0013491 infores:hetionet CHEBI:9434 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0033774 infores:hetionet CHEBI:3219 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0686347 infores:hetionet GO:1902869 biolink:causes GO:0003407 infores:ubergraph knowledge_assertion manual_agent GO:1902869 GO:0003407 CAID:CA392337255 biolink:causes MONDO:0007947 infores:clingen CAID:CA392337255 MONDO:0007947 PMID: Uncertain Significance PP2, PM2_Supporting PM6, PVS1, PP3, PP1, PP4, BS2, BP1, BP4, BP2, BP3, BA1, PS2, PS3, PS1, PS4, PM1, PM3, PM4, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.6185A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2062 (p.Tyr2062Cys). It has been reported 2 times in ClinVar as likely pathogenic (1) and of uncertain significance (1) (Variation ID: 547338). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue in a TGFβ binding-protein-like (TB) domain, in which cysteine residues are believed to form disulfide bridges involved in proper protein folding; however, the effect of a novel cysteine in this domain is uncertain. Computational prediction tools and conservation analysis are unclear about this variant’s predicted impact on the protein (REVEL = 0.608). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). Due to the insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP2, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392337255/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:34385 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0002994 infores:hetionet GO:1904118 biolink:causes GO:0043583 infores:ubergraph knowledge_assertion manual_agent GO:1904118 GO:0043583 CHEBI:144093 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0016204 infores:hetionet CHEBI:7444 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0021775 infores:hetionet CAID:CA16020721 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020721 MONDO:0009861 PMID:26503515 Uncertain Significance PM2, PP4_Moderate PP3 VUS: The c.59A>C (p.Q20P) variant in PAH has been reported in one Chinese patient with PKU (PMID: 26503515), however no genotype information was provided for this patient. This variant is absent from population databases, including gnomAD, ESP, and 1000 Genomes. Computation predictors are inconclusive on protein structure and function. In summary, this variant meets the criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_M. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020721/MONDO:0009861/006 2019-03-10 2019-08-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3638 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0547030 infores:hetionet CHEBI:9123 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013456 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0041912 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232498 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0033777 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0033566 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C1112436 infores:hetionet CHEBI:61049 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018965 infores:hetionet CAID:CA10360821 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360821 MONDO:0010725 PMID: Likely Benign BP7, BP4 BS1, PM2 The NM_000330.4(RS1):c.69G>A variant is a synonymous variant at amino acid 23. The splicing impact predictor SpliceAI gives a delta score of 0.06, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This silent variant c.69G>A causing a synonymous variant at codon 23 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.06 for donor loss which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on splicing (BP7). This variant is present in gnomAD v.4.1.0 at a frequency of 0.000007727 among hemizygotes, with 3 variant alleles / 388269 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP thresholds of >0.00002 and <0.000002 and fails to meet either BS1 or PM2_supporting. In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BP7 and BP4_supporting. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360821/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:45979 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0020649 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0021053 infores:hetionet CHEBI:3738 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0085593 infores:hetionet CHEBI:231425 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0039070 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0345904 infores:hetionet CHEBI:16755 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C3665386 infores:hetionet CHEBI:92712 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0235063 infores:hetionet CHEBI:4356 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C3665346 infores:hetionet CHEBI:32315 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0043094 infores:hetionet CHEBI:31644 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085631 infores:hetionet CHEBI:3696 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151908 infores:hetionet CHEBI:73274 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0423791 infores:hetionet CHEBI:28241 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0231218 infores:hetionet CHEBI:4325 biolink:causes EFO:0009445 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0003130 infores:hetionet CHEBI:9086 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020443 infores:hetionet CHEBI:35778 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0003862 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151736 infores:hetionet CHEBI:3077 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0234632 infores:hetionet CHEBI:38940 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0006277 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0003864 infores:hetionet CHEBI:9332 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0018524 infores:hetionet CHEBI:47781 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C1320835 infores:hetionet GO:0035169 biolink:causes CL:0000733 infores:ubergraph knowledge_assertion manual_agent GO:0035169 CL:0000733 CHEBI:7494 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151836 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0027932 infores:hetionet CAID:CA6198221 biolink:causes MONDO:0019497 infores:clingen CAID:CA6198221 MONDO:0019497 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong The NM_000260.4:c.3862G>C variant in the MYO7A gene is a missense variant predicted to cause substitution of alanine to proline at amino acid 1288 (p.Ala1288Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (7/110006 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.833, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in five individuals with hearing loss or clinical features of Usher syndrome who were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. However, for each individual phase was unknown (PMID: 10094549, 26969326, SCV001533246.2, 2.5 PM3 points) (PM3_Strong, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PM3_Strong, PM2_Supporting, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6198221/MONDO:0019497/005 2022-12-21 2023-02-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:64310 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0039070 infores:hetionet NCBIGene:6714 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:11283 MONDO:0005575 uuid:08d98cd5-9869-4381-b304-ae751f6d0ef4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63581 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0017178 infores:hetionet CHEBI:3504 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0232462 infores:hetionet CHEBI:6846 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0000737 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001956 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0343084 infores:hetionet CHEBI:93635 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0152032 infores:hetionet NCBIGene:9939 biolink:causes MONDO:0010121 infores:monarchinitiative not_provided not_provided HGNC:9905 MONDO:0010121 uuid:c0899e4a-45c3-4fd8-af4e-155d39eedb38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0031212 infores:hetionet CHEBI:31236 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0856054 infores:hetionet CHEBI:9599 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C2363731 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0020651 infores:hetionet CHEBI:9168 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011175 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C2973529 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0039971 infores:hetionet CHEBI:110423 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0026636 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0039971 infores:hetionet CHEBI:31623 biolink:causes MONDO:0024616 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0027134 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0267596 infores:hetionet CHEBI:7954 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0030193 infores:hetionet CHEBI:168396 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0026826 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0442874 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151828 infores:hetionet CHEBI:45409 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020443 infores:hetionet CHEBI:45863 biolink:causes HP:0030248 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0267412 infores:hetionet CHEBI:77260 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0232849 infores:hetionet CHEBI:520985 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0007859 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0011616 infores:hetionet UNII:D27V6190PM biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0032781 infores:hetionet CHEBI:16714 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0013144 infores:hetionet CHEBI:31711 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151315 infores:hetionet CHEBI:94392 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0011991 infores:hetionet CHEBI:4681 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0035243 infores:hetionet CAID:CA412741161 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741161 MONDO:0100437 PMID: Uncertain Significance PP1, PM2_Supporting, PP3_Moderate PS4 NM_001034853.2(RPGR):c.920C>A (p.Thr307Lys) is a missense variant encoding substitution of threonine with lysine at amino acid 307. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). The computational predictor REVEL gives a score of 0.909, which is between the ClinGen X-linked IRD VCEP thresholds of 0.773 and 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The splicing impact predictor SpliceAI gives a score of 0.02, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant has been reported in at least 1 proband, however, the patient was diagnosed with primary ciliary dyskinesia (PCD) and no visual testing was done (PMID: 32253119), so PS4_Supporting was not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting and PP3_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741161/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Inconclusive true NCBIGene:161497 biolink:causes MONDO:0011364 infores:monarchinitiative not_provided not_provided HGNC:16035 MONDO:0011364 uuid:921761c7-eff5-4acc-bde2-716ddf4763f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0011701 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0042109 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0236075 infores:hetionet CHEBI:291342 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0041834 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0009782 infores:hetionet CHEBI:66899 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0151827 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232431 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0162119 infores:hetionet CHEBI:50730 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0022107 infores:hetionet CHEBI:31236 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0522055 infores:hetionet CAID:CA8622835 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622835 MONDO:0100326 PMID: Benign BP7, BA1, BP4 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.57G>T (p.Ala19=), no individuals with Glanzmann thrombasthenia were reported with the variant. This variant was observed by Ilumina as part of a predisposition screen in an ostensibly healthy population. Moreover, the variant has a minor allele frequency of 0.01423 (144/10122 alleles) in gnomAD, found in the African/African American population, which is considerably higher than the expected frequency of the disease (BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of 0.669 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622835/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9137 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0006118 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0858797 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0175167 infores:hetionet CHEBI:8327 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0392176 infores:hetionet CHEBI:82716 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0042487 infores:hetionet NCBIGene:146754 biolink:causes MONDO:0033671 infores:monarchinitiative not_provided not_provided HGNC:2948 MONDO:0033671 uuid:8f157fee-81b1-4708-8362-7202db7487ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0231528 infores:hetionet CHEBI:84500 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011603 infores:hetionet NCBITaxon:5873 biolink:causes MONDO:0005978 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5873 MONDO:0005978 CHEBI:136040 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0151830 infores:hetionet CHEBI:23765 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0687713 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0013378 infores:hetionet CHEBI:7798 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0004096 infores:hetionet CHEBI:134990 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0040264 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0232492 infores:hetionet CHEBI:6792 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0038990 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0040046 infores:hetionet CAID:CA367398869 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398869 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.1121T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to glutamic acid at codon 374 (p.(Val374Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.968, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1120G>A p.(Val374Met), has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). This variant was identified in two unrelated individuals with hypglycemia; however, this number does not meet the MDEP cutoff for PS4_Moderate (Solano et al. 2019. Rev Esp Endocrinol Pediatr 10(2):69-73, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting . Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398869/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:27834 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0917801 infores:hetionet NCBIGene:114548 biolink:causes MONDO:0033261 infores:monarchinitiative not_provided not_provided HGNC:16400 MONDO:0033261 uuid:a33d5d7e-9419-495e-b8c7-bce4319f2448 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes UMLS:C0877035 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0877035 infores:hetionet CHEBI:52010 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0040264 infores:hetionet NCBIGene:51091 biolink:causes MONDO:0013438 infores:monarchinitiative not_provided not_provided HGNC:30605 MONDO:0013438 uuid:0b3c8760-af1f-47b3-ad4a-fca537019a3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0917801 infores:hetionet CHEBI:72690 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0028081 infores:hetionet CHEBI:49575 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C3203358 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1167965 infores:hetionet NCBIGene:2778 biolink:causes MONDO:0012912 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0012912 uuid:dc2c37ee-1475-4458-95c3-1fd06aa708b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0231528 infores:hetionet CHEBI:101853 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151905 infores:hetionet CHEBI:8499 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0085631 infores:hetionet CHEBI:35553 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0000737 infores:hetionet GO:0002273 biolink:causes CL:0000784 infores:ubergraph knowledge_assertion manual_agent GO:0002273 CL:0000784 CHEBI:47381 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151825 infores:hetionet CHEBI:64310 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085635 infores:hetionet UBERON:0010298 biolink:causes UBERON:0010300 infores:ubergraph knowledge_assertion manual_agent UBERON:0010298 UBERON:0010300 CHEBI:63605 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0546884 infores:hetionet CHEBI:17334 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0002878 infores:hetionet CHEBI:2379 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0010200 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0020517 infores:hetionet CHEBI:44423 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0013144 infores:hetionet CAID:CA040715 biolink:causes MONDO:0007750 infores:clingen CAID:CA040715 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PVS1, PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, BS2 The NM_000527.5(LDLR):c.2416dup (p.Val806fs) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is frameshift upstream of amino acid 830, so PVS1 is met.PP1_strong - variant segregates with the FH phenotype in- 1 informative meiosis from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative with the phenotype has the variant;- 7 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): data from 4 families: 6 relatives with the phenotype have the variant plus 1 relative without the phenotype does not have the variant;8 informative meiosis support co-segregation, so PP1_Strong is met.PS4 - variant meets PM2 and was identified in - 6 unrelated index cases with DLCN>6 from Roberts Research Institute, Canada;- 1 index case with DLCN>6 from COLOR, USA;- 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 5 unrelated index cases who fulfill SB criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;14 cases, so PS4 is metPM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - variant meets PM2 and was identified in 14 unrelated index cases from different labs (please see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040715/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:52717 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0314719 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0039971 infores:hetionet CHEBI:7478 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0026821 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C1142412 infores:hetionet GO:1900383 biolink:causes GO:0048167 infores:ubergraph knowledge_assertion manual_agent GO:1900383 GO:0048167 UMLS:C0209366 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0000768 infores:hetionet CHEBI:17823 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0239935 infores:hetionet CHEBI:4672 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0030196 infores:hetionet CHEBI:135622 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06771 UMLS:C0151827 infores:hetionet CHEBI:205919 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0015230 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0235706 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235706 infores:hetionet NCBIGene:85021 biolink:causes MONDO:0054763 infores:monarchinitiative not_provided not_provided HGNC:15578 MONDO:0054763 uuid:fe720b0c-2888-4adc-a92d-d9f12e17d577 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0021053 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0009806 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0282005 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0282005 infores:hetionet CHEBI:28177 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0042963 infores:hetionet CHEBI:68575 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0948594 infores:hetionet CHEBI:231425 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0011991 infores:hetionet CHEBI:3561 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0022346 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0021167 infores:hetionet NCBITaxon:2560319 biolink:causes MONDO:0005875 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2560319 MONDO:0005875 CHEBI:38545 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0574067 infores:hetionet CHEBI:43968 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0037299 infores:hetionet CAID:CA229426 biolink:causes MONDO:0009861 infores:clingen CAID:CA229426 MONDO:0009861 PMID:21307867PMID:15319459PMID:21147011 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5, PS3 The c.1289T>C (p.Leu430Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21307867). This variant is absent in population databases. This variant was detected with pathogenic variants: p.R241C (PMID: 21147011); p.S70del, p.R241C (PMID: 30050108); c.728G>A, p.R243Q (PMID: 31355225). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229426/MONDO:0009861/006 2020-08-17 2021-12-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA315411422 biolink:causes MONDO:0015967 infores:clingen CAID:CA315411422 MONDO:0015967 PMID: Pathogenic PS3_Supporting, PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4, PP1_Strong PM1, BA1, BP4, BS1 The c.734G>A variant in the HNF4A gene causes an amino acid change of arginine to histidine at codon 245 (p.Arg254His) of NM_175914.4. Functional studies demonstrated the p.Arg254His protein has transactivation below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 30325586). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab collaborators, PMIDs: 30325586, 21922456). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.733C>T p.Arg245Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg345His (PM5_Supporting). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab collaborators). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.92, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and personal history of being large for gestational age) (PP4_Moderate; internal lab collaborators). In summary, c.734G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS3_Supporting, PS4, PM2_Supporting, PM5_Supporting, PP1_Strong, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA315411422/MONDO:0015967/085 2023-09-15 2023-09-15 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:139212 biolink:causes MONDO:0010517 infores:monarchinitiative not_provided not_provided HGNC:28570 MONDO:0010517 uuid:a3e37064-6ffc-41dd-8a2a-62d1af41ce4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0040822 infores:hetionet GO:0090128 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0090128 GO:0007275 CHEBI:253342 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0013415 infores:hetionet NCBIGene:5621 biolink:causes MONDO:0011703 infores:monarchinitiative not_provided not_provided HGNC:9449 MONDO:0011703 uuid:e2b563b8-225a-4443-8e21-349ec40aac9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA073621 biolink:causes MONDO:0100150 infores:clingen CAID:CA073621 MONDO:0100150 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The c.9472+1G>A (NM_000540.3(RYR1):c.9472+1G>A) variant in RYR1 occurs within the canonical splice donor site (+ 1) of intron 63. It is predicted to cause skipping of biologically-relevant-exon 63, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The total grpmax in gnomAD v4.1.0 is 0.00000068 or 0.000068% in the European (non-Finnish) population (3/1179972) (PM2_supporting). This variant was found in a compound heterozygous state with a variant of uncertain significance (p.Arg282Trp (c.844C>T)) in an affected proband (phase unknown). The proband with the variants displayed susceptibility to heat hyperthermia, single type 1 congenital neuromuscular disease, and micronuclear myopathy with extraocular muscle paraplegia, features highly specific for autosomal recessive RYR1-related myopathy (PP4; 10.3760/cma.j.cn511374-20200729-00564). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PP4 (Congenital Myopathies VCEP specifications Version 1: 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA073621/MONDO:0100150/179 2024-08-07 2024-10-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119486 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0038663 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0521591 infores:hetionet UMLS:C0005740 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0020580 infores:hetionet CHEBI:39112 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0232487 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0007222 infores:hetionet CHEBI:209807 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0002878 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0151828 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002622 infores:hetionet CHEBI:63619 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0028084 infores:hetionet CHEBI:3723 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0236075 infores:hetionet CHEBI:61049 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0041834 infores:hetionet CHEBI:50173 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0870082 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0852733 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0021845 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037274 infores:hetionet CHEBI:8356 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0268000 infores:hetionet CHEBI:116278 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0009676 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0015397 infores:hetionet CHEBI:145499 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011124 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0267596 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0175167 infores:hetionet CHEBI:478164 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C1443060 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0025061 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0853089 infores:hetionet CHEBI:240107 biolink:causes HP:0100583 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0339293 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0232933 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0232933 infores:hetionet CHEBI:3223 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0026205 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0745528 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0745528 infores:hetionet CHEBI:474180 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0009676 infores:hetionet CHEBI:6128 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0033774 infores:hetionet CHEBI:8024 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0003862 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027441 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033117 infores:hetionet CHEBI:391960 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0042029 infores:hetionet CHEBI:3504 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0008031 infores:hetionet CHEBI:5103 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0549249 infores:hetionet NCBIGene:84894 biolink:causes MONDO:0020846 infores:monarchinitiative not_provided not_provided HGNC:21205 MONDO:0020846 uuid:25b9a044-01b0-48f8-9792-c192278a13fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151746 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002418 infores:hetionet CHEBI:18248 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0162297 infores:hetionet CHEBI:9449 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0151436 infores:hetionet CAID:CA121215 biolink:causes MONDO:0019169 infores:clingen CAID:CA121215 MONDO:0019169 PMID: Pathogenic PP4, PVS1_Moderate, PM2, PS2_Very Strong PM1, BS2 The c.1142_c.1145dup variant in the PDHA1 gene is a frameshift variant in the final exon of PDHA1, which is predicted to escape nonsense mediated decay and result in amino acid truncation that removes less than 10% of the predicted protein product (PVS1_moderate PMID: 30192042). This variant is absent from population databases (PM2). This variant has been reported in several patients with presentations consistent with PDHA1-related disease in the literature. While this variant has been reported several times before, only five cases met criteria for scoring, including four assumed de novo cases in PMID: 10679936 and PMID: 20002461, and one maternity confirmed de novo case in PMID: 26865159. Several commercial testing laboratories (GeneDx, Illumina, and Ambry) have identified this variant was harbored by maternity confirmed de novo probands with presentations consistent with PDHA1-related disease (minimum of 3 and maximum of 6 probands- SCV001251622.1, SCV000252046.3, SCV000742395.2). Upon further review, the expert panel determined that while unable to confirm the identity of these patients, taken together these data in conjunction with the cases reported in the literature were sufficient to support elevating scoring to PS2_Very Strong per SVI de novo variant scoring criteria v1.0. PMID: 1779625 and PMID: 8504309 reported elevated pyruvate in the blood, and blood and CSF of the respective probands. PMID: 23021068 performed PDC activity assays < 3rd percentile in fibroblasts (PP4). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PVS1_moderate, PM2, PS2_Very Strong, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/18/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA121215/MONDO:0019169/014 2021-05-06 2021-05-06 X-linked inheritance HP:0001417 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8356 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0031350 infores:hetionet CHEBI:35854 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0016204 infores:hetionet CAID:CA10014225 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014225 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.994G>A (p.Asp332Asn) is a missense variant. This variant has a MAF of 0.0009758 (0.09758%, 5/5124, 5124 alleles) in the East Asian subpopulation of the gnomAD cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score < 0.50 (0.316) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014225/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:77733 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0018681 infores:hetionet NCBIGene:96459 biolink:causes MONDO:0030528 infores:monarchinitiative not_provided not_provided HGNC:29418 MONDO:0030528 uuid:7fd736aa-6774-40de-bcf2-950e1a13635f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51380 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0232487 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0018099 infores:hetionet CHEBI:64312 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0016204 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151752 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0233494 infores:hetionet CHEBI:10124 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C2830004 infores:hetionet CHEBI:5847 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0015376 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0031039 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0033975 infores:hetionet CHEBI:10023 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0021368 infores:hetionet CHEBI:52010 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0013384 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235218 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235218 infores:hetionet CHEBI:3749 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0020757 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0027813 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152517 infores:hetionet CHEBI:40237 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C1565489 infores:hetionet CHEBI:175901 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0011615 infores:hetionet CHEBI:83531 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0221423 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2010560 infores:hetionet CHEBI:31623 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0020615 infores:hetionet CHEBI:7824 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0041657 infores:hetionet CHEBI:32139 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0005778 infores:hetionet CHEBI:45951 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0013384 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0332534 infores:hetionet CHEBI:3082 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0010200 infores:hetionet NCBIGene:144811 biolink:causes MONDO:0032920 infores:monarchinitiative not_provided not_provided HGNC:26789 MONDO:0032920 uuid:2c39efed-c67b-4127-bb40-3f316da7414a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28787 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0011616 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0020649 infores:hetionet CHEBI:84500 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0239739 infores:hetionet CHEBI:367163 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C2830004 infores:hetionet CHEBI:472657 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C1565489 infores:hetionet CHEBI:80630 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0152227 infores:hetionet CHEBI:5128 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0042963 infores:hetionet CHEBI:75722 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C3665624 infores:hetionet CAID:CA212349 biolink:causes MONDO:0007648 infores:clingen CAID:CA212349 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.1137+86T>G variant has an allele frequency of 0.0165 (1.65%, 144/8728 alleles) in the African subpopulation of the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA212349/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63607 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151596 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0018939 infores:hetionet CHEBI:5778 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0035078 infores:hetionet CHEBI:64317 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0027497 infores:hetionet CHEBI:16469 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0232462 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0022116 infores:hetionet GO:0045592 biolink:causes GO:0048165 infores:ubergraph knowledge_assertion manual_agent GO:0045592 GO:0048165 CHEBI:480999 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0028643 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0029134 infores:hetionet CHEBI:5165 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0497156 infores:hetionet CHEBI:4784 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0042384 infores:hetionet CHEBI:171719 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0039231 infores:hetionet CAID:CA494462159 biolink:causes MONDO:0700272 infores:clingen CAID:CA494462159 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting The c.839del (p.Asn280fs) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 4 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1, PM5_Supporting, PM2_Supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA494462159/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:61049 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040264 infores:hetionet CHEBI:63584 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042963 infores:hetionet CHEBI:41423 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018681 infores:hetionet CHEBI:3479 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0017178 infores:hetionet CHEBI:3419 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0013144 infores:hetionet GO:0043313 biolink:causes GO:0002283 infores:ubergraph knowledge_assertion manual_agent GO:0043313 GO:0002283 CHEBI:3219 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0521591 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0035854 infores:hetionet CHEBI:3752 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0011603 infores:hetionet NCBIGene:64902 biolink:causes MONDO:0008860 infores:monarchinitiative not_provided not_provided HGNC:14412 MONDO:0008860 uuid:6cef3020-87aa-48d8-820a-eb8e145672d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3508 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0040046 infores:hetionet UBERON:0004209 biolink:causes UBERON:0000084 infores:ubergraph knowledge_assertion manual_agent UBERON:0004209 UBERON:0000084 CHEBI:63627 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0003123 infores:hetionet CHEBI:16899 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0042024 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0015967 infores:hetionet CHEBI:3077 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C2242996 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0025061 infores:hetionet CHEBI:7573 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0917801 infores:hetionet CHEBI:5441 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0001973 infores:hetionet CHEBI:9123 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0231837 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020456 infores:hetionet CHEBI:5790 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0162297 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011570 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042373 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0741453 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0741453 infores:hetionet CHEBI:45783 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009676 infores:hetionet CHEBI:7822 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0038362 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0042109 infores:hetionet CHEBI:6950 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151908 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0023895 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0852913 infores:hetionet CAID:CA380145361 biolink:causes MONDO:0000572 infores:clingen CAID:CA380145361 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting PS3 The NM_000448.3:c.76T>C variant in RAG1 is a missense variant predicted to cause a substitution of serine by proline at amino acid 26 (p.Ser26Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one entry without the information of the second allele, and the variant was classified as Uncertain Significance (Ambry Genetics, SCV003601680.1). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145361/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:94449 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0011603 infores:hetionet CHEBI:31176 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0037036 infores:hetionet CHEBI:5818 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0018524 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0242350 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0002170 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0149931 infores:hetionet CHEBI:48273 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0344232 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0027051 infores:hetionet CAID:CA2697546419 biolink:causes MONDO:0021057 infores:clingen CAID:CA2697546419 MONDO:0021057 PMID: Uncertain Significance PM2_Supporting BS2, PVS1 The NM_000038.6(APC):c.8488dup (p.Ser2830fs*3) variant in APC is a frameshift variant located downstream of codon 2645, therefore PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in one individual without a colorectal cancer/polyposis associated phenotype not meeting criteria for BS2 (BS2 not met; Ambry internal data). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697546419/MONDO:0021057/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6456 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0005758 infores:hetionet CHEBI:37941 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0917801 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0042571 infores:hetionet CHEBI:2379 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0013404 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0029445 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235351 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0742006 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0742006 infores:hetionet CHEBI:6904 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0010520 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0007971 infores:hetionet CHEBI:135736 biolink:causes HP:0005542 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151563 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042109 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032285 infores:hetionet CHEBI:5141 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0151505 infores:hetionet CHEBI:9555 biolink:causes UMLS:C0852925 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0852925 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0033687 infores:hetionet CHEBI:9139 biolink:causes UMLS:C2242621 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2242621 infores:hetionet CHEBI:3175 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0456909 infores:hetionet CHEBI:3568 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037036 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009938 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0162429 infores:hetionet CHEBI:53691 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0522055 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0040034 infores:hetionet CHEBI:63637 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0026858 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0000737 infores:hetionet CHEBI:16755 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0023218 infores:hetionet CHEBI:5103 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0001807 infores:hetionet GO:0061132 biolink:causes GO:0031016 infores:ubergraph knowledge_assertion manual_agent GO:0061132 GO:0031016 CAID:CA32686185 biolink:causes MONDO:0020367 infores:clingen CAID:CA32686185 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting BP7, BS1, BS3, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BA1, BP4 The c.781G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 261 (p.Glu261Lys). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.628, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMID: 10916185), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA32686185/MONDO:0020367/019 2022-12-14 2022-12-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42820 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0022107 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020538 infores:hetionet CHEBI:27565 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0013378 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017152 infores:hetionet CAID:CA10603553 biolink:causes MONDO:0010725 infores:clingen CAID:CA10603553 MONDO:0010725 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PVS1 The NM_000330.4(RS1):c.520del variant is a frameshift variant due to 1 nucleotide deletion introducing a premature stop codon and causing a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 30551202, 17852193, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PVS1, and PS4_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603553/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:4953 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C2979982 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0011616 infores:hetionet CHEBI:7824 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027796 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0040261 infores:hetionet CHEBI:64321 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0575081 infores:hetionet CHEBI:6761 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0085593 infores:hetionet CAID:CA8129872 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129872 MONDO:0007648 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM1, PM3, PM5, PM4, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS3, PS4, PS2, PS1 The c.522C>A (p.Asn174Lys) variant has an allele frequency: 2:251288 (0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.13 for acceptor gain, which is below the ClinGen X-linked IRD VCEP recommended PP3 threshold of >0.2 but above the BP4 threshold of <0.1, so neither in silico code is met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385351/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:18332 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0018801 infores:hetionet CHEBI:17303 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020453 infores:hetionet CHEBI:119915 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020580 infores:hetionet HP:0030126 biolink:causes HP:0000132 infores:drugmechdb knowledge_assertion manual_agent HP:0030126 MESH:D008595 DB00717_MESH_D008595_2 CHEBI:85078 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0546817 infores:hetionet CAID:CA2017997778 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997778 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1351del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 451 (NM_000162.5), adding 163 novel amino acids before encountering a stop codon (p.(Leu451TrpfsTer163)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with diabetes/elevated HbA1c; however, this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributors) One of these individuals has a clinical history suggestive of GCK-MODY; however, PP4 was unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, the c.1351del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997778/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Supports CHEBI:7565 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0231528 infores:hetionet CHEBI:3213 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0017979 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0392176 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0853760 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0019158 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0005940 infores:hetionet CHEBI:8871 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234133 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013298 infores:hetionet CHEBI:36704 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042963 infores:hetionet NCBIGene:5317 biolink:causes MONDO:0011472 infores:monarchinitiative not_provided not_provided HGNC:9023 MONDO:0011472 uuid:0cca0025-d5c6-43e0-b21a-71b72451b70d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31485 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C1761613 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0857246 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0857246 infores:hetionet CHEBI:9943 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011603 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0030305 infores:hetionet GO:0010807 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0010807 GO:0007268 CHEBI:68579 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0039070 infores:hetionet CHEBI:3723 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235086 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0042571 infores:hetionet GO:1905304 biolink:causes GO:0032989 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0032989 CHEBI:6149 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0085610 infores:hetionet CAID:CA367401753 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401753 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate The c.502A>G variant in the glucokinase gene, GCK causes an amino acid change of Thr to Ala at codon 168 (p.(Thr168Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with diabetes (PS4_Moderate; PMID: 30592380, 23155716, 25015100, 18382660, 18571549, internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies/ OGTT glucose increment < 3 mmol/L) (PP4_Moderate; PMIDs: 30592380, 18382660). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Thr168Ala variant has RAI<0.50 (PS3_Moderate; PMID 18571549). This variant resides in an amino acid within the GCK glucose interaction domain that makes an H-bond interaction with glucose, which is defined as critical for the protein’s function by the GlinGen MDEP (PM1). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): PM2_Supporting, PP2, PM1, PP3, PS3_Moderate, PP4_Moderate, PS4_Moderate . Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401753/MONDO:0015967/086 2023-07-28 2023-07-28 Semidominant inheritance HP:0032113 Supports CHEBI:75722 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0007222 infores:hetionet CHEBI:51141 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0036396 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0234215 infores:hetionet CHEBI:17347 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0036974 infores:hetionet CHEBI:4856 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0036974 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0001418 infores:hetionet CAID:CA10650432 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650432 MONDO:0011071 PMID: Benign BA1, BP2 PS3, PS1, PS2, PS4, BP3, BP1, BP4, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, BS2, PP4, PP1, PP2, PP3 NM_001754.5(RUNX1):c.*613A>T is a 3' UTR variant. MAF of 0.004884(0.4884%, 332/67974) in the European(Non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%)(BA1). One homozygote found in gnomAD v33.1.2 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650432/MONDO:0011071/008 2022-02-11 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4530 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0032617 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0948594 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0008035 infores:hetionet CHEBI:188986 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0020452 infores:hetionet CHEBI:18358 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0234894 infores:hetionet CAID:CA637749759 biolink:causes MONDO:0011071 infores:clingen CAID:CA637749759 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.-59-9G>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.24) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637749759/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:38940 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0025874 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0032285 infores:hetionet CHEBI:134991 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0278134 infores:hetionet UMLS:C0145867 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0040822 infores:hetionet CHEBI:7575 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0027497 infores:hetionet CHEBI:6078 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0232493 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0919671 infores:hetionet CHEBI:70718 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0178298 infores:hetionet CHEBI:180905 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0026919 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0026919 infores:hetionet CHEBI:119486 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0392525 infores:hetionet CHEBI:63635 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020458 infores:hetionet CAID:CA319100 biolink:causes MONDO:0012589 infores:clingen CAID:CA319100 MONDO:0012589 PMID: Likely Benign BP4, PM2_Supporting, BS2 BA1, BS1 The p.Thr138Ser variant in TCF4 is absent from gnomAD (PM2_Supporting). The p.Thr138Ser variant is observed in at least 3 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Thr138Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 3 unaffected individuals, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion. In summary, the p.Thr138Ser variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA319100/MONDO:0012589/032 2023-12-06 2023-12-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2687 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C1443060 infores:hetionet CHEBI:2668 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0236075 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009241 infores:hetionet CAID:CA386966376 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966376 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PP3 The c.817A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamine at codon 273 (p.(Lys273Gln) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.817, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, c.817A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966376/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:287 biolink:causes MONDO:0009061 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:287 MESH:D003550 DB06151_MESH_D003550_1 CAID:CA410203895 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203895 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.209A>G (p.Lys70Arg) is a missense variant which has a REVEL score < 0.50 (0.373) and a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203895/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:122173801 biolink:causes HP:0033188 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0010666 infores:hetionet CHEBI:52717 biolink:causes MONDO:0044872 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013363 infores:hetionet CHEBI:50859 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0010200 infores:hetionet CHEBI:9168 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042963 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0542149 infores:hetionet CHEBI:2453 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0020523 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0341012 infores:hetionet CAID:CA10585680 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585680 MONDO:0007750 PMID: Likely Pathogenic PP1_Strong, PM5, PM2, PP4 BA1, BP4, BP2, PS3, PS2, PS1, PS4, BS1, BS3, BS4, BP7, PM1, PM4, PM3, PM6, PVS1, BS2, PP3 The NM_000527.5(LDLR):c.1916T>G (p.Val639Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PM5 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025.The supporting evidence is as follows:PM2: PopMax MAF = 0.00002196 (0.002196%) in South Asian exomes+genomes (gnomAD v4.1.0).PM5: 1 other missense variant in the same codon is classified as Pathogenic by these guidelines:- NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) (ClinVar ID 200922). PP4: Variant meets PM2 and is identified in only 1 proband with MEDPED criteria for FH from Pakistan (PMID 22311046 – Ahmed et al., 2012), after alternative causes of high cholesterol were excluded.PP1_Strong: Variant segregates with FH phenotype in 9 informative meiosis from 1 family from Pakistan (PMID 22311046 – Ahmed et al., 2012): 6 affected family members have the variant and 3 unaffected family members do not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585680/MONDO:0007750/013 2025-01-31 2025-03-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8863 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0008031 infores:hetionet UMLS:C0120107 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085633 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0027720 infores:hetionet CHEBI:135613 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0085614 infores:hetionet CHEBI:3077 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0577559 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042769 infores:hetionet CAID:CA210750 biolink:causes MONDO:0013144 infores:clingen CAID:CA210750 MONDO:0013144 PMID: Pathogenic PS4_Moderate, PM5, PM1, PP1_Strong, PP3, PP4, PM2_Supporting The c.1246G>C variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by proline at amino acid 416 (p.Ala416Pro). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL and abnormal crossed electrophoresis, which is highly specific for autosomal dominant hereditary antithrombin deficiency (PP4, PMID:4082101). This variant has been reported in two more probands meeting an antithrombin activity level of < 0.8 IU/mL and a family history of disease with reported decreased antithrombin activity levels (PS4_Moderate; PMID:24583439, 2093312). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in at least 9 affected meioses from 4 families (PP1_Strong; PMID:33725558, 4082101, 24583439, 2093312).This variant resides within an reactive site residues (Ala416) of SERPINC1 that is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PM1). Another missense variant c.1246G>T (p.Ala416Ser) (ClinVarID:18023) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5).The computational predictor REVEL gives a score of 0.837, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic forautosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1_strong, PM1, PM5, PS4_moderate, PP3, PP4, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210750/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42797 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020676 infores:hetionet CHEBI:31709 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0015967 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0043250 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0013395 infores:hetionet CHEBI:5004 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C2047937 infores:hetionet CHEBI:7986 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C1368065 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0026848 infores:hetionet CHEBI:17334 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0027540 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0020283 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D014605 DB02703_MESH_D014605_1DB00684_MESH_D014605_1 CHEBI:80630 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0039070 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0040034 infores:hetionet CAID:CA291015 biolink:causes MONDO:0012999 infores:clingen CAID:CA291015 MONDO:0012999 PMID: Benign BA1, BP4, BP7 The NM_000156.6:c.279C>T (p.Asp93=) is a synonymous variant in GAMT that is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00484 (87/17976 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). This variant does not appear to have been previously reported in the published literature. It is noted in ClinVar (Variation ID 137434). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BA1, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291015/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3077 biolink:causes MONDO:0006875 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0028840 infores:hetionet CHEBI:63632 biolink:causes MONDO:0024879 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C1384494 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0018418 infores:hetionet CHEBI:6030 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0040034 infores:hetionet CHEBI:2904 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0344232 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018799 infores:hetionet CHEBI:4470 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0027769 infores:hetionet CAID:CA8423237 biolink:causes MONDO:0019497 infores:clingen CAID:CA8423237 MONDO:0019497 PMID: Benign BP4, BA1 The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8423237/MONDO:0019497/005 2021-06-15 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:63620 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0206061 infores:hetionet CHEBI:45652 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0340865 infores:hetionet GO:0044509 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0044509 GO:0051716 CHEBI:46195 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0241705 infores:hetionet CHEBI:51380 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0022107 infores:hetionet CHEBI:5120 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0019147 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040479 infores:hetionet CHEBI:8356 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085631 infores:hetionet CHEBI:16796 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0149745 infores:hetionet CHEBI:59560 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0003862 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020517 infores:hetionet CHEBI:9763 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0037036 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C1861172 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0002878 infores:hetionet CHEBI:50673 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0022346 infores:hetionet CHEBI:66876 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0232487 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0018801 infores:hetionet CHEBI:8863 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0040822 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0027765 infores:hetionet CHEBI:9137 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085632 infores:hetionet CHEBI:8863 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0549249 infores:hetionet CHEBI:5383 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0687713 infores:hetionet GO:0010001 biolink:causes CL:0000125 infores:ubergraph knowledge_assertion manual_agent GO:0010001 CL:0000125 CHEBI:36791 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085635 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0012739 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020456 infores:hetionet CHEBI:9086 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0008031 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0236071 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0021400 infores:hetionet CHEBI:27834 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0522224 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005670 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0005681 infores:hetionet CHEBI:251408 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0011991 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0027947 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0002871 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007222 infores:hetionet CHEBI:8354 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0012569 infores:hetionet CHEBI:42820 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C2363731 infores:hetionet CAID:CA410147646 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147646 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1252A>C (p.Met418Leu) is a missense variant which has a REVEL score < 0.50 (0.219), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147646/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:167309 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C2830004 infores:hetionet CHEBI:6741 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0018965 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235969 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0035078 infores:hetionet NCBIGene:9138 biolink:causes MONDO:0032763 infores:monarchinitiative not_provided not_provided HGNC:681 MONDO:0032763 uuid:5785ec11-6ab1-46a9-b8dc-f250738318ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2922 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0232462 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0032285 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0003460 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0015376 infores:hetionet NCBIGene:5925 biolink:causes MONDO:0001187 infores:monarchinitiative not_provided not_provided HGNC:9884 MONDO:0001187 uuid:1e687879-3fed-4abf-97b9-e0e197b504e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1527344 infores:hetionet CAID:CA172210 biolink:causes MONDO:0019497 infores:clingen CAID:CA172210 MONDO:0019497 PMID:31160754PMID:31160754PMID:31160754 Pathogenic PP1_Strong, PM3, PS4 BS4, PP3, BS2, BA1, PS3 The filtering allele frequency (the lower threshold of the 95% CI of 143/1558, including 8 homozygous observations) of the c.109G>A (p.Val37Ile) variant in the GJB2 gene is 7.9% for East Asian genomes in gnomAD.This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 139 homozygous affected probands, 17 affected probands with the p.Met34Thr variant in trans, 131 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans. However, because the variant is also very frequent in the general population, this criteria has been applied at the strength of Moderate. (PM3; PMID: 31160754). The p.Val37Ile variant in GJB2 has been reported to segregate with hearing loss in at least 21 family members (PP1_Strong; PMID: 31160754). Although homozygous or compound heterozygous observations have been identified in individuals with normal hearing, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance (PMID: 27308839). Furthermore, in dye transfer and electrical coupling assays, both functional studies have shown that the variant impacts protein function (PMID: 26088551, 12505163, 16300957) and knock-in mouse model demonstrated that the p.Val37Ile variant leads to the phenotype. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, and the dye transfer and coupling assays have limited validation and correlation with pathogenicity, neither was not counted as functional evidence. (PMID: 27623246). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Val37Ile in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA172210/MONDO:0019497/005 2019-06-24 2025-09-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63577 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0023787 infores:hetionet CHEBI:6375 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030794 infores:hetionet CHEBI:5775 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0013404 infores:hetionet CHEBI:51041 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C2937350 infores:hetionet CHEBI:9927 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0687713 infores:hetionet CHEBI:9398 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0003811 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0038454 infores:hetionet CHEBI:63717 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0041349 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0349506 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C3160944 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C3160944 infores:hetionet UMLS:C0120107 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0004093 infores:hetionet CHEBI:9123 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0016658 infores:hetionet CHEBI:4315 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0242429 infores:hetionet CHEBI:367163 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0011124 infores:hetionet CHEBI:59773 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0018524 infores:hetionet CHEBI:9757 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0234708 infores:hetionet CHEBI:4681 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0018790 infores:hetionet CHEBI:168396 biolink:causes HP:0020071 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042749 infores:hetionet CHEBI:63605 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0162557 infores:hetionet NCBIGene:4287 biolink:causes MONDO:0007182 infores:monarchinitiative not_provided not_provided HGNC:7106 MONDO:0007182 uuid:d44d94b1-a971-47ed-b52b-bad7176e86af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0522224 infores:hetionet CHEBI:7986 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0014591 infores:hetionet CAID:CA410146710 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146710 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1412G>T (p.Arg471Leu) is a missense variant which has a REVEL score < 0.50 (0.409) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146710/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10014562 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014562 MONDO:0011071 PMID: Uncertain Significance PS1, BP1, BP4, BP3, BP2, BA1, PM2, PVS1, BP7, BS1, PM5, PM4, PM1, PM3, PP4, PP2, PP3 NM_001754.5(RUNX1):c.250G>A (p.Asp84Asn) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014562/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1527344 infores:hetionet CHEBI:10102 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0030252 infores:hetionet GO:1903541 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1903541 GO:0051641 CHEBI:3082 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0018099 infores:hetionet CHEBI:31439 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00265 UMLS:C0011603 infores:hetionet CHEBI:45367 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0034155 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033581 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0018418 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0014868 infores:hetionet CAID:CA183392 biolink:causes MONDO:0021060 infores:clingen CAID:CA183392 MONDO:0021060 PMID: Likely Benign PP2, BS2 PP3, BP4 The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. The computational predictor REVEL gives a score of 0.318, which is neither above nor below the thresholds predicting a damaging or benign impact on BRAF function. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant (BS2; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS2, PP2 (RASopathy VCEP specifications version 1; 8/11/22). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA183392/MONDO:0021060/004 2022-08-23 2022-08-23 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6904 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0547030 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0002871 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009319 infores:hetionet CHEBI:3506 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0040034 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0019348 infores:hetionet CAID:CA410148302 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148302 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1058T>C (p.Phe353Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148302/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31711 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0600228 infores:hetionet NCBITaxon:2104 biolink:causes MONDO:0006668 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2104 MESH:D003234 DB00365_MESH_D003234_1DB01137_MESH_D003234_2 CHEBI:46195 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0019158 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0002871 infores:hetionet CHEBI:61058 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C1274594 infores:hetionet CAID:CA410203348 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203348 MONDO:0011071 PMID:34166225 Pathogenic PS3, PM5_Supporting, PVS1, PM2_Supporting PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.349A>T (p.Lys117Ter) is a nonsense variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1). There is evidence of very low or abnormal mRNA/protein expression of the c.349A>T (p.Lys117Ter) variant allele as a functional consequence of a null variant or incorrect mRNA/protein products (PS3; PMID: 34166225). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS3, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203348/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4975 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C1704272 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0009450 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0234215 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0151559 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0027813 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C2973529 infores:hetionet CHEBI:4877 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0029134 infores:hetionet CHEBI:3478 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0038990 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0038362 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0549209 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0039971 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0009938 infores:hetionet CHEBI:681848 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0020578 infores:hetionet CHEBI:7824 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013428 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0009782 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0041969 infores:hetionet CHEBI:63617 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0003467 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0349506 infores:hetionet NCBIGene:4047 biolink:causes MONDO:0030009 infores:monarchinitiative not_provided not_provided HGNC:6708 MONDO:0030009 uuid:402fc44e-ec6e-44e4-a912-3659fe4790b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0033975 infores:hetionet CHEBI:7514 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0026205 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1458155 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0520893 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0015734 infores:hetionet CHEBI:6633 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0012739 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042075 infores:hetionet CAID:CA402996427 biolink:causes MONDO:0012999 infores:clingen CAID:CA402996427 MONDO:0012999 PMID:24415674 Likely Pathogenic PP4, PM2_Supporting, PP3_Moderate, PM3_Supporting, PS3_Supporting The NM_000156.6:c.274A>G variant in GAMT is a missense variant predicted to cause the substitution of an asparagine by an aspartate at amino acid position 92 (p.Asn92Asp). This variant has been previously reported in one individual with elevated urine guanidinoacetate and low urine creatine (PP4) who was homozygous for the variant (PMID: 19288536, 24415674, 33996490) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001705 (2/1172782 alleles; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, evidence that correlates with impact to GAMT function (PP3_Moderate applied for REVEL score range 0.773-0.932). This variant was shown to result in <15% GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 2446453). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3_Moderate, PP4.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402996427/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Supports UNII:UMD7G2653W biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0003467 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0042571 infores:hetionet CHEBI:31401 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0025222 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0003123 infores:hetionet CAID:CA000131 biolink:causes MONDO:0017623 infores:clingen CAID:CA000131 MONDO:0017623 PMID:29785012PMID:29706350 Likely Pathogenic PP3, PP2, PS3_Moderate, PM2_Supporting PM6, PVS1, BP7, BP5, BS1, BS3, BS4, BS2, PP1, PP4, PM5, PM4, PM1, PM3, BP4, BP1, BP3, BP2, BA1, PS1, PS4, PS2 PTEN c.170T>G (p.Leu57Trp) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 9256433, 29706350)PM2: Absent in large sequenced populationsPP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000131/MONDO:0017623/003 2025-08-01 2025-10-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6437 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0042963 infores:hetionet CAID:CA16020940 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020940 MONDO:0009861 PMID: Uncertain Significance PM2 PM3, PM5, PP3, PP4 The c.1103A>G (p.Glu368Gly) variant in PAH has been reported in an Indian family with an affected patient with classical PKU. BH4 deficiency not reportedly ruled out. The patient is deceased and was not available for genotyping, but each parent was a heterozygous carrier of this variant. (PMID: 24130151) This variant is absent from 1000G, ESP, ExAC and gnomAD. Computational evidence is conflicting. The p.Glu368Lys variant is interpreted as Pathogenic by 1 submitter in ClinVar, and as likely pathogenic by PAH VCEP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020940/MONDO:0009861/006 2021-05-28 2021-05-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA16603348 biolink:causes MONDO:0044970 infores:clingen CAID:CA16603348 MONDO:0044970 PMID: Uncertain Significance PP3 PS4, PS3, PS2, PM2, PM6 The m.4132G>A (p.A276T) variant in MT-ND1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on May 23, 2023. There is one family reported in the medical literature with this variant (PMID: 17454741). The six affected individuals in this family had non-arteritic anterior ischemic optic neuropathy. The variant was present at homoplasmy in all affected family members and information is not provided on testing status in unaffected family members, precluding consideration for segregation evidence. There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.015%, 9/61,883; gnomAD v3.1.2: 0.019%, 11/56,428 homoplasmic occurrences; Helix: 0.041%, 80/195,893 homoplasmic occurrences). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.58 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603348/MONDO:0044970/015 2023-05-23 2025-06-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:40279 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038238 infores:hetionet CHEBI:17026 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0030193 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0919591 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0919591 infores:hetionet CAID:CA120631 biolink:causes MONDO:0044970 infores:clingen CAID:CA120631 MONDO:0044970 PMID: Uncertain Significance PP1, PP3, PM2_Supporting PP4, PS4, PS2, PS3, PM6 The m.13084A>T (p.S250C) variant in MT-ND5 has been reported in one family with primary mitochondrial disease to date (PMIDs: 12509858, 33062892). The proband was a boy with features and brain imaging findings consistent with both Leigh syndromes spectrum disorder and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) including neurodegeneration, stroke-like episodes, seizures, myoclonic jerks, bradykinesia, ataxia, dysarthria, decreased visual acuity, ptosis, hearing loss, and right bundle branch block. Complex I activity was mildly reduced in muscle. The variant was present at 85% in muscle, 82% in blood, 99% in buccal cells, 67% in urine, and 72% in fibroblast cell line. The proband’s mother was more mildly affected with migraines and Leber Hereditary Optic Neuropathy (LHON). The variant was present at 75% in lymphocytes and 48% in fibroblasts. The proband’s sister had brisk reflexes and diffuse slow wave activity on electroencephalogram (EEG) and had the variant present at 41% in lymphocytes and 13% in fibroblasts (PP1). There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.61 (Min=0, Max=1; APOGEE2 score is 0.883), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120631/MONDO:0044970/015 2023-11-13 2024-08-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5280 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0149745 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020615 infores:hetionet GO:1900154 biolink:causes GO:0048705 infores:ubergraph knowledge_assertion manual_agent GO:1900154 GO:0048705 CHEBI:17026 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042790 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0236106 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0236106 infores:hetionet CAID:CA358784 biolink:causes MONDO:0010315 infores:clingen CAID:CA358784 MONDO:0010315 PMID:7632950 Pathogenic PM1_Strong, PS3_Supporting, PM6, PP4, PM2_Supporting, PS4 PM5, PP3 The NM_000206.3(IL2RG):c.676C>T (p.Arg226Cys) missense variant resides within a CpG dinucleotide region, cDNA 676-677 encoding amino acid R226, of IL2RG that is defined as a mutational hotspot (PMID: 7668284; PM1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The male (0.5pt) patient of PMID: 14966353 has a T-B+NK- lymphocyte subset profile (0.5pt) [CD3: 2.5%; CD19: 95.4%; CD16/CD56: 0.5%] which is specific for SCID due to gamma chain deficiency (1pt; PP4). In a second case, the R226C variant arose de novo as a somatic mutation early in embryogenesis in the mother of the patient, 1 pt, PM6_Moderate (PMID: 23683512).At least eight additional male X-SCID patients have been reported (PMIDs: 9058718, 11129345, 22936741, 7668284) with this hemizygous variant (total 4.5pt; PS4). PMID: 7632950 Examined the mutant 7 chain distribution by confocal microscopy in transiently transfected COS-7 cells, comparing it with the wild-type 7 chain distribution. The mutant 7 chain could not be detected by an antihuman IL-2 receptor 7 chain monoclonal antibody, TUGh4, on the cell surface of the transfected COS-7 cells. This result was in sharp contrast to that obtained with the wild-type γ chain, which was clearly stained by TUGh4 on the transfected cells. PS3_Supporting is met.In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PS4, PM1_Strong, PM6_Moderate, PM2_Supporting, PS3_Supporting, and PP4. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA358784/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:2950 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0027441 infores:hetionet CHEBI:41423 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042384 infores:hetionet CHEBI:9570 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0039231 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0178298 infores:hetionet CHEBI:7936 biolink:causes MONDO:0007122 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003079 infores:hetionet CHEBI:474180 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595916 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020557 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0006266 infores:hetionet CHEBI:171719 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0085593 infores:hetionet CHEBI:8665 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0000731 infores:hetionet CAID:CA915940791 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940791 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The frameshift variant NM_000419.5(ITGA2B):c.1973del (p.Ala658GlufsTer?) has been reported in one individual with a disorder of platelet function, (TGP0048 in PMID:31064749). Communication with the authors confirmed a diagnosis of Glanzmann thrombasthenia. The patient had impaired platelet aggregation and prolonged bleeding after dental extraction. This individual, TGP0048, is compound heterozygous for this frameshift variant and a variant of uncertain significance (NM_000419.5(ITGA2B):c.188+5G>T). The c.1973del frameshift variant causes a premature stop codon in exon 20/30, which is predicted to undergo nonsense mediated decay in a disease that is loss of function (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00006335 (1/15786 alleles) in the African/African American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1 and PM2_supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940791/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6741 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0010200 infores:hetionet CHEBI:6067 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009421 infores:hetionet CHEBI:72690 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0004238 infores:hetionet CHEBI:63631 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085616 infores:hetionet CHEBI:127780 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0015967 infores:hetionet GO:0043321 biolink:causes GO:0002323 infores:ubergraph knowledge_assertion manual_agent GO:0043321 GO:0002323 CHEBI:6887 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0008031 infores:hetionet CHEBI:6456 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0080274 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034150 infores:hetionet CHEBI:44032 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0014724 infores:hetionet CHEBI:194135 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0855775 infores:hetionet CHEBI:28001 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0017178 infores:hetionet CHEBI:6916 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0003862 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0034063 infores:hetionet CHEBI:63613 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0020456 infores:hetionet CHEBI:10101 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0424295 infores:hetionet CHEBI:35778 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0020672 infores:hetionet CHEBI:63580 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0041834 infores:hetionet CHEBI:465284 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0575081 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0235774 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0235774 infores:hetionet CHEBI:51364 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C2830004 infores:hetionet CHEBI:119486 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018681 infores:hetionet CHEBI:49040 biolink:causes MONDO:0018328 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0342881 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0003467 infores:hetionet CHEBI:8356 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013362 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0004238 infores:hetionet CHEBI:9586 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0007859 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0014742 infores:hetionet NCBIGene:3425 biolink:causes MONDO:0011758 infores:monarchinitiative not_provided not_provided HGNC:5391 MONDO:0011758 uuid:234865dc-d712-4aef-8ec3-220a481a8aac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0009763 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0018799 infores:hetionet UNII:D27V6190PM biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0015967 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0003123 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002878 infores:hetionet CHEBI:8364 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0021167 infores:hetionet CHEBI:41774 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0232462 infores:hetionet CHEBI:66913 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0027765 infores:hetionet CHEBI:9586 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151786 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0021400 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0233794 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0264714 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0264714 infores:hetionet CHEBI:50729 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0018965 infores:hetionet CAID:CA226485 biolink:causes MONDO:0100368 infores:clingen CAID:CA226485 MONDO:0100368 PMID: Likely Pathogenic PM5, PM3, PP3_Moderate, PP4, PP1, PM2_Supporting BP4 NM_000329.3:c.1103A>G(p.Tyr368His) is a missense variant that replaces tyrosine with cysteine at position 368 in RPE65. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.200T>G (p.Leu67Arg) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 point, PMID: 22509104, PM3). At least one proband harboring this variant exhibits a phenotype including poor visual acuity (1 pt), nyctalopia (0.5 pts), nystagmus (1 pt), pigmentary retinopathy with attenuation of retinal blood vessels (0.5 pts), decreased dark-adapted (0.5 pts) and light-adapted (1 pt) electroretinogram responses, which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 22509104, PP4). The variant co-segregated with childhood-onset severe retinal dystrophy in the proband's family through at least 1 affected meiosis (PP1; PMID: 22509104). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) in the same codon has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5). SpliceAI confirms that neither variant is strongly predicted to cause a splicing defect. The computational predictor REVEL gives a score of 0.961, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PM5, PP1, PP3_Moderate, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226485/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4856 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0039070 infores:hetionet CHEBI:408174 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0035455 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0039503 infores:hetionet CHEBI:50122 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0033774 infores:hetionet CHEBI:367163 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0877055 infores:hetionet CAID:CA270384 biolink:causes MONDO:0010726 infores:clingen CAID:CA270384 MONDO:0010726 PMID: Pathogenic PM2_Supporting, PM1, PS2_Very Strong The p.Ala131Asp variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage confirmed) in an individual with features of Rett syndrome (internal database - GeneDx) and reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with features of Rett syndrome (PMID 15737703 and 26984561) (PS2_Very strong). The p.Ala131Asp variant occurs in the well-characterized Methyl-DNA binding [MDB] functional domain of the MECP2 (PM1). The p.Ala131Asp variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ala131Asp variant in MECP2 (NM_004992.3) is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_Very strong, PM1, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270384/MONDO:0010726/036 2024-08-30 2024-10-25 X-linked inheritance HP:0001417 Supports UMLS:C0025241 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0948441 infores:hetionet CHEBI:2659 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0016382 infores:hetionet CHEBI:6965 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0085631 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151763 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013781 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0042571 infores:hetionet NCBIGene:9698 biolink:causes MONDO:0958231 infores:monarchinitiative not_provided not_provided HGNC:14957 MONDO:0958231 uuid:55692407-5bfe-41aa-8af2-a43b38c68eda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16041900 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041900 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting BA1, BS1 The NM_000152.5:c.2213G>A (p.Trp738Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001666 (1/60024 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). One patient with this variant has been reported with infantile onset Pompe disease and has deficient GAA activity (PMID: 27927596) (PP4). There is a ClinVar entry for this variant (Variation ID: 370222). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041900/MONDO:0009290/010 2024-12-19 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7565 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0009763 infores:hetionet CHEBI:6128 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0017152 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020557 infores:hetionet CHEBI:8461 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0234133 infores:hetionet CHEBI:8768 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0232462 infores:hetionet CHEBI:80630 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0221423 infores:hetionet CHEBI:125354 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0011603 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0042401 infores:hetionet CHEBI:15551 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0026821 infores:hetionet CHEBI:5134 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0152030 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0006145 infores:hetionet CHEBI:47381 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0038999 infores:hetionet CHEBI:5103 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0428977 infores:hetionet CHEBI:7601 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0027424 infores:hetionet CHEBI:6129 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0404521 infores:hetionet CHEBI:167638 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C2830004 infores:hetionet CHEBI:9434 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0015672 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004245 infores:hetionet CHEBI:3207 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0332601 infores:hetionet CHEBI:2038 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0232462 infores:hetionet CHEBI:64355 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0575081 infores:hetionet CHEBI:28901 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0004093 infores:hetionet GO:1903975 biolink:causes GO:0042063 infores:ubergraph knowledge_assertion manual_agent GO:1903975 GO:0042063 CHEBI:6375 biolink:causes UMLS:C0948484 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948484 infores:hetionet CHEBI:404903 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0037011 infores:hetionet CHEBI:8871 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085688 infores:hetionet CHEBI:8059 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0232492 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0267596 infores:hetionet CHEBI:7494 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C2364111 infores:hetionet CHEBI:6402 biolink:causes HP:0003109 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0948023 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0080194 infores:hetionet CHEBI:2549 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0231218 infores:hetionet CHEBI:10110 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0019054 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151849 infores:hetionet CHEBI:63627 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0151539 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0003811 infores:hetionet CHEBI:4445 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0085631 infores:hetionet CHEBI:27690 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0017979 infores:hetionet CHEBI:171719 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0028738 infores:hetionet CHEBI:40279 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0019209 infores:hetionet CAID:CA410203854 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203854 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.226C>T (p.Arg76Cys) is a missense variant which has a REVEL score ≥ 0.88 (0.911) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203854/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31401 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0039231 infores:hetionet CHEBI:3207 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0027441 infores:hetionet CAID:CA2573157365 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157365 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.968-3C>T is an intronic variant which is not predicted to impact splicing. This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157365/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:36791 biolink:causes MONDO:0005392 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036439 infores:hetionet CHEBI:231594 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0011124 infores:hetionet CHEBI:10650 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0231274 infores:hetionet CHEBI:37941 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0041657 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005311 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004153 infores:hetionet CHEBI:2611 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0026838 infores:hetionet CAID:CA172189 biolink:causes MONDO:0100040 infores:clingen CAID:CA172189 MONDO:0100040 PMID: Benign BA1 The allele frequency of the p.Gly224= variant in FOXG1 is 0.136% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Gly224= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172189/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853619 infores:hetionet CHEBI:10125 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0149725 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0518015 infores:hetionet CHEBI:45327 biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0520886 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0543467 infores:hetionet CHEBI:46081 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0018681 infores:hetionet CHEBI:6838 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0151763 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0010200 infores:hetionet CHEBI:68534 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0149725 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0240322 infores:hetionet CHEBI:567361 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0235025 infores:hetionet CHEBI:8232 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0042963 infores:hetionet CHEBI:17823 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0032617 infores:hetionet CAID:CA024925 biolink:causes MONDO:0018493 infores:clingen CAID:CA024925 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 2840 of the RYR1 protein, p.(Arg2840Trp). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000131, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 not implemented (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.659 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024925/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:135888 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0030554 infores:hetionet CHEBI:9150 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C2004489 infores:hetionet CHEBI:6437 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0033774 infores:hetionet CAID:CA367398928 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398928 MONDO:0015967 PMID: Likely Pathogenic PM5, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PP1 The c.1113C>G variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tryptophan at codon 371 (p.(Cys371Trp)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.891, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Cys371Trp has a greater Grantham distance. (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0 approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5 . Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398928/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:8207 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085641 infores:hetionet CAID:CA10652907 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652907 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS4, PS3, BP4, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM5, PM1, PM4, PP1, PP3 The NM_001754.4:c.*3574A>G variant in the 3' UTR has an MAF of 0.085 (8%, 3384/41962 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 121 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652907/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:5105 biolink:causes MONDO:0009866 infores:monarchinitiative not_provided not_provided HGNC:8724 MONDO:0009866 uuid:4380e310-30f6-4cf7-81a5-d407ef32a2e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes UMLS:C0859062 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0859062 infores:hetionet CHEBI:9137 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0023530 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0270810 infores:hetionet CHEBI:5383 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0015672 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0038587 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1565489 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1443060 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0178298 infores:hetionet CHEBI:32139 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0011175 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0042075 infores:hetionet CHEBI:6970 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0017160 infores:hetionet CHEBI:5613 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0085612 infores:hetionet CHEBI:5147 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0039240 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0031117 infores:hetionet CHEBI:3423 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0520966 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1140680 infores:hetionet CAID:CA376060149 biolink:causes MONDO:0011225 infores:clingen CAID:CA376060149 MONDO:0011225 PMID: Likely Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM3_Strong PP2, PP3, BP1, BP4 The NM_001033855.3:c.406G>A variant in DCLRE1C is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 136 (p.Asp136Asn). This variant is absent from population databases (gnomAD v2.2.1) (PM2_Supporting) and has been observed in two probands with SCID that carried a co-occurring variant in trans. The first proband has a clinical diagnosis of severe combined immunodeficiency (SCID) (0.5p) with a T-B-NK+ immunophenotype (0.5p) who was tested using a large 407 gene immunodeficiency panel (0.5p) and carried a co-occurring variant (c.629del p.Tyr210Leufs*14) in trans (Invitae, PP4 1.5p). The second proband is patient ART007 reported in PMID: 36566626, who has a clinical diagnosis of Artemis-related SCID (0.5p) that was corrected by DLCRE1C lentiviral gene therapy (1p) and carried a co-occurring variant (Deletion of exons 1-5) in trans (PP4 1.5p). For both patients, the co-occurring variant was confirmed in trans and would be classified as Likely Pathogenic or Pathogenic (PM3_Strong, 2p (1p per proband)). An in vitro study reported that this variant exhibited < 25% of wildtype V(D)J recombinase activity as well as undetectable endonucleolytic cleavage activity in an in vitro cleavage assay (PMID: 15071507, PS3_Moderate). In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied, PP4, PM3_Strong, PS3_Moderate, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376060149/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0231218 infores:hetionet NCBIGene:221496 biolink:causes MONDO:0008925 infores:monarchinitiative not_provided not_provided HGNC:21244 MONDO:0008925 uuid:4af57b5d-e23f-493f-a1c6-90c7b99ffb86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0018834 infores:hetionet CHEBI:167638 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0009806 infores:hetionet NCBIGene:85378 biolink:causes MONDO:0009624 infores:monarchinitiative not_provided not_provided HGNC:18127 MONDO:0009624 uuid:b59c4c2c-7618-4a0f-9b74-d769d9f1f217 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0025241 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0019158 infores:hetionet CHEBI:6640 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0549249 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0017178 infores:hetionet NCBIGene:2706 biolink:causes MONDO:0011245 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0011245 uuid:d25b7a50-98c4-4f8f-a75b-163a74a2789f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6904 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018681 infores:hetionet CHEBI:10110 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151610 infores:hetionet CHEBI:45327 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0013404 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0235338 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235338 infores:hetionet CAID:CA277606 biolink:causes MONDO:0015152 infores:clingen CAID:CA277606 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.1834C>T p.(Gln612Ter) variant in DYSF, which is also known as NM_001130987.2: c.1888C>T p.(Gln630Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 20/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least seven individuals with dysferlinopathy (PMID: 11053681, 18832576, 18853459, 21522182, 25493284, 36983702), including in unconfirmed phase with a pathogenic variant in two patients (NM_003494.4: c.5768-51_5946+50del (exon 52 deletion), 0.5 pts, PMID: 36983702; NM_003494.4: c.4886+1249G>T, 0.5 pts, PMID: 25493284) (PM3). At least one individual with two presumed diagnostic DYSF variants displayed slow progressive muscle weakness and reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 18832576, 18853459, 21522182, 25493284, 36983702; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000028602 (based on 24/1180048 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/30/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA277606/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4710 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0031256 infores:hetionet CHEBI:63621 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1519353 infores:hetionet CHEBI:4315 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0022354 infores:hetionet CHEBI:7915 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0038325 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0267792 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0011615 infores:hetionet CHEBI:15367 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019214 infores:hetionet CHEBI:30659 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0002994 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0037199 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0302295 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013922 infores:hetionet CHEBI:2904 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018800 infores:hetionet CHEBI:6339 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0000731 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0410158 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0410158 infores:hetionet CHEBI:6775 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0438142 infores:hetionet CHEBI:75045 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0424790 infores:hetionet CHEBI:4672 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0034063 infores:hetionet CHEBI:3077 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0033845 infores:hetionet NCBIGene:124976 biolink:causes MONDO:0032762 infores:monarchinitiative not_provided not_provided HGNC:26992 MONDO:0032762 uuid:bf124ecd-9bf1-4ee6-a2fe-b404ea7234ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0235431 infores:hetionet CHEBI:31536 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0003862 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0027769 infores:hetionet NCBIGene:318 biolink:causes MONDO:0859240 infores:monarchinitiative not_provided not_provided HGNC:8049 MONDO:0859240 uuid:2da1628c-eb32-4ec0-9863-0edc039a764b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0553713 infores:hetionet CHEBI:61033 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1291077 infores:hetionet CHEBI:100241 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0600142 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0036572 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151544 infores:hetionet CHEBI:63681 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0007222 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0948089 infores:hetionet CHEBI:8890 biolink:causes MONDO:0700217 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0456103 infores:hetionet CAID:CA410208255 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208255 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.26C>T (p.Ser9Leu) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208255/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6912 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0018939 infores:hetionet CHEBI:31705 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0013378 infores:hetionet CHEBI:5128 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0013144 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0277884 infores:hetionet UMLS:C0657912 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085635 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0021122 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0007787 infores:hetionet CHEBI:3510 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0036830 infores:hetionet GO:2000800 biolink:causes GO:0003188 infores:ubergraph knowledge_assertion manual_agent GO:2000800 GO:0003188 CHEBI:6965 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0040822 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1145628 infores:hetionet NCBIGene:51218 biolink:causes MONDO:0014804 infores:monarchinitiative not_provided not_provided HGNC:20134 MONDO:0014804 uuid:7f7e6c8a-7a0a-45c8-a017-c5d3d11e9ba2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:131512 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0043352 infores:hetionet CAID:CA016520 biolink:causes MONDO:0004994 infores:clingen CAID:CA016520 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.597A>G (p.Ala199=) variant in the MYH7 gene is 1.44% (1013/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016520/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:92712 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0003811 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0020649 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002871 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0002871 infores:hetionet CHEBI:40050 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0023787 infores:hetionet CHEBI:72690 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0009806 infores:hetionet CHEBI:182080 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0011991 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0235876 infores:hetionet CHEBI:31397 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C2607914 infores:hetionet CHEBI:3032 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0040822 infores:hetionet CAID:CA5950037 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950037 MONDO:0000572 PMID: Likely Benign BS1 BS2, PP1, PP4, PM5, PM1, PM3, PS1, PS3 The c.725A>G, NM_000448.3, variant in RAG1 is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 242 (p.Gln242Arg).The filtering allele frequency (the lower threshold of the 95% CI of 477/128678) of the c.725A>G variant in RAG1 is 0.003627 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (0.00195) for BS1, and therefore meets this criterion (BS1).This variant has been detected in at least one individual with Omenn syndrome. The patient is compound heterozygous for the variant R404Q and also carries another variant in RAG1: N766I. There is no information about family segregation. Phase unknown. (PMID: 32311393). No homozygous are found. This patient displays Diagnostic criteria for Omenn syndrome, which reaches 0.5pt, not enough to apply PP4 in any strength (PMID: 32311393, PP4 Not_Met).In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950037/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:50275 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027540 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0006145 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0549405 infores:hetionet CHEBI:63618 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0344232 infores:hetionet CHEBI:31705 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0013144 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0004497 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:C536774 DB01053_MESH_C536774_1DB09320_MESH_C536774_1 CHEBI:465284 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151723 infores:hetionet CHEBI:32221 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0042023 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0239279 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0239279 infores:hetionet CHEBI:9241 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0231218 infores:hetionet NCBITaxon:5039 biolink:causes MONDO:0005672 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5039 MONDO:0005672 CHEBI:135736 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0039591 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0018939 infores:hetionet CHEBI:50777 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0003467 infores:hetionet CHEBI:47898 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0028734 infores:hetionet CHEBI:71219 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0085682 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042769 infores:hetionet CHEBI:31624 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0085593 infores:hetionet CHEBI:5165 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151827 infores:hetionet CAID:CA410147876 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147876 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS2, PS4, PS3, BP1, BP2, BP3, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS4, BS3, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 The c.1172C>G (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of alanine by glycine at amino acid 391 (p.A391G). The highest population minor allele frequency in gnomAD v2 is 0.00004155 (1/24068 alleles) in the South Asian population, and the variant has not been reported in patients. The computational predictor REVEL gives a score of 0.015, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147876/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes NCIT:C122529 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0857494 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030846 infores:hetionet CHEBI:28445 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151701 infores:hetionet CHEBI:7447 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0853813 infores:hetionet CHEBI:5134 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0013595 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0040479 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0877661 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0008031 infores:hetionet CHEBI:8768 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0391870 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0012833 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013295 infores:hetionet CHEBI:28748 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030196 infores:hetionet CHEBI:480999 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1443060 infores:hetionet CHEBI:70718 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0851341 infores:hetionet CHEBI:9434 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0231528 infores:hetionet NCBIGene:154288 biolink:causes MONDO:0013671 infores:monarchinitiative not_provided not_provided HGNC:33699 MONDO:0013671 uuid:085f7b1a-a285-437d-8d0b-9721d496344b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0023530 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040147 infores:hetionet CHEBI:3499 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0014457 infores:hetionet CHEBI:27690 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0267792 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0162429 infores:hetionet CHEBI:8805 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0041834 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037195 infores:hetionet CHEBI:3013 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C1167965 infores:hetionet CHEBI:3568 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151539 infores:hetionet CAID:CA203404964 biolink:causes MONDO:0011225 infores:clingen CAID:CA203404964 MONDO:0011225 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM3 PM5 The c.95C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Phenylalanine at amino acid 32 (p.Ser32Phe).The filtering allele frequency (the upper threshold of the 95% CI of 2/1111892 alleles) of the c.95C>T variant in DCLRE1C is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total 1 pt; Which is highly specific for SCID. PP4_Supporting (PMIDs: 18223550 and 25917813 - same patient). The proband is compound heterozygous, in trans, for del Ex1-3 (at least LP according to our SCID VCEP specifications;) 1 point, PM3_Moderate. (PMID: 25917813).Activity levels in % of WT activity = Recombination: Mean (SD): 5.14 (0.34) and DNA repair (36h after IR): Mean (SD): 20.95 (6.17). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level(PMID: 25917813).In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Supporting, PM3_Moderate, and PS3_Moderate. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA203404964/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9434 biolink:causes HP:0032510 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0231529 infores:hetionet NCBIGene:1832 biolink:causes MONDO:0012323 infores:monarchinitiative not_provided not_provided HGNC:3052 MONDO:0012323 uuid:43519052-2b56-499f-b078-d5a919cbc71d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0547030 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0012797 infores:hetionet CHEBI:63791 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018681 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0267033 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0267033 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0155169 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0029456 infores:hetionet CHEBI:6062 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042345 infores:hetionet CHEBI:36795 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0035410 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0233494 infores:hetionet CHEBI:50275 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0236075 infores:hetionet CHEBI:47898 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026826 infores:hetionet CHEBI:114785 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0009782 infores:hetionet CHEBI:77733 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0423791 infores:hetionet CHEBI:4911 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0549410 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0178298 infores:hetionet CHEBI:4995 biolink:causes DOID:9007 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038644 infores:hetionet CHEBI:119573 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1320474 infores:hetionet CHEBI:4784 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C2004489 infores:hetionet CHEBI:2636 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0014742 infores:hetionet CHEBI:8874 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C3665386 infores:hetionet CHEBI:50275 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013404 infores:hetionet CAID:CA902209 biolink:causes MONDO:0100368 infores:clingen CAID:CA902209 MONDO:0100368 PMID: Benign BP4, BA1, BP7 NM_000329.3(RPE65):c.1302G>A (p.Ala434=) is a synonymous variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.02695, with 734 alleles / 24954 total alleles and 7 homozygotes in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.07 for donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902209/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31236 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0521592 infores:hetionet CHEBI:8107 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0086565 infores:hetionet CHEBI:50131 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0239981 infores:hetionet CHEBI:36791 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020598 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0023533 infores:hetionet CHEBI:31515 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0917801 infores:hetionet CAID:CA607887175 biolink:causes MONDO:0015967 infores:clingen CAID:CA607887175 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS3, PS4_Moderate, PP1_Strong, PP4_Moderate, PP3 The c.526+5G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to alter the splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Minigene-splicing assay demonstrates that this variant results in abnormal splicing and the deletion of the last 32 nucleotides of exon 2 (PS3; Bouvet et al., 2023). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative GAD and IA2 antibodies) (PP4_Moderate; internal lab contributors). This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant segregated with diabetes, with four informative meioses in two families (PP1_Strong; internal lab contributors). In summary, c.526+5G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PS3, PP4_Moderate, PS4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA607887175/MONDO:0015967/017 2025-04-17 2025-04-17 Autosomal dominant inheritance HP:0000006 Supports CAID:CA274070 biolink:causes MONDO:0010134 infores:clingen CAID:CA274070 MONDO:0010134 PMID:22285650 Likely Pathogenic PS3_Supporting, PP3, PP4, PM3, PM2_Supporting The c.554G>A variant in SLC26A4 is a missense variant predicted to cause substitution of arginine by threonine at amino acid 185 (p.Arg185Thr). The variant was present in 0.0165% (1/6062) of Middle Eastern alleles, which is the highest population minor allele frequency in gnomAD v4.1.0, and PM2_Supporting was applied at the recommendation of the expert panel. This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as in three probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650, 34680964). The variant was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Additionally, it was observed in one proband with hearing loss, enlarged vestibular aqueduct, and Mondini malformation who was compound heterozygous with a second pathogenic variant with phase unknown (PMID: 34599368). The variant was also seen in an infant with mild congenital bilateral sensorineural hearing loss who also had two pathogenic OTOG variants in trans (Invitae internal data ClinVar SCV002243689.3). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3, PS3_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA274070/MONDO:0010134/005 2024-10-16 2025-01-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:28593 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0232493 infores:hetionet NCBIGene:3000 biolink:causes MONDO:0008764 infores:monarchinitiative not_provided not_provided HGNC:4689 MONDO:0008764 uuid:86b50c19-ae13-44c0-819e-f78b1c9e86c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0029442 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0022660 infores:hetionet CHEBI:8707 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018524 infores:hetionet CHEBI:51041 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0008031 infores:hetionet NCBIGene:23594 biolink:causes MONDO:0013430 infores:monarchinitiative not_provided not_provided HGNC:17151 MONDO:0013430 uuid:b0a5e5aa-d302-4f7c-9d31-36d3bbf99181 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0012817 infores:hetionet CHEBI:261649 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0235309 infores:hetionet CHEBI:135342 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0008031 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0031542 infores:hetionet CAID:CA9043673 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043673 MONDO:0012999 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong PM3 The NM_000156.6:c.402C>G (p.Tyr134Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in one individual with GAMT deficiency (PMID: 19027335). This individual had elevated GAA and low creatine in plasma and significantly decreased creatine peak and visible GAA peak on brain MRS with full GAMT gene sequencing (PMID: 19027335) (PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 947458, 2 star review status) with 3 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043673/MONDO:0012999/026 2023-05-25 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4717 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0030252 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0020456 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0022408 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0549475 infores:hetionet CAID:CA248655 biolink:causes MONDO:0019501 infores:clingen CAID:CA248655 MONDO:0019501 PMID:19683999PMID:25773295PMID:28944237PMID:28653555PMID:19683999PMID:25773295PMID:28944237PMID:28653555PMID:22004887PMID:25262649 Benign BA1 BP5, BP7, BS4, BS1, PP1, PP4, PP3, BS2, PM1, PM3, PM4, PM5, PM6, PM2, PVS1, BP2, BP3, BP4, PS3, PS4, PS2, PS1 The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA248655/MONDO:0019501/005 2020-12-24 2020-12-24 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA123181 biolink:causes MONDO:0009276 infores:clingen CAID:CA123181 MONDO:0009276 PMID: Likely Pathogenic PS3_Supporting, PP3, PP1, PP4, PM3 BS1, PM2, PM5 The c.70T>C (p.Cys24Arg) variant in GP9 is a missense variant predicted to cause substitution of cystine by arginine at amino acid 24. This variant has been detected in at least 14 probands with Bernard-Soulier syndrome. All 14 of these individuals were homozygous for this variant at least 2 of those were confirmed in trans by parental testing (PMIDs:23402648, 21699652, 21173099, 11167791, 29119711; PM3). At least one patient (Patient BSS2.01 in PMID:23402648) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus one affected family member, both with the homozygous genotype with the p.Cys24Arg variant. (PP1; PMID:21173099). The computational predictor REVEL gives a score of 0.732, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). The human copy of this variant failed to rescue thrombocytopenia when expressed in mutant thrombocytopenic zebrafish embryos.In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP1, PP3, PP4, PS3_supporting. (VCEP specifications version 1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123181/MONDO:0009276/083 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0034186 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020456 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1274594 infores:hetionet CHEBI:6129 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0019270 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009938 infores:hetionet CHEBI:5959 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0008031 infores:hetionet CHEBI:45863 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0162830 infores:hetionet CAID:CA157980 biolink:causes MONDO:0007648 infores:clingen CAID:CA157980 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BP3, BP1, BP4, BP2, BA1, PS3, PS4, PS2, PS1 The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157980/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:17263 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0025218 infores:hetionet CHEBI:47898 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0015967 infores:hetionet GO:0080092 biolink:causes GO:0044706 infores:ubergraph knowledge_assertion manual_agent GO:0080092 GO:0044706 CHEBI:3561 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0851578 infores:hetionet CAID:CA032357 biolink:causes MONDO:0007750 infores:clingen CAID:CA032357 MONDO:0007750 PMID: Likely Benign BP4, BP7 BA1, BS1, PM2 The NM_000527.5(LDLR):c.1167G>A (p.Thr389=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence codes: BP4, BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - No REVEL, splicing evaluation needed.Functional data on splicing not available.A) not on limitsB) does not create GTVariant is not predicted to alter splicingBP7 - Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA032357/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15551 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0027051 infores:hetionet CHEBI:50861 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0039070 infores:hetionet CHEBI:144093 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0687713 infores:hetionet CAID:CA1706103 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706103 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.2163-2A>G variant in DYSF, which is also known as NM_001130987.2: c.2217-2A>G, occurs within the canonical splice acceptor site of intron 22. SpliceAI gives a delta score of 0.99 for loss of the canonical acceptor and of 0.79 for gain of a cryptic acceptor 4 bp into the exon. RNAseq analysis showed this variant either results in a 4 bp deletion at the start of exon 23 or skipping of exon 23, both leading to frameshifts (p.Gln722LeufsTer26 and p.Gln722ProfsTer51, respectively), with nonsense mediated decay expected (PMID: 36983702; PVS1_RNA). This variant has been reported in three patients with either dysferlinopathy or suspected LGMD (PMID: 33715265, 33927379, 36983702), including in unknown phase in two individuals with pathogenic variants NM_003494.4: c.5668-7G>A (0.5 pts, PMID: 33927379) and NM_003494.4: c.2875C>T p.(Arg959Trp) (0.5 pts, PMID: 33715265) (PM3). At least one patient with this variant had a second presumed diagnostic variant in DYSF, clinical presentation highly suggestive of dysferlinopathy and absent dysferlin expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong). The highest minor allele frequency for this variant is 0.000001799 (2/1112008 exome alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the VCEP threshold of 0.0001 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 10/07/2025): PVS1_RNA, PP4_Strong, PM3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706103/MONDO:0015152/180 2025-10-07 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CAID:CA412745351 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745351 MONDO:0100437 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PM2_Supporting, PP3_Moderate NM_001034853.2(RPGR):c.308C>T (p.Thr103Ile) is a missense variant in the final codon of exon 4 and is predicted to encode substitution of threonine with isoleucine in codon 103. The computational predictor REVEL gives a score of 0.819, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The splicing impact predictor SpliceAI gives a score of 0.63 for donor loss and 0.59 for acceptor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), family history consistent with X-linked inheritance (2) including delayed or milder phenotype in females (1 pt), genotyping by next-generation sequencing-based retinal panel identifying no alternative cause of disease (2 pts), rod involvement greater than cone (1 pt), decreased central vision acuity (0.5 pts), and bone spicule pigmentation (0.5 pts) which together are highly specific for RPGR-related retinopathy (8 points, communication with clinical researcher regarding unpublished proband, PP4_moderate). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_moderate; communication with clinical researcher regarding unpublished proband). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PP1_moderate, PP3_moderate, and PP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745351/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:9328 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0237849 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0036572 infores:hetionet CHEBI:6640 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0033774 infores:hetionet CHEBI:5693 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00756 UMLS:C0011603 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042134 infores:hetionet CHEBI:8081 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0012833 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020649 infores:hetionet UMLS:C0657912 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0043352 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0009450 infores:hetionet CHEBI:7773 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0039070 infores:hetionet CHEBI:64354 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0042109 infores:hetionet CHEBI:5165 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0039231 infores:hetionet CHEBI:5855 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0917801 infores:hetionet CHEBI:50275 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017979 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0086543 infores:hetionet NCBIGene:8925 biolink:causes MONDO:0014863 infores:monarchinitiative not_provided not_provided HGNC:4867 MONDO:0014863 uuid:c20c7465-5e0e-4874-82be-c0b00bc34980 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0020686 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0001361 infores:hetionet NCBIGene:3978 biolink:causes MONDO:0030693 infores:monarchinitiative not_provided not_provided HGNC:6598 MONDO:0030693 uuid:73758f91-022c-4dd5-a085-03b9dbd990cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27300 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0029456 infores:hetionet CAID:CA137952 biolink:causes MONDO:0021060 infores:clingen CAID:CA137952 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.525C>T (p.Ile175=) variant in the MAP2K2 gene is 0.255% (11/2418) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137952/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:0060842 biolink:causes CL:1000413 infores:ubergraph knowledge_assertion manual_agent GO:0060842 CL:1000413 CHEBI:4681 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0917798 infores:hetionet CHEBI:15854 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0013404 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0233494 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0021053 infores:hetionet CHEBI:9654 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0232462 infores:hetionet CHEBI:8364 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0011603 infores:hetionet CHEBI:51450 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0019079 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005369 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0007095 infores:hetionet CHEBI:91834 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0035455 infores:hetionet CHEBI:167638 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0002792 infores:hetionet CHEBI:7824 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0700590 infores:hetionet CHEBI:5134 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0085932 infores:hetionet CHEBI:63624 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0019158 infores:hetionet CHEBI:10124 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0018965 infores:hetionet CHEBI:2038 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0042963 infores:hetionet CHEBI:135351 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0268000 infores:hetionet NCBIGene:2799 biolink:causes MONDO:0009658 infores:monarchinitiative not_provided not_provided HGNC:4422 MONDO:0009658 uuid:acaeaa77-6f7d-4f6d-961b-b4af29224c20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017566 infores:hetionet CAID:CA229330 biolink:causes MONDO:0009861 infores:clingen CAID:CA229330 MONDO:0009861 PMID:9634518PMID:8097261 Pathogenic PP4_Moderate, PVS1, PM2 The c.1076C>G (p.Ser359Ter) variant in PAH has been reported in an individual with PKU; BH4 deficiency excluded (PP4_Moderate; PMID: 8097261; (PMID: 9634518). This variant is absent in population databases (PM2). It is a nonsense variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229330/MONDO:0009861/006 2020-06-26 2020-06-26 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:286 biolink:causes MONDO:0008447 infores:monarchinitiative not_provided not_provided HGNC:492 MONDO:0008447 uuid:5cf7c249-122d-47c0-a403-5e8dac29a87e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229275 biolink:causes MONDO:0009861 infores:clingen CAID:CA229275 MONDO:0009861 PMID: Uncertain Significance PM2 PM5, PP3 The c.1022A>G (p.Lys341Arg) variant in PAH has not been reported in a patient with PAH deficiency (to our knowledge). It was submitted to the PAHdb/McGill by Cadiou in 1994. This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. There are conflicting interpretations of pathogenicity: SIFT (T); PolyPhen2 (P); MutationTaster (D), REVEL=0.831. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229275/MONDO:0009861/006 2019-12-15 2021-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:72296 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0178298 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235522 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0233494 infores:hetionet CHEBI:32315 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151786 infores:hetionet CHEBI:18332 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0042109 infores:hetionet CHEBI:37924 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0423791 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0019270 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0178298 infores:hetionet CHEBI:4784 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0600142 infores:hetionet CHEBI:8382 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0036974 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018418 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0002871 infores:hetionet CHEBI:46081 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0027497 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017160 infores:hetionet CHEBI:63617 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1142135 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0006285 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020538 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013395 infores:hetionet CHEBI:9570 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C2830004 infores:hetionet CHEBI:94686 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0151908 infores:hetionet CHEBI:8364 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0030554 infores:hetionet CHEBI:28001 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0030252 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0007114 infores:hetionet CHEBI:51041 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C1443060 infores:hetionet CHEBI:17334 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0013604 infores:hetionet CHEBI:9434 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0232849 infores:hetionet CAID:CA8314774 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314774 MONDO:0009276 PMID: Likely Pathogenic PP4, PP1, PP3_Moderate, PM3, PS3_Supporting PM2, BS1 The NM_000173.7(GP1BA):c.434T>C (p.Leu145Pro) missense variant occurs in the first amino acid of the fifth leucine-rich repeat of the GPIbα polypeptide and the computational predictor REVEL gives a score of 0.862, which is above the ClinGen PD VCEP threshold of >0.773 to predict a damaging effect on function (PP3_Moderate). At least three BSS patients have been reported with this variant, including 2 homozygotes (PMID: 10996832 and PMID: 7579348; PM3) and one compound heterozygote (PMID: 10089893) in trans with c.1601_1602del. At least one patient (Patient 1 in PMID: 7579348) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Patient 1 and their affected cousin are both homozygous for the variant (PMID: 7579348; PP1). Functional analysis was performed with both wild-type and mutant GPIbα cDNAs transiently transfected into L cells that had been previously transformed with stable constructs expressing GPIbβ and IX. Measured by flow cytometry, 43% of cells expressed GPIbα protein on their surface when transfected with normal GPIbα cDNA under the described conditions. However, no GPIbα expression could be appreciated on the surface of the cells transfected with the mutant GPIbα cDNA (PMID: 7579348; PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP1, PP3_Moderate, and PP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314774/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:127342 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1760428 infores:hetionet CHEBI:82960 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017979 infores:hetionet CHEBI:9150 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C1443060 infores:hetionet CHEBI:9588 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0038325 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1510472 infores:hetionet CHEBI:63611 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018965 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020175 infores:hetionet CHEBI:32221 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0085932 infores:hetionet CHEBI:9086 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0009421 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0267792 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0038362 infores:hetionet NCBIGene:745 biolink:causes MONDO:0020853 infores:monarchinitiative not_provided not_provided HGNC:1181 MONDO:0020853 uuid:a04b51b1-7304-4cad-8785-2d2dc8827d9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4683 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:7652 MONDO:0013108 uuid:7fdf8457-d831-47f2-a75d-8812ada5b2eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0002063 infores:hetionet NCBIGene:80326 biolink:causes MONDO:0009145 infores:monarchinitiative not_provided not_provided HGNC:13829 MONDO:0009145 uuid:f9877666-e797-4b81-aff6-4a3087de19d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027051 infores:hetionet CHEBI:2704 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0085932 infores:hetionet CHEBI:8354 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0151786 infores:hetionet CHEBI:63608 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0015230 infores:hetionet CHEBI:3441 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235198 infores:hetionet CHEBI:31980 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C1443060 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002127 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0041974 infores:hetionet CHEBI:8382 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0338656 infores:hetionet CHEBI:50673 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0497156 infores:hetionet GO:0002315 biolink:causes CL:0000845 infores:ubergraph knowledge_assertion manual_agent GO:0002315 CL:0000845 GO:0007317 biolink:causes GO:0009952 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0009952 CHEBI:72296 biolink:causes UMLS:C0856150 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0856150 infores:hetionet CHEBI:9588 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0002390 infores:hetionet CAID:CA287533367 biolink:causes MONDO:0100453 infores:clingen CAID:CA287533367 MONDO:0100453 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000180.4(GUCY2D):c.2766C>G (p.Tyr922Ter) is a nonsense variant that introduces a premature stop codon into exon 15 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, VCEP member-provided data, PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA287533367/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9654 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0231218 infores:hetionet CHEBI:6690 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0424295 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0948586 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0039971 infores:hetionet CHEBI:10023 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0040822 infores:hetionet CHEBI:47780 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C3160741 infores:hetionet CHEBI:4046 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C1443060 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0149904 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042373 infores:hetionet CHEBI:6402 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0231218 infores:hetionet CHEBI:70735 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0027849 infores:hetionet CHEBI:30659 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0038990 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0039520 infores:hetionet CAID:CA001204 biolink:causes MONDO:0018875 infores:clingen CAID:CA001204 MONDO:0018875 PMID: Benign BP4, BS3, BS2, PM2_Supporting BA1, PS4, PS2, PS1, PS3, PM5, PM1, BS4, BS1, PP1, PP4, PP3 The NM_000546.6: c.949C>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 317 (p.Gln317Lys). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). This variant has an allele frequency of 0.000008674 (14/1614016 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.1674; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.2; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001204/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50663 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0013404 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0860207 infores:hetionet CHEBI:3650 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0011991 infores:hetionet CHEBI:63580 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0221264 infores:hetionet CHEBI:8764 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085641 infores:hetionet CHEBI:10119 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040485 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0027651 infores:hetionet CAID:CA031425 biolink:causes MONDO:0007750 infores:clingen CAID:CA031425 MONDO:0007750 PMID: Benign BA1, BP4, BP7 PS3, PS4, BS1, BS3, BS4, PM1, PM2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.1056C>T (p.Cys352=) variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows: BA1: FAF = 0.007247 (0.7%) in East Asian exomes; since FAF ≥0.5% (gnomAD v4.1.0), BA1 is met.BP4: No REVEL score. Splicing evaluation is required. Functional data on splicing not available. A) not on limits, B) it creates a GT --- MES scores: de novo donor = -3.87, authentic donor = 5.88 --- de novo score is negative, so it is not used. Variant is not predicted to alter splicing, BP4 is met.BP7: Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031425/MONDO:0007750/013 2025-03-28 2025-06-04 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:163175 biolink:causes MONDO:0060486 infores:monarchinitiative not_provided not_provided HGNC:18712 MONDO:0060486 uuid:ff783b07-ce6b-491d-823d-718e1b2b9bf1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0027947 infores:hetionet CHEBI:28939 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0035508 infores:hetionet NCBIGene:6324 biolink:causes MONDO:0014155 infores:monarchinitiative not_provided not_provided HGNC:10586 MONDO:0014155 uuid:2c1c4167-eeea-4d55-b83f-fbc4588e3510 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72296 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0267792 infores:hetionet CHEBI:4887 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0011603 infores:hetionet CHEBI:36704 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0024305 infores:hetionet CHEBI:9398 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0220870 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0853895 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0853895 infores:hetionet CHEBI:231594 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0006142 infores:hetionet CHEBI:17334 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0033687 infores:hetionet CHEBI:2663 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0002994 infores:hetionet CHEBI:47898 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085593 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0343863 infores:hetionet CHEBI:2469 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0016658 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C1609512 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0025061 infores:hetionet CHEBI:77260 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0004093 infores:hetionet CHEBI:10650 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0027796 infores:hetionet CHEBI:6759 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0002994 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0595877 infores:hetionet CHEBI:6339 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037287 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0543467 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0497365 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1274594 infores:hetionet CHEBI:38545 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0853875 infores:hetionet CHEBI:47426 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0022354 infores:hetionet CHEBI:101278 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0023530 infores:hetionet CHEBI:8802 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0851578 infores:hetionet CAID:CA10549344 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549344 MONDO:0010305 PMID: Benign BS1, BS2 BP4 The NM_005629.4:c.912+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 5. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004083 in the Latino/Admixed American population, meeting the ClinGen CCDS VCEP allele frequency threshold for BS1 (>0.0002) (BS1). The variant is present in 25 hemizygotes and 2 homozygotes in gnomAD v2.1.1 (BS2). The computational predictor, SpliceAI, predicts that the variant has no impact on splicing, and varSEAK indicates an unknown effect on splicing due to possible strengthening of a cryptic splice site in intron 5. To our knowledge, this variant has not been reported in any patients with features of creatine transporter deficiency the literature and no results of functional or splicing assays are unavailable. There is a ClinVar entry for this variant (Variation ID: 383888). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549344/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:7936 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030193 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0849916 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0849916 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0595877 infores:hetionet CAID:CA6831838 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831838 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4, PP4_Moderate, PP3 The c.833G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 278 (p.(Arg278Gln)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.7839, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.800e-7, which is below the MDEP threshold of 0.000003 (PM2_Supporting). This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:20950394, PMID:33115208, internal lab contributors). At least 3 of these individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies) (PP4_Moderate; internal lab contributors). In summary, the c.833G>A variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS4, PM2_Supporting, PP3, PP4_Moderate, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831838/MONDO:0015967/017 2025-11-18 2025-11-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31705 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0004238 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0006849 infores:hetionet CHEBI:16755 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042029 infores:hetionet CHEBI:6950 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042029 infores:hetionet CHEBI:100241 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0024902 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0034902 infores:hetionet CHEBI:8863 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042029 infores:hetionet CHEBI:135361 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0004093 infores:hetionet CHEBI:3176 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0151827 infores:hetionet CHEBI:3176 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C1384353 infores:hetionet CHEBI:7789 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0009806 infores:hetionet CAID:CA226709 biolink:causes MONDO:0010725 infores:clingen CAID:CA226709 MONDO:0010725 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PS3_Supporting, PP3, PP4 NM_000330.4(RS1):c.38T>C (p.Leu13Pro) is a missense variant encoding the substitution of leucine with proline at amino acid 13. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 30652005, PP4). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 10533068, PMID: 20809529, PS4_Supporting). The computational predictor REVEL gives a score of 0.732, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. COS-7 cells exogenously expressing the variant exhibit reduced levels of RS1 in the cell lysate relative to the wild-type control and loss of detectable RS1 secretion into the medium (PMID: 20809529, 12746437, PS3_Supporting). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PS3_supporting, PP4, PS4_supporting, and PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226709/MONDO:0010725/126 2025-09-22 2025-09-22 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:16796 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0855242 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0086543 infores:hetionet CHEBI:18357 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0003467 infores:hetionet CHEBI:182080 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0012569 infores:hetionet CHEBI:50841 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0018681 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013295 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C2363730 infores:hetionet CHEBI:7601 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0018418 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0542184 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0033860 infores:hetionet CHEBI:4814 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0042029 infores:hetionet CHEBI:2682 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0023518 infores:hetionet CHEBI:3814 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0011168 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0028961 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009763 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009450 infores:hetionet CHEBI:9086 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023066 infores:hetionet CHEBI:34967 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0600142 infores:hetionet NCBITaxon:40355 biolink:causes MONDO:0015908 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:40355 MESH:D002862 DB01026_MESH_D002862_1 CAID:CA915944919 biolink:causes MONDO:0015967 infores:clingen CAID:CA915944919 MONDO:0015967 PMID: Uncertain Significance PM4_Supporting, PP4_Moderate, PM2_Supporting PM1 The c.638_640del variant in the glucokinase gene, GCK, is a 3 base pair deletion resulting in the in-frame deletion of 1 amino acid at codon 213 (p.(p.Cys213del)) within exon 6 of NM_000162.5. The c.638_640 variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.638_640del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP4_Moderate, PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915944919/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:3723 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149931 infores:hetionet CHEBI:7931 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0030305 infores:hetionet CHEBI:8069 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0020598 infores:hetionet CHEBI:75246 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0036974 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233632 infores:hetionet CHEBI:80630 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0011175 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0039503 infores:hetionet CHEBI:7025 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0041834 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C2047937 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013595 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149904 infores:hetionet GO:0072112 biolink:causes CL:0000653 infores:ubergraph knowledge_assertion manual_agent GO:0072112 CL:0000653 CHEBI:3175 biolink:causes MONDO:0002307 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0005743 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0853692 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020255 infores:hetionet CHEBI:194135 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0026896 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0033975 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002442 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023976 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0034150 infores:hetionet CHEBI:31859 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0002792 infores:hetionet CHEBI:76010 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0015230 infores:hetionet CHEBI:5130 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0040822 infores:hetionet CHEBI:8435 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0011168 infores:hetionet CHEBI:8346 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0041582 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0037274 infores:hetionet CHEBI:3756 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018989 infores:hetionet CHEBI:47780 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011175 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020039 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0011991 infores:hetionet CHEBI:135736 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035243 infores:hetionet NCBIGene:3998 biolink:causes MONDO:0009206 infores:monarchinitiative not_provided not_provided HGNC:6631 MONDO:0009206 uuid:9775f5ec-17e2-477c-a62c-7f98a3e3576b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C1306341 infores:hetionet CHEBI:3752 biolink:causes MONDO:0008608 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013080 infores:hetionet NCBIGene:283446 biolink:causes MONDO:0030537 infores:monarchinitiative not_provided not_provided HGNC:13879 MONDO:0030537 uuid:91206fd2-7a80-4a7b-97dd-6a65f687a0e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0013390 infores:hetionet CHEBI:6832 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0042963 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0020517 infores:hetionet CHEBI:17263 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0030193 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0858979 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0858979 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0024355 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D012141 DB00417_MESH_D012141_1DB12190_MESH_D012141_1DB08795_MESH_D012141_1 CHEBI:4798 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0030196 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021053 infores:hetionet GO:1905304 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0009653 CHEBI:8081 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0042373 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1328537 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1328537 infores:hetionet CHEBI:681569 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0013604 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1368065 infores:hetionet CHEBI:144551 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0028084 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0151505 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0152198 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0039520 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0497327 infores:hetionet CHEBI:5001 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0947912 infores:hetionet CHEBI:94501 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0011991 infores:hetionet NCBIGene:51004 biolink:causes MONDO:0013836 infores:monarchinitiative not_provided not_provided HGNC:20233 MONDO:0013836 uuid:80c34aa6-7c77-4386-bc7a-be806cac9328 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75988 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0030232 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0013595 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0019158 infores:hetionet CHEBI:49575 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013144 infores:hetionet CHEBI:64019 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0015230 infores:hetionet CHEBI:4670 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0030252 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0011991 infores:hetionet CAID:CA16611623 biolink:causes MONDO:0021056 infores:clingen CAID:CA16611623 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PM2_Supporting, PS3_Moderate The c.1626+3A>G variant in APC is an intronic variant which is located at the 3rd nucleotide in intron 13. This variant has been reported in 4 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, Ambry Genetics, GeneDX internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from more than 2 in silico splicing predictors indicate that this variant may affect splicing by disrupting the donor splice site of intron 13 of APC (PP3). This is confirmed by RT-PCR which demonstrate that the variant impacts splicing by leading to an in-frame exon skipping event in exon 13 r.1549_1626del78 (p.Ala517_Gln542del) (PS3_Moderate, Ambry internal data). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16611623/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8382 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011849 infores:hetionet CHEBI:31643 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C1443060 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0235431 infores:hetionet CAID:CA2695201453 biolink:causes MONDO:0011071 infores:clingen CAID:CA2695201453 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.311del (p.Thr104SerfsTer18)is a frameshift variant which terminates 18 amino acids downstream and is predicted to undergo nonsense-mediated decay (as per the modified RUNX1 PVS1 decision tree) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). It is a frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695201453/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63610 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0687707 infores:hetionet CHEBI:6846 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0033687 infores:hetionet GO:0080092 biolink:causes GO:0048868 infores:ubergraph knowledge_assertion manual_agent GO:0080092 GO:0048868 CHEBI:27834 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0085593 infores:hetionet CHEBI:15544 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020564 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0021167 infores:hetionet UBERON:0001277 biolink:causes MONDO:0006254 infores:ubergraph knowledge_assertion manual_agent UBERON:0001277 MONDO:0006254 CHEBI:7444 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C3665347 infores:hetionet CHEBI:404903 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0699744 infores:hetionet CHEBI:8024 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1142412 infores:hetionet CAID:CA199485 biolink:causes MONDO:0010726 infores:clingen CAID:CA199485 MONDO:0010726 PMID: Uncertain Significance PP1, PM4_Strong PM2 The p.Pro400_Pro479del variant in MECP2 (NM_004992.3) causes an in-frame deletion of 80 amino acids, including a deletion of 62 amino acids in a non-repeat region of MECP2. This results in a deletion of greater than 10% of the total protein length (PM4_strong). The variant has been reported to segregate with mild non-syndromic intellectual disability in males in two informative meioses (PMID 11807877) (PP1). In summary, the p.Pro388_Pro467del variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM4_strong, PP1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199485/MONDO:0010726/016 2022-10-13 2022-12-02 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:28830 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0030312 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0013604 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0029927 infores:hetionet CHEBI:27796 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C1325847 infores:hetionet CHEBI:46081 biolink:causes UMLS:C2363980 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C2363980 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0017611 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0032019 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0009450 infores:hetionet CHEBI:7915 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013390 infores:hetionet CHEBI:38940 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0013404 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0035078 infores:hetionet CHEBI:168396 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0546884 infores:hetionet CHEBI:10110 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0239571 infores:hetionet CHEBI:43968 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0004604 infores:hetionet NCBIGene:4607 biolink:causes MONDO:0014163 infores:monarchinitiative not_provided not_provided HGNC:7551 MONDO:0014163 uuid:41d96cfc-a25a-4d8d-af8c-7d4a3f136f26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2676 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0011991 infores:hetionet NCBIGene:2623 biolink:causes MONDO:0008040 infores:monarchinitiative not_provided not_provided HGNC:4170 MONDO:0008040 uuid:7daa1316-2dba-425b-86f2-61ee8c563677 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0039070 infores:hetionet CHEBI:473990 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0340865 infores:hetionet CAID:CA401324961 biolink:causes MONDO:0009290 infores:clingen CAID:CA401324961 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PVS1_Moderate The NM_000152.5:c.2332-2A>G variant in GAA occurs within the canonical splice acceptor site of intron 16. While abolishment of this splice site could result in skipping of exon 17 and inframe deletion of 5.3% of the protein, no GAA cross-reactive immunological material was detected in peripheral blood mononuclear cells from a patient who is homozygous for the variant (Clinical Diagnostic Laboratory). Consistent with this finding, in silico splice site predictors SpliceAI and varSEAK both predict loss of the acceptor splice site and possible use of cryptic splice site 43 bp downstream in exon 17, which is predicted to result in nonsense-mediated decay (PVS1_Moderate). The homozygous patient was identified by newborn screening and subsequent confirmatory testing revealed GAA deficiency in dried blood spot as well as CRIM-negative status and positive family history (PP4_Moderate, PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PVS1_Moderate, PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen LSD VCEP on December 20, 2022) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401324961/MONDO:0009290/010 2022-12-20 2022-12-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3013 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0011603 infores:hetionet CHEBI:31236 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019079 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0021400 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151763 infores:hetionet CHEBI:3650 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0033774 infores:hetionet CHEBI:61033 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151529 infores:hetionet CAID:CA000085 biolink:causes MONDO:0018875 infores:clingen CAID:CA000085 MONDO:0018875 PMID:30224644PMID:12826609 Likely Benign BP4, BS3 BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, PP3, PP1, PP4, BS2 The NM_000546.6: c.250G>A variant in TP53 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 84 (p.Ala84Thr). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0501; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BP4_Moderate, BS3. (Bayesian Points: -6; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000085/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94686 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0085649 infores:hetionet CHEBI:125354 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0038999 infores:hetionet CHEBI:3061 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0039239 infores:hetionet CHEBI:490877 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0231218 infores:hetionet CHEBI:74947 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003811 infores:hetionet CHEBI:8863 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006277 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0040034 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0948594 infores:hetionet CHEBI:31981 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0235063 infores:hetionet CHEBI:9907 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002994 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0038454 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0518015 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014118 infores:hetionet GO:0120141 biolink:causes GO:0071390 infores:ubergraph knowledge_assertion manual_agent GO:0120141 GO:0071390 CHEBI:28864 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151601 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235315 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0267596 infores:hetionet CAID:CA143409 biolink:causes MONDO:0019501 infores:clingen CAID:CA143409 MONDO:0019501 PMID: Benign BA1 The filtering allele frequency of the p.Ser5188Gly variant in the USH2A gene is 6.8% (2200/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143409/MONDO:0019501/005 2018-09-17 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA512341379 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341379 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1):c.1008C>T (p.Phe336=) variant is completely absent from all population databases with at least 20x coverage for RUNX1. The REVEL score is not calculable for a synonymous variant. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. Evolutionary conservation prediction algorithms predict the site as being conserved (PhyloP, 3.7408). However, this variant is present as a reference nucleotide in 3 mammals (Dolphin, Killer Whale, Platypus). In summary, the clinical significance of this variant is likely benign ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341379/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15552 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0009450 infores:hetionet CAID:CA10558644 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558644 MONDO:0010726 PMID: Benign BS1, BS2 BP4 The allele frequency of the p.Arg89Cys variant in MECP2 (NM_004992.3) is 0.013% in Ashkenazi Jewish sub population in gnomAD v2.1.1, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Arg89Cys variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). In summary, the p.Arg89Cys variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558644/MONDO:0010726/036 2024-04-18 2024-07-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:6717 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0038238 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0037274 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0017178 infores:hetionet NCBIGene:2937 biolink:causes MONDO:0009947 infores:monarchinitiative not_provided not_provided HGNC:4624 MONDO:0009947 uuid:e37fedf0-f04f-4b4e-877b-cc6651b53de7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232292 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235431 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0040034 infores:hetionet CHEBI:52010 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0152032 infores:hetionet CHEBI:52172 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085593 infores:hetionet CHEBI:7465 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0002994 infores:hetionet CHEBI:15640 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0012833 infores:hetionet CHEBI:2611 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0003862 infores:hetionet CAID:CA410207998 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207998 MONDO:0011071 PMID: Uncertain Significance PM1, PM2_Supporting, PS4_Supporting, PP3 PS2, PS3, PS1, BP1, BP4, BP2, BP3, BA1, PM6, PVS1, BP5, BP7, BS1, BS4, BS3, PM3, PM5, PM4, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.582A>C (p.Lys194Asn) is a missense variant which affects one of the hotspot residues within the Runt Homology Domain (RHD) established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases (gnomAD v2.1.1 and v3) with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.826, which is greater than 0.75 (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMIDs: 27210295, 28659335, 31309983). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PP3, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207998/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:VL0L558GCB biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0836924 infores:hetionet CHEBI:8499 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0007682 infores:hetionet CHEBI:4511 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0031542 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0027497 infores:hetionet CHEBI:4784 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0007859 infores:hetionet CHEBI:74947 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1443060 infores:hetionet CHEBI:75722 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0038990 infores:hetionet CHEBI:5001 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0008031 infores:hetionet CHEBI:8597 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0344232 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0240811 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0240811 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0020517 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042401 infores:hetionet CHEBI:194135 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0001925 infores:hetionet CHEBI:6954 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0270611 infores:hetionet CHEBI:9086 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1456784 infores:hetionet CHEBI:50729 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0206061 infores:hetionet CHEBI:2675 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0027849 infores:hetionet CHEBI:6539 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0041834 infores:hetionet CHEBI:42797 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006277 infores:hetionet UMLS:C0657912 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234632 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0018801 infores:hetionet CHEBI:6078 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0024205 infores:hetionet CAID:CA346329080 biolink:causes MONDO:0800472 infores:clingen CAID:CA346329080 MONDO:0800472 PMID:19234632 Pathogenic PM2_Supporting, PM3_Strong, PVS1 PP1, PP3, BP4, BA1, PS3, PS1, PS2, PM1, PM4, PM5, BP7, BS1, BS4 The c.517G>T variant in CYP1B1 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 173 (p.Glu173Ter). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1) = 0.000001736 (2 alleles out of 1,151,750), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This nonsense variant was predicted to undergo NMD, meeting PVS1. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 19234632). This variant has been identified in four individuals with a CYP1B1-related phenotype. These individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) (PMIDs: 23218183, 36343799). Total proband points = 2, meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 13 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Strong, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346329080/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030469 infores:hetionet CHEBI:51450 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0022107 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0242350 infores:hetionet CHEBI:72296 biolink:causes NCIT:C35135 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0079027 infores:hetionet CHEBI:52172 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151662 infores:hetionet GO:0060420 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0060420 GO:0072359 CHEBI:5775 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0023518 infores:hetionet CHEBI:63617 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151825 infores:hetionet CHEBI:16899 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0041969 infores:hetionet CHEBI:3723 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0852911 infores:hetionet CHEBI:136040 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020443 infores:hetionet CHEBI:15367 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1720775 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0009806 infores:hetionet NCBIGene:9215 biolink:causes MONDO:0013158 infores:monarchinitiative not_provided not_provided HGNC:6511 MONDO:0013158 uuid:bca40545-126a-4b3a-b8e4-59bad422e16f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013604 infores:hetionet CHEBI:31236 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1320474 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038367 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0022081 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0151828 infores:hetionet CHEBI:49575 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0344232 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0699744 infores:hetionet CHEBI:15367 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151825 infores:hetionet CHEBI:17650 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0000737 infores:hetionet CHEBI:4877 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0014742 infores:hetionet CHEBI:6129 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0004604 infores:hetionet CHEBI:16469 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0236082 infores:hetionet CAID:CA136024 biolink:causes MONDO:0019497 infores:clingen CAID:CA136024 MONDO:0019497 PMID:30675382 Likely Benign BS1, BP4 PM3, BA1, PS4 The p.Asn687Lys variant in TECTA has been identified in 1 patient with Asperger syndrome who was hypersensitive to sound (PMID: 30675382). However, the filtering allele frequency of the p.Asn687Lys variant is 0.3% for European chromosomes by gnomAD (399/126054, including one homozygous observation, with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA136024/MONDO:0019497/005 2019-03-25 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:131512 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0009806 infores:hetionet CHEBI:37924 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0040264 infores:hetionet CAID:CA512318821 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318821 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.334C>T (p.Leu112=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318821/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0020649 infores:hetionet CHEBI:46345 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0019080 infores:hetionet CHEBI:2675 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0030446 infores:hetionet CHEBI:63613 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0085605 infores:hetionet UMLS:C0065374 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151636 infores:hetionet CHEBI:5779 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0026858 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0559031 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0014745 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0014745 infores:hetionet GO:2000764 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:2000764 GO:0003007 CHEBI:31643 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0018681 infores:hetionet CHEBI:6073 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0003467 infores:hetionet NCBIGene:771 biolink:causes MONDO:0007747 infores:monarchinitiative not_provided not_provided HGNC:1371 MONDO:0007747 uuid:ad9c7f29-a225-45c9-bbd0-d44360fb2d58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16347 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0002418 infores:hetionet CHEBI:50648 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019572 infores:hetionet CHEBI:6076 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0424790 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0442874 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0040034 infores:hetionet CHEBI:92712 biolink:causes HP:0001310 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0234162 infores:hetionet CHEBI:8232 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0011603 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020456 infores:hetionet CHEBI:63618 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0010200 infores:hetionet NCBIGene:55280 biolink:causes MONDO:0014503 infores:monarchinitiative not_provided not_provided HGNC:25613 MONDO:0014503 uuid:3cf7cc9e-8296-4a37-b4c3-c0402a6c6dac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0855775 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0233494 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1096035 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0234215 infores:hetionet CHEBI:6149 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0040264 infores:hetionet CHEBI:8871 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085593 infores:hetionet GO:0060768 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0060768 GO:0061458 CHEBI:3478 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151849 infores:hetionet CHEBI:8428 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0040034 infores:hetionet CHEBI:44423 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0023473 infores:hetionet CHEBI:6444 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0086439 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0002418 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0040479 infores:hetionet CHEBI:9654 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C2830004 infores:hetionet CHEBI:94807 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0037763 infores:hetionet CAID:CA7542807 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542807 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4, PS3_Supporting The NM_001482.3:c.985C>G variant in GATM is a missense variant that is predicted to result in the substitution of leucine by valine at position 329 (p.Leu329Val). This variant was reported as a single heterozygous variant in one control individual, and follow-up functional assays (site-directed mutagenesis in HeLa cells) demonstrated that it resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). The authors of this report have deposited it in ClinVar (variant ID 225919). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001695 (2/1179822 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.04 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). SpliceAI predicts that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542807/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:68855 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0030193 infores:hetionet CHEBI:8597 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C2047937 infores:hetionet GO:1902256 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:1902256 GO:0003007 CHEBI:8356 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011253 infores:hetionet CHEBI:175901 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0438717 infores:hetionet CHEBI:3127 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0015672 infores:hetionet CAID:CA10585195 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585195 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.919G>A (p.Asp307Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PP1_Moderate, PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines(https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis from 2 different families (PMID: 32706999, Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)). PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PS4_Moderate:Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill SBpossible or definite criteria for FH from different labs (PMID: 32706999, Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3: REVEL = 0.865PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definiteFH after alternative causes of high cholesterol were excluded (PMID: 32706999). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585195/MONDO:0007750/013 2023-06-23 2023-07-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6541 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002871 infores:hetionet CHEBI:27666 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0042963 infores:hetionet CHEBI:49575 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0232462 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018418 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0855242 infores:hetionet CHEBI:3048 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0030446 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0948525 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0497365 infores:hetionet CHEBI:7823 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0085631 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0162429 infores:hetionet CAID:CA923726222 biolink:causes MONDO:0100326 infores:clingen CAID:CA923726222 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.2444_2445del (p.Tyr815Ter) variant in exon 24 of ITGA2B is a frameshift variant predicted to cause an immediate premature stop codon in biologically-relevant-exon 24/30 and is predicted to lead to nonsense mediated decay (PVS1). GT16 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate).Additionally, αIIb surface expression was reduced to 0.1%, as measured by flow cytometry. GT16 (PMID: 32237906) is compound heterozygous for c.2444_2445del and Arg977Ter (classified Pathogenic by the PD-VCEP; PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA923726222/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6775 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0043352 infores:hetionet NCBIGene:4634 biolink:causes MONDO:0012111 infores:monarchinitiative not_provided not_provided HGNC:7584 MONDO:0012111 uuid:56859754-abee-4a05-83b1-b589683a593a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030554 infores:hetionet NCBIGene:55182 biolink:causes MONDO:0030514 infores:monarchinitiative not_provided not_provided HGNC:25552 MONDO:0030514 uuid:adef2624-93e8-40b9-ae8a-fe9080b25fea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6904 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0948594 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0574002 infores:hetionet CHEBI:83527 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0011551 infores:hetionet CHEBI:39867 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0156404 infores:hetionet CHEBI:6887 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0086565 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0039971 infores:hetionet NCBIGene:8878 biolink:causes MONDO:0014640 infores:monarchinitiative not_provided not_provided HGNC:11280 MONDO:0014640 uuid:920aae5d-34c8-4f86-a861-3348bd35cb96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66876 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0016199 infores:hetionet CHEBI:2704 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0002994 infores:hetionet CAID:CA410148609 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148609 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BP3, BP1, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1012G>A (p.Ala338Thr) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.053) and SpliceAI is ≤0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148609/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63631 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030312 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0877322 infores:hetionet CHEBI:85161 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0027497 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020676 infores:hetionet CL:0001063 biolink:causes MONDO:0018876 infores:drugmechdb knowledge_assertion manual_agent CL:0001063 MESH:D020522 DB06287_MESH_D020522_1 CHEBI:70746 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0004093 infores:hetionet CHEBI:5147 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0015967 infores:hetionet CHEBI:41879 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0019080 infores:hetionet CHEBI:23765 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0015967 infores:hetionet CHEBI:50305 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0005758 infores:hetionet CHEBI:7565 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C2047937 infores:hetionet CHEBI:6916 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0236075 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0743668 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0743668 infores:hetionet CHEBI:50885 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0151671 infores:hetionet CHEBI:6690 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011124 infores:hetionet CHEBI:46081 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0002994 infores:hetionet CHEBI:6761 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0085631 infores:hetionet CHEBI:31980 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0012833 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020621 infores:hetionet CHEBI:9137 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020580 infores:hetionet CHEBI:63635 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0004134 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235969 infores:hetionet CHEBI:18385 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0033774 infores:hetionet CHEBI:175901 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0015230 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003864 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0243026 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0234215 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0020538 infores:hetionet CAID:CA386294434 biolink:causes MONDO:0009861 infores:clingen CAID:CA386294434 MONDO:0009861 PMID:27121329 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS1 This c.865G>A (p.Gly289Arg) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 27121329) detected with the pathogenic variant p.Gly272* and the likely pathogenic variant p.Arg155Cys. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant has the same amino acid change as a previously established pathogenic variant in ClinVar (Variation ID: 102882). This variant is absent in population databases. Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS1, PM2, PP4_moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386294434/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020456 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0239571 infores:hetionet CAID:CA10585815 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585815 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BP3, BP2, BA1, PS1, PS3, PS2, PS4, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP3, PP1, BS2 The NM_000527.5(LDLR):c.2296A>G (p.Thr766Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows: PM2: PopMax MAF= 0.00001600 (0.0016%) in Remaining group exomes (gnomAD v4.1.0).BP4: REVEL=0.481. it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limits.B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT.C) there is a GT nearby.MES scores: variant cryptic = -26.75, wt cryptic = -35.70, canonical donor = 9.06.Scores are negative, splice site not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in 1 case who fulfills Simon Broome criteria for possible FH after alternative causes of high cholesterol excluded, in PMID 20236128 (Taylor et al., 2010), UK. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585815/MONDO:0007750/013 2024-10-28 2025-01-20 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3176 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0700184 infores:hetionet CHEBI:15367 biolink:causes MONDO:0013592 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0221260 infores:hetionet CHEBI:28901 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151539 infores:hetionet CHEBI:135736 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009676 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009782 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0004936 infores:hetionet NCBIGene:286053 biolink:causes MONDO:0014991 infores:monarchinitiative not_provided not_provided HGNC:26513 MONDO:0014991 uuid:c139f1b0-d695-4e08-a5f3-ae064c6a4bd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3848 biolink:causes MONDO:0859574 infores:monarchinitiative not_provided not_provided HGNC:6412 MONDO:0859574 uuid:98a5c715-00fc-4bf6-a384-6232e7e36526 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0426576 infores:hetionet CHEBI:27958 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0014549 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0041969 infores:hetionet CHEBI:2611 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0026961 infores:hetionet CHEBI:47898 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151636 infores:hetionet CHEBI:7601 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0003123 infores:hetionet CHEBI:15407 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C1443060 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151717 infores:hetionet CHEBI:30830 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020458 infores:hetionet CL:0000767 biolink:causes GO:0002556 infores:ubergraph knowledge_assertion manual_agent CL:0000767 GO:0002556 CHEBI:15367 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0233514 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151744 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0266998 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0266998 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022660 infores:hetionet CHEBI:4562 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0030554 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0948594 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151763 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0015663 infores:hetionet CHEBI:3172 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0220870 infores:hetionet CAID:CA229598 biolink:causes MONDO:0009861 infores:clingen CAID:CA229598 MONDO:0009861 PMID:23430918PMID:26600521PMID:26600521PMID:23430918 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.966; PP4_Moderate: Detected in PKU patients. BH4 deficiency assessed. Upgraded per ClinGen PAH EP. (PMID:26600521; PMID:23430918); PM3_Strong: Detected with c.611A>G (P/LP) and R408W (P). Upgraded per ClinGen SVI workgroup. (PMID:23430918; PMID:26600521). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229598/MONDO:0009861/006 2018-08-10 2019-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135005 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0041657 infores:hetionet CHEBI:80630 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0086439 infores:hetionet CHEBI:63620 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1384353 infores:hetionet CHEBI:6444 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0013428 infores:hetionet CAID:CA2573130348 biolink:causes MONDO:0005338 infores:clingen CAID:CA2573130348 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BS1, BS3, BP7, PVS1, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.599del variant in MYOC is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 16 of the frameshift, or amino acid 215 (p.Arg200LysfsTer16). Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with juvenile or primary open angle glaucoma is not loss-of-function. This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022, Pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573130348/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63620 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0032326 infores:hetionet CHEBI:63631 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233762 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0003123 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0302810 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0302810 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0442874 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006325 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0027813 infores:hetionet CHEBI:63631 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2830004 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0595877 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0574067 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0521839 infores:hetionet CHEBI:3640 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0015230 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042571 infores:hetionet CHEBI:47426 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0014742 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0031350 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0162429 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0232492 infores:hetionet CHEBI:31355 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0030193 infores:hetionet CAID:CA415086358 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086358 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong The NM_005629.4:c.1190C>T variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a proline for a leucine at amino acid 397 (p.Pro397Leu). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and deficient creatine uptake in cultured fibroblasts (PMID: 23644449) (PP4_Strong). This variant was reported to result in “residual” creatine transporter activity in SLC6A8 deficient fibroblasts without further specifications; thus, neither PS3 nor BS3 are met. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.896 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086358/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Supports CHEBI:119915 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151723 infores:hetionet CHEBI:10101 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0014457 infores:hetionet CHEBI:3082 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0428977 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0020538 infores:hetionet NCBIGene:51057 biolink:causes MONDO:0014443 infores:monarchinitiative not_provided not_provided HGNC:28027 MONDO:0014443 uuid:42be0c1f-e829-4779-8d79-14e3c18cee5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8802 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0027765 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0314719 infores:hetionet CAID:CA2801988 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801988 MONDO:0001586 PMID:12559846PMID:33198351 Pathogenic PP3_Moderate, PM3_Supporting, PM1, PS3_Supporting, PM2_Supporting PM5, PP4 The NM_000203.5:c.544G>A variant in IDUA is predicted to result in the missense substitution of glutamine by lysine at amino acid 182 (p.Glu182Lys). This residue, Glu182 is one of the active site residues of IDUA; a role that has been shown by multiple homology modeling, crystallography, and functional studies (PMID: 11555618, 15862278, 23959878, 24036510, 24480078). Two patients with MPS 1 have been reported with the variant but there is insufficient evidence to apply PP4. One of these patients, with severe MPS 1 is compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (ClinGen Variation ID: 11908). The phase is unknown (PMID: 11555618, 12559846). Another patient, with attenuated symptoms, is compound heterozygous for the variant and c.712T>A (p.Leu238Gln); The allelic data for this patient will be used in the assessment of p.Leu238Gln and is not included here to avoid circular logic. (PM3_Supporting). As noted, Glu182 has been shown to be important in the active site of IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 23959878, 24036510, 24480078) (PM1). When expressed in CHO cells and HAP1 cells , the variant resulted in no IDUA activity across multiple studies (PMID: 11555618, 12559846, 33198351) (PS3_Supporting). The computational predictor REVEL gives a score of 0.928 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1179960 alleles) in the European non-Finnish population which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Other missense substitutions at the same amino acid have been reported in affected individuals, including c.546G>C (p.Glu182Asp) (PMID: 21480867), and c.544G>C (p.Glu182Gln) (homozygous individual reported in the Iran Variome MPS Database, https://variome.ir/lovd/genes/IDUA). The LD VCEP has not yet classified these variants and therefore, this data will not be used to support the classification of c.544G>A (p.Glu182Lys). There is a ClinVar entry for this variant (Variation ID: 2198440). The classification has been modified from likely pathogenic to pathogenic based on extensive evidence showing that Glu182 is an active site residue, with multiple functional, crystallography, and modeling studies (stacking evidence). In summary, these variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM1, PP3_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801988/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50648 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0039503 infores:hetionet CHEBI:3084 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0037036 infores:hetionet CHEBI:63580 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0740394 infores:hetionet CHEBI:68478 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018926 infores:hetionet CHEBI:9328 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0040264 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0549259 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0549259 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0948296 infores:hetionet CHEBI:36795 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235309 infores:hetionet CHEBI:72296 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0031256 infores:hetionet CHEBI:73274 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0009806 infores:hetionet CAID:CA143401 biolink:causes MONDO:0019501 infores:clingen CAID:CA143401 MONDO:0019501 PMID:25999674PMID:28041643PMID:20591486PMID:23591405PMID:27353947PMID:20829743PMID:20507924 Benign BP4, BA1 BP5, BP7, BS4, BS1, BS2, PP4, PP1, PP3, PM3, PM1, PM4, PM5, PM6, PM2, PVS1, BP2, BP3, PS4, PS2, PS3, PS1 The p.Val5145Ile variant in USH2A has been identified in at least 5 individuals with Usher syndrome; however, in 3 individuals no variant on the second allele was identified and in two individuals, no information about the other allele was provided (PMIDs 28041643, 25999674, 20829743, 27353947, 23591405). Additionally, the p.Val5145Ile variant was identified in 2 alleles of 56 retinitis pigmentosa patients, however it is unclear in which one or two patients these alleles were found (PMID 20591486). The filtering allele frequency of the p.Val5145Ile variant in the USH2A gene is 0.7% for European (Finnish) chromosomes by gnomAD (201/25124 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4) .In summary, this variant meets criteria to be classified as benign based primarily on population frequency data and the absence of cases with biallelic variants. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143401/MONDO:0019501/005 2019-01-14 2019-10-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:70735 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0178298 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0034065 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020039 infores:hetionet CHEBI:4681 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0428977 infores:hetionet CHEBI:17698 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0009676 infores:hetionet NCBIGene:57007 biolink:causes MONDO:0030976 infores:monarchinitiative not_provided not_provided HGNC:23692 MONDO:0030976 uuid:ef133cd8-7fc1-41d6-a47e-29aeab9da0c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0009241 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0015256 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0041948 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017601 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0235431 infores:hetionet CAID:CA409105413 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105413 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting PP1, PS4 The c.331G>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 111 (p.(Glu111Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant segregated with diabetes with two informative meioses in this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.331G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105413/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8863 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0438142 infores:hetionet CHEBI:168396 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0043144 infores:hetionet NCBIGene:3188 biolink:causes MONDO:0010512 infores:monarchinitiative not_provided not_provided HGNC:5042 MONDO:0010512 uuid:3c9d9535-43fb-43ee-9f4a-2b2d37126e24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2364111 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0231919 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0024312 infores:hetionet UMLS:C0004609 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013362 infores:hetionet CHEBI:5134 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0234708 infores:hetionet CHEBI:6933 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C2830004 infores:hetionet CHEBI:83804 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0403673 infores:hetionet CAID:CA6402913 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402913 MONDO:0019565 PMID: Likely Benign PP4, BS1 PP3, BS2, BP4, PM5 NM_000552.5:c.2900G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 967. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02526 (based on 967/75012 alleles in the African / African-American population, with 34 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in at least 1 patient with a diagnosis of VWD Type 3 and a phenotype including reduced quantity of VWF antigen. However, PP4 was not met due to the absence of other phenotype details and the presence of two additional variants (p.C350AfsX107 and p.C2774W) without reported confirmation of phase (PMID:23777763). This variant has also been reported in the heterozygous state in at least 7 reported healthy control individuals with no bleeding history and normal lab values (PMID: 22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, PP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402913/MONDO:0019565/090 2024-08-12 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:4672 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0017181 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0549209 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0012833 infores:hetionet CHEBI:64355 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232462 infores:hetionet CHEBI:75984 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0009806 infores:hetionet CHEBI:50648 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013456 infores:hetionet CHEBI:63631 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0149741 infores:hetionet CHEBI:8382 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0019521 infores:hetionet CHEBI:8028 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0024141 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0574067 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017675 infores:hetionet CHEBI:2687 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0000737 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0549478 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0549478 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0086543 infores:hetionet CHEBI:6129 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1579838 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0009806 infores:hetionet CHEBI:4027 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0156404 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0011615 infores:hetionet CHEBI:7565 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0007859 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0011570 infores:hetionet CAID:CA386959158 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959158 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4, PP1 The c.368T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 123 (p.(Leu123Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18433912, internal lab contributor). These two individuals have a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 18433912, internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 18433912). Additionally, another missense variant, c.368T>G (p.Leu123Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.368T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959158/MONDO:0015967/017 2021-12-09 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:36795 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232462 infores:hetionet NCBIGene:84909 biolink:causes MONDO:0030455 infores:monarchinitiative not_provided not_provided HGNC:1361 MONDO:0030455 uuid:adfac697-a253-40cb-95dd-e1210fc67838 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10644612 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644612 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, PVS1, PM2, PM6, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*3944G>A is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644612/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7640 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0013144 infores:hetionet NCBIGene:4438 biolink:causes MONDO:0007161 infores:monarchinitiative not_provided not_provided HGNC:7327 MONDO:0007161 uuid:4cba546d-d14e-412a-a175-134021cb884f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151544 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018824 infores:hetionet CHEBI:28748 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020625 infores:hetionet CHEBI:31624 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0003537 infores:hetionet CHEBI:3215 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0003467 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0005545 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1280 MONDO:0005545 CHEBI:63627 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0235290 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0020649 infores:hetionet CHEBI:9599 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0030252 infores:hetionet CHEBI:5384 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0040822 infores:hetionet CHEBI:240107 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0155169 infores:hetionet CHEBI:45783 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030193 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042571 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0853700 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0014742 infores:hetionet CHEBI:585948 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0014743 infores:hetionet CAID:CA392329016 biolink:causes MONDO:0007947 infores:clingen CAID:CA392329016 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PP1_Moderate PM6, PP2, PP3, BS2, BA1, BP1, BP4, BP2, PS1, PS3, PS2, PS4, PM5, PM1, PM3, BP7, BS1, BS3, BS4 The NM_000138 c.7204+1G>T variant in FBN1 is a splice site variant predicted to affect a donor splice site in intron 57 of the gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome (PP4). The variant segregates with the disease in 4 family members (PP1_moderate). This variant has been reported 2 times in ClinVar as pathogenic/ likely pathogenic (Variation ID: 549394). At least 3 other probands with Marfan syndrome carry an alternative nucleotide change at this position (PMID: 30101859, PMID: 29357934, PMID: 19293843). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant was identified as de novo in one patient (PM6; Invitae data in ClinVar). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PP1_moderate, PM6, PM2_supporting, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392329016/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:136040 biolink:causes HP:0030155 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0236078 infores:hetionet CHEBI:291342 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0006145 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0037199 infores:hetionet CHEBI:31981 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0686347 infores:hetionet CHEBI:91583 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0011991 infores:hetionet GO:0002813 biolink:causes GO:0050829 infores:ubergraph knowledge_assertion manual_agent GO:0002813 GO:0050829 CHEBI:17688 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0700590 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0002792 infores:hetionet CHEBI:31199 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0333641 infores:hetionet CHEBI:17823 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0011175 infores:hetionet CAID:CA10583674 biolink:causes MONDO:0018875 infores:clingen CAID:CA10583674 MONDO:0018875 PMID: Likely Pathogenic BP4, PS3, PM5_Supporting, PP4, PM2_Supporting BA1, PS2, PS4, PM1, BS1, BS3, BS4, PP3, PP1, BS2 The NM_000546.6(TP53):c.1009C>G variant in TP53 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 337 (p.Arg337Gly). This variant has an allele frequency of 0.000001545 (1/647194 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). This variant received a total of 0.5 point in one proband. (PS4 not met; Internal lab contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.157822; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). Three missense variants (p.Arg337Ser, p.Arg337Pro, p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, BP4, PM2_Supporting, PM5_Supporting, PP4. (Bayesian Points: 6; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583674/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5296 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0036572 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0037274 infores:hetionet CHEBI:39585 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0026858 infores:hetionet CHEBI:2453 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013362 infores:hetionet CHEBI:10650 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030193 infores:hetionet NCBIGene:6609 biolink:causes MONDO:0009756 infores:monarchinitiative not_provided not_provided HGNC:11120 MONDO:0009756 uuid:222a0a8e-235d-45fe-99af-d95f326469f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0003537 infores:hetionet CHEBI:32599 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0085628 infores:hetionet NCBITaxon:1319 biolink:causes MONDO:0700218 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1319 MONDO:0700218 CHEBI:51173 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0017178 infores:hetionet CHEBI:5118 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0080274 infores:hetionet CHEBI:9123 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0041834 infores:hetionet NCBIGene:64324 biolink:causes MONDO:0019349 infores:monarchinitiative not_provided not_provided HGNC:14234 MONDO:0019349 uuid:4d4e52fd-61f6-4c4d-98d2-ebe262678a2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10443889 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443889 MONDO:0010315 PMID: Benign BS1, BS2 PM2, BP4 The NM_000206.3(IL2RG):c.325G>A (p.Glu109Lys) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. It occurs at an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0006719 (based on 74/92629 alleles in the non-Finnish European population) which is below the SCID VCEP established threshold of >0.00249 for BS1 and above the PM2 threshold of <0.000124. However, the highest MAF is in the Finnish population at 0.004561 (85/18638 alleles, 28 hemizygotes and 1 homozygote) which is above the SCID VCEP established threshold of >0.00249. As this population is not known to have a higher prevalence of this is considered to meet BS1. Sixty-two adult hemizygous males with this variant are present in the gnomADv2.1.1 dataset as well as a homozygous female (BS2). In summary, this variant is classified as Benign. Criteria applied: BS1, BS2 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443889/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Contradicts true CHEBI:10101 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027339 infores:hetionet CHEBI:3756 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0028084 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0020649 infores:hetionet CAID:CA409120283 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120283 MONDO:0007064 PMID: Pathogenic PP4_Moderate, PM3_Very Strong, PM2_Supporting NM_000022.4:c.716G>A is a missense variant predicted to cause the substitution of Glycine by Aspartic acid at amino acid 239 (p.Gly239Asp). The highest population minor allele frequency in gnomAD v4 is 0.00001098 (1/91084 alleles) in the South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD v4.1.0.Patient #12, 13 and 26 (PMID: 26255240) presented with: Reduced ADA enzyme activity in patient cells and increased dAdo nucleotides (dATP) in pretreatment erythrocytes (5 pts.) (PP4_Moderate; total: 5 pts).This variant has been observed to be homozygous in many individuals affected with ADA-deficient severe combined immunodeficiency (PMIDs: 31858364, 32307643, 26255240, and 30858051). Four of them are from consanguineous families: 0.5 pts each, 2 pts. Five of them are from non-consanguineous families. However, the five individuals are reported by two teams from the same hospital (PMIDs: 26255240, 31858364). To avoid potential unreported overlap of probands, only one report is counted (PMID: 26255240). 1 pt each, 3 pts. 5 points in total, PM3_Very_Strong.In summary, this variant meets the criteria to be classified as Pathogenic variant for autosomal recessive adenosine deaminase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4_Moderate, and PM3_Very_Strong (VCEP specifications version 2.1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120283/MONDO:0007064/114 2025-11-04 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0040038 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0015397 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0011991 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0009450 infores:hetionet CHEBI:9328 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0001824 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0018681 infores:hetionet CHEBI:6437 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1260880 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042109 infores:hetionet CHEBI:9738 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0241934 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0002878 infores:hetionet CHEBI:63631 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0149745 infores:hetionet CHEBI:16469 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0035243 infores:hetionet CHEBI:8713 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0015230 infores:hetionet CHEBI:2673 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0041657 infores:hetionet CHEBI:4514 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0085631 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085584 infores:hetionet CHEBI:9586 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0021177 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0004096 infores:hetionet CAID:CA023600 biolink:causes MONDO:0007750 infores:clingen CAID:CA023600 MONDO:0007750 PMID: Likely Benign BP4, BP2, BP7, PP1 BA1, BP3, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP3, PP4, BS2 The NM_000527.5(LDLR):c.1875C>T (p.Asn625=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence codes PP1, BP2, BP4, and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). Variant has 3 supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 supporting evidence codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign.The supporting evidence is as follows: PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. So PP1 is met. BP2: 1 individual from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with LDLR c.1598G>A. Phenotype LDL 168mg/dl under statins - Htz phenotype, c.1598G>A - Pathogenic by these guidelines. BP4: No REVEL available, splicing evaluation needed.Functional data on splicing not available.A) variant not on limits.B) variant is exonic and at least 50bp upstream from the canonical donor site, but it does not create AG.C) there is an AG nearby.MES scores: variant cryptic = -1.41, wt cryptic = -2.30, canonical acceptor = 9.58.Ratio variant cryptic/wt cryptic: -1.41/-2.30 = 0.61 --- it is not above 1.1Ratio variant cryptic/canonical acceptor: -1.41/9.58 = 0.15--- it is not above 0.9Variant is not predicted to alter splicing. So BP4 is met. BP7: Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023600/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:75988 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0019080 infores:hetionet CHEBI:36795 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0008031 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0851341 infores:hetionet CHEBI:8707 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0242339 infores:hetionet CAID:CA10603162 biolink:causes MONDO:0017623 infores:clingen CAID:CA10603162 MONDO:0017623 PMID:10866302 Likely Pathogenic PS3_Supporting, PP2, PP3, PS4_Supporting, PM2_Supporting, PS2 BS3 NM_000314.8(PTEN):c.80A>C (p.Tyr27Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. [internal laboratory contributor(s)]PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. Hans, et al. PMID: 10866302: demonstrated low phosphatase activity.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. [internal laboratory contributor(s)]PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: in silico REVEL score of 0.966 (>0.7) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603162/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4672 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0442874 infores:hetionet CHEBI:421707 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0029118 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0027769 infores:hetionet CHEBI:3380 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0002994 infores:hetionet CHEBI:71417 biolink:causes MONDO:0001889 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0747102 infores:hetionet CHEBI:17303 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011168 infores:hetionet CHEBI:94449 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0004093 infores:hetionet CHEBI:5001 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013491 infores:hetionet CAID:CA915940701 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940701 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.2014+5G>A intronic variant is predicted to affect splicing by splicing predictor SpliceAI which gives a score of 0.9 for donor loss, predicting that the variant disrupts the donor splice site of intron 12 (PP3). The highest population minor allele frequency in gnomAD v4.1 is 8.507e-7 (1/1175540 alleles) in the European (non-Finnish) genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). At least one patient (GT54 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PP4_strong, PM2_supporting. (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940701/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50777 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C3665386 infores:hetionet CHEBI:4877 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0029132 infores:hetionet CHEBI:87681 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0023530 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0034150 infores:hetionet CHEBI:61058 biolink:causes HP:0012669 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0221046 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0349506 infores:hetionet CL:0000233 biolink:causes GO:0002555 infores:ubergraph knowledge_assertion manual_agent CL:0000233 GO:0002555 CHEBI:3757 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0428977 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014544 infores:hetionet GO:2000248 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:2000248 GO:0007399 CHEBI:100147 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0004093 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0024299 infores:hetionet NCBIGene:84919 biolink:causes MONDO:0014785 infores:monarchinitiative not_provided not_provided HGNC:14951 MONDO:0014785 uuid:9861bdf3-bd31-4947-b69d-8051cbf9c7ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0030252 infores:hetionet GO:0030516 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0007399 UMLS:C0657912 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006840 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020517 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0233571 infores:hetionet CHEBI:119486 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0042963 infores:hetionet CHEBI:8764 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085681 infores:hetionet CHEBI:28262 biolink:causes UMLS:C0403639 infores:sider not_provided not_provided DRUGBANK:DB01093 UMLS:C0403639 infores:hetionet CHEBI:64064 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0040460 infores:hetionet CAID:CA280990 biolink:causes MONDO:0100488 infores:clingen CAID:CA280990 MONDO:0100488 PMID:9537325 Likely Pathogenic PM2_Supporting, PS3, PS4_Moderate, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM1, PM5, PM4, PM3, PM6, BS2, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, BA1, PS1, PS2 The c.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 9537325). Additionally, the variant has also been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 9537325 and internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4_Moderate. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA280990/MONDO:0100488/007 2024-11-25 2024-12-17 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA16020866 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020866 MONDO:0009861 PMID:11142755PMID:11142755 Uncertain Significance PM2, PP4_Moderate, PP3 PM3 The c.817T>C (p.Ser273Pro) variant in PAH has been reported in a Japanese patient with classic PKU. (Biopterin deficiency excluded. PMID: 1114275, PP4_Moderate) It was detected with c.442-2G>A (not in ClinVar). This variant is absent from ExAC, gnomAD, 1000G and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.976. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020866/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7823 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0086565 infores:hetionet CAID:CA312288 biolink:causes MONDO:0008723 infores:clingen CAID:CA312288 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1375dup (p.Arg459ProfsTer4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008794 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (VCEP specifications version1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312288/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8212 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0023530 infores:hetionet CHEBI:6710 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0857305 infores:hetionet GO:2000495 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000495 GO:0007275 CHEBI:63630 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0025362 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018801 infores:hetionet CHEBI:4822 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0008031 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151479 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042075 infores:hetionet CHEBI:3077 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020488 infores:hetionet CHEBI:47426 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0008372 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C3160769 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C3160769 infores:hetionet CHEBI:367163 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0003467 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0042373 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0234458 infores:hetionet CHEBI:8481 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0917801 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0003864 infores:hetionet CHEBI:3216 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011551 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027497 infores:hetionet CHEBI:30830 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151836 infores:hetionet CHEBI:31236 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017168 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0456909 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009782 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151970 infores:hetionet CHEBI:3011 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0008031 infores:hetionet CHEBI:3314 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0020649 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0027051 infores:hetionet CHEBI:3752 biolink:causes MONDO:0024519 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1619700 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002170 infores:hetionet CHEBI:2950 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0019348 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0151602 infores:hetionet CHEBI:4315 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0002170 infores:hetionet CHEBI:134936 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0037383 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0162830 infores:hetionet CHEBI:4511 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0149904 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0013395 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0476280 infores:hetionet CHEBI:2453 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C1260880 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0027339 infores:hetionet CAID:CA16020966 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020966 MONDO:0009861 PMID:26503515PMID:31102715PMID:30747360PMID:28915855 Pathogenic PVS1, PM2, PP4_Moderate, PM3_Supporting This c.1200-1G>C (IVS11-1G>C) variant in PAH was reported in 5 patients with PAH deficiency (PMID: 26503515, 30747360, 31102715). This variant was also documented in one Thai patient diagnosed with Classic PKU with the pathogenic variant c.611A>G (PMID: 28915855). This variant is absent from the population databases ExAC and gnomAD. This variant in the -1 splice acceptor site results in exon skipping, which disrupts the reading frame. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_very strong, PM2, PP4_moderate, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020966/MONDO:0009861/006 2019-11-05 2019-11-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6367 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0026650 infores:hetionet CHEBI:65173 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0037763 infores:hetionet NCBIGene:4726 biolink:causes MONDO:0032615 infores:monarchinitiative not_provided not_provided HGNC:7713 MONDO:0032615 uuid:5af492d3-044f-4332-a489-d59ba6f96d9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6792 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0027497 infores:hetionet CHEBI:17347 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0236024 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0023530 infores:hetionet CAID:CA10575944 biolink:causes MONDO:0700268 infores:clingen CAID:CA10575944 MONDO:0700268 PMID: Likely Benign BP5, BP1_Strong PM2, PS3, BS1, BS3 The c.4159T>C variant in BRCA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 1387 (p.Ser1387Pro). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.00, score threshold ≤0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.364 (based on Family History LR=0.364), within the thresholds for supporting benign evidence (LR >0.23 & ≤0.48) (BP5 met; PMID 31853058). In summary, this variant meets the criteria to be classified as a likely benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BP5). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10575944/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA6831835 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831835 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PP1_Strong, PP4_Moderate, PP3 PS3, PM5 The c.812G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 271 (p.(Arg271Gln) of NM_000545.8. This variant was identified in 19 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.945, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Arg271Gln protein has DNA binding 110% of wild type and transactivation 50-60% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 26853433). The p.Arg271Trp and p.Arg271Gly variants have been interpreted as pathogenic and likely pathogenic, respectively, by the MDEP. Arg271Gln has a lower Grantham distance than both and was used as the base variant to apply PM5, and therefore, PM5 will not be applied to Arg271Gln. In summary, c.814C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PS4, PP1_Strong, PM1, PP3, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831835/MONDO:0015967/017 2022-04-15 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:567361 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0023380 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0022408 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0347602 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0347602 infores:hetionet CHEBI:2636 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C3665624 infores:hetionet CHEBI:3757 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0018681 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0004936 infores:hetionet CHEBI:6909 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0030305 infores:hetionet CHEBI:8863 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0043094 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0021053 infores:hetionet CHEBI:6532 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0178298 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0018801 infores:hetionet CHEBI:30830 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0702166 infores:hetionet CAID:CA229557 biolink:causes MONDO:0009861 infores:clingen CAID:CA229557 MONDO:0009861 PMID:26322415PMID:16256386PMID:19915519PMID:26503515 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The PAH variant c.460T>C (p.Tyr154His) has been reported in three Chinese individuals with PHA deficiency (Phe levels >120 μM). The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl). All mutations identified were confirmed by analyzing parental DNA. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386). This variant was also reported in two other Chinese patients with undetermined PKU/MHP phenotype (PMID: 26503515, and PMID: 19915519). The PAH variant c.460T>C (p.Tyr154His) is absent from the gnomAD, ExAC, 1000 Genomes, and ESP population databases. In silico modeling, predictions support that this missense variant could have a deleterious effect on the PAH gene or gene product. This variant is predicted to be deleterious by SIFT, probably damaging by PolyPhen2- HumVar, and disease-causing by Mutation Taster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229557/MONDO:0009861/006 2019-12-22 2019-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7466 biolink:causes MONDO:0000088 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0034013 infores:hetionet GO:1904051 biolink:causes GO:0006914 infores:ubergraph knowledge_assertion manual_agent GO:1904051 GO:0006914 CHEBI:2636 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0020517 infores:hetionet CHEBI:46345 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C1384353 infores:hetionet CHEBI:101278 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0004245 infores:hetionet CHEBI:3242 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013447 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0035258 infores:hetionet UMLS:C0879264 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0019521 infores:hetionet CHEBI:188986 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C2363731 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027947 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1971624 infores:hetionet CHEBI:51860 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0030196 infores:hetionet CHEBI:64312 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235086 infores:hetionet CHEBI:63577 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0009782 infores:hetionet CHEBI:4995 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151723 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0015695 infores:hetionet CAID:CA3231851 biolink:causes MONDO:0012163 infores:clingen CAID:CA3231851 MONDO:0012163 PMID: Likely Benign BP7, BS1 BS2 The c.132C>T (p.Ser44=) variant (NM_002185.5) variant in IL7R is a synonymous (silent) variant that is not predicted to impact splicing (BP7). The filtering allele frequency (the lower threshold of the 95% CI of 342/24962) of the c.132C>T variant in IL7R is 0.01271 in exomes and 0.01082 in genomes for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1).In summary, this variant meets the criteria to be classified as likely benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP7 and BS1. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3231851/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63845 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0014518 infores:hetionet CAID:CA400033003 biolink:causes MONDO:0100326 infores:clingen CAID:CA400033003 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000212.3(ITGB3):c.1990G>T (p.Glu664Ter) nonsense variant is predicted to cause a premature stop codon in biologically-relevant-exon 12/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Patient 6, of PMID: 31029159, is reported to have a clinical diagnosis of GT and is homozygous for this variant (PM3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400033003/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:2955 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151907 infores:hetionet CHEBI:231594 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C2830004 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0086543 infores:hetionet CHEBI:17630 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0040264 infores:hetionet CHEBI:6128 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0018965 infores:hetionet CHEBI:31859 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0033774 infores:hetionet CHEBI:16914 biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0266813 infores:hetionet CHEBI:9328 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0015230 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0017160 infores:hetionet CHEBI:408174 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0438142 infores:hetionet CHEBI:2668 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0152198 infores:hetionet CHEBI:6710 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0409974 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0018524 infores:hetionet CHEBI:7983 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0020649 infores:hetionet CHEBI:7822 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0235996 infores:hetionet UMLS:C0004609 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013144 infores:hetionet GO:0070365 biolink:causes CL:0000182 infores:ubergraph knowledge_assertion manual_agent GO:0070365 CL:0000182 CHEBI:135736 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0744727 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030848 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0521500 infores:hetionet CHEBI:63621 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0037299 infores:hetionet CAID:CA386965434 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965434 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS2, PM1_Supporting, PP4_Moderate, PP3 The c.709A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to aspartic acid at codon 237 (p.(Asn237Asp)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.893, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PS2; PMID: 31098941). Lastly, the c.709A>G variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). In summary, c.709A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PS2, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP3 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965434/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:78543 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0004936 infores:hetionet NCBIGene:90268 biolink:causes MONDO:0014912 infores:monarchinitiative not_provided not_provided HGNC:25118 MONDO:0014912 uuid:8ac62145-c59e-4cad-8836-6a44e276702c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013144 infores:hetionet CHEBI:6367 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085593 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009763 infores:hetionet CHEBI:617099 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0002878 infores:hetionet CHEBI:9139 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0344232 infores:hetionet NCBIGene:7169 biolink:causes MONDO:0007157 infores:monarchinitiative not_provided not_provided HGNC:12011 MONDO:0007157 uuid:68fb381a-fe5f-4b90-9a78-851d5a9fec17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0031542 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0162830 infores:hetionet CHEBI:6413 biolink:causes MONDO:0001339 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0155773 infores:hetionet CHEBI:49603 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0002792 infores:hetionet CHEBI:135530 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0687713 infores:hetionet CHEBI:3032 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0278134 infores:hetionet NCBIGene:150094 biolink:causes MONDO:0014595 infores:monarchinitiative not_provided not_provided HGNC:11142 MONDO:0014595 uuid:fc9616af-2f50-423e-b7e6-595ffa67e068 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0006277 infores:hetionet CAID:CA390864484 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864484 MONDO:0100216 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PM6, BA1, BP4, BP2, PP3, PP1, PP4, BS2, PM5, PS1, PS3, PS4, PS2, BS1, BS3, BS4 NM_177438.3(DICER1):c.5514G>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 1838 (p.Met1838Ile). This variant has an allele frequency of 0.00000186 (3/1614140 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.594, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function; splice predictors MaxEntScan and SpliceAI indicate no impact on splicing (PP3 and BP4 not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864484/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3534 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0008370 infores:hetionet CHEBI:47898 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030794 infores:hetionet CHEBI:63580 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0497156 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1142135 infores:hetionet CHEBI:3994 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C2830004 infores:hetionet CHEBI:63580 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0041657 infores:hetionet CHEBI:6128 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0018681 infores:hetionet CHEBI:91583 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0015672 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027051 infores:hetionet CHEBI:5134 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0004096 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020651 infores:hetionet CHEBI:134991 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042075 infores:hetionet CAID:CA034538 biolink:causes MONDO:0007750 infores:clingen CAID:CA034538 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP2, PS3, PS1, PS4, PS2, BP5, BS1, BS3, BS4, PM1, PM5, PM3, PM6, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1496C>G (p.Ser499Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: PopMax MAF = 0.00003764 (0.004%) in European (Finnish) exomes (gnomAD v4.0.0).PP3: REVEL = 0.811. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034538/MONDO:0007750/013 2024-02-23 2024-10-07 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:16714 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0423153 infores:hetionet CHEBI:63618 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0232462 infores:hetionet CHEBI:23765 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0023066 infores:hetionet CHEBI:8768 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1458155 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0162429 infores:hetionet CHEBI:8707 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0022346 infores:hetionet CHEBI:15854 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0018790 infores:hetionet CHEBI:3996 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C1456784 infores:hetionet CAID:CA000451 biolink:causes MONDO:0017623 infores:clingen CAID:CA000451 MONDO:0017623 PMID: Pathogenic PM2, PP2, PS4_Supporting, PS3, PS2 PTEN c.407G>A (p.C136Y) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222113.9)PS3: Phosphatase activity <50% of wild-type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 10866302)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Probands with specificity score of 1-1.5. (PMID 9735393, internal laboratory contributor(s) SCV000222113.9) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000451/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4888 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0917801 infores:hetionet CHEBI:9599 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0035357 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0004936 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030578 infores:hetionet GO:1905000 biolink:causes GO:0086003 infores:ubergraph knowledge_assertion manual_agent GO:1905000 GO:0086003 NCBIGene:2108 biolink:causes MONDO:0009282 infores:monarchinitiative not_provided not_provided HGNC:3481 MONDO:0009282 uuid:7180c4fe-dcb3-4945-a8fe-5020c9156a50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0917801 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0020598 infores:hetionet CHEBI:8802 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0011991 infores:hetionet CHEBI:4868 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0033774 infores:hetionet NCBIGene:23405 biolink:causes MONDO:0859046 infores:monarchinitiative not_provided not_provided HGNC:17098 MONDO:0859046 uuid:e51b6ed1-1e7e-4b11-ada3-1e1b4d95fc5f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31536 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0017979 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042035 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011570 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0877126 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0877126 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0743668 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0743668 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0010709 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042373 infores:hetionet NCBIGene:9445 biolink:causes MONDO:0008306 infores:monarchinitiative not_provided not_provided HGNC:6174 MONDO:0008306 uuid:7b46a53c-e7b7-4a89-9dcc-d0a0ebd12dc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4657 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0541799 infores:hetionet UMLS:C0145867 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0015967 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0009763 infores:hetionet CHEBI:15854 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0002962 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0007642 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0022660 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0267792 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0005940 infores:hetionet CHEBI:31711 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0237849 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1142135 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0233632 infores:hetionet CHEBI:18385 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C2939147 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0042075 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0853813 infores:hetionet CHEBI:2567 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0013378 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0855704 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0025061 infores:hetionet CAID:CA023880 biolink:causes MONDO:0007783 infores:clingen CAID:CA023880 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 367 of the RYR1 protein, p.(Arg367Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual who has a personal or family history of a malignant hyperthermia reaction and has a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:19191329). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.866) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023880/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63598 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151559 infores:hetionet CHEBI:6402 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0853034 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0235416 infores:hetionet CHEBI:9588 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0024141 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0267596 infores:hetionet CHEBI:253342 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0221170 infores:hetionet CHEBI:7915 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018926 infores:hetionet CHEBI:4735 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0011991 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018799 infores:hetionet CHEBI:94686 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0020621 infores:hetionet CAID:CA410206700 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206700 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.781C>T (p.Pro261Ser) is a missense variant, which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206700/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:F64QU97QCR biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0019080 infores:hetionet CHEBI:5118 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0549249 infores:hetionet CHEBI:83804 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0002792 infores:hetionet CHEBI:4681 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0160390 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0271412 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0271412 infores:hetionet CHEBI:75045 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0017565 infores:hetionet CHEBI:8028 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0232462 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0009806 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0012833 infores:hetionet CHEBI:6402 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0232462 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0031117 infores:hetionet CHEBI:7809 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0948586 infores:hetionet GO:1901210 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1901210 GO:0072359 GO:0150011 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0150011 GO:0007275 CHEBI:9571 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0023518 infores:hetionet CHEBI:6710 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0002878 infores:hetionet CHEBI:135005 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0011124 infores:hetionet NCBIGene:5159 biolink:causes MONDO:0976136 infores:monarchinitiative not_provided not_provided HGNC:8804 MONDO:0976136 uuid:eefe2a69-c49f-4ca9-972a-6547717d4000 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45951 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0002874 infores:hetionet CHEBI:6912 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0242350 infores:hetionet CAID:CA011391 biolink:causes MONDO:0004994 infores:clingen CAID:CA011391 MONDO:0004994 PMID: Uncertain Significance PM2 PM3, BA1, PM5, PM1, PS3, PM6, PP3, PP1, PP2, PP4, BS2, BS1, BS3, BS4, BP1, PS1, PS4, PS2, BP4, BP2, BP5, PVS1 The NM_000257.4(MYH7):c.1888+1G>A variant has been identified in at least 1 individual with LVNC and a reduced ejection fraction (GeneDx pers. comm.); however, this is insufficient to apply the PS4 criterion. This variant was identified in 0.003% (1/30600) of South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This splice variant is predicted to abolish the canonical splice site and impact splicing, which often leads to a truncated or absent protein; however, the contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood and therefore PVS1 was not applied. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011391/MONDO:0004994/002 2021-09-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49662 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0033687 infores:hetionet CHEBI:51041 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085932 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0028738 infores:hetionet CHEBI:142290 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0206062 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0687133 infores:hetionet CHEBI:50173 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0086565 infores:hetionet NCBIGene:26258 biolink:causes MONDO:0013606 infores:monarchinitiative not_provided not_provided HGNC:8549 MONDO:0013606 uuid:60a11020-7256-4e1e-bc53-15afce678b07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151735 infores:hetionet CHEBI:3286 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0033575 infores:hetionet CHEBI:50131 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013428 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0162529 infores:hetionet CHEBI:71940 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0043352 infores:hetionet CHEBI:9599 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0014591 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0521839 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0015927 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0344365 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0344365 infores:hetionet NCBIGene:114548 biolink:causes MONDO:0007849 infores:monarchinitiative not_provided not_provided HGNC:16400 MONDO:0007849 uuid:4e47d0e7-72c3-49f9-b289-2bd4b2051de2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0037763 infores:hetionet CAID:CA410202515 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202515 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP2, BP1, BP4, BP3, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM3, PM5, PM4, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.482T>A (p.Leu161His) is a missense variant which has a REVEL score ≥ 0.88 (0.981) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202515/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10102 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011168 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0233494 infores:hetionet NCBIGene:23291 biolink:causes MONDO:0030057 infores:monarchinitiative not_provided not_provided HGNC:13607 MONDO:0030057 uuid:9f10fb31-d8b8-4b67-8491-513011d24ead biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA251538 biolink:causes MONDO:0009861 infores:clingen CAID:CA251538 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM3_Very Strong, PVS1_Strong PM2, PP3, BP4, BA1, PS3, BS1 The c.1066-11G>A variant in PAH occurs within intron 10. It is predicted to impact splicing of biologically-relevant-exon 11/13. This prediction is confirmed by RT-PCR analysis which showed an in-frame insertion of Gly, Leu, Gln between exon 10 and 11 (PMID: 1769645). Nonsense mediated decay does not occur, but the resulting protein has no enzymatic activity (altered region is critical to protein function, PVS1_strong). At least one patient with this variant displayed blood Phe > 30 mg/dl, which is highly specific for PAH deficiency (PMID: 8990013). BH4 deficiency was ruled out in 1 study (PMID: 23500595). This variant has been detected in at least 23 individuals with PAH deficiency. Of those individuals, 15 were compound heterozygous for the variant and a pathogenic variant [p.R252W, p.R243X, p.R261Q (4 patients), p.R270K, p.I65T (2 patients); 5.5 points] (PMID: 23500595; PMID: 8990013) (PM3_Very strong). The population allele frequency in gnomAD v4 is 0.0003248, which is higher than the PAH VCEP cutoff for PM2 (<0.0002). In summary, this variant meets criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1_strong, PP4_Moderate, PM3_very-strong. (VCEPspecifications version 2; 12/06/24) Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251538/MONDO:0009861/006 2024-12-30 2024-12-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50859 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013491 infores:hetionet UMLS:C0004609 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0001925 infores:hetionet GO:0034444 biolink:causes GO:0097006 infores:ubergraph knowledge_assertion manual_agent GO:0034444 GO:0097006 CHEBI:4798 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0004604 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0553732 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0002170 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0041349 infores:hetionet CHEBI:75984 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0011603 infores:hetionet CHEBI:49960 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0004093 infores:hetionet NCBITaxon:89940 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:89940 MONDO:0001867 CHEBI:8207 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0542571 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0262977 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0262977 infores:hetionet CHEBI:119573 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0497156 infores:hetionet CHEBI:5790 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0311394 infores:hetionet CHEBI:68584 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0003537 infores:hetionet CHEBI:3738 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0042023 infores:hetionet CHEBI:45863 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2047937 infores:hetionet CHEBI:10101 biolink:causes UMLS:C3665444 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C3665444 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0003123 infores:hetionet CHEBI:6887 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0231218 infores:hetionet CHEBI:3176 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0085635 infores:hetionet CHEBI:3223 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013384 infores:hetionet CHEBI:63631 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042024 infores:hetionet CHEBI:5165 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0018790 infores:hetionet CHEBI:47781 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0011071 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0687133 infores:hetionet CHEBI:9123 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0023066 infores:hetionet CHEBI:6888 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C1443060 infores:hetionet CAID:CA220505 biolink:causes MONDO:0001586 infores:clingen CAID:CA220505 MONDO:0001586 PMID: Likely Pathogenic PM3_Strong, PVS1_Moderate, PP4, PM2_Supporting PS3, BS3 The NM_000203.5(IDUA):c.1799del (p.Ser600Ter) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed. (PVS1_Moderate). At least 5 patients with this variant have been reported with this variant, four with documented clinical features consistent with MPS 1 and IDUA deficiency within the affected range in leukocytes; two had mildly elevated GAGs, one after receiving HSCT and one was possibly on treatment (clinical laboratory data) (PP4). Three patients were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP (c.208C>T (p.Gln70Ter), c.1728-2A>G, and c.1898C>G (p.Ser633Trp)) and none of those were confirmed in trans (clinical diagnostic lab). At least two individuals were homozygous for the variant PMID: 22976768, clinical diagnostic lab) (PM3_Strong). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 92636). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1_Moderate, PP4, PM3_Strong, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220505/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16469 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0004936 infores:hetionet CHEBI:85083 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0015230 infores:hetionet CHEBI:5784 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0003123 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0013395 infores:hetionet CHEBI:7773 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0009806 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0019348 infores:hetionet NCBIGene:269 biolink:causes MONDO:0009857 infores:monarchinitiative not_provided not_provided HGNC:465 MONDO:0009857 uuid:0fb2722a-cee8-4f83-9c66-f3480dce5a25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0036572 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085606 infores:hetionet CHEBI:404903 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151904 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0034882 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0039971 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0549399 infores:hetionet CHEBI:79699 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042487 infores:hetionet CHEBI:7466 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0015230 infores:hetionet CHEBI:31624 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0034063 infores:hetionet CHEBI:135736 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C3160741 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042769 infores:hetionet CHEBI:36791 biolink:causes EFO:0011023 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006107 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0031039 infores:hetionet CHEBI:5138 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002994 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0011616 infores:hetionet CHEBI:5613 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0018681 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C2225524 infores:hetionet CHEBI:39867 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1167965 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2242996 infores:hetionet UMLS:C0657912 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025323 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0004134 infores:hetionet CHEBI:50648 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0023518 infores:hetionet CAID:CA14860307 biolink:causes MONDO:0011071 infores:clingen CAID:CA14860307 MONDO:0011071 PMID: Benign BP4, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.351+301A>G is an intronic variant with a MAF of 0.35279 (3065/8688 alleles) in the African population of gnomAD 2.1 which is is ≥ 0.0015 (0.15%) (BA1). Splice AI predicts no impact to splicing (score: 0.00). (BP4). This variant has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.537) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14860307/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:R43D2573WO biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0162287 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0041912 infores:hetionet CHEBI:8871 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034880 infores:hetionet CAID:CA213784 biolink:causes MONDO:0015967 infores:clingen CAID:CA213784 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5, PP2, PP3, PM2_Supporting The c.449T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 150 (p.(Phe150Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.0.0 Popmax filtering allele frequency of 0 (below the MDEP threshold of 0.000003), and ≤ 2 copies observed in the European non-Finnish population and any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in at least 28 unrelated individuals with hyperglycemia (PS4; PMIDs: 15305805, 30191644, internal lab contributors). This variant segregated with hyperglycemia, with at least 19 informative meioses in multiple families (PP1_Strong; internal lab contributors). Another missense variant, c.449T>A p.Phe150Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Ser has a greater Grantham distance (PM5). In summary, c.449T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PS4, PP1_Strong, PM2_Supporting, PP3, PP2, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213784/MONDO:0015967/086 2024-03-22 2024-03-22 Semidominant inheritance HP:0032113 Supports CHEBI:47780 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1145670 infores:hetionet CHEBI:107736 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0428977 infores:hetionet CHEBI:71272 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0012833 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0699893 infores:hetionet CHEBI:50173 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0028754 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0700184 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0853619 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0007514 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0007514 uuid:07f863a0-bcfe-4625-9f59-22c09c7c642d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5627 biolink:causes MONDO:0013791 infores:monarchinitiative not_provided not_provided HGNC:9456 MONDO:0013791 uuid:8bd3e608-a997-4596-9819-f82fcf0483d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0011701 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C2363731 infores:hetionet CHEBI:63607 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0002792 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1167965 infores:hetionet CAID:CA320642839 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642839 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.203C>T (p.Ala68Val) is a missense variant which has a REVEL score < 0.50 (0.313) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642839/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2740089968 biolink:causes MONDO:0010880 infores:clingen CAID:CA2740089968 MONDO:0010880 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The NM_000020.3: c.620del (p.Cys207Leufs*51) variant in ACVRL1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5 (out of 10) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA2740089968/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68558 biolink:causes UMLS:C0151966 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0151966 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1384353 infores:hetionet CAID:CA386964305 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964305 MONDO:0015967 PMID:28410371PMID:12453420PMID:10585442 Uncertain Significance PM2_Supporting, PM1, PS3_Supporting, PP3 PS4, PP4, PP1 The c.613A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamine at codon 205 (p.(Lys205Gln)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.867, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, this variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Lys205Gln protein has nuclear transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 10585442). In summary, c.613A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP3, PM1, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964305/MONDO:0015967/017 2022-08-04 2022-08-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:82960 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C2711227 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0040479 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0027765 infores:hetionet CHEBI:6909 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0687713 infores:hetionet CHEBI:50861 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0019079 infores:hetionet CHEBI:83804 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0010200 infores:hetionet GO:0006954 biolink:causes MONDO:0004849 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D011656 DB00901_MESH_D011656_1 UMLS:C0879264 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0022660 infores:hetionet NCBIGene:6295 biolink:causes MONDO:0013407 infores:monarchinitiative not_provided not_provided HGNC:10521 MONDO:0013407 uuid:57d327c9-90fb-44f3-88d8-e5de2a722901 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6710 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0027497 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0039520 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0021400 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0034065 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0852679 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0852679 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0086543 infores:hetionet CHEBI:188986 biolink:causes HP:0030947 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0860499 infores:hetionet CL:0000097 biolink:causes GO:0002552 infores:ubergraph knowledge_assertion manual_agent CL:0000097 GO:0002552 CHEBI:64318 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0948594 infores:hetionet NCBIGene:79152 biolink:causes MONDO:0012866 infores:monarchinitiative not_provided not_provided HGNC:21197 MONDO:0012866 uuid:f5c8d933-aa2b-4b80-a907-6950f029022d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63638 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026650 infores:hetionet CHEBI:17303 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020580 infores:hetionet CHEBI:63589 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0039070 infores:hetionet CHEBI:4708 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C3665347 infores:hetionet CHEBI:29007 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0017675 infores:hetionet CHEBI:10125 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002962 infores:hetionet CHEBI:231425 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0043352 infores:hetionet NCBIGene:11081 biolink:causes MONDO:0009014 infores:monarchinitiative not_provided not_provided HGNC:6309 MONDO:0009014 uuid:af4825c4-8bc2-40bf-919c-1ed8c41549a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8481 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0242350 infores:hetionet CHEBI:2208 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0011991 infores:hetionet CAID:CA405667924 biolink:causes MONDO:0007783 infores:clingen CAID:CA405667924 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Isoleucine with Asparagine at codon 2358 of the RYR1 protein, p.(Ile2358Asn). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has an entry in ClinVar but no reports could be identified in the literature of an association with MH. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.867) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405667924/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true UNII:UMD7G2653W biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0033771 infores:hetionet CAID:CA915949641 biolink:causes MONDO:0011132 infores:clingen CAID:CA915949641 MONDO:0011132 PMID:37419334 Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PP1_Moderate PS3 The NM_001369369.1(FOXN1):c.1392_1401del (p.Pro465ArgfsTer?) variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 546. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. This variant had 1.4% luciferase activity compared to WT (PMID: 37419334). P15 (PMID: 33464451) has a highly specific phenotype with moderate lymphopenia, including a low T cell number for age, CD4 and CD8 levels markedly reduced in the first few months, and <20% CD4+CD45RA+ naive cells, as well as nail dystrophy, and absent eyebrows at 0.3 months (PP4). The family of P15 has 5 affected heterozygous family members; 5/5 nail dystrophy, 4/5 alopecia, 4/5 SCID-like phenotype (PMID: 33464451; PP1_Moderate). The variant is absent from gnomADv4.0 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, PP4, PP1_Moderate as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949641/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:31859 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0030554 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0021053 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0863111 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0863111 infores:hetionet CHEBI:9649 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0085632 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0232492 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0015397 infores:hetionet CHEBI:4495 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C2364111 infores:hetionet CHEBI:16899 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0017178 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0267792 infores:hetionet CHEBI:31624 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0039231 infores:hetionet CHEBI:7565 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0027497 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0235416 infores:hetionet CHEBI:5383 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0033774 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0243026 infores:hetionet NCBIGene:1497 biolink:causes MONDO:0100151 infores:monarchinitiative not_provided not_provided HGNC:2518 MONDO:0100151 uuid:599d7200-ab27-4d9a-9432-06684381a4b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3757 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0043094 infores:hetionet CHEBI:94848 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0235146 infores:hetionet NCBIGene:54704 biolink:causes MONDO:0012120 infores:monarchinitiative not_provided not_provided HGNC:9279 MONDO:0012120 uuid:0a06fe61-3156-4a34-854a-671c68934ead biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8802 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0234238 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0233494 infores:hetionet CHEBI:16480 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0040034 infores:hetionet CHEBI:31236 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004134 infores:hetionet CHEBI:3738 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0233494 infores:hetionet CAID:CA10014365 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014365 MONDO:0011071 PMID: Likely Benign BS3_Supporting, BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.737C>T (p.Thr246Met) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002942 (2/67986 alleles) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.4) and a SpliceAI score ≤ 0.20 (0.01) (BP4). Transactivation assays in HeLa cells showed no significant decrease in transactivation compared to the WT allele (88.74% with luciferase reporter and 112.2% with GMZA reporter), indicating that this variant does not impact protein function (PMID 34166225) (BS3_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014365/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36795 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020473 infores:hetionet CHEBI:100241 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085649 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1619702 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0232461 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0521509 infores:hetionet CHEBI:36704 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0016436 infores:hetionet CHEBI:6472 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0023518 infores:hetionet CAID:CA410147715 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147715 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1237T>G (p.Ser413Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score < 0.50 (0.27) and a SpliceAI score ≤ 0.20 (0) (BP4). In summary, this variant meets criteria to be classified as VUS. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147715/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94385 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0003578 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0231875 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0231875 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0857353 infores:hetionet GO:0051282 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0051282 GO:0051641 CHEBI:41879 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0234916 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0521495 infores:hetionet CHEBI:7822 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0022346 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877126 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877126 infores:hetionet CHEBI:63618 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C2239176 infores:hetionet CHEBI:28748 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020639 infores:hetionet NCBIGene:8621 biolink:causes MONDO:0044302 infores:monarchinitiative not_provided not_provided HGNC:1733 MONDO:0044302 uuid:8ecd22fe-5a2b-42fb-ab49-e55fb83a2029 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA396459763 biolink:causes MONDO:0007648 infores:clingen CAID:CA396459763 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2 The c.940A>T (p.Lys314Ter) variant is predicted to result in a premature termination codon in exon 7 (PVS1, PM5_Supporting). The variant is absent from the gnomAD population database (PM2_Supporting; https://gnomad.broadinstitute.org/). This variant has previously been reported in one individual meeting IGCLC criteria for HDGC (PS4_Supporting; PMID: 26182300). In summary, this variant meets criteria to be classified as pathogenic based on ACMP/AMP criteria as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396459763/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:8863 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0023218 infores:hetionet CHEBI:2676 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0033774 infores:hetionet CHEBI:4636 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0030252 infores:hetionet CHEBI:7822 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0003467 infores:hetionet CHEBI:2668 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0013428 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0701836 infores:hetionet NCBIGene:3060 biolink:causes MONDO:0008062 infores:monarchinitiative not_provided not_provided HGNC:4847 MONDO:0008062 uuid:2840dde8-ab9a-4c35-b6a0-c1fbb927e283 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0046013 biolink:causes GO:0043029 infores:ubergraph knowledge_assertion manual_agent GO:0046013 GO:0043029 CHEBI:63629 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011603 infores:hetionet CAID:CA2573157357 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157357 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.58+5G>A is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157357/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:478164 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0017178 infores:hetionet CAID:CA226075 biolink:causes MONDO:0100453 infores:clingen CAID:CA226075 MONDO:0100453 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4, PP1, PM2_Supporting NM_000180.4(GUCY2D):c.2302C>T is a missense variant predicted to replace arginine with tryptophan at position p.768. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0002728, with 440 alleles / 1,612,990 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 23035049) and in at least 6 probands with early-onset severe retinal dystrophy who were compound heterozygous, including 2 with either the NM_000180.4(GUCY2D):c.2516del (p.Thr839fs) or NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) variants suspected in trans (1 point, PMID: 23035049, PMID: 16505055), both of which have been previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset at 3 months (1 pt), night blindness (0.5 pts), nystagmus (1 pt), and visual acuity limited to light perception (1 pt), which together are specific for GUCYD2-related recessive retinopathy (total 4 pts, PMID: 16505055, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 23035049, PP1). The computational predictor REVEL gives a score of 0.817, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on GUCY2D function (PP3_Moderate). The splicing impact predictor SpliceAI gives scores of 0.16 for donor loss and 0.15 for acceptor loss, which are below the ClinGen LCA/eoRD VCEP recommended threshold of 0.2 and do not strongly predict an impact on splicing. The variant exhibited ~0% enzymatic activity when co-expressed with GCAP1 or GCAP2 in a guanylate cyclase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 23035049, PMID: 33997691). The variant when co-expressed with GCAP1 and RD3 exhibited dispersal of GCAP1 and RD3 throughout the cell rather than proper localization to the plasma membrane, indicating failure of the variant to interact with either factor (PMID: 33109612). The variant also showed reduced RD3 binding by western blot when co-immunoprecipitated by either anti-GUCY2D or anti-RD3 antibody (PMID: 25477517, PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226075/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CAID:CA354671566 biolink:causes MONDO:0021060 infores:clingen CAID:CA354671566 MONDO:0021060 PMID: Likely Pathogenic PS2, PS3_Supporting, PM1, PM5, PP3, PS4_Supporting, PM2_Supporting The c.67G>C (p.Gly23Arg) variant in MRAS is a missense variant predicted to cause substitution of glycine by arginine at amino acid 23. This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.906, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). A different missense variant, c.68G>T (p.Gly23Val) PMID:28289718, ClinVar ID:635781, in the same codon has been classified as likely pathogenic for RASopathy by the ClinGen RASopathy VCEP (PM5). This variant resides within the P-loop (amino acids 20 – 27) of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). ERK and AKT activation assays in HEK 293T cells showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:31108500) (PS3_Supporting). This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:31108500). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:31108500). Given the Moderate strength of gene-disease relationship between MRAS and autosomal dominant RASopathy, ClinGen’s sequence variant interpretation working group does not recommend the classification of variants in this gene beyond likely pathogenic. Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as pathogenic; however, the RASopathy VCEP has downgraded this classification to likely pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM1, PM5, PS3_P, PS4, P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA354671566/MONDO:0021060/087 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4653 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0014724 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0007760 infores:hetionet CHEBI:4911 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0016382 infores:hetionet CHEBI:63617 biolink:causes HP:0012151 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019123 infores:hetionet CHEBI:59773 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0006266 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0001824 infores:hetionet CHEBI:101853 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0039070 infores:hetionet CHEBI:63631 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085649 infores:hetionet CHEBI:617099 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0042373 infores:hetionet CHEBI:51209 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0439857 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020676 infores:hetionet CHEBI:100246 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0012569 infores:hetionet CHEBI:3504 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0036830 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0549373 infores:hetionet CHEBI:46557 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151577 infores:hetionet CHEBI:9130 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0002792 infores:hetionet CAID:CA410146607 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146607 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1427T>C (p.Val476Ala) is not present in the gnomAD database (PM2_supporting). No other evidence is available. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146607/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017675 infores:hetionet CHEBI:85161 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020461 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015397 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0435002 infores:hetionet NCBIGene:4068 biolink:causes MONDO:0024551 infores:monarchinitiative not_provided not_provided HGNC:10820 MONDO:0024551 uuid:5d62b9f1-d1ce-4230-8598-551dda622944 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA343722844 biolink:causes MONDO:0020367 infores:clingen CAID:CA343722844 MONDO:0020367 PMID: Likely Pathogenic PP1_Moderate, PS4_Supporting, PS3_Moderate, PM2_Supporting BP7, BS1, BS3, PM6, PP3, PM5, PM4, PS1, PS2, BP4, BA1 The c.1495A>T variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 499 (p.Ile499Phe). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.67, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Ile499Phe protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12872267, 9328473), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343722844/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9725 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0028778 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0002871 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0014130 infores:hetionet CHEBI:4710 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042420 infores:hetionet CHEBI:32184 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0013595 infores:hetionet CHEBI:63791 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0000768 infores:hetionet CAID:CA915940646 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940646 MONDO:0100326 PMID: Pathogenic PM4, PP4_Moderate, PM2_Supporting, PS3, PM3_Supporting PP1 The NM_000419.5(ITGA2B):c.575_576insGACAAG (p.Phe191_Ser192insArgThr) variant is predicted to cause a change in the length of the protein due to an in-frame insertion of two amino acids in a non-repeat region (PM4). At least one patient (Patient KO in PMID: 9739052) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). The patient's platelets had normal amounts of surface alphaIIb and beta3 but failed to bind the ligand mimetic, IIb3-specific mAb, OP-G2. This patient was homozygous for the variant (PM3_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in 293 cells transiently co-transfected with the c.575_576insGACAAG (p.Phe191_Ser192insArgThr) variant αIIb and wild type β3 had normal surface expression but showed minimal binding (0%) to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 9739052)(PS3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PP4_Moderate, PM4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940646/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50742 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0156404 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0149931 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0392176 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0030305 infores:hetionet CHEBI:6078 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0039591 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235620 infores:hetionet CAID:CA2582121421 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582121421 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.1299_1309del variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 9/13 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (p.Pro434LeufsTer27) (PVS1). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582121421/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:127342 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0278106 infores:hetionet CHEBI:52172 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C2939147 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0233494 infores:hetionet CHEBI:8404 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0003708 infores:hetionet CHEBI:15940 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0085624 infores:hetionet CHEBI:45783 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0854467 infores:hetionet CHEBI:4445 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0520888 infores:hetionet CHEBI:9654 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0011603 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011991 infores:hetionet CHEBI:5778 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0015967 infores:hetionet NCBIGene:2147 biolink:causes MONDO:0013361 infores:monarchinitiative not_provided not_provided HGNC:3535 MONDO:0013361 uuid:eaf1cc9d-1731-42bc-b4af-8155d5d2f660 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013456 infores:hetionet CHEBI:49575 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011603 infores:hetionet CHEBI:3286 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0003862 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0687707 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0859192 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0859192 uuid:35e32e91-f364-4b21-9504-11df42322cf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229781 biolink:causes MONDO:0009861 infores:clingen CAID:CA229781 MONDO:0009861 PMID:21871829PMID:23856132PMID:21871829PMID:23856132PMID:27620137 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong, PS3_Supporting PM5 The c.809G>A (p.Arg270Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 21871829, 23856132). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant has 11% residual PAH activity (PMID: 27620137). This variant was detected with multiple pathogenic variants: IVS10nt-11G>A (2 patients), L348V, S349P, R158Q, E390G, D415N (PMID: 21871829); and IVS4+5G>T (PMID: 23856132). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229781/MONDO:0009861/006 2020-06-08 2020-06-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0013456 infores:hetionet CHEBI:47898 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0028961 infores:hetionet CAID:CA213958 biolink:causes MONDO:0015967 infores:clingen CAID:CA213958 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PM2_Supporting, PM1_Supporting PP3, PP4 The c.553G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to proline at codon 185 (p.(Ala185Pro)) of NM_175914.5. This variant is located in the ligand binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It has a REVEL score of 0.624, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID: 36354). Additionally, another missense variant, c.553G>A (p.Ala185Thr), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.553G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213958/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41423 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011991 infores:hetionet CHEBI:71417 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0019825 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1258215 infores:hetionet CHEBI:3441 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020580 infores:hetionet CHEBI:15367 biolink:causes HP:0033832 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0332579 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011616 infores:hetionet NCBIGene:6855 biolink:causes MONDO:0010429 infores:monarchinitiative not_provided not_provided HGNC:11506 MONDO:0010429 uuid:61e1cbe6-7a08-4e88-bfc4-4ce440b77568 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9328 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0018524 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0042109 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020517 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042134 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0009450 infores:hetionet CHEBI:64354 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0015672 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2830004 infores:hetionet CHEBI:9637 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C3160741 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0037199 infores:hetionet CHEBI:29688 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0151878 infores:hetionet CHEBI:7494 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151636 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017160 infores:hetionet CHEBI:9763 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085605 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0426576 infores:hetionet CHEBI:6775 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0206062 infores:hetionet CHEBI:9637 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0027497 infores:hetionet CHEBI:4530 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0036572 infores:hetionet CHEBI:4911 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C2047937 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233632 infores:hetionet CHEBI:41423 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017181 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1510472 infores:hetionet CHEBI:53766 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0151763 infores:hetionet CHEBI:61049 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1458155 infores:hetionet CHEBI:9927 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0043352 infores:hetionet UMLS:C0145867 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0085633 infores:hetionet CHEBI:209807 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0014742 infores:hetionet CHEBI:72297 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0151904 infores:hetionet CHEBI:10110 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0020429 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0340464 infores:hetionet CHEBI:135888 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0033774 infores:hetionet GO:1900206 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:1900206 GO:0072001 CHEBI:28593 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0085631 infores:hetionet CHEBI:3614 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0013390 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0857353 infores:hetionet CHEBI:134966 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0004604 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0434437 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011615 infores:hetionet CAID:CA6748705 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748705 MONDO:0009861 PMID:26503515PMID:17096675PMID:18346471 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PM5, PP3, PS3 The c.1256A>G (p.Gln419Arg) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 17096675, PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant was detected in trans with multiple pathogenic variants: p.S231P (PMID: 18346471); p.Ala434Asp (PMID: 25456745); c.1068C>A (p.Y356*) (PMID: 26322415); p.Arg413Pro; p.Ala403Val; p.Val399=; p.Arg243Gln (2 patients); p.Arg53His (US); EX6-96A＞G (PMID: 28982351). Computational prediction tools are conflicting. PAH-specific ACMG/AMP criteria applied: PM3_ very-strong, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748705/MONDO:0009861/006 2020-06-22 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8461 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0027424 infores:hetionet NCBIGene:5740 biolink:causes MONDO:0007781 infores:monarchinitiative not_provided not_provided HGNC:9603 MONDO:0007781 uuid:90f33aa6-46e5-4f8a-a898-78c960244536 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7492 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0042109 infores:hetionet CHEBI:66964 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0011570 infores:hetionet CAID:CA2849481719 biolink:causes MONDO:0015967 infores:clingen CAID:CA2849481719 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3 PP1 The c.326+4A>C variant in the HNF1 homeobox A gene, HNF1A, alters a nucleotide two base pairs downstream of the canonical splice donor site in intron 1 of transcript NM_000545.8. The computational splicing predictor SpliceAI gives a score of 0.20 for donor loss, predicting that the c.326+4A>C variant may disrupt splicing at the donor site of intron 1 of HNF1A (PP3). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.326+4A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2849481719/MONDO:0015967/017 2024-10-14 2024-10-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49375 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151907 infores:hetionet CHEBI:31348 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085633 infores:hetionet CAID:CA401364293 biolink:causes MONDO:0009290 infores:clingen CAID:CA401364293 MONDO:0009290 PMID:29422078 Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.955+1G>A, alters the donor splice site of intron 5 in the GAA gene. Assuming that skipping of exon 5 occurs, this would cause a frameshift, resulting in a premature termination codon and lack of GAA gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in GAA, c.1438-2A>G, in a patient who also meets the ClinGen LSD VCEP's PP4 specifications (PMID 29422078). The phase is unknown. This data meets PM3_Supporting. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401364293/MONDO:0009290/010 2020-02-14 2020-05-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:15940 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0002418 infores:hetionet CHEBI:135925 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0011991 infores:hetionet CHEBI:75722 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151632 infores:hetionet CHEBI:204928 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0232807 infores:hetionet CAID:CA410206841 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206841 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.715A>T (p.Ser239Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206841/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:66876 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0027441 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0948349 infores:hetionet CAID:CA10360641 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360641 MONDO:0010725 PMID: Uncertain Significance BS1, PM2, BP4, PP3 The NM_000330.4(RS1):c.433G>A missense variant encoding the substitution of Aspartic acid with Asparagine at amino acid 145. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00001511 among hemizygous individuals, with 6 variant alleles / 397081 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.556, which is between the ClinGen X-linked IRD VCEP thresholds of 0.664 and 0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes do not apply. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: no codes apply (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360641/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:61049 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2047937 infores:hetionet CAID:CA512341388 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341388 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PM2, PVS1, BP5, BP7, BS3, BS4, BS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.990C>T (p.Phe330=) is a synonymous variant which has a spliceAI score of 0, indicating a low likelihood of affecting splicing (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341388/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0020523 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0160390 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0518015 infores:hetionet CHEBI:4911 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0220981 infores:hetionet CHEBI:8665 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0000729 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0009806 infores:hetionet CHEBI:404903 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0015732 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0001416 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0014130 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0423602 infores:hetionet CHEBI:3749 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0263386 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0855242 infores:hetionet CHEBI:7915 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018520 infores:hetionet CHEBI:5134 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0018681 infores:hetionet CHEBI:4027 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C2939419 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0027051 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0036572 infores:hetionet CHEBI:63599 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0008350 infores:hetionet CAID:CA512341066 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341066 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1311C>A (p.Thr437=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-3.62) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341066/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3485 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0020538 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0012797 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009324 infores:hetionet CHEBI:3479 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0036830 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0023067 infores:hetionet CHEBI:119573 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151872 infores:hetionet CHEBI:5132 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C2939419 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0520459 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0087169 infores:hetionet NCBIGene:26235 biolink:causes MONDO:0014198 infores:monarchinitiative not_provided not_provided HGNC:13601 MONDO:0014198 uuid:492d9bb3-1080-48ca-82ce-9b6753a252be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94449 biolink:causes MONDO:0002803 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0021847 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0234215 infores:hetionet CHEBI:8713 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C2047937 infores:hetionet CAID:CA915942594 biolink:causes MONDO:0021056 infores:clingen CAID:CA915942594 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting PM4 The c.1105TTG[1] or c.1108_1110del variant in APC is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Leu370del). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was not observed in internal data from Ambry Genetics, Invitae, Bonn or Melbourne. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PM2_Supporting (VCEP specifications version 1.0; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA915942594/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:G4PX8C4HKV biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0030552 infores:hetionet CHEBI:490877 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0221423 infores:hetionet CHEBI:31981 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C2830004 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0036572 infores:hetionet CHEBI:8428 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0001824 infores:hetionet CAID:CA10583885 biolink:causes MONDO:0011071 infores:clingen CAID:CA10583885 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.232A>T (p.Met78Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583885/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2017997767 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997767 MONDO:0015967 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS4, PP4 The c.1312_1314del variant in the glucokinase gene, GCK, is a three base pair deletion resulting in the in-frame deletion of one amino acid codon 438 (p.(Phe438del)) within exon 10 of NM_000162.5. The c.1312_1314del variant is predicted to change the length of the protein due an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of GCK-MODY; however, PP4 could not be evaluated due to insufficient clinical information (internal lab contributor). In summary, the c.1312_1314del variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997767/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA10652906 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652906 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*3619A>G variant in the 3' UTR has an MAF of 0.02813 (2.8%, 384/13650 alleles) in the Latino subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 11 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652906/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28445 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0162830 infores:hetionet CHEBI:2948 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0011603 infores:hetionet CHEBI:4657 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C2047937 infores:hetionet CHEBI:42944 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0016204 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0028738 infores:hetionet CHEBI:15367 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030232 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0012833 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0267596 infores:hetionet CHEBI:63845 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0018939 infores:hetionet CHEBI:31980 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C3665347 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0235293 infores:hetionet CHEBI:31643 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0042963 infores:hetionet CHEBI:6965 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0020649 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233459 infores:hetionet CHEBI:36791 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232461 infores:hetionet CHEBI:28925 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0007114 infores:hetionet CAID:CA409107643 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107643 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PP4 The c.821A>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of aspartic acid to valine at codon 274 (p.(Asp274Val)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information; therefore, PP4 cannot be applied (internal lab contributors). In summary, c.821A>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PP3 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107643/MONDO:0015967/085 2025-07-25 2025-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2611 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C2607914 infores:hetionet CHEBI:92998 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151908 infores:hetionet CAID:CA410208105 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208105 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.533C>T (p.Thr178Ile) is a missense variant which has a REVEL score ≥ 0.88 (0.925) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208105/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:161680 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0235431 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0151828 infores:hetionet CHEBI:63630 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0033774 infores:hetionet CAID:CA121988 biolink:causes MONDO:0007648 infores:clingen CAID:CA121988 MONDO:0007648 PMID: Likely Benign BS2, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM5, PM6, PVS1, PP1, PP2, PP3, PP4, BP1, BP4, BP2, BP3, BA1, PS4, PS3, PS1, PS2 The c.2131C>G variant is <1/50,000 alleles (0.002%, 2/128,916 alleles) in the non-Finnish European subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). Use of the Bayesian point system for this variant with conflicting evidence. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA121988/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:8869 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0019270 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0034065 infores:hetionet CHEBI:43968 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0002884 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0033687 infores:hetionet CHEBI:194135 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0015371 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0025202 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0029408 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0006826 infores:hetionet CHEBI:9137 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0033036 infores:hetionet CAID:CA10014357 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014357 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BA1, BP3, BP2, BP1, BP4, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP4, PP1, PP2, PP3, BS2 The NM_001754.5(RUNX1):c.790C>G (p.Gln264Glu) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014357/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10102 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0014335 infores:hetionet CHEBI:6715 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0547030 infores:hetionet CHEBI:6717 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0344232 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0031099 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0038663 infores:hetionet CHEBI:4710 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020433 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0040479 infores:hetionet CHEBI:184555 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0018681 infores:hetionet CHEBI:182080 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0001824 infores:hetionet CHEBI:31859 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0001824 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0427008 infores:hetionet CHEBI:5959 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0022346 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0595883 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151736 infores:hetionet CHEBI:7496 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0438142 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013922 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003864 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0242350 infores:hetionet CHEBI:15544 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0033036 infores:hetionet CHEBI:68575 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0043352 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0018799 infores:hetionet CHEBI:134966 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0035455 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0029927 infores:hetionet CHEBI:6073 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0002792 infores:hetionet CHEBI:6076 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0522055 infores:hetionet CHEBI:50223 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0311468 infores:hetionet CHEBI:31625 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0013378 infores:hetionet CHEBI:465284 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0037763 infores:hetionet CHEBI:15407 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0002962 infores:hetionet CHEBI:63617 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0024282 infores:hetionet CHEBI:4636 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0009676 infores:hetionet CHEBI:8214 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0600142 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0240417 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0002170 infores:hetionet CAID:CA211306 biolink:causes MONDO:0010726 infores:clingen CAID:CA211306 MONDO:0010726 PMID: Benign BS2, BA1 The allele frequency of the p.Glu397Lys variant in MECP2 (NM_004992) is 0.393% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as Benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Glu397Lys variant is observed in at least 2 unaffected individuals (PMID 10577905,12384770, RettBASE) (BS2). In summary, the p.Glu397Lys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA211306/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:49375 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0004093 infores:hetionet CHEBI:55346 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0750426 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0035435 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0920102 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006826 infores:hetionet CHEBI:9168 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0037299 infores:hetionet CHEBI:6931 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0013132 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009763 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0518015 infores:hetionet CHEBI:94807 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0024115 infores:hetionet CAID:CA270401 biolink:causes MONDO:0010726 infores:clingen CAID:CA270401 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PM1, PP3, PP4, PM6, PS4, PM2_Supporting The p.Lys135Glu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 22182064) (PM6). The p.Lys135Glu variant has been observed in at least 6 other individuals with Rett syndrome (PMID 11241840, 22982301, 18842453, 16473305, 17387578) (PS4 and PP4). The p.Lys135Glu variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Lys135Glu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). MECP2 chromatin binding assays and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). In summary, the p.Lys135Glu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PS3_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270401/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:10023 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017979 infores:hetionet CHEBI:45951 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0040822 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0019158 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0234222 infores:hetionet CHEBI:6129 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0687713 infores:hetionet GO:0150011 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0150011 GO:0007399 CHEBI:2208 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0162429 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0013404 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0234458 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013298 infores:hetionet CHEBI:74947 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014724 infores:hetionet CHEBI:135342 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1443060 infores:hetionet CHEBI:4798 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235086 infores:hetionet CHEBI:39585 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0004134 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0162830 infores:hetionet GO:0060034 biolink:causes CL:0007005 infores:ubergraph knowledge_assertion manual_agent GO:0060034 CL:0007005 CHEBI:28748 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004093 infores:hetionet CHEBI:30659 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0002962 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0241618 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0241618 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0009806 infores:hetionet CHEBI:8214 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0008031 infores:hetionet CL:0000066 biolink:causes MONDO:0004534 infores:ubergraph knowledge_assertion manual_agent CL:0000066 MONDO:0004534 GO:1904127 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:1904127 GO:0061053 CHEBI:7852 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0549249 infores:hetionet CHEBI:63617 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1274594 infores:hetionet CHEBI:15854 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0947912 infores:hetionet CHEBI:9605 biolink:causes MONDO:0005783 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0019064 infores:hetionet CHEBI:4495 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0030554 infores:hetionet GO:1902890 biolink:causes GO:0010015 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0010015 CAID:CA10558640 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558640 MONDO:0010726 PMID: Pathogenic PS4_Moderate, PM1, PS2_Very Strong, PP3 PM2 The p.Arg115His variant in MECP2 (NM_004992.4) has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 male individuals with neurodevelopmental disorders (internal database - GeneDx) (PS2_Very Strong). The p.Arg115His variant has been observed in 3 male individuals with neurodevelopmental disorders (internal database) (PS4_Moderate). The p.Arg115His variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg115His variant in MECP2 is absent from gnomAD v4.1; however, this variant is present in 1 XX individual in gnomAD v2.1.1. In summary, the p.Arg115His variant in MECP2 (NM_004992.4) is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_Very Strong, PS4_Moderate, PM1, PP3). (MECP2 Specification v.3.0.0, curation approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558640/MONDO:0010726/036 2024-08-30 2024-12-23 X-linked inheritance HP:0001417 Supports CHEBI:48390 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0020437 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0235818 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0242350 infores:hetionet CHEBI:8107 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0009676 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0236071 infores:hetionet CAID:CA229520 biolink:causes MONDO:0009861 infores:clingen CAID:CA229520 MONDO:0009861 PMID: Benign BA1, BP7 The c.353-22C>T variant in PAH has a MAF of 0.7066 in the gnomAD East Asian population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229520/MONDO:0009861/006 2020-03-27 2020-03-27 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:9757 biolink:causes MONDO:0015004 infores:monarchinitiative not_provided not_provided HGNC:15840 MONDO:0015004 uuid:ce18d299-3529-4646-af57-5f044385e15f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0020580 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0002453 infores:hetionet CHEBI:17347 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0231218 infores:hetionet CHEBI:63622 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C1142412 infores:hetionet CAID:CA120646 biolink:causes MONDO:0044970 infores:clingen CAID:CA120646 MONDO:0044970 PMID:22079202PMID:10976107PMID:35383288PMID:15720387PMID:15883259PMID:15342361 Pathogenic PP3, PS3_Moderate, PS4, PM6_Supporting, PP1_Moderate PM2 The m.3460G>A (p.A52T) variant in MT-ND1 has been reported in affected individuals from more than 50 kindreds (PS4, PMIDs: 1928099, 1674640, 7629530, 1734726, 1550131, 8496715, 8024249, 8556281, 8571959, 12205655, 11906302, 12807863, 12518276, 16738010, 17122117, 18216301, 18562849, 20232220, 21887510, 25338955, 25053773, 28314831, 30053855, 30591017). While this variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353), affected individuals can also have other features. Indeed, several individuals have been reported with multiple sclerosis. Other features have been variably seen in affected individuals including sensorineural hearing loss, auditory neuropathy, epilepsy, migraines, Parkinsonism, dystonia, Leigh syndrome, spinal cord lesions, myoclonus, myopathy, hypertension, high triglycerides, diabetes, and cardiac involvement. Testing excluding separate etiologies for these features has been limited. Heteroplasmy levels in affected individuals ranged from 58% to homoplasmy. Age of onset varied from four years old to 75 years old. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 1734726, 8571959, 11906302). There is one reported de novo occurrence to our knowledge (PM6_supporting; PMID: 12518276). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.86 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Extensive cybrid studies supported the functional impact of this variant, as do E. coli and mouse studies (PS3_moderate PMIDs: 35383288, 22079202, 15720387, 15883259, 15342361, 10976107). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM6_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120646/MONDO:0044970/015 2023-04-25 2023-05-19 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:63589 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020456 infores:hetionet CHEBI:9352 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0030554 infores:hetionet CHEBI:3310 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0042401 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019158 infores:hetionet CHEBI:144093 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0019270 infores:hetionet CHEBI:15940 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0030252 infores:hetionet CHEBI:521033 biolink:causes HP:0040307 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C1112443 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0037274 infores:hetionet CHEBI:6690 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0006384 infores:hetionet CHEBI:42797 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0221269 infores:hetionet CAID:CA410206697 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206697 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.782C>T (p.Pro261Leu) is a missense variant which is completely absent from population databases (PM2_Supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. It has a REVEL score of 0.519. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206697/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020678 infores:hetionet CHEBI:9763 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0022346 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0011616 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0032961 infores:hetionet CHEBI:44185 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0010520 infores:hetionet CHEBI:63631 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0040460 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042075 infores:hetionet CHEBI:3077 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0017979 infores:hetionet CHEBI:3347 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0001824 infores:hetionet CHEBI:68647 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151744 infores:hetionet CAID:CA414784550 biolink:causes MONDO:0044970 infores:clingen CAID:CA414784550 MONDO:0044970 PMID: Uncertain Significance PP3, PM2 PS4, PS3 The m.6526T>C (p.Met208Thr) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date, with features of developmental delay, hypotonia, and myopathy (PMID: 32652755). The variant was present at 86.6% heteroplasmy in skeletal muscle. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.550 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414784550/MONDO:0044970/015 2024-10-28 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:66899 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0085636 infores:hetionet CHEBI:6950 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0392525 infores:hetionet CAID:CA1139654950 biolink:causes MONDO:0020367 infores:clingen CAID:CA1139654950 MONDO:0020367 PMID:35196929 Uncertain Significance PP1, PM2_Supporting, PS3_Moderate, PM4_Supporting BS1, BS3, BP7, PM6, PP3, PM5, PS4, PS1, PS2, BA1, BP4 The c.1187_1188insCCCAGA variant in MYOC is predicted to cause a change in the length of the protein due to an in-frame insertion of 2 amino acids (p.Asp395_Glu396insAspPro). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. A previous study (PMID: 35196929) demonstrated that the Asp395_Glu396insAspPro protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 23566828), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 23566828), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1, PM2_Supporting, PM4_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139654950/MONDO:0020367/019 2022-03-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028738 infores:hetionet NCBIGene:256764 biolink:causes MONDO:0013181 infores:monarchinitiative not_provided not_provided HGNC:26790 MONDO:0013181 uuid:a8fb6ecb-5cd6-4395-b581-bd923b7768b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0017152 infores:hetionet CHEBI:45409 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0010481 infores:hetionet CHEBI:3508 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0027947 infores:hetionet CHEBI:28787 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0011615 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0858259 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0413252 infores:hetionet CAID:CA10584814 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584814 MONDO:0007750 PMID: Pathogenic PS4, PS3_Supporting, PM2, PVS1, PP4 BA1, BP3, BP2, BP1, BP4, PS1, PS2, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PM6, BS2, PP1, PP2, PP3 The NM_000527.5(LDLR):c.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met.PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180.PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584814/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA1244285 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244285 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.384G>C variant in MYOC is a synonymous variant (p.Arg128=). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 16148883), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244285/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50223 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0542149 infores:hetionet CHEBI:38940 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027497 infores:hetionet CHEBI:47780 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003811 infores:hetionet CHEBI:175901 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0027497 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020615 infores:hetionet NCBIGene:1747 biolink:causes MONDO:0007093 infores:monarchinitiative not_provided not_provided HGNC:2916 MONDO:0007093 uuid:ec3d7941-fd2e-488d-bf7d-d8770b2df722 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000025 biolink:causes MONDO:0018875 infores:clingen CAID:CA000025 MONDO:0018875 PMID: Uncertain Significance BP4, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS3, BS4, PP3, PP4, PP1, BS2 The NM_000546.6: c.105G>T variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.078; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests there is no impact on the native site, and following expert review the variant is considered to have no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; date of approval) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000025/MONDO:0018875/009 2024-09-06 2024-09-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA415086241 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086241 MONDO:0010305 PMID: Likely Pathogenic PS3_Supporting, PM2_Supporting, PP4_Strong, BP4 PP3 The NM_005629.4(SLC6A8):c.1171C>T (p.Arg391Trp) variant in SLC6A8 is a missense variant predicted to cause substitution of Tryptophan for Arginine at amino acid 391 (p.Arg391Trp). There is a ClinVar entry for this variant (Variation ID:465141, Conflicting Interpretations) with classifications as Pathogenic (n=2) and as a Variant of Uncertain Significance (n=1). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable. The p.Arg391Trp variant has been reported in a male with intellectual disability, speech delay, and seizures who had biochemical studies including elevated Creatine:Creatinine ratio in urine and MRS demonstrating reduced Creatine peak in brain (Patient 2; [PMID:21910234]), which meets criteria for PP4_Strong. The patient from Mencarelli, 2011 [PMID:21910234] was also found to have the c.1171C>T (p.Arg391Trp) variant de novo, meeting criteria for PS2. Site directed mutagenesis and creatine uptake studies were performed with the p.Arg391Trp variant, and these studies demonstrated creatine uptake <10% wildtype cells (<150 μM creatine used), meeting PS3_Supporting criteria [PMID:30885608]. This variant has also been identified in a male with intellectual disability and/or seizures but without biochemical evidence of creatine transporter deficiency (elevated urine creatine:creatine, MRS demonstrating reduced creatine peak) [PMID:16738945], and given the absence of biochemical evidence of Creatine Transporter Deficiency in this individual evidence for pathogenicity was not scored. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PS2, PS3_Supporting, PM2_Supporting, BP4. Classification changed from VUS to LP given the only benign/conflicting evidence for this variant is in silico evidence. Using the new point scoring system from Tavtigian et.al 2020 [PMID:32720330], this variant meets criteria for Likely Pathogenic (Score: 4+4+1+1-1 = 9 points; Likely Pathogenic).(Classification approved by the CCDS VCEP Nov 10, 2022) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086241/MONDO:0010305/027 2024-02-11 2024-02-11 X-linked inheritance HP:0001417 Supports UMLS:C0657912 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235710 infores:hetionet CHEBI:63791 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0206062 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0037199 infores:hetionet GO:2000345 biolink:causes GO:0061008 infores:ubergraph knowledge_assertion manual_agent GO:2000345 GO:0061008 CHEBI:8863 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017675 infores:hetionet CHEBI:3996 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0009676 infores:hetionet CHEBI:9763 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0013604 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1141959 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1141959 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0281825 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0281825 infores:hetionet CHEBI:52717 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C3665386 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0162287 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042109 infores:hetionet CHEBI:8776 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0027947 infores:hetionet CHEBI:31711 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C3263723 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0012833 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0152517 infores:hetionet NCBIGene:4649 biolink:causes MONDO:0032597 infores:monarchinitiative not_provided not_provided HGNC:7608 MONDO:0032597 uuid:57f1f083-9246-430d-ae0b-d9e75d797fcc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7956 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0037274 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0042109 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0234215 infores:hetionet CHEBI:63611 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0021368 infores:hetionet CHEBI:7444 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0043094 infores:hetionet CHEBI:53766 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0042963 infores:hetionet CHEBI:9613 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C1443060 infores:hetionet NCBIGene:610 biolink:causes MONDO:0100519 infores:monarchinitiative not_provided not_provided HGNC:4846 MONDO:0100519 uuid:2de36397-1a40-44ca-875f-4496dc7447f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA011843 biolink:causes MONDO:0005045 infores:clingen CAID:CA011843 MONDO:0005045 PMID:16630450PMID:27532257PMID:19150014PMID:27532257PMID:17097032PMID:11113006 Pathogenic PP1_Strong, PM1, PM5, PM2, PP3, PS4 The c.2167C>G (p.Arg723Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PS4; PMID:11113006; PMID:19150014; PMID:17097032; Partners LMM ClinVar SCV000059422.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:11113006). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>T p.Arg723Cys - ClinVar Variation ID 14095). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011843/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3568 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235818 infores:hetionet GO:0060058 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:0060058 GO:0030879 CHEBI:119915 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014724 infores:hetionet CHEBI:7488 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0010038 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0036508 infores:hetionet CHEBI:75246 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C1260880 infores:hetionet CHEBI:51041 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0003862 infores:hetionet CHEBI:8093 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0020452 infores:hetionet CHEBI:6339 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C2830004 infores:hetionet CHEBI:6775 biolink:causes MONDO:0018646 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0008313 infores:hetionet CHEBI:9445 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0033774 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0497327 infores:hetionet CHEBI:8874 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0015967 infores:hetionet CHEBI:16469 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0005778 infores:hetionet CHEBI:63618 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0024141 infores:hetionet CHEBI:8461 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0039070 infores:hetionet CHEBI:8863 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0014591 infores:hetionet CHEBI:46345 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0033774 infores:hetionet CHEBI:50692 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0600327 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0233494 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0233494 infores:hetionet CHEBI:52172 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0476280 infores:hetionet CHEBI:119573 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0043352 infores:hetionet UMLS:C0879264 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0003862 infores:hetionet NCBIGene:8241 biolink:causes MONDO:0010711 infores:monarchinitiative not_provided not_provided HGNC:9896 MONDO:0010711 uuid:46e69d5d-cf5d-4ac4-b031-d93a07078646 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0014033 biolink:causes CL:0000333 infores:ubergraph knowledge_assertion manual_agent GO:0014033 CL:0000333 CHEBI:51380 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C2047937 infores:hetionet NCBIGene:6529 biolink:causes MONDO:0014633 infores:monarchinitiative not_provided not_provided HGNC:11042 MONDO:0014633 uuid:5a943b8e-16c0-43f1-b249-1a5e2262c24d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0002170 infores:hetionet CHEBI:87715 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0019080 infores:hetionet CHEBI:3994 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0006266 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042373 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0040409 infores:hetionet CHEBI:5106 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0030193 infores:hetionet CHEBI:61033 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0036974 infores:hetionet CHEBI:27786 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0011991 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0031117 infores:hetionet CHEBI:8871 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0340865 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042134 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0038362 infores:hetionet CHEBI:135736 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0231807 infores:hetionet NCBIGene:84570 biolink:causes MONDO:0014538 infores:monarchinitiative not_provided not_provided HGNC:18603 MONDO:0014538 uuid:35d74785-7d04-459c-bc21-9e5a2ccd5db1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0002871 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020437 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0018799 infores:hetionet CHEBI:10125 biolink:causes MONDO:0043494 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003860 infores:hetionet CAID:CA244536194 biolink:causes MONDO:0015967 infores:clingen CAID:CA244536194 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP5 BP4, PM1, PM5, PP3 The c.1637A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to alanine at codon 546 (p.(Asp546Ala)) of NM_000545.8. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant has a REVEL score of 0.625, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with an alternate molecular basis for disease (BP5; internal lab contributors). Another missense variant at this codon, c.1637A>G p.(Asp546Gly), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1637A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244536194/MONDO:0015967/017 2024-11-27 2024-11-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6916 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0042963 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0521490 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0858635 infores:hetionet CHEBI:6761 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0002874 infores:hetionet CHEBI:50922 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0036974 infores:hetionet CHEBI:135285 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0085593 infores:hetionet CHEBI:9086 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0152198 infores:hetionet CHEBI:167309 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0030193 infores:hetionet CHEBI:31536 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0004604 infores:hetionet GO:0060297 biolink:causes GO:0055002 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0055002 CHEBI:52717 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037763 infores:hetionet CHEBI:36704 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0039231 infores:hetionet CHEBI:3127 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0014518 infores:hetionet CHEBI:29688 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0004604 infores:hetionet CHEBI:3638 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0344232 infores:hetionet CHEBI:3510 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0085593 infores:hetionet CHEBI:6690 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042023 infores:hetionet CHEBI:8890 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0033774 infores:hetionet CHEBI:161680 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0014457 infores:hetionet GO:0051090 biolink:causes GO:0006355 infores:ubergraph knowledge_assertion manual_agent GO:0051090 GO:0006355 CHEBI:6715 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011124 infores:hetionet CHEBI:15552 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0037299 infores:hetionet NCBIGene:10560 biolink:causes MONDO:0009575 infores:monarchinitiative not_provided not_provided HGNC:10938 MONDO:0009575 uuid:c80099af-2bc9-4257-b8e9-f4a5ac71d32e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85161 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0018681 infores:hetionet CHEBI:18332 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0036974 infores:hetionet UMLS:C0025241 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0034642 infores:hetionet CHEBI:31199 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0234233 infores:hetionet CHEBI:3732 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0018524 infores:hetionet CHEBI:41977 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0039240 infores:hetionet NCBIGene:10083 biolink:causes MONDO:0011192 infores:monarchinitiative not_provided not_provided HGNC:12597 MONDO:0011192 uuid:2336369f-d791-49d5-a78c-140a6c9c80eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0030193 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0854448 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0854448 infores:hetionet CHEBI:70707 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0699828 infores:hetionet CHEBI:2666 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0856054 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0018799 infores:hetionet CHEBI:4885 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0020615 infores:hetionet CHEBI:9763 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0042963 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0314719 infores:hetionet CHEBI:4046 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0232292 infores:hetionet CHEBI:3654 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0034063 infores:hetionet CAID:CA397726275 biolink:causes MONDO:0008723 infores:clingen CAID:CA397726275 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PM4 The c.1967G>C variant is predicted to cause a change in the length of the protein (p.Ter656SerextTer54) due to a predicted in-frame insertion of 53 amino acids in a non-repeat region (PM4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. In summary, this variant meets the criteria to be classified as UNCERTAIN SIGNIFICANCE for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM4, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1.0; approved 12-29-22). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397726275/MONDO:0008723/021 2023-06-29 2023-06-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50381 biolink:causes MONDO:0004960 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C1136085 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0020538 infores:hetionet CL:0000788 biolink:causes MONDO:0004478 infores:ubergraph knowledge_assertion manual_agent CL:0000788 MONDO:0004478 CHEBI:3723 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006145 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0948808 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0948808 infores:hetionet CHEBI:44185 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0021051 infores:hetionet CHEBI:8028 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0009676 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0037274 infores:hetionet CHEBI:4495 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0001925 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423602 infores:hetionet CHEBI:6710 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C3665346 infores:hetionet CHEBI:4903 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0015672 infores:hetionet CHEBI:51364 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020473 infores:hetionet CHEBI:6539 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0015230 infores:hetionet CHEBI:16586 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0026848 infores:hetionet CHEBI:50275 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151603 infores:hetionet CAID:CA226343 biolink:causes MONDO:0100437 infores:clingen CAID:CA226343 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.1100del (p.Pro367LeufsTer14) is a frameshift variant due to deletion of 1 nucleotide and introduces a premature stop codon after 14 amino acids in exon 10 of 15 that is predicted to result in nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 36017691, PMID: 10937588, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226343/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance (primarily recessive with milder female expression) Supports CAID:CA350341904 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341904 MONDO:0015924 PMID: Likely Pathogenic PS1_Moderate, PP3, PM2_Supporting, PS4_Supporting, PM1_Strong BP4, BA1, PM5, BS1 The BMPR2 c.1228G>C variant is a missense variant predicted to cause a glycine to arginine substitution at amino acid position 410 (p.Gly410Arg). The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). The variant was reported in one individual with pulmonary arterial hypertension in ClinVar and two affected twins (https://doi.org/10.1164/ajrccm-conference.2012.185.1_MeetingAbstracts.A6192) (PS4_supporting). Gly410Arg is located in the catalytic kinase domain and Gly410 is known to be an indispensable residue (PM1_strong). A different variant affecting the same amino acid, c.1228 G>A (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate). Other pathogenic missense variants causing a different amino acid change at the same residue have not been reported (PM5 not met). The REVEL score for this variant is 0.984, which meets the threshold of >=0.75 (PP3 met, BP4 not met). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence, and BS3 and PS3 due to the lack of functional data. In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1_moderate, PS4_supporting, PM1_strong, PM2_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341904/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45409 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013604 infores:hetionet CHEBI:6775 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0239571 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0020517 infores:hetionet CHEBI:45327 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0012833 infores:hetionet CHEBI:17347 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020578 infores:hetionet CHEBI:6904 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0039070 infores:hetionet CHEBI:8713 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0917801 infores:hetionet CHEBI:7445 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0025345 infores:hetionet CHEBI:134936 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0020517 infores:hetionet CHEBI:28593 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0024141 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009319 infores:hetionet CHEBI:135005 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0017168 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040034 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0497327 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0239293 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0239293 infores:hetionet CAID:CA10014394 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014394 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-7A>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014394/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9727 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0023530 infores:hetionet CHEBI:2704 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0041582 infores:hetionet CHEBI:45783 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042963 infores:hetionet CHEBI:3723 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0542571 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0000932 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0000932 infores:hetionet CHEBI:17650 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0338831 infores:hetionet CHEBI:36791 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0035410 infores:hetionet CAID:CA748915368 biolink:causes MONDO:0011071 infores:clingen CAID:CA748915368 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS3, PS4, BP1, BP3, BP2, BA1, BP5, PVS1, BP7, BS1, BS4, BS3, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.58+8C>T is an intronic variant which is completely absent from gnomAD 2.0 with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA748915368/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:261649 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0009450 infores:hetionet CHEBI:8481 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0042963 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005976 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0039128 infores:hetionet CAID:CA3231898 biolink:causes MONDO:0012163 infores:clingen CAID:CA3231898 MONDO:0012163 PMID: Likely Pathogenic PM2_Supporting, PVS1 BS2 The NM_002185.5(IL7R):c.265C>T (p.Gln89Ter) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/8, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 3/113430 alleles) is 0.000007030 in gnomAD v2.1.1, which is below the SCID-VCEP threshold (<0.00004129; PM2_Supporting). This variant has been reported in ClinVar and LOVD without patient information; however, it has not been reported in the literature to our knowledge. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3231898/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0553732 infores:hetionet CHEBI:127780 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0595916 infores:hetionet CHEBI:27690 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0013144 infores:hetionet CHEBI:79699 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011603 infores:hetionet CAID:CA343724106 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724106 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting BS1, BS3, BP7, PM6, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.1267A>C variant in MYOC is a missense variant predicted to cause substitution of Lysine by Glutamine at amino acid 423 (p.Lys423Gln). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.795, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 35946471), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724106/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6149 biolink:causes MONDO:0005693 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0392548 infores:hetionet CHEBI:31236 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0237314 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0028738 infores:hetionet CHEBI:31709 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0003811 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0522061 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0522061 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0267792 infores:hetionet CHEBI:109549 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0012833 infores:hetionet NCBIGene:3248 biolink:causes MONDO:0024546 infores:monarchinitiative not_provided not_provided HGNC:5154 MONDO:0024546 uuid:db016f1e-55f0-4828-b68c-fad198400c6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0232492 infores:hetionet CHEBI:51141 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0013604 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0020538 infores:hetionet CHEBI:72297 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0575081 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0029882 infores:hetionet CHEBI:91541 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0031350 infores:hetionet CHEBI:78543 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0004093 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0039971 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0702266 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0005586 infores:hetionet CHEBI:48538 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0855242 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0041912 infores:hetionet CHEBI:6438 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0002170 infores:hetionet CHEBI:5147 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0231218 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0518015 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0015397 infores:hetionet CHEBI:209807 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0023530 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0541799 infores:hetionet NCBIGene:80217 biolink:causes MONDO:0009366 infores:monarchinitiative not_provided not_provided HGNC:26684 MONDO:0009366 uuid:c4902003-bd3b-4423-88b3-cc5cb1d37966 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3945 biolink:causes MONDO:0013587 infores:monarchinitiative not_provided not_provided HGNC:6541 MONDO:0013587 uuid:899139cc-29ce-45c6-b887-299f7bb78298 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0003467 infores:hetionet CHEBI:6761 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0003811 infores:hetionet CAID:CA345144077 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144077 MONDO:0100084 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PP4_Moderate, PS2 BS2, PVS1, BP1, BP4, BP2, BP3, BA1, PS3, PS1, BP7, BS1, BS3, PM3, PM4, PM1, PM5 The variant NM_001100.4:c.1127G>C in ACTA1 is a missense variant predicted to cause substitution of cysteine by serine at amino acid 376 (p.Cys376Ser) in exon 7/7. The variant is absent from gnomAD v2.1.1 with adequate coverage (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.946, which is above the threshold necessary to apply PP3. In addition, ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The Z-score in gnomAD v2.1.1 is 4.53 which is above the threshold necessary to apply PP2. This variant has been reported in two probands with congenital nemaline myopathy (PS4_Supporting, PP4_Moderate PMID:25890230,19562689), and as a de novo observation with confirmed parental relationships in one of the probands (PS2, PMID:25890230). In summary, the variant meets the criteria to be classified as Pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PP4_Moderate, PS4_Supporting, PP2, PP3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144077/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8310 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C2830004 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017152 infores:hetionet CAID:CA2581998917 biolink:causes MONDO:0021056 infores:clingen CAID:CA2581998917 MONDO:0021056 PMID: Pathogenic PP1, PVS1, PS4_Supporting, PM2_Supporting The NM_000038.6(APC):c.2546_2552del p.(Asp849Valfs*10) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has been reported in 1 family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting [PMID: 11247896 plus internal information from Institute of Human Genetics, Bonn, Germany]). This variant has been reported to segregate with FAP in at least 3 meioses in the same family (PP1 [internal information from Institute of Human Genetics, Bonn, Germany]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: criteria PVS1, PS4_Supporting, PM2_Supporting and PP1 applied (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2581998917/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28148 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0009450 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0013395 infores:hetionet UMLS:C0120107 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0026826 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0853813 infores:hetionet CAID:CA007311 biolink:causes MONDO:0100316 infores:clingen CAID:CA007311 MONDO:0100316 PMID: Benign BS3_Supporting, BS1, BS4 BP2, BP4, PS4, BP5, PM3, PP3, PP4 NM_000218.3(KCNQ1):c.514G>A is a missense variant that substitutes valine with methionine at codon 172 (p.Val172Met). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001317, with 12 alleles / 91,084 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0001 (BS1). At least two patients affected with long QT syndrome have been identified with the p.Val172Met and p.Arg293Cys variants in cis, in the homozygous state (PMID: 28944242, PMID: 28438721). However, PM3 is not met because the variant is not sufficiently rare. The variant has been observed in a family with long QT syndrome but fails to segregate with the disease phenotype in at least 2 affected members (PMID: 28438721; BS4). This variant has been observed in at least 2 probands with a possible alternate molecular basis for disease, however, the alternative variants are located within KCNQ1 itself and the phenotype does not match another form of LQTS, so this evidence is not considered eligible for the BP5 code (PMID: 28944242, PMID: 28438721). Exogenously expressed KCNQ1 harboring this variant has an IKs of 1.117 (expressed as a fraction of the wild-type), which indicates higher-than-wild-type activity within the near-normal range (PMID: 30571187). The Meiler Lab functional impact predictor gave this variant a classification of normal for IKs, V1/2_classification, Tau of activation, and Tau of deactviation, consistent with benign impact on the protein product (PMID: 29021305, BS3_Moderate). In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BS1, BS4, and BS3_Moderate. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007311/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:51733 biolink:causes MONDO:0013164 infores:monarchinitiative not_provided not_provided HGNC:16297 MONDO:0013164 uuid:9c76c1d4-c634-42b9-89e5-c9ea73cc29cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes UMLS:C0263978 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0263978 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0847033 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0025289 infores:hetionet CHEBI:9352 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0003862 infores:hetionet CHEBI:85083 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0151908 infores:hetionet CAID:CA229357 biolink:causes MONDO:0009861 infores:clingen CAID:CA229357 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PM3, PM5, PP3 The NM_000277.2(PAH):c.1130A>G (p.Tyr377Cys) variant is a missense variant in exon 11/13 of PAH. The variant has been previously reported in trans with p.R243* (Pathogenic in ClinVar and per ClinGen PAH VCEP) in a PKU patient (plasma Phe 765 umol/L); BH4 deficiency was excluded by analysis of urinary pterins and dihydropterine reductase assays (PMID: 22526846) (PM3; PP4_Moderate). One heterozygote and zero homozygotes are present for the variant in gnomAD, corresponding to a global frequency of 0.00000398 and a maximum population frequency (non-Finnish European) of 0.00000879, under the frequency cutoff of 0.0002 for use of PM2 (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.849), so PP3 is met. PM5 also applies because a different missense variant at the same amino acid residue, p.Y377D, qualifies as Likely Pathogenic: the p.Y377D variant has been previously reported in trans with the known pathogenic c.1066-11G>A splicing mutation in a proband with PKU (plasma Phe 20-30mg/dL; BH4 formally excluded by urinary pterin and DHPR analysis) (PMID: 21890392) (PM3; PP4_Moderate), is absent in ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2), and is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.874) (PP3).Classification: Likely Pathogenic Supporting Criteria: PM2; PM3; PP4_Moderate; PM5, PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229357/MONDO:0009861/006 2022-03-11 2022-03-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3127 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C1368065 infores:hetionet CHEBI:17474 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0149741 infores:hetionet CHEBI:3013 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0037763 infores:hetionet CHEBI:28915 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0043352 infores:hetionet NCBIGene:201163 biolink:causes MONDO:0008259 infores:monarchinitiative not_provided not_provided HGNC:27310 MONDO:0008259 uuid:14a92bfc-e7f8-46ef-8a97-5f57a32a6390 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:125354 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0518015 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0852913 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0009938 infores:hetionet CHEBI:36791 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011168 infores:hetionet CHEBI:48273 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0233565 infores:hetionet CHEBI:7514 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0858635 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0002871 infores:hetionet CHEBI:17347 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0151662 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0205707 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0205707 infores:hetionet CHEBI:9586 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0026826 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0235032 infores:hetionet CHEBI:41774 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0002962 infores:hetionet CHEBI:32588 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0017181 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0022104 infores:hetionet CHEBI:17630 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0015967 infores:hetionet CHEBI:8888 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011253 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0233973 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233973 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0040479 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0020517 infores:hetionet CHEBI:72564 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0026858 infores:hetionet CHEBI:6950 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0030193 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0029134 infores:hetionet CHEBI:84883 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0151744 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0009806 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0017160 infores:hetionet CHEBI:6888 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0003467 infores:hetionet CHEBI:4887 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0019521 infores:hetionet CHEBI:231594 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0030252 infores:hetionet CHEBI:8888 biolink:causes MONDO:0100431 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0338480 infores:hetionet CHEBI:8874 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019557 infores:hetionet CHEBI:50648 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0852911 infores:hetionet CHEBI:135193 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0020649 infores:hetionet CHEBI:31932 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0023380 infores:hetionet CHEBI:44032 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0016382 infores:hetionet CHEBI:2549 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0002994 infores:hetionet CHEBI:36704 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0404521 infores:hetionet CHEBI:16899 biolink:causes UMLS:C1167761 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1167761 infores:hetionet CHEBI:28748 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2939419 infores:hetionet CHEBI:63623 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0035455 infores:hetionet GO:0110107 biolink:causes GO:0048707 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0048707 CAID:CA412370595 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370595 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3_Strong PM5 NM_000330.4(RS1):c.532G>A (p.Gly178Ser) is a missense variant encoding the substitution of glycine with serine at amino acid 178. Another missense variant in the same codon, NM_000330.4(RS1):c.533G>A (p.Gly178Asp), (PMID: 31087526, 12928282, 31149861, 11738458, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. However, the present variant has a lower Grantham’s distance (56) than the comparison variant (94), so PM5 cannot be met. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.981, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.02 for Acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting and PP3_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370595/MONDO:0010725/126 2025-09-18 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:68478 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019158 infores:hetionet CAID:CA377484223 biolink:causes MONDO:0017623 infores:clingen CAID:CA377484223 MONDO:0017623 PMID:23335809PMID:29706350 Pathogenic PM2, PP2, PS4_Supporting, PS2, PS3 PM6, PVS1, BP5, BP7, BS4, BS3, BS1, BS2, PP1, PP3, PM5, PM1, PM4, BP2, BP4, BA1, PS1 PTEN c.493G>A (p.Gly165Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor SCV000617324.2)PS3: Phosphatase activity <50% of wild type (PMID 29706350, 9256433, 10866302)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809, internal laboratory contributor SCV000617324.2) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377484223/MONDO:0017623/003 2019-11-22 2020-01-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3228 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0233494 infores:hetionet CHEBI:4888 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0020580 infores:hetionet CHEBI:2618 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0030554 infores:hetionet CHEBI:9150 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0042384 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0003123 infores:hetionet CHEBI:71255 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C2242588 infores:hetionet CHEBI:51164 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0232487 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0032285 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0031350 infores:hetionet CHEBI:3696 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0392525 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0948594 infores:hetionet CAID:CA7511313 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511313 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP3, PM3_Very Strong PM2, PS1 The NM_000070.3: c.1303G>A variant in CAPN3 is a missense variant expected to result in the substitution of glutamine for lysine at amino acid 435, p.(Glu435Lys). This variant has been detected in at least 8 individuals with features of LGMD (PMID: 20635405, 35157181, 18854869, 38812636, 33931068, 30564623; LOVD CAPN3_000134), including in a homozygous state in two unrelated patients without reported familial consanguinity (0.5 pts x2 = 1.0 pt, PMID: 35157181, 30564623, LOVD Individual #00222544). In addition, the variant was confirmed in trans with a likely pathogenic or pathogenic variant in at least three individuals (c.598_612del (p.Phe200_Leu204del), 1.0 pt, PMID: 33931068; c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 38812636; c.967G>T p.(Glu323Ter), 1.0 pt, PMID: 18854869) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18854869) (PP4_Strong). The highest population minor allele frequency of this variant is 0.0003357 (15/44684 exome chromosomes) for the Admixed American population in gnomAD v4.1.0), which is higher than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.815, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511313/MONDO:0015152/187 2025-05-14 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:167638 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0041657 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151479 infores:hetionet CHEBI:47780 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009676 infores:hetionet CHEBI:30830 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042963 infores:hetionet CHEBI:9943 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0699828 infores:hetionet CHEBI:9622 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0497327 infores:hetionet CAID:CA426699920 biolink:causes MONDO:0015152 infores:clingen CAID:CA426699920 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1_Strong, PM2_Supporting The NM_003494.4: c.907-3C>A variant in DYSF, which is also known as NM_001130987.2: c.1003-3C>A, occurs within the splice acceptor region of intron 9. SpliceAI gives a score of 0.46 for acceptor loss. RNAseq analysis has demonstrated abnormal splicing due to this variant, including skipping of exon 10 and skipping of both exons 9 and 10. Both events led to a frameshift and premature truncation with nonsense mediated decay expected: p.Cys1685SerfsTer36 and p.Ser1687TyrfsTer20; however, the possibility for retention of some degree of constitutive splicing was not ruled out (PVS1_Strong_RNA; PMID: 36983702). This variant has been reported in at least two individuals with features consistent with LGMD (PMID: 24488599, 36983702), including in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.3805dup p.(Glu1269GlyfsTer7), 0.5 pts, PMID: 36983702) (PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant had both a clinical suspicion of LGMD and severely reduced or absent dysferlin protein expression on blood monocyte assay, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702, 24488599). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/26/2025): PVS1_Strong_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA426699920/MONDO:0015152/180 2025-08-26 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6375 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0036974 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0004691 infores:hetionet CHEBI:68554 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0003862 infores:hetionet CHEBI:63611 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017181 infores:hetionet CHEBI:75984 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0023530 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0854466 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0854466 infores:hetionet CHEBI:72297 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0750426 infores:hetionet CHEBI:251408 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0152198 infores:hetionet CHEBI:94686 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0015732 infores:hetionet CHEBI:17549 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0018681 infores:hetionet CHEBI:8890 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042510 infores:hetionet CHEBI:50275 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0149745 infores:hetionet CHEBI:7798 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0234238 infores:hetionet CHEBI:63791 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0034642 infores:hetionet CHEBI:2618 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0162830 infores:hetionet CHEBI:63925 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0012833 infores:hetionet NCBIGene:79577 biolink:causes MONDO:0007767 infores:monarchinitiative not_provided not_provided HGNC:16783 MONDO:0007767 uuid:c2e533b0-5ed0-4a16-a4e2-7b191122edfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0235146 infores:hetionet CHEBI:27446 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0020517 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0259768 infores:hetionet CHEBI:7025 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0242301 infores:hetionet CHEBI:50841 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0751494 infores:hetionet CHEBI:28593 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0023530 infores:hetionet CHEBI:6129 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014518 infores:hetionet CHEBI:5103 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0043352 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0027339 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0013922 infores:hetionet NCBIGene:26121 biolink:causes MONDO:0010828 infores:monarchinitiative not_provided not_provided HGNC:15446 MONDO:0010828 uuid:6ba84c23-f0df-4418-b0b3-ff11bd17db95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8776 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0221512 infores:hetionet CHEBI:135935 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0699828 infores:hetionet CHEBI:39112 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0009782 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0021053 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0019158 infores:hetionet CHEBI:8356 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0237849 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006611 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0036203 infores:hetionet CHEBI:10023 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0476273 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0344320 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0518015 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0040034 infores:hetionet CHEBI:36795 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0030196 infores:hetionet CL:0000313 biolink:causes MONDO:0002362 infores:ubergraph knowledge_assertion manual_agent CL:0000313 MONDO:0002362 CHEBI:7959 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0232492 infores:hetionet CHEBI:31859 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0518988 infores:hetionet CHEBI:27436 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0011124 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0344320 infores:hetionet NCBIGene:6010 biolink:causes MONDO:0013395 infores:monarchinitiative not_provided not_provided HGNC:10012 MONDO:0013395 uuid:71c85dd2-e289-4856-b8ca-9f9bc7bfcff6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0022107 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0314719 infores:hetionet CHEBI:5893 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0740394 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0341751 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0341751 infores:hetionet CHEBI:31236 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038999 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0017178 infores:hetionet CHEBI:35854 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0040822 infores:hetionet NCBIGene:2812 biolink:causes MONDO:0009276 infores:monarchinitiative not_provided not_provided HGNC:4440 MONDO:0009276 uuid:7bee8c19-7e80-4ad6-9a57-e632cca69040 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0007097 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0020615 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020649 infores:hetionet CHEBI:63630 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0016658 infores:hetionet CHEBI:71272 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0000737 infores:hetionet CHEBI:421707 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0023787 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0009806 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0948594 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0853013 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0853013 infores:hetionet CHEBI:2659 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0004238 infores:hetionet CHEBI:31236 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042024 infores:hetionet CHEBI:3223 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C2363731 infores:hetionet CHEBI:231594 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042998 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0019054 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0022658 infores:hetionet HGNC:5541 biolink:causes MONDO:0020729 infores:monarchinitiative not_provided not_provided HGNC:5541 MONDO:0020729 uuid:ffdd2e0b-bf34-4f27-ba29-ccf7f7995433 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6801 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0000731 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0161679 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0392620 infores:hetionet CHEBI:47780 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0015672 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0497365 infores:hetionet CHEBI:51041 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002622 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019340 infores:hetionet CAID:CA063661 biolink:causes MONDO:0007783 infores:clingen CAID:CA063661 MONDO:0007783 PMID: Uncertain Significance PP3, PS4_Supporting, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 885 of the RYR1 protein (p.Arg885His). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00042, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, the MAF in the SAS population in gnomAD does not allow PS4 to be utilized (PMID:30236257). No functional studies were identified for this variant.This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.609 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA063661/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:17474 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0019572 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020676 infores:hetionet NCBIGene:221322 biolink:causes MONDO:0009795 infores:monarchinitiative not_provided not_provided HGNC:21485 MONDO:0009795 uuid:16e0f758-63fa-4ca9-9d83-ee54b7254f27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0010692 infores:hetionet CHEBI:17549 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0234233 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0162830 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0020517 infores:hetionet CHEBI:119486 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151836 infores:hetionet CHEBI:9943 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004134 infores:hetionet CHEBI:6912 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0037822 infores:hetionet CHEBI:5123 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0027424 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0038587 infores:hetionet CAID:CA382548273 biolink:causes MONDO:0700270 infores:clingen CAID:CA382548273 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PVS1 The c.5763-1G>C variant in ATM occurs within the canonical splice acceptor site (-1,2) of intron 38. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382548273/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0242422 infores:hetionet CAID:CA120540 biolink:causes MONDO:0044970 infores:clingen CAID:CA120540 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS3 The m.5549G>A variant in MT-TW has been reported in two individuals with primary mitochondrial disease to date (PMIDs: 7695240, 34276539; PS4_supporting). The first reported case was a man with onset at age 40 years of personality and behavioral changes followed by progressive cognitive decline, hearing loss, ataxia, chorea, dysarthria, and axonal neuropathy, and he died at age 53 years (PMID: 7695240). Brain imaging showed atrophy of the cerebrum, cerebellum, and brainstem. Muscle biopsy showed COX-negative and ragged red fibers. The variant was present at 40% heteroplasmy in blood, 83-86% in skeletal muscle, and 51-93% in organs on autopsy (liver, optic nerve, lung, heart, kidney, cerebral cortex, cerebellum). There was no mention of testing in family members. The second reported case was a 26-year-old man with onset in adolescence of epilepsy, ataxia, dystonia, impaired cognition, and hearing loss (PMID: 34276539). Brain imaging showed leukoencephalopathy and cerebral atrophy in addition to calcifications of the bilateral basal ganglia, thalamus, and cerebellar dentate nuclei. Muscle biopsy showed ragged blue and COX-deficient fibers. The variant was present at 5.4% heteroplasmy in blood and 61.5% in muscle. The variant was absent in his mother’s blood (PMID: 34276539; PM6_supporting). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (88.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.35 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120540/MONDO:0044970/015 2024-04-23 2025-07-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9168 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019360 infores:hetionet CAID:CA214937 biolink:causes MONDO:0044970 infores:clingen CAID:CA214937 MONDO:0044970 PMID: Pathogenic PS3_Supporting, PP1_Moderate, PS4 PP3, PS2, PM2, PM6 The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID: 32906214): PS4, PP1_moderate, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA214937/MONDO:0044970/014 2022-11-14 2023-01-05 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:5558 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0011606 infores:hetionet CAID:CA377484387 biolink:causes MONDO:0017623 infores:clingen CAID:CA377484387 MONDO:0017623 PMID: Pathogenic PM2, PP2, PS4_Supporting, PS3, PS2 PTEN c.542T>C (p.Leu181Pro) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) SCV001524663.1)PS3: Phosphatase activity <50% (PMID 29706350, PMID 21828076)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 17526801, internal laboratory contributor(s) SCV000579246.1) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377484387/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:55367 biolink:causes MONDO:0030785 infores:monarchinitiative not_provided not_provided HGNC:16491 MONDO:0030785 uuid:3def87af-c6a1-426b-9f58-13e7ffcfbf38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes HP:0001319 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0270971 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0037195 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0878544 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0026946 infores:hetionet CHEBI:63617 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0451641 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0549373 infores:hetionet CHEBI:8768 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151878 infores:hetionet CAID:CA157165 biolink:causes MONDO:0700270 infores:clingen CAID:CA157165 MONDO:0700270 PMID: Benign BA1, BP4, BP2_Strong PS1, BS1, PM2, PP3 The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA157165/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9123 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0024894 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0025061 infores:hetionet CHEBI:3176 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0002170 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234894 infores:hetionet CHEBI:9137 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011168 infores:hetionet CHEBI:16914 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0013144 infores:hetionet CHEBI:63621 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023467 infores:hetionet CHEBI:85161 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0033774 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0011570 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1609512 infores:hetionet CHEBI:3723 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232943 infores:hetionet CHEBI:9622 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0003467 infores:hetionet CHEBI:50924 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020625 infores:hetionet CHEBI:9763 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0010200 infores:hetionet CHEBI:6444 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0010520 infores:hetionet CHEBI:39112 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0003862 infores:hetionet CHEBI:2659 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0000729 infores:hetionet CAID:CA410146870 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146870 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS3, BS1, BS4, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1395C>A (p.Asn465Lys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score of 0.108 (< 0.15), and SSF and MES predict no change in the canonical splice site score, with no creation of putative cryptic splice sites, supporting BP4. The variant is reported in an individual with MDS in PMID: 26884589; however, a germline sample was not used for genetic testing, so the evidence does not meet the criteria for PS4_supporting. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146870/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5106 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0013390 infores:hetionet CHEBI:17474 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0011603 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0151436 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0240557 infores:hetionet CHEBI:83804 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013404 infores:hetionet CHEBI:74947 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0424295 infores:hetionet NCBIGene:5176 biolink:causes MONDO:0013515 infores:monarchinitiative not_provided not_provided HGNC:8824 MONDO:0013515 uuid:4fb1de1d-4cac-494f-b707-2e2a30e4bd74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042420 infores:hetionet NCBIGene:4254 biolink:causes MONDO:0007771 infores:monarchinitiative not_provided not_provided HGNC:6343 MONDO:0007771 uuid:8dcc20f0-095c-4f2d-bbeb-0191a2bd1b08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2687 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0039239 infores:hetionet CHEBI:4798 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151603 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0584995 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0584995 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0855242 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235431 infores:hetionet CHEBI:135929 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C1368065 infores:hetionet CHEBI:32139 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0022107 infores:hetionet CAID:CA024297 biolink:causes MONDO:0007783 infores:clingen CAID:CA024297 MONDO:0007783 PMID: Likely Pathogenic PP1, PM1, PS4_Moderate, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with leucine at codon 539 of the RYR1 protein, p.Phe539Leu. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three individuals with a personal or family history of an MH episode, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, PMID:18564801 (reported two individuals, may be related with shared haplotype)). This variant segregates with MHS with three informative meiosis, PP1_Supporting (PMID:18564801). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.934) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1, PP1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024297/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CAID:CA234191 biolink:causes MONDO:0021060 infores:clingen CAID:CA234191 MONDO:0021060 PMID:20949621 Pathogenic PP3, PP2, PM2_Supporting, PS4, PS3_Supporting, PS2_Very Strong BP4, BA1, BS1 The c.15A>T variant in the KRAS gene is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 5 (p.Lys5Asn). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.764 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in at least 5 individuals with clinical features of a RASopathy, in 2 confirmed de novo occurrences (PS4, PS2_VeryStrong; PMID: 17056636; Ambry, EGL Genetics, Invitae internal data, ClinVar SCV000742406.3, SCV000202928.7). In vitro functional studies showed that the p.Val14Ile variant enhanced MEK activation (PS3_Supporting; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA234191/MONDO:0021060/044 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47426 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0038325 infores:hetionet CHEBI:2666 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0042023 infores:hetionet NCBIGene:10082 biolink:causes MONDO:0009779 infores:monarchinitiative not_provided not_provided HGNC:4454 MONDO:0009779 uuid:ccb62a33-9265-47aa-9894-731c185bcc40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0221201 infores:hetionet CHEBI:63621 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013378 infores:hetionet CHEBI:52010 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0012833 infores:hetionet CHEBI:8707 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0520888 infores:hetionet CHEBI:4798 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0043094 infores:hetionet CAID:CA007191 biolink:causes MONDO:0100316 infores:clingen CAID:CA007191 MONDO:0100316 PMID: Benign BA1, BP4, BP7 NM_000218.3(KCNQ1):c.477+9C>T is a variant in intron 2. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03492 (2612 / 74792 alleles, with 48 homozygotes) in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.001 (BA1). The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.1 for donor loss which is below the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and does not strongly predict a splicing defect (BP4). This intronic variant is not located within either of the regions immediately flanking the exon (between +1 and +7 or between -1 and -21), and the conservation tool PhyloP gives this variant a score of -2.693, which is below the Potassium Channel Arrhythmia VCEP BP7 threshold of <2.0 and indicates a low level of evolutionary conservation at this site (BP7). In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007191/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0041969 infores:hetionet CHEBI:46195 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0013384 infores:hetionet CAID:CA377482840 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482840 MONDO:0017623 PMID: Pathogenic PM6, PVS1, PM2_Supporting, PS4_Supporting BS1, BS3, BS4, BP7, BP5, BS2, PP2, PP3, PP1, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 NM_000314.8(PTEN):c.492+1G>T (IVS5+1G>T) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 28677221).PM2_P: Absent in large sequenced populations.PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482840/MONDO:0017623/003 2024-04-10 2024-04-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6437 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0033975 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002965 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0853619 infores:hetionet CHEBI:9139 biolink:causes MONDO:0024291 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0158570 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034882 infores:hetionet CHEBI:478164 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0018524 infores:hetionet GO:0039653 biolink:causes GO:0006351 infores:ubergraph knowledge_assertion manual_agent GO:0039653 GO:0006351 CHEBI:8874 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C2830004 infores:hetionet CHEBI:36795 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0750426 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0234215 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022660 infores:hetionet CHEBI:61049 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040822 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0031350 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0162830 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0392197 infores:hetionet CHEBI:10110 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0231218 infores:hetionet CAID:CA135128 biolink:causes MONDO:0021060 infores:clingen CAID:CA135128 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.483G>C (p.Leu161=) variant in the BRAF gene is 0.0315% (7/10404) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135128/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63610 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0948089 infores:hetionet CHEBI:38940 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C3665346 infores:hetionet CHEBI:10650 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013144 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0521170 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0521170 infores:hetionet NCBITaxon:157 biolink:causes MONDO:0006865 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:157 MESH:D005892 DB00257_MESH_D005892_1 CHEBI:33325 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0020461 infores:hetionet CHEBI:9943 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0012569 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0021053 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151585 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151585 infores:hetionet NCBITaxon:10566 biolink:causes MONDO:0005647 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10566 MESH:D003218 DB01266_MESH_D003218_1DB01179_MESH_D003218_1DB11152_MESH_D003218_1DB00724_MESH_D003218_1DB00105_MESH_D003218_1 CHEBI:63598 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0031350 infores:hetionet CHEBI:135930 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0700590 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235818 infores:hetionet CHEBI:135613 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C1698480 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0973461 infores:hetionet CAID:CA229822 biolink:causes MONDO:0009861 infores:clingen CAID:CA229822 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 The c.850T>C (p.Cys284Arg) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 30050108). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variant p.EX6-96A>G (VarID590; PM3). Computational evidence predicts a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229822/MONDO:0009861/006 2019-12-08 2021-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0024437 infores:hetionet CHEBI:119915 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0086439 infores:hetionet CHEBI:39867 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013447 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0001339 infores:hetionet CHEBI:4495 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0152227 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0036572 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0857353 infores:hetionet CHEBI:36795 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0037763 infores:hetionet CHEBI:2659 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0162297 infores:hetionet CHEBI:76010 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0027765 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0948594 infores:hetionet CHEBI:7986 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0036974 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0426576 infores:hetionet CHEBI:6715 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0008350 infores:hetionet GO:1905600 biolink:causes GO:0032367 infores:ubergraph knowledge_assertion manual_agent GO:1905600 GO:0032367 CHEBI:75722 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004093 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0474378 infores:hetionet NCBIGene:998 biolink:causes MONDO:0014757 infores:monarchinitiative not_provided not_provided HGNC:1736 MONDO:0014757 uuid:66c3cf6e-9518-4108-aede-ba830cdc0810 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0520966 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0033975 infores:hetionet CHEBI:3286 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0542571 infores:hetionet CHEBI:36791 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039231 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0038362 infores:hetionet CHEBI:8863 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0041582 infores:hetionet CHEBI:50859 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0037299 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0235431 infores:hetionet CHEBI:28901 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0019209 infores:hetionet CHEBI:2636 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0231218 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0001824 infores:hetionet CAID:CA410208053 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208053 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM5, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.557T>G (p.Val186Gly)is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant has a REVEL score ≥ 0.88 (0.957) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208053/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA312251 biolink:causes MONDO:0008723 infores:clingen CAID:CA312251 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PM5_Supporting PM1 The c.482C>T (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by valine at amino acid 161 (p.Ala161Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000001313 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Another missense variant, c.481G>A (p.Ala161Thr), in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM5_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312251/MONDO:0008723/021 2024-08-13 2024-08-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7822 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0017675 infores:hetionet CAID:CA401364879 biolink:causes MONDO:0009290 infores:clingen CAID:CA401364879 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting The NM_000152.5:c.1076-1G>C variant in GAA occurs within the canonical splice acceptor site of intron 6. RT-PCR of fibroblast RNA from a patient who is heterozygous for the variant revealed the inclusion of 79 bp of intron 6 and and 89 bp of intron 7 into the transcript, which is predicted to lead to a frameshift and nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 16917947) (PVS1). Six patients have been reported including one who is homozygous for the variant with symptoms consistent with infantile onset Pompe disease and documentation of deficient GAA activity meeting the specifications of the ClinGen LD VCEP, two compound heterozygous patients with later onset symptoms and documentation of deficient GAA activity, and three patients with symptoms of Pompe disease and re[ported to have reduced GAA activity but for whom individual residual GAA activity was not provided or did not meet criteria (PMID: 16917947, 17616415) (PP4_Moderate). This variant was the second most common variant in a Spanish cohort with Pompe disease, accounting for 6/44 alleles (14%) (PMID: 17616415). One patient is compound heterozygous for the variant and another pathogenic variant in GAA, c.-32-13T>G, phase unknown, 0.5 points (PMID: 16917947), and one patient is homozygous for the variant, 0.5 points (PMID: 17616415). Another four patients are compound heterozygous for the variant and another GAA variant. The allelic data from these patients will be used in the assessment of the second variant and it not included here to avoid circular logic (PMID: 17616415). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1353052). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (specifications version 2.0): PVS1, PP4_Moderate, PM3, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401364879/MONDO:0009290/010 2023-03-07 2023-03-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5280 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0007859 infores:hetionet CHEBI:32221 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C2979982 infores:hetionet CHEBI:3423 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0009782 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0014130 infores:hetionet CHEBI:94501 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0004093 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0349506 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027947 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0877606 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0877606 infores:hetionet CHEBI:9352 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0002878 infores:hetionet CHEBI:2950 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0040460 infores:hetionet CHEBI:367163 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020473 infores:hetionet CHEBI:7494 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0024902 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151586 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151586 infores:hetionet CHEBI:3479 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151872 infores:hetionet CHEBI:31000 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0042963 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0030312 infores:hetionet CHEBI:9939 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0036974 infores:hetionet CHEBI:44185 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004509 infores:hetionet CHEBI:31643 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0041834 infores:hetionet CHEBI:32139 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0025637 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0162429 infores:hetionet GO:0002329 biolink:causes CL:0000817 infores:ubergraph knowledge_assertion manual_agent GO:0002329 CL:0000817 CHEBI:100241 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0012833 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005684 infores:hetionet CHEBI:53691 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0033774 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948586 infores:hetionet CHEBI:64355 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151904 infores:hetionet CHEBI:6931 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0015230 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1368065 infores:hetionet CAID:CA024084 biolink:causes MONDO:0018493 infores:clingen CAID:CA024084 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with aspartic acid at codon 4638 of the RYR1 protein, p.(Gly4638Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted.This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 not implemented (PMID: 16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.917) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024084/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA232823 biolink:causes MONDO:0100437 infores:clingen CAID:CA232823 MONDO:0100437 PMID: Benign PP4, BP4, BA1 NM_001034853.2(RPGR):c.785C>G (p.Ala262Gly) is a missense variant predicted to cause substitution of alanine by glycine at amino acid 262. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01285 among hemizygous individuals, with 240 variant alleles / 395,133 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.179, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function (BP4_moderate). Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.08, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing. At least one proband harboring this variant has been genotyped by whole exome sequencing without the identification of an alternative explanation for disease (2 pts), and exhibits a phenotype including onset before age 30 years (required), reduced rod and extinguished cone ERG responses, poor central vision (0.5 pts), photophobia (0.5 pts), macular atrophy (0.5 pts), optic disc pallor (0.5 pts), and attenuated retinal arteries (0.5 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 23776498, PP4). While the authors of the study did not identify the variant as the cause of the patient's disease, the PP4 code is met. In summary, this variant meets the criteria to be classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA232823/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:31236 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016655 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042075 infores:hetionet CHEBI:10650 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0002994 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151838 infores:hetionet CAID:CA333154 biolink:causes MONDO:0021060 infores:clingen CAID:CA333154 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.457C>T (p.Leu153=) variant in the SHOC2 gene is 1.574% (1104/66696) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA333154/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:10262 biolink:causes MONDO:0007943 infores:monarchinitiative not_provided not_provided HGNC:10771 MONDO:0007943 uuid:5972681e-0e0c-4a58-979c-468bd4653b45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0023533 infores:hetionet CHEBI:51364 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0004134 infores:hetionet CHEBI:6846 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0011991 infores:hetionet CHEBI:52172 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018808 infores:hetionet CHEBI:6456 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C1761613 infores:hetionet CAID:CA8602976 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602976 MONDO:0100326 PMID: Uncertain Significance BP4 BS1, PM2, PP4, BA1 The NM_000419.5:c.1708G>A variant in ITGA2B/ is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 570 (p.Gly570Arg). The computational predictor REVEL gives a score of 0.025, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602976/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5296 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0042109 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0013395 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0342579 infores:hetionet CHEBI:6965 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0027497 infores:hetionet CAID:CA2588340082 biolink:causes MONDO:0100437 infores:clingen CAID:CA2588340082 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2933_2937del (p.Glu978GlyfsTer?) is a frameshift variant due to a five-nucleotide deletion introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 3 years (1 pt), family history consistent with X-linked inheritance, reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with peripheral pigment deposits (0.5 pts), mild macular degeneration, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2588340082/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:36791 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043352 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0042401 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0024115 infores:hetionet CHEBI:77733 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0235660 infores:hetionet CHEBI:31348 biolink:causes MONDO:0006687 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006430 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018801 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0269993 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0269993 infores:hetionet CAID:CA10581303 biolink:causes MONDO:0000572 infores:clingen CAID:CA10581303 MONDO:0000572 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 PP4 The nonsense variant NM_000448.3(RAG1):c.775del (p.Ser259AlafsTer5) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense mediated decay but does truncate 75% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). This variant is absent from gnomADv2.1.1 (PM2_Supporting). It has been reported homozygous in one patient with Omenn syndrome (PM3_supporting) with insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581303/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49375 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027059 infores:hetionet CHEBI:17141 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0030353 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0948594 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0178298 infores:hetionet CHEBI:3242 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013604 infores:hetionet CHEBI:94385 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0008031 infores:hetionet CHEBI:391960 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0017178 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0042233 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:C536777 DB00681_MESH_C536777_1 CHEBI:6640 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0041834 infores:hetionet CHEBI:134990 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0030554 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0233414 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0042373 infores:hetionet CHEBI:94392 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0010200 infores:hetionet CAID:CA367400665 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400665 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP2, PP3, PP4, PM2_Supporting The c.736G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 246 (p.(Gly246Arg)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in 3 families (PP1_Strong; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.905, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 33852230, 34469064, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in 3 families (PP1_Strong; internal lab contributors). In summary, c.736G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP2, PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400665/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:18358 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027424 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0574067 infores:hetionet CHEBI:4511 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0002871 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011570 infores:hetionet CAID:CA412370385 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370385 MONDO:0010725 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PP1_Strong, PP4_Moderate, PP3_Strong NM_000330.4(RS1):c.581T>A (p.Ile194Asn) is a missense variant encoding the substitution of isoleucine with asparagine at position 194. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 29739629, PMID: 19324861, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, and showing retinal detachment, which together are highly specific for X-linked retinoschisis (PMID: 32300273, PP4_Moderate). The variant has been reported to segregate with affected status through 3 meioses within 1 family (PP1_Strong; PMID: 24505212). The computational predictor REVEL gives a score of 0.956, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PP1_Strong, PP4_Moderate, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370385/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports UNII:3QJA87N40S biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1291077 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0009806 infores:hetionet CHEBI:134745 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0232487 infores:hetionet CHEBI:38545 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0016204 infores:hetionet NCBITaxon:2104 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2104 MESH:D001991 DB00759_MESH_D001991_1DB01059_MESH_D001991_1DB01017_MESH_D001991_1DB02703_MESH_D001991_1 CHEBI:41774 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C2939419 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013595 infores:hetionet CHEBI:17549 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0040038 infores:hetionet CHEBI:31348 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0007859 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011570 infores:hetionet CAID:CA2580098645 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098645 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS2, PS3, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS4, BS3, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG (p.Ala142TyrfsTer14) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 31709191). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098645/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28925 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0011603 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0178298 infores:hetionet CAID:CA123173 biolink:causes MONDO:0009276 infores:clingen CAID:CA123173 MONDO:0009276 PMID: Pathogenic PP1_Strong, PS3_Supporting, PP4_Moderate, PP3, PM3 The c.182A>G (p.Asn61Ser) variant in GP9 is known for being frequently reported in BSS patients of European ancestry. It has been detected in at least 30 probands with Bernard-Soulier syndrome. At least 16 probands included in this curation have origin in Central or Northern Europe (France, Finland, Sweden, Germany, Belgium, Austria, and England). The literature supports the hypothesis of Koskela et al., which suggests that the c.182A>G (p.Asn61Ser) variant is an ancient founder mutation in this region (PMID:10227459). At least one patient with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes (PP4_moderate, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. At least 2 of the probands included in this curation were homozygous for the variant and were confirmed to have the variants in trans (PM3; PMIDs: 8049428, 14510954, 8856096, 10227459, 11297032). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus 3 (>2) affected family members, all with the homozygous genotype. (PP1_strong; PMID:19404517). The Grp max filtering allele frequency in gnomAD v4.1 is 0.0008047 (1001/1179870 alleles) in the European (Non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0007 for GP9), and therefore meets this criterion (BS1), however since this is a known founder variant BS1 will not be applied. The computational predictor REVEL gives a score of 0.721, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). A zebrafish model made by deleting 17bps in exon 2 of gp9 using CRISPR-Cas9 demonstrated thrombocytopenia and abnormal bleeding. The thrombocytopenia phenotype in the zebrafish was rescued using a wild-type copy of human GP9. The human copy of GP9 containing the c.182A>G variant failed to rescue the same phenotype, indicating that this variant impacts protein function (PMID:34407604)(PS3_Supporting).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP3, PP4_moderate, PP1_Strong, PS3_Supporting. (VCEP specifications version 1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123173/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10585207 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585207 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 PS3, PM5 The NM_000527.5 (LDLR):c.937T>C (p.Cys313Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM1, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.978.PM1: Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation.PP4: Variant meets PM2 and is identified in ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases reported in PubMed: one case fulfil Simon Broome criteria for definite or possible FH in PMID 22881376, reported by Usifo et al, 2012, from British Heart Foundation Laboratories, University College London, UK; one case fulfil DLCN ≥6 in PMID 19318025 reported by Alonso et al, 2009, from Lipid Clinic, Fundacion Jimenez Diaz, Spain. PS3 not met: Functional data is not available.PM5 not met: Three other missense variants at same codon: NM_000527.5 (LDLR):c.937T>G (p.Cys313Gly), ClinVarID 251538, is classified as Uncertain significance; NM_000527.5 (LDLR):c.939C>G (p.Cys313Trp), ClinVarID 251540, is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.938G>A (p.Cys313Tyr), ClinVarID 226339, is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585207/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:407 biolink:causes MONDO:0049221 infores:monarchinitiative not_provided not_provided HGNC:710 MONDO:0049221 uuid:19774ed8-6aa5-4ee2-bb93-7ac2147f7336 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UBERON:0015777 biolink:causes MONDO:0003790 infores:ubergraph knowledge_assertion manual_agent UBERON:0015777 MONDO:0003790 CHEBI:2666 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0221490 infores:hetionet CHEBI:59560 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0017152 infores:hetionet CHEBI:9332 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0014457 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0009806 infores:hetionet CHEBI:51860 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0008031 infores:hetionet GO:0110082 biolink:causes GO:1903475 infores:ubergraph knowledge_assertion manual_agent GO:0110082 GO:1903475 CAID:CA412489610 biolink:causes MONDO:0100039 infores:clingen CAID:CA412489610 MONDO:0100039 PMID: Pathogenic PM1, PP3, PM5_Strong, PS2, PM2_Supporting The p.Gly20Val variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in this individual (PS2). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23064044, 20397747) (PM5_Strong). The p.Gly20Val variant in CDKL5 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gly20Val variant in CDKL5 is classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PS2, PM5_strong, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412489610/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf NCBIGene:2778 biolink:causes MONDO:0008153 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0008153 uuid:f52b1a2c-8765-4576-88f7-4381cfb598b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31401 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0518988 infores:hetionet CHEBI:9332 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0011606 infores:hetionet NCBIGene:920 biolink:causes MONDO:0013497 infores:monarchinitiative not_provided not_provided HGNC:1678 MONDO:0013497 uuid:f376123b-3d81-4933-b926-0c8fea7a7f45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0699893 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0234215 infores:hetionet CHEBI:5118 biolink:causes EFO:0011046 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0858970 infores:hetionet CHEBI:6067 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011175 infores:hetionet CHEBI:3723 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028961 infores:hetionet CHEBI:4027 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151692 infores:hetionet CHEBI:5123 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0009806 infores:hetionet CHEBI:3749 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0011606 infores:hetionet CHEBI:9943 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020433 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0029408 infores:hetionet CHEBI:63629 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0001925 infores:hetionet CHEBI:94609 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0221423 infores:hetionet CAID:CA367396925 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396925 MONDO:0015967 PMID: Likely Pathogenic PM5, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1345G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 449 (p.(Ala449Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.878, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and 3-generation family history of diabetes) (PP4_Moderate; PMID: 19410318). Another missense variant, c.1345G>A p.Ala449Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala449Ser has a greater Grantham distance (PM5). In summary, c.1345G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM5, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396925/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports PUBCHEM.COMPOUND:45357473 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1291077 infores:hetionet CHEBI:72292 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0042963 infores:hetionet CHEBI:37333 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0004134 infores:hetionet CHEBI:46345 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0041582 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020615 infores:hetionet CHEBI:9555 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0740394 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0521505 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0521505 infores:hetionet CHEBI:6797 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0022107 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0006147 infores:hetionet CAID:CA347214076 biolink:causes MONDO:0015152 infores:clingen CAID:CA347214076 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1_Moderate, PM2, PP1 PS1 The NM_003494.4: c.2643+1G>C variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>C, occurs within the canonical splice donor site of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids (PVS1_Moderate). This variant has been confirmed in trans with a likely pathogenic variant in an individual with a clinical diagnosis of LGMD (c.4194C>A p.(Cys1398Ter), 1.0 pt, PMID: 21522182) (PM3). This patient also showed absent dysferlin expression, which is highly specific for DYSF-related LGMD (PP4_Strong). The variant was reported to co-segregate with the disease in one affected family member (PP1). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate, PM3, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347214076/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CL:0000066 biolink:causes MONDO:0005626 infores:ubergraph knowledge_assertion manual_agent CL:0000066 MONDO:0005626 CHEBI:3994 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0037274 infores:hetionet CHEBI:9943 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0041948 infores:hetionet CHEBI:6950 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020625 infores:hetionet CHEBI:10110 biolink:causes UMLS:C1963822 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1963822 infores:hetionet CHEBI:31705 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0001122 infores:hetionet NCBIGene:1409 biolink:causes MONDO:0011413 infores:monarchinitiative not_provided not_provided HGNC:2388 MONDO:0011413 uuid:a56e19c9-1e2c-433c-94d8-47e0899aab96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0027769 infores:hetionet CHEBI:7476 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0015967 infores:hetionet CHEBI:9599 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0030554 infores:hetionet CHEBI:7494 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013604 infores:hetionet CHEBI:4868 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0948089 infores:hetionet CHEBI:63638 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0022408 infores:hetionet CHEBI:63617 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1306341 infores:hetionet CHEBI:142290 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042024 infores:hetionet CHEBI:5062 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C2937350 infores:hetionet CHEBI:8212 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0235660 infores:hetionet CHEBI:47898 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036690 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0574067 infores:hetionet CHEBI:5855 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0003578 infores:hetionet CHEBI:52172 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0870082 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0009450 infores:hetionet CHEBI:47519 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085612 infores:hetionet GO:1903302 biolink:causes GO:0006096 infores:ubergraph knowledge_assertion manual_agent GO:1903302 GO:0006096 CHEBI:61058 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0239571 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0023533 infores:hetionet CAID:CA10585704 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585704 MONDO:0007750 PMID: Uncertain Significance BS3, PM2 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1976C>A (p.Thr659Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00002413 (0.002413%) in African/African American genomes (gnomAD v3.1.2).BS3 - Level 1 assays: PMID 32015373:Heterologous cells, FACS assays - result - 96% cell surface LDLR, 99% LDL-LDLR binding and 97% uptake.---- functional study is consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585704/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:2243 biolink:causes MONDO:0007099 infores:monarchinitiative not_provided not_provided HGNC:3661 MONDO:0007099 uuid:6ce641f1-1d78-4e45-ba10-2b545829a401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6030 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0234215 infores:hetionet CHEBI:5128 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0085631 infores:hetionet CHEBI:63717 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0016204 infores:hetionet CHEBI:55346 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020615 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0037822 infores:hetionet CHEBI:39585 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0085932 infores:hetionet CHEBI:66964 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0018524 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0574067 infores:hetionet CHEBI:16755 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0030193 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0035078 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011053 infores:hetionet CAID:CA9090685 biolink:causes MONDO:0021060 infores:clingen CAID:CA9090685 MONDO:0021060 PMID: Uncertain Significance BP5 BS1 The c.1187C>T (p.Thr396Met) variant in MAP2K2 is present in 0.017% (11/61632) non-Finnish European alleles in gnomAD. This variant has been identified in a patient with an alternate molecular basis for disease (BP5; SCV000699629.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr396Met variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9090685/MONDO:0021060/004 2019-12-05 2019-12-05 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:29007 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0030305 infores:hetionet NCBIGene:23729 biolink:causes MONDO:0014969 infores:monarchinitiative not_provided not_provided HGNC:1492 MONDO:0014969 uuid:badcfcfc-3c51-41cd-9ae2-f03caf47584e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:9179 biolink:causes MONDO:0013048 infores:monarchinitiative not_provided not_provided HGNC:574 MONDO:0013048 uuid:45001980-c888-4704-89c9-0bcf34d9a6d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31547 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0002962 infores:hetionet CHEBI:3479 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0013395 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0278079 infores:hetionet CHEBI:50173 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020473 infores:hetionet NCBIGene:5972 biolink:causes MONDO:0009970 infores:monarchinitiative not_provided not_provided HGNC:9958 MONDO:0009970 uuid:0012a906-852e-438d-bffb-68f8f0f2aee4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018794 infores:hetionet CHEBI:75998 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0149745 infores:hetionet UMLS:C1709429 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0003862 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0542052 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0542052 infores:hetionet CHEBI:8502 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C1320835 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0037199 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0853777 infores:hetionet CHEBI:2682 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0340865 infores:hetionet CHEBI:3650 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0151474 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0031117 infores:hetionet CHEBI:2666 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0039231 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014742 infores:hetionet CHEBI:3568 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0025222 infores:hetionet NCBIGene:5728 biolink:causes MONDO:0700275 infores:monarchinitiative not_provided not_provided HGNC:9588 MONDO:0700275 uuid:de674d86-7057-4c2f-ade4-1ba3e2f7968e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002878 infores:hetionet NCBIGene:3897 biolink:causes MONDO:0010559 infores:monarchinitiative not_provided not_provided HGNC:6470 MONDO:0010559 uuid:7b7c6f4a-889f-4c24-8d13-ecee439b6faf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6123 biolink:causes MONDO:0030300 infores:monarchinitiative not_provided not_provided HGNC:10351 MONDO:0030300 uuid:435120a7-ddb3-476f-8247-8cd82ebea12a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4976 biolink:causes MONDO:0008858 infores:monarchinitiative not_provided not_provided HGNC:8140 MONDO:0008858 uuid:21632682-7938-4847-9dba-3acea630d74b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019158 infores:hetionet CHEBI:17823 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0032343 infores:hetionet CHEBI:71940 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0476281 infores:hetionet CHEBI:5138 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085632 infores:hetionet CHEBI:9168 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151766 infores:hetionet CHEBI:9588 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0085605 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0031117 infores:hetionet CHEBI:175901 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0041834 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0521839 infores:hetionet CHEBI:45783 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0311468 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0009806 infores:hetionet CHEBI:17650 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0013595 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0521839 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042035 infores:hetionet CHEBI:2549 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0009763 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0234987 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0037278 infores:hetionet CHEBI:4792 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0235378 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151996 infores:hetionet CHEBI:40279 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002874 infores:hetionet CHEBI:48947 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0036572 infores:hetionet GO:0032306 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:0032306 GO:0007267 CHEBI:37941 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151705 infores:hetionet CHEBI:93635 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0040822 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151883 infores:hetionet CHEBI:10119 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013491 infores:hetionet CHEBI:472657 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0027497 infores:hetionet CHEBI:52717 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0476281 infores:hetionet CHEBI:8764 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0149745 infores:hetionet CHEBI:6149 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0018790 infores:hetionet NCBIGene:54344 biolink:causes MONDO:0013049 infores:monarchinitiative not_provided not_provided HGNC:3007 MONDO:0013049 uuid:0bf7bfe4-7984-4b01-8034-9c65e3e2f546 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0267792 infores:hetionet CHEBI:7025 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0687713 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0030305 infores:hetionet CHEBI:8874 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0235490 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018099 infores:hetionet NCBITaxon:520 biolink:causes MONDO:0005077 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:520 MESH:D014917 DB00199_MESH_D014917_1 CHEBI:3723 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017565 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0234913 infores:hetionet CHEBI:3568 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013384 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0015230 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038362 infores:hetionet CHEBI:45081 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0003126 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0855242 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0162119 infores:hetionet CHEBI:64354 biolink:causes HP:0001908 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0178416 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0239276 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0239276 infores:hetionet CHEBI:27470 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0033774 infores:hetionet CHEBI:92607 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0018799 infores:hetionet CHEBI:3723 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232292 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0021400 infores:hetionet CHEBI:7577 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0015230 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0004936 infores:hetionet CHEBI:50305 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0033774 infores:hetionet NCBIGene:79770 biolink:causes MONDO:0030819 infores:monarchinitiative not_provided not_provided HGNC:20652 MONDO:0030819 uuid:725b3ec5-0d26-4b27-a4d2-a6d945a94307 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0018799 infores:hetionet CHEBI:47381 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0017181 infores:hetionet CHEBI:27470 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C2047937 infores:hetionet CHEBI:134991 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0232292 infores:hetionet CHEBI:16469 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0549567 infores:hetionet CHEBI:29007 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0392525 infores:hetionet CHEBI:4909 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0017181 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0518015 infores:hetionet CHEBI:34967 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0018524 infores:hetionet CHEBI:31638 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0231528 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0007041 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0007041 uuid:449faacb-3cd4-434f-8912-c94cae8811c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70746 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0037274 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235876 infores:hetionet UMLS:C0065374 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0038990 infores:hetionet CHEBI:4814 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0600142 infores:hetionet CHEBI:6128 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0030554 infores:hetionet CHEBI:63925 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0022081 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0025517 infores:hetionet CHEBI:84050 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0232462 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0234458 infores:hetionet CHEBI:3219 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030554 infores:hetionet CHEBI:15552 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0030554 infores:hetionet CHEBI:3478 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0085631 infores:hetionet CHEBI:10101 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0022346 infores:hetionet CHEBI:40050 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0013415 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0428895 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0428895 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020615 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0948594 infores:hetionet CHEBI:9927 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0162830 infores:hetionet CHEBI:63115 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0006277 infores:hetionet CHEBI:8428 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0232807 infores:hetionet CHEBI:3655 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C1443060 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0042075 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0005940 infores:hetionet NCBIGene:5700 biolink:causes MONDO:0859296 infores:monarchinitiative not_provided not_provided HGNC:9547 MONDO:0859296 uuid:dadbd4ef-84e6-4241-b634-1872985f20db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0013144 infores:hetionet CHEBI:31711 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0520887 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042514 infores:hetionet CHEBI:9654 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0233715 infores:hetionet CHEBI:9570 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0034063 infores:hetionet CHEBI:9398 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0027497 infores:hetionet GO:0141104 biolink:causes GO:0007186 infores:ubergraph knowledge_assertion manual_agent GO:0141104 GO:0007186 CHEBI:15367 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0155169 infores:hetionet CHEBI:3756 biolink:causes HP:0002075 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0234979 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0003123 infores:hetionet CHEBI:7577 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0036974 infores:hetionet CHEBI:6888 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018681 infores:hetionet CHEBI:10101 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0034642 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0023067 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0017160 infores:hetionet CHEBI:41879 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0023518 infores:hetionet CHEBI:85078 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020458 infores:hetionet GO:0006954 biolink:causes MONDO:0005492 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D014581 DB01069_MESH_D014581_1DB01114_MESH_D014581_1DB00434_MESH_D014581_1DB00719_MESH_D014581_1DB11591_MESH_D014581_1DB00950_MESH_D014581_1DB01084_MESH_D014581_1DB00405_MESH_D014581_1DB00557_MESH_D014581_1DB01246_MESH_D014581_1 CHEBI:94501 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0009806 infores:hetionet CAID:CA006598 biolink:causes MONDO:0100316 infores:clingen CAID:CA006598 MONDO:0100316 PMID:11761407PMID:11761407 Benign BA1 BP2, BP1, BP4, BP3, PS4, PS2, PS3, PS1, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM4, PM1, PM5, PP1, PP4, PP2, PP3, BS2 NM_000218.3(KCNQ1):c.1927G>A is a missense variant predicted to cause substitution of glycine by serine at amino acid 643 (p.Gly643Ser). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.04778, with 2,047 alleles / 42,844 total alleles and 53 homozygotes in the East Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been identified in individuals with LQTc interval including 3 who had QTc interval over 480ms, as well as an individual with sudden unexplained death, however their phenotypes do not meet criteria for being highly specific to LQTS (PMID 15028050; PMID: 26385840). The variant is seen frequently in control individuals vs cases (PMID: 26159999; PMID: 18426444). From in-vitro studies, this variant is thought to have a weak dominant-negative effect without much alteration to its kinetic properties (PMID: 11761407; PMID: 22378279). This variant is thought to be a risk factor/predisposition to arrhythmias or acquired LQTS, but is not thought to be a risk factor for congenital LQTS. The computational predictor REVEL gives a score of 0.566, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.2 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmias VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006598/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5855 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151766 infores:hetionet CHEBI:8764 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151692 infores:hetionet CHEBI:45863 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0029118 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0410158 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0410158 infores:hetionet CHEBI:27470 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0011603 infores:hetionet CHEBI:31705 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0235490 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0024137 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0003864 infores:hetionet CHEBI:567361 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0018133 infores:hetionet CHEBI:3561 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1443060 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0006266 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0852733 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0038661 infores:hetionet CAID:CA274134 biolink:causes MONDO:0009290 infores:clingen CAID:CA274134 MONDO:0009290 PMID: Likely Pathogenic PM2, PP4, PM3_Strong, PVS1_Moderate This variant, c.2646+2T>A, alters the canonical donor splice site of intron 18. RT-PCR analysis revealed that the variant results in the use of a cryptic splice site in exon 18, deleting the last 21 nucleotides of the exon, corresponding to the loss of 7 amino acids (PMID 11854868). As <10% of the protein in lost, PVS1_Moderate was applied. The variant is not in gnomAD v2.1.1, meeting PM2. Four individuals with this variant have been reported to have Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. These individuals are compound heterozygous for the variant and another pathogenic variant in GAA, either an 8 kb deletion extending from intron 7 to intron 15 (PMID 11854868; in trans, 1 point), c.2481+102_2646+31del (PMID 17616415; phase unknown), c.573C>A (p.Tyr191Ter) (PMID 11738358; phase unknown), and c.1942G>A (p.Gly648Ser) (PMID 29422078; note that in trans data from this patient will be used in the classification of p.Gly648Ser and is not included here in order to avoid a circular argument). This in trans data meets PM3_Strong. Another patient has been reported but was not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 28380188). There is a ClinVar entry for this variant (Variation ID: 188924, 1 star status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1_Moderate, PM2, PM3_Strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274134/MONDO:0009290/010 2020-04-20 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:135925 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0340279 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020295 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0435001 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0435001 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0687133 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0040409 infores:hetionet CHEBI:29007 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0038325 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0278107 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0278107 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023895 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042769 infores:hetionet CHEBI:63580 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0000731 infores:hetionet CHEBI:68579 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0039231 infores:hetionet CHEBI:45783 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0549567 infores:hetionet CHEBI:94686 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0011991 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0549209 infores:hetionet CAID:CA618001458 biolink:causes MONDO:0015152 infores:clingen CAID:CA618001458 MONDO:0015152 PMID: Likely Benign BP4, BP7 PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BP1, BP3, BP2, BA1, BS2, PP2, PP3, PP4, PP1, BP5, BS1, BS3, BS4, PS1, PS3, PS4, PS2 The NM_000070.3: c.-25G>C variant is located in the 5’UTR of CAPN3. Because the variant is located in the 5’UTR, it is not expected to alter the amino acid sequence. The c.-25G>C variant is not predicted by SpliceAI to impact splicing (score 0) (BP4, BP7). The highest minor allele frequency of the variant is 0.0001310 for Admixed American genome alleles in gnomAD v3.1.2 (2/15270), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA618001458/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8874 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232462 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0520887 infores:hetionet CHEBI:18243 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0004238 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011849 infores:hetionet CHEBI:5147 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0011991 infores:hetionet CHEBI:6438 biolink:causes MONDO:0002307 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0005743 infores:hetionet CHEBI:5778 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151539 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020557 infores:hetionet GO:0070608 biolink:causes GO:0042546 infores:ubergraph knowledge_assertion manual_agent GO:0070608 GO:0042546 NCBIGene:1188 biolink:causes MONDO:0011822 infores:monarchinitiative not_provided not_provided HGNC:2027 MONDO:0011822 uuid:162a80c1-1d3a-4ebb-a991-17d4c15bcd86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0008370 infores:hetionet CHEBI:2654 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0030312 infores:hetionet CHEBI:5790 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0037763 infores:hetionet NCBIGene:220202 biolink:causes MONDO:0009097 infores:monarchinitiative not_provided not_provided HGNC:13907 MONDO:0009097 uuid:eca41de5-8932-4ebe-8bd4-d6344ec093df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0024115 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006145 infores:hetionet CHEBI:231594 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0035455 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0678222 infores:hetionet CHEBI:180905 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C2363730 infores:hetionet CHEBI:135736 biolink:causes MONDO:0018381 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0029429 infores:hetionet CHEBI:8774 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0011168 infores:hetionet CHEBI:9738 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0033774 infores:hetionet CHEBI:2682 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0000731 infores:hetionet CHEBI:50378 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0000737 infores:hetionet CHEBI:8356 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0043144 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0007642 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0518015 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0854097 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0025061 infores:hetionet CHEBI:5558 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0009676 infores:hetionet CHEBI:41423 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1527344 infores:hetionet CHEBI:64019 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0013404 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042109 infores:hetionet CHEBI:6847 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0037023 infores:hetionet CHEBI:63580 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020598 infores:hetionet CHEBI:17650 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0042384 infores:hetionet CHEBI:119915 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0855775 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0595930 infores:hetionet CHEBI:31348 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009676 infores:hetionet CHEBI:142290 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0035455 infores:hetionet CHEBI:8768 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0039070 infores:hetionet CHEBI:7565 biolink:causes UMLS:C1328327 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1328327 infores:hetionet CHEBI:39867 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0231530 infores:hetionet CHEBI:175901 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151578 infores:hetionet NCBIGene:4620 biolink:causes MONDO:0011577 infores:monarchinitiative not_provided not_provided HGNC:7572 MONDO:0011577 uuid:17a9907d-369b-453b-82b8-01206eef5ff2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0015672 infores:hetionet CAID:CA410146634 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146634 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM6, BP5, PVS1, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1423G>A (p.Ala475Thr) is a missense variant which has a REVEL score < 0.50 (0.142) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146634/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1384353 infores:hetionet CHEBI:6413 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0030554 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0037199 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0015256 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011570 infores:hetionet CHEBI:63619 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0014868 infores:hetionet NCBIGene:2122 biolink:causes MONDO:0014758 infores:monarchinitiative not_provided not_provided HGNC:3498 MONDO:0014758 uuid:4fa79084-aca2-49e2-bb25-8f8ef4e5be7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020625 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0152027 infores:hetionet CHEBI:61049 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018784 infores:hetionet NCBIGene:699 biolink:causes MONDO:0859342 infores:monarchinitiative not_provided not_provided HGNC:1148 MONDO:0859342 uuid:380e0901-6113-43a3-a180-0937c4a14c89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135930 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0232286 infores:hetionet CHEBI:6413 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042023 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0853942 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0853942 infores:hetionet CHEBI:9352 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0085593 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085584 infores:hetionet CHEBI:63617 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0006625 infores:hetionet CHEBI:80630 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0011991 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020538 infores:hetionet CHEBI:61033 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0003467 infores:hetionet UMLS:C0657912 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013390 infores:hetionet CAID:CA10641201 biolink:causes MONDO:0015967 infores:clingen CAID:CA10641201 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting The c.*1071G>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the 3' untranslated region of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, c.*1071G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10641201/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:146862 biolink:causes MONDO:0030927 infores:monarchinitiative not_provided not_provided HGNC:14304 MONDO:0030927 uuid:904203ba-8793-47b3-b897-c03d403c8e71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes NCIT:C3236 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0025568 infores:hetionet NCBIGene:3766 biolink:causes MONDO:0010933 infores:monarchinitiative not_provided not_provided HGNC:6256 MONDO:0010933 uuid:87b6bb9f-e166-4d41-bac3-8cd5b65c2ab3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0085631 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0043352 infores:hetionet CL:0000451 biolink:causes MONDO:0020082 infores:ubergraph knowledge_assertion manual_agent CL:0000451 MONDO:0020082 CAID:CA10014575 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014575 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS3, BA1, BP2, PM6, PM2, PVS1, BS4, BS3, BS1, PM5, PM1, PM4, PP1, PP3 This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created, and although evolutionary conservation prediction algorithms predict the site as being weakly conserved (PhyloP score: 1.66 > 0.1 [-14.1;6.4]), the variant is the reference nucleotide in one primate and/or three mammal species (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014575/MONDO:0011071/008 2021-01-12 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50131 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0004093 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0020651 infores:hetionet CHEBI:6076 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0000768 infores:hetionet CHEBI:53760 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0232849 infores:hetionet CHEBI:30659 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0011991 infores:hetionet CHEBI:8356 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023518 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0221165 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0033975 infores:hetionet CHEBI:94449 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0002792 infores:hetionet CHEBI:194135 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013144 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0234215 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0178298 infores:hetionet CHEBI:71255 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0085932 infores:hetionet CHEBI:4702 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0010200 infores:hetionet NCBIGene:494513 biolink:causes MONDO:0012445 infores:monarchinitiative not_provided not_provided HGNC:29502 MONDO:0012445 uuid:db46b4a9-42ec-4182-a224-0f0412cdc7a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0024894 infores:hetionet CHEBI:142290 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0011168 infores:hetionet CHEBI:28001 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0040264 infores:hetionet CHEBI:31302 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0018524 infores:hetionet CHEBI:8435 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0027424 infores:hetionet CHEBI:4672 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0917801 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0030305 infores:hetionet CHEBI:75722 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0008031 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020517 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0302590 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0302590 infores:hetionet CHEBI:520985 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0085593 infores:hetionet CHEBI:66964 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0015230 infores:hetionet CAID:CA136097 biolink:causes MONDO:0021060 infores:clingen CAID:CA136097 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2167+6T>G variant in the SOS1 gene is 1.442% (169/10278) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136097/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5818 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0018681 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0349506 infores:hetionet CHEBI:4868 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0030312 infores:hetionet CHEBI:31515 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0033774 infores:hetionet CHEBI:92998 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085624 infores:hetionet CHEBI:8214 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0220870 infores:hetionet CHEBI:5441 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0344232 infores:hetionet GO:2001212 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:2001212 GO:0001944 CHEBI:9086 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1167965 infores:hetionet NCBIGene:3476 biolink:causes MONDO:0010333 infores:monarchinitiative not_provided not_provided HGNC:5461 MONDO:0010333 uuid:928cece4-9194-4fb8-a7be-b74d7ac38d34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009782 infores:hetionet GO:1900193 biolink:causes GO:0009994 infores:ubergraph knowledge_assertion manual_agent GO:1900193 GO:0009994 CHEBI:127780 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0002871 infores:hetionet CAID:CA2695232679 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695232679 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1147_1150del (p.Thr383AlafsTer13) is a frameshift variant due to a four-nucleotide deletion that introduces a premature stop codon in exon 10 of 15 that is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in one proband diagnosed with retinitis pigmentosa with a rod-cone phenotype (PMID: 28863407). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses was fewer than the 2 unrelated probands required to meet PS4_Supporting. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695232679/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:7852 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0014724 infores:hetionet CAID:CA2573320441 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573320441 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP4, PP2, PP1, BS2 NM_001754.5(RUNX1):c.805+5G>A is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). Although it does not have an available REVEL score, multiple other predictors (dbscSNV, MaxEntScan) predict a deleterious impact, and it has a SpliceAI score ≥ 0.38 (0.77), supporting application of PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573320441/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes UMLS:C0340613 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0340613 infores:hetionet CHEBI:31980 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0020580 infores:hetionet UMLS:C1738934 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0013378 infores:hetionet CHEBI:75998 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0024312 infores:hetionet CHEBI:45327 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0020580 infores:hetionet CHEBI:72690 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0011991 infores:hetionet CAID:CA412744898 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744898 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PP4, PS4 NM_001034853.2(RPGR):c.501T>A (p.Asn167Lys) is a missense variant encoding substitution of asparagine with lysine at amino acid 167. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.784, which is between the ClinGen X-linked IRD VCEP thresholds of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. This variant has been reported in at least 1 proband meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, and/or decreased or absent cone and/or rod electroretinogram / fundus autofluorescence responses (PMID: 28559085). PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting and PP3_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744898/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Inconclusive true CHEBI:2904 biolink:causes MONDO:0002070 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018818 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0042373 infores:hetionet CHEBI:59773 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0020580 infores:hetionet CHEBI:35778 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0004093 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0242656 infores:hetionet CHEBI:9086 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0686347 infores:hetionet CHEBI:2955 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0085605 infores:hetionet CHEBI:9654 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0030252 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0041912 infores:hetionet NCBIGene:2961 biolink:causes MONDO:0014841 infores:monarchinitiative not_provided not_provided HGNC:4651 MONDO:0014841 uuid:f506e842-5d70-4e34-ab15-f46b76796040 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0017152 infores:hetionet CHEBI:3219 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C3263723 infores:hetionet CHEBI:9352 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0033774 infores:hetionet CHEBI:5118 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151908 infores:hetionet NCBIGene:57215 biolink:causes MONDO:0975800 infores:monarchinitiative not_provided not_provided HGNC:23194 MONDO:0975800 uuid:5bd294b8-7b1e-4e45-a544-c2d6e61408e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes NCIT:C61050 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0853711 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0267537 infores:hetionet CHEBI:8772 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042963 infores:hetionet CHEBI:15765 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0427086 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027707 infores:hetionet UBERON:0012287 biolink:causes MONDO:0018907 infores:ubergraph knowledge_assertion manual_agent UBERON:0012287 MONDO:0018907 CHEBI:72323 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0015230 infores:hetionet CHEBI:9139 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0234632 infores:hetionet CHEBI:2788 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0235309 infores:hetionet CAID:CA16614422 biolink:causes MONDO:0007947 infores:clingen CAID:CA16614422 MONDO:0007947 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Moderate, PM6_Supporting PVS1, BS2, PP2, PP1, BP1, BP4, BP3, BP2, BA1, PS2, PS1, PS3, PM4, PM3, PM1, PM5, BP7, BP5, BS1, BS4, BS3 The NM_000138.5 c.4583-5A>G variant in FBN1 is a variant in the splice acceptor region of intron 37. Computational splice prediction algorithms predict that this variant impacts splicing (PP3). This variant was identified in the literature and public databases in two individuals with clinical diagnoses of Marfan syndrome including once as de novo in an individual with phenotype consistent with but not highly specific to FBN1 and in an individual with aortic aneurysm and other features suggestive of Marfan syndrome; it was also found to segregate with disease in at least one affected family member (PS4_moderate, PM6_supporting; PMID: 25101912, Invitae internal data, ClinVar ID: 406332). It was also identified in a third individual with a clinical diagnosis of Marfan syndrome (PP4; Johns Hopkins). This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP (PS4_moderate, PM2_supporting, PM6_supporting, PP3, PP4). FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614422/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:68855 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0232461 infores:hetionet CAID:CA497694556 biolink:causes MONDO:0008723 infores:clingen CAID:CA497694556 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PM1, PM4 The c.1882del (p.Gln628LysfsTer52) variant in ACADVL is a frameshift in the last exon of a gene in which loss-of-function is an established disease mechanism (PVS1_moderate: PMIDs 9973285, 11590124). While this may not lead to nonsense-mediated decay, this variant is predicted to replace the final 28 conserved amino acids in ACADVL with functional significance (PMID: 18227065). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as VUS based on PVS1_moderate+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA497694556/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9460 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0027497 infores:hetionet CHEBI:4868 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0028081 infores:hetionet CHEBI:9586 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0026827 infores:hetionet NCBIGene:7802 biolink:causes MONDO:0957250 infores:monarchinitiative not_provided not_provided HGNC:14353 MONDO:0957250 uuid:f31f496c-a985-4cb0-b890-cd159d09571b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50859 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013447 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0041834 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0037274 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0162830 infores:hetionet CAID:CA961450348 biolink:causes MONDO:0100040 infores:clingen CAID:CA961450348 MONDO:0100040 PMID: Benign BA1, BP3 PS4 The highest population minor allele frequency of the c.237_239del (p.Pro80del) variant in FOXG1 in gnomAD v4.1 is 0.00054 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Pro80del variant is an in-frame deletion present in a repetitive region of FOXG1 (BP3). In summary, the p.Pro80del variant in FOXG1 is classified as a benign variant based on the ACMG/AMP criteria (BA1, BP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA961450348/MONDO:0100040/035 2024-06-25 2024-06-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:131512 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0011603 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0037199 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020517 infores:hetionet CAID:CA916084356 biolink:causes MONDO:0011071 infores:clingen CAID:CA916084356 MONDO:0011071 PMID:9533875PMID:11276260PMID:12807882PMID:9533875PMID:11276260PMID:12807882PMID:19808697PMID:23958918PMID:12807882PMID:11276260PMID:28231333PMID:12393679PMID:27294619PMID:12377125 Uncertain Significance PM5_Supporting, PM1, PM2_Supporting, PP3 PS2, PS3, PS4, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, BP5, BP7, PM6, PVS1, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.484_485delinsGC (p.Arg162Ala) is a missense variant which has not been reported in gnomAD (v2 and v3) (PM2_supporting) or in case reports. However, it is located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918) (PM1). Transactivation studies are not available for the variant, but it has been associated with decreased DNA-binding only (PMID: 12807882, 11276260, 9533875). The missense variant's REVEL score is not available, but other computational evidence supports a deleterious effect for this variant (PP3), and another missense variant at the same residue (i.e., p.R162G) is classified as likely pathogenic by the ClinGen MM-VCEP (PM5_supporting). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, and PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084356/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:51079 biolink:causes MONDO:0032632 infores:monarchinitiative not_provided not_provided HGNC:17194 MONDO:0032632 uuid:b032dbbe-7e29-4fad-a0e7-0e196b28af84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA404768497 biolink:causes MONDO:0010938 infores:clingen CAID:CA404768497 MONDO:0010938 PMID: Uncertain Significance PM2_Supporting PVS1 The variant NM_000215.4(JAK3):c.1915-1G>A is predicted to disrupt an acceptor splice site in intron 14; however, this variant falls into a NAGNAG sequence, which may indicate a frame restoring splice site (PVS1 not met). The variant has an allele frequency that is too low to calculate a popmax allele frequency accurately; there is a single heterozygous case (1/112366 alleles or MAF of 0.000008899 in the European non-Finnish population), and no homozygous cases were reported in gnomAD v2.1.1. This is below the SCID VCEP threshold of <0.000115 (PM2_supporting). To our knowledge, the variant has not been reported in the literature in any individuals with JAK3 deficiency. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting. (SCID VCEP Specification Version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA404768497/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:478164 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0002874 infores:hetionet CHEBI:4887 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0041969 infores:hetionet CHEBI:87681 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C2830004 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0018965 infores:hetionet CAID:CA2580098681 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098681 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-12_614-11delinsCT is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098681/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6339 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0018799 infores:hetionet CHEBI:9599 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0020615 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0030305 infores:hetionet CHEBI:135920 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C1443060 infores:hetionet UMLS:C0010592 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0011168 infores:hetionet CAID:CA401327498 biolink:causes MONDO:0009290 infores:clingen CAID:CA401327498 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, PS1_Supporting, PVS1_Moderate The NM_000152.5:c.2799+2C>A variant in GAA alters the consensus donor splice site of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.63 for donor loss, predicting that the variant disrupts splicing. Assuming that this results in skipping of exon 19, an in frame deletion of ~5% of the length of GAA would occur. Of note, the first two nucleotides of the intron are GC, rather than the typical GT (PVS1_Moderate). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies to investigate its impact on splicing are not available. Additional variants in this splice region have been identified including c.2799+2C>T (classified by the ClinGen LD VCEP as a VUS), c.2799+4A>G (PMID: 26873529, 30564623) (classified by the ClinGen LD VCEP as likely pathogenic) and c.2799+5G>A (PMID: 28265479) (classified by the ClinGen LD VCEP as a VUS) (PS1_Supporting based on a likely pathogenic variant in the same splice region; Walker et al, 2023; https://www.medrxiv.org/content/10.1101/2023.02.24.23286431v1). There is a ClinVar entry for the variant (Variant ID: 556975). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PVS1_Moderate, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401327498/MONDO:0009290/010 2023-06-27 2023-09-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CAID:CA2573051044 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051044 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP4 The c.1803dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 602 (NM_000545.8), adding 47 novel amino acids before encountering a stop codon (p.(Asp602ArgfsTer47)). While this variant, located at c.1803 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain, which is defined as critical for protein function by the ClinGen MDEP (PVS1_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of information about when insulin treatment was initiated, and HNF4A was not tested (internal lab contributors). Therefore, PP4 cannot be applied. In summary, c.1803dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051044/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2955 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0014457 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004364 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233414 infores:hetionet CHEBI:75998 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0015672 infores:hetionet CHEBI:7798 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0235996 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042401 infores:hetionet CHEBI:28177 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C1963951 infores:hetionet CHEBI:175901 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0919924 infores:hetionet CAID:CA274538 biolink:causes MONDO:0010726 infores:clingen CAID:CA274538 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PM1, PP4, PP3, PS2_Very Strong, PM5_Strong, PS4, PM2_Supporting The p.Arg133His variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 4 individuals with classic or atypical Rett syndrome (PMID 30569584, 17089071, 30945278) (PS2_very strong, PP4). The p.Arg133His variant has been observed in at least 3 other individuals with classic or atypical Rett syndrome (PMID 16473305, RettBASE) (PS4). Four additional pathogenic missense variants (p.Arg133Cys, p.Arg133Leu, p.Arg133Pro, p.Arg133Gly) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23421866, 11738879, 26418480, 16473305, 22368975, 10854091, 11960578, 12180070, Invitae - internal database) (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Luciferase reporter and immunofluorescence assays have shown that this variant impacts protein function (PMID 21831886, 12843318) (PS3_supporting). The p.Arg133His variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg133His variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM5_strong, PS3_supporting, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274538/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf UMLS:C0879264 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0019048 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0150450 infores:hetionet CHEBI:8461 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0002874 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0030353 infores:hetionet CHEBI:2922 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0002994 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0017178 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1565489 infores:hetionet NCBIGene:57728 biolink:causes MONDO:0013719 infores:monarchinitiative not_provided not_provided HGNC:18340 MONDO:0013719 uuid:9e644648-cede-4cc8-9519-c220dc111433 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68584 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0041969 infores:hetionet CAID:CA410203630 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203630 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.293T>C (p.Leu98Pro) is a missense variant which has a REVEL score ≥ 0.88 (0.934) (PP3). This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203630/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:168396 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0012833 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0281981 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0178298 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151698 infores:hetionet CHEBI:3478 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0014591 infores:hetionet NCBIGene:79977 biolink:causes MONDO:0054832 infores:monarchinitiative not_provided not_provided HGNC:2799 MONDO:0054832 uuid:4a9889f0-6dcb-410d-8b40-c406cba82707 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0003578 infores:hetionet CHEBI:8888 biolink:causes NCIT:C50526 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235827 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022667 infores:hetionet CHEBI:7565 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0028734 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0002871 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0339916 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017574 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0085606 infores:hetionet CHEBI:51041 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018524 infores:hetionet CHEBI:52172 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0152031 infores:hetionet CHEBI:17026 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0012569 infores:hetionet CHEBI:8874 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0149745 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0023067 infores:hetionet CHEBI:23765 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002962 infores:hetionet CHEBI:83804 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013384 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034150 infores:hetionet GO:0003427 biolink:causes GO:0060350 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0060350 CHEBI:3814 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0013404 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0013395 infores:hetionet CHEBI:61033 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1443060 infores:hetionet CHEBI:8707 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0277890 infores:hetionet CHEBI:3419 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0042571 infores:hetionet CAID:CA2695215276 biolink:causes MONDO:0700270 infores:clingen CAID:CA2695215276 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.3856del p.Cys1286Alafs*7 variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been reported in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v4.1.0. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695215276/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68575 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0002962 infores:hetionet CHEBI:63598 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013404 infores:hetionet CHEBI:73274 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0030305 infores:hetionet CHEBI:84500 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0039070 infores:hetionet CHEBI:83531 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0018524 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0014549 infores:hetionet NCBIGene:23067 biolink:causes MONDO:0033559 infores:monarchinitiative not_provided not_provided HGNC:29187 MONDO:0033559 uuid:9579c194-fd7b-4c7e-99d8-5a6d50babd3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027947 infores:hetionet CHEBI:5280 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151786 infores:hetionet CHEBI:7444 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0018524 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017566 infores:hetionet CHEBI:6965 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0013144 infores:hetionet CHEBI:35778 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0013378 infores:hetionet CHEBI:168396 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0010200 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0000833 infores:hetionet CHEBI:31236 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020473 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0342579 infores:hetionet CHEBI:27777 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C1443060 infores:hetionet CAID:CA9871465 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871465 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting BS2, BA1, BS1 The c.934A>C (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Lysine by Glutamine at amino acid 312 (p.Lys312Gln).The filtering allele frequency (the upper threshold of the 95% CI of 9/59258) of the c.934A>C variant in ADA is 0.00007920 for African/African American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Another missense variant [c.935A>G; p.Lys312Arg] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871465/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5165 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085610 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1321686 infores:hetionet CHEBI:63681 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0040822 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0006384 infores:hetionet CHEBI:5165 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1306341 infores:hetionet CHEBI:194135 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0028084 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014863 infores:hetionet CHEBI:47898 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0232462 infores:hetionet CHEBI:15367 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085649 infores:hetionet CHEBI:6076 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0025345 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0085082 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085082 infores:hetionet CHEBI:63681 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0042963 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151849 infores:hetionet CAID:CA410147457 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147457 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1300A>G (p.Asn434Asp) is a missense variant located in exon 9. This variant is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, which provide at least 20x coverage for the RUNX1 gene at this position (PM2_supporting). It has a REVEL score of 0.169 (≤0.50), and no evidence supports an impact on splicing, as indicated by a SpliceAI score of 0.00 (BP4). This variant has not been previously reported, and no pathogenic or likely pathogenic amino acid changes have been documented at the same residue. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147457/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6775 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0008325 infores:hetionet CHEBI:50729 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0013491 infores:hetionet CHEBI:17549 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0392699 infores:hetionet CHEBI:6541 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0014457 infores:hetionet CHEBI:63621 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0022346 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0006266 infores:hetionet CHEBI:6935 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0021845 infores:hetionet CHEBI:6909 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0030193 infores:hetionet CHEBI:5893 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0037287 infores:hetionet CHEBI:63611 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085593 infores:hetionet CHEBI:16469 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042024 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0948594 infores:hetionet CHEBI:63619 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C1368065 infores:hetionet CHEBI:3084 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0079043 infores:hetionet CHEBI:30830 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0019521 infores:hetionet CHEBI:9654 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0008031 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0037199 infores:hetionet CHEBI:6792 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0003811 infores:hetionet CHEBI:6149 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020440 infores:hetionet CAID:CA024001 biolink:causes MONDO:0018493 infores:clingen CAID:CA024001 MONDO:0018493 PMID: Likely Pathogenic PS4_Moderate, PP3_Moderate, PP1_Strong PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with leucine at codon 4324 of the RYR1 protein, p.(Val4234Leu); c.12700G>C. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 30236257, 12208234, 21965348, 22696611, 24053352, 28290972). This variant segregates with MHS in nine meiosis, PP1_Strong (personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024001/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63581 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1145670 infores:hetionet CHEBI:46295 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0026826 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0027765 infores:hetionet CHEBI:2663 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0019079 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0948594 infores:hetionet CHEBI:36791 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0428977 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0018418 infores:hetionet NCBIGene:81562 biolink:causes MONDO:0014815 infores:monarchinitiative not_provided not_provided HGNC:19263 MONDO:0014815 uuid:8cd898e7-cf00-4c30-b896-704418042fc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72690 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0000768 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0037274 infores:hetionet CHEBI:35854 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0017178 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0302295 infores:hetionet NCBIGene:9378 biolink:causes MONDO:0013690 infores:monarchinitiative not_provided not_provided HGNC:8008 MONDO:0013690 uuid:781452de-72bf-49a1-aea3-675470284c91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4974 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0013390 infores:hetionet CHEBI:9139 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0002962 infores:hetionet CHEBI:31949 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0036341 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0040034 infores:hetionet CHEBI:39867 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0549249 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042109 infores:hetionet CHEBI:7476 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0006142 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0497201 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0815316 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2004521 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0232492 infores:hetionet CHEBI:7447 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0020517 infores:hetionet CHEBI:47898 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151603 infores:hetionet CHEBI:63621 biolink:causes MONDO:0020686 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0001361 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020473 infores:hetionet NCBIGene:9319 biolink:causes MONDO:0033565 infores:monarchinitiative not_provided not_provided HGNC:12307 MONDO:0033565 uuid:59a0d017-e50d-4c99-8840-f5df3ff3ce30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232602 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0009806 infores:hetionet CHEBI:7577 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0152227 infores:hetionet NCBIGene:581 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:959 MONDO:0013108 uuid:7057c587-3f0e-43b7-b63d-3821a52a6fdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5165 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1443060 infores:hetionet CHEBI:31236 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039591 infores:hetionet CHEBI:3175 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0036454 infores:hetionet CHEBI:63619 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085614 infores:hetionet CHEBI:10100 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0235378 infores:hetionet NCBIGene:5618 biolink:causes MONDO:0014249 infores:monarchinitiative not_provided not_provided HGNC:9446 MONDO:0014249 uuid:c1479ec2-ebb3-4304-88e3-a107faa2c69b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28445 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0011570 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0521654 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0521654 infores:hetionet CHEBI:9328 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151798 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0025160 infores:hetionet CHEBI:3213 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0015672 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0085681 infores:hetionet CHEBI:41977 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0027497 infores:hetionet CAID:CA16020857 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020857 MONDO:0009861 PMID:23357515PMID:23357515PMID:20179079 Pathogenic PM3, PM2, PP4, PP3, PS3 The c.788T>C (p.Phe263Ser) variant in PAH has been reported in 1 patient with hyperphenylalaninemia (BH4 deficiency not excluded) and was detected with known pathogenic variant c.1066-11G>A (PP4, PM3; PMID: 23357515). This variant is absent in population databases (PM2). This variant has 4% enzyme activity (PS3; PMID:20179079). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020857/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16664 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0042963 infores:hetionet NCBIGene:10159 biolink:causes MONDO:0010319 infores:monarchinitiative not_provided not_provided HGNC:18305 MONDO:0010319 uuid:722367b0-88bc-45eb-933d-306aea9030f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0032961 infores:hetionet NCBIGene:50814 biolink:causes MONDO:0010441 infores:monarchinitiative not_provided not_provided HGNC:13398 MONDO:0010441 uuid:be5bf5f1-ea78-4fed-bae8-b8ff6220aea3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31624 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0234238 infores:hetionet CHEBI:63717 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0032617 infores:hetionet CHEBI:6954 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0002622 infores:hetionet GO:0060787 biolink:causes GO:0021990 infores:ubergraph knowledge_assertion manual_agent GO:0060787 GO:0021990 CHEBI:5118 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151610 infores:hetionet CHEBI:18067 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0020649 infores:hetionet CHEBI:36795 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2830004 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011053 infores:hetionet CHEBI:4975 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0009676 infores:hetionet CHEBI:10127 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042029 infores:hetionet CHEBI:70746 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0311468 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0023067 infores:hetionet GO:1902872 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0150063 CHEBI:6887 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0037763 infores:hetionet CHEBI:55346 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0003813 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0033975 infores:hetionet CAID:CA367358198 biolink:causes MONDO:0015967 infores:clingen CAID:CA367358198 MONDO:0015967 PMID: Uncertain Significance PP2, PP4, PM2_Supporting PP3, BP4 The c.17C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 6 (p.(Ala6Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.55, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.0000029 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). In summary, c.17C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367358198/MONDO:0015967/086 2025-02-28 2025-02-28 Semidominant inheritance HP:0032113 Inconclusive true UMLS:C0145867 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0010520 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0013395 infores:hetionet CAID:CA213758 biolink:causes MONDO:0015967 infores:clingen CAID:CA213758 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM3, PS3_Supporting, PP2, PP3, PP4, PM2_Supporting PM1 The c.1345G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 449 (p.(Ala449Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.89, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the relative stability index was below the MDEP cutoff of 0.5 (PS3_Supporting; PMID: 25015100). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 25015100, internal lab contributors). This variant has been detected in the homozygous state in 3 individuals with permanent neonatal diabetes (PNDM) and negative testing for ABCC8, KCNJ11, and INS (PM3). This variant segregated in the homozygous state with permanent neonatal diabetes and the in the heterozygous state with hyperglycemia, with 6 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1345G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PM3, PS4_Moderate, PP2, PP3, PP4, PM2_Moderate, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213758/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:10102 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0022408 infores:hetionet CHEBI:48538 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0018188 infores:hetionet NCBIGene:55081 biolink:causes MONDO:0054770 infores:monarchinitiative not_provided not_provided HGNC:17367 MONDO:0054770 uuid:587220cc-c078-487c-ad4b-02236e5048be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6621 biolink:causes MONDO:0957791 infores:monarchinitiative not_provided not_provided HGNC:11137 MONDO:0957791 uuid:738ff938-d35a-4d26-a74f-64febf26d7d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA294376 biolink:causes MONDO:0700270 infores:clingen CAID:CA294376 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 PM5 The c.6976-2A>C variant in ATM occurs within the canonical splice acceptor site (+/- 1,2) of intron 47. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID: 31843900; Ambry internal data). This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000088 in the European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (≤.00001) for PM2_Supporting, meeting this criterion. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. (PVS1(RNA), PM3_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA294376/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:59560 biolink:causes MONDO:0021680 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0038395 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009763 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0019158 infores:hetionet GO:1903332 biolink:causes GO:0051604 infores:ubergraph knowledge_assertion manual_agent GO:1903332 GO:0051604 CHEBI:5098 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0006266 infores:hetionet CAID:CA033568 biolink:causes MONDO:0007750 infores:clingen CAID:CA033568 MONDO:0007750 PMID: Benign BP4, BP7, BS1, BS2 BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4 The NM_000527.4(LDLR):c.1323C>T (p.Ile441=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS1 - FAF = 0.003722 (0.37%) in African exomes (gnomAD v2.1.1).BS2 - Variant is observed in heterozygosity in 5 normolipidemic adults.BP4 - no REVEL, splicing evaluation required. No functional study performed. A) not on limits B) does not create GT C) no GT nearby.BP7 - Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033568/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0236075 infores:hetionet CHEBI:9570 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0740394 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0018799 infores:hetionet CHEBI:142290 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0012569 infores:hetionet CHEBI:7822 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0855775 infores:hetionet CHEBI:9241 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0027497 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0410959 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0410959 infores:hetionet CHEBI:9613 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0001824 infores:hetionet CHEBI:4903 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C3665347 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0687133 infores:hetionet CHEBI:45783 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0043094 infores:hetionet CHEBI:7959 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0011603 infores:hetionet CHEBI:421707 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0231528 infores:hetionet CHEBI:490877 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0020615 infores:hetionet CHEBI:45409 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151315 infores:hetionet CHEBI:51860 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018524 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0442886 infores:hetionet CHEBI:50777 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0018681 infores:hetionet CHEBI:26333 biolink:causes HP:0012531 infores:drugmechdb knowledge_assertion manual_agent MESH:D011453 HP:0012531 DB00945_MESH_D001416_1 UMLS:C0145867 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0000833 infores:hetionet CHEBI:50173 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0024902 infores:hetionet CHEBI:127780 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0037299 infores:hetionet CHEBI:7907 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0011603 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018801 infores:hetionet NCBITaxon:12058 biolink:causes MONDO:0005709 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12058 MESH:D003139 DB00748_MESH_D003139_1 CHEBI:7852 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0520887 infores:hetionet CHEBI:4975 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0043144 infores:hetionet CHEBI:9073 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0042963 infores:hetionet CHEBI:29688 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0003862 infores:hetionet CHEBI:47426 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0344232 infores:hetionet CHEBI:50173 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0000768 infores:hetionet CAID:CA2832612269 biolink:causes MONDO:0015152 infores:clingen CAID:CA2832612269 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PP1, PM2_Supporting The NM_003494.4: c.533del p.(Gly178GlufsTer49) variant in DYSF, which is also known as NM_001130987.2: c.629del (p.Gly210GlufsTer49), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 7/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant has been reported in one individual with suspected LGMD, where it was confirmed in trans with a pathogenic variant (NM_003494.4: c.1861G>A p.(Gly621Arg), 1.0 pt, PMID: 36983702; PM3). This patient displayed slowly progressive muscle weakness and disease range dysferlin by blood monocyte assay, which is highly specific for DYSF-related LGMD (PP4_Strong). The variant also co-segregated with the LGMD phenotype in one affected family member (PMID: 36983702; PP1). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/03/2025): PVS1, PM3, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2832612269/MONDO:0015152/180 2025-04-03 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports PUBCHEM.COMPOUND:122173801 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018944 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042514 infores:hetionet CHEBI:3504 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0542571 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151740 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1142412 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003537 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0002871 infores:hetionet CHEBI:3175 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0030554 infores:hetionet CHEBI:6909 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2242588 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0039971 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0232459 infores:hetionet CHEBI:87681 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0002994 infores:hetionet CHEBI:4027 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0235996 infores:hetionet CHEBI:31348 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019209 infores:hetionet CHEBI:3996 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0026826 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0233494 infores:hetionet CHEBI:72296 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151904 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0004936 infores:hetionet NCBITaxon:36827 biolink:causes MONDO:0016453 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36827 MONDO:0016453 CHEBI:3561 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0233472 infores:hetionet UMLS:C0879264 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0085593 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0948594 infores:hetionet CHEBI:6950 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0233471 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0403632 infores:hetionet CHEBI:77733 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0028738 infores:hetionet CHEBI:50663 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0012833 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0858797 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042267 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0042514 infores:hetionet UMLS:C0004599 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0030193 infores:hetionet CHEBI:32221 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0037763 infores:hetionet CHEBI:6754 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0011603 infores:hetionet CHEBI:10119 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0036974 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0518015 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033581 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0038362 infores:hetionet CHEBI:5118 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0232943 infores:hetionet CHEBI:17688 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0520966 infores:hetionet CHEBI:10124 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C2047937 infores:hetionet CHEBI:6339 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0020580 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0494165 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0494165 infores:hetionet CHEBI:47780 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0236075 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0851341 infores:hetionet CAID:CA10360704 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360704 MONDO:0010725 PMID: Benign BA1 BP4, BP2, PP3 The NM_000330.4(RS1):c.295A>G variant is a missense variant encoding the substitution of Asparagine with Aspartic acid at amino acid 99. This variant is present in gnomAD v4.1.0 at a frequency of 0.002748 among hemizygous individuals, with 1090 variant alleles / 396588 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). This variant has been observed in cis with the variant c.608C>T (p.Pro203Leu) (PMID: 35456481) which has been previously classified as pathogenic by the ClinGen X-linked IRD VCEP for X-linked retinoschisis, with the phase of the variants confirmed by maternal genotype testing. However, BP2 has not been recommended for RS1, so this code is not met. The computational predictor REVEL gives a score of 0.443, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 and <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes do not apply. In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360704/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:5959 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0002962 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0854097 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0023533 infores:hetionet CHEBI:39867 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020625 infores:hetionet CHEBI:8768 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011071 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0267596 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0857172 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0857172 infores:hetionet CHEBI:8863 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042133 infores:hetionet CHEBI:50924 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0017672 infores:hetionet CHEBI:45951 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0027849 infores:hetionet CAID:CA214281 biolink:causes MONDO:0015967 infores:clingen CAID:CA214281 MONDO:0015967 PMID: Likely Benign PM2_Supporting, BP5, BS2 PS4, PP3 The c.1663C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 555(p.(Leu555Phe)) of NM_000545.8. This variant has an allele frequency of 0.00001797 in Non-Finnish Europeans, below the MDEP threshold of 0.00002, and no copies in other subpopulations, in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in the homozygous state in a 56 year old normoglycemic individual (BS2; PMID: 22341299). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; PMID: 22341299). This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1663C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM2_Supporting, BS2, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214281/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47499 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0151611 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0521490 infores:hetionet CHEBI:3504 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0237849 infores:hetionet CHEBI:45863 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0600142 infores:hetionet CHEBI:2654 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0020676 infores:hetionet CHEBI:9139 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027424 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0030305 infores:hetionet CHEBI:48273 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0232462 infores:hetionet CAID:CA146035 biolink:causes MONDO:0100437 infores:clingen CAID:CA146035 MONDO:0100437 PMID: Benign BA1, BP4, BP7 NM_001034853.2(RPGR):c.1572+11A>G is a non-coding variant within intron 13 that is located outside of the splice donor region (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v4.1.0 at a frequency of 0.0658891 among hemizygous individuals, with 17,309 variant alleles / 262,699 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA146035/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:5128 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0009421 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0043241 infores:hetionet CHEBI:68595 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0001175 infores:hetionet NCBIGene:4210 biolink:causes MONDO:0009572 infores:monarchinitiative not_provided not_provided HGNC:6998 MONDO:0009572 uuid:4439c08b-0386-46cb-83c5-d44d55fee81d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011168 infores:hetionet CHEBI:63610 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0042963 infores:hetionet CHEBI:135738 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0004238 infores:hetionet CHEBI:31174 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0011616 infores:hetionet CHEBI:36795 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085649 infores:hetionet CHEBI:5128 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0011991 infores:hetionet CHEBI:49713 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0009676 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0018801 infores:hetionet CHEBI:16914 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0013295 infores:hetionet CHEBI:76010 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0020517 infores:hetionet CHEBI:4702 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0013604 infores:hetionet CAID:CA229418 biolink:causes MONDO:0009861 infores:clingen CAID:CA229418 MONDO:0009861 PMID:16256386PMID:26503515PMID:8019568PMID:8019568 Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong PS3, BS3 The c.1252A>C (p.Thr418Pro) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00003) in gnomAD. It was detected in trans with multiple pathogenic variants: p.Arg243Gln, p.Arg408Gln, p.Arg176*, EX6-96A＞G, p.Tyr356*, p.Arg111* (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229418/MONDO:0009861/006 2020-06-08 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CAID:CA024451 biolink:causes MONDO:0007783 infores:clingen CAID:CA024451 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PM1, PP3_Moderate PS4, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamine with lysine at codon 155 of the RYR1 protein, p.(Gln155Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two individuals without sufficient details to determine if there was a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not implemented, (PMID:16732084). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:31841587). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.886) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024451/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ NCBIGene:5519 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:9303 MONDO:0008903 uuid:ff696beb-2060-4418-8ef3-550975d39b53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0036454 infores:hetionet CHEBI:135929 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0011609 infores:hetionet CHEBI:8707 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0019521 infores:hetionet CHEBI:5106 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C1527344 infores:hetionet CAID:CA320250463 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250463 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.*1078A>G is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250463/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64310 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0268000 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0497327 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0004936 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0221714 infores:hetionet CHEBI:32221 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0085661 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0005940 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0003123 infores:hetionet CHEBI:28748 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0024902 infores:hetionet CHEBI:4708 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011071 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001584 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028850 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0234215 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0006826 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0041912 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027813 infores:hetionet CAID:CA2580610939 biolink:causes MONDO:0009276 infores:clingen CAID:CA2580610939 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PM3 The c.952del (p.Ala318ProfsTer17) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BSS-1 in PMID:23300803) with this variant had aggregation absent for ristocetin and present for all other agonists as well as less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was compound heterozygous for this variant and the c.1562_1563del variant in GP1BA which was classified as Pathogenic by the PD VCEP criteria. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610939/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6706 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0017675 infores:hetionet CHEBI:9130 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0017979 infores:hetionet CHEBI:7573 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0018965 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0013395 infores:hetionet CHEBI:100241 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0162298 infores:hetionet CHEBI:17141 biolink:causes HP:0012088 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0278045 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0227791 infores:hetionet CAID:CA512341384 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341384 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.999G>A (p.Pro333=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.13)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341384/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4909 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0014518 infores:hetionet CHEBI:41774 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0026821 infores:hetionet CHEBI:63619 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0002962 infores:hetionet CHEBI:38562 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0042384 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0031046 infores:hetionet CHEBI:63616 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0235025 infores:hetionet CHEBI:7824 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085631 infores:hetionet CHEBI:6741 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0086565 infores:hetionet CHEBI:31236 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2363730 infores:hetionet CHEBI:32315 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0035455 infores:hetionet CHEBI:51860 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085593 infores:hetionet NCBIGene:7234 biolink:causes MONDO:0859354 infores:monarchinitiative not_provided not_provided HGNC:12348 MONDO:0859354 uuid:f88ddcc6-1530-4dcd-b021-4520013beb63 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes MONDO:0020108 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0002880 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0233414 infores:hetionet CHEBI:9586 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013384 infores:hetionet CHEBI:135736 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018681 infores:hetionet CHEBI:5103 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C2830004 infores:hetionet CHEBI:68554 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0019048 infores:hetionet CHEBI:41423 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0013456 infores:hetionet NCBIGene:7134 biolink:causes MONDO:0013195 infores:monarchinitiative not_provided not_provided HGNC:11943 MONDO:0013195 uuid:5d868909-0a82-45c0-97bd-bea8620fb191 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1142135 infores:hetionet CHEBI:45327 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0015230 infores:hetionet GO:0090325 biolink:causes GO:0007626 infores:ubergraph knowledge_assertion manual_agent GO:0090325 GO:0007626 CHEBI:10127 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0424295 infores:hetionet CHEBI:41423 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0438717 infores:hetionet CAID:CA000548 biolink:causes MONDO:0017623 infores:clingen CAID:CA000548 MONDO:0017623 PMID:9425889 Likely Pathogenic PVS1, PM2_Supporting PM6, BP5, BP7, BS4, BS3, BS1, PP1, PP4, PP3, PP2, BS2, PM3, PM5, PM4, PM1, BP2, BP4, BP1, BP3, BA1, PS4, PS2, PS3, PS1 NM_000314.8(PTEN):c.696del (p.Arg233AspfsTer23) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PM2_P: Absent in large sequenced populations in the gnomAD cohort (PMID:27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000548/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0044037 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085642 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0948715 infores:hetionet CHEBI:9215 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0340865 infores:hetionet CHEBI:3403 biolink:causes HP:0100718 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042143 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0024115 infores:hetionet CHEBI:114785 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0041657 infores:hetionet CAID:CA402998053 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998053 MONDO:0012999 PMID:24415674 Likely Pathogenic PP3, PM2_Supporting, PP4_Strong, PM3, PS3_Supporting The NM_000156.6:c.152A>C variant in GAMT is a missense variant that is predicted to result in the substitution of histidine by proline at amino acid 51 (p.His51Pro). One proband has been reported with mild developmental delay, anti-epileptic drug responsive seizures, and autistic features, with a normal brain MRI. This individual had elevated guanidinoacetate in urine and, on MRS, creatine peak was partially absent and guanidinoacetate was absent (PMID: 15108290, 24415674) (PP4_Strong). This individual is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.526dupG. The variants were confirmed to be in trans by parental testing (PM3). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). When the variant was expressed in a primary GAMT-deficient human fibroblast cell line, no detectable expression could be seen on Western blot and the GAMT activity was very low (<4%)(PMID 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.814 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998053/MONDO:0012999/026 2023-09-12 2023-09-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7852 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0009450 infores:hetionet CHEBI:3403 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0013404 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0162429 infores:hetionet CHEBI:45409 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0018965 infores:hetionet CHEBI:7640 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0021141 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0033774 infores:hetionet CHEBI:75722 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037763 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018799 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022660 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018021 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0035078 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0021053 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0151698 infores:hetionet CHEBI:28915 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0022354 infores:hetionet NCBIGene:5888 biolink:causes MONDO:0014986 infores:monarchinitiative not_provided not_provided HGNC:9817 MONDO:0014986 uuid:3df7fd99-8076-4335-9003-f7ffde043bab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:140621 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0340865 infores:hetionet CHEBI:6909 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0028738 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0919980 infores:hetionet CHEBI:63605 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0520966 infores:hetionet CHEBI:16469 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0038999 infores:hetionet CHEBI:63598 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0162834 infores:hetionet CHEBI:38562 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0018681 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0026946 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026946 infores:hetionet GO:1905310 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0007275 CHEBI:4708 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151936 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0302295 infores:hetionet CHEBI:46345 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0013362 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1443060 infores:hetionet CHEBI:367163 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018965 infores:hetionet CHEBI:2675 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0241934 infores:hetionet CHEBI:17334 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018932 infores:hetionet CHEBI:76010 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0741494 infores:hetionet CHEBI:5856 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0428977 infores:hetionet CHEBI:5778 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C1443060 infores:hetionet CHEBI:75722 biolink:causes HP:0011227 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0742906 infores:hetionet CHEBI:3223 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C3495440 infores:hetionet CHEBI:4027 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0017181 infores:hetionet CHEBI:50131 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0497156 infores:hetionet CHEBI:10023 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0001925 infores:hetionet CHEBI:3568 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0237849 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0235032 infores:hetionet CAID:CA2739267612 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267612 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.891_904del (p.Pro298Phefs*297) is a frameshift variant in biologically relevant exon 8/9, predicted to alter the C-terminus of the protein, a region critical to protein function (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting). Although the variant has not been reported in the literature, other nonsense/frameshift variants in exon 8 have been reported as pathogenic/likely pathogenic (PMID: 35764482) (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267612/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119486 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0424000 infores:hetionet CHEBI:15544 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0085624 infores:hetionet CHEBI:10119 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0023380 infores:hetionet CAID:CA16614267 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614267 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, BA1, PM5, PM1, PS4, PS2, BS1 The NM_177438.3:c.1430A>G variant in DICER1 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 477 (p.Asn477Ser). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001363 (22/1613880 alleles) with a highest population minor allele frequency of 0.00001667 (1/60000 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.293; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 10/22/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614267/MONDO:0100216/024 2024-10-22 2024-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17347 biolink:causes UMLS:C0151464 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151464 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0221717 infores:hetionet GO:0061074 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0061074 GO:0007275 CHEBI:17347 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235750 infores:hetionet CHEBI:75275 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0002792 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0012833 infores:hetionet CAID:CA024202 biolink:causes MONDO:0018493 infores:clingen CAID:CA024202 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with threonine at codon 4880 of the RYR1 protein, p.(Met4880Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:15731587). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.956) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024202/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3568 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0243026 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0919582 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0919582 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0033687 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0042075 infores:hetionet CHEBI:7465 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0948008 infores:hetionet CHEBI:75722 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003873 infores:hetionet NCBIGene:148738 biolink:causes MONDO:0011216 infores:monarchinitiative not_provided not_provided HGNC:4887 MONDO:0011216 uuid:4cb7ac34-a405-4010-bcf8-055c049d54c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151849 infores:hetionet CAID:CA239802 biolink:causes MONDO:0012589 infores:clingen CAID:CA239802 MONDO:0012589 PMID: Benign BP5, BS2, BA1 The allele frequency of the p.Ala315Val variant in TCF4 is 0.1% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala315Val variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ala315Val variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Ala315Val variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA239802/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:145499 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0086439 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0442874 infores:hetionet CHEBI:49713 biolink:causes HP:0009798 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0302859 infores:hetionet CHEBI:6887 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0014742 infores:hetionet CAID:CA512341317 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341317 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP2, BP3, BP5, BS1, BS3, BS4, PM6, PVS1, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1083C>G (p.Thr361=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.9)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341317/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5118 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020624 infores:hetionet CHEBI:61033 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0017565 infores:hetionet CHEBI:31236 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018681 infores:hetionet CHEBI:391960 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0038362 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0034063 infores:hetionet CHEBI:50859 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0024282 infores:hetionet UMLS:C0010592 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020461 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005236 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0302314 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0178298 infores:hetionet CHEBI:61049 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0035243 infores:hetionet CHEBI:17823 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0085681 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0549386 infores:hetionet NCBIGene:3614 biolink:causes MONDO:0008379 infores:monarchinitiative not_provided not_provided HGNC:6052 MONDO:0008379 uuid:2c266640-78d1-422a-8ffb-68dd57b0207b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0013604 infores:hetionet CHEBI:47898 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013144 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0022107 infores:hetionet NCBIGene:9180 biolink:causes MONDO:0024522 infores:monarchinitiative not_provided not_provided HGNC:8507 MONDO:0024522 uuid:133500f7-f4a1-455d-ad39-475825d26388 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31515 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0027769 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0520559 infores:hetionet CHEBI:78320 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0041834 infores:hetionet CHEBI:6129 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009676 infores:hetionet CHEBI:32221 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0236075 infores:hetionet CHEBI:4469 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0017178 infores:hetionet CHEBI:15367 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018965 infores:hetionet CAID:CA354447939 biolink:causes MONDO:0009276 infores:clingen CAID:CA354447939 MONDO:0009276 PMID: Likely Pathogenic PM3_Supporting, PVS1_Strong, PP4, PM2_Supporting The c.285T>G (p.Tyr95Ter) variant in GP9 is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BSS15.01 in PMID: 23995613) with this variant had aggregation absent for ristocetin and present for all other agonists as well as less than 10% expression of GPIba and GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting, and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA354447939/MONDO:0009276/083 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15854 biolink:causes UMLS:C0151555 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0151555 infores:hetionet CHEBI:79699 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0006277 infores:hetionet CHEBI:31397 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0151662 infores:hetionet CHEBI:8713 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C1443060 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0032584 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1368065 infores:hetionet NCBIGene:2260 biolink:causes MONDO:0007400 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0007400 uuid:52f6c541-57ec-4d45-868e-3841c7b65240 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0743516 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0743516 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0231365 infores:hetionet CHEBI:63618 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0002994 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0032961 infores:hetionet NCBITaxon:3052230 biolink:causes MONDO:0005354 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:3052230 MESH:D019698 DB06290_MESH_D019698_1DB12026_MESH_D019698_1DB00105_MESH_D019698_1DB11574_MESH_D019698_2DB11613_MESH_D019698_1DB09183_MESH_D019698_1DB09027_MESH_D019698_1DB11929_MESH_D019698_1DB09296_MESH_D019698_1DB09102_MESH_D019698_1DB00008_MESH_D019698_2DB09297_MESH_D019698_1DB11575_MESH_D019698_1DB00811_MESH_D019698_1DB11574_MESH_D019698_1DB08873_MESH_D019698_2DB00022_MESH_D019698_1DB08934_MESH_D019698_1DB05521_MESH_D019698_1DB00008_MESH_D019698_1DB08873_MESH_D019698_1 CHEBI:17474 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0178298 infores:hetionet CHEBI:47519 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0152030 infores:hetionet CHEBI:53760 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0149745 infores:hetionet CHEBI:7466 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0853813 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0858775 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0858775 infores:hetionet CHEBI:3423 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0008031 infores:hetionet CHEBI:9398 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0042029 infores:hetionet NCBIGene:3815 biolink:causes MONDO:0011719 infores:monarchinitiative not_provided not_provided HGNC:6342 MONDO:0011719 uuid:57f4259a-b994-4bd0-babf-20a3cc7bd3e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3423 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0575081 infores:hetionet CHEBI:82960 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1522133 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0021053 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0332575 infores:hetionet CHEBI:3441 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0423791 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0521839 infores:hetionet CHEBI:59773 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0022281 infores:hetionet CHEBI:5002 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0917801 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020507 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034067 infores:hetionet CHEBI:145499 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013447 infores:hetionet CHEBI:7789 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0027497 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0017178 infores:hetionet CHEBI:9448 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0744727 infores:hetionet CHEBI:4445 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0220981 infores:hetionet CHEBI:63612 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020621 infores:hetionet CHEBI:4445 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0036974 infores:hetionet GO:1905518 biolink:causes GO:0099054 infores:ubergraph knowledge_assertion manual_agent GO:1905518 GO:0099054 CHEBI:63620 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042594 infores:hetionet CHEBI:46295 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0033117 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0043241 infores:hetionet CHEBI:135925 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0018524 infores:hetionet NCBIGene:1474 biolink:causes MONDO:0032804 infores:monarchinitiative not_provided not_provided HGNC:2478 MONDO:0032804 uuid:5001b94d-561a-46c8-8c6a-0bbab52d9a28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0231528 infores:hetionet CHEBI:9605 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0027051 infores:hetionet CHEBI:68579 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151744 infores:hetionet NCBIGene:152110 biolink:causes MONDO:0032914 infores:monarchinitiative not_provided not_provided HGNC:18592 MONDO:0032914 uuid:d42de4b0-1a5a-4589-8811-b12923910e62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4911 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C3160947 infores:hetionet CHEBI:47381 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0036974 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151904 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0003123 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0031350 infores:hetionet CHEBI:585948 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0027497 infores:hetionet CHEBI:92998 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0013604 infores:hetionet CHEBI:75722 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0518988 infores:hetionet GO:1905902 biolink:causes GO:0048332 infores:ubergraph knowledge_assertion manual_agent GO:1905902 GO:0048332 CHEBI:9352 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0235290 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0155169 infores:hetionet CHEBI:45409 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027796 infores:hetionet CHEBI:52717 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011206 infores:hetionet CHEBI:61033 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0030196 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0029882 infores:hetionet CHEBI:101278 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0030193 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0020517 infores:hetionet CHEBI:15407 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0030232 infores:hetionet CHEBI:63632 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0026821 infores:hetionet CHEBI:31401 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0750394 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0235431 infores:hetionet CHEBI:15367 biolink:causes UMLS:C1611174 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1611174 infores:hetionet CHEBI:9667 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0340865 infores:hetionet CHEBI:52172 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0032227 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0948594 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019158 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0522224 infores:hetionet CHEBI:3640 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0022346 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027651 infores:hetionet CHEBI:63612 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0011991 infores:hetionet CHEBI:367163 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0043352 infores:hetionet CHEBI:4710 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152030 infores:hetionet CAID:CA512341235 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341235 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1194C>T (p.Ala398=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). Synonymous variant therefore no REVEL score and SpliceAI is ≤0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341235/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:499361 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013604 infores:hetionet CAID:CA1139665134 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665134 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PM5, PM4, PS1, BP7 The c.79_100del (p.Leu27fs) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 12/10/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665134/MONDO:0008723/021 2022-04-06 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63622 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0002622 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033575 infores:hetionet UMLS:C0879264 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0022346 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020517 infores:hetionet CHEBI:16755 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0019557 infores:hetionet CHEBI:28901 biolink:causes MONDO:0015129 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0001403 infores:hetionet CHEBI:6375 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0037763 infores:hetionet CHEBI:5098 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0002792 infores:hetionet CHEBI:3314 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0013378 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0022660 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027947 infores:hetionet CHEBI:15367 biolink:causes UMLS:C2721737 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2721737 infores:hetionet CHEBI:92998 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0019270 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002871 infores:hetionet CHEBI:31397 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0017160 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0033975 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0032961 infores:hetionet CHEBI:404903 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C2047937 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0031542 infores:hetionet CHEBI:63618 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0600142 infores:hetionet CHEBI:3223 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0015672 infores:hetionet CHEBI:17026 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0026821 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0162429 infores:hetionet UMLS:C0065374 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0023518 infores:hetionet CHEBI:4702 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0034642 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0439857 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0013186 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0013186 uuid:be18dafe-bd2b-4302-9518-97ba3c88db3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40237 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C2830004 infores:hetionet CHEBI:7581 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0030252 infores:hetionet CHEBI:5441 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0002170 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042571 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0019360 infores:hetionet CAID:CA16020832 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020832 MONDO:0009861 PMID:26322415PMID:30050108PMID:26322415 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PP3 The c.659A>C (p.His220Pro) variant in PAH has been reported in 3 individuals with MHP or classic PKU (BH4 deficiency excluded, PMID 26322415 ) detected in trans with pathogenic variant p.R241C in 2 patients (PMID: 30050108). This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020832/MONDO:0009861/006 2020-03-08 2020-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151529 infores:hetionet CHEBI:79699 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020443 infores:hetionet CHEBI:3242 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0018524 infores:hetionet NCBIGene:4035 biolink:causes MONDO:0958037 infores:monarchinitiative not_provided not_provided HGNC:6692 MONDO:0958037 uuid:f7f46658-ea4b-4a44-9685-0110b16dfb97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:8517 biolink:causes MONDO:0020740 infores:monarchinitiative not_provided not_provided HGNC:5961 MONDO:0020740 uuid:18ab5125-1e12-4d9c-a50f-0e056af4706c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1761613 infores:hetionet CHEBI:8382 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0235259 infores:hetionet CHEBI:49713 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0042024 infores:hetionet CHEBI:63581 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0004093 infores:hetionet CHEBI:474180 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0423791 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011616 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0032285 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020557 infores:hetionet CHEBI:4511 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151904 infores:hetionet CHEBI:6950 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0003811 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151547 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038454 infores:hetionet CHEBI:5847 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0039239 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0011630 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0542184 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0035455 infores:hetionet NCBIGene:9442 biolink:causes MONDO:0859137 infores:monarchinitiative not_provided not_provided HGNC:2377 MONDO:0859137 uuid:d5f36d39-fe5d-458b-a89f-1eaff1ada9f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0393760 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0549399 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0019158 infores:hetionet NCBIGene:79092 biolink:causes MONDO:0008251 infores:monarchinitiative not_provided not_provided HGNC:16446 MONDO:0008251 uuid:3b1e410d-eaa8-4685-9184-1b5e7f68bc41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0002792 infores:hetionet CHEBI:44915 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0033036 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018939 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0227791 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0178298 infores:hetionet CAID:CA346729443 biolink:causes MONDO:0005835 infores:clingen CAID:CA346729443 MONDO:0005835 PMID: Likely Pathogenic PVS1, PM2_Supporting PM5 The MSH2 c.2210+2T>C variant affects the donor consensus splicing site in intron 13. Exon 13 skipping is predicted to disrupt reading frame and undergo NMD (r.2006_2210del; p.Pro670Leufs*7). It is absent in GnomAD v2.1.1 non-cancer dataset and gnomAD v4.1. Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA346729443/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:61049 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009806 infores:hetionet NCBIGene:2243 biolink:causes MONDO:0008737 infores:monarchinitiative not_provided not_provided HGNC:3661 MONDO:0008737 uuid:390ae924-50ca-4eaf-9312-ac88e32a88ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0039520 infores:hetionet CHEBI:31711 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018944 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0017152 infores:hetionet CHEBI:3175 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0017178 infores:hetionet CHEBI:5551 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0012833 infores:hetionet CHEBI:17303 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0016382 infores:hetionet CHEBI:31176 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0085631 infores:hetionet CHEBI:7936 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0001925 infores:hetionet CHEBI:63791 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0016512 infores:hetionet CHEBI:4495 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0024103 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0178298 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0004936 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0233494 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042075 infores:hetionet NCBIGene:401 biolink:causes MONDO:0011181 infores:monarchinitiative not_provided not_provided HGNC:691 MONDO:0011181 uuid:be1981a3-1dc1-4ca0-b37a-89a3a66a92f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23154 biolink:causes MONDO:0859162 infores:monarchinitiative not_provided not_provided HGNC:17597 MONDO:0859162 uuid:c3ab0ce2-835d-4244-9380-b05468f09d6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31709 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0035078 infores:hetionet CHEBI:35854 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0033774 infores:hetionet UNII:R43D2573WO biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0016204 infores:hetionet NCBITaxon:1301 biolink:causes MONDO:0005972 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1301 MESH:D011018 DB00535_MESH_D011018_1DB00456_MESH_D011018_1DB00560_MESH_D011018_1DB00274_MESH_D011018_1DB01598_MESH_D011018_1DB00601_MESH_D011018_1DB01044_MESH_D011018_1 CAID:CA374989708 biolink:causes MONDO:0008535 infores:clingen CAID:CA374989708 MONDO:0008535 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PS4, PM5_Strong, PVS1_Strong The NM_001114753.3: c.2T>G variant in ENG may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID:12920067, 32300199, 15024723, ClinVar, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). Four different missense variants, c.3G>A, c.1A>T, c.2T>C, c.1A>G, in the same codon have been classified as pathogenic/likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PVS1_Strong, PS4, PP4_Moderate, PM5_Strong (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374989708/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4909 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0027051 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0039503 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011616 infores:hetionet CHEBI:4027 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0948441 infores:hetionet CHEBI:9907 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0010200 infores:hetionet CHEBI:9168 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018800 infores:hetionet CHEBI:18332 biolink:causes HP:0008441 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0014571 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0009806 infores:hetionet CHEBI:136040 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0028081 infores:hetionet CHEBI:31932 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0017979 infores:hetionet UMLS:C0004609 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0036690 infores:hetionet CHEBI:8597 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0039231 infores:hetionet CHEBI:6520 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0232462 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235416 infores:hetionet CAID:CA410206983 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206983 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting BP2, PM3, PP4 NM_001754.5(RUNX1):c.662T>G (p.Phe221Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206983/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31547 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0003862 infores:hetionet NCBIGene:2006 biolink:causes MONDO:0008504 infores:monarchinitiative not_provided not_provided HGNC:3327 MONDO:0008504 uuid:49ad7cef-cad1-4080-ba87-ee4df65a9859 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0948594 infores:hetionet CHEBI:6067 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0575081 infores:hetionet CHEBI:7959 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0003467 infores:hetionet CHEBI:3814 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0948594 infores:hetionet CHEBI:8356 biolink:causes HP:0001920 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0035067 infores:hetionet CHEBI:6402 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0004604 infores:hetionet CHEBI:9137 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013404 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003460 infores:hetionet GO:0097713 biolink:causes GO:0035269 infores:ubergraph knowledge_assertion manual_agent GO:0097713 GO:0035269 CHEBI:63620 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0035455 infores:hetionet CAID:CA229861 biolink:causes MONDO:0009861 infores:clingen CAID:CA229861 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PP3_Moderate, PS3_Supporting PM5, BP4, BS3 The NM_000277.3:c.938C>T variant in PAH is a missense variant predicted to cause substitution of alanine by valine at amino acid 313 (p.Ala313Val). This variant has been detected in at least 8 unrelated individuals with PAH deficiency (PMID: 32668217, PMID: 27121329, PMID: 33465300, PMID: 10234516, PMID: 23500595). Of these individuals, 6 were compound heterozygotes for the variant and pathogenic variants, p.Ala104Asp, c.1066-11G>A, p.Arg408Trp, p.Ex5del4232ins268, p.Gln267Ter, in unknown phase (PMID: 32668217, PMID: 27121329, PMID: 33465300) (3pts total, PM3_Strong). Of these individuals, two had plasma phenylalanine >120 μmol/L with the exclusion of a defect of BH4 cofactor metabolism (PP4_Moderate) (PMID: 10234516, PMID: 23500595). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In a PAH enzyme assay, this variant showed 32% (<50%) of wild-type PAH enzyme activity (PMID: 18590700) (PS3_Supporting). The computational predictor REVEL gives a score of 0.907 which is above the threshold of 0.75, evidence that correlates with impact to PAH function (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 102903, 1 star review status) with one submitter classifying the variant as pathogenic and one submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229861/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27974 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0011570 infores:hetionet CHEBI:9671 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0022660 infores:hetionet CHEBI:16347 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0015967 infores:hetionet CHEBI:28901 biolink:causes EFO:0008501 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0334044 infores:hetionet CHEBI:6801 biolink:causes UMLS:C1167654 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1167654 infores:hetionet CHEBI:46557 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0033687 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0948349 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0031117 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0234215 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0020517 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042075 infores:hetionet CHEBI:6538 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0042769 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0042769 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877097 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877097 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0475746 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0475746 infores:hetionet CHEBI:37941 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0002874 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042769 infores:hetionet CHEBI:17698 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0033774 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004936 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0030305 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0003469 infores:hetionet CHEBI:10023 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0004093 infores:hetionet CHEBI:6933 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0267792 infores:hetionet CAID:CA384884778 biolink:causes MONDO:0100038 infores:clingen CAID:CA384884778 MONDO:0100038 PMID: Likely Pathogenic PM5_Supporting, PM1, PM2_Supporting, PM6_Supporting, PP3_Moderate PM4, PVS1, PP1, BS2, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3 The NM_001330260.2:c.2534C>G variant in SCN8A is a missense variant predicted to cause substitution of serine by cysteine at amino acid 845 (p.Ser845Cys). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual meeting criteria for a complex neurodevelopmental disorder (PM6_Supporting; internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.882, which is above the threshold of 0.773, evidence that correlates with impact to SCN8A function (PP3_Moderate). Another missense variant (c.2534C>T (p.Ser845Phe), ClinVar Variation ID: 207109) in the same codon has been classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP (PM5_Supporting). This variant resides within a region, amino acids 844-852, of SCN8A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM1, PP3_Moderate, PM2_Supporting, PM5_Supporting, PM6_Supporting. (VCEP specifications version 2.0.0; approved 1/7/25). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA384884778/MONDO:0100038/070 2025-09-23 2025-09-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8888 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085635 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0160390 infores:hetionet CHEBI:9570 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0015230 infores:hetionet CHEBI:92712 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0023212 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0178298 infores:hetionet CHEBI:135530 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0011206 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0020538 infores:hetionet CHEBI:2704 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0392171 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0037199 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020619 infores:hetionet CHEBI:75045 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0231528 infores:hetionet CHEBI:6717 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0025289 infores:hetionet CHEBI:16755 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C1384353 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0403632 infores:hetionet CHEBI:2567 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0029443 infores:hetionet CHEBI:16347 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0004238 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0235763 infores:hetionet CHEBI:7931 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0019572 infores:hetionet CAID:CA343718550 biolink:causes MONDO:0005338 infores:clingen CAID:CA343718550 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.365G>C variant in MYOC is a missense variant predicted to cause substitution of Glycine by Alanine at amino acid 122 (p.Gly122Ala). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.064, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with JOAG or PCG had been reported (PMID: 37530275), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343718550/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:29013 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0232462 infores:hetionet CHEBI:93635 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0349506 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0029878 infores:hetionet CAID:CA5416777 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416777 MONDO:0011225 PMID: Likely Benign BS1, BS2_Supporting PM2 The c.572G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Glutamine at amino acid 191 (p.Arg191Gln).The filtering allele frequency (the upper threshold of the 95% CI of 4/91084 alleles) of the c.572G>A variant in DCLRE1C is 0.00001425 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting. However, 2 homozygous individuals have been reported in the Middle Eastern population: 18/6062 alleles, freq: 0.002969. Therefore, PM2 is not applicable, and BS2 is met at the Supporting level (BS2_Supporting).The Middle Eastern population: 18/6062 alleles, freq: 0.002969, meet the BS1 threshold (>0.00078), so BS1 is met.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2_Supporting and BS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416777/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:84433 biolink:causes MONDO:0054697 infores:monarchinitiative not_provided not_provided HGNC:16393 MONDO:0054697 uuid:0d5d7983-5f4c-4558-884b-caa0964314a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0027051 infores:hetionet NCBIGene:11232 biolink:causes MONDO:0012415 infores:monarchinitiative not_provided not_provided HGNC:9180 MONDO:0012415 uuid:af4dccd7-9205-446c-a3e5-67ab852a757b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020615 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0021400 infores:hetionet CHEBI:8694 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0013395 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C3665596 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0235431 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0860239 infores:hetionet CHEBI:4466 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020458 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151955 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151955 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0242350 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0277925 infores:hetionet CAID:CA036837 biolink:causes MONDO:0007750 infores:clingen CAID:CA036837 MONDO:0007750 PMID: Likely Benign BP4, BP7 BA1, BS1 The NM_000527.5(LDLR):c.1836C>T (p.Ala612=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence code BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.- Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT.- There is a GT nearby.MES scores: variant cryptic = -16.82, wt cryptic = -12.61, canonical donor = 4.48.Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9Variant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036837/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:134991 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0037036 infores:hetionet CHEBI:10127 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0023518 infores:hetionet CHEBI:10119 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0242422 infores:hetionet CHEBI:4856 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C1145670 infores:hetionet CHEBI:17347 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0012569 infores:hetionet CHEBI:4453 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0000737 infores:hetionet CHEBI:7825 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0011603 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005520 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0035579 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0860207 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152029 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0149904 infores:hetionet NCBIGene:1289 biolink:causes MONDO:0859151 infores:monarchinitiative not_provided not_provided HGNC:2209 MONDO:0859151 uuid:2e2734ee-c639-4bae-bf0f-b15eaa1a7312 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0003467 infores:hetionet CHEBI:40050 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0011603 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0026848 infores:hetionet CHEBI:31709 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0020550 infores:hetionet CAID:CA314780 biolink:causes MONDO:0012999 infores:clingen CAID:CA314780 MONDO:0012999 PMID: Uncertain Significance PM2, BP4 The NM_000156.6:c.331A>C variant in GAMT is a missense variant predicted to cause the substitution of an isoleucine by a leucine at amino acid position 111 (p.Ile111Leu). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0003566 (16/44870 alleles) in the East Asian population, which is lower than the CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.215 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205566). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314780/MONDO:0012999/026 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:46557 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0029408 infores:hetionet CHEBI:5864 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1145670 infores:hetionet CHEBI:51364 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0041105 infores:hetionet GO:0070808 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0070808 GO:0061458 CHEBI:5004 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0012569 infores:hetionet CHEBI:6909 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0004134 infores:hetionet CHEBI:2950 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0018681 infores:hetionet CHEBI:63610 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0039070 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0575090 infores:hetionet CHEBI:18248 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0018965 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019348 infores:hetionet NCBIGene:23321 biolink:causes MONDO:0014208 infores:monarchinitiative not_provided not_provided HGNC:15974 MONDO:0014208 uuid:8a47a347-5f7e-4918-bf94-894c2f1d7669 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68642 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0151849 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0032961 infores:hetionet CHEBI:9150 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0234233 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0243026 infores:hetionet CHEBI:168396 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151766 infores:hetionet CHEBI:4511 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0231528 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1608954 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1608954 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0542184 infores:hetionet CAID:CA2499226690 biolink:causes MONDO:0100437 infores:clingen CAID:CA2499226690 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.2420_2435del (p.Glu807GlyfsTer3) is a frameshift variant due to 16-nucleotide deletion starting in codon 807, introducing a premature stop codon after 3 amino acids in exon 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 24938718, 36445968, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499226690/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:63599 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0152032 infores:hetionet CHEBI:4027 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0030193 infores:hetionet CHEBI:31236 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0686347 infores:hetionet CHEBI:4909 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0025289 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0018801 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0003123 infores:hetionet CHEBI:7444 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0009806 infores:hetionet CHEBI:5790 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0000731 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0038454 infores:hetionet CHEBI:32315 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085593 infores:hetionet CHEBI:71219 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0034155 infores:hetionet CHEBI:9649 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0041657 infores:hetionet CHEBI:63581 biolink:causes UMLS:C1142357 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1142357 infores:hetionet CHEBI:27899 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C3160858 infores:hetionet CHEBI:2654 biolink:causes MONDO:0000088 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0034013 infores:hetionet CHEBI:10119 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018800 infores:hetionet CHEBI:2663 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C2047937 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0856554 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0856554 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0021400 infores:hetionet CHEBI:3310 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0042963 infores:hetionet CHEBI:63619 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0035078 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027651 infores:hetionet CHEBI:16586 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0013404 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0042373 infores:hetionet CAID:CA410208227 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208227 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.40C>T (p.Pro14Ser) is a missense variant which has a REVEL score < 0.50 (0.32) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208227/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63619 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030920 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0020625 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0020651 infores:hetionet CHEBI:4975 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0030193 infores:hetionet CHEBI:8382 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0019572 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0012833 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0243026 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0006145 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0029882 infores:hetionet CHEBI:6129 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014236 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002418 infores:hetionet CHEBI:87681 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0030252 infores:hetionet CAID:CA297121 biolink:causes MONDO:0021060 infores:clingen CAID:CA297121 MONDO:0021060 PMID: Uncertain Significance BS2 PS4, BS1, PM1, PP2, BP4, BP1 The c.835G>A (p.Asp279Asn) variant in RAF1 has been identified in 0.01786% (lower bound of the 95% CI of 7/18394) of East Asian chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. It was also seen in 13 individuals clinically unaffected with a RASopathy (BS2; GeneDx internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297121/MONDO:0021060/004 2019-09-24 2019-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:142290 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0023473 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151828 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0004238 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0016397 infores:hetionet CHEBI:45081 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151723 infores:hetionet CAID:CA915940224 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940224 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting, PM3_Supporting PP4 The NM_000419.5(ITGA2B):c.409-3C>G intronic variant was identified in a patient with a clinical diagnosis of GT, but insufficient information to be highly specific, and is predicted to impact splicing through loss of an acceptor site. Splicing was predicted to be impacted with the loss of an acceptor site by Splice AI (0.72) and varSEAK (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was homozygous in the reported individual (Patient 8, PMID: 31029159) with a clinical diagnosis of GT. Since this was a homozygous occurrence and this variant was not seen in the literature elsewhere; per SVI recommendations this receives 0.5pt since this variant has a MAF of <0.0001 (PM3_Supporting). This variant was identified as heterozygous in parents and not homozygous in healthy individuals in the family. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_Supporting, PP3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940224/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:180905 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0018681 infores:hetionet CHEBI:9168 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151578 infores:hetionet UMLS:C0010592 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0026821 infores:hetionet CAID:CA10605474 biolink:causes MONDO:0015152 infores:clingen CAID:CA10605474 MONDO:0015152 PMID: Uncertain Significance PVS1_Moderate, PM2_Supporting PS1, PS3, BP5, BS1, BS3, PM5, PM4, PM1, PM3, PP2, PP3, BP1, BP4, BP3, BA1 The NM_213599.3: c.139-1del variant in ANO5 occurs within the canonical splice acceptor site (-1, -2 dinucleotide) of intron 3. It is predicted to cause skipping of biologically relevant exon 4/22, resulting in an in-frame deletion of exon 4 (42 amino acids) and premature truncation of <10% the protein (PVS1_Moderate). This variant has been observed in the heterozygous state in at least five individuals with a clinical suspicion of LGMD, but no other variants in ANO5 were identified in these individuals (PMID: 30564623; ClinVar SCV000570206.4 internal data communication, ClinVar SCV000933284.6 internal data communication) (PM3 not met). The filtering allele frequency of this variant is 0.000031407 (the upper threshold of the 95% CI of 25/1111726 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, due to the limited evidence available, this variant is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605474/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10119 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0024236 infores:hetionet CAID:CA410207973 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207973 MONDO:0011071 PMID: Likely Pathogenic PM5, PM1, PM2_Supporting, PS4_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.593A>G (p.Asp198Gly) is a missense variant that affects a hotspot residue within the Runt Homology Domain: D198 (PM1). This variant is at the same residue (p.Asp198) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 627342) based on MM-VCEP rules for RUNX1 and RNA data (PM5). This variant does not have an available REVEL score, but multiple other predictors (SIFT,PolyPhen2-HDIV, PolyPhen2-HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, MetaLR, FATHMM-MKL) predict a deleterious impact (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID: 28855357, SCV005332537.1) (PS4_ Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5,PP3, PM2_Supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207973/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28901 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0002874 infores:hetionet CHEBI:65173 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0085631 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0027707 infores:hetionet CHEBI:4798 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0033774 infores:hetionet CHEBI:64355 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036974 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020456 infores:hetionet CHEBI:478164 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0021368 infores:hetionet CHEBI:75722 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027424 infores:hetionet CHEBI:7865 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0233407 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0553732 infores:hetionet CHEBI:3013 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C1368065 infores:hetionet CHEBI:724125 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0013595 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0948282 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0948282 infores:hetionet CHEBI:31980 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0006266 infores:hetionet CHEBI:8871 biolink:causes HP:0002533 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0231471 infores:hetionet CHEBI:10110 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0085593 infores:hetionet CHEBI:231594 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0019112 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016053 infores:hetionet CHEBI:6539 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0852911 infores:hetionet NCBIGene:148789 biolink:causes MONDO:0014071 infores:monarchinitiative not_provided not_provided HGNC:28596 MONDO:0014071 uuid:10a3dee3-82ed-4a7a-952e-62b000a9271d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0042571 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0008325 infores:hetionet CHEBI:119573 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0518988 infores:hetionet CHEBI:4975 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0206061 infores:hetionet CHEBI:6775 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0234233 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0022660 infores:hetionet CHEBI:110423 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0031350 infores:hetionet CHEBI:7936 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039591 infores:hetionet CHEBI:3756 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0014394 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0152025 infores:hetionet CHEBI:10102 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013404 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0015397 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0031350 infores:hetionet CAID:CA222801 biolink:causes MONDO:0010726 infores:clingen CAID:CA222801 MONDO:0010726 PMID: Benign BA1 BP4, PM1 The allele frequency of the p.Ala439Ser variant in MECP2 (NM_004992.3) is 0.04208% in the African/African-American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Ala439Ser variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222801/MONDO:0010726/036 2022-10-11 2024-03-13 X-linked inheritance HP:0001417 Contradicts true CHEBI:6375 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0028259 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002878 infores:hetionet CHEBI:28918 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0042510 infores:hetionet CHEBI:75984 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0004245 infores:hetionet CAID:CA386953149 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953149 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BS3_Supporting PM5, PP4 The c.140G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to glutamate at codon 47 (p.(Gly47Glu)) of NM_000545.8. Functional studies demonstrated the p.Gly47Arg protein has normal nuclear localization and transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 12574234) (BS3_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.139G>C (p.(Gly47Arg)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PP4 cannot be applied (PMID: 12574234, internal lab contributor). In summary, c.140G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): BS3_Supporting, PM2_supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953149/MONDO:0015967/017 2022-04-02 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA202389 biolink:causes MONDO:0100438 infores:clingen CAID:CA202389 MONDO:0100438 PMID:27268253 Benign BS2, BA1, PP3_Moderate BS3 NM_014336.5(AIPL1):c.401A>T (p.Tyr134Phe) is a missense variant in exon 3 of 6 that is predicted to replace tyrosine with phenylalanine at amino acid p.134. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.006905, with 8,298 alleles / 1,180,030 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). It has also been found in the homozygous state in 49 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.845, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing. The variant exhibited >90% enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, as well as cytoplasmic and nuclear localization similar to the wild-type (PMID: 27268253), however, these assays are not approved to meet BS3_Supporting. In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA202389/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63629 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0006852 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0014335 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0026946 infores:hetionet CHEBI:35854 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0011991 infores:hetionet CHEBI:36791 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011175 infores:hetionet CHEBI:6704 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0015230 infores:hetionet CHEBI:6715 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013378 infores:hetionet CHEBI:8346 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0018790 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0019193 infores:hetionet CHEBI:63631 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0393760 infores:hetionet CAID:CA10014364 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014364 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS3, PS1, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.743A>C (p.Asn248Thr) is a missense variant. This variant is present in two alleles in the South Asian population at a MAF of 0.0065% in gnomAD v2.1.1. This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (Thrombocytopenia) (PS4_supporting). This missense variant has a REVEL score <0.50 (0.213) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014364/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6128 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0085932 infores:hetionet CHEBI:7956 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0233407 infores:hetionet CHEBI:135736 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085636 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151505 infores:hetionet CHEBI:50692 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0151786 infores:hetionet CHEBI:135930 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0002962 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0553690 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0553690 infores:hetionet CHEBI:6078 biolink:causes HP:0034751 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0578736 infores:hetionet CHEBI:7956 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0013390 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0022660 infores:hetionet CHEBI:2675 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0013378 infores:hetionet CHEBI:4530 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0001824 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042075 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020550 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1269683 infores:hetionet CAID:CA10653564 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653564 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.*1455A>G is 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). No clinical or functional data for this variant has been reported to our knowledge. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653564/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004604 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235889 infores:hetionet CHEBI:8874 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0234133 infores:hetionet CHEBI:6801 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0162275 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0178298 infores:hetionet CAID:CA229471 biolink:causes MONDO:0009861 infores:clingen CAID:CA229471 MONDO:0009861 PMID:10234516PMID:10234516PMID:27121329 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PP3 The c.183C>G (p.Asn61Lys) variant in PAH has been reported in 3 individuals with mild hyperphenylalaninaemia and mild PKU (BH4 deficiency excluded). (PMID: 10234516, 27121329). This variant is at extremely low frequency in ExAC: MAF=0.00017. This variant was detected with pathogenic variants p.R176L, IVS1nt5G>T (c.60+5G>T) and IVS10-11G>A (PMID: 10234516, 27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229471/MONDO:0009861/006 2020-04-10 2020-04-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64312 biolink:causes HP:0032553 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0232132 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042109 infores:hetionet CHEBI:47612 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0030312 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0040034 infores:hetionet CHEBI:3347 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0013404 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0233479 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0233479 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011991 infores:hetionet CHEBI:5893 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085649 infores:hetionet GO:2000006 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000006 GO:0072001 CHEBI:63791 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030305 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0006266 infores:hetionet CHEBI:38545 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0687133 infores:hetionet CHEBI:4659 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C2830004 infores:hetionet CAID:CA222170 biolink:causes MONDO:0015152 infores:clingen CAID:CA222170 MONDO:0015152 PMID: Likely Pathogenic PM3_Strong, PP3, PP4, PM2_Supporting PM5, PS3, BP2, PP1 The NM_003494.4: c.4439A>C variant in DYSF, which is also known as NM_001130987.2: c.4556A>C p.(Lys1519Thr), is a missense variant predicted to cause the substitution of lysine for threonine at amino acid position 1480, p.(Lys1480Thr). This variant has been reported in at least nine individuals with features consistent with LGMD, including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.3618C>G p.(Tyr1206Ter), 1.0 pt x2, PMID: 30919934, 15827562; LOVD Individual #00215274) (PM3_Strong). It has also been reported in a homozygous state in at least six patients who were also homozygous for NM_003494.4: c.4060_4062del p.(Ser1354del), indicating these two variants occur in cis (PMID: 30564623; PMID: 36983702; LOVD Individual #00219454; LOVD Individual #00222227; Jain Foundation Dysferlin Registry internal data communication). At least one patient was also reported to carry the c.4439A>C p.(Lys1480Thr) and c.4060_4062del p.(Ser1354del) variants in a compound heterozygous state (LOVD Individuals #00215628, #00215714). At least one patient with this variant and a second presumed diagnostic DYSF variant (NM_003494.4: c.3618C>G p.(Tyr1206Ter)) displayed progressive limb girdle muscle weakness (PP4; PMID: 30919934; PMID: 15827562). The highest minor allele frequency for this variant in gnomAD v4.1.0 exomes is 0.00002337 in the South Asian population (2/85572 chromosomes), which is less than the LGMD VCEP threshold of 0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025): PM3_Strong, PP4, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222170/MONDO:0015152/180 2025-04-22 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030662 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0700184 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0426732 infores:hetionet CHEBI:63605 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0003862 infores:hetionet CHEBI:2682 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232462 infores:hetionet NCBIGene:7388 biolink:causes MONDO:0859321 infores:monarchinitiative not_provided not_provided HGNC:12590 MONDO:0859321 uuid:ff73a79c-1acd-4493-a627-31ffd65105b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0005874 biolink:causes GO:0007017 infores:ubergraph knowledge_assertion manual_agent GO:0005874 GO:0007017 CHEBI:43968 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C1609512 infores:hetionet NCBIGene:472 biolink:causes MONDO:0008840 infores:monarchinitiative not_provided not_provided HGNC:795 MONDO:0008840 uuid:38eecf27-df6f-4347-bc5c-684d51700276 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes MONDO:0006716 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0010072 infores:hetionet CHEBI:46557 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0015672 infores:hetionet CHEBI:5790 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0011124 infores:hetionet CAID:CA221620 biolink:causes MONDO:0018214 infores:clingen CAID:CA221620 MONDO:0018214 PMID: Likely Benign PP3_Moderate, BS1 PM2, PM6, BA1, PS4, PS2, PS1, PM1, PM5 The c.83G>A variant in SCN1A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 28 (p.Arg28His). The variant has been identified in 4 individuals with seizures with variable ages of onset, inconsistent segregation patterns and/or in the presence of variants in other epilepsy-associated genes (PMID:36801247; internal data, Invitae. PS4_not met). A novel missense variant at the same position in SCN1A (p.R28C) has been previously reported, in addition to missense variants at the corresponding position in a paralogous gene (SCN2A: p.R28C & p.R28H), however, none of these variants met PLP classification per these criteria (PS1_not met; PM5_not met). The variant is present at a relatively high frequency (0.0006%, 7 alleles) in non-Finnish European population in gnomAD v4.1 (BS1). It was also identified in multiple individuals referred for testing for non-neurological indications for which an alternative genetic diagnosis was identified (internal data, GeneDx). The computational predictor REVEL gives a score of 0.83, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BS1, PP3_Moderate (version 1.0, approved August 27, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA221620/MONDO:0018214/067 2024-09-03 2024-11-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6887 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0236124 infores:hetionet CAID:CA2573334965 biolink:causes MONDO:0100216 infores:clingen CAID:CA2573334965 MONDO:0100216 PMID: Likely Pathogenic PP3, PP1, PP4, PS4_Supporting, PM2_Supporting, PS3 BA1, BP4, BP2, PM1, PS2, BS1, BS3, BP7 The NM_177438.2:c.1752+213A>G variant in DICER1 is an intronic variant located 213 base pairs downstream of exon 10. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 37883719). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing (PMID: 37883719), which is highly specific for DICER1 syndrome (PP4, PMID: 34398502). The variant has been reported to segregate with DICER1-spectrum tumors in 3 meioses from 1 family (PP1; PMID: 37883719). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an in-frame splicing impact resulting in a premature stop codon and NMD, indicating that this variant impacts protein function (PS3; Invitae, UT Southwestern). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1, PM2_Supporting, PS3, PP3, (Bayesian Points: 9; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573334965/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16617781 biolink:causes MONDO:0008667 infores:clingen CAID:CA16617781 MONDO:0008667 PMID: Likely Benign BS2_Supporting, BS1 PS4 The variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16617781/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0060651 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060651 GO:0007275 CHEBI:32221 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0403632 infores:hetionet CHEBI:135285 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0178298 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0948586 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020517 infores:hetionet CHEBI:8888 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0012569 infores:hetionet CHEBI:7824 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0033687 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0016436 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020676 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0009144 infores:hetionet UNII:9430ZR8ZAN biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0233407 infores:hetionet CAID:CA405689929 biolink:causes MONDO:0018493 infores:clingen CAID:CA405689929 MONDO:0018493 PMID: Likely Pathogenic PM1_Supporting, PS4_Moderate, PP3_Moderate, PM5_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with valine at codon 539 of the RYR1 protein, p.(Phe539Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, The UK (Leeds) MH Unit). No functional studies were identified for this variant. Another variant assessed as likely pathogenic occurs at this codon, p.(Phe539Leu), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.937) supports a pathogenic status for this variant, PP3_Moderate. This variant is assessed as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405689929/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6717 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0243026 infores:hetionet CHEBI:53691 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0162297 infores:hetionet CHEBI:50648 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0424489 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853760 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151763 infores:hetionet CHEBI:66913 biolink:causes UMLS:C1696574 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C1696574 infores:hetionet CHEBI:109549 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0015672 infores:hetionet CHEBI:4907 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0017675 infores:hetionet CAID:CA399805691 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805691 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The c.574+1G>A variant on ITGA2B is a canonical splice donor variant located in intron 4 and predicted to cause skipping of exon 4. It is present in very low frequencies (0.001%) in large population databases (gnomAD). This variant has been previously reported in at least one individual who meets diagnostic criteria of for the GT phenotype. This variant meets GT specific criteria for PVS1, PP4_strong and PM2_supporting, and is therefore classified as Pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805691/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4814 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0151474 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020507 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0518015 infores:hetionet NCBIGene:818 biolink:causes MONDO:0032795 infores:monarchinitiative not_provided not_provided HGNC:1463 MONDO:0032795 uuid:d40c6d64-f858-47e8-b91f-29e20b1f904b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0035410 infores:hetionet CHEBI:37941 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0008031 infores:hetionet CAID:CA229570 biolink:causes MONDO:0009861 infores:clingen CAID:CA229570 MONDO:0009861 PMID:9634518PMID:1307609PMID:10429004PMID:23430918PMID:14681498 Pathogenic PP4_Moderate, PM2, PP3, PS3, PM3_Strong PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229570/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:54499 biolink:causes MONDO:0800436 infores:monarchinitiative not_provided not_provided HGNC:18188 MONDO:0800436 uuid:8c26a781-1ad1-4b36-b95d-fd326543ec4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0040261 infores:hetionet CHEBI:2618 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0013595 infores:hetionet CHEBI:6129 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0740394 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042109 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0423271 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0423271 infores:hetionet CAID:CA327914093 biolink:causes MONDO:0100437 infores:clingen CAID:CA327914093 MONDO:0100437 PMID: Benign BA1 BP4 NM_001034853.2(RPGR):c.*233A>C is a variant in the 3' untranslated region of the RPGR gene. This variant is present in gnomAD v4.1.0 at a frequency of 0.06327 among hemizygous individuals, with 20,369 variant alleles / 321,928 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing. However, BP4 is not considered applicable to 3' UTR variants in RPGR, so this code was not met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327914093/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:5165 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151889 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0034150 infores:hetionet CHEBI:5109 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0162835 infores:hetionet CHEBI:5088 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0233494 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0013404 infores:hetionet CHEBI:3219 biolink:causes EFO:0011023 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006107 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0021400 infores:hetionet CHEBI:64064 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0026837 infores:hetionet NCBIGene:7139 biolink:causes MONDO:0011095 infores:monarchinitiative not_provided not_provided HGNC:11949 MONDO:0011095 uuid:b272bef7-c8d2-43dd-8f89-1d8ac45ec80e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9430ZR8ZAN biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0017178 infores:hetionet CAID:CA16020752 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020752 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting BP2 The NM_000277.3(PAH):c.226G>T (p.Glu76Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP (PM2_supporting). The variant has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID: 17096675) with BH4 deficiency not noted to have been formally excluded (PP4), in cis with the c.1089delG variant (ClinVar Pathogenic, see ID 102518). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020752/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039520 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0009319 infores:hetionet CHEBI:10110 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0231530 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0497247 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0548823 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0575090 infores:hetionet CHEBI:8802 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0427086 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0948089 infores:hetionet CHEBI:3723 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1291077 infores:hetionet CAID:CA145980 biolink:causes MONDO:0009861 infores:clingen CAID:CA145980 MONDO:0009861 PMID:23690520 Benign BA1 PP4, BP4 PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.44942 in ExAC. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA145980/MONDO:0009861/006 2019-02-26 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63617 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0699893 infores:hetionet CHEBI:63631 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020473 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235025 infores:hetionet NCBITaxon:11086 biolink:causes MONDO:0005829 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11086 MONDO:0005829 CHEBI:8888 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0043094 infores:hetionet CHEBI:31644 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0025874 infores:hetionet CHEBI:3082 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0015672 infores:hetionet CHEBI:135961 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0030193 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042035 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030567 infores:hetionet CHEBI:27899 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0013604 infores:hetionet CHEBI:6541 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0014591 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0521839 infores:hetionet UMLS:C0145867 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0008031 infores:hetionet CHEBI:465284 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003537 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0851341 infores:hetionet CHEBI:50742 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0014742 infores:hetionet CHEBI:63629 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0040264 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0270458 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151828 infores:hetionet CHEBI:119573 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0003862 infores:hetionet CHEBI:5134 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0013604 infores:hetionet CHEBI:9637 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0011603 infores:hetionet CHEBI:3380 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0004134 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020550 infores:hetionet CHEBI:2453 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0424489 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018939 infores:hetionet CHEBI:50173 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0424790 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0020517 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0877690 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0877690 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0162316 infores:hetionet CHEBI:7494 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0233477 infores:hetionet CHEBI:10124 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151825 infores:hetionet CHEBI:119486 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151825 infores:hetionet CHEBI:2682 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0037763 infores:hetionet CHEBI:5613 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0151766 infores:hetionet CHEBI:31401 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0020453 infores:hetionet CHEBI:7824 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0039231 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0948594 infores:hetionet CAID:CA273113 biolink:causes MONDO:0009861 infores:clingen CAID:CA273113 MONDO:0009861 PMID:23764561PMID:26666653 Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong The c.204A>T (p.Arg68Ser) variant in PAH was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). It was detected in trans with several pathogenic variants including p.Ala300Ser, p.Asp415Asn, p.Arg158Gln, and c.1315+1G>A (PMID 27121329, 22841515). This variant was found in low frequency in gnomAD (MAF=0.00016) and was predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3 very strong, PM2, PP4 Moderate, and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273113/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes UMLS:C0233479 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233479 infores:hetionet CHEBI:16714 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0039231 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030807 infores:hetionet GO:2000101 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:2000101 GO:0030879 CHEBI:5779 biolink:causes EFO:0009618 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0272774 infores:hetionet CHEBI:8874 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1527344 infores:hetionet CHEBI:4885 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0040034 infores:hetionet CHEBI:6792 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0009024 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0232492 infores:hetionet CHEBI:31643 biolink:causes UMLS:C0151588 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0151588 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0020569 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0007869 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0027947 infores:hetionet CHEBI:37941 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0041582 infores:hetionet CHEBI:6775 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0017181 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0027051 infores:hetionet CHEBI:8863 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0242184 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0158687 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0158687 infores:hetionet CHEBI:101853 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042164 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0006852 infores:hetionet CHEBI:5062 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0015230 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0018802 infores:hetionet NCBIGene:154881 biolink:causes MONDO:0012721 infores:monarchinitiative not_provided not_provided HGNC:21957 MONDO:0012721 uuid:d6470335-d7dd-4c27-a8d6-5a764756ef85 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA294379 biolink:causes MONDO:0007648 infores:clingen CAID:CA294379 MONDO:0007648 PMID: Benign BS2, BP2_Strong BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BA1, PS1, PS3, PS2, PS4 The c.2399G>A (p.Arg800His) variant has an allele frequency of 0.00003 (0.003%, 1/30,614 alleles) in the South Asian gnomAD subpopulation (http://gnomad.broadinstitute.org). The variant has been seen in >10 individuals without DCG, SRC tumors, or LBC and whose families do notsuggest HDGC (BS2; PMID: 26072394, SCV000186429.5, SCV000210876.13, SCV000254822.4). The variant has been identified in the homozygous state in an individual without personal and family history of DGC, LBC, or SRC tumors (BP2_Strong; SCV000186429.5). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294379/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:93635 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0037317 infores:hetionet CAID:CA410148319 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148319 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1054G>A (p.Ala352Thr) is a missense variant which has a REVEL score < 0.50 (0.083) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148319/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4356 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0030193 infores:hetionet NCBIGene:149775 biolink:causes MONDO:0011301 infores:monarchinitiative not_provided not_provided HGNC:24872 MONDO:0011301 uuid:ef677f19-bb38-4882-b744-ca42f6aa1025 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0034150 infores:hetionet CHEBI:404903 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0026821 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0023530 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0162429 infores:hetionet CHEBI:4903 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0011603 infores:hetionet CHEBI:40303 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0015230 infores:hetionet CHEBI:3441 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020433 infores:hetionet CHEBI:7865 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0547030 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0232492 infores:hetionet CHEBI:9448 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0013447 infores:hetionet CHEBI:3756 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013604 infores:hetionet CHEBI:77260 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085632 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0006277 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020651 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011991 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0585186 infores:hetionet CHEBI:75988 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0030312 infores:hetionet CHEBI:5855 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1142412 infores:hetionet CHEBI:71028 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0015967 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0003864 infores:hetionet CHEBI:3504 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0033774 infores:hetionet CHEBI:72296 biolink:causes UMLS:C3203457 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C3203457 infores:hetionet CHEBI:7789 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0004093 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0235818 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0004096 infores:hetionet CHEBI:87681 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0428977 infores:hetionet CHEBI:45716 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0020621 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0002871 infores:hetionet CHEBI:61033 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0040053 infores:hetionet CHEBI:7514 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0000737 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0011849 infores:hetionet CHEBI:87681 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0151878 infores:hetionet CHEBI:27834 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0041657 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0010692 infores:hetionet CAID:CA10640432 biolink:causes MONDO:0015967 infores:clingen CAID:CA10640432 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 The c.327-14T>C variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within intron 1 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Also, the computational splicing predictor SpliceAI gives a score of 0.00 for acceptor loss, suggesting that the variant has no impact on splicing (BP4). In summary, c.327-14T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10640432/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:11093 biolink:causes MONDO:0010122 infores:monarchinitiative not_provided not_provided HGNC:1366 MONDO:0010122 uuid:4ebbc0d2-315e-4ce4-8313-37d4fcc3dde9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA902618 biolink:causes MONDO:0100368 infores:clingen CAID:CA902618 MONDO:0100368 PMID: Likely Benign BP4, BP7 The NM_000329.3(RPE65):c.94+10G>A variant is a noncanonical splice variant in RPE65. The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This intronic variant at position c.94+10 is located outside of the donor/acceptor +/-1,2 dinucleotide positions and so also meets BP7 (BP7). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00006, with 6/90966 alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002. This rule was not applied because the variant meets criteria for a benign classification and the rarity of the variant should not outweigh other types of benign evidence. In summary, this variant meets the criteria to be classified as Likely Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BP4, BP7 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902618/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6640 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0020649 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0860866 infores:hetionet CHEBI:10119 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0231530 infores:hetionet CHEBI:63598 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085636 infores:hetionet CAID:CA414782018 biolink:causes MONDO:0044970 infores:clingen CAID:CA414782018 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PS4, PS3 The m.6145G>A (p.Trp81Ter) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease however clinical details were not provided (PMID: 32652755). The variant was present at 61.7% in skeletal muscle. This variant results in a truncation of more than 80% of the protein (PVS1_strong). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414782018/MONDO:0044970/015 2024-10-28 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4445 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0080203 infores:hetionet CHEBI:5775 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0042384 infores:hetionet CHEBI:6904 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0006145 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0022362 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022362 infores:hetionet CHEBI:100241 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0338831 infores:hetionet CHEBI:28915 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C2240374 infores:hetionet CHEBI:48390 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0030196 infores:hetionet CHEBI:42797 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037672 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1142412 infores:hetionet CHEBI:31644 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0018965 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0021400 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0948089 infores:hetionet CHEBI:64354 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0687713 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020456 infores:hetionet CHEBI:7931 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0678222 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0036508 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0021843 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018801 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0018801 infores:hetionet CHEBI:5893 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0039240 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0018099 infores:hetionet UMLS:C0903898 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0042963 infores:hetionet CHEBI:3213 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0040034 infores:hetionet CAID:CA10014226 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014226 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.994G>T (p.Asp332Tyr) is a missense variant which has a REVEL score < 0.50 (0.411), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014226/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5959 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020458 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0027051 infores:hetionet CHEBI:3077 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0231528 infores:hetionet CHEBI:31638 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0018681 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001650 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0149523 infores:hetionet CHEBI:45599 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0030554 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032285 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235416 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0541947 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0541947 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0042109 infores:hetionet CHEBI:28177 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0687713 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0233494 infores:hetionet CHEBI:125354 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0027765 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0262397 infores:hetionet GO:0010082 biolink:causes GO:0048364 infores:ubergraph knowledge_assertion manual_agent GO:0010082 GO:0048364 CHEBI:9943 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085632 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020542 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0007097 infores:hetionet CHEBI:6887 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151766 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0277925 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0037199 infores:hetionet CHEBI:47426 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0005758 infores:hetionet CHEBI:45599 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0013404 infores:hetionet GO:1904910 biolink:causes GO:0006403 infores:ubergraph knowledge_assertion manual_agent GO:1904910 GO:0006403 CAID:CA226054 biolink:causes MONDO:0100453 infores:clingen CAID:CA226054 MONDO:0100453 PMID: Pathogenic BP2, PM3_Strong, PP1_Strong, PS3_Supporting, PP4, PM2_Supporting PP3 NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) is a missense variant predicted to replace phenylalanine with serine at position p.565. This variant is present in gnomAD v4.1.0 at a total allele frequency of 6.197e-7, with 1 allele / 1613704 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in a homozygous proband with early-onset severe retinal dystrophy in cis with the NM_000180.4(GUCY2D):c.2633_2636del (p.Gln878ArgfsTer17) variant, which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (VCEP member-provided data, BP2). This variant has also been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 8944027), and in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the variant confirmed in trans with the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant (1 pt, PMID: 16505055), which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). Please note that one of these patients has been genotyped in a way that did not rule out the presence or absence of another GUCY2D variant in cis (PMID: 16505055). This proband exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset at 3 months (1 pt), night blindness (0.5 pts), nystagmus (1 pt), and visual acuity limited to light perception (1 pt), which together are specific for GUCYD2-related recessive retinopathy (total 4 pts, PMID: 16505055, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 3 similarly affected relatives in two different families, with the variant present in the homozygous state (PMID: 8944027, PP1_Strong). The computational predictor REVEL gives a score of 0.494, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 protein function. The variant exhibited inability to be stimulated by GCAP1 (PMID: 9888789), reduced RD3 binding by co-immunoprecipitation (PMID: 25477517), and failure to localize to the plasma membrane along with RD3 and GCAP1 when exogenously expressed (PMID: 25477517), indicating that it triggers a severe defect in protein function (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1_Strong, PP4, and BP2. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226054/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:101278 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0233494 infores:hetionet GO:0031383 biolink:causes GO:0000753 infores:ubergraph knowledge_assertion manual_agent GO:0031383 GO:0000753 CHEBI:8802 biolink:causes NCIT:C9271 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0919726 infores:hetionet CHEBI:17688 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0003537 infores:hetionet CHEBI:9667 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0231528 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0001824 infores:hetionet NCBIGene:2773 biolink:causes MONDO:0011234 infores:monarchinitiative not_provided not_provided HGNC:4387 MONDO:0011234 uuid:0cf6f9a7-a01d-4b89-b065-a3467fa4aa8b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5132 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C2242588 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1268766 infores:hetionet CHEBI:72564 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0852911 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0042571 infores:hetionet CHEBI:42797 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042029 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0234215 infores:hetionet CHEBI:66876 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0014591 infores:hetionet CHEBI:17141 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0018681 infores:hetionet CHEBI:15366 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB03166 UMLS:C0677500 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0001122 infores:hetionet CHEBI:28918 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0700590 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0040034 infores:hetionet CHEBI:135005 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0030554 infores:hetionet CHEBI:4876 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0151766 infores:hetionet CHEBI:46195 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0038450 infores:hetionet GO:0061046 biolink:causes GO:0060541 infores:ubergraph knowledge_assertion manual_agent GO:0061046 GO:0060541 UMLS:C0903898 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0033774 infores:hetionet CHEBI:71219 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0003862 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0006277 infores:hetionet CHEBI:3077 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0235259 infores:hetionet CAID:CA512318986 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318986 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.123G>C (p.Thr41=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318986/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:209807 biolink:causes UMLS:C0554309 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0554309 infores:hetionet CHEBI:2549 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0034063 infores:hetionet CHEBI:7936 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025222 infores:hetionet NCBIGene:9562 biolink:causes MONDO:0030438 infores:monarchinitiative not_provided not_provided HGNC:7102 MONDO:0030438 uuid:2ace6a02-7280-4fb4-a784-b8e0049dec8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50381 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0011124 infores:hetionet CHEBI:63622 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0151942 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0017160 infores:hetionet CHEBI:3504 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0236082 infores:hetionet CHEBI:50131 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0028081 infores:hetionet NCBIGene:3784 biolink:causes MONDO:0100316 infores:monarchinitiative not_provided not_provided HGNC:6294 MONDO:0100316 uuid:d1b242e1-722e-49e2-92ab-4aaf7533033c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151717 infores:hetionet CAID:CA340747 biolink:causes MONDO:0015152 infores:clingen CAID:CA340747 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM6, BS2, PP2, PP3, PP1 The NM_000337.6: c.493C>T p.(Arg165Ter) variant in SGCD is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/9, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three patients with limb girdle muscular dystrophy, including in homozygous state in at least two patients from two families (1.0 pt, PMID: 19770540, 10735275) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent delta-sarcoglycan protein expression in skeletal muscle by IHC, which is highly specific for SGCD-related LGMD (PP4_Strong; PMID: 19770540). The highest population minor allele frequency for this variant is 0.00004827 (2/41432 genome chromosomes) in the African/African American population of gnomAD v3.1.2, which is lower than the ClinGen LGMD VCEP threshold for PM2_Supporting (<0.00009), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PP4_Strong, PM3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747/MONDO:0015152/186 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CAID:CA254837 biolink:causes MONDO:0044970 infores:clingen CAID:CA254837 MONDO:0044970 PMID:12737626PMID:19618438PMID:15100439PMID:15477393 Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PM6_Supporting, PS3_Supporting PP1 The m.8313G>A variant in MT-TK has been reported in two unrelated probands with primary mitochondrial disease (PS4_supporting). One of these individuals had a severe gastroenteropathy, peripheral neuropathy, seizures, dementia, ataxia, retinitis pigmentosa, deafness, and died by age 15 years (PMID: 9380435). The other individual had onset in her 20s of myopathy, nasal speech and swallowing difficulty, peripheral neuropathy, ptosis, and osteoporosis. Her condition was progressive and after several years she was non-ambulatory, had bulbar failure, and required tracheostomy and tube feeding (PMID: 19618438). In both individuals, the variant was heteroplasmic, ranging from 54% in fibroblasts to 74-82% in muscle. In one of the reported cases, the variant was reported de novo as it was absent in blood from the proband’s mother, maternal aunt, and two brothers (PMID: 9380435), however no additional tissues were tested (including that blood in the proband was not tested) and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. In the other case, multiple tissues from the mother were tested as was muscle from two healthy brothers and the variant was not detectable (PMID: 19618438), confirming de novo occurrence (PM6_supporting). Of note, three additional unrelated probands in a large cohort of individuals with autism spectrum disorder were reported to have this variant (PMID: 35778412), however additional clinical details were not provided and there was no evidence these individuals had other features of primary mitochondrial disease. There is one occurrence of this variant in population databases (MITOMAP GenBank sequences, 1/59,389 or 0.002%; absent in Helix dataset and gnomAD v3.1.2). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (73.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Several functional studies reported show the deleterious effects of this variant (PS3_supporting). A single fiber study (PMID: 19618438) demonstrated higher levels of variant in COX-negative fibers (96.44%; n =10) than in COX-positive fibers (72.11%; n= 10; P<0.001). A cybrid study (PMID: 12737626) showed that cybrids with high levels of the variant had severe respiratory chain defects, diminished O2 consumption, and translational defects. Furthermore, a 7000-fold loss of aminoacylation efficiency was reported (PMIDs: 15477393, 15100439). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given consistent functional evidence of a severe deleterious effect across multiple assays. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PM6_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254837/MONDO:0044970/015 2023-03-13 2023-03-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3534 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0027947 infores:hetionet CHEBI:119915 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0547030 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018418 infores:hetionet CHEBI:145499 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0016655 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151694 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151694 infores:hetionet CAID:CA410208063 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208063 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.553C>T (p.Gln185Ter) is a variant predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications, exon 6/9) (PVS1). This variant is a nonsense variant before c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, insufficient evidence suggests the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208063/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9086 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0021843 infores:hetionet NCBIGene:54463 biolink:causes MONDO:0013142 infores:monarchinitiative not_provided not_provided HGNC:25964 MONDO:0013142 uuid:6725c8c5-63d3-45f1-b6e4-ac15ab24b484 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7956 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0014518 infores:hetionet CHEBI:41977 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1720798 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0032285 infores:hetionet CHEBI:85083 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0013404 infores:hetionet CHEBI:71417 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0015230 infores:hetionet CHEBI:66919 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0009938 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151623 infores:hetionet CHEBI:136040 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0004093 infores:hetionet CHEBI:9671 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0011991 infores:hetionet CHEBI:2569 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0015672 infores:hetionet CHEBI:47780 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1510410 infores:hetionet CHEBI:4562 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0030252 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0031046 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0030920 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0009443 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014868 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011570 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0221490 infores:hetionet CHEBI:144093 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0234233 infores:hetionet CHEBI:31981 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0015230 infores:hetionet CHEBI:45863 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234233 infores:hetionet CHEBI:7454 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0027497 infores:hetionet GO:0090189 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0072006 CHEBI:6715 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042487 infores:hetionet CHEBI:27777 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0426576 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0700184 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0178298 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0575090 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0022658 infores:hetionet CAID:CA7331572 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331572 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, BA1, BP2, PP3, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.742T>A variant in DICER1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 248 (p.Ser248Thr). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.0.0 is 0.000003433 (5/1456418 alleles) with a highest population minor allele frequency of 0.00001661 (1/60202 alleles) in a mixed population of unknown ancestry followed by 0.000003613 (4/1107216) in a European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.173; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 08/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331572/MONDO:0100216/024 2024-08-27 2024-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:478164 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0042109 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0041912 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034359 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009319 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017574 infores:hetionet CHEBI:3175 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0155365 infores:hetionet GO:1901993 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1901993 GO:0051321 CHEBI:28001 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0002871 infores:hetionet CHEBI:5893 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0033774 infores:hetionet CHEBI:68554 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0085641 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151936 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0018839 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018839 infores:hetionet NCBIGene:50511 biolink:causes MONDO:0010052 infores:monarchinitiative not_provided not_provided HGNC:18130 MONDO:0010052 uuid:9a3bc9af-de33-415e-8c98-15f3a8d0ecbf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8485 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0518015 infores:hetionet UMLS:C0004609 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0085636 infores:hetionet CAID:CA392342530 biolink:causes MONDO:0007947 infores:clingen CAID:CA392342530 MONDO:0007947 PMID: Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong PM5 The NM_00138 c.5558G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1853 (p.Cys1853Tyr). This variant was found in a proband with aortic aneurysm and dissection and skeletal features who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (Internal lab data, PP4). This variant has been reported twice in ClinVar: once as likely pathogenic, and once as uncertain significance (Variation ID: 632189). This variant has also been identified in individuals with clinical diagnosis of Marfan syndrome and/or features of Marfan syndrome (Invitae ClinVar entry, internal data; PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.992, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Mod, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392342530/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:44185 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0032285 infores:hetionet CHEBI:6375 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0001925 infores:hetionet NCBIGene:9570 biolink:causes MONDO:0013526 infores:monarchinitiative not_provided not_provided HGNC:4431 MONDO:0013526 uuid:965a6be7-84a6-4b73-bde6-7ca80a68c555 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027121 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0162429 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021765 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034544 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0017178 infores:hetionet CHEBI:7496 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0030305 infores:hetionet CHEBI:63791 biolink:causes MONDO:0024388 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009062 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0549262 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0549262 infores:hetionet CHEBI:2618 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0233407 infores:hetionet CHEBI:3508 biolink:causes UMLS:C1112626 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C1112626 infores:hetionet CHEBI:31644 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0041834 infores:hetionet CHEBI:64321 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0036974 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0042075 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0013922 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019348 infores:hetionet CAID:CA512318914 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318914 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BP7, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.213G>A (p.Leu71=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318914/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10385415 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385415 MONDO:0100437 PMID: Benign BA1 BS2, BP4 NM_001034853.2(RPGR):c.1721C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 574. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001361 among hemizygous individuals, with 54 variant alleles / 396,721 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1).This variant has been observed in at least 1 individual with no features or family history of RPGR-related RP, a condition with full penetrance at an early age (PMID: 31213501). However, it is not clear whether this individual underwent a complete visual examination, so BS2 was not met. The computational predictor REVEL gives a score of 0.008, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives a delta score of 0.15 for donor loss, which falls in the intermediate range above the ClinGen X-linked IRD VCEP recommended BP4 threshold of <0.1 but below the PP3 threshold of >0.2, so neither in silico code is met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385415/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:63618 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0016382 infores:hetionet CHEBI:585948 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0014742 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0038525 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0553713 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0023895 infores:hetionet CHEBI:31932 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0542571 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0025637 infores:hetionet CHEBI:567361 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0041969 infores:hetionet CHEBI:45924 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0020615 infores:hetionet CHEBI:10110 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0026858 infores:hetionet NCBIGene:1593 biolink:causes MONDO:0008948 infores:monarchinitiative not_provided not_provided HGNC:2605 MONDO:0008948 uuid:c1afa2f2-92df-4c95-a1e7-e4b43e3f2528 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0030232 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151479 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0262469 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0262469 infores:hetionet CHEBI:50922 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0023530 infores:hetionet CHEBI:63613 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0151904 infores:hetionet CHEBI:681848 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0013384 infores:hetionet CAID:CA229507 biolink:causes MONDO:0009861 infores:clingen CAID:CA229507 MONDO:0009861 PMID: Likely Pathogenic PP3, PP4, PM3_Strong PM2, PM5, PM1 The c.283A>T (p.Ile95Phe) variant in PAH has been reported in multiple patients with mild and moderate phenylketonuria. It was detected with pathogenic variants: p.R408W (PMID: 10495930); p.R158Q, p.A403V, p.T323del (PMID: 18299955); and p.E280K (PMID: 31623983). This variant has a MAF of 0.00060 in gnomAD in the Ashkenazi Jewish population, which is above our cutoff for PM2 (<0.0002) and below our cutoff for BS1 (>0.002). Computational evidence support a deleterious effect (REVEL=0.658). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229507/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47780 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085628 infores:hetionet CHEBI:5864 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0018965 infores:hetionet CHEBI:28001 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0014742 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042373 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0497247 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009144 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0037315 infores:hetionet CHEBI:35778 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0003467 infores:hetionet CHEBI:4887 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0022107 infores:hetionet CAID:CA386959145 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959145 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PP4_Moderate, PP3 PS4, PM5 The c.367C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 123 (p.(Leu123Val)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.777, which is greater than the MDEP threshold of 0.70 (PP3) and is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate (ClinVar ID 994547, internal lab contributor). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes in at least 5 meioses in 1 family (internal lab contributors). Two other missense variants, c.368T>C (p.Leu123Pro) and c.368T>G (p.Leu123Arg), have been classified as VUS by the ClinGen MDEP; therefore PM5 will not be applied. In summary, c.367C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959145/MONDO:0015967/017 2023-08-23 2023-08-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes UMLS:C0271412 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0271412 infores:hetionet NCBIGene:84433 biolink:causes MONDO:0014081 infores:monarchinitiative not_provided not_provided HGNC:16393 MONDO:0014081 uuid:ef2582c8-c327-460d-8265-b9fb07ef4d5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0038454 infores:hetionet CHEBI:4974 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0853034 infores:hetionet GO:0060762 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060762 GO:0007275 CAID:CA114158 biolink:causes MONDO:0015628 infores:clingen CAID:CA114158 MONDO:0015628 PMID:31935285PMID:34136746PMID:30645640PMID:8622978PMID:33047469PMID:11264172PMID:24598842 Pathogenic PS2_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4_Supporting, PS3, PM5 The NM_000552.5(VWF):c.8317T>C (p.Cys2773Arg) missense variant is absent from gnomADv4.1 (PM2_Supporting) and the computational predictor REVEL gives a score of 0.903, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted (PMID: 11264172; PS3). Similar results were also reported in PMID:24598842. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of very low VWF activity measured by VWF:CBA (0.07 units/ml) and with VWF:Ag at 1.19, a low activity/VWF:Ag ratio, and multimeric structure typical for type IID which includes loss of HMWM. this combination is highly specific for VWD type 2A. (PP4_moderate; PMID: 8622978 patient 1). Additional consistent phenotypes were also reported in the patient including a normal FVIII activity consistent with VWF antigen. This was a de novo occurrence (PS2_supporting). This variant has been reported in 1 additional proband meeting PP4 criteria (PS4_supporting; PMID: 8622978 patient 2). Another missense variant in the same codon has been reported in a patient with VWD Type 2A NM_000552.5(VWF):c.8318G>C (p.Cys2773Ser) and has been classified as pathogenic by the ClinGen VWD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP4_Moderate, PS2_Supporting, PS4_Supporting, PS3, PP3, PM2_Supporting, PM5_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114158/MONDO:0015628/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4672 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0021053 infores:hetionet NCBIGene:1528 biolink:causes MONDO:0009605 infores:monarchinitiative not_provided not_provided HGNC:2570 MONDO:0009605 uuid:d9623019-3b05-4c13-a302-bb0dfb41fb6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31401 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0231528 infores:hetionet CHEBI:64355 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036396 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0021141 infores:hetionet CHEBI:46195 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0013144 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0035455 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0267792 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0036572 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151547 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0574067 infores:hetionet CHEBI:32888 biolink:causes MONDO:0006564 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0162823 infores:hetionet CHEBI:6367 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151907 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040485 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0042514 infores:hetionet CHEBI:18248 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0085649 infores:hetionet CHEBI:7476 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0003467 infores:hetionet CAID:CA213745 biolink:causes MONDO:0015967 infores:clingen CAID:CA213745 MONDO:0015967 PMID: Likely Benign BP7, BP4, BP2 PS4, BS1, PM2, BA1 The c.1285A>C variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 429 (p.(Arg429=)) of NM_000162.5. The Popmax filtering frequency of the c.1285A>C variant in gnomAD v2.1.1 is 0.000007310, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.068, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant has been observed in unknown phase with the variant c.106C>T p.Arg36Trp, which is classified as likely pathogenic by the ClinGen MDEP (BP2). In summary, c.1285A>C meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): BP2, BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213745/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Contradicts true CHEBI:5613 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0009676 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0007097 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027947 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0007193 infores:hetionet CHEBI:2549 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0026858 infores:hetionet NCBIGene:6301 biolink:causes MONDO:0060577 infores:monarchinitiative not_provided not_provided HGNC:10537 MONDO:0060577 uuid:74484e00-767b-44ae-a535-cd5e4c38ed2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0019158 infores:hetionet CHEBI:45924 biolink:causes MONDO:0019170 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0031036 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0392618 infores:hetionet CHEBI:3647 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0549209 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0003123 infores:hetionet CHEBI:92712 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0022568 infores:hetionet CHEBI:291342 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0013395 infores:hetionet CHEBI:3219 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015967 infores:hetionet CHEBI:8426 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0152169 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009241 infores:hetionet CAID:CA410203693 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203693 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.281G>C (p.Ser94Thr) is a missense variant with a REVEL score ≥ 0.88 (0.931) (PP3). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported as likely pathogenic by clinical testing by the Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center (ClinVar ID 3068220), however, PS1 was not applied because it was not curated using the MM-VCEP rules for RUNX1. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203693/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA000249 biolink:causes MONDO:0018875 infores:clingen CAID:CA000249 MONDO:0018875 PMID:11313981 Likely Benign BS3, PP3, PM2_Supporting BP4, BA1, PS3, PS4, PS1, PS2, PM5, PM1, BP7, BS1, BS4, PVS1, PP1, PP4, BS2 The NM_000546.6:c.511G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 171 (p.Glu171Lys). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.3088; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, PP3. (Bayesian Points: -2; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000249/MONDO:0018875/009 2025-03-04 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:39112 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0232498 infores:hetionet UMLS:C0657912 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025874 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019088 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0432487 infores:hetionet CAID:CA012790 biolink:causes MONDO:0005045 infores:clingen CAID:CA012790 MONDO:0005045 PMID: Uncertain Significance PM2, PS4_Moderate, PM4_Supporting PM1, PM6, PP1, BA1, PS3, BS1, BS3, BS4, BP3, PS2, BP7, PVS1 The c.2652_2654delGAA (p.Lys884del) variant in MYH7, also reported as c.2649_2651GAA[1], has been identified in 7 individuals with HCM (PS4_Moderate; Ambry pers comm; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with disease in 1 affected relative with HCM (Invitae pers. comm.). However, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). This variant is a deletion of 1 amino acid at position 884 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PM4_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012790/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:23765 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0040409 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0851341 infores:hetionet NCBIGene:374969 biolink:causes MONDO:0032816 infores:monarchinitiative not_provided not_provided HGNC:29204 MONDO:0032816 uuid:acd3d001-639b-41d5-b091-7ea0e77d1749 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410203539 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203539 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.310A>G (p.Thr104Ala) is a missense variant which is located within the Runt Homology Domain (AA 89–204), but does not occur in an established hotspot residue (PM1_Supporting). This variant is extremely rare, having been detected in only one individual in gnomAD v2.1.1 and absent from gnomAD v3.1.2. The REVEL score is 0.604, which does not meet thresholds for applying PP3 or BP4. No other missense variants at this residue, or with the same amino acid substitution, have been classified as pathogenic. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203539/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:659 biolink:causes MONDO:0020713 infores:monarchinitiative not_provided not_provided HGNC:1078 MONDO:0020713 uuid:b724a42c-b79e-4f32-b4fc-b14f140d738e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0027051 infores:hetionet CHEBI:9586 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0003578 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0151734 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0234215 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042109 infores:hetionet CHEBI:3723 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0000737 infores:hetionet CHEBI:9654 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0038354 infores:hetionet CAID:CA213808 biolink:causes MONDO:0015967 infores:clingen CAID:CA213808 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP4_Moderate, PP2, PM2_Supporting PS4, PP3, PP1 The c.604A>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to valine at codon 202 (p.(Met202Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6% and persistent impaired fasting glucose) (PP4_Moderate; internal lab contributors). Another missense variant, c.605T>C p.Met202Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met202Val (PM5_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant has a REVEL score of 0.596, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. In summary, c.604A>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PM5_Supporting, PP2, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213808/MONDO:0015967/086 2024-02-19 2024-02-19 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:31348 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042345 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020039 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0040034 infores:hetionet GO:1902875 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1902875 GO:0009790 CHEBI:3172 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0015967 infores:hetionet CHEBI:32139 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020580 infores:hetionet CHEBI:5120 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0002453 infores:hetionet CAID:CA314576 biolink:causes MONDO:0100040 infores:clingen CAID:CA314576 MONDO:0100040 PMID: Benign BS1, BS2, BP4 The allele frequency of the p.Pro74Gln variant in FOXG1 is 0.018% in Admixed American sub population in gnomAD v4.0, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro74Gln variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). Computational analysis prediction tools suggest that the p.Pro74Gln variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro74Gln variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS2, BP4, BS1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314576/MONDO:0100040/035 2024-04-18 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6437 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0023530 infores:hetionet NCBIGene:23646 biolink:causes MONDO:0033481 infores:monarchinitiative not_provided not_provided HGNC:17158 MONDO:0033481 uuid:b5abee91-61b4-455c-b1f1-8af499094549 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:93635 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0043352 infores:hetionet UMLS:C0009315 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0232487 infores:hetionet UMLS:C0657912 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0086769 infores:hetionet CHEBI:6067 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013604 infores:hetionet CAID:CA287436447 biolink:causes MONDO:0008723 infores:clingen CAID:CA287436447 MONDO:0008723 PMID: Likely Benign PM2_Supporting, BP4, BP7 PP2, PP3, PM5, PM4, BA1, BP1, BP3, PS1, PVS1, BS1 The c.579C>T (p.Gly193=) variant is a synonymous (silent) variant that is not predicted by Splice AI, MaxEntScn or NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). To our knowledge, this variant is not reported in the medical literature. This variant is absent from gnomAD v2.1.1; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287436447/MONDO:0008723/021 2023-02-13 2023-02-13 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135736 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085694 infores:hetionet CAID:CA10604927 biolink:causes MONDO:0009290 infores:clingen CAID:CA10604927 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PS3_Moderate The NM_000152.5:c.1000G>T variant in GAA is a missense variant predicted to cause substitution of glycine by cysteine at amino acid 334 (p.Gly334Cys). It has been reported in two individuals in the literature with infantile-onset Pompe disease, at least one of whom is receiving enzyme replacement therapy (PMIDs: 28196920, 39835171) (PP4_moderate). Both individuals were compound heterozygous for the variant and c.[271G>A, 307T>G] p.[Asp91Asn, Cys103Gly], phase unreported; c.307T>G (p.Cys103Gly) is classified as pathogenic by the ClinGen LD VCEP (PM3). This variant has also been reported in infantile-onset Pompe disease in the Pompe Variant Database (PMIDs: 31342611, 33560568). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000025 (3/1180038 alleles) in the Non-Finnish European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in HEK293 cells using a previously published in vitro assay (PMID: 36246652), GAA enzyme activity was undetectable when compared to wild type and no GAA protein was detectable on western blot (unpublished data) (PS3_moderate). The computational predictor REVEL gives a score of 0.854, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 284864). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PP4_moderate, PM3, PS3_moderate, PM2_supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, Sept. 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604927/MONDO:0009290/010 2025-09-02 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5138 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0026826 infores:hetionet CAID:CA397397299 biolink:causes MONDO:0100438 infores:clingen CAID:CA397397299 MONDO:0100438 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3_Moderate, PS3_Supporting PM3 NM_014336.5(AIPL1):c.214T>C (p.Trp72Arg) is a missense variant predicted to replace tryptophan with arginine at amino acid p.72. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the M_014336.5(AIPL1):c.265T>C (p.Cys89Arg) variant suspected in trans (PMID: 20702822, PMID: 23847139, PMID: 33067476), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (0.25 points), so the PM3_Supporting code was not met. At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by a next-generation sequencing panel of 163 known inherited retinal disease-associated genes (2 pts), severe visual disturbances in infancy or early childhood (1 pt), visual acuity limited to light perception (1 pt), moderate hypermetropia, kinetic visual field extent not detectable (1 pt), keratoconus (0.5 pts), nystagmus (1 pt), posterior subcapsular cataract (0.5 pts), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are highly specific for AIPL1-related retinopathy (total 9 points, PMID: 20702822, PMID: 23847139, PP4_Moderate). The variant was associated with ~40% PDE6 enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, which was comparable to the negative control lacking AIPL1, indicating that it triggers a severe defect in protein function (PMID: 33067476, PS3_Supporting). The computational predictor REVEL gives a score of 0.836, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP4_Moderate, PS3_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397397299/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C2979982 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0549433 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0001824 infores:hetionet CHEBI:42820 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C1291078 infores:hetionet CHEBI:472657 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0025289 infores:hetionet CHEBI:8764 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018965 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853692 infores:hetionet CHEBI:2659 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0085129 infores:hetionet CHEBI:64354 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0004604 infores:hetionet CHEBI:31236 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0455204 infores:hetionet CAID:CA1393449 biolink:causes MONDO:0019501 infores:clingen CAID:CA1393449 MONDO:0019501 PMID: Likely Pathogenic PP4, PM3_Very Strong PP3, PM5, PM2, BP2 The c.12574C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 4192 (p.Arg4192Cys). The highest population minor allele frequency in gnomAD v4.0 is 0.012% (144/1180032 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.599, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant was observed in at least 2 individuals with Usher syndrome and at least 10 individuals with isolated retinitis pigmentosa (RP) who were either homozygous or who carried a second P/LP variant in USH2A (PMID: 24516651, 27460420, 23940504, 27157150, 34906470, 24625443, 28127548, 28041643, 30190494, 29912909, 32176120, 33576794, 34781295, 36785559). At least one of these individuals was clinically evaluated and confirmed to have both sensorineural hearing loss and retinitis pigmentosa, which are highly specific for Usher syndrome (PP4; PMID: 27460420). Of note, an additional proband harbored this variant in cis with the known pathogenic p.Cys759Phe variant (PMID: 29912909), however the VCEP felt that the evidence supporting the pathogenicity of the p.Arg4192Cys variant outweighed this observation. Patients with this variant may present with either autosomal recessive (AR) Usher syndrome or with AR isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, the clinical significance of this variant is likely pathogenic based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2, 11.15.2023) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1393449/MONDO:0019501/005 2023-11-15 2024-04-01 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:31624 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0023052 infores:hetionet CHEBI:7773 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0036973 infores:hetionet CHEBI:17303 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0043387 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0233794 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234458 infores:hetionet CHEBI:3561 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0015402 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0027051 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0026946 infores:hetionet CHEBI:168396 biolink:causes HP:0033431 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0341335 infores:hetionet CHEBI:10124 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0231528 infores:hetionet CHEBI:61058 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0002878 infores:hetionet CAID:CA8603459 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603459 MONDO:0100326 PMID: Uncertain Significance BS1, PM2, PP3, PP4, BP4 The NM_000419.5:c.457G>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 153 (p.Ala153Thr). This variant is listed in LOVD and reported in ClinVar in an Iranian female but has not been reported in the literature in association with Glanzmann thrombasthenia. No ACMG codes could be applied to this variant under the PD VCEP rules. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603459/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:3441 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0917801 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0027726 infores:hetionet NCBIGene:3547 biolink:causes MONDO:0010475 infores:monarchinitiative not_provided not_provided HGNC:5948 MONDO:0010475 uuid:bba551dc-c333-40e1-88ed-0e8232243bfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0000731 infores:hetionet CHEBI:367163 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1145670 infores:hetionet CHEBI:64318 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0039231 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0006852 infores:hetionet CHEBI:49575 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0085631 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0267792 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0853050 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0853050 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040485 infores:hetionet NCBIGene:4171 biolink:causes MONDO:0014853 infores:monarchinitiative not_provided not_provided HGNC:6944 MONDO:0014853 uuid:cf9ae063-4305-472d-804a-14b60de9f5e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45081 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0038454 infores:hetionet CHEBI:23765 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0025323 infores:hetionet CHEBI:8890 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1141930 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0497201 infores:hetionet CHEBI:4511 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0014457 infores:hetionet CHEBI:8502 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0160390 infores:hetionet CHEBI:31932 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002792 infores:hetionet CHEBI:68534 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0004093 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0233528 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233528 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0178298 infores:hetionet GO:0060114 biolink:causes CL:0000609 infores:ubergraph knowledge_assertion manual_agent GO:0060114 CL:0000609 CHEBI:50648 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0039070 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151883 infores:hetionet CHEBI:6121 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0855775 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0851341 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020676 infores:hetionet CHEBI:465284 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0030193 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0687133 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0021368 infores:hetionet GO:1903587 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0072359 CHEBI:41879 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0340726 infores:hetionet CHEBI:7903 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0424790 infores:hetionet CHEBI:50729 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0004093 infores:hetionet CHEBI:8364 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C2830004 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020517 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0392197 infores:hetionet CHEBI:6437 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151907 infores:hetionet CAID:CA343777358 biolink:causes MONDO:0013144 infores:clingen CAID:CA343777358 MONDO:0013144 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PS4, PM5, PM1 The c.362T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of methionine by threonine at the highly conserved amino acid 121 (p.Met121Thr), which is located in an alpha-helix secondary structure in the serpin domain. In addition, an amino acid residue in the vicinity forms part of a disulfide bond (residue 127) and another undergoes glycosylation (residue 128). The variant is absent from gnomAD v4.1.0 (PM2_supporting). Reported in a single proband with family history and IIPE/Conformational deficiency type with a mean AT cof activity of 69% and mean antigen levels of 81%. (PP4: PMID: 28300866). The computational predictor REVEL gives a score of 0.943, which is above the threshold of 0.6 (PP3). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis VCEP: PP4, PM2_Supporting, PP3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343777358/MONDO:0013144/084 2025-09-19 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5864 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015732 infores:hetionet CHEBI:6339 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0085605 infores:hetionet GO:0048324 biolink:causes GO:0048320 infores:ubergraph knowledge_assertion manual_agent GO:0048324 GO:0048320 CHEBI:9123 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030920 infores:hetionet CHEBI:4868 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0023530 infores:hetionet CHEBI:6801 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0700361 infores:hetionet CHEBI:3655 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0017181 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0003123 infores:hetionet NCBIGene:2937 biolink:causes MONDO:0009284 infores:monarchinitiative not_provided not_provided HGNC:4624 MONDO:0009284 uuid:7e30b0ba-6f78-4970-95aa-8bf5234d747b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017566 infores:hetionet GO:0003250 biolink:causes GO:0003179 infores:ubergraph knowledge_assertion manual_agent GO:0003250 GO:0003179 CHEBI:6437 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0040435 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0005745 infores:hetionet CHEBI:6062 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0000737 infores:hetionet UMLS:C0005740 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0013604 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0037199 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0019348 infores:hetionet CHEBI:3732 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0030554 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030305 infores:hetionet CHEBI:28748 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0003862 infores:hetionet CHEBI:17026 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151798 infores:hetionet CHEBI:3441 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0007222 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1368065 infores:hetionet CHEBI:4466 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085612 infores:hetionet CHEBI:4814 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0011991 infores:hetionet CHEBI:5790 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0027066 infores:hetionet CHEBI:6912 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0040822 infores:hetionet NCBIGene:7516 biolink:causes MONDO:0014987 infores:monarchinitiative not_provided not_provided HGNC:12829 MONDO:0014987 uuid:81eb5c16-4b74-4d7c-b1af-c2cb38839082 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0010200 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151849 infores:hetionet CHEBI:47898 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011606 infores:hetionet CHEBI:3219 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1260880 infores:hetionet CAID:CA2579830404 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830404 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS4_Moderate, PM1_Supporting, PP1_Strong PS3 The c.-169C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within a conserved region of the HNF1A/HNF1B binding site in the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 20546279, 29408271, 38855865, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and a family h/o neonatal hypoglycemia) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes with six informative meioses in three families (PP1_Strong; PMID: 20546279, 29408271, 38855865). Functional studies provide conflicting evidence regarding whether the c.-169C>T variant results in transactivation below 60% of wildtype (PMID: 20546279, internal lab contributor). Therefore, PS3_Supporting will not be applied. In summary, c.-169C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PS4_Moderate, PP1_Strong, PP4_Moderate, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830404/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38940 biolink:causes HP:6000139 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0333286 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020538 infores:hetionet CAID:CA512232244 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232244 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.879T>A (p.Ser293=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.04) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232244/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45409 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0003862 infores:hetionet NCBIGene:90993 biolink:causes MONDO:0014544 infores:monarchinitiative not_provided not_provided HGNC:18856 MONDO:0014544 uuid:f0431764-9c2a-42ac-b313-a6951d14d77f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030193 infores:hetionet CHEBI:15765 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0030807 infores:hetionet CHEBI:61049 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0015967 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0270994 infores:hetionet NCBIGene:514 biolink:causes MONDO:0013547 infores:monarchinitiative not_provided not_provided HGNC:838 MONDO:0013547 uuid:351bd76a-f169-47d5-893c-08caa3af31f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0028738 infores:hetionet CHEBI:7936 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0043352 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0020649 infores:hetionet CHEBI:47780 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0043352 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030312 infores:hetionet CAID:CA2061499 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061499 MONDO:0015924 PMID: Likely Benign BS1 PM2, PP3, BP4, BA1, PM5, PM1, PS1 The NM_001204.7(BMPR2) c.2186G>C variant is a missense variant predicted to cause substitution of glycine by alanine at amino acid 729 (p.Gly729Ala). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001639 (21/12810 alleles) in Swedish population, which is higher than the ClinGen PH VCEP threshold (>0.1%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.36, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061499/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50122 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0235996 infores:hetionet CHEBI:17347 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151603 infores:hetionet CHEBI:8356 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027497 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0041912 infores:hetionet NCBITaxon:6231 biolink:causes MONDO:0005871 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6231 MONDO:0005871 CHEBI:65173 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0011206 infores:hetionet GO:1900011 biolink:causes GO:0009755 infores:ubergraph knowledge_assertion manual_agent GO:1900011 GO:0009755 CHEBI:44185 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0016655 infores:hetionet CHEBI:50922 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0026826 infores:hetionet CHEBI:5165 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0037822 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0855242 infores:hetionet CHEBI:7822 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0002994 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0026946 infores:hetionet CHEBI:6950 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0003862 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0037274 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0948594 infores:hetionet CHEBI:49668 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0010200 infores:hetionet CHEBI:68841 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C1510410 infores:hetionet CHEBI:6149 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020598 infores:hetionet CHEBI:50275 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0740394 infores:hetionet MONDO:0035437 biolink:causes NCBIGene:1053 infores:ubergraph knowledge_assertion manual_agent MONDO:0035437 HGNC:1836 CHEBI:2666 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0037317 infores:hetionet CHEBI:49040 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0017168 infores:hetionet CHEBI:145499 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0026821 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0030312 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0023067 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0035258 infores:hetionet CHEBI:31705 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0600228 infores:hetionet CHEBI:6129 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C2047937 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0687133 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0011991 infores:hetionet CHEBI:3561 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0497156 infores:hetionet CHEBI:10100 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C2047937 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0014868 infores:hetionet CHEBI:72297 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C2938875 infores:hetionet CHEBI:9763 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151825 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0085096 infores:hetionet CHEBI:17026 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0005778 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0032285 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0037274 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018799 infores:hetionet CHEBI:44915 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0013378 infores:hetionet CHEBI:50131 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0009676 infores:hetionet CHEBI:45081 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0003467 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0041912 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0039584 infores:hetionet CHEBI:63581 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0015672 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0004936 infores:hetionet CHEBI:50777 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0019080 infores:hetionet CHEBI:10650 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0016204 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0036572 infores:hetionet CAID:CA913169907 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169907 MONDO:0044970 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting PS3 The m.12264C>T variant in MT-TS2 has been reported in two individuals with primary mitochondrial disease to date (PMIDs: 22369973, 22378285, 31965079; PS4_supporting). The first reported case was a man with developmental delay and intellectual disability, retinitis pigmentosa, cataracts, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, hypotonia, bilateral severe mixed hearing loss, sleep apnea, truncal obesity, non-insulin dependent diabetes mellitus, hypogonadotropic hypogonadism, short stature, and growth hormone deficiency (PMIDs: 22369973, 31965079). Blood lactate and alanine were elevated. Muscle biopsy showed ragged red and blue fibers, and COX-deficient fibers. Rotenone-sensitive I–III activity was mildly reduced to 54% of the mean in skeletal muscle. The variant was present at homoplasy in skeletal muscle, cataract, and buccal samples, and was present at 34% heteroplasmy in blood. Of note, he also had a congenital open neural tube defect and hydrocephalus, Chiari malformation, bilateral lower-extremity paralysis, bowel and bladder incontinence with an irregularly thickened bladder wall, scoliosis, restrictive lung disease, osteopenia, and proximal femur and acetabulum deformities. The second reported case had developmental delay, autism, unsteady gait, failure to thrive and feeding difficulty, seizures, and sensorineural hearing loss (PMID: 22378285). Muscle biopsy showed COX-deficient fibers and reduced activities of complexes I and IV. The variant was present at ≥93% in blood, urine and cultured skin fibroblasts and was near homoplasmy in skeletal muscle. The variant was present at 1% heteroplasmy in blood and 18% in buccal sample from the maternal grandmother of the first case (PMID: 22369973) and at lower levels in the mother of the second case (9% to 36% in blood, urine, fibroblasts, muscle, PMID: 22378285; PP1). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.55 (PP3). Single-fiber testing showed high levels of the variant in both COX-positive (98.4±1.5% n=11) and COX-deficient fibers (98.2±2.1% n=11), however northern blot in cultured skin fibroblasts from the second reported patient showed a 70% reduction in the corresponding mature tRNA steady state levels and BN-PAGE in skeletal muscle showed a decrease in the amount of fully-assembled complex I, and a lesser decrease in the amount of complex IV levels (PMID: 22378285). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169907/MONDO:0044970/015 2024-12-03 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:31932 biolink:causes HP:4000194 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0948309 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030305 infores:hetionet CHEBI:3310 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C2242996 infores:hetionet CHEBI:28925 biolink:causes UMLS:C0427564 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0427564 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0004096 infores:hetionet CHEBI:3614 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0237849 infores:hetionet CAID:CA10652926 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652926 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS3, PS2, PS4, BP1, BP4, BP3, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This 3' UTR variant has a MAF of 0.023 (2.3%, 201/8712 alleles) in the African subpopulation of the gnomAD cohort is ≥ 0.0015 (0.15%) (BA1).This variant has been reported in 2 homozygotes in gnomAD v2.1.1 (BP2).In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652926/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3478 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0021053 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0008035 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0474381 infores:hetionet CHEBI:28748 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0029118 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0549418 infores:hetionet CHEBI:5778 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0017181 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0006840 infores:hetionet CAID:CA412350200 biolink:causes MONDO:0100039 infores:clingen CAID:CA412350200 MONDO:0100039 PMID: Uncertain Significance PM2_Supporting, PS4_Moderate PP3, PM1, PM6, BP4, PS1, PS2, PS3 The p.Ala122Thr variant has been observed in 3 individuals with CDKL5 disorder (PMIDs: 22872100, 31313283) (PS4_Moderate). The p.Ala122Thr variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Ala122Thr variant in CDKL5 is classified as uncertain significance based on the ACMG/AMP criteria (PS4_Moderate, PM2_Supporting). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412350200/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3723 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233762 infores:hetionet CHEBI:7494 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0002792 infores:hetionet CHEBI:63791 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0012569 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0001122 infores:hetionet CHEBI:63681 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0009782 infores:hetionet CHEBI:17688 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0003811 infores:hetionet CHEBI:63598 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0025323 infores:hetionet CHEBI:6640 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0040264 infores:hetionet CHEBI:5001 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042029 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0038362 infores:hetionet CHEBI:584020 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0016382 infores:hetionet CHEBI:63608 biolink:causes MONDO:0015459 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C2931822 infores:hetionet CHEBI:15544 biolink:causes MONDO:0045003 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0268919 infores:hetionet CHEBI:3082 biolink:causes HP:0012155 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0859996 infores:hetionet CHEBI:7936 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0234047 infores:hetionet GO:0060141 biolink:causes GO:0006949 infores:ubergraph knowledge_assertion manual_agent GO:0060141 GO:0006949 CAID:CA16618465 biolink:causes MONDO:0015967 infores:clingen CAID:CA16618465 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PM2_Supporting PP4, PP1 The c.1339del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 167 novel amino acids before encountering a stop codon (p.(Arg447GlyfsTer167)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 6 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PMID 22761713; ClinVar ID 421604.2; internal lab contributors) (PS4_Moderate). This variant was identified in individuals with diabetes consistent with a GCK-MODY phenotype; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 22761713, internal lab contributors). This variant segregated with disease with 2 informative meioses in a family with MODY, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributors). In summary, c.1339del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618465/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Supports CHEBI:8356 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0043387 infores:hetionet CHEBI:51380 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0042963 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0039103 infores:hetionet CHEBI:64321 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0015672 infores:hetionet CHEBI:28445 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0004093 infores:hetionet CHEBI:5109 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0030193 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0392196 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0392196 infores:hetionet CHEBI:40279 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0239571 infores:hetionet CHEBI:17688 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0043094 infores:hetionet CHEBI:59773 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0221512 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0543467 infores:hetionet CHEBI:27690 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0017178 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0042373 infores:hetionet CHEBI:31397 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0001622 infores:hetionet CHEBI:27732 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1442826 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0227791 infores:hetionet CHEBI:17263 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0700345 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0813230 infores:hetionet CAID:CA16616706 biolink:causes MONDO:0700270 infores:clingen CAID:CA16616706 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting BP4, PP3 The c.6116A>T variant in ATM is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 2039 (p.Glu2039Val). This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.429, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616706/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:4088 biolink:causes MONDO:0013426 infores:monarchinitiative not_provided not_provided HGNC:6769 MONDO:0013426 uuid:1b9a2054-231d-4702-bd53-4a76d8621313 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040409 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030312 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0001883 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013922 infores:hetionet CHEBI:28901 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0231856 infores:hetionet CHEBI:8888 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011603 infores:hetionet CHEBI:9137 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0001925 infores:hetionet GO:1905902 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1905902 GO:0009790 CHEBI:8024 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042023 infores:hetionet CHEBI:3568 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014724 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0267537 infores:hetionet CHEBI:75722 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C3665386 infores:hetionet CHEBI:9635 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0014173 infores:hetionet CHEBI:28593 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0232333 infores:hetionet CHEBI:8024 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0851578 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0855242 infores:hetionet CHEBI:9435 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0013144 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040046 infores:hetionet CHEBI:17263 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0006142 infores:hetionet NCBIGene:57010 biolink:causes MONDO:0012490 infores:monarchinitiative not_provided not_provided HGNC:1386 MONDO:0012490 uuid:b6f26862-0eda-4bc3-9d75-d7d539859ee6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009763 infores:hetionet CHEBI:63621 biolink:causes HP:6000500 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235248 infores:hetionet CHEBI:119486 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0237849 infores:hetionet CHEBI:3561 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0040264 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0041912 infores:hetionet CHEBI:10650 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013378 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0178298 infores:hetionet CHEBI:8228 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0017178 infores:hetionet CHEBI:23765 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085649 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1167760 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1167760 infores:hetionet CHEBI:47519 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085593 infores:hetionet CHEBI:63617 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027121 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0021053 infores:hetionet CHEBI:7577 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011991 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0009806 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0021053 infores:hetionet CHEBI:92712 biolink:causes MONDO:0017989 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0039235 infores:hetionet CHEBI:8890 biolink:causes HP:6000264 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0410918 infores:hetionet CAID:CA143592 biolink:causes MONDO:0019501 infores:clingen CAID:CA143592 MONDO:0019501 PMID: Benign BA1 PP3, PM3, BP4 The variant NM_206933.4:c.7334C>T in USH2A is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 2445 (p.Ser2445Phe). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0054 (489/91072 alleles, 3 homozygotes) for the South Asian population, which is higher than the ClinGen Hearing Loss USH2A threshold (≥0.005) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.358, which meets no codes. This variant was reported in one individual with Usher syndrome and one with Retinitis Pigmentosa, though without any evidence of pathogenicity (PM3 not met; PMIDs: 28041643, 33926394). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143592/MONDO:0019501/005 2025-03-12 2025-03-28 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:127780 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0018965 infores:hetionet NCBIGene:7084 biolink:causes MONDO:0012301 infores:monarchinitiative not_provided not_provided HGNC:11831 MONDO:0012301 uuid:671cdb05-8cb5-4720-acd1-4b5c98bcf5d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009806 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0948089 infores:hetionet CHEBI:42944 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0039231 infores:hetionet CHEBI:6538 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0232461 infores:hetionet CHEBI:681848 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0009024 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0009450 infores:hetionet CHEBI:7852 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0036974 infores:hetionet CHEBI:10112 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0020433 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0234215 infores:hetionet CAID:CA2586970245 biolink:causes MONDO:0100135 infores:clingen CAID:CA2586970245 MONDO:0100135 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PVS1_Strong The c.5511delG (p.(Pro1838Leufs*20)) variant in SCN1A is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1921-1934) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). This variant has been reported in one individual with Dravet syndrome in the published literature, however no parental segregation studies were performed (PMID: 33067208; PS4_Moderate). This variant is absent from the population database, gnomADv4.0 (PM2_Supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic for Autosomal Dominant Dravet syndrome based on the ACMG/AMP criteria applied: PVS1_Strong, PS4_Moderate, PM2_Supporting, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 12/11/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586970245/MONDO:0100135/067 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3696 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0235431 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0233632 infores:hetionet CHEBI:119573 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C3263723 infores:hetionet CHEBI:72690 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0232462 infores:hetionet CHEBI:63610 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013456 infores:hetionet CHEBI:5959 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013491 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0205204 infores:hetionet CHEBI:135005 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0086769 infores:hetionet CHEBI:2549 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042029 infores:hetionet CHEBI:9727 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0917801 infores:hetionet CHEBI:7959 biolink:causes MONDO:0009303 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0403529 infores:hetionet CHEBI:75922 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0151692 infores:hetionet NCBIGene:100128908 biolink:causes MONDO:0859222 infores:monarchinitiative not_provided not_provided HGNC:53647 MONDO:0859222 uuid:ca34c88b-24f8-4d02-b1ec-e51e8a2bfff2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10650413 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650413 MONDO:0011071 PMID: Benign BP2, BA1 PS3, PS1, PS4, BP4, PVS1, PM6, PM2, BS3, BS4, BS1, BP7, PM1, PM4, PM5, PP3, PP1 The NM_001754.4:c.*3380A>G variant in the 3' UTR has an MAF of 0.08 (8%, 3561/42024 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 131 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650413/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45409 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0233414 infores:hetionet CHEBI:3636 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0001122 infores:hetionet CAID:CA1619791 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619791 MONDO:0800472 PMID: Likely Benign BP4, BP7 PP3, PP1, BA1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, PVS1, PM2 The c.1392A>T variant in CYP1B1 is a synonymous variant (p.Ser464=). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.008862 (665 alleles out of 75,040), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact CYP1B1 function. This synonymous variant is located outside of the first and the last 3 bases of the exon and BP4 is met, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in an individual in laboratory testing (ClinVar database), however BP4 is met, therefore PM3 was not assessed. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619791/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:8526 biolink:causes MONDO:0014005 infores:monarchinitiative not_provided not_provided HGNC:2852 MONDO:0014005 uuid:693ebf9b-4f60-4eef-8f4b-a2100c41f225 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:175901 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0302295 infores:hetionet CHEBI:27882 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0028961 infores:hetionet CHEBI:6741 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0002792 infores:hetionet CHEBI:63717 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0033687 infores:hetionet CHEBI:84883 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0003873 infores:hetionet GO:0110107 biolink:causes GO:0007476 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0007476 CHEBI:3757 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0233459 infores:hetionet CHEBI:134745 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0027497 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0012833 infores:hetionet CHEBI:63631 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0015732 infores:hetionet CHEBI:44185 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C2939186 infores:hetionet CHEBI:5134 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0235266 infores:hetionet CHEBI:9674 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0026838 infores:hetionet NCBIGene:4796 biolink:causes MONDO:0010068 infores:monarchinitiative not_provided not_provided HGNC:7801 MONDO:0010068 uuid:e74f909d-9770-4e09-904e-d07974950491 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002962 infores:hetionet CHEBI:2663 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151786 infores:hetionet CHEBI:9586 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0032617 infores:hetionet CHEBI:6909 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0085624 infores:hetionet CHEBI:51860 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0851578 infores:hetionet CHEBI:75275 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0042109 infores:hetionet CHEBI:10112 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C2830004 infores:hetionet CHEBI:4551 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0018681 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0852810 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0009450 infores:hetionet GO:0060251 biolink:causes GO:0042063 infores:ubergraph knowledge_assertion manual_agent GO:0060251 GO:0042063 CHEBI:4710 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027769 infores:hetionet CHEBI:465284 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1619702 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0039971 infores:hetionet CHEBI:3084 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0042023 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0549386 infores:hetionet CHEBI:2682 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151636 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0013395 infores:hetionet CHEBI:36791 biolink:causes MONDO:0044339 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0158252 infores:hetionet CHEBI:135738 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0948089 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013395 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0854717 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0854717 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0876973 infores:hetionet GO:0072106 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0072006 NCBIGene:387700 biolink:causes MONDO:0012786 infores:monarchinitiative not_provided not_provided HGNC:23094 MONDO:0012786 uuid:0b899b98-8876-4bd0-9d67-84e0ad1eb295 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6904 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0022346 infores:hetionet UNII:T58MSI464G biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0022346 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0020538 infores:hetionet CHEBI:51364 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0549567 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020557 infores:hetionet CHEBI:15551 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0018790 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0948089 infores:hetionet CAID:CA355946488 biolink:causes MONDO:0001586 infores:clingen CAID:CA355946488 MONDO:0001586 PMID: Likely Pathogenic PP3_Moderate, PM3, PP4, PM2_Supporting PS1, PS3, PS2, PM5, PM1, BP5, BS3, PM6, BP4, BP2 The NM_000203.5(:c.250G>C variant in IDUA is a missense variant that results in the substitution of glycine by arginine at amino acid 84 (p.Gly84Arg). This variant has been reported in 5 patients with a milder phenotype (MPSI Hurler-Scheie or MPSI Scheie). In two patients homozygous for this genetic change (PMID 31386236), a specific combination of clinical and biochemical evidence diagnostic of MPSI has been reported (PP4). All other probands are also reported to have a confirmed enzymatic diagnosis. One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as likely pathogenic for MPS I by the ClinGen LD VCEP, c.826G>A (p.Glu273Lys) (PMID 21394825); the phase of the variants is unconfirmed (0.25 points). At least 4 patients have been reported to be homozygous for the variant (PMID: 31386236, 35141277) (max 2 x 0.5). Total 1.25 points (PM3). The computational predictor REVEL gives a score of 0.948 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 8.487e-7 (1/1178256 alleles) in the non-Finnish European population, which meets this criterion at the PM2_Supporting level. Another amino acid change at the same position, c.250G>A (p.Gly84Ser), has been reported (ClinVar Variation ID: 726495); this variant has not yet been classified by the ClinGen LD VCEP. This variant therefore meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3, PP3_Moderate, PP4, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel n May 23, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355946488/MONDO:0001586/091 2025-05-23 2025-05-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0016059 infores:hetionet CHEBI:29013 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0085616 infores:hetionet CHEBI:45783 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151905 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0042769 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0155169 infores:hetionet CHEBI:8890 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0003467 infores:hetionet CHEBI:32139 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C2242996 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0700184 infores:hetionet CHEBI:64028 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0851578 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011991 infores:hetionet CHEBI:51364 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0427086 infores:hetionet CHEBI:3403 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0700200 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0024115 infores:hetionet CHEBI:46557 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0040460 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0853813 infores:hetionet CHEBI:4784 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0242429 infores:hetionet CHEBI:3757 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0221201 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0852911 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0233414 infores:hetionet UNII:D27V6190PM biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0027497 infores:hetionet CAID:CA5416981 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416981 MONDO:0011225 PMID: Likely Benign BS1 BS2, BA1, PM2 The c.169G>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause a substitution of Valine by Phenylalanine at amino acid 57 (p.Val57Phe).The popmax filtering allele frequency in gnomAD v2.1. is 0.0001675 (based on 29/128916 alleles in the non-Finnish European population), which is below the SCID VCEP established threshold of >0.00078.However, the highest MAF is in the Ashkenazi Jewish population at 0.005896 (61/10346 alleles and NO homozygotes reported), which is above the SCID VCEP established threshold of >00078. As this population is not known to have a higher disease prevalence, this is considered to meet BS1.After a comprehensive literature search, the variant has not been found in individuals with SCID due to DCLRE1C deficiency.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416981/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9566 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0008370 infores:hetionet UMLS:C0010592 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0086565 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0852696 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0852696 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006285 infores:hetionet CHEBI:27666 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0031542 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0160390 infores:hetionet CAID:CA229521 biolink:causes MONDO:0009861 infores:clingen CAID:CA229521 MONDO:0009861 PMID: Pathogenic PM3, PM2, PP4, PP3, PS2 (PAH):c.353-6T>A is an intronic variant predicted to be splice altering/deleterious by multiple lines of in silico data. This variant was reported in trans with the pathogenic variant p.Tyr414Cys in a patient with mild PKU in a Norwegian cohort (PMID 8807331). This variant was confirmed to be de novo by parental sequencing (PMID 8807331). (PAH):c.353-6T>A is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS2, PM2, PM3, PP3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229521/MONDO:0009861/006 2020-07-25 2020-07-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4710 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004096 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0341505 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0341505 infores:hetionet CHEBI:3568 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020580 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151517 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0740858 infores:hetionet CHEBI:520985 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020580 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0856088 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0856088 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0233632 infores:hetionet UNII:3U02EL437C biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0340865 infores:hetionet CHEBI:63577 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0032617 infores:hetionet CHEBI:74947 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1368065 infores:hetionet CHEBI:9654 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0085631 infores:hetionet GO:2000356 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000356 GO:0072001 CHEBI:64312 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0853225 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0036679 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0036679 infores:hetionet CHEBI:66901 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0015230 infores:hetionet CHEBI:2666 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0011253 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0233632 infores:hetionet CHEBI:681848 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0031542 infores:hetionet CHEBI:5138 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151907 infores:hetionet CHEBI:35778 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C2830004 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0027051 infores:hetionet CHEBI:63717 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0015967 infores:hetionet CHEBI:567361 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0014591 infores:hetionet CHEBI:5118 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004509 infores:hetionet CHEBI:194135 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0034155 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0349506 infores:hetionet CHEBI:142290 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0000737 infores:hetionet CHEBI:61049 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0856054 infores:hetionet CHEBI:17334 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0033774 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027765 infores:hetionet CHEBI:10119 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0026827 infores:hetionet CHEBI:35778 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0041657 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0031542 infores:hetionet CAID:CA229342 biolink:causes MONDO:0009861 infores:clingen CAID:CA229342 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4, PM3_Supporting The frameshift variant c.1099dup (p.Leu367Profs*27) occurs in exon 11 of 13 and is predicted to result in NMD. The variant is found at an extremely low allele frequency of 0.000003980 overall in gnomAD with a MAF of 0.000008804 (1/113590) in the European population. One classical PKU patient has been reported (PMID: 16256386) with this variant in trans with Arg243Gln (ClinVar 591, Pathogenic by multiple submitters). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229342/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:65018 biolink:causes MONDO:0011613 infores:monarchinitiative not_provided not_provided HGNC:14581 MONDO:0011613 uuid:bc8927a8-7507-43f4-9884-d4b88d28762b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:63895 biolink:causes MONDO:0007158 infores:monarchinitiative not_provided not_provided HGNC:26270 MONDO:0007158 uuid:5897fdcb-755f-4267-91f6-e9c35779d5b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0162830 infores:hetionet CHEBI:6935 biolink:causes UMLS:C0032320 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0032320 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0497247 infores:hetionet CHEBI:7820 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0019572 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0152086 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0152086 infores:hetionet CAID:CA024665 biolink:causes MONDO:0007783 infores:clingen CAID:CA024665 MONDO:0007783 PMID: Likely Benign PP1, BS2, PS3_Moderate, PM1, BS1 PP3, PS4, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with serine at codon 2342 of the RYR1 protein p.(Asn2342Ser). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00206, which is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in over ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, at least nine of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted)( PMID:30236257, PMID:23558838, PMID:24433488, personal communication) However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been shown to segregate with IVCT status in at least three individuals across two families, PP1 (PMID:30236257, personal communication). In other families at least two genotype positive IVCT negative individuals have been reported, BS2 (PMID:15221887, personal communication). HEK293 assay shows increased sensitivity to 4CmC, PS3_Moderate (PMID: 15221887). A functional study published using B-lymphocytes showed increased acidification rates, however, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:19191333). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.639 supports neither a pathogenic or a benign status. Criteria implemented include: PS3_Moderate, PM1, PP1, BS1, BS2. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024665/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63620 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0836924 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0520806 infores:hetionet CHEBI:28787 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0013144 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011385 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0158266 infores:hetionet CHEBI:4887 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0085631 infores:hetionet CHEBI:3654 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C1318520 infores:hetionet CAID:CA410208229 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208229 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.40C>A (p.Pro14Thr) is a missense variant which has a REVEL score of < 0.50 (0.295) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208229/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2668 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0034150 infores:hetionet CAID:CA134749 biolink:causes MONDO:0021060 infores:clingen CAID:CA134749 MONDO:0021060 PMID: Likely Benign BP7, BP4 BS1 Computational prediction tools and conservation analysis suggest that the c.680+6T>C variant in the RAF1 gene does not impact the protein (BP4). This is an intronic variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). In addition, this variant is observed in many individuals in the normal population suggesting it is an unlikely cause of a RASopathy (BS1 not met). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134749/MONDO:0021060/004 2019-07-25 2019-12-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:45783 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151603 infores:hetionet CHEBI:465284 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0595916 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0037274 infores:hetionet NCBIGene:728294 biolink:causes MONDO:0024554 infores:monarchinitiative not_provided not_provided HGNC:28358 MONDO:0024554 uuid:6a3e3098-c917-46f4-b132-82dbd54d76bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6916 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0039070 infores:hetionet CHEBI:9943 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151746 infores:hetionet CAID:CA404083811 biolink:causes MONDO:0007750 infores:clingen CAID:CA404083811 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PS3, PM5 The NM_000527.5 (LDLR):c.1156G>T (p.Asp386Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP3: REVEL score = 0.883, it is above the threshold of 0.75. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404083811/MONDO:0007750/013 2022-03-25 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6741 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030193 infores:hetionet CHEBI:64312 biolink:causes HP:0032552 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235472 infores:hetionet CHEBI:2663 biolink:causes HP:0004751 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0030591 infores:hetionet CHEBI:17650 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0271738 infores:hetionet CHEBI:79699 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020473 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0001824 infores:hetionet CAID:CA229488 biolink:causes MONDO:0009861 infores:clingen CAID:CA229488 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting, PS3_Supporting PM5, PP1 The c.208T>C (p.Ser70Pro) variant in PAH has been reported in at least four individuals with hyperphenylalanemia, including at least one for whom BH4 deficiency was excluded (PMID: 9860305, PMID: 21307867). Of these, two were siblings who also had p.Arg241His (PMID: 22330942), which is classified as pathogenic by PAH VCEP (Variation ID: 102804), without documentation of parental testing to establish phase. In-vitro studies show 20% enzyme activity (PMID: 9860305). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4, PM2, PM3_Supporting, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229488/MONDO:0009861/006 2022-03-11 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31638 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0020517 infores:hetionet CHEBI:5855 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013404 infores:hetionet CHEBI:6923 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C1443060 infores:hetionet CHEBI:17549 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0035229 infores:hetionet CHEBI:32221 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0040822 infores:hetionet CHEBI:135530 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C1527344 infores:hetionet CHEBI:8871 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0019080 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020456 infores:hetionet CAID:CA317886 biolink:causes MONDO:0100038 infores:clingen CAID:CA317886 MONDO:0100038 PMID: Likely Pathogenic PP3_Moderate, PM1, PM6, PM2_Supporting, PS4_Supporting PS1, PS2, PS3, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM5, PVS1, BS2, PP2, PP1, PP4, BA1, BP2, BP3, BP1, BP4 The c.2657T>C variant in SCN2A is a missense variant predicted to cause a substitution of leucine by serine at amino acid 886 (p.Leu886Ser). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with a complex neurodevelopmental disorder (PM6); (PMID: 3541799; internal data GeneDx). It has also been identified in an additional proband with a complex neurodevelopmental disorder (PS4_supporting) (internal data, Labcorp). This variant is absent from gnomAD v4.0) (PM2_supporting). The computational predictor REVEL gives a score of 0.971, evidence that correlates with impact to SCN2A function (PP3_moderate). This variant resides within a region of SCN2A that is defined as a mutation hotspot by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: (PP3_moderate, PM1, PM6, PM2_supporting, PS4_supporting). Approved March 25, 2025. Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA317886/MONDO:0100038/068 2025-03-25 2025-04-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36704 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0015230 infores:hetionet CHEBI:75246 biolink:causes HP:0012701 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0426636 infores:hetionet CHEBI:42355 biolink:causes HP:0034754 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0232599 infores:hetionet CHEBI:48390 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0042963 infores:hetionet CHEBI:65349 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0376358 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0242350 infores:hetionet CHEBI:31638 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0030193 infores:hetionet CHEBI:100241 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0000731 infores:hetionet CHEBI:63619 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0028961 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003529 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0520575 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0242350 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0600260 infores:hetionet CHEBI:135351 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0236075 infores:hetionet UMLS:C0010592 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0043094 infores:hetionet CHEBI:6775 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020598 infores:hetionet CHEBI:167309 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0085593 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0020517 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0178298 infores:hetionet NCBIGene:4322 biolink:causes MONDO:0009597 infores:monarchinitiative not_provided not_provided HGNC:7159 MONDO:0009597 uuid:c6e604ac-f8c4-4766-8ae9-300fe18681e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0575081 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0026848 infores:hetionet CHEBI:6121 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0428977 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151705 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0013395 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0235919 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0235919 infores:hetionet CHEBI:41774 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C2981158 infores:hetionet CAID:CA343722726 biolink:causes MONDO:0020367 infores:clingen CAID:CA343722726 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PM2_Supporting, PM4_Supporting BS1, BS3, BP7, PM6, PP3, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.1515A>G variant in MYOC is a single nucleotide change, predicted to substitute the terminating codon by Tryptophan and extending the protein by an additional 42 amino acids (p.Ter505TrpextTer42). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. 20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 34923728), which fulfilled PP1_Moderate (≥ 5 meioses in ≥ 1 family, but not the ≥ 7 meioses in > 1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 34923728), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PM2_Supporting, PM4_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343722726/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2453 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0036572 infores:hetionet CHEBI:63617 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004134 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0006679 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0005694 infores:hetionet CHEBI:16469 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0015967 infores:hetionet CHEBI:6437 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027424 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027339 infores:hetionet CHEBI:7494 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0019270 infores:hetionet CAID:CA658795262 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795262 MONDO:0009290 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1654del (p.Leu552SerfsTer26), is a frameshift variant which is predicted to result in a premature termination codon and nonsense mediated decay resulting in lack of gene product. This is supported by absence of cross-reactive immunological material on Western blot of protein from cultured skin fibroblasts from an individual with this variant (PMID 22252923). Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. One patient with infantile-onset Pompe disease and residual GAA activity meeting PP4 specifications has been reported. This patient is compound heterozygous for the variant and c.2560C>T (p.Arg854Ter) (PMIDs 25741864, 27493997, 29122469), meeting PM3_Supporting. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795262/MONDO:0009290/010 2020-04-20 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31709 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0015230 infores:hetionet CHEBI:49575 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0549249 infores:hetionet CHEBI:3082 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0004093 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0012833 infores:hetionet CAID:CA251526 biolink:causes MONDO:0009861 infores:clingen CAID:CA251526 MONDO:0009861 PMID:9860305PMID:1301187PMID:2816939PMID:26322415PMID:15503242 Pathogenic PP4_Moderate, PVS1, PM3_Very Strong PM2 PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4_Moderate: Seen in multiple Chinese PKU patients. BH4 deficiency excluded. (PMID:1301187; PMID:2816939; PMID:9860305); PM3_very-strong: Detected in trans with 6 known pathogenic variants: p.R158Q; p.R241C; p.R243Q; p.E280K; p.Y356*; p.R413P (PMID:15503242, 26322415). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4_Moderate, PM3_very-strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251526/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:30830 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0002170 infores:hetionet CAID:CA157969 biolink:causes MONDO:0007648 infores:clingen CAID:CA157969 MONDO:0007648 PMID:12216071PMID:17668349PMID:22850631PMID:19017792PMID:12944922PMID:20921021PMID:12216071PMID:12216071PMID:17668349PMID:22850631PMID:19017792PMID:12944922 Benign BS1, BS2 BP5, BP7, BS4, BS3, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP3, PP2, PP4, PP1, BP4, BP1, BP3, BP2, BA1, PS3, PS1, PS4, PS2 The c.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (BS1). This variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157969/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:17334 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0027769 infores:hetionet CHEBI:8768 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0015402 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0009806 infores:hetionet CHEBI:31624 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C1145670 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0037822 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0023067 infores:hetionet CHEBI:94807 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0013456 infores:hetionet CHEBI:135929 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0033774 infores:hetionet CHEBI:4903 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0006277 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0015230 infores:hetionet CHEBI:109549 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0917801 infores:hetionet CAID:CA012420 biolink:causes MONDO:0013699 infores:clingen CAID:CA012420 MONDO:0013699 PMID: Uncertain Significance PP4, PP3, PM3 PS3, PM2 The NM_000535.7: c.614A>C variant in PMS2 is a missense variant predicted to cause substitution of Glutamin by Prolin at amino acid 205 (p.Gln205Pro). This alteration was detected in trans with a mutation in PMS2 (c.1A>G) in an individual meeting the clinical criteria for CMMR-D (≥3 points, table 3 of the ClinGen_InSiGHTColorectalCancer/Polyposis_ACMG_Specifications_v1), (PM3 met). The Frequency of this variant in gnomAD V4.1.0 is 0.000037 (0.0037%), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore PM2_supporting is not met. The variant was detected in at least one CRC/Endometrial MSI-H tumour using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). This missense variant mets the criteria for PP3 (MAPP+PolyPhen-2 prior probability for pathogenicity >0.68 & ≤0.81). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM3, PP3, PP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA012420/MONDO:0013699/139 2025-05-30 2025-05-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7573 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0020538 infores:hetionet CHEBI:3216 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042963 infores:hetionet CAID:CA390886334 biolink:causes MONDO:0100216 infores:clingen CAID:CA390886334 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PVS1, BA1, BP2, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PS1, PS3, PS2, PS4, BP7, BS1, BS3, BS4 The NM_177438.3:c.1282G>A variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 428 (p.Glu428Lys). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.206; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390886334/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50859 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0162429 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0234987 infores:hetionet NCBITaxon:4751 biolink:causes UMLS:C0040250 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D014006 DB00400_MESH_D014006_1 CHEBI:4856 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013428 infores:hetionet CHEBI:9605 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0018926 infores:hetionet CAID:CA211397 biolink:causes MONDO:0007648 infores:clingen CAID:CA211397 MONDO:0007648 PMID: Benign BS1, BS2 BP5, BP7, BS3, BS4, PM3, PM5, PM4, PM1, PVS1, PM2, PM6, PP1, PP3, PP2, PP4, BP2, BP4, BP1, BP3, BA1, PS3, PS1, PS4, PS2 The c.892G>A (p.Ala298Thr) variant has an allele frequency of 0.00133 (0.1%, 41/30,782 alleles) in the South Asian subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA211397/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true NCBIGene:8517 biolink:causes MONDO:0010386 infores:monarchinitiative not_provided not_provided HGNC:5961 MONDO:0010386 uuid:22f88b3d-1940-41dd-bef0-6c5f1e035ffa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68579 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0030193 infores:hetionet CAID:CA085719 biolink:causes MONDO:0007750 infores:clingen CAID:CA085719 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 The NM_000527.5(LDLR):c.4G>C (p.Gly2Arg) variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.00016 (0.016%) in African exomes (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in one index cases who fulfills SB criteria for FH (1 case from CGMC, UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA085719/MONDO:0007750/013 2022-04-29 2025-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4856 biolink:causes MONDO:0006803 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0340305 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018099 infores:hetionet CHEBI:8364 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0020651 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020517 infores:hetionet CHEBI:6904 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0151766 infores:hetionet CAID:CA367403451 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403451 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5, PP2, PP3, PP4, PM2_Supporting, PS3_Moderate The c.127C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 43 (p.(Arg43Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.924, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, established functional studies demonstrated the p.Arg43Cys protein has a relative activity index (RAI) < 0.5, indicating that this variant impacts protein function (PS3_Moderate; PMID: 25015100). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least eight unrelated individuals with hyperglycemia/diabetes (PS4; PMIDs: 30592380, 21348868, PMID 23771172, 25015100). One of these individuals was homozygous for c.127C>T and had permanent neonatal diabetes mellitus (PNDM) and negative testing for ABCC8, KCNJ11, INS and EIF2AK3 (PP4; PMID 25015100). This variant also segregated with diabetes/hyperglycemia, with 5 informative meioses in one family (PP1_Strong; PMID 21348868). Another missense variant, c.128G>A (p.Arg43His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg43Cys has a greater Grantham distance (PM5). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PM5, PP2, PP3, PP4, PM2_Supporting, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403451/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Supports CHEBI:42797 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151603 infores:hetionet CHEBI:15552 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0027497 infores:hetionet CHEBI:9073 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C3203358 infores:hetionet CHEBI:4659 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0302809 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0919980 infores:hetionet CHEBI:3310 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0020517 infores:hetionet CHEBI:7798 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0030193 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0236068 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0085617 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0006826 infores:hetionet CHEBI:8597 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0022346 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0549373 infores:hetionet CAID:CA295620 biolink:causes MONDO:0012999 infores:clingen CAID:CA295620 MONDO:0012999 PMID: Benign BA1, BS3_Supporting PP3 NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID: 24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID: 24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BA1, BS3_Supporting.(Classification approved by the ClinGen CCDS VCEP on February 8, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA295620/MONDO:0012999/026 2023-02-08 2023-03-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63589 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0015672 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0019372 infores:hetionet CHEBI:6413 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0024236 infores:hetionet CHEBI:92712 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0231274 infores:hetionet CHEBI:45599 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0546817 infores:hetionet CHEBI:63622 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0151636 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232431 infores:hetionet CHEBI:4653 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0037763 infores:hetionet CHEBI:6888 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0152459 infores:hetionet CHEBI:51860 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0015967 infores:hetionet CHEBI:51450 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0003467 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0041582 infores:hetionet GO:2001210 biolink:causes GO:0008299 infores:ubergraph knowledge_assertion manual_agent GO:2001210 GO:0008299 CHEBI:2955 biolink:causes UMLS:C0032529 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0032529 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0043246 infores:hetionet CHEBI:7445 biolink:causes MONDO:0011972 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0085083 infores:hetionet CHEBI:17026 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027497 infores:hetionet CHEBI:4814 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0522055 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0001339 infores:hetionet CHEBI:3387 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0043094 infores:hetionet CHEBI:8069 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C1306341 infores:hetionet CHEBI:5165 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0030252 infores:hetionet CAID:CA412376881 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376881 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 The NM_000330.4(RS1):c.61G>C variant is a missense variant encoding the substitution of Glycine with Arginine at amino acid 61. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.601, which is between the ClinGen X-linked IRD VCEP thresholds of 0.664 and 0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes do not apply. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376881/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:404903 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027424 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0235146 infores:hetionet CHEBI:17650 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C1443060 infores:hetionet CHEBI:43968 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0039070 infores:hetionet CHEBI:5118 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0451641 infores:hetionet CHEBI:5893 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0232461 infores:hetionet CHEBI:4495 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0011880 infores:hetionet CHEBI:145499 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020433 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020621 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232431 infores:hetionet CHEBI:9137 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0039231 infores:hetionet CHEBI:36791 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151907 infores:hetionet CHEBI:77260 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0030193 infores:hetionet CHEBI:100241 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0016382 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030846 infores:hetionet CHEBI:72297 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0030554 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0243026 infores:hetionet CHEBI:28901 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020625 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0857353 infores:hetionet CHEBI:135351 biolink:causes MONDO:0013577 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0398370 infores:hetionet CHEBI:119915 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0242184 infores:hetionet CAID:CA410206900 biolink:causes MONDO:0100083 infores:clingen CAID:CA410206900 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.685G>A (p.Glu229Lys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206900/MONDO:0100083/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61033 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0039231 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0595928 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0595928 infores:hetionet CHEBI:4636 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0344232 infores:hetionet CHEBI:31859 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0917801 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0029134 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006373 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0032000 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1510410 infores:hetionet CHEBI:9316 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0003578 infores:hetionet CHEBI:135929 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C1141861 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020039 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0232431 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0877144 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0877144 infores:hetionet CHEBI:6923 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0037763 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0795692 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1368065 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853193 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0007221 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0007221 uuid:660be67c-b26d-4446-a075-be26f12616d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48390 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0012833 infores:hetionet CHEBI:3380 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0546884 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0040046 infores:hetionet CHEBI:9150 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0085593 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0011849 infores:hetionet CHEBI:51041 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151908 infores:hetionet NCBIGene:55596 biolink:causes MONDO:0032865 infores:monarchinitiative not_provided not_provided HGNC:25265 MONDO:0032865 uuid:fb7c1808-78da-4fcf-baa9-07877fbdd20b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0019079 infores:hetionet CAID:CA8602661 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602661 MONDO:0100326 PMID: Benign BA1, BP4 The c.2511G>C variant in ITGA2B is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 837 (p.Gln837His). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01740 (530/30456 alleles) in the South Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.197, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602661/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:2904 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0036974 infores:hetionet CHEBI:3441 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0162830 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0855242 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0015397 infores:hetionet CHEBI:5002 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0151735 infores:hetionet CHEBI:4798 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0027497 infores:hetionet NCBIGene:7291 biolink:causes MONDO:0007399 infores:monarchinitiative not_provided not_provided HGNC:12428 MONDO:0007399 uuid:a9136d80-4b63-49f6-8be7-c190ac762070 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3061 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0344232 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0162429 infores:hetionet CHEBI:100241 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027540 infores:hetionet CAID:CA8815383 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815383 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PS3_Moderate, PM2_Supporting The NM_000152.5:c.1552-3C>G variant in GAA is an intronic variant which occurs within intron 10 and is predicted to impact splicing by disrupting the acceptor splice site (PP3). Experimental studies in fibroblasts from a patient that was homozygous for the variant demonstrated that the variant results in the full inclusion of intron 10, which is predicted to introduce a premature termination codon. However, there was some evidence of normal splicing (PMID 6838077, 25243733) (PS3_Moderate). At least 3 patients with Pompe disease have been reported with this variant including 2 patients with documented GAA deficiency (PP4_Moderate) (PMID 16838077, 28196920, 23430949). Of these patients, one is homozygous for the variant (PMID 16838077) and one is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16838077) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002713 (35/129024 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 419722, 2 star review status) with 10 submitters classifying as likely pathogenic or pathogenic and 1 submitter classifying as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/Amp criteria met, as specified by the ClinGen LSD VCEP: PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815383/MONDO:0009290/010 2022-06-03 2022-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5784 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0009806 infores:hetionet CHEBI:3286 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0026858 infores:hetionet CHEBI:6539 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0851578 infores:hetionet CHEBI:6754 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0026205 infores:hetionet UMLS:C0657912 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014866 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0009241 infores:hetionet CHEBI:2663 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0043094 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0010709 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0022354 infores:hetionet CHEBI:64312 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020625 infores:hetionet CHEBI:7822 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0004096 infores:hetionet CHEBI:134936 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0021400 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0178421 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0020538 infores:hetionet CHEBI:40279 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1145670 infores:hetionet CHEBI:142290 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233471 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038362 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0392386 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020538 infores:hetionet CHEBI:50922 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0438215 infores:hetionet NCBIGene:4653 biolink:causes MONDO:0007664 infores:monarchinitiative not_provided not_provided HGNC:7610 MONDO:0007664 uuid:65d19c87-694e-4aaf-af27-9c5c32732ac8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0702166 infores:hetionet CHEBI:107736 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0085631 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0851578 infores:hetionet CHEBI:45367 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0009782 infores:hetionet CHEBI:5558 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0042571 infores:hetionet CHEBI:50692 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0242172 infores:hetionet CHEBI:9086 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151937 infores:hetionet CHEBI:10023 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151636 infores:hetionet NCBIGene:763 biolink:causes MONDO:0014332 infores:monarchinitiative not_provided not_provided HGNC:1377 MONDO:0014332 uuid:5964ff75-fcf5-443e-a8b1-fb5b12790892 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94440 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0038362 infores:hetionet CAID:CA386966192 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966192 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PP3 PM5 The c.794A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to serine at codon 265 (p.Tyr265Ser) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Also, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.938, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.794A>G (p.Tyr265Cys), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.794A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PP3 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966192/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3738 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0340464 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1384353 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0019158 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020456 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151698 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0017152 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029408 infores:hetionet CHEBI:23765 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0522055 infores:hetionet GO:2000977 biolink:causes GO:0030900 infores:ubergraph knowledge_assertion manual_agent GO:2000977 GO:0030900 CHEBI:5613 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0025061 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0262385 infores:hetionet CAID:CA8814833 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814833 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3, BS3_Supporting PM5 "The NM_000152.5:c.266G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 89 (p.Arg89His). Two individuals with this variant have been reported to exhibit clinical symptoms of infantile onset Pompe disease, one of them on enzyme replacement therapy (PMID: 22644586 25626711) (PP4_Moderate). One of them is homozygous for c.[266G>A, 546+45G>C] (PMID: 22644586), and the other is compound heterozygous for c.266G>A and c.104T>C (p.Phe35Ser) (PMID: 25626711). The clinical significance of c.[266G>A, 546+45G>C] and c.104T>C (p.Phe35Ser) is unknown. The variant was also found in compound heterozygosity with c.2237G>C (p.Trp746Ser) (LP based on classification by the ClinGen Lysosomal Diseases VCEP) by exome sequencing in a proband, confirmed in trans; three siblings have the same genotype. Three of the siblings have GAA activity consistent with late onset disease, and GAA activity was slightly above this range in the remaining sibling. However, none of them have developed clinical symptoms of Pompe disease yet (see ClinVar Variation ID: 283219; SCV003927052.1). Individuals identified by newborn screen, and so far clinically asymptomatic, have the genotype c.-32-13T>G/c.266G>A; c.1377C>G (PMID: 33202836); or are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.1655T>C (p.Leu552Pro) (PMID: 33202836) or c.525delT (PMID: 28196920). Another individual, with dual molecular diagnoses of GSD 1, and Pompe is homozygous for c.266G>A (p.Arg89His) but no clinical details are available (PMID: 28600779). Therefore, without reports of any symptomatic individuals who have this variant in trans with a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.001168 in the Ashkenazi Jewish population (12/10272; no homozygotes). The highest population minor allele frequency in a continental population in gnomAD v2.1.1. is 0.00016 (5/30550) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.819 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). When expressed in COS cells, this variant was classified as Class E (""presumably nonpathogenic"") by Kroos et al, 2012 (PMID:22644586). This includes 43.5% GAA activity in cells and 20% in medium, and is normally synthesized (though less than normal) and processed on Western blot (BS3_Supporting). Three other missense variants at the same position have been reported - c.265C>T (p.Arg89Cys) (VUS based on classification by the ClinGen LD VCEP; ClinVar Variation ID: 456412, SCV002817439.1), c.265C>A (p.Arg89Ser) (ClinVar Variation ID: 1989151), and c.266G>T (p.Arg89Leu) (ClinVar Variation ID: 2754338) (not yet classified by the ClinGen LD VCEP).There is a ClinVar entry for this variant (Variation ID: 283219). In summary, this variant meets the criteria to be classified as a Variant of Unknown Significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PP3, PM2_Supporting, BS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 16, 2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814833/MONDO:0009290/010 2024-04-16 2024-04-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:17474 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0035455 infores:hetionet CHEBI:71940 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0015672 infores:hetionet CHEBI:17141 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0023222 infores:hetionet CHEBI:6838 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0011071 infores:hetionet CHEBI:4551 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0042514 infores:hetionet CHEBI:2682 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0032227 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853777 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0858667 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0858667 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0032961 infores:hetionet CHEBI:4027 biolink:causes HP:0033670 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0264383 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0403632 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0270994 infores:hetionet CHEBI:4445 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0008370 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234988 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234988 infores:hetionet CHEBI:17823 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C1291078 infores:hetionet CHEBI:5004 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0018681 infores:hetionet NCBIGene:5087 biolink:causes MONDO:0060549 infores:monarchinitiative not_provided not_provided HGNC:8632 MONDO:0060549 uuid:655fca3e-3ed2-4c9f-a7e0-75cff546f9dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55521 biolink:causes MONDO:0008791 infores:monarchinitiative not_provided not_provided HGNC:16280 MONDO:0008791 uuid:e2b98b0a-790f-4281-8e16-2fcbff39ad0e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92607 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0155626 infores:hetionet CHEBI:92511 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0677500 infores:hetionet CHEBI:29688 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0009782 infores:hetionet CHEBI:204734 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0085649 infores:hetionet CHEBI:168396 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0043094 infores:hetionet CHEBI:4909 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0014848 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001294 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0019937 infores:hetionet CHEBI:8093 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C3665347 infores:hetionet CHEBI:3441 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0016204 infores:hetionet CHEBI:28487 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0013428 infores:hetionet CAID:CA8815306 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815306 MONDO:0009290 PMID:11738358PMID:17616415PMID:19862843 Pathogenic PM2, PP4, PP3, PM3, PM4_Supporting, PS3 This variant, c.1408_1410del (p.Asn470del), results in an in frame deletion of a single amino acid in GAA, meeting PM4_Supporting. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005447 in the East Asian population, meeting PM2. This variant was found in two Spanish individuals with infantile-onset Pompe disease, who meet the ClinGen LSD VCEP’s PP4 specifications, in compound heterozygosity with c.1222A>G (p.Met408Val) (PMIDs 11738358, 17616415). In one patient, the phase was confirmed in trans (PMID 11738358). This in trans data meets PM3. When expressed in COS-7 cells, this variant had 1.4% wild type GAA activity, meeting PS3 (PMID 19862843). PROVEAN and Mutation Taster predict that this variant is deleterious, meeting PP3. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a pathogenic variant for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PM4_Supporting, PP3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815306/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7824 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020649 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015397 infores:hetionet CHEBI:64312 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027849 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0022568 infores:hetionet CHEBI:4798 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0009763 infores:hetionet CHEBI:2955 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0022346 infores:hetionet CHEBI:63581 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0033774 infores:hetionet CHEBI:6444 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C1145670 infores:hetionet CHEBI:520985 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0162830 infores:hetionet CHEBI:15367 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011606 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0239150 infores:hetionet CHEBI:10023 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0043352 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948586 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0007117 infores:hetionet CHEBI:42944 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0233471 infores:hetionet CHEBI:4717 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0020456 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0558489 infores:hetionet CHEBI:53760 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C3263723 infores:hetionet CHEBI:499361 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0036508 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0036454 infores:hetionet CHEBI:9586 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013378 infores:hetionet CHEBI:6128 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151827 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0392176 infores:hetionet CAID:CA401366755 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366755 MONDO:0009290 PMID: Pathogenic PM2, PVS1, PP4, PM3 The c.1438-2A>G variant alters the canonical acceptor splice site of intron 9 and has been shown by RT-PCR to causing skipping of exon 10, resulting in an in frame deletion that removes about 4% of the gene product (PMID 24158270). Exon 10 forms part of the GAA catalytic barrel, including two residues, Trp481 and Trp516, which are part of the GAA active site (PMIDs 1856189; 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity, and PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two individuals with Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4, and who are compound heterozygotes for this variant and a second pathogenic variant, c.-32-13T>G in one case (PMIDs 24158270), and c.955+1G>A in the other (PMID 29422078), meeting PM3. Other variants altering the same canonical splice site, c.1438-1G>T (PMID 18425781) and c.1438-1G>C (PMIDs 22538254, 24495340), have been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 526521) with one submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366755/MONDO:0009290/010 2020-03-30 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6754 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0855223 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0518015 infores:hetionet CHEBI:5864 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0575081 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0234193 infores:hetionet CHEBI:3696 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0019209 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042373 infores:hetionet CAID:CA386952736 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952736 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4, PP1 The c.82C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 28 (p.(Gln28Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:12355088, PMID:16496320, internal lab contributor). One of these individuals has a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, so PP4 cannot be applied (internal lab contributor). This variant segregated with diabetes with two informative meioses in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.82C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952736/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7478 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0030193 infores:hetionet CHEBI:15367 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0039070 infores:hetionet CHEBI:7773 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0004093 infores:hetionet CHEBI:72564 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0235886 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014130 infores:hetionet CHEBI:93363 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0423153 infores:hetionet CHEBI:52010 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0162830 infores:hetionet GO:0140415 biolink:causes GO:0140546 infores:ubergraph knowledge_assertion manual_agent GO:0140415 GO:0140546 CHEBI:68642 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0042075 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042075 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0341439 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0341439 infores:hetionet CHEBI:2611 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0033774 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0518015 infores:hetionet CHEBI:499361 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0016382 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0009450 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020649 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0851341 infores:hetionet CAID:CA392339801 biolink:causes MONDO:0007947 infores:clingen CAID:CA392339801 MONDO:0007947 PMID: Pathogenic PM6, PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong PM5 The NM_00138 c.5966G>T, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 1989 (p.Cys1989Phe). This variant was found in a proband diagnosed with typical Marfan syndrome (internal lab data, PP4); in this family, the variant was found to be de novo in the proband’s symptomatic mother (internal lab data, PM6). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 638559). At least three other probands with Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (PMID 29848614, Petrovsky National Research Centre of Surgery ClinVar entry, Cologne University ClinVar entry, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.947, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Mod, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392339801/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:31236 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0242528 infores:hetionet CHEBI:144551 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151766 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0948594 infores:hetionet CHEBI:240107 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0035309 infores:hetionet CHEBI:61390 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0010200 infores:hetionet CHEBI:15640 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0002792 infores:hetionet CHEBI:3228 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0018681 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0700184 infores:hetionet CHEBI:127342 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0003862 infores:hetionet CHEBI:4856 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C3665386 infores:hetionet CHEBI:37333 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0085593 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0020649 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C1443060 infores:hetionet CHEBI:53691 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0042510 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042164 infores:hetionet CAID:CA2831039231 biolink:causes MONDO:0011071 infores:clingen CAID:CA2831039231 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PP4 NM_001754.5(RUNX1):c.777_778dup (p.Asn260fs) is a nonsense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is a nonsense/frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PVS1, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2831039231/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6887 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0026821 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020458 infores:hetionet CHEBI:63635 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0003467 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0029408 infores:hetionet NCBIGene:64581 biolink:causes MONDO:0013140 infores:monarchinitiative not_provided not_provided HGNC:14558 MONDO:0013140 uuid:6599f1c6-9b3b-447d-8811-cd5a03d16252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0600228 infores:hetionet CAID:CA404041079 biolink:causes MONDO:0018947 infores:clingen CAID:CA404041079 MONDO:0018947 PMID: Pathogenic PS4, PS2, PP2, PP3, PM2_Supporting, PS3_Moderate BA1, BP4, BS1 The c.1852G>A (p.Ala618Thr) variant in DNM2 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 618. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.818, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in four probands with features of centronuclear myopathy, two of which were de novo with parental relationships confirmed (PS4, PS2; PMIDs:17932957, 28357410, 34463354, 32154989). In vitro assays showed an increase in GTPase activity and oligomer stability indicating that this variant impacts protein function (PMIDs: 26199319, 20700106, 34744632)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PS2, PS3_Moderate, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA404041079/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:499361 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0025061 infores:hetionet CAID:CA000437 biolink:causes MONDO:0017623 infores:clingen CAID:CA000437 MONDO:0017623 PMID: Pathogenic PM2, PM6_Very Strong, PP2, PM1, PS3, PS4 PTEN c.389G>A (p.R130Q) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_VS: At least four assumed de novo observations in a patient with the disease and no family history. (PMID 22595938, PMID 22327138, internal laboratory contributor(s) SCV000222111.11)PS3: Phosphatase activity <50% of wild type (PMID 10866302)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 26798346, PMID 17526801, PMID 23335809, PMID 22266152)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000437/MONDO:0017623/003 2017-10-18 2024-09-23 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0005740 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0746883 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0548823 infores:hetionet CHEBI:51450 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018965 infores:hetionet CHEBI:7445 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0030252 infores:hetionet CHEBI:6931 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0011253 infores:hetionet CHEBI:82941 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0392525 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026603 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004936 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004652 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0004626 infores:hetionet CHEBI:7936 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C3665386 infores:hetionet NCBIGene:1497 biolink:causes MONDO:0009066 infores:monarchinitiative not_provided not_provided HGNC:2518 MONDO:0009066 uuid:202e97a8-c89a-4986-bf2f-a7e9202eca5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0022650 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036572 infores:hetionet CHEBI:8774 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0085631 infores:hetionet CHEBI:31413 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0027497 infores:hetionet CHEBI:3723 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2242737 infores:hetionet CHEBI:5801 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0007682 infores:hetionet GO:0006954 biolink:causes MONDO:0005083 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D011565 DB08908_MESH_D011565_1 CHEBI:3647 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0002453 infores:hetionet CHEBI:28148 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0344232 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0162429 infores:hetionet CHEBI:3716 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0011991 infores:hetionet CHEBI:15765 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013395 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0036508 infores:hetionet CAID:CA1905697 biolink:causes MONDO:0018958 infores:clingen CAID:CA1905697 MONDO:0018958 PMID: Likely Benign BS1 BA1, BP4, PM3, PM2, PP3 The c.25463A>G (p.Lys8488Arg) variant in NEB is a missense variant predicted to cause substitution of lysine by arginine at amino acid 8488. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0009555 (1161/1179882 alleles) in the European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.174, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1905697/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:4089 biolink:causes MONDO:0008278 infores:monarchinitiative not_provided not_provided HGNC:6770 MONDO:0008278 uuid:ac899491-82bc-4220-b2df-d8b026fe50e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0029878 infores:hetionet CHEBI:8378 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0002994 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0581912 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0948525 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0020615 infores:hetionet CAID:CA210748 biolink:causes MONDO:0013144 infores:clingen CAID:CA210748 MONDO:0013144 PMID:2615648 Pathogenic PS4, PM1, PM5, PP1_Strong, PP3, PP4 PM2 The c.235C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 79 (p.Arg79Cys). This variant has been reported in at least 31 probands meeting an antithrombin activity level of <0.8 IU/mL and several more are reported in the literature (PS4_Very Strong; PMID:28300866). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 18 affected family meioses from 32 families (PP1_Strong; 28300866). One of 50 individuals within 45 families who had a mean AT activity of 53% and AT antigen level of 106%, which is highly specific for hereditary antithrombin deficiencies. The curators confirmed with lead author that most individuals AT levels were confirmed with at least two samples since this is not specified in the publication. The ClinGen Thrombosis VCEP members have agreed that all probands in this paper can be counted at full strength for PP4 (PP4_Supporting; PMID:28300866). The computational predictor REVEL gives a score of 0.743, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant resides within a region, Arg79, of SERPINC1 that would impact heparin binding site residues and is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PMID:2615648; PM1). Another missense variant c.236G>A (p.Arg79His) (ClinVarID:18014) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PS4_Very strong, PM1, PM5, PP3, PP4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210748/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63631 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020580 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0267792 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0007642 infores:hetionet CAID:CA1139665161 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665161 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 The c.1752-3_1755del variant in ACADVL deletes the canonical splice acceptor site (- 1,2) of intron 18. It is predicted to cause skipping of biologically-relevant-exon 19/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 9973285, 11590124). At least one patient with this variant displayed increased acylcarnitines, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. (PP4, PMID: 30626930). Additionally, at least two individuals with this variant were identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305, 35281663). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665161/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:54880 biolink:causes MONDO:0010261 infores:monarchinitiative not_provided not_provided HGNC:20893 MONDO:0010261 uuid:8cb13eb9-433f-4b10-8ee5-9327a89dcd4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0085605 infores:hetionet CAID:CA3530486 biolink:causes MONDO:0015152 infores:clingen CAID:CA3530486 MONDO:0015152 PMID: Uncertain Significance PP3 BP1, BP4, BP3, BP2, BA1, PS4, PS3, PS2, PS1, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PVS1, PM2, PM6, BS2, PP2, PP1, PP4 The NM_000337.6: c.91C>T variant in SGCD is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 31 (p.Arg31Trp). The highest minor allele frequency for this variant is 0.00009898 in the South Asian population of gnomAD v2.1.1 (3/30310 exome chromosomes), which is higher than the LGMD VCEP threshold for PM2_Supporting (0.00009) (criterion not met). The computational predictor REVEL gives a score of 0.835, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCD function (PP3). In summary, at this time there is insufficient evidence to classify this variant as pathogenic or benign, and it remains a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3530486/MONDO:0015152/186 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6832 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0015230 infores:hetionet CHEBI:47499 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0600142 infores:hetionet NCBIGene:1073 biolink:causes MONDO:0012538 infores:monarchinitiative not_provided not_provided HGNC:1875 MONDO:0012538 uuid:703b8e83-2577-4209-bc15-95699fd159de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45924 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C1384353 infores:hetionet CHEBI:584020 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0687713 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027765 infores:hetionet CAID:CA2499225871 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225871 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 The c.1219_1221delinsGGGATCGTTCGGA (p.Tyr407Glyfs*196) (NM_001754.5) variant in RUNX1 - whose mechanism of disease is established to be loss-of-function - is a protein extension variant that is predicted to escape nonsense-mediated decay but alters a region critical to protein function (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). This variant is absent from gnomAD v2, v3, and v4 with at least 20 coverage (PM2_Supporting). Only the somatic variant has been reported in a patient with mixed phenotype acute leukemia (ClinVar SCV001573164.1), but it is of note that other pathogenic/likely pathogenic frameshift alterations in exon 8 have been reported (PMID: 35764482), and other C-terminal frameshift variants have shown loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1_Strong, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval) Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225871/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40279 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0009806 infores:hetionet CHEBI:51380 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C1443060 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0009806 infores:hetionet CHEBI:8430 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0003578 infores:hetionet CAID:CA244533104 biolink:causes MONDO:0015967 infores:clingen CAID:CA244533104 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate BP4, PS4, PM5, PP3 The c.866C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 289 (p.(Pro289Arg)) of NM_000545.8. This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 6.80e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant has a REVEL score of 0.679, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-sensitive) (PP4_Moderate; internal lab contributors). Other missense variants this amino acid position, c.866C>A (p.Pro289His) and c.865C>T (p.Pro289Ser), have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.866C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244533104/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:136040 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0042029 infores:hetionet NCBIGene:258 biolink:causes MONDO:0014560 infores:monarchinitiative not_provided not_provided HGNC:452 MONDO:0014560 uuid:3a97a2e2-76f7-4477-ac62-7e235ff67309 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003864 infores:hetionet CHEBI:31981 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0009806 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0855242 infores:hetionet CHEBI:4659 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0019158 infores:hetionet CHEBI:4876 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0027497 infores:hetionet CHEBI:2955 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0424295 infores:hetionet CHEBI:8768 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0155365 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0040409 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C1527407 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C1269683 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0042373 infores:hetionet CHEBI:3752 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0000768 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0009806 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037286 infores:hetionet CHEBI:6375 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0392525 infores:hetionet CHEBI:63617 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011175 infores:hetionet CHEBI:4315 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0151942 infores:hetionet CHEBI:51380 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0039231 infores:hetionet CHEBI:63599 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0085593 infores:hetionet CHEBI:30830 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0235063 infores:hetionet CAID:CA414436678 biolink:causes MONDO:0010604 infores:clingen CAID:CA414436678 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PP3, PS4_Very Strong PM5, PM1 The NM_000133.4(F9):c.277G>A (p.Asp93Asn) variant is completely absent from gnomAD v2.1.1 and v3.1.2 meeting PM2_Supporting. At least 8 individuals with moderate-severe hemophilia B are found in the literature (PMIDs: 29296726, 11013449, 8091381, 22103590, 10698280, 2198809, 24656159) meeting criteria for PS4_Very strong. This missense variant has a REVEL score of 0.754 (>0.6), and the nucleotide is the last in exon 3 which SpliceAI predicts results in the loss of the splice donor of intron 3 (delta score of 0.93) meeting PP3. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414436678/MONDO:0010604/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Supports CHEBI:44032 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0235639 infores:hetionet CHEBI:31932 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0006277 infores:hetionet CAID:CA915940265 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940265 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.1524_1533del (p.Gln508HisfsTer3) variant was identified in a patient (Patient 4, PMID 28888044) with a severe bleeding phenotype and diagnosis of GT. This indel results in the substitution of a Glutamine with a Histidine at amino acid residue 508 leading to a frameshift and eventual premature stop codon at codon 511 (PMID 28888044). Since this deletion occurs before the c.3011 in ITGA2B, the altered mRNA is predicted to undergo nonsense-mediated decay (PVS1). This variant was identified in a patient (Patient 4, PMID 28888044) with a severe bleeding type; common presentations in this cohort included recurrent epistaxis, bleeding in the oral cavity, and easy bruising spontaneously or after trauma. Platelet aggregation was negative for the agonists collagen, ADP, and arachidonic acid but was normal for ristocetin. Flow cytometry to analyze the platelet surface for CD41 and CD61 showed reduced expression in all patients. Sequencing of ITGB3 and ITGA2B was completed using whole exome sequencing although only this deletion was found by their exome sequencing (PP4_moderate). This variant is not reported in the gnomAD database v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940265/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:16335 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0085614 infores:hetionet CHEBI:29013 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0037274 infores:hetionet CHEBI:6541 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0039070 infores:hetionet CHEBI:6741 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0041582 infores:hetionet NCBIGene:128178 biolink:causes MONDO:0013983 infores:monarchinitiative not_provided not_provided HGNC:14341 MONDO:0013983 uuid:1f826d2d-6883-4bf8-8e8c-79f18b59254b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0003400 biolink:causes GO:0048207 infores:ubergraph knowledge_assertion manual_agent GO:0003400 GO:0048207 CHEBI:8871 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020649 infores:hetionet CHEBI:472657 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0014742 infores:hetionet CHEBI:4562 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C2242996 infores:hetionet CHEBI:7640 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0085631 infores:hetionet CHEBI:51860 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0039070 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0522224 infores:hetionet CHEBI:64317 biolink:causes NCIT:C100076 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0232201 infores:hetionet CHEBI:42944 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0004134 infores:hetionet CAID:CA1139655404 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139655404 MONDO:0015967 PMID: Pathogenic PVS1, PM2_Supporting, PP1_Strong PP4, BA1, PS4, BS1 The c.256_257del variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes a frameshift in the protein at codon 86 in transcript NM_175914.5, adding 25 novel amino acids before encountering a stop codon (p.(Lys86GlufsTer25)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805 ). This variant segregated with diabetes with 5 informative meioses in a single family (PP1_Strong; PMID: 10447526). In summary, c.256_257del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139655404/MONDO:0015967/085 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49575 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0030193 infores:hetionet CHEBI:50730 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0014394 infores:hetionet CHEBI:32139 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0028643 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0234215 infores:hetionet CHEBI:83804 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0025323 infores:hetionet CHEBI:49668 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0036508 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0302295 infores:hetionet NCBIGene:55714 biolink:causes MONDO:0014059 infores:monarchinitiative not_provided not_provided HGNC:29944 MONDO:0014059 uuid:35e119a4-2a9f-4598-bc03-523a952c41f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134966 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0851341 infores:hetionet CHEBI:63681 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0392171 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0027497 infores:hetionet CHEBI:46557 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042029 infores:hetionet CHEBI:4907 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0014742 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0018099 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0037822 infores:hetionet CHEBI:8774 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0003467 infores:hetionet CHEBI:76010 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0037274 infores:hetionet CAID:CA10584810 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584810 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, PM5, PP3 The NM_000527.5(LDLR):c.251C>G (p.Pro84Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).: PP4 - Variant meets PM2 and is identified in one index case from PMID 16159606 who fulfill SB criteria for FH. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584810/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7496 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C1262113 infores:hetionet CL:0000178 biolink:causes MONDO:0036595 infores:ubergraph knowledge_assertion manual_agent CL:0000178 MONDO:0036595 CHEBI:9599 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0009676 infores:hetionet CHEBI:91541 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0037274 infores:hetionet GO:1901434 biolink:causes GO:0071466 infores:ubergraph knowledge_assertion manual_agent GO:1901434 GO:0071466 CHEBI:145499 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020580 infores:hetionet UMLS:C0025241 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0030554 infores:hetionet CHEBI:6888 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0231218 infores:hetionet GO:0072674 biolink:causes CL:0000779 infores:ubergraph knowledge_assertion manual_agent GO:0072674 CL:0000779 CHEBI:3696 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151904 infores:hetionet CHEBI:63637 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0042963 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0020517 infores:hetionet CAID:CA496153150 biolink:causes MONDO:0007648 infores:clingen CAID:CA496153150 MONDO:0007648 PMID: Likely Pathogenic PS4_Supporting, PM2_Supporting, PVS1_Moderate, PP3_Moderate BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP1, PP4, BS2, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2 The c.1137G>T p. (Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant affects the same splice site as a well-characterized splice variant with similar or worse in silico/ RNA predictions (PP3_Moderate). Additionally, this variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 26182300). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PP3_Moderate, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA496153150/MONDO:0007648/007 2023-08-30 2023-08-30 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:47780 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0240717 infores:hetionet CAID:CA8622959 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622959 MONDO:0100326 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.414G>C (p.Val138=), no individuals with glanzmann thrombasthenia were reported with the variant. The variant has a minor allele frequency of 0.00001758 (2/113758 alleles) in the European (Non-Finnish) population in gnomAD, which meets the threshold criteria for PM2_supporting. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -.103 shows that the nucleotide position is not highly conserved (BP4, BP7). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, BP4, BP7. (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622959/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7494 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0744727 infores:hetionet CHEBI:3561 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0086565 infores:hetionet CAID:CA145772 biolink:causes MONDO:0009290 infores:clingen CAID:CA145772 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.2446G>A (p.Val816Ile) in gnomAD v2.1.1 is 0.14249 in the African population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92477; 2 star review status) with four submitters classifying the variant as benign, and two as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145772/MONDO:0009290/010 2020-01-23 2020-05-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3650 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0003123 infores:hetionet NCBIGene:5880 biolink:causes MONDO:0033554 infores:monarchinitiative not_provided not_provided HGNC:9802 MONDO:0033554 uuid:73425faf-6a4c-4146-95c6-5d69951a33a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C2047937 infores:hetionet CHEBI:3061 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0011071 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0858259 infores:hetionet CHEBI:3001 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0006266 infores:hetionet NCBIGene:2632 biolink:causes MONDO:0009292 infores:monarchinitiative not_provided not_provided HGNC:4180 MONDO:0009292 uuid:a121a66a-c762-4726-a11b-8446995f8ae0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0026821 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033046 infores:hetionet CHEBI:6954 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0037036 infores:hetionet CHEBI:3223 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0002170 infores:hetionet CHEBI:32888 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0012833 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0037822 infores:hetionet CAID:CA120583 biolink:causes MONDO:0044970 infores:clingen CAID:CA120583 MONDO:0044970 PMID:8254046PMID:9372914PMID:10332045 Pathogenic PP3, PM2_Supporting, PM6_Strong, PS4_Moderate, PS3_Supporting PP1 The m.5703G>A variant in MT-TN has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate). These four individuals were from three different backgrounds including African American (one individual), Chinese (one individual), and Caucasian (two individuals, one from France and one from Spain). Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), as well as exercise intolerance, severe underweight, and hearing loss (PMIDs: 8254046, 14518831, 30897601, 32419253). The variant in these four cases was seen at varying degrees of heteroplasmy in muscle (14-80%), blood (5-48%), urine (4-11%), and buccal (7-59%). The variant was reported to have arisen de novo in three of the four affected individuals (PM6_strong, PMIDs: 8254046, 30897601, 32419253) and no details about family member testing were provided for the other individual. Furthermore, the variant’s presence in individuals of different ethnic backgrounds was also considered as indirect evidence of a de novo occurrence at some time in the past. There are no other large families reported in the medical literature to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP predicts this variant to be pathogenic, scoring in the 89.9 percentile and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). Multiple independent studies support the functional impact of this variant (PS3_supporting). Single-fiber testing in two of the four affected individuals was performed and showed that the variant was present at higher heteroplasmy in COX-negative fibers than COX-positive fibers (93% heteroplasmy in COX-negative fibers compared to 2% in COX-positive fibers in one individual, P<.0001, PMID: 32419253; and 97-100% in COX-negative fibers compared to 3-63% in COX-positive fibers in the other individual, PMID: 8254046). Furthermore, cybrids with high levels of the variant demonstrated a severe mitochondrial protein synthesis defect and impaired oxidative phosphorylation (PMIDs: 8254046, 9372914). tRNA conformational studies showed impaired aminoacylation with severe reduction of the tRNA Asn pool (PMID: 9372914). In summary, this variant meets criteria to be classified as likely pathogenic however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given consistent functional evidence of severe deleterious effect across multiple independent studies and given repeated apparent de novo occurrences across individuals of different ethnic backgrounds. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_supporting, PP3, PM2_supporting, PM6_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120583/MONDO:0044970/015 2023-02-13 2023-03-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:9943 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011253 infores:hetionet CAID:CA2654377535 biolink:causes MONDO:0011071 infores:clingen CAID:CA2654377535 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968-3C>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.14) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2654377535/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0005740 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0151205 infores:hetionet CHEBI:44185 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0242528 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0877661 infores:hetionet CHEBI:72297 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0750394 infores:hetionet CHEBI:135342 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0034886 infores:hetionet CHEBI:6822 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0040264 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0002878 infores:hetionet CHEBI:52172 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030193 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0004623 infores:hetionet CHEBI:6888 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0338831 infores:hetionet CHEBI:3994 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0039231 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0575090 infores:hetionet CHEBI:47898 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006384 infores:hetionet CHEBI:49713 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0042963 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0878544 infores:hetionet CHEBI:7496 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0030554 infores:hetionet CAID:CA011032 biolink:causes MONDO:0004994 infores:clingen CAID:CA011032 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1605A>G (p.Glu535=) variant in the MYH7 gene is 10.63% (1162/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011032/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:18248 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0027769 infores:hetionet CHEBI:45409 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0018681 infores:hetionet CHEBI:40303 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0030196 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0013595 infores:hetionet CHEBI:2453 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0042963 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0035455 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0001339 infores:hetionet CAID:CA400180251 biolink:causes MONDO:0015152 infores:clingen CAID:CA400180251 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3, PP3 The NM_000023.4: c.585-1G>A variant in SGCA occurs within the canonical splice acceptor site (-1) of intron 5. It is predicted to cause skipping of biologically relevant exon 6/10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified with a second SGCA variant in a patient with progressive limb girdle muscle weakness and decreased expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002 (1/41404 alleles) in the African American population, which is below the LGMD VCEP threshold (<0.00009), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA400180251/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports GO:0002316 biolink:causes CL:0000843 infores:ubergraph knowledge_assertion manual_agent GO:0002316 CL:0000843 CAID:CA386964398 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964398 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PM5_Supporting, PP3 PP4 The c.618G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tryptophan to cysteine at codon 206 (p.(Trp206Cys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.923, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, this variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Lastly, another missense variant, c.616T>A p.(Trp206Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.618G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP3, PM1, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964398/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:32315 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0004096 infores:hetionet CHEBI:72297 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0232495 infores:hetionet CHEBI:64355 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0014591 infores:hetionet CAID:CA023956 biolink:causes MONDO:0007783 infores:clingen CAID:CA023956 MONDO:0007783 PMID:23459219 Pathogenic PP1, PS3_Moderate, PM5, PS4_Moderate, PM1_Supporting, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 401 of the RYR1 protein p.(Arg401Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate ( PMID:30236257, PMID:12434264, PMID:24433488, PMID:25735680). This variant segregates with MHS in three individuals, PP1 (PMID:12066726, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate, (PMID:23459219). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5 (PMID:16917943). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score > 0.85 (0.886) supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023956/MONDO:0007783/012 2022-03-29 2022-03-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:5165 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0424295 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0011849 infores:hetionet CHEBI:7443 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0702166 infores:hetionet CHEBI:3176 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0022107 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0413234 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0413234 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0031542 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0023474 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0023474 infores:hetionet NCBIGene:55250 biolink:causes MONDO:0014996 infores:monarchinitiative not_provided not_provided HGNC:18248 MONDO:0014996 uuid:797be65e-6a9f-4069-a26c-ee35d6e84550 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9566 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0022346 infores:hetionet CHEBI:3478 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0019080 infores:hetionet UMLS:C0120107 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0011124 infores:hetionet CAID:CA348802582 biolink:causes MONDO:0018958 infores:clingen CAID:CA348802582 MONDO:0018958 PMID: Likely Pathogenic PVS1_Strong, PM5, PM2_Supporting BA1, PM3, BS1 The c.6076-1G>T variant in NEB occurs within the canonical splice acceptor site -1 of intron 47. It is predicted to cause skipping of biologically-relevant-exon 48/182, resulting in an in-frame deletion (removes amino acids 2026-2061) that is predicted to escape nonsense mediated decay (PVS1_Strong). The highest population minor allele frequency in gnomAD 4.1.0 is 0.00002698 (2/74116) in the African American population which meets the threshold to apply PM2_Supporting (MAF≤0.0000559). An additional pathogenic variant was identified in multiple affected probands at the same canonical splice acceptor site (c.6076-2A>C) (Invitae, SCV001204195.4) (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM5, PM2_Supporting. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA348802582/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8107 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0232492 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234987 infores:hetionet CHEBI:9434 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0030196 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042109 infores:hetionet CHEBI:28925 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0040034 infores:hetionet CHEBI:2663 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0013404 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042109 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0178298 infores:hetionet CHEBI:42068 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C1720798 infores:hetionet CAID:CA266014 biolink:causes MONDO:0007064 infores:clingen CAID:CA266014 MONDO:0007064 PMID: Likely Pathogenic PP4_Moderate, PM2, PS3_Moderate PM5, BS1 The NM_000022.4:c.445C>T (p.Arg149Trp) variant in ADA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 149 (p.Arg149Trp). This variant has been reported in an individual with severe combined immunodeficiency and elevated pre-treatment erythrocyte dAXP (2pts, PMID: 10200056) (PP4_Moderate). In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID: 9758612) (PS3_Moderate). The highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population, which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4_Moderate, PS3_Moderate (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA266014/MONDO:0007064/114 2024-01-16 2024-01-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6067 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0267596 infores:hetionet CHEBI:63584 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0017168 infores:hetionet CHEBI:5128 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0852911 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0004987 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0005695 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042571 infores:hetionet CAID:CA10585351 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585351 MONDO:0007750 PMID: Likely Pathogenic PS4, PM4, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM1, PM3, PVS1, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM4, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 19 unrelated FH index cases (18 with DLCN criteria>=6 from PMID: 18243212 (Alonso et al., 2008), and 1 with DLCN criteria from PMID 27784735 (Sánchez-Hernández et al.,2016)). So PS4 is met.PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM4: Variant meets PM2 and is in frame deletion. So PM4 is met. PP4: Variant meets PM2 and is identified in 19 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585351/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:29007 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0016204 infores:hetionet CHEBI:5790 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C3665347 infores:hetionet CHEBI:480999 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0023530 infores:hetionet CAID:CA9871584 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871584 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4 :c.618G>T is a missense variant predicted to cause substitution of Lysine by Asparagine at amino acid 222 (p.Lys206Asn). The filtering allele frequency (the upper threshold of the 95% CI of 13/59022) of the c.618G>T variant in ADA is 0.0001231 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871584/MONDO:0007064/114 2024-06-10 2024-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:74947 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0750394 infores:hetionet NCBITaxon:11676 biolink:causes MONDO:0005109 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:11676 MESH:D015658 DB01232_MESH_D015658_1DB00224_MESH_D015658_1DB00932_MESH_D015658_1DB00943_MESH_D015658_1DB00900_MESH_D015658_1DB00109_MESH_D015658_1DB00701_MESH_D015658_1DB00649_MESH_D015658_1DB00879_MESH_D015658_1DB06817_MESH_D015658_1DB09101_MESH_D015658_1DB01048_MESH_D015658_2DB08930_MESH_D015658_1DB01264_MESH_D015658_1DB00238_MESH_D015658_1DB00709_MESH_D015658_1DB01601_MESH_D015658_1DB00705_MESH_D015658_1DB00220_MESH_D015658_1DB00625_MESH_D015658_1DB00503_MESH_D015658_1DB01072_MESH_D015658_1DB01319_MESH_D015658_1 CHEBI:4636 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0020649 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0442874 infores:hetionet CHEBI:49960 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0003811 infores:hetionet CHEBI:5138 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033046 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0037274 infores:hetionet CHEBI:17303 biolink:causes MONDO:0015129 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0001403 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027051 infores:hetionet CHEBI:9654 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0013384 infores:hetionet CHEBI:70746 biolink:causes MONDO:0004431 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018924 infores:hetionet CHEBI:9566 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0015230 infores:hetionet CHEBI:553473 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0002871 infores:hetionet CHEBI:8871 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085635 infores:hetionet CAID:CA410208003 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208003 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.580A>G (p.Lys194Glu) is a missense variant which has a REVEL score ≥ 0.88 (0.956) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208003/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47781 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0080274 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0039971 infores:hetionet CHEBI:6846 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0042109 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0014742 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022408 infores:hetionet CHEBI:63580 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235378 infores:hetionet CHEBI:5165 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0009676 infores:hetionet CHEBI:31401 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0027497 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235969 infores:hetionet CAID:CA024200 biolink:causes MONDO:0018493 infores:clingen CAID:CA024200 MONDO:0018493 PMID: Pathogenic PS3_Moderate, PS4_Moderate, PM1_Supporting, PP1_Strong, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of lysine with arginine at codon 4876 of the RYR1 protein, p.(Lys4876Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:15731587, PMID:16163667, PMID:19191329, PMID:24433488). This variant segregates with MHS in seven individuals, PP1_Strong (PMID:27854207, Noda et al. 2023). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (Noda et al. 2023). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024200/MONDO:0018493/012 2023-12-15 2023-12-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:92511 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0027769 infores:hetionet CHEBI:50841 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0278134 infores:hetionet CHEBI:144551 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151827 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0151838 infores:hetionet CHEBI:5118 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006384 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0151919 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151919 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027441 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011991 infores:hetionet CHEBI:204734 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0237849 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0010346 infores:hetionet CHEBI:3647 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0686347 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0038363 infores:hetionet CHEBI:5893 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1096355 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0857483 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0857483 infores:hetionet CHEBI:5856 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0018681 infores:hetionet CHEBI:5130 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0011124 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0027051 infores:hetionet CHEBI:100241 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023052 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0019158 infores:hetionet CHEBI:63611 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014724 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030312 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0036572 infores:hetionet CHEBI:31348 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022603 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0042769 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0242350 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0004936 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151559 infores:hetionet CHEBI:31236 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0001807 infores:hetionet CHEBI:107736 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0040822 infores:hetionet CHEBI:3504 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0030554 infores:hetionet CHEBI:9150 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0231528 infores:hetionet NCBIGene:7080 biolink:causes MONDO:0021011 infores:monarchinitiative not_provided not_provided HGNC:11825 MONDO:0021011 uuid:0c1c7cb7-03ca-481f-a5f7-783462ed0ed6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022354 infores:hetionet CHEBI:31397 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C2363731 infores:hetionet CHEBI:7798 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0027441 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018801 infores:hetionet CHEBI:9139 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018681 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0038587 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040425 infores:hetionet CHEBI:63580 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013456 infores:hetionet CHEBI:51041 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085593 infores:hetionet NCBIGene:7532 biolink:causes MONDO:0033365 infores:monarchinitiative not_provided not_provided HGNC:12852 MONDO:0033365 uuid:27691a12-1456-4fc5-a687-890d2d19bcfb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0042373 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0025061 infores:hetionet CHEBI:31348 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085605 infores:hetionet CHEBI:4024 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0011603 infores:hetionet NCBIGene:51360 biolink:causes MONDO:0100213 infores:monarchinitiative not_provided not_provided HGNC:15455 MONDO:0100213 uuid:a374acd8-9f52-4a5a-8b12-2e469ddcbd11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0243026 infores:hetionet CHEBI:27899 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0043144 infores:hetionet CHEBI:7824 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0424790 infores:hetionet CHEBI:16755 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0003862 infores:hetionet CHEBI:4445 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0855775 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0025061 infores:hetionet CHEBI:7959 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0023518 infores:hetionet CHEBI:131512 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0020546 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0221706 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0031350 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0087169 infores:hetionet CHEBI:9448 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0162834 infores:hetionet CHEBI:50648 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018965 infores:hetionet CHEBI:135361 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0553721 infores:hetionet CHEBI:63631 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020672 infores:hetionet CHEBI:71255 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0232461 infores:hetionet CHEBI:3286 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0015230 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0009806 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018939 infores:hetionet NCBIGene:57167 biolink:causes MONDO:0011812 infores:monarchinitiative not_provided not_provided HGNC:15924 MONDO:0011812 uuid:12d4ecf3-86d3-435c-9907-c1cd8e9edfb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034067 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0040034 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0948089 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0032285 infores:hetionet CHEBI:5118 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004134 infores:hetionet CHEBI:3655 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0013395 infores:hetionet CHEBI:30830 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0917801 infores:hetionet CHEBI:35778 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0149871 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0031117 infores:hetionet CHEBI:9168 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0032227 infores:hetionet CHEBI:31980 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0476273 infores:hetionet CHEBI:3504 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0000731 infores:hetionet CHEBI:5558 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0085631 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0241513 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0241513 infores:hetionet CHEBI:7573 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0027497 infores:hetionet CHEBI:47898 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0086439 infores:hetionet CHEBI:17026 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0156404 infores:hetionet CHEBI:4858 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0231528 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0267792 infores:hetionet CHEBI:465284 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0023530 infores:hetionet CHEBI:8707 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011606 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0852733 infores:hetionet CHEBI:132233 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0233472 infores:hetionet CHEBI:77260 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151723 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0376358 infores:hetionet CHEBI:231594 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042133 infores:hetionet CHEBI:91834 biolink:causes MONDO:0010787 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0022541 infores:hetionet CHEBI:9435 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0600260 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0015230 infores:hetionet CAID:CA400031679 biolink:causes MONDO:0100326 infores:clingen CAID:CA400031679 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting The NM_000212.3(ITGB3):c.118C>T (p.Gln40Ter) variant in exon 2/15 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient (Patient GT8 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and Western blot. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PVS1, PM2_supporting. (VCEP specifications version 2; date of approval 02/03/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400031679/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51164 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0027066 infores:hetionet CHEBI:32588 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0011991 infores:hetionet CAID:CA891843861 biolink:causes MONDO:0007648 infores:clingen CAID:CA891843861 MONDO:0007648 PMID:17221870 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP3, BP1, BP4, BP2, BA1, PS1, PS3, PS2 The c.1107del (p.Asn369Lysfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 17221870). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843861/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:3752 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013604 infores:hetionet CHEBI:5784 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0034150 infores:hetionet CAID:CA314868 biolink:causes MONDO:0012996 infores:clingen CAID:CA314868 MONDO:0012996 PMID:27233232 Benign BP4, BA1, BS3_Supporting PP3, PS3, PM2 The NM_001482.3:c.407C>T variant in GATM is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007357 (95/129130 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in >50% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.049 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205613). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): BA1, BS3_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on January 25, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314868/MONDO:0012996/025 2023-01-25 2023-01-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8665 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0034063 infores:hetionet CHEBI:7573 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0206061 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0001824 infores:hetionet CHEBI:72296 biolink:causes UMLS:C1262109 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C1262109 infores:hetionet CHEBI:37941 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0014457 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085606 infores:hetionet CHEBI:7798 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0267792 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0227791 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042109 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018790 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151736 infores:hetionet CHEBI:16335 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0085624 infores:hetionet UMLS:C0025241 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0013404 infores:hetionet NCBIGene:80816 biolink:causes MONDO:0014205 infores:monarchinitiative not_provided not_provided HGNC:29357 MONDO:0014205 uuid:67a84a5e-b5ef-4ba4-b05b-65521dc5e48e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2453 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0003862 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0009450 infores:hetionet CHEBI:8597 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0026961 infores:hetionet CHEBI:7773 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0026858 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027051 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0595930 infores:hetionet CHEBI:82941 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0231528 infores:hetionet UBERON:0006914 biolink:causes MONDO:0002195 infores:ubergraph knowledge_assertion manual_agent UBERON:0006914 MONDO:0002195 CHEBI:47381 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0239571 infores:hetionet GO:1905553 biolink:causes GO:0060562 infores:ubergraph knowledge_assertion manual_agent GO:1905553 GO:0060562 CHEBI:17263 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0016977 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0700590 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0678222 infores:hetionet CHEBI:36791 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151904 infores:hetionet CHEBI:28445 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C1167965 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020615 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0574067 infores:hetionet NCBIGene:229 biolink:causes MONDO:0009249 infores:monarchinitiative not_provided not_provided HGNC:417 MONDO:0009249 uuid:36e91c88-aaaa-41f7-bda1-7929f0cd5292 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0021053 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0032285 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0028754 infores:hetionet CHEBI:6444 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0013384 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0234987 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020039 infores:hetionet CHEBI:66901 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0013456 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042401 infores:hetionet CHEBI:31980 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0037763 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0858520 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0858520 infores:hetionet CHEBI:3175 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0003862 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027651 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0024894 infores:hetionet CAID:CA10585609 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585609 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5_strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.959.It is above 0.75, so PP3 is Met.PM5_strong - 2 other missense variants in the same codon:- NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) (ClinVar ID: 183126) - Pathogenic by these guidelinesThere are 2 variants in the same codon classified as Pathogenic by these guidelines, so PM5_Strong is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585609/MONDO:0007750/013 2022-02-01 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:7454 biolink:causes MONDO:0010518 infores:monarchinitiative not_provided not_provided HGNC:12731 MONDO:0010518 uuid:e18a6453-c269-4324-95b5-53b70b4f63f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65346 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C1384353 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0687133 infores:hetionet CHEBI:15854 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0018681 infores:hetionet CHEBI:7936 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0947912 infores:hetionet CHEBI:2663 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0030554 infores:hetionet CHEBI:6129 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0016204 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0020517 infores:hetionet CHEBI:7565 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0039070 infores:hetionet CHEBI:40050 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0021368 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0087169 infores:hetionet NCBIGene:8473 biolink:causes MONDO:0030907 infores:monarchinitiative not_provided not_provided HGNC:8127 MONDO:0030907 uuid:207fe55d-d727-4c63-ace8-8f3b8c07d26a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0423773 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0392025 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019348 infores:hetionet NCBIGene:3426 biolink:causes MONDO:0012594 infores:monarchinitiative not_provided not_provided HGNC:5394 MONDO:0012594 uuid:4996eda7-ba2c-4d86-82fa-36ec26458bf5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0311468 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0242350 infores:hetionet CAID:CA291037 biolink:causes MONDO:0012996 infores:clingen CAID:CA291037 MONDO:0012996 PMID: Benign BP4, BA1, BP7 PP3, PM2 The NM_001482.3:c.669T>C (p.Tyr223=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00501 (125/24958 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 137449). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on January 25, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291037/MONDO:0012996/025 2023-01-25 2023-01-25 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA390876326 biolink:causes MONDO:0100216 infores:clingen CAID:CA390876326 MONDO:0100216 PMID: Likely Benign BP4, PM2_Supporting, BP7 BS2, PS4 The NM_177438.3:c.3249A>G (p.Arg1083=) variant in DICER1 is a synonymous (silent) variant that is not predicted to impact splicing by MaxEntScan or SpliceAI (BP4, BP7). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, BP7. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390876326/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA386493290 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493290 MONDO:0009861 PMID:31355225 Likely Pathogenic PM3, PM2, PP4_Moderate PP3 The c.1109A>G (p.Glu370Gly) variant in PAH has been reported in a Uygur patient with moderate PKU (BH4 deficiency ruled out) (PP4_Moderate; PMID: 31355225). This variant was detected with p.Val230Ile (Likely pathogenic in ClinVar) (PM3; PMID: 31355225). The variant is absent from population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493290/MONDO:0009861/006 2020-03-26 2020-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32139 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0011603 infores:hetionet CHEBI:77260 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1167965 infores:hetionet CHEBI:63605 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0392699 infores:hetionet CHEBI:8356 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033036 infores:hetionet CHEBI:63617 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0024141 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0027947 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1291078 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030305 infores:hetionet CHEBI:5123 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0018790 infores:hetionet CHEBI:465284 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0917801 infores:hetionet CHEBI:7025 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0234233 infores:hetionet CHEBI:135791 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0175167 infores:hetionet CHEBI:77260 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0018965 infores:hetionet CHEBI:4728 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0239937 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0155003 infores:hetionet CHEBI:144551 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042963 infores:hetionet CAID:CA285294 biolink:causes MONDO:0008723 infores:clingen CAID:CA285294 MONDO:0008723 PMID: Pathogenic PP3, PM1, PM3_Strong, PP4_Moderate, PS3_Supporting PM2 The c.848T>C variant in ACADVL is a missense variant predicted to cause substitution of valine by alanine at amino acid 283 (p.Val283Ala). This variant is also known as Val243Ala when numbered from the mature peptide. The variant accounts for up to 29% of individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency identified by newborn screen (PMID:20301763). This variant has been reported in at least 12 individuals with VLCAD in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 17999356, 26385305, 20107901, 14517516). The variant was detected at least 9 times in the homozygous state as well as at least 1 confirmed in-trans with another pathogenic variant (PM3_Strong; PMID: 20107901; 17999356, 17999356). In vitro expression showed 20-25% residual enzyme activity when expressed in COS7 cells (PS3_supporting; PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002238 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The variant is located in a well-studied outer loop with structural importance with high homology to medium-chain acyl-CoA dehydrogenase (PM1; PMID: 14517516). The computational predictor REVEL gives a score of 0.905, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM1, PP3, PS3_supporting (ACADVL specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA285294/MONDO:0008723/021 2022-08-23 2022-08-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8707 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040822 infores:hetionet NCBIGene:7428 biolink:causes MONDO:0008667 infores:monarchinitiative not_provided not_provided HGNC:12687 MONDO:0008667 uuid:ead5a0b9-cd7b-4bed-bbd2-734c7c51015b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16170 biolink:causes MONDO:0018020 infores:ubergraph knowledge_assertion manual_agent CHEBI:25195 MONDO:0018020 CHEBI:4858 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0038990 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0015230 infores:hetionet CHEBI:3561 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0085631 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0549249 infores:hetionet CHEBI:2549 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0041657 infores:hetionet CAID:CA10443768 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443768 MONDO:0010315 PMID: Likely Benign BS2 BS1, PM2, BP4 The NM_000206.3(IL2RG):c.977G>A (p.Ser326Asn) is a missense variant that has been reported in ClinVar (SCV001722571.2), without patient information, however it has not been reported in the literature to our knowledge. It occurs at an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0003945 (based on 10/14743 alleles in the East Asian population) which is below the SCID VCEP established threshold of >0.00249 for BS1 and above the PM2 threshold of <0.000124. Six adult hemizygous males with this variant are present in the East Asian population in gnomADv2.1.1 (BS2). In summary, this variant is classified as Likely Benign. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443768/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Contradicts true CHEBI:31348 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0021400 infores:hetionet CHEBI:8665 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0011991 infores:hetionet CHEBI:408174 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004604 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0042075 infores:hetionet CHEBI:5778 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0015672 infores:hetionet CHEBI:31236 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019572 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0003123 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0085096 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0239816 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0239816 infores:hetionet CHEBI:27504 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0344232 infores:hetionet CHEBI:134743 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0178298 infores:hetionet CHEBI:182080 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0014742 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D001991 DB13092_MESH_D001991_1DB00618_MESH_D001991_1DB00595_MESH_D001991_1DB01000_MESH_D001991_1DB00954_MESH_D001991_1DB00978_MESH_D001991_1DB00254_MESH_D001991_1 CHEBI:3561 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1368065 infores:hetionet CHEBI:2654 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0020517 infores:hetionet CHEBI:465284 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0022346 infores:hetionet CAID:CA412370011 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370011 MONDO:0010725 PMID:12746437 Likely Pathogenic PM2_Supporting, PS3_Supporting, PS1_Moderate, PP3_Strong PM5, PM1 NM_000330.4(RS1):c.668G>C (p.Cys223Ser) is a missense variant encoding the substitution of cystine with serine at amino acid 223. A missense variant encoding the same amino acid substitution, NM_000330.4(RS1):c.667T>A (p.Cys223Ser) has been classified as likely pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PS1_Moderate). Another missense variant in the same codon, NM_000330.4(RS1):c.667T>C (p.Cys223Arg), (PMIDs: 34645606, 10533068, 30652005, 33460243, 16361673) has been classified as pathogenic. However, the present variant has a lower Grantham’s distance(112) than the comparison variant (180), so PM5 cannot be met. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.953, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control, as well as aberrant immunofluorescent localization of RS1 to the ER/Golgi relative to the wild-type control (PMID: 12746437, PS3_Supporting). This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). However, the PP3_Strong code has been met, which is ineligible to be used in combination with the PM1 code at any strength, so the PM1 code was not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PS1_Moderate, and PS3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370011/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:44185 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0162835 infores:hetionet CHEBI:9130 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0013428 infores:hetionet CHEBI:6741 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0038325 infores:hetionet CHEBI:16347 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0151786 infores:hetionet CHEBI:231425 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0740394 infores:hetionet CHEBI:119486 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085641 infores:hetionet CAID:CA367398729 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398729 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting The c.1150G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 384 (p.(Ala384Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant at the same codon, c.1151C>A (p.Ala384Glu), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala384Pro (PM5_Supporting). In summary, c.1150G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PM2_Supporting, PM5_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398729/MONDO:0015967/086 2025-06-06 2025-06-06 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:100241 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0040264 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027765 infores:hetionet CHEBI:6413 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0423791 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0948594 infores:hetionet CHEBI:7936 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0028084 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0151824 infores:hetionet CHEBI:65173 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0085633 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019348 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151717 infores:hetionet CHEBI:93635 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0042023 infores:hetionet NCBIGene:8029 biolink:causes MONDO:0100156 infores:monarchinitiative not_provided not_provided HGNC:2548 MONDO:0100156 uuid:3cec42af-8fe3-4ed2-995e-987b360752ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030252 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0028259 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020437 infores:hetionet CAID:CA5416848 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416848 MONDO:0011225 PMID: Uncertain Significance BS2, BA1, BS1, PM2 The c.423A>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 141 (p.Gln141His).The filtering allele frequency (the upper threshold of the 95% CI of 52/1180004 alleles) of the c.423A>C variant in DCLRE1C is 0.00003422 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416848/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:75246 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0017178 infores:hetionet CHEBI:28148 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C1291077 infores:hetionet CHEBI:10023 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0039070 infores:hetionet CAID:CA254855 biolink:causes MONDO:0044970 infores:clingen CAID:CA254855 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS4 The m.12770A>G (p.E145G) variant in MT-ND5 has been reported in one individual with primary mitochondrial disease to date, in a child with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). The variant was present at 48% heteroplasmy in muscle and 15% in blood (PMID: 12509858). The variant was absent in blood from the mother (PM6_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (0.91, range 0-1; PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254855/MONDO:0044970/015 2023-11-28 2025-06-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2950 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0235290 infores:hetionet CHEBI:31397 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0476280 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0010692 infores:hetionet CAID:CA16020815 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020815 MONDO:0009861 PMID:21307867 Pathogenic PVS1, PM2, PP4_Moderate The frameshift variant c.551del generates a stop codon in exon 6 of 13 and is predicted to undergo NMD. The variant is absent from population databases, including gnomAD. It has been in at least one HPA patient (PMID: 21307867). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020815/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68579 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0002994 infores:hetionet CHEBI:6129 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0349790 infores:hetionet CHEBI:83804 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085583 infores:hetionet NCBITaxon:451507 biolink:causes MONDO:0019136 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:451507 MONDO:0019136 CHEBI:4888 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0012569 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0600142 infores:hetionet CHEBI:3175 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0151908 infores:hetionet CHEBI:46295 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0085636 infores:hetionet CHEBI:231594 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0424109 infores:hetionet CHEBI:8772 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0043094 infores:hetionet CHEBI:15544 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0235063 infores:hetionet CHEBI:28593 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0162820 infores:hetionet CHEBI:2914 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0428977 infores:hetionet CAID:CA16608769 biolink:causes MONDO:0012589 infores:clingen CAID:CA16608769 MONDO:0012589 PMID: Likely Pathogenic PM1, PP3, PS2, PM2_Supporting The p.Leu609Pro variant in TCF4 occurs in the de novo state (biological parentage confirmed) in an affected individual (PS2). The p.Leu609Pro variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of TCF4 (PM1). The p.Leu609Pro variant in TCF4 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu609Pro variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2, PM1, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608769/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:8107 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0032285 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0018799 infores:hetionet CHEBI:47780 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0031924 infores:hetionet CL:0000084 biolink:causes MONDO:0015760 infores:ubergraph knowledge_assertion manual_agent CL:0000084 MONDO:0015760 UNII:Y2V2R4W9TQ biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0015967 infores:hetionet NCBIGene:10280 biolink:causes MONDO:0011585 infores:monarchinitiative not_provided not_provided HGNC:8157 MONDO:0011585 uuid:ce4e1fa1-1c61-4d14-9fd9-81933a459d64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367401917 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401917 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting PP4 The c.458C>A variant in the glucokinase gene, GCK, causes an amino acid change of proline to histidine at codon 153 (p.(Pro153His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia; however PP4 was unable to be evaluated due to insufficient clinical information (PS4_Moderate; internal lab contributors). This variant was segregated with hyperglycemia, with seven informative meioses in five families (PP1_Strong; internal lab contributors). In summary, c.458C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401917/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:52717 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042384 infores:hetionet CHEBI:3654 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0020621 infores:hetionet CHEBI:9123 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038325 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0027769 infores:hetionet CHEBI:3403 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0037763 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0853008 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0853008 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027726 infores:hetionet CHEBI:5138 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0851578 infores:hetionet CHEBI:6402 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0041582 infores:hetionet CAID:CA383496428 biolink:causes MONDO:0015630 infores:clingen CAID:CA383496428 MONDO:0015630 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PP1 The NM_000552.5(VWF):c.5140G>C (p.Ala1714Pro) missense variant has been reported in one patient (P9; PMID: 28083987), with excessive mucocutaneous bleeding (bleeding score = 7) as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio of 0.69, and abnormal collagen binding assay (VWF:CIIIB: 11.3% and VWF:CIIIB/VWF:Ag ratio 0.31), which together are highly specific for VWD type 2M. (PP4_moderate). This variant is absent from gnomAD v4.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.662, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, the variant meets the criteria to be classified as Uncertain Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP3, PP4_moderate, and PM2_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383496428/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8774 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0004936 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0031350 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0006849 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0243026 infores:hetionet UMLS:C0065374 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0271710 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0017160 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0424000 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0018801 infores:hetionet CHEBI:6438 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0030554 infores:hetionet CHEBI:91541 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0012833 infores:hetionet CHEBI:9123 biolink:causes NCIT:C54685 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0001511 infores:hetionet CHEBI:31622 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0019521 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018991 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0235231 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235231 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0242350 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0006145 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0021141 infores:hetionet CAID:CA10644639 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644639 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1)c.*682dup is a 3'UTR variant which has a MAF of 0.000453 (0.0453%, 30/66,226 alleles) in the European (non-Finnish) subpopulation of the gnomAD 4.1 cohort, meeting the threshold between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644639/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15854 biolink:causes UMLS:C0858318 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0858318 infores:hetionet CHEBI:10023 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0023218 infores:hetionet CHEBI:75998 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0019080 infores:hetionet CHEBI:50648 biolink:causes HP:0033832 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0332579 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006044 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027719 infores:hetionet CHEBI:48273 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013428 infores:hetionet CHEBI:2663 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0036980 infores:hetionet CHEBI:31184 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0263449 infores:hetionet CHEBI:5138 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0022346 infores:hetionet CAID:CA030996 biolink:causes MONDO:0007750 infores:clingen CAID:CA030996 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS3, BS4, BS1, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.979C>T (p.His327Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022.The supporting evidence is as follows: PM2 - Variant is found in South Asian (gnomAD v2.1.1 (Popmax MAF = 0.0004900 (0.049%), total alleles number = 15), gnomAD v4.0.0 (Popmax MAF = 0.0006492 (0.06492%), total alleles number = 56)). Variant is absent from other populations in gnomAD v2.1.1 and is found in only 1 case from Remaining population in gnomAD v4.0.0 (Popmax MAF = 0.00001656 ( 0.001656%)). We assume founder effect due to isolated occurrence in the South Asian population. For this reason, we excluded the SA population from PM2 assessment.PP3 - REVEL = 0.958.PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.PS4_Supporting - Variant meets PM2 and is identified in 3 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria in PMID: 9259195 (Day et al., 1997), UK; 1 case with DLCN criteria>=6 in PMID: 11810272 (Fouchier et al., 2001), The Netherlands). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA030996/MONDO:0007750/013 2022-07-22 2025-03-07 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:0106396 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0007275 CHEBI:10127 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085633 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0314719 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0000833 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042373 infores:hetionet CAID:CA180944 biolink:causes MONDO:0015280 infores:clingen CAID:CA180944 MONDO:0015280 PMID: Pathogenic PS4, PS2, PM2, PM6, PP2 The c.619G>A (p.Glu207Lys) variant in MAP2K2 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in 6 individuals with clinical features of a RASopathy (PS4; SCV000204213.4, SCV000207959.10, SCV000815593.1, Otto von Guericke University Magdeburg internal data). One of these cases was a confirmed de novo occurrence and another was an unconfirmed de novo occurrence (PS2; PM6; SCV000815593.1, Otto von Guericke University Magdeburg internal data). Additionally, the c.619G>A (p.Glu207Lys) is located in MAP2K2, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PS2, PM6, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180944/MONDO:0015280/004 2020-06-25 2020-06-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7465 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0020538 infores:hetionet CHEBI:5790 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0040264 infores:hetionet CHEBI:3510 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0030554 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151605 infores:hetionet CHEBI:4798 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0344232 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0020649 infores:hetionet CHEBI:8890 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0034886 infores:hetionet CHEBI:7852 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0010200 infores:hetionet CHEBI:4903 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0010200 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002170 infores:hetionet CHEBI:8768 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0232461 infores:hetionet CHEBI:31236 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0575081 infores:hetionet CHEBI:8060 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0013144 infores:hetionet CHEBI:63589 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0004364 infores:hetionet CHEBI:23765 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C2047937 infores:hetionet NCBIGene:128240 biolink:causes MONDO:0020781 infores:monarchinitiative not_provided not_provided HGNC:18453 MONDO:0020781 uuid:51061cff-2494-488d-9577-3e36ff06a6bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:136040 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0018799 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0149801 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0149801 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0040034 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0235620 infores:hetionet CHEBI:9943 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018188 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0423271 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0423271 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0917798 infores:hetionet NCBIGene:5224 biolink:causes MONDO:0009865 infores:monarchinitiative not_provided not_provided HGNC:8889 MONDO:0009865 uuid:0db0415d-c75b-4687-a05b-25e9ee931070 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1384353 infores:hetionet CHEBI:4798 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0037317 infores:hetionet CAID:CA226577 biolink:causes MONDO:0100368 infores:clingen CAID:CA226577 MONDO:0100368 PMID: Pathogenic PP4_Moderate, PVS1, PP1, PM2_Supporting PM3, BS1 NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) is a nonsense variant that introduces a premature stop codon in exon 7 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 6 probands have been reported with this variant, one of whom displayed nystagmus (1 pt), night blindness (0.5 pts), reduced visual acuity (1 pt), narrowing of retinal vessels (0.5 pts), moderate pallor of the optic discs (0.5 pts), difficulty discriminating any color (1 pt), unrecordable ERG (0.5 pts), absent autofluorescence (2 pts), and onset at birth (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMIDs: 9326927, PMID: 11264131 PMID: 15288992, PP4_moderate). Additionally, the variant has been reported to segregate with the phenotype (confirmed by absent ERG) in the proband plus one similarly affected sibling harboring the variant in the compound heterozygous state (PP1; PMID: 9326927). PM3 was not considered to avoid circularity, despite the presence of compound heterozygous cases harboring this variant as well as the p.Asn356fs, c.991_993dup (p.Trp331dup), or p.Arg124Ter variant. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002299, with 3 alleles / 34580 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, PM2_Supporting, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226577/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63681 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0002792 infores:hetionet CHEBI:38940 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151878 infores:hetionet CHEBI:4868 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0085633 infores:hetionet NCBIGene:84665 biolink:causes MONDO:0015023 infores:monarchinitiative not_provided not_provided HGNC:23246 MONDO:0015023 uuid:1a5e3dc7-7ded-4103-9bcb-ddee62aa42bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0037011 infores:hetionet CAID:CA367402542 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402542 MONDO:0015967 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting, PS1_Supporting The c.363+2T>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 3 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 4 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). The variant segregated with diabetes with 4 informative meiosis in this individual's family (PP1_Moderate; internal lab contributor). Additionally, the c.363+2T>C variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.363+2T>A has a greater predicted impact by Splice AI (PS1_Supporting). In summary, the c.363+2T>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 3/23/2023): PVS1, PP1_moderate, PP4, PM2_Supporting, PS1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402542/MONDO:0015967/086 2023-05-26 2023-05-26 Semidominant inheritance HP:0032113 Supports CHEBI:3723 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039503 infores:hetionet CHEBI:194135 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020461 infores:hetionet CHEBI:18332 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0027769 infores:hetionet CHEBI:45863 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0595916 infores:hetionet CHEBI:68642 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0010200 infores:hetionet CHEBI:63611 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022568 infores:hetionet CHEBI:116735 biolink:causes HP:0032143 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0877717 infores:hetionet CAID:CA320251671 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251671 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.968C>G (p.Thr323Arg) is a missense variant. This variant is absent from both gnomAD v2.1 and gnomAD v3.1.2 (PM2_supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. This missense variant has a REVEL score <0.50 (0.055) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251671/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:91834 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0017565 infores:hetionet CHEBI:68554 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0220981 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0027765 infores:hetionet CHEBI:145499 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0016658 infores:hetionet CAID:CA003681 biolink:causes MONDO:0011450 infores:clingen CAID:CA003681 MONDO:0011450 PMID: Pathogenic PP3, PM2_Supporting, PP4_Strong PS3, BS3 The c.5509T>G variant in BRCA1 is a missense variant predicted to cause substitution of Tryptophan by Glycine at amino acid 1837 (p.Trp1837Gly). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.533, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies with discordant results. Exhibits protein function similar to pathogenic control variants (PMIDs: 30209399, 30765603) and between what was observed for benign and pathogenic control variants (PMID: 30257991) (PS3 and BS3 not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2004.67 (based on Co-occurrence LR=1.067; Family History LR=1878.3), above the threshold for very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMIDs: 17924331, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003681/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45599 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0018802 infores:hetionet CHEBI:92998 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0015672 infores:hetionet CHEBI:4911 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0030554 infores:hetionet CHEBI:3310 biolink:causes UMLS:C0522171 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0522171 infores:hetionet CHEBI:7915 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0023518 infores:hetionet NCBIGene:6439 biolink:causes MONDO:0009929 infores:monarchinitiative not_provided not_provided HGNC:10801 MONDO:0009929 uuid:256ef7ea-5eb3-478a-abe5-6f5595e3d767 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7447 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0040414 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0036572 infores:hetionet CHEBI:9599 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0349790 infores:hetionet CHEBI:2469 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0029442 infores:hetionet CHEBI:4868 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0020437 infores:hetionet CHEBI:17026 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0497156 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020538 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0019158 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020039 infores:hetionet CHEBI:4672 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0033771 infores:hetionet CHEBI:17026 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0003862 infores:hetionet CAID:CA916083886 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083886 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.2655_2656del (p.Glu886GlyfsTer?) is a frameshift variant due to 2-nucleotide deletion in codon 886 introducing a premature stop codon within exon 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 32679846, 17325176, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083886/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:5384 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0162533 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0020538 infores:hetionet CHEBI:31711 biolink:causes UMLS:C1510450 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C1510450 infores:hetionet CHEBI:31705 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151908 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0029134 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0851341 infores:hetionet CAID:CA390881979 biolink:causes MONDO:0100216 infores:clingen CAID:CA390881979 MONDO:0100216 PMID:36813958PMID:36813958 Uncertain Significance PM2_Supporting BA1, BP4, BS2, PP3, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.3:c.2461C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 821 (p.Arg821Cys). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.747, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function; splice predictors MaxEntScan and SpliceAI indicate no impact on splicing (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting. (Bayesian Points: 1; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390881979/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50381 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0338656 infores:hetionet CHEBI:50922 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0497156 infores:hetionet CHEBI:52172 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0014591 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0036572 infores:hetionet CAID:CA9301563 biolink:causes MONDO:0010938 infores:clingen CAID:CA9301563 MONDO:0010938 PMID: Likely Benign BS1 BS3, PS1, PS3, PM5, PM1, PM3, PP4, BS2 The c.2636A>G (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 879 (p.His879Arg).The filtering allele frequency (the lower threshold of the 95% CI of 63/24964) of the c.2636A>G variant in JAK3 is 0.001911 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00100) for BS1, and therefore meets this criterion (BS1).To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9301563/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2682 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0239981 infores:hetionet CHEBI:6073 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0039070 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0863147 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0863147 infores:hetionet CHEBI:2639 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0013404 infores:hetionet CHEBI:68575 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0017178 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006668 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0009768 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151826 infores:hetionet CHEBI:84883 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0268000 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020538 infores:hetionet CHEBI:7581 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0040409 infores:hetionet CHEBI:63577 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0151904 infores:hetionet CAID:CA445752659 biolink:causes MONDO:0021056 infores:clingen CAID:CA445752659 MONDO:0021056 PMID: Likely Benign BP4, PM2_Supporting, BP7 BS2 The c.123A>G (p.Ala41=) variant in APC is synonymous (silent) variant that is not predicted by SpliceAI and VarSEAK to impact splicing (BP4 and BP7 met). This variant is absent from gnomAD v2.1.1 (PM2_supporting). This variant has been observed in heterozygous state in 1 healthy adult individual worth 0.5 healthy individual points in total (BS2_supporting not met; Invitae internal data). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BP4, BP7 (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA445752659/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63631 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0023222 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0002170 infores:hetionet CHEBI:63630 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042029 infores:hetionet CHEBI:3011 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0042023 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0027765 infores:hetionet CHEBI:9570 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0015967 infores:hetionet CHEBI:9605 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0162119 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0011991 infores:hetionet CAID:CA386952398 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952398 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4 The c.34C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 12 (p.(Leu12Val)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).  Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributor).  Lastly, another missense variant at the same amino acid position, c.34C>T (p.Leu12Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952398/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6532 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0027497 infores:hetionet CHEBI:15765 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0018524 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0027765 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0031212 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0162119 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0235431 infores:hetionet CHEBI:73274 biolink:causes MONDO:0007018 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042996 infores:hetionet UBERON:0000176 biolink:causes HP:0025095 infores:drugmechdb knowledge_assertion manual_agent UBERON:0000176 HP:0025095 DB00972_MESH_D065631_1DB00972_MESH_D006255_1 CHEBI:6775 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0034068 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017178 infores:hetionet CHEBI:7931 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0728899 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0027813 infores:hetionet CHEBI:9086 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085595 infores:hetionet CHEBI:31199 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0152459 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0232498 infores:hetionet CHEBI:205919 biolink:causes MONDO:0002922 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0034212 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0031350 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0017160 infores:hetionet CHEBI:2950 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C2047937 infores:hetionet CHEBI:3216 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0235195 infores:hetionet CHEBI:7444 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0011991 infores:hetionet CHEBI:4514 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0009806 infores:hetionet CHEBI:63791 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151825 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0853019 infores:hetionet CHEBI:61058 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0017178 infores:hetionet NCBIGene:5295 biolink:causes MONDO:0010026 infores:monarchinitiative not_provided not_provided HGNC:8979 MONDO:0010026 uuid:19f3046b-9e47-480d-b7f0-ce3974b650af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes HP:0000685 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235357 infores:hetionet CHEBI:3207 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0085641 infores:hetionet CHEBI:465284 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0018681 infores:hetionet CHEBI:7956 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0014742 infores:hetionet CHEBI:4562 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042510 infores:hetionet CHEBI:8356 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020598 infores:hetionet CHEBI:6541 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0700225 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0522172 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151735 infores:hetionet CHEBI:31859 biolink:causes MONDO:0008062 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0007384 infores:hetionet CHEBI:32315 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018524 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0520587 infores:hetionet CHEBI:135736 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085610 infores:hetionet CHEBI:50729 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0042029 infores:hetionet NCBIGene:55703 biolink:causes MONDO:0013722 infores:monarchinitiative not_provided not_provided HGNC:30348 MONDO:0013722 uuid:5173b3f1-4f21-426a-b60e-5f5d064f19fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0149904 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0022660 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0497247 infores:hetionet UBERON:0006799 biolink:causes MONDO:0002369 infores:ubergraph knowledge_assertion manual_agent UBERON:0006799 MONDO:0002369 CHEBI:50859 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0037763 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0518015 infores:hetionet CAID:CA8622972 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622972 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PP4 The NM_000212.3(ITGB3):c.538G>A (p.Gly180Arg) missense variant has been reported in one patient (Patient 5, PMID: 31029159) stated to have clinical diagnosis of Glanzmann thrombasthenia but insufficient information was available to determine if the phenotype is highly specific to GT. It has a REVEL score of 0.958, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00003266 (1/30614 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622972/MONDO:0100326/011 2023-04-06 2023-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6062 biolink:causes MONDO:0004601 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0023223 infores:hetionet CHEBI:16469 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1458155 infores:hetionet CHEBI:49575 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0037317 infores:hetionet CHEBI:27796 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0026821 infores:hetionet NCBIGene:6452 biolink:causes MONDO:0007315 infores:monarchinitiative not_provided not_provided HGNC:10825 MONDO:0007315 uuid:2ce262ab-78b3-4b58-90d7-a4141b81f410 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0549386 infores:hetionet CHEBI:7444 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0020538 infores:hetionet NCBIGene:3560 biolink:causes MONDO:0032782 infores:monarchinitiative not_provided not_provided HGNC:6009 MONDO:0032782 uuid:9cfc864f-0e78-47a3-9753-146f30a57f35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0002453 infores:hetionet CHEBI:45783 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0156404 infores:hetionet CHEBI:27565 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0027497 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0006826 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085096 infores:hetionet GO:2001212 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:2001212 GO:0072359 CHEBI:2618 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0855242 infores:hetionet CHEBI:2611 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0424296 infores:hetionet CHEBI:3077 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0232462 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0856115 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0856115 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0015376 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0549386 infores:hetionet CHEBI:16347 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0426576 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0221203 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0040046 infores:hetionet CAID:CA377781898 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781898 MONDO:0017623 PMID:29706350PMID:29785012PMID:29706350PMID:29785012 Uncertain Significance PP2, PM2_Supporting, BP4 BS1, BS3, PP3, PM5, BA1, BP1, PS3 NM_000314.8(PTEN):c.35A>G (p.Asn12Ser) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BP4: REVEL score < 0.5 (score=0.287)Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 2 pathogenic supporting and 1 benign supporting codes get (1*2) + (- 1*1) points = total is 1 (VUS). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781898/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6761 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0038325 infores:hetionet CHEBI:72564 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151827 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0017152 infores:hetionet CHEBI:82960 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020505 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0013395 infores:hetionet CHEBI:77260 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0497156 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0456909 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0242350 infores:hetionet CHEBI:47381 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0237938 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0546947 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0546947 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0042075 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023067 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009782 infores:hetionet CHEBI:7956 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C1510410 infores:hetionet NCBIGene:55249 biolink:causes MONDO:0011243 infores:monarchinitiative not_provided not_provided HGNC:30935 MONDO:0011243 uuid:cc7425a4-944b-483c-bd40-627536d03f74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512319034 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319034 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS4, PS1, BA1, BP3, BP2, BP1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, PP4, PP1, PP2, PP3, BS2 NM_001754.5(RUNX1):c.84T>C is a synonymous variant not predicted to impact splicing (BP4). This variant is completely absent from gnomAD with at least 20x coverage for RUNX1 (PM2_supporting) and is located in a position which is relatively conserved (PhyloP = 2.67) (BP7 not applied). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319034/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:80630 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0031924 infores:hetionet CHEBI:168396 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0022346 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151735 infores:hetionet NCBIGene:4126 biolink:causes MONDO:0009562 infores:monarchinitiative not_provided not_provided HGNC:6831 MONDO:0009562 uuid:726efdaa-a2bb-4567-9919-a8134ca4d885 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014868 infores:hetionet CHEBI:52717 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0423006 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151734 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0151689 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0042373 infores:hetionet CHEBI:3757 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030252 infores:hetionet CAID:CA1244183 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244183 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.728C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Asparagine at amino acid 243 (p.Thr243Asn). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000005085 (6 alleles out of 1,179,948), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.082, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244183/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:367163 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0033771 infores:hetionet CAID:CA024187 biolink:causes MONDO:0100150 infores:clingen CAID:CA024187 MONDO:0100150 PMID: Pathogenic PP1, PP3, PM5, PM2_Supporting, PS2, PS4, PS3_Supporting BS2, PP4, PM4, PM3, PM1, BP3, BP2, BA1, PS1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1 The NM_000540.3:c.14582G>A variant in RYR1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 4861 (p.Arg4861His). The highest population minor allele frequency in gnomAD v4.1 is 0.0000008475 (1/1180004 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (absent with 1 allele allowed) for PM2_Supporting, meeting this criterion (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.912, which is above the threshold necessary to apply PP3. Four different missense variants, c.14581C>A (p.Arg4861Ser), c.14581C>G (p.Arg4861Gly), c.14581C>T (p.Arg4861Cys), c.14582G>C (p.Arg4861Pro) (ClinVar IDs: 2027376, 943431, 65986, 1066439), in the same codon have been classified as pathogenic/likely pathogenic for RYR1-related myopathy (PM5). This variant has been reported in at least five probands with RYR1-related myopathy which meets the criteria for PS4, two of which were confirmed to be de novo occurrences meeting PS2 (PMIDs:11709545, 35428369, 35081925). The variant has also been reported to segregate in one affected sibling from a family (PP1, PMID:11709545). Calcium homeostasis analysis of immortalized B-lymphocytes from patients showed significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals, indicating that this variant may impact protein function (PS3_Supporting, PMID:11741831). In summary, the variant meets the criteria to be classified as pathogenic for autosomal dominant RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PS2, PS3_Supporting, PM5, PM2_Supporting, PP1, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2; 8/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024187/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71272 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0016204 infores:hetionet CHEBI:17347 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0917801 infores:hetionet CHEBI:27666 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0030312 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0175167 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0037023 infores:hetionet GO:0120194 biolink:causes GO:0048653 infores:ubergraph knowledge_assertion manual_agent GO:0120194 GO:0048653 CHEBI:9352 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0344232 infores:hetionet CHEBI:27882 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0026821 infores:hetionet CHEBI:6367 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0037763 infores:hetionet NCBIGene:3868 biolink:causes MONDO:0008173 infores:monarchinitiative not_provided not_provided HGNC:6423 MONDO:0008173 uuid:aace01df-1349-421b-86a3-c97e88cf66ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA916084342 biolink:causes MONDO:0015967 infores:clingen CAID:CA916084342 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 PS4, PP4 The c.1137dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 380 (NM_000545.8), adding 39 novel amino acids before encountering a stop codon (p.(Val380CysfsTer39)). This variant, located in biologically-relevant exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; PMID: 32741144, internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32741144, internal lab contributors). Neither met the ClinGen MDEP criteria for PP4. In summary, c.1137dup meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084342/MONDO:0015967/017 2022-04-16 2022-04-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63580 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011071 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0001122 infores:hetionet CHEBI:87681 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0026821 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0038362 infores:hetionet CHEBI:5134 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C1260880 infores:hetionet CHEBI:82960 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C2173677 infores:hetionet CAID:CA409109838 biolink:causes MONDO:0015967 infores:clingen CAID:CA409109838 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong The c.1A>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.4. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). In summary, c.1A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Strong, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409109838/MONDO:0015967/085 2025-06-02 2025-06-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64321 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0851341 infores:hetionet CHEBI:9763 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0700590 infores:hetionet CHEBI:83527 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0043387 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011053 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0020651 infores:hetionet GO:0110082 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0110082 GO:0000278 CHEBI:6741 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0004604 infores:hetionet CHEBI:10101 biolink:causes NCIT:C78280 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0221727 infores:hetionet CHEBI:5893 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020621 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0795692 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948089 infores:hetionet CHEBI:3723 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028081 infores:hetionet CHEBI:65173 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C1443060 infores:hetionet CHEBI:8774 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0015672 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027051 infores:hetionet CHEBI:101278 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0016382 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0340464 infores:hetionet CHEBI:5132 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0013144 infores:hetionet NCBIGene:64837 biolink:causes MONDO:0012297 infores:monarchinitiative not_provided not_provided HGNC:20716 MONDO:0012297 uuid:b465413a-24d0-4bfb-88c9-b331e2aba068 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50729 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0036572 infores:hetionet CAID:CA1251313 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251313 MONDO:0013144 PMID: Likely Benign BS1, BP4 BP7 The c.910T>C (p.Leu304=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4). The BP7 code is not applied due to a non-qualifying PhyloP score. The filtering allele frequency (the lower threshold of the 95% CI of 77/1614210) of the c.910T>C variant in SERPINC1 is 0.0002422 for African/African American chromosomes by gnomAD v4.1.0, which is higher than the ClinGen Thrombosis VCEP threshold (>0.0002) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: BP4, BS1. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251313/MONDO:0013144/084 2025-10-17 2025-10-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50692 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0009782 infores:hetionet CHEBI:31536 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0035410 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0085584 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0227791 infores:hetionet CHEBI:6754 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0018790 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0853761 infores:hetionet CHEBI:167309 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0162297 infores:hetionet CHEBI:135351 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0237849 infores:hetionet CHEBI:3347 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0015967 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0025061 infores:hetionet CHEBI:5050 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0851578 infores:hetionet CHEBI:3441 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0018965 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0013395 infores:hetionet CHEBI:6741 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151662 infores:hetionet CHEBI:4445 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0017178 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0009806 infores:hetionet CHEBI:134966 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0085631 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0042109 infores:hetionet CHEBI:2379 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0011570 infores:hetionet CHEBI:3286 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0042571 infores:hetionet CAID:CA010341 biolink:causes MONDO:0005045 infores:clingen CAID:CA010341 MONDO:0005045 PMID: Uncertain Significance PM1 PP2, BS2, PM2, PM4, PM5, PM6, PP3, PP1, PS3, BA1, BP3, BP1, BS3, BS1, BS4, PS1, PS2, PS4, BP4, BP7, PVS1 The NM_000257.4(MYH7):c.1193G>A (p.Gly398Glu) variant has been identified in at least 4 individuals with HCM (Olivotto 2008 PMID:18533079; Homburger 2016 PMID:27247428; Invitae pers. comm.). This variant has been identified in 0.00524% (FAF 95% CI; 3/15414) of European chromosomes in genomes only by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is too high to apply PM2. However, this represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant. Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010341/MONDO:0005045/002 2021-10-01 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5775 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0019209 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0006852 infores:hetionet NCBIGene:200734 biolink:causes MONDO:0030679 infores:monarchinitiative not_provided not_provided HGNC:17722 MONDO:0030679 uuid:93c4d6f4-35c0-42e8-8748-1470672db5cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1141861 infores:hetionet CHEBI:9435 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C2830004 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034150 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004967 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0023449 infores:hetionet CHEBI:7907 biolink:causes UMLS:C0475746 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0475746 infores:hetionet NCBIGene:2554 biolink:causes MONDO:0014328 infores:monarchinitiative not_provided not_provided HGNC:4075 MONDO:0014328 uuid:eec68373-10d5-4bac-8a48-53357c34defa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020453 infores:hetionet NCBIGene:23064 biolink:causes MONDO:0018996 infores:monarchinitiative not_provided not_provided HGNC:445 MONDO:0018996 uuid:15129c8d-62ba-4588-892d-93fc2ba4b2df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:617099 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0234215 infores:hetionet CAID:CA367401892 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401892 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP2, PP3, PP1, PM2_Supporting The c.466C>T variant in the glucokinase gene, GCK, causes an amino acid change of histidine to tyrosine at codon 156 (p.(His156Tyr)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.88 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.466C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/12/2023): PP4_Moderate, PP1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401892/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Supports CHEBI:4046 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0013395 infores:hetionet CHEBI:82960 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0221150 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003635 infores:hetionet CHEBI:83804 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0030252 infores:hetionet CAID:CA337263623 biolink:causes MONDO:0010726 infores:clingen CAID:CA337263623 MONDO:0010726 PMID: Benign BS1, BP5_Strong, BS2 BP4, PP3 The allele frequency of the p.Val275Ala variant in MECP2 (NM_004992.3) is 0.016% in African/African American sub population in gnomAD v4, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Val275Ala variant is observed in the heterozygous state in at least 2 unaffected individuals (internal database - Invitae) (BS2). The p.Val275Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - Invitae) (BP5_strong). In summary, the p.Val275Ala variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA337263623/MONDO:0010726/036 2024-02-23 2024-06-27 X-linked inheritance HP:0001417 Contradicts true CAID:CA024775 biolink:causes MONDO:0007783 infores:clingen CAID:CA024775 MONDO:0007783 PMID: Likely Pathogenic PS4_Supporting, PM1, PS2_Moderate, PP3_Moderate PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with threonine at codon 2453 of the RYR1 protein, p.(Ile2453Thr). This variant was not present in a large population database (gnomAD) at the time it was interpreted. This variant has been reported in an individual with a personal history of an MH episode and a positive in vitro contracture test (IVCT), PS4_Supporting (PMID:12434264). The mother was positive for the variant and was determined to be IVCT positive, and the variant was determined to be de novo in the mother with confirmed parentage, PS2_Moderate. A functional study using sarcoplasmic reticulum membrane vesicles was published for this variant; this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS and PS3 was not applied (PMID:16958617). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.891) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS2_Moderate, PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024775/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3176 biolink:causes UMLS:C0595900 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0595900 infores:hetionet CAID:CA409109839 biolink:causes MONDO:0015967 infores:clingen CAID:CA409109839 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong The c.2T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype highly specific for HNF4A-monogenic diabetes (MPC > 50% and had a macrosomic infant with the variant with diazoxide-responsive hyperinsulinemic hypoglycemia (PP4_Moderate; Internal lab contributor). In summary, c.2T>A meets the criteria to be classified as Likely Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Strong, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409109839/MONDO:0015967/085 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA2543984220 biolink:causes MONDO:0021056 infores:clingen CAID:CA2543984220 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting BS2, PVS1, BP2 The NM_000038.6(APC):c.7964_7965del (p.Glu2655fs) variant in APC is a frameshift variant located downstream of codon 2645, therefore PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant was observed in a 30 years old patient with 3 to 5 histologically confirmed adenomas, a desmoid and a positive FAP family history, who also carried, in unknown phase, NM_000038.6(APC):c.426_427del (p.Leu143fs) (classified as Pathogenic in ClinVar - Variation ID: 142574) (BP2 not met; internal data Labcorp Genetics (formerly Invitae)). The variant has been reported in 4 additional probands without a colorectal cancer/polyposis associated phenotype worth 0.5 healthy individual points in total (BS2 not met, internal data Ambry and Labcorp Genetics (formerly Invitae)). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PM2_Supporting applied (VCEP specifications v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2543984220/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63630 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0018991 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0178298 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0042514 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0948089 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0236048 infores:hetionet CAID:CA10588346 biolink:causes MONDO:0015152 infores:clingen CAID:CA10588346 MONDO:0015152 PMID: Pathogenic PM3, PP1_Moderate, PP4_Moderate, PVS1, PM2_Supporting The NM_003494.4: c.331C>T p.(Gln111Ter) variant in DYSF, which is also known as NM_001130987.2: c.334C>T p.(Gln112Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least four unrelated patients with features of LGMD (PMID: 21522182, 36983702), including in a homozygous state in two unrelated patients without reported consanguinity (1.0 pt; PMID: 21522182) (PM3). It has also been observed to co-segregate with autosomal recessive LGMD in two affected family members from two families (PMID: 21522182; PP1_Moderate). At least one patient with this variant and two presumed diagnostic DYSF alleles had both progressive limb girdle muscle weakness or a clinical diagnosis of LGMD and severely reduced or absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 21522182, 36983702; PP4_Moderate (capped with PP1). The highest population allele frequency for this variant in gnomAD v4.1.0 is 8.475e-7 in the European (non-Finnish) population (1/1179978 chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3, PP1_Moderate, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588346/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:55346 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0004936 infores:hetionet CHEBI:8214 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0030252 infores:hetionet CHEBI:63611 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002792 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0012307 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0012307 uuid:e4b0a596-244c-4302-ba4a-001f21009ca8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31536 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0042963 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151559 infores:hetionet CHEBI:6954 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0041969 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0086543 infores:hetionet CAID:CA410207092 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207092 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.640A>G (p.Thr214Ala) is a missense variant which has a REVEL score < 0.50 (0.374), and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207092/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3654 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0008370 infores:hetionet CHEBI:82941 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0042075 infores:hetionet CHEBI:6456 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0028778 infores:hetionet CAID:CA2466570248 biolink:causes MONDO:0010726 infores:clingen CAID:CA2466570248 MONDO:0010726 PMID: Likely Benign BP2, BS2 BS1 The p.Ser411del variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected hemizygous individuals (GeneDx internal database) (BS2). The p.Ser411del variant (reported as c.1225_1227delAGC) was observed in the MECP2 gene where a second pathogenic variant in the same gene was present in the patient (PMID 28394482) (BP2). The highest population minor allele frequency of the p.Ser411del variant in MECP2 in gnomAD v4.1 is 0.00000166 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Ser411del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP2). (MECP2 Specifications v4.1.; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2466570248/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Contradicts true NCBIGene:1050 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:1833 MONDO:0018874 uuid:86f7c979-3f96-46c0-999a-43ba436842e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0687713 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0022104 infores:hetionet CHEBI:681569 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0020458 infores:hetionet CHEBI:63598 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040264 infores:hetionet CHEBI:3504 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0700590 infores:hetionet CHEBI:15765 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0002878 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004238 infores:hetionet CHEBI:7514 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0003862 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0151479 infores:hetionet CHEBI:45783 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0232461 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0030469 infores:hetionet CHEBI:44032 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0013604 infores:hetionet CHEBI:72690 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0004093 infores:hetionet CHEBI:50922 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1262144 infores:hetionet CHEBI:63115 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0151904 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031350 infores:hetionet CHEBI:44185 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0233715 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015695 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0022354 infores:hetionet CHEBI:8245 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0026821 infores:hetionet CHEBI:64354 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0042487 infores:hetionet CHEBI:63584 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0036983 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042571 infores:hetionet CHEBI:28915 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C2830004 infores:hetionet NCBIGene:7381 biolink:causes MONDO:0014064 infores:monarchinitiative not_provided not_provided HGNC:12582 MONDO:0014064 uuid:96d1c36f-43fd-478a-9cb3-8010a669ac83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA202700 biolink:causes MONDO:0100453 infores:clingen CAID:CA202700 MONDO:0100453 PMID:18682808 Benign BP4, BA1, BP7, BS2 NM_000180.4(GUCY2D):c.1371C>T (p.Cys457=) is a synonymous variant in exon 4 of 20. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016. (BA1). This variant has been found in the homozygous state in 325 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA202700/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3698 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0018099 infores:hetionet CHEBI:5558 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0151766 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0836924 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0022660 infores:hetionet CHEBI:7824 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0040822 infores:hetionet CHEBI:135686 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0016204 infores:hetionet CHEBI:6520 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0235031 infores:hetionet CHEBI:6067 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042023 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0549350 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0549350 infores:hetionet CHEBI:27869 biolink:causes MONDO:0019545 infores:ubergraph knowledge_assertion manual_agent CHEBI:27869 MONDO:0019545 CHEBI:31624 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0020649 infores:hetionet CHEBI:63717 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0027497 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0541919 infores:hetionet CHEBI:61049 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0239935 infores:hetionet CHEBI:4681 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0015230 infores:hetionet GO:0060687 biolink:causes GO:0030850 infores:ubergraph knowledge_assertion manual_agent GO:0060687 GO:0030850 UMLS:C0209366 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0038999 infores:hetionet CAID:CA658658499 biolink:causes MONDO:0100488 infores:clingen CAID:CA658658499 MONDO:0100488 PMID: Pathogenic PM5_Supporting, PM2_Supporting, PS4, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The NM_004360.5:c.2474dup (p.Pro826AlafsTer3) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region (removes last 57 amino acids of the protein) is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID: 29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). This variant has been reported in 5 families meeting HDGC criteria (PS4; NCI hereditary gastric study, Ambry, Invitae). In summary, this variant meets the criteria to be classified as pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PS4, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 5/6/2022) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658499/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:51364 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0152128 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0541832 infores:hetionet CHEBI:9123 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0024305 infores:hetionet CHEBI:5134 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C2364111 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0234913 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0857183 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0857183 infores:hetionet CHEBI:10650 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0232602 infores:hetionet CAID:CA10014382 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014382 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP3, PM2, PM6, PVS1, BS3, BS4, BP5, BP7, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.666C>T (p.Ser222=) is a synonymous variant. This variant has been seen 11x in gnomADv2.1 with a MAF of 0.00026 (0.026%, 8/30616 in the South Asian sub-population (BS1). REVEL score not applicable and SpliceAI ≤0.20 (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1 and BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014382/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:8438 biolink:causes MONDO:0011508 infores:monarchinitiative not_provided not_provided HGNC:9826 MONDO:0011508 uuid:100c4209-3824-4216-9843-9fec36a3431b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0037299 infores:hetionet NCBITaxon:186540 biolink:causes MONDO:0005737 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:186540 MONDO:0005737 CHEBI:168396 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0024305 infores:hetionet CHEBI:68579 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0002962 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020621 infores:hetionet CHEBI:66919 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0027765 infores:hetionet CHEBI:6129 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014591 infores:hetionet CHEBI:9398 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0002418 infores:hetionet CHEBI:6759 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0020517 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151888 infores:hetionet CAID:CA8815730 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815730 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting The NM_000152.5:c.2408A>G variant in GAA is a missense variant predicted to cause substitution of Gln by Arg at amino acid 803 (p.Gln803Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (12/126838 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.808 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. It has not been reported in the literature as causative for GAA-related disease. There is a ClinVar entry for this variant (Variation ID: 496900, 2 star review status) with 8 submitters classifying the variant as Uncertain significance. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815730/MONDO:0009290/010 2024-06-06 2024-06-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:28593 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0518015 infores:hetionet NCBIGene:91801 biolink:causes MONDO:0032789 infores:monarchinitiative not_provided not_provided HGNC:25189 MONDO:0032789 uuid:743c5b9f-3124-4617-80dc-ceb84618618a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0877055 infores:hetionet CHEBI:135342 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0003467 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0003123 infores:hetionet CAID:CA4239711 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239711 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1, BS1 The c.162T>G variant in the glucokinase gene, GCK, causes an amino acid change of serine to arginine at codon 54 (p.(Ser54Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.713, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to zero copies present in the European non-Finnish subpopulation and any other non-Founder subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting. There are three copies present in the European Finnish population; however, given that this is a Founder sub-population, PM2_Supporting will still be applied (PM2_Supporting). This variant was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however PS4_Moderate will not be applied at this time given that all cases were identified in the Finnish population (internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes, with at least 4 informative meioses in multiple families (PP1_Strong; internal lab contributors). In summary, c.162T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239711/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:61049 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007642 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0919599 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0919599 infores:hetionet CHEBI:2636 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0036572 infores:hetionet CHEBI:31401 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C2937358 infores:hetionet NCBIGene:6513 biolink:causes MONDO:0012143 infores:monarchinitiative not_provided not_provided HGNC:11005 MONDO:0012143 uuid:c800691c-f17b-4996-be6d-01a56d201a36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020598 infores:hetionet CHEBI:15365 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C1565489 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1956346 infores:hetionet CHEBI:9907 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020458 infores:hetionet CAID:CA287436033 biolink:causes MONDO:0008723 infores:clingen CAID:CA287436033 MONDO:0008723 PMID: Benign BA1 The c.478-106del variant in ACADVL is an intronic variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.62 in the European Finnish population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287436033/MONDO:0008723/021 2021-11-19 2022-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3127 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0575090 infores:hetionet CHEBI:2904 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0035078 infores:hetionet CHEBI:231594 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1384606 infores:hetionet CHEBI:3219 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0039240 infores:hetionet CHEBI:27565 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0002871 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006607 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036502 infores:hetionet CAID:CA400022022 biolink:causes MONDO:0100326 infores:clingen CAID:CA400022022 MONDO:0100326 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.450G>A (p.Met150Ile) has a computational predictor REVEL gives a score of 0.908, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Another missense variant NM_000212.3(ITGB3):c.448A>G (p.Met150Val) in the same codon has been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5_supporting). The highest population minor allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180040 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Platelet Disorders VCEP threshold (<0.0001; PM2_Supporting). At least one homozygous (PM3_supporting) patient (Patient 6 in PMID: 40239810) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 2.7% (<25%), as measured by flow cytometry (PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_moderate, PM3_supporting, PM2_supporting, PP3, PM5_supporting. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400022022/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA023408 biolink:causes MONDO:0007750 infores:clingen CAID:CA023408 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Variant meets PM2 and alters Cys340, one of the cysteine residues listed.PM2 - PopMax MAF = 0.00005782 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1).PP3 - REVEL: 0,98. PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria and in 1 FH case published in PMID: 30592178 who fulfills DLCN criteria.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases with clinical FH criteria. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023408/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:52717 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0700292 infores:hetionet CHEBI:46557 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042164 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0019112 infores:hetionet CHEBI:8888 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085636 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0233414 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0178298 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0027947 infores:hetionet CAID:CA16613046 biolink:causes MONDO:0700270 infores:clingen CAID:CA16613046 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.4318A>T (p.Lys1440*) variant in ATM gene is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613046/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0239739 infores:hetionet CHEBI:205919 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0030554 infores:hetionet CHEBI:135939 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0015672 infores:hetionet CHEBI:480999 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1142499 infores:hetionet CHEBI:3387 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0497156 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0232492 infores:hetionet CHEBI:39867 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0086565 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0021400 infores:hetionet NCBIGene:51134 biolink:causes MONDO:0014374 infores:monarchinitiative not_provided not_provided HGNC:17966 MONDO:0014374 uuid:cfee10d9-c103-4aa2-8890-2b3493c78aac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35553 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0575090 infores:hetionet CHEBI:3756 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0027497 infores:hetionet CHEBI:47898 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0947912 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0030305 infores:hetionet CAID:CA1139532272 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139532272 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PM3_Supporting, PVS1 The c.1444_1448del variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 15/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant was reported in a patient with ACADVL deficiency who carried the pathogenic p.Val283Ala allele(PM3_Supporting, PMID: 25834949). Deficient VLCAD enzyme activity (below 20% of normal) was also measured from this patient's cultured fibroblasts (PP4, PMID: 25834949). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). In summary the ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1+PM2_Supporting+PM3_supporting+PP4. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532272/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:35778 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0009806 infores:hetionet CHEBI:72297 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0332563 infores:hetionet CHEBI:8869 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0151786 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0234215 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0853149 infores:hetionet CHEBI:63577 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0021655 infores:hetionet CHEBI:6359 biolink:causes UMLS:C0877617 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0877617 infores:hetionet CHEBI:5384 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C3665386 infores:hetionet NCBIGene:4352 biolink:causes MONDO:0800452 infores:monarchinitiative not_provided not_provided HGNC:7217 MONDO:0800452 uuid:80f59ec8-0f81-4c24-93f1-3b8d612b2b47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0004936 infores:hetionet CHEBI:63638 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013456 infores:hetionet CHEBI:35854 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0702166 infores:hetionet CHEBI:3219 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011175 infores:hetionet CHEBI:68647 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0687713 infores:hetionet CAID:CA213755 biolink:causes MONDO:0015967 infores:clingen CAID:CA213755 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1332del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 445 (NM_000162.5), adding 169 novel amino acids before encountering a stop codon (p.(Ser445ValfsTer169)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold, and PP4 could not be evaluated due to lack of clinical information (ClinVar ID 36197, internal lab contributor). In summary, the c.1332del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213755/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Supports CHEBI:4670 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0008031 infores:hetionet CHEBI:5130 biolink:causes NCIT:C26921 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0085594 infores:hetionet CAID:CA151521 biolink:causes MONDO:0007648 infores:clingen CAID:CA151521 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149761.14, SCV000185618.5, SCV000288464.7). Although functional impact of this variant was reported from in vitro assays, functional assays except splicing assay are not applicable to CDH1 according to the CDH1 specific variant interpretation criteria. In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA151521/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:8874 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0032617 infores:hetionet CHEBI:102216 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0027497 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013395 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0020649 infores:hetionet CHEBI:63617 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042023 infores:hetionet CHEBI:9555 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0268000 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0853619 infores:hetionet CHEBI:27565 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0232462 infores:hetionet CHEBI:4356 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0038999 infores:hetionet CAID:CA414914392 biolink:causes MONDO:0010602 infores:clingen CAID:CA414914392 MONDO:0010602 PMID: Likely Pathogenic PM5, PS1_Moderate, PM2_Supporting, PP3 PM1, PS4 The variant, NM_000132.3(F8):c.1420G>C, predicts a missense change, Gly474Arg, which is not reported in gnomAD v2.1.1 or v3. This variant has not been reported in any patients with Hemophilia A in the literature, to the best of our knowledge. The variant has a REVEL score of 0.972 (threshold >0.6). Another nucleotide change at this position (G>A) results in the same amino acid change, Gly474Arg, currently evaluated to be a likely pathogenic meeting PS1_Moderate criteria. Another variant at the same codon (c.1421G>A (p.Gly474Glu)) is classified as pathogenic by CFD-VCEP, meeting the PM5 criteria. In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS1_Moderate, PM5, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414914392/MONDO:0010602/071 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Supports CHEBI:8232 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0162429 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0853813 infores:hetionet CHEBI:6437 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0011603 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0235409 infores:hetionet CHEBI:3696 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0003467 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019112 infores:hetionet CHEBI:10125 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020473 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017152 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0233494 infores:hetionet CHEBI:7025 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0005741 infores:hetionet CHEBI:7820 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0024117 infores:hetionet CHEBI:3756 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0002994 infores:hetionet CHEBI:119915 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0518988 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0153676 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0153676 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0015376 infores:hetionet CHEBI:63620 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003467 infores:hetionet CHEBI:194135 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0036974 infores:hetionet CHEBI:4466 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0017178 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0006266 infores:hetionet CHEBI:49603 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0011991 infores:hetionet CHEBI:5818 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0013144 infores:hetionet CHEBI:75045 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0042164 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0700345 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027796 infores:hetionet CHEBI:45783 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0040264 infores:hetionet CAID:CA020404 biolink:causes MONDO:0008667 infores:clingen CAID:CA020404 MONDO:0008667 PMID: Pathogenic PS4_Moderate, PM2_Supporting, PVS1 This variant has been identified in at least 9 unrelated probands (and other related family members not counted within each) all meeting Danish VHL criteria, from literature evaluated in both CIViC and Hypothes.is VHL datasets. CIViC EIDs (https://civicdb.org): 8292;7606;5776;9374;6806;6538. This corresponds to Strong evidence (5-15 probands) (PS4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 3 probands/families meeting meeting either VHL Type 1 or affected with VHL-related cancers. (2.25 points, PS4_Moderate; PMID: 11114638, 12114494, 9829911). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020404/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63629 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0243026 infores:hetionet CHEBI:5004 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0030252 infores:hetionet NCBIGene:23219 biolink:causes MONDO:0030695 infores:monarchinitiative not_provided not_provided HGNC:29046 MONDO:0030695 uuid:b66061c2-f913-4d90-b9bf-f022ff6c4355 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0231530 infores:hetionet CHEBI:3723 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030252 infores:hetionet CAID:CA409120729 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120729 MONDO:0007064 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.606+1G>T (NM_000022.4) variant in ADA occurs within the canonical donor splice site (+1) of intron 6. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 6, resulting in a frameshift (p.(Asn160Argfs*48) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4 is 0.00002994 (1/33402 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120729/MONDO:0007064/114 2024-06-19 2024-06-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7514 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0020649 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0856108 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0856108 infores:hetionet CHEBI:38940 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0011175 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0235874 infores:hetionet CHEBI:171719 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0221242 infores:hetionet NCBIGene:1630 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:2701 MONDO:0005575 uuid:03f30b84-8d3b-42ab-bb8c-94ab9d6b24ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0231749 infores:hetionet NCBIGene:1615 biolink:causes MONDO:0014115 infores:monarchinitiative not_provided not_provided HGNC:2678 MONDO:0014115 uuid:bcb2268c-1eea-4452-a55b-33bae67c4ada biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9150 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0032533 infores:hetionet CHEBI:45599 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0036974 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0434437 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0009763 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0020538 infores:hetionet CAID:CA255378 biolink:causes MONDO:0010604 infores:clingen CAID:CA255378 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3 PM1 The c.1009G>C (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by proline at amino acid 337 (p.Ala337Pro). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been previously reported in at least one patient with mild hemophilia B (PMID: 1998585), meeting phenotypic criteria for F9. An additional proband with severe hemophilia B has been reported in the EAHAD Factor IX (F9) variant database. The computational predictor REVEL gives a score of 0.617, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Different missense variants causing a change at the same residue (p.Ala337Thr and p.Ala337Val) have been established as pathogenic for F9 and SpliceAI predicts no impact on splicing meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Moderate + PM2_Supporting + PP3 + PM5. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255378/MONDO:0010604/080 2024-09-30 2024-10-01 X-linked inheritance HP:0001417 Supports CHEBI:18248 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0019080 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0041912 infores:hetionet CHEBI:4657 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0080274 infores:hetionet CHEBI:404903 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0232462 infores:hetionet UNII:K2J09EMJ52 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0027497 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0019340 infores:hetionet CHEBI:4653 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0040034 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0003862 infores:hetionet CHEBI:9434 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042790 infores:hetionet CHEBI:8356 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0338831 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0021167 infores:hetionet NCBIGene:4137 biolink:causes MONDO:0010997 infores:monarchinitiative not_provided not_provided HGNC:6893 MONDO:0010997 uuid:ebb01af7-a948-49e5-b884-cc2c7792eda7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0023067 infores:hetionet CHEBI:6339 biolink:causes MONDO:0010030 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1527336 infores:hetionet CAID:CA287530833 biolink:causes MONDO:0100453 infores:clingen CAID:CA287530833 MONDO:0100453 PMID:36274938 Pathogenic PM3_Strong, PP1_Strong, PS3_Supporting, PP4_Moderate, PM2_Supporting PP3 The NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp) variant is predicted to replace the arginine at position p.588 with tryptophan. The variant protein exhibited <1.5% of wild-type activity when stimulated with GCAP1, GCAP2, or GCAP3, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function. In addition, the variant protein failed to co-localize with GCAP1 when co-expressed in HEK293 cells (PS3_Supporting, PMID: 36274938). The computational predictor REVEL gives a score of 0.592, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. The splicing impact predictor SpliceAI gives a score of 0.2 for an acceptor site gain, which meets the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, however, this variant has been curated based on protein function rather than spliceogenicity, so the PP3 code has not been considered. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000008678, with 14 alleles / 1,613,262 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 29068479, 37327959). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000180.4(GUCY2D):c.2516del (p.Thr839ArgfsTer27) or the NM_000180.4(GUCY2D):c.307G>A (p.Glu103Lys) variant suspected but not confirmed in trans (PMID: 36274938, VCEP member-provided data), which have been previously classified as either pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state, and through a second proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID:37327959, VCEP member-provided data, PP1_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of early onset retinitis pigmentosa (0.5 pts) with onset in infancy (1 pt), genotyping by an LCA gene panel with no additional likely pathogenic findings (2 pts), electroretinogram showing altered responses from both cones and rods (1.5 pts), dyschromatopsia (1 pt), visual field loss (1 pt), attenuated blood vessels with peripheral pigment (0.5 pts), and night blindness (0.5 pts), which together are specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 37327959, PP4_moderate). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1_Strong, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA287530833/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51041 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0021400 infores:hetionet CHEBI:63577 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0036974 infores:hetionet CHEBI:6690 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0009676 infores:hetionet CHEBI:63611 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085932 infores:hetionet CHEBI:3504 biolink:causes UMLS:C2242583 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C2242583 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042769 infores:hetionet CAID:CA229669 biolink:causes MONDO:0009861 infores:clingen CAID:CA229669 MONDO:0009861 PMID:26666653 Pathogenic PVS1, PM2, PP4, PM3_Supporting The c.648C>G (p.Tyr216Ter) variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Glu280Lys (ClinVar 580). This variant is absent from 1000G, ESP, and gnomAD databases. This variant creates a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229669/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135929 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0042109 infores:hetionet CHEBI:7936 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C3665347 infores:hetionet CHEBI:9398 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0030193 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0518015 infores:hetionet CHEBI:45599 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0020488 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037274 infores:hetionet CHEBI:5864 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0011253 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0008325 infores:hetionet CHEBI:44423 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0011633 infores:hetionet CHEBI:116278 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0041657 infores:hetionet CHEBI:5118 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003811 infores:hetionet NCBIGene:8518 biolink:causes MONDO:0009131 infores:monarchinitiative not_provided not_provided HGNC:5959 MONDO:0009131 uuid:ee58c617-548c-4944-8b2c-cef60ee26935 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0497327 infores:hetionet CHEBI:31622 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0003467 infores:hetionet CAID:CA414914381 biolink:causes MONDO:0010602 infores:clingen CAID:CA414914381 MONDO:0010602 PMID: Uncertain Significance PM5, PM2_Supporting, PP3 PM1, PS4 The variant, NM_000132.3(F8):c.1421G>T, predicts a missense change, Gly474Val, is not reported in gnomAD v2.1.1 or v3. This variant has been reported in at least one patient with mild hemophilia A in the literature (PMID: 18184865); however they do not meet the F8 phenotype criteria as VWD exclusion is not specified. The variant has a REVEL score of 0.92 meeting PP3 (threshold >0.6). Another nucleotide change at the same position, c.1421G>A (p.Gly474Glu) is classified as pathogenic by CFD-VCEP meeting PM5 criteria. In summary, the clinical significance of this variant is variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PM5, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414914381/MONDO:0010602/071 2025-06-06 2025-08-23 X-linked inheritance HP:0001417 Inconclusive true CHEBI:7494 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085631 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002871 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0235874 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0039971 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0877406 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0877406 infores:hetionet CHEBI:75722 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0476280 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0037274 infores:hetionet NCBIGene:6103 biolink:causes MONDO:0010227 infores:monarchinitiative not_provided not_provided HGNC:10295 MONDO:0010227 uuid:5e53174b-f2e1-4cae-afb6-e9db35821575 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085932 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0004239 infores:hetionet CHEBI:16469 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0025218 infores:hetionet CAID:CA8338063 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338063 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4(ACADVL); c.1316del(p.Gly439Valfs*5) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338063/MONDO:0008723/021 2023-03-27 2023-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:74947 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023380 infores:hetionet CHEBI:4953 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0030196 infores:hetionet CHEBI:100241 biolink:causes MONDO:0021718 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0032541 infores:hetionet CHEBI:135005 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0011991 infores:hetionet CHEBI:7577 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0032227 infores:hetionet CAID:CA274088 biolink:causes MONDO:0009861 infores:clingen CAID:CA274088 MONDO:0009861 PMID:22526846 Pathogenic PM3, PVS1, PM2, PP4_Moderate PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PVS1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA274088/MONDO:0009861/006 2018-08-27 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9654 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0278134 infores:hetionet CAID:CA412744987 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744987 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PP1_Strong NM_001034853.2(RPGR):c.469+1G>T is a canonical splice site variant in intron 5 that is predicted to induce skipping of exon 5, which is expected to disrupt a critical functional domain in RPGR (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 2 families (PP1_Strong; PMID: 30917587, PMID: 1733835). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) including female carriers showing milder phenotypes (1 pt), childhood-onset (1 pt), reduced visual acuity (0.5 pts), night blindness (0.5 pts), nonrecordable electroretinogram responses, and genotyping by next-generation sequencing with a panel of 111 genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (7 points, PMID: 30917587, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP4, and PP1_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744987/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports UMLS:C1738934 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0497156 infores:hetionet CAID:CA325327 biolink:causes MONDO:0008535 infores:clingen CAID:CA325327 MONDO:0008535 PMID: Benign BA1, BP5 PP3 The NM_001114753.3: c.572G>A variant in ENG is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 191 (p.Gly191Asp). The filtering allele frequency (the lower threshold of the 95% CI of 1725/109328) of the c.572G>A variant in ENG is 0.01669 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). This variant has been observed in at least 2 patients with an alternate molecular basis for disease (patients also carry likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 32573726, Internal lab contributors). The computational predictor REVEL gives a score of 0.275, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BA1, BP5 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA325327/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6931 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0600228 infores:hetionet GO:0042478 biolink:causes GO:0001654 infores:ubergraph knowledge_assertion manual_agent GO:0042478 GO:0001654 CHEBI:9667 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0029408 infores:hetionet NCBIGene:147495 biolink:causes MONDO:0011549 infores:monarchinitiative not_provided not_provided HGNC:15718 MONDO:0011549 uuid:93b015db-02da-479a-95b7-ffbae15f3111 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018801 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0860207 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0852361 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0852361 infores:hetionet CHEBI:18067 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0021368 infores:hetionet CHEBI:8228 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0037763 infores:hetionet CHEBI:5847 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0521839 infores:hetionet CHEBI:8802 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0855329 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C2747793 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151740 infores:hetionet NCBIGene:7125 biolink:causes MONDO:0859335 infores:monarchinitiative not_provided not_provided HGNC:11944 MONDO:0859335 uuid:c97759ea-5838-474d-bb9e-2122105fed25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0037384 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042769 infores:hetionet CHEBI:32221 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0004093 infores:hetionet CHEBI:79699 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020621 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0086543 infores:hetionet CHEBI:63631 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011175 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005300 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0748318 infores:hetionet CHEBI:7931 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011603 infores:hetionet CHEBI:6933 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0018799 infores:hetionet CHEBI:94392 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0750426 infores:hetionet CHEBI:50663 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0011253 infores:hetionet UMLS:C0657912 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0338831 infores:hetionet CHEBI:7466 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0004509 infores:hetionet CHEBI:5088 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0029574 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0029408 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0027651 infores:hetionet CHEBI:6633 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0038999 infores:hetionet NCBIGene:116228 biolink:causes MONDO:0033645 infores:monarchinitiative not_provided not_provided HGNC:26970 MONDO:0033645 uuid:a79a7b3f-4226-4a55-a823-75545986a7cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17141 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C2830004 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0019360 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0232459 infores:hetionet NCBIGene:4763 biolink:causes MONDO:0008672 infores:monarchinitiative not_provided not_provided HGNC:7765 MONDO:0008672 uuid:216843be-cc04-40ab-8071-336b3b29a1f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes UMLS:C0857256 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0857256 infores:hetionet CHEBI:50841 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0013362 infores:hetionet CHEBI:51450 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0030252 infores:hetionet CHEBI:7915 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011175 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0314719 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151479 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0035309 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0042109 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0020538 infores:hetionet CHEBI:31638 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0085605 infores:hetionet CHEBI:10110 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C2047937 infores:hetionet CAID:CA226348 biolink:causes MONDO:0100437 infores:clingen CAID:CA226348 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PS4_Supporting, PM2_Supporting, PP1_Strong PP3, PS3 NM_001034853.2(RPGR):c.1245+3A>G is an intronic variant near the boundary of intron 10 and exon 10 of RPGR. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including childhood onset, undetectable dark-adapted electroretinogram, a family history consistent with X-linked inheritance, delayed or milder onset in females, pigmentary deposits in the retina, and night blindness, which together are specific for RPGR-related retinopathy (4 points, PMID: 21326217, PP4). A second proband has met the PS4 requirement of some functional vision impairment in affected males by age 30, with decreased or absent cone and/or rod ERG responses (PMID: 9326322). The combination of a proband eligible for the PP4 code and a second apparently unrelated proband who meets the requirements for the PS4 code met PS4 at the supporting level (PS4_Supporting). The variant segregates with the phenotype through 8 affected meioses from 1 family and through 4 affected meioses from a second family (PP1_Strong; PMID: 21326217, PMID: 9326322). The splicing impact predictor SpliceAI gives the variant a score of 0.81, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. Functional studies from patient fibroblast cells confirm that the variant triggers skipping of exon 10 in all transcripts (PMID: 25630948). While these in silico and experimental findings would normally be counted under the PP3 and PS3_Supporting codes, respectively, in combination, they have been counted as evidence of a loss-of-function effect (PMID: 37352859, PVS1). In summary, this variant meets the criteria to be classified as pathogenic for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen XLIRD VCEP: PVS1 (PP3+PS3_supporting), PS4_Supporting, PM2_Supporting, PP1_Strong, and PP4. (VCEP specifications version 1.0.0; date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226348/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Supports CHEBI:4708 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0740394 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0233632 infores:hetionet CAID:CA000455 biolink:causes MONDO:0017623 infores:clingen CAID:CA000455 MONDO:0017623 PMID: Uncertain Significance PP2, PP3, PM2_Supporting, BS3_Supporting BS1, PM5, BA1, BP1, BP4, PS1, PS3 NM_000314.8(PTEN):c.424C>T (p.Arg142Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.45) per Mighell et al. 2018 (PMID: 29706350). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.716).PM2_P: Absent in gnomAD. Although this variant has been observed de novo in published literature (PMID 38335860) and internal laboratory cases, many of these patients and several others did not have features consistent with PTEN Hamartoma Tumor syndrome (PMID 26534844). This variant occurs as a CpG dinucleotide site; such sites have an increased rate of spontaneous deamination leading to de novo mutation (PMID 16570853). We believe that de novo observations of this variant are most likely incidental findings due to the hypermutable nature of this nucleotide position, and are not awarding de novo criteria as evidence towards pathogenicity given the inconsistent phenotypes present. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000455/MONDO:0017623/003 2024-05-17 2024-05-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46195 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0349506 infores:hetionet CHEBI:63599 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0009676 infores:hetionet CAID:CA415086484 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086484 MONDO:0010305 PMID: Likely Pathogenic PM6, PM2_Supporting, PP4_Strong PP3, BP4 The NM_005629.4:c.1210G>C variant in SLC6A8 is predicted to result in the substitution of alanine by proline at amino acid 404 (p.Ala404Pro). A 3 year old male, hemizygous for this variant, with clinical features consistent with creatine transporter deficiency has been reported who also had elevated urine creatine/creatine on three occassions, reduced creatine peak on brain MRS, and 6% normal creatine uptake in fibroblasts (with 25 uM creatine) (PP4_Strong). The variant was not identified in either of two independent samples from the patient's mother (PM6). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.601 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI predicts that the variant has no impact on splicing. To our knowledge, the results of functional studies on this variant have not been reported. In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PM6, PM2_Supporting.(Classification approved by the ClinGen CCDS, June 21, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086484/MONDO:0010305/027 2023-06-21 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:4657 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0278134 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0001824 infores:hetionet CHEBI:64312 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013404 infores:hetionet NCBIGene:64802 biolink:causes MONDO:0031007 infores:monarchinitiative not_provided not_provided HGNC:17877 MONDO:0031007 uuid:2f6fa0f0-942d-4ec5-a0bd-071d91364560 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0740425 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0037274 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0004623 infores:hetionet NCBIGene:8604 biolink:causes MONDO:0013056 infores:monarchinitiative not_provided not_provided HGNC:10982 MONDO:0013056 uuid:93225714-e350-4a9a-8626-43255b9ee7c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0004134 infores:hetionet CHEBI:171719 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0003467 infores:hetionet CHEBI:40279 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0017181 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0232492 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0856049 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0856049 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0017160 infores:hetionet CHEBI:8502 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0001824 infores:hetionet CHEBI:27436 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0002453 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0151313 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0031117 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0015230 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0100338 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D014552 DB00681_MESH_D014552_1 CHEBI:28830 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0026650 infores:hetionet CHEBI:7959 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0086565 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0004096 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0746883 infores:hetionet CHEBI:77733 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0043352 infores:hetionet CHEBI:50841 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0700075 infores:hetionet CHEBI:8713 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0162830 infores:hetionet NCBIGene:4990 biolink:causes MONDO:0008927 infores:monarchinitiative not_provided not_provided HGNC:10892 MONDO:0008927 uuid:5bcb19fe-27a9-43c2-bd43-0e28c31bb3cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7823 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0023530 infores:hetionet CAID:CA404084653 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084653 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, PS3, PM5, PP3 The NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code (PM2) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP3/BP4 not met: REVEL=0.566, it is not above 0.75 but between 0.5-0.75, splicing evaluation required. Functional data on splicing is not available. In scenario A, acceptor site: The variant is located at -20 to +3 bases of canonical acceptor splicing site of exon 9. Wild type canonical acceptor motif: CTCGCTCCCCGGACCCCCAGGCT, MES: 6.59; Variant canonical acceptor motif: CTCGCTCCCCGGACCCCCAGACT, MES: 6.16. Var/Wt ratio = 0.93, greater than 0.8 and less than 1.0. Alternative splicing is not predicted.PS3 not met: Functional data not available.PP4, PS4 not met: Variant meets PM2, however clinical data is not available.PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg), (ClinVarID 870321). None is classified as Pathogenic by these guidelines, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084653/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63617 biolink:causes MONDO:0005032 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151468 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0424605 infores:hetionet CHEBI:68554 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0009782 infores:hetionet CHEBI:94385 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0000737 infores:hetionet CHEBI:9763 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151905 infores:hetionet CHEBI:37924 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0019214 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0021400 infores:hetionet CHEBI:4717 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0018418 infores:hetionet CHEBI:47781 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C2225524 infores:hetionet CHEBI:63791 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151908 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0009782 infores:hetionet CHEBI:9587 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0002792 infores:hetionet CHEBI:5138 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040264 infores:hetionet CHEBI:45716 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0037763 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0233494 infores:hetionet CHEBI:8805 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0030554 infores:hetionet NCBIGene:29760 biolink:causes MONDO:0013289 infores:monarchinitiative not_provided not_provided HGNC:14211 MONDO:0013289 uuid:75bc4d9f-f399-49b1-b487-87e4712aca66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes UMLS:C0877267 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0877267 infores:hetionet CHEBI:3371 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0015230 infores:hetionet CHEBI:8874 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0025222 infores:hetionet CAID:CA415077248 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077248 MONDO:0010305 PMID: Pathogenic PM6, PP4, PM2_Supporting, PS1, PVS1_Strong The NM_005629.4:c.263-1G>C variant in SLC6A8 occurs within the canonical splice acceptor site of intron 1. RT-PCR revealed skipping of the first 21 amino acids of exon 2 (r.263_325del; p.Gly88_Leu108del) for 90% of transcripts and wild type splicing for about 10% of transcripts (PMID: 20717164).While this is <10% of the protein length, the region includes Phe107. The variant p.Phe107del is pathogenic based on classification by the ClinGen CCDS VCEP (ClinVar Variation ID: 21448, SCV002600174.1) indicating that Phe107 is an important residue for creatine transporter function. Therefore, PVS1 will be applied at strong rather than moderate (PVS1_Strong). The variant has been identified in one female patient with mild intellectual disability and chronic hallucinatory psychosis who has a reduced creatine level on brain MRS, and urine creatine level at the upper limit of normal (PMID: 20717164) (PP4). The variant appears to be de novo in this patient; maternity and paternity were not confirmed (PMID: 20717164) (PM6). The variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Another variant at the same acceptor splice site dinucleotide, c.263-2A>G has been reported in an affected individual and has a similar impact on splicing as shown by RT-PCR (PMID: 20717164). That variant, c.263-2A>G, been classified as pathogenic by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP) (ClinVar Variation ID: 11701), which allows PS1 to be applied (PMID: 37352859). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS1, PVS1_Strong, PM6, PP4, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 12, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077248/MONDO:0010305/027 2024-12-12 2025-08-13 X-linked inheritance HP:0001417 Supports CHEBI:3215 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020440 infores:hetionet CHEBI:63608 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0005745 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0026848 infores:hetionet CHEBI:8404 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0041657 infores:hetionet CAID:CA400021329 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021329 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 NM_000212.3(ITGB3):c.361+1G>A occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3/15, resulting in a frameshift (p.Ala56Metfs*23) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). GT3 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.61%, as measured by flow cytometry. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PP3. (VCEP specifications version 2; date of approval 09/02/2021). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021329/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:74947 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C2830004 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0003123 infores:hetionet CHEBI:8356 biolink:causes MONDO:0100312 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235927 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0012833 infores:hetionet CHEBI:6950 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0023212 infores:hetionet NCBIGene:125336 biolink:causes MONDO:0013119 infores:monarchinitiative not_provided not_provided HGNC:26521 MONDO:0013119 uuid:a0d9c576-dbd0-45e8-97c5-8076a6b16415 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA382533339 biolink:causes MONDO:0700270 infores:clingen CAID:CA382533339 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, BP4 PM3 The c.1262C>T variant in ATM is a missense variant predicted to cause substitution of serine by leucine at amino acid 421 (p.Ser421Leu). The variant is absent in the gnomAD v2.1.1 cohort. The computational predictor, Revel (Score: 0.151), does not predict a damaging effect on ATM function. In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM2_Supporting, BP4) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382533339/MONDO:0700270/020 2023-11-20 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17334 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0011606 infores:hetionet CHEBI:7852 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0234238 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014130 infores:hetionet CHEBI:4995 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0026205 infores:hetionet CHEBI:7459 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0016382 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0028259 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0018799 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0039971 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853193 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0037274 infores:hetionet CHEBI:66903 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0006145 infores:hetionet CAID:CA14870738 biolink:causes MONDO:0011071 infores:clingen CAID:CA14870738 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS4, PS3, PS2, BP1, BP3, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 The c.-59+103A>G variant is a deep intronic variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -1.85391 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The variant's highest population minor allele frequency in gnomAD v3 is 0.1436 (11062/67898 alleles) in the non-Finnish European population, which is higher than the ClinGen Myeloid Malignancy threshold (>0.0015) for BA1; in addition, this allele count includes 1672 homozygotes, and there are no reports of probands with homozygous pathogenic variants plus RUNX1-deficient mice are embryonic lethal (BP2). The variant also has not been reported in germline cases (PMID: 29472484), although there is some suggestion that this variant may represent an quantitative trait locus (PMID: 25685889, PMID: 31748747) and/or functional SNP (PMID: 28238063). In summary, this variant meets the criteria to be classified as benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BA1, BP2, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14870738/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50742 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0036974 infores:hetionet CHEBI:6822 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C1167965 infores:hetionet CHEBI:6375 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0033774 infores:hetionet CHEBI:5002 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0023518 infores:hetionet CHEBI:6822 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0001824 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0006145 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151849 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020538 infores:hetionet CHEBI:3508 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0011603 infores:hetionet NCBIGene:2355 biolink:causes MONDO:0968978 infores:monarchinitiative not_provided not_provided HGNC:3798 MONDO:0968978 uuid:6bdb38ca-c5a5-4dbb-9ab0-715265740bac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020978 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020978 MONDO:0009861 PMID:26503515PMID:21462123 Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Strong The c.1243G>T (p.Asp415Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21462123, 26503515). This variant is absent in population databases. This variant was detected in trans with pathogenic variants: p.Val399= (PMID: 28982351); and p.Ala345Thr (LP by PAH VCEP, PMID: 30050108). Computational evidence support a deleterious effect. Another missense change at the same amino acid (p.Asp415Asn) is interpreted as pathogenic by multiple submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020978/MONDO:0009861/006 2021-10-10 2021-10-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5280 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0947912 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0234215 infores:hetionet CHEBI:94440 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0152227 infores:hetionet NCBIGene:3736 biolink:causes MONDO:0008047 infores:monarchinitiative not_provided not_provided HGNC:6218 MONDO:0008047 uuid:b45f136d-e2fd-40a6-b563-5465a30a6189 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226519 biolink:causes MONDO:0100368 infores:clingen CAID:CA226519 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.1543C>T is a missense variant predicted to replace arginine with tryptophan at position 515. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000002980, with 2 alleles / 126782 total alleles in the European (non-Finnish population), which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 25495949). This variant has also been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) (PMID: 34492281)), NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) (PMID: 32032261), NM_000329.3(RPE65):c.1067dup (p.Asn356fs) (PMID: 35129589), or NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) variant (PMID: 30025081) variants suspected in trans (2 pts), which were all previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) based on exome sequencing-based genotyping that did not provide an alternative explanation for visual impairment (2 pts), night blindness (0.5 pts) with onset during the first year of life (1 pt), attenuated retinal vessels (0.5 pts), macular atrophy (0.5 pts), bone spicule pigmentation (0.5 pts), non-recordable electroretinogram pattern in rod (0.5 pts) and cone (1 pt) responses, and decreased central visual acuity (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMID: 25495949, PP4_Moderate). The computational predictor REVEL gives a score of 0.935, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited less than 10% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 25752820, PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226519/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75246 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0024282 infores:hetionet CHEBI:27504 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0011603 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0009450 infores:hetionet CHEBI:9130 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0001925 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0232492 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0233472 infores:hetionet CHEBI:171719 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0278061 infores:hetionet CHEBI:50659 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0011603 infores:hetionet CHEBI:205919 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0162834 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0035455 infores:hetionet CHEBI:3814 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0008350 infores:hetionet CHEBI:5004 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0022667 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0020456 infores:hetionet CHEBI:45863 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019079 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1739418 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1739418 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0559031 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0011551 infores:hetionet CHEBI:6402 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0018965 infores:hetionet CHEBI:3441 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235490 infores:hetionet CHEBI:9168 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019521 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002871 infores:hetionet CHEBI:63635 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0003862 infores:hetionet CHEBI:47499 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0039239 infores:hetionet CHEBI:5855 biolink:causes EFO:0009852 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0392674 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027947 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018801 infores:hetionet CAID:CA2497030041 biolink:causes MONDO:0011071 infores:clingen CAID:CA2497030041 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1036del (p.Arg346AlafsTer?) is a frameshift variant that is not predicted to undergo nonsense mediated decay, but occurs in a part of the protein that is essential for the protein function (PVS1_strong) and occurs downstream of c.98 (PM5_supporting). It does not occur in any population database (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497030041/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49575 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0001807 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1112214 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0021053 infores:hetionet CHEBI:6904 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C2363730 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0542184 infores:hetionet CHEBI:29688 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C1167965 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0234987 infores:hetionet CHEBI:71229 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0041582 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0002871 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0036572 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0152027 infores:hetionet CAID:CA145978 biolink:causes MONDO:0009861 infores:clingen CAID:CA145978 MONDO:0009861 PMID: Benign BP4, BA1 PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.16641; BP4: no impact on gene in SIFT, Polyphen2, MutationTaster. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1, BP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA145978/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true UNII:D27V6190PM biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0858259 infores:hetionet CHEBI:3696 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0149745 infores:hetionet CHEBI:7465 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0239783 infores:hetionet CHEBI:8356 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0004134 infores:hetionet CHEBI:167638 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0278134 infores:hetionet CHEBI:51041 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011991 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0012813 infores:hetionet CHEBI:47426 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0027497 infores:hetionet CHEBI:63681 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C3665347 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024225 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0241742 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0002170 infores:hetionet NCBIGene:2629 biolink:causes MONDO:0009267 infores:monarchinitiative not_provided not_provided HGNC:4177 MONDO:0009267 uuid:bb5ab005-5e07-4271-9d17-4ffa81ced21c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA7330841 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330841 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, BA1, PP3, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.4475T>C variant in DICER1 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 1492 (p.Met1492Thr). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.049; MaxEntScan and SpliceAI: no effect on splicing) (BP4). The total allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1614146 alleles) with highest population minor allele frequencies of 0.00001334 (1/74954alleles) and 0.000002542 (3/1180050) in the African American and European (non-Finnish) populations, respectively (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 02/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330841/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040264 infores:hetionet NCBIGene:4123 biolink:causes MONDO:0030770 infores:monarchinitiative not_provided not_provided HGNC:6827 MONDO:0030770 uuid:5cc8988e-8111-4caf-b7e9-bff3a9f17fa7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036572 infores:hetionet CHEBI:9649 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0013604 infores:hetionet CHEBI:9328 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0023530 infores:hetionet CHEBI:7476 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0025345 infores:hetionet CHEBI:60761 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0004093 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0948089 infores:hetionet CHEBI:17347 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0741494 infores:hetionet CHEBI:9137 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151827 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0009324 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0018801 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151883 infores:hetionet CHEBI:39867 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042963 infores:hetionet CHEBI:171719 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0004245 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042109 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0234458 infores:hetionet CHEBI:28748 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006384 infores:hetionet CHEBI:42797 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0302809 infores:hetionet CHEBI:3398 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0020458 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0015734 infores:hetionet CHEBI:9150 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0022354 infores:hetionet CHEBI:7478 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0003537 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0242350 infores:hetionet CHEBI:4315 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C2363731 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005855 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0026393 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018790 infores:hetionet CHEBI:51450 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0003962 infores:hetionet CHEBI:17347 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0687713 infores:hetionet CHEBI:16469 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0577559 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020542 infores:hetionet CHEBI:31413 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0232462 infores:hetionet CHEBI:50838 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0014742 infores:hetionet CHEBI:65173 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0040485 infores:hetionet CHEBI:51230 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0018681 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0549385 infores:hetionet CHEBI:9435 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0235063 infores:hetionet CHEBI:50156 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0234518 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0270795 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0270795 infores:hetionet NCBIGene:5828 biolink:causes MONDO:0013933 infores:monarchinitiative not_provided not_provided HGNC:9717 MONDO:0013933 uuid:8b47d43c-ab48-46f4-98fb-c2268fb4847c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA023789 biolink:causes MONDO:0007750 infores:clingen CAID:CA023789 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM6, PP2, PP3, PP1, PP4, BS2 NM_000527.5(LDLR):c.908G>A (p.Arg303Gln) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.00004627 (0.004627%) in European (Finnish) exomes+genomes (gnomAD v2.1.1).BP4 - REVEL = 0.294. It is below 0.5, splicing evaluation required. Functional data on splicing not available. Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023789/MONDO:0007750/013 2022-01-19 2022-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:9091 biolink:causes MONDO:0032808 infores:monarchinitiative not_provided not_provided HGNC:14135 MONDO:0032808 uuid:ed1fa96e-1ff4-45bb-aaa8-4a2a9e1a78b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1861 biolink:causes MONDO:0100218 infores:monarchinitiative not_provided not_provided HGNC:3098 MONDO:0100218 uuid:c61e3498-688b-44c1-81b3-80fef0255114 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1103 biolink:causes MONDO:0009689 infores:monarchinitiative not_provided not_provided HGNC:1912 MONDO:0009689 uuid:ad115c73-01b1-4fde-8959-dcecfe6bc09a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3209 biolink:causes MONDO:0008301 infores:monarchinitiative not_provided not_provided HGNC:5102 MONDO:0008301 uuid:cbf092b4-74f4-48d7-8812-af369ea0e658 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0016242 infores:hetionet CHEBI:16467 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0023380 infores:hetionet NCBIGene:4716 biolink:causes MONDO:0033560 infores:monarchinitiative not_provided not_provided HGNC:7696 MONDO:0033560 uuid:b155b689-2fe8-4fb9-a30a-4a7d1048b0a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0521592 infores:hetionet CHEBI:4657 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0011991 infores:hetionet CHEBI:63599 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0011168 infores:hetionet CHEBI:50648 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0220870 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1302752 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0267792 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0242350 infores:hetionet CHEBI:9943 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151691 infores:hetionet CHEBI:2549 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013378 infores:hetionet CHEBI:6888 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0233514 infores:hetionet CHEBI:51380 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0235063 infores:hetionet CHEBI:8428 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0039240 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0152027 infores:hetionet CAID:CA229395 biolink:causes MONDO:0009861 infores:clingen CAID:CA229395 MONDO:0009861 PMID:12409276PMID:23062575PMID:23062575PMID:9391881 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.1200-8G>A variant in PAH has been reported in multiple patients with PAH deficiency. BH4 deficiency excluded (PMID: 9391881, 23062575). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with known pathogenic variants IVS10-11G>A, p.A403V (PM3). Computational evidence supports a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229395/MONDO:0009861/006 2019-09-29 2019-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:84050 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0003123 infores:hetionet CHEBI:2955 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0041657 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042267 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0149931 infores:hetionet CHEBI:5100 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0242973 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0022660 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0042514 infores:hetionet CHEBI:28918 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0030318 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0004936 infores:hetionet CHEBI:5127 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0162820 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0178298 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0442874 infores:hetionet NCBIGene:54790 biolink:causes MONDO:0018881 infores:monarchinitiative not_provided not_provided HGNC:25941 MONDO:0018881 uuid:24e79dc8-e31b-4ce2-be70-a708a57e4992 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011168 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020542 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0549373 infores:hetionet UMLS:C0025241 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0206061 infores:hetionet UMLS:C0009315 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0016204 infores:hetionet CHEBI:5098 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C1257843 infores:hetionet NCBIGene:54471 biolink:causes MONDO:0957824 infores:monarchinitiative not_provided not_provided HGNC:25979 MONDO:0957824 uuid:75b5c847-f54d-46a7-94ac-f4e81d194429 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4822 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0428977 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042075 infores:hetionet CHEBI:50729 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0013378 infores:hetionet CHEBI:4798 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0019521 infores:hetionet CHEBI:87715 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0027497 infores:hetionet NCBITaxon:100816 biolink:causes MONDO:0016823 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:100816 MESH:D008271 DB01263_MESH_D008271_1 CHEBI:6437 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233472 infores:hetionet CHEBI:5790 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0018524 infores:hetionet NCBIGene:3973 biolink:causes MONDO:0008303 infores:monarchinitiative not_provided not_provided HGNC:6585 MONDO:0008303 uuid:b0fcfd15-ca9d-4f1f-8d8b-f29b36499b60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020443 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0003123 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042109 infores:hetionet CHEBI:50381 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C2047937 infores:hetionet CHEBI:45081 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0035455 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0014868 infores:hetionet CHEBI:7936 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040460 infores:hetionet NCBIGene:89970 biolink:causes MONDO:0014748 infores:monarchinitiative not_provided not_provided HGNC:29420 MONDO:0014748 uuid:27d3de6b-ec95-4cc7-9065-71adb261bd97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50381 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0037763 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0233632 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042109 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0546817 infores:hetionet CHEBI:63618 biolink:causes HP:0001595 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0157733 infores:hetionet CHEBI:4779 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0152227 infores:hetionet CHEBI:63605 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0017178 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0521592 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0541832 infores:hetionet CHEBI:3312 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0015376 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0029408 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0019147 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1321686 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027726 infores:hetionet CHEBI:84883 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0041657 infores:hetionet CHEBI:9599 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0006145 infores:hetionet CHEBI:72292 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0015230 infores:hetionet UMLS:C0017797 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0000731 infores:hetionet CHEBI:5296 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0022346 infores:hetionet CHEBI:465284 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1306341 infores:hetionet CHEBI:6888 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018800 infores:hetionet CHEBI:3996 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0014457 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0042373 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004096 infores:hetionet CHEBI:9586 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019521 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0015230 infores:hetionet NCBIGene:5428 biolink:causes MONDO:0008758 infores:monarchinitiative not_provided not_provided HGNC:9179 MONDO:0008758 uuid:2eb26ad5-6060-46a1-a694-0fbce32d08f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0028643 infores:hetionet CHEBI:135351 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0037763 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0235396 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0235396 infores:hetionet CHEBI:9586 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C2830004 infores:hetionet CHEBI:47780 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085641 infores:hetionet CHEBI:6792 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0039231 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0836924 infores:hetionet CHEBI:15940 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C3665386 infores:hetionet CHEBI:45327 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0043352 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0042373 infores:hetionet CHEBI:114785 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0016204 infores:hetionet CHEBI:142290 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0007859 infores:hetionet CHEBI:6067 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0040264 infores:hetionet CAID:CA10014160 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014160 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.*88G>T variant in the 3' UTR has an MAF of 0.06896 (~7%, 2880/41766 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 104 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014160/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:157570 biolink:causes MONDO:0100253 infores:monarchinitiative not_provided not_provided HGNC:27230 MONDO:0100253 uuid:b3859282-d798-4347-a5aa-026ac7c89c04 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0010075 biolink:causes GO:0048507 infores:ubergraph knowledge_assertion manual_agent GO:0010075 GO:0048507 CHEBI:6129 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018965 infores:hetionet CHEBI:5441 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0018681 infores:hetionet CHEBI:29013 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0423153 infores:hetionet CHEBI:44915 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0035410 infores:hetionet CAID:CA229433 biolink:causes MONDO:0009861 infores:clingen CAID:CA229433 MONDO:0009861 PMID: Benign BA1, BP7 The c.1316-35C>T variant in PAH has a MAF of 0.02321 in the gnomAD European (Non-Finnish) population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229433/MONDO:0009861/006 2020-03-27 2020-03-27 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:75722 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0346156 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0039971 infores:hetionet CHEBI:16469 biolink:causes MONDO:0021723 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2004487 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027947 infores:hetionet CHEBI:71272 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0231528 infores:hetionet CHEBI:8707 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030794 infores:hetionet CHEBI:10101 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017181 infores:hetionet CHEBI:50922 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0030554 infores:hetionet CHEBI:8310 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0042109 infores:hetionet CHEBI:7983 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0002888 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0948976 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0948976 infores:hetionet CHEBI:70735 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0039231 infores:hetionet CHEBI:75722 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013390 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1456784 infores:hetionet CAID:CA386296582 biolink:causes MONDO:0009861 infores:clingen CAID:CA386296582 MONDO:0009861 PMID: Likely Pathogenic PM3, PM2, PP4, PP3 This c.679C>G (p.Leu227Val) variant in PAH was reported in trans with pathogenic variant p.Arg243Gln in 1 patient with PAH deficiency (1134μmol/L Phe) (PMID: 28982351). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease causing (MutationTaster). This variant is absent from population databases gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386296582/MONDO:0009861/006 2020-12-09 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0423791 infores:hetionet CHEBI:17474 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042345 infores:hetionet CHEBI:17334 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0040414 infores:hetionet CAID:CA16020730 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020730 MONDO:0009861 PMID:22513348PMID:22513348 Uncertain Significance PM2, PP4 PM3, PP3 The c.134T>C (p.Val45Ala) PAH variant has been reported in a patient with mild hyperphenylalaninemia (PMID: 22513348). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant with conflicting predictions of pathogenicity: SIFT: Tolerated, PolyPhen: Benign, MutationTaster: Disease causing, REVEL=0.697. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020730/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8768 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013604 infores:hetionet CHEBI:64355 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151662 infores:hetionet CHEBI:472657 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0002874 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0032285 infores:hetionet CAID:CA10360541 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360541 MONDO:0100039 PMID: Likely Benign BS2, BP4 BS1 The p.Arg822His variant in CDKL5 is present in 3 XX and 1 XY individuals in gnomAD v3.1.2 (0.0076%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Arg822His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Arg822His variant is observed in at least 2 unaffected individuals (internal database-GeneDX) (BS2). In summary, the p.Arg822His variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360541/MONDO:0100039/016 2023-02-20 2023-12-08 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7465 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0014591 infores:hetionet CHEBI:17026 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0014743 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0349506 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0022660 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009763 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0021400 infores:hetionet GO:0061344 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:0061344 GO:0003007 CHEBI:45783 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0014742 infores:hetionet CHEBI:85161 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0002792 infores:hetionet CHEBI:2682 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0016436 infores:hetionet CHEBI:31176 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0023066 infores:hetionet CHEBI:75722 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013456 infores:hetionet CAID:CA410147938 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147938 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1154A>G (p.Tyr385Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147938/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10110 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0031542 infores:hetionet CHEBI:553473 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0020517 infores:hetionet CHEBI:31236 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2242737 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001875 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014488 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0033975 infores:hetionet CHEBI:6437 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0149745 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005982 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0040247 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0039971 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038362 infores:hetionet CHEBI:135276 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0009806 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0021400 infores:hetionet CHEBI:16914 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0003123 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1142412 infores:hetionet CHEBI:6888 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0042963 infores:hetionet CHEBI:83804 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0039621 infores:hetionet CHEBI:4779 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0022281 infores:hetionet CHEBI:6822 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0030554 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040034 infores:hetionet CAID:CA1705706 biolink:causes MONDO:0015152 infores:clingen CAID:CA1705706 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.1254del p.(Phe419LeufsTer41) variant in DYSF, which is also known as NM_001130987.2: c.1350del p.(Phe451LeufsTer41), is a frameshift variant expected to introduce a premature stop codon in exon 15/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). In the literature, this variant has also been described as p.(Pro418ProfsTer123). This variant has been reported in at least three patients with features consistent with LGMD (PMID: 27647186, 26404900, 26404900), including in a homozygous state without reported familial consanguinity (0.5 pts, PMID: 17994539; PM3_Supporting). This homozygous individual had both progressive limb girdle muscle weakness and absent dysferlin expression in skeletal muscle via both immunohistochemistry and Western blot (PMID: 17994539; PP4_Strong). The highest population allele frequency for this variant is 8.475e-7 in gnomAD v4.1.0 (1/1180008 European (non-Finnish) alleles), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/17/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1705706/MONDO:0015152/180 2025-09-17 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49713 biolink:causes MONDO:0001741 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020502 infores:hetionet CHEBI:9086 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0232461 infores:hetionet UBERON:0001304 biolink:causes MONDO:0002229 infores:ubergraph knowledge_assertion manual_agent UBERON:0001304 MONDO:0002229 CHEBI:44185 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0040264 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0877339 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0877339 infores:hetionet CHEBI:617099 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0151934 infores:hetionet CAID:CA242744496 biolink:causes MONDO:0009861 infores:clingen CAID:CA242744496 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PVS1_Strong PM3 The c.970-1G>C variant in PAH occurs within the canonical splice acceptor site of intron 9. This is predicted to cause in-frame skipping of exon 10. It has been detected in a patient with PAH deficiency with second allele not reported (PMID: 31332730). The variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on this ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP4_moderate, PVS1_strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA242744496/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:194135 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011603 infores:hetionet CAID:CA013861 biolink:causes MONDO:0005045 infores:clingen CAID:CA013861 MONDO:0005045 PMID: Uncertain Significance PP3 PP2, PP1, PM2, PM1, BP4, PS3, PS4, BS4 NM_000258.3(MYL3):c.461G>A (p.Arg154His). This variant has been reported in individuals with HCM and other cardiomyopathies (ClinVar Variation ID: 14062), and has also been identified in 8 out of 282774 (0.005% FAF 95% CI) of pan-ethnic chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v2.1). This variant is not statistically increased in individuals with HCM compared to controls; [OR lower 95% CI <5]. Therefore, the PS4 criteria has not been applied and the PM2_Supporting criterion has not been applied. This variant segregated with disease in 1 affected relative with HCM (Ross 2017 PMID: 28615295). However, this data is currently insufficient to establish co-segregation with disease and apply PP1. In vitro functional studies provide some evidence that this variant could impact protein function (Lossie 2012 PMID: 22131351); however, this data is currently insufficient to establish functional impact and apply PS3. Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied. MYL2-specific ACMG/AMP criteria applied: PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013861/MONDO:0005045/103 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA354145 biolink:causes MONDO:0009861 infores:clingen CAID:CA354145 MONDO:0009861 PMID:21307867PMID:26503515PMID:24078561 Uncertain Significance PM2, PP4_Moderate, PP3 PM5 PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD ( 0.00001, 0.000004063); PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.975; PP4_Moderate: Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup. (PMID:21307867; PMID:24078561; PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA354145/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:1904942 biolink:causes GO:0003208 infores:ubergraph knowledge_assertion manual_agent GO:1904942 GO:0003208 CHEBI:465284 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151773 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0006145 infores:hetionet CHEBI:135736 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032231 infores:hetionet CHEBI:4445 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0241057 infores:hetionet CHEBI:9667 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0231218 infores:hetionet CHEBI:6909 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0917801 infores:hetionet CHEBI:16796 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0344232 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0013395 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0497201 infores:hetionet CHEBI:17303 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0851578 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0333641 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0029134 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0677500 infores:hetionet CHEBI:6888 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0041834 infores:hetionet CHEBI:3437 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0036974 infores:hetionet CHEBI:44915 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0004238 infores:hetionet CHEBI:6775 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0232461 infores:hetionet CHEBI:3640 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0221185 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002871 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0022658 infores:hetionet CHEBI:66919 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0851341 infores:hetionet CHEBI:31932 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0151662 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0559031 infores:hetionet CHEBI:161680 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0700590 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0026848 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0553732 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0042514 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0009806 infores:hetionet CHEBI:71272 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0001339 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020649 infores:hetionet CHEBI:5801 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C2363730 infores:hetionet CHEBI:28925 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0040046 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0027769 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0003123 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0855242 infores:hetionet CHEBI:135613 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0162297 infores:hetionet CHEBI:4798 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0040435 infores:hetionet GO:0090235 biolink:causes GO:0098813 infores:ubergraph knowledge_assertion manual_agent GO:0090235 GO:0098813 CHEBI:61049 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042035 infores:hetionet CHEBI:6129 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022346 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013146 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0027765 infores:hetionet NCBITaxon:5206 biolink:causes MONDO:0005723 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5206 MESH:D016919 DB00196_MESH_D016919_1 CAID:CA267675 biolink:causes MONDO:0009861 infores:clingen CAID:CA267675 MONDO:0009861 PMID:26503515 Uncertain Significance PP4_Moderate, PM2, PP3 PM5 PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.957; PP4_Moderate: H271L seen in a Chinese PKU patient. BH4 deficiencies excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267675/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:10388 biolink:causes MONDO:0009776 infores:monarchinitiative not_provided not_provided HGNC:11490 MONDO:0009776 uuid:ea6efa80-ecfc-455a-b084-f9eaf57608e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0042384 infores:hetionet CHEBI:49662 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0600142 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948594 infores:hetionet CHEBI:167638 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C3665347 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1368065 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0042109 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0521591 infores:hetionet CHEBI:9137 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013428 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0022660 infores:hetionet CHEBI:47898 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0010200 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0039584 infores:hetionet CAID:CA386964799 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964799 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM1_Supporting, PS4, PP1_Strong, PP4_Moderate, PP3 The c.653A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 218 (p.Tyr218Cys)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 10872540, PMID: 17286239, internal lab contributors). At least one individual had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and sensitive to sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; PMID: 17286239, internal lab contributors). In summary, c.653A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964799/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0426576 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0009450 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0009782 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0518015 infores:hetionet CHEBI:63580 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034155 infores:hetionet CHEBI:10125 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0232487 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151998 infores:hetionet CHEBI:5103 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0042963 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0521160 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0521160 infores:hetionet CHEBI:4027 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0162283 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0027765 infores:hetionet CHEBI:3240 biolink:causes UMLS:C0236083 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0236083 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042267 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027769 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0235409 infores:hetionet CHEBI:3561 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0311468 infores:hetionet NCBIGene:587 biolink:causes MONDO:0100058 infores:monarchinitiative not_provided not_provided HGNC:977 MONDO:0100058 uuid:0bd757bb-d446-4380-812c-f13463818218 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0751711 infores:hetionet CHEBI:5130 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002874 infores:hetionet CHEBI:8435 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0013595 infores:hetionet CHEBI:8871 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0149745 infores:hetionet CHEBI:6887 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0033774 infores:hetionet NCBIGene:23288 biolink:causes MONDO:0060550 infores:monarchinitiative not_provided not_provided HGNC:29171 MONDO:0060550 uuid:7569aba9-d28e-4067-ba7f-c26ba4453dd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0235439 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151736 infores:hetionet CHEBI:9150 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0023530 infores:hetionet CHEBI:28971 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0151596 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0042109 infores:hetionet CHEBI:16469 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0030193 infores:hetionet CHEBI:82960 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0595916 infores:hetionet CAID:CA405680045 biolink:causes MONDO:0018493 infores:clingen CAID:CA405680045 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with arginine at codon 2885 of the RYR1 protein, p.(Thr2885Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual also had a second variant of uncertain significance in RYR1, PS4 not implemented (PMID:25735680). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.656 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: None. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405680045/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:71255 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0027765 infores:hetionet CHEBI:490877 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0002792 infores:hetionet CAID:CA410207969 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207969 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM5_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.595G>A (p.Gly199Arg) is a missense variant which has a REVEL score ≥ 0.88 (0.947) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Additionally, this variant is a missense change at the same residue (p.Gly199) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 627343) based on MM-VCEP rules for RUNX1, and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207969/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA320644122 biolink:causes MONDO:0011071 infores:clingen CAID:CA320644122 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS1, PS3, PS4, PS2, BP2, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM5, PM1, PP3, PP1 The variant NM_001754.5:c.98-1411_98-1410del is an intronic deletion located in exon 3. Its minor allele frequency (MAF) of 0.006880 (0.688%, 198/28780 alleles) in the general population and 0.02188 (2.188%, 180/8226 alleles) in the African/African American subpopulation of the gnomAD v2.1.1 cohort exceeds ≥ 0.0015 (0.15%) (BA1). Additionally, evolutionary conservation prediction algorithms indicate that the site is not conserved (PhyloP100way score < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7), while SpliceAI predicts no impact on the splice consensus sequence nor creation of a new splice site (BP4). Furthermore, to our knowledge, this variant has not been reported in any patients with RUNX1-related diseases. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320644122/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49375 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151905 infores:hetionet GO:2000733 biolink:causes GO:0072080 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0072080 CHEBI:3082 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0009676 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0029456 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0001824 infores:hetionet CHEBI:74947 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0010200 infores:hetionet CHEBI:2038 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0038002 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0025061 infores:hetionet CHEBI:91541 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0011168 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0042571 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0035309 infores:hetionet CHEBI:5441 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0857305 infores:hetionet CAID:CA290780 biolink:causes MONDO:0011229 infores:clingen CAID:CA290780 MONDO:0011229 PMID: Benign BS2, BA1 PM5, PP3, PP4, BP4, PS2, PS1, PS3, PM2, PM6, PVS1, BP5, BS3 The allele frequency of the c.61G>T variant in the ETHE1 gene is 0.7% in gnomAD, including 33 homozygotes which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen ETHE1 Variant Curation Expert Panel (>0.1% in gnomAD- BA1 and BS2). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1 specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the ETHE1 expert panel on 2/23/2021 and approved on 2/23/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA290780/MONDO:0011229/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:64312 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0035078 infores:hetionet CHEBI:45081 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0041296 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0162638 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0162638 infores:hetionet CHEBI:6128 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0020625 infores:hetionet CHEBI:29688 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0013390 infores:hetionet CHEBI:63611 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003862 infores:hetionet CHEBI:6887 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1963951 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013238 infores:hetionet CAID:CA025290 biolink:causes MONDO:0012933 infores:clingen CAID:CA025290 MONDO:0012933 PMID: Benign BP5_Strong, BS2, BP7_Strong, BP4, BA1 The c.7806-40A>G variant is an intronic variant occurring in intron 16 of the BRCA2 gene. The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.02867 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). This variant has been observed in >10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score >4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.008 (based on Pathology LR=0.81; Case-Control LR=0.0095), within the thresholds for Strong benign evidence (LR ≥0.00285 & <0.05) (BP5_Strong met; Internal lab contributors). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BP7_Strong (RNA), BS2, BP5_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025290/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3393 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0023530 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151609 infores:hetionet CHEBI:31624 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0030554 infores:hetionet CHEBI:5959 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0004096 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0233472 infores:hetionet CHEBI:2654 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0015230 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0281774 infores:hetionet CHEBI:5296 biolink:causes MONDO:0004037 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0242420 infores:hetionet CHEBI:135342 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0522055 infores:hetionet CHEBI:36791 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0220870 infores:hetionet CHEBI:9571 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0002453 infores:hetionet CHEBI:9139 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020453 infores:hetionet CHEBI:8228 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0016655 infores:hetionet CHEBI:44032 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0018681 infores:hetionet CHEBI:94501 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C1443060 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0003864 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0344315 infores:hetionet CAID:CA255031 biolink:causes MONDO:0010602 infores:clingen CAID:CA255031 MONDO:0010602 PMID: Pathogenic PVS1, PP4_Moderate, PS2_Moderate, PM2_Supporting, PP1, PS4 PS3 The c.1063C>T (p.Arg355Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 8/26 and expected to result in nonsense-mediated mRNA decay, which meets PVS1 criteria. At least 20 probands from the literature reviewed below are reported to be hemizygous for the Arg355Ter variant, with severe Hemophilia A (FVIII:C <1%), which meets the PP4_Moderate and PS4_Very strong criteria. Inhibitors are reported in a few of these patients. One de novo occurrence without confirmation of maternity or paternity and an expected severe phenotype is reported in PMID: 29381227, which meets the PS2_Moderate criteria. Two siblings in one family in PMID: 15996930 are noted to have severe HA and the Arg355Ter variant, which meets PP1 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PS2_Moderate, PP1, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255031/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:9599 biolink:causes MONDO:0002136 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0155177 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0948525 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0302295 infores:hetionet CHEBI:9137 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0000731 infores:hetionet CHEBI:5100 biolink:causes UMLS:C2242583 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C2242583 infores:hetionet CHEBI:3310 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0030193 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013295 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009782 infores:hetionet CHEBI:47898 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0008031 infores:hetionet CHEBI:47499 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011253 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0851341 infores:hetionet CHEBI:10125 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085628 infores:hetionet CHEBI:4027 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042510 infores:hetionet CHEBI:6822 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0002792 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027932 infores:hetionet CHEBI:3011 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0034068 infores:hetionet CHEBI:63631 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014457 infores:hetionet CHEBI:9168 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019079 infores:hetionet CHEBI:7565 biolink:causes MONDO:0016028 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014804 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0235431 infores:hetionet CHEBI:63589 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C2047937 infores:hetionet CHEBI:134991 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0003811 infores:hetionet CHEBI:9137 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020433 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151882 infores:hetionet CHEBI:50730 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0085631 infores:hetionet CHEBI:194135 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0035229 infores:hetionet NCBIGene:25973 biolink:causes MONDO:0032752 infores:monarchinitiative not_provided not_provided HGNC:30563 MONDO:0032752 uuid:b60441ef-8d4a-4846-a6b8-11c530c92010 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66964 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0233632 infores:hetionet CHEBI:6149 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0033117 infores:hetionet CHEBI:8863 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1368065 infores:hetionet CHEBI:28748 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0037299 infores:hetionet CAID:CA16020973 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020973 MONDO:0009861 PMID:26542770 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The variant c.1228T>A (p.Phe410Ile) in PAH has been reported in 1 Danish patient with mild/moderate PKU (BH4 deficiency not excluded) (PMID: 26542770; PP4). This same patient carried this variant in trans with the previously reported c.1315+1G>A variant which has been reported as Pathogenic in ClinVar (PMID: 26542770; PM3). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.969 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020973/MONDO:0009861/006 2020-06-01 2020-06-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10124 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C2242996 infores:hetionet CHEBI:92712 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0085612 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0027769 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0021364 infores:hetionet CHEBI:87715 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0085649 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0162119 infores:hetionet CHEBI:135939 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C2830004 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0003864 infores:hetionet GO:1904444 biolink:causes GO:0046661 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0046661 CHEBI:49375 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0010200 infores:hetionet CHEBI:17688 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0234233 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011616 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0227791 infores:hetionet NCBIGene:54084 biolink:causes MONDO:0013929 infores:monarchinitiative not_provided not_provided HGNC:1268 MONDO:0013929 uuid:94529300-2fd9-4437-bd12-528061790bcf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8080 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0020542 infores:hetionet CHEBI:50567 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0020621 infores:hetionet CHEBI:3696 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0038325 infores:hetionet CHEBI:16469 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013447 infores:hetionet CHEBI:7852 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0043144 infores:hetionet CAID:CA287525681 biolink:causes MONDO:0100453 infores:clingen CAID:CA287525681 MONDO:0100453 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000180.4(GUCY2D):c.1561C>T (p.Arg521Ter) is a nonsense variant that introduces a premature stop codon into exon 6 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000003147, with 5 alleles / 1,588,950 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant. Because these two probands may be related only 1 is counted towards PM3 (0.5 points, PM3_Supporting; PMIDs: 26626312, 36819107). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA287525681/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49662 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020517 infores:hetionet CAID:CA3054201774 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201774 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1088_1100del (p.Gly363fs) is a frameshift variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (frameshift (–) c.759–c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201774/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7809 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C2047937 infores:hetionet CHEBI:36795 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2363731 infores:hetionet CHEBI:41423 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0236075 infores:hetionet NCBIGene:54361 biolink:causes MONDO:0008019 infores:monarchinitiative not_provided not_provided HGNC:12783 MONDO:0008019 uuid:2b876456-07bf-4c2d-913e-144f9ae21cd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0015672 infores:hetionet CHEBI:5280 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C2363731 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0020517 infores:hetionet CHEBI:114785 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0162834 infores:hetionet CHEBI:3696 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0497156 infores:hetionet CHEBI:50173 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C3665347 infores:hetionet CHEBI:6909 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1112214 infores:hetionet NCBIGene:114548 biolink:causes MONDO:0008633 infores:monarchinitiative not_provided not_provided HGNC:16400 MONDO:0008633 uuid:50075000-a0aa-46f2-8fe9-c05641af2e26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75179 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0030193 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0041969 infores:hetionet CAID:CA340936 biolink:causes MONDO:0044970 infores:clingen CAID:CA340936 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS2, PS4, PS3, PM6 The m.13730G>A (p.G465E) variant in MT-ND5 has been reported in one individual from one family to date (PMID: 8213825), in a male with Leber Hereditary Optic Neuropathy (LHON). The variant was present at 80% heteroplasmy in blood. The variant was presumed to have occurred de novo as it was absent in blood from his mother, maternal grandmother, and two maternal uncles (PMID: 8213825), however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.83, which predicts a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340936/MONDO:0044970/015 2023-11-13 2024-03-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:65173 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0162285 infores:hetionet CHEBI:2038 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0917801 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0042075 infores:hetionet CAID:CA022758 biolink:causes MONDO:0012933 infores:clingen CAID:CA022758 MONDO:0012933 PMID: Likely Benign BP1_Strong PM2, BS1, BA1 The c.5632_5634del variant in BRCA2 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid (p.Asn1878del). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This in-frame deletion variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold <0.1) (BP1_Strong met).In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA022758/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA8337875 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337875 MONDO:0008723 PMID: Likely Pathogenic PVS1_Moderate, PM3_Strong, PP4_Moderate PM2 The c.878+1G>C variant in ACADVL, also known as IVS9+1G>C, occurs within the canonical splice donor of intron 9. It is predicted to cause skipping of biologically-relevant exon 9/20, resulting in an in-frame deletion (removes amino acids 753-878) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The variant has been described in at least two individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency who displayed increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Moderate; PMIDs: 26927351, 31844625). Each of these affected patients were compound heterozygous for this variant distinct likely pathogenic variants confirmed by parental testing (PM3_Strong; PMIDs: 26927351, 31844625). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM3_Strong, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337875/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7931 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0043144 infores:hetionet CHEBI:51860 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0033893 infores:hetionet CHEBI:8871 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0242301 infores:hetionet CHEBI:10127 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0001807 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0007097 infores:hetionet GO:0048774 biolink:causes CL:0000747 infores:ubergraph knowledge_assertion manual_agent GO:0048774 CL:0000747 CHEBI:16469 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0340865 infores:hetionet CHEBI:4814 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C1167965 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1142135 infores:hetionet CAID:CA91167878 biolink:causes MONDO:0001586 infores:clingen CAID:CA91167878 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting PS3, BS3 The NM_000203.5:c.667G>T variant in IDUA is a missense variant predicted to cause substitution of aspartic acid by tyrosine at amino acid 223 (p.Asp223Tyr). To our knowledge, the results of functional assays have not been reported for this variant and this variant has not been reported in the literature in any individuals with MPS1. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008029 (6/74728 alleles; no homozygotes) in the African / African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.87 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 1406350). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PP3_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA91167878/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7983 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0036974 infores:hetionet CAID:CA401361056 biolink:causes MONDO:0009290 infores:clingen CAID:CA401361056 MONDO:0009290 PMID:14972326PMID:14972326 Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.399C>A (p.Tyr133Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and absence of gene product, meeting PVS1. When expressed in COS-1 cells, the variant results in no GAA activity and the mutant protein cannot be detected on Western blot, (PMID 14972326) supporting that it is a loss of function variant. The variant is absent in gnomAD v2.1.1, meeting PM2. A patient with infantile onset Pompe disease meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported who is homozygous for the variant; both parents were confirmed to be heterozygotes (PMID 14972326), meeting PM3_Supporting. There is no ClinVar entry for this varint. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401361056/MONDO:0009290/010 2020-02-14 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:10119 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018965 infores:hetionet CHEBI:5893 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0014518 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0234193 infores:hetionet CHEBI:6931 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0030554 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007114 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0858797 infores:hetionet CHEBI:9139 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009782 infores:hetionet NCBIGene:176 biolink:causes MONDO:0100462 infores:monarchinitiative not_provided not_provided HGNC:319 MONDO:0100462 uuid:c35fe8ea-798a-46a8-902e-dab9e2973f42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0017181 infores:hetionet CHEBI:10124 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1458155 infores:hetionet CHEBI:8888 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004604 infores:hetionet CHEBI:2914 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0178298 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151601 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0041912 infores:hetionet CHEBI:63635 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020621 infores:hetionet CHEBI:8356 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0236075 infores:hetionet CHEBI:6520 biolink:causes EFO:0008501 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0334044 infores:hetionet CHEBI:4792 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0042963 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0160390 infores:hetionet CHEBI:24564 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C1140680 infores:hetionet GO:0039606 biolink:causes GO:0006412 infores:ubergraph knowledge_assertion manual_agent GO:0039606 GO:0006412 CAID:CA058144 biolink:causes MONDO:0007783 infores:clingen CAID:CA058144 MONDO:0007783 PMID: Uncertain Significance BP4 PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with valine at codon 4022 of the RYR1 protein, p.(Met4022Val). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00027, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. As well, that individual harbored an additional variant in RYR1, p.(Arg2676Trp), PS4 was not implemented (PMID:21157159). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.491) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA058144/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:16755 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0267792 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024437 infores:hetionet CHEBI:16899 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0080274 infores:hetionet NCBIGene:4352 biolink:causes MONDO:0009692 infores:monarchinitiative not_provided not_provided HGNC:7217 MONDO:0009692 uuid:7693286c-6a21-48aa-8e93-2bd567761347 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151744 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0010709 infores:hetionet CAID:CA135058 biolink:causes MONDO:0021060 infores:clingen CAID:CA135058 MONDO:0021060 PMID: Benign BP7, BP5, BA1, BP4 The filtering allele frequency of the c.1227A>G (p.Ser409=) variant in the BRAF gene is 0.313% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (233/66620 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additionally, this variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The p.Ser409= variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL Genetics internal data; GTR ID's: 21766, 26957, 500060; SCV000057203.8; SCV000061570.5; SCV000112807.7). Computational prediction tools and conservation analysis suggest that the p.Ser409= variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP7, BP5, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135058/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6715 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0014742 infores:hetionet CAID:CA320603653 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603653 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.738G>A (p.Thr246=) is a synonymous variant. REVEL score is not applicable and SpliceAI is ≤0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.464 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603653/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5893 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0027497 infores:hetionet CHEBI:2611 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0037036 infores:hetionet CHEBI:47898 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0039231 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0018799 infores:hetionet UMLS:C0005740 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0595916 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022573 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0162429 infores:hetionet CHEBI:167638 biolink:causes MONDO:0010138 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0040156 infores:hetionet CHEBI:474053 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0014518 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0235431 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018802 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037195 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0014130 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0497247 infores:hetionet CHEBI:17474 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0021368 infores:hetionet NCBIGene:23152 biolink:causes MONDO:0030910 infores:monarchinitiative not_provided not_provided HGNC:14214 MONDO:0030910 uuid:9fd0fe2a-dafe-4c69-a4a0-36ca0494b070 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4254 biolink:causes MONDO:0014738 infores:monarchinitiative not_provided not_provided HGNC:6343 MONDO:0014738 uuid:697ae065-1eb2-479f-9251-f51ddcc627ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27446 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0015967 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0015230 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0021400 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0574067 infores:hetionet NCBIGene:4645 biolink:causes MONDO:0009635 infores:monarchinitiative not_provided not_provided HGNC:7603 MONDO:0009635 uuid:30b3d579-2ff3-4d3e-b110-c6c8e924b048 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8499 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0042109 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0031046 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0162429 infores:hetionet CHEBI:68841 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0521491 infores:hetionet CHEBI:18358 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0013378 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0877306 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0877306 infores:hetionet CHEBI:9086 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0037036 infores:hetionet UMLS:C0005740 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0234233 infores:hetionet CHEBI:46345 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0000786 infores:hetionet CHEBI:4470 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0009676 infores:hetionet CHEBI:3723 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085593 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0040584 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002957 infores:hetionet CHEBI:16469 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0231218 infores:hetionet CHEBI:408174 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0043352 infores:hetionet CHEBI:6931 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0016658 infores:hetionet CHEBI:42797 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018926 infores:hetionet CHEBI:3127 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0041834 infores:hetionet CHEBI:71023 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0030193 infores:hetionet CHEBI:8764 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0039070 infores:hetionet CHEBI:50378 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0002170 infores:hetionet CHEBI:9737 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0004093 infores:hetionet CHEBI:585948 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0002871 infores:hetionet NCBIGene:6125 biolink:causes MONDO:0012937 infores:monarchinitiative not_provided not_provided HGNC:10360 MONDO:0012937 uuid:33ef4414-3af8-49e7-91a2-3ab14f75ce50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:161680 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0040264 infores:hetionet CAID:CA228671 biolink:causes MONDO:0015628 infores:clingen CAID:CA228671 MONDO:0015628 PMID:29186156 Pathogenic PS3_Supporting, PP4_Moderate, PP3, PP1, PM2_Supporting, PS1 The NM_000552.5(VWF):c.4885G>C (p.Gly1629Arg) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The same amino acid change (p.Gly1629Arg), resulting from a different nucleotide change c.4885G>C, is classified as likely pathogenic by the ClinGen VWD VCEP (PS1_moderate). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 4 IU/dl ), low activity/VWF:Ag ratio (0.13), and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID: 30044032). Additional consistent phenotypes were also reported in the patient including FVIII activity consistent with VWF antigen and a reduced RIPA. In PMID: 10203106 The variant segregated in four type 2A vWD patients from a Spanish family who bled excessively and all showed a lack of HMW multimers and had a low RIPA (PP1). In PMID: 29186156, G1629R rVWF was expressed from HEK293 cells concentrated, quantified by ELISA and multimeric structure analyzed by gel electrophoresis displayed a full range of VWF multimers. With ADAMTS13 incubation there was partial proteolysis with loss of only higher MW multimers compared to minimal evidence of ADAMTS13 proteolysis for WT. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PP1, PM2_Supporting, PP3, PS1_Moderate, PS3_Supporting. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228671/MONDO:0015628/081 2025-05-06 2025-05-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31401 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0017160 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0542215 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0542215 infores:hetionet CHEBI:125354 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0020458 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0474395 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C1536696 infores:hetionet CAID:CA347487 biolink:causes MONDO:0015152 infores:clingen CAID:CA347487 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting PP1 The NM_000070.3:c.1194-9A>G variant in CAPN3 is located in intron 9 of 23 and is expected to disrupt the canonical splice acceptor site (SpliceAI score 0.97 for acceptor loss) and create an alternative acceptor site (SpliceAI score 1.0 for acceptor gain). RNA analysis has demonstrated a splice effect of this variant, resulting in inclusion of the last eight nucleotides of intron 9, which is expected to lead to a frameshift, premature truncation, and subsequent nonsense mediated decay (PVS1_RNA). This variant has been detected in at least 9 unrelated individuals with clinical features of limb girdle muscular dystrophy (PMID: 30564623, 22158424, 12461690, 18055493, 25135358, 10330340, 11525884; LOVD CAPN3_000088; ClinVar SCV003922313.1), including in a homozygous state (0.75 pts) (PMID: 12461690, 11525884) and in unknown phase with a pathogenic variant (c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV003922313.1 (PM3). At least one individual with this variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PP4). The minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113748 chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/18/2025): PVS1_RNA, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347487/MONDO:0015152/187 2025-03-18 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:84500 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0152029 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0232462 infores:hetionet CHEBI:6067 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0917801 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0413252 infores:hetionet CHEBI:100241 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151610 infores:hetionet CHEBI:63598 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018681 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014742 infores:hetionet CAID:CA226509 biolink:causes MONDO:0100368 infores:clingen CAID:CA226509 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PM2_Supporting The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant is a missense variant in RPE65 causing a substitution of valine with glycine at position 452. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.00001064, with 3/74896 alleles in the African/African American population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.945, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Arg91Trp variant or the c.11+5G>A variant confirmed in trans (2 points, PMID: 9501220; laboratory-provided internal data), which were previously classified pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3_Strong (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226509/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5959 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020517 infores:hetionet CHEBI:63619 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0006384 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042109 infores:hetionet CAID:CA512232260 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232260 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.862C>T (p.Leu288=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232260/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45783 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020437 infores:hetionet CHEBI:5147 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004245 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0877322 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0221490 infores:hetionet CHEBI:367163 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151904 infores:hetionet CHEBI:35778 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0023052 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0522570 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0522570 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027707 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0033975 infores:hetionet GO:1904155 biolink:causes CL:0000806 infores:ubergraph knowledge_assertion manual_agent GO:1904155 CL:0000806 CHEBI:8435 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0002874 infores:hetionet CHEBI:52717 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151908 infores:hetionet CAID:CA2573131754 biolink:causes MONDO:0100326 infores:clingen CAID:CA2573131754 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.2390del (p.Gly797ValfsTer29) frameshift variant in exon 24 is predicted to cause a premature stop codon in biologically-relevant-exon 25/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Case 9 in PMID: 34066320) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573131754/MONDO:0100326/011 2022-09-20 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3723 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0700361 infores:hetionet CHEBI:5280 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151746 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0007055 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0007055 uuid:d9f8e87f-9d66-4da0-a83f-6511fc5bc783 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31623 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0851341 infores:hetionet CHEBI:7565 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0424295 infores:hetionet CHEBI:63632 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0206062 infores:hetionet CHEBI:6539 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C1306341 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0854697 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0854697 infores:hetionet CAID:CA10585116 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585116 MONDO:0007750 PMID: Pathogenic PM3, PVS1, PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM6, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM3 - variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493).-- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met.PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China, so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585116/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6367 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0026766 infores:hetionet CHEBI:6367 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085632 infores:hetionet CHEBI:3127 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0812387 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042769 infores:hetionet CHEBI:92607 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0000737 infores:hetionet CAID:CA228922 biolink:causes MONDO:0100438 infores:clingen CAID:CA228922 MONDO:0100438 PMID: Benign BS2, BP4, BA1 NM_014336.5(AIPL1):c.937G>T (p.Ala313Ser) is a missense variant in exon 6 of 6. The variant is predicted to change the amino acid alanine at position p.313 to serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.01581, with 1,244 alleles / 75,040 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). The variant has been found in the homozygous state in 16 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.069, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on AIPL1 protein function. In addition, the phyloP score is 1.28882 (suggesting low conservation) and the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA228922/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63618 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0852911 infores:hetionet CHEBI:15940 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0023530 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0036572 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0037274 infores:hetionet CAID:CA234991 biolink:causes MONDO:0012589 infores:clingen CAID:CA234991 MONDO:0012589 PMID: Benign BS2, BA1, BP4 The allele frequency of the p.Asn90Ser variant in TCF4 is 1.5% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Asn90Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn90Ser variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA234991/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7494 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151827 infores:hetionet CHEBI:135925 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0011071 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C3263723 infores:hetionet CHEBI:10650 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0728899 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0595883 infores:hetionet CHEBI:68595 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0024312 infores:hetionet CHEBI:9943 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013404 infores:hetionet CHEBI:135613 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0015732 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0019158 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0521491 infores:hetionet CHEBI:8774 biolink:causes HP:0030249 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0014034 infores:hetionet CHEBI:8768 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030252 infores:hetionet GO:0039522 biolink:causes GO:0006406 infores:ubergraph knowledge_assertion manual_agent GO:0039522 GO:0006406 CHEBI:9599 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0549373 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0149904 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038663 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0022573 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0392025 infores:hetionet CAID:CA512341251 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341251 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1173G>A (p.Ala391=) is a synonymous variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341251/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2668 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0003811 infores:hetionet CHEBI:584020 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0013428 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0032961 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0024115 infores:hetionet CHEBI:48273 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0700200 infores:hetionet CHEBI:3752 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0043094 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0751249 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0751249 infores:hetionet CHEBI:8774 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0003862 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0521591 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0031542 infores:hetionet CAID:CA401359804 biolink:causes MONDO:0009290 infores:clingen CAID:CA401359804 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM3, PM2_Supporting The NM_000152.5:c.2T>C variant in GAA is an initiator codon variant that is predicted to abolish the start codon (p.Met1?). The next in-frame methionine is at position 122 but, even if used, the gene product would be missing the signal sequence (PMID 22252923). This variant results in 3.6% GAA activity in medium and 0% GAA activity in cells and is abnormally synthesized when expressed in HEK293 cells, and is classified as Class B (“potentially less severe”) by Kroos et al, 2012 (PMID: 22644586) PVS1_Strong for initiator codon variant in GAA upgraded to PVS1 based on availability of functional evidence (PVS1). Two patients with the variant have been reported in the literature, both with late-onset Pompe disease. One had diminished GAA activity, but residual activity was not provided (PMID: 29124014). The second patient had documented laboratory values indicating reduced GAA activity but was also heterozygous for a pseudodeficiency variant. The patient was on enzyme replacement therapy (PMID: 21757382) (PP4). Two patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, including c.1826dup (p.Tyr609Ter) (PMID: 29124014) and c.1935C>A (p.Asp645Gln) (PMID: 21757382). The phase was not confirmed in either case (PM3). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). Of note, additional initiator codon variants, including c.1A>G, c.1A>T, and c.3G>A, have been reported in patients with Pompe disease (see http://www.pompevariantdatabase.nl/). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Disease Variant Curation Expert Panel, April 4, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401359804/MONDO:0009290/010 2023-04-04 2023-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8499 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0178298 infores:hetionet CHEBI:15552 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C1142412 infores:hetionet CHEBI:2549 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0035455 infores:hetionet NCBIGene:338917 biolink:causes MONDO:0012409 infores:monarchinitiative not_provided not_provided HGNC:1975 MONDO:0012409 uuid:069d7eaa-5952-4461-b395-a20f52f3381f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0004093 infores:hetionet CHEBI:4995 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011175 infores:hetionet CHEBI:408174 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0036689 infores:hetionet CHEBI:2618 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0011603 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0030252 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0155169 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0340726 infores:hetionet NCBIGene:931 biolink:causes MONDO:0013285 infores:monarchinitiative not_provided not_provided HGNC:7315 MONDO:0013285 uuid:28daca8b-d2e3-4ff3-87a1-099bb3e5b8b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes UMLS:C0267055 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0267055 infores:hetionet CHEBI:8776 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0006145 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0041969 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0151596 infores:hetionet NCBIGene:6927 biolink:causes MONDO:0012919 infores:monarchinitiative not_provided not_provided HGNC:11621 MONDO:0012919 uuid:67b3dcc4-093f-437c-84dd-f88eaa6979ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0004238 infores:hetionet CHEBI:7798 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011991 infores:hetionet CHEBI:31859 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0001807 infores:hetionet CAID:CA248609 biolink:causes MONDO:0011071 infores:clingen CAID:CA248609 MONDO:0011071 PMID: Pathogenic PP1_Strong, PVS1, PM2, PS4_Supporting PS3, PS1, BP2, BP4, BA1, PM6, BS4, BS1, BS3, BP7, PM1, PM4, PM5, PP3 The NM_001754.4:c.352-1G>T variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1; PMID: 10508512). This variant was found to co-segregate with disease in multiple affected family members, with more than seven meioses (at least 25 affected individuals) observed in one family/across X families (PP1_Strong; 10508512). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1_Strong, PM2, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248609/MONDO:0011071/008 2019-08-01 2019-08-02 Autosomal dominant inheritance HP:0000006 Supports GO:0072034 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0072028 CHEBI:9352 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0042109 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0038454 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0853021 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0853021 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0549385 infores:hetionet CHEBI:8805 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0042963 infores:hetionet CHEBI:50156 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0234146 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0009450 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0008311 infores:hetionet CHEBI:4681 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0948594 infores:hetionet NCBIGene:2706 biolink:causes MONDO:0007852 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0007852 uuid:6dfc7480-626d-40b2-9757-6a23d6d26e8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127342 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1260880 infores:hetionet CHEBI:65173 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0030252 infores:hetionet CHEBI:63607 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0000737 infores:hetionet GO:0010632 biolink:causes GO:0090132 infores:ubergraph knowledge_assertion manual_agent GO:0010632 GO:0090132 CHEBI:6847 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0002878 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0522061 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0522061 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0015397 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0235763 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0015395 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0015395 infores:hetionet CHEBI:4027 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0038999 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0038362 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006644 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0023891 infores:hetionet CHEBI:5109 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0033774 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0036572 infores:hetionet CHEBI:63630 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151744 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0042075 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0853692 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0033777 infores:hetionet CHEBI:36795 biolink:causes MONDO:0010030 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1527336 infores:hetionet CHEBI:8228 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0030196 infores:hetionet CHEBI:47780 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011603 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0973461 infores:hetionet CAID:CA226483 biolink:causes MONDO:0100368 infores:clingen CAID:CA226483 MONDO:0100368 PMID: Pathogenic PS3_Supporting, PP4_Moderate, PP3, PP1, PM3_Very Strong, PM2_Supporting BA1, BS1 The NM_000329.3(RPE65):c.11+5G>A variant is a putative splicing variant in intron 1 of the RPE65 gene. The computational splicing predictor SpliceAI lists a change score of 0.58 for splice donor gain, predicting a deleterious impact on splicing (PP3). VCEP-member provided data from a mini-gene assay in HEK-293 cells show that this variant reduces normal splicing and leads to >400x reduction of mature mRNA, relative to the wild-type control (PS3_Supporting, Guan et al., 2024). At least 3 patients with this variant have been reported with detailed phenotypes (PMID: 21211845, PMID: 11786058), one of whom exhibited nonrecordable ERG responses from rods (0.5 pts) and cones (1 pt), congenital night blindness (0.5 pts), absence of autofluorescence (2 pts), optic nerve pallor (0.5 pts), RPE granularity (0.5 pts), onset between birth and age 5 years (1 pt), OCT preserved at macula (1 pt), constricted Goldmann visual field (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are highly specific for recessive RPE65 retinopathy (10 pts total, VCEP member-provided data, PP4_Moderate). This variant has been detected in at least 7 published cases with recessive retinopathy, including at least two individuals homozygous for the variant (1 pt) and three individuals compound heterozygous for this variant in trans with either the c.615_616del (p.Ile206Cysfs*27), p.Glu102Ter, or c.89dup (p.Thr31fs) variant, all which have been classified Pathogenic by this VCEP (4pts, PMID: 11095629, PMID: 17525851, PMID: 35129589), (PM3_Very-Strong). Two publications contain segregation data (PMID: 11786058 and PMID: 35001204), with one set of genotype-positive siblings exhibiting the required phenotype of absent or severely decreased rod electroretinogram response (PP1). The GrpMax Filtering AF for this variant in gnomAD v2.1.1 is 0.0001017 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Very-Strong, PP4_Moderate, PP1, PM2_Supporting, PP3, PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226483/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15551 biolink:causes HP:0011891 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0032797 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1384666 infores:hetionet CHEBI:42797 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0043094 infores:hetionet CHEBI:5165 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0018946 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0020672 infores:hetionet CHEBI:64045 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0404521 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018099 infores:hetionet NCBIGene:7187 biolink:causes MONDO:0013920 infores:monarchinitiative not_provided not_provided HGNC:12033 MONDO:0013920 uuid:d9ca30d5-2e8d-4971-b660-48c0c5c0339b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1770 biolink:causes MONDO:0032664 infores:monarchinitiative not_provided not_provided HGNC:2953 MONDO:0032664 uuid:8567cbc5-ae3f-4c0f-a46a-1fe5fafa33d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135342 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0392156 infores:hetionet CHEBI:17303 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0027066 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020580 infores:hetionet CHEBI:8888 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003962 infores:hetionet CHEBI:180905 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0036974 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0853761 infores:hetionet CHEBI:44185 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0917801 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004936 infores:hetionet CHEBI:7565 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C3665347 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151736 infores:hetionet CHEBI:7444 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0015230 infores:hetionet CAID:CA343725177 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725177 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.997A>T variant in MYOC is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 333 (p.Ser333Cys). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.568, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 22933836), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725177/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4672 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0234913 infores:hetionet CHEBI:7931 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085628 infores:hetionet CHEBI:31348 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0041657 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0854082 infores:hetionet CHEBI:7824 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1527344 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037274 infores:hetionet CHEBI:4466 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0032227 infores:hetionet CHEBI:9649 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0039231 infores:hetionet CHEBI:83804 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040822 infores:hetionet CAID:CA320251605 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251605 MONDO:0011071 PMID: Uncertain Significance PS4_Supporting PS3, PS1, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1): c.1008C>G (p.Phe336Leu) is a missense variant which has a minor allele frequency (MAF) of 0.000001805 (0.0001805%, 2/1108180 alleles) in the European (non-Finnish) population of gnomAD v4 (PM2_supporting not met). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (Thrombocytopenia/impaired platelet aggregation) (PS4_supporting). The REVEL score for this missense variant is 0.62, indicating a conflicting interpretation of pathogenicity. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251605/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63612 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0002622 infores:hetionet CHEBI:63611 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002994 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0023530 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0020651 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0149904 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0162287 infores:hetionet CHEBI:50922 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0004134 infores:hetionet CHEBI:145499 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151905 infores:hetionet CAID:CA349020765 biolink:causes MONDO:0100038 infores:clingen CAID:CA349020765 MONDO:0100038 PMID: Uncertain Significance PM6_Supporting, PP3_Moderate, PM2_Supporting PM1 The c.1108C>T variant in SCN2A is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 370 (p.Phe370Leu). The variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with a consistent phenotype (early infantile developmental and epileptic encephalopathy) in the published literature (PMID:35431799) (PM6_Supporting). It is absent from the population database gnomAD v2.1.1 and v4.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.977, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6_Supporting, PM2_Supporting, PP3_Moderate. (version 1.0; March 26, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349020765/MONDO:0100038/068 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2379 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0151904 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0005741 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0036572 infores:hetionet CHEBI:50742 biolink:causes MONDO:0016642 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0025286 infores:hetionet CAID:CA10591598 biolink:causes MONDO:0700268 infores:clingen CAID:CA10591598 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP4, BP5 The c.4963T>C variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1655 (p.(Ser1655Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.5, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.64 (based on Pathology LR=0.64), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10591598/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32293 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0314719 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003864 infores:hetionet GO:1903859 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0048666 CHEBI:45409 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0030193 infores:hetionet CHEBI:8764 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013447 infores:hetionet CHEBI:50648 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235710 infores:hetionet CHEBI:68584 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0011168 infores:hetionet CHEBI:3223 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0009763 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0019360 infores:hetionet CHEBI:4877 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0014457 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027769 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0232409 infores:hetionet CHEBI:9588 biolink:causes MONDO:0000702 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0400821 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0010692 infores:hetionet CHEBI:36791 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040822 infores:hetionet CHEBI:50223 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151904 infores:hetionet CHEBI:64312 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151825 infores:hetionet CHEBI:3752 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0220870 infores:hetionet CHEBI:66901 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0231528 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020039 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005543 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0520463 infores:hetionet CHEBI:2611 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0232292 infores:hetionet CHEBI:8356 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027424 infores:hetionet CHEBI:7640 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0004245 infores:hetionet CHEBI:9588 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0030193 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C1527344 infores:hetionet CHEBI:18332 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0018213 infores:hetionet CHEBI:521033 biolink:causes HP:6000135 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0855521 infores:hetionet CHEBI:3723 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235592 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0595862 infores:hetionet CHEBI:3223 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0151786 infores:hetionet CHEBI:101278 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0040822 infores:hetionet CHEBI:7565 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0013404 infores:hetionet CHEBI:4672 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0038325 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0221776 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235213 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235213 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0162429 infores:hetionet CHEBI:135888 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0027441 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0002418 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0027769 infores:hetionet CHEBI:63608 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0085605 infores:hetionet CHEBI:6538 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0002170 infores:hetionet CHEBI:3647 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0014457 infores:hetionet GO:1902205 biolink:causes GO:0071352 infores:ubergraph knowledge_assertion manual_agent GO:1902205 GO:0071352 CHEBI:9599 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0041912 infores:hetionet CHEBI:31397 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0010200 infores:hetionet CHEBI:7954 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0027497 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0026113 infores:hetionet CAID:CA410202786 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202786 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.355G>A (p.Val119Met) is a missense variant which has a REVEL score ≥ 0.88 (0.936) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202786/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9586 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151766 infores:hetionet CHEBI:135342 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0039239 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0018799 infores:hetionet CHEBI:499361 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020580 infores:hetionet CHEBI:34911 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0677500 infores:hetionet NCBIGene:5660 biolink:causes MONDO:0012719 infores:monarchinitiative not_provided not_provided HGNC:9498 MONDO:0012719 uuid:81ddfa14-0de9-4906-a06b-c6b19110aec1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0026827 infores:hetionet CHEBI:4909 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0019080 infores:hetionet CHEBI:63631 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0917801 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0015256 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0520589 infores:hetionet CHEBI:4858 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0023530 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0853254 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0853254 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0232492 infores:hetionet CAID:CA345149129 biolink:causes MONDO:0100084 infores:clingen CAID:CA345149129 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM6, PM5 PS4 The variant NM_001100.4:c.442G>T in ACTA1 is a missense variant predicted to cause substitution of glycine by valine at amino acid 148 (p.Gly148Val). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.963, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Two different missense variants, p.Gly148Ser and p.Gly148Arg (Variation IDs: 1364817 and 280732), in the same codon have been classified as likely pathogenic for alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). This variant has been reported in 1 proband with alpha-actinopathy, and had a de novo occurrence of the variant with parental relationships unconfirmed (PM6; PMID: 32668698). In summary, this variant meets the criteria to be classified as likely pathogenic for AD alpha-actinopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP (Specification Version 2.0.0): PM2_Supporting, PP3, PP2, PM5, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 3/10/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345149129/MONDO:0100084/147 2025-03-10 2025-04-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:134966 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0013428 infores:hetionet CHEBI:42944 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0016382 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0948089 infores:hetionet CHEBI:5147 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0086439 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0028738 infores:hetionet NCBIGene:8517 biolink:causes MONDO:0010631 infores:monarchinitiative not_provided not_provided HGNC:5961 MONDO:0010631 uuid:d85fdf8e-0d8c-45b2-a136-49e545e0ada1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1900214 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:1900214 GO:0072001 GO:0044079 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0044079 GO:0051641 CHEBI:4681 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0021308 infores:hetionet CHEBI:6367 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0024282 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0518015 infores:hetionet CAID:CA748900507 biolink:causes MONDO:0011071 infores:clingen CAID:CA748900507 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*1400G>A is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA748900507/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:34385 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0042963 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0151735 infores:hetionet CHEBI:3215 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0035232 infores:hetionet NCBIGene:6487 biolink:causes MONDO:0012612 infores:monarchinitiative not_provided not_provided HGNC:10866 MONDO:0012612 uuid:73fecd59-611f-43d6-bca8-d88356ec1113 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020649 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0032285 infores:hetionet CHEBI:68595 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0011603 infores:hetionet CHEBI:116278 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013404 infores:hetionet CHEBI:6954 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0009782 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0863113 infores:hetionet CHEBI:4659 biolink:causes HP:0007141 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C1112256 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0233632 infores:hetionet CHEBI:3213 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0740394 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853762 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853762 infores:hetionet CHEBI:3441 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0206062 infores:hetionet CHEBI:3219 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013378 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0332798 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0332798 infores:hetionet CHEBI:9586 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0040264 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0018799 infores:hetionet CHEBI:7465 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0497156 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004712 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0854331 infores:hetionet CHEBI:31515 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C2004489 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0878544 infores:hetionet CHEBI:135276 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C2830004 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0152029 infores:hetionet CHEBI:15428 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0002962 infores:hetionet CHEBI:31859 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0338908 infores:hetionet CAID:CA023422 biolink:causes MONDO:0007750 infores:clingen CAID:CA023422 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PM3, PM2, PP3, PP4 NM_000527.5(LDLR):c.1133A>C (p.Gln378Pro) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate, PM3, PP1_Moderate, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2: PopMax MAF = 0.00001760 (0.001760%) in European (non-Finnish) exomes (gnomAD v2.1.1).PP3: REVEL = 0.754.PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PS4_moderate: Variant meets PM2 and is identified in at least 6 unrelated index cases: 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome definite criteria; 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6; 1 case from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory with Dutch lipid clinic network >=6; 1 case from South Africa in PMID: 9664576; 1 case from Spain in PMID: 15241806; 1 case from Italy in PMID: 23375686.PM3: PMID: 27784735 - variant identified in two children with homozygous FH: in one patient confirmed in trans with LDLR p.Ile792Thr and in the second patient confirmed in trans with a LP/P LDLR exonic deletion; given this exonic deletion is LP/P, PM3 applies.PP4: Variant meets PM2 and is identified in >1 index case who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded.Note: BS3 not met: PMID: 32015373 - Level 1 assay: Heterologous cells, FACS assays – results - cell surface LDLR (96%), binding (101%) were normal; LDL uptake (80%) activity is not above 90%, so BS3 not met. This result suggests this variant may only have a minor effect (i.e. 20% reduction in LDL uptake), although this is not insignificant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023422/MONDO:0007750/013 2022-05-06 2022-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBITaxon:6035 biolink:causes MONDO:0005743 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6035 MONDO:0005743 CHEBI:145499 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0221395 infores:hetionet CHEBI:7465 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0030196 infores:hetionet CHEBI:78543 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C3665624 infores:hetionet CHEBI:77733 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0497156 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018674 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011849 infores:hetionet CHEBI:5165 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0027066 infores:hetionet CHEBI:39867 biolink:causes UMLS:C1868980 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1868980 infores:hetionet CHEBI:3216 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0033774 infores:hetionet CAID:CA386965461 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965461 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4 The c.710A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 237 (p.(Asn273Ser)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.706, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.709A>G (p.Asn237Asp) has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.710A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP4_Moderate, PM5_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965461/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6950 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0022408 infores:hetionet CHEBI:27834 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0015672 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0235416 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0027765 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0549356 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0151559 infores:hetionet CHEBI:64355 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040264 infores:hetionet CAID:CA380145244 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145244 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.19A>G is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 7 (p.Thr7Ala). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP:PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145244/MONDO:0000573/124 2024-04-29 2024-04-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8772 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0023067 infores:hetionet CHEBI:63607 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0042963 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009938 infores:hetionet CHEBI:47780 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1321898 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0575090 infores:hetionet CAID:CA036598 biolink:causes MONDO:0007750 infores:clingen CAID:CA036598 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP1 The NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supportign and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PM5 - 1 other missense variant in the same codon, NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP, so PM5 is met.PP3 - REVEL = 0.951. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met.PP4 - variant meets PM2 and was identified in 3 index cases with clinical FH criteria (please see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036598/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7478 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0017979 infores:hetionet CHEBI:16755 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0085593 infores:hetionet NCBIGene:10661 biolink:causes MONDO:0975829 infores:monarchinitiative not_provided not_provided HGNC:6345 MONDO:0975829 uuid:508db0e3-8801-4eab-83e1-63b81c384df8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0020517 infores:hetionet CAID:CA2695201440 biolink:causes MONDO:0011071 infores:clingen CAID:CA2695201440 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.805+12723_805+12724del is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (Δ score: 0.00) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.17)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695201440/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA293061 biolink:causes MONDO:0000573 infores:clingen CAID:CA293061 MONDO:0000573 PMID: Benign BA1, BS2_Supporting The NM_000536.4:c.1158C>A variant in RAG2 is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 386 (p.Phe386Leu). This variant has a population max filtering allele frequency of 0.01649 in the European (non-Finnish) population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for RAG2 (>0.00872). In addition, this variant is present in 23 homozygotes in gnomAD (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA293061/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:48273 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C1443060 infores:hetionet CHEBI:30659 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0030252 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0700184 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003123 infores:hetionet CHEBI:9086 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085639 infores:hetionet CHEBI:50223 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0001824 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022408 infores:hetionet NCBIGene:6603 biolink:causes MONDO:0044208 infores:monarchinitiative not_provided not_provided HGNC:11107 MONDO:0044208 uuid:e5077f50-8391-4001-a66c-6beab1ec23c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1167965 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0027765 infores:hetionet CHEBI:2639 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0011991 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0948525 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018799 infores:hetionet CHEBI:7809 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0015967 infores:hetionet CHEBI:2682 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151714 infores:hetionet CHEBI:5856 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0039240 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0029882 infores:hetionet CAID:CA16020928 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020928 MONDO:0009861 PMID:15503242 Uncertain Significance PP4_Moderate, PM2, PP3 PM3 The c.1066-3C>G variant in PAH has been reported in a Korean patient with PKU (BH4 deficiency excluded, PMID: 15503242). This variant is absent from 1000G, ESP, ExAC and gnomAD. Multiple lines of computational evidence support a deleterious splicing effect (HSF, MaxENT). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020928/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8874 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151825 infores:hetionet CHEBI:31524 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0041657 infores:hetionet CHEBI:3077 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0041834 infores:hetionet CHEBI:4995 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0009676 infores:hetionet CHEBI:9398 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0012833 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014518 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0027051 infores:hetionet CHEBI:7494 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0039231 infores:hetionet CHEBI:8713 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0020461 infores:hetionet NCBIGene:1798 biolink:causes MONDO:0013883 infores:monarchinitiative not_provided not_provided HGNC:2995 MONDO:0013883 uuid:060b9fe5-f66e-4605-bea6-868b37ae7d31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0023530 infores:hetionet CHEBI:31859 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011124 infores:hetionet CHEBI:478164 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0015967 infores:hetionet CHEBI:94449 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0012833 infores:hetionet CHEBI:8802 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0002622 infores:hetionet CHEBI:64064 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0221170 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0019158 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0233494 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0025061 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0003811 infores:hetionet CHEBI:8212 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0424295 infores:hetionet CHEBI:63584 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0037763 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0015734 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0004239 infores:hetionet CHEBI:42797 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019079 infores:hetionet CHEBI:85161 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0030554 infores:hetionet CHEBI:61033 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0018944 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0836924 infores:hetionet CHEBI:2675 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0002170 infores:hetionet CAID:CA8459177 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459177 MONDO:0011132 PMID: Benign BA1, BP4 BS3 The variant NM_001369369.1(FOXN1):c.205C>T is predicted to cause an arginine to cysteine substitution at amino acid position 69. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. The variant has a gnomAD popmax filtering allele frequency of 0.2496 based upon the Latino population, which is greater than 0.00447 and thus meets BA1. Additionally, the in-silico meta predictor REVEL suggests the variant has no effect on gene function with a score of 0.277, which is less than 0.290 and thus meets BP4. The variant is associated with the following publication: PMID:18006695. In summary, this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4 and BA1. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459177/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:100241 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151613 infores:hetionet CHEBI:28901 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0919924 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0023895 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005236 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0302314 infores:hetionet CHEBI:184555 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0376358 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042075 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0235416 infores:hetionet CHEBI:6950 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017565 infores:hetionet NCBITaxon:3052230 biolink:causes GO:0140374 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:3052230 GO:0140374 DB00022_MESH_D019698_1 CHEBI:9654 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0235195 infores:hetionet CHEBI:9649 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0858635 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1262013 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0042075 infores:hetionet GO:0072199 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:0072199 GO:0072001 CHEBI:38562 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0014742 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0518015 infores:hetionet NCBIGene:513 biolink:causes MONDO:0020858 infores:monarchinitiative not_provided not_provided HGNC:837 MONDO:0020858 uuid:0ab1b4a1-453f-411e-bb90-ea72ba6b7edc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17026 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0025345 infores:hetionet CHEBI:29688 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0011615 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001134 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085580 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0040034 infores:hetionet CHEBI:28748 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0016867 infores:hetionet UMLS:C0065374 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0011603 infores:hetionet NCBIGene:9517 biolink:causes MONDO:0013337 infores:monarchinitiative not_provided not_provided HGNC:11278 MONDO:0013337 uuid:d1d304b2-49e1-4258-b24c-2a2c1b098139 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8815829 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815829 MONDO:0009290 PMID:25526786PMID:27417441PMID:25626711PMID:31743840PMID:18458862PMID:25455803PMID:17723315PMID:21232767PMID:24269976PMID:28394184PMID:16531044 Pathogenic PVS1, PM2, PP4, PM3 This variant, c.2662G>T (p.Glu888Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00027 in the East Asian population, meeting PM2. At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044), and another is homozygous for the variant (PMID 17723315). This data meets PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). There is a ClinVar entry for this variant (Variation ID: 578595) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815829/MONDO:0009290/010 2020-05-04 2020-05-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:145499 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015371 infores:hetionet CHEBI:17347 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042029 infores:hetionet CHEBI:16480 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0428977 infores:hetionet CHEBI:3485 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0022346 infores:hetionet CHEBI:63577 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013404 infores:hetionet CHEBI:63584 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0232849 infores:hetionet CHEBI:4562 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0037036 infores:hetionet CHEBI:50663 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0041657 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0235431 infores:hetionet CHEBI:114785 biolink:causes HP:0100583 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0339293 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0020517 infores:hetionet CHEBI:2618 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0027849 infores:hetionet CHEBI:82960 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0497156 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0027051 infores:hetionet CHEBI:8874 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030232 infores:hetionet CHEBI:3242 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0520966 infores:hetionet CHEBI:4710 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0028734 infores:hetionet CHEBI:75984 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0017178 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020538 infores:hetionet CAID:CA10529715 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529715 MONDO:0010604 PMID: Benign BP7, BP4, BA1 The NM_000133.4(F9):c.60A>G (p.Leu20=) synonymous variant is reported at an MAF of 0.0009351 (7/7486 alleles) in the Ashkenazi Jewish population in gnomAD v2.1.1 with 4 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. SpliceAI predicts no splicing impact with a score of 0.0, meeting BP4 and BP7 criteria (<0.01). In summary, based on the evidence available at this time, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4 and BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529715/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:15552 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C2939447 infores:hetionet GO:0001759 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0001759 GO:0007275 CHEBI:6888 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0042571 infores:hetionet CHEBI:45409 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0851578 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020649 infores:hetionet CHEBI:36795 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042963 infores:hetionet CHEBI:10101 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0026821 infores:hetionet NCBIGene:112752 biolink:causes MONDO:0036483 infores:monarchinitiative not_provided not_provided HGNC:29669 MONDO:0036483 uuid:28e1ceca-a6cf-45fc-8813-f6261b25ef07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7959 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0206061 infores:hetionet CHEBI:6797 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0002878 infores:hetionet CHEBI:2569 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0231837 infores:hetionet GO:0003264 biolink:causes GO:0060914 infores:ubergraph knowledge_assertion manual_agent GO:0003264 GO:0060914 NCBITaxon:562 biolink:causes MONDO:0020920 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:562 MONDO:0020920 CHEBI:82960 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0004364 infores:hetionet CHEBI:32293 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0004238 infores:hetionet CHEBI:134966 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0015672 infores:hetionet CHEBI:9123 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042963 infores:hetionet CHEBI:5132 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0023530 infores:hetionet CHEBI:63622 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0162529 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0948266 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0948266 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042571 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0009319 infores:hetionet CHEBI:119915 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C3263723 infores:hetionet CHEBI:36791 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042963 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0002622 infores:hetionet NCBIGene:3265 biolink:causes MONDO:0008093 infores:monarchinitiative not_provided not_provided HGNC:5173 MONDO:0008093 uuid:00ca7c86-2976-4d37-9433-a598bb58ff6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA392256552 biolink:causes MONDO:0012996 infores:clingen CAID:CA392256552 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_001482.3:c.1006A>G in GATM is a missense variant that is predicted to result in the substitution of threonine by alanine at amino acid 336 (p.Thr336Ala). The variant is absent in gnomAD v4.01.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.127 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). To our knowledge, this variant has not been reported in an individual with phenotypic features of AGAT deficiency. It has been reported as a single heterozygous variant segregating in a family with autosomal dominant renal Fanconi syndrome and kidney failure (PMID: 29654216). However, classification with respect to this alternative disorder is outside the scope of this curation. There is a ClinVar entry for this variant (Variation ID: 917494). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 10, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392256552/MONDO:0012996/025 2025-04-10 2025-04-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17474 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0349790 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0040409 infores:hetionet CHEBI:2453 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0009421 infores:hetionet CHEBI:4702 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0036974 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0262385 infores:hetionet NCBIGene:343637 biolink:causes MONDO:0008798 infores:monarchinitiative not_provided not_provided HGNC:16175 MONDO:0008798 uuid:eac16d9c-593e-440a-96d0-c5915af7901a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0233494 infores:hetionet CHEBI:45783 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0232462 infores:hetionet CHEBI:5141 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0002871 infores:hetionet CHEBI:9939 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0522224 infores:hetionet CHEBI:9667 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0232461 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0002170 infores:hetionet NCBITaxon:55194 biolink:causes MONDO:0005915 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:55194 MONDO:0005915 CHEBI:50924 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C2363730 infores:hetionet CHEBI:2682 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0017675 infores:hetionet GO:0031522 biolink:causes GO:0043952 infores:ubergraph knowledge_assertion manual_agent GO:0031522 GO:0043952 CHEBI:5441 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0151474 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0162830 infores:hetionet CHEBI:31547 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0037763 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015230 infores:hetionet CHEBI:27732 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0013404 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0332575 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011551 infores:hetionet CHEBI:50922 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151907 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0020437 infores:hetionet CHEBI:9671 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0020621 infores:hetionet CHEBI:31711 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0522224 infores:hetionet GO:0061265 biolink:causes CL:1000022 infores:ubergraph knowledge_assertion manual_agent GO:0061265 CL:1000022 CHEBI:7936 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019270 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0852792 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0852792 infores:hetionet CHEBI:3764 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0019080 infores:hetionet CHEBI:40237 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0011603 infores:hetionet CHEBI:32315 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0542571 infores:hetionet CHEBI:39112 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0001339 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0221392 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0349506 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0149931 infores:hetionet CHEBI:27999 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0232459 infores:hetionet CHEBI:63632 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0003862 infores:hetionet CHEBI:3048 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0015230 infores:hetionet CHEBI:7454 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0020649 infores:hetionet CHEBI:367163 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0015672 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0178298 infores:hetionet CHEBI:3723 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025345 infores:hetionet CHEBI:63631 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0392525 infores:hetionet CHEBI:41879 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1443060 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0021053 infores:hetionet CHEBI:82941 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0016204 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021843 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0007097 infores:hetionet CHEBI:8768 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0853034 infores:hetionet GO:0045191 biolink:causes GO:0002520 infores:ubergraph knowledge_assertion manual_agent GO:0045191 GO:0002520 CHEBI:6456 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0162835 infores:hetionet CAID:CA010370 biolink:causes MONDO:0007356 infores:clingen CAID:CA010370 MONDO:0007356 PMID: Benign BP4, BS1, BS4, BP7 BP3, BP1, BP2, BA1, PS1, PS4, PS2, PS3, PM4, PM5, PM1, PM3, BS3, BP5, PM2, PVS1, PM6, PP2, PP3, PP1, PP4, BS2 The NM_000249.4(MLH1):c.42A>C (p.Thr14=) variant is a synonymous (silent) variant in exon 1 of MLH1. The highest population minor allele frequency in gnomAD v2.1 non-cancer cohort is 0.0009 (26/19,252 alleles) in the East Asian population and GnomAD v4.1 Grpmax AF is 0.0002524, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (0.0001) for BS1, meeting this criterion (BS1). The variant does not segregate with disease (BS4; Australian Colon Cancer Family Registry). The results from 3/3 in silico splice predictors, (SpliceAI, NNSplice, MaxEntScan), predict no splice impact (BP4). The variant is a synonymous variant outside the splice region with no predicted impact on splicing (BP7). In summary, this variant meets the criteria to be classified as benign for Lunch syndrome. ACMG/AMP criteria met, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: BS1, BS4, BP4, BP7. InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA010370/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5893 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0149931 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020456 infores:hetionet CHEBI:63629 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0039231 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0042373 infores:hetionet CHEBI:63598 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014457 infores:hetionet CHEBI:6541 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0004238 infores:hetionet CHEBI:16480 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0027765 infores:hetionet NCBIGene:51102 biolink:causes MONDO:0015003 infores:monarchinitiative not_provided not_provided HGNC:19691 MONDO:0015003 uuid:f6848964-c25d-40da-bb37-7260706c008d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7581 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C2697368 infores:hetionet CHEBI:8356 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0423791 infores:hetionet CHEBI:6761 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0013491 infores:hetionet CHEBI:2618 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0424295 infores:hetionet CHEBI:6909 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0520966 infores:hetionet CAID:CA2797727079 biolink:causes MONDO:0015967 infores:clingen CAID:CA2797727079 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PS4, PM1, PP4 The c.-197C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the 5' UTR of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Additionally, PP4 cannot be applied as the calculated MODY probability is <50% (internal lab contributors). In summary, c.-197C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2797727079/MONDO:0015967/017 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10023 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018681 infores:hetionet CHEBI:119915 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037011 infores:hetionet CHEBI:27974 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0149871 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004238 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0041969 infores:hetionet CHEBI:5383 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0036974 infores:hetionet CHEBI:51209 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0030252 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0236071 infores:hetionet CHEBI:3568 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0002962 infores:hetionet CHEBI:6958 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0428977 infores:hetionet CHEBI:31302 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C2830004 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009806 infores:hetionet NCBIGene:54148 biolink:causes MONDO:0957992 infores:monarchinitiative not_provided not_provided HGNC:14027 MONDO:0957992 uuid:37b6824b-d6c5-43c9-b481-d3eb9af1c668 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4359 biolink:causes MONDO:0007790 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0007790 uuid:f4a19894-5ba4-49fb-bf4d-29b7a869e5e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23522 biolink:causes MONDO:0011365 infores:monarchinitiative not_provided not_provided HGNC:17582 MONDO:0011365 uuid:b52e0ec1-1872-4458-a2c5-d83156d3ae70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020580 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0017574 infores:hetionet CHEBI:10110 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0232462 infores:hetionet CHEBI:131512 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0028643 infores:hetionet CHEBI:50378 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0001824 infores:hetionet CHEBI:38545 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0003811 infores:hetionet NCBIGene:3181 biolink:causes MONDO:0014178 infores:monarchinitiative not_provided not_provided HGNC:5033 MONDO:0014178 uuid:2cebfd9a-c9f9-4f1a-a615-f7b935d1d215 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6741 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0002170 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0033246 infores:hetionet CHEBI:94385 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0030193 infores:hetionet CHEBI:15367 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0231919 infores:hetionet CHEBI:29745 biolink:causes MONDO:0004599 infores:ubergraph knowledge_assertion manual_agent CHEBI:29745 MONDO:0004599 CHEBI:41423 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1384353 infores:hetionet CHEBI:8884 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0039231 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0424000 infores:hetionet CHEBI:8502 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0231528 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0553732 infores:hetionet CHEBI:52717 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024305 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027051 infores:hetionet CAID:CA10584711 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584711 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 PS3 The NM_000527.5 (LDLR): c.-101T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP4 Met: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for FH diagnosis (British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London,London, UK, PMID 22881376).PS3 not met: Heterologous cells (Huh7) were used in luciferase assay (level 3 functional assay), and have shown 64% reporter gene expression, which is greater than 50% compared to wild-type (Khamis et al 2015, Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute Cardiovascular Science, University College London Medicine School, London, UK, PMID 25248394). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584711/MONDO:0007750/013 2022-02-10 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:92923 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0687713 infores:hetionet CHEBI:4636 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0232292 infores:hetionet CHEBI:8888 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151772 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235960 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235960 infores:hetionet CHEBI:119915 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0002792 infores:hetionet CHEBI:28177 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0027765 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0877322 infores:hetionet CHEBI:8805 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0015230 infores:hetionet CHEBI:7465 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0002962 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1328447 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1328447 infores:hetionet CHEBI:3216 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042029 infores:hetionet CHEBI:8356 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0221269 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0038358 infores:hetionet CHEBI:63581 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C2225524 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0025061 infores:hetionet CHEBI:15553 biolink:causes NCIT:C78694 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0567085 infores:hetionet CHEBI:8776 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0003811 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0151602 infores:hetionet NCBIGene:57192 biolink:causes MONDO:0010425 infores:monarchinitiative not_provided not_provided HGNC:13356 MONDO:0010425 uuid:94c49900-3e53-43c8-a350-23904e84e90a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1142412 infores:hetionet CHEBI:6912 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0040034 infores:hetionet CHEBI:8028 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0686347 infores:hetionet CHEBI:34829 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0235266 infores:hetionet CHEBI:119573 biolink:causes HP:0400007 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0032519 infores:hetionet CHEBI:5123 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0018681 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0497247 infores:hetionet CHEBI:4027 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0232462 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027697 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0852911 infores:hetionet UNII:R43D2573WO biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0546884 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0150077 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0150077 infores:hetionet CHEBI:28445 biolink:causes UMLS:C2955673 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C2955673 infores:hetionet CHEBI:8346 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0003862 infores:hetionet CHEBI:9927 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0015230 infores:hetionet CHEBI:28748 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085605 infores:hetionet CHEBI:474180 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0030196 infores:hetionet CHEBI:9150 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0008031 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0854114 infores:hetionet CHEBI:4514 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0011253 infores:hetionet CHEBI:5790 biolink:causes HP:0033842 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0239233 infores:hetionet CHEBI:2549 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0546817 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023067 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0026827 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0004096 infores:hetionet CHEBI:8481 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0002792 infores:hetionet CHEBI:8802 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0476273 infores:hetionet CHEBI:68579 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0019080 infores:hetionet CHEBI:40279 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020488 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0235169 infores:hetionet CHEBI:16586 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0152227 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001956 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0343084 infores:hetionet CHEBI:100246 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0042963 infores:hetionet CHEBI:116278 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0687713 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0595862 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020542 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0553732 infores:hetionet CHEBI:5847 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0023530 infores:hetionet NCBIGene:79650 biolink:causes MONDO:0011405 infores:monarchinitiative not_provided not_provided HGNC:25792 MONDO:0011405 uuid:3bc612b8-b019-4139-8298-a2e23750e832 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5558 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0023218 infores:hetionet HGNC:12029 biolink:causes MONDO:0014160 infores:monarchinitiative not_provided not_provided HGNC:12029 MONDO:0014160 uuid:b3e94e91-9840-472f-b9b5-ec5a06dd3fa8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0522055 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151824 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0009938 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0016034 infores:hetionet NCBIGene:8936 biolink:causes MONDO:0032876 infores:monarchinitiative not_provided not_provided HGNC:12732 MONDO:0032876 uuid:a5c5c34b-ba68-4a46-89eb-14ef45d4fb6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17026 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0037822 infores:hetionet NCBIGene:2244 biolink:causes MONDO:0014452 infores:monarchinitiative not_provided not_provided HGNC:3662 MONDO:0014452 uuid:e6f0c01e-1a7d-45d8-806b-c7454829020f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0919980 infores:hetionet CHEBI:40303 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0015672 infores:hetionet NCBIGene:2332 biolink:causes MONDO:0010383 infores:monarchinitiative not_provided not_provided HGNC:3775 MONDO:0010383 uuid:4be58155-9edb-4cd0-9777-39a65f7e67a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32588 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0004093 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0853813 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040435 infores:hetionet CHEBI:63631 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151611 infores:hetionet CHEBI:3082 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0041657 infores:hetionet CAID:CA235342 biolink:causes MONDO:0018997 infores:clingen CAID:CA235342 MONDO:0018997 PMID:21784453PMID:23487764PMID:29493581PMID:21387466PMID:19020799 Pathogenic PS3, PM1, PM2, PM6, PP2, PP3 The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466). In vitro functional studies provide some evidence that the p.Lys170Glu variant may impact protein function (PS3; PMID 21784453, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Lys170Glu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235342/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:31401 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018926 infores:hetionet CHEBI:51209 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0042510 infores:hetionet NCBIGene:54658 biolink:causes MONDO:0009383 infores:monarchinitiative not_provided not_provided HGNC:12530 MONDO:0009383 uuid:b5a2777c-1e84-456c-97d5-7e707b6c2a80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1911 biolink:causes MONDO:0014173 infores:monarchinitiative not_provided not_provided HGNC:3182 MONDO:0014173 uuid:de0cfa2f-6b22-4d4c-a9ef-66936b4e3252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0034642 infores:hetionet CHEBI:31413 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0042963 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0009319 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0234215 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0010709 infores:hetionet CAID:CA229337 biolink:causes MONDO:0009861 infores:clingen CAID:CA229337 MONDO:0009861 PMID:1975559PMID:1975559 Likely Pathogenic PM3, PM4, PM2, PP4 The c.1092_1094delTCT variant in PAH has been previously reported as a single variant, found in trans with the Pathogenic variant (per internal PAH ClinGen Working Group classification, see ClinVar allele ID 15635) p.Gly272Ter in one proband with classic PKU (PMID: 1975559); phase was confirmed via parental testing (PM3). Apart from stating that the proband was identified via newborn screening further detail is provided regarding the proband’s phenotype, including whether BH4 deficiency was formally excluded (PP4?). The variant is a protein-length changing variant in a non-repeat region (PM4). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229337/MONDO:0009861/006 2019-05-04 2019-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49668 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151626 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152227 infores:hetionet CHEBI:94807 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0040822 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0010709 infores:hetionet CHEBI:45863 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085593 infores:hetionet CHEBI:17549 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C3544060 infores:hetionet GO:2000090 biolink:causes GO:0061247 infores:ubergraph knowledge_assertion manual_agent GO:2000090 GO:0061247 CHEBI:31644 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0043352 infores:hetionet CHEBI:8871 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020672 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C1384353 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0340726 infores:hetionet UMLS:C0657912 biolink:causes HP:0007379 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042065 infores:hetionet NCBIGene:2255 biolink:causes MONDO:0008397 infores:monarchinitiative not_provided not_provided HGNC:3666 MONDO:0008397 uuid:e4d9f6b8-85cf-4dac-a759-4e267b4c3814 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0852911 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0403632 infores:hetionet CHEBI:5280 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0022568 infores:hetionet CHEBI:51450 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0687713 infores:hetionet CHEBI:27958 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C1145670 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0016204 infores:hetionet CAID:CA2573054000 biolink:causes MONDO:0015152 infores:clingen CAID:CA2573054000 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting PP3, PS1 The NM_000070.3: c.1194-2del variant in CAPN3 occurs within the canonical splice acceptor site of intron 9. This variant is predicted to abolish the consensus splice acceptor site, with a SpliceAI score of 0.99, and strengthen two alternative acceptor sites in exon 10 at +13 and +37 (SpliceAI score 0.65 and 0.41). Skipping of exon 10, which is out of frame, would be expected to disrupt the reading frame, leading to nonsense mediated RNA decay in a gene in which loss of function is an established mechanism of disease. Use of either of the alternative acceptor sites would also be expected to disrupt the reading frame (PVS1). This variant has been observed in unknown phase with a pathogenic variant in one individual with muscle weakness and clinical features consistent with LGMD (c.2120A>G p.(Asp707Gly), 0.5 pts, GRASP-LGMD Consortium internal data communication; PM3_Supporting, PP4). This variant is absent from the gnomAD v4.1.0 population database (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/09/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573054000/MONDO:0015152/187 2025-10-09 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:6870 biolink:causes MONDO:0013913 infores:monarchinitiative not_provided not_provided HGNC:11528 MONDO:0013913 uuid:740e91c6-2bd4-4f20-a285-534dcaaf6b94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1460 biolink:causes MONDO:0032889 infores:monarchinitiative not_provided not_provided HGNC:2460 MONDO:0032889 uuid:0aed0230-0ec5-491a-ae38-6a5fabe9383a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3242 biolink:causes UMLS:C0235131 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0235131 infores:hetionet CAID:CA8459655 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459655 MONDO:0011132 PMID: Likely Benign BP4, BS1 The missense variant NM_001369369.1(FOXN1):c.1886C>T (p.Thr629Met) has a gnomADv4.0.0 popmax filtering allele frequency of 0.0003313 based on the Admixed American population, which is below the BS1 threshold of >0.00141 but above the PM2 threshold of <0.0000447, however the gnomADv4.0.0 highest MAF is in the Ashkenazi Jewish population at 0.002602 (77/29596 alleles) which meets the BS1 threshold of >0.00141. The variant has a REVEL score of 0.209, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1, BP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459655/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:50742 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0018965 infores:hetionet CHEBI:63610 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0040264 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0847033 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0015230 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0005808 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D003235 DB00681_MESH_D003235_1 CHEBI:66876 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0015672 infores:hetionet CHEBI:68584 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0152032 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001397 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0494491 infores:hetionet CHEBI:31236 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0271710 infores:hetionet CAID:CA410202716 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202716 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.389T>A (p.Val130Asp) is a missense variant which multiple lines of computational evidence (REVEL: 0.982; phyloP100way: 8.947) support as having a deleterious effect on the gene/gene product (PP3). In addition, this variant affects an amino acid residue between 89-204 within the RHD (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202716/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4530 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0234215 infores:hetionet CHEBI:135361 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0242350 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0022408 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0162830 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0020517 infores:hetionet CHEBI:15367 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235031 infores:hetionet CHEBI:5118 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011168 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0035455 infores:hetionet NCBIGene:9056 biolink:causes MONDO:0009109 infores:monarchinitiative not_provided not_provided HGNC:11065 MONDO:0009109 uuid:4889e568-459e-4632-8685-debd4580312b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27779 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0020517 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0234458 infores:hetionet CHEBI:8665 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0700590 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0010692 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0235353 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235353 infores:hetionet CHEBI:6706 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0011124 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006798 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020579 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0002622 infores:hetionet NCBIGene:4858 biolink:causes MONDO:0030024 infores:monarchinitiative not_provided not_provided HGNC:7887 MONDO:0030024 uuid:1c102945-e7ac-4b57-8ab7-43929f2dd4e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8212 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0043094 infores:hetionet CHEBI:145499 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1456784 infores:hetionet CHEBI:2675 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0085611 infores:hetionet CHEBI:63599 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0009421 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1443060 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0341012 infores:hetionet CHEBI:9598 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0948594 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0036572 infores:hetionet CHEBI:4710 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0016204 infores:hetionet NCBIGene:4141 biolink:causes MONDO:0014206 infores:monarchinitiative not_provided not_provided HGNC:6898 MONDO:0014206 uuid:89571931-91ab-478d-9999-b1e8492b4b38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0162429 infores:hetionet CHEBI:37941 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042963 infores:hetionet CHEBI:39112 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0042963 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0015397 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0038454 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151698 infores:hetionet CHEBI:3127 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0851578 infores:hetionet CHEBI:92712 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C1443060 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0234215 infores:hetionet CHEBI:50567 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0039231 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0011991 infores:hetionet CHEBI:47499 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C1443060 infores:hetionet CHEBI:6067 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042029 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005032 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0151468 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0009443 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0221752 infores:hetionet GO:0060472 biolink:causes GO:0007343 infores:ubergraph knowledge_assertion manual_agent GO:0060472 GO:0007343 CHEBI:51173 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0162297 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0037274 infores:hetionet CHEBI:8764 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042963 infores:hetionet CHEBI:3215 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1368065 infores:hetionet CHEBI:35778 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0041834 infores:hetionet CHEBI:3175 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0231528 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0014868 infores:hetionet CHEBI:2675 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0015230 infores:hetionet CHEBI:32293 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151544 infores:hetionet CAID:CA1139667471 biolink:causes MONDO:0100437 infores:clingen CAID:CA1139667471 MONDO:0100437 PMID: Pathogenic PP4_Moderate, PVS1, PP1, PS4_Supporting, PM2_Supporting PP3, PS3 NM_001034853.2(RPGR):c.779-5T>G is a variant in intron 7. The splicing impact predictor SpliceAI gives a score of 0.81 for acceptor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, while cells transected with the variant minigene construct yielded a smaller product size in comparison to the wild-type control (PMID: 33467000, PVS1). The PP3 and PS3_Supporting codes were not met as PVS1 has been applied instead. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) with relatively mildly affected carrier female relatives (1 pt), childhood onset (1 pt), night blindness (0.5 pts), photophobia (0.5 pts), reduced visual acuity (0.5 pts), bone spicule pigmentation (0.5 pts), mild myopia, and genotyping by whole exome sequencing that did not identify an alternative basis for retinal disease (2 pts), which together are highly specific for RPGR-related retinopathy (8 points, PP4_Moderate). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, in addition to the second apparently unrelated proband previously used for the PP4 code (PMIDs: 32970112, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from at least 1 family (PP1; PMID: 32970112). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, PP1, PP4_Moderate, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139667471/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:9622 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0030193 infores:hetionet CHEBI:71272 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C1384353 infores:hetionet CHEBI:83531 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0011615 infores:hetionet CHEBI:6015 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0036104 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0029134 infores:hetionet CAID:CA161776 biolink:causes MONDO:0021060 infores:clingen CAID:CA161776 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.53A>G (p.Asn18Ser) variant in the PTPN11 gene is 0.056% (15/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA161776/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:2000939 biolink:causes GO:0009664 infores:ubergraph knowledge_assertion manual_agent GO:2000939 GO:0009664 CHEBI:6909 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0020538 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235639 infores:hetionet CHEBI:490877 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0520573 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0016426 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D060585 DB00582_MESH_D060585_1 CHEBI:3561 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042024 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0006145 infores:hetionet CHEBI:4856 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0232462 infores:hetionet CHEBI:5613 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0424295 infores:hetionet CHEBI:45863 biolink:causes HP:0006846 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1306587 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027051 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0021400 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017178 infores:hetionet CHEBI:8107 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020621 infores:hetionet CHEBI:9943 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0558489 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0004936 infores:hetionet CHEBI:8435 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0156404 infores:hetionet CHEBI:50173 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085932 infores:hetionet CHEBI:38562 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0018834 infores:hetionet CHEBI:3084 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C2047937 infores:hetionet CHEBI:51860 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011206 infores:hetionet CHEBI:47499 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0004093 infores:hetionet CHEBI:4672 biolink:causes HP:0025088 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0263540 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0002622 infores:hetionet CHEBI:6970 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0263449 infores:hetionet CHEBI:5296 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0035410 infores:hetionet CAID:CA015682 biolink:causes MONDO:0004994 infores:clingen CAID:CA015682 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.5106G>A (p.Ala1702=) variant in the MYH7 gene is 22.43% (2414/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015682/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8212 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0013384 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0271650 infores:hetionet CHEBI:3568 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0036974 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0027707 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0162429 infores:hetionet CHEBI:15940 biolink:causes UMLS:C1963943 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C1963943 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1142080 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1142080 infores:hetionet UMLS:C0879264 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0015967 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0003123 infores:hetionet CAID:CA410147494 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147494 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1289C>T (p.Pro430Leu) is a missense variant. This variant is present on one allele (European Non-Finnish) in gnomAD v2.1.1 (54876 alleles tested, mean depth coverage 38.9x) and is absent in gnomAD v3.1.2 (mean depth coverage 30x). This missense variant has a REVEL score < 0.50 (0.303) and SpliceAI score is ≤ 0.20 (0) (BP4).In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147494/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7825 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0162820 infores:hetionet CHEBI:17141 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C1112525 infores:hetionet CAID:CA16020871 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020871 MONDO:0009861 PMID:25863075PMID:25863075 Uncertain Significance PM2, PP4, PP3 PM3, PS1 The c.842+4A>T PAH variant has been reported in PKU patients (PMID: 25863075). This variant is absent from 1000G, ESP, and gnomAD databases. This is an intronic variant in a highly conserved nucleotide, and computational analyses predict that this variant abolishes the donor splice site of intron 7. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020871/MONDO:0009861/006 2019-06-09 2019-06-09 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4530 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0039231 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011606 infores:hetionet NCBITaxon:1257 biolink:causes MONDO:0024412 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1257 MONDO:0024412 CHEBI:5864 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002453 infores:hetionet CHEBI:61049 biolink:causes MONDO:0043106 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0265962 infores:hetionet CAID:CA400030171 biolink:causes MONDO:0100326 infores:clingen CAID:CA400030171 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM3, PM5, PP3, PM2_Supporting The NM_000212.3:c.1641C>G variant in ITGB3 is a missense variant predicted to cause substitution of cysteine by tryptophan at amino acid 547 (p.Cys547Trp). This is a critical cysteine residues for regulation of integrin alphaIIbbeta3 (PMID: 14690453). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.891, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Another missense variant (c.1639T>G (p.Cys547Gly)) in the same codon has been provisionally classified as pathogenic for Glanzmann thrombasthenia by the ClinGen Platelet Disorders VCEP (PM5). Splicing prediction using SpliceAI revealed no expected effects on splicing due to either of these variants. There are at least four homozygous (reported unrelated) GT patients (PMID: 32558238, 19691478; PM3). At least one patient (Patient GT4 in PMID: 32558238) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong) In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PM5, PP3, PP4_Strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400030171/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3219 biolink:causes HP:0041220 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0159321 infores:hetionet CHEBI:5138 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0232849 infores:hetionet CHEBI:7986 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0021053 infores:hetionet CHEBI:17026 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040053 infores:hetionet CAID:CA512232137 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232137 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting BP1, BS1, BP7, PP2, PP3 NM_001754.5(RUNX1):c.1383C>T (p.Asn461=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.00) (BP4). No REVEL score is applicable. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232137/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50381 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0004093 infores:hetionet CAID:CA1624560 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624560 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.1705C>G (p.Leu569Val) variant in the SOS1 gene is 0.0336% (31/66714) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624560/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50777 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1384606 infores:hetionet CHEBI:63791 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0043352 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0019158 infores:hetionet CHEBI:63611 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0033774 infores:hetionet CHEBI:28001 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0424790 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0234913 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0234192 infores:hetionet CHEBI:68554 biolink:causes UMLS:C1096256 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C1096256 infores:hetionet CHEBI:63620 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1609512 infores:hetionet CHEBI:50381 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0019080 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0037199 infores:hetionet CHEBI:9086 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085610 infores:hetionet CHEBI:9137 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0344232 infores:hetionet CHEBI:3175 biolink:causes HP:0030947 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0860499 infores:hetionet CHEBI:3479 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0012833 infores:hetionet CHEBI:6073 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0085649 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0162119 infores:hetionet CHEBI:100241 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0262662 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0001418 infores:hetionet CHEBI:6801 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0037763 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151735 infores:hetionet CHEBI:5130 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013447 infores:hetionet CHEBI:2379 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0016204 infores:hetionet CHEBI:64355 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0340279 infores:hetionet CHEBI:9598 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0003862 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0853777 infores:hetionet CHEBI:68610 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0851341 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0020517 infores:hetionet CHEBI:52010 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0009676 infores:hetionet CHEBI:2682 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151872 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0013395 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0037274 infores:hetionet CHEBI:33325 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0042963 infores:hetionet CAID:CA410205754 biolink:causes MONDO:0100083 infores:clingen CAID:CA410205754 MONDO:0100083 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.70G>A (p.Gly24Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205754/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63627 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0013378 infores:hetionet CHEBI:28593 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0085932 infores:hetionet CHEBI:84500 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0520966 infores:hetionet CHEBI:8764 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030232 infores:hetionet CHEBI:50663 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0003862 infores:hetionet NCBIGene:146862 biolink:causes MONDO:0014565 infores:monarchinitiative not_provided not_provided HGNC:14304 MONDO:0014565 uuid:069289a9-a87a-4db7-8b55-00b3c906e6fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C3263723 infores:hetionet CHEBI:10101 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0006625 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0023530 infores:hetionet CHEBI:127780 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151907 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0029882 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0043345 infores:hetionet CHEBI:135285 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0018681 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0002170 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038325 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0746731 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0746731 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0242350 infores:hetionet CHEBI:40279 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0235378 infores:hetionet CHEBI:63638 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0018524 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0403632 infores:hetionet CHEBI:10101 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0086439 infores:hetionet CHEBI:5959 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0036974 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0022658 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0743680 infores:hetionet CHEBI:63791 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149745 infores:hetionet CHEBI:8869 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0349790 infores:hetionet NCBIGene:668 biolink:causes MONDO:0007201 infores:monarchinitiative not_provided not_provided HGNC:1092 MONDO:0007201 uuid:f8edc418-2c1f-4911-a3a8-50f292108965 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2379 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0004604 infores:hetionet CHEBI:3011 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0027497 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006152 infores:hetionet NCBIGene:2770 biolink:causes MONDO:0859243 infores:monarchinitiative not_provided not_provided HGNC:4384 MONDO:0859243 uuid:dfcd05ef-e51e-4d36-8e59-3bd3fa4f1895 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA404075600 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075600 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP1, BP4, BP2, BP3, PS1, PS3, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PVS1, PM6, PP2, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR): c.242G>A (p.Arg81His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00004005 (0.004%) in African/African American exomes+genomes (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075600/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7773 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0521465 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0027769 infores:hetionet CHEBI:101085 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0020621 infores:hetionet CHEBI:31413 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0234518 infores:hetionet CHEBI:9943 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014591 infores:hetionet CHEBI:46081 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C3665347 infores:hetionet CAID:CA386952505 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952505 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PP4 The c.47T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 16 (p.(Leu16Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, c.47T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952505/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135935 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0520966 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0009450 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0030332 infores:hetionet CHEBI:2639 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0239571 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004936 infores:hetionet CHEBI:3696 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0037763 infores:hetionet CHEBI:48273 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0270996 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0023530 infores:hetionet CHEBI:6539 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0032326 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0009450 infores:hetionet CAID:CA627699647 biolink:causes MONDO:0009290 infores:clingen CAID:CA627699647 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000152.5: c.1579_1580del (p.Arg527GlyfsTer3) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two Korean patients with this variant and Pompe disease have been reported. For one of the patients, residual GAA activity was provided and was <10% normal mean in leukocytes (PMID 29869463). The second patient had reduced GAA activity (value not provided) and was on enzyme replacement therapy (PMID 30360039)(PP4_Moderate). Both patients are compound heterozygous for the variant and a missense change, either c.1316T>A (p.Met439Lys)(PMID 30360039) or c.1857C>G (p.Ser619Arg)(PMID 29869463). The in trans data from these patients will be used in the assessment of the respective missense changes and was not included her in order to avoid circular logic. Therefore, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD is 0.000008804 in the European non-Finnish population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1072906, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PVS1, PP4_Moderate, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA627699647/MONDO:0009290/010 2022-06-03 2022-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UNII:3U02EL437C biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0700345 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005201 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0007196 infores:hetionet CHEBI:72690 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0151908 infores:hetionet CHEBI:31413 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0022107 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0040034 infores:hetionet CHEBI:31859 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0034359 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0150450 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022346 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0025061 infores:hetionet CHEBI:31515 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0013144 infores:hetionet CHEBI:82960 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0392525 infores:hetionet CHEBI:39669 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0039070 infores:hetionet CHEBI:9566 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0278061 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0853813 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022660 infores:hetionet CHEBI:72564 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0231528 infores:hetionet CHEBI:43968 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151905 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0242656 infores:hetionet CAID:CA400034189 biolink:causes MONDO:0100326 infores:clingen CAID:CA400034189 MONDO:0100326 PMID: Pathogenic PP4_Strong, PS3_Supporting, PVS1, PM2_Supporting PM3 The c.2222G>A (p.Trp741Ter) variant in exon 14 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Surface expression of αIIb and β3 measured by Western blot in HEK293T cells transiently co-transfected with the c.2222G>A (p.Trp741Ter) variant β3 and wild type αIIb and β3 showed decreased expression at 0% WT levels, indicating that this variant impacts protein function (PMID: 37604334) (PS3_supporting). This variant has been detected in at least 1 proband with Glanzmann thrombasthenia (PMID: 37604334). This individual was compound heterozygous for this variant and a SINE-VNTR-Alu (SVA) retrotransposon insertion in ITGB3. This patient (Proband from PMID: 37604334) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0.25% as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong). This variant is absent from gnomAD v4.0.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PS3_supporting, PP4_Strong and PM2_Supporting (VCEP specifications version 2; date of approval 05/02/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400034189/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:47657 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0231218 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0178298 infores:hetionet CAID:CA343777244 biolink:causes MONDO:0013144 infores:clingen CAID:CA343777244 MONDO:0013144 PMID: Uncertain Significance PM5, PP4, PP3, PM2_Supporting The NM_000488.4:c.391C>G variant in SERPINC1 is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 131 (p.Leu131Val). This variant is also known as antithrombin Southport (Legacy nomenclature: Leu99Val) in the literature. One proband from PMID: 7734360 with AT deficiency (type II-HBS) meets criteria for PP4. At least one patient with this variant displayed AT deficiency (type II- HBS) which is highly specific for SERPINC1 (PP4, PMID: 7734360). Another missense variant, c.391C>T (p.Leu131Phe), in the same codon has been classified as pathogenic for antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.764, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 gene function (PP3). This variant is absent from gnomAD v2.1.1-v4. In summary, this variant meets the criteria to be classified as a variant of uncertain significance forantithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP. (Specifications version 1.0.0; date of approval: 7/17/2023) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343777244/MONDO:0013144/084 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4995 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0021843 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0029456 infores:hetionet NCBIGene:4306 biolink:causes MONDO:0008329 infores:monarchinitiative not_provided not_provided HGNC:7979 MONDO:0008329 uuid:20e79eb2-a3ef-4a46-808d-14cb863f62b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6539 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C1527311 infores:hetionet CHEBI:63618 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0162830 infores:hetionet CHEBI:6339 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151786 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0025061 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0919874 infores:hetionet CHEBI:9943 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085623 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151505 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0549430 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0549430 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020651 infores:hetionet CHEBI:94848 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0349506 infores:hetionet CHEBI:521033 biolink:causes MONDO:0005628 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0238033 infores:hetionet CHEBI:23765 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151517 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0042109 infores:hetionet CHEBI:9588 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0003862 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151464 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151464 infores:hetionet UMLS:C1738934 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0043352 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020538 infores:hetionet CHEBI:74947 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030554 infores:hetionet CHEBI:15544 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0018965 infores:hetionet NCBIGene:523 biolink:causes MONDO:0020632 infores:monarchinitiative not_provided not_provided HGNC:851 MONDO:0020632 uuid:a6671efa-3272-4b45-ae2b-21728ab0444c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0546817 infores:hetionet CAID:CA2918306 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918306 MONDO:0015152 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_000232.5: c.744G>A (p.Glu248=) variant in SGCB is a synonymous (silent) variant that is not predicted to influence splicing by SpliceAI (score 0) (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002892 (10/34578 alleles) in the Admixed American population (PM2_Supporting, BS1, BA1 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918306/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7824 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009946 infores:hetionet CHEBI:2453 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013390 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031350 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0340726 infores:hetionet CAID:CA013702 biolink:causes MONDO:0005045 infores:clingen CAID:CA013702 MONDO:0005045 PMID: Uncertain Significance PM2, PP3, PS4_Moderate PM5, PM1, PM6, BA1, PP1, PS3, BS1, BS3, BS4, PS1, PS2, BP4, BP5, BP2 The c.343T>C (p.Tyr115His) variant in MYH7 has been reported in at least 12 individuals with HCM (PS4_Moderate; Van Driest 2004 PMID:15358028; Homberger 2016 PMID:27247418; Walsh 2017 PMID:27532257; CHEO pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.), 2 of whom also had additional variants in other HCM-associated genes (Invitae pers. comm.; LMM pers. comm.). This variant also segregated with disease in 1 affected relative with HCM (OMGL pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was identified in 0.0009% (1/113572) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013702/MONDO:0005045/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49375 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013395 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0017178 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0037822 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0008301 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028754 infores:hetionet CHEBI:47381 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0235198 infores:hetionet CHEBI:9570 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0011175 infores:hetionet CHEBI:135285 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0085932 infores:hetionet CAID:CA226548 biolink:causes MONDO:0100368 infores:clingen CAID:CA226548 MONDO:0100368 PMID: Benign BA1, BP4, BP7 NM_000329.3(RPE65):c.399T>C (p.Leu133=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.02168, with 1732 alleles/75042 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). Additionally, there are 20 homozygotes in this population. The splicing impact predictor SpliceAI gives delta scores of 0.07 for acceptor gain and donor gain, which are below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and do not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226548/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:71417 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0016382 infores:hetionet CAID:CA023502 biolink:causes MONDO:0007750 infores:clingen CAID:CA023502 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM2, PP3, PP4 BP4, BP3, BP2, BA1, PS3, PS2, PS1, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1 The NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00009 (0.009%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.945. PS4, PP4: Variant meets PM2 and is identified in at least 14 unrelated index cases who fulfill criteria for FH (3 cases with Simon-Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 3 cases with DLCN score >=6 and 1 case with Simon-Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 3 cases with DLCN score >=6 from Robarts Research Institute, Canada; 3 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; 1 case with DLCN score>=6 from Color Health, Inc, USA). PP1_Strong: Variant segregates with FH phenotype in at least 11 informative meioses in 4 families from different labs (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 8 affected family members have the variant and 3 unaffected family members do not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023502/MONDO:0007750/013 2023-06-23 2024-09-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:61033 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0015402 infores:hetionet GO:0044759 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0044759 GO:0007268 CHEBI:31302 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0232462 infores:hetionet CHEBI:36791 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1291077 infores:hetionet CHEBI:3213 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0033038 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0233472 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006277 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0302507 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0302507 infores:hetionet CHEBI:75246 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C2364111 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0027051 infores:hetionet CHEBI:32588 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0042963 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0039520 infores:hetionet CHEBI:7986 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0016204 infores:hetionet CHEBI:6437 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0242429 infores:hetionet CHEBI:8069 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0349231 infores:hetionet CAID:CA137935 biolink:causes MONDO:0021060 infores:clingen CAID:CA137935 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.405G>C (p.Gly135=) variant in the MAP2K2 gene is 14.69% (1588/10368) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137935/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6775 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0232462 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0948525 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0854504 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0854504 infores:hetionet CAID:CA902169 biolink:causes MONDO:0100368 infores:clingen CAID:CA902169 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP1, PP4, PM2_Supporting The NM_000329.3(RPE65):c.1445A>G (p.Asp482Gly) variant is a missense variant predicted to replace aspartic acid with glycine at amino acid 482 in RPE65. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00006, with [4/64040 total alleles in the European, Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.974, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Additionall, the splicing impact predictor SpliceAI gives a score of 0.69 for splice donor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This variant has been reported in at least 2 proband(s) with early-onset severe retinal dystrophy who were either compound heterozygous with the p.Tyr431Cys confirmed in trans (1 pt, Invitae-provided data) or with the p.Arg234* suspected in trans (0.5 points, VCEP member-provided data) which were previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). In addition, this variant has been reported in another patient with early-onset severe retinal dystrophy and his similarly affected brother who were compound heterozygous with the p.Tyr431Cys variant suspected in trans (VCEP member-provided data). As it is possible that these this the same proband provided by Invitae, they were not counted for additional PM3 points. This variant has also been reported in one proband in who was compound heterozygous with the Tyr79His variant suspected in trans, but was not counted due to insufficient clinical information (PMID: 30268864). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through this proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; VCEP member-provided data). At least one proband harboring this variant exhibits a phenotype including nyctalopia (0.5), abnormal fundus appearance (2), optic nerve pallor (0.5), RPE mottling (0.5), symptomatic onset between birth and five years (1), decreased peripheral vision (1), abnormal color vision (1), and decreased central visual acuity (1), which together are specific for RPE65-related recessive retinopathy (7.5 points, VCEP member-provided data, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRP VCEP: PP3_Moderate, PM3, PM2_Supporting, PP1, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902169/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2666 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0034150 infores:hetionet CHEBI:6504 biolink:causes HP:0001945 infores:drugmechdb knowledge_assertion manual_agent MESH:D016651 MESH:D005334 DB01356_MESH_D005334_1 CHEBI:7577 biolink:causes UMLS:C0271240 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0271240 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0860803 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018021 infores:hetionet CHEBI:231425 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0017178 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0019158 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0152027 infores:hetionet CHEBI:4514 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0011615 infores:hetionet CHEBI:367163 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020433 infores:hetionet CHEBI:16469 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0011603 infores:hetionet CHEBI:4466 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020433 infores:hetionet CHEBI:6909 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0026821 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0595879 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0234215 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0151736 infores:hetionet CHEBI:7476 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0003578 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0085622 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0024299 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0002871 infores:hetionet CHEBI:44185 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0003578 infores:hetionet CHEBI:70735 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0040822 infores:hetionet CHEBI:2379 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0008033 infores:hetionet CHEBI:53760 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0019270 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0851341 infores:hetionet CAID:CA386960483 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960483 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP4_Moderate, PP3 The c.485T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 162 (p.(Leu162Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 21224407, 29927023; internal lab contributors). In summary, c.485T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PP3, PM1_Supporting, PM2_supporting, PP4_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960483/MONDO:0015967/017 2025-06-27 2025-06-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63681 biolink:causes MONDO:0002153 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0263518 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0233472 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005086 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0007134 infores:hetionet CHEBI:3561 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0600142 infores:hetionet GO:0141135 biolink:causes GO:0070098 infores:ubergraph knowledge_assertion manual_agent GO:0141135 GO:0070098 CHEBI:40279 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002170 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0018799 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0041912 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0041969 infores:hetionet CHEBI:8871 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085612 infores:hetionet NCBIGene:6328 biolink:causes MONDO:0033371 infores:monarchinitiative not_provided not_provided HGNC:10590 MONDO:0033371 uuid:c4bc4d6f-1116-46dc-a221-adf8214a71bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA405675895 biolink:causes MONDO:0018493 infores:clingen CAID:CA405675895 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 2669 of the RYR1 protein, p.(Glu2669Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results (PMID:21157159), PS4 was not implemented. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.82 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405675895/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:28925 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0002792 infores:hetionet NCBIGene:3490 biolink:causes MONDO:0013640 infores:monarchinitiative not_provided not_provided HGNC:5476 MONDO:0013640 uuid:4f50977a-3458-4373-ac39-f3932ba14d84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0012569 infores:hetionet CHEBI:32293 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0020453 infores:hetionet CHEBI:2549 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0005779 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0748536 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0748536 infores:hetionet CHEBI:32221 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0043352 infores:hetionet NCBIGene:10020 biolink:causes MONDO:0958325 infores:monarchinitiative not_provided not_provided HGNC:23657 MONDO:0958325 uuid:202d8bbe-dddf-47fc-97d3-af803b4b2449 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0085649 infores:hetionet CHEBI:15544 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0015230 infores:hetionet CHEBI:5050 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0004604 infores:hetionet CHEBI:6437 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027497 infores:hetionet CHEBI:8764 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085633 infores:hetionet CHEBI:135342 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0013404 infores:hetionet CHEBI:63599 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C1443060 infores:hetionet CHEBI:4027 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C2047937 infores:hetionet CHEBI:2788 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0423153 infores:hetionet CHEBI:2704 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0011991 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0002884 infores:hetionet CHEBI:8863 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0855775 infores:hetionet CHEBI:10101 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027121 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038367 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0858217 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0858217 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0858678 infores:hetionet CHEBI:41423 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020443 infores:hetionet CHEBI:3419 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0016382 infores:hetionet CHEBI:7575 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0151849 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038663 infores:hetionet CHEBI:39112 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0231528 infores:hetionet NCBIGene:335 biolink:causes MONDO:0032766 infores:monarchinitiative not_provided not_provided HGNC:600 MONDO:0032766 uuid:c537ecaa-ce8e-4aa4-bb03-8c55d42ae15c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013144 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1608954 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1608954 infores:hetionet CHEBI:5855 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0340865 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006145 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0039070 infores:hetionet CHEBI:61033 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0011175 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0349506 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0029408 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0232910 infores:hetionet CHEBI:6717 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002874 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151717 infores:hetionet CAID:CA158285 biolink:causes MONDO:0100216 infores:clingen CAID:CA158285 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting, BS1 BA1, PM1, PM5 The NM_177438.3:c.1013A>C variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by alanine at amino acid position 338 (p.Glu338Ala). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMID: 32973888, Internal lab contributors). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00049 (22/44890 alleles) in East Asian population, which is higher than the ClinGen DICER1 VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.141; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2_Supporting, BP4. (Bayesian Points: -6; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA158285/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA170462 biolink:causes MONDO:0100039 infores:clingen CAID:CA170462 MONDO:0100039 PMID: Likely Benign BP5, BS2 BS1, PM2, BP4 The p.Arg65Gln variant in CDKL5 is present in 2 female and 1 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg65Gln variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Arg65Gln variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Arg65Gln variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170462/MONDO:0100039/034 2023-08-23 2023-09-14 X-linked inheritance HP:0001417 Contradicts true UNII:G4PX8C4HKV biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0346156 infores:hetionet CHEBI:4551 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0039231 infores:hetionet CHEBI:9241 biolink:causes UMLS:C2363829 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C2363829 infores:hetionet CHEBI:4953 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0030193 infores:hetionet CAID:CA405649517 biolink:causes MONDO:0007783 infores:clingen CAID:CA405649517 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with serine at codon 3631 of the RYR1 protein, p.(Ala3631Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.85 supports a pathogenic status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405649517/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7915 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0235290 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020542 infores:hetionet CHEBI:9139 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085612 infores:hetionet CHEBI:4887 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0001807 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0011053 infores:hetionet CHEBI:7577 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0542571 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0033581 infores:hetionet NCBIGene:54862 biolink:causes MONDO:0012037 infores:monarchinitiative not_provided not_provided HGNC:30237 MONDO:0012037 uuid:4cd9067d-a9e0-401d-a6f3-1a0e925b6124 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA320618036 biolink:causes MONDO:0011071 infores:clingen CAID:CA320618036 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP2, BP3, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.509-18T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (Donor Loss 0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (Donor Loss 0.01) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (0.75)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320618036/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49375 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151604 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0017160 infores:hetionet CHEBI:9943 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0000737 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0015397 infores:hetionet CHEBI:46345 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0023518 infores:hetionet CHEBI:64312 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235198 infores:hetionet CHEBI:64198 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0000833 infores:hetionet CHEBI:261649 biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0266813 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020456 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0031542 infores:hetionet CHEBI:17141 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0009806 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023530 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0005940 infores:hetionet CHEBI:7496 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0267792 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0032326 infores:hetionet NCBIGene:4854 biolink:causes MONDO:0000914 infores:monarchinitiative not_provided not_provided HGNC:7883 MONDO:0000914 uuid:4c822219-6988-4ba9-928b-fdd73bede8c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0038663 infores:hetionet CHEBI:3638 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0038325 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0149931 infores:hetionet NCBIGene:3852 biolink:causes MONDO:0007556 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0007556 uuid:4265545e-f994-433e-a747-d3b5c0478ebc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019080 infores:hetionet CAID:CA8314695 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314695 MONDO:0009276 PMID: Benign BA1 PP3, BP4, BP2 The NM_000173.7(GP1BA):c.106A>G (p.Arg36Gly) missense variant occurs at a frequency too high for disease; the Grpmax filtering allele frequency in gnomAD v4.1 is 0.01679 (based on 1319/75016 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.001; BA1). Therefore this variant is classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP (specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314695/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:40237 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0009450 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0392702 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0034011 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0034011 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0020649 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0948349 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1269683 infores:hetionet CHEBI:50742 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0085593 infores:hetionet CHEBI:9654 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C3665347 infores:hetionet CHEBI:36795 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0151786 infores:hetionet NCBIGene:768206 biolink:causes MONDO:0012523 infores:monarchinitiative not_provided not_provided HGNC:32528 MONDO:0012523 uuid:3db373a3-f5b8-451b-a7d2-67005f69602a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0149931 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0022408 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0010073 infores:hetionet CHEBI:9571 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0151889 infores:hetionet CHEBI:9434 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0009763 infores:hetionet CHEBI:135929 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0017178 infores:hetionet CHEBI:367163 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0016382 infores:hetionet CAID:CA913169025 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169025 MONDO:0044970 PMID: Likely Pathogenic PP3, PP1, PS4_Supporting, PM2_Supporting, PS3_Supporting PM6 The m.3258T>C variant in MT-TL1 has been reported in at least three probands to date. The first case report was a young adult with severe hyperlactatemia associated with mild exercise intolerance and mild lipidosis. This individual had a combined respiratory chain deficiency in liver with normal activities in muscle. This proband’s mother died in early adulthood from an unexplained cause The variant was listed as being heteroplasmic but the levels were not reported (PMID: 11335700). The second case was a young adult with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) characterized by fatigue, acidosis, hyperCKemia, stroke-like episodes, and tonic clonic seizures; with ragged red fibers and COX negative fibers on muscle biopsy. The variant was present at 96% in muscle and 57% in blood (PMID: 12798797). The third case was younger at presentation with neurological involvement (ataxia, regression, myoclonic epilepsy) as well as decreased complex I and IV activities in muscle, increased lactate in blood and CSF, and a normal brain MRI. Heteroplasmy levels were not provided (PMID: 23847141). Haplogroup information was not reported for all cases however given the features and biochemistry reported in these cases, this Expert Panel agreed to consider them as a supporting line of evidence (PS4_supporting). The variant segregated with features of primary mitochondrial disease and unaffected status in three family members from one family. The variant was present at 96% in muscle and 57% in blood in the proband whereas in her healthy mother had the variant at 19% in blood, one healthy brother had the variant at 30% in blood, and another healthy brother had the variant at 48% in blood (PP1; PMID:12798797). There is one occurrence of this variant in GenBank dataset, however this is from an individual with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 82.6%, as does HmtVar with a score of 0.8 (PP3). Single fiber analysis in muscle showed that the ragged red fiber had extremely high levels of variant (n = 7; 99.4% +/- 0.9%), whereas normal muscle fibers had significantly lower levels (n = 8; 90.1 +/- 5.1%; P < 0:05, Mann–Whitney’s U-test) (PS3_supporting, PMID: 12798797). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the evidence shown in single fibers studies for this variant and because the phenotype reported in these cases is consistent with mitochondrial tRNA-related diseases. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP1, PP3, PS4_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169025/MONDO:0044970/015 2022-08-08 2022-09-02 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:135736 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0025061 infores:hetionet CHEBI:3219 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0039070 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0027051 infores:hetionet CHEBI:45979 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0018965 infores:hetionet CHEBI:92998 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0011606 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0042267 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151699 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0037274 infores:hetionet CHEBI:31980 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0000737 infores:hetionet CHEBI:3504 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0042963 infores:hetionet CHEBI:63599 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0039240 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0027947 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018799 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0029928 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0349506 infores:hetionet CHEBI:44915 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0023066 infores:hetionet NCBIGene:4921 biolink:causes MONDO:0010077 infores:monarchinitiative not_provided not_provided HGNC:2731 MONDO:0010077 uuid:b66183a5-84ae-45b5-b19f-25b75a12ecf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0015672 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011334 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0424605 infores:hetionet CHEBI:9168 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042023 infores:hetionet CHEBI:51860 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0028778 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0234215 infores:hetionet CHEBI:3441 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0030196 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C1262144 infores:hetionet GO:1902746 biolink:causes GO:0002088 infores:ubergraph knowledge_assertion manual_agent GO:1902746 GO:0002088 CHEBI:6916 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0948594 infores:hetionet CHEBI:6067 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0010520 infores:hetionet CAID:CA340742778 biolink:causes MONDO:0100368 infores:clingen CAID:CA340742778 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1243+2T>A is a non-coding variant that disrupts a canonical splice donor site in intron 11 at the junction with exon 11 and is predicted to impact splicing. This prediction has been confirmed by a minigene assay showing complete disruption of splicing and production of an alternative transcript with an out-of-frame insertion of 94 bp. Sequencing of minigene products indicate that this insertion corresponds to the insertion of the complete intron 11 into the transcript, which upon manual review of predicted sequencing and amino acid products appears to results in a termination codon (PMID 25383945, PVS1(RNA)). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of early onset severe retinal dystrophy congenital night blindness (0.5), pigmentary retinopathy with attenuated vessels (0.5), white/yellow dots on color photography (2), and symptomatic onset between birth and age five years (1), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 25383945, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1(RNA), PM2_Supporting, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340742778/MONDO:0100368/120 2025-03-31 2025-03-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63631 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0541798 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0008093 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0008093 uuid:56c9e7c6-edca-4cdd-8d6a-8dd350d1b43a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014274 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014274 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.883_885del (p.Ser295del) is an in-frame deletion. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014274/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:9430ZR8ZAN biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0000731 infores:hetionet CHEBI:134743 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0917801 infores:hetionet CHEBI:134966 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0917801 infores:hetionet CHEBI:116278 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0039070 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0042109 infores:hetionet CHEBI:48390 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0232462 infores:hetionet CHEBI:75246 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0013428 infores:hetionet CHEBI:63791 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0547030 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0001711 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D006501 DB00199_MESH_D006501_1DB01421_MESH_D006501_1 CHEBI:31348 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022573 infores:hetionet CHEBI:7852 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013428 infores:hetionet CHEBI:31547 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0016204 infores:hetionet NCBIGene:23554 biolink:causes MONDO:0013218 infores:monarchinitiative not_provided not_provided HGNC:21641 MONDO:0013218 uuid:e34767d8-29a3-47ce-8d45-cec1706f1b32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6741 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0007286 infores:hetionet CHEBI:28901 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1306577 infores:hetionet NCBIGene:3773 biolink:causes MONDO:0859167 infores:monarchinitiative not_provided not_provided HGNC:6262 MONDO:0859167 uuid:7f687ea8-4b26-48e9-a24b-5b7eae5f0fab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0037274 infores:hetionet CHEBI:4653 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0018794 infores:hetionet NCBIGene:84947 biolink:causes MONDO:0013875 infores:monarchinitiative not_provided not_provided HGNC:21061 MONDO:0013875 uuid:513a403f-91e2-41be-a86f-59a2933ee1bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63632 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0030312 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040046 infores:hetionet CHEBI:31236 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037763 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0024115 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235818 infores:hetionet CHEBI:63632 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0242379 infores:hetionet CAID:CA5950417 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950417 MONDO:0000573 PMID: Uncertain Significance PP4, PM2_Supporting, PM1, PM3_Supporting PM5, PS1, PS3 The c.1421A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 474 (p.Asn474Ser).The filtering allele frequency (the upper threshold of the 95% CI of 2/30614 alleles) of the c.1421A>G variant in RAG2 is 0.00001082 for South Asian chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate.However, two functional assays published in the literature showed that this variant did not show differences in contrast with wild-type, both in the quantitative assay: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 97.5% (SEM 5.9), which is higher than the SCID VCEP threshold for Moderate (<25%) or Supporting (25-60%) level of evidence (PMID 29772310) AND in the qualitative assay: The analyses had not yet identified any particular defect associated with the N474S mutation (PMID: 20234091); Thus, PS3 is not applied.Diagnostic criteria for SCID (Criterion 1: Very Low T cells <0.05x109/L + Criterion 3 No alternate explanation for low t-cell count AND <20% of CD4+ T cell have naive cell surface markers - based on CD45RA and CD45R0 count) 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (PMID: 11133745). This patient is homozygous, 0.5 pts, PM3 is met at supporting level.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PP4, and PM3_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950417/MONDO:0000573/124 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:101278 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018790 infores:hetionet CHEBI:7465 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0043387 infores:hetionet CHEBI:17141 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0012833 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0497247 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020255 infores:hetionet GO:0022003 biolink:causes GO:0022001 infores:ubergraph knowledge_assertion manual_agent GO:0022003 GO:0022001 CHEBI:70735 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0007398 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0162830 infores:hetionet CHEBI:3312 biolink:causes UMLS:C1328540 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C1328540 infores:hetionet CHEBI:45081 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027497 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0006145 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0178298 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002897 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0149985 infores:hetionet CHEBI:9086 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0009676 infores:hetionet CAID:CA4516861 biolink:causes MONDO:0021060 infores:clingen CAID:CA4516861 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1772A>G (p.Asn591Ser) variant in the SOS1 gene is 0.054% (11/11524) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA4516861/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:41423 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0007785 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0038525 infores:hetionet CHEBI:63580 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2939186 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0235146 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0853141 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0853141 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020676 infores:hetionet CAID:CA274328 biolink:causes MONDO:0009290 infores:clingen CAID:CA274328 MONDO:0009290 PMID:23825616 Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.525_526del (p.Asn177ProfsTer11), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of this variant in an individual with no GAA cross-reactive immunological material in cultured skin fibroblasts (PMID 22252923, 23825616, 31342611). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003288 in the South Asian population, meeting PM2. One individual with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied. There is a ClinVar entry for this variant (Variation ID: 189057, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274328/MONDO:0009290/010 2020-11-02 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:52717 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037284 infores:hetionet CHEBI:63617 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0003862 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027092 infores:hetionet CHEBI:50885 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0031256 infores:hetionet CHEBI:63580 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013182 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0003123 infores:hetionet CHEBI:35854 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0018965 infores:hetionet CHEBI:44423 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0151514 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0234215 infores:hetionet CHEBI:3638 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0027947 infores:hetionet CHEBI:4672 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0242379 infores:hetionet NCBIGene:83938 biolink:causes MONDO:0014070 infores:monarchinitiative not_provided not_provided HGNC:23405 MONDO:0014070 uuid:027037bc-cb00-44ce-8553-8b9e282d84d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0041582 infores:hetionet CHEBI:5132 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0020538 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151735 infores:hetionet CHEBI:53760 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1510410 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0855775 infores:hetionet CHEBI:2904 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0040264 infores:hetionet CHEBI:10127 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0232849 infores:hetionet CHEBI:51230 biolink:causes UMLS:C1142111 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1142111 infores:hetionet CHEBI:30830 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151578 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0022408 infores:hetionet UMLS:C0004609 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0028084 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0018099 infores:hetionet CHEBI:47898 biolink:causes UMLS:C2243088 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2243088 infores:hetionet CHEBI:4562 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0231528 infores:hetionet GO:0021879 biolink:causes CL:0012001 infores:ubergraph knowledge_assertion manual_agent GO:0021879 CL:0012001 CAID:CA16043215 biolink:causes MONDO:0010725 infores:clingen CAID:CA16043215 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP3_Strong, PM5, PP4 PM1, PP1 The NM_000330.4(RS1):c.668G>A variant is a missense variant encoding the substitution of Cysteine with Tyrosine at position 223. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family consisting of a mother and an affected son, however, the mother was apparently unaffected so PP1 was not met (PMID: 38317323). At least one proband harboring this variant exhibits a phenotype including the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 22245991, PP4). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 20061330, 38317323, 39293640, PS4_moderate). This variant p.Cys223Tyr disrupts a site defined as a critical amino acid residue involved in disulfide bridge formation by the ClinGen X-linked IRD VCEP (PMIDs: 26812435). The PM1_strong code is ineligible to be used in combination with the PP3 code, and therefore, this code was not met. Another missense variant in the same codon, NM_000330.4(RS1):c.667T>C (p.Cys223Arg), (PMIDs: 34645606, 10533068, 30652005, 33460243, 16361673) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (194) than the comparison variant (180), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_strong, PP4, PM5, and PS4_moderate (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043215/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports UNII:Z5N076G8YQ biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0018681 infores:hetionet CHEBI:9398 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0039070 infores:hetionet CHEBI:9086 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042963 infores:hetionet CHEBI:168396 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C2363730 infores:hetionet CHEBI:41423 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151699 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0002957 infores:hetionet GO:0070799 biolink:causes GO:0070787 infores:ubergraph knowledge_assertion manual_agent GO:0070799 GO:0070787 CHEBI:65173 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0042373 infores:hetionet CHEBI:180905 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0007859 infores:hetionet CHEBI:44032 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0028734 infores:hetionet NCBIGene:10149 biolink:causes MONDO:0010511 infores:monarchinitiative not_provided not_provided HGNC:4516 MONDO:0010511 uuid:d2040e03-afdc-4af7-b72a-89b684c2085e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013447 infores:hetionet CHEBI:45924 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0036974 infores:hetionet CHEBI:63623 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0042963 infores:hetionet CHEBI:6078 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C1325847 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0037274 infores:hetionet UMLS:C0145867 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0011175 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0234913 infores:hetionet CHEBI:61033 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0917801 infores:hetionet CHEBI:6710 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0004093 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0027765 infores:hetionet CHEBI:691037 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0030193 infores:hetionet CAID:CA023463 biolink:causes MONDO:0007750 infores:clingen CAID:CA023463 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PVS1, PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, BS2 The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is in canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs*51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met.PP1_strong - variant segregates with FH phenotype in 9 informative meiosis from at least 5 families:- 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile.- 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile.--- so PP1_Strong is met.PS4 - variant meets PM2 and was identified in:- 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same;- 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada;- 1 index case with DLCN >= 6 from Color Health, Inc., USA.--- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met.PM2 - PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met.PP4 - variant meets PM2 and was identified in at least 29 unrelated index cases (see PS4 for details), so PP4 is met.PS3_supporting - Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51)--- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023463/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:32020 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0035410 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0020517 infores:hetionet CHEBI:2904 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0242429 infores:hetionet CAID:CA10443881 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443881 MONDO:0010315 PMID: Likely Benign BS2 BS1, PM2, PM1, PM3, PM5, BA1, PS4 NM_000206.3(IL2RG):c.407G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 136 (p.Arg136Gln). This variant is observed in 7 hemizygotes in gnomAD v4 (BS2). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Benign variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2 (VCEP specifications version 2.1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443881/MONDO:0010315/129 2025-11-19 2025-11-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:5775 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0241705 infores:hetionet CHEBI:64318 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0020580 infores:hetionet CHEBI:75984 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0016204 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0403632 infores:hetionet CHEBI:50659 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0042963 infores:hetionet CHEBI:8081 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0039231 infores:hetionet CHEBI:4710 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0041969 infores:hetionet CHEBI:8430 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0013604 infores:hetionet CHEBI:18248 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0043144 infores:hetionet CHEBI:8890 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0002792 infores:hetionet CHEBI:134991 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0031212 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042075 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0795692 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0521592 infores:hetionet CAID:CA6402465 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402465 MONDO:0019565 PMID:19422453 Likely Benign BP4, BP5 PM2, PP4, BS2, BS1, BS3 The NM_000552.5:c.4748G>A variant encodes a missense substitution of arginine by glutamine at codon 1583 in VWF. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo / VWF:Ag ratio, which is specific for VWD type 2A. However, segregation evidence within the family indicated that another variant (p.Cys849Tyr) was responsible for the phenotype (PMID: 19422453, PMID: 35452508). p.Cys849Arg has been classified likely pathogenic by the ClinGen VWD VCEP (BP5). The computational predictor REVEL gives a score of 0.229, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0005148 (based on 59/91064 alleles in the South Asian population, with 2 homozygotes). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold (>0.01) for BS1 but higher than the threshold (<0.005 for type 2N OR <0.0001 for type 2A/B/M) for PM2_Supporting. Multimerization assay performed with the (p.Arg1583Gln) recombinant mutant and wild-type control vWF expressed by COS-7 cells showed nearly normal multimers (with only slight decrease in ultra-high MW multimers), indicating that this variant does not have a damaging effect on protein function consistent with the multimerization defect observed in the proband (PMID: 19422453). Electrophoretic analysis of recombinant VWF multimeric patterns also showed normal susceptibility of the recombinant mutant to ADAMTS-13 proteolysis (PMID: 19422453). In summary, this variant meets the criteria to be classified as likely benign for hereditary VWD based on the application of ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP4, BP5. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402465/MONDO:0019565/090 2024-07-09 2024-08-09 Undetermined mode of inheritance Contradicts true CAID:CA367399833 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399833 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.976A>C variant in the glucokinase gene, GCK, causes an amino acid change of threonine to proline at codon 326 (p.(Thr326Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.822, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PMID: 19564454, 31595705, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributor). This variant segregated with hyperglycemia, with six informative meioses in three families (PP1_Strong; internal lab contributors, PMID: 31595705). In summary, c.976A>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399833/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports NCBIGene:5897 biolink:causes MONDO:0011338 infores:monarchinitiative not_provided not_provided HGNC:9832 MONDO:0011338 uuid:6a92da95-9bd5-4a41-8ee2-91c4ca374de8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0003864 infores:hetionet UNII:0RK7M7IABE biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0677500 infores:hetionet CHEBI:9586 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1167965 infores:hetionet CHEBI:48273 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0026858 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0239571 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011991 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038663 infores:hetionet CAID:CA2695203125 biolink:causes MONDO:0015967 infores:clingen CAID:CA2695203125 MONDO:0015967 PMID: Pathogenic PS3, PS1, PP4_Moderate, PP3, PP1, PM2_Supporting PS4 The c.679+5G>C variant in the glucokinase gene, GCK, is a non-canonical splice region variant in intron 6 of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.43 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3). Additionally, RNA studies of this non-canonical splicing variant demonstrate that it results in aberrant splicing, indicating that this variant impacts protein function (PS3; PMID: 31529753). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 28726111, 31529753). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; PMID: 28726111). Additionally, this variant segregated with hyperglycemia with 3 informative meioses in one family (PP1; PMID: 31529753). The c.679+5G>A variant at the same non-canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.679+5G>C has a greater predicted impact by Splice AI (0.43 vs. 0.26) (PS1). In summary, c.679+5G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS1, PS3, PP4_Moderate, PP1, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695203125/MONDO:0015967/086 2025-09-17 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:75045 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C1861172 infores:hetionet CHEBI:5088 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0013144 infores:hetionet NCBIGene:2189 biolink:causes MONDO:0013565 infores:monarchinitiative not_provided not_provided HGNC:3588 MONDO:0013565 uuid:cc05955c-d277-4ef8-ae19-9b44d5a9a688 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0005119 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003175 infores:hetionet CHEBI:7444 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0013604 infores:hetionet CHEBI:2673 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0036974 infores:hetionet CHEBI:83531 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0009763 infores:hetionet CHEBI:135613 biolink:causes UMLS:C1321523 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C1321523 infores:hetionet CHEBI:63608 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0238106 infores:hetionet CHEBI:35677 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0042963 infores:hetionet CHEBI:144093 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0003811 infores:hetionet CHEBI:3082 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0042963 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0233494 infores:hetionet CHEBI:32139 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0042487 infores:hetionet CHEBI:68606 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0035078 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0027769 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0677500 infores:hetionet CHEBI:8768 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1167965 infores:hetionet CHEBI:8874 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0035455 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0022660 infores:hetionet GO:0048889 biolink:causes CL:0000852 infores:ubergraph knowledge_assertion manual_agent GO:0048889 CL:0000852 CHEBI:3716 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C2830004 infores:hetionet CAID:CA171658 biolink:causes MONDO:0100039 infores:clingen CAID:CA171658 MONDO:0100039 PMID: Likely Benign BP7, BS2 BS1, PM2, BA1 The p.Arg31= variant in CDKL5 is present in 3 female and 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg31= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Arg31= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Arg31= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171658/MONDO:0100039/016 2022-09-01 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7443 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0011570 infores:hetionet CHEBI:119915 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234022 infores:hetionet CAID:CA337284 biolink:causes MONDO:0018875 infores:clingen CAID:CA337284 MONDO:0018875 PMID: Likely Benign BP4, PP4, BS2, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS3, BS4, PP3, PP1 The NM_000546.6: c.149T>C variant in TP53 is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 50 (p.Ile50Thr). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: LabCorp Genetics). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: LabCorp Genetics). This variant has an allele frequency of 0.000001239 (2/1614026 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.0655; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PP4, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.1.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA337284/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50156 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0728899 infores:hetionet CHEBI:10023 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0028961 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0595878 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0544618 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0544618 infores:hetionet CHEBI:2654 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0003123 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0011848 infores:hetionet CHEBI:175901 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0232462 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0234215 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0022104 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0243026 infores:hetionet CHEBI:4027 biolink:causes UMLS:C2242496 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C2242496 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0853149 infores:hetionet CHEBI:3387 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0038999 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C1384666 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0162429 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0267792 infores:hetionet CHEBI:35677 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0013404 infores:hetionet GO:0141071 biolink:causes GO:0000165 infores:ubergraph knowledge_assertion manual_agent GO:0141071 GO:0000165 CHEBI:51450 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042963 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019372 infores:hetionet CHEBI:10125 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151904 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027813 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0233523 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233523 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0332575 infores:hetionet CHEBI:9649 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0036980 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0853149 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0037274 infores:hetionet CAID:CA344824 biolink:causes MONDO:0044970 infores:clingen CAID:CA344824 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS1, PM5 PP1, PS4, PS2, PS3, PM6 The m.14482C>G (p.M64I) variant in MT-ND6 has been reported in one proband from an extended consanguineous kindred with primary mitochondrial disease. The predominant feature in this family was bilateral optic atrophy consistent with Leber Hereditary Optic Neuropathy (LHON). The variant was present at homoplasmy in affected and unaffected individuals from this family and, when affected, the age of onset was early adulthood (PMID: 9443868). It appears some individuals from this family were reported multiple times (PMIDs: 21887510, 8742999). There are no reported de novo occurrences of this variant to our knowledge. The variant was homoplasmic in family members of the only reported proband, precluding consideration for segregation evidence. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this nucleotide position leading to the same amino acid change was classified as likely pathogenic by this expert panel, m.14482C>A (p.M64I, PS1). Furthermore, a different variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant, m.14484T>C (p.M64V, PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt uncertain significance was a more appropriate classification given the only reported family was consanguineous and nuclear genetic etiologies were not assessed. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS1, PM5, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA344824/MONDO:0044970/015 2022-07-11 2023-03-29 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria NCBIGene:171558 biolink:causes MONDO:0975761 infores:monarchinitiative not_provided not_provided HGNC:21290 MONDO:0975761 uuid:ee32ec91-42c7-4c0a-abb6-f993dc7b317f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0424448 infores:hetionet CHEBI:3423 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0242528 infores:hetionet CHEBI:36791 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0236000 infores:hetionet CHEBI:94501 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020621 infores:hetionet CHEBI:4710 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0028084 infores:hetionet CHEBI:45863 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151662 infores:hetionet NCBIGene:8452 biolink:causes MONDO:0030994 infores:monarchinitiative not_provided not_provided HGNC:2553 MONDO:0030994 uuid:4380dd8d-5b9f-4aa2-af4f-ca826e61abaf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0233471 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1368065 infores:hetionet NCBITaxon:4751 biolink:causes MONDO:0005984 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D014008 DB00400_MESH_D014008_1DB00735_MESH_D014008_1DB04815_MESH_D014008_1DB09321_MESH_D014008_1DB00793_MESH_D014008_1DB01188_MESH_D014008_1DB01091_MESH_D014008_1DB00525_MESH_D014008_1 CHEBI:3499 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0027947 infores:hetionet CHEBI:135193 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0017178 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085136 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0002170 infores:hetionet CHEBI:48538 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0013491 infores:hetionet CAID:CA386965448 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965448 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PM5, PP4_Moderate, PP3 The c.709A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to histidine at codon 237 (p.(Asn237His)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, the c.709A>C variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.816, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, (c.709A>G, p.Asn237Asp), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). In summary, c.709A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM1_Supporting, PM2_supporting, PM5_Supporting, PP4_Moderate, PP3 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965448/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:66876 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C2830004 infores:hetionet CHEBI:2569 biolink:causes NCIT:C122529 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0857494 infores:hetionet CHEBI:9445 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0026858 infores:hetionet CHEBI:50156 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0003811 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004096 infores:hetionet CHEBI:75045 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C2363731 infores:hetionet CHEBI:63638 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0042029 infores:hetionet CHEBI:584020 biolink:causes MONDO:0003330 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0178879 infores:hetionet CHEBI:64064 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0018834 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1868693 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1868693 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0877661 infores:hetionet CHEBI:2675 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0023530 infores:hetionet CHEBI:10100 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0020433 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0026848 infores:hetionet CHEBI:82960 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0011603 infores:hetionet CHEBI:480999 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1145670 infores:hetionet NCBIGene:4070 biolink:causes MONDO:0008777 infores:monarchinitiative not_provided not_provided HGNC:11530 MONDO:0008777 uuid:0492d593-7550-494f-b7cc-784076ff9fcf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7601 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0002418 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0314719 infores:hetionet CHEBI:5790 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0917801 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0423636 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0423636 infores:hetionet CHEBI:41879 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0152459 infores:hetionet CHEBI:74947 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0947912 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0023890 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0340464 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018801 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0017160 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C1565489 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151740 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0853813 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0857353 infores:hetionet CHEBI:63589 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0017152 infores:hetionet CAID:CA226043 biolink:causes MONDO:0100453 infores:clingen CAID:CA226043 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter) is a nonsense variant that introduces a premature stop codon into exon 4 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00001242, with 20 alleles / 1610586 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) during the first year of life (1 pt), as well as nystagmus (1 pt), non-recordable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), and normal fundus, which together are specific for GUCY2D-related recessive retinopathy (total 4 points, PMID: 10951519, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226043/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3756 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011253 infores:hetionet CHEBI:101853 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0520966 infores:hetionet UMLS:C0004609 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0015967 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151849 infores:hetionet CHEBI:3568 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011175 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0700345 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0595879 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018500 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0027726 infores:hetionet CHEBI:18358 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0018681 infores:hetionet CHEBI:9757 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0013144 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0035078 infores:hetionet GO:0005874 biolink:causes GO:0099111 infores:ubergraph knowledge_assertion manual_agent GO:0005874 GO:0099111 CHEBI:3723 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022104 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013395 infores:hetionet CHEBI:75998 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0017178 infores:hetionet CHEBI:32315 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C1328337 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0349506 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0403632 infores:hetionet CHEBI:4708 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0028084 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0149931 infores:hetionet CHEBI:61049 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151474 infores:hetionet CHEBI:5801 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0001824 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233632 infores:hetionet CAID:CA16020836 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020836 MONDO:0009861 PMID:26481238PMID:29654578PMID:26481238 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The c.676C>A (p.Gln226Lys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID 26481238, 29654578). This variant is absent in population databases. This variant was detected in trans with pathogenic variants p.Gln20* and p.Ile306Val. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020836/MONDO:0009861/006 2020-03-14 2020-03-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6456 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0004096 infores:hetionet CHEBI:2208 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0024523 infores:hetionet CHEBI:8874 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020458 infores:hetionet NCBIGene:477 biolink:causes MONDO:0030472 infores:monarchinitiative not_provided not_provided HGNC:800 MONDO:0030472 uuid:b5245be6-b8cb-4766-8eef-7ddc04c27f21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38545 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0040034 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0152165 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0152165 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0016579 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0016579 infores:hetionet CHEBI:47499 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0231218 infores:hetionet CHEBI:4356 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0035078 infores:hetionet CHEBI:8888 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0028081 infores:hetionet CHEBI:8093 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0034642 infores:hetionet CHEBI:63577 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0038002 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0013922 infores:hetionet CAID:CA226542 biolink:causes MONDO:0100368 infores:clingen CAID:CA226542 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PM5_Supporting, PP4, PM2_Supporting NM_000329.3(RPE65):c.311G>T (p.Gly104Val) is a missense variant resulting in replacement of glycine by valine at amino acid p.104. Another missense variant in the same codon (NM_000329.3(RPE65):c.311G>A (p.Gly104Asp)) has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5_Supporting, PMID: 19117922). Splicing prediction using SpliceAI found all scores below the threshold of <0.1 for both of these variants. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) variant suspected in trans (0.5 points, PMID: 28945494) or the NM_000329.3(RPE65):c.95-2A>T variant confirmed in trans (1 point, PMID: 32347917, PMID: 34492281, PMID: 38219857), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset of nystagmus (1 pt) before age 1 year (1 pt), central visual acuity limited to fixation and following by age 4 years (1 pt), normal fundus appearance, hypermetropia, and frequent sun gazing (1 pt), which together are specific for RPE65-related recessive retinopathy (total 4.5 points, PMID: 28945494, PP4). The computational predictor REVEL gives a score of 0.97, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.08 for acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PM5_Supporting, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226542/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:10846 biolink:causes MONDO:0044637 infores:monarchinitiative not_provided not_provided HGNC:8772 MONDO:0044637 uuid:ea08e39e-3498-4491-bcca-703ac3698964 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231425 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0015967 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0340464 infores:hetionet CHEBI:53691 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0151578 infores:hetionet CAID:CA8815181 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815181 MONDO:0009290 PMID:29122469PMID:25155446PMID:30564623PMID:29315315PMID:22676651 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1143del (p.Ala382LeufsTer10), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 0.000008946 in the European non-Finnish population, meeting PM2. At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting is met based on the specifications on the Clingen LSD VCEP. There is a ClinVar entry for this variant (Variation ID: 370263, 1 star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815181/MONDO:0009290/010 2020-08-31 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UNII:9430ZR8ZAN biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0011991 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0009806 infores:hetionet CHEBI:2549 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0030252 infores:hetionet CAID:CA410202667 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202667 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, PM5, PM4, PM3, PP2, PP4, BS2 NM_001754.5(RUNX1):c.412G>A (p.Glu138Lys) is a missense variant which has a REVEL score of 0.945, which is ≥ 0.88 (PP3). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). It is also absent from population databases (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202667/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10127 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0424605 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0039584 infores:hetionet CHEBI:64312 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0016658 infores:hetionet CHEBI:45863 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018681 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0031350 infores:hetionet CAID:CA132454 biolink:causes MONDO:0019501 infores:clingen CAID:CA132454 MONDO:0019501 PMID:25468891PMID:8900236PMID:18700726 Likely Benign BS1, BP2, BS3_Supporting BP5 The filtering allele frequency of the c.905G>A (p.Arg302His) variant in the MYO7A gene is 0.4% for European chromosomes by gnomAD (587/126276 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). While this variant has been reported in several individuals with Usher syndrome, in 2 individuals it was identified in cis with another pathogenic MYO7A variant (BP2; PMID 8900236). This variant has also been reported in at least 2 additional individuals with Usher syndrome who had alternate genetic etiologies identified (PMID: 25468891). In addition, in vitro functional evidence from one study suggests that the Arg302His variant had little effect on motor activity of MYO7A (BS3_Supporting PMID: 18700726). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1, BP2, BS3_Supporting. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132454/MONDO:0019501/005 2018-10-22 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:15765 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0018834 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0857751 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0857751 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009760 infores:hetionet CHEBI:45863 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013456 infores:hetionet CHEBI:71229 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0016204 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0034150 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0020456 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0006112 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0006112 infores:hetionet CHEBI:39112 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1519353 infores:hetionet CHEBI:46195 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0013404 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0521839 infores:hetionet CHEBI:28864 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235710 infores:hetionet CAID:CA015985 biolink:causes MONDO:0005045 infores:clingen CAID:CA015985 MONDO:0005045 PMID: Uncertain Significance PM2, PP3, PS4_Moderate PM5, PM1, PM6, PP1, PS3, BS3, BS4, PS1, PS2, BP4 The c.5342G>A (p.Arg1781His) variant in MYH7 has been identified in at least 12 individuals with HCM (PS4_Moderate; Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). This variant was identified in 0.00116% (FAF 95% CI; 2/30616) of South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015985/MONDO:0005045/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA038604 biolink:causes MONDO:0007750 infores:clingen CAID:CA038604 MONDO:0007750 PMID: Uncertain Significance BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.2106G>A (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia as no ACMG/AMP evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038604/MONDO:0007750/013 2024-08-30 2024-10-03 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15940 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0002962 infores:hetionet CHEBI:2675 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0235198 infores:hetionet CAID:CA000275 biolink:causes MONDO:0017623 infores:clingen CAID:CA000275 MONDO:0017623 PMID:21343951PMID:21659347PMID:26580448PMID:26898890PMID:25980754PMID:29785012PMID:29706350 Likely Benign BS1, PP2, BS3_Supporting, BP4 PVS1, PM2, PM6, BP7, BP5, BS4, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln) variant meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF of this variant=0.0001051.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function. This variant: score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350).BP4: REVEL score < 0.5 (score=0.497).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign strong and 2 benign supporting = -6. 1 pathogenic supporting = 1. Total = – 5 (likely benign). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000275/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6690 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0023530 infores:hetionet CHEBI:9586 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1142135 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0233472 infores:hetionet GO:0048399 biolink:causes GO:0048390 infores:ubergraph knowledge_assertion manual_agent GO:0048399 GO:0048390 CHEBI:6690 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0030312 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0032584 infores:hetionet CHEBI:8888 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013390 infores:hetionet NCBIGene:29967 biolink:causes MONDO:0020793 infores:monarchinitiative not_provided not_provided HGNC:31708 MONDO:0020793 uuid:136d779b-1f5b-4b3a-a6df-183590e164da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:24564 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0004134 infores:hetionet CHEBI:9763 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C2830004 infores:hetionet CHEBI:42797 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009917 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0021053 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0034150 infores:hetionet CHEBI:9398 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0011991 infores:hetionet CHEBI:92712 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0429097 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0015967 infores:hetionet CHEBI:10023 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020458 infores:hetionet CHEBI:17334 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0035410 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0018799 infores:hetionet CHEBI:132233 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0220870 infores:hetionet CHEBI:168396 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020639 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013295 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011551 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004844 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023532 infores:hetionet NCBIGene:2301 biolink:causes MONDO:0012456 infores:monarchinitiative not_provided not_provided HGNC:3808 MONDO:0012456 uuid:c20d1896-20ef-4325-ac60-d46b7a5ab831 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94392 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0012833 infores:hetionet CHEBI:75246 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0085649 infores:hetionet CHEBI:144551 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1306341 infores:hetionet CHEBI:116735 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0041834 infores:hetionet CHEBI:31711 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0016382 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002965 infores:hetionet GO:1903593 biolink:causes GO:0002279 infores:ubergraph knowledge_assertion manual_agent GO:1903593 GO:0002279 CHEBI:17549 biolink:causes UMLS:C1698818 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C1698818 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0007642 infores:hetionet CHEBI:135930 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0041834 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0026946 infores:hetionet CHEBI:3077 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C3665347 infores:hetionet GO:1900193 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1900193 GO:0019953 CHEBI:7915 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0039520 infores:hetionet CHEBI:15551 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0151827 infores:hetionet CHEBI:50729 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0743400 infores:hetionet CHEBI:7444 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0027424 infores:hetionet CHEBI:9130 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0085605 infores:hetionet CHEBI:3699 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0235660 infores:hetionet CHEBI:51137 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0003862 infores:hetionet GO:0072007 biolink:causes CL:0000650 infores:ubergraph knowledge_assertion manual_agent GO:0072007 CL:0000650 CHEBI:31236 biolink:causes UMLS:C0854171 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0854171 infores:hetionet CHEBI:42797 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040822 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0035455 infores:hetionet NCBIGene:29071 biolink:causes MONDO:0957495 infores:monarchinitiative not_provided not_provided HGNC:24338 MONDO:0957495 uuid:268936c7-5e3f-42ce-a7b6-a2d151ad51ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0302295 infores:hetionet CHEBI:15544 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020615 infores:hetionet CHEBI:31348 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003811 infores:hetionet CHEBI:6887 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0728899 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0853700 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0522172 infores:hetionet CHEBI:3699 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0015967 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0042075 infores:hetionet CAID:CA119178 biolink:causes MONDO:0020367 infores:clingen CAID:CA119178 MONDO:0020367 PMID:15069026 Likely Pathogenic PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS1, PS2, BA1, BP4 The c.1267A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Glutamic Acid at amino acid 423 (p.Lys423Glu). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.876, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Lys423Glu protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 80 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12860809, 9697688), which fulfilled PP1_Strong (≥7 meioses in >1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 12189160, 12860809, 9697688), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119178/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49603 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0917801 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0085584 infores:hetionet CHEBI:3216 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0424790 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0041657 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0004936 infores:hetionet CHEBI:465284 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0030201 infores:hetionet CHEBI:46557 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0039231 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0006285 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0948594 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0027441 infores:hetionet CAID:CA120639 biolink:causes MONDO:0044970 infores:clingen CAID:CA120639 MONDO:0044970 PMID:14705112 Pathogenic PS3_Supporting, PM2_Supporting, PM6_Strong, PP3, PP1, PS4 PM5, PM4, BS2, BA1, BP2, PS1, PVS1, BS1, BS3, BS4, BP7, BP5 The m.10158T>C (p.S34P) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood and who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or lactic acidosis (PS4; PMID: 14705112; PMID: 14684687; PMID: 27348141; PMID: 28050007; PMID: 27742419; PMID: 28916229; PMID: 14764913; PMID: 22115768; PMID: 15576045; PMID: 30128709; PMID: 29237403; PMID: 31178082; https://doi.org/10.1111/ncn3.17). This variant has been identified as a de novo occurrence in at least seven probands with primary mitochondrial disease (PM6_strong; PMID: 28916229; PMID: 14764913; PMID: 14705112; PMID: 14684687; PMID: 31178082). This variant segregated with disease in multiple members in at least two families (PP1; PMID: 27742419; PMID: 14705112) and one healthy mother was found to have the variant at low heteroplasmy level (PMID: 14705112). This variant is absent from Mitomap's GenBank sequences and gnomAD v3.1.2 (PM2_Supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies showed tight correlation between variant heteroplasmy level and complex I activity (PS3_supporting; PMID: 14705112). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM6_strong, PP1, PP3). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120639/MONDO:0044970/014 2021-10-26 2021-10-26 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:73275 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0007222 infores:hetionet UNII:R15UI3245N biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0011603 infores:hetionet CHEBI:50729 biolink:causes UMLS:C1096403 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C1096403 infores:hetionet CHEBI:31236 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0687713 infores:hetionet CHEBI:5384 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0239571 infores:hetionet CHEBI:63624 biolink:causes NCIT:C78341 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0522067 infores:hetionet CHEBI:31624 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0013378 infores:hetionet CHEBI:45081 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0015672 infores:hetionet CHEBI:7640 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C1368065 infores:hetionet CHEBI:17688 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0015672 infores:hetionet CHEBI:47657 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0013395 infores:hetionet NCBIGene:10161 biolink:causes MONDO:0010206 infores:monarchinitiative not_provided not_provided HGNC:15520 MONDO:0010206 uuid:e4f84d68-41f0-432e-9192-84350acb43ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes HP:0005101 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0018780 infores:hetionet CHEBI:94449 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0022107 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0086543 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0002792 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001405 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1384589 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0027769 infores:hetionet CHEBI:101278 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C3665347 infores:hetionet NCBIGene:4598 biolink:causes MONDO:0012481 infores:monarchinitiative not_provided not_provided HGNC:7530 MONDO:0012481 uuid:fd579ad6-3266-4035-a7df-b4554c9a5c5b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0004604 infores:hetionet CHEBI:31705 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C3160741 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0948525 infores:hetionet CHEBI:3437 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0423153 infores:hetionet CHEBI:175901 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0009782 infores:hetionet CHEBI:8214 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0027497 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233494 infores:hetionet CHEBI:7959 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0030807 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0232498 infores:hetionet NCBIGene:2528 biolink:causes MONDO:0013462 infores:monarchinitiative not_provided not_provided HGNC:4017 MONDO:0013462 uuid:c6d45868-da61-4f78-a71c-083bda5d87d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233407 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0424605 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085606 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0025061 infores:hetionet CHEBI:10102 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020578 infores:hetionet NCBITaxon:1463975 biolink:causes MONDO:0004584 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1463975 MONDO:0004584 CHEBI:6067 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011991 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027441 infores:hetionet CAID:CA410147492 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147492 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1291C>G (p.Pro431Ala) is a missense variant which has a REVEL score < 0.50 (0.165) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147492/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:134991 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0034150 infores:hetionet CHEBI:617099 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0003862 infores:hetionet CHEBI:9667 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013378 infores:hetionet CHEBI:8212 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0037036 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0032285 infores:hetionet CHEBI:32293 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0018681 infores:hetionet CHEBI:48273 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0014591 infores:hetionet NCBIGene:51083 biolink:causes MONDO:0014650 infores:monarchinitiative not_provided not_provided HGNC:4114 MONDO:0014650 uuid:9c718f0e-fe60-403b-b096-e6a0ba2cfb2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0234146 infores:hetionet CAID:CA387460663 biolink:causes MONDO:0019497 infores:clingen CAID:CA387460663 MONDO:0019497 PMID: Uncertain Significance PM2_Supporting BP5, BP7, BS1, BS3, BS4, PP1, PP4, PP3, PP2, BS2, PM5, PM4, PM3, PM1, PVS1, PM6, BP3, BP4, BP1, BP2, BA1, PS1, PS3, PS4, PS2 The NM_004004.6:c.677T>A variant in GJB2 is a missense variant predicted to cause substitution of valine by aspartic acid at amino acid 226 (p.Val226Asp). The variant was absent from gnomAD v2.1.1 meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.57 (PP3/BP4 not met). This variant has been identified in a heterozygous state in one individual with sensorineural hearing loss (PMID: 20201936). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 8/22/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387460663/MONDO:0019497/005 2023-08-22 2024-01-10 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:9168 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0740394 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0003864 infores:hetionet CHEBI:75045 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0743400 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009938 infores:hetionet CHEBI:3996 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0231528 infores:hetionet CHEBI:10101 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0043349 infores:hetionet CHEBI:9168 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020461 infores:hetionet CHEBI:6950 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0086439 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151828 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013395 infores:hetionet CHEBI:85078 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0041969 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037195 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0021053 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0017675 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040409 infores:hetionet CHEBI:71255 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0392156 infores:hetionet CHEBI:3723 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0086769 infores:hetionet CHEBI:75984 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0027497 infores:hetionet CHEBI:194135 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0007820 infores:hetionet CHEBI:47657 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0004093 infores:hetionet CAID:CA4432923 biolink:causes MONDO:0010134 infores:clingen CAID:CA4432923 MONDO:0010134 PMID: Benign BP7, BP4, BA1 The filtering allele frequency (the lower threshold of the 95% CI of 1456/25104) of the c.1708-18T>A variant in the SLC26A4 gene is 5.55% for European (Finnish) chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). This silent variant in SLC26A4 is not predicted by the computational prediction analysis using MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP7, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA4432923/MONDO:0010134/005 2020-03-18 2020-03-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA2918450 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918450 MONDO:0015152 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_000232.5: c.249A>G p.(Thr83=) variant in SGCB is a synonymous (silent) variant that is not predicted to influence splicing by SpliceAI (score 0) (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0005227 (16/30612 exome alleles) in the East Asian population (PM2_Supporting, BS1, BA1 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918450/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8382 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0240417 infores:hetionet CHEBI:5130 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0009421 infores:hetionet CHEBI:64312 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0024305 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0009450 infores:hetionet NCBIGene:3034 biolink:causes MONDO:0009345 infores:monarchinitiative not_provided not_provided HGNC:4806 MONDO:0009345 uuid:ad6576e8-642d-4ce7-b226-9508014cec38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23149 biolink:causes MONDO:0030898 infores:monarchinitiative not_provided not_provided HGNC:29002 MONDO:0030898 uuid:1b03aad4-2a4d-4de6-bb2d-aa05a99881a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231425 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0042023 infores:hetionet CHEBI:10124 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0036974 infores:hetionet CHEBI:50692 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0015967 infores:hetionet CHEBI:29007 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0017672 infores:hetionet CHEBI:9943 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0039070 infores:hetionet CAID:CA308129882 biolink:causes MONDO:0018493 infores:clingen CAID:CA308129882 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 3290 of the RYR1 protein, p.(Glu3290Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual had a second variant of uncertain significance in RYR1 (p.Glu2880Lys), PS4 not implemented (PMID:19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.848 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: None. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308129882/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0149745 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0687707 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011053 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0022104 infores:hetionet GO:2000235 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:2000235 GO:0032774 CHEBI:8774 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0020517 infores:hetionet CHEBI:3219 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0021177 infores:hetionet CHEBI:4562 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C2830004 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853875 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0036572 infores:hetionet CHEBI:3638 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0340865 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0010037 infores:hetionet CHEBI:4511 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0235032 infores:hetionet CHEBI:3387 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0221269 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0281981 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0025061 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1504422 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1504422 infores:hetionet CHEBI:10102 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151766 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0595883 infores:hetionet CHEBI:66913 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0009450 infores:hetionet CHEBI:8024 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0947912 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0042373 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042075 infores:hetionet CHEBI:5818 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0549249 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0020517 infores:hetionet CHEBI:4672 biolink:causes HP:0011032 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C2364164 infores:hetionet CHEBI:3398 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0043144 infores:hetionet CHEBI:63629 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C1609512 infores:hetionet NCBIGene:6521 biolink:causes MONDO:0012700 infores:monarchinitiative not_provided not_provided HGNC:11027 MONDO:0012700 uuid:b089afae-6779-4fbb-bab0-66f70d6f0066 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9430ZR8ZAN biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0004093 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0019158 infores:hetionet CHEBI:7454 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0042963 infores:hetionet CHEBI:6129 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020458 infores:hetionet NCBIGene:2706 biolink:causes MONDO:0009076 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0009076 uuid:4d898522-b0b0-4632-9b27-f84d52d4dc54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231594 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0149931 infores:hetionet CHEBI:28864 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0020598 infores:hetionet NCBITaxon:12939 biolink:causes MONDO:0005989 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12939 MONDO:0005989 CHEBI:6062 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0009450 infores:hetionet CHEBI:3082 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0558489 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C1112470 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C1112470 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009806 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0009450 infores:hetionet CHEBI:61049 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085633 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0030578 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006277 infores:hetionet CHEBI:3757 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0012833 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1392046 infores:hetionet CHEBI:64355 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085681 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0027441 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0020651 infores:hetionet CHEBI:61033 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151604 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0027769 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0155169 infores:hetionet NCBIGene:5188 biolink:causes MONDO:0030007 infores:monarchinitiative not_provided not_provided HGNC:8849 MONDO:0030007 uuid:4a535dd5-1c4e-48aa-9b99-442a7b64b9dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0233414 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0002170 infores:hetionet CHEBI:72690 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0015672 infores:hetionet CHEBI:6538 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0002994 infores:hetionet CHEBI:16714 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0151740 infores:hetionet CHEBI:188986 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0234632 infores:hetionet CHEBI:10119 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0026821 infores:hetionet CHEBI:37941 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C3665346 infores:hetionet CHEBI:7627 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0002453 infores:hetionet CHEBI:8707 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030232 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0267792 infores:hetionet CHEBI:50924 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0033774 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0162429 infores:hetionet UNII:U6XF9NP8HM biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0036104 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0020538 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0030554 infores:hetionet NCBIGene:9451 biolink:causes MONDO:0009192 infores:monarchinitiative not_provided not_provided HGNC:3255 MONDO:0009192 uuid:cdcace7d-839c-49da-b22d-0e950387123c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5801 biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0344375 infores:hetionet CHEBI:6539 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0011206 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0006840 infores:hetionet CHEBI:3176 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0027424 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0234458 infores:hetionet NCBIGene:54332 biolink:causes MONDO:0012014 infores:monarchinitiative not_provided not_provided HGNC:15968 MONDO:0012014 uuid:08e11650-c9ec-45e0-82ec-37dbfee50eb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5551 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0022650 infores:hetionet CHEBI:68478 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027497 infores:hetionet CHEBI:4636 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0003123 infores:hetionet CHEBI:44032 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0232461 infores:hetionet CHEBI:2666 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0019158 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0014457 infores:hetionet CHEBI:9720 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0235146 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0017160 infores:hetionet CHEBI:52010 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0042023 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040485 infores:hetionet CHEBI:49668 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0000737 infores:hetionet CHEBI:94686 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0018681 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022573 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0853348 infores:hetionet CHEBI:4975 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0702166 infores:hetionet CHEBI:9649 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0036974 infores:hetionet CHEBI:8888 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0015967 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0152227 infores:hetionet CHEBI:135930 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0015230 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1268766 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0150450 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0003615 infores:hetionet CHEBI:72297 biolink:causes UMLS:C1142086 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C1142086 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235653 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235653 infores:hetionet CHEBI:8768 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013378 infores:hetionet CHEBI:76607 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0027765 infores:hetionet CHEBI:4551 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0009676 infores:hetionet CHEBI:3636 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0013144 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0687133 infores:hetionet UMLS:C2607955 biolink:causes GO:0008219 infores:drugmechdb knowledge_assertion manual_agent UMLS:C2607955 GO:0008219 DB00078_MESH_D008224_1 CHEBI:75984 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0427108 infores:hetionet CHEBI:7476 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0041657 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0151888 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0849918 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0178298 infores:hetionet CHEBI:94392 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0008031 infores:hetionet CHEBI:32315 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0024902 infores:hetionet CHEBI:2682 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0026766 infores:hetionet NCBITaxon:1980519 biolink:causes MONDO:0020501 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1980519 MONDO:0020501 CHEBI:17334 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020458 infores:hetionet NCBIGene:2019 biolink:causes MONDO:0030979 infores:monarchinitiative not_provided not_provided HGNC:3342 MONDO:0030979 uuid:d50b9f2e-860b-4565-817b-7aed6b9ed84f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0038525 infores:hetionet NCBIGene:847 biolink:causes MONDO:0013571 infores:monarchinitiative not_provided not_provided HGNC:1516 MONDO:0013571 uuid:127bbc87-848c-47b2-a354-aaa2b78405ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7954 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0917801 infores:hetionet CHEBI:10125 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0231218 infores:hetionet CHEBI:37941 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0015672 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0003469 infores:hetionet CAID:CA405683571 biolink:causes MONDO:0007783 infores:clingen CAID:CA405683571 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of histidine with asparagine at codon 382 of the RYR1 protein, p.(His382Asn). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:19346234). This variant segregates with MHS in two individuals, PP1 not implemented ( PMID: 19346234). An ex vivo assay in lymphoblasts from a single patient showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.739 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405683571/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3175 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0035243 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0234458 infores:hetionet CHEBI:71941 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0043094 infores:hetionet CHEBI:8764 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007398 infores:hetionet CHEBI:47780 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085583 infores:hetionet CHEBI:101853 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0001824 infores:hetionet CHEBI:5123 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0022354 infores:hetionet NCBIGene:23218 biolink:causes MONDO:0007686 infores:monarchinitiative not_provided not_provided HGNC:31928 MONDO:0007686 uuid:8c3ce33e-ca46-498f-a817-8eb4a5c2c924 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6965 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0037763 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042790 infores:hetionet GO:0048209 biolink:causes GO:0048193 infores:ubergraph knowledge_assertion manual_agent GO:0048209 GO:0048193 CHEBI:36791 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002453 infores:hetionet CHEBI:2904 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0004238 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0010200 infores:hetionet CHEBI:31705 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085612 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0243065 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0497365 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0023218 infores:hetionet CHEBI:8707 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0702166 infores:hetionet CHEBI:63623 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0027947 infores:hetionet NCBIGene:488 biolink:causes MONDO:0007048 infores:monarchinitiative not_provided not_provided HGNC:812 MONDO:0007048 uuid:dc40e809-47db-4b93-b0b0-db11f4e795e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes UMLS:C1740836 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1740836 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0024115 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0042109 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0036572 infores:hetionet CHEBI:6128 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0036974 infores:hetionet GO:0090210 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0090210 GO:0007417 CHEBI:63617 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020456 infores:hetionet NCBITaxon:121759 biolink:causes MONDO:0005894 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:121759 MESH:D010229 DB01026_MESH_D010229_1 CHEBI:2955 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0232462 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017574 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009450 infores:hetionet CHEBI:23765 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013447 infores:hetionet CHEBI:10023 biolink:causes HP:0025066 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0221265 infores:hetionet CHEBI:63791 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0497156 infores:hetionet CHEBI:6539 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0018790 infores:hetionet CHEBI:45409 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C3665347 infores:hetionet CHEBI:53760 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011603 infores:hetionet CHEBI:83804 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085631 infores:hetionet CHEBI:8805 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0002962 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0948594 infores:hetionet CHEBI:42944 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0428974 infores:hetionet NCBIGene:4929 biolink:causes MONDO:0859257 infores:monarchinitiative not_provided not_provided HGNC:7981 MONDO:0859257 uuid:68ef37f6-f982-4cc5-9cb0-bf39eb288dc8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0006840 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0015397 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0233472 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0267792 infores:hetionet CHEBI:4911 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0023066 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0241164 infores:hetionet NCBIGene:10273 biolink:causes MONDO:0014339 infores:monarchinitiative not_provided not_provided HGNC:11427 MONDO:0014339 uuid:643c3629-16b4-4d0a-a1cf-d8f6bc62705a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3044 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0042109 infores:hetionet CHEBI:9398 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0004238 infores:hetionet CHEBI:32139 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0233407 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151849 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004681 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0751265 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0474381 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1096267 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1096267 infores:hetionet CHEBI:92712 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0023066 infores:hetionet NCBIGene:9319 biolink:causes MONDO:0054736 infores:monarchinitiative not_provided not_provided HGNC:12307 MONDO:0054736 uuid:a553e31f-96fb-46b2-94f7-1f33faa4a646 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013491 infores:hetionet NCBIGene:474 biolink:causes MONDO:0859528 infores:monarchinitiative not_provided not_provided HGNC:797 MONDO:0859528 uuid:2e5d9f21-2801-495d-b834-e20a01af0fcb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91541 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0241705 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0036572 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0232492 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0851578 infores:hetionet CHEBI:63791 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018944 infores:hetionet CHEBI:82960 biolink:causes NCIT:C78440 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0578050 infores:hetionet CHEBI:82941 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0027121 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0007222 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009450 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0233494 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020651 infores:hetionet CHEBI:10650 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0022281 infores:hetionet CHEBI:27882 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0000729 infores:hetionet CHEBI:135925 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0011124 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0020649 infores:hetionet CAID:CA9870243 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870243 MONDO:0015967 PMID: Likely Benign BP4, BP7 PM2, BS1 The c.408G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 136 (p.(Ala136=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -1.087, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.408G>A variant in gnomAD v2.1.1 is 0.00002619, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.408G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870243/MONDO:0015967/085 2023-01-12 2023-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119915 biolink:causes UMLS:C0919599 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0919599 infores:hetionet CAID:CA413496034 biolink:causes MONDO:0010315 infores:clingen CAID:CA413496034 MONDO:0010315 PMID: Uncertain Significance PM2_Supporting The c.655T>C (NM_000206.3) variant in IL2RG is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 219 (p.Tyr219His).This variant is absent from gnomAD v4.1.0 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/IL2RG-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413496034/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:2260 biolink:causes MONDO:0008150 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0008150 uuid:05da30d0-77f6-453d-830a-beb00220e4dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0014868 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0025061 infores:hetionet CHEBI:50777 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0004093 infores:hetionet CHEBI:3698 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0015230 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2937358 infores:hetionet CHEBI:8356 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014335 infores:hetionet CHEBI:84050 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0001824 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0027051 infores:hetionet CHEBI:28148 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0042487 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0853662 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0853662 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0007097 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0948807 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0085584 infores:hetionet CHEBI:66964 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0043352 infores:hetionet NCBITaxon:5833 biolink:causes MONDO:0005920 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5833 MESH:D016778 DB00263_MESH_D016778_1DB00468_MESH_D016778_1DB13132_MESH_D016778_1DB01131_MESH_D016778_1DB00608_MESH_D016778_1DB01218_MESH_D016778_1DB12975_MESH_D016778_2DB01117_MESH_D016778_1DB12975_MESH_D016778_1DB09274_MESH_D016778_1DB01611_MESH_D016778_1DB06708_MESH_D016778_1DB00468_MESH_D016778_2 CHEBI:17823 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0027709 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0020517 infores:hetionet CHEBI:10125 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151786 infores:hetionet CHEBI:7577 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013604 infores:hetionet GO:2000826 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000826 GO:0007275 CHEBI:8768 biolink:causes MONDO:0002356 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030286 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018799 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151602 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0243026 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1458155 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020550 infores:hetionet CHEBI:41879 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0085633 infores:hetionet CHEBI:5778 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0232461 infores:hetionet CHEBI:6775 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0019080 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0027051 infores:hetionet CHEBI:2788 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0041834 infores:hetionet CHEBI:31859 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042029 infores:hetionet CHEBI:31705 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0232286 infores:hetionet CAID:CA120206 biolink:causes MONDO:0015967 infores:clingen CAID:CA120206 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, BS2, PP1_Strong, BP5, BS1 PM1, PS4 The c.340C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 114 (p.(Arg114Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000074, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in over 80 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 27486234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with 31 informative meioses (PP1_Strong; internal lab contributors). This variant was identified in at least 3 nondiabetic individuals >70 years old, and the expected penetrance for HNF4A-monogenic diabetes is 95% by age 70 (BS2; PMID: 9313765. internal lab contributors) (BS2). This variant was identified in five individuals with an alternate molecular basis for disease, including two siblings with the HNF1A variant NM_000545.8:c872dup (p.Gly292fs*25) (BP5; PMID: 2351881, internal lab contributors). This variant has previously been considered to be pathogenic for a low penetrance form of MODY, and reporting has been of clinical utility for considering treatment with sulfonylureas, which have ~48% effectiveness in individuals with this variant (PMID: 27486234). In summary, c.340C>T meets phenotype, segregation, and computational criteria to be classified as likely pathogenic. While adding its population frequency, penetrance, and co-occurrence (which may have synergistic impact) criteria would lead to a likely benign classification, the MDEP consensus is that this should be considered a reportable likely pathogenic variant with reduced penetrance that may respond to sulfonylurea treatment. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BS2, PP1_Strong, BP5, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA120206/MONDO:0015967/085 2023-12-02 2023-12-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0043352 infores:hetionet CHEBI:66899 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0314719 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037199 infores:hetionet CHEBI:10125 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0855775 infores:hetionet CHEBI:77032 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0027497 infores:hetionet CAID:CA1442820 biolink:causes MONDO:0100084 infores:clingen CAID:CA1442820 MONDO:0100084 PMID: Benign BA1, BP4, BP7 The NM_001100.4:c.617-5C>T variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 4. The population filtering allele frequency in gnomAD v4.1.0 is 0.01304 (1030/75010 alleles) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The results from the in silico predictor, SpliceAI, suggest that the variant does not impact ACTA1 function and it occurs at a nucleotide that is not conserved as shown by the UCSC Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1442820/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9316 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0042075 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0233472 infores:hetionet CAID:CA115930 biolink:causes MONDO:0700270 infores:clingen CAID:CA115930 MONDO:0700270 PMID: Pathogenic PS3_Moderate, PM3_Very Strong, PS4, PP3, PP1 PM2, PP4 The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI ≥1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA115930/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135930 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0042373 infores:hetionet CAID:CA367403522 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403522 MONDO:0015967 PMID: Likely Pathogenic PM5, PP4_Moderate, PP2, PM2_Supporting PM1, PP3, PP1, BP4 The c.113A>T variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to leucine at codon 38 (p.(Gln38Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.657, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID: 24550216, internal lab contributors). This variant segregated with hyperglycemia with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 24550216, internal lab contributors). Another missense variant, c.113A>C p.Gln38Pro, has been interpreted as pathogenic by the ClinGen MDEP, and p.Gln38Leu has a greater Grantham distance (PM5). In summary, c.113A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM5, PP2, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403522/MONDO:0015967/086 2024-01-05 2024-01-05 Semidominant inheritance HP:0032113 Supports CHEBI:5132 biolink:causes MONDO:0024879 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C1384494 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0011991 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235146 infores:hetionet CHEBI:8069 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0428977 infores:hetionet CAID:CA410147387 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147387 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, BA1, BP1, BP3, BP2, BS1, BS3, PM4, PM3, PP4, PP2, PP3 NM_001754.5(RUNX1):c.1318G>C (p.Ala440Pro) is a missense variant which has a REVEL score < 0.50 (0.085) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147387/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5001 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0006852 infores:hetionet CHEBI:50729 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0027497 infores:hetionet CHEBI:8228 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0002962 infores:hetionet CHEBI:6970 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0002792 infores:hetionet CAID:CA038064 biolink:causes MONDO:0007750 infores:clingen CAID:CA038064 MONDO:0007750 PMID: Uncertain Significance PP3 PS4, PM2, PP4 The NM_000527.5(LDLR):c.1988-5C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PP3: No REVEL. Splicing evaluation required. Functional data on splicing not available. Variant is located at -20 to +3 bases from canonical acceptor splice site. MES scores: variant score = 7.59; wt score = 15.87. Ratio var score/wt score = 0.478. It is below 0.8 so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038064/MONDO:0007750/013 2025-01-31 2025-03-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7936 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085636 infores:hetionet CHEBI:8772 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0006277 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0027497 infores:hetionet CHEBI:5001 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027121 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004936 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0022660 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0002871 infores:hetionet GO:1903059 biolink:causes GO:0042158 infores:ubergraph knowledge_assertion manual_agent GO:1903059 GO:0042158 CHEBI:49575 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0034880 infores:hetionet CHEBI:75722 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0000737 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0015376 infores:hetionet CHEBI:37941 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0235490 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020538 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0233571 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0032285 infores:hetionet NCBIGene:4719 biolink:causes MONDO:0032610 infores:monarchinitiative not_provided not_provided HGNC:7707 MONDO:0032610 uuid:866d69a3-d929-4005-a0a1-a9ed9b5a1ffc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5050 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0013395 infores:hetionet CHEBI:5165 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085631 infores:hetionet CHEBI:53760 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0242301 infores:hetionet CHEBI:29013 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0151827 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010692 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011334 infores:hetionet CHEBI:68554 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0020458 infores:hetionet UNII:9YCX42I8IU biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0919671 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0029882 infores:hetionet CHEBI:4356 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0041834 infores:hetionet CHEBI:3215 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0086439 infores:hetionet CHEBI:92998 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0023518 infores:hetionet CHEBI:60761 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0235146 infores:hetionet CHEBI:84883 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0085595 infores:hetionet CAID:CA399804402 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804402 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting BS1, PM5, BA1, BP4 The ITGA2B missense variant NM_000419.5:c.1139G>T replaces the glycine residue with a valine residue (p.Gly380Val). This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT28, PMID: 16463284; PM3_supporting). All requirements for PP4_Moderate are met (GT28 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is absent from gnomADv4.0 (PM2_supporting) and the in silico meta-predictor REVEL score for this variant is 0.853, exceeding the VCEP-established threshold of ≥0.7 and suggestive of a damaging effect on protein function (PP3). Another missense change at this amino acid codon has been observed (c.1139G>A (p.Gly380Asp), Patient GM in PMID: 12083483) and classified as uncertain significance by the Platelet Disorders VCEP. In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PP4_moderate, PM2_supporting, PM3_supporting, and PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804402/MONDO:0100326/011 2024-04-16 2024-04-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA16615993 biolink:causes MONDO:0018875 infores:clingen CAID:CA16615993 MONDO:0018875 PMID:29979965PMID:12826609PMID:30224644 Likely Benign BP4, BS3, PM2_Supporting PS3, PS1, PS4, PS2, PM1, PM5, BS4, BS2, PP3, PP1, PP4 The NM_000546.6: c.875A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 292 (p.Lys292Arg). This variant has an allele frequency of 6.196e-7 (1/1614016 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.00998; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.2; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615993/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63638 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0344232 infores:hetionet CHEBI:31705 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0687713 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0743516 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0743516 infores:hetionet CHEBI:4315 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0018378 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0403632 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0003123 infores:hetionet CHEBI:168396 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013447 infores:hetionet CHEBI:3387 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0264886 infores:hetionet CHEBI:3216 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0004604 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0409974 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0010346 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0001969 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0001969 infores:hetionet GO:1904133 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0007399 CHEBI:5138 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0038663 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042109 infores:hetionet CHEBI:39585 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0017181 infores:hetionet CHEBI:8232 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0023530 infores:hetionet CHEBI:3398 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C1443060 infores:hetionet CHEBI:5558 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0039070 infores:hetionet CHEBI:50131 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151539 infores:hetionet UMLS:C0065374 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030193 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0037023 infores:hetionet CHEBI:144551 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0085631 infores:hetionet CHEBI:31397 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0264267 infores:hetionet CHEBI:3757 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0001807 infores:hetionet CAID:CA023827 biolink:causes MONDO:0007783 infores:clingen CAID:CA023827 MONDO:0007783 PMID:26115329 Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate, BS2_Supporting BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glycine with arginine at codon 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023827/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3504 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0014457 infores:hetionet CHEBI:51860 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151636 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018834 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0456677 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0456677 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0006849 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0013221 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013221 infores:hetionet CHEBI:37924 biolink:causes EFO:0008501 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0334044 infores:hetionet CAID:CA10576330 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576330 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PM5, PP4 The NM_000527.5(LDLR):c.2149G>A (p.Ala717Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.002229%) in East Asian exomes (gnomAD v4.1.0).BP4: REVEL = 0.384, it is below 0.50, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant does not create AG/GT. C) there is a AG nearby.MES scores: variant cryptic = -16.32. wt cryptic = -14.92. Canonical acceptor = 8.76. De novo score is negative, so it is not used. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576330/MONDO:0007750/013 2025-02-28 2025-04-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:45409 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0277925 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235431 infores:hetionet CHEBI:63577 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0033774 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0042790 infores:hetionet UMLS:C0145867 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020598 infores:hetionet CHEBI:50924 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0017675 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0332575 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0002453 infores:hetionet CHEBI:16467 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0521591 infores:hetionet CHEBI:63627 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0003862 infores:hetionet CHEBI:8871 biolink:causes MONDO:0011479 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1299624 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0035232 infores:hetionet CHEBI:45951 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0242422 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0020517 infores:hetionet CHEBI:15367 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003537 infores:hetionet NCBIGene:84189 biolink:causes MONDO:0009082 infores:monarchinitiative not_provided not_provided HGNC:23503 MONDO:0009082 uuid:6d7a7f80-743f-4382-9394-bc045a3009ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0242350 infores:hetionet CHEBI:194135 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0231835 infores:hetionet CHEBI:8890 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0700590 infores:hetionet CHEBI:188986 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0235266 infores:hetionet CAID:CA229789 biolink:causes MONDO:0009861 infores:clingen CAID:CA229789 MONDO:0009861 PMID:24705691PMID:20123475PMID:24705691PMID:20123475 Pathogenic PM5, PP4_Moderate, PM2, PP3, PM3_Strong The c.823C>T (p.Pro275Ser) variant in PAH is absent from all population databases, and is in the same codon as two other likely pathogenic variants. In silico algorithms agree on a damaging effect. It has been identified in trans with two independent pathogenic variants (R408W and c.669delC; PMID: 20123475, 24705691), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in multiple patients. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229789/MONDO:0009861/006 2018-12-09 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8707 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0236075 infores:hetionet CHEBI:261649 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0232462 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0032227 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0278079 infores:hetionet CHEBI:9123 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C2129214 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0020538 infores:hetionet CHEBI:6078 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0013604 infores:hetionet CHEBI:3172 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0016382 infores:hetionet NCBIGene:8242 biolink:causes MONDO:0010355 infores:monarchinitiative not_provided not_provided HGNC:11114 MONDO:0010355 uuid:ea300a6d-9781-48da-a6b5-a8c6280b02d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0025323 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0851341 infores:hetionet CHEBI:119573 biolink:causes NCIT:C96935 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0149707 infores:hetionet CHEBI:8245 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0003467 infores:hetionet CAID:CA512341236 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341236 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1191A>G (p.Gln397=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341236/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3347 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C2830004 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0853019 infores:hetionet CHEBI:52717 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027497 infores:hetionet CHEBI:51141 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0042963 infores:hetionet CHEBI:4907 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0009806 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0234894 infores:hetionet CHEBI:82960 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0021368 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0243026 infores:hetionet CAID:CA229004 biolink:causes MONDO:0100326 infores:clingen CAID:CA229004 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000419.5(ITGA2B):c.798G>A (p.Trp266Ter) variant in exon 7 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 7 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is reported in ClinVar, but no phenotype data are available (SCV000120031.1, SCV000155134.1). This variant is also absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA229004/MONDO:0100326/011 2025-05-02 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3504 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0024282 infores:hetionet CHEBI:52717 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151786 infores:hetionet CHEBI:9086 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0235086 infores:hetionet NCBIGene:2775 biolink:causes MONDO:0014199 infores:monarchinitiative not_provided not_provided HGNC:4389 MONDO:0014199 uuid:267e5829-8b56-488d-abc4-b89d763dfcab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8814879 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814879 MONDO:0009290 PMID:21803581PMID:9196050PMID:21550241PMID:11071489PMID:30155607PMID:26873529PMID:28648663PMID:32248831 Pathogenic PVS1, PM2, PP4, PM3 This variant, c.482_483del (p.Pro161GlnfsTer15), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001836 in the European non-Finnish population, meeting PM2. Five individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, three are compound heterozygous for c.-32-13T>G (PMID 9196050, 26873529), one is compound heterozygous for c.-32-3C>A (PMID 21550241; a patient with a similar description is reported in PMIDs 30155607, 21803581), and the second variant was unidentified in the remaining patient (PMID 9196050). The phase of the variants is unknown in these cases. The in trans data for the patient who is compound heterozygous for c.-32-3C>A will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, PM3_Supporting is met. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831). There is a ClinVar entry for this variant (Variation ID: 596146, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814879/MONDO:0009290/010 2020-11-02 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6887 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0037199 infores:hetionet GO:0001754 biolink:causes CL:0000287 infores:ubergraph knowledge_assertion manual_agent GO:0001754 CL:0000287 CHEBI:9123 biolink:causes HP:0040307 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1112443 infores:hetionet CHEBI:50378 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0151827 infores:hetionet CHEBI:7447 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0231528 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0014457 infores:hetionet CHEBI:50223 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C2979982 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0235146 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0018801 infores:hetionet CHEBI:5613 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0233565 infores:hetionet CHEBI:7852 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0001973 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085584 infores:hetionet CHEBI:75722 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033774 infores:hetionet GO:1902119 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1902119 GO:0019953 CHEBI:51380 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0033774 infores:hetionet CHEBI:9445 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C2981158 infores:hetionet CHEBI:3219 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037384 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0851536 infores:hetionet CAID:CA2061617 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061617 MONDO:0015924 PMID: Likely Benign BS1 PM2, PP3, BS2, BA1, BP4, PS1, PM1, PM5 The NM_001204.7(BMPR2):c.2948G>A variant is a missense variant predicted to cause substitution of arginine to glutamine at amino acid position 983 (p.Arg983Gln). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.0034 (8/2358) in the Ashkenazi Jew population, which is higher than the ClinGen PH VCEP threshold (>0.1%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.4, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061617/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135342 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0031350 infores:hetionet CHEBI:7565 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0547030 infores:hetionet CHEBI:50648 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0162834 infores:hetionet CHEBI:33748 biolink:causes MONDO:0005481 infores:ubergraph knowledge_assertion manual_agent CHEBI:33748 MONDO:0005481 CHEBI:45652 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0018790 infores:hetionet CHEBI:3286 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0011991 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0595930 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0858833 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0858833 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0235792 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235792 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162429 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0948807 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0162830 infores:hetionet CHEBI:63635 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0852911 infores:hetionet CHEBI:93635 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0085631 infores:hetionet CHEBI:3013 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0003123 infores:hetionet GO:0039602 biolink:causes GO:0006367 infores:ubergraph knowledge_assertion manual_agent GO:0039602 GO:0006367 NCBIGene:80152 biolink:causes MONDO:0032875 infores:monarchinitiative not_provided not_provided HGNC:25787 MONDO:0032875 uuid:179f670e-2943-4556-a6da-d0497862077b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64028 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0012833 infores:hetionet CHEBI:52717 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019080 infores:hetionet CHEBI:94501 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151603 infores:hetionet CAID:CA024262 biolink:causes MONDO:0100150 infores:clingen CAID:CA024262 MONDO:0100150 PMID: Uncertain Significance PP3, PM2_Supporting The variant NM_000540.3:c.14815G>A in RYR1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 4939 (p.Asp4939Asn). The highest population minor allele frequency in gnomAD v4.1 is 0.00001562 (1/64012 alleles) for the European) non-Finnish population, meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.811, which is above the threshold necessary to apply PP3. Since this variant has not been noted in any probands, the mode of inheritance is unknown. In summary, this variant meets the criteria to be classified as uncertain significance for AD/AR RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3, PM2_Supporting. (Congenital Myopathies VCEP specifications version 2; 8/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024262/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94686 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0016655 infores:hetionet UNII:D27V6190PM biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0018681 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0233414 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0020538 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0854082 infores:hetionet CHEBI:55346 biolink:causes MONDO:0024388 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0009062 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152227 infores:hetionet CHEBI:48273 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0008031 infores:hetionet CHEBI:91541 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0018843 infores:hetionet CHEBI:404903 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0031154 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0000755 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0032987 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151735 infores:hetionet CHEBI:27306 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00165 UMLS:C0018681 infores:hetionet CHEBI:50841 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0232292 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0007222 infores:hetionet NCBIGene:54974 biolink:causes MONDO:0032923 infores:monarchinitiative not_provided not_provided HGNC:26053 MONDO:0032923 uuid:a5089d14-dcce-4c0c-8601-11712cbfda73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4903 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0030846 infores:hetionet CHEBI:41977 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0854467 infores:hetionet CHEBI:2666 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0013395 infores:hetionet CHEBI:6931 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0151799 infores:hetionet CHEBI:5134 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0004245 infores:hetionet CHEBI:47780 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033774 infores:hetionet CHEBI:36791 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028961 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015397 infores:hetionet CHEBI:47426 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0036974 infores:hetionet CHEBI:6437 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009676 infores:hetionet CHEBI:39585 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0004093 infores:hetionet CHEBI:27796 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0011991 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0948586 infores:hetionet CHEBI:6904 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0031212 infores:hetionet CHEBI:2682 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0041657 infores:hetionet CHEBI:2682 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085679 infores:hetionet CHEBI:29013 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0005940 infores:hetionet CHEBI:3698 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0009676 infores:hetionet CHEBI:5109 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0237849 infores:hetionet CAID:CA231406 biolink:causes MONDO:0044970 infores:clingen CAID:CA231406 MONDO:0044970 PMID: Uncertain Significance PP3, PM2 BS2, BP4 The c.3293 A>C (p.Asn1098Thr) variant in POLG is absent in population databases ExAC, gnomAD, 1000 Genomes, and ESP (PM2). Computational prediction tool Revel score is 0.953 (PP3). This variant has not been reported in the literature. In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA231406/MONDO:0044970/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5001 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0700225 infores:hetionet CHEBI:8863 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085593 infores:hetionet CHEBI:10127 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151576 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0853692 infores:hetionet CHEBI:4710 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0151905 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0002170 infores:hetionet CHEBI:8412 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0027765 infores:hetionet CHEBI:453011 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0037274 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005111 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0149678 infores:hetionet CHEBI:3636 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0042109 infores:hetionet CAID:CA16020965 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020965 MONDO:0009861 PMID:24301756PMID:21147011PMID:21147011 Pathogenic PVS1, PM2, PP4_Moderate PM3 The c.1200-2A>G variant in PAH is a null variant (canonical - 2 splice site); Loss of function is a known mechanism of disease, exon skipping disrupts reading frame and is predicted to undergo NMD (not located in last 50bp of preliminary exon). Coding exon 12/13 is present in biologically-relevant transcript. This variant has been reported in 2 individuals with PKU (BH4 deficiency excluded, PMID: 21147011, 24301756). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020965/MONDO:0009861/006 2020-08-10 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:70746 biolink:causes UMLS:C2242494 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C2242494 infores:hetionet CHEBI:15367 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235378 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0241164 infores:hetionet CHEBI:2453 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0917801 infores:hetionet CAID:CA16020839 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020839 MONDO:0009861 PMID:23357515PMID:23357515PMID:31208052 Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PP3_Moderate, PS3_Supporting The c.686A>G (p.Asp229Gly) variant in PAH has been reported in 1 individual with PAH deficiency, detected with pathogenic variant p.R408W (PMID: 23357515). This variant is absent in population databases. Computational evidence supports a deleterious effect (REVEL=0.922). Functional studies show the p.Asp229Gly mutant had 0% residual activity as compared to WT PAH activity and decreased protein levels (PMID: 31208052). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PP4, PM2_supporting, PM3_supporting, PP3_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020839/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42797 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0035243 infores:hetionet CHEBI:15940 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0017178 infores:hetionet CHEBI:71223 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0030312 infores:hetionet NCBIGene:5594 biolink:causes MONDO:0033669 infores:monarchinitiative not_provided not_provided HGNC:6871 MONDO:0033669 uuid:de26be71-5890-4004-8a6e-d20f1156de2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0010200 infores:hetionet CHEBI:63617 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004604 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0003864 infores:hetionet CHEBI:64312 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0424295 infores:hetionet CHEBI:9654 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0013404 infores:hetionet CHEBI:35854 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0558489 infores:hetionet CHEBI:50859 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0039070 infores:hetionet CHEBI:50648 biolink:causes HP:6000793 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0521172 infores:hetionet CHEBI:5893 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0030193 infores:hetionet CHEBI:5050 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0000737 infores:hetionet CHEBI:135342 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0011991 infores:hetionet CHEBI:3723 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1260922 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0032231 infores:hetionet CHEBI:63598 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0232462 infores:hetionet CAID:CA389474673 biolink:causes MONDO:0100040 infores:clingen CAID:CA389474673 MONDO:0100040 PMID: Likely Benign BP5, BS2, PM2_Supporting, BP4 The p.Pro76Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro76Leu variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Computational analysis prediction tools suggest that the p.Pro76Leu variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Pro76Leu variant in FOXG1 is absent from gnomAD v2.1.1 (PM2_supporting). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in multiple unaffected individuals and at least two individuals with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified this variant as likely benign (BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389474673/MONDO:0100040/035 2024-04-18 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135530 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0009450 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0011206 infores:hetionet NCBIGene:79621 biolink:causes MONDO:0012429 infores:monarchinitiative not_provided not_provided HGNC:25671 MONDO:0012429 uuid:0200f5b0-22ff-450d-8995-53071964b2c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0036974 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0027769 infores:hetionet CHEBI:68579 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018989 infores:hetionet CHEBI:9738 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0004093 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011609 infores:hetionet CHEBI:404903 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0237849 infores:hetionet CHEBI:5106 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0020580 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0027765 infores:hetionet CHEBI:66876 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0037763 infores:hetionet CHEBI:5296 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0231528 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0029408 infores:hetionet CHEBI:10112 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0013395 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0022116 infores:hetionet CAID:CA512232102 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232102 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1432A>C (p.Arg478=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.87) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232102/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:74947 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0001824 infores:hetionet CHEBI:9598 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0424605 infores:hetionet CHEBI:3001 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0152227 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0178298 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0272426 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0272426 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0156312 infores:hetionet CHEBI:3001 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0042109 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0852913 infores:hetionet CHEBI:6706 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0242350 infores:hetionet CHEBI:4495 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0011603 infores:hetionet CHEBI:92998 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0041657 infores:hetionet CHEBI:7581 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0009450 infores:hetionet CAID:CA377484997 biolink:causes MONDO:0017623 infores:clingen CAID:CA377484997 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PP1, PM2_Supporting, PS4_Supporting, PS2 PS3, PS1 PTEN c.752G>T (p.Gly251Val) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) ClinVar submitter ID 26957).PP3: REVEL score > 0.7 (score of this variant = 0.968).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (internal laboratory contributor(s) SCV002669136.2).PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (internal laboratory contributor(s) SCV002669136.2).PM2_P: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377484997/MONDO:0017623/003 2025-04-04 2025-06-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8346 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0018799 infores:hetionet CHEBI:6715 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042133 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040046 infores:hetionet CHEBI:6520 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0042963 infores:hetionet CHEBI:9316 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0151828 infores:hetionet CHEBI:37941 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0036974 infores:hetionet CHEBI:144551 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0039520 infores:hetionet CHEBI:42797 biolink:causes HP:0003487 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034935 infores:hetionet NCBIGene:55906 biolink:causes MONDO:0026762 infores:monarchinitiative not_provided not_provided HGNC:24931 MONDO:0026762 uuid:2b485d36-897c-48d4-b800-30bdab08afa8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0010200 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0012833 infores:hetionet CHEBI:2453 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0014518 infores:hetionet CAID:CA014494 biolink:causes MONDO:0005045 infores:clingen CAID:CA014494 MONDO:0005045 PMID: Pathogenic PM2, PP3, PP1_Strong, PS4 PS3, BA1, PM1, PM6, PM3, PM4, PM5, BS2, BS1, BS3, BS4, BP3, BP4, BP2, BP7, PS2, PS1 The NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met) variant in MYH7 has been reported in >30 individuals with HCM (PS4; Richard 2003 PMID: 12707239; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Millat 2010 PMID: 20624503; Witjas-Paalberends 2013 PMID: 23674513; Berge 2014 PMID: 24111713; Helms 2014 PMID: 25031304; Adler 2016 PMID: 26743238; Montag 2017 PMID: 29101517; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >10 affected relatives with HCM in at least 4 families (PP1_strong; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; LMM pers. comm.). This variant was identified in 0.0009% (1/113754) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM2; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014494/MONDO:0005045/002 2021-11-23 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:31286 biolink:causes MONDO:0021941 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:31286 MONDO:0021941 CHEBI:2922 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0017675 infores:hetionet CHEBI:2682 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0009676 infores:hetionet CHEBI:31625 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0022568 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0011849 infores:hetionet CHEBI:36795 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0002994 infores:hetionet CAID:CA320603666 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603666 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS2, PS3, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1 This synonymous variant is predicted by SSF, MES, and SpliceAI to lead to either no change/an increase/a decrease by no more than 10% in the canonical splice site score and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score = 0.975787 in GRCh37/1.06724 in GRCh38 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603666/MONDO:0011071/008 2021-06-25 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28593 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0020615 infores:hetionet CHEBI:6950 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0497156 infores:hetionet NCBIGene:51651 biolink:causes MONDO:8000012 infores:monarchinitiative not_provided not_provided HGNC:24265 MONDO:8000012 uuid:8eeaeced-1ad5-44c9-8365-2cab44e8ae5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28364 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0013378 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0043352 infores:hetionet CHEBI:63617 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0086439 infores:hetionet CHEBI:37941 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019080 infores:hetionet CHEBI:4710 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0016655 infores:hetionet CHEBI:84500 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0236075 infores:hetionet CAID:CA8423917 biolink:causes MONDO:0019497 infores:clingen CAID:CA8423917 MONDO:0019497 PMID: Likely Benign BS2, BS1_Supporting PM3, BP4 The c.4497G>T variant in MYO15A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 1499. The filtering allele frequency of this variant in gnomAD v4.1 is 0.1325% in the Admixed American population, which is higher than the ClinGen Hearing Loss threshold of 0.07% for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.448, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO15A function (BP4 and PP3 not met). This variant has been identified in 1 proband with hearing loss with a variant of uncertain significance suspected in trans (Partners LMM internal data SCV000711130.2). The variant has also been detected in the homozygous state in three unaffected parents (BS2; GeneDx internal data SCV001982245.2). In summary, this variant meets criteria to be classified as likely benign for autosomal recessive nonsyndromic hearing based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8423917/MONDO:0019497/023 2025-03-12 2025-04-22 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf true CHEBI:3175 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0085624 infores:hetionet CHEBI:4995 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0042024 infores:hetionet CHEBI:30659 biolink:causes MONDO:0006809 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0007780 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042267 infores:hetionet CAID:CA412731451 biolink:causes MONDO:0100437 infores:clingen CAID:CA412731451 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2101G>T (p.Glu701Ter) is a nonsense variant introducing a premature stop in codon 701 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in a submission to the Leiden Open Variation Database (LOVD 3.0) as a disease-causing variant (DB-ID RPGR_000065), however, no affected individual was described meeting one of the PS4 requirements of some functional vision impairment in an affected male by age 30 years, or decreased or absent electroretinogram responses, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412731451/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:31536 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0015672 infores:hetionet CAID:CA404086021 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086021 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM3, PP1_Moderate, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, BS2 The NM_000527.5(LDLR):c.1436T>A (p.Leu479Gln) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD v4.0.0.PP3: REVEL= 0.938.PS4_Supporting, PP4: Identified in two index cases who fulfil FH criteria, reported in PMID 33732287 (Moradi et al., 2021; LDLC 391 mg/dl at age of 24 years) and PMID 29213121 (Fairoozy et al., 2017; LDL-C 15 mmol/L at age of 15 years). Both index cases are homozygous for the variant.PP1_Moderate: Variant segregates with FH phenotype in five informative meiosis in two families, the affected relatives are positive for the variant, reported in PMID 33732287 and 29213121.PM3: Variant observed in a true homozygous case who had HoFH phenotype with LDLC of 15 mmol/L, reported in PMID 29213121. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086021/MONDO:0007750/013 2024-02-23 2025-02-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:32315 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0232459 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0008489 infores:hetionet CAID:CA915940728 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940728 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The ITGB3 frameshift variant NM_000212.3:c.153del (p.Trp51CysfsTer16) introduces a frameshift in exon 2 of 15 total exons and a premature termination codon in exon 3. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT07, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM3_Supporting, PP4_Moderate, and PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940728/MONDO:0100326/011 2021-07-14 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5098 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0006840 infores:hetionet CHEBI:29007 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0022346 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003864 infores:hetionet CHEBI:8869 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0151766 infores:hetionet CHEBI:9168 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0041657 infores:hetionet CAID:CA16020841 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020841 MONDO:0009861 PMID:28982351 Pathogenic PM2, PVS1, PP4 This c.690_691insG (p.Ser231ValfsTer?) variant in PAH was reported in one patient with Hyperphenylalaninemia (PMID: 28982351). This variant is absent from controls in population databases. This is a frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020841/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8356 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0347390 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015230 infores:hetionet CHEBI:6640 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0003123 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0018801 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0234987 infores:hetionet CHEBI:261649 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C1443060 infores:hetionet CHEBI:3499 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0030312 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0030312 infores:hetionet CAID:CA347212236 biolink:causes MONDO:0015152 infores:clingen CAID:CA347212236 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PS1_Supporting PM3 The NM_003494.4: c.1053+1G>C variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>C, occurs within the canonical splice donor site of intron 11 and is predicted to cause skipping of biologically relevant exon 11/55, resulting in a frameshift and premature truncation leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in one individual with features of LGMD, where it was observed in unknown phase with a likely pathogenic DYSF variant (NM_003494.4: c.4024C>T p.(Arg1342Trp), 0.25 pts, Jain Foundation Dysferlin Registry internal data communication) (PM3_Supporting not met). This patient had a clinical suspicion of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Another nucleotide change affecting the same splice donor dinucleotide position and with the same predicted splice effect, NM_003494.4: c.1053+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/17/2025): PVS1, PP4_Strong, PM2_Supporting, PS1_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347212236/MONDO:0015152/180 2025-04-17 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135342 biolink:causes HP:0003149 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0948643 infores:hetionet CHEBI:15940 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0019270 infores:hetionet CHEBI:63612 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0549249 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151828 infores:hetionet NCBIGene:79648 biolink:causes MONDO:0009617 infores:monarchinitiative not_provided not_provided HGNC:6954 MONDO:0009617 uuid:1c0235a3-00ab-4fbc-95c8-593fc5ee921d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5384 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0003862 infores:hetionet CHEBI:6761 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0002994 infores:hetionet CHEBI:8774 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0009763 infores:hetionet CHEBI:9649 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020598 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0012833 infores:hetionet CHEBI:135679 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0027497 infores:hetionet CHEBI:6121 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0009024 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0520893 infores:hetionet CHEBI:63621 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0003962 infores:hetionet CHEBI:50275 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151723 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0020517 infores:hetionet CHEBI:8764 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0036974 infores:hetionet CAID:CA16020790 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020790 MONDO:0009861 PMID:21147011PMID:15589814 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Supporting The c.443G>A (p.Gly148Asp) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 21147011, 15589814). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant IVS4nt5G>T (c.441+5G>T). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020790/MONDO:0009861/006 2020-01-26 2020-01-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8888 biolink:causes MONDO:1030008 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0026266 infores:hetionet CHEBI:3732 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0234238 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0000833 infores:hetionet CHEBI:61033 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0039070 infores:hetionet CHEBI:41423 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0744727 infores:hetionet CHEBI:3723 biolink:causes MONDO:0019098 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0920163 infores:hetionet CHEBI:36795 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0007859 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0948594 infores:hetionet CHEBI:474180 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0236075 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0234215 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0027765 infores:hetionet CHEBI:2611 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0027424 infores:hetionet CHEBI:50777 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0392171 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0746883 infores:hetionet NCBIGene:29927 biolink:causes MONDO:0958017 infores:monarchinitiative not_provided not_provided HGNC:18276 MONDO:0958017 uuid:66187ba8-31cf-4550-b492-480e6aae026f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50122 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0019158 infores:hetionet CHEBI:50730 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0037672 infores:hetionet GO:0044477 biolink:causes GO:0042060 infores:ubergraph knowledge_assertion manual_agent GO:0044477 GO:0042060 CHEBI:2379 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0007166 infores:hetionet CHEBI:45951 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0018790 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0010709 infores:hetionet GO:1901210 biolink:causes GO:0003206 infores:ubergraph knowledge_assertion manual_agent GO:1901210 GO:0003206 CHEBI:42797 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0699893 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0151436 infores:hetionet CHEBI:6129 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0239571 infores:hetionet CHEBI:16469 biolink:causes NCIT:C78694 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0567085 infores:hetionet CHEBI:31709 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0037763 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0017152 infores:hetionet CHEBI:44423 biolink:causes MONDO:0006795 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0020532 infores:hetionet CHEBI:3996 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0018524 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0013922 infores:hetionet CHEBI:3515 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0149514 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1527407 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0235431 infores:hetionet CHEBI:6690 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0085631 infores:hetionet CHEBI:8499 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0015230 infores:hetionet CAID:CA415166799 biolink:causes MONDO:0010726 infores:clingen CAID:CA415166799 MONDO:0010726 PMID: Likely Benign BS2 BP4, BA1, PM2, BS1, PP3 The p.Asp407Asn variant in MECP2 (NM_004992.4) is present in 3 XX and 1 XY individual(s) in gnomAD (0.002171%) (not sufficient to meet BS1 criteria). The p.Asp407Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Asp407Asn variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415166799/MONDO:0010726/036 2023-12-06 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:7903 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0332534 infores:hetionet CAID:CA409107570 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107570 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting PM1 The c.789G>C variant in the hepatocyte nuclear factor-4-alpha gene, HNF4A, causes an amino acid change of glutamic acid to aspartic acid at codon 263 (p.(Glu263Asp)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.787G>C p.Glu263Gln, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8289, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result nearly 50%, negative genetic testing for HNF1A, childhood hypoglycemia, strong family history of diabetes, antibody negative) (PP4_Moderate; internal lab collaborator). In summary, c.789G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PM2_Supporting, PM5_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107570/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5855 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017178 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0340464 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0003123 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0392025 infores:hetionet CHEBI:27834 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0010200 infores:hetionet CAID:CA414907101 biolink:causes MONDO:0010602 infores:clingen CAID:CA414907101 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4_Moderate The c.6542T>A (p.Leu2181His) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. The c.6542T>A (p.Leu2181His) missense variant has a REVEL score of 0.936 (>0.6) meeting PP3. The variant has been reported in at least 3 probands meeting phenotypic criteria for F8 meeting PS4_Moderate and PP4_Moderate (PMID: 29296726). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM2_Supporting, PP3, PS4_Moderate, and PP4_Moderate. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414907101/MONDO:0010602/071 2025-10-03 2025-10-07 X-linked inheritance HP:0001417 Supports CHEBI:2704 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0085633 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0002884 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0155003 infores:hetionet UMLS:C1738934 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0040264 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0038661 infores:hetionet CHEBI:63617 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0026827 infores:hetionet CAID:CA226781 biolink:causes MONDO:0010725 infores:clingen CAID:CA226781 MONDO:0010725 PMID: Uncertain Significance PP3 BS1, PS4, PM2, PP1, PP4 NM_000330.4(RS1):c.554C>T (p.Thr185Met) is a missense variant encoding the substitution of threonine with methionine at amino acid 185. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00001101 among hemizygous individuals, with 4 variant alleles / 399,408 total alleles, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.000002 and lower than the BS1 threshold of >0.00002 and fails to meet either criterion. This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 33124204). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The proband exhibits a phenotype including reduced visual acuity and foveo-lamellar schisis in the inner and outer nuclear layer, however, the age of onset does not meet the requirement to establish specificity to X-linked retinoschisis (PMID: 33124204), so PP4 is not met. The variant has been reported to segregate through 1 meiosis in a family with a mother and an affected son, however, the mother is unaffected so PP1 is not met (PMID: 33124204). The computational predictor REVEL gives a score of 0.733, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226781/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:3048 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0027769 infores:hetionet CHEBI:52172 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0041657 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0036572 infores:hetionet NCBIGene:23474 biolink:causes MONDO:0011229 infores:monarchinitiative not_provided not_provided HGNC:23287 MONDO:0011229 uuid:0302bccb-319c-4d13-9b18-d2b382a2eefe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0038363 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0853761 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009450 infores:hetionet CAID:CA400021992 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021992 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The c.444C>G (p.Tyr148Ter) variant in exon 4 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000001799] (2/1112006 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant is reported in ClinVar (SCV002515562.1) in a homozygous Glanzmann thrombasthenia patient (PM3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3_Supporting and PM2_Supporting (VCEP specifications version 2; date of approval 04/16/2024. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021992/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9123 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019209 infores:hetionet CAID:CA9090795 biolink:causes MONDO:0021060 infores:clingen CAID:CA9090795 MONDO:0021060 PMID: Likely Benign BP7, BP4 BS1, BS2 The variant c.919+4C>T is an intronic variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Also, computational prediction tools and conservation analysis suggests that the variant does not impact the protein (BP4). In summary, the clinical significance of the c.919+4C>T variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9090795/MONDO:0021060/004 2019-07-25 2019-12-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:10023 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020649 infores:hetionet CHEBI:75984 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0000737 infores:hetionet UNII:9430ZR8ZAN biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0005778 infores:hetionet CAID:CA412730484 biolink:causes MONDO:0100437 infores:clingen CAID:CA412730484 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2506G>T (p.Glu836Ter) is a nonsense variant that introduces a premature stop in codon 836 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with poor visual acuity (0.5 pts) with onset at age 3 years (1 pt), reduced rod electroretinogram responses, fundus appearance showing widespread retinal pigment epithelium degeneration with mid-periphery pigment deposits (0.5 pts), optic disc pallor (0.5 pts), cataract, severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a panel of 483 genes identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412730484/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:6970 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0542101 infores:hetionet CHEBI:63635 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0037763 infores:hetionet CHEBI:3403 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0010200 infores:hetionet NCBIGene:4851 biolink:causes MONDO:0014459 infores:monarchinitiative not_provided not_provided HGNC:7881 MONDO:0014459 uuid:d746528c-0412-43fd-bae1-35feb9bd2c11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6759 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0042963 infores:hetionet CHEBI:4046 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C2830004 infores:hetionet CHEBI:4907 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0042963 infores:hetionet NCBIGene:2068 biolink:causes MONDO:0011125 infores:monarchinitiative not_provided not_provided HGNC:3434 MONDO:0011125 uuid:64d1d63c-24bd-4097-8237-4641fe36fb2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0022660 infores:hetionet CHEBI:31236 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013456 infores:hetionet CHEBI:17303 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0039070 infores:hetionet CHEBI:2469 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151825 infores:hetionet NCBIGene:3290 biolink:causes MONDO:0013842 infores:monarchinitiative not_provided not_provided HGNC:5208 MONDO:0013842 uuid:a5280868-5477-414c-835d-f7c9b47e5d1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0031350 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0021843 infores:hetionet CHEBI:33325 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C1112525 infores:hetionet CHEBI:61033 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0014591 infores:hetionet CHEBI:50749 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0020437 infores:hetionet CHEBI:87715 biolink:causes UMLS:C1696110 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C1696110 infores:hetionet CHEBI:7903 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0041948 infores:hetionet CHEBI:84500 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233477 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0267792 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0040034 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0019348 infores:hetionet CHEBI:15552 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0042029 infores:hetionet CAID:CA024903 biolink:causes MONDO:0018493 infores:clingen CAID:CA024903 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 2764 of the RYR1 protein, p.(Glu2764Lys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000109, a frequency consistent with pathogenicity for MHS. To our knowledge, this variant has not been reported in any individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.842 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024903/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8713 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0020651 infores:hetionet CHEBI:9137 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0006384 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0876980 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0876980 infores:hetionet CHEBI:63619 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020473 infores:hetionet CHEBI:31401 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0030193 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005881 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0079924 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0233414 infores:hetionet CHEBI:5790 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235086 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0235639 infores:hetionet CHEBI:42797 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019270 infores:hetionet CAID:CA891843978 biolink:causes MONDO:0010305 infores:clingen CAID:CA891843978 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, PP3, BP4, PS1 The NM_005629.4:c.611_612delinsAC variant in SLC6A8 is a multi-nucleotide variant that replaces CT with AC, resulting in the substitution of an alanine by an aspartate at amino acid position 204 (p.Ala204Asp). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1, the highest population minor allele frequency is 0.0001094 (3/27411 alleles) in the Admixed American population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. Of the 3 total alleles in gnomAD v2.1.1, there is one hemizygote reported, which is less than the ClinGen CCDS VCEP’s threshold for BS2 (≥2 hemizygotes), such that BS2 is not met. The computational predictor REVEL gives a score of 0.148 for the Ala204Asp substitution (BP4). There is a ClinVar entry for this variant (Variation ID: 588254, one-star review status), with conflicting interpretations of pathogenicity (two submitters: uncertain significance; one submitter: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843978/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true UNII:8NZ41MIK1O biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0041834 infores:hetionet CHEBI:8869 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0011603 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0948525 infores:hetionet CHEBI:9667 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0221166 infores:hetionet CHEBI:7565 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0032617 infores:hetionet CHEBI:8080 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0027497 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017601 infores:hetionet CHEBI:50859 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0015672 infores:hetionet CHEBI:119915 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0262431 infores:hetionet CHEBI:5118 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020443 infores:hetionet CHEBI:61033 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0406834 infores:hetionet CAID:CA256755 biolink:causes MONDO:0021060 infores:clingen CAID:CA256755 MONDO:0021060 PMID: Uncertain Significance PP2 The c.1232C>T (p.Thr411Met) variant PTPN11 is present in 0.003% (3/113264) non-Finnish European alleles in gnomAD. The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Observed cases from laboratories and publications lack sufficient clinical phenotypic information to support or refute pathogenicity (Institut Universitaire d'Hématologie internal data; Institute of Human Genetics, University Hospital Magdeburg, Germany internal data; PMID:15384080). In summary, the clinical significance of the p.Thr411Met variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256755/MONDO:0021060/004 2019-12-05 2019-12-05 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:39112 biolink:causes UMLS:C0032300 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0032300 infores:hetionet CAID:CA297118 biolink:causes MONDO:0021060 infores:clingen CAID:CA297118 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1141G>A (p.Asp381Asn) variant in the RAF1 gene is 0.162% (36/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297118/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63631 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0038663 infores:hetionet GO:2000356 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000356 GO:0007275 CHEBI:6887 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0036572 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0235431 infores:hetionet CHEBI:5118 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085636 infores:hetionet CHEBI:3756 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0497156 infores:hetionet CHEBI:194135 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018965 infores:hetionet CHEBI:64354 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0085680 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042075 infores:hetionet CHEBI:3478 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0018524 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0027051 infores:hetionet CHEBI:47781 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0917801 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0233494 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0349506 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0549356 infores:hetionet CHEBI:2682 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020672 infores:hetionet CHEBI:6887 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002792 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007787 infores:hetionet CHEBI:2639 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C2830004 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0006840 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0853776 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0853776 infores:hetionet CHEBI:41879 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0027540 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0009806 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0019196 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0042109 infores:hetionet CHEBI:8356 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019294 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0234894 infores:hetionet GO:0141157 biolink:causes GO:0006887 infores:ubergraph knowledge_assertion manual_agent GO:0141157 GO:0006887 CHEBI:78543 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0860864 infores:hetionet CHEBI:15544 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0004690 infores:hetionet CHEBI:5296 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0010200 infores:hetionet CHEBI:75722 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0001925 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0851578 infores:hetionet CHEBI:63607 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0018681 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0221203 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0039971 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1112320 infores:hetionet CHEBI:17334 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C1142412 infores:hetionet CHEBI:3732 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004093 infores:hetionet CHEBI:63589 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C2830004 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019917 infores:hetionet CHEBI:4907 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0030920 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0010692 infores:hetionet GO:0051797 biolink:causes GO:0043588 infores:ubergraph knowledge_assertion manual_agent GO:0051797 GO:0043588 CHEBI:94686 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0014544 infores:hetionet CHEBI:34967 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0020458 infores:hetionet CHEBI:15551 biolink:causes NCIT:C92716 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0018811 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0020458 infores:hetionet CAID:CA7511304 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511304 MONDO:0015152 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong PM5, PS3 The NM_000070.3: c.1257T>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 419 (p.Asp419Glu). This variant has been detected in at least ten unrelated individuals with LGMD (PMID: 18055493, 25079074, 30564623; LOVD CAPN3_000280; ClinVar SCV000953543.3 internal data communication, ClinVar SCV002025057.3 internal data communication, ClinVar SCV001879783.1 internal data communication), including in unknown phase with a pathogenic variant in six cases (c.550delA p.(Thr184ArgfsTer36), 1.0 pt, PMID: 18055493, SCV002025057.3; c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1027G>T p.(Glu343Ter), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1838del p.(Lys613ArgfsTer49), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.643_663del p.(Ser215_Gly221del), 0.5 pts, ClinVar SCV001879783.1 internal data communication) (PM3_Strong). In four individuals, a second variant in CAPN3 was not identified. At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 18055493) (PP4). The filtering allele frequency of this variant is 0.00006819 (the upper threshold of the 95% CI of 3/113704 European (non-Finnish) exome alleles) by gnomAD v2.1.1, which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511304/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7809 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0234215 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002170 infores:hetionet CHEBI:44915 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0005779 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0018801 infores:hetionet CHEBI:3534 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0404521 infores:hetionet NCBIGene:3543 biolink:causes MONDO:0013287 infores:monarchinitiative not_provided not_provided HGNC:5870 MONDO:0013287 uuid:d318036c-8001-4395-8e7d-afa1a9e37234 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0003339 biolink:causes GO:0003338 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0003338 CHEBI:3082 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0085633 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0034150 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0025517 infores:hetionet CHEBI:63584 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0438717 infores:hetionet CHEBI:408174 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0002994 infores:hetionet CHEBI:32315 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0026827 infores:hetionet CHEBI:52717 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015732 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0015397 infores:hetionet CHEBI:4911 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0549567 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011615 infores:hetionet CHEBI:7959 biolink:causes MONDO:0019127 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0085655 infores:hetionet CHEBI:3398 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0232292 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0000833 infores:hetionet CHEBI:52717 biolink:causes HP:0002176 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037926 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002170 infores:hetionet CHEBI:41977 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0025222 infores:hetionet CHEBI:7466 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0020564 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235416 infores:hetionet CHEBI:7565 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0028961 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0010823 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0235146 infores:hetionet CHEBI:3077 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015967 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0032326 infores:hetionet CHEBI:136040 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0027849 infores:hetionet CHEBI:4856 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0018681 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0150450 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0019158 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0574067 infores:hetionet CHEBI:10102 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0233795 infores:hetionet CHEBI:8212 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0014457 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0032285 infores:hetionet CHEBI:48669 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C2047937 infores:hetionet CHEBI:9130 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0033036 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0342579 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0948586 infores:hetionet GO:0046773 biolink:causes GO:0006412 infores:ubergraph knowledge_assertion manual_agent GO:0046773 GO:0006412 CHEBI:10125 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0040053 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0033975 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0494559 infores:hetionet GO:0010807 biolink:causes GO:0007269 infores:ubergraph knowledge_assertion manual_agent GO:0010807 GO:0007269 CHEBI:4903 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0024103 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0030305 infores:hetionet GO:0060509 biolink:causes CL:0002062 infores:ubergraph knowledge_assertion manual_agent GO:0060509 CL:0002062 CHEBI:36795 biolink:causes UMLS:C0235222 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235222 infores:hetionet CHEBI:3127 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0007398 infores:hetionet CHEBI:31401 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018790 infores:hetionet CHEBI:63617 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0232461 infores:hetionet CAID:CA658799240 biolink:causes MONDO:0011229 infores:clingen CAID:CA658799240 MONDO:0011229 PMID: Pathogenic PM3_Supporting, PVS1, PM2, PP4_Moderate PP1, BS2, BA1, PS3, BS1 The c.604dupG; p.V202FsX220 variant in the ETHE1 gene is a frameshift variant resulting in truncation greater than 50 bp upstream of the final exon and is predicted to undergo nonsense mediated decay (PVS1). This variant is absent from population databases (PM2). A single homozygote is reported in multiple publications (PMID: 14732903, PMID: 16183799, PMID: 18593870), confirmed through linkage analysis (PM3_supporting; scored 0.5 per SVI PM3 guidance v1.). PMID: 14732903 reports this patient initially with a classic presentation of ethylmalonic encephalopathy, including acrocyanosis, petechiae, chronic diarrhea and developmental delay with urinary ethylmalonic aciduria of 320 mg/g creatine (PP4_moderate). In summary, this variant meets criteria to be classified as a pathogenic of ETHE1-related ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied: (PVS1, PM2, PM3_supporting, PP4_moderate,). This was reviewed with the ETHE1 expert panel on 2/23/2021 and approved on 2/23/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799240/MONDO:0011229/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:7444 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0013395 infores:hetionet CHEBI:100246 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C2242996 infores:hetionet CHEBI:5147 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0025222 infores:hetionet CHEBI:63610 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0011175 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0948525 infores:hetionet CHEBI:41423 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0039070 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0277925 infores:hetionet CHEBI:6904 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0701811 infores:hetionet CAID:CA314564 biolink:causes MONDO:0100040 infores:clingen CAID:CA314564 MONDO:0100040 PMID: Benign BS1, BS2, BP3 The highest population minor allele frequency of the c.153_161del (p.His55_His57del) variant in FOXG1 in gnomAD v4.1 is 0.00023 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.His55_His57del variant is observed in at least 2 unaffected individuals (Internal database - Invitae, Internal database - GeneDx) (BS2). The p.His55_His57del variant is an in-frame deletion present in a repetitive region of FOXG1 (BP3). In summary, the p.His55_His57del variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314564/MONDO:0100040/035 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:9430ZR8ZAN biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0037036 infores:hetionet UMLS:C0657912 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0001807 infores:hetionet CHEBI:45285 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0033774 infores:hetionet CHEBI:8707 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0015732 infores:hetionet CHEBI:3732 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0233407 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0233494 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018939 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002418 infores:hetionet CHEBI:3127 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0600142 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0010414 infores:hetionet CHEBI:3371 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0000833 infores:hetionet CHEBI:15551 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0013404 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0233571 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0847631 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0847631 infores:hetionet UMLS:C0011701 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0085633 infores:hetionet CHEBI:63577 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0035410 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027765 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006325 infores:hetionet CHEBI:52717 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0857305 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020538 infores:hetionet CHEBI:16335 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0020578 infores:hetionet CHEBI:135738 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0042963 infores:hetionet CHEBI:3752 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0022107 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0031085 infores:hetionet CHEBI:8212 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0028734 infores:hetionet CHEBI:52172 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0002962 infores:hetionet CHEBI:3082 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0018524 infores:hetionet CAID:CA005245 biolink:causes MONDO:0005045 infores:clingen CAID:CA005245 MONDO:0005045 PMID: Likely Benign BP2, BS1 BP4, PS1, PS3, BS3, PM5, PM1, PM2, PP2, PP3 NM_001276345.2(TNNT2):c.862C>T (p.Arg288Cys). This variant has been reported in individuals with HCM and other cardiomyopathies, many of whom carried a second clinically significant variant in another gene (BP2). Segregation analysis in families has yielded inconclusive results as it is reported to have incomplete penetrance and to cause mild and late onset HCM (LMM data, Watkins 1995 PMID: 7898523, Elliott 1999 PMID: 10610467, Van Driest 2003 PMID: 12860912, Garcia_Castro 2003 PMID: 12881443, Torricelli 2003 PMID: 14636924, Ingles 2005 PMID: 16199542, Zeller 2006 PMID: 16715312, Garcia-Castro 2007 PMID: 17101185, Garcia_Castro 2009 PMID: 19150014, Kaskai 2009 PMID: 20031618, Gimeno 2009 PMID: 20038417, Millat 2010 PMID: 20624503, Narsupalli 2010 PMID: 20663266, Gruner 2011 PMID: 21511876, Millat 2011 PMID: 21846512, Pasquale 2012 PMID: 22144547, Pan 2012 PMID: 23074333, Coppini 2014 PMID: 25524337, Ripoll-Vera 2016 PMID: 26507537, Song 2016 PMID: 26681313, Murphy 2016 PMID: 26914223, Whiffin 2017 PMID: 28518168, Viswanathan 2017 PMID: 29121657, Aljeaid 2019 PMID: 30762279). This variant has also been identified in 76 out of 125670 (0.05% GroupMax FAF 95% CI) of European chromosomes in gnomAD (BS1; https://gnomad.broadinstitute.org/; v.2.1). This variant is not statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI <5] and thus the PS4 criterion is not invoked. Experimental studies evaluating the functional impact of this variant are conflicting: Animal models have shown that this variant does not cause significant hypertrophy or ventricular fibrosis even after chronic exercise challenge, and no difference in either ATPase calcium sensitivity or contractile force in muscle fibers ex vivo and in vitro (Hernandez 2005 PMID: 16115869), while in vitro functional studies show that this variant increases Ca2+ sensitivity and leads to abnormal myosin cross-bridges (Morimoto 1999 PMID 10405326, Yanaga 1999 PMID 10085122, Szczesna 2000 PMID 10617660, Schuldt 2021 PMID 33148509). Computational prediction tools do not provide evidence for or against an impact to the protein (REVEL score <0.70). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner based on BS1 and BP2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA005245/MONDO:0005045/099 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36704 biolink:causes HP:0000369 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0239234 infores:hetionet CHEBI:9168 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085633 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0079043 infores:hetionet CHEBI:16469 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0236075 infores:hetionet CHEBI:135961 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0015230 infores:hetionet CHEBI:7822 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013144 infores:hetionet CHEBI:63791 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0238106 infores:hetionet CAID:CA226439 biolink:causes MONDO:0100437 infores:clingen CAID:CA226439 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.730A>T (p.Lys244Ter) is a nonsense variant that introduces a premature stop codon into exon 7 of 15, and is predicted to lead to nonsense-mediated decay in the RPGR gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family pedigree consistent with X-linked inheritance (2 points), night blindness (0.5 points), delayed or milder phenotype in females (1 point), rod involvement relatively greater than cone involvement (1 point), and peripheral visual field constriction (0.5 points), which together are specific for RPGR-related retinopathy (5 points, PMIDs: 11180598, 21857984, PP4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 1 family (PP1_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, PP1_Moderate, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226439/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:10127 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017152 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0011991 infores:hetionet CHEBI:28748 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0476280 infores:hetionet UMLS:C0120107 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0241633 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0151865 infores:hetionet CHEBI:7514 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0036974 infores:hetionet CHEBI:31644 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C2939147 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0015393 infores:hetionet CHEBI:6775 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013491 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0020517 infores:hetionet CHEBI:28748 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0034886 infores:hetionet CHEBI:3478 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0009676 infores:hetionet CHEBI:391960 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0013378 infores:hetionet CHEBI:63598 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0010200 infores:hetionet NCBIGene:92609 biolink:causes MONDO:0044724 infores:monarchinitiative not_provided not_provided HGNC:23656 MONDO:0044724 uuid:66504333-e956-4c90-a165-5f27e38cb03e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135285 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0017168 infores:hetionet CHEBI:6931 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0013404 infores:hetionet GO:1902553 biolink:causes GO:0097237 infores:ubergraph knowledge_assertion manual_agent GO:1902553 GO:0097237 CHEBI:63627 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0036572 infores:hetionet CHEBI:17823 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0085932 infores:hetionet CHEBI:9757 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0700590 infores:hetionet CHEBI:9139 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0043094 infores:hetionet CAID:CA024827 biolink:causes MONDO:0018493 infores:clingen CAID:CA024827 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with histidine at codon 2510 of the RYR1 protein, p.(Tyr2510His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual has a second variant of uncertain significance in RYR1, p.Met1814Lys, PS4 not implemented (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024827/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:205919 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0152459 infores:hetionet CHEBI:134990 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0015672 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0403632 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0014544 infores:hetionet CHEBI:63620 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0575081 infores:hetionet CHEBI:3175 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0013378 infores:hetionet CHEBI:51364 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0085649 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0344232 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0836924 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0006840 infores:hetionet CHEBI:7986 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0019080 infores:hetionet CHEBI:50305 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0019080 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0234215 infores:hetionet CHEBI:10650 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0025345 infores:hetionet CHEBI:45367 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0853847 infores:hetionet NCBIGene:6773 biolink:causes MONDO:0014715 infores:monarchinitiative not_provided not_provided HGNC:11363 MONDO:0014715 uuid:e753fd9b-ddf3-4f3b-a6de-41751d69470d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0236075 infores:hetionet CHEBI:31643 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C2129214 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0006444 infores:hetionet CHEBI:7466 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0027497 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042075 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0267596 infores:hetionet CAID:CA376062491 biolink:causes MONDO:0011225 infores:clingen CAID:CA376062491 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The NM_001033855.3:c.247-1G>C variant in DCLRE1C occurs within the canonical splice acceptor site (-1) of intron 3. It is predicted to cause skipping of biologically relevant exon 4, resulting in an in-frame deletion (removes amino acids 83-102). The variant removes <10% of the protein (20/692 amino acids) (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C/SCID conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PVS1_Moderate and PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376062491/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2673 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0549249 infores:hetionet CHEBI:42944 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0023222 infores:hetionet CHEBI:64355 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004134 infores:hetionet CHEBI:29688 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0038325 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0021364 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0036572 infores:hetionet CHEBI:38940 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1519353 infores:hetionet CHEBI:7640 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0003467 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0857257 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0031117 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0012813 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001266 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014733 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004936 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026113 infores:hetionet CHEBI:3082 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020461 infores:hetionet CHEBI:50729 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0003467 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151729 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151729 infores:hetionet NCBIGene:5298 biolink:causes MONDO:0859525 infores:monarchinitiative not_provided not_provided HGNC:8984 MONDO:0859525 uuid:682fc443-0189-4715-b753-bd22d20df15b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94449 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0027424 infores:hetionet CAID:CA410208106 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208106 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.533C>G (p.Thr178Ser) is a missense variant affecting one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). It has a REVEL score >0.88 (0.893) (PP3). The variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 1496240). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208106/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA120804 biolink:causes MONDO:0100437 infores:clingen CAID:CA120804 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PP1_Strong PS4 NM_001034853.2(RPGR):c.3092_3093del (p.Glu1031GlyfsTer?) is a frameshift variant due to a two-nucleotide deletion introducing a premature stop codon after 47 amino acids within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 14 affected meioses total from at least 2 families (PP1_Strong; PMID: 11857109, 9443860, 28559085). This variant has been reported in at least 3 apparently unrelated probands (PMID: 11857109, PMID: 9443860, PMID: 28559085, PMID: 34985506), however, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA120804/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:16469 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018944 infores:hetionet CAID:CA343723197 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723197 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BS1, BS3, PM6, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BP4, BA1 The c.1432G>T variant in MYOC is a missense variant predicted to cause substitution of Aspartic Acid by Tyrosine at amino acid 478 (p.Asp478Tyr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.894, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 30076350), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723197/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6690 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0429098 infores:hetionet GO:0060622 biolink:causes GO:0070591 infores:ubergraph knowledge_assertion manual_agent GO:0060622 GO:0070591 NCBIGene:55214 biolink:causes MONDO:0013670 infores:monarchinitiative not_provided not_provided HGNC:19317 MONDO:0013670 uuid:565a0097-65c9-479a-b35a-06dbe6165dd8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27470 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0013395 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0271547 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0271547 infores:hetionet CHEBI:5558 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C2047937 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0004936 infores:hetionet GO:0106396 biolink:causes GO:0045466 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0045466 CHEBI:4562 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042571 infores:hetionet CHEBI:499361 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0030252 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013295 infores:hetionet CHEBI:8863 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0033774 infores:hetionet CHEBI:17076 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0011606 infores:hetionet CHEBI:35778 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1565489 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003864 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006846 infores:hetionet CHEBI:31348 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0033774 infores:hetionet CHEBI:6715 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0022346 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0259799 infores:hetionet CHEBI:520985 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0000729 infores:hetionet CHEBI:167309 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0042963 infores:hetionet CHEBI:63605 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1384353 infores:hetionet CHEBI:4562 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0010692 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0015397 infores:hetionet CHEBI:49668 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0221776 infores:hetionet CHEBI:46195 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0042963 infores:hetionet CAID:CA10119025 biolink:causes MONDO:0021060 infores:clingen CAID:CA10119025 MONDO:0021060 PMID: Likely Benign BP4, BS1 PM2, PP2, PP3, BA1 The NM_006767.4:c.1700G>A variant in LZTR1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 567 (p.Arg567His). The filtering allele frequency (the lower threshold of the 95% CI of 9/19946) of the c.1700G>A variant in LZTR1 is 0.0002546 for East Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.157, which is below the threshold of 0.3, evidence that does not predict a damaging effect on LZTR1 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10119025/MONDO:0021060/094 2024-12-03 2025-04-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4784 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C1527344 infores:hetionet CHEBI:42797 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014591 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022408 infores:hetionet CHEBI:119573 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014518 infores:hetionet CHEBI:5864 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0040264 infores:hetionet CHEBI:6078 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0242429 infores:hetionet CAID:CA342803099 biolink:causes MONDO:0021060 infores:clingen CAID:CA342803099 MONDO:0021060 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting, PM1 PP2 The c.233G>A (p.Gly78Glu) variant in RIT1 was absent from both versions of gnomAD (PM2_Supporting; gnomad.broadinstitute.org). The p.Gly78Glu variant was observed in 1 proband with phenotypes suggestive of a RASopathy (PS4_Supporting; GeneDx internal data). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RIT1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly78Glu variant may impact the protein (PP3). In summary, the clinical significance of the p.Gly78Glu variant is uncertain; however, the current limited evidence suggests this uncertain variant is leaning towards likely pathogenic. RASopathy-specific ACMG/AMP criteria applied: PS4_Supporting, PM1, PM2_Supporting, PP3 (Version 2.1; 09/27/24). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA342803099/MONDO:0021060/047 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3699 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0004093 infores:hetionet CHEBI:64064 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0026858 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0017178 infores:hetionet CHEBI:49040 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0042384 infores:hetionet CAID:CA213906 biolink:causes MONDO:0015967 infores:clingen CAID:CA213906 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, BS2, PM1 The c.1187G>C variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of cysteine to serine at codon 396 (p.(Cys396Ser)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1187G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 11/16/2022): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213906/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:134991 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0029408 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027441 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1258215 infores:hetionet CHEBI:18067 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0002792 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020621 infores:hetionet NCBIGene:90411 biolink:causes MONDO:0013331 infores:monarchinitiative not_provided not_provided HGNC:18451 MONDO:0013331 uuid:a0040804-c7a3-4410-b896-67ab1fefe4b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA404086496 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086496 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1516G>C (p.Val506Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). BP4: REVEL= 0.296. It is below 0.5, so splicing evaluation is required.A) not on limits.B) does not create AG or GT.C) There is an AG nearby.Wt score: 6.76, Wt cryptic score: -25.36, Var cryptic score: -24.4.Var cryptic score/Wt cryptic score: 0.96. Var cryptic score/Wt score: -3.6.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086496/MONDO:0007750/013 2024-02-23 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3219 biolink:causes UMLS:C0151966 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151966 infores:hetionet CHEBI:3176 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0014591 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034880 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005543 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0520463 infores:hetionet CHEBI:3749 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0003123 infores:hetionet CHEBI:231425 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0085602 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035455 infores:hetionet CHEBI:8871 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003578 infores:hetionet CHEBI:9435 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0001824 infores:hetionet CHEBI:64064 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0027424 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0021053 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0242350 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233571 infores:hetionet CHEBI:9763 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C2242737 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042571 infores:hetionet CHEBI:63791 biolink:causes HP:0020071 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042749 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0549433 infores:hetionet NCBIGene:55187 biolink:causes MONDO:0011811 infores:monarchinitiative not_provided not_provided HGNC:23595 MONDO:0011811 uuid:c5198bf1-8f1a-4c51-a077-ab0017f8f6c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0004093 infores:hetionet CHEBI:465284 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042023 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0019360 infores:hetionet CHEBI:125354 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0018681 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151547 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0232208 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027765 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0018213 infores:hetionet CAID:CA5416893 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416893 MONDO:0011225 PMID: Pathogenic PP4, PS3_Moderate, PM2_Supporting, PVS1 PM3 The c.356C>G (p.Ser119Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 2/1110550) of the c.356C>G variant in DCLRE1C is 0.0000003 for European (Non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The variant displayed a recombination activity of 0% compared to WT levels (PMID:25917813) in one assay with impaired DNA repair activity (15.59%), which is below the criteria of the 25% threshold set by the SCID VCEP to meet PS3_moderate.At least one patient with this variant displayed Diagnostic criteria for SCID: 0.5pt + Increased cellular radiosensitivity: 0.5pt = Total 1.0 pt, which is highly specific for SCID (PP4_Supporting, PMID:15770702).In summary, this variant meets the criteria to be classified as Pathogenic for or autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PS3_Moderate, and PP4_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416893/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:127342 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0015256 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0233571 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0040034 infores:hetionet CHEBI:47612 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0015230 infores:hetionet CHEBI:465284 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011603 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1269683 infores:hetionet CHEBI:72690 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0033774 infores:hetionet CHEBI:10100 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0020580 infores:hetionet CHEBI:63631 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151786 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0235431 infores:hetionet CHEBI:8382 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0027540 infores:hetionet CHEBI:8060 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0009421 infores:hetionet CHEBI:17698 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0040034 infores:hetionet CHEBI:135613 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C1096250 infores:hetionet CHEBI:66899 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0235266 infores:hetionet CHEBI:50924 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0011603 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0017178 infores:hetionet CHEBI:28901 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0029118 infores:hetionet CHEBI:15765 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0021177 infores:hetionet CHEBI:6359 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0232462 infores:hetionet CHEBI:3756 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0026827 infores:hetionet CAID:CA16020787 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020787 MONDO:0009861 PMID:23430918 Pathogenic PVS1, PM2, PP4, PM3_Supporting This c.441+2T>G variant in PAH was reported in 1 Caucasian patient with PAH deficiency (PMID: 23430918) detected with the pathogenic variant p.Arg408Trp. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the +2 splice donor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020787/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9763 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0012833 infores:hetionet NCBITaxon:1980459 biolink:causes MONDO:0017879 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1980459 MONDO:0017879 CAID:CA913187393 biolink:causes MONDO:0009290 infores:clingen CAID:CA913187393 MONDO:0009290 PMID:29095812 Pathogenic PVS1, PP4_Moderate, PM2 PM3 This variant, c.2161del (p.Glu721ArgfsTer?), is a frameshift variant predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was identified by a clinical diagnostic laboratory in a compound heterozygous individual with c.841C>T (p.Arg281Trp). Pseudodeficiency variants are absent in this individual, allowing PP4_Moderate to be applied. The in trans data from this patient was used in the classification of p.Arg281Trp and is not included here in order to avoid a circular argument. An additional case has been reported with p.Glu721ArgfsTer (cDNA sequence not provided), identified by newborn screening and compound heterozygous for p.Trp746Leu and the psuedodeficiency variant p.Asp91Asn (PMIDs 28196920, 29095812). There is no ClinVar entry for this variant and, to our knowledge, functional studies are unavailable. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913187393/MONDO:0009290/010 2020-04-20 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:30061 biolink:causes MONDO:0011631 infores:monarchinitiative not_provided not_provided HGNC:10909 MONDO:0011631 uuid:adcff746-4259-4e16-96d1-49b2b20cef14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1903551 biolink:causes GO:0097734 infores:ubergraph knowledge_assertion manual_agent GO:1903551 GO:0097734 CHEBI:135920 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0178298 infores:hetionet CHEBI:7476 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0040264 infores:hetionet NCBIGene:1836 biolink:causes MONDO:0010966 infores:monarchinitiative not_provided not_provided HGNC:10994 MONDO:0010966 uuid:b5b0a501-1b0f-42d5-8ba2-bf09373b0b8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020939 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020939 MONDO:0009861 PMID:19915519 Uncertain Significance PM2, PP4, PP3 The c.1100T>G (p.Leu367Arg) variant in PAH is reported in a Chinese patient with PKU. BH4 deficiencies were not assessed/reported. (PMID: 19915519) This variant is absent in population databases. It is predicted deleterious by PolyPhen-2, MutationTaster, and SIFT. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020939/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:5459 biolink:causes MONDO:0011226 infores:monarchinitiative not_provided not_provided HGNC:9220 MONDO:0011226 uuid:22c3cc41-15c6-4533-95dd-f901761c2c5b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28487 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0036974 infores:hetionet CHEBI:6375 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0206061 infores:hetionet NCBIGene:55780 biolink:causes MONDO:0014240 infores:monarchinitiative not_provided not_provided HGNC:21056 MONDO:0014240 uuid:a60b0b9e-4e55-4d2e-acda-19a4dab6b151 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0004093 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0854082 infores:hetionet CHEBI:6909 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0020580 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0008311 infores:hetionet GO:0090256 biolink:causes GO:0048737 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0048737 UMLS:C0010592 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151539 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235290 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0036572 infores:hetionet NCBITaxon:186538 biolink:causes MONDO:0005737 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:186538 MONDO:0005737 CHEBI:45863 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0041912 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0948294 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018099 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0042075 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0853748 infores:hetionet CHEBI:7865 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0008031 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004096 infores:hetionet CHEBI:31644 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0232726 infores:hetionet CAID:CA913171880 biolink:causes MONDO:0044970 infores:clingen CAID:CA913171880 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting PP1, PM6 The m.14710G>A variant in MT-TE has been reported in two affected individuals from two families (PMIDs: 15670724, 23847141; PS4_supporting). These two individuals had similar courses, as both were women with onset in childhood or adolescence of progressive external ophthalmoplegia (PEO), myopathy, pigmentary retinopathy, and migraines. Muscle biopsies performed in these two individuals showed ragged red fibers and COX-negative fibers. Respiratory chain enzyme activities were normal except for reduced complex I activity in one individual. Heteroplasmy levels were only reported in one individual (PMID: 15670724), but were 67-77% in muscle, trace amounts to 14% in hair roots, and were undetectable in buccal, blood, and fibroblasts. Of note, exercise testing in one subject (PMID: 15670724) is described in other manuscripts (PMIDs: 11506394 and 12538407), and her case is also included in a cohort study (PMID: 19718780). One of the affected individuals has a son with autism but he was not tested for this variant. The variant was not detected in blood from the subject’s mother and three sisters but it was also undetectable in the subject's blood, so de novo status could not be confirmed (PMID: 15670724). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (93 ± 1.0%) than in COX positive fibers (59 ± 28%), p<0.005. Furthermore, COX-positive fibers showed a much greater range of mutated mtDNA than COX-negative fibers (9–89% vs 92–95%; PMID: 15670724; PS3_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (51.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of likely pathogenic given the evidence of pathogenicity (strong single fiber studies, absent in population databases and present in two individuals with similar features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 15, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913171880/MONDO:0044970/015 2022-12-15 2023-01-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:53691 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0022658 infores:hetionet CHEBI:204928 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0042109 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0006444 infores:hetionet CAID:CA386952266 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952266 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS4 The c.22C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to methionine at codon 8 (p.(Leu8Met)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is located within the DNA binding domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.814, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, Internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea responsive) (PP4_Moderate; PMID: 18003757, Internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supoprting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952266/MONDO:0015967/085 2023-10-05 2023-10-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:188986 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0428977 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0877009 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0877009 infores:hetionet CHEBI:45409 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0023052 infores:hetionet NCBIGene:4773 biolink:causes MONDO:0859369 infores:monarchinitiative not_provided not_provided HGNC:7776 MONDO:0859369 uuid:635dbf15-8f0f-4c0a-aa33-38b5944749cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75179 biolink:causes HP:0012040 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0474444 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033575 infores:hetionet CHEBI:101853 biolink:causes UMLS:C1262535 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C1262535 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0009782 infores:hetionet CHEBI:31485 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0022081 infores:hetionet CHEBI:36791 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2364111 infores:hetionet CHEBI:4469 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0043352 infores:hetionet CHEBI:100246 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0041834 infores:hetionet NCBIGene:7476 biolink:causes MONDO:0013077 infores:monarchinitiative not_provided not_provided HGNC:12786 MONDO:0013077 uuid:8838e8c5-7a73-4319-b018-2f23ac223d52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0855335 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0855335 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005160 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003486 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0021053 infores:hetionet CAID:CA270421 biolink:causes MONDO:0010726 infores:clingen CAID:CA270421 MONDO:0010726 PMID:12180070 Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1, PP3, PP4 The p.Asp151Gly variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15173251) (PP4). The p.Asp151Gly variant has been observed in at least 3 other individuals with atypical Rett syndrome or clinical features of Rett syndrome (PMID 15173251, 32472557, internal database - University of Chicago, internal database - Invitae) (PS4_Moderate). The p.Asp151Gly variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). The p.Asp151Gly variant in MECP2 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Asp151Gly variant in MECP2 is classified as Likely Pathogenic based on the ACMG/AMP criteria (PS4_moderate, PM1, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270421/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Supports CHEBI:134990 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0004093 infores:hetionet CAID:CA410148750 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148750 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS4, PS3, PS2, BA1, BP3, BP2, BP1, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM5, PM4, PM3, PM1, BS2, PP4, PP1, PP2, PP3 NM_001754.5(RUNX1):c.991A>C (p.Ser331Arg) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.106, and the splice site predictor SpliceAI indicated no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148750/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9738 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0027497 infores:hetionet CHEBI:71417 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0018524 infores:hetionet CHEBI:9588 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0017181 infores:hetionet CAID:CA367402543 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402543 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PP4_Moderate, PM2_Supporting The c.363+2T>C variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 3 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 4 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 30977832, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and persistent fasting hyperglycemia) (PP4_Moderate; internal lab contributor). In summary, c.363+2T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP4_moderate, PS4_Moderate, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402543/MONDO:0015967/086 2024-07-04 2024-07-04 Semidominant inheritance HP:0032113 Supports NCBIGene:8642 biolink:causes MONDO:0011070 infores:monarchinitiative not_provided not_provided HGNC:13681 MONDO:0011070 uuid:760a48f3-09a3-46f4-b00a-02bd345a9f8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011206 infores:hetionet CHEBI:6741 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0038999 infores:hetionet CHEBI:28445 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0687713 infores:hetionet CAID:CA251524 biolink:causes MONDO:0009861 infores:clingen CAID:CA251524 MONDO:0009861 PMID:23842451PMID:9634518PMID:26666653PMID:22841515PMID:21871829PMID:27121329PMID:19609714PMID:18590700 Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong, PS3_Supporting PM5, PS1 The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID: 9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID: 23842451) p.Y386C (PMID: 22841515) p.R261Q (PMID: 21871829) c.842+5G>A (PMID: 19609714) p.Gly257Asp (PMID: 26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID: 27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251524/MONDO:0009861/006 2020-02-22 2020-02-22 Supports CHEBI:3175 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0008031 infores:hetionet CHEBI:8382 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0542571 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0033777 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0233632 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039584 infores:hetionet CHEBI:4728 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0340464 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C1504494 infores:hetionet CHEBI:30659 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0000737 infores:hetionet CHEBI:2666 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0043352 infores:hetionet CHEBI:63624 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0033774 infores:hetionet NCBIGene:7504 biolink:causes MONDO:0018945 infores:monarchinitiative not_provided not_provided HGNC:12811 MONDO:0018945 uuid:944c28d5-61a2-4cab-b1ef-f3518a42d7fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0600142 infores:hetionet CHEBI:6129 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015403 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0027769 infores:hetionet CHEBI:51032 biolink:causes HP:6000420 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0234655 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0038362 infores:hetionet CHEBI:32221 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0015230 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020517 infores:hetionet CHEBI:140621 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0033774 infores:hetionet CHEBI:8764 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0233471 infores:hetionet CHEBI:7476 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C2830004 infores:hetionet CHEBI:584020 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0016199 infores:hetionet CHEBI:65173 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0014869 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042109 infores:hetionet CHEBI:31932 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0035078 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0234930 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0017152 infores:hetionet CHEBI:4856 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013604 infores:hetionet CAID:CA415076119 biolink:causes MONDO:0010305 infores:clingen CAID:CA415076119 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_005629.4(SLC6A8):c.70G>C (p.Ala24Pro) variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Proline at amino acid 24 (p.Ala24Pro). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000159 (1/62731 alleles) in the European population, with no hemi- or homozygotes, which is <0.0002 therefore PM2_Supporting criteria applicable. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID: 465148). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415076119/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CAID:CA367398793 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398793 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1136C>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glycine at codon 379 (p.(Ala379Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0 0.922, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.1136C>A p.Ala379Glu and c.1136C>T p.Ala379Val, have been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398793/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CAID:CA10585188 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585188 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM1, PM4, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_strong - Four more missense variants described in same codon, of which 2 variants classified as Pathogenic, so PM5_Strong is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.982. PP4 - Variant meets PM2. Identified in 1 FH case who fulfills Simon-Broome criteria for FH in PMID 1301940. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585188/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA151456 biolink:causes MONDO:0700270 infores:clingen CAID:CA151456 MONDO:0700270 PMID: Benign BS1, BP2_Strong BP4, BA1, PM2 The ATM c.1066-6T>G variant has a GnomAD (v2.1.1) filtering allele frequency of 0.2081% (NFE) which is above the ATM BS1 threshold of .05% (BS1). In silico predictors (SpliceAI Acceptor Loss 0.62; MaxEntScan -2.49) are indeterminate about whether this variant affects splicing. This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 26957, 500031). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA151456/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47499 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0037274 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0235969 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0002888 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0877096 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0877096 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0029456 infores:hetionet CHEBI:16469 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0021177 infores:hetionet CHEBI:75984 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0015672 infores:hetionet CHEBI:4798 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C2129214 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020651 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0027441 infores:hetionet NCBIGene:6901 biolink:causes MONDO:0010543 infores:monarchinitiative not_provided not_provided HGNC:11577 MONDO:0010543 uuid:3c99e485-c661-4934-8d6a-d5c4b87d1912 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011570 infores:hetionet CHEBI:68595 biolink:causes UMLS:C2955673 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C2955673 infores:hetionet CHEBI:6904 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0030848 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0024115 infores:hetionet CHEBI:63638 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233514 infores:hetionet CHEBI:45951 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0020456 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151735 infores:hetionet CHEBI:28445 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0002792 infores:hetionet NCBIGene:10079 biolink:causes MONDO:0859377 infores:monarchinitiative not_provided not_provided HGNC:13540 MONDO:0859377 uuid:279e7fed-0442-4bd0-b915-e390e6c294d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0227791 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0026946 infores:hetionet UMLS:C1738934 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017565 infores:hetionet CHEBI:48844 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0268000 infores:hetionet CHEBI:50924 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0003862 infores:hetionet CHEBI:49375 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0239981 infores:hetionet CHEBI:31348 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0025874 infores:hetionet CHEBI:27666 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0520962 infores:hetionet CHEBI:2914 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0011603 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0442874 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1262064 infores:hetionet CHEBI:4717 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0002792 infores:hetionet CHEBI:6076 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0239571 infores:hetionet CHEBI:10102 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0423791 infores:hetionet CAID:CA410147291 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147291 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS4, PS2, PS3, PS1, BP2, BP3, BP1, BA1, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1336C>T (p.Leu446Phe) is a missense variant predicted to substitute leucine with phenylalanine at amino acid 446. This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting) and has not been reported in relevant cases in the literature. The computational predictor REVEL gives a score of 0.315, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147291/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:32020 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0027121 infores:hetionet CHEBI:76010 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0041969 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0161479 infores:hetionet CHEBI:75246 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232726 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0012797 infores:hetionet CHEBI:6062 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0026821 infores:hetionet NCBIGene:65082 biolink:causes MONDO:0015012 infores:monarchinitiative not_provided not_provided HGNC:18179 MONDO:0015012 uuid:ff436630-880c-4de0-967c-81da5f6a2554 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512318711 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318711 MONDO:0011071 PMID: Likely Benign BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.627A>G (p.Lys209=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v4.0 (PM2_supporting). SpliceAI predicts no impact on splicing (score: 0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 1.57) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318711/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64355 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1260880 infores:hetionet CHEBI:9150 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0852911 infores:hetionet CHEBI:135876 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0034886 infores:hetionet CAID:CA16603051 biolink:causes MONDO:0018875 infores:clingen CAID:CA16603051 MONDO:0018875 PMID: Pathogenic PS3, PM1_Supporting, PP3_Moderate, PP4_Moderate, PM2_Supporting, PS4_Supporting BP4, BA1, PS2, PS1, PM5, BP7, BS1, BS3, BS4, PVS1, PP1, BS2 The NM_000546.6:c.332T>A variant in TP53 is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 111 (p.Leu111Gln). This variant has been reported in2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = 0.36783; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has 4 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PS4_Supporting, PP3_Moderate, PM1_Supporting, PM2_Supporting, PP4_Moderate: Bayesian Points: 11; VCEP specifications version 2.3. TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603051/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83804 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015672 infores:hetionet CHEBI:3387 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0270611 infores:hetionet CHEBI:10100 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0012833 infores:hetionet CHEBI:63618 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C2981158 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0235169 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0149778 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0149778 infores:hetionet CHEBI:5280 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0037763 infores:hetionet GO:1904857 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:1904857 GO:0070887 NCBIGene:375056 biolink:causes MONDO:0031010 infores:monarchinitiative not_provided not_provided HGNC:24008 MONDO:0031010 uuid:5fc63785-a8b3-4c86-aef8-b526a8fae226 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0008031 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027947 infores:hetionet CHEBI:55346 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0015230 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0038358 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013415 infores:hetionet CHEBI:2922 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C3665347 infores:hetionet CHEBI:4784 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C2830004 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0877338 infores:hetionet CHEBI:63620 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C2937350 infores:hetionet CHEBI:8107 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0034880 infores:hetionet CHEBI:48273 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0231274 infores:hetionet CHEBI:15367 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042029 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1258215 infores:hetionet CHEBI:53760 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011551 infores:hetionet CHEBI:61049 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0080274 infores:hetionet CAID:CA512341264 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341264 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1158C>T (p.Pro386=) is a synonymous variant; therefore, no REVEL score is applicable. SpliceAI score is ≤ 0.20 (0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -4.82834 < 2.0), or the variant is the reference nucleotide in one primate and/or three mammal species (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341264/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3699 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0012833 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0021845 infores:hetionet CHEBI:63599 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0085631 infores:hetionet CAID:CA023778 biolink:causes MONDO:0007750 infores:clingen CAID:CA023778 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Supporting, PM2, PP3, PP4 BA1, BP4, BP3, BP2, PS2, PS1, BS1, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 25647241:HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3).---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023778/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8768 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023533 infores:hetionet CHEBI:5062 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0018418 infores:hetionet CHEBI:5103 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0037822 infores:hetionet CHEBI:3223 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0011551 infores:hetionet CHEBI:47426 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0877055 infores:hetionet CHEBI:6690 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0039239 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009938 infores:hetionet CHEBI:94411 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0000731 infores:hetionet CHEBI:63605 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0024312 infores:hetionet CHEBI:39585 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0026961 infores:hetionet CHEBI:100246 biolink:causes UMLS:C3160944 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C3160944 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0031350 infores:hetionet CHEBI:94686 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0034886 infores:hetionet CHEBI:34385 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0004093 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0233414 infores:hetionet CAID:CA345144479 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144479 MONDO:0100084 PMID: Uncertain Significance PP2, PP3, PS4_Supporting, PM2_Supporting The c.1071G>C variant in ACTA1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 357 (legacy nomenclature: p.Met355Ile). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 2 adult probands with features of muscle weakness (PS4_Supporting; Invitae, SCV001199812.3, GeneDx, SCV001989742.1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144479/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28748 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0007642 infores:hetionet CHEBI:135961 biolink:causes UMLS:C1868730 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C1868730 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2225524 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0033975 infores:hetionet CHEBI:28901 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151517 infores:hetionet CAID:CA320637507 biolink:causes MONDO:0011071 infores:clingen CAID:CA320637507 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, PS2, BP1, BP4, BP3, PM2, PM6, PVS1, BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM5, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.508+275T>G is an intronic variant with no predicted splice effect. MAF of 0.03675 (3.675%, 320/8708 alleles) in the African/African American subpopulation of the gnomADv2.1.1 cohort is ≥ 0.0015 (0.15%) (BA1). Variant observed in homozygous state (2) in gnomAD v2.1.1 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320637507/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA645592050 biolink:causes MONDO:0011132 infores:clingen CAID:CA645592050 MONDO:0011132 PMID:31566583PMID:37419334 Pathogenic PP4, PM2_Supporting, PS4_Moderate, PS3, PM6_Supporting, PVS1_Strong The NM_001369369.1(FOXN1):c.1465del (p.Gln489ArgfsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). The variant was detected by exome sequencing with Sanger confirmation in one patient (Pt 2) with normal hair and nails but T–/loB+NK+ leaky SCID. They had undetectable TRECs (0.25pt), CD3 122 cells/uL (0.25pt), CD8 17 cells/uL, CD4CD45RA 2 cells/uL, NK 505 cells/uL, and CD19+ 1079 cells/uL (PMID: 31566583; PP4). This was a de novo occurrence of the variant in Pt 2 (PM6_supporting). Two additional patients (Pt 3 and Pt 4) were also detected with this variant by exome sequencing. They each had low CD3 and CD8 cell counts for their age (PMID: 31566583; PS4_moderate). This variant is absent from gnomADv2.1.1 (PM2_supporting). CRISPR/Cas9 generated Foxn1 Q489Rfs/Q489Rfs mice have a nude/SCID phenotype, evident 4 to 5 days postnatally and had significantly reduced numbers and percentages of thymocyte subsets at the adult stages (PMID: 27618451; PS3). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, PP4, PM6_supporting, PS4_moderate, and PS3 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA645592050/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:10127 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013404 infores:hetionet CHEBI:8404 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0003467 infores:hetionet CHEBI:51209 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0040822 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0149931 infores:hetionet CHEBI:8346 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0040147 infores:hetionet CHEBI:3181 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0438215 infores:hetionet CHEBI:3032 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0012833 infores:hetionet NCBIGene:7305 biolink:causes MONDO:0020749 infores:monarchinitiative not_provided not_provided HGNC:12449 MONDO:0020749 uuid:3242e0f9-9252-49e0-9d81-e75669a6171e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6706 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0008489 infores:hetionet CHEBI:68558 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0004238 infores:hetionet NCBIGene:2697 biolink:causes MONDO:0007083 infores:monarchinitiative not_provided not_provided HGNC:4274 MONDO:0007083 uuid:92fb794e-b3e9-4d24-a556-2801e1a524bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0034902 infores:hetionet CHEBI:3393 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C2129214 infores:hetionet NCBIGene:2273 biolink:causes MONDO:0010414 infores:monarchinitiative not_provided not_provided HGNC:3702 MONDO:0010414 uuid:d3a7d941-9432-4e39-87bb-af94fe0563d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0560024 infores:hetionet CHEBI:71255 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C2830004 infores:hetionet CHEBI:9571 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0043352 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0036983 infores:hetionet CHEBI:231594 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0033046 infores:hetionet NCBITaxon:57077 biolink:causes MONDO:0005729 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:57077 MONDO:0005729 CAID:CA278691 biolink:causes MONDO:0019501 infores:clingen CAID:CA278691 MONDO:0019501 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong BS1, BA1, BP4 The c.5804T>C variant in MYO7A is a missense variant predicted to cause substitution of leucine by proline at amino acid 1935 (p.Leu1935Pro). The highest population minor allele frequency in gnomAD v4.1 is 0.00002204 (26/1179460 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 2 individuals with autosomal recessive Usher syndrome. Both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (2 PM3 points, SCV001239772.1, SCV000059855.6, Blueprint Genetics, Laboratory for Molecular Medicine) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000059855.6, Laboratory for Molecular Medicine). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278691/MONDO:0019501/005 2024-09-24 2024-09-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:61049 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0392025 infores:hetionet NCBIGene:51206 biolink:causes MONDO:0013623 infores:monarchinitiative not_provided not_provided HGNC:14388 MONDO:0013623 uuid:12dcb890-0523-44ec-93a8-2e14e91c04f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3510 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0014724 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0009450 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0023533 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0018799 infores:hetionet NCBIGene:11181 biolink:causes MONDO:0012803 infores:monarchinitiative not_provided not_provided HGNC:12266 MONDO:0012803 uuid:121a8d9a-96fc-41e1-a454-eab722b0a356 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0687713 infores:hetionet CHEBI:63580 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020580 infores:hetionet UMLS:C0065374 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030554 infores:hetionet CHEBI:63598 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0392171 infores:hetionet CHEBI:50692 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0015672 infores:hetionet CHEBI:8776 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0011206 infores:hetionet CHEBI:45367 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0030193 infores:hetionet CHEBI:9123 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235086 infores:hetionet CHEBI:9123 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0699828 infores:hetionet CHEBI:63617 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C3665347 infores:hetionet CAID:CA366744765 biolink:causes MONDO:0013699 infores:clingen CAID:CA366744765 MONDO:0013699 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.241G>T (p.Glu81Ter) (NM_000535.7) variant in PMS2 is a nonsense variant predicted to cause a premature stop codon in exon 3 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is extremely rare (1 in 1594104 alleles) in gnomAD v4.1 (PM2_Supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1, PM2_SUP (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA366744765/MONDO:0013699/139 2024-09-18 2025-08-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9654 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0003811 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005191 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860594 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0043251 infores:hetionet CHEBI:5050 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0030252 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0851341 infores:hetionet CHEBI:48669 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C1322281 infores:hetionet CAID:CA7140659 biolink:causes MONDO:0100040 infores:clingen CAID:CA7140659 MONDO:0100040 PMID: Likely Benign BP5_Strong, BS2_Supporting, BP4 BS1 The c.1119G>A (p.Pro373=) variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - Invitae) (BP5_strong). The c.1119G>A (p.Pro373=) variant is observed in at least 1 unaffected individuals (internal database - Invitae) (BS2_supporting). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.1119G>A (p.Pro373=) variant in FOXG1 is classified as Likely Benign based on the ACMG/AMP criteria (BP5_strong, BS2_supporting, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7140659/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8245 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0019825 infores:hetionet CHEBI:27796 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C2830004 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0015397 infores:hetionet CHEBI:8356 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0231835 infores:hetionet CHEBI:4046 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0036572 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0021053 infores:hetionet CHEBI:4672 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0004093 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0003123 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030920 infores:hetionet CHEBI:50378 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0019080 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0022650 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0017178 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0027765 infores:hetionet CHEBI:27504 biolink:causes HP:0002835 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0700198 infores:hetionet CHEBI:16469 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013404 infores:hetionet CHEBI:204928 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0036572 infores:hetionet CHEBI:63610 biolink:causes EFO:1001799 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0812470 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0041912 infores:hetionet CAID:CA9871639 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871639 MONDO:0007064 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.516C>A (p.Tyr172Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The filtering allele frequency (the upper threshold of the 95% CI of 5/86250) of the c.516C>A variant in ADA is 0.00002194 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871639/MONDO:0007064/114 2024-05-28 2024-05-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50173 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0917801 infores:hetionet CHEBI:3510 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0020517 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0027765 infores:hetionet CHEBI:50648 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0476273 infores:hetionet CAID:CA8337806 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337806 MONDO:0008723 PMID: Likely Benign BP4, BP7, BS1 The NM_000018.4(ACADVL):c.663C>T (p.Ser221=) variant is a synonymous (silent) variant that is not predicted by SpliceAI, MaxEntScn and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00353 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4, BP7. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337806/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:74947 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002874 infores:hetionet CHEBI:3423 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0919924 infores:hetionet CHEBI:2038 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0019348 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0027947 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0542313 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0542313 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0856151 infores:hetionet CHEBI:50648 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0542571 infores:hetionet CHEBI:36791 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235592 infores:hetionet CHEBI:7640 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0018681 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0853761 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0007114 infores:hetionet CHEBI:144551 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0392156 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033975 infores:hetionet CAID:CA397842518 biolink:causes MONDO:0018875 infores:clingen CAID:CA397842518 MONDO:0018875 PMID: Pathogenic PS3, PS2, PM1_Supporting, PP3, PM2_Supporting BA1, BP4, PS1, PS4, PM5, BS1, BS3, PP4, BS2 The NM_000546.6: c.428T>C variant in TP53 is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 143 (p.Val143Ala). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 6 phenotype points (PS2; PMID: 19701813, 25318593). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.1806; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of >15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 7 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot critical functional domain by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PM2_Supporting, PS3, PP3, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397842518/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31623 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0016242 infores:hetionet CAID:CA10585191 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585191 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP1, BS2 The NM_000527.5(LDLR):c.915G>C (p.Trp305Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.91. It is above 0.75, so PP3 is met. PP4: Variant meets PM2, and is identified in 1 case from 16250003, after alternative causes of high cholesterol were excluded. So, PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585191/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:51412 biolink:causes MONDO:0032770 infores:monarchinitiative not_provided not_provided HGNC:160 MONDO:0032770 uuid:f37d01af-8806-407f-9682-f5c7f63aaa46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0234233 infores:hetionet CHEBI:17303 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0028961 infores:hetionet CHEBI:31859 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0010692 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018799 infores:hetionet CHEBI:27779 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0917801 infores:hetionet CHEBI:4975 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0494475 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0878544 infores:hetionet CHEBI:7931 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011206 infores:hetionet CAID:CA7511744 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511744 MONDO:0015152 PMID: Pathogenic PP3, PP4, PM3_Strong, PP1_Strong PM2, BS1 The NM_000070.3: c.2120A>G variant in CAPN3 is a missense variant predicted to cause substitution of asparagine with glycine at amino acid position 707, p.(Asp707Gly). This variant has been reported in over 20 patients with features of LGMD and is particularly common among patients with East Asian ancestry (PMID: 28403181, 17258832, 10567047, 19556129, 27066573, 37974208, 32994280, 33899113, 30127231, 39188286, 11525884; LOVD CAPN3_000118). These reports include at least five unrelated homozygous cases without reported familial consanguinity (1.0 pt; PMID: 17258832, 10567047, 32994280, 11525884) and at least one observation where the variant was confirmed in trans with a likely pathogenic or pathogenic variant (c.2201_2202del p.(Tyr734Ter), 1.0 pt, PMID: 33899113) (PM3_Strong). It has also been reported to segregate with the LGMD phenotype in six affected family members from four families (PP1_Strong; PMID: 37974208, 32994280, 39188286, 11525884). At least one patient with this variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 26632398, 19556129, 10567047, 17258832; PP4 (capped with PP1_Strong)). The filtering allele frequency in gnomAD v4.1.0 exomes is 0.001250 (the lower threshold of the 95% CI of 62/39700 East Asian chromosomes), which is above the LGMD VCEP threshold (0.001) for BS1. However, this variant is one of the most commonly described CAPN3 variants reported in patients in this population, and the VCEP opted not to apply this code (BS1 exception). The computational predictor REVEL gives a score of 0.966, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025): PM3_Strong, PP1_Strong, PP4, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511744/MONDO:0015152/187 2025-04-22 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3479 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0042109 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1868855 infores:hetionet CHEBI:8890 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0034642 infores:hetionet CHEBI:40237 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0011991 infores:hetionet CHEBI:9168 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0242528 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0006277 infores:hetionet CHEBI:42944 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0232602 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0042401 infores:hetionet NCBIGene:8838 biolink:causes MONDO:0008827 infores:monarchinitiative not_provided not_provided HGNC:12771 MONDO:0008827 uuid:8e98b110-3e99-481a-b2dd-f8eb1a704394 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0011124 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0343886 infores:hetionet CHEBI:71417 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0023380 infores:hetionet CHEBI:3125 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0037763 infores:hetionet CHEBI:64064 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037317 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0018801 infores:hetionet CHEBI:31932 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0231528 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0017675 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1269683 infores:hetionet CHEBI:6472 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0015230 infores:hetionet CHEBI:51380 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0002792 infores:hetionet UMLS:C0065374 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004604 infores:hetionet CHEBI:4702 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0028084 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0151626 infores:hetionet CHEBI:16347 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0017178 infores:hetionet CHEBI:60761 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0041834 infores:hetionet NCBIGene:6868 biolink:causes MONDO:0013693 infores:monarchinitiative not_provided not_provided HGNC:195 MONDO:0013693 uuid:1ebb9807-fb4d-41ef-b443-bdac68c4a855 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0039971 infores:hetionet CHEBI:205919 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0234233 infores:hetionet NCBIGene:128989 biolink:causes MONDO:0018820 infores:monarchinitiative not_provided not_provided HGNC:25439 MONDO:0018820 uuid:50cb004d-a073-4491-b85f-c1c17dd9fa4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C2364111 infores:hetionet CHEBI:2549 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0003862 infores:hetionet CHEBI:7627 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0156404 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0020517 infores:hetionet NCBIGene:1294 biolink:causes MONDO:0009179 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0009179 uuid:af16fe7d-bc21-4a3b-b451-e9bedbba609b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0232462 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0233632 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018939 infores:hetionet CHEBI:145499 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020625 infores:hetionet CHEBI:6073 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0028643 infores:hetionet CAID:CA404081046 biolink:causes MONDO:0007750 infores:clingen CAID:CA404081046 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP1, PP4, BS2 The NM_000527.5(LDLR):c.915G>T (p.Trp305Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.91. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404081046/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:171719 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0003578 infores:hetionet CHEBI:15765 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0338614 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0020517 infores:hetionet CAID:CA258142 biolink:causes MONDO:0100084 infores:clingen CAID:CA258142 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PP4_Moderate, PS3 PS4 The variant NM_001100.4:c.414C>G in ACTA1 is a missense variant predicted to cause substitution of isoleucine by methionine at amino acid 138 (p.Ile138Met). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.799, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In addition, functional studies have demonstrated that this variant severely reduces co-polymerization compared to wild-type actin, and reduces flight ability in Drosophila (PS3; PMIDs: 15226407, 23294764). This variant has been reported in one proband, who has nemaline rods and thin filament accumulation present on muscle biopsy (PP4_Moderate; PMIDs: 11333380, 10838259). In summary, the variant meets criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PS3, PP4_Moderate, PM2_Supporting, PP2, PP3, (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA258142/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68579 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018681 infores:hetionet CAID:CA147753 biolink:causes MONDO:0015152 infores:clingen CAID:CA147753 MONDO:0015152 PMID: Benign BP2, BA1 BP4 The NM_003494.4: c.3992G>T variant in DYSF, which is also known as NM_001130987.2: c.4046G>T p.(Arg1349Leu), is a missense variant predicted to cause substitution of arginine by leucine at amino acid 1331 (p.Arg1331Leu). The filtering allele frequency of the variant is 0.03441 for European (non-Finnish) genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 943/31374), which is higher than the VCEP threshold of 0.003 (BA1). This variant has also been observed in cis with the variant c.5836_5839del p.(Gln1946TrpfsTer19), which is classified as pathogenic by the ClinGen LGMD VCEP (PMID: 19528035) (BP2). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP2. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147753/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:64312 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007286 infores:hetionet CHEBI:3077 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015403 infores:hetionet CHEBI:6456 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0041657 infores:hetionet CHEBI:8207 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C3263723 infores:hetionet CHEBI:52717 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011168 infores:hetionet CHEBI:27953 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00981 UMLS:C0042963 infores:hetionet CHEBI:5050 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0344232 infores:hetionet NCBIGene:9254 biolink:causes MONDO:0032788 infores:monarchinitiative not_provided not_provided HGNC:1400 MONDO:0032788 uuid:eeedb6d6-f87b-4ea5-b20c-653e4f3c3a1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0041969 infores:hetionet CHEBI:63605 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0015672 infores:hetionet CHEBI:194135 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018790 infores:hetionet CHEBI:9316 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0003811 infores:hetionet CHEBI:8890 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0027497 infores:hetionet CHEBI:50275 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042023 infores:hetionet CAID:CA875124281 biolink:causes MONDO:0100437 infores:clingen CAID:CA875124281 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PS4_Supporting, PM2_Supporting, PP1_Strong NM_001034853.2(RPGR):c.3092del (p.Glu1031GlyfsTer?) is a frameshift variant due to a 1-nucleotide deletion in codon 1031 introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygotes in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 34745198, PMID: 29528978, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), onset at age 15 years, electroretinogram responses severely reduced from cones and mildly reduced from rods (1 pt), photophobia (1 pt), reduced visual acuity (0.5 pts), high myopia (1 pt), and genotyping by exome sequencing identifying no alternative basis for retinal disease (2 pts) which together are specific for RPGR-related retinopathy (7.5 points, PMID: 31645972, PP4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 2 families (PP1_Strong, PMID: 30105367, PMID: 31645972). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, PM2_Supporting, PP1_Strong, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA875124281/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:17347 biolink:causes HP:0011458 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0740651 infores:hetionet CHEBI:78543 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0037763 infores:hetionet CHEBI:3219 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019572 infores:hetionet CHEBI:4672 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0024440 infores:hetionet CAID:CA410148181 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148181 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, BA1, BP2, PVS1, PM6, BS1, BS3, BP7, PM4, PM1, PP3 NM_001754.5(RUNX1):c.1085C>T (p.Ser362Leu) is a missense variant which has a REVEL score <0.50 (0.223) (BP4). This variant is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148181/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47381 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023066 infores:hetionet CHEBI:175901 biolink:causes HP:0001937 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0221021 infores:hetionet CHEBI:132233 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0917801 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0037274 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0541820 infores:hetionet CAID:CA120556 biolink:causes MONDO:0044970 infores:clingen CAID:CA120556 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS4, PS2, PM6 The m.8342G>A variant in MT-TK has been reported in one individual with primary mitochondrial disease to date (PMID: 10220860), in a woman with ophthalmoplegia, ptosis, fatigue, muscle weakness, resting tremor, and myoclonic jerks. Muscle biopsy showed COX-negative fibers and decreased electron transport chain enzyme activities. The variant was present at 80% heteroplasmy in muscle and was undetectable in blood lymphocytes. The variant was also undetectable in blood lymphocytes from her asymptomatic mother, maternal aunt, and daughter. As the variant was also undetectable in this tissue in the proband, this cannot be considered a confirmed de novo occurrence. Single fiber testing in the proband showed higher levels of the variant in COX negative fibers (74%, n=26) than in COX positive fibers (53%, n=28), p<0.0003 (PS3_supporting, PMID: 10220860). There are no cybrids or other functional analyses reported for this variant. There is one additional reported individual with the variant in the medical literature, however the heteroplasmy levels are too low (3-4%) to be causative of the clinical features noted (febrile infection-related epilepsy syndrome, or FIRES; PMID: 37077567). This variant is absent in the MITOMAP GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (77.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120556/MONDO:0044970/015 2023-07-24 2025-06-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA410204087 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204087 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.157A>G (p.Ser53Gly) is a missense variant which has a REVEL score < 0.50 (0.391) and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204087/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8481 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0857257 infores:hetionet CHEBI:2950 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0015672 infores:hetionet CHEBI:4445 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0235266 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0027765 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0025061 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0858581 infores:hetionet CAID:CA9043619 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043619 MONDO:0012999 PMID: Pathogenic PM2_Supporting, PM3, PP4_Strong, PVS1_Strong The NM_000156.6:c.521G>A (p.Trp174Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of a total of 6 exons. The variant occurs at the border of the last 50 nucleotides of the penultimate exon of GAMT. As a result, nonsense-mediated decay may not occur. In that case, >10% of the protein is predicted to be lost (PVS1_Strong). The variant has been identified in a female Spanish patient with clinical features consistent with GAMT deficiency, elevated urine guanidinoacetate, and very low GAMT activity in fibroblasts (PMID: 15108290, 16855203, 21140503) (PP4_Strong). This patient is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303; SCV004009593.1). The variants were confirmed to be in trans by parental DNA sequencing. 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002196 (2/91090 alleles; no homozygotes) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Another variant resulting in p.Trp174Ter (c.522G>A) (ClinVar Variation ID: 205584) has been reported and has been classified as pathogenic by the ClinGen CCDS VCEP. There is a ClinVar entry for the variant (Variation ID 801414). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. ACMG/AMP GANT-specific criteria applied, as specified by the ClinGen CCDS VCEP (Version 2.0.0): PVS1_Strong, PM3, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043619/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64321 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0000731 infores:hetionet CHEBI:3752 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0006142 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0087169 infores:hetionet CHEBI:6402 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0702166 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0948299 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0948299 infores:hetionet CHEBI:9566 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0392684 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0853692 infores:hetionet CHEBI:8356 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C3495920 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005741 infores:hetionet CHEBI:168396 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085641 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027769 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232431 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0041969 infores:hetionet CHEBI:5118 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019572 infores:hetionet CHEBI:51860 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013404 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0442874 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0858259 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C2711227 infores:hetionet CAID:CA10014275 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014275 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BP2, BP1, BP3, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.883T>C (p.Ser295Pro) is a missense variant that has a REVEL score < 0.50 (0.184) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014275/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:80630 biolink:causes UMLS:C1142015 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1142015 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0011991 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0010709 infores:hetionet CHEBI:8430 biolink:causes MONDO:0015270 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0268379 infores:hetionet CHEBI:2673 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0151559 infores:hetionet CHEBI:28901 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151723 infores:hetionet CHEBI:45367 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0009676 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0002928 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0002928 infores:hetionet CAID:CA256126 biolink:causes MONDO:0001586 infores:clingen CAID:CA256126 MONDO:0001586 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting PM5 The NM_000203.5:c.1091C>T variant in IDUA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 364 (p.Thr364Met). This variant has been identified in at least 6 probands with MPS I. Three individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.613_617dup (p.Glu207fs) (ClinVar Variation ID: 11921); phase unconfirmed (PMID: 15521993) (max 2 x 0.5 points = 1 point). Two individuals were apparently homozygous for the variant (PMID: 9391892, 16435211; 2 x 0.5 points; one of them is possibly compound heterozygous for the variant and a gene deletion) (PMID: 9391892). Another individual is compound heterozygous for the variant and c.589G>A p.(Gly197Ser) (PMID: 33301762). The allelic data from this patient will be used in the assessment of p.Gly197Ser and is not included here to avoid circular logic. Total 2 points (PM3_Strong). Patients reported with this variant had features specific to MPS I, including one patient with clinical symptoms consistent with the diagnosis, documented IDUA deficiency, and elevated urine GAGs that reduced upon treatment with ERT (PMID: 16435211) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002245 (1/44544 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in COS-7 cells resulted in ~1% wild type IDUA activity and evidence of abnormal IDUA synthesis and processing indicating that this variant may impact protein function (PMIDs: 9391892, 10466419; PS3_Supporting). The computational predictor REVEL gives a score of 0.908 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997; PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: : 11925). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PP3_Moderate, PP4_Moderate,, PM2_Supporting, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, May 16, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA256126/MONDO:0001586/091 2025-05-16 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6715 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0152267 infores:hetionet CAID:CA367403894 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403894 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PVS1, PP4_Moderate, PM2_Supporting The c.46-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 27256595, 30447144; internal lab contributors). Furthermore, at least three of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595, 30447144; internal lab contributors). This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1_Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors). In summary, c.46-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting, PP4_Moderate, PP1_Strong, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403894/MONDO:0015967/086 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3568 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040213 infores:hetionet CHEBI:5098 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0232462 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038454 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0700184 infores:hetionet CHEBI:5613 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020625 infores:hetionet CHEBI:3504 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0015967 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0036974 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0037199 infores:hetionet CHEBI:6444 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0009676 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0007177 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027339 infores:hetionet CHEBI:63616 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151744 infores:hetionet CHEBI:6402 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030193 infores:hetionet CHEBI:4995 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0221423 infores:hetionet CHEBI:75722 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0036973 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0518015 infores:hetionet NCBIGene:2741 biolink:causes MONDO:0007868 infores:monarchinitiative not_provided not_provided HGNC:4326 MONDO:0007868 uuid:454d6bca-9461-4d49-b953-fe033dfd3da6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:F64QU97QCR biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0000737 infores:hetionet CHEBI:8346 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0002994 infores:hetionet CHEBI:9130 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0013604 infores:hetionet CHEBI:6640 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C2830004 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002878 infores:hetionet CHEBI:71417 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0014518 infores:hetionet CHEBI:7494 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085636 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0038362 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0235146 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0026975 infores:hetionet CHEBI:9605 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0040034 infores:hetionet CHEBI:5959 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0000737 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0004238 infores:hetionet NCBIGene:355 biolink:causes MONDO:0011158 infores:monarchinitiative not_provided not_provided HGNC:11920 MONDO:0011158 uuid:839263a2-dd58-41ac-90ec-97ca866dc7b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27953 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00981 UMLS:C0428977 infores:hetionet CHEBI:31236 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013604 infores:hetionet CHEBI:5280 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0030554 infores:hetionet CHEBI:7931 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0030252 infores:hetionet CHEBI:63629 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0003811 infores:hetionet CHEBI:8461 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0011570 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0004093 infores:hetionet CHEBI:145499 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013456 infores:hetionet CHEBI:3723 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0393760 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042134 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0021167 infores:hetionet CHEBI:64355 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0025287 infores:hetionet CHEBI:8776 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0037011 infores:hetionet CAID:CA000286 biolink:causes MONDO:0017623 infores:clingen CAID:CA000286 MONDO:0017623 PMID: Likely Benign PP2, BS1_Supporting, BP4 PM6, PVS1, BP7, BP5, BS3, BS4, PP3, PP1, PP4, BS2, PM4, PM5, PM1, PM3, BA1, BP3, BP1, BP2, PS1, PS3, PS2, PS4 NM_000314.8(PTEN):c.1078A>G (p.Ser360Gly) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00001171.BP4: REVEL score < 0.5 (score of this variant=0.441).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 2 benign supporting and 1 pathogenic supporting codes get (-1*2) + 1 points; total is –1 (likely benign). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000286/MONDO:0017623/003 2023-10-11 2023-10-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2659 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0233571 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0853692 infores:hetionet CHEBI:142290 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013604 infores:hetionet UNII:Z5N076G8YQ biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0232498 infores:hetionet CHEBI:144093 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018681 infores:hetionet CHEBI:101853 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C3665386 infores:hetionet NCBIGene:5660 biolink:causes MONDO:0012517 infores:monarchinitiative not_provided not_provided HGNC:9498 MONDO:0012517 uuid:90d999f2-49e1-42df-93d4-f801c0385174 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0549259 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549259 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0236072 infores:hetionet CHEBI:8060 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0009806 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0042373 infores:hetionet UMLS:C1709429 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0476280 infores:hetionet CHEBI:42944 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0006384 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009938 infores:hetionet CHEBI:3219 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085632 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0750394 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0009319 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042164 infores:hetionet CHEBI:3508 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0016382 infores:hetionet CHEBI:61390 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0027441 infores:hetionet CHEBI:63598 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013390 infores:hetionet CHEBI:63611 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C3665386 infores:hetionet CHEBI:4995 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085605 infores:hetionet CHEBI:465284 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151904 infores:hetionet CHEBI:9671 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0349506 infores:hetionet CHEBI:9086 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004093 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027765 infores:hetionet CHEBI:3647 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0242422 infores:hetionet CHEBI:204928 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0009319 infores:hetionet CHEBI:3176 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0232487 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0042373 infores:hetionet CHEBI:63580 biolink:causes MONDO:0024625 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235228 infores:hetionet CHEBI:31348 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004134 infores:hetionet NCBIGene:4026 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:6679 MONDO:0018874 uuid:b1e0e321-674e-4bca-b619-a5c81037aee6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0853619 infores:hetionet CHEBI:48669 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0036980 infores:hetionet CHEBI:92998 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0021368 infores:hetionet CHEBI:63611 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151878 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0152025 infores:hetionet CHEBI:6761 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0085649 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002184 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1262760 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042401 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0004238 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C1971624 infores:hetionet CHEBI:3640 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0344232 infores:hetionet CHEBI:5384 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0035317 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151736 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0242073 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0037822 infores:hetionet CHEBI:74947 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0024312 infores:hetionet GO:0046602 biolink:causes GO:0007098 infores:ubergraph knowledge_assertion manual_agent GO:0046602 GO:0007098 CHEBI:5130 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013595 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0029408 infores:hetionet NCBIGene:51319 biolink:causes MONDO:0032729 infores:monarchinitiative not_provided not_provided HGNC:24152 MONDO:0032729 uuid:4bfbbadb-9ad9-4520-b0ff-cfda8fce0413 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151908 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0022573 infores:hetionet CHEBI:18248 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0025222 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0542203 infores:hetionet CAID:CA160114 biolink:causes MONDO:0012163 infores:clingen CAID:CA160114 MONDO:0012163 PMID: Benign BS2_Supporting, BA1 The c.1066A>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 356 (p.Ile356Val).The filtering allele frequency (the lower threshold of the 95% CI of 25619/74900 alleles) of the c.1066A>G variant in IL7R is 0.3385 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 55069 adult homozygous occurrences are described in gnomAD (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160114/MONDO:0012163/119 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:44423 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0024141 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0341742 infores:hetionet CHEBI:2379 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0232462 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014742 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0235299 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0235299 infores:hetionet CHEBI:87715 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0015672 infores:hetionet NCBIGene:113612 biolink:causes MONDO:0014015 infores:monarchinitiative not_provided not_provided HGNC:20582 MONDO:0014015 uuid:89cac061-a1a5-4b34-9a5c-c08eee967cee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0003123 infores:hetionet CHEBI:5855 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019080 infores:hetionet CHEBI:27436 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0028960 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0854082 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151998 infores:hetionet CHEBI:15544 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0027497 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020557 infores:hetionet CHEBI:6339 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0016512 infores:hetionet NCBIGene:60676 biolink:causes MONDO:0859182 infores:monarchinitiative not_provided not_provided HGNC:14615 MONDO:0859182 uuid:bfa78637-1503-4c4d-b493-e3b882f4a6d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9362 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0085636 infores:hetionet CHEBI:10101 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0267940 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018799 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151736 infores:hetionet CHEBI:51137 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0022346 infores:hetionet CHEBI:84500 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0000731 infores:hetionet CHEBI:15854 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0013604 infores:hetionet CHEBI:49960 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151905 infores:hetionet CHEBI:9139 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085593 infores:hetionet CHEBI:16467 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0015376 infores:hetionet CAID:CA10646015 biolink:causes MONDO:0100326 infores:clingen CAID:CA10646015 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 The c.2085C>T variant in ITGB3 is a single nucleotide substitution that does not alter the protein sequence (p.Tyr695=). This variant is predicted by SpliceAI to have no significant splicing motif alteration detected (Delta score 0.00) and the nucleotide is not highly conserved (PhyloP score 0.24806) (BP4, BP7). This variant occurs at a very low allele frequency overall in gnomAD v4.0.0 of 0.00004523 with a MAF of 0.00004005 (3/74910) in African/ African American subpopulation (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP7, PM2_Supporting, BP4 Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10646015/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:23765 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0227791 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0235416 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0340464 infores:hetionet CHEBI:7936 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038450 infores:hetionet CHEBI:64321 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020580 infores:hetionet CHEBI:135342 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042024 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0235735 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235735 infores:hetionet GO:0110079 biolink:causes GO:0001890 infores:ubergraph knowledge_assertion manual_agent GO:0110079 GO:0001890 CHEBI:5132 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0002886 infores:hetionet UMLS:C1709429 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0004604 infores:hetionet CHEBI:3441 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0027497 infores:hetionet CHEBI:4445 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151578 infores:hetionet UMLS:C1738934 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0022281 infores:hetionet CHEBI:94686 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1167965 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018799 infores:hetionet CHEBI:291342 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0018681 infores:hetionet CAID:CA325622 biolink:causes MONDO:0007113 infores:clingen CAID:CA325622 MONDO:0007113 PMID:9792887PMID:9792887PMID:29915382 Pathogenic PP1, PP4, PVS1, PM2_Supporting, PS4_Supporting The p.Trp768Ter variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Trp768Ter variant in the UBE3A gene is absent from gnomAD (PM2_supporting). The p.Trp768Ter variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 9792887) (PP1). This variant has been observed in at least 1 other individuals with Angelman syndrome (PMID 29915382) (PS4_supporting). The variant has been reported to segregate in two informative meioses (PMID 9792887) (PP1). In summary, the p.Trp768Ter variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4_supporting, PM2_supporting, PP1, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA325622/MONDO:0007113/016 2021-03-01 2021-05-05 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:5778 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0233494 infores:hetionet CHEBI:15940 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0027497 infores:hetionet NCBIGene:50945 biolink:causes MONDO:0010554 infores:monarchinitiative not_provided not_provided HGNC:11600 MONDO:0010554 uuid:93490e0d-df05-4fde-9011-0ff95a18ab84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0018418 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018790 infores:hetionet CHEBI:3568 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0392171 infores:hetionet CHEBI:8802 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0015967 infores:hetionet CHEBI:8228 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0268000 infores:hetionet CHEBI:7601 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0031350 infores:hetionet CHEBI:15544 biolink:causes MONDO:0006977 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0037859 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018099 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151734 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020517 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004238 infores:hetionet CHEBI:28748 biolink:causes MONDO:0018881 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026985 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027947 infores:hetionet CHEBI:9654 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0003578 infores:hetionet CAID:CA274330 biolink:causes MONDO:0009290 infores:clingen CAID:CA274330 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting NM_000152.5:c.365del (p.Met122ArgfsTer20) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with late onset Pompe disease has been reported with documentation of laboratory values showing GAA deficiency (~7% lower limit of normal) in cultured fibroblasts (2 points) and who is on enzyme replacement therapy (1 point)(PMID: 20638881). (Total 3 points, PP4_Moderate). This patient is compound heterozygous, with unknown phase, for the variant and a pathogenic variant in GAA, c.-32-13T>G (0.5 points, PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 189059, two star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PP4_Moderate, PM3_Supporting, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274330/MONDO:0009290/010 2021-08-19 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9137 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0014534 infores:hetionet GO:0009909 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0009909 GO:0061458 CAID:CA16021856 biolink:causes MONDO:0021056 infores:clingen CAID:CA16021856 MONDO:0021056 PMID: Likely Benign BP1, PM2_Supporting, BS2_Supporting The c.235A>G variant in APC is a missense variant predicted to cause substitution of serine by glycine at amino acid 79 (p.Ser79Gly). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in 6 heterozygous individuals with no features of FAP, worth 3 healthy individual points (BS2_Supporting; Ambry Genetics Internal Data; Invitae Internal Data). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2_supporting, BP1. (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16021856/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6062 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0006384 infores:hetionet CHEBI:724125 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0234215 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0009319 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002871 infores:hetionet CHEBI:231594 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0085633 infores:hetionet CHEBI:5165 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0015967 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0426732 infores:hetionet CHEBI:175901 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151904 infores:hetionet CHEBI:50659 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0041834 infores:hetionet CHEBI:8214 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0042571 infores:hetionet CHEBI:65346 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0042075 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0006266 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0009450 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0037199 infores:hetionet CHEBI:2663 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151701 infores:hetionet CHEBI:80630 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0025160 infores:hetionet CHEBI:50173 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0033774 infores:hetionet CHEBI:38545 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0018965 infores:hetionet NCBITaxon:36855 biolink:causes MONDO:0001857 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36855 MONDO:0001857 CHEBI:9738 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C1443060 infores:hetionet CHEBI:47781 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0234708 infores:hetionet CHEBI:73275 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0006826 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0003467 infores:hetionet CHEBI:6073 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0231218 infores:hetionet CHEBI:3510 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0035078 infores:hetionet CHEBI:50173 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0009763 infores:hetionet CHEBI:5959 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0239488 infores:hetionet CHEBI:8378 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0240735 infores:hetionet UNII:F64QU97QCR biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0235378 infores:hetionet CHEBI:17303 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0035410 infores:hetionet CAID:CA229588 biolink:causes MONDO:0009861 infores:clingen CAID:CA229588 MONDO:0009861 PMID:23430918 Pathogenic PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. ExAC MAF: 0.00001.; PP4: Detected in PKU patient in international phase II clinical trial for sapropterin. (PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229588/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10119 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0033975 infores:hetionet CHEBI:3077 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0085932 infores:hetionet CHEBI:2038 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0043144 infores:hetionet CHEBI:36791 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0423791 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0541832 infores:hetionet CHEBI:9448 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0344232 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0424741 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0424741 infores:hetionet CHEBI:64312 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0022107 infores:hetionet CAID:CA158273 biolink:causes MONDO:0100216 infores:clingen CAID:CA158273 MONDO:0100216 PMID: Benign BP4, BS2, BS1 PM2, PVS1, PM6, BP1, BP3, BP2, BA1, PP2, PP3, PP1, PP4, PM4, PM1, PM3, PM5, PS2, PS3, PS4, PS1, BP7, BP5, BS4, BS3 The NM_177438.2:c.3553G>A variant in DICER1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1185 (p.Ala1185Thr). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; ClinVar SCV: SCV000661803.4, SCV000291663.10; PMIDs: 24728327). The highest population minor allele frequency in gnomAD v3.1.2 is 0.002 (45/15,076 alleles) in Latino/Admixed American populations, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.048; MaxEntScan and SpliceAI: no effect on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2, BP4. (Bayesian Points: -9; VCEP specifications version 1.2.0; 08/22/23) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA158273/MONDO:0100216/024 2023-08-22 2023-09-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27834 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0392171 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0023530 infores:hetionet CHEBI:83804 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0010692 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0086132 infores:hetionet CHEBI:5790 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C3263723 infores:hetionet CHEBI:41977 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0232292 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0020557 infores:hetionet CHEBI:61049 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0522055 infores:hetionet CAID:CA220390 biolink:causes MONDO:0009290 infores:clingen CAID:CA220390 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3_Moderate The NM_000152.5:c.1465G>A variant in GAA is a missense variant that is predicted to result in the substitution of aspartate by asparagine at amino acid 489 (p.Asp489Asn). This variant has been detected in at least 10 patients reported to have Pompe disease including 7 individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 17151339, 22081099, 22658377, 24395639, 24844452, 24923245, 29422078, 31193175), and three for whom GAA activity was not reported but who were treated by enzyme replacement (PMIDs: 25626711, 28574618). Nine individuals were compound heterozygous, phase unknown, for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 16917947, 2208109, 24395639, 24844452, 24923245, 28574618), c.40_47del8 (PMID: 29422078), c.307T>G (p.Cys103Gly) (PMID: 18429042), c.1799G>A (p.Arg600His) (PMID: 22711147), c.2014C>T (p.Arg672Trp) (PMID: 16917947, 2208109), and another individual was compound heterozygous for the variant and c.2481+110_2646+39del (labeled as c.IVS17 + 102_IVS18 + 31 in the paper) confirmed in trans (PMID: 25626711). The variant was also detected in a parent of two affected children, now deceased, with c.1962_1964delAGA (p.Glu655del) in the other parent. However, as these variants were not confirmed to be present in the affected children, the data is not included (PMID: 22711147). Another individual was reported to have the variant but the cDNA sequence was not provided (PMID: 17616415 (PM3_VeryStrong). The highest population minor allele frequency in gnomAD is 0.00005 (1/21638) in the European Finnish population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In two different studies, this variant results in <2% GAA activity when expressed in COS-7 cells or Ad5-SV40 immortalized human GAA-deficient fibroblasts and, on Western blot, most of the gene product remained as the 110 kDa inactive precursor (PMID: 17915575, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.938 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 92465). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP, February 7, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220390/MONDO:0009290/010 2023-02-07 2023-03-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:16899 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0344232 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0162429 infores:hetionet CHEBI:135930 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0687713 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042401 infores:hetionet CHEBI:3756 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0232461 infores:hetionet CHEBI:9398 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0027429 infores:hetionet CHEBI:231594 biolink:causes MONDO:0020686 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0001361 infores:hetionet CHEBI:9674 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0011053 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151828 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0042109 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151970 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042134 infores:hetionet CHEBI:45409 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0232849 infores:hetionet CHEBI:584020 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0027497 infores:hetionet CHEBI:63631 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0278134 infores:hetionet CHEBI:2038 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0032781 infores:hetionet CHEBI:47898 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0003962 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0026946 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0031350 infores:hetionet NCBITaxon:36831 biolink:causes MONDO:0016453 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36831 MONDO:0016453 CHEBI:10023 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C3665347 infores:hetionet CHEBI:135930 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0015672 infores:hetionet CHEBI:63638 biolink:causes MONDO:0007741 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0266316 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042769 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0221742 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1142412 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0020538 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1384353 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0027765 infores:hetionet CHEBI:63577 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0001125 infores:hetionet CHEBI:408174 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0013404 infores:hetionet CHEBI:3175 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0030252 infores:hetionet CHEBI:134966 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0018965 infores:hetionet CHEBI:9086 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023222 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0026848 infores:hetionet GO:0010543 biolink:causes GO:0007596 infores:ubergraph knowledge_assertion manual_agent GO:0010543 GO:0007596 CHEBI:9448 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0014518 infores:hetionet MONDO:0002012 biolink:causes MONDO:0002320 infores:drugmechdb knowledge_assertion manual_agent HP:0002912 HP:0000707 DB00115_MESH_D001361_1DB00115_MESH_D014806_1 CHEBI:6775 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011991 infores:hetionet CHEBI:5050 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0085631 infores:hetionet CHEBI:490877 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0852911 infores:hetionet CHEBI:3749 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0015230 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034063 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0011991 infores:hetionet CHEBI:92511 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0042109 infores:hetionet CHEBI:9599 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0026896 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0024115 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0233632 infores:hetionet CHEBI:6950 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0428974 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0026113 infores:hetionet CAID:CA404084657 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084657 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP4, PS1, BS1, PM5, PP3 The NM_000527.5(LDLR):c.1190C>T (p.Ser397Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084657/MONDO:0007750/013 2023-06-23 2025-09-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63605 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0014356 infores:hetionet CHEBI:28864 biolink:causes HP:0003537 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0221333 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0018802 infores:hetionet CHEBI:144551 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011615 infores:hetionet CHEBI:2704 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0011603 infores:hetionet CHEBI:64318 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0010520 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0018790 infores:hetionet CHEBI:87681 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0917801 infores:hetionet CHEBI:42944 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C1456784 infores:hetionet NCBIGene:2244 biolink:causes MONDO:0008737 infores:monarchinitiative not_provided not_provided HGNC:3662 MONDO:0008737 uuid:5dbce092-ec9a-4d7c-a0f2-20818065dd00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0029408 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0013395 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011053 infores:hetionet CHEBI:94686 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0700590 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0004936 infores:hetionet CHEBI:10102 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0024902 infores:hetionet CHEBI:94392 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0034063 infores:hetionet CAID:CA200657 biolink:causes MONDO:0100453 infores:clingen CAID:CA200657 MONDO:0100453 PMID: Benign BP4, BA1, BS2 NM_000180.4(GUCY2D):c.2101C>T (p.Pro701Ser) is a missense variant that is predicted to replace proline at position p.701 with serine. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.2041, with 9318 / 44874 alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 2099 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of >6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.27, which is below the ClinGen LCA / eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP:BA1, BS2, BP4 (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA200657/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:10023 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085692 infores:hetionet CHEBI:31644 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0033774 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0029442 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0233472 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009144 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0001339 infores:hetionet CHEBI:3654 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0022354 infores:hetionet CHEBI:2914 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0151786 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0740425 infores:hetionet CHEBI:63629 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018965 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0853813 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0259799 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0006145 infores:hetionet CHEBI:31981 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0033117 infores:hetionet CHEBI:15367 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019080 infores:hetionet CHEBI:16469 biolink:causes NCIT:C54056 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0521987 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0020649 infores:hetionet CHEBI:32588 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0020461 infores:hetionet CHEBI:5134 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0033774 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019158 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151826 infores:hetionet CAID:CA16616523 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616523 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.741C>T (p.Pro247=) is a synonymous variant. As such, a REVEL score is not calculable, and there is no predicted effect on protein function. SpliceAI predicted the following: Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. As such, there is no in silico evidence of an effect on splicing(BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.06724 < 2.0)(BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1(PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616523/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7443 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0001824 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0032285 infores:hetionet CHEBI:31981 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0018418 infores:hetionet CHEBI:17026 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1306341 infores:hetionet CAID:CA023492 biolink:causes MONDO:0007750 infores:clingen CAID:CA023492 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PM2, PP4 BP4, PM5, PM3, PP3 The NM_000527.4(LDLR):c.1414G>T (p.Asp472Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PP4 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0001098 (0.01098%) in South Asian exomes+genomes (gnomAD v4.1.0). PS3_Supporting: Level 3 assay – PMID:25647241 (Thormaehlen et al., 2015): In vitro microscopy assays in HeLa cells- LDLR expression in the ER was reduced by 36% compared to the wild-type, and reduction of free cholesterol, which indicated an impact on either LDLR biosynthesis or turnover. PS4, PP4: Variant meets PM2 and is identified in 13 unrelated index cases (1 case fulfilling DLCN criteria ≥ 6 from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France; 3 cases fulfilling DLCN criteria ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine, Italy; 4 cases with MedPed criteria from PMID:22698793 (Tichý et al., 2012), Czech Republic; 3 cases with MedPed criteria from PMID:27824480 (Gabčová et al., 2017), Slovakia; 1 case with MedPed criteria from PMID:29870584 (Saracoglu et al., 2018), Turkey; 1 case fulfilling Japanese Atherosclerosis Society criteria from PMID: 36229376 (Tada et al., 2022), Japan). PP1_Strong - Variant segregates with FH phenotype in at least 6 informative meioses from 3 families from Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine, Italy, PMID 17196209 and 27542166: 5 affected family members have the variant and 1 unaffected family member does not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023492/MONDO:0007750/013 2025-01-31 2025-09-16 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:64355 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011071 infores:hetionet CHEBI:16796 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0023530 infores:hetionet CAID:CA000418 biolink:causes MONDO:0017623 infores:clingen CAID:CA000418 MONDO:0017623 PMID:29706350 Pathogenic PM2, PM6, PP2, PM1, PS3 PTEN c.368A>G (p.His123Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 10234502)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000418/MONDO:0017623/003 2021-04-29 2021-04-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:23765 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0014591 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0235146 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0234913 infores:hetionet CHEBI:80630 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0340865 infores:hetionet CAID:CA10014370 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014370 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM2, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1): c.712G>A (p.Val238Ile) is a missense variant has a REVEL score < 0.50 (0.288) and a SpliceAI score ≤ 0.20 (0.03) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014370/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes MONDO:0024280 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0162323 infores:hetionet GO:0061168 biolink:causes GO:0043588 infores:ubergraph knowledge_assertion manual_agent GO:0061168 GO:0043588 CHEBI:6339 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0010200 infores:hetionet NCBIGene:1834 biolink:causes MONDO:0007441 infores:monarchinitiative not_provided not_provided HGNC:3054 MONDO:0007441 uuid:c715e22c-399b-48fe-b2e4-b453ecd7add7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0023380 infores:hetionet CHEBI:7640 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2584688 infores:hetionet CHEBI:8245 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0036974 infores:hetionet CHEBI:135930 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0004093 infores:hetionet CHEBI:31859 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0028754 infores:hetionet CHEBI:63620 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0036974 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0008325 infores:hetionet CHEBI:31413 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0004096 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0007787 infores:hetionet CHEBI:2666 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0042510 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0677500 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031085 infores:hetionet CHEBI:4885 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0011991 infores:hetionet CHEBI:51860 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0043352 infores:hetionet CHEBI:9654 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0002622 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0948594 infores:hetionet CHEBI:2955 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0015967 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034065 infores:hetionet CHEBI:64318 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0030193 infores:hetionet CAID:CA10578906 biolink:causes MONDO:0017623 infores:clingen CAID:CA10578906 MONDO:0017623 PMID: Pathogenic PS2_Very Strong, PS3_Supporting, PP3, PP2, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PP4, PP1, BS2, PM3, PM4, PM1, PM5, BA1, BP4, BP1, BP2, BP3, PS1 NM_000314.8(PTEN):c.103A>G (p.Met35Val) meets criteria to be classified as Pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: At least two proven de novo observations in a patient with the disease and no family history. (internal laboratory contributors: SCV000275912.7, SCV000565444.8).PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3 (Post et al. 2020 PMID: 32350270: pAKT levels similar to C124S).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 27531073, internal laboratory contributor: SCV000275912.7).PM2_P: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.953) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578906/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:474180 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151849 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018939 infores:hetionet CHEBI:9123 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038450 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0521491 infores:hetionet CHEBI:39669 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0220870 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011849 infores:hetionet UBERON:0034769 biolink:causes MONDO:0006075 infores:ubergraph knowledge_assertion manual_agent UBERON:0034769 MONDO:0006075 CHEBI:7496 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0031350 infores:hetionet CHEBI:47499 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0002170 infores:hetionet CHEBI:3757 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030193 infores:hetionet CHEBI:8382 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0033774 infores:hetionet CAID:CA2801940 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801940 MONDO:0001586 PMID: Likely Benign BS1, BP4 The NM_000203.5:c.493+10C>T variant is located in the donor splice consensus region of intron 4 of IDUA. The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (all scores <0.1) (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004778 (357/74718; 1 homozygote; GrpMax Filtering Allele Frequency (95% confidence) = 0.004369) in the African/African-American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.0025), and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature. There is a ClinVar entry for this variant (Variation ID: 785720). In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801940/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6715 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151786 infores:hetionet CHEBI:8024 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0004093 infores:hetionet CHEBI:28901 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0011206 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0178298 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151736 infores:hetionet CHEBI:231594 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0033774 infores:hetionet GO:1901249 biolink:causes GO:0030324 infores:ubergraph knowledge_assertion manual_agent GO:1901249 GO:0030324 CHEBI:6129 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0162830 infores:hetionet CAID:CA421942697 biolink:causes MONDO:0013144 infores:clingen CAID:CA421942697 MONDO:0013144 PMID: Likely Benign BP7, PM2_Supporting, BP4 PS4 The NM_000488.4(SERPINC1):c.51T>C variant predicts a synonymous change at residue Tyr 117. The variant has not been reported in any individuals with AT deficiency in the literature at this time, to the best of our knowledge. The variant is absent in gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). It has a VarSEAK score of 1, and Splice AI gives an acceptor loss score of 0.01 (BP4). The nucleotide appears to be not conserved, with a PhyloP score of 0.02 (BP7). In summary, based on the evidence available at this time, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BP4, BP7, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA421942697/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7820 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0042755 infores:hetionet CHEBI:63616 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0237849 infores:hetionet NCBIGene:25981 biolink:causes MONDO:0033204 infores:monarchinitiative not_provided not_provided HGNC:2940 MONDO:0033204 uuid:c74f2e57-be78-434c-bf58-5c1a74d232e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3504 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0040822 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0235032 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0021122 infores:hetionet CHEBI:49713 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0042571 infores:hetionet CHEBI:77733 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C2830004 infores:hetionet CHEBI:8874 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0086439 infores:hetionet CHEBI:5062 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C2225524 infores:hetionet CHEBI:3504 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0595916 infores:hetionet CHEBI:10023 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1519353 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0013395 infores:hetionet CHEBI:38940 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0016382 infores:hetionet CHEBI:3082 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0016382 infores:hetionet CHEBI:6935 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0687713 infores:hetionet CHEBI:31547 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0004093 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0042075 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0013604 infores:hetionet CHEBI:17141 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0015967 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0014868 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0917798 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0016053 infores:hetionet CHEBI:3286 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0231218 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025637 infores:hetionet CHEBI:65349 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0004093 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0267596 infores:hetionet CHEBI:17026 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0011603 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0036572 infores:hetionet NCBIGene:2218 biolink:causes MONDO:0013156 infores:monarchinitiative not_provided not_provided HGNC:3622 MONDO:0013156 uuid:267dd52d-9b95-44ba-818c-79637ae447e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes MONDO:0020677 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011057 infores:hetionet CHEBI:4975 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0003862 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038367 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0004096 infores:hetionet CHEBI:168396 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004604 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002209 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0158322 infores:hetionet NCBIGene:6121 biolink:causes MONDO:0032873 infores:monarchinitiative not_provided not_provided HGNC:10294 MONDO:0032873 uuid:6c118e88-c472-48d4-b18f-1507605b1a73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0234913 infores:hetionet CHEBI:47898 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030196 infores:hetionet CHEBI:6954 biolink:causes UMLS:C1955743 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1955743 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0349506 infores:hetionet CHEBI:29688 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0238106 infores:hetionet CAID:CA012832 biolink:causes MONDO:0005045 infores:clingen CAID:CA012832 MONDO:0005045 PMID:27532257PMID:27532257 Pathogenic PP3, PM1, PM2, PP1_Moderate, PS4 The c.2681A>G (p.Glu894Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:PMID:27532257; PMID:15358028; PMID:15858117; PMID:21511876; PMID:23396983; PMID:24510615; SHaRe consortium, PMID: 30297972, Partners LMM ClinVar SCV000059463.5; AGCMC Sydney ClinVar SCV000212641.2; Invitae ClinVar SCV000253683.5). This variant segregated with disease in 6 affected individuals (PP1_Moderate: AGCMC Sydney ClinVar SCV000212641.2; Partners LMM ClinVar SCV000059463.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012832/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31401 biolink:causes UMLS:C0079035 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0079035 infores:hetionet CHEBI:9907 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0003862 infores:hetionet CHEBI:7825 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0033774 infores:hetionet CAID:CA410147753 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147753 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS2, PS4, PS1, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM1, PM3, PM5, PP2, PP3, PP4, PP1, BS2 The c.1219T>A (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of tyrosine by asparagine at amino acid 407 (p.Y407N). This variant is absent from gnomAD v2 and v3 (PM2_Supporting) but also has not been reported in the literature. The computational predictor REVEL gives a score of 0.565, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, but the splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting. (Version 2; date of approval) Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147753/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7773 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0000737 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0037199 infores:hetionet CHEBI:66903 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0027497 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005711 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0019284 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0340464 infores:hetionet CHEBI:367163 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0001339 infores:hetionet CAID:CA354672474 biolink:causes MONDO:0021060 infores:clingen CAID:CA354672474 MONDO:0021060 PMID: Likely Pathogenic PS2, PM1, PP3, PM2_Supporting, PS4_Supporting The c.212A>G (p.Gln71Arg) variant in MRAS is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 71. This variant is absent from gnomAD v2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.926, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). This variant resides within the Switch II domain (amino acids 67 – 74), of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:31173466). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:31173466). In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM1, PS4_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.4; 12/03/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA354672474/MONDO:0021060/087 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31236 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020517 infores:hetionet CHEBI:8597 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0012833 infores:hetionet CHEBI:48273 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0027497 infores:hetionet CHEBI:3181 biolink:causes MONDO:0002695 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0338575 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0403632 infores:hetionet CHEBI:145499 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011168 infores:hetionet CAID:CA10652908 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652908 MONDO:0011071 PMID: Likely Benign BS1 PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*3527T>G is a 3' UTR variant. MAF of 0.0001764 (0.01764%, 12/68040) in the European (non-finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.00015 (0.015%) (BS1). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652908/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45409 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0024282 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005479 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0546959 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009806 infores:hetionet CHEBI:114785 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0424790 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0549336 infores:hetionet CHEBI:27882 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0012739 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0008035 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019348 infores:hetionet CHEBI:72297 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0151905 infores:hetionet CHEBI:3207 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0033774 infores:hetionet CAID:CA024467 biolink:causes MONDO:0007783 infores:clingen CAID:CA024467 MONDO:0007783 PMID:26115329PMID:16163667 Pathogenic PS3_Moderate, PM1, PS4_Moderate, PP3_Moderate, PP1_Moderate PM5, BS3, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 163 of the RYR1 protein p.(Arg163Leu). This variant is absent from a large population databases (gnomAD). This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:16163667). This variant segregates with MHS in five individuals, PP1_Moderate (PMID:35718563). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:16163667, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). Another variant assessed as pathogenic occurs at this codon, p.(Arg163Cys), however PM5 was not applied as Arg→Cys is predicted to be more disruptive based on a higher Grantham score as compared to Arg→Leu. A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). Criteria implemented: PS4_Moderate, PS3_Moderate, PM1, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024467/MONDO:0007783/012 2023-05-22 2023-05-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:127342 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0233494 infores:hetionet CHEBI:17474 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0003862 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0022658 infores:hetionet CHEBI:10102 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0027066 infores:hetionet CHEBI:3650 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0162830 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0010709 infores:hetionet CHEBI:39669 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0232462 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0001824 infores:hetionet GO:0003420 biolink:causes GO:0060348 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0060348 CHEBI:45783 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018926 infores:hetionet CHEBI:8485 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0423153 infores:hetionet CHEBI:6710 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0009763 infores:hetionet CHEBI:2453 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0038325 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0575090 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0019348 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0000731 infores:hetionet CHEBI:168396 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0037299 infores:hetionet CHEBI:29007 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C2047937 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0858277 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0858277 infores:hetionet UMLS:C0009315 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0151539 infores:hetionet CHEBI:28445 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0000729 infores:hetionet CAID:CA410202687 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202687 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PS4_Moderate, PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP3, BP2, BP1, BP4, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP4, PP2, PP1, BS2 NM_001754.5(RUNX1):c.403G>A (p.Gly135Ser) is a missense variant which has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_moderate; PMID: 27479822, 32935436). This variant has a REVEL score > 0.88 (0.961) (PP3). It is located within the Runt Homology Domain (RHD; AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). Additionally, the variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_moderate, PP3, PM1_supporting, and PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202687/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17823 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0240211 infores:hetionet CHEBI:31348 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018965 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011168 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0040046 infores:hetionet CHEBI:144551 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0152198 infores:hetionet CHEBI:7476 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018926 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1167779 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1167779 infores:hetionet UMLS:C1709429 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0042963 infores:hetionet CHEBI:10125 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233514 infores:hetionet CAID:CA180967 biolink:causes MONDO:0021060 infores:clingen CAID:CA180967 MONDO:0021060 PMID: Uncertain Significance PP2, PP3 BS1, BS2 The c.281C>T (p.Ser94Leu) variant in MAP2K2 has been identified in 2 independent occurrences in patients with a RASopathy; however, in both cases it was inherited from an apparently unaffected parent (BS2 not met; GeneDx, LMM internal data; ClinVar SCV000204231.4; SCV000207977.8). The p.Ser94Leu variant was present in 0.012% (3/24906) of African alleles in gnomAD (PM2 not met, gnomad.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that this variant may impact protein function (PP3). In summary, the clinical significance of the p.Ser94Leu variant is uncertain. ACMG/AMP criteria applied: PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180967/MONDO:0021060/004 2020-05-18 2020-07-01 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true UMLS:C0145867 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0236071 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0016436 infores:hetionet CHEBI:6846 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0022107 infores:hetionet CHEBI:7903 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0026858 infores:hetionet CHEBI:41423 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0016655 infores:hetionet CHEBI:48273 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0340865 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0041976 infores:hetionet CHEBI:3127 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C3160741 infores:hetionet CHEBI:63611 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085611 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042075 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0392171 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0877517 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0036572 infores:hetionet CHEBI:3314 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0009421 infores:hetionet CHEBI:10127 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0000768 infores:hetionet CHEBI:68478 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0497156 infores:hetionet CHEBI:61049 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0033774 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0018099 infores:hetionet NCBIGene:9567 biolink:causes MONDO:0975745 infores:monarchinitiative not_provided not_provided HGNC:4669 MONDO:0975745 uuid:66172f9b-7312-4c29-95ca-8c8d4f487cf0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0019348 infores:hetionet NCBIGene:5058 biolink:causes MONDO:0032568 infores:monarchinitiative not_provided not_provided HGNC:8590 MONDO:0032568 uuid:871a942f-a7f6-4cd2-874f-92b7a5c54956 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0016655 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151828 infores:hetionet CHEBI:4495 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0030252 infores:hetionet CHEBI:8499 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0428977 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085681 infores:hetionet CHEBI:31547 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020625 infores:hetionet CHEBI:5280 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0010034 infores:hetionet CHEBI:71219 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0019080 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0040435 infores:hetionet CHEBI:50859 biolink:causes HP:0005542 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151563 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0007682 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019348 infores:hetionet CHEBI:71417 biolink:causes HP:0004447 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0221281 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0423602 infores:hetionet CHEBI:47781 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0039231 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0003864 infores:hetionet CHEBI:63681 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0018524 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0027769 infores:hetionet NCBIGene:6874 biolink:causes MONDO:0957536 infores:monarchinitiative not_provided not_provided HGNC:11537 MONDO:0957536 uuid:9be3c365-2f2d-4cd3-baaa-ffa9be758550 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020517 infores:hetionet CHEBI:6149 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013404 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020456 infores:hetionet CHEBI:39585 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C2047937 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0948594 infores:hetionet CHEBI:50749 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0521491 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0033777 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0857353 infores:hetionet CHEBI:83804 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0392156 infores:hetionet CHEBI:46081 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0013378 infores:hetionet CAID:CA013774 biolink:causes MONDO:0005045 infores:clingen CAID:CA013774 MONDO:0005045 PMID: Uncertain Significance PP3, PS3_Supporting PP2, BP4, PS4, BS3 NM_000258.3(MYL3):c.427G>A (p.Glu143Lys). This variant has been reported in individuals with HCM and other cardiomyopathies (Olsen 2002 PMID: 12021217, Caleshu 2011 PMID: 21823217, Walsh 2017 PMID: 27532257, Whiffin 2017 PMID: 28518168) and has also been identified in 4 out of 35436 (0.03% FAF 95% CI) of Latino chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). Recessive inheritance has been described in two pedigrees (Olsen 2002 PMID: 12021217, Caleshu 2011 PMID: 21823217); in both families, homozygous individuals presented with early onset hypertrophic or restrictive cardiomyopathy and heterozygous adult relatives had normal echocardiograms and ECGs. This variant is not statistically increased in individuals with HCM compared to controls; [OR lower 95% CI <5]. Therefore, the PS4 criteria has not been applied and the PM2_Supporting criterion has not been applied either. Functional studies, including mouse models provide some evidence that this variant impacts protein function (PS3_Supporting; Lossie 2012 PMID: 22131351, McNamara 2017 PMID: 28658286, Yuan 2017 PMID: 28371863, Wang 2018 PMID: 29669825). Additionally, computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS3_Supporting, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013774/MONDO:0005045/103 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37924 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0021368 infores:hetionet CHEBI:8481 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0027769 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030305 infores:hetionet CHEBI:68478 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004604 infores:hetionet CHEBI:3756 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0028734 infores:hetionet UMLS:C0657912 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0575081 infores:hetionet CHEBI:145499 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0221423 infores:hetionet CHEBI:6128 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0002874 infores:hetionet CHEBI:28830 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0002453 infores:hetionet CHEBI:8707 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011175 infores:hetionet CHEBI:28901 biolink:causes MONDO:0020547 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0867389 infores:hetionet CHEBI:77260 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0036572 infores:hetionet CHEBI:63791 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0014591 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0234458 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0020517 infores:hetionet CHEBI:5856 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0035078 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0392025 infores:hetionet CHEBI:28001 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0235280 infores:hetionet CHEBI:4530 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0041834 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0234913 infores:hetionet CAID:CA10604166 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604166 MONDO:0015152 PMID: Pathogenic PP4_Strong, BP2, PM3_Very Strong, PM2_Supporting PM5, PS3, BP7, PP3, PP1 The NM_003494.4: c.1168G>A variant in DYSF, which is also known as NM_001130987.2: c.1264G>A p.(Asp422Asn), is expected to cause the substitution of aspartic acid for asparagine at amino acid position 390, p.(Asp390Asn). This variant has been reported in at least 8 individuals with features consistent with LGMD or dysferlinopathy (PMID: 32934002, 33927379, 33927379, 30564623, 26273692, 18853459, 25783436; LOVD DYSF_000030), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, LOVD Individual #00215139). It has also been reported in unknown phase with a pathogenic variant in at least five patients (NM_003494.4: c.1177C>T p.(Glu393Ter), 0.5 pts, LOVD Individual #00215611; NM_003494.4: c.896G>A p.(Gly299Glu), 0.5 pts, PMID: 36983702; NM_003494.4: c.5302C>T p.(Arg1768Trp), 0.5 pts x3 = 1.5 pt, PMID: 32934002, 25783436, 33927379, 30564623, LOVD Individuals #00281785, #00215583, #00220676) and confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.4886+1249G>T, 1.0 pt, PMID: 26273692) (PM3_Very Strong). An affected sibling was shown to have the same two DYSF variants, but phase was not confirmed (PMID: 32934002, 25783436). In another patient, the c.1168G>A p.(Asp422Asn) variant was confirmed in cis with a likely pathogenic or pathogenic variant (NM_003494.4: c.3181del p.(Gln1061ArgfsTer59), LOVD Individual #00215537; BP2). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD/Miyoshi myopathy and severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 36983702; PMID: 33610434; PP4_Strong). The filtering allele frequency for this variant is 0.000022226 for gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 16/1093372 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). RNAseq and minigene analysis have indicated this variant does not influence splicing (PMID: 36983702; PMID: 26273692), but the computational predictor REVEL gives a score of 0.414, suggesting an effect of the protein change cannot be ruled out (PP3, BP4 not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy. Although there is benign evidence for this variant, this observation is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Very Strong, PP4_Strong, PM2_Supporting, BP2. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604166/MONDO:0015152/180 2025-07-29 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68558 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0031256 infores:hetionet CHEBI:142290 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0039231 infores:hetionet CHEBI:5106 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0018834 infores:hetionet CHEBI:94686 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0030554 infores:hetionet CHEBI:10124 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0003467 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0011991 infores:hetionet CAID:CA410208119 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208119 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.527C>A (p.Thr176Asn) is a missense variant which has a REVEL score ≥ 0.88 (0.94) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-294) but does not impact a residue which has been established as a hotspot (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208119/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:6232 biolink:causes MONDO:0044310 infores:monarchinitiative not_provided not_provided HGNC:10416 MONDO:0044310 uuid:b3ba1f95-31da-4a6b-b4b1-c5ec160b8d8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50841 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0855775 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0004926 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D003607 DB00684_MESH_D003607_1 CHEBI:9123 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027051 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0860801 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0860801 infores:hetionet CHEBI:9737 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0700225 infores:hetionet CHEBI:3207 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C3665347 infores:hetionet CHEBI:71028 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0000737 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0010709 infores:hetionet CHEBI:9139 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0086168 infores:hetionet CHEBI:94807 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0012833 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0034063 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0423271 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0423271 infores:hetionet CHEBI:4562 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0027497 infores:hetionet CHEBI:142290 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C2047937 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0853149 infores:hetionet CHEBI:8772 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0036974 infores:hetionet CHEBI:51860 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233514 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0349506 infores:hetionet CHEBI:63580 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0232462 infores:hetionet CAID:CA9043740 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043740 MONDO:0012999 PMID: Likely Benign BP4, BP7 PM2, BS1 The NM_000156.6:c.315G>A (p.Arg105=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.854) (BP4, BP7). To our knowledge, this variant has not been reported in the literature among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004959 (21/42344 alleles in the E. Asian population, which is lower than the CCDS VCEP's threshold for BS1 (>0.001) and higher than the threshold for PM2_Supporting (<0.0004) (no population codes are met).There is a ClinVar entry for this v iant (Variation ID: 516094). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043740/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:94686 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0008031 infores:hetionet CHEBI:7640 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0028084 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020517 infores:hetionet CHEBI:28445 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0242528 infores:hetionet CHEBI:6916 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0023530 infores:hetionet CHEBI:9763 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0042023 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0008408 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0008408 uuid:0a32975f-6291-4186-bdc8-0c136f2247be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:11154 biolink:causes MONDO:0013552 infores:monarchinitiative not_provided not_provided HGNC:575 MONDO:0013552 uuid:b0dbb535-0d4b-43e7-be5d-828cedca3fed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94807 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0013428 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042514 infores:hetionet CAID:CA10584590 biolink:causes MONDO:0018875 infores:clingen CAID:CA10584590 MONDO:0018875 PMID: Likely Pathogenic PS4, PP3, PS3_Moderate, PM2_Supporting BP4, BA1, PS2, PS1, PM1, PM5, BS1, BS3, BS4, PM6, PP1, PP4 The NM_000546.6: c.538G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 180 (p.Glu180Lys). This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.262; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4; PM2_Supporting, PS3_Moderate; PP3. (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584590/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:100246 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0027947 infores:hetionet NCBIGene:4233 biolink:causes MONDO:0031045 infores:monarchinitiative not_provided not_provided HGNC:7029 MONDO:0031045 uuid:aa1518b6-3bc5-48c7-8912-5b2862221129 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0014130 infores:hetionet CHEBI:43968 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0034063 infores:hetionet CHEBI:3561 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1322281 infores:hetionet NCBIGene:10461 biolink:causes MONDO:0013469 infores:monarchinitiative not_provided not_provided HGNC:7027 MONDO:0013469 uuid:2a8c6b2e-e703-4acf-8f1f-6723955e74ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9566 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0014457 infores:hetionet CHEBI:47780 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014724 infores:hetionet CHEBI:3655 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0231218 infores:hetionet CHEBI:116735 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0020517 infores:hetionet CHEBI:61058 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0019158 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038358 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017675 infores:hetionet UMLS:C0657912 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040264 infores:hetionet CHEBI:6887 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0023530 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0020514 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0029408 infores:hetionet NCBIGene:1716 biolink:causes MONDO:0014899 infores:monarchinitiative not_provided not_provided HGNC:2858 MONDO:0014899 uuid:a459c0eb-ff7e-473c-8111-72fb87924e02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63717 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0003467 infores:hetionet CAID:CA181051 biolink:causes MONDO:0021060 infores:clingen CAID:CA181051 MONDO:0021060 PMID: Benign BP7, BP4, BA1 The c.*4C>T variant in SOS1 is classified as benign because it has been identified in 0.05383% (95% CI of 27/35402) of Latino alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). It does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA181051/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:71219 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0948586 infores:hetionet CHEBI:29013 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0042963 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0004096 infores:hetionet CAID:CA024477 biolink:causes MONDO:0007783 infores:clingen CAID:CA024477 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with glycine at codon 166 of the RYR1 protein, p.(Asp166Gly). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode but without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, this is insufficient for PS4 to be implemented. This individual also had an additional variant in RYR1 assessed as likely pathogenic, p.(Arg2163His), phase unknown (PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.967) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024477/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:4315 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0007286 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0522570 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0522570 infores:hetionet CHEBI:50861 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0013395 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0859350 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0859350 infores:hetionet CHEBI:9649 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C2937358 infores:hetionet CAID:CA1433050681 biolink:causes MONDO:0001586 infores:clingen CAID:CA1433050681 MONDO:0001586 PMID: Likely Pathogenic PM4_Supporting, PM3_Strong, PS3_Supporting, PP4, PP3, PM2_Supporting PM1 The NM_000203.5:c.144_146del variant is predicted to cause a change in the length of the protein (p.Arg48del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4_Supporting). This variant has been detected in four probands and one sibling with clinical features and diagnosis of MPS I. At least three patients with this variant had documented deficient IDUA activity, one patient had documented enzyme replacement therapies with the stabilized reduction in urine GAGs, and one patient had documented hematopoietic cell transplantation (PMID: 12559846, 27896125, 29976218, https://doi.org/10.46531/sinapse/CC/210086/2022) (PP4). All four probands were compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, including two individuals with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 12559846, DOI: https://doi.org/10.46531/sinapse/CC/210086/2022; 1 point), one proband and a sibling with p.Glu404Ter (ClinVar Variation ID: 552095) (PMID: 27896125; 0.5 point), and one individual with p.Pro533Arg (ClinVar Variation ID: 11910) (PMID: 29976218; 0.5 point). (PM3_Strong, 2 points). The highest population minor allele frequency in gnomAD v4.1.0 is 8.828e-7 (1/1132742 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in CHO-K1 cells resulted in 0.92% (<2%) wild-type IDUA activity and evidence of abnormal IDUA processing, indicating that this variant may impact protein function (PMID: 12559846) (PS3_Supporting). The in silico predictor MutPredIndel gave a score of 0.74519. This is above the threshold of 0.5, suggesting that the variant may impact IDUA function (PP3). There is a ClinVar entry for this variant (Variation ID: 1518010). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 1.0.0): PM3_Strong, PP4, PP3, PS3_Supporting, PM2_Supporting, PM4_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 4, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA1433050681/MONDO:0001586/091 2025-05-04 2025-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10101 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0007867 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0019372 infores:hetionet CHEBI:9763 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0022408 infores:hetionet CHEBI:7581 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C1443060 infores:hetionet CAID:CA023607 biolink:causes MONDO:0007750 infores:clingen CAID:CA023607 MONDO:0007750 PMID: Pathogenic PS4, PM3, PM2, PP1, PP4 BA1, BP4, BP2, PS3, PS2, PS1, BS1, BS3, BS4, BP7, PM1, PM4, PM5, PM6, PVS1, BS2, PP3 The NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PM3, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PS4, PP4: Variant meets PM2 and is identified in 10 unrelated index cases from different labs (2 cases with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 1 case with DLCN>=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with DLCN>=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with DLCN=9 from Germany (PMID 11462246 – Nauck et al., 2001); at least 1 case with definite FH from The Netherlands (PMID 16250003 – Fouchier et al., 2005); 1 case with DLCN>=6 from Argentina (PMID 28502510 – Bañares et al., 2017); 1 case with Simon Broome criteria for FH from Poland (PMID 35741760 – Rutkowska et al. 2022); 1 true homozygous case with clinical diagnosis of HoFH from Spain (PMID 27784735); 1 case with homozygous FH phenotype (LDL-C= 13.52 mmol/L) from Germany (PMID 29502162).PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic: 2 affected family members have the variant.PM3: Variant meets PM2 and is identified in 1 index case with homozygous FH phenotype (LDL-C=11.7 mmol/L) and LDLR c. 2043C>T/p.(Cys681*), classified as Pathogenic by these guidelines, in trans, from Germany (PMID 29502162 – Klaus et al., 2018). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023607/MONDO:0007750/013 2025-01-31 2025-03-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8888 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0233632 infores:hetionet CHEBI:64312 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151908 infores:hetionet CHEBI:68478 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0231528 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0027339 infores:hetionet CHEBI:691037 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0162820 infores:hetionet CHEBI:9445 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0004604 infores:hetionet CHEBI:31644 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0015672 infores:hetionet CHEBI:7492 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0003864 infores:hetionet CAID:CA645614067 biolink:causes MONDO:0011071 infores:clingen CAID:CA645614067 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1207_1210dup (p.His404fs) is a frameshift variant which is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (frameshift (+) c.780–c.1440 as per VCEP specifications) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645614067/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0145867 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020550 infores:hetionet CHEBI:17650 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0019572 infores:hetionet CAID:CA233930 biolink:causes MONDO:0015152 infores:clingen CAID:CA233930 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PP1 PM2 The NM_003494.4: c.2779del p.(Ala927LeufsTer21) variant in DYSF, which is also known as NM_001130987.2: c.2833del p.(Ala945LeufsTer21), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 27/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 13 individuals with limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant (c.857T>A (p.Val286Glu), 1.0 pt, PMID: 18832576), and 10 were homozygous (0.75 pts, PMID: 16010686, 17825554) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18832576, 17825554). The variant was also reported to co-segregate with the disease in 10 affected family members and has been described as a founder variant among Jews of the Caucus region, with an estimated carrier frequency of 4% (PP1 (capped with PP4_Strong); PMID: 17825554). The filtering allele frequency of the variant is 0.0006 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 4/15288), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3, PP4_Strong, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA233930/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:134990 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0027497 infores:hetionet CHEBI:66919 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0033774 infores:hetionet CHEBI:5779 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0220870 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040128 infores:hetionet CAID:CA16041905 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041905 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The NM_000152.5: c.2281delinsAT (p.Ala761IlefsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 3 patients with Pompe disease including one individual with documentation of laboratory values showing GAA deficiency, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 17056254), and another stated to have deficient GAA activity (laboratory values not available) and on enzyme replacement therapy, meeting PP4 (PMID 29181627)(PP4_Moderate was applied). Both of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (2 x 0.5 points = 1 point, PM3). Another patient was identified by newborn screening and was compound heterozygous for the variant, c.2238G>C (p.Trp746Cys), and a pseudodeficiency variant, c.2065G>A (PMID 33202836). This data may be used in the assessment of p.Trp746Cys and was not included here to avoid circular logic. The c.2281delinsAT variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370993, 2 star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041905/MONDO:0009290/010 2021-08-27 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31401 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0027765 infores:hetionet CHEBI:31859 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0030193 infores:hetionet CHEBI:31949 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0012833 infores:hetionet CHEBI:6904 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0851578 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0232492 infores:hetionet CHEBI:49375 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0019079 infores:hetionet CHEBI:6129 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0007859 infores:hetionet CHEBI:6909 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0030554 infores:hetionet CAID:CA631301051 biolink:causes MONDO:0012999 infores:clingen CAID:CA631301051 MONDO:0012999 PMID: Pathogenic PVS1, PM2_Supporting, PM3, PP4_Strong The NM_000156.6:c.64dup (p.Ala22GlyfsTer63) variant in GAMT is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two affected unrelated individuals, previously reported (PMID: 27650626, PMID: 15108290), were homozygous for the variant; one of these individuals (PMID: 15108290) had elevated urinary guanidinoacetate and absent GAMT enzyme activity in fibroblasts with full GAMT gene sequencing performed, and the other proband (PMID: 27650626) had low serum and urine creatinine and absent creatine peak on brain MRS. (PM3, PP4_Strong), This variant is absent from population databases (PM2_Supporting). This variant has also been reported in ClinVar (Variation ID: 1402763). In summary, this variant meets criteria to be classified as pathogenic for guanidinoacetate methyltransferase deficiency. GAMT-specific ACMG/AMP criteria applied (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting, PM3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631301051/MONDO:0012999/026 2023-03-09 2023-03-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030193 infores:hetionet CHEBI:3996 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0023530 infores:hetionet CHEBI:3216 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1258215 infores:hetionet CHEBI:68579 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0001824 infores:hetionet CHEBI:9288 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0042963 infores:hetionet CHEBI:136040 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0003467 infores:hetionet CHEBI:6690 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0039231 infores:hetionet CHEBI:66903 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0013378 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035258 infores:hetionet CHEBI:2666 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0018524 infores:hetionet CHEBI:68647 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0015672 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0027765 infores:hetionet CHEBI:8768 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0036974 infores:hetionet CHEBI:8805 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0002170 infores:hetionet CHEBI:5120 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0030554 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0003123 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0002871 infores:hetionet CHEBI:2038 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0011603 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0233414 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0012833 infores:hetionet CAID:CA172098 biolink:causes MONDO:0018947 infores:clingen CAID:CA172098 MONDO:0018947 PMID: Pathogenic PS3, PS4, PP1_Strong, PP3 BA1, BS1, PM2 The variant NM_001005361.3:c.1393C>T in DNM2 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 465 (p.Arg465Trp). The highest population minor allele frequency in gnomAD v4.1 is 0.000001695 (2/1180018 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL computational prediction analysis tool produced a score of 0.83, which is above the threshold necessary to apply PP3. This variant has been reported in at least six probands with confirmed centronuclear myopathy (PS4; PMID: 16227997, 19130742, 22613877, 26908122, 28740838, 34463354, 34595679). In addition, it segregated in five affected individuals in one family (PP1_Strong; PMID: 16227997). Functional studies have demonstrated that this variant increases GTPase activity compared to wildtype dynamin (PMIDs: 20529869, 26199319). Several knock-in mouse models with the variant have been created and show muscle defects, progressive atrophy and morphological abnormalities similar to those observed in human biopsies, and DNM2 reduction has been shown to rescue the phenotype in mice (PS3; PMIDs: 20858595, 30291191). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3, PS4, PP1_Strong, PS3. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA172098/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6717 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0151664 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0424813 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0424813 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037052 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0026946 infores:hetionet CHEBI:7903 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0231528 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0015397 infores:hetionet CAID:CA410781220 biolink:causes MONDO:0021060 infores:clingen CAID:CA410781220 MONDO:0021060 PMID: Pathogenic PS2_Very Strong, PS4_Supporting, PM2_Supporting PP3, BA1, BP4, BS1 The NM_006767.4:c.842C>T variant in LZTR1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 281 (p.Pro281Leu). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.591, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 3 probands with RASopathy (PS4_Supporting; SCV000808488.6, SCV002677796.3, GeneDx, Ambry Genetics). This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals with RASopathy (PS2_VeryStrong; SCV000808488.6, SCV002677796.3, GeneDx, Ambry Genetics). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4_Supporting, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410781220/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10102 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0424295 infores:hetionet NCBIGene:10243 biolink:causes MONDO:0014212 infores:monarchinitiative not_provided not_provided HGNC:15465 MONDO:0014212 uuid:c4d9176e-4458-4c96-94a9-64f3c0f60d05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64321 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0023380 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0234215 infores:hetionet CHEBI:8354 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0030193 infores:hetionet CHEBI:82960 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0035410 infores:hetionet CAID:CA16020828 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020828 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PM3, PP3 The c.605C>T (p.A202V) variant in PAH has been reported without confirmed phase with p.Arg408Gln, which is classified as pathogenic by the PAH VCEP (Variation ID 612). It has also been observed in trans to c.442-1G>A (classified as pathogenic by PAH VCEP Variation ID 594) in a patient with classic PKU (PMID: 15319459). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020828/MONDO:0009861/006 2021-11-12 2021-11-14 Autosomal recessive inheritance HP:0000007 Supports CAID:CA415164787 biolink:causes MONDO:0010726 infores:clingen CAID:CA415164787 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, PM1, BS1, PP3 The p.Gln437Lys variant in MECP2 (NM_004992.4) is observed in at least 5 unaffected individuals (internal database - Ambry, internal database - Invitae) (BS2). The p.Gln437Lys variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The highest population minor allele frequency of the p.Gln437Lys variant in MECP2 in gnomAD v4.1 is 0.00002186 in the Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Gln437Lys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415164787/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true GO:0060998 biolink:causes GO:0016358 infores:ubergraph knowledge_assertion manual_agent GO:0060998 GO:0016358 CHEBI:75722 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0162830 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0027765 infores:hetionet CHEBI:64321 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0038160 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0234458 infores:hetionet CHEBI:2666 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0686347 infores:hetionet CHEBI:6950 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0392156 infores:hetionet CHEBI:2955 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0016204 infores:hetionet CHEBI:63620 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0520966 infores:hetionet CHEBI:63577 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0014742 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0020649 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020615 infores:hetionet CHEBI:116278 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0855775 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0035078 infores:hetionet CHEBI:7824 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0001807 infores:hetionet NCBITaxon:621 biolink:causes MONDO:0019345 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:621 MONDO:0019345 CHEBI:31644 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0034886 infores:hetionet CHEBI:3761 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0018681 infores:hetionet CHEBI:47381 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0016382 infores:hetionet CHEBI:6775 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0015967 infores:hetionet CHEBI:27300 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0002871 infores:hetionet CHEBI:71417 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C2939419 infores:hetionet CHEBI:50648 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042029 infores:hetionet CHEBI:16796 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0041969 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004674 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0008513 infores:hetionet CHEBI:53760 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1142135 infores:hetionet CAID:CA279764 biolink:causes MONDO:0021056 infores:clingen CAID:CA279764 MONDO:0021056 PMID:15459959 Pathogenic PS2_Moderate, PS3_Moderate, PM2_Supporting, PS4_Very Strong The NM_000038.6(APC):c.1312+3A>G variant in APC is an intronic variant which is located at the 3rd nucleotide in intron 10. This variant has been reported in more than 16 cases meeting phenotypic criteria resulting in a total phenotype score of 16 points (internal data Labcorp Genetics [formerly Invitae], Peter MacCallum Cancer Centre, Victoria, Australia, GeneDx, Ambry; PMID: 8381580, 15459959, 20223039, 17489848, 19793053, 20685668) (PS4_Very Strong). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with FAP, resulting in a total de novo score of 1 (PS2_Moderate, Ambry internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RNA studies demonstrated that the variant impacts splicing by causing exon 10 skipping (PMID: 15459959, Ambry internal data) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PS4_Very Strong, PS2_Moderate, PM2_Supporting, PS3_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA279764/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28864 biolink:causes MONDO:0005551 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0852875 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0919882 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0919882 infores:hetionet CHEBI:71223 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0014518 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0178298 infores:hetionet CHEBI:84050 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0013404 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0424295 infores:hetionet CHEBI:92712 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0917801 infores:hetionet CHEBI:32588 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C1258215 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0006145 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034150 infores:hetionet CHEBI:10112 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0917801 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020517 infores:hetionet CHEBI:63581 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0917801 infores:hetionet CHEBI:3749 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0011603 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0030305 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3665596 infores:hetionet CHEBI:94686 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0040435 infores:hetionet CHEBI:7640 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0002874 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0232492 infores:hetionet NCBIGene:79876 biolink:causes MONDO:0014933 infores:monarchinitiative not_provided not_provided HGNC:23230 MONDO:0014933 uuid:eb49da0e-aef3-4a13-b77e-f7983aec8737 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:57572 biolink:causes MONDO:0013635 infores:monarchinitiative not_provided not_provided HGNC:19189 MONDO:0013635 uuid:b660f5ed-d2ad-43f8-a20d-bbdae84cbce6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0042492 biolink:causes CL:0000798 infores:ubergraph knowledge_assertion manual_agent GO:0042492 CL:0000798 CHEBI:15552 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0027765 infores:hetionet CAID:CA239730 biolink:causes MONDO:0009290 infores:clingen CAID:CA239730 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 BP7 The NM_000152.5:c.1722C>T (p.Leu574=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by PhyloP score of 0.218, so BP7 cannot be applied. The highest population minor allele frequency in gnomAD v4.10. is 0.0006477 (59/91092 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). It has not been reported in any individuals with Pompe disease to our knowledge. There is a ClinVar entry for this variant (Variation ID: 193975). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 3, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA239730/MONDO:0009290/010 2024-09-03 2024-09-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:38562 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C3267047 infores:hetionet CHEBI:3387 biolink:causes HP:0025088 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0263540 infores:hetionet CHEBI:63577 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1167965 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0079043 infores:hetionet CHEBI:50859 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018681 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0006840 infores:hetionet CHEBI:52172 biolink:causes UMLS:C3495797 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C3495797 infores:hetionet CHEBI:3207 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C1368065 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0020517 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0151623 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0033774 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0021400 infores:hetionet CHEBI:2675 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0004093 infores:hetionet NCBIGene:3043 biolink:causes MONDO:0011382 infores:monarchinitiative not_provided not_provided HGNC:4827 MONDO:0011382 uuid:ab4af4f1-b766-4ac0-aa1f-fbacb11e10b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70707 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0017160 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040147 infores:hetionet CHEBI:6931 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C2939147 infores:hetionet NCBIGene:3861 biolink:causes MONDO:0007550 infores:monarchinitiative not_provided not_provided HGNC:6416 MONDO:0007550 uuid:3005de45-a9fd-41d9-adb8-20210690c693 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3398 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0012569 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0234458 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0521839 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0233494 infores:hetionet CHEBI:45285 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0040034 infores:hetionet CHEBI:63611 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151662 infores:hetionet CHEBI:2675 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C2830004 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0025061 infores:hetionet CAID:CA117145 biolink:causes MONDO:0019501 infores:clingen CAID:CA117145 MONDO:0019501 PMID:22381527PMID:18395802PMID:15660226PMID:22381527PMID:18395802PMID:15660226 Uncertain Significance PP3 BP7, BP5, BS1, BS4, BS3, BS2, PP2, PP4, PP1, PM5, PM1, PM3, PM4, PVS1, PM2, PM6, BP1, BP4, BP2, BP3, BA1, PS1, PS2, PS4, PS3 The c.9565C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 3189. The only evidence resulting in a classification code was determined by the computational predictor REVEL which gives a score of 0.783, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v4.1 is 0.000338 (10/29592) in the Ashkenazi Jewish Population (PM2_Supporting and BS1_Supporting are not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 6/30/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA117145/MONDO:0019501/005 2025-07-02 2025-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:32192 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0013604 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004830 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015645 infores:hetionet CHEBI:47898 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0232726 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020039 infores:hetionet CHEBI:567361 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0033774 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0948594 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0087169 infores:hetionet CHEBI:4514 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0233715 infores:hetionet CHEBI:31536 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0020443 infores:hetionet NCBIGene:5053 biolink:causes MONDO:0009861 infores:monarchinitiative not_provided not_provided HGNC:8582 MONDO:0009861 uuid:e356d66a-7ec8-4eec-a833-e20f74dd3ce3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0595916 infores:hetionet NCBIGene:8879 biolink:causes MONDO:0033203 infores:monarchinitiative not_provided not_provided HGNC:10817 MONDO:0033203 uuid:0f010149-c745-4f14-8d7d-0f13b03de7ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0392702 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0033246 infores:hetionet CHEBI:82941 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0017178 infores:hetionet CHEBI:408174 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0015672 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0518015 infores:hetionet CHEBI:421707 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0030554 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0041912 infores:hetionet CHEBI:38940 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0017672 infores:hetionet CHEBI:8232 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0240671 infores:hetionet CHEBI:6690 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0031256 infores:hetionet CHEBI:17474 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0023222 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0476089 infores:hetionet CHEBI:7865 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0013395 infores:hetionet CHEBI:16335 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0030252 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0019348 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0424605 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0948594 infores:hetionet CHEBI:135351 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0009676 infores:hetionet CHEBI:2611 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013390 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002622 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0233632 infores:hetionet CHEBI:3723 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0021177 infores:hetionet CHEBI:47898 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085692 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0036572 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0428886 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0428886 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0023895 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042769 infores:hetionet CHEBI:17303 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151827 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0424000 infores:hetionet CHEBI:2469 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0004093 infores:hetionet CHEBI:82960 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0043352 infores:hetionet CHEBI:27777 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0149871 infores:hetionet CHEBI:2567 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0014742 infores:hetionet CHEBI:38940 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C2364111 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0018799 infores:hetionet CHEBI:71219 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0027497 infores:hetionet CHEBI:63115 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0553692 infores:hetionet NCBIGene:54476 biolink:causes MONDO:0008935 infores:monarchinitiative not_provided not_provided HGNC:21698 MONDO:0008935 uuid:92fc4017-2b83-4daa-9c8b-95c2db96c68c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4023 biolink:causes MONDO:0007759 infores:monarchinitiative not_provided not_provided HGNC:6677 MONDO:0007759 uuid:01142c08-57d7-47d4-8def-a6df4b3d4d64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40237 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0877322 infores:hetionet CHEBI:63599 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0033774 infores:hetionet CHEBI:3568 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1527344 infores:hetionet CHEBI:64028 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0043352 infores:hetionet CHEBI:9449 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0016382 infores:hetionet CHEBI:64312 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0232849 infores:hetionet CHEBI:92998 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C3263723 infores:hetionet CHEBI:4027 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0040038 infores:hetionet CHEBI:5050 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0042963 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027947 infores:hetionet CHEBI:9168 biolink:causes HP:0011004 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151489 infores:hetionet CHEBI:2469 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151747 infores:hetionet CHEBI:8461 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0030252 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0010399 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0001824 infores:hetionet CHEBI:27899 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0022107 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0233472 infores:hetionet CHEBI:40279 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0234533 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0553732 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0004096 infores:hetionet CHEBI:205919 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0030196 infores:hetionet CHEBI:32184 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0237849 infores:hetionet CHEBI:4325 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0001925 infores:hetionet CAID:CA033501 biolink:causes MONDO:0007750 infores:clingen CAID:CA033501 MONDO:0007750 PMID: Uncertain Significance BP4, BP2, PM5, PM2, PP4 BA1, BP3, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1301C>T (p.Thr434Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP4, BP2, and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.00007 (0.007%) in South Asian exomes+genomes (gnomAD v2.1.1). So PM2 is met. PM5: 3 other missense variants in the same codon:- NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines- NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines.PP4: Variant meets PM2 and is identified in 1 case with DLCN criteria>=6 from Robarts Research Institue. So PP4 is met. BP2: 1 case with DLCN≥6 and LDL-C 7.44 mmol/l and NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) variant from Robarts Research Institue (The APOB variant, although not classified with FH VCEP approved guidelines, is considered Pathogenic by the FH VCEP). BP4: REVEL = 0.47. It is below 0.5. Splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site, but it doesn't create AG or GT. Variant is not predicted to alter splicing. So BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033501/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4909 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0085636 infores:hetionet CHEBI:2453 biolink:causes UMLS:C1096543 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C1096543 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0153690 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0153690 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025061 infores:hetionet CHEBI:6822 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0015230 infores:hetionet CHEBI:2668 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0004093 infores:hetionet CHEBI:2682 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0004093 infores:hetionet CAID:CA2497030002 biolink:causes MONDO:0100368 infores:clingen CAID:CA2497030002 MONDO:0100368 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting PM3 NM_000329.3(RPE65):c.859delG (p.Val287PhefsTer38) is a frameshift variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts), loss of visual acuity (1 pt) since age 1 year (1 pt), nystagmus (1 pt), night blindness (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), and pale optic disc (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 points, PMID: 34492281, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the compound heterozygous state (PMID: 34492281, PP1_moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_supporting, and PP1_moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497030002/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410202484 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202484 MONDO:0011071 PMID: Uncertain Significance PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.500G>C (p.Ser167Thr) is a missense variant which affects at least one of the following hotspot residues within the RHD: S167 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.921) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202484/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8356 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0028961 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0004096 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0160390 infores:hetionet CHEBI:77260 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0008031 infores:hetionet CHEBI:9570 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0687713 infores:hetionet CHEBI:8364 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0030305 infores:hetionet CHEBI:135351 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0027441 infores:hetionet CHEBI:4027 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0002792 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0235409 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009450 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0042571 infores:hetionet CHEBI:7465 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0518988 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0016385 infores:hetionet CHEBI:75045 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0016436 infores:hetionet CHEBI:408174 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0010692 infores:hetionet CHEBI:15367 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2242996 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0014868 infores:hetionet CAID:CA916083905 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083905 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2293_2297del (p.Glu765ArgfsTer3) is a frameshift variant due to a 5-nucleotide deletion introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands (PMID: 27620828, PMID: 34985506). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, decreased or absent electroretinogram responses, or a female proband with an affected male family member, was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083905/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports UMLS:C0657912 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085610 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0039446 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0695236 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0695236 infores:hetionet CHEBI:53766 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0015967 infores:hetionet CAID:CA10603125 biolink:causes MONDO:0017623 infores:clingen CAID:CA10603125 MONDO:0017623 PMID: Pathogenic PS2_Very Strong, PP2, PP3, PM2_Supporting, PS4_Moderate PM6, PM1, PS3 PTEN c.633C>G (p.Cys211Trp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2_VS: Three pediatric patients (Internal lab contribution) confirmed de novo with WES trio. PP3: REVEL score >.7 (Score: 0.856). PS4_P: Vanderver et al (PMID 24375884) patient #21 with macrocephaly, developmental delay, and enlarged periventricular spaces. Phenotype score of +6, +1 proband point. Confirmed de novo pediatric patient with extreme macrocephaly (+4 SD), developmental delay, hemihypertrophy, autism and ID (Internal laboratory contribution). Phenotype score +5, +1 proband point.PM2_P: Absent in large sequenced populations (gnomad v4). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603125/MONDO:0017623/003 2025-10-03 2025-10-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2618 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0852733 infores:hetionet CAID:CA2580612188 biolink:causes MONDO:0100368 infores:clingen CAID:CA2580612188 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000329.3(RPE65):c.1459_1460del (p.Leu487GlufsTer25) is a frameshift variant that introduces a premature stop codon into exon 14 of 14, which is predicted not to trigger nonsense-mediated decay but rather to C-terminally truncate the protein product before position 528, disrupting functionally critical residues required for the active site (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 23105016, PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612188/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6067 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0029134 infores:hetionet CHEBI:2948 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0015230 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0017178 infores:hetionet CHEBI:63580 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0039231 infores:hetionet CHEBI:3441 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0014518 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0549395 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0549395 infores:hetionet CHEBI:45409 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1510410 infores:hetionet CHEBI:63605 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0438717 infores:hetionet CHEBI:10119 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020580 infores:hetionet CHEBI:6375 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019521 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0853026 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042134 infores:hetionet GO:0007596 biolink:causes MONDO:0000831 infores:drugmechdb knowledge_assertion manual_agent GO:0007596 MESH:D013927 DB00945_MESH_D013927_1 CHEBI:50275 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017181 infores:hetionet CHEBI:7824 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0040264 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0085622 infores:hetionet CHEBI:135530 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0011606 infores:hetionet CAID:CA120573 biolink:causes MONDO:0044970 infores:clingen CAID:CA120573 MONDO:0044970 PMID: Uncertain Significance PP1, PP4, PM2_Supporting PP3, PS3 The m.4291T>C variant in MT-TI has been reported in five probands with primary mitochondrial disease (PMIDs: 15498972, 34607911; PS4_moderate). Affected individuals had variable hypomagnesemia and hypokalemia (consistent with Gitelman-like syndrome), migraines, sensorineural hearing loss, and hypertrophic cardiomyopathy. In one affected individual, ragged red fibers, increased subsarcolemmal staining, cytoplasmic lipid accumulation, increased glycogen, and dysmorphic cristae were seen on muscle biopsy (PMID: 15498972). The variant was present at homoplasmy or near homoplasmy in all reported individuals. While the variant was also present at high levels in unaffected family members, no children of affected fathers had clinical features in one large pedigree (PMID: 15498972, PP1). Fibroblasts from affected individuals showed decreased maximal mitochondrial respiration and reduced complex IV activity (PMID: 34607911; PP4). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly benign (31.8 percentile) but HmtVAR predicts it to be deleterious with a score of 0.4. There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. Of note, this is a highly compelling variant of uncertain significance given the consistent phenotype in affected individuals. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PP4, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120573/MONDO:0044970/015 2024-04-23 2025-07-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:49375 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C3665347 infores:hetionet CHEBI:136040 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0242422 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011334 infores:hetionet NCBIGene:19 biolink:causes MONDO:0011393 infores:monarchinitiative not_provided not_provided HGNC:29 MONDO:0011393 uuid:191d0bdc-8fbe-4482-ae1d-c326a1003954 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0021359 infores:hetionet CHEBI:10112 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0007859 infores:hetionet CAID:CA399806022 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806022 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The missense variant NM_000419.5(ITGA2B):c.423G>T (p.Trp141Cys) has been reported in at least one patient (GT14 in PMID: 25728920), with mucocutaneous bleeding and impaired aggregation against all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to<5%, as measured by flow cytometry (PP4_strong). GT14 of PMID: 25728920 is compound heterozygous for Trp141Cys and c.2902del (classified as Pathogenic by the PD-EP), confirmation of trans phase was not reported (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.879, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806022/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:52717 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026946 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0948594 infores:hetionet CHEBI:6759 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0041657 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0853761 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0700184 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0233632 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0016385 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0015376 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037284 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0006147 infores:hetionet CHEBI:253342 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0151825 infores:hetionet CHEBI:27732 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C2937358 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0159076 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0159076 infores:hetionet NCBIGene:388698 biolink:causes MONDO:0054852 infores:monarchinitiative not_provided not_provided HGNC:33276 MONDO:0054852 uuid:5444e3dc-7be6-4dcf-bc9f-e68c2c53c90b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55651 biolink:causes MONDO:0013519 infores:monarchinitiative not_provided not_provided HGNC:14377 MONDO:0013519 uuid:4f2f3b36-1036-428a-8c09-b6f95e6d9125 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0267792 infores:hetionet CHEBI:36791 biolink:causes HP:0012710 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027343 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020621 infores:hetionet NCBIGene:10755 biolink:causes MONDO:0030134 infores:monarchinitiative not_provided not_provided HGNC:1226 MONDO:0030134 uuid:7a9a5044-c68c-4cca-b6ed-bf675dd427a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0027497 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0040034 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0521008 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0521008 infores:hetionet CHEBI:29007 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0030252 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0029882 infores:hetionet CHEBI:51230 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0041834 infores:hetionet CHEBI:8207 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013428 infores:hetionet CHEBI:175901 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0234233 infores:hetionet CHEBI:27899 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0740394 infores:hetionet CHEBI:9622 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0392171 infores:hetionet CHEBI:44032 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151827 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0011609 infores:hetionet CHEBI:3568 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1443060 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0024117 infores:hetionet CHEBI:6541 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0851578 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027441 infores:hetionet CHEBI:144551 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1142412 infores:hetionet CHEBI:135679 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0031350 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0020039 infores:hetionet CHEBI:7986 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0003467 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0034150 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0015230 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0575090 infores:hetionet CHEBI:87681 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C3665347 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001208 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0264490 infores:hetionet UNII:D27V6190PM biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0231218 infores:hetionet CAID:CA213742 biolink:causes MONDO:0015967 infores:clingen CAID:CA213742 MONDO:0015967 PMID: Uncertain Significance PM4, PP4, PM2_Supporting PS4, PM1 The c.1279_1358delinsTTACA variant in the glucokinase gene, GCK, is an 80 base pair deletion/ 5 base pair insertion resulting in the in-frame deletion of 27 amino acid(s) and insertion of 2 novel amino acids between codons 427 and 453 (p.(Val427_Ser453delinsLeuGln)) within exon 10 of NM_000162.5. The c.1279_1358delinsTTACA variant is predicted to change the length of the protein due an in-frame deletion of 27 amino acids and insertion of 2 novel amino acids for a net loss of 25 amino acids in a nonrepeat region (PM4). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 28726111, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID:28726111). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1279_1358delinsTTACA meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM4, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213742/MONDO:0015967/086 2023-12-02 2023-12-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0012569 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0025061 infores:hetionet CHEBI:63630 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0032617 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0039971 infores:hetionet CHEBI:77260 biolink:causes HP:0500167 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0853890 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0024115 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0028259 infores:hetionet CAID:CA023595 biolink:causes MONDO:0007750 infores:clingen CAID:CA023595 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.1837G>A (p.Val613Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.00005340 (0.005%) in African/African American exomes+genomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases meeting FH criteria (1 case in PMID 19837725 (Whittall et al., 2010), UK; 1 case in PMID 16250003 (Fouchier et al., 2005), Netherlands). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023595/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8874 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0233763 infores:hetionet CHEBI:41774 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0262988 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0162830 infores:hetionet CHEBI:63621 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038002 infores:hetionet CHEBI:31348 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0000731 infores:hetionet CHEBI:75045 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0234894 infores:hetionet CHEBI:8382 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151786 infores:hetionet NCBIGene:1968 biolink:causes MONDO:0010258 infores:monarchinitiative not_provided not_provided HGNC:3267 MONDO:0010258 uuid:1fde5be5-87e9-46fe-8b76-b8d5d4df3f3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3011 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0948586 infores:hetionet CHEBI:7025 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0018681 infores:hetionet CHEBI:39669 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0038325 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0233401 infores:hetionet CHEBI:3757 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0917801 infores:hetionet CHEBI:6904 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0043094 infores:hetionet CHEBI:8707 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151691 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0009806 infores:hetionet CHEBI:63613 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0542571 infores:hetionet CHEBI:5779 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0600142 infores:hetionet GO:0002521 biolink:causes CL:0000738 infores:ubergraph knowledge_assertion manual_agent GO:0002521 CL:0000738 CHEBI:175901 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0836924 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0424230 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0423602 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0038363 infores:hetionet CAID:CA063246 biolink:causes MONDO:0018493 infores:clingen CAID:CA063246 MONDO:0018493 PMID: Likely Benign PS4_Supporting, BS2_Supporting, BS3_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with leucine at codon 816 of the RYR1 protein, p.(Pro816Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000046, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit). Functional studies in HEK293 cells do not show a significant increased sensitivity to RYR1 agonists BS3_Supporting (PMID: 31903994). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of .758 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA063246/MONDO:0018493/012 2021-11-09 2021-11-09 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63580 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0023380 infores:hetionet UMLS:C0879264 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0340865 infores:hetionet UMLS:C0004609 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0231218 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0042373 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0041349 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0456909 infores:hetionet CHEBI:5551 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0042109 infores:hetionet CHEBI:27732 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0015230 infores:hetionet UBERON:0004820 biolink:causes MONDO:0003455 infores:ubergraph knowledge_assertion manual_agent UBERON:0004820 MONDO:0003455 CHEBI:6909 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013144 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0342579 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0039971 infores:hetionet CHEBI:2453 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0338831 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020621 infores:hetionet CHEBI:3125 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0027765 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034902 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0034065 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0011609 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0009806 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0019158 infores:hetionet CHEBI:31401 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0040053 infores:hetionet CAID:CA157954 biolink:causes MONDO:0007648 infores:clingen CAID:CA157954 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP4, PP3, PP2, PP1, BS2, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.1774G>A (p.Ala592Thr) variant has an allele frequency of 0.00481 (0.48%, 609/126,710 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157954/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:27834 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0521839 infores:hetionet CHEBI:42944 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003862 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0403632 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020676 infores:hetionet CHEBI:8871 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0404521 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0936254 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0936254 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235146 infores:hetionet CHEBI:9086 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020903 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0012833 infores:hetionet CHEBI:7494 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0021177 infores:hetionet CHEBI:3636 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0036974 infores:hetionet CHEBI:63630 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151836 infores:hetionet CHEBI:4315 biolink:causes MONDO:0002177 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0020459 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040213 infores:hetionet CHEBI:5118 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038450 infores:hetionet CHEBI:94807 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0002453 infores:hetionet CHEBI:178699 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0041582 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0007682 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0039971 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0037199 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0035078 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0037274 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0221100 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016479 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151596 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0042514 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009806 infores:hetionet CHEBI:3723 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0231528 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0392176 infores:hetionet CHEBI:45783 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0023473 infores:hetionet CHEBI:49662 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0016382 infores:hetionet CAID:CA409106057 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106057 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.514C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 172 (p.(Gln172Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 5 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least two individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID: 488999). In summary, c.514C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106057/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3207 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0010346 infores:hetionet CHEBI:43968 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0030794 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0020517 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0518015 infores:hetionet CHEBI:52172 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0041834 infores:hetionet CHEBI:9086 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233763 infores:hetionet CHEBI:3215 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0033771 infores:hetionet CAID:CA000167 biolink:causes MONDO:0017623 infores:clingen CAID:CA000167 MONDO:0017623 PMID:20223021 Pathogenic PM2, PVS1, PS4_Supporting PTEN c.50_51delAA (p.Q17RfsX26) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 20223021) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000167/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10125 biolink:causes UMLS:C0235573 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235573 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1142135 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232197 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0006849 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162287 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0039584 infores:hetionet CHEBI:119486 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0231528 infores:hetionet CHEBI:64354 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0232462 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0149904 infores:hetionet CHEBI:2914 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0242528 infores:hetionet CHEBI:10124 biolink:causes UMLS:C2349423 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C2349423 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0043251 infores:hetionet CHEBI:17334 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0340865 infores:hetionet CHEBI:7514 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0428977 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0574067 infores:hetionet CHEBI:17474 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0026821 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0002871 infores:hetionet CHEBI:6367 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085583 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0009450 infores:hetionet CHEBI:3752 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0546884 infores:hetionet CHEBI:43968 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C1257843 infores:hetionet CAID:CA023412 biolink:causes MONDO:0007750 infores:clingen CAID:CA023412 MONDO:0007750 PMID: Benign BS3_Supporting, BA1 BP2 The NM_000527.5 (LDLR):c.1061-8T>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:BA1: PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1).BS3_Supporting: Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023412/MONDO:0007750/013 2022-03-25 2022-04-25 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8874 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0026821 infores:hetionet CHEBI:63115 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0017160 infores:hetionet CHEBI:7575 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0037763 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042109 infores:hetionet GO:0001829 biolink:causes CL:1000274 infores:ubergraph knowledge_assertion manual_agent GO:0001829 CL:1000274 CAID:CA166473 biolink:causes MONDO:0007648 infores:clingen CAID:CA166473 MONDO:0007648 PMID: Likely Benign BS2 BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM1, PM4, PM5, PP2, PP3, PP4, PP1, BP1, BP4, BP2, BP3, BA1, PS3, PS1, PS4, PS2 The c.724G>A (p.Val242Ile) missense variant has a frequency of 0.01002% in South Asians (2 of 19954 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in ≥10 (22) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000185325.6, SCV000259887.6). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166473/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63621 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0002622 infores:hetionet CHEBI:9137 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0917801 infores:hetionet CHEBI:61049 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037763 infores:hetionet CHEBI:7573 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0206062 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0086066 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0086066 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0012813 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006277 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0006145 infores:hetionet CHEBI:63635 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0085649 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0013395 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0442886 infores:hetionet NCBIGene:79934 biolink:causes MONDO:0014257 infores:monarchinitiative not_provided not_provided HGNC:19041 MONDO:0014257 uuid:c6b7c8d0-601c-424a-aa58-dcf15429578d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27732 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0011603 infores:hetionet CHEBI:63618 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0037317 infores:hetionet CHEBI:4024 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0424295 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0003123 infores:hetionet CAID:CA036508 biolink:causes MONDO:0007750 infores:clingen CAID:CA036508 MONDO:0007750 PMID: Uncertain Significance BP4 PS4, BP5, PM5, PM2 The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available.A) variant not on limits.B) does not create AG or GTVariant is not predicted to alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036508/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:465284 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0018790 infores:hetionet CHEBI:50922 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0236000 infores:hetionet CHEBI:83804 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027849 infores:hetionet CHEBI:119915 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011206 infores:hetionet CHEBI:3286 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0851578 infores:hetionet CHEBI:168396 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C3665347 infores:hetionet CHEBI:28787 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0035455 infores:hetionet CHEBI:45783 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030554 infores:hetionet GO:1901844 biolink:causes GO:0061337 infores:ubergraph knowledge_assertion manual_agent GO:1901844 GO:0061337 GO:0045766 biolink:causes MONDO:0005086 infores:drugmechdb knowledge_assertion manual_agent GO:0045766 MESH:D002292 DB00398_MESH_D002292_1 CHEBI:9139 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017601 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0017152 infores:hetionet CHEBI:4356 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0522153 infores:hetionet CHEBI:87681 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0003811 infores:hetionet CAID:CA414447354 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447354 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3 The c.1325G>T (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 442 (p.Gly442Val). This variant has been reported in at least 2 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Moderate; PMID: 34590426). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.906, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Another missense variant c.1234G>A, p.Gly442Arg in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PM5, PS4_Moderate, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447354/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Supports GO:0072095 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0072001 CAID:CA200294 biolink:causes MONDO:0005338 infores:clingen CAID:CA200294 MONDO:0005338 PMID:16466712PMID:35196929 Benign BP4, BS3_Supporting, BA1 BP7, BS1, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2 The c.227G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 76 (p.Arg76Lys). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.3414, which met the ≥ 0.01 threshold set for BA1 (31,088 alleles out of 91,050, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.203, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. The Arg76Lys protein had similar solubility and secretion levels to wild type myocilin protein in these studies (PMIDs: 35196929, 16466712). The assays met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BA1, BS3_Moderate, BP4 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA200294/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31709 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0151735 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0233494 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0011570 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0001824 infores:hetionet CHEBI:6706 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0030554 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0020538 infores:hetionet CAID:CA340747132 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747132 MONDO:0100368 PMID: Pathogenic PM1, PM5, PM3_Strong, PP3_Moderate, PM2_Supporting The NM_000329.3(RPE65):c.545A>G (p.His182Arg) variant in RPE65 is a missense variant resulting in a substitution of histidine by arginine at codon 182 . This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 19117922, 27102010). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant confirmed in trans (1 point, PMID: 31273949), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). This variant is a missense substitution at p.His182, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). The computational predictor REVEL gives a score of 0.900, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Another missense variant in the same codon (NM_000329.3(RPE65):c.544C>T (p.His182Tyr) has been classified as Pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5, ClinVar Variation ID: 98875). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PM1, PP3_Moderate, PM5. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747132/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31859 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018965 infores:hetionet CHEBI:17688 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013390 infores:hetionet CHEBI:15544 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020452 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003123 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233632 infores:hetionet CHEBI:46345 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0017181 infores:hetionet CHEBI:36795 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0010200 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0006325 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0012833 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019061 infores:hetionet CHEBI:39867 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0428977 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549346 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549346 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0040441 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040441 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0019158 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0233472 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042373 infores:hetionet CHEBI:4784 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0015672 infores:hetionet CAID:CA10014579 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014579 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.165G>T (p.Ala55=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.33)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014579/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:168396 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0080274 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0877173 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0877173 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0178298 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0152010 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0152010 infores:hetionet CHEBI:119486 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0009676 infores:hetionet CHEBI:51209 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0003123 infores:hetionet CHEBI:9137 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C2979982 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0162429 infores:hetionet CAID:CA170316 biolink:causes MONDO:0010726 infores:clingen CAID:CA170316 MONDO:0010726 PMID: Likely Benign BP5, PP3, BS2 BS1 The highest population minor allele frequency of the p.Pro173Arg variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00005278 in the South Asian population (not sufficient to meet BS1 criteria). The p.Pro173Arg variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro173Arg variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro173Arg variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170316/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Contradicts true CHEBI:68841 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0700590 infores:hetionet CHEBI:114785 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0010200 infores:hetionet CHEBI:94440 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0575081 infores:hetionet CHEBI:101085 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0033774 infores:hetionet CHEBI:8428 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0264906 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0152029 infores:hetionet CHEBI:8871 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013404 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0948525 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0851341 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0020517 infores:hetionet NCBIGene:2898 biolink:causes MONDO:0012614 infores:monarchinitiative not_provided not_provided HGNC:4580 MONDO:0012614 uuid:c069d582-d1e9-4b34-b605-e5797a576cdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9328 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0027720 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0009806 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0234215 infores:hetionet CHEBI:101278 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0853034 infores:hetionet CHEBI:44915 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151744 infores:hetionet CHEBI:16755 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0026113 infores:hetionet CHEBI:23765 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0019079 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151767 infores:hetionet CHEBI:94609 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0033774 infores:hetionet CHEBI:51860 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0007820 infores:hetionet CHEBI:3732 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0018965 infores:hetionet NCBITaxon:2037 biolink:causes MONDO:0006921 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2037 MONDO:0006921 CHEBI:71219 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1519353 infores:hetionet CHEBI:45409 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C3665386 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0549373 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0240417 infores:hetionet CHEBI:16755 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0702166 infores:hetionet CHEBI:6339 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0003467 infores:hetionet CHEBI:31348 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0031345 infores:hetionet CHEBI:39867 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014518 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017675 infores:hetionet CHEBI:7581 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0221423 infores:hetionet CHEBI:63611 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0687713 infores:hetionet NCBIGene:5913 biolink:causes MONDO:0100102 infores:monarchinitiative not_provided not_provided HGNC:9863 MONDO:0100102 uuid:b57bf548-d2f2-4a8b-b506-64dbdbe258e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151754 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0152027 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0038362 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0948089 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004096 infores:hetionet CHEBI:66903 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0016199 infores:hetionet CHEBI:291342 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0011603 infores:hetionet CHEBI:63629 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0036974 infores:hetionet CHEBI:9667 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0162834 infores:hetionet GO:0015459 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:0015459 GO:0071805 CHEBI:3640 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0023530 infores:hetionet UBERON:0004128 biolink:causes UBERON:0004880 infores:ubergraph knowledge_assertion manual_agent UBERON:0004128 UBERON:0004880 CHEBI:6888 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0028754 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038587 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0042401 infores:hetionet CHEBI:63580 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0041582 infores:hetionet CHEBI:7936 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003873 infores:hetionet CHEBI:15367 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235857 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0152025 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0023067 infores:hetionet GO:1903859 biolink:causes GO:0031175 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0031175 CHEBI:64312 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0852911 infores:hetionet CHEBI:68841 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0030554 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0227791 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151547 infores:hetionet NCBIGene:145873 biolink:causes MONDO:0012097 infores:monarchinitiative not_provided not_provided HGNC:29659 MONDO:0012097 uuid:45fb5d38-f2a0-4a25-8868-11be6e8b3ed2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0043352 infores:hetionet CHEBI:91583 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0234215 infores:hetionet CHEBI:2950 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0004604 infores:hetionet CHEBI:6456 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0030554 infores:hetionet CAID:CA512341192 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341192 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, BA1, BP2, PVS1, PM6, BS1, BS3, BS4, BP7, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1242C>T (p.=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). Splicing algorithms predict no effect on splicing (SpliceAI ∆ score = 0.00) (BP4). However, evolutionary conservation algorithms predict the site as being conserved (PhyloP score 3.668), and therefore BP7 does not apply. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341192/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3636 biolink:causes UMLS:C0456677 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0456677 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0006277 infores:hetionet CHEBI:52717 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0231530 infores:hetionet CHEBI:8107 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0030554 infores:hetionet NCBIGene:7019 biolink:causes MONDO:0014943 infores:monarchinitiative not_provided not_provided HGNC:11741 MONDO:0014943 uuid:ab0e1bee-dcf9-44bf-8ce9-f451ee325f2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75246 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0233794 infores:hetionet CHEBI:3749 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0013604 infores:hetionet CHEBI:9586 biolink:causes HP:0001482 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151811 infores:hetionet CHEBI:7492 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0017178 infores:hetionet CHEBI:78320 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0031256 infores:hetionet CHEBI:8863 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2830004 infores:hetionet CHEBI:16899 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0020578 infores:hetionet CHEBI:7852 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0043387 infores:hetionet CHEBI:2682 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0015732 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0017574 infores:hetionet CAID:CA10014194 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014194 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP2, BP3, BP1, BA1, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1183C>G (p.Pro395Ala) is a missense variant which is present in one allele (0.01026%) in the African/African American population in gnomAD v2.1.1. This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. It has a REVEL score of 0.13 (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014194/MONDO:0011071/008 2024-07-31 2024-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8776 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0234215 infores:hetionet CHEBI:28901 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0423791 infores:hetionet CHEBI:3219 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0393760 infores:hetionet CHEBI:7824 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0549249 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0235409 infores:hetionet CHEBI:83804 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0242422 infores:hetionet CHEBI:6015 biolink:causes NCIT:C50599 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0700363 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0018799 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0424000 infores:hetionet CHEBI:47898 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017565 infores:hetionet CHEBI:3223 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0156404 infores:hetionet CHEBI:85161 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0010520 infores:hetionet CAID:CA180890 biolink:causes MONDO:0021060 infores:clingen CAID:CA180890 MONDO:0021060 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM1, PS3_Supporting BA1, BP4, BS3, BS1 The c.401A>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 134 (p.Tyr134Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 128-138). This variant has been identified in at least 4 patients with RASopathy (PS4_Moderate; PMID: 18413255, 18039235, 21062266, 23885229). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID: 17981815, 18413255). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180890/MONDO:0021060/048 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CAID:CA2695224152 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224152 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.1436dup (p.Leu479PhefsTer19) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BSS18.01 in PMID: 23995613) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224152/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4657 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C2830004 infores:hetionet CHEBI:8378 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0232461 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0392197 infores:hetionet CHEBI:8776 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0022346 infores:hetionet CHEBI:6149 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0015967 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027121 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0221203 infores:hetionet NCBIGene:2583 biolink:causes MONDO:0012213 infores:monarchinitiative not_provided not_provided HGNC:4117 MONDO:0012213 uuid:3cedb977-3951-488b-a24b-aa941a863272 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018965 infores:hetionet CHEBI:3219 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0007286 infores:hetionet CHEBI:17026 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0085605 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003864 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0232191 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0232191 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0021400 infores:hetionet CHEBI:63584 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042024 infores:hetionet CHEBI:28748 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151604 infores:hetionet CHEBI:68642 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0009782 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013395 infores:hetionet CHEBI:27666 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0085593 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020651 infores:hetionet GO:0070808 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0070808 GO:0019953 CHEBI:29688 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0015672 infores:hetionet CHEBI:17698 biolink:causes UMLS:C0259756 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0259756 infores:hetionet CHEBI:92712 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0027497 infores:hetionet CHEBI:8871 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0231530 infores:hetionet CHEBI:567361 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0231218 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017574 infores:hetionet UMLS:C0657912 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013384 infores:hetionet GO:0038201 biolink:causes GO:0031929 infores:ubergraph knowledge_assertion manual_agent GO:0038201 GO:0031929 CHEBI:48669 biolink:causes MONDO:0006820 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0022656 infores:hetionet CHEBI:63791 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003467 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0242350 infores:hetionet CHEBI:47612 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0151786 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0009319 infores:hetionet NCBIGene:6472 biolink:causes MONDO:0030866 infores:monarchinitiative not_provided not_provided HGNC:10852 MONDO:0030866 uuid:fe50e3c9-7f04-4d54-9872-182296e17819 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0037763 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0851341 infores:hetionet CHEBI:5855 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0000731 infores:hetionet CHEBI:3756 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0024902 infores:hetionet CHEBI:63611 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026827 infores:hetionet CHEBI:3181 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0013404 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0043246 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151824 infores:hetionet CHEBI:63617 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0036974 infores:hetionet CAID:CA229546 biolink:causes MONDO:0009861 infores:clingen CAID:CA229546 MONDO:0009861 PMID:23932990PMID:16256386PMID:26503515PMID:25894915PMID:28982351PMID:30050108 Pathogenic PP4_Moderate, PM2, PM3_Very Strong PP3 This c.441+3G>C (IVS4+3G>C) variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108). This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU (PMID: 30050108). This variant was documented 12 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515, 16256386, 23932990). This variant is absent from the population databases ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very strong, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229546/MONDO:0009861/006 2019-10-18 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27834 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0424295 infores:hetionet CHEBI:3215 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0036973 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001754 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013537 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009319 infores:hetionet CHEBI:8382 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0040038 infores:hetionet CHEBI:499361 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0002994 infores:hetionet CHEBI:75246 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0039070 infores:hetionet CHEBI:8245 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0042963 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0235295 infores:hetionet CHEBI:182080 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0232487 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0259749 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0037199 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0242350 infores:hetionet CHEBI:9150 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0026821 infores:hetionet CHEBI:5002 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0004604 infores:hetionet CHEBI:45783 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0497156 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0044872 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013363 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0520893 infores:hetionet CHEBI:32184 biolink:causes UMLS:C1610049 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C1610049 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0687133 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0030312 infores:hetionet CHEBI:5165 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0002063 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0019360 infores:hetionet CHEBI:9168 biolink:causes MONDO:0012833 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0403592 infores:hetionet CHEBI:6846 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0233494 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042769 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0042109 infores:hetionet CHEBI:3636 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0039231 infores:hetionet CHEBI:7514 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0013362 infores:hetionet CAID:CA410203780 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203780 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.259G>A (p.Gly87Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203780/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7577 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0149745 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0162429 infores:hetionet CAID:CA518490677 biolink:causes MONDO:0010278 infores:clingen CAID:CA518490677 MONDO:0010278 PMID: Uncertain Significance PM2_Supporting, BP4 The c.237G>A (p.Leu79=) variant in SLC9A6 (NM_006359.2) is absent from gnomAD (PM2_supporting). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the p.Leu79= variant in SLC9A6 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA518490677/MONDO:0010278/033 2023-10-13 2023-12-11 X-linked inheritance HP:0001417 Inconclusive true CAID:CA400029436 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029436 MONDO:0100326 PMID:26829726 Pathogenic PS3_Supporting, PVS1, PM2_Supporting "The ITGB3 variant c.1476G>A (p.Trp492Ter) is a nonsense variant causing a premature stop codon in exon 10/15, and is predicted to undergo nonsense mediated decay. The variant is demonstrated to cause reduced GPIIIa protein expression in transfection experiments in CHO cells (PMID:26829726). The variant is absent from population databases. This variant has not yet been associated with any individual with Glanzmann thrombasthenia. The variant was first identified in relation to HPA antigen genotyping research from a chinese blood donor, zygosity unkown. In summary, based on the available evidence at this time, the c.1476G>A variant is classified ""Pathogenic"". GT-specific criteria applied: PS3_supporting, PM2_Supporting, PVS1." Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029436/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4495 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0036454 infores:hetionet NCBIGene:2332 biolink:causes MONDO:0010706 infores:monarchinitiative not_provided not_provided HGNC:3775 MONDO:0010706 uuid:11833cb0-9f48-4720-b3ba-47ac9ac94bfb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0020538 infores:hetionet CHEBI:4562 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0013404 infores:hetionet CHEBI:42797 biolink:causes NCIT:C90501 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0553668 infores:hetionet CAID:CA023984 biolink:causes MONDO:0018493 infores:clingen CAID:CA023984 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with threonine at codon 4138 of the RYR1 protein, p.(Ile4138Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual who has a personal history of a malignant hyperthermia reaction (CGS 25), this individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID: 24433488). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.96) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023984/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:39867 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C2979982 infores:hetionet NCBIGene:64801 biolink:causes MONDO:0014868 infores:monarchinitiative not_provided not_provided HGNC:29561 MONDO:0014868 uuid:1659a657-74bc-47a1-a389-cbd1def2a0b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51173 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C2711227 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0031542 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0343886 infores:hetionet NCBIGene:6261 biolink:causes MONDO:0009712 infores:monarchinitiative not_provided not_provided HGNC:10483 MONDO:0009712 uuid:2dd21a88-f12c-4ae5-b3cb-563abf544c5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013456 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002418 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0029882 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0006277 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020538 infores:hetionet CHEBI:27899 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0013362 infores:hetionet CHEBI:8874 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019080 infores:hetionet CHEBI:63791 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020598 infores:hetionet CAID:CA124390 biolink:causes MONDO:0012163 infores:clingen CAID:CA124390 MONDO:0012163 PMID: Benign BA1 NM_002185.5(IL7R):c.197T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 66 (p.Ile66Thr). The filtering allele frequency (the lower threshold of the 95% CI of 56371/74906 alleles) of the c.197T>C variant in IL7R is 0.7458 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 353136 homozygotes have been described.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA124390/MONDO:0012163/119 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9570 biolink:causes MONDO:0020546 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0856825 infores:hetionet CHEBI:9763 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0014591 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0021845 infores:hetionet CHEBI:4466 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0242184 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0151500 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151500 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0332534 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0039971 infores:hetionet CHEBI:125354 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0012833 infores:hetionet CHEBI:4868 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0040038 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0014742 infores:hetionet CHEBI:45716 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0085649 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0009938 infores:hetionet CAID:CA119016 biolink:causes MONDO:0800472 infores:clingen CAID:CA119016 MONDO:0800472 PMID: Uncertain Significance PP3, PP1_Strong, BS1, PS3_Supporting, PS2_Supporting BP4, BA1, PM5, PM3, PM1, PM4, PS1, BP7, BS4, PVS1, PM2 The c.1103G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 368 (p.Arg368His). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.03079, which met the ≥ 0.01 threshold set for BS1 (2,804 alleles out of 91,076, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.751, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 19643970) demonstrated that the Arg368His protein had reduced 17B Estradiol Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. Other assays reporting this variant either did not meet the OddsPath threshold (> 2.1) (PMIDs: 23028769, 18622259, 27243976) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 11980847, 30108387, ANZRAG), which fulfilled PP1_Strong. There were more family studies published than presented here. As BS1 was met, PM3 did not apply and occurrence of this variant with another CYP1B1 variant was not assessed. One assumed de novo proband with PCG has been identified (PMID: 15037581). Total proband points = 0.5, meeting PS2_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 15.05.2024): BS1, PP1_Strong, PP3, PS2_Supporting, PS3_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119016/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0145185 biolink:causes UMLS:C1456863 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C1456863 infores:hetionet CHEBI:28864 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0013456 infores:hetionet CHEBI:63624 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0858635 infores:hetionet CHEBI:3696 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0025222 infores:hetionet CHEBI:367163 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085610 infores:hetionet CHEBI:27974 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0917801 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0036572 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0006266 infores:hetionet CHEBI:15552 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0030232 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0349506 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0027769 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0014868 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009806 infores:hetionet CHEBI:50648 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0022107 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0039503 infores:hetionet NCBIGene:916 biolink:causes MONDO:0014278 infores:monarchinitiative not_provided not_provided HGNC:1674 MONDO:0014278 uuid:ec039406-8c7b-4840-a10b-9ca79b14bbda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes HP:0001883 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1301937 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002465 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006271 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0853619 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0302295 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0004238 infores:hetionet CHEBI:39867 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0029453 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0151763 infores:hetionet CHEBI:8863 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042024 infores:hetionet CHEBI:2668 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0012569 infores:hetionet CHEBI:2654 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0001623 infores:hetionet CHEBI:5779 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0043352 infores:hetionet CHEBI:31236 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002792 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0162429 infores:hetionet CHEBI:7565 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0030794 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151849 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0241705 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0028259 infores:hetionet CHEBI:9586 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085641 infores:hetionet CHEBI:9763 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0016382 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0025061 infores:hetionet CHEBI:84500 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038325 infores:hetionet CHEBI:8382 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1368065 infores:hetionet CHEBI:2611 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020578 infores:hetionet CHEBI:63580 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0039591 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0155305 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0392025 infores:hetionet CHEBI:68647 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151908 infores:hetionet UMLS:C1738934 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0025874 infores:hetionet CHEBI:63577 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0497156 infores:hetionet CAID:CA2061614 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061614 MONDO:0015924 PMID: Likely Benign BS1 PM2, PP3, BA1, BP4, PM1, PS4 The BMPR2 c.2887G>T variant is a missense variant predicted to cause a glycine to cysteine substitution at amino acid 963 (p.Gly963Cys). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.001015 (13/12804 alleles) in the Swedish population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met as the computational predictor, REVEL, gives a score of 0.418, which is below the threshold of 0.75 (and above the threshold of >=0.25 for PP3). No functional data was available for review and SpliceAI did not predict an effect on splicing. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061614/MONDO:0015924/125 2024-05-02 2024-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes UMLS:C0016579 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016579 infores:hetionet CHEBI:37941 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0152169 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0020538 infores:hetionet CHEBI:4798 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0016204 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0006852 infores:hetionet CHEBI:6904 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0236075 infores:hetionet CHEBI:567361 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0041364 infores:hetionet CHEBI:3568 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085631 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0948594 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0520806 infores:hetionet GO:0044760 biolink:causes GO:0007271 infores:ubergraph knowledge_assertion manual_agent GO:0044760 GO:0007271 CHEBI:63637 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0423791 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948692 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005993 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0040923 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015469 infores:hetionet CHEBI:93305 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0033774 infores:hetionet CHEBI:4710 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0018524 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0009450 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017605 infores:hetionet CHEBI:465284 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0392699 infores:hetionet UMLS:C0145867 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0085631 infores:hetionet CAID:CA10585463 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585463 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, PS1, BS1, PM5, PP3, PP4 The NM_000527.5(LDLR):c.1457G>A (p.Ser486Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).BP4: REVEL = 0.297. It is below 0.5, splicing evaluation needed.Functional data on splicing not available.A) Not on limitsB) Does not create a DeNovo AG or GTC) There is no GT or AG nearby.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585463/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63619 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2240374 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0687713 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0019158 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003537 infores:hetionet CHEBI:7986 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0002792 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0349506 infores:hetionet CHEBI:17303 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0004604 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0559031 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020615 infores:hetionet CHEBI:5147 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C1458155 infores:hetionet CHEBI:41423 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C2364111 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0860239 infores:hetionet CHEBI:63577 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013378 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0740481 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0740481 infores:hetionet CHEBI:9727 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0001824 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0152227 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1322281 infores:hetionet CHEBI:4708 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151827 infores:hetionet CHEBI:15551 biolink:causes MONDO:0021723 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C2004487 infores:hetionet CHEBI:50275 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0022107 infores:hetionet CHEBI:135935 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C1306341 infores:hetionet NCBIGene:1277 biolink:causes MONDO:0020521 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0020521 uuid:386da697-179a-4119-8ac0-7d758ee75bd2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002871 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037315 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038362 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0162429 infores:hetionet CHEBI:68584 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0231218 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0233414 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0518015 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0149904 infores:hetionet CHEBI:63620 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0428974 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0023895 infores:hetionet CHEBI:9123 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0156404 infores:hetionet CHEBI:48273 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0423153 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0027769 infores:hetionet CHEBI:10101 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0032617 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030846 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0178298 infores:hetionet CHEBI:47781 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0038362 infores:hetionet CHEBI:32139 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C1443060 infores:hetionet NCBIGene:2064 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:3430 MONDO:0008903 uuid:0ca679ec-3771-4545-bb75-83a0da9909ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948089 infores:hetionet CHEBI:45924 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0010200 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0233494 infores:hetionet CHEBI:49668 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0085649 infores:hetionet CHEBI:50275 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002792 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0919980 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0014742 infores:hetionet CHEBI:6375 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042023 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0016770 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0016770 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0015397 infores:hetionet CHEBI:4469 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0042963 infores:hetionet CHEBI:16755 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0268000 infores:hetionet GO:0060014 biolink:causes CL:0000501 infores:ubergraph knowledge_assertion manual_agent GO:0060014 CL:0000501 CHEBI:5893 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0086543 infores:hetionet CHEBI:60761 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0233407 infores:hetionet CHEBI:63584 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0000737 infores:hetionet CHEBI:42797 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1456784 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0596170 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0302295 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0019158 infores:hetionet NCBIGene:79147 biolink:causes MONDO:0011688 infores:monarchinitiative not_provided not_provided HGNC:17997 MONDO:0011688 uuid:b082b09b-995e-4803-9e49-da7158ffe34f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0037763 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0015397 infores:hetionet CHEBI:9460 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0041834 infores:hetionet CHEBI:50173 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011606 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0948594 infores:hetionet CHEBI:7565 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0033774 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005942 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0035400 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0857122 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0857122 infores:hetionet CHEBI:63635 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0151908 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0002888 infores:hetionet CHEBI:28830 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0206061 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0022354 infores:hetionet CHEBI:39867 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0003862 infores:hetionet CHEBI:83804 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C2830004 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0012833 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0162429 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018916 infores:hetionet CHEBI:52717 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085593 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0241075 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0241075 infores:hetionet CHEBI:5004 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0035078 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0001824 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0036572 infores:hetionet CAID:CA208027 biolink:causes MONDO:0012589 infores:clingen CAID:CA208027 MONDO:0012589 PMID: Uncertain Significance BS1 PP3 "The highest population minor allele frequency of the p.Gly452Arg variant in TCF4 in gnomAD v4.1 is 0.0001120 in ""remaining"" populations, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). Computational prediction analysis tools are inconclusive for this variant. The p.Gly452Arg variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Gly452Arg variant in TCF4 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS1). (TCF4 Specifications v.4.0; curation approved on [5/7/2025])" Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208027/MONDO:0012589/032 2025-05-07 2025-06-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8382 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0042571 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0037199 infores:hetionet CHEBI:7478 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0010200 infores:hetionet CHEBI:52717 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1510410 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0149931 infores:hetionet CHEBI:194135 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018944 infores:hetionet CHEBI:5778 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0034152 infores:hetionet CHEBI:5138 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013362 infores:hetionet CHEBI:40050 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0030554 infores:hetionet CHEBI:8481 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0004093 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0020538 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005543 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0520463 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0042109 infores:hetionet CHEBI:7865 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0151740 infores:hetionet CHEBI:9637 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0009806 infores:hetionet CAID:CA6831842 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831842 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PVS1 PS4, PM2 The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant failed QC in gnomAD and the frequency data is considered unreliable, therefore PM2_Supporting will not be applied. While this variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting (PMID: 26287533, internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PP4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831842/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15544 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0041834 infores:hetionet CHEBI:51230 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0042571 infores:hetionet CHEBI:16796 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0004604 infores:hetionet CHEBI:15940 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0014868 infores:hetionet CHEBI:135888 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0235266 infores:hetionet CHEBI:4887 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0004134 infores:hetionet CHEBI:7494 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C3665386 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0011570 infores:hetionet CAID:CA229715 biolink:causes MONDO:0009861 infores:clingen CAID:CA229715 MONDO:0009861 PMID:11139255PMID:11139255 Likely Pathogenic PM2, PM3, PP3, PP4 PM5 The c.719T>C (p.Phe240Ser) variant in PAH has been reported in 1 individual with classic PKU detected with pathogenic variant p.R261Q (PMID: 11139255). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229715/MONDO:0009861/006 2020-11-09 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47381 biolink:causes UMLS:C0853746 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0853746 infores:hetionet CHEBI:9943 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0438142 infores:hetionet CHEBI:3504 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0014591 infores:hetionet CHEBI:8874 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0851578 infores:hetionet CHEBI:27974 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0037763 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0241863 infores:hetionet CAID:CA410208141 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208141 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.517T>C (p.Phe173Leu) is a missense variant which is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score ≥ 0.88 (0.94) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208141/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:145499 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0007787 infores:hetionet CHEBI:6129 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018926 infores:hetionet CHEBI:64354 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0151908 infores:hetionet NCBIGene:7010 biolink:causes MONDO:0014998 infores:monarchinitiative not_provided not_provided HGNC:11724 MONDO:0014998 uuid:91d71ef3-6ebc-466a-8ba3-124989ccdb84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020580 infores:hetionet CHEBI:125354 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0021053 infores:hetionet NCBITaxon:513045 biolink:causes MONDO:0000298 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:513045 MONDO:0000298 CHEBI:53691 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0035455 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151966 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151966 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1384353 infores:hetionet CHEBI:5864 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085602 infores:hetionet CHEBI:75722 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2363731 infores:hetionet CHEBI:3314 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0003123 infores:hetionet CHEBI:63629 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020443 infores:hetionet CHEBI:16714 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0428977 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151740 infores:hetionet CHEBI:5120 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0019572 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0853149 infores:hetionet CHEBI:10124 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0025222 infores:hetionet CHEBI:3441 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0007820 infores:hetionet CHEBI:35677 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0014742 infores:hetionet CHEBI:83527 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0085593 infores:hetionet CHEBI:63621 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2129214 infores:hetionet CHEBI:5847 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0007642 infores:hetionet CHEBI:6931 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C1443060 infores:hetionet CHEBI:188986 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0008031 infores:hetionet CHEBI:64355 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0242301 infores:hetionet CAID:CA16020920 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020920 MONDO:0009861 PMID:26503515 Pathogenic PVS1, PP4_Moderate, PM2 This c.1029T>A (p.Y343*) variant in PAH was reported in one Chinese patient with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515). This variant is absent from ExAC and gnomAD. This nonsense variant in exon 10 out of 13 is predicted to undergo nonsense mediated mRNA decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020920/MONDO:0009861/006 2019-10-17 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4514 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0220870 infores:hetionet CAID:CA146040 biolink:causes MONDO:0100437 infores:clingen CAID:CA146040 MONDO:0100437 PMID: Benign BP4, BA1 BS3 The NM_001034853.2(RPGR):c.1697G>A (p.Gly566Glu) variant is a missense variant encoding the substitution of Glycine with Glutamic acid at amino acid 566. This variant is present in gnomAD v.4.1.0 at a frequency of 0.06732 among hemizygous individuals, with 26691 variant alleles / 396470 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant was shown to have normal protein function and localization (PMID: 30622176). The computational predictor REVEL gives a score of 0.063, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.05, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate).In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0: BA1 and BP4_moderate (date of approval 05/15/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA146040/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CAID:CA228561 biolink:causes MONDO:0015630 infores:clingen CAID:CA228561 MONDO:0015630 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS4_Moderate, PS3, PM4, PP1_Strong BS4 NM_000552.5(VWF):c.4222_4224del (p.Lys1408del), in vWF is an in-frame deletion predicted to cause deletion of amino acid residue 1408, which is predicted to cause a change in the length of the protein in a non-repeat region meeting criteria for PM4. The variant is absent in gnomAD v4.1 meeting criteria for PM2_Supporting. At least 3 probands have displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio and decreased platelet/GP1b binding assay, which is highly specific for VWD type 2M (PP4_Moderate PMID: ; PS4_Moderate PMID: 28971901 & 10959688). The variant has been reported to segregate with VWD type 2M through at least 12 meioses across 3 different families (PP1_Strong; PMID: 28971901 & 10959688). Platelet/GP1b binding assay performed with the c.4222_4224del recombinant mutant vWF expressed by cos-7 cells showed decreased binding indicating that this variant has a damaging effect on protein function meeting criteria for PS3 (PMID:10959688). In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2M. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PS4_Moderate, PM4, PP1_Strong, PP4_Moderate, PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228561/MONDO:0015630/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31644 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C2830004 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0687133 infores:hetionet CAID:CA025483 biolink:causes MONDO:0012933 infores:clingen CAID:CA025483 MONDO:0012933 PMID:33293522PMID:33609447 Pathogenic PP3, PP1_Strong, PS3 PM2, BP5, BS1, PP4, BA1 The c.8168A>C variant in BRCA2 is a missense variant predicted to cause substitution of Aspartic acid by Alanine at amino acid 2723 (p.Asp2723Ala). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.576, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.557 (based on Pathology LR=0.214; Co-occurrence LR=1.102; Family History LR=2.36), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; 31853058, Internal lab contributors). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 74321.3, above the thresholds for Very strong pathogenic evidence (LR >350) (PP1_Very strong; Internal lab contributors).In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PP1_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025483/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47612 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0149931 infores:hetionet CHEBI:31397 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0011603 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019112 infores:hetionet CAID:CA10583380 biolink:causes MONDO:0700272 infores:clingen CAID:CA10583380 MONDO:0700272 PMID: Uncertain Significance PM2_Supporting, BP1 BS1, PP3, BP4, BA1 The c.871G>A variant in PALB2 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 291 (p.Ala291Thr). This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BP1, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583380/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9352 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0948594 infores:hetionet CAID:CA1139660051 biolink:causes MONDO:0007453 infores:clingen CAID:CA1139660051 MONDO:0007453 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4, PP1 The c.1284_1362del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 429 (NM_000162.5), adding 159 novel amino acids before encountering a stop codon (p.(Arg429fsX159)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two individuals with diabetes/hyperglycemia consistent with GCK-MODY; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1284_1362del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139660051/MONDO:0007453/086 2023-11-03 2023-11-03 Semidominant inheritance HP:0032113 Supports CHEBI:49040 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0035410 infores:hetionet CAID:CA229581 biolink:causes MONDO:0009861 infores:clingen CAID:CA229581 MONDO:0009861 PMID:26666653PMID:26666653 Uncertain Significance PM2, PP4, PP3 PM3 The c.493G>C (p.Ala165Pro) variant in PAH has been reported in a French patient with mild PKU with p.Glu390Gly, but parents were not tested (PP4; PMID: 26666653) This variant is absent from 1000G and ESP, and has extremely low frequency in ExAC/gnomAD: MAF 0.00001 (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.956 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229581/MONDO:0009861/006 2019-04-07 2019-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36795 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1167965 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0221100 infores:hetionet CAID:CA226074 biolink:causes MONDO:0100453 infores:clingen CAID:CA226074 MONDO:0100453 PMID: Pathogenic PM3, PVS1, PP1, PM2_Supporting NM_000180.4(GUCY2D):c.226_239del (p.Ala76ArgfsTer?) is a frameshift variant that introduces a premature stop codon into exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 unrelated proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 10951519). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.389del, p.Pro130Leufs*36 variant confirmed in trans (1 point, PMID: 37327959), which was previously classified Pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226074/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8707 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085612 infores:hetionet CHEBI:63617 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0520966 infores:hetionet CHEBI:45863 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0549567 infores:hetionet CHEBI:3312 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0009421 infores:hetionet CHEBI:3510 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0013395 infores:hetionet CHEBI:7565 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0017181 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0233414 infores:hetionet CHEBI:3403 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0340865 infores:hetionet CHEBI:408174 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0030252 infores:hetionet CHEBI:63681 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0027497 infores:hetionet CHEBI:6121 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0600260 infores:hetionet CAID:CA414791198 biolink:causes MONDO:0044970 infores:clingen CAID:CA414791198 MONDO:0044970 PMID: Uncertain Significance PP3 PP1, PS4, PS3, PM2 The m.7092T>C (p.F397L) variant in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There is one occurrence in the GenBank sequences queried through MITOMAP on 6/29/2020 (1 individual from haplogroup I4a). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414791198/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:10023 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014868 infores:hetionet CHEBI:4876 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0011053 infores:hetionet CHEBI:175901 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0428974 infores:hetionet CAID:CA2017997775 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997775 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4 The c.1343del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 448 (NM_000162.5), adding 166 novel amino acids before encountering a stop codon (p.(Gly448AlafsTer166)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and a three generation family history of diabetes) (PP4_Moderate; internal lab contributor). In summary, the c.1343del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP4_Moderate, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997775/MONDO:0015967/086 2023-06-24 2023-06-24 Semidominant inheritance HP:0032113 Supports CHEBI:43968 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0018790 infores:hetionet CHEBI:7476 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0041582 infores:hetionet CHEBI:63607 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0038325 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0948525 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0015469 infores:hetionet CHEBI:8869 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0006277 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001556 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041972 infores:hetionet CHEBI:5138 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011071 infores:hetionet CHEBI:23765 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002878 infores:hetionet CHEBI:30659 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0043144 infores:hetionet CAID:CA367402205 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402205 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting The c.371A>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to valine at codon 124 (p.(Asp124Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.370G>A, p.(Asp124Asn)​ has been interpreted as pathogenic by the ClinGen MDEP, and p.(Asp124Val) has a greater Grantham distance (PM5). In summary, c.449T>C meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402205/MONDO:0015967/086 2024-03-14 2024-03-14 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:61033 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0005758 infores:hetionet NCBIGene:51251 biolink:causes MONDO:0009946 infores:monarchinitiative not_provided not_provided HGNC:17820 MONDO:0009946 uuid:2e706f0a-7147-49cd-af7c-026be2fddbd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0040034 infores:hetionet CHEBI:8863 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030554 infores:hetionet CAID:CA119395 biolink:causes MONDO:0010880 infores:clingen CAID:CA119395 MONDO:0010880 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting The NM_000020.3: c.1232G>A variant in ACVRL1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 411 (p.Arg411Gln). The overall minor allele frequency in gnomAD v2.1.1 is 0.000007980 (2/250642 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 8640225, 31400083, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 32300199). The variant has been reported to segregate with HHT in 8 affected family members from one family (PP1_Strong; PMID: 8640225). The computational predictor REVEL gives a score of 0.904, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, binding assays in cell lines showed no BMP9 response indicating that this variant impacts protein function (PS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP1_Strong, PP4_Moderate, PM2_Supporting, PP3, PS3_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA119395/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51860 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0033975 infores:hetionet CHEBI:45367 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0003862 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0031350 infores:hetionet CHEBI:6538 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0042023 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0027769 infores:hetionet CAID:CA386973444 biolink:causes MONDO:0015967 infores:clingen CAID:CA386973444 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 PS4, PP4 The c.1768+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 9 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant also segregated with diabetes, with 7 informative meioses in 1 family with MODY (PP1_Strong; PMID: 8945470). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 8945470, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50%); however, HNF4A was not tested (internal lab contributors). Therefore, PP4 could not be applied. In summary, c.1768+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PP1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386973444/MONDO:0015967/017 2022-06-03 2022-06-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15365 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0009421 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234930 infores:hetionet CHEBI:6775 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027497 infores:hetionet CHEBI:3216 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0006277 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235984 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235984 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0242350 infores:hetionet CHEBI:17474 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1384353 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0016436 infores:hetionet CHEBI:5118 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013491 infores:hetionet CHEBI:28864 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235063 infores:hetionet CHEBI:6887 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0039070 infores:hetionet NCBIGene:2771 biolink:causes MONDO:0008648 infores:monarchinitiative not_provided not_provided HGNC:4385 MONDO:0008648 uuid:b0df26a3-f8d8-47e9-a5cd-dd5c993f3625 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2737 biolink:causes MONDO:0008272 infores:monarchinitiative not_provided not_provided HGNC:4319 MONDO:0008272 uuid:03b21b49-56dc-4fb7-8155-01a76e3c804f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0438717 infores:hetionet CHEBI:50131 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0476280 infores:hetionet CHEBI:5558 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0037763 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0003467 infores:hetionet CHEBI:3485 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0015967 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0332575 infores:hetionet CHEBI:42068 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0040046 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0031117 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0025517 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0149904 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0232492 infores:hetionet CHEBI:31709 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0042075 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002622 infores:hetionet CHEBI:9555 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0019209 infores:hetionet CHEBI:63632 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0018681 infores:hetionet GO:0003420 biolink:causes GO:0003416 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0003416 CHEBI:5779 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0030554 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0234215 infores:hetionet CHEBI:63621 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015468 infores:hetionet CHEBI:94686 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0026821 infores:hetionet CHEBI:2663 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0028084 infores:hetionet CHEBI:46345 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0030805 infores:hetionet CHEBI:127780 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0005818 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151740 infores:hetionet CHEBI:50275 biolink:causes MONDO:0019610 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0043515 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0011991 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0037274 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0038990 infores:hetionet GO:0019068 biolink:causes MONDO:0005109 infores:drugmechdb knowledge_assertion manual_agent GO:0019068 MESH:D015658 DB09065_MESH_D015658_1 CHEBI:45599 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0027709 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011570 infores:hetionet CHEBI:71941 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0013428 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0152029 infores:hetionet CHEBI:71415 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0151904 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0032285 infores:hetionet CHEBI:49603 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0743400 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0027765 infores:hetionet CHEBI:78543 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0007222 infores:hetionet CHEBI:584020 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0012833 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0149931 infores:hetionet NCBIGene:51371 biolink:causes MONDO:0054700 infores:monarchinitiative not_provided not_provided HGNC:20330 MONDO:0054700 uuid:78456ab2-a1be-44a5-9dab-ef490ae1ac62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0036104 infores:hetionet CAID:CA396451182 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451182 MONDO:0007648 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Moderate BP5, BP7, BS3, BS4, BS1, PM3, PM5, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS3, PS2, PS1 The c.2T>G (p.Met1Arg) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in two probands/families meeting HDGC clinical criteria (PS4_Moderate; SCV000760846.2 and internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 2 as specified by the CDH1 Variant Curation Expert Panel (v3.1): PVS1, PM2_supporting, PS4_Moderate. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451182/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7986 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0023067 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0574067 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0023895 infores:hetionet CHEBI:2950 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0039231 infores:hetionet NCBIGene:8120 biolink:causes MONDO:0015000 infores:monarchinitiative not_provided not_provided HGNC:567 MONDO:0015000 uuid:eae6e1ed-3aff-4cf3-b9f9-c34c5b555f0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3655 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0002792 infores:hetionet CHEBI:63621 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0231218 infores:hetionet NCBIGene:283375 biolink:causes MONDO:0014411 infores:monarchinitiative not_provided not_provided HGNC:20502 MONDO:0014411 uuid:2ce8cadc-adeb-4c32-8dbe-8d6a9bb56fe1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63622 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0030252 infores:hetionet NCBIGene:7128 biolink:causes MONDO:0800045 infores:monarchinitiative not_provided not_provided HGNC:11896 MONDO:0800045 uuid:4f6f9005-0559-4a92-8b49-cec93b1eb2da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0600228 infores:hetionet CHEBI:240107 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0344232 infores:hetionet CHEBI:2668 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0424790 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040409 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0162830 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0014130 infores:hetionet CHEBI:161680 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0043144 infores:hetionet NCBITaxon:85004 biolink:causes MONDO:0006706 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:85004 MONDO:0006706 CHEBI:17303 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0424295 infores:hetionet GO:0072106 biolink:causes GO:0001657 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0001657 CAID:CA2573320470 biolink:causes MONDO:0011132 infores:clingen CAID:CA2573320470 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PS4 The NM_001369369.1(FOXN1):c.1275_1278del (p.Leu426ThrfsTer?) frameshift variant results in a premature stop codon in the final exon (exon 9). It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). The variant is absent from gnomADv4.0 (PM2_Supporting). At least one heterozygous patient has been reported with profound T cell lymphocytopenia and absent TRECs (P7 from PMID: 27484032, PP4). The variant was also found in the heterozygous state in a patient with athymia and T cell lymphopenia (P2, PMID:34860543). The patient 7 was also panel sequenced for other SCID causative genes. In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, and PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573320470/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:70735 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0162429 infores:hetionet CHEBI:3077 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0239295 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0009450 infores:hetionet UMLS:C0005740 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0030554 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0018949 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0018949 infores:hetionet CHEBI:71940 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0035302 infores:hetionet CHEBI:72564 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0162830 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0026636 infores:hetionet CHEBI:5118 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0024902 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0013395 infores:hetionet CHEBI:28901 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151662 infores:hetionet CHEBI:51209 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0013404 infores:hetionet CHEBI:5118 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018926 infores:hetionet CHEBI:8874 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C2047937 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0040479 infores:hetionet CHEBI:3732 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151904 infores:hetionet CHEBI:47780 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151889 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0236101 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0236101 infores:hetionet CHEBI:63629 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011606 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0855704 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0036572 infores:hetionet CHEBI:71223 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0011991 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0022650 infores:hetionet CHEBI:3219 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1456784 infores:hetionet NCBIGene:124590 biolink:causes MONDO:0011748 infores:monarchinitiative not_provided not_provided HGNC:16356 MONDO:0011748 uuid:c56c4490-07a0-48bb-b514-c5ded8ab9503 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8603275 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603275 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PP4 The 945+9C>A variant in ITGA2B is an intronic variant located in intron 10. The variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of 0.977402 (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000007628 (9/1179914 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Although the variant is reported in ClinVar, no cases of the variant segregating in GT patients were found in the literature. Due to conflicting evidence, this variant is classified as likely benign for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BP4, BP7 and PM2_Supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603275/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6067 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009319 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0006145 infores:hetionet CHEBI:6456 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0522224 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006826 infores:hetionet GO:0048686 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0048686 GO:0007275 CHEBI:50648 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003467 infores:hetionet CHEBI:63577 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C2363730 infores:hetionet CHEBI:10125 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011603 infores:hetionet CHEBI:5088 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0023530 infores:hetionet CHEBI:3423 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0237849 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0403632 infores:hetionet NCBIGene:58484 biolink:causes MONDO:0014472 infores:monarchinitiative not_provided not_provided HGNC:16412 MONDO:0014472 uuid:5e89a83b-a21f-47e7-b0f3-4574a133756c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8129814 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129814 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP5, BP7, BS1, BS4, BS3, PVS1, PM6, PM3, PM1, PM4, PM5, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.225C>G p.(Phe75Leu)variant is present in <1/100,000 alleles in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). No additional evidence met criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129814/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6741 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0009806 infores:hetionet CHEBI:47612 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0151766 infores:hetionet CHEBI:18248 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0004604 infores:hetionet CHEBI:63589 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0009676 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0948594 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0011570 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0232492 infores:hetionet CHEBI:3127 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0018524 infores:hetionet CHEBI:28748 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0024236 infores:hetionet CHEBI:94440 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0003467 infores:hetionet CHEBI:135929 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0039231 infores:hetionet CHEBI:9448 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0014742 infores:hetionet CHEBI:27899 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0026821 infores:hetionet CHEBI:3061 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0085610 infores:hetionet NCBIGene:9990 biolink:causes MONDO:0031068 infores:monarchinitiative not_provided not_provided HGNC:10914 MONDO:0031068 uuid:2a651ea6-613d-4421-8aa3-0c0b2ea2f84b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0340865 infores:hetionet CHEBI:66899 biolink:causes UMLS:C0423847 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0423847 infores:hetionet CHEBI:5775 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0152025 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151717 infores:hetionet NCBIGene:3321 biolink:causes MONDO:0007871 infores:monarchinitiative not_provided not_provided HGNC:5950 MONDO:0007871 uuid:7281448e-a758-4f1b-8181-37f9cc3bfdec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92998 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0040264 infores:hetionet CHEBI:9763 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0028084 infores:hetionet CHEBI:3723 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235198 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1262005 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1262005 infores:hetionet CHEBI:15551 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0600142 infores:hetionet CHEBI:2453 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151539 infores:hetionet CHEBI:2469 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0035078 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0033975 infores:hetionet CHEBI:51364 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0021177 infores:hetionet CHEBI:31622 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0011603 infores:hetionet CHEBI:4653 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0030252 infores:hetionet CHEBI:8597 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0011991 infores:hetionet CAID:CA16619252 biolink:causes MONDO:0700270 infores:clingen CAID:CA16619252 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PVS1 BP4, BA1, BS1 The ATM c.8268+1G>A variant is at a canonical splice position and is expected to produce an NMD-escaping transcript that adversely affects the critical FATKIN domain (PVS1). This variant is absent in the GnomAD v2.1.1 cohort (PM2_Supporting) In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619252/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CAID:CA278736 biolink:causes MONDO:0019501 infores:clingen CAID:CA278736 MONDO:0019501 PMID: Likely Pathogenic PP3, PP1, PP4, PM3, PM2_Supporting The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278736/MONDO:0019501/005 2022-12-21 2023-02-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CAID:CA064960 biolink:causes MONDO:0018493 infores:clingen CAID:CA064960 MONDO:0018493 PMID: Uncertain Significance BP4 PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with isoleucine at codon 1176 of the RYR1 protein, p.(Tyr1176Ile). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0005879, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257). However, the high MAF in the SAS population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.162) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA064960/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:18258 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0948089 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0553702 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0041912 infores:hetionet CHEBI:3761 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0012833 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0857361 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0857361 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235146 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0746883 infores:hetionet CAID:CA277563 biolink:causes MONDO:0007648 infores:clingen CAID:CA277563 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.1937-423G>A variant is an intronic variant within intron 12. The variant has an allele frequency of 0.00289 (89/30842) in gnomAD (BA1; http://gnomad.broadinstitute.org). The allele is observed exclusively in the African subpopulation, with a frequency of 0.01022 (89/8708) and including one homozygote, suggesting that it may be a polymorphism in this population. In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA277563/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:84500 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0004096 infores:hetionet UMLS:C0145867 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0156404 infores:hetionet CAID:CA5416778 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416778 MONDO:0011225 PMID:25917813 Pathogenic PM2_Supporting, PS3_Moderate, PVS1 BS2 The c.571C>T (p.Arg191Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).The filtering allele frequency (the upper threshold of the 95% CI of 2/86258 alleles) of the c.571C>T variant in DCLRE1C is 0.000003850 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.87) and DNA repair (36h after IR): Mean (SD): 0 (12.11). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID: 25917813).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_Supporting, and PS3_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416778/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7820 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0151578 infores:hetionet CAID:CA134709 biolink:causes MONDO:0021060 infores:clingen CAID:CA134709 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1755A>G (p.Val585=) variant in the RAF1 gene is 6.222% (690/10404) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134709/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:2567 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0002871 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011551 infores:hetionet CHEBI:4814 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0003862 infores:hetionet NCBIGene:6389 biolink:causes MONDO:0100294 infores:monarchinitiative not_provided not_provided HGNC:10680 MONDO:0100294 uuid:14da34ba-eda5-4ec5-a10b-d7276f544106 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0015967 infores:hetionet CHEBI:391960 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0004093 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0085584 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0442874 infores:hetionet CHEBI:61058 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0013604 infores:hetionet CHEBI:92712 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0015672 infores:hetionet CHEBI:16664 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0022660 infores:hetionet CHEBI:64045 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0043352 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0041969 infores:hetionet CHEBI:4710 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0035854 infores:hetionet CHEBI:31205 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0027497 infores:hetionet CHEBI:50378 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0010520 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0032285 infores:hetionet CHEBI:63605 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0232462 infores:hetionet NCBIGene:406932 biolink:causes MONDO:0032835 infores:monarchinitiative not_provided not_provided HGNC:31527 MONDO:0032835 uuid:c0a5d661-6179-41b3-8ad7-518e45d9196d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020538 infores:hetionet CHEBI:3561 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0002994 infores:hetionet CHEBI:9139 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0232462 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0849918 infores:hetionet UNII:3QJA87N40S biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0233407 infores:hetionet CHEBI:16469 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0086565 infores:hetionet CHEBI:5558 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0030196 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0234913 infores:hetionet CHEBI:135736 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0268000 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0020649 infores:hetionet NCBIGene:60 biolink:causes MONDO:0100433 infores:monarchinitiative not_provided not_provided HGNC:132 MONDO:0100433 uuid:b910764a-c683-4fe8-84c1-3ae911ac1d63 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:477 biolink:causes MONDO:0859204 infores:monarchinitiative not_provided not_provided HGNC:800 MONDO:0859204 uuid:7edefacb-22fa-4e55-bc7f-88922ee62e01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151610 infores:hetionet CHEBI:18357 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0546884 infores:hetionet CHEBI:2682 biolink:causes HP:0011899 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0919890 infores:hetionet CHEBI:9587 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0014742 infores:hetionet CHEBI:7444 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0020649 infores:hetionet CHEBI:6538 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0231218 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151828 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0026650 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011570 infores:hetionet CHEBI:72690 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0009676 infores:hetionet CHEBI:66876 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0522055 infores:hetionet CHEBI:3216 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0030554 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0011849 infores:hetionet CHEBI:6076 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1262144 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0155003 infores:hetionet CHEBI:9586 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0022408 infores:hetionet CAID:CA024415 biolink:causes MONDO:0007783 infores:clingen CAID:CA024415 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Serine with Glycine at codon 1342 of the RYR1 protein, p.(Ser1342Gly). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.1566, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024415/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:3845 biolink:causes MONDO:0015278 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0015278 uuid:c280e77f-2666-415a-b551-3086e8994d4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004134 infores:hetionet CHEBI:53760 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0019572 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0038661 infores:hetionet CHEBI:465284 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0032227 infores:hetionet CAID:CA012667 biolink:causes MONDO:0005045 infores:clingen CAID:CA012667 MONDO:0005045 PMID: Uncertain Significance PP3, PS4_Supporting BS1, BS3, PP2, PM5, PM1, PM2, PM6, BP4, BP2, BA1, PS1, PS3, PS2 NM_000256.3(MYBPC3):c.2573G>A (p.Ser858Asn). This variant has been in individuals with HCM (ClinVar Variation ID: 164070) and has also been identified in 2 out of 124800 (0.005% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). This variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>5), therefore, the PS4 criterion has been applied at supporting strength (PS4_Supporting) and the PM2_Supporting criterion has not been applied. Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Supporting, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012667/MONDO:0005045/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4909 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C1096250 infores:hetionet CHEBI:5847 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0026826 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151601 infores:hetionet NCBIGene:9131 biolink:causes MONDO:0010275 infores:monarchinitiative not_provided not_provided HGNC:8768 MONDO:0010275 uuid:c81359ff-555d-4074-84c0-258f29ed0276 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0522058 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0522058 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0037199 infores:hetionet CAID:CA226517 biolink:causes MONDO:0100368 infores:clingen CAID:CA226517 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting PM5, PP1 NM_000329.3(RPE65):c.1451G>A is a predicted missense variant substituting glycine by aspartic acid at position 484. The computational predictor REVEL gives a score of 0.984, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Additionally, the splicing impact predictor SpliceAI gives a score of 0.23, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00005447, with 1/18360 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002. This variant has been reported in least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30025081, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts), absent or severely decreased rod electroretinogram response (0.5 pts), abnormal cone ERG responses (1 pt), white dots on color photography in the context of severe retinal dysfunction (2 pts), poor pupillary light response (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), decreased central visual acuity (1 pt), RPE mottling (0.5 pts), macular atrophy (0.5 pts), and symptomatic onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total points, PMID: 20811047, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226517/MONDO:0100368/120 2024-01-31 2024-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9571 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C2225524 infores:hetionet CAID:CA294670 biolink:causes MONDO:0010726 infores:clingen CAID:CA294670 MONDO:0010726 PMID: Likely Benign BS2 PM1, BP4, BS1 The p.Pro403Leu variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions. The p.Pro403Leu variant in MECP2 is present in 3 female individuals in gnomAD (0.0015%) (not sufficient to meet BS1 criteria). In summary, the p.Pro403Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294670/MONDO:0010726/032 2023-05-22 2023-06-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:465284 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020598 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0235431 infores:hetionet CHEBI:7627 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0002170 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020621 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0574067 infores:hetionet CHEBI:3176 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0235266 infores:hetionet CAID:CA410147868 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147868 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1175A>C (p.Gln392Pro) is a missense variant which has a REVEL score < 0.50 (0.245), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147868/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019158 infores:hetionet CHEBI:15367 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038325 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0021141 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020649 infores:hetionet CHEBI:7601 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0032285 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034065 infores:hetionet CAID:CA16616511 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616511 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria, but PS4 can not be applied with BS1 (PS4 not applied). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616511/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47898 biolink:causes EFO:0010671 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0549124 infores:hetionet CHEBI:4887 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C2979982 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0025061 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0239739 infores:hetionet CHEBI:101278 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0002878 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006892 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0236018 infores:hetionet CHEBI:53760 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0221423 infores:hetionet CHEBI:50922 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0004093 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018799 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0522351 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0522351 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0043012 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0043012 infores:hetionet CHEBI:6375 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0008031 infores:hetionet CHEBI:480999 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0015672 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0038826 infores:hetionet CHEBI:5165 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011168 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0003123 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0019087 infores:hetionet GO:0008284 biolink:causes MONDO:0011719 infores:drugmechdb knowledge_assertion manual_agent GO:0008284 MESH:D046152 DB08896_MESH_D046152_1 CHEBI:18248 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0015376 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011606 infores:hetionet CAID:CA9487766 biolink:causes MONDO:0011229 infores:clingen CAID:CA9487766 MONDO:0011229 PMID: Benign BS2, BA1 PM2, BP7, BS1 The filtering allele frequency of the c.712+88 G>A variant in the ETHE1 gene is >35% by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Mito Variant Curation Expert Panel (BA1) Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA9487766/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6792 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0042109 infores:hetionet CHEBI:8426 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0030193 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0009806 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042075 infores:hetionet CHEBI:31638 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0235996 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0162287 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0036572 infores:hetionet CHEBI:49662 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0016204 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020649 infores:hetionet CHEBI:7852 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0542571 infores:hetionet CHEBI:8888 biolink:causes MONDO:0019086 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0152018 infores:hetionet CHEBI:5864 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0041364 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017152 infores:hetionet CHEBI:9123 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030232 infores:hetionet CAID:CA229351 biolink:causes MONDO:0009861 infores:clingen CAID:CA229351 MONDO:0009861 PMID:16091306 Likely Pathogenic PP4_Moderate, PM2, PM3 PM5, PP3, PS3 The c.1117G>A (p.Ala373Thr) variant in PAH has been reported in multiple individuals with mild HPA (BH4 deficiency excluded, PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants c.442-1G>A (PMID: 10484807) and in trans with p.Arg261Gln (PMID: 29316886). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229351/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51137 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0231528 infores:hetionet CHEBI:4953 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0023530 infores:hetionet CHEBI:31711 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0003460 infores:hetionet CHEBI:7565 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0728899 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0018802 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0009806 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0152029 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151826 infores:hetionet CHEBI:83527 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0080274 infores:hetionet NCBIGene:860 biolink:causes MONDO:0007340 infores:monarchinitiative not_provided not_provided HGNC:10472 MONDO:0007340 uuid:fe3ed613-f7c3-483f-ba02-843414c93865 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3757 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037052 infores:hetionet CHEBI:9123 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020903 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0085584 infores:hetionet CHEBI:8024 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0020903 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0575090 infores:hetionet CAID:CA2497028745 biolink:causes MONDO:0015967 infores:clingen CAID:CA2497028745 MONDO:0015967 PMID: Uncertain Significance PS4_Moderate, PP4, PM2_Supporting The c.-97G>A variant in the glucokinase gene, GCK, is a single nucleotide variant within the 5' UTR of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). In summary, the c.-97G>A variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497028745/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:5165 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085633 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002356 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030286 infores:hetionet CHEBI:31980 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0542571 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027051 infores:hetionet CHEBI:2038 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0017178 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0853748 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0040034 infores:hetionet CHEBI:4657 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0020621 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0948594 infores:hetionet CHEBI:42820 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0030554 infores:hetionet CHEBI:8707 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0032617 infores:hetionet CHEBI:77260 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0086565 infores:hetionet NCBIGene:6473 biolink:causes MONDO:0009588 infores:monarchinitiative not_provided not_provided HGNC:10853 MONDO:0009588 uuid:cdf984bb-8414-419c-845f-36ab74927ad4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0012569 infores:hetionet CHEBI:135613 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0151699 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042075 infores:hetionet CHEBI:42355 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0030305 infores:hetionet CHEBI:92712 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0151889 infores:hetionet CHEBI:49668 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0003813 infores:hetionet CHEBI:421707 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0014518 infores:hetionet CHEBI:63717 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0877192 infores:hetionet CHEBI:3387 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0014743 infores:hetionet CHEBI:2549 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0349790 infores:hetionet CHEBI:17263 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0022354 infores:hetionet NCBIGene:23511 biolink:causes MONDO:0032926 infores:monarchinitiative not_provided not_provided HGNC:17859 MONDO:0032926 uuid:9707d933-faa6-4254-9a76-5c9d0fd0152b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0027765 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0795692 infores:hetionet CHEBI:5893 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0546884 infores:hetionet CHEBI:6367 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C3263723 infores:hetionet NCBIGene:54832 biolink:causes MONDO:0014796 infores:monarchinitiative not_provided not_provided HGNC:23594 MONDO:0014796 uuid:5002472b-59b1-4697-9923-ac0b66d9e1cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0494475 infores:hetionet UMLS:C0145867 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0220870 infores:hetionet CHEBI:32315 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0030554 infores:hetionet CHEBI:72564 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0018989 infores:hetionet CHEBI:7809 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0023052 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0013922 infores:hetionet CHEBI:9137 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235198 infores:hetionet CHEBI:6539 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C1145670 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1956346 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0403632 infores:hetionet CAID:CA10118715 biolink:causes MONDO:0021060 infores:clingen CAID:CA10118715 MONDO:0021060 PMID: Likely Pathogenic PVS1, PM3 PM2, BA1, BS1 The NM_006767.4:c.1084C>T (p.Arg362Ter) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 10/21 and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population filtering allele frequency in gnomAD v2.1 is 0.00003426 (15/251042 alleles) in the European (non-Finnish) population. Evidence supports that this variant is associated with AR NS and is not associated with AD NS. This variant has been detected in 1 individual with NS. That individual was compound heterozygous for the variant and another loss of function pathogenic variant confirmed in trans by parental testing (c.1149+1G>T) (PM3, PMID:31182298). Schwannomatosis has been observed in individuals harboring this variant (PMID:29384852). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM3, PVS1. (RASopathy VCEP specifications version 1.1; 9/17/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10118715/MONDO:0021060/094 2024-09-17 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:114785 biolink:causes NCIT:C80119 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C2609319 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007971 infores:hetionet NCBIGene:3043 biolink:causes MONDO:0013517 infores:monarchinitiative not_provided not_provided HGNC:4827 MONDO:0013517 uuid:fe37f723-90e7-4eb4-a82d-8875815187c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71223 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0011603 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0027765 infores:hetionet CHEBI:180905 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C3665347 infores:hetionet CHEBI:64355 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030554 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0006840 infores:hetionet GO:0070951 biolink:causes GO:0050829 infores:ubergraph knowledge_assertion manual_agent GO:0070951 GO:0050829 CHEBI:6367 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0232462 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020517 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0027339 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0948594 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0001824 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0426390 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0522061 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0522061 infores:hetionet CHEBI:82941 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0020456 infores:hetionet CHEBI:68478 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0016059 infores:hetionet CHEBI:93635 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0009806 infores:hetionet UMLS:C0657912 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0000731 infores:hetionet CHEBI:107736 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0235378 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0025419 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D005667 DB02703_MESH_D005667_1 CHEBI:119915 biolink:causes UMLS:C0948425 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948425 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042075 infores:hetionet CHEBI:28787 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0012833 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042769 infores:hetionet CHEBI:9086 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151827 infores:hetionet CHEBI:9434 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0015967 infores:hetionet CHEBI:63637 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0085593 infores:hetionet NCBIGene:1629 biolink:causes MONDO:0023693 infores:monarchinitiative not_provided not_provided HGNC:2698 MONDO:0023693 uuid:32b3498d-d017-4445-b615-448ec9de1ba4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026837 infores:hetionet CAID:CA410202792 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202792 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, BS2, PP4, PP2, PP1 NM_001754.5(RUNX1):c.352G>A (p.Val118Met) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score ≥ 0.88 (0.923) (PP3). It is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202792/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39112 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0948594 infores:hetionet CHEBI:72690 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0041969 infores:hetionet CHEBI:72690 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0037763 infores:hetionet NCBITaxon:51028 biolink:causes MONDO:0005746 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:51028 MESH:D017229 DB00643_MESH_D017229_1DB00730_MESH_D017229_1DB00592_MESH_D017229_1 UMLS:C0010592 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020569 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018991 infores:hetionet GO:1904441 biolink:causes GO:0035270 infores:ubergraph knowledge_assertion manual_agent GO:1904441 GO:0035270 CHEBI:8356 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0333243 infores:hetionet CHEBI:681848 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0006266 infores:hetionet CHEBI:28748 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151904 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0302295 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0015397 infores:hetionet CHEBI:6741 biolink:causes UMLS:C1535970 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1535970 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0009450 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0010399 infores:hetionet CHEBI:6413 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0344232 infores:hetionet CHEBI:15367 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0043094 infores:hetionet CHEBI:17650 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0023380 infores:hetionet CHEBI:4995 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0035229 infores:hetionet CHEBI:63622 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0007398 infores:hetionet CHEBI:32221 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0015672 infores:hetionet CHEBI:10124 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0231530 infores:hetionet CHEBI:42355 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0152030 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0004789 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D002761 DB00798_MESH_D002761_1DB01327_MESH_D002761_1DB02703_MESH_D002761_1DB00479_MESH_D002761_1DB00199_MESH_D002761_1 CHEBI:15367 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027497 infores:hetionet CHEBI:9398 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0040435 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1112346 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1112346 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0018839 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018839 infores:hetionet CHEBI:7575 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0033774 infores:hetionet CHEBI:93635 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0162830 infores:hetionet CHEBI:92998 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151907 infores:hetionet CAID:CA120624 biolink:causes MONDO:0044970 infores:clingen CAID:CA120624 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PM6_Supporting, PVS1_Strong PP3, BP4, PS4, PS3 The m.14787_14790delTTAA (p.Ile14ThrfsTer27) variant in MT-CYB has been reported in one individual to date, in a man with features consistent with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and akinetic rigid syndrome. Clinical features included fine motor incoordination, concentration difficulty, fatigue, periods with regressive behavior, Wolff-Parkinson-White arrhythmia, mild left ventricular hypertrophy, seizures, and cortical blindness. He walked with a flexed body posture, reduced arm swing, mild shuffling gait, had resting tremor of the hands, and increased muscle tone. Brain MRI showed diffuse atrophy and lesions consistent with cerebral infarcts in the left and right parietooccipital region. Blood and cerebrospinal fluid lactate levels were elevated. Muscle biopsy electron microscopy showed aggregates of subsarcolemmal mitochondria. He had an isolated complex III deficiency in muscle (14% lowest normal value). The variant was present at 60% heteroplasmy in blood, 60% in hair, 60% in buccal, 60% in fibroblasts, and 95% muscle (PMID: 9894888). As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and hair samples from his healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in a frame shift from codon 13 onward and is predicted to result in a nonsense stretch of amino acids terminating at an early stop at codon 50 (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120624/MONDO:0044970/015 2023-12-11 2024-03-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8888 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151613 infores:hetionet CHEBI:30659 biolink:causes HP:0008441 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0014571 infores:hetionet CHEBI:135451 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0000833 infores:hetionet GO:0045765 biolink:causes GO:0048514 infores:ubergraph knowledge_assertion manual_agent GO:0045765 GO:0048514 CHEBI:100241 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0239377 infores:hetionet CHEBI:5128 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0013378 infores:hetionet CHEBI:17026 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0549249 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0038367 infores:hetionet CHEBI:681569 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0002170 infores:hetionet CHEBI:3499 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0020517 infores:hetionet CHEBI:17334 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0040822 infores:hetionet CHEBI:4779 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0018681 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0855242 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0008370 infores:hetionet CHEBI:36704 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0019080 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0034150 infores:hetionet CHEBI:50859 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020458 infores:hetionet CHEBI:37924 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018965 infores:hetionet NCBIGene:2806 biolink:causes MONDO:0032880 infores:monarchinitiative not_provided not_provided HGNC:4433 MONDO:0032880 uuid:0fd748f6-e25f-4adc-b240-495e7bc42c19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:1280 biolink:causes MONDO:0005249 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D011014 DB01165_MESH_D011014_1 CHEBI:9086 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0349506 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0003864 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024117 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0037199 infores:hetionet CHEBI:3752 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0041657 infores:hetionet CHEBI:3510 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0033975 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0877338 infores:hetionet CHEBI:31397 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0012833 infores:hetionet CHEBI:135351 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0085649 infores:hetionet CHEBI:50173 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0033687 infores:hetionet CHEBI:59560 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C1260880 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0221203 infores:hetionet CHEBI:8077 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0039231 infores:hetionet CHEBI:44423 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0005758 infores:hetionet CHEBI:92511 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0012833 infores:hetionet CHEBI:66901 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0741494 infores:hetionet CHEBI:10119 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0241934 infores:hetionet CHEBI:4445 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0022346 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0005741 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019360 infores:hetionet NCBIGene:6900 biolink:causes MONDO:0014167 infores:monarchinitiative not_provided not_provided HGNC:2172 MONDO:0014167 uuid:281d460b-6853-4ebe-899f-b6c73f66ff82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7444 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0858678 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011849 infores:hetionet CHEBI:74947 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0234428 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0233632 infores:hetionet CAID:CA16020850 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020850 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting The c.745del (p.Leu249fs) variant in PAH has been reported in 1 Chilean patient with mild PKU; Phe = 600-900umol/L (PMID: 29288420; PP4). This variant was detected with V388M - reported at Pathogenic in ClinVar (VarID:610, 7 submitters); phase not confirmed - 0.5 points (PMID: 29288420; PM3_supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 7 out of 13 coding exons; 7 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020850/MONDO:0009861/006 2021-05-15 2021-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:39112 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0041912 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002622 infores:hetionet CHEBI:31859 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013404 infores:hetionet CHEBI:28177 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0020649 infores:hetionet CHEBI:64312 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0038325 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0878544 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0003123 infores:hetionet CHEBI:9622 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0041912 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0017152 infores:hetionet CHEBI:5280 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151827 infores:hetionet CHEBI:5118 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011253 infores:hetionet CHEBI:46295 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0155305 infores:hetionet CHEBI:6128 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0542571 infores:hetionet CHEBI:4735 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0027726 infores:hetionet CHEBI:5296 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0017178 infores:hetionet CHEBI:204928 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0014742 infores:hetionet CHEBI:3127 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0547030 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0239093 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0239093 infores:hetionet CAID:CA16615708 biolink:causes MONDO:0018875 infores:clingen CAID:CA16615708 MONDO:0018875 PMID: Pathogenic PS3, PS2_Moderate, PM1, PS1_Moderate, PP4_Moderate, PM2_Supporting BA1, BP4, PS4, BS1, BS3, BS4, PM6, BS2, PP3, PP1 The NM_000546.6: c.537T>A variant in TP53 is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 179 (p.His179Gln). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 12 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369). The same amino acid change (p.His179Gln), resulting from a different nucleotide change (c.537T>G) (ClinVar Variation ID: 376607; PMIDs: 18511570, 31119730), is classified as likely pathogenic for Li-Fraumeni syndrome by following the ClinGen TP53 VCEP’s specifications. Splicing prediction using SpliceAI revealed no expected impact on splicing due to either variant (PS1_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 19556618). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000664423.4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, PS1_Moderate, PS2_Moderate, PP4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615708/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3723 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0000729 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0022081 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022104 infores:hetionet CHEBI:49668 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0043352 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0017675 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0085649 infores:hetionet GO:0061050 biolink:causes GO:0055013 infores:ubergraph knowledge_assertion manual_agent GO:0061050 GO:0055013 CHEBI:63620 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0009676 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0032584 infores:hetionet CHEBI:681848 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0242184 infores:hetionet CHEBI:6402 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0010200 infores:hetionet CHEBI:3387 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0032708 infores:hetionet CAID:CA10014512 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014512 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.451A>G (p.Met151Val) is a missense variant which has a REVEL score ≥ 0.88 (0.907) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014512/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:10320 biolink:causes MONDO:0014810 infores:monarchinitiative not_provided not_provided HGNC:13176 MONDO:0014810 uuid:cc5af14b-e777-4432-9ca1-cc5ce918f02c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0160390 infores:hetionet CAID:CA287523530 biolink:causes MONDO:0100453 infores:clingen CAID:CA287523530 MONDO:0100453 PMID: Pathogenic PVS1, PP1, PM2_Supporting The NM_000180.4(GUCY2D):c.722-1G>T variant disrupts a canonical splice site in intron 2 and is predicted to lead to skipping of a critical exon. The subsequent frameshift is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 34662339). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP1, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA287523530/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0036508 infores:hetionet CHEBI:28925 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0040264 infores:hetionet CHEBI:49040 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0009782 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1565489 infores:hetionet CHEBI:3723 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0600142 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233472 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018799 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0021053 infores:hetionet CHEBI:3732 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0040264 infores:hetionet CHEBI:3242 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0003811 infores:hetionet CHEBI:31236 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020452 infores:hetionet CAID:CA120610 biolink:causes MONDO:0044970 infores:clingen CAID:CA120610 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS3, PS4, PS2 The m.6721T>C (p.M273T) variant in MT-CO1 has been reported in one individual to date, in a 58-year-old woman with acquired idiopathic sideroblastic anemia (PMID: 9389715). The variant was present in bone marrow from the proband and absent in her mother’s blood (PM6_supporting). There have not been additional affected individuals reported to date. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.72 (Min=0, Max=1; APOGEE2 score is 0.834), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3, PM2_supporting, PM6_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120610/MONDO:0044970/015 2024-03-11 2024-11-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA410148525 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148525 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1025T>C (p.Ile342Thr) is a missense variant which has a REVEL score < 0.50 (0.248) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148525/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6741 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0041912 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0580493 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0580493 infores:hetionet NCBIGene:9786 biolink:causes MONDO:0014664 infores:monarchinitiative not_provided not_provided HGNC:19960 MONDO:0014664 uuid:faed6f59-066c-4fd7-8733-9e04fa733547 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0233414 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013985 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0005984 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D014008 DB00257_MESH_D014008_1DB00239_MESH_D014008_1DB06820_MESH_D014008_1 CHEBI:119915 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0019360 infores:hetionet CHEBI:63635 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027424 infores:hetionet CHEBI:47426 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0233471 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0243026 infores:hetionet CHEBI:9448 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0000729 infores:hetionet CHEBI:63581 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0035455 infores:hetionet CAID:CA220218 biolink:causes MONDO:0008723 infores:clingen CAID:CA220218 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM1, PM3_Supporting, PP4_Moderate The c.664G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 222 (p.Gly222Arg). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and a distinct variants not yet evaluated by the ACADVL VCEP, at least one individual was compound het for this variant and a variant determined by the ACADVL VCEP as likely pathogenic, and at least one individual was homozygous for the variant (PM3_Supporting, PMID: 24801231, 20060901, 16443431, 28771436, 31844625). At least one patient with this variant displayed increased C14:1 levels and another patient showed significantly reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 24801231, PMID: 20060901). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.981, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). This variant resides within a region, amino acids 214-223, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, 18227065, 20060901; PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_supporting, PM3_Supporting, PP3, PP4_moderate ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220218/MONDO:0008723/021 2023-02-13 2023-02-13 Autosomal recessive inheritance HP:0000007 Supports GO:0045601 biolink:causes GO:0003158 infores:ubergraph knowledge_assertion manual_agent GO:0045601 GO:0003158 CHEBI:100147 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0038999 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235639 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0025061 infores:hetionet CHEBI:44423 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0042963 infores:hetionet GO:0045700 biolink:causes GO:0007286 infores:ubergraph knowledge_assertion manual_agent GO:0045700 GO:0007286 GO:0080113 biolink:causes GO:0048316 infores:ubergraph knowledge_assertion manual_agent GO:0080113 GO:0048316 CHEBI:3215 biolink:causes UMLS:C0456677 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0456677 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0003123 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151883 infores:hetionet CHEBI:79699 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011606 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0003123 infores:hetionet NCBIGene:525 biolink:causes MONDO:0009968 infores:monarchinitiative not_provided not_provided HGNC:853 MONDO:0009968 uuid:a4cd18f7-a866-4a88-9f20-9f1b50cbad17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes HP:0005206 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030299 infores:hetionet GO:0002319 biolink:causes CL:0000787 infores:ubergraph knowledge_assertion manual_agent GO:0002319 CL:0000787 CAID:CA410148813 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148813 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.978C>A (p.Asp326Glu) is a missense variant which has a REVEL score < 0.50 (0.075), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148813/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:8803 biolink:causes MONDO:0012791 infores:monarchinitiative not_provided not_provided HGNC:11448 MONDO:0012791 uuid:b9938271-38ff-4e7a-af07-0f2e57f3a312 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3437 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0547030 infores:hetionet CHEBI:204734 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0263449 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0037290 infores:hetionet CHEBI:7640 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0002170 infores:hetionet CAID:CA8602549 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602549 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2, PP4, BA1 The c.2862G>A (p.Val954=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of 1.07117 (BP7 and BP4). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, it is not found in the literature to segregate in any GT patients. In summary, this variant meets the criteria to be classified as Likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and BP7 (VCEP specifications version 2; date of approval 12/17/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602549/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA10581289 biolink:causes MONDO:0044970 infores:clingen CAID:CA10581289 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, BA1, PS4, PS2, PS3, BS1, PM2, PM6 The m.8803A>T variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. This variant has been reported twice in the medical literature in affected individuals but there was no attribution of pathogenic involvement in either case (one case had Leber Hereditary Optic Neuropathy, PMID 15465027; one case had Alzheimer disease, PMID 20700462). There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 was 22/56,434 (0.039%) with all 22 being homoplasmic and in top level haplogroup H. The frequency in the MITOMAP GenBank sequences was 8/59,389 (0.013%); all eight of these individuals (100%) are in H5a haplogroup, with one of them being the individual with Alzheimer disease discussed above. The frequency of homoplasmic occurrences in the Helix dataset was 159/195,983 (0.081%); 152 of these Helix variants were in haplogroup H; seven were in haplogroup U. An additional five variants were reported as heteroplasmic; these were all in haplogroup H. Of note, the individual with Leber Hereditary Optic Neuropathy discussed above types to haplogroup U1a. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign (>0.5%). The computational predictor APOGEE gives a consensus rating of benign with scores of 0.37 (“neutral”) in APOGEE1 and 0.101 (“likely benign” in APOGEE2; Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays found in the literature for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581289/MONDO:0044970/015 2023-07-10 2023-08-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:499361 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0017152 infores:hetionet CHEBI:6950 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0424295 infores:hetionet CHEBI:8884 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0002792 infores:hetionet CHEBI:6129 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0268000 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0020649 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0242350 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0340726 infores:hetionet CAID:CA241298 biolink:causes MONDO:0100453 infores:clingen CAID:CA241298 MONDO:0100453 PMID: Benign BP4, BS1, BS2 The NM_000180.4(GUCY2D):c.271G>C (p.Ala91Pro) variant is predicted to substitute the alanine at position p.91 with proline. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.006915, with 581/78368 total alleles in the South Asian population, which is within the ClinGen LCA/eoRD VCEP BS1 range of 0.0016 - 0.016 (BS1). This variant has also been found in the homozygous state in 6 adult individuals in gnomAD which meets the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2) The computational predictor REVEL gives a score of 0.219, which is below the ClinGen LCA/eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA241298/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:66899 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0010200 infores:hetionet NCBIGene:54795 biolink:causes MONDO:0032801 infores:monarchinitiative not_provided not_provided HGNC:17993 MONDO:0032801 uuid:086c33ee-8b1f-4e5c-a56a-7928acc1827d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0009782 infores:hetionet CHEBI:6792 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0231528 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0855242 infores:hetionet CHEBI:68606 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0011991 infores:hetionet CHEBI:6909 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0085641 infores:hetionet CAID:CA071335 biolink:causes MONDO:0018493 infores:clingen CAID:CA071335 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with phenylalanine at codon 2685 of the RYR1 protein, p.(Ser2685Phe). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.777 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA071335/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:61033 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0036572 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042514 infores:hetionet CAID:CA347219330 biolink:causes MONDO:0015152 infores:clingen CAID:CA347219330 MONDO:0015152 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PM5, PS3, BP2, PP4 The NM_003494.4: c.4526T>G variant in DYSF, which is also known as NM_001130987.2: c.4643T>G p.(Leu1548Arg), is a missense variant predicted to cause substitution of leucine by arginine at amino acid 1509, p.(Leu1509Arg). In two unrelated individuals with LGMD, this variant has been observed in unknown phase with the NM_003494.4: c.4024C>T p.(Arg1342Trp) variant, which is classified as pathogenic by the LGMD VCEP (PMID: 36983702; ClinVar SCV003223254.2). Each of these patients had a third variant in DYSF that was also classified as likely pathogenic or pathogenic, suggesting c.4526T>G p.(Leu1509Arg) likely occurred in cis with c.4024C>T p.(Arg1342Trp), but phase was not confirmed (BP2, PP4, PM3 not met). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, due to the limited evidence available, this variant is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347219330/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6950 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0019521 infores:hetionet CHEBI:8024 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0010200 infores:hetionet CHEBI:4708 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0233471 infores:hetionet CHEBI:64354 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0038999 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011849 infores:hetionet CHEBI:408174 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020621 infores:hetionet CHEBI:188986 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0030193 infores:hetionet CHEBI:36704 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0034152 infores:hetionet CAID:CA400029054 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029054 MONDO:0100326 PMID:22308022 Likely Pathogenic PP4_Strong, PP3, PP1, PM2_Supporting, PM3_Supporting PS3 The NM_000212.3(ITGB3):c.1388G>C (p.Cys463Ser) missense variant has been observed in at least one GT patient (Patient 7 in PMID: 34267460), whom displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0.5-1.7%, as measured by flow cytometry (PP4_strong). The variant was been reported to segregate with Glanzmann thrombasthenia in Patient 7 plus one affected family member, both with the homozygous Cys463Ser genotype. (PM3_supporting, PP1; PMID: 34267460). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91078 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP1, PP3, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029054/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:64312 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040038 infores:hetionet NCBIGene:10716 biolink:causes MONDO:0011627 infores:monarchinitiative not_provided not_provided HGNC:11590 MONDO:0011627 uuid:58880c30-901d-49b4-a0c7-4dafea75a434 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9605 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0518015 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042035 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0011991 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002871 infores:hetionet CHEBI:84500 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0151908 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1318314 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1318314 infores:hetionet CHEBI:135005 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0039240 infores:hetionet CAID:CA487844850 biolink:causes MONDO:0100216 infores:clingen CAID:CA487844850 MONDO:0100216 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Supporting, PS3 PVS1, BA1, BP4, BP2, PP1, BS2, PM4, PM5, PM1, PS2, PS1, BP7, BS1, BS3, BS4 The NM_177438.3:c.2523A>G (p.Gln841=) variant is a synonymous (silent) variant that is predicted to impact splicing. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 36922881). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 36922881). This variant has an allele frequency of 6.197e-7 (1/1613606 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; PMIDs: 36922881, 39484203; Internal lab contributors). The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PS3, PP3. (Bayesian Points: 8; VCEP specifications version 1.3.0; 4/22/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA487844850/MONDO:0100216/024 2025-04-22 2025-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50131 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0003862 infores:hetionet CHEBI:71229 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0011991 infores:hetionet UMLS:C0004609 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0542571 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0917799 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0442874 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0162287 infores:hetionet CHEBI:72323 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0038325 infores:hetionet CHEBI:36704 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0019348 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021203 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0271453 infores:hetionet CHEBI:94501 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0014591 infores:hetionet CHEBI:47657 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0027497 infores:hetionet CHEBI:84500 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037384 infores:hetionet CHEBI:31401 biolink:causes HP:0001892 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C1458140 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0423773 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0027051 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0025061 infores:hetionet CAID:CA320741232 biolink:causes MONDO:0011071 infores:clingen CAID:CA320741232 MONDO:0011071 PMID: Benign BA1 PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 The c.-59-1G>A variant (NM_001754.5) is a canonical splice site substitution in the 5' UTR of RUNX1. Because the variant is located in the 5' UTR, it is not expected to alter the amino acid sequence. However, the computational splicing predictor SpliceAI gives a Δ score of 0.71 for acceptor loss at c.-59 and 0.30 for donor loss at c.-60, predicting that the variant disrupts both the acceptor and donor splice sites of intron 1 of RUNX1. As this variant represents c.-161847G>A in NM_001001890.3 (isoform B) and NM_001122607.2 (isoform A), meaning the effect is not the same across isoforms and less detrimental in isoforms A and B, PVS1 would not apply per the MM-VCEP. Furthermore, it is of note that other splicing algorithms (i.e., SSF-like and MES) do not predict an effect on the canonical donor splice site and do predict the creation of a cryptic acceptor splice site at c.-58 (SpliceAI Δ score of 0.10), which would only lead to loss of a single nucleotide (G at c.-59) if real. Finally, the highest population minor allele frequency in gnomAD v3 is 0.003601 (55/15274 alleles) in the Latino/Admixed American population, which is higher than the ClinGen MM-VCEP threshold of >0.0015 (BA1). Given this frequency, it is not surprising that the variant has been reported in patients who do not meet the RUNX1 phenotype criteria (PMID: 26046366, PMID: 26689913, PMID: 32778766). In summary, this variant meets the criteria to be classified as benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen MM-VCEP: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741232/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8207 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0031350 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0344357 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0344357 infores:hetionet CHEBI:28593 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0428977 infores:hetionet CHEBI:17823 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0015967 infores:hetionet CHEBI:28830 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0004134 infores:hetionet NCBIGene:7737 biolink:causes MONDO:0010495 infores:monarchinitiative not_provided not_provided HGNC:12974 MONDO:0010495 uuid:a8a3af1c-1305-4c42-aeb8-6f34e9a07c4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes UMLS:C1096444 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1096444 infores:hetionet CHEBI:6538 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0021053 infores:hetionet CAID:CA386959080 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959080 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting BP5 The c.260G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to asparagine at codon 120 (p.(Lys120Asn)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.8169, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). The c.260G>C variant was found in an an infant with diabetes attributed to a de novo pathogenic INS variant. The age of the child and INS variant precluded deriving evidence in support of or against an impact of the HNF1A variant, which is generally expected to manifest at or near puberty. Notably, the HNF1A variant was inherited from the father, who had a clinical presentation consistent with HNF1A-monogenic diabetes. Finally, another missense variant, c.358A>G (p.Lys120Glu), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.360G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959080/MONDO:0015967/085 2023-09-20 2023-09-20 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0065374 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0018524 infores:hetionet CAID:CA1624490 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624490 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2010G>C (p.Leu670Phe) variant in the SOS1 gene is 0.055% (9/8572) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624490/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:32315 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151888 infores:hetionet NCBIGene:2034 biolink:causes MONDO:0012729 infores:monarchinitiative not_provided not_provided HGNC:3374 MONDO:0012729 uuid:9f04f906-2286-403c-bf81-5c26fac824a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013295 infores:hetionet CHEBI:38545 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C3263723 infores:hetionet CHEBI:31705 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042420 infores:hetionet CHEBI:63607 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0456909 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0039971 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0427108 infores:hetionet CHEBI:27732 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0085631 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020517 infores:hetionet CHEBI:2637 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0235280 infores:hetionet CAID:CA229522 biolink:causes MONDO:0009861 infores:clingen CAID:CA229522 MONDO:0009861 PMID:19786003 Pathogenic PM2, PVS1, PP4, PM3_Supporting Variant c.359G>A (p.Trp120Ter) in PAH was found in 1 Moroccan patient with Phe levels >600 umol/L (PMID: 19786003) (PP4). This is a nonsense variant in exon 4 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). Patient was found to be homozygous for p.W125X (PMID:19786003) (PM3). Parental and familial DNA was sequenced. Variant was absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied:PVS1, PM3_supporting, PP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229522/MONDO:0009861/006 2020-05-08 2020-05-08 Autosomal recessive inheritance HP:0000007 Supports CAID:CA279968 biolink:causes MONDO:0015280 infores:clingen CAID:CA279968 MONDO:0015280 PMID: Pathogenic PS3, PS2, PM1, PM6, PM2, PP2, PP3 The c.736G>C (p.Ala246Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262). In vitro functional studies provide some evidence that the p.Ala246Pro variant may impact protein function (PS3; 16474404, 19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ala246Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS2, PS3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279968/MONDO:0015280/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:49713 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0013604 infores:hetionet CAID:CA010422 biolink:causes MONDO:0021056 infores:clingen CAID:CA010422 MONDO:0021056 PMID: Benign BA1, BP1 The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA010422/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:61049 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020580 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0010399 infores:hetionet CHEBI:9445 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0010200 infores:hetionet CHEBI:6437 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151599 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018470 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0542519 infores:hetionet CHEBI:100246 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0018834 infores:hetionet CAID:CA1020746 biolink:causes MONDO:0021060 infores:clingen CAID:CA1020746 MONDO:0021060 PMID: Uncertain Significance BS1, PM2, BA1, BP4, PP3 The NM_002524.5:c.272C>T variant in NRAS is a missense variant predicted to cause substitution of alanine by valine at amino acid 91 (p.Ala91Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006392 (5/30616 alleles) in the South Asian population. The computational predictor REVEL gives a score of 0.301, which is neither above nor below the thresholds predicting a damaging or benign impact on NRAS function. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: No codes applied. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1020746/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9150 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0151849 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0149931 infores:hetionet CHEBI:4814 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0017152 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0022568 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0948594 infores:hetionet NCBIGene:3982 biolink:causes MONDO:0014111 infores:monarchinitiative not_provided not_provided HGNC:6610 MONDO:0014111 uuid:9358f863-92cd-4bd5-8bcb-b6caecf80c42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0233407 infores:hetionet NCBIGene:5800 biolink:causes MONDO:0013619 infores:monarchinitiative not_provided not_provided HGNC:9678 MONDO:0013619 uuid:caf9520f-6d32-4a90-b3f2-12db8584b196 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0021843 infores:hetionet CHEBI:35854 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0338831 infores:hetionet CHEBI:23765 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003467 infores:hetionet CAID:CA199494 biolink:causes MONDO:0010726 infores:clingen CAID:CA199494 MONDO:0010726 PMID: Likely Benign BS1, BP4 PP4 The allele frequency of the c.377+24C>A variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+24C>A variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199494/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:5383 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C1142412 infores:hetionet CHEBI:10125 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0014724 infores:hetionet CHEBI:5893 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0039070 infores:hetionet CHEBI:63629 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0016204 infores:hetionet CHEBI:31536 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0021368 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1142135 infores:hetionet CHEBI:50922 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0017675 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151838 infores:hetionet CHEBI:16469 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0423798 infores:hetionet CHEBI:6741 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151578 infores:hetionet CHEBI:5001 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0917801 infores:hetionet CHEBI:64355 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013428 infores:hetionet CHEBI:6715 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0026821 infores:hetionet CHEBI:10101 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037299 infores:hetionet CHEBI:2666 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0022346 infores:hetionet CHEBI:8207 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0000737 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0010043 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0333641 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018099 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027769 infores:hetionet CHEBI:127780 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151754 infores:hetionet CAID:CA136183 biolink:causes MONDO:0021060 infores:clingen CAID:CA136183 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.749T>C (p.Val250Ala) variant in the SOS1 gene is 0.089% for African chromosomes by the Exome Aggregation Consortium (15/10392 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136183/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:32221 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0014518 infores:hetionet CHEBI:135929 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0006145 infores:hetionet CHEBI:408174 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0033774 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0021400 infores:hetionet CHEBI:2469 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0027497 infores:hetionet CHEBI:44915 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0520887 infores:hetionet CHEBI:7488 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0030554 infores:hetionet CHEBI:64045 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0392156 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018021 infores:hetionet CHEBI:5893 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085680 infores:hetionet CAID:CA280993 biolink:causes MONDO:0007648 infores:clingen CAID:CA280993 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.2095C>T (p.Gln699Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA280993/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:64321 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0853697 infores:hetionet CHEBI:3757 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0027424 infores:hetionet CHEBI:38545 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0022346 infores:hetionet CHEBI:3478 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0030193 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0151580 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151580 infores:hetionet CHEBI:6761 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0235146 infores:hetionet CAID:CA378386067 biolink:causes MONDO:0021060 infores:clingen CAID:CA378386067 MONDO:0021060 PMID: Uncertain Significance PM2, PP2, PS4_Supporting The c.556A>T (p.Tyr189Phe) variant in the SHOC2 gene is absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the SHOC2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Tyr189Phe variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA378386067/MONDO:0021060/004 2019-09-16 2019-12-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:75722 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151936 infores:hetionet CHEBI:2666 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0030446 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003864 infores:hetionet CHEBI:10124 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0542571 infores:hetionet CHEBI:119915 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026827 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0860239 infores:hetionet CHEBI:50131 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151825 infores:hetionet CHEBI:49668 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0240211 infores:hetionet CHEBI:8768 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0000737 infores:hetionet CHEBI:8069 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0023066 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0852733 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0040034 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151735 infores:hetionet CHEBI:6958 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0340865 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0007971 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0158350 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0947999 infores:hetionet CHEBI:9434 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0740394 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020456 infores:hetionet CHEBI:70746 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0013404 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0423847 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423847 infores:hetionet CHEBI:28918 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0085631 infores:hetionet CHEBI:31859 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0009676 infores:hetionet CHEBI:7915 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0392525 infores:hetionet CHEBI:87681 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0011603 infores:hetionet CHEBI:48844 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0004096 infores:hetionet CHEBI:75722 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549448 infores:hetionet CHEBI:5123 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C1167965 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0948594 infores:hetionet CHEBI:16714 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C2830004 infores:hetionet CHEBI:7445 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0240557 infores:hetionet NCBIGene:8022 biolink:causes MONDO:0009091 infores:monarchinitiative not_provided not_provided HGNC:6595 MONDO:0009091 uuid:bbe670d4-1a2e-48c1-9cdc-6792cf8b0d32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512318953 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318953 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP3, BP2, BP1, BS1, BS4, BS3, BP5, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP1, PP4, PP2, PP3 NM_001754.5(RUNX1):c.166T>C (p.Leu56=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.496)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318953/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5118 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151752 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037284 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0003864 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033777 infores:hetionet CHEBI:9671 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0022661 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0038941 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0038941 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036130 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0010034 infores:hetionet NCBIGene:7543 biolink:causes MONDO:0958322 infores:monarchinitiative not_provided not_provided HGNC:12869 MONDO:0958322 uuid:98a7e8c2-4b0d-4ed9-b469-278d2bc83b5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:274 biolink:causes MONDO:0009709 infores:monarchinitiative not_provided not_provided HGNC:1052 MONDO:0009709 uuid:e9c6e424-b887-4e92-a5eb-55b11a06817f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes UMLS:C2720436 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C2720436 infores:hetionet CHEBI:4877 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0014518 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027339 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026650 infores:hetionet CHEBI:4995 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0000737 infores:hetionet CHEBI:6437 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151889 infores:hetionet NCBIGene:881 biolink:causes MONDO:0970952 infores:monarchinitiative not_provided not_provided HGNC:1568 MONDO:0970952 uuid:4055b82f-5161-4316-8d71-ecea499315ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45599 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0028961 infores:hetionet CHEBI:28748 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042963 infores:hetionet CHEBI:16714 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0018790 infores:hetionet CHEBI:6909 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0231218 infores:hetionet NCBITaxon:2129 biolink:causes MONDO:0007007 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2129 MONDO:0007007 CHEBI:31174 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0237849 infores:hetionet CHEBI:94449 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0013428 infores:hetionet CHEBI:6076 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0013404 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0162429 infores:hetionet CHEBI:3636 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0002994 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C1258215 infores:hetionet NCBIGene:11055 biolink:causes MONDO:0030716 infores:monarchinitiative not_provided not_provided HGNC:15662 MONDO:0030716 uuid:fb494221-ab47-4cf0-8662-c64d833ca6fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226400 biolink:causes MONDO:0100437 infores:clingen CAID:CA226400 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.28+1G>A is a canonical splice site variant in intron 1 that is predicted to disrupt splicing and induce exon skipping, which is expected to disrupt a critical functional domain in RPGR (PVS1). This variant is absent from hemizygotes in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 10937588, PMID: 23681342, PS4_Supporting). Other publications report on probands carrying this variant but did not meet the requirements for inclusion in the PS4 code (PMID: 10480356, PMID: 10737996, PMID: 17724181). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226400/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:36791 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002878 infores:hetionet CHEBI:31348 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2363730 infores:hetionet CHEBI:7465 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0008350 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2711227 infores:hetionet CHEBI:50659 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0687713 infores:hetionet CHEBI:490877 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0018681 infores:hetionet CAID:CA16043602 biolink:causes MONDO:0044970 infores:clingen CAID:CA16043602 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS3, BS1, PM2 The m.14598T>C (p.I26V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on August 14, 2023. There are no individuals with this variant reported in the medical literature to our knowledge. There are two prior reports in ClinVar for this variant, however details are not provided precluding consideration of these cases for this curation. As such, there are no reported de novo occurrences or large families to consider for evidence of variant segregation. This variant is present in population databases including in Mitomap GenBank sequences (7/61,168 (0.012%) and seen across five top level (single letter) haplogroups with European, Asian, and African ancestry), Helix database (26/195,983 sequences (0.013%), in addition to three heteroplasmic occurrences and seen across six top level haplogroups with European, Asian, and African ancestry), and gnomAD v3.1.2 (9/56,416 sequences (0.016%) in addition to three heteroplasmic occurrences and seen across seven top level haplogroups with European, Asian, and African ancestry). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.31 (Min=0, Max=1; APOGEE2 scores on 0.0499), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other key functional assays reported for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two expert panel members felt likely benign was the more appropriate classification (compared to five who agreed with uncertain significance). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043602/MONDO:0044970/015 2023-08-14 2024-08-12 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA512318690 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318690 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.645G>A (p.Lys215=) is a synonymous variant not predicted to affect splicing (BP4). However, evolutionary conservation prediction algorithms predict the site as being moderately conserved (PhyloP score: 5.81) and the variant is not the reference nucleotide in one primate and/or three mammal species. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318690/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6149 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0041834 infores:hetionet CAID:CA2693440397 biolink:causes MONDO:0100437 infores:clingen CAID:CA2693440397 MONDO:0100437 PMID: Likely Pathogenic PP4, PP3, PM2_Supporting, PS2_Moderate, PS1 PS3 NM_001034853.2(RPGR):c.1572+3A>G is a non-coding variant in intron 13 that is located outside the +/- 1,2 dinucleotide. The splicing impact predictor SpliceAI gives delta scores of 0.83 for donor gain and 0.47 for donor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing (PP3). Another predicted splicing variant in the same nucleotide, NM_001034853.2(RPGR):c.1572+3A>T, was previously classified as pathogenic for RPGR-related retinopathy by ClinGen X-linked IRD VCEP (PS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early age of onset (1 pt), night blindness (0.5 pts), pigmentary retinopathy (0.5 pts) optic disc pallor (0.5 pts), decreased central visual acuity (0.5 pts), and visual field constriction (0.5 pts), with genotyping by next-generation sequencing identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5.5 points, personal communication with an expert related to the X-linked IRD VCEP, PP4). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual meeting the PS2 requirement of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (1 point, PS2_Moderate, personal communications with an expert related to X-linked IRD VCEP). The exon skipping was reportedly validated by splicing assay showing exon skipping (personal communication with an expert related to the X-linked IRD VCEP). This finding was not applied to meet PS3_Supporting as it comes from an unpublished study. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PS1, PS2_Moderate, PM2_Supporting, PP3, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2693440397/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:9571 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0014457 infores:hetionet CAID:CA126211 biolink:causes MONDO:0015967 infores:clingen CAID:CA126211 MONDO:0015967 PMID: Pathogenic PS4, PS2, PP1_Strong, PM3, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PM1 "The c.781G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the ""Other"" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 38 unrelated individuals with diabetes (PS4; PMIDs: 29417725, 33324081, 21518409, 25015100, 22611063, 17573900, internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 30 informative meioses in 18 families (PP1_Strong; PMID 33324081, 21518409, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (PS2; internal lab contributors). This variant has been detected in at least 2 individuals with neonatal diabetes who were both homozygous for the variant, confirmed in trans (PM3: PMID 33324081, 25015100, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetews. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2." Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA126211/MONDO:0015967/086 2023-08-12 2023-08-12 Semidominant inheritance HP:0032113 Supports CHEBI:4325 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0034068 infores:hetionet CHEBI:73274 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0015672 infores:hetionet CHEBI:61049 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232807 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0041657 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0029443 infores:hetionet CHEBI:3387 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0232462 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0001883 infores:hetionet CHEBI:40279 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0040822 infores:hetionet CHEBI:36791 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085624 infores:hetionet NCBITaxon:84529 biolink:causes MONDO:0004666 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:84529 MONDO:0004666 CHEBI:7773 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0017178 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0017152 infores:hetionet CHEBI:28487 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0015230 infores:hetionet CHEBI:63598 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003811 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042571 infores:hetionet CHEBI:2618 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0040822 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151723 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0003123 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0595877 infores:hetionet CHEBI:38562 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C1443060 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0151971 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1442903 infores:hetionet CHEBI:3216 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013390 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0424823 infores:hetionet GO:0072106 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0009790 CHEBI:3723 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043241 infores:hetionet CHEBI:31711 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0234146 infores:hetionet CHEBI:68554 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0151205 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235919 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235919 infores:hetionet CHEBI:71023 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0677500 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020517 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0314719 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0012359 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0024115 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0013404 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0178298 infores:hetionet CHEBI:63577 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020443 infores:hetionet CHEBI:3207 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0015403 infores:hetionet CHEBI:48538 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0036974 infores:hetionet CHEBI:9445 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0042571 infores:hetionet CHEBI:38940 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0038325 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0240925 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0240925 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0001339 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0011991 infores:hetionet CAID:CA343867 biolink:causes MONDO:0010602 infores:clingen CAID:CA343867 MONDO:0010602 PMID: Benign BA1, BP4 BP7 The c.3864A>C (p.Ser1288=) variant is reported at an MAF of 0.3377 (6437/19059 alleles) in the South Asian population in gnomAD v2.1.,1 with 3958 hemizygotes and 424 homozygotes, meeting BA1 criteria of MAF > 0.000333. The synonymous variant is predicted to have no impact on splicing based on SpliceAI score of 0.0, meeting BP4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: BA1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA343867/MONDO:0010602/071 2024-02-01 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:63599 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0242184 infores:hetionet CHEBI:72297 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0085932 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0022660 infores:hetionet CAID:CA227864 biolink:causes MONDO:0100438 infores:clingen CAID:CA227864 MONDO:0100438 PMID: Benign BP7, BS2, BA1, BP4 NM_014336.5(AIPL1):c.111C>T (p.Phe37=) is a synonymous variant in exon 2 of 6. The change from C to T at c.111 is not predicted to change the amino acid phenylalanine at position p.37. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.03109, with 37005 alleles / 1,179,952 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). Additionally, the variant has been found in the homozygous state in 748 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The splicing impact predictor SpliceAI gives a delta score of 0.08, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227864/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3757 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0027765 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1262064 infores:hetionet CHEBI:7936 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014335 infores:hetionet CAID:CA410146806 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146806 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1400C>A (p.Ala467Glu) is a missense variant which has a REVEL score ≤0.50 (0.09) and a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146806/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63621 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018681 infores:hetionet CHEBI:465284 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020625 infores:hetionet CHEBI:68606 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C2830004 infores:hetionet CHEBI:7025 biolink:causes UMLS:C0949070 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0949070 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0162287 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027339 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0024894 infores:hetionet CHEBI:8228 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0042029 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1384353 infores:hetionet CHEBI:135930 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0042023 infores:hetionet CHEBI:15367 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0025345 infores:hetionet CHEBI:6888 biolink:causes MONDO:0040753 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C1609538 infores:hetionet CHEBI:6367 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042029 infores:hetionet CHEBI:28901 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0014743 infores:hetionet CHEBI:68579 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0011991 infores:hetionet CHEBI:4858 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0010200 infores:hetionet CAID:CA367398670 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398670 MONDO:0015967 PMID: Pathogenic PS4, PS2_Moderate, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1163G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 388 (p.(Gly388Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.871, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; PMID:35737141, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). Another one of these individuals was identified as a de novo occurrence with confirmed parental relationships whose clinical picture was consistent with but not highly specific for GCK-hyperglycemia (PS2_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 3 families (PP1_Moderate; internal lab contributors). In summary, c.1163G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PS4, PP1_Moderate, PP4_Moderate, PS2_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398670/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:60761 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0040046 infores:hetionet CHEBI:5050 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0011603 infores:hetionet CHEBI:31413 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0020458 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0522224 infores:hetionet CAID:CA8603161 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603161 MONDO:0100326 PMID: Uncertain Significance BP4 BS1, PM2, BS2 The NM_000419.5:c.1366G>A variant in ITGA2B is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 456 (p.Val456Ile). After a comprehensive literature search, the variant has not been identified in any individuals with Glanzmann thrombasthenia. The computational predictor REVEL gives a score of 0.078, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). The variant has an allele frequency of 0.0009522 (19/19954 alleles) and has been found once in the homozygous state in the East Asian population in gnomAD v2.1.1 (BS1 not met). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603161/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:93635 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0041657 infores:hetionet CHEBI:17026 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020488 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005089 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1261473 infores:hetionet CHEBI:17303 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0027497 infores:hetionet CHEBI:63115 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0151827 infores:hetionet CHEBI:40279 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1443060 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0152029 infores:hetionet CHEBI:47381 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0428977 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005530 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0524662 infores:hetionet CAID:CA340748262 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748262 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting PM5 NM_000329.3(RPE65):c.311G>A (p.Gly104Asp) is a missense variant resulting in replacement of glycine by aspartic acid at amino acid 104. Another missense variant in the same codon, NM_000329.3(RPE65):c.310G>A (p.Gly104Ser), has been reported in relation to RPE65-related recessive retinopathy (PMID: 26667666), however, the SpliceAI score of 0.01 for the NM_000329.3(RPE65):c.311G>A (p.Gly104Asp) variant and the score of 0.29 for the NM_000329.3(RPE65):c.310G>A (p.Gly104Ser) comparison variant were not within 10% of one another, so PM5 is not met. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.000000847, with 1 allele / 1,180,012 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) variant suspected in trans (0.5 points, PMID: 19117922) or the NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variant confirmed in trans (1 point, PMID: 34830511, PMID: 25356976), both of which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of early onset severe retinal dystrophy (0.5 pts) with onset of night blindness (0.5 pts) at age 3 years (1 pt), reduced central visual acuity (1 pt), and genotyping by a targeted exome sequencing panel of 188 known inherited retinal degeneration genes (2 pts), which together are specific for RPE65-related recessive retinopathy (total 5 points, PMID: 34830511, PP4). The computational predictor REVEL gives a score of 0.962, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748262/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63605 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020453 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0030312 infores:hetionet CHEBI:31348 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0870082 infores:hetionet CHEBI:3125 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0000729 infores:hetionet CAID:CA10549204 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549204 MONDO:0010305 PMID: Benign BS1, BS2, BP4 The NM_005629.4:c.544G>A variant in SLC6A8 is a missense variant predicted to cause substitution of valine by methionine at amino acid 182 (p.Val182Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (16/19086 alleles) in the African/African American population, meeting the CCDS VCEP’s allele frequency threshold for BS1 (>0.0002) (BS1). This variant is present in 5 or more hemizygotes in gnomAD v2.1.1 (BS2). Furthermore, the variant did not segregate with intellectual disability in multiple brothers, and the proband with the variant had normal urine creatine and normal cerebral creatine on 1H-magnetic resonance spectroscopy (PMID 16738945). The computational predictor REVEL gives a score of 0.184, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact of the variant on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465147). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549204/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:7852 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0041948 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0856554 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0856554 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0853926 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0853926 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009450 infores:hetionet CHEBI:27899 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0041582 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0020649 infores:hetionet CHEBI:3504 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C2242737 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014130 infores:hetionet CHEBI:29007 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0404521 infores:hetionet CHEBI:681569 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0000737 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0040797 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0040797 infores:hetionet CHEBI:3534 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0015230 infores:hetionet CHEBI:48273 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0004093 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0021053 infores:hetionet CHEBI:45863 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0003811 infores:hetionet CHEBI:5959 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027121 infores:hetionet CHEBI:253342 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0851578 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0877606 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0877606 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0349506 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151479 infores:hetionet CHEBI:50924 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0232487 infores:hetionet CHEBI:6149 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0034880 infores:hetionet CHEBI:9907 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0085649 infores:hetionet CHEBI:9599 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0033774 infores:hetionet CHEBI:63577 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020580 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0497247 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0010709 infores:hetionet CHEBI:7454 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0011551 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027765 infores:hetionet CAID:CA312806 biolink:causes MONDO:0009861 infores:clingen CAID:CA312806 MONDO:0009861 PMID:18299955 Likely Pathogenic PM2, PP4, PVS1_Strong, PM3_Supporting This c.1065+1G>T variant in PAH was reported in 1 patient with moderate PKU (PMID: 18299955) detected with the pathogenic variant p.Leu48Ser. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the +1 splice donor site results in exon skipping. The variant does not disrupt the reading frame, but the altered region is critical to protein function. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA312806/MONDO:0009861/006 2020-10-19 2020-10-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119915 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0475858 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0860713 infores:hetionet CHEBI:31236 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151908 infores:hetionet CHEBI:10101 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C3665347 infores:hetionet CHEBI:45863 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0014518 infores:hetionet CHEBI:51380 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0043352 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0027769 infores:hetionet CHEBI:29688 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0017178 infores:hetionet CAID:CA181090 biolink:causes MONDO:0021060 infores:clingen CAID:CA181090 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.303+8C>G variant in the MAP2K2 gene is 0.154% (22/9636) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA181090/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:45863 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042571 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0041912 infores:hetionet CAID:CA8622991 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622991 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 "The c.602del (p.Asn201ThrfsTer6) variant in exon 4 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient GTa in PMID:11722423) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This individuals was compound heterozygous for this variant (reported by the authors as ""a deletion at the 3' end of exon 3 resulting in a premature stop codon,"" but confirmed as c.602del from entry 57 in the GT database) and a likely pathogenic variant (NM_000212.3:c.655G>A (p.Val219Met)). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, and PM2_Supporting (VCEP specifications version 2.1)." Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622991/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6121 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0232849 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040034 infores:hetionet CHEBI:28748 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151908 infores:hetionet CAID:CA2695224149 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224149 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.941dup (p.Thr316HisfsTer35) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BSS10.01 in PMID: 23995613) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224149/MONDO:0009276/079 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA8815679 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815679 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5, PM3_Strong PM1 The NM_000152.5:c.2297A>G variant in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 766 (p.Tyr766Cys. At least five patients diagnosed with Pompe disease, all late onset symptoms, have been reported with this variant. Three of these patients have documented laboratory values showing deficiency GAA activity (PMID: 29124014, 35071497, 37087815) (PP4_Moderate). Four patients are compound heterozygous for the variant and another variant that has been classified as pathogenic by the ClinGen LD VCEP, all phase unconfirmed, including c.2481+110_2646+39del (ClinVar Variation ID: 657307) (PMID: 37087815, 0.5 points), c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 35071497, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 30564623, 0.5 points), and c.1309C>T (p.Arg437Cys) (ClinVar Variation ID: 189082, SCV002540662.1) (PMID: 29124014, 0.5 points). Total 2 points (PM3_Strong).Another patient is reported with variant c.2297A>G (p.Tyr765Cys), which presumably is a typo for the amino acid number but cannot be confirmed (PMIDs: 21605996, 22676651). Another individual was identified by newborn screen, compound heterozygous for c.-32-13T>G (PMID: 33073003) but is not yet symptomatic, so was not included. One patient is compound heterozygous for the variant and c.1879_1881delTCC (p.Ser627del) ((PMID: 35071497), The allelic data from this patient will be used in the assessment of p.Ser627del and is not included here to avoid circular logic. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006534 (2/30610 alleles) in the South Asian population. In gnomAD v4.1, the highest MAF is 0.00002227 (1/44894 alleles) in the East Asian population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.967 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another amino acid change at the same position, c.2297A>C (p.Tyr766Ser)(ClinVar Variation ID: 420102), has been classified as pathogenic based on the specifications of the ClinGen LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 285197). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PM5, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815679/MONDO:0009290/010 2024-06-06 2024-06-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9352 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0018681 infores:hetionet CAID:CA229718 biolink:causes MONDO:0009861 infores:clingen CAID:CA229718 MONDO:0009861 PMID:21147011PMID:1363786PMID:21147011PMID:24190797PMID:1363786 Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong PM5 The c.724C>T (p.Leu242Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 1363786, 21147011). This variant is absent in population databases. It was detected with multiple pathogenic/likely pathogenic variants: p.R158Q (PMID: 24190797); IVS10-11G>A (PMID: 21147011); p.R252W (PMID: 1363786); p.V399V (PMID: 26600521); c.1315+4A>G (PMID: 25456745); p.R408W (PMID: 19244369); p.R241C (PMID: 30050108); c.1068C>A p.Tyr356* (2 patients), p.Arg243Gln (PMID: 28982351) 7.75 pts. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229718/MONDO:0009861/006 2020-09-14 2021-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:66913 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0521490 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038663 infores:hetionet CHEBI:36791 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020546 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233494 infores:hetionet CHEBI:408174 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0031345 infores:hetionet CHEBI:50885 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0013491 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0021053 infores:hetionet CHEBI:31711 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0428977 infores:hetionet CHEBI:4798 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0035410 infores:hetionet CHEBI:35778 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C2363731 infores:hetionet CHEBI:135930 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C2047937 infores:hetionet GO:0035203 biolink:causes GO:0002164 infores:ubergraph knowledge_assertion manual_agent GO:0035203 GO:0002164 CHEBI:3219 biolink:causes UMLS:C0004601 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0004601 infores:hetionet CAID:CA16614939 biolink:causes MONDO:0007648 infores:clingen CAID:CA16614939 MONDO:0007648 PMID:10433926PMID:17545690 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.377delC p.(Pro126Argfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 10433926). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614939/MONDO:0007648/007 2023-08-28 2023-08-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:47780 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017979 infores:hetionet CHEBI:142290 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0017565 infores:hetionet CHEBI:92511 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0033774 infores:hetionet CHEBI:2611 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0162830 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0546817 infores:hetionet CHEBI:10100 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0033774 infores:hetionet CHEBI:4670 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0033774 infores:hetionet CHEBI:17823 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0151904 infores:hetionet CAID:CA913190951 biolink:causes MONDO:0008723 infores:clingen CAID:CA913190951 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1102_1103del; p.Gln368Valfs*26 variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 11/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1,PM2_supporting). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190951/MONDO:0008723/021 2022-09-20 2022-09-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8435 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0015230 infores:hetionet CHEBI:5130 biolink:causes HP:0011886 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020581 infores:hetionet CHEBI:63925 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0009763 infores:hetionet CHEBI:50841 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0013404 infores:hetionet CHEBI:3499 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0311468 infores:hetionet CHEBI:4445 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0006266 infores:hetionet CHEBI:145499 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020473 infores:hetionet UMLS:C0005740 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0011603 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027441 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1269683 infores:hetionet CHEBI:4717 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0039231 infores:hetionet CHEBI:52717 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0240211 infores:hetionet CHEBI:18248 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0036974 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0860645 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0860645 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0038661 infores:hetionet CHEBI:175901 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0003811 infores:hetionet CHEBI:75045 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0917801 infores:hetionet CHEBI:9449 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0030554 infores:hetionet CHEBI:10023 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018800 infores:hetionet CHEBI:10110 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0013428 infores:hetionet CHEBI:8364 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0042109 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0948586 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0948349 infores:hetionet CHEBI:102216 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0855775 infores:hetionet CHEBI:45783 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151578 infores:hetionet CHEBI:3181 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0004134 infores:hetionet CHEBI:119486 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0041657 infores:hetionet CAID:CA16020825 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020825 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, PM3_Supporting PP3, PS3 This c.599C>A (p.Thr200Asn) variant in PAH was reported in 1 patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe), detected with pathogenic variant p.Arg243* (PMID: 23357515). Computational evidence for this variant is conflicting; predicted to be damaging (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is absent from population databases gnomAD, 1000 Genomes, and ESP. Functional studies have been reported with no major impact on enzyme activity as compared to wild type (PMID: 31208052). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3 supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020825/MONDO:0009861/006 2020-12-07 2022-03-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63619 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0032227 infores:hetionet CHEBI:49668 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0149745 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029878 infores:hetionet CHEBI:6965 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0043094 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042075 infores:hetionet CHEBI:16347 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0009806 infores:hetionet CHEBI:64318 biolink:causes HP:0032554 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0277899 infores:hetionet CHEBI:4672 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0234909 infores:hetionet CHEBI:4909 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0032617 infores:hetionet CHEBI:6970 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0010200 infores:hetionet NCBIGene:4137 biolink:causes MONDO:0009839 infores:monarchinitiative not_provided not_provided HGNC:6893 MONDO:0009839 uuid:1510ad0c-57b6-4226-b06d-1c6e4549c81d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66876 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0041912 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0741983 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0741983 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018939 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0019193 infores:hetionet CHEBI:28148 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0038999 infores:hetionet CAID:CA413496954 biolink:causes MONDO:0010315 infores:clingen CAID:CA413496954 MONDO:0010315 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting The c.269+1G>T (NM_000206.3) variant in IL2RG occurs within the canonical donor splice site (+1) of intron 2. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 2 resulting in a frameshift (p.Asp39Glyfs*57) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :2.5 pts (PP4_Moderate) PMID: 33628209.In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1,PM2_supporting,PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413496954/MONDO:0010315/129 2024-01-30 2024-01-30 X-linked inheritance HP:0001417 Supports CHEBI:4027 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027059 infores:hetionet CHEBI:7476 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0558489 infores:hetionet CHEBI:8863 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031256 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0006840 infores:hetionet CHEBI:9086 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0012569 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0041912 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0497365 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0851341 infores:hetionet CAID:CA16614702 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614702 MONDO:0100216 PMID: Uncertain Significance PP3 PM2, BA1, PS4, BS1 The NM_177438.3:c.1353A>G (p.Arg451=) variant in DICER1 is a synonymous (silent) variant. Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000001 (2/1613688 alleles) across gnomAD v4.1.0 with a highest population minor allele frequency of 0.00004 (2/44884 alleles) in East Asian population and with multiple alleles present in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614702/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52717 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004239 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1096049 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1096049 infores:hetionet CHEBI:47898 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023380 infores:hetionet CHEBI:6541 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0043094 infores:hetionet GO:1904242 biolink:causes GO:0030157 infores:ubergraph knowledge_assertion manual_agent GO:1904242 GO:0030157 CHEBI:4514 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C2830004 infores:hetionet CHEBI:65346 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C1527344 infores:hetionet CAID:CA512318929 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318929 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.195T>C (p.Ala65=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318929/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4445 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0035078 infores:hetionet CAID:CA5416379 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416379 MONDO:0011225 PMID: Benign BA1, BS2_Supporting The c.1894G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 632 (p.Glu632Lys).The filtering allele frequency (the lower threshold of the 95% CI of 431/91076) of the c.1894G>A variant in DCLRE1C is 0.004306 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, 6 adult homozygous have been reported in the same population (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416379/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:55346 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151872 infores:hetionet NCBIGene:5308 biolink:causes MONDO:0007662 infores:monarchinitiative not_provided not_provided HGNC:9005 MONDO:0007662 uuid:590bc8fe-d042-49bf-a1ca-da106fee3fbf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3508 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0687713 infores:hetionet CHEBI:472657 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0002994 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0012797 infores:hetionet CHEBI:10110 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0085633 infores:hetionet CHEBI:9943 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013491 infores:hetionet UMLS:C0023610 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0040038 infores:hetionet CHEBI:7577 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0027121 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017178 infores:hetionet CHEBI:3175 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0022073 infores:hetionet GO:2000733 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0009790 CHEBI:44185 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0002871 infores:hetionet CAID:CA347210094 biolink:causes MONDO:0015152 infores:clingen CAID:CA347210094 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PM2_Supporting BP2 The NM_003494.4: c.863A>T variant in DYSF, which is also known as NM_001130987.2: c.959A>T p.(Asp320Val), is a missense variant predicted to cause the substitution of valine for aspartic acid at codon 288. This variant has been reported in at least 11 individuals with features consistent with limb-girdle muscular dystrophy (PMID: 34559919, 28403181, 27647186, 25591676), including in a homozygous state in two individuals without reported consanguinity (0.5 pts x2 = 1.0 pt; PMID 28403181, 27647186), confirmed in trans with a pathogenic variant in one case (NM_003494.4: c.5077C>T p.(Arg1693Trp), 1.0 pt, PMID: 28403181), and in unconfirmed phase with a pathogenic variant in three unrelated individuals (NM_003494.4: c.3137G>A p.(Arg1046His), 0.5 pts, PMID: 25591676; NM_003494.4: c.5077C>T p.(Arg1693Trp), 0.5 pts, PMID: 27647186; NM_003494.4: c.1667T>C p.(Leu556Pro), 0.5 pts, PMID: 27647186) (PM3_Strong). All of these patients were of Chinese ancestry. At least one of the patients with this variant had a second presumed diagnostic DYSF variant, a clinical diagnosis of LGMD, and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID 27647186; PP4_Strong). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/29/2025): PM3_Strong, PP4_Strong, PP3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347210094/MONDO:0015152/180 2025-10-29 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63631 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025345 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0235146 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1096272 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1096272 infores:hetionet NCBIGene:112802 biolink:causes MONDO:0014390 infores:monarchinitiative not_provided not_provided HGNC:28927 MONDO:0014390 uuid:c6b0da7b-1ab7-401a-bc87-c8aaa9047ba8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4747 biolink:causes MONDO:0011894 infores:monarchinitiative not_provided not_provided HGNC:7739 MONDO:0011894 uuid:c99ed3df-aa01-45b0-9bb0-79cc0fac2a5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0000731 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0854375 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0521622 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0521622 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0022660 infores:hetionet CHEBI:48390 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0015672 infores:hetionet GO:0075260 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0075260 GO:0007275 CHEBI:8346 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0085632 infores:hetionet CHEBI:70735 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0917801 infores:hetionet CHEBI:4911 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C2830004 infores:hetionet CAID:CA410208250 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208250 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.29T>C (p.Phe10Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208250/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3371 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0015967 infores:hetionet CHEBI:132233 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0040435 infores:hetionet CHEBI:63598 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0035243 infores:hetionet CHEBI:50922 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0004245 infores:hetionet CHEBI:4681 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0041657 infores:hetionet CHEBI:4907 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0035410 infores:hetionet CHEBI:46345 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0009421 infores:hetionet CHEBI:7798 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0042963 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020437 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0029456 infores:hetionet CHEBI:2682 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235031 infores:hetionet CAID:CA10579342 biolink:causes MONDO:0700270 infores:clingen CAID:CA10579342 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP3 The c.9103C>T variant in ATM is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 3035 (p.Leu3035Phe). This variant has been detected in at least two unrelated individuals with Ataxia-Telangiectasia (PMIDs: 16941484, 30549301). This variant is absent in gnomAD v4.1.0. The computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_ Strong, PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10579342/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4784 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011124 infores:hetionet CHEBI:6539 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C2830004 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0948594 infores:hetionet CHEBI:5118 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0220870 infores:hetionet CHEBI:92607 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0027424 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0857093 infores:hetionet CHEBI:8863 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0028734 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0003834 infores:hetionet CAID:CA229813 biolink:causes MONDO:0009861 infores:clingen CAID:CA229813 MONDO:0009861 PMID:17557229PMID:21307867PMID:1349576PMID:17557229PMID:17557229 Pathogenic PP4_Moderate, PM2, PVS1, PM3_Strong The c.842+2T>A variant in PAH is a splice-site variant predicted to result in skipping of exon 8, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Pathogenic in Clinvar (ID 614). It has been reported among multiple patients with classic PKU, with BH4 deficiency formally excluded (PMID: 17557229; PMID: 21307867) (PP4_Moderate) and has been reported in trans with multiple Pathogenic and Likely Pathogenic mutations, including R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) (PMID: 17557229) (PM3_Strong).Classification: PathogenicSupporting Criteria: PVS1, PM2, PM3_Strong, PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229813/MONDO:0009861/006 2020-04-16 2020-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7820 biolink:causes MONDO:0005339 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0162311 infores:hetionet CHEBI:63613 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C2830004 infores:hetionet CHEBI:5855 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0011603 infores:hetionet CHEBI:10023 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0034155 infores:hetionet CHEBI:134743 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0002871 infores:hetionet CHEBI:9588 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0018681 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0549385 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0018801 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0161479 infores:hetionet CAID:CA231135 biolink:causes MONDO:0015967 infores:clingen CAID:CA231135 MONDO:0015967 PMID:22761713 Pathogenic PS4, PP1_Moderate, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PM1 The c.449T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 150 (p.(Phe150Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 25306193, 19564454, 32086287, 30663027, 28726111, 22761713, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 28726111). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 22761713). In summary, c.449T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Moderate, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA231135/MONDO:0015967/086 2024-01-06 2024-01-06 Semidominant inheritance HP:0032113 Supports CHEBI:171719 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0409974 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0151814 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151814 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0853760 infores:hetionet CHEBI:3515 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0018681 infores:hetionet CHEBI:63577 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0016204 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0023895 infores:hetionet NCBIGene:26153 biolink:causes MONDO:0859332 infores:monarchinitiative not_provided not_provided HGNC:20226 MONDO:0859332 uuid:a929cf19-0b96-4b84-8a02-fa2d49599c3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0025061 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151883 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0018802 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011991 infores:hetionet CHEBI:63598 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0025222 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0027947 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009241 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018799 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0232726 infores:hetionet CHEBI:10112 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0042109 infores:hetionet CHEBI:8874 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011168 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0015459 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015459 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0276680 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0017574 infores:hetionet CHEBI:168396 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020580 infores:hetionet UBERON:0001013 biolink:causes MONDO:0005060 infores:ubergraph knowledge_assertion manual_agent UBERON:0001013 MONDO:0005060 CHEBI:35854 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0037274 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235750 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0037199 infores:hetionet CHEBI:65173 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0009782 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0853761 infores:hetionet CAID:CA913175634 biolink:causes MONDO:0044970 infores:clingen CAID:CA913175634 MONDO:0044970 PMID:17878308 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP1, PS4, PM6 The m.618T>C variant in MT-TF has been reported in one individual with primary mitochondrial disease (PMID: 9636664). This person had myopathy with ragged red fibers on muscle biopsy and reduced activities of electron transport chain enzyme complexes I and III in muscle. The variant was present at 95% heteroplasmy in skeletal muscle and 20% in blood. The variant was undetectable in blood from his healthy sister. There are no other families or de novo occurrences of this variant reported to our knowledge. There is one heteroplasmic occurrence of this variant in the Helix dataset and this variant is absent in the MITOMAP GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (65.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). No cybrid or single-fiber studies were performed. However, a significant loss in aminoacylation efficiency was demonstrated and, when a compensatory variant was introduced to restore Watson–Crick base pairing in the anti-codon stem, the double mutant fully restored aminoacylation (PS3_supporting; PMID: 17878308). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913175634/MONDO:0044970/015 2024-09-09 2025-05-14 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63631 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0033575 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0314719 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040046 infores:hetionet CHEBI:3996 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0022107 infores:hetionet CHEBI:71255 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0427086 infores:hetionet CHEBI:49575 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C3665386 infores:hetionet CHEBI:5138 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009676 infores:hetionet CHEBI:9328 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C1320835 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0008370 infores:hetionet CHEBI:83531 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C2830004 infores:hetionet CHEBI:63605 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027497 infores:hetionet CHEBI:6149 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0042963 infores:hetionet CHEBI:87681 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0009676 infores:hetionet CHEBI:6950 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042963 infores:hetionet CHEBI:8028 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0409974 infores:hetionet CHEBI:4911 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0028643 infores:hetionet CHEBI:15367 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011175 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020039 infores:hetionet CAID:CA024172 biolink:causes MONDO:0018493 infores:clingen CAID:CA024172 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with glycine at codon 4856 of the RYR1 protein, p.Ala4856Gly. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without details for in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results (PMID:16917943). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.937) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024172/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:100246 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0003537 infores:hetionet CAID:CA320618002 biolink:causes MONDO:0011071 infores:clingen CAID:CA320618002 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.558C>T (p.Val186=) is synonymous variant. No REVEL score because synonymous variant and SpliceAI is ≤0.20 (0.00) meeting BP4 . Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP -1.3873 < 2.0) meeting BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320618002/MONDO:0011071/008 2022-02-10 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63631 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009782 infores:hetionet CHEBI:4907 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0041834 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006678 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005683 infores:hetionet CHEBI:8212 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0001824 infores:hetionet CHEBI:49603 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0178298 infores:hetionet CHEBI:50777 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0011603 infores:hetionet CHEBI:37941 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0231528 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0032326 infores:hetionet CHEBI:50730 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0239571 infores:hetionet CHEBI:6709 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0002792 infores:hetionet CAID:CA10585383 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585383 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM3, PP1_Moderate, PM2, PP3, PP4 BA1, BP4, BP3, BP2, PS3, PS1, BP7, BS1, BS3, BS4, PM4, PM1, PM5, PVS1, BS2 The NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4_Moderate, PM2, PM3, PP1_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0). So, PM2 is met. PP3: REVEL=0.883. It is above 0.75, so PP3 is met. PS4_Moderate, PP4: Variant meets PM2 and is identified in 9 unrelated index cases (2 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 5 cases with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille, France, published on ClinVar; 1 case with possible/definite FH by Simon-Broome criteria in PMID 33269076 (Miroshnikova et al., 2021); 1 case with DLCN score 9 in PMID 9763532 (Mak et al., 1998)). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France: 4 affected family members have the variant.PM3: A homozygous proband is reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies with LDL of 860 mg/dL. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585383/MONDO:0007750/013 2025-01-31 2025-03-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8772 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0340726 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0030552 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0042075 infores:hetionet NCBIGene:4552 biolink:causes MONDO:0009354 infores:monarchinitiative not_provided not_provided HGNC:7473 MONDO:0009354 uuid:615edc89-7860-407e-9d07-c354e859c870 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4910 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0023066 infores:hetionet CHEBI:63608 biolink:causes HP:0025234 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0030508 infores:hetionet CHEBI:64312 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C2047937 infores:hetionet CAID:CA412376057 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376057 MONDO:0010725 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PP1_Strong, PM1_Strong, PM5, PP4 PP3 NM_000330.4(RS1):c.175T>G (p.Cys59Gly) is a missense variant encoding the substitution of cysteine with glycine at amino acid 59, which is a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). Another missense variant in the same codon, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 31174210, 10450864, 17987333, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (159) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 34645606, PMID: 33460243, PP4). This variant has been reported in at least 1 other proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis, in addition to the apparently unrelated proband previously used for the PP4 code (PMIDs: 30652005, PS4_Supporting). The variant has been reported to segregate with X-linked retinoschisis through at least 3 meioses in two families with multiple affected brothers (PP1_Strong; PMID: 30652005). The computational predictor REVEL gives a score of 0.868, which is within the linGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function. PP3 is not met since this code is ineligible in combination with PM1_Strong. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, PP1_Strong, PP4, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376057/MONDO:0010725/126 2025-10-03 2025-10-03 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:45652 biolink:causes UMLS:C1142397 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C1142397 infores:hetionet CHEBI:8069 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0855775 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0746731 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0746731 infores:hetionet CAID:CA384900118 biolink:causes MONDO:0010880 infores:clingen CAID:CA384900118 MONDO:0010880 PMID: Pathogenic PS4, PP1_Strong, PP3, PM2_Supporting The NM_000020.3: c.706G>A variant in ACVRL1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 236 (p.Glu236Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 4 probands with a phenotype consistent of HHT (PS4; PMID: 25970827, ClinVar, Internal lab contributors). The variant has been reported to segregate with HHT in 5 affected members from 1 family, and in 2 affected siblings from a different family (PP1_Strong; PMID: 25970827, personal communication). The computational predictor REVEL gives a score of 0.668, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4, PP1_Strong, PP3 (specification version 1.0.0; 1/04/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA384900118/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31485 biolink:causes UMLS:C0423226 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0423226 infores:hetionet CAID:CA10602335 biolink:causes MONDO:0009861 infores:clingen CAID:CA10602335 MONDO:0009861 PMID:26322415PMID:24705691PMID:26322415PMID:24327145PMID:24327145 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting PS3 The NM_000277.3:c.971T>A (p.Ile324Asn) variant is a missense variant in exon 10 of 13 of PAH. It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.889) (PP3).Classification: PathogenicSupporting Criteria: PM3_VeryStrong; PM2_supporting; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602335/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31644 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0041969 infores:hetionet CHEBI:231594 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0004093 infores:hetionet CAID:CA512341325 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341325 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1077G>A (p.Pro359=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). SpliceAI predicts no impact to splicing (score: 0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -2.875) (BP7). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 943908). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341325/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:54Z8M50D6Q biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0009450 infores:hetionet CHEBI:5106 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0001622 infores:hetionet CAID:CA170266 biolink:causes MONDO:0010726 infores:clingen CAID:CA170266 MONDO:0010726 PMID: Benign BA1 The allele frequency of the p.Pro56= (NM_004992.3) variant in MECP2 is 0.231% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro56= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170266/MONDO:0010726/016 2021-12-13 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:63581 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0021655 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042373 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0004936 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0700184 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0684249 infores:hetionet CHEBI:8871 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011071 infores:hetionet NCBIGene:3043 biolink:causes MONDO:0011381 infores:monarchinitiative not_provided not_provided HGNC:4827 MONDO:0011381 uuid:eb1b32a5-3837-4976-9acd-1368c07bdbca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020473 infores:hetionet CHEBI:3756 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C2830004 infores:hetionet CHEBI:4903 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0018681 infores:hetionet CHEBI:37924 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020443 infores:hetionet CHEBI:36791 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027424 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0006145 infores:hetionet CHEBI:17303 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0004144 infores:hetionet CHEBI:9316 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0855775 infores:hetionet CHEBI:681569 biolink:causes UMLS:C1412002 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1412002 infores:hetionet CHEBI:3380 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0231528 infores:hetionet CHEBI:44032 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0013404 infores:hetionet GO:0039593 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0039593 GO:0140014 CHEBI:61049 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0155862 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0005940 infores:hetionet CHEBI:35854 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0009421 infores:hetionet CHEBI:32221 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0013144 infores:hetionet CHEBI:17334 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0030252 infores:hetionet CHEBI:134991 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0014724 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0555358 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0555358 infores:hetionet CHEBI:64354 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0151799 infores:hetionet CHEBI:421707 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0035222 infores:hetionet CHEBI:465284 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085593 infores:hetionet GO:1904748 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:1904748 GO:0048856 CHEBI:5001 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0021400 infores:hetionet CAID:CA410147839 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147839 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1183C>T (p.Pro395Ser) is a missense variant which has a REVEL score < 0.50 (0.16), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147839/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6437 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0011175 infores:hetionet CHEBI:33325 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0031542 infores:hetionet CHEBI:40279 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0043144 infores:hetionet CAID:CA343772853 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772853 MONDO:0013144 PMID: Pathogenic PS4_Very Strong, PP3, PP1, PP4, PM2_Supporting PS3 The c.1157T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 386 (p.Ile386Thr). This variants alters a conserved residue among the serpin superfamily located in the loop connecting two secondary structures (helix I with strand s5A). There is one allele present in gnomAD (NFE population) in v2.1.1 with a Popmax MAF <0.00002, which meets criteria for PM2_Supporting. The computational predictor REVEL gives a score of 0.752, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant has been reported in at least 20 probands meeting an antithrombin activity level of <0.8 IU/mL and several more are reported in the literature (PS4_Very Strong >8 points proband count per Thrombosis VCEP guidelines). In addition, there is evidence to support this is a Founder variant in the Polish population (Weronska et al., 2023 PMID: 37021543) with a common haplotype defined by six additional SNVs. In addition, p.Ile386Thr causes an aberrant AT with slower electrophoretic mobility was observed in native Western blot gels, in comparison to three non-carriers. There is also evidence of increased clot lysis time in carriers of p.Ile386Thr with Type I deficiency (137 mins) when compared to healthy controls (~95 mins) suggesting a prothrombotic fibrin clot phenotype. Of note, crossed immunoelectrophoresis confirmed the mild type I deficiency without increased levels of forms with low heparin affinity (such as those seen in p.Arg79His). Finally, seven individuals from four families with mean AT heparin cofactor activity (COF) of 59% and AT antigen levels of 65% were reported in a French Cohort (Alhenc-Gelas et al., 2017; PMID: 28300866). Conservatively, we are counting three meiosis for application of PP1 in the absence of detailed pedigrees. In summary, based on the evidence available at this time, this is a pathogenic variant. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel Guidelines (Version 1.0.0) for AT Deficiency for SERPINC1 are PS4_VeryStrong, PM2_supporting, PP1, PP3 and PP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772853/MONDO:0013144/084 2025-07-08 2025-07-08 Semidominant inheritance HP:0032113 Supports UNII:G4PX8C4HKV biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0423791 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0233472 infores:hetionet CHEBI:4753 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0030193 infores:hetionet CHEBI:2788 biolink:causes HP:0500043 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0234665 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C2047937 infores:hetionet CHEBI:84050 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C2242588 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011630 infores:hetionet CAID:CA294202 biolink:causes MONDO:0100488 infores:clingen CAID:CA294202 MONDO:0100488 PMID: Benign BP2_Strong, BS2 BP7, BS1, PM1, PM3, PM4, PVS1, PM2, PP2, PP3, BP1, BP4, BP3, BA1, PS1, PS4 The NM_004360.5(CDH1):c.1178T>A (p.Ile393Asn) variant has been observed in more than 10 (85) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant co-occurs in trans with a pathogenic CDH1 deletion in a carrier with a congenital malformation of the palate and family history of GC (BP2_Strong; internal laboratory contributors). This variant is known in one family with HDGC criteria (internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign based on BS2 and BP2_Strong. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294202/MONDO:0100488/007 2023-08-28 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:53760 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018418 infores:hetionet CHEBI:24564 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0235032 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027765 infores:hetionet CHEBI:5120 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0042755 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0029408 infores:hetionet CHEBI:31644 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0041657 infores:hetionet CHEBI:61049 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151578 infores:hetionet NCBIGene:2235 biolink:causes MONDO:0008319 infores:monarchinitiative not_provided not_provided HGNC:3647 MONDO:0008319 uuid:28a78bc0-01e7-4d04-926c-755880f0a7e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011334 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022890 infores:hetionet CHEBI:63681 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0015230 infores:hetionet CHEBI:2682 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C2979982 infores:hetionet CAID:CA7511349 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511349 MONDO:0015152 PMID: Pathogenic PM4, PP4_Moderate, PM2_Supporting, PM3_Very Strong The NM_000070.3: c.1401_1403del variant in CAPN3 is expected to cause an in-frame deletion of one amino acid, p.(Glu467del) (PM4). This variant has been identified in at least 8 individuals with features consistent with LGMD (PMID: 16141003, 17994539, 16650086, 31555977, 18854869, 38391941, LOVD CAPN3_000200), including in a homozygous state without reported consanguinity in at least one patient (0.5 pts, PMID: 17994539, LOVD Individual # 00214553), confirmed in trans with a likely pathogenic or pathogenic variant in two patients (c.2148G>T p.(Glu716Asp), 1.0 pt, PMID: 37526466; c.967G>T (p.Glu323Ter), 1.0 pt, PMID: 38391941), and in unknown phase with a pathogenic variant in three patients (c.2242C>T p.(Arg748Ter), 0.5 pts x2 = 1.0 pt, PMID: 16141003, 18854869, LOVD Individuals 00214012, 00214187; c.1865_1866del p.(Glu622GlyfsTer9), 0.5 pts, PMID: 16650086, LOVD Individual #00214391) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 displayed progressive limb girdle muscle weakness and significantly reduced expression of calpain-3 protein in skeletal muscle, which is specific for CAPN3-related LGMD (PMID: 18854869; PP4_Moderate). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.000027195 (the upper threshold of the 95% CI of 21/1111998 European (non-Finnish) chromosomes) , which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PM3_Very Strong, PP4_Moderate, PM2_Supporting, PM4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511349/MONDO:0015152/187 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46195 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0006266 infores:hetionet CHEBI:47898 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013428 infores:hetionet CHEBI:135736 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0236000 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0242350 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0031085 infores:hetionet CHEBI:2208 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0149744 infores:hetionet CHEBI:9123 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0008031 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0038363 infores:hetionet CHEBI:31236 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009918 infores:hetionet CHEBI:8888 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0520966 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020517 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0020456 infores:hetionet CHEBI:28748 biolink:causes UMLS:C2937222 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2937222 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0041912 infores:hetionet CHEBI:144551 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0003813 infores:hetionet CHEBI:8774 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027796 infores:hetionet CHEBI:6539 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0017086 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0036508 infores:hetionet CHEBI:63638 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C3665347 infores:hetionet CAID:CA512341224 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341224 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1206C>G (p.Ser402=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (0.0) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341224/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68579 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0030196 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0003123 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0002418 infores:hetionet CHEBI:473990 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0019163 infores:hetionet CHEBI:10023 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0015402 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0178298 infores:hetionet CHEBI:4470 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0009806 infores:hetionet CHEBI:6067 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0231218 infores:hetionet CHEBI:5864 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030196 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0017178 infores:hetionet CHEBI:6030 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0014457 infores:hetionet CHEBI:5128 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0020649 infores:hetionet CHEBI:47612 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0151905 infores:hetionet CHEBI:6129 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0003862 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0024299 infores:hetionet CHEBI:6541 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0036974 infores:hetionet CAID:CA023567 biolink:causes MONDO:0007750 infores:clingen CAID:CA023567 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM3, PM2, PP3, PP4 BP1, BP4, BP3, BA1, PS1, PS2, BP5, BP7, BS1, BS3, PM5, PM4, PM1, PM6, PVS1, PP2 "The NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.001203 (0.12%) in East Asian (gnomAD v2.1.1). PopMax MAF > 0.02% (PM2 is ""not met""), however, after reviewing literature cases, a founder effect - mostly Asian ancestry - seems to be associated (PMID 27206935 - Chiou et al. 2016; several case reports used for PS4). This variant was also found in other populations: PopMax MAF = 0.016% in South Asian (gnomAD v2.1.1). PP3: REVEL = 0.884. PS3: Functional studies reported in PMID 32695144 (Dušková et al., 2020) performed using heterologous cells (CHO), WB and FACS - results - 52% expression and 44% internalization. The variant showed a deleterious effect on the protein localization and function, and was associated with the accumulation of the protein in the ER. Results are below 70%, so PS3 is met. // Functional studies reported in PMID 21511053 (Zhao et al., 2011) performed using retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays - results - approximately 50% cell surface LDLR, 50-60% LDL-LDLR uptake and normal LDL-LDLR binding. Results are below 70%, so PS3 is met. -------- Overall, both functional studies are consistent with damaging effect.PS4, PP4: Variant meets PM2 and is identified in at least 17 unrelated index cases fulfilling criteria for FH (2 index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; at least 15 cases from PMID 20538126, 22353362, 21376320, 25846081, 19318025).PP1_Strong: Variant segregates with FH phenotype in at least 9 informative meioses (minimum 6) from 3 families from different PMIDs (23155708, 2923363, 22353362): 9 affected family members have the variant.PM3: Variant meets PM2 and is identified in 1 index case (PMID 7903864) with homozygous FH phenotype and a deletion of LDLR exons 4-11, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 23155708) with homozygous FH phenotype and the LDLR c.2054C>T, p.(Pro685Leu) variant, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 29233637) with homozygous FH phenotype and the LDLR c.724C>T, p.(Gln242*) variant, confirmed in trans, classified as Pathogenic by these guidelines." Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023567/MONDO:0007750/013 2023-11-07 2024-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:23765 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0162834 infores:hetionet CHEBI:48273 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0575081 infores:hetionet GO:0010002 biolink:causes CL:0002664 infores:ubergraph knowledge_assertion manual_agent GO:0010002 CL:0002664 CHEBI:85083 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0232487 infores:hetionet UMLS:C0009315 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0241729 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0243026 infores:hetionet CHEBI:40279 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038220 infores:hetionet CHEBI:74947 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0497156 infores:hetionet CHEBI:4735 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0085593 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0038661 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019360 infores:hetionet CAID:CA404086610 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086610 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1, PP4 NM_000527.5(LDLR):c.1577C>T (p.Pro526Leu) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.951 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086610/MONDO:0007750/013 2022-01-18 2022-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31643 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0015230 infores:hetionet CHEBI:31236 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037383 infores:hetionet CHEBI:8378 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0005758 infores:hetionet CHEBI:40050 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0027497 infores:hetionet CHEBI:64312 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0014591 infores:hetionet CHEBI:3723 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037384 infores:hetionet CHEBI:50861 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0242184 infores:hetionet CHEBI:52717 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235710 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0037199 infores:hetionet CHEBI:8232 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C1368065 infores:hetionet CHEBI:6444 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0085633 infores:hetionet NCBIGene:5792 biolink:causes MONDO:0014450 infores:monarchinitiative not_provided not_provided HGNC:9670 MONDO:0014450 uuid:3dcc8a37-91b7-4cfb-aad8-c8f315088f11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7822 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0041657 infores:hetionet CHEBI:15552 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0023218 infores:hetionet CHEBI:8764 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0033774 infores:hetionet CHEBI:8214 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0231528 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0549386 infores:hetionet GO:0039520 biolink:causes GO:0006914 infores:ubergraph knowledge_assertion manual_agent GO:0039520 GO:0006914 CHEBI:4562 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0151205 infores:hetionet CHEBI:63631 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085636 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027051 infores:hetionet CHEBI:78543 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0750394 infores:hetionet CHEBI:585948 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0003811 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0009450 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0392197 infores:hetionet CHEBI:8764 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003962 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040053 infores:hetionet CHEBI:59560 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0042963 infores:hetionet CHEBI:3216 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0344315 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0232459 infores:hetionet CHEBI:4646 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0020538 infores:hetionet CHEBI:6438 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0018794 infores:hetionet CHEBI:6078 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0000737 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0002622 infores:hetionet CHEBI:100246 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0033687 infores:hetionet CHEBI:5801 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0152198 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0021053 infores:hetionet NCBIGene:87178 biolink:causes MONDO:0012103 infores:monarchinitiative not_provided not_provided HGNC:23166 MONDO:0012103 uuid:f808a975-c53f-43b9-b79e-f8caeadda464 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63618 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0014742 infores:hetionet CHEBI:17347 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002994 infores:hetionet CHEBI:4681 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0085649 infores:hetionet CHEBI:15365 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0013144 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0423602 infores:hetionet NCBIGene:11231 biolink:causes MONDO:0014860 infores:monarchinitiative not_provided not_provided HGNC:21082 MONDO:0014860 uuid:c72927d1-41f0-4d9b-9b68-a554a4afb8f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47519 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0314719 infores:hetionet NCBIGene:3039 biolink:causes MONDO:0011399 infores:monarchinitiative not_provided not_provided HGNC:4823 MONDO:0011399 uuid:e23fc2c4-e0e8-40b5-9f0a-e7027c967ecd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0086439 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151849 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027765 infores:hetionet CAID:CA410148771 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148771 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS4, PS3, BA1, BP1, BP2, PVS1, PM6, BP5, BS1, BS4, BS3, PM5, PM1, PM3, PP2, PP3, PP1 NM_001754.5(RUNX1):c.988T>G (p.Phe330Val) is a missense variant which is absent from gnomAD v2 and v3 (PM2_supporting). This variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.474, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148771/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3175 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0041657 infores:hetionet CHEBI:8802 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0242184 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013595 infores:hetionet CHEBI:31536 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0085641 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0011991 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0003123 infores:hetionet NCBIGene:7716 biolink:causes MONDO:0859381 infores:monarchinitiative not_provided not_provided HGNC:12949 MONDO:0859381 uuid:3492fc6c-27ca-4c5a-9886-5ad9b4140733 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0037199 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0854212 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0854212 infores:hetionet CHEBI:10102 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0234518 infores:hetionet CHEBI:5141 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0028738 infores:hetionet GO:0002718 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0002718 GO:0006955 CHEBI:3568 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020473 infores:hetionet CAID:CA410203842 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203842 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.232A>G (p.Met78Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203842/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:681848 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0030554 infores:hetionet CHEBI:92712 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0033036 infores:hetionet CHEBI:8768 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1320474 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0003123 infores:hetionet CHEBI:68845 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0002994 infores:hetionet CHEBI:27786 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0151636 infores:hetionet CHEBI:91541 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0344232 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0152198 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0021843 infores:hetionet CHEBI:6375 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013390 infores:hetionet CHEBI:85078 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0009782 infores:hetionet CAID:CA136073 biolink:causes MONDO:0021060 infores:clingen CAID:CA136073 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1074+5G>C variant in the SOS1 gene is 1.551% (837/50942) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136073/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:80208 biolink:causes MONDO:0014726 infores:monarchinitiative not_provided not_provided HGNC:11226 MONDO:0014726 uuid:2c14a743-27e0-4cc9-969c-b2a072c92528 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060142 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0060142 GO:0009653 NCBIGene:23385 biolink:causes MONDO:0007728 infores:monarchinitiative not_provided not_provided HGNC:17091 MONDO:0007728 uuid:4a1931f1-6ee6-4bb3-9058-8c1e8f77f7f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4315 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0547030 infores:hetionet CHEBI:194135 biolink:causes UMLS:C2363980 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C2363980 infores:hetionet CHEBI:5383 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0162566 infores:hetionet CHEBI:31711 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018965 infores:hetionet CHEBI:10023 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0033036 infores:hetionet NCBIGene:2324 biolink:causes MONDO:0011191 infores:monarchinitiative not_provided not_provided HGNC:3767 MONDO:0011191 uuid:9380abe4-d47c-4c70-ae25-b482f0561674 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0018681 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0010043 infores:hetionet CAID:CA404089220 biolink:causes MONDO:0007750 infores:clingen CAID:CA404089220 MONDO:0007750 PMID: Uncertain Significance PM2 BP2, BP4, BA1, PS1, PS4, PS3, PS2, BP7, BS1, BS4, BS3, PM5, PM4, PM1, PM3, PM6, PVS1, PP4, PP1, PP3, BS2 The NM_000527.5(LDLR):c.1661C>G (p.Ser554Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 May 2025.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404089220/MONDO:0007750/013 2025-05-09 2025-10-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15544 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0015967 infores:hetionet CHEBI:681848 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0427086 infores:hetionet CHEBI:15367 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0233762 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0233571 infores:hetionet CHEBI:5384 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0011124 infores:hetionet CHEBI:47898 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0497156 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0033975 infores:hetionet CHEBI:63791 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0026764 infores:hetionet CHEBI:31623 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0013378 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0521500 infores:hetionet CHEBI:3650 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0002878 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0018801 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0037274 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0392025 infores:hetionet CAID:CA213707 biolink:causes MONDO:0015967 infores:clingen CAID:CA213707 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM2, PP2, PP3, PP4 PM1, PP1 The c.1042A>T variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to phenylalanine at codon 348 (p.(Ile348Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.83, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 30386132 and 28095440, ClinVar ID:36172, internal lab contributors). One of these individual had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with diabetes with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 28095440). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213707/MONDO:0015967/086 2024-01-28 2024-01-28 Semidominant inheritance HP:0032113 Supports CHEBI:100241 biolink:causes MONDO:0030602 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0519030 infores:hetionet CHEBI:17334 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C2973529 infores:hetionet CAID:CA386964662 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964662 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3 PS4, PP1, PP4 The c.638T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 213 (p.(Ile213Thr)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19169489). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 19169489). Additionally, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 19169489). Another missense variant, c.637A>T p.(Ile213Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.638T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964662/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16755 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042109 infores:hetionet CHEBI:31413 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0151786 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0277925 infores:hetionet CHEBI:2663 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0085605 infores:hetionet CHEBI:8764 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151772 infores:hetionet CHEBI:6061 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0041657 infores:hetionet NCBIGene:54870 biolink:causes MONDO:0060707 infores:monarchinitiative not_provided not_provided HGNC:24713 MONDO:0060707 uuid:8aaf727c-f7bc-4b06-85db-25d4eb8ec800 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0475858 infores:hetionet CHEBI:7915 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C3665347 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0281981 infores:hetionet CHEBI:6078 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0039231 infores:hetionet CHEBI:55346 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0011175 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0017601 infores:hetionet CHEBI:7824 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0008350 infores:hetionet CHEBI:50742 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0019270 infores:hetionet CHEBI:16469 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151825 infores:hetionet CHEBI:8093 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0234708 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0031117 infores:hetionet CHEBI:6149 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0036973 infores:hetionet MONDO:0800182 biolink:causes NCBIGene:7010 infores:ubergraph knowledge_assertion manual_agent MONDO:0800182 HGNC:11724 CHEBI:567361 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0032285 infores:hetionet CHEBI:83527 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0003467 infores:hetionet CAID:CA023666 biolink:causes MONDO:0007750 infores:clingen CAID:CA023666 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.241C>T (p.Arg81Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP3, PS4_supporting, and PS3_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00001758 (0.001758%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.817PP4 - Variant meets PM2 and is identified 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PS3_supporting - Level 3 assay: PMID 25647241. HeLa cells, alternative microscopy assay, results - LDL-uptake 68%.PS4_supporting - Variant meets PM2 and is identified in 5 index cases (2 cases with DLCN criteria>=6 from in PMID: 33418990 (Meshkov et al., 2021); at least 1 case with DLCN definite in PMID: 11810272 (Fouchier et al., 2001); 1 case with DLCN definite in PMID: 9712531 (Nissen et al., 1998); 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023666/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:17026 biolink:causes MONDO:0016064 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0008925 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0160390 infores:hetionet CHEBI:55346 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0005779 infores:hetionet CHEBI:3752 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0040053 infores:hetionet CHEBI:2636 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0038325 infores:hetionet CHEBI:71941 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0042963 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0027765 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0239978 infores:hetionet CAID:CA053108 biolink:causes MONDO:0100150 infores:clingen CAID:CA053108 MONDO:0100150 PMID: Pathogenic PVS1, PM3_Very Strong BS1, PM2, BA1 The NM_000540.3:c.10347+1G>A variant in RYR1 occurs within the canonical splice donor site (+1) of intron 68. It is predicted to cause skipping of biologically-relevant-exon 68/106, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001666 (1/60016 alleles) in the Admixed American population, which meets no population codes. This variant has been observed in trans with a pathogenic variant in four individuals (4pts) and as phase unknown in one individual (0.5pt) with congenital myopathy (4.5pt, PM3_VeryStrong, PMIDs: 25957634, 25356970, 30652412, 36697461, 36833224). In summary, this variant is classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM3_VeryStrong. (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; September 8th, 2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA053108/MONDO:0100150/179 2025-09-08 2025-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32293 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0038990 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0439857 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0595877 infores:hetionet CHEBI:29007 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0151579 infores:hetionet CHEBI:35778 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C3665347 infores:hetionet CHEBI:9586 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085636 infores:hetionet CHEBI:8805 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0033774 infores:hetionet CAID:CA016422 biolink:causes MONDO:0005021 infores:clingen CAID:CA016422 MONDO:0005021 PMID: Likely Pathogenic PM2, PM6, PP3 PP1, BA1, PS3, BS1, BS4, BS3, PS2, PS1, PS4, BP4 The c.5726G>C (p.Arg1909Pro) variant in MYH7 has been reported as a de novo occurrence in 1 individual with dilated cardiomyopathy and myopathy features (PM6; Partners LMM ClinVar SCV000059632.5). Additionally, this variant reportedly segregated with DCM and in 2 affected relatives (Partners LMM ClinVar SCV000059632.5); however this data is currently insufficient to establish co-segregation and apply PP1. This variant was absent from large population studies (PM2; https://gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). This variant was previously classified as likely pathogenic for DCM by this expert panel (EP) based on clinical judgement; however, upon re-evaluation, the EP has deemed that uncertain significance was more appropriate based on the available evidence. In summary, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM6, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016422/MONDO:0005021/002 2021-03-22 2021-10-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36795 biolink:causes UMLS:C2609096 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2609096 infores:hetionet CHEBI:9907 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0030252 infores:hetionet GO:0060762 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:0060762 GO:0030879 CHEBI:36795 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085612 infores:hetionet UNII:D27V6190PM biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0151827 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040264 infores:hetionet CHEBI:4530 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0085631 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0424823 infores:hetionet CHEBI:6129 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0024440 infores:hetionet CHEBI:63635 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0687713 infores:hetionet CHEBI:51041 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0232461 infores:hetionet CHEBI:8774 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0085624 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0033687 infores:hetionet NCBIGene:6023 biolink:causes MONDO:0009601 infores:monarchinitiative not_provided not_provided HGNC:10031 MONDO:0009601 uuid:b8637a55-1405-4dda-92b5-d789941b94b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002994 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0031117 infores:hetionet CHEBI:5134 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0016658 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004096 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151689 infores:hetionet CHEBI:61033 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151539 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0234215 infores:hetionet CHEBI:6073 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0013404 infores:hetionet CHEBI:6367 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027796 infores:hetionet CHEBI:6073 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0004604 infores:hetionet CAID:CA386303850 biolink:causes MONDO:0009861 infores:clingen CAID:CA386303850 MONDO:0009861 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PM2 The p.L11* variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one Ugyur proband (PMID: 31355225) with classic PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). The patient was compound heterozygous for the variant (confirmed by parental testing) and carried it in trans with the p.R413P variant (known pathogenic per PAH ClinGen working group) (PM3). It is also reported in ClinVar (ID 625287) as a de novo variant by one lab, in a case with PKU; no further information is given. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386303850/MONDO:0009861/006 2020-04-09 2020-04-09 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:344 biolink:causes MONDO:0008810 infores:monarchinitiative not_provided not_provided HGNC:609 MONDO:0008810 uuid:40506ca4-7f60-4cf5-9843-1542926d48bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40050 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0027121 infores:hetionet CHEBI:135613 biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0277885 infores:hetionet GO:0003339 biolink:causes GO:0072088 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0072088 CHEBI:15367 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235266 infores:hetionet CHEBI:39585 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0231218 infores:hetionet UMLS:C0879264 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0021368 infores:hetionet NCBIGene:55791 biolink:causes MONDO:0030354 infores:monarchinitiative not_provided not_provided HGNC:30299 MONDO:0030354 uuid:a12472e2-e81b-417f-85ad-bd5f2a499d33 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0155626 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027339 infores:hetionet CHEBI:87681 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0033774 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0948594 infores:hetionet CHEBI:7865 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0012569 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019372 infores:hetionet CHEBI:7492 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0042790 infores:hetionet CHEBI:119486 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0231218 infores:hetionet NCBIGene:202018 biolink:causes MONDO:0014821 infores:monarchinitiative not_provided not_provided HGNC:26887 MONDO:0014821 uuid:773d56bf-2fe7-42eb-9401-b5a1d89192a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0062056 biolink:causes CL:0001658 infores:ubergraph knowledge_assertion manual_agent GO:0062056 CL:0001658 CHEBI:44185 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0221165 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015230 infores:hetionet UMLS:C1738934 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027497 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0559546 infores:hetionet CHEBI:5864 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020598 infores:hetionet GO:0003400 biolink:causes GO:0090114 infores:ubergraph knowledge_assertion manual_agent GO:0003400 GO:0090114 CHEBI:63617 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011630 infores:hetionet CHEBI:9571 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0039231 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0518015 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0029408 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006944 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0238621 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013295 infores:hetionet CHEBI:38562 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0018418 infores:hetionet CHEBI:83531 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0151908 infores:hetionet NCBIGene:6400 biolink:causes MONDO:0976130 infores:monarchinitiative not_provided not_provided HGNC:10717 MONDO:0976130 uuid:112d0ce9-9a47-4cd6-b0ea-8b63a7892f10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0018681 infores:hetionet CHEBI:49375 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C3160858 infores:hetionet CHEBI:5384 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151907 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0234215 infores:hetionet CHEBI:15407 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0220870 infores:hetionet CHEBI:6775 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151754 infores:hetionet NCBIGene:3777 biolink:causes MONDO:0014136 infores:monarchinitiative not_provided not_provided HGNC:6278 MONDO:0014136 uuid:bef404b3-24a3-4ca0-92e3-f15de329fb5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013428 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020557 infores:hetionet CHEBI:5558 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0000737 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0151602 infores:hetionet CHEBI:63584 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0476280 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009938 infores:hetionet CHEBI:5778 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0003862 infores:hetionet CHEBI:64355 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0428977 infores:hetionet CHEBI:8888 biolink:causes HP:0041081 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1542178 infores:hetionet CHEBI:3738 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0003123 infores:hetionet CHEBI:6640 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0728899 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C3489393 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0009806 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0022408 infores:hetionet CHEBI:3994 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0037822 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042109 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0392175 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0392175 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0151736 infores:hetionet CHEBI:10023 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042963 infores:hetionet CHEBI:5138 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019521 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0086543 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042109 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0036572 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0242350 infores:hetionet CHEBI:6121 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0003578 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0235416 infores:hetionet UMLS:C0004599 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0242528 infores:hetionet CHEBI:8412 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C1760428 infores:hetionet CHEBI:47780 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014335 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0006849 infores:hetionet CHEBI:31949 biolink:causes MONDO:0008599 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0040997 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0035078 infores:hetionet CHEBI:45367 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0151904 infores:hetionet CHEBI:48947 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0019158 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0039971 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0024115 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0031350 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0021400 infores:hetionet CHEBI:136040 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0017605 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0039971 infores:hetionet GO:0110037 biolink:causes GO:0046661 infores:ubergraph knowledge_assertion manual_agent GO:0110037 GO:0046661 CHEBI:135736 biolink:causes MONDO:0042485 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003869 infores:hetionet CHEBI:7444 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0030805 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0030193 infores:hetionet CAID:CA414794543 biolink:causes MONDO:0044970 infores:clingen CAID:CA414794543 MONDO:0044970 PMID:14733964 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP1, PS4, PS2, PM6 The m.7989T>C (p.L135P) variant in MT-CO2 has been reported in one individual with primary mitochondrial disease to date, in a man with acute onset of muscle pain and weakness after strenuous lifting, who then had recurrent episodes of myoglobinuria, fatigue, weakness, bowel dysmotility, and paroxysmal orthostatic tachycardia syndrome (PMIDs: 9066365, 14733964). He had high levels of the variant in muscle and the variant was undetectable in leukocytes from the proband and his unaffected mother. Single fiber testing showed higher levels of the variant in COX deficient fibers (>90%) than in COX positive fibers (<52%; PS3_supporting, PMID: 14733964). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (0.71, range 0-1; PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414794543/MONDO:0044970/015 2024-01-22 2025-06-11 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA337099193 biolink:causes MONDO:0044970 infores:clingen CAID:CA337099193 MONDO:0044970 PMID: Benign BA1 PS4 The m.11467A>G (p.L236L) variant in MT-ND4 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on January 13, 2025. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. This variant is present at high frequencies in population databases (13% of individuals in MITOMAP, 16% in gnomAD v3.1.2, and 20% in the Helix dataset; BA1). Furthermore, this variant is a marker for European haplogroups U and K, where it is found at >99%, however the presence of this variant in an individual with primary mitochondrial disease outside of haplogroups U and K may warrant further consideration to rule out any detrimental effect of the variant. There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 13, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337099193/MONDO:0044970/015 2025-01-13 2025-05-28 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9649 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0038325 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0426576 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0033687 infores:hetionet CHEBI:7496 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C3263723 infores:hetionet CHEBI:10101 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085593 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0024528 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0024528 infores:hetionet CHEBI:8310 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0025287 infores:hetionet CHEBI:16467 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0003123 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0086543 infores:hetionet CHEBI:135888 biolink:causes MONDO:0004471 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C1692886 infores:hetionet CHEBI:9586 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0009676 infores:hetionet CHEBI:2673 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0004144 infores:hetionet CHEBI:4974 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0042963 infores:hetionet CAID:CA16611764 biolink:causes MONDO:0021056 infores:clingen CAID:CA16611764 MONDO:0021056 PMID:20685668 Likely Pathogenic PP3, PS4_Moderate, PS3_Moderate, PM2_Supporting BS2 The NM_000038.6(APC):c.1409-5A>G variant in APC is an intronic variant which is located at the 5th nucleotide upstream of exon 12. This variant has been reported in 5 probands meeting phenotypic criteria resulting in a total phenotype score of 3.0 points (PS4_Moderate, Invitae internal data, PMID: 24599579, 20685668, 20223039, 15459959, 11247896). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the acceptor site of intron 11 of APC by creating a strong alternate acceptor site 5 nucleotides upstream (PP3). Mini-gene assay demonstrated that the variant impacts splicing by skipping of exon 12 resulting in a frameshift and premature termination (PS3_Moderate [PMID: 20685668, 24599579]). The mini-gene assay demonstrated also the retention of the last 4 nucleotides of the upstream intron as a minor effect, corresponding to the creation of an alternate acceptor site 5 nucleotides upstream and also resulting in a frameshift and premature termination (internal data Normandy University, Rouen, France). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: criteria PS3_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version 2.0.3; date of approval: 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16611764/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135351 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0178298 infores:hetionet CHEBI:8764 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023218 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0233494 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0700345 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0948586 infores:hetionet CHEBI:2469 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0023895 infores:hetionet CHEBI:63617 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013404 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0162429 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1384666 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0013395 infores:hetionet CHEBI:48390 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0016658 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0232492 infores:hetionet CHEBI:63617 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0497156 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0581164 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0581164 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027765 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0005741 infores:hetionet CHEBI:9168 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0026827 infores:hetionet CHEBI:6887 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0917801 infores:hetionet CHEBI:6916 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0700590 infores:hetionet CHEBI:6149 biolink:causes UMLS:C2747853 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C2747853 infores:hetionet CHEBI:7956 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0151505 infores:hetionet NCBIGene:9409 biolink:causes MONDO:0013942 infores:monarchinitiative not_provided not_provided HGNC:8857 MONDO:0013942 uuid:df99a102-5a01-42f6-b3fe-b881c9992753 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0702166 infores:hetionet CHEBI:31638 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0013404 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0011849 infores:hetionet CHEBI:31624 biolink:causes MONDO:0002250 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0004812 infores:hetionet CHEBI:2704 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0019080 infores:hetionet GO:0003420 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0001501 CHEBI:2922 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0011168 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0020456 infores:hetionet CHEBI:253342 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0003467 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0038367 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019158 infores:hetionet CHEBI:51364 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0033117 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036454 infores:hetionet NCBIGene:60506 biolink:causes MONDO:0010690 infores:monarchinitiative not_provided not_provided HGNC:8082 MONDO:0010690 uuid:3502027e-238a-4805-8090-54a1977d89a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA343725131 biolink:causes MONDO:0020367 infores:clingen CAID:CA343725131 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PM6, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.1008C>T variant in MYOC is a synonymous variant (p.Phe336=). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The CADD score (v1.6) = 7.603, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 3.56 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for juvenile open angle glaucoma (JOAG) (PMID: 19688280), not meeting the ≥ 3 segregations required for PP1. Only 1 proband with JOAG had been reported (PMID: 19688280), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725131/MONDO:0020367/019 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51041 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0024282 infores:hetionet CHEBI:5088 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0039231 infores:hetionet NCBIGene:7852 biolink:causes MONDO:8000006 infores:monarchinitiative not_provided not_provided HGNC:2561 MONDO:8000006 uuid:3e9493e1-893f-4c6e-8c25-742cebf73b00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0002994 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0151730 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151730 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0234215 infores:hetionet CHEBI:71223 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0023530 infores:hetionet CHEBI:63619 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2830004 infores:hetionet CAID:CA396451185 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451185 MONDO:0007648 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Moderate BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP3, BP1, BP4, BP2, BA1, PS1, PS3, PS2 The c.2T>C (p.Met1Thr) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 2 probands/families meeting HDGC clinical criteria (PS4_moderate; PMID: 20373070, SCV000760804.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_moderate, PM2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451185/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:2663 biolink:causes UMLS:C0151859 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151859 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0027769 infores:hetionet CHEBI:63611 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085702 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037274 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0029134 infores:hetionet UMLS:C1709429 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0015967 infores:hetionet CHEBI:31236 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085932 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042373 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0006145 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0021053 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0031542 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0005741 infores:hetionet CHEBI:135530 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0014742 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0233494 infores:hetionet CHEBI:50777 biolink:causes NCIT:C127841 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0476427 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027609 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0242350 infores:hetionet CHEBI:85078 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C1167965 infores:hetionet CHEBI:45327 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0036974 infores:hetionet CHEBI:37333 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0040822 infores:hetionet CAID:CA222152 biolink:causes MONDO:0015152 infores:clingen CAID:CA222152 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PS3_Moderate PM5, PM2 The NM_003494.4: c.3137G>A variant in DYSF, which is also known as NM_001130987.2: c.3191G>A p.(Arg1064His), is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1064, p.(Arg1046His). This variant has been identified in approximately 13 individuals with clinical features consistent with LGMD, including in a homozygous state in two patients without reported familial consanguinity (1.0 pt, PMID: 27647186, 34559919, 11468312), confirmed in trans with a pathogenic variant in at least one patient (NM_003494.4: c.3477C>A p.(Tyr1159Ter), 1.0 pt, PMID: 18853459, 16010686), and in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.1375dup p.(Met459AsnfsTer15), 0.5 pts, PMID: 34559919, 27647186; LOVD Individual #00375899) (PM3_Strong). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 25591676, 18853459; PP4_Strong). In addition, the variant co-segregated with the LGMD phenotype in one affected family member (PMID: 18853459; PP1). The filtering allele frequency (the upper threshold of the 95% CI of 3/44704 exome chromosomes) is 0.0001734 for the Admixed American population in gnomAD v4.1.0, which is higher than the ClinGen LGMD VCEP threshold (0.0001) for PM2_Supporting (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.826, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1046Cys protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Strong, PP4_Strong, PP1, PP3, PS3_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222152/MONDO:0015152/180 2025-07-29 2025-08-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6402 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0851578 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0149931 infores:hetionet NCBIGene:644 biolink:causes MONDO:0013595 infores:monarchinitiative not_provided not_provided HGNC:1062 MONDO:0013595 uuid:4a0d684f-aacf-4e80-ae00-017367952d0e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0031970 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0438242 infores:hetionet NCBIGene:2074 biolink:causes MONDO:0014843 infores:monarchinitiative not_provided not_provided HGNC:3438 MONDO:0014843 uuid:e13f8ca2-eb23-4147-82b0-d560820a0f7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17987 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0701836 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0018802 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0541974 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0541974 infores:hetionet CHEBI:83804 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0233565 infores:hetionet CHEBI:68606 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0008350 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0854382 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042571 infores:hetionet CHEBI:8405 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0042963 infores:hetionet CHEBI:50659 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C2973529 infores:hetionet CAID:CA6748738 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748738 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate, PP3 The c.1136T>C (p.Val379Ala) PAH variant has been reported in at least two mild HPA probrands with exclusion of BH4 deficiency (PMID: 21307867). This variant is found at an extremely low frequency (0.0001737) in the gnomAD Latino population. It is a missense variant predicted deleterious by SIFT (damaging) and MutationTaster (disease causing), with a REVEL score of 0.796. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748738/MONDO:0009861/006 2020-05-08 2021-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15365 biolink:causes HP:0032368 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0268030 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0948089 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0234458 infores:hetionet CHEBI:94686 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0236075 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0004936 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0032285 infores:hetionet CHEBI:61049 biolink:causes MONDO:0015758 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0079773 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0020507 infores:hetionet CHEBI:6704 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0042109 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0178298 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0413252 infores:hetionet CHEBI:8871 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043387 infores:hetionet CHEBI:3084 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0000737 infores:hetionet UMLS:C0023610 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0015672 infores:hetionet CAID:CA2693438924 biolink:causes MONDO:0100437 infores:clingen CAID:CA2693438924 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting NM_001034853.2(RPGR):c.2944del (p.Glu982LysfsTer?) is a frameshift variant due to a 1-nucleotide deletion introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v.4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 27620828). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2693438924/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:6375 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0033247 infores:hetionet CHEBI:45716 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0033774 infores:hetionet CHEBI:63620 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0162835 infores:hetionet CHEBI:8481 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0235238 infores:hetionet CAID:CA274655 biolink:causes MONDO:0010726 infores:clingen CAID:CA274655 MONDO:0010726 PMID: Benign BP5, BS1, BS2 PS4 The allele frequency of the p.Leu386_Pro389del variant in MECP2 (NM_004992.3) is 0.019% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Leu386_Pro389del variant is observed in 3 unaffected individuals (internal database) (BS2). The p.Leu386_Pro389del variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). The p.Leu386_Pro389del variant has been observed in 2 individuals with neurological disorders (PMID: 19914908, 23262346) (PS4 not met). In summary, the p.Leu386_Pro389del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274655/MONDO:0010726/016 2022-12-09 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:85161 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0178298 infores:hetionet CHEBI:194135 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0025222 infores:hetionet UMLS:C0011701 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0027497 infores:hetionet CHEBI:3508 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0014742 infores:hetionet CHEBI:46295 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0085298 infores:hetionet CHEBI:2904 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0011570 infores:hetionet CHEBI:3380 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0151632 infores:hetionet CHEBI:8802 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1619712 infores:hetionet CHEBI:3310 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0232462 infores:hetionet NCBIGene:5264 biolink:causes MONDO:0009958 infores:monarchinitiative not_provided not_provided HGNC:8940 MONDO:0009958 uuid:41626b57-d055-44bb-a978-30a62ac986a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0009763 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001240 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002891 infores:hetionet CHEBI:59773 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0010200 infores:hetionet CHEBI:5118 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0037763 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0700345 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233794 infores:hetionet CHEBI:7983 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0549249 infores:hetionet NCBIGene:4594 biolink:causes MONDO:0009612 infores:monarchinitiative not_provided not_provided HGNC:7526 MONDO:0009612 uuid:a7ac8013-9e27-4436-8786-6bfa191295e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003467 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0001125 infores:hetionet CHEBI:9943 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0025345 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0035309 infores:hetionet CHEBI:64310 biolink:causes HP:0012581 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0268800 infores:hetionet CHEBI:8024 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0011606 infores:hetionet NCBIGene:2657 biolink:causes MONDO:0008832 infores:monarchinitiative not_provided not_provided HGNC:4214 MONDO:0008832 uuid:a3c0ec44-35ff-4c95-967d-471d532443ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C0221030 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0221030 infores:hetionet CHEBI:63631 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085635 infores:hetionet CHEBI:51860 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085641 infores:hetionet CHEBI:31644 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0026826 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0852908 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009782 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0518015 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0032461 infores:hetionet CHEBI:31623 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0009782 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0016512 infores:hetionet CHEBI:36795 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235660 infores:hetionet CAID:CA96772381 biolink:causes MONDO:0015152 infores:clingen CAID:CA96772381 MONDO:0015152 PMID: Benign BP7, BA1, BP4 BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BP3, BP1, BP2, PS1, PS3, PS4, PS2, PM4, PM5, PM1, PM3 The NM_000232.5: c.*3043A>G variant is located in the 3’UTR of SGCB. Because the variant is located in the 3’UTR, it is not expected to alter the amino acid sequence. The filtering allele frequency of this variant is 0.006250 (the lower threshold of the 95% CI of 460/68042 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (0.002) for BA1, meeting this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.00 for donor and acceptor loss, suggesting that the variant has no impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA96772381/MONDO:0015152/184 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63619 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042109 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0086543 infores:hetionet CAID:CA413497548 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497548 MONDO:0010315 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting The c.115+1G>T (NM_000206.3) variant in IL2RG occurs within the canonical donor splice site (+1) of intron 1. It is expected to disrupt RNA splicing, disrupt the reading frame, and is predicted to undergo NMD. (PVS1). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), exome sequencing conducted (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :2.5 pts (PP4_Moderate) (PMID: 9058718).In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1,PM2_supporting,PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497548/MONDO:0010315/129 2024-05-28 2024-05-28 X-linked inheritance HP:0001417 Supports CHEBI:45783 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0014518 infores:hetionet CHEBI:75988 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0687713 infores:hetionet CHEBI:4974 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0009676 infores:hetionet CAID:CA000330 biolink:causes MONDO:0017623 infores:clingen CAID:CA000330 MONDO:0017623 PMID:11748304PMID:11748304PMID:21828076PMID:17942903PMID:29706350PMID:11748304 Likely Pathogenic PM2, PM6, PP2, PS3 BP7, BP5, BS1, BS3, BS4, PVS1, PP3, PP1, PP4, BS2, PM4, PM5, PM1, PM3, BA1, BP3, BP4, BP1, BP2, PS1, PS4, PS2 PTEN c.181C>G (p.His61Asp) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350, PMID 17942903, PMID 21828076)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 11748304)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000330/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports GO:0009966 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0009966 GO:0051716 GO:0141069 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0141069 GO:0051716 CHEBI:64312 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030193 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013595 infores:hetionet CAID:CA179692 biolink:causes MONDO:0800406 infores:clingen CAID:CA179692 MONDO:0800406 PMID: Pathogenic PVS1, PM2_Supporting, PS4 The NM_000350.3: c.1222C>T; p.Arg408Ter variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 9 of 50 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v4.1.0 is 0.0000167 (27/1613972 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). This variant was reported in numerous individuals with ABCA4-related retinopathy (PMID: 140709597, 23755871, 30060493, 30771335, 32619608, 33301772, 33369172). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The odds ratio is 111.5 and the confidence interval (CI) is 34.41 to 571.57, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PVS1, PS4, PM2_Supporting. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA179692/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9738 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0043094 infores:hetionet CHEBI:75722 biolink:causes HP:0031965 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948014 infores:hetionet CHEBI:83531 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C1443060 infores:hetionet CHEBI:4909 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0085641 infores:hetionet CHEBI:5088 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C2830004 infores:hetionet CHEBI:8499 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0162529 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0042373 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151752 infores:hetionet GO:1904596 biolink:causes GO:0090594 infores:ubergraph knowledge_assertion manual_agent GO:1904596 GO:0090594 UNII:G4PX8C4HKV biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009806 infores:hetionet NCBIGene:5468 biolink:causes MONDO:0019182 infores:monarchinitiative not_provided not_provided HGNC:9236 MONDO:0019182 uuid:819563c1-8593-41a7-9857-6ef3bfcfb134 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8461 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0003467 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0919671 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0018099 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235653 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235653 infores:hetionet CHEBI:84883 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0020473 infores:hetionet CHEBI:17303 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0039231 infores:hetionet CHEBI:9674 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0520966 infores:hetionet CHEBI:6067 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2937358 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0032285 infores:hetionet NCBIGene:2317 biolink:causes MONDO:0007875 infores:monarchinitiative not_provided not_provided HGNC:3755 MONDO:0007875 uuid:66fa73b5-ecde-4267-88af-b6be571e8f17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4885 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0022346 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0042769 infores:hetionet CHEBI:9725 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0085631 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0007642 infores:hetionet NCBIGene:4942 biolink:causes MONDO:0009796 infores:monarchinitiative not_provided not_provided HGNC:8091 MONDO:0009796 uuid:75df28f8-989c-4a03-ba7d-233e27d38ef3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0162830 infores:hetionet CHEBI:39585 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0338614 infores:hetionet CAID:CA273972 biolink:causes MONDO:0009290 infores:clingen CAID:CA273972 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3 The NM_000152.5:c.925G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 309 (p.Gly309Arg). In a cohort of 54 Dutch patients with Pompe disease, the allele frequency of the variant was 5.5%, and evidence suggests that it is a founder variant in that population (PMID 9660056). This variant has been reported in more than 13 individuals diagnosed with Pompe disease; for at least 6 individuals, residual GAA activity is available and is in the deficient range (PMIDs 9660056, 16838077, 23430847, 23601496, 24495340, 27189384), with some patients also reported to be on enzyme replacement therapy and/or to have documentation of symptoms consistent with infantile onset Pompe disease (PMID 23402890, 23430847, 23601496, 24495340) (PP4_Moderate). More data is available in the literature but the maximum strength of evidence for PP4, as specified by the ClinGen LSD VCEP, can already be applied.. Ten of these individuals are compound heterozygous for the variant and a pathogenic variant (PMID: 9660056, 16838077, 16917947, 23402890, 23430847), phase unknown in all cases, and one is homozygous (PMID: 23601496)(PM3_Very strong). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In functional studies, when expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188797; 2 star review status) with 8 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved on August 17, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273972/MONDO:0009290/010 2021-09-07 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9123 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018681 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0403632 infores:hetionet CAID:CA658658492 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658492 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1636del p.(Ala546fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658492/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:465284 biolink:causes UMLS:C0032787 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0032787 infores:hetionet CHEBI:50173 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0600142 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0243026 infores:hetionet CHEBI:7514 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0013404 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0518015 infores:hetionet CHEBI:2676 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C2973529 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007114 infores:hetionet CAID:CA347493 biolink:causes MONDO:0015152 infores:clingen CAID:CA347493 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Strong The NM_000070.3: c.146G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 49 (p.Arg49His). This variant has been detected in at least six unrelated individuals with limb girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358; ClinVar SCV003459936.1 internal data communication, ClinVar SCV001164521.1 internal data communication), including in a homozygous state in one individual (ClinVar SCV001164521.1 internal data communication, 0.5 pts), confirmed in trans with a pathogenic variant (c.967G>T p.(Glu323Ter), 1.0 pt, PMID: 17318636), and confirmed in trans with two variants not yet curated by the VCEP and considered VUS (0.5 pts) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 16650086). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347493/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63632 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0340865 infores:hetionet CHEBI:6761 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0014457 infores:hetionet CHEBI:119486 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151474 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0024137 infores:hetionet CAID:CA9870528 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870528 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, PP4, PM1, BP4 The c.1291G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 431 (p.(Val431Ile)) of NM_175914.5. This variant has a REVEL score of 0.224, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation, 1 copy in the East Asian subpopulation, 1 copy in the South Asian subpopulation and 1 copies in the remaining individuals subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (internal lab contributors). In summary, c.1291G>A meets the criteria to be classified as a variant of uncertain significane for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870528/MONDO:0015967/085 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA16020778 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020778 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4_Moderate, PM5, PM2_Supporting The c.361T>G (p.Phe121Val) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded) (PP4_Moderate; PMID: 26503515) This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.99. A different pathogenic missense change (p.Phe121Leu) has been seen before. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2_supporting, PP3_strong, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020778/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9398 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C1322281 infores:hetionet NCBIGene:7498 biolink:causes MONDO:0010209 infores:monarchinitiative not_provided not_provided HGNC:12805 MONDO:0010209 uuid:f2ae2749-d0b7-4d77-b5fd-4d12c637e713 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010414 infores:hetionet CHEBI:15407 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0080274 infores:hetionet CHEBI:8382 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0016658 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0017601 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0027765 infores:hetionet CHEBI:119573 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0237849 infores:hetionet NCBIGene:3717 biolink:causes MONDO:0013794 infores:monarchinitiative not_provided not_provided HGNC:6192 MONDO:0013794 uuid:f62fc9d2-9943-41c1-9cc3-084f1a032e42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0221269 infores:hetionet CAID:CA132713 biolink:causes MONDO:0010134 infores:clingen CAID:CA132713 MONDO:0010134 PMID: Uncertain Significance BP7, BP5, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2291C>T (NM_000441.2(SLC26A4):c.2291C>T (p.Thr764Met)) variant is a missense variant predicted to cause substitution of threonine by methionine at amino acid 764. The highest MAF in gnomAD v4.0.0 is 0.03221 % (2/6022 alleles) in the Middle Eastern population. The next highest MAF in gnomAD is 0.0175 % (13/74302 alleles) in the African/African American population (no population codes met by either frequency). In-silico predictons are conflicting (ie. damaging, neutral, and tolerated). Also, the nucleotide is very poorly conserved among 1000 vertebrates. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Pendred Syndrome (no codes met; ClinGen Hearing Loss VCEP Specifications Version 2; 02/19/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132713/MONDO:0010134/005 2025-02-19 2025-03-18 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:75275 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0042963 infores:hetionet CHEBI:47898 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002792 infores:hetionet CAID:CA002656 biolink:causes MONDO:0018875 infores:clingen CAID:CA002656 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PS4_Moderate, BS2_Supporting, PM2_Supporting BA1, BP4, PS1, PS3, PS2, PM5, PM1, BP7, BS1, BS4, PVS1, PP3, PP1, PP4 The NM_000546.6: c.393C>A variant in TP53 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 131 (p.Asn131Lys). This variant has been reported in 3 unrelated families] meeting Revised Chompret criteria with one of these cases including an individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). This variant has an allele frequency of 0.000008055 (13/1613958 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, BS2_Supporting, PM2_Supporting, BS3_Supporting. (Bayesian Points: 1; VCEP specifications version 2.2; 2/6/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002656/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45652 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0016382 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0030305 infores:hetionet CHEBI:3175 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0011570 infores:hetionet CHEBI:116278 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0392171 infores:hetionet CAID:CA7331606 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331606 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, PM6, BP2, BA1, PP3, PP4, PM5, PM1, PS1, PS3, PS2, PS4, BS1, BS3, BS4 The NM_177438.3(DICER1):c.646C>A variant in DICER1 is a missense variant predicted to cause substitution of proline by threonine at amino acid 216 (p.Pro216Thr). The total allele frequency in gnomAD v4.1.0 is 0.000004790 (7/1461408 alleles) with highest population minor allele frequencies of 0.00001656 (1/60388 alleles) and 0.000005397 (6/1111798) in a population of undescribed ancestry and the European (non-Finnish) population, respectively (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.283; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/27/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331606/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:107736 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0037763 infores:hetionet CHEBI:6076 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0546817 infores:hetionet CHEBI:3723 biolink:causes MONDO:0044339 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0158252 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0006266 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0011616 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018799 infores:hetionet GO:1901993 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1901993 GO:0019953 CHEBI:28148 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0011168 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0687133 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0030305 infores:hetionet CHEBI:6149 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0010200 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0878544 infores:hetionet CAID:CA220541 biolink:causes MONDO:0018947 infores:clingen CAID:CA220541 MONDO:0018947 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate The NM_000252.3:c.688T>C variant in DNM2 is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 230 (p.Trp230Arg). This variant is absent from gnomAD v4.1.0 (PM2_supporting). The computational predictor REVEL gives a score of 0.932, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in 3 probands with X-linked myotubular myopathy (PS4_moderate; PMIDs: 15725586, 30884204, Invitae Internal Data). At least one patient with this variant displayed round muscle fibers that were both peripheral halo and centrally located (PP4_moderate; PMID: 30884204). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_moderate, PP4_moderate, PM2_supporting, PP3 (ClinGen Congenital Myopathies VCEP Specifications Version 1.0.0; 5/12/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA220541/MONDO:0018947/149 2025-05-12 2025-06-23 X-linked inheritance HP:0001417 Supports CHEBI:42797 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0344232 infores:hetionet CHEBI:3561 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0037036 infores:hetionet CHEBI:16347 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0030252 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233472 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0265031 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0031542 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0086543 infores:hetionet UMLS:C0145185 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0030232 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0019158 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0085649 infores:hetionet CHEBI:144093 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151825 infores:hetionet CHEBI:4672 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0156404 infores:hetionet CHEBI:5384 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0547030 infores:hetionet CHEBI:135342 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042029 infores:hetionet CHEBI:4445 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0019158 infores:hetionet GO:0044477 biolink:causes GO:0070527 infores:ubergraph knowledge_assertion manual_agent GO:0044477 GO:0070527 CHEBI:80630 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0013604 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0021053 infores:hetionet CAID:CA2802462 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802462 MONDO:0001586 PMID: Pathogenic PVS1_Moderate, PP4_Moderate, PM2_Supporting, PM3_Very Strong The NM_000203.5(IDUA):c.1882C>T (p.Arg628Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). This variant has been detected in at least 16 individuals with MPS I. This variant has been detected in at least 17 individuals with MPS I. Of those individuals, 6 were compound heterozygous for the variant and a variant that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen LD VCEP, including c.236C>T (p.Ala79Val) (ClinVar Variation ID: 1458769) (PMID: 27520059, LP, 0.25 pts); c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 15081804, 25614311, 2 x 0.5 pts); c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 12509712, 19396826, 19954743; one confirmed in trans, one unconfirmed, 1 + 0.5 pt) and c.2T>C (p.Met1?) (PMID: 34813777, 0.5 pts). Ten individuals were homozygous for the variant (PMIDs: 27511503, 24798265, 21521498, 12203999, 11735025, 35141277, 35893030, 22718273, 35123515) (max 2 x 0.5 pt). Another proband was compound heterozygous for the variant and c.809T>G (p.Ile270Ser) (PMID: 16435195); the allelic data from this patient has been used in the classification of p.Ile270Ser and is not included here to avoid circular logic. Total 4.25 pts (PM3_VeryStrong). At least 4 patients with this variant had documented IDUA deficiency within the affected range in leukocytes and/or clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, and corneal involvement (PMIDs: 27520059, 21521498, 19396826, 11735025; PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00004459 (2/44852 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 550421). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_VeryStrong, PVS1_Moderate, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 7, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802462/MONDO:0001586/091 2025-07-07 2025-07-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8707 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018799 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041912 infores:hetionet CHEBI:3561 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0014394 infores:hetionet CHEBI:94392 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0231218 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0948594 infores:hetionet NCBIGene:23090 biolink:causes MONDO:0013916 infores:monarchinitiative not_provided not_provided HGNC:16762 MONDO:0013916 uuid:1be8b160-3ebd-4bf6-b613-af2e3f008d56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0860207 infores:hetionet CHEBI:27779 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0221490 infores:hetionet CHEBI:15407 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0039231 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0005940 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0041969 infores:hetionet CHEBI:50859 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0031256 infores:hetionet CHEBI:5959 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0011603 infores:hetionet CHEBI:4798 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0522153 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0033975 infores:hetionet CHEBI:9086 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027497 infores:hetionet CHEBI:6923 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0017672 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0020517 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0236083 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0236083 infores:hetionet CHEBI:63635 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0085682 infores:hetionet CHEBI:135566 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0020452 infores:hetionet CHEBI:17823 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0013144 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0032226 infores:hetionet CHEBI:134991 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0003862 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018802 infores:hetionet CAID:CA8815016 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815016 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3, PM5, BP4, PS3, BS3 The NM_000152.5:c.781G>A variant in GAA is a missense variant predicted to cause substitution of Ala by Thr at amino acid 261 (p.Ala261Thr). One patient with infantile-onset Pompe disease who was homozygous for this variant has been reported;, the parents were confirmed to be heterozygous (PMID 31510962) (PM3_Supporting). The patients symptoms included dyspnea, poor feeding, failure to thrive, delayed motor milestone, short PR interval, biventricular hypertrophy, and severe intellectual disability. GAA activity was 0.43% of normal (PMID 31510962)(PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (3/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant results in reduced GAA activity (66% in cell extract and 5% in culture medium comparing to wildtype) and is classified as class D for the severity rating (PMID 31510962) (BS3_Supporting). The computational predictor REVEL gives a score of 0.584 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The computational splicing predictor SpliceAI predicts no impact on splicing. Two different missense variants, c.781G>C (p.Ala261Pro) and c.782C>T (p.Ala261Val) in the same codon have been reported in patients with Pompe disease. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 456438). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specification Version 2.0): PM2_supporting, PM3_supporting, PP4_Moderate, BS3_supporting.(Classification approved by the ClinGen LSD VCEP on Nov 1, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815016/MONDO:0009290/010 2024-02-11 2024-02-11 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:6067 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0162820 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151602 infores:hetionet CHEBI:60761 biolink:causes MONDO:0006633 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0267841 infores:hetionet CHEBI:92607 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0020458 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151738 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151738 infores:hetionet CHEBI:63608 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0042963 infores:hetionet CHEBI:6897 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0014591 infores:hetionet CHEBI:27899 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1262036 infores:hetionet CHEBI:4027 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0234233 infores:hetionet CHEBI:3387 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0024141 infores:hetionet CHEBI:10100 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0018926 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0178298 infores:hetionet CAID:CA8603502 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603502 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.310+1G>A variant disrupts the donor splice site in intron 2, which is predicted to cause the skipping of exon 2, leading to a frameshift with a premature stop codon in exon 3 which may trigger nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 3 in PMID:19172520/GT database record 160) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <10%, as measured by flow cytometry. Patient 3 (PMID: 19172520/GT database record 160) is homozygous for this variant (0.5pt; PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001771 (2/112928 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603502/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7798 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0027765 infores:hetionet CHEBI:31236 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014394 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0042075 infores:hetionet CHEBI:4858 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0013456 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0004936 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0877153 infores:hetionet CHEBI:16586 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0020517 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C2721563 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C2721563 infores:hetionet CHEBI:47898 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042963 infores:hetionet CHEBI:3347 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0033774 infores:hetionet CHEBI:8212 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0151889 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042376 infores:hetionet CHEBI:8694 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0015672 infores:hetionet CHEBI:6888 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151686 infores:hetionet CHEBI:3504 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0151904 infores:hetionet CHEBI:28864 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0004604 infores:hetionet CAID:CA120570 biolink:causes MONDO:0044970 infores:clingen CAID:CA120570 MONDO:0044970 PMID: Uncertain Significance PP3, PS3_Supporting, PM2 PS4 The m.4269A>G variant in MT-TI has been reported in one individual with primary mitochondrial disease to date, in a boy with encephalopathy, progressive cardiomyopathy, growth failure, focal segmental glomerulosclerosis, hearing loss, seizures, and fatigue (PMID: 1632786). The variant was heteroplasmic in blood and muscle but the level was not specified, and his mother was found to have lower levels than the proband. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (82.8 percentile) and HmtVAR predicts it to be pathogenic with a score of 1 (PP3). Cybrid studies support the deleterious effect of this variant (PMID: 7518448; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120570/MONDO:0044970/015 2025-02-04 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:50692 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0162429 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006840 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036983 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0019158 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0036572 infores:hetionet UMLS:C0011701 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0041834 infores:hetionet CHEBI:9943 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0021177 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0022660 infores:hetionet CHEBI:7465 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0030554 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020676 infores:hetionet CAID:CA5689584 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689584 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.377C>T (p.Thr126Ile) variant in the SHOC2 gene is 0.0384% (8/10346) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689584/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:2208 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0235416 infores:hetionet CHEBI:6402 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0038325 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0013922 infores:hetionet CHEBI:15544 biolink:causes UMLS:C1619718 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C1619718 infores:hetionet GO:0051584 biolink:causes GO:0001963 infores:ubergraph knowledge_assertion manual_agent GO:0051584 GO:0001963 CHEBI:49575 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0241705 infores:hetionet CHEBI:8802 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0019079 infores:hetionet CAID:CA915946411 biolink:causes MONDO:0100216 infores:clingen CAID:CA915946411 MONDO:0100216 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3 The NM_177438.3:c.1753-9A>G variant in DICER1 is an intronic variant located in intron 10. This variant received a total of 1 phenotype point across 1 unrelated family, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributors). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PM2_Supporting, PS3, PP3. (Bayesian Points: 7; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946411/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42355 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0235378 infores:hetionet CHEBI:9434 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0036974 infores:hetionet CHEBI:499361 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0852911 infores:hetionet CHEBI:119486 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0162283 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0948089 infores:hetionet CHEBI:15544 biolink:causes DOID:113 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0032319 infores:hetionet UMLS:C0657912 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013604 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0004936 infores:hetionet CHEBI:85078 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0011175 infores:hetionet CHEBI:7565 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0015967 infores:hetionet CHEBI:101853 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0014457 infores:hetionet CHEBI:35854 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0006277 infores:hetionet CHEBI:50859 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0025222 infores:hetionet UNII:3U02EL437C biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0423791 infores:hetionet CHEBI:31401 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0004093 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0025061 infores:hetionet CHEBI:72690 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0151905 infores:hetionet CHEBI:5118 biolink:causes HP:0030051 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0427144 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0039971 infores:hetionet NCBIGene:6911 biolink:causes MONDO:0007389 infores:monarchinitiative not_provided not_provided HGNC:11605 MONDO:0007389 uuid:a244f858-6c58-4a84-a145-5f82c00e4b9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1145670 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C1368065 infores:hetionet CHEBI:9241 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0011603 infores:hetionet CHEBI:2611 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0700590 infores:hetionet CHEBI:63791 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235490 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0948594 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0027726 infores:hetionet CHEBI:59560 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0018681 infores:hetionet CHEBI:100246 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0011168 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0853813 infores:hetionet CAID:CA410147801 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147801 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1197C>G (p.Ser399Arg) is a missense mutation that is not present in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has a REVEL score < 0.50 (0.126), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147801/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8874 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013604 infores:hetionet CHEBI:31348 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085661 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009319 infores:hetionet CHEBI:465284 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0424295 infores:hetionet CHEBI:168396 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151603 infores:hetionet CHEBI:64045 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0007222 infores:hetionet CHEBI:6367 biolink:causes NCIT:C185320 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0349410 infores:hetionet CHEBI:116278 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0029191 infores:hetionet CHEBI:66899 biolink:causes UMLS:C1536146 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C1536146 infores:hetionet CHEBI:82941 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0042963 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0041969 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0018799 infores:hetionet CHEBI:9571 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0011168 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0003123 infores:hetionet CHEBI:45409 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151610 infores:hetionet NCBIGene:7466 biolink:causes MONDO:0007287 infores:monarchinitiative not_provided not_provided HGNC:12762 MONDO:0007287 uuid:9422f117-8fb5-4bed-b19d-0afc6018c1aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0017178 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0028738 infores:hetionet CHEBI:7565 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018681 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233632 infores:hetionet CHEBI:8356 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014724 infores:hetionet CHEBI:6950 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1443060 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0037199 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027441 infores:hetionet CHEBI:4798 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0851578 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0009450 infores:hetionet CHEBI:64028 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0085631 infores:hetionet CAID:CA414917679 biolink:causes MONDO:0010602 infores:clingen CAID:CA414917679 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PP3, PP1, PS4 PM5, PP4 The c.979C>G (p.Leu327Val) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.657 (>0.6) and meets criteria for PP3. At least 8 probands reported with mild hemophilia A (PMID: 18691168, PMID: 11857744, PMID: 29296726, PMID: 31064749, PMID: 20860608 and internal VCEP data) meeting F8 phenotype criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very strong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414917679/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5004 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C1368065 infores:hetionet CHEBI:131512 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0002871 infores:hetionet CHEBI:6015 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0019521 infores:hetionet CHEBI:28748 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017979 infores:hetionet CHEBI:92511 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0917801 infores:hetionet NCBIGene:4744 biolink:causes MONDO:0014836 infores:monarchinitiative not_provided not_provided HGNC:7737 MONDO:0014836 uuid:60fbb8ec-96a6-4bb8-b0a2-87b979b186be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8060 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0220981 infores:hetionet CHEBI:7956 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0687713 infores:hetionet CHEBI:10023 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0015967 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0009806 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0031117 infores:hetionet CHEBI:465284 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0007859 infores:hetionet CHEBI:7936 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013384 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0017178 infores:hetionet CHEBI:6437 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0038220 infores:hetionet NCBIGene:10058 biolink:causes MONDO:0012204 infores:monarchinitiative not_provided not_provided HGNC:47 MONDO:0012204 uuid:29488e39-a353-48ef-aec3-d332f1dbaaf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:340024 biolink:causes MONDO:0009324 infores:monarchinitiative not_provided not_provided HGNC:27960 MONDO:0009324 uuid:b3d29f32-d5b3-498a-bb5b-1b162e7b464e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0016242 infores:hetionet NCBIGene:83544 biolink:causes MONDO:0013525 infores:monarchinitiative not_provided not_provided HGNC:23247 MONDO:0013525 uuid:35d6e102-dd87-4f52-85fb-6172c649adc8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0003467 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0549452 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549452 infores:hetionet CHEBI:63598 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151579 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0030305 infores:hetionet CHEBI:3127 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0917801 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233794 infores:hetionet CHEBI:4877 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0018681 infores:hetionet NCBIGene:29954 biolink:causes MONDO:0013160 infores:monarchinitiative not_provided not_provided HGNC:19743 MONDO:0013160 uuid:0dbf061f-2a6c-4058-9021-d883b5b88e7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0033845 infores:hetionet CHEBI:50663 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0232461 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0036572 infores:hetionet CHEBI:3655 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0522153 infores:hetionet CHEBI:63631 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085628 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1096300 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1096300 infores:hetionet CHEBI:7577 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0039070 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0007412 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0007412 uuid:4a79f952-437b-420c-9db8-9e6f0b76b02b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085633 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0851341 infores:hetionet CHEBI:3223 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0021177 infores:hetionet CHEBI:127342 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027424 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0574002 infores:hetionet CHEBI:4530 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0003467 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0086543 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0022408 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0034065 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020456 infores:hetionet CHEBI:15544 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020440 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0021400 infores:hetionet CHEBI:15544 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0016059 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0948594 infores:hetionet CAID:CA304067345 biolink:causes MONDO:0012999 infores:clingen CAID:CA304067345 MONDO:0012999 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_000156.6:c.54C>T (p.Pro18=) variant in GAMT is a synonymous variant in exon 1 which is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). The highest population minor allele frequency in a continental population of >2,000 alleles is 0.00008 in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004). The site is covered in fewer than 50% of individuals in gnomAD v2.1.1 exomes, and therefore the allele frequency estimates may not be reliable but PM2_Supporting. This variant does not appear to have been previously reported in the published literature. However, it is noted in ClinVar (Variation ID: 696471). Although this variant may be rare, it has been classified as likely benign by the ClinGen CCDS VCEP based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GAMT-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA304067345/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:68584 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0151907 infores:hetionet CHEBI:2611 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0004093 infores:hetionet CHEBI:64355 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0016867 infores:hetionet CHEBI:51141 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0030193 infores:hetionet CHEBI:71223 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0011175 infores:hetionet CHEBI:15365 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0015230 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0687133 infores:hetionet CHEBI:4046 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0036974 infores:hetionet CHEBI:9137 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011071 infores:hetionet NCBIGene:200205 biolink:causes MONDO:0014644 infores:monarchinitiative not_provided not_provided HGNC:27302 MONDO:0014644 uuid:6dd24d58-b3ef-4082-a7c1-13d878d98ed4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0853149 infores:hetionet CHEBI:6950 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0428977 infores:hetionet CHEBI:71940 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0007222 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0020517 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085614 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0162429 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0015397 infores:hetionet CHEBI:168396 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0008031 infores:hetionet CHEBI:27999 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0022354 infores:hetionet CHEBI:6121 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0037036 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027441 infores:hetionet CAID:CA404080610 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080610 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP3, PS3, PS4, PS2, PS1, BS1, BS3, BS4, PM4, PM1, PM5, PM6, PVS1, PP1, PP4, BS2 The NM_000527.5(LDLR):c.844T>C (p.Phe282Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.985. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080610/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:64064 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0042029 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020651 infores:hetionet CHEBI:8764 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018188 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0006277 infores:hetionet CAID:CA343772391 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772391 MONDO:0013144 PMID: Pathogenic PS4, PP1_Strong, PP3 BS1, PM2 The c.1311C>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 437 (p.Asn437Lys). The computational predictor REVEL gives a score of 0.683, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. The variant has been reported in at least 8 probands with AT deficiency in the literature (7.5 points applied PMID 28300866; PMID 24684277; PMID 12755798; PMID 1469094). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 7 affected family meioses from 4 families (PP1_strong; PMID: 1469094; PMID: 12755798; PMID: 28300866). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_Strong, PS4, PP3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772391/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27470 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0036572 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0001339 infores:hetionet CHEBI:17263 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0004096 infores:hetionet CHEBI:127780 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0235896 infores:hetionet CAID:CA322328053 biolink:causes MONDO:0021060 infores:clingen CAID:CA322328053 MONDO:0021060 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PVS1_Moderate BA1, BS1 The c.1149+1G>T variant in LZTR1 occurs within the canonical splice donor site (+1) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/21, resulting in an in-frame deletion (removes amino acids 332-383) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The filtering allele frequency (the upper threshold of the 95% CI of 1/34210) of the c.1149+1G>A variant in LZTR1 is 0 for Admixed American chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in 3 individuals with RASopathy. Of those individuals, all were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by parental testing (c.1339T>G (p.Phe447Val), c.993+1G>A, c.27delG p.Q10fs, 2.25 PM3 points, PMID: 29469822, SCV000620457.7, GeneDx) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM3_Strong, PVS1_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA322328053/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:91583 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0013144 infores:hetionet CHEBI:71255 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0041657 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0005586 infores:hetionet CAID:CA024593 biolink:causes MONDO:0007783 infores:clingen CAID:CA024593 MONDO:0007783 PMID: Pathogenic BS2, PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 2163 of the RYR1 protein, p.(Arg2163His). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 16 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 14 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:9497245, PMID:21455645, PMID:15731587, PMID:23558838). This variant has been identified in three individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). Additional functional studies in dyspedic myotubes were published for this variant, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:12732639, PMID:15347586). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in seven families, PP1_Strong (PMID:30236257, PMID:9497245). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024593/MONDO:0007783/012 2022-03-29 2022-03-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6909 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1384353 infores:hetionet CHEBI:3387 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018790 infores:hetionet CHEBI:32293 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0041657 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0018500 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042514 infores:hetionet CAID:CA397723118 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723118 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 PM3 The c.541dup (p.His181fs)variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed enzyme activity levels measured in lymphocytes of 6% of control values, which is highly specific for VLCAD deficiency (PP4_moderate, PMID 32463482). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied,as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM2_supporting. VCEP specifications version2; 10/15/21. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723118/MONDO:0008723/021 2022-03-08 2022-04-28 Autosomal recessive inheritance HP:0000007 Supports GO:0072043 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072028 CHEBI:47898 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1142499 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042373 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0221392 infores:hetionet UMLS:C0879264 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0014591 infores:hetionet CHEBI:10124 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0002962 infores:hetionet CHEBI:404903 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0549249 infores:hetionet CHEBI:6759 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0018681 infores:hetionet CHEBI:41423 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018524 infores:hetionet CHEBI:94848 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0015672 infores:hetionet CHEBI:8327 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0085631 infores:hetionet CHEBI:27504 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0020538 infores:hetionet CHEBI:4779 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0020452 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0020651 infores:hetionet NCBIGene:253827 biolink:causes MONDO:0013386 infores:monarchinitiative not_provided not_provided HGNC:27375 MONDO:0013386 uuid:d4a4fd73-94c2-47c3-b98d-591aa0b2f1da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1901626 biolink:causes GO:0099173 infores:ubergraph knowledge_assertion manual_agent GO:1901626 GO:0099173 CHEBI:8428 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C1320835 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0039520 infores:hetionet CHEBI:59560 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0015967 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0030312 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0235431 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0025061 infores:hetionet CHEBI:32221 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0004096 infores:hetionet CHEBI:6472 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0014868 infores:hetionet CHEBI:5128 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0022107 infores:hetionet GO:0110037 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0110037 GO:0007275 CAID:CA10603803 biolink:causes MONDO:0015152 infores:clingen CAID:CA10603803 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.4090C>T p.(Gln1364Ter) variant in DYSF, which is also known as NM_001130987.2: c.4144C>T (p.Gln1382Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 38/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two patients with features of LGMD (PMID: 30564623; 36983702; 24488599; 27602406; LOVD Individual #00219787), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.5296G>A p.(Glu1766Lys), 1.0 pt, PMID: 36983702; 24488599; 27602406) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent or severely reduced dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). The highest population allele frequency for this variant is 0.0000008474 (1/1180034 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/21/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603803/MONDO:0015152/180 2025-04-21 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:82716 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0546817 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0012833 infores:hetionet CHEBI:64312 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085593 infores:hetionet CAID:CA10585364 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585364 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2 The NM_000527.5(LDLR):c.1223A>T (p.Glu408Val) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PP1_Moderate, PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis (data from 3 families: F1 - 2 affected family members have the variant, F2 - 2 affected family members have the variant, F3 - 1 affected family member has the variant) from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PP1_Moderate is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PS4_moderate - variant meets PM2 and was identified in 6 unrelated index cases, all fulfilling Simon-Broome criteria of definite FH, from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PS4_Moderate is met.PP3 - REVEL = 0.908. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 6 unrelated index cases (see details in PS4), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585364/MONDO:0007750/013 2021-12-16 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:135342 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0017675 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0152227 infores:hetionet CHEBI:40279 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0231528 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2129214 infores:hetionet CHEBI:16796 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0235660 infores:hetionet CHEBI:2904 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0042571 infores:hetionet CHEBI:64355 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0743400 infores:hetionet CAID:CA10014578 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014578 MONDO:0011071 PMID:23817177 Benign BP2, BA1, BS3 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BP7, BS4, BS1, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID: 23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BS3, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014578/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0028643 infores:hetionet CHEBI:9654 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0036974 infores:hetionet CHEBI:16469 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0003862 infores:hetionet NCBIGene:2936 biolink:causes MONDO:0019531 infores:monarchinitiative not_provided not_provided HGNC:4623 MONDO:0019531 uuid:11c737ba-5494-41e0-9180-98b2c06c2e3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0858635 infores:hetionet CHEBI:43968 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0042963 infores:hetionet CHEBI:8768 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C3665347 infores:hetionet CHEBI:27436 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0027497 infores:hetionet CHEBI:10650 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013390 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0855242 infores:hetionet CAID:CA7435542 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435542 MONDO:0007113 PMID: Uncertain Significance PP4, PS2 PM2, PP3, BA1, PS4, BS1 "The c.1310G>A (p.Arg437Gln) variant in the UBE3A gene has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with clinical features of Angelman syndrome and the described phenotype meets PP4 criteria (PS2, PP4; GeneDx: internal database). The p.Arg437Gln variant has been reported in 1 additional proband with a neurodevelopmental phenotype consistent with Angelman syndrome. However, PS4 cannot be applied because PM2 does not apply (PS4_not met). The highest population minor allele frequency of the p.Arg437Gln variant in UBE3A in gnomAD v4.1 is 0.00003 in ""Remaining"" populations (not sufficient to meet BS1 criteria). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.329). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Angelman syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Rett and Angelman-like Disorders VCEP (PS2, PP4). (UBE3A specifications version 4.0; 02/28/2025)." Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435542/MONDO:0007113/037 2025-02-28 2025-03-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5558 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0033774 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0027726 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0919567 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0919567 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013595 infores:hetionet CHEBI:101853 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0860864 infores:hetionet CHEBI:8871 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0240717 infores:hetionet NCBIGene:2294 biolink:causes MONDO:0009934 infores:monarchinitiative not_provided not_provided HGNC:3809 MONDO:0009934 uuid:b49cee07-5211-452a-85e1-2466fd3bde28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0002268 biolink:causes CL:0000442 infores:ubergraph knowledge_assertion manual_agent GO:0002268 CL:0000442 UNII:T58MSI464G biolink:causes HP:0002584 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0267373 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0019158 infores:hetionet CHEBI:39867 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1167709 infores:hetionet CHEBI:8356 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0028081 infores:hetionet CHEBI:49713 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0026826 infores:hetionet CHEBI:75722 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0858635 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0456909 infores:hetionet NCBIGene:2512 biolink:causes MONDO:0011638 infores:monarchinitiative not_provided not_provided HGNC:3999 MONDO:0011638 uuid:b73251e6-7b57-4b60-8212-e1513a3d7d1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3U02EL437C biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0237849 infores:hetionet CHEBI:4681 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0002962 infores:hetionet CHEBI:49662 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0231218 infores:hetionet CHEBI:3127 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0016655 infores:hetionet CHEBI:64028 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0015672 infores:hetionet CAID:CA16020715 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020715 MONDO:0009861 PMID:26503515PMID:26322415PMID:26322415 Pathogenic PVS1, PM2, PP4_Moderate, PM3_Supporting The PAH: c.30_31insC variant is a frameshift variant occurring in exon 1 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). The variant has been previously reported with the known pathogenic p.R243Q allele (PM3-supporting, no parental analysis reported) in 1 Chinese case with classic PKU (PMID: 26322415), as assessed by plasma Phe levels; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4_Moderate). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020715/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15552 biolink:causes MONDO:0006795 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020532 infores:hetionet CHEBI:47780 biolink:causes HP:0002519 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233773 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0035455 infores:hetionet NCBIGene:2071 biolink:causes MONDO:0012531 infores:monarchinitiative not_provided not_provided HGNC:3435 MONDO:0012531 uuid:7f2a3dd3-4547-407d-90a2-ccca6089c3b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:125354 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0013404 infores:hetionet CHEBI:5147 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0162297 infores:hetionet CHEBI:127780 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0001122 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0521839 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0221165 infores:hetionet CHEBI:5613 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0033774 infores:hetionet CHEBI:6759 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0025289 infores:hetionet CAID:CA10014554 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014554 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.300C>T (p.Ser100=) is a synonymous variant that is not predicted to impact splicing. Since it is a synonymous variant, there is no REVEL score, and SpliceAI is ≤ 0.20 (0.01 33bp Donor Gain) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.302402 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014554/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0071542 biolink:causes CL:0000700 infores:ubergraph knowledge_assertion manual_agent GO:0071542 CL:0000700 CHEBI:29013 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1306341 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0002170 infores:hetionet CHEBI:16796 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0151766 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0019158 infores:hetionet CHEBI:8245 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0149931 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0007682 infores:hetionet CAID:CA404764797 biolink:causes MONDO:0010938 infores:clingen CAID:CA404764797 MONDO:0010938 PMID: Likely Pathogenic PVS1, PM2_Supporting PM5 The c.2989G>T (p.Glu997Ter) (NM_000215.4) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 22/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_supporting).In summary, this variant is classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PVS1. (VCEP specifications version 2.1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA404764797/MONDO:0010938/121 2025-10-31 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7936 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021177 infores:hetionet CAID:CA2825002848 biolink:causes MONDO:0011071 infores:clingen CAID:CA2825002848 MONDO:0011071 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.465_467dup (p.Ala156dup) is an in-frame duplication which affects a residue within the Runt Homology Domain (AA 89-204) but does not affect an established hotspot residue (PM4_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2825002848/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5959 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0014518 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0024205 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0271420 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0271420 infores:hetionet NCBIGene:8402 biolink:causes MONDO:0032767 infores:monarchinitiative not_provided not_provided HGNC:10981 MONDO:0032767 uuid:79286b09-7258-4aa8-98d4-c1819075a09e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151904 infores:hetionet CHEBI:31236 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162285 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0015397 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0027339 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151885 infores:hetionet CHEBI:9434 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0008031 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0002871 infores:hetionet CHEBI:83527 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0151766 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0233472 infores:hetionet CHEBI:63611 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151539 infores:hetionet CHEBI:6761 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0011991 infores:hetionet NCBIGene:339829 biolink:causes MONDO:0013434 infores:monarchinitiative not_provided not_provided HGNC:25244 MONDO:0013434 uuid:b878c903-81e2-44ef-8292-ed77d2f18555 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0018965 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0021400 infores:hetionet GO:0006954 biolink:causes HP:0012532 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D059350 DB00861_MESH_D059350_1 UMLS:C0025241 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0017178 infores:hetionet CHEBI:6062 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0041657 infores:hetionet CHEBI:80630 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0085593 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020538 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0342579 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0428977 infores:hetionet UMLS:C0657912 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151786 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0948349 infores:hetionet CHEBI:4877 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0340865 infores:hetionet NCBIGene:84839 biolink:causes MONDO:0859308 infores:monarchinitiative not_provided not_provided HGNC:18286 MONDO:0859308 uuid:28ac1183-a9d2-490e-8873-0965d809e19c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7445 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0520589 infores:hetionet CHEBI:8378 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0003811 infores:hetionet CHEBI:391960 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0043352 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0003123 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0004936 infores:hetionet NCBIGene:6663 biolink:causes MONDO:0012698 infores:monarchinitiative not_provided not_provided HGNC:11190 MONDO:0012698 uuid:a544e706-3930-475d-b1ae-3d928723fc9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0018965 infores:hetionet NCBIGene:55325 biolink:causes MONDO:0060702 infores:monarchinitiative not_provided not_provided HGNC:25640 MONDO:0060702 uuid:9615f2e5-0af6-49b9-89e1-27dd85670706 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28001 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0014457 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0521839 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0155169 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0425945 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0701836 infores:hetionet NCBIGene:2645 biolink:causes MONDO:0011236 infores:monarchinitiative not_provided not_provided HGNC:4195 MONDO:0011236 uuid:f37afc85-5283-4ed1-806e-b645640111db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0011168 infores:hetionet CHEBI:3515 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0010200 infores:hetionet CHEBI:18295 biolink:causes GO:0071420 infores:drugmechdb knowledge_assertion manual_agent MESH:D006632 GO:0071420 DB07615_MESH_D001249_1DB00885_MESH_D003233_1DB00885_MESH_D001249_1DB00885_MESH_D065631_1DB07615_MESH_D065631_1DB07615_MESH_D003876_1DB07615_MESH_D017439_1DB07615_MESH_D007627_1DB00768_MESH_D003233_1DB00768_MESH_D065631_1DB00768_MESH_D006255_1 CHEBI:5790 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013384 infores:hetionet CAID:CA891844470 biolink:causes MONDO:0011071 infores:clingen CAID:CA891844470 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS3, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The c.166_193dup (p.Ala65Valfs*82) variant is a 28-bp duplication causing a frameshift that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2.1.1 and v3) with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported in FPD/AML patients in the literature to the best of our knowledge; however one patient meeting RUNX1-phenotype criteria is reported from a clinical laboratory (PS4_Supporting; SCV000820350.2). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844470/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:2316 biolink:causes MONDO:0024550 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0024550 uuid:6311794e-8309-4dc4-8edb-ba90f3818b8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10568547 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568547 MONDO:0010602 PMID: Uncertain Significance BS1 PM5, PP3, BP4 The c.748A>G variant in F8 is a missense variant predicted to cause substitution of methionine by valine at amino acid 250 (p.Met250Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004277 (12/28057 alleles) in the Admixed American population and the Grpmax Filtering AF is 0.0002519 (exomes), which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>0.0000333) for BS1, and therefore meets this criterion (BS1). In summary, due to insufficient evidence, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP (version 1.0.0, released 10/5/2023): BS1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568547/MONDO:0010602/071 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Inconclusive true CHEBI:70746 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0438717 infores:hetionet GO:1905005 biolink:causes GO:0003272 infores:ubergraph knowledge_assertion manual_agent GO:1905005 GO:0003272 CHEBI:64354 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0085593 infores:hetionet CHEBI:8707 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151827 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0014868 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0031117 infores:hetionet CHEBI:83531 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0030252 infores:hetionet CHEBI:8597 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0018681 infores:hetionet CHEBI:84500 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1456784 infores:hetionet CHEBI:8356 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003467 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0948594 infores:hetionet GO:1902890 biolink:causes GO:0048364 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0048364 CHEBI:3723 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0847033 infores:hetionet CHEBI:49575 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0039070 infores:hetionet CHEBI:15553 biolink:causes EFO:0020915 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0269842 infores:hetionet CHEBI:6149 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0023052 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0423773 infores:hetionet CHEBI:72564 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0015672 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0004936 infores:hetionet CHEBI:31709 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0220870 infores:hetionet CHEBI:231425 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020625 infores:hetionet CHEBI:3478 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0042963 infores:hetionet CHEBI:135929 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C1735601 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0011609 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0860160 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0860160 infores:hetionet CHEBI:2618 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0259799 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018799 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0349231 infores:hetionet CHEBI:142290 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0206061 infores:hetionet CHEBI:7573 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0042029 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0595862 infores:hetionet CHEBI:17347 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0277890 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002311 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0154833 infores:hetionet CAID:CA16020958 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020958 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 The NM_000277.3(PAH):c.1177_1178insT (p.Asn393IlefsTer2) frameshift variant has not been reported in the literature to our knowledge. This frameshift variant is in exon 11 where it creates a premature stop codon, which is predicted to result in NMD and is absent from population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1 and PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020958/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2955 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C3665347 infores:hetionet CHEBI:6887 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C2363730 infores:hetionet CHEBI:44032 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0018965 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0005952 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D012541 DB00417_MESH_D012541_1DB09320_MESH_D012541_1DB01053_MESH_D012541_2DB01053_MESH_D012541_1 CHEBI:3215 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0085612 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0520559 infores:hetionet CHEBI:3223 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020578 infores:hetionet CHEBI:3082 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0028643 infores:hetionet CHEBI:30659 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0016927 infores:hetionet CHEBI:46295 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0007222 infores:hetionet CHEBI:49040 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0852911 infores:hetionet CHEBI:9130 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0033774 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0740425 infores:hetionet CHEBI:3738 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0009946 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0002170 infores:hetionet CHEBI:681569 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0042963 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013395 infores:hetionet CHEBI:145499 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003811 infores:hetionet UMLS:C0145867 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0013604 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0032285 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0520588 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020615 infores:hetionet CHEBI:48538 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0009938 infores:hetionet CHEBI:8707 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006152 infores:hetionet NCBIGene:2248 biolink:causes MONDO:0012541 infores:monarchinitiative not_provided not_provided HGNC:3681 MONDO:0012541 uuid:6b1f0fce-bc5a-406a-8969-b8a9792cb41b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7573 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0013395 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0040034 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0232492 infores:hetionet CHEBI:94609 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0002871 infores:hetionet CHEBI:3479 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0042267 infores:hetionet CHEBI:10100 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0011991 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0948586 infores:hetionet CHEBI:71219 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0085649 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030517 infores:hetionet CHEBI:61390 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0022568 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0006266 infores:hetionet CHEBI:3723 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0035410 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0852203 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0852203 infores:hetionet CHEBI:6149 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0033774 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0006325 infores:hetionet CHEBI:9943 biolink:causes HP:0030804 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0546956 infores:hetionet CHEBI:7465 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0020458 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0151786 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013595 infores:hetionet CHEBI:46557 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042023 infores:hetionet CHEBI:7627 biolink:causes UMLS:C3544094 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C3544094 infores:hetionet CHEBI:50378 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0035229 infores:hetionet CHEBI:9448 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0015230 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085762 infores:hetionet CHEBI:3213 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0015230 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041582 infores:hetionet CHEBI:8874 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0423791 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027651 infores:hetionet CHEBI:10023 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0037763 infores:hetionet CHEBI:2788 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0237314 infores:hetionet CHEBI:51137 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0039070 infores:hetionet CHEBI:16335 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0039239 infores:hetionet GO:2000702 biolink:causes GO:0016331 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0016331 CHEBI:100241 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1142412 infores:hetionet CHEBI:51364 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0039070 infores:hetionet CHEBI:63612 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0004134 infores:hetionet CHEBI:6741 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0003862 infores:hetionet CAID:CA10604967 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604967 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting PM4, PM1, PM5, PVS1, PM6, BP1, BP4, BP3, BP2, BA1, BS2, PP2, PP1, BP5, BP7, BS1, BS3, BS4, PS3, PS1, PS4, PS2 The NM_000070.3: c.633G>C variant in CAPN3 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 211 (p.Lys211Asn). This variant has been detected in at least nine individuals with limb girdle muscular dystrophy (PMID: 16411092, 20694146, 18055493, 18334579, 16141003, 30564623; LOVD CAPN3_000437; Washington University internal clinic data communication), including two observations in unknown phase with a variant classified as at least likely pathogenic (c.1319G>A p.(Arg440Gln), 0.5 pts, PMID: 18334579, 18055493, 20694146). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18055493, 20694146). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.859, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604967/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10127 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0549249 infores:hetionet NCBIGene:147372 biolink:causes MONDO:0009337 infores:monarchinitiative not_provided not_provided HGNC:29426 MONDO:0009337 uuid:cd979163-83e6-4de1-8137-13602d246e16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013415 infores:hetionet CHEBI:29688 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0311468 infores:hetionet CHEBI:9763 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0019521 infores:hetionet CHEBI:16796 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0037036 infores:hetionet CHEBI:3011 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0039070 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0031350 infores:hetionet CHEBI:10110 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0149745 infores:hetionet CHEBI:63617 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0021177 infores:hetionet CHEBI:6715 biolink:causes MONDO:0007500 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0266589 infores:hetionet NCBIGene:650 biolink:causes MONDO:0100297 infores:monarchinitiative not_provided not_provided HGNC:1069 MONDO:0100297 uuid:839423c8-a2d4-4d80-8968-55a6349fa107 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853697 infores:hetionet CHEBI:46195 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0036974 infores:hetionet GO:0060622 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0060622 GO:0051321 GO:1904717 biolink:causes GO:0001941 infores:ubergraph knowledge_assertion manual_agent GO:1904717 GO:0001941 CHEBI:31174 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0241136 infores:hetionet CAID:CA410207207 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207207 MONDO:0011071 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PP3 PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM5, PM1, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.619C>T (p.Arg207Trp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.8109, PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000436615.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_supporting, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207207/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31413 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0085631 infores:hetionet CHEBI:28787 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0004093 infores:hetionet CHEBI:8081 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0027424 infores:hetionet CHEBI:421707 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0013415 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0521839 infores:hetionet CAID:CA10014385 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014385 MONDO:0011071 PMID: Uncertain Significance PS4, PS2, PS1, PS3, BP1, BP4, BP2, BP3, BA1, PM2, PVS1, PM6, BS1, BS4, BS3, BP5, BP7, PM3, PM5, PM1, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014385/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA120647 biolink:causes MONDO:0044970 infores:clingen CAID:CA120647 MONDO:0044970 PMID:15466014 Likely Pathogenic PP1_Moderate, PS3_Supporting, PM2_Supporting, PS4_Moderate PM5, PM4, BP4, PS1, PS2, PVS1, PM6 The m.3697G>A (p.G131S) variant in MT-ND1 has been reported in at least 14 individuals with primary mitochondrial disease from 8 families. Affected individuals had onset ranging from the first week of life to adulthood; and with features variably consistent with Leigh syndrome, MELAS, and LHON (PS4_moderate; PMIDs: 31996177, 30623604, 28429146, 24830958, 18977334, 17562939, 15466014). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 24830958, 17562939, 16969869, 15466014). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Functional studies supported the deleterious impact of this variant (PS3_supporting; PMID: 15466014). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4_moderate, PM2_supporting, PP1_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120647/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:135939 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0575081 infores:hetionet CAID:CA512341270 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341270 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1149G>T (p.Pro383=) is a synonymous variant that is not predicted to impact splicing. This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.254)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341270/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8871 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0702166 infores:hetionet NCBIGene:5610 biolink:causes MONDO:0030513 infores:monarchinitiative not_provided not_provided HGNC:9437 MONDO:0030513 uuid:6edaebdb-6480-46fb-9f07-da8af77c2e24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3175 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C2939147 infores:hetionet CHEBI:4710 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0019048 infores:hetionet CHEBI:8871 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004134 infores:hetionet CHEBI:3380 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0022346 infores:hetionet CHEBI:9943 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0043352 infores:hetionet CHEBI:94501 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0043352 infores:hetionet CHEBI:28925 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0242528 infores:hetionet CHEBI:4511 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151905 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011334 infores:hetionet CAID:CA915946393 biolink:causes MONDO:0100216 infores:clingen CAID:CA915946393 MONDO:0100216 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3 BA1, BP4, BP2, BS2, PP1, PP4, PM1, PS1, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.2256+5G>C variant in DICER1 is an intronic variant which is located in intron 14, 5 nucleotides downstream from exon 14. This variant received a total of 1 phenotype point across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributors). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PM2_Supporting, PS3, PP3. (Bayesian Points: 7; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946393/MONDO:0100216/024 2025-02-25 2025-06-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3504 biolink:causes UMLS:C0581395 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0581395 infores:hetionet CAID:CA6748769 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748769 MONDO:0009861 PMID: Uncertain Significance PM2 PP3 The c.1002C>T (p.Cys334=) variant in PAH has not been reported in the literature to our knowledge. This variant has an extremely low frequency in ExAC, gnomAD, and ESP (MAF=0.00004). Multiple lines of computational evidence are conflicting regarding splicing impact (Potential alteration of splicing in HSF, TraP=0.058). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748769/MONDO:0009861/006 2020-01-26 2020-01-31 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3207 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0029456 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0020517 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0233459 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0553732 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0851341 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0007787 infores:hetionet CHEBI:474180 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0023066 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0002871 infores:hetionet NCBIGene:841 biolink:causes MONDO:0011804 infores:monarchinitiative not_provided not_provided HGNC:1509 MONDO:0011804 uuid:66b3e9bb-9fe4-4124-b291-972c3339d990 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0234930 infores:hetionet CHEBI:253342 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0037763 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0022354 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0232409 infores:hetionet CHEBI:77260 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235857 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0947999 infores:hetionet CHEBI:8805 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0035455 infores:hetionet CHEBI:6792 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0344232 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0233494 infores:hetionet CHEBI:6339 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040822 infores:hetionet CHEBI:45409 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0392525 infores:hetionet CAID:CA341584 biolink:causes MONDO:0015967 infores:clingen CAID:CA341584 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM3, PVS1, PM2_Supporting PP4 The c.1019+2T>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. It is predicted to cause an in-frame deletion of biologically-relevant exon 8 of 10, removing an important region of the protein (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 8 informative meioses in a family with MODY (PP1_Strong; PMID 16026363). This variant was identified individuals with diabetes; however, there was insufficient clinical information to evaluate for PP4. This variant has been detected in at least 2 individuals with neonatal diabetes. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans by parental/family testing (PMID 16026363). 1 individual was homozygous for the variant (PMID 16026363) (PM3). In summary, the evidence supports the classification of c.1019+2T>G as a pathogenic variant for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PVS1, PM3, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA341584/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Supports CHEBI:50173 biolink:causes UMLS:C0521854 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0521854 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0009450 infores:hetionet CAID:CA8815294 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815294 MONDO:0009290 PMID: Likely Benign BP4, BS1 PP4, PM3 The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg).The highest population minor allele frequency in gnomAD v4.1.0 is 0.004835 (363/75080) alleles, including 4 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID: 29149851). The variant was also reported in a patient with autism spectrum disorder but no reported diagnosis of Pompe disease (PMID: 37492102). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert panel on May 20, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815294/MONDO:0009290/010 2025-05-20 2025-05-20 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:75998 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0042029 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013447 infores:hetionet CHEBI:3013 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0009806 infores:hetionet CHEBI:6367 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004093 infores:hetionet CHEBI:6062 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020473 infores:hetionet CHEBI:42944 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011603 infores:hetionet CHEBI:15367 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151632 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235639 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002342 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007302 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0235431 infores:hetionet CHEBI:5050 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0010200 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0338908 infores:hetionet CHEBI:31643 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0030554 infores:hetionet NCBIGene:7358 biolink:causes MONDO:0032918 infores:monarchinitiative not_provided not_provided HGNC:12525 MONDO:0032918 uuid:c155446a-938a-4b54-88dc-7a5b61cb4c76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C1384353 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0029443 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0000772 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0000772 infores:hetionet CHEBI:31536 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0018681 infores:hetionet CHEBI:135351 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0392676 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0232492 infores:hetionet CHEBI:3696 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020461 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0011603 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0008325 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0020517 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0497247 infores:hetionet CHEBI:10125 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0043387 infores:hetionet CHEBI:6073 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0020580 infores:hetionet CHEBI:71255 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0022107 infores:hetionet CHEBI:5147 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C3665347 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0021845 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0268948 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0268948 infores:hetionet CHEBI:3215 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235086 infores:hetionet CHEBI:4717 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0041657 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003366 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1253936 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0853330 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0853330 infores:hetionet CHEBI:45863 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085633 infores:hetionet CHEBI:8455 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0027497 infores:hetionet CHEBI:7565 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0152031 infores:hetionet CHEBI:87681 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0011615 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151736 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0006145 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0560024 infores:hetionet CHEBI:92712 biolink:causes HP:0011841 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0152173 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0011570 infores:hetionet CHEBI:3515 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0262988 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0268000 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0013395 infores:hetionet CHEBI:63630 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0149745 infores:hetionet CHEBI:9139 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020473 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001703 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0242225 infores:hetionet CHEBI:72564 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1510410 infores:hetionet CAID:CA392343534 biolink:causes MONDO:0007947 infores:clingen CAID:CA392343534 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1, PM5 The NM_00138 c.1468G>T is a missense variant in FBN1 predicted to cause a substitution of a aspartic acid by tyrosine at amino acid 490 (p.Asp490Tyr). This variant impacts an aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (PMID 35058154, internal lab data, PP4). This variant has been reported three times in ClinVar: twice as pathogenic and once as uncertain significance (Variation ID: 549019). This variant has also been identified in at least 2 individuals with a clinical diagnosis of MFS as well as in an individual with clinical features of MFS (PMID 11826022, 20886638, Invitae ClinVar entry; PS4_Mod). A different missense variant at this position, c.1468G>C (p.Asp490His), has previously been previously established as (likely) pathogenic and has been found in at least 3 individuals with clinical features of MFS and was found to segregate with disease (PMID 25652356, internal data; PM5), Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.965, PP3). This variant is located in the last nucleotide of the exon. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_Moderate, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392343534/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8077 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0027424 infores:hetionet CHEBI:63115 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0018681 infores:hetionet CHEBI:2618 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0700590 infores:hetionet CHEBI:61049 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151907 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020514 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0549405 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0948594 infores:hetionet CHEBI:49662 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0234233 infores:hetionet CHEBI:18248 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0023518 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0475858 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017160 infores:hetionet CHEBI:465284 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0009676 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235750 infores:hetionet CHEBI:29007 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0013604 infores:hetionet CHEBI:7773 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0014742 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018790 infores:hetionet CHEBI:15553 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085631 infores:hetionet CAID:CA251620 biolink:causes MONDO:0021056 infores:clingen CAID:CA251620 MONDO:0021056 PMID: Pathogenic PVS1, PS2, PS4, PM2_Supporting The c.1311_1312+1del variant in APC occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of exon 10, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in a family with FAP and CHRPE (father [index] and two affected children), resulting in a total phenotype score of 1 (PS4_supporting). The variant occurred de novo in the index patient (paternity/ maternity confirmed; PS2). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS2, PS4_supporting and PM2_supporting (VCEP specifications version 1; date of approval: 10/12/22). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA251620/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:472657 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0019080 infores:hetionet NCBIGene:6263 biolink:causes MONDO:0957215 infores:monarchinitiative not_provided not_provided HGNC:10485 MONDO:0957215 uuid:73bff906-47ec-4163-b24d-ee79e439bb67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0019348 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0038663 infores:hetionet GO:0106088 biolink:causes GO:0002040 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0002040 CHEBI:8232 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0014457 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0151828 infores:hetionet CHEBI:8874 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0033036 infores:hetionet CHEBI:36795 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013604 infores:hetionet CAID:CA16608642 biolink:causes MONDO:0008723 infores:clingen CAID:CA16608642 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM3, PVS1_Moderate, PP4_Moderate PM5 The c.1843C>T (p.Arg615Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove about 10% of the protein from the C-terminus (PVS1_Moderate; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also detected and confirmed in-trans with the likely pathogenic p.Glu130del in a patient with VLCAD-deficiency (PM3, PMID:10431122). The patient with this variant also displayed elevated C14:1, which is highly specific for Very long chain acyl coenzyme A dehydrogenase deficiency (PP4_moderate, PMID:10431122). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on: PVS1_moderate+PM3+PM2_supporting+PP4_moderate. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608642/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45783 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162429 infores:hetionet CHEBI:8232 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0026827 infores:hetionet CHEBI:50861 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0011175 infores:hetionet NCBITaxon:1773 biolink:causes MONDO:0006042 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1773 MESH:D014390 DB00339_MESH_D014390_1 CHEBI:135888 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0015403 infores:hetionet NCBIGene:5119 biolink:causes MONDO:0013990 infores:monarchinitiative not_provided not_provided HGNC:8740 MONDO:0013990 uuid:767740c1-2f70-4f88-9c90-fe39f464325f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0424109 infores:hetionet CHEBI:46081 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151905 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0032285 infores:hetionet CHEBI:53766 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0232462 infores:hetionet CHEBI:520985 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0004604 infores:hetionet CHEBI:144551 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0040264 infores:hetionet NCBIGene:2626 biolink:causes MONDO:0013747 infores:monarchinitiative not_provided not_provided HGNC:4173 MONDO:0013747 uuid:0bcc8c1f-bc2b-4c4e-82cf-d53a0738356c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4636 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0039231 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0040034 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0558368 infores:hetionet CHEBI:3698 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C1565489 infores:hetionet CHEBI:75722 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233514 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0232492 infores:hetionet CAID:CA410148812 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148812 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting BP1, BP3, BP5, PM3, PP2, PP4, BS2 NM_001754.5(RUNX1):c.978C>G (p.Asp326Glu) is a missense variant which is absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score <0.50 (0.075) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148812/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10588544 biolink:causes MONDO:0015967 infores:clingen CAID:CA10588544 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PM5, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 The c.811C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 271 (p.(Arg271Trp) of transcript, e.g. NM_000545.8. This variant was identified in over 26 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with at least four informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated the p.Arg271Trp protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 21170474) (PS3_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Another missense variant, c. 812G>A (p.Arg271Gln), has been interpreted as pathogenic by the ClinGen MDEP and p. Arg271Trp has a greater Grantham distance (PM5). The variant was identified in at least 8 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate). This variant failed QC in gnomAD v2.1.1. The variant was absent other than two heterozygotes filtered out due to poor quality which even if real would place the frequency below the ClinGen MDEP cutoff for PM2_Supporting (PM2_Supporting). Lastly, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.814C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PS4, PP1_Strong, PS3_Supporting, PM1, PM5, PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588544/MONDO:0015967/017 2022-04-14 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4445 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0239571 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1442903 infores:hetionet CHEBI:41423 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0392525 infores:hetionet CHEBI:63620 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085632 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0409962 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0409962 infores:hetionet CHEBI:9654 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0231528 infores:hetionet NCBIGene:81624 biolink:causes MONDO:0012196 infores:monarchinitiative not_provided not_provided HGNC:15480 MONDO:0012196 uuid:e057b445-54b8-49f3-8930-90f7beda9cf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0235437 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018801 infores:hetionet CHEBI:8346 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0278134 infores:hetionet CHEBI:63717 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0019209 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0029408 infores:hetionet NCBIGene:990 biolink:causes MONDO:0013432 infores:monarchinitiative not_provided not_provided HGNC:1744 MONDO:0013432 uuid:448bb201-8db1-473e-903e-f76456bb3737 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6970 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0151514 infores:hetionet CHEBI:5138 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019079 infores:hetionet CHEBI:5165 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0043352 infores:hetionet CHEBI:63638 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0424295 infores:hetionet CHEBI:6822 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0009676 infores:hetionet CHEBI:7931 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0162298 infores:hetionet CHEBI:66901 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0043144 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0009938 infores:hetionet CHEBI:79699 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0149871 infores:hetionet CHEBI:4792 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0003811 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0009938 infores:hetionet CHEBI:31622 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0018681 infores:hetionet CHEBI:48273 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0043144 infores:hetionet CHEBI:7798 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0038325 infores:hetionet CHEBI:31397 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0027441 infores:hetionet CHEBI:50648 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020672 infores:hetionet CHEBI:6438 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0006266 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020557 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0036572 infores:hetionet CHEBI:135530 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0239340 infores:hetionet NCBIGene:5663 biolink:causes MONDO:0008243 infores:monarchinitiative not_provided not_provided HGNC:9508 MONDO:0008243 uuid:568db652-bc3d-44bb-91a8-be3fcc21ce9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0041969 infores:hetionet CHEBI:45979 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0151763 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0004239 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0015397 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011551 infores:hetionet CHEBI:142290 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0014591 infores:hetionet CHEBI:27899 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0016382 infores:hetionet CHEBI:3387 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0857305 infores:hetionet CHEBI:6472 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0151766 infores:hetionet CAID:CA229549 biolink:causes MONDO:0009861 infores:clingen CAID:CA229549 MONDO:0009861 PMID:21147011 Uncertain Significance PM2, PP4_Moderate, PP3 PM3 The c.441+6T>C variant in PAH has been reported before in the homozygous state in a patient with PKU and BH4 deficiency excluded (PMID: 21147011). It is absent in population databases. Multiple lines of computational evidence support a deleterious effect (MaxENT, Splice AI, dbsSNV Ada, and RF). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229549/MONDO:0009861/006 2020-07-02 2021-09-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:49040 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0162429 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020517 infores:hetionet CHEBI:4495 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0497156 infores:hetionet CHEBI:167638 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020550 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002170 infores:hetionet CHEBI:3738 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0020458 infores:hetionet CHEBI:3479 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0021359 infores:hetionet CHEBI:3312 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0020517 infores:hetionet CHEBI:64355 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151611 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0027424 infores:hetionet CHEBI:75722 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020625 infores:hetionet CHEBI:94440 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0018801 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0857501 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0857501 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0041969 infores:hetionet CHEBI:50749 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0858797 infores:hetionet UNII:G4PX8C4HKV biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040460 infores:hetionet CHEBI:8665 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C1291077 infores:hetionet CHEBI:2636 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0004238 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0549373 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0040147 infores:hetionet CHEBI:65349 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0017178 infores:hetionet CAID:CA294362 biolink:causes MONDO:0700272 infores:clingen CAID:CA294362 MONDO:0700272 PMID:33964450 Benign BS2, BP1, BA1 BS3, PM3, PM2, PP3, BP4 The c.2027T>C variant in PALB2 is a missense variant predicted to cause a substitution of isoleucine by threonine at amino acid 676 (p.Ile676Thr). This variant has been observed in the homozygous state in multiple individuals without Fanconi Anemia (Ambry Genetics). This variant has a gnomAD v.2.1.1 filtering allele frequency of 0.005 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in a protein assay (PMID 33964450); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BA1, BS2, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA294362/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3387 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0242350 infores:hetionet CHEBI:5118 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151836 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0023895 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0948824 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0948824 infores:hetionet GO:1902890 biolink:causes GO:0010054 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0010054 CHEBI:50742 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0575081 infores:hetionet CHEBI:84500 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0455204 infores:hetionet CHEBI:36791 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0278106 infores:hetionet CHEBI:31348 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0015967 infores:hetionet CHEBI:74947 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003962 infores:hetionet CHEBI:28787 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0016382 infores:hetionet CHEBI:3723 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038990 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C1861172 infores:hetionet CAID:CA4239800 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239800 MONDO:0015967 PMID: Likely Benign PP2, BS2, BP2 BS1, PM2, PP3, BP4 The c.10G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 4 (p.(Asp4Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.312, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function.The Popmax filtering allele frequency of the c.10G>A variant in gnomAD v2.1.1 is 0.00001687, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. This variant was identified in an individual with a normal fasting glucose and HbA1c less than or equal to 5.5% (BS2; internal lab contributors). This variant has been observed in unknown phase with the variant c.835G>T p.Glu279* (PMID: 8433729), which meets the criteria for as pathogenic by the ClinGen MDEP (BP2). In summary, c.10G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS2, BP2, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239800/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Contradicts true CL:0000775 biolink:causes GO:0002446 infores:ubergraph knowledge_assertion manual_agent CL:0000775 GO:0002446 CHEBI:2639 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0036974 infores:hetionet UNII:F64QU97QCR biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0038999 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0851341 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0392618 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0349506 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0019193 infores:hetionet CHEBI:4445 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0009763 infores:hetionet CHEBI:6741 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0022346 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0522055 infores:hetionet CAID:CA320642849 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642849 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.190G>A (p.Gly64Ser) is a missense variant. Multiple lines of computational evidence (REVEL 0.353, SpliceAI: Δ score 0.02) suggest no impact on gene /gene product (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642849/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8107 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0009450 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0003864 infores:hetionet CAID:CA658824657 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824657 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP1, BP4, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 This late duplication which results in a frameshift is not expected to result in nonsense mediated mRNA decay, but will alter the transactivation domain/inhibitory domain/VWRPY motif and elongate the protein (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). Although it has not been described, it is of note that other C-terminal frameshift variants have been reported with some showing loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824657/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51364 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0232461 infores:hetionet CHEBI:9907 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0917801 infores:hetionet CHEBI:63584 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0015967 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0948594 infores:hetionet CHEBI:3044 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0040822 infores:hetionet UMLS:C0004609 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0085633 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020649 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027769 infores:hetionet CHEBI:3504 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0392703 infores:hetionet CHEBI:6076 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235378 infores:hetionet CHEBI:71940 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0456909 infores:hetionet CHEBI:3504 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0744727 infores:hetionet CHEBI:3508 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0002874 infores:hetionet CHEBI:23765 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0010200 infores:hetionet CAID:CA5417011 biolink:causes MONDO:0011225 infores:clingen CAID:CA5417011 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BA1, BS1 The c.131C>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Alanine by Aspartic Acid at amino acid 44 (p.Ala44Asp).The filtering allele frequency (the upper threshold of the 95% CI of 36/1177718) of the c.131C>A variant in DCLRE1C is 0.00002087 for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5417011/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8871 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0476280 infores:hetionet CHEBI:6129 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0080274 infores:hetionet CHEBI:7478 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0013415 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0242350 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0403639 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0403639 infores:hetionet CHEBI:10125 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1510410 infores:hetionet CHEBI:6078 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0155169 infores:hetionet CHEBI:63115 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0149725 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020615 infores:hetionet CAID:CA244520160 biolink:causes MONDO:0015967 infores:clingen CAID:CA244520160 MONDO:0015967 PMID: Uncertain Significance PM1_Supporting, PP4_Moderate PS4, PS3, BS1, BS3, PM2 The c.-218T>C variant in the HNF1 homeobox 1 gene, HNF1A gene, is a single nucleotide variant within the promoter region of NM_000545.8. This variant is located within the overlapping HNF3 and NF-Y sites (c.-209 to c.-227) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). The frequency of the c.-218T>C variant in gnomAD v4.1.0 is 0.00000941, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors); however, PS4 cannot be applied because the gnomAD v4.1. Grpmax is above the ClinGen MDEP-established cutoffs for PM2_Supporting. One of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea responsive) (PP4_Moderate; internal lab contributor). Functional studies demonstrated the variant has transactivation activity at 70% of wildtype, suggesting that this variant does not impact protein function; however, sufficient controls were not used per MDEP guidelines, and therefore BS3 cannot be applied (PMID: 10649494). Taken together, this evidence supports the classification of this variant as a variant of uncertain significance. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PM1_Supporting, PP4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244520160/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63613 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0151662 infores:hetionet CHEBI:5558 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C1443060 infores:hetionet CAID:CA343719476 biolink:causes MONDO:0005338 infores:clingen CAID:CA343719476 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.164G>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Threonine at amino acid 55 (p.Ser55Thr). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.16, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 14642164), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343719476/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27899 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0027497 infores:hetionet CHEBI:7514 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0233514 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0232431 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151736 infores:hetionet CHEBI:28925 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0162834 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0001824 infores:hetionet CHEBI:3441 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020625 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0520886 infores:hetionet NCBITaxon:52283 biolink:causes MONDO:0004525 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:52283 MESH:D012532 DB04930_MESH_D012532_1DB00431_MESH_D012532_1 CHEBI:28445 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0232488 infores:hetionet CHEBI:3698 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0242528 infores:hetionet CAID:CA10581225 biolink:causes MONDO:0015967 infores:clingen CAID:CA10581225 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PS2_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.89T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 30 (p.(Leu30Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in five individuals with hyperglycemia (PS4_Moderate; PMID: 19564454, 28555465, ClinVar, internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies), and in another individual, the variant was identified as a de novo occurrence with unconfirmed parental relationships (PP4_Moderate, PS2_Moderate; PMID: 28555465, ClinVar). In summary, c.89T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PS2_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581225/MONDO:0015967/086 2025-07-16 2025-07-25 Semidominant inheritance HP:0032113 Supports CHEBI:44185 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042373 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0036341 infores:hetionet CHEBI:5855 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017181 infores:hetionet CHEBI:119486 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0036974 infores:hetionet NCBIGene:4704 biolink:causes MONDO:0032630 infores:monarchinitiative not_provided not_provided HGNC:7693 MONDO:0032630 uuid:f5729722-cf44-4fe3-9ef3-41f91ecbcdc5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0080194 infores:hetionet CHEBI:63617 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019079 infores:hetionet CHEBI:78543 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0030196 infores:hetionet CHEBI:9927 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0033774 infores:hetionet CHEBI:167638 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0023380 infores:hetionet CHEBI:78543 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0241136 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0002871 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0851341 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018801 infores:hetionet CHEBI:70707 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0338831 infores:hetionet CHEBI:107736 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0423791 infores:hetionet CHEBI:53691 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0028643 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0015397 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0857160 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0857160 infores:hetionet CAID:CA10578330 biolink:causes MONDO:0021056 infores:clingen CAID:CA10578330 MONDO:0021056 PMID:24599579 Uncertain Significance BP1, PM2_Supporting BP4, PS3, PS4 The NM_000038.6(APC):c.1902T>G (p.Ser634Arg) variant in APC is a missense variant predicted to cause substitution of Serine by Arginine at amino acid position 634 (p.Ser634Arg). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 0.5 (PS4 not met [Ambry]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 27696107). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236788 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). RT-PCR of cDNA and mini-gene splicing assays demonstrated that the variant impacts splicing by skipping of exon 15 resulting in a premature stop codon (PMID: 24599579). However, since alternative splicing/skipping of this exon is known and in PMID: 24599579 no pronounced skipping compared to controls is described, PS3 is not applicable. Moreover, the results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) support that this variant does not affect splicing. APC, in which the variant was identified, is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). Due to conflicting evidence, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PM2_Supporting, BP1 (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578330/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50777 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0002994 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1609512 infores:hetionet CHEBI:27899 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0003811 infores:hetionet CHEBI:9605 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0151705 infores:hetionet CHEBI:182080 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0026821 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0010692 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0032961 infores:hetionet CHEBI:4708 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0392525 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030552 infores:hetionet CHEBI:175901 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0340865 infores:hetionet CHEBI:9907 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0037763 infores:hetionet CHEBI:2611 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085631 infores:hetionet CHEBI:61390 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0151904 infores:hetionet CHEBI:9130 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C1262144 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038362 infores:hetionet CHEBI:5778 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030252 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0948594 infores:hetionet CHEBI:7822 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0014518 infores:hetionet GO:0090077 biolink:causes CL:0000891 infores:ubergraph knowledge_assertion manual_agent GO:0090077 CL:0000891 CHEBI:63631 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0231274 infores:hetionet CHEBI:6129 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0003811 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0855304 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0855304 infores:hetionet CHEBI:3176 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0035455 infores:hetionet CHEBI:5855 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009421 infores:hetionet CHEBI:64312 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C2979982 infores:hetionet CHEBI:8884 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0036974 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0442874 infores:hetionet CHEBI:63621 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020598 infores:hetionet CHEBI:80630 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0034882 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0858598 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013595 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1510472 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0029408 infores:hetionet CHEBI:27300 biolink:causes MONDO:0004937 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C1442839 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0012833 infores:hetionet NCBIGene:535 biolink:causes MONDO:0859265 infores:monarchinitiative not_provided not_provided HGNC:865 MONDO:0859265 uuid:ab321d02-da35-4659-ac45-84efd8865003 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002994 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013395 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020517 infores:hetionet CHEBI:66876 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0009806 infores:hetionet CHEBI:8874 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0015672 infores:hetionet CAID:CA512341389 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341389 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP2, BP3, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.987G>T (p.Ala329=) is a synonymous variant. This variant is absent from the population database gnomAD v3 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.6) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341389/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA346837 biolink:causes MONDO:0015152 infores:clingen CAID:CA346837 MONDO:0015152 PMID: Likely Pathogenic PP1_Moderate, PP4, PM3, PVS1_Strong BP5, BP7, BS4, BS1, BS3, PM2, PM6, PP2, PP3, BS2, PM4, PM5, PM1, BA1, BP2, BP3, BP1, BP4, PS3, PS1, PS2, PS4 The NM_000231.3: c.525del p.(Phe175LeufsTer20) variant in SGCG is a frameshift variant that is predicted to introduce a premature stop codon. The resulting transcript is predicted to escape nonsense mediated decay but truncate >10% of the protein (PVS1_Strong). This variant has been detected in at least five apparently unrelated patients with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least four individuals (1.0 pt, PMID: 16616845, 10993494, 18285821, 10942431; ClinVar SCV001164546.1) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). While absent gamma-sarcoglycan protein expression has been reported in the skeletal muscle of patients with this variant, detection may be dependent on the antibody used due to the production of a truncated protein (PMID: 10993494, 16616845, 10942431). The variant has been reported to segregate with autosomal recessive LGMD in four affected family members from two families (PP1_Moderate; PMID: 10942431, ClinVar SCV001164546.1). The highest minor allele frequency of this variant is 0.0002619 (4/15274 genome chromosomes) in the Admixed American population in gnomAD v3.2.1, which is greater than the VCEP threshold (0.00009) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Strong, PM3, PP4, PP1_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346837/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7565 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C2830004 infores:hetionet CHEBI:3515 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0149745 infores:hetionet UMLS:C0004609 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0018932 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042769 infores:hetionet CHEBI:37924 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1368065 infores:hetionet NCBIGene:79796 biolink:causes MONDO:0012117 infores:monarchinitiative not_provided not_provided HGNC:15672 MONDO:0012117 uuid:f376f697-29fd-49d1-9863-2b114210fa66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68606 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0015230 infores:hetionet CHEBI:5778 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0011606 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0235721 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0235721 infores:hetionet CHEBI:4995 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013378 infores:hetionet NCBIGene:9289 biolink:causes MONDO:0014333 infores:monarchinitiative not_provided not_provided HGNC:4512 MONDO:0014333 uuid:4c992e4d-83a5-436c-abfb-a59bde80c562 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0039070 infores:hetionet CHEBI:5855 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085593 infores:hetionet CHEBI:36791 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002792 infores:hetionet CHEBI:94848 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0232462 infores:hetionet NCBIGene:1108 biolink:causes MONDO:0014946 infores:monarchinitiative not_provided not_provided HGNC:1919 MONDO:0014946 uuid:94a2d54e-ee6f-49ee-9b65-0e67bdf2acdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0110065 biolink:causes GO:0120109 infores:ubergraph knowledge_assertion manual_agent GO:0110065 GO:0120109 CHEBI:50275 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0001807 infores:hetionet CHEBI:34829 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0017601 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0029408 infores:hetionet MONDO:0034106 biolink:causes NCBIGene:11342 infores:ubergraph knowledge_assertion manual_agent MONDO:0034106 HGNC:10057 CHEBI:63608 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0026846 infores:hetionet CHEBI:28593 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0012569 infores:hetionet CHEBI:3207 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0011991 infores:hetionet CAID:CA386960701 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960701 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PP4_Moderate, PP3 PS3 The c.511C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 171 (p.(Arg171Gly)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.888, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 26853433 and 31291970, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.511C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PS4_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960701/MONDO:0015967/017 2024-01-28 2024-01-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63598 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0392699 infores:hetionet CAID:CA410203806 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203806 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, BP2, BP3, BA1, BS1, BS3, PM3, PM4 NM_001754.5(RUNX1):c.248C>T (p.Ala83Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203806/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4814 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0018801 infores:hetionet CAID:CA8602997 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602997 MONDO:0100326 PMID: Uncertain Significance BP4 BS1, PM5, PM2, PP4 The c.1628G>A variant in ITGA2B is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 543 (p.Arg543Gln). The computational predictor REVEL gives a score of 0.206, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, but was not found in the literature in any patient with Glanzmann thrombasthenia. The highest population minor allele frequency in gnomAD v 4.0.0 is 0.0001602 (189/1179970 alleles) in the European (non-Finnish) population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. In summary, this variant is classified as uncertain significance based on ACMG/AMP criteria as specified by the PD VCEP: BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602997/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63791 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0034065 infores:hetionet CHEBI:71940 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0017152 infores:hetionet CHEBI:5855 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0235063 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027651 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0009938 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0235169 infores:hetionet CHEBI:2636 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0948089 infores:hetionet CHEBI:9757 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0039971 infores:hetionet CHEBI:73275 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0037274 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0234913 infores:hetionet CHEBI:5001 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0085649 infores:hetionet CHEBI:83531 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0039231 infores:hetionet CHEBI:204734 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0031350 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027769 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0038367 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0035078 infores:hetionet CHEBI:3515 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0041834 infores:hetionet CHEBI:4653 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0232461 infores:hetionet CHEBI:72296 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0018926 infores:hetionet CHEBI:144093 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0002962 infores:hetionet NCBIGene:132884 biolink:causes MONDO:0008673 infores:monarchinitiative not_provided not_provided HGNC:19747 MONDO:0008673 uuid:48015645-576b-446b-99c8-1999b383f71d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:4890 biolink:causes MONDO:0001699 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:4890 MONDO:0001699 NCBITaxon:173087 biolink:causes MONDO:0009237 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:173087 MONDO:0009237 CHEBI:4876 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0015967 infores:hetionet CHEBI:31401 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151908 infores:hetionet CHEBI:4858 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0013390 infores:hetionet CHEBI:51450 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0010200 infores:hetionet CHEBI:10125 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013144 infores:hetionet CHEBI:64355 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0855333 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0016034 infores:hetionet CAID:CA915940782 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940782 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting, PM3_Supporting PP4, PS1 The c.574+5G>A variant in ITGA2B is an intronic variant in intron 4. This variant has been detected in the homozygous form in at least 1 proband in the ThromboGenetics cohort (TGP0375, PMID:31064749) Total points: 0.5 (PM3_Supporting). TGP0375 was not reported with supporting phenotypic information and did not meet criteria for PP4 (PMID:31064749).This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.8 for donor loss, predicting that the variant disrupts the donor splice site of intron 4 (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3, PM3_supporting. (VCEP specifications version 2; date of approval 06/06/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940782/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9570 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0019209 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0243026 infores:hetionet CAID:CA163550 biolink:causes MONDO:0017623 infores:clingen CAID:CA163550 MONDO:0017623 PMID: Uncertain Significance PM6, PM2, PVS1, BP5, BP7, BS4, BS1, BS3, PP1, PP4, PP2, PP3, BS2, PM3, PM5, PM4, PM1, BA1, BP2, BP1, BP4, BP3, PS4, PS2, PS3, PS1 PTEN c.-1170C>A, also described as c.-1171C>A (NC_000010.10:g.89623056C>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA163550/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2549 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013456 infores:hetionet CHEBI:71940 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0039231 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0039520 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020456 infores:hetionet CHEBI:16586 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0027497 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027765 infores:hetionet CAID:CA414772918 biolink:causes MONDO:0044970 infores:clingen CAID:CA414772918 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP1, PP3, PS4, PS2, PS3, PM6 The m.3502T>C (p.S66P) variant in MT-ND1 has been reported in one individual with primary mitochondrial disease to date however clinical details are not provided (PMID: 32652755). There is also a ClinVar submission from the Undiagnosed Diseases Network however it is not clear if this is a second unrelated case or the same case as reported in the medical literature. There are no additional individuals or families reported with de novo occurrences of this variant or with this variant segregating with clinical manifestations to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.36 (Min=0, Max=1; APOGEE2 score is 0.824). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414772918/MONDO:0044970/015 2024-09-24 2024-11-21 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2663 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0018188 infores:hetionet CHEBI:4953 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0236075 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031039 infores:hetionet CHEBI:131512 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0020580 infores:hetionet CHEBI:48390 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0018681 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0000833 infores:hetionet CHEBI:5147 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0520888 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0234458 infores:hetionet CHEBI:63607 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020580 infores:hetionet CHEBI:27786 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0013395 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0019061 infores:hetionet CAID:CA018423 biolink:causes MONDO:0005045 infores:clingen CAID:CA018423 MONDO:0005045 PMID: Benign BA1 BS1, PM2 NM_001018005.2(TPM1):c.845C>G (p.Thr282Ser) - This variant has been identified in 0.0012 FAF (49/30422) of South Asian alleles by gnomAD v2.1.1.(BA1; http://gnomad.broadinstitute.org). In summary, this variant is classified as Benign for HCM in an autosomal dominant manner based on this allele frequency. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA018423/MONDO:0005045/100 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4672 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0040034 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002886 infores:hetionet CHEBI:5004 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0040034 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235315 infores:hetionet CHEBI:168396 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0001127 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0087169 infores:hetionet CHEBI:2659 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0003467 infores:hetionet CHEBI:127342 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042963 infores:hetionet CHEBI:31981 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0022346 infores:hetionet CHEBI:116278 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0018524 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034882 infores:hetionet CHEBI:6541 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0035410 infores:hetionet CHEBI:135005 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0015230 infores:hetionet CHEBI:2668 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0014591 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0948594 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040409 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0852733 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0028173 infores:hetionet CHEBI:180905 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0011991 infores:hetionet CHEBI:8802 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0221170 infores:hetionet CHEBI:74947 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085633 infores:hetionet CHEBI:64355 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004093 infores:hetionet CHEBI:47780 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0034880 infores:hetionet CHEBI:7954 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C2363730 infores:hetionet CAID:CA347212124 biolink:causes MONDO:0015152 infores:clingen CAID:CA347212124 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4_Strong, PP3, PM2_Supporting PM5, PS3 The NM_003494.4: c.1004G>A variant in DYSF, which is also known as NM_001130987.2: c.1100G>A p.(Gly367Asp), is a missense variant predicted to cause substitution of glycine to aspartic acid at amino acid 335, p.(Gly335Asp). This variant has been reported in two patients with dysferlinopathy (PMID: 26088049, 32400077), including in a confirmed trans phase with a pathogenic variant (c.4497del p.(Phe1499LeufsTer4), 1.0 pt, PMID: 26088049) (PM3). At least one of these patients with a second presumed diagnostic DYSF variant and a clinical diagnosis of LGMD displayed absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 26088049) (PP4_Strong). The highest minor allele frequency for this variant is 0.00001562 (1/64034 alleles) in the European (Finnish) population in gnomAD v4.1.0, which is less than the VCEP threshold of 0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.95, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/04/2025): PM2_Supporting, PM3, PP4_Strong, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347212124/MONDO:0015152/180 2025-03-04 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3568 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0521839 infores:hetionet CHEBI:31236 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0025323 infores:hetionet CHEBI:4907 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0037763 infores:hetionet CHEBI:42797 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0035455 infores:hetionet CHEBI:8871 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033036 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0541881 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0541881 infores:hetionet CHEBI:6832 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C3263723 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0009806 infores:hetionet CHEBI:83804 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0021141 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033046 infores:hetionet CHEBI:66876 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0344232 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006527 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003028 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002871 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011615 infores:hetionet CHEBI:36795 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232461 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0020649 infores:hetionet CHEBI:5109 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0020456 infores:hetionet CHEBI:63635 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042029 infores:hetionet CAID:CA147048 biolink:causes MONDO:0100084 infores:clingen CAID:CA147048 MONDO:0100084 PMID: Benign BA1, BP4, BP7 The NM_001100.4:c.809-14G>C variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The population filtering allele frequency in gnomAD v4.1.0 is 0.4599 (34684/74748 alleles with 8023 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0025 for AR, ≥0.00000781 for AD) for BA1, and therefore meets this criterion (BA1). The results from the in silico predictor, SpliceAI, suggest that the variant does not impact ACTA1 function and it occurs at a nucleotide that is not conserved as shown by the UCSC Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA147048/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:77733 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0030554 infores:hetionet CAID:CA2573157368 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157368 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.133_135del (p.Thr45del) is an inframe deletion which does not affect a known functional domain. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157368/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:145499 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020443 infores:hetionet CHEBI:78543 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0268000 infores:hetionet CHEBI:63621 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018808 infores:hetionet CHEBI:167309 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0039070 infores:hetionet CHEBI:50378 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0423791 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0032285 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0233472 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0857305 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0795692 infores:hetionet CHEBI:64028 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0028768 infores:hetionet CAID:CA209032 biolink:causes MONDO:0100039 infores:clingen CAID:CA209032 MONDO:0100039 PMID: Benign BP7, BA1 The allele frequency of the p.Pro574= variant in CDKL5 in South Asian sub population in gnomAD, which is high enough to be classified as benign based on the thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Pro574 variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Pro574= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA209032/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:68478 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020295 infores:hetionet CHEBI:136040 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0344232 infores:hetionet CHEBI:8060 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0043352 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C1443060 infores:hetionet NCBIGene:95681 biolink:causes MONDO:0013763 infores:monarchinitiative not_provided not_provided HGNC:12370 MONDO:0013763 uuid:e124f6a5-6093-4fda-adad-2e687d92b753 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0026857 infores:hetionet CHEBI:31413 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0014518 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0004936 infores:hetionet CHEBI:3216 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0851578 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0149931 infores:hetionet CHEBI:28925 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0240322 infores:hetionet CHEBI:41774 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0206061 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151838 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0034065 infores:hetionet CHEBI:5138 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0004134 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0151735 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0851341 infores:hetionet CAID:CA181422 biolink:causes MONDO:0021060 infores:clingen CAID:CA181422 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.558G>T (p.Arg186=) variant in the PTPN11 gene is 0.231% (49/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA181422/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:84050 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0027540 infores:hetionet CHEBI:125354 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C2047937 infores:hetionet CHEBI:7852 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0002792 infores:hetionet CAID:CA010221 biolink:causes MONDO:0004994 infores:clingen CAID:CA010221 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1119G>A (p.Ala373=) variant in the MYH7 gene is 0.12% (21/11578) of Latino chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010221/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10100 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C2363730 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0036983 infores:hetionet NCBIGene:1302 biolink:causes MONDO:0012333 infores:monarchinitiative not_provided not_provided HGNC:2187 MONDO:0012333 uuid:176940a1-d19a-49d8-8fbb-e9e7bb3c8a32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2218 biolink:causes MONDO:0012704 infores:monarchinitiative not_provided not_provided HGNC:3622 MONDO:0012704 uuid:568967ae-66ab-4ac2-9fc7-4d182f002f99 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167638 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0030252 infores:hetionet CHEBI:2948 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0040034 infores:hetionet CAID:CA915952604 biolink:causes MONDO:0011071 infores:clingen CAID:CA915952604 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968-7C>T is an intronic variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is predicted to not affect splicing (SpliceAI ∆ scores 0.00 < 0.20) (BP4) and is not evolutionarily conserved (PhyloP100way score 0.323 < 2.0) (BP7). To our knowledge, this variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria, and functional studies are not available. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952604/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0011701 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0231218 infores:hetionet NCBIGene:9512 biolink:causes MONDO:0054785 infores:monarchinitiative not_provided not_provided HGNC:9119 MONDO:0054785 uuid:a167812e-d524-470e-bac5-b2ea43c7a18f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4530 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013491 infores:hetionet CHEBI:2668 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0008370 infores:hetionet CHEBI:6954 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0018965 infores:hetionet CHEBI:7931 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0043352 infores:hetionet CHEBI:9738 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0000729 infores:hetionet CHEBI:33130 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0015967 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0027769 infores:hetionet CHEBI:2663 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0234133 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151737 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151737 infores:hetionet CHEBI:45409 biolink:causes MONDO:0018660 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0684275 infores:hetionet CHEBI:7494 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013456 infores:hetionet CHEBI:2788 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0017178 infores:hetionet CHEBI:6916 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0009676 infores:hetionet CHEBI:71219 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0043352 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0042373 infores:hetionet NCBIGene:5702 biolink:causes MONDO:0859159 infores:monarchinitiative not_provided not_provided HGNC:9549 MONDO:0859159 uuid:b34c01a3-6ff3-4272-a50a-7fb77b5b59d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes MONDO:0042981 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003507 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0232431 infores:hetionet CHEBI:474180 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0038450 infores:hetionet CHEBI:391960 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0002792 infores:hetionet CAID:CA134619 biolink:causes MONDO:0021060 infores:clingen CAID:CA134619 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.804C>G (p.Ala268=) variant in the MAP2K1 gene is 1.234% (228/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134619/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9123 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0233472 infores:hetionet CHEBI:4702 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0039070 infores:hetionet CHEBI:5855 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1442826 infores:hetionet CHEBI:4856 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0042963 infores:hetionet CHEBI:50659 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0160390 infores:hetionet CHEBI:5280 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0004604 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0040261 infores:hetionet CAID:CA367398533 biolink:causes MONDO:0007453 infores:clingen CAID:CA367398533 MONDO:0007453 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP2, PP3, PP4, PP1, PM2_Supporting The c.1190G>A variant in the glucokinase gene, GCK, causes an amino acid change of Arg to His at codon 397 (p.(Arg397His)) of NM_000162.5. Another missense variant, c.1190G>T p.Arg397Leu, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg397His (PM5_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.779 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 2 informative meioses in 2 families with MODY (PP1; internal lab contributors). In summary, c.1190G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Supporting, PP2, PM2_Supporting, PP3, PP4, PS4_Moderate, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398533/MONDO:0007453/086 2023-09-08 2023-09-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44185 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0027947 infores:hetionet CHEBI:38940 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0236075 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0039971 infores:hetionet CHEBI:72297 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C2242737 infores:hetionet CHEBI:9168 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0009676 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020538 infores:hetionet CHEBI:3732 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0423791 infores:hetionet CHEBI:3510 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0011603 infores:hetionet CHEBI:135935 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0152032 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0030846 infores:hetionet CHEBI:94440 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0006266 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085298 infores:hetionet CHEBI:8874 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1443060 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0017152 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0233494 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026636 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038367 infores:hetionet CHEBI:2549 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0018808 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0009450 infores:hetionet CHEBI:70735 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0017152 infores:hetionet NCBIGene:123624 biolink:causes MONDO:0014228 infores:monarchinitiative not_provided not_provided HGNC:26504 MONDO:0014228 uuid:5848fda1-48b2-4e72-9f32-02b410e41064 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50305 biolink:causes HP:0200041 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0241069 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0039971 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0029456 infores:hetionet CHEBI:6888 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0017979 infores:hetionet GO:1904653 biolink:causes GO:0030324 infores:ubergraph knowledge_assertion manual_agent GO:1904653 GO:0030324 CHEBI:7936 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019521 infores:hetionet NCBIGene:1523 biolink:causes MONDO:0032680 infores:monarchinitiative not_provided not_provided HGNC:2557 MONDO:0032680 uuid:0ffc468c-046e-4904-8218-615179a8727e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA497619538 biolink:causes MONDO:0008723 infores:clingen CAID:CA497619538 MONDO:0008723 PMID: Likely Benign BP4, BP7 The c.96G>A (p.Arg32=) variant is a synonymous (silent) variant that is not predicted by MaxEntScn and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). This variant is absent from gnomAD v.2.1.1; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7. (ACADVL VCEP specifications version 1; approved February 28, 2023) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA497619538/MONDO:0008723/021 2023-02-28 2023-02-28 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63598 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0080274 infores:hetionet CHEBI:82960 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0917801 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0018802 infores:hetionet CHEBI:6532 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0030446 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0521839 infores:hetionet CHEBI:6538 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0027497 infores:hetionet CHEBI:6916 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0019521 infores:hetionet GO:1905044 biolink:causes GO:0014012 infores:ubergraph knowledge_assertion manual_agent GO:1905044 GO:0014012 NCBIGene:6323 biolink:causes MONDO:0012320 infores:monarchinitiative not_provided not_provided HGNC:10585 MONDO:0012320 uuid:6f68f90b-9925-4d2e-a704-f725f8af85f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:F64QU97QCR biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C1291078 infores:hetionet CHEBI:36791 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232602 infores:hetionet CHEBI:49040 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C2047937 infores:hetionet CHEBI:47898 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002874 infores:hetionet CHEBI:4046 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0009676 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0035455 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0022667 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0015397 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151736 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007097 infores:hetionet CHEBI:15544 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0340279 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0042373 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0518015 infores:hetionet CHEBI:51209 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C1456784 infores:hetionet CHEBI:4708 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0240717 infores:hetionet CHEBI:64064 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0011615 infores:hetionet CHEBI:8772 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0039070 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000931 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151622 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0080194 infores:hetionet CHEBI:63631 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0008031 infores:hetionet CAID:CA059963 biolink:causes MONDO:0007947 infores:clingen CAID:CA059963 MONDO:0007947 PMID: Benign BA1 PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, PM5, PM4, PM1, PM3, BP7, BP5, BS1, BS3, BS4 The NM_00138 c.8363C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by methionine at amino acid 2788 (p.Thr2788Met). The variant in FBN1 has been reported 13 times in ClinVar: 12 times as likely benign and once as benign (Variation ID: 263832). This variant has been identified in 44 individuals of African origin (gnomAD version 3.1.1, MAF: 0.1%, one homozygous) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.356). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA059963/MONDO:0007947/022 2023-02-01 2023-02-01 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3723 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151714 infores:hetionet CAID:CA120303 biolink:causes MONDO:0010938 infores:clingen CAID:CA120303 MONDO:0010938 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PS3, PP3 The NM_000215.4(JAK3):c.1695C>A (p.Cys565Ter) variant in exon 11 of JH2 domain of JAK3 results in a disrupted protein product PVS1. The variant is also known as the C1790A variant (PMID 17433830). The filtering allele frequency in gnomAD v4.1.0 is 0.000002470 (7/1179982 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed in gnomAD. (PM2_Supporting). At least one patient in the literature presents Diagnostic criteria for SCID (0.5pt) + Reduced cytokine-induced phosphorylation of STAT5 in patient-derived T or B cells (1pt) + No kinase activity data for this mutation PMID 14615376 PID v2 panel confirmed this mutation by NGS in Kid_6 (0.5pt). Total 2 points PP4_Moderate (PMID: 7481768).In summary, this variant meets the criteria to be classified as a Pathogenic for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA120303/MONDO:0010938/121 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7465 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0917801 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0030305 infores:hetionet CHEBI:10023 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003811 infores:hetionet CHEBI:9907 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0043094 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0038525 infores:hetionet CHEBI:31623 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0699744 infores:hetionet CHEBI:5130 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0917801 infores:hetionet CHEBI:36791 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C3251821 infores:hetionet CHEBI:9671 biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0860433 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1565489 infores:hetionet CHEBI:6690 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0262988 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0015397 infores:hetionet GO:2000589 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000589 GO:0072001 CHEBI:135935 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0003467 infores:hetionet GO:2000200 biolink:causes GO:0042254 infores:ubergraph knowledge_assertion manual_agent GO:2000200 GO:0042254 CHEBI:27974 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0037274 infores:hetionet CHEBI:41774 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042029 infores:hetionet CHEBI:31401 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0687713 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1695897 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1695897 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0234656 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0234656 infores:hetionet CAID:CA274477 biolink:causes MONDO:0009290 infores:clingen CAID:CA274477 MONDO:0009290 PMID:25673129PMID:14643388PMID:23632174PMID:25026126PMID:12923862PMID:19862843PMID:14643388PMID:12923862 Pathogenic PM2, PP4, PM3_Strong, PS3 PP3, BP4 This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. All of these individuals are compound heterozygous for the variant and a unique pathogenic variant, including c.-32-13T>G (PMID 25673129; phase unknown), c.525delT (PMID 12923862; phase unknown), c.763C > T (p.Gln255Ter) (PMID 25026126, confirmed in trans), c.2237G>A (p.Trp746Ter) (PMID 12923862; phase unknown), c.1064T>C (p.Leu355Pro)(PMID 23632174; confirmed in trans), and c.1979G>A (p.Arg660His) (PMID 14643388; phase unknown). These data meet PM3_Strong. Note that the in trans data from the patients with c.1064T>C (p.Leu355Pro) and c.1979G>A (p.Arg660His) will be used in the assessment of those variants and was not used here in order to avoid a circular argument. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. The score for the in silico meta-predictor REVEL, does not meet PP3 or BP4. However, when expressed in COS cells, this variant results in significantly reduced GAA activity, <10% of wild type (PMID 12923862, 14643388, 19862843), meeting PS3. There is a ClinVar entry for this variant (Variation ID: 189188, 1 star review status), with two submitters classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274477/MONDO:0009290/010 2020-05-03 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8863 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011991 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0851341 infores:hetionet CHEBI:135736 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085602 infores:hetionet CHEBI:3216 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C3203358 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017178 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0232492 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0017160 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1565489 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0859253 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0859253 infores:hetionet GO:0052562 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0052562 GO:0006955 CHEBI:32184 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0241136 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0541799 infores:hetionet CHEBI:50223 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0038362 infores:hetionet CHEBI:7492 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0013456 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0003123 infores:hetionet CHEBI:3568 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0028734 infores:hetionet CHEBI:4653 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0018790 infores:hetionet GO:0110107 biolink:causes GO:0002165 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0002165 CHEBI:3223 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0027497 infores:hetionet CHEBI:100246 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0085932 infores:hetionet CHEBI:7640 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0040409 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0085636 infores:hetionet CHEBI:8707 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0025345 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0233494 infores:hetionet CHEBI:6367 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0344232 infores:hetionet CHEBI:5138 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0149745 infores:hetionet CHEBI:63577 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0004093 infores:hetionet CHEBI:50122 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0016655 infores:hetionet CHEBI:50777 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042029 infores:hetionet CHEBI:5147 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151315 infores:hetionet CHEBI:4551 biolink:causes UMLS:C1412000 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C1412000 infores:hetionet CHEBI:7601 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0009806 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0025061 infores:hetionet CHEBI:5383 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0011206 infores:hetionet NCBIGene:1954 biolink:causes MONDO:0013998 infores:monarchinitiative not_provided not_provided HGNC:3233 MONDO:0013998 uuid:0e40f1c5-7984-4d42-b4e4-0dc312407cc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0007222 infores:hetionet CHEBI:10127 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0043094 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0235431 infores:hetionet NCBIGene:5984 biolink:causes MONDO:0975848 infores:monarchinitiative not_provided not_provided HGNC:9972 MONDO:0975848 uuid:0cc70aaf-bada-4847-908a-72ef5f483e98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA147721 biolink:causes MONDO:0015152 infores:clingen CAID:CA147721 MONDO:0015152 PMID: Benign BA1 BP4 The NM_003494.4: c.1369G>A variant in DYSF, which is also known as NM_001130987.2: c.1465G>A (p.Glu489Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 457 (p.Glu457Lys). The filtering allele frequency of the variant is 0.02368 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 4291/251472), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.28 and the computational predictor REVEL gives a score of 0.41. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147721/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:52717 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018802 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151717 infores:hetionet UNII:T58MSI464G biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0426576 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0020649 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151825 infores:hetionet CHEBI:80630 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0000737 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0020557 infores:hetionet CHEBI:4710 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0037763 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0948594 infores:hetionet CAID:CA636174167 biolink:causes MONDO:0007064 infores:clingen CAID:CA636174167 MONDO:0007064 PMID: Pathogenic PM3_Supporting, PP4, PVS1, PM2_Supporting The NM_000022.4:c.532del (p.Val178*) variant in ADA creates a premature translational stop signal in exon 6 (of 12) and is expected to result in nonsense-mediated decay in a loss of function gene (PVS1). This variant was reported as homozygous in an infant with T-B- severe combined immunodeficiency (SCID) (PMID: 30290665) (PP4, PM3_Supporting). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.0001 (2/19948 alleles) in the East Asian population, which is lower than the ADA cutoff (gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PP4, PM3_Supporting, PM2_Supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA636174167/MONDO:0007064/114 2024-01-16 2024-01-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7476 biolink:causes UMLS:C1695895 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1695895 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0000879 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D002179 DB01127_MESH_D002179_1DB01026_MESH_D002179_1DB01188_MESH_D002179_1 CHEBI:77260 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0004936 infores:hetionet CHEBI:9943 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0035410 infores:hetionet CHEBI:4717 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0003467 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0034150 infores:hetionet CHEBI:3213 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0038325 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0024305 infores:hetionet CAID:CA303333 biolink:causes MONDO:0100135 infores:clingen CAID:CA303333 MONDO:0100135 PMID: Likely Pathogenic PM2_Supporting, PM6, PS4_Moderate, PP3_Moderate The c.2303C>T (NM_001165963.4) variant in SCN1A is a missense variant predicted to cause substitution of proline by leucine at amino acid 768 (p.Pro768Leu). This variant has been reported in one patient meeting phenotypic criteria for Dravet syndrome with unknown inheritance (PMID: 35074891; PS4_SUPPORTING) and in another patient also meeting phenotypic criteria for Dravet syndrome as a de novo occurrence with unconfirmed parental relationships (PMID: 20431604; PM6). This variant is absent from gnomAD v2 and v3 (PM2_SUPPORTING). The computational predictor REVEL gives a score of 0.927 which is above the threshold of 0.773 but under 0.932, evidence that correlates with impact to SCN1A function (PMID: 36413997; PP3_MODERATE). In summary, this variant has been classified as likely pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the Epilepsy Sodium Channel VCEP: PM6, PS4_SUPPORTING, PM2_SUPPORTING, PP3_MODERATE (version 1.0, approved 7/11/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA303333/MONDO:0100135/067 2024-05-07 2024-05-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:59773 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C2830004 infores:hetionet CHEBI:83527 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0043352 infores:hetionet CAID:CA010092 biolink:causes MONDO:0005045 infores:clingen CAID:CA010092 MONDO:0005045 PMID: Uncertain Significance PM1 PP3, PP1, BA1, PM2, PM5, PS3, PM6, PM4, BS1, BS3, BS4, PS4, PS1, PS2, BP4, BP2, BP5, BP7, PVS1 The c.1046T>C (p.Met349Thr) variant in MYH7 has been reported in at least 6 individuals with HCM (PS4_Supporting; Jeschke 1998 PMID:9544842; GeneDx: pers comm., Ambry: pers comm, Invitae: pers comm), 1 of whom also had additional variants in other HCM-associated genes (Ambry pers comm;). Additionally, one of these individuals also had severe, early-onset (<20 yo) presentation of HCM and carried a second de novo MYH7 variant on the second allele that was classified as pathogenic by this expert panel (p.Arg719Trp, ClinVar variation ID:14104). This variant has also been reported in 1 individual with unspecified heart disease, 1 with LVH, and 1 with arrhythmia, and 1 with LVNC with atrial and ventricular septal defect (Ambry pers comm.; GeneDX pers comm.; Invitae pers comm.; OMGL pers comm.). This variant has also been identified in 0.007% (1/15378) of European chromosomes, in gnomAD (v2.1.1; http://gnomad.broadinstitute.org). This represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant and apply PM2. Additionally, since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010092/MONDO:0005045/002 2021-06-16 2021-06-16 Inconclusive true CHEBI:47499 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0015230 infores:hetionet CAID:CA915944059 biolink:causes MONDO:0015152 infores:clingen CAID:CA915944059 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.3220_3221delCT p.(Leu1074PheTer39) variant in DYSF, which is also known as NM_001130987.2: c.3274_3275del p.(Leu1092PhefsTer39), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 30/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in trans with a pathogenic variant in at least one patient with LGMD (c.1662C>T p.(Arg555Trp), 1.0 pt, PMID: 25591676) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 25591676). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915944059/MONDO:0015152/180 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:196528 biolink:causes MONDO:0033492 infores:monarchinitiative not_provided not_provided HGNC:18037 MONDO:0033492 uuid:bb1df3e8-c645-4b67-acc6-620eb4b2d418 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151514 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0009450 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0150450 infores:hetionet NCBIGene:50640 biolink:causes MONDO:0016825 infores:monarchinitiative not_provided not_provided HGNC:28900 MONDO:0016825 uuid:991f5bf6-ccef-4077-b484-a3d72c35cda4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA005005 biolink:causes MONDO:0100316 infores:clingen CAID:CA005005 MONDO:0100316 PMID: Pathogenic PM2_Supporting, PS3, PS4, PP3, PP4 BA1, BP4, BS1 NM_000218.3(KCNQ1):c.1032G>A is a synonymous variant (p.Ala344=) predicted to affect KCNQ1 mRNA splicing. The computational splicing predictor SpliceAI gives scores of 0.49 for donor gain and 0.38 for donor loss, which are higher than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of greater than or equal to 0.2 and predict that the variant disrupts KCNQ1 splicing (PP3). The variant is observed at an extremely low frequency in the population with a maximum allele frequency (gnomAD 4.1.0) of 0.000001701, with 2 in 1,175,668 individuals of European (non-Finnish) ancestry (PM2_Supporting). Functional studies have been performed on this variant and meet criteria with demonstrated deleterious effects on electrophysiology and RNA metabolism (PS3, PMID: 29857160, 10477533, 17292394). There are 23 reported probands in the literature with a clinical diagnosis of Long QT syndrome (PS4; PMID: 26118460, PMID: 21810471, PMID: 9654228, PMID: 29497013, PMID: 17292394). An additional case reports provides specific details that are highly specific for a diagnosis of Long QT syndrome in an individual with the variant who had a significantly prolonged QTc at rest and exercise-triggered events (PP4, PMID: 21810471). In summary, this variant meets the criteria to be classified as pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3, PS4, PM2_Supporting, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA005005/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:82960 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0011849 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013781 infores:hetionet CHEBI:4514 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0030252 infores:hetionet CAID:CA000567 biolink:causes MONDO:0017623 infores:clingen CAID:CA000567 MONDO:0017623 PMID: Uncertain Significance PM2 PTEN c.-765G>A (AKA c.-764G>A, NC_000010.10:g.89623462G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000567/MONDO:0017623/003 2021-10-29 2021-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7936 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034069 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0751295 infores:hetionet CHEBI:144551 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0424295 infores:hetionet NCBIGene:3717 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:6192 MONDO:0018874 uuid:2f290c66-0df2-4959-ba2c-d3459fb5691e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135285 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0002994 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006145 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0002871 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151596 infores:hetionet CHEBI:4735 biolink:causes EFO:1000003 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0235950 infores:hetionet CHEBI:5120 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0595930 infores:hetionet CHEBI:171719 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0000737 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0002418 infores:hetionet CHEBI:72564 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085593 infores:hetionet CHEBI:2379 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0151827 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0235639 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0235266 infores:hetionet CAID:CA10014200 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014200 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1106C>T (p.Ser369Leu) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014200/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6375 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2242737 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0857093 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1145670 infores:hetionet CHEBI:7852 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0039240 infores:hetionet CHEBI:78543 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0027497 infores:hetionet NCBIGene:4323 biolink:causes MONDO:0010201 infores:monarchinitiative not_provided not_provided HGNC:7160 MONDO:0010201 uuid:a89dcfb4-1593-4a71-a45f-8e9c26d91dc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA029258 biolink:causes MONDO:0007750 infores:clingen CAID:CA029258 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PM6, PVS1, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.758G>A (p.Arg253Gln) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000096 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.44; score is below 0.5 threshold, splicing evaluation required. Functional data on splicing not available. Category B) - variant is exonic and at least 50bp upstream from the canonical donor site, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79; ratio = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>C (p.Arg253Pro); however, both are VUS by these LDLR guidelines (PM5 not applicable). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA029258/MONDO:0007750/013 2022-04-22 2022-04-22 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:75988 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0015230 infores:hetionet CHEBI:68606 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C2225524 infores:hetionet CHEBI:8871 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0428977 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948349 infores:hetionet CHEBI:4903 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0236075 infores:hetionet CHEBI:27779 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0011991 infores:hetionet CHEBI:4907 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0016204 infores:hetionet CHEBI:7465 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0004093 infores:hetionet CAID:CA068627 biolink:causes MONDO:0018493 infores:clingen CAID:CA068627 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2248 of the RYR1 protein, p.Arg2248His. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual had a second RYR1 variant of unknown significance (p.Ile2358Leu) and PS4 was not implemented (PMID:23558838). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.654 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA068627/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:72297 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0232492 infores:hetionet CAID:CA120557 biolink:causes MONDO:0044970 infores:clingen CAID:CA120557 MONDO:0044970 PMID:11857739PMID:9932960 Uncertain Significance PP3 PP1, PS4, PS2, PS3, PM6, PM2 The m.8296A>G variant in MT-TK has been reported in 18 unrelated individuals with primary mitochondrial disease with varying phenotypes (diabetes, hypertrophic cardiomyopathy, optic atrophy, sensorineural hearing loss, and generalized epilepsy; 10 subjects reported in PMIDs: 9802769, 9571188, 10525672; additional subjects reported in PMIDs: 10737988, 12504210, 18651333, 20143911, 37573175), however analyses for other genetic etiologies were limited in these affected individuals precluding their inclusion in this curation. The variant was present in some affected individuals at homoplasmy and in others at heteroplasmy. In at least one family, the variant was present at homoplasmy in the proband and in his healthy mother and sister (PMID: 18651333). There are no reported de novo occurrences to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.061%, 38/61,883; gnomAD v3.1.2: 0.044%, 25/56,432 homoplasmic occurrences, one heteroplasmic occurrence; Helix: 0.048%, 94/195,893 homoplasmic occurrences). The computational predictor MitoTIP suggests this variant is pathogenic (72.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Single fiber testing showed similar levels of the variant in COX-negative ragged red fibers and normal fibers (PMID: 9932960), and cybrid studies showed no significant differences from wild type (PMID: 11857739). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120557/MONDO:0044970/015 2025-02-04 2025-05-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9599 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0037274 infores:hetionet CHEBI:3752 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0008031 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0031117 infores:hetionet CHEBI:4858 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0003811 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009806 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0521839 infores:hetionet CHEBI:3216 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0267792 infores:hetionet CHEBI:7443 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0018965 infores:hetionet CHEBI:7025 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0035455 infores:hetionet CHEBI:7492 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0549386 infores:hetionet CHEBI:65173 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0009676 infores:hetionet CAID:CA410203890 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203890 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.211C>A (p.Leu71Met) is a missense variant which has a REVEL score < 0.50 (0.467), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203890/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49662 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0004096 infores:hetionet CHEBI:31176 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0040822 infores:hetionet NCBIGene:3651 biolink:causes MONDO:0011667 infores:monarchinitiative not_provided not_provided HGNC:6107 MONDO:0011667 uuid:af2eb88e-12ad-4a4b-82d4-a490bb80620b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4911 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0027497 infores:hetionet CHEBI:52172 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151827 infores:hetionet CAID:CA340747862 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747862 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting BP4, BA1, BS1 NM_000329.3(RPE65):c.419G>A is a missense variant causing substitution of glycine by glutamic acid at position 140. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 30870047). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) and NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) variants confirmed in trans (2 points, PMID: 30870047), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts) by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (10 total points, PMID: 30870047, PP4_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00003893, with 5 alleles / 35438 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.847, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747862/MONDO:0100368/120 2024-02-01 2024-02-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0008489 infores:hetionet CHEBI:63616 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0023530 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011551 infores:hetionet CHEBI:2663 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040136 infores:hetionet CHEBI:3213 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0026821 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0855242 infores:hetionet CAID:CA386941084 biolink:causes MONDO:0015967 infores:clingen CAID:CA386941084 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting BP4, PP3, BS2 The c.1825C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to tyrosine at codon 609 (p.(His609Tyr)) of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has a REVEL score of 0.628, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in a normoglycemic individual of 57 years old, which is younger than the MDEP-established cutoff (70 years old) for BS2 (internal lab contributors). In summary, c.1825C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386941084/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0232849 infores:hetionet CHEBI:47780 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0012569 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0235431 infores:hetionet UNII:8NZ41MIK1O biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0021368 infores:hetionet CHEBI:6832 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0013395 infores:hetionet CHEBI:171719 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0162830 infores:hetionet CHEBI:6775 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1260880 infores:hetionet CHEBI:6761 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0242461 infores:hetionet GO:0060314 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0060314 GO:0023052 CHEBI:68478 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0948594 infores:hetionet CHEBI:83527 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0020458 infores:hetionet CHEBI:63577 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C2830004 infores:hetionet CAID:CA8130206 biolink:causes MONDO:0007648 infores:clingen CAID:CA8130206 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM5, PM4, BS2, PP4, PP1, PP2, PP3, BP3, BP1, BP4, PS2, PS4, PS3, PS1 The NM_004360.5(CDH1):c.2164+17dup variant has an allele frequency of 0.1034 (10%, 3634/35146 alleles, 197 homozygotes) in the Latino subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8130206/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:30830 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0037763 infores:hetionet CHEBI:31348 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085649 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0740394 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235876 infores:hetionet CHEBI:4903 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0025323 infores:hetionet CHEBI:132233 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0232459 infores:hetionet CAID:CA1619865 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619865 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM1_Supporting, PP1_Strong PP3, BP4, BA1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4, PVS1, PM2 The c.1090G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 364 (p.Val364Met). This missense variant is located in the I-helix, meeting PM1_Supporting. The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.0005791 (26 alleles out of 44,896), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The REVEL score = 0.609, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on CYP1B1 function. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in 6 individuals with a CYP1B1-related phenotype. These individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (2 confirmed in trans and 4 with phase unknown) (PMIDs: 39158757, 20151268, 11527932, 21850185, 20664688). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 30662834, 20151268, 39158757), which fulfilled PP1_Strong. There were more family studies published than presented here. In summary, this variant met the criteria to receive a score of 13 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very-Strong, PP1_Strong, PM1_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619865/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53691 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0518015 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0033775 infores:hetionet NCBITaxon:633 biolink:causes MONDO:0007024 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:633 MONDO:0007024 CHEBI:93363 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0027769 infores:hetionet CHEBI:61049 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235063 infores:hetionet CHEBI:9654 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0234238 infores:hetionet GO:0042173 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0042173 GO:0048856 CHEBI:3176 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0085649 infores:hetionet CHEBI:9137 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0039070 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013395 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0267792 infores:hetionet CHEBI:9738 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0001824 infores:hetionet CAID:CA10581404 biolink:causes MONDO:0044970 infores:clingen CAID:CA10581404 MONDO:0044970 PMID: Uncertain Significance BP4 PS2, PS3, PS4, PM6, PM2 The m.9152T>C (p.I209T) variant in MT-ATP6 has been reported in one case to date, in an individual with autism, fatigue, reflux, and constipation (PMID: 30763462) who had the variant present at 23% in blood. The proband's healthy mother had the variant present at 10% in blood. There are no reported de novo occurrences to our knowledge. The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.47 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581404/MONDO:0044970/015 2023-06-26 2024-07-24 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7443 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0019080 infores:hetionet CHEBI:46195 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0014742 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0858598 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0858797 infores:hetionet NCBIGene:6103 biolink:causes MONDO:0010443 infores:monarchinitiative not_provided not_provided HGNC:10295 MONDO:0010443 uuid:7c6f4fc0-d5b4-4413-a65f-910a020c27ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:8626 biolink:causes MONDO:0957216 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0957216 uuid:850799cd-3d64-40af-9ced-740ab4fd0b74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915940685 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940685 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000419.5:c.1919_1920del (p.Val640AlafsTer20) variant in ITGA2B exon 19 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 20/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least two probands with Glanzmann thrombasthenia. However, it is unclear if the reported probands (GT32 and GT67, PMID: 19691478) were homozygous for this variant or if a second ITGA2B variant was identified in either individual. At least one patient (Patient GT32 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting, PP4_Moderate. (VCEP specifications version 2; date of approval 05/17/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940685/MONDO:0100326/011 2022-05-17 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:10101 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0018801 infores:hetionet CHEBI:51041 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C1306341 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0857236 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0857236 infores:hetionet NCBIGene:23370 biolink:causes MONDO:0044314 infores:monarchinitiative not_provided not_provided HGNC:17090 MONDO:0044314 uuid:5fba4f03-665d-4628-a254-7e357c6a2973 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9435 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0028738 infores:hetionet CHEBI:3242 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0040264 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0264863 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0264863 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0041969 infores:hetionet CHEBI:50885 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0234708 infores:hetionet CHEBI:8863 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151772 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042514 infores:hetionet CHEBI:9130 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0023066 infores:hetionet CHEBI:50885 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0423791 infores:hetionet CHEBI:6375 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0232462 infores:hetionet CHEBI:77733 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0039070 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0549398 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0549398 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0006444 infores:hetionet CAID:CA658820951 biolink:causes MONDO:0010604 infores:clingen CAID:CA658820951 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate PS4 The NM_000133.4(F9):c.969_975del variant deletes 7bp in exon 8 of the F9 gene, causing a frameshift and premature termination of translation. NMD is not predicted to occur, but the truncation of the peptidase S1 domain is expected to be detrimental to protein function (PVS1). The variant is absent from gnomAD v2.1 (PM2_Supporting). The variant is reported in at least one individual with severe Hemophilia B with full gene sequencing and deletion/duplication analysis in the literature (PP4_Moderate - PMID: 26612714). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PVS1, PP4_Moderate, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA658820951/MONDO:0010604/080 2024-12-06 2024-12-06 X-linked inheritance HP:0001417 Supports CHEBI:49575 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0021167 infores:hetionet CHEBI:8024 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0014591 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0005940 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233571 infores:hetionet CHEBI:4877 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0036454 infores:hetionet CHEBI:6846 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0004134 infores:hetionet GO:0075193 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0075193 GO:0009653 CHEBI:47898 biolink:causes UMLS:C0333494 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0333494 infores:hetionet GO:0010568 biolink:causes GO:0007114 infores:ubergraph knowledge_assertion manual_agent GO:0010568 GO:0007114 CHEBI:7915 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0521839 infores:hetionet CHEBI:8802 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0030193 infores:hetionet CHEBI:63608 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0004364 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0021400 infores:hetionet CHEBI:2208 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0854467 infores:hetionet CHEBI:75246 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0010200 infores:hetionet NCBIGene:1641 biolink:causes MONDO:0010239 infores:monarchinitiative not_provided not_provided HGNC:2714 MONDO:0010239 uuid:3f74e18a-733f-4b64-801a-b34befc1face biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038661 infores:hetionet NCBIGene:57122 biolink:causes MONDO:0014752 infores:monarchinitiative not_provided not_provided HGNC:29914 MONDO:0014752 uuid:5e88cc80-5dfd-4377-a6dd-a793dda40e83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233477 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018099 infores:hetionet CHEBI:2659 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C1963951 infores:hetionet CHEBI:4659 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0151798 infores:hetionet CHEBI:23765 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0851578 infores:hetionet CAID:CA229589 biolink:causes MONDO:0009861 infores:clingen CAID:CA229589 MONDO:0009861 PMID: Pathogenic PVS1, PP4_Moderate, PM2 Variant c.509+1G>A in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). This null variant, canonical +1 splice site, is in a gene where LOF is a known mechanism of disease. Exon skipping disrupts reading frame. Predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 5 out of 13 coding exons (PVS1). Variant identified in 1/66684 European alleles in ExAC. This variant is present in European (non-Finnish) populations at a frequency of 0.00001 (Gnomad, ExAC) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4-Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229589/MONDO:0009861/006 2020-05-14 2020-05-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32588 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0518015 infores:hetionet CHEBI:41423 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027121 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0948594 infores:hetionet CHEBI:6541 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0151539 infores:hetionet CHEBI:15407 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C2937358 infores:hetionet CHEBI:87681 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0039070 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033975 infores:hetionet CAID:CA392324369 biolink:causes MONDO:0007947 infores:clingen CAID:CA392324369 MONDO:0007947 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PM1 The NM_00138 c.3677G>T is a missense variant in FBN1 predicted to cause a substitution of a glycine by valine at amino acid 1226 (p.Gly1226Val), in a cbEGF-like domain of the protein. This variant was found in a pediatric proband with ectopia lentis and severe annuloaortic ectasia, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 26796135; PP4). This variant has been reported twice in ClinVar: once as likely pathogenic and once as uncertain significance (Variation ID: 495598). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.912). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392324369/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63621 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0010709 infores:hetionet NCBIGene:56172 biolink:causes MONDO:0007319 infores:monarchinitiative not_provided not_provided HGNC:15492 MONDO:0007319 uuid:4c466def-67e2-4e66-8375-7816cdc0bf68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681850 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020649 infores:hetionet CHEBI:51450 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0030196 infores:hetionet CHEBI:3561 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0037763 infores:hetionet CAID:CA121521 biolink:causes MONDO:0100039 infores:clingen CAID:CA121521 MONDO:0100039 PMID: Pathogenic PM1, PP3, PS2_Very Strong, PS4, PM2_Supporting The p.Ala40Val variant in CDKL5 has been reported in at least 4 unconfirmed de novo occurrences in patients with CDKL5 disorder (PMID 27779742, 17993579, 22678952, 19793311) (PM6_VS). It is also reported in the mosaic state in a male patient with CDKL5 disorder (PMID 25819767) and therefore confirmed to be de novo (PS2). The p.Ala40Val variant has been observed in at least 10 other individuals with CDKL5 disorder (27779742, 25819767, 17993579, 22678952, 19793311, 21309761, 19780792) (PS4). The variant is absent in gnomAD (PM2_supporting). The variant is located in a well-characterized (ATP binding region: aa 19-43) functional domain of CDKL5 (PMID: 28544139, 17993579, 23064044, 29264392) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ala40Val in CDKL5 is classified as Pathogenic based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4_strong, PM1, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121521/MONDO:0100039/016 2021-03-30 2021-05-17 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:4027 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0030554 infores:hetionet CHEBI:66901 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0018418 infores:hetionet CHEBI:5864 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023467 infores:hetionet CHEBI:116278 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0019521 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0037274 infores:hetionet CHEBI:63630 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0041657 infores:hetionet CHEBI:63623 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0017178 infores:hetionet CAID:CA308122919 biolink:causes MONDO:0018493 infores:clingen CAID:CA308122919 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 492 of the RYR1 protein, p.(Arg492His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00008, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.81 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308122919/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7459 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0000737 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0004238 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0235238 infores:hetionet CHEBI:6539 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0234133 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0011551 infores:hetionet CAID:CA387461043 biolink:causes MONDO:0019497 infores:clingen CAID:CA387461043 MONDO:0019497 PMID: Uncertain Significance PP3 PM3, PM2 The c.488T>C (p.Met163Thr) variant in GJB2 is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 163. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000934 (7/74950) in the African/African-American population, which is higher than the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (<0.007%), and thus does not meet the criterion for PM2. The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3. This variant has been detected in individuals diagnosed with hearing loss (PMID: 17666888), but not in the homozygous state nor in compound heterozygosity with a known pathogenic/likely pathogenic GJB2 variant. The one likely pathogenic entry in ClinVar for this variant, was reported in an infant with an alternative genetic diagnosis explaining respiratory distress and pulmonary hypertension in whom the GJB2 variant was reported at clinician request due to a half-sibling diagnosed with childhood-onset hearing loss (PMID: 30755392, SCV000854502.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387461043/MONDO:0019497/005 2024-11-20 2025-01-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:75722 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0559031 infores:hetionet CHEBI:63638 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0015672 infores:hetionet CHEBI:7466 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0020538 infores:hetionet CHEBI:6128 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0018926 infores:hetionet CHEBI:6933 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0027765 infores:hetionet CAID:CA340750220 biolink:causes MONDO:0100368 infores:clingen CAID:CA340750220 MONDO:0100368 PMID: Likely Pathogenic PM3, PP4_Moderate, PP1, PM2_Supporting PP3 The NM_000329.3(RPE65):c.55G>A (p.Val19Met) missense variant is predicted to replace the valine at position 19 with methionine. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts) , decreased rod responses on ERG (0.5 pts), large gene panel testing without other significant findings (2 pts) , hypoautofluorescence (2 pts), optic nerve pallor (0.5 pts), pigmentary retinopathy (0.5 pts), posterior subcapsular cataract (0.5 pts), RPE mottling (0.5.pts), partial macular atrophy (0.5 pts), symptomatic onset before age 5 (1 pt), OCT preserved with respect to vision loss (1 pt), decreased peripheral vision (1 pt), ERG demonstrated cone involvement (1 pt), and decreased central visual acuity (1 pt) which together are highly specific for RPE65-related recessive retinopathy (total 12.5 points, PP4_Moderate).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.65T>C (p.Leu22Pro) confirmed in trans (1 point) which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1.0 total points, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1).In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP4_Moderate, PM3, PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340750220/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:83804 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015732 infores:hetionet CHEBI:7476 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1443060 infores:hetionet GO:0044793 biolink:causes GO:0016032 infores:ubergraph knowledge_assertion manual_agent GO:0044793 GO:0016032 CHEBI:71415 biolink:causes MONDO:0005543 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0520463 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0439857 infores:hetionet CAID:CA2654378574 biolink:causes MONDO:0011071 infores:clingen CAID:CA2654378574 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+12710T>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.29) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2654378574/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10102 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0023067 infores:hetionet CHEBI:9168 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085605 infores:hetionet CHEBI:5855 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042024 infores:hetionet CHEBI:7640 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0001824 infores:hetionet CHEBI:135935 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0042963 infores:hetionet CHEBI:3508 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0404521 infores:hetionet CHEBI:63791 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011175 infores:hetionet CHEBI:79699 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0018965 infores:hetionet CHEBI:6541 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0022346 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002070 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018818 infores:hetionet CAID:CA386952842 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952842 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM5_Supporting PP3, PP4 The c.98C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 33 (p.(Pro33Arg)) of NM_000545.8. This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due 1 copy in the East Asian population and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information; therefore, PP4 cannot be applied (internal lab contributors). Another missense variant, c.98C>T (p.Pro33Leu), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant has a REVEL score of 0.524, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.98C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM5_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952842/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:6326 biolink:causes MONDO:0030064 infores:monarchinitiative not_provided not_provided HGNC:10588 MONDO:0030064 uuid:3013cdb0-ab5d-4557-9a92-fa7df656aeb8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8428 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0036572 infores:hetionet CHEBI:4710 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C2242996 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0009806 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151849 infores:hetionet CHEBI:44915 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0262662 infores:hetionet CAID:CA16020772 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020772 MONDO:0009861 PMID:26322415PMID:26322415 Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The c.353-2A>T variant in PAH has been reported in 1 patient with classic PKU, detected in trans with p.R111*. BH4 deficiency was excluded. (PP4_Moderate, PM3; PMID: 26322415). This variant is absent from controls in ExAC/gnomAD, 1000 Genomes, or ESP (PM2_supporting). It is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 4 is present in biologically-relevant transcript. (PVS1) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020772/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:11212 biolink:causes MONDO:0015005 infores:monarchinitiative not_provided not_provided HGNC:9457 MONDO:0015005 uuid:dbabc0ec-bd3d-4624-9a6c-78f180cd7fb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55969 biolink:causes MONDO:0859567 infores:monarchinitiative not_provided not_provided HGNC:15870 MONDO:0859567 uuid:f632d50c-151c-4b8b-8b82-9134dacc5e5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7286 biolink:causes MONDO:0957307 infores:monarchinitiative not_provided not_provided HGNC:12422 MONDO:0957307 uuid:682da51a-d55b-436a-b051-829557e2a5cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:80630 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1565489 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0857245 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0857245 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0001824 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085393 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0234215 infores:hetionet CAID:CA409109938 biolink:causes MONDO:0015967 infores:clingen CAID:CA409109938 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PP1_Strong PS4 The c.48C>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 16 (p.(Tyr16*)) of NM_175914.5. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes/neonatal hyperinsulinism, with 13 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes or diazoxide-responsive hyperinsulinemic hypoglycemia; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 20164212, 16917892, 17407387, 18268044, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). In summary, c.48C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP1_Strong, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409109938/MONDO:0015967/085 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7459 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0034063 infores:hetionet NCBIGene:5261 biolink:causes MONDO:0013091 infores:monarchinitiative not_provided not_provided HGNC:8931 MONDO:0013091 uuid:b74481d9-6acd-4855-8d5c-e685f551a9b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0000731 infores:hetionet CHEBI:5123 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C1527311 infores:hetionet CHEBI:2668 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085632 infores:hetionet CHEBI:9720 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0009806 infores:hetionet CHEBI:27834 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0035455 infores:hetionet CHEBI:4469 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0917801 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0521592 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0151601 infores:hetionet NCBIGene:1352 biolink:causes MONDO:0033635 infores:monarchinitiative not_provided not_provided HGNC:2260 MONDO:0033635 uuid:39e9b673-8455-4e60-bade-ab9fd5551b7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0010692 infores:hetionet CHEBI:8346 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0018794 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0023895 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0425449 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0425449 infores:hetionet CHEBI:50173 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0392699 infores:hetionet CHEBI:5118 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042029 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235280 infores:hetionet CHEBI:31401 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0600142 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151888 infores:hetionet CHEBI:31622 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0002622 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001889 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0747102 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0034150 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0003864 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1619712 infores:hetionet CHEBI:28748 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151594 infores:hetionet UBERON:0003292 biolink:causes MONDO:0001279 infores:ubergraph knowledge_assertion manual_agent UBERON:0003292 MONDO:0001279 CHEBI:8024 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0032617 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0027769 infores:hetionet CHEBI:64312 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0428974 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0007760 infores:hetionet CHEBI:6067 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0000731 infores:hetionet CHEBI:17263 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0008489 infores:hetionet CAID:CA10014376 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014376 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, PM2, PVS1, PM6, PM5, PM4, PM1, PM3, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.695G>A (p.Arg232Gln) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014376/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:101278 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0541782 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0271650 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0032584 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0013395 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042373 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0025061 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019348 infores:hetionet NCBIGene:4884 biolink:causes MONDO:0859334 infores:monarchinitiative not_provided not_provided HGNC:7952 MONDO:0859334 uuid:99ceb8ff-8a95-4139-8ea6-68c085cbf7a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0021400 infores:hetionet CHEBI:2663 biolink:causes HP:0033670 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0264383 infores:hetionet CHEBI:5004 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0040822 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0917798 infores:hetionet CHEBI:2659 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0600228 infores:hetionet CHEBI:4672 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0028961 infores:hetionet CHEBI:7476 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0012569 infores:hetionet CHEBI:3636 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0003467 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0178298 infores:hetionet CHEBI:9086 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0003635 infores:hetionet CHEBI:8707 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151907 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151717 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0027765 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0020649 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0037199 infores:hetionet CAID:CA377484731 biolink:causes MONDO:0017623 infores:clingen CAID:CA377484731 MONDO:0017623 PMID: Pathogenic PM2, PVS1, PS4_Supporting PM6, BS4, BS3, BS1, BP5, BP7, PP1, PP3, PP2, BS2, PM1, PM4, PM5, BA1, BP2, BP4, PS2, PS3, PS1 PTEN c.634+2T>C (IVS6+2T>C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populationsPS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377484731/MONDO:0017623/003 2020-03-23 2020-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6076 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0003862 infores:hetionet CHEBI:9674 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0392699 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0086132 infores:hetionet CHEBI:32139 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0010520 infores:hetionet CHEBI:17263 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C1291077 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0030312 infores:hetionet CHEBI:47780 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042023 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011570 infores:hetionet CHEBI:15367 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0344232 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0745153 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0745153 infores:hetionet GO:1903722 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:1903722 GO:0044085 CHEBI:50223 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0020437 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1720775 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0442874 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0019158 infores:hetionet CHEBI:31949 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0948594 infores:hetionet CHEBI:7986 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0042963 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004936 infores:hetionet CAID:CA2573132575 biolink:causes MONDO:0100368 infores:clingen CAID:CA2573132575 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000329.3(RPE65):c.1059dup (p.Lys354GlufsTer11) is a frameshift variant that introduces a premature stop codon into exon 10 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant suspected in trans (0.5 points, PMID: 17197551), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting). The variant has also been reported in a second proband with early-onset retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.997G>C (p.Gly333Arg) variant confirmed in trans (PMID: 31273949, PMID: 21602930); however, this case was not considered for this variant to avoid circularity. In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573132575/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8890 biolink:causes MONDO:0005693 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0392548 infores:hetionet CHEBI:7565 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0022408 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0232492 infores:hetionet CAID:CA210760 biolink:causes MONDO:0013144 infores:clingen CAID:CA210760 MONDO:0013144 PMID: Likely Pathogenic PM5, PM1, PP3, PS4_Supporting, PM2_Supporting PS3 The c.235C>A variant in SEPRINC1 is a missense variant predicted to cause substitution of arginine by serine at amino acid 79 (p.Arg79Ser). This variant has been reported in one family with an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. (PS4_Supporting; PMID:3350974). This variant is absent from gnomAD v[2.1.1] (PM2_Supporting). This variant resides within a region, Arg79, of SERPINC1 that is defined as a critical functional domain that would impact heparin binding site residues by the ClinGen Thrombosis Variant Curation Expert Panel (PM1). Another missense variant c.236G>A (p.Arg79His) (ClinVarID:18014) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis Variant Curation Expert Panel (PM5). The computational predictor REVEL gives a score of 0.718, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis Variant Curation Expert Panel: PM1, PM5, PP3, PM2_Supporting, PS4_Supporting. (Required: ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210760/MONDO:0013144/084 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:59773 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0023895 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0413252 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0231218 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006849 infores:hetionet NCBIGene:8085 biolink:causes MONDO:0035651 infores:monarchinitiative not_provided not_provided HGNC:7133 MONDO:0035651 uuid:8c147e53-8e72-434e-a4fe-4a3dc40eea1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3994 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0150450 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0032285 infores:hetionet CHEBI:2704 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0041834 infores:hetionet CHEBI:134991 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0424790 infores:hetionet CHEBI:31397 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0020522 infores:hetionet CHEBI:47898 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085661 infores:hetionet CHEBI:39669 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0018524 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235653 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235653 infores:hetionet NCBIGene:55691 biolink:causes MONDO:0014787 infores:monarchinitiative not_provided not_provided HGNC:25491 MONDO:0014787 uuid:0527a388-ea34-42de-bce6-2730c14d9056 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0013595 infores:hetionet CAID:CA512318599 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318599 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.735C>A (p.Pro245=) is a synonymous variant. This variant has a SpliceAI score ≤ 0.20 (Donor Loss: 0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318599/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2573051040 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051040 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 The c.1719delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 574 of NM_000545.8, adding 86 novel amino acids before encountering a stop codon (p.(Ser574AlafsTer86)). While this variant, located in exon 9 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylurea) (PP4_Moderate; internal lab contributor). In summary, c.1719delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051040/MONDO:0015967/017 2022-06-15 2022-06-15 Autosomal dominant inheritance HP:0000006 Supports CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0859350 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0859350 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0018802 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002270 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0563238 infores:hetionet CHEBI:63631 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0404521 infores:hetionet CHEBI:8888 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0268000 infores:hetionet CHEBI:6887 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0001925 infores:hetionet CHEBI:71219 biolink:causes UMLS:C1142111 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1142111 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0016436 infores:hetionet CAID:CA222130 biolink:causes MONDO:0015152 infores:clingen CAID:CA222130 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.1481-1G>A variant in DYSF, which is also known as NM_001130987.2: c.1577-1692G>A , occurs within the canonical splice acceptor site (+/- 1,2) of intron 16. SpliceAI gives a delta score of 0.76 for loss of the canonical acceptor and of 0.41 for gain of a cryptic acceptor at the +2 position in exon 17. RNAseq analysis has demonstrated disrupted splicing as a result of this variant, resulting in use of the cryptic acceptor site, a 2 bp deletion, and a frameshift and premature truncation, p.Glu494GlyfsTer16 (PMID: 36983702; PVS1_RNA). Of note, while exon 17 is not present in the MANE SELECT transcript NM_001130987.2, which is expressed in blood, the transcript highly expressed in skeletal tissue muscle, NM_003494.4, contains exon 17 and is expected to be affected by this variant. This variant has been identified in at least four patients with features consistent with LGMD (PMID: 20544924, 27602406, 36983702), including in unknown phase with a pathogenic variant in at least two individuals (NM_003494.4: c.1392dup p.(Asp465ArgfsTer9), 0.5 pts, PMID: 27602406, 27602406; NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19), 0.5 pts, PMID: 20544924) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF allele had a clinical suspicion of LGMD or progressive limb girdle muscle weakness as well as severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 20544924, 27602406, 36983702). The filtering allele frequency of this variant is 0.000017496 in gnomAD v4.1.0 (the upper bound of the 95% CI of 12/1111262 European (non-Finnish) exome chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_RNA, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222130/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8874 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018681 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018799 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0028738 infores:hetionet CHEBI:63619 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0001824 infores:hetionet CHEBI:68841 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0013378 infores:hetionet CHEBI:9654 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0009806 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0019158 infores:hetionet CHEBI:31547 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011603 infores:hetionet CHEBI:8871 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0575081 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0040435 infores:hetionet CHEBI:2955 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0235378 infores:hetionet CHEBI:27779 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0005779 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0041969 infores:hetionet CAID:CA1703634895 biolink:causes MONDO:0015967 infores:clingen CAID:CA1703634895 MONDO:0015967 PMID: Uncertain Significance PM4_Supporting, PP4, PM2_Supporting The c.811_813del variant in the glucokinase gene, GCK, is a 3 base pair deletion resulting in the in-frame deletion of 1 amino acid at codon 271 (p.(Leu271del)) within exon 7 of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (HbA1c between 5.6-7.6% and fasting glucose between 5.5-8mmol/L) (PP4; internal lab contributor). This variant is absent in gnomAD v2.1.1 (PM2_Supporting).The c.811_813del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). In summary, c.811_813del meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4, PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1703634895/MONDO:0015967/086 2023-12-15 2023-12-15 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:51860 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0152030 infores:hetionet CHEBI:8774 biolink:causes MONDO:0021718 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0032541 infores:hetionet CHEBI:6339 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1443060 infores:hetionet CHEBI:38940 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151766 infores:hetionet CHEBI:10127 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0031256 infores:hetionet CHEBI:75722 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0036396 infores:hetionet CHEBI:4710 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0235857 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0026946 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0013395 infores:hetionet NCBIGene:26057 biolink:causes MONDO:0859186 infores:monarchinitiative not_provided not_provided HGNC:23575 MONDO:0859186 uuid:67e40a1c-9c20-4ad5-90b0-c11a90a79a86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013395 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151898 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151898 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0037199 infores:hetionet CHEBI:17650 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0023518 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0027651 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0021400 infores:hetionet CHEBI:85161 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0000737 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0029882 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0034065 infores:hetionet CHEBI:9449 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0151828 infores:hetionet CHEBI:47499 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0001824 infores:hetionet CHEBI:9316 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0039231 infores:hetionet CHEBI:49668 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0014742 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0031085 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0011849 infores:hetionet CAID:CA658498409 biolink:causes MONDO:0044970 infores:clingen CAID:CA658498409 MONDO:0044970 PMID:33279600 Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate, PM6_Supporting The m.7453G>A variant in MT-TS1 has been reported in three individuals with primary mitochondrial disease (PMIDs: 22453297, 32313153, 33279600; PS4_moderate). Two presented with neonatal lactic acidosis. One died at 10 days old, and the variant was present at homoplasmy in muscle (PMID: 22453297). This child had severely decreased amounts of fully assembled complex I in heart, complex I deficiency in skeletal muscle and liver, and complex IV deficiency in brain, heart, liver, and skeletal muscle. There was combined complex I/IV deficiency in skeletal muscle. The variant was absent in the asymptomatic mother’s blood (PM6_supporting). The second child with neonatal lactic acidosis developed weakness, exercise intolerance, and fatigue by three years old. The variant was homoplasmic in blood (PMID: 32313153). The third reported case had myopathy onset early in life, and was described as having high heteroplasmy levels of the variant in skeletal muscle, urine, and buccal mucosa (PMID: 33279600). This variant is absent in the GenBank dataset. There are two heteroplasmic occurrences in gnomAD v3.1.2 and two heteroplasmic occurrences in the Helix dataset (PM2_supporting). MitoTIP predicts the variant is possibly pathogenic (68th percentile) and HmtVAR predicts the variant is pathogenic (score of 0.35; PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (96.7%, n=14) than in non-COX-positive fibers (25.1%, n=14) p<0.0001 (PMID: 33279600). Additionally, cybrid studies showed reduction in tRNASer(UCN) levels and reduced oxygen consumption in mutant cybrids (PS3_moderate; PMID: 33279600). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658498409/MONDO:0044970/015 2024-10-28 2025-11-06 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:34385 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0917801 infores:hetionet CHEBI:168396 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042023 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011334 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0852995 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0852995 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018418 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0015397 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0015397 infores:hetionet CHEBI:75998 biolink:causes UMLS:C1096403 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C1096403 infores:hetionet CAID:CA16020982 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020982 MONDO:0009861 PMID:10693064 Likely Pathogenic PM2, PM5, PP3, PP4 The c.1249T>G (p.Tyr417Asp) variant in PAH has been reported in 1 individual with PAH deficiency (PMID: 10693064). This variant is absent in population databases. Computational evidence support a deleterious effect. Another missense variant at the same amino acid (p.Tyr417His) is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020982/MONDO:0009861/006 2020-08-13 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:39867 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232910 infores:hetionet CHEBI:2659 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0270611 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0860967 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0019360 infores:hetionet CHEBI:6073 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0151766 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0015230 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0847631 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0847631 infores:hetionet CHEBI:3175 biolink:causes HP:6000420 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0234655 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001011 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006144 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0004096 infores:hetionet CAID:CA10585656 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585656 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP3, PP4, PP1 PM5 The NM_000527.5 (LDLR): c.1856T>G (p.Phe619Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP3 Met: REVEL = 0.856, which is above the threshold of 0.75.PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Supporting Met: Variant meets PM2, and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2).PP1 Met: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1).There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585656/MONDO:0007750/013 2022-02-10 2022-04-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8874 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151564 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011630 infores:hetionet CHEBI:144551 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0851578 infores:hetionet CHEBI:3011 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0038325 infores:hetionet CHEBI:6761 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0233571 infores:hetionet CHEBI:16796 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0600142 infores:hetionet CHEBI:3638 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0023646 infores:hetionet CHEBI:3756 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0236024 infores:hetionet CHEBI:2611 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0549622 infores:hetionet CHEBI:7496 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0235996 infores:hetionet GO:0060040 biolink:causes CL:0000748 infores:ubergraph knowledge_assertion manual_agent GO:0060040 CL:0000748 UMLS:C1738934 biolink:causes MONDO:0005753 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0014541 infores:hetionet CHEBI:64317 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0039231 infores:hetionet CHEBI:9435 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0855775 infores:hetionet CHEBI:2922 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0014457 infores:hetionet NCBITaxon:783 biolink:causes MONDO:0019359 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:783 MESH:D012373 DB00595_MESH_D012373_1DB13092_MESH_D012373_1DB00254_MESH_D012373_1DB00759_MESH_D012373_1DB01017_MESH_D012373_1DB00618_MESH_D012373_1DB02703_MESH_D012373_1 CHEBI:194135 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0973461 infores:hetionet CHEBI:38562 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0151798 infores:hetionet CHEBI:71255 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0009806 infores:hetionet CHEBI:5138 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234133 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0178298 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0151786 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0595930 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0267792 infores:hetionet CHEBI:134991 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0002622 infores:hetionet CHEBI:92607 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0039231 infores:hetionet CHEBI:5855 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0040264 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033247 infores:hetionet CHEBI:9168 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0010200 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0037274 infores:hetionet CHEBI:45409 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013428 infores:hetionet CHEBI:6904 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0040034 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034065 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0851341 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0018524 infores:hetionet GO:0061295 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:0061295 GO:0001823 CHEBI:6067 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0022116 infores:hetionet CHEBI:4888 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0033036 infores:hetionet CHEBI:135935 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0013604 infores:hetionet CHEBI:32315 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0026826 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0038454 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0851341 infores:hetionet CHEBI:5441 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C1368065 infores:hetionet CAID:CA9091086 biolink:causes MONDO:0021060 infores:clingen CAID:CA9091086 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.141C>T (p.Asp47=) variant in the MAP2K2 gene is 0.054% (9/8646) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9091086/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63631 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0040264 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0010692 infores:hetionet CAID:CA8815481 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815481 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM1, PM5, PM2_Supporting, PS3_Moderate, PM3_Strong BA1 The NM_000152.5:c.1798C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 600 (p.Arg600Cys). At least 15 patients with Pompe disease have been reported with this variant. Of these patients, at least 8 have documented laboratory values showing GAA deficiency, some of whom also have documentation of symptoms consistent with infantile onset Pompe disease, and/or on enzyme replacement therapy, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 14695532, 18458862, 19609281, 21984055, 24384324, 26497565, 29124014) (PP4_Moderate). Additional patients were reported to be on enzyme replacement therapy, without GAA activity values provided, meeting PP4 (PMID 20202878), and others were reported to have Pompe disease but did not have sufficient data for PP4 to be applied (PMID 11053688, 14643388, 26253708, 27417441, 29124014). The patients with Pompe disease and this variant include three patients who are compound heterozygous for the variant and a pathogenic variant in GAA, either c.525delT (PMID 14695532; phase unknown), or c.546G>T (PMID 20202878, 21984055; phase unknown in both cases), and one homozygote (PMID 11053688)(PM3_Strong). The variant was also reported to be in cis with c.199G>A (p.Asp67Asn) and in trans with c.546G>T in one patient; this data was not counted for PM3 due to the presence of the in cis variant, which is rare and has not yet been assessed by the LSD VCEP (PMID 19609281). In addition, the variant was found in compound heterozygosity with the following variants; the allelic data for the following patients will be used in the assessment of the second variant and is not included here to avoid circular logic - c.871C>T (p.Leu291Phe)(PMID 26253708, 27417441), c.872T>C (p.Leu291Pro)(PMID 18458862), c.1211A>G (p.Asp404Gly)(PMID 24384324), c.1309C>T (p.Arg437Cys)(PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 20202878), c.1857C>G (p.Ser619Arg)(PMID 29124014), c.1979G>A (p.Arg660His)(PMID 14643388), c.2105G>T (p.Arg702Leu)(PMID 26497565), c.2481+1G>A (PMID 29124014). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant alters an amino acid, Arg600, that has been deduced to be important in the active site architecture of GAA, based on the crystal structure of native and recombinant GAA (PMID: 29061980; DOI 10.1101/212837)(PM1). Indeed, when expressed in either COS cells or GAA-deficient SV40 immortalized fibroblasts, the variant had <1% wild type GAA activity, and Western blot showed abnormal synthesis and processing of the enzyme (PMID 11053688, 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.915 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Three additional missense changes in the same codon have been reported in patients with Pompe disease; c.1799G>A (p.Arg600His) is pathogenic based on assessment by the ClinGen LSD VCEP (PM5); c.1799G>C (p.Arg600Pro) and c.1799G>T (p.Arg600Leu) have also been reported. There is a ClinVar entry for this variant (Variant ID 640911; 2 star review status) with three submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM1, PM5, PP3, PS3_Moderate, PM3_Strong, PM2_Supporting, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815481/MONDO:0009290/010 2021-09-30 2021-12-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31709 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0020517 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0021053 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018799 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0018802 infores:hetionet CHEBI:61390 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0032285 infores:hetionet CAID:CA229645 biolink:causes MONDO:0009861 infores:clingen CAID:CA229645 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.608G>A (p.Cys203Tyr) variant in PAH has been reported in 3 individuals with mild PKU and HPA (BH4 deficiency excluded). (PMID: 27121329, 23842451). This variant is absent in population databases. This variant was detected with pathogenic variants p.A300S in 2 patients (once confirmed in trans PMID: 23352389, 23500595, 27121329) and p.L348V PMID: 23842451 (2.0 points). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229645/MONDO:0009861/006 2020-02-23 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45924 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0018681 infores:hetionet CAID:CA2802275 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802275 MONDO:0001586 PMID: Likely Pathogenic PM3_Strong, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting PS1, PM1, PM5 The NM_000203.5:c.1487C>G variant in IDUA is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 496 p.(Pro496Arg). At least 8 patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP including c.793G>C (p.Gly265Arg) (ClinVar Variation ID: 638074) (PMID: 21394825, LP, 0.25), c.152G>A (p.Gly51Asp) (ClinVar Variation ID: 193061) (PMID: 21394825, P, 2 x 0.5), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 21394825, P, 4 patients, max 2 x 0.5), and c.1598C>G (p.Pro533Arg) (PMID: 34408967, P, 0.5 points). One individual is homozygous for the variant (PMID: 34408967, 0.5 points). This variant has also been reported in compound heterozygosity with p.Arg89Trp (PMID: 21394825), c.1727+1G>A (PMID: 21394825), c.1854C>A (p.Tyr618Ter) (PMID: 27520059) and c.878_889dup (PMID 28752568). The allelic data from these patients will be used in the subsequent classification of then second variant and is not included here to avoid circular logic. Total 3.25 points (PM3_Strong). In one report (PMID: 27520059), there was evidence of decreased IDUA enzyme activity, increased urine glycosaminoglycans and a specific clinical phenotype, allowing for application of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000003515 (4/1137936 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). and has some experimental evidence suggesting absence of IDUA activity when the variant is expressed in Cos-7 cells (PMID: 11735025) (PS3_Supporting). Computational predictor tools (REVEL score 0.72) suggest that this variant may be deleterious to IDUA function (PP3). A different missense variant, c.1487C>G (p.Pro496Leu) [ClinVar Variation ID 551675] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen VCEP, however PM5 was not assigned to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 496861). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel: PM3_Strong, PP4_Moderate. PS3_Supporting, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802275/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports CAID:CA2577483399 biolink:causes MONDO:0011071 infores:clingen CAID:CA2577483399 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1259GCG[3] (p.Gly421_Glu422insGly) is an in-frame insertion variant that does not affect any known functional domain (PM4 not applicable). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2577483399/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3757 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011570 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0340464 infores:hetionet CHEBI:4657 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0002994 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0002871 infores:hetionet CHEBI:135005 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020546 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0085631 infores:hetionet CHEBI:63580 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151907 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0151828 infores:hetionet NCBIGene:23334 biolink:causes MONDO:0014201 infores:monarchinitiative not_provided not_provided HGNC:29040 MONDO:0014201 uuid:e7a70a55-a139-4568-9121-b66668635938 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0687707 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0008311 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0231528 infores:hetionet UMLS:C0209366 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0151735 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0003467 infores:hetionet CHEBI:9086 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0006277 infores:hetionet CHEBI:63621 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151904 infores:hetionet NCBIGene:5133 biolink:causes MONDO:0975847 infores:monarchinitiative not_provided not_provided HGNC:8760 MONDO:0975847 uuid:c6045b27-9ae2-455c-8547-709bbb1b743c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0085631 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0003864 infores:hetionet CHEBI:140621 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0011603 infores:hetionet CHEBI:2618 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0011124 infores:hetionet NCBIGene:4967 biolink:causes MONDO:0008759 infores:monarchinitiative not_provided not_provided HGNC:8124 MONDO:0008759 uuid:74cd35ae-a0cd-4cb4-8361-f49ee8bf77a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015230 infores:hetionet CHEBI:135005 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0042023 infores:hetionet CHEBI:490877 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0033774 infores:hetionet CHEBI:72564 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020580 infores:hetionet CHEBI:6715 biolink:causes MONDO:0018309 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019569 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0005779 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0236051 infores:hetionet CHEBI:4681 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0151736 infores:hetionet CHEBI:3723 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043094 infores:hetionet CHEBI:28925 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0042571 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0004936 infores:hetionet CHEBI:4046 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0013604 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0520547 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0520547 infores:hetionet CHEBI:180905 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0151636 infores:hetionet CHEBI:46557 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0851578 infores:hetionet CHEBI:37941 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0034152 infores:hetionet CHEBI:6717 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0023530 infores:hetionet CHEBI:4822 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0042571 infores:hetionet CAID:CA214046 biolink:causes MONDO:0012163 infores:clingen CAID:CA214046 MONDO:0012163 PMID: Uncertain Significance PP4, PM2 NM_002185.5(IL7R):c.539A>C is a missense variant predicted to cause substitution of Histidine by Proline at amino acid 180 (p.His180Pro). The highest population minor allele frequency in gnomAD v4 is 0.0002710 (16/59030 alleles) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met).2 patients (PMID: 23810098) with SCID (0.5 pt.) having T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total :0.75 pts.) (PP4 not met). Both patients had maternal cell engraftment. One patient (PMID: 23810098) was found heterozygous for H180P & F71S (pre-curated as VUS) and another patient (PMID: 23810098) was found heterozygous for H180P & I94fs (not classified by SCID VCEP) (0.25 pt.). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: No criteria met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214046/MONDO:0012163/119 2024-01-24 2024-01-24 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0005740 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0002871 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1321686 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0036572 infores:hetionet CHEBI:5128 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C1306341 infores:hetionet CHEBI:16796 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0030252 infores:hetionet GO:0106023 biolink:causes GO:0035210 infores:ubergraph knowledge_assertion manual_agent GO:0106023 GO:0035210 CHEBI:68642 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0151904 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0948594 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0178298 infores:hetionet CHEBI:9671 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0022650 infores:hetionet CHEBI:251408 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0023066 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004169 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0376356 infores:hetionet CHEBI:6067 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0152459 infores:hetionet CHEBI:17489 biolink:causes GO:0044557 infores:drugmechdb knowledge_assertion manual_agent MESH:D000242 GO:0044557 DB00816_MESH_D001249_1DB00816_MESH_D001991_1 CAID:CA211324 biolink:causes MONDO:0010880 infores:clingen CAID:CA211324 MONDO:0010880 PMID: Likely Benign BS3_Supporting, BP5, BS1, PP3, PM5 The NM_000020.3: c.1445C>T variant in ACVRL1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 482 (p.Ala482Val). Another missense variant, c.1445C>A, Ala482Glu (PMID: 17786384, 21158752), in the same codon has been classified as likely pathogenic for autosomal dominant Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). However, the filtering allele frequency (the lower threshold of the 95% CI of 395/129122) of the c.1445C>T variant in ACVRL1 is 0.002819 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has also been observed in 3 patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ENG variant) (BP5; PMID: 15517393, Internal lab contributors). The computational predictor REVEL gives a score of 0.839, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). However, functional assays (BRE assay, Western blot analysis of Smad1/5 phosphorylation) in NIH-3T3 cells showed that the variant protein responded to BMP9 stimulation either measured in the BRE assay or by Smad1/5 phosphorylation, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 20501893). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting, PP3, PM5 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA211324/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101278 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0040264 infores:hetionet CHEBI:50885 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C1368065 infores:hetionet CHEBI:3419 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0036572 infores:hetionet CHEBI:7773 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C2047937 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017160 infores:hetionet CAID:CA274153 biolink:causes MONDO:0009290 infores:clingen CAID:CA274153 MONDO:0009290 PMID: Pathogenic PVS1, PM2, PP4, PM3 This variant, c.1827delC (p.Tyr609Terfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This is supported by the absence of cross reactive immunological material studies in cultured fibroblasts from a patient with the variant (PMID 22252923). The highest maximum population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00007181 in the European non-Finnish population. This meets the ClinGen LSD VCEP’s threshold for PM2. This variant was found in compound heterozygosity with a unique pathogenic variant in GAA in two patients with Pompe disease who also meet the ClinGen LSD VCEP's specifications for PP4; one of these patients is compound heterozygous for p.Tyr609Terfs and c.2481+102_2646 + 31del, and the other is compound heterozygous for p.Tyr609Terfs and c.-32-13T>G (PMIDs 26693141, 30655185). Therefore, PP4 and PM3 can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 14695532, 30564623). There is a ClinVar entry for this variant (Variation ID: 188936, 2 star review status) with 3 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274153/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6909 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0021400 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0042401 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0233494 infores:hetionet CHEBI:7936 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235086 infores:hetionet CHEBI:6375 biolink:causes HP:6000686 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0241254 infores:hetionet CHEBI:27899 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0037928 infores:hetionet NCBIGene:1056 biolink:causes MONDO:0012348 infores:monarchinitiative not_provided not_provided HGNC:1848 MONDO:0012348 uuid:994115b7-6d25-4f4e-afea-438accce9c78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020649 infores:hetionet CHEBI:681569 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0017565 infores:hetionet CHEBI:135342 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0428977 infores:hetionet NCBIGene:54332 biolink:causes MONDO:0008961 infores:monarchinitiative not_provided not_provided HGNC:15968 MONDO:0008961 uuid:286d5bd6-30f6-44b5-88d5-a7cc5e471d5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0025637 infores:hetionet CHEBI:31515 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0236075 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0037274 infores:hetionet NCBIGene:348 biolink:causes MONDO:0010017 infores:monarchinitiative not_provided not_provided HGNC:613 MONDO:0010017 uuid:514615a9-a3a9-43b4-bc22-0dac64d84a1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10110 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0231856 infores:hetionet CAID:CA10385456 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385456 MONDO:0100437 PMID: Benign BA1 PP3, BP4 NM_001034853.2(RPGR):c.1508C>G is a missense variant encoding substitution of threonine with arginine at amino acid 503. This variant is present in gnomAD v4.1.0 at a frequency of 0.00006126 among hemizygous individuals, with 15 variant alleles / 244877 total hemizygous alleles (All European (non-Finnish)), which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.409, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 and <0.290 and does not predict a damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.03, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes are not met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385456/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:3723 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0010399 infores:hetionet CHEBI:6375 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0149745 infores:hetionet NCBIGene:4329 biolink:causes MONDO:0013579 infores:monarchinitiative not_provided not_provided HGNC:7179 MONDO:0013579 uuid:e317652d-4135-4db6-b421-4b0112ae4d02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0037274 infores:hetionet CHEBI:135351 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0030662 infores:hetionet CHEBI:5141 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0547030 infores:hetionet CHEBI:70746 biolink:causes UMLS:C1328411 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C1328411 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0027339 infores:hetionet CHEBI:6015 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0267792 infores:hetionet CHEBI:253342 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0027497 infores:hetionet CHEBI:15854 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0009421 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151734 infores:hetionet CHEBI:63580 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030196 infores:hetionet CHEBI:7959 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C3263723 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0149732 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149732 infores:hetionet CHEBI:6715 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002792 infores:hetionet UMLS:C0145185 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0042963 infores:hetionet NCBIGene:8289 biolink:causes MONDO:0013819 infores:monarchinitiative not_provided not_provided HGNC:11110 MONDO:0013819 uuid:c9939d89-f925-480a-b3d9-9e4014f627cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6846 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0017178 infores:hetionet CHEBI:3696 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0034880 infores:hetionet CHEBI:31859 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0006277 infores:hetionet CHEBI:63925 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0002962 infores:hetionet CHEBI:681569 biolink:causes MONDO:0043994 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0149520 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0235446 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0235446 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0006266 infores:hetionet CHEBI:83804 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0232462 infores:hetionet NCBIGene:526 biolink:causes MONDO:0007420 infores:monarchinitiative not_provided not_provided HGNC:854 MONDO:0007420 uuid:2a2ec737-ca01-493f-bb2b-e96b1edfbc99 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0232849 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0233494 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0039971 infores:hetionet CHEBI:5801 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0041657 infores:hetionet CHEBI:47898 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1260926 infores:hetionet CHEBI:61390 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0042963 infores:hetionet CHEBI:6775 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0014457 infores:hetionet CHEBI:3515 biolink:causes HP:0032004 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0033778 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233794 infores:hetionet CHEBI:5893 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0006277 infores:hetionet CHEBI:63577 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0231530 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0032285 infores:hetionet CHEBI:64028 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0011991 infores:hetionet CHEBI:5855 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020621 infores:hetionet NCBIGene:79796 biolink:causes MONDO:0009890 infores:monarchinitiative not_provided not_provided HGNC:15672 MONDO:0009890 uuid:cf9f78f9-1ecd-4435-84d5-49cc6d61b37c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0016655 infores:hetionet CHEBI:110423 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0013404 infores:hetionet NCBIGene:283987 biolink:causes MONDO:0031028 infores:monarchinitiative not_provided not_provided HGNC:15736 MONDO:0031028 uuid:0d54a868-ce92-49d6-9718-1ecdf32a3159 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0030252 infores:hetionet CHEBI:64354 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0546884 infores:hetionet CHEBI:64312 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0232461 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005790 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0019159 infores:hetionet CHEBI:17141 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0237938 infores:hetionet CHEBI:17026 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0702166 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0006849 infores:hetionet CHEBI:5118 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0917801 infores:hetionet CHEBI:5383 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0019158 infores:hetionet CHEBI:59445 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0016204 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151505 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151898 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151898 infores:hetionet CHEBI:3696 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020473 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1142080 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1142080 infores:hetionet CAID:CA6197659 biolink:causes MONDO:0019501 infores:clingen CAID:CA6197659 MONDO:0019501 PMID: Uncertain Significance PP3 BS1, PM2 The c.1997G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by glycine at amino acid 666. The highest population minor allele frequency in gnomAD v4.1 is 0.0001865 (14/75048 alleles) in the African/African-American population (PM2_Supporting and BS1_Supporting are not met). The computational predictor REVEL gives a score of 0.841, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been observed in one proband with Usher syndrome, four probands with hearing loss, and two probands with retinal disease. However, they all harbored another variant of uncertain significance c.3527G>A (p.Ser1176Asn) with phase unknown, and two who were found to have an alternate molecular basis for disease (PM3_Supporting not met; ClinVar ID: 196099; PMIDs: 27460420, 31479088, 33297549, 27344577, LabCorp Genetics (formerly Invitae) internal data ClinVar SCV001498602.2, GeneDx internal data). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6197659/MONDO:0019501/005 2025-03-12 2025-06-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA1251215 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251215 MONDO:0013144 PMID: Likely Benign BS1, BP4 BP7 The c.1350C>T (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Asn450=). The variant is reported at a POPMAX FAF of 0.0002003 (5/24962) in the African/African American population in gnomAD v2.1.1 meeting BS1 criteria (allele frequency > 0.0002 w/min of 5 alleles). SpliceAI predicts no splicing impact for this variant meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251215/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7936 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022660 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007867 infores:hetionet CAID:CA10014175 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014175 MONDO:0011071 PMID: Likely Benign BP4, BP7, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, BP5, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1401G>A (p.Ala467=) is a synonymous variant which has a minor allele frequency (MAF) of 0.0002416 (0.02416%, 10/41392 alleles) in the African/African American population of gnomAD v3.1.2 cohort, between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). It has a SpliceAI score of 0.00 (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.503315 < 2.0) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014175/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:41879 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0025289 infores:hetionet NCBIGene:3572 biolink:causes MONDO:0800131 infores:monarchinitiative not_provided not_provided HGNC:6021 MONDO:0800131 uuid:12e8b080-d7f1-48c5-8288-ee15d01efafb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0948594 infores:hetionet GO:0007317 biolink:causes GO:0007351 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0007351 PUBCHEM.COMPOUND:4786 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0027497 infores:hetionet CHEBI:3479 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0037763 infores:hetionet CHEBI:145499 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0043352 infores:hetionet CHEBI:35778 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0152227 infores:hetionet CHEBI:31980 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0428974 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0233494 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0242350 infores:hetionet CHEBI:63619 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0010200 infores:hetionet CHEBI:63791 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0344232 infores:hetionet CAID:CA318510 biolink:causes MONDO:0010278 infores:clingen CAID:CA318510 MONDO:0010278 PMID: Likely Benign BS2, BP4, BP5 BS1 The p.Arg26Gly variant in SLC9A6 (NM_006359.2) is present in 2 XX and 1 XY individual(s) in gnomAD v2 (0.004%) (not sufficient to meet BS1 criteria). The p.Arg26Gly variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Arg26Gly variant is found in a patient with an alternate molecular basis of disease (internal database -GeneDx) (BP5). Computational analysis prediction tools suggest that the p.Arg26Gly variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Arg26Gly variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA318510/MONDO:0010278/033 2024-02-23 2024-03-31 X-linked inheritance HP:0001417 Contradicts true CHEBI:15940 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0037286 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0340464 infores:hetionet CHEBI:82960 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0852911 infores:hetionet CHEBI:135530 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0080274 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0853891 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0853891 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0085096 infores:hetionet CHEBI:7494 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020625 infores:hetionet CHEBI:100241 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018965 infores:hetionet CHEBI:6129 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030232 infores:hetionet GO:2000696 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000696 GO:0072001 CHEBI:82941 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0021655 infores:hetionet CHEBI:5165 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0035455 infores:hetionet CHEBI:50749 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0151908 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0034882 infores:hetionet CAID:CA10602281 biolink:causes MONDO:0044970 infores:clingen CAID:CA10602281 MONDO:0044970 PMID: Uncertain Significance PM5_Supporting, PP3, PM3_Supporting, PM2 PS1 The c.3572 A>G (p.Lys1191Arg) variant in POLG is absent in population databases (PM2). Computational prediction tool Revel score 0.938 (PP3). This variant has been reported in trans with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) in a 1 year old who presented with Childhood myocerebrohepatopathy spectrum and pancreatisis (PM3_supporting; PMID: 18546365). There is a likely pathogenic variant at the same amino acid position p.Lys1191Asn seen in 3 cases as compound heterozygotes. Two cases with Ala467Thr presenting with Alpers syndrome and one with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM5_supporting; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, there is insufficient evidence to characterize this variant and therefore it remains a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3, PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602281/MONDO:0044970/014 2021-05-06 2021-05-06 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:5932 biolink:causes MONDO:0009622 infores:monarchinitiative not_provided not_provided HGNC:9891 MONDO:0009622 uuid:9c3ed891-1732-4dc4-baa6-306b244122e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386953604 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953604 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3 PM1, PP4 The c.194G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to glutamate at codon 65 (p.(Gly65Glu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.792, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor); therefore, PP4 could not be applied. In summary, c.194G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953604/MONDO:0015967/017 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7445 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0020458 infores:hetionet CHEBI:145499 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0236075 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0035305 infores:hetionet CHEBI:408174 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151907 infores:hetionet NCBIGene:7407 biolink:causes MONDO:0060621 infores:monarchinitiative not_provided not_provided HGNC:12651 MONDO:0060621 uuid:e7914443-1044-46e5-8284-8b04ecd5ca6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0231218 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0038454 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0152027 infores:hetionet CHEBI:68606 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0877192 infores:hetionet CAID:CA023439 biolink:causes MONDO:0007750 infores:clingen CAID:CA023439 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM2, PP1, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, BS2 NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases.PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory.PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023439/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0044560 biolink:causes GO:0005216 infores:ubergraph knowledge_assertion manual_agent GO:0044560 GO:0005216 CHEBI:7936 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0242422 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0497247 infores:hetionet CHEBI:2549 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0040264 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0152025 infores:hetionet CHEBI:9445 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0009763 infores:hetionet CHEBI:6129 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013447 infores:hetionet CHEBI:8888 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0858635 infores:hetionet CHEBI:17141 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0036454 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0007971 infores:hetionet CHEBI:3696 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0857305 infores:hetionet CHEBI:63605 biolink:causes HP:0031274 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020683 infores:hetionet CHEBI:63621 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0008350 infores:hetionet CHEBI:66876 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C2363731 infores:hetionet CHEBI:7773 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151904 infores:hetionet CHEBI:5147 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0040586 infores:hetionet NCBIGene:90459 biolink:causes MONDO:0958006 infores:monarchinitiative not_provided not_provided HGNC:23994 MONDO:0958006 uuid:408b84ac-8f8c-4630-84e2-b75ccbd4dcf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9927 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0041912 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022658 infores:hetionet CHEBI:10124 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0020517 infores:hetionet CHEBI:31705 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151205 infores:hetionet CHEBI:194135 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C3665386 infores:hetionet NCBIGene:7137 biolink:causes MONDO:0013369 infores:monarchinitiative not_provided not_provided HGNC:11947 MONDO:0013369 uuid:978f9327-ca78-4959-a0dd-351ade3c38f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40303 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0919980 infores:hetionet CHEBI:17303 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0032617 infores:hetionet CHEBI:3441 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0476273 infores:hetionet CHEBI:61049 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0022346 infores:hetionet CHEBI:135351 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0023380 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0030193 infores:hetionet CHEBI:36704 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0017178 infores:hetionet CHEBI:36791 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014591 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0019158 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0009421 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0232462 infores:hetionet CAID:CA343724574 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724574 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting BP7, BS1, BS3, PM6, PP1, PM5, PM4, PS3, PS1, PS2, BP4, BA1 The c.1138G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 380 (p.Asp380Asn). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.842, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMID: 12362081), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724574/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6067 biolink:causes HP:6000793 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0521172 infores:hetionet CHEBI:63598 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0007820 infores:hetionet CHEBI:41423 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151798 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0041912 infores:hetionet CHEBI:144093 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0206062 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0031085 infores:hetionet CHEBI:64019 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0022660 infores:hetionet CAID:CA000367 biolink:causes MONDO:0018875 infores:clingen CAID:CA000367 MONDO:0018875 PMID: Pathogenic PS3, PS4, PM1, PS2_Moderate, PP4_Moderate, PP3, PM2_Supporting BP4, BA1, PS1, PM5, BS3, BS1, BS4, PVS1, PP1, BS2 The NM_000546.6: c.733G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 245 (p.Gly245Ser). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor: SCV000184981.8). This variant has been reported in an additional individual meeting Classical criteria and 11 individuals meeting Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 11370630, 32156018, 32888145, 33245408, 34670578, 35974385, 20522432, 24122735, Internal lab contributor: SCV000184981.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000184981.8). This variant has an allele frequency of 0.000002543 (3/1179926 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.5536; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2_Moderate, PS4_Very Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000367/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40050 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0234215 infores:hetionet CHEBI:107736 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0033117 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002569 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038353 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0006384 infores:hetionet CHEBI:4995 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0392676 infores:hetionet CHEBI:142290 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0032227 infores:hetionet CHEBI:38545 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0004093 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0038362 infores:hetionet CHEBI:28445 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0009782 infores:hetionet CHEBI:6129 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0546884 infores:hetionet CHEBI:63610 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0018681 infores:hetionet CHEBI:8871 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037763 infores:hetionet CHEBI:63599 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0011991 infores:hetionet GO:0160068 biolink:causes GO:0044706 infores:ubergraph knowledge_assertion manual_agent GO:0160068 GO:0044706 CHEBI:28748 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004096 infores:hetionet GO:2000310 biolink:causes GO:0034220 infores:ubergraph knowledge_assertion manual_agent GO:2000310 GO:0034220 CHEBI:46081 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0021051 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0855242 infores:hetionet CHEBI:8428 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0032227 infores:hetionet CHEBI:49575 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0009763 infores:hetionet CHEBI:4024 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0009763 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011849 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0085605 infores:hetionet CHEBI:119573 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0000731 infores:hetionet CHEBI:3310 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0011991 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0011991 infores:hetionet GO:2000980 biolink:causes GO:0048839 infores:ubergraph knowledge_assertion manual_agent GO:2000980 GO:0048839 CHEBI:134990 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0338831 infores:hetionet CHEBI:4868 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0877359 infores:hetionet CHEBI:180905 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0424295 infores:hetionet CHEBI:9362 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0518015 infores:hetionet CAID:CA1139655498 biolink:causes MONDO:0100368 infores:clingen CAID:CA1139655498 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting PP4 NM_000329.3(RPE65):c.1209_1210insCTGG (p.Glu404LeufsTer4) is a frameshift variant that introduces a premature stop codon into exon 11 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who is compound heterozygous with the NM_000329.3(RPE65):c.246-11A>G variant confirmed in trans (1 point, per ClinGen VCEP member), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (1 total points, PM3). At least one proband harboring this variant has a clinical phenotype including LCA diagnosis (0.5pts), photoattraction (1pt), and a flat ERG from both rods (0.5 pts) and cones (1 pt), which together are not sufficiently specific for RPE65-related recessive retinopathy (3 points, VCEP member-provided data). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139655498/MONDO:0100368/120 2025-03-31 2025-03-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:35854 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0001807 infores:hetionet CHEBI:63611 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0233407 infores:hetionet CAID:CA341742696 biolink:causes MONDO:0021060 infores:clingen CAID:CA341742696 MONDO:0021060 PMID: Uncertain Significance PM1 BS1, PM2, BA1 The NM_002524.5:c.31G>A variant in NRAS is a missense variant predicted to cause substitution of alanine by threonine at amino acid 11 (p.Ala11Thr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002891 (1/34592 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within a region, P-loop (AA 10-17), of NRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM1. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA341742696/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002792 infores:hetionet CHEBI:2618 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0232462 infores:hetionet CHEBI:2208 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0011603 infores:hetionet CHEBI:28445 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0039231 infores:hetionet CHEBI:6062 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085636 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0007642 infores:hetionet CHEBI:5864 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020621 infores:hetionet CHEBI:63638 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0003467 infores:hetionet CHEBI:75722 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0231530 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011991 infores:hetionet GO:0060221 biolink:causes CL:0000604 infores:ubergraph knowledge_assertion manual_agent GO:0060221 CL:0000604 CAID:CA294556 biolink:causes MONDO:0700272 infores:clingen CAID:CA294556 MONDO:0700272 PMID: Likely Pathogenic PM5_Supporting, PVS1 PM2, PP1 The c.2074C>T (p.Gln692Ter) variant in PALB2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA294556/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:134966 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0025061 infores:hetionet CHEBI:50922 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C2047937 infores:hetionet CHEBI:49375 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0008031 infores:hetionet CHEBI:64354 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0030554 infores:hetionet CHEBI:135929 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0178415 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0151736 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0413252 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005642 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D003233 DB02703_MESH_D003233_1 CHEBI:63631 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018681 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0018801 infores:hetionet GO:1901207 biolink:causes GO:0060972 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0060972 CHEBI:85078 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0038454 infores:hetionet CHEBI:9599 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0013378 infores:hetionet CHEBI:5165 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0028738 infores:hetionet CHEBI:17334 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0023052 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0027765 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020538 infores:hetionet CHEBI:4672 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0220870 infores:hetionet CHEBI:2639 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0232462 infores:hetionet NCBIGene:10329 biolink:causes MONDO:0014022 infores:monarchinitiative not_provided not_provided HGNC:13530 MONDO:0014022 uuid:cdc83605-318d-4a80-bf55-72734a6a86a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042376 infores:hetionet CHEBI:3654 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0014518 infores:hetionet CAID:CA16020901 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020901 MONDO:0009861 PMID:24130151PMID:24130151 Uncertain Significance PM2, PP4, PP3 PM3 The c.934G>C (p.Gly312Arg) variant in PAH is absent from population databases, and predicted damaging by in silico algorithms. It is identified in a single patient with phenylketonuria, in trans with a VUS (IVS8-7A>G) Defect in BH4 metabolism was not excluded in this publication (Bashyam, 2014. PMID: 24130151). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020901/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3216 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0152032 infores:hetionet CHEBI:63631 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0549249 infores:hetionet CHEBI:50924 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0015230 infores:hetionet NCBIGene:25885 biolink:causes MONDO:0958018 infores:monarchinitiative not_provided not_provided HGNC:17264 MONDO:0958018 uuid:61f13c49-21d2-4482-b152-073e01777f53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030252 infores:hetionet CAID:CA346366546 biolink:causes MONDO:0021060 infores:clingen CAID:CA346366546 MONDO:0021060 PMID:29493581 Likely Pathogenic PM1, PM2, PP3, PP2, PS4_Supporting The c.1276C>A (p.Gln426Lys) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 1 individual with a diagnosis of Noonan syndrome (PS4_Supporting; GeneDx internal data, ClinVar SCV000808402.1). SOS1 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln426Lys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2, PP3, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346366546/MONDO:0021060/004 2020-07-27 2020-07-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:15367 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0012739 infores:hetionet CHEBI:45409 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0575081 infores:hetionet CHEBI:421707 biolink:causes MONDO:0020689 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0001849 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020651 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027339 infores:hetionet CHEBI:70735 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0015230 infores:hetionet CAID:CA658795229 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795229 MONDO:0009290 PMID: Likely Pathogenic PP4, PM4, PM2_Supporting, PS3_Moderate, PM3_Supporting PP3, BP4 The NM_000152.5:c.457_465del variant in GAA is predicted to cause a change in the length of the protein (p.Arg154_Thr156del) due to an in-frame deletion of 3 amino acids in a non-repeat region (PM4). One patient with this variant and a diagnosis of Pompe disease has been reported with decreased enzyme activity and treated by enzyme replacement therapy (PMID: 18757064, 23013746) (PP4). This individual is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 18757064, 23013746) PM3_Supporting. Computational evidence is conflicting; the PROVEAN score is -11.8 (meeting the threshold of <-2.5 for deleterious), and Mutation Taster predicts that this variant is a ”polymorphism”. Therefore, neither PP3 nor BP4 is met. When expressed in cultured cells, this variant results in 0.5% wild type GAA activity and is abnormally synthesized and processed (PMID 22644586) (PS3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM4, PS3_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795229/MONDO:0009290/010 2024-06-17 2024-06-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:209807 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0009319 infores:hetionet CHEBI:65173 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0009763 infores:hetionet CAID:CA269540 biolink:causes MONDO:0700272 infores:clingen CAID:CA269540 MONDO:0700272 PMID: Likely Pathogenic PM5_Supporting, PVS1 PS3, PM2, PP3 The c.2559C>T (p.Gly853=) variant is a synonymous (silent) variant in PALB2. This variant has a minor allele frequency in gnomAD of 0.00001758 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This alteration is observed to introduce a cryptic splice site causing a 29 base pair deletion in exon 6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 31843900, 32133419). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM5_supporting criteria) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA269540/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030578 infores:hetionet CHEBI:5138 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003467 infores:hetionet NCBIGene:57192 biolink:causes MONDO:0009653 infores:monarchinitiative not_provided not_provided HGNC:13356 MONDO:0009653 uuid:b4da41ba-03d8-4a22-bac0-086e1f453673 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C2830004 infores:hetionet CHEBI:47780 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0149745 infores:hetionet CHEBI:9130 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0080274 infores:hetionet CHEBI:66903 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0151539 infores:hetionet CHEBI:100241 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030252 infores:hetionet CHEBI:3242 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0030554 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0027769 infores:hetionet CHEBI:84500 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0393760 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034065 infores:hetionet CHEBI:63631 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0260662 infores:hetionet CHEBI:3650 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0001824 infores:hetionet CHEBI:567361 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0232462 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0009319 infores:hetionet CHEBI:5106 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0235710 infores:hetionet CAID:CA10529780 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529780 MONDO:0010604 PMID: Benign BA1 BP4 The c.391+7A>G variant is reported at an MAF of 0.1296 (2458/18960 alleles) in the African/African-American population in gnomAD v2.1.1 with 620 hemizygotes and 123 homozygotes, meeting BA1 criteria of MAF > 0.0000556. SpliceAI predicts WT canonical donor loss at -7bp with a delta score of 0.05; however, does not meet criteria for PP3 or BP4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529780/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:31397 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0037199 infores:hetionet GO:1904118 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1904118 GO:0009790 NCBIGene:246213 biolink:causes MONDO:0011568 infores:monarchinitiative not_provided not_provided HGNC:20151 MONDO:0011568 uuid:b315002b-5ed4-4a97-a128-91f24545e43c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0456909 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0020456 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004747 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0008924 infores:hetionet CHEBI:2453 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0014742 infores:hetionet CHEBI:6690 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0021141 infores:hetionet CHEBI:4911 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0013378 infores:hetionet CHEBI:50742 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0009782 infores:hetionet CHEBI:135285 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0013604 infores:hetionet CHEBI:45409 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085593 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1527311 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027707 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006585 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027822 infores:hetionet CHEBI:7444 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0040264 infores:hetionet GO:2000495 biolink:causes GO:0001745 infores:ubergraph knowledge_assertion manual_agent GO:2000495 GO:0001745 CHEBI:50749 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0015230 infores:hetionet CHEBI:76010 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0917801 infores:hetionet CHEBI:6897 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C2830004 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0021400 infores:hetionet CHEBI:136040 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0015371 infores:hetionet CAID:CA410208016 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208016 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.574G>A (p.Ala192Thr) is a missense variant where the variant is within the Runt Homology Domain between the residues (AA 89-204) (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). Even though this variant does not have an available REVEL score or a SpliceAI score ≥ 0.38 (0.00), multiple other predictors (SIFT, PolyPhen2-HDIV, PolyPhen2-HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, MetaLR, FATHMM-MKL) predict a deleterious impact of this variant (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting, PM2_Supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208016/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75045 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0027497 infores:hetionet NCBITaxon:1279 biolink:causes MONDO:0006668 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1279 MESH:D003234 DB00759_MESH_D003234_1DB00440_MESH_D003234_1DB00207_MESH_D003234_1DB01165_MESH_D003234_1DB00781_MESH_D003234_1DB01137_MESH_D003234_1 CAID:CA376059549 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059549 MONDO:0011225 PMID: Uncertain Significance BS2, BA1, PM2, BS1 The c.589A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 197 (p.Ser197Gly).The filtering allele frequency (the upper threshold of the 95% CI of 6/59982) of the c.589A>G variant in DCLRE1C is 0.00004285 for Admixed American chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059549/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15551 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0520588 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0549373 infores:hetionet CHEBI:5613 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0043094 infores:hetionet CHEBI:8412 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0009782 infores:hetionet CHEBI:63681 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C2047937 infores:hetionet NCBITaxon:562 biolink:causes MONDO:1010128 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D010538 DB01598_MESH_D010538_1 CHEBI:4356 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0014549 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0178298 infores:hetionet CHEBI:87681 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0151578 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1510471 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0029134 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0521592 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0033975 infores:hetionet CAID:CA010805 biolink:causes MONDO:0005045 infores:clingen CAID:CA010805 MONDO:0005045 PMID: Uncertain Significance PM1, PM2_Supporting, PS4_Moderate PM3, PP3, PP1, BA1, PM5, PM4, PS3, PM6, BS2, BP3, BS1, BS3, BS4, BP4, BP7, BP2, BP5, PS1, PS2, PVS1 The c.1477A>G (p.Met493Val) variant in MYH7 has been reported in at least 8 individuals with HCM (PS4_Moderate; Meyer 2013 PMID:23816408; Marsiglia 2013 PMID:24093860; Walsh 2017 PMID:27532257; LMM pers. comm.; Ambry pers. comm.; GeneDx pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2_Supporting; PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010805/MONDO:0005045/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6775 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0007859 infores:hetionet CHEBI:8871 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020505 infores:hetionet CHEBI:49662 biolink:causes MONDO:0006952 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0035344 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0030554 infores:hetionet CHEBI:68575 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0033774 infores:hetionet CHEBI:17688 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0017178 infores:hetionet NCBIGene:5339 biolink:causes MONDO:0007555 infores:monarchinitiative not_provided not_provided HGNC:9069 MONDO:0007555 uuid:9a62eed3-3258-49c8-a372-36cb504f3ae9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585501 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585501 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.1555C>T (p.Pro519Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 4 March 2025.The supporting evidence is as follows:PM2: This variant is absent from gnomAD v4.1.0. PP3: REVEL = 0.864. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH from different labs (1 case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; 2 cases with definite FH by Simon Broome criteria from PMID 35047021 (Rimbert et al., 2022)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585501/MONDO:0007750/013 2025-03-04 2025-03-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:39867 biolink:causes UMLS:C0014431 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014431 infores:hetionet CAID:CA410147836 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147836 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS2, BA1, BP1, BP4, BP2, BP3, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM5, PM1, PM3, PM4, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1184C>T (p.Pro395Leu) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147836/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:2N4O9L084N biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0004604 infores:hetionet CHEBI:3181 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0428977 infores:hetionet CHEBI:499361 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0149725 infores:hetionet CHEBI:7465 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0036974 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0014742 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0036572 infores:hetionet CHEBI:167309 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0220870 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0178298 infores:hetionet CHEBI:50659 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0013595 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0948594 infores:hetionet CHEBI:8356 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026821 infores:hetionet CHEBI:41977 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0038362 infores:hetionet CHEBI:71219 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151723 infores:hetionet CHEBI:49960 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0008350 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0006277 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0021053 infores:hetionet CHEBI:4356 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0428977 infores:hetionet CHEBI:9649 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0035455 infores:hetionet CHEBI:3181 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C1260880 infores:hetionet CAID:CA16020846 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020846 MONDO:0009861 PMID:19292873 Pathogenic PM3, PM2, PVS1, PP4 The c.707-2delA variant in PAH has been reported in one patient, who carried a second pathogenic missense variant (p.Pro281Leu; BH4 deficiency not ruled out) (PMID: 19292873). The pre-treatment serum phenylalanine was reported at > 1500 micromolar. This variant is absent from gnomAD and ESP population databases, and disrupts the canonical splice acceptor site of intron 6, resulting in a frameshift and truncated protein (PMID: 19292873). Overall, the c.707-2delA variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PVS1, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020846/MONDO:0009861/006 2019-07-15 2019-07-15 Autosomal recessive inheritance HP:0000007 Supports GO:0090049 biolink:causes GO:0048514 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0048514 CHEBI:6520 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0002170 infores:hetionet CHEBI:10127 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085636 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0162119 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0020517 infores:hetionet CHEBI:6062 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151936 infores:hetionet CHEBI:36795 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2242588 infores:hetionet CAID:CA145867 biolink:causes MONDO:0001586 infores:clingen CAID:CA145867 MONDO:0001586 PMID: Benign BA1 The NM_000203.5: c.1164G>C (p.Thr388=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (25114/84382 alleles; 3978 homozygotes; Grpmax Filtering AF 95% confidence = 0.2945) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92625). In summary, this variant meets the criteria to be classified as benign for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145867/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5118 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018681 infores:hetionet CHEBI:3403 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0040485 infores:hetionet CHEBI:2668 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0026826 infores:hetionet CHEBI:50922 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0014724 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0023798 infores:hetionet CHEBI:46295 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0152198 infores:hetionet CHEBI:46081 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0018524 infores:hetionet CHEBI:101085 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0013144 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0851341 infores:hetionet CHEBI:5004 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0232849 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020538 infores:hetionet GO:0007317 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0019953 CHEBI:72564 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0917801 infores:hetionet GO:0002898 biolink:causes GO:0002340 infores:ubergraph knowledge_assertion manual_agent GO:0002898 GO:0002340 CHEBI:5296 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0008350 infores:hetionet CHEBI:94411 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0018681 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0015397 infores:hetionet CHEBI:7936 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004093 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0699885 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0034150 infores:hetionet CHEBI:94807 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0009806 infores:hetionet CHEBI:6520 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0004134 infores:hetionet CHEBI:4735 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0011603 infores:hetionet CHEBI:134991 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020578 infores:hetionet CHEBI:5855 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085610 infores:hetionet CHEBI:74947 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002994 infores:hetionet CHEBI:4710 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030232 infores:hetionet CHEBI:44185 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0041834 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0549386 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0021400 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0700345 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020517 infores:hetionet CHEBI:5106 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0086439 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040479 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0003864 infores:hetionet CHEBI:6775 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0015732 infores:hetionet CHEBI:41977 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0031039 infores:hetionet CHEBI:180905 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0018965 infores:hetionet CHEBI:15640 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0002170 infores:hetionet CAID:CA242485549 biolink:causes MONDO:0009861 infores:clingen CAID:CA242485549 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting BP7 The NM_000277.3:c.456T>C variant in PAH is a synonymous (silent) variant (p.Pro152=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. This variant is absent in gnomAD v2.1.1 (PM2_Supporting).There is a ClinVar entry for this variant (Variation ID: 725756, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA242485549/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6909 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042256 infores:hetionet CHEBI:7798 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011615 infores:hetionet CHEBI:4953 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0231218 infores:hetionet CHEBI:15765 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0042023 infores:hetionet CHEBI:9927 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0011603 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0011991 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0038454 infores:hetionet CHEBI:135961 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0003811 infores:hetionet CAID:CA16614980 biolink:causes MONDO:0007648 infores:clingen CAID:CA16614980 MONDO:0007648 PMID:22020549PMID:25315765PMID:22020549PMID:25315765PMID:22020549PMID:26182300PMID:18391748PMID:23709761PMID:26072394PMID:25315765 Pathogenic PP1_Moderate, PM5_Supporting, PM2_Supporting, PS4, PP3_Moderate, PVS1_Strong BS1, BS4, BS3, BP7, BP5, PM4, PM3, PM1, PM6, BS2, PP2, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS2, PS3 The c.1565+2dupT variant is a intronic variant in the donor region of intron 10 (PVS1_Strong, PM5_Supporting). This variant affects the same splice site as a well-characterized splice variant with similar or worse in silico/RNA predictions (PP3_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). It has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2), and was also found to co-segregate with disease in multiple affected family members with 5 meioses observed (PP1_Moderate; PMID: 25315765, 22020549, SCV000665426.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS4, PM2_Supporting, PM5_Supporting, PP1_Moderate, PP3_Moderate. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614980/MONDO:0007648/007 2023-08-30 2023-08-30 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf UMLS:C0025241 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0023895 infores:hetionet CHEBI:3699 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0013144 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0023533 infores:hetionet CAID:CA1442746 biolink:causes MONDO:0100084 infores:clingen CAID:CA1442746 MONDO:0100084 PMID: Pathogenic PM3_Strong, PVS1_Strong PP2, PP3, PP1, BP2, BP1, BP4, BP3, BA1, PS3, PS1, BP7, BS1, BS3, BS4, PM4, PM1, PM5, PM2 The variant c.990+1G>T in ACTA1 occurs within the canonical splice donor site (+1) of intron 6. It is predicted to cause skipping of biologically-relevant-exon resulting in an out of frame deletion. However, it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). The highest minor allele frequency in gnomAD v4.1.0 is 0.00001883 (31/1180028 alleles) in the European (non-Finnish) population (no population codes met). This variant has been reported in trans with a pathogenic variant in two probands with nemaline myopathy (PMID:19562689, LOVD (https://www.dmd.nl/)), and homozygous in one proband with nemaline myopathy (https://helda.helsinki.fi/handle/10138/157180) which meets PM3_Strong. In summary, the variant meets the criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Strong (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1442746/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027769 infores:hetionet CHEBI:367163 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C3665347 infores:hetionet CHEBI:17650 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0029118 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002170 infores:hetionet CHEBI:10023 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0423791 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1167785 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1167785 infores:hetionet CHEBI:8707 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011253 infores:hetionet CAID:CA5922947 biolink:causes MONDO:0015152 infores:clingen CAID:CA5922947 MONDO:0015152 PMID: Likely Benign BP7, BS1, BP4 The NM_213599.3: c.567A>G variant in ANO5 is a synonymous (silent) variant that is not expected to change the amino acid sequence, p.(Ala189=). The filtering allele frequency for this variant is 0.001135 for the African/African American population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 115/86256 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). This variant is not located in a splice region, and the SpliceAI prediction score for this variant is 0, which is less than the LGMD threshold of 0.05 (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5922947/MONDO:0015152/188 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:4094 biolink:causes MONDO:0012437 infores:monarchinitiative not_provided not_provided HGNC:6776 MONDO:0012437 uuid:c78d87ea-8d19-49fb-a762-410efa68c347 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C3160858 infores:hetionet CHEBI:52717 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0035222 infores:hetionet CHEBI:50859 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020433 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0151763 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0264009 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0264009 infores:hetionet CHEBI:92998 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151723 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0020667 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0020667 uuid:d4f82c8e-b174-4d60-95ea-c8cb97140175 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85161 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0033771 infores:hetionet CHEBI:17688 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0038363 infores:hetionet CHEBI:8080 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0008031 infores:hetionet CHEBI:10124 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0236000 infores:hetionet GO:1903341 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1903341 GO:0051321 CAID:CA10585701 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585701 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1, PP4 The NM_000527.5(LDLR):c.1968C>G (p.His656Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), PM2 is met.PP3 - REVEL = 0.864. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585701/MONDO:0007750/013 2021-12-14 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:52172 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0027441 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0033775 infores:hetionet CHEBI:50223 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0013404 infores:hetionet CHEBI:9570 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0030554 infores:hetionet CHEBI:63631 biolink:causes HP:0030223 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233651 infores:hetionet CHEBI:2618 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0003467 infores:hetionet NCBIGene:3587 biolink:causes MONDO:0013153 infores:monarchinitiative not_provided not_provided HGNC:5964 MONDO:0013153 uuid:56a85239-c8b8-4d54-a26f-e670fe12ba64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0012833 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0015397 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0022660 infores:hetionet CHEBI:7478 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020473 infores:hetionet CHEBI:209807 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0014457 infores:hetionet CHEBI:10119 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2937350 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0007642 infores:hetionet CHEBI:27834 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0003811 infores:hetionet NCBIGene:7056 biolink:causes MONDO:0013775 infores:monarchinitiative not_provided not_provided HGNC:11784 MONDO:0013775 uuid:1ccc4f19-0737-4446-9c6d-c2ba01e12759 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002418 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0030305 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0409974 infores:hetionet NCBITaxon:487 biolink:causes MONDO:0021108 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:487 MESH:D008581 DB01172_MESH_D008581_1 CAID:CA915940948 biolink:causes MONDO:0007947 infores:clingen CAID:CA915940948 MONDO:0007947 PMID: Likely Pathogenic PVS1, PM2_Supporting PP2, PP3, BS2, BP1, BP4, BP3, PM1, PM4, BP7 The NM_000138 c.2364dup, is a frameshift variant in FBN1 predicted to cause a substitution of a Valine acid by Cysteine at amino acid 789 (p.Val789CysfsTer13). It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant has not been reported in ClinVar and has not been reported in the literature. This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940948/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ NCBITaxon:1717 biolink:causes MONDO:0005504 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1717 MONDO:0005504 CHEBI:8382 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0021053 infores:hetionet CHEBI:7915 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1274594 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0020649 infores:hetionet CHEBI:161680 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0020649 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0002453 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0022660 infores:hetionet CAID:CA229876 biolink:causes MONDO:0009861 infores:clingen CAID:CA229876 MONDO:0009861 PMID:21147011PMID:21147011 Pathogenic PM4, PP4_Moderate, PM2, PM3_Strong PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD: 0.000008131; PM4: Protein length change as a results of in-frame deletion; PP4_Moderate: T323del found in 2 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:21147011); PM3_Strong: T323del detected with P281 in 1 PKU patient, and L48S in another PKU patient. Both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:21147011). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229876/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31709 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0002792 infores:hetionet CHEBI:474180 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C2830004 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009319 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0541947 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0541947 infores:hetionet CHEBI:3077 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151827 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040479 infores:hetionet CHEBI:44185 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0024314 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0149931 infores:hetionet CHEBI:135939 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0040264 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0010692 infores:hetionet CHEBI:16755 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0037763 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0235567 infores:hetionet CHEBI:8764 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0917801 infores:hetionet CAID:CA170296 biolink:causes MONDO:0010726 infores:clingen CAID:CA170296 MONDO:0010726 PMID: Benign BP7, BP4, BA1 PP4, BS2 The allele frequency of the c.393C>G (p.Ala131=) variant in MECP2 (NM_004992.3) is 0.1698% in the Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent c.393C>G (p.Ala131=) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.393C>G (p.Ala131=) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170296/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UMLS:C0903898 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0032617 infores:hetionet CHEBI:131512 biolink:causes HP:0033188 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0010666 infores:hetionet CHEBI:37333 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0002792 infores:hetionet CHEBI:8869 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0004604 infores:hetionet CAID:CA286507 biolink:causes MONDO:0009861 infores:clingen CAID:CA286507 MONDO:0009861 PMID:8268925PMID:9429153 Pathogenic PM5, PP4_Moderate, PM2, PP3, PM3_Strong PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC, gnomAD, 1000G, ESP (0.000077- 0.0001518); PP3: Predicted deleterious in SIFT, PolyPhen2, MutationTaster; PM5: R241C (VarID 102803) is Pathogenic in ClinVar based on 3 submitters; PP4_Moderate: R241H seen in 1 PKU patient. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_Strong: R241H detected in trans with pathogenic variants (IVS10, R408W, R252W). Upgraded per ClinGen SVI Workgroup. (PMID:9429153). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286507/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:367163 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0162429 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0008325 infores:hetionet CHEBI:5118 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085633 infores:hetionet CHEBI:10127 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0033774 infores:hetionet CHEBI:32588 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C1112525 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005594 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C2004491 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042109 infores:hetionet CHEBI:4784 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0003811 infores:hetionet CHEBI:168396 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0038999 infores:hetionet CHEBI:7936 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0455204 infores:hetionet CHEBI:31348 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0231807 infores:hetionet NCBIGene:6329 biolink:causes MONDO:0008195 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0008195 uuid:241d1bbd-e9aa-46a4-ab1e-78ccd0d80724 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0018524 infores:hetionet CHEBI:61049 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151878 infores:hetionet CHEBI:100246 biolink:causes MONDO:0001521 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0021776 infores:hetionet CHEBI:50122 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0085649 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0151736 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0036572 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018099 infores:hetionet CHEBI:145499 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011253 infores:hetionet CAID:CA10586372 biolink:causes MONDO:0011225 infores:clingen CAID:CA10586372 MONDO:0011225 PMID: Likely Pathogenic PP1, PM2_Supporting, PVS1_Moderate, PP4_Moderate PS3, PM3 The NM_001033855.3(DCLRE1C):c.1669dup (p.Thr557AsnfsTer21) variant in DCLRE1C is a frameshift variant that may cause loss of function of the protein; however, it is predicted that the transcript likely escapes nonsense-mediated decay (PMID: 26476407 supports this notion). Additionally, no downstream pathogenic variants have been curated to date (curated following SCID VCEP specifications). Thus, currently, this variant is limited to PVS1 at moderate strength.This variant is absent from gnomAD v2.1.1 (PM2_Supporting).There are 2 patients who are siblings (Family A, P4, and P5) (PMID: 26476407, PP1_supporting).At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P5, 2 pts, PMID:26476407, PP4_Moderate).In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied: PVS1_Moderate, PM2_Supporting, PP1_Supporting, and PP4_Moderate, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586372/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0065374 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C1565489 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0012833 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0149931 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0038362 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0424605 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0009450 infores:hetionet CHEBI:50730 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0151905 infores:hetionet CHEBI:6015 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0011603 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0035455 infores:hetionet CHEBI:29013 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0023380 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0007154 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0007154 uuid:cafebd22-c68c-4474-883a-d8db34c5ea09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9130 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0027497 infores:hetionet CHEBI:28748 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0040264 infores:hetionet CHEBI:8069 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0003862 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0040409 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0033117 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0009450 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0002871 infores:hetionet CHEBI:17823 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0000729 infores:hetionet CHEBI:5130 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0235063 infores:hetionet CHEBI:7444 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0039070 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1368065 infores:hetionet CAID:CA239352 biolink:causes MONDO:0019497 infores:clingen CAID:CA239352 MONDO:0019497 PMID:17850630PMID:22899989 Uncertain Significance PM3, PM2 PP1, PP3 The allele frequency of the c.902G>A (p.Arg301Gln) variant in the CDH23 gene is 0.0046% (3/64572) of European (non-Finnish) chromosomes by gnomAD v3, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss. This variant was detected in 4 individuals with sensorineural hearing loss with the P240L variant in CDH23. For 2 of these probands the pathogenic P240L variant in CDH23 was present in trans; however, because all the families were of East Asian descent and this variant was always observed with the P240L variant, PM3 was kept at the moderate level (PM3, PMIDs: 17850630, 22443853, 22899989). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA239352/MONDO:0019497/005 2020-11-02 2020-11-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6541 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0037011 infores:hetionet CHEBI:31236 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0220870 infores:hetionet CHEBI:48390 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0011175 infores:hetionet NCBIGene:1798 biolink:causes MONDO:0011964 infores:monarchinitiative not_provided not_provided HGNC:2995 MONDO:0011964 uuid:f7002a22-53bd-4108-9763-451235e3c701 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019572 infores:hetionet NCBIGene:84277 biolink:causes MONDO:0958183 infores:monarchinitiative not_provided not_provided HGNC:16410 MONDO:0958183 uuid:2d88b943-bab7-420b-815b-a9b99976af1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C3665386 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0851536 infores:hetionet CHEBI:92607 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0011603 infores:hetionet CAID:CA045974 biolink:causes MONDO:0007947 infores:clingen CAID:CA045974 MONDO:0007947 PMID: Uncertain Significance PP3, PM1, BS1 PM2, PM6, PP2, PP4, PP1, BS2, BP4, BP3, BP2, BA1, PS4, PS3, PS1, PS2, PM4, PM5, PM3, BS3, BS4 NM_00138 c.1825C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 609 (p.Arg609Cys). This variant was found in a proband with thoracic aortic aneurysm and dissection (TAAD) and a proband with minor skeletal features (PMID: 32154576; Bichat internal data). This variant is present in gnomAD (BS1; 2/18384 [0.011%] East Asian alleles; https://gnomad.broadinstitute.org/). It has been submitted to ClinVar twice, once as likely pathogenic and once as of uncertain significance (Variation ID: 439709). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein’s structure or function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: Due to the conflicting and insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, PM1, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA045974/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3403 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042029 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011071 infores:hetionet NCBIGene:7155 biolink:causes MONDO:0012243 infores:monarchinitiative not_provided not_provided HGNC:11990 MONDO:0012243 uuid:3379230c-0b47-4fd6-9ae6-3d6e35f31e3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0040034 infores:hetionet CHEBI:72297 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0008031 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0264714 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0264714 infores:hetionet CAID:CA291224655 biolink:causes MONDO:0100326 infores:clingen CAID:CA291224655 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PP3, BP4 After a comprehensive literature search, the missense variant NM_000212.3:c.487A>C (p.Lys163Gln) was not identified in any individuals with Glanzmann thrombasthenia. The variant was absent from gnomAD (PM2_supporting). The computational predictor REVEL gives a score of 0.593, which is intermediate between PP3 and BP4. The variant was identified in relation to severe neonatal alloimmune thrombocytopenia and the very low frequency human platelet antigen HPA-19bw. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291224655/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true UMLS:C0010592 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020615 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1302752 infores:hetionet CHEBI:408174 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0002792 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0518015 infores:hetionet CHEBI:63621 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0014724 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151883 infores:hetionet CHEBI:17303 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013362 infores:hetionet CHEBI:4511 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0042109 infores:hetionet CHEBI:8107 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018681 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0233414 infores:hetionet CHEBI:10127 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0014518 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020676 infores:hetionet CHEBI:50742 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0004096 infores:hetionet CHEBI:49668 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0221245 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015397 infores:hetionet CHEBI:8404 biolink:causes UMLS:C1096529 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C1096529 infores:hetionet CHEBI:8346 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0011603 infores:hetionet CHEBI:6456 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0234518 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034882 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0042571 infores:hetionet NCBIGene:11128 biolink:causes MONDO:0011897 infores:monarchinitiative not_provided not_provided HGNC:30074 MONDO:0011897 uuid:90b3cf2e-0e5b-4120-b5f1-12b2bd5fd899 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042963 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002888 infores:hetionet GO:1904412 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1904412 GO:0072359 CHEBI:28939 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0232292 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0919715 infores:hetionet CAID:CA219803 biolink:causes MONDO:0000572 infores:clingen CAID:CA219803 MONDO:0000572 PMID: Pathogenic PP4, PM3_Very Strong, PS3_Moderate, PM2_Supporting, PM1 NM_000448.3(RAG1):c.1361T>A is a missense variant predicted to cause substitution of Leucine by Glutamine at amino acid 454 (p.Leu454Gln). The missense variant is located in the NBD domain (amino acids 394-460) (PM1). The variant is absent in gnomAD v4 (PM2_supporting). Two patients in PMID: 32311393; 24290284 and 6 patients in PMID: 29051008 were found homozygous for this mutation; total points: 4.0pt (PM3_Very Strong). The VDJ recombination activity was found to be 5.4 +/- 0.7 % of WT (mean +/- SE) (PMID: 24290284; PS3_Moderate). Patient with SCID (0.5 pt.),genome sequencing conducted (1 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) ; total points : 2, PP4_met. (PMID : 29051008). In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1, PM2_Supporting, PM3_Very_Strong, PS3_Moderate, PP4 (VCEP specifications version 2.1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA219803/MONDO:0000572/123 2025-11-19 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CAID:CA9871472 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871472 MONDO:0007064 PMID: Likely Pathogenic PS3_Supporting, PP4_Moderate, PM3, PM2_Supporting PM5, BS3 "The c.890C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 297 (p.Pro297Leu).The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported.This variant was described in at least one patient in the literature, who presents *Reduced ADA enzyme activity in patient cells (1pt); *Reported also reported ""a definite increase in intracellular metabolites"" (dAdo nucleotides), (2 pts); *SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate (PMID: 34975878).The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence.In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Moderate, and PS3_Supporting." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871472/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CAID:CA2695215245 biolink:causes MONDO:0700270 infores:clingen CAID:CA2695215245 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.2862_2863del (p.Pro955Trpfs*13) variant in ATM is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695215245/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40237 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0042075 infores:hetionet GO:0003311 biolink:causes CL:0000173 infores:ubergraph knowledge_assertion manual_agent GO:0003311 CL:0000173 CHEBI:472657 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0020517 infores:hetionet CHEBI:52717 biolink:causes MONDO:0007018 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042996 infores:hetionet CHEBI:3077 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0031256 infores:hetionet CAID:CA386493121 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493121 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PVS1, PM2, PM3_Strong The c.1200-2A>C variant in PAH is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 12 is present in biologically-relevant transcript (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in two Ugyur probands (PMID: 31355225) with classic PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). Both cases were compound heterozygous for the variant (confirmed by parental testing): one carried it in trans with the p.A104D variant (known pathogenic per PAH ClinGen working group) and the other in trans with p.P147L variant (Likely Pathogenic per PAH ClinGen working group) (PM3_Strong). It is reported pathogenic in Clinvar (ID 625286) as a de novo variant by one lab, in a case with PKU; no further information is given. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493121/MONDO:0009861/006 2020-04-09 2020-04-09 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10014500 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014500 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP3, PM2, PM6, BP5, BS1, BS3, BS4, PVS1, PM3, PM1, PM4, PM5, PP4, PP2, PP3, PP1, BS2 The NM_001754.5(RUNX1):c.508+4C>A is a variant is located in Intron 5. It affects a nucleotide within the consensus splice site. However, splice prediction algorithms do not predict an effect on splicing (BP4). This variant is present at a MAF of 0.00006 (0.006%, 1/16256 alleles) in the African/African American population of gnomADv2.1.1. The nucleotide is not highly conserved with a phyloP score of -2.61. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014500/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17263 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C1609512 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013146 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0162429 infores:hetionet CHEBI:116278 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0018681 infores:hetionet UNII:R15UI3245N biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0027497 infores:hetionet NCBIGene:246329 biolink:causes MONDO:0009722 infores:monarchinitiative not_provided not_provided HGNC:28423 MONDO:0009722 uuid:16d3abeb-ecac-4917-aa2e-a87c3d53c0c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0349506 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0003123 infores:hetionet CHEBI:49040 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0015230 infores:hetionet CHEBI:144551 biolink:causes HP:0012733 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0332573 infores:hetionet CAID:CA226154 biolink:causes MONDO:0100453 infores:clingen CAID:CA226154 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.91dup (p.Arg31ProfsTer?) is a frameshift variant that introduces a premature stop codon into exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000009890, with 15 alleles / 1516748 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), visual acuity limited to light perception (1 pt) since birth (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), high hypermetropia, being drawn to bright light, sluggish pupillary responses (0.5 pts), eye poking, and normal appearing fundus, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 29178642, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226154/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029878 infores:hetionet CHEBI:32221 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0162830 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0006840 infores:hetionet CHEBI:6804 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0010200 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0009806 infores:hetionet NCBIGene:10381 biolink:causes MONDO:0010912 infores:monarchinitiative not_provided not_provided HGNC:20772 MONDO:0010912 uuid:db74c9e9-1824-4dd8-9d63-0305f22b551c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3423 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020580 infores:hetionet CHEBI:3215 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030486 infores:hetionet CHEBI:31236 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042963 infores:hetionet CHEBI:6541 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0038990 infores:hetionet CAID:CA16020747 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020747 MONDO:0009861 PMID:21307867 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.209C>T (p.Ser70Phe) variant in PAH was reported in a Spanish patient with Mild HPA. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). This variant was detected in trans with pathogenic variant p.Ala300Ser. It is absent in population databases and was predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4 moderate, and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020747/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50275 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0234913 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151311 infores:hetionet CHEBI:83531 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0029408 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009241 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040409 infores:hetionet CHEBI:63638 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0231528 infores:hetionet CHEBI:94807 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0013604 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0004096 infores:hetionet CHEBI:85083 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0009782 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0032285 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0008325 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0042075 infores:hetionet CHEBI:31859 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0085593 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0856968 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0856968 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0521839 infores:hetionet NCBITaxon:2039 biolink:causes MONDO:0005116 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2039 MONDO:0005116 CHEBI:47898 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2979982 infores:hetionet CHEBI:142290 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0008031 infores:hetionet CHEBI:3814 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0016204 infores:hetionet CHEBI:7986 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0036454 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0855242 infores:hetionet CHEBI:77032 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0232492 infores:hetionet CHEBI:44185 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0404521 infores:hetionet CHEBI:5130 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0235266 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151541 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151541 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0497365 infores:hetionet CHEBI:64355 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0034886 infores:hetionet NCBIGene:1385 biolink:causes MONDO:0012809 infores:monarchinitiative not_provided not_provided HGNC:2345 MONDO:0012809 uuid:ba9f83e2-5446-4e33-ad31-cc6639d0ed13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:229219 biolink:causes MONDO:0005672 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:229219 MESH:D001759 DB00681_MESH_D001759_1 CHEBI:4672 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0162529 infores:hetionet NCBIGene:2314 biolink:causes MONDO:0957984 infores:monarchinitiative not_provided not_provided HGNC:3750 MONDO:0957984 uuid:1a97e1ff-ef5e-4ba8-871d-919acfdf9910 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0236051 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0475858 infores:hetionet CHEBI:585948 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C2004489 infores:hetionet CHEBI:50567 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0162119 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0036130 infores:hetionet CHEBI:41423 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0085932 infores:hetionet CHEBI:42797 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018946 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0041969 infores:hetionet UNII:3QJA87N40S biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0220870 infores:hetionet CHEBI:4514 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0553721 infores:hetionet CHEBI:29013 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0344232 infores:hetionet CHEBI:51860 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0042384 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027651 infores:hetionet CHEBI:4469 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0221512 infores:hetionet CHEBI:31624 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0271051 infores:hetionet CHEBI:7577 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0917801 infores:hetionet CHEBI:17650 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C2586050 infores:hetionet CHEBI:8499 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0917801 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0014175 infores:hetionet CHEBI:15367 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0333355 infores:hetionet CHEBI:68558 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C1112525 infores:hetionet CHEBI:7956 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0151766 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0439857 infores:hetionet CHEBI:45285 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0017178 infores:hetionet CHEBI:64064 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0013604 infores:hetionet CHEBI:28864 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0011606 infores:hetionet CHEBI:4445 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0010520 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0005940 infores:hetionet CHEBI:47781 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0042963 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0035455 infores:hetionet CHEBI:94411 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0042109 infores:hetionet CHEBI:3387 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0700590 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043246 infores:hetionet CHEBI:8228 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0333243 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0267792 infores:hetionet CHEBI:8863 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0021177 infores:hetionet CHEBI:46295 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0030554 infores:hetionet CAID:CA409108460 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108460 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PP1, PS4 The c.981G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, results in a premature termination at codon 327 (p.(Trp327Ter)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold. This individual did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative and persistent C peptide) (PP4_Moderate; PMID:16731861; internal lab contributors). This variant segregated with diabetes with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.981G>A meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108460/MONDO:0015967/085 2024-11-27 2024-11-27 Autosomal dominant inheritance HP:0000006 Supports CAID:CA8815636 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815636 MONDO:0009290 PMID: Uncertain Significance PP3, PM5, PM2_Supporting PP4, PM3 The NM_000152.5:c.2174G>A variant in GAA is a missense variant predicted to cause substitution of Arg by Gln at amino acid 725 (p.Arg725Gln). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. It only has been reported in one case with a positive newborn screening result for GAA-related disease, in which has concurrence of c.664 G>A (benign or likely benign) (PMID: 23430949). Thus there is insufficient data to apply PP4 nor PM3. Another missense variant c.2173C>T (p.Arg725Trp) (PMID: 8401535, 17616415, 19588081, 28648663, 30155607; ClinVar Variation ID: 4024), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. Thus PM5 is applied. There is a ClinVar entry for this variant (Variation ID: 555727, 1 star review status) with 2 submitters classifying the variant as Uncertain significance, and 2 submitters classifying it as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP3, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 3, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815636/MONDO:0009290/010 2023-10-03 2024-06-18 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3723 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038358 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0178298 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038661 infores:hetionet CAID:CA000416 biolink:causes MONDO:0018875 infores:clingen CAID:CA000416 MONDO:0018875 PMID: Likely Benign PP3, BS2, PM2_Supporting BA1, BP4, BP2, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS3, BS4, PP1, PP4 The NM_000546.6: c.784G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 262 (p.Gly262Ser). This variant received a total of 0.5 points in one individual (PS4 not met; Internal lab contributors). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor). This variant has an allele frequency of 0.00002358 (38/1611646 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.52, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, PP3. (Bayesian Points: -2; VCEP specifications version 2.2; date of approval) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000416/MONDO:0018875/009 2025-04-03 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4672 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0149871 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0009938 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0038663 infores:hetionet NCBIGene:83552 biolink:causes MONDO:0012605 infores:monarchinitiative not_provided not_provided HGNC:18121 MONDO:0012605 uuid:d72336fb-9b00-4dc4-9354-cecce5184153 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020517 infores:hetionet CHEBI:31643 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0549249 infores:hetionet CHEBI:5296 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0016204 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0026857 infores:hetionet CHEBI:94440 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0017178 infores:hetionet CHEBI:119486 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0700590 infores:hetionet CHEBI:119573 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0027540 infores:hetionet NCBIGene:3848 biolink:causes MONDO:0010962 infores:monarchinitiative not_provided not_provided HGNC:6412 MONDO:0010962 uuid:736d19c6-c8a1-4521-a0b8-60705aa3492f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5801 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0026848 infores:hetionet NCBIGene:89876 biolink:causes MONDO:0030926 infores:monarchinitiative not_provided not_provided HGNC:24010 MONDO:0030926 uuid:584af33b-ed12-4cae-b5be-04bc6f518f6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020433 infores:hetionet CHEBI:10127 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0149745 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0155320 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0022660 infores:hetionet NCBIGene:5350 biolink:causes MONDO:0012362 infores:monarchinitiative not_provided not_provided HGNC:9080 MONDO:0012362 uuid:9510e27c-e4b4-478f-8856-3be2d88b106f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63925 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0003862 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1141861 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038826 infores:hetionet CHEBI:7915 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018965 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020538 infores:hetionet CHEBI:63580 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C3160741 infores:hetionet CHEBI:35778 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0018681 infores:hetionet CHEBI:8024 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002994 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0948594 infores:hetionet CHEBI:16469 biolink:causes HP:0002371 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0542223 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0178298 infores:hetionet CHEBI:47426 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0220870 infores:hetionet GO:0060141 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0060141 GO:0048856 CHEBI:7496 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0220981 infores:hetionet CHEBI:68558 biolink:causes UMLS:C3203457 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C3203457 infores:hetionet CHEBI:8232 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0022346 infores:hetionet CHEBI:40050 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0011581 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0236068 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0574067 infores:hetionet CHEBI:94609 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0017178 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027769 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0037763 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1443060 infores:hetionet CHEBI:6128 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0231528 infores:hetionet CHEBI:6633 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0015256 infores:hetionet CHEBI:82866 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0241136 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0012833 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0017178 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0151476 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0151476 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0038363 infores:hetionet CHEBI:31401 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0268000 infores:hetionet CHEBI:63611 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0392699 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0574067 infores:hetionet CHEBI:61049 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0852911 infores:hetionet CHEBI:48273 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0232461 infores:hetionet NCBITaxon:157 biolink:causes MONDO:0000979 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:157 MESH:D010874 DB01053_MESH_D010874_1DB09320_MESH_D010874_1 CHEBI:28901 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0221264 infores:hetionet CHEBI:18332 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0011175 infores:hetionet CHEBI:31515 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0009763 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0037274 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0595902 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0595902 infores:hetionet CHEBI:9674 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0012833 infores:hetionet CHEBI:71417 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0012833 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0037315 infores:hetionet CHEBI:5098 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0009782 infores:hetionet CHEBI:9086 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151662 infores:hetionet CHEBI:3207 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0035243 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0948594 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020039 infores:hetionet CHEBI:391960 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0043094 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0521490 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0040034 infores:hetionet CHEBI:119915 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0080274 infores:hetionet CHEBI:78543 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0853697 infores:hetionet CHEBI:31348 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0700590 infores:hetionet CHEBI:68610 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0231528 infores:hetionet CHEBI:5132 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0018418 infores:hetionet CHEBI:3286 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0030193 infores:hetionet CHEBI:102216 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0036104 infores:hetionet CHEBI:47780 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0006384 infores:hetionet NCBIGene:6866 biolink:causes MONDO:0013912 infores:monarchinitiative not_provided not_provided HGNC:11521 MONDO:0013912 uuid:90600a92-4764-4e1b-b646-a03d7dddfa88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0085628 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0233571 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003123 infores:hetionet CHEBI:6887 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0043352 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001935 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0003892 infores:hetionet CHEBI:9555 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0003962 infores:hetionet CHEBI:119573 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0038325 infores:hetionet CHEBI:10127 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0023218 infores:hetionet UMLS:C0657912 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004093 infores:hetionet CHEBI:9448 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0085932 infores:hetionet CHEBI:6912 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0015371 infores:hetionet CHEBI:31174 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0013595 infores:hetionet CHEBI:40303 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C1368065 infores:hetionet CHEBI:50861 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0019080 infores:hetionet CHEBI:63717 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0016658 infores:hetionet GO:1905298 biolink:causes GO:0055123 infores:ubergraph knowledge_assertion manual_agent GO:1905298 GO:0055123 CHEBI:8764 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0035333 infores:hetionet CHEBI:72564 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0041834 infores:hetionet CHEBI:135285 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0004093 infores:hetionet CHEBI:3423 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020621 infores:hetionet CHEBI:37333 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C1142412 infores:hetionet CHEBI:27974 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0036508 infores:hetionet CAID:CA229344 biolink:causes MONDO:0009861 infores:clingen CAID:CA229344 MONDO:0009861 PMID:21307867 Uncertain Significance PP4_Moderate, PM2, PP3 The c.1100T>C (p.Leu367Pro) variant in PAH is reported in a Japanese patient with PKU, BH4 deficiency was excluded. (PMID: 21307867) This variant is absent in population databases. It is predicted deleterious by SIFT, Polyphen-2 and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229344/MONDO:0009861/006 2018-12-08 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63607 biolink:causes UMLS:C0522061 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0522061 infores:hetionet CHEBI:35854 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C2717961 infores:hetionet CHEBI:94807 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0558489 infores:hetionet CHEBI:3752 biolink:causes HP:0100879 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0392039 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0027813 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0332575 infores:hetionet CHEBI:31413 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0012833 infores:hetionet CHEBI:4858 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0028734 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0282074 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0282074 infores:hetionet CAID:CA160001 biolink:causes MONDO:0015967 infores:clingen CAID:CA160001 MONDO:0015967 PMID: Benign BA1, BP7 The c.225C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 75 (p.(Asp75=)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0007829, which is greater than or equal to the MDEP VCEP threshold for BA1 (≥0.0001) (BA1). Additionally, the c.225C>T variant is not predicted by SpliceAI to impact splicing (BP7). In summary, c.225C>T meets the criteria to be classified as benign for HNF1A-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 6/4/2021): BA1, BP7.  Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA160001/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4027 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019360 infores:hetionet CHEBI:36791 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1456784 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0521491 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0235437 infores:hetionet CHEBI:42797 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0086525 infores:hetionet CHEBI:6067 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030252 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0549399 infores:hetionet CHEBI:16335 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0042510 infores:hetionet CHEBI:27446 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0036830 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011849 infores:hetionet NCBIGene:8647 biolink:causes MONDO:0011156 infores:monarchinitiative not_provided not_provided HGNC:42 MONDO:0011156 uuid:9e715b8f-b3c7-4ac3-973d-b077779a37fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905962 biolink:causes CL:0000679 infores:ubergraph knowledge_assertion manual_agent GO:1905962 CL:0000679 CHEBI:7565 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0162429 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0857807 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0037274 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0429098 infores:hetionet CHEBI:50729 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0085681 infores:hetionet NCBIGene:1974 biolink:causes MONDO:0957541 infores:monarchinitiative not_provided not_provided HGNC:3284 MONDO:0957541 uuid:fb734746-e1a9-4270-86ec-b527e65c62f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0003123 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0020517 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0017178 infores:hetionet CHEBI:63598 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0220870 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151907 infores:hetionet CAID:CA142762 biolink:causes MONDO:0019497 infores:clingen CAID:CA142762 MONDO:0019497 PMID: Benign BA1 The filtering allele frequency (the lower threshold of the 95% CI of 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA142762/MONDO:0019497/005 2022-05-13 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true NCBIGene:6531 biolink:causes MONDO:0054835 infores:monarchinitiative not_provided not_provided HGNC:11049 MONDO:0054835 uuid:7fb69056-55c5-4c3d-8c1b-c8b2dbaf0c64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7447 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0015230 infores:hetionet CHEBI:4466 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0086565 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015624 infores:hetionet CHEBI:3387 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002994 infores:hetionet CHEBI:8228 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0004604 infores:hetionet CHEBI:119573 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0023218 infores:hetionet CHEBI:63613 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0042963 infores:hetionet CHEBI:7575 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0011603 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0575090 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0233401 infores:hetionet CHEBI:63610 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0011168 infores:hetionet CHEBI:5613 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0151878 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C1258215 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0877305 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0877305 infores:hetionet CHEBI:7577 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011168 infores:hetionet CAID:CA1139655403 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139655403 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PP1_Strong The c.185del variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, , causes a frameshift in the protein at codon 62 in transcript NM_175914.5, adding 42 novel amino acids before encountering a stop codon (p.(Phe62Serfs*42)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805 ). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; PMID:9920109). This variant segregated with diabetes with 5 meioses in one family (PP1_Strong; PMID:9920109). In summary, c.185del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139655403/MONDO:0015967/085 2024-09-09 2024-09-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3757 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0042373 infores:hetionet CHEBI:107736 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0015230 infores:hetionet CHEBI:3752 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0027497 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0008492 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0008492 uuid:8f10e3aa-5874-4ee1-ad27-02bcc56dd1db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66919 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0017178 infores:hetionet CHEBI:47612 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0221490 infores:hetionet CHEBI:3699 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0009806 infores:hetionet CHEBI:9654 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042384 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001164 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003431 infores:hetionet CHEBI:6931 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0221170 infores:hetionet CHEBI:7931 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0549249 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0009450 infores:hetionet CHEBI:8069 biolink:causes MONDO:0001244 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0042880 infores:hetionet CHEBI:5855 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0041834 infores:hetionet CHEBI:36791 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235939 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0079035 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0079035 infores:hetionet CHEBI:53691 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0026821 infores:hetionet CAID:CA145778 biolink:causes MONDO:0009290 infores:clingen CAID:CA145778 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.2780C>T (p.Thr927Ile) in gnomAD v2.1.1 is 0.1317 in the African population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92482; 2 star review status) with six submitters classifying the variant as benign, and two as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145778/MONDO:0009290/010 2020-01-23 2020-05-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:8356 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015403 infores:hetionet CHEBI:4453 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0017178 infores:hetionet CAID:CA180888 biolink:causes MONDO:0021060 infores:clingen CAID:CA180888 MONDO:0021060 PMID: Benign BP5, BA1 BS1, PM2, PP3, BP4 The c.257A>C variant in the HRAS gene is a missense variant predicted to cause substitution of asparagine by threonine at amino acid 86 (p.Asn86Thr). The filtering allele frequency in gnomAD v2.1.1 is 0.0006669 (22/24924 alleles) in the Latino/Admixed American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.367, which is neither above nor below the thresholds predicting a damaging or benign impact on HRAS function. This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data GTR ID: 21766, 26957, ClinVar SCV000204177.4, SCV000207861.7). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180888/MONDO:0021060/046 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:82960 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017168 infores:hetionet UMLS:C0657912 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018681 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0234930 infores:hetionet CHEBI:61049 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232292 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0031350 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0234458 infores:hetionet CHEBI:7903 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0009676 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0010709 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0404572 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0429468 infores:hetionet CHEBI:499361 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0002170 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0852909 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0852909 infores:hetionet CHEBI:61058 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0003862 infores:hetionet CAID:CA254829 biolink:causes MONDO:0044970 infores:clingen CAID:CA254829 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP1, PS2, PS4, PM6 The m.5888delT variant in MT-TY has been reported in one individual with primary mitochondrial disease to date (PMID: 11756614). This woman had bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance onset in her 30s. Muscle biopsy showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, and decreased activities of complexes I and IV. The variant was present at 78% in muscle and was undetectable in blood. The variant was also undetectable in blood from her mother, three siblings, and three children (although this cannot be considered a de novo occurrence as the variant was also undetectable in the proband’s blood; PMID 11756614). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (53.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (79.4%) than in COX positive fibers (19.8%), p<0.0001 (PS3_supporting, PMID: 11756614). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254829/MONDO:0044970/015 2024-06-24 2025-04-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:17026 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0036974 infores:hetionet CHEBI:3216 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0264906 infores:hetionet CHEBI:68647 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0853225 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0241705 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011849 infores:hetionet CHEBI:31711 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0042963 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0541832 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0035078 infores:hetionet CHEBI:4710 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C2047937 infores:hetionet UMLS:C0657912 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025345 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151479 infores:hetionet CHEBI:59773 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0003467 infores:hetionet CHEBI:5100 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0015230 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0005575 uuid:0422f65a-d446-4980-b4a8-df9a84e698c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0750394 infores:hetionet CHEBI:63623 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0003123 infores:hetionet CHEBI:52010 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0043352 infores:hetionet CHEBI:480999 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0003811 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0041969 infores:hetionet CHEBI:63580 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003811 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0039103 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0267596 infores:hetionet CHEBI:7824 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0029453 infores:hetionet NCBIGene:9469 biolink:causes MONDO:0007738 infores:monarchinitiative not_provided not_provided HGNC:1971 MONDO:0007738 uuid:e4de3088-5c8c-4eac-afc0-2c2b4d3185ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0553704 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0233494 infores:hetionet CHEBI:36791 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013384 infores:hetionet CHEBI:3013 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0857353 infores:hetionet CHEBI:53760 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0028084 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0011570 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0006145 infores:hetionet CHEBI:63598 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017979 infores:hetionet CHEBI:29688 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0438717 infores:hetionet CHEBI:180905 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0020580 infores:hetionet NCBIGene:3239 biolink:causes MONDO:0008516 infores:monarchinitiative not_provided not_provided HGNC:5136 MONDO:0008516 uuid:8ade5b36-3238-4694-8efc-b302c41b1bfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0038325 infores:hetionet CHEBI:10110 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0085636 infores:hetionet CHEBI:49375 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151878 infores:hetionet CHEBI:2955 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0022354 infores:hetionet CHEBI:4798 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0002962 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0948089 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020550 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233494 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0020517 infores:hetionet CHEBI:28918 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C2242996 infores:hetionet CHEBI:50156 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0232487 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041349 infores:hetionet CHEBI:3568 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042907 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0026946 infores:hetionet CHEBI:6754 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0022107 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0004936 infores:hetionet CHEBI:8404 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0001122 infores:hetionet CHEBI:4995 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0042029 infores:hetionet CHEBI:367163 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0029453 infores:hetionet GO:0003339 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0001656 CHEBI:119915 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0687133 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042571 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0020456 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0403632 infores:hetionet CHEBI:6375 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0000731 infores:hetionet CHEBI:46557 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0428977 infores:hetionet CHEBI:4681 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0002994 infores:hetionet CHEBI:63624 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0392171 infores:hetionet CHEBI:3127 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2363730 infores:hetionet CAID:CA285811 biolink:causes MONDO:0100368 infores:clingen CAID:CA285811 MONDO:0100368 PMID: Benign BA1 BP4, BP7 The NM_000329.3:c.1056G>A variant is a synonymous variant in codon 352 of RPE65, and is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.3944, with 8033 alleles / 19884 total alleles in the East Asian population with 1627 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant does not have a strong prediction of impact at splicing sites according to SpliceAI, which calculates a delta score of 0.12 for splice acceptor gain. Because this score is higher than the ClinGen LCA / eoRD VCEP BP4 / BP7 threshold of <0.1 and lower than the PP3 threshold of >0.2, no in silico predictive codes are met. In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA285811/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA308110136 biolink:causes MONDO:0018493 infores:clingen CAID:CA308110136 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of cysteine with arginine at codon 64 of the RYR1 protein, p.(Cys64Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), this individual also carried variant p.Ala3421Val, do not count for PS4 (PMID:21455645). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1, (PMID: 21118704). A REVEL score of 0.809 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308110136/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true GO:0090173 biolink:causes GO:0045143 infores:ubergraph knowledge_assertion manual_agent GO:0090173 GO:0045143 CHEBI:45783 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0221345 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0027051 infores:hetionet CHEBI:31622 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0011253 infores:hetionet CHEBI:50859 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0947912 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0235416 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0021400 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0004936 infores:hetionet CAID:CA260419 biolink:causes MONDO:0010315 infores:clingen CAID:CA260419 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.710G>A (p.Trp237Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts), total is 1 point, PP4 is met (PMID: 28702026).In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PVS1, and PP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA260419/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Supports CHEBI:64064 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0008049 infores:hetionet CHEBI:144093 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0037299 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011570 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0019212 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011849 infores:hetionet CHEBI:116278 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013604 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0027769 infores:hetionet CHEBI:39669 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0349506 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011630 infores:hetionet CHEBI:15940 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0018834 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0042373 infores:hetionet CHEBI:8212 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0233514 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0043251 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0011570 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042109 infores:hetionet CAID:CA401360518 biolink:causes MONDO:0009290 infores:clingen CAID:CA401360518 MONDO:0009290 PMID:25526786 Pathogenic PM2, PVS1, PP4 PM3 This variant, c.281C>T (p.Gln81Ter), is a nonsense variant which is predicted to cause nonsense mediated decay and lack of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. Three siblings, all with low residual GAA activity meeting PP4, were reported to be compound heterozygous for the variant and a pathogenic missense change, c.2238G>C (p.Trp746Cys) (PMID 25526786). However, the intrans data was used in the assessment of p.Trp746Cys and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 557360, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401360518/MONDO:0009290/010 2020-06-15 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6847 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C1368065 infores:hetionet UNII:D27V6190PM biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0920171 infores:hetionet CHEBI:63791 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027424 infores:hetionet CHEBI:2675 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0040264 infores:hetionet NCBIGene:7273 biolink:causes MONDO:0012714 infores:monarchinitiative not_provided not_provided HGNC:12403 MONDO:0012714 uuid:486d6229-8959-4692-9846-c045becbf7f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0018681 infores:hetionet CHEBI:45409 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022346 infores:hetionet CHEBI:31624 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0162297 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0038363 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0022116 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011991 infores:hetionet CHEBI:31932 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0085631 infores:hetionet CHEBI:63580 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042023 infores:hetionet CHEBI:50841 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0236071 infores:hetionet CHEBI:47780 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030318 infores:hetionet CHEBI:63611 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C2830004 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0858259 infores:hetionet CHEBI:135736 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0022346 infores:hetionet NCBIGene:23516 biolink:causes MONDO:0007765 infores:monarchinitiative not_provided not_provided HGNC:20858 MONDO:0007765 uuid:b9b26d57-1e00-4c74-bf19-72bef8297238 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0017178 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0851341 infores:hetionet CHEBI:15765 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0017181 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0151763 infores:hetionet CHEBI:63619 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0311468 infores:hetionet CHEBI:5118 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0032227 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0030332 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151559 infores:hetionet CHEBI:101853 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0023530 infores:hetionet CAID:CA024384 biolink:causes MONDO:0007783 infores:clingen CAID:CA024384 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, PS4, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 999 of the RYR1 protein, p.(Arg999His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00012, a frequency consistent with pathogenicity for MHS. This variant has been reported in two siblings with central core disease and multi-minicore disease (PMID:16372898). A functional study using patient lymphoblasts was published for this variant, this ex vivo assay did not show a significant shift in the EC50 for calcium release in response to RYR1 agonist as compared to wildtype lymphoblasts (PMID:16372898). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.817 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024384/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45863 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011991 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0031039 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0178298 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0018418 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014868 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0008311 infores:hetionet CHEBI:17026 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0002792 infores:hetionet CAID:CA5923182 biolink:causes MONDO:0015152 infores:clingen CAID:CA5923182 MONDO:0015152 PMID: Likely Benign BS1 BP7, BP4 The NM_213599.3: c.1215A>G variant in ANO5 is a synonymous (silent) variant (p.Gln405=) that is not located in a splice region. The filtering allele frequency for this variant is 0.001230 for the South Asian population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 94/85460 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.190, which is greater than the VCEP threshold of 0.05 (BP4, BP7 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5923182/MONDO:0015152/188 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7444 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0015672 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0031350 infores:hetionet GO:0044475 biolink:causes GO:0008331 infores:ubergraph knowledge_assertion manual_agent GO:0044475 GO:0008331 CHEBI:127780 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0231218 infores:hetionet NCBIGene:6778 biolink:causes MONDO:0957807 infores:monarchinitiative not_provided not_provided HGNC:11368 MONDO:0957807 uuid:0a7af1ef-e894-4235-8e30-74f59656da42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4551 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0855329 infores:hetionet CHEBI:71417 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0242379 infores:hetionet CHEBI:63630 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0015672 infores:hetionet CHEBI:4868 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0242350 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0267792 infores:hetionet NCBIGene:5621 biolink:causes MONDO:0010808 infores:monarchinitiative not_provided not_provided HGNC:9449 MONDO:0010808 uuid:da00e8fa-83ff-4b60-ad11-aef1def2cdd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0038454 infores:hetionet CHEBI:4814 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0151905 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151888 infores:hetionet CHEBI:4784 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0022107 infores:hetionet CHEBI:6847 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0740394 infores:hetionet CHEBI:93363 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0155169 infores:hetionet CHEBI:63681 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0004134 infores:hetionet CHEBI:9763 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0428977 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0424000 infores:hetionet CHEBI:52172 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0206062 infores:hetionet CHEBI:4681 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C3263723 infores:hetionet CAID:CA333472 biolink:causes MONDO:0007113 infores:clingen CAID:CA333472 MONDO:0007113 PMID:29737008PMID:25212744PMID:29737008 Pathogenic PP4, PP1, PM6, PVS1, PS4_Moderate, PM2_Supporting The p.M1? variant in UBE3A is predicted to cause a truncated or absent protein by altering the start codon of the coding sequence in a UBE3A where loss-of-function is an established disease mechanism. Pathogenic variants affecting the start site have been described in affected patients (PVS1). The p.M1? variant has been observed in 3 other individuals with Angelman syndrome (PMID 29737008, 25212744) (PS4_Moderate). The p.M1? variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.M1? variant in UBE3A has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Angelman syndrome (PMID 29737008) (PM6). The variant has been reported to segregate in two informative meioses (PP1). The p.M1? variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 29737008, 25212744) (PP4). In summary, the p.M1? variant in UBE3A is classified as pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4_moderate, PM2_supporting, PM6, PP1, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333472/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:3756 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0575081 infores:hetionet CHEBI:100241 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C3665347 infores:hetionet CHEBI:45951 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0151786 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0236068 infores:hetionet CHEBI:3699 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C2973529 infores:hetionet NCBIGene:6469 biolink:causes MONDO:0012709 infores:monarchinitiative not_provided not_provided HGNC:10848 MONDO:0012709 uuid:ad4d8467-a8a5-4f7e-afd6-9b0776065094 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0033975 infores:hetionet CAID:CA10014387 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014387 MONDO:0100083 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.647C>T (p.Pro216Leu) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014387/MONDO:0100083/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8455 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0162429 infores:hetionet CAID:CA512318910 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318910 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS4, PS3, PS1, BA1, BP2, PVS1, PM6, PM2, BS4, BS3, BS1, PM1, PM5, PM4, PP1, PP3 This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score 0.04 < 0.1[-14.1;6.4]) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318910/MONDO:0011071/008 2020-04-10 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6149 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0042024 infores:hetionet CHEBI:83804 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0424295 infores:hetionet CHEBI:2569 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0010200 infores:hetionet CHEBI:63617 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0008031 infores:hetionet CHEBI:66913 biolink:causes UMLS:C1096001 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C1096001 infores:hetionet CAID:CA349032 biolink:causes MONDO:0017623 infores:clingen CAID:CA349032 MONDO:0017623 PMID: Likely Pathogenic PP3, PP2, PM2_Supporting, PS4_Supporting, PS2 BP4 NM_000314.8(PTEN):c.521A>G (p.Tyr174Cys) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000602123.1)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s) SCV000602123.1).PM2_P: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score=0.978). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA349032/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6950 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0021843 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1263960 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1263960 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0004936 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1565489 infores:hetionet CHEBI:3568 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018965 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004936 infores:hetionet CHEBI:7444 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0018800 infores:hetionet CHEBI:31236 biolink:causes HP:5200424 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0424024 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0232492 infores:hetionet CHEBI:4315 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0019080 infores:hetionet CHEBI:135276 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0030446 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0040435 infores:hetionet CAID:CA6748773 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748773 MONDO:0009861 PMID:21147011 Uncertain Significance PP4_Moderate, PM2 PP3, BP4 The c.970-7A>G variant in PAH has been reported in the homozygous state in a Turkish patient with classic PKU (BH4 deficiency excluded) (PMID: 21147011) This variant has an extremely low frequency in ExAC and gnomAD (MAF=0.00016). computational evidence is conflicting: CADD 0.83088; HSF No significant splicing motif alteration detected; Splice AI Benign; TraP Score probably damaging. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748773/MONDO:0009861/006 2020-08-13 2021-11-21 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:75722 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1142412 infores:hetionet CHEBI:47519 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0041834 infores:hetionet NCBIGene:340061 biolink:causes MONDO:0014405 infores:monarchinitiative not_provided not_provided HGNC:27962 MONDO:0014405 uuid:5bba08e2-df9c-4234-8f5c-f8bf9dba1b6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0086543 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042023 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0860713 infores:hetionet CAID:CA10014735 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014735 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.4G>A (p.Ala2Thr) is a missense variant which has a REVEL score < 0.50 (0.393) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014735/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10558659 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558659 MONDO:0010726 PMID: Likely Benign BS2 BP4, PM1, BS1, PP3 The p.Asp23Glu variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). The highest population minor allele frequency of the p.Asp23Glu variant in MECP2 in gnomAD v4.1 is 0.00006532 in the Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Asp23Glu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558659/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CAID:CA147728 biolink:causes MONDO:0015152 infores:clingen CAID:CA147728 MONDO:0015152 PMID: Benign BA1 PM5, PM4, PM1, PM3, PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4 The NM_003494.4: c.1860C>T (p.Tyr620=) variant in DYSF, which is also known as NM_001130987.2: c.1914C>T (p.Tyr638=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency is 0.05612 for South Asian exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 1787/30616), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI prediction score for this variant is 0.08, which is greater than the VCEP threshold of <0.05 (BP4 and BP7 not applied). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147728/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA157919943 biolink:causes MONDO:0015967 infores:clingen CAID:CA157919943 MONDO:0015967 PMID: Likely Benign BS2, PP2, PP3, BS3_Supporting, BP2 PS4, BS1, PM2, PP4 The c.203G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 68 (p.(Gly68Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9829, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). However, functional studies demonstrated the p.Gly68Asp protein has no impact on function, with a relative activity index (RAI) > 0.5, a relative stability index (RSI) >0.5 and normal GKRP IC50 and GKA fold activation (BS3_Supporting; PMIDs: 25015100, 22611063). The Popmax filtering allele frequency of the c.203G>A variant in gnomAD v2.1.1 is 0.00001123, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in at least 6 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 26611063, PMID: 30191644, PMID: 25555642, PMID: 33046911, internal lab contributors). This variant was identified in an individual with a clinical history suggestive GCK-MODY, but there was insufficient clinical information to evaluate for PP4 (internal lab contributor). However, the variant was identified in an individual with a normal fasting glucose (BS2; PMIDs: 23799006, 22611063). Lastly, this variant has been observed in an individual who had GCK-hyperglycemia and not permanent neonatal diabetes in trans with the variant c.128G>A, p.Arg43His (PMID: 22611063), which is classified as pathogenic by the ClinGen MDEP (BP2). In summary, c.203G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version1.3.0, approved 8/11/2023): BS2, BS3_Supporting, BP2, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA157919943/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Contradicts true CHEBI:8707 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006142 infores:hetionet CHEBI:46081 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0086439 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1384666 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0235318 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235318 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0010709 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0031542 infores:hetionet CHEBI:188986 biolink:causes MONDO:0002136 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0155177 infores:hetionet CHEBI:4753 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0035305 infores:hetionet CHEBI:63621 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0149745 infores:hetionet CHEBI:7852 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0009676 infores:hetionet CHEBI:68478 biolink:causes MONDO:0011441 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034931 infores:hetionet CHEBI:38562 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0041657 infores:hetionet CHEBI:6950 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085631 infores:hetionet CHEBI:465284 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0021141 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0233632 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0947999 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0022408 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020295 infores:hetionet NCBIGene:80036 biolink:causes MONDO:0859365 infores:monarchinitiative not_provided not_provided HGNC:17992 MONDO:0859365 uuid:4cb97060-a205-4f21-b9de-65b8e400a541 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0019345 infores:hetionet CAID:CA2580098643 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098643 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.509-10del is an intronic variant which is not detected in any population databases, allowing for the application of PM2_supporting. This variant has a SpliceAI score of 0.01 and a PhyloP score of 0.48, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098643/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17347 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0029456 infores:hetionet CHEBI:3614 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0017565 infores:hetionet CHEBI:50861 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0030232 infores:hetionet CHEBI:50924 biolink:causes MONDO:0006687 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0006430 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0033687 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0549475 infores:hetionet CHEBI:5779 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0080274 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037274 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0162830 infores:hetionet CHEBI:3380 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0015672 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0003864 infores:hetionet CHEBI:2668 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0002622 infores:hetionet CAID:CA410202730 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202730 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.382A>T (p.Thr128Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score of 0.94 (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202730/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7478 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0699828 infores:hetionet CHEBI:5778 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0850149 infores:hetionet CHEBI:45951 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0027424 infores:hetionet CHEBI:3215 biolink:causes HP:6000500 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235248 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0392162 infores:hetionet NCBIGene:286464 biolink:causes MONDO:0025354 infores:monarchinitiative not_provided not_provided HGNC:26708 MONDO:0025354 uuid:123367ea-b08b-49e8-b951-dbac75cd9860 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:79699 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0021400 infores:hetionet CHEBI:63638 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233471 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0699828 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0016034 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0015397 infores:hetionet CHEBI:194135 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0025874 infores:hetionet CHEBI:31980 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0038450 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0037195 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0427008 infores:hetionet CHEBI:5893 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011124 infores:hetionet GO:0045694 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0045694 GO:0019953 CHEBI:2955 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0162119 infores:hetionet CHEBI:51450 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0030332 infores:hetionet CHEBI:4702 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0042571 infores:hetionet CHEBI:8093 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0423153 infores:hetionet NCBIGene:7369 biolink:causes MONDO:0008073 infores:monarchinitiative not_provided not_provided HGNC:12559 MONDO:0008073 uuid:9c60b573-4891-4ef7-b6dd-a0e792040455 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0026858 infores:hetionet NCBIGene:6197 biolink:causes MONDO:0010447 infores:monarchinitiative not_provided not_provided HGNC:10432 MONDO:0010447 uuid:1920736d-2151-4ed8-8887-8b721223f1cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0011701 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0009782 infores:hetionet CHEBI:171719 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0349231 infores:hetionet CHEBI:4877 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0019158 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0347950 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0347950 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0003123 infores:hetionet CAID:CA9870171 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870171 MONDO:0015967 PMID: Likely Pathogenic PP3, PP1, PM2_Supporting, PS4, PM1_Supporting PP4 The c.124G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to arginine at codon 42 (p.(Gly42Arg)) of NM_175914.5. This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as crucial for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 26552609, internal lab contributors). However, the MODY probability is either unable to be calculated due to lack of clinical information or the calculated MODY probability is <50% (PMID:26552609, internal lab contributors). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID:26552609). In summary, c.124G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870171/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CAID:CA10584700 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584700 MONDO:0007750 PMID: Likely Pathogenic PS4, PP1_Moderate, PM2, PP4 BA1, BP4, BP2, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PM6, PVS1, PP3, BS2 The NM_000527.4(LDLR):c.-149C>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4, PP4, PP1_moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PS4 - Variant meets PM2 and is identified in 10 unrelated index cases who fulfill Simon Broome criteria for FH (4 definite FH and 6 possible FH) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)(PMID: 28379029), so PS4 is Met.PP4 - Variant meets PM2 and is identified in 10 unrelated index cases who fulfill Simon Broome criteria for FH (see PS4 for details), so PP4 is Met.PP1_Moderate - Variant segregates with FH phenotype in 4 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)(PMID: 28379029), so PP1_Moderate is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584700/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:36791 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027769 infores:hetionet CHEBI:6339 biolink:causes HP:0010742 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0522035 infores:hetionet CHEBI:119573 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0022346 infores:hetionet CHEBI:27974 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0004096 infores:hetionet CHEBI:3387 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0232487 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020578 infores:hetionet NCBIGene:2153 biolink:causes MONDO:0008560 infores:monarchinitiative not_provided not_provided HGNC:3542 MONDO:0008560 uuid:8425fe1b-5eca-40c8-a193-7883ba6c8ddb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17823 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0231528 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0020538 infores:hetionet CAID:CA2837995504 biolink:causes MONDO:0015967 infores:clingen CAID:CA2837995504 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.797delinsAA variant in the glucokinase gene, GCK, results in the insertion of a glutamine and a frameshift in the protein at codon 266 in NM_000162.5, adding nine novel amino acids before encountering a stop codon (p.(Leu266GlnfsTer9)). This variant, located in biologically-relevant exon 7 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). It is absent in gnomAD v4.1 and v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 19790256). In summary, c.797delinsAA meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 2/17/2025): PVS1, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2837995504/MONDO:0015967/086 2025-04-17 2025-04-17 Semidominant inheritance HP:0032113 Supports CHEBI:71223 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0243026 infores:hetionet CHEBI:10119 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0554976 infores:hetionet CHEBI:64312 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C3263723 infores:hetionet UMLS:C0065374 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0008031 infores:hetionet CHEBI:63605 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0854467 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0877077 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0877077 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0026846 infores:hetionet CHEBI:9720 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0233494 infores:hetionet CHEBI:31236 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0023066 infores:hetionet CHEBI:142290 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0019080 infores:hetionet CHEBI:41774 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0152031 infores:hetionet CAID:CA10580066 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580066 MONDO:0007648 PMID: Uncertain Significance BS2_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4 The c.61C>G (p.Leu21Val) variant results in a non-synonymous amino acid change in exon 2. This variant is present in 5 of 188,446 alleles (0.00003) in gnomAD, present exclusively in the East Asian subpopulation with 5 of 12,882 alleles (0.00039). This variant has been observed in at least three individuals without DGC, SRC tumour or LBC and whose families do not suggest HDGC (BS2_supporting). In summary, the clinical significance of this variant is uncertain based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580066/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:9763 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0013378 infores:hetionet CHEBI:28830 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0156312 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0178298 infores:hetionet GO:0044071 biolink:causes GO:0007049 infores:ubergraph knowledge_assertion manual_agent GO:0044071 GO:0007049 CHEBI:36795 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0234133 infores:hetionet NCBIGene:9380 biolink:causes MONDO:0009824 infores:monarchinitiative not_provided not_provided HGNC:4570 MONDO:0009824 uuid:35b87261-0b0b-4c58-a9c6-3c8689d38c8e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0023066 infores:hetionet CHEBI:50122 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0011603 infores:hetionet NCBIGene:3479 biolink:causes MONDO:0012110 infores:monarchinitiative not_provided not_provided HGNC:5464 MONDO:0012110 uuid:84f4cc5b-fb9a-4cb3-a7a1-6162f85a9463 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48669 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0037199 infores:hetionet CHEBI:4858 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0018524 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005291 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0007766 infores:hetionet CHEBI:6715 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085649 infores:hetionet CHEBI:68584 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C1384353 infores:hetionet NCBIGene:84334 biolink:causes MONDO:0033652 infores:monarchinitiative not_provided not_provided HGNC:20492 MONDO:0033652 uuid:83a57d44-0b8d-4140-a8ca-7f8aadace1c4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1167965 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0009319 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0856151 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0242350 infores:hetionet CHEBI:7575 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0018944 infores:hetionet CHEBI:3561 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0242301 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020550 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013220 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0003537 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0423273 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0423273 infores:hetionet CHEBI:9434 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0035455 infores:hetionet CHEBI:5296 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0020453 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233414 infores:hetionet CHEBI:49713 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0085631 infores:hetionet CHEBI:7575 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0948594 infores:hetionet CHEBI:3207 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0234708 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0009760 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0038238 infores:hetionet CHEBI:2611 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0232462 infores:hetionet CHEBI:18067 biolink:causes HP:0032552 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0235472 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020621 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0853760 infores:hetionet CHEBI:28864 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C3665624 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0027059 infores:hetionet CHEBI:65349 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0027497 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0011991 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0023890 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0233632 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005543 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0520463 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0854082 infores:hetionet CHEBI:2704 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0687713 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018939 infores:hetionet UMLS:C0011701 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0018681 infores:hetionet CHEBI:7581 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0003467 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027947 infores:hetionet CHEBI:61049 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0497156 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0024312 infores:hetionet CHEBI:77733 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0851578 infores:hetionet NCBIGene:197131 biolink:causes MONDO:0009479 infores:monarchinitiative not_provided not_provided HGNC:16808 MONDO:0009479 uuid:46d37e36-aedf-4359-8752-f2d659bbb957 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10290 biolink:causes MONDO:0014418 infores:monarchinitiative not_provided not_provided HGNC:16901 MONDO:0014418 uuid:a8608ae4-38b3-4921-9b5b-ad67443f0c3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:724125 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0009450 infores:hetionet UMLS:C0657912 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0039240 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0021400 infores:hetionet CHEBI:145499 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151576 infores:hetionet CHEBI:5778 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0011991 infores:hetionet CHEBI:5613 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0002792 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0948089 infores:hetionet CHEBI:135961 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0041834 infores:hetionet CHEBI:61058 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0002962 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423602 infores:hetionet CL:0000062 biolink:causes MONDO:0045053 infores:ubergraph knowledge_assertion manual_agent CL:0000062 MONDO:0045053 CHEBI:2948 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0042384 infores:hetionet CHEBI:16899 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0031350 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0039971 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0948594 infores:hetionet NCBIGene:5193 biolink:causes MONDO:0009959 infores:monarchinitiative not_provided not_provided HGNC:8854 MONDO:0009959 uuid:60a36092-ccdb-4309-90bf-1e15cd887ed3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C0948002 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0948002 infores:hetionet CHEBI:42797 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030794 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0233494 infores:hetionet CHEBI:7824 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0032617 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0011615 infores:hetionet GO:1905276 biolink:causes GO:0060562 infores:ubergraph knowledge_assertion manual_agent GO:1905276 GO:0060562 NCBIGene:3752 biolink:causes MONDO:0011819 infores:monarchinitiative not_provided not_provided HGNC:6239 MONDO:0011819 uuid:0bf4d3fd-ba88-40f5-ae7a-5cfabee127b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135920 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0017168 infores:hetionet NCBIGene:10531 biolink:causes MONDO:0030318 infores:monarchinitiative not_provided not_provided HGNC:17663 MONDO:0030318 uuid:89393d35-a8f9-4da1-b943-90a28a78f75a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7986 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0242429 infores:hetionet CHEBI:3219 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2584688 infores:hetionet CHEBI:45367 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0311468 infores:hetionet CHEBI:8080 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0235146 infores:hetionet CHEBI:102216 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0018681 infores:hetionet CHEBI:4027 biolink:causes MONDO:0020076 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027022 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0541879 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0541879 infores:hetionet CHEBI:47381 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0235996 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0221345 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0006849 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0332575 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0002871 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0021400 infores:hetionet CHEBI:51364 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0040264 infores:hetionet CHEBI:478164 biolink:causes HP:0031475 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0751523 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0029145 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0029145 uuid:94e39816-ca48-48a6-bc4a-3b487a50976d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038325 infores:hetionet CHEBI:72690 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0027947 infores:hetionet NCBIGene:3075 biolink:causes MONDO:0012350 infores:monarchinitiative not_provided not_provided HGNC:4883 MONDO:0012350 uuid:89d86525-1339-4ffd-a0fc-cd32d4deafea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7581 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0236068 infores:hetionet CHEBI:6067 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0332563 infores:hetionet CHEBI:6067 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009676 infores:hetionet CHEBI:4910 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0020649 infores:hetionet CHEBI:10124 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0025323 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0003864 infores:hetionet CHEBI:7820 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0268000 infores:hetionet CHEBI:9139 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0015672 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0856604 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0856604 infores:hetionet CHEBI:408174 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0028734 infores:hetionet CHEBI:63631 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085631 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0034150 infores:hetionet NCBIGene:9821 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:15574 MONDO:0016419 uuid:1a95f7de-f15e-42b0-9356-f31a3b5fc754 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0267792 infores:hetionet CHEBI:7476 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002962 infores:hetionet CHEBI:8428 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0004238 infores:hetionet NCBITaxon:2 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 GO:0006954 DB15566_MESH_D003234_1 CHEBI:94501 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0162830 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0948594 infores:hetionet CHEBI:52010 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0011991 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0233494 infores:hetionet CHEBI:72296 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151905 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0149931 infores:hetionet CHEBI:127342 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0013428 infores:hetionet CHEBI:8404 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0018790 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0018799 infores:hetionet CAID:CA386972269 biolink:causes MONDO:0015967 infores:clingen CAID:CA386972269 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4 The c.1623+2T>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 8 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 8 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). The MODY probability in one case is unable to be calculated due to lack of information about when insulin was started, and therefore PP4 cannot be applied. In the other case, the calculated MODY probability was >50%; however, HNF4A was not tested, and therefore PP4 cannot be applied. In summary, c.1623+2T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386972269/MONDO:0015967/017 2025-02-07 2025-02-07 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16603064 biolink:causes MONDO:0018875 infores:clingen CAID:CA16603064 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PM1_Supporting, PM5_Supporting, PM2_Supporting BA1, BP4, PS3, PS4, PS1, PS2, BS1, BS4, PP3, PP4, PP1 The NM_000546.6: c.431A>T variant in TP53 is a missense variant predicted to cause substitution of Glutamine by Leucine at amino acid 144 (p.Gln144Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity, indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met). Another missense variant with equal or lesser predicted impact c.431A>C (p.Gln144Pro) (ClinVar Variation ID: 186594), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3_Supporting, PM2_Supporting, PM5_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603064/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0497156 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0234215 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0027051 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0234894 infores:hetionet CHEBI:15367 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038999 infores:hetionet GO:1903722 biolink:causes GO:0000226 infores:ubergraph knowledge_assertion manual_agent GO:1903722 GO:0000226 CHEBI:480999 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0032617 infores:hetionet CHEBI:63621 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0008031 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018099 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0948089 infores:hetionet CAID:CA10014372 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014372 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.701C>T (p.Thr234Ile) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014372/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40279 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151735 infores:hetionet CHEBI:5138 biolink:causes UMLS:C1868709 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1868709 infores:hetionet NCBIGene:23414 biolink:causes MONDO:0008542 infores:monarchinitiative not_provided not_provided HGNC:16700 MONDO:0008542 uuid:6b493471-5ebb-46dd-a01d-db44b20fb97d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0030232 infores:hetionet CHEBI:3223 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0016204 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0549622 infores:hetionet CHEBI:94686 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0015230 infores:hetionet CHEBI:39867 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013456 infores:hetionet CAID:CA229617 biolink:causes MONDO:0009861 infores:clingen CAID:CA229617 MONDO:0009861 PMID:26542770PMID:10541324 Likely Pathogenic PM3, PP4_Moderate, PM2, PP1, PP3 The NM_000277.3:c.545A>G (p.Glu182Gly) variant is a missense variant in exon 6/13 of PAH. The variant was reported in confirmed trans with the p.R261Q allele (Pathogenic per ClinGen PAH VCEP) among two siblings with mild hyperphenylalanemia; BH4 deficiency was not noted to have been formally excluded (PMID: 26542770) (PP1; PM3). The variant has also been previously reported among “two alleles” in a cohort of Armenian PKU patients among whom BH4 deficiency was excluded; no further detail appears to be given (PMID: 10541324) (PP4_Moderate). It has also been noted in ClinVar (ID 102731), without a classification. Three heterozygotes and zero homozygotes for the variant are present in gnomAD, corresponding to a global AF of 0.0000119 and maximum population frequency of 0.0000264 (non-Finnish European population), under the frequency cutoff of 0.0002 for use of PM2 (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.929) (PP3).Classification: Likely PathogenicSupporting Criteria: PM2; PM3; PP1; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229617/MONDO:0009861/006 2020-07-25 2020-07-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:70707 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0030252 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0085606 infores:hetionet CHEBI:100241 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085593 infores:hetionet CHEBI:6073 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0030196 infores:hetionet CHEBI:63618 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0020458 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0853026 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1096658 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1096658 infores:hetionet CHEBI:5778 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0009676 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011609 infores:hetionet CHEBI:7565 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0034642 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0235567 infores:hetionet NCBIGene:55624 biolink:causes MONDO:0013155 infores:monarchinitiative not_provided not_provided HGNC:19139 MONDO:0013155 uuid:f7a318fa-4024-47ff-a5d2-37313fb85e22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0149931 infores:hetionet CHEBI:35677 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0018524 infores:hetionet GO:2000595 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:2000595 GO:0007399 CHEBI:3437 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0241863 infores:hetionet CHEBI:367163 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0023524 infores:hetionet CHEBI:51860 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0042963 infores:hetionet CHEBI:32020 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0004604 infores:hetionet CHEBI:2663 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0003811 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0231170 infores:hetionet NCBIGene:79731 biolink:causes MONDO:0014547 infores:monarchinitiative not_provided not_provided HGNC:26274 MONDO:0014547 uuid:9e13af86-2df1-456a-99c5-550c47c637dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2061053 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061053 MONDO:0015924 PMID: Likely Benign PM1, BS1 PM2, PP3, BP4, PM5, PS1 The NM_001204.7(BMPR2) c.220A>G variant is a missense variant predicted to cause substitution of lysine by glutamate at amino acid 74 (p.Lys74Glu). The highest minor allele frequency in gnomAD v2.1.1 (controls) is 0.002155 (5/2320 alleles) in the Ashkenazi Jewish population, which exceeds the ClinGen PH VCEP threshold (>0.1%) for BS1 (BS1 met). The computational predictor REVEL gives a score of 0.353, which is neither above nor below the thresholds predicting a damaging (≥0.75) or benign (≤0.25) impact on BMPR2 function. SpliceAI analysis indicates the variant does not alter normal splicing. The missense change is located within the conserved ligand-binding domain but there are no functional data to support the amino acid residue as critical or non-critical (PM1 met). In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PM1 (VCEP specification version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061053/MONDO:0015924/125 2024-08-02 2024-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36704 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0009763 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1510472 infores:hetionet CHEBI:17347 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042024 infores:hetionet CHEBI:474053 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0086565 infores:hetionet CAID:CA213824 biolink:causes MONDO:0015967 infores:clingen CAID:CA213824 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS3, PM1 The c.661A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 221 (p.(Glu221Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.789, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP. This variant was identified in 4 unelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; PMID: 23295292, internal lab contributors). This variant has been identified in 25 unrelated individuals with hyperglycemia and segregated with the phenotype, with 17 informative meioses in at least 7 families (PS4, PP1_Strong; PMIDs: 10694920, 12955723, 31658956, 34462253, 35592779, 35733065, 23295292, and 30592380). A relative activity index (RAI) was calculated for this variant but the wild type parameters are outside of MDEP's recommendations; therefore, this data cannot be used towards PS3 (PMID: 30592380). In summary, c.661A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213824/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:50381 biolink:causes HP:0002317 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0231686 infores:hetionet CHEBI:2618 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0010037 infores:hetionet CHEBI:63611 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042998 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0009450 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0003864 infores:hetionet CHEBI:9139 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0542571 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0235431 infores:hetionet CHEBI:68584 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0221345 infores:hetionet CHEBI:184555 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0085633 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0018681 infores:hetionet CHEBI:473990 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0085649 infores:hetionet CHEBI:63622 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0231528 infores:hetionet CHEBI:63599 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0020456 infores:hetionet GO:0043304 biolink:causes GO:0002279 infores:ubergraph knowledge_assertion manual_agent GO:0043304 GO:0002279 NCBIGene:4791 biolink:causes MONDO:0014260 infores:monarchinitiative not_provided not_provided HGNC:7795 MONDO:0014260 uuid:6dbb9fe3-2b34-427c-b071-5a253752717c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0080274 infores:hetionet CHEBI:64312 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0023222 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0034065 infores:hetionet CHEBI:168396 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0268000 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0234215 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020649 infores:hetionet CHEBI:5893 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0542571 infores:hetionet CHEBI:83527 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0036974 infores:hetionet NCBIGene:8913 biolink:causes MONDO:0060758 infores:monarchinitiative not_provided not_provided HGNC:1394 MONDO:0060758 uuid:3f22a799-e4b4-40b2-8220-8c091763ae30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0232461 infores:hetionet CHEBI:83804 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0039231 infores:hetionet CAID:CA645293797 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293797 MONDO:0015924 PMID: Uncertain Significance PM2, BP4 PP3, BA1, PS4, BS1 The NM_001204.7 (BMPR2) c.419-10T>C variant is a splice region variant located in the polypyrimidine tract of intron 3. The variant is absent from gnomAD v2.1.1 controls and v4.1.0 (PM2_supporting) and was reported in a single proband with childhood-onset idiopathic PAH (PMID: 23298310). In silico prediction (SpliceAI = 0) indicates no impact on splicing (BP4) but no functional analysis has been reported. No familial segregation data were available. In summary, the variant meets the criteria to be classified as uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, BP4 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293797/MONDO:0015924/125 2025-10-07 2025-10-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41423 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0007642 infores:hetionet CHEBI:50648 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C3665347 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0852810 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0012833 infores:hetionet CHEBI:3082 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020580 infores:hetionet CHEBI:87715 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0015967 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0267596 infores:hetionet CHEBI:48538 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0004604 infores:hetionet CHEBI:3757 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037317 infores:hetionet CHEBI:5847 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0002871 infores:hetionet CHEBI:6402 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030554 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0541887 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0541887 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0274435 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0274435 infores:hetionet CHEBI:63619 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0027497 infores:hetionet CHEBI:3640 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0034150 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0010037 infores:hetionet CHEBI:7824 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0852911 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020517 infores:hetionet CHEBI:161680 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0014518 infores:hetionet CAID:CA213827 biolink:causes MONDO:0015967 infores:clingen CAID:CA213827 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM1, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting The c.676G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 261 (p.(Val226Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.789, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in more than 70 unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with more than 20 informative meioses in more than 30 families (PP1_Strong; internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Val226Met variant has a relative activity index (RAI) of 0.009 to 0.198, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID: 10525657, 25015100, https://doi.org/10.1159/isbn.978-3-318-01080-0​). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP2, PP4_Moderate, PP3, PM1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213827/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Supports CHEBI:50749 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0152030 infores:hetionet CHEBI:36795 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0428974 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0000731 infores:hetionet CAID:CA2259632 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259632 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.907A>G (p.Thr303Ala) variant in the RAF1 gene is 0.0284% (7/11568) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259632/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:51450 biolink:causes UMLS:C0948168 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0948168 infores:hetionet CAID:CA10385143 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385143 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.3430G>A (p.Val1144Ile) is a missense variant predicted to replace valine with isoleucine at amino acid 1144. This variant is present in gnomAD v.4.1.0 at a frequency of 0.1054 among hemizygous individuals, with 41,850 variant alleles / 397,045 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.081, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385143/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true UNII:T58MSI464G biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0021053 infores:hetionet CHEBI:7931 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0022661 infores:hetionet CHEBI:145499 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0023218 infores:hetionet CHEBI:84883 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C2242737 infores:hetionet CHEBI:5280 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0010038 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018099 infores:hetionet CHEBI:8435 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0026961 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0033975 infores:hetionet CAID:CA413495931 biolink:causes MONDO:0010315 infores:clingen CAID:CA413495931 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.703C>T (p.Gln235Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature present: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts) + T-B+NK- lymphocyte subset profile (0.5 pts), the total is 1.5 pts, PP4 is met (PMID: 11129345).In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413495931/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Supports CHEBI:617099 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0231528 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0006663 infores:hetionet CAID:CA412371717 biolink:causes MONDO:0010725 infores:clingen CAID:CA412371717 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1, PP1 The NM_000330.4(RS1):c.441G>A variant is a nonsense variant in amino acid 147, which results in a premature stop codon and causes a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family (PP1; PMID: 33851411). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 34645606, 33851411, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PVS1, PP1, and PS4_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412371717/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:66913 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0018681 infores:hetionet CHEBI:168396 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0231807 infores:hetionet CAID:CA397724510 biolink:causes MONDO:0008723 infores:clingen CAID:CA397724510 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL):c.1173T>A (p.Tyr391Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 11 leading to nonsense mediate decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724510/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7865 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0003123 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0497327 infores:hetionet CHEBI:9654 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0549622 infores:hetionet CHEBI:135351 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0020458 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0853875 infores:hetionet CHEBI:9316 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0020517 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0876973 infores:hetionet CAID:CA044327 biolink:causes MONDO:0007750 infores:clingen CAID:CA044327 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Moderate, PM2, PVS1, PP4 NM_000527.5(LDLR):c.682G>T (p.Glu228Ter) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PS3, PS4, PM2, PP1_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006530 (0.006%) in African/African American exomes (gnomAD v2.1.1). PVS1 - Variant leads to stop at codon 228, amino-terminal of amino acid 830. PS3 - Two studies contribute to PS3 attribution. One (PMID: 1301956) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay (PMID: 17087781) performed on Heterologous cells (COS7). FACS, CLSM and WB results in <5% LDLR activity. LDLR precursor protein does not mature. PS4 - Variant meets PM2 and is identified in 22 index cases who fulfil SB criteria for FH (n=2 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=4 Color Health, Inc.; n=14 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=2 Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) PP1_Moderate - Variant segregate with FH in 3 informatives meiosis (LDL-C > 75th percentile) and not segregate with variant in 1 relative with LDL-C <25th percentile from at least 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). PP4 - Variant meets PM2 and is identified in 22 index cases who fulfil SB criteria for FH (n=2 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=4 Color Health, Inc.; n=14 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=2 Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA044327/MONDO:0007750/013 2022-04-30 2022-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:10585 biolink:causes MONDO:0013159 infores:monarchinitiative not_provided not_provided HGNC:9202 MONDO:0013159 uuid:83d2867a-60c1-488f-a45f-766a20627a52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0025323 infores:hetionet CAID:CA2578878305 biolink:causes MONDO:0015967 infores:clingen CAID:CA2578878305 MONDO:0015967 PMID: Pathogenic PS3, PP1_Strong, PP4_Moderate, PP3, PM2_Supporting PS4 The c.679+5G>A variant in the glucokinase gene, GCK, is a non-canonical splice region variant in intron 6 of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.26 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3). Additionally, RNA studies of this non-canonical splicing variant demonstrate that it results in aberrant splicing, indicating that this variant impacts protein function (PS3; PMID: 40225161). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 17573900; internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with hyperglycemia with 4 informative meioses in two families (PP1_Strong; PMID: 17573900; internal lab contributors). In summary, c.679+5G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS3, PP1_Strong, PP4_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2578878305/MONDO:0015967/086 2025-09-17 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:9332 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0031117 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0919823 infores:hetionet CHEBI:36704 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0700590 infores:hetionet CHEBI:63589 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0018681 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0917801 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0018799 infores:hetionet CAID:CA229783 biolink:causes MONDO:0009861 infores:clingen CAID:CA229783 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.810_814del (p.His271fs) variant in PAH has been reported in 1 Czech PKU patient; plasma Phe >20mg/100ml; BH4 deficiency not excluded (PMID: 9391881; PP4). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 7 out of 13 coding exons; 7 out of total exons) (PVS1). This variant is absent from population databases (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229783/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:617099 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0037274 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0853700 infores:hetionet NCBIGene:51728 biolink:causes MONDO:0030263 infores:monarchinitiative not_provided not_provided HGNC:14121 MONDO:0030263 uuid:9a775542-739a-43d5-87e4-47973a36abb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0026858 infores:hetionet NCBIGene:7072 biolink:causes MONDO:0030885 infores:monarchinitiative not_provided not_provided HGNC:11802 MONDO:0030885 uuid:68cb16a4-bf24-4807-be8a-0ef9c250edac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000274 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000274 GO:0007275 CHEBI:6640 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0855775 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009241 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0403632 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1861172 infores:hetionet CHEBI:71255 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0027947 infores:hetionet CHEBI:15552 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0232487 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020517 infores:hetionet CHEBI:61033 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0546817 infores:hetionet CHEBI:5138 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0007859 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0948586 infores:hetionet CAID:CA409110117 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110117 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The c.1139T>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of valine to Glycine at codon 380 (p.(Val380Gly)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.352, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.1139T>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110117/MONDO:0015967/085 2024-12-06 2024-12-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011991 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0178298 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0033975 infores:hetionet CAID:CA16020848 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020848 MONDO:0009861 PMID:26542770PMID:26542770 Likely Pathogenic PM2, PM3, PP3, PP4 PM5 The c.730C>T (p.Pro244Ser) variant in PAH has been reported in 1 individual with classic PKU, detected in trans with pathogenic variant p.R158Q (PMID: 26542770). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020848/MONDO:0009861/006 2020-08-07 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3504 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0040409 infores:hetionet CHEBI:4995 biolink:causes MONDO:0017078 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014065 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0854082 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0580417 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0580417 infores:hetionet CHEBI:4784 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0003862 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007117 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0042109 infores:hetionet GO:1901490 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1901490 GO:0007275 CHEBI:47381 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011570 infores:hetionet CHEBI:76010 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0151905 infores:hetionet NCBIGene:11178 biolink:causes MONDO:0007576 infores:monarchinitiative not_provided not_provided HGNC:13861 MONDO:0007576 uuid:67bca8f5-29bf-428a-a64e-2d6d72a625a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94449 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0344232 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020538 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0235282 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235282 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0029882 infores:hetionet CHEBI:9907 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0008372 infores:hetionet CHEBI:2682 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0028081 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151763 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0877047 infores:hetionet CAID:CA891842405 biolink:causes MONDO:0009290 infores:clingen CAID:CA891842405 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, PM4_Supporting PP3, BP4 The NM_000152.5:c.1398_1400dup variant in GAA is predicted to cause a change in the length of the protein due to an in-frame duplication of one amino acid in a non-repeat region p.Phe467_Ile468insPhe) (PM4_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. Computational evidence is conflicting; PROVEAN predicts that the variant will impact the function of GAA, while Mutation Taster predicts no impact. No impact on splicing is predicted by SpliceAI. As a result, neither PP4 nor BP4 can be applied. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, PM4_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 13, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA891842405/MONDO:0009290/010 2023-03-13 2023-03-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:92998 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1971624 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0031350 infores:hetionet CHEBI:8245 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0233494 infores:hetionet CHEBI:119573 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0344232 infores:hetionet CHEBI:42820 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0242429 infores:hetionet GO:0042478 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0042478 GO:0150063 CHEBI:28748 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0000731 infores:hetionet UMLS:C0145867 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0016204 infores:hetionet CHEBI:28918 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0020621 infores:hetionet CHEBI:63617 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0023052 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0022660 infores:hetionet CHEBI:7822 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013378 infores:hetionet CHEBI:31949 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0006266 infores:hetionet CHEBI:119573 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C2047937 infores:hetionet UMLS:C1738934 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037036 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0013395 infores:hetionet CHEBI:4466 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0034063 infores:hetionet CHEBI:16347 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0020437 infores:hetionet CHEBI:136040 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0033687 infores:hetionet CHEBI:61390 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0333355 infores:hetionet CHEBI:4911 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0008031 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0574067 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151765 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151765 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0340726 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0855242 infores:hetionet CAID:CA024723 biolink:causes MONDO:0007783 infores:clingen CAID:CA024723 MONDO:0007783 PMID: Uncertain Significance PP1, PM1 PP3, PS4, PS3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 2404 of the RYR1 protein, p.(Glu2404Lys). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000127, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:19191329). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. An ex vivo assay in lymphoblasts from multiple related individuals showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested (PMID:19191329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:19191329). A REVEL score of 0.676 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024723/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6539 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0030312 infores:hetionet CHEBI:63632 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0027497 infores:hetionet CAID:CA340932 biolink:causes MONDO:0044970 infores:clingen CAID:CA340932 MONDO:0044970 PMID: Pathogenic PP3, PS3_Moderate, PS4, PM6_Supporting, PM5 PP1, BS2, PM2 The m.14484T>C (p.M64V) variant in MT-ND6 has been reported in >50 unrelated individuals with primary mitochondrial disease (PS4). This variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353) and is associated with a less severe phenotype, with visual recovery seen in some individuals. The age of onset ranges from adolescence to adulthood. While most affected individuals with this variant have LHON, other features have been seen including migraines (PMID: 12601121), tremor (PMID: 8931573), multiple sclerosis (PMIDs: 10098545, 35773337), and cardiac involvement (PMIDs: 12807863, 22749828). This variant is consistently seen in the homoplasmic state (PMIDs: 9484365, 24508359, 28392196, PMID: 9339703, 8659531, 7611298, 7604366, 7603534, 8071952, 7877803, 1463007, 1417830, 1732158, 2018041). Several extended families have been reported in the medical literature however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for segregation evidence of pathogenicity. There is at least one de novo occurrence reported in the medical literature (PM6_supporting; PMID: 9339703). Furthermore, the presence of this variant in individuals from different haplogroups suggests this variant occurred de novo in the ancestors of these individuals of different backgrounds. This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Other variants at this amino acid position leading to a different amino acid change are known disease-associated variants – m.14482C>G and m.14482C>A that both result in p.M64I (PM5). Multiple independent studies support the functional impact of this variant (PS3_moderate). Eleven cybrid studies revealed various effects including decreased ND6, ND1, and ND4L levels; decreased complex I activity; respiratory deficiency; diminished mitochondrial ATP production; reduced membrane potential; and increased production of reactive oxygen species (ROS). Cybrid cells also had increased apoptosis, autophagy, and mitophagy (PMIDs: 35567411, 25909222, 20943885, 19047048, 18806273, 15883259, 15342361, 12446713, 12379308, 35858578). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PM5, PM6_supporting, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340932/MONDO:0044970/015 2022-09-12 2023-04-03 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:7931 biolink:causes MONDO:0020675 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C2004435 infores:hetionet CHEBI:367163 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0259817 infores:hetionet GO:0080113 biolink:causes GO:0010154 infores:ubergraph knowledge_assertion manual_agent GO:0080113 GO:0010154 CHEBI:84500 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038362 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151479 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027339 infores:hetionet CHEBI:5004 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0024902 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0242350 infores:hetionet CHEBI:5147 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0039231 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0040034 infores:hetionet NCBIGene:4292 biolink:causes MONDO:0012249 infores:monarchinitiative not_provided not_provided HGNC:7127 MONDO:0012249 uuid:89cbfa64-49bd-4d47-a780-1ca0321c1e73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9352 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0008325 infores:hetionet CHEBI:8871 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0036974 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027720 infores:hetionet CHEBI:2379 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0011603 infores:hetionet NCBIGene:4683 biolink:causes MONDO:0009623 infores:monarchinitiative not_provided not_provided HGNC:7652 MONDO:0009623 uuid:e80d3de7-24a8-43ec-9e0b-9e206b27343d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0312420 infores:hetionet CHEBI:9288 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0001807 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0243026 infores:hetionet GO:1902692 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1902692 GO:0007399 CHEBI:31623 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0018681 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040034 infores:hetionet CHEBI:45979 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0232462 infores:hetionet CHEBI:584020 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0018808 infores:hetionet CAID:CA10580713 biolink:causes MONDO:0700268 infores:clingen CAID:CA10580713 MONDO:0700268 PMID:30209399 Likely Pathogenic PP3, PM2_Supporting, PS3 The c.74C>T variant in BRCA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 25 (p.Pro25Leu). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.35, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 35659930) (PS3 met). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580713/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:672 biolink:causes MONDO:0054748 infores:monarchinitiative not_provided not_provided HGNC:1100 MONDO:0054748 uuid:9ac9edd9-1cf4-4f0b-89a3-091a87b8278b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0853908 infores:hetionet CHEBI:9588 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0027497 infores:hetionet CAID:CA386965780 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965780 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PM5_Supporting, PP3 PS4, PP4 The c.722G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to tyrosine at codon 241 (p.(Cys241Tyr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding of HNF1A (codons 107-174 and 201-280), which is critical for the protein’s function (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.963, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributors). One of these individuals also has a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor). This variant segregated with diabetes with six informative meioses in two families (PP1_Strong; PMID: 27236918, internal lab contributors). Additionally, two other missense variants at the same codon, c.721T>G (p.Cys241Gly) and c.721T>C (p.Cys241Arg), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.722G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2023): PP1_Strong, PM2_Supporting, PP3, PM1_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965780/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2979982 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0034150 infores:hetionet CHEBI:3515 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0152031 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151849 infores:hetionet CHEBI:4469 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0011124 infores:hetionet CAID:CA287523615 biolink:causes MONDO:0100453 infores:clingen CAID:CA287523615 MONDO:0100453 PMID: Likely Pathogenic PM3, PP3, PP1, PP4, PM2_Supporting The NM_000180.4(GUCY2D):c.839C>G (p.Thr280Arg) variant predicts the substitution of arginine for threonine at position p.280. While the REVEL score is indeterminate (0.58) and does not support a deleterious effect on protein structure, the splicing impact predictor SpliceAI gives a score of 0.46 which is above the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) and has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant. (1 point, PMIDs: 2642740, 29068479, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PP1; PMID: 29068479). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), significantly reduced rod ERG (0.5 pts) and extinguished cone ERG (1 pt), decreased peripheral vision (1 pt) and decreased visual acuity (1 pt). The patient's OCT showed retinal structure preserved relative to vision loss (1 pt). (Total points 5.0, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3, PP1, PP3, PP4, PM2 supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA287523615/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63611 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0019080 infores:hetionet CHEBI:77733 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0008031 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006145 infores:hetionet CHEBI:63925 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0018681 infores:hetionet UBERON:0000473 biolink:causes MONDO:0020808 infores:ubergraph knowledge_assertion manual_agent UBERON:0000473 MONDO:0020808 CHEBI:6954 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1384353 infores:hetionet CHEBI:17026 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0028081 infores:hetionet CAID:CA410206679 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206679 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS3, PS4, BA1, BP3, BP2, BP1, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PM5, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.792G>C (p.Gln264His) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting) and has only been reported in a patient with oligopolyposis (PMID: 31942411). The computational predictor REVEL gives a score of 0.392, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206679/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27974 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0002994 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151849 infores:hetionet CHEBI:72690 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020598 infores:hetionet CHEBI:53766 biolink:causes HP:0100762 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0018994 infores:hetionet CHEBI:63845 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0041834 infores:hetionet CHEBI:101853 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151662 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0851341 infores:hetionet CHEBI:63580 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0423153 infores:hetionet CHEBI:9649 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0035078 infores:hetionet CHEBI:30830 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0233794 infores:hetionet CHEBI:4858 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0007859 infores:hetionet CHEBI:47381 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085641 infores:hetionet GO:2000592 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:2000592 GO:0001656 CHEBI:7573 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0547030 infores:hetionet CAID:CA400034691 biolink:causes MONDO:0100326 infores:clingen CAID:CA400034691 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3 The NM_000212.3:c.2315T>C variant in ITGB3 is a missense variant predicted to cause substitution of leucine by proline at amino acid 772 (p.Leu772Pro). This variant has been observed in homozygosity in one individual (GT3 in PMID: 19691478) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1 is 0.00004007 (3/74870 alleles) in the African/African American population, which is lower than the ClinGen Platelet Disorders VCEP threshold (<0.0001; PM2_Supporting). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM3_Supporting, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400034691/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7773 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0006826 infores:hetionet CHEBI:253342 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0232849 infores:hetionet CHEBI:63617 biolink:causes HP:0033400 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0000727 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0010037 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0858041 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0858041 infores:hetionet CAID:CA410148456 biolink:causes MONDO:0100083 infores:clingen CAID:CA410148456 MONDO:0100083 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1037G>A (p.Arg346His) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148456/MONDO:0100083/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085612 infores:hetionet CHEBI:63620 biolink:causes HP:0031189 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0231666 infores:hetionet CHEBI:8874 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0015423 infores:hetionet CL:0000031 biolink:causes MONDO:0005072 infores:ubergraph knowledge_assertion manual_agent CL:0000031 MONDO:0005072 CHEBI:51860 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011616 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0032285 infores:hetionet CHEBI:4445 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1443060 infores:hetionet CHEBI:72297 biolink:causes HP:0033842 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0239233 infores:hetionet CHEBI:50749 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0151514 infores:hetionet NCBIGene:57582 biolink:causes MONDO:0014002 infores:monarchinitiative not_provided not_provided HGNC:18865 MONDO:0014002 uuid:a71bbddb-33d7-4213-a07e-061695076d73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027765 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0404521 infores:hetionet CHEBI:38562 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0023222 infores:hetionet CHEBI:4798 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0312420 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0037822 infores:hetionet CHEBI:9586 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0542571 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0233494 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003467 infores:hetionet CAID:CA023633 biolink:causes MONDO:0007750 infores:clingen CAID:CA023633 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Moderate, PM2, PP4 BA1, BP4, BP2, PS2, PS1, BP7, BS1, BS3, BS4, PM1, PM3, PM5, PM4, PVS1, PM6, PP3, PP1, BS2 The NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PS4_supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006199 (0.006199%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met.PS3_Moderate - Level 2 assays: PMID 34869944:Heterologous cells (CHO), FACS assays - result - 20% uptake.---- functional study is consistent with damaging effect, so PS3_Moderate is Met.PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with DLCN>=6 from Color Health, Inc, and 1 index case with Simon Broome criteria (TC of 9.8 mmol/L and personal or family history of CHD) from UK (PMID: 23669246), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in 2 unrelated index cases (see PS4 for details), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023633/MONDO:0007750/013 2022-03-25 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:135613 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0746961 infores:hetionet CHEBI:63616 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0006826 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0027441 infores:hetionet CHEBI:9927 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0041657 infores:hetionet CHEBI:9445 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0030554 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1368065 infores:hetionet CHEBI:29007 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0024312 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0017152 infores:hetionet CHEBI:59773 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0239571 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0410198 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0410198 infores:hetionet CHEBI:8382 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0232461 infores:hetionet UMLS:C0010592 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151786 infores:hetionet CHEBI:28148 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0011175 infores:hetionet UMLS:C0065374 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0026826 infores:hetionet CHEBI:135005 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0000737 infores:hetionet CHEBI:2682 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0017979 infores:hetionet NCBIGene:84062 biolink:causes MONDO:0013559 infores:monarchinitiative not_provided not_provided HGNC:17328 MONDO:0013559 uuid:a96c84b9-e076-40e7-a3bd-a6ee09aa222f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0086565 infores:hetionet CHEBI:3242 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0008031 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0007222 infores:hetionet CHEBI:63630 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011168 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0037274 infores:hetionet CHEBI:27666 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0232462 infores:hetionet CHEBI:6887 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0162835 infores:hetionet CAID:CA000551 biolink:causes MONDO:0017623 infores:clingen CAID:CA000551 MONDO:0017623 PMID:29706350PMID:12085208PMID:29785012PMID:12085208PMID:28755079PMID:29706350PMID:12085208PMID:29785012 Uncertain Significance PP2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PP3, PP4, PP1, BS2, PM5, PM4, PM1, PM3, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2, PS4 NM_000314.8(PTEN):c.701G>A (p.Arg234Gln) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_Supporting: Absent in large sequenced populations in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000551/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16899 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0020625 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0541941 infores:hetionet CHEBI:2469 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0016655 infores:hetionet NCBIGene:374462 biolink:causes MONDO:0013249 infores:monarchinitiative not_provided not_provided HGNC:9679 MONDO:0013249 uuid:39f560ba-7fb5-4440-895f-6e29793a9cc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135613 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0281856 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0006285 infores:hetionet CHEBI:27436 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0003467 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085584 infores:hetionet CHEBI:39669 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0030554 infores:hetionet CHEBI:135451 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0015230 infores:hetionet CHEBI:9570 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0237849 infores:hetionet CHEBI:63791 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017672 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0027769 infores:hetionet CAID:CA16621289 biolink:causes MONDO:0010725 infores:clingen CAID:CA16621289 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3 PS4 The NM_000330.4(RS1):c.170T>C variant is a missense variant encoding the substitution of Leucine with Serine at amino acid 57. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.653, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.01 for donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. This variant has been reported in at least 1 individual (PMID: 30464253), however, the publication did not include any retinal test or diagnosis of retinoschisis. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting and PP3 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621289/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:168396 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009782 infores:hetionet CHEBI:4495 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0917801 infores:hetionet CHEBI:6413 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0015967 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0855242 infores:hetionet CHEBI:46195 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0022672 infores:hetionet CHEBI:32599 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0549249 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0442874 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022904 infores:hetionet CHEBI:9168 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0024236 infores:hetionet CHEBI:251408 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0522224 infores:hetionet GO:0061001 biolink:causes GO:0060996 infores:ubergraph knowledge_assertion manual_agent GO:0061001 GO:0060996 CHEBI:49662 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0041657 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0149931 infores:hetionet CHEBI:5001 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151662 infores:hetionet CHEBI:9445 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0231218 infores:hetionet CHEBI:31705 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0041657 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0699893 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0236071 infores:hetionet NCBIGene:114034 biolink:causes MONDO:0013993 infores:monarchinitiative not_provided not_provided HGNC:15954 MONDO:0013993 uuid:0ef1908c-cd90-41c7-a090-32595d91e285 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229300 biolink:causes MONDO:0009861 infores:clingen CAID:CA229300 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 The c.1046C>A (p.Ser349Ter) variant in PAH is a null variant (nonsense variant) in exon 10 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has previously been reported in one classic PKU case per the BioPKU database (PMID: 24939588), without additional information. Classification: Likely PathogenicSupporting criteria: PVS1, PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229300/MONDO:0009861/006 2020-04-13 2020-04-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:101085 biolink:causes NCIT:C34642 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0017650 infores:hetionet CHEBI:231425 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C2047937 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0009806 infores:hetionet CHEBI:18385 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0010520 infores:hetionet CAID:CA320638298 biolink:causes MONDO:0011071 infores:clingen CAID:CA320638298 MONDO:0011071 PMID: Likely Benign BP4, BP2, BP7, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BA1, BP5, BS3, BS4, PM2, PM6, PVS1, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 MAF of 0.00001617(0.001617%, 11/68046 alleles) in the NFE subpopulation of the gnomAD 3.1.2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This variant is detected in a homozygous state in an individual or in a population database 64 times (gnomAD 3.1.2) (BP2). This synonymous/intronic/UTR/frameshift variant has a SpliceAI score ≤ 0.20 (Donor Loss 0.01) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.01 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320638298/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:46345 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0700361 infores:hetionet CHEBI:16335 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0004093 infores:hetionet CHEBI:68558 biolink:causes HP:0034807 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C1956415 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038661 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0011053 infores:hetionet NCBIGene:538 biolink:causes MONDO:0010572 infores:monarchinitiative not_provided not_provided HGNC:869 MONDO:0010572 uuid:fda41d58-89a3-4604-b856-9bfe288fb6de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2580098653 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098653 MONDO:0011071 PMID: Pathogenic PS4, PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, BP2, BP3, BP1, BP4, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.146del (p.Pro49GlnfsTer4) is a nonsense variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong). This variant has been reported in four or more probands meeting at least one of the RUNX1-phenotypic criteria (PS4). It is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is located downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting, PM5_supporting, PS4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098653/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3723 biolink:causes UMLS:C0235002 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235002 infores:hetionet CHEBI:68478 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0001807 infores:hetionet CHEBI:10023 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020461 infores:hetionet CAID:CA343719989 biolink:causes MONDO:0005338 infores:clingen CAID:CA343719989 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BA1 The c.55C>A variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Lysine at amino acid 19 (p.Gln19Lys). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.08, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMID: 39998747), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting, PS4_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343719989/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17688 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0031350 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0409974 infores:hetionet CHEBI:3640 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0014742 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151970 infores:hetionet CHEBI:8412 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0004936 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0018799 infores:hetionet CHEBI:4822 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0018681 infores:hetionet CHEBI:50729 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0033687 infores:hetionet CAID:CA024750 biolink:causes MONDO:0007783 infores:clingen CAID:CA024750 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP3_Moderate, PP1_Strong BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2435 of the RYR1 protein, p.(Arg2435His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 26 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 24 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 16163667, 21965348, 23842196, 12059893, 17081152, 17710899, 20681998, 31559918, 16732084, 19513315). Functional studies in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 9334205, 27586648). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 10 families individuals, PP1_Strong (PMID: 12059893, 30236257, 32919876). A REVEL score >0.85 (0.944) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024750/MONDO:0007783/012 2021-03-19 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:168396 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151763 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0015397 infores:hetionet CHEBI:367163 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0428977 infores:hetionet CHEBI:40303 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0026858 infores:hetionet CHEBI:145499 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0231218 infores:hetionet CHEBI:72323 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0041912 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0001056 uuid:9caf3bbc-46c0-4e36-bfdd-c438c6fed549 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410148185 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148185 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1084T>G (p.Ser362Ala) is a missense variant that has a REVEL score < 0.50 (0.085) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148185/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50659 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0015230 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0234215 infores:hetionet CAID:CA413497161 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497161 MONDO:0010315 PMID: Likely Pathogenic PM1_Strong, PP4_Moderate, PM2_Supporting NM_000206.3(IL2RG):c.184T>A is a missense variant predicted to cause substitution of Cysteine by Serine at amino acid 62 (p.Cys62Ser). This variant affects a conserved cysteine residue Cys62 (PM1_strong).The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.) ,total :2 pts. (PMID : 35874699) (PP4_Moderate).In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_strong,PM2_supporting, PP4_moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497161/MONDO:0010315/129 2024-05-28 2024-05-28 X-linked inheritance HP:0001417 Supports UMLS:C0065374 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0232849 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0000833 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027651 infores:hetionet CHEBI:2611 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013384 infores:hetionet CHEBI:84883 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0013404 infores:hetionet CHEBI:5864 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C3248383 infores:hetionet NCBIGene:3156 biolink:causes MONDO:0957270 infores:monarchinitiative not_provided not_provided HGNC:5006 MONDO:0957270 uuid:80650959-5945-4d14-8391-45a945000536 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0015672 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0015397 infores:hetionet CHEBI:168396 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0242429 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020649 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0022660 infores:hetionet CAID:CA023446 biolink:causes MONDO:0007750 infores:clingen CAID:CA023446 MONDO:0007750 PMID: Likely Pathogenic PM5, PM3, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1291G>C (p.Ala431Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PM5, PP3 and PP4, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PM3 - variant meets PM2 and was identified in:- index case who is homozygous for the variant and has LDL at least 550mg/dl (figure 2A in the paper) from PMID 29502162 (Klaus et al. 2018), Germany.--- individual is homozygous for variant and has an homozygous phenotype, so PM3 is met.PM5 - one other missense variant in the same codon:- NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr)- 2 stars, Pathogenic/Likely pathogenic​ in ClinVar- Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.939. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 8 (untreated LDL at least 550mg/dl) from PMID 29502162 (Klaus et al., 2018), Germany, so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023446/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:31348 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0149745 infores:hetionet CHEBI:6715 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0003126 infores:hetionet CHEBI:23765 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0011991 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0549475 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0442886 infores:hetionet CHEBI:135935 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0040822 infores:hetionet CHEBI:9137 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0033774 infores:hetionet CHEBI:5855 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042798 infores:hetionet CHEBI:47898 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030193 infores:hetionet CHEBI:5123 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0085649 infores:hetionet CHEBI:9586 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0004134 infores:hetionet CHEBI:31348 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0311468 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549249 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0559031 infores:hetionet CHEBI:180905 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C3665386 infores:hetionet CHEBI:6923 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0004093 infores:hetionet CHEBI:38940 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0231528 infores:hetionet CHEBI:17549 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0406834 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151736 infores:hetionet CHEBI:4975 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0033774 infores:hetionet CHEBI:231594 biolink:causes MONDO:0004169 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0376356 infores:hetionet CAID:CA10603795 biolink:causes MONDO:0009290 infores:clingen CAID:CA10603795 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PVS1_Strong, PS1_Moderate PP3 The NM_000152.5:c.546G>C variant alters that last nucleotide of exon 2 of GAA, but does not result in an amino acid change (p.Thr182=). Study using minigene analysis showed that the variant disrupts normal splicing, resulting in skipping of exon 2, with a low proportion of normal transcripts produced (PMID: 31301153). In addition, deletion of exon 2 results in complete loss of enzyme activity when expressed in heterologous cells (PMID: 7881425, 7717400). As this variant appears to allow a low level of normal splicing to occur, PVS1 was applied at the strong level (PVS1_Strong). At least 4 late-onset Pompe Disease patient with this variant had documented GAA deficiency or activity in the affected range in any appropriate tissue (PMID: 17616415, clinical lab data) (PP4_Moderate). One patient is compound heterozygous for the variant and c.-32-13T>G that has been classified as pathogenic by the ClinGen LD VCEP, phase not confirmed (PMID: 17616415). This variant has also been detected in a Pompe disease patient who was heterozygous with c.2608C>T (p.Arg870*, Pathogenic by LD VCEP), and in 3 additional patients with homozygous (Revvity Omics and Duke lab data) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000008496 (10/1177056 alleles) in the European Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants at the same nucleotide position (c.546G>T, c.546G>A), and in the same splice region (c.546+1G>T, c.546+2T>C, c.546+5G>T, and c.546del2‐5) have been reported in individuals with Pompe disease (https://www.pompevariantdatabase.nl/). All of these variants have been shown to result in skipping of exon 2 using a minigene assay (PMID: 31301153, 39905333). c.546G>T and c.546G>A have been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PS1_Moderate).The computational splicing predictor SpliceAI gives a score of 0.84 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA. But PP3 was not applied as PVS1 was applied. There is a ClinVar entry for this variant (Variation ID: 281056; 2 star review status) with 4 submitters classifying the variant as pathogenic, and 4 submitters classifying it as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based in the specification of the ClinGen Lysosomal Diseases VCEP: PVS1_Strong, PS1_Moderate, PM3_Strong, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 1, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603795/MONDO:0009290/010 2025-04-01 2025-05-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:85161 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0004936 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151313 infores:hetionet CHEBI:2659 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0085631 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151828 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0178298 infores:hetionet NCBIGene:11267 biolink:causes MONDO:0968946 infores:monarchinitiative not_provided not_provided HGNC:17028 MONDO:0968946 uuid:57df6fe3-88a2-4bba-9f22-953568bdb751 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:6286 biolink:causes MONDO:0015636 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6286 MONDO:0015636 UMLS:C0209366 biolink:causes MONDO:0008608 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0013080 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0021053 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0020538 infores:hetionet CHEBI:63631 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234708 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0152128 infores:hetionet GO:0043921 biolink:causes GO:0019083 infores:ubergraph knowledge_assertion manual_agent GO:0043921 GO:0019083 CHEBI:10102 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0026826 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0022650 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0002871 infores:hetionet CHEBI:9720 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0011253 infores:hetionet CAID:CA2695224151 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224151 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.1064dup (p.Pro357ThrfsTer2) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BSS16.01 in PMID: 23995613) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224151/MONDO:0009276/079 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9570 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0026766 infores:hetionet CHEBI:75246 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0027497 infores:hetionet NCBIGene:84833 biolink:causes MONDO:0032869 infores:monarchinitiative not_provided not_provided HGNC:30889 MONDO:0032869 uuid:4238a4de-3011-414e-99b4-e4cd4d1cc15a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63638 biolink:causes UMLS:C0521554 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0521554 infores:hetionet CHEBI:28177 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0270611 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0521839 infores:hetionet CHEBI:50861 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0002871 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0041582 infores:hetionet CHEBI:63635 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0008311 infores:hetionet CHEBI:681569 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1619702 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042134 infores:hetionet CAID:CA267688 biolink:causes MONDO:0009861 infores:clingen CAID:CA267688 MONDO:0009861 PMID:18985011 Pathogenic PVS1, PP4_Moderate, PM2 The c.916delA (p.Ile306Leufs) in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120296); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one Korean proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L); BH4 deficiency was formally excluded via urinary pterin analysis and DHPR assays (PMID: 18985011) (PP4_Moderate). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (see ClinVar ID 608) c.143T>C (p.Leu48Ser) variant; while the manuscript stated that samples from proband’s family members were collected, it does not appear to specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.The sequence change results in a frameshift variant which occurs in exon 9 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267688/MONDO:0009861/006 2019-09-29 2019-10-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50922 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0022904 infores:hetionet CHEBI:10101 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0751494 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042109 infores:hetionet CHEBI:31705 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0037036 infores:hetionet CHEBI:3994 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0033774 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0019080 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020456 infores:hetionet CAID:CA270373 biolink:causes MONDO:0010726 infores:clingen CAID:CA270373 MONDO:0010726 PMID: Pathogenic PM1, PP3, PP4, PS4, PM2_Supporting, PM6_Strong PS3 The p.Pro127Leu variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID: 16225173, 22182064) (PM6_strong, PP4). This variant has been observed in at least 5 other individuals with Rett syndrome (PMID: 11245712, 16473305, 11960578, internal database - Invitae) (PS4). The p.Pro127Leu variant occurs in the well-characterized methyl binding domain (MBD) functional domain of MECP2 (PMID: 21326358, 23770565) (PM1). The p.Pro127Leu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro127Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4, PM1, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270373/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:2038 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0018944 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024117 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0034150 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0525045 infores:hetionet CHEBI:30830 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0231528 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020649 infores:hetionet CAID:CA402998326 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998326 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, PM5, PP3_Moderate The NM_000156.6:c.59G>T variant in GAMT is a missense variant that is predicted to result in the substitution of tryptophan by leucine at amino acid 20 (p.Trp20Leu). To our knowledge, this variant has not been reported in individuals with GAMT deficiency and functional studies have not been performed. The computational predictor REVEL gives a score of 0.804 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). Another missense variant, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303)) has been reported at the same amino acid position and has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP (PM5). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005886 (4/67960 alleles) in the African / African-American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 588631). In summary, this variant meets the criteria to be classified as uncertain significance for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM5, PP3_Moderate, PM2_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998326/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8871 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C2711227 infores:hetionet CHEBI:72564 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042029 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020456 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027051 infores:hetionet CHEBI:63580 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0242184 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042075 infores:hetionet CHEBI:85161 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020621 infores:hetionet CHEBI:142290 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0151766 infores:hetionet CAID:CA410206722 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206722 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.772G>A (p.Ala258Thr) is a missense variant which has a REVEL score < 0.50 (0.298), and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206722/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31536 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0549475 infores:hetionet CHEBI:2618 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0034063 infores:hetionet CHEBI:50922 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0015402 infores:hetionet CHEBI:94807 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0042963 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0271650 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0948594 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042109 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0010034 infores:hetionet CHEBI:9763 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0011603 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017601 infores:hetionet CAID:CA645580198 biolink:causes MONDO:0007648 infores:clingen CAID:CA645580198 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS4, BS1, BS3, PM6, PM3, PM1, PM4, BS2, PP4, PP1, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1993del p.(Ile665fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645580198/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:27834 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0039070 infores:hetionet CHEBI:6916 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0015230 infores:hetionet CHEBI:2788 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0013378 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0001416 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0341163 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0341163 infores:hetionet CHEBI:6887 biolink:causes HP:0011893 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0580531 infores:hetionet CHEBI:29007 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0031542 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0009450 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0042514 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018021 infores:hetionet CHEBI:17141 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0687713 infores:hetionet CHEBI:3698 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0033687 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027813 infores:hetionet CHEBI:2687 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0018965 infores:hetionet CAID:CA412489863 biolink:causes MONDO:0100039 infores:clingen CAID:CA412489863 MONDO:0100039 PMID: Uncertain Significance PM1, PM2_Supporting BS1, BS3, PP3, BP4, BA1, PS3, PS1 The p.Cys30Tyr variant occurs in the well-characterized ATP binding region of the CDKL5 (PM1). The p.Cys30Tyr variant in CDKL5 is absent from gnomAD (PM2_Supporting). In summary, the p.Cys30Tyr variant in CDKL5 is classified as variant of unknown significance based on the ACMG/AMP criteria (PM1, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412489863/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:39112 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0018681 infores:hetionet CHEBI:3223 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013362 infores:hetionet CHEBI:36791 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0000731 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0521591 infores:hetionet CHEBI:68558 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0595916 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0086543 infores:hetionet CHEBI:44032 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0037011 infores:hetionet CHEBI:5098 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0242429 infores:hetionet CHEBI:50648 biolink:causes HP:0003249 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151281 infores:hetionet CHEBI:3732 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0028084 infores:hetionet CHEBI:9605 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0155626 infores:hetionet CHEBI:39585 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0700590 infores:hetionet CHEBI:3215 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0042963 infores:hetionet CHEBI:50663 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0042963 infores:hetionet CHEBI:6933 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0018500 infores:hetionet CAID:CA017709 biolink:causes MONDO:0007947 infores:clingen CAID:CA017709 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate PM5, PM1 The NM_00138 c.8378A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2793 (p.Tyr2793Cys), located within the C-terminal region of the protein. This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as likely pathogenic, 2 times as uncertain significance (Variation ID: 42443). This variant has also been identified in at least 1 individual with a clinical diagnosis of MFS, as well as in individuals with clinical features of MFS (PMID 17663468, 34916231, 37558401, Invitae ClinVar, PS4_Moderate). A different missense variant at this position, c.8377T>C p.Tyr2793His, has previously been reported in individuals with MFS and/or MFS-related features (PMID 21542060, ClinVar), however the p.Tyr2793His variant has not yet been reviewed the FBN1 Variant Curation Expert Panel. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Moderate, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017709/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:42944 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0004604 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0006266 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019348 infores:hetionet NCBIGene:2978 biolink:causes MONDO:0011193 infores:monarchinitiative not_provided not_provided HGNC:4678 MONDO:0011193 uuid:a9ae1e2c-c1ab-49c6-ac8b-edc023f4efe2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0428977 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151736 infores:hetionet CHEBI:84883 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0232461 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006444 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0948240 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0948240 infores:hetionet CHEBI:28593 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0016382 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0010692 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0042109 infores:hetionet CAID:CA367401309 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401309 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PM6, PP2, PP3, PM2_Supporting PS2 The c.626C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to methionine at codon 209 (p.(Thr209Met)) of NM_000162.5. This variant was identified as a de novo occurrence with unconfirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1C 5.6-7.6% and antibody negative) (PM6; internal lab contributors). This variant was identified in 25 unrelated individuals with hyperglycemia (PS4; PMIDs: 38550917, 8168652, 25174781, internal lab contributors). This variant is absent from gnomAD v2.1.1 and has an incomputable GrpMax filtering allele frequency in v4.1 due to one copy in the ENF subpopulation and no copies in any other subpopulation (PM2_Supporting). This variant segregated with hyperglycemia, with at least 12 informative meioses in 9 families (PP1_Strong; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.626C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 02/17/2025): PS4, PM6, PM2_Supporting, PM5_Supporting, PP1_Strong, PP2, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401309/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports UMLS:C0657912 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025222 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0036572 infores:hetionet CHEBI:3485 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0302809 infores:hetionet CHEBI:168396 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0025222 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0043246 infores:hetionet CHEBI:71940 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0041969 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0012797 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0349231 infores:hetionet CHEBI:28971 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0017675 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0021141 infores:hetionet CHEBI:291342 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0232461 infores:hetionet CHEBI:7565 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0041657 infores:hetionet CHEBI:4356 biolink:causes HP:0007641 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0858618 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0039503 infores:hetionet CHEBI:17347 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0152030 infores:hetionet CHEBI:9316 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0002792 infores:hetionet CHEBI:7476 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0520966 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0014860 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0014860 infores:hetionet NCBIGene:6247 biolink:causes MONDO:0010725 infores:monarchinitiative not_provided not_provided HGNC:10457 MONDO:0010725 uuid:ac853ea9-9b46-4cab-af08-ab395b188029 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011570 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0032285 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0004238 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0340726 infores:hetionet CHEBI:78320 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0546817 infores:hetionet CHEBI:63925 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0033774 infores:hetionet CHEBI:63619 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018944 infores:hetionet CHEBI:9139 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0026961 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018799 infores:hetionet CHEBI:7565 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0600142 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C2939465 infores:hetionet CHEBI:16914 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0018681 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0007987 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0007987 uuid:38959f22-f8f5-4620-a33c-741695d9e6fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0011615 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0020615 infores:hetionet CHEBI:15765 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0009676 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0853960 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0853960 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0232693 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0232693 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0012833 infores:hetionet CHEBI:7601 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0009676 infores:hetionet CHEBI:6339 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037299 infores:hetionet CHEBI:92712 biolink:causes HP:0031777 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0152219 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0877237 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0877237 infores:hetionet CHEBI:6375 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013404 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0340726 infores:hetionet CHEBI:5130 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0038990 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0004936 infores:hetionet CHEBI:33325 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0042487 infores:hetionet CHEBI:184555 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0035317 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0037274 infores:hetionet CHEBI:135961 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0011603 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0949083 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0949083 infores:hetionet CHEBI:9586 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0016204 infores:hetionet NCBIGene:80201 biolink:causes MONDO:0030619 infores:monarchinitiative not_provided not_provided HGNC:23302 MONDO:0030619 uuid:292b3538-c131-4f98-830a-b215a9efc314 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45979 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0160390 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0009806 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038362 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0343863 infores:hetionet CHEBI:45409 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0004134 infores:hetionet CHEBI:8597 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C2225524 infores:hetionet CHEBI:9352 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C2830004 infores:hetionet CHEBI:3723 biolink:causes HP:0003987 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041601 infores:hetionet CAID:CA405650194 biolink:causes MONDO:0007783 infores:clingen CAID:CA405650194 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with histidine at codon 3696 of the RYR1 protein, p.(Asp3696His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.809 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405650194/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:135736 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085631 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0013395 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027339 infores:hetionet CHEBI:3485 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0086565 infores:hetionet NCBIGene:6495 biolink:causes MONDO:0012025 infores:monarchinitiative not_provided not_provided HGNC:10887 MONDO:0012025 uuid:7c26a9a6-b14a-4ac5-a5f9-ad6ca1bc247a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0232910 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017601 infores:hetionet CAID:CA913203553 biolink:causes MONDO:0015967 infores:clingen CAID:CA913203553 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3 The computational splicing predictor SpliceAI gives a score of greater than 0.20 for donor loss, predicting that the variant disrupts the donor site of intron 1 of HNF1A (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.326+2dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PP4_Moderate, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913203553/MONDO:0015967/017 2022-04-07 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7915 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0085593 infores:hetionet NCBIGene:10661 biolink:causes MONDO:0013355 infores:monarchinitiative not_provided not_provided HGNC:6345 MONDO:0013355 uuid:8d133d2c-78fc-4abb-b3b5-67e784a00896 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127342 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0541798 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0038358 infores:hetionet CAID:CA350171 biolink:causes MONDO:0700272 infores:clingen CAID:CA350171 MONDO:0700272 PMID: Likely Benign BP7, BS1, BP4 The c.1794G>A (p.Leu598=) variant in PALB2 is a synonymous (silent) variant that is not predicted by MaxEntScan or SpliceAI to impact splicing. The highest population filtering allele frequency in gnomAD v2.1.1 is 0.0005689 in the African population, which is higher than the HBOP VCEP threshold (>0.0001) for BS1, and therefore meets this criterion. In summary, this variant meets criteria to be classified as likely benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (BS1, BP4, BP7). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA350171/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0004096 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0013609 infores:hetionet CHEBI:4653 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0002170 infores:hetionet CHEBI:132233 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0009806 infores:hetionet CHEBI:4562 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0013456 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0035078 infores:hetionet CHEBI:47781 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0015967 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0518015 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0014130 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0037274 infores:hetionet CHEBI:175901 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C2939419 infores:hetionet CHEBI:47499 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0013144 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0483455 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0483455 infores:hetionet CHEBI:47780 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233471 infores:hetionet CHEBI:31348 biolink:causes MONDO:0700226 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0016470 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009938 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0392162 infores:hetionet NCBIGene:8036 biolink:causes MONDO:0054637 infores:monarchinitiative not_provided not_provided HGNC:15454 MONDO:0054637 uuid:10411608-e294-4ff7-bf15-004b945b1787 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78320 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0015967 infores:hetionet CHEBI:3504 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0000729 infores:hetionet CAID:CA000811 biolink:causes MONDO:0011450 infores:clingen CAID:CA000811 MONDO:0011450 PMID:32546644 Benign BS1, BS3, BP1_Strong The c.1233T>G variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 411 (p.Asp411Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0002413 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.07, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000811/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8428 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0232492 infores:hetionet CHEBI:6149 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0220870 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0795692 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0025061 infores:hetionet CHEBI:31174 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0022568 infores:hetionet CHEBI:5779 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0007859 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0012833 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0029408 infores:hetionet CAID:CA337096951 biolink:causes MONDO:0044970 infores:clingen CAID:CA337096951 MONDO:0044970 PMID: Benign BA1, BP7 The m.4769A>G (p.M100M) variant in MT-ND2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen at high frequencies in numerous haplogroups and the overall allele frequency in GenBank database (per Mitomap; queried 6/29/2020) is 97.6% (BA1). This is a synonymous variant (BP7). In summary, this variant meets criteria to be classified as benign given its synonymous nature and high frequency in the general population. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP7. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337096951/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBITaxon:36831 biolink:causes MONDO:0015803 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36831 MONDO:0015803 CHEBI:9599 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0019209 infores:hetionet CHEBI:8024 biolink:causes MONDO:0000947 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0033953 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013395 infores:hetionet CHEBI:53691 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0009676 infores:hetionet CHEBI:465284 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0008350 infores:hetionet CAID:CA355961530 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961530 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PM2_Supporting PP4 The NM_000203.5:c.457A>T (p.Lys153Ter) in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Furthermore, SpliceAI predicts that the variant may impact splicing (score for loss of intron 3 acceptor = 0.55; score for loss of intron 4 donor = 0.42). Three individuals reported in the MPS I registry are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, two with a reported severe phenotype with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908), and one with an attenuated phenotype with c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910). The phase is unknown is all three cases (PM3, based on 3 x 0.5 points). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003332 (2/60024 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PVS1, PM3, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961530/MONDO:0001586/091 2025-04-21 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CAID:CA219824 biolink:causes MONDO:0000572 infores:clingen CAID:CA219824 MONDO:0000572 PMID: Likely Pathogenic PP4, PM3, PS3_Moderate, PM2_Supporting, PM1_Supporting NM_000448.3(RAG1):c.2095C>T is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 699 (p.Arg699Trp).The filtering allele frequency (the upper threshold of the 95% CI of 5/1179830) of the c.2095C>T variant in RAG1 is 0.000001320 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This missense variant is located in the core domain (amino acids 387-1011) (PM1_supporting).Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) Total :1.5 pts. (PMID: 29107076) (PP4). The VDJ recombination activity was found to be 19.3 +/- 1.8 % of WT (mean +/- SE) in a flow cytometry based assay. PMID : 24290284 (PS3_Moderate).The patient (PMID: 21771083) was found heterozygous for R699W & Y1001X (not yet curated by SCID VCEP); p.R699W & p.393fsX402 (not yet curated by SCID VCEP)(PMID: 21184155); homozygous in 3 individuals (PMIDs: 24122031,31503426, 32447396) (Pt.: 1)(PM3).In summary, this variant meets the criteria to be classified as Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_Supporting, PP4,PS3_Moderate,PM3(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA219824/MONDO:0000572/123 2024-05-09 2024-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50275 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1384353 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006145 infores:hetionet CHEBI:27504 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0027497 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0040479 infores:hetionet CHEBI:3387 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0037763 infores:hetionet CHEBI:8232 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0038325 infores:hetionet CHEBI:3398 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0235710 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0236071 infores:hetionet CHEBI:8080 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0040822 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0878544 infores:hetionet CHEBI:46557 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0039621 infores:hetionet CHEBI:3752 biolink:causes MONDO:0016240 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0018987 infores:hetionet CHEBI:7447 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0023066 infores:hetionet CHEBI:2955 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0036974 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006031 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0149516 infores:hetionet CHEBI:37924 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0015967 infores:hetionet CHEBI:9086 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0575081 infores:hetionet CHEBI:15544 biolink:causes UMLS:C1504465 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C1504465 infores:hetionet CHEBI:3504 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0002874 infores:hetionet CHEBI:145499 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2363731 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0035854 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0001416 infores:hetionet CHEBI:17303 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013182 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042267 infores:hetionet CHEBI:9649 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0011991 infores:hetionet CAID:CA367400579 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400579 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting The c.776C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 259 (p.(Ala259Val)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in 15 unrelated individuals with hyperglycemia (PS4; PMID:22035297, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 16 informative meioses in 5 families (PP1_Strong; PMID: 22035297, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Another missense variant, c.775G>A, p.Ala259Thr has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala259Val has a greater Grantham distance (PM5). Lastly, this variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). In summary, c. 776C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PM2_Supporting, PS4, PP1_Strong, PP2, PM5, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400579/MONDO:0015967/086 2023-08-12 2023-08-12 Semidominant inheritance HP:0032113 Supports CHEBI:6741 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0020517 infores:hetionet CHEBI:51137 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0086132 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0008471 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0008471 uuid:0a11a37a-b2e8-4cff-9deb-2e6ecd0738d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10583388 biolink:causes MONDO:0700272 infores:clingen CAID:CA10583388 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7 The c.7G>T (p.Glu3Ter) variant in PALB2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_supporting, PM2_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583388/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8764 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0235567 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151828 infores:hetionet CHEBI:9168 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0231528 infores:hetionet CHEBI:5106 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0035455 infores:hetionet NCBIGene:6833 biolink:causes MONDO:0030088 infores:monarchinitiative not_provided not_provided HGNC:59 MONDO:0030088 uuid:01cb6f6d-7e71-45dd-8080-7fa3e556b346 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA025410 biolink:causes MONDO:0012933 infores:clingen CAID:CA025410 MONDO:0012933 PMID: Pathogenic PVS1, PP4_Strong BS1, PM2, BA1 The c.8023A>G variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 2675 (p.Ile2675Val). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and mini-gene assays demonstrated that the variant impacts splicing by creation of a donor site, resulting in skipping of 309nt of exon 18 (PMIDs: 18424508, 22505045, 28339459). All studies report no wild-type transcript from the variant allele. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1612 (based on Cosegregation LR=605.1; Pathology LR=0.88; Co-occurrence LR=1.05; Family History LR=2.88), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025410/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:61049 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0024115 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0004936 infores:hetionet CHEBI:43968 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C1443060 infores:hetionet CAID:CA6832103 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832103 MONDO:0015967 PMID: Benign BA1, BP5, PP3 The c.1541A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to arginine at codon 514 (p.(His514Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). However, this variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001150, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1541A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): BA1, BP5, PP3. While this variant is benign for HNF1A-monogenic diabetes, there is evidence to suggest that this variant may act as a risk allele for type 2 diabetes (PMID: 11692182, 27899486, 36216889, 33046911). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832103/MONDO:0015967/017 2025-02-20 2025-02-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3515 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042963 infores:hetionet CHEBI:68610 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0948594 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0521839 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0029928 infores:hetionet UMLS:C0657912 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162285 infores:hetionet CHEBI:49960 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0855333 infores:hetionet CHEBI:100241 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0236075 infores:hetionet NCBIGene:57216 biolink:causes MONDO:0020705 infores:monarchinitiative not_provided not_provided HGNC:15511 MONDO:0020705 uuid:2addb1b0-70ba-4694-965b-c2eeeda13633 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94449 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0043352 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0233494 infores:hetionet CAID:CA5045803 biolink:causes MONDO:0009595 infores:clingen CAID:CA5045803 MONDO:0009595 PMID: Likely Benign BS1 The NC_000009.12:g.35657751del variant is a single adenine deletion in an A-rich repetitive region located at the 3' end of the transcribed region of the RMPR gene. This variant is also known as NR_003051.3(RMRP):n.268del or g.35657746del. The Grpmax Filtering allele frequency of this variant is 0.002376 in gnomAD v4.1.0, which is higher than the SCID-VCEP's threshold for BS1_Strong (>0.00089) (BS1_Strong). This variant is known as g.35657745-CA-C in gnomAD. In summary, this variant is classified as likely benign for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1_Strong (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5045803/MONDO:0009595/088 2025-09-25 2025-09-26 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6909 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0002874 infores:hetionet CAID:CA026042 biolink:causes MONDO:0012933 infores:clingen CAID:CA026042 MONDO:0012933 PMID: Benign BP5, BP7_Strong, BP4 BS1, PM2, BA1 The c.9234C>T variant in BRCA2 is a synonymous variant (p.Val3078=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates small or no impact on splicing (PMIDs: 31143303, 20215541 and pers comm E Velasco, Ambry internal contributor), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.055 (based on Family History LR=0.055), within the thresholds for Moderate benign evidence (LR ≥0.05 & <0.23) (BP5_Moderate met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, BP7_Strong (RNA), BP5_Moderate). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA026042/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039520 infores:hetionet CHEBI:70718 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0151602 infores:hetionet CAID:CA274024 biolink:causes MONDO:0009290 infores:clingen CAID:CA274024 MONDO:0009290 PMID:20817528PMID:20033296PMID:22676651PMID:24923245PMID:25455803PMID:20817528PMID:22676651 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1051delG (p.Val351Cysfs), is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The variant is absent in gnomAD v 2.1.1, meeting PM2. This variant has been reported in three individuals with Pompe disease and residual GAA activating meeting PP4 specifications (PMIDs 20033296, 20817528, 22676651). Two of these individuals are compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMIDs 20817528, 22676651). The other individual is compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) (PMID 20033296). However, this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 24923245, 25455803). PM3_Supporting is met. There is a ClinVar entry for this variant (Variation ID 188841; 2 star review status) with one submitter classifying the variant as likely pathogenic and one a likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274024/MONDO:0009290/010 2020-05-03 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:1854 biolink:causes MONDO:0859288 infores:monarchinitiative not_provided not_provided HGNC:3078 MONDO:0859288 uuid:431aeb66-d2fa-49fc-8441-c1afbbfec5c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6709 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C2830004 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0027051 infores:hetionet CHEBI:9635 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0344232 infores:hetionet CAID:CA389475686 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475686 MONDO:0100040 PMID: Likely Pathogenic PS2, PM1, PP3, PM2_Supporting The c.706A>G (p.Asn236Asp) variant in FOXG1 has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with FOXG1 disorder (GeneDx: internal data) (PS2). The p.Asn236Asp variant occurs in the well-characterized forkhead functional domain (aa 181-275) of FOXG1 (PM1). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to FOXG1 function (PP3). The p.Asn236Asp variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Asn236Asp variant in FOXG1 is classified as Likely Pathogenic for FOXG1 syndrome based on the ACMG/AMP criteria (PS2, PM1, PP3, PM2_supporting) (FOXG1 specifications version 3.0; curation approved on 2/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475686/MONDO:0100040/035 2025-02-28 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports GO:1900211 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:1900211 GO:0072001 CHEBI:47426 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0015672 infores:hetionet CAID:CA401370504 biolink:causes MONDO:0009290 infores:clingen CAID:CA401370504 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM5, PM3_Supporting PP4 The NM_000152.5:c.12105G>C variant in GAA is a missense variant predicted tocause substitution of arginine by proline at amino acid 702 (p.Arg702Pro). It has been reported in one individual in national mutation database for the country of Oman (PMID: 26594346). However, no clinical details were provided and thus points can not be applied for PP4. This individual was compound heterozygous for the variant and variant classified as pathogenic by the ClinGen LD VCEP (c.2560C>T, p.Arg854Ter; ClinVar Variation ID: Variation ID: 4034, SCV001371731.1), phase unknown (PMID: 26594346) (PM3_supporting). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.2105G>T, p.Arg702Leu] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (ClinVar Variation ID: Variation ID: 92472) (PM5). There is a ClinVar entry for this variant (Variation ID: 593593). Due to insufficient evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): (PM5, PM3_supporting, PM2_supporting, PP3).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401370504/MONDO:0009290/010 2024-03-05 2024-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true GO:0072301 biolink:causes GO:0072223 infores:ubergraph knowledge_assertion manual_agent GO:0072301 GO:0072223 CHEBI:145499 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0014549 infores:hetionet CHEBI:72296 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0018944 infores:hetionet CHEBI:28901 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0237849 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0948594 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0856099 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0856099 infores:hetionet CHEBI:135930 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0011606 infores:hetionet CHEBI:63630 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085649 infores:hetionet CHEBI:3223 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0232462 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0236072 infores:hetionet CHEBI:3219 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030318 infores:hetionet CHEBI:3561 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020453 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0269268 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0269268 infores:hetionet CHEBI:3506 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0001824 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0030920 infores:hetionet CHEBI:75998 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0000737 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034150 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0020538 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0003123 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006826 infores:hetionet CHEBI:92607 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0428977 infores:hetionet CL:0000988 biolink:causes MONDO:0044881 infores:ubergraph knowledge_assertion manual_agent CL:0000988 MONDO:0044881 CHEBI:39867 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042267 infores:hetionet CHEBI:6129 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0549249 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0595939 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0024117 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027765 infores:hetionet CHEBI:2666 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C1306341 infores:hetionet CHEBI:16335 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0151744 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0860987 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860987 infores:hetionet CHEBI:8461 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0011206 infores:hetionet CHEBI:47780 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013384 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0152227 infores:hetionet CAID:CA400023428 biolink:causes MONDO:0100326 infores:clingen CAID:CA400023428 MONDO:0100326 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.646T>C (p.Tyr216His) missense variant was identified in a patient with GT type II (UPN 12, PMID 17083650). This variant is absent from the gnomAD database v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.964; predicting a deleterious impact. This score is greater than the threshold set by the PD VCEP of >/= 0.70 (PP3). This variant was detected in a homozygous state in a patient with GT type II (UPN 12; PMID 17083650; PM3_supporting). This variant was identified in a patient with GT type II (UPN 12, PMID 17083650) who had mucocutaneous bleeding. The patient showed no platelet aggregation in response to ADP, epinephrine, and collagen but had a weak response to ristocetin. Flow cytometry showed 32.7% of aIIbB3 present but there was no fibrinogen binding present (PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PM2_supporting, PP3, PM3_Supporting, PM5 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400023428/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5106 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0006277 infores:hetionet GO:0045697 biolink:causes GO:0009553 infores:ubergraph knowledge_assertion manual_agent GO:0045697 GO:0009553 CHEBI:45924 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0542184 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0035204 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151601 infores:hetionet CHEBI:4657 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0541782 infores:hetionet GO:1904444 biolink:causes GO:0008584 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0008584 PUBCHEM.COMPOUND:122173801 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0004093 infores:hetionet NCBIGene:10457 biolink:causes MONDO:0054765 infores:monarchinitiative not_provided not_provided HGNC:4462 MONDO:0054765 uuid:60ab58ce-f805-435a-b49e-6bb8a5071594 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42355 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0027497 infores:hetionet CHEBI:681569 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0019080 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0973461 infores:hetionet CHEBI:63598 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085631 infores:hetionet CHEBI:66903 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0232462 infores:hetionet CHEBI:85161 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0017979 infores:hetionet CHEBI:75722 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0005758 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018802 infores:hetionet CHEBI:6067 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030193 infores:hetionet CHEBI:724125 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0042907 infores:hetionet NCBIGene:51633 biolink:causes MONDO:0044319 infores:monarchinitiative not_provided not_provided HGNC:24281 MONDO:0044319 uuid:7d9e35bf-6340-4a3e-8b67-1af88c724658 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009450 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0233494 infores:hetionet GO:2000006 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000006 GO:0007275 CHEBI:75722 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853348 infores:hetionet CAID:CA386966008 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966008 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 The c.767C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 256 (p.(Ser256Phe)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Also, this variant is absent from gnomAD v2.1.1 and 4.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.897, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.767C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966008/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17303 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232292 infores:hetionet CHEBI:4653 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0040264 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006840 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0017152 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0003123 infores:hetionet CHEBI:6062 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042790 infores:hetionet CHEBI:2666 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0231218 infores:hetionet CHEBI:68554 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0015672 infores:hetionet CHEBI:9570 biolink:causes MONDO:0023073 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0742965 infores:hetionet CHEBI:7954 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0085633 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0004936 infores:hetionet CAID:CA288472 biolink:causes MONDO:0700272 infores:clingen CAID:CA288472 MONDO:0700272 PMID: Benign BA1 BS1, BS3, PM2, PP3, BS2, BP4 The c.3249G>C (p.Glu1083Asp) variant in PALB2 is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 1083 (p.Glu1083Asp). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.001331 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays; however, due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP (PMID: 31636395). PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA288472/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8707 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0860803 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0001824 infores:hetionet CHEBI:2569 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0042963 infores:hetionet CHEBI:119573 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011606 infores:hetionet CHEBI:91541 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0015672 infores:hetionet NCBITaxon:10798 biolink:causes MONDO:0017453 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10798 MONDO:0017453 CHEBI:135736 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0033777 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0031350 infores:hetionet CHEBI:71255 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0030196 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0038663 infores:hetionet CHEBI:50922 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C3665386 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0020517 infores:hetionet NCBIGene:54914 biolink:causes MONDO:0859273 infores:monarchinitiative not_provided not_provided HGNC:23377 MONDO:0859273 uuid:1d5e5e0d-e0bc-4150-bc9f-8db6a1f09507 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017178 infores:hetionet CHEBI:45979 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0014742 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020615 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038363 infores:hetionet CHEBI:63635 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0035305 infores:hetionet CHEBI:72564 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0040822 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0161479 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0541799 infores:hetionet CHEBI:8776 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0220870 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151849 infores:hetionet CAID:CA10385671 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385671 MONDO:0100437 PMID: Likely Benign BP4, BS1 BP7 NM_001034853.2(RPGR):c.311-4G>A is a variant within intron 4 of RPGR. This variant is present in gnomAD v4.1.0 at a frequency of 0.000005030 among hemizygous individuals, with 2 variant alleles / 397,605 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.05 for acceptor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1, and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385671/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:119573 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0039591 infores:hetionet CHEBI:63638 biolink:causes HP:0001133 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0235095 infores:hetionet GO:1903538 biolink:causes GO:0001556 infores:ubergraph knowledge_assertion manual_agent GO:1903538 GO:0001556 CHEBI:135920 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0015230 infores:hetionet CAID:CA214333 biolink:causes MONDO:0015967 infores:clingen CAID:CA214333 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PM5_Supporting, PP4_Moderate, PP3 The c.827C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glycine at codon 276 (p.(Ala276Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant has a minor allele frequency of 0.000007816 in the gnomAD v2.1.1 European non-Finnish population and one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributor). Another missense variant, c.827C>A (p.Ala276Asp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala276Gly (PM5_Supporting). In summary, c.827C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214333/MONDO:0015967/017 2022-05-03 2022-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8214 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C3665347 infores:hetionet UMLS:C0657912 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011071 infores:hetionet CHEBI:7447 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0151904 infores:hetionet CAID:CA340744630 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744630 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3, PP4, PM2_Supporting The NM_000329.3(RPE65):c.982C>T (p.Leu328Phe) variant is a missense variant causing a substitution of leucine with phenylalanine at position 328. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000003650, with 2/91076 in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.737, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.644 and predicts a damaging effect on RPE65 function (PP3). This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the p.Tyr275Ter variant confirmed in trans (Pathogenic by VCEP, 1 point, PMID: 31630094); the NM_000329.3(RPE65):c.639dup (p.Ala214SerfsTer20) variant suspected in trans (Pathogenic by VCEP, 0.5 pt, PMID: 28393863); the p.Glu254Asp variant suspected in trans (LP by VCEP, 0.25 pt, PMID: 35129589 with additional information presented in ARVO meeting abstract https://iovs.arvojournals.org/article.aspx?articleid=2767855); or the p.Leu447Pro variant confirmed in trans (VUS by VCEP, 0.25 pt, PMID: 38002999), all of which were previously classified as described above by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), White/yellow dot deposits (2 pt), previous exome testing that did not provide an alternative explanation for visual impairment (2 pt), and symptomatic onset between birth and 5 years (1 pt), which together are specific for RPE65-related recessive retinopathy (6 points, PMIDs: 31630094, 34830511, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3, PP4, PM3_Strong (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744630/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8768 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0041657 infores:hetionet CHEBI:31932 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042963 infores:hetionet CHEBI:31199 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0030193 infores:hetionet NCBIGene:1811 biolink:causes MONDO:0008964 infores:monarchinitiative not_provided not_provided HGNC:3018 MONDO:0008964 uuid:ce4f1be5-c574-4be8-a26b-88607219e165 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0017178 infores:hetionet CHEBI:94848 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0030554 infores:hetionet CHEBI:9434 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C1145628 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0009806 infores:hetionet CHEBI:6832 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0520966 infores:hetionet CHEBI:10124 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0340865 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0694536 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0150450 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0027769 infores:hetionet CHEBI:7865 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0041657 infores:hetionet CAID:CA320704233 biolink:causes MONDO:0011071 infores:clingen CAID:CA320704233 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.59-53465A>T is a deep intronic variant which may impact splicing; this variant has a SpliceAI score ≥ 0.38 (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320704233/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63681 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0002874 infores:hetionet CHEBI:63580 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002962 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0007194 infores:hetionet CHEBI:31709 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0042420 infores:hetionet CAID:CA410206974 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206974 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.664T>C (p.Ser222Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206974/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3698 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0016382 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0030312 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C3665347 infores:hetionet NCBIGene:50937 biolink:causes MONDO:0013642 infores:monarchinitiative not_provided not_provided HGNC:17104 MONDO:0013642 uuid:69d1a98b-ab64-498f-84b0-fc8764c48b3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0003467 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0151773 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0033575 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0014742 infores:hetionet CHEBI:8802 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1260880 infores:hetionet CHEBI:94392 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0948594 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0233494 infores:hetionet CAID:CA16622098 biolink:causes MONDO:0011071 infores:clingen CAID:CA16622098 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS2, PS3, PS1, PS4, BP3, BP2, BP1, BP4, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP1, PP2, PP3, BS2 NM_001754.5(RUNX1):c.252C>G (p.Asp84Glu) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The germline variant has not been published or reported in any individuals meeting RUNX1-defined phenotype criteria (PMID: 27153395). The computational predictor, REVEL, gives a score of 0.621, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. Note that the results from the in silico splicing predictor, SpliceAI, support that this variant does not affect splicing. In summary, this variant meets the criteria to be classified as VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16622098/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40050 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0018681 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0028738 infores:hetionet CHEBI:28830 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0013384 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0581879 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0581879 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0231170 infores:hetionet CHEBI:75722 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0023218 infores:hetionet CHEBI:4356 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0037763 infores:hetionet CHEBI:2469 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0085682 infores:hetionet CHEBI:4027 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0002878 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C2225524 infores:hetionet CHEBI:63617 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0002962 infores:hetionet CHEBI:28364 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0015230 infores:hetionet CAID:CA497711354 biolink:causes MONDO:0018875 infores:clingen CAID:CA497711354 MONDO:0018875 PMID: Likely Pathogenic PS4_Moderate, PVS1_Moderate, PP1, PM2_Supporting BA1, PS3, PM1, BS1, BS3, PP4 The NM_000546.6 c.1146del (p.Lys382AsnfsTer?) is a TP53 frameshift variant inducing a stop codon read-through. The variant is predicted to escape nonsense mediated decay, targeting a region of unknown function representing <10% of the protein and introducing a C-terminal extension of 28 residues in the protein (PVS1_Moderate). This variant has been reported in 3 unrelated families meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal lab contributors). This variant has an allele frequency of 6.196e-7 (1/1614052 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1_Moderate, PS4_Moderate, PP1, PM2_Supporting. (Bayesian Points: 6; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA497711354/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31981 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0017601 infores:hetionet CHEBI:75045 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0022603 infores:hetionet CHEBI:37941 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0036830 infores:hetionet CHEBI:3125 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0002792 infores:hetionet CHEBI:4315 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0019572 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0041969 infores:hetionet CHEBI:8707 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0232849 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0011570 infores:hetionet CHEBI:40279 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042510 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0740425 infores:hetionet CHEBI:3125 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0042963 infores:hetionet CAID:CA2837582288 biolink:causes MONDO:0100453 infores:clingen CAID:CA2837582288 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.2633_2636del (p.Gln878ArgfsTer17) is a frameshift variant that introduces a premature stop codon into exon 14 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), onset in the first 3 months of life (1 pt). unremarkable fundus with thin vessels (0.5 pts), nystagmus (1 pt), eye poking, visual acuity limited to light perception (1 pt), and high hypermetropia, which together are specific for GUCY2D-related recessive retinopathy (total 4 points, PMID: 31704230, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2837582288/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CAID:CA397318655 biolink:causes MONDO:0009276 infores:clingen CAID:CA397318655 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting PP3, PP4 The c.790T>C variant in GP1BA is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 264 (p.Cys264Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in at least 1 proband with Bernard-Soulier syndrome (PMID 31302646) This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting and PM3_Supporting (VCEP specifications version 1.0.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397318655/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0011701 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0000729 infores:hetionet NCBIGene:11193 biolink:causes MONDO:0971043 infores:monarchinitiative not_provided not_provided HGNC:12739 MONDO:0971043 uuid:8bd3a35f-6337-4dad-bf13-bfbe6acaa457 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:9885 biolink:causes MONDO:0014594 infores:monarchinitiative not_provided not_provided HGNC:15761 MONDO:0014594 uuid:f31d8feb-6c2e-4c00-940e-9494ba45e8e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0015230 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042769 infores:hetionet CHEBI:9168 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C2830004 infores:hetionet CHEBI:4495 biolink:causes MONDO:0021718 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0032541 infores:hetionet CHEBI:74947 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0025345 infores:hetionet CHEBI:6367 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0338908 infores:hetionet CHEBI:29688 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0547030 infores:hetionet CHEBI:51137 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0004093 infores:hetionet CHEBI:47898 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0016204 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020651 infores:hetionet CHEBI:47898 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0086565 infores:hetionet CHEBI:47426 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0030193 infores:hetionet NCBIGene:7045 biolink:causes MONDO:0007380 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0007380 uuid:7f168136-526a-4f58-8360-d123e010b7fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386959359 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959359 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.382A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to valine at codon 128 (p.(Ile128Val)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.7519, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v4.1.0 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis in their family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.382A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959359/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:116278 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0015230 infores:hetionet CHEBI:8871 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0025222 infores:hetionet CHEBI:46295 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0030193 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0267792 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235353 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235353 infores:hetionet CHEBI:7983 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0009676 infores:hetionet CHEBI:142290 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0014724 infores:hetionet CHEBI:75998 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020598 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0019158 infores:hetionet CHEBI:3441 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0025222 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0009450 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0541941 infores:hetionet CAID:CA273414 biolink:causes MONDO:0021060 infores:clingen CAID:CA273414 MONDO:0021060 PMID:18413255PMID:19206169PMID:16474404 Pathogenic PS3, PS2, PS4_Moderate, PM2, PP3, PP2 PM5 The c.1455G>C (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 4 patients with clinical features of a RASopathy, 1 of which was reported as a de novo case with parentage confirmation (PS4_Moderate; PS2; 19206169, 16474404, SCV000197149.4). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID: 18413255). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Additionally, computational prediction tools and conservation analysis suggest that this variant may affect the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PS2, PS3, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA273414/MONDO:0021060/004 2020-02-27 2020-04-09 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CAID:CA2499225883 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225883 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP2, BP3, BA1, PM6, BS3, BS4, BS1, BP5, BP7, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.247dup (p.Ala83GlyfsTer?) is an insertion frameshift variant which results in a termination sequence 55 residues later. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98. This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225883/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119915 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032326 infores:hetionet CHEBI:7494 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0033247 infores:hetionet CHEBI:5959 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0699744 infores:hetionet CHEBI:3441 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020461 infores:hetionet CAID:CA346365661 biolink:causes MONDO:0021060 infores:clingen CAID:CA346365661 MONDO:0021060 PMID:31219622 Uncertain Significance PP2 PS4, BS1, PM1, PM5, PM6, BP4 The c.1666G>A (p.Val556Ile) variant in SOS1 was present in 0.005437% (1/18392) of East Asian alleles in gnomAD v2.1.1 and was absent from v3. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 31219622; GeneDx internal data, SCV000808076.1; Invitae internal data; BC Children’s Hospital internal data). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346365661/MONDO:0021060/004 2020-03-09 2020-03-09 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7936 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017181 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042109 infores:hetionet CHEBI:39669 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0015967 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0392386 infores:hetionet CHEBI:75246 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0030193 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002871 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0855242 infores:hetionet CAID:CA915940291 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940291 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The ITGB3 frameshift variant NM_000212.3:c.1129dupA/p.Ile377AsnfsTer4 has been observed in a compound heterozygote individual presenting with phenotypes specific to GT (TE; PMID: 21113249) with the trans ITGB3 variant (c.856G>A/p.Gly286Arg). This frameshift variant occurs in exon 9 results in 3 altered amino acids followed by an early termination codon. Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PP4_Strong. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940291/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:64045 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0013395 infores:hetionet CAID:CA294734 biolink:causes MONDO:0007113 infores:clingen CAID:CA294734 MONDO:0007113 PMID: Uncertain Significance BP4 BS1, PP4, PM2, PS4 The c.139A>G p.(Ile47Val) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.00088% in the European non-Finnish sub population (no criteria met). The p.(Ile47Val) variant has been observed in at least 3 individuals with neurodevelopmental phenotypes consistent with UBE3A-related disease (ClinVar SCV000191055.4, SCV001445014.1); however, PS4 cannot be applied due to the gnomAD frequency. Computational analysis prediction tools suggest that the p.(Ile47Val) variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.139A>G p.(Ile47Val) variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294734/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:77260 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027707 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027769 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0220870 infores:hetionet NCBIGene:79717 biolink:causes MONDO:0032592 infores:monarchinitiative not_provided not_provided HGNC:25686 MONDO:0032592 uuid:ab5fd05d-41d8-4af7-9df7-7ded3392ccd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0027497 infores:hetionet NCBIGene:7317 biolink:causes MONDO:0010532 infores:monarchinitiative not_provided not_provided HGNC:12469 MONDO:0010532 uuid:900a81a4-8758-49b5-91ce-d5886e7216e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151723 infores:hetionet CAID:CA396458162 biolink:causes MONDO:0007648 infores:clingen CAID:CA396458162 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PS3_Supporting, PP1, PM2_Supporting, PVS1_Strong, PS4_Moderate BP5, BS1, BS3, BS4, PM6, BS2, BP2, BA1, PS2 The c.687+1G>A is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in three families meeting IGCLC criteria for HDGC (PS4_Moderate; PMID: 15235021 and 30306390, SCV000815329.1). The variant was also found to co-segregate with HDGC in a family with HDGC and cleft lip/palete (PP1_Supporting; PMID: 30306390). RNA analysis demonstrated an in-frame deletion of 14 amino acids from exon 5, r.646_687del p.(V216_T229del) (PS3_Supporting; PMID: 30306390 and internal laboratory data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS3_Supporting, PM2_Supporting, PS4_Moderate, PM5_Supporting and PP1_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396458162/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA2061080 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061080 MONDO:0015924 PMID: Likely Benign PM1, BS1 PM2, PP3, BS2, BP4, BA1, PM5, PS1 The BMPR2 c.276A>C variant is a missense variant predicted to cause substitution of glutamine to histidine at amino acid position 92 (p.(Gln92His)). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001589 in the East Asian population (Korean) (BS1 met but not PM2 or BA1). Computational predictor REVEL score is 0.57, which is in between the PH-VCEP specified threshold of ≤0.25 and ≥0.75, so neither PP3 nor BP4 are met. This variant is located in the extracellular domain, critical for ligand binding (PM1 met), but does not affect a known critical or non-critical amino acid (no up- or downward adjustment for PM1). BS2 was not met due to absence of homozygous individuals (gnomAD v.2.1.1 controls). PS4 was not applied as PM2 was not met. PP1, PS2, PM6 were not met due to the absence of co-segregation data. PS3 and BS3 were not met due to the lack of experimental evidence. Although other variants in the same amino acid been reported, for pulmonary arterial hypertension, the variants were not deemed pathogenic or likely pathogenic by the PH-VCEP (PS1, PM5 not met). In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PM1 (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061080/MONDO:0015924/125 2024-11-01 2024-11-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63611 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038990 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0585186 infores:hetionet CAID:CA119186 biolink:causes MONDO:0020367 infores:clingen CAID:CA119186 MONDO:0020367 PMID:35196929 Likely Pathogenic PP1_Moderate, PP3, PS3_Moderate, PM2_Supporting BP7, BS1, BS3, PM6, PM5, PM4, PS4, PS1, PS2, BP4, BA1 The c.1138G>C variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Histidine at amino acid 380 (p.Asp380His). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.965, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 35196929) demonstrated that the Asp380His protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 9 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 17499207), which fulfilled PP1_Moderate (≥ 5 meioses in ≥ 1 family, but not the ≥ 7 meioses in > 1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 17499207), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119186/MONDO:0020367/019 2022-03-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:63746 biolink:causes MONDO:0005354 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:63746 MESH:D019698 DB12225_MESH_D019698_1 CHEBI:91834 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0497156 infores:hetionet CHEBI:48669 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0008031 infores:hetionet CHEBI:135361 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0152032 infores:hetionet CHEBI:92712 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0039240 infores:hetionet CHEBI:64045 biolink:causes UMLS:C1735368 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C1735368 infores:hetionet CHEBI:63631 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014236 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0041912 infores:hetionet CHEBI:7492 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0042769 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0041969 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042571 infores:hetionet CHEBI:51041 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085606 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0232492 infores:hetionet CAID:CA8337481 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337481 MONDO:0008723 PMID: Benign BP4, BA1 The c.-64T>C variant in ACADVL is a 5' UTR variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.008890 in the European non-Finnish population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from in silico splicing predictors (Alamut) support that this variant does not affect splicing, nor create a start codon (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337481/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:64028 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0013491 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0149931 infores:hetionet CHEBI:31236 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0149725 infores:hetionet CHEBI:75984 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0086565 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0041969 infores:hetionet CHEBI:47657 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0376358 infores:hetionet CHEBI:100241 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013144 infores:hetionet CHEBI:5001 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151754 infores:hetionet CHEBI:53760 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0040409 infores:hetionet CAID:CA025568 biolink:causes MONDO:0012933 infores:clingen CAID:CA025568 MONDO:0012933 PMID:33293522 Benign BP1_Strong, BP5, BS3, BS1_Supporting The c.831T>G variant in BRCA2 is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 277 (p.Asn277Lys). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00008331 in the European (non-Finnish) population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.06 (based on Cosegregation LR=0.3; Pathology LR=1.27; Co-occurrence LR=1.88; Family History LR=0.0888), within the thresholds for Moderate benign evidence (LR ≥0.05 & <0.23) (BP5_Moderate met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP1_Strong, BS3, BP5_Moderate). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025568/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020517 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1306341 infores:hetionet CHEBI:47426 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0002878 infores:hetionet CHEBI:5138 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085631 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0009763 infores:hetionet CHEBI:4657 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0033774 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0853761 infores:hetionet CHEBI:4466 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0018794 infores:hetionet GO:0061017 biolink:causes CL:1000488 infores:ubergraph knowledge_assertion manual_agent GO:0061017 CL:1000488 CHEBI:4858 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0041657 infores:hetionet CHEBI:10125 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0030554 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039971 infores:hetionet NCBIGene:347733 biolink:causes MONDO:0012399 infores:monarchinitiative not_provided not_provided HGNC:30829 MONDO:0012399 uuid:2e542dd5-4ae8-4a78-aea0-6614073c472e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:Z5N076G8YQ biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0392386 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020456 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0013928 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026946 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235763 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0009806 infores:hetionet CHEBI:47657 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0017178 infores:hetionet CHEBI:7931 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020615 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0006145 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0234215 infores:hetionet CHEBI:231594 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0037763 infores:hetionet CHEBI:27666 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C2047937 infores:hetionet CHEBI:50173 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0026826 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0267994 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0267994 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0013922 infores:hetionet CHEBI:66919 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0030312 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0404521 infores:hetionet CHEBI:23765 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085631 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0235063 infores:hetionet CHEBI:480999 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151786 infores:hetionet CHEBI:9671 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0162830 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011991 infores:hetionet CHEBI:49575 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233795 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0015397 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0162429 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0149931 infores:hetionet CAID:CA10576309 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576309 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.1555C>A (p.Pro519Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation (specification version 1.2) on 4 March 2025. The supporting evidence is as follows:PM2: This variant is absent from a distinct subpopulation in gnomAD v4.1.0 and is found in 1/62500 alleles in the Remaining subpopulation. PP3: REVEL = 0.778. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6 after alternative causes of high cholesterol were excluded (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576309/MONDO:0007750/013 2025-03-04 2025-03-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4995 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0428974 infores:hetionet CHEBI:125354 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0018944 infores:hetionet CAID:CA367398735 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398735 MONDO:0015967 PMID: Likely Pathogenic PM5, PP1_Moderate, PP2, PP3, PM2_Supporting The c.1148C>G variant in the glucokinase gene, GCK, causes an amino acid change of serine to tryptophan at codon 383 (p. (Ser383Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2) This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1148C>T (p.Ser383Leu), has been interpreted as pathogenic by the ClinGen MDEP, and p.Ser383Trp has an equal or greater Grantham distance (PM5). This variant was found in one family, and segregated with hyperglycemia, with four informative meioses (PP1_Moderate; PMID: 3385223). In summary, c.1148C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PP2, PP1_Moderate, PM5, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398735/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:44185 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0025061 infores:hetionet CHEBI:175901 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0035455 infores:hetionet CHEBI:45924 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0232462 infores:hetionet NCBIGene:1759 biolink:causes MONDO:0957248 infores:monarchinitiative not_provided not_provided HGNC:2972 MONDO:0957248 uuid:ee405eb0-be44-46a7-ae05-7816959d5abf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235086 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0001824 infores:hetionet CHEBI:7915 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0039070 infores:hetionet CHEBI:45652 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0026896 infores:hetionet CHEBI:209807 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0031542 infores:hetionet CHEBI:70707 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0917801 infores:hetionet CAID:CA229867 biolink:causes MONDO:0009861 infores:clingen CAID:CA229867 MONDO:0009861 PMID:23690520PMID:18590700 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting PM5, BS3 The NM_000277.1(PAH):c.941C>A (p.Pro314His) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 15% of wild-type PAH enzyme activity in a standard cDNA system and 5% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3_supporting). It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID: 24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 28593914). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.91) (PP3).Classification: PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229867/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9150 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0162830 infores:hetionet CHEBI:520985 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0027497 infores:hetionet CHEBI:2038 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0085593 infores:hetionet CHEBI:3478 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0015967 infores:hetionet CHEBI:6375 biolink:causes MONDO:0043994 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0149520 infores:hetionet CHEBI:3696 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C2830004 infores:hetionet CHEBI:175901 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C3160858 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0016033 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0016033 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011609 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0232459 infores:hetionet CHEBI:132233 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0015230 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0162429 infores:hetionet NCBIGene:10594 biolink:causes MONDO:0010806 infores:monarchinitiative not_provided not_provided HGNC:17340 MONDO:0010806 uuid:bcb8530e-efe4-40bf-857c-d18ed352bb89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0232493 infores:hetionet CHEBI:10100 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0020517 infores:hetionet CHEBI:5384 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0017181 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1140680 infores:hetionet CHEBI:32221 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0018834 infores:hetionet CAID:CA10585777 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585777 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 PS3, PM5, PP3 The NM_000527.5 (LDLR): c.2113G>T (p.Ala705Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: PopMAX MAF = 0.00004 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria or Simon Broome criteria for FH from 2 different labs: 1 case met DLCN criteria from Robarts Research Institute, Canada; 1 case met Simon Broome criteria from Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London, UK, PMID 17142622.PP3 not met: REVEL score = 0.673, which is below the threshold of 0.75. Functional data on splicing is not available, in silico splicing prediction is required. Variant is exonic and at least 50bp downstream from acceptor site and creates GT. MES scores: de novo donor = -6.49, authentic donor = 7.81. De novo score is negative and not used, therefore the variant is not predicted to alter splicing.BP4 not applicable: REVEL score is > 0.5, therefore BP4 is not applicable.PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>C (p.Ala705Pro) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585777/MONDO:0007750/013 2022-02-25 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA512318581 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318581 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, BP5, BS1, BS3, BS4, PM6, PVS1, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.757C>T (p.Leu253=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (1.67) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318581/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4911 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1142499 infores:hetionet CHEBI:7822 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0033687 infores:hetionet CHEBI:63619 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0019080 infores:hetionet CHEBI:10101 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0041582 infores:hetionet GO:1901668 biolink:causes GO:0071451 infores:ubergraph knowledge_assertion manual_agent GO:1901668 GO:0071451 CHEBI:10124 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0002622 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0020517 infores:hetionet CHEBI:35778 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0036104 infores:hetionet CAID:CA10612411 biolink:causes MONDO:0100038 infores:clingen CAID:CA10612411 MONDO:0100038 PMID: Likely Benign PM6_Supporting, BS1, PS4_Supporting, BP4 PS1, PS3, BP5, PM5, PM1, PM2, BS2, PP3, PP1, BP2, BA1 The NM_001040142.2:c.3043G>A variant in SCN2A is a missense variant predicted to cause substitution of Aspartic Acid by Asparagine at amino acid 1015 (p.Asp1015Asn). This variant has been reported in one proband meeting phenotypic criteria for Complex Neurodevelopmental Disorder (MONDO:0100038) (PS4_Supporting; PMID 30564305); however, this variant was inherited from a parent whose affected status is unknown. This variant was also found to occur de novo in one proband meeting criteria for Complex Neurodevelopmental Disorder (MONDO:0100038) with unconfirmed parental relationships (PM6_Supporting; PMID 35431799). The minor allele frequency in the European (non-Finnish) genetic ancestry group in gnomAD v4.1.0 is 0.000006780 (0.0007%, or 8/1179964 alleles), which is higher than the ClinGen Epilepsy Sodium Channel threshold (>0.0002%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.287, which is below the threshold of 0.290, evidence that does not predict a damaging effect on SCN2A function (BP4). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant Complex Neurodevelopmental Disorder. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4_Supporting, PM6_Supporting, BP4, BS1. (Epilepsy Sodium Channel VCEP Specifications version 1.0.0; Approved 1/26/2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA10612411/MONDO:0100038/068 2024-11-26 2024-12-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9123 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002994 infores:hetionet CAID:CA16044155 biolink:causes MONDO:0019501 infores:clingen CAID:CA16044155 MONDO:0019501 PMID: Uncertain Significance PM2_Supporting, PM3 The variant NM_206933.4:c.9921T>G in USH2A is a missense variant predicted to cause substitution of cysteine by tryptophan at amino acid 3307 (p.Cys3307Trp). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.585, which meets no codes. The variant has been reported in three compound heterozygous probands, two who were diagnosed with retinitis pigmentosa, and all with a likely pathogenic/pathogenic second USH2A variant in phase unknown (PM3; PMIDs: 32531858, 34906470, 36819107). In summary, this variant meets the criteria to be classified as uncertain significance for AR Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 2/21/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA16044155/MONDO:0019501/005 2024-02-21 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true NCBITaxon:562 biolink:causes MONDO:0005280 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D011472 DB01059_MESH_D011472_1DB00537_MESH_D011472_1DB01165_MESH_D011472_1DB00567_MESH_D011472_1 CHEBI:135925 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0004936 infores:hetionet CHEBI:3508 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0600228 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0017152 infores:hetionet GO:0010695 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0000278 UNII:15G12L5X8K biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0521591 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0542052 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0542052 infores:hetionet GO:0043923 biolink:causes GO:0019083 infores:ubergraph knowledge_assertion manual_agent GO:0043923 GO:0019083 CHEBI:63791 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151692 infores:hetionet CHEBI:10650 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0232292 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0025061 infores:hetionet CHEBI:7488 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0013404 infores:hetionet CHEBI:3181 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0032227 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0020538 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0018772 infores:hetionet UNII:T58MSI464G biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0027497 infores:hetionet CHEBI:3175 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0013604 infores:hetionet CHEBI:188986 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0003467 infores:hetionet CHEBI:2379 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C2363731 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014175 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0003123 infores:hetionet CHEBI:4672 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1260880 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0000833 infores:hetionet CHEBI:5165 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151603 infores:hetionet CHEBI:92607 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0002792 infores:hetionet CHEBI:5118 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030193 infores:hetionet CHEBI:6887 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0392156 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151736 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038362 infores:hetionet CL:0000049 biolink:causes MONDO:0004653 infores:ubergraph knowledge_assertion manual_agent CL:0000049 MONDO:0004653 CHEBI:6909 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0029132 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0010520 infores:hetionet CHEBI:63610 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0002792 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0424000 infores:hetionet CHEBI:16796 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0017979 infores:hetionet CHEBI:50777 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0011124 infores:hetionet CHEBI:31302 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0009676 infores:hetionet CHEBI:4877 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0027059 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0020517 infores:hetionet CHEBI:45599 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0039231 infores:hetionet GO:1904956 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:1904956 GO:0007420 CAID:CA401370075 biolink:causes MONDO:0009290 infores:clingen CAID:CA401370075 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting PM3 The NM_000152.5:c.2015G>T variant in GAA is a missense variant that results in the substitution of an arginine for a leucine at amino acid 672 (p.Arg672Leu). One Indian patient with late onset Pompe disease has been reported, with <1% normal GAA activity in skin fibroblasts, and muscle histology consistent with the condition (PMID: 33741225) (PP4_Moderate). This individual is compound heterozygous for the variant and another variant in GAA that has been classified as likely pathogenic for Pompe disease by the ClinGen LD VCEP, c.2783A>G (p.Tyr928Cys); phase unconfirmed (0.25 points) (Insufficient to apply PM3). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). Two other variants at the same amino acid position have been classified as pathogenic (c.2014C>T, p.Arg672Trp, ClinVar Variation ID: 188773) or likely pathogenic (c.2015G>A p.Arg672Gln, ClinVar Variation ID: 371126) for Pompe disease by the ClinGen LD VCEP (PM5). The computational predictor REVEL gives a score of 0.955 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 2675756) with one submitter classifying the variant as pathogenic. In summary, these variant meets the criteria to be classified a likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0.0.): PM5, PP4_Moderate, PP3, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, August 31, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401370075/MONDO:0009290/010 2025-08-31 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63631 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0542571 infores:hetionet NCBIGene:4041 biolink:causes MONDO:0011877 infores:monarchinitiative not_provided not_provided HGNC:6697 MONDO:0011877 uuid:dd1e9a38-ff57-434d-8a31-dae3e6ca030a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0026826 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030305 infores:hetionet CAID:CA7177004 biolink:causes MONDO:0021060 infores:clingen CAID:CA7177004 MONDO:0021060 PMID: Likely Benign BP4, BS1 BA1, PM2 The c.2600A>G (NM_006939.4(SOS2):c.2600A>G (p.Asn867Ser)) variant in SOS2 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 867. The filtering allele frequency in gnomAD v2.1.1 is 0.03346 % (BS1). The computational predictor REVEL gives a score of 0.182 which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4 (Version 2.3; 12/3/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7177004/MONDO:0021060/042 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:30830 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151904 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0948594 infores:hetionet CHEBI:114785 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0013604 infores:hetionet CHEBI:9332 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0014518 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0035455 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0015294 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1619692 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0027765 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0013395 infores:hetionet CHEBI:116735 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0234233 infores:hetionet CHEBI:184555 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0011175 infores:hetionet CHEBI:5775 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0038002 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030353 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0027765 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0009806 infores:hetionet CHEBI:194135 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0021368 infores:hetionet CHEBI:101278 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0037188 infores:hetionet CHEBI:3013 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0012833 infores:hetionet NCBIGene:58528 biolink:causes MONDO:0859328 infores:monarchinitiative not_provided not_provided HGNC:19903 MONDO:0859328 uuid:ff4572d7-4984-4745-8809-4076cfe29746 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA022539 biolink:causes MONDO:0005835 infores:clingen CAID:CA022539 MONDO:0005835 PMID: Likely Benign BS3_Supporting, PP3_Moderate, BP5, BS4_Supporting, BS2 BS1 The MSH2 c.913G>A variant is predicted as a missense variant, p.(Ala305Thr). Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.81 (http://priors.hci.utah.edu/PRIORS). It showed lack of co-segregation with disease with Bayes Likelihood Ratio >0.05 & ≤0.482 (Insight database). It was identified in 2 individuals with CRC showing MSS or inconsistent MMR protein expression pattern. It has been functionally analyzed in several studies: functional Odds for Pathogenicity is >0.05 & ≤0.482 (Drost et al., 2011 PMID 22102614); proficient function, expression and localization (PMID 18822302); proficient function (PMID 33357406). It has been identified in co-occurrence in trans with a MSH2 known pathogenic variant (Invitae internal data). Therefore, this variant is classified as likely benign. InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA022539/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:653361 biolink:causes MONDO:0009309 infores:monarchinitiative not_provided not_provided HGNC:7660 MONDO:0009309 uuid:f0d316b9-8c49-46ee-b992-bb810fc08f13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015672 infores:hetionet GO:1902033 biolink:causes GO:0030097 infores:ubergraph knowledge_assertion manual_agent GO:1902033 GO:0030097 CAID:CA1139655485 biolink:causes MONDO:0100368 infores:clingen CAID:CA1139655485 MONDO:0100368 PMID: Likely Pathogenic PM3, PVS1_Strong, PM2_Supporting PP3, PP4 NM_000329.3(RPE65):c.1596dup (p.Ser533IlefsTer30) is a single nucleotide duplication that replaces serine with isoleucine as the last amino acid of RPE65, causes a frameshift, and adds 30 amino acids to the end of the RPE65 protein (PVS1_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_000329.3(RPE65):c.1443_1445del (p.Glu481del) variant confirmed in trans, which has been classified as likely pathogenic by the ClinGen LCA / eoRD VCEP (PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of congenital stationary night blindness (0.5 pts), which is not sufficiently specific for RPE65-related recessive retinopathy (0.5 points total, VCEP member-provided data) so the PP4 code is not met. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1_Strong, PM2_Supporting, and PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139655485/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7494 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151883 infores:hetionet NCBITaxon:123737 biolink:causes MONDO:0000301 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:123737 MONDO:0000301 CHEBI:28748 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0000833 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0152029 infores:hetionet CHEBI:28830 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0149745 infores:hetionet CAID:CA405669968 biolink:causes MONDO:0007783 infores:clingen CAID:CA405669968 MONDO:0007783 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate, PM5_Supporting PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with proline at codon 2452 of the RYR1 protein, p.(Arg2452Pro). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant was reported in an individual who had a positive in vitro contracture test (IVCT) result, however, it was not clear that the individual had a personal or family history of an MH event and therefor PS4 was not implemented (PMID:19191333). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant assessed as likely pathogenic occurs at this codon, p.(Arg2452Trp), PM5_Supporting (PMID:30236257). A REVEL score >0.85 (0.953) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405669968/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8863 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004604 infores:hetionet CHEBI:72690 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0012833 infores:hetionet CAID:CA772703383 biolink:causes MONDO:0009276 infores:clingen CAID:CA772703383 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP4, PM3 The NM_000173.7(GP1BA):c.1436del frameshift variant in exon 2, of 2, results in an immediate premature stop codon. It is not predicted to trigger NMD, instead truncating 27% of the protein, including the critical transmembrane domain (PVS1_strong). The Grpmax filtering allele frequency in gnomADv4.1 is 0.000002470 (based on 7/1179834 alleles) in the European (non-Finnish) population, which is below the <0.0001114 threshold for PM2_supporting. One internal patient has been identified with macrothrombocytopenia and bleeding. Flow cytometry was suggestive of type I BSS but there is insufficient information for PP4. The patient is compound heterozygote with Gln196Ter, which is classified VUS by the PD EP (PM3_NotMet). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA772703383/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:421707 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0311468 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002871 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0205707 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0205707 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0149801 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149801 infores:hetionet CHEBI:5558 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0040264 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042373 infores:hetionet CAID:CA000009 biolink:causes MONDO:0018875 infores:clingen CAID:CA000009 MONDO:0018875 PMID: Likely Benign BS3, BS2_Supporting, PP3, PM2_Supporting BP4, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PP4, PP1 The NM_000546.6: c.1003C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 335 (p.Arg335Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; ClinVar SCV: SCV000629764.4). This variant has an allele frequency of 0.000001859 (3/1613806 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.275; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, PP3. (Bayesian Points: -3; VCEP specifications version 2.2; 2/6/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000009/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63620 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085684 infores:hetionet CHEBI:36795 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0497156 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0002871 infores:hetionet CAID:CA229556 biolink:causes MONDO:0009861 infores:clingen CAID:CA229556 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 The c.460T>A (p.Tyr154Asn) variant in PAH has not been reported in a patient with PKU in the literature. It was reported to the PAH database (McGill University) by Guldberg in 1994. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229556/MONDO:0009861/006 2020-01-26 2020-01-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:408174 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027765 infores:hetionet CHEBI:6367 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0043387 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0020542 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0856150 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0856150 infores:hetionet CHEBI:7936 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0028734 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0162429 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027051 infores:hetionet CHEBI:3001 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0271738 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0031117 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0011991 infores:hetionet CHEBI:135351 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0043094 infores:hetionet NCBIGene:1009 biolink:causes MONDO:0030674 infores:monarchinitiative not_provided not_provided HGNC:1750 MONDO:0030674 uuid:9522a5a3-8aab-457a-8cae-16c9d57f2887 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0037822 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0011053 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0009806 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0015230 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0035078 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027651 infores:hetionet GO:0046773 biolink:causes GO:0006415 infores:ubergraph knowledge_assertion manual_agent GO:0046773 GO:0006415 CHEBI:94807 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0151578 infores:hetionet CHEBI:9555 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0001973 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0008370 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042109 infores:hetionet CHEBI:9674 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0220870 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0392386 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0037274 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0948594 infores:hetionet CHEBI:51137 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0033774 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0027726 infores:hetionet CAID:CA214298 biolink:causes MONDO:0015967 infores:clingen CAID:CA214298 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong The c.313dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 105 (NM_000545.8), adding 83 novel amino acids before encountering a stop codon (p.(Glu105GlyfsTer83)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). In summary, c.313dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214298/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6456 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0032961 infores:hetionet CHEBI:68478 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151905 infores:hetionet CHEBI:50648 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0333355 infores:hetionet CHEBI:92511 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0030554 infores:hetionet CHEBI:17026 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020578 infores:hetionet GO:1902026 biolink:causes GO:0061448 infores:ubergraph knowledge_assertion manual_agent GO:1902026 GO:0061448 CHEBI:116278 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0240717 infores:hetionet CHEBI:8212 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0011168 infores:hetionet CHEBI:101278 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1320474 infores:hetionet CHEBI:29007 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0009319 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0518015 infores:hetionet CHEBI:16469 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2979982 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0042109 infores:hetionet CHEBI:63607 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0016204 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0442874 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0262576 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0262576 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0021843 infores:hetionet CHEBI:6456 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0344232 infores:hetionet CHEBI:71940 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0085649 infores:hetionet CHEBI:68534 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0243026 infores:hetionet CHEBI:2639 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0030252 infores:hetionet CHEBI:71940 biolink:causes MONDO:0000498 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C2242711 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0149931 infores:hetionet CAID:CA220207 biolink:causes MONDO:0008723 infores:clingen CAID:CA220207 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4, PM3_Supporting PP1, PM5, PM1, PM4, PS1, PVS1 The c.425T>C variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 142 (p.Phe142Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is above the threshold 0.75, evidence that correlates with impact to ACADVL function (PP3). At least one patient with this variant displayed organic acidemia and fatty acid oxidation issues, which are highly specific for VLCAD deficiency (PP4, PMID: 27629047, PMID: 28980192). This individual was also reported homozygous for the variant (PMID: 27629047; points=0.5; PM3_supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2,PM3_supporting PP3, PP4 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220207/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0657912 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0031099 infores:hetionet NCBIGene:89884 biolink:causes MONDO:0009880 infores:monarchinitiative not_provided not_provided HGNC:21734 MONDO:0009880 uuid:fc0dda6b-2567-43bd-a51c-59ada6f0f39b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135613 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0002994 infores:hetionet GO:1905174 biolink:causes GO:0090677 infores:ubergraph knowledge_assertion manual_agent GO:1905174 GO:0090677 CHEBI:3387 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0549249 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0860434 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0860434 infores:hetionet CHEBI:17698 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0030193 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0233494 infores:hetionet CHEBI:6759 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0013604 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0029443 infores:hetionet CHEBI:51041 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0014457 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0948594 infores:hetionet CHEBI:8863 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0039621 infores:hetionet CHEBI:7581 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0151610 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017160 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0543698 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011551 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0024115 infores:hetionet CHEBI:3393 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0042963 infores:hetionet CHEBI:31624 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C1443060 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0031542 infores:hetionet CHEBI:28593 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0004134 infores:hetionet CHEBI:4470 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0013144 infores:hetionet NCBIGene:4615 biolink:causes MONDO:0100281 infores:monarchinitiative not_provided not_provided HGNC:7562 MONDO:0100281 uuid:691824f7-81f4-45b8-bb43-873af8ebc3d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4653 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0042373 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042769 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0003123 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0027651 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0085622 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1535975 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1535975 infores:hetionet CHEBI:64355 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0392525 infores:hetionet UMLS:C0011701 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0549249 infores:hetionet CHEBI:3568 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C3665347 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0178298 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0038454 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0243026 infores:hetionet CHEBI:66899 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0920171 infores:hetionet CHEBI:4469 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0085633 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0040034 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0860901 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0860901 infores:hetionet CHEBI:32588 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0030554 infores:hetionet CHEBI:9622 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0017168 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002170 infores:hetionet CHEBI:43968 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0017675 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005479 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0546959 infores:hetionet CHEBI:6715 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0404521 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004471 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1692886 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0158350 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0236071 infores:hetionet CHEBI:5790 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0002792 infores:hetionet CHEBI:7936 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030232 infores:hetionet CAID:CA10583771 biolink:causes MONDO:0007750 infores:clingen CAID:CA10583771 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 PS3 The NM_000527.5 (LDLR):c.-188C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for definite FH. One case submitted to ClinVar from U4M - Lille University & CHRU Lille, France; 1 case reported by Fouchier et al, 2005, from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583771/MONDO:0007750/013 2022-08-26 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7824 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0033117 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020538 infores:hetionet CHEBI:41774 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0522224 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0860603 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0860603 infores:hetionet CHEBI:46557 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0242528 infores:hetionet CHEBI:7822 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0003811 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0236065 infores:hetionet CHEBI:4514 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0080274 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0020649 infores:hetionet CHEBI:134936 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0423602 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0546817 infores:hetionet CHEBI:10650 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018524 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0235431 infores:hetionet CHEBI:92998 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0019521 infores:hetionet CHEBI:5103 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0424109 infores:hetionet CHEBI:50777 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0015230 infores:hetionet CHEBI:28001 biolink:causes UMLS:C1306792 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C1306792 infores:hetionet GO:0044479 biolink:causes GO:0043303 infores:ubergraph knowledge_assertion manual_agent GO:0044479 GO:0043303 CHEBI:63635 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0233459 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0332534 infores:hetionet CHEBI:64064 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0009782 infores:hetionet CAID:CA2802038 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802038 MONDO:0001586 PMID: Likely Benign BP7, BP4 BS1, PM2 The NM_000203.5:c.630C>T (p.Arg210=) variant in IDUA is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (all scores are <0.1). In addition, the variant is not in the first nucleotide or last three nucleotides of an exon (BP4, BP7). The GrpMax Filtering Allele Frequency (95% confidence) is 0.002326 in the Middle Eastern population, which is below the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.0025) and higher than the threshold for PM2_Supporting (<0.00025). Therefore, no population codes are met. To our knowledge, this variant has not been reported in the literature. There is a ClinVar entry for this variant (Variation ID: 350222). In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802038/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63627 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0004093 infores:hetionet CHEBI:28748 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0016382 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0005741 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0242350 infores:hetionet CAID:CA409105430 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105430 MONDO:0015967 PMID: Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1, PS4, PP1_Strong The c.335G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 112 (p.(Arg112Gln)) of NM_175914.5. This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 36257325, 25306193, 26552609, 18356407, internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 12 informative meioses in 11 families (PP1_Strong; PMID: 18356407, internal lab contributors). Another missense variant, c.334C>T p.Arg112Trp, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg112Gln (PM5_Supporting). In summary, c.335A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS4, PP1_Strong, PM1, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105430/MONDO:0015967/085 2023-09-29 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41977 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0575081 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0178298 infores:hetionet CHEBI:6950 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151937 infores:hetionet CHEBI:64355 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0025222 infores:hetionet CHEBI:10125 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0015967 infores:hetionet CHEBI:48131 biolink:causes MONDO:0008661 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0042900 infores:hetionet CHEBI:5847 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0149745 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0042373 infores:hetionet CHEBI:51450 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0231530 infores:hetionet CHEBI:36704 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0018681 infores:hetionet CHEBI:63631 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018520 infores:hetionet CHEBI:6931 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0004093 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0041969 infores:hetionet CAID:CA241481 biolink:causes MONDO:0021060 infores:clingen CAID:CA241481 MONDO:0021060 PMID: Benign BS2, PP2, BP4, BP5, BS1 PM4, PM3, PM1, PVS1, PP1, PP3, PP4, PM2, PM6, BP1, BP3, BP2, BA1, PS4, PS2, PS3, BP7, BS4, BS3 The c.94A>G (p.Ile32Val) variant in the RAF1 gene has been identified in patients who underwent testing for a RASopathy, however it has also been identified in multiple adults who did not have clinical features of a RASopathy (BS2, BP5; Invitae, EGL Diagnostics, GeneDx internal data; GTR Lab ID: 500031, 500060; SCV000287747.4, SCV000227277.5, SCV000209002.14). The filtering allele frequency of the p.Ile32Val variant is 0.017% for European (non-Finnish) genomes in the gnomAD database (8/31404 with 95% CI) which is a high enough frequency to be considered strong evidence that the variant is benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1). Computational prediction tools and conservation analysis suggest that the p.Ile32Val variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2, BP5, BS1, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA241481/MONDO:0021060/040 2019-06-27 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64355 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2129214 infores:hetionet NCBIGene:10747 biolink:causes MONDO:0013423 infores:monarchinitiative not_provided not_provided HGNC:6902 MONDO:0013423 uuid:419713e6-76e0-44db-89a7-e49b334293f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:219285 biolink:causes MONDO:0008038 infores:monarchinitiative not_provided not_provided HGNC:1349 MONDO:0008038 uuid:8277180e-ecb5-41da-b14c-2fa33d960349 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70735 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0037036 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0038362 infores:hetionet CAID:CA396467967 biolink:causes MONDO:0007648 infores:clingen CAID:CA396467967 MONDO:0007648 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP4, PP1, BS2, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2 The c.2161C>G (p.Leu721Val) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). Additionally, this variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; internal laboratory contributor). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP3, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396467967/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true GO:0141085 biolink:causes GO:0006954 infores:ubergraph knowledge_assertion manual_agent GO:0141085 GO:0006954 CHEBI:7824 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0015967 infores:hetionet CHEBI:3515 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151632 infores:hetionet CAID:CA214284 biolink:causes MONDO:0015967 infores:clingen CAID:CA214284 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.169del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 57 (NM_000545.8), adding 98 novel amino acids before encountering a stop codon (p.(Leu57TrpfsTer98)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 23348805) and is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was previously reported in ClinVar, but no clinical information was provided, so PP4 could not be applied. In summary, c.169del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214284/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50381 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0028643 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0178298 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0858678 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0011603 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0020517 infores:hetionet CHEBI:9434 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0006277 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0006266 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017601 infores:hetionet CHEBI:50859 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013604 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019360 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0003460 infores:hetionet CHEBI:64355 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0850149 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0011849 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0023890 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151505 infores:hetionet CHEBI:9086 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C3263723 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0746883 infores:hetionet CAID:CA512232177 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232177 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.957T>C (p.Ser319=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 1.10604 < 2.0), and the variant is seen in three mammal species (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232177/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17474 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0038454 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0004936 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0031117 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0686377 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0686377 infores:hetionet CHEBI:6916 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0004093 infores:hetionet CHEBI:9943 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151539 infores:hetionet CHEBI:251408 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0012569 infores:hetionet CHEBI:28148 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0005778 infores:hetionet CHEBI:5004 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0497156 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018799 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027092 infores:hetionet CHEBI:2950 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C1443060 infores:hetionet CHEBI:55346 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0476273 infores:hetionet CHEBI:8713 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C1142412 infores:hetionet CHEBI:64064 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0002792 infores:hetionet CAID:CA410147626 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147626 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS2, PS1, PS4, BA1, BP3, BP1, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM1, PM3, PM5, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.1256T>G (p.Val419Gly) is a missense variant with a REVEL score < 0.50 (0.239) and SpliceAI predicts no impact on splicing (score: 0.00) (BP4). This variant is found in one individual with thrombocytopenia and a bleeding phenotype (PMID 32935436), but PS4_supporting cannot be applied because the variant is present more than two times (5) in gnomAD v3.1.2. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147626/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135935 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0242350 infores:hetionet CHEBI:3614 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0231528 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0018213 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0015230 infores:hetionet CHEBI:5893 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013491 infores:hetionet UMLS:C0004609 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0152031 infores:hetionet CHEBI:5106 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0027497 infores:hetionet CHEBI:3216 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0030232 infores:hetionet CAID:CA645373344 biolink:causes MONDO:0044970 infores:clingen CAID:CA645373344 MONDO:0044970 PMID:19853445 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PP1, PS2, PS4, PM6 The m.12283G>A variant in MT-TL2 has been reported in one individual with primary mitochondrial disease. This individual was a male with chronic progressive external ophthalmoplegia (CPEO), ptosis, exercise intolerance, and COX-deficient fibers. The variant was present at 18% heteroplasmy in muscle and 4% in urine (PMID: 19853445). The variant was undetectable in his healthy mother’s blood, urine, and buccal sample, however the variant was also undetectable in the proband's buccal and blood, and was seen at very low levels in the urine (4%), therefore this is not included as a de novo occurrence (PMID: 19853445). Of note, this individual also had maternally inherited HPRT-related renal failure and a demyelinating neuropathy related to a PMP22 duplication (PMID: 19853445). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (98%) than in COX-positive fibers (1.38%), p<0.001 (PS3_supporting, PMID: 19853445). Computational predictors are conflicting as MitoTIP predicts this variant to be benign (43.2%) and HmtVAR predicts it to be damaging (score of 1). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA645373344/MONDO:0044970/015 2024-03-11 2025-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9168 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0023218 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0031117 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235966 infores:hetionet GO:1903538 biolink:causes GO:0048599 infores:ubergraph knowledge_assertion manual_agent GO:1903538 GO:0048599 CHEBI:63622 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0013404 infores:hetionet CHEBI:63589 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0015230 infores:hetionet CHEBI:50663 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0024312 infores:hetionet CHEBI:7478 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151766 infores:hetionet CHEBI:10650 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0237314 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0595877 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0948089 infores:hetionet CAID:CA10581714 biolink:causes MONDO:0100437 infores:clingen CAID:CA10581714 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP3, PS4 NM_001034853.2(RPGR):c.1572+1del occurs at a canonical splice site in intron 13 and is predicted to disrupt splicing and induce exon skipping, which is expected to introduce a premature stop codon or disrupt a critical functional domain in RPGR (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband (PMID: 27208204). However, the number of individuals meeting the PS4 requirement of some functional vision impairment in affected males by age 30, or decreased/absent cone and/or rod ERG responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant meets the criteria to be classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PVS1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581714/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:9137 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0035455 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1384353 infores:hetionet CAID:CA404085998 biolink:causes MONDO:0007750 infores:clingen CAID:CA404085998 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - 2 other missense variants in the same codon:(1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg)- 1 star, Conflicting interpretations of pathogenicity​: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4)- Pathogenic by these guidelines (FH VCEP training Aug 2021)(2) NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp)- 1 star, VUS in ClinVar- VUS by these guidelines--- there is 1 Pathogenic variant in the same codon, so PM5 is met.PP3 - REVEL = 0.984. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404085998/MONDO:0007750/013 2022-01-31 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:30830 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0855242 infores:hetionet CHEBI:45081 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0206061 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029134 infores:hetionet CHEBI:48947 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0023530 infores:hetionet CHEBI:28918 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0812387 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042401 infores:hetionet CHEBI:63619 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0003467 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0004096 infores:hetionet NCBIGene:54658 biolink:causes MONDO:0021020 infores:monarchinitiative not_provided not_provided HGNC:12530 MONDO:0021020 uuid:112b8293-bdf1-48f8-a0d7-ba5bdef0f211 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0031616 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423281 infores:hetionet CHEBI:8024 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0003467 infores:hetionet CHEBI:32139 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0027709 infores:hetionet CHEBI:5790 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0023530 infores:hetionet CHEBI:49713 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0232462 infores:hetionet CHEBI:68579 biolink:causes HP:0040242 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151702 infores:hetionet CHEBI:585948 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0014591 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085096 infores:hetionet CHEBI:116735 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0010520 infores:hetionet CAID:CA10585257 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585257 MONDO:0007750 PMID: Pathogenic PP1_Strong, PM5, PM3, PM2, PP3, PP4 PS3 The NM_000527.5 (LDLR):c.1027G>T (p.Gly343Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PP1_Strong, PM5, PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent in gnomAD (gnomAD v2.1.1).PP3: REVEL=0.92, it is above 0.75.PP4: Variant meets PM2 and is identified in 1 index case who fulfil criteria for FH after alternative causes of high cholesterol were excluded. The patient had LDL-C level of 16.62 mmol/L with xanthomas and CHD, reported by Jelassi et al, 2009 and 2010, from Research Unit of Genetic and Biologic Factors of Atherosclerosis, Faculty of Medicine, Monastir, Tunisia, PMID 18757057 and 20144596. PP1_Strong: Variant segregates with FH phenotype in 6 informative meiosis from 1 family: 5 affected relatives were positive, 1 unaffected relative was negative for the variant, reported by Jelassi et al, PMID 18757057 and 20144596.PM5: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5 is met.PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype with plasma LDL-C 16.62 mmol/L, reported by Jelassi et al, PMID 18757057. This variant met enough pathogenic criteria toward Pathogenic classification by these guidelines before PM3 code applied.PS4 not met: Variant meets PM2 and is reported in 1 index case fulfil FH criteria and with homozygous FH phenotype, by Jelassi et al, PMID 18757057 and 20144596.PS3 not met: Functional data is not available. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585257/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6472 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0040264 infores:hetionet CHEBI:3215 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0042510 infores:hetionet NCBIGene:23279 biolink:causes MONDO:0032582 infores:monarchinitiative not_provided not_provided HGNC:18017 MONDO:0032582 uuid:0d93ac76-4f89-473a-9e2e-0019cd114623 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9241 biolink:causes UMLS:C0235756 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0235756 infores:hetionet CHEBI:6078 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C2363731 infores:hetionet CHEBI:6129 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0003467 infores:hetionet CHEBI:50841 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0040822 infores:hetionet CHEBI:5118 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015371 infores:hetionet NCBIGene:1291 biolink:causes MONDO:0009681 infores:monarchinitiative not_provided not_provided HGNC:2211 MONDO:0009681 uuid:62464944-0fc6-4d3f-932a-387296930417 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8129871 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129871 MONDO:0007648 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM1, PM3, PM5, PM4, PP1, PP4, PP2, PP3, BP2, BP3, BP1, BP4, BA1, PS3, PS4, PS2, PS1 The c.512T>G (p.Phe171Cys) variant has an allele frequency: 1:251320 (A (NM_000018.4) variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant been reported in one individual with very long chain acyl-CoA dehydrogenase deficiency in the literature with decreased VLCAD enzyme activity (PP4_moderate; PMID: 30194637). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1, PM2_supporting, PP4_Moderate. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724300/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75998 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0038363 infores:hetionet CHEBI:64355 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0041834 infores:hetionet CHEBI:75922 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0162281 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0086543 infores:hetionet CHEBI:63621 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0917801 infores:hetionet CHEBI:63610 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0151942 infores:hetionet CHEBI:6062 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0424790 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040034 infores:hetionet CHEBI:44185 biolink:causes MONDO:0043771 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0034561 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0009450 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0009450 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0005940 infores:hetionet CHEBI:3398 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0027424 infores:hetionet CHEBI:2675 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0011603 infores:hetionet CHEBI:28748 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0232462 infores:hetionet CHEBI:68554 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0011175 infores:hetionet NCBIGene:7204 biolink:causes MONDO:0014892 infores:monarchinitiative not_provided not_provided HGNC:12303 MONDO:0014892 uuid:de4be87c-bc7a-447b-b020-bc6506341509 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151825 infores:hetionet NCBIGene:10020 biolink:causes MONDO:0010028 infores:monarchinitiative not_provided not_provided HGNC:23657 MONDO:0010028 uuid:89eceb43-8137-4567-9ce7-59f9f70aabf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0043251 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042109 infores:hetionet CHEBI:75246 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0032617 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0038362 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0235723 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0235723 infores:hetionet CHEBI:3393 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0232462 infores:hetionet CAID:CA405635961 biolink:causes MONDO:0018493 infores:clingen CAID:CA405635961 MONDO:0018493 PMID: Likely Pathogenic PS4_Moderate, PP1_Strong This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with histidine at codon 1056 of the RYR1 protein, p.Asp1056His. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in two families with a total of fourteen informative meioses, PP1_Strong (PMID:24013571, The UK (Leeds) MH Unit). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405635961/MONDO:0018493/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CAID:CA120618 biolink:causes MONDO:0044970 infores:clingen CAID:CA120618 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS3_Supporting PP3, PP1, PS2, PS4, PM4, PM6 The m.15242G>A (p.Gly166Ter) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This individual had exercise intolerance, lactic acidosis, encephalomyopathy, hallucinations, depression, memory loss, and seizures. The variant was present at 87-92% heteroplasmy in muscle, 0.7% in blood, and 4-14% in hair roots (PMID:11047755). This variant was also seen in her unaffected sister (<0.2% in blood) and was undetectable in blood from her healthy mother, however this cannot be considered evidence for segregation nor de novo occurrence as the variant was detected at very low levels in the proband’s blood. This variant causes a premature stop in the MT-CYB gene (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in ragged red fibers (89±8%) than in non-ragged red fibers (66±26%) p<0.0001 (PS3_supporting, PMID: 11047755). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PVS1_strong, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120618/MONDO:0044970/015 2024-01-08 2024-07-24 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:41423 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0268000 infores:hetionet CHEBI:23765 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085614 infores:hetionet CHEBI:9588 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0035078 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0020538 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0022904 infores:hetionet CHEBI:10127 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0028734 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017675 infores:hetionet CHEBI:3441 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0038999 infores:hetionet GO:0006954 biolink:causes MONDO:0004979 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D001249 DB00901_MESH_D001249_1DB05266_MESH_D001249_1DB00885_MESH_D001249_1DB00549_MESH_D001249_1 CHEBI:6912 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0003467 infores:hetionet CHEBI:63598 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0234518 infores:hetionet CHEBI:60761 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0038362 infores:hetionet CHEBI:60761 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0014335 infores:hetionet CHEBI:46557 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0242429 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041969 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006898 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0031037 infores:hetionet CHEBI:408174 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C3665347 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0010073 infores:hetionet CHEBI:4466 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0042029 infores:hetionet CHEBI:64064 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0039240 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0010854 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0010854 uuid:5558562e-c26b-4214-b516-a5244b646423 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28787 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0027765 infores:hetionet CHEBI:9137 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0947912 infores:hetionet CAID:CA367398877 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398877 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1120G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 374 (p.(Val374Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; Zubkova et al. World Journal of Personalized Medicine. 2017;1(1):40-48, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398877/MONDO:0015967/086 2023-11-03 2023-11-03 Semidominant inheritance HP:0032113 Supports CHEBI:52717 biolink:causes UMLS:C0580546 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0580546 infores:hetionet CHEBI:8228 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0033687 infores:hetionet CHEBI:5100 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0008031 infores:hetionet CHEBI:7936 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020672 infores:hetionet CHEBI:3756 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0005779 infores:hetionet CAID:CA658655976 biolink:causes MONDO:0013699 infores:clingen CAID:CA658655976 MONDO:0013699 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 The c.1571dup (p.Gly525ArgfsTer17) (NM_000535.7) variant in PMS2 is a frameshift variant located between codon 525 and 542 and predicted to cause a premature stop codon in exon 11 in a gene in which loss-of-function is an established disease mechanism (PVS1). This alteration was detected in homozygous state (PMID: 26391938) in an individual meeting the clinical criteria for CMMR-D (≥3 points, table 3 of the ClinGen_InSiGHTColorectalCancer/Polyposis_ACMG_Specifications_v1), (PM3_supporting met). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1, PM2_SUP, PM3_SUP (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655976/MONDO:0013699/139 2025-03-13 2025-03-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8774 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0085661 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0021053 infores:hetionet CHEBI:47898 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151539 infores:hetionet CHEBI:46557 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0006142 infores:hetionet CHEBI:75722 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948008 infores:hetionet CHEBI:72564 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0206061 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0027339 infores:hetionet CHEBI:72564 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0404521 infores:hetionet CHEBI:16467 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0543467 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0877661 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0036508 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0029134 infores:hetionet CHEBI:3228 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0012833 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0006849 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0236106 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0236106 infores:hetionet CAID:CA386960511 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960511 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 The c.490A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to proline at codon 164 (p.(Thr164Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) who was also antibody negative (PP4_Moderate; internal lab contributors). In summary, c.490A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960511/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119573 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0000833 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151736 infores:hetionet CHEBI:52172 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0039231 infores:hetionet CHEBI:135930 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0009676 infores:hetionet CHEBI:5613 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0542571 infores:hetionet CHEBI:9137 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0221201 infores:hetionet CHEBI:15407 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0018524 infores:hetionet CAID:CA891843077 biolink:causes MONDO:0015967 infores:clingen CAID:CA891843077 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.1054del variant in the glucokinase gene, GCK, results in a premature termination at codon 352 (p.Leu352Ter) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1054del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843077/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CHEBI:144551 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0003467 infores:hetionet CHEBI:70735 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0686347 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0162429 infores:hetionet CHEBI:6129 biolink:causes HP:0100583 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0339293 infores:hetionet CHEBI:8768 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0231218 infores:hetionet CHEBI:135193 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027651 infores:hetionet CAID:CA410203889 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203889 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.211C>G (p.Leu71Val) is a missense variant which has a REVEL score < 0.50 (0.402) and a SpliceAI score ≤ 0.20 (Donor Gain 0.17) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203889/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3638 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0000737 infores:hetionet GO:2001074 biolink:causes GO:0003338 infores:ubergraph knowledge_assertion manual_agent GO:2001074 GO:0003338 CHEBI:4953 biolink:causes MONDO:0018381 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0029429 infores:hetionet CHEBI:5280 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0041834 infores:hetionet CHEBI:49375 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0231218 infores:hetionet CHEBI:51380 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0030252 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0036572 infores:hetionet CHEBI:44032 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0270996 infores:hetionet CHEBI:17823 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0728899 infores:hetionet CHEBI:3216 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0026821 infores:hetionet CHEBI:3757 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C2981158 infores:hetionet CHEBI:15552 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0009676 infores:hetionet CHEBI:17987 biolink:causes MONDO:0006609 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0221244 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0032290 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0004936 infores:hetionet CAID:CA400032983 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032983 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.1980C>A (p.Tyr660Ter) nonsense variant creates a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT23 of PMID: 29675921 meets the criteria for PP4_strong. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032983/MONDO:0100326/011 2021-06-30 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:135613 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0020517 infores:hetionet CHEBI:7915 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0026821 infores:hetionet CHEBI:6541 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0231528 infores:hetionet CHEBI:135451 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0020625 infores:hetionet CHEBI:36791 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011603 infores:hetionet CAID:CA229287 biolink:causes MONDO:0009861 infores:clingen CAID:CA229287 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, PP3, PM3_Supporting PM5, PS3 The c.1030G>C (p.Gly344Arg) variant in PAH has been reported in 1 individual with with classic PKU, detected with pathogenic variant c.1315+1G>A (aka IVS12+1G>A, PMID: 23430918). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Other missense changes at the same amino acid residue have been seen before (p.Gly344Val, p.Gly344Asp and p.Gly344Ser are likely pathogenic by PAH VCEP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4, PM2, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229287/MONDO:0009861/006 2021-06-11 2021-06-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4903 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0024902 infores:hetionet CHEBI:3647 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0152115 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0017160 infores:hetionet CHEBI:31413 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0014457 infores:hetionet CHEBI:131512 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0036974 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0042109 infores:hetionet CHEBI:4708 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0030193 infores:hetionet CHEBI:63610 biolink:causes GO:0070471 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0042130 infores:hetionet CHEBI:8863 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0542571 infores:hetionet CHEBI:5558 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0011168 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0234458 infores:hetionet CHEBI:51364 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0022346 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011991 infores:hetionet CHEBI:180905 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0003813 infores:hetionet CHEBI:17650 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0577559 infores:hetionet CHEBI:6775 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0349790 infores:hetionet NCBIGene:10019 biolink:causes MONDO:0009692 infores:monarchinitiative not_provided not_provided HGNC:29605 MONDO:0009692 uuid:3d658c7c-5f55-4e95-a2bc-8bf1b6f91612 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7478 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020443 infores:hetionet CHEBI:70746 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0041969 infores:hetionet CHEBI:3757 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0013428 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0009450 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0948594 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0281856 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0035258 infores:hetionet CHEBI:5001 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0497156 infores:hetionet CHEBI:7476 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0003862 infores:hetionet CHEBI:27899 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0234146 infores:hetionet CHEBI:5558 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0008031 infores:hetionet CHEBI:44032 biolink:causes HP:0012710 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027343 infores:hetionet CHEBI:17688 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0039231 infores:hetionet CHEBI:3764 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0030193 infores:hetionet CAID:CA347798 biolink:causes MONDO:0044970 infores:clingen CAID:CA347798 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PS4 The m.7443A>G (p.*514G) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID: 10577941), in a child enrolled at the School for Deaf and Blind in Mongolia. He was reported to have been deaf since infancy. The variant appeared to be homoplasmic. Information was not provided on the family history of this individual. There are no additional case reports to our knowledge. There are several occurrences of this variant in population databases (Mitomap: 1/61,134, gnomAD: 1/56,434, Helix: 4/195,893). Although there are several occurrences, the frequency is still low (PM2_supporting). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Functional studies showed inefficient processing (29% of wild type) by tRNAseZ in the presence of this variant (PS3_supporting; PMID: 16361254). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA347798/MONDO:0044970/015 2024-07-08 2024-12-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2639 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0009806 infores:hetionet CHEBI:8863 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002390 infores:hetionet CHEBI:8713 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0013404 infores:hetionet NCBIGene:3251 biolink:causes MONDO:0010298 infores:monarchinitiative not_provided not_provided HGNC:5157 MONDO:0010298 uuid:768d9fc1-1109-494b-a32c-dfea106ececa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0042401 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0013220 infores:hetionet CHEBI:168396 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085681 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011991 infores:hetionet CHEBI:4858 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0086439 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0014431 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0014431 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0015376 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020625 infores:hetionet CHEBI:45979 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0020517 infores:hetionet CAID:CA274107 biolink:causes MONDO:0009290 infores:clingen CAID:CA274107 MONDO:0009290 PMID:17723315PMID:30564623PMID:17723315 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.2140delC (p.His714Thrfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and no gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two patients who also carry a second variant in GAA. One of these cases meets the ClinGen LSD VCEP’s specifications for PP4 and is compound heterozygous for p.His714Thrfs and a missense variant, c.1561G>A (p.Glu521Lys); the phase is unknown (PMID 17723315). The in trans data from this patient will be used in the assessment of p.Glu521Lys and, therefore, was not included here in order to avoid circular logic. The second case is compound heterozygous for the variant and c.-32-13T>G (PMID 30564623) but the GAA activity was not reported and PP4 cannot be assessed. There is a ClinVar entry for this variant (Variation ID: 188904, 2 star review status) with 2 submtters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274107/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63619 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0340279 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0027765 infores:hetionet CHEBI:6437 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1760428 infores:hetionet CHEBI:94449 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0009676 infores:hetionet CHEBI:32221 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0038990 infores:hetionet CHEBI:84500 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0030252 infores:hetionet CHEBI:63630 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0040264 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0013609 infores:hetionet NCBIGene:4478 biolink:causes MONDO:0010514 infores:monarchinitiative not_provided not_provided HGNC:7373 MONDO:0010514 uuid:06c412b5-0fa5-47d9-a903-81f4e9930465 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA015829 biolink:causes MONDO:0007947 infores:clingen CAID:CA015829 MONDO:0007947 PMID: Uncertain Significance BP2 PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM3, PM4, BP5, BP7, BS1, BS3, BS4 NM_00138 c.5443G>A is a missense variant in FBN1 predicted to cause a substitution of a Glycine by Serine at amino acid 1815 (p.Gly1815Ser). This variant has been reported 3 times in ClinVar: once as likely pathogenic and twice as a variant of uncertain significance (Variation ID: 200064). This variant has been reported in the literature in 2 probands. It was identified in the homozygous state in an individual with autism spectrum disorder, global developmental delays, arachnodactyly, and dysmorphic features (PMID: 32655337); of note, homozygous variants of uncertain significance were identified in two other genes in this individual, and all 3 homozygous variants were found to segregate with disease in a similarly affected sibling. It was identified in another individual with sudden unexplained death in epilepsy, for which an autopsy did not identify any cardiac abnormalities (PMID: 27930701). This variant was also identified in an internal proband with thoracic aortic dissection and a systemic score >7 however, a pathogenic nonsense variant in FBN1 was also identified in this individual (BP2) and was considered to explain the phenotype . This variant has been identified in 0.0033% of individuals of South Asian origin in gnomAD v2.1.1. (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets the criteria to be classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BP2 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA015829/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:75722 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0852733 infores:hetionet NCBIGene:1482 biolink:causes MONDO:0007173 infores:monarchinitiative not_provided not_provided HGNC:2488 MONDO:0007173 uuid:4e2ee4a8-6f4d-411b-bc93-a394ac2a189d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0151836 infores:hetionet CHEBI:9570 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0003811 infores:hetionet CHEBI:38562 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0022354 infores:hetionet NCBIGene:3183 biolink:causes MONDO:0958203 infores:monarchinitiative not_provided not_provided HGNC:5035 MONDO:0958203 uuid:9c4850c3-e679-4e55-9bc4-89ac6dce5194 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes UMLS:C0749389 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0749389 infores:hetionet CHEBI:7478 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0038358 infores:hetionet NCBIGene:8573 biolink:causes MONDO:0010318 infores:monarchinitiative not_provided not_provided HGNC:1497 MONDO:0010318 uuid:e354dc1d-f7fc-43ad-aa26-72339859a004 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes UMLS:C0033844 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0033844 infores:hetionet CHEBI:75922 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C1096274 infores:hetionet CHEBI:10101 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0221170 infores:hetionet NCBIGene:5122 biolink:causes MONDO:0010961 infores:monarchinitiative not_provided not_provided HGNC:8743 MONDO:0010961 uuid:74747a34-814e-49b0-b82d-006db00c3c7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232462 infores:hetionet CHEBI:28864 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151578 infores:hetionet CAID:CA8603369 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603369 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 After a comprehensive literature search of the synonymous variant NM_000419.5(ITGA2B):c.690A>C (p.Pro230=), no individuals with Glanzmann thrombasthenia were reported with the variant. The variant has a minor allele frequency of 0.00002891 (1/34592 alleles) in the Latino population population in gnomAD, which meets the threshold criteria for PM2_supporting. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -0.982 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant is classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, BP4, BP7. (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603369/MONDO:0100326/011 2023-08-15 2023-09-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6950 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0947912 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0268948 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0268948 infores:hetionet CAID:CA400033923 biolink:causes MONDO:0100326 infores:clingen CAID:CA400033923 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.2147G>T (p.Gly716Val) missense has been identified in at least 1 proband, GT23 of PMID: 29675921 meeting the criteria for PP4_strong, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). GT23 of PMID: 29675921 is compound heterozygous for Gly716Val and Tyr660Ter (classified Pathogenic by the PD-VCEP; PM3_supporting). The computational predictor REVEL gives a score of 0.802, which predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting, PP3, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400033923/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5165 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085641 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0035078 infores:hetionet CHEBI:8768 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0438142 infores:hetionet CHEBI:53760 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011206 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0853785 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0853785 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0392386 infores:hetionet GO:2000025 biolink:causes GO:0048366 infores:ubergraph knowledge_assertion manual_agent GO:2000025 GO:0048366 CAID:CA337098169 biolink:causes MONDO:0044970 infores:clingen CAID:CA337098169 MONDO:0044970 PMID:32461654PMID:24104924PMID:25489354 Benign BA1, BP4 The m.9055G>A (p.A177T) variant in MT-ATP6 is a missense variant that reaches benign stand-alone criteria (BA1). The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%) and U8b (100%). Therefore, this meets this criterion (BA1). As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%) and K2 (99.7%). Additionally, the computational predictor APOGEE gives a consensus rating of neutral with an extremely low pathogenicity predictor score, 0.2 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. However, if this variant is identified in an individual who is a member of a different haplogroup than described above, consider further evaluation of this variant. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337098169/MONDO:0044970/014 2021-12-10 2022-01-05 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:57724 biolink:causes MONDO:0009452 infores:monarchinitiative not_provided not_provided HGNC:29331 MONDO:0009452 uuid:90384c0e-3483-4bd9-9caf-a8c5d2417328 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0029134 infores:hetionet CHEBI:32020 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0338656 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0023530 infores:hetionet CHEBI:28001 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0015230 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0007962 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0007962 uuid:546cad7c-b2e9-46cf-9afd-a010a9b071e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59445 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0015230 infores:hetionet CHEBI:7640 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0030252 infores:hetionet CHEBI:63599 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002962 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0023895 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0003123 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0021061 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0021061 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0349506 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0006444 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0178298 infores:hetionet CHEBI:24261 biolink:causes MONDO:0000757 infores:ubergraph knowledge_assertion manual_agent CHEBI:24261 MONDO:0000757 CHEBI:17549 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0020453 infores:hetionet CHEBI:28445 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0015230 infores:hetionet CHEBI:9086 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0424295 infores:hetionet CHEBI:3286 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0013390 infores:hetionet CHEBI:40303 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0009676 infores:hetionet CHEBI:9445 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0036974 infores:hetionet CHEBI:6367 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042024 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0037274 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0239375 infores:hetionet CHEBI:17347 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1519353 infores:hetionet CHEBI:6413 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0004604 infores:hetionet NCBIGene:3930 biolink:causes MONDO:0008974 infores:monarchinitiative not_provided not_provided HGNC:6518 MONDO:0008974 uuid:b9827276-9e86-4323-9702-b70d536f45d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151578 infores:hetionet CAID:CA404089836 biolink:causes MONDO:0007750 infores:clingen CAID:CA404089836 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PM5 The NM_000527.5 (LDLR): c.1817C>A (p.Ala606Asp) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: PopMax MAF = 0.00002637in European (non-Finnish) population in gnomAD (gnomAD v2.1.1).PP3 Met: REVEL = 0.756, which is above the threshold of 0.75.There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1816G>A (p.Ala606Thr), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404089836/MONDO:0007750/013 2022-02-10 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31625 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0547030 infores:hetionet CAID:CA409108715 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108715 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS4 The c.1033G>C variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of apartic acid to histidine at codon 345 (p.(Asp345His)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.908, which is greater than the MDEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.1033G>T p.(Asp345Tyr), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in two individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21105491, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID: 21105491). In summary, c.1033G>C meets the criteria to be classified as a likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108715/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151477 infores:hetionet CHEBI:17303 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0018524 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0033575 infores:hetionet CHEBI:9332 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027497 infores:hetionet CL:0001063 biolink:causes MONDO:0018874 infores:drugmechdb knowledge_assertion manual_agent CL:0001063 MESH:D015470 DB00352_MESH_D015470_1 CHEBI:50648 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0332563 infores:hetionet NCBIGene:4043 biolink:causes MONDO:0014183 infores:monarchinitiative not_provided not_provided HGNC:6701 MONDO:0014183 uuid:9ed3b83e-5931-4480-b9c5-0231f5f0e1ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:29968 biolink:causes MONDO:0012596 infores:monarchinitiative not_provided not_provided HGNC:19129 MONDO:0012596 uuid:3a441115-3142-490e-a584-fbc7c118052b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5103 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C1142412 infores:hetionet CAID:CA226843 biolink:causes MONDO:0010725 infores:clingen CAID:CA226843 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS3_Supporting, PP3_Strong PS4, PM1 NM_000330.4(RS1):c.655T>G (p.Cys219Gly) is a missense variant encoding the substitution of cysteine with glycine at amino acid 219. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 9618178, PMID: 15937075). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The computational predictor REVEL gives a score of 0.984, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. Exogenously expressed RS1 harboring the variant was subjected to gel filtration-based separation and PAGE analysis on a non‐reducing gel and exhibits defective oligomerization indicating no formation of octamers (PMID: 16361673, PS3_Supporting). This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). PM1_Strong is not met as this code is ineligible to be used in combination with PP3_Strong. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, and PS3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226843/MONDO:0010725/126 2025-10-04 2025-10-05 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports UNII:3U02EL437C biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0013609 infores:hetionet UMLS:C0010592 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151908 infores:hetionet CHEBI:119573 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013378 infores:hetionet CHEBI:72564 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0043094 infores:hetionet NCBIGene:1327 biolink:causes MONDO:0033651 infores:monarchinitiative not_provided not_provided HGNC:2265 MONDO:0033651 uuid:e684e268-2692-42ce-ac4a-95a085a62870 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013395 infores:hetionet CHEBI:27690 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C2242996 infores:hetionet CHEBI:3216 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0041657 infores:hetionet CHEBI:9328 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151799 infores:hetionet CHEBI:4856 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0035508 infores:hetionet CHEBI:31348 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1260880 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0030552 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0155169 infores:hetionet CAID:CA16613415 biolink:causes MONDO:0700270 infores:clingen CAID:CA16613415 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3, PP3 The c.6530A>C variant in ATM is a missense variant predicted to cause substitution of glutamine by proline at amino acid 2177 (p.Gln2177Pro). This variant is absent from gnomAD v2.1.1. This variant has been detected in 1 individual with Ataxia-Telangiectasia (PMID: 26896183). The computational predictor, Revel (Score: 0.883) predicts a damaging effect on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM2_supporting, PM3, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613415/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63616 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0027051 infores:hetionet CHEBI:119915 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C2363731 infores:hetionet CHEBI:7936 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020443 infores:hetionet CHEBI:8802 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C2830004 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0041912 infores:hetionet CHEBI:6541 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0027707 infores:hetionet CHEBI:6375 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030252 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0342592 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0342592 infores:hetionet CHEBI:3441 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0032343 infores:hetionet CHEBI:2788 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0022568 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0162830 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0027051 infores:hetionet CHEBI:8059 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C2973725 infores:hetionet GO:0010609 biolink:causes GO:0010608 infores:ubergraph knowledge_assertion manual_agent GO:0010609 GO:0010608 UMLS:C0011701 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0948594 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0002170 infores:hetionet CHEBI:3752 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1291077 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0232492 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020649 infores:hetionet CHEBI:6887 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C2830004 infores:hetionet CHEBI:8774 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0043094 infores:hetionet CHEBI:27882 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0000737 infores:hetionet CHEBI:27786 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0231218 infores:hetionet NCBIGene:8642 biolink:causes MONDO:0011915 infores:monarchinitiative not_provided not_provided HGNC:13681 MONDO:0011915 uuid:48830d74-c527-4bb6-85ad-1bc6689dcbe9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9332 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0687713 infores:hetionet CHEBI:77733 biolink:causes HP:0003750 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0242979 infores:hetionet CHEBI:9674 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0042963 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0687133 infores:hetionet CHEBI:9907 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0040264 infores:hetionet CHEBI:71940 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0042963 infores:hetionet CHEBI:6129 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0019521 infores:hetionet CHEBI:3387 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0040822 infores:hetionet CAID:CA010360 biolink:causes MONDO:0005045 infores:clingen CAID:CA010360 MONDO:0005045 PMID:7662452PMID:17612745PMID:8254035PMID:27532257 Pathogenic PP1_Strong, PM1, PM5, PM2, PP3, PS4 The c.1207C>T (p.Arg403Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy and segregated with disease in >20 affected family members (PS4 and PP1_Strong; PMID:1052196; PMID:7662452; PMID:7848420; PMID:8254035; PMID:8268932; PMID:12707239; PMID:12974739; PMID:15010274; PMID:15856146; PMID:17612745; PMID:20428263; PMID:21239446; PMID:26383716; Partners LMM ClinVar SCV000059358.5; AGCMC Sydney ClinVar SCV000212643.1; SHaRe consortium, PMID: 30297972). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1208G>A p.Arg403Gln - Variation ID 14087). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM1; PM2; PM5; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010360/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4903 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0002994 infores:hetionet CHEBI:45951 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0022346 infores:hetionet CHEBI:68478 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0016204 infores:hetionet CAID:CA410147404 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147404 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1313G>A (p.Gly438Asp) is a missense variant which has a REVEL score < 0.50 (0.282) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147404/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:4359 biolink:causes MONDO:0007307 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0007307 uuid:e937a198-817e-4ced-b9c3-b3f7fe61cd3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013491 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0027709 infores:hetionet CHEBI:68478 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0015967 infores:hetionet CHEBI:465284 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C3665386 infores:hetionet CHEBI:63580 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0086769 infores:hetionet CHEBI:28593 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0040822 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0585186 infores:hetionet CHEBI:4646 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0003811 infores:hetionet CHEBI:10650 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235660 infores:hetionet CHEBI:71223 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0003123 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0009806 infores:hetionet CAID:CA229863 biolink:causes MONDO:0009861 infores:clingen CAID:CA229863 MONDO:0009861 PMID:24401910PMID:14722928PMID:14722928 Pathogenic PP4_Moderate, PM3_Very Strong, PM2_Supporting, PS3_Supporting PP3, BA1, BS1, BS3 The NM_000277.1(PAH):c.940C>A (p.Pro314Thr) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 25% of wild-type PAH enzyme activity in a standard cDNA system and 19% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3_supporting). It has been reported in at least five PKU patients, including those with BH4 deficiency excluded and in trans with Pathogenic variants (PM3_VeryStrong (4.25 points); PP4_Moderate). It has been previously reported in a Taiwanese proband in trans with p.V399V (Pathogenic in ClinVar and per ClinGen PAH VCEP) with mild hyperphenylalanemia and BH4 deficiency excluded by urinary pterins, dihydropteridine reductase activity in erythrocytes, and sequencing of the genes in the BH4 cofactor metabolism pathway (PMID: 14722928). It has also been found in trans with p.V399V (Pathogenic in ClinVar and per ClinGen PAH VCEP) in a Chinese patient with classic PKU (plasma Phe 1230 umol/L) and BH4 deficiency excluded (PMID: 28982351). It has been noted in a Chinese patient with plasma Phe 184 umol/L and BH4 deficiency excluded in trans with a deletion of exons 1-3 (unclassified) (PMID: 29499199). It has been also noted in a Chinese patient with mild hyperphenylalanemia (plasma Phe 148 umol/L) in trans with the p.S70del (Pathogenic in ClinVar and per ClinGen PAH VCEP) variant and in trans with the p.R243Q (Pathogenic in ClinVar and per ClinGen PAH VCEP) variant in a patient with classic PKU (plasma Phe 1561 umol/L); BH4 deficiency was excluded in both cases (PMID: 30459323). Another missense variant at the same site, c.941C>A (p.P314H) is classified as Pathogenic/Likely Pathogenic in ClinVar (ID 102907) (PM5). Two heterozygotes and zero homozygotes for the variant are present in gnomAD, corresponding to a global frequency of 0.00000796 and a maximum population frequency of 0.000109 (South Asian), under the 0.0002 frequency cutoff for use of PM2 (PM2_supporting). The variant is predicted damaging by multiple in-silico predictors, including REVEL (REVEL score 0.867), but tolerated by SIFT; thus, PP3 is not met. Classification: PathogenicSupporting Criteria: PS3_supporting; PM3_VeryStrong; PM2_supporting; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229863/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10585053 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585053 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4_Supporting, PM1, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM3, PM6, PVS1, BS2, PP1 The NM_000527.5(LDLR):c.665G>T (p.Cys222Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PS3_Moderate, PP3, PP4, PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1: Variant meets PM2 and is missense in exon 4PM2: This variant is absent from gnomAD v 2.1.1.PS3_Moderate: PMID: 24671153 Heterologous cells, 30 % cell surface LDLR and internalizationPP3: REVEL is 0.971, which is greater than 0.75.PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH from PMID 24671153, after alternative causes of high cholesterol were excluded..PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases. 1 index case from PMID 11810272 who fulfilled unspecified clinical criteria for FH, and 1 index case from PMID 24671153 who fulfilled DLCN>6 criteria for FH. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585053/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:63629 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0392525 infores:hetionet CHEBI:8356 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018979 infores:hetionet CHEBI:4495 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0235660 infores:hetionet CAID:CA10652925 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652925 MONDO:0011071 PMID: Benign BA1 PS4, PS3, PS1, BP2, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*1720C>T variant in the 3' UTR has an MAF of 0.002298 (0.23%, 7/3046 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652925/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:18332 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C1443060 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020517 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0235416 infores:hetionet NCBIGene:118856 biolink:causes MONDO:0014762 infores:monarchinitiative not_provided not_provided HGNC:14357 MONDO:0014762 uuid:958f5ce1-188b-4330-99ff-15ea3443099d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0855775 infores:hetionet NCBIGene:5077 biolink:causes MONDO:0007862 infores:monarchinitiative not_provided not_provided HGNC:8617 MONDO:0007862 uuid:1c58e209-1e3e-4d37-9757-9f2ed6a4e6da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042075 infores:hetionet CHEBI:92712 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0013362 infores:hetionet CHEBI:116278 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0040822 infores:hetionet CHEBI:63791 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0026766 infores:hetionet CHEBI:8874 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0152030 infores:hetionet CHEBI:5384 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C2047937 infores:hetionet CHEBI:7492 biolink:causes UMLS:C0857493 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0857493 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0678222 infores:hetionet CHEBI:45924 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0233514 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0235851 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235851 infores:hetionet CHEBI:480999 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0311468 infores:hetionet CHEBI:45081 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0032231 infores:hetionet CHEBI:17823 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0005758 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015397 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0015397 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018799 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030517 infores:hetionet CAID:CA186229 biolink:causes MONDO:0007648 infores:clingen CAID:CA186229 MONDO:0007648 PMID:18427545PMID:15831593PMID:27995193PMID:15831593PMID:17545690PMID:21681551PMID:17221870PMID:18427545PMID:15831593PMID:18427545PMID:15831593PMID:27995193PMID:15831593PMID:17545690PMID:21681551PMID:17221870 Pathogenic PM2_Supporting, PS3, PS4, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PM6, BS2, PP3, PP2, PP4, PP1, BP4, BP1, BP3, BP2, BA1, PS1, PS2 The c.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 15831593, 17545690, 17221870, 21681551, 27995193). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA186229/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:5296 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0009319 infores:hetionet CAID:CA658658968 biolink:causes MONDO:0100437 infores:clingen CAID:CA658658968 MONDO:0100437 PMID:28714225 Pathogenic PVS1, PP4, PP1, PM2_Supporting PP3, PS1, PS3 NM_001034853.2(RPGR):c.1572+3A>T is a non-coding variant in intron 13 that is located outside the +/- 1,2 dinucleotide. The splicing impact predictor SpliceAI gives delta scores of 0.84 for donor gain and 0.60 for donor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. A minigene assay reveals variant-induced aberrant splicing from the minigene harboring the variant, with no wild-type transcripts produced (PMID: 28714225). These findings have not been applied to PP3 or PS3_Supporting, but rather combined as evidence of a null impact on RPGR (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) with less severe presentation in females (1 pt), early onset ((1 pt), poor vision (0.5 pts), night blindness (0.5 pt), visual field constriction (0.5 pts), and flat electroretinogram responses, with genotyping by next-generation sequencing identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (7.5 points, PMID: 28714225, PP4). The variant has been reported to segregate with retinal dystrophy through an affected mother and son (PP1; PMID: 28714225). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP4, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658968/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:10101 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085628 infores:hetionet CHEBI:3561 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151827 infores:hetionet CHEBI:44241 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0020649 infores:hetionet CHEBI:251408 biolink:causes MONDO:0001329 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0152196 infores:hetionet CHEBI:10102 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0392163 infores:hetionet CHEBI:50378 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0023518 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020437 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0027339 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0027765 infores:hetionet CHEBI:15940 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151786 infores:hetionet CHEBI:64064 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0035243 infores:hetionet CAID:CA10014594 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014594 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.98-21T>C is an intronic variant. This variant has a MAF of 0.0002794 (0.028%, 19/67998, 19 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This variant may impact splicing (Splice AI: Acceptor Loss Score = 0.35). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014594/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:44915 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0948594 infores:hetionet CHEBI:64312 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0008350 infores:hetionet CHEBI:6367 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014518 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151477 infores:hetionet GO:1905933 biolink:causes GO:0045165 infores:ubergraph knowledge_assertion manual_agent GO:1905933 GO:0045165 NCBITaxon:1773 biolink:causes MONDO:0018076 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1773 MONDO:0018076 CHEBI:47781 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0040822 infores:hetionet CHEBI:47519 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0241157 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0029882 infores:hetionet CHEBI:3419 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C1291078 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0595879 infores:hetionet CHEBI:6950 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0030554 infores:hetionet CHEBI:6456 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0025289 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018099 infores:hetionet CHEBI:8435 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0857305 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0023067 infores:hetionet CHEBI:9130 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0018790 infores:hetionet CHEBI:3723 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0010200 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0100310 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0238154 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0019147 infores:hetionet CHEBI:8874 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004604 infores:hetionet CHEBI:3614 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0035455 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0025290 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018799 infores:hetionet CHEBI:8707 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0917801 infores:hetionet CAID:CA007144 biolink:causes MONDO:0100316 infores:clingen CAID:CA007144 MONDO:0100316 PMID: Likely Benign BP5, BS1 BP4, BA1, BS3, PM2, PM1, PP3 NM_000218.3(KCNQ1):c.458C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 153 (p.Thr153Met). This variant has been observed in 1 patient with an alternate molecular basis for disease with a phenotype that is not sufficiently specific. The patient has a KCNH2 variant, p.Arg752Trp, that is P/LP in ClinVar. (BP5; PMID: 28794082). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0006396, with 48 alleles / 75052 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 (BS1). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BP5, BS1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007144/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3568 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018843 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0162429 infores:hetionet CHEBI:6375 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0043144 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018099 infores:hetionet CAID:CA2802184 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802184 MONDO:0001586 PMID:15300847 Likely Pathogenic PM3_Supporting, PP3_Moderate, PM1, PP4, PM2_Supporting, PS3_Moderate PM5 "The NM_000203.5:c.1087C>T variant in IDUA is predicted to result in the substitution of arginine by cysteine at amino acid 363 (p.Arg363Cys). This variant alters amino acid Arg363, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMIDs: 23959878, 24036510) (PM1). When the variant was expressed in CHO cells, no IDUA activity was detected, and synthesis and processing was abnormal (PMID: 15300847). The computational predictor REVEL gives a score of 0.845 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). Two patients with the variant have clinical symptoms consistent with MPS1 and one has ""undetectable"" IDUA activity (PMID: 15300847, 32781600). One of these patients is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP with unconfirmed phase, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 32781600). The other patient is compound heterozygous for the variant and c.1804T>A (p.Phe602Ile) (PMID: 15300847). The allelic data from this patient will be used in the classification of p.Phe602Ile and is not included here to avoid circular logic (PM3_Supporting). Another variant at the same amino acid position, c.1088G>A (p.Arg363His) has been identified in an individual with MPS 1 (PMID: 21734815). This variant has not yet been classified by the ClinGen LD VCEP. There is a Clinvar entry for this variant (Variation ID: 557205). In summary, this variant meet the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0): PM1, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802184/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:474180 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0009806 infores:hetionet CAID:CA397722868 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722868 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The c.419G>A (p.Gly140Glu) variant in ACADVL is a missense in exon 6. This variant has been described in one reportedly affected individual, but this individual does not meet our guidelines for consideration of phenotypic or genotypic data (PMID: 15210884). However, information provided to the ACADVL VCEP by an external clinical lab shows increased C14:1 level in a pattern consistent with very long chain acyl-CoA dehydrogenase (VLCAD) in at least two individuals (PP4_moderate). These individuals also had an additional likely pathogenic variant detected confirmed in trans (PM3). This variant is absent from gnomAD population database v2.1.1 (PM2_supporting), and the computational predictor REVEL gives a score of 0.96, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PM3, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). This variant was originally curated July 12, 2022 and the recurated classification was approved by the expert panel on April 11, 2023. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722868/MONDO:0008723/021 2023-04-11 2023-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16469 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014175 infores:hetionet CHEBI:68584 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C1760428 infores:hetionet CHEBI:520985 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0033774 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0009806 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034065 infores:hetionet CHEBI:8764 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0438142 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002418 infores:hetionet CHEBI:4024 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0259799 infores:hetionet CHEBI:52717 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0016382 infores:hetionet CHEBI:7773 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0003811 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002334 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0376545 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0013395 infores:hetionet CHEBI:42797 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0033774 infores:hetionet CHEBI:7823 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0018939 infores:hetionet CHEBI:8888 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0043144 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0040034 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0018839 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018839 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002871 infores:hetionet UNII:0RK7M7IABE biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0011991 infores:hetionet CAID:CA390866114 biolink:causes MONDO:0100216 infores:clingen CAID:CA390866114 MONDO:0100216 PMID: Uncertain Significance PM2, BP2, BP3, BP4, BA1, PM4, PM5, PM1, PS3, PS1, BS1, BS3 The NM_177438.2:c.5007T>G variant in DICER1 is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 1669 (p.Phe1669Leu). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00001543 (1/64,798 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.573, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390866114/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3314 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0020517 infores:hetionet CHEBI:3723 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085631 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023530 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0178298 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0227791 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018802 infores:hetionet CHEBI:18332 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C1112320 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0232462 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0011496 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0011496 uuid:9741bf41-c55e-4a7a-943c-9e54fa93c03a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2676 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0751494 infores:hetionet CHEBI:6375 biolink:causes MONDO:0008599 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0040997 infores:hetionet NCBIGene:9631 biolink:causes MONDO:0014340 infores:monarchinitiative not_provided not_provided HGNC:8063 MONDO:0014340 uuid:4463ca98-274f-42ab-b578-fb9e799227a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:1 biolink:causes MONDO:0005550 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1 MONDO:0005550 CAID:CA637749749 biolink:causes MONDO:0011071 infores:clingen CAID:CA637749749 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS2, PS4, PS3, BP1, BP2, BP3, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM1, PM5, PM4, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.58+12C>T is an intronic variant that is located at a nucleotide conserved according to an evolutionary conservation algorithm (PhyloP score = 2.23102 in GRCh38), so BP7 is not met. However, the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). The highest population minor allele frequency in gnomAD v4.1 is 0.00001099 (1/90,956 alleles) in the South Asian population, so BS1 is not met. This variant has not been reported in the literature. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637749749/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8499 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0242350 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0851341 infores:hetionet CAID:CA031958 biolink:causes MONDO:0007750 infores:clingen CAID:CA031958 MONDO:0007750 PMID: Uncertain Significance BP4 BP2, BA1, PS1, PS4, BS1, PM5, PM2, PP3, PP4 The NM_000527.5(LDLR):c.1080T>G (p.Asp360Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:BP4: REVEL = 0.404. it is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) not on limitsB) it creates a de novo AG, but de novo score is below 0.8. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031958/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:2811 biolink:causes MONDO:0007930 infores:monarchinitiative not_provided not_provided HGNC:4439 MONDO:0007930 uuid:e4430fab-9450-4b90-abc6-527e2b606b7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9241 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0026821 infores:hetionet CHEBI:4653 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0236075 infores:hetionet CHEBI:3403 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0043144 infores:hetionet CHEBI:16335 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0040264 infores:hetionet CHEBI:180905 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0013395 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0242656 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0392197 infores:hetionet CAID:CA414796661 biolink:causes MONDO:0044970 infores:clingen CAID:CA414796661 MONDO:0044970 PMID: Uncertain Significance PP3 PS2, PS4, PS3, PM6, PM2 The m.8553C>T (p.F9F in MT-ATP6; p.S63L in MT-ATP8) was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.023%, 14/61,883; gnomAD v3.1.2: 0.041%, 23/56,428 homoplasmic occurrences; Helix: 0.009%, 18/195,893 homoplasmic occurrences). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.7 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414796661/MONDO:0044970/015 2023-06-26 2025-06-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true UNII:3U02EL437C biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0702166 infores:hetionet CHEBI:3223 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0344232 infores:hetionet CHEBI:119486 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0038325 infores:hetionet CHEBI:2618 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0002792 infores:hetionet CHEBI:5134 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0220870 infores:hetionet GO:0048686 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:0048686 GO:0030182 CHEBI:8871 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011849 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0860433 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034065 infores:hetionet CHEBI:2675 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0030554 infores:hetionet CHEBI:17347 biolink:causes MONDO:0000945 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042485 infores:hetionet CHEBI:5613 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0427086 infores:hetionet CHEBI:31176 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0085593 infores:hetionet CHEBI:5778 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0917801 infores:hetionet CHEBI:5775 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0033687 infores:hetionet CHEBI:5280 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0016204 infores:hetionet CHEBI:15940 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0015732 infores:hetionet CHEBI:131512 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0015230 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235901 infores:hetionet CHEBI:29688 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0016382 infores:hetionet CHEBI:8774 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C3665347 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011849 infores:hetionet CHEBI:31644 biolink:causes UMLS:C1283048 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1283048 infores:hetionet CHEBI:46557 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0039070 infores:hetionet CHEBI:135939 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0011603 infores:hetionet CHEBI:4657 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0429097 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0856151 infores:hetionet CHEBI:92998 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020598 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0541941 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0033975 infores:hetionet NCBIGene:5148 biolink:causes MONDO:0013315 infores:monarchinitiative not_provided not_provided HGNC:8789 MONDO:0013315 uuid:5e11e0ca-1b1c-4b22-9304-17b39a37e160 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0851578 infores:hetionet CHEBI:45599 biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C2748540 infores:hetionet CHEBI:27899 biolink:causes HP:0005101 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0018780 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0149931 infores:hetionet CHEBI:6062 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004245 infores:hetionet CHEBI:7565 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085593 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0858603 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0858603 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0518015 infores:hetionet CAID:CA2573106102 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573106102 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PP1, PM2_Supporting The c.1319_1323dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 442 (NM_000162.5), adding 174 novel amino acids before encountering a stop codon (p.(Glu442SerfsTer174)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD (PM2_Supporting). This variant was identified in at least 2 individuals with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 2 informative meioses in 2 families with MODY (PP1; internal lab contributors). In summary, the c.1319_1323dup variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4_Moderate, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106102/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:4562 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0040822 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0541820 infores:hetionet CHEBI:45716 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0948089 infores:hetionet CHEBI:75045 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0232495 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0151773 infores:hetionet CAID:CA294856548 biolink:causes MONDO:0009290 infores:clingen CAID:CA294856548 MONDO:0009290 PMID:17723315PMID:24337590PMID:17723315PMID:24337590PMID:29149851 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.2269C>T (p.Gln757Ter), which results in a premature termination codon, is expected to undergo nonsense medicated decay resulting in absence of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. One patient meeting the ClinGen LSD VCEP’s specifications for PP4 and compound heterozygous for this variant and c.925G>A (p.Gly309Arg) in GAA has been reported (PMID 24337590). The phase of the variants was not confirmed. In trans data from this patient was used in the assessment of p.Gly309Arg and was not included here in order to avoid circular logic. Additional cases have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 17723315, 29149851). There is a ClinVar entry for this variant (Variation ID: 429727, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GSD Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294856548/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8499 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0034150 infores:hetionet CHEBI:3181 biolink:causes MONDO:0006966 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0030569 infores:hetionet CHEBI:68647 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0011603 infores:hetionet CHEBI:167309 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0027497 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0022660 infores:hetionet CHEBI:10125 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085932 infores:hetionet CHEBI:8080 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0013395 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0009450 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0019348 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027765 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0035258 infores:hetionet CHEBI:63618 biolink:causes UMLS:C1868980 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C1868980 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0042571 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0015376 infores:hetionet CHEBI:73274 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0017178 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0023895 infores:hetionet CHEBI:27436 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0032461 infores:hetionet NCBIGene:343641 biolink:causes MONDO:0013485 infores:monarchinitiative not_provided not_provided HGNC:16255 MONDO:0013485 uuid:8b6c0665-5b11-4453-8a6d-d053030ffaf5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5775 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0030446 infores:hetionet CHEBI:50729 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0015672 infores:hetionet NCBIGene:3708 biolink:causes MONDO:0007298 infores:monarchinitiative not_provided not_provided HGNC:6180 MONDO:0007298 uuid:54edd180-7ab9-4aee-93cf-fb6e47f9882a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151599 infores:hetionet CHEBI:10127 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0036974 infores:hetionet CHEBI:194135 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038325 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0085633 infores:hetionet CHEBI:66876 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0018808 infores:hetionet CHEBI:135876 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0151830 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020649 infores:hetionet CHEBI:94385 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0019080 infores:hetionet CHEBI:8871 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0237849 infores:hetionet CHEBI:10110 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1142520 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0033774 infores:hetionet CHEBI:205919 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0020456 infores:hetionet CHEBI:3403 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0235710 infores:hetionet CHEBI:3640 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0232462 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013395 infores:hetionet CHEBI:4653 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0027497 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0233632 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0033975 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0030922 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030922 infores:hetionet CHEBI:4046 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0085631 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0033975 infores:hetionet CHEBI:32315 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0232849 infores:hetionet CHEBI:6359 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0003123 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0006849 infores:hetionet NCBIGene:1861 biolink:causes MONDO:0007492 infores:monarchinitiative not_provided not_provided HGNC:3098 MONDO:0007492 uuid:a28c921b-e864-45b2-9942-f03861418039 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0518015 infores:hetionet CHEBI:31236 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151683 infores:hetionet CAID:CA2499226682 biolink:causes MONDO:0100437 infores:clingen CAID:CA2499226682 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.3212_3218del (p.Glu1071AlafsTer16) is a frameshift variant due to deletion of 7 nucleotides and introduces a premature stop codon after 16 amino acids in exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of cone-rod dystrophy with onset at age 48 years, electroretinogram showing cone involvement greater than rod (1 pt), bull’s eye appearance of the macula (1 pt), loss of visual acuity (0.5 pts), moderate myopia (0.5 pts), optic disc pallor (0.5 pts), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (PMID: 32012938, 4 points, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499226682/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:127342 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0156404 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0006826 infores:hetionet CHEBI:39867 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0018926 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0032461 infores:hetionet CHEBI:47519 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0600142 infores:hetionet CHEBI:46195 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0004144 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0232492 infores:hetionet CHEBI:100241 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042256 infores:hetionet CHEBI:46557 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0376358 infores:hetionet CL:0000084 biolink:causes GO:0002456 infores:ubergraph knowledge_assertion manual_agent CL:0000084 GO:0002456 CHEBI:100246 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151740 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018418 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0234547 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0234547 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C1142135 infores:hetionet UNII:UMD7G2653W biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151578 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0267792 infores:hetionet CHEBI:27690 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0009676 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151736 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0271650 infores:hetionet CHEBI:7936 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0031154 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0151763 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013595 infores:hetionet CHEBI:41977 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0013378 infores:hetionet CHEBI:7824 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0002994 infores:hetionet CHEBI:5001 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0687713 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0677500 infores:hetionet CHEBI:63611 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0040264 infores:hetionet CHEBI:4672 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0020580 infores:hetionet CHEBI:31547 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0595929 infores:hetionet CHEBI:45409 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0877192 infores:hetionet CHEBI:42355 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0232462 infores:hetionet CHEBI:8107 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085682 infores:hetionet CAID:CA400023344 biolink:causes MONDO:0100326 infores:clingen CAID:CA400023344 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP1, PP4 The c.614+1G>T variant on ITGB3 gene is a canonical splice donor variant that has been reported previously in the context of Glanzmann Thrombasthenia (PMID: 25728920). It is predicted to cause a disruption of the canonical donor splice site in intron 4, this is expected to cause a frameshift with premature stop at codon 122 (exon 5 of 15), therefore NMD would be expected. (PVS1). It is absent from all major population cohorts in gnomADv4.1 (PM2_supporting). This variant has been reported in homozygosity in two symptomatic siblings who meet diagnostic criteria for GT phenotype (PMID: 25728920). However, the siblings are homozygous for both c.614+1G>T and Arg228His and while this splice variant is Likely Pathogenic an impact of the missense variant can not be excluded so this case has not been considered in the classification of this variant. This variant meets GT-specific criteria for PVS1 and PM2_supporting and is therefore classified as Likely Pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400023344/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51209 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0030193 infores:hetionet NCBIGene:6337 biolink:causes MONDO:0029132 infores:monarchinitiative not_provided not_provided HGNC:10599 MONDO:0029132 uuid:5933f5d9-0d5e-4d6d-8a19-2a44c2fd9c32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4735 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0042963 infores:hetionet CAID:CA414899265 biolink:causes MONDO:0010602 infores:clingen CAID:CA414899265 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PVS1_Strong, PS4 The c.6429+2T>A variant causes in frame skipping of exon 22 resulting in a protein lacking 52 aa of the C2 domain (PMID: 15670040), which meets PVSS1_Strong criteria. This variant has been identified in at least 4 individuals with severe hemophilia A (PMID: 15670040, 19740093, 12195713) and is completely absent from gnomAD v2.1.1 and v3.1.1, which meets criteria for PS4_Strong and PM2_Supporting. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1_Strong, PS4, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414899265/MONDO:0010602/071 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:31859 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0001925 infores:hetionet CHEBI:45863 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0028081 infores:hetionet CHEBI:7640 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0040822 infores:hetionet CHEBI:4753 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0010709 infores:hetionet NCBIGene:126326 biolink:causes MONDO:0011160 infores:monarchinitiative not_provided not_provided HGNC:18183 MONDO:0011160 uuid:77dfada4-acdd-4d94-a368-2c388df3cc14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399806036 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806036 MONDO:0100326 PMID: Likely Pathogenic PM3, PP4_Strong, PP3, PM2_Supporting The ITGA2B missense variant NM_000419.5:c.416C>T replaces the alanine residue with a valine residue (p.Ala139Val). This variant is absent from population databases including gnomADv4.1.0 (PM2_supporting), but has been observed in homozygosity in two individuals suspected to have Glanzmann's thrombasthenia (GT) (Patient PF in PMID: 12083483; GT22 in PMID: 16463284) (PM3). At least one of these individuals (Patient PF in PMID: 12083483) has a phenotype specific for GT (PP4_strong); bleeding phenotype strongly indicative of Glanzmann's thrombasthenia; impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin; <10% expression of GPIIb/IIIa; direct sequencing of all coding regions and intron/exon boundaries of ITGA2B and ITGB3. The variant is predicted by in silico tools to be damaging to protein function (REVEL score 0.794; PP3). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3, PP3, PP4_strong. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806036/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:72690 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0267792 infores:hetionet CHEBI:53760 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0004134 infores:hetionet CHEBI:9086 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020461 infores:hetionet CHEBI:17347 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0030196 infores:hetionet CHEBI:3013 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0020621 infores:hetionet CHEBI:28830 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0029124 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0677500 infores:hetionet CHEBI:85083 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0162119 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0003469 infores:hetionet NCBIGene:6253 biolink:causes MONDO:0011489 infores:monarchinitiative not_provided not_provided HGNC:10468 MONDO:0011489 uuid:af43c99e-d0b8-44cb-8a78-c18fd8559330 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0423791 infores:hetionet NCBIGene:63910 biolink:causes MONDO:0014479 infores:monarchinitiative not_provided not_provided HGNC:16192 MONDO:0014479 uuid:37b9cdbe-ea6d-477c-84b6-9b4760b37e15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:T58MSI464G biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0023895 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0018801 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0233494 infores:hetionet CHEBI:3125 biolink:causes HP:0032545 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0159066 infores:hetionet CHEBI:8346 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0003811 infores:hetionet CAID:CA7177479 biolink:causes MONDO:0021060 infores:clingen CAID:CA7177479 MONDO:0021060 PMID: Uncertain Significance BA1, BP4 The c.674G>A (NM_006939.4(SOS2):c.674G>A (p.Arg225Gln)) variant in RIT1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 225. No ACMG/AMP evidence codes are met. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy (Version 2.1; 09/17/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7177479/MONDO:0021060/042 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA512232107 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232107 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1425C>T (p.Ala475=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.62)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232107/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:92923 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0036508 infores:hetionet CAID:CA355961718 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961718 MONDO:0001586 PMID: Pathogenic PP3_Moderate, PP4_Moderate, PM3_Very Strong, PM2_Supporting PS1, PM1, PM5 The NM_000203.4:c.536C>G variant in IDUA is a missense variant predicted to cause substitution of Threonine by Arginine at amino acid 179 (p.Thr179Arg). This variant has been reported in at least eight individuals with MPS I (PMID: 35433540, 21480867, 29095814, 34813777). This variant has been reported in at least eight individuals with MPS I (PMID: 35433540, 21480867, 29095814, 34813777): one is homozygous for this variant (PMID: 21480867, 0.5 points), six are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP including c.877G>A p.(Trp626Ter) (PMID: 35433540, phase confirmed, 1 point), c.236C>T p.(Ala79Val) (PMID: 21480867, 2 patients, phase unconfirmed, 2 x 0.5 points), c.1898C>T p.(Ser633Leu) (PMID: 21480867, 2 patients, phase unconfirmed, 2 x 0.5 points), c.1601C>A p.(Ser534Ter) (PMID: 34813777, phase not confirmed, 0.5 point). One additional patient had a clinical diagnosis and carried this variant but a second variant was not detected. 4 points (PM3_VeryStrong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of Hurler syndrome, presenting with delayed development, macrocephaly, congenital dermal melanocytosis, and hepatosplenomegaly; this patient also had reduced IDUA enzyme activity (0.1 nmol/h/mg, reference range 27.2-52) and increased excretion of urinary dermatan sulfate and heparan sulfate (PMID: 21480867) (PP4_moderate). The population minor allele frequency in gnomAD v4.1.0 is 8.5e-7 (1/1,179,952 alleles), which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.927 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>T p.(Thr179Met) (PMID: 32670797, ClinVar ID: 1455223), and p.Thr179Lys (PMID: 28752568, ClinVar ID: 1455223). The classification of c.536C>G (p.Thr179Arg) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 556358). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_very strong; PP3_moderate; PP4_moderate; PM2_supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961718/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94385 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C1145670 infores:hetionet CAID:CA10014283 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014283 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS4, PS3, PS1, BP2, BA1, PVS1, PM6, PM2, BS4, BS3, BS1, PM1, PM5, PM4, PP1, PP3 This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -2.38 < 0.1 [-14.1;6.4]) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014283/MONDO:0011071/008 2020-04-10 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51860 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0015397 infores:hetionet CAID:CA397723589 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723589 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.746G>A (p.Trp249Ter) NM_000018.3 variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723589/MONDO:0008723/021 2024-05-14 2024-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44915 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151827 infores:hetionet CHEBI:7478 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151825 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0020517 infores:hetionet CHEBI:3380 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030920 infores:hetionet CAID:CA148292 biolink:causes MONDO:0010726 infores:clingen CAID:CA148292 MONDO:0010726 PMID: Benign BS2, BA1 The allele frequency of the c.1126C>T, p.(Pro376Ser) variant in MECP2(NM_004992.4) is 0.13% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.(Pro376Ser) variant is observed in at least 2 unaffected individuals (PMID 10944854, PMID 14560307, RettBASE) (BS1). In summary, the p.(Pro376Ser) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA148292/MONDO:0010726/016 2022-04-28 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UMLS:C0010592 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0002994 infores:hetionet CAID:CA340742354 biolink:causes MONDO:0100368 infores:clingen CAID:CA340742354 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP4_Moderate, PVS1, PP1, PM2_Supporting PS3, PP3 NM_000329.3(RPE65):c.1338G>T is a missense variant that substitutes arginine with serine at position 446. The variant is found in multiple probands affected with early-onset severe retinal dystrophy. At least one patient genotyped by whole exome sequencing (2 pts) has a diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), and flat rod (0.5 pts) and cone (1 pt) ERG responses, which together are highly specific for RPE65-related recessive retinopathy (9.5 pts, PMID: 30870047, PP4_Moderate). At least 3 reported probands harbor the variant in the homozygous state, while an additional proband harbors this maternal variant in compound heterozygosity with a paternal c.361dup (p.Ser121Phefs*10 variant (previously classified pathogenic by the ClinGen LCA/eoRD VCEP)(PMID: 30870047, PM3_Strong). Three pairs of siblings have been reported (PMID: 30870047) harboring the variant in either the homozygous or compound heterozygous state (PP1). This variant has a Grpmax Filtering AF of 0.000009610 (2/34488, with no homozygotes) in the Latino/Admixed American population in gnomAD v2.1.1 which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002. Although the meta-predictor REVEL gives a score of 0.571, which is below the ClinGen LCA/eoRD VCEP PP3 threshold of >0.7, the computational splicing predictor SpliceAI indicates that the variant triggers the loss of a splice donor site, with a change score of 0.45. The variant was confirmed to exhibit a complete splicing defect in two minigene assays relative to the wild-type control, showing skipping of the 95-bp exon 12, indicating that it triggers nonsense-mediated decay (PMID: 30996589, PMID: 28714225, PVS1). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3_Strong, PP1, PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340742354/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1140680 infores:hetionet CHEBI:391960 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C1306341 infores:hetionet CHEBI:44915 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0040053 infores:hetionet CHEBI:59773 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0151827 infores:hetionet CHEBI:2675 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C1320835 infores:hetionet CHEBI:8707 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042963 infores:hetionet CHEBI:4885 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0038362 infores:hetionet CHEBI:50173 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151578 infores:hetionet CHEBI:31236 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085623 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0080233 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0080233 infores:hetionet CHEBI:3125 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0021053 infores:hetionet CHEBI:8093 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0013378 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0015397 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0015397 infores:hetionet CAID:CA157914367 biolink:causes MONDO:0015967 infores:clingen CAID:CA157914367 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting The c.1017G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to aspartic acid at codon 339 (p.(Glu339Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.845, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1016A>G p.Glu339Gly, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Glu339Asp (PM5_Supporting). In summary, c.1017G>C meets the criteria to be classified as a variant of uncertain significance] for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA157914367/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA013197 biolink:causes MONDO:0004994 infores:clingen CAID:CA013197 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.2907C>T (p.His969=) variant in the MYH7 gene is 0.15% (23/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013197/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5864 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0018790 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0038358 infores:hetionet CHEBI:175901 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151825 infores:hetionet CHEBI:6792 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0085593 infores:hetionet CHEBI:7465 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0043352 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0243026 infores:hetionet CHEBI:6822 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0392525 infores:hetionet CHEBI:31859 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018524 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0011630 infores:hetionet CAID:CA122864 biolink:causes MONDO:0000573 infores:clingen CAID:CA122864 MONDO:0000573 PMID: Benign BA1, BS2_Supporting "The c.644C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 215 (p.Thr215Ile).The filtering allele frequency (the lower threshold of the 95% CI of 2177/91084 alleles) of the c.644C>T variant in RAG2 is 0.02308 for South Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 42 homozygous individuals have been described (40 and 2 individuals in South Asian and ""Remaining"" populations, respectively (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0)." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA122864/MONDO:0000573/124 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true UNII:15G12L5X8K biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020625 infores:hetionet GO:0009937 biolink:causes GO:0071370 infores:ubergraph knowledge_assertion manual_agent GO:0009937 GO:0071370 CHEBI:2453 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C1443060 infores:hetionet CHEBI:71255 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0006384 infores:hetionet CHEBI:2659 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0039231 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0035309 infores:hetionet CHEBI:32192 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0013404 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0026946 infores:hetionet CHEBI:142290 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0151825 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011570 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0853692 infores:hetionet CHEBI:9445 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C2830004 infores:hetionet CHEBI:3219 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085595 infores:hetionet NCBITaxon:31285 biolink:causes MONDO:0021932 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:31285 MONDO:0021932 CHEBI:10650 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0392197 infores:hetionet CHEBI:135876 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0022107 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020557 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0162287 infores:hetionet CHEBI:408174 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0003873 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0027051 infores:hetionet CAID:CA267677 biolink:causes MONDO:0009861 infores:clingen CAID:CA267677 MONDO:0009861 PMID:10598814PMID:26666653PMID:10598814PMID:26666653 Pathogenic PM3, PVS1, PM2, PP4 The c.837del frameshift variant has been identified in at least 2 probands with classic PKU, BH4 deficiency not excluded (PMIDs: 10598814, 26666653). It has been detected in trans with pathogenic variants V388M (PMID: 10598814) and c.1315+1G>A (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. C.837delC generates a frameshift predicted to result in a premature stop codon 61 residues downstream in exon 10 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267677/MONDO:0009861/006 2019-07-14 2019-07-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0002871 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0005940 infores:hetionet CHEBI:84500 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0547030 infores:hetionet CHEBI:145499 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0002878 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013395 infores:hetionet CHEBI:8665 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C1963818 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028866 infores:hetionet CHEBI:520985 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0036454 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0017152 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0027651 infores:hetionet CHEBI:63607 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0268000 infores:hetionet CHEBI:9352 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0013404 infores:hetionet CHEBI:119915 biolink:causes HP:0002781 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0740852 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0018801 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0018099 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0020517 infores:hetionet CHEBI:3172 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0039070 infores:hetionet CHEBI:52717 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042029 infores:hetionet CHEBI:50663 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0030193 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0013395 infores:hetionet CHEBI:40303 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0028866 infores:hetionet GO:1905207 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1905207 GO:0072359 CHEBI:135361 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0020517 infores:hetionet CHEBI:119915 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151603 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040213 infores:hetionet CHEBI:8430 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0162297 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030332 infores:hetionet CAID:CA386959939 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959939 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PM1, PP4_Moderate, PP3 The c.427C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to tyrosine at codon 143 (p.(His143Tyr)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 10102714​, PMID: 9075819, PMID: 15928245, internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with at least 8 informative meioses in one family with MODY (PP1_Strong; PMID 10102714/internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PP1_Strong, PP4_moderate, PM1, PS4_moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959939/MONDO:0015967/017 2021-08-24 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28001 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0040034 infores:hetionet CHEBI:8107 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0016059 infores:hetionet CHEBI:3640 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C1368065 infores:hetionet CHEBI:5280 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0162285 infores:hetionet CHEBI:4710 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0003467 infores:hetionet CAID:CA024575 biolink:causes MONDO:0007783 infores:clingen CAID:CA024575 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP1_Moderate PP3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with glutamic acid at codon 2129 of the RYR1 protein, p.Asp2129Glu. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:12059893, PMID:24433488). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 6 individuals, PP1_Moderate (PMID:12059893, PMID:11241852). A REVEL score of 0.683 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP1_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024575/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63620 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013404 infores:hetionet CHEBI:61033 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0085649 infores:hetionet CHEBI:367163 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0032617 infores:hetionet CHEBI:6958 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0002792 infores:hetionet CHEBI:7640 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0022107 infores:hetionet CHEBI:9168 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027497 infores:hetionet CHEBI:31624 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0042963 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233632 infores:hetionet CHEBI:127342 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0085605 infores:hetionet CHEBI:8665 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0015230 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0235431 infores:hetionet NCBIGene:51196 biolink:causes MONDO:0012546 infores:monarchinitiative not_provided not_provided HGNC:17175 MONDO:0012546 uuid:ffb19da3-3ad2-46fe-af78-481f48cd9444 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4530 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0042109 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0475765 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0475765 infores:hetionet CHEBI:5165 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0042024 infores:hetionet CHEBI:7465 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0028081 infores:hetionet CHEBI:39867 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0032617 infores:hetionet CHEBI:68558 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0013491 infores:hetionet GO:1900123 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:1900123 GO:0007154 CHEBI:2950 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0009806 infores:hetionet CHEBI:5098 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0231528 infores:hetionet NCBIGene:3912 biolink:causes MONDO:0014077 infores:monarchinitiative not_provided not_provided HGNC:6486 MONDO:0014077 uuid:3caea5e9-7187-44d6-8ccf-9f8b3e1142b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C1368065 infores:hetionet CHEBI:27974 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0011603 infores:hetionet CHEBI:73274 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0015230 infores:hetionet CAID:CA626224378 biolink:causes MONDO:0100326 infores:clingen CAID:CA626224378 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The c.224del (p.Gly75AlafsTer36) variant in exon 2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1 is 0.00001677 (1/59616 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant has not been reported in patients with GT in the literature, to the best of our knowledge. A homozygous GT case has been reported from internal data (PM3_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting, PM3_supporting. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626224378/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ GO:1904882 biolink:causes GO:0022613 infores:ubergraph knowledge_assertion manual_agent GO:1904882 GO:0022613 CHEBI:15544 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0033575 infores:hetionet CHEBI:50922 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085612 infores:hetionet CHEBI:100241 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232849 infores:hetionet CHEBI:46557 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0037011 infores:hetionet CHEBI:5123 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0007398 infores:hetionet CHEBI:7581 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0234518 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0013395 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004690 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151625 infores:hetionet CHEBI:3380 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0005758 infores:hetionet CHEBI:39867 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151827 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042373 infores:hetionet CHEBI:45409 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0549249 infores:hetionet CHEBI:3699 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0085610 infores:hetionet CHEBI:63607 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0032617 infores:hetionet CHEBI:28748 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0086565 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0543467 infores:hetionet CAID:CA229719 biolink:causes MONDO:0009861 infores:clingen CAID:CA229719 MONDO:0009861 PMID:12655553 Likely Pathogenic PM2, PM5, PP3, PP4, PM3_Supporting The c.728G>T (p.Arg243Leu) variant in PAH has been reported in 1 individual with PKU detected with pathogenic variant p.R261Q (P 9 submitters) PMID: 12655553, 20217238. This variant is absent in population databases. Computational evidence supports a deleterious effect. Another missense change at the same amino acid,p .Arg243Gln, is pathogenic in ClinVar by multiple submitters (variation ID 591). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229719/MONDO:0009861/006 2021-02-14 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71255 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0267792 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0022660 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0242350 infores:hetionet CHEBI:72296 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151662 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233494 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015469 infores:hetionet CHEBI:61390 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0012833 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0235832 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235832 infores:hetionet CAID:CA390865421 biolink:causes MONDO:0100216 infores:clingen CAID:CA390865421 MONDO:0100216 PMID: Pathogenic PP3, PM2_Supporting, PS4_Supporting, PM1, PS2, PS3_Supporting BA1, BP4, BS2, PP4, PM5, BS1, BS3 The NM_177438.2:c.5113G>A variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 1705 (p.Glu1705Lys). This variant has been identified as a de novo occurrence with constitutional mosaicism in one individual with pleuropulmonary blastoma type I and cystic nephroma (PS2; PS4_supporting; 26925222). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assays performed in different cell lines have demonstrated that this variant fails to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; 22187960, 23132766, 28862265). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.925) (PP3). This variant resides in the p.E1705 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1; PMID: 31342592). In summary, this variant meets the criteria to be classified as Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS2, PM2_Supporting, PS4_supporting, PS3_Supporting, PP3, PM1. (Bayesian Points: 10; VCEP specifications version 1.2.0; 01/09/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390865421/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2569 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0003578 infores:hetionet CHEBI:8764 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0041296 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0009450 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0021053 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151752 infores:hetionet CHEBI:3423 biolink:causes MONDO:0043327 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0023182 infores:hetionet NCBIGene:7783 biolink:causes MONDO:0032696 infores:monarchinitiative not_provided not_provided HGNC:13188 MONDO:0032696 uuid:cafdbf09-e690-40ff-b294-4084a598c97a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235660 infores:hetionet CHEBI:4735 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0004093 infores:hetionet CHEBI:31236 biolink:causes HP:0034805 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0231710 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018799 infores:hetionet CHEBI:46345 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0162820 infores:hetionet CHEBI:5098 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0857305 infores:hetionet CHEBI:6539 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0085612 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0020457 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020457 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0029408 infores:hetionet CHEBI:63791 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0851578 infores:hetionet CHEBI:8455 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0010200 infores:hetionet CHEBI:7444 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0030193 infores:hetionet UMLS:C0120107 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0041834 infores:hetionet CHEBI:8028 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0341047 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020456 infores:hetionet CHEBI:36704 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042029 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0221742 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0016034 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0034530 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0025061 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020538 infores:hetionet CHEBI:3696 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002792 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042267 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0004936 infores:hetionet CHEBI:45863 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0231528 infores:hetionet CHEBI:5118 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020598 infores:hetionet CHEBI:5050 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0027497 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017152 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1167965 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0243026 infores:hetionet CHEBI:4562 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0018681 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235639 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0007642 infores:hetionet CAID:CA2637031 biolink:causes MONDO:0021060 infores:clingen CAID:CA2637031 MONDO:0021060 PMID: Benign BA1 The c.453G>A (p.Pro151=) variant in MRAS is a synonymous variant at position 151. This variant has a filtering allele frequency of 1.748% in the South Asian population in gnomAD v2, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1 (RASopathy VCEP specifications version 1.4; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2637031/MONDO:0021060/087 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7494 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0030252 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0018799 infores:hetionet CHEBI:6413 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0024902 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0013595 infores:hetionet CHEBI:27565 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0022346 infores:hetionet CHEBI:7915 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0037036 infores:hetionet CHEBI:45979 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0033774 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0014868 infores:hetionet CHEBI:31859 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0162830 infores:hetionet NCBIGene:55112 biolink:causes MONDO:0014214 infores:monarchinitiative not_provided not_provided HGNC:21862 MONDO:0014214 uuid:428ae327-85a2-45f4-8560-71c1b86cfa91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84050 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0000737 infores:hetionet CHEBI:6801 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0027424 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1262144 infores:hetionet CL:0000059 biolink:causes MONDO:0006079 infores:ubergraph knowledge_assertion manual_agent CL:0000059 MONDO:0006079 NCBIGene:5290 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0008903 uuid:247e077f-35ef-4c47-ba14-dc29543d3741 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5165 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0037036 infores:hetionet CHEBI:171719 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0085636 infores:hetionet CHEBI:8863 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0032227 infores:hetionet CHEBI:5790 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020672 infores:hetionet CHEBI:68575 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0349790 infores:hetionet CHEBI:31980 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0017178 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0221706 infores:hetionet CHEBI:78543 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0042029 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085584 infores:hetionet CHEBI:2704 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0235378 infores:hetionet CHEBI:4653 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0039231 infores:hetionet CHEBI:4672 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0036974 infores:hetionet NCBIGene:1000 biolink:causes MONDO:0030065 infores:monarchinitiative not_provided not_provided HGNC:1759 MONDO:0030065 uuid:c32c7ec1-afeb-45e2-bf06-776e49b3154c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0042029 infores:hetionet CAID:CA16608675 biolink:causes MONDO:0009290 infores:clingen CAID:CA16608675 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong The NM_000152.5:c.1478C>T variant in GAA is predicted to result in the substitution of proline by leucine at amino acid 493 (p.Pro493Leu). At least 7 probands have been reported with this variant, including one adult and an affected sibling with documented values showing GAA activity below the normal range on dried blood spot assay, and treated with enzyme replacement therapy (ERT) (PMID 24495340), and another four individuals with features consistent with Pompe disease, three of them on enzyme replacement therapy (PMID: 25455803, 29181627, 31545528, 33188503). Furthermore, three individuals with the same genotype (thought to be unrelated but cannot be confirmed) were identified in a clinical diagnostic laboratory with GAA activity below the normal range on dried blood spot (PP4_Moderate). Two additional patients have been reported with P493L, but the cDNA change was not provided and, one patient was heterozygous without the identification of a second variant, therefore, this data will not be included (PMID: 20033296, 23160972, 31545528), and patient with suspected late onset Pompe disease was identified by newborn screening but was asymptomatic (PMID: 33202836). The 7 probands are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. The phase is unconfirmed in all of these patients. The second variant is either c.525delT (PMID: 25455803, and 3 presumably unrelated patients identified by a clinical diagnostic laboratory, max 2 patients counted, ClinVar Variation ID: 4033, SCV001443331.1; 2 x 0.5 points), c.1134C>G (p.Tyr378Ter), phase unknown (PMID: 29181627, ClinVar Variation ID: 595469, SCV001443283.2, 0.5 points), c.307T>G (p.Cys103Gly) (PMID: 24495340, ClinVar Variation ID: 92483, SCV002817442.1, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1, 0.5 points), c.1655T>C (p.Leu552Pro) (PMID: 31545528, ClinVar Variation ID: 279811, SCV001371750.2) or c.-32-13T>G (PMID: 33188503, ClinVar Variation ID: 4027). 7 x 0.5 points = 3.5 points (PM3_Strong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003 (4/128962 alleles) in the European non-Finnish population, and in gnomAD v4.1. the MAF is 0.00001695 (20/1180038) in the European non-Finnish population. Both are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.911 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, results of functional studies are not available for this variant. There is a ClinVar entry for this variant (Variation ID 379593). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 21, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608675/MONDO:0009290/010 2024-07-21 2024-09-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4710 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0015371 infores:hetionet CAID:CA8814966 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814966 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong The NM_000152.5:c.692+5G>T variant in GAA is located in intron 3 and is predicted to disrupt the 5' donor splice site of the intron. At least 6 individuals have been reported with this variant and late-onset Pompe disease, including individuals with documented GAA enzyme deficiency and symptoms consistent with LOPD and receiving enzyme replacement therapy (PMIDs: 24384324, 26873529,27408821,29181627, 30155607). At least three individuals with confirmed Pompe disease are compound heterozygous for this variant and a second pathogenic variant (phase unconfirmed) including c.1076-22T>G (PMID: 27408821 ), c.953T>C (PMIDs: 3015560 and 29181627), and c.482_483del (PMID: 26873529) (PM3_strong). One individual with LOPD was reported to have this variant and c.1211A>G, classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP; however, points were not given for PP4 or PM3 to avoid circular logic as data from this publication were used to support the classification of c.1211A>G (PMID: 2438432). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001195 (14/1171164 alleles) in the European non-Finnish population which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.54 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 of GAA (PP3). There is a ClinVar entry for this variant (Variation ID: 526532 , 2-star review status) with 4 submitters classifying the variant as pathogenic (n=2) or likely pathogenic (n=2). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0.0): PP4_moderate, PM3_strong, PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814966/MONDO:0009290/010 2025-04-15 2025-05-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7824 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0026827 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013395 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0023895 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011053 infores:hetionet CHEBI:6073 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0013144 infores:hetionet GO:0060860 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060860 GO:0007275 UMLS:C0879264 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0022658 infores:hetionet CHEBI:9667 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0041582 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0232492 infores:hetionet CHEBI:31622 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0851578 infores:hetionet CHEBI:9434 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0004604 infores:hetionet CAID:CA10603467 biolink:causes MONDO:0021060 infores:clingen CAID:CA10603467 MONDO:0021060 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PS2 PM5, PM1 The c.323G>T variant in MAP2K1 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 108 (p.Arg108Leu, NM_002755.4). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.831, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to MAP2K1 function (PP3). MAP2K1, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 3 probands with features of RASopathy (PS4_supporting; 2.5 pts.; PMID: 35524774, Fulgent Genetics & Baylor College of Medicine internal data (SCV000894927 & SCV005871135, respectively)). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with features of RASopathy (PS2; 3.0 pts.; Fulgent Genetics & Baylor College of Medicine internal data (SCV000894927 & SCV005871135, respectively)). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy, based on the ACMG/AMP Criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_supporting, PP3, PP2, PS4_supporting, PS2; Specifications Version 2.3.0). This variant was originally evaluated by the VCEP as pathogenic on 06/25/2020. It was re-evaluated on 07/08/2025 and downgraded to likely pathogenic, despite one new case of genetic evidence (PMID: 35524774). The change in classification was due to changes in guidelines (downgrading PM2 to PM2_supporting and combining PS2 & PM6). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603467/MONDO:0021060/045 2025-07-08 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:29688 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0038363 infores:hetionet NCBIGene:87178 biolink:causes MONDO:0013977 infores:monarchinitiative not_provided not_provided HGNC:23166 MONDO:0013977 uuid:e43f466b-d25c-408a-8028-f3ca75c94dca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64310 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0547030 infores:hetionet NCBIGene:2022 biolink:causes MONDO:0008535 infores:monarchinitiative not_provided not_provided HGNC:3349 MONDO:0008535 uuid:c5841abf-b8d2-4454-956e-8ea152c49d31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0085612 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0012739 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0025061 infores:hetionet UMLS:C0011701 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0028084 infores:hetionet NCBIGene:3798 biolink:causes MONDO:0014979 infores:monarchinitiative not_provided not_provided HGNC:6323 MONDO:0014979 uuid:b5e7e35f-ce28-4636-9f7c-b67bff6b78c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3814 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C2830004 infores:hetionet CHEBI:63631 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233407 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0003864 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0026946 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0085682 infores:hetionet CHEBI:77260 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0404521 infores:hetionet CHEBI:107736 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0427086 infores:hetionet CHEBI:9130 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0340865 infores:hetionet NCBIGene:4976 biolink:causes MONDO:0014820 infores:monarchinitiative not_provided not_provided HGNC:8140 MONDO:0014820 uuid:6447b555-1153-4383-823a-a59e5f6727df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29688 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0019158 infores:hetionet CHEBI:253342 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0019080 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0021053 infores:hetionet CHEBI:100246 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0040264 infores:hetionet CHEBI:2666 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C2225524 infores:hetionet CAID:CA915940767 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940767 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.2555del (p.Gln852ArgfsTer58) frameshift variant leading to a premature stop codon in biologically-relevant-exon 26/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one homozygous (PM3_supporting) patient (Patient VA in PMID:12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 2.8% of normal, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 01/18/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940767/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:6324 biolink:causes MONDO:0033361 infores:monarchinitiative not_provided not_provided HGNC:10586 MONDO:0033361 uuid:661cbb06-8ec8-437a-b0ca-5a3338c0c095 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27300 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0234238 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0234215 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0015230 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0040034 infores:hetionet NCBIGene:122622 biolink:causes MONDO:0014877 infores:monarchinitiative not_provided not_provided HGNC:20093 MONDO:0014877 uuid:841ea4fd-8218-44fc-bde5-9464e177de6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94501 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0178298 infores:hetionet CHEBI:5138 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002792 infores:hetionet CAID:CA902362 biolink:causes MONDO:0100368 infores:clingen CAID:CA902362 MONDO:0100368 PMID: Uncertain Significance BP4, PM2_Supporting BP7 NM_000329.3(RPE65):c.859-11C>T is a non-coding variant located in intron 8. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001046, with 149 alleles / 1461652 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting and BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902362/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2904 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0236075 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0019158 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009450 infores:hetionet CHEBI:4907 biolink:causes HP:0011986 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0029396 infores:hetionet CHEBI:6541 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011124 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002871 infores:hetionet CHEBI:63791 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151905 infores:hetionet CHEBI:52010 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0043144 infores:hetionet CHEBI:85078 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0016655 infores:hetionet CHEBI:6078 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0009806 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018939 infores:hetionet CHEBI:3387 biolink:causes HP:0001923 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0206160 infores:hetionet CHEBI:6846 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0011603 infores:hetionet CHEBI:6715 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C2047937 infores:hetionet CHEBI:3761 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C1443060 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0855242 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0040409 infores:hetionet CHEBI:44915 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0026827 infores:hetionet CHEBI:4551 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0086168 infores:hetionet CHEBI:134990 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0001807 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0004936 infores:hetionet UMLS:C0004609 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0031256 infores:hetionet CHEBI:127780 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085932 infores:hetionet NCBITaxon:630 biolink:causes MONDO:0042370 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:630 MONDO:0042370 CHEBI:3647 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0085688 infores:hetionet CHEBI:64321 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0038362 infores:hetionet CHEBI:72564 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0012569 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0429028 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0429028 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042075 infores:hetionet CHEBI:3011 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0231528 infores:hetionet CHEBI:85161 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0014591 infores:hetionet CAID:CA208886 biolink:causes MONDO:0010726 infores:clingen CAID:CA208886 MONDO:0010726 PMID: Likely Benign BP5, BS2 BS1, PS4 The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.007% in the Latino/Admixed American sub population including 2 hemizygous males (not sufficient for BS1). The p.Val481Met variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Val481Met variant has been observed in 1 individual with a Rett like disorder (PMID 22277191) and 1 individual with nonspecific neurological phenotypes (PMID 29655203) (Not sufficient for PS4_supporting). In summary, the p.Val481Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208886/MONDO:0010726/016 2022-02-18 2022-06-30 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:92511 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0043352 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0234953 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0234953 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0018801 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0233414 infores:hetionet CHEBI:68606 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0027497 infores:hetionet CAID:CA013536 biolink:causes MONDO:0004994 infores:clingen CAID:CA013536 MONDO:0004994 PMID: Benign BA1, BP7 The filtering allele frequency of the c.327C>T (p.Tyr109=) silent variant in the MYH7 gene is 0.13% (31/16512) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1, BP7; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013536/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:83804 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0016204 infores:hetionet CHEBI:10650 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0162529 infores:hetionet CAID:CA135582 biolink:causes MONDO:0021060 infores:clingen CAID:CA135582 MONDO:0021060 PMID: Benign BA1, BP4, BP7 PP3, BS1, PM2 The c.519T>C variant in the KRAS gene is a synonymous (silent) variant (p.Asp173=) at a nucleotide that is not conserved as shown by UCSC browser, and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v2.1.1 is 0.2201 (28382/128282 alleles with 3073 homozygotes) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP7 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135582/MONDO:0021060/044 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63631 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0043352 infores:hetionet CHEBI:45951 biolink:causes HP:0002362 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0231688 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0687133 infores:hetionet CHEBI:64355 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0028734 infores:hetionet CHEBI:50275 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0012569 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0027769 infores:hetionet CAID:CA229350 biolink:causes MONDO:0009861 infores:clingen CAID:CA229350 MONDO:0009861 PMID:8807319PMID:21147011PMID:8807319PMID:21147011 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PM5, PP3 The c.1114A>T (p.Thr372Ser) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8807319, 21147011, 30050108). This variant has an extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with multiple pathogenic/likely pathogenic variants: p.R408W, c.1066-11G>A (PMID: 21147011); p.A300S (PMID: 8807319); p.P281L (2 patients, LP), delF39 (PMID: 10947211). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229350/MONDO:0009861/006 2020-08-14 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:78543 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0015397 infores:hetionet CHEBI:63617 biolink:causes HP:0003149 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0948643 infores:hetionet CHEBI:40279 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0497156 infores:hetionet CHEBI:100246 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151579 infores:hetionet GO:1904133 biolink:causes GO:0030902 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0030902 CHEBI:5856 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0036974 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0919823 infores:hetionet CHEBI:567361 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1306577 infores:hetionet CHEBI:2788 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0021368 infores:hetionet CHEBI:39867 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0032227 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0162830 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0151834 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151834 infores:hetionet CHEBI:51860 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C3248383 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013922 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0042373 infores:hetionet CHEBI:6888 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0235325 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042571 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0017160 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0178298 infores:hetionet GO:1903587 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0007275 CHEBI:50729 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0002170 infores:hetionet CHEBI:2948 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0018681 infores:hetionet CHEBI:3215 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1258215 infores:hetionet CAID:CA8130235 biolink:causes MONDO:0007648 infores:clingen CAID:CA8130235 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP3, PP2, PP4, PP1, BS2, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is present in <1/100,000 alleles in the ExAC and gnomAD cohort (PM2_Supporting). Furthermore, it has been observed in > 10 individuals (34) without DGC, SRC tumours or LBC and whose families do not suggest HDGC. This variant has been reported in four families meeting HDGC clinical criteria, however, this represents only 11% of all families carrying this variant (threshold is 30% to consider applying PS4). Given that multiple families with this variants meet the HDGC criteria, CDH1-VCEP recommended not to apply BS2 code. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8130235/MONDO:0007648/007 2023-08-28 2023-09-27 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:27565 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0031117 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0240417 infores:hetionet CHEBI:6444 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0003811 infores:hetionet CHEBI:6541 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0039231 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0009450 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0034150 infores:hetionet CHEBI:5141 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0085631 infores:hetionet CHEBI:80630 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0036104 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0009806 infores:hetionet CHEBI:28748 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042487 infores:hetionet CHEBI:75722 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020438 infores:hetionet CHEBI:6149 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013604 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0234215 infores:hetionet CHEBI:16469 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0025874 infores:hetionet CAID:CA2573106066 biolink:causes MONDO:0007453 infores:clingen CAID:CA2573106066 MONDO:0007453 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.1303_1306dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 436 (NM_000162.5), adding 24 novel amino acids before encountering a stop codon (p.(Ile436ArgfsTer24)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly consistent with GCK-MODY, but there was insufficient clinical information to evaluate for PP4 (internal lab contributors). In summary, c.1303_1306dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106066/MONDO:0007453/086 2023-09-08 2023-09-08 Semidominant inheritance HP:0032113 Supports CAID:CA200253 biolink:causes MONDO:0100039 infores:clingen CAID:CA200253 MONDO:0100039 PMID: Benign BP7, BS2_Supporting, BA1 The allele frequency of the p.Glu60= variant in CDKL5 is 0.9% in East Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Glu60= variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). The silent p.Glu60= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Glu60= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2_supporting, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA200253/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:71219 biolink:causes UMLS:C0239293 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0239293 infores:hetionet CHEBI:31643 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0011991 infores:hetionet CHEBI:50223 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0027947 infores:hetionet CHEBI:9588 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0011606 infores:hetionet UMLS:C0005740 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0241136 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0013395 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0002963 infores:hetionet CHEBI:63598 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0022346 infores:hetionet CHEBI:31705 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0036974 infores:hetionet CHEBI:66876 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C1260880 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233472 infores:hetionet CHEBI:6887 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009676 infores:hetionet CHEBI:50275 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0030252 infores:hetionet CHEBI:63619 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235996 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0233494 infores:hetionet CHEBI:10650 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0021368 infores:hetionet CHEBI:6375 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011168 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0003811 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0235763 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0232492 infores:hetionet CHEBI:5959 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0030554 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0025202 infores:hetionet CHEBI:5779 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0236075 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0162281 infores:hetionet GO:0033084 biolink:causes GO:0033077 infores:ubergraph knowledge_assertion manual_agent GO:0033084 GO:0033077 CHEBI:49960 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151479 infores:hetionet CHEBI:4470 biolink:causes MONDO:0009249 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0016751 infores:hetionet CHEBI:5775 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0017178 infores:hetionet CHEBI:71940 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0030196 infores:hetionet CHEBI:27565 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0015230 infores:hetionet CHEBI:7492 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0013595 infores:hetionet CHEBI:50777 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0020555 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020517 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232492 infores:hetionet CAID:CA913183983 biolink:causes MONDO:0010305 infores:clingen CAID:CA913183983 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting PP4 The NM_005629.4(SLC6A8):c.950dup (p.Tyr317Ter) variant in SLC6A8 is predicted to cause a premature stop codon in biologically-relevant-exon 6/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This is supported by failure of the variant to restore creatine uptake when it was transiently expressed in SLC6A8-deficient fibroblasts (PMID: 7465020). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in a patient with X-linked disability (PMID 15154114). However, results of urine creatine measurement and cerebral creatine level from brain proton-MRS were not provided. There is a ClinVar entry for this variant (Variation ID: 11699). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. The classification of this variant has been upgraded to pathogenic based on the availability of functional data (included as PVS1_observed) and the report of the variant in an individual with clinical features consistent with creatine transporter deficiency with insufficient data to apply PP4.SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specification Version 1.1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on February 23, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913183983/MONDO:0010305/027 2023-02-23 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:28148 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0003123 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0020517 infores:hetionet CHEBI:3223 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0039231 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233472 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0020517 infores:hetionet CHEBI:4027 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0022346 infores:hetionet CHEBI:27882 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0017181 infores:hetionet CHEBI:87715 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0034155 infores:hetionet CHEBI:135930 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0010200 infores:hetionet CHEBI:83804 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0231530 infores:hetionet CAID:CA409108350 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108350 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting, PS4_Moderate, PP1_Strong PS3, BS3 The c.956T>C variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a missense variant at codon 319 (p.(Leu319Pro)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.995, which is greater than the MDEP VCEP threshold of 0.70 (PP3).This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:27810688, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-sensitive)(PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 6 meioses in 3 Exeter families (PP1_Strong; internal lab contributors). Functional studies are inconclusive in evaluating the effect of this variant on transactivation activity, as it displayed no statistical difference from WT activity when evaluated using the HNF4A/1A promoter, but a reduction in activity with the PDZK1 promoter; therefore neither PS3 nor BS3 will be applied (PMID: 30191603). In summary, c.956T>C meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108350/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68554 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0178298 infores:hetionet CAID:CA410147924 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147924 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1157C>G (p.Pro386Arg) is a missense variant which has a REVEL score < 0.50 (0.457) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147924/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:54Z8M50D6Q biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0004096 infores:hetionet CHEBI:134991 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0034933 infores:hetionet CHEBI:5109 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0010481 infores:hetionet CHEBI:6121 biolink:causes HP:0012282 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0234918 infores:hetionet CHEBI:8863 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0580413 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0010709 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0031117 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0235431 infores:hetionet CHEBI:7627 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0022354 infores:hetionet NCBIGene:9927 biolink:causes MONDO:0007908 infores:monarchinitiative not_provided not_provided HGNC:16877 MONDO:0007908 uuid:db77a9c8-b3aa-43c6-8e78-cf9caf6762d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020175 infores:hetionet CHEBI:31515 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0393593 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0034150 infores:hetionet CHEBI:50173 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0438142 infores:hetionet CHEBI:80630 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0024312 infores:hetionet CHEBI:3223 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0520966 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004239 infores:hetionet CHEBI:4530 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013390 infores:hetionet CHEBI:4708 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0004093 infores:hetionet CAID:CA351291 biolink:causes MONDO:0100326 infores:clingen CAID:CA351291 MONDO:0100326 PMID: Benign BP4, BA1 The NM_000419.5:c.439C>G variant in ITGA2B is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 147 (p.Leu147Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01420 (1822/128308 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.053, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant is also classified as Benign/Likely benign in ClinVar and was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PDVCEP: BA1 and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA351291/MONDO:0100326/011 2023-02-02 2023-02-23 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:64310 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0015967 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0021053 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0235431 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0542184 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0340464 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0027051 infores:hetionet CHEBI:50275 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0547030 infores:hetionet CHEBI:17790 biolink:causes MONDO:0017860 infores:ubergraph knowledge_assertion manual_agent CHEBI:17790 MONDO:0017860 CHEBI:6375 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020473 infores:hetionet NCBIGene:3767 biolink:causes MONDO:0012522 infores:monarchinitiative not_provided not_provided HGNC:6257 MONDO:0012522 uuid:775e0ed0-36b6-443e-9635-191bd8bc347b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8069 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0028084 infores:hetionet CHEBI:18248 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C1096035 infores:hetionet CHEBI:28748 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0231807 infores:hetionet NCBIGene:9900 biolink:causes MONDO:0958330 infores:monarchinitiative not_provided not_provided HGNC:20566 MONDO:0958330 uuid:38116368-7189-454c-9913-a5938153a453 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0017797 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0009806 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0006607 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0029485 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0442886 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0520806 infores:hetionet CHEBI:28918 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0030252 infores:hetionet CHEBI:4469 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0011991 infores:hetionet CHEBI:9570 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085669 infores:hetionet UMLS:C0004609 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0233477 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0233612 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233612 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0234215 infores:hetionet CHEBI:53760 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085649 infores:hetionet CHEBI:4728 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0032617 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1096701 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1096701 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0521208 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0521208 infores:hetionet CHEBI:46081 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042963 infores:hetionet NCBIGene:2657 biolink:causes MONDO:0013463 infores:monarchinitiative not_provided not_provided HGNC:4214 MONDO:0013463 uuid:285e6ad7-a18c-48d4-8318-c902a01cbcce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0011124 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C1956346 infores:hetionet CHEBI:4027 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C3160858 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0595877 infores:hetionet CHEBI:2567 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0008031 infores:hetionet CHEBI:7936 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0010200 infores:hetionet CAID:CA5949900 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949900 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting PS3 The NM_000448.3:c.86A>G variant in RAG1 is a missense variant predicted to cause a substitution of lysine by arginine at amino acid 29 (p.Lys29Arg). The Popmax filtering allele frequency of this variant in gnomAD v2.1.1 is 0.00000702, which is lower than the SCID-VCEP’s threshold for PM2 (<0.000102). No homozygous individual has been observed in the gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in two affected individuals who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV003292718.1). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949900/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:73274 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0043352 infores:hetionet CHEBI:135736 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0232602 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0518015 infores:hetionet CAID:CA16041901 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041901 MONDO:0009290 PMID:22676651PMID:20033296PMID:26575883PMID:21644219PMID:29523196 Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.2214G>A (p.Trp738Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, meeting PM2. An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). This data meets PM3_Supporting. In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). There is a ClinVar entry for this variant (Variation ID: 370223; 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041901/MONDO:0009290/010 2020-10-05 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6402 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0019360 infores:hetionet CHEBI:7773 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0013447 infores:hetionet NCBIGene:8243 biolink:causes MONDO:0026771 infores:monarchinitiative not_provided not_provided HGNC:11111 MONDO:0026771 uuid:b07554a9-f4b3-40a0-95de-19ea0664b35d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6078 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0033774 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0011616 infores:hetionet CAID:CA8623481 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623481 MONDO:0100326 PMID: Uncertain Significance BS1, PP3 PM5, PP4, PS1 The c.2249G>A variant in ITGB3 is a missense variant predicted tocause substitution of Arginine by Glutamine at amino acid 750 (p.Arg750Gln). The highest population minor allele frequency in gnomAD v4.0.0 is 0.001679 (126/75042 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.00158) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.912, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BS1 and PP3 (VCEP specifications version 2; date of approval 05/02/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623481/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8869 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0037274 infores:hetionet CAID:CA256490 biolink:causes MONDO:0021060 infores:clingen CAID:CA256490 MONDO:0021060 PMID: Pathogenic PS4_Moderate, PS2_Very Strong, PP3, PM2_Supporting, PS3_Moderate BS3, BS1, BA1, BP4 The c.350A>G variant in the HRAS gene is a missense variant predicted to cause substitution of lysine by arginine at amino acid 117 (p.Lys117Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 3 were reported as confirmed de novo cases while 1 was an unconfirmed de novo occurrence (PS2_VeryStrong, PS4_Moderate; PMID: 16443854, 17979197, 35595280, 32313153). In vitro functional assays showed that the variant increased RAS/MEK/ERK activation compared to wildtype (PS3_Moderate; PMID: 17979197, 21850009). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PS3_Modertae, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256490/MONDO:0021060/046 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4514 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0233763 infores:hetionet CHEBI:5778 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151908 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0027651 infores:hetionet CHEBI:7798 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0009676 infores:hetionet GO:0042478 biolink:causes GO:0048592 infores:ubergraph knowledge_assertion manual_agent GO:0042478 GO:0048592 CHEBI:9943 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0149741 infores:hetionet CHEBI:8499 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0009806 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020456 infores:hetionet CHEBI:9599 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0003862 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0948089 infores:hetionet CHEBI:8768 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030193 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0239295 infores:hetionet CHEBI:6715 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011603 infores:hetionet CHEBI:465284 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1443060 infores:hetionet CHEBI:3084 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0234193 infores:hetionet CHEBI:8356 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0086439 infores:hetionet CHEBI:31859 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013491 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0009806 infores:hetionet CHEBI:64064 biolink:causes UMLS:C3495832 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C3495832 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0030252 infores:hetionet CHEBI:9555 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0040034 infores:hetionet CHEBI:44032 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0038325 infores:hetionet CAID:CA2017997780 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997780 MONDO:0015967 PMID: Uncertain Significance PM4, PP1_Moderate, PM2_Supporting PS4, PP4 The c.1373_1384del variant in the glucokinase gene, GCK, is a 12 base pair deletion resulting in the in-frame deletion of 4 amino acids at codon 458 (p.(Lys458_Cys461del)) within exon 10 of NM_000162.5. The c.1373_1384del variant is predicted to change the length of the protein due an in-frame deletion of 4 amino acids in a nonrepeat region (PM4). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune/insulin-deficient diabetes; however, this number does not meet the MDEP cutoff for PS4_Moderate (PMID: 30105470; internal lab contributor). This variant is present in an individual reported to have GCK-MODY; however, there was insufficient information to evaluate for PP4 (PMID: 30105470). This variant segregates with disease with 3 meioses in 2 families with MODY (PP1_Moderate; PMID 30105470). In summary, c.1373_1384del meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM4, PM2_Supporting, PP1_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997780/MONDO:0015967/086 2023-06-18 2023-06-18 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:9907 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0231303 infores:hetionet CHEBI:8871 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0241633 infores:hetionet CAID:CA269566885 biolink:causes MONDO:0007947 infores:clingen CAID:CA269566885 MONDO:0007947 PMID: Likely Benign BP4, BS1 PVS1, PM2, BS2, PP2, PP3, PP1, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PM5, PM1, PM4, PM3, BP5, BP7, BS3, BS4 The NM_000138 c.985A>G, is a missense variant in FBN1 predicted to cause a substitution of an isoleucine by a valine at amino acid 329 (p.Ile329Val). This variant has been identified in one individual with a Marfan syndrome-like phenotype and was also found in one affected family member with systemic features of Marfan syndrome (internal data). It was also identified in one individual with Marfan syndrome who carried a pathogenic variant in FBN1, p.Cys1326Tyr, however segregation studies were not performed (internal data). The variant was also identified in one proband with aortic root dilatation who also carried a variant of uncertain clinical significance in TGFBR2; the proband’s brother was unaffected and carried the FBN1 p.Ile329Val variant (PMID 29875124, internal data). This variant has been reported three times in ClinVar: twice as uncertain significance and once as likely benign (Variation ID: 549475). This variant has been identified in 4 individuals of African origin (MAF: 0.02%) (BS1; https://gnomad.broadinstitute.org/, version 2.1.1). Computational prediction tools and conservation analysis suggests no impact on the protein (REVEL: 0.274) (BP4). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA269566885/MONDO:0007947/022 2023-02-01 2023-02-01 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3504 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0004604 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037274 infores:hetionet CHEBI:6887 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0023380 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0008325 infores:hetionet CAID:CA120597 biolink:causes MONDO:0044970 infores:clingen CAID:CA120597 MONDO:0044970 PMID:20056103PMID:19160410 Pathogenic PP1_Moderate, PS3_Supporting, PM5, PP3, PS4 BA1, BP4, PS1, PS2, PM2, PM6, PVS1, BS1 The m.9176T>C (p.L217P) variant in MT-ATP6 has been reported in more than 16 unrelated individuals with features of primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to 20s). Features included Leigh syndrome (including several cases with adult-onset Leigh syndrome) and NARP, as well as seizures, ataxia, muscle weakness, dystonia, axonal neuropathy, migraines, sensorineural hearing loss, hypertrophic cardiomyopathy, ophthalmoplegia, ptosis, and pigmentary retinopathy. Heteroplasmy levels were generally >90% in affected individuals (PS4; PMIDs: 17209980, 15709156, 11198506, 27408822, 30136164, 20656066, 21819970, 19747204, 9631394, 9501263, 9270604, 7668837). There are no reports of de novo occurrences of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 21819970, 9270604, 7668837). This variant is present in three sequences from GenBank dataset, however 2/3 sequences are from individuals with primary mitochondrial disease. This variant is not present in the homoplasmic state in any individuals in the gnomAD v3.1.2 dataset, however two individuals have this variant in the 50-60% heteroplasmy range and one in the 80-90% heteroplasmy range. There is one homoplasmic occurrence in the Helix dataset. This variant is located at the same amino acid position as another well-known pathogenic variant, m.9176T>G (p.L217R) (PM5). While cybrid studies were performed (PMID: 19160410), there was insufficient evidence reported to meet criteria for cybrid scoring per the specified guidelines for variant curation. Studies in yeast (PMID: 20056103) support the functional impact of this variant (PS3_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.92 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on January 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PP1_moderate, PM5, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120597/MONDO:0044970/014 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:31625 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0042769 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0001622 infores:hetionet CHEBI:47426 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0038990 infores:hetionet CHEBI:68575 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0002871 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011616 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0020538 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0877338 infores:hetionet CHEBI:231425 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0011175 infores:hetionet GO:0060945 biolink:causes CL:0010022 infores:ubergraph knowledge_assertion manual_agent GO:0060945 CL:0010022 CHEBI:36791 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037036 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0340464 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0027765 infores:hetionet NCBIGene:5859 biolink:causes MONDO:0014335 infores:monarchinitiative not_provided not_provided HGNC:9751 MONDO:0014335 uuid:ae11f839-5d7a-4929-9045-a39901453f66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020517 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0014518 infores:hetionet CHEBI:10127 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C2830004 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0006145 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020538 infores:hetionet CHEBI:585948 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0002962 infores:hetionet CHEBI:4356 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0036974 infores:hetionet CAID:CA1244093 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244093 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BS1, BS3, BP7, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.1024A>G variant in MYOC is a missense variant predicted to cause substitution of Arginine by Glycine at amino acid 342 (p.Arg342Gly). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00002228 (1 allele out of 44,886), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.590, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244093/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1456784 infores:hetionet CHEBI:8863 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0917801 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027765 infores:hetionet CHEBI:3515 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0424295 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0574067 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019147 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0007642 infores:hetionet CHEBI:9139 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027497 infores:hetionet CAID:CA412739485 biolink:causes MONDO:0100437 infores:clingen CAID:CA412739485 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PS4_Supporting, PM2_Supporting, PP1_Strong PS2 NM_001034853.2(RPGR):c.1345C>T (p.Arg449Ter) is a nonsense variant that introduces a premature stop codon in exon 11 of 15 that is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 35432464, PMID: 29528978, PS4_Supporting). The variant has been reported in additional male probands that did not meet the phenotype requirement (PMID: 33090715, PMID: 32860923, PMID: 11992260, PMID: 23150612, PMID: 37217489). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), early nyctalopia (0.5 pts), decreased peripheral visual field (0.5 pts), macular dystrophy (0.5 pts), bone spicule pigmentation (0.5 pts), myopia (0.5 pts), and reduced visual acuity (0.5 pts), with genotyping by next-generation sequencing panel identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (7 points, PP4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from at least 2 families (PP1_Strong; PMID: 30105367, PMID: 29528978, PMID: 35432464). This variant has been identified as a de novo occurrence with confirmed maternal relationships in 1 individual, however, the requirement of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses were not met, so PS2_Supporting was not applied (ARVO Abstract, Demirci et al., 2023, https://iovs.arvojournals.org/article.aspx?articleid=2414118). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PS4_Supporting, PP4, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412739485/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:94440 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C2830004 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0014742 infores:hetionet CHEBI:63598 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C3665347 infores:hetionet CHEBI:585948 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C1167965 infores:hetionet CHEBI:8093 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0232493 infores:hetionet CHEBI:9448 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0853034 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0235146 infores:hetionet CHEBI:7936 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019572 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0023067 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0019158 infores:hetionet CHEBI:61049 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0546817 infores:hetionet CHEBI:48844 biolink:causes UMLS:C1735630 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C1735630 infores:hetionet CHEBI:28487 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0011991 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0021400 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0948586 infores:hetionet CHEBI:453011 biolink:causes UMLS:C1504422 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C1504422 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0006266 infores:hetionet CAID:CA000119 biolink:causes MONDO:0018875 infores:clingen CAID:CA000119 MONDO:0018875 PMID: Uncertain Significance BP4, PS4_Moderate, PM1_Supporting, PP4, BS2, PM2_Supporting BA1, PS1, PS3, PS2, PM5, BS1, BS3, PP3, PP1 The NM_000546.6: c.328C>T (p.Arg110Cys) variant in TP53 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 110 (p.Arg110Cys). This variant has been reported in 5 unrelated families meeting Revised Chompret criteria and one family meeting Classic criteria. Based on this evidence, this variant scores 3.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). This variant has an allele frequency of 0.00001427 (23/1612280 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present.(PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0367; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). This variant has 6 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP4, BS2_Moderate, PM2_Supporting, BP4, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000119/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410202678 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202678 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, BP5, BP7, BS1, BS3, PM6, PM4, PM3, PM5, PP2, PP4, BS2 NM_001754.5(RUNX1):c.407A>T (p.Asn136Ile) is a missense variant which has a REVEL score ≥ 0.88 (0.941) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202678/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:136040 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0085649 infores:hetionet CHEBI:46081 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0423153 infores:hetionet CHEBI:31624 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0085616 infores:hetionet CHEBI:10112 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0017178 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0005779 infores:hetionet CHEBI:119915 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015402 infores:hetionet CAID:CA10583401 biolink:causes MONDO:0007648 infores:clingen CAID:CA10583401 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP2, PP4, PP1, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.79C>T (p.Pro27Ser) variant has allele frequency <1 out of 100, 000 in the gnomAD cohort (1/156646 in gnomAD v2.1.1; PM2_Supporting). No additional evidence met criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583401/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:10125 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0039621 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0015393 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0497247 infores:hetionet CAID:CA229311 biolink:causes MONDO:0009861 infores:clingen CAID:CA229311 MONDO:0009861 PMID:7913581 Pathogenic PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency in ExAC, MAF=0.00002.; PP4: Identified in a pair of siblings with PKU. (PMID:7913581). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229311/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:84173 biolink:causes MONDO:0014182 infores:monarchinitiative not_provided not_provided HGNC:26158 MONDO:0014182 uuid:1de9441a-88d8-4585-8764-67d87d7b9aa6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50729 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0750394 infores:hetionet CHEBI:63717 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0232462 infores:hetionet CHEBI:8024 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0236075 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0038358 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0518015 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020039 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0039971 infores:hetionet CHEBI:64355 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018965 infores:hetionet CHEBI:10124 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0002792 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011849 infores:hetionet CHEBI:10125 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0600142 infores:hetionet CHEBI:5864 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0231530 infores:hetionet CHEBI:34385 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0009806 infores:hetionet CHEBI:17303 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0520966 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0853149 infores:hetionet UMLS:C0004609 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0344232 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151734 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0036572 infores:hetionet UMLS:C0065374 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0016199 infores:hetionet CHEBI:28748 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030794 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0013295 infores:hetionet CHEBI:3568 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0231218 infores:hetionet CHEBI:3380 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0947912 infores:hetionet CHEBI:6846 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C2830004 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0026946 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0029445 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0349506 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0349506 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0687133 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0017178 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0027765 infores:hetionet CHEBI:7466 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0028960 infores:hetionet CHEBI:3398 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0085631 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0001824 infores:hetionet GO:0045765 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:0045765 GO:0001568 CHEBI:10102 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0018965 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042373 infores:hetionet GO:0032954 biolink:causes GO:0051301 infores:ubergraph knowledge_assertion manual_agent GO:0032954 GO:0051301 CAID:CA273939 biolink:causes MONDO:0009290 infores:clingen CAID:CA273939 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PM5_Supporting, PS3_Supporting The NM_000152.5:c.2014C>T variant in GAA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 672 (p.Arg672Trp). The variant has been reported in 5 patients with a diagnosis of Pompe disease supported by <10% normal GAA activity in muscle (PMID 9535769), <1% GAA activity in cultured fibroblasts (PMID 16917947), or GAA activity in the affected range in leukocytes or lymphocytes (PMID 22676651, 25526786) in addition to at least 5 patients stated to have symptoms consistent with Pompe disease and deficient GAA activity but values not provided (PMID 16917947, 21803581, 27692865)(PP4_Moderate). At least 5 patients are compound heterozygous for the variant and a variant in GAA classified as pathogenic by the ClinGen LSD VCEP, phase unknown - c.-32-13T>G (PMID 16917947), c.2385delG (PMID 21484825), c.1411_1414del (PMID 27692865), c.766_785delinsC (PMID 9535769), and c.1951_1952insT (clinical laboratory data) (PM3_Strong). The variant has also been reported in compound heterozygotes with c.1748C>T(p.Ser583Phe)(PMID 21484825), c.323G>A (p.Cys108Tyr) (PMID 25526786), c.1465G>A (p.Asp489Asn)(PMID 16917947), c.1703A>T (p.His568Leu)(PMID 17027861, 22676651), c.2474C>G (p.Pro825Arg)(PMID 30564623). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/29806 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in SV40-immortalized GAA-deficient fibroblasts revealed activity of <1% of the control value (PMID 9535769), and <2% activity in COS cells (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.9 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.2015G>A (p.Arg672Gln)(see Table 1 in PMID 33578445) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (likely pathogenic without PM5 data from c.2014C>T (p.Arg672Trp) PM5_Supporting). c.2015G>T (p.Arg672Leu) has also been reported but has not yet met the criteria to be classified as pathogenic or likely pathogenic. There is a ClinVar entry for this variant (Variation ID: 188773; 2 star status) with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP: PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273939/MONDO:0009290/010 2022-01-04 2022-01-04 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6532 biolink:causes MONDO:0002105 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0025162 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0026858 infores:hetionet CHEBI:7936 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151529 infores:hetionet CHEBI:3441 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0220870 infores:hetionet CHEBI:6413 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0010200 infores:hetionet CHEBI:5141 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0438717 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0021053 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042109 infores:hetionet CHEBI:50275 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042847 infores:hetionet CHEBI:8890 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0030193 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042267 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0038454 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0027765 infores:hetionet CHEBI:107736 biolink:causes UMLS:C1386135 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C1386135 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0013609 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0347390 infores:hetionet NCBIGene:79053 biolink:causes MONDO:0054743 infores:monarchinitiative not_provided not_provided HGNC:23161 MONDO:0054743 uuid:76f29e86-5a3c-4de9-b6be-4ba59e02f131 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0010399 infores:hetionet CHEBI:35854 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0027497 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0014868 infores:hetionet CHEBI:75984 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0036454 infores:hetionet CHEBI:134966 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0014591 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0522224 infores:hetionet CHEBI:31413 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0004093 infores:hetionet CHEBI:4315 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0015672 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0853692 infores:hetionet NCBITaxon:29169 biolink:causes MONDO:0005645 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:29169 MONDO:0005645 CHEBI:367163 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0392525 infores:hetionet CHEBI:465284 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0497156 infores:hetionet CHEBI:78543 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0024312 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0011991 infores:hetionet CHEBI:2666 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0006384 infores:hetionet CHEBI:8346 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0234518 infores:hetionet CHEBI:9434 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C2830004 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0027765 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0006670 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D016920 DB00760_MESH_D016920_1 GO:1903023 biolink:causes GO:0044091 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0044091 CHEBI:68534 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0004604 infores:hetionet CHEBI:71219 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0162835 infores:hetionet CAID:CA1251325 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251325 MONDO:0013144 PMID: Likely Benign BS1, BP4 BP7 The c.870C>T (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Phe290=). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003730 (48/128676 alleles) in the European population, which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). SpliceAI predicts no splicing impact for this variant meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4, BP7. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251325/MONDO:0013144/084 2024-08-16 2024-08-21 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA10585843 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585843 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP1, BS2 The NM_000527.5(LDLR):c.2389+5G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). So PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: No REVEL, splicing evaluation needed.Functional data on splicing not available.A) variant located -3 to +6 from canonical donor siteMES scores: canonical site variant = 4.93; canonical donor wt = 9.86.Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8Variant is predicted to alter splicing. So PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585843/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:585948 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0149904 infores:hetionet CHEBI:31643 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0151315 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0043094 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020651 infores:hetionet CHEBI:6761 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0041657 infores:hetionet CHEBI:75984 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0020580 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0014742 infores:hetionet CAID:CA410207000 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207000 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, BA1, BP1, BP4, BP3, BP2, PVS1, BP7, BS1, BS3, PM5, PM4, PM1, PM3, PP4, PP2, PP3 NM_001754.5(RUNX1):c.658T>G (p.Ser220Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207000/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:65173 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0018418 infores:hetionet CAID:CA421939411 biolink:causes MONDO:0005338 infores:clingen CAID:CA421939411 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.423C>T variant in MYOC is a synonymous variant (p.Ala141=). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0.01, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 23922489). Although at least one variant carrier had been identified in another study (PMID: 20664688), it was not clear as to how many there were, and whether they had open angle glaucoma or not. Thus the ≥ 2 probands threshold required for PS4_Supporting was not met. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, BP7, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421939411/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7445 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0027932 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0036572 infores:hetionet CHEBI:37924 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0233407 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020542 infores:hetionet CHEBI:53760 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013428 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0235140 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0235140 infores:hetionet GO:0061930 biolink:causes GO:0043354 infores:ubergraph knowledge_assertion manual_agent GO:0061930 GO:0043354 CHEBI:4877 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0040034 infores:hetionet CHEBI:7907 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0340865 infores:hetionet CHEBI:6067 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0234632 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0162287 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0235639 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0349506 infores:hetionet CHEBI:29013 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0152227 infores:hetionet CHEBI:7478 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0032617 infores:hetionet CHEBI:9448 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C1443060 infores:hetionet CHEBI:116735 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0011616 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0403632 infores:hetionet UMLS:C0004599 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0015230 infores:hetionet NCBIGene:8216 biolink:causes MONDO:0014693 infores:monarchinitiative not_provided not_provided HGNC:6742 MONDO:0014693 uuid:d22d5d8a-40d2-415c-bc68-c7f8c6c57cf2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0002170 infores:hetionet CHEBI:63624 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0239134 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0036220 infores:hetionet CAID:CA645373276 biolink:causes MONDO:0015967 infores:clingen CAID:CA645373276 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM4_Supporting The c.473_475del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 158 (p.(Lys158del)) within exon 5 of NM_174914.5. The c.473_475del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.473_475del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645373276/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135193 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0855775 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0006266 infores:hetionet CHEBI:8426 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0002874 infores:hetionet CAID:CA637689160 biolink:causes MONDO:0011071 infores:clingen CAID:CA637689160 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*1158C>G is a 3' UTR variant with a SpliceAI score of 0.00, which is ≤ 0.20 (BP4). Additionally, evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score of 0.62, which is ≤ 2.0 (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637689160/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:G4PX8C4HKV biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0085593 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0034065 infores:hetionet CAID:CA145769 biolink:causes MONDO:0009290 infores:clingen CAID:CA145769 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.2338G>A (p.Val780Ile) in gnomAD v2.1.1 is 0.8129 in the South Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92476; 2 star review status) with six submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145769/MONDO:0009290/010 2020-01-23 2020-05-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:52172 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0392699 infores:hetionet CHEBI:4027 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019156 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0087169 infores:hetionet CHEBI:127342 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0233407 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042373 infores:hetionet CHEBI:46081 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0020458 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0027441 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0027765 infores:hetionet CAID:CA327914176 biolink:causes MONDO:0100437 infores:clingen CAID:CA327914176 MONDO:0100437 PMID: Benign BA1 BP4, BP7 NM_001034853.2(RPGR):c.*125del is a 1-base pair deletion in the 3' untranslated region of RPGR. This variant is present in gnomAD v4.1.0 at a frequency of 0.2260 among hemizygous individuals, with 65,271 variant alleles / 288,830 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.02 for acceptor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing. However, BP4 is not considered applicable to 3' UTR variants in RPGR, so this code was not met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327914176/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:15940 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0013595 infores:hetionet CAID:CA211415 biolink:causes MONDO:0008535 infores:clingen CAID:CA211415 MONDO:0008535 PMID: Likely Benign BS3_Supporting, BS1, BP5 PP3 The NM_001114753.3: c.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 15712270). The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062, 22022569). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA211415/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011168 infores:hetionet CHEBI:2955 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0013404 infores:hetionet CHEBI:52717 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030252 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0033975 infores:hetionet CHEBI:68595 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0014742 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0019087 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0152227 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0178298 infores:hetionet CAID:CA2586969535 biolink:causes MONDO:0015152 infores:clingen CAID:CA2586969535 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3, PP1 The NM_003494.4: c.5159del p.(Arg1720LeufsTer2) variant in DYSF, which is also known as NM_001130987.2: c.5276del p.(Arg1759LeufsTer2), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 46/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in one individual with a diagnosis of Miyoshi myopathy, where it was identified in unknown phase with a second DYSF variant that can be classified as likely pathogenic independent of its observation in this patient (NM_003494.4: c.125dup p.(Asn43GlufsTer6), 0.25 pts, PMID: 36983702; PM3_Supporting not met). This patient showed both progressive limb girdle muscle weakness and disease range dysferlin expression in blood monocytes (PMID: 36983702, Jain Foundation Dysferlin Registry internal data communication; PP4_Strong). The affected sibling of this patient carried the same two DYSF variants and also had disease range dysferlin protein expression in blood monocytes, but segregation could not be scored since the phase of the variants was not confirmed (PP1 not met). This variant is absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586969535/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CAID:CA401366177 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366177 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PVS1_Strong The NM_000152.5:c.1327-2A>G variant in GAA occurs within the canonical splice acceptor site of intron 8. It is predicted to cause skipping of biologically-relevant-exon 9 (GAA has 20 exons) resulting in an in-frame deletion of 37 amino acids (amino acids 443-479; ~3.9% of the protein) which forms part of the GAA catalytic barrel (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837). As expected, SpliceAI predicts that the variant will obliterate the normal splice acceptor site (score= 0.99). However, SpliceAI also predicts a possible acceptor gain 16 bp upstream from the normal splice site (score= 0.79). If this site were to be used when the normal acceptor site is broken, a frameshift is predicted. However, the report that an individual who is homozygous for this variant and is CRIM-positive is consistent with an in frame deletion (PMID 22252923). PVS1_Strong is applied, based on the specifications of the ClinGen LD VCEP due to predicted loss of an exon that includes a critical region of the protein (PVS1_Strong). At least three probands and a sibling with infantile onset Pompe disease have been reported with this variant and documented GAA activity in the affected range. Two of them were on enzyme replacement therapy; follow up was reported for one patient with clinical improvement (PMID 19067231, 20821053, 31510962). In addition, one individual, identified in a clinical laboratory, is compound heterozygous for the variant and pseudodeficiency variants were shown to be absent (PP4_Moderate). This variant was found in homozygosity in at least two individuals of Emirati origin (PMIDs 19067231, 20821053, 23430803, 24273659, 29122469) (max 2 x 0.5 points allowed for homozygous individuals = 1 point). In addition, an individual has been reported who is compound heterozygous for the variant and another variant in GAA phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP (clinical laboratory data) (0.5 points); and another individual is compound heterozygous for the variant confirmed in trans with c.1437G>C (p.Lys479Asn) (likely pathogenic without use of allelic data from the patient to avoid circular logic) (1 point). Total 2.5 points (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002297 (2/8708 alleles) in the African / African American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 972762). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 17, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366177/MONDO:0009290/010 2024-09-17 2024-09-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:47898 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0233494 infores:hetionet CHEBI:4710 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0017168 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0542247 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0542247 infores:hetionet CHEBI:391960 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0151904 infores:hetionet CAID:CA229576 biolink:causes MONDO:0009861 infores:clingen CAID:CA229576 MONDO:0009861 PMID:23942198PMID:11244681PMID:23942198PMID:11244681 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PP3 PAH-specific ACMG/AMP criteria applied: PM2: ExAC MAF: 0.00012; PP4_Moderate: Detected in patients with PKU/HPA. BH4 deficiency excluded. (PMID:11244681; PMID:23942198); PM3_Strong: Detected with D145V, A403V (Pathogenic) (PMID:11244681; PMID:23942198). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229576/MONDO:0009861/006 2018-08-13 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31705 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0027769 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0041969 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0549356 infores:hetionet CHEBI:36795 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011124 infores:hetionet CAID:CA512318555 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318555 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.798G>A (p.Gln266=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318555/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6970 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0521839 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0015376 infores:hetionet NCBIGene:152816 biolink:causes MONDO:0013906 infores:monarchinitiative not_provided not_provided HGNC:26300 MONDO:0013906 uuid:116e2cde-7530-4725-a9cc-d72266fd6d43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5106 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0863093 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042571 infores:hetionet CHEBI:15367 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0162834 infores:hetionet CHEBI:7444 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0232487 infores:hetionet CHEBI:27834 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0239571 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0041912 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0152517 infores:hetionet CHEBI:3723 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0010520 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151773 infores:hetionet CHEBI:64310 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151878 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151601 infores:hetionet CHEBI:41879 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0031256 infores:hetionet CHEBI:51364 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0009782 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027813 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0020651 infores:hetionet CHEBI:8212 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0242422 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0270795 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0270795 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0018799 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1698088 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1698088 infores:hetionet CHEBI:8863 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151603 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038663 infores:hetionet GO:0033638 biolink:causes GO:0010286 infores:ubergraph knowledge_assertion manual_agent GO:0033638 GO:0010286 CHEBI:47898 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0039070 infores:hetionet CHEBI:9622 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0013428 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0007642 infores:hetionet CHEBI:49668 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C1384353 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0004936 infores:hetionet CHEBI:5558 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0428977 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0149904 infores:hetionet CAID:CA10650416 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650416 MONDO:0011071 PMID: Likely Benign BP2, BS1 PS4, PS3, PS2, PS1, BP1, BP4, BP3, BA1, BP7, BP5, BS3, BS4, PM2, PM6, PVS1, PM3, PM4, PM1, PM5, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.*3021A>G is a substitution in the 3' UTR of RUNX1. Since the variant is located in the 3' UTR, it is not expected to alter the amino acid sequence. The highest continental population minor allele frequency in gnomAD v2, v3, and v4 is 0.0005834 (9/15,428), 0.0006908 (47/68,040), and 0.0007621 (90/118,088), respectively, in the non-Finnish European population (BS1). This variant has been observed in one homozygous individual of Ashkenazi Jewish descent in gnomAD v3/v4, and hereditary thrombocytopenia and hematologic cancer predisposition syndrome is a condition with full penetrance at an early age (BP2). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS1 and BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650416/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68595 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0039070 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0853760 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0349506 infores:hetionet CHEBI:45951 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0156404 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1443060 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0003123 infores:hetionet CHEBI:9654 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0392156 infores:hetionet CHEBI:15367 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003811 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0859062 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0859062 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042075 infores:hetionet CHEBI:18248 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0220870 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0018799 infores:hetionet CHEBI:9168 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0041296 infores:hetionet CHEBI:7466 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0549448 infores:hetionet UMLS:C0657912 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151904 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0037274 infores:hetionet CHEBI:3696 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020578 infores:hetionet CHEBI:9635 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0002170 infores:hetionet CHEBI:5441 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042373 infores:hetionet CHEBI:8327 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0012833 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0041912 infores:hetionet CHEBI:8768 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0008031 infores:hetionet CHEBI:17141 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0004093 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013298 infores:hetionet CHEBI:51137 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0015672 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014544 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027121 infores:hetionet CHEBI:70746 biolink:causes NCIT:C121557 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0333271 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0002878 infores:hetionet CAID:CA16041882 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041882 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.393del (p.Ser132AlafsTer10) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 371580). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041882/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63598 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0426576 infores:hetionet CHEBI:3647 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0037290 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0010399 infores:hetionet CHEBI:63598 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027121 infores:hetionet CHEBI:3478 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0231528 infores:hetionet CHEBI:144551 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0030252 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0036572 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0007177 infores:hetionet CHEBI:28830 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0018524 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0027769 infores:hetionet CHEBI:3001 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0037383 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0234193 infores:hetionet CHEBI:49668 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0009763 infores:hetionet CHEBI:135791 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0234894 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233494 infores:hetionet CHEBI:6887 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085595 infores:hetionet CHEBI:63599 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C3665347 infores:hetionet CHEBI:75998 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0870082 infores:hetionet CHEBI:168396 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0549463 infores:hetionet CHEBI:6916 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0037822 infores:hetionet CHEBI:94501 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0039231 infores:hetionet NCBIGene:286077 biolink:causes MONDO:0007538 infores:monarchinitiative not_provided not_provided HGNC:24797 MONDO:0007538 uuid:56f5b197-a262-47f2-bd23-65d9f3560fc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0231218 infores:hetionet CHEBI:47898 biolink:causes GO:0006955 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020964 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0010034 infores:hetionet CHEBI:75045 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0024312 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011991 infores:hetionet CHEBI:37924 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0015672 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0020538 infores:hetionet CHEBI:6539 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0022107 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0585186 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C1456784 infores:hetionet CHEBI:50378 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0017152 infores:hetionet CHEBI:43968 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0020621 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0233459 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003460 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0019158 infores:hetionet CHEBI:6456 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C3160947 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1142412 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0162429 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002878 infores:hetionet CHEBI:42944 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0004245 infores:hetionet CAID:CA16615233 biolink:causes MONDO:0007648 infores:clingen CAID:CA16615233 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP4, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.793G>T (p.Glu265Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615233/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:71417 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0025222 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151779 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0231303 infores:hetionet GO:1904444 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0060429 CHEBI:3125 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0018932 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0015397 infores:hetionet CHEBI:49668 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0027497 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0948594 infores:hetionet CHEBI:40050 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0015230 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0267792 infores:hetionet CHEBI:5138 biolink:causes HP:0100716 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085271 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C1384666 infores:hetionet CHEBI:102216 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0011206 infores:hetionet CHEBI:7514 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0011603 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0003123 infores:hetionet CHEBI:135736 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020461 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0339916 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0687707 infores:hetionet NCBIGene:1638 biolink:causes MONDO:0030899 infores:monarchinitiative not_provided not_provided HGNC:2709 MONDO:0030899 uuid:7968f606-afa4-43b0-b549-8713d3e3a9a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes HP:0033821 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0149726 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0032617 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0267596 infores:hetionet CHEBI:6887 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0042384 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0032285 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0011304 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011304 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0010709 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0262397 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0424000 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0235431 infores:hetionet CHEBI:43968 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151578 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0021053 infores:hetionet CHEBI:100241 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0016204 infores:hetionet CHEBI:63631 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233471 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0497247 infores:hetionet CHEBI:50659 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0025061 infores:hetionet CHEBI:31348 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0234632 infores:hetionet CHEBI:70735 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0232462 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0520459 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0549297 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0549297 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0028738 infores:hetionet CHEBI:75722 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151744 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020456 infores:hetionet CHEBI:94440 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0004093 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0006145 infores:hetionet CHEBI:51209 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0340464 infores:hetionet NCBIGene:10535 biolink:causes MONDO:0012472 infores:monarchinitiative not_provided not_provided HGNC:18518 MONDO:0012472 uuid:987609d0-c313-4b4b-b57e-169259de093a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28487 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0013604 infores:hetionet CHEBI:6931 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0234233 infores:hetionet CHEBI:10127 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013384 infores:hetionet CHEBI:63608 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151576 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001703 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242225 infores:hetionet CHEBI:6437 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0015230 infores:hetionet CAID:CA414445354 biolink:causes MONDO:0010604 infores:clingen CAID:CA414445354 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PP3 PM1 The c.1009G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 337 (p.Ala337Thr). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been reported in at least 8 unique probands with mild to severe hemophilia B (PMID: 8091381; PMID: 11013449; PMID: 2726481), meeting phenotypic criteria for F9. The computational predictor REVEL gives a score of 0.783, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very Strong + PM2_Supporting + PP3. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414445354/MONDO:0010604/080 2024-04-26 2024-07-11 X-linked inheritance HP:0001417 Supports GO:1903388 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1903388 GO:0051641 UMLS:C0120107 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0231528 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0027651 infores:hetionet CHEBI:16899 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0600260 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151740 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0259768 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0236993 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0236993 infores:hetionet CHEBI:31348 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0039070 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039103 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0877517 infores:hetionet CHEBI:93305 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0085624 infores:hetionet CHEBI:2549 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0015672 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0162429 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0027051 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0034068 infores:hetionet CHEBI:27565 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0000731 infores:hetionet CAID:CA4516796 biolink:causes MONDO:0021060 infores:clingen CAID:CA4516796 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1150A>G (p.Arg384Gly) variant in the BRAF gene is 0.116% (16/8646) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA4516796/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8481 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0012833 infores:hetionet CHEBI:3013 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0011849 infores:hetionet CHEBI:6367 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0009676 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019348 infores:hetionet CHEBI:4858 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085632 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0521491 infores:hetionet CHEBI:92923 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0017152 infores:hetionet CHEBI:31711 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0340865 infores:hetionet CHEBI:49040 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0239571 infores:hetionet CHEBI:5165 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020578 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0041969 infores:hetionet CAID:CA410147512 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147512 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1283T>G (p.Ile428Ser) is a missense variant which has a REVEL score < 0.50 (0.315), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147512/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7465 biolink:causes MONDO:0004975 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0002395 infores:hetionet CAID:CA412371854 biolink:causes MONDO:0010725 infores:clingen CAID:CA412371854 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PP3_Strong, PM5 NM_000330.4(RS1):c.422G>T (p.Arg141Leu) is a missense variant encoding the substitution of arginine with leucine at amino acid 141. Another missense variant in the same codon, NM_000330.4(RS1):c.422G>A (p.Arg141His), (PMID: 29851975, PMID: 34645606, PMID: 30450322, PMID: 29739629, PMID: 35984651, PMID: 30652005, PMID: 19093009, PMID: 30630865, PMID: 30040949, PMID: 17525175, PMID: 30630865, PMID: 30040949) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (102) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMID: 34645606, PMID: 28771251, PMID: 34822951, PMID: 38219857, PS4_Moderate). The computational predictor REVEL gives a score of 0.939, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.02 for acceptor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked Retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PM5, and PS4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412371854/MONDO:0010725/126 2025-09-22 2025-09-22 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:63638 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0851341 infores:hetionet CHEBI:42797 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0423791 infores:hetionet CHEBI:64317 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0036572 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042401 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011630 infores:hetionet CHEBI:3077 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0005745 infores:hetionet CAID:CA340747238 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747238 MONDO:0100368 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting This variant disrupts a canonical splice site in intron 5 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including Absent or severely decreased rod electroretinogram (ERG) responses (0.5 pts); Congenital night blindness (0.5 pts); Clinical diagnosis of Leber congenital amaurosis (0.5 pts); Previous exome, genome or 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts); decreased central visual acuity (1 pt), nystagmus (1 pt); Symptomatic onset between birth and age five years (1 pt); OCT is preserved with respect to vision loss (1 pt); Pigmentary retinopathy with attenuated vessels (0.5 pts); and Abnormal color vision (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 points, PP4_Moderate). In summary, this variant meets the criteria to be classified as pathogenic by the ClinGen Leber Congenital Amaurosis / early onset Retinal Dystrophy VCEP; PVS1, PP4_Moderate, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747238/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6375 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017181 infores:hetionet CHEBI:3219 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020453 infores:hetionet CHEBI:132233 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0013404 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0243026 infores:hetionet CHEBI:4784 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0235896 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038362 infores:hetionet CHEBI:63580 biolink:causes MONDO:0019338 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0036202 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0281774 infores:hetionet CHEBI:50924 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0854069 infores:hetionet CHEBI:681848 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0012833 infores:hetionet CAID:CA123254 biolink:causes MONDO:0100326 infores:clingen CAID:CA123254 MONDO:0100326 PMID:20020534 Uncertain Significance PS3_Supporting, PP3, PM2_Supporting PM3, PP4 The ITGB3 missense variant NM_000212.3:c.836A>T replaces the lysine residue with a methionine residue (p.Lys279Met). The highest population minor allele frequency in gnomAD v4.1 is 0.00004005 (3/74904 alleles) in the African/African-American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The variant is predicted by in silico tools to be damaging to protein function (REVEL 0.744; PP3). The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number cells positive for the αIIbβ3 complex (estimated to be ~7% compared to wild type; PMID: 20020534; PS3_supporting). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123254/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6916 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0036980 infores:hetionet CHEBI:47657 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C2047937 infores:hetionet CHEBI:4814 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020625 infores:hetionet CHEBI:2611 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0030554 infores:hetionet CHEBI:47381 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151746 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0857468 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0857468 infores:hetionet CHEBI:71417 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0003862 infores:hetionet CHEBI:51230 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0270996 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0687707 infores:hetionet NCBIGene:26007 biolink:causes MONDO:0032927 infores:monarchinitiative not_provided not_provided HGNC:24552 MONDO:0032927 uuid:be0be351-5d7d-4ebc-9332-a862e095aa38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0020625 infores:hetionet CHEBI:3698 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0002994 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0006849 infores:hetionet CHEBI:42355 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0151878 infores:hetionet CHEBI:6832 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0016382 infores:hetionet CHEBI:63638 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0038325 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0017574 infores:hetionet CHEBI:135930 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0011603 infores:hetionet NCBIGene:89891 biolink:causes MONDO:0014287 infores:monarchinitiative not_provided not_provided HGNC:28296 MONDO:0014287 uuid:8cd29b99-9ed9-400a-92b5-297d7d6d887e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0011609 infores:hetionet CHEBI:94807 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0011603 infores:hetionet CHEBI:27690 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0025222 infores:hetionet CHEBI:134991 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0037763 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004936 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0243026 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0037274 infores:hetionet CHEBI:7959 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0206062 infores:hetionet CHEBI:50648 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0086769 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0027769 infores:hetionet CHEBI:8069 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0011603 infores:hetionet CHEBI:63620 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C2830004 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0029927 infores:hetionet CHEBI:28787 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0687713 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0018418 infores:hetionet CHEBI:45783 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0010200 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0853149 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C1306341 infores:hetionet CHEBI:52172 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0037299 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0341012 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0877144 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0877144 infores:hetionet CHEBI:10125 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C2047937 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0234930 infores:hetionet CHEBI:27974 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1112214 infores:hetionet CHEBI:73274 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0022660 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020651 infores:hetionet CHEBI:3650 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0013395 infores:hetionet CHEBI:9168 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151905 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C2047937 infores:hetionet CHEBI:9571 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022408 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0027441 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0042075 infores:hetionet CHEBI:66899 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0027441 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0007222 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0006852 infores:hetionet NCBIGene:55034 biolink:causes MONDO:0011346 infores:monarchinitiative not_provided not_provided HGNC:18234 MONDO:0011346 uuid:db00a7f4-8332-4423-8a59-203021b33795 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018790 infores:hetionet CHEBI:8871 biolink:causes HP:0002599 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1608410 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0009806 infores:hetionet CHEBI:63599 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0013604 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0042963 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0027441 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0032285 infores:hetionet CHEBI:9757 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0011168 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0009450 infores:hetionet CHEBI:77733 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0026821 infores:hetionet CHEBI:28177 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0035410 infores:hetionet CHEBI:101853 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0030193 infores:hetionet CHEBI:8707 biolink:causes EFO:0020923 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151821 infores:hetionet CHEBI:52717 biolink:causes MONDO:0044037 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085642 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0012833 infores:hetionet CHEBI:18248 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0016204 infores:hetionet CHEBI:15765 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C1368065 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027769 infores:hetionet CHEBI:47898 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014518 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009241 infores:hetionet CHEBI:5147 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C2830004 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0456495 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0456495 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0012359 infores:hetionet GO:0014819 biolink:causes GO:0050881 infores:ubergraph knowledge_assertion manual_agent GO:0014819 GO:0050881 CHEBI:63631 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042267 infores:hetionet CHEBI:64321 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0042023 infores:hetionet CHEBI:7565 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0549622 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0036508 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0018801 infores:hetionet CAID:CA028363 biolink:causes MONDO:0100316 infores:clingen CAID:CA028363 MONDO:0100316 PMID: Likely Benign BS1 BA1, BP1, BP4, BP3, PS4, PS3, PS2, BS3, BS4, BP5, PVS1, PM2, PM6, PP1, PP2, PP3, PP4, BS2, PM4, PM1 NM_000218.3(KCNQ1):c.1252G>A is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 418 (p.Val418Ile). This variant has not been published in the literature for individuals with prolonged QTc interval. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0005001 (30/59992 alleles) in the Admixed American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 (BS1). This variant does not have available experimental data. The computational predictor REVEL gives a score of 0.587, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.02 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA028363/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:474180 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0344232 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1167965 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0029560 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0029560 infores:hetionet CHEBI:63617 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018965 infores:hetionet CHEBI:5280 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0271298 infores:hetionet CAID:CA355964392 biolink:causes MONDO:0001586 infores:clingen CAID:CA355964392 MONDO:0001586 PMID: Likely Pathogenic PVS1_Strong, PM3, PP4_Moderate, PM2_Supporting PS1 The NM_000203.5:c.1402+2T>G variant alters the canonical donor splice site dinucleotide of intron 9 of IDUA. This variant is predicted to result in skipping of biologically-relevant-exon 9 (IDUA has 14 exons), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). Two patients with this variant had documented IDUA deficiency within the affected range in leukocytes (0.2-3.4 versus normal range 27.2–52 nmol/h/mg protein), and clinical features specific to MPS I including macrocephaly, arthropathy, hepatomegaly, and airway disease. These patients also had documented increased urinary excretion of HS and DS. Thus three areas are met, giving the evidence to meet PP4 at the moderate level (PP4_Moderate). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927). The variants were confirmed to be in trans by parental testing (PMID: 21480867) (1 point). Another patient is compound heterozygous for the variant and c.98A>C (p.His33Pro). This variant has not yet been classified by the ClinGen LD VCEP. The allelic data from the second patient will be used in the classification of p.His33Pro and is not included here to avoid circular logic. Total points for PM3 = 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002819 (3/1064228 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Two additional variants at this canonical splice donor site c.1402+1G>A and c.1402+1G>T) have been classified as likely pathogenic by the ClinGen LD VCEP. However PS1 does not apply (Table 2, PMID: 37352859). There is a ClinVar entry for this variant (ClinVar Variation ID: 553131). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PVS1_Strong, PM3, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355964392/MONDO:0001586/091 2025-04-21 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41774 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030305 infores:hetionet CHEBI:135939 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0030252 infores:hetionet CAID:CA16042098 biolink:causes MONDO:0021056 infores:clingen CAID:CA16042098 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting, BS2_Supporting PM4, BA1, PS3, BS1, BS3 The c.6796_6810del variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 5 amino acids (p.Thr2266_Ser2270del). This variant has been observed in 3 heterozygous individuals over the age of 50 with no features of FAP or family history of FAP, which is worth 3 healthy individual points (BS2_Supporting; Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BS2_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042098/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75722 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0034882 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0233746 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233746 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0549209 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018099 infores:hetionet CHEBI:73274 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0085641 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0020649 infores:hetionet CHEBI:55346 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0010200 infores:hetionet CHEBI:31981 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C1096355 infores:hetionet CAID:CA320251372 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251372 MONDO:0011071 PMID: Uncertain Significance BP4 PS4, PS1, PS3, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.4(RUNX1):c.1196G>T (p.Ser399Ile) is a missense variant which has a REVEL score < 0.50 (0.116) and SpliceAI does not predict (Δ scores ≤ 0.20) a significant impact on the canonical splice sites or the creation of putative cryptic splice sites (BP4). The variant has been published in a pediatric patient with B-ALL, which was confirmed to be in the germline based on assessment in a remission sample (PMID: 34166225). It was also identified in a male patient with primary myelofibrosis, but the germline assessment was based on a buccal mucosa sample (PMID: 31135094), and in a 58-year-old Greek patient with ovarian cancer who also carried RAD51C c.90del/p.F32Sfs*8 (LOVD: Individual #00021433). However, PS4_supporting cannot be applied because the variant presents more than 2 times in gnomAD (5 heterozygotes in v2 and 1 heterozygote in v3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251372/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63577 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013395 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0234458 infores:hetionet CAID:CA257181 biolink:causes MONDO:0009595 infores:clingen CAID:CA257181 MONDO:0009595 PMID: Pathogenic PM3_Very Strong, PM2, PP4, PP1 This variant is present in gnomAD v.4 at a Total allele frequency of 0.00003942, with [6 alleles / 152220 total alleles] in the European (Finnish) population, which is lower than the ClinGen SCID VCEP has specified PM2_Supporting threshold of <0.0000447. At least one patient presented Methapyseal dysplasia (+1.0 points) and hypotrichosis (+0.5 points). This variant is reported in trans with the variant (70A>g) in 6 independent families (+1.0 points each), reaching a total score of 6.0, and PM3_VeryStrong is met. A multiple-case family with this variant in trans with n.70A>C is reported with two affected siblings, meeting PP1.In summary, this variant meets the criteria to be classified as Pathogenic for Autosomal recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM3_VeryStrong, PM2_Supporting, PP4, and PP1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA257181/MONDO:0009595/088 2025-08-20 2025-08-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019079 infores:hetionet CHEBI:4953 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0151744 infores:hetionet CHEBI:45863 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0232495 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0162429 infores:hetionet CHEBI:40303 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0085605 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0042109 infores:hetionet CHEBI:68558 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0740394 infores:hetionet CAID:CA8328379 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328379 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PM3 NM_014336.5(AIPL1):c.796G>T (p.Ala266Ser) is a missense variant replacing the alanine at position p.266 with serine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00002431, with 39 /1604002 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa who harbored the variant in the heterozygous state (VCEP member-provided data, GeneDx). However, the proband was not counted for PM3_Supporting because no second AIPL1 variant was detected, and because the available phenotype details were not sufficiently compatible with the expected severity or age of onset. In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3_moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328379/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17698 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0023530 infores:hetionet NCBIGene:9381 biolink:causes MONDO:0010986 infores:monarchinitiative not_provided not_provided HGNC:8515 MONDO:0010986 uuid:e0d486c2-b0cd-49f4-9233-37962b3121a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0014394 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0162119 infores:hetionet CHEBI:3387 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0039070 infores:hetionet CAID:CA327013112 biolink:causes MONDO:0100039 infores:clingen CAID:CA327013112 MONDO:0100039 PMID: Benign BP5_Strong, BS1, BS2, BP4 PM2 The highest population minor allele frequency of the p.Arg981Gly variant in CDKL5 (NM_003159.2) in gnomAD v4.1 is 0.00008376 in the Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Arg981Gly variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Arg981Gly variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_strong). The computational predictor REVEL gives a score of 0.078, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). RS1 (NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2941C>G (p.Arg981Gly) variant in CDKL5 transcript (NM_003159.2) (NM_000330.4 (RS1):c.185-3221G>C) is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong, BP4). (CDKL5 Specifications v.4.1; curation approved on 06/25/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA327013112/MONDO:0100039/034 2025-06-25 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:27436 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0022354 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0027765 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0541896 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0541896 infores:hetionet CHEBI:52717 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002994 infores:hetionet CHEBI:6128 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C1368065 infores:hetionet CAID:CA183538 biolink:causes MONDO:0021060 infores:clingen CAID:CA183538 MONDO:0021060 PMID: Uncertain Significance BP4 BS1, PM2, BA1, PP3 The NM_002524.5:c.553C>T variant in NRAS is a missense variant predicted to cause substitution of proline by serine at amino acid 185 (p.Pro185Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006663 (14/129152 alleles) in the European (non-Finnish) population (Optional: PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.051, which is below the threshold of 0.3, evidence that does not predict a damaging effect on NRAS function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA183538/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA274462 biolink:causes MONDO:0700270 infores:clingen CAID:CA274462 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1, PM2 BA1, BS1 The c.5515C>T (p.Gln1839*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID: 9792409, 10873394, 22649200, 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Very Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA274462/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63584 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0011991 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0518015 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040409 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0085606 infores:hetionet CAID:CA410150178 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150178 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.847C>T (p.Gln283Ter) is a nonsense variant that is predicted to cause a premature stop codon in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1).This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This nonsense variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150178/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes MONDO:0000474 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0265122 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002170 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0004096 infores:hetionet CHEBI:73274 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0700345 infores:hetionet CHEBI:9168 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030252 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1384666 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0024115 infores:hetionet CHEBI:63598 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013428 infores:hetionet CHEBI:8707 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0014457 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0749249 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0749249 infores:hetionet CHEBI:9667 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0043352 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0086132 infores:hetionet CHEBI:42820 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C1720775 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0039971 infores:hetionet CAID:CA229689 biolink:causes MONDO:0009861 infores:clingen CAID:CA229689 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 The c.676C>T (p.Gln226Ter) variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It does not appear to have been reported in detail in the published literature, but has been noted in the BioPKU database (PMID: 24939588) and in Clinvar (Variation ID 102782), without further case-level information. Classification: Likely PathogenicSupporting Criteria: PVS1, PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229689/MONDO:0009861/006 2020-04-05 2020-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5551 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0234215 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015469 infores:hetionet NCBIGene:222662 biolink:causes MONDO:0012460 infores:monarchinitiative not_provided not_provided HGNC:21253 MONDO:0012460 uuid:a1a80623-64f5-40ad-9b7b-0b80e52f2e43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA5779338 biolink:causes MONDO:0021060 infores:clingen CAID:CA5779338 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.291-6T>G variant in the HRAS gene is 0.051% (14/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5779338/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:40009 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0030554 infores:hetionet CHEBI:64310 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0011603 infores:hetionet CAID:CA402531414 biolink:causes MONDO:0012589 infores:clingen CAID:CA402531414 MONDO:0012589 PMID: Likely Pathogenic PP3, PS2, PM2_Supporting The p.Gly496Cys variant in TCF4 occurs in the confirmed de novo state in an individual with a neurodevelopmental disorder consistent with TCF4 abnormality (PS2). The p.Gly496Cys variant in TCF4 is absent from gnomAD (PM2_supporting). This variant occurs at the last amino acid residue in exon 16 and is predicted to affect the canonical splice donor site in intron 16 by several splice prediction programs. In summary, the p.Gly496Cys variant in TCF4 is classified as Likely Pathogenic based on the ACMG/AMP criteria (PS2, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA402531414/MONDO:0012589/016 2021-05-11 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA014310 biolink:causes MONDO:0005045 infores:clingen CAID:CA014310 MONDO:0005045 PMID:15483641PMID:27532257PMID:15483641 Likely Benign BA1, BS4 PP3, PM2, BS1, PS4, BP4 The c.3981C>A (p.Asn1327Lys) variant in MYH7 has been identified in 0.16% (FAF 95% CI; 24/10156) of Ashkenazi Jewish chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; Kelly 2018 PMID:29300372). Based on criteria selected, this variant should be classified as benign; however, the expert panel felt that since frequency in other populations is not as elevated as in the Ashkenazi Jewish population, it warrants adjusting in the final classification to likely benign. Therefore, this variant is classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1 with expert panel adjustment. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014310/MONDO:0005045/002 2020-04-24 2021-06-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45924 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0011609 infores:hetionet CAID:CA343725124 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725124 MONDO:0005338 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BS1, BS3, PP1, PM5, PM4, PS1, PS4, PS3, PS2, BA1, BP4 The c.1009C>G variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Glutamic Acid at amino acid 337 (p.Gln337Glu). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.728, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 10916185), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725124/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:10133 biolink:causes MONDO:0100553 infores:monarchinitiative not_provided not_provided HGNC:17142 MONDO:0100553 uuid:c0ad12aa-e803-4aec-b8d5-c90d47042465 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027813 infores:hetionet CHEBI:48669 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0004245 infores:hetionet CHEBI:50567 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0017178 infores:hetionet CHEBI:9139 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0019079 infores:hetionet NCBIGene:7750 biolink:causes MONDO:0859190 infores:monarchinitiative not_provided not_provided HGNC:12989 MONDO:0859190 uuid:b9784d1b-f697-4caf-81b1-441c3c483039 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0152031 infores:hetionet CHEBI:9137 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0014591 infores:hetionet CHEBI:367163 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0522055 infores:hetionet CHEBI:3387 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0220981 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0521495 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0017178 infores:hetionet CHEBI:3176 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0547030 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2047937 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0522570 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0522570 infores:hetionet CHEBI:6367 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151786 infores:hetionet CHEBI:119915 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0023066 infores:hetionet CHEBI:63598 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151611 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0041969 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0036572 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0232288 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0232288 infores:hetionet CHEBI:5790 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0023218 infores:hetionet CHEBI:6715 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085631 infores:hetionet CHEBI:49668 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0015672 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0233494 infores:hetionet CHEBI:64028 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0392156 infores:hetionet CHEBI:4717 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0039070 infores:hetionet CAID:CA10568278 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568278 MONDO:0010602 PMID:24108539 Likely Benign BA1, PS3 PP3, BP4 The c.2840C>G variant in F8 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 947 (p.Pro947Arg). In gnomAD v2.1.1, the Grpmax total for exomes is 0.0003539 and for genomes is 0.0003564, which are both higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>0.000333) for BA1. In gnomAD v3.1.2, the Grpmax total for genomes is 0.0007292, which is also above the cut off to apply BA1. An one stage clotting assay in HEK293T cells showed reduced FVIII:C of about 30% indicating that this variant impacts protein function (PMID: 24108539)(PS3). The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging (>=0.6) or benign impact (<=0.3) on F8 function. this variant is classified as a likely benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1, PS3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568278/MONDO:0010602/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Contradicts true GO:0010946 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:0010946 GO:0007127 CHEBI:5138 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0041657 infores:hetionet CHEBI:50859 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0232462 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0235763 infores:hetionet CHEBI:41774 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0024437 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0038454 infores:hetionet CHEBI:47519 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0235266 infores:hetionet CHEBI:8107 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0035455 infores:hetionet CHEBI:6950 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0008031 infores:hetionet CHEBI:2682 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0041948 infores:hetionet CHEBI:53691 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0039231 infores:hetionet CAID:CA396472624 biolink:causes MONDO:0007648 infores:clingen CAID:CA396472624 MONDO:0007648 PMID:29798843 Uncertain Significance PM2_Supporting, PVS1_Moderate BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM5, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.2594G>A p.(Trp865Ter) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region and is downstream of the most 3' pathogenic variant, c.2506G>T p.(Glu836Ter), PVS1_Moderate. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Moderate, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396472624/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7573 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151539 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0015230 infores:hetionet CHEBI:87681 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0023380 infores:hetionet CHEBI:2948 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0549463 infores:hetionet NCBIGene:84074 biolink:causes MONDO:0032686 infores:monarchinitiative not_provided not_provided HGNC:25326 MONDO:0032686 uuid:323b4eaa-38b7-4572-947b-e25047c3d470 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0041969 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0015230 infores:hetionet CHEBI:8869 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0024523 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0010692 infores:hetionet CHEBI:6076 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0012569 infores:hetionet CAID:CA254013 biolink:causes MONDO:0019497 infores:clingen CAID:CA254013 MONDO:0019497 PMID: Likely Pathogenic PP1_Strong, PP3, PM2_Supporting PM3 The c.6337A>T is a missense variant in MYO15A predicted to cause a substitution of isoleucine to phenylalanine at amino acid 2113. This variant is absent in gnomAD v4.1 (PM2_Supporting). However, it has been described as a founder variant with a carrier frequency of 25/100 in Bengkala, Bali (PMID: 9603736). This variant has been identified in the homozygous state in 1 Bengkala kindred with hearing loss and in the heterozygous state in one Chinese individual with hearing loss (PMIDs: 9603736, 27018975). The p.Ile2113Phe variant has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; PMID: 9603736). The REVEL computational prediction analysis tool produced a score of 0.91, which is above the threshold necessary to apply PP3 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PP3, PM2_Supporting. (The ClinGen Hearing Loss VCEP Specifications Version 1, 07/17/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA254013/MONDO:0019497/023 2024-07-17 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf UNII:UMD7G2653W biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011570 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0034069 infores:hetionet CHEBI:3699 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0002792 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0006145 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0020517 infores:hetionet CHEBI:64354 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0014742 infores:hetionet CAID:CA183381 biolink:causes MONDO:0019497 infores:clingen CAID:CA183381 MONDO:0019497 PMID: Pathogenic PP1, PM2_Supporting, PS4_Supporting, PVS1 BP5, BP7, BS1, BS4, BS3, BS2, PP4, PP3, PP2, PM3, PM1, PM5, PM4, PM6, BP2, BP4, BP1, BP3, BA1, PS2, PS3, PS1 The NM_004999.4:c.238C>T (p.Arg80Ter) variant in MYO6 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/113330 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.002%) for PM2_Supporting. This variant has been reported in 2 families with teenage onset progressive sensorineural hearing loss, both displaying an autosomal dominant pattern of inheritance (PS4_Supporting; PMID: 32143290, 33111345). The variant has been reported to segregate with hearing loss in 2 affected family members from 1 family (PP1; PMID:33111345). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PVS1, PM2_Supporting, PS4_Supporting, PP1). (VCEP specifications version 2.0.0; December 21, 2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA183381/MONDO:0019497/005 2023-01-24 2023-02-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:9086 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0162429 infores:hetionet CHEBI:3393 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0541799 infores:hetionet CHEBI:45409 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151539 infores:hetionet CHEBI:63580 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0014518 infores:hetionet CHEBI:50173 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151908 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0009450 infores:hetionet CAID:CA409108340 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108340 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4, BP4, BA1, PS4, BS1 The c.953T>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of leucine to glutamine at codon 318 (p.(Leu318Gln)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). In summary, c.953T>A meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108340/MONDO:0015967/085 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038362 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0267596 infores:hetionet CHEBI:3568 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151825 infores:hetionet CHEBI:35778 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0039070 infores:hetionet CHEBI:2379 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0003862 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0033117 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031542 infores:hetionet CHEBI:45863 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042024 infores:hetionet CHEBI:2379 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0020580 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021163 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0022665 infores:hetionet CHEBI:134743 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0017178 infores:hetionet CHEBI:9137 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151905 infores:hetionet CHEBI:51230 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0027441 infores:hetionet CHEBI:28241 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0232487 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0021400 infores:hetionet CHEBI:84050 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0011991 infores:hetionet CHEBI:63613 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C1443060 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027813 infores:hetionet CHEBI:40237 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0036396 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0022893 infores:hetionet CHEBI:3534 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0015672 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1266194 infores:hetionet CHEBI:9586 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020625 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022904 infores:hetionet GO:0160083 biolink:causes CL:0011025 infores:ubergraph knowledge_assertion manual_agent GO:0160083 CL:0011025 CAID:CA044260 biolink:causes MONDO:0007750 infores:clingen CAID:CA044260 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM3, PM2, PP4, PP3 The NM_000527.5(LDLR):c.664T>C (p.Cys222Arg) variant is classified as a Likely pathogenic variant for Familial Hypercholesterolemia by applying evidence codes PM2, PM1, PM3, PS4_supporting, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2: PopMax MAF = 0.0001098 (0.01%) in East Asian exomes (gnomAD v2.1.1)PM1: Variant meets PM2 and alters Cys222, one of the cysteine residues listed.PM3: Variant meets PM2 and is identified in two index cases with homozygous FH phenotype (LDL mmol/L = 17.9 and 14.09 respectively), PMID: 15823276PS4_supporting: Variant meets PM2 and is identified in at least 5 index cases who fulfill SB possible/definite FH or DLCN>=6 criteria for FH from GeneDx Inc., Ambry Genetics, and the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)PP3 : REVEL = 0.966.PP4: Variant meets PM2 and identified in at least 2 FH case from GeneDx Inc, 1 FH case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), and 1 FH case from Ambry Genetics, all of them fulfilling SB criteria for possible/definite FH or DLCN > 6. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA044260/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:367163 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0036974 infores:hetionet CHEBI:8713 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0042963 infores:hetionet CHEBI:9434 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0010692 infores:hetionet CAID:CA916081984 biolink:causes MONDO:0011132 infores:clingen CAID:CA916081984 MONDO:0011132 PMID:37419334 Uncertain Significance PS3_Moderate, PM2_Supporting, PM4 PP4 NM_001369369.1(FOXN1):c.1850_1854del (p.Tyr617CysfsTer?) is a frameshift variant in the final exon which alters the remaining 5% of the protein and is predicted to cause a stop loss with elongation of the protein by 124 amino acids (PM4). This variant is absent from gnomADv2.1.1 (PM2_supporting). Functional analysis was performed in a luciferase reporter construct, which was cotransfected into heterologous cells with an expression vector containing mutant or wild-type FOXN1. This variant had 32% luciferase activity compared to wild-type, which is below the <50% threshold for PS3_Moderate (PMID: 37419334). One patient has been reported heterozygous for this variant (P25 in PMID: 31447097) however there was insufficient phenotypic information to determine if it is specific to FOXN1. In summary this variant meets criteria to be classified as uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM4, PM2_Supporting, PS3_Moderate as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081984/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:408174 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0007785 infores:hetionet CHEBI:7936 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039240 infores:hetionet CHEBI:3508 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C1257843 infores:hetionet CAID:CA058500 biolink:causes MONDO:0007783 infores:clingen CAID:CA058500 MONDO:0007783 PMID: Uncertain Significance PP3, PS4, PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with methionine at codon 4081 of the RYR1 protein, p.(Thr4081Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00033, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). A functional study using [3H]ryanodine in HEK293 cells showed altered activity of this variant compared to wild-type but this study did not meet the VCEP criteria for a well-established functional study (PMID:27558158). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.649 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA058500/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6759 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0020458 infores:hetionet CHEBI:59750 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0175167 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0948594 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0009450 infores:hetionet CHEBI:4784 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151908 infores:hetionet NCBIGene:2661 biolink:causes MONDO:0044777 infores:monarchinitiative not_provided not_provided HGNC:4224 MONDO:0044777 uuid:82bc446c-354c-41b6-8ae5-626ba6ffe20d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75988 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0011071 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0002962 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0518015 infores:hetionet CHEBI:6717 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013456 infores:hetionet CHEBI:119915 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231530 infores:hetionet CHEBI:3723 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041657 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0005940 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549393 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549393 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0233494 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0037274 infores:hetionet CHEBI:50885 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0262431 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030312 infores:hetionet CHEBI:4975 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0016382 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0178298 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018621 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0403632 infores:hetionet CHEBI:48390 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0003862 infores:hetionet CHEBI:63589 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0015967 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0003850 infores:hetionet CHEBI:75984 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0231218 infores:hetionet CHEBI:75246 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0034886 infores:hetionet CHEBI:7494 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0010200 infores:hetionet CHEBI:46345 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0015967 infores:hetionet CAID:CA253338 biolink:causes MONDO:0019497 infores:clingen CAID:CA253338 MONDO:0019497 PMID:17850630PMID:22899989PMID:25963016PMID:26264712PMID:24164807PMID:17850630PMID:24618850PMID:22899989PMID:30367262 Pathogenic PP1_Strong, PM2_Supporting, PM3_Strong, PS4 PP3, BP4 The allele frequency of the c.719C>T (p.Pro240Leu) variant in the CDH23 gene is 0.05% (10/17246) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been reported in > 10 probands with hearing loss without evidence of retinal disease, including >5 homozygotes, at least 1 compound heterozygote with c.6712+1G>A variant, and >5 compound heterozygotes with rare variants of uncertain significance (PM3_Strong; PMID:24164807, 24618850, 25963016, 26264712, 17850630, 22899989). This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID: 17850630, 22899989). The variant was identified in the heterozygous state in a patient with Usher syndrome who also harbored a homozygous missense variant in MYO7A (PMID: 24618850). A case-control meta analysis found that the p.Pro240Leu variant was associated with a 12-fold higher risk of hearing loss compared to the wild-type allele (OR = 11.68; 95% CI = 3.16–43.24; PS4), though it should be noted that it appears that some probands were included in more than one study included in the meta-analysis (PMID 30367262). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PM2_Supporting, PS4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA253338/MONDO:0019497/005 2019-07-22 2019-10-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:7931 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0033975 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0234458 infores:hetionet CAID:CA16020727 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020727 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, BP7 PP4 The NM_000277.3(PAH):c.84C>T variant is a synonymous (silent) variant (p.N28=) that is not predicted by SpliceAI to impact splicing (BP7). This variant has been detected in at least 1 individual suspected with Phenylketonuria. This individual was compound heterozygous for the variant and a pathogenic variant, c.473G>A (p.R158Q) (PMID: 17502162, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: BP7, PM2_supporting, PM3_supporting (Version 2.0, 7/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020727/MONDO:0009861/006 2025-07-18 2025-07-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63598 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C2047937 infores:hetionet CHEBI:3176 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0858635 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0032285 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0920235 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0920235 infores:hetionet CHEBI:3044 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0085631 infores:hetionet CHEBI:64028 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0006145 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0277925 infores:hetionet NCBIGene:808 biolink:causes MONDO:0032915 infores:monarchinitiative not_provided not_provided HGNC:1449 MONDO:0032915 uuid:a872cdd3-ddab-4572-95eb-ede793966157 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:27247 biolink:causes MONDO:0011582 infores:monarchinitiative not_provided not_provided HGNC:16287 MONDO:0011582 uuid:b767a1df-1077-40b8-a6b8-f286872af7ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4315 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0036974 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1306341 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0042769 infores:hetionet CHEBI:47519 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0011603 infores:hetionet NCBIGene:81562 biolink:causes MONDO:0029465 infores:monarchinitiative not_provided not_provided HGNC:19263 MONDO:0029465 uuid:141533c9-be29-4429-bb10-c6941a786563 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0009782 infores:hetionet UNII:K2J09EMJ52 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0547030 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0497247 infores:hetionet CHEBI:8461 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0004093 infores:hetionet NCBIGene:2737 biolink:causes MONDO:0008266 infores:monarchinitiative not_provided not_provided HGNC:4319 MONDO:0008266 uuid:f605a588-2ab4-4d16-8682-6365b9027b1b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0343863 infores:hetionet CHEBI:5383 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0235198 infores:hetionet CHEBI:63635 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0853034 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0948594 infores:hetionet CHEBI:9332 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0015672 infores:hetionet CHEBI:8713 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0000737 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0549622 infores:hetionet CHEBI:87715 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0004604 infores:hetionet CHEBI:75984 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0013604 infores:hetionet CHEBI:47612 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0011991 infores:hetionet CAID:CA2695233285 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695233285 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.69del (p.Glu24LysfsTer?) is a frameshift variant due to a 1-nucleotide deletion within exon 2 of 15, which results in a premature stop codon and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), reduced electroretinogram B-wave (1 pt), and reduced visual acuity (0.5 pts), with genotyping by next-generation sequencing with a panel of genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 28863407, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PVS1, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695233285/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:3752 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0151827 infores:hetionet CHEBI:8869 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0007859 infores:hetionet CHEBI:46557 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0036974 infores:hetionet CHEBI:4907 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0349790 infores:hetionet NCBIGene:3861 biolink:causes MONDO:0008059 infores:monarchinitiative not_provided not_provided HGNC:6416 MONDO:0008059 uuid:cb549ef1-cd33-4371-94fa-1b3d9df590ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399804764 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804764 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The c.964C>T variant in ITGA2B is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 322 (p.His322Tyr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804764/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA386966092 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966092 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Moderate, PP3, PP4 The c.781G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 261 (p.(Glu261Lys)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP threshold of 0.70 (PP3). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.80e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID:16917892, internal lab contributor). This variant segregated with diabetes, with four informative meioses in this individual's family (PP1_Moderate; internal lab contributor). Taken together, this evidence supports the classification of c.781G>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP1_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966092/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CAID:CA163840 biolink:causes MONDO:0700270 infores:clingen CAID:CA163840 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5_Supporting, PVS1 PM2 The c.1402_1403del (p.Lys468Glufs*18) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 23807571, 26896183, 31691010). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003 in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA163840/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63598 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042963 infores:hetionet CHEBI:9448 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0040264 infores:hetionet CHEBI:63605 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0002170 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0005741 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0027769 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0030312 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019112 infores:hetionet CAID:CA10385145 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385145 MONDO:0100437 PMID: Benign BA1, BP4 PS4 NM_001034853.2(RPGR):c.3407G>A (p.Gly1136Asp) variant is a missense variant encoding the substitution of glycine with aspartic acid at amino acid 1136. The computational predictor REVEL gives a score of 0.053, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). This variant is present in gnomAD v.4.1.0 at a frequency of 0.0008861 among hemizygous individuals, with 352 variant alleles / 397,264 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in at least 1 male proband and 2 females. The male proband had insufficient reported details and did not meet the PS4 requirement of some functional vision impairment in an affected male by age 30 years, or decreased/absent cone and/or rod electroretinogram responses (PMID: 32679846), so PS4_supporting was not met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385145/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:28787 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C2939465 infores:hetionet CAID:CA355964379 biolink:causes MONDO:0001586 infores:clingen CAID:CA355964379 MONDO:0001586 PMID: Likely Pathogenic PVS1_Strong, PM3, PP4, PM2_Supporting The NM_000203.5:c.1402+1G>A variant in IDUA occurs within the canonical splice donor site of intron 9. While the effect of this change has not been proven experimentally, it is predicted to cause skipping of biologically-relevant-exon 9 out of 14 total exons, resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been detected in at least two individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and c.502G>T p.(Gly168Ter), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PMID: 33301762). The other individual was homozygous for the variant (PMID: 27146977) (PM3). These two patients had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including coarse facies, hepatosplenomegaly, corneal opacity, recurrent infections, intellectual disability, hernia, and/or cardiomegaly, cardiomyopathy, and dysostosis multiplex (PP4)(PMIDs: 33301762, 27146977). This variant is absent in gnomAD v4.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555490). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): (PVS1_Strong, PM3, PP4, PM2_Supporting).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355964379/MONDO:0001586/091 2024-12-05 2025-03-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5127 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0151907 infores:hetionet CHEBI:144551 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0231919 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0029134 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0009450 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0005586 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0031350 infores:hetionet CHEBI:10119 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013390 infores:hetionet CHEBI:6931 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0042420 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0040034 infores:hetionet CHEBI:63612 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0039239 infores:hetionet CHEBI:17303 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0428977 infores:hetionet CHEBI:45285 biolink:causes MONDO:0015194 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0002896 infores:hetionet CHEBI:145499 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0041834 infores:hetionet CHEBI:47780 biolink:causes MONDO:0007122 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003079 infores:hetionet CHEBI:7824 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0010200 infores:hetionet CHEBI:7823 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0221242 infores:hetionet CHEBI:4551 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0600125 infores:hetionet CAID:CA410203410 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203410 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PM5, PP4, BS2 NM_001754.5(RUNX1):c.332C>G (p.Thr111Ser) is a missense variant which is found within the runt homology domain but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203410/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6015 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0020440 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0234215 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0542075 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0542075 infores:hetionet CAID:CA260620 biolink:causes MONDO:0015967 infores:clingen CAID:CA260620 MONDO:0015967 PMID: Pathogenic PS4, PS2, PM3_Supporting, PP1_Strong, PM1, PS3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.683C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to methionine at codon 228 (p.(Thr228Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds glucose and ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In an assay in which the ATPkm was above the MDEP threshold for evaluation of relative activity index (RAI), the Kcat/S0.5 ratio of the Thr228Met variant was 0.0001, which is less than 0.5 of wild type (PS3_Supporting; PMID: 11372010). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in at least 26 unrelated individuals with hyperglycemia (PS4; PMIDs: 21720051, 2721189, 36836406, 36723869, 32741144, 34756319, 11372010, 1502186, 31639168, 24323243, internal lab contributors). At least 2 of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 36723869). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PS2; PMID: 24323243). This variant has been detected in one individual with neonatal diabetes who was found to be homozygous for the c.683C>T variant (PM3_Supporting; PMID: 11372010). In summary, c.683C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PS4, PS2, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA260620/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:9757 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0233414 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0000729 infores:hetionet CHEBI:44185 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0041582 infores:hetionet CAID:CA006724 biolink:causes MONDO:0100316 infores:clingen CAID:CA006724 MONDO:0100316 PMID: Uncertain Significance PS4_Moderate, BP5 BP4, PS3, BS1, BS3, PM2, PP3, PP1 NM_000218.3(KCNQ1):c.217C>A (p.Pro73Thr) is a missense variant that causes substitution of proline with threonine at amino acid 73. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0002533, with 287 alleles / 1132988 total alleles in the European non-Finnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1 (PS4_Moderate; PMID: 15840476, PMID: 19716085, PMID: 22949429, PMID: 24606995, PMID: 20851114). The variant has been reported to segregate with long QT syndrome 1 through a proband and 1 affected family member (PMID: 26743238), which is not sufficient to meet PP1. This variant has been observed in 1 patient with an alternate molecular basis for disease (NM_000335.5(SCN5A):c.1231G>A (p.Val411Met)) with a phenotype that matches long QT syndrome 3 (BP5; PMID: 28588847, PMID: 23098067). This variant has also been observed in 1 patient with additional variants in KCNQ1 present both in cis (NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)) and in trans (listed as p.Asp454Thrfs*7) providing an alternate molecular basis for disease (PMID: 24667783), however, BP5 is only applicable when the phenotypes match another form of LQTS. The computational predictor REVEL gives a score of 0.566, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.01 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing. The Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29) was unable to generate a prediction of functional impact for this variant due to a limitation of the model and the unavailability of secondary structure at this residue (PMID: 29021305), so neither PS3_Supporting nor BS3_Supporting was met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4_Moderate, BP5. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006724/MONDO:0100316/112 2025-07-01 2025-07-01 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0065374 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0162830 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0012833 infores:hetionet CHEBI:42797 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C2830004 infores:hetionet CHEBI:5613 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0085637 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0026821 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0022660 infores:hetionet GO:0030710 biolink:causes GO:0030855 infores:ubergraph knowledge_assertion manual_agent GO:0030710 GO:0030855 UMLS:C0657912 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029134 infores:hetionet CHEBI:63607 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0438215 infores:hetionet NCBIGene:6730 biolink:causes MONDO:0957809 infores:monarchinitiative not_provided not_provided HGNC:11302 MONDO:0957809 uuid:f7453468-6e22-4c2e-82fa-c83fae0ef95c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2654 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0011603 infores:hetionet CHEBI:10650 biolink:causes MONDO:0043537 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009088 infores:hetionet CHEBI:2955 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0750857 infores:hetionet CHEBI:49960 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C3665624 infores:hetionet CHEBI:4909 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0231528 infores:hetionet CHEBI:16469 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0030196 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014534 infores:hetionet CHEBI:47898 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0012569 infores:hetionet CHEBI:83531 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0018834 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0521499 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0521499 infores:hetionet CHEBI:45409 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C2939147 infores:hetionet CHEBI:3614 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0332575 infores:hetionet CHEBI:94848 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0340464 infores:hetionet CHEBI:50922 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0152198 infores:hetionet CAID:CA10558616 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558616 MONDO:0010726 PMID: Benign BP5, BS2, BA1 PP3 "The c.378-3C>T variant in MECP2 (NM_004992.3) has an allele frequency of 0.038% in ""Other"" sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The c.378-3C>T variant is observed in at least 2 unaffected individuals (Invitae internal database) (BS2). The c.378-3C>T variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). In summary, the c.378-3C>T variant in MECP2 is classified as benign for Rett Syndrome based on the ACMG/AMP criteria (BA1, BS2, BP5)." Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558616/MONDO:0010726/016 2022-02-18 2022-06-30 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:39112 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0160390 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0235431 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0007642 infores:hetionet CHEBI:2567 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0162830 infores:hetionet CHEBI:31348 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042024 infores:hetionet CAID:CA3054201763 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201763 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, BP4, PM6, BS1, BS3, BS4, PM4, PM1, PM3, PP4, PP1, PP2, PP3 NM_001754.5(RUNX1):c.400_404del (p.Ala134fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98–c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201763/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CAID:CA397842713 biolink:causes MONDO:0018875 infores:clingen CAID:CA397842713 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PM5_Supporting, PP3, PP4, PM2_Supporting BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1, PM4, PM1, PM3, BP7, BP5, BS1, BS4, PVS1, PM6, PP2, PP1, BS2 The NM_000546.6: c.412G>A variant in TP53 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 138 (p.Ala138Thr). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644, [16007150]). Computational predictor scores (BayesDel = 0.4548; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.412G>C (p.Ala138Pro)) (ClinVar Variation ID: 12376), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). In summary, this variant meets the criteria to be classified as of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3_supporting, PP3, PM2_supporting, PM5_supporting, PP4. (Bayesian Points: 3; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397842713/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:2259 biolink:causes MONDO:0859340 infores:monarchinitiative not_provided not_provided HGNC:3671 MONDO:0859340 uuid:68038357-4b91-4e84-9bc0-7d76da87ff55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0021843 infores:hetionet CHEBI:5118 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013144 infores:hetionet CHEBI:7447 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0027497 infores:hetionet CHEBI:6061 biolink:causes UMLS:C0520540 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0520540 infores:hetionet CHEBI:8107 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0019079 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0151849 infores:hetionet CAID:CA367398581 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398581 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting The c.1181G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 394 (p.(Arg394Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.851, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L)(PP4_Moderate; internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). Additionally, it segregated with diabetes with 2 informative meioses in 2 families (PP1; internal lab contributors). In summary, c.1181G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398581/MONDO:0015967/086 2025-04-22 2025-04-23 Semidominant inheritance HP:0032113 Supports CHEBI:10119 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0541941 infores:hetionet GO:0019914 biolink:causes GO:0051726 infores:ubergraph knowledge_assertion manual_agent GO:0019914 GO:0051726 UNII:5V9KLZ54CY biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0009806 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0553548 infores:hetionet CHEBI:3568 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0392525 infores:hetionet CHEBI:10112 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0026826 infores:hetionet CHEBI:584020 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0013604 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0242073 infores:hetionet CHEBI:4953 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0014173 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0424000 infores:hetionet CHEBI:9316 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0235146 infores:hetionet CHEBI:180905 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0013447 infores:hetionet CHEBI:8768 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0014518 infores:hetionet CHEBI:78543 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1384353 infores:hetionet CHEBI:46195 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0232292 infores:hetionet CHEBI:9599 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0038990 infores:hetionet NCBIGene:3704 biolink:causes MONDO:0013461 infores:monarchinitiative not_provided not_provided HGNC:6176 MONDO:0013461 uuid:a7718be9-5c66-4363-8c58-e425b325b555 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030794 infores:hetionet CHEBI:116278 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0001122 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0553690 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0553690 infores:hetionet CHEBI:7573 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0017178 infores:hetionet CHEBI:18385 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0236071 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0009938 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0038325 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042373 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030552 infores:hetionet CHEBI:9448 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0162830 infores:hetionet CHEBI:135929 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0027497 infores:hetionet CHEBI:6717 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0000737 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0518015 infores:hetionet CAID:CA387460893 biolink:causes MONDO:0019497 infores:clingen CAID:CA387460893 MONDO:0019497 PMID: Likely Pathogenic PP3, PM2_Supporting, PM3_Strong PS3 The NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting). This variant has been reported in at least three probands with hearing loss (2.5 PM3_Strong points). Two probands were compound heterozygous (one confirmed trans, the other one assumed trans) with the pathogenic c.35delG, p.G12Vfs variant (Clinvar ID: 17004, PMID 17666888, internal data from GeneDx). Another proband was compound heterozygous for the pathogenic variant p.Leu90Pro (ClinVar ID: 17016, University of Minnesota internal data). The REVEL computational prediction analysis tool produced a score of 0.9 meeting PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP3 (VCEP specifications version 2; 01.17.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387460893/MONDO:0019497/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:7915 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0518015 infores:hetionet CHEBI:10125 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1443060 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0149836 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0027765 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0037822 infores:hetionet CHEBI:8805 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0085649 infores:hetionet CHEBI:17303 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0006118 infores:hetionet CHEBI:4466 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0003467 infores:hetionet CAID:CA120632 biolink:causes MONDO:0044970 infores:clingen CAID:CA120632 MONDO:0044970 PMID: Pathogenic PP1_Moderate, PM5, PM6_Strong, PP3, PS4 The m.13513G>A (p. D393N) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset typically in childhood with some reports of onset in adolescence who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or mitochondrial encephalopathy (PS4; PMID: 25681084; PMID: 27344355; PMID: 30128709; PMID: 12624137; PMID: 14520659; PMID: 17400793; PMID: 18495510). This variant has been identified as a de novo occurrence in at least 5 probands with primary mitochondrial disease (PM6_strong; PMID: 27344355; PMID: 17400793; PMID: 18495510). This variant heteroplasmy level segregated with severity in 6 families where healthy mothers were found to have the variant at low heteroplasmy levels (PP1_moderate; PMID: 25681084; PMID: 12624137; PMID: 14520659). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by mitomap.org and ClinVar – m.13514A>G (p.D393G; PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PM5, PP1_moderate, PP3). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120632/MONDO:0044970/014 2021-10-26 2021-10-26 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:9570 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0036690 infores:hetionet CHEBI:100241 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151662 infores:hetionet CHEBI:5106 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0917801 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0026848 infores:hetionet CHEBI:3219 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0858635 infores:hetionet CHEBI:63584 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0016382 infores:hetionet CHEBI:9667 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0030305 infores:hetionet CHEBI:8776 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0002792 infores:hetionet CHEBI:18258 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0600228 infores:hetionet CHEBI:9586 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0037763 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042790 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0162830 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0178298 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006908 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0032001 infores:hetionet CHEBI:4868 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0236075 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0038367 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0041969 infores:hetionet CHEBI:71219 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0042963 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0220983 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0020538 infores:hetionet CHEBI:16469 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007859 infores:hetionet CHEBI:9086 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151907 infores:hetionet GO:0039593 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0039593 GO:0000278 CHEBI:17549 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0018799 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233459 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0442874 infores:hetionet CAID:CA512341158 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341158 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1266G>A (p.Glu422=) is a synonymous variant. REVEL score not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.378488 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341158/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5138 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020624 infores:hetionet CHEBI:261649 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0014742 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0948594 infores:hetionet CHEBI:100246 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0000729 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1535879 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1535879 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0435002 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0021053 infores:hetionet CHEBI:15551 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0002792 infores:hetionet NCBIGene:324 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:583 MONDO:0007256 uuid:f1ab1b5c-6c1c-489e-866b-6ecad9b72813 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA312279 biolink:causes MONDO:0008723 infores:clingen CAID:CA312279 MONDO:0008723 PMID: Likely Pathogenic PM1, PM3, PM2, PP4_Moderate PP3 The NM_000018.4(ACADVL):c.1532G>A p.(Arg511Gln) in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 511 in the last codon of exon 15. The highest population minor allele frequency in gnomAD v4.1 is 0.00003 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.651 which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. However, in silico splicing predictor SpliceAI indicates that this variant may affect splicing by disrupting the donor splice site of intron 15 of ACADVL. This variant resides within a region, amino acids 481–516, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 18227065, 20060901 ) (PM1_Moderate). This variant has been detected in at least 5 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 3 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variants (PM3_Moderate, PMIDs: PMID: 35400565, 29519241, PMID: 25652019). At least 3 patients with this variant displayed abnormal enzyme levels and NBS, which is highly specific for VLCAD (PP4_Moderate, PMIDs: 35400565, 29519241, PMID: 25652019, 18670371). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1_moderate, PM3_Moderate, PP4_Moderate, PP3_Supporting, PM2_Supporting (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312279/MONDO:0008723/021 2025-08-12 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8863 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0038525 infores:hetionet CHEBI:50859 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0917801 infores:hetionet CHEBI:64318 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0030554 infores:hetionet CHEBI:49040 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0037763 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1443060 infores:hetionet CAID:CA2573106063 biolink:causes MONDO:0007453 infores:clingen CAID:CA2573106063 MONDO:0007453 PMID: Pathogenic PS4_Moderate, PVS1, PP4_Moderate, PM2_Supporting The c.1309_1310del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 437 (NM_000162.5), adding 21 novel amino acids before encountering a stop codon (p.(Thr437LeufsTer21)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and dominant family history of diabetes) (PP4_Moderate; internal lab contributors). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.1309_1310del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PVS1, PM2_supporting, PP4_moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106063/MONDO:0007453/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports NCBIGene:1956 biolink:causes MONDO:0014481 infores:monarchinitiative not_provided not_provided HGNC:3236 MONDO:0014481 uuid:faa545a5-52af-4c76-a77d-b959599cb944 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4659 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0030554 infores:hetionet NCBIGene:64175 biolink:causes MONDO:0012581 infores:monarchinitiative not_provided not_provided HGNC:19316 MONDO:0012581 uuid:e552423c-1696-4716-a072-8bb4177cb518 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18067 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0151735 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030578 infores:hetionet CHEBI:107736 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0917801 infores:hetionet CHEBI:31236 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037672 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0033581 infores:hetionet CHEBI:5138 biolink:causes NCIT:C50547 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1704212 infores:hetionet CHEBI:47898 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0033774 infores:hetionet CHEBI:7936 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151878 infores:hetionet CHEBI:6715 biolink:causes MONDO:0008608 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013080 infores:hetionet CHEBI:5893 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0030252 infores:hetionet CHEBI:6532 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0021053 infores:hetionet CHEBI:45783 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018790 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0015230 infores:hetionet CHEBI:8597 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0011124 infores:hetionet CHEBI:3749 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0020621 infores:hetionet CHEBI:49375 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018944 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0855242 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0032285 infores:hetionet CHEBI:204928 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C1257843 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0021308 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018790 infores:hetionet CHEBI:18358 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0021368 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0007114 infores:hetionet CHEBI:30830 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0039070 infores:hetionet CHEBI:7852 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0009782 infores:hetionet CHEBI:100246 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0162830 infores:hetionet CHEBI:7601 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0006266 infores:hetionet CHEBI:5141 biolink:causes UMLS:C0333494 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0333494 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030319 infores:hetionet CHEBI:27300 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0004093 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0019348 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0267596 infores:hetionet CHEBI:100246 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0027497 infores:hetionet CHEBI:45599 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0020598 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0042401 infores:hetionet CHEBI:5128 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0009676 infores:hetionet CHEBI:36791 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2939147 infores:hetionet CAID:CA390865930 biolink:causes MONDO:0100216 infores:clingen CAID:CA390865930 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting BA1, BP2, PP3, PP1, PP4, BS2, PM5, PS1, PS4, PS3, PS2, BS1, BS3, BS4 The NM_177438.2:c.5077C>A variant in DICER1 is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 1693 (p.His1693Asn). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.476; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting. (Bayesian Points: 1; VCEP specifications version 1.3.0; 02/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390865930/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5138 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0267596 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0855247 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0855247 infores:hetionet CHEBI:45081 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151878 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0151529 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0152517 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011616 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0015397 infores:hetionet CHEBI:3011 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0030807 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0013295 infores:hetionet CHEBI:10124 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151610 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0026821 infores:hetionet CHEBI:2950 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0041582 infores:hetionet CHEBI:2687 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0023530 infores:hetionet CHEBI:27834 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0015967 infores:hetionet CHEBI:3561 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0005747 infores:hetionet CHEBI:9927 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0151934 infores:hetionet CHEBI:3698 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0687713 infores:hetionet CHEBI:44915 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0018681 infores:hetionet CHEBI:4856 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0020458 infores:hetionet CHEBI:75045 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0013604 infores:hetionet CHEBI:47657 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0004238 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011630 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0010709 infores:hetionet CHEBI:9332 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0231528 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0162830 infores:hetionet CAID:CA410148125 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148125 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1102A>C (p.Met368Leu) is a missense variant which has a REVEL score < 0.50 (0.451) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148125/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:2000074 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000074 GO:0007275 CHEBI:6339 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0030252 infores:hetionet CAID:CA10580105 biolink:causes MONDO:0100488 infores:clingen CAID:CA10580105 MONDO:0100488 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1137+1delG is a canonical splice variant and cDNA sequencing shows use of cryptic splice site leading to a frameshift (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in one family meeting HDGC criteria (PS4_Supporting, SCV000275921.4). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580105/MONDO:0100488/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:4995 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0027720 infores:hetionet CHEBI:71272 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0003862 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0009806 infores:hetionet CHEBI:9434 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C1368065 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1262141 infores:hetionet CAID:CA229354 biolink:causes MONDO:0009861 infores:clingen CAID:CA229354 MONDO:0009861 PMID:16256386 Pathogenic PVS1, PM2, PP4 The c.112dupG variant in PAH has been previously reported as a single variant (no second mutation detected) in 1 Chinese patient with classic PKU (PMID: 16256386); BH4 deficiency was not excluded (PP4). The variant is a frameshift variant occurring in exon 2 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229354/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6690 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0015672 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0002792 infores:hetionet CAID:CA10579920 biolink:causes MONDO:0700272 infores:clingen CAID:CA10579920 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BS1, BS2, PP3, BP4, BA1 The c.3350G>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 1117 (p.Arg1117Lys); however, RNA analysis demonstrated that the variant impacts splicing, leading to exon 12 skipping (r.3202_3350del149, p.Gly1068ValfsTer5) and a translational frameshift with 100% allele bias and no wild-type splice events harboring the variant (Ambry Genetics). The resulting mRNA is not predicted to undergo nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region. This variant is absent from gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been observed in combination with a PALB2 exon 11 duplication, which is classified as pathogenic, in at least four adult individuals without Fanconi Anemia (Ambry Genetics and Invitae). Although the phase of the variants was not confirmed, evidence from these individuals was not used to apply BS2 on the basis that multiple co-occurrences of this variant with the exon 11 duplication in unrelated individuals suggests these variants are more likely to be in cis. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM2_Supporting, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10579920/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8382 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0026846 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0265031 infores:hetionet CHEBI:5775 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C2242996 infores:hetionet CHEBI:63581 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1262113 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C1443060 infores:hetionet CAID:CA410146845 biolink:causes MONDO:0100083 infores:clingen CAID:CA410146845 MONDO:0100083 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1397T>G (p.Met466Arg) is a missense variant. This missense variant has a REVEL score < 0.50 (0.313), phyloP100 = 6.572, spliceAI Δ score 0.00 (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146845/MONDO:0100083/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0023418 infores:hetionet CHEBI:4856 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C1443060 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0008325 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0392160 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0392160 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0042267 infores:hetionet CHEBI:17823 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0042963 infores:hetionet CHEBI:142290 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0392171 infores:hetionet CHEBI:8485 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0011616 infores:hetionet CHEBI:6888 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0085570 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235416 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0030305 infores:hetionet CAID:CA383520272 biolink:causes MONDO:0015628 infores:clingen CAID:CA383520272 MONDO:0015628 PMID:19422453 Likely Pathogenic PP3, PP4, PM2_Supporting, PS3 BP5 The NM_000552.5:c.2546G>A variant encodes a missense substitution of cysteine by tyrosine at codon 849 in VWF. The variant has been reported in at least 1 patient displaying excessive mucocutaneous bleeding as well as laboratory phenotypes of low activity/VWF:Ag ratio and loss of high molecular weight multimers, which together are specific for VWD type 2A. (PP4, PMID: 19422453, PMID: 35452508). The patient had three heterozygous missense mutations (R202W, C849Y, and R1583Q) in the VWF gene. R1583Q is classified Likely Benign by the VWD VCEP and R202W (ClinVar 619940 VUS) is also considered a VUS at this time. The variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.579, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. However, the splicing predictor SpliceAI gives a delta score of 0.72 for donor loss (PP3), which has been functionally confirmed to result in an aberrant splicing product in an affected individual (Figure 3, PMID: 19422453). Multimerization assay performed with the p.Cys849Tyr recombinant mutant and a wild-type control vWF expressed by COS-7 cells showed absence of higher-MW multimers, indicating that this variant has a damaging effect on protein function consistent with the multimerization defect observed in the proband (PS3, PMID: 19422453). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP3, PP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383520272/MONDO:0015628/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6775 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0702166 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0022073 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0267792 infores:hetionet CHEBI:8884 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0004096 infores:hetionet CHEBI:61033 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0019079 infores:hetionet CHEBI:3312 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0428977 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0022660 infores:hetionet CAID:CA228508 biolink:causes MONDO:0015630 infores:clingen CAID:CA228508 MONDO:0015630 PMID: Pathogenic PP3, PP1, PM2_Supporting, PS4_Supporting, PS3, PM5 PP4 The NM_000552.5(VWF):c.3971G>C (p.Gly1324Ala) missense variant has been reported in at least one type 2M patient with VWF:RCo/VWF:Ag ratio of 0.44 (PMID: 12008946; PS4_supporting). The variant segregated with VWD type 2M through 3 affected meioses from this family (PP1; PMID:12008946). Another missense variant in the same codon has been reported in a patient with VWD type 2 Gly1324Ser, which has been classified likely pathogenic by the ClinGen VWD VCEP (PM5). The computational predictor REVEL gives a score of 0.719, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Platelet/GP1b binding assays performed with the Gly1324Ala recombinant mutant vWF expressed by COS-7 showed no binding indicating that this variant has a damaging effect on protein function (PMIDs: 12008946, 10845912; PS3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PM5, PP1, PP3, PS4_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228508/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5118 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009806 infores:hetionet CHEBI:7852 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0424295 infores:hetionet CHEBI:7445 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0018681 infores:hetionet CHEBI:480999 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0016382 infores:hetionet CHEBI:63635 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0032227 infores:hetionet CAID:CA891862619 biolink:causes MONDO:0009290 infores:clingen CAID:CA891862619 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The c.1057del (p.Gln353SerfsTer39) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant displayed clinical features consistent with infantile-onset Pompe disease and was treated with enzyme replacement therapy (PP4_Moderate)(PMID: 29181627). This individual is compound heterozygous for the variant and a pathogenic variant, c.1057del, phase unconfirmed (PM3_Supporting)(PMID 29181627). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved on August 17th, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA891862619/MONDO:0009290/010 2021-08-19 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:37924 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0041969 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0015397 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0020517 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0017574 infores:hetionet CHEBI:79699 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0016436 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0039971 infores:hetionet CHEBI:6775 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151539 infores:hetionet CHEBI:40279 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0003862 infores:hetionet CHEBI:64312 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151578 infores:hetionet CAID:CA512340989 biolink:causes MONDO:0011071 infores:clingen CAID:CA512340989 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 The c.1356G>C (p.Val452=) (NM_001754.5) is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (0). In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100 (0.3) (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (1/11550 alleles) in East Asian population (PM2_Supporting, BS1, and BA1 are not met).In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512340989/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006145 infores:hetionet CHEBI:8107 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0917801 infores:hetionet GO:1903772 biolink:causes GO:0019068 infores:ubergraph knowledge_assertion manual_agent GO:1903772 GO:0019068 UNII:2N4O9L084N biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0344232 infores:hetionet CHEBI:32293 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0001925 infores:hetionet CHEBI:10110 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151603 infores:hetionet CHEBI:41879 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0234632 infores:hetionet CHEBI:3013 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0039971 infores:hetionet CHEBI:75246 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0027441 infores:hetionet NCBIGene:27040 biolink:causes MONDO:0044721 infores:monarchinitiative not_provided not_provided HGNC:18874 MONDO:0044721 uuid:2a63a0ab-48bb-4d0f-9396-8b204c0eb3ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5995 biolink:causes MONDO:0013414 infores:monarchinitiative not_provided not_provided HGNC:9990 MONDO:0013414 uuid:f68f4ef0-6d24-48e2-834e-55ccb70c3b20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0036830 infores:hetionet CHEBI:4702 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0015672 infores:hetionet GO:0061046 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0061046 GO:0007275 CHEBI:16796 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0236065 infores:hetionet CHEBI:46295 biolink:causes NCIT:C96935 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0149707 infores:hetionet CAID:CA135990 biolink:causes MONDO:0021060 infores:clingen CAID:CA135990 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.477G>A (p.Leu159=) variant in the HRAS gene is 0.185% (140/65296) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135990/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5864 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0151799 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0036572 infores:hetionet CHEBI:72564 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085649 infores:hetionet CAID:CA10360343 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360343 MONDO:0100039 PMID: Benign BS1, BP5, BS2 PM1 The allele frequency of the p.Arg355Gln variant in CDKL5 is 0.011% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Additionally, the p.Arg355Gln variant is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2) and the variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5). In summary, the p.Arg355Gln variant in CDKL5 is classified as Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BS1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360343/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7915 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0917801 infores:hetionet CHEBI:63581 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0085633 infores:hetionet CHEBI:9943 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017181 infores:hetionet CHEBI:2682 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0016204 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151491 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151491 infores:hetionet CHEBI:7986 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0020538 infores:hetionet CHEBI:47780 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011253 infores:hetionet CHEBI:10127 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0338656 infores:hetionet CHEBI:42797 biolink:causes HP:0001482 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151811 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0232197 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0034150 infores:hetionet CHEBI:63619 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0009782 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0010399 infores:hetionet CHEBI:63623 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0151905 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C2047937 infores:hetionet NCBIGene:6049 biolink:causes MONDO:0007576 infores:monarchinitiative not_provided not_provided HGNC:10069 MONDO:0007576 uuid:df5f9b97-b284-43d7-84fc-2024fda2c8a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681850 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes HP:0001508 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0231246 infores:hetionet NCBIGene:5430 biolink:causes MONDO:0032829 infores:monarchinitiative not_provided not_provided HGNC:9187 MONDO:0032829 uuid:98e3522f-a5c1-45bb-ba4f-2ddc69534934 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0019521 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0038358 infores:hetionet CHEBI:27666 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C1720798 infores:hetionet CHEBI:31705 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0008031 infores:hetionet CHEBI:8890 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0852911 infores:hetionet CHEBI:6801 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0085649 infores:hetionet CHEBI:2654 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0001824 infores:hetionet CHEBI:5138 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013428 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0851341 infores:hetionet CHEBI:63612 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0015672 infores:hetionet CHEBI:10119 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002064 infores:hetionet CAID:CA343717998 biolink:causes MONDO:0005338 infores:clingen CAID:CA343717998 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.539T>A variant in MYOC is a missense variant predicted to cause substitution of Leucine by Glutamine at amino acid 180 (p.Leu180Gln). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008474 (1 allele out of 1,180,018), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.516, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (Pasutto et al, pers. comm.), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343717998/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7577 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0002170 infores:hetionet CHEBI:465284 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C2830004 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0027765 infores:hetionet CAID:CA210783 biolink:causes MONDO:0013144 infores:clingen CAID:CA210783 MONDO:0013144 PMID: Uncertain Significance PP3, PP1, PM2_Supporting, PS4_Supporting The c.1141T>C variant in SERPINC1 is a missense variant predicted to cause substitution of serine by proline at amino acid 381 (p.Ser381Pro). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. Only one had a family history of disease supported with reported antithrombin activity levels (PS4_Supporting; PMIDs: 1551681, 30975910). The variant has been reported to segregate with hereditary antithrombin deficiency in two affected meioses from one family (PP1; PMID:1551681). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.616, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PP3, PM2_Supporting, PS4_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210783/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2379 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0043144 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0242350 infores:hetionet CHEBI:6846 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0001807 infores:hetionet CHEBI:8024 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0600142 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151713 infores:hetionet CHEBI:5138 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1112442 infores:hetionet NCBIGene:5781 biolink:causes MONDO:0011908 infores:monarchinitiative not_provided not_provided HGNC:9644 MONDO:0011908 uuid:2be7703a-43e5-4829-9a7a-983f5e85cb2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020615 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0022660 infores:hetionet CHEBI:3207 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0220870 infores:hetionet CHEBI:68534 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0035455 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038358 infores:hetionet CAID:CA658824790 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824790 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.2617dup (p.Tyr873LeufsTer11) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon at the junction of biologically-relevant-exons 18 and 19 (GAA has 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 550478). The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824790/MONDO:0009290/010 2024-04-05 2024-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7444 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0034063 infores:hetionet CHEBI:135005 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0278106 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0860803 infores:hetionet NCBIGene:1802 biolink:causes MONDO:0100217 infores:monarchinitiative not_provided not_provided HGNC:3004 MONDO:0100217 uuid:5f812359-f8d6-460a-83e0-921103e32c42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0149931 infores:hetionet CAID:CA628018663 biolink:causes MONDO:0009290 infores:clingen CAID:CA628018663 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4, PM4_Supporting The NM_000152.5:c.93_95del variant in GAA is predicted to cause a change in the length of the protein (p.Leu32del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001149 (1/8700 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. PROVEAN and Mutation Taster predict that the variant will have no impact on GAA function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 526535). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, PM4_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 28, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA628018663/MONDO:0009290/010 2023-05-28 2023-05-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:68554 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0019079 infores:hetionet NCBIGene:3040 biolink:causes MONDO:0054802 infores:monarchinitiative not_provided not_provided HGNC:4824 MONDO:0054802 uuid:a56b0709-ab9c-4ced-81c8-ea4d39fa8258 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA137969 biolink:causes MONDO:0021060 infores:clingen CAID:CA137969 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.823C>T (p.Leu275=) variant in the MAP2K2 gene is 0.2% (19/6224) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137969/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:72297 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0011175 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020615 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1096658 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1096658 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0860453 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0860453 infores:hetionet CHEBI:80630 biolink:causes UMLS:C1142335 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1142335 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0277925 infores:hetionet CHEBI:4814 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0008031 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0239385 infores:hetionet UMLS:C0010592 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0036690 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040034 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0151726 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151726 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0553698 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0553698 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004623 infores:hetionet CHEBI:68558 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0028961 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0232492 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0009938 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042571 infores:hetionet CHEBI:4708 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0542571 infores:hetionet CHEBI:71219 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0600142 infores:hetionet CHEBI:7476 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0028734 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0039971 infores:hetionet CHEBI:63631 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003126 infores:hetionet CHEBI:51380 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0027497 infores:hetionet CHEBI:15367 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0040822 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0234215 infores:hetionet CHEBI:66903 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0231528 infores:hetionet NCBIGene:7075 biolink:causes MONDO:0030316 infores:monarchinitiative not_provided not_provided HGNC:11809 MONDO:0030316 uuid:d2545eb2-c03d-4bc1-9164-3a6f10192c20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0085932 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0003123 infores:hetionet CHEBI:8356 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152031 infores:hetionet GO:0030224 biolink:causes CL:0000576 infores:ubergraph knowledge_assertion manual_agent GO:0030224 CL:0000576 CHEBI:31547 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0151662 infores:hetionet CHEBI:45599 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0009806 infores:hetionet CHEBI:50924 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0018944 infores:hetionet CHEBI:61049 biolink:causes MONDO:0020642 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0022680 infores:hetionet CHEBI:10110 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0878544 infores:hetionet CHEBI:51164 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0233407 infores:hetionet CHEBI:7465 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C2129214 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0231218 infores:hetionet NCBIGene:64711 biolink:causes MONDO:0030298 infores:monarchinitiative not_provided not_provided HGNC:14178 MONDO:0030298 uuid:54f50aa7-e3ba-4544-94ff-5edcc8100a73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3310 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0033774 infores:hetionet CHEBI:4708 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C2242737 infores:hetionet NCBITaxon:5691 biolink:causes MONDO:0005459 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5691 MONDO:0005459 CHEBI:404903 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0036974 infores:hetionet CHEBI:5441 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0012569 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0026113 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020453 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001266 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014733 infores:hetionet CHEBI:27666 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0019209 infores:hetionet NCBITaxon:5693 biolink:causes MONDO:0001444 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5693 MONDO:0001444 CHEBI:39867 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0001807 infores:hetionet GO:2000032 biolink:causes GO:0048367 infores:ubergraph knowledge_assertion manual_agent GO:2000032 GO:0048367 CHEBI:65346 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0015397 infores:hetionet CHEBI:6541 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0014518 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002453 infores:hetionet CHEBI:9654 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042023 infores:hetionet CHEBI:75722 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151683 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0235639 infores:hetionet CHEBI:40303 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0917801 infores:hetionet CHEBI:15544 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0011603 infores:hetionet CHEBI:49668 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0232462 infores:hetionet CAID:CA254162 biolink:causes MONDO:0012589 infores:clingen CAID:CA254162 MONDO:0012589 PMID:19235238PMID:17436254PMID:22045651PMID:17436254PMID:22045651PMID:17436254PMID:22045651 Pathogenic PS3_Supporting, PM1, PP3, PP4, PS4_Supporting, PM6_Strong, PM2_Supporting The p.Arg580Gln variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 22045651, 17436254) (PM6_strong, PS4_supporting, PP4). Transcriptional reporter assay has shown that this variant impacts protein function (PMID 19235238) (PS3_supporting). The p.Arg580Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Gln variant in TCF4 is classified as Pathogenic for autosomal dominant Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PS4_supporting, PP1, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA254162/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:40237 biolink:causes UMLS:C0343378 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0343378 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0242350 infores:hetionet CHEBI:10125 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0424790 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0544618 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0544618 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006978 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037998 infores:hetionet CHEBI:29007 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0085702 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0042109 infores:hetionet CAID:CA8970200 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970200 MONDO:0012589 PMID: Likely Benign BP4, BP5, BS2 BS1 The c.1486+4G>C variant in TCF4 is present in 2 XX and 1 XY individual(s) in gnomAD v2 (0.005%) (not sufficient to meet BS1 criteria). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.1486+4G>C variant is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The c.1486+4G>C variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the c.1486+4G>C variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BP4, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970200/MONDO:0012589/032 2024-02-23 2024-03-31 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8214 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0011603 infores:hetionet CHEBI:47780 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018524 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0037274 infores:hetionet CHEBI:28445 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0027066 infores:hetionet CHEBI:253342 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0015230 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233459 infores:hetionet CHEBI:63581 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C3263723 infores:hetionet CHEBI:37924 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0232461 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0687133 infores:hetionet CHEBI:94411 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0042963 infores:hetionet CHEBI:3127 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0011606 infores:hetionet CHEBI:78320 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0009450 infores:hetionet NCBIGene:652 biolink:causes MONDO:0010906 infores:monarchinitiative not_provided not_provided HGNC:1071 MONDO:0010906 uuid:92bdc963-efe6-4e15-b488-3c4b644f3521 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0018802 infores:hetionet CHEBI:31536 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0010200 infores:hetionet CAID:CA16612528 biolink:causes MONDO:0008535 infores:clingen CAID:CA16612528 MONDO:0008535 PMID: Pathogenic PP1, PM2_Supporting, PP4_Moderate, PS4, PS3 PP3 The NM_001114753.3: c.991G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 331 (p.Gly331Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 19767588, 34872578, 16690726, 34880085, 15517393, 25970827, 29171923, 32573726, 21158752, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 19767588, 21158752). The variant has been reported to segregate with HHT in 3 affected meioses from 2 families (PP1; PMID: 19767588, 34872578). The computational predictor REVEL gives a score of 0.202, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, RT-PCR analysis of cDNA demonstrated that the variant impacts splicing by leading to exon 7 skipping (PS3; PMID: 16690726). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS3, PS4, PP4_Moderate, PP1, PM2_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16612528/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9571 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0012833 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0852711 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0852711 infores:hetionet CHEBI:6888 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0231528 infores:hetionet CHEBI:4653 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0036974 infores:hetionet CHEBI:40303 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0038325 infores:hetionet CHEBI:188986 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0030252 infores:hetionet CHEBI:51450 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0036973 infores:hetionet CHEBI:31515 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C2225524 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030312 infores:hetionet CHEBI:46195 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0231856 infores:hetionet CHEBI:3207 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0151632 infores:hetionet CAID:CA410206852 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206852 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.709A>G (p.Arg237Gly) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206852/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63621 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019348 infores:hetionet CHEBI:465284 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0004134 infores:hetionet CHEBI:94686 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0014724 infores:hetionet CHEBI:2704 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0009676 infores:hetionet GO:2000136 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:2000136 GO:0072359 CHEBI:50275 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0034359 infores:hetionet UMLS:C0065374 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0231218 infores:hetionet CHEBI:48844 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0014457 infores:hetionet CAID:CA404075004 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075004 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP4, BP2, BA1, PS1, PS3, PS2, PS4, BS1, BS3, BS4, PM5, PM3, PM6, BS2, PP4, PP1 The NM_000527.5(LDLR):c.170A>C (p.Asp57Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met.PP3: REVEL= 0.959. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075004/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA16616518 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616518 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS3, BP2, BA1, PVS1, PM6, PM2, BS4, BS3, BS1, PM5, PM1, PM4, PP1, PP3 The synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score: -0.68 < 0.1 [-14.1;6.4]) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616518/MONDO:0011071/008 2020-04-10 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013404 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0020676 infores:hetionet CHEBI:51209 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0042963 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0699893 infores:hetionet CHEBI:9654 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020625 infores:hetionet CAID:CA164201 biolink:causes MONDO:0100488 infores:clingen CAID:CA164201 MONDO:0100488 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1132A>C (p.Thr378Pro) missense variant has a maximum subpopulation frequency of 0.026% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 80 probands not meeting HDGC phenotype criteria (BS2; SCV000184088.7, SCV000637698.8, SCV001801305.4). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA164201/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:52717 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0231218 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0234936 infores:hetionet NCBIGene:7068 biolink:causes MONDO:0007784 infores:monarchinitiative not_provided not_provided HGNC:11799 MONDO:0007784 uuid:b6f4242b-967e-404a-a1e1-adc6779b27e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0403632 infores:hetionet CHEBI:28001 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0013146 infores:hetionet CHEBI:3387 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011606 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1443060 infores:hetionet CHEBI:45285 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0019158 infores:hetionet CHEBI:93305 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0241164 infores:hetionet CHEBI:7903 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0026764 infores:hetionet CHEBI:51860 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0040517 infores:hetionet CHEBI:66964 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C2830004 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C1956346 infores:hetionet CHEBI:101853 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0020437 infores:hetionet CHEBI:194135 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042023 infores:hetionet NCBITaxon:287 biolink:causes GO:0042710 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:287 GO:0042710 DB06151_MESH_D003550_1 CHEBI:7936 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021053 infores:hetionet CHEBI:7496 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0085932 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0855331 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0855331 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0009806 infores:hetionet GO:1902956 biolink:causes GO:0042775 infores:ubergraph knowledge_assertion manual_agent GO:1902956 GO:0042775 UNII:UMD7G2653W biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0392171 infores:hetionet NCBIGene:10715 biolink:causes MONDO:0014545 infores:monarchinitiative not_provided not_provided HGNC:14253 MONDO:0014545 uuid:5382cedb-7dd9-4b99-9a12-41865fec1b9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0008031 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085617 infores:hetionet CHEBI:9086 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020639 infores:hetionet CHEBI:47499 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0003467 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0006266 infores:hetionet CHEBI:3176 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0033774 infores:hetionet CHEBI:3403 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0023380 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0009450 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0025061 infores:hetionet CHEBI:59560 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0085631 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0243026 infores:hetionet CHEBI:59582 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0009450 infores:hetionet CAID:CA10576288 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576288 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PM5_Strong, PS4, PM2, PP3, PP1, PP4 BA1, BP1, BP4, BP2, BP3, PS2, PS1, BS1, BS3, BS4, BP5, BP7, PM1, PM3, PM4, PM6, PVS1, BS2, PP2 The NM_000527.5(LDLR):c. c.796G>A (p.Asp266Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM5_Strong, PS3_Moderate, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID: 12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory);PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1);PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines.There are 2 variants in the same codon classified as Pathogenic by these guidelines.PS3_Moderate - Level 2 assay: PMID 12414836: Homozygous patient cells, 125I assays - result - <2% LDL-LDLR binding and internalisation. Functional study is consistent with damaging effect;PP1 - 3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation);PP3 - REVEL = 0,83;PP4 - Variant meets PM2. Identified in at least 1 FH case fulfilling Simon-Broome criteria published in PMID 12414836. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576288/MONDO:0007750/013 2022-05-04 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA000602 biolink:causes MONDO:0017623 infores:clingen CAID:CA000602 MONDO:0017623 PMID: Uncertain Significance BS1_Supporting PVS1, PM2, PM6, BP7, BP5, BS4, PP2, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS2, PS4 PTEN c.-835C>T, also described as c.-834C>T (NC_000010.10:g.89623392C>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1_P: Allele frequency of 0.0002207 (0.02207%, 15/67980 alleles) in the European subpopulation of the gnomAD cohort, v3.1.2. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000602/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:10133 biolink:causes MONDO:0013264 infores:monarchinitiative not_provided not_provided HGNC:17142 MONDO:0013264 uuid:bf51eb65-1bc6-4572-ae7a-d3cee5f14ab9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0085681 infores:hetionet CHEBI:5134 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0009782 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0026848 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0009375 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0152436 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0235706 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0235706 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0018799 infores:hetionet CHEBI:100246 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0038999 infores:hetionet NCBIGene:6323 biolink:causes MONDO:0030268 infores:monarchinitiative not_provided not_provided HGNC:10585 MONDO:0030268 uuid:7bd22d48-2e88-4d19-9f13-0007f4413794 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:27019 biolink:causes MONDO:0009484 infores:monarchinitiative not_provided not_provided HGNC:2954 MONDO:0009484 uuid:cc3e9a2f-ac5c-4420-a4c6-dcbac73641f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75246 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0009676 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0006849 infores:hetionet CHEBI:6775 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033247 infores:hetionet CHEBI:70746 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0086565 infores:hetionet CHEBI:2453 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0023518 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042134 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0023530 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0277925 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151313 infores:hetionet CHEBI:68841 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C3665386 infores:hetionet CAID:CA10585767 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585767 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP3, PP4, PP1 PS3, PM5 The NM_000527.5 (LDLR):c.2089G>C (p.Ala697Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL=0.78.PS4_Supporting, PP4: Variant meets PM2, and is identified in at least 5 unrelated index cases who fulfil FH criteria. One index case who fulfils Simon Broome definite FH criteria reported in PMID 23669246 (supplementary Table 2) by Futema et al, 2013 from University College London, UK. One index case who fulfils Simon Broome criteria for FH reported in PMID 17094996 (Table 2) by Tosi et al, 2007 from Imperial College London, UK. Three index cases fulfil DLCN ≥6 reported in PMID 33418990 (Appendix Table A1) by Meshkov et al, 2021 from National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia.PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family, 2 affected relatives with definite FH by Simon Broome criteria and tested positive for the variant, reported in PMID 23669246 (supplementary Table 2) by Futema et al, 2013 from University College London, UK. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585767/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:38562 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0020580 infores:hetionet CHEBI:3310 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0036974 infores:hetionet CHEBI:39867 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0038999 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0340726 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034150 infores:hetionet CHEBI:204734 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0015230 infores:hetionet CAID:CA10585616 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585616 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM2, PP3, PP4 PS3, PM5, PP1 The NM_000527.5(LDLR):c.1796T>C (p.Leu599Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022.The supporting evidence is as follows:PM2: Variant is absent from gnomAD v2.1.1.PP3: REVEL = 0.779. PS4, PP4: Variant meets PM2 and is identified in 9 unrelated index cases fulfilling FH clinical criteria (5 cases with DLCN score ≥6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 meeting Simon Broome criteria from PMID 12436241 (Amsellem et al., 2002), APHP Saint Antoine Hospital, Paris, France; 1 meeting Simon Broome criteria from PMID 17094996 (Tosi et al., 2007), UK; 1 with DLCN score ≥6 from PMID 19318025 (Alonso et al., 2009), Spain; and 1 with DLCN score ≥6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585616/MONDO:0007750/013 2022-07-22 2025-09-16 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:2453 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0231528 infores:hetionet CHEBI:31711 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026826 infores:hetionet CHEBI:47519 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0021099 infores:hetionet CAID:CA000204 biolink:causes MONDO:0018875 infores:clingen CAID:CA000204 MONDO:0018875 PMID: Pathogenic PS3, PS4, PP3_Moderate, PM1, PP4_Moderate, PP1, PM2_Supporting BA1, BP4, PS2, PS1, PM5, BS3, BS4, BS1, PVS1, BS2 The NM_000546.6: c.455C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 152 (p.Pro152Leu). This variant has been reported in 14 unrelated probands/families meeting Classic or Revised Chompret criteria, and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 8.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs26014290, 15654278, 10486318, 25584008, 17308077, Internal lab contributors; SCV000218779.10, SCV000187230.8). The variant has been reported to segregate with LFS-associated cancers in 4 meioses in 2 families (PP1; PMID: 10486318, Internal lab contributors SCV000187230.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors SCV000187230.8). This variant has an allele frequency of 0.000001695 (2/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).. In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 28 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (PM1, ≥ 10 somatic occurrences, PMID: 30311369). Computational predictor scores (BayesDel =0.558; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PP4_Moderate, PP1, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000204/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4798 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0241426 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0033860 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0239521 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0239521 infores:hetionet NCBIGene:3914 biolink:causes MONDO:0009182 infores:monarchinitiative not_provided not_provided HGNC:6490 MONDO:0009182 uuid:2eda0173-3950-4613-9722-2d4f060f39e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71223 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0600228 infores:hetionet CHEBI:75722 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003126 infores:hetionet CHEBI:6904 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C2981158 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0575090 infores:hetionet CHEBI:9398 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0917801 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0031542 infores:hetionet CHEBI:135961 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0029453 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0746883 infores:hetionet NCBIGene:3198 biolink:causes MONDO:0011099 infores:monarchinitiative not_provided not_provided HGNC:5099 MONDO:0011099 uuid:0c22c9cf-0fe5-4d5f-89c8-7c51753c2802 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0149745 infores:hetionet CHEBI:5383 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0012833 infores:hetionet CHEBI:7931 biolink:causes UMLS:C1412000 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C1412000 infores:hetionet CHEBI:134990 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0040822 infores:hetionet CAID:CA415091134 biolink:causes MONDO:0010305 infores:clingen CAID:CA415091134 MONDO:0010305 PMID: Likely Benign BS2, BP4 BS1, PM2 The NM_005629.4:c.1810T>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a leucine by a methionine at amino acid position 604 (p.Leu604Met). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency is 0.00006641 (3/45177 alleles, 2 hemizygotes) in the Admixed American population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. Overall, there are 12 hemizygotes in gnomAD v4.1.0 (10 in the European non-Finnish and 2 in the Admixed American population) (BS2). The computational predictor REVEL gives a score of 0.189 suggesting that the variant has no impact on protein function. SpliceAI predict no impact in splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 583226). In summary, this variant meets criteria to be classified as likely benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415091134/MONDO:0010305/027 2025-03-18 2025-03-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:48273 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0018681 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020615 infores:hetionet CHEBI:8863 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017181 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0037315 infores:hetionet CHEBI:3994 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0002792 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022650 infores:hetionet CHEBI:71941 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0035078 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0022568 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1142135 infores:hetionet CHEBI:7915 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0344232 infores:hetionet CHEBI:9649 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0231528 infores:hetionet CHEBI:23765 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003126 infores:hetionet CHEBI:8597 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0042963 infores:hetionet NCBIGene:56262 biolink:causes MONDO:0013290 infores:monarchinitiative not_provided not_provided HGNC:19027 MONDO:0013290 uuid:c4468b4c-2664-4ca6-a8fc-e3dca344df6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5002 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0151754 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0178298 infores:hetionet CHEBI:63599 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0020461 infores:hetionet CHEBI:36791 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025323 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0332575 infores:hetionet NCBIGene:55107 biolink:causes MONDO:0958202 infores:monarchinitiative not_provided not_provided HGNC:21625 MONDO:0958202 uuid:c9bef441-17e7-4368-9801-bba0b1a2a268 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:83737 biolink:causes MONDO:0013245 infores:monarchinitiative not_provided not_provided HGNC:13890 MONDO:0013245 uuid:6d5cb008-0bfa-4422-b9d6-ade9c0f433b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1639 biolink:causes MONDO:0011879 infores:monarchinitiative not_provided not_provided HGNC:2711 MONDO:0011879 uuid:32c6d89a-7b3b-4e4e-bfd8-b6d2fdf94799 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1139532474 biolink:causes MONDO:0007947 infores:clingen CAID:CA1139532474 MONDO:0007947 PMID: Likely Pathogenic PVS1, PM2 BS2, PP1, PP2, BP1, BA1, PS3, PS1, PS4, PM1, PM5, BS1, BS3, BS4 The NM_00138 c.2034_2052del, is a frameshift variant in FBN1 predicted to cause a substitution of a threonine acid by alanine at amino acid 679 (p.Thr679Alafs*33). It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant has not been reported in ClinVar and has not been reported in the literature. This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532474/MONDO:0007947/022 2023-02-01 2023-02-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:70718 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0015967 infores:hetionet CHEBI:2950 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0043352 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0004096 infores:hetionet CHEBI:7514 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0152227 infores:hetionet CHEBI:3479 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0018681 infores:hetionet CHEBI:71415 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0014457 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0178298 infores:hetionet CHEBI:7445 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0151908 infores:hetionet CHEBI:31980 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0009782 infores:hetionet CHEBI:135361 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0009806 infores:hetionet CHEBI:6792 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0026821 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0162830 infores:hetionet CHEBI:9137 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037299 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042109 infores:hetionet CAID:CA291227621 biolink:causes MONDO:0100326 infores:clingen CAID:CA291227621 MONDO:0100326 PMID:9790984 Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting PM5, PS3 The NM_000212.3(ITGB3):c.1813G>A (p.Gly605Ser) missense variant has been reported in at least one patient (Patient GT4 in PMID:25373348) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and function was pathological. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). GT4 of PMID: 25373348 is compound heterozygous for Arg242Gln (classified Pathogenic by the PD-EP) and Gly605Ser. Confirmation of trans phase was not reported (PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00002668 (2/74954 alleles) in the African/African American genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.959, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting, PP3, PP4_strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291227621/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50173 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0234913 infores:hetionet CHEBI:194135 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011175 infores:hetionet CHEBI:42797 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009676 infores:hetionet CHEBI:49713 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0013362 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0178298 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0021053 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0332575 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0034150 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0574067 infores:hetionet CHEBI:134745 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0013395 infores:hetionet CHEBI:8768 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023518 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030332 infores:hetionet CHEBI:9586 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019572 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0858934 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0858934 infores:hetionet CHEBI:4710 biolink:causes HP:0002835 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0700198 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0032961 infores:hetionet GO:1901668 biolink:causes GO:0097237 infores:ubergraph knowledge_assertion manual_agent GO:1901668 GO:0097237 CHEBI:50859 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151754 infores:hetionet CAID:CA1139655085 biolink:causes MONDO:0020367 infores:clingen CAID:CA1139655085 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PM2_Supporting, PM4 BS1, BS3, BP7, PM6, PP3, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.1009delC variant in MYOC is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 9 of the frameshift, or amino acid 346 (p.Gln337ArgfsTer9). This variant is predicted to cause a deletion of ≥ 10% of the protein within the conserved olfactomedin domain (PM4). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. 14 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 18776955), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 18776955), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM4, PP1_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139655085/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17688 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0700184 infores:hetionet CHEBI:8346 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0242429 infores:hetionet CHEBI:28864 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0004093 infores:hetionet CHEBI:94440 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0853619 infores:hetionet CHEBI:9332 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0232462 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0848309 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0848309 infores:hetionet CAID:CA235350 biolink:causes MONDO:0018997 infores:clingen CAID:CA235350 MONDO:0018997 PMID: Pathogenic PS3, PM1, PS2_Very Strong, PM2, PP2, PP3 The c.1654A>G (p.Arg552Gly) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID: 17143282). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg552Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235350/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9649 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020443 infores:hetionet NCBIGene:435 biolink:causes MONDO:0008815 infores:monarchinitiative not_provided not_provided HGNC:746 MONDO:0008815 uuid:aabb80d3-bc4a-4218-a37d-67f8ee5e5404 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042164 infores:hetionet CHEBI:9435 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0233407 infores:hetionet CHEBI:47426 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0009676 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0522063 infores:hetionet CHEBI:8214 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0009806 infores:hetionet CHEBI:71417 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0013604 infores:hetionet CHEBI:144551 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011124 infores:hetionet CHEBI:8707 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0858635 infores:hetionet CHEBI:28901 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0231528 infores:hetionet CHEBI:4702 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0022568 infores:hetionet CHEBI:8768 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0033774 infores:hetionet CHEBI:7903 biolink:causes HP:0031846 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0015802 infores:hetionet CHEBI:3219 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002994 infores:hetionet CHEBI:87715 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0002994 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001439 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0014583 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0267792 infores:hetionet GO:0070805 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0070805 GO:0061458 CHEBI:8428 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C1443060 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0233472 infores:hetionet CHEBI:31623 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0007859 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0036572 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0233494 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C3263723 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0037274 infores:hetionet CHEBI:61033 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0010520 infores:hetionet GO:1905304 biolink:causes GO:0055007 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0055007 CHEBI:49040 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0549209 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0948525 infores:hetionet CHEBI:15552 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0004604 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235082 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0851341 infores:hetionet CHEBI:408174 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0003811 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0027765 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2973529 infores:hetionet CHEBI:7443 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0010200 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020538 infores:hetionet CHEBI:6904 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C1306341 infores:hetionet CAID:CA8337891 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337891 MONDO:0008723 PMID: Benign BA1 BP4 The c.879-50G>T variant in ACADVL is an intronic variant in intron 9. The highest population minor allele frequency in gnomAD v2.1.1 is 0.06975 (6.975%) in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337891/MONDO:0008723/021 2023-04-25 2023-04-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3176 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0005741 infores:hetionet CHEBI:34967 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0028081 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0021400 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0032584 infores:hetionet NCBIGene:23509 biolink:causes MONDO:0014130 infores:monarchinitiative not_provided not_provided HGNC:14988 MONDO:0014130 uuid:9ac42c7e-d65e-4919-9094-cda42b88f145 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8028 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0030446 infores:hetionet CAID:CA10606682 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606682 MONDO:0015152 PMID: Likely Pathogenic PM3, PVS1_Moderate, PP4, PM2_Supporting PS1 The NM_003494.4: c.792+1G>A variant in DYSF, which is also known as NM_001130987.2: c.888+1G>A, occurs within the splice donor motif of exon 7. SpliceAI gives a score of 0.99 for donor loss and 0.57 for gain of a cryptic splice donor site in intron 7. Skipping of exon 7 would be expected to result in an in-frame deletion of less than 10% of the protein (PVS1_Moderate). However, use of the cryptic splice donor would be expected to introduce a frameshift. This variant has been reported in at least six individuals with features consistent with LGMD (PMID 27647186, 31268554, 36580222; ClinVar SCV005060896.1 internal data communication; Jain Foundation Dysferlin Registry internal data communication), including in a homozygous state in five patients from India, Brazil, and UAE, with likely familial consanguinity (0.25 pts x4 = 1.0 pt; PMID: 36580222, 31268554; ClinVar SCV005060896.1, ClinVar SCV003524621.3 internal data communications; Jain Foundation Dysferlin Registry internal data communication). In the fifth patient, it was identified in unconfirmed phase with a variant classified as at least likely pathogenic (NM_003494.4: c.965T>C p.(Leu322Pro), 0.25 pts, PMID: 27647186) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness (PMID: 27647186; ClinVar SCV005060896.1 internal data communication; Jain Foundation Dysferlin Registry internal data communication; PP4). The highest population minor allele frequency of this variant is 0.0000008 in the European (non-Finnish) population of gnomAD v4.1.0 (1/1180028), which is less than the VCEP threshold (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP specifications version 2.0.0; 09/30/2025): PVS1_Moderate, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606682/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5864 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0014038 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0034065 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0151735 infores:hetionet CHEBI:31643 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0011603 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020517 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0027651 infores:hetionet CHEBI:8707 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017168 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0021359 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0011609 infores:hetionet CHEBI:2788 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0085649 infores:hetionet CHEBI:50122 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0027497 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0221717 infores:hetionet CAID:CA10580711 biolink:causes MONDO:0700268 infores:clingen CAID:CA10580711 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP4 The c.122A>T variant in BRCA1 is a missense variant predicted to cause substitution of histidine by leucine at amino acid 41 (p.(His41Leu)). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.56, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID: 30209399, 35659930). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.78 (based on family history), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580711/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3499 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0038826 infores:hetionet UMLS:C0120107 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013491 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042109 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0162429 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0232841 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0006145 infores:hetionet CHEBI:8869 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0014236 infores:hetionet CHEBI:63598 biolink:causes UMLS:C3665444 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C3665444 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0015393 infores:hetionet CHEBI:64321 biolink:causes UMLS:C3203457 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C3203457 infores:hetionet CHEBI:63791 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0022281 infores:hetionet CHEBI:9130 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0041969 infores:hetionet CHEBI:63621 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015732 infores:hetionet CHEBI:31348 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0043352 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0243026 infores:hetionet CHEBI:4995 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011253 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042373 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0011991 infores:hetionet CHEBI:68595 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C1608945 infores:hetionet CHEBI:5138 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085633 infores:hetionet UMLS:C0657912 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085612 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0281981 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030517 infores:hetionet CAID:CA298980 biolink:causes MONDO:0007648 infores:clingen CAID:CA298980 MONDO:0007648 PMID: Pathogenic PP3, PM2_Supporting, PS4, PS3 BP5, BP7, BS3, BS1, BS4, PM1, PM4, PM3, PM5, PM6, PVS1, PP2, PP4, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS2 The c.715G>A (p.Gly239Arg) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 16 families (18) meeting HDGC clinical criteria (PS4_very strong; PMID: 17545690, 23264079, 23264079, 26182300; SCV000153869.9, SCV000273881.6, internal laboratory contributors). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). There are RNA assays demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690, 33619332). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (v3.1): PS4_very strong, PS3, PM2_supporting, PP3. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA298980/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:10102 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020580 infores:hetionet CHEBI:49375 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0232462 infores:hetionet CHEBI:167309 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0033774 infores:hetionet CHEBI:9943 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027540 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0026650 infores:hetionet CHEBI:5280 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C2830004 infores:hetionet CHEBI:5778 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0016382 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0025061 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030578 infores:hetionet CHEBI:45951 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0012833 infores:hetionet CHEBI:7577 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0085641 infores:hetionet CAID:CA320251280 biolink:causes MONDO:0100083 infores:clingen CAID:CA320251280 MONDO:0100083 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1354G>A (p.Val452Met) is a missense variant which has a REVEL score < 0.50 (0.083). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251280/MONDO:0100083/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50275 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0025345 infores:hetionet CAID:CA410147414 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147414 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1310C>T (p.Thr437Ile) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.337) and a spliceAI score <0.2 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147414/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:6598 biolink:causes MONDO:0013820 infores:monarchinitiative not_provided not_provided HGNC:11103 MONDO:0013820 uuid:bf560b61-eef0-4f12-a89c-297a559fb856 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0030554 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0037822 infores:hetionet CHEBI:9587 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0036572 infores:hetionet CHEBI:40303 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0018418 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017574 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0033246 infores:hetionet CHEBI:66876 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0041969 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0853117 infores:hetionet CAID:CA1139532761 biolink:causes MONDO:0020367 infores:clingen CAID:CA1139532761 MONDO:0020367 PMID:16297911 Likely Pathogenic PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting, PP1_Strong BP7, BS1, BS3, PM6, PP3, PM5, PS1, PS2, BA1, BP4 The c.1100_1103delinsT variant is predicted to cause a change in the length of the myocilin protein due to an in-frame deletion of Gly367 and Gln368 with an insertion of Valine (p.Gly367_Gln368delinsVal). This variant is predicted to cause a deletion of < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. A previous study (PMID: 10545602) demonstrated that the Gly367_Gln368delinsVal protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 20 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9639450), which fulfilled PP1_Strong (≥7 meioses in >1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9639450), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532761/MONDO:0020367/019 2022-03-06 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4445 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0242184 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0235431 infores:hetionet CHEBI:4027 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151701 infores:hetionet CHEBI:8356 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020625 infores:hetionet CHEBI:367163 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151766 infores:hetionet CHEBI:49375 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018946 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0025061 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0015397 infores:hetionet CHEBI:64321 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0040264 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0948594 infores:hetionet UMLS:C1738934 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0010200 infores:hetionet NCBIGene:1906 biolink:causes MONDO:0013013 infores:monarchinitiative not_provided not_provided HGNC:3176 MONDO:0013013 uuid:3719c07a-c987-4e17-bf4d-d6d0a2fc9db9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA034649 biolink:causes MONDO:0007750 infores:clingen CAID:CA034649 MONDO:0007750 PMID: Uncertain Significance PP3 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP1, PP4 The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PP3: REVEL=0.757. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034649/MONDO:0007750/013 2024-02-23 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:119573 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013456 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011991 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0037274 infores:hetionet CHEBI:144093 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020443 infores:hetionet CHEBI:135888 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0013456 infores:hetionet CAID:CA1244342 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244342 MONDO:0005338 PMID: Benign BP7, BA1, BP4 BS1, BS3, PM2, PP3, PP1, PM5, PM4, PS4, PS3, PS1, PS2 The c.39T>G variant in MYOC is a synonymous variant (p.Pro13=). The highest minor allele frequency of this variant was in the African/African-American genetic ancestry group of gnomAD (v4.1.0) = 0.07326, which met the ≥ 0.01 threshold set for BA1 (5,497 alleles out of 75032, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BA1, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244342/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3387 biolink:causes UMLS:C0859023 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0859023 infores:hetionet CHEBI:49713 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0344232 infores:hetionet CHEBI:50156 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0042487 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0235639 infores:hetionet NCBIGene:58 biolink:causes MONDO:0014800 infores:monarchinitiative not_provided not_provided HGNC:129 MONDO:0014800 uuid:46573e8b-fee2-4da4-986b-95044653f7d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64045 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0043094 infores:hetionet CHEBI:10125 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020443 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0085932 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0917798 infores:hetionet CHEBI:9123 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011603 infores:hetionet CHEBI:75984 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0016382 infores:hetionet CHEBI:7025 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0013456 infores:hetionet CHEBI:7824 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018979 infores:hetionet CHEBI:7865 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0152032 infores:hetionet CHEBI:7565 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0231530 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0009450 infores:hetionet CHEBI:5106 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0019825 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0042109 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0270934 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0270934 infores:hetionet CHEBI:7494 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018418 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0027051 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0009450 infores:hetionet CHEBI:59445 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0234233 infores:hetionet CHEBI:29007 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0038362 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0013595 infores:hetionet CHEBI:2549 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235710 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0010709 infores:hetionet CHEBI:15854 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0085636 infores:hetionet CHEBI:17303 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042963 infores:hetionet CHEBI:16586 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0027121 infores:hetionet CHEBI:47657 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0011991 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0004238 infores:hetionet CHEBI:66919 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0015967 infores:hetionet CHEBI:209807 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0026896 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0007137 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0006145 infores:hetionet CHEBI:71940 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0011603 infores:hetionet CHEBI:94392 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0039621 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0027765 infores:hetionet CHEBI:3534 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C1443060 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0009450 infores:hetionet NCBIGene:6888 biolink:causes MONDO:0011624 infores:monarchinitiative not_provided not_provided HGNC:11559 MONDO:0011624 uuid:918d59c8-627c-44a2-808d-652c2ba3b77f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017178 infores:hetionet CHEBI:31236 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C3248383 infores:hetionet GO:1904441 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1904441 GO:0007275 CHEBI:3640 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0041834 infores:hetionet CAID:CA158288 biolink:causes MONDO:0100216 infores:clingen CAID:CA158288 MONDO:0100216 PMID: Likely Benign BP4, BS2, PM1_Supporting PM2, PVS1, BA1, BP2, PP3, PP4, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BP7, BS1, BS3, BS4 The NM_177438.2:c.5516G>A variant in DICER1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1839 (p.Arg1839Gln). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.0001060 (171/1613922 alleles) with a highest population minor allele frequency of 0.0001415 (167/1180020 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.234, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, PM1_Supporting, BP4. (Bayesian Points: -4; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA158288/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68579 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C1384353 infores:hetionet CHEBI:8768 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0033247 infores:hetionet CHEBI:3398 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0039231 infores:hetionet CAID:CA16602491 biolink:causes MONDO:0011071 infores:clingen CAID:CA16602491 MONDO:0011071 PMID:19808697PMID:12377125PMID:28231333PMID:12807882PMID:12393679PMID:11276260PMID:27294619 Pathogenic PM5_Supporting, PM1, PS3_Moderate, PM2_Supporting, PS4_Supporting, PP3, PP1 PS2, PS1, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS4, BS3, BP7, BP5, PM4, PM3, PP2, PP4, BS2 The c.484A>G variant in RUNX1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 162 (p.R162G), which is a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) (PM1). This variant is absent from gnomAD v2 and v3 (PM2_Supporting), and has been reported in a proband meeting RUNX1-phenotypic criteria: history of bruising, menorrhagia, anemia, and a platelet defect with atypical platelet function tests, abnormal electron microscopy study, and atypical macrophages on bone marrow biopsy (PS4_Supporting; SCV001375396.1 and National Human Genome Research Institute). In addition, her older son (non-carrier) is unaffected, her younger son (carrier) has a history of thrombocytopenia (easy bleeding and bruising), frequent epistaxis, petechiae at 9 months, and an abnormal platelet electron microscopy study, and her mother (carrier) was diagnosed with AML at 45 (BMT done) and has a history of easy bleeding (PP1; National Human Genome Research Institute); finally, there is a supportive family history of AML in deceased relatives. Note that all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). Functionally, the variant demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoiesis (PMID: 17234761, 21725049 (PS3_Moderate), which is in line with computational evidence (REVEL score of 0.885 ≥ 0.88 threshold; PP3). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_Moderate, PS4_Supporting, PM1, PM2_Supporting, PP1, and PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602491/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3996 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0151773 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0037199 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0267596 infores:hetionet CHEBI:45924 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0024141 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009241 infores:hetionet CHEBI:6375 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017565 infores:hetionet CHEBI:6541 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002792 infores:hetionet CHEBI:9150 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0030554 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0403632 infores:hetionet CHEBI:9927 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0037763 infores:hetionet CAID:CA409109842 biolink:causes MONDO:0015967 infores:clingen CAID:CA409109842 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong PP1, PS4 The c.3G>A variant in the hepatocyte nuclear factor -4 alpha gene, HNF4A, results in a start loss at the initiation codon in NM_175914.4. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). In addition, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative diabetes autoantibodies (PP4_Moderate; PMID: 30977832, internal lab contributors). In summary, c.3G>A meets the criteria to be classified as Likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023: PVS1_Strong, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409109842/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4024 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0036572 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0243026 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0235238 infores:hetionet CHEBI:9137 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0005758 infores:hetionet CHEBI:8884 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0035229 infores:hetionet CHEBI:15367 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0040264 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0241832 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0241832 infores:hetionet GO:0021914 biolink:causes GO:0021510 infores:ubergraph knowledge_assertion manual_agent GO:0021914 GO:0021510 CHEBI:40303 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0234233 infores:hetionet CAID:CA134644 biolink:causes MONDO:0021060 infores:clingen CAID:CA134644 MONDO:0021060 PMID: Benign BA1, BP4 The filtering allele frequency of the c.1658C>T (p.Thr553Met) variant in the PTPN11 gene (NM_002834.5(PTPN11):c.1658C>T (p.Thr553Met)) is 0.048% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (49/66556 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Computational prediction tools and conservation analysis suggest that the p.Thr553Met variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied: BA1, BP4 (Version 2.1; 09/17/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134644/MONDO:0021060/043 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:74947 biolink:causes MONDO:0017858 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023440 infores:hetionet CAID:CA9091070 biolink:causes MONDO:0021060 infores:clingen CAID:CA9091070 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.240G>A (p.Ala80=) variant in the MAP2K2 gene is 0.0284% (9/16506) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9091070/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7915 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0085636 infores:hetionet CHEBI:145499 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042963 infores:hetionet CHEBI:36704 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0085593 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0344320 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0021400 infores:hetionet NCBIGene:57165 biolink:causes MONDO:0013278 infores:monarchinitiative not_provided not_provided HGNC:17494 MONDO:0013278 uuid:c5befe99-8103-46db-ab63-5eaada3a6871 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0917801 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151826 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0021605 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0021605 infores:hetionet GO:0035034 biolink:causes GO:0006338 infores:ubergraph knowledge_assertion manual_agent GO:0035034 GO:0006338 CAID:CA000116 biolink:causes MONDO:0017623 infores:clingen CAID:CA000116 MONDO:0017623 PMID: Likely Benign BP7, BS3 PVS1, PM6, PM2, BP5, BS4, BS1, BS2, PP1, PP4, PP2, PP3, PM3, PM5, PM4, PM1, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS1, PS3 PTEN c.114T>G (p.Pro38=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (internal laboratory contributor Accession: SCV000213708.7)BP7: Variant is synonymous (silent) OR intronic and at or beyond +7/-21 and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000116/MONDO:0017623/003 2024-12-06 2024-12-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45599 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0012833 infores:hetionet NCBIGene:57728 biolink:causes MONDO:0013717 infores:monarchinitiative not_provided not_provided HGNC:18340 MONDO:0013717 uuid:db31d613-623d-4712-8bf0-c476da19f5f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0919980 infores:hetionet NCBIGene:57728 biolink:causes MONDO:0030809 infores:monarchinitiative not_provided not_provided HGNC:18340 MONDO:0030809 uuid:3b537fb4-b2ee-4502-bfc3-fd69a8db9241 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0033774 infores:hetionet CHEBI:4877 biolink:causes MONDO:0004892 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0034951 infores:hetionet CHEBI:27834 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0042963 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0031350 infores:hetionet CHEBI:10101 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0149744 infores:hetionet CHEBI:68558 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0030554 infores:hetionet NCBIGene:1013 biolink:causes MONDO:0012946 infores:monarchinitiative not_provided not_provided HGNC:1754 MONDO:0012946 uuid:278d7008-ce7d-4c42-a980-c32d1b78fa34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011603 infores:hetionet REACT:R-HSA-2454202 biolink:causes GO:0043303 infores:drugmechdb knowledge_assertion manual_agent REACT:R-HSA-2454202 GO:0043303 DB00043_MESH_D001249_1DB01003_MESH_D034721_1DB00043_MESH_D000080223_1DB01003_MESH_D001249_1DB01003_MESH_D003233_1DB01003_MESH_D065631_1 CHEBI:10100 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0231528 infores:hetionet CHEBI:15367 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013456 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0392618 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0031039 infores:hetionet CHEBI:8107 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011206 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0035455 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0018799 infores:hetionet CHEBI:63630 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0002962 infores:hetionet CHEBI:4551 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C1443060 infores:hetionet CHEBI:40303 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0231528 infores:hetionet NCBIGene:5961 biolink:causes MONDO:0007639 infores:monarchinitiative not_provided not_provided HGNC:9942 MONDO:0007639 uuid:2c1f2541-8c3d-4036-8b15-89befe31468d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2739267613 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267613 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.806-11A>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.03), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.25)) (BP4, BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267613/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8874 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006840 infores:hetionet CHEBI:9566 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0026205 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0034069 infores:hetionet CAID:CA320249638 biolink:causes MONDO:0011071 infores:clingen CAID:CA320249638 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.*2347C>A is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320249638/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6633 biolink:causes HP:0032007 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0558143 infores:hetionet CAID:CA16020867 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020867 MONDO:0009861 PMID:15503242PMID:15503242 Likely Pathogenic PM5, PM2, PP4_Moderate, PM3_Supporting PP3 The c.833C>G (p.Thr278Ser) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded), detected with pathogenic variant IVS4-1G>A (PMID: 15503242). This variant is absent in population databases. Computational evidence is conflicting. There is another missense variant at the same amino acid that is interpreted as pathogenic (p.T278I, Variant ID:102863). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020867/MONDO:0009861/006 2020-06-15 2020-06-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47519 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0030353 infores:hetionet CHEBI:7640 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0600142 infores:hetionet CHEBI:27899 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0700225 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0002871 infores:hetionet CHEBI:3654 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0020456 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005451 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0013473 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1167965 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0013604 infores:hetionet CHEBI:47381 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0040460 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0349231 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0027051 infores:hetionet CHEBI:71255 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0917801 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0332534 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0037274 infores:hetionet CHEBI:68579 biolink:causes MONDO:0004001 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0009492 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0027765 infores:hetionet CHEBI:27470 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0233571 infores:hetionet CHEBI:5109 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0039446 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0032285 infores:hetionet CHEBI:3061 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0917801 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0030319 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0178298 infores:hetionet CAID:CA2710873 biolink:causes MONDO:0100283 infores:clingen CAID:CA2710873 MONDO:0100283 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_006218.4(PIK3CA): c.2040T>C (p.Val680=) variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as Likely benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BP4, BP7; -2 points (VCEP specifications version 1; Approved: 1/31/2021) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA2710873/MONDO:0100283/018 2022-02-11 2022-02-11 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Contradicts https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:42797 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018965 infores:hetionet CHEBI:64312 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235939 infores:hetionet CHEBI:42944 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151825 infores:hetionet CHEBI:17303 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0030554 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0021400 infores:hetionet NCBIGene:79633 biolink:causes MONDO:0014242 infores:monarchinitiative not_provided not_provided HGNC:23109 MONDO:0014242 uuid:eb02c6bb-5363-496e-9169-1d0b2fc6905d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63616 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0009319 infores:hetionet CAID:CA410202554 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202554 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM5_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.466G>A (p.Ala156Thr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score ≥ 0.88 (0.923) (PP3). This variant is a missense change at the same residue (p.A129) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 14471) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) showing no splicing effects (PM5_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202554/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5001 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0020649 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0006852 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0549229 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0549229 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0234215 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0575090 infores:hetionet CHEBI:8890 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0037383 infores:hetionet CHEBI:6413 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0151744 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0271412 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0271412 infores:hetionet CHEBI:31644 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151827 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0031350 infores:hetionet CHEBI:142290 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0085611 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005989 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040558 infores:hetionet CHEBI:31515 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0018834 infores:hetionet CHEBI:51230 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0009782 infores:hetionet CHEBI:7824 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042029 infores:hetionet CHEBI:7507 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0595916 infores:hetionet CHEBI:31547 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0024902 infores:hetionet CHEBI:61049 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0023524 infores:hetionet CHEBI:47780 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018989 infores:hetionet CHEBI:2469 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0042963 infores:hetionet CHEBI:66876 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0033774 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0497365 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0948594 infores:hetionet NCBIGene:6476 biolink:causes MONDO:0009114 infores:monarchinitiative not_provided not_provided HGNC:10856 MONDO:0009114 uuid:4ff19b2b-016f-4e3f-b67d-ad9fe4c6294d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA214218 biolink:causes MONDO:0000573 infores:clingen CAID:CA214218 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3, PM1_Supporting, PM5_Supporting PS1 The c.217C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 73 (p.Arg73Cys).The filtering allele frequency (the upper threshold of the 95% CI of 2/16256) of the c.217C>T variant in RAG2 is 0.00002132 for African/African American chromosomes by gnomAD v2.1.1 (no homozygous reported), which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting).PMID: 24481607: Proband compound heterozygous (comp het ( R73C/C178X, Pathogenic according to SCID VCEP specifications, 1 pt, PM3_met).NM_000536.4(RAG2):c.218G>A (p.Arg73His), LP according to SCID VCEP specifications, PM5_Supporting.At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and T-B-NK+ lymphocyte subset profile (0.5pt), totalizing 1 pt, which is highly specific for SCID (PP4, PMID: 20603253). In summary, this variant is classified as Likely Pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4, PM1_Supporting, PM3, PM5_Supporting, and PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214218/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:72292 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0017178 infores:hetionet CHEBI:6715 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0346156 infores:hetionet UMLS:C0011701 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C3665347 infores:hetionet CAID:CA410202527 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202527 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP1_Moderate, PM2_Supporting, PS4_Supporting PS1, PS2, PS3, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM5, BS2, PP2, PP3, PP4 NM_001754.5(RUNX1):c.477T>G (p.Asn159Lys) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 38019014). Additionally, this variant was found to co-segregate with disease in multiple affected family members, with four meioses observed in one family (PP1; PMID: 38019014). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, PS4_supporting, PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202527/MONDO:0011071/008 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3654 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0085631 infores:hetionet CHEBI:6633 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0032708 infores:hetionet CHEBI:3310 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0041657 infores:hetionet CAID:CA512341014 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341014 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM6, BP5, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1338C>A (p.Leu446=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.0)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341014/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2668 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0149931 infores:hetionet CHEBI:5130 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1167965 infores:hetionet CAID:CA16613142 biolink:causes MONDO:0017623 infores:clingen CAID:CA16613142 MONDO:0017623 PMID:29706350PMID:29785012 Likely Pathogenic PP2, PS3_Moderate, PM6_Strong, PM2_Supporting PVS1, BS1, BS3, BS4, BP5, BP7, BS2, PP3, PP1, PP4, PM3, PM4, PM1, PM5, BA1, BP4, BP1, BP2, BP3, PS4, PS2, PS1 NM_000314.8(PTEN):c.44G>A (p.Arg15Lys) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Absent in large sequenced populations (PMID 27535533). PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (internal laboratory contributor: SCV000573362.4)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.65 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613142/MONDO:0017623/003 2024-04-05 2024-04-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6970 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0264267 infores:hetionet CAID:CA023767 biolink:causes MONDO:0007750 infores:clingen CAID:CA023767 MONDO:0007750 PMID: Likely Benign BP2, PP1_Moderate, BS2 BA1, BP1, BP4, BP3, PS3, PS1, PS4, PS2, BP7, BP5, BS4, BS1, BS3, PM5, PM3, PM4, PM1, PM2, PM6, PVS1, PP2, PP3, PP4 The NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BP2 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 - variant identified in 2 Index cases with heterozygous FH phenotype and a 2nd LDLR variant classified as Pathogenic by these guidelines.PP1_moderate - variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023767/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA340948 biolink:causes MONDO:0044970 infores:clingen CAID:CA340948 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Moderate PP1, PS3, PS2, PM6 The m.4171C>A (p.L289M) variant in MT-ND1 has been reported in 13 individuals with primary mitochondrial disease with features falling under the LHON and/or Leigh syndrome spectrums with variable brain lesions (PS4_moderate, PMIDs: 12112111, 19555656, 20491810, 22879922, 24884847, 32652755, 34670133, 35104579, 32045392; Cui et al., 2006 with no PMID; of note, the two families in PMID: 12112111 might be in the same haplogroup although there is no known kinship). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are no reports of de novo occurrences to our knowledge. Although typically homoplasmic in kindreds, the variant has been reported to segregate with features of primary mitochondrial disease in two family members from one family (PMID: 12112111) however this did not meet criteria to be considered for PP1. This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (two occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.60 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). An E. coli model (homoplasmic for this variant) showed only a 13% decrease in enzyme activity, which did not reach statistical significance and therefore did not meet criteria to be considered for PS3 (PMID: 19616643). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. In the future, once three or more unrelated cases are reported, criteria for a likely pathogenic classification would be met. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022 (PMID: 32906214): Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340948/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:40279 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0009450 infores:hetionet CHEBI:50924 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C2239176 infores:hetionet CHEBI:5138 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C2830004 infores:hetionet CHEBI:119573 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013491 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0085649 infores:hetionet CHEBI:70735 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0231528 infores:hetionet CHEBI:101278 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0542571 infores:hetionet CHEBI:45863 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0015672 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0025061 infores:hetionet CHEBI:135679 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0041834 infores:hetionet CHEBI:77260 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0037317 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0243026 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0040046 infores:hetionet CHEBI:43968 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0030554 infores:hetionet CHEBI:9328 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0028961 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0013595 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0700594 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0042373 infores:hetionet NCBIGene:27329 biolink:causes MONDO:0011505 infores:monarchinitiative not_provided not_provided HGNC:491 MONDO:0011505 uuid:e19d10a5-9c78-4fa5-bf30-a85a80ca9b92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0455769 infores:hetionet CAID:CA9043627 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043627 MONDO:0012999 PMID: Pathogenic PM3, PP4_Strong, PM2_Supporting, PVS1_Strong The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). This variant has been detected in in 7 unrelated individuals with GAMT deficiency, all of whom were homozygous for the variant (PMID: 29302074, PMID: 32214227, PMID: 15234333, PMID: 23660394, PMID: 15108290) (1pt, PM3). One of these individuals had elevated GAA in plasma, elevated GAA in urine, deficient GAMT enzyme activity (<5% wild-type) in fibroblasts, and significantly reduced creatine peak with present GAA peak on brain MRS (PMID: 15234333) and one of these individuals had elevated urine GAA and undetectable GAMT enzyme activity in fibroblasts (PMID: 15108290) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001607 (4/24886 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 810628, 2 star review status) with 7 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043627/MONDO:0012999/026 2023-05-25 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6887 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038999 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0042109 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020649 infores:hetionet CAID:CA410148192 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148192 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1082C>G (p.Thr361Ser) is a missense variant which has a REVEL score < 0.50 (0.031) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148192/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA120580 biolink:causes MONDO:0044970 infores:clingen CAID:CA120580 MONDO:0044970 PMID:15048886PMID:7726154PMID:7726155PMID:12393175 Likely Pathogenic PP3, PM2_Supporting, PS4, PP1_Moderate, PS3_Supporting PS2, PM6 The m.14709T>C variant in MT-TE has been reported in at least 39 affected individuals from 20 kindreds (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15048886, 15880407, 15607216, 17161635, 17891417, 20045353, 26469001, 26885883, 29941710, 32313153, 33304817, 32948797; web story: https://www.chop.edu/stories/mitochondrial-disease-noras-story; PS4). Age of onset ranged from shortly after birth to 50s, although there are some reports of decreased fetal movements and hydrops fetalis. Features in affected individuals include myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, hearing loss, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Furthermore, this variant has been reported in some individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap and myoclonic epilepsy with ragged red fibers (MERRF). Muscle biopsies in affected individuals showed ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities. The variant was present at variable levels in affected and unaffected individuals. Some healthy family members had the variant present at homoplasmy, however heteroplasmy levels were generally higher in more severely affected individuals. The variant was present at 78% to homoplasmy in muscle and was variable among tissues from the same individual. There are no reported de novo occurrences to our knowledge. The variant segregates with manifestations in several families (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15607216, 17161635, 17891417, 20045353; PP1_moderate). The computational predictor MitoTIP suggests this variant is pathogenic (56.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID: 7726154), and cybrid studies, Northern blot analyses, and protein synthesis assays further support the functional impact of this variant (PMIDs: 15048886, 7726155, 12393175; PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120580/MONDO:0044970/015 2023-01-23 2023-03-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:84883 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0003862 infores:hetionet NCBIGene:57679 biolink:causes MONDO:0011797 infores:monarchinitiative not_provided not_provided HGNC:443 MONDO:0011797 uuid:32f4b8dc-b571-4c40-9562-685fcb0f6f88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:175901 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0235025 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0027765 infores:hetionet CHEBI:4046 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0042109 infores:hetionet NCBIGene:70 biolink:causes MONDO:0012799 infores:monarchinitiative not_provided not_provided HGNC:143 MONDO:0012799 uuid:b845bbf1-efa0-451c-8fc7-0a00ac00e96e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0151786 infores:hetionet CHEBI:75246 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0917801 infores:hetionet CHEBI:68579 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0008370 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0392025 infores:hetionet CHEBI:7465 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0151904 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0025061 infores:hetionet CHEBI:6909 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0016382 infores:hetionet NCBIGene:4854 biolink:causes MONDO:0012072 infores:monarchinitiative not_provided not_provided HGNC:7883 MONDO:0012072 uuid:1bfe3c11-9245-49a0-9e97-5484ab60ba6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235750 infores:hetionet CHEBI:3181 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0028084 infores:hetionet CHEBI:60761 biolink:causes HP:0025088 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0263540 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0877104 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0877104 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0870082 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034359 infores:hetionet NCBIGene:80217 biolink:causes MONDO:0054723 infores:monarchinitiative not_provided not_provided HGNC:26684 MONDO:0054723 uuid:9a6a1d69-938e-45ca-9c5e-04075e99960e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0277885 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0314719 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0017178 infores:hetionet CHEBI:30830 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042024 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010043 infores:hetionet CHEBI:5959 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0017979 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015469 infores:hetionet CHEBI:3242 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0032343 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0393947 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0393947 infores:hetionet CHEBI:7444 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0242429 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0040409 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002871 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005073 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027962 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853074 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853074 infores:hetionet CHEBI:3125 biolink:causes UMLS:C0948733 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0948733 infores:hetionet CHEBI:71255 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0686347 infores:hetionet CAID:CA314859 biolink:causes MONDO:0012996 infores:clingen CAID:CA314859 MONDO:0012996 PMID: Benign BA1, BP4 The NM_001482.3:c.1030A>G variant in GATM is a missense variant predicted to cause the substitution of an isoleucine by a valine at amino acid position 344 (p.Ile344Val). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00080 (16/19954 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.056 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205608). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314859/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:119915 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085932 infores:hetionet CHEBI:8212 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0002878 infores:hetionet CHEBI:64354 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0017979 infores:hetionet CAID:CA312270 biolink:causes MONDO:0008723 infores:clingen CAID:CA312270 MONDO:0008723 PMID:20060901PMID:17999356PMID:20060901 Pathogenic PM2_Supporting, PP2_Moderate, PM1, PM3_Supporting, PP4_Moderate, PP3_Strong, PS3_Supporting PM5 The c.1316G>A variant in ACADVL has been reported in three individuals with very long chain acyl-CoA dehydrogenase deficiency in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, two displaying both phenotypes at once (PP4_strong; PMIDs: 31031081, 23480858, 17999356). In these same probands, the variant was detected three times not confirmed in-trans with several different variants including the pathogenic variant c.848T>C (PM3_supporting; PMIDs: 31031081, 23480858, 17999356). Fibroblast analysis and E. coli transfected with constructs harboring the variant both showed significantly deficient enzyme activity (PS3_supporting; PMIDs: 23480858, 17999356). This variant has a MAF of 0.00005012 in the East Asian population (PM2_supporting; https://gnomad.broadinstitute.org). The variant is located in a well-studied Gly-Gly-x-Gly motif which is critical for the protein's dimer interaction with FAD (PM1; PMID: 20060901). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: PP4; PM3; PS3; PM2; PM1; PP3 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312270/MONDO:0008723/021 2025-04-16 2025-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7476 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0340865 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0038362 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0026846 infores:hetionet CHEBI:8776 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0151905 infores:hetionet CHEBI:9588 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0151480 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0596170 infores:hetionet CHEBI:4779 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0344232 infores:hetionet CHEBI:50692 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0085593 infores:hetionet CAID:CA120596 biolink:causes MONDO:0044970 infores:clingen CAID:CA120596 MONDO:0044970 PMID:19160410 Pathogenic PP1_Moderate, PS3_Supporting, PM5, PP3, PS4 PS1, PS2, PM6, PVS1 The m.8993T>C (p.L156P) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and who had features variably consistent with Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (PS4; PMIDs: 8395787, 16532470, 30128709, 29101127, 28003964, 26265210, 22819295, 19046652, 18055910, 16049925, 10604142). Per our literature review and a recently published review, there are no published de novo occurrences of this variant (PMID: 30763462). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>G (p.L156R) (PM5). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMID: 10604142). In silico tools predict this variant to be pathogenic (PP3). Cybrid studies (homoplasmic for this variant) showed reduced ATP production compared to Rho+ control cell lines (PS3_supporting; PMID: 19160410). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on February 17, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5, PP1_moderate, PP3). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120596/MONDO:0044970/014 2021-05-05 2021-06-10 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8764 biolink:causes MONDO:0006981 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014122 infores:hetionet CAID:CA341471 biolink:causes MONDO:0015152 infores:clingen CAID:CA341471 MONDO:0015152 PMID: Pathogenic PP4_Moderate, PVS1, PP1, PM2_Supporting PM3, PM4, PM5, PM1, PM6, BA1, BP2, BP3, BP1, BP4, PP2, PP3, BS2, BP5, BP7, BS1, BS4, BS3, PS2, PS1, PS3, PS4 The NM_000070.3: c.328C>T p.(Arg110Ter) variant in CAPN3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in trans with a second CAPN3 variant in at least three unrelated individuals with LGMD (PMID: 26677118, 18854869). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 18854869). The variant has also been reported to co-segregate with the disease in one affected family member (PP1; PMID: 26677118). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008793 (1/113722 exome alleles) in the European (non-Finnish) population, which is less than the VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PP4_Moderate, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA341471/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135961 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0151849 infores:hetionet CHEBI:116278 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1368065 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0037274 infores:hetionet CHEBI:6931 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0038999 infores:hetionet CHEBI:9907 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C2830004 infores:hetionet CHEBI:8069 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C1760428 infores:hetionet CHEBI:42068 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C1142499 infores:hetionet CHEBI:5893 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0022107 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0017178 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013298 infores:hetionet CHEBI:15765 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0080274 infores:hetionet GO:2001049 biolink:causes GO:0035992 infores:ubergraph knowledge_assertion manual_agent GO:2001049 GO:0035992 CHEBI:17141 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0151849 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0039070 infores:hetionet CHEBI:8378 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0038435 infores:hetionet CHEBI:16755 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013491 infores:hetionet CHEBI:4995 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0024305 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0242350 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0011609 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0027769 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0597457 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0597457 infores:hetionet CAID:CA040318 biolink:causes MONDO:0007750 infores:clingen CAID:CA040318 MONDO:0007750 PMID: Uncertain Significance BP4 BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BS2 The NM_000527.4(LDLR):c.2389+8C>T variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by evaluating evidence codes (BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: BP4 - no REVEL, splicing evaluation required. No functional assay on splicing. not on splicing limits, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040318/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:135736 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0162298 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151752 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0549475 infores:hetionet CHEBI:83527 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0002994 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0007971 infores:hetionet CAID:CA10576265 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576265 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, BP2, PS3_Supporting, PM2, PP4, PP1 BA1, BP1, BP4, BP3, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, BS2 The NM_000527.4(LDLR):c.-120C>T variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP4, PS3_Supporting, PS4_Supporting and BP2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00001470 (0.001470%) in European non-Finnish (gnomAD v3.2.1). It is below 0.02%, so met.PP1 - Variant segregates with the FH phenotype in:- 2 relatives from 1 family from Francová et al. 2004 (PMID: 15303010): 2 relatives with the phenotype (LDL cholesterol concentration between 93 and 99.5 percentile for age and sex) have the variant;- 1 relative from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 1 relative without the phenotype and without the variant.3 segregations, so PP1 is met.PS3_supporting - Level 3 FS: Francová et al. 2004 (PMID: 15303010) : Heterologous cells (HepG2), luciferase assays - results: 3% reporter gene transcription (Reported as c.-27C>T in the paper).--- it is below 50%, so PS3_Supporting is met.PS4_supporting - variant meets PM2 and was identified in:- 1 index case with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 1 index case with Simon Broome possible from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 1 index case with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia.3 cases, so PS4_Supporting is metPP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical FH criteria from different labs (please see PS4 for details), so PP4 is met.BP2 - Variant identified in 1 index case and 1 relative, both carriers of NM_000527.4(LDLR):c.2416dupG (p.Val806Glyfs*11) in trans with LDLc values of 4.3 mmol/l (16y) and 5.9 mmol/l (11y), respectively. 2nd variant is classified as Pathogenic by these guidelines and phenotype is clearly of heterozygous FH, so BP2 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576265/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50648 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0746883 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0043251 infores:hetionet CAID:CA5949888 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949888 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting The NM_000448.3:c.15C>G variant in RAG1 is a missense variant predicted to cause a substitution of phenylalanine by leucine at amino acid 5 (p.Phe5Leu). The Popmax filtering allele frequency of this variant in gnomAD v2.1.1 is 0.00000292, which is lower than the SCID-VCEP’s threshold for PM2 (<0.000102). No homozygous individual has been observed in the gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV001420312.4). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949888/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:404903 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0004093 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0033687 infores:hetionet CHEBI:5103 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0039240 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0040034 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0267792 infores:hetionet CHEBI:465284 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0026821 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0006145 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0853692 infores:hetionet CHEBI:17474 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0013428 infores:hetionet CHEBI:17987 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0015256 infores:hetionet CHEBI:63605 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0033774 infores:hetionet CHEBI:10119 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011606 infores:hetionet GO:2000014 biolink:causes GO:0048316 infores:ubergraph knowledge_assertion manual_agent GO:2000014 GO:0048316 GO:0052029 biolink:causes GO:0007165 infores:ubergraph knowledge_assertion manual_agent GO:0052029 GO:0007165 CAID:CA120545 biolink:causes MONDO:0044970 infores:clingen CAID:CA120545 MONDO:0044970 PMID:16950817 Uncertain Significance PP3, PS4_Supporting, PM2_Supporting PP1, PS3, PM1 The m.12207G>A variant in MT-TS2 has been reported in three individuals with primary mitochondrial disease to date. One person had clinical features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; PMID: 16950817), had complex I deficiency in muscle, and had the variant present at 92% heteroplasmy in muscle. The variant was undetectable in the mother’s blood. Another individual was reported as part of a primary mitochondrial disease cohort (PMID: 27450679) and was found to have the variant present at >60% in muscle and was undetectable in blood from the proband and mother. The variant was also seen in a Japanese family with diabetes, epilepsy, deafness, and developmental delay. The variant was found in the proband at 31.3% heteroplasmy in blood, 52.6% in saliva, and 73.9% in urinary sediment while the variant was found in the mother at 13.8%, 22.1%, and 29.4%, respectively (PMID: 36967720; PS4_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (76.4 percentile) and HmtVAR predicts it to be deleterious with a score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120545/MONDO:0044970/015 2024-05-13 2024-11-26 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6909 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0021167 infores:hetionet CHEBI:6741 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0043352 infores:hetionet CHEBI:50729 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0039231 infores:hetionet CHEBI:8356 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013378 infores:hetionet CHEBI:77260 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0268000 infores:hetionet CHEBI:34967 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0023380 infores:hetionet CHEBI:63580 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0231807 infores:hetionet CHEBI:45409 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0041657 infores:hetionet CHEBI:10101 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085682 infores:hetionet CHEBI:52717 biolink:causes HP:0030843 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0268407 infores:hetionet CHEBI:8597 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0018794 infores:hetionet CHEBI:8874 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003467 infores:hetionet CAID:CA658658488 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658488 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1390delG p.(Val464fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658488/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:135888 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0021099 infores:hetionet CHEBI:7444 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0000731 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042109 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0025061 infores:hetionet CHEBI:17347 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0030193 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0022408 infores:hetionet CHEBI:9943 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0019080 infores:hetionet CHEBI:63598 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013447 infores:hetionet CHEBI:49713 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0015967 infores:hetionet CHEBI:8499 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0547030 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002418 infores:hetionet CHEBI:68558 biolink:causes HP:0001933 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0854107 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0314719 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033777 infores:hetionet CHEBI:63611 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011168 infores:hetionet CHEBI:6520 biolink:causes MONDO:0005272 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C2826318 infores:hetionet CHEBI:6061 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0011603 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013395 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1262144 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002418 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0332534 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0011615 infores:hetionet CAID:CA380152323 biolink:causes MONDO:0000572 infores:clingen CAID:CA380152323 MONDO:0000572 PMID: Pathogenic PM2_Supporting, PVS1, PM5_Supporting The NM_000448.3:c.1348C>T variant in RAG1 is a nonsense variant that may cause a premature stop codon that is predicted not to cause nonsense-mediated decay. It causes a truncation of a functionally important region (removes amino acids 450-1043) which includes the whole DDBD domain (PVS1). The variant is absent in the gnomAD v4.0 database (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID, and there is no functional evidence for this variant. At least two premature termination variants (p.Trp959Ter, p.Arg829_Lys830delinsSerTer) in the same exon has been classified as Pathogenic by the SCID VCEP without use of PM5 and without use of only PVS1 plus PM2. Total: 2 pts, PM5_Supporting is met. In summary, this variant is classified as a pathogenic variant for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PM5_Supporting (SCID VCEP specifications version 2). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380152323/MONDO:0000572/123 2025-11-19 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:34967 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0040822 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0003537 infores:hetionet CHEBI:52010 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0018524 infores:hetionet CHEBI:9215 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0027497 infores:hetionet NCBIGene:6297 biolink:causes MONDO:0009002 infores:monarchinitiative not_provided not_provided HGNC:10526 MONDO:0009002 uuid:8d0034ac-5ad0-485d-be9a-feb78ff4856c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0016382 infores:hetionet CHEBI:31624 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0036974 infores:hetionet CHEBI:10110 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0232849 infores:hetionet CHEBI:8863 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151636 infores:hetionet CHEBI:31644 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0028643 infores:hetionet CHEBI:38545 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0027497 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042401 infores:hetionet CAID:CA410147522 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147522 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1280G>C (p.Arg427Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.499) (BP4). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2089328). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147522/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64355 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042963 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C1443060 infores:hetionet GO:1903538 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1903538 GO:0019953 CHEBI:50692 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0853692 infores:hetionet NCBIGene:2072 biolink:causes MONDO:0012590 infores:monarchinitiative not_provided not_provided HGNC:3436 MONDO:0012590 uuid:e21365f9-9e5d-4bfb-8d3a-f32cd2354bf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72690 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0006285 infores:hetionet CHEBI:3207 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0038354 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0456909 infores:hetionet CAID:CA412348584 biolink:causes MONDO:0100039 infores:clingen CAID:CA412348584 MONDO:0100039 PMID: Uncertain Significance BS2_Supporting, PM6 BS1, PP3, PM1, PM5, PM2, BP4, BA1 The highest population minor allele frequency of the p.Arg59Gln variant in CDKL5 in gnomAD v4.1 is 0.00000112 in Non-Finnish European population (not sufficient to meet BS1 criteria). The p.Arg59Gln variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2-supporting). Computational prediction analysis tools are inconclusive for this variant. The p.Arg59Gln variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with epileptic encephalopathy (internal database - Équipe Génétique des Anomalies du Développement (GAD)) (PM6). In summary, the p.Arg59Gln variant in CDKL5 is classified as uncertain significance based on the ACMG/AMP criteria (BS2_Supporting, PM6). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412348584/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:50924 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0007097 infores:hetionet UMLS:C0145867 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0424295 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0016579 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0016579 infores:hetionet CHEBI:45081 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0086565 infores:hetionet CHEBI:7824 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0699744 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0948594 infores:hetionet CAID:CA114168 biolink:causes MONDO:0015631 infores:clingen CAID:CA114168 MONDO:0015631 PMID:15461624 Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3, PM3_Supporting The NM_000552.5(VWF):c.2411G>T (p.Cys804Phe) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.935, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Factor VIII binding assay performed with the C804F recombinant mutant showed severely impaired binding indicating that this variant has a damaging effect on protein function (PMID: 15461624; PS3). At least 1 patient (Patient B) with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (20 IU/dl) and dramatically decreased VWF:FVIII binding, which is highly specific for VWD type 2N. (PP4_moderate, PMID:15213842). Patient B (PMID: 15461624) is compound heterozygous for R854Q (classified Pathogenic by the VWD VCEP; PM3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3_supporting, PP4_moderate, PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114168/MONDO:0015631/090 2025-02-04 2025-02-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50173 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0022408 infores:hetionet CHEBI:63791 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0333243 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0948089 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0234215 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0241863 infores:hetionet CHEBI:102216 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0030201 infores:hetionet CHEBI:453011 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0013595 infores:hetionet CHEBI:51364 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0038990 infores:hetionet CHEBI:29688 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0085649 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0004239 infores:hetionet CHEBI:63611 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085633 infores:hetionet CHEBI:6950 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0152198 infores:hetionet CHEBI:2639 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0040264 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151602 infores:hetionet CHEBI:9137 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151474 infores:hetionet UMLS:C0025241 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0035410 infores:hetionet CHEBI:52172 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020473 infores:hetionet UBERON:0002073 biolink:causes MONDO:0002527 infores:ubergraph knowledge_assertion manual_agent UBERON:0002073 MONDO:0002527 NCBIGene:54892 biolink:causes MONDO:0032764 infores:monarchinitiative not_provided not_provided HGNC:21904 MONDO:0032764 uuid:c148a838-c600-4fdc-9a63-c3afd52a6c6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75275 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0018621 infores:hetionet CHEBI:36795 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0024031 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1963818 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0007682 infores:hetionet CAID:CA8129891 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129891 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong, PS4, PS3 BS1, BS3, PM6, BS2, BA1, PS2 The c.532-1G>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is present once (1/245,906 alleles) in the gnomAD v2 cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Additionally, this variant has been reported in six families meeting HDGC clinical criteria (PS4; internal laboratory data). RNA analysis demonstrated that this variant results in an out-of-frame transcript, r.532_547del p.(I178Tfs*32) (PS3; internal laboratory data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4, PS3, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129891/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7478 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0340865 infores:hetionet CHEBI:35553 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0020615 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0042075 infores:hetionet CHEBI:61058 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0009782 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235168 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235168 infores:hetionet NCBIGene:6445 biolink:causes MONDO:0009677 infores:monarchinitiative not_provided not_provided HGNC:10809 MONDO:0009677 uuid:d3cb4309-1bd4-435d-a564-e197fcf0efd8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9316 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0020538 infores:hetionet CHEBI:38562 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0003862 infores:hetionet CAID:CA6831957 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831957 MONDO:0015967 PMID: Uncertain Significance PP1_Strong, BS1, PM5_Supporting, PP3, PP4 BP4, BA1, PS4, PM1, PM2, BS2 The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831957/MONDO:0015967/017 2023-08-14 2023-08-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1510410 infores:hetionet NCBIGene:970 biolink:causes MONDO:0034054 infores:monarchinitiative not_provided not_provided HGNC:11937 MONDO:0034054 uuid:45159ac6-478f-4c01-8a18-6596c12e47e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151907 infores:hetionet CHEBI:15552 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0428977 infores:hetionet NCBIGene:1594 biolink:causes MONDO:0020723 infores:monarchinitiative not_provided not_provided HGNC:2606 MONDO:0020723 uuid:3b39c4fb-a604-43e2-957f-f5f34ee5891f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229742 biolink:causes MONDO:0009861 infores:clingen CAID:CA229742 MONDO:0009861 PMID:9634518PMID:1363786PMID:9799096 Pathogenic PM5, PM2, PP4_Moderate, PP3, PS3 The c.754C>G (p.Arg252Gly) variant in PAH has been reported in multiple individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 1363786, 9634518). This variant is absent in population databases (PM2). This variant has 3% enzyme activity (PS3; PMID: 9799096). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). This missense change is at an amino acid residue where different pathogenic missense changes have been seen before (p.Arg252Gln/Trp). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229742/MONDO:0009861/006 2018-12-08 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CAID:CA1907955 biolink:causes MONDO:0018958 infores:clingen CAID:CA1907955 MONDO:0018958 PMID: Likely Benign BS1 BA1, BP4, PM2, PP3 The c.18464A>C (p.Tyr6155Ser) variant in NEB is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 6155. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.004863 (391/73822 alleles, 3 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.271, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1907955/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3723 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043352 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0234215 infores:hetionet CHEBI:474053 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0595916 infores:hetionet CHEBI:3310 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C1142412 infores:hetionet CHEBI:8228 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0232461 infores:hetionet CHEBI:52172 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151636 infores:hetionet CHEBI:135005 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0015967 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1096691 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1096691 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0151569 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151569 infores:hetionet CHEBI:116278 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0497156 infores:hetionet CHEBI:9649 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018790 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0005886 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D002180 DB00646_MESH_D002180_1DB00257_MESH_D002180_1 CHEBI:7915 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0037763 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0267792 infores:hetionet CHEBI:49040 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0008350 infores:hetionet CHEBI:49040 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0542476 infores:hetionet CHEBI:6846 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0013144 infores:hetionet CHEBI:7565 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0017565 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027769 infores:hetionet CHEBI:391960 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0917801 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0032584 infores:hetionet CHEBI:10125 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151539 infores:hetionet CHEBI:17263 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0014742 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0399459 infores:hetionet CHEBI:5103 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0917801 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0852733 infores:hetionet CHEBI:8080 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0917801 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0267537 infores:hetionet CHEBI:7809 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0018965 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0041969 infores:hetionet CHEBI:4027 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0025323 infores:hetionet CHEBI:261649 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0347390 infores:hetionet CHEBI:16469 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0023218 infores:hetionet CHEBI:94440 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0039231 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1262013 infores:hetionet CHEBI:31624 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0155626 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0037274 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027769 infores:hetionet NCBIGene:51715 biolink:causes MONDO:0008710 infores:monarchinitiative not_provided not_provided HGNC:14263 MONDO:0008710 uuid:f59128cb-5ca9-4728-bb00-1aec3471af75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0085593 infores:hetionet CHEBI:63598 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0233407 infores:hetionet CHEBI:63599 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0235896 infores:hetionet NCBIGene:7454 biolink:causes MONDO:0010294 infores:monarchinitiative not_provided not_provided HGNC:12731 MONDO:0010294 uuid:0e7175fa-57c6-4a1e-a40c-1388cbe9e917 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233414 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011860 infores:hetionet CAID:CA658760369 biolink:causes MONDO:0009276 infores:clingen CAID:CA658760369 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM4, PM3 The NM_000174.5(GP9):c.305_313del (p.Asp102_Pro105delinsAla) deletion variant is predicted to cause a change in the length of the protein due to an in-frame replacement of 3 amino acids with 1 amino acid in a non-repeat region (PM4). The Grpmax filtering allele frequency in gnomaDv4.1 is 0.000003590 (based on 9/1179800 alleles) in the European (non-Finnish) population, which is below the <0.0000329 threshold for PM2_supporting. At least one patient (case in PMID:15609295) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). There was ~9% of GP9 expression compared to controls. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. The patient in PMID: 15609295 is compound heterozygous with Pathogenic variant Asn61Ser (reported as Asn45Ser) confirmed in trans by parental testing (PM3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM4, PM2_supporting, PP4, PM3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760369/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4995 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0549249 infores:hetionet CHEBI:8107 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0015672 infores:hetionet CHEBI:7915 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1291077 infores:hetionet CHEBI:6076 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0030554 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0003864 infores:hetionet CHEBI:72564 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013604 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1262109 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1262109 infores:hetionet CAID:CA512341366 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341366 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 This variant NM_001754.5(RUNX1):c.1020C>G (p.Pro340=) is a synonymous variant. As it is a synonymous variant there is no REVEL score but SpliceAI is ≤0.20 (0.00) (BP4). The PhyloP Score is <2.0 (-0.628) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341366/MONDO:0011071/008 2022-01-20 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17303 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013220 infores:hetionet CHEBI:28901 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0206062 infores:hetionet UNII:G4PX8C4HKV biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0025345 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853761 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0029445 infores:hetionet CAID:CA000604 biolink:causes MONDO:0017623 infores:clingen CAID:CA000604 MONDO:0017623 PMID: Likely Benign BP5, BS1_Supporting PVS1, PM2, PM6, BP7, BS3, BS4, PP1, PP2, PP3, PP4, BS2, PM3, PM4, PM1, PM5, BA1, BP1, BP4, BP2, BP3, PS4, PS3, PS1, PS2 NM_000314.8(PTEN):c.-837C>T meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00003249 [0.003249%] in gnomAD v3.BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributor(s)) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000604/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119915 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011615 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0029408 infores:hetionet CHEBI:231594 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0028949 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0025061 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027765 infores:hetionet CHEBI:8028 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0022354 infores:hetionet CAID:CA16621944 biolink:causes MONDO:0100437 infores:clingen CAID:CA16621944 MONDO:0100437 PMID: Benign BA1 BP4 NM_001034853.2(RPGR):c.*72A>G is a substitution of 1 base pair in the 3' untranslated region of RPGR. This variant is present in gnomAD v4.1.0 at a frequency of 0.02316 among hemizygous individuals, with 9,088 variant alleles / 392,403 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing. However, BP4 is not considered applicable to 3' UTR variants in RPGR, so this code was not met. In summary, this variant is classified as benign for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621944/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:53760 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0030554 infores:hetionet CHEBI:32588 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0234233 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0025061 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0424000 infores:hetionet CHEBI:39585 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0005747 infores:hetionet CHEBI:77260 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0040822 infores:hetionet CHEBI:4975 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0003467 infores:hetionet CHEBI:5856 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0018802 infores:hetionet CHEBI:15367 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0239571 infores:hetionet CHEBI:3001 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0017601 infores:hetionet CAID:CA410147746 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147746 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1221C>A (p.Tyr407Ter) is a nonsense variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147746/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64321 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0003467 infores:hetionet CHEBI:45409 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151474 infores:hetionet CHEBI:5959 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0600142 infores:hetionet CHEBI:37941 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0235437 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549393 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549393 infores:hetionet CHEBI:261649 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0033774 infores:hetionet CHEBI:50275 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151798 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0003868 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0851341 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0031350 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0027765 infores:hetionet GO:0098905 biolink:causes GO:0086028 infores:ubergraph knowledge_assertion manual_agent GO:0098905 GO:0086028 CHEBI:31348 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0577559 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0019372 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0856864 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0856864 infores:hetionet CHEBI:135530 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0231919 infores:hetionet CHEBI:3757 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0006145 infores:hetionet CHEBI:135530 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0151766 infores:hetionet CHEBI:23765 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0033774 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0700184 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0267596 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0042029 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0746883 infores:hetionet CHEBI:4708 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0028734 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0006277 infores:hetionet CHEBI:32293 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0008031 infores:hetionet CHEBI:44241 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0011615 infores:hetionet CAID:CA10443749 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443749 MONDO:0010315 PMID: Uncertain Significance BS2_Supporting PM2 NM_000206.3(IL2RG):c.1105A>G (p.Thr369Ala) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. It occurs at a low allele frequency in gnomAD v2.1. of 0.00002258 which is below the SCID VCEP established threshold of <0.000124, however this includes two adult hemizygotes (PM2_NotMet, BS2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: BS2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443749/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance HP:0001417 Inconclusive true CAID:CA1624825 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624825 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.280A>G (p.Ile94Val) variant in the SOS1 gene is 0.0253% (6/10300) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624825/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6129 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0314719 infores:hetionet CAID:CA367403318 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403318 MONDO:0015967 PMID: Likely Pathogenic PM3_Supporting, PM5, PP2, PP3, PP4, PM2_Supporting The c.170T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 57 (p.(Met57Arg)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, it has been detected in the homozygous state in one individual with neonatal diabetes (PM3_Supporting, PMID: 38970407). Another missense variant at the same codon, c.171G>A, p.(Met57Ile), has been interpreted as pathogenic by the ClinGen MDEP, and p.(Met57Arg) has a greater Grantham distance (PM5). In summary, c.170T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4, PM3_Supporting, PM5). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403318/MONDO:0015967/086 2024-10-31 2025-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:367163 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0007787 infores:hetionet CHEBI:6775 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C2363730 infores:hetionet CAID:CA10650425 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650425 MONDO:0011071 PMID: Benign BP4, BS1, BP7 PS1, PS3, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*1096A>C is an intronic variant. Highest MAF of 0.00032 (0.032%) (5/15428) in European (non-Finnish) population in gnomAD v2 is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). REVEL score not applicable and SpliceAI score of score ≤ 0.20 (Acceptor Loss 0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.37 < 2.0). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650425/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA340742683 biolink:causes MONDO:0100368 infores:clingen CAID:CA340742683 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting NM_000329.3(RPE65):c.1253T>A is a missense variant predicted to replace phenylalanine with tyrosine at position 418. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.997G>C (p.Gly333Arg) variant confirmed in trans, which was previously classified as likely pathogenic by the ClinGen LCA / eoRD VCEP (1 point, PMID: 34830511, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pt), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), macular dystrophy (0.5 pt), and absent ERG responses from rods (0.5 pt) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 points, PMID: 34830511, PP4). The computational predictor REVEL gives a score of 0.895, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 22745121). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340742683/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports GO:0090049 biolink:causes GO:0002040 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0002040 CHEBI:63624 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0234215 infores:hetionet CHEBI:64321 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020621 infores:hetionet CHEBI:6909 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0085932 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011609 infores:hetionet CHEBI:16796 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C1167965 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0022658 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0700345 infores:hetionet NCBIGene:1674 biolink:causes MONDO:0011076 infores:monarchinitiative not_provided not_provided HGNC:2770 MONDO:0011076 uuid:398cc273-5c46-4940-95eb-8c1a019e3c45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4717 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0021141 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0034069 infores:hetionet CHEBI:135930 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0013378 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004610 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0020517 infores:hetionet NCBITaxon:662 biolink:causes MONDO:0007014 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:662 MONDO:0007014 CHEBI:100241 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0015397 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0234193 infores:hetionet UNII:3U02EL437C biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0016204 infores:hetionet NCBIGene:9524 biolink:causes MONDO:0013528 infores:monarchinitiative not_provided not_provided HGNC:4551 MONDO:0013528 uuid:151e040e-dca1-4155-845e-372829dbeb71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C3665386 infores:hetionet CHEBI:63623 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0595930 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0314719 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0855242 infores:hetionet CHEBI:47381 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018524 infores:hetionet CHEBI:3242 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0023222 infores:hetionet CHEBI:59773 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0038999 infores:hetionet CHEBI:8871 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0162285 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0009450 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0011849 infores:hetionet CHEBI:63631 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013404 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0016542 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0016542 infores:hetionet CAID:CA229665 biolink:causes MONDO:0009861 infores:clingen CAID:CA229665 MONDO:0009861 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong PM5 The NM_000277.3:c.620A>G variant in PAH is a missense variant predicted to cause substitution of asparagine by serine at amino acid 207 (p.Asn207Ser). This variant has been detected in at least 5 unrelated individuals with PAH deficiency (PMID: 32668217, PMID: 9048935). Of these individuals, one was a compound heterozygote for the variant and a likely pathogenic variant, p.Pro281Leu, in trans (phase confirmed by parental testing) (PMID: 9048935), and four were compound heterozygotes for the variant and pathogenic variants, p.Ala300Ser, p.Ala403Val, p.Glu390Gly, p.Arg252Gln, in unknown phase (PMID: 32668217) (3pts total, PM3_Strong). One of these individuals had plasma phenylalanine >120 μmol/L without the exclusion of a defect of BH4 cofactor metabolism (PMID: 9048935) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.77 which is above the threshold of 0.75, evidence that correlates with impact to PAH function (PP3). There is a ClinVar entry for this variant (Variation ID: 102765, 1 star review status) with one submitter classifying the variant as pathogenic, one submitter classifying the variant as likely pathogenic, and one submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Strong, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229665/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6775 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022661 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027051 infores:hetionet CHEBI:474053 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0041657 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020615 infores:hetionet CHEBI:135285 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0005758 infores:hetionet CHEBI:63115 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0030554 infores:hetionet CHEBI:61049 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019080 infores:hetionet CHEBI:63635 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1260880 infores:hetionet CHEBI:40279 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0013428 infores:hetionet CAID:CA2582129988 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582129988 MONDO:0010305 PMID: Uncertain Significance PP4, PS4_Supporting, PM2_Supporting, PM4 PP3 The NM_005629.4:c.428_430del variant in SLC6A8 is a deletion of 3 nucleotides within exon 3/13 of the SLC6A8 gene and is predicted to lead to an in-frame deletion of 1 amino acid (p.Tyr143del) (PM4). This variant has been previously reported in two unrelated hemizygous male individuals (PS4_Supporting) with elevated urinary creatine/creatinine (PMID: 23644449, PMID: 21556832) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS4_Supporting, PM2_Supporting, PM4, PP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582129988/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3752 biolink:causes MONDO:0016755 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0162678 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0423271 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423271 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0007222 infores:hetionet CHEBI:31859 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0014457 infores:hetionet CHEBI:53760 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085636 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0042571 infores:hetionet CAID:CA145775 biolink:causes MONDO:0009290 infores:clingen CAID:CA145775 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.2553G>A (p.Gly851=) in gnomAD v2.1.1 is 0.63818 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.70216) and European Finnish (0.64436) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92481, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145775/MONDO:0009290/010 2020-01-23 2020-05-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:50173 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0015397 infores:hetionet CHEBI:47426 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0085602 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0037199 infores:hetionet CHEBI:6539 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0233795 infores:hetionet CHEBI:39669 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002436 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0028432 infores:hetionet NCBIGene:6091 biolink:causes MONDO:0957208 infores:monarchinitiative not_provided not_provided HGNC:10249 MONDO:0957208 uuid:ee75cfca-c143-4ff0-9e27-adefedbc674e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041657 infores:hetionet CHEBI:65173 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0338831 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0001824 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0027769 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0040034 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0151735 infores:hetionet CHEBI:6909 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0004604 infores:hetionet CHEBI:144093 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0015967 infores:hetionet CHEBI:480999 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0023380 infores:hetionet CHEBI:50859 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042024 infores:hetionet CHEBI:585948 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0009806 infores:hetionet CAID:CA399805884 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805884 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting PM3, PP3 The NM_000419.5(ITGA2B):c.483C>G (p.Cys161Trp) missense variant has been reported in at least one patient (DC in PMID: 11798398) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805884/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:51860 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009763 infores:hetionet CHEBI:3181 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0000729 infores:hetionet CHEBI:3001 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0002994 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0021400 infores:hetionet CHEBI:50777 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0033046 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0004936 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022354 infores:hetionet CHEBI:6129 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014724 infores:hetionet NCBIGene:6390 biolink:causes MONDO:0011719 infores:monarchinitiative not_provided not_provided HGNC:10681 MONDO:0011719 uuid:72a49289-1769-4332-8b27-755e262cc7dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229615 biolink:causes MONDO:0009861 infores:clingen CAID:CA229615 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.535T>C (p.Tyr179His) variant in PAH has been reported in multiple individuals with PKU, including in patients with classic PKU in whom BH4 deficiency has been excluded (PMID: 29997390, PMID: 16256386, PMID: 20920871, PMID: 32668217, PMID: 30389586). p.Tyr179His has been detected with multiple variants classified as likely pathogenic or pathogenic by PAH VCEP, including p.Arg176*, c.1066-11G>A, c.1199+1G>C, p.Ala403Val, p.Ile406Met, p.Arg408Trp, p.Val230Ile (PMID: 32668217). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229615/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63629 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0007859 infores:hetionet CHEBI:47898 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004245 infores:hetionet NCBIGene:9927 biolink:causes MONDO:0014906 infores:monarchinitiative not_provided not_provided HGNC:16877 MONDO:0014906 uuid:2731c329-e2d1-4a92-ab81-588cc278d3ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0242184 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0034065 infores:hetionet CHEBI:17650 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C3263723 infores:hetionet CHEBI:134743 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0013404 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1443060 infores:hetionet CHEBI:5613 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0235660 infores:hetionet CHEBI:10119 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0039231 infores:hetionet GO:1900055 biolink:causes GO:0048366 infores:ubergraph knowledge_assertion manual_agent GO:1900055 GO:0048366 CAID:CA10650515 biolink:causes MONDO:0015152 infores:clingen CAID:CA10650515 MONDO:0015152 PMID: Likely Benign BP4, BP7 BP1, BP3, BP2, BA1, PM5, PM4, PM1, PM3, PS1, PS3, PS4, PS2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, BS2, PP2, PP3, PP1, PP4 The NM_000023.4: c.*227G>A variant is located in the 3’UTR of SGCA. Because the variant is located in the 3’UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001447 (6/41458 genome chromosomes) in the African/African American population, which is greater than the ClinGen LGMD VCEP threshold (<0.00009) for PM2_Supporting (criterion not met). The computational splicing predictor SpliceAI gives a score of 0.00 for donor and acceptor loss, suggesting the variant has no impact on splicing (threshold for no impact: ≤0.05) (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650515/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:119573 biolink:causes UMLS:C0541923 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0541923 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235234 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0877661 infores:hetionet CAID:CA386304277 biolink:causes MONDO:0009861 infores:clingen CAID:CA386304277 MONDO:0009861 PMID:30159852 Pathogenic PM3, PM2, PVS1, PP4 This c.169-1G>A (aka IVS2-1G>A) variant in PAH has been observed in at least two patients with PAH deficiency (PMID: 18294361 and 30159852) in trans with pathogenic variant c.168+5G>C. One patient was homozygous for this variant (PMID: 30159852). This variant is absent in controls from population databases. This variant in the -1 splice acceptor site of intron 2 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay. This variant breaks the splice site in intron 2 according to computational models. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386304277/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:145499 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019080 infores:hetionet NCBIGene:4848 biolink:causes MONDO:0032832 infores:monarchinitiative not_provided not_provided HGNC:7878 MONDO:0032832 uuid:34f70187-55f3-4afe-99ca-a751c95bd829 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101853 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0085649 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0037274 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0038454 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0007256 uuid:a9380efb-5be9-477d-912a-e6147c9ec8f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9435 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0549249 infores:hetionet CHEBI:6809 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0011991 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042109 infores:hetionet UMLS:C0657912 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042023 infores:hetionet CHEBI:45367 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0022346 infores:hetionet CHEBI:17303 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0035229 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0027051 infores:hetionet CHEBI:16469 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0000729 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0856151 infores:hetionet CAID:CA270390 biolink:causes MONDO:0010726 infores:clingen CAID:CA270390 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PP3, PP4, PM6, PM5_Strong, PM2_Supporting, PS4_Supporting The p.Arg133Leu variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome (PMID 10854091) (PM6). The p.Arg133Leu variant has been observed in at least 1 other individual with classic Rett syndrome (PMID 19722030) (PS4_supporting, PP4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 30569584, 23421866, 11738879, 26418480, 16473305, 22368975; ClinVar) (PM5_strong). The p.Arg133Leu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). MECP2 chromatin binding assays have shown that this variant impacts protein function (PMID 27929079, 22923521) (PS3_supporting). In summary, the p.Arg133Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PM6, PS3_supporting, PS4_supporting, PM2_supporting, PP3 + PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270390/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:63612 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0152027 infores:hetionet GO:2000492 biolink:causes GO:0071351 infores:ubergraph knowledge_assertion manual_agent GO:2000492 GO:0071351 CHEBI:47898 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027339 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0853697 infores:hetionet CHEBI:9598 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0030193 infores:hetionet CHEBI:8869 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0013404 infores:hetionet CHEBI:6128 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0162830 infores:hetionet CHEBI:4672 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0687713 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151692 infores:hetionet CHEBI:9907 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0014724 infores:hetionet CHEBI:68642 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0235710 infores:hetionet CHEBI:161680 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0031256 infores:hetionet NCBIGene:10466 biolink:causes MONDO:0013325 infores:monarchinitiative not_provided not_provided HGNC:14857 MONDO:0013325 uuid:ce64d521-ef2a-4b43-b533-712864117c36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0010200 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0006147 infores:hetionet CAID:CA410147569 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147569 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS4, PS3, PS2, BP3, BP2, BP1, PVS1, PM6, BP5, BP7, BS4, BS3, PM4, PM3, PM1, PP4, PP1, PP2, BS2 NM_001754.5(RUNX1):c.1268G>C (p.Arg423Pro) is a missense variant. MAF of 0.0001793 (0.01793%, 5/27882 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD v4.1.0 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score < 0.50 (0.486) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147569/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:32139 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0149514 infores:hetionet CHEBI:85083 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0030193 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0233746 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0233746 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015397 infores:hetionet CHEBI:135276 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0041969 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0522165 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0522165 infores:hetionet CHEBI:93635 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0027066 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0017566 infores:hetionet CHEBI:2549 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0151744 infores:hetionet CHEBI:5098 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0041969 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0235639 infores:hetionet CHEBI:45979 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0028643 infores:hetionet CHEBI:5778 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0085612 infores:hetionet CHEBI:3314 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0027497 infores:hetionet CHEBI:4868 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0011124 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0034359 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C2047937 infores:hetionet NCBITaxon:5658 biolink:causes MONDO:0005859 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5658 MESH:D007897 DB09031_MESH_D007897_1 NCBIGene:3785 biolink:causes MONDO:0007365 infores:monarchinitiative not_provided not_provided HGNC:6296 MONDO:0007365 uuid:2709e4e6-0e5a-43b4-b7ce-b1520edd21ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853692 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0006846 infores:hetionet CHEBI:8890 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0549249 infores:hetionet CHEBI:3996 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0002792 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0474381 infores:hetionet CHEBI:8764 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020580 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0037199 infores:hetionet CHEBI:9288 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0009676 infores:hetionet CHEBI:17026 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C3489393 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0015230 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0003123 infores:hetionet CHEBI:52172 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0014457 infores:hetionet CHEBI:82960 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0030196 infores:hetionet CHEBI:3561 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0018965 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0038358 infores:hetionet CHEBI:75984 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0003862 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0520893 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0030554 infores:hetionet CHEBI:3478 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0017152 infores:hetionet CHEBI:3752 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0152198 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0017178 infores:hetionet CHEBI:4681 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0013404 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020456 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0037822 infores:hetionet CHEBI:70746 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0017152 infores:hetionet CHEBI:42797 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0497156 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0003123 infores:hetionet CHEBI:47780 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017168 infores:hetionet CHEBI:171719 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0029124 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0023530 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0333291 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0333291 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0020651 infores:hetionet CHEBI:38545 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C3267047 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0406317 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0406317 infores:hetionet CHEBI:6067 biolink:causes MONDO:0013592 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0221260 infores:hetionet CHEBI:32293 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151786 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0948594 infores:hetionet CHEBI:2904 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0220870 infores:hetionet CHEBI:9725 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0232333 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0003123 infores:hetionet NCBIGene:23514 biolink:causes MONDO:0030506 infores:monarchinitiative not_provided not_provided HGNC:28971 MONDO:0030506 uuid:6df31fb3-5f00-4ead-9dde-2b624f2678f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2676 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0037274 infores:hetionet CHEBI:4315 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0030252 infores:hetionet CHEBI:49662 biolink:causes HP:0034705 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0234962 infores:hetionet CHEBI:92712 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0151827 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0341177 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0341177 infores:hetionet CHEBI:50693 biolink:causes UMLS:C0750197 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0750197 infores:hetionet CHEBI:61049 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0014356 infores:hetionet CHEBI:51860 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C3263723 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0003123 infores:hetionet UMLS:C0023610 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0018681 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0030312 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0008031 infores:hetionet CHEBI:7476 biolink:causes MONDO:0024335 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085582 infores:hetionet CAID:CA114139 biolink:causes MONDO:0015631 infores:clingen CAID:CA114139 MONDO:0015631 PMID: Pathogenic PP4_Moderate, PP1, PM3_Strong, PS3 PM2, PP3, BP4, PM5, BS1 The NM_000552.5(VWF):c.2561G>A variant in VWF is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 854. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.005857 (based on 7050/1180026 alleles, with 24 homozygotes) in the European non-Finnish population. This allele frequency is above the ClinGen VWD VCEP threshold for VWD Type 2N (<0.005) for PM2_Supporting but below the threshold (>0.01) for BS1 and therefore does not meet any population criterion. At least 9 patients with this variant displayed excessive mucocutaneous bleeding, low FVIII activity, and decreased VWF:FVIII binding, which is highly specific for VWD type 2N (PP4_Moderate, PMID: 28971901, PMID: 22875612). Four individuals were homozygous for the variant (PMID: 28971901, PMID: 22875612, PMID: 1832934) and one of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Arg816Trp) confirmed in trans (PMID: 1832934), additional compound heterozygotes have been reported but were not considered here (PM3_Strong). In one family, the variant segregated with VWD type 2N in the proband and a second affected family member (PP1; PMID: 28971901). A hydrodynamic mouse model showed reduced factor VIII stability and impaired binding of factor VIII to VWF, indicating that this variant has a damaging effect on protein function (PMID: 28581694)(PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PM3_Strong, PP4_Moderate, PP1. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114139/MONDO:0015631/090 2024-07-09 2024-08-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA405677091 biolink:causes MONDO:0018493 infores:clingen CAID:CA405677091 MONDO:0018493 PMID: Uncertain Significance PM1, PS4_Moderate PP1, PP3, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with aspartic acid at codon 176 of the RYR1 protein, p.(Glu176Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five individuals with a personal or family history of an MH episode, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (Kaulins, 2008; Prevention Genetics; MH Investigation Unit, UHN, Toronto). An ex vivo assay from a single patient showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested (Kaulins, 2008). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in two individuals, PP1 not met (Kaulins, 2008). A REVEL score of 0.504 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405677091/MONDO:0018493/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA412370589 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370589 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PP3_Strong, PP1 PS4, PM5 The NM_000330.4(RS1):c.533G>C variant is a missense variant encoding the substitution of Glycine with Alanine at amino acid 178. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.941, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. Another missense variant in the same codon, c.533G>A, p.Gly178Asp (PMID: 31087526, 12928282, 31149861, 11738458, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. However, the present variant has a lower Grantham’s distance than the comparison variant, so PM5 cannot be met. The variant has been reported to segregate with retinal dystrophy through two affected males of the same family (PP1; PMID: 31087526). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 31087526), however, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP1, and PP3_strong (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370589/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:17303 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0547030 infores:hetionet CHEBI:3640 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0020456 infores:hetionet CHEBI:5002 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0151578 infores:hetionet CHEBI:77733 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0009806 infores:hetionet CHEBI:94440 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0426576 infores:hetionet CHEBI:6062 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0007820 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0262576 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0262576 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003635 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0700184 infores:hetionet CHEBI:8028 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0027424 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0025061 infores:hetionet CHEBI:3752 biolink:causes MONDO:0850154 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0558353 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0234222 infores:hetionet CAID:CA294892605 biolink:causes MONDO:0009290 infores:clingen CAID:CA294892605 MONDO:0009290 PMID:29122469PMID:28814660PMID:32802993PMID:30214072 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1292_1295dup (p.Gln433AlafsTer74), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. A patient who is compound heterozygous for the variant and p.Arg854Ter (a known pathogenic variant and CRIM-negative allele), has no GAA cross-reactive immunological material on Western blot of protein from cultured skin fibroblasts (PMID 28814660), supporting that c.1292_1295dup results in lack of gene product. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000074 in the African population, meeting PM2. Three patients with Pompe disease and meeting the ClinGen LSD VCEP's specifications have been reported (PMIDs 28814660, 29122469, 30214072, 32802993, personal communication). One of these patients is compound heterozygous for the variant and c.2560C>T (p.Arg854Ter). The phase is unknown (PMIDs 28814660, 29122469, personal communication). The other two patients are compound heterozygous for the variant and a missense variant, either c.1019A>G (p.Tyr340Cys) (PMID 32802993) or c.953T>C (p.Met318Thr) (PMID 30214072). The phase is unknown. The in trans data from these latter two patients may be used in the assessment of the missense variants and was not included here in order to avoid circular logic. PM3_Supporting is met. There is a ClinVar entry for this variant (Variation ID: 552165, 2 star review status) with one submitter classifying the variant as pathogenic and one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294892605/MONDO:0009290/010 2020-09-21 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4530 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0231218 infores:hetionet CHEBI:45924 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C1443060 infores:hetionet CHEBI:134991 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0015672 infores:hetionet CHEBI:7915 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232495 infores:hetionet CHEBI:180905 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0042571 infores:hetionet CHEBI:8228 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0151603 infores:hetionet CAID:CA023860 biolink:causes MONDO:0100150 infores:clingen CAID:CA023860 MONDO:0100150 PMID: Benign BP7, BA1, BP4 BS1, PM2 The variant NM_000540.3:c.1077T>C in RYR1 is a synonymous (silent) variant (p.Ala359=). The filtering allele frequency (the lower threshold of the 95% CI of 19809/19952, 9835 homozygotes) of the c.1077T>C variant in RYR1 is 0.9807 for East Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.1077T>C (p.Ala359=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA023860/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CAID:CA512318731 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318731 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.432G>A (p.Leu144=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.05)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318731/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:617099 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0009450 infores:hetionet CHEBI:41977 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0004238 infores:hetionet CHEBI:49603 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0030252 infores:hetionet CHEBI:5801 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C1260926 infores:hetionet CHEBI:3181 biolink:causes MONDO:0006711 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0031048 infores:hetionet CHEBI:40303 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0004604 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0162429 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0013404 infores:hetionet CHEBI:3219 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0043352 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0851341 infores:hetionet CAID:CA226559 biolink:causes MONDO:0100368 infores:clingen CAID:CA226559 MONDO:0100368 PMID: Pathogenic PM3_Strong, PM1, PP3_Moderate, PS3_Supporting, PP1_Moderate, PM2_Supporting PM5 The NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant in RPE65 is a missense variant resulting in a substitution of histidine by tyrosine at codon 182. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 unrelated proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMID: 27874104). This variant has also been reported in 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) confirmed in trans (2 points, PMID: 9501220, PMID: 27102010), which was previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 27874104).This variant is a missense substitution at p.His182, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). The variant exhibited approximately 10% enzymatic activity in a retinoid isomerase assay relative to the wildtype control, which meets the ClinGen LCA / eoRD PS3_Supporting threshold of ≤10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16150724). The computational predictor REVEL gives a score of 0.912, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP1_Moderate, PM1, PS3_Supporting, PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226559/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31981 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0150450 infores:hetionet CHEBI:16899 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0033771 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020615 infores:hetionet CHEBI:135285 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0009450 infores:hetionet CHEBI:7577 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0018808 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003615 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0003123 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0041834 infores:hetionet CHEBI:27666 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0038362 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0037274 infores:hetionet CHEBI:50648 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0239783 infores:hetionet CHEBI:9737 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0027947 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0040479 infores:hetionet CHEBI:10101 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0600142 infores:hetionet CHEBI:8028 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0030193 infores:hetionet CHEBI:45409 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0023530 infores:hetionet NCBIGene:100 biolink:causes MONDO:0007064 infores:monarchinitiative not_provided not_provided HGNC:186 MONDO:0007064 uuid:6e1ebec6-89d9-40a0-b46d-b53d43191ca7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9332 biolink:causes UMLS:C0151788 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0151788 infores:hetionet CHEBI:6413 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0011603 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0162429 infores:hetionet CHEBI:9586 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0030193 infores:hetionet CHEBI:132233 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0002792 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0277925 infores:hetionet CHEBI:71028 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0232462 infores:hetionet CHEBI:31184 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0016436 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0004601 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004601 infores:hetionet CHEBI:194135 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151908 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0854082 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0434437 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0853619 infores:hetionet CHEBI:8871 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151827 infores:hetionet CHEBI:9571 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0037763 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002170 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0080203 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0008478 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0008478 uuid:8d5db8b3-0949-49d1-b697-fb44e4476a81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0004604 infores:hetionet CHEBI:6801 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0013604 infores:hetionet CHEBI:6846 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0426576 infores:hetionet CHEBI:7581 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0040822 infores:hetionet CHEBI:63611 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151599 infores:hetionet CHEBI:8768 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151905 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1266194 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0349506 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0235169 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018418 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0152965 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0152965 infores:hetionet CHEBI:31355 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0031542 infores:hetionet CHEBI:49575 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0220870 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005452 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2267227 infores:hetionet CHEBI:27899 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0019521 infores:hetionet CHEBI:7476 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013144 infores:hetionet CHEBI:499361 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0333355 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0034359 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0259749 infores:hetionet CHEBI:84883 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0004093 infores:hetionet CHEBI:5134 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0149725 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020538 infores:hetionet CHEBI:3485 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0917801 infores:hetionet CHEBI:87715 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0017181 infores:hetionet CHEBI:53691 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0242528 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0022408 infores:hetionet NCBIGene:3800 biolink:causes MONDO:0014116 infores:monarchinitiative not_provided not_provided HGNC:6325 MONDO:0014116 uuid:79e286d1-8e58-4c7b-84a4-b5d9c4f87a0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0025241 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0237849 infores:hetionet CHEBI:7454 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0015967 infores:hetionet CHEBI:3223 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0011603 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002871 infores:hetionet CHEBI:6887 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0424295 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0042109 infores:hetionet CHEBI:79699 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0002390 infores:hetionet UMLS:C0065374 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0023222 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0856151 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027932 infores:hetionet CHEBI:63581 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1280433 infores:hetionet CHEBI:45783 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042029 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0243026 infores:hetionet CHEBI:9139 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085649 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1258215 infores:hetionet CHEBI:175901 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C2047937 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0006840 infores:hetionet CHEBI:28001 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0043144 infores:hetionet CHEBI:38545 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0010200 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0030312 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0003123 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0234215 infores:hetionet CHEBI:5280 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0018965 infores:hetionet CHEBI:7573 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151825 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0033581 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0006663 infores:hetionet CAID:CA915940264 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940264 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting NM_000419.5(ITGA2B):c.113del (p.Gln38ArgfsTer73) found in a homozygous proband (PMID: 29084015; PM3_supporting) causes a premature stop codon at exon 3 and is predicted to undergo nonsense mediated decay (PVS1). The affected individual displayed abnormal bleeding and an impaired response to agonists, with a normal response to ristocetin, which is characteristic of GT. Additionally, αIIbβ3 surface expression was absent (<25%), as measured by flow cytometry (PP4_strong). The variant was not found in gnomAD v2.1.1 (PM2_supporting). In conclusion the criteria PVS1, PP4_strong, PM2_supporting, and PM3_supporting, were applied to reach a classification of pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940264/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA262109 biolink:causes MONDO:0019501 infores:clingen CAID:CA262109 MONDO:0019501 PMID:18641288PMID:20507924PMID:18641288 Likely Pathogenic PVS1_Moderate, PP4, PM3, PM2_Supporting The c.5857+2T>C variant in USH2A has been identified in at least 3 probands: in a compound heterozygous state in one individual with autosomal recessive retinitis pigmentosa, one patient with usher syndrome who was compound heterozygous for a second pathogenic (phase unknown); and in a heterozygous state in two individuals with Usher syndrome type II (PM3, PP4; PMID 20507924,18641288, LMM unpublished data SCV000065566.6 ). The allele frequency of this variant is 0.001% (11/ 1179534) of European non-finnish chromosomes by gnomAD v.4, which is lower than the thresholds defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing, though the exact impact is unknown. Exon 29 is in-frame, and if the variant results in exon skipping, it would remove <10% of the USH2A protein. However, two truncating pathogenic / likely pathogenic variants in this exon have been reported in ClinVar, which may suggest it is required for normal protein function (PVS1_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PVS1_Moderate, PM3, PP4, PM2_Supporting) (ClinGen Hearing Loss VCEP specifications version 2; 7/16/2025) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA262109/MONDO:0019501/005 2025-07-16 2025-09-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:28593 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0233571 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0020517 infores:hetionet CHEBI:34911 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0027497 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0017160 infores:hetionet GO:1905282 biolink:causes GO:0003015 infores:ubergraph knowledge_assertion manual_agent GO:1905282 GO:0003015 CHEBI:3510 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0014742 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0011053 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0040034 infores:hetionet CHEBI:7907 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0006266 infores:hetionet CHEBI:6067 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0039070 infores:hetionet CHEBI:35778 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0015230 infores:hetionet UMLS:C0879264 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020488 infores:hetionet CHEBI:5134 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0016655 infores:hetionet CAID:CA8970387 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970387 MONDO:0012589 PMID: Benign BA1, BP5_Strong, BS2 The highest population minor allele frequency of the c.790-9T>C variant in TCF4 in gnomAD v4.1 is 0.006579 in the Amish population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The c.790-9T>C variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The c.790-9T>C variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). In summary, the c.790-9T>C variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970387/MONDO:0012589/032 2024-08-30 2024-11-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9654 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1142412 infores:hetionet CAID:CA132732 biolink:causes MONDO:0010134 infores:clingen CAID:CA132732 MONDO:0010134 PMID: Benign BA1 The filtering allele frequency of the p.Ala1898Ser variant in the SLC26A4 gene is 1.2% (324/24040) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132732/MONDO:0010134/005 2018-09-28 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA000076 biolink:causes MONDO:0018875 infores:clingen CAID:CA000076 MONDO:0018875 PMID: Likely Benign BP4, BS3, PM2_Supporting BA1, PS3, PS1, PS4, PS2, PM1, PM5, BS1, BS4, PP3, PP1, PP4, BS2 The NM_000546.6: c.21T>A variant in TP53 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 7 (p.Asp7Glu). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0153; Align GVGD Class C0 are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_moderate). This variant has an allele frequency of 0.000001859 (3/1613882 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BP4_moderate, PM2_Supporting (Bayesian Points: -5; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000076/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50223 biolink:causes UMLS:C0853347 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0853347 infores:hetionet CHEBI:474053 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0016204 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0034065 infores:hetionet CAID:CA051220 biolink:causes MONDO:0005045 infores:clingen CAID:CA051220 MONDO:0005045 PMID: Uncertain Significance BP4 PM5, PM1, BS1, PM2, BA1, PS1 NM_000363.5(TNNI3):c.318G>C (p.Lys106Asn) - This variant has been reported in association with HCM (PMIDs: 24793961), but is not statistically increased in individuals with HCM compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied. This variant is present in gnomAD (v2.1.1), but did not meet the threshold for PM2 nor BS1. Computational prediction tools suggest that this variant does not impact the protein (REVEL score <0.4; BP4). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on BP4. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA051220/MONDO:0005045/098 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3640 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0034063 infores:hetionet CHEBI:72296 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0027497 infores:hetionet CHEBI:8890 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0011991 infores:hetionet GO:1904118 biolink:causes GO:0042471 infores:ubergraph knowledge_assertion manual_agent GO:1904118 GO:0042471 CHEBI:10650 biolink:causes NCIT:C34642 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017650 infores:hetionet CHEBI:2687 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0041956 infores:hetionet CHEBI:4798 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0026858 infores:hetionet CHEBI:8890 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042024 infores:hetionet CHEBI:6062 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0702166 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0241705 infores:hetionet CHEBI:63629 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151827 infores:hetionet NCBITaxon:2 biolink:causes HP:0200042 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D012883 DB05245_MESH_D012883_1 CHEBI:92712 biolink:causes MONDO:0001817 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0154946 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0855242 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0031117 infores:hetionet CHEBI:10124 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085649 infores:hetionet CHEBI:3441 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C2242588 infores:hetionet CAID:CA392325981 biolink:causes MONDO:0007947 infores:clingen CAID:CA392325981 MONDO:0007947 PMID: Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4, PM1_Strong, PM6_Supporting PVS1, PP1, BS2, BA1, BP1, BP4, BP3, BP2, PS3, PS2, PS1, PM4, PM3, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.3476G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1159 (p.Cys1159Tyr). This variant was found in a 2-year-old proband with thoracic aortic aneurysm (TAA), ectopia lentis, and a systemic score ≥ 7, which is a highly specific phenotype for Marfan syndrome (MFS) (PP4; UZG internal data). This variant has been reported 3 times in ClinVar as pathogenic (2) and of uncertain significance (1) (Variation ID: 547309). This variant has been identified in 4 other individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS, as de novo in a neonate with severe TAA and a systemic score of 6, and in 2 additional individuals who did not meet diagnostic criteria either but have phenotypes strongly suggestive of MFS (PS4, PM6_supporting; PMIDs: 35831148, 31523900, 34628919; UZG, Mayo, & Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL = 0.981). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1_strong, PP2, PP3, PP4, PM2_supporting, PM6_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392325981/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10119 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011175 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0267792 infores:hetionet CAID:CA226500 biolink:causes MONDO:0100368 infores:clingen CAID:CA226500 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting PM5 NM_000329.3(RPE65):c.1292A>G is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 431. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 1/113326 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.907A>T (p.Lys303Ter) or c.1102T>C (p.Tyr368His) variants confirmed in trans (2 point, PMIDs: 14962443, 30268864), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), absent or severely decreased rod electroretinogram responses (0.5 pts), congenital night blindness (0.5 pts), optic nerve pallor (0.5 pts), Pigmentary retinopathy with attenuated vessels (0.5 pts), macular atrophy (0.5 pts), symptomatic onset between birth and age five years (1 pt), decreased central visual acuity (1 pt), abnormal color vision or evidence of cone involvement on ERG (1 pt), nystagmus (1 pt), and significant improvement following gene therapy (8 pt) which together are highly specific for RPE65-related recessive retinopathy (PMIDs: 14962443, 19117922, 22323828, 15 points, PP4_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRP VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226500/MONDO:0100368/120 2024-01-31 2024-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:30830 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0041969 infores:hetionet CHEBI:70707 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0019087 infores:hetionet GO:0060787 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:0060787 GO:0043009 CHEBI:8874 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0241060 infores:hetionet CHEBI:499361 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0014742 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011630 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0027765 infores:hetionet CHEBI:17026 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0025874 infores:hetionet CHEBI:49960 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0700225 infores:hetionet NCBIGene:4041 biolink:causes MONDO:0009820 infores:monarchinitiative not_provided not_provided HGNC:6697 MONDO:0009820 uuid:35a1d9f2-8f15-4b83-856b-30a76bbc275c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014868 infores:hetionet CHEBI:9586 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0424295 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032290 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0037199 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0585186 infores:hetionet CHEBI:8874 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018926 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0748536 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0748536 infores:hetionet CHEBI:34911 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0012833 infores:hetionet CHEBI:182080 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C1443060 infores:hetionet CHEBI:404903 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0080274 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0040409 infores:hetionet CAID:CA386952304 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952304 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PVS1 PP4 The c.25C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 9 (p.(Gln9Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 24905847, internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952304/MONDO:0015967/017 2022-03-25 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51137 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0018939 infores:hetionet CHEBI:3723 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085641 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0007760 infores:hetionet NCBIGene:55790 biolink:causes MONDO:0030029 infores:monarchinitiative not_provided not_provided HGNC:24290 MONDO:0030029 uuid:4f85b1fd-82e4-4dc4-9bb2-35a90b91ba2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0004652 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004626 infores:hetionet CHEBI:6062 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0039070 infores:hetionet CHEBI:168396 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018989 infores:hetionet CHEBI:261649 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0020625 infores:hetionet CHEBI:93635 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0013428 infores:hetionet CHEBI:47381 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0033774 infores:hetionet CHEBI:3441 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0344232 infores:hetionet CHEBI:9566 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0085649 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0038367 infores:hetionet CHEBI:64321 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0855775 infores:hetionet CHEBI:127780 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0013404 infores:hetionet CHEBI:72323 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0014742 infores:hetionet CHEBI:6710 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0001824 infores:hetionet NCBIGene:7386 biolink:causes MONDO:0032909 infores:monarchinitiative not_provided not_provided HGNC:12587 MONDO:0032909 uuid:b827cf74-fa56-41d5-969f-56d897fd3e40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10110 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0020458 infores:hetionet CHEBI:71941 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0017152 infores:hetionet CHEBI:64321 biolink:causes NCIT:C35135 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0079027 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0041976 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0152115 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0687707 infores:hetionet CHEBI:4672 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0023530 infores:hetionet CHEBI:47780 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1456784 infores:hetionet CHEBI:3561 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0085649 infores:hetionet CHEBI:9139 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020488 infores:hetionet CAID:CA023635 biolink:causes MONDO:0007750 infores:clingen CAID:CA023635 MONDO:0007750 PMID: Uncertain Significance PP1_Moderate, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP2, PP4 NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1_Moderate and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_moderate - Variant segregates with FH phenotype in 4 informative meioses in 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PP3 - REVEL: 0,754. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023635/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7959 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0002871 infores:hetionet CHEBI:135530 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0151786 infores:hetionet UNII:D27V6190PM biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0234632 infores:hetionet CHEBI:93635 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0233794 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005301 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0026769 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0033777 infores:hetionet CAID:CA10549150 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549150 MONDO:0010305 PMID: Uncertain Significance BP4 PM2 The NM_005629.4(SLC6A8):c.89C>T (p.Ala30Val) variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Valine at amino acid 30 (p.Ala30Val). In gnomAD v2.1.1, the highest population minor allele frequency is 0.001205 (1/830 alleles) in the European population with 1 hemizygote, which is <0.0002 and >1 hemizygote, therefore PM2_Supporting criteria is not applicable. The computational predictor REVEL gives a score of 0.096 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing (BP4). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:650071). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549150/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CHEBI:15552 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C1619702 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0948089 infores:hetionet NCBIGene:4081 biolink:causes MONDO:0032774 infores:monarchinitiative not_provided not_provided HGNC:6757 MONDO:0032774 uuid:3da7f740-3278-4447-9d37-8f7621e1c297 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:5806 biolink:causes MONDO:0015474 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5806 MESH:D003457 DB00507_MESH_D003457_1 CHEBI:84500 biolink:causes UMLS:C0235756 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235756 infores:hetionet CHEBI:3242 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C1145670 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0010709 infores:hetionet CHEBI:205919 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0009782 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0856151 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0234215 infores:hetionet CHEBI:63618 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0853034 infores:hetionet CHEBI:84883 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0017178 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0009806 infores:hetionet CHEBI:15765 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0003811 infores:hetionet CHEBI:53760 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0015672 infores:hetionet CHEBI:46195 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0018524 infores:hetionet CHEBI:2788 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0004093 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0853777 infores:hetionet CHEBI:3423 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0002170 infores:hetionet CHEBI:64321 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0006840 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0006670 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D016920 DB01112_MESH_D016920_1DB00493_MESH_D016920_1DB00479_MESH_D016920_1DB00479_MESH_D016920_2DB00684_MESH_D016920_1DB01212_MESH_D016920_1DB00798_MESH_D016920_1DB02703_MESH_D016920_1 CHEBI:2687 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0036572 infores:hetionet CHEBI:47780 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030554 infores:hetionet CHEBI:3568 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040822 infores:hetionet NCBIGene:8863 biolink:causes MONDO:0014814 infores:monarchinitiative not_provided not_provided HGNC:8847 MONDO:0014814 uuid:df6a0b8f-5e83-4b1f-9c98-7805f36b9a77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023380 infores:hetionet CHEBI:3223 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0392171 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1306341 infores:hetionet CHEBI:6916 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0002962 infores:hetionet CHEBI:681569 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0013404 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020517 infores:hetionet CHEBI:3172 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0009763 infores:hetionet CHEBI:3216 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042024 infores:hetionet CHEBI:6904 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0541782 infores:hetionet CHEBI:2567 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0026821 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0011570 infores:hetionet CHEBI:8863 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0016204 infores:hetionet CAID:CA515652037 biolink:causes MONDO:0100437 infores:clingen CAID:CA515652037 MONDO:0100437 PMID: Likely Benign PM2_Supporting, BP4, BP7 NM_001034853.2(RPGR):c.39T>C (p.Ala13=) is a synonymous variant at codon 13 within exon 2 of 15, with no predicted impact on splicing (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.01 for donor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, BP4 and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA515652037/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:41423 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0041582 infores:hetionet CHEBI:5138 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0028734 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0400823 infores:hetionet CHEBI:31932 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0003811 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0857189 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0857189 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0036974 infores:hetionet CHEBI:100241 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042164 infores:hetionet CHEBI:2469 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0015624 infores:hetionet CHEBI:50859 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0023218 infores:hetionet NCBITaxon:745 biolink:causes MONDO:0005901 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:745 MONDO:0005901 CHEBI:45863 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0014591 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0340278 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0340278 infores:hetionet CHEBI:4814 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0011603 infores:hetionet CHEBI:3216 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0028084 infores:hetionet CHEBI:8382 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0016655 infores:hetionet CHEBI:7809 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0036830 infores:hetionet CHEBI:2379 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0023380 infores:hetionet CHEBI:6076 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0858635 infores:hetionet CHEBI:51860 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002962 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0162429 infores:hetionet CHEBI:2666 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0009421 infores:hetionet UMLS:C0657912 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035410 infores:hetionet CAID:CA913191005 biolink:causes MONDO:0009290 infores:clingen CAID:CA913191005 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1030_1031del (p.Gly344ProfsTer161) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in a patient with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 597147). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913191005/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:64355 biolink:causes MONDO:0003767 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0026265 infores:hetionet CHEBI:8764 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010200 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0438243 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0438243 infores:hetionet CAID:CA10014373 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014373 MONDO:0011071 PMID: Likely Benign BS1 PS4, PS3, PS1, BP2, BP4, BA1, PM6, PM2, PVS1, BP7, BS4, BS3, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.698G>A (p.Arg233His) variant has a MAF of 0.00142 (0.142%, 34/23,970 alleles) in the African subpopulation of the gnomAD cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). We allow a variant to reach a likely benign classification based on BS1 alone if there is no contradictory evidence supporting pathogenicity. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014373/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:29958 biolink:causes MONDO:0011610 infores:monarchinitiative not_provided not_provided HGNC:24475 MONDO:0011610 uuid:dcbe9954-4452-4faa-84cd-33db94399242 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0854372 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0854372 infores:hetionet CHEBI:17347 biolink:causes NCIT:C83495 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151685 infores:hetionet CHEBI:4858 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085606 infores:hetionet CHEBI:94501 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0014457 infores:hetionet CAID:CA10360565 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360565 MONDO:0100039 PMID: Likely Benign BP7, BP4 BS1 The c.2556G>A p.Pro852= variant in CDKL5 (NM_001323289.2) is present in 2 female individuals in gnomAD (0.0072%) (not sufficient to meet BS1 criteria). The silent p.Pro852= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the p.Pro852= variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360565/MONDO:0100039/034 2023-06-15 2023-12-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:63577 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0040822 infores:hetionet CHEBI:100241 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0007820 infores:hetionet CHEBI:188986 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009806 infores:hetionet CHEBI:45924 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0033774 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0035304 infores:hetionet CHEBI:8871 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018965 infores:hetionet CHEBI:68554 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0011603 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041671 infores:hetionet CAID:CA319122 biolink:causes MONDO:0012589 infores:clingen CAID:CA319122 MONDO:0012589 PMID: Likely Benign BP4, BP5, BS2 BA1, BS1, PM2 The p.Asn195Ser variant in TCF4 is present in 3 female and 5 male individuals in gnomAD (0.005%) (not sufficient to meet BS1 criteria). The p.Asn195Ser variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn195Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Asn195Ser variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Asn195Ser variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA319122/MONDO:0012589/032 2023-08-28 2024-03-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:231425 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020488 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0234215 infores:hetionet CHEBI:8356 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0424295 infores:hetionet CHEBI:231594 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042023 infores:hetionet NCBIGene:1131 biolink:causes MONDO:0007032 infores:monarchinitiative not_provided not_provided HGNC:1952 MONDO:0007032 uuid:e8769a14-209e-4261-9490-8b772d1d7024 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0009676 infores:hetionet CHEBI:27899 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0234518 infores:hetionet CHEBI:68558 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0041969 infores:hetionet CHEBI:3216 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0009806 infores:hetionet CHEBI:93363 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0020456 infores:hetionet CHEBI:9725 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0015230 infores:hetionet CHEBI:15765 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0917801 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0039971 infores:hetionet CHEBI:2666 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0234708 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0009450 infores:hetionet NCBIGene:55746 biolink:causes MONDO:0032581 infores:monarchinitiative not_provided not_provided HGNC:18016 MONDO:0032581 uuid:359420b0-b997-48a4-8670-c234d292aa67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0013144 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0042373 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020538 infores:hetionet CL:0000216 biolink:causes MONDO:0000378 infores:ubergraph knowledge_assertion manual_agent CL:0000216 MONDO:0000378 GO:1903332 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:1903332 GO:0010467 NCBIGene:2566 biolink:causes MONDO:0011891 infores:monarchinitiative not_provided not_provided HGNC:4087 MONDO:0011891 uuid:2c71fdb4-3f1f-4d3a-a1f6-a41a8c579311 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18332 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0021359 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0021400 infores:hetionet NCBIGene:1716 biolink:causes MONDO:8000013 infores:monarchinitiative not_provided not_provided HGNC:2858 MONDO:8000013 uuid:210bb045-bfc0-40ce-9486-c4929e1d5efa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0085632 infores:hetionet CAID:CA10603294 biolink:causes MONDO:0021060 infores:clingen CAID:CA10603294 MONDO:0021060 PMID: Uncertain Significance PM1, PM2, PP2 PS4, PM5, PP3 The c.782T>G (p.Leu261Arg) variant in PTPN11 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in several individuals whose features appear suggestive of a RASopathy; however, none were sufficiently phenotyped or received clinical diagnoses of a RASopathy (PS4 not met). This variant occurs in a region defined by the ClinGen RASopathy Expert Panel as a mutational hotspot of PTPN11 (PM1; PMID: 29493581). Additionally, the Expert Panel has defined PTPN11 as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of this variant is uncertain based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM1, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603294/MONDO:0021060/004 2020-03-16 2020-03-24 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50859 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151766 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018965 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0020039 infores:hetionet CHEBI:4653 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0085593 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0018418 infores:hetionet CHEBI:83804 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040264 infores:hetionet CAID:CA377781939 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781939 MONDO:0017623 PMID:29706350PMID:29706633 Uncertain Significance PP2, PP3, PM2_Supporting, BS3_Supporting PVS1, BS1, BP7, PM5, PM1, BA1, BP4, PS1, PS3 NM_000314.8(PTEN):c.46T>C (p.Tyr16His) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: This variant is absent from gnomAD database.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.866)BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.34095) per Mighell et al. 2018 (PMID: 29706350).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 3 pathogenic supporting codes get -1 + (1*3) points; total is 2 (Uncertain significance). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781939/MONDO:0017623/003 2023-10-11 2023-10-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61033 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0034150 infores:hetionet CHEBI:28177 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0009450 infores:hetionet NCBIGene:5881 biolink:causes MONDO:0032820 infores:monarchinitiative not_provided not_provided HGNC:9803 MONDO:0032820 uuid:783ce2a6-eb7c-4701-8647-d2eae6ce36e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0242656 infores:hetionet CHEBI:3013 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C1291078 infores:hetionet CHEBI:8874 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042029 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0041912 infores:hetionet NCBIGene:781 biolink:causes MONDO:0859327 infores:monarchinitiative not_provided not_provided HGNC:1399 MONDO:0859327 uuid:2e97441e-af0d-47c8-82fc-0854fd1b1701 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151937 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0851341 infores:hetionet NCBIGene:8996 biolink:causes MONDO:0100093 infores:monarchinitiative not_provided not_provided HGNC:7869 MONDO:0100093 uuid:9128ec29-334e-4509-acb7-2b6404a79fcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0015397 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0015376 infores:hetionet CHEBI:499361 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0015672 infores:hetionet CAID:CA913179100 biolink:causes MONDO:0044970 infores:clingen CAID:CA913179100 MONDO:0044970 PMID:11335700 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PS4 The m.8362T>G variant in MT-TK has been reported in two individuals with primary mitochondrial disease (PMIDs: 11335700, 23847141). The first reported individual was a woman with isolated limb muscle weakness. Muscle biopsy showed numerous ragged red and COX-negative fibers. The variant was present in muscle at 67% heteroplasmy (PMID: 11335700). The second reported individual was a woman with cerebellar ataxia, deafness, diabetes mellitus, and fibromas. The variant was described as heteroplasmic but tissue and heteroplasmy level were not provided (PMID: 23847141). An additional two families were known to members of this expert panel, however limited phenotypic details were provided so these cases are not included as part of this curation. This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). MitoTIP predicts the variant is likely pathogenic (93 percentile) and HmtVAR predicts the variant is pathogenic (score of 0.75; PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (79.3%, range 75.4-83.3, n=12) than in COX-positive fibers (49.3%, range 33.2-65.4, n=13) p<0.001 (PS3_supporting, PMID: 11335700). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913179100/MONDO:0044970/015 2024-08-27 2025-11-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:17650 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0034063 infores:hetionet CAID:CA024143 biolink:causes MONDO:0018493 infores:clingen CAID:CA024143 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with phenylalanine at codon 4817 of the RYR1 protein, p.(Ile4817Phe). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.911) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024143/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:5132 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0015230 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018799 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0027709 infores:hetionet CHEBI:15553 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0018790 infores:hetionet CHEBI:50378 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0017181 infores:hetionet CHEBI:167638 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0235439 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0040034 infores:hetionet UMLS:C0657912 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009421 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0031117 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0011570 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0020517 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0232910 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011053 infores:hetionet CHEBI:53760 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0003467 infores:hetionet CHEBI:3061 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0017178 infores:hetionet CHEBI:50275 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0039231 infores:hetionet CHEBI:119486 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0039070 infores:hetionet CHEBI:16586 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0001824 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002105 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0025162 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0040046 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0854375 infores:hetionet CAID:CA10603030 biolink:causes MONDO:0015967 infores:clingen CAID:CA10603030 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.1163dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 389 in NM_000162.5, adding 70 novel amino acids before encountering a stop codon (p.(Val389ArgfsTer70)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1163dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603030/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:9448 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0017152 infores:hetionet CAID:CA165821 biolink:causes MONDO:0007648 infores:clingen CAID:CA165821 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM5, PM3, PM1, PM4, PVS1, PM2, PM6, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS1, PS4, PS2, PS3 The NM_004360.5(CDH1):c.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA165821/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:135342 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151662 infores:hetionet NCBITaxon:37296 biolink:causes MONDO:0005055 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:37296 MESH:C554498 DB00105_MESH_C554498_1 GO:0030510 biolink:causes GO:0071773 infores:ubergraph knowledge_assertion manual_agent GO:0030510 GO:0071773 CHEBI:8212 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0020672 infores:hetionet CHEBI:31236 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0870082 infores:hetionet CHEBI:3011 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0687713 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0948873 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014863 infores:hetionet CHEBI:15367 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030554 infores:hetionet CHEBI:63598 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235378 infores:hetionet CHEBI:3732 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014335 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0234215 infores:hetionet CAID:CA1705673 biolink:causes MONDO:0015152 infores:clingen CAID:CA1705673 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.1180+5G>A variant in DYSF, which is also known as NM_001130987.2: c.1276+5G>A, occurs within the splice donor region of intron 12 and has a SpliceAI score of 0.87 for donor loss and 0.44 for gain of an alternative donor. RNAseq analysis has demonstrated abnormal splicing due to this variant, which resulted in either an insertion of 28bp or a deletion of 28bp. Both events led to a frameshift and premature truncation: p.(Met394SerfsTer27) and p.(Val385TrpfsTer5) (PMID: 36983702; PVS1_RNA). This variant has been reported in at least nine individuals with dysferlinopathy (PMID: 18853459, 25574751, 27647186, 28403181, 32400077, 36983702), including in unknown phase with a pathogenic variant in at least two patients (c.3112C>T p.(Arg1038Ter), 0.5 pts, PMID: 36983702; c.6124C>T p.(Arg2042Cys), 0.5 pts, PMID: 25574751) and in a homozygous state in one individual (0.5 pts, PMID: 27647186, 28403181) (PM3). At least one patient with this variant displayed progressive muscle weakness and reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 18853459, 25574751, 28403181, 36983702; PP4_Strong). The filtering allele frequency of this variant is 0.000028265 (the upper threshold of the 95% CI of 22/1111436 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/03/2025): PVS1_RNA, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1705673/MONDO:0015152/180 2025-04-03 2025-07-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63610 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0011991 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0020676 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0021400 infores:hetionet NCBITaxon:12967 biolink:causes MONDO:0005671 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12967 MONDO:0005671 GO:1902337 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:1902337 GO:0009653 UMLS:C0657912 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034063 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0236068 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0038941 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0038941 infores:hetionet CAID:CA16025124 biolink:causes MONDO:0021056 infores:clingen CAID:CA16025124 MONDO:0021056 PMID: Likely Pathogenic PS4_Supporting, PM2_Supporting, PVS1_Strong The NM_000038.6(APC):c.1743G>C (p.?) variant in APC is a G to non-G change at the last nucleotide of exon 14. It is predicted to cause skipping of exon 14, resulting in an in-frame deletion of an exon with sufficient supportive clinical data (PVS1_Strong). This variant has been reported in 1 family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting [Ambry Genetics]). The variant has been reported in 5 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (internal data Labcorp Genetics [formerly Invitae] and Ambry Genetics) and 1 proband without any clinical information (GeneDX). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PVS1_Strong, PS4_Supporting and PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16025124/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10125 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042023 infores:hetionet CAID:CA269775 biolink:causes MONDO:0100084 infores:clingen CAID:CA269775 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PP4_Moderate The c.1074G>T (p.Trp358Cys) variant in ACTA1 is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 358. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 2 probands, one with nemaline rods in muscle biopsy (as well as dilated cardiomyopathy) and the other an infant with hypotonia (PS4_Supporting, PP4_Moderate; PMID: 23650303, Invitae SCV001393788.5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP4_Moderate, PS4_Supporting, PM2_Supporting, PP2, PP3. (Congenital Myopathies VCEP specifications version 2; 08/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA269775/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31638 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0687713 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0012813 infores:hetionet CAID:CA512318907 biolink:causes MONDO:0100083 infores:clingen CAID:CA512318907 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BS1, BS3, BS4, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.222C>T (p.Gly74=) is a synonymous variant. REVEL score is not applicable and SpliceAI ∆ scores ≤ 0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.088874 < 2.0) (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318907/MONDO:0100083/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3181 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0038454 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0162429 infores:hetionet CHEBI:75179 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0344232 infores:hetionet CHEBI:15544 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0026961 infores:hetionet CHEBI:6541 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0151786 infores:hetionet CHEBI:31236 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002962 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0038454 infores:hetionet CHEBI:48844 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0232462 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020651 infores:hetionet NCBIGene:4952 biolink:causes MONDO:0010359 infores:monarchinitiative not_provided not_provided HGNC:8108 MONDO:0010359 uuid:6452ae71-5524-49b5-b627-22aa1201f0c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61390 biolink:causes UMLS:C0520863 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0520863 infores:hetionet NCBIGene:3921 biolink:causes MONDO:0010066 infores:monarchinitiative not_provided not_provided HGNC:6502 MONDO:0010066 uuid:f8726ca2-51cc-4461-bd8b-d1606f385636 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64318 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0028643 infores:hetionet CHEBI:8028 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0013595 infores:hetionet GO:2000004 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000004 GO:0007275 CHEBI:7565 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0392025 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0014591 infores:hetionet CHEBI:100241 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042963 infores:hetionet CHEBI:75722 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039239 infores:hetionet CHEBI:9939 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0002994 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0162429 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C1971624 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019158 infores:hetionet CHEBI:9123 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019521 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151883 infores:hetionet CHEBI:50749 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0011603 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0041912 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0014544 infores:hetionet CHEBI:3219 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002792 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0027765 infores:hetionet CAID:CA226414 biolink:causes MONDO:0100437 infores:clingen CAID:CA226414 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.356del (p.Leu119TrpfsTer14) is a frameshift variant located in exon 5 of 15, which results in a premature stop codon after 14 amino acids and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 17325176, PMID: 21857984, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226414/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:116278 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0008031 infores:hetionet NCBIGene:3815 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:6342 MONDO:0018874 uuid:09a30ae6-2844-4cee-bc58-b4ae825992ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2948 biolink:causes MONDO:0017255 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0030343 infores:hetionet CHEBI:47499 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0018794 infores:hetionet CHEBI:75998 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0004604 infores:hetionet CHEBI:8107 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020580 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0001339 infores:hetionet NCBITaxon:1392 biolink:causes MONDO:0005119 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1392 MESH:D000881 DB09320_MESH_D000881_1DB01059_MESH_D000881_1DB00759_MESH_D000881_1DB00618_MESH_D000881_1DB00537_MESH_D000881_1DB01017_MESH_D000881_1DB01053_MESH_D000881_1DB00254_MESH_D000881_1DB01165_MESH_D000881_1DB01137_MESH_D000881_1DB00595_MESH_D000881_1DB02703_MESH_D000881_2DB02703_MESH_D000881_1 CAID:CA333316 biolink:causes MONDO:0007113 infores:clingen CAID:CA333316 MONDO:0007113 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Moderate PM6, BS2, PP4, BA1, BP2, PS3, PS2, BS1, BS3, BP5, PM1, PM3 The p.Phe474fs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Phe474fs variant has been observed in 3 individuals with Angleman syndrome (PMID 25212744, internal database - Invitae) (PS4_moderate). This variant is absent from gnomAD v4 (PM2_supporting). In summary, the p.Phe474fs variant in UBE3A is classified as Pathogenic based on the ACMG/AMP criteria (PVS1, PS4_moderate, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333316/MONDO:0007113/037 2023-12-06 2023-12-11 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports CHEBI:9130 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0027769 infores:hetionet CHEBI:63610 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0026821 infores:hetionet CHEBI:6822 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0085605 infores:hetionet CHEBI:9598 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0012833 infores:hetionet CHEBI:7936 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002874 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0021843 infores:hetionet CHEBI:2618 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0042075 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0012833 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0021053 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0005940 infores:hetionet CHEBI:3752 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0040136 infores:hetionet CHEBI:71940 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0014742 infores:hetionet CHEBI:8888 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033893 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0003123 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0040479 infores:hetionet GO:0048214 biolink:causes GO:0048193 infores:ubergraph knowledge_assertion manual_agent GO:0048214 GO:0048193 CHEBI:50173 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0021053 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0234930 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151735 infores:hetionet CHEBI:9566 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0011991 infores:hetionet CHEBI:40279 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0242301 infores:hetionet CHEBI:5613 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C2973529 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0030552 infores:hetionet CHEBI:167638 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0232493 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0020517 infores:hetionet NCBITaxon:5500 biolink:causes MONDO:0005706 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5500 MESH:D003047 DB01026_MESH_D003047_1DB00681_MESH_D003047_1 CHEBI:3223 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085636 infores:hetionet NCBITaxon:783 biolink:causes MONDO:0019359 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:783 MONDO:0019359 CHEBI:37941 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0027497 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0024312 infores:hetionet GO:0090178 biolink:causes GO:0014020 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0014020 UNII:R43D2573WO biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085605 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0948594 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009763 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029927 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0006147 infores:hetionet CHEBI:7798 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0004604 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0038362 infores:hetionet CHEBI:9168 biolink:causes EFO:0011046 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0858970 infores:hetionet CHEBI:8207 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0423153 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009760 infores:hetionet NCBIGene:79023 biolink:causes MONDO:0032583 infores:monarchinitiative not_provided not_provided HGNC:29929 MONDO:0032583 uuid:ecc23019-2a61-4335-bb68-80a79a52def9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0011991 infores:hetionet UMLS:C0657912 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0041657 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002309 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0854165 infores:hetionet CHEBI:8597 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0011603 infores:hetionet CHEBI:7936 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151754 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0151908 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017160 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853946 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853946 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0038454 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020473 infores:hetionet CAID:CA8602704 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602704 MONDO:0100326 PMID: Uncertain Significance BP4 BS1, PM2, PP4, BA1 The c.2363C>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Aspartic Acid at amino acid 788 (p.Ala788Asp). The computational predictor REVEL gives a score of 0.179, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating with Glanzmann thrombasthenia were found in the literature. In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602704/MONDO:0100326/011 2023-11-02 2023-11-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:3696 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0015230 infores:hetionet CHEBI:5855 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0002878 infores:hetionet CHEBI:135342 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0002453 infores:hetionet CHEBI:2904 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0011124 infores:hetionet CHEBI:28445 biolink:causes HP:0002495 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C1295585 infores:hetionet NCBIGene:79902 biolink:causes MONDO:0032580 infores:monarchinitiative not_provided not_provided HGNC:8734 MONDO:0032580 uuid:6eb6d29d-65e1-4111-ac22-093fde5bdc92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51137 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0041657 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0041912 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036416 infores:hetionet CHEBI:84883 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0009376 infores:hetionet CHEBI:38940 biolink:causes HP:0005224 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0149770 infores:hetionet CHEBI:45409 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0036974 infores:hetionet CHEBI:167638 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0013604 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0242656 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0003123 infores:hetionet CAID:CA8337932 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337932 MONDO:0008723 PMID:25834949 Uncertain Significance PM2_Supporting, PM3, PP4_Moderate PP3, PS3 The c.1072A>G (p.Lys358Glu) variant in ACADVL is a missense in exon 10. This variant has been reported twice as compound heterozygote with pathogenic variants (p.V283A & p.His181Profs72) in patients with ACADVL deficiency (PMID: 25834949, 21932095, PM3). Both patients with this variant displayed reduced enzyme activity, which is highly specific for ACADVL deficiency (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.69, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limiting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP4_moderate, PM3. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337932/MONDO:0008723/021 2023-06-13 2023-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:167638 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0085612 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0521839 infores:hetionet CHEBI:9654 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0025637 infores:hetionet CHEBI:32184 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0085932 infores:hetionet CHEBI:145499 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151754 infores:hetionet CHEBI:7903 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027497 infores:hetionet UBERON:0005409 biolink:causes MONDO:0006231 infores:ubergraph knowledge_assertion manual_agent UBERON:0005409 MONDO:0006231 CHEBI:194135 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002994 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029882 infores:hetionet CHEBI:48390 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0002871 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011551 infores:hetionet CAID:CA9487892 biolink:causes MONDO:0011229 infores:clingen CAID:CA9487892 MONDO:0011229 PMID: Uncertain Significance PM5, BS2, PP3, BP4, BA1, PS1, PS3, PM2, BS1, BS3 This variant was classified as a variant of uncertain significance as there has not been sufficient evidence to support either a benign or a pathogenic classification. Specifically, this variant has not been reported in the literature in affected or unaffected patients, has no published functional data, and although present in population databases with an allele frequency of 0.009%, it does not meet any of the cutoffs supporting a pathogenic or benign classification. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA9487892/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true GO:0141074 biolink:causes GO:0140896 infores:ubergraph knowledge_assertion manual_agent GO:0141074 GO:0140896 CHEBI:5855 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042075 infores:hetionet CHEBI:61049 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0553692 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0233494 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0549259 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0549259 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0521839 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0015695 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0518015 infores:hetionet CHEBI:261649 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0677500 infores:hetionet CHEBI:8890 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042029 infores:hetionet CHEBI:15544 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2937350 infores:hetionet CHEBI:3698 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0236075 infores:hetionet CHEBI:47499 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0028084 infores:hetionet CHEBI:2469 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0009782 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0155626 infores:hetionet UMLS:C0010592 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0270996 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0392034 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0392034 infores:hetionet CHEBI:63580 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235490 infores:hetionet CHEBI:8802 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0085612 infores:hetionet CHEBI:10124 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013456 infores:hetionet GO:0051610 biolink:causes MONDO:0002009 infores:drugmechdb knowledge_assertion manual_agent GO:0051610 MESH:D003865 DB00476_MESH_D003865_1 CHEBI:5132 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0041834 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948525 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235431 infores:hetionet CHEBI:15367 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035243 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0024894 infores:hetionet CAID:CA000055 biolink:causes MONDO:0018875 infores:clingen CAID:CA000055 MONDO:0018875 PMID:12826609PMID:30224644PMID:29979965 Likely Benign BP4, BS3, PM2_Supporting BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, BS2, PP3, PP1, PP4 The NM_000546.6:c.144C>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 48 (p.Asp48Glu). This variant has an allele frequency of 0.000001695 (2/1180034 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.224; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -5; VCEP specifications version 2.0; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000055/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:77260 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0423791 infores:hetionet CHEBI:83527 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0017178 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0039503 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0518015 infores:hetionet CHEBI:50131 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0042963 infores:hetionet CHEBI:83527 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0040822 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0015397 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1306341 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0021053 infores:hetionet CHEBI:3504 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0014742 infores:hetionet NCBIGene:57534 biolink:causes MONDO:0014042 infores:monarchinitiative not_provided not_provided HGNC:21086 MONDO:0014042 uuid:dc7844d4-fb3a-44b3-80bc-875e9f0a1d76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes MONDO:0019454 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0002894 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0030353 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006826 infores:hetionet CHEBI:168396 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0002063 infores:hetionet CAID:CA401364275 biolink:causes MONDO:0009290 infores:clingen CAID:CA401364275 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Supporting The NM_000152.5:c.953T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 318 (p.Met318Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was found in compound heterozygosity (phase unknown) with a unique pathogenic variant in GAA in one patient with Pompe disease (PMID: 21484825). Additional cases (PMID: 18425781) have been reported but were not included because a second variant and/or zygosity was not specified (PP4_Moderate, PM3_Supporting). Expression of the variant in COS cells resulted in 3.2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.926 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 558700; 1 star review status) with 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401364275/MONDO:0009290/010 2021-10-26 2021-10-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7936 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0162429 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0005779 infores:hetionet CHEBI:15940 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0039070 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0041912 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0014742 infores:hetionet CHEBI:74947 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0033774 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0013922 infores:hetionet CHEBI:5001 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0022408 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018799 infores:hetionet CHEBI:10101 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0023530 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0581912 infores:hetionet NCBIGene:4254 biolink:causes MONDO:0030983 infores:monarchinitiative not_provided not_provided HGNC:6343 MONDO:0030983 uuid:6fcd87c8-dc7c-44ed-a8fa-2b8b1dad80cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0027651 infores:hetionet CAID:CA294719 biolink:causes MONDO:0010726 infores:clingen CAID:CA294719 MONDO:0010726 PMID: Benign BS2, BA1 The allele frequency of the p.Ala234Gly variant in MECP2 (NM_004992.3) is 0.26% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala234Gly variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Ala234Gly variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294719/MONDO:0010726/016 2022-12-08 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:4975 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0017574 infores:hetionet CHEBI:31981 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0002994 infores:hetionet NCBIGene:10846 biolink:causes MONDO:0014835 infores:monarchinitiative not_provided not_provided HGNC:8772 MONDO:0014835 uuid:a99003aa-ee04-468d-b4b1-a4d0e097e82e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5775 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0009806 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0239816 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0239816 infores:hetionet CHEBI:30830 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0740394 infores:hetionet CHEBI:5147 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0011603 infores:hetionet CHEBI:8364 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0242350 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027051 infores:hetionet CHEBI:27834 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0031256 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085606 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042401 infores:hetionet CHEBI:76607 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0021400 infores:hetionet CHEBI:8707 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0015967 infores:hetionet CHEBI:9398 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0013404 infores:hetionet CHEBI:2618 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0002622 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0852913 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0400823 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0235874 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0014868 infores:hetionet CHEBI:7809 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0036974 infores:hetionet CHEBI:31638 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0020458 infores:hetionet CHEBI:4953 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0027497 infores:hetionet CHEBI:4495 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0019572 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0007859 infores:hetionet CHEBI:8212 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0686347 infores:hetionet NCBIGene:11141 biolink:causes MONDO:0010256 infores:monarchinitiative not_provided not_provided HGNC:5996 MONDO:0010256 uuid:86443cc7-8a0e-4b15-afb5-caf35a958d03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0151686 infores:hetionet CHEBI:3698 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0917801 infores:hetionet CHEBI:9137 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0232462 infores:hetionet CHEBI:182080 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0235295 infores:hetionet CHEBI:3176 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0003811 infores:hetionet CHEBI:7936 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1527344 infores:hetionet CHEBI:63605 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0030554 infores:hetionet CHEBI:27834 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C3160947 infores:hetionet CAID:CA390865041 biolink:causes MONDO:0100216 infores:clingen CAID:CA390865041 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting PVS1, PM6, BP1, BP2, BP3, BA1, PP2, PP3, PP1, PP4, BS2, PM5, PM3, PM4, PS3, PS1, PS2, PS4, BP5, BP7, BS1, BS3, BS4 The NM_177438.2:c.5282T>C variant in DICER1 is a missense variant predicted to cause substitution of valine by alanine at amino acid 1761 (p.Val1761Ala). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.365; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting. (Bayesian Points: 1; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390865041/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:84500 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0086168 infores:hetionet CHEBI:9599 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0024141 infores:hetionet CHEBI:2950 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0038367 infores:hetionet CAID:CA10584803 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584803 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR): c.241C>A (p.Arg81Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (v2.1.1).PP4 - Variant meet PM2. PMID: 21382890 (Graaf et al., 2011) - 1 case with LDL-C level >95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, ie, at least 1 biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease. Alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584803/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63632 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0032285 infores:hetionet CHEBI:68642 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0042023 infores:hetionet NCBIGene:7138 biolink:causes MONDO:0011539 infores:monarchinitiative not_provided not_provided HGNC:11948 MONDO:0011539 uuid:b8562408-0f60-4904-b9a3-063bdcdc2610 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8245 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0037763 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020039 infores:hetionet CHEBI:45599 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0000731 infores:hetionet GO:2000074 biolink:causes GO:0031016 infores:ubergraph knowledge_assertion manual_agent GO:2000074 GO:0031016 CAID:CA402996483 biolink:causes MONDO:0012999 infores:clingen CAID:CA402996483 MONDO:0012999 PMID: Likely Pathogenic PP4_Moderate, PP3_Strong, PM2_Supporting, PM3_Supporting The NM_000156.6:c.268G>A variant in GAMT is a missense variant that is predicted to result in the substitution of glutamate by lysine at amino acid 90 (p.Glu90Lys). One individual, who is homozygous for this variant, has developmental delay and seizures, in addition to elevated guanidinoacetate in urine and plasma, and low creatine in urine and plasma (PMID: 24440240) (PP4_Moderate, PM3_Supporting). The computational predictor REVEL gives a score of 0.943 which is >0.932, evidence that correlates with impact to GAMT function at the strong level (PMID: 36413997) (PP3_Strong). To our knowledge, the results of functional studies are not available. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003384 (3/88658 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The variant is noted in ClinVar (Variation ID: 916122). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PP3_Strong, PP4_Moderate, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402996483/MONDO:0012999/026 2025-05-20 2025-05-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6970 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0004604 infores:hetionet CHEBI:41423 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151603 infores:hetionet NCBIGene:7345 biolink:causes MONDO:0859363 infores:monarchinitiative not_provided not_provided HGNC:12513 MONDO:0859363 uuid:9cc2c68b-fe22-4f24-b1df-beba477cc238 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4975 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0002871 infores:hetionet CHEBI:8805 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0020615 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0235416 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0344232 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009806 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037199 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0037199 infores:hetionet CHEBI:7514 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0234518 infores:hetionet CHEBI:50922 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0025345 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0029134 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0242350 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011616 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0558919 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0558919 infores:hetionet CHEBI:47898 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2047937 infores:hetionet CHEBI:63608 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018681 infores:hetionet CHEBI:5001 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0231218 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0005940 infores:hetionet CHEBI:63607 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151905 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0017178 infores:hetionet CHEBI:5118 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0005758 infores:hetionet CHEBI:520985 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0026826 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0855625 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0855625 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0022650 infores:hetionet CHEBI:100241 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0851578 infores:hetionet UNII:R15UI3245N biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0012833 infores:hetionet CHEBI:4551 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0004245 infores:hetionet CHEBI:47780 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0025218 infores:hetionet CHEBI:6909 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2981158 infores:hetionet CAID:CA16042455 biolink:causes MONDO:0021060 infores:clingen CAID:CA16042455 MONDO:0021060 PMID:22465605PMID:22465605PMID:22465605 Likely Pathogenic PM1_Strong, PM2, PP3, PP2, PS4_Supporting PS2, PS1, PS3, BP7, BP5, BS3, BS4, BS1, PM5, PM4, PM6, PP1, BS2, BP3, BP2, BP4, BP1, BA1 The c.1654A>T (p.Arg552Trp) variant has been identified in 1 patient with clinical features of a RASopathy (PS4_Supporting; PMID: 22465605). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Of note this p.Arg552 residue is defined as a hotspot by the RAS VCEP. This variant would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore the PM1 rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Trp variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1_Strong, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042455/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10127 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011609 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0855242 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0016977 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0006737 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0013418 infores:hetionet CHEBI:10125 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0026821 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0549209 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0020538 infores:hetionet CHEBI:36791 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009917 infores:hetionet NCBIGene:4261 biolink:causes MONDO:0971005 infores:monarchinitiative not_provided not_provided HGNC:7067 MONDO:0971005 uuid:12f586a0-4bb8-43dc-ba7a-8a5abc0d6562 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0239571 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0006145 infores:hetionet CHEBI:8890 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0855775 infores:hetionet CAID:CA367399230 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399230 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PS2_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1, PP1 The c.1055T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 352 (p.(Leu352Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 genomes (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.99, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 29056535, Sertedaki et al. 2004 Horm Res 62(suppl 2),147, P3-532; internal lab contributors). Additionally, two of these individuals had a a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors), and in one of the individuals the variant was identified as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1055T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_Supporting, PP4_Moderate, PS2_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399230/MONDO:0015967/086 2025-07-18 2025-07-25 Semidominant inheritance HP:0032113 Supports CHEBI:24564 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0042963 infores:hetionet CHEBI:31638 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C3263723 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018802 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0233472 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0854431 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0854431 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0233472 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0027339 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0152029 infores:hetionet CHEBI:8346 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0018681 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0031039 infores:hetionet CHEBI:82960 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085649 infores:hetionet CHEBI:52172 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0016199 infores:hetionet CHEBI:50742 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0009421 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0031117 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0041834 infores:hetionet CHEBI:3752 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0232487 infores:hetionet CHEBI:75246 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0033687 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0036572 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0277925 infores:hetionet CHEBI:27732 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0022107 infores:hetionet CHEBI:135738 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0746961 infores:hetionet CHEBI:63607 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0233407 infores:hetionet CHEBI:28177 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0004238 infores:hetionet CHEBI:68478 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0549463 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0024205 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0948294 infores:hetionet CHEBI:63681 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C2129214 infores:hetionet CHEBI:92511 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0022107 infores:hetionet CHEBI:617099 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0040034 infores:hetionet GO:0099148 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:0099148 GO:0099504 CHEBI:63631 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0851341 infores:hetionet CAID:CA7331435 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331435 MONDO:0100216 PMID: Uncertain Significance BP4, PS4_Supporting PM2, BP2, BA1, BS2, PP3, PP1, PP4, PM1, PM5, PS2, PS3, PS1, BS1, BS4, BS3 The NM_177438.3:c.1745T>C variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 582 (p.Ile582Thr). This variant received a total of 1 phenotype point(s) across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID 26925222). The total allele frequency in gnomAD v4.1.0 is 0.000001861 (3/1611810 alleles) with a highest population minor allele frequency of 0.00003201 (2/62476 alleles) in a population of unknown ancestry (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.493; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 10/22/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331435/MONDO:0100216/024 2024-10-22 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17698 biolink:causes MONDO:0100244 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0024790 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0021053 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0037274 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0267792 infores:hetionet CHEBI:63589 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0009806 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151505 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0000833 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0677500 infores:hetionet CHEBI:51364 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0026826 infores:hetionet CHEBI:7494 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151908 infores:hetionet CHEBI:27974 biolink:causes HP:0033840 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0032776 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0013378 infores:hetionet NCBIGene:2050 biolink:causes MONDO:0015009 infores:monarchinitiative not_provided not_provided HGNC:3395 MONDO:0015009 uuid:4ff352be-a289-49b2-94f0-8973b47ecca7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0233471 infores:hetionet CHEBI:101278 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0242698 infores:hetionet CHEBI:2788 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0031350 infores:hetionet CHEBI:8874 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0242301 infores:hetionet CHEBI:15765 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C1443060 infores:hetionet CHEBI:41423 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0149871 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0033687 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0018799 infores:hetionet CHEBI:8874 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005747 infores:hetionet CHEBI:6030 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0017178 infores:hetionet CHEBI:10127 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0035455 infores:hetionet CHEBI:101853 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151937 infores:hetionet CHEBI:37941 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0206062 infores:hetionet CHEBI:6912 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0009676 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0424000 infores:hetionet CHEBI:18357 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0151826 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0919894 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0919894 infores:hetionet CAID:CA296133 biolink:causes MONDO:0021060 infores:clingen CAID:CA296133 MONDO:0021060 PMID: Uncertain Significance PM2, PP3, PP2, PS4_Supporting PS2, PS1, PS3, BP7, BP5, BS4, BS3, BS1, PM5, PM4, PM1, PM6, BS2, PP1, BP3, BP2, BP4, BP1, BA1 The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296133/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA010192 biolink:causes MONDO:0005021 infores:clingen CAID:CA010192 MONDO:0005021 PMID: Likely Pathogenic PM2, PM6, PP1, PS4 PM1, PM5, PM4, BA1, PP3, PS3, BP3, BS1, BS4, BS3, PS2, PS1, BP4, BP5, BP7, PVS1 The NM_000257.4(MYH7):c.1106G>A (p.Arg369Gln) variant has been identified in >20 individuals with DCM, including 1 individual who also had LVNC (PS4; Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID:24503780; Klauke 2017 PMID: 29253866; Walsh 2017 PMID: 27532257; Horvat 2019 PMID: 29892087; Quiat 2020 PMID: 32458740; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; Mayo clinic pers. comm.; OMGL pers comm.) and at least 2 individuals with assumed de novo occurrences (PM6; Lakdawala 2012 PMID: 22464770; Quiat 2020 PMID: 32458740; Klauke 2017 PMID: 29253866; LMM pers. comm.). This variant was also identified in >10 individuals with isolated LVNC, including 1 with an assumed de novo occurrence (Dellefave 2009 PMID: 20031619; Hoedemaekers 2010 PMID: 20530761; Tian 2015 PMID: 24691700; Li 2018 PMID: 30371277; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm). This variant segregated with DCM in at least 3 affected individuals from 3 families (PP1; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.), and with LVNC in at least 5 individuals from 4 families (Centenary Institute Sydney pers. comm.; LMM pers. comm.; OMGL pers. comm.) . This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1, PM6, PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010192/MONDO:0005021/002 2021-12-22 2021-12-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63621 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004364 infores:hetionet CHEBI:4974 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0043352 infores:hetionet CHEBI:41774 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0028949 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0012833 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0234215 infores:hetionet CHEBI:51041 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151904 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1527358 infores:hetionet CHEBI:84050 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0151905 infores:hetionet CHEBI:17823 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0006663 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023067 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0518015 infores:hetionet CAID:CA8815357 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815357 MONDO:0009290 PMID: Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.1496G>A (p.Trp499Ter) is a nonsense variant which is predicted to cause nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross reactive immunological material in cultured skin fibroblasts from a patient with this variant (PMIDs 19775921, 22252923, and 25741864). Therefore, PVS1 can be applied. This patient, who has infantile onset Pompe disease, meets the ClinGen LSD VCEP’s specifications for PP4, and is homozygous for the variant, meeting PM3_Supporting. Additional patients have been reported, including 2 homozygous Tunisian patients (PMID 32125626), but the residual GAA activity was not provided, and this data was not included. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which meets PM2. There is a ClinVar entry for this variant (Variation ID 556959, 1 star review status), with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815357/MONDO:0009290/010 2020-10-05 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3082 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011168 infores:hetionet CHEBI:408174 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0085649 infores:hetionet CHEBI:27834 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0151908 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0007642 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0087169 infores:hetionet UNII:D27V6190PM biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0162285 infores:hetionet NCBIGene:3098 biolink:causes MONDO:0011534 infores:monarchinitiative not_provided not_provided HGNC:4922 MONDO:0011534 uuid:f8932e61-99f3-4c5e-8ba6-8c84fd756e8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0035455 infores:hetionet CHEBI:2922 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0015230 infores:hetionet CHEBI:16714 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C1610069 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0234215 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151883 infores:hetionet CHEBI:4868 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0042963 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0013395 infores:hetionet CHEBI:480999 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0013404 infores:hetionet CHEBI:184555 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0233472 infores:hetionet NCBIGene:90332 biolink:causes MONDO:0975799 infores:monarchinitiative not_provided not_provided HGNC:30162 MONDO:0975799 uuid:88670aa2-0360-4d75-9086-f69828bfc5f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0009938 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0031039 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0521839 infores:hetionet CAID:CA397726273 biolink:causes MONDO:0008723 infores:clingen CAID:CA397726273 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PM4 PP3, PP4, PM5 The c.1966T>A variant in ACADVL is a stop-loss predicted to result in a 32-aa peptide extension at the C-terminus (PM4). This variant has been identified in one individual as a heterozygote identified by abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 30194637). This study also showed reduced VLCAD activity in patient lymphocytes, however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).In summary, this variant meets the criteria to be classified as uncertain for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: (PM4, PM2_Supporting) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397726273/MONDO:0008723/021 2022-09-23 2022-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:567361 biolink:causes MONDO:0019065 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0002726 infores:hetionet CHEBI:3757 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0042023 infores:hetionet CHEBI:40050 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0011991 infores:hetionet CHEBI:6078 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0018681 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004238 infores:hetionet CHEBI:4858 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0040136 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0014868 infores:hetionet CHEBI:3696 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0595916 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0010709 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235851 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235851 infores:hetionet GO:1905044 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:1905044 GO:0030182 CHEBI:64312 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0236075 infores:hetionet CHEBI:72292 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0011603 infores:hetionet CHEBI:51860 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0006277 infores:hetionet CHEBI:7936 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013604 infores:hetionet CHEBI:4710 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020461 infores:hetionet CHEBI:51230 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0024440 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0037199 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038454 infores:hetionet CHEBI:6931 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0036974 infores:hetionet CAID:CA410147722 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147722 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1232C>T (p.Ala411Val) is a missense variant which has a REVEL score < 0.50 (0.296) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147722/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:667 biolink:causes MONDO:0014180 infores:monarchinitiative not_provided not_provided HGNC:1090 MONDO:0014180 uuid:1ee9ddfb-073c-49bd-9320-5c322a184b9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7507 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0858617 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017574 infores:hetionet CHEBI:63611 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011603 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001687 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011876 infores:hetionet CHEBI:107736 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C3665347 infores:hetionet CHEBI:31236 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234022 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235074 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235074 infores:hetionet CAID:CA10014281 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014281 MONDO:0100083 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.847C>A (p.Gln283Lys) is a missense variant which has a REVEL score < 0.50 (0.439) and SpliceAI Δ score < 0.2 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014281/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:474180 biolink:causes UMLS:C0858667 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0858667 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0006826 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0018799 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020615 infores:hetionet CHEBI:63631 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011206 infores:hetionet CHEBI:49375 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C2979982 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0553704 infores:hetionet CHEBI:42944 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011991 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0858797 infores:hetionet CHEBI:63637 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0015672 infores:hetionet CAID:CA387460849 biolink:causes MONDO:0019497 infores:clingen CAID:CA387460849 MONDO:0019497 PMID: Likely Pathogenic PP3, PM3, PM5, PM2_Supporting, PS3_Moderate The c.584T>C is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 195 (p.Met195Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0022% (4/60018, CI 95%) in the Admixed American population (PM2_Supporting). The c.584T>C variant has been detected in trans with c.35delG in one individual with moderate-severe hearing loss (PMID: 19235794). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Another missense variant c.583G>C (p.Met195Val; ClinVar Variation ID: 22537) in the same codon has been classified as pathogenic for hearing loss by the ClinGen Hearing Loss VCEP (PM5). Analysis in Hela cells demonstrated that the CX26-p.Met195Thr protein formed a gap junction but with significantly decreased dye transfer. Additionally, electrophysiological characterization of the mutant in Xenopus oocytes resulted in a completely non-functional channel (PS3_Moderate; PMID: 23967136). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PP3, PM3, PM5, PS3_Moderate; Version 2; 5/15/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387460849/MONDO:0019497/005 2024-05-15 2024-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63580 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003467 infores:hetionet CHEBI:52172 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C3665347 infores:hetionet CHEBI:31643 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0017574 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0677500 infores:hetionet GO:0060787 biolink:causes GO:0001839 infores:ubergraph knowledge_assertion manual_agent GO:0060787 GO:0001839 CHEBI:8707 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0033117 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0006277 infores:hetionet CHEBI:5001 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151576 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020517 infores:hetionet CAID:CA277611 biolink:causes MONDO:0015152 infores:clingen CAID:CA277611 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PS1, PS3, PP3, PM2_Supporting PM3, PM4, PM5, PM1, PS4, PS2, BP1, BP4, BP2, BP3, BA1, BP7, BP5, BS4, BS1, BS3, PVS1, PM6, PP1, PP2, BS2 The NM_003494.4: c.1852G>C variant in DYSF, which is also known as NM_001130987.2: c.1906G>C p.(Gly636Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 618 (p.Gly618Arg). This variant has been detected in one individual with a clinical diagnosis or suspicion of LGMD and absent dysferlin protein expression (PP4_Strong), in whom it was identified in unknown phase with a variant classified as at least likely pathogenic (c.5836_5839del p.(Gln1946Trpfs*19), 0.25 pts, PMID: 30564623, Jain Foundation Dysferlin Registry internal data communication) (PM3_Supporting not met). This variant is absent from gnomAD v2.1.1 and 3.1.2 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.928, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). The same amino acid change, p.(Gly618Arg), resulting from a different nucleotide change, c.1852G>A (NM_003494.4), is classified as pathogenic for autosomal recessive LGMD by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PP4_Strong, PS1, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA277611/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4315 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0206062 infores:hetionet NCBIGene:65055 biolink:causes MONDO:0859279 infores:monarchinitiative not_provided not_provided HGNC:25786 MONDO:0859279 uuid:4ac1a374-9daa-4fb8-8d35-fe4ed097c980 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4445 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0020440 infores:hetionet CAID:CA251903 biolink:causes MONDO:0008723 infores:clingen CAID:CA251903 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate, PS3_Supporting PM1 The c.1837C>T variant in ACADVL is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 613 (p.Arg613Trp). This variant has been reported in ACADVL deficiency in numerous studies, including PMIDs:7479827, 8554073, 35281659, 17374501, 30194637. This variant is associated with increased C14:1 acylcarnitine levels in patients with ACADVL deficiency (PMID: 33986768, PP4_moderate). This variant was also detected in compound heterozygote with pathogenic variants from multiple patients (PM3, PMID: 7479827, 8554073, 30194637). This variant causes significantly reduced enzyme activity determined from lymphocytes, mammalian, and bacterial cell expression systems (PMID: 30194637, 8554073, 17374501, 33986768) and results in unstable protein product (PMID:8554073, PS3_supporting). This variant is also part of a C-terminal domain critical for mitochondiral membrane binding (PMID: 18227065). The highest population minor allele frequency in gnomAD is 0.0001 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary the ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PS3_supporting+PM3+PP3+PP4_moderate+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA251903/MONDO:0008723/021 2023-06-13 2023-06-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6129 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0178298 infores:hetionet CHEBI:3175 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0855775 infores:hetionet CHEBI:9649 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020473 infores:hetionet CHEBI:4469 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0233477 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0014724 infores:hetionet CHEBI:63791 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1510431 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0233632 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0018801 infores:hetionet CHEBI:36795 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0004604 infores:hetionet CHEBI:92712 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0038450 infores:hetionet CHEBI:100246 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0149745 infores:hetionet CHEBI:28148 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0000731 infores:hetionet CAID:CA390864581 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864581 MONDO:0100216 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PVS1, PM6, BP3, BP2, BP1, BP4, BA1, PP2, PP3, PP1, PP4, BS2, PM4, PM3, PM5, PS2, PS1, PS4, PS3, BP5, BP7, BS1, BS4 The NM_177438.2:c.5470G>C variant in DICER1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1824 (p.Gly1824Arg). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614126 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, PM2_Supporting. (Bayesian Points: 2; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864581/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:30830 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C3263723 infores:hetionet GO:0048082 biolink:causes GO:0007593 infores:ubergraph knowledge_assertion manual_agent GO:0048082 GO:0007593 CHEBI:63637 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0870082 infores:hetionet CHEBI:31348 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221150 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0035455 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0541919 infores:hetionet CHEBI:35778 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0000737 infores:hetionet CHEBI:32192 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0041969 infores:hetionet CHEBI:31401 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0030554 infores:hetionet CHEBI:31980 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0040264 infores:hetionet UNII:0RK7M7IABE biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0151735 infores:hetionet CHEBI:63612 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0018989 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033775 infores:hetionet CHEBI:63620 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C3263723 infores:hetionet CHEBI:10650 biolink:causes HP:0100678 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037301 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020649 infores:hetionet CHEBI:94449 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0018681 infores:hetionet CAID:CA421938611 biolink:causes MONDO:0005338 infores:clingen CAID:CA421938611 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.960G>A variant in MYOC is a synonymous variant (p.Arg320=). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (ANZRAG [E Souzeau pers. comm.]), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421938611/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64312 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030312 infores:hetionet CHEBI:4953 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0038990 infores:hetionet CHEBI:8871 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C2979982 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0036572 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004238 infores:hetionet CHEBI:3437 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0085636 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0009450 infores:hetionet CHEBI:7577 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0231218 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0006840 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037822 infores:hetionet CHEBI:131512 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0015967 infores:hetionet NCBITaxon:6182 biolink:causes MONDO:0044344 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6182 MONDO:0044344 CHEBI:17347 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0011603 infores:hetionet CHEBI:2663 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151746 infores:hetionet CAID:CA229288 biolink:causes MONDO:0009861 infores:clingen CAID:CA229288 MONDO:0009861 PMID:26503515 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1031G>A (p.Gly344Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 26503515). This variant is absent in population databases. This variant was detected in with multiple pathogenic variants: p.Arg241Cys (PMID: 18985011); p.R252Q (PMID: 26322415); EX6-96A＞G (PMID: 29316886); p.Q232* (PMID: 30050108). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229288/MONDO:0009861/006 2021-06-11 2021-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:188986 biolink:causes UMLS:C1096278 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1096278 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0012833 infores:hetionet CHEBI:64354 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0003862 infores:hetionet GO:0044828 biolink:causes GO:0019058 infores:ubergraph knowledge_assertion manual_agent GO:0044828 GO:0019058 CHEBI:3082 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0231528 infores:hetionet CHEBI:2549 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0232461 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0011991 infores:hetionet CHEBI:4868 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0037763 infores:hetionet CHEBI:125354 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0036974 infores:hetionet CHEBI:2948 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0026896 infores:hetionet CHEBI:40279 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085681 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009782 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2363730 infores:hetionet CHEBI:100241 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0019521 infores:hetionet CHEBI:41879 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0014236 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035328 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235431 infores:hetionet CHEBI:4470 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0018524 infores:hetionet CHEBI:3638 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0014457 infores:hetionet CHEBI:4470 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C1443060 infores:hetionet CHEBI:31348 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0235266 infores:hetionet CHEBI:49713 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0855329 infores:hetionet CHEBI:50173 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0043352 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0086132 infores:hetionet CHEBI:63617 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042029 infores:hetionet CHEBI:3223 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0151827 infores:hetionet CHEBI:4469 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0162830 infores:hetionet CHEBI:7575 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0013404 infores:hetionet NCBIGene:57465 biolink:causes MONDO:0011970 infores:monarchinitiative not_provided not_provided HGNC:29203 MONDO:0011970 uuid:eacb7677-90ff-401a-af1e-a2d302520ff3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0033774 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151735 infores:hetionet CAID:CA10584692 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584692 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 PS4, PS3, BS3 The NM_000527.4(LDLR):c.-215A>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for FH from PMID 22881376 (Usifo et al., 2012) after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584692/MONDO:0007750/013 2025-01-31 2025-02-03 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:85446 biolink:causes MONDO:0958106 infores:monarchinitiative not_provided not_provided HGNC:20152 MONDO:0958106 uuid:cecd959e-7cae-4128-8c6e-6bb1a5babb50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151772 infores:hetionet NCBIGene:5071 biolink:causes MONDO:0010820 infores:monarchinitiative not_provided not_provided HGNC:8607 MONDO:0010820 uuid:b4a3e3ac-b594-4abb-b219-d6b52cb395b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0019080 infores:hetionet CHEBI:8107 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0032290 infores:hetionet CHEBI:6402 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0021368 infores:hetionet CHEBI:9943 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0041657 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0031542 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0006826 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235351 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0851578 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0161679 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0392620 infores:hetionet CHEBI:9123 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015371 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017178 infores:hetionet NCBIGene:93953 biolink:causes MONDO:0024773 infores:monarchinitiative not_provided not_provided HGNC:15805 MONDO:0024773 uuid:58d7227f-2066-4daf-a06c-47c57d3a0e03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013378 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0033975 infores:hetionet CHEBI:63632 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0021843 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018099 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0022660 infores:hetionet CHEBI:144551 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0231218 infores:hetionet CHEBI:9588 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0019080 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0009450 infores:hetionet CHEBI:3534 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C1384353 infores:hetionet CHEBI:28939 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0002994 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0917798 infores:hetionet CHEBI:16469 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0085649 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1287298 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0029878 infores:hetionet CHEBI:9435 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0004134 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0006145 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0042109 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0003862 infores:hetionet CHEBI:49960 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0017181 infores:hetionet CHEBI:8764 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011168 infores:hetionet CHEBI:63599 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0024314 infores:hetionet CHEBI:168396 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020473 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0004936 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0009450 infores:hetionet CHEBI:3478 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0853986 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0012797 infores:hetionet CHEBI:3723 biolink:causes HP:0004411 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549397 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0008325 infores:hetionet CHEBI:116278 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1609512 infores:hetionet CHEBI:3061 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0700361 infores:hetionet CHEBI:27882 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0854467 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0020517 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0024894 infores:hetionet CHEBI:28971 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0027497 infores:hetionet CHEBI:135351 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0021122 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0025061 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042267 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0028738 infores:hetionet CAID:CA410208126 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208126 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.524T>A (p.Leu175Gln) is a missense variant which has a REVEL score ≥ 0.88 (0.952) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208126/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:85083 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0027441 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0241705 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004169 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0376356 infores:hetionet CHEBI:3723 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015672 infores:hetionet NCBIGene:6234 biolink:causes MONDO:0011639 infores:monarchinitiative not_provided not_provided HGNC:10418 MONDO:0011639 uuid:678afe62-4777-463c-8c0f-0ccd24834750 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64028 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0042963 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0038454 infores:hetionet CHEBI:3756 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0855775 infores:hetionet NCBIGene:5573 biolink:causes MONDO:0007044 infores:monarchinitiative not_provided not_provided HGNC:9388 MONDO:0007044 uuid:9347d350-59bf-45e0-be8b-9449a9847676 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0032584 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009319 infores:hetionet CAID:CA397849034 biolink:causes MONDO:0018875 infores:clingen CAID:CA397849034 MONDO:0018875 PMID: Uncertain Significance PP3, PM2_Supporting BP4, BP2, BA1, PS3, PS1, PS4, PS2, PM1, PM5, BS1, BS3, BS4, PM6, BS2, PP1 The NM_000546.6:c.46C>A variant in TP53 is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 16 (p.Gln16Lys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMID:34196900) This variant is absent from gnomAD v4.1.0 (PM2_Supporting). BS3 met but not applied due to caveat that functional codes not be applied to any missense variant that has splicing effect on SpliceAI where PP3 is applied. The computational splicing predictor SpliceAI gives a score of 0.84, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3). In summary, this variant meets the criteria to be classified as variant of uncertain significance for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, PP3. (Bayesian Points: 2; VCEP specifications version 2.2; 2/6/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397849034/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8764 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022346 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005551 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0852875 infores:hetionet CHEBI:404903 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0028961 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020651 infores:hetionet CHEBI:8378 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0151937 infores:hetionet CHEBI:2618 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0004093 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018099 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0521839 infores:hetionet CHEBI:63624 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0037763 infores:hetionet CHEBI:3398 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0080274 infores:hetionet CHEBI:16469 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019572 infores:hetionet CHEBI:42068 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0003811 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0085618 infores:hetionet CHEBI:68584 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0027066 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0344320 infores:hetionet CHEBI:7822 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013404 infores:hetionet CHEBI:144551 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0232849 infores:hetionet CHEBI:23765 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151579 infores:hetionet NCBITaxon:43075 biolink:causes MONDO:0030906 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:43075 MONDO:0030906 CHEBI:3082 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0022904 infores:hetionet CHEBI:52172 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0043094 infores:hetionet CHEBI:5062 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0549622 infores:hetionet CHEBI:6904 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0042963 infores:hetionet CHEBI:63617 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0037299 infores:hetionet CAID:CA003216 biolink:causes MONDO:0700268 infores:clingen CAID:CA003216 MONDO:0700268 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3 BP1, BP4, PS1 The c.5075A>T variant in BRCA1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1692 (p.Asp1692Val). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant has a SpliceAI score of 0.32, predicting an impact on splicing (score threshold ≥0.2) (PP3 met). Missense variant predicted to alter splicing, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 15.2 (based on Family History LR=15.2), within the thresholds for moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID, 3185305). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP4_Moderate). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003216/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5790 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0152032 infores:hetionet NCBIGene:54538 biolink:causes MONDO:0032783 infores:monarchinitiative not_provided not_provided HGNC:17985 MONDO:0032783 uuid:9498b9f4-41be-43be-abcc-a1ab927fe291 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3223 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085593 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0574067 infores:hetionet CHEBI:6690 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0015230 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0029928 infores:hetionet CL:0000623 biolink:causes GO:0002228 infores:ubergraph knowledge_assertion manual_agent CL:0000623 GO:0002228 CHEBI:107736 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0011603 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030319 infores:hetionet CHEBI:51364 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027497 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0149931 infores:hetionet CAID:CA16615316 biolink:causes MONDO:0700272 infores:clingen CAID:CA16615316 MONDO:0700272 PMID: Uncertain Significance PM2_Supporting, BP1 BS1, PP3, BA1 The c.82T>A variant in PALB2 is a missense variant predicted to cause substitution of tyrosine by asparagine at amino acid 28 (p.Tyr28Asn). This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (PM2_Supporting, BP1). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615316/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:3052 biolink:causes MONDO:0024552 infores:monarchinitiative not_provided not_provided HGNC:4837 MONDO:0024552 uuid:b2e934ab-e43e-42bc-9094-0d80e1ca076b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50749 biolink:causes HP:6000933 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0263367 infores:hetionet CHEBI:2950 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0017675 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0851341 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0041969 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003123 infores:hetionet CHEBI:36791 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036396 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0006277 infores:hetionet CHEBI:7514 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0043144 infores:hetionet CHEBI:7865 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0003467 infores:hetionet CHEBI:134966 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0004134 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0836924 infores:hetionet CAID:CA229320 biolink:causes MONDO:0009861 infores:clingen CAID:CA229320 MONDO:0009861 PMID: Benign BA1, BP7 The c.1065+97G>A variant in PAH has a MAF of 0.2430 in the gnomAD non-Finnish European population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229320/MONDO:0009861/006 2020-08-07 2020-08-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4784 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027121 infores:hetionet CHEBI:46295 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0013404 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0040046 infores:hetionet CHEBI:43968 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0016204 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0037023 infores:hetionet CHEBI:6073 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0042963 infores:hetionet NCBIGene:8456 biolink:causes MONDO:0032928 infores:monarchinitiative not_provided not_provided HGNC:12765 MONDO:0032928 uuid:210748bf-2829-48a7-b75b-aa4b42c92dee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes UMLS:C0877365 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0877365 infores:hetionet CHEBI:71940 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C1384353 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0021845 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0151723 infores:hetionet CHEBI:4868 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0018418 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1142111 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1142111 infores:hetionet CHEBI:91541 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0233407 infores:hetionet CHEBI:6472 biolink:causes MONDO:0002105 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0025162 infores:hetionet CHEBI:9445 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0520966 infores:hetionet CHEBI:63608 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0002965 infores:hetionet CHEBI:17474 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0030252 infores:hetionet CHEBI:135736 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0017672 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0009144 infores:hetionet CHEBI:3437 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0018681 infores:hetionet CHEBI:71940 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0009782 infores:hetionet CHEBI:52717 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040822 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004835 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0238124 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0002871 infores:hetionet CHEBI:2950 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0006266 infores:hetionet CHEBI:49575 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0043352 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0948594 infores:hetionet CHEBI:472657 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C1320835 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030846 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0037274 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0948089 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0392025 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042769 infores:hetionet CHEBI:63845 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0677500 infores:hetionet CHEBI:68558 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0039070 infores:hetionet CHEBI:64355 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0423791 infores:hetionet CHEBI:6339 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0042029 infores:hetionet CAID:CA2602698 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602698 MONDO:0009276 PMID: Benign BA1 BP4, PS4, PP4 The c.368C>T variant in GP9 is a missense variant predicted to cause substitution of proline by leucine at amino acid 123 (p.Pro123Leu). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.001561 (based on 1906/1175218 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.196, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP9 function and the computational splicing predictor SpliceAI reported a delta score 0.01 for acceptor gain (BP4_NotMet). In summary, this variant meets the criteria to be classified as benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602698/MONDO:0009276/083 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2955 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0085393 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0236071 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020517 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0010108 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0010108 uuid:4e83ab0a-e24f-4ff6-9ef2-ff82a0671d51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9316 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0428977 infores:hetionet CHEBI:7496 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0549622 infores:hetionet CHEBI:83804 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0043144 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021141 infores:hetionet CHEBI:9316 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0012833 infores:hetionet NCBIGene:100144748 biolink:causes MONDO:0014046 infores:monarchinitiative not_provided not_provided HGNC:37212 MONDO:0014046 uuid:eb9646c2-1e5f-4e09-b4ae-a266236927e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3636 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0004604 infores:hetionet CHEBI:50922 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0027497 infores:hetionet CHEBI:2549 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0018965 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0040034 infores:hetionet CHEBI:6539 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0031039 infores:hetionet CHEBI:78543 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0235378 infores:hetionet CHEBI:71028 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0162119 infores:hetionet CHEBI:9332 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0024141 infores:hetionet CHEBI:3286 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0917801 infores:hetionet CHEBI:102216 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0003578 infores:hetionet CHEBI:65173 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0015230 infores:hetionet CHEBI:5856 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0151636 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017178 infores:hetionet CHEBI:17303 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235086 infores:hetionet CHEBI:53691 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0027540 infores:hetionet CHEBI:5779 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0015672 infores:hetionet CHEBI:24564 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0012833 infores:hetionet NCBIGene:5167 biolink:causes MONDO:0013219 infores:monarchinitiative not_provided not_provided HGNC:3356 MONDO:0013219 uuid:6df00dbf-93c3-4802-9bf4-0c4b4e75ce1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5128 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0008031 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0836924 infores:hetionet CHEBI:4856 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0085932 infores:hetionet CHEBI:8060 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0033774 infores:hetionet CHEBI:5088 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C1443060 infores:hetionet CHEBI:3716 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0027497 infores:hetionet NCBITaxon:33278 biolink:causes MONDO:0018500 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:33278 MESH:D007815 DB00730_MESH_D007815_1 CHEBI:9139 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042373 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0553704 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020701 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0032285 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0007642 infores:hetionet CHEBI:8356 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1320474 infores:hetionet CHEBI:28364 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0162429 infores:hetionet CHEBI:3387 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C2830004 infores:hetionet CAID:CA8338126 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338126 MONDO:0008723 PMID: Likely Benign BP4, BP7 The c.1473A>G (p.Leu491=) variant (NM_000018.3) is a synonymous (silent) variant that is not predicted by NNSplice, MaxEntScan, and SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1 is 0.0013 in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338126/MONDO:0008723/021 2025-03-27 2025-10-03 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA658795804 biolink:causes MONDO:0015152 infores:clingen CAID:CA658795804 MONDO:0015152 PMID: Pathogenic PM3_Strong, PVS1, PP4, PM2_Supporting PP1 The NM_003494.4: c.5668-824C>T variant in DYSF, which is also known as NM_001130987.2: c.5785-824C>T, is located in intron 50. SpliceAI predicts it will strengthen alternative splice donor and acceptor sites, with a score of 0.67 and 0.51, respectively. RNAseq and RNA + RT-PCR analysis have shown that this variant results in the inclusion of a portion of intron 50, creating a pseudoexon that is predicted to lead to a frameshift, premature truncation, and nonsense mediated decay in a gene for which loss of function is a known mechanism of disease (PVS1_RNA; PMID: 31019989; 36983702). This variant has been reported in at least 16 individuals with progressive limb girdle muscle weakness (PMID: 31019989; 36983702; PP4), including in a homozygous state without reported familial consanguinity in nine patients (1.0 pt; PMID: 31019989) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 31019989; 36983702; NM_003494.4: c.855+1del, 0.5 pts, PMID: 31019989) (PM3_Strong). This variant has been identified with a second presumed diagnostic DYSF variant in six affected family members from four families, but phase was not confirmed (PMID: 31019989; PP1_Strong not met). This variant is absent from gnomAD v4.1.0 in a region with good genome coverage (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/25/2025): PVS1_RNA, PM3_Strong, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795804/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:59560 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0027441 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C1527344 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0149931 infores:hetionet CHEBI:63623 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C2129214 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020456 infores:hetionet CHEBI:9570 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009676 infores:hetionet CHEBI:6847 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0014742 infores:hetionet CHEBI:63629 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042133 infores:hetionet CHEBI:63617 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151908 infores:hetionet CAID:CA415086073 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086073 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong PP2, PS4 The NM_005629.4:c.1145C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 382 (p.Pro382Leu). This variant is absent from gnomADv2.1.1, and has been reported in two individuals in the literature. In one affected individual in the literature, the ratio of urine Creatine to Creatinine was >99th percentile of normal, and reduced creatine uptake in patient fibroblasts was reported. In silico predictor REVEL suggests this variant will have a damaging / pathogenic effect on the protein (score=0.906). There is a ClinVar entry for this variant (Variation ID: 533700, 1 star review status) with 5 submitters classifying the variant with conflicting interpretations (Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)).In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine transporter deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PP4_Strong, PM2_Supporting, PP3. Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086073/MONDO:0010305/027 2022-12-08 2024-02-11 X-linked inheritance HP:0001417 Supports CAID:CA1244317 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244317 MONDO:0020367 PMID:35196929 Uncertain Significance BS3_Supporting BP7, BS1, PM2, PM6, PP3, PP1, PM5, PM4, PS4, PS3, PS1, PS2, BP4, BA1 The c.158T>C variant in MYOC is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 53 (p.Val53Ala). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0008520 (17 alleles out of 19,954), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.369, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 35196929) demonstrated that the Val53Ala protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function. Although probands for juvenile or primary open angle glaucoma have been identified carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021) : BS3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244317/MONDO:0020367/019 2023-11-14 2023-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9445 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0149931 infores:hetionet NCBIGene:4626 biolink:causes MONDO:0008016 infores:monarchinitiative not_provided not_provided HGNC:7578 MONDO:0008016 uuid:5ebe1fd6-c804-442c-a04c-67cc90f932ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003467 infores:hetionet CHEBI:4530 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0002170 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0032961 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0332575 infores:hetionet CHEBI:82941 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0012833 infores:hetionet CHEBI:465284 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0008031 infores:hetionet CHEBI:6759 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0002792 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151828 infores:hetionet NCBIGene:11151 biolink:causes MONDO:0014168 infores:monarchinitiative not_provided not_provided HGNC:2252 MONDO:0014168 uuid:b6dc2528-57a8-4af1-ac48-b0e14abf53c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235901 infores:hetionet CHEBI:38940 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0016204 infores:hetionet CHEBI:3077 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0029118 infores:hetionet CHEBI:2950 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0009763 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019112 infores:hetionet CHEBI:28830 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0234533 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0003811 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0029878 infores:hetionet CHEBI:5118 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2937350 infores:hetionet CHEBI:63577 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0030554 infores:hetionet CHEBI:41774 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030805 infores:hetionet UMLS:C0657912 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022346 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002325 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040436 infores:hetionet CHEBI:4975 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0002994 infores:hetionet NCBIGene:23189 biolink:causes MONDO:0013033 infores:monarchinitiative not_provided not_provided HGNC:19309 MONDO:0013033 uuid:2b7135cd-eee5-479d-91a6-5c4ed8c33c14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0017979 infores:hetionet CAID:CA2573157348 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157348 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.566_584dup (p.Thr196ProfsTer23) is a frameshift variant predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). This variant affects the critical functional T196 amino acid residue within the RHD (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157348/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2682 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0037274 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0947999 infores:hetionet CHEBI:7478 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0344232 infores:hetionet CHEBI:59773 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027424 infores:hetionet CAID:CA16041891 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041891 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The NM_000152.5:c.1193del (p.Leu398ArgfsTer42) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). This variant has been reported in one patient with POmpe disease; however residual GAA activity was not provided and the second variant is not reported (PMID 30155607). There is a ClinVar entry for this variant (Variation ID: 371457). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041891/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8869 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0030332 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0086543 infores:hetionet CHEBI:32139 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0009676 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235874 infores:hetionet NCBITaxon:157 biolink:causes MONDO:0007000 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:157 MONDO:0007000 CHEBI:40303 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0016382 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0004936 infores:hetionet CHEBI:50275 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0016382 infores:hetionet CHEBI:8776 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0700225 infores:hetionet CHEBI:2453 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0020433 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0234458 infores:hetionet CAID:CA8623279 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623279 MONDO:0100326 PMID: Benign BA1, BP4 BP7 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1533A>G (p.Glu511=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19944) in gnomAD, found in the East Asian population, which is considerably higher than the expected frequency of the disease (BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623279/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8356 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0345904 infores:hetionet CAID:CA279701 biolink:causes MONDO:0021056 infores:clingen CAID:CA279701 MONDO:0021056 PMID: Likely Pathogenic PS4, PM2_Supporting, PVS1_Moderate PS3 The c.645+1G>A variant in APC occurs within the canonical splice donor site +1 of intron 6. It is predicted to result in an inframe skipping of exon 6 (PVS1_Moderate). The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 6 (PP3 supplanted by PVS1_Moderate). RT-PCR of patient blood demonstrated that the variant impacts splicing by removing exon 6 from the transcript, resulting in an NMD-escaping in-frame event with uncertain impact (PMID: 22987206, PS3 supplanted by PVS1_Moderate). This variant has been reported in 9 families with FAP with a total phenotype score of 6 points (PS4; Ambry, Invitae, GeneDX, Barcelona, Edinburgh and Leiden internal data; PMID 22987206; PMID 17411426; PMID 20685668; PMID 8381580). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1_Moderate, PS4, and PM2_Supporting; (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA279701/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9907 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0037299 infores:hetionet CHEBI:15365 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0033774 infores:hetionet CAID:CA410150174 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150174 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.848A>G (p.Gln283Arg) is a missense variant which has a REVEL score < 0.50 (0.447) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150174/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63605 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0000737 infores:hetionet CHEBI:6437 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0877359 infores:hetionet CHEBI:36795 biolink:causes HP:0012088 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0278045 infores:hetionet CHEBI:3568 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020458 infores:hetionet CHEBI:31932 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0853034 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0856081 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0856081 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0027813 infores:hetionet CHEBI:28593 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C1291078 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020517 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0349506 infores:hetionet UMLS:C0657912 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030554 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0030252 infores:hetionet CHEBI:553473 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0027947 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0031542 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017152 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018021 infores:hetionet CAID:CA160084 biolink:causes MONDO:0012163 infores:clingen CAID:CA160084 MONDO:0012163 PMID: Likely Benign BS1 NM_002185.5(IL7R):c.152C>T is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 51 (p.Ser51Leu). The filtering allele frequency (the lower threshold of the 95% CI of 110/74978) of the c.152C>T variant in IL7R is 0.001270 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies.As per SCID VCEP specifications, 1 Strong criteria is enough to reach Likely Benign classification. In summary, this variant meets the criteria to be classified as a Likely Benign variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160084/MONDO:0012163/119 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7478 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0038999 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0013595 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0343263 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0343263 infores:hetionet CHEBI:135888 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0242429 infores:hetionet CHEBI:77260 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0022346 infores:hetionet CHEBI:31348 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0424790 infores:hetionet CHEBI:8888 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013378 infores:hetionet CHEBI:17698 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0011206 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0853954 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0853954 infores:hetionet CHEBI:9332 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0233471 infores:hetionet CHEBI:31236 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085605 infores:hetionet CHEBI:9667 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0005758 infores:hetionet CHEBI:63611 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0006625 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005291 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007766 infores:hetionet CHEBI:94686 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0042963 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0948594 infores:hetionet CHEBI:6715 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1443060 infores:hetionet CHEBI:4514 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0027540 infores:hetionet CHEBI:135935 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0151662 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0948089 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0549373 infores:hetionet NCBIGene:3728 biolink:causes MONDO:0012684 infores:monarchinitiative not_provided not_provided HGNC:6207 MONDO:0012684 uuid:bf5adb08-da0b-41a6-847e-62c4d89faa4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1384353 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0344315 infores:hetionet CHEBI:45081 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C1443060 infores:hetionet CHEBI:35553 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0019158 infores:hetionet CHEBI:63791 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011071 infores:hetionet CHEBI:63580 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0040460 infores:hetionet CHEBI:7823 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0027497 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0948594 infores:hetionet CHEBI:119915 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018946 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0015230 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0030312 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0031117 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0005940 infores:hetionet NCBIGene:57038 biolink:causes MONDO:0012683 infores:monarchinitiative not_provided not_provided HGNC:21406 MONDO:0012683 uuid:24bf7a80-0dc1-427f-ab6f-f030da14ac74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:60761 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0231218 infores:hetionet CHEBI:3699 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0042963 infores:hetionet CHEBI:50729 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0022346 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151723 infores:hetionet CHEBI:5147 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0030794 infores:hetionet CHEBI:37924 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0004604 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0856088 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0856088 infores:hetionet CHEBI:3636 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0003708 infores:hetionet CHEBI:4708 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C2047937 infores:hetionet CHEBI:6950 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0687713 infores:hetionet GO:0072160 biolink:causes CL:1000494 infores:ubergraph knowledge_assertion manual_agent GO:0072160 CL:1000494 CHEBI:6538 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0013395 infores:hetionet CHEBI:50173 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0010200 infores:hetionet CHEBI:4469 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0232462 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0014549 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0042109 infores:hetionet CHEBI:61049 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0600142 infores:hetionet CHEBI:6909 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0003862 infores:hetionet CHEBI:15551 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0151907 infores:hetionet CHEBI:16347 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0011570 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0001824 infores:hetionet CAID:CA170371 biolink:causes MONDO:0010726 infores:clingen CAID:CA170371 MONDO:0010726 PMID: Likely Benign BS2 BP4, PM1, BS1, PM2, PP3 The p.Arg250His variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (RettBASE, internal database - GeneDx) (BS2). The highest population minor allele frequency of the p.Arg250His variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00002955 in East Asian population (not sufficient to meet BS1 criteria). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Arg250His variant in MECP2 (NM_004992.4) is classified as likely benign for Rett syndrome based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170371/MONDO:0010726/036 2024-08-30 2024-12-23 X-linked inheritance HP:0001417 Contradicts true CHEBI:8245 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C1443060 infores:hetionet CHEBI:3181 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0030554 infores:hetionet CHEBI:27796 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0018939 infores:hetionet CHEBI:7444 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0162529 infores:hetionet CAID:CA229527 biolink:causes MONDO:0009861 infores:clingen CAID:CA229527 MONDO:0009861 PMID:23062575PMID:26666653PMID:23357515PMID:27121329PMID:8981952 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.386A>G (p.Asp129Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8981952). This variant has extremely low frequency in gnomAD (MAF: 0.00001; PM2). This variant was detected in trans with known pathogenic variant c.1066-11G>A (PM3; PMID: 27121329). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229527/MONDO:0009861/006 2019-04-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA229703 biolink:causes MONDO:0009861 infores:clingen CAID:CA229703 MONDO:0009861 PMID:30747360PMID:28754886 Pathogenic PM2, PVS1, PP4_Moderate, PM3_Supporting The PAH variant c.707-1G>A (IVS6-1G>A) is a null variant (acceptor site) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. This variant causes exon skipping that results in the removal of more than 10% of the transcript. This variant is predicted to disrupt the reading frame, altering regions critical to protein function (63 pathogenic non-nonsense variants in skipped exons have been reported). The mRNA transcript is predicted to undergo NMD. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.572). HSF (-31.55% variation) and MaxEnt (-114.25% variation) agree that this alteration of the WT acceptor site most probably affects splicing. The PAH variant c.707-1G>A (IVS6-1G>A) was identified in three alleles from Chinese patients with classical PKU. The patients had a plasma Phe level above 120 μmol/L. DHPR activity, biopterin, and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 28754886, 30747360). The PAH variant c.707-1G>A (IVS6-1G>A) was detected in two Chinese patients with classic PKU (cPKU Phe more than 1200 μmol/L). These two patients were identified with the likely pathogenic PAH variant c.1285C>A (p.Gln429Lys) (ClinVar ID: 551555) and with the pathogenic PAH variant c.526C>T (p.Arg176Ter) (ClinVar ID: 102723) Pathogenic PM3 Points: 0.75 (Supporting) (PMID: 28754886)This variant is absent in the gnomAD, ExAC , and PAGE population databases. In summary, this variant meets the criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4_Moderate, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229703/MONDO:0009861/006 2020-05-09 2020-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0023067 infores:hetionet CHEBI:8107 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027497 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0015230 infores:hetionet CHEBI:17474 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0004093 infores:hetionet CHEBI:46081 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151798 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0023530 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0863093 infores:hetionet CHEBI:36795 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0080274 infores:hetionet CHEBI:7936 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0032617 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0021400 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0027697 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0162429 infores:hetionet CHEBI:71940 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0027424 infores:hetionet CAID:CA226597 biolink:causes MONDO:0100368 infores:clingen CAID:CA226597 MONDO:0100368 PMID: Likely Benign BP4, BP7, BS1 The variant NM_000329.3(RPE65):c.978G>T, p.Val326= is a synonymous (silent) variant in exon 9. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.004399, with 376 alleles/74964 total alleles in the African/African American population, which is greater than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226597/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:499361 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0555120 infores:hetionet CHEBI:3077 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0000737 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0497327 infores:hetionet CAID:CA8423128 biolink:causes MONDO:0019497 infores:clingen CAID:CA8423128 MONDO:0019497 PMID: Likely Benign BP4, BS1_Supporting The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8423128/MONDO:0019497/005 2021-07-22 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:8888 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009806 infores:hetionet CHEBI:5001 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C2830004 infores:hetionet CHEBI:5138 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151772 infores:hetionet CHEBI:31236 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151786 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0003123 infores:hetionet CHEBI:135285 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0085649 infores:hetionet CHEBI:135925 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0547030 infores:hetionet CHEBI:32221 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0002962 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0008350 infores:hetionet CHEBI:135939 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0033687 infores:hetionet CHEBI:8212 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0151611 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0011991 infores:hetionet CHEBI:6847 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0042571 infores:hetionet CHEBI:31644 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0853034 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020651 infores:hetionet CHEBI:36704 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0013428 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0027769 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027339 infores:hetionet CHEBI:168396 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0232462 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042373 infores:hetionet CHEBI:84883 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0014724 infores:hetionet CHEBI:41977 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0333355 infores:hetionet CHEBI:36791 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023218 infores:hetionet CHEBI:46345 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0004134 infores:hetionet CHEBI:63681 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0023530 infores:hetionet CHEBI:28787 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0220870 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0392025 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0178298 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0040034 infores:hetionet CHEBI:68647 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0014518 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0267792 infores:hetionet GO:0060222 biolink:causes GO:0060041 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0060041 CHEBI:31622 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0015672 infores:hetionet CHEBI:40279 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1368065 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0013395 infores:hetionet CHEBI:72296 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0232943 infores:hetionet NCBITaxon:5722 biolink:causes MONDO:0030708 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5722 MONDO:0030708 CHEBI:75722 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151754 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019158 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C1443060 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0005940 infores:hetionet NCBIGene:2006 biolink:causes MONDO:0007411 infores:monarchinitiative not_provided not_provided HGNC:3327 MONDO:0007411 uuid:317d3d58-7a77-4162-a8ab-871c886c9c13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0018802 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0948298 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0948298 infores:hetionet CHEBI:125354 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0009782 infores:hetionet CHEBI:15940 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0423791 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0015376 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0521839 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0205204 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0001824 infores:hetionet CHEBI:3172 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0003467 infores:hetionet CHEBI:16347 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0015230 infores:hetionet CHEBI:6970 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0042029 infores:hetionet CHEBI:404903 biolink:causes HP:0030835 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0239266 infores:hetionet CAID:CA341589 biolink:causes MONDO:0015967 infores:clingen CAID:CA341589 MONDO:0015967 PMID: Pathogenic PS4, PM3_Strong, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS3, PM1 The c.790G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 264 (p.(Gly264Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 11508276, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; PMID: 16026363s, internal lab contributors). This variant has been detected in two individuals with neonatal diabetes. Both were compound heterozygous (confirmed in trans) for this variant and another variant classified as pathogenic by ClinGen MDEP (PM3_Strong; PMIDs: 14578306, 16026363, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Relative Activity Index (RAI) of this variant was found to be above the MDEP cutoff (0.5) for PS3_Moderate. While the p.Gly264Ser variant has been reported to cause protein misfolding, this is not considered to meet criteria for applying PS3_Supporting by the ClinGen MDEP (PMIDs: 22820548, 14578306, 16731834, https://doi.org/10.1159/000079009). In summary, c.790G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PM3_Strong, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA341589/MONDO:0015967/086 2023-11-02 2023-11-02 Semidominant inheritance HP:0032113 Supports CHEBI:15940 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0234193 infores:hetionet CHEBI:31705 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0004096 infores:hetionet CHEBI:5106 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0497156 infores:hetionet CHEBI:44185 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0016867 infores:hetionet CHEBI:4995 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038220 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004747 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0008924 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0242350 infores:hetionet CHEBI:28593 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0947912 infores:hetionet CHEBI:2618 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0015230 infores:hetionet CHEBI:72296 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0014591 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0027769 infores:hetionet NCBIGene:55623 biolink:causes MONDO:0859272 infores:monarchinitiative not_provided not_provided HGNC:23807 MONDO:0859272 uuid:89eeb31f-d44e-4c23-a137-19b297911193 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0085631 infores:hetionet CHEBI:4814 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0004604 infores:hetionet CHEBI:68642 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0011603 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0278134 infores:hetionet NCBIGene:81790 biolink:causes MONDO:0030512 infores:monarchinitiative not_provided not_provided HGNC:25358 MONDO:0030512 uuid:df2b98b8-d946-4c75-a540-29ed4f6c517d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0039240 infores:hetionet CHEBI:51230 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0085649 infores:hetionet CHEBI:45783 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0039070 infores:hetionet CAID:CA229272 biolink:causes MONDO:0009861 infores:clingen CAID:CA229272 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting The c.1021A>T (p.Lys341Ter) nonsense variant occurs in exon 10 of 13 and is predicted to result in NMD. It absent from population databases, including gnomAD. It has been reported in at least one patient with cPKU (PMID: 9452062), compound heterozygous with R408W c.1315+1G>A (ClinVar 576, Pathogenic reviewed by PAH VCEP). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229272/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94848 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0011603 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0003123 infores:hetionet CHEBI:6775 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0043094 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0392386 infores:hetionet NCBIGene:22873 biolink:causes MONDO:0012569 infores:monarchinitiative not_provided not_provided HGNC:20908 MONDO:0012569 uuid:41ae9da7-ad9f-4125-811e-708abe190db5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134966 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0426576 infores:hetionet CHEBI:50381 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0020580 infores:hetionet CHEBI:27834 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027796 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1167965 infores:hetionet CHEBI:2682 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0035410 infores:hetionet CHEBI:31949 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0917801 infores:hetionet CAID:CA031936 biolink:causes MONDO:0007750 infores:clingen CAID:CA031936 MONDO:0007750 PMID: Uncertain Significance BP4, BA1, PS1, BS1, PM5, PM2, PP3, PP4 The NM_000527.5(LDLR):c.1078G>C (p.Asp360His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031936/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:49575 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0232461 infores:hetionet CHEBI:3310 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0013378 infores:hetionet CHEBI:119486 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0024523 infores:hetionet GO:0090173 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:0090173 GO:0007127 CHEBI:52717 biolink:causes MONDO:0003366 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1253936 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0009782 infores:hetionet CAID:CA3054201773 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201773 MONDO:0011071 PMID: Pathogenic PVS1, PM5, PM2_Supporting PS3, BP1, BP3, BP5, PM3, BS2, PP2, PP4 NM_001754.5(RUNX1):c.1117_1132del (p.Ser373fs) is a nonsense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_strong). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201773/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50742 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0178298 infores:hetionet UMLS:C0209366 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0600142 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018991 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0004936 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020649 infores:hetionet CHEBI:41879 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015672 infores:hetionet CHEBI:8707 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0234133 infores:hetionet CHEBI:3242 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0232461 infores:hetionet CAID:CA404089716 biolink:causes MONDO:0007750 infores:clingen CAID:CA404089716 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM1, PM4, PM3, PVS1, PM6, BS2, PP2, PP1, PP4 NM_000527.5(LDLR):c.1749C>G (p.His583Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.805. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404089716/MONDO:0007750/013 2023-11-07 2024-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6541 biolink:causes MONDO:0000960 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011875 infores:hetionet CHEBI:36795 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0023380 infores:hetionet CHEBI:47780 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0699828 infores:hetionet CHEBI:30830 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0008031 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002884 infores:hetionet CHEBI:6061 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0039070 infores:hetionet CHEBI:3756 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011124 infores:hetionet CAID:CA044039 biolink:causes MONDO:0007750 infores:clingen CAID:CA044039 MONDO:0007750 PMID: Likely Pathogenic PM1, PP1_Moderate, PM2, PP3, PP4 NM_000527.5(LDLR):c.590G>T (p.Cys197Phe) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2 PP1, PP3_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.00006 (0.006%) in African exomes (gnomAD v2.1.1).PP3 - REVEL = 0.945. It is above 0.75PM1 - Variant meets PM2 and located in highly conserved Cystein 197.PP1_Moderate - Variant segregate with phenotype in 4 informative meioses in 1 family.PP4 - Variant meets PM2 and is identified in 1 index case who fulfil SB criteria for FH (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA044039/MONDO:0007750/013 2022-03-09 2022-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6532 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0232493 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0314719 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0009806 infores:hetionet CHEBI:51230 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0085636 infores:hetionet CHEBI:8890 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1443060 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0314719 infores:hetionet CAID:CA229459 biolink:causes MONDO:0009861 infores:clingen CAID:CA229459 MONDO:0009861 PMID:21147011PMID:21147011 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PM5, PP3 The c.168G>T (p.Glu56Asp) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID: 21147011, 23932990, 30050108). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID: 8019568); R408W and T356X (PMID: 21147011); p.V399V, c.442-1G>A, p.I65T, p.R261Q (PMID: 30050108). Computational prediction tools and conservation analysis do not agree on the impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229459/MONDO:0009861/006 2020-06-29 2021-07-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:77260 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085631 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0853089 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0853193 infores:hetionet CHEBI:63598 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041582 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020615 infores:hetionet CHEBI:32221 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0232462 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0024115 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0031542 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002418 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0005758 infores:hetionet NCBIGene:23094 biolink:causes MONDO:0014799 infores:monarchinitiative not_provided not_provided HGNC:23801 MONDO:0014799 uuid:0deb34bd-a1f5-4b59-ae39-018592c46de3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0029163 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0042514 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0002622 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006277 infores:hetionet CHEBI:17334 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0038362 infores:hetionet CAID:CA226553 biolink:causes MONDO:0100368 infores:clingen CAID:CA226553 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3, PP1, PM2_Supporting PS3 NM_000329.3(RPE65):c.444G>T (p.Glu148Asp) is a missense variant predicted to replace glutamate with aspartic acid at amino acid p.148. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 probands with early onset severe retinal dystrophy who harbored the variant in the compound heterozygous state, confirmed in trans with either the NM_000329.3(RPE65):c.131G>A (p.Arg44Gln) variant (PMID: 15024725), which been classified as pathogenic by the ClinGen LCA / eoRD VCEP, or with the NM_000329.3(RPE65):c.1451G>A (p.Gly484Asp) variant (PMID: 30268864), which has been classified as likely pathogenic by the ClinGen LCA / eoRD VCEP (total 2 points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 15024725, VCEP member-provided data). The computational predictor REVEL gives a score of 0.696, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). The splicing impact predictor SpliceAI gives a score of 0.06 for acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Introducing the equivalent Glu150Asp substitution into the SynACO enzyme (an ortholog from the unicellular bacterium Synechocystis) reduced its catalytic efficiency to ~9% of the wild-type enzyme (PMID: 34607013). However, PS3_Supporting is not met as this functional assay has not yet been approved by the ClinGen LCA / eoRD VCEP. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, and PP3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226553/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8212 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0178298 infores:hetionet NCBIGene:10382 biolink:causes MONDO:0007493 infores:monarchinitiative not_provided not_provided HGNC:20774 MONDO:0007493 uuid:fbf4e255-0b48-4146-9c0b-f5861fb95844 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes HP:0001072 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0241165 infores:hetionet NCBIGene:92335 biolink:causes MONDO:0012611 infores:monarchinitiative not_provided not_provided HGNC:30172 MONDO:0012611 uuid:1bff9fa1-7b1f-4d3d-ab62-748faaf0ae90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA165678 biolink:causes MONDO:0700270 infores:clingen CAID:CA165678 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS1_Moderate PP3 The ATM c.3284G>A (p.Arg1095Lys) variant in ATM is a missense variant occurring in last base pair of exon 22. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Another variant at the same nucleotide position (c.3284G>C) is classified as likely pathogenic by the HBOP VCEP. The SpliceAI predictions indicate that the two variants are likely to lead to the same event (disruption of the donor splice site of intron 21 in ATM). These observations suggest that the variant has an impact on splicing consistent with pathogenicity. The highest population minor allele frequency in gnomAD v4.1.0 is 0.000005932 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1_Strong, PS1_Moderate(Splicing), PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA165678/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9398 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0042963 infores:hetionet NCBIGene:4948 biolink:causes MONDO:0008746 infores:monarchinitiative not_provided not_provided HGNC:8101 MONDO:0008746 uuid:7712963e-5cea-4873-98d1-1e929c8dd851 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0149745 infores:hetionet CHEBI:52717 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009421 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0497365 infores:hetionet CHEBI:31515 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0277585 infores:hetionet CHEBI:9943 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0851578 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013595 infores:hetionet CHEBI:17334 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C1257843 infores:hetionet CHEBI:3013 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0019151 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014869 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0037822 infores:hetionet CHEBI:50648 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0575081 infores:hetionet CHEBI:44032 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0162834 infores:hetionet NCBIGene:23476 biolink:causes MONDO:0957921 infores:monarchinitiative not_provided not_provided HGNC:13575 MONDO:0957921 uuid:43de4a54-f1f4-4943-b3b4-62ac4d0ad204 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5100 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0242528 infores:hetionet CHEBI:52172 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0428977 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235431 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0859061 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0859061 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005684 infores:hetionet CHEBI:3215 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235031 infores:hetionet CHEBI:6741 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151746 infores:hetionet CHEBI:45599 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0013378 infores:hetionet CAID:CA404080953 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080953 MONDO:0007750 PMID: Uncertain Significance PM2 BP2, BP4, BA1, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM3, PM1, PM4, PM5, PM6, PVS1, BS2, PP4, PP1, PP3 The NM_000527.5(LDLR):c.890A>G (p.Asn297Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080953/MONDO:0007750/013 2022-02-14 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:40237 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0007859 infores:hetionet CHEBI:9654 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042963 infores:hetionet CAID:CA902478 biolink:causes MONDO:0100368 infores:clingen CAID:CA902478 MONDO:0100368 PMID: Likely Benign BP4, BS1 BP7, PM2 NM_000329.3(RPE65):c.496-4G>A is a non-coding variant near the junction of intron 5 with exon 6. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.001437, with 59 alleles / 24910 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.01 for either acceptor loss or acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1, BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902478/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31236 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0149741 infores:hetionet CHEBI:8024 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0392525 infores:hetionet CHEBI:68579 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0014591 infores:hetionet CHEBI:59750 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0011603 infores:hetionet CHEBI:63608 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0917801 infores:hetionet CHEBI:63627 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0014742 infores:hetionet CHEBI:36791 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033247 infores:hetionet CHEBI:52717 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232487 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0439857 infores:hetionet GO:0110057 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0110057 GO:0072359 NCBIGene:200894 biolink:causes MONDO:0012855 infores:monarchinitiative not_provided not_provided HGNC:25419 MONDO:0012855 uuid:258d80ed-c367-4377-90f0-1d19757020c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0033845 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0003467 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018799 infores:hetionet CAID:CA10567943 biolink:causes MONDO:0010602 infores:clingen CAID:CA10567943 MONDO:0010602 PMID: Benign BA1, BP4 BP7, PS4 The c.5703C>A variant in F8 is a synonymous (silent) variant (p.Ile1901=) that is not predicted by SpliceAI to impact splicing. This variant is located in Exon 17, within the A3 domain of FVIII. However, BP7 was not applied as the nucleotide is conserved. This variant has been reported in 1 proband with mild Hemophilia A. However, PS4_Supporting cannot be applied because VWD 2N was not ruled out (PMID: 16128892) and BA1 was met. The c.5703C>A (p.Ile1901=) variant is reported at an MAF of 0.007915 (151/19078 alleles) in the South Asian population in gnomAD v2.1.1 with 105 hemizygotes, meeting BA1 criteria of MAF >= 0.000333. The computational predictor REVEL has a score of 0 which is below the threshold of 0.3, and the splice site predictor Splice AI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on F8 function (BP4_Supporting). In summary, this variant meets the criteria to be classified as benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1, BP4_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10567943/MONDO:0010602/071 2024-10-11 2024-10-11 X-linked inheritance HP:0001417 Contradicts true UMLS:C0120107 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0023380 infores:hetionet NCBIGene:26038 biolink:causes MONDO:0859249 infores:monarchinitiative not_provided not_provided HGNC:16816 MONDO:0859249 uuid:12ff9b9c-d8ab-44e9-a11c-ebfe4d21ba59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135351 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0043352 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151849 infores:hetionet CHEBI:50922 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0575081 infores:hetionet CHEBI:107736 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0232807 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013395 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085584 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0234215 infores:hetionet CAID:CA501111 biolink:causes MONDO:0700270 infores:clingen CAID:CA501111 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3, PP3 The c.7661A>G variant in ATM is a missense variant predicted to cause substitution of histidine by arginine at amino acid 2554 (p.His2554Arg). This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.2.1.1. The computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA501111/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27446 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0031117 infores:hetionet CHEBI:107736 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0022346 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0032285 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022081 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0152010 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0152010 infores:hetionet CHEBI:209807 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0040034 infores:hetionet NCBIGene:22880 biolink:causes MONDO:0030835 infores:monarchinitiative not_provided not_provided HGNC:23573 MONDO:0030835 uuid:19e69a5a-5929-401c-b0ec-0e6e6bd218d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92998 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020625 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020517 infores:hetionet CHEBI:31348 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151636 infores:hetionet CHEBI:6715 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0149741 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0014112 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0014112 uuid:cd9722a3-d6f3-4216-a24b-ad5fcb74c961 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0018802 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0036572 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0013415 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005628 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0238033 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0033975 infores:hetionet CHEBI:49575 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0015732 infores:hetionet GO:0042697 biolink:causes MONDO:0001410 infores:ubergraph knowledge_assertion manual_agent GO:0042697 MONDO:0001410 UMLS:C0657912 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C3665347 infores:hetionet CHEBI:7983 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0012833 infores:hetionet CHEBI:82960 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151576 infores:hetionet CHEBI:3441 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0851578 infores:hetionet CHEBI:4885 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0042963 infores:hetionet NCBIGene:4883 biolink:causes MONDO:0859194 infores:monarchinitiative not_provided not_provided HGNC:7945 MONDO:0859194 uuid:8052599a-6558-4755-8b40-3185bce461ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:80781 biolink:causes MONDO:0030038 infores:monarchinitiative not_provided not_provided HGNC:2195 MONDO:0030038 uuid:f9bdd632-ad98-47a2-8af4-fd58305a5a43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:391960 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0030252 infores:hetionet CHEBI:64355 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235266 infores:hetionet CHEBI:6965 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0037036 infores:hetionet CHEBI:75998 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0852911 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0877661 infores:hetionet CHEBI:17347 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042755 infores:hetionet CAID:CA512318733 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318733 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.432G>C (p.Leu144=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 [0.05]) (BP4, BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318733/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5280 biolink:causes MONDO:0002136 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0155177 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0004238 infores:hetionet CHEBI:45409 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085631 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0948594 infores:hetionet CHEBI:2682 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0014724 infores:hetionet CHEBI:421707 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0017152 infores:hetionet CHEBI:49662 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0033774 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020538 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0007642 infores:hetionet CHEBI:144551 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018524 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0152517 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0004936 infores:hetionet CHEBI:75045 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151699 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004830 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0015645 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0854100 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0085624 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013922 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0011053 infores:hetionet GO:0060762 biolink:causes GO:0061180 infores:ubergraph knowledge_assertion manual_agent GO:0060762 GO:0061180 CHEBI:7931 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0029408 infores:hetionet CHEBI:68584 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0039070 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0020649 infores:hetionet NCBIGene:11340 biolink:causes MONDO:0014485 infores:monarchinitiative not_provided not_provided HGNC:17035 MONDO:0014485 uuid:bde0c337-4515-4a28-8008-91936008b8aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0580546 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0580546 infores:hetionet CHEBI:17474 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0030196 infores:hetionet CHEBI:52172 biolink:causes UMLS:C1141948 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1141948 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034882 infores:hetionet CHEBI:3286 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0042963 infores:hetionet CHEBI:50663 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0015230 infores:hetionet CHEBI:135342 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151636 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0033975 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0860967 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0521839 infores:hetionet CHEBI:10650 biolink:causes MONDO:0017611 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0032019 infores:hetionet NCBIGene:25788 biolink:causes MONDO:0011508 infores:monarchinitiative not_provided not_provided HGNC:17228 MONDO:0011508 uuid:717ebb7f-060c-4aa0-a523-897f1ab75b27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2250 biolink:causes MONDO:0008593 infores:monarchinitiative not_provided not_provided HGNC:3683 MONDO:0008593 uuid:f830bf2a-6113-4dcd-a08a-229fb5b2a662 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0699893 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0585186 infores:hetionet CAID:CA195169 biolink:causes MONDO:0700270 infores:clingen CAID:CA195169 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP3 The ATM c.3137T>C (p.Leu1046Pro) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico protein predictors (REVEL Impact: 0.854; Align-GVGD: C65) predict that this alteration is deleterious (PP3). This variant has also been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with ataxia-telangiectasia (PMIDs: 27664052, 31429931) (PM3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA195169/MONDO:0700270/020 2022-03-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7824 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009806 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085637 infores:hetionet CHEBI:465284 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0035455 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0014431 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014431 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1112413 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1112413 infores:hetionet CHEBI:94440 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C1443060 infores:hetionet CHEBI:63617 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011206 infores:hetionet CHEBI:135935 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0232462 infores:hetionet NCBIGene:55603 biolink:causes MONDO:0044329 infores:monarchinitiative not_provided not_provided HGNC:18345 MONDO:0044329 uuid:7ff8c27a-79f9-4493-9e1d-5fb74676ce6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA013242 biolink:causes MONDO:0004994 infores:clingen CAID:CA013242 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.2967T>C (p.Ile989=) variant in the MYH7 gene is 70.48% (7476/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013242/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0032231 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0265935 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0265935 infores:hetionet NCBIGene:3914 biolink:causes MONDO:0009180 infores:monarchinitiative not_provided not_provided HGNC:6490 MONDO:0009180 uuid:f8bac06b-c5ef-43b6-88d5-0308cb3785d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003621 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0026848 infores:hetionet CHEBI:5118 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013384 infores:hetionet NCBIGene:3549 biolink:causes MONDO:0011907 infores:monarchinitiative not_provided not_provided HGNC:5956 MONDO:0011907 uuid:a1c1865a-eb31-4654-b56e-683ac153f256 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0024305 infores:hetionet UNII:D27V6190PM biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0041834 infores:hetionet NCBIGene:10397 biolink:causes MONDO:0011085 infores:monarchinitiative not_provided not_provided HGNC:7679 MONDO:0011085 uuid:922ba577-e186-4263-aa3c-ba868348d19e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018681 infores:hetionet CHEBI:135920 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C1704272 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0024894 infores:hetionet NCBIGene:10059 biolink:causes MONDO:0013726 infores:monarchinitiative not_provided not_provided HGNC:2973 MONDO:0013726 uuid:d3d9b376-8313-4670-baf3-02855b2bed7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0048931 biolink:causes CL:1000236 infores:ubergraph knowledge_assertion manual_agent GO:0048931 CL:1000236 CHEBI:101853 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0035317 infores:hetionet CHEBI:41879 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0017979 infores:hetionet CHEBI:8214 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0234238 infores:hetionet CHEBI:63632 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0002994 infores:hetionet CAID:CA9043555 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043555 MONDO:0012999 PMID:24415674 Likely Pathogenic PP3, PM2_Supporting, PP4_Strong, PM3_Supporting, PS3_Supporting PM5 The NM_000156.6:c.623G>C variant in GAMT is a missense variant predicted to cause substitution of arginine by proline at amino acid 208 (p.Arg208Pro). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). It has been reported in homozygosity in one individual with clinical symptoms consistent with GAMT deficiency (severe intellectual impairment, intractable seizures, movement disorder), deficienct GAMT activity, and reduction of creatine on brain MRS, who showed clinical improvement on dietary treatment (PMID 24415674, 29506905) (PM3_Supporting, PP4_Strong). When expressed in GAMT-deficient fibroblasts, the variant resulted in ~4% wild type GAMT activity (PMID 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.751, which is in the range (0.644-0.773) that predicts impact to GAMT function at the supporting level (Pejaver et al, 2022, PMID: 36413997) (PP3). Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478), and c.622C>T (p.Arg208Cys) (ClinVar ID: 544261). Both of these variants have been classified as variants of uncertain significance by the ClinGen CCDS VCEP. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043555/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:474180 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0476273 infores:hetionet NCBIGene:114798 biolink:causes MONDO:0013189 infores:monarchinitiative not_provided not_provided HGNC:20297 MONDO:0013189 uuid:b8c1bf9e-d081-4386-94b9-0047b8dfd46c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0011175 infores:hetionet CHEBI:45783 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030252 infores:hetionet CHEBI:3749 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0020456 infores:hetionet CHEBI:4995 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0019521 infores:hetionet CHEBI:63620 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1443060 infores:hetionet CHEBI:31401 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0040264 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0033581 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020649 infores:hetionet NCBIGene:5205 biolink:causes MONDO:0008892 infores:monarchinitiative not_provided not_provided HGNC:3706 MONDO:0008892 uuid:f565d86b-b72a-4877-9bf3-b76f8981da65 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018674 infores:hetionet CHEBI:8212 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0002871 infores:hetionet CHEBI:2379 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0220870 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0033975 infores:hetionet CHEBI:3380 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0151798 infores:hetionet CHEBI:5130 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0030193 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013404 infores:hetionet CHEBI:421707 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0231218 infores:hetionet CHEBI:64064 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1384353 infores:hetionet CAID:CA2580098644 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098644 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.509-11T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098644/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4681 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0012833 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0029882 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0877042 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877042 infores:hetionet CAID:CA9043535 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043535 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The NM_000156.6:c.668dupA (p.Tyr223fs) variant in GAMT is a frameshift variant in the last exon (exon 6/6; amino acid 223/237) of GAMT, and is therefore predicted to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002543 (3/1179898 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency. However, itt is noted in ClinVar (Variation ID 445930). In addition, a different nucleotide change that results in the same molecular consequence (c.669C>G (p.Tyr223Ter), has also been reported in ClinVar (Variation ID: 1394775).In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PVS1_Moderate, PM2_Supporting(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043535/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31705 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0015672 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0518015 infores:hetionet CHEBI:27953 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00981 UMLS:C0027497 infores:hetionet CHEBI:16796 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0236075 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0013395 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0017601 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0021053 infores:hetionet CHEBI:7798 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0235378 infores:hetionet CHEBI:5118 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0231218 infores:hetionet CHEBI:188986 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0022575 infores:hetionet GO:0006954 biolink:causes MONDO:0006004 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D012223 DB00719_MESH_D012223_1DB08936_MESH_D012223_1DB09555_MESH_D012223_1DB00967_MESH_D012223_1DB00972_MESH_D012223_1DB01069_MESH_D012223_1DB01176_MESH_D012223_1 CHEBI:7852 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0019348 infores:hetionet CHEBI:85083 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0011603 infores:hetionet CAID:CA8622965 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622965 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PM5, PP3 The NM_000212.3(ITGB3):c.473A>G (p.Gln158Arg) missense variant was detected in an individual without GT who was heterozygous for this variant, where it resulted in the Woa human platelet alloantigen (PMID: 31859394). This variant is reported in gnomAD v2.1.1 in the non-Finnish European population with a MAF of 0.000008790 (1/113760 alleles). This MAF is less than the 0.0001 MAF established by the PD VCEP to assign this code (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622965/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:135930 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0549373 infores:hetionet CHEBI:7931 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085636 infores:hetionet CHEBI:6339 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0085631 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0235966 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015397 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002957 infores:hetionet CHEBI:2676 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0086565 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018801 infores:hetionet CHEBI:6375 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0016204 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085637 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0851341 infores:hetionet CHEBI:59560 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0000737 infores:hetionet CHEBI:63631 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020598 infores:hetionet CHEBI:3738 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0018681 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0037274 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0521498 infores:hetionet CHEBI:7459 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0017178 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0000833 infores:hetionet CHEBI:6715 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0234022 infores:hetionet CHEBI:4672 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0858635 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0687707 infores:hetionet CHEBI:15854 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0162820 infores:hetionet CHEBI:45081 biolink:causes HP:0005542 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151563 infores:hetionet CHEBI:3219 biolink:causes HP:0012701 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0426636 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0026826 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1096343 infores:hetionet CAID:CA380145403 biolink:causes MONDO:0000572 infores:clingen CAID:CA380145403 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting PS3 The NM_000448.3:c.82T>C variant in RAG1 is a missense variant predicted to cause a substitution of tryptophan by arginine at amino acid 28 (p.Trp28Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV001210547.4). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145403/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:10479 biolink:causes MONDO:0976236 infores:monarchinitiative not_provided not_provided HGNC:11079 MONDO:0976236 uuid:a986fba6-15cc-4cf4-9f80-84aa62f80906 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085593 infores:hetionet CHEBI:63598 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0497156 infores:hetionet CHEBI:3996 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0017152 infores:hetionet CAID:CA382523925 biolink:causes MONDO:0700270 infores:clingen CAID:CA382523925 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PP3 The c.8732C>A variant in ATM is a missense variant predicted to cause substitution of threonine by asparagine at amino acid 2911 (p.Thr2911Asn). This individual was homozygous for the variant; however, the information provided was not sufficient to meet the HBOP VCEP requirements for phenotyping as the diagnosis was based on biallelic variants (PMID: 38917355). This variant is absent from gnomAD v4.1.0. The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.7333, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382523925/MONDO:0700270/020 2025-11-11 2025-11-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:85161 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020649 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0699893 infores:hetionet CHEBI:4798 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020433 infores:hetionet CHEBI:8665 biolink:causes UMLS:C2939427 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C2939427 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C1510472 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0009557 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0009557 uuid:9125b228-403e-4439-913b-a61229948a4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042109 infores:hetionet GO:0048923 biolink:causes CL:2000037 infores:ubergraph knowledge_assertion manual_agent GO:0048923 CL:2000037 CHEBI:51041 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0917801 infores:hetionet CHEBI:47381 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0423791 infores:hetionet CHEBI:16469 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0149741 infores:hetionet CHEBI:63611 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0438142 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0004936 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002363 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0030354 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0028738 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0004936 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020456 infores:hetionet CHEBI:32315 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0086769 infores:hetionet CHEBI:5002 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0020649 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0018099 infores:hetionet CHEBI:3732 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151662 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0020039 infores:hetionet CHEBI:64355 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004245 infores:hetionet CHEBI:4702 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0004604 infores:hetionet CHEBI:47381 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0038325 infores:hetionet CHEBI:6149 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0034063 infores:hetionet CHEBI:31644 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042029 infores:hetionet CAID:CA202650 biolink:causes MONDO:0019565 infores:clingen CAID:CA202650 MONDO:0019565 PMID: Likely Benign PP4, BS1, BP5 PP3, BP4, PS4, BS3 NM_000552.5(VWF):c.6187C>T is a missense variant that replaces proline with serine at position 2063. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.04661 (based on 4353/91066 alleles in the South Asian population, with 145 homozygotes), which is higher than the ClinGen VWD VCEP BS1 threshold of >0.01 (BS1). At least 1 proband harboring the variant in the homozygous state exhibits a history of severe bleeding and a quantitative defect in VWF, consistent with VWD Type 3 (PMID: 23354996), however, it is not yet clear whether this phenotype is sufficiently specific to meet PP4. While this variant is also reported to be present in the homozygous state in multiple other affected probands (PMID: 23354996), PS4 cannot be considered because BS1 is met. The recombinant p.Pro2063Ser variant in COS-7 cells matches properties of the wild-type recombinant protein, including normal expression, secretion, and multimer formation, inconsistent with a quantitative defect relevant to VWD Type 3 (PMID: 19566550). BS3_Supporting is not met because this criterion is considered not applicable to this gene-disease relationship. This variant has been observed in affected cases with an alternate molecular basis for disease, including in VWD Type 3 in cis with either the NM_000552.5(VWF):c.970C>T (p.Arg324Ter) variant (PMID: 33550700) or the NM_000552.5(VWF):c.5200C>T (p.Gln1734Ter) variant (PMID: 23702511). Both comparison variants have been classified as Pathogenic by the ClinGen VWD VCEP. Three other reported cases with diverse VWD diagnoses harbor this variant as well as a second variant in VWF (PMID: 19404524, PMID: 21534937, PMID: 16985174), however, the comparison variants have not yet been classified by the ClinGen VWD VCEP. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, PP4. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA202650/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true CHEBI:135925 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0012569 infores:hetionet CHEBI:63612 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0038220 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0948594 infores:hetionet NCBITaxon:55194 biolink:causes MONDO:0005915 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:55194 MESH:D014010 DB01127_MESH_D014010_1DB01026_MESH_D014010_1DB00857_MESH_D014010_1 CHEBI:145499 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0010200 infores:hetionet NCBIGene:841 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:1509 MONDO:0007256 uuid:bedd4707-d664-470b-ab03-34c875589195 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585340 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585340 MONDO:0007750 PMID: Likely Benign BP4, BP7, PM2 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1185G>C (p.Val395=) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4 and BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -3 to +6 bases of canonical donor splicing site. MES scores: de novo donor = 9.1, authentic donor = 7.23. Ratio variant/wt = 1.26. It is above 1.0. Score ≥ 1.0 is supportive evidence of benign. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met.BP7 - Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585340/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63791 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019917 infores:hetionet CHEBI:63627 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0011615 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020517 infores:hetionet UMLS:C0657912 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017979 infores:hetionet CHEBI:2948 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0012813 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0034065 infores:hetionet CHEBI:9086 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0014591 infores:hetionet CAID:CA10585529 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585529 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 "The NM_000527.5(LDLR):c.1618G>T (p.Ala540Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - variant was not identified in gnomAD (gnomAD v2.1.1), so met.PM5 - 1 other missense variant in the same codon:- NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr)- 2 stars, Pathogenic/Likely pathogenic- Pathogenic by these guidelinesso PM5 is met.PP3 - REVEL = 0.821. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in:- at least 1 index case with definite FH ((in the paper: ""All patients were clinically diagnosed with definite heterozygous hypercholesterolemia by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000]."") from PMID 16250003 (Fouchier et al., 2005), The Netherlands.so PP4 is met." Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585529/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:175901 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0085932 infores:hetionet CHEBI:50173 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151474 infores:hetionet CHEBI:10650 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085632 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0021400 infores:hetionet CHEBI:7959 biolink:causes HP:6000076 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0152002 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018801 infores:hetionet CHEBI:37924 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0424295 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0349506 infores:hetionet CHEBI:68595 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0034886 infores:hetionet CHEBI:4717 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C2830004 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013922 infores:hetionet CHEBI:3032 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0234535 infores:hetionet CHEBI:53691 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C3263723 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017168 infores:hetionet CHEBI:39112 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0011991 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0339961 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0339961 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0025061 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0031212 infores:hetionet CHEBI:167638 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0687713 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0034150 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0027765 infores:hetionet CHEBI:6801 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0220870 infores:hetionet CHEBI:84883 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0030193 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0011991 infores:hetionet CHEBI:51364 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0041834 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002453 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0040425 infores:hetionet CHEBI:75722 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037317 infores:hetionet UMLS:C0065374 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037763 infores:hetionet CHEBI:3048 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0085632 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0008301 infores:hetionet CHEBI:3568 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0000731 infores:hetionet NCBIGene:79977 biolink:causes MONDO:0014460 infores:monarchinitiative not_provided not_provided HGNC:2799 MONDO:0014460 uuid:3653f086-19b8-4b03-a823-d9dcb4522c4f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0542203 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151854 infores:hetionet CHEBI:134991 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C1368065 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0015376 infores:hetionet NCBIGene:652 biolink:causes MONDO:0011936 infores:monarchinitiative not_provided not_provided HGNC:1071 MONDO:0011936 uuid:7fc12b14-666c-40f8-8978-44fce2414784 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585029 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585029 MONDO:0007750 PMID: Pathogenic PVS1, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark.so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585029/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7565 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014518 infores:hetionet NCBIGene:5741 biolink:causes MONDO:0007796 infores:monarchinitiative not_provided not_provided HGNC:9606 MONDO:0007796 uuid:e1abe260-74bd-4396-8f54-2b97d093abb7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0000737 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0015397 infores:hetionet CHEBI:2567 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0152031 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0497365 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011991 infores:hetionet CAID:CA410148400 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148400 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1042C>T (p.His348Tyr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148400/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6402 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0000737 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0740471 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0740471 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0152517 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0854286 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0854286 infores:hetionet CHEBI:7478 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042963 infores:hetionet CHEBI:6759 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C2830004 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233571 infores:hetionet CHEBI:3698 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C3665386 infores:hetionet CHEBI:6402 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027796 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020651 infores:hetionet CHEBI:2666 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0042963 infores:hetionet CHEBI:15765 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0151539 infores:hetionet CHEBI:6923 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C2004489 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0011053 infores:hetionet CHEBI:52717 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085679 infores:hetionet CHEBI:8774 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0042963 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003864 infores:hetionet GO:2000332 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:2000332 GO:0048856 CHEBI:4995 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0009763 infores:hetionet GO:1902608 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:1902608 GO:0071805 CHEBI:2682 biolink:causes UMLS:C1504419 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1504419 infores:hetionet NCBIGene:5660 biolink:causes MONDO:0009590 infores:monarchinitiative not_provided not_provided HGNC:9498 MONDO:0009590 uuid:d9d5dc6c-8e93-4106-a301-f82d34c18c7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003873 infores:hetionet CHEBI:36791 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013456 infores:hetionet CHEBI:4868 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0011570 infores:hetionet NCBIGene:7545 biolink:causes MONDO:0032892 infores:monarchinitiative not_provided not_provided HGNC:12872 MONDO:0032892 uuid:da86b341-581f-4d89-b3bb-dc6bec350b93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes MONDO:0001577 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0035235 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0035078 infores:hetionet NCBIGene:55901 biolink:causes MONDO:0859379 infores:monarchinitiative not_provided not_provided HGNC:17754 MONDO:0859379 uuid:1d4b839f-bc41-4c8e-973c-3030b461a8d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0236075 infores:hetionet CHEBI:167638 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0018681 infores:hetionet CHEBI:9137 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085932 infores:hetionet CAID:CA512341144 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341144 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1275G>C (p.Pro425=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-1.62) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341144/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10650 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018794 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020437 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0687133 infores:hetionet CAID:CA10652909 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652909 MONDO:0011071 PMID: Benign BP2, BA1 PS3, PS1, PS4, BP4, PM6, PM2, PVS1, BP7, BS3, BS4, BS1, PM1, PM4, PM5, PP3, PP1 The NM_001754.4:c.*3345A>T variant in the 3' UTR has an MAF of 0.09 (9%, 145/1560 alleles) in the East Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 16 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652909/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16586 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0040053 infores:hetionet CAID:CA340748193 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748193 MONDO:0100368 PMID: Pathogenic PM3_Strong, PM1, PP3_Moderate, PP4, PM2_Supporting NM_000329.3(RPE65):c.329A>G (p.Asp110Gly) is a missense variant predicted to replace aspartic acid with glycine at position 110. This variant is a located within the membrane-interacting region between amino acids 107 and 125, which is a well-characterized functional domain required for proper localization to the ER membrane (PM1, PMID: 36265895). This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.0000007 with 4 alleles / 1180028 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), onset by age 2 years (1 pt), extinguished electroretinogram responses from both rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), attenuated retinal vessels with bone spicule pigmentation (0.5 pts), and optic nerve atrophy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 total points, PMID: 26626312, PP4). This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 26626312). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant suspected in trans (0.5+0.5 points, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). The computational predictor REVEL gives a score of 0.945, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748193/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64312 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004238 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002418 infores:hetionet CAID:CA410150272 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150272 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.829C>G (p.Pro277Ala) is a missense variant which has a REVEL score < 0.50 (0.466) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150272/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17303 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151740 infores:hetionet CHEBI:100241 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0019080 infores:hetionet CHEBI:68554 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0151905 infores:hetionet CHEBI:421707 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C2711227 infores:hetionet CAID:CA8623105 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623105 MONDO:0100326 PMID: Likely Benign PP3, BA1 The c.970A>G variant in ITGB3 is a missense variant predicted to cause substitution of lycine by glutamic acid at amino acid 324. The variant has a high population minor allele frequency in gnomAD v2.1.1 of 0.003164 (79/24968 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold for BA1 (>0.0024). The computational predictor REVEL gives a score of 0.905, which is above the ClinGen PD VCEP PP3 threshold of >0.7 and predicts a damaging effect on ITGB3 function. No individuals with Glanzmann thrombasthenia have been reported with the variant to our knowledge. GeneDx reports an affected individual with this variant but their condition is not reported (SCV001875222.1). In summary, the allele frequency was considered as the more convincing of the conflicting evidence and a classification of Likely Benign was assigned for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, PP3. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623105/MONDO:0100326/011 2023-04-06 2023-04-07 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:17347 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0234894 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0027769 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0235416 infores:hetionet CHEBI:7798 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0302809 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235002 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235002 infores:hetionet CHEBI:3419 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0040822 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0037274 infores:hetionet CHEBI:3176 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0015672 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0853193 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0687133 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0041912 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0021364 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0041912 infores:hetionet CHEBI:3996 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0013604 infores:hetionet NCBIGene:5627 biolink:causes MONDO:0012868 infores:monarchinitiative not_provided not_provided HGNC:9456 MONDO:0012868 uuid:f9232e44-42d0-4782-bd5f-b5d8059a05fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0043352 infores:hetionet CHEBI:135930 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0014742 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151613 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0241164 infores:hetionet CHEBI:50648 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018524 infores:hetionet CHEBI:31623 biolink:causes EFO:0009472 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0206504 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020701 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027051 infores:hetionet NCBIGene:3909 biolink:causes MONDO:0030747 infores:monarchinitiative not_provided not_provided HGNC:6483 MONDO:0030747 uuid:3843ccef-4d8a-43e7-81b1-6ae98c0bfe7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0004096 infores:hetionet CHEBI:9635 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0151766 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0037199 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0232492 infores:hetionet CAID:CA345144596 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144596 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PM6 The variant NM_001100.3:c.1054T>C in ACTA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 352 (p.Ser352Pro). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.942, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). There is no published data on this variant, however Invitae has reported the variant in three unrelated probands, two of which presented with hypotonia (PS4_Supporting; SCV000638354.5). In addition, one of these probands had a de novo occurrence of the variant with parental relationships unconfirmed (PM6). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PM2_Supporting, PP2, PP3, PS4_Supporting, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144596/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40237 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C2047937 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0746883 infores:hetionet CHEBI:47499 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0004245 infores:hetionet CHEBI:50922 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0030252 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0267792 infores:hetionet CHEBI:50275 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0010200 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0948525 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0011616 infores:hetionet CHEBI:50922 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013378 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0267792 infores:hetionet NCBIGene:29123 biolink:causes MONDO:0007846 infores:monarchinitiative not_provided not_provided HGNC:21316 MONDO:0007846 uuid:338caba1-019d-4270-b11d-d7555b3d3943 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45081 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0085593 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0035455 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0917801 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0948294 infores:hetionet CHEBI:84500 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0026961 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0855242 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0002418 infores:hetionet CHEBI:50173 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0043349 infores:hetionet CHEBI:8802 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0086565 infores:hetionet CHEBI:8888 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022107 infores:hetionet CHEBI:9599 biolink:causes HP:0012155 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0859996 infores:hetionet CHEBI:71255 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0013362 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0014130 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0021061 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0021061 infores:hetionet CHEBI:47781 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0520966 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0011991 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0022081 infores:hetionet CHEBI:4453 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0006142 infores:hetionet CHEBI:8059 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0016382 infores:hetionet CHEBI:75984 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0034069 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0022660 infores:hetionet UMLS:C0025241 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0232462 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233459 infores:hetionet CHEBI:7915 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C3665386 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151773 infores:hetionet CHEBI:9073 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0085631 infores:hetionet NCBIGene:128866 biolink:causes MONDO:0011547 infores:monarchinitiative not_provided not_provided HGNC:16171 MONDO:0011547 uuid:ca3c9a6f-ef52-4802-998b-6fb189efd7b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135888 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0004604 infores:hetionet CAID:CA114362 biolink:causes MONDO:0009861 infores:clingen CAID:CA114362 MONDO:0009861 PMID:22526846PMID:21871829PMID:26542770PMID:9399896PMID:17935162PMID:22526846PMID:2044609 Pathogenic PM5, PP4_Moderate, PP3, PM3_Very Strong, PS3 PM2 PAH-specific ACMG/AMP criteria applied: PM5: c.1240T>C likely pathogenic in ClinVar; PP3: All computational evidence supports deleterious effect. REVEL=0.982; PS3: 50% activity, 50% immunoreactivity (PMID:2044609); PM3_VeryStrong: Patient #41 p.R408W / p.Y414C, Phe 744 @dx and two homozygous individuals. Total of 9 patients with this variant (PMID:22526846; PMID:17935162; PMID:9399896; PMID:21871829; PMID:26542770); PP4_Moderate: BH4 defect excluded in all patients (PMID:22526846). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114362/MONDO:0009861/006 2018-07-27 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51164 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0009450 infores:hetionet CHEBI:8871 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030252 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0234215 infores:hetionet CHEBI:8028 biolink:causes HP:0000011 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0005697 infores:hetionet CAID:CA8603102 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603102 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the synonymous variant NM_000419.5(ITGA2B):c.1413C>T (p.Tyr471=), no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.0005513 (11/19954 alleles) based off the East Asian population, which does not meet threshold for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -1.38 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603102/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31932 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0040034 infores:hetionet CHEBI:71028 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0699744 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0426576 infores:hetionet CHEBI:35854 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0149745 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0948089 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0015929 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0015929 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0233494 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002962 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0023530 infores:hetionet NCBITaxon:5037 biolink:causes MONDO:0002099 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5037 MONDO:0002099 CHEBI:6062 biolink:causes MONDO:0006763 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0311223 infores:hetionet CHEBI:53691 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0031256 infores:hetionet CHEBI:127780 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085631 infores:hetionet CHEBI:85161 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0235266 infores:hetionet NCBIGene:2917 biolink:causes MONDO:0030063 infores:monarchinitiative not_provided not_provided HGNC:4599 MONDO:0030063 uuid:043b8623-6981-430d-a1ce-f08b20a5cbdd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5384 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0013144 infores:hetionet CHEBI:2379 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0035455 infores:hetionet CHEBI:101085 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0015672 infores:hetionet CHEBI:84500 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0522055 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0019521 infores:hetionet CAID:CA915940803 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940803 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000212.3(ITGB3):c.55dup (p.Ala19GlyfsTer?) is a frameshift variant in exon 1 predicted to cause a premature stop codon in biologically-relevant-exon 2/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Patient TGP0454, PMID:31064749, is reported to have a clinical diagnosis of GT type 1 and is homozygous for this variant (PM3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940803/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:31236 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152030 infores:hetionet CHEBI:66919 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0037274 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014038 infores:hetionet CHEBI:63622 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0917801 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0020557 infores:hetionet CHEBI:3994 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0030193 infores:hetionet CHEBI:63623 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0242429 infores:hetionet CHEBI:8863 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2047937 infores:hetionet CHEBI:72564 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0024902 infores:hetionet CHEBI:119573 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0041296 infores:hetionet CHEBI:5106 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0018681 infores:hetionet CHEBI:50378 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0023903 infores:hetionet CHEBI:50173 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C2830004 infores:hetionet CHEBI:50131 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0231856 infores:hetionet CHEBI:9667 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0235259 infores:hetionet CHEBI:194135 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0392163 infores:hetionet CHEBI:71028 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0018681 infores:hetionet CHEBI:42068 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0011175 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020175 infores:hetionet CHEBI:52172 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0014356 infores:hetionet CHEBI:6923 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0009450 infores:hetionet CHEBI:31236 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040822 infores:hetionet CHEBI:6456 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0085932 infores:hetionet NCBIGene:84842 biolink:causes MONDO:0033614 infores:monarchinitiative not_provided not_provided HGNC:28242 MONDO:0033614 uuid:ef245407-d503-403c-b242-26a921d393ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes MONDO:0009943 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0265294 infores:hetionet NCBIGene:8854 biolink:causes MONDO:0859571 infores:monarchinitiative not_provided not_provided HGNC:15472 MONDO:0859571 uuid:a3cf3891-373e-43e4-a5f2-95cfd8aad1d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31623 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0012833 infores:hetionet CHEBI:5165 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1510410 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0221185 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018799 infores:hetionet CHEBI:74947 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020473 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0040479 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1443060 infores:hetionet NCBIGene:4613 biolink:causes MONDO:0958279 infores:monarchinitiative not_provided not_provided HGNC:7559 MONDO:0958279 uuid:70eaac57-1d53-49d1-8cb5-347d7f4b2a71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085584 infores:hetionet NCBIGene:966 biolink:causes MONDO:0012858 infores:monarchinitiative not_provided not_provided HGNC:1689 MONDO:0012858 uuid:ca4c6ddc-67cf-4c37-9d8d-8145b1e5f627 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0032617 infores:hetionet CAID:CA913170150 biolink:causes MONDO:0044970 infores:clingen CAID:CA913170150 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PS3 The m.12335T>C variant in MT-TL2 has been reported in one individual with primary mitochondrial disease to date, however clinical details were not provided (PMID: 31965079). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (60.2 percentile) and HmtVAR predicts it to be neutral with a score of 0.05. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913170150/MONDO:0044970/015 2024-12-03 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:61049 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029877 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013395 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0948594 infores:hetionet CHEBI:9586 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0028734 infores:hetionet CHEBI:9757 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0030232 infores:hetionet CHEBI:4027 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0008031 infores:hetionet GO:2000367 biolink:causes GO:0007338 infores:ubergraph knowledge_assertion manual_agent GO:2000367 GO:0007338 CHEBI:8597 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0040264 infores:hetionet CAID:CA658824843 biolink:causes MONDO:0008723 infores:clingen CAID:CA658824843 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL);c.1283del(p.Lys428Argfs*2) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824843/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9445 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0016204 infores:hetionet CHEBI:135925 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0042963 infores:hetionet CHEBI:71940 biolink:causes NCIT:C96935 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0149707 infores:hetionet CHEBI:8214 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0547030 infores:hetionet CHEBI:9130 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C1443060 infores:hetionet CAID:CA397723611 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723611 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1_Moderate, PS1 PP2, PM4, PM5, BA1, BP1, BP4, BP3, BS1, BP7 The NM_000018.4(ACADVL):c.753-2A>G variant in ACADVL occurs within the canonical splice acceptor site (-2) of intron 8. It is predicted to cause skipping of biologically-relevant-exon 9/20, resulting in an in-frame deletion (removes amino acids Ser-His) that is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate; PMIDs 9973285, 11590124). However, a different nucleotide change at the same position within the canonical splice acceptor site of intron 8 [c.753-2A>C; ClinVar ID: 92290] is classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PS1). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PS1, PVS1_Moderate, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723611/MONDO:0008723/021 2023-05-23 2023-05-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68558 biolink:causes UMLS:C3160770 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C3160770 infores:hetionet CHEBI:8024 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018944 infores:hetionet CHEBI:131512 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0151699 infores:hetionet NCBIGene:2735 biolink:causes MONDO:0008269 infores:monarchinitiative not_provided not_provided HGNC:4317 MONDO:0008269 uuid:033e633f-8f2a-44bf-947d-656e8f3e4bc8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235431 infores:hetionet CHEBI:2950 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0035455 infores:hetionet CHEBI:17688 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0040460 infores:hetionet CHEBI:91541 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0018524 infores:hetionet CHEBI:17141 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0152459 infores:hetionet CHEBI:51032 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0033774 infores:hetionet CAID:CA10650684 biolink:causes MONDO:0100438 infores:clingen CAID:CA10650684 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate NM_014336.5(AIPL1):c.73C>A (p.Pro25Thr) is a missense variant replacing the proline at position p.25 with threonine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00001115, with 18 / 1614198 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.836, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). Additionally, the splicing impact predictor SpliceAI gives a score of 0.0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. There are no reports in the literature of this variant. In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3_moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650684/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5296 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0002792 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0040034 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0022408 infores:hetionet CHEBI:9086 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020621 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027707 infores:hetionet CHEBI:6129 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0010200 infores:hetionet CHEBI:7581 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0004093 infores:hetionet CHEBI:3219 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0012569 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0009450 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0149931 infores:hetionet NCBIGene:92482 biolink:causes MONDO:0014446 infores:monarchinitiative not_provided not_provided HGNC:28093 MONDO:0014446 uuid:cb2ae921-e3fa-4f01-b560-d725cde6c512 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50378 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0009450 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0025061 infores:hetionet CHEBI:119573 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0043094 infores:hetionet CHEBI:63580 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011124 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005665 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0376175 infores:hetionet CHEBI:5558 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0011991 infores:hetionet CHEBI:8888 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151744 infores:hetionet CHEBI:10124 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0018524 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0919980 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0856882 infores:hetionet CHEBI:144551 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042029 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0700184 infores:hetionet CAID:CA2499225881 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225881 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS4, PS3, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-7A>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.14) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225881/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6888 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0541820 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0002453 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0574067 infores:hetionet CHEBI:6520 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0029408 infores:hetionet CHEBI:6822 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0038325 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0027051 infores:hetionet CHEBI:161680 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0152031 infores:hetionet CHEBI:17303 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0023530 infores:hetionet CHEBI:3061 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C1142412 infores:hetionet CHEBI:47426 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1443060 infores:hetionet CHEBI:6887 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C2937358 infores:hetionet CHEBI:64019 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0004093 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0012833 infores:hetionet CHEBI:8805 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0687713 infores:hetionet CAID:CA023436 biolink:causes MONDO:0007750 infores:clingen CAID:CA023436 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Moderate, PM3, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1216C>A (p.Arg406=) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS3_Moderate, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1).PM3 - Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines.PS3_moderate - Level 2 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount.PP4 - Variant meets PM2. Variant identified in 2 index cases.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023436/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UMLS:C0120107 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151908 infores:hetionet CHEBI:15854 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0014742 infores:hetionet CHEBI:7465 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0027497 infores:hetionet UNII:5V9KLZ54CY biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0278134 infores:hetionet CHEBI:584020 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0004134 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004822 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006267 infores:hetionet CHEBI:8207 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0022568 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017605 infores:hetionet NCBIGene:4750 biolink:causes MONDO:0009894 infores:monarchinitiative not_provided not_provided HGNC:7744 MONDO:0009894 uuid:ea10a830-96ca-4a88-8775-4dea78088ff4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94411 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0344232 infores:hetionet UMLS:C0657912 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0231218 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0520532 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0520532 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0149904 infores:hetionet CHEBI:79699 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0003467 infores:hetionet CHEBI:38940 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151825 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0231365 infores:hetionet CHEBI:28925 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0037299 infores:hetionet CHEBI:50922 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0015672 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0404521 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0392525 infores:hetionet CHEBI:5123 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0344232 infores:hetionet CHEBI:63605 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0237849 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0021053 infores:hetionet CHEBI:8404 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0011615 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020580 infores:hetionet CHEBI:167638 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0013395 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0521490 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0024225 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0853149 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0010043 infores:hetionet CHEBI:119915 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231807 infores:hetionet GO:0021953 biolink:causes CL:2000029 infores:ubergraph knowledge_assertion manual_agent GO:0021953 CL:2000029 CHEBI:182080 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0018681 infores:hetionet CHEBI:78543 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0149871 infores:hetionet CHEBI:4798 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0221170 infores:hetionet CHEBI:6775 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0015672 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0011551 infores:hetionet CHEBI:6846 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0018965 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0009806 infores:hetionet CHEBI:2666 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0232462 infores:hetionet CHEBI:4708 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085593 infores:hetionet CHEBI:63580 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0404521 infores:hetionet CHEBI:72564 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085605 infores:hetionet CHEBI:32315 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002994 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0015397 infores:hetionet UMLS:C0145185 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0151799 infores:hetionet CHEBI:39867 biolink:causes MONDO:0008294 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0162565 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0009324 infores:hetionet CHEBI:6931 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0031542 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0041912 infores:hetionet CHEBI:9086 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151825 infores:hetionet CHEBI:59773 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0042023 infores:hetionet CAID:CA386966635 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966635 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting BP4, PS4, PM5, PP4, PP3, PP1 The c.865C>T variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 289 (p.(Pro289Ser)) of NM_000545.8. This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 6.9e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant has a REVEL score of 0.604, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In one of these individuals the MODY probability is unable to be calculated due to age of diagnosis over 35 and the other has a MODY probability less than 50%, so PP4 cannot be applied for either case. This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributors). Two other missense variants at the same residue, c.866C>A (p.Pro289His) and c.866C>G (p.Pro289Arg), have been classified as VUS by the ClinGen MDEP; therefore PM5 will not be applied. In summary, c.865C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966635/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA204980 biolink:causes MONDO:0021060 infores:clingen CAID:CA204980 MONDO:0021060 PMID: Likely Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4_Supporting, PS2 PP1, BP4, BA1, BS1, BS3 The NM_006767.4:c.850C>T variant in LZTR1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 284 (p.Arg284Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.801, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). This variant has been reported in 1 proband meeting NS diagnostic criteria (PS4_Supporting; PMID:25795793). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with Noonan syndrome (PS2; PMID:25795793). RAS, MEK, and ERK activation in HEK293T cells showed increased level of endogenous active, GTP-bound RAS and increased phosphorylation of MEK and ERK, indicating that this variant impacts protein function (PMID:30481304)(PS3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS3_Moderate, PS4_Supporting, PM2_Supporting, PP3. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA204980/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0010592 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027497 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C1167965 infores:hetionet CHEBI:50567 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0042510 infores:hetionet CAID:CA024459 biolink:causes MONDO:0100150 infores:clingen CAID:CA024459 MONDO:0100150 PMID: Uncertain Significance PP3 PM3, BA1, BP4, PS4, BS1, PM2 The c.4729G>A variant in RYR1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1577. The filtering allele frequency (the lower threshold of the 95% CI of 8/73780) of the c.4729G>A variant in RYR1 is 0.00006033 for African/African American chromosomes by gnomAD v4.1 (BA1, BS1, PM2 not met). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been reported in 2 probands with RYR1-related myopathy and has been detected in 1 individual with RYR1-related myopathy, compound heterozygous for the variant and a rare VUS, confirmed in trans by family testing (c.14818G>A (p.A4940T), SCV000852639.1). In summary, this variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy with multiple patterns of inheritance reported, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024459/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:57709 biolink:causes MONDO:0014323 infores:monarchinitiative not_provided not_provided HGNC:29326 MONDO:0014323 uuid:8c74c1fc-db51-4a60-9d9d-1e72de86b359 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1187 biolink:causes MONDO:0000909 infores:monarchinitiative not_provided not_provided HGNC:2026 MONDO:0000909 uuid:6456b5d4-16fc-4f8a-96ab-f6b0834e2c10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68647 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0014742 infores:hetionet CAID:CA512341212 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341212 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.1227C>G (p.Ala409=) variant is completely absent from all population databases with at least 20x coverage for RUNX1. REVEL score is not calculable for a synonymous variant; SpiceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.752969 < 2.0). In summary, using a Bayesian approach, this variant is classified as Likely Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341212/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:681569 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0162834 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0080276 infores:hetionet CHEBI:85161 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0085614 infores:hetionet CHEBI:9215 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0085593 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0041912 infores:hetionet CHEBI:52717 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0575081 infores:hetionet CHEBI:9434 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0239571 infores:hetionet NCBIGene:6144 biolink:causes MONDO:0014384 infores:monarchinitiative not_provided not_provided HGNC:10313 MONDO:0014384 uuid:161b3ad7-0808-4271-8cfb-e4cb21bc97dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0424000 infores:hetionet CHEBI:4909 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0004093 infores:hetionet CHEBI:291342 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0002994 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0019348 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0427108 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1167945 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1167945 infores:hetionet CHEBI:50841 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0008031 infores:hetionet CHEBI:63580 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0206062 infores:hetionet CHEBI:63612 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0151904 infores:hetionet NCBIGene:64423 biolink:causes MONDO:0013191 infores:monarchinitiative not_provided not_provided HGNC:23791 MONDO:0013191 uuid:61362f12-46f7-497b-aaad-b25edfc6ffec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0008325 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0152128 infores:hetionet CHEBI:4911 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0010200 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0243026 infores:hetionet CHEBI:408174 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C1527344 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0038663 infores:hetionet CHEBI:3996 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0043094 infores:hetionet CHEBI:8805 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0003811 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0852810 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0001122 infores:hetionet CAID:CA410204103 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204103 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.154A>G (p.Met52Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204103/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5383 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020433 infores:hetionet CHEBI:5778 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0017168 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0232492 infores:hetionet CHEBI:5384 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0009763 infores:hetionet CHEBI:64355 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232726 infores:hetionet CHEBI:50859 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085633 infores:hetionet CHEBI:50841 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0009806 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151626 infores:hetionet CAID:CA501019 biolink:causes MONDO:0021060 infores:clingen CAID:CA501019 MONDO:0021060 PMID: Uncertain Significance PS4_Supporting PM2, PP3, BP4, BA1, BS1 The NM_006767.4:c.1234C>T (p.Arg412Cys) variant in LZTR1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 412. Evidence supports that this variant is associated with AD NS and is not associated with AR NS. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003850 (1/25972 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.351, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:32981126). Schwannomatosis has not been observed in individuals harboring this variant. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS4_Supporting. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA501019/MONDO:0021060/094 2024-09-17 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0065374 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0006277 infores:hetionet CHEBI:4735 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0033687 infores:hetionet CHEBI:2666 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0018794 infores:hetionet CHEBI:28830 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0038325 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020295 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0038454 infores:hetionet CHEBI:63608 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0041657 infores:hetionet HP:0002591 biolink:causes MONDO:0011122 infores:drugmechdb knowledge_assertion manual_agent HP:0002591 MESH:D009765 DB00579_MESH_D009765_1 CHEBI:175901 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0018681 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027609 infores:hetionet CHEBI:77260 biolink:causes UMLS:C2242595 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C2242595 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0022660 infores:hetionet CHEBI:724125 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0013604 infores:hetionet CHEBI:47381 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013404 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0235431 infores:hetionet CAID:CA10385287 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385287 MONDO:0100437 PMID: Benign BP4_Strong, BA1 NM_001034853.2(RPGR):c.2411G>A (p.Arg804Lys) is a missense variant predicted to cause substitution of arginine by lysine at amino acid 804. This variant is present in gnomAD v4.1.0 at a frequency of 0.001070 among hemizygous individuals, with 334 variant alleles / 312,147 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.011, which is below the ClinGen X-linked IRD VCEP threshold of <0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385287/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CAID:CA10014161 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014161 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS3, PS4, BP4, PVS1, PM6, PM2, BP7, BS3, BS4, BS1, PM4, PM5, PM1, PP3, PP1 The NM_001754.4:c.*70T>C variant in the 3' UTR has an MAF of 0.099 (10%, 4129/41702 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 190 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014161/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6129 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022408 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948525 infores:hetionet CHEBI:8888 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039240 infores:hetionet CHEBI:8890 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C3160947 infores:hetionet CAID:CA179956 biolink:causes MONDO:0800472 infores:clingen CAID:CA179956 MONDO:0800472 PMID: Benign BA1, BP4 PP3, PP1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, BP7, PM2, PVS1 The c.-1-12C>T variant in CYP1B1 is a single nucleotide intronic variant. The highest minor allele frequency of this variant, in a genetic ancestry group of at least 2,000 alleles, was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.3684, which met the ≥ 0.05 threshold set for BA1 (33,401 alleles out of 90,674, meeting the threshold of ≥ 5 observed alleles). The SpliceAI score = 0.04, which met the ≤ 0.1 threshold for BP4. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1, BP4. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA179956/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5001 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0018099 infores:hetionet CHEBI:9599 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0231528 infores:hetionet UMLS:C0011701 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0039231 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0020517 infores:hetionet CHEBI:8871 biolink:causes HP:0034805 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0231710 infores:hetionet CHEBI:31236 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030252 infores:hetionet CHEBI:49960 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0018790 infores:hetionet CHEBI:8069 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0036974 infores:hetionet CHEBI:5106 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0020458 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014549 infores:hetionet CHEBI:3228 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0424295 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235146 infores:hetionet GO:1904020 biolink:causes GO:0002029 infores:ubergraph knowledge_assertion manual_agent GO:1904020 GO:0002029 CHEBI:28918 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0004936 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042769 infores:hetionet CHEBI:31236 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040264 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0265031 infores:hetionet CAID:CA412736938 biolink:causes MONDO:0100437 infores:clingen CAID:CA412736938 MONDO:0100437 PMID: Likely Benign BP4, BS1 PS4 NM_001034853.2(RPGR):c.1699A>T (p.Ile567Phe) is a missense variant encoding the substitution of isoleucine with phenylalanine at amino acid 567. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000005017 among hemizygous individuals, with 2 variant alleles / 398,644 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.132, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses (PMID: 23150612). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1 and BP4_Moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412736938/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:9566 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0015371 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0015230 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0019360 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0853117 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042075 infores:hetionet CHEBI:17334 biolink:causes UMLS:C1167750 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C1167750 infores:hetionet CHEBI:47426 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0013378 infores:hetionet CHEBI:38562 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0027497 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1565489 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0020457 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020457 infores:hetionet NCBIGene:22800 biolink:causes MONDO:0032839 infores:monarchinitiative not_provided not_provided HGNC:17271 MONDO:0032839 uuid:830ccd92-af2c-4bdb-82f5-d75590534252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0034155 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0234215 infores:hetionet CAID:CA244533124 biolink:causes MONDO:0015967 infores:clingen CAID:CA244533124 MONDO:0015967 PMID: Benign BP2, BS1, BS2, PP4 PS4, PM1, BP5, PM2, PP3 The c.871C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 291 (p.(Pro291Ala)) of NM_000545.8. This variant has a Grpmax filtering allele frequency of 0.000053 in gnomAD v4.1.0, which is above the ClinGen MDEP cutoff for BS1 (0.000033) (BS1). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant was identified in a patient with different HNF1A variant curated by MDEP as pathogenic (BP2; internal lab contributors). Additionally, this variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2; internal lab contributors). This variant has a REVEL score of 0.28, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.871C>G meets the criteria to be classified benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1, BS2, BP5, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244533124/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:404903 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0853761 infores:hetionet CHEBI:18258 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0031542 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0037290 infores:hetionet CHEBI:9150 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0239571 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0150450 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0038454 infores:hetionet NCBIGene:4359 biolink:causes MONDO:0020765 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0020765 uuid:8f1ada63-bb25-4e78-91b3-336c71ee2a96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020488 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0233494 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0000819 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0002902 infores:hetionet CHEBI:94807 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0023218 infores:hetionet CHEBI:46295 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0002994 infores:hetionet CHEBI:9943 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006384 infores:hetionet CHEBI:18357 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0008031 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0033860 infores:hetionet CHEBI:46557 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0000737 infores:hetionet CHEBI:100241 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038220 infores:hetionet CHEBI:64355 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235996 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0020456 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0340726 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0038454 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027051 infores:hetionet CHEBI:5134 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C3665347 infores:hetionet CHEBI:8888 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005778 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0033845 infores:hetionet CHEBI:68478 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029453 infores:hetionet CHEBI:9123 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011206 infores:hetionet CHEBI:6073 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0043352 infores:hetionet CHEBI:6375 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009676 infores:hetionet CHEBI:46295 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0004604 infores:hetionet CAID:CA343727113 biolink:causes MONDO:0020367 infores:clingen CAID:CA343727113 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PM2_Supporting BP7, BS1, BS3, PM6, PP3, PM5, PM4, PS4, PS1, PS3, PS2, BP4, BA1 The c.622G>T variant in MYOC is a missense variant predicted to cause substitution of Aspartate by Tyrosine at amino acid 208 (p.Asp208Tyr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.299, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 5 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 32945492), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 32945492), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343727113/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA414813690 biolink:causes MONDO:0044970 infores:clingen CAID:CA414813690 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS3, PM2 The m.12544A>G (p.T70A) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There are two occurrences in the GenBank sequences queried through MITOMAP on 6/29/2020 (1 individual from haplogroup U2e and 1 from L2a). In silico tools (APOGEE) predict this variant to be neutral (score of 0.39, BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414813690/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3756 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0435002 infores:hetionet CHEBI:3479 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151754 infores:hetionet CHEBI:8888 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0231528 infores:hetionet CHEBI:66876 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C1322281 infores:hetionet CHEBI:50156 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0041582 infores:hetionet NCBIGene:775 biolink:causes MONDO:0010979 infores:monarchinitiative not_provided not_provided HGNC:1390 MONDO:0010979 uuid:ea037c35-fd0a-4d15-ad98-9a868652e317 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0027497 infores:hetionet NCBIGene:7535 biolink:causes MONDO:0010023 infores:monarchinitiative not_provided not_provided HGNC:12858 MONDO:0010023 uuid:4aa8beca-9f19-4ece-a010-b920424811dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410147614 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147614 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1259G>A (p.Gly420Asp) is a missense variant. Multiple lines of computational evidence (REVEL: 0.238. Splice AI: Δ score 0.00) suggest no impact on gene /gene product. In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147614/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0065374 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042373 infores:hetionet CHEBI:6030 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0042384 infores:hetionet CAID:CA16020845 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020845 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 The NM_000277.3(PAH):c.703C>T (p.Gln235Ter) nonsense variant occurs in exon 6 of 13 and is predicted to result in NMD. It has been reported in one classic PKU patient (http://www.fedoa.unina.it/9088/1/TESI%20DOTTORATO%20ALESSIA%20PALMIERI.pdf) and is found at an extremely low allele frequency in gnomAD (MAF of 0.00006152 in the African/African-American population). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020845/MONDO:0009861/006 2020-12-08 2022-03-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51032 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0031350 infores:hetionet CHEBI:5558 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0009806 infores:hetionet CHEBI:8404 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0231530 infores:hetionet NCBIGene:57449 biolink:causes MONDO:0014154 infores:monarchinitiative not_provided not_provided HGNC:29105 MONDO:0014154 uuid:cf5158cc-56d1-470f-a39e-9edbaca51aa1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018834 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0022104 infores:hetionet NCBIGene:388753 biolink:causes MONDO:0014668 infores:monarchinitiative not_provided not_provided HGNC:18025 MONDO:0014668 uuid:082b4d2d-1ae6-4cd4-bdb8-cc78468ff83d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0020538 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042373 infores:hetionet CHEBI:251408 biolink:causes GO:0030432 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0031133 infores:hetionet CHEBI:3181 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0235031 infores:hetionet CHEBI:68595 biolink:causes UMLS:C1565662 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C1565662 infores:hetionet CHEBI:61033 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0015672 infores:hetionet CHEBI:16469 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0234238 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027051 infores:hetionet CHEBI:6339 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037278 infores:hetionet CHEBI:100241 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042024 infores:hetionet CHEBI:5790 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0027441 infores:hetionet CHEBI:6916 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0038325 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0151763 infores:hetionet CHEBI:39867 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042384 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0272426 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0272426 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0007642 infores:hetionet CHEBI:46295 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0017168 infores:hetionet CAID:CA7331488 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331488 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, BA1, PS1, PS3, PS4, BS1, BS3 The NM_177438.3:c.1381A>T variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by leucine at amino acid 461 (p.Ile461Leu). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1613764 alleles) with a highest population minor allele frequency of 0.0001114 (5/44872 alleles) in the East Asian population and with multiple alleles present in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.282: MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331488/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16755 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0037274 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0025061 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0240515 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0004096 infores:hetionet NCBIGene:11315 biolink:causes MONDO:0011658 infores:monarchinitiative not_provided not_provided HGNC:16369 MONDO:0011658 uuid:9c9aed3e-561c-47f7-984f-b924c17ba18d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134745 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0016204 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0018802 infores:hetionet CHEBI:100246 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0002792 infores:hetionet NCBIGene:6535 biolink:causes MONDO:0010305 infores:monarchinitiative not_provided not_provided HGNC:11055 MONDO:0010305 uuid:e76d073b-9abf-42e3-afc2-6aae56b290fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA214587 biolink:causes MONDO:0100062 infores:clingen CAID:CA214587 MONDO:0100062 PMID: Benign BA1, BP4 PS2, PM6 The c.3250G>A variant in SCN3A is a missense variant predicted to cause the subsitution of valine by isoleucine at amino acid 1084 (p.Val1084Ile). The variant is present in 0.5% of the total population, and 0.7% of the European (non-Finnish) population, in gnomAD v2.1.1, which exceeds the threshold of 0.01% for BA1. The in silico predictor REVEL score for this variant is 0.155 which meets the criteria for BP4_Moderate. The variant has not been reported in an individual with developmental and epileptic encepathalopathy in the reported literature to date, and does not fall within a pathogenic enriched region. In summary, this variant meets the criteria to be classified as benign for autosomal dominant developmental and epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4_Moderate (specification v1.0; approved 6/27/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA214587/MONDO:0100062/069 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50131 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C2047937 infores:hetionet NCBITaxon:810 biolink:causes MONDO:0000918 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:810 MESH:D004716 DB01059_MESH_D004716_1 CHEBI:41879 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0027765 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235886 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004892 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0034951 infores:hetionet CHEBI:7640 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0036974 infores:hetionet CHEBI:7496 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C2047937 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0041912 infores:hetionet CHEBI:4798 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0015672 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005810 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0021345 infores:hetionet CHEBI:46557 biolink:causes MONDO:0018373 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027543 infores:hetionet CHEBI:94449 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0018790 infores:hetionet CHEBI:6950 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1760428 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0037274 infores:hetionet CHEBI:85083 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0030312 infores:hetionet CHEBI:6923 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0221776 infores:hetionet GO:1905137 biolink:causes GO:0019068 infores:ubergraph knowledge_assertion manual_agent GO:1905137 GO:0019068 CHEBI:2948 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1266194 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0276680 infores:hetionet CHEBI:75722 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0025222 infores:hetionet CHEBI:83527 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0002170 infores:hetionet CHEBI:2549 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1443060 infores:hetionet CHEBI:8502 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0042109 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007286 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0750016 infores:hetionet CAID:CA267673 biolink:causes MONDO:0009861 infores:clingen CAID:CA267673 MONDO:0009861 PMID:23430918PMID:26666653PMID:23430918 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.796A>C (p.Thr266Pro) variant in PAH is reported in 1 classic PKU patient with BH4 deficiency excluded. (PMID: 26666653, 23430918) It was detected with p.V190A, which is interpreted as pathogenic by our PAH VCEP. (PMID: 23430918) This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen-2, MutationTaster, and REVEL=0.98. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267673/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4858 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0030193 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0235431 infores:hetionet GO:1905651 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1905651 GO:0072359 CHEBI:61049 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020639 infores:hetionet CHEBI:16347 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0027497 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0149904 infores:hetionet CAID:CA410203786 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203786 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.257C>T (p.Pro86Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The variant has been published in a patient with AML M0 as a potentially homozygous variant (PMID: 17485549) and in a 73-year-old male with CMML along with R135S (PMID: 20421268), but germline origin is unclear for both cases; it was also detected in a patient with personal and family history of early-onset breast cancer (MSK-IMPACT at Memorial Sloan Kettering Cancer Center). It is not located at a hotspot or critical region of the Runt Homology Domain. The REVEL score is 0.854 and there is no splicing impact per SpliceAI. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203786/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes UMLS:C0348801 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0348801 infores:hetionet CAID:CA270169359 biolink:causes MONDO:0012996 infores:clingen CAID:CA270169359 MONDO:0012996 PMID:27233232 Uncertain Significance PM2_Supporting, BP4, PS3_Supporting The NM_001482.3:c.314C>T variant in GATM is a missense variant that is predicted to result in the substitution of proline by leucine and amino acid position 105 (p.Pro105Leu). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. It is absent in gnomAD v4.1.0. (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in 0.6% wild-type activity (PMID: 27233232; ClinVar Variation ID: 225913 - see Germline Functional Evidence section) which is below the threshold of the CCDS VCEP of <15% wild-type activity, indicating the the variant may impact the function of the protein (PS3_Supporting). The computational predictor REVEL gives a score of 0.066 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 225913). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA270169359/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9137 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0043387 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235431 infores:hetionet CHEBI:48273 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0020453 infores:hetionet CAID:CA033088 biolink:causes MONDO:0007750 infores:clingen CAID:CA033088 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006164 (0.006%) in African/African American (gnomAD v2.1.1). PM5 - Two other missense variants described in the same codon (accessed 19 August 2020): --- 1 variant classified as Pathogenic by these guidelines.PP3 - REVEL: 0,809. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling Simon-Broome criteria.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (PMID: 10882754 - 1 case with Simon-Broome criteria; PMID: 17094996 - 1 case with Simon-Broome criteria). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033088/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:253342 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0008325 infores:hetionet CHEBI:9137 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0000737 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0178298 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042514 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0042109 infores:hetionet CHEBI:5280 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0010043 infores:hetionet CHEBI:6456 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0004604 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001617 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0338591 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0043037 infores:hetionet NCBIGene:83449 biolink:causes MONDO:0020852 infores:monarchinitiative not_provided not_provided HGNC:17728 MONDO:0020852 uuid:46b7ffc0-2788-4b75-97ec-9a0bbb282b09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0086168 infores:hetionet CHEBI:2682 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0016382 infores:hetionet NCBITaxon:35792 biolink:causes MONDO:0000234 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:35792 MONDO:0000234 UMLS:C1738934 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0270996 infores:hetionet CHEBI:48844 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0022346 infores:hetionet CHEBI:7476 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0522055 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0858797 infores:hetionet CHEBI:125354 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0948594 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0018944 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0020651 infores:hetionet UMLS:C0657912 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030232 infores:hetionet CHEBI:35553 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0041657 infores:hetionet CHEBI:7478 biolink:causes UMLS:C2349423 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2349423 infores:hetionet GO:1904967 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1904967 GO:0019953 CHEBI:8802 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0032326 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0014742 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0021390 infores:hetionet CAID:CA291225782 biolink:causes MONDO:0100326 infores:clingen CAID:CA291225782 MONDO:0100326 PMID: Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting, PS3 PM5 The NM_000212.3:c.1639T>G variant in ITGB3 is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 547 (p.Cys547Gly). This is a critical cysteine residues for regulation of integrin alphaIIbbeta3 (PMID: 14690453). This variant has been observed in compound heterozygosity in one individual (Patient 3 in PMID: 28748566) in combination with ITGB3 variant c.1192delG (p.Ala398ProfsTer24, provisionally classified as pathogenic by the Platelet Disorders VCEP, trans phase not confirmed). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). An additional patient reported in DOI: 10.26502/acmcr.96550268 is compound heterozygous for this variant and the ITGB3 variant c.1552C>T (p.Gln518Ter), classified as pathogenic by the Platelet Disorders VCEP, trans phase confirmed (PM3). The highest population minor allele frequency in gnomAD v4.1 is 0.00001610 (19/1179874 alleles) in the non-Finnish European population, which is lower than the ClinGen Platelet Disorders VCEP threshold (<0.0001; PM2_Supporting). Surface expression of β3 and αIIbβ3 measured by Western blot and flow cytometry (respectively) in HEK293 cells transiently co-transfected with p.Cys547Gly variant β3 and wild type αIIb showed decreased expression at <5%, indicating that this variant impacts protein function (PMID: 25827233) (PS3). Furthermore, the computational predictor REVEL gives a score of 0.993, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PM2_Supporting, PM3, PP3, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291225782/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50924 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0426576 infores:hetionet CHEBI:66876 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0376358 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0012833 infores:hetionet CHEBI:27666 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0005779 infores:hetionet CHEBI:3614 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0149745 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085682 infores:hetionet GO:1900157 biolink:causes GO:0043931 infores:ubergraph knowledge_assertion manual_agent GO:1900157 GO:0043931 CHEBI:2611 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0948594 infores:hetionet CHEBI:188986 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0392163 infores:hetionet CHEBI:9435 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0001807 infores:hetionet CHEBI:53766 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0017178 infores:hetionet NCBIGene:10599 biolink:causes MONDO:0009379 infores:monarchinitiative not_provided not_provided HGNC:10959 MONDO:0009379 uuid:180fc590-4c16-45c6-a952-c4910a20f68b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127342 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0016204 infores:hetionet CHEBI:135939 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0027497 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151828 infores:hetionet CHEBI:127342 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0917801 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0037199 infores:hetionet CAID:CA2739267608 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267608 MONDO:0011071 PMID:34166225PMID:34166225 Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.696dup (p.Arg233AlafsTer28) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This frameshift variant is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267608/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38940 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0002170 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011849 infores:hetionet GO:2000061 biolink:causes GO:0072191 infores:ubergraph knowledge_assertion manual_agent GO:2000061 GO:0072191 CHEBI:135736 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009319 infores:hetionet CHEBI:49575 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0086565 infores:hetionet CHEBI:131512 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0042024 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0037274 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0019158 infores:hetionet CHEBI:83531 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0042963 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0235169 infores:hetionet NCBIGene:26040 biolink:causes MONDO:0010010 infores:monarchinitiative not_provided not_provided HGNC:15573 MONDO:0010010 uuid:a506d37f-3407-4a35-9104-f136bc1c36d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0015230 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0162429 infores:hetionet CAID:CA404093213 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093213 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, BP5, BP7, BS1, BS3, BS4, PM4, PM5, PM3, PM1, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1961T>C (p.Leu654Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL = 0.911. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill modified DLCN criteria >=6 from Setia et al., 2020 (PMID 32044282). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093213/MONDO:0007750/013 2024-10-28 2025-01-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:37333 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0039231 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0006277 infores:hetionet CHEBI:7773 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0152198 infores:hetionet CHEBI:6888 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0085633 infores:hetionet CAID:CA637749748 biolink:causes MONDO:0011071 infores:clingen CAID:CA637749748 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP2, BP1, BP3, PM2, PM6, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.58+15G>A is an intronic variant which has not been featured in functional or case studies. Computational data have been used to evaluate this variant. It has a SpliceAI score of 0.03 and a PhyloP score of -0.30, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637749748/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3423 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0442874 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0235807 infores:hetionet CHEBI:144093 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0085605 infores:hetionet NCBIGene:6598 biolink:causes MONDO:0012252 infores:monarchinitiative not_provided not_provided HGNC:11103 MONDO:0012252 uuid:f6b1915d-e848-4653-99f4-c62df0525646 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2379 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0022281 infores:hetionet NCBIGene:56521 biolink:causes MONDO:0044304 infores:monarchinitiative not_provided not_provided HGNC:28908 MONDO:0044304 uuid:3f39d633-4100-4b1c-8b41-ddc168c334fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes UMLS:C1704381 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1704381 infores:hetionet CHEBI:6950 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018800 infores:hetionet CHEBI:6754 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0013144 infores:hetionet CHEBI:9150 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0014742 infores:hetionet CHEBI:10110 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0423791 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151763 infores:hetionet CHEBI:28148 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0234233 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0034150 infores:hetionet GO:0021914 biolink:causes GO:0021513 infores:ubergraph knowledge_assertion manual_agent GO:0021914 GO:0021513 CHEBI:6717 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0034150 infores:hetionet NCBIGene:54112 biolink:causes MONDO:0014839 infores:monarchinitiative not_provided not_provided HGNC:4539 MONDO:0014839 uuid:24f47592-ce48-441e-9487-5eff55e81b90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0239488 infores:hetionet CHEBI:15640 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0041834 infores:hetionet CHEBI:64355 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0001925 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027430 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0399459 infores:hetionet CHEBI:45409 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151766 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0002871 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0006939 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D011704 DB01137_MESH_D011704_2DB01059_MESH_D011704_1DB01165_MESH_D011704_1DB06211_MESH_D011704_1DB09060_MESH_D011704_1DB01137_MESH_D011704_1 UMLS:C0657912 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0001122 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0031542 infores:hetionet CHEBI:5118 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0236075 infores:hetionet CAID:CA033001 biolink:causes MONDO:0007750 infores:clingen CAID:CA033001 MONDO:0007750 PMID: Likely Benign BP4, BP7, BS1 The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows:BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1).BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.Variant is not located within the limits of canonical splicing sitesVariant is exonic and at least 50bp upstream from canonical donor site but does not creates AGThere is no AG NearbyVariant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033001/MONDO:0007750/013 2022-07-22 2024-12-02 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA9871496 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871496 MONDO:0007064 PMID: Pathogenic PVS1_Strong, PP4_Moderate, PM2_Supporting, PM3_Strong PM5 The c.845G>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 282 (p.Arg282Gln). This variant is considered in the PVS1 criteria based on experimental evidence indicating that it has the effect of affecting the splicing site. In line with the predictions of splicing algorithms, experimental validation (from Dr. Mike Hershfield - Internal Communication) has established that the variant occurs at the splice junction between exon 9 and intron 10 and has been shown to cause aberrant splicing in peripheral blood leukocytes (PBL) of a female Arab patient with ADA-SCID. Based on this, we classify PVS1 at a Strong level, as it results in the loss of more than 10% of the protein, and other pathogenic variants have already been described downstream (e.g., NM_000022.4(ADA):c.870C>A (p.Tyr290Ter), Pathogenic according to SCID VCEP specifications).The highest population minor allele frequency in gnomAD v4 is 0.000005310 (12/1180048 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). PMID: 19830125: 14-month-old Arab boy: Family history of SCID 0.5pts + T-B-NK- profile 0.5pts + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + Reduced ADA enzyme activity 1pt, total=2.5 pts, PP4_Moderate. PMID: 32307643, Patients 3 and 25, both are homozygous, reaching the maximum of 1 point for homozygous occurrence. From the same report, patient 2: Compound heterozygous,c.221G>T, p.G74V, Likely Pathogenic according to SCID VCEP specifications; 1 point. Total 2 points, PM3_Strong.In summary, this variant meets the criteria to be classified as Pathogenic for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1_Strong, PM2_Supporting, PP4_Moderate, and PM3_Strong. (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871496/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3515 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0851341 infores:hetionet CHEBI:2904 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C2363730 infores:hetionet CAID:CA367399913 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399913 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.952G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 318 (p.(Gly318Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.855, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthemore, this variant was identified in over 40 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 28663157, 31416898, 31595705, 32375122, 34440516, 34496959, 36257325, 36400171, 37812285, 12627330, 22332836, 26552609, 26641800, 35472491, and 36208343). This variant segregated with hyperglycemia with at least 17 informative meioses in multiple families (PP1_Strong; PMIDs: 31595705, 34440516, 36257325). Additionally, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3mmol/L) (PP4_Moderate; PMID: 31416898). In summary, c.952G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399913/MONDO:0015967/086 2025-01-16 2025-01-29 Semidominant inheritance HP:0032113 Supports UMLS:C0145867 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0600228 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0031542 infores:hetionet CHEBI:31236 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007398 infores:hetionet CHEBI:9168 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034186 infores:hetionet CHEBI:6931 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0018524 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0020517 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0027769 infores:hetionet CHEBI:3219 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019294 infores:hetionet CHEBI:31711 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0030554 infores:hetionet CHEBI:8232 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151594 infores:hetionet CHEBI:6715 biolink:causes NCIT:C127841 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0476427 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0012813 infores:hetionet CAID:CA8422996 biolink:causes MONDO:0019497 infores:clingen CAID:CA8422996 MONDO:0019497 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting The allele frequency of the c.996C>G (p.Tyr332Ter) variant in the MYO15A gene is 0.004% (50/1179998) of European non-Finnish alleles by gnomAD v4.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The p.Tyr332Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 2/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). One proband with SNHL with a loss of function pathogenic variant but without parent testing was found in LMM internal data (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PVS1, PM3_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 7/23/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8422996/MONDO:0019497/023 2024-07-23 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:51041 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0023890 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020621 infores:hetionet CHEBI:63621 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0392525 infores:hetionet CAID:CA229603 biolink:causes MONDO:0009861 infores:clingen CAID:CA229603 MONDO:0009861 PMID:18299955 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 "PAH-specific ACMG/AMP criteria applied: PM2: Not found in any population databases; PP3: All predictors agree--damaging; PM3: Single patient IVS4+5G>T (null) / I174V (Bercovich 2008 PMID 18299955) (PMID:18299955); PP4: Two independent patients (one in Zschocke (PMID 10394930) and one in Bercovich (PMID 18299955) with ""PKU"". While no specific levels are mentioned, they are followed in clinic and were diagnosed with Phe >120umol/L. BH4 defect WAS NOT excluded in either paper.. In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3, PP4)." Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229603/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38545 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0002622 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011615 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0271650 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0037290 infores:hetionet NCBIGene:5689 biolink:causes MONDO:0859287 infores:monarchinitiative not_provided not_provided HGNC:9537 MONDO:0859287 uuid:3ee98bd1-2978-4c91-8edb-d5e00ac06ac2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5132 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0085649 infores:hetionet CHEBI:64312 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013447 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002878 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0234215 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0041912 infores:hetionet CAID:CA16043530 biolink:causes MONDO:0100326 infores:clingen CAID:CA16043530 MONDO:0100326 PMID: Likely Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting "The c.749A>G variant in ITGB3 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 250. The variant has been reported in at least one patient (Glanzmann Patient, ""HEMOSTAZA SKOZI KLINIČNE PRIMERE"" August 2022) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This individual is compound heterozygous for this variant and pathogenic variant c.1699C>T (p.Gln567Ter) (PM3). The variant is absent from gnomADv4.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.988, which is above the ClinGen PD VCEP PP3 threshold of >0.7 and predicts a damaging effect on ITGB3 function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3, PP4_moderate, and PM3. (VCEP specifications version 2.1)" Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043530/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:480999 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1262013 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0277589 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0277589 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235573 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235573 infores:hetionet CHEBI:68554 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0012569 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151828 infores:hetionet CHEBI:72564 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C2047937 infores:hetionet CHEBI:6437 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0015672 infores:hetionet CHEBI:5778 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0264886 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0314719 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151736 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027769 infores:hetionet CHEBI:17026 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0022107 infores:hetionet CAID:CA10601917 biolink:causes MONDO:0700268 infores:clingen CAID:CA10601917 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.121C>A variant in BRCA1 is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 41 (p.His41Asn). Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMID:30209399, 35659930) (PS3 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.32, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold ≤0.1) (PP3 met).In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PM2_Supporting, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10601917/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50838 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0007785 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0595939 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0037036 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151539 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151311 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0235222 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0235222 infores:hetionet CHEBI:31705 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0005779 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948594 infores:hetionet CHEBI:28001 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0042384 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009782 infores:hetionet CHEBI:10127 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0494475 infores:hetionet CHEBI:51364 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0030252 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0520893 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0004238 infores:hetionet NCBIGene:25782 biolink:causes MONDO:8000008 infores:monarchinitiative not_provided not_provided HGNC:17168 MONDO:8000008 uuid:3a7879da-6c65-41d7-8642-a293d67d4ed1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0259749 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0023418 infores:hetionet CHEBI:28001 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0027947 infores:hetionet CHEBI:15407 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C1456784 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0234936 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042134 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0038367 infores:hetionet CHEBI:3215 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0392699 infores:hetionet NCBIGene:7528 biolink:causes MONDO:0044738 infores:monarchinitiative not_provided not_provided HGNC:12856 MONDO:0044738 uuid:9114d56d-a4aa-4620-9546-6808542025e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0002418 infores:hetionet UNII:R43D2573WO biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0558489 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0021359 infores:hetionet CHEBI:61033 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0030193 infores:hetionet CHEBI:31302 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0013395 infores:hetionet CHEBI:119486 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0344232 infores:hetionet CAID:CA8130334 biolink:causes MONDO:0007648 infores:clingen CAID:CA8130334 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM1, PM4, PM5, PP4, PP2, PP3, PP1, BS2, BP3, BP1, BP4, PS2, PS3, PS4, PS1 The NM_004360.5(CDH1):c.*774A>G variant has an allele frequency of 0.01471 (1.471%, 328/22292 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8130334/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:43968 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0546817 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0024117 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0042109 infores:hetionet CHEBI:16899 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0010200 infores:hetionet CHEBI:3696 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0004134 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0399459 infores:hetionet CHEBI:83804 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0004093 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0438142 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0009806 infores:hetionet CAID:CA2573130154 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573130154 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM4_Supporting, PS3_Supporting, PP4_Moderate PS4 The c.380_382del variant in the HNF1 homeobox A gene, HNF1A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 127 (p.(Asn127del)) within exon two of NM_000545.8. The c.380_382del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Functional studies have also demonstrated the p.Asn127del protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 12530534). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.380_382del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, Approved 9/30/21): PP4_Moderate, PM1_Supporting, PM2_Supporting, PM4_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573130154/MONDO:0015967/017 2022-06-15 2022-06-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38940 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0149745 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0004936 infores:hetionet CHEBI:42797 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037763 infores:hetionet CHEBI:27732 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0151908 infores:hetionet CHEBI:178699 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0032285 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0235416 infores:hetionet CHEBI:8802 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0034063 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038661 infores:hetionet CAID:CA913184978 biolink:causes MONDO:0009861 infores:clingen CAID:CA913184978 MONDO:0009861 PMID:25863075PMID:23271928 Pathogenic PVS1, PP4_Moderate, PM2 The c.189_190dupTGAC variant in PAH has been previously reported as a single heterozygous variant in a 2.5 year old Chinese proband with PKU, with a second mutation not detected; exact plasma Phe levels were not given, but said to be >20mg/dL and BH4 deficiency was formally excluded by urinary pterin analysis and blood neopterin dihydropteridine reductase assays (PMID: 23271928; PMID: 25863075) (PP4_Moderate).The variant is a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184978/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63580 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0267792 infores:hetionet CHEBI:474053 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0404521 infores:hetionet CHEBI:585948 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0016204 infores:hetionet CHEBI:68595 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0015230 infores:hetionet CHEBI:6954 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0013384 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085622 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1609496 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1609496 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0240972 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0240972 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0020538 infores:hetionet CHEBI:31401 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0014591 infores:hetionet CHEBI:7465 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1456784 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0013395 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042373 infores:hetionet CHEBI:31302 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0016658 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0032290 infores:hetionet CHEBI:8378 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0151692 infores:hetionet NCBIGene:1053 biolink:causes MONDO:0009842 infores:monarchinitiative not_provided not_provided HGNC:1836 MONDO:0009842 uuid:5ee88f0b-2492-43cc-bb6e-b79091472c40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0016199 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0021053 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0234215 infores:hetionet CHEBI:65173 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0025874 infores:hetionet CHEBI:50648 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085636 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018991 infores:hetionet CHEBI:7823 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0012833 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0021400 infores:hetionet CHEBI:3312 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0003811 infores:hetionet CHEBI:3723 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016382 infores:hetionet CHEBI:9445 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0000737 infores:hetionet CAID:CA512318600 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318600 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP3, BP1, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.735C>G (p.Pro245=) is a synonymous variant. This is a synonymous variant. There is no REVEL score. SpliceAI was <0.20 (Donor Loss score of 0.02 at 24 bp) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318600/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31859 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0149745 infores:hetionet CHEBI:75722 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085682 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0018500 infores:hetionet CHEBI:2663 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0013604 infores:hetionet CHEBI:127342 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1443060 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0162627 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0009450 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233414 infores:hetionet NCBIGene:54795 biolink:causes MONDO:0011474 infores:monarchinitiative not_provided not_provided HGNC:17993 MONDO:0011474 uuid:a339ea5a-c6ae-4562-981e-aef8c0729098 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0424790 infores:hetionet CHEBI:17263 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0234233 infores:hetionet CAID:CA023681 biolink:causes MONDO:0007750 infores:clingen CAID:CA023681 MONDO:0007750 PMID:11389828PMID:11389828 Likely Pathogenic PS4, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, BS2 NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria published in PMID: 7573037.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP3 - REVEL: 0,939. PP4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria for FH published in PMID: 7573037. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023681/MONDO:0007750/013 2021-06-22 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7865 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0549249 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022408 infores:hetionet CAID:CA415085315 biolink:causes MONDO:0010305 infores:clingen CAID:CA415085315 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting The NM_005629.4:c.1048G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a glycine by arginine at amino acid position 350 (p.Gly350Arg). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.824 (PP3), which is higher than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) suggesting that this variant impacts the function of the creatine transporter (PP3). To our knowledge, this variant has not been reported in the literature in an individual with creatine transporter deficiency. There is a ClinVar entry for this variant (Variation ID: 1429635). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP3, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415085315/MONDO:0010305/027 2025-03-18 2025-03-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:9332 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0178298 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042075 infores:hetionet CHEBI:64321 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0013362 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0234215 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027932 infores:hetionet CHEBI:8768 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020578 infores:hetionet CHEBI:9667 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0020458 infores:hetionet CHEBI:10102 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1328337 infores:hetionet CHEBI:585948 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0013404 infores:hetionet NCBIGene:5167 biolink:causes MONDO:0014227 infores:monarchinitiative not_provided not_provided HGNC:3356 MONDO:0014227 uuid:deaeecca-f2e0-4a65-93d9-8efee78df4bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0017178 infores:hetionet NCBIGene:23193 biolink:causes MONDO:0010916 infores:monarchinitiative not_provided not_provided HGNC:4138 MONDO:0010916 uuid:bee2f1d2-0cc8-4605-86f4-0c27697e911a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0853193 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0011240 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0011240 uuid:8431e394-de1f-44d3-bef8-a62cd68efa9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C1384353 infores:hetionet NCBIGene:5339 biolink:causes MONDO:0013390 infores:monarchinitiative not_provided not_provided HGNC:9069 MONDO:0013390 uuid:af7ba6cc-fb48-4d28-adcf-d8d9f7591234 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:1280 biolink:causes MONDO:0005898 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D010304 DB02703_MESH_D010304_1DB00798_MESH_D010304_1 CAID:CA000383 biolink:causes MONDO:0017623 infores:clingen CAID:CA000383 MONDO:0017623 PMID:21659347PMID:25669429PMID:20600018PMID:21194675PMID:28526761PMID:29706350PMID:21828076 Pathogenic PM6, PM2, PP2, PS4_Supporting, PS3 PVS1, BS4, BS3, BS1, BP5, BP7, PP1, PP3, BS2, PM1, PM5, PM4, BP2, BP4, BA1, PS1, PS2 PTEN c.284C>T (p.Pro95Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076, PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000383/MONDO:0017623/003 2019-06-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5280 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0014236 infores:hetionet CHEBI:119486 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0013378 infores:hetionet CAID:CA16608976 biolink:causes MONDO:0010315 infores:clingen CAID:CA16608976 MONDO:0010315 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS4 NM_000206.3(IL2RG):c.202G>A is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 68 (p.Glu68Lys). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.), Absent CD132 expression (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :3.5 pts PMID: 30778343 (PP4_moderate). This variant is found in multiple unrelated affected probands (total pts. >16) (PS4_very strong) (PMIDs: 9058718, 24534054,11129345, 32477911,31456805, 27484032,31031743,30778343).As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 Very Strong,1 Moderate and 1 Supporting criteria results in a Pathogenic classification. In summary, this variant meets the criteria to be classified as Pathogenic for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PP4_moderate,PS4_very strong (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608976/MONDO:0010315/129 2024-01-31 2024-01-31 X-linked inheritance HP:0001417 Supports CHEBI:9332 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0042075 infores:hetionet CAID:CA034080 biolink:causes MONDO:0007750 infores:clingen CAID:CA034080 MONDO:0007750 PMID: Likely Benign BP4, BP7, PM2 The NM_000527.5(LDLR):c.1383C>T (p.Gly461=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001157 (0.01157%) in the Latino-admixed population exomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required: A) not on limits B) does not create GT. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. This variant has two supporting strength evidence codes towards Benign, enough to classify as Likely Benign, and only one moderate strength evidence code towards Pathogenic. VCEP consensus is that PM2 is not strong enough evidence to upgrade the classification of an otherwise Benign or Likely Benign variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034080/MONDO:0007750/013 2024-07-02 2024-09-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UNII:G4PX8C4HKV biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0015397 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1527344 infores:hetionet CHEBI:8768 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0424295 infores:hetionet CHEBI:6846 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0027497 infores:hetionet CHEBI:144551 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018520 infores:hetionet CAID:CA023426 biolink:causes MONDO:0007750 infores:clingen CAID:CA023426 MONDO:0007750 PMID: Benign BA1, BP4, BP2, BS2 BP1, BP3, PS3, PS4, PS2, PS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PVS1, PM2, PM6, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5%BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals.BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype.BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023426/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4779 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0004093 infores:hetionet CHEBI:28748 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0231528 infores:hetionet CHEBI:32315 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0000768 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0022658 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022650 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0542149 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0347390 infores:hetionet CHEBI:29007 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0595916 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015397 infores:hetionet CAID:CA405635960 biolink:causes MONDO:0007783 infores:clingen CAID:CA405635960 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with asparagine at codon 1056 of the RYR1 protein, p.Asp1056Asn. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:20681998). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.685 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405635960/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:5010 biolink:causes MONDO:0025701 infores:monarchinitiative not_provided not_provided HGNC:8514 MONDO:0025701 uuid:5c791de4-cbd5-41bf-ba6f-9eaa73c2a973 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0038362 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020649 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042514 infores:hetionet CHEBI:50730 biolink:causes MONDO:0015943 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0008728 infores:hetionet CHEBI:8772 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0008350 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0015397 infores:hetionet CHEBI:135351 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C2047937 infores:hetionet CAID:CA658824065 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824065 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, PVS1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.-19G>A is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEl score not applicable and SpliceAI is ≤0.20 (0.02) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.31 < 2.0) (BP7).In summary, the clinical significance of this variant is Likely Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824065/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA401369553 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369553 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PM5_Supporting PS3 The NM_000152.5:c.1831G>A variant in GAA is a missense variant predicted to cause substitution of glycine by serine at amino acid 611 (p.Gly611Ser). This variant has been detected in at least 2 individuals with Pompe disease (PMIDs: 34020684, 33073003; Clinical diagnostic Laboratory data). Of those individuals, at least 1 was compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, confirmed in trans by parental testing (PMID: 34020684, and clinical diagnostic laboratory data, unclear if this is the same individual) (PM3). At least 2 patients with this variant had documented GAA deficiency with activity in the affected range in lymphocytes, whole blood or dried blood spot (PMID: 33073003, 34020684, clinical diagnostic laboratory data) (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34334 alleles) in the Latino/Admixed American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.767 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1832G>A, p.Gly611Asp) (ClinVar Variation ID: : 371226) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 935199, 1 star review status) with 1 submitter classifying the variant as likely pathogenic and one as a VUS. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369553/MONDO:0009290/010 2022-09-06 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7936 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0232462 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0232492 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151878 infores:hetionet CHEBI:5864 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002390 infores:hetionet CAID:CA10585126 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585126 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.770G>T (p.Arg257Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585126/MONDO:0007750/013 2022-08-29 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:61033 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0600142 infores:hetionet CHEBI:64312 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0026826 infores:hetionet CHEBI:3048 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0080274 infores:hetionet CHEBI:51860 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0086769 infores:hetionet CHEBI:15640 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0038362 infores:hetionet CHEBI:63791 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151907 infores:hetionet CAID:CA116598 biolink:causes MONDO:0009290 infores:clingen CAID:CA116598 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Supporting The NM_000152.5:c.2173C>T variant in GAA is a missense variant predicted to cause substitution of Arg by Trp at amino acid 725 (p.Arg725Trp). This variant is present in gnomAD V2.1.1 with the highest population minor allele frequency of 0.00077 (7/9058 alleles) in the Ashkenazi Jewish population, which is lower than the ClinGen LSD VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.909 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. This variant results in 6.5% GAA activity when expressed in COS cells (PMID: 8401535), meeting the ClinGen LSD VCEP specifications for PS3. This variant has been detected in at least 12 individuals with Pompe disease. Of those individuals, 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant including 2 with c.573C>A-pathogenic (PMID: 30155607), 1 with ex18 deletion-pathogenic (PMID: 28648663), 3 with c.-32-13T>G-pathogenic (PMID: 27711114, 17616415), 1 with c.-32-3C>A-likely pathogenic (PMID: 19588081), 2 with c.1076-1G>C pathogenic variants (PMID: 17616415). 1 individual was homozygous for the variant (PMID: 27711114). A total of 4.25 points were awarded. Thus meets PM3-Very Strong. At least 4 individuals have been reported with this variant and GAA activity <10% normal in leukocytes/muscle samples or <30% normal in cultured fibroblasts. Patient 5 (PMID: 21550241) has 0.2% normal GAA activity in fibroblast. Patient 3 has 1.1% normal GAA activity in fibroblasts, patient 15 has 5.2% normal GAA activity in fibroblasts (PMID: 17616415). Patient 1 (PMID: 3865697) has GAA activity in affected range in muscle, cultured fibroblasts, and leucocytes when compared to the laboratory’s control range. This meets the criteria for PP4. There is a ClinVar entry for this variant (Variation ID: 4024; 2 star review status) with 9 submitters classifying the variant as pathogenic with no conflict. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PS3-supporting, PM2-supporting, PM3-very strong, PP3, and PP4-moderate.(Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 3, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116598/MONDO:0009290/010 2023-10-03 2023-11-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2682 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085593 infores:hetionet CHEBI:38940 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0035243 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0015230 infores:hetionet CHEBI:5959 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0035410 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013395 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020651 infores:hetionet CHEBI:10101 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0404521 infores:hetionet CHEBI:36795 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0151662 infores:hetionet CAID:CA915946683 biolink:causes MONDO:0009861 infores:clingen CAID:CA915946683 MONDO:0009861 PMID: Pathogenic PM3, PVS1, PM2, PP4_Moderate The c.346_347del (p.Asp116fs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in an Ugyur proband (PMID: 31355225) with mild PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). The patient was compound heterozygous for the variant (confirmed by parental testing) and carried it in trans with the p.E390G variant (Likely Pathogenic per ClinGen PAH working group) (PM3). It is also reported pathogenic in Clinvar (ID 635217) by one lab, in a case with PKU; no further information is given. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946683/MONDO:0009861/006 2020-04-16 2020-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0020615 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0949059 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0027947 infores:hetionet CHEBI:8871 biolink:causes MONDO:0009022 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0175754 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009938 infores:hetionet CAID:CA16619143 biolink:causes MONDO:0700270 infores:clingen CAID:CA16619143 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PVS1 The c.2639-22_2639-20del variant in ATM causes a 3-nucleotide deletion in a splice acceptor site. It is predicted to cause skipping of biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in agene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RNA studies (Ambry internal data, PMID: 37438524). This variant has been identified in at least three individuals with Ataxia-Telangiectasia (PMID: 26896183, 37438524). This variant is absent from gnomAD v.4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1[RNA], PM3_Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619143/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8346 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0032961 infores:hetionet CHEBI:17026 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0877359 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002871 infores:hetionet NCBIGene:653509 biolink:causes MONDO:0030608 infores:monarchinitiative not_provided not_provided HGNC:10798 MONDO:0030608 uuid:7e15da49-4dd5-4e10-9122-51399802f73f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233414 infores:hetionet GO:0001826 biolink:causes CL:2000020 infores:ubergraph knowledge_assertion manual_agent GO:0001826 CL:2000020 UMLS:C0004609 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0220870 infores:hetionet CHEBI:40237 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0687713 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0020517 infores:hetionet CHEBI:6797 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0020517 infores:hetionet CAID:CA392448489 biolink:causes MONDO:0007947 infores:clingen CAID:CA392448489 MONDO:0007947 PMID: Uncertain Significance PP2, PP4, PS4_Moderate PM2, PP3, PM1 The NM_00138 c.188A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 63 (p.Tyr63Cys). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (PMID 17657824) (PP4). This variant in FBN1 has been reported three times in ClinVar: 1 time as uncertain significance, 1 time as likely pathogenic, and 1 time as pathogenic (Variation ID: 547296). This variant has previously been reported in at least two apparently unrelated individuals with ectopia lentis (PMID 25053872, 28941062) and in an individual with a suspected or confimed diagnosis of Marfan syndrome (Centre for Human Genetics, Inc. ClinVar entry) (PS4_mod). This variant has been identified in 1/112420 (0.0004%) individuals of European non-Finnish origin (https://gnomad.broadinstitute.org/version 2.1.1). Computational prediction tools and conservation analysis are inconclusive data with regards to a possible impact on this variant protein function and structure (REVEL: 0.72). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PP2, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392448489/MONDO:0007947/022 2023-12-21 2023-12-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:61049 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0428974 infores:hetionet NCBIGene:7439 biolink:causes MONDO:0008662 infores:monarchinitiative not_provided not_provided HGNC:12703 MONDO:0008662 uuid:0f3bce2d-51d4-4bfe-a43d-2024a9bd7b70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009806 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0340464 infores:hetionet CHEBI:6904 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0233407 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0162429 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0030305 infores:hetionet GO:1905936 biolink:causes GO:0007276 infores:ubergraph knowledge_assertion manual_agent GO:1905936 GO:0007276 CHEBI:9635 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0086543 infores:hetionet CHEBI:10127 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0231530 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042075 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0152227 infores:hetionet CHEBI:142290 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0036974 infores:hetionet CHEBI:71255 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0001824 infores:hetionet CHEBI:16469 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0026826 infores:hetionet CHEBI:63925 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0235270 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0037199 infores:hetionet CHEBI:3568 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011603 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011551 infores:hetionet CAID:CA397846727 biolink:causes MONDO:0018875 infores:clingen CAID:CA397846727 MONDO:0018875 PMID:12826609PMID:30224644PMID:29979965 Likely Benign BP4, BS3, PM2_Supporting BP2, BA1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, BS2, PP3, PP1 The NM_000546.6:c.143A>G variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 48 (p.Asp48Gly). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.086; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -5; VCEP specifications version 2.0; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397846727/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:37941 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0021775 infores:hetionet NCBIGene:3145 biolink:causes MONDO:0958224 infores:monarchinitiative not_provided not_provided HGNC:4982 MONDO:0958224 uuid:721a1d9c-65c1-4794-9674-bfdbcb27dd27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0040046 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0232492 infores:hetionet NCBIGene:823 biolink:causes MONDO:0014827 infores:monarchinitiative not_provided not_provided HGNC:1476 MONDO:0014827 uuid:d0beaf34-bc4d-4abd-8033-ea2c36f0adc8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4728 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0231835 infores:hetionet GO:0042387 biolink:causes CL:0000394 infores:ubergraph knowledge_assertion manual_agent GO:0042387 CL:0000394 CHEBI:45863 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0149745 infores:hetionet CHEBI:63630 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0037763 infores:hetionet CHEBI:8499 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0031350 infores:hetionet CHEBI:6741 biolink:causes HP:0034431 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0231592 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0017160 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0015397 infores:hetionet CAID:CA405669539 biolink:causes MONDO:0018493 infores:clingen CAID:CA405669539 MONDO:0018493 PMID: Uncertain Significance PS4_Moderate, PP3_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with valine at codon 4178 of the RYR1 protein, p.(Gly4178Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID 23558838, 25735680, 30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405669539/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8890 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0018965 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0151313 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0001364 infores:hetionet CHEBI:135876 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C1328337 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0948594 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0020517 infores:hetionet NCBIGene:7535 biolink:causes MONDO:0014861 infores:monarchinitiative not_provided not_provided HGNC:12858 MONDO:0014861 uuid:863b311e-4f13-4163-832e-707b0105cea9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0038454 infores:hetionet CHEBI:4784 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0340865 infores:hetionet CHEBI:63599 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0035078 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0040034 infores:hetionet CHEBI:5050 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0042109 infores:hetionet CAID:CA10385638 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385638 MONDO:0100437 PMID: Likely Benign BP4, BS1 BS2, BP2, BP7, BS4, BS3 NM_001034853.2(RPGR):c.470-19C>T is an intron 5 variant located 19 nucleotides before exon 6. This variant is present in gnomAD v4.1.0 at a frequency of 0.00001563 among hemizygous individuals, with 6 variant alleles / 383,877 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.01 for donor gain, which is below the ClinGen X- linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1, BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385638/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:63621 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030193 infores:hetionet CHEBI:40303 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0151798 infores:hetionet CHEBI:75246 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0018932 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020517 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0008311 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017574 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232492 infores:hetionet CHEBI:5134 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0006840 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0042109 infores:hetionet CHEBI:94501 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0085593 infores:hetionet NCBIGene:55975 biolink:causes MONDO:0013052 infores:monarchinitiative not_provided not_provided HGNC:15646 MONDO:0013052 uuid:4c33619a-bd23-45fb-b5c3-212e0d8a7985 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0022281 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017178 infores:hetionet CHEBI:7476 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085633 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0012833 infores:hetionet CAID:CA347227869 biolink:causes MONDO:0015152 infores:clingen CAID:CA347227869 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PM2_Supporting PM5, BS3 The NM_003494.4:c.6217A>G variant in DYSF, which is also known as NM_001130987.2: c.6334A>G p.(Met2112Val), is a missense variant expected to cause the substitution of valine for methionine at amino acid 2073, p.(Met2073Val). This variant has been reported in at least three patients with features consistent with LGMD or dysferlinopathy (PMID: 39350328, 37974208, 33560664, 17828519, 17129727; LOVD Individual #00313788); in two of these individuals, it was identified in a compound heterozygous state with a likely pathogenic or pathogenic variant (NM_003494.4: c.5350C>T p.(Gln1784Ter), 1.0 pt, PMID: 39350328, 37974208, 33560664; NM_003494.4: c.1813C>T p.(Gln605Ter), 1.0 pt, PMID: 17828519, 17129727) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant exhibited muscle weakness with a clinical diagnosis of LGMD and had severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 37974208, 33560664; LOVD Individual #00455530; PP4_Strong). The highest population allele frequency for this variant 8.475e-7 in gnomAD v4.1.0 (1/1180004 European (non-Finnish) alleles), which is less than the VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.838, which is greater than the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/15/2025): PM3_Strong, PP4_Strong, PP3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347227869/MONDO:0015152/180 2025-10-15 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44185 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0019158 infores:hetionet CAID:CA145791 biolink:causes MONDO:0009290 infores:clingen CAID:CA145791 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.668G>A (p.Arg223His) in gnomAD v2.1.1 is 0.74034 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92488; 2 star review status) with six submitters classifying the variant as benign, and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145791/MONDO:0009290/010 2020-01-22 2020-05-19 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:36791 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023798 infores:hetionet CHEBI:8707 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0014394 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0042514 infores:hetionet CHEBI:63622 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0852795 infores:hetionet CHEBI:51450 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042029 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0033575 infores:hetionet CHEBI:10119 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0575081 infores:hetionet CAID:CA915951018 biolink:causes MONDO:0100437 infores:clingen CAID:CA915951018 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1217dup (p.Ser407IlefsTer?) is a frameshift variant due to the duplication of one nucleotide that introduces a premature stop codon in exon 10 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including childhood onset (1 pt), reduced visual acuity (0.5 pts), visual field constriction (0.5 pts), and genetic testing with a next-generation sequencing panel of more than 100 genes that did not identify an alternative basis for disease, which together are specific for RPGR-related retinopathy (4 points, PMID: 28863407, PMID: 32531858, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915951018/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:94449 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0239134 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0019360 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0008325 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0004238 infores:hetionet CHEBI:6690 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011168 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0150450 infores:hetionet CHEBI:7443 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0700590 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0042373 infores:hetionet CHEBI:47781 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0009806 infores:hetionet CHEBI:45652 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0002792 infores:hetionet CHEBI:9720 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0151908 infores:hetionet CAID:CA295170 biolink:causes MONDO:0010278 infores:clingen CAID:CA295170 MONDO:0010278 PMID: Benign BA1, BP4 The allele frequency of the p.Ala9Ser variant in SLC9A6 is 0.307% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Computational analysis prediction tools suggest that the p.Ala9Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala9Ser variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA295170/MONDO:0010278/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true NCBIGene:24 biolink:causes MONDO:0011395 infores:monarchinitiative not_provided not_provided HGNC:34 MONDO:0011395 uuid:0ce140e2-d5e1-4504-b832-ef70c7f176bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3213 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0011603 infores:hetionet NCBITaxon:1678 biolink:causes MONDO:0024410 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1678 MONDO:0024410 CHEBI:6375 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0851341 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0042109 infores:hetionet CHEBI:31485 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0005741 infores:hetionet CHEBI:64354 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0011991 infores:hetionet CHEBI:8093 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0031924 infores:hetionet CHEBI:50692 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0476280 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0043037 infores:hetionet CHEBI:42068 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0008031 infores:hetionet CHEBI:46345 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0042029 infores:hetionet CHEBI:28748 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026827 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040485 infores:hetionet CHEBI:8028 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0018790 infores:hetionet CHEBI:231594 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0019080 infores:hetionet CHEBI:617099 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0015967 infores:hetionet CHEBI:52717 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0541782 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0034359 infores:hetionet CHEBI:71219 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0344232 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009763 infores:hetionet CHEBI:4858 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0016204 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0010692 infores:hetionet CHEBI:2904 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0002170 infores:hetionet CAID:CA10385542 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385542 MONDO:0100437 PMID: Likely Benign BP4, BS1 NM_001034853.2(RPGR):c.1099C>G (p.Pro367Ala) is a missense variant predicted to cause the substitution of proline by alanine at amino acid 367. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00004278 among hemizygous individuals, with 17 variant alleles / 397,359 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.285, which is below the ClinGen X-linked IRD VCEP threshold of < 0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BS1, BP4. (VCEP specifications version 1.0.0; date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385542/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:7936 biolink:causes UMLS:C0151729 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151729 infores:hetionet CHEBI:50861 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0036974 infores:hetionet NCBIGene:1537 biolink:causes MONDO:0014194 infores:monarchinitiative not_provided not_provided HGNC:2579 MONDO:0014194 uuid:fbe102e7-9adc-4b20-a9ad-d56c7815f2c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7445 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0025218 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0152128 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0919560 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0919560 infores:hetionet CAID:CA355961650 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961650 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PP4_Moderate, PVS1, PM2_Supporting The NM_000203.5:c.501C>A (p.Tyr167Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients with the variant have been reported to have clinical features consistent with MPS and both with IDUA deficiency, and one is reported to have elevated urinary dermatan sulfate and heparan sulfate although no values to reference range were provided (PMID: 11735025, 19396826) (PP4). One of these individuals is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909), phase not confirmed (PMID: 19396826, 0.5 points). The other patient is compound heterozygous for the variant and c.614G>A (p.Cys205Tyr) (PMID: 11735025). The allelic data from this patient will be used in the assessment of p.Cys205Tyr and is not included here to avoid circular logic. Total 0.5 points (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 8.476e-7 (1/1179740 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDIA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961650/MONDO:0001586/091 2025-04-07 2025-04-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8356 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0393761 infores:hetionet CHEBI:3814 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0011991 infores:hetionet CHEBI:119915 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003126 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038454 infores:hetionet CHEBI:6715 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0010481 infores:hetionet CAID:CA312264 biolink:causes MONDO:0008723 infores:clingen CAID:CA312264 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM1, PM3, PP4_Moderate, PM5_Supporting PS3 The NM_000018.4 c.1096C>T p.(Arg366Cys) in ACADVL is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 366. It has also been reported in the literature as p.Arg326Cys. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). It has been reported in patients with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency or increased C14:1 acylcarnitine levels (PP4_Moderate; PMID: 32793418, 8845838). At least one individual with this variant was identified with VLCADD clinical phenotype, who also carried a pathogenic variant c.848T>C in trans, displaying reduced enzyme levels (PM3 score = 1.0, PM3, PMID: 8845838). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). This variant resides within a region defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, PM1). A different aminoacid change in the same codon (p.Arg366His, ClinVar ID: 203580) has been classified as likely pathogenic for VLCAD deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Moderate, PP4_Moderate, PM2_Supporting, PP3_Supporting, PM5_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312264/MONDO:0008723/021 2025-03-25 2025-04-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004096 infores:hetionet CHEBI:94609 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0018681 infores:hetionet CHEBI:10125 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085633 infores:hetionet CHEBI:2676 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0423791 infores:hetionet CHEBI:5138 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0016655 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0038362 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151883 infores:hetionet CHEBI:84500 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0006277 infores:hetionet CHEBI:35677 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0232459 infores:hetionet CHEBI:5864 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015967 infores:hetionet NCBIGene:7092 biolink:causes MONDO:0013123 infores:monarchinitiative not_provided not_provided HGNC:11843 MONDO:0013123 uuid:b3121834-e8ad-433b-97e4-afa430739481 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0423153 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040409 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0009450 infores:hetionet CHEBI:63620 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0016199 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0042109 infores:hetionet CHEBI:15367 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018681 infores:hetionet CHEBI:71417 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0041657 infores:hetionet CHEBI:53760 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042029 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020473 infores:hetionet CHEBI:8378 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0156404 infores:hetionet CHEBI:31705 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0013456 infores:hetionet CAID:CA404084654 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084654 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, PS3, PM5, PP3 The NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code (PM2) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP3/BP4 not met: REVEL=0.668, it is not above 0.75 but between 0.5-0.75, splicing evaluation required. Functional data on splicing is not available. In Scenario A, acceptor site: The variant is located at -20 to +3 bases of canonical acceptor splicing site of exon 9. Wild type canonical acceptor motif: CTCGCTCCCCGGACCCCCAGGCT, MES: 6.59; Variant canonical acceptor motif: CTCGCTCCCCGGACCCCCAGTCT, MES: 5.33. Var/Wt ratio = 0.81, which is greater than 0.8 and less than 1.0. Alternative splicing is not predicted.PS3 not met: Functional data not available.PP4, PS4 not met: Variant meets PM2, however clinical data is not available.PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630), NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg), (ClinVarID 870321). None is classified as Pathogenic by these guidelines, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084654/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:0141155 biolink:causes GO:0006412 infores:ubergraph knowledge_assertion manual_agent GO:0141155 GO:0006412 CHEBI:5959 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0040034 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2242996 infores:hetionet CHEBI:4681 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0008031 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0030305 infores:hetionet CHEBI:6076 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020458 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014130 infores:hetionet NCBIGene:7319 biolink:causes MONDO:0010461 infores:monarchinitiative not_provided not_provided HGNC:12472 MONDO:0010461 uuid:71394d2b-833a-44b2-ac50-0728fa87157f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5123 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0036508 infores:hetionet CHEBI:63580 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030193 infores:hetionet CHEBI:63581 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0027497 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006266 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0542101 infores:hetionet CHEBI:65349 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0043352 infores:hetionet CHEBI:5384 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0575081 infores:hetionet CHEBI:8024 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0043352 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0002871 infores:hetionet CHEBI:5118 biolink:causes HP:0033400 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0000727 infores:hetionet CHEBI:9168 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085631 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0424000 infores:hetionet CHEBI:114785 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0005758 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0080276 infores:hetionet CHEBI:9332 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0038325 infores:hetionet CHEBI:180905 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0030252 infores:hetionet CHEBI:49375 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0015672 infores:hetionet CHEBI:31638 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0232462 infores:hetionet CHEBI:6129 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1260880 infores:hetionet CHEBI:64355 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018681 infores:hetionet UNII:0RK7M7IABE biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0017178 infores:hetionet CHEBI:3228 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0011606 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0343863 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0267792 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0025061 infores:hetionet CHEBI:50381 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C3665347 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0020458 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0235194 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235194 infores:hetionet CHEBI:27796 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0013144 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0232197 infores:hetionet CHEBI:3001 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0043144 infores:hetionet CAID:CA019969 biolink:causes MONDO:0007356 infores:clingen CAID:CA019969 MONDO:0007356 PMID:32849802 Pathogenic PS3, PP3_Moderate, PP4_Strong, PM2_Supporting The NM_000251.3(MSH2):c.2075G>T (p.Gly692Val) variant is a missense variant and leads to a change of Glycin to Valin at position 692. This variant has been reported in at least 3 independent CRC/Endometrial MSI-H tumours in ≥2 families using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PMID: 29212164, PMID: 21879275; ClinVar submission: VCV000090880.2) (PP4_STR met)Furthermore, the variant has been detected in a 9y old patient with CMMR-D in combination with a other pathogenic variant in MSH2/EPCAM. (PM3 met)The CIMRA functional odds is 150.82, which exceeds the threshold of 18.7 (PS3 met). The prior probability is 93.9 which exceeds the threshold of 18.7 (PP3_MOD met). The variant is not reported in gnomAD v4.1 (PM2_supporting met). In summary, this variant meets the criteria to be classified as pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS3, PP3_MOD, PP4_STR, PM3 and PM2_supporting applied. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA019969/MONDO:0007356/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27666 biolink:causes UMLS:C0333472 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0333472 infores:hetionet CHEBI:5138 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0043094 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0521592 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0027765 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0853813 infores:hetionet CHEBI:45951 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0013132 infores:hetionet CHEBI:63620 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0149745 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0518015 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007787 infores:hetionet CAID:CA000029 biolink:causes MONDO:0018875 infores:clingen CAID:CA000029 MONDO:0018875 PMID: Benign BP4, BS1, BS2 BA1, PS3, PS1, PS4, PS2, PM5, PM1, BS3, BS4, PM2, PP3, PP1, PP4 The NM_000546.6: c.1079G>C variant in TP53 is a missense variant predicted to cause substitution of glycine by alanine at amino acid 360 (p.Gly360Ala). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributor: SCV000185669.8). The filtering allele frequency is 0.0005306 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). Computational predictor scores (BayesDel = -0.3336; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS1 BP4_Moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000029/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:100241 biolink:causes MONDO:0002105 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025162 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020517 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0332575 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0036508 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0178298 infores:hetionet NCBIGene:57647 biolink:causes MONDO:0032888 infores:monarchinitiative not_provided not_provided HGNC:17210 MONDO:0032888 uuid:4197c4fe-cf35-4550-be8b-592729fce00c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0033975 infores:hetionet NCBIGene:116519 biolink:causes MONDO:0007762 infores:monarchinitiative not_provided not_provided HGNC:17288 MONDO:0007762 uuid:427c3488-7cd3-4a66-a984-98118180b4cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37941 biolink:causes MONDO:0000702 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0400821 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0038454 infores:hetionet CHEBI:66899 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0152227 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0038362 infores:hetionet CHEBI:50131 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0033774 infores:hetionet CHEBI:6717 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013404 infores:hetionet CHEBI:135925 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C3248383 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020538 infores:hetionet NCBIGene:11149 biolink:causes MONDO:0014782 infores:monarchinitiative not_provided not_provided HGNC:1152 MONDO:0014782 uuid:3e55e913-c859-42bd-bf17-1d13cee7fdcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes UMLS:C0347950 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0347950 infores:hetionet GO:0106088 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0007275 CHEBI:2611 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1443060 infores:hetionet CHEBI:18248 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0236075 infores:hetionet CHEBI:4798 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013384 infores:hetionet CHEBI:48669 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0149512 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022408 infores:hetionet CHEBI:94449 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0080274 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0424000 infores:hetionet CHEBI:47898 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0333355 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0017979 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151826 infores:hetionet CHEBI:7824 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151786 infores:hetionet CHEBI:3286 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C3665386 infores:hetionet CAID:CA134641 biolink:causes MONDO:0021060 infores:clingen CAID:CA134641 MONDO:0021060 PMID: Likely Benign BP7, BP2, BP4 BP5, PP2 The filtering allele frequency of the c.1449T>G (p.Gly483=) variant in the PTPN11 gene is .01% (13/129134 with CI 95%) of non-Finnish European alleles in gnomAD (BS1 not met). Computational prediction tools and conservation analysis suggest that the p.Gly483= variant does not impact the protein or splicing (BP4). This is a synonymous variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). This variant has been observed with another pathogenic variant in PTPN11 for a fully penetrant dominant gene/disorder (BP2; VCV000013326.4; Laboratory for Molecular Medicine internal data). This variant has been observed in many individuals with varying clinical presentations that lack clear associations with a RASopathy (VCV000013326.4; VCV000045358.1). In summary, the clinical significance of the p.Gly483= variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP2, BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134641/MONDO:0021060/004 2019-08-19 2019-12-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7936 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006444 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020437 infores:hetionet NCBIGene:6304 biolink:causes MONDO:0030988 infores:monarchinitiative not_provided not_provided HGNC:10541 MONDO:0030988 uuid:83f3624e-8033-46fc-8117-d41c535ce86c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027051 infores:hetionet CHEBI:2453 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0009676 infores:hetionet CHEBI:28901 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151636 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0041912 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0033975 infores:hetionet CHEBI:45409 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0231528 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0855242 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0162830 infores:hetionet CAID:CA6831648 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831648 MONDO:0015967 PMID: Uncertain Significance BS1 The c.-6C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the 5'UTR of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00007572, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.-6C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831648/MONDO:0015967/017 2022-03-04 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52717 biolink:causes UMLS:C0274435 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0274435 infores:hetionet CHEBI:51450 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0086565 infores:hetionet CHEBI:63599 biolink:causes UMLS:C1306600 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C1306600 infores:hetionet CAID:CA346326874 biolink:causes MONDO:0800472 infores:clingen CAID:CA346326874 MONDO:0800472 PMID:23028769PMID:27243976 Pathogenic PM2_Supporting, PM3_Supporting, PP1_Strong, PP3_Strong BP4, BA1, PM5, PM1, PM4, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.1568G>C variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Threonine at amino acid 523 (p.Arg523Thr). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.968, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) (PMIDs: 23028769, 27243976) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 16688110), which fulfilled PP1_Strong. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is homozygous (non-consanguineous) for the variant (PMID: 16688110). Total proband points = 0.5, meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PP1_Strong, PP3_Strong, PM2_Supporting, PM3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346326874/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:391960 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0009676 infores:hetionet CHEBI:84883 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0042963 infores:hetionet CHEBI:63635 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C2363730 infores:hetionet CHEBI:119486 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0030554 infores:hetionet CHEBI:6923 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0020517 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001956 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0343084 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151971 infores:hetionet CHEBI:291342 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0042963 infores:hetionet CHEBI:6437 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0014591 infores:hetionet CHEBI:2663 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0032231 infores:hetionet CHEBI:17347 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0239935 infores:hetionet CHEBI:144551 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151908 infores:hetionet CHEBI:4027 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027497 infores:hetionet CHEBI:3723 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151662 infores:hetionet CHEBI:5134 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0041582 infores:hetionet CAID:CA333443 biolink:causes MONDO:0007113 infores:clingen CAID:CA333443 MONDO:0007113 PMID: Benign BS1, BS2, BP4 The allele frequency of the p.Asn272Ser variant in UBE3A is 0.013% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Asn272Ser variant is observed in at least 4 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn272Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn272Ser variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333443/MONDO:0007113/016 2022-08-25 2022-09-06 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:50173 biolink:causes UMLS:C0549536 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0549536 infores:hetionet CHEBI:28939 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0575081 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0029408 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0011053 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0018799 infores:hetionet CHEBI:4974 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0027947 infores:hetionet CAID:CA207604 biolink:causes MONDO:0010726 infores:clingen CAID:CA207604 MONDO:0010726 PMID: Benign BS2_Supporting, BA1 The allele frequency of the p.Ser396= variant in MECP2 (NM_004992.3) is 0.15% in European (Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ser396= variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Ser396= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA207604/MONDO:0010726/016 2022-12-09 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:5959 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0162298 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0034065 infores:hetionet CHEBI:10119 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0852911 infores:hetionet CHEBI:84500 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0438142 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0009806 infores:hetionet CHEBI:3761 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0043352 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0012833 infores:hetionet CHEBI:6375 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0041657 infores:hetionet CHEBI:6847 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0030554 infores:hetionet CHEBI:3506 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0015230 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0042109 infores:hetionet CAID:CA137912 biolink:causes MONDO:0021060 infores:clingen CAID:CA137912 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1093-6T>C variant in the MAP2K2 gene is 0.166% (9/2834) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137912/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:659 biolink:causes MONDO:0024533 infores:monarchinitiative not_provided not_provided HGNC:1078 MONDO:0024533 uuid:acf9b0be-d80b-4a94-9cd3-c1d90b9ad5df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101853 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151576 infores:hetionet CHEBI:75984 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0235490 infores:hetionet UMLS:C0010592 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0233763 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018799 infores:hetionet CHEBI:48390 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0026766 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0022116 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0549622 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0042514 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0234215 infores:hetionet CAID:CA16614591 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614591 MONDO:0100216 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PVS1, PM6, BP1, BP4, BP3, BP2, BA1, BS2, PP2, PP3, PP1, PP4, PM4, PM5, PM3, PS2, PS1, PS3, PS4, BP7, BP5, BS1, BS3, BS4 The NM_177438.2:c.5461A>G variant in DICER1 is a missense variant predicted to cause substitution of methionine by valine at amino acid 1821 (p.Met1821Val). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.0000012 (2/1614154 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.54, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, PM2_Supporting. (Bayesian Points: 2; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614591/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61058 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0009806 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042401 infores:hetionet CHEBI:6456 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0231530 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0033975 infores:hetionet CHEBI:134991 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C1142135 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023895 infores:hetionet CHEBI:46081 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0085605 infores:hetionet CHEBI:91834 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0009806 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0034150 infores:hetionet CHEBI:3207 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0234238 infores:hetionet CHEBI:8707 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0549249 infores:hetionet CHEBI:520985 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0015230 infores:hetionet CHEBI:64354 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0030193 infores:hetionet CHEBI:61390 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0151905 infores:hetionet CAID:CA2697547491 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547491 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1162_1163delinsAA (p.Ser388Lys) is a deletion and insertion which results in a change of Serine 388 to a Lysine. This residue is not part of any established functional domain. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547491/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7565 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0020580 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014130 infores:hetionet CHEBI:5280 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0040822 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0026848 infores:hetionet NCBIGene:2658 biolink:causes MONDO:0014217 infores:monarchinitiative not_provided not_provided HGNC:4217 MONDO:0014217 uuid:b5d0d467-fd58-4e5f-8385-f85abf417fb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2666 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0021141 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006826 infores:hetionet CHEBI:61049 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151603 infores:hetionet CAID:CA2573106200 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573106200 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4 The c.876_877insT variant in the Hepatocyte nuclear factor 4 alpha, HNF4A, causes a frameshift in the protein at codon 293 in NM_175914.5, adding 15 novel amino acids before encountering a stop codon (p.(Val293CysfsTer15)). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; PMID:22060211). In summary, c.876_877insT meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106200/MONDO:0015967/085 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42944 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0030554 infores:hetionet CHEBI:9168 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0025345 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151773 infores:hetionet NCBIGene:1759 biolink:causes MONDO:0014598 infores:monarchinitiative not_provided not_provided HGNC:2972 MONDO:0014598 uuid:1cd58659-bb49-49d1-9c23-9806e8be1324 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6761 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0033246 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0178298 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020517 infores:hetionet CHEBI:3061 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0039070 infores:hetionet CHEBI:10101 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0009676 infores:hetionet NCBITaxon:6252 biolink:causes MONDO:0005654 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6252 MESH:D001196 DB00592_MESH_D001196_1DB00848_MESH_D001196_1DB00643_MESH_D001196_1DB00730_MESH_D001196_1 CAID:CA8603038 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603038 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The p.Ile518Asn variant on ITGA2B gene is a missense variant that is present in extremely low frequencies (0.00087%, 1/118416 alleles) in the European non_Finnish subpopulation of gnomAD. One proband harboring this variant in the compound heterozygous state with a likely pathogenic splice site variant, c.1946+3G>T, met PD-VECP criteria for the Glanzmann thrombasthenia phenotype. Multiple in silico predictors predict this variant to be deleterious (REVEL score=0.809). This variant meets PD-VCEP criteria for PP4_strong, PM2_supporting, PM3_supporting and PP3, and is classified as likely pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603038/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6715 biolink:causes UMLS:C0877089 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0877089 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0541799 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004936 infores:hetionet CHEBI:9086 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017181 infores:hetionet CAID:CA10652927 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652927 MONDO:0011071 PMID: Benign BP2, BA1 PS3, PS4, PS2, PS1, BP1, BP4, BP3, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.4(RUNX1):c.*919A>G is a 3' UTR variant. MAF of 0.04974 (4.974%, 433/8706 alleles) in the African subpopulation in gnomAD v.2.1.1 cohort is ≥ 0.0015 (0.15%)(BA1) and 9 homozygotes found on gnomAD (BP2).In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652927/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:726 biolink:causes MONDO:0100450 infores:monarchinitiative not_provided not_provided HGNC:1482 MONDO:0100450 uuid:fb6a8f7f-0271-41d4-b8b4-556e0f23e3d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31401 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0162287 infores:hetionet CAID:CA228435 biolink:causes MONDO:0019565 infores:clingen CAID:CA228435 MONDO:0019565 PMID: Likely Benign BP4, BP5, BS1 PP1, PP4, PS4, BS3 NM_000552.5(VWF):c.3692A>C is a missense variant encoding a substitution of asparagine by threonine at position 1231. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID: 8134377, PMID: 17190853, PMID: 31064749, PMID: 16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID: 8134377, PMID: 2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least two control individuals (PMID: 22197721). REVEL gives a score of 0.069, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID: 16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01138 (based on 900/74802 alleles in the African/African-American population, including 7 homozygotes), which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228435/MONDO:0019565/090 2024-08-12 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:10023 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0948089 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0038358 infores:hetionet CHEBI:42797 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0041657 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038362 infores:hetionet CHEBI:5123 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0039231 infores:hetionet CHEBI:4657 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0032343 infores:hetionet CHEBI:31205 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0017178 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0025061 infores:hetionet CHEBI:92607 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0012833 infores:hetionet CHEBI:6717 biolink:causes HP:0004386 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1535950 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020517 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017178 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0149931 infores:hetionet CHEBI:7986 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C1384353 infores:hetionet NCBIGene:3910 biolink:causes MONDO:0014095 infores:monarchinitiative not_provided not_provided HGNC:6484 MONDO:0014095 uuid:9bd5653b-c069-4f67-92c4-eb438b44e023 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:453011 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0021053 infores:hetionet CHEBI:9137 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0006277 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0043251 infores:hetionet CHEBI:47780 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0024141 infores:hetionet CAID:CA355961948 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961948 MONDO:0001586 PMID: Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting, PS3_Moderate The NM_000203.5:c.623G>A variant in IDUA is a missense variant in exon 6, where glycine at amino acid position 208 is replaced with an aspartic acid (p.Gly208Asp). This variant has been reported in at least seven probands with MPS I (PMID: 21480867, 29976218, 26446585, 24480078). At least 5 probands are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 12509712, 24480078) (confirmed in trans by parental testing, 1 point), c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910) (PMID: 29976218; 2 patients who may be sibs, unconfirmed phase; 0.5 points), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 12559846; phase unconfirmed, 0.5 points), and c.657dupG (typo as there is no G in the reference sequence at this position; therefore data not included) (PMID: 21480867). There is also one patient who is homozygous for the variant (PMID: 29976218) (0.5 points) (total 2.5 points; PM3_Strong). Another patient is compound heterozygous for the variant and a variant reported by the authors as p.Pro520Arg (PMID: 26446585). The amino acid Proline at location 520 was not found in any reference sequence for IDUA. One patient with the variant is a 10-month-old male with a Hurler phenotype, with IDUA activity leukocytes of 1.5 nmol/h/mg protein (Normal range in Chinese controls: 27.2–52 nmol/h/mg protein). The proband exhibits delayed mental development, macrocephaly, joint stiffness, Mongolian macula, hepatosplenomegaly, hernia, cardiac disease, and airway obstruction (PMID: 21480867) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000013 (1/74860 alleles) in the African/African American population , which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expressing the mutation in CHO-K1 cells resulted in 0.0006% normal alpha-iduronidase activity compared to the wild-type control, as shown by western blots (PMID: 12559846). Western blots show no full-length protein (PS3_Moderate). The computational predictor REVEL yields a score of 0.959, which exceeds the threshold of 0.773, indicating a correlation with the impact on IDUA function, as specified in the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (ClinVar variation ID: 554590). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PP3_Moderate, PP4_Moderate, PS3_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, Sept. 15, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961948/MONDO:0001586/091 2025-09-15 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7809 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0006266 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0012813 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0239093 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0239093 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0014549 infores:hetionet CHEBI:32293 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0020580 infores:hetionet CHEBI:681850 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0042023 infores:hetionet CHEBI:7496 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0016204 infores:hetionet CHEBI:63791 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018790 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0860210 infores:hetionet CAID:CA10014257 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014257 MONDO:0100083 PMID: Likely Benign BP4, BP7, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS3, BS4, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.967+8A>T is an intronic variant. MAF of 0.00048 (0.048%, 12/24970 alleles) in the African subpopulation of the gnomAD V2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). REVEL score not applicable and SpliceAI ∆ scores ≤ 0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.997, <2) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014257/MONDO:0100083/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:7298 biolink:causes MONDO:0031057 infores:monarchinitiative not_provided not_provided HGNC:12441 MONDO:0031057 uuid:807cbb79-78f5-4c44-8f72-fe8b15af708d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0234233 infores:hetionet CHEBI:2904 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0013395 infores:hetionet CHEBI:6950 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0035455 infores:hetionet CHEBI:7476 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002063 infores:hetionet NCBIGene:5880 biolink:causes MONDO:0011988 infores:monarchinitiative not_provided not_provided HGNC:9802 MONDO:0011988 uuid:6ffaef98-1c49-4b8f-b110-d738d34a200e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA232434 biolink:causes MONDO:0021060 infores:clingen CAID:CA232434 MONDO:0021060 PMID: Benign BA1, BP4, BP5, BP7 The c.1433-19A>G in BRAF is an intronic variant located in intron 11. The minor allele frequency of this variant in gnomAD v4 is 0.2572% (3030/1178128) in the European (non-Finnish) population, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved (BP4, BP7). This variant has been identified in at least 2 patients with clinical features of a RASopathy (PS4_Supporting not met; GeneDx, Greenwood Genetics, Otto von Guericke University Magdeburg, internal data, GTR ID's: 26957, 1019; ClinVar SCV000207632.1, SCV000167210.14). However, this variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, GTR ID's: 26957; ClinVar SCV000167210.14). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA232434/MONDO:0021060/049 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:46195 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0344232 infores:hetionet CHEBI:116278 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0085636 infores:hetionet CHEBI:110423 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0085681 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0853700 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0699744 infores:hetionet CHEBI:4672 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0041834 infores:hetionet CHEBI:6909 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0241057 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011551 infores:hetionet CHEBI:5106 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0042963 infores:hetionet CHEBI:64312 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0851578 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0002871 infores:hetionet CHEBI:3127 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0023066 infores:hetionet CHEBI:42797 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0268000 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0027765 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0520806 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0022660 infores:hetionet NCBIGene:222663 biolink:causes MONDO:0030953 infores:monarchinitiative not_provided not_provided HGNC:13655 MONDO:0030953 uuid:a88e8b6a-37cd-47d8-a25a-3fd90549fcef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0030554 infores:hetionet CHEBI:2675 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0917801 infores:hetionet CAID:CA359425853 biolink:causes MONDO:0012163 infores:clingen CAID:CA359425853 MONDO:0012163 PMID: Uncertain Significance PP4, PM2_Supporting, PM3_Supporting NM_002185.5(IL7R):c.41T>C is a missense variant predicted to cause substitution of Leucine by Serine at amino acid 14 (p.Leu14Ser). The highest population minor allele frequency in gnomAD v4 is 0.00001160 (1/86214 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient P1 was found homozygous for this mutation (0.5 pt.) (PM3_supporting) (PMID: 33599911).Patient with SCID (0.5 pt.) and exome sequencing conducted (0.5 pt.) (total :1 pt.) (PP4) (PMID: 33599911).In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PM3_supporting, PP4(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359425853/MONDO:0012163/119 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8768 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002792 infores:hetionet CHEBI:8869 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0040264 infores:hetionet NCBIGene:2627 biolink:causes MONDO:0010802 infores:monarchinitiative not_provided not_provided HGNC:4174 MONDO:0010802 uuid:e530bae8-8d7c-4640-b5e1-b0a079c76d27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042384 infores:hetionet CHEBI:9241 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0023380 infores:hetionet CHEBI:47898 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018800 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0020517 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0858259 infores:hetionet CHEBI:70735 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0020456 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020456 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C1368065 infores:hetionet CHEBI:63618 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0028734 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0234215 infores:hetionet CHEBI:8310 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0016382 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0870082 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0001883 infores:hetionet CHEBI:63580 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2129214 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0149931 infores:hetionet CAID:CA386940950 biolink:causes MONDO:0015967 infores:clingen CAID:CA386940950 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP4, PP1 The c.1769-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 10 of NM_000545.8. This variant, located in the donor site of exon 10 of 10, is predicted to disrupt a significant part of the transactivation domain, a functionally important region of the protein. Even though this truncated transcript is predicted to escape nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease, there is clinical evidence that variants in this region lead to a monogenic diabetes phenotype. (PVS1_Strong; PMID: 23348805). Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes and negative testing for HNF4A; however, the calculated MODY probability is <50%. Therefore, PP4 could not be applied (Internal lab contributor). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (Internal lab contributor). In summary, c.1769-1G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025: PVS1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386940950/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63630 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0234458 infores:hetionet CHEBI:51450 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0016382 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0595879 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0041969 infores:hetionet CHEBI:9123 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013390 infores:hetionet CHEBI:16347 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0003467 infores:hetionet CHEBI:3077 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0039446 infores:hetionet CHEBI:72564 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C3665347 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0037274 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0028259 infores:hetionet CHEBI:408174 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0011175 infores:hetionet CHEBI:5784 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0018681 infores:hetionet CHEBI:15765 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0338831 infores:hetionet CHEBI:3441 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0034642 infores:hetionet NCBIGene:57582 biolink:causes MONDO:0013989 infores:monarchinitiative not_provided not_provided HGNC:18865 MONDO:0013989 uuid:f8b92db1-f7e2-4af8-8098-b1acc9f6b6bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0004093 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0006840 infores:hetionet CHEBI:231425 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0009782 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0012833 infores:hetionet CHEBI:3393 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0003123 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0728899 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0030552 infores:hetionet CAID:CA274997 biolink:causes MONDO:0008723 infores:clingen CAID:CA274997 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3, PVS1 PP4 The NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant was detected and confirmed in-trans with the pathogenic c.1349G>A (p.R450H) in a patient with VLCAD-deficiency (PM3, PMID:33150772). This variant was also reported in one patient with a positive newborn screen for VLCAD-deficiency (PMID:26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM3,PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA274997/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10124 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037763 infores:hetionet CHEBI:127780 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0497156 infores:hetionet CHEBI:171719 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0242528 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1142135 infores:hetionet CHEBI:2567 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0016204 infores:hetionet CHEBI:52717 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042963 infores:hetionet CHEBI:74947 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151904 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0973461 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0029134 infores:hetionet CHEBI:7478 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0004093 infores:hetionet CHEBI:3515 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0030193 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0018799 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0267792 infores:hetionet CHEBI:28915 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0018965 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042571 infores:hetionet CHEBI:17347 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151691 infores:hetionet CHEBI:45409 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011175 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001158 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009595 infores:hetionet CHEBI:47499 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0036974 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0009946 infores:hetionet CHEBI:6801 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0011603 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0032961 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0521591 infores:hetionet NCBIGene:5216 biolink:causes MONDO:0013891 infores:monarchinitiative not_provided not_provided HGNC:8881 MONDO:0013891 uuid:9829f902-5a6a-405a-b61f-8a5aaa1433ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0006266 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0001925 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0155169 infores:hetionet CHEBI:47781 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0235347 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1443060 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017160 infores:hetionet CHEBI:135888 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0149514 infores:hetionet UMLS:C0120107 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0038990 infores:hetionet CAID:CA229763 biolink:causes MONDO:0009861 infores:clingen CAID:CA229763 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PS3_Supporting PM3, PM5 The c.794G>A (p.Cys265Tyr) variant in PAH is reported in a Japanese patient with phenylketonuria (BH4 deficiency excluded, PMID: 9860305). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. PAH activity in COS cell expression system was 0% (PMID: 9860305). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PM2, PS3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229763/MONDO:0009861/006 2022-02-25 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53760 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233632 infores:hetionet CHEBI:92511 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0687713 infores:hetionet CHEBI:3387 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162566 infores:hetionet CHEBI:92712 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C1145670 infores:hetionet CHEBI:46195 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0032227 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0442856 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0442856 infores:hetionet CHEBI:4636 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0917801 infores:hetionet CHEBI:5118 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0392156 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0234930 infores:hetionet CAID:CA2573157344 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157344 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+9C>G is an intronic variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157344/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7577 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0855242 infores:hetionet CAID:CA10014259 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014259 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS2, PS1, PS3, BP1, BP3, BP2, BA1, PM2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.967A>G (p.Thr323Ala) is a missense variant which has a REVEL score < 0.50 (0.063) and a SpliceAI score ≤ 0.20 (Δ score acceptor gain 0.04; Δ score donor gain 0.02) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014259/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4784 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0014518 infores:hetionet CHEBI:27899 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0231218 infores:hetionet CHEBI:9927 biolink:causes MONDO:0001245 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0085576 infores:hetionet CHEBI:724125 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0241057 infores:hetionet CHEBI:32139 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0040586 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0149801 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0149801 infores:hetionet CAID:CA512341344 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341344 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1053C>T (p.Gly351=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-.004)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting), it also has not been reported in cases or the literature. In summary, this variant meets criteria to be classified as a likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341344/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8707 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0023518 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151763 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0574067 infores:hetionet CHEBI:16914 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0013378 infores:hetionet CHEBI:28971 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0011603 infores:hetionet CHEBI:68845 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0012833 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020621 infores:hetionet CHEBI:17688 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013456 infores:hetionet CHEBI:63638 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C2047937 infores:hetionet CAID:CA505743141 biolink:causes MONDO:0007750 infores:clingen CAID:CA505743141 MONDO:0007750 PMID: Uncertain Significance BP4, BP7, PM2 The NM_000527.5(LDLR):c.1221C>T (p.His407=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).BP4 - No REVEL, splicing evaluation required.Functional data not availableA) not on limitsB) does not create AGVariant not predicted to alter splicingBP7 - Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA505743141/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10125 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0007820 infores:hetionet CHEBI:4514 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0013182 infores:hetionet CHEBI:136040 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0013404 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0003864 infores:hetionet CHEBI:45285 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0013428 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020039 infores:hetionet CHEBI:4511 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0020517 infores:hetionet CHEBI:6128 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0035317 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0700345 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232459 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0017178 infores:hetionet CAID:CA409107461 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107461 MONDO:0015967 PMID: Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS4 The c.740T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 247 (p.(Leu247Pro)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.979​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23771925, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose SU ) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.733G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1_moderate, PP3, PP4_moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107461/MONDO:0015967/085 2024-08-30 2024-08-30 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:7480 biolink:causes MONDO:0014901 infores:monarchinitiative not_provided not_provided HGNC:12775 MONDO:0014901 uuid:f9de3b17-7ae4-4ce3-9121-271b7c2a4d8b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0549336 infores:hetionet CHEBI:5384 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C2242588 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0855242 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042109 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0041969 infores:hetionet CHEBI:9123 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1306341 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0003123 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0022116 infores:hetionet CHEBI:15940 biolink:causes MONDO:0007035 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0000889 infores:hetionet CHEBI:10110 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0030193 infores:hetionet UNII:R43D2573WO biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085593 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0002170 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0027765 infores:hetionet CHEBI:50275 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2242737 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151474 infores:hetionet CHEBI:4027 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0010200 infores:hetionet CHEBI:6402 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027497 infores:hetionet CAID:CA16620258 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620258 MONDO:0007648 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM5, PM4, PM1, PVS1, PM6, BS2, PP1, PP4, PP2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.2164+2dup variant actually affects +3 location and is not considered as a canonical splice site variant. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000569527.3). Multiple splicing predictors indicate damaging changes (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Supporting, PP3. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620258/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:31236 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151888 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020517 infores:hetionet CHEBI:567361 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0037278 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0151736 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0027769 infores:hetionet CHEBI:80630 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0423153 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0595878 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0022408 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0040128 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0233494 infores:hetionet CHEBI:2950 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0149745 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1565489 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0040034 infores:hetionet NCBIGene:79053 biolink:causes MONDO:0011969 infores:monarchinitiative not_provided not_provided HGNC:23161 MONDO:0011969 uuid:aeabd3fd-a683-4d51-a8f1-e4a8ed04c100 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5050 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0033774 infores:hetionet CHEBI:4909 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0022346 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0221165 infores:hetionet CHEBI:53760 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0043094 infores:hetionet CHEBI:7915 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0010200 infores:hetionet CHEBI:5120 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0005778 infores:hetionet CHEBI:41879 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0019209 infores:hetionet CHEBI:4469 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0011570 infores:hetionet CAID:CA117001 biolink:causes MONDO:0011225 infores:clingen CAID:CA117001 MONDO:0011225 PMID: Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM3_Supporting, PVS1 The NM_001033855.3:c.241C>T (p.Arg81Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The filtering allele frequency (the upper threshold of the 95% CI of 38/1177816 alleles) of the c.241C>T variant in DCLRE1C is 0.00002205 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).Activity levels in % of WT activity = Recombination: Mean (SD): 19.48 (1.56) and DNA repair (36h after IR): Mean (SD): 16.05 (4.77). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level. (PMID: 25917813).At least one patient with this variant displayed Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, which is highly specific for SCID (PP4_Supporting, PMID: 11336668). The proband (P2) is homozygous (Table 1) for this variant (0.5pt; PM3_Supporting).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3_Supporting, PS3_Moderate, and PP4_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA117001/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8502 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0014743 infores:hetionet CHEBI:3561 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0043094 infores:hetionet CHEBI:36704 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0014742 infores:hetionet CHEBI:6375 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0234233 infores:hetionet CHEBI:5856 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0041657 infores:hetionet CAID:CA392347578 biolink:causes MONDO:0007947 infores:clingen CAID:CA392347578 MONDO:0007947 PMID: Likely Pathogenic PM2, PP4, PP2, PP3, PS4_Supporting, PM1, PM5 PM6, PVS1, PP1, BS2, BA1, BP1, BP4, BP2, BP3, PS1, PS2, PS3, PM3, PM4, BP7, BP5, BS1, BS4, BS3 NM_00138 c.1073G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 358(p.Cys358Tyr). This variant has been found in two probands, one with the clinical diagnosis of Marfan syndrome but without a specified phenotype and one with ectopia lentis, thoracic aortic aneurysm and dissection, and a systemic score of 9 (PP4, PS4_supporting; PMID: 35058154; UZG internal data). This variant has been reported two times in ClinVar, once as likely pathogenic and once as of uncertain significance (Variation ID: 549001). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a TGFβ binding-protein-like (TB) domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). Other variants altering this codon are pathogenic or likely pathogenic (p.Cys358Trp, p.Cys358Arg), supporting the functional importance of this amino acid position (PM5). Computational prediction tools and conservation analysis suggest that this variant may impact protein structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_supporting, PM2_supporting, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392347578/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3213 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0011175 infores:hetionet GO:0140619 biolink:causes GO:0006310 infores:ubergraph knowledge_assertion manual_agent GO:0140619 GO:0006310 CHEBI:404903 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0040046 infores:hetionet CHEBI:6754 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0080274 infores:hetionet CHEBI:2682 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0242528 infores:hetionet CAID:CA340748300 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748300 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PS3_Supporting, PM2_Supporting The NM_000329.3(RPE65):c.302C>T (p.Thr101Ile) variant is a missense variant in RPE65 causing a substitution of threonine with isoleucine at position 101. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 8.474e-7, with 1 / 1180026 alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.88, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 1.27% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 19431183). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.271C>T p.Arg91Trp variant confirmed in trans by next-generation sequencing data (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PS3_Supporting, PM3 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748300/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:84050 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0151662 infores:hetionet CHEBI:9727 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0014549 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0023067 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0948586 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0151828 infores:hetionet UMLS:C0903898 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0085649 infores:hetionet CAID:CA269554328 biolink:causes MONDO:0007947 infores:clingen CAID:CA269554328 MONDO:0007947 PMID:10486319 Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong, PS3_Supporting PVS1, PM6, BS2, PP1, BA1, BP4, BP3, BP2, PS1, PS2, PM5, PM4, PM3, BS1, BS3, BS4, BP5 NM_00138 c.1708T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 570 (p.Cys570Arg). This variant has been found in two probands with ectopia lentis (EL), one of whom was also reported to have numerous systemic features of Marfan syndrome without thoracic aortic aneurysm and dissection (TAAD), as well as a proband with isolated TAAD (PS4_moderate; PMID: 10486319; 3billion & Invitae internal data, ClinVar Variation ID: 956400). An additional proband with a severe Marfan syndrome phenotype including EL, TAAD, and major skeletal involvement (PP4; Bichat internal data). Functional studies performed on patient fibroblasts with this variant demonstrated reduced fibrillin synthesis and secretion (50% and 28% of controls, respectively) (PS3_supporting; PMID: 10486319). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys570Gly, p.Cys570SerSer, p.Cys570Trp, p.Cys570Tyr). Computational prediction tools and conservation analysis support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PS3_supporting, PM2_supporting, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA269554328/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9943 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015672 infores:hetionet CHEBI:6904 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0002170 infores:hetionet CHEBI:6444 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0027497 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0026113 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0040822 infores:hetionet CHEBI:41977 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0002170 infores:hetionet CAID:CA147743 biolink:causes MONDO:0015152 infores:clingen CAID:CA147743 MONDO:0015152 PMID: Benign BA1 BP4 The NM_003494.4: c.3065G>A variant in DYSF, which is also known as NM_001130987.2: c.3119G>A p.(Arg1040Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1022 (p.Arg1022Gln). The filtering allele frequency of the variant is 0.03338 for African/African American genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 3745/152196), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.02, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147743/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA386493311 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493311 MONDO:0009861 PMID: Uncertain Significance PM2, PM3, PP4 PM5, PP3 This c.1096C>G (p.Pro366Ala) variant in PAH was seen in a patient with PKU in trans with the likely pathogenic variant p.Gly247Arg (PMID: 28982351). This variant was absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493311/MONDO:0009861/006 2022-10-14 2022-10-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:46557 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0037274 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0242350 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0035455 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0005940 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022893 infores:hetionet CHEBI:119915 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0016204 infores:hetionet CHEBI:9445 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0917801 infores:hetionet CHEBI:4814 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0027497 infores:hetionet CHEBI:9654 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0403673 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0038663 infores:hetionet CHEBI:5384 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0020458 infores:hetionet CHEBI:28593 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0009676 infores:hetionet CHEBI:4672 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0260662 infores:hetionet CHEBI:3757 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0002170 infores:hetionet NCBITaxon:121224 biolink:causes MONDO:0003482 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:121224 MONDO:0003482 CHEBI:9613 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0018834 infores:hetionet NCBIGene:3759 biolink:causes MONDO:0008222 infores:monarchinitiative not_provided not_provided HGNC:6263 MONDO:0008222 uuid:f3f5be43-ae2b-4668-aee2-972729de13f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9073 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0549249 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0948296 infores:hetionet CHEBI:94848 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0012833 infores:hetionet CHEBI:8764 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030794 infores:hetionet CHEBI:17987 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0877098 infores:hetionet CHEBI:6847 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0042384 infores:hetionet CHEBI:45652 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C1262144 infores:hetionet GO:0098694 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:0098694 GO:0099504 CHEBI:27899 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151904 infores:hetionet CHEBI:47499 biolink:causes UMLS:C1290864 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C1290864 infores:hetionet CHEBI:39867 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0043094 infores:hetionet CHEBI:64354 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C2363730 infores:hetionet NCBIGene:348980 biolink:causes MONDO:0032777 infores:monarchinitiative not_provided not_provided HGNC:4845 MONDO:0032777 uuid:f527f528-556a-4b97-b9f6-a0d52b859f2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0010692 infores:hetionet CAID:CA253922 biolink:causes MONDO:0015152 infores:clingen CAID:CA253922 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting PP1 The NM_003494.4: c.5429G>A variant in DYSF, which is also known as NM_001130987.2: c.5546G>A (p.Arg1849Lys), is a missense variant predicted to cause substitution of arginine by lysine at amino acid 1810, p.(Arg1810Lys). This variant affects the last amino acid of exon 48 and is thus located in the splice donor motif. RNAseq analysis has demonstrated this variant affects splicing, causing skipping of exon 48 and resulting in a frameshift and premature truncation, p.Gly1781ValfsTer17 (PMID: 36983702, 20535123). This is consistent with the SpliceAI prediction score of 0.78 for donor loss. Low levels of transcripts with skipping of exons 48-49 and 48-50 were also detected, though these were more commonly expressed in blood over muscle and were also present in controls. (PVS1_RNA) This variant has been identified in at least eight patients with LGMD, including in a homozygous state in seven individuals, some with known familial consanguinity (0.5 pts, PMID: 36983702, 20535123; PM3_Supporting). Haplotype analysis suggests the c.5429G>A variant may be a founder variant in a region in northern Portugal (PMID: 20535123). At least one patient homozygous for this variant displayed a clinical suspicion or diagnosis of LGMD and absent or severely reduced dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 20535123). The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.000001696 (2/1179470 European (non-Finnish) chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA253922/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61058 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0025061 infores:hetionet UMLS:C0010592 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0236024 infores:hetionet NCBIGene:5925 biolink:causes MONDO:0008433 infores:monarchinitiative not_provided not_provided HGNC:9884 MONDO:0008433 uuid:3c2b17dd-55ba-4e49-8a73-6d01e4749415 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410206696 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206696 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The c.784C>T (p.Gln262Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2 and v3, ESP) with at least 20x coverage for RUNX1 (PM2_supporting). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID: 22430633) (PS4_ Supporting). It is of note that this variant was also found to co-segregate with disease in multiple affected family members of the aforementioned proband, but not in a sufficient number of individuals (PMID: 22430633). Note that the variant has also been reported in other individuals without definitive germline origin: patients with an unspecified platelet function disorder (PMID: 31064749), AML (PMID: 23958918), an esophageal tumor (PMID: 23525077), and the somatic/likely somatic variant has been identified in MDS/AML (Arcila, 2015, Presentation at USCAP Annual Meeting; Milosevic Feenstra et al., 2015, ASH Abstract 1626; PMID: 24030381) and solid tumors (COSMIC ID: COSV55866493; PMID: 30543347). Other downstream null variants have been frequently described in association with hereditary thrombocytopenia and hematologic cancer predisposition syndrome (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_supporting, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206696/MONDO:0011071/008 2021-06-12 2022-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63621 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2242737 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0919823 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0039503 infores:hetionet CHEBI:94686 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0085605 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0392197 infores:hetionet CAID:CA012843 biolink:causes MONDO:0021056 infores:clingen CAID:CA012843 MONDO:0021056 PMID: Uncertain Significance BS2, PS4_Supporting PVS1, PM2, BA1, BS1 The NM_000038.6(APC):c.70C>T (p.Arg24Ter) in APC is a nonsense variant located 5’ of codon 49, thus PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00002 (6/268,098 alleles), however, no value is given for the “filtering allele frequency” (FAF) (PM2_Supporting and BS1 not met). This variant has been observed in heterozygous state in 67 individuals, which are reported either with a very mild polyposis phenotype (only 3 carriers fulfilled 0.5 phenotype points each; PS4_Supporting) or without a colorectal cancer/polyposis associated phenotype (at least 10 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total; BS2) (PMID: 28135145 and 18433509, internal data Ambry Genetics, GeneDX and Labcorp Genetics (formerly Invitae)). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criterion PS4_Supporting and BS2 applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA012843/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4653 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0518015 infores:hetionet CHEBI:5132 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0024103 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0024115 infores:hetionet CHEBI:4909 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0028961 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0017178 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027769 infores:hetionet CHEBI:10102 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0027121 infores:hetionet CHEBI:63611 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0040822 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0031542 infores:hetionet CAID:CA386959170 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959170 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4 The c.370C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 124 (p.(Gln124Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15928245, 25953829). In summary, c.370C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959170/MONDO:0015967/017 2024-12-09 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:83475 biolink:causes MONDO:0859293 infores:monarchinitiative not_provided not_provided HGNC:28662 MONDO:0859293 uuid:48050242-ac7a-4bb7-9568-e025e971b799 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151736 infores:hetionet CHEBI:3534 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0085631 infores:hetionet CHEBI:3441 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151691 infores:hetionet NCBIGene:3070 biolink:causes MONDO:0014829 infores:monarchinitiative not_provided not_provided HGNC:4861 MONDO:0014829 uuid:145ebd42-5413-4051-9f48-5c2a4e6315cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0267792 infores:hetionet CHEBI:50859 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020443 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0022904 infores:hetionet NCBIGene:79574 biolink:causes MONDO:0013017 infores:monarchinitiative not_provided not_provided HGNC:21297 MONDO:0013017 uuid:796bf86c-2740-46ee-9919-d3a81071ee56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0034063 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0919874 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0021400 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0009806 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0232492 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017160 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0548823 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0026650 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0031117 infores:hetionet CHEBI:6532 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0011991 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0497247 infores:hetionet CHEBI:17076 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0015967 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004967 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023449 infores:hetionet CHEBI:17263 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0042133 infores:hetionet CHEBI:8764 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0549463 infores:hetionet CHEBI:5296 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0042963 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0041969 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020456 infores:hetionet GO:1902026 biolink:causes GO:0048705 infores:ubergraph knowledge_assertion manual_agent GO:1902026 GO:0048705 CHEBI:8207 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C1609512 infores:hetionet UMLS:C0879264 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020458 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0037274 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0002622 infores:hetionet CAID:CA16020989 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020989 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong This variant c.1282del (p.Gln428SerfsTer24) in PAH was documented 1 time in a patient with PAH deficiency (>120 μmol/L Phe) in the Czech Republic (PMID 23357515.) This is a frameshift variant in exon 12 out of 13 coding exons, not predicted to undergo nonsense mediated mRNA decay. The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020989/MONDO:0009861/006 2021-05-15 2021-05-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50730 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0015967 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0037274 infores:hetionet CHEBI:7773 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0011603 infores:hetionet CHEBI:4995 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0004093 infores:hetionet CAID:CA000203 biolink:causes MONDO:0017623 infores:clingen CAID:CA000203 MONDO:0017623 PMID: Uncertain Significance PM2, BP7 PVS1, PM6, BP5, BS1, BS3, BS4, BS2, PP1, PP2, PP3, PM4, PM1, PM5, BP4, BP2, BA1, PS3, PS1, PS2, PS4 PTEN c.78C>T (p.T26=) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000203/MONDO:0017623/003 2020-03-23 2020-03-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7627 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C2830004 infores:hetionet CAID:CA282088 biolink:causes MONDO:0021060 infores:clingen CAID:CA282088 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.333-3T>C variant in the PTPN11 gene is 0.0276% (6/9456) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA282088/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:4204 biolink:causes MONDO:0010397 infores:monarchinitiative not_provided not_provided HGNC:6990 MONDO:0010397 uuid:156f8edc-953f-4777-8661-fbb493a49662 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0687713 infores:hetionet CHEBI:92511 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0015423 infores:hetionet CHEBI:3380 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0039070 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0038454 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151883 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0079043 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0162429 infores:hetionet CHEBI:127780 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085593 infores:hetionet GO:0048349 biolink:causes GO:0048341 infores:ubergraph knowledge_assertion manual_agent GO:0048349 GO:0048341 CAID:CA2580098655 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098655 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.97+6T>G is a splice-site insertion variant. This variant alters the first three bases of an exon following an acceptor splice site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098655/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:2000011 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000011 GO:0007275 CHEBI:7915 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017160 infores:hetionet CAID:CA512318800 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318800 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.354G>C (p.Val118=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318800/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37333 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0013604 infores:hetionet CHEBI:27690 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017979 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0006285 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0434437 infores:hetionet CHEBI:49375 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0041364 infores:hetionet CHEBI:39585 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0019521 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235146 infores:hetionet CHEBI:83531 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C1167965 infores:hetionet CAID:CA386970409 biolink:causes MONDO:0015967 infores:clingen CAID:CA386970409 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS1 The c.1501+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 7 of NM_000545.8. This variant is predicted to cause an in-frame deletion of biologically-relevant exon 7 of 10, removing more than 18% of the transactivation domain, a region important for protein function (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). The nucleotide change, c.1501+1G>T, which causes the same splice donor loss, has been reported in a patient with monogenic diabetes; however, the c.1501+1G>T variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.1501+1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting.  Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386970409/MONDO:0015967/017 2022-04-17 2022-04-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50673 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0023530 infores:hetionet CAID:CA401370663 biolink:causes MONDO:0009290 infores:clingen CAID:CA401370663 MONDO:0009290 PMID: Pathogenic PM2, PVS1, PP4, PM3 This variant, c.2188G>T (p.Glu730Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product. This is supported by functional studies in HEK293T cells and COS-1 cells, which showed undetectable GAA activity (PMIDs 12923862, 21972175). This variant is absent in gnomAD v2.1.1. It has been reported in 3 patients with Pompe disease who meet the ClinGen LSD VCEP specifications for PP4; two are compound heterozygous for the variant and c.-31-13T>G (PMIDs 28196920, 28951071; phase unknown) and one is compound heterozygous for the variant and a frameshift variant, c.829_851del, confirmed in trans (PMID 12923862), meeting PM3. There is a ClinVar entry for this variant (Variation ID: 495665, one star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401370663/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3441 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0234533 infores:hetionet CHEBI:36791 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027497 infores:hetionet CHEBI:168396 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0026821 infores:hetionet CHEBI:35778 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0002792 infores:hetionet CAID:CA017009 biolink:causes MONDO:0005045 infores:clingen CAID:CA017009 MONDO:0005045 PMID: Uncertain Significance PM2, PM1, PS4_Supporting PS3, BA1, PM5, PM6, PM3, PP3, PP1, BS2, PP2, PP4, BS1, BS3, BS4, BP1, BP4, BP2, BP5, PS1, PS2 The NM_000257.4(MYH7):c.964T>A (p.Ser322Thr) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA017009/MONDO:0005045/002 2021-04-21 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8707 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0917799 infores:hetionet CAID:CA281995 biolink:causes MONDO:0021060 infores:clingen CAID:CA281995 MONDO:0021060 PMID:30732632 Pathogenic PS2, PM1, PM6, PM2, PP3, PP2, PS4_Supporting PM5 The c.1796C>T (p.Thr599Ille) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been reported as a de novo occurrence with parentage confirmed in 1 proband diagnosed with cardiofaciocutaneous syndrome (PS2, PS4_Supporting; PMID 30732632). This variant was also observed as a de novo occurrence without parentage confirmed in proband with phenotypic features of a RASopathy but no clinical diagnosis (PM6; GeneDx internal data, SCV000057239.11). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr599Ile variant may impact the protein (PP3). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM1, PM2, PM6, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA281995/MONDO:0021060/004 2020-03-24 2020-03-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:49375 biolink:causes UMLS:C0542007 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0542007 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0029456 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042109 infores:hetionet CAID:CA386960848 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960848 MONDO:0015967 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PS1_Supporting, PM2_Supporting, PS4 The c.526+1G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting).  This variant was identified in nine unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 21242637, internal lab contributors), including an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4, internal lab contributor). This variant segregated with diabetes, with three informative meioses in three families (PP1_Moderate, internal lab collaborators). The HNF1A(NM_000545.8):c.526+1G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>C has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33 bp 64% vs. 65%).  In summary, c.526+1G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PS4, PP1_Moderate, PS1_Supporting, PP4, PM2_Supporting.     Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960848/MONDO:0015967/085 2023-12-02 2023-12-02 Autosomal dominant inheritance HP:0000006 Supports UNII:15G12L5X8K biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0178298 infores:hetionet CAID:CA16020793 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020793 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4_Moderate, PP3_Strong, PM2_Supporting PM5 The c.453T>A (p.Asp151Glu) variant in PAH has been reported in two patients with PAH deficiency: a patient with mild HPA, detected with pathogenic variant T380M (PMID: 11552030); and a patient with classic PKU, detected with pathogenic variant c.1066-11G>A (PMID: 23856132). This variant is absent from gnomAD. Multiple lines of computational evidence support a deleterious effect (REVEL=0.935). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3, PP3_strong, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020793/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:167309 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0002453 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006026 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005686 infores:hetionet GO:0014902 biolink:causes CL:0002372 infores:ubergraph knowledge_assertion manual_agent GO:0014902 CL:0002372 NCBIGene:65217 biolink:causes MONDO:0011186 infores:monarchinitiative not_provided not_provided HGNC:14674 MONDO:0011186 uuid:7db20f71-60fa-4ba6-89a5-7b0c266644b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0231528 infores:hetionet UMLS:C0025241 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0239571 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0160390 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0018799 infores:hetionet CHEBI:32293 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0035317 infores:hetionet CHEBI:40050 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0042963 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0036341 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0234215 infores:hetionet CHEBI:34829 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0026961 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151734 infores:hetionet CHEBI:6438 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0018790 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0160390 infores:hetionet CHEBI:75246 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0016204 infores:hetionet CHEBI:77260 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020625 infores:hetionet CHEBI:28787 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0039070 infores:hetionet NCBIGene:1495 biolink:causes MONDO:0012162 infores:monarchinitiative not_provided not_provided HGNC:2509 MONDO:0012162 uuid:5805f33e-342e-4938-ade0-7d2bb642c7da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:73275 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0037763 infores:hetionet CAID:CA145911 biolink:causes MONDO:0015152 infores:clingen CAID:CA145911 MONDO:0015152 PMID: Benign BA1 BP4 The NM_000232.5: c.92G>T variant in SGCB is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 31 (p.Ser31Ile). The filtering allele frequency of this variant is 0.007653 in the African/African American population in gnomAD v3.1.2 (the lower threshold of the 95% CI of 347/41414 genome chromosomes), which is higher than the LGMD VCEP threshold (>0.002) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.18, which is above the LGMD VCEP threshold predicting a benign impact on sarcoglycan β function (<0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA145911/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5383 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020458 infores:hetionet CHEBI:50378 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0085605 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151763 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0234215 infores:hetionet CHEBI:5050 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0235710 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0005886 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D002180 DB00681_MESH_D002180_1 NCBIGene:25914 biolink:causes MONDO:0018764 infores:monarchinitiative not_provided not_provided HGNC:18654 MONDO:0018764 uuid:979685f0-3536-46f2-8e8f-57dca0375928 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0038661 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0019360 infores:hetionet CHEBI:2038 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0007859 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0240035 infores:hetionet UMLS:C0065374 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0007859 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0029882 infores:hetionet UNII:R43D2573WO biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0043094 infores:hetionet CHEBI:7573 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0231218 infores:hetionet CAID:CA3060570860 biolink:causes MONDO:0011071 infores:clingen CAID:CA3060570860 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS4, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.255_258delinsTGCC (p.Pro86Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3060570860/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3698 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020517 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235890 infores:hetionet CHEBI:71941 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0013144 infores:hetionet CHEBI:82941 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0151905 infores:hetionet CHEBI:6073 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0023530 infores:hetionet CHEBI:8107 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151604 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085606 infores:hetionet CHEBI:5002 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0151539 infores:hetionet CAID:CA260413 biolink:causes MONDO:0010315 infores:clingen CAID:CA260413 MONDO:0010315 PMID: Pathogenic PP4_Strong, PM2_Supporting, PS4 The NM_000206.3:c.455T>C variant in IL2RG is a missense variant predicted to cause substitution of valine by alanine at amino acid 152 (p.Val152Ala). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported in five patients from four families meeting the PP4 phenotypic criteria (PMIDs 33628209, 8557662, 11129345, 25326637) (PS4_Strong). One male patient with this variant presented with SCID within a year of life (PMID 11129345). The patient showed a T-B+NK- lymphocyte profile, with T cell 18/mm3 (normal range 1700-3600/mm3); B cell 1120/mm3 (normal range 500-1500/mm3) and NK cell 31/mm3 (normal range 300-700/mm3). A flow cytometry assay showed that surface expression of CD132 was absent on patient blood cells (PP4_Strong). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4_Strong, PM2_Supporting, PS4_Strong (VCEP specifications version 2.1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA260413/MONDO:0010315/129 2025-11-18 2025-11-21 X-linked inheritance HP:0001417 Supports CAID:CA214665 biolink:causes MONDO:0015967 infores:clingen CAID:CA214665 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP4, PP1 The c.1747C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 583 (p.(Arg583Gly)) of NM_000545.8. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% and HNF4A was not tested (PMID: 9313763). This variant segregated with diabetes with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 9313763). In summary, c.1747C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0 approved 8/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214665/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8768 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0152009 infores:hetionet CHEBI:34385 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0009782 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0003460 infores:hetionet CHEBI:18358 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0009450 infores:hetionet CHEBI:41879 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0085570 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0340909 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0340909 infores:hetionet CHEBI:6375 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085649 infores:hetionet CHEBI:6438 biolink:causes HP:0012155 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0859996 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0018802 infores:hetionet CHEBI:10100 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0018681 infores:hetionet CHEBI:10650 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0025222 infores:hetionet CHEBI:6847 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0037763 infores:hetionet CHEBI:63717 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0085682 infores:hetionet CHEBI:100246 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0002453 infores:hetionet CHEBI:46557 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0085682 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0812387 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042075 infores:hetionet CHEBI:42797 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0520966 infores:hetionet CHEBI:27974 biolink:causes MONDO:0006256 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0853879 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0000833 infores:hetionet CHEBI:63599 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0021051 infores:hetionet CHEBI:8207 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0002962 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0600327 infores:hetionet CHEBI:63791 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0025222 infores:hetionet CHEBI:94609 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0027497 infores:hetionet CHEBI:119915 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085624 infores:hetionet CHEBI:68554 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0311468 infores:hetionet CHEBI:31624 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0040822 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027720 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0549225 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0549225 infores:hetionet CAID:CA367400529 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400529 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.802G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 268 (p.(Glu268Lys)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.727, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.802G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400529/MONDO:0015967/086 2023-10-05 2023-10-05 Semidominant inheritance HP:0032113 Supports CHEBI:63598 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0232807 infores:hetionet CHEBI:63629 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011168 infores:hetionet CHEBI:6062 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0001925 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2939147 infores:hetionet CHEBI:52172 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030252 infores:hetionet CHEBI:16480 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0151699 infores:hetionet CHEBI:2611 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0234708 infores:hetionet NCBIGene:207 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:391 MONDO:0005575 uuid:b95bb2f4-8439-45b5-9f10-a58f8c5c5a62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0043352 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042998 infores:hetionet GO:0060651 biolink:causes GO:0060443 infores:ubergraph knowledge_assertion manual_agent GO:0060651 GO:0060443 CHEBI:4868 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0038454 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020615 infores:hetionet CHEBI:75722 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0424295 infores:hetionet CHEBI:49603 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0206062 infores:hetionet CHEBI:7025 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0521491 infores:hetionet CHEBI:47898 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019209 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0233472 infores:hetionet CAID:CA037448 biolink:causes MONDO:0007750 infores:clingen CAID:CA037448 MONDO:0007750 PMID: Benign BA1, BS3_Supporting, BP4, BP7 BP2, PS4, BS4, PP4, PP1 The NM_000527.5 (LDLR):c.1920C>T (p.Asn640=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BP4, BP7, BS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:BA1: FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1).BP4: No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing.BP7: Variant is synonymous and meets BP4.BS3_Supporting: Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect.PP4, PS4 not met: Variant did not meet PM2.PP1 not met: There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BS4 not met: There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.BP2 not met: Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037448/MONDO:0007750/013 2023-01-27 2023-04-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50885 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0018800 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0006145 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027765 infores:hetionet CHEBI:9667 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0033845 infores:hetionet CHEBI:17141 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0151827 infores:hetionet CHEBI:30830 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0013604 infores:hetionet CHEBI:7640 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0236075 infores:hetionet NCBIGene:4313 biolink:causes MONDO:0009809 infores:monarchinitiative not_provided not_provided HGNC:7166 MONDO:0009809 uuid:1ba9d3ff-a064-4dfb-959e-d5e07ad90270 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0035222 infores:hetionet CHEBI:45327 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0037188 infores:hetionet CHEBI:40303 biolink:causes GO:0042696 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0025274 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029456 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151872 infores:hetionet CHEBI:3001 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0240557 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0522224 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0015734 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0024299 infores:hetionet CHEBI:41423 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0002792 infores:hetionet CHEBI:28830 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0085631 infores:hetionet CHEBI:8060 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0013395 infores:hetionet CHEBI:36791 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037011 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006277 infores:hetionet CHEBI:7822 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0019080 infores:hetionet CHEBI:9654 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0016382 infores:hetionet CAID:CA021957 biolink:causes MONDO:0005045 infores:clingen CAID:CA021957 MONDO:0005045 PMID: Pathogenic PM1, PM2, PP3, PS4_Supporting, PS3_Moderate, PS2 PM5, BS1, BS3, PM6, BA1, PS1 NM_000363.5(TNNI3):c.575G>A (p.Arg192His) - This variant has been reported predominantly in individuals with HCM and RCM (LMM data, PMIDs: 12531876, 19449150, 20617149, 24474965, 25611685, 26741492, 27532257, 29176140, 30279906) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >5]. Therefore, the PS4_Supporting criterion has been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been confirmed as de novo in multiple occurrences (PS2; PMID: 12531876, 24474965, 26741492, 30279906). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1; PMID: 30696458). Functional studies have been reported and are sufficient to apply PS3_Moderate (PMID: 20161772, 17027633, 18408133, 22675533, 19289050, 28239629, 15961398, 16531415). Another variant involving this codon (p.Arg193Cys) has been identified in individuals with HCM and is classified as likely pathogenic by this VCEP; however, PM5 cannot be applied in combination with PM1. Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). Therefore, this variant meets criteria to be classified as Pathogenic based on PS4_Supporting, PM2_Supporting, PS2, PM1, PS3_Moderate, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA021957/MONDO:0005045/098 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49603 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0234894 infores:hetionet CHEBI:83804 biolink:causes HP:0002599 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1608410 infores:hetionet CAID:CA229398 biolink:causes MONDO:0009861 infores:clingen CAID:CA229398 MONDO:0009861 PMID:27121329PMID:10234516PMID:28754886PMID:10234516 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong The c.1217T>C (p.Ile406Thr) variant in PAH is reported in 2 unrelated patients with PKU; BH4 cofactor deficiency was ruled out. (PMID: 10234516, 27121329, 28754886) This variant was reported in trans with known pathogenic variants p.I65T (PMID: 10234516) and IVS4-1G>A (PMID: 28754886). It is absent in population databases, and multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229398/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51041 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0574067 infores:hetionet CHEBI:3749 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C2830004 infores:hetionet CHEBI:47657 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0017168 infores:hetionet CHEBI:27958 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0233494 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0031350 infores:hetionet CHEBI:3485 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0038362 infores:hetionet GO:0072539 biolink:causes CL:0000899 infores:ubergraph knowledge_assertion manual_agent GO:0072539 CL:0000899 UNII:R43D2573WO biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0003460 infores:hetionet CHEBI:6754 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0241934 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235032 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0162429 infores:hetionet CHEBI:63577 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0038325 infores:hetionet CHEBI:3176 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0002962 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0520587 infores:hetionet UNII:DJJ95FJP1H biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0855775 infores:hetionet CHEBI:72564 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0233471 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0027051 infores:hetionet CHEBI:8207 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0004604 infores:hetionet CHEBI:45327 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0220870 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005723 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0085436 infores:hetionet CHEBI:47381 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151786 infores:hetionet CHEBI:46345 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0234518 infores:hetionet CHEBI:136040 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020580 infores:hetionet CAID:CA410148093 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148093 MONDO:0011071 PMID: Uncertain Significance PS4, PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1109C>T (p.Ala370Val) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148093/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3568 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0043251 infores:hetionet CHEBI:3723 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0686347 infores:hetionet CHEBI:36791 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0162298 infores:hetionet CHEBI:10101 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0019209 infores:hetionet CHEBI:9086 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018800 infores:hetionet CHEBI:10125 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042024 infores:hetionet CHEBI:45599 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0016204 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0234215 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0023895 infores:hetionet CHEBI:53760 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0019209 infores:hetionet CHEBI:3061 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0041657 infores:hetionet CHEBI:7936 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014724 infores:hetionet CHEBI:4784 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0037763 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0036572 infores:hetionet CAID:CA512341282 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341282 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1137C>T (p.Thr379=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -1.12745 < 2.0), and the variant is the reference nucleotide in 3 mammal species (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341282/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50131 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0041969 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0005940 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015734 infores:hetionet CHEBI:51230 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0438142 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0022661 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020550 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0497247 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0155862 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0332575 infores:hetionet CHEBI:4027 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0041296 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0851341 infores:hetionet CAID:CA404080212 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080212 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.805G>A (p.Gly269Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - Variant meets PM2 and was identified in 1 index case who fulfills DLCN criteria of probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583742.1 in ClinVar), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080212/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:68642 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0852911 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0851341 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011630 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0020517 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0032285 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011616 infores:hetionet CHEBI:39867 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013404 infores:hetionet GO:0060685 biolink:causes GO:0030850 infores:ubergraph knowledge_assertion manual_agent GO:0060685 GO:0030850 GO:0072034 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0060993 CHEBI:10125 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0404521 infores:hetionet CHEBI:6073 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C2242996 infores:hetionet CHEBI:8871 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0231218 infores:hetionet CHEBI:8356 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042024 infores:hetionet CAID:CA383503586 biolink:causes MONDO:0015628 infores:clingen CAID:CA383503586 MONDO:0015628 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PS4 NM_000552.5(VWF):c.4241T>G is a missense variant in VWF predicted to encode substitution of valine by glycine at amino acid 1263. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.943, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (measured by VWF:RCo), low activity/VWF:Ag ratio, FVIII activity consistent with VWF antigen, low collagen binding, and loss of VWF high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID: 28971901, PMID: 29924855 ). This variant is classified as a variant of unknown significance for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PM2_Supporting, PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383503586/MONDO:0015628/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6067 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0349506 infores:hetionet CHEBI:72323 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0002792 infores:hetionet GO:1900234 biolink:causes GO:0036216 infores:ubergraph knowledge_assertion manual_agent GO:1900234 GO:0036216 CHEBI:47780 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0852733 infores:hetionet CHEBI:8069 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0012833 infores:hetionet CHEBI:61049 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3263723 infores:hetionet CHEBI:8430 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0004245 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0043241 infores:hetionet CHEBI:136040 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0151636 infores:hetionet CAID:CA5950633 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950633 MONDO:0000573 PMID: Uncertain Significance PM1_Supporting PM2 NM_000536.4(RAG2):c.35T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 12 (p.Ile12Thr).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The highest population minor allele frequency in gnomAD v4 is 0.001750 (151/75030) in African/African American population. (PM2_Supporting, BS1 and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950633/MONDO:0000573/124 2024-06-10 2024-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:46081 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0233494 infores:hetionet CHEBI:3568 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027497 infores:hetionet CHEBI:27974 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0002170 infores:hetionet NCBITaxon:69773 biolink:causes MONDO:0004549 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:69773 MONDO:0004549 UMLS:C0004609 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0034065 infores:hetionet CHEBI:94501 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020433 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0003864 infores:hetionet CHEBI:2955 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0017152 infores:hetionet CHEBI:48273 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0428977 infores:hetionet CHEBI:36795 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0041105 infores:hetionet GO:1902733 biolink:causes GO:0003416 infores:ubergraph knowledge_assertion manual_agent GO:1902733 GO:0003416 CHEBI:107736 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0036572 infores:hetionet NCBIGene:442721 biolink:causes MONDO:0030887 infores:monarchinitiative not_provided not_provided HGNC:6648 MONDO:0030887 uuid:079ec7d5-81dd-422a-98fd-c81e891ac919 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0231530 infores:hetionet UMLS:C0010592 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0232462 infores:hetionet CAID:CA367401978 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401978 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PM3, PP2, PP3, PP4, PP1, PM2_Supporting, PS3_Moderate The c.437T>C variant in the glucokinase gene, GCK causes an amino acid change of leucine to proline at codon 146 (p.(Leu146Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with diabetes/hyperglycemia (PS4_Moderate; PMID: 25015100, 31441606, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 3 informative meioses in 1 family (PP1; internal lab contributors). This variant has been detected in the homozygous state in at least 3 individuals with permanent neonatal diabetes (PP4 and PM3; PMIDs: 25015100, 31441606, internal lab contributor). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Leu146Pro variant has a relative activity index (RAI) <0.50 (PS3_Moderate; PMID: 25015100). In summary, the c.437T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PM3, PP4, PP1, PM2_Supporting, PP2, PP3, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401978/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Supports CHEBI:64312 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007787 infores:hetionet CHEBI:2673 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0002994 infores:hetionet CHEBI:101278 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0032617 infores:hetionet CAID:CA1139666840 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666840 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.844_856del (p.Asp282fs) is a frameshift variant which is not predicted to result in nonsense-mediated mRNA decay but the truncated region is critical to protein function (PVS1_strong). This variant is downstream of c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has not been reported in individuals meeting the RUNX1 phenotypic criteria. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666840/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4562 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0151744 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0877661 infores:hetionet CHEBI:44032 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0022346 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0233494 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0038661 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019340 infores:hetionet CHEBI:33325 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0011991 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151626 infores:hetionet CHEBI:4814 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0027121 infores:hetionet NCBIGene:5376 biolink:causes MONDO:0007309 infores:monarchinitiative not_provided not_provided HGNC:9118 MONDO:0007309 uuid:a38d20dd-7590-42dc-b5b0-353824a01252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410206802 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206802 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1): c.731C>T (p.Ala244Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206802/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7936 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151636 infores:hetionet CHEBI:4530 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0232286 infores:hetionet CHEBI:5134 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C2607914 infores:hetionet NCBIGene:64145 biolink:causes MONDO:0975797 infores:monarchinitiative not_provided not_provided HGNC:20759 MONDO:0975797 uuid:f01d6fd8-2261-4341-bf4f-528f0163952b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66964 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0027769 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0151773 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549346 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549346 infores:hetionet GO:0010695 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0044085 CHEBI:7936 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020458 infores:hetionet CHEBI:2038 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0231807 infores:hetionet CHEBI:48273 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0009806 infores:hetionet CHEBI:17303 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0000737 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0080203 infores:hetionet NCBIGene:3035 biolink:causes MONDO:0014711 infores:monarchinitiative not_provided not_provided HGNC:4816 MONDO:0014711 uuid:8fcdc54e-9bff-428a-9727-fdd08d01a165 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63616 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0162119 infores:hetionet CHEBI:41977 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0009763 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0037274 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1258215 infores:hetionet CHEBI:7936 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0577559 infores:hetionet CHEBI:51860 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0041582 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0018939 infores:hetionet CHEBI:3485 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0018965 infores:hetionet CHEBI:8764 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020443 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151883 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0700184 infores:hetionet CHEBI:6754 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0020458 infores:hetionet CHEBI:9763 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0040264 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014742 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0006277 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0015397 infores:hetionet CHEBI:28901 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0743400 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0003467 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0855242 infores:hetionet CHEBI:7822 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0042384 infores:hetionet CHEBI:8212 biolink:causes GO:0030432 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0031133 infores:hetionet CHEBI:65346 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0043352 infores:hetionet UMLS:C1738934 biolink:causes HP:0001147 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0240897 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0233494 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0015672 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018075 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0027794 infores:hetionet CHEBI:94392 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C1443060 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0034063 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0233494 infores:hetionet CHEBI:4995 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C2979982 infores:hetionet CHEBI:5128 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0023380 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1443060 infores:hetionet CHEBI:63631 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013390 infores:hetionet CHEBI:41879 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0004093 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0005779 infores:hetionet CHEBI:7824 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0030252 infores:hetionet CHEBI:3515 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0015967 infores:hetionet CHEBI:30659 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0042963 infores:hetionet CHEBI:7507 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0010043 infores:hetionet CAID:CA014901 biolink:causes MONDO:0004994 infores:clingen CAID:CA014901 MONDO:0004994 PMID: Likely Benign PP3, BS1 The filtering allele frequency of the c.4377G>T (p.Lys1459Asn) variant in the MYH7 gene is 0.0375% (34/66566) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; PMID:29300372). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3; BS1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014901/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3478 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0311468 infores:hetionet CHEBI:35677 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0027497 infores:hetionet CHEBI:6076 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151662 infores:hetionet CHEBI:51041 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0037763 infores:hetionet NCBIGene:4878 biolink:causes MONDO:0014329 infores:monarchinitiative not_provided not_provided HGNC:7939 MONDO:0014329 uuid:8828e0fd-024a-4159-a478-e1f95483d83a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0043352 infores:hetionet CHEBI:71223 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0027497 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0518015 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030312 infores:hetionet CAID:CA405677115 biolink:causes MONDO:0018493 infores:clingen CAID:CA405677115 MONDO:0018493 PMID: Likely Pathogenic PP1, PS4_Supporting, PM1, PS2_Moderate, PP3_Moderate PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with cysteine at codon 178 of the RYR1 protein, p.(Tyr178Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:16163667). In one individual the variant was determined to be de novo with confirmed parentage, PS2_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1 (PMID:16163667). A REVEL score >0.85 (0.951) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS2_Moderate, PS4_Supporting, PM1, PP1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405677115/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6741 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0037274 infores:hetionet CHEBI:46557 biolink:causes HP:0033331 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0001349 infores:hetionet CHEBI:3215 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0162297 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C1096343 infores:hetionet CHEBI:28748 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023467 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0521854 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0521854 infores:hetionet CHEBI:45924 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0085631 infores:hetionet CHEBI:33130 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0019054 infores:hetionet CHEBI:48390 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0030554 infores:hetionet CAID:CA414774272 biolink:causes MONDO:0044970 infores:clingen CAID:CA414774272 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6 PS4 The m.4142G>A (p.Arg279Gln) variant in MT-ND1 has been reported in three individuals with primary mitochondrial disease (PMIDs: 32652755, 23463613). The first reported individual had developmental delay, seizures, and hypotonia. The variant was present at 68.7% in blood and 85.7% in muscle (PMID: 23463613). The variant was not detected in the asymptomatic mother’s blood. Another reported individual had developmental delay, hypotonia, stroke, seizures, macrocephaly, and elevated lactate on brain magnetic resonance spectroscopy (MRS). The variant was present at 80% in muscle (PMID: 32652755). The variant was not detected in the asymptomatic matrilineal relatives, although tissue was not specified. The third reported case had epilepsy and stroke. The variant was present at 31% in blood and 65.3% in muscle (PMID: 32652755). The variant was not detected in the mother or maternal aunt however tissue was not specified (PM6, PMID: 32652755). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.74 (Min=0, Max=1), which predicts a damaging effect on gene function, and APOGEE2 similarly predicts this variant is pathogenic with a score of 0.972 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414774272/MONDO:0044970/015 2024-09-24 2025-11-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:17026 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0030554 infores:hetionet CHEBI:32139 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0027540 infores:hetionet CAID:CA410150321 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150321 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP3, BP1, BP4, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.820C>T (p.Q274*) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/8, leading to nonsense-mediated decay in a gene where loss-of-function is an established disease mechanism (PVS1). This variant is not predicted by SpliceAI to impact splicing and is absent from gnomAD v2, v3, and v4 (PM2_supporting). Although the variant has not been reported in the literature, other null variants in exon 7 have been classified as likely pathogenic (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150321/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16020996 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020996 MONDO:0009861 PMID:26322415 Pathogenic PM3, PM2, PP4_Moderate, PVS1_Strong Variant c.1316-2A>C in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). Null variant, canonical -2 splice sites, is in a gene where LOF is a known mechanism of disease. Exon skipping disrupts the reading frame. Altered region is critical to protein function. Not predicted to undergo NMD, because coding exon number is 13 out of 13 coding exons (PVS1-Strong). Variant was found in trans with a pathogenic variant p.R241C (PMID: 26322415). All mutations identified in patients were confirmed by analyzing parental DNA via Sanger automated sequencing (PM3). Variant is absent from controls in gnomAD, PAGE, 1000 Genomes, or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1-Strong, PM2, PP4-Moderate, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020996/MONDO:0009861/006 2020-05-14 2020-05-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0022281 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0015397 infores:hetionet CHEBI:6801 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0035455 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0549343 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0549343 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1384353 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0019158 infores:hetionet CHEBI:8107 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0034886 infores:hetionet CHEBI:7507 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0015403 infores:hetionet CAID:CA410204003 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204003 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BA1, BS1, BS3, BS4, BP7, PVS1, PM6, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.178G>C (p.Ala60Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score of 0.411, which is less than 0.50 and a spliceAI score <0.2 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204003/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3216 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0030193 infores:hetionet NCBIGene:10269 biolink:causes MONDO:0012074 infores:monarchinitiative not_provided not_provided HGNC:12877 MONDO:0012074 uuid:75ae6053-104e-4aa5-af38-ee8a50316609 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes NCIT:C122529 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0857494 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0007193 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042109 infores:hetionet CHEBI:8888 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235266 infores:hetionet NCBIGene:79576 biolink:causes MONDO:0026733 infores:monarchinitiative not_provided not_provided HGNC:29873 MONDO:0026733 uuid:e74675f2-ef11-4b49-babd-6f1258dab9a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0002878 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151838 infores:hetionet CHEBI:4027 biolink:causes MONDO:0018301 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0282488 infores:hetionet CHEBI:35778 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0030554 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0012833 infores:hetionet CHEBI:7809 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0231218 infores:hetionet CHEBI:7494 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0027796 infores:hetionet CHEBI:8502 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0015230 infores:hetionet CHEBI:16467 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0038999 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0853748 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0038363 infores:hetionet CHEBI:182080 biolink:causes GO:0070471 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0042130 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0038454 infores:hetionet CHEBI:29688 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0038362 infores:hetionet CHEBI:43968 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0033774 infores:hetionet CAID:CA124487 biolink:causes MONDO:0015967 infores:clingen CAID:CA124487 MONDO:0015967 PMID: Benign BA1, BS3_Supporting, PM1_Supporting BP4, PS4, PP3, PP4 The c.92G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 31 (p.(Gly31Asp)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While this variant has been noted to be a pathogenic variant in the literature, there are numerous pieces of evidence that refute this classification. Functional studies demonstrated the p.Gly31Asp protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant has a REVEL score of 0.591, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on HNF1A function. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.000772 (0.0772%), which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). It has been was identified in >30 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31365591, 31638168, 19169489, 26431509, 28395978, 20950394, 26059258, 19929997, 22432108, 27899486, 23551881, 24041679, 16917892, 21696527, and others). In summary, c.92G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BA1, BS3_Supporting, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124487/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101278 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027424 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0003864 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096034 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096034 infores:hetionet CHEBI:3181 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0015230 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0036454 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0018799 infores:hetionet CHEBI:100246 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0344232 infores:hetionet CAID:CA10586373 biolink:causes MONDO:0011225 infores:clingen CAID:CA10586373 MONDO:0011225 PMID: Pathogenic PM2_Supporting, PP1_Strong, PM3_Strong, PP4_Moderate PS3 The c.194C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 65 p.Thr65Ile.This variant is absent from gnomAD v2.1.1 (PM2_Supporting).This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID: 26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID: 26476407) (PM3_moderate); For 1 individual (PMID: 25917813), the second allele information wasn't available. The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID: 26476407). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PP4_Moderate, PP1_Strong, PM3_Strong, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586373/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:182080 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0002792 infores:hetionet CHEBI:45863 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0004604 infores:hetionet CHEBI:291342 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C1145628 infores:hetionet GO:0140620 biolink:causes GO:0006310 infores:ubergraph knowledge_assertion manual_agent GO:0140620 GO:0006310 CHEBI:3723 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038587 infores:hetionet UBERON:0003902 biolink:causes MONDO:0024341 infores:ubergraph knowledge_assertion manual_agent UBERON:0003902 MONDO:0024341 CHEBI:8228 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0085605 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0043144 infores:hetionet CHEBI:4728 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0001925 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0497365 infores:hetionet CAID:CA915940720 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940720 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PM3, PP4 The NM_000419.5 (ITGA2B):c.1211-78A>G intronic variant occurs at a nucleotide that is modestly conserved (phyloP score 0.988) but is not predicted by SpliceAI (or varSEAK) to have an impact splicing (BP4, BP7). It has been reported heterozygous in potential GT patient MB (PMID: 11798398; insufficient to meet any criteria). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940720/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:23765 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0575081 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011849 infores:hetionet CHEBI:27999 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0002874 infores:hetionet CHEBI:9943 biolink:causes MONDO:0009891 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0032463 infores:hetionet CHEBI:49575 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0085628 infores:hetionet CHEBI:171719 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1145670 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0022354 infores:hetionet CHEBI:41879 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0019521 infores:hetionet CHEBI:6437 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0001925 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042075 infores:hetionet CHEBI:35553 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0030554 infores:hetionet CHEBI:18243 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0428977 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0021400 infores:hetionet CHEBI:168396 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0233471 infores:hetionet CHEBI:10125 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037763 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0009782 infores:hetionet CHEBI:8107 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0040822 infores:hetionet CHEBI:8713 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0042029 infores:hetionet NCBIGene:3908 biolink:causes MONDO:0029136 infores:monarchinitiative not_provided not_provided HGNC:6482 MONDO:0029136 uuid:4eb57e9c-d250-4031-986d-b8e217bb2e55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0014591 infores:hetionet CHEBI:3994 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0040822 infores:hetionet CHEBI:75722 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0231835 infores:hetionet CHEBI:175901 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0014518 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1443060 infores:hetionet CHEBI:2682 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0004604 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0021400 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0575090 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0004238 infores:hetionet CHEBI:2904 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0036980 infores:hetionet CHEBI:51450 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0011603 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0024225 infores:hetionet UMLS:C1872203 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0020443 infores:hetionet CHEBI:27300 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0003123 infores:hetionet CHEBI:135939 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0041834 infores:hetionet CHEBI:4798 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0015230 infores:hetionet CHEBI:101278 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0428977 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0235146 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0018799 infores:hetionet CHEBI:5775 biolink:causes MONDO:0021718 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0032541 infores:hetionet CHEBI:52172 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0033774 infores:hetionet CHEBI:6801 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0015672 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0032781 infores:hetionet CHEBI:5134 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0085631 infores:hetionet NCBIGene:1414 biolink:causes MONDO:0012688 infores:monarchinitiative not_provided not_provided HGNC:2397 MONDO:0012688 uuid:34d8f83b-5bb3-4354-8fa9-28e3b9a157f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905708 biolink:causes GO:0000747 infores:ubergraph knowledge_assertion manual_agent GO:1905708 GO:0000747 CAID:CA308743496 biolink:causes MONDO:0011229 infores:clingen CAID:CA308743496 MONDO:0011229 PMID: Pathogenic PM3_Supporting, PM2, PVS1, PP4_Moderate PP1, BS2, BA1, PS2, PM6, BS1 The c.505+1G>A variant (NM_014297.5) in ETHE1 occurs within the canonical splice donor/acceptor site (+1) of exon/intron 4 boundary (exon 4/7). It is predicted to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 14732903). There is another pathogenic variant at this position (c.505+1G>T) for which Western blot analyses provided supportive evidence for nonsense mediated decay (PMID: 14732903). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (2/251,460 alleles) in the general population, which is lower than the ClinGen ETHE1 threshold < 0.00002 for PM2, meeting this criterion (PM2). This variant was originally reported in a homozygote with developmental delay, petechiae, orthostatic acrocyanosis, chronic diarrhea, and ethylmalonic aciduria which is a phenotype highly specific to ethylmalonic encephalopathy (PP4_moderate; PMID: 14732903 patient O). While there are at least 2 homozygotes of this variant with ethylmalonic encephalopathy reported to date, parental analyses have only been performed in one of these patients to confirm the variants were in trans (PM3_supporting; PMID: 29526615). In summary, this variant meets the criteria to be classified as pathogenic for Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): PVS1, PM2, PM3_supporting, PP4_Moderate. Approved 7/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA308743496/MONDO:0011229/014 2021-07-27 2021-07-27 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:9332 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027769 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005647 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0009663 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0264522 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0264522 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0853141 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0853141 infores:hetionet CHEBI:18332 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0033845 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0042373 infores:hetionet CHEBI:71940 biolink:causes UMLS:C2609264 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C2609264 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002878 infores:hetionet CHEBI:4784 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027497 infores:hetionet CAID:CA16614121 biolink:causes MONDO:0700269 infores:clingen CAID:CA16614121 MONDO:0700269 PMID: Likely Benign BP1_Strong BS1, BS3, BS4, BP5, PM2, PP1, PP4, BA1, PS3 The c.2482T>C variant in BRCA2 is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 828 (p.(Tyr828His)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.00, score threshold ≤0.1) (BP1_Strong met). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (v1.2) (BP1_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614121/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9943 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0242073 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0233414 infores:hetionet CHEBI:2611 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0851578 infores:hetionet CHEBI:472657 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0030312 infores:hetionet CHEBI:94501 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0042029 infores:hetionet CHEBI:6715 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0149745 infores:hetionet CHEBI:6078 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0022073 infores:hetionet CHEBI:6832 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0220870 infores:hetionet CHEBI:46345 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0023380 infores:hetionet CHEBI:8461 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0085631 infores:hetionet CHEBI:51041 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0016658 infores:hetionet CHEBI:92712 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0023518 infores:hetionet CAID:CA386492936 biolink:causes MONDO:0009861 infores:clingen CAID:CA386492936 MONDO:0009861 PMID:31332730PMID:31355225 Likely Pathogenic PM3, PM2, PP4_Moderate PP3 The c.1304A>T (p.Asp435Val) variant in PAH has been reported in a Uygur patient with moderate PKU (BH4 deficiency ruled out) (PP4_Moderate; PMID: 31355225). This variant was detected with p.Ala434Asp (Likely pathogenic in ClinVar) (PM3; PMID: 31355225). The variant is absent from population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386492936/MONDO:0009861/006 2020-04-10 2020-04-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8024 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013395 infores:hetionet CHEBI:82960 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0233762 infores:hetionet CHEBI:7903 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0151825 infores:hetionet GO:0072095 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0007275 GO:0099150 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0099150 GO:0007399 CHEBI:6950 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0032617 infores:hetionet CHEBI:44032 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0003862 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0019360 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006978 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037998 infores:hetionet CHEBI:3698 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0004238 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002871 infores:hetionet CHEBI:46295 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0002962 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0033975 infores:hetionet CHEBI:6923 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0162820 infores:hetionet CHEBI:7454 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0020538 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0549445 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0549445 infores:hetionet CHEBI:135361 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0018681 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013395 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011849 infores:hetionet CHEBI:4858 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0018965 infores:hetionet CHEBI:61033 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0013378 infores:hetionet CHEBI:480999 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0741494 infores:hetionet NCBIGene:64802 biolink:causes MONDO:0012056 infores:monarchinitiative not_provided not_provided HGNC:17877 MONDO:0012056 uuid:132a41cb-dc6b-4ea7-8fc4-c7dba826137d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:401474 biolink:causes MONDO:0010985 infores:monarchinitiative not_provided not_provided HGNC:31750 MONDO:0010985 uuid:74f18dde-da02-42c7-b158-49c6207c9d30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68855 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0043352 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0278008 infores:hetionet CHEBI:61033 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0030554 infores:hetionet CHEBI:521033 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0006142 infores:hetionet NCBIGene:367 biolink:causes MONDO:0019154 infores:monarchinitiative not_provided not_provided HGNC:644 MONDO:0019154 uuid:ba3ff828-8186-483b-860d-b5d5ac84882b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0235032 infores:hetionet UMLS:C0023610 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0000768 infores:hetionet CHEBI:7931 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151904 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C1258215 infores:hetionet CHEBI:29013 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0042109 infores:hetionet CHEBI:63630 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003811 infores:hetionet CHEBI:8382 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1443060 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0178298 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0235290 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0851341 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0155003 infores:hetionet CHEBI:45924 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0011606 infores:hetionet CHEBI:7575 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0085616 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004585 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020224 infores:hetionet CAID:CA658824375 biolink:causes MONDO:0007947 infores:clingen CAID:CA658824375 MONDO:0007947 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong The NM_00138 c.8416dup, is predicted to cause a frameshift resulting in a premature stop codon at position 2833, leading to a truncated protein. This variant is located in the coding exon 65 of the gene and is not expected to undergo nonsense-mediated decay. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). This variant was found in a proband with thoracic aortic dissection and a systemic score >7, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data, PMID 29875124, PP4). This variant has been reported twice in ClinVar, once as pathogenic and once as uncertain significance (Variation ID: 547349). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PM2_Sup, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824375/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:61049 biolink:causes UMLS:C1444565 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1444565 infores:hetionet NCBIGene:163786 biolink:causes MONDO:0014623 infores:monarchinitiative not_provided not_provided HGNC:25403 MONDO:0014623 uuid:1bcc558a-443a-415e-9e1c-0a2bcef672a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2677 biolink:causes MONDO:0010187 infores:monarchinitiative not_provided not_provided HGNC:4247 MONDO:0010187 uuid:9d5b2518-f221-4af3-a950-62fdff0d6592 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2579984167 biolink:causes MONDO:0100437 infores:clingen CAID:CA2579984167 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting PP1 NM_001034853.2(RPGR):c.2625dup (p.Gly876ArgfsTer?) is a frameshift variant due to a one-nucleotide insertion introducing a premature stop codon into exon 15 of 15 after 203 amino acids and causing a truncated protein, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 21857984, PMID: 28738413, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0: PVS1, PS4_Supporting, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579984167/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:47898 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0237849 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0038587 infores:hetionet CHEBI:85078 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C1384353 infores:hetionet CHEBI:63629 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013144 infores:hetionet CHEBI:2673 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0042963 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020437 infores:hetionet CHEBI:3423 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0231528 infores:hetionet CAID:CA512318673 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318673 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP2, BP1, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.660C>A (p.Ser220=) is a synonymous variant which has a SpliceAI score of ≤ 0.20 (BP4). This variant is completely absent from gnomAD v2.1.1 with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318673/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45409 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0006840 infores:hetionet CHEBI:44915 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0231835 infores:hetionet CAID:CA000295 biolink:causes MONDO:0017623 infores:clingen CAID:CA000295 MONDO:0017623 PMID:29706350 Uncertain Significance PM2, PP2, BS3_Supporting PVS1, PM6, BS4, BS1, BP7, BP5, BS2, PP1, PP3, PM4, PM1, PM5, BP2, BP4, BA1, PS2, PS4, PS3, PS1 PTEN c.1105G>A (p.Val369Ile) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populationsPP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of diseaseBS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000295/MONDO:0017623/003 2020-03-23 2020-03-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA631044734 biolink:causes MONDO:0012999 infores:clingen CAID:CA631044734 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong The NM_000156.6:c.440_441del (p.His147ProfsTer43) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001666 (1/60034 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 854960). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Strong, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 25, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631044734/MONDO:0012999/026 2025-04-25 2025-04-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA400025722 biolink:causes MONDO:0100326 infores:clingen CAID:CA400025722 MONDO:0100326 PMID:15634267 Likely Pathogenic PM3, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting The NM_000212.3(ITGB3):c.989T>A (p.Ile330Asn) missense variant has been reported in at least one patient (in PMID: 15634267) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was remarkably reduced, as measured by flow cytometry. Similarly, when mutant β3 cDNA/pSG5 were cotransfected into COS7 cells with WT αIIb/pSG5 and the percentage of positive transfected cells was determined by flow cytometry only 4% of COS7 cells were positive (15% of the WT level, 27%; PS3_supporting). The patient in PMID: 15634267 is compound heterozygous for the maternal Ile330Asn and paternal His306Pro (classified Likely Pathogenic by the PD-VCEP) variants (PM3). The computational predictor REVEL gives a score of 0.97 for Ile330Asn, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_supporting, PM2_supporting, PM3, PP3, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400025722/MONDO:0100326/011 2024-11-07 2025-02-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:480999 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0027497 infores:hetionet CHEBI:4798 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0030554 infores:hetionet CHEBI:31705 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0013604 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0032285 infores:hetionet CAID:CA7143097 biolink:causes MONDO:0019497 infores:clingen CAID:CA7143097 MONDO:0019497 PMID: Benign BA1 The filtering allele frequency of the c.629+5C>T variant in the COCH gene is 0.1% for European chromosomes by gnomAD (162/126474 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA7143097/MONDO:0019497/005 2019-02-25 2019-07-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:135351 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0004936 infores:hetionet CHEBI:421707 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0085605 infores:hetionet CHEBI:5103 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039584 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040261 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0042769 infores:hetionet CHEBI:10119 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0271710 infores:hetionet CAID:CA658824771 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824771 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The NM_000152.5:c.-32-1G>C variant in GAA alters the canonical acceptor splice site of intron 2 and is predicted cause skipping of exon 2, resulting in an in frame deletion that removes ~19% of the primary amino acid sequence of GAA. Exon 2 contains the start methionine and signal sequence for GAA (amino acids 1-27; https://www.uniprot.org/uniprot/P10253). Another variant in the same region, c.-32-13T>G, is one of the most common known pathogenic variants in GAA and results in leaky skipping of exon 2. Deletion of exon 2 causes complete loss of enzyme activity when expressed in heterologous cells (PMIDs 7881425, 7717400). PVS1 was applied, based on the specifications of the ClinGen Lysosomal Diseases VCEP. The variant is absent in gnomAD v2.1.1, meeting PM2_Supporting. This variant was reported in a French patient with late-onset Pompe disease (PMID 30155607). No additional details regarding enzyme activity, or other variant(s) found in the case were provided, and therefore neither PM3 nor PP4 were applied. There is a ClinVar entry for this variant (Variation ID: 557429). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf )GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824771/MONDO:0009290/010 2023-05-26 2023-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:10110 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0022107 infores:hetionet CHEBI:6067 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0014518 infores:hetionet CAID:CA5416498 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416498 MONDO:0011225 PMID: Likely Benign BS1 BS2 The c.1334G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 445 (p.Arg445His).The filtering allele frequency (the lower threshold of the 95% CI of 58/44884 alleles) of the c.1334G>A variant in DCLRE1C is 0.001026 for East Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00078) for BS1, and therefore meets this criterion (BS1)To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416498/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Contradicts true NCBITaxon:666 biolink:causes MONDO:0015766 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:666 MONDO:0015766 CHEBI:63624 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0041912 infores:hetionet CHEBI:9943 biolink:causes HP:0011896 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038534 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0031350 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0018965 infores:hetionet CHEBI:9332 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0042164 infores:hetionet NCBIGene:5373 biolink:causes MONDO:0008907 infores:monarchinitiative not_provided not_provided HGNC:9115 MONDO:0008907 uuid:756e5b53-a39f-413c-af66-5e45640479b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:520985 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0178298 infores:hetionet CHEBI:32020 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0011603 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0029408 infores:hetionet NCBIGene:9927 biolink:causes MONDO:0011002 infores:monarchinitiative not_provided not_provided HGNC:16877 MONDO:0011002 uuid:dc11e4fd-2d27-4918-93f0-a531f910b528 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6399 biolink:causes MONDO:0010737 infores:monarchinitiative not_provided not_provided HGNC:23068 MONDO:0010737 uuid:b65ff12d-51a3-44c7-9f3d-cef25b3519a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:205327 biolink:causes MONDO:0030378 infores:monarchinitiative not_provided not_provided HGNC:26799 MONDO:0030378 uuid:2a1266c0-3bb5-41ca-9d80-522217b90f42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0035078 infores:hetionet CHEBI:119573 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0030252 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0497247 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0022354 infores:hetionet CHEBI:94440 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0009806 infores:hetionet CAID:CA512319106 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319106 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP3, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM3, PM5, PM1, PM4, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.549A>G (p.Pro183=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4) and is predicted by evolutionary conservation algorithms to occur at a site that is not conserved (PhyloP score ≤ 2.0 (-2.8)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319106/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7476 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C3495920 infores:hetionet CHEBI:63791 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020488 infores:hetionet CHEBI:53760 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233471 infores:hetionet CHEBI:2950 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0014591 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0007642 infores:hetionet CHEBI:63621 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0392699 infores:hetionet CHEBI:63584 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0236075 infores:hetionet CHEBI:9448 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0034155 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0236065 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0237326 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0020649 infores:hetionet CHEBI:72564 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0235996 infores:hetionet CHEBI:31859 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013456 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013395 infores:hetionet CHEBI:4511 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C2697368 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151596 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0233472 infores:hetionet NCBIGene:28962 biolink:causes MONDO:0009817 infores:monarchinitiative not_provided not_provided HGNC:21652 MONDO:0009817 uuid:715006ea-4737-417a-a74e-c9b286f03986 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8665 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0948594 infores:hetionet CHEBI:23765 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0033036 infores:hetionet CHEBI:8081 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0877303 infores:hetionet CHEBI:49960 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020546 infores:hetionet CHEBI:44915 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0264893 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0031350 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0000731 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0003123 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0025061 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0003864 infores:hetionet CHEBI:63598 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0019079 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0040409 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0036416 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0267792 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151539 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0521509 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151717 infores:hetionet CHEBI:3437 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0497365 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0004936 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020517 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017178 infores:hetionet CHEBI:3504 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0151872 infores:hetionet CHEBI:8093 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0015403 infores:hetionet CAID:CA410150121 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150121 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.859T>C (p.Tyr287His) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150121/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5280 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020453 infores:hetionet GO:1904130 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:1904130 GO:0048513 CHEBI:7565 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0518015 infores:hetionet CHEBI:7959 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0085631 infores:hetionet CHEBI:7476 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0039070 infores:hetionet CHEBI:31236 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151754 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0014868 infores:hetionet CHEBI:2682 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0013447 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151596 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0525045 infores:hetionet CHEBI:28001 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0027497 infores:hetionet CHEBI:93635 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0085593 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0018099 infores:hetionet CHEBI:3223 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0037036 infores:hetionet CHEBI:2922 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0009763 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0973461 infores:hetionet CAID:CA297273 biolink:causes MONDO:0021060 infores:clingen CAID:CA297273 MONDO:0021060 PMID: Uncertain Significance PM2, PP2 PS4, BS1, PM1, PM5, PP3, BA1 The c.1646C>A (p.Thr549Lys) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297273/MONDO:0021060/004 2020-03-23 2020-03-23 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:74947 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003578 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0022346 infores:hetionet CHEBI:9139 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035455 infores:hetionet CHEBI:8346 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0004093 infores:hetionet CHEBI:5118 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013362 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0019054 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0853750 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0853750 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0002871 infores:hetionet CHEBI:3698 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C1368065 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0521491 infores:hetionet CHEBI:17334 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0036974 infores:hetionet CAID:CA410202778 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202778 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.358G>A (p.Ala120Thr) is a missense variant which affects one of the hotspot residues in the RHD established by the MM-VCEP for RUNX1 (AA Val120) (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score > 0.88 (0.901) (PP3). This variant has been reported in ClinVar; however, no phenotypic data was provided. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202778/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:101278 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0026858 infores:hetionet CAID:CA5779258 biolink:causes MONDO:0021060 infores:clingen CAID:CA5779258 MONDO:0021060 PMID:31040167 Benign BA1 PS4, PP3 The c.488_507delTCTGGGACCCCCCGGGACCC (p.Leu163HisfsTer30) variant in HRAS is classified as benign because it has been identified in 0.07227% (lower bound of the 95% CI of 21/19470) of East Asian chromosomes in gnomAD (BA1; gnomad.broadinstitute.org). This variant was observed in 1 fetus and 1 older proband with clinical presentations that lacked clear associations with a RASopathy. In summary, this variant meets criteria to be classified as benign. ACMG/AMP Criteria applied: BA1. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5779258/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63681 biolink:causes UMLS:C0235162 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0235162 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0178298 infores:hetionet CHEBI:15940 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0013404 infores:hetionet CHEBI:9123 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0423791 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0233494 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0018802 infores:hetionet CHEBI:116735 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0025637 infores:hetionet CHEBI:41774 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0024902 infores:hetionet CHEBI:15854 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0151636 infores:hetionet CAID:CA16041862 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041862 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 The c.644_647del (p.Phe214_Cys215insTer) variant in ACADVL is aframeshift variant predicted to cause a prematurestop codon in biologically-relevant-exon 8/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00006549 in Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with this variant displayed enzyme levels which is highly specific for VLCAD (PP4, PMID: 15210884).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the PVS1, PM2, PP4. (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041862/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49713 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0013395 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0149931 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0238707 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0238707 infores:hetionet CAID:CA402995088 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995088 MONDO:0012999 PMID:24415674 Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PP3_Moderate, PS3_Supporting PM5 The NM_000156.6:c.439C>T variant in GAMT is predicted to result in the substitution of histidine by tyrosine at amino acid 147 (p.His147Tyr). This variant has been identified in an individual with a diagnosis of guanidinoacetate methyltransferase deficiency confirmed by deficient enzyme activity in cultured fibroblasts (PMID: 24415674) (PP4_Moderate). This individual is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.11_36dup (p.Gly13fs) (ClinVar Variation ID: 858462); the phase is unconfirmed (PMID: 24415674) (0.5 points) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74918 alleles) in the African / African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). This variant was shown to result in 4% of wild-type enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.888 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 2446460). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 2.0.0): PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995088/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32184 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0521490 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0948586 infores:hetionet NCBIGene:2760 biolink:causes MONDO:0010099 infores:monarchinitiative not_provided not_provided HGNC:4367 MONDO:0010099 uuid:06aa69a2-5cc7-4db0-b88d-54946ab41cc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6073 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0011124 infores:hetionet CHEBI:31348 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0034886 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0851341 infores:hetionet UMLS:C0657912 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013362 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0021053 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0233494 infores:hetionet CHEBI:8356 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151786 infores:hetionet CHEBI:28939 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0039231 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002418 infores:hetionet CHEBI:94807 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0151905 infores:hetionet CHEBI:7565 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085633 infores:hetionet UNII:3U02EL437C biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0030193 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0020517 infores:hetionet CHEBI:10124 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0424295 infores:hetionet CHEBI:3510 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0003123 infores:hetionet GO:1905600 biolink:causes GO:0010876 infores:ubergraph knowledge_assertion manual_agent GO:1905600 GO:0010876 CHEBI:32139 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020598 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0267792 infores:hetionet CHEBI:6690 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0278134 infores:hetionet CHEBI:78320 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0030193 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0008325 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018021 infores:hetionet CHEBI:45081 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019209 infores:hetionet CHEBI:27777 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0232462 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0040409 infores:hetionet CHEBI:16755 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042963 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0017178 infores:hetionet UMLS:C0145867 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0011603 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1527311 infores:hetionet CHEBI:7445 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0024902 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018801 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0021053 infores:hetionet CHEBI:7915 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0022346 infores:hetionet CHEBI:5165 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0018800 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0221392 infores:hetionet CAID:CA377784501 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784501 MONDO:0017623 PMID: Pathogenic PS2_Very Strong, PP2, PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting NM_000314.8(PTEN):c.113C>T (p.Pro38Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: Two proven de novo observations in a patient with the disease and no family history. (internal laboratory contributor: SCV002757182.1).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.772 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor: SCV002757182.1).PM2_P: Absent in gnomAD.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.923) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784501/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports CAID:CA399801004 biolink:causes MONDO:0100326 infores:clingen CAID:CA399801004 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.1993C>T (p.Gln665Ter) nonsense variant creates a premature stop codon in exon 20/30 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT37 of PMID: 29675921 who meets the criteria for PP4_strong. GT37 is homozygous for Gln665Ter (PM3_supporting). The highest population minor allele frequency in gnomAD 2.1.1 is 0.00005461 (1/18310alleles) in the East Asian population (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399801004/MONDO:0100326/011 2021-06-30 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7565 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0040034 infores:hetionet CHEBI:231594 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0000737 infores:hetionet CHEBI:32293 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0017178 infores:hetionet CHEBI:15544 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0038999 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0521839 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0030552 infores:hetionet CAID:CA147747 biolink:causes MONDO:0015152 infores:clingen CAID:CA147747 MONDO:0015152 PMID: Benign BA1 PM3, BP4, PP3 The NM_003494.4: c.383G>A variant in DYSF, which is also known as NM_001130987.2: c.386G>A p.(Gly129Glu), is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 128, p.(Gly128Glu). The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.03324 (the lower threshold of the 95% CI of 223/5988 Middle Eastern chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been reported with a second heterozygous DYSF variant in an individual with reduced dysferlin expression (PMID: 21522182), its frequency in control populations is high relative to disease prevalence (PM3 not met). The SpliceAI score for this variant is 0.01, suggesting it does not impact splicing. The computational predictor REVEL gives a score of 0.45 (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/19/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147747/MONDO:0015152/180 2025-05-19 2025-06-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:465284 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020621 infores:hetionet NCBIGene:5332 biolink:causes MONDO:0957544 infores:monarchinitiative not_provided not_provided HGNC:9059 MONDO:0957544 uuid:f0f3b11a-0022-4f76-801f-61cdbc6c937b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0231530 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002884 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033975 infores:hetionet CAID:CA402998364 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998364 MONDO:0012999 PMID: Pathogenic PVS1, PM3, PP4_Strong PM2 "The NM_000156.6:c.48C>A (p.Cys16Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 but coverage of this region is <20X and therefore PM2_Supporting is not met. First cousins who are homozygous for the variant (PMID 31559727), and siblings who are compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown, have been reported (PMID: 24268530) (PM3). These individuals all had clinical symptoms consistent with GAMT deficiency; in one of them elevated guanidinoacetate values were documented in urine and creatine peak was ""sharply"" decreased on MRS (PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 2412845). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific criteria met, as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0), PVS1, PP4_Strong, PM3.(CLassification approved by the ClinGen CCDS VCEP, August 8, 2023)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998364/MONDO:0012999/026 2023-08-08 2023-09-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27974 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0262397 infores:hetionet CHEBI:91834 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013378 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0553704 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018099 infores:hetionet CHEBI:7931 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0438215 infores:hetionet CHEBI:6438 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0027424 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0340464 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005451 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013473 infores:hetionet CHEBI:3216 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0019521 infores:hetionet CHEBI:50924 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0015672 infores:hetionet NCBIGene:5009 biolink:causes MONDO:0010703 infores:monarchinitiative not_provided not_provided HGNC:8512 MONDO:0010703 uuid:a26be9b4-f1d6-4743-bb60-bb67515bf551 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0151517 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0003864 infores:hetionet UMLS:C1738934 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0232462 infores:hetionet CHEBI:7496 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0004604 infores:hetionet CHEBI:63584 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0018965 infores:hetionet CAID:CA8365861 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365861 MONDO:0100453 PMID: Likely Benign BP4 The NM_000180.4(GUCY2D):c.1721G>A (p.Arg574His) variant is predicted to replace the arginine at position p.574 with histidine. The computational predictor REVEL gives a score of 0.182, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RETGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.00005950, with 96 alleles / 1,613,430 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 but is not considered due to the evidence supporting a benign classification. In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365861/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true UNII:R43D2573WO biolink:causes UMLS:C0861120 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0861120 infores:hetionet CHEBI:617099 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0239571 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0011991 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235889 infores:hetionet CHEBI:9139 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2939447 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034152 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0038362 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0023510 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0009450 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085584 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018621 infores:hetionet NCBIGene:631 biolink:causes MONDO:0012665 infores:monarchinitiative not_provided not_provided HGNC:1040 MONDO:0012665 uuid:e9d07c11-13b8-4049-8d62-6e9555f5b589 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38545 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0013395 infores:hetionet CHEBI:5775 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0233407 infores:hetionet CHEBI:37333 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0011991 infores:hetionet CHEBI:119573 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0012569 infores:hetionet CAID:CA266820 biolink:causes MONDO:0012589 infores:clingen CAID:CA266820 MONDO:0012589 PMID:21671391PMID:18728071PMID:21671391PMID:18728071PMID:21671391PMID:18728071 Pathogenic PS3_Supporting, PM1, PP4, PP3, PS4_Moderate, PM6_Strong, PM2_Supporting The p.Arg578His variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt-Hopkins syndrome (PMID 18728071) (PP4). This variant appears to be de novo in this patient and has been reported in the de novo state (biological parentage unconfirmed) in at least two additional patients with Pitt-Hopkins syndrome (PMID 21671391) (PM6_strong, PS4_moderate). In vitro binding assays have shown that this variant impacts impacts protein function (PMID 22460224) (PS3_supporting). This variant is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg578His variant in TCF4 is absent from gnomAD (PM2_supporting). In summary, the Arg578His variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA266820/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf UNII:R43D2573WO biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0948586 infores:hetionet CHEBI:7565 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042963 infores:hetionet CHEBI:31711 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0233407 infores:hetionet CHEBI:7907 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0036104 infores:hetionet NCBITaxon:787 biolink:causes MONDO:0001118 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:787 MONDO:0001118 NCBIGene:23287 biolink:causes MONDO:0032650 infores:monarchinitiative not_provided not_provided HGNC:17258 MONDO:0032650 uuid:98e2e13b-8242-4f58-b461-8eca9f61edfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0000833 infores:hetionet GO:0039592 biolink:causes GO:0000086 infores:ubergraph knowledge_assertion manual_agent GO:0039592 GO:0000086 CHEBI:5134 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0021053 infores:hetionet CHEBI:9434 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0011991 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0948281 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0948281 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0392025 infores:hetionet CHEBI:31624 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0340865 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0006266 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0243026 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0001824 infores:hetionet CHEBI:135920 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0041969 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151763 infores:hetionet CHEBI:5779 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0042029 infores:hetionet CHEBI:50777 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0026821 infores:hetionet CHEBI:9288 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0022661 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0233571 infores:hetionet CHEBI:63630 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0039070 infores:hetionet CHEBI:114785 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0014742 infores:hetionet CHEBI:75722 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019521 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0042769 infores:hetionet CHEBI:8327 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0042109 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042571 infores:hetionet CHEBI:17303 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0037763 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003123 infores:hetionet GO:0002244 biolink:causes CL:0008001 infores:ubergraph knowledge_assertion manual_agent GO:0002244 CL:0008001 CAID:CA346732539 biolink:causes MONDO:0007356 infores:clingen CAID:CA346732539 MONDO:0007356 PMID: Likely Pathogenic PVS1_Strong, PP4, PM2_Supporting BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, BS2 The NM_000251.3:c.792+1G>T variant alters canonical donor splice site of exon 4 and is predicted to cause in-frame exon 4 skipping (the altered region is critical to protein function) or cryptic donor usage in intron 4 (38 bp out of frame intron inclusion) (PVS1_Strong met). There is 1 colon tumour with MSH2 loss reported (Australian Colon Cancer Family Registry) (PP4 met). The variant is absent in gnomAD v2.1, v3.1 and v4.1 (PM2_Supporting met). Therefore, this variant meets the criteria to be classified as Likely Pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA346732539/MONDO:0007356/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9586 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0423791 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0851341 infores:hetionet UMLS:C0120107 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013404 infores:hetionet CAID:CA10583884 biolink:causes MONDO:0011071 infores:clingen CAID:CA10583884 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP4, PP2, PP1, BS2 NM_001754.5(RUNX1):c.667G>A (p.Glu223Lys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583884/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9123 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009946 infores:hetionet NCBIGene:4935 biolink:causes MONDO:0021019 infores:monarchinitiative not_provided not_provided HGNC:20145 MONDO:0021019 uuid:b7f24b4f-d38c-4d47-b283-74d8fa0317f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042384 infores:hetionet CHEBI:43968 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0014518 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0013395 infores:hetionet CHEBI:74947 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011168 infores:hetionet CHEBI:72296 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0009782 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0036572 infores:hetionet CHEBI:7465 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0030193 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0162316 infores:hetionet CAID:CA10014189 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014189 MONDO:0011071 PMID: Likely Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, PM2, BS3, BS4, BP5, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1269C>T (p.Arg423=) is a synonymous variant which has a MAF of 0.0003400 (0.034%, 23/67652 alleles) in the European non-Finnish subpopulation of the gnomAD v3 cohort, meeting the threshold for BS1. This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.62)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014189/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5138 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033774 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009450 infores:hetionet CHEBI:135930 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020461 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0235453 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0235453 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151826 infores:hetionet CHEBI:6904 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0036980 infores:hetionet CHEBI:10124 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0030554 infores:hetionet CHEBI:4495 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020621 infores:hetionet CHEBI:7798 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0013447 infores:hetionet CHEBI:9587 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0038325 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020437 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0497217 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0497217 infores:hetionet CHEBI:45783 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018944 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0042109 infores:hetionet CAID:CA210798 biolink:causes MONDO:0013144 infores:clingen CAID:CA210798 MONDO:0013144 PMID: Pathogenic PS4, PP1_Strong, PP3, PP4, PM2_Supporting PM5 The NM_000488.4(SERPINC1):c.655A>G (p.Asn219Asp) missense variant is reported at a Popmax FAF of 0.00000488 (non-Finnish European) in gnomAD v3.1.2 and a frequency of 0.000008792 (1/113744) in gnomAD v2.1.1, meeting criteria for PM2_Supporting. It has a REVEL score of 0.898 (PP3 is >0.6). One proband from PMID: 28300866 (family of four affected individuals), 2 probands from PMID: 15630491, 1 proband from PMID: 7989582, and 1 proband from PMID: 7795154 meet phenotype criteria for PS4, PP4 and PP1_Strong. Of note, PMID: 30005274 reports that the Asn219Asp variant associated with Type II RS is hardly detected by the different anti-FXa or anti-FIIa assay methods. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Strong, PP3, PP4, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210798/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0065374 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0038325 infores:hetionet NCBIGene:317761 biolink:causes MONDO:0030938 infores:monarchinitiative not_provided not_provided HGNC:19849 MONDO:0030938 uuid:1a8c1d14-a3f0-4a43-a105-e708fad8dfea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085631 infores:hetionet CHEBI:4466 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0007166 infores:hetionet CHEBI:4708 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0039070 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151838 infores:hetionet CHEBI:31348 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0016382 infores:hetionet CHEBI:46195 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0085649 infores:hetionet NCBITaxon:786 biolink:causes MONDO:0019360 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:786 MONDO:0019360 CHEBI:63581 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0025517 infores:hetionet CHEBI:49662 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0232462 infores:hetionet NCBIGene:27429 biolink:causes MONDO:0044723 infores:monarchinitiative not_provided not_provided HGNC:14348 MONDO:0044723 uuid:12465f2a-2db7-4451-80f9-f8a6fbbd3d23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7773 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0332575 infores:hetionet CHEBI:18248 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020461 infores:hetionet UMLS:C0011701 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0038999 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0854303 infores:hetionet CAID:CA400029664 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029664 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000212.3(ITGB3):c.1525C>T (p.Gln509Ter) found in a compound heterozygous proband PMID:28748566) causes a premature stop codon at exon 10 and is predicted to undergo nonsense mediated decay (PVS1). The variant was not found in gnomAD v2.1.1 (PM2_supporting). The variant has been reported as compound heterozygous with pathogenic variant,(NM_000212.3(ITGB3):c.567del (p.Tyr190ThrfsTer17), phase unknown (PM3_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029664/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7931 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0032285 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022658 infores:hetionet NCBIGene:154197 biolink:causes MONDO:0030439 infores:monarchinitiative not_provided not_provided HGNC:21185 MONDO:0030439 uuid:de376e68-bc9d-4f1b-9c75-8ca65a8b19e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0022408 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030312 infores:hetionet CHEBI:37924 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020433 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0029408 infores:hetionet CHEBI:4798 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0030662 infores:hetionet CHEBI:71417 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0011168 infores:hetionet CHEBI:3001 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0041582 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0948089 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235398 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235398 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0042514 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1291078 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234913 infores:hetionet CHEBI:4511 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C2129214 infores:hetionet CHEBI:2611 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233471 infores:hetionet CHEBI:41879 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0039070 infores:hetionet UMLS:C0023610 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0025320 infores:hetionet CAID:CA1251431 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251431 MONDO:0013144 PMID: Likely Benign BS1, BP4 BP7 The NM_000488.4(SERPINC1):c.408+4C>T variant is an intronic variant reported at a POPMAX FAF of 0.0003794 in the South Asian population (18/30616 alleles) meeting BS1 criteria. SpliceAI and VarSEAK predict no splicing impact for this variant; however the nucleotide may be conserved based on PhyloP and PhastCons scores (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BS1, BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251431/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:46295 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C3257803 infores:hetionet CHEBI:8888 biolink:causes MONDO:0044937 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007113 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0919569 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0919569 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0347390 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0032584 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0343863 infores:hetionet CHEBI:64028 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0232462 infores:hetionet CAID:CA258144 biolink:causes MONDO:0100084 infores:clingen CAID:CA258144 MONDO:0100084 PMID: Pathogenic PP2, PP3, PM2_Supporting, PP4_Moderate, PS3, PP1_Moderate PS4 The c.493G>A variant in ACTA1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 165 (legacy nomenclature: p.Val163Met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In vitro studies in C2C12 myoblasts showed that V165M formed intranuclear actin aggregates with low levels of cytoplasmic aggregates, indicating that this variant impacts protein function. These oblong intranuclear aggregates closely resembled intranuclear bodies observed in muscle samples from patients with intranuclear myopathy. Additionally, Drosophila heterozygous for V165M show that V165M can severely affect Z-disc assembly and the stability of the sarcomere. Heterozygous V165M Drosophila presented with zebra bodies, Z-rings, and intranuclear rods (PS3; PMID:15198992, 17705262, 23294764). This variant has been reported in 1 proband with intranuclear rod myopathy confirmed by biopsy (PP4_Moderate; PMID:12921789). The variant has been reported to segregate with nemaline myopathy in 2 affected family members from 1 family (PP1_Moderate; PMID: 12921789). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS3, PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PP2 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA258144/MONDO:0100084/147 2024-08-27 2024-12-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10112 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0549373 infores:hetionet CAID:CA213788 biolink:causes MONDO:0015967 infores:clingen CAID:CA213788 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting PP4 The c.457C>T variant in the glucokinase gene, GCK, causes an amino acid change of proline to serine at codon 153 (p.(Pro153Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 28726111, internal lab contributors). Another missense variant, c.458C>A p.Pro153His, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to FBG above the guideline range (internal lab contributors). In summary, c.457C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM5_Supporting, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213788/MONDO:0015967/086 2024-04-22 2024-04-22 Semidominant inheritance HP:0032113 Supports CHEBI:17141 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0013395 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0037274 infores:hetionet CHEBI:8764 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0152009 infores:hetionet CHEBI:101278 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0085612 infores:hetionet NCBITaxon:10335 biolink:causes MONDO:0017372 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10335 MONDO:0017372 CHEBI:5106 biolink:causes HP:0025017 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0006905 infores:hetionet CHEBI:7915 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0003811 infores:hetionet CHEBI:49575 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0028084 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020676 infores:hetionet CHEBI:681848 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0020458 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0015397 infores:hetionet GO:1905421 biolink:causes GO:0099402 infores:ubergraph knowledge_assertion manual_agent GO:1905421 GO:0099402 CHEBI:7824 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0575081 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0037199 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549264 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549264 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0008370 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030312 infores:hetionet CHEBI:48669 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0016382 infores:hetionet CHEBI:68478 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0858635 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0233632 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042373 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0020649 infores:hetionet CHEBI:6061 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0012833 infores:hetionet CAID:CA6748814 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748814 MONDO:0009861 PMID:16198137PMID:12409276PMID:16198137 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PP3 The c.859C>G (p.Leu287Val) variant in PAH is found with low allele frequency in population databases (3.0e-5). It has been identified in trans with pathogenic variants in two individuals in the literature (P281L and A300S, PMID: 12409276), and in one of those patients a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 16198137). . In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748814/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:499361 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013295 infores:hetionet CHEBI:3219 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151936 infores:hetionet CHEBI:8871 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017181 infores:hetionet CHEBI:83531 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0232462 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0004936 infores:hetionet CHEBI:135738 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0022660 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151736 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0162429 infores:hetionet CHEBI:4798 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0016382 infores:hetionet CHEBI:4514 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0039231 infores:hetionet CHEBI:63791 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0035410 infores:hetionet CAID:CA405668242 biolink:causes MONDO:0007783 infores:clingen CAID:CA405668242 MONDO:0007783 PMID: Likely Pathogenic PS4_Supporting, PM5, PM1_Supporting, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glycine with arginine at codon 2375 of the RYR1 protein, p.(Gly2375Arg).This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). No functional studies were identified for this variant. Another variant that has been assessed as pathogenic occurs at this codon, p.Gly2375Ala, PM5 (PMID: 12434264). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (.9) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Supporting, PM1_Supporting, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405668242/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:119573 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0038999 infores:hetionet GO:0060920 biolink:causes CL:0002072 infores:ubergraph knowledge_assertion manual_agent GO:0060920 CL:0002072 CHEBI:2663 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0023895 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0853074 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0853074 infores:hetionet CHEBI:135342 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0391870 infores:hetionet CHEBI:8863 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020580 infores:hetionet CHEBI:7773 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0020621 infores:hetionet CHEBI:44185 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151942 infores:hetionet CHEBI:144551 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0039070 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0234458 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0032584 infores:hetionet GO:2000043 biolink:causes GO:0060911 infores:ubergraph knowledge_assertion manual_agent GO:2000043 GO:0060911 CHEBI:10127 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0162429 infores:hetionet CHEBI:63619 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235266 infores:hetionet CHEBI:68478 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0700225 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0016169 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0016169 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235119 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235119 infores:hetionet CAID:CA410206879 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206879 MONDO:0011071 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.694C>T (p.Arg232Trp) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 33075818 - AML and FPD).In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PS4_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206879/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52010 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0026961 infores:hetionet CAID:CA10568260 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568260 MONDO:0010602 PMID: Likely Benign BS1, BP4 PS4 The c.2961G>C variant in F8 is a missense variant predicted to cause substitution of glutamic acid by aspartic Acid at amino acid 987 (p.Glu987Asp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001835 (5/27255 alleles) in the Admixed American population, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>0.0000333) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.224, which is below the threshold of <=0.3 and the splice site predictor Splice AI indicated that the variant has no impact on splicing (score = 0.00, 0.00, 0.00, 0.00, threshold <=0.05), evidence that does not predict a damaging effect on F8 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BS1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568260/MONDO:0010602/071 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Contradicts true PUBCHEM.COMPOUND:3467 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0023380 infores:hetionet NCBIGene:3043 biolink:causes MONDO:0018023 infores:monarchinitiative not_provided not_provided HGNC:4827 MONDO:0018023 uuid:8c2d74fd-bce0-4b7a-bbd0-cbe62502eed6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:93363 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0344232 infores:hetionet CAID:CA624861219 biolink:causes MONDO:0008723 infores:clingen CAID:CA624861219 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1, PP4_Moderate PP1 The NM_000018.4: c.103_112dup10 (p.Arg38ProfsTer24) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in at least 2 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency identified by increased C14:1 levels by newborn screen and one of these individuals had an acylcarnitine analysis consistent with VLCAD deficiency (PP4_moderate; PMID: 29519241, 29768383). One of these individuals was homozygous for the variant (PM3_supporting; PMID: 29768383). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM3_supporting, PM2_supporting (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624861219/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Supports UNII:G4PX8C4HKV biolink:causes MONDO:0000385 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0497538 infores:hetionet CHEBI:51860 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0232461 infores:hetionet CHEBI:261649 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0019054 infores:hetionet CHEBI:10650 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0577559 infores:hetionet CHEBI:31236 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011253 infores:hetionet CHEBI:52717 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0039231 infores:hetionet CHEBI:7476 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151799 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0858854 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0858854 infores:hetionet CHEBI:114785 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0019080 infores:hetionet CHEBI:135736 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019080 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013298 infores:hetionet CHEBI:4728 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0021141 infores:hetionet NCBIGene:29851 biolink:causes MONDO:0011864 infores:monarchinitiative not_provided not_provided HGNC:5351 MONDO:0011864 uuid:df366119-08d3-4297-8c53-901e4aa56b05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0043352 infores:hetionet CHEBI:3515 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0000729 infores:hetionet CHEBI:31980 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0270996 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0233494 infores:hetionet CHEBI:9674 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0030252 infores:hetionet CHEBI:39867 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151908 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030312 infores:hetionet CHEBI:4514 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0033774 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017563 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0019087 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0235560 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0235560 infores:hetionet CHEBI:7459 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C1260880 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0020517 infores:hetionet CHEBI:28748 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030554 infores:hetionet CHEBI:31980 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0600142 infores:hetionet CHEBI:17474 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042133 infores:hetionet CHEBI:5118 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0039231 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151888 infores:hetionet CHEBI:51137 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0424000 infores:hetionet CHEBI:71940 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0006277 infores:hetionet CAID:CA2573332240 biolink:causes MONDO:0001586 infores:clingen CAID:CA2573332240 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting PP4 "The NM_000203.5:c.540_544del (p.Trp180Ter) variant is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients from the UK with a severe/Hurler phenotype have been reported with this variant. The individuals in the study have ""a biochemical diagnosis of MPS I"" (PMID: 28752568) (Insufficient data to apply PP4) .One of these patients has been reported who is compound heterozygous, phase unconfirmed, for c.540_544delGAATG and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909, 0.5 points, PMID: 28752568). Another patient is compound heterozygous for the variant and c.386-2A>G. The allelic data from the second patient will be used in the classification of c.386-2A>G and is not included here to avoid circular logic ( PMID: 28752568) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000005085 (6/1179966 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Note that another variant, NM_000203.5(IDUA):c.540G>A, resulting in the same change, p.Trp180Ter, has been reported (ClinVar Variation ID: 1321357). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PVS1, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573332240/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports CAID:CA273952 biolink:causes MONDO:0009290 infores:clingen CAID:CA273952 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PVS1_Strong The NM_000152.5:c.1A>G (p.Met1Val, aka p.Met1?) start loss variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong; PMIDs 22644586, 30192042, 22252923). This variant is absent in gnomAD v2.1.1. (PM2_Supporting).This variant has been detected in at least 5 individuals with Pompe disease. Three individuals are compound heterozygous for the variant and another pathogenic or likely pathogenic variant in GAA, including c.2608T>C (pArg870Ter) (pathogenic based on classification by the ClinGen LD VCEP, confirmed in trans, 1 point, PMID: 33301762), exon 6-10 deletion (pathogenic, phase confirmed, 1 point, PMID: 37542277), and c.1831G>A (p.Gly611Ser), LP based on classification by the ClinGen LD VCEP; phase unconfirmed, 0.25 points, PMID:33250842). One individual was homozygous for the variant (0.5 point, 29422078). Another patient is compound heterozygous for the variant and another variant in GAA, either c.1714C>G (p.His572Asp) (PMID: 33301762). The allelic data from this patient will be used in the assessment of the second variant and is not included here to avoid circular logic. Total 2.75 points (PM3_Strong). At least two patients with this variant had documented GAA deficiency with <10% of the normal mean control level of GAA activity in dried blood spots (PMID: 33301762, 37542277). One homozygous patient had documented symptoms of severe infantile onset of the disease and was reported to be on enzyme replacement therapy for Pompe disease, and CRIM negative (PMID: 29422078) (PP4_Moderate).Three different missense variants (c.2T>C, c.1A>T, c.3G>A) (ClinVar Variation IDs: 984802, 984798, 972816, respectively], in the same codon have been classified as Pathogenic/Likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP.In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 8, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273952/MONDO:0009290/010 2024-06-08 2024-12-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7822 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013428 infores:hetionet CHEBI:49603 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0876994 infores:hetionet CHEBI:116278 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0014518 infores:hetionet CHEBI:15940 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C2242996 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151763 infores:hetionet CHEBI:49960 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0037299 infores:hetionet CHEBI:7454 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0085606 infores:hetionet CHEBI:6437 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1141861 infores:hetionet CHEBI:85161 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0040264 infores:hetionet CHEBI:71255 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0152198 infores:hetionet CHEBI:32221 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0349506 infores:hetionet CHEBI:6073 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0278134 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002237 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0007078 infores:hetionet CHEBI:7640 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0039231 infores:hetionet CHEBI:4681 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0003467 infores:hetionet CHEBI:135961 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0037763 infores:hetionet CAID:CA410146724 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146724 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1409C>T (p.Ala470Val) is a missense variant. This variant is 0.00002915(0.002447%, 1/40860) in the East Asian population of gnomAD v4.1.0. This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. This missense variant has a REVEL score <0.5 (0.092)(BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146724/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63618 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0003811 infores:hetionet CHEBI:3082 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0025345 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020538 infores:hetionet CHEBI:63598 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151908 infores:hetionet CHEBI:8024 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C3665347 infores:hetionet NCBITaxon:2 biolink:causes EFO:1001753 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D018784 DB01597_MESH_D018784_1DB00916_MESH_D018784_1DB01598_MESH_D018784_1DB06211_MESH_D018784_1DB01331_MESH_D018784_1 CHEBI:6933 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0428977 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011570 infores:hetionet CHEBI:9445 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0003862 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038587 infores:hetionet GO:0044829 biolink:causes GO:0019079 infores:ubergraph knowledge_assertion manual_agent GO:0044829 GO:0019079 CHEBI:49668 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0002170 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0036572 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0021053 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0038454 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0948586 infores:hetionet CHEBI:3723 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0522055 infores:hetionet CHEBI:6375 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0004604 infores:hetionet NCBITaxon:121759 biolink:causes MONDO:0005894 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:121759 MONDO:0005894 CHEBI:85078 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0024115 infores:hetionet CHEBI:31711 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0236075 infores:hetionet CHEBI:144093 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0030193 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027697 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018099 infores:hetionet CHEBI:6933 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0042023 infores:hetionet CHEBI:9570 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085605 infores:hetionet CHEBI:63584 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0013404 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0553548 infores:hetionet CHEBI:63631 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0600142 infores:hetionet GO:1903684 biolink:causes GO:0030855 infores:ubergraph knowledge_assertion manual_agent GO:1903684 GO:0030855 CHEBI:63620 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0007286 infores:hetionet CHEBI:94848 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0009676 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0020649 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020456 infores:hetionet CHEBI:52172 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0008031 infores:hetionet NCBIGene:57511 biolink:causes MONDO:0013810 infores:monarchinitiative not_provided not_provided HGNC:18621 MONDO:0013810 uuid:ce24286c-e605-4754-8439-81c29be8e98b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10112 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0011991 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0948525 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0155003 infores:hetionet CHEBI:3077 biolink:causes HP:0001382 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0022410 infores:hetionet CAID:CA410147946 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147946 MONDO:0011071 PMID:27294619 Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1151C>T (p.Pro384Leu) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 1986052). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147946/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9598 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0004604 infores:hetionet CHEBI:8871 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151636 infores:hetionet CAID:CA399801096 biolink:causes MONDO:0100326 infores:clingen CAID:CA399801096 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.1947-2A>G splice variant is predicted to result in skipping of exon 20 causing a shift in the reading frame and a premature stop codon in exon 21 leading to nonsense mediated decay in a disease that is loss of function (PVS1). The variant is absent from gnomAD (PM2_supporting). At least one patient, presumed homozygous, with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia, in addition to αIIbβ3 surface expression of 9-11% compared to WT (PMID:9663713, PP4_moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP4_moderate, PVS1 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399801096/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:44915 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0428977 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0023533 infores:hetionet UMLS:C1872203 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0232462 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027726 infores:hetionet CHEBI:194135 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042384 infores:hetionet CHEBI:31236 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003873 infores:hetionet CHEBI:367163 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0233407 infores:hetionet CHEBI:27899 biolink:causes UMLS:C3495931 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C3495931 infores:hetionet CHEBI:3310 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0009806 infores:hetionet CHEBI:3181 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0013384 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042109 infores:hetionet CHEBI:16796 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0002994 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0033774 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042109 infores:hetionet CHEBI:107736 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0086525 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0149931 infores:hetionet CHEBI:45863 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0242698 infores:hetionet CHEBI:4024 biolink:causes NCIT:C182450 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0542044 infores:hetionet CHEBI:47898 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0016382 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0030552 infores:hetionet GO:1903406 biolink:causes GO:0010248 infores:ubergraph knowledge_assertion manual_agent GO:1903406 GO:0010248 CHEBI:49375 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0021053 infores:hetionet CHEBI:36791 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151662 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0042109 infores:hetionet CHEBI:7936 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0152009 infores:hetionet NCBITaxon:615 biolink:causes EFO:1001421 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:615 MESH:D016868 DB01061_MESH_D016868_1DB01332_MESH_D016868_1DB00798_MESH_D016868_1DB00479_MESH_D016868_1 CHEBI:4659 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0442874 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0042109 infores:hetionet CAID:CA10014369 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014369 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.714C>T (p.Val238=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.04) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014369/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16796 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0022107 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0023895 infores:hetionet CHEBI:8107 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0232766 infores:hetionet NCBIGene:158401 biolink:causes MONDO:0030984 infores:monarchinitiative not_provided not_provided HGNC:26535 MONDO:0030984 uuid:0f0c30c2-30b0-4b5e-a9ce-046a60e90b1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030312 infores:hetionet CHEBI:391960 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0151905 infores:hetionet CHEBI:3478 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0687713 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004936 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004610 infores:hetionet CHEBI:63627 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0013428 infores:hetionet CHEBI:72323 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0001339 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0221490 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0035258 infores:hetionet CHEBI:3001 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0015230 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0029408 infores:hetionet CAID:CA415075922 biolink:causes MONDO:0010305 infores:clingen CAID:CA415075922 MONDO:0010305 PMID: Likely Benign BS1, BP4 The NM_005629.4: c.26G>T variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Valine at amino acid 9 (p.Gly9Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00019 (14/74655 alleles) in the European population. Additionally, there are 5 hemizygotes in gnomAD v2.1.1, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (<5 hemizygotes in gnomAD). The computational predictor REVEL gives a score of 0.146 which is below the threshold of 0.25, evidence that does not predict a damaging effect on SLC6A8 function (PP3). To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:571505). In summary, this variant meets the criteria to be classified as Likely Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415075922/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:39112 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0001824 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0009806 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0029134 infores:hetionet CHEBI:63618 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0242339 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151767 infores:hetionet NCBIGene:5313 biolink:causes MONDO:0007067 infores:monarchinitiative not_provided not_provided HGNC:9020 MONDO:0007067 uuid:df478b48-2b73-46ca-bfef-a63c5f2c977a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1872203 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0232492 infores:hetionet CHEBI:6539 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0021141 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0003123 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1306341 infores:hetionet CHEBI:63791 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002390 infores:hetionet CHEBI:5855 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0043352 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0221165 infores:hetionet CHEBI:60761 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0015967 infores:hetionet CHEBI:3732 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013428 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0041912 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0267792 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020619 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0162119 infores:hetionet NCBIGene:10577 biolink:causes MONDO:0011873 infores:monarchinitiative not_provided not_provided HGNC:14537 MONDO:0011873 uuid:11eafdc4-32a7-43c1-848d-c038bf582cca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0072298 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:0072298 GO:0001656 CHEBI:66913 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0151205 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0017160 infores:hetionet CHEBI:68575 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0013404 infores:hetionet CHEBI:7773 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0013404 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0425945 infores:hetionet CHEBI:4495 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0687713 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0009806 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0006444 infores:hetionet CHEBI:5165 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011206 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0006444 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0011168 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0162835 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0740411 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0740411 infores:hetionet CHEBI:6078 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C2129214 infores:hetionet CHEBI:7465 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C2363731 infores:hetionet CHEBI:50693 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0040479 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0040034 infores:hetionet CHEBI:15544 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0019080 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0027765 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0012371 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0012371 uuid:c3867eb6-fa66-48d9-a6d3-fd24488c9cf9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0042963 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0008325 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0009806 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0017152 infores:hetionet CHEBI:3286 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0036974 infores:hetionet CHEBI:63638 biolink:causes HP:0001105 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0521694 infores:hetionet CHEBI:5280 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C3665386 infores:hetionet NCBIGene:7384 biolink:causes MONDO:0036193 infores:monarchinitiative not_provided not_provided HGNC:12585 MONDO:0036193 uuid:dfe7086c-5409-420b-8c24-36a82e69b254 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0856054 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020542 infores:hetionet CAID:CA270431 biolink:causes MONDO:0010726 infores:clingen CAID:CA270431 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PM1, PM5, PP3, PM2, PS4_Moderate, PM6_Strong PP4 The p.Asp156Gly variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with phenotype consistent with Rett syndrome (PMID 11309679, 11241840) (PM6_strong). The p.Asp156Gly variant in MECP2 has been observed in at least 2 other individuals with clinical features of Rett syndrome (PMID 11309679, 11241840) (PS4_moderate). The p.Asp156Gly variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). A pathogenic missense variant (p.Asp156Glu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11524741, 15737703, 26984561, 27354166, 12843318, 26418480, internal database - Invitae) (PM5). The p.Asp156Gly variant in MECP2 is absent from gnomAD (PM2_supporting). Chromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Asp156Gly variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM5, PS3_supporting, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270431/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA010061 biolink:causes MONDO:0005045 infores:clingen CAID:CA010061 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PS4_Moderate, PP1_Moderate PM5, PM4, PM6, BA1, PP3, PS3, BP3, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 The NM_000257.4(MYH7):c.1012G>A (p.Val338Met) variant in MYH7 has been identified in at least 11 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry, pers. comm.; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.), and at least in a presumably unaffected individual (<40 years old) with a family history of HCM (Valente 2013 PMID: 23690394; Captur 2014 PMID:25228707). This variant segregated with disease in 6 affected relatives with HCM from 3 families (PP1_Moderate, GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Moderate; PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010061/MONDO:0005045/002 2021-09-27 2021-10-01 Supports CHEBI:8502 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0085605 infores:hetionet CHEBI:51230 biolink:causes UMLS:C1536146 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1536146 infores:hetionet CHEBI:8378 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0344232 infores:hetionet CHEBI:3371 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0027697 infores:hetionet CHEBI:3441 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0231528 infores:hetionet CHEBI:63627 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0026821 infores:hetionet CHEBI:50859 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0023066 infores:hetionet CHEBI:17026 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0011124 infores:hetionet CHEBI:28939 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0004096 infores:hetionet CHEBI:6149 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0024902 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0267792 infores:hetionet CHEBI:3175 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0085636 infores:hetionet CHEBI:3752 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0035317 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235807 infores:hetionet GO:0017080 biolink:causes GO:0035725 infores:ubergraph knowledge_assertion manual_agent GO:0017080 GO:0035725 CHEBI:100246 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0002878 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0700184 infores:hetionet CHEBI:8228 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0002792 infores:hetionet NCBIGene:11160 biolink:causes MONDO:0012639 infores:monarchinitiative not_provided not_provided HGNC:1356 MONDO:0012639 uuid:3fb23ef7-a099-4c94-8d11-91664d540c32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes UMLS:C0085625 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085625 infores:hetionet CHEBI:135351 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0015672 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0001339 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0018799 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0032285 infores:hetionet CHEBI:17688 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0015967 infores:hetionet CHEBI:2549 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0085631 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042075 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0039971 infores:hetionet CHEBI:8890 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0028961 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007028 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0263912 infores:hetionet CHEBI:3380 biolink:causes MONDO:0016056 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0025958 infores:hetionet NCBIGene:1419 biolink:causes MONDO:0014075 infores:monarchinitiative not_provided not_provided HGNC:2409 MONDO:0014075 uuid:51dca741-a83c-401c-9bb7-66cf8762846d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2469 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151746 infores:hetionet CHEBI:75246 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011168 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0017160 infores:hetionet CHEBI:168396 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151692 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0020517 infores:hetionet CHEBI:6402 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042963 infores:hetionet CHEBI:119573 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014591 infores:hetionet CHEBI:63617 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0231218 infores:hetionet CHEBI:2666 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0018681 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0948594 infores:hetionet CHEBI:3347 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0018681 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0008546 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0008546 uuid:67e31be6-2e37-4bbb-ad04-91c671245834 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0039520 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0015376 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0037763 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0029408 infores:hetionet CHEBI:4445 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0013404 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C1536459 infores:hetionet CHEBI:6690 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0700590 infores:hetionet CHEBI:8713 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0020546 infores:hetionet CAID:CA274535 biolink:causes MONDO:0010726 infores:clingen CAID:CA274535 MONDO:0010726 PMID: Benign BA1 The allele frequency of the p.Pro388Ser (NM_004992.3) variant in MECP2 is 0.039% in a sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro388Ser variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274535/MONDO:0010726/016 2021-12-22 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:4356 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0027765 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020651 infores:hetionet CHEBI:9086 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151818 infores:hetionet CHEBI:6950 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0917801 infores:hetionet CHEBI:9720 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0424295 infores:hetionet GO:1901246 biolink:causes GO:0060428 infores:ubergraph knowledge_assertion manual_agent GO:1901246 GO:0060428 NCBIGene:6569 biolink:causes MONDO:0013247 infores:monarchinitiative not_provided not_provided HGNC:11019 MONDO:0013247 uuid:b8541b40-61f2-44b9-983d-1e77fbea1e7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0041969 infores:hetionet CAID:CA5417048 biolink:causes MONDO:0011225 infores:clingen CAID:CA5417048 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2 The c.13G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Glutamine at amino acid 5 (p.Glu5Gln).The highest population minor allele frequency in gnomAD v4 is 0.00002773 (1/36060 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266 ) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5417048/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBITaxon:36330 biolink:causes MONDO:0001601 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36330 MONDO:0001601 CHEBI:43968 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0041834 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0266998 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0266998 infores:hetionet CHEBI:5818 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0011609 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0004238 infores:hetionet CHEBI:40237 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0013390 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1269683 infores:hetionet CHEBI:53766 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0239937 infores:hetionet CHEBI:8874 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0040264 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020621 infores:hetionet CHEBI:63681 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0428977 infores:hetionet CAID:CA2740067583 biolink:causes MONDO:0015967 infores:clingen CAID:CA2740067583 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate PP1 The c.215A>G variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within a region of the promoter (–c.-209 to c.-227) of HNF1A which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A and SU sensitivity) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.-215A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2740067583/MONDO:0015967/017 2024-03-31 2024-03-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37941 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1443060 infores:hetionet CHEBI:63619 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151480 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0863113 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002170 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0549399 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0040046 infores:hetionet CHEBI:72690 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C1535939 infores:hetionet CHEBI:31705 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0007820 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0014591 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0002622 infores:hetionet CHEBI:66901 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0476280 infores:hetionet CHEBI:71415 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0028643 infores:hetionet CHEBI:6759 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0037383 infores:hetionet CHEBI:15765 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0026858 infores:hetionet CHEBI:39585 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0424295 infores:hetionet NCBIGene:80173 biolink:causes MONDO:0030463 infores:monarchinitiative not_provided not_provided HGNC:21424 MONDO:0030463 uuid:c1fb84d5-efb1-488c-8a61-6408785281d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0151610 infores:hetionet NCBIGene:10159 biolink:causes MONDO:0010482 infores:monarchinitiative not_provided not_provided HGNC:18305 MONDO:0010482 uuid:1f7696d2-0f95-4230-90b7-9006747e1b93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:128338 biolink:causes MONDO:0014669 infores:monarchinitiative not_provided not_provided HGNC:28769 MONDO:0014669 uuid:396139cd-8238-44d5-abed-dc5cb4097f23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0032584 infores:hetionet CAID:CA317553 biolink:causes MONDO:0100135 infores:clingen CAID:CA317553 MONDO:0100135 PMID: Pathogenic PM2_Supporting, PM5_Strong, PS4_Moderate, PP3_Moderate, PM1 PP1, BS2, PM6, BP2, BA1, PS3, PS1, PS2, PM3, BP5, BS1, BS3, BS4 The c.4916G>C variant in SCN1A is a missense variant predicted to cause substitution of arginine by proline at amino acid 1639 (p.Arg1639Pro). This variant has been reported in at least one individual with Dravet syndrome and another individual with epilepsy with no additional details (PMIDs:35087721, 29655203) (PS4_Moderate). Multiple missense variants in SCN1A and in paralogous genes have previously been reported and meet P/LP per these criteria, including SCN1A: p.R1639G (PMIDs:18930999), SCN2A: p.R1629L, p.R1629H and SCN8A: p.R1620L (PMIDs 28330790, 3061509). (PM5_Strong). An identical amino acid substitution at the corresponding position in the paralogous gene, SCN2A has been reported as de novo (p.R1629P), however this did not meet P/LP per these criteria so PS1 was not met. This variant is absent from the population database, gnomAD v2.1.1 (PM2_Supporting). It falls within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4_Moderate, PM5_Strong, PM1, PM2_Supporting, PP3_Moderate (version 1.0; 5/9/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA317553/MONDO:0100135/067 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50841 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0042963 infores:hetionet CHEBI:204928 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0020517 infores:hetionet NCBIGene:498 biolink:causes MONDO:0020727 infores:monarchinitiative not_provided not_provided HGNC:823 MONDO:0020727 uuid:54474aa5-f3a2-47e9-b22f-53bb488340ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0024299 infores:hetionet CHEBI:144551 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0003862 infores:hetionet CHEBI:8890 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1368065 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004701 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0156369 infores:hetionet CHEBI:15765 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0085631 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036689 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151717 infores:hetionet CHEBI:3738 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0232462 infores:hetionet CHEBI:6775 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0024141 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0007222 infores:hetionet CHEBI:7492 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0155169 infores:hetionet CHEBI:48538 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0011175 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0239725 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0239725 infores:hetionet CHEBI:63618 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0000737 infores:hetionet CHEBI:41977 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C3665386 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0162429 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015376 infores:hetionet NCBIGene:5971 biolink:causes MONDO:0054696 infores:monarchinitiative not_provided not_provided HGNC:9956 MONDO:0054696 uuid:9836e531-03e6-4635-9235-e618dfa39523 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020621 infores:hetionet CHEBI:36704 biolink:causes HP:0030155 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0236078 infores:hetionet CHEBI:63621 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0152169 infores:hetionet CHEBI:367163 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0037763 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0021400 infores:hetionet CHEBI:71219 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151578 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017160 infores:hetionet CHEBI:253342 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0026837 infores:hetionet CHEBI:5775 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0015230 infores:hetionet CHEBI:3814 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0015230 infores:hetionet CHEBI:32221 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0233407 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151883 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002170 infores:hetionet CHEBI:5134 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0039231 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011991 infores:hetionet GO:0110082 biolink:causes GO:0051301 infores:ubergraph knowledge_assertion manual_agent GO:0110082 GO:0051301 CHEBI:3508 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0344232 infores:hetionet CHEBI:85083 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0392386 infores:hetionet CHEBI:31174 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0151907 infores:hetionet CHEBI:94501 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C3665347 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0023895 infores:hetionet CHEBI:2955 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0038325 infores:hetionet CHEBI:50173 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C2047937 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0574002 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0019158 infores:hetionet CHEBI:47519 biolink:causes MONDO:0022096 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085653 infores:hetionet CHEBI:4798 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0011603 infores:hetionet CHEBI:7627 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0000737 infores:hetionet CHEBI:553473 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0042963 infores:hetionet CHEBI:6690 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0033774 infores:hetionet CHEBI:9738 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0040264 infores:hetionet CHEBI:3696 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085593 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0032285 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0027769 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0877154 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0877154 infores:hetionet CHEBI:9763 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0917801 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0149931 infores:hetionet CHEBI:5100 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0242422 infores:hetionet CHEBI:15367 biolink:causes HP:0003249 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151281 infores:hetionet CHEBI:5558 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C1368065 infores:hetionet CHEBI:421707 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0001125 infores:hetionet CHEBI:10125 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0575081 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1443060 infores:hetionet CAID:CA015893 biolink:causes MONDO:0005045 infores:clingen CAID:CA015893 MONDO:0005045 PMID:24047955PMID:15358028PMID:24047955 Uncertain Significance PM2, PP3, PS4_Moderate PM5, PM1, BA1, PS3, BS1, BS3, PS1, BP4 The c.5302G>A (p.Glu1768Lys) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Murphy 2016 PMID:26914223; Berge 2014 PMID:24111713; Homburger 2016 PMID:27247418; Cecconi 2016 PMID:27600940; LMM SCV000059606.5). In vitro studies showed this variant had a slight effect on protein structure, but no effect on the ability to incorporate into muscle sarcomeres in an experimental system (Wolny 2013 PMID:24047955); however, this evidence is insufficient to apply PS3. Additionally this variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015893/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46345 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0877661 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0009450 infores:hetionet NCBIGene:2782 biolink:causes MONDO:0014855 infores:monarchinitiative not_provided not_provided HGNC:4396 MONDO:0014855 uuid:46280c92-ddbb-45d7-9a7c-3db79fdeca1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1167965 infores:hetionet CHEBI:68647 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0038325 infores:hetionet CHEBI:3650 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0042109 infores:hetionet CHEBI:92998 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C2047937 infores:hetionet CAID:CA16619057 biolink:causes MONDO:0017623 infores:clingen CAID:CA16619057 MONDO:0017623 PMID:29706350PMID:11051241 Uncertain Significance PS3_Moderate, PM2_Supporting NM_000314.8(PTEN):c.595_597del (p.Met199del) meets criteria to be classified as a variant of uncertain significant for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_moderateWell-established functional studies show a deleterious effectPS3_moderateMighell et al. 2018 PMID: 29706350: Lipid phosphatase activity score, -4.58 (TRUE). And Kato et al. 2000 PMID: 11051241 The purified wild-type PTEN protein dephosphorylated PIP4 in this in vitro assay, whereas all of the PTEN mutants including M199del did not, indicating loss of normal PTEN function.PM2_supportingAbsent in population databasesAbsent in gnomAD v2 and v4 PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619057/MONDO:0017623/003 2025-08-01 2025-11-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4887 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0027765 infores:hetionet NCBIGene:221927 biolink:causes MONDO:0020841 infores:monarchinitiative not_provided not_provided HGNC:21701 MONDO:0020841 uuid:620aa5fe-27b4-4936-9659-52ba03a06bd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0314719 infores:hetionet CAID:CA376066110 biolink:causes MONDO:0011225 infores:clingen CAID:CA376066110 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting "The c.25G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid 9 (p.Ala9Thr).The highest population minor allele frequency in gnomAD v4 is 0.00003022 (1/33086 alleles) in the ""Remaining"" population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting. Despite the ""Remaining"" being considered a bottleneck population in gnomad v4, as no other alleles have been described in all other populations, PM2_Supporting still can be applied (PM2_Supporting). Allele frequency considering all exomes is 0.000001591, 1/628590 alleles.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1c-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376066110/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0003307 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:0003307 GO:0007507 CHEBI:5050 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0002994 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0001418 infores:hetionet CHEBI:45863 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0033771 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0858667 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0858667 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040479 infores:hetionet CAID:CA512341149 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341149 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1272G>A (p.Ser424=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.00)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341149/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6761 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0011603 infores:hetionet PR:000000028 biolink:causes GO:0007264 infores:ubergraph knowledge_assertion manual_agent PR:000000028 GO:0007264 CHEBI:5864 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0948594 infores:hetionet CHEBI:50922 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085649 infores:hetionet CHEBI:3286 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0151205 infores:hetionet NCBIGene:55870 biolink:causes MONDO:0030918 infores:monarchinitiative not_provided not_provided HGNC:19088 MONDO:0030918 uuid:e760a554-4d86-44c2-80ec-48bafaf99a2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020649 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0878544 infores:hetionet CHEBI:6909 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0438142 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0026857 infores:hetionet CHEBI:9757 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0235198 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020569 infores:hetionet CHEBI:40237 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0037763 infores:hetionet CHEBI:83531 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0013144 infores:hetionet CHEBI:2955 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0162830 infores:hetionet CHEBI:7773 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0855333 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006241 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0745754 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0344232 infores:hetionet CHEBI:9943 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013604 infores:hetionet CHEBI:5864 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0239937 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0002871 infores:hetionet CHEBI:31348 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0333355 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037822 infores:hetionet CHEBI:474180 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0220981 infores:hetionet CHEBI:3011 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0016382 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0235234 infores:hetionet CHEBI:9434 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0004093 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0010692 infores:hetionet NCBIGene:50846 biolink:causes MONDO:0009301 infores:monarchinitiative not_provided not_provided HGNC:2865 MONDO:0009301 uuid:a63ef5e2-a16e-4f1d-b6e8-a0f278bdcdef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0853748 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0425946 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0425946 infores:hetionet CHEBI:3082 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1145670 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0012833 infores:hetionet CHEBI:5002 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0027769 infores:hetionet CHEBI:29688 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0023530 infores:hetionet CHEBI:7936 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013362 infores:hetionet CHEBI:6067 biolink:causes MONDO:0012105 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C3495801 infores:hetionet GO:0002572 biolink:causes CL:0000827 infores:ubergraph knowledge_assertion manual_agent GO:0002572 CL:0000827 CHEBI:63621 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0021655 infores:hetionet CHEBI:16347 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0043094 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037278 infores:hetionet CHEBI:72297 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0037763 infores:hetionet CHEBI:6067 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004364 infores:hetionet CHEBI:681569 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0023530 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009763 infores:hetionet CHEBI:91834 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0038362 infores:hetionet CAID:CA244520882 biolink:causes MONDO:0015967 infores:clingen CAID:CA244520882 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PM5, PP1 The c.203G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 68 (p.(Arg68Gln)) of NM_000545.8. This variant has a minor allele frequency of 0.00001965 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). Another missense variant, c.202C>T (p.(Arg68Trp)), has been classified as a VUS by the ClinGen MDEP; therefore PM5 will not be applied. In summary, c.203G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244520882/MONDO:0015967/017 2022-04-04 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:168396 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0031039 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0033777 infores:hetionet CHEBI:51041 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085641 infores:hetionet NCBIGene:6443 biolink:causes MONDO:0011423 infores:monarchinitiative not_provided not_provided HGNC:10806 MONDO:0011423 uuid:7c458c57-ae45-4073-aaaf-dfd7822b00e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:201973 biolink:causes MONDO:0014177 infores:monarchinitiative not_provided not_provided HGNC:26575 MONDO:0014177 uuid:58776a6a-b1ea-41a7-ab3f-d1c4b0f664ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35854 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0851578 infores:hetionet CHEBI:31711 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018681 infores:hetionet CAID:CA386966358 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966358 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM5_Strong, PM1, PP1_Strong, PP3 PS4, PP4 The c.814C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 272 (p.(Arg272Ser)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Two other missense variants, c.814C>T (p.Arg272Cys) and c.815G>A (p.Arg272His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg272Ser has a greater Grantham distance than p.Arg272His. (PM5_Strong). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 31165087 and 18003757, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.814C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PP1_Strong, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966358/MONDO:0015967/017 2022-04-15 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0004609 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0018965 infores:hetionet CHEBI:114785 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0234894 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042109 infores:hetionet NCBIGene:1781 biolink:causes MONDO:0032779 infores:monarchinitiative not_provided not_provided HGNC:2964 MONDO:0032779 uuid:2a73e984-09cd-44b9-a41c-8492082cc478 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0025061 infores:hetionet CHEBI:31709 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0151611 infores:hetionet GO:1903722 biolink:causes GO:0007098 infores:ubergraph knowledge_assertion manual_agent GO:1903722 GO:0007098 CHEBI:40279 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0232459 infores:hetionet CHEBI:4909 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013404 infores:hetionet CHEBI:3216 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151878 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0242350 infores:hetionet CHEBI:8871 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020443 infores:hetionet CHEBI:135888 biolink:causes MONDO:0019472 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0392788 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0948594 infores:hetionet CHEBI:27779 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0018681 infores:hetionet CHEBI:72296 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0017178 infores:hetionet GO:0031630 biolink:causes GO:0007269 infores:ubergraph knowledge_assertion manual_agent GO:0031630 GO:0007269 CHEBI:15765 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0002170 infores:hetionet CHEBI:15940 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0042267 infores:hetionet CHEBI:50648 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2937358 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0948594 infores:hetionet CHEBI:8364 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0016382 infores:hetionet CHEBI:135935 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0022107 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042401 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018021 infores:hetionet CHEBI:6887 biolink:causes HP:0033694 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233767 infores:hetionet CAID:CA16620228 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620228 MONDO:0007648 PMID: Uncertain Significance BS2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM2, PM6, PVS1, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS3, PS2, PS1, PS4 The c.49-3C>A variant has been observed in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_supporting; SCV000822625.1, SCV000570129.4, SCV000665064.2). In summary, the clinical significance of this variant is uncertain based on ACMP/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620228/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:75922 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0085636 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020456 infores:hetionet CHEBI:7496 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0423791 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0233414 infores:hetionet CHEBI:7494 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0019080 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011630 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0948586 infores:hetionet NCBIGene:1371 biolink:causes MONDO:0030048 infores:monarchinitiative not_provided not_provided HGNC:2321 MONDO:0030048 uuid:73ba52ce-e37a-4aa2-8255-5246e18ea7fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0090256 biolink:causes GO:0048707 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0048707 CHEBI:68606 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0004093 infores:hetionet CHEBI:167309 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0520888 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0740425 infores:hetionet CHEBI:28748 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0520966 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0015230 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0019348 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0041969 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0162628 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0162628 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0041912 infores:hetionet CHEBI:6822 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0232462 infores:hetionet CHEBI:2636 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0428977 infores:hetionet CHEBI:7494 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0423791 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C1443060 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0086543 infores:hetionet CHEBI:9649 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0003811 infores:hetionet CHEBI:47657 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0231528 infores:hetionet CHEBI:10101 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151723 infores:hetionet CHEBI:10112 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0858635 infores:hetionet CHEBI:24564 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0003123 infores:hetionet CHEBI:3213 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0020578 infores:hetionet CHEBI:16899 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0027720 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011849 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0001824 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0041912 infores:hetionet NCBIGene:6261 biolink:causes MONDO:0020485 infores:monarchinitiative not_provided not_provided HGNC:10483 MONDO:0020485 uuid:52c75ecd-656c-4ca2-a925-4b40a67a199d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020433 infores:hetionet CHEBI:167309 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0022107 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011848 infores:hetionet CHEBI:520985 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0699828 infores:hetionet CHEBI:68584 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0011603 infores:hetionet CHEBI:71223 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0040034 infores:hetionet CAID:CA6266499 biolink:causes MONDO:0700270 infores:clingen CAID:CA6266499 MONDO:0700270 PMID: Likely Pathogenic PM3, PVS1 BA1, BS1, PM2 The c.8987+2T>A variant in ATM occurs within the canonical splice donor site (+/- 1,2) of intron 62. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been detected in at least two individuals with Ataxia-Telangiectasia (PMID: 26896183). The highest minor allele frequency in gnomAD v4.1.0 is 0.00002196 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6266499/MONDO:0700270/020 2025-09-25 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:291342 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0015230 infores:hetionet CHEBI:261649 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0042963 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0234930 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151779 infores:hetionet CHEBI:9667 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0039231 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0037274 infores:hetionet CAID:CA000632 biolink:causes MONDO:0017623 infores:clingen CAID:CA000632 MONDO:0017623 PMID:29706350 Uncertain Significance PM2, PP2, BS3_Supporting PVS1, PM6, BP5, BP7, BS4, BS1, PP1, PP3, BS2, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS4, PS3, PS1 PTEN c.914G>A (p.S305N) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000632/MONDO:0017623/003 2019-03-05 2019-07-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63681 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C1443060 infores:hetionet CHEBI:9130 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0917801 infores:hetionet CHEBI:68575 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0020621 infores:hetionet CHEBI:480999 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0020453 infores:hetionet CHEBI:10102 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085633 infores:hetionet CHEBI:50729 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0085610 infores:hetionet CHEBI:3732 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0042963 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0548823 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013447 infores:hetionet CAID:CA319121 biolink:causes MONDO:0012589 infores:clingen CAID:CA319121 MONDO:0012589 PMID: Likely Pathogenic PVS1, PM2_Supporting The p.Q670HfsX40 variant in TCF4 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Q670HfsX40 variant in TCF4 is absent from gnomAD (PM2_Supporting). In summary, the p.Q670HfsX40 variant in TCF4 is classified as likely pathogenic based on the ACMG/AMP criteria (PVS1, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA319121/MONDO:0012589/016 2021-04-02 2021-05-05 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:3032 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0232487 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0243026 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151763 infores:hetionet UNII:DJJ95FJP1H biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0220870 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0235567 infores:hetionet CHEBI:9139 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151827 infores:hetionet CHEBI:8404 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0013604 infores:hetionet NCBITaxon:562 biolink:causes EFO:1001753 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D018784 DB00303_MESH_D018784_1DB00537_MESH_D018784_1DB01059_MESH_D018784_1DB01165_MESH_D018784_1DB00319_MESH_D018784_1DB01606_MESH_D018784_1DB00560_MESH_D018784_1 CHEBI:5855 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0033774 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0178298 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0000833 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0027947 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0008031 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0006145 infores:hetionet CHEBI:367163 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018681 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0037274 infores:hetionet CHEBI:28748 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085669 infores:hetionet CHEBI:9086 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233407 infores:hetionet CHEBI:63580 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0242429 infores:hetionet CHEBI:499361 biolink:causes HP:0030142 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0159060 infores:hetionet CHEBI:6717 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013144 infores:hetionet UMLS:C0004609 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0080274 infores:hetionet CHEBI:59445 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0000833 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0235169 infores:hetionet CHEBI:6741 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0010828 infores:hetionet CHEBI:6706 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0080274 infores:hetionet CHEBI:7822 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0004093 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0013144 infores:hetionet CHEBI:142290 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0235896 infores:hetionet CHEBI:3752 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0702166 infores:hetionet CHEBI:5132 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0438717 infores:hetionet GO:0090183 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0090183 GO:0007275 CHEBI:7824 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085633 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0424091 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0424091 infores:hetionet CHEBI:63618 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0003862 infores:hetionet CHEBI:63925 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0030193 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018801 infores:hetionet CHEBI:63589 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0232602 infores:hetionet CHEBI:6801 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0023380 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0267792 infores:hetionet CHEBI:3441 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011124 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0006014 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D002181 DB01110_MESH_D002181_1DB00406_MESH_D002181_1DB00251_MESH_D002181_1DB00646_MESH_D002181_1DB01152_MESH_D002181_1DB00257_MESH_D002181_1 CHEBI:135351 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0019521 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0151595 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151595 infores:hetionet CHEBI:9727 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0234215 infores:hetionet CHEBI:8768 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0039231 infores:hetionet CHEBI:63791 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009376 infores:hetionet CHEBI:47898 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0344232 infores:hetionet CHEBI:6897 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0018681 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0006145 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0558919 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0558919 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0521839 infores:hetionet CHEBI:2675 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0043094 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0041657 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0549373 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0003864 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0236068 infores:hetionet CHEBI:50729 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0522153 infores:hetionet GO:0075120 biolink:causes GO:0007186 infores:ubergraph knowledge_assertion manual_agent GO:0075120 GO:0007186 CHEBI:6437 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0270458 infores:hetionet CHEBI:93363 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0234708 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043246 infores:hetionet CHEBI:9907 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0039070 infores:hetionet CHEBI:3638 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0241442 infores:hetionet CHEBI:6061 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0027497 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0007787 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0948594 infores:hetionet CHEBI:10124 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013404 infores:hetionet CHEBI:6375 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042963 infores:hetionet CHEBI:9622 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0006277 infores:hetionet CHEBI:135929 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0403673 infores:hetionet CHEBI:3732 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0035410 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0027765 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002878 infores:hetionet CAID:CA16020849 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020849 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4 This variant c.740del (p.Gly247AlafsTer?) in PAH was reported 1 time in a patient with PAH deficiency in the Czech Republic (PMID 23357515). This is a frameshift variant in exon 7 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay. The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020849/MONDO:0009861/006 2020-11-24 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50223 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0041834 infores:hetionet CHEBI:83527 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0011991 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0151865 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0037822 infores:hetionet CHEBI:40237 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0002994 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0017178 infores:hetionet CHEBI:9445 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C3665386 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0027769 infores:hetionet CHEBI:9737 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C1443060 infores:hetionet CHEBI:8485 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0030193 infores:hetionet CHEBI:8060 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0917801 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0948594 infores:hetionet CAID:CA005169 biolink:causes MONDO:0021056 infores:clingen CAID:CA005169 MONDO:0021056 PMID: Benign BA1, BP4, BP7 PM2, PS3 The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA005169/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA392325892 biolink:causes MONDO:0007947 infores:clingen CAID:CA392325892 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PP1, PM2_Supporting PM6, BS2, PP2, PP3, BA1, BP1, BP4, BP2, BP3, PM3, PM1, PM4, PM5, PS3, PS1, PS2, PS4, BS1, BS4, BS3, BP7, BP5 The NM_000138 c.7540G>T variant is a nonsense variant in FBN1 that is expected to introduce a premature stop codon at this position, likely resulting in an absent or disrupted protein product (PVS1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome and segregates with disease in three affected family members (PP4, PP1; Bichat), as well as in an individual with features suggestive of or consistent with Marfan syndrome (PMID: 17627385). This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting, PP1, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392325892/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:161680 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0149745 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0948594 infores:hetionet CHEBI:4672 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0035222 infores:hetionet CHEBI:8776 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0239571 infores:hetionet CHEBI:2922 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0042963 infores:hetionet CHEBI:6792 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0004093 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0018799 infores:hetionet NCBIGene:26503 biolink:causes MONDO:0011449 infores:monarchinitiative not_provided not_provided HGNC:10933 MONDO:0011449 uuid:0aea2f19-be2e-4342-b3a5-b5f663cf3402 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C3665386 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0002957 infores:hetionet CHEBI:2668 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0017152 infores:hetionet CHEBI:75922 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0012833 infores:hetionet CAID:CA2580098651 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098651 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.968-9G>T is an intronic variant. SpliceAI predicts no impact on splicing (score: 0.01), supporting BP4. Additionally, evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score of 1.154 (≤ 2.0), supporting BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098651/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3286 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0312420 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0151735 infores:hetionet CHEBI:27565 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0024305 infores:hetionet CHEBI:71219 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0162830 infores:hetionet CHEBI:61390 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0004936 infores:hetionet CHEBI:2673 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0233494 infores:hetionet CHEBI:45081 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0041657 infores:hetionet CHEBI:6067 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0016204 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029878 infores:hetionet CHEBI:3515 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C1320835 infores:hetionet CHEBI:47519 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151908 infores:hetionet CHEBI:15765 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0231530 infores:hetionet CHEBI:681569 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C2939147 infores:hetionet CHEBI:4907 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0014868 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0233472 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020569 infores:hetionet CHEBI:28445 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0232462 infores:hetionet CHEBI:4530 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013428 infores:hetionet CHEBI:3219 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0023518 infores:hetionet CHEBI:41774 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0008370 infores:hetionet CHEBI:45863 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0852911 infores:hetionet CHEBI:9086 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0852911 infores:hetionet CHEBI:8713 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0002878 infores:hetionet GO:2000810 biolink:causes GO:0043297 infores:ubergraph knowledge_assertion manual_agent GO:2000810 GO:0043297 CHEBI:7959 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0332563 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0677500 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0029408 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003123 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0000833 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0035243 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0019158 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0009450 infores:hetionet NCBIGene:7874 biolink:causes MONDO:0958071 infores:monarchinitiative not_provided not_provided HGNC:12630 MONDO:0958071 uuid:0a9453aa-6ccc-4e54-886b-f8fa6c1004d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020453 infores:hetionet CHEBI:8364 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0151827 infores:hetionet CAID:CA8337678 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337678 MONDO:0008723 PMID: Uncertain Significance BP4, PM2 The NM_000018.4(ACADVL):c.343-14T>C is an intronic variant that is not predicted by SpliceAI to impact splicing (BP4). However, this variant exists within the minimal splice region, so BP7 is not applicable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, PM2_Supporting ( (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337678/MONDO:0008723/021 2024-08-13 2024-08-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36791 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0877046 infores:hetionet CHEBI:63607 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0015672 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0341164 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0341164 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0004936 infores:hetionet CAID:CA902254 biolink:causes MONDO:0100368 infores:clingen CAID:CA902254 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PP4_Moderate, PVS1, PM2_Supporting BA1, BS1 This is a nonsense variant that introduces a premature stop codon into exon 11 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least one patient was analyzed on a 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts), displayed non-detectable ERG responses from rods (0.5 pts) and cones (1 pt), visual acuity 20/400 (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (0.5 pts), and no pigment in peripheral retina (0.5 pts), which together are specific for RPE65 retinopathy (7.5 pts total, PMID: 23847139, PP4). This variant has also been reported in at least 8 probands, one of whom exhibited LCA and was compound heterozygous with the p.Leu341Ser suspected in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PMID: 23847139, PM3_Supporting). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00008316, with 9 alleles / 24960 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/23/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902254/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10023 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0033687 infores:hetionet CHEBI:465284 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085932 infores:hetionet CHEBI:2038 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0036689 infores:hetionet CHEBI:48669 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0033893 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C2225524 infores:hetionet GO:0060019 biolink:causes CL:0000681 infores:ubergraph knowledge_assertion manual_agent GO:0060019 CL:0000681 CAID:CA386965365 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965365 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS3, PS4 The c.703G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamate to glutamine at codon 235 (p.(Glu235Gln)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.816, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to its absence in the European non-Finnish subpopulation and only 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in a single individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19336507). This variant does not meet the MDEP criteria of reduced function in either transactivation or nuclear localization assays, as defined as < 40% of WT activity (PMID: 26853433). In summary, c.703G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965365/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63618 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0030305 infores:hetionet CHEBI:9566 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0001824 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549622 infores:hetionet CHEBI:28901 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0023212 infores:hetionet CHEBI:31709 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0034063 infores:hetionet CHEBI:46345 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0231528 infores:hetionet CHEBI:63630 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0035455 infores:hetionet CHEBI:65173 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0015672 infores:hetionet CHEBI:8382 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0015672 infores:hetionet CHEBI:3044 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0018824 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0235146 infores:hetionet CHEBI:140621 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0013404 infores:hetionet NCBIGene:1836 biolink:causes MONDO:0009107 infores:monarchinitiative not_provided not_provided HGNC:10994 MONDO:0009107 uuid:86304943-6fd6-4c43-9945-1c05978c2c38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0061183 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0061183 GO:0009790 CHEBI:499361 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0032781 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0227791 infores:hetionet CHEBI:31397 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0043094 infores:hetionet CHEBI:474180 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0040822 infores:hetionet CHEBI:3814 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0151904 infores:hetionet CHEBI:66964 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0011551 infores:hetionet CHEBI:73275 biolink:causes UMLS:C0262469 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0262469 infores:hetionet CHEBI:94848 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0042109 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1142112 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1142112 infores:hetionet NCBIGene:114902 biolink:causes MONDO:0011579 infores:monarchinitiative not_provided not_provided HGNC:14344 MONDO:0011579 uuid:ef2fde9d-f95e-4628-8393-e01a0c993ceb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA268663502 biolink:causes MONDO:0005021 infores:clingen CAID:CA268663502 MONDO:0005021 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting PM1, PP3, BA1, BS1 NM_005159.5(ACTC1):c.166G>A (p.Val56Ile) - This variant has been reported in individuals with DCM (personal communication: UK Laboratory) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >5]. Therefore, PS4_Supporting criteria has been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Computational prediction tools are inconclusive about the potential impact of this variant (REVEL score <0.7). Therefore, this variant is classified as Uncertain Significance for DCM in an autosomal dominant manner based on PS4_Supporting and PM2_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA268663502/MONDO:0005021/101 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA397723333 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723333 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL):c.623-1G>A variant in ACADVL occurs within the canonical splice acceptor site (-1) of intron 7. It is predicted to cause skipping of biologically-relevant-exon 8, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting) and reported in an infant patient with dilated cardiomyopathy/sudden death, co-identified with c.932del; p.Phe311Serfs*42 in trans (PMID: 10077518). Although computational splicing predictor SpliceAI gives a score of 0.92 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 of ACADVL, PP3 is not applicable since this evidence is already weighed in PVS1. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723333/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Supports UNII:15G12L5X8K biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151905 infores:hetionet CHEBI:17026 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0030196 infores:hetionet CAID:CA10607009 biolink:causes MONDO:0015152 infores:clingen CAID:CA10607009 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3_Supporting, PP3, PM2_Supporting PM5 The NM_003494.4: c.6038C>G variant in DYSF, which is also known as NM_001130987.2: c.6155C>G p.(Pro2052Arg), is a missense variant predicted to cause substitution of proline by arginine at amino acid 2013, p.(Pro2013Arg). This variant has been reported in unknown phase with a pathogenic variant in at least one individual with LGMD (NM_003494.4: c.3137G>A p.(Arg1064His), 0.5 pts, PMID: 36983702, 30564623; LOVD Individual #00221252) (PM3_Supporting). This individual displayed progressive limb girdle muscle weakness and disease range dysferlin expression by blood monocyte assay, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function. In addition, SpliceAI gives a score of 0.31 for donor gain. (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/10/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10607009/MONDO:0015152/180 2025-06-10 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119573 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085649 infores:hetionet CAID:CA229445 biolink:causes MONDO:0009861 infores:clingen CAID:CA229445 MONDO:0009861 PMID: Likely Pathogenic PM2, PM3, PP3, PP4 PM5 This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID: 28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229445/MONDO:0009861/006 2021-05-29 2021-07-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9637 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0039070 infores:hetionet NCBIGene:6772 biolink:causes MONDO:0013427 infores:monarchinitiative not_provided not_provided HGNC:11362 MONDO:0013427 uuid:7fdccb75-7c57-42f0-b206-c7ab3be8267c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3996 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0042023 infores:hetionet CHEBI:585948 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0232487 infores:hetionet CAID:CA10577405 biolink:causes MONDO:0017623 infores:clingen CAID:CA10577405 MONDO:0017623 PMID: Uncertain Significance PM2 BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.-802G>A, also described as c.-801G>A (NC_000010.11:g.87863668G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577405/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10580948 biolink:causes MONDO:0018875 infores:clingen CAID:CA10580948 MONDO:0018875 PMID: Pathogenic PS3, PM1, PS2_Moderate, PM2_Supporting, PS4_Supporting BP4, BP2, BA1, PS1, PM5, BS1, BS3, BS4, PM6, BS2, PP3, PP1, PP4 The NM_000546.6: c.329G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 110 (p.Arg110Pro). This variant has been reported in 2 unrelated families meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs: 30455982, 23894400; Internal lab contributors). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a moderately LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 29070607). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 11 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, PS2_Moderate, PM2_Supporting, PS4_Supporting. (Bayesian Points: 10; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580948/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CAID:CA205646 biolink:causes MONDO:0010726 infores:clingen CAID:CA205646 MONDO:0010726 PMID: Benign BP5, BS2, BA1 The allele frequency of the p.Gly92= variant in MECP2 (NM_004992.3) is 0.084% in African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Gly92= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Gly92= variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly92= variant in MECP2 (NM_004992.3) is classified as Benign based on the ACMG/AMP criteria (BA1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA205646/MONDO:0010726/016 2022-12-09 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:38940 biolink:causes UMLS:C0027627 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027627 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151559 infores:hetionet CHEBI:7465 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1384353 infores:hetionet NCBIGene:26047 biolink:causes MONDO:0012400 infores:monarchinitiative not_provided not_provided HGNC:13830 MONDO:0012400 uuid:ad97b295-849f-4b46-8414-dada8cd9660d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0271710 infores:hetionet CHEBI:4672 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0014356 infores:hetionet CHEBI:28918 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0001125 infores:hetionet CHEBI:83527 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0030554 infores:hetionet CHEBI:64312 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0039240 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1262144 infores:hetionet CHEBI:94848 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0039231 infores:hetionet CHEBI:6950 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0549249 infores:hetionet CHEBI:2639 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0040822 infores:hetionet CAID:CA2499225878 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225878 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, BS1, BS3, BS4, PM6, PVS1, BP7, BP5, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.352-12_352-9del is an intronic deletion outside of the typical splicing region. It is not predicted to impact splicing, with a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225878/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28787 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0002792 infores:hetionet CHEBI:16714 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0037763 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011551 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020538 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0239978 infores:hetionet UMLS:C1738934 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030554 infores:hetionet CHEBI:63617 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0003578 infores:hetionet CHEBI:6015 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0855775 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003864 infores:hetionet CHEBI:63598 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0022281 infores:hetionet CHEBI:40303 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0042384 infores:hetionet CHEBI:6076 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C3665347 infores:hetionet CHEBI:2687 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0009676 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0022073 infores:hetionet CHEBI:94609 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0028643 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1737224 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1737224 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0027769 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0004936 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0033246 infores:hetionet CHEBI:27504 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0015967 infores:hetionet CAID:CA38817036 biolink:causes MONDO:0100084 infores:clingen CAID:CA38817036 MONDO:0100084 PMID: Likely Benign BP4, BP7 PP2, PP3, PP1, PP4, BS2, PM2, PM6, PVS1, BA1, BP1, BP2, BP3, PS4, PS2, PS3, PS1, BP5, BS1, BS4, BS3, PM3, PM4, PM1, PM5 The variant NM_001100.4:c.36C>T is a synonymous (silent) variant (p.Cys12=) in exon 2/7. The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002478 (3/1180002 alleles) in European (non-Finnish) population (no population codes met). This silent variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as likely benign for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA38817036/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63618 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0042109 infores:hetionet CAID:CA10577540 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577540 MONDO:0007648 PMID:32133419 Likely Pathogenic PP3, PM2_Supporting, PS3, PS4_Moderate BP5, BP7, BS3, BS1, BS4, PM1, PM3, PM4, PM5, PM6, PVS1, PP2, PP4, PP1, BS2, BA1, BP1, BP4, BP3, PS1, PS2 The c.1057G>A (p.Glu353Lys) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_moderate; SCV001378233.1, SCV000580696.4). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 32133419). This variant is predicted to affect splicing by SpliceAI (Donor Gain: score = 0.54 at -3 bp) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (v3.1): PS3, PS4_moderate, PM2_supporting, PP3. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577540/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:39585 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0041912 infores:hetionet CAID:CA1624827 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624827 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.225A>G (p.Gln75=) variant in the SOS1 gene is 0.042% (12/16448) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624827/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9927 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0497247 infores:hetionet CHEBI:71219 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1384353 infores:hetionet CHEBI:16347 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0004604 infores:hetionet CHEBI:31236 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018808 infores:hetionet CHEBI:6916 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0013144 infores:hetionet CHEBI:50156 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0042963 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018021 infores:hetionet CHEBI:71229 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C1112525 infores:hetionet CHEBI:63598 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017181 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0221490 infores:hetionet CHEBI:18358 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0033774 infores:hetionet CHEBI:7443 biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0266813 infores:hetionet CHEBI:70718 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0687713 infores:hetionet CHEBI:7494 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0004134 infores:hetionet CHEBI:9328 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0002792 infores:hetionet CHEBI:8214 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0009676 infores:hetionet CHEBI:15367 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0546817 infores:hetionet NCBIGene:10804 biolink:causes MONDO:0007510 infores:monarchinitiative not_provided not_provided HGNC:4288 MONDO:0007510 uuid:8f5a4c42-52b5-4b39-9b34-fd98547a746f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002962 infores:hetionet CHEBI:31623 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0085641 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0008370 infores:hetionet CHEBI:41879 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151908 infores:hetionet CHEBI:63630 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1140680 infores:hetionet CHEBI:8378 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0019209 infores:hetionet CHEBI:8502 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0042963 infores:hetionet CHEBI:3756 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0025323 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0575090 infores:hetionet CHEBI:8802 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0027497 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013238 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0854456 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0854456 infores:hetionet CHEBI:8093 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0040822 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0030312 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0948594 infores:hetionet CAID:CA004294 biolink:causes MONDO:0005045 infores:clingen CAID:CA004294 MONDO:0005045 PMID: Likely Pathogenic PM1_Supporting, PS4_Moderate, PM6, PP3, PM2_Supporting BA1, BP1, PS1, PS2, BS1, PM5, PP2 NM_001276345.2(TNNT2):c.311G>A (p.Arg104His) - This variant has been reported in individuals with HCM (PMIDs: 19659763, 20031602, 20624503, 25524337, 26507537, 27532257) and is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criterion has been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been confirmed as de novo (PM6; LMM Data, PMID: 20624503). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Supporting; PMID: 30696458). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity (PP3). In summary, this variant has been classified as Likely Pathogenic for HCM in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PM6, PM1_Supporting, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA004294/MONDO:0005045/099 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3614 biolink:causes UMLS:C1536052 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C1536052 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009938 infores:hetionet CHEBI:5138 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0699828 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003123 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1096034 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1096034 infores:hetionet CHEBI:36791 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040460 infores:hetionet CHEBI:50692 biolink:causes MONDO:0009050 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0221406 infores:hetionet CHEBI:64064 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0004096 infores:hetionet CHEBI:119915 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0600228 infores:hetionet CHEBI:7931 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0036974 infores:hetionet CHEBI:167638 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0023066 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020538 infores:hetionet CHEBI:9398 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0030252 infores:hetionet CHEBI:114785 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0011991 infores:hetionet CHEBI:64321 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0013404 infores:hetionet UMLS:C0010592 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0023380 infores:hetionet CHEBI:9398 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0026205 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0521490 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151849 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006898 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0031037 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0149931 infores:hetionet CHEBI:64321 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0231218 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0234458 infores:hetionet GO:0002338 biolink:causes CL:0000821 infores:ubergraph knowledge_assertion manual_agent GO:0002338 CL:0000821 CHEBI:8871 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033860 infores:hetionet CHEBI:2682 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020433 infores:hetionet CHEBI:6128 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0028084 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0007971 infores:hetionet CHEBI:71417 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0019079 infores:hetionet CHEBI:6847 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0011603 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0853198 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0853198 infores:hetionet CHEBI:5118 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0232461 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0010692 infores:hetionet CHEBI:3387 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0016655 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0005779 infores:hetionet CHEBI:8884 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0033774 infores:hetionet CHEBI:9943 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C3263723 infores:hetionet CHEBI:94848 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0162830 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0522224 infores:hetionet CAID:CA229429 biolink:causes MONDO:0009861 infores:clingen CAID:CA229429 MONDO:0009861 PMID:9521426PMID:9452062PMID:9521426 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PP3 The c.1315+2T>C variant is at the 3' canonical splice site in the penultimate exon of PAH. It is absent form population databases and has been identified in trans with pathogenic variants in three independent patients (F39del, Y414C, and R261X; PMID: 9452062; 9521426). A defect of BH4 metabolism was excluded as a cause of elevated phenylalanine in all patients. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229429/MONDO:0009861/006 2018-12-09 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0221269 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013595 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017601 infores:hetionet CHEBI:17823 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0151539 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0474378 infores:hetionet CAID:CA383511196 biolink:causes MONDO:0013304 infores:clingen CAID:CA383511196 MONDO:0013304 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, BP5 PM5 The NM_000552.5(VWF):c.3515G>T (p.Gly1172Val) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.839, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). One type 2A patient with VWF:RCo/VWF:Ag <0.6 has been reported (PMID: 26986123; PS4_supporting). A type 2B case was reported (PMID: 35452508) with this variant as well as Arg1308Cys (Classified pathogenic for type 2B by the VWD VCEP; BP5). In summary, the variant meets the criteria to be classified as a Variant of Uncertain Significance for von Willebrand disease type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP5, PS4_Supporting, PP3, and PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383511196/MONDO:0013304/081 2025-02-04 2025-02-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0233414 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0015397 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0009319 infores:hetionet CHEBI:3738 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0040822 infores:hetionet CAID:CA413497310 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497310 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.116-1G>A (NM_000206.3) variant in IL2RG occurs within the canonical acceptor splice site (-1) of intron 1. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 2, resulting in a frameshift (p.Asp39Glyfs*57) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). The variant is absent in gnomAD v4 (PM2_supporting). Patient with SCID (0.5 pt.) and whole exome sequencing conducted (1 pt.) (Total :1.5 pts.; PP4; PMID: 34093558)In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_supporting,PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497310/MONDO:0010315/129 2024-06-21 2024-06-21 X-linked inheritance HP:0001417 Supports CHEBI:5613 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0037763 infores:hetionet NCBIGene:23236 biolink:causes MONDO:0013389 infores:monarchinitiative not_provided not_provided HGNC:15917 MONDO:0013389 uuid:b0477590-b347-4b00-b685-3594860924ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes UMLS:C1167661 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1167661 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0271240 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0271240 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042267 infores:hetionet CHEBI:50841 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0231530 infores:hetionet CHEBI:2453 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0026821 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002453 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042373 infores:hetionet CHEBI:37941 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151578 infores:hetionet CHEBI:49575 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0023530 infores:hetionet CAID:CA233937 biolink:causes MONDO:0015152 infores:clingen CAID:CA233937 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.3832C>T p.(Gln1278Ter) variant in DYSF, which is also known as NM_001130987.2: c.3886C>T p.(Gln1296Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 34/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of LGMD (PMID: 27602406, 36983702, 16010686, 17698709, 18853459), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 16010686) and confirmed in trans with a pathogenic variant (NM_003494.4: c.1663C>T p.(Arg555Trp), 1.0 pt, PMID: 16010686). It was also identified in unknown phase with a pathogenic variant (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 27602406) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16010686, 18853459). The filtering allele frequency (the upper threshold of the 95% CI of 48/1111982 exome chromosomes) is 0.000054905 for the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/06/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA233937/MONDO:0015152/180 2025-03-06 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51450 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0855775 infores:hetionet CHEBI:82960 biolink:causes MONDO:0024415 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0341245 infores:hetionet CHEBI:10023 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0041948 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038362 infores:hetionet CHEBI:135005 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0013404 infores:hetionet CHEBI:2618 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0235086 infores:hetionet CHEBI:6717 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0022346 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0006285 infores:hetionet CHEBI:4995 biolink:causes MONDO:0016056 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0025958 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0009450 infores:hetionet CHEBI:8597 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0028643 infores:hetionet CHEBI:63635 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0086565 infores:hetionet CHEBI:100241 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023222 infores:hetionet CHEBI:47898 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151799 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151883 infores:hetionet CHEBI:3286 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0086565 infores:hetionet CHEBI:46081 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0004093 infores:hetionet CHEBI:9907 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042963 infores:hetionet CHEBI:45783 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042023 infores:hetionet CHEBI:42944 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0040264 infores:hetionet NCBIGene:10000 biolink:causes MONDO:0014407 infores:monarchinitiative not_provided not_provided HGNC:393 MONDO:0014407 uuid:18ee1c05-ba5b-4e46-aead-0a3d0d930a47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0019091 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0006287 infores:hetionet CHEBI:9445 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0031350 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0015397 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0030305 infores:hetionet CHEBI:10023 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018965 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0012739 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0036572 infores:hetionet CHEBI:39112 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0004604 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151723 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0030305 infores:hetionet CHEBI:3387 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0025289 infores:hetionet NCBIGene:4593 biolink:causes MONDO:0014587 infores:monarchinitiative not_provided not_provided HGNC:7525 MONDO:0014587 uuid:a5080a98-8f45-4b71-9a8c-d7c621f45074 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0030516 biolink:causes GO:0048667 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0048667 CHEBI:8382 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151686 infores:hetionet CHEBI:8874 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0016204 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0042075 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0851341 infores:hetionet CHEBI:4995 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013362 infores:hetionet CHEBI:4315 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0702166 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0855775 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0548823 infores:hetionet CHEBI:17688 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0009806 infores:hetionet CHEBI:50381 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0278134 infores:hetionet CHEBI:6437 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0014457 infores:hetionet CAID:CA400032596 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032596 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM5_Supporting, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1814G>A (p.Gly605Asp) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Another missense variant c.1813G>A (p.Gly605Ser) in the same codon has been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5_supporting). This variant has been reported in one GT patient (PMID: 29615672), this patient displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced to 6-7%, as measured by flow cytometry (PP4_strong). This patient is compound heterozygous for Gly605Asp and Asn470Ter (classified Pathogenic by the PD-EP; confirmation of trans phase was not reported, PM3_supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporitng, PM5_supporting, PP3, PP4_strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032596/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6444 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0151735 infores:hetionet CHEBI:9943 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C3665386 infores:hetionet CHEBI:63610 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0034882 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0274702 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0274702 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0037274 infores:hetionet CHEBI:84050 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0917801 infores:hetionet CAID:CA327919345 biolink:causes MONDO:0100437 infores:clingen CAID:CA327919345 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.1507-101A>T is an intron 12 variant located 101 nucleotides from exon 13. This variant is present in gnomAD v4.1.0 at a frequency of 0.2820 among hemizygous individuals, with 11,532 variant alleles / 40,892 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). The variant is located outside of the splice acceptor region (BP7). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327919345/MONDO:0100437/106 2025-08-01 2025-11-22 X-linked inheritance HP:0001417 Contradicts true CHEBI:68478 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0040822 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0021400 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027769 infores:hetionet CAID:CA2580064231 biolink:causes MONDO:0100038 infores:clingen CAID:CA2580064231 MONDO:0100038 PMID: Uncertain Significance PM6_Supporting, PP3_Moderate, PM2 PS3 The c.1035-7A>G (NM_021007.3) variant in SCN2A is an intronic variant which is located in intron 8. The computational splicing predictor SpliceAI gives a score of [0.9] for acceptor loss and gain, predicting that the variant leads to the inclusion of 2 additional amino acids in exon 9 of SCN2A (PP3). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with early infantile epileptic encephalopathy (PM6_Supporting; PMID 35711923). This variant is absent from gnomAD v4.1 (PM2_Supporting). A minigene assay in HEK293T cells showed that this variant activated a cryptic intronic acceptor site leading to the elongation of intron 8 by 6 nucleotides, with a protein effect of p.Gly345_Gln346insTyrSer. However, this assay does not meet the requirements for use by the ClinGen Epilepsy Sodium Channel VCEP (PS3_Not Met). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for early infantile epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by theClinGen Epilepsy Sodium Channel VCEP: PM6_Supporting, PM2_Supporting, PP3. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 10/22/2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580064231/MONDO:0100038/068 2024-10-22 2025-02-20 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:6334 biolink:causes MONDO:0019444 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6334 MESH:D014235 DB00730_MESH_D014235_1DB01234_MESH_D014235_1 CHEBI:9398 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0086543 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011615 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022660 infores:hetionet CHEBI:3699 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0027497 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0040034 infores:hetionet CHEBI:63621 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020625 infores:hetionet CHEBI:9168 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151904 infores:hetionet UMLS:C0004609 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0085612 infores:hetionet CHEBI:32315 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151610 infores:hetionet CAID:CA314855 biolink:causes MONDO:0012999 infores:clingen CAID:CA314855 MONDO:0012999 PMID: Benign BA1, BP4 PM2, PP3, BS1 The NM_000156.6(GAMT):c.581T>C variant in GAMT is a missense variant predicted to cause substitution of valine by alanine at amino acid 194 (p.Val194Ala). Population allele frequency of this variant is higher than 0.3% in two populations in gnomAD v2.1.1 (BA1 met). In silico predictors predict no damaging effect (REVEL<0.5) and no effect on splicing (SpliceAI<0.05; varSEAK - class 1). To our knowledge, this variant has not been reported in the literature in any individuals with GAMT deficiency. In summary, this variant meets the criteria to be classified as Benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): BA1, BP4. Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314855/MONDO:0012999/026 2023-01-30 2023-03-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46345 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0746883 infores:hetionet GO:1904136 biolink:causes GO:0048570 infores:ubergraph knowledge_assertion manual_agent GO:1904136 GO:0048570 CHEBI:4702 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0242461 infores:hetionet CHEBI:92998 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085631 infores:hetionet NCBIGene:107 biolink:causes MONDO:0012421 infores:monarchinitiative not_provided not_provided HGNC:232 MONDO:0012421 uuid:5f22d585-5c6c-48e1-accb-8db8a0a4512a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA5416968 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416968 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BA1, BS1 The c.242G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Glutamine at amino acid 81 (p.Arg81Gln).The filtering allele frequency (the upper threshold of the 95% CI of 2/1109854) of the c.242G>A variant in DCLRE1C is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416968/MONDO:0011225/116 2024-02-15 2024-10-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7824 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013456 infores:hetionet CAID:CA387462304 biolink:causes MONDO:0019497 infores:clingen CAID:CA387462304 MONDO:0019497 PMID: Pathogenic PP1_Moderate, PM2_Supporting, PM3, PVS1 The c.2T>G (p.Met1Arg) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 550716, 2070085, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in an individual with prelingual and profound hearing loss in a compound heterozygous manner with the pathogenic variant c.35delG, p.G12Vfs (1 PM3 point, Clinvar ID: 17004) and segregated in two affected siblings (PP1_Moderate, PMID: 36472766). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3, PP1_Moderate (VCEP specifications version 2; 10.24.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387462304/MONDO:0019497/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:27834 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0033774 infores:hetionet CHEBI:92712 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0013378 infores:hetionet CHEBI:47499 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0017605 infores:hetionet CHEBI:87681 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C1510410 infores:hetionet CHEBI:45599 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0001122 infores:hetionet CHEBI:63577 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C3263723 infores:hetionet CAID:CA16602438 biolink:causes MONDO:0017623 infores:clingen CAID:CA16602438 MONDO:0017623 PMID:29706350PMID:29617666 Uncertain Significance PP2, PP3, PS3_Moderate, PM2_Supporting PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PP1, PP4, BS2, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS4, PS2 PTEN c.477G>T (p.Arg159Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602438/MONDO:0017623/003 2025-10-03 2025-10-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3082 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151754 infores:hetionet CHEBI:2668 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085633 infores:hetionet UMLS:C0004609 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C2830004 infores:hetionet CHEBI:72297 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C2004489 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0013395 infores:hetionet CHEBI:10101 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0520966 infores:hetionet CHEBI:8665 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0497247 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0042401 infores:hetionet CHEBI:63599 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0851578 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0024299 infores:hetionet UMLS:C0657912 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014591 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1443060 infores:hetionet NCBIGene:115399 biolink:causes MONDO:0032637 infores:monarchinitiative not_provided not_provided HGNC:25430 MONDO:0032637 uuid:ad6b640e-888e-494a-baaf-518792780d71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72690 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0917801 infores:hetionet CHEBI:2663 biolink:causes MONDO:0800029 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1800706 infores:hetionet CHEBI:5062 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0006145 infores:hetionet CAID:CA401328025 biolink:causes MONDO:0009290 infores:clingen CAID:CA401328025 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The NM_000152.5:c.2853G>A (p.Trp951Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in the penultimate codon of the gene, thereby escaping nonsense-mediated decay and resulting in a 2 amino acid C-terminal truncation of GAA (PVS1_Moderate). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in a patient with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 552839). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: PVS1_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on April 7, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401328025/MONDO:0009290/010 2023-04-07 2023-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63608 biolink:causes MONDO:0002381 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0038987 infores:hetionet CAID:CA10576963 biolink:causes MONDO:0005045 infores:clingen CAID:CA10576963 MONDO:0005045 PMID: Uncertain Significance PM1, PM2_Supporting, PS4_Moderate PM3, BA1, PM6, PM4, PM5, PP1, PP3, PS3, BS2, PP4, BP3, BS1, BS4, BS3, PS2, PS1, BP4, BP2, BP5, BP7, PVS1 The c.677C>T (p.Ala226Val) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID:30297972; Toepfer 2020 PMID:31983222; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2_Supporting; PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576963/MONDO:0005045/002 2022-07-30 2022-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020557 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0027813 infores:hetionet CAID:CA10585290 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585290 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM3, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID: 30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID: 19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines).PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID: 11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID: 28502510 (Bañares et al., 2017), Argentina).PP3 - REVEL = 0.976.PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585290/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8871 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948294 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0042109 infores:hetionet CAID:CA119170 biolink:causes MONDO:0020367 infores:clingen CAID:CA119170 MONDO:0020367 PMID:15069026 Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3_Moderate, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS1, PS2, BP4, BA1 The c.1091G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 364 (p.Gly364Val). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.896, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Gly364Val protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 18 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMID: 10196380), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119170/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5296 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0852911 infores:hetionet CHEBI:16914 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0033774 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0020649 infores:hetionet GO:1903722 biolink:causes GO:0051298 infores:ubergraph knowledge_assertion manual_agent GO:1903722 GO:0051298 CHEBI:63621 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020443 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0018802 infores:hetionet CAID:CA377785053 biolink:causes MONDO:0017623 infores:clingen CAID:CA377785053 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, BS3_Supporting, PS2, PS4_Moderate BP4 NM_000314.8(PTEN):c.198G>T (p.Lys66Asn) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor: SCV002526496.2)PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor: SCV002526496.2)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant=0.791)PM2_P: Absent in large sequenced populations (gnomAD).BS3_P: Functional studies showing no damaging effect on protein function. Score of this variant = 0.045 (>0, WT-like range) on high throughput phosphatase assay (PMID:29706350).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic strong, 1 pathogenic moderate and 3 pathogenic supporting codes get -1 + 4 + 2 + (1*3) points; total is 8 (Likely Pathogenic). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377785053/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4779 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0033774 infores:hetionet CHEBI:63637 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0006826 infores:hetionet CAID:CA405690291 biolink:causes MONDO:0100150 infores:clingen CAID:CA405690291 MONDO:0100150 PMID: Likely Pathogenic PP3, PM1, PM2_Supporting, PS4_Moderate BA1, BS1 The c.14690G>A variant in RYR1 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 4897. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.835, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant resides within the pore region (amino acids 4800-4950), of RYR1 that is defined as a mutation hotspot/critical functional domain by the ClinGen Congenital Myopathies VCEP (PM1). This variant has been reported in 2 probands with RYR1-related myopathy (PS4_Moderate; PMIDs: 24561095, 35428369). Additionally, the variant was identified in a third individual with c.9989A>G (p.Asp3330Gly) likely in cis, although variants phasing could not be confirmed at this time (PMID: 23919265, SCV000852450.1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM1, PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications version 2; 8/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA405690291/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:175901 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0009450 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0027765 infores:hetionet CHEBI:50742 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0023530 infores:hetionet CHEBI:5893 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0231528 infores:hetionet CHEBI:134991 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0016382 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0010692 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0019158 infores:hetionet CHEBI:16664 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0014742 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0029408 infores:hetionet CHEBI:35553 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0151786 infores:hetionet CAID:CA114370 biolink:causes MONDO:0009861 infores:clingen CAID:CA114370 MONDO:0009861 PMID:9634518PMID:23514811PMID:27121329PMID:11326337PMID:24368688 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PP3, PS3 The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID: 24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114370/MONDO:0009861/006 2020-05-22 2020-05-22 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:1020 biolink:causes MONDO:0014596 infores:monarchinitiative not_provided not_provided HGNC:1774 MONDO:0014596 uuid:a2caf464-1e59-4a98-8177-101c1a55a7d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51230 biolink:causes HP:0034808 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1142349 infores:hetionet CHEBI:3504 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C1443060 infores:hetionet CAID:CA410146656 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146656 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1420G>A (p.Glu474Lys) is a missense variant which has a REVEL score < 0.50 (0.407) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146656/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:567361 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004238 infores:hetionet CHEBI:50729 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C2830004 infores:hetionet CHEBI:50859 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018946 infores:hetionet CHEBI:167638 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0085633 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0042401 infores:hetionet NCBITaxon:42862 biolink:causes MONDO:0019364 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:42862 MONDO:0019364 CHEBI:63630 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0031117 infores:hetionet CHEBI:135925 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0233477 infores:hetionet CHEBI:6916 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0151766 infores:hetionet CAID:CA386952722 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952722 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4 The c.80T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 27 (p.(Ile27Thr)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.844, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested and therefore PP4 could not be applied (PMID: 18003757). Another missense variant, c.80T>G (p.Ile27Ser), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 could not be applied. In summary, c.80T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952722/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10650 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018965 infores:hetionet CHEBI:3647 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0033117 infores:hetionet CHEBI:63619 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004134 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041956 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0234458 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151596 infores:hetionet CHEBI:135342 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0152198 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030193 infores:hetionet CHEBI:7454 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0013604 infores:hetionet CHEBI:85083 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0917801 infores:hetionet CHEBI:5893 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151825 infores:hetionet CHEBI:8502 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0042571 infores:hetionet CHEBI:28901 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C2242737 infores:hetionet CHEBI:31711 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027720 infores:hetionet NCBIGene:412 biolink:causes MONDO:0010622 infores:monarchinitiative not_provided not_provided HGNC:11425 MONDO:0010622 uuid:d98a4e7a-bc8b-4346-8779-0159a7729ee6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0232849 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0009450 infores:hetionet CHEBI:92998 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0028961 infores:hetionet CHEBI:724125 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0560024 infores:hetionet CHEBI:71219 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0232495 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0548823 infores:hetionet NCBIGene:9075 biolink:causes MONDO:0025356 infores:monarchinitiative not_provided not_provided HGNC:2041 MONDO:0025356 uuid:199b8a0a-a167-44d1-85fd-766f55282e1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63599 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0023524 infores:hetionet CHEBI:9674 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0040822 infores:hetionet NCBIGene:3211 biolink:causes MONDO:0013880 infores:monarchinitiative not_provided not_provided HGNC:5111 MONDO:0013880 uuid:3aa503f9-9f20-4e17-a2cd-da0dadd24ae8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63115 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0015672 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018799 infores:hetionet CHEBI:23765 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0231218 infores:hetionet NCBIGene:55593 biolink:causes MONDO:0025351 infores:monarchinitiative not_provided not_provided HGNC:25402 MONDO:0025351 uuid:a3ea9c48-9b1a-4daf-bb27-089247b6531e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0030196 infores:hetionet NCBIGene:100151683 biolink:causes MONDO:0008871 infores:monarchinitiative not_provided not_provided HGNC:34016 MONDO:0008871 uuid:79bcde44-a916-4177-9158-8a0b2a2aca03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0232849 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0024115 infores:hetionet CAID:CA229470 biolink:causes MONDO:0009861 infores:clingen CAID:CA229470 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM5, PP3, PM2_Supporting, PM3_Supporting The NM_000277.3(PAH):c.181A>G variant in PAH is a missense variant predicted to cause substitution of asparagine to aspartic acid at amino acid 61 (p.Asn61Asp). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PMID:12501224) (PP4_Moderate). This individual was compound heterozygous for the variant and a pathogenic variant p.R261Q in unknown phase (PMID: 12501224, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.703, which is above the threshold of 0.644 but below 0.773, evidence that correlates with supporting impact to PAH function (PP3). 2 different missense variants c.182A>G (p.Asn61Ser) and c.183C>A (p.Asn61Lys) in the same codon have been classified as pathogenic/likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria VCEP: PP4_moderate, PP3, PM2_supporting, PM3_supporting, PM5 (Version 2.0, 7/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229470/MONDO:0009861/006 2025-07-18 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:66903 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0003862 infores:hetionet CAID:CA1244108 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244108 MONDO:0020367 PMID:35196929 Benign BP7, BA1, BP4, BS3_Supporting BS1, PM2, PM6, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2 The c.975G>A variant in MYOC is a synonymous variant (p.Thr325=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.08643, which met the ≥ 0.01 threshold set for BA1 (2,157 alleles out of 24,956 which meets the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.008 which met the ≤ 10 threshold for BP4, and the GERP score = -11.5 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. A previous study (PMID: 35196929) demonstrated that the Thr325= protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP: BA1, BP4, BP7, BS3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244108/MONDO:0020367/019 2023-11-14 2023-11-14 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C1872203 biolink:causes MONDO:0009050 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0221406 infores:hetionet NCBIGene:23187 biolink:causes MONDO:0957988 infores:monarchinitiative not_provided not_provided HGNC:23697 MONDO:0957988 uuid:01dadc1d-e3d9-4eac-9cc0-02fc644d4eb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0424823 infores:hetionet CAID:CA10014553 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014553 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.303G>A (p.Val101=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.47)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014553/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:204928 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0030193 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0003864 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0009806 infores:hetionet CAID:CA341587 biolink:causes MONDO:0015967 infores:clingen CAID:CA341587 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM3, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting The c.1190G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 397 (p.(Arg397Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:17186219 , internal lab contributors). This variant segregated with diabetes, with at least 7 informative meioses in 14 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:17186219). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg397Leu has RAI=0.72, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 17186219). This variant has been detected in the homozygous state in at least 5 individuals with neonatal diabetes (PM3; internal lab contributors). In summary, c.1190G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA341587/MONDO:0015967/086 2023-07-16 2023-07-16 Semidominant inheritance HP:0032113 Supports NCBIGene:2316 biolink:causes MONDO:0010753 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010753 uuid:feb7de60-36df-4e11-975c-2b6c9a1d8505 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000977 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:2000977 GO:0007420 CHEBI:9086 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027651 infores:hetionet NCBIGene:111 biolink:causes MONDO:0859211 infores:monarchinitiative not_provided not_provided HGNC:236 MONDO:0859211 uuid:6de9d330-ac7b-4865-b802-5153e0b62c90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:178699 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0423153 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003537 infores:hetionet CHEBI:31348 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0030252 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0021359 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0853254 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0853254 infores:hetionet CHEBI:6704 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0019158 infores:hetionet CHEBI:31624 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0041834 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042109 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235762 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235762 infores:hetionet CHEBI:7936 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0035317 infores:hetionet CHEBI:8245 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0004604 infores:hetionet CHEBI:64355 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020443 infores:hetionet CHEBI:8764 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014724 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0160390 infores:hetionet CAID:CA6831669 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831669 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BS3_Supporting, PS4_Moderate PM5, PP4 The c.139G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 47 (p.(Gly47Arg)) of NM_000545.8. This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; (PMID: 23274891, internal lab contributors). The calculated MODY probability was <50% for each of these 4 individuals; therefore PP4 could not be applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Gly47Arg protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 32910913). Another missense variant, c.140G>A (p.(Gly47Glu)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.139G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PS4_Moderate, PM2_Supporting, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831669/MONDO:0015967/017 2022-04-02 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41774 biolink:causes MONDO:0005210 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0338113 infores:hetionet CHEBI:31348 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0270810 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0011053 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0006147 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0039971 infores:hetionet CHEBI:50275 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0232462 infores:hetionet CHEBI:7565 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0024902 infores:hetionet GO:1903023 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0009653 CAID:CA013417 biolink:causes MONDO:0005045 infores:clingen CAID:CA013417 MONDO:0005045 PMID:15556047PMID:24888384PMID:27532257PMID:15556047 Pathogenic PP1_Strong, PM2, PP3, PS4 PM5, PM1, PM6, BA1, PS3, BS1, BS3, PS1, PS2, BP4 The NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >35 individuals with hypertrophic cardiomyopathy (HCM), a large proportion of which are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected individuals with HCM in 9 families (PP1_Moderate; Kärkkäinen 2004 PMID:15556047; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.040% (FAF 95% CI; 16/25124) of Finnish chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), but was absent from other populations and is an established Finnish founder variant. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013417/MONDO:0005045/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:167309 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0013604 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0012833 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0000772 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0000772 infores:hetionet CHEBI:66876 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0004604 infores:hetionet CHEBI:64310 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0027796 infores:hetionet CHEBI:8093 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0017178 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1956346 infores:hetionet CHEBI:77260 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0026826 infores:hetionet CHEBI:194135 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151872 infores:hetionet CHEBI:3175 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0013144 infores:hetionet CHEBI:63627 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0037763 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0267792 infores:hetionet CHEBI:3504 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0019080 infores:hetionet CHEBI:404903 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C2830004 infores:hetionet CHEBI:53691 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0008031 infores:hetionet CAID:CA367401655 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401655 MONDO:0015967 PMID: Uncertain Significance PS1_Moderate, PP2, PP3, PM2_Supporting PS4, PM5 The c.531A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to aspartic acid at codon 177 (p.(Glu177Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.86, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant resulting in the same amino acid substitution, c.531A>T (p.Glu177Asp), has been classified as likely pathogenic by the ClinGen MDEP (PS1_Moderate). This variant was identified in one individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold, and there is insuffient clinical data to evaluate PP4 (internal lab contributors). Another missense variant at the same codon, c.530A>G (p.Glu177Gly), has been classified as a VUS by the ClinGen MDEP, therefore, PM5 does not apply. In summary, c.531A>C meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PP2, PP3, PM2_Supporting, PS1_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401655/MONDO:0015967/086 2025-09-29 2025-09-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:127780 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0030312 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0233494 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0021400 infores:hetionet CHEBI:38545 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0026826 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0855242 infores:hetionet CHEBI:10101 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0392525 infores:hetionet CHEBI:92712 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C1456784 infores:hetionet CHEBI:10101 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0042963 infores:hetionet CHEBI:5118 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0024236 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0005940 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151911 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0947999 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085620 infores:hetionet CHEBI:42797 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004134 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0022354 infores:hetionet CAID:CA658658485 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658485 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1031_1032dupTG p.(Val345fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658485/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:17303 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0033774 infores:hetionet CHEBI:171719 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0033774 infores:hetionet CHEBI:691037 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0026113 infores:hetionet GO:0031445 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:0031445 GO:0044085 CHEBI:80630 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0085669 infores:hetionet CHEBI:9649 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0030196 infores:hetionet CHEBI:31980 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0010200 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0018799 infores:hetionet NCBIGene:6810 biolink:causes MONDO:0958277 infores:monarchinitiative not_provided not_provided HGNC:11439 MONDO:0958277 uuid:87eb172f-881d-48bc-b218-dbd3f3e6af59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0098904 biolink:causes GO:0061337 infores:ubergraph knowledge_assertion manual_agent GO:0098904 GO:0061337 CHEBI:31644 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0853813 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0004936 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0011991 infores:hetionet CAID:CA016070 biolink:causes MONDO:0005021 infores:clingen CAID:CA016070 MONDO:0005021 PMID: Uncertain Significance PM2, PS4_Supporting, PP1_Moderate PM6, PM5, PM1, PS3, PP3, BS3, PS2, PS1, BP4 The NM_000257.4(MYH7):c.5399C>T (p.Ala1800Val) variant has been identified in 2 individuals with DCM (PS4_Supporting; GeneDx pers. comm.; LMM pers. comm.) and segregated with DCM in 6 affected relatives from 1 family (PP1_Moderate; GeneDx pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis did not provide evidence for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy (DCM) in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PP1_Moderate, PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016070/MONDO:0005021/002 2022-04-27 2022-04-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7824 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0235198 infores:hetionet CHEBI:47519 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0022346 infores:hetionet CHEBI:2453 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0011603 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034359 infores:hetionet CHEBI:131512 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0026961 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001584 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0028850 infores:hetionet NCBITaxon:5553 biolink:causes MONDO:0001827 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5553 MONDO:0001827 CHEBI:135566 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0151827 infores:hetionet CHEBI:7798 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0019158 infores:hetionet CHEBI:9763 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0030554 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0343863 infores:hetionet CAID:CA10014388 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014388 MONDO:0100083 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.641C>T (p.Thr214Ile) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014388/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:10841 biolink:causes MONDO:0009240 infores:monarchinitiative not_provided not_provided HGNC:3974 MONDO:0009240 uuid:3e08353b-72b0-4019-ba82-beec045d7538 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386958995 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958995 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4, PP3 PS4, PP1 The c.353T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of methionine to threonine at codon 10 (p.(Met118Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, the variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.844, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). However, one of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.353T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958995/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50381 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0009241 infores:hetionet CHEBI:8028 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0036104 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009450 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034065 infores:hetionet CHEBI:3515 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0020458 infores:hetionet CAID:CA024148 biolink:causes MONDO:0018493 infores:clingen CAID:CA024148 MONDO:0018493 PMID: Uncertain Significance PS4_Moderate, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with proline at codon 4824 of the RYR1 protein, p.(Leu4824Pro). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, PMID:15448513). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.984) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Moderate, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024148/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8093 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0235259 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0042769 infores:hetionet CHEBI:50692 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0423791 infores:hetionet CHEBI:2453 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0016204 infores:hetionet CHEBI:63599 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0854467 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0040034 infores:hetionet CHEBI:5864 biolink:causes EFO:0003952 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015970 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0042373 infores:hetionet CHEBI:8888 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007859 infores:hetionet CAID:CA228541 biolink:causes MONDO:0013304 infores:clingen CAID:CA228541 MONDO:0013304 PMID: Pathogenic PP1_Moderate, PP3, PP4, PM2_Supporting, PS3, PS4_Very Strong PM5 NM_000552.5(VWF):c.4121G>A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 1374. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor computational predictor REVEL gives a score of 0.879, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Family M proband I.1 (PMID: 7734373) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a complete set of vWF multimers present but relative reduction of the larger multimers, low VWF:RCo/VWF:Ag ratio (<0.4), and VWF:RCo <3-10 IU/dl (PP4). Additional consistent phenotypes included FVIII activity consistent with VWF antigen. This variant has been reported in >8 additional probands with consistent laboratory phenotypes (PS4_VeryStrong; PMIDs: 7620154, 9031470, 11154147, 7734373, 38315875, 28083987, 28536718). The variant has been reported to segregate with VWD type [2A/2M] through at least 2 affected meioses in at least 2 families (PP1_Moderate; PMID: 7734373, PMID: 7620154). A platelet binding assay in COS-7 cells expressing the recombinant VWF variant showed decreased binding indicating that this variant has a damaging effect on protein function relative to the rVWF wild-type control (PMID: 10845912, PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS4_VeryStrong, PM2_supporting, PP1_Moderate, PP3, PP4.Recent analysis (PMID: 38315875) reports that patients with R1374H have severely reduced VWF:GPIbR/VWF:Ag and a modest decrease in VWF:CB/VWF:Ag ratios. This can be explained by 2 defects, (1) a reduced VWF A1 domain binding to GPIb and (2) an altered VWF multimeric pattern in which patients showed a slightly diminished proportion of HMWM and little increase of low and intermediate multimers. They hypothesize that the slight reduction of HMWM (characteristic of type 2A) is primarily responsible for marginally reduced VWF:CB/VWF:Ag ratio, whereas the markedly reduced VWF:GPIbR/VWF:Ag ratio is mainly because of a type 2M defect (diminished binding of A1-GPIb) and propose a subtype designation of 2M/2A for this variant. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228541/MONDO:0013304/081 2024-12-03 2024-12-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75988 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C1142499 infores:hetionet CHEBI:3723 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0541798 infores:hetionet CHEBI:45951 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0041105 infores:hetionet CHEBI:17141 biolink:causes MONDO:0018905 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0079744 infores:hetionet CHEBI:6710 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0027947 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0006840 infores:hetionet CHEBI:5801 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0086565 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0314719 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0877154 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0877154 infores:hetionet CHEBI:37333 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0018524 infores:hetionet CHEBI:18248 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0010200 infores:hetionet CHEBI:61033 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0239571 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0011616 infores:hetionet CHEBI:6970 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0011991 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0677500 infores:hetionet CHEBI:16714 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0011175 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0018939 infores:hetionet NCBIGene:22861 biolink:causes MONDO:0014089 infores:monarchinitiative not_provided not_provided HGNC:14374 MONDO:0014089 uuid:79d5105a-3a82-48df-aaa4-d0235700e7f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:80630 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0042373 infores:hetionet UMLS:C0120107 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0019572 infores:hetionet CHEBI:63622 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0522224 infores:hetionet CHEBI:63598 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0026766 infores:hetionet NCBIGene:10734 biolink:causes MONDO:0030507 infores:monarchinitiative not_provided not_provided HGNC:11356 MONDO:0030507 uuid:bdc28e9f-fe34-44ce-b1e6-23aca7962375 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9757 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0423232 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0006145 infores:hetionet CHEBI:51209 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0027497 infores:hetionet CHEBI:78543 biolink:causes MONDO:1040016 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1504438 infores:hetionet CHEBI:52717 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0010481 infores:hetionet CHEBI:9086 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020580 infores:hetionet CHEBI:63577 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C2363731 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1696685 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1696685 infores:hetionet CAID:CA2588340080 biolink:causes MONDO:0100437 infores:clingen CAID:CA2588340080 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2144_2145insCTGAG (p.Arg715SerfsTer2) is a frameshift variant due to a 5-nucleotide insertion that introduces a premature stop codon within exon 15 of 15 after 2 amino acids that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 10 years (1 pt), reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with pigment deposits (0.5 pts), optic disc pallor (0.5 pts), cataract, severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2588340080/MONDO:0100437/106 2025-08-04 2025-08-04 X-linked inheritance HP:0001417 Supports CAID:CA288028 biolink:causes MONDO:0007648 infores:clingen CAID:CA288028 MONDO:0007648 PMID: Likely Benign BS2 BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM5, PM4, PVS1, PM2, PM6, PP3, PP2, PP4, PP1, BP4, BP1, BP2, BP3, BA1, PS3, PS4, PS2, PS1 The c.1297G>A (p.Asp433Asn) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288028/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5893 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0237314 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C2242996 infores:hetionet CHEBI:46195 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0162557 infores:hetionet CHEBI:45716 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0042963 infores:hetionet CHEBI:63577 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0015230 infores:hetionet CHEBI:3393 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0018681 infores:hetionet CHEBI:3403 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0220870 infores:hetionet CHEBI:72296 biolink:causes MONDO:0004001 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0009492 infores:hetionet CHEBI:32315 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0235287 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0018799 infores:hetionet CHEBI:7478 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0231528 infores:hetionet CHEBI:125354 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0013395 infores:hetionet CHEBI:5855 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151746 infores:hetionet CHEBI:180905 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0344232 infores:hetionet CHEBI:2675 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0015371 infores:hetionet CHEBI:6909 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027424 infores:hetionet CHEBI:45863 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042023 infores:hetionet NCBIGene:56603 biolink:causes MONDO:0013740 infores:monarchinitiative not_provided not_provided HGNC:20581 MONDO:0013740 uuid:2c1f66f3-f592-4d28-9484-d745a33a54ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085932 infores:hetionet CHEBI:16347 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0020461 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038525 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0042373 infores:hetionet CHEBI:145499 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C3489393 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0401013 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0401013 infores:hetionet NCBIGene:7450 biolink:causes MONDO:0013304 infores:monarchinitiative not_provided not_provided HGNC:12726 MONDO:0013304 uuid:19ad4ff2-a532-44e9-9455-6d5421ecbd22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0033687 infores:hetionet CHEBI:50841 biolink:causes UMLS:C1735368 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C1735368 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018939 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0242073 infores:hetionet CHEBI:83804 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085602 infores:hetionet CHEBI:2453 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0018965 infores:hetionet CAID:CA320642691 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642691 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP3, BP2, BP1, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP4, PP1, PP2, PP3 NM_001754.5(RUNX1):c.255C>T (p.His85=) is a synonymous variant (no REVEL score applicable) which has a SpliceAI score ≤0.20 (0.00) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642691/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45285 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0003862 infores:hetionet CHEBI:135738 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0027497 infores:hetionet CHEBI:367163 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151662 infores:hetionet CHEBI:4702 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0042907 infores:hetionet UNII:T58MSI464G biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0016204 infores:hetionet CHEBI:49662 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0036974 infores:hetionet CHEBI:18248 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0151907 infores:hetionet CHEBI:65349 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0042075 infores:hetionet CHEBI:6413 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0008031 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0007642 infores:hetionet GO:2000248 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:2000248 GO:0048699 CHEBI:3568 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040261 infores:hetionet CAID:CA409120239 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120239 MONDO:0007064 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting The c.736C>T (p.Gln246Ter)(NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_Supporting). One patient (U444) was found homozygous for this mutation (PMID: 17185467,PM3_Supporting).Based on the above evidence, this variant can be classified as pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PVS1_Met,PM2_Supporting,PM3_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120239/MONDO:0007064/114 2024-01-24 2024-01-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151313 infores:hetionet CHEBI:39867 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085636 infores:hetionet CHEBI:9586 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027497 infores:hetionet GO:0002688 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:0002688 GO:0070887 CAID:CA340749010 biolink:causes MONDO:0100368 infores:clingen CAID:CA340749010 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PP1, PM2_Supporting NM_000329.3(RPE65):c.200T>G is a missense variant that causes substitution of leucine with arginine at position 67. This variant is present in gnomAD v.2.1.1 at a maximum allele frequency of 0.00005437, with 1 allele / 18392 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.596dup (p.Asn199LysfsTer?) or NM_000329.3(RPE65):c.893del (Lys298Asnfs*27) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total pts, PMID: 34830511, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by targeted exome sequencing finding no alternative cause of disease among 188 known inherited retinal degeneration genes (2 pts), onset before the age of 5 years (1 pt), reduced central visual acuity (1 pt), nystagmus (1 pt), hypo-autofluorescence (2 pts), and extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 pts, PMID: 34830511, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative in two different families, with the variant present in the compound heterozygous state in both instances (PMID: 22509104, PMID: 23661369, PP1). The computational predictor REVEL gives a score of 0.98, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340749010/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4466 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0015967 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0009763 infores:hetionet GO:1905310 biolink:causes GO:0061307 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0061307 CHEBI:6061 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C1328539 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0020456 infores:hetionet CHEBI:3568 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0026603 infores:hetionet CHEBI:47781 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0852911 infores:hetionet CAID:CA658795226 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795226 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000152.5(GAA):c.340_341insT (p.Lys114Ilefs) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant has been reported with infantile onset Pompe disease and a GAA enzyme activity level from dried blood of 0.13 pmol/punch/hr (PMID: 20821053) (PP4_Moderate). This patient, in addition to two other patients, is homozygous for the c.340_341insT variant in GAA (PMIDs: 14695532, 20821053, 21483992) (PM3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1068640). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795226/MONDO:0009290/010 2024-02-06 2024-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:10102 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0948594 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022650 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151559 infores:hetionet CHEBI:6413 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0028081 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009763 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030312 infores:hetionet CHEBI:4814 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0231528 infores:hetionet NCBITaxon:237561 biolink:causes UMLS:C0011974 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D003963 DB00257_MESH_D003963_1DB01110_MESH_D003963_1 CHEBI:4027 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0403632 infores:hetionet CHEBI:16914 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0011053 infores:hetionet CHEBI:7581 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0575081 infores:hetionet CHEBI:5893 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0008031 infores:hetionet CHEBI:63638 biolink:causes MONDO:0008101 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0266011 infores:hetionet CHEBI:15544 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0011991 infores:hetionet CHEBI:8356 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017979 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0011991 infores:hetionet CHEBI:9649 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C1167965 infores:hetionet CHEBI:63580 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019080 infores:hetionet CAID:CA296087 biolink:causes MONDO:0021060 infores:clingen CAID:CA296087 MONDO:0021060 PMID: Uncertain Significance PM2, PP2 PS4, PM1 The c.508A>T (p.Met170Leu) variant in KRAS was absent from large population studies (PM2; https://gnomad.broadinstitute.org). It was reported in 1 individual with a presentation that lacked a clear association with a RASopathy (PS4 not applied; SCV000310757.1) Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants, and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296087/MONDO:0021060/004 2019-09-24 2019-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9943 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085593 infores:hetionet CHEBI:64355 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017181 infores:hetionet CHEBI:9654 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0041657 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0242073 infores:hetionet NCBIGene:2590 biolink:causes MONDO:0030043 infores:monarchinitiative not_provided not_provided HGNC:4124 MONDO:0030043 uuid:47a76a63-a78c-415f-80f0-364f43fe1f81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C3203358 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0518015 infores:hetionet CHEBI:42068 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0162834 infores:hetionet GO:0045694 biolink:causes GO:0009553 infores:ubergraph knowledge_assertion manual_agent GO:0045694 GO:0009553 CHEBI:50173 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0016867 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0041912 infores:hetionet CHEBI:135930 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C1527344 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0234215 infores:hetionet CHEBI:16755 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0030554 infores:hetionet CAID:CA024286 biolink:causes MONDO:0007783 infores:clingen CAID:CA024286 MONDO:0007783 PMID: Pathogenic PP1, PS4_Supporting, PM1, PS3, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of tyrosine with serine at codon 522 of the RYR1 protein, p.(Tyr522Ser). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, one of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:7829078, PMID:19020143). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists. A knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, as well ex vivo studies showed increased response to agonist with increased calcium release, PS3 (PMID:31607937, PMID:9334205).This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1 ( PMID:7829078). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Supporting, PS3, PM1, PP1, PP3_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024286/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:61033 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0016382 infores:hetionet UBERON:0005425 biolink:causes MONDO:0008380 infores:ubergraph knowledge_assertion manual_agent UBERON:0005425 MONDO:0008380 NCBIGene:4635 biolink:causes MONDO:0015001 infores:monarchinitiative not_provided not_provided HGNC:7585 MONDO:0015001 uuid:0606dc08-497d-4a1d-a4e9-d069c0c6ecfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027796 infores:hetionet CHEBI:64321 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0009763 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1963718 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1963718 infores:hetionet CHEBI:31623 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0011630 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027051 infores:hetionet CHEBI:5134 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0027424 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031212 infores:hetionet CHEBI:8713 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0011633 infores:hetionet CHEBI:472657 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0033777 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0007785 infores:hetionet CAID:CA023980 biolink:causes MONDO:0007783 infores:clingen CAID:CA023980 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3, PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with tyrosine at codon 4119 of the RYR1 protein, p.(Asn4119Tyr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000016, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:15731587). A functional study using [3H]ryanodine in HEK293 cells showed altered activity of this variant compared to wild-type but this study did not meet the VCEP criteria for a well-established functional study (PMID:27558158). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.813 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023980/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63619 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0080274 infores:hetionet CHEBI:27834 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0000737 infores:hetionet CHEBI:188986 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151827 infores:hetionet CHEBI:76607 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0002871 infores:hetionet CHEBI:6933 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0000737 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0040046 infores:hetionet CHEBI:39867 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0856054 infores:hetionet CHEBI:63624 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0007859 infores:hetionet CHEBI:42944 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C1443060 infores:hetionet CHEBI:9907 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C1443060 infores:hetionet CHEBI:75246 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0162830 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018939 infores:hetionet CHEBI:28001 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0041948 infores:hetionet NCBIGene:182 biolink:causes MONDO:0030458 infores:monarchinitiative not_provided not_provided HGNC:6188 MONDO:0030458 uuid:98a5a7ec-6f19-46b2-b0b1-0f7c7c096221 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020651 infores:hetionet CHEBI:48273 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013404 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0030552 infores:hetionet CHEBI:16335 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0151699 infores:hetionet CHEBI:144093 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0039070 infores:hetionet CHEBI:9288 biolink:causes MONDO:0008369 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0268435 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0549336 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022573 infores:hetionet CHEBI:9635 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0004093 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011849 infores:hetionet CHEBI:5118 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013378 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0034150 infores:hetionet CHEBI:75984 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C3665347 infores:hetionet GO:1905140 biolink:causes GO:0048736 infores:ubergraph knowledge_assertion manual_agent GO:1905140 GO:0048736 CHEBI:31859 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0041657 infores:hetionet GO:1905140 biolink:causes GO:0035107 infores:ubergraph knowledge_assertion manual_agent GO:1905140 GO:0035107 CHEBI:473990 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0027765 infores:hetionet CHEBI:131512 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0233407 infores:hetionet CHEBI:78320 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0015230 infores:hetionet CHEBI:63607 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0037299 infores:hetionet CHEBI:64019 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C2973529 infores:hetionet GO:2000800 biolink:causes GO:0003170 infores:ubergraph knowledge_assertion manual_agent GO:2000800 GO:0003170 CHEBI:52172 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0242350 infores:hetionet CHEBI:8356 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0008031 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0267596 infores:hetionet GO:2000592 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:2000592 GO:0072006 CHEBI:6887 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019080 infores:hetionet CHEBI:180905 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0030193 infores:hetionet CHEBI:70735 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0241934 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0427008 infores:hetionet CHEBI:3403 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0011603 infores:hetionet CHEBI:63599 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0278134 infores:hetionet CHEBI:6931 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0231530 infores:hetionet CHEBI:28971 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0040034 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0036572 infores:hetionet CHEBI:42797 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013384 infores:hetionet CHEBI:30830 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C1320474 infores:hetionet CAID:CA024918 biolink:causes MONDO:0100150 infores:clingen CAID:CA024918 MONDO:0100150 PMID: Benign BP7, BP4, BA1 The variant NM_000540.3:c.8400+28A>G in RYR1 is an intronic variant located in intron 53. The filtering allele frequency (the lower threshold of the 95% CI of 37922/85572, 8751 homozygotes) of the c.8400+28A>G variant in RYR1 is 0.4383 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.8400+28A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024918/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CHEBI:64355 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C3263723 infores:hetionet CAID:CA9871621 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871621 MONDO:0007064 PMID: Likely Benign BS1 BS2, PP3, PM2, BA1 The NM_000022.4:c.591T>A variant in ADA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 197 (p.His197Gln). This variant has a MAF of 0.005546 (57/10278 alleles) in the Ashkenazi Jewish population in gnomAD, which is greater than the frequency specified for BS1 by the SCID VCEP for ADA (>0.00161). As per SCID VCEP specifications for ADA, we are allowed to count bottleneck populations for BS1. Therefore, BS1 is met. There are no homozygotes in gnoMAD. This variant has not been reported in the literature in individuals with severe combined immunodeficiency (SCID), and no functional experimental data has been published for this variant. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871621/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15367 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0005741 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0041912 infores:hetionet CHEBI:7915 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151578 infores:hetionet NCBIGene:1145 biolink:causes MONDO:0012157 infores:monarchinitiative not_provided not_provided HGNC:1966 MONDO:0012157 uuid:f803f7b0-c934-4d0d-8391-988ec7267d84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0242350 infores:hetionet CHEBI:3732 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0003467 infores:hetionet CAID:CA916083526 biolink:causes MONDO:0008723 infores:clingen CAID:CA916083526 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PM5, PM4, PM1, PS1, BP7 The c.128del (p.Gly43Valfs*18) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. In summary, this variant has been classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 11/10/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083526/MONDO:0008723/021 2022-04-06 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10110 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0004604 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0221752 infores:hetionet CHEBI:8461 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0017086 infores:hetionet GO:1905219 biolink:causes GO:0036344 infores:ubergraph knowledge_assertion manual_agent GO:1905219 GO:0036344 CHEBI:408174 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0018965 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019112 infores:hetionet CHEBI:6965 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0015371 infores:hetionet CHEBI:63620 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0947912 infores:hetionet CHEBI:65346 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0085614 infores:hetionet CHEBI:4784 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0687713 infores:hetionet CHEBI:480999 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0085692 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0851341 infores:hetionet CHEBI:43968 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0018681 infores:hetionet CHEBI:135342 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0011551 infores:hetionet CHEBI:8412 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C3665347 infores:hetionet CHEBI:64064 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0006266 infores:hetionet CHEBI:6375 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0231528 infores:hetionet CHEBI:5893 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013144 infores:hetionet CHEBI:135961 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0027497 infores:hetionet CHEBI:6970 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C1325847 infores:hetionet CAID:CA397397594 biolink:causes MONDO:0100438 infores:clingen CAID:CA397397594 MONDO:0100438 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PP3_Moderate NM_014336.5(AIPL1):c.152A>G (p.Asp51Gly) is a missense variant predicted to replace the aspartic acid at position p.51 with glycine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). This variant has also been reported in 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the p.Gln141Ter variant confirmed in trans (2 points, PMID: 31630094), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts) with onset at age 1 (1 pt) and has photophobia (1 pt), severely reduced electroretinogram responses from both rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), decreased central visual acuity (1 pt), and has had gene panel testing with no additional likely cause found (2 pts). Together these are highly specific for AIPL1-related retinopathy (8 points, PMID: 31630094, PP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting, (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397397594/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235996 infores:hetionet CHEBI:135736 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0028081 infores:hetionet CHEBI:70746 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0000737 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0022660 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0242350 infores:hetionet CHEBI:8212 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0427086 infores:hetionet CHEBI:76010 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0042075 infores:hetionet CHEBI:49603 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0027497 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0600041 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0600041 infores:hetionet CHEBI:5138 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0004093 infores:hetionet CAID:CA134595 biolink:causes MONDO:0021060 infores:clingen CAID:CA134595 MONDO:0021060 PMID: Pathogenic PP3, PP2, PM6, PM2, PM1, PS2, PS4 The c.169A>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 57 (p.Lys57Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.726, evidence that the p.Lys57Gln variant may impact the protein function (PP3). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). The variant is located in a specific region supporting pathogenicity (PM1, aa 43-61). This variant has been reported in at least 6 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 1 as an unconfirmed de novo occurrence (PS2, PS4; Partners LMM, GeneDx, Invitae, Baylor, Otto von Guericke University Magdeburg internal data; ClinVar SCV000061249.5, SCV000207949.3, SCV001568953.4, PMID: 35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PS4, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134595/MONDO:0021060/045 2024-12-03 2025-03-27 Autosomal dominant inheritance HP:0000006 Supports GO:2000014 biolink:causes GO:0010154 infores:ubergraph knowledge_assertion manual_agent GO:2000014 GO:0010154 CHEBI:52717 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151474 infores:hetionet CHEBI:28864 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0041969 infores:hetionet CHEBI:6149 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0002994 infores:hetionet CHEBI:32139 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0021845 infores:hetionet CHEBI:3534 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0001824 infores:hetionet CAID:CA9870271 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870271 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, PM1 The c.427A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNFA, causes an amino acid change of isoleucine to valine at codon 143 (p.(Ile143Val)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant has a REVEL score of 0.445, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, the c.427A>G variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870271/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45367 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0917801 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0027765 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0855652 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0855652 infores:hetionet CHEBI:3127 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042384 infores:hetionet CHEBI:135005 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0151636 infores:hetionet CHEBI:3216 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0026858 infores:hetionet CHEBI:3723 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085628 infores:hetionet CHEBI:3647 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0242429 infores:hetionet CHEBI:64310 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0012833 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151626 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018965 infores:hetionet CHEBI:7465 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1268766 infores:hetionet CHEBI:9352 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0017152 infores:hetionet CHEBI:175901 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0004604 infores:hetionet CHEBI:4469 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0231530 infores:hetionet CHEBI:2950 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0011551 infores:hetionet CHEBI:63617 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015967 infores:hetionet CHEBI:3508 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0009421 infores:hetionet CHEBI:51209 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0232462 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0004096 infores:hetionet CHEBI:17263 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0014173 infores:hetionet CHEBI:31413 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0018524 infores:hetionet CHEBI:3756 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0010692 infores:hetionet CAID:CA1244309 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244309 MONDO:0020367 PMID:16466712 Likely Benign BS3_Supporting BP7, BS1, PM2, PM6, PP3, PP1, PM5, PM4, PS4, PS3, PS1, PS2, BP4, BA1 The c.244C>T variant in MYOC is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 82 (p.Arg82Cys). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.0001695 (6 alleles out of 35 404), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.268, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Arg82Cys protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 2 segregations had been reported in a family with mild glaucomatous disc changes (PMID: 11133859), not meeting the ≥ 3 segregations required for PP1. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244309/MONDO:0020367/019 2022-03-06 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:18332 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0015672 infores:hetionet CHEBI:31859 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0020672 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0018799 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0042384 infores:hetionet CHEBI:3698 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0004134 infores:hetionet CHEBI:40237 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0042029 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0031117 infores:hetionet CHEBI:101278 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013404 infores:hetionet GO:1901232 biolink:causes GO:0003401 infores:ubergraph knowledge_assertion manual_agent GO:1901232 GO:0003401 CHEBI:478164 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0006852 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0947999 infores:hetionet CHEBI:175901 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0231218 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151763 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0239295 infores:hetionet CAID:CA213820 biolink:causes MONDO:0015967 infores:clingen CAID:CA213820 MONDO:0015967 PMID: Likely Pathogenic PM3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.658T>C variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to arginine at codon 220 (p.(Cys220Arg)) of NM_000162.5. This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 4097065, 25755231, internal lab contributors). This variant was identified in in the homozygous state in 2 siblings with neonatal diabetes, negative testing for ABCC8, KCNJ11, and INS, and a 3+ generation family history of diabetes (PP4_Moderate, PM3_Supporting; PMID: 25755231, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.658T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213820/MONDO:0015967/086 2023-12-01 2023-12-01 Semidominant inheritance HP:0032113 Supports CHEBI:9943 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038454 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0948594 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0700217 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D000071074 DB00493_MESH_D000071074_1DB00479_MESH_D000071074_1DB00684_MESH_D000071074_1DB01053_MESH_D000071074_1DB00798_MESH_D000071074_1 CHEBI:142290 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0009676 infores:hetionet CHEBI:84500 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0003862 infores:hetionet CHEBI:50859 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0032227 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0039503 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0025061 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0007642 infores:hetionet CHEBI:7903 biolink:causes MONDO:0100313 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0017668 infores:hetionet CHEBI:3764 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0085932 infores:hetionet CHEBI:31348 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013604 infores:hetionet CHEBI:31622 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0231218 infores:hetionet CAID:CA410147728 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147728 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS2, PS3, PS1, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1229C>T (p.Ser410Leu) is a missense variant which has a REVEL score < 0.50 (0.339) and a SpliceAI score ≤ 0.20 (0.00) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147728/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3207 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042963 infores:hetionet CHEBI:16347 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0025222 infores:hetionet CAID:CA16020762 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020762 MONDO:0009861 PMID:26503515PMID:26600521PMID:28982351 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PP3 The c.301G>A (p.Asp101Asn) variant in PAH has been reported in 3 patients with PKU (BH4 deficiency excluded) (PMID: 26503515, 26600521, 28982351). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, ESP. Conflicting computational evidence: SIFT (T); PolyPhen-2 (B); MutationTaster (D); REVEL=0.465. It is detected in trans with pathogenic variants Q267E and p.Arg158Trp. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020762/MONDO:0009861/006 2020-04-10 2020-04-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46081 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0001824 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0836924 infores:hetionet CHEBI:7986 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0022346 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0020517 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0011991 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1392046 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235890 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0521592 infores:hetionet CHEBI:6912 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0020517 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0427008 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027769 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0022073 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013395 infores:hetionet CAID:CA367402681 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402681 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.324C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 108 (p.(Tyr108Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; 19790256). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 14517956, internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.324C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402681/MONDO:0015967/086 2023-12-15 2023-12-15 Semidominant inheritance HP:0032113 Supports CAID:CA145890 biolink:causes MONDO:0001586 infores:clingen CAID:CA145890 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.891C>T variant in IDUA is a synonymous (silent) variant (p.Asn297=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.1382 in the Middle Eastern population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92649). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disorders Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145890/MONDO:0001586/091 2025-01-02 2025-01-02 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15365 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0151746 infores:hetionet CHEBI:3387 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0022107 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0392525 infores:hetionet CHEBI:32139 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0018681 infores:hetionet CHEBI:8428 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0220870 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0162830 infores:hetionet CAID:CA902659 biolink:causes MONDO:0100368 infores:clingen CAID:CA902659 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 NM_000329.3(RPE65):c.10C>T (p.Gln4Ter) is a nonsense variant that introduces a premature stop codon into exon 1 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000008797, with 1 allele/113674 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset before age 5 years (1 pt), undetectable ERG responses from both rods (0.5 pts) and cones (1 pt), reduced visual acuity (1 pt), and retinal pigment epithelial mottling (0.5 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total points, PMID: 35129589, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902659/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7936 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0001339 infores:hetionet CHEBI:2611 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0036104 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0236083 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0236083 infores:hetionet CHEBI:6402 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0206062 infores:hetionet UMLS:C0657912 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020461 infores:hetionet NCBIGene:7171 biolink:causes MONDO:0957580 infores:monarchinitiative not_provided not_provided HGNC:12013 MONDO:0957580 uuid:d7760b93-b43c-4b44-9550-0fa70902b8b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0040460 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002453 infores:hetionet CHEBI:7581 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0023530 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0267792 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0020517 infores:hetionet CHEBI:47499 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0038362 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0020538 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0031350 infores:hetionet CHEBI:28918 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C2830004 infores:hetionet CHEBI:116278 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1167965 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0029408 infores:hetionet CHEBI:7798 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C3263723 infores:hetionet CAID:CA16043128 biolink:causes MONDO:0015967 infores:clingen CAID:CA16043128 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PM1, PS2, PS4_Moderate The c.188G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 63 (p.(Arg63Gln)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributors). It was also identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF4A-MODY (persistent neonatal hypoglycemia and negative testing for ABCC8 and KCNJ11) (PS2; internal lab contributor). Additionally, this variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.188G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS2, PP4_Moderate, PM1, PS4_Moderate, PP1, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043128/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9637 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0036974 infores:hetionet CHEBI:3506 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0020517 infores:hetionet NCBIGene:3690 biolink:causes MONDO:0030996 infores:monarchinitiative not_provided not_provided HGNC:6156 MONDO:0030996 uuid:1e733b61-6fa1-4e58-abd4-c90ecbea8e55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3636 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0085631 infores:hetionet CHEBI:41774 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020458 infores:hetionet CHEBI:6832 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0020517 infores:hetionet CHEBI:7565 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018834 infores:hetionet CHEBI:8764 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0008031 infores:hetionet CHEBI:75722 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0338656 infores:hetionet CAID:CA10585372 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585372 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Moderate, PM2, PP4 The NM_000527.5(LDLR):c.1244A>G (p.Asp415Gly) variant is classified as Likely Pathogenic, for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP1_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated cases who fulfill criteria for FH (at least 1 case from PMID 11810272 (Fouchier et al., 2001), The Netherlands; 1 case from PMID 10978268 (Bertolini et al., 2000), Italy).PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis (minimum 4) from 1 family in PMID 10978268 (Bertolini et al., 2000), Italy. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585372/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3757 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0151766 infores:hetionet CHEBI:6438 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0030193 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0037383 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0860564 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0860564 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0497247 infores:hetionet CHEBI:64355 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0851578 infores:hetionet CHEBI:553473 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0019080 infores:hetionet CHEBI:167638 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C2047937 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002334 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0376545 infores:hetionet CHEBI:47898 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0242301 infores:hetionet CAID:CA171613 biolink:causes MONDO:0100039 infores:clingen CAID:CA171613 MONDO:0100039 PMID: Pathogenic PP4, PM2_Supporting, PM6_Strong, PVS1 The c.146-1G>A variant in CDKL5 (NM_001323289.2) is absent from gnomAD v2 (PM2_supporting). The c.146-1G>A variant in CDKL5 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a CDKL5 where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.146-1G>A variant has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database - International CDKL5 Disorder Database) (PP4). The c.146-1G>A variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (internal database - International CDKL5 Disorder Database) (PM6_strong). In summary, the c.146-1G>A variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM2_supporting, PVS1, PP4, PM6_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171613/MONDO:0100039/034 2024-06-25 2024-07-31 X-linked inheritance HP:0001417 Supports CHEBI:83527 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0017181 infores:hetionet NCBIGene:699 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:1148 MONDO:0005575 uuid:e3fe518e-fe29-4649-b9c6-d3a6458c021c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151671 infores:hetionet CHEBI:101278 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0003811 infores:hetionet GO:0099158 biolink:causes GO:0099532 infores:ubergraph knowledge_assertion manual_agent GO:0099158 GO:0099532 CHEBI:28148 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020580 infores:hetionet CHEBI:2639 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0009676 infores:hetionet GO:0003427 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0007275 NCBIGene:5340 biolink:causes MONDO:0009009 infores:monarchinitiative not_provided not_provided HGNC:9071 MONDO:0009009 uuid:8ae6b933-5457-4930-b8ce-1c36f32b1c3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135613 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0027765 infores:hetionet CHEBI:100241 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018681 infores:hetionet CHEBI:7476 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011175 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0040034 infores:hetionet NCBIGene:6853 biolink:causes MONDO:0010339 infores:monarchinitiative not_provided not_provided HGNC:11494 MONDO:0010339 uuid:6871df65-586b-4a66-a86f-13b4f4f7381f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47499 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0241934 infores:hetionet CAID:CA228715 biolink:causes MONDO:0015630 infores:clingen CAID:CA228715 MONDO:0015630 PMID: Likely Pathogenic PP4_Moderate, PP3, PS3 PM2, PS4 The c.5347T>G variant in VWF is a missense variant predicted to cause substitution of Serine by Alanine at amino acid 1783 (p.Ser1783Ala). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio and abnormal collagen binding assay, which together are highly specific for VWD type 2M. (PP4_moderate, PMID: 19687512). A hydrodynamic mouse model expressing the p.Ser1783Ala variant showed severely reduced type I and type III collagen binding, indicating that this variant has a damaging effect on protein function (PMID: 25051961)(PS3). The computational predictor REVEL gives a score of 0.687, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal dominant von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS3 and PP3 (VCEP specifications version 1.0.0). von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228715/MONDO:0015630/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31643 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0151828 infores:hetionet NCBIGene:9247 biolink:causes MONDO:0024570 infores:monarchinitiative not_provided not_provided HGNC:4198 MONDO:0024570 uuid:4a3012b7-3edc-4c04-bee8-e6c0051bf9fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0007222 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151849 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0235416 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013395 infores:hetionet CHEBI:15407 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0020538 infores:hetionet CHEBI:2637 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0948594 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0012833 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0033844 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0033844 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853149 infores:hetionet GO:0030300 biolink:causes GO:0044241 infores:ubergraph knowledge_assertion manual_agent GO:0030300 GO:0044241 CHEBI:6015 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0015967 infores:hetionet CHEBI:7824 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0028084 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0033860 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0235409 infores:hetionet CHEBI:4681 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0011603 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0008325 infores:hetionet CHEBI:3654 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0037763 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0004239 infores:hetionet UNII:R15UI3245N biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0232487 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0020649 infores:hetionet CHEBI:8356 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0702166 infores:hetionet CHEBI:4995 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0005818 infores:hetionet CHEBI:52717 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0332563 infores:hetionet CHEBI:50924 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0030196 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0241863 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0857353 infores:hetionet CHEBI:3181 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027497 infores:hetionet CHEBI:63580 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011603 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0027769 infores:hetionet CHEBI:92607 biolink:causes UMLS:C0919567 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0919567 infores:hetionet CHEBI:48669 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0340865 infores:hetionet NCBIGene:3665 biolink:causes MONDO:0014597 infores:monarchinitiative not_provided not_provided HGNC:6122 MONDO:0014597 uuid:3e25864b-1050-4353-8c51-be156d142eea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:U6XF9NP8HM biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0009450 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0518015 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006944 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0238621 infores:hetionet CHEBI:3423 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0030193 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0003460 infores:hetionet CHEBI:36791 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2830004 infores:hetionet CHEBI:4653 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0151636 infores:hetionet CHEBI:63598 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085605 infores:hetionet CHEBI:63618 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0231528 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0023418 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0948089 infores:hetionet CHEBI:474180 biolink:causes NCIT:C34791 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853698 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0024137 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0497247 infores:hetionet CHEBI:50648 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0231218 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0855242 infores:hetionet CHEBI:63631 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0028754 infores:hetionet CHEBI:50922 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0522224 infores:hetionet CAID:CA404081038 biolink:causes MONDO:0007750 infores:clingen CAID:CA404081038 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, PM4, PM1, PM3, PVS1, PM6, BS2, PP1, PP4 The NM_000527.5(LDLR):c.910G>C (p.Asp304His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PM5 - 4 other missense variants in the same codon:- NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines- NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.PP3 - REVEL = 0.99.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404081038/MONDO:0007750/013 2021-11-11 2022-04-05 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5775 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0017658 infores:hetionet CHEBI:5864 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020458 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009450 infores:hetionet CHEBI:2904 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0162529 infores:hetionet CHEBI:8772 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0574067 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0267596 infores:hetionet GO:1905879 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1905879 GO:0019953 NCBIGene:9863 biolink:causes MONDO:0033262 infores:monarchinitiative not_provided not_provided HGNC:18957 MONDO:0033262 uuid:c0a1598e-53c6-4c3a-a9f2-060e05f1e261 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45081 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0009763 infores:hetionet CHEBI:72297 biolink:causes UMLS:C1142530 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C1142530 infores:hetionet CAID:CA658655578 biolink:causes MONDO:0100216 infores:clingen CAID:CA658655578 MONDO:0100216 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Moderate, PS3_Supporting PVS1, PM6, BP1, BP4, BP3, BP2, BA1, BS2, PP2, PP1, PM4, PM3, PM1, PM5, PS2, PS1, BP7, BP5, BS1, BS3, BS4 The NM_177438.2:c.1509+16A>G variant in DICER1 is an intronic variant located 16 base pairs downstream of exon 9. This variant received a total of 3.5 phenotype points across 4 probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate, PMID:37883719, Internal lab contributors). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID:37883719, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an in-frame splicing impact resulting in a premature stop codon and NMD, indicating that this variant impacts protein function; however, this evidence was conservatively downgraded due to lower than typical percent spliced in (PSI) values (PS3_Supporting; PMID:37883719, Invitae, UT Southwestern). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PS4_Moderate, PP4, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655578/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50305 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0518015 infores:hetionet NCBIGene:64221 biolink:causes MONDO:0020790 infores:monarchinitiative not_provided not_provided HGNC:13433 MONDO:0020790 uuid:03b4f4a7-0c97-47d9-bd82-916c18a800ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64028 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0018939 infores:hetionet CHEBI:32020 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C1443060 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0234913 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0332575 infores:hetionet CHEBI:59560 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C1167965 infores:hetionet CHEBI:3011 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0020625 infores:hetionet NCBIGene:10026 biolink:causes MONDO:0030037 infores:monarchinitiative not_provided not_provided HGNC:8965 MONDO:0030037 uuid:730b3d86-d212-4716-953d-2b32d89855a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0206061 infores:hetionet CAID:CA400028389 biolink:causes MONDO:0100326 infores:clingen CAID:CA400028389 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PM5, PP3 The NM_000212.3:c.59T>C variant in ITGB3 is a missense variant predicted to cause substitution of leucine by proline at amino acid 20 (p.Leu20Pro). This variant has been observed in homozygosity in one individual (GT10 in PMID: 19691478) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1 is 0.00001460 (1/68502alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM3_Supporting, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400028389/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:144551 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0549373 infores:hetionet NCBITaxon:5550 biolink:causes MONDO:0005984 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5550 MONDO:0005984 CHEBI:63619 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0040053 infores:hetionet CHEBI:6129 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0231919 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0948594 infores:hetionet CHEBI:4868 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0023218 infores:hetionet CHEBI:6710 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0002170 infores:hetionet CHEBI:45924 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0038325 infores:hetionet CHEBI:64310 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0575081 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038367 infores:hetionet CHEBI:47426 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0015967 infores:hetionet CHEBI:63115 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0002170 infores:hetionet CAID:CA409105441 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105441 MONDO:0015967 PMID: Uncertain Significance PS3_Supporting, PP3, PM2_Supporting, PM1 PP4 The c.337G>T variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 113 (p.(Asp113Tyr)) of NM_175914.5. This variant resides in an amino acid within the HNF-4α DNA binding domain that directly binds DNA and is necessary for homodimer formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1; PMID: 18829458). Functional studies demonstrated the p.Asp113Tyr protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_supporting; PMID: 12110948). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, HNF1A was not tested, and the individual had positive anti-GAD antibodies; thus, PP4 criteria was not applied (PMID: 11232004). In summary, c.337G>T meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PS3_suppporting, PM1, PM2_supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105441/MONDO:0015967/085 2024-02-25 2024-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5864 biolink:causes UMLS:C1411873 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1411873 infores:hetionet CHEBI:51137 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0043352 infores:hetionet NCBIGene:54664 biolink:causes MONDO:0054791 infores:monarchinitiative not_provided not_provided HGNC:22407 MONDO:0054791 uuid:3c9c8727-ab65-4384-844a-9cf820b1ff11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8665 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0027497 infores:hetionet CHEBI:135005 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0036974 infores:hetionet CAID:CA645287847 biolink:causes MONDO:0010305 infores:clingen CAID:CA645287847 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The NM_005629.4:c.92del (p.Pro31ArgfsTer?) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). An adult female, heterozygous for the variant, has been reported with IQ in the low normal range, normal urine creatine level and 85% normal creatine level on brain MRS. Her son is reported to be affected but individual clinical and biochemical data is unavailable PMID: 20528887, 23644449). There is insufficient data to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf )In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP: PVS1, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645287847/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Supports CHEBI:8871 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0015230 infores:hetionet GO:0044071 biolink:causes GO:0044770 infores:ubergraph knowledge_assertion manual_agent GO:0044071 GO:0044770 CAID:CA16020938 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020938 MONDO:0009861 PMID:26322415PMID:10693064PMID:26503515 Uncertain Significance PP4_Moderate, PM2 PM3, PP3 The c.1099C>G (p.Leu367Val) variant in PAH is reported in 2 unrelated patients with PKU (from Italy and China). BH4 deficiencies were assessed in the Chinese patient. (PMID: 10693064, 26503515) It was detected in the Chinese patient with c.1174T>A (p.F392I) (not in ClinVar). This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020938/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4974 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0917801 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0242350 infores:hetionet CHEBI:3314 biolink:causes UMLS:C0522171 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0522171 infores:hetionet GO:1904409 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1904409 GO:0010256 CHEBI:4911 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1384353 infores:hetionet CHEBI:142290 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0015672 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0020649 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0011991 infores:hetionet CHEBI:82960 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C2047937 infores:hetionet CHEBI:45863 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0016436 infores:hetionet CHEBI:36791 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043144 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020517 infores:hetionet CHEBI:7956 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0023530 infores:hetionet CHEBI:28901 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0036830 infores:hetionet CHEBI:4470 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0004093 infores:hetionet CHEBI:15544 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0016655 infores:hetionet CHEBI:63598 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0028961 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0852810 infores:hetionet CHEBI:10102 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0542571 infores:hetionet CHEBI:100241 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030193 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1443060 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019112 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151625 infores:hetionet CHEBI:68647 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0038362 infores:hetionet CAID:CA8337916 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337916 MONDO:0008723 PMID: Likely Benign BP4, BP7, BS1 The NM_000018.4(ACADVL): c.963C>T (p.Asn321=) is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP and PhastCons (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00523 in South Asian population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4, BP7 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337916/MONDO:0008723/021 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3723 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235660 infores:hetionet CHEBI:63613 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0022346 infores:hetionet CHEBI:31397 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0035455 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0030252 infores:hetionet CHEBI:68478 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0085605 infores:hetionet CHEBI:7496 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0013604 infores:hetionet CHEBI:6129 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0043094 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0030353 infores:hetionet CAID:CA410147589 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147589 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BA1, BP1, BP2, BP3, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1265A>C (p.Glu422Ala) is a missense variant which is absent from gnomAD v2, and while the highest continental population minor allele frequency in gnomAD v3 is below BA1/BS1 thresholds, the highest minor allele frequency in gnomAD v4 is 0.004662 (137/29388 alleles) in the East Asian population. However, the allele balance in gnomAD v3 and v4 is heavily skewed, and site quality appears lower compared to some common, known pathogenic variants (BA1 not met). Despite the high MAF, this variant has been recurrently reported in various neoplasms, including MDS (PMID: 35470277; PMID: 35470277; PMID: 36932114), MPN (PMID: 37671053), pleomorphic xanthoastrocytoma (PMID: 30496796), esophageal SCC (PMID: 31700061), melanoma (PMID: 35988589), and other cancers (PMID: 38028607). However, the confirmation status of the alteration and/or confirmation of germline origin was not available for these cases, and the variant's presence in gnomAD precludes the use of PS4. The computational predictor REVEL gives a score of 0.052, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, suggesting it does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147589/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50742 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042376 infores:hetionet CHEBI:27504 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0854467 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040479 infores:hetionet CHEBI:7852 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0036973 infores:hetionet CHEBI:78543 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0033774 infores:hetionet CHEBI:3650 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0030312 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018500 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0027441 infores:hetionet CHEBI:5893 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085612 infores:hetionet CHEBI:7852 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0023530 infores:hetionet CHEBI:6809 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0040822 infores:hetionet NCBIGene:8659 biolink:causes MONDO:0009401 infores:monarchinitiative not_provided not_provided HGNC:406 MONDO:0009401 uuid:34c0f14c-1ff7-410e-9950-94d3e4db587f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0239571 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0026946 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0948594 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235280 infores:hetionet CAID:CA6403810 biolink:causes MONDO:0019565 infores:clingen CAID:CA6403810 MONDO:0019565 PMID: Likely Benign BP4, BS1 BS2 NM_000552.5:c.391G>A is a missense variant in VWF that replaces glycine with serine at position 131. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02093 (based on 1636/75004 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). This variant has been reported in the heterozygous state in at least 5 reported healthy control individuals with no bleeding history and normal lab values (PMID: 22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. The computational predictor REVEL gives a score of 0.141, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6403810/MONDO:0019565/090 2024-08-12 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:61049 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040053 infores:hetionet UMLS:C0011701 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0030554 infores:hetionet CHEBI:6710 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0030554 infores:hetionet CHEBI:35854 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0000737 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0080203 infores:hetionet CHEBI:8093 biolink:causes HP:0004325 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0041667 infores:hetionet CHEBI:8485 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0022081 infores:hetionet CHEBI:29013 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0033774 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0037284 infores:hetionet CHEBI:84500 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0027497 infores:hetionet CHEBI:44185 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0015967 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020517 infores:hetionet CHEBI:85161 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020598 infores:hetionet CHEBI:3084 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0014724 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0023890 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017605 infores:hetionet CHEBI:7852 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0015672 infores:hetionet CAID:CA000056 biolink:causes MONDO:0018875 infores:clingen CAID:CA000056 MONDO:0018875 PMID: Benign BP4, BS3, BS2, PM2_Supporting BA1, PS3, PS1, PS2, PM5, PM1, BS1, BS4, PP1, PP4 The NM_000546.6 :c.145G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 49 (p.Asp49Asn). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; ClinVar SCV: SCV000216702.6). This variant has an allele frequency of 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.232; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000056/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:499361 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0018681 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0427008 infores:hetionet CHEBI:72690 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0085593 infores:hetionet CHEBI:17549 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0023518 infores:hetionet UMLS:C0657912 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004604 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235874 infores:hetionet CHEBI:4814 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0002962 infores:hetionet CHEBI:114785 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0027947 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0155169 infores:hetionet CHEBI:17303 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0038999 infores:hetionet CHEBI:7565 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085688 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0013595 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0020039 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0006266 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0232910 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0948089 infores:hetionet CHEBI:45367 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0700361 infores:hetionet CHEBI:6456 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0233407 infores:hetionet CHEBI:31644 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0917801 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0262977 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0262977 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0851341 infores:hetionet CHEBI:6846 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0020452 infores:hetionet CHEBI:8502 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0023530 infores:hetionet CHEBI:7959 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0221264 infores:hetionet CHEBI:6909 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0016204 infores:hetionet UNII:0RK7M7IABE biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0037274 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023067 infores:hetionet CHEBI:61058 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0220870 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0161479 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0574067 infores:hetionet CHEBI:7798 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0017181 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0006266 infores:hetionet CHEBI:31644 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0003467 infores:hetionet CHEBI:6456 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235063 infores:hetionet CAID:CA170257 biolink:causes MONDO:0010726 infores:clingen CAID:CA170257 MONDO:0010726 PMID: Likely Pathogenic PS4_Supporting, PM4_Strong, PM2_Supporting The p.*487Trpext*27 variant in MECP2 (NM_004992.3) occurs at the stop codon and causes a change in the length of the protein and an elongated mRNA transcript of MECP2 (PM4_strong). The p.*487Trpext*27 variant has been observed in at least 2 individuals with features of Rett syndrome (PMID 21807996, internal database - Invitae) (PS4_supporting). The p.*487Trpext*27 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.*487Trpext*27 variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM4_strong, PS4_supporting, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170257/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf UNII:9430ZR8ZAN biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0017979 infores:hetionet CHEBI:132233 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0011124 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0031117 infores:hetionet CHEBI:17650 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0152031 infores:hetionet CHEBI:9434 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0041657 infores:hetionet CHEBI:64028 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0006277 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0740425 infores:hetionet CAID:CA16020886 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020886 MONDO:0009861 PMID:18346471PMID:17096675PMID:18346471PMID:21820508 Likely Pathogenic PM5, PM2, PS3 PM3, PP3 The c.890G>T (p.Arg297Leu) variant in PAH has been reported in at least 1 patient with mild PKU who carried in trans the nonsense variant R243X (BH4 deficiency was not excluded) (PMID: 17096675). This variant is absent from the gnomAD and ESP population databases. Biochemical assays demonstrate a loss of ~50% enzyme activity (PMID: 18346471 & 21820508). Other amino acid changes at this codon have been reported. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020886/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6539 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0003811 infores:hetionet NCBIGene:478 biolink:causes MONDO:0007496 infores:monarchinitiative not_provided not_provided HGNC:801 MONDO:0007496 uuid:52c78f05-2bea-42cd-ad01-61bc476606e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49668 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0020621 infores:hetionet NCBIGene:9699 biolink:causes MONDO:0033543 infores:monarchinitiative not_provided not_provided HGNC:17283 MONDO:0033543 uuid:0bd95c3f-38b6-4927-b52e-4da09a6d01a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA015335 biolink:causes MONDO:0004994 infores:clingen CAID:CA015335 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.480C>T (p.Asn160=) variant in the MYH7 gene is 0.37% (49/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015335/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135736 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016382 infores:hetionet CHEBI:8871 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151825 infores:hetionet CHEBI:50922 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1167965 infores:hetionet UMLS:C0023610 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0030193 infores:hetionet CAID:CA16043557 biolink:causes MONDO:0007783 infores:clingen CAID:CA16043557 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate PM1, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with serine at codon 4178 of the RYR1 protein, p.(Gly4178Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 24433488). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.979) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043557/MONDO:0007783/012 2023-04-10 2023-04-10 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63598 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030554 infores:hetionet CHEBI:48669 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0085612 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0027765 infores:hetionet CHEBI:3723 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0236000 infores:hetionet CHEBI:7459 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0039231 infores:hetionet CHEBI:6887 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233762 infores:hetionet GO:0001751 biolink:causes CL:2000019 infores:ubergraph knowledge_assertion manual_agent GO:0001751 CL:2000019 CHEBI:68610 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0021053 infores:hetionet CL:0000784 biolink:causes GO:0002373 infores:ubergraph knowledge_assertion manual_agent CL:0000784 GO:0002373 CHEBI:63635 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0040034 infores:hetionet NCBIGene:9581 biolink:causes MONDO:0044299 infores:monarchinitiative not_provided not_provided HGNC:30228 MONDO:0044299 uuid:a8c40fd6-f9d6-444d-b5d9-54e7796b366e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0017178 infores:hetionet CHEBI:4887 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0851578 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0000833 infores:hetionet CHEBI:3614 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0022408 infores:hetionet CHEBI:408174 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0002962 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0040046 infores:hetionet CHEBI:83804 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151904 infores:hetionet CHEBI:4708 biolink:causes UMLS:C2363829 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C2363829 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0011849 infores:hetionet CHEBI:39867 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151825 infores:hetionet CHEBI:52717 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1142499 infores:hetionet CHEBI:91583 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0231218 infores:hetionet NCBIGene:6908 biolink:causes MONDO:0011781 infores:monarchinitiative not_provided not_provided HGNC:11588 MONDO:0011781 uuid:8cbca1db-e7ac-44ba-b718-3dddfda1108f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0026838 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0746883 infores:hetionet CHEBI:3403 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C1145670 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0017601 infores:hetionet CHEBI:39867 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232849 infores:hetionet CHEBI:167309 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C1443060 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0497209 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0497209 infores:hetionet CHEBI:5280 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0030252 infores:hetionet CHEBI:9763 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0687713 infores:hetionet CHEBI:6923 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0042109 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151505 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042109 infores:hetionet CHEBI:43968 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0021843 infores:hetionet CHEBI:7852 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C2004489 infores:hetionet CHEBI:204928 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0085932 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0234215 infores:hetionet CAID:CA410147504 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147504 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1286T>C (p.Leu429Pro) is a missense variant which has a REVEL score < 0.50 (0.417) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147504/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63635 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0016204 infores:hetionet CHEBI:75246 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011615 infores:hetionet CHEBI:9014 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0042109 infores:hetionet CHEBI:188986 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0237314 infores:hetionet CHEBI:63598 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0547030 infores:hetionet NCBIGene:9731 biolink:causes MONDO:0014770 infores:monarchinitiative not_provided not_provided HGNC:24866 MONDO:0014770 uuid:717946f8-01d2-4c92-bd8d-1095fd0dab6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042384 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0007642 infores:hetionet CHEBI:2950 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C1306341 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0178298 infores:hetionet CHEBI:31709 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0010200 infores:hetionet CHEBI:9328 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0011603 infores:hetionet CHEBI:119915 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234535 infores:hetionet NCBIGene:3000 biolink:causes MONDO:0024539 infores:monarchinitiative not_provided not_provided HGNC:4689 MONDO:0024539 uuid:93d9c206-74ba-48d2-b859-bc5902693842 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0497156 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0424605 infores:hetionet CHEBI:51173 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0041657 infores:hetionet CHEBI:68841 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0011603 infores:hetionet CHEBI:15544 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C1443060 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0038367 infores:hetionet CHEBI:31644 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0004093 infores:hetionet CHEBI:9398 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0038325 infores:hetionet CHEBI:5123 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0234233 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0948089 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0031350 infores:hetionet CAID:CA220404 biolink:causes MONDO:0009290 infores:clingen CAID:CA220404 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong PM5 The NM_000152.5: c.307T>G variant in GAA is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 103 (p.Cys103Gly). This variant has been reported in at least 12 patients who have been diagnosed with Pompe disease, including patients with documented GAA deficiency in the affected range in dried blood spot, leukocytes, and fibroblasts and <10% normal GAA activity in muscle (PMIDs: 16838077, 18285536, 21109266, 22676651, 24011652, 24158270, 29803406; Pediatr Pol 2021; 96 (3): 220–222; https://doi.org/10.5114/polp.2021.109310) and three on enzyme replacement therapy (PMID: 18607768, 29565424, 29803406, 23160972) (PP4_Moderate). Of note, in some of these patients, the variant was noted to be in cis with another variant (p.Asp91Asn) which can falsely lower GAA activity in in vitro assays when the substrate is glycogen, but not when the substrate is an artificial substrate, 4-MU. This was taken into account when utilizing GAA activity data. Of the reported patients, at least 11 patients compound heterozygous for the variant, phase unknown, and a known pathogenic variant in GAA including c.-32-13T>G (9 patients, PMID: 16838077, 18285536, 18607768, 21109266, 22676651, 23160972, 24011652, 24158270, 29803406; Pediatr Pol 2021; 96 (3): 220–222; https://doi.org/10.5114/polp.2021.109310), c.525delT (PMID: 14695532) and c.2481+102_c.2646+31del (PMID: 29565424). In addition, one patient is compound heterozygous for the variant and c.1465G>A (p.Asp489Asn) (PMID: 18429042). The allelic data from this patient will be used in the assessment of p.Asp489Asn and is not included here to avoid circular logic. For another patient, the cDNA change for the variants was not provided and therefore the data was not included (PMID: 28196920). The highest population minor allele frequency in gnomAD is 0.00001 (1/126998 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in 1.5% normal activity, and evidence of abnormal GAA processing on Western blot (PMID: 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other amino acid substitutions at the same position have been reported in patients with Pompe disease - c.307T>C (p.Cys103Arg) (PMIDs 21984055, 22644586) and c.309C>G (p.Cys103Trp) (PMID 27142047); the classification of p.Cys103Gly will be used to support the classification of these other variants. Therefore, the data is not used here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 92483, 2 star review status) with 8 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Approved by the ClinGen LSD VCEP on Sept. 21, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220404/MONDO:0009290/010 2022-09-21 2022-10-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9434 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0030193 infores:hetionet CHEBI:4798 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0023218 infores:hetionet CHEBI:135342 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0027497 infores:hetionet CAID:CA10014359 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014359 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM2, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.785A>G (p.Gln262Arg) is a missense variant which has a REVEL score < 0.50 (0.384) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014359/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8707 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0404521 infores:hetionet CAID:CA10650446 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650446 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.-67G>A is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650446/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:194135 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027121 infores:hetionet CHEBI:46195 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0043144 infores:hetionet CHEBI:10102 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0271710 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0022660 infores:hetionet GO:0072124 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0072124 GO:0072359 UNII:R43D2573WO biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085631 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0035309 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0030846 infores:hetionet CHEBI:36791 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233407 infores:hetionet CAID:CA10568618 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568618 MONDO:0010602 PMID: Uncertain Significance PP4_Moderate, PP3, PS4_Moderate BS1, PM2 The NM_000132.4(F8):c.248C>G (p.Pro83Arg) variant is a missense variant in F8 that has been observed in multiple patients in the literature with mild hemophilia A meeting PP4_Moderate and PS4_Moderate (PMID: 29296726, PMID:18403393, PMID:18184865). This variant is predicted to have a deleterious effect with a REVEL score of 0.891, which is greater than the ClinGen CFD threshold (>0.6) meeting PP3. In summary, this variant meets criteria to be classified as a variant of uncertain significance for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PP3. PP4_Moderate, PS4_Moderate. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568618/MONDO:0010602/071 2025-11-07 2025-11-07 X-linked inheritance HP:0001417 Inconclusive true CHEBI:15407 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0233494 infores:hetionet CHEBI:9637 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0020456 infores:hetionet CHEBI:4885 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0000737 infores:hetionet CHEBI:8665 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0037036 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0020517 infores:hetionet CHEBI:9570 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0003862 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0042109 infores:hetionet CAID:CA000381 biolink:causes MONDO:0017623 infores:clingen CAID:CA000381 MONDO:0017623 PMID:15805158PMID:25647146PMID:21828076PMID:22505997PMID:29785012PMID:20718038PMID:29373119PMID:29706350PMID:26579216PMID:21194675PMID:24345843PMID:15805158PMID:15805158PMID:15805158 Pathogenic PM2, PS3_Supporting, PP2, PS4_Supporting, PM1, PS2 PM6, PVS1, BS4, BS3, BS1, BP5, BP7, BS2, PP4, PP1, PP3, PM4, PM5, BP2, BP4, BA1, PS1 PTEN c.278A>G (p.His93Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) ClinVar Organization ID: 26957)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 26579216, 25647146, 20718038, 21828076, 29373119, 29785012, 29706350)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158, internal laboratory contributor(s) ClinVar Organization ID: 26957) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000381/MONDO:0017623/003 2018-11-28 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:46295 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0234632 infores:hetionet CHEBI:55346 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C1510431 infores:hetionet GO:0010058 biolink:causes GO:0010015 infores:ubergraph knowledge_assertion manual_agent GO:0010058 GO:0010015 CHEBI:31348 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0031256 infores:hetionet CHEBI:52172 biolink:causes NCIT:C35017 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0036982 infores:hetionet GO:1900457 biolink:causes GO:0071367 infores:ubergraph knowledge_assertion manual_agent GO:1900457 GO:0071367 CAID:CA405639477 biolink:causes MONDO:0007783 infores:clingen CAID:CA405639477 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PM1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamine with proline at codon 1219 of the RYR1 protein, p.Gln1219Pro. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this variant was identified with a second variant of uncertain significance (p.Asp708Asn) and PS4 was not implemented (PMID:21965348). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.891) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405639477/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3478 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0003862 infores:hetionet CHEBI:75045 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0004604 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020651 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0035078 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0152128 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0278079 infores:hetionet CHEBI:2208 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0010828 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0858635 infores:hetionet CHEBI:8874 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0026826 infores:hetionet CHEBI:75722 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1291077 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0002170 infores:hetionet CHEBI:70735 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0235309 infores:hetionet CHEBI:16714 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0037383 infores:hetionet CHEBI:465284 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1535939 infores:hetionet CHEBI:74947 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C3263723 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002871 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0242973 infores:hetionet CHEBI:63619 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085615 infores:hetionet CHEBI:63612 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020255 infores:hetionet CHEBI:4315 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0039231 infores:hetionet CHEBI:68478 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0008350 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002170 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0038358 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0494559 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0086132 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0038826 infores:hetionet CHEBI:65173 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0025323 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0024299 infores:hetionet CHEBI:7025 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0007642 infores:hetionet CHEBI:87681 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0030554 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0475858 infores:hetionet NCBIGene:147912 biolink:causes MONDO:0012575 infores:monarchinitiative not_provided not_provided HGNC:10891 MONDO:0012575 uuid:657b392e-5cac-40f9-a528-f619d1f3a9e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0019080 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151828 infores:hetionet UNII:3QJA87N40S biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0027540 infores:hetionet CHEBI:9086 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0268000 infores:hetionet CHEBI:135791 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0152459 infores:hetionet NCBIGene:1071 biolink:causes MONDO:0007744 infores:monarchinitiative not_provided not_provided HGNC:1869 MONDO:0007744 uuid:5530b399-c9ad-4937-8048-d454717e2f7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1145670 infores:hetionet CHEBI:8356 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011603 infores:hetionet CAID:CA340767 biolink:causes MONDO:0012999 infores:clingen CAID:CA340767 MONDO:0012999 PMID: Pathogenic PVS1, PP4_Strong, PM3, PM2_Supporting The NM_000156.6:c.299_311dup (p. Arg105GlyfsTer26) in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant 3/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 probands with biochemical and clinical features consistent with GAMT deficiency have been reported, including patients with elevated plasma guanidinoacetate, and absent creatine peak and evidence of guanidinoacetate peak on magnetic resonance spectroscopy (PMIDs 8651275, 19027335, 19388150, 23660394, 29506905) (PP4_Strong). These patients include one homozygote (with a homozygous affected sibling) (PMID 23234264; 0.5 points; possibly same patient reported in PMID 29506905); and a proband who is compound heterozygous for the variant and c.327G>A (pathogenic based on assessment by the ClinGen CCDS VCEP), confirmed in trans (PMID 8651275, 19027335, 24268530) (PM3). Another patient is compound heterozygous for the variant and c.233T>A (p.Val78Glu)(PMID 23660394), and another patient and her affected sibling are compound heterozygous for the variant and c.403G>A (p.Asp135Asn) (PMID 19388150), The in trans data from the latter patients will be used in the analysis of p.Val78Glu and p.Asp135Asn and is not included here to avoid circular logic (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001175 in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 8302). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PM3, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA340767/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50841 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0085602 infores:hetionet CHEBI:17823 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0011603 infores:hetionet NCBIGene:256297 biolink:causes MONDO:0012192 infores:monarchinitiative not_provided not_provided HGNC:23734 MONDO:0012192 uuid:90b3e2c0-116c-411f-8dca-439565746836 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5279 biolink:causes MONDO:0040500 infores:monarchinitiative not_provided not_provided HGNC:8960 MONDO:0040500 uuid:5ba9c9ab-2387-4fe8-805c-6d98deed166a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8597 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0235293 infores:hetionet CAID:CA410150195 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150195 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.844G>C (p.Asp282His) is a missense variant which has a REVEL score < 0.50 (0.393), and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150195/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10124 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0349506 infores:hetionet CHEBI:9654 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0029261 infores:hetionet CHEBI:6950 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0043094 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0020651 infores:hetionet CHEBI:8499 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0687713 infores:hetionet CHEBI:7565 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0231218 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0852733 infores:hetionet CHEBI:5100 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0162830 infores:hetionet CHEBI:45327 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0003467 infores:hetionet NCBIGene:23126 biolink:causes MONDO:0014606 infores:monarchinitiative not_provided not_provided HGNC:18801 MONDO:0014606 uuid:11779f9a-4b5c-476a-be04-887d23904c26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C1443060 infores:hetionet CHEBI:2038 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0085077 infores:hetionet NCBIGene:5455 biolink:causes MONDO:0032830 infores:monarchinitiative not_provided not_provided HGNC:9216 MONDO:0032830 uuid:8fe91cf0-3094-4b9e-9ef7-84b2376937bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6923 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0017160 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0232492 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017160 infores:hetionet NCBITaxon:71585 biolink:causes MONDO:0005662 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:71585 MONDO:0005662 CHEBI:50859 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0034063 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020701 infores:hetionet CHEBI:9727 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0033774 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0577115 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0577115 infores:hetionet CHEBI:3403 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0004604 infores:hetionet NCBIGene:8812 biolink:causes MONDO:0029143 infores:monarchinitiative not_provided not_provided HGNC:1596 MONDO:0029143 uuid:4234704d-1650-474e-89ad-a8b89c0d5455 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:8481 biolink:causes MONDO:0010702 infores:monarchinitiative not_provided not_provided HGNC:2567 MONDO:0010702 uuid:199fff2f-f338-4984-aab2-71e4995fdf4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:184555 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C1328337 infores:hetionet CHEBI:2469 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0687713 infores:hetionet CAID:CA120584 biolink:causes MONDO:0044970 infores:clingen CAID:CA120584 MONDO:0044970 PMID:11335700 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PS4 The m.5692T>C variant in MT-TN has been reported in two individuals with primary mitochondrial disease (PMIDs: 7980504, 9384601). The first reported case had chronic progressive external ophthalmoplegia (CPEO), muscle weakness, neuropathy, cerebellar signs, and cardiac involvement. Few ragged red fibers were noted on muscle biopsy. The variant was present at 56% heteroplasmy in muscle (PMID: 7980504). The second reported case had CPEO, exercise intolerance, myopathy, ataxia, deafness, peripheral neuropathy, and hypertrophic cardiomyopathy. Muscle biopsy showed ragged red and COX-negative fibers. The variant was present at 46% heteroplasmy in muscle and was undetectable in blood and fibroblasts. The variant was also undetectable in blood from the mother (PMID: 9384601). This variant is absent in the Helix dataset and gnomAD v3.1.2, and there is one occurrence in the GenBank dataset (PM2_supporting). MitoTIP predicts the variant is possible benign (46.6 percentile) and HmtVAR predicts the variant is pathogenic (score of 0.85). Single fiber testing showed higher levels of the variant in COX-negative fibers (88.2%, range 83.8-92.6%, n=11) than in COX-positive fibers (28.3%, range 9.4-47.2%, n=12) p<0.0001 (PS3_supporting, PMID: 11335700). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120584/MONDO:0044970/015 2024-05-28 2025-10-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:26012 biolink:causes MONDO:0013911 infores:monarchinitiative not_provided not_provided HGNC:29843 MONDO:0013911 uuid:14d8916b-737d-48ed-9cb9-4dd6cd0235a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46345 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0042963 infores:hetionet CHEBI:142290 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0039070 infores:hetionet UMLS:C0004599 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0011603 infores:hetionet CHEBI:63589 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0009763 infores:hetionet CHEBI:36795 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1262141 infores:hetionet CHEBI:4953 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0011991 infores:hetionet CHEBI:52717 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037299 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0039971 infores:hetionet CHEBI:3515 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0000737 infores:hetionet CHEBI:3387 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0040264 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0151828 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0948586 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1384606 infores:hetionet CAID:CA028774 biolink:causes MONDO:0100316 infores:clingen CAID:CA028774 MONDO:0100316 PMID: Uncertain Significance BA1, BP4, BS1, PM2, PM1, PP3 NM_000218.3(KCNQ1):c.1343C>A is a missense variant predicted to cause substitution of proline by glutamine at amino acid 448 (p.Pro448Gln). To our knowledge, this variant has not been reported in the literature in any individuals with long QT syndrome 1. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001538, with 14 alleles / 91008 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. To our knowledge, functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.512, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00 for donor and acceptor gain and loss, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of greater than or equal to 0.2 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance due to insufficient evidence for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA028774/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA120600 biolink:causes MONDO:0044970 infores:clingen CAID:CA120600 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS3_Supporting PP1, PS2, PS4, PM6 The m.9487_9501del (p.Phe94Ter) variant in MT-CO3 has been reported in one individual to date, in a teenager with myopathy and recurrent myoglobinuria (PMID: 8630495). Her muscle biopsy showed type 1 fiber predominance, many ragged red fibers (RRF) that stained heaving for SDH and were COX-negative, and 64% COX-negative fibers. Electron microscopy showed scattered areas of increased numbers of mitochondria, some of which were enlarged and irregular with disordered cristae. Complex IV activity was 14% of controls. Heteroplasmy levels were reported as 92% in muscle, 0.7% leukocytes, 0.5% in lymphocytes, and undetectable in fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was not detected in her healthy mother’s leukocytes. However, this expert panel noted the very low heteroplasmy levels reported in the proband’s leukocytes was unusual given the technology at the time, therefore this was not considered a de novo occurrence. Given no additional family members were tested, segregation evidence (PP1) could not be applied. There are no additional reported de novo occurrences of this variant to our knowledge. Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This 15 base pair microdeletion results in loss of the last 167 amino acids (64% of the protein, PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative non-RRF fibers (97.4 ± 1.4%) and in COX-negative RRF (98.6 ± 0.8%) than in COX-positive fibers (25.2 ± 25.1%; PS3_supporting; PMID: 8630495). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120600/MONDO:0044970/015 2024-02-26 2024-03-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6690 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0019158 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0162281 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0233632 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1443060 infores:hetionet CHEBI:8707 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030193 infores:hetionet NCBIGene:1747 biolink:causes MONDO:0008592 infores:monarchinitiative not_provided not_provided HGNC:2916 MONDO:0008592 uuid:2d55d173-0901-45a6-976e-7c3022f27519 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0044469 biolink:causes GO:0007596 infores:ubergraph knowledge_assertion manual_agent GO:0044469 GO:0007596 CHEBI:3215 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0080274 infores:hetionet CAID:CA410208052 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208052 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PS4_Moderate, PP3 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.559G>A (p.Ala187Thr) is a missense variant affecting one of the residues within the Runt Homology Domain (PM1_supporting). This variant has a REVEL score ≥0.88 (0.96) and SpliceAI predicts no impact on splicing (score: 0.00) (PP3). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 34166225, internal lab evidence). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PP3, PS4_Moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208052/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17698 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0015397 infores:hetionet CAID:CA6748729 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748729 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM3 PP3 The c.1187A>G (p.Lys396Arg) variant in PAH has been reported in multiple individuals with mild HPA and PKU (BH4 deficiency excluded). (PMID: 21147011, 23357515). This variant has extremely low frequency in ExAC and gnomAD (MAF=0.00006). This variant was detected with pathogenic variants IVS10-11G>A in 2 patients (PMID: 21147011) and p.Arg408Trp (PMID: 23357515). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748729/MONDO:0009861/006 2020-08-13 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53691 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0080203 infores:hetionet CHEBI:31236 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019080 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031039 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0302295 infores:hetionet CHEBI:9588 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0011991 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0003123 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0852908 infores:hetionet CHEBI:42797 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0917801 infores:hetionet CHEBI:134991 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0014591 infores:hetionet UMLS:C0011701 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0001807 infores:hetionet CHEBI:47781 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0011991 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0018799 infores:hetionet CHEBI:63632 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0002792 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0549209 infores:hetionet CHEBI:9943 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0039240 infores:hetionet CHEBI:32020 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0206062 infores:hetionet CAID:CA386966083 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966083 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting The c.779C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to arginine at codon 260 (p.(Thr260Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Arg (PM5_Supporting). In summary, c.779C>G p.Thr260Arg meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966083/MONDO:0015967/085 2023-09-19 2023-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9445 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0038990 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0039584 infores:hetionet CAID:CA10014284 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014284 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.834G>A (p.Pro278=) is a synonymous variant. REVEL score is not applicable and SpliceAI ≤0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -4.96 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014284/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0178298 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040584 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0009450 infores:hetionet CHEBI:10112 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0018681 infores:hetionet CHEBI:71417 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0030312 infores:hetionet CHEBI:10119 biolink:causes HP:0003146 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151718 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0238113 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0238113 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042133 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0009450 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0497201 infores:hetionet CHEBI:8356 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0220983 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017152 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0015230 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030312 infores:hetionet CHEBI:3534 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151539 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0149931 infores:hetionet CHEBI:4798 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0019825 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0948594 infores:hetionet CHEBI:50223 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151754 infores:hetionet CHEBI:3213 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0000737 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232197 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0031117 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0011438 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D000152 DB13092_MESH_D000152_1DB00254_MESH_D000152_1DB01190_MESH_D000152_1 CHEBI:46195 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0239981 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0027051 infores:hetionet CHEBI:7798 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C3665347 infores:hetionet CHEBI:3568 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030201 infores:hetionet CHEBI:6904 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0235266 infores:hetionet GO:0070445 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0070445 GO:0007275 CHEBI:16347 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0009450 infores:hetionet CAID:CA10577553 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577553 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate BP5, BP7, BS1, BS4, BS3, PM6, PM5, PM1, PM4, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2, PS3 The c.2547_2548insA (p.Ser850IlefsTer11) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and downstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Moderate, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Moderate, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577553/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true UNII:15G12L5X8K biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151740 infores:hetionet CHEBI:567361 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C2830004 infores:hetionet CHEBI:33325 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0000833 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0314719 infores:hetionet CHEBI:8871 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0549225 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0549225 infores:hetionet CHEBI:116278 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0032617 infores:hetionet CHEBI:49575 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0030252 infores:hetionet CHEBI:28487 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0011603 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0919625 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0919625 infores:hetionet CHEBI:9435 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0015371 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019348 infores:hetionet CHEBI:3756 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0040435 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0239150 infores:hetionet CHEBI:3181 biolink:causes MONDO:0020773 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0007815 infores:hetionet CHEBI:37941 biolink:causes UMLS:C1963943 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1963943 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0001824 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0235416 infores:hetionet CHEBI:4325 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0239981 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0858833 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0858833 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0003123 infores:hetionet CHEBI:8707 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0023380 infores:hetionet CHEBI:6149 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0007222 infores:hetionet NCBIGene:79983 biolink:causes MONDO:0010373 infores:monarchinitiative not_provided not_provided HGNC:13711 MONDO:0010373 uuid:cd51fb8b-b779-49ba-a33a-0bd9dd165982 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7934 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01421 UMLS:C0000729 infores:hetionet CHEBI:93363 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0234215 infores:hetionet CHEBI:45979 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0497156 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0863090 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0863090 infores:hetionet CHEBI:28177 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0009421 infores:hetionet CHEBI:119573 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0026821 infores:hetionet CHEBI:5147 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0242379 infores:hetionet GO:1905902 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:1905902 GO:0007369 CHEBI:29007 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0028961 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0007867 infores:hetionet CHEBI:28148 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0041582 infores:hetionet GO:0014038 biolink:causes GO:0007422 infores:ubergraph knowledge_assertion manual_agent GO:0014038 GO:0007422 CHEBI:80630 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0000731 infores:hetionet CHEBI:40279 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085932 infores:hetionet CHEBI:8694 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0012833 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0349506 infores:hetionet CHEBI:71219 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0235325 infores:hetionet CHEBI:44185 biolink:causes HP:5200231 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235013 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0023530 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018790 infores:hetionet CHEBI:6904 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0009676 infores:hetionet CHEBI:7954 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0162529 infores:hetionet CHEBI:64355 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0038325 infores:hetionet CHEBI:499361 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C2363731 infores:hetionet CL:0000059 biolink:causes MONDO:0017795 infores:ubergraph knowledge_assertion manual_agent CL:0000059 MONDO:0017795 CHEBI:17026 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1384353 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0031350 infores:hetionet CHEBI:3127 biolink:causes UMLS:C2939062 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2939062 infores:hetionet CHEBI:6888 biolink:causes UMLS:C1960509 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C1960509 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0033975 infores:hetionet CHEBI:50742 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0232462 infores:hetionet CHEBI:83531 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0232726 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0029134 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0234458 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006566 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0022593 infores:hetionet CHEBI:9727 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0002170 infores:hetionet CHEBI:6078 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0023380 infores:hetionet GO:0021822 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0060322 CHEBI:71415 biolink:causes UMLS:C1444565 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C1444565 infores:hetionet CHEBI:8597 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0018524 infores:hetionet NCBIGene:54543 biolink:causes MONDO:0957953 infores:monarchinitiative not_provided not_provided HGNC:21648 MONDO:0957953 uuid:34bbfb23-e9c5-4143-aba4-d64dd033d042 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0234987 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0236106 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0236106 infores:hetionet CAID:CA367402227 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402227 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PM2, PP4_Moderate, PP2, PP3 The c.365T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 122 (p.(Leu122Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia) (PP4_Moderate; internal lab contributors). Another missense variant, c.364C>T, p.Leu122Phe has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.365T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402227/MONDO:0015967/086 2024-03-07 2024-03-07 Semidominant inheritance HP:0032113 Supports CHEBI:5118 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020672 infores:hetionet CHEBI:5132 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0010692 infores:hetionet CHEBI:8212 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0855329 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0023890 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040425 infores:hetionet NCBIGene:55315 biolink:causes MONDO:0011273 infores:monarchinitiative not_provided not_provided HGNC:23096 MONDO:0011273 uuid:e8884e3e-623a-4cf1-bc1f-93167c631277 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47519 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C3544060 infores:hetionet CHEBI:68610 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0237849 infores:hetionet CHEBI:5778 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0014868 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0574067 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0009319 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0033860 infores:hetionet CHEBI:171719 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0085633 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001245 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085576 infores:hetionet CHEBI:50156 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0030193 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0549622 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0017178 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018801 infores:hetionet CHEBI:8869 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0030193 infores:hetionet CHEBI:52172 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042963 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011630 infores:hetionet NCBIGene:773 biolink:causes MONDO:0014917 infores:monarchinitiative not_provided not_provided HGNC:1388 MONDO:0014917 uuid:0b5b3a24-9414-473d-98fb-e831ed79fb3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0694536 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042267 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0010692 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233632 infores:hetionet GO:0061102 biolink:causes CL:1000222 infores:ubergraph knowledge_assertion manual_agent GO:0061102 CL:1000222 CHEBI:3077 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0018681 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004934 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031111 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0031350 infores:hetionet CHEBI:50173 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0015672 infores:hetionet CHEBI:9654 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0232849 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0232197 infores:hetionet CHEBI:8776 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0162830 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027651 infores:hetionet NCBITaxon:745 biolink:causes MONDO:0005901 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:745 MESH:D010326 DB01053_MESH_D010326_1 CHEBI:9328 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0004134 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0948594 infores:hetionet CHEBI:4325 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0039231 infores:hetionet CAID:CA401368911 biolink:causes MONDO:0009290 infores:clingen CAID:CA401368911 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PS3_Moderate PP3, PM5, BP4 The NM_000152.5:c.1669A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 557 (p.Ile557Phe). Three probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMIDs 23884227, 25612604, clinical laboratory data), two with documented deficiency of GAA activity (PMIDs 23884227, 25612604) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.1978C>T (p.Arg660Cys) (clinical laboratory data); the variants are confirmed in trans by parental testing. The other two patients are compound heterozygous for the variant and a variant classified as uncertain significance by the ClinGen LSD VCEP, either c.2132C>G (p.Thr711Arg) or c.1385T>C (p.Leu462Pro). The allelic data for these latter two patients will be used in the assessment of p.Thr711Arg or p.Leu462Pro and is not included here to avoid circular logic (PM3). Two additional patients have been reported who were identified by newborn screening and carry pseudodeficiency variants; one asymptomatic and compound heterozygous for the variant and p.Thr711Arg (PMID: 20080426), and the other heterozygous for the variant and presumably unaffected (PMID 31076647). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 2.7% GAA activity in cells and 0.3% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.662 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1669A>G (p.Ile557Val) (ClinVar Variation ID: 856959) and c.1670T>G (p.Ile557Ser) (PMID: 26474166), in the same codon have been reported in patients with Pompe disease. However, these variants have been classified as variants of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 558634; 1 star review status) with one submitter classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401368911/MONDO:0009290/010 2022-03-01 2022-07-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA7176854 biolink:causes MONDO:0021060 infores:clingen CAID:CA7176854 MONDO:0021060 PMID: Uncertain Significance BP4 BA1, BS1, PM2 The c.3235A>G (NM_006939.4(SOS2):c.3235A>G (p.Thr1079Ala)) variant in SOS2 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 1079. The highest MAF in gnomAD v2.1.1 is 0.01703 % in the European (non-Finnish) population (no population codes met). The computational predictor REVEL gives a score of 0.257, which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7176854/MONDO:0021060/042 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119573 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085633 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233494 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1257843 infores:hetionet CHEBI:49375 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151205 infores:hetionet CHEBI:70718 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0017178 infores:hetionet CHEBI:27834 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0542571 infores:hetionet CHEBI:94449 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0030196 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0023518 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0038362 infores:hetionet CHEBI:46081 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0542571 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0015230 infores:hetionet GO:0014719 biolink:causes CL:0008016 infores:ubergraph knowledge_assertion manual_agent GO:0014719 CL:0008016 CHEBI:63580 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151827 infores:hetionet CHEBI:5165 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0006625 infores:hetionet CHEBI:68610 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0085129 infores:hetionet CAID:CA8622836 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622836 MONDO:0100326 PMID: Benign BA1, BP4 BP7 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.58C>T (p.Leu20=), no individuals with Glanzmann thrombasthenia were reported with the variant. This variant was observed by Ilumina as part of a predisposition screen in an ostensibly healthy population. Moreover, the variant has a minor allele frequency of 0.01438 (146/10154 alleles) in gnomAD, found in the African/African American population, which is considerably higher than the expected frequency of the disease (BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing. However, BP7 was not applied as the nucleotide position is conserved. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622836/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63613 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0234238 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0003838 infores:hetionet CHEBI:6950 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0232461 infores:hetionet CHEBI:44241 biolink:causes UMLS:C0850569 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0850569 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0438142 infores:hetionet CHEBI:65349 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0006142 infores:hetionet CHEBI:27690 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0015672 infores:hetionet CHEBI:6690 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0036974 infores:hetionet CHEBI:3175 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0231919 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0035455 infores:hetionet CHEBI:63584 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C2937358 infores:hetionet NCBIGene:92255 biolink:causes MONDO:0859218 infores:monarchinitiative not_provided not_provided HGNC:25287 MONDO:0859218 uuid:5c2b84db-92ea-421f-8a1e-d764931c583b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7066 biolink:causes MONDO:0957575 infores:monarchinitiative not_provided not_provided HGNC:11795 MONDO:0957575 uuid:e035589b-c023-4838-917b-44bce020602d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2948 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0085077 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0038363 infores:hetionet CHEBI:367163 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0016204 infores:hetionet CHEBI:31644 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1443060 infores:hetionet CHEBI:27834 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0011168 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0518015 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0006145 infores:hetionet CHEBI:3175 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0234708 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0235146 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0160390 infores:hetionet CHEBI:63605 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0015967 infores:hetionet GO:0042692 biolink:causes CL:0000187 infores:ubergraph knowledge_assertion manual_agent GO:0042692 CL:0000187 CHEBI:3127 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0040034 infores:hetionet CAID:CA392324483 biolink:causes MONDO:0007947 infores:clingen CAID:CA392324483 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PM1 PM6, BS2, PP1, BP1, BP4, BP2, BA1, PS1, PS3, PS2, PM5, PM3, BP5, BS1, BS3, BS4 The NM_00138 c.3650G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by aspartic acid at amino acid 1217 (p.Gly1217Asp). This cysteine-creating variant impacts a critical glycine between Cys3 and Cys4 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant was found in a pediatric proband with a systemic score >7 and thoracic aortic dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (internal lab data, PP4). In this family, the variant was found to be inherited from the probands affected father (internal lab data). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 549180). This variant has also been reported in at least 4 individuals with a clinical diagnosis of MFS or clinical features of MFS (PS4_Mod; PMID 27112580, Petrovsky National Research Centre of Surgery ClinVar entry, Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.987, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Mod, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392324483/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:85078 biolink:causes MONDO:0002184 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C1262760 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0277986 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0277986 infores:hetionet CHEBI:63632 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0011603 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0017178 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0152027 infores:hetionet CHEBI:209807 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0040046 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234952 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234952 infores:hetionet CHEBI:6532 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0042963 infores:hetionet CHEBI:404903 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0520966 infores:hetionet CHEBI:3048 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0043352 infores:hetionet CHEBI:63635 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011603 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0027765 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0031350 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0855242 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0006444 infores:hetionet CHEBI:8245 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0039070 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0235113 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235113 infores:hetionet NCBIGene:359 biolink:causes MONDO:0007451 infores:monarchinitiative not_provided not_provided HGNC:634 MONDO:0007451 uuid:3ac7fcaa-3e82-45d5-b034-c43e59404f71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6935 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0000731 infores:hetionet CHEBI:32588 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0027497 infores:hetionet CHEBI:64064 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1527344 infores:hetionet CHEBI:3215 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C3263723 infores:hetionet CHEBI:7494 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0004093 infores:hetionet CAID:CA10652928 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652928 MONDO:0011071 PMID: Benign BA1, BP2 PS3, PS4, PS1, PS2, BP1, BP4, BP3, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM1, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*484T>C is an intronic variant. MAF of 0.02894 (2.89%, 252/8708 alleles) in the African subpopulation of the gnomAD cohort is greater than 0.00015 (0.015%) (BA1). This variant is reported in 3 homozygotes in gnomAD v2.1.1 (BP2). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652928/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:50939 biolink:causes MONDO:0014509 infores:monarchinitiative not_provided not_provided HGNC:18362 MONDO:0014509 uuid:49338f63-3319-4ed5-8cf9-0df2172b3cdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10583400 biolink:causes MONDO:0007648 infores:clingen CAID:CA10583400 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The CDH1 c.5G>T (p.Gly2Val) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583400/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6775 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0549493 infores:hetionet CAID:CA228760 biolink:causes MONDO:0019565 infores:clingen CAID:CA228760 MONDO:0019565 PMID: Uncertain Significance PS3_Supporting PM2, PP3, PP4, BS2, BP4, BP5, BS1 NM_000552.5:c.6859C>T is a missense variant in VWF that replaces arginine with tryptophan at position 2287. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.008368 (based on 670/75044 alleles in African / African-American population, with 3 homozygotes). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) but higher than the threshold for PM2_Supporting (<0.0001). At least 2 patients harboring this variant displayed a laboratory phenotype that led to a diagnosis of either VWD Type 2A (PMID: 23340442) or VWD Type 2M (PMID: 16321553), with the former patient exhibiting loss of high-molecular weight VWF multimers and VWF:CB/VWF:Ag ratio <0.7. However, this phenotype was not sufficiently detailed to meet the PP4 code. This variant has been observed once in the homozygous state in gnomAD, and two other healthy controls harboring the variant have been reported with normal lab values (PMID: 22197721). However, BS2 has not been evaluated because this code is not considered applicable to VWD due to incomplete penetrance. A number of published control individuals have been found to harbor this variant, but were associated with a 35-40 IU/dL per allele decrease in VWF:Ag level and a smaller (non-significant) decrease in FVIII:C level (PMID: 23690449). Exogenous expression of the variant in COS-1 cells showed normal multimerization but subnormal levels of protein secreted into the medium (50-70% of wild-type, though evidence of abnormal retention in the cell was absent). This quantitative but not qualitative defect does not meet the requirements for use by the ClinGen VWD VCEP for functional evaluation of VWD Type 2 variants, but may be a match for VWD Type 1. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3_Supporting. While published data do not make a conclusive case that this variant is disease-causing by itself, they indicate that this variant has functional impact and raise the possibility that it may act as a risk factor. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228760/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Inconclusive true CHEBI:38940 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0042373 infores:hetionet CAID:CA320250868 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250868 MONDO:0011071 PMID: Likely Benign BS1 BP1, BP4, BP3, BP7, BP5, PM3, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.*267C>A is a 3' UTR variant with an MAF of 0.0002561 (0.02561%, 2/7810 alleles) in South Asian subpopulation of the gnomAD cohort v4 which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250868/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3387 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0040038 infores:hetionet CHEBI:171719 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0547030 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009806 infores:hetionet CHEBI:28787 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0013595 infores:hetionet CHEBI:66899 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0033774 infores:hetionet CHEBI:68606 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0015672 infores:hetionet CHEBI:31302 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0037822 infores:hetionet CHEBI:127342 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0043352 infores:hetionet CHEBI:3207 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0000731 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0233632 infores:hetionet CHEBI:8080 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0439857 infores:hetionet CAID:CA000271 biolink:causes MONDO:0017623 infores:clingen CAID:CA000271 MONDO:0017623 PMID:29706350 Uncertain Significance PM2, BS3_Supporting PVS1, PM6, BS4, BS1, BP7, BP5, BS2, PP3, PP2, PP1, PM5, PM1, PM4, BP2, BP4, BA1, PS4, PS2, PS1, PS3 PTEN c.1052_1054delTAG (p.Val351del) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000271/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0903898 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0010200 infores:hetionet CHEBI:7956 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0027947 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0234458 infores:hetionet CHEBI:48390 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0033774 infores:hetionet CHEBI:9649 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0006277 infores:hetionet CHEBI:46557 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020453 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0442874 infores:hetionet UMLS:C1872203 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0004604 infores:hetionet CHEBI:2682 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020458 infores:hetionet CHEBI:47519 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0002994 infores:hetionet CHEBI:9168 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0023524 infores:hetionet CHEBI:4784 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C3665347 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0006145 infores:hetionet CHEBI:7903 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0033774 infores:hetionet CHEBI:231594 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0025345 infores:hetionet CHEBI:35677 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0002994 infores:hetionet CHEBI:37924 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0232462 infores:hetionet CHEBI:7476 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0231528 infores:hetionet CAID:CA367402185 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402185 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PM1, PP4 The c.377T>C variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to threonine at codon 126 (p.(Ile126Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.97, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributor). In summary, c.377T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402185/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Inconclusive true GO:0044492 biolink:causes GO:0035725 infores:ubergraph knowledge_assertion manual_agent GO:0044492 GO:0035725 CHEBI:7445 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0036974 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0022650 infores:hetionet CHEBI:3614 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0030193 infores:hetionet CHEBI:9332 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0042963 infores:hetionet CHEBI:70746 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0009782 infores:hetionet CHEBI:4681 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0522224 infores:hetionet CHEBI:5138 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019080 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0038363 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0017178 infores:hetionet CHEBI:75722 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232943 infores:hetionet CHEBI:15940 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C2939147 infores:hetionet NCBIGene:51807 biolink:causes MONDO:0030827 infores:monarchinitiative not_provided not_provided HGNC:12410 MONDO:0030827 uuid:7a94f468-d185-470e-a76c-8249efb87e49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA012524 biolink:causes MONDO:0004994 infores:clingen CAID:CA012524 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.2514G>A (p.Pro838=) variant in the MYH7 gene is 0.18% (27/10404) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012524/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3207 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0851341 infores:hetionet CHEBI:8888 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151599 infores:hetionet CHEBI:48538 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0030196 infores:hetionet CHEBI:8768 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151766 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0851341 infores:hetionet CHEBI:49375 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0271051 infores:hetionet CHEBI:3647 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0027424 infores:hetionet CHEBI:5118 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0021177 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0021400 infores:hetionet CAID:CA1017833980 biolink:causes MONDO:0015967 infores:clingen CAID:CA1017833980 MONDO:0015967 PMID: Pathogenic PP4, PM2_Supporting, PS4, PP1_Strong PM1 The c.-192C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the 5' UTR of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in at least 14 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 16731855, 16731861, internal lab contributors). Furthermore, at least one of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4, PMID:16731861). This variant segregated with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes with at least 15 informative meioses in 5 families (PP1_Strong; PMIDs: 16731861, 38855865, internal lab contributors). In summary, c.-192C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PS4, PP1_Strong, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1017833980/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28971 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0014457 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0919823 infores:hetionet CHEBI:3698 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0002170 infores:hetionet CHEBI:3286 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0027424 infores:hetionet CL:1001428 biolink:causes MONDO:0003442 infores:ubergraph knowledge_assertion manual_agent CL:1001428 MONDO:0003442 CHEBI:68534 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0236075 infores:hetionet CAID:CA410779341 biolink:causes MONDO:0021060 infores:clingen CAID:CA410779341 MONDO:0021060 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP2, PM3, BP4, BA1, BS1 The NM_006767.4:c.361C>G variant in LZTR1 is a missense variant predicted to cause substitution of histidine by aspartic acid at amino acid 121 (p.His121Asp). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.762, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). Localization assay in COS-1 cells showed a prevalent localization at the Golgi, even though a more spread localization suggestive of endosome targeting was also noted indicating that this variant impacts protein function (PMID: 30481304) (PS3_Supporting). This variant has been detected in 1 individual with RASopathy, compound heterozygous for the variant and a pathogenic or likely pathogenic variant and confirmed in trans by parental testing (c.2264G>A p.Arg755Gln, 0.25 PM3 points, PMID: 29469822). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS3_Supporting, PM2_Supporting, PP3. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410779341/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA410207146 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207146 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, BP2, PM5, PM1, PM3, PP4 NM_001754.5(RUNX1):c.631G>C (p.Asp211His) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207146/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0879264 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0239571 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0034063 infores:hetionet NCBIGene:3868 biolink:causes MONDO:0013073 infores:monarchinitiative not_provided not_provided HGNC:6423 MONDO:0013073 uuid:3dcd567d-bf15-4bfb-887a-a4bec444dbcf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042134 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0403632 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0700184 infores:hetionet CHEBI:55346 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151798 infores:hetionet NCBIGene:120766137 biolink:causes MONDO:0100522 infores:monarchinitiative not_provided not_provided HGNC:55085 MONDO:0100522 uuid:f0f0b0f3-fdb8-47bc-bf51-b66b217ace30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0006277 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002957 infores:hetionet CHEBI:135736 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0549448 infores:hetionet NCBIGene:714 biolink:causes MONDO:0958188 infores:monarchinitiative not_provided not_provided HGNC:1245 MONDO:0958188 uuid:99f9b423-431a-4472-a29b-1d8d39c7f23b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C2830004 infores:hetionet CAID:CA16041861 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041861 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.497_498del (p.Ile166SerfsTer5) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 7/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature either in a patient with VLCAD or ACADVL associated disease or in functional studies. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. VCEP specifications version 2; 10/15/21. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041861/MONDO:0008723/021 2022-05-22 2022-05-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64312 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030252 infores:hetionet CHEBI:135613 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0428977 infores:hetionet CHEBI:6690 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C2242996 infores:hetionet CHEBI:8772 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0006826 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0023530 infores:hetionet CHEBI:50692 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0013604 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1305875 infores:hetionet NCBIGene:8867 biolink:causes MONDO:0033362 infores:monarchinitiative not_provided not_provided HGNC:11503 MONDO:0033362 uuid:a28ff7fd-6fd2-4c05-aa8f-4daf57ea82d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes UMLS:C0856880 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0856880 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038663 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151736 infores:hetionet NCBITaxon:652611 biolink:causes MONDO:0005143 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:652611 MONDO:0005143 CHEBI:3077 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0026896 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0042109 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0003537 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0232492 infores:hetionet CHEBI:18332 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0011603 infores:hetionet CAID:CA16619939 biolink:causes MONDO:0007947 infores:clingen CAID:CA16619939 MONDO:0007947 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong, PM6_Supporting PP1, PM5 The NM_00138 c.7775G>T, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 2592 (p.Cys2592Phe). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 423498). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant has been identified in an individual with ectopia lentis and a systemic score >7 and was reported to be de novo without confirmation of parental relationships (internal lab data, PM6_Sup). At least two additional individuals with clinical features of Marfan syndrome carry this variant (internal lab data, Invitae ClinVar, PS4_Mod). In one individual with thoracic aortic aneurysm and skeletal features, the variant was found to segregate in an affected sister (Internal lab data). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.839, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Moderate, PM2_Sup, PM6_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619939/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:50729 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0003862 infores:hetionet CHEBI:474180 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151905 infores:hetionet CHEBI:168396 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0852911 infores:hetionet CHEBI:6375 biolink:causes EFO:0004952 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0679254 infores:hetionet CHEBI:3738 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C1443060 infores:hetionet CHEBI:50729 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0024305 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004096 infores:hetionet CHEBI:85161 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C3203358 infores:hetionet CHEBI:4636 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0015672 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0520589 infores:hetionet CHEBI:16899 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0035455 infores:hetionet CHEBI:3387 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0917801 infores:hetionet CHEBI:17549 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0003537 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0574067 infores:hetionet CHEBI:47381 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0235063 infores:hetionet CAID:CA10443761 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443761 MONDO:0010315 PMID: Likely Benign BS2 PM2 NM_000206.3(IL2RG):c.1061A>G is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 354 (p.His354Arg). The filtering allele frequency (the upper threshold of the 95% CI of 7/30447) of the c.1061A>G variant in IL2RG is 0.0001216 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000124 ) for PM2_Supporting. However, 4 hemizygotes were reported (PM2 not met).The variant is observed in 4 hemizygotes in gnomAD v4 (BS2_Strong). To our knowledge, this variant has not been reported in the literature in individuals affected with IL2RG related conditions or in functional studies. In summary, this variant meets the criteria to be classified as likely benign variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443761/MONDO:0010315/129 2024-01-26 2024-01-26 X-linked inheritance HP:0001417 Contradicts true CHEBI:8028 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0009450 infores:hetionet CHEBI:4562 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0009676 infores:hetionet CHEBI:7494 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085605 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0855242 infores:hetionet CHEBI:2687 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0035078 infores:hetionet CHEBI:68606 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0235431 infores:hetionet CHEBI:5138 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020580 infores:hetionet CAID:CA345922 biolink:causes MONDO:0044970 infores:clingen CAID:CA345922 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS4, PS3 The m.8989G>C (p.A155P) variant in MT-ATP6 has been reported in one individual with primary mitochondrial disease to date (PMID: 23266623, case also included in PMID: 30763462), in a man with features consistent with neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP). He had difficulty with night vision in his 20s with late-stage retinitis pigmentosa noted in his 40s, cataracts, ataxia, neuropathy, and sensorineural hearing loss. Brain imaging showed cerebellar atrophy. Complex V activity was reduced in muscle. The variant was present in the proband at 94% heteroplasmy in urine, 92% in muscle, 88% in buccal mucosa, and 33% in blood. The variant was undetectable in blood from the healthy mother (PM6_supporting, PMID: 23266623). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.895 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345922/MONDO:0044970/015 2024-08-27 2025-08-06 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:45367 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0018681 infores:hetionet CHEBI:37924 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0002994 infores:hetionet CHEBI:135929 biolink:causes MONDO:0041775 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C1688637 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014742 infores:hetionet CHEBI:5147 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027424 infores:hetionet CHEBI:75722 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020461 infores:hetionet GO:0072095 biolink:causes GO:0072080 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0072080 CHEBI:15940 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0740394 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0030312 infores:hetionet CHEBI:520985 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0008031 infores:hetionet GO:0044077 biolink:causes GO:0006898 infores:ubergraph knowledge_assertion manual_agent GO:0044077 GO:0006898 CHEBI:473990 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0002170 infores:hetionet CHEBI:9763 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0003467 infores:hetionet CHEBI:16347 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0017152 infores:hetionet CHEBI:63599 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0041364 infores:hetionet CHEBI:2904 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0039231 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1368065 infores:hetionet CHEBI:63613 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0267792 infores:hetionet CHEBI:3176 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423006 infores:hetionet CHEBI:50648 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0152459 infores:hetionet NCBIGene:7287 biolink:causes MONDO:0010827 infores:monarchinitiative not_provided not_provided HGNC:12423 MONDO:0010827 uuid:4d18d9b7-cbca-4357-acf7-135345f09f25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:34905 biolink:causes MONDO:0017862 infores:ubergraph knowledge_assertion manual_agent CHEBI:34905 MONDO:0017862 CHEBI:51450 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0043352 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042373 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0018021 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0424605 infores:hetionet CHEBI:53760 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0558489 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0029408 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0235416 infores:hetionet CHEBI:2453 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0018524 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1167965 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0009319 infores:hetionet CHEBI:5130 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0497156 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0026857 infores:hetionet CHEBI:64198 biolink:causes UMLS:C0858854 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0858854 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042109 infores:hetionet CHEBI:24564 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0031117 infores:hetionet CHEBI:63617 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1456784 infores:hetionet CAID:CA409110466 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110466 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PVS1_Supporting The c.1306A>T variant in the hepatocyte nuclear factor-4-alpha gene, HNF4A, results in a premature termination at codon 436 (p.(Lys436Ter)) of NM_175914.4. This nonsense variant, located 3’ of codon 420 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript nor significantly disrupt the transactivation domain of the protein. There is insufficient clinical evidence that variants in this region lead to a monogenic diabetes phenotype. (PVS1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1306A>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP specification version 1.0.0, approved 11/16/2022): PVS1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110466/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0090256 biolink:causes GO:0007476 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0007476 CHEBI:45863 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0854467 infores:hetionet CHEBI:45979 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0687713 infores:hetionet CHEBI:10023 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0010520 infores:hetionet CAID:CA891844332 biolink:causes MONDO:0015967 infores:clingen CAID:CA891844332 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PS4 The c.670+5G>C variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a single nucleotide variant within intron 6 of NM_175914.5. The computational splicing predictor SpliceAI gives a score of 0.72 for donor gain, predicting that the variant disrupts the donor site of intron 6 of HNF4A (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID: 586020). In summary, c.670+5G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844332/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0034776 biolink:causes MONDO:0005642 infores:drugmechdb knowledge_assertion manual_agent GO:0034776 MESH:D003233 DB00748_MESH_D003233_1 CHEBI:9137 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0702166 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0026975 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017152 infores:hetionet CHEBI:50275 biolink:causes EFO:0008501 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0334044 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0162820 infores:hetionet CHEBI:71028 biolink:causes MONDO:0009377 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0268543 infores:hetionet CHEBI:31981 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0011071 infores:hetionet NCBIGene:348 biolink:causes MONDO:0012725 infores:monarchinitiative not_provided not_provided HGNC:613 MONDO:0012725 uuid:8f14ef30-7e25-41fd-beaa-5c35179c12c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0085624 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151736 infores:hetionet CHEBI:63629 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020639 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C2830004 infores:hetionet CHEBI:9168 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0010481 infores:hetionet CHEBI:51209 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0080274 infores:hetionet CHEBI:2687 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0085633 infores:hetionet CHEBI:10650 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020458 infores:hetionet CHEBI:9448 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0030305 infores:hetionet CAID:CA229707 biolink:causes MONDO:0009861 infores:clingen CAID:CA229707 MONDO:0009861 PMID:12905706PMID:26503515 Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Strong PM5 The NM_000277.3(PAH):c.716G>A variant is PAH is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 239 (p.Gly239Asp). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) and showed defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4_moderate; PMID 26503515;PMID: 16256386; PMID 12905706; PMID:23932990). This variant has been detected in at least 4 individuals. Of those individuals, 3 were compound heterozygous for the variant and distinct pathogenic (2)/likely pathogenic (1) variant (V399V, R241C, p.R241Pfs*100) and 3 of those were confirmed in trans by parental analysis and sanger sequencing (PM3_strong, PMID: 16256386; PMID: 30050108). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.982, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3_strong, PP4_Moderate, PP3_strong. Version 2.0, 7/16/2024. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229707/MONDO:0009861/006 2025-08-15 2025-08-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:404903 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0015230 infores:hetionet GO:0141159 biolink:causes GO:0090382 infores:ubergraph knowledge_assertion manual_agent GO:0141159 GO:0090382 CHEBI:31711 biolink:causes UMLS:C0233796 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0233796 infores:hetionet CAID:CA213814 biolink:causes MONDO:0015967 infores:clingen CAID:CA213814 MONDO:0015967 PMID: Pathogenic PS1, PM5_Strong, PP2, PP3, PM2_Supporting PS4, PP4 The c.630G>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 210 (p.(Met210Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (ClinVar ID 36236). Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). The nucleotide change c.630G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). Taken together, the c.630G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Strong, PS1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213814/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:15544 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0035455 infores:hetionet CAID:CA8603095 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603095 MONDO:0100326 PMID: Uncertain Significance PM3, BP7, BS1, BS3, BS4, PM2, PM6, PP3, PP1, PP4, BS2, BA1, BP2, PS3, PS2 The c.1439+8C>T variant in ITGA2B is an intronic variant located in intron 14 of 28. The highest population minor allele frequency in gnomAD v4.1.0 is 0.002770(82/29608 alleles) in the Ashkenazi Jewish population, which is higher than the threshold (<0.0001) for PM2_Supporting. The highest continental population minor allele frequency in gnomAD v4.1.0 is 0.000009322 (11/1180044 alleles) in the European (non-Finnish) population, which is below the BS1 threshold of >0.00158. This intronic variant is not predicted by SpliceAI to impact splicing with a score of 0.01. However, BP7 was not applied because the nucleotide is highly conserved, as shown by phyloP score of 1.9773. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the lack of ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603095/MONDO:0100326/011 2024-11-07 2024-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042267 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0700184 infores:hetionet CHEBI:4868 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0151671 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009319 infores:hetionet CHEBI:50924 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020598 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0234215 infores:hetionet NCBIGene:7707 biolink:causes MONDO:0014994 infores:monarchinitiative not_provided not_provided HGNC:12933 MONDO:0014994 uuid:80a84dae-8f93-414c-b52f-a1c145cb5683 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27958 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0041582 infores:hetionet CHEBI:7822 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0687713 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0852913 infores:hetionet CHEBI:3515 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0014518 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036396 infores:hetionet CHEBI:27504 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0013604 infores:hetionet CHEBI:4708 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013384 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0041912 infores:hetionet CHEBI:15640 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C2047937 infores:hetionet CHEBI:63618 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0035410 infores:hetionet CHEBI:28364 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0151905 infores:hetionet CHEBI:16914 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0009676 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0019158 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0227791 infores:hetionet CHEBI:9150 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0002994 infores:hetionet CHEBI:18067 biolink:causes UMLS:C0240840 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0240840 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0024894 infores:hetionet CHEBI:45409 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1167965 infores:hetionet CHEBI:41774 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0917801 infores:hetionet CHEBI:31711 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0080274 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0009450 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0008031 infores:hetionet UMLS:C0657912 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020429 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0008101 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0266011 infores:hetionet CHEBI:7852 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0033774 infores:hetionet NCBIGene:23102 biolink:causes MONDO:0859148 infores:monarchinitiative not_provided not_provided HGNC:29183 MONDO:0859148 uuid:15e7faf0-a9b4-4a39-b849-69629fcfbb66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA658683945 biolink:causes MONDO:0007648 infores:clingen CAID:CA658683945 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.455_465delAGAAGAGAGAC p.(Gln152Leufs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683945/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf UNII:D27V6190PM biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0030193 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0948594 infores:hetionet CHEBI:4551 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0085612 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0233632 infores:hetionet NCBIGene:85301 biolink:causes MONDO:0014061 infores:monarchinitiative not_provided not_provided HGNC:22986 MONDO:0014061 uuid:1d5b5417-1f7d-4ed5-9dfe-4daaed2d1364 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004604 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0004936 infores:hetionet NCBIGene:29893 biolink:causes MONDO:0013689 infores:monarchinitiative not_provided not_provided HGNC:17928 MONDO:0013689 uuid:c7fa5466-bdd1-40ae-8d04-ab92b439829c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31624 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0600142 infores:hetionet NCBIGene:9210 biolink:causes MONDO:0010349 infores:monarchinitiative not_provided not_provided HGNC:1068 MONDO:0010349 uuid:c010324e-ed08-4476-9af9-fcc54759598e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0038999 infores:hetionet CHEBI:47381 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0012569 infores:hetionet CHEBI:3215 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0522224 infores:hetionet CHEBI:101853 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0013404 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0521540 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0521540 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0037199 infores:hetionet CHEBI:3127 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0037763 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019061 infores:hetionet CHEBI:6954 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0001807 infores:hetionet CHEBI:4909 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0497156 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020615 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038663 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521592 infores:hetionet CHEBI:8107 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0231530 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037274 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038587 infores:hetionet CAID:CA414434500 biolink:causes MONDO:0010604 infores:clingen CAID:CA414434500 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3, PS3_Supporting The c.88G>A (NM_000133.3) variant in F9 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 30 (p.Val30Ile). This variant has been reported in at least 5 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4; PMID: 10094553, 23093250, 1680287, 11122099). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). Secreted conformation-specific reporter (SCSR) assay in HEK293T cells showed decreased SCSR level at ~60% of that of the WT, indicating that this variant impacts protein function (PMID: 32766856; the study is approved by the VCEP, applicable at the Supporting strength; PS3_Supporting). The computational predictor REVEL gives a score of 0.787, which is above the threshold of 0.6, evidence that correlates with impact to F9 function. The variant is the last amino acid of exon 1. The computational splicing predictor SpliceAI gives a score of 0.96 for donor loss, predicting that the variant disrupts the donor splice site of intron 1 of F9 (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4, PP3, PS3_Supporting, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414434500/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:9123 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0338831 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030305 infores:hetionet CHEBI:8665 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0007859 infores:hetionet CHEBI:63638 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1456784 infores:hetionet CHEBI:4708 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013456 infores:hetionet CHEBI:6367 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0162835 infores:hetionet CHEBI:499361 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0424790 infores:hetionet NCBIGene:2186 biolink:causes MONDO:0060596 infores:monarchinitiative not_provided not_provided HGNC:3581 MONDO:0060596 uuid:c04bb7c1-d713-48cc-a5b4-7ac8d181aee5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C3263723 infores:hetionet CHEBI:3478 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0017178 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0234547 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0234547 infores:hetionet GO:0006954 biolink:causes MONDO:0019338 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D012507 DB00860_MESH_D012507_1 CHEBI:6741 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0001925 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0037199 infores:hetionet CHEBI:55346 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0015967 infores:hetionet CHEBI:63620 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0037763 infores:hetionet CHEBI:63599 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C1145670 infores:hetionet CHEBI:71028 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0042963 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0151602 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0001824 infores:hetionet CHEBI:3647 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C2363731 infores:hetionet CHEBI:465284 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0040264 infores:hetionet CHEBI:2639 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0740394 infores:hetionet CAID:CA300594 biolink:causes MONDO:0017623 infores:clingen CAID:CA300594 MONDO:0017623 PMID: Benign BA1 PTEN c.-1059C>G (NC_000010.10:g.89623167C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.0138 (1.38%, 120/8698 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA300594/MONDO:0017623/003 2016-09-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5959 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0233494 infores:hetionet CHEBI:134991 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0018681 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0549391 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0549391 infores:hetionet CHEBI:4708 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235198 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042373 infores:hetionet NCBITaxon:60516 biolink:causes MONDO:0015260 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:60516 MONDO:0015260 CAID:CA226778 biolink:causes MONDO:0010725 infores:clingen CAID:CA226778 MONDO:0010725 PMID: Pathogenic PP3_Moderate, PS4_Very Strong, PS3_Supporting BS1, PM2 NM_000330.4(RS1):c.544C>T (p.Arg182Cys) is a missense variant encoding the substitution of arginine with cysteine at amino acid 182. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002506 among hemizygous individuals, with 1 variant alleles / 399013 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 threshold of 0.000002 to 0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.917, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. COS7 cells exogenously expressing the variant exhibit reduced RS1 secretion into the medium relative to the wild-type control (PMID: 16361673, PMID: 29851975, PS3_Supporting). This variant has been reported in at least 9 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 19568363, PMID: 34645606, PMID: 29851975, PMID: 34828422, PMID: 30652005, PMID: 34822951, PMID: 36377647, PMID: 39462066, PMID: 33546218, PS4_VeryStrong). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PP3_Moderate, PS3_Supporting, and PS4_VeryStrong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226778/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance HP:0001417 Supports CHEBI:2453 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0700590 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0017574 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011991 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0087169 infores:hetionet CHEBI:9943 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0024282 infores:hetionet CHEBI:119573 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0234238 infores:hetionet CAID:CA386965972 biolink:causes MONDO:0010894 infores:clingen CAID:CA386965972 MONDO:0010894 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4 The c.760C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Leucine to Methionine at codon 254 (p.(Leu254Met)) of NM_000545.8. This variant is located within the DNA binding of HNF1A, which is critical for the protein’s function (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.799 (PP3). The variant was identified in 2 individuals with diabetes, however this number does not meet the MDEP cutoff for PS4_Supporting. The MODY probability is unable to be calculated for these individuals due to lack of clinical information (PMIDs: 11942313, 9287055). Another missense variant, c.761T>A p.Leu254Gln, has been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.760C>A meets the criteria to be classified as variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/21): PM2_Supporting, PM1, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965972/MONDO:0010894/017 2022-04-21 2022-04-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52717 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0428977 infores:hetionet CHEBI:5784 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0392176 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0687133 infores:hetionet CHEBI:47781 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0085631 infores:hetionet CHEBI:10119 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0035243 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0015397 infores:hetionet NCBIGene:4047 biolink:causes MONDO:0014673 infores:monarchinitiative not_provided not_provided HGNC:6708 MONDO:0014673 uuid:d13b14b8-c28f-410e-af85-c8145259272d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0015672 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0854100 infores:hetionet CHEBI:3127 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0085649 infores:hetionet CHEBI:135736 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020598 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020517 infores:hetionet CHEBI:4911 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0022346 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0004238 infores:hetionet CHEBI:28787 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0010520 infores:hetionet CHEBI:10127 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0022107 infores:hetionet GO:0044514 biolink:causes GO:0007186 infores:ubergraph knowledge_assertion manual_agent GO:0044514 GO:0007186 CHEBI:16755 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0004093 infores:hetionet CHEBI:36791 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0686347 infores:hetionet CHEBI:75722 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0239783 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0007642 infores:hetionet UNII:VL0L558GCB biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0340865 infores:hetionet NCBITaxon:10298 biolink:causes MONDO:0004609 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10298 MESH:D006561 DB00787_MESH_D006561_1 CHEBI:50648 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0521491 infores:hetionet CHEBI:8665 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0152227 infores:hetionet CHEBI:16755 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0311468 infores:hetionet CHEBI:478164 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0009806 infores:hetionet CHEBI:71229 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0015967 infores:hetionet CHEBI:7492 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0042963 infores:hetionet CHEBI:3216 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0549622 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0555971 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0555971 infores:hetionet CHEBI:74947 biolink:causes UMLS:C3544094 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C3544094 infores:hetionet CHEBI:16796 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0267792 infores:hetionet CHEBI:8764 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C2830004 infores:hetionet CHEBI:3723 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0278106 infores:hetionet CAID:CA184835 biolink:causes MONDO:0021060 infores:clingen CAID:CA184835 MONDO:0021060 PMID: Likely Pathogenic PS4_Moderate, PM2, PM6, PP2 PM5 The c.769T>C (p.Ser257Pro) variant in RAF1 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in 3 patients with clinical features of a RASopathy (PS4_Moderate, SCV000206160.5; SCV000209015.10; PMID 23321623). In one proband the variant occurred de novo without parental confirmation (PM6). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13957) Furthermore, the p.Ser257Pro variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1, PM2, PM6, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA184835/MONDO:0021060/004 2020-07-23 2020-07-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:2659 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0015967 infores:hetionet CHEBI:520985 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0030196 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0036572 infores:hetionet CHEBI:6149 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0085612 infores:hetionet CHEBI:15551 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0151604 infores:hetionet CHEBI:47898 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041364 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0162316 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0002871 infores:hetionet CAID:CA6402562 biolink:causes MONDO:0015630 infores:clingen CAID:CA6402562 MONDO:0015630 PMID: Uncertain Significance PP4_Moderate, PS4_Supporting PM2, PP3, BP4, BS1, BP5 The NM_000552.5(VWF):c.4276C>A (p.Arg1426Ser) missense variant has been reported in two VWD patients. At least 1 patient with this variant (PMID: 30046717) displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.53), and decreased binding assay (VWF:RCo 9 IU/dl), which together are highly specific for VWD type 2M. (PP4_moderate). The patient (PMID: 30046717) also has the heterozygous variant p.Pro1648fs*45 (de novo; mosaic on paternal allele) which has been reported with a quantitative defect. An additional proband was reported with RCoF 45% and Ratio RCoF/vWF:Ag 0.4 (PS4_supporting; ClinVar SCV002525488.1). In summary, the variant meets the criteria to be classified as a Variant of Uncertain Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402562/MONDO:0015630/081 2025-05-06 2025-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:G4PX8C4HKV biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0030193 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0161479 infores:hetionet CHEBI:31638 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0011603 infores:hetionet CHEBI:8107 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0024141 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0162429 infores:hetionet CHEBI:4708 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0032533 infores:hetionet CHEBI:6690 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0014742 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0031117 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0919936 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0919936 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0027051 infores:hetionet CHEBI:145499 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1305875 infores:hetionet NCBIGene:5159 biolink:causes MONDO:0014004 infores:monarchinitiative not_provided not_provided HGNC:8804 MONDO:0014004 uuid:d0a11793-59ab-4325-8c26-923c6ac54cc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0033774 infores:hetionet CHEBI:68478 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0014591 infores:hetionet CHEBI:10102 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0033774 infores:hetionet CAID:CA915940299 biolink:causes MONDO:0015967 infores:clingen CAID:CA915940299 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM4_Supporting, PM1_Supporting The c.711_713del variant in the HNF1 homeobox A gene, HNF1A, is a 3 base pair deletion resulting in the replacement of asparagine with lysine at codon 237 and and in frame deletion of arginine at codon 238 (p.Asn237_Arg238delinsLys) within exon 3 of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). The c.711_713del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). In summary, c.711_713del variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940299/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135613 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0010200 infores:hetionet CHEBI:15854 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C1096355 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0746883 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0155169 infores:hetionet NCBIGene:8720 biolink:causes MONDO:0032721 infores:monarchinitiative not_provided not_provided HGNC:15456 MONDO:0032721 uuid:b07b18cb-712b-458c-8fc0-05687fa75af9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9763 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0162830 infores:hetionet CHEBI:63608 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0023530 infores:hetionet CHEBI:6402 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0008350 infores:hetionet CHEBI:7577 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0151766 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020517 infores:hetionet CHEBI:3698 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0033774 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004936 infores:hetionet CHEBI:63632 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C2047937 infores:hetionet CHEBI:6078 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0235710 infores:hetionet CHEBI:53760 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013144 infores:hetionet NCBIGene:6314 biolink:causes MONDO:0016163 infores:monarchinitiative not_provided not_provided HGNC:10560 MONDO:0016163 uuid:3c64c476-5b8b-4b68-92bd-ef66e8752848 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0042109 infores:hetionet CHEBI:3640 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0015967 infores:hetionet CAID:CA658795264 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795264 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000152.5:c.1705dup (p.Tyr569LeufsTer67) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient, with infantile onset Pompe disease, has been reported with residual GAA activity <10%, CRIM-negative, and with clinical improvements on enzyme replacement therapy (PMID 23601496, 33972680) (PP4_Moderate). This patient is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, c.1396del (PMID 23601496, 33972680). The phase is unknown. 0.5 points (PM3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795264/MONDO:0009290/010 2022-06-03 2022-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8863 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020621 infores:hetionet CHEBI:40050 biolink:causes HP:0011458 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0740651 infores:hetionet CHEBI:135613 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0231528 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0002871 infores:hetionet NCBIGene:54809 biolink:causes MONDO:0014888 infores:monarchinitiative not_provided not_provided HGNC:1348 MONDO:0014888 uuid:e9909eb8-f601-43c1-8b48-6cab245fdc7a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0595877 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0027769 infores:hetionet CHEBI:2663 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0917801 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0239652 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0239652 infores:hetionet GO:0090189 biolink:causes GO:0001657 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0001657 CHEBI:101278 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0152031 infores:hetionet NCBITaxon:37162 biolink:causes MONDO:0005866 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:37162 MONDO:0005866 CHEBI:6067 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085641 infores:hetionet CHEBI:17026 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0085649 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0020517 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0413252 infores:hetionet CHEBI:94609 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0042963 infores:hetionet CHEBI:71941 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0001824 infores:hetionet CHEBI:4877 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0234632 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0235966 infores:hetionet CHEBI:194135 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0917801 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0004936 infores:hetionet CAID:CA398592848 biolink:causes MONDO:0019497 infores:clingen CAID:CA398592848 MONDO:0019497 PMID: Pathogenic PM2_Supporting, PM3, PVS1 The p.Tyr1392Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 10/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The variant was absent from gnomAD v2.1.1 ( PM2_Supporting). This variant is a proposed founder variant ain Pakistan and has been detected in 5 homozygous individuals with hearing loss from Pakistan, Iran, and Northern China (PM3; PMIDs 1754664, 26445815, DOI: https://doi.org/10.21203/rs.3.rs-20906/v1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3, PM2_Supporting. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA398592848/MONDO:0019497/005 2021-09-28 2022-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:64355 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030232 infores:hetionet CAID:CA2737742321 biolink:causes MONDO:0011071 infores:clingen CAID:CA2737742321 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP2, BP3, PM6, PVS1, BP5, BS1, BS3, BS4, PM1, PM3, PM4, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.509-17C>T is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score ≤ 0.20 (0) and evolutionary conservation algorithms predict the site are not available. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2737742321/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8028 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0026961 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0029445 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0243026 infores:hetionet CHEBI:5959 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0236075 infores:hetionet CHEBI:6741 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0043144 infores:hetionet CAID:CA10653555 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653555 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*2642A>G variant in the 3' UTR has an MAF of 0.01828 (1.8%, 282/15424 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 9 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653555/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63611 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0162830 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0206171 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0206171 infores:hetionet CHEBI:63617 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013378 infores:hetionet CHEBI:6633 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0001122 infores:hetionet CAID:CA073935 biolink:causes MONDO:0018493 infores:clingen CAID:CA073935 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with methionine at codon 3218 of the RYR1 protein, p.(Val3218Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00004, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.608 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA073935/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9130 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0019080 infores:hetionet CHEBI:9168 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1535939 infores:hetionet CHEBI:50924 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0017168 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020615 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003864 infores:hetionet CHEBI:28748 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235886 infores:hetionet CHEBI:77260 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0012569 infores:hetionet NCBIGene:220296 biolink:causes MONDO:0013491 infores:monarchinitiative not_provided not_provided HGNC:26361 MONDO:0013491 uuid:b322f055-4787-4bb1-a41a-055fdb9c96f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA010299 biolink:causes MONDO:0005045 infores:clingen CAID:CA010299 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PM6, PP3, PS4_Supporting PM5, PS1, BP4 The NM_000257.4(MYH7):c.1157A>G (p.Tyr386Cys) variant has been reported as a de novo occurence in 2 infants with early-onset/severe cardiomyopathy that presented with variable features (1 with features of HCM and RCM, and 1 with features of HCM and LVNC that progressed to DCM; Lakdawala 2012 PMID:22464770; Greenway 2012 PMID:23170025; Alfares 2015 PMID:25611685; LMM pers. comm.) and in an additional case with RCM (age unknown; GeneDx pers. comm.). Collectively, this data meets criteria for PS4_Supporting and PM6. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for complex cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM6, PM2, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010299/MONDO:0005045/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:284119 biolink:causes MONDO:0013225 infores:monarchinitiative not_provided not_provided HGNC:9688 MONDO:0013225 uuid:aa3bda00-ce4b-48d9-aa1f-9c0e91c2fe2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0033774 infores:hetionet CHEBI:63622 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0004093 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0003123 infores:hetionet CHEBI:28748 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085593 infores:hetionet CHEBI:15552 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0034063 infores:hetionet CHEBI:8207 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0018965 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0429029 infores:hetionet CHEBI:6715 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0340865 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0234215 infores:hetionet GO:1901207 biolink:causes GO:0048562 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0048562 CHEBI:4514 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0040046 infores:hetionet CHEBI:9398 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C3263723 infores:hetionet CHEBI:3215 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0018681 infores:hetionet CHEBI:49662 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0018965 infores:hetionet CHEBI:36791 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151878 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0521495 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0040046 infores:hetionet CHEBI:135351 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0011991 infores:hetionet CHEBI:6339 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0595916 infores:hetionet CHEBI:63717 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0151747 infores:hetionet CHEBI:8673 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0014742 infores:hetionet CHEBI:50922 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0037036 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027932 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0017178 infores:hetionet CHEBI:134743 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0231528 infores:hetionet CHEBI:27974 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0021177 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020649 infores:hetionet CHEBI:41977 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0002871 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0006266 infores:hetionet CHEBI:3732 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0231528 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002453 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0948089 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020517 infores:hetionet CHEBI:45863 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0040264 infores:hetionet CHEBI:4562 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0043387 infores:hetionet CHEBI:36791 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011253 infores:hetionet CHEBI:28445 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0004604 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0021400 infores:hetionet CHEBI:6076 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1527344 infores:hetionet CHEBI:135939 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0030554 infores:hetionet CHEBI:4046 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0344232 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0442874 infores:hetionet CHEBI:4315 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0014457 infores:hetionet CHEBI:10124 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0520966 infores:hetionet CHEBI:4754 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01127 UMLS:C0033771 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0002418 infores:hetionet NCBIGene:10525 biolink:causes MONDO:0009305 infores:monarchinitiative not_provided not_provided HGNC:16931 MONDO:0009305 uuid:d6e5de10-afbf-4a76-bd3f-ea12f13956a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72323 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0036830 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0235146 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C1384666 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0031117 infores:hetionet CAID:CA10653572 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653572 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.*587T>A is a 3'UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653572/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA349727 biolink:causes MONDO:0100216 infores:clingen CAID:CA349727 MONDO:0100216 PMID: Likely Benign BP4, PM2_Supporting, BS2_Supporting PVS1, BA1, BP2, PP3, PP1, PP4, PM4, PM5, PM1, PS1, PS3, PS2, PS4, BS1, BS3, BS4, BP7 The NM_177438.2:c.4874C>A variant in DICER1 is a missense variant predicted to cause substitution of serine by tyrosine at amino acid 1625 (p.Ser1625Tyr). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; GTR ID: 61756). This variant has an allele frequency of 0.000004222 (1/236838 alleles) across gnomAD v2.1.1 (non-cancer) with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.128; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, PM2_Supporting, BP4. (Bayesian Points: -1; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA349727/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:64127 biolink:causes MONDO:0008523 infores:monarchinitiative not_provided not_provided HGNC:5331 MONDO:0008523 uuid:113dd89a-7774-40b8-a13e-408a704217ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes MONDO:0004369 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0021313 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0497327 infores:hetionet CHEBI:70718 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0011603 infores:hetionet CHEBI:119915 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0019080 infores:hetionet CHEBI:92998 biolink:causes HP:0011032 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C2364164 infores:hetionet CHEBI:10112 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0009763 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0015397 infores:hetionet CHEBI:6715 biolink:causes HP:0032004 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0033778 infores:hetionet CHEBI:63791 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0028081 infores:hetionet NCBIGene:4604 biolink:causes MONDO:0013698 infores:monarchinitiative not_provided not_provided HGNC:7549 MONDO:0013698 uuid:9dd5ad78-1df0-457d-825a-71467e8190ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0015376 infores:hetionet NCBIGene:83636 biolink:causes MONDO:0013674 infores:monarchinitiative not_provided not_provided HGNC:25443 MONDO:0013674 uuid:69b97f69-e2cc-4a0f-8a9f-8cae3ca386eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0037383 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0877046 infores:hetionet CHEBI:38562 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0392171 infores:hetionet CAID:CA421821556 biolink:causes MONDO:0013144 infores:clingen CAID:CA421821556 MONDO:0013144 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1 The c.1275T>C (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Arg425=). SpliceAI predicts no splicing impact for this variant meeting BP4. The variant is reported at a POPMAX FAF of 0.000008797 (1/113670) in the European population in gnomAD v2.1.1 which meets PM2_supporting criteria (MAF < 2.0 X 10-5 in gnomAD). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA421821556/MONDO:0013144/084 2024-10-02 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63584 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0017181 infores:hetionet CHEBI:6931 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0085631 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018801 infores:hetionet CHEBI:45081 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027540 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002871 infores:hetionet UMLS:C0011701 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0015672 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0043037 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0021053 infores:hetionet CHEBI:41977 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0232726 infores:hetionet CHEBI:3515 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0027497 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0032285 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0015397 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0004936 infores:hetionet CHEBI:70746 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0013491 infores:hetionet CHEBI:63611 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0019521 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0276684 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0276684 infores:hetionet CHEBI:50861 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0030196 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014742 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0027051 infores:hetionet CHEBI:10119 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0344232 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0267596 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151883 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0003864 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0242350 infores:hetionet CHEBI:79699 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0017565 infores:hetionet CHEBI:134966 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0003467 infores:hetionet CHEBI:48538 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0021177 infores:hetionet CHEBI:15407 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0428977 infores:hetionet CHEBI:3504 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0085932 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039971 infores:hetionet CHEBI:5103 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0040409 infores:hetionet CHEBI:44423 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1262013 infores:hetionet CHEBI:78543 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0004238 infores:hetionet CHEBI:3215 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013604 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0262977 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0262977 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042109 infores:hetionet CHEBI:5141 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0011991 infores:hetionet NCBIGene:79797 biolink:causes MONDO:0014652 infores:monarchinitiative not_provided not_provided HGNC:20041 MONDO:0014652 uuid:16edc267-2089-4709-9f0b-ceb94afbdd61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51173 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0020649 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0004245 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0221714 infores:hetionet CHEBI:9654 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0004134 infores:hetionet CHEBI:15940 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0003862 infores:hetionet NCBIGene:23036 biolink:causes MONDO:0030934 infores:monarchinitiative not_provided not_provided HGNC:18410 MONDO:0030934 uuid:07237da1-e777-4933-afc9-f1e1ef45bd06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes HP:0002273 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0270790 infores:hetionet CHEBI:50861 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0011991 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0036572 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0917801 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029927 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042075 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0035078 infores:hetionet CHEBI:10127 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0019079 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0232910 infores:hetionet CHEBI:125354 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0041834 infores:hetionet CHEBI:5118 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0025345 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013922 infores:hetionet CHEBI:66901 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0018681 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018801 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1258215 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0340464 infores:hetionet CHEBI:2611 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0231528 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0429098 infores:hetionet NCBIGene:7124 biolink:causes MONDO:0975832 infores:monarchinitiative not_provided not_provided HGNC:11892 MONDO:0975832 uuid:bba3f649-34c6-4be3-a135-07663cd33dba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000589 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000589 GO:0007275 CHEBI:421707 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0085593 infores:hetionet CHEBI:17141 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0040822 infores:hetionet NCBIGene:51360 biolink:causes MONDO:0010486 infores:monarchinitiative not_provided not_provided HGNC:15455 MONDO:0010486 uuid:635dae07-1be1-4b99-9c3c-5f6fe61b3693 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0004093 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0235639 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0575090 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0855704 infores:hetionet GO:0060472 biolink:causes GO:0007338 infores:ubergraph knowledge_assertion manual_agent GO:0060472 GO:0007338 CHEBI:37924 biolink:causes UMLS:C0948198 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0948198 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0037199 infores:hetionet CHEBI:7983 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C1145670 infores:hetionet CHEBI:7915 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151825 infores:hetionet CHEBI:28445 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151786 infores:hetionet CHEBI:8364 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0030193 infores:hetionet CHEBI:6375 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011124 infores:hetionet CHEBI:114785 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0003862 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0017178 infores:hetionet CHEBI:4974 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0151662 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0151828 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0006266 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013395 infores:hetionet CHEBI:6402 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042345 infores:hetionet CHEBI:45951 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0023052 infores:hetionet CHEBI:101853 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0017152 infores:hetionet CAID:CA409106099 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106099 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate PM1 The c.535T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of tryptophan to arginine at codon 179 (p.(Trp179Arg)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). In summary, c.535T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PS4_Moderate, PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106099/MONDO:0015967/085 2025-08-12 2025-08-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:91834 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0028643 infores:hetionet CHEBI:3228 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C1145670 infores:hetionet CHEBI:31622 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0039231 infores:hetionet UBERON:0001207 biolink:causes MONDO:0005484 infores:ubergraph knowledge_assertion manual_agent UBERON:0001207 MONDO:0005484 CHEBI:367163 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C2711227 infores:hetionet NCBIGene:113220 biolink:causes MONDO:0030505 infores:monarchinitiative not_provided not_provided HGNC:21495 MONDO:0030505 uuid:3fb64939-ac42-4f8b-9f3f-43c50afed4be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235146 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0013595 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026846 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0232910 infores:hetionet NCBIGene:30817 biolink:causes MONDO:0007447 infores:monarchinitiative not_provided not_provided HGNC:3337 MONDO:0007447 uuid:1ad92f85-b57a-416e-a31c-b49804e26bb7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:73274 biolink:causes UMLS:C0342257 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0342257 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0332575 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0027765 infores:hetionet CHEBI:32139 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0005779 infores:hetionet CHEBI:92712 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0014394 infores:hetionet CHEBI:9943 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015644 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0002962 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042109 infores:hetionet CHEBI:6904 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0085614 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0015967 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0018799 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0020649 infores:hetionet CHEBI:3082 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020443 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0948594 infores:hetionet CHEBI:65346 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0035455 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0267792 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0232492 infores:hetionet CHEBI:5790 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0014724 infores:hetionet CHEBI:204928 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0027497 infores:hetionet CHEBI:48844 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0020517 infores:hetionet CHEBI:6067 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0014743 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0012833 infores:hetionet CHEBI:70707 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0006145 infores:hetionet CHEBI:15407 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C1739363 infores:hetionet CHEBI:4887 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0424295 infores:hetionet NCBIGene:5631 biolink:causes MONDO:0010577 infores:monarchinitiative not_provided not_provided HGNC:9462 MONDO:0010577 uuid:adc509b4-7c0b-46ee-8988-8cc0237ef9c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0087169 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0860646 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0860646 infores:hetionet GO:0098907 biolink:causes GO:0086018 infores:ubergraph knowledge_assertion manual_agent GO:0098907 GO:0086018 CHEBI:9943 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018926 infores:hetionet CHEBI:17688 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0017574 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0025061 infores:hetionet CHEBI:40279 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020458 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0006840 infores:hetionet CHEBI:64045 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0686347 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0232498 infores:hetionet GO:1903132 biolink:causes GO:0035239 infores:ubergraph knowledge_assertion manual_agent GO:1903132 GO:0035239 NCBIGene:3033 biolink:causes MONDO:0012382 infores:monarchinitiative not_provided not_provided HGNC:4799 MONDO:0012382 uuid:0ab0d6a4-d283-4055-adc1-6bf4e0caa288 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6706 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0036974 infores:hetionet CHEBI:2704 biolink:causes NCIT:C78341 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0522067 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0026857 infores:hetionet CHEBI:8890 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0015732 infores:hetionet CHEBI:42944 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C3263723 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0948594 infores:hetionet CHEBI:8863 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0037299 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0004936 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0035078 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0022081 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0232492 infores:hetionet CHEBI:8871 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151904 infores:hetionet CHEBI:4530 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0015230 infores:hetionet CAID:CA343725270 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725270 MONDO:0005338 PMID:36267417 Uncertain Significance PP1, PM2_Supporting, PP3_Moderate, BS3_Supporting BS1, BP7, PM5, PM4, PS4, PS1, PS3, PS2, BA1, BP4 The c.976G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 326 (p.Gly326Ser). The highest minor allele frequency of this variant was in the Remaining genetic ancestry group of gnomAD (v4.1.0) = 0.00001600 (1 allele out of 62,504), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.869, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Gly326Ser protein had similar solubility and secretion levels to wild type myocilin protein in this study (PMID: 36267417). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. 3 segregations in 1 family, with primary open angle glaucoma (POAG), have been reported (PMID: 22879734), which fulfilled PP1 (3-4 meioses). Only 1 proband with POAG had been reported (PMID: 22879734), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3_Moderate, BS3_Moderate, PP1, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725270/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9570 biolink:causes UMLS:C0748052 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0748052 infores:hetionet CHEBI:145499 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0002962 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0518015 infores:hetionet CHEBI:94807 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0043352 infores:hetionet CHEBI:10650 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C3665346 infores:hetionet CHEBI:6933 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0013395 infores:hetionet NCBIGene:27249 biolink:causes MONDO:0700298 infores:monarchinitiative not_provided not_provided HGNC:25221 MONDO:0700298 uuid:d20103a5-a208-43d1-9a82-a39a49d30410 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011206 infores:hetionet CHEBI:47657 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0000737 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0031117 infores:hetionet NCBIGene:2720 biolink:causes MONDO:0009262 infores:monarchinitiative not_provided not_provided HGNC:4298 MONDO:0009262 uuid:3e21ca2d-8f0a-4393-af1a-11a49c5f0e9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1527344 infores:hetionet CHEBI:49662 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013404 infores:hetionet CHEBI:2663 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0427086 infores:hetionet CHEBI:27666 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0027947 infores:hetionet CHEBI:4822 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0034063 infores:hetionet CHEBI:53691 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0235266 infores:hetionet UMLS:C0657912 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003862 infores:hetionet CHEBI:6149 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0522224 infores:hetionet CHEBI:63619 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0522055 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027720 infores:hetionet CHEBI:4511 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0020649 infores:hetionet CHEBI:8871 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043144 infores:hetionet CHEBI:93635 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0018524 infores:hetionet CHEBI:77733 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0019158 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0851341 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0852733 infores:hetionet GO:0060224 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0150063 UMLS:C0209366 biolink:causes MONDO:0005711 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0019284 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853813 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0015230 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0013395 infores:hetionet CHEBI:9649 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0009782 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0242350 infores:hetionet CHEBI:5118 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151786 infores:hetionet CHEBI:6061 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0039231 infores:hetionet CHEBI:8888 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2979982 infores:hetionet CHEBI:5123 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C1321686 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151785 infores:hetionet CHEBI:31184 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0033774 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0339807 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0339807 infores:hetionet CHEBI:127780 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0006625 infores:hetionet CHEBI:231594 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0020580 infores:hetionet CHEBI:167309 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0038999 infores:hetionet CHEBI:51137 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0017178 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0349506 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0027769 infores:hetionet CHEBI:3638 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0751494 infores:hetionet CHEBI:64310 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0086565 infores:hetionet CHEBI:3508 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0030312 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0042109 infores:hetionet CHEBI:4657 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0086168 infores:hetionet NCBIGene:9860 biolink:causes MONDO:0014049 infores:monarchinitiative not_provided not_provided HGNC:20889 MONDO:0014049 uuid:1fb4ac3d-8ce7-40bf-a4ce-0e6b02cc9179 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0220983 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0001515 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0155118 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003123 infores:hetionet CHEBI:4702 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0428977 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0039971 infores:hetionet NCBIGene:56172 biolink:causes MONDO:0007397 infores:monarchinitiative not_provided not_provided HGNC:15492 MONDO:0007397 uuid:6e7c8bbb-66c0-439c-accf-90a875fe5fb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0520966 infores:hetionet CHEBI:16796 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0017152 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0019061 infores:hetionet CHEBI:63599 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0038362 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0520893 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0029408 infores:hetionet CHEBI:16755 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0007859 infores:hetionet CHEBI:66901 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0151904 infores:hetionet CHEBI:119573 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0917801 infores:hetionet CHEBI:168396 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030201 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0018802 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0032226 infores:hetionet CHEBI:194135 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0242172 infores:hetionet CHEBI:31184 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0442886 infores:hetionet NCBIGene:7450 biolink:causes MONDO:0008668 infores:monarchinitiative not_provided not_provided HGNC:12726 MONDO:0008668 uuid:4a64d033-d5a4-485a-85fa-b81169106575 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412379033 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379033 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3 NM_000330.4(RS1):c.38T>G (p.Leu13Arg) is a missense variant encoding the substitution of leucine with arginine at amino acid 13. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.689, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting and PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379033/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:37941 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0003862 infores:hetionet CHEBI:31643 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0023066 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0860967 infores:hetionet CHEBI:31348 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0086565 infores:hetionet CHEBI:8802 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0039070 infores:hetionet CHEBI:31348 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0002962 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0543698 infores:hetionet CHEBI:49575 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0497156 infores:hetionet CHEBI:50729 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0333355 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1739422 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1739422 infores:hetionet CAID:CA170449 biolink:causes MONDO:0100039 infores:clingen CAID:CA170449 MONDO:0100039 PMID: Benign BS1, BS2, BP4 The allele frequency of the p.Ile508Thr variant in CDKL5 is 0.018% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ile508Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Ile508Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ile508Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170449/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:94686 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0031117 infores:hetionet CHEBI:35854 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0015967 infores:hetionet CHEBI:134991 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0438142 infores:hetionet CHEBI:8024 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0423153 infores:hetionet CHEBI:73274 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0033771 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0856151 infores:hetionet CHEBI:8764 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020639 infores:hetionet CHEBI:16796 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0040409 infores:hetionet CHEBI:70735 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0002994 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0234458 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0014236 infores:hetionet NCBIGene:776 biolink:causes MONDO:0014200 infores:monarchinitiative not_provided not_provided HGNC:1391 MONDO:0014200 uuid:05715eaa-d8bc-49df-bd10-aa261f0abd01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0152031 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0428895 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0428895 infores:hetionet CHEBI:94449 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0033774 infores:hetionet CHEBI:16755 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0851578 infores:hetionet CHEBI:171719 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0041969 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0009450 infores:hetionet CHEBI:3437 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0027497 infores:hetionet NCBIGene:29078 biolink:causes MONDO:0032620 infores:monarchinitiative not_provided not_provided HGNC:21034 MONDO:0032620 uuid:77776c9c-abf8-4dc4-a52b-9fffbbb37e01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51209 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0027769 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2225524 infores:hetionet CHEBI:6754 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0855775 infores:hetionet CHEBI:2469 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0085605 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0031039 infores:hetionet CHEBI:52717 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0344232 infores:hetionet CHEBI:31236 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042023 infores:hetionet CHEBI:135351 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0312420 infores:hetionet CHEBI:17688 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013146 infores:hetionet CHEBI:50742 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0043094 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018939 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004936 infores:hetionet NCBIGene:755 biolink:causes MONDO:0011211 infores:monarchinitiative not_provided not_provided HGNC:1260 MONDO:0011211 uuid:ece3ada8-ea52-4f3b-aed7-91f06299d667 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C3665347 infores:hetionet CHEBI:8768 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003862 infores:hetionet CHEBI:6538 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0015672 infores:hetionet CHEBI:71940 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0018965 infores:hetionet NCBIGene:137392 biolink:causes MONDO:0032603 infores:monarchinitiative not_provided not_provided HGNC:30452 MONDO:0032603 uuid:59353fc6-aec8-4ee6-b3b6-5a64654adea1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48538 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0039070 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020649 infores:hetionet CHEBI:46557 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0032227 infores:hetionet CHEBI:4653 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0013604 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0086543 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0030193 infores:hetionet CAID:CA024556 biolink:causes MONDO:0007783 infores:clingen CAID:CA024556 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Glycine with Cysteine at codon 2060 of the RYR1 protein, p.(Gly2060Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.1562, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024556/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:65173 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0024902 infores:hetionet CHEBI:10102 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0039070 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0028259 infores:hetionet CHEBI:15553 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0546817 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0024295 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D017192 DB12190_MESH_D017192_1 CHEBI:4657 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0015230 infores:hetionet CHEBI:135961 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0015967 infores:hetionet CHEBI:50742 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042133 infores:hetionet CHEBI:4681 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0039070 infores:hetionet CHEBI:114785 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0015230 infores:hetionet CHEBI:7514 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0232292 infores:hetionet CHEBI:63580 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017181 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0687133 infores:hetionet CHEBI:60761 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0013298 infores:hetionet CHEBI:49575 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0085649 infores:hetionet CAID:CA5416932 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416932 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2, BA1, BS1 The c.281C>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Tyrosine at amino acid 94 (p.Ser94Tyr).The filtering allele frequency (the upper threshold of the 95% CI of 20/1097996 alleles) of the c.281C>A variant in DCLRE1C is 0.00001189 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (specification version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416932/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:75722 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011253 infores:hetionet CHEBI:3441 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0040264 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0027769 infores:hetionet CHEBI:8364 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0042384 infores:hetionet CHEBI:474180 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0001175 infores:hetionet CHEBI:8871 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011175 infores:hetionet CHEBI:8888 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0032617 infores:hetionet NCBIGene:29880 biolink:causes MONDO:0031062 infores:monarchinitiative not_provided not_provided HGNC:20266 MONDO:0031062 uuid:b3824920-ff5c-48db-9b28-70734d9840e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0406834 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0232459 infores:hetionet CAID:CA367399686 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399686 MONDO:0015967 PMID: Pathogenic PS4, PS3, PS1, PP1_Moderate, PP3, PP4, PM2_Supporting The c.1019G>A variant in the glucokinase gene, GCK, causes an amino acid change of serine to asparagine at codon 340 (p.(Ser340Asn)) of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in ten unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 28323911, 34440516, internal lab contributors). Furthermore, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 34440516). This variant segregated with hyperglycemia with three informative meioses in two families (PP1_Moderate; PMID: 34440516, internal lab contributors). While this variant has a REVEL score of 0.513, which does not meet ClinGen MDEP cutoffs for PP3 or BP4, the computational splicing predictor SpliceAI gives a score of 0.94 for donor loss, predicting that the variant disrupts the donor site of intron 8 (PP3). Additionally, there is evidence from RNA studies that this non-canonical splicing variant results in aberrant splicing, indicating that this variant impacts protein function (PS3; PMID: 40225161). The c.1019G>C variant at the same non-canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1019G>A has a similar predicted impact by Splice AI (0.93 and 0.94, respectively) (PS1). In summary, c.1019G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS1, PS3, PS4, PP1_Moderate, PM2_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399686/MONDO:0015967/086 2025-11-18 2025-11-18 Semidominant inheritance HP:0032113 Supports CHEBI:8764 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1145670 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014868 infores:hetionet CAID:CA6573123 biolink:causes MONDO:0010880 infores:clingen CAID:CA6573123 MONDO:0010880 PMID: Likely Benign BS1 PP3 The NM_000020.3: c.1348A>G variant in ACVRL1 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 450 (p.Thr450Ala). The filtering allele frequency (the lower threshold of the 95% CI of 53/10366) of the c.1348A>G variant in ACVRL1 is 0.004015 for Ashkenazi Jewish chromosomes by gnomAD v2.1.1, which is higher than the ClinGen HHT VCEP threshold (>0.002) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.245, which is neither above nor below the thresholds predicting a damaging or benign impact on ACVRL1 function. In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA6573123/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16664 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0027947 infores:hetionet CHEBI:52172 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0231807 infores:hetionet CAID:CA8338202 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338202 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4_Moderate The c.1678+3_1678+6del variant in ACADVL is an intronic variant which occurs in intron 16. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold. The computational splicing predictor SpliceAI gives a score of 0.85 for donor loss, predicting that the variant disrupts the donor splice site of intron 16 of ACADVL (PP3). This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (internal lab contributor). At least one patient with this variant displayed abnormal NBS with follow-up Plasma Acylcarnitine analysis consistent with VLCAD deficiency, which is highly specific for VLCAD deficiency (PP4_moderate, Internal lab contributors). This variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PP3, PP4_moderate. (ACADVL VCEP specifications version 1; approved November 9, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338202/MONDO:0008723/021 2023-09-27 2023-09-27 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:4625 biolink:causes MONDO:0009708 infores:monarchinitiative not_provided not_provided HGNC:7577 MONDO:0009708 uuid:20b0e2d8-32ff-4d2e-8132-d5b623a05b73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0029118 infores:hetionet CHEBI:194135 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0549249 infores:hetionet NCBIGene:9496 biolink:causes MONDO:0007841 infores:monarchinitiative not_provided not_provided HGNC:11603 MONDO:0007841 uuid:5eaff810-9f26-4628-88ac-53ac0b3c5036 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94501 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0160390 infores:hetionet NCBIGene:93649 biolink:causes MONDO:0032879 infores:monarchinitiative not_provided not_provided HGNC:16067 MONDO:0032879 uuid:7a56adf1-2c94-46c6-83c3-b9f462c49296 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA170185 biolink:causes MONDO:0010726 infores:clingen CAID:CA170185 MONDO:0010726 PMID: Benign BS1, BS2 The allele frequency of the p.Pro387Leu (NM_004992.3) variant in MECP2 is 0.026% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro387Leu variant is observed in at least 2 unaffected individuals (PMID 12161600, GeneDx internal database) (BS2). In summary, the p.Pro387Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170185/MONDO:0010726/016 2021-12-13 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UMLS:C1738934 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0002453 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085096 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0853777 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233414 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029927 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0392386 infores:hetionet CHEBI:9674 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013604 infores:hetionet CHEBI:5118 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0575081 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0427108 infores:hetionet CHEBI:71417 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0004134 infores:hetionet CHEBI:65173 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0039591 infores:hetionet GO:0045704 biolink:causes GO:0007431 infores:ubergraph knowledge_assertion manual_agent GO:0045704 GO:0007431 CHEBI:5775 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0040822 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020557 infores:hetionet CHEBI:404903 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0004144 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0037199 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1510472 infores:hetionet GO:0046669 biolink:causes GO:0048749 infores:ubergraph knowledge_assertion manual_agent GO:0046669 GO:0048749 CHEBI:50924 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0014742 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042373 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021353 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042138 infores:hetionet CAID:CA229541 biolink:causes MONDO:0009861 infores:clingen CAID:CA229541 MONDO:0009861 PMID:27121329PMID:24941924PMID:10234516PMID:15589814 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong PM5 This c.439C>T (p.Pro147Ser) variant in PAH was reported in at least 5 patients with PAH deficiency, detected with pathogenic variants p.Arg243Gln (PMID: 27121329), p.S349P (PMID: 15589814), c.1045T>C, c.782G>A (PMID: 24941924) and p.A403V (PMID: 10234516). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is present at an extremely low frequency in gnomAD (MAF=0.00003). Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229541/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:40279 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0019080 infores:hetionet CAID:CA336926 biolink:causes MONDO:0018875 infores:clingen CAID:CA336926 MONDO:0018875 PMID: Likely Benign BS2_Supporting, BS3, PM2_Supporting BA1, BP4, BP2, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, PP3, PP1 The NM_000546.6:c.851C>T variant in TP53 is a missense variant predicted to cause the substitution of threonine by isoleucine at amino acid position 284 (p.Thr284Ile). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; ClinVar SCV000254641.9 and SCV000664389.5, Internal lab contributors). This variant has an allele frequency of 0.000001239 (2/1613996 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, PM2_supporting, BS3. (Bayesian Points: -4; VCEP specifications version 2.2; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA336926/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:83804 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042487 infores:hetionet NCBIGene:23325 biolink:causes MONDO:0014354 infores:monarchinitiative not_provided not_provided HGNC:29174 MONDO:0014354 uuid:3bf4b7c5-ae64-40b7-8dd7-11409ef6a8e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3213 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0242528 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0028738 infores:hetionet CHEBI:8364 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0020517 infores:hetionet CHEBI:6062 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0019209 infores:hetionet CHEBI:4974 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0040264 infores:hetionet CHEBI:28593 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0028077 infores:hetionet CHEBI:61390 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0013378 infores:hetionet CHEBI:10124 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0007859 infores:hetionet CHEBI:63637 biolink:causes MONDO:0044704 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0280313 infores:hetionet NCBIGene:7048 biolink:causes MONDO:0007576 infores:monarchinitiative not_provided not_provided HGNC:11773 MONDO:0007576 uuid:384b6215-ccb6-4eb8-a555-0120d87e58d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0031350 infores:hetionet CHEBI:50742 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C2239176 infores:hetionet CHEBI:7601 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0042109 infores:hetionet CHEBI:71255 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0017178 infores:hetionet NCBIGene:3887 biolink:causes MONDO:0700341 infores:monarchinitiative not_provided not_provided HGNC:6458 MONDO:0700341 uuid:71c989d6-7040-4f3e-bdd0-a80f48ad395e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68579 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0009760 infores:hetionet CHEBI:63616 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151577 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004936 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0744727 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042373 infores:hetionet CHEBI:9460 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C1443060 infores:hetionet CHEBI:42797 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038999 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0863084 infores:hetionet CHEBI:50861 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0858635 infores:hetionet CHEBI:6690 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0851578 infores:hetionet CHEBI:49375 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0014743 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0008325 infores:hetionet CHEBI:9445 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0542571 infores:hetionet CHEBI:47381 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0016204 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0349790 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0948806 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0948806 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0027051 infores:hetionet CHEBI:28748 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013384 infores:hetionet CAID:CA2695224140 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224140 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.266dup (p.Asp89GlufsTer63) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however the truncation includes the functionally important transmembrane domain (removes amino acids 532-553) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BSS13.01 in PMID:23995613) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224140/MONDO:0009276/079 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0424790 infores:hetionet CHEBI:16347 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0917801 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0948525 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042075 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0030312 infores:hetionet CHEBI:3732 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0851578 infores:hetionet CHEBI:3732 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0086565 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0858581 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0005779 infores:hetionet CHEBI:63622 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0015230 infores:hetionet CHEBI:3441 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C1443060 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0277585 infores:hetionet CHEBI:66964 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0009676 infores:hetionet CHEBI:15551 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0020538 infores:hetionet CHEBI:17263 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0000731 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0007787 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0017152 infores:hetionet NCBIGene:36 biolink:causes MONDO:0012392 infores:monarchinitiative not_provided not_provided HGNC:91 MONDO:0012392 uuid:6e3726ae-169a-4ba7-90b4-d22bdc782caa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0005586 infores:hetionet CHEBI:5784 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0030305 infores:hetionet CHEBI:31623 biolink:causes MONDO:0021036 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0263383 infores:hetionet CHEBI:51450 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0235063 infores:hetionet CHEBI:64355 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151889 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0018801 infores:hetionet CHEBI:136040 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0001807 infores:hetionet CHEBI:51860 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0004093 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0011616 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0020538 infores:hetionet CHEBI:65173 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0011991 infores:hetionet CHEBI:77733 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0013395 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235876 infores:hetionet CHEBI:3176 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0027497 infores:hetionet CHEBI:80630 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0852911 infores:hetionet CHEBI:5784 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0020517 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0039971 infores:hetionet CHEBI:18248 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0006826 infores:hetionet CHEBI:3749 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0232493 infores:hetionet CHEBI:75722 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235063 infores:hetionet CHEBI:7496 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0023787 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0235416 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0948594 infores:hetionet GO:0044075 biolink:causes GO:0007033 infores:ubergraph knowledge_assertion manual_agent GO:0044075 GO:0007033 CHEBI:4672 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0014868 infores:hetionet CHEBI:4710 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0011253 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0039971 infores:hetionet CHEBI:3127 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C1456822 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020538 infores:hetionet CHEBI:6073 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0015672 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0227791 infores:hetionet CHEBI:63619 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013491 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002968 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0024248 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0016479 infores:hetionet CHEBI:17347 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0080274 infores:hetionet CHEBI:63589 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0877192 infores:hetionet CHEBI:47499 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0278134 infores:hetionet CHEBI:31644 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0012569 infores:hetionet NCBIGene:10295 biolink:causes MONDO:0013970 infores:monarchinitiative not_provided not_provided HGNC:16902 MONDO:0013970 uuid:9fe06b62-4fba-4304-b5ce-3818f7e46de8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6539 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0013362 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0876973 infores:hetionet CHEBI:75045 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C1519353 infores:hetionet CHEBI:8412 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0028738 infores:hetionet CHEBI:6916 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0428977 infores:hetionet CHEBI:45863 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0242429 infores:hetionet CHEBI:42797 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037299 infores:hetionet CHEBI:2676 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0857305 infores:hetionet CHEBI:49040 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0008031 infores:hetionet CHEBI:63589 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0021368 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0518015 infores:hetionet GO:0060808 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0060808 GO:0009790 CHEBI:31980 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0037274 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0025061 infores:hetionet CHEBI:7822 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0017181 infores:hetionet CHEBI:71229 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0015376 infores:hetionet CHEBI:3614 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0043251 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151596 infores:hetionet CAID:CA229761 biolink:causes MONDO:0009861 infores:clingen CAID:CA229761 MONDO:0009861 PMID:12126628PMID:11999982 Uncertain Significance PM1, PM2, PP3 PM5 The c.791A>T (p.His264Leu) variant in PAH has not been reported in the literature, to our knowledge. References in BioPKU/PAHdb (Cardoso 2001) cannot be located. This variant is absent from ExAC, GnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.949. The H264 residue interacts directly with the BH4 cofactor. (PMID: 12126628). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM1, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229761/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50742 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042109 infores:hetionet CHEBI:16714 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0043387 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0002453 infores:hetionet CAID:CA915952206 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952206 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PP1_Moderate, PS3_Supporting The m.5537insT variant in MT-TW has been reported in seven affected individuals from two families (PS4_supporting; PMIDs: 9266739, 12776230). Ages of onset included infancy, childhood, adolescence, and adulthood. Features in affected individuals included Leigh syndrome spectrum disorder, optic atrophy, migraine, gastrointestinal dysmotility, and mood disorders. Muscle biopsies showed ragged red fibers, subsarcolemmal accumulation of mitochondria, COX-negative fibers, and complex IV deficiency (and to a lesser extent, complex I deficiency). Heteroplasmy levels were >95% in the two individuals with Leigh syndrome, and were variable in the other affected family members. The variant segregated with clinical manifestations in both reported families (PP1_moderate; PMIDs: 9266739, 12776230). The variant segregated in the first reported family (PMID: 9266739) as the severely affected male proband with Leigh syndrome had the variant at >95% heteroplasmy; his generally healthy sister with optic nerve pallor and incoordination had the variant at 89%; his mother with thin habitus, depression, irritable bowel, and migraines had the variant present at 75%; and his maternal grandmother maternal aunt with depression had the variant present at 42% and 78% respectively). Furthermore, the variant was present at a lower heteroplasmy level in the healthy mother of the second case (PMID: 12776230). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). While there are no in silico predictors for this variant type, an insertion at this location in the tRNA is highly likely to disrupt its structure, and other variants at this position are predicted to be deleterious (PP3). Single fiber testing showed higher levels of the variant in abnormally appearing muscle fibers (such as ragged red fibers, 97% +/- 2%) than in normal appearing fibers (90% +/- 6%), p<0.0005 (PS3_supporting; PMID: 9266739). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952206/MONDO:0044970/015 2023-05-23 2024-07-23 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:7476 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0025222 infores:hetionet CHEBI:39867 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0012569 infores:hetionet CHEBI:50841 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0025061 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020039 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013595 infores:hetionet CHEBI:87681 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0004093 infores:hetionet GO:0035168 biolink:causes CL:0000735 infores:ubergraph knowledge_assertion manual_agent GO:0035168 CL:0000735 CAID:CA10588347 biolink:causes MONDO:0015152 infores:clingen CAID:CA10588347 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1_Moderate, PM2_Supporting PS1, PP1 The NM_003494.4: c.1639-6T>A variant in DYSF, which is also known as NM_001130987.2: c.1693-6T>A, occurs within the splice acceptor region of intron 18. SpliceAI gives a delta score of 0.4 for weakening of the canonical acceptor (alt score 0.59) and of 0.98 for the creation of a cryptic acceptor at the -4 position. RNAseq analysis has demonstrated use of the cryptic splice acceptor site that results in the retention of 4 bp of intronic DNA, which leads to a frameshift and premature truncation, p.Gly547AlafsTer24, with nonsense mediated decay expected; however, the extent to which use of the canonical acceptor was retained was not quantitatively determined (PVS1_Moderate_RNA; PMID: 36983702). This variant has been reported in at least five individuals with features consistent with LGMD (PMID: 36983702, 21522182, 30564623, 32528171, 19154541; LOVD Individual #00313788; MYO-SEQ study internal data communication), including in a homozygous state without reported consanguinity in two unrelated cases (1.0 pt, PMID: 21522182, 19154541) and confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.6217A>G p.(Met2073Val), 1.0 pt, LOVD Individual #00313788). At least one individual with this variant and a second DYSF variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 21522182, 36983702, 19154541; PP4_Strong). One affected family member was shown to have the same two DYSF variants as their affected sibling, but phase was not confirmed (PMID: 36983702; PP1 not met). The filtering allele frequency for this variant is 0.000013033 in gnomAD v4.1.0 exomes (the upper bound of the 95% CI of 8/1107558 European (non-Finnish) chromosomes), which is lower than the ClinGen LGMD VCEP threshold (0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_Moderate_RNA, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588347/MONDO:0015152/180 2025-07-29 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51380 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0031924 infores:hetionet CHEBI:3756 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020903 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030305 infores:hetionet CHEBI:9150 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0206062 infores:hetionet CHEBI:4856 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0151907 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549264 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549264 infores:hetionet CHEBI:140621 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0043144 infores:hetionet CHEBI:93363 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0332575 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0549346 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0549346 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0162429 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022658 infores:hetionet GO:0080036 biolink:causes GO:0071368 infores:ubergraph knowledge_assertion manual_agent GO:0080036 GO:0071368 CHEBI:4856 biolink:causes UMLS:C0340861 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0340861 infores:hetionet CAID:CA234989 biolink:causes MONDO:0012589 infores:clingen CAID:CA234989 MONDO:0012589 PMID: Benign BA1, BS2 BP4, PP3 The highest population minor allele frequency of the p.Arg114Lys variant in TCF4 in gnomAD v4.1 is 0.0018 in the African population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Arg114Lys variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). In summary, the p.Arg114Lys variant in TCF4 is classified as a benign variant based on the ACMG/AMP criteria (BA1, BS2). (TCF4 Specifications v.3; approved on 6/25/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA234989/MONDO:0012589/032 2024-06-25 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA169145 biolink:causes MONDO:0007648 infores:clingen CAID:CA169145 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.269G>A (p.Arg90Gln) missense variant has a frequency of 0.00001989 (5 of 251,334) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00004401 (5 of 113,622) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 (55) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000567761.3, SCV000254829.7). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA169145/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:40279 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018801 infores:hetionet UMLS:C0025241 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0232849 infores:hetionet CHEBI:64028 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0009676 infores:hetionet CAID:CA512232267 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232267 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PVS1, PM6, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.849G>A (p.Gln283=) is a synonymous variant whcih has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (1.01) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232267/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8768 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0037763 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853926 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853926 infores:hetionet CHEBI:63619 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042024 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0162529 infores:hetionet CHEBI:4995 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0039240 infores:hetionet CHEBI:63621 biolink:causes HP:0001993 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0220982 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0541941 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0242453 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0242453 infores:hetionet CHEBI:50777 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C2830004 infores:hetionet CHEBI:4702 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0002792 infores:hetionet CHEBI:9654 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1262141 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0160390 infores:hetionet CHEBI:31980 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0026858 infores:hetionet CHEBI:17823 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0043352 infores:hetionet CHEBI:32315 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C1142135 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0027947 infores:hetionet CHEBI:5118 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027121 infores:hetionet CHEBI:63613 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0005758 infores:hetionet CHEBI:8863 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0497156 infores:hetionet CAID:CA020148 biolink:causes MONDO:0008667 infores:clingen CAID:CA020148 MONDO:0008667 PMID: Benign BA1 The variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0004281 (543/1179690 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). Therefore this variant meets the criterion for (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020148/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2904 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0855242 infores:hetionet CHEBI:63598 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004144 infores:hetionet CHEBI:127780 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0152009 infores:hetionet NCBIGene:10804 biolink:causes MONDO:0012977 infores:monarchinitiative not_provided not_provided HGNC:4288 MONDO:0012977 uuid:d3bf8500-af73-40c5-884b-1ae05e3ec0b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009319 infores:hetionet CHEBI:3479 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0001824 infores:hetionet CHEBI:16469 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0003467 infores:hetionet CHEBI:37941 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0037299 infores:hetionet CHEBI:6129 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0085636 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0235339 infores:hetionet CHEBI:6887 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0040822 infores:hetionet CHEBI:9123 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014518 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0036454 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0037274 infores:hetionet CHEBI:2950 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0030554 infores:hetionet CHEBI:37941 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151701 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0340464 infores:hetionet CHEBI:15765 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0026961 infores:hetionet CHEBI:127342 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0013390 infores:hetionet CHEBI:9737 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0009676 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027765 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013447 infores:hetionet CAID:CA226556 biolink:causes MONDO:0100368 infores:clingen CAID:CA226556 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting BA1, BP1, BP4, BP3, PS1, PS3, PM5, PM4, PM1, BP7, BS1, BS3, PP2, PP3, PP4, BS2 The NM_000329.3(RPE65): c.495+1dup variant disrupts a canonical splice site in intron 5 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMID: 26656277). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy, one of whom was compound heterozygous with the c.130C>T p.Arg44Ter variant confirmed in trans (1 pt, PMID: 26626312) which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3_strong, PM2_supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226556/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9763 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0236075 infores:hetionet CHEBI:64355 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0239981 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0020538 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002622 infores:hetionet CHEBI:31348 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0232495 infores:hetionet CHEBI:38545 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0006277 infores:hetionet CAID:CA2602667 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602667 MONDO:0009276 PMID: Benign BA1 BP4, PP4 The c.236C>T variant in GP9 is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 79. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.001800 (based on 126/60030 alleles) in Admixed American population, which is higher than the ClinGen PD VCEP threshold (>0.001 for GP9), and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1. (VCEP specifications version 1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602667/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3534 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0027765 infores:hetionet NCBIGene:23347 biolink:causes MONDO:0011323 infores:monarchinitiative not_provided not_provided HGNC:29090 MONDO:0011323 uuid:df6575cd-486c-42ef-9662-1d8e591a1365 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6970 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0240557 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011991 infores:hetionet CHEBI:5959 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0033687 infores:hetionet CHEBI:194135 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018524 infores:hetionet CHEBI:5893 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0917801 infores:hetionet CHEBI:50648 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085631 infores:hetionet CHEBI:84500 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0017979 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0015397 infores:hetionet CHEBI:41423 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151539 infores:hetionet CHEBI:50131 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0231218 infores:hetionet CHEBI:6541 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0085610 infores:hetionet NCBIGene:51524 biolink:causes MONDO:0013764 infores:monarchinitiative not_provided not_provided HGNC:26944 MONDO:0013764 uuid:6fe29128-94ba-4b72-94b8-ee8a79a279c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0149931 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0003864 infores:hetionet CHEBI:4710 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0023380 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151752 infores:hetionet CHEBI:5002 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0853149 infores:hetionet UMLS:C0145867 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0030554 infores:hetionet CAID:CA000118 biolink:causes MONDO:0017623 infores:clingen CAID:CA000118 MONDO:0017623 PMID:29785012PMID:29706350PMID:30993208 Uncertain Significance PM2, BS3, PP2 PM6, PVS1, BS4, BS1, BP7, BP5, PP1, PP3, BS2, PM5, PM1, PM4, BA1, BP2, BP4, PS4, PS2, PS1, PS3 PTEN c.1171C>T (p.Pro391Ser)PTEN c.1171C>T (p.Pro391Ser) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 30993208, 29785012, 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000118/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:140621 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0043251 infores:hetionet CHEBI:136040 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0015230 infores:hetionet CHEBI:3213 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0020456 infores:hetionet CHEBI:4975 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0011124 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0009450 infores:hetionet NCBIGene:3043 biolink:causes MONDO:0054801 infores:monarchinitiative not_provided not_provided HGNC:4827 MONDO:0054801 uuid:9a45cf4f-1544-4898-9f84-24027412958c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013182 infores:hetionet NCBIGene:26523 biolink:causes MONDO:0859531 infores:monarchinitiative not_provided not_provided HGNC:3262 MONDO:0859531 uuid:9d685433-9c07-45d2-9d0b-5281a2aecdc0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7822 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0002871 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0027947 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0221717 infores:hetionet CAID:CA222196 biolink:causes MONDO:0015152 infores:clingen CAID:CA222196 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PP1 PM2 The NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19) variant in DYSF, which is also known as NM_001130987.2: c.5953_5956del p.(Gln1985TrpfsTer19)), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 52/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 3 unrelated individuals with limb girdle muscular dystrophy (PMID: 30564623, 19528035), including in unknown phase with a pathogenic variant (c.1852G>C p.(Gly618Arg), 0.5 pt, PMID: 30564623) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 19528035, 30564623). The variant was also reported to co-segregate with the disease in one affected family member (PMID: 19528035) (PP1). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Supporting, PP4_Strong, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222196/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9449 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0013144 infores:hetionet CHEBI:40237 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0038325 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006849 infores:hetionet CHEBI:9725 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0013384 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0027769 infores:hetionet CHEBI:16347 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0019080 infores:hetionet NCBITaxon:5037 biolink:causes MONDO:0018312 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5037 MESH:D006660 DB01026_MESH_D006660_1DB01167_MESH_D006660_1 CHEBI:45951 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0002878 infores:hetionet CHEBI:51364 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0013404 infores:hetionet CHEBI:49960 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0008031 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0020649 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0021053 infores:hetionet CHEBI:63635 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027497 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0007137 infores:hetionet CHEBI:9637 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0019080 infores:hetionet CAID:CA2695224294 biolink:causes MONDO:0100453 infores:clingen CAID:CA2695224294 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 NM_000180.4(GUCY2D):c.726del (p.Ile243SerfsTer3) is a frameshift variant that introduces a premature stop codon into exon 3 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by exome sequencing identifying no alternative basis for retinal disease (4 pts), which together are specific for GUCY2D-related recessive retinopathy (total 4.5 points, PMID: 27375279, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224294/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75722 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0028081 infores:hetionet CHEBI:82981 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0231218 infores:hetionet CHEBI:8863 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151744 infores:hetionet CHEBI:9727 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0030312 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0392197 infores:hetionet CHEBI:3347 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0741494 infores:hetionet CHEBI:31302 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0851578 infores:hetionet CHEBI:9599 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0004093 infores:hetionet CHEBI:6367 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011124 infores:hetionet CHEBI:29688 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0404521 infores:hetionet CHEBI:64198 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0037763 infores:hetionet NCBIGene:2492 biolink:causes MONDO:0011972 infores:monarchinitiative not_provided not_provided HGNC:3969 MONDO:0011972 uuid:9cd7e295-1fb1-449f-9859-2c6f46513c61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0687133 infores:hetionet CHEBI:50742 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0162830 infores:hetionet CHEBI:134990 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0018524 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0349217 infores:hetionet CHEBI:9927 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0027121 infores:hetionet CHEBI:6444 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0042963 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009763 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027441 infores:hetionet CHEBI:8382 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0029118 infores:hetionet NCBITaxon:6236 biolink:causes MONDO:0005943 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6236 MONDO:0005943 NCBIGene:4728 biolink:causes MONDO:0032606 infores:monarchinitiative not_provided not_provided HGNC:7715 MONDO:0032606 uuid:6dad414e-6004-432b-ab29-18dc4bec3c83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0003864 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151830 infores:hetionet CAID:CA1139663040 biolink:causes MONDO:0700269 infores:clingen CAID:CA1139663040 MONDO:0700269 PMID: Likely Pathogenic PM2_Supporting, PM3, PS3 PVS1, BS1, BA1 The c.-40+1G>A variant is an intronic variant within the native donor 1,2 splice site occurring in intron 1 of the BRCA2 gene. This variant is absent from gnomAD v4.1 (read depth ≥25) (PM2_Supporting met). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:24395671) (PS3 met). This variant has been detected in one individual with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least one clinical feature of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage are seen in this individual. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed to be in trans. Total points equated to 2 (PM3 met; PMIDs: 12065746, 12750298, 24395671, 26183081). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by partial exon skipping (PMID: 24395671). The percent reference (full-length) and aberrant transcripts produced from the variant allele assessed using gel electrophoresis was not stated. Final code strength determined by the rubric: PVS1_N/A (RNA). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PM3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139663040/MONDO:0700269/097 2025-08-25 2025-08-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5855 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013395 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0020517 infores:hetionet CHEBI:10102 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0028084 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0021053 infores:hetionet CHEBI:3393 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0022281 infores:hetionet NCBIGene:213 biolink:causes MONDO:0014449 infores:monarchinitiative not_provided not_provided HGNC:399 MONDO:0014449 uuid:22b76b29-c785-4cf2-90c1-6f247d4b773e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0037299 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151849 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013595 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1368065 infores:hetionet CHEBI:46345 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0007820 infores:hetionet CHEBI:6539 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151766 infores:hetionet CHEBI:10023 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0547030 infores:hetionet CHEBI:4469 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0037822 infores:hetionet CHEBI:472657 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0311468 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085096 infores:hetionet CHEBI:64321 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0013428 infores:hetionet CHEBI:40009 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0040822 infores:hetionet CAID:CA638054611 biolink:causes MONDO:0011071 infores:clingen CAID:CA638054611 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.98-17G>A is located in the upstream, untranslated region of RUNX1. This variant is not predicted to impact splicing, as indicated by a SpliceAI score of 0 (<0.20) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054611/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9449 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0013404 infores:hetionet CHEBI:681569 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0018965 infores:hetionet CAID:CA410204317 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204317 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP2, BP1, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.101C>A (p.Ala34Asp) is a missense variant which has a REVEL score of 0.456, which is less than 0.50, and a SpliceAI score of ≤ 0.20. This variant is completely absent from gnomAD v2.1.1 with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204317/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:131512 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0013604 infores:hetionet CHEBI:4710 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0026603 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027051 infores:hetionet CHEBI:64318 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0004093 infores:hetionet CHEBI:5959 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0231528 infores:hetionet CHEBI:6706 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0036572 infores:hetionet CHEBI:7915 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0744727 infores:hetionet CHEBI:5098 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0178298 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0277925 infores:hetionet CHEBI:474180 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0038990 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0155862 infores:hetionet CAID:CA915940801 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940801 MONDO:0100326 PMID: Uncertain Significance PM4, PM2_Supporting, PM3_Supporting PP4 The NM_000419.5(ITGA2B):c.3061-6C>G intronic variant is predicted by varSEAK (class 5) to cause loss of the canonical splice acceptor site. In PMID: 11798398, the authors found that study of platelet mRNA showed the addition of six bases between exons 29 and 30, resulting in an insertion of two amino acids (Lys989_Val990insProGln; PM4). GT type I patient TG (PMID: 11798398) is homozygous for this variant (PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91074 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM4, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940801/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:10124 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0428977 infores:hetionet NCBIGene:857 biolink:causes MONDO:0011714 infores:monarchinitiative not_provided not_provided HGNC:1527 MONDO:0011714 uuid:346b863f-ca95-4aed-8694-0fc9e80779ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020621 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0919980 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1956346 infores:hetionet CHEBI:107736 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0004093 infores:hetionet CHEBI:31401 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151662 infores:hetionet CAID:CA10524601 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524601 MONDO:0010278 PMID: Benign BA1 The allele frequency of the p.Arg51= variant in SLC9A6 is 0.058% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Arg51= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524601/MONDO:0010278/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3380 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0022660 infores:hetionet CHEBI:63608 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027497 infores:hetionet CHEBI:27786 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C1325847 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0007785 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0024299 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0233494 infores:hetionet NCBIGene:783 biolink:causes MONDO:0012743 infores:monarchinitiative not_provided not_provided HGNC:1402 MONDO:0012743 uuid:d948d615-c25f-4726-9843-342cc90fa119 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0039971 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0037274 infores:hetionet CHEBI:3638 biolink:causes HP:0001103 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0730362 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0004245 infores:hetionet CHEBI:8768 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0232849 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0857172 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0857172 infores:hetionet CHEBI:8874 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037299 infores:hetionet CHEBI:47781 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0013378 infores:hetionet CHEBI:17823 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0233471 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096460 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096460 infores:hetionet CHEBI:31176 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0038999 infores:hetionet UMLS:C0145867 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0009421 infores:hetionet CHEBI:51041 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0003467 infores:hetionet CAID:CA410147103 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147103 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1368G>C (p.Glu456Asp) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This missense variant has a REVEL score <0.50 (0.09) and SpliceAI score is ≤ 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147103/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:23400 biolink:causes MONDO:0011706 infores:monarchinitiative not_provided not_provided HGNC:30213 MONDO:0011706 uuid:d6d27161-2387-4b43-87e1-d88f467c7539 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31638 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0042401 infores:hetionet CHEBI:8364 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0018681 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0022660 infores:hetionet CHEBI:61049 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0016204 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0042075 infores:hetionet CAID:CA774743623 biolink:causes MONDO:0008723 infores:clingen CAID:CA774743623 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1059_1060del (p.Gly354Hisfs*4) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA774743623/MONDO:0008723/021 2024-12-10 2024-12-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45783 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0149745 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0010823 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0018801 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0424741 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0424741 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0008370 infores:hetionet CAID:CA539000938 biolink:causes MONDO:0015924 infores:clingen CAID:CA539000938 MONDO:0015924 PMID: Benign BP4, BA1, BS2_Supporting PP3, BP1 The BMPR2 NM_001247.7 c.-924A>G variant is a 5' UTR variant with ClinVar variation ID: 897238 and allele ID: 883358. The highest population minor allele frequency in gnomAD v3.1.2 controls is 1.45% (115/7926 alleles, including 2 homozygotes) in the African/African American population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). BS2_supporting was met based on the 2 observed homozygotes among gnomAD controls. BP4 was met based on the computational predictor, CADD, giving a score of 9.47 which is below the PH VCEP threshold of <=10.0. In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1, BS2_supporting, BP4 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA539000938/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15367 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1443060 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0023533 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0020651 infores:hetionet CHEBI:50729 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C1142520 infores:hetionet UMLS:C0209366 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0236075 infores:hetionet CHEBI:7494 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0043352 infores:hetionet CHEBI:136040 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0014742 infores:hetionet CHEBI:15552 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0232488 infores:hetionet CHEBI:7936 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013144 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0007848 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0007848 uuid:e96741f0-212f-443b-ace3-d43fb04a597c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0011991 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0853784 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0853784 infores:hetionet CHEBI:3506 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0151754 infores:hetionet CAID:CA025005 biolink:causes MONDO:0007783 infores:clingen CAID:CA025005 MONDO:0007783 PMID: Likely Pathogenic PS4_Supporting, PM1, PP3_Moderate, PM6_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of lysine with glutamic acid at codon 33 of the RYR1 protein, p.(Lys33Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual diagnosed with King-Denborough syndrome with a personal history of an MH episode and a positive caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID:18765655). In this individual the variant was determined to be de novo without confirmed parentage PM6_Supporting. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.92) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic: PM6_Supporting, PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA025005/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:42797 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1142135 infores:hetionet CHEBI:63627 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0038990 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0040409 infores:hetionet CHEBI:85083 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0853986 infores:hetionet CHEBI:8378 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0234708 infores:hetionet CHEBI:31981 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0040822 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0012833 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0042571 infores:hetionet CHEBI:3077 biolink:causes HP:0001518 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0024032 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0027947 infores:hetionet CHEBI:63623 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0020517 infores:hetionet CAID:CA246741 biolink:causes MONDO:0100438 infores:clingen CAID:CA246741 MONDO:0100438 PMID: Benign BS2, BA1 BP5, BP4, PM3 NM_014336.5(AIPL1):c.971G>T (p.Arg324Leu) is a missense variant resulting in replacement of arginine by leucine at amino acid p.324. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.006701, with 8,053 alleles / 1,179,896 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). This variant has been found in the homozygous state in 21 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The variant has been reported in at least one individual from a cohort of healthy control patients, but the occurrence has not been considered for inclusion in BS2 due to the unreported state of zygosity (PMID: 22412862). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state, however, they were not counted for PM3 because no second AIPL1 variant was identified (PMID: 21153841). At least one proband with early-onset severe retinal dystrophy who was heterozygous for the variant lacks a second AIPL1 variant and has an alternative basis for disease in the RPE65 gene, harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.361del (p.Ser121fs) variants (PMID: 21153841). However, BP5 is not applicable to AIPL1 variant curation as cases like this simply represent carrier status and do not provide evidence of benign impact. The computational predictor REVEL gives a score of 0.403, which is above the ClinGen LCA/eoRD VCEP threshold of <0.290 and does not predict a non-damaging effect on AIPL1 protein function. The splicing impact predictor SpliceAI gives a delta score of 0.10 for acceptor loss, which is above the ClinGen LCA/eoRD VCEP threshold of <0.1 and represents an intermediate prediction of impact on AIPL1 splicing. In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1 and BS2. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA246741/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8869 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0018799 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0020488 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0006266 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0521591 infores:hetionet CHEBI:2675 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0020580 infores:hetionet CHEBI:5790 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0019521 infores:hetionet NCBIGene:23556 biolink:causes MONDO:0013563 infores:monarchinitiative not_provided not_provided HGNC:8967 MONDO:0013563 uuid:36c7659e-b762-4ed0-80d0-d6dc66e13fcc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5106 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0231528 infores:hetionet NCBIGene:5277 biolink:causes MONDO:0010466 infores:monarchinitiative not_provided not_provided HGNC:8957 MONDO:0010466 uuid:5f490c61-c910-436c-9104-120d412060a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64321 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0011991 infores:hetionet CHEBI:119915 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0497156 infores:hetionet CHEBI:9139 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151701 infores:hetionet CHEBI:5103 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0004044 infores:hetionet CHEBI:35778 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0002962 infores:hetionet CHEBI:45979 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0011991 infores:hetionet CHEBI:31643 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0037036 infores:hetionet CAID:CA367401942 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401942 MONDO:0015967 PMID:28842611 Likely Pathogenic PM5, PP2, PP3, PM2_Supporting, PS3_Moderate PS4, PP4 The c.450C>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 150 (p.(Phe150Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 16602010, 20337973, 24918535). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.13, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 28842611). Another missense variant, c.449T>A p.Phe150Tyr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Leu has an equal Grantham distance (PM5). In summary, c.450C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PM5, PS3_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401942/MONDO:0015967/086 2024-03-22 2024-03-22 Semidominant inheritance HP:0032113 Supports CHEBI:5138 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0030252 infores:hetionet CHEBI:52717 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018926 infores:hetionet CHEBI:8212 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0700075 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0277884 infores:hetionet CHEBI:50729 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0235996 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016436 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0549373 infores:hetionet CHEBI:31302 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0033774 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0025061 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0011991 infores:hetionet CHEBI:63623 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0011991 infores:hetionet CHEBI:3478 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0039070 infores:hetionet CHEBI:42797 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037036 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0025061 infores:hetionet GO:0048515 biolink:causes CL:0000018 infores:ubergraph knowledge_assertion manual_agent GO:0048515 CL:0000018 CHEBI:49960 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0027497 infores:hetionet CAID:CA206112 biolink:causes MONDO:0100040 infores:clingen CAID:CA206112 MONDO:0100040 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, BP4 PS1, PM1, PM5, PVS1 The p.Glu144Lys variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). The p.Glu144Lys variant has been observed in at least 2 individuals with neurodevelopmental phenotypes (internal databases - GeneDx and University of Chicago) (PS4_Supporting). The computational predictor REVEL gives a score of 0.112, which is below the threshold of 0.290, evidence that does not predict a damaging effect on FOXG1 function (BP4). In summary, the p.Glu144Lys variant in FOXG1 is classified as uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, PS4_Supporting, BP4). (FOXG1 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA206112/MONDO:0100040/035 2025-08-27 2025-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3814 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0004093 infores:hetionet CAID:CA1139770890 biolink:causes MONDO:0005338 infores:clingen CAID:CA1139770890 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PVS1, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.375del variant in MYOC is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 35 of the frameshift, or amino acid 159 (p.Arg125SerfsTer35). Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with primary open angle glaucoma is not loss-of-function. The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00001098 (1 allele out of 91,068), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 22736945), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139770890/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:9276 biolink:causes MONDO:0859253 infores:monarchinitiative not_provided not_provided HGNC:2232 MONDO:0859253 uuid:72965954-5e9c-40f3-8b36-a6fce5b33489 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028173 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0020039 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007222 infores:hetionet CHEBI:3207 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0235761 infores:hetionet CHEBI:4877 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0027497 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020517 infores:hetionet CHEBI:3757 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0235857 infores:hetionet CHEBI:40279 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020473 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C1328308 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C1328308 infores:hetionet CHEBI:92998 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085680 infores:hetionet CHEBI:9150 biolink:causes GO:0042696 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0025274 infores:hetionet CHEBI:4784 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0014457 infores:hetionet CHEBI:50275 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0231835 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0018099 infores:hetionet CAID:CA1139660056 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139660056 MONDO:0015967 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting PS4 The c.1148del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 383 (NM_000162.5), adding 19 novel amino acids before encountering a stop codon (p. (Ser383Trpfs*19)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), but has been detected in two unrelated probands with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (Internal lab contributors). One proband, along with his sister, was diagnosed with neonatal diabetes; they have this variant in the homozygous state (PP4, PM3_Supporting; internal lab contributor). In summary, c.1148del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v 1.3.0; approved 8/11/2023): PVS1, PM2_Supporting, PM3_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139660056/MONDO:0015967/086 2024-03-12 2024-03-12 Semidominant inheritance HP:0032113 Supports CHEBI:10101 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0744727 infores:hetionet CHEBI:63622 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0428977 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0036572 infores:hetionet NCBIGene:3848 biolink:causes MONDO:0011881 infores:monarchinitiative not_provided not_provided HGNC:6412 MONDO:0011881 uuid:045a9c3e-9be9-43b1-97f7-25d7eb13eca0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085688 infores:hetionet NCBIGene:4913 biolink:causes MONDO:0014630 infores:monarchinitiative not_provided not_provided HGNC:8028 MONDO:0014630 uuid:0bd1e7e8-bbb4-49d1-870d-8eab3ae30136 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:83394 biolink:causes MONDO:0010969 infores:monarchinitiative not_provided not_provided HGNC:21043 MONDO:0010969 uuid:bfd26683-5c92-4bfb-acc9-2f8fc7c95a9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135342 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0037274 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0004610 infores:hetionet CHEBI:140621 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C1527311 infores:hetionet CHEBI:4659 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0151827 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151905 infores:hetionet CHEBI:85083 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C1384353 infores:hetionet CAID:CA198490 biolink:causes MONDO:0700270 infores:clingen CAID:CA198490 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PP3 PVS1 The ATM c.8578_8580delTCT (p.S2860del) variant has been observed in the compound heterozygous state (presumed) in two individuals affected with ataxia-telangiectasia and it has also been observed in the compound heterozygous state (confirmed) in an individual affected with generalized dystonia, without classical AT features (PMIDs: 22213089, 31920950 PM3_verystrong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In silico structural impact predictors (Provean, -11.099) predict that this alteration is deleterious (PP3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA198490/MONDO:0700270/020 2022-03-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17650 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0015300 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0018681 infores:hetionet CHEBI:63620 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0542571 infores:hetionet CHEBI:15367 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0023518 infores:hetionet CHEBI:8768 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0040053 infores:hetionet CHEBI:4356 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0023218 infores:hetionet CHEBI:8428 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0018524 infores:hetionet CHEBI:63681 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C2830004 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0162429 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0241705 infores:hetionet GO:0072304 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:0072304 GO:0072210 CHEBI:9086 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0010520 infores:hetionet CAID:CA16020802 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020802 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, PM3_Supporting PP3, PS3 This c.499A>T (p.Asn167Tyr) variant in PAH was reported in 1 patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe), it was detected with pathogenic variant p.Arg408Trp (PMID: 23357515). Computational evidence for this variant is conflicting; predicted to be damaging (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant was found at an extremely low frequency in gnomAD (MAF=0.00005723). Functional studies have been reported with no major impact on enzyme activity as compared to wild type (PMID: 31208052). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3 supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020802/MONDO:0009861/006 2020-12-07 2021-01-15 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:2000356 biolink:causes GO:0001822 infores:ubergraph knowledge_assertion manual_agent GO:2000356 GO:0001822 CHEBI:94609 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0015230 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0012813 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042267 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0037274 infores:hetionet CHEBI:9434 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0404521 infores:hetionet CHEBI:521033 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0234022 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0155003 infores:hetionet CAID:CA229550 biolink:causes MONDO:0009861 infores:clingen CAID:CA229550 MONDO:0009861 PMID:21307867PMID:14681498PMID:14681498PMID:9860305PMID:14681498 Pathogenic PVS1, PP4_Moderate, PM2 PM3, PS3 PAH-specific ACMG/AMP criteria applied: PM2: Not present in ExAC or 1000 genomes (PMID:9860305); PVS1: Canonical -1 splice site where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 5 is present in biologically-relevant transcript. PP4_Moderate: Reported in a mild PKU patient. BH4 deficiency assessed. (PMID:14681498). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229550/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2704 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0852911 infores:hetionet CHEBI:18248 biolink:causes MONDO:0800385 infores:ubergraph knowledge_assertion manual_agent CHEBI:18248 MONDO:0800385 NCBIGene:4867 biolink:causes MONDO:0012308 infores:monarchinitiative not_provided not_provided HGNC:7905 MONDO:0012308 uuid:6f516218-f682-4aaf-9bc4-22ba7442bff1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9445 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C2047937 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0027441 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1142172 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1142172 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006809 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0007780 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0022893 infores:hetionet CAID:CA058826 biolink:causes MONDO:0018493 infores:clingen CAID:CA058826 MONDO:0018493 PMID: Uncertain Significance PP3, PS4_Supporting PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 4133 of the RYR1 protein, p.(Glu4133Gly). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0000649, a frequency consistent with pathogenicity for MHS. This variant has been identified in an individual reported to have undergone an MH episode (CGS 10), the individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 24433488). The MAF in the SAS population in gnomAD is 0.000065, assuming ~3,000 MH cases described in the literature an odds ratio calculation would allow for PS4_Supporting. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.881) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA058826/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA2573157361 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157361 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS2, BP1, PM6, BS3, PP2, PP4 NM_001754.5(RUNX1):c.259_260delinsAA (p.Gly87Asn) is a variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157361/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45081 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0014742 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235876 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0235431 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0023533 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0027627 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0027627 infores:hetionet CHEBI:6775 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0231218 infores:hetionet NCBIGene:6017 biolink:causes MONDO:0011838 infores:monarchinitiative not_provided not_provided HGNC:10024 MONDO:0011838 uuid:21cf9800-cb72-45fb-ab22-3da808a31f68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1142412 infores:hetionet CHEBI:94392 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0003811 infores:hetionet NCBIGene:29089 biolink:causes MONDO:0014638 infores:monarchinitiative not_provided not_provided HGNC:25009 MONDO:0014638 uuid:d03f4321-576a-432e-a472-921b27e7ba1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA116610 biolink:causes MONDO:0009290 infores:clingen CAID:CA116610 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM5, PS3_Moderate, PM3_Very Strong PM2 The NM_000152.5:c.1935C>A variant in GAA is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 645 (p.Asp645Glu). At least 50 individuals with this variant have been reported with GAA activity in the affected range for Pompe disease in fibroblasts, lymphocytes, or dried blood spots (PMID: 8094613, 9554747, 18458862). This variant is reported to be the most common variant identified in patients with infantile onset Pompe disease from China, Taiwan, and Thailand (PMID 9554747, 18458862, 21039225, 31342611), although it has also been reported in other populations (PMID: 8094613). It has been found to be associated with a specific haplotype, which includes the pseudodeficiency variant, indicating that it is a founder variant (PMID: 9554747). However, other studies have not found an association with this specific haplotype (PMID: 8094613, 18458862) (PP4_Moderate). This variant was found in compound heterozygosity with a pathogenic variant in 5 patients (PMID: 8094613, 9554747, 18458862, 28394184), as well as over 30 homozygotes (PMID: 9554747, 18458862, 28394184). More data is available in the literature but the maximum amount of evidence required for PM3_Strong has been reached. The highest population minor allele frequency in gnomAD is 0.001729 in the East Asian population. This is higher than the ClinGen LSD VCEP threshold (<0.001) for PM2, and therefore does not meet this criterion. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Measurement of GAA activity in COS cells transfected with the variant showed <10% normal GAA activity indicating that this variant impacts protein function (PMID: 8094613, 19862843). In addition, little to no mature 76 kDa protein was detected by pulse-chase analysis, suggesting abnormal synthesis and/or processing of the protein (PMID: 8094613) (PS3_Moderate). Another missense variant, c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Storage Disorders VCEP (PM5). There is a ClinVar entry for this variant (Variation ID 4029; 2 star review status) with seven laboratory submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PM5, PS3_Moderate, PP4_Moderate, PP3.(Classification approved on August 17, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116610/MONDO:0009290/010 2021-09-07 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31859 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0023218 infores:hetionet CHEBI:46195 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0022107 infores:hetionet NCBITaxon:203492 biolink:causes MONDO:0006925 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:203492 MONDO:0006925 CHEBI:100246 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0004093 infores:hetionet CHEBI:16755 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151905 infores:hetionet NCBIGene:23269 biolink:causes MONDO:0976129 infores:monarchinitiative not_provided not_provided HGNC:14010 MONDO:0976129 uuid:e8c77d06-ca62-4928-8c5c-7bf120190757 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410148642 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148642 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1007T>G (p.Phe336Cys) is a missense variant, which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148642/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA229412 biolink:causes MONDO:0009861 infores:clingen CAID:CA229412 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 PP4 The variant c.1237C>T (p.Arg313Cys) in PAH is not currently reported in patients in the literature. This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.937 (PP3), and has an extremely low frequency in gnomAD (PM2). This variant is at the same codon as c.1238G>C (p.Arg413Pro) which has been curated as pathogenic by the ClinGen PAH VCEP (ClinVarID:592) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229412/MONDO:0009861/006 2020-05-14 2020-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28001 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C1320835 infores:hetionet CHEBI:41774 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0043352 infores:hetionet CHEBI:7915 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151744 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0343863 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0853813 infores:hetionet CAID:CA293899 biolink:causes MONDO:0700270 infores:clingen CAID:CA293899 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5_Supporting, PVS1 PM2 The c.8266A>T (p.Lys2756*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 10330348, 12552559, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003887 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA293899/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3757 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0239113 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0004936 infores:hetionet CHEBI:39112 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1443060 infores:hetionet CAID:CA399804787 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804787 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Supporting The NM_000419.5(ITGA2B):c.953C>T (p.Ser318Leu) missense variant has been reported in at least one patient (UPN 3 in PMID: 16879215) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 20.1%, as measured by flow cytometry. UPN 3 is homozygous for this variant (PM3_supporting; PMID: 16879215). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.852, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). HEK 293 cells were transfected with Ser318Leu αIIb and wildtype β3 with immunoblotting from cell lysates finding mature αIIb in the normal αIIbβ3 cells, but only 6% of the normal value of mature αIIb in the Ser318Leu mutant. Expression <25% WT levels, indicates that this variant impacts protein function (PS3_moderate; PMID: 16359515). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_moderate, PM2_supporting, PM3_supporting, PP4_moderate, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804787/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6931 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0040460 infores:hetionet NCBIGene:2697 biolink:causes MONDO:0033013 infores:monarchinitiative not_provided not_provided HGNC:4274 MONDO:0033013 uuid:b30e2cf3-50d7-4566-8fa0-8a302b3b02ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0021053 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0020649 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020757 infores:hetionet CHEBI:6690 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0232461 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0015230 infores:hetionet GO:0008284 biolink:causes MONDO:0005086 infores:drugmechdb knowledge_assertion manual_agent GO:0008284 MESH:D002292 DB00398_MESH_D002292_1 CHEBI:51173 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0152128 infores:hetionet CHEBI:18358 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0037274 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0087169 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0042373 infores:hetionet CHEBI:41977 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1167965 infores:hetionet CHEBI:80630 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0036974 infores:hetionet CHEBI:4858 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085628 infores:hetionet CHEBI:6717 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0014724 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038661 infores:hetionet NCBIGene:4629 biolink:causes MONDO:0007568 infores:monarchinitiative not_provided not_provided HGNC:7569 MONDO:0007568 uuid:faa78365-9529-4c38-939e-56b2a5429392 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:573 biolink:causes MONDO:0030603 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:573 MESH:D007710 DB00766_MESH_D007710_1DB01155_MESH_D007710_1DB01332_MESH_D007710_1DB01060_MESH_D007710_1 CHEBI:61049 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0001925 infores:hetionet CHEBI:15765 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0600142 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151838 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151626 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022904 infores:hetionet CHEBI:40279 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0013144 infores:hetionet CHEBI:2611 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1142135 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0039971 infores:hetionet CHEBI:47898 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0392699 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0233414 infores:hetionet CHEBI:63620 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0040822 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0004936 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0040034 infores:hetionet CHEBI:32020 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0015230 infores:hetionet NCBIGene:55806 biolink:causes MONDO:0008757 infores:monarchinitiative not_provided not_provided HGNC:5172 MONDO:0008757 uuid:a5148b03-4380-4053-98b1-376e6bf3084e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7248 biolink:causes MONDO:0011818 infores:monarchinitiative not_provided not_provided HGNC:12362 MONDO:0011818 uuid:84c2a2ca-6c74-4f13-821a-cf3a24afd2d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10576423 biolink:causes MONDO:0005365 infores:clingen CAID:CA10576423 MONDO:0005365 PMID: Likely Benign BP7, BP4 BP5, BS4, BS1, PP4, PP1, PP3, BS2, PM3, PM1, PM4, PM5, PVS1, PM6, BP2, BP3, BA1, PS2, PS4, PS3, PS1 The silent p.Thr240= variant in KCNQ4 is not predicted by computational tools to impact splicing (BP7. BP4). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org), however this is not considered evidence against a likely benign classification. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP7, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576423/MONDO:0005365/005 2018-09-28 2019-07-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:9943 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0021141 infores:hetionet CHEBI:50922 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0019521 infores:hetionet CHEBI:41774 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C2939420 infores:hetionet CHEBI:47426 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0041969 infores:hetionet CAID:CA410206793 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206793 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.737C>A (p.Thr246Lys) is a missense variant which has not been featured in functional or case studies. Computational and population data have been used to evaluate this variant. It is detected in the gnomAD population database (1/1179366 alleles in the European (Non-Finnish) v4 cohort). This variant has a SpliceAI score of 0.01 and a PhyloP score of 7.8, supporting the application of BP4. In summary, this variant meets criteria to be classified as a variant of uncertain significance (VUS). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206793/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63627 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0023530 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027121 infores:hetionet NCBIGene:7922 biolink:causes MONDO:0030519 infores:monarchinitiative not_provided not_provided HGNC:4927 MONDO:0030519 uuid:55872e2c-ae2d-4c84-af39-f54b1c0a3cae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2950 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0038363 infores:hetionet NCBIGene:55181 biolink:causes MONDO:0859136 infores:monarchinitiative not_provided not_provided HGNC:25551 MONDO:0859136 uuid:a951d2c7-809f-4917-9e3a-adfa28a993bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410148673 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148673 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The 1003C>T (p.Gln335Ter) variant is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 335-480) is critical to protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge; however one unpublished proband meeting at least one of the RUNX1 phenotype criteria is noted (PS4_Supporting; SCV000807750.1). This variant is a nonsense/frameshift variant that is downstream of c.98 (PM5_Supporting).In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148673/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8107 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0392176 infores:hetionet CHEBI:2379 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0033774 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0043345 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017574 infores:hetionet CHEBI:10119 biolink:causes HP:0020064 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0853644 infores:hetionet CHEBI:27786 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0034063 infores:hetionet CHEBI:27974 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C2225524 infores:hetionet CAID:CA5416783 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416783 MONDO:0011225 PMID: Likely Benign BS1 BS2 The c.556G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause a substitution of Valine by Leucine at amino acid 186 (p.Val186Leu).The filtering allele frequency (the lower threshold of the 95% CI of 160/75040) of the c.556G>C variant in DCLRE1C is 0.001831 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00078) for BS1, and therefore meets this criterion (BS1). No homozygotes have been reported. To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied: BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416783/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:567361 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0042109 infores:hetionet CHEBI:3077 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0262431 infores:hetionet CHEBI:3001 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0220870 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037199 infores:hetionet NCBITaxon:6269 biolink:causes MONDO:0015200 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6269 MONDO:0015200 NCBIGene:554 biolink:causes MONDO:0010356 infores:monarchinitiative not_provided not_provided HGNC:897 MONDO:0010356 uuid:b3bcf211-9705-4cf2-a264-02b2977f654a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013404 infores:hetionet CHEBI:7565 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014742 infores:hetionet NCBIGene:5457 biolink:causes MONDO:0859158 infores:monarchinitiative not_provided not_provided HGNC:9218 MONDO:0859158 uuid:12b95b9f-cac6-4dc3-9c23-29b43fce1943 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28939 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0041657 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0854453 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0854453 infores:hetionet CHEBI:6532 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0041657 infores:hetionet CHEBI:63630 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027849 infores:hetionet CHEBI:3223 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0030554 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0234930 infores:hetionet CHEBI:9763 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C1145670 infores:hetionet CAID:CA16616640 biolink:causes MONDO:0010305 infores:clingen CAID:CA16616640 MONDO:0010305 PMID: Pathogenic PVS1, PM2, PP4_Strong The NM_005629.4:c.972_973del (p.Thr325SerfsTer139) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two maternal half-brothers have been reported to be hemizygous for the variant, both with clinical features consistent with creatine transporter deficiency, markedly reduced creatine level on brain MRS, elevated urine creatine/creatinine ratio, and <3% transporter activity in fibroblasts (PMID 20602486) (PP4_Strong). This variant is not in gnomAD v2.1.1. or v4.1.0 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 410218). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on May 2, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616640/MONDO:0010305/027 2024-05-02 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:64321 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0042075 infores:hetionet CHEBI:9674 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0041657 infores:hetionet CHEBI:404903 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0700225 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0002170 infores:hetionet CHEBI:2569 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0023066 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0027765 infores:hetionet CHEBI:521033 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0033038 infores:hetionet CAID:CA000189 biolink:causes MONDO:0017623 infores:clingen CAID:CA000189 MONDO:0017623 PMID: Uncertain Significance PP2, PM2_Supporting, BP4 PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PP1, PP4, PP3, BS2, PM4, PM5, PM1, PM3, BA1, BP3, BP2, BP1, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.715A>G (p.Met239Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_Supporting: Absent in large sequenced populations in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BP4: REVEL score < 0.5 (score=0.421).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting = -1. 2 pathogenic supporting = 2. Total = 1 (VUS). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000189/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2759533407 biolink:causes MONDO:0100326 infores:clingen CAID:CA2759533407 MONDO:0100326 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PM2_Supporting "The NM_000419.5(ITGA2B):c.480del (p.Cys161AlafsTer22) (also referred as ""c.512delC"") variant in ITGA2B is a deletion in exon 4, resulting in a shift of the reading frame and a premature stop signal (p.Cys161Alafs*22). This variant is predicted to cause a premature stop codon in biologically relevant exon (exon 4) leading to nonsense mediated decay (PVS1). This variant has been detected in trans with a pathogenic variant NM_000419.4:c.1654del (mentioned as ""c.1686delG"" in the article) in an individual with Glanzmann thrombasthenia (PMID: 27416581; PM3). The patient (PMID: 27416581) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry. This variant is absent from gnomAD v4.1.0 population databases (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3, PM2_Supporting, PP4_Moderate." Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2759533407/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:71219 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0027765 infores:hetionet CHEBI:83527 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0206062 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0267994 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0267994 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0836924 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0021359 infores:hetionet CHEBI:17263 biolink:causes UMLS:C2609183 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C2609183 infores:hetionet UMLS:C0004609 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0011603 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0027765 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235416 infores:hetionet CHEBI:6801 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C2129214 infores:hetionet CHEBI:145499 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151578 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0948525 infores:hetionet CHEBI:28901 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0600142 infores:hetionet CHEBI:9571 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0039070 infores:hetionet CHEBI:8764 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0546817 infores:hetionet CHEBI:6413 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0018989 infores:hetionet CHEBI:63617 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0035305 infores:hetionet CHEBI:7798 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0014591 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0162429 infores:hetionet GO:0031932 biolink:causes GO:0038203 infores:ubergraph knowledge_assertion manual_agent GO:0031932 GO:0038203 CHEBI:35778 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151826 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033575 infores:hetionet CHEBI:51230 biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0009759 infores:hetionet CHEBI:3510 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0042109 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011616 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0085584 infores:hetionet CHEBI:55346 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0015732 infores:hetionet CHEBI:6710 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0028734 infores:hetionet CHEBI:5001 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C1142412 infores:hetionet CHEBI:3561 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0004134 infores:hetionet CHEBI:3423 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1306341 infores:hetionet CHEBI:5118 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0600142 infores:hetionet CHEBI:47612 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0231528 infores:hetionet NCBIGene:2121 biolink:causes MONDO:0008673 infores:monarchinitiative not_provided not_provided HGNC:3497 MONDO:0008673 uuid:a09b9183-f297-467d-86cf-4d1eb0c02793 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61390 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0015967 infores:hetionet CHEBI:135920 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0018681 infores:hetionet CHEBI:16899 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0546817 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0000833 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001142 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0036093 infores:hetionet CHEBI:27834 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0025287 infores:hetionet CHEBI:3437 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C3665347 infores:hetionet CHEBI:27786 biolink:causes EFO:0020913 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0948857 infores:hetionet CHEBI:27899 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0027540 infores:hetionet CHEBI:7577 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C2830004 infores:hetionet CHEBI:8871 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026826 infores:hetionet CHEBI:4868 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C2697368 infores:hetionet CHEBI:18248 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0239377 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0020538 infores:hetionet CHEBI:101085 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0027497 infores:hetionet CHEBI:7476 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002874 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0006266 infores:hetionet NCBIGene:64421 biolink:causes MONDO:0011338 infores:monarchinitiative not_provided not_provided HGNC:17642 MONDO:0011338 uuid:743264c0-f2fb-4e9d-9f80-344a94118de2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0231218 infores:hetionet CHEBI:2618 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0917801 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235416 infores:hetionet CHEBI:2668 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0030193 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0678222 infores:hetionet CHEBI:63580 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0221776 infores:hetionet NCBIGene:3872 biolink:causes MONDO:0008485 infores:monarchinitiative not_provided not_provided HGNC:6427 MONDO:0008485 uuid:a90c3d25-5c7c-488d-a925-7b93b3ca2de0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:53436 biolink:causes MONDO:0001714 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:53436 MONDO:0001714 PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0029877 infores:hetionet CHEBI:4798 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0037763 infores:hetionet NCBIGene:55157 biolink:causes MONDO:0012622 infores:monarchinitiative not_provided not_provided HGNC:25538 MONDO:0012622 uuid:3d42a0f3-f401-4822-9fd0-387acc73caa0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40303 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0024141 infores:hetionet CHEBI:16469 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0497156 infores:hetionet CHEBI:5106 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0040822 infores:hetionet CHEBI:53691 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0018965 infores:hetionet CHEBI:9449 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0015230 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0021775 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0227791 infores:hetionet CHEBI:75922 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0033774 infores:hetionet CHEBI:27899 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C3665347 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040479 infores:hetionet CHEBI:8212 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0392156 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0017160 infores:hetionet CHEBI:9907 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0030554 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0018799 infores:hetionet CHEBI:100241 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0015672 infores:hetionet CHEBI:4027 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0018790 infores:hetionet CHEBI:6149 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030201 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006384 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0019158 infores:hetionet CHEBI:10650 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151827 infores:hetionet CHEBI:6715 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011644 infores:hetionet CHEBI:46081 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0011991 infores:hetionet CAID:CA392324980 biolink:causes MONDO:0007947 infores:clingen CAID:CA392324980 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP1, PM2_Supporting, PS4, PM1 PVS1, PM6, BS2, PP4, BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS2, PM3, PM4, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.3557A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by a cysteine at amino acid 1186 (p.Tyr1186Cys). It has been identified in at least five individuals with diagnoses or suspicion of Marfan syndrome including the following: a pediatric patient with bilateral ectopia lentis (EL), severe thoracic aortic aneurysm and dissection (TAAD), and a systemic score of 9; an adult patient with EL and a systemic score of 6; a patient with bilateral EL, TAAD, and systemic features; an individual reported to have Marfan syndrome without specific details provided; and an individual with bilateral EL, TAAD, retinal detachment, and systemic features (PS4; PMIDs: 31061752, 11933199; UZG, Bichat, & Invitae internal data). It was also found to segregate with Marfan syndrome in two other members of an aforementioned family (PP1; Bichat internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.974). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PP1, PP2, PP3, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392324980/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ GO:0061074 biolink:causes GO:0060041 infores:ubergraph knowledge_assertion manual_agent GO:0061074 GO:0060041 CHEBI:144551 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009319 infores:hetionet CHEBI:6402 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151907 infores:hetionet CHEBI:32192 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0015230 infores:hetionet CHEBI:7577 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0023530 infores:hetionet CHEBI:15640 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0040034 infores:hetionet CHEBI:6832 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0013144 infores:hetionet CHEBI:9671 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0027497 infores:hetionet CHEBI:41774 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0038325 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017178 infores:hetionet CHEBI:44185 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C2830004 infores:hetionet CHEBI:4672 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0039231 infores:hetionet CHEBI:8871 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0852795 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030312 infores:hetionet CHEBI:5050 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0011991 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0424000 infores:hetionet CHEBI:2676 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0038325 infores:hetionet CHEBI:9215 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C1287298 infores:hetionet CHEBI:47426 biolink:causes UMLS:C2712871 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C2712871 infores:hetionet CHEBI:41774 biolink:causes HP:0001407 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0267834 infores:hetionet CHEBI:8802 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0019521 infores:hetionet CAID:CA229724 biolink:causes MONDO:0009861 infores:clingen CAID:CA229724 MONDO:0009861 PMID:8659548PMID:24368688PMID:8659548PMID:11161839 Pathogenic PM3, PM2, PP3, PP4, PS3_Supporting The c.733G>C (p.Val245Leu) variant in PAH has been reported in 3 individuals with PAH deficiency, detected with pathogenic variants p.R408Q and p.A104D (PMID: 8659548, 24368688). This variant has an extremely low allele frequency (0.000008972) in gnomAD. This variant has 13% enzyme activity (PMID: 11161839). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PS3, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229724/MONDO:0009861/006 2020-06-26 2023-04-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28901 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0037274 infores:hetionet NCBIGene:10606 biolink:causes MONDO:0859244 infores:monarchinitiative not_provided not_provided HGNC:8587 MONDO:0859244 uuid:9de502ed-70bf-45e0-9bf7-68a0498c8e49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2061380 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061380 MONDO:0015924 PMID: Uncertain Significance PP3, PM1, BS1 PM2, PM5, PS1, PS3, PS4 "The BMPR2 c.1481C>T variant is a missense variant predicted to result in an alanine to valine substitution at amino acid 494 (p.Ala494Val). The minor allele frequency in gnomAD v2.1.1 controls “Other East Asian"" is 0.0016% (11/7044 alleles), which exceeds the PH VCEP threshold of >0.1% for BS1. The variant is located in the kinase domain of BMPR2 (amino acids 203-504) but there is no functional evidence for or against this residue being critical, thus meeting PM1 without modification. The REVEL score is 0.872, exceeding the threshold of 0.75 (PP3). In summary, the variant meets the criteria to be classified as uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PM1, PP3 (VCEP specification version 1.1, 1/18/2024)." Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061380/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8805 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0021053 infores:hetionet CHEBI:8802 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0012833 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0009782 infores:hetionet CAID:CA2579753928 biolink:causes MONDO:0012999 infores:clingen CAID:CA2579753928 MONDO:0012999 PMID: Likely Pathogenic PM2_Supporting, PVS1_Moderate, PM3_Supporting, PP4_Moderate The NM_000156.6:595dupG (p.Glu199GlyfsTer68) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). This variant has been detected in one individual with an absent creatine peak on brain MRS and low plasma creatine (PMID: 32606525) (PP4_Moderate). This individual was homozygous for the variant (PMID: 32606525) (0.5pts, PM3_Supporting). This individual had an absent creatine peak on brain MRS (PMID: 32606525) (PP4_Moderate). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2570639). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Moderate, PM2_Supporting, PM3_Supporting, PP4_Moderate.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579753928/MONDO:0012999/025 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes HP:0010822 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235068 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0006840 infores:hetionet CHEBI:136040 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0002962 infores:hetionet CHEBI:2663 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151905 infores:hetionet CHEBI:35553 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0232462 infores:hetionet CHEBI:9137 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020443 infores:hetionet CAID:CA10014476 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014476 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.564C>T (p.Thr188=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.85)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014476/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0025241 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0019156 infores:hetionet CHEBI:6950 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011606 infores:hetionet CHEBI:63619 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017979 infores:hetionet CHEBI:135005 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0235710 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0851341 infores:hetionet CHEBI:9588 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0027121 infores:hetionet CHEBI:3441 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C1142135 infores:hetionet CHEBI:8871 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027080 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0746883 infores:hetionet CHEBI:167638 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C1443060 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0241075 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0241075 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0029878 infores:hetionet CHEBI:31536 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C1262113 infores:hetionet CHEBI:184555 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0162830 infores:hetionet CHEBI:3996 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0011603 infores:hetionet CHEBI:63612 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0013378 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0149931 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0021400 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0009806 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0242350 infores:hetionet CHEBI:45652 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0011603 infores:hetionet CHEBI:63681 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0013404 infores:hetionet CHEBI:8890 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0004245 infores:hetionet CAID:CA6831743 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831743 MONDO:0015967 PMID:32910913 Pathogenic PM2_Supporting, PS4, PM1_Supporting, PP1_Strong, PP4_Moderate, PP3 PS3 The c.347C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 116 (p.(Ala116Val)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.951, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 as the transactivation values were not consistently within or outside the cutoffs for PS3_Moderate or BS3_Supporting (PMID: 32910913). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in at least 20 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 36257325, 31658956, 12453976, internal lab contributors). At least 4 of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies or SU-sensitivity) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 24 informative meioses in multiple families (PP1_Strong; PMID: 12453976, internal lab contributors). In summary, c.347C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831743/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:114785 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0011570 infores:hetionet CHEBI:68579 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C2363731 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0004936 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009946 infores:hetionet CHEBI:63589 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0149744 infores:hetionet GO:0075198 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0075198 GO:0009653 CHEBI:31236 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036396 infores:hetionet CAID:CA410206653 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206653 MONDO:0011071 PMID: Pathogenic PS2_Supporting, PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS3, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.802C>T (p.Gln268Ter) is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant exon 7/9 which is present in all biologically transcripts. The variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1).This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This nonsense variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 36736831). The same case was proven to be de novo (PS2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting, PS2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206653/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45863 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0231919 infores:hetionet CHEBI:7447 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0948594 infores:hetionet NCBIGene:8665 biolink:causes MONDO:0032662 infores:monarchinitiative not_provided not_provided HGNC:3275 MONDO:0032662 uuid:e4f84ece-f322-4d49-b7b4-9b7b010d966f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1720775 infores:hetionet CHEBI:3310 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0039070 infores:hetionet CAID:CA16020754 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020754 MONDO:0009861 PMID:26503515 Uncertain Significance PP4_Moderate, PM2, PP3 The c.232G>C (p.Glu78Gln) variant in PAH has been reported in a patient with PAH deficiecy (BH4 deficiency excluded) (PP4_Moderate; PMID: 26503515) This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020754/MONDO:0009861/006 2019-11-10 2019-11-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5959 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0232493 infores:hetionet CHEBI:2453 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0242429 infores:hetionet CHEBI:48273 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0004134 infores:hetionet CHEBI:231594 biolink:causes UMLS:C1142383 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1142383 infores:hetionet CAID:CA393747895 biolink:causes MONDO:0044970 infores:clingen CAID:CA393747895 MONDO:0044970 PMID: Likely Pathogenic PM2, PVS1 The c.3523 C>T (p.Gln1175Ter) variant in POLG is not in any databases (PM2). There are no publications of cases with this variant and there is no computational evidence available. This variant is a loss of function which predicts a premature stop codon (PVS1). In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA393747895/MONDO:0044970/014 2021-05-23 2021-05-23 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:5856 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0027497 infores:hetionet CHEBI:49603 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0948594 infores:hetionet CHEBI:52717 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0542571 infores:hetionet CHEBI:63584 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0015672 infores:hetionet CHEBI:7820 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0019080 infores:hetionet UMLS:C1738934 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0036974 infores:hetionet CHEBI:6775 biolink:causes MONDO:0800029 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1800706 infores:hetionet CHEBI:3215 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030193 infores:hetionet CHEBI:63580 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0149725 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0239739 infores:hetionet CAID:CA410147293 biolink:causes MONDO:0100083 infores:clingen CAID:CA410147293 MONDO:0100083 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1336C>G (p.Leu446Val) is a missense variant. This missense variant has a REVEL score &< 0.50 (0.294) (BP4) This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147293/MONDO:0100083/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7601 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0011124 infores:hetionet CHEBI:28830 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0023530 infores:hetionet CHEBI:2666 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0235347 infores:hetionet CHEBI:5132 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0019360 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018916 infores:hetionet CAID:CA000075 biolink:causes MONDO:0018875 infores:clingen CAID:CA000075 MONDO:0018875 PMID: Benign BP4, BS3, BS2 BA1, PS3, PS1, PM5, PM1, BS1, PM2, PP3 The NM_000546.6: c.217G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 73 (p.Val73Met). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; ClinVar SCV: SCV000186461.7). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.001037 (11/10608 alleles) in European (Finnish) population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (PMIDs: 12826609, 29979965, 30224644) (BS3). Computational predictor scores (BayesDel = -0.1673; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BS2_Moderate, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000075/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2668 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0020517 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0019360 infores:hetionet CHEBI:8871 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C3665347 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0016436 infores:hetionet NCBIGene:1144 biolink:causes MONDO:0009668 infores:monarchinitiative not_provided not_provided HGNC:1965 MONDO:0009668 uuid:74fe53ac-5ffd-4326-bcf7-26f67160cae2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61058 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0948594 infores:hetionet CHEBI:3756 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235439 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0917798 infores:hetionet NCBIGene:10733 biolink:causes MONDO:0014516 infores:monarchinitiative not_provided not_provided HGNC:11397 MONDO:0014516 uuid:061c851c-43ea-46c3-a6c4-7a65be135a38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6754 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0036572 infores:hetionet CHEBI:4974 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0014742 infores:hetionet CHEBI:9137 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002962 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0034882 infores:hetionet CHEBI:50885 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0152459 infores:hetionet NCBITaxon:38301 biolink:causes MONDO:0002885 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:38301 MESH:D004894 DB00199_MESH_D004894_1 CHEBI:10119 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C3665386 infores:hetionet CHEBI:3387 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0038325 infores:hetionet CHEBI:127342 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0029261 infores:hetionet CHEBI:3219 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026603 infores:hetionet CHEBI:71940 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0085610 infores:hetionet NCBIGene:867 biolink:causes MONDO:0011908 infores:monarchinitiative not_provided not_provided HGNC:1541 MONDO:0011908 uuid:e4da35e3-3ecf-4c85-b6e2-15b5da6d7071 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0262988 infores:hetionet CHEBI:132233 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0233494 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0009450 infores:hetionet CHEBI:39867 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1306341 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005306 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0038013 infores:hetionet CHEBI:135736 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0013428 infores:hetionet CAID:CA012904 biolink:causes MONDO:0005021 infores:clingen CAID:CA012904 MONDO:0005021 PMID: Pathogenic PM2, PM6, PM5, PP3, PP1_Strong, PS4_Moderate PP4, BS2, PM3, PM1, PM4, PS3, BA1, BP3, BS4, BS1, BS3, PS2, PS1, BP4, BP2, BP5, BP7, PVS1 The NM_000257.4:c.2710C>T (p.Arg904Cys) variant in MYH7 has been identified in 4 individuals with DCM in the literature (1 of whom also had LVNC; van Spaendonck-Zwarts 2013 PMID:23349452; van der Zwaag 2011 PMID:20573160; Walsh 2017 PMID:27532257; Miller 2017 PMID29212898) and 3 individuals with LVNC (2 of which were pediatric; Yang 2014 PMID:25326635; Wang 2017 PMID:28855170; van Waning 2018 PMID:29447731). This variant was identified in 8 individuals with DCM and 1 proband with LVNC by clinical laboratories (GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm.). Only probands with DCM are counted towards PS4 (n=12; PS4_Moderate). This variant segregated with DCM in 15 affected individuals from 4 families (PP1_Strong; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.) and was assumed de novo in 1 of the above cases (PM6; GeneDx pers. comm.). This variant has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but was absent from all other populations. A different pathogenic missense variant has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5; c.2711G>A p.Arg904His - Variation ID 42926). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Strong, PM6, PM2, PM5, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012904/MONDO:0005021/002 2021-09-27 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4657 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0018681 infores:hetionet CHEBI:2549 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0015230 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0036572 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0041912 infores:hetionet CHEBI:31401 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0004238 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001221 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0014867 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0332575 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011991 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0151717 infores:hetionet NCBIGene:339453 biolink:causes MONDO:0011833 infores:monarchinitiative not_provided not_provided HGNC:25186 MONDO:0011833 uuid:8b9fccdb-d6ff-4c49-a7b5-ecbfb65b8bfc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C1619712 infores:hetionet CAID:CA10549449 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549449 MONDO:0010305 PMID: Likely Benign BP7, BS2, BP4 BS1, PM2 The NM_005629.4:c.1221C>T variant in SLC6A8 is a synonymous variant (p.Phe407=) with no predicted impact on splicing (BP4, BP7). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.0001849 (6/32453 alleles; 1 hemizygote) in the East Asian population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 2 hemizygotes in gnomAD v4.1.0.; one in the East Asian population and one in the remaining population (BS2). There is a ClinVar entry for this variant (Variation ID: 795105). In summary, this variant meets criteria to be classified as likely benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549449/MONDO:0010305/027 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA267645 biolink:causes MONDO:0009861 infores:clingen CAID:CA267645 MONDO:0009861 PMID:26666653PMID:26666653 Pathogenic PVS1, PM2, PP4, PM3_Supporting The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported in one proband with classic PKU (PMID: 26666653) (PP4). The proband was heterozygous for the variant and also harbor the pathogenic allele (per ClinGen VCEP) c. 1315+1G>A; however, the phase of the variants was not confirmed via parental testing. (PM3_supporting). The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267645/MONDO:0009861/006 2019-05-26 2019-05-26 Autosomal recessive inheritance HP:0000007 Supports GO:0002065 biolink:causes CL:0000075 infores:ubergraph knowledge_assertion manual_agent GO:0002065 CL:0000075 CHEBI:65173 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0033581 infores:hetionet CHEBI:47781 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0020580 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085584 infores:hetionet CHEBI:253342 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009676 infores:hetionet CHEBI:474180 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0030252 infores:hetionet CAID:CA257019 biolink:causes MONDO:0021060 infores:clingen CAID:CA257019 MONDO:0021060 PMID:19966803 Pathogenic PM2_Supporting, PS3_Moderate, PS4, PM6_Very Strong BS1, PS1, BP4, BA1, PM5, PM1, PP2, PP3, PP1 The c.149C>T (p.Thr50Ile) variant in NRAS is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 50. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.693, which is neither above nor below the thresholds predicting a damaging or benign impact on NRAS function. This variant has been reported in over 6 probands with features of RASopathy (PS4; PMIDs: 22855653, 28594414, 31219622, GeneDx). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 4 individuals with autosomal dominant RASopathy (PM6_VeryStrong; PMIDs: 19966803, 29752777, APHP-Robert Debré). MEK and ERK activation assays in COS-7 cells showed enhanced phosphorylation of MEK and ERK in the presence of serum or after EGF stimulation indicating that this variant impacts protein function (PMID: 19966803)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM6_VeryStrong, PS4, PS3_Moderate, PM2_Supporting. (RASopathy VCEP specifications version 2.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA257019/MONDO:0021060/039 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47499 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0151596 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0030196 infores:hetionet CHEBI:5864 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085593 infores:hetionet NCBIGene:8192 biolink:causes MONDO:0013588 infores:monarchinitiative not_provided not_provided HGNC:2084 MONDO:0013588 uuid:88745d60-41f0-4f0f-81e9-765cc585487b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0014591 infores:hetionet CHEBI:5165 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0026827 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0542007 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0542007 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042075 infores:hetionet CHEBI:5001 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151578 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151826 infores:hetionet CHEBI:44915 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0000737 infores:hetionet CHEBI:3219 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152031 infores:hetionet CHEBI:8207 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0005818 infores:hetionet CAID:CA8815004 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815004 MONDO:0009290 PMID: Uncertain Significance PP3, PS3_Supporting PM2, PP4, PM3, BS1 The NM_000152.5:c.726G>A variant in GAA is a synonymous (silent) variant (p.Ala242=) that is predicted to impact splicing. This variant has been detected in at least 10 individuals with low GAA activity. Of those individuals, 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.726G>A/c.525delT; 5 patients with the genotype c.−32-13T>G; 726G>A, confirmed in trans in 3 patients, PMID: 36310651; c.726G>A / c.671G>A; c.726G>A / c.1979G>A; c.726G>A and c.2560C>T), however there is no diagnosis of Pompe disease and PM3 and PP4 are not met. The computational splicing predictor SpliceAI gives a score of 0.96 for acceptor gain, predicting that the variant creates a new cryptic splice site that is stronger than the original splice site. VarSeak also classifies this variant as having a likely splicing effect by generating a cryptic splice site 35 nucleotides downstream of the authentic splice site with a higher score, meeting PP3. This is confirmed by RNA sequencing data for an individual with the c.726G>A variant demonstrated that the variant impacts splicing by introducing an alternate splice site that results in exon shrinkage. The data suggest that this results in a frameshift and introduces a premature termination codon, however the expression is not reduced, indicating a truncated protein is produced (PMID: 35304488), meeting PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 285366, 1 star review status) with 10 submitters classifying the variant as VUS (4 submitters), likely benign (3 submitters), and benign (1 submitter). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PP3, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on Sept. 19, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815004/MONDO:0009290/010 2023-09-19 2023-11-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:135736 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151799 infores:hetionet CHEBI:8888 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0015371 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0302295 infores:hetionet CHEBI:23765 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0014743 infores:hetionet CHEBI:135451 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0232487 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0020649 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0851341 infores:hetionet CHEBI:51860 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0040460 infores:hetionet GO:0060808 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:0060808 GO:0007369 CHEBI:31638 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0162429 infores:hetionet CHEBI:39669 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0014742 infores:hetionet CHEBI:6775 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0004093 infores:hetionet CHEBI:63581 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020443 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1112353 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1112353 infores:hetionet CHEBI:41977 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0030312 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019158 infores:hetionet CAID:CA10585464 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585464 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 PS4 The NM_000527.5(LDLR):c.1460A>G (p.Asn487Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0000008475 (0.00008475%) in European (non-Finnish) genomes (gnomAD v4.1.0). PP3: REVEL = 0.802. PP4: Variant meets PM2 and is identified in at least 1 index case (1 case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585464/MONDO:0007750/013 2025-02-20 2025-06-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3723 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0700200 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0020649 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003838 infores:hetionet CHEBI:188986 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0041834 infores:hetionet CHEBI:63621 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013362 infores:hetionet CHEBI:83804 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0438717 infores:hetionet CHEBI:6640 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0027497 infores:hetionet CHEBI:17303 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0018790 infores:hetionet CHEBI:31980 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0240211 infores:hetionet CHEBI:119573 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017565 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0042075 infores:hetionet CAID:CA023858 biolink:causes MONDO:0007783 infores:clingen CAID:CA023858 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Glutamic Acid with Glutamine at codon 3583 of the RYR1 protein, p.(Glu3583Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0241, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023858/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3756 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233477 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0241558 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0241558 infores:hetionet CHEBI:7577 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0041657 infores:hetionet NCBIGene:170825 biolink:causes MONDO:0020762 infores:monarchinitiative not_provided not_provided HGNC:24959 MONDO:0020762 uuid:9b158007-d907-46a9-b240-ee93818f4c06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29688 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0151763 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0234458 infores:hetionet CHEBI:64355 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151827 infores:hetionet NCBITaxon:469 biolink:causes MONDO:0006635 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:469 MONDO:0006635 CHEBI:44032 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0340865 infores:hetionet NCBIGene:11198 biolink:causes MONDO:0859179 infores:monarchinitiative not_provided not_provided HGNC:11465 MONDO:0859179 uuid:518a5ba1-8c38-4767-9f95-afdcbb82da1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0456909 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0034150 infores:hetionet CHEBI:28593 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0008031 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0004093 infores:hetionet CHEBI:32293 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0021368 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0018799 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0030305 infores:hetionet CHEBI:51860 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0030193 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0234894 infores:hetionet CHEBI:31859 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C3263723 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0027769 infores:hetionet NCBIGene:5631 biolink:causes MONDO:0010699 infores:monarchinitiative not_provided not_provided HGNC:9462 MONDO:0010699 uuid:d7f99f47-1b2e-423d-95d2-9d90e09dbd03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010037 infores:hetionet CHEBI:83804 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235660 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0277884 infores:hetionet NCBIGene:3032 biolink:causes MONDO:0958185 infores:monarchinitiative not_provided not_provided HGNC:4803 MONDO:0958185 uuid:d12e83c2-cb66-4dc5-b6f4-7efadc4e82f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31981 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0020621 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0031542 infores:hetionet CHEBI:47381 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0004604 infores:hetionet CHEBI:9599 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C2830004 infores:hetionet CHEBI:3723 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036396 infores:hetionet CHEBI:38940 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0019080 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0233632 infores:hetionet CAID:CA401327117 biolink:causes MONDO:0009290 infores:clingen CAID:CA401327117 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.2740C>T (p.Gln914Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon (PTC) in biologically-relevant-exon 19/20, in a gene in which loss-of-function is an established disease mechanism. While the PTC occurs in the penultimate exon of GAA, it is still predicted to lead to nonsense mediated decay (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 456415). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401327117/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5847 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0003123 infores:hetionet GO:2000790 biolink:causes GO:0030324 infores:ubergraph knowledge_assertion manual_agent GO:2000790 GO:0030324 CHEBI:8713 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0009450 infores:hetionet CAID:CA10583404 biolink:causes MONDO:0007648 infores:clingen CAID:CA10583404 MONDO:0007648 PMID:25123297 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS4, BS3, BP5, BP7, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.220C>T p.(Arg74Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000288456.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583404/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf GO:0061058 biolink:causes GO:0042742 infores:ubergraph knowledge_assertion manual_agent GO:0061058 GO:0042742 CHEBI:28445 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0917801 infores:hetionet CHEBI:8426 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0038325 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0013220 infores:hetionet CHEBI:3441 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020615 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0853149 infores:hetionet CHEBI:4735 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0015672 infores:hetionet CHEBI:61049 biolink:causes UMLS:C3495916 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3495916 infores:hetionet CHEBI:205919 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0151514 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0521503 infores:hetionet CHEBI:6931 biolink:causes HP:0002781 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0740852 infores:hetionet CHEBI:31949 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0027497 infores:hetionet CHEBI:3698 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0006277 infores:hetionet CHEBI:3485 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0151904 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0034882 infores:hetionet CHEBI:46557 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0030252 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0948226 infores:hetionet CAID:CA396471928 biolink:causes MONDO:0007648 infores:clingen CAID:CA396471928 MONDO:0007648 PMID:29798843 Likely Pathogenic PS3_Supporting, PM5_Supporting, PM2_Supporting, PVS1_Strong BS1, BS4, BS3, BP5, BP7, PM6, PM1, PM3, PM4, BS2, PP4, PP1, PP2, PP3, BA1, BP1, BP4, BP2, BP3, PS4, PS2, PS1 The c.2440-2A>G variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal splicing (PS3_Moderate; SCV000700319.2). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS3_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396471928/MONDO:0007648/007 2023-08-30 2023-08-30 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf NCBIGene:51135 biolink:causes MONDO:0011888 infores:monarchinitiative not_provided not_provided HGNC:17967 MONDO:0011888 uuid:7229772c-75c2-453b-aa1c-b03e28da7336 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0404521 infores:hetionet CHEBI:135939 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0151517 infores:hetionet CHEBI:4315 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0033774 infores:hetionet CHEBI:4995 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0424790 infores:hetionet GO:0030057 biolink:causes MONDO:0006594 infores:ubergraph knowledge_assertion manual_agent GO:0030057 MONDO:0006594 CHEBI:8694 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C1306341 infores:hetionet CHEBI:100241 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0340865 infores:hetionet CHEBI:7496 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0027497 infores:hetionet NCBIGene:2707 biolink:causes MONDO:0033010 infores:monarchinitiative not_provided not_provided HGNC:4285 MONDO:0033010 uuid:e7b38e40-4f66-4777-ad54-1aaeb3f41ab3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0014457 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0574067 infores:hetionet CHEBI:16914 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0004096 infores:hetionet CHEBI:10124 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0686347 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0006277 infores:hetionet CHEBI:7986 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0008372 infores:hetionet CHEBI:37941 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0423791 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027765 infores:hetionet CHEBI:8093 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0151799 infores:hetionet CHEBI:3764 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0151766 infores:hetionet CHEBI:7465 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0038999 infores:hetionet CHEBI:8461 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0027849 infores:hetionet CHEBI:474180 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0043144 infores:hetionet NCBIGene:3516 biolink:causes MONDO:0013895 infores:monarchinitiative not_provided not_provided HGNC:5724 MONDO:0013895 uuid:8c9cbe0d-97da-4933-a93d-5b56dcd6ef73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0853692 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027651 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0340726 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042075 infores:hetionet CHEBI:9587 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0332534 infores:hetionet CHEBI:9139 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014724 infores:hetionet CHEBI:2618 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0023518 infores:hetionet CHEBI:8461 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0033774 infores:hetionet CHEBI:6062 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0030252 infores:hetionet CHEBI:31515 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0015230 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0085649 infores:hetionet CHEBI:5118 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0232849 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0029882 infores:hetionet CHEBI:6129 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1761613 infores:hetionet CHEBI:63598 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0008031 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0521491 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0027765 infores:hetionet CHEBI:30830 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0085593 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0025202 infores:hetionet CHEBI:63580 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0424790 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0151735 infores:hetionet CHEBI:9943 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007398 infores:hetionet CHEBI:8863 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0947912 infores:hetionet CHEBI:75722 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C3263723 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0746883 infores:hetionet CHEBI:9635 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0011603 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0021775 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151883 infores:hetionet CHEBI:8228 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0017979 infores:hetionet CHEBI:6062 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085649 infores:hetionet CAID:CA10585384 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585384 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, PS3, PM5, PP3 The NM_000527.5 (LDLR):c.1283A>G (p.Asn428Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 17 April 2024.The supporting evidence is as follows:PM2: Variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfills MedPed criteria for FH after alternative causes of high cholesterol were excluded, reported in PMID 16627557 (Blesa et al., 2006), Spain. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585384/MONDO:0007750/013 2024-04-17 2024-10-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UMLS:C0011701 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0042373 infores:hetionet CAID:CA021951 biolink:causes MONDO:0005045 infores:clingen CAID:CA021951 MONDO:0005045 PMID: Likely Pathogenic PM5, PP3, PS4_Supporting, PM2_Supporting, PS2 BS4, PM1, PM6, PP1, PS1, PS3 NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys) - This variant has been reported in individuals with HCM and RCM (LMM data, PMIDs: 20800588, 21533915) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >5]. Therefore, the PS4_Supporting criterion has been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been confirmed as de novo in multiple occurrences (PS2; LMM data). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PMID: 30696458); however, PM1 cannot be applied in combination with PM5. Another variant involving this codon (p.Arg193His) has been identified in individuals with HCM and is classified as pathogenic in ClinVar/this VCEP (PM5). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Likely Pathogenic for HCM in an autosomal dominant manner based on PS4_Supporting, PM2_Supporting, PS2, PM5, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA021951/MONDO:0005045/098 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3752 biolink:causes UMLS:C0231557 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0231557 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0700345 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0033774 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018790 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0026846 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0221203 infores:hetionet CHEBI:80630 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0016382 infores:hetionet CHEBI:5103 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0344315 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0031350 infores:hetionet NCBIGene:56683 biolink:causes MONDO:0014211 infores:monarchinitiative not_provided not_provided HGNC:1301 MONDO:0014211 uuid:5e448823-7b33-4e2a-84cc-6e27dec442ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5551 biolink:causes MONDO:0011508 infores:monarchinitiative not_provided not_provided HGNC:9360 MONDO:0011508 uuid:afb49650-18ea-4ef0-a767-6e58bc6cb656 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84883 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0032285 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0006849 infores:hetionet CAID:CA10014279 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014279 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.869C>G (p.Ser290Cys) is a missense variant in exon 8 (of 9). This variant has not been observed in any population according to gnomAD (PM2_Supporting). The nucleotide substitution is not predicted to disrupt splicing (SpliceAI score = 0.00), and the amino acid change is permissive (REVEL score 0.175, < 0.5). Functional evidence is not available in the literature, and there are no published cases with this variant. In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014279/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5296 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0151786 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007222 infores:hetionet CHEBI:6710 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0023530 infores:hetionet CHEBI:44423 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0151723 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0006147 infores:hetionet CHEBI:28177 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0032343 infores:hetionet CHEBI:44032 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020433 infores:hetionet CHEBI:7936 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0220870 infores:hetionet CHEBI:36791 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2979982 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0221776 infores:hetionet CHEBI:144093 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0206061 infores:hetionet CHEBI:63638 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1306341 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020615 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0853777 infores:hetionet CHEBI:28925 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0162627 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0521490 infores:hetionet GO:0031284 biolink:causes GO:0006182 infores:ubergraph knowledge_assertion manual_agent GO:0031284 GO:0006182 CHEBI:9943 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0231528 infores:hetionet CAID:CA10604828 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604828 MONDO:0015152 PMID: Likely Pathogenic PM5_Supporting, PP3, PP4, PM2_Supporting, PM3_Strong PM4, PM1, PM6, PVS1, BP1, BP4, BP3, BP2, BA1, BS2, PP2, PP1, BP7, BP5, BS1, BS3, BS4, PS1, PS3, PS4, PS2 The NM_000070.3: c.1256A>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 419 (p.Asp419Gly). This variant has been detected in at least 5 individuals with limb girdle muscular dystrophy (PMID: 18055493, 30564623, ClinVar SCV003828989.2, Washington University internal clinic data communication), including in unknown phase with a pathogenic variant (c.643_663del p.(Ser215_Gly221del), 0.5 pts, PMID: 18055493; c.756_758del p.(Lys254del) x2, 1.0 pts, PMID: 30564623; Washington University internal clinic data communication) and confirmed in trans with a likely pathogenic or pathogenic variant (c.2440-1G>A, 1.0 pt, ClinVar SCV003828989.2 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4; PMID: 18055493). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113712 exome alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.98, which exceeds the threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1257T>G p.(Asp419Glu), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Strong, PP4, PM2_Supporting, PP3, PM5_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604828/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2687 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0235431 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0025061 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0041912 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1384666 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0231528 infores:hetionet NCBITaxon:784 biolink:causes MONDO:0019365 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:784 MONDO:0019365 CHEBI:16899 biolink:causes UMLS:C1961112 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1961112 infores:hetionet CHEBI:3387 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0026821 infores:hetionet CAID:CA6748767 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748767 MONDO:0009861 PMID: Uncertain Significance PM2, PM5, PP3, BP4, BS1 The NM_000277.3:c.1010G>A variant in PAH is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 337 (p.Gly337Glu). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4 is 0.0007575 in the East Asian population, which is higher than the ClinGen PAH VCEP’s threshold for PM2 (<0.0002), but lower than the threshold for BS1 (>0.002). The computational predictor REVEL gives a score of 0.531 which is neither above nor below the thresholds predicting a damaging (≥0.644) or benign (≤0.183) impact on PAH function. There is a ClinVar entry for this variant (Variation ID: 763076, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748767/MONDO:0009861/006 2025-04-18 2025-04-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3696 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0039070 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0013395 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009782 infores:hetionet CHEBI:7496 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0740394 infores:hetionet NCBIGene:26249 biolink:causes MONDO:0013781 infores:monarchinitiative not_provided not_provided HGNC:6354 MONDO:0013781 uuid:5342b1fc-b333-4e02-8001-791b3c8d86ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0231365 infores:hetionet CHEBI:40279 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042963 infores:hetionet CAID:CA414779707 biolink:causes MONDO:0044970 infores:clingen CAID:CA414779707 MONDO:0044970 PMID: Likely Benign BP2, BP4 BS2, PM2 The m.5293G>A (p.S275N) variant in MT-ND2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is present in 1/49,487 sequences (1/509 in H1c) in Genbank per MITOMAP queried 10/29/2019. This variant is seen at homoplasmy in a proband, healthy brother, and healthy mother (PMID: 23813926). The proband had a pathogenic mtDNA variant, m.14487T>C, present at high heteroplasmy levels (BP2). The proband was particularly severe having Leigh syndrome at 6 months old however the m.5293G>A variant is homoplasmic in all family members including healthy individuals. Of note, this family is haplogroup H1 as is report in GenBank sequences. Additionally, the computational predictor APOGEE gives a consensus rating of neutral with a low pathogenicity predictor score, 0.46 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). In summary, this variant meets criteria to be classified as likely benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP2, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414779707/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4814 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0019348 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0039971 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005790 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0019159 infores:hetionet CHEBI:7825 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C2242996 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0948594 infores:hetionet CHEBI:8707 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0149745 infores:hetionet CHEBI:47426 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0260662 infores:hetionet CHEBI:7454 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0015230 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0033860 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0277925 infores:hetionet GO:0044742 biolink:causes GO:0019233 infores:ubergraph knowledge_assertion manual_agent GO:0044742 GO:0019233 CHEBI:32020 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0037763 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020557 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017178 infores:hetionet CHEBI:167638 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0080274 infores:hetionet CAID:CA16620824 biolink:causes MONDO:0100150 infores:clingen CAID:CA16620824 MONDO:0100150 PMID: Likely Pathogenic PP3, PM4, PS4_Supporting, PM2_Supporting, PS2 The c.958_960del (NM_000540.2(RYR1):c.958_960del) variant is predicted to cause a change in the length of the protein (p.Glu320del) due to an in-frame deletion of 1 amino acid in a non-repeat region (PM4). This variant is absent from gnomAD v4.1.0 (PM2_supporting). The computational predictor SpliceAI gives scores of 1.00 and 0.94 for acceptor loss and gain, which are both above the threshold of 0.5, evidence that correlates with impact to RYR1 function (PP3). This variant has been reported in 2 probands with clinical features of RYR1-related myopathy (PS4_supporting; PMID: 23919265, LabCorp Genetics internal data). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with RYR1-related myopathy (PS2; PMID: 23919265). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM4, PM2_ supporting, PP3, PS4_supporting, PS2 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 11/18/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620824/MONDO:0100150/150 2024-11-18 2025-04-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31981 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0425945 infores:hetionet CHEBI:136040 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0017168 infores:hetionet CHEBI:6754 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0011124 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042571 infores:hetionet CHEBI:9654 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0022281 infores:hetionet CHEBI:48390 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0015967 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0031350 infores:hetionet CHEBI:68647 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0040822 infores:hetionet CHEBI:60761 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0162830 infores:hetionet CHEBI:7601 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0030193 infores:hetionet CHEBI:47381 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022346 infores:hetionet NCBITaxon:622 biolink:causes MONDO:0019345 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:622 MESH:D004405 DB01059_MESH_D004405_1 CHEBI:64312 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0231528 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0039971 infores:hetionet CHEBI:27834 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C3665347 infores:hetionet CHEBI:404903 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0278061 infores:hetionet CHEBI:119915 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014236 infores:hetionet CHEBI:6710 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0024141 infores:hetionet CHEBI:63632 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0008033 infores:hetionet NCBIGene:8443 biolink:causes MONDO:0009112 infores:monarchinitiative not_provided not_provided HGNC:4416 MONDO:0009112 uuid:bd3054d4-60a3-4cc6-ad5e-75a32d7599a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0017168 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009324 infores:hetionet CHEBI:3996 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0011253 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0158281 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0158281 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0027813 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0041912 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007547 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014511 infores:hetionet CAID:CA377781810 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781810 MONDO:0017623 PMID:32350270PMID:29785012PMID:29706350PMID:32366478 Pathogenic PS2_Very Strong, PM2, PS3_Supporting, PP2, PS4_Moderate PTEN c.16A>G (p.Lys6Glu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: One proven plus two assumed de novo observations in a patient with the disease and no family history. (internal laboratory contributor(s) SCV001369131.2, SCV001819316.1)PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) SCV001819316.1)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 32366478, PMID 32350270, PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781810/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28918 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0037274 infores:hetionet CAID:CA214197 biolink:causes MONDO:0000572 infores:clingen CAID:CA214197 MONDO:0000572 PMID: Uncertain Significance PM1_Supporting PM2 NM_000448.3(RAG1):c.2603C>T is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 868 (p.Ala868Val). This missense variant is located in the core domain (amino acids 387-1011) (PM1_Supporting). The highest population minor allele frequency in gnomAD v4 is 0.0001585 (187/1180040) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214197/MONDO:0000572/123 2024-02-12 2024-02-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63580 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020557 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0917801 infores:hetionet CHEBI:3371 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C1720775 infores:hetionet CHEBI:2673 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0027769 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0085119 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085119 infores:hetionet CHEBI:63791 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0740394 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0234215 infores:hetionet CAID:CA8602880 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602880 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 After a comprehensive literature search, the NM_000419.5(ITGA2B):c.1958C>T (p.Pro653Leu) variant has not been identified in any individuals with Glanzmann thrombasthenia. The variant is has a low minor allele frequency, the highest being 0.000008914 (1/112184 alleles) in the European (Non-Finnish) population (<1/10,000; PM2_supporting). The computational predictor REVEL gives a score of 0.217, predicting no deleterious effect on gene function (BP4). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting and BP4 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602880/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6339 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0853034 infores:hetionet UMLS:C0209366 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0332575 infores:hetionet CHEBI:8485 biolink:causes UMLS:C0920192 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0920192 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0021843 infores:hetionet CAID:CA399804774 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804774 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3 PM3 The NM_000419.5(ITGA2B):c.959T>C variant in ITGA2B is a missense variant predicted to cause substitution of Phenylalanine by Serine at amino acid 320 (p.Phe320Ser). At least one patient (Patient 1 in PMID: 9722314) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5% of normal, as measured by flow cytometry (PP4_Moderate). Surface expression of αIIbβ3 measured by flow cytometry in CHO cells transiently co-transfected with c.959T>C (p.Phe320Ser) variant αIIb and wild type β3 showed decreased expression at 3% WT levels, indicating that this variant impacts protein function (PMID: 9722314)(PS3). The computational predictor REVEL gives a score of 0.885, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804774/MONDO:0100326/011 2023-08-15 2023-09-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:45367 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0522153 infores:hetionet CHEBI:9654 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0004245 infores:hetionet CHEBI:8404 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0549249 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004238 infores:hetionet NCBIGene:2077 biolink:causes MONDO:0010929 infores:monarchinitiative not_provided not_provided HGNC:3444 MONDO:0010929 uuid:9c9296a9-9c70-4806-a8cf-66e3d40bed08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7986 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0002874 infores:hetionet GO:0060127 biolink:causes CL:0000439 infores:ubergraph knowledge_assertion manual_agent GO:0060127 CL:0000439 CAID:CA2573051046 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051046 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4 PP1 The c.1840_1841del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 614, adding 34 novel amino acids before encountering a stop codon (p.(Asn614ProfsTer34) in NM_000545.8. While this variant, located 5' of c.1854 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family with MODY; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1840_1841del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1_Strong, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051046/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71219 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0026858 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0036572 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0040409 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0178298 infores:hetionet CHEBI:71223 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0010200 infores:hetionet CHEBI:8481 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0037036 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0000833 infores:hetionet CHEBI:51450 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0014457 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0034186 infores:hetionet CHEBI:68642 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0239783 infores:hetionet CHEBI:41879 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042907 infores:hetionet CHEBI:585948 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0022107 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521495 infores:hetionet UMLS:C0120107 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0003862 infores:hetionet CHEBI:2704 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0700590 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0014457 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0003864 infores:hetionet CHEBI:9073 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0011603 infores:hetionet CHEBI:27786 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0020621 infores:hetionet CHEBI:16335 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0235710 infores:hetionet CHEBI:45863 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0021845 infores:hetionet CHEBI:4511 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0231218 infores:hetionet CHEBI:31624 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0024437 infores:hetionet NCBIGene:9693 biolink:causes MONDO:0054847 infores:monarchinitiative not_provided not_provided HGNC:16854 MONDO:0054847 uuid:81e7da18-fc70-495f-b252-c2a3d71d9052 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0013404 infores:hetionet CAID:CA114368 biolink:causes MONDO:0009861 infores:clingen CAID:CA114368 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Supporting PM5 The c.293T>C (p.Leu98Ser) variant in PAH has been reported as homozygous in a Pakistani patient with mild PKU (BH4 deficiency excluded) (PMID: 8364546, 9634518, 26542770) This variant has an extremely low frequency in gnomAD v2.1.1 (MAF=0.0001307). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114368/MONDO:0009861/006 2022-01-14 2022-01-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64355 biolink:causes UMLS:C1331537 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1455780 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020621 infores:hetionet CHEBI:32315 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0012569 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0852908 infores:hetionet CHEBI:44185 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0038325 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0236053 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0236053 infores:hetionet CHEBI:135925 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0038325 infores:hetionet CHEBI:5134 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0040822 infores:hetionet CHEBI:49575 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0035455 infores:hetionet CHEBI:180905 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0016382 infores:hetionet CHEBI:5141 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0039231 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0040034 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0948586 infores:hetionet CHEBI:9907 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0039231 infores:hetionet GO:0048374 biolink:causes GO:0048368 infores:ubergraph knowledge_assertion manual_agent GO:0048374 GO:0048368 CHEBI:3647 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0236071 infores:hetionet CHEBI:5441 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0085605 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0233494 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0030193 infores:hetionet CHEBI:15551 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0023067 infores:hetionet CAID:CA359427024 biolink:causes MONDO:0012163 infores:clingen CAID:CA359427024 MONDO:0012163 PMID: Uncertain Significance PM2_Supporting NM_002185.5(IL7R):c.205C>G is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 69 (p.Leu69Val). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359427024/MONDO:0012163/119 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9649 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042023 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0002871 infores:hetionet CHEBI:6067 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0311468 infores:hetionet CHEBI:408174 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0025222 infores:hetionet CHEBI:15366 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB03166 UMLS:C0030193 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013295 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0857448 infores:hetionet CHEBI:51364 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151907 infores:hetionet CHEBI:47657 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0017152 infores:hetionet CHEBI:64317 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0917801 infores:hetionet CHEBI:39585 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0030807 infores:hetionet CHEBI:9599 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1142412 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0859350 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0859350 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0024528 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0024528 infores:hetionet CAID:CA6904346 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904346 MONDO:0019497 PMID: Likely Pathogenic BS1, PS3_Supporting, PP1, PM3_Very Strong BP7, BP5, BS3, BS4, BS2, PP3, PP2, PP4, PM4, PM1, PM5, PM2, PVS1, PM6, BP4, BP1, BP2, BP3, BA1, PS4, PS2, PS1 The filtering allele frequency of the c.-22-2A>C variant in the GJB2 gene is 0.35% for Ashkenazi Jewish chromosomes in gnomAD v2.1.1 (95% CI of 47/10344), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. The c.-22-2A>C variant in the GJB2 gene has been detected in at least 9 patients with hearing loss in trans with the pathogenic c.35delG variant (PM3_Very Strong; PMID: 25401782, 24039984, 33096615; Invitae internal data, SCV000935680.2; Children’s Hospital of Philadelphia internal data, Molecular Otolaryngology and Renal Research Laboratories internal data) and one individual with the the p.Leu90Pro variant suspected in trans (PMID: 19814620). Phase was confirmed in at least 6 of these 10 observations.This variant has been reported to segregate with hearing loss in at least 2 family members (PP1; PMID: 24039984). It was also identified in the heterozygous state without a second variant in 8 individuals with hearing loss, and in the biallelic state (with c.35delG) in one individual with reportedly normal hearing (GeneDx, ARUP internal data, SCV000680741.2, SCV000603828.1). Of note, the severity of hearing loss is reported to be mild-moderate in affected probands, some with onset in the third to fourth decade, suggesting that this variant may be a hypomorphic allele. RNA analysis using patient cells demonstrated that the c.-22-2A>C variant leads to expression of a novel GJB2 transcript with a slightly longer 5' UTR but otherwise normal coding region. The alternate transcript was shown to have reduced expression, but it is not clear if the lower expression is sufficient to lead to a phenotype (PS3_Supporting; PMID: 24039984). In summary, the VCEP has used expert judgement to classify this variant as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Very Strong, PP1, PS3_Supporting, BS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904346/MONDO:0019497/005 2021-04-12 2024-01-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:71417 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0518015 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0040034 infores:hetionet CHEBI:6538 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0042963 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0043251 infores:hetionet GO:1903903 biolink:causes GO:0042110 infores:ubergraph knowledge_assertion manual_agent GO:1903903 GO:0042110 CHEBI:6775 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0038362 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0235524 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0235524 infores:hetionet CHEBI:465284 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013456 infores:hetionet CHEBI:45081 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0231528 infores:hetionet CHEBI:17650 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0043094 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009450 infores:hetionet CHEBI:135939 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0558401 infores:hetionet CHEBI:7640 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0234708 infores:hetionet CHEBI:3636 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0041834 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005659 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0035459 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0233494 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0027947 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0011570 infores:hetionet CHEBI:28748 biolink:causes HP:0031657 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0577822 infores:hetionet CAID:CA252228 biolink:causes MONDO:0019501 infores:clingen CAID:CA252228 MONDO:0019501 PMID:9624053PMID:20440071PMID:9624053PMID:20440071PMID:18665195PMID:18641288PMID:9624053PMID:20440071PMID:15325563PMID:18641288PMID:18665195PMID:9624053PMID:20440071PMID:15325563PMID:18641288PMID:18665195PMID:9624053PMID:20440071PMID:15325563PMID:20613545PMID:10729113 Pathogenic PP1_Moderate, PP4, PM3_Very Strong, PM2, PVS1 BP5, BP7, BS4, BS1, BS2, PP3, PM1, PM4, PM5, PM6, BP2, BP3, BP4, BA1, PS2, PS4, PS3, PS1 The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID: 20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA252228/MONDO:0019501/005 2018-09-25 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CAID:CA274532 biolink:causes MONDO:0044970 infores:clingen CAID:CA274532 MONDO:0044970 PMID: Uncertain Significance PP1, PM2_Supporting, PS3_Supporting PP3, PS2, PS4, PM6 The m.5610G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease to date, in a 69-year-old woman with progressive limb girdle muscle weakness, dysarthria, and myopathic facies. Ragged red fibers and COX-negative fibers were noted on muscle biopsy. The variant was present at 91% heteroplasmy in muscle and 87% heteroplasmy in blood (PMID: 25873012). The variant was present at lower (9-26% heteroplasmy) to undetectable levels in healthy family members although this expert panel notes some of these family members were not yet the age of the proband when she began to experience symptoms (PP1; PMID: 25873012). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (98%; n=20) than in COX-positive fibers (78%; n=21, P = 0.0002; PS3_supporting, PMID: 25873012). Additionally, studies have shown decreased steady-state levels of tRNA Alanine in muscle from the proband (PMID: 25873012). Computational predictors are discordant as MitoTIP suggests this variant is benign (38.7 percentile) and HmtVAR predicts it to be pathogenic (0.55). Of note, this variant is highly conserved among primates at 83%. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274532/MONDO:0044970/015 2024-02-12 2024-07-31 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:7306 biolink:causes MONDO:0008747 infores:monarchinitiative not_provided not_provided HGNC:12450 MONDO:0008747 uuid:35b70024-71ed-417b-99dd-511541aa69d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA342802293 biolink:causes MONDO:0021060 infores:clingen CAID:CA342802293 MONDO:0021060 PMID: Uncertain Significance PP3, PM2 The c.367C>T (p.Arg123Cys) variant in RIT1 was absent in gnomAD v2.1.1 and present in 0.00001% (3/38022 CI 95%) of non-Finnish European chromosomes in gnomAD v3.1.1 (No population codes met). The computational predictor REVEL gives a score of 0.422, which is neither above nor below the thresholdspredicting a damaging or benign impact on RIT1 function (no codes met). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP guidelines (Version 2.1; 09/27/24). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA342802293/MONDO:0021060/047 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4888 biolink:causes MONDO:0003397 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0017567 infores:hetionet CAID:CA415079397 biolink:causes MONDO:0010305 infores:clingen CAID:CA415079397 MONDO:0010305 PMID: Likely Pathogenic PS3_Supporting, PM2_Supporting, PP4_Strong PP3, PP1, BP4 "The NM_005629.4:c.619C>T (p.Arg207Trp) variant in SLC6A8 is a missense variant predicted to result in the substitution of arginine by tryptophan at amino acid 207 (p.Arg207Trp). One male patient has been described with this variant and with clinical symptoms consistent with creatine transporter deficiency, absent creatine peak on MRS, elevated creatine in urine, and <10% creatine uptake in fibroblasts (PP4_Strong). His mother was confirmed to be heterozygous, ""low functioning"" and with normal urine creatine. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). When expressed in HeLa cells, the variant resulted in impaired creatine transport with 2 mM unlabeled substrate (PMID: 27408820). Based on review of this data by the ClinGen CCDS VCEP, this data meets PS3_Supporting. The computational predictor REVEL gives a score of 0.578 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. There is a ClinVar entry for this variant (Variation ID: 211026). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications version 1.1.0): PP4_Strong, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023)." Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415079397/MONDO:0010305/027 2023-03-09 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:3696 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0178298 infores:hetionet CHEBI:28939 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0151827 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0012739 infores:hetionet NCBIGene:3708 biolink:causes MONDO:0008795 infores:monarchinitiative not_provided not_provided HGNC:6180 MONDO:0008795 uuid:f5238b68-d253-4091-aa58-a6abd2b5118c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA232911 biolink:causes MONDO:0010726 infores:clingen CAID:CA232911 MONDO:0010726 PMID: Benign BP2, BA1 PP4 The p.Pro390_Pro391del variant in MECP2 (NM_004992.3) has been reported in an individual with intellectual disability (PMID 21982064). The allele frequency of the p.Pro390_Pro391del variant in MECP2 is 0.1158% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Pro390_Pro391del variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID: 23696494) (BP2). In summary, the p.Pro390_Pro391del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA232911/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:5118 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0856054 infores:hetionet CAID:CA915940322 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940322 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM4, PM3, PM2_Supporting The NM_000419.5(ITGA2B):c.3091del variant causes a frameshift and subsequent stop loss, Leu1031TrpfsTer97. This results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain (PM4). This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patient (Patient GT10 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry (PP4_strong). GT10 of PMID: 25373348 is compound heterozygous for the paternal c.1210+105A>G (classified Likely Pathogenic by the PD-EP) and the maternal c.3091delC variants (PM3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3, PM4. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940322/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBITaxon:5475 biolink:causes MONDO:0044070 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D058387 DB00681_MESH_D058387_1 CHEBI:47519 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0011606 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0009806 infores:hetionet CHEBI:9927 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0010200 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151609 infores:hetionet UBERON:0004347 biolink:causes UBERON:0003081 infores:ubergraph knowledge_assertion manual_agent UBERON:0004347 UBERON:0003081 CHEBI:50922 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0010520 infores:hetionet NCBIGene:8893 biolink:causes MONDO:0957873 infores:monarchinitiative not_provided not_provided HGNC:3261 MONDO:0957873 uuid:ac46a21b-d9d2-4543-b867-1f6ff74baab1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226501 biolink:causes MONDO:0100368 infores:clingen CAID:CA226501 MONDO:0100368 PMID:16150724 Benign BA1, BS3_Supporting, BS2 BP4, PS3, PP3 The NM_000329.3(RPE65):c.1301C>T (p.Ala434Val) missense variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.07646, with 1976 alleles / 24962 total alleles in the African / African-American population with 72 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant has been reported in at least one patient with retinal dystrophy, however the phenotype is not specific to RPE65 and no second variant was described in trans (PMID: 9501220). Three separate publications on families who carry this variant have reported unaffected individuals who harbor it in homozygous state (PMID: 19431183, PMID: 9501220, PMID: 19920137, BS2). The computational predictor REVEL gives a score of 0.418, which is below the ClinGen LCA / eoRD VCEP threshold of ≥ 0.7 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.14, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant exhibited 110% or 55% enzymatic activity in two retinoid isomerase assays relative to the wild-type control, which are higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves normal protein function (PMID: 19431183, PMID: 16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226501/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:47898 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085641 infores:hetionet CHEBI:8707 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235086 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0152227 infores:hetionet CHEBI:63791 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085077 infores:hetionet NCBIGene:9313 biolink:causes MONDO:0012926 infores:monarchinitiative not_provided not_provided HGNC:7167 MONDO:0012926 uuid:2a470ac7-8163-400b-86bc-7267583b68a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135888 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0007137 infores:hetionet CAID:CA410203594 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203594 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP7, PM5, PM4, PM3, PP4, PP2, PP1, BS2 NM_001754.5(RUNX1):c.299C>T (p.Ser100Phe) is a missense variant which has a REVEL score ≥ 0.88 (0.955) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_Supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 39822584). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_Supporting, PM2_Supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203594/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6339 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0149744 infores:hetionet CHEBI:16796 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0020625 infores:hetionet CHEBI:7903 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0086565 infores:hetionet CHEBI:48669 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0042963 infores:hetionet CAID:CA6572962 biolink:causes MONDO:0010880 infores:clingen CAID:CA6572962 MONDO:0010880 PMID: Likely Benign BS1, PP3 The NM_000020.3: c.652C>T variant in ACVRL1 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 218 (p.Arg218Trp). The filtering allele frequency (the lower threshold of the 95% CI of 54/19950) of the c.652C>T variant in ACVRL1 is 0.002551 for East Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.816, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, PP3 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA6572962/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:39669 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0015230 infores:hetionet GO:0035987 biolink:causes CL:0000223 infores:ubergraph knowledge_assertion manual_agent GO:0035987 CL:0000223 CHEBI:367163 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0162298 infores:hetionet CHEBI:15367 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085641 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151736 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0861149 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0861149 infores:hetionet CHEBI:7936 biolink:causes HP:0000164 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040427 infores:hetionet CHEBI:16755 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013182 infores:hetionet CAID:CA10606659 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606659 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.1071del p.(Ser358LeufsTer17) variant in DYSF, which is also known as NM_001130987.2: c.1167del (p.Ser390LeufsTer17), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 12/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in one individual with a pathogenic variant in unknown phase (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 36983702) (PM3_Supporting). This patient displayed progressive muscle weakness and disease range dysferlin expression in blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/06/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606659/MONDO:0015152/180 2025-10-06 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4315 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0851578 infores:hetionet NCBIGene:778 biolink:causes MONDO:0010241 infores:monarchinitiative not_provided not_provided HGNC:1393 MONDO:0010241 uuid:43dfe65b-8a13-4bea-991b-d7a1790c3f72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0000731 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0476089 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0234215 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0595878 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233414 infores:hetionet CHEBI:28001 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0085932 infores:hetionet CAID:CA015719 biolink:causes MONDO:0005045 infores:clingen CAID:CA015719 MONDO:0005045 PMID:31130376PMID:31130376 Likely Pathogenic PM2, PP3, PS4_Moderate, PP1_Moderate PM4, PM1, PM6, PM5, BA1, PS3, PP4, BS1, BS3, BS4, PS2, PS1, BP4, BP7, BP2, BP5 The c.5134C>T (p.Arg1712Trp) variant in MYH7 has been reported in the heterozygous state in at least 13 individuals with HCM, 2 of whom also had additional variants in other HCM-associated genes (PS4_Moderate; Hougs 2005 PMID:15483641; Gruner 2011 PMID:21511876; Jensen 2013 PMID:23197161; Hagen 2013 PMID:24498601; Mu 2019 https://www.actamedicamediterranea.com/archive/2019/medica-5/pathogenic-mutation-detection-and-correlation-analysis-between-genotype-and-phenotype-of-familial-hypertrophic-cardiomyopathy-in-chinese-han-nationality/pdf; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in at least 6 affected relatives from 4 families (PP1_Moderate; Hougs 2005 PMID:15483641; Mu 2019; Ambry pers comm.; Centenary Institute Sydney pers comm.). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). Data from the gnomAD population database (v2.1.1) is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (PM2; http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate; PM2; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015719/MONDO:0005045/002 2021-06-16 2021-06-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0917801 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0151828 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0011570 infores:hetionet CHEBI:72297 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C1291078 infores:hetionet CHEBI:36791 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085641 infores:hetionet CHEBI:3215 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0037383 infores:hetionet CHEBI:31705 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0428977 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042373 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0332575 infores:hetionet CHEBI:6954 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0235996 infores:hetionet UBERON:0003220 biolink:causes UBERON:0000084 infores:ubergraph knowledge_assertion manual_agent UBERON:0003220 UBERON:0000084 CHEBI:64310 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0428977 infores:hetionet CHEBI:135930 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0014518 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151763 infores:hetionet CHEBI:7601 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0857305 infores:hetionet CHEBI:3994 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0080274 infores:hetionet CHEBI:135939 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0004238 infores:hetionet CHEBI:42797 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014724 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0042373 infores:hetionet CHEBI:94411 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0009806 infores:hetionet CHEBI:50922 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0043352 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0037274 infores:hetionet CHEBI:9137 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040517 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C2242582 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C2242582 infores:hetionet CHEBI:28864 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0014591 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0009450 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0022650 infores:hetionet CHEBI:78320 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0520893 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0020517 infores:hetionet CHEBI:5855 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0268000 infores:hetionet CAID:CA392324303 biolink:causes MONDO:0007947 infores:clingen CAID:CA392324303 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PM1_Strong PVS1, PM6, PP1, BS2, BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS2, PM3, PM4, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.3707G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1236 (p.Cys1236Tyr). This variant has been identified in at least three individuals including two probands with clinical diagnoses of Marfan syndrome, with neonatal onset in one case, and one proband with a highly specific Marfan syndrome phenotype including thoracic aortic aneurysm and dissection (TAAD), ectopia lentis, and systemic features of Marfan syndrome (PS4_moderate, PP4; UZG, Mayo, & Bichat internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.960). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392324303/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9635 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C3665386 infores:hetionet CAID:CA035940 biolink:causes MONDO:0007750 infores:clingen CAID:CA035940 MONDO:0007750 PMID: Likely Benign BS3_Supporting, BS1, PP1_Moderate BP4, BP2, BA1, PS3, PS1, PS2, PS4, BP7, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP3, PP4 The NM_000527.5(LDLR):c.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met.BS3_supporting - 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing.PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells.---- Aberrant transcripts are not detected, so BS3_Supporting is Met.PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met.Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA035940/MONDO:0007750/013 2022-03-16 2022-04-19 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6950 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0022650 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0021053 infores:hetionet NCBIGene:567 biolink:causes MONDO:0009434 infores:monarchinitiative not_provided not_provided HGNC:914 MONDO:0009434 uuid:e2e36bc3-6851-4d10-9b5f-b48675569dcb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0023052 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0521839 infores:hetionet CHEBI:3082 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0038990 infores:hetionet CHEBI:63617 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085633 infores:hetionet CHEBI:6375 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002874 infores:hetionet CHEBI:2469 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0018681 infores:hetionet CHEBI:7936 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018794 infores:hetionet CHEBI:49662 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0018681 infores:hetionet NCBIGene:196 biolink:causes MONDO:0975805 infores:monarchinitiative not_provided not_provided HGNC:348 MONDO:0975805 uuid:4ff2e95e-37b2-467e-a522-1361b75aa7ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0149931 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0042075 infores:hetionet CHEBI:48844 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0030554 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0012833 infores:hetionet CHEBI:7025 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0038999 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042075 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042267 infores:hetionet CHEBI:40279 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0428977 infores:hetionet CHEBI:3756 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235198 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0456909 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002453 infores:hetionet CHEBI:23765 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085593 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0004936 infores:hetionet CAID:CA415167910 biolink:causes MONDO:0010726 infores:clingen CAID:CA415167910 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, BS1, PP3 The p.Glu374Gln variant in MECP2 (NM_004992.4) is observed in at least 3 unaffected individuals (internal database - Invitae, internal database - Ambry) (BS2). The p.Glu374Gln variant is found in a patient with an alternate molecular basis of disease (internal database - Ambry) (BP5). The highest population minor allele frequency of the p.Glu374Gln variant in MECP2 in gnomAD v4.1 is 0.000005595 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Glu374Gln variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415167910/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:2668 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0423791 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0032326 infores:hetionet CHEBI:31236 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0236075 infores:hetionet NCBIGene:6708 biolink:causes MONDO:0007533 infores:monarchinitiative not_provided not_provided HGNC:11272 MONDO:0007533 uuid:bcf0184e-ed96-4f9f-9bb1-4c3cbf1a6eb9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50156 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C1443060 infores:hetionet CHEBI:3423 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0023518 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0151436 infores:hetionet CHEBI:47898 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085680 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0005779 infores:hetionet CHEBI:391960 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0151908 infores:hetionet CHEBI:6690 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0233407 infores:hetionet CHEBI:31413 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0035229 infores:hetionet CHEBI:31859 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151786 infores:hetionet CAID:CA2695216034 biolink:causes MONDO:0015628 infores:clingen CAID:CA2695216034 MONDO:0015628 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM4 The NM_000552.5(VWF):c.4678_4680dup (p.Asp1560_Ile1561insAsp) variant is predicted to cause a change in the length of the protein due to an in-frame insertion of 1 amino acid in a non-repeat region (PM4). It is absent from gnomADv4.1 (PM2_supporting). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of very low VWF activity (VWF:Rco 5 U/dL), low activity/VWF:Ag ratio (0.26), and loss of high molecular weight multimers, which is highly specific for VWD type 2A. (PP4_Moderate, PMID: 28971901). In summary, this variant classifies as uncertain significance based on ACMG criteria as specified by the VWD VCEP: PM4, PM2_supporting, and PP4_Moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695216034/MONDO:0015628/081 2024-09-03 2024-09-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:84883 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0008031 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0948594 infores:hetionet CHEBI:9738 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0015967 infores:hetionet CHEBI:2666 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0043094 infores:hetionet CHEBI:63631 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0149871 infores:hetionet CHEBI:408174 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0017178 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0027497 infores:hetionet CHEBI:47381 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003467 infores:hetionet CHEBI:171719 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1443060 infores:hetionet CHEBI:5855 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014591 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020538 infores:hetionet NCBIGene:7701 biolink:causes MONDO:0032741 infores:monarchinitiative not_provided not_provided HGNC:12927 MONDO:0032741 uuid:29dbff98-bc2d-4046-9089-9b834bb3dc82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51164 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0497327 infores:hetionet CHEBI:5109 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0009450 infores:hetionet CHEBI:6030 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0086565 infores:hetionet CHEBI:7581 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0042024 infores:hetionet CHEBI:63791 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042963 infores:hetionet CHEBI:52010 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0917801 infores:hetionet CHEBI:7581 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0151786 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0006849 infores:hetionet CHEBI:9352 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0522153 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0020651 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0853875 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0861157 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0861157 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853089 infores:hetionet CHEBI:3568 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0032231 infores:hetionet CHEBI:61058 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0151480 infores:hetionet CAID:CA638054560 biolink:causes MONDO:0011071 infores:clingen CAID:CA638054560 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.98-148_98-147dup is an intronic duplication which has a MAF of 0.1875 (18.75%, 15/80, 15 alleles) in the Middle Eastern subpopulation of the gnomAD 3.1.2 cohort which is ≥ 0.0015 (0.15%) (BA1). This intronic variant has a SpliceAI score ≤ 0.20 (0.05) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.05) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.50) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054560/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8356 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0877322 infores:hetionet CHEBI:9943 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C3665347 infores:hetionet CHEBI:421707 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0020565 infores:hetionet CHEBI:53760 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085932 infores:hetionet CHEBI:9434 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235437 infores:hetionet CHEBI:7936 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233407 infores:hetionet CHEBI:135738 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0013404 infores:hetionet CHEBI:31397 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0040425 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C1565489 infores:hetionet CHEBI:8356 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014591 infores:hetionet CHEBI:2469 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0017979 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015734 infores:hetionet CHEBI:2618 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0010038 infores:hetionet CHEBI:4027 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0039231 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235522 infores:hetionet CHEBI:8871 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0553721 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C2830004 infores:hetionet CHEBI:64028 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0233407 infores:hetionet CHEBI:681569 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0022346 infores:hetionet NCBIGene:6390 biolink:causes MONDO:0011740 infores:monarchinitiative not_provided not_provided HGNC:10681 MONDO:0011740 uuid:fdd1b1d8-338b-4136-8c70-564c2758399b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0038663 infores:hetionet CHEBI:51041 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0009676 infores:hetionet CHEBI:8212 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0041657 infores:hetionet CHEBI:64312 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0575081 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0231874 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0231874 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1384353 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0013395 infores:hetionet CHEBI:63599 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0031039 infores:hetionet CHEBI:9139 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0016204 infores:hetionet UMLS:C0065374 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151632 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0033975 infores:hetionet CHEBI:8774 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0340865 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009144 infores:hetionet CHEBI:42355 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C1325847 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0023530 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014335 infores:hetionet CHEBI:84050 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0011175 infores:hetionet CAID:CA380140542 biolink:causes MONDO:0000573 infores:clingen CAID:CA380140542 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM1, PM3_Supporting The c.1357T>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 453 (p.Trp453Arg).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It resides within a region, [amino acids 414 – 487, PHD domain], of RAG2 that is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Moderate).The results found by Tirosh et al., show a mean recombination activity (% of WT hRAG2): 0.6, SEM 0.1., which is below the threshold described by our VCEP (<25% of wild-type activity), so PS3 is met at a moderate level of evidence (PS3_moderate).One patient is homozygous for this variant (0.5 pt, reported in PMID: 12200379 and PMID: 29772310). One patient is heterozygous for G95R (Reported in PMID: 29772310 and PMID: 10891502). Despite the LP level of the G95R, we already applied points for this heterozygous occurrence evaluating that variant, so we will not apply here to avoid circularity - according to SVI Recommendation for in trans Criterion (PM3) - Version 1.0. (PM3_supporting).At least one patient in the literature present: T-/lowB-/low lymphocyte subset profile (0.5 pt) + Diagnostic criteria for Omenn syndrome (0.5 pt), total 1.0 pt, PP4 met (PMID: 10891502). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PM1, PS3_moderate, PP4, PM2_supporting, and PM3_supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380140542/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9599 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0002170 infores:hetionet CHEBI:4858 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0020578 infores:hetionet CHEBI:63617 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027796 infores:hetionet CHEBI:27504 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0876994 infores:hetionet CAID:CA410150149 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150149 MONDO:0011071 PMID: Uncertain Significance PS2, PS4, PS1, PS3, BP3, BP1, BP4, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS4, BS3, PM4, PM1, PM5, PM3, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.854A>G (p.Tyr285Cys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150149/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135939 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0521592 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042373 infores:hetionet CHEBI:6030 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0020456 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0039971 infores:hetionet CHEBI:94449 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0030193 infores:hetionet CHEBI:10110 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0014518 infores:hetionet CHEBI:5959 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C1322281 infores:hetionet NCBIGene:18 biolink:causes MONDO:0013166 infores:monarchinitiative not_provided not_provided HGNC:23 MONDO:0013166 uuid:c21c19c0-8795-4cf7-be6b-23ed61a535a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28939 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C1260880 infores:hetionet CHEBI:7640 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0341047 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0024225 infores:hetionet CAID:CA16602437 biolink:causes MONDO:0017623 infores:clingen CAID:CA16602437 MONDO:0017623 PMID:19457929PMID:25669429PMID:20926450PMID:21659347PMID:24778394PMID:29785012PMID:21828076PMID:19457929PMID:10866302PMID:29706350PMID:20926450 Pathogenic PM2, PP2, PM5, PM1, PS3 PM6, PVS1, BP5, BP7, BS4, BS3, BS1, BS2, PP1, PP3, PM4, BP2, BP4, BA1, PS1, PS2, PS4 PTEN c.388C>G (p.Arg130Gly) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 21828076, PMID 29706350)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7829, SCV000840465.2).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602437/MONDO:0017623/003 2019-06-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7478 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0041657 infores:hetionet CHEBI:75984 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0008031 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0521490 infores:hetionet CHEBI:140621 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0023066 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0033975 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0027769 infores:hetionet CHEBI:36704 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0016382 infores:hetionet CAID:CA229378 biolink:causes MONDO:0009861 infores:clingen CAID:CA229378 MONDO:0009861 PMID: Likely Pathogenic PM3, PM2, PP4, PVS1_Strong The NM_000277.3(PAH):c.1196_1199del (p.Val399Glyfs*52) is a frameshift variant in exon 11 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong). At least one patient (Case 154 in PMID: 8807331) with this variant had classical PKU with a serum phenylalanine level of 2131 μmol/L (above the >120 μmol/L requirement). Exclusion of a defect of BH4 cofactor metabolism was not reported (PP4). Case 154 (PMID: 8807331) is compound heterozygous for c.196_1199del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP; PM3). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1_strong, PP4, PM3, PM2. (PAH VCEP specifications version 1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229378/MONDO:0009861/006 2022-10-14 2022-10-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3403 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0031542 infores:hetionet CHEBI:94686 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0085932 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020437 infores:hetionet CHEBI:7478 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0236000 infores:hetionet CHEBI:9738 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0014457 infores:hetionet CHEBI:74947 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0278061 infores:hetionet CHEBI:27958 biolink:causes MONDO:0019544 infores:ubergraph knowledge_assertion manual_agent CHEBI:27958 MONDO:0019544 CHEBI:75998 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0010709 infores:hetionet CHEBI:51164 biolink:causes UMLS:C2720436 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C2720436 infores:hetionet CHEBI:16335 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0027497 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0549405 infores:hetionet CHEBI:10124 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0014457 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0033975 infores:hetionet CHEBI:17688 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1096250 infores:hetionet CAID:CA658795234 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795234 MONDO:0009290 PMID:31606152PMID:14695532 Pathogenic PM2, PVS1, PP4 PM3 This variant, c.716delT (p.Leu239ArgfsTer29), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. One patient with this variant meets the ClinGen LSD VCEP’s specifications for PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Another patient who is compound heterozygous for the variant has been reported (PMID 14695532). However, residual GAA activity was not provided and this data was not included. Therefore, PM3 is not currently met. This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 556853, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795234/MONDO:0009290/010 2020-09-20 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5959 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0024312 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0011732 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0011732 uuid:85192ba3-dd2e-487c-9a02-35ee47a2e185 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011603 infores:hetionet CHEBI:7565 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0162298 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0234215 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0030312 infores:hetionet CHEBI:71219 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0013404 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0002957 infores:hetionet CHEBI:17823 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0033774 infores:hetionet CHEBI:9398 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0687713 infores:hetionet CAID:CA253906 biolink:causes MONDO:0015152 infores:clingen CAID:CA253906 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PP1_Moderate, PP4_Moderate, PVS1, PM2_Supporting The NM_003494.4: c.5057+5G>A variant in DYSF, which is also known as NM_001130987.2: c.5174+5G>A, occurs within the splice donor motif of intron 45. RNAseq and cDNA analysis has demonstrated that this variant disrupts splicing, resulting in a frameshift and premature truncation, with no detectable normally spliced transcript (PMID: 36983702, 10766988; PVS1_RNA). This variant has been identified in at least two patients with LGMD, including in a homozygous state (0.25 pts, PMID: 10766988) and in unknown phase with a pathogenic variant (c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 36983702) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Moderate, PMID: 36983702, 10766988). The variant was shown to co-segregate with the LGMD phenotype in five affected members of a consanguineous family of Yemenite Jewish descent (PP1_Moderate; PMID: 10766988). The highest population minor allele frequency is 0.00002196 (2/91068 exome alleles) in the South Asian population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/18/2025): PVS1_RNA, PM3_Supporting, PP4_Moderate, PP1_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA253906/MONDO:0015152/180 2025-03-18 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16714 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0020649 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0851341 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0271051 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0020538 infores:hetionet CAID:CA8337906 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337906 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 NM_000018.4(ACADVL):c.932del (p.Phe311SerfsTer42) variant in ACADVL is a frameshift variant predicted cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one individual with this variant was identified by very long chain acyl-CoA dehydrogenase (VLCAD) clinical phenotype, who also carried a pathogenic splicing variant c.623-1G>A in trans, but this information is insufficient for to use toward classification (PMID: 10077518). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337906/MONDO:0008723/021 2023-09-26 2023-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8028 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0241442 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027769 infores:hetionet CAID:CA891862608 biolink:causes MONDO:0021060 infores:clingen CAID:CA891862608 MONDO:0021060 PMID:11333268PMID:11333268 Uncertain Significance PM2, PP2 PS1, PS2, PS3, PS4, PM5, PM4, PM1, BS4, BS3, BS1, BP7, BP5, PM6, PP1, PP3, BS2, BP3, BP2, BP1, BP4, BA1 The c.1867_1869delinsGAA p.Phe623Glu variant in SOS1 has not been reported in patients with clinical features of a RASopathy to date. In vitro functional studies provide some evidence that the p.Phe623Glu variant may impact protein function, however this assay has not been defined by the ClinGen RASopathy Expert panel as criteria for PS3 (PS3 not met; PMID: 11333268). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Of note, 2 different pathogenic missense variants have been previously reported at this codon of SOS1 (p.Phe623Val and p.Phe623Ile) which may indicate that this residue is critical to the function of the protein, however these variants have not yet met the criteria to be classified as pathogenic (PM5 not met). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Phe623Glu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PP2 RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA891862608/MONDO:0021060/004 2019-02-28 2019-07-15 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:52717 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0005818 infores:hetionet CHEBI:32139 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0041582 infores:hetionet CHEBI:31536 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0033771 infores:hetionet CHEBI:3764 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0013604 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029445 infores:hetionet CHEBI:16899 biolink:causes NCIT:C50524 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0520837 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233472 infores:hetionet CAID:CA410203565 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203565 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PS4_Supporting, PM2_Supporting, PP3 PS3, PS2, PS1, BP1, BP4, BP2, BP3, BA1, BP5, BP7, PVS1, BS1, BS3, BS4, PM6, PM3, PM4, PM5, PP2, PP4, PP1, BS2 NM_001754.4(RUNX1):c.305T>A (p.Leu102Gln) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is absent from gnomAD v2 and v3 (PM2_supporting). It has also been reported in a family where the proband met RUNX1-phenotypic criteria (PS4_supporting), and the variant segregated with thrombocytopenia in 2 affected family members (ClinVar: SCV000807772.1); however, PP1_supporting cannot be applied due to insufficient meioses for segregation. The computational predictor, REVEL, gives a score of 0.925, which is above the threshold of 0.88, evidence that correlates with impact to RUNX1 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PS4_supporting, PM1_supporting, PM2_supporting, and PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203565/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9763 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0030252 infores:hetionet CHEBI:28001 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0595916 infores:hetionet NCBIGene:5538 biolink:causes MONDO:0009744 infores:monarchinitiative not_provided not_provided HGNC:9325 MONDO:0009744 uuid:a0f4892a-f977-4afa-b8ac-7abff3f5bc33 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:51567 biolink:causes MONDO:0014846 infores:monarchinitiative not_provided not_provided HGNC:17768 MONDO:0014846 uuid:4bb1900a-bc61-41b9-905a-ceee4e6d42ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0152030 infores:hetionet CHEBI:50885 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0019080 infores:hetionet CHEBI:10100 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0004093 infores:hetionet CHEBI:8764 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018790 infores:hetionet CHEBI:31547 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0259749 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0002170 infores:hetionet CHEBI:72296 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0006145 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0004936 infores:hetionet CHEBI:68579 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0027497 infores:hetionet CHEBI:6367 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0231528 infores:hetionet CHEBI:31236 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151825 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0002170 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0158369 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0158369 infores:hetionet NCBIGene:55084 biolink:causes MONDO:0013353 infores:monarchinitiative not_provided not_provided HGNC:29256 MONDO:0013353 uuid:288dcde7-5b35-4efc-8ae5-5acd86f6bfd5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes UMLS:C0853946 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0853946 infores:hetionet CHEBI:94501 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0000731 infores:hetionet CHEBI:4672 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085593 infores:hetionet CHEBI:145499 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042024 infores:hetionet CHEBI:681850 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0858635 infores:hetionet CAID:CA10585420 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585420 MONDO:0007750 PMID: Uncertain Significance PS3_Supporting, PM2, PP4 PS4 The NM_000527.5(LDLR):c.1359-31_1359-23delinsCGGCT variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:- PM2: This variant is absent from gnomAD (gnomAD v2.1.1).- PP4: Variant meets PM2. Identified in 1 FH case from PMID: 8872473 meeting Simon-Broome criteria of possible FH , after alternative causes of high cholesterol were excluded.- PS3: Level 3 assay: PMID 8872473:Heterozygous patient's Epstein-Barr virus transformed lymphoblasts, RNA assays; Heterologous cells (COS), RNA assays: Retention of intron 9 (p.Ser453Argfs*2)---- functional study is consistent with damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585420/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15407 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0012833 infores:hetionet CAID:CA5894276 biolink:causes MONDO:0021060 infores:clingen CAID:CA5894276 MONDO:0021060 PMID: Benign BA1, BP4, BP7 BS1, PM2 The c.409-16A>T variant in RRAS2 is an intronic variant which is located in intron 4. It is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.6134 (97382/231122 alleles) in the Latino/Admixed American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5894276/MONDO:0021060/127 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63619 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0009450 infores:hetionet CHEBI:28487 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0018681 infores:hetionet CHEBI:94848 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0700590 infores:hetionet CHEBI:49375 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0149871 infores:hetionet CHEBI:5106 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0235761 infores:hetionet CHEBI:3176 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C1761613 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0007642 infores:hetionet CHEBI:36704 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0020453 infores:hetionet CAID:CA405671894 biolink:causes MONDO:0007783 infores:clingen CAID:CA405671894 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with alanine at codon 40 of the RYR1 protein, p.(Gly40Ala). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:23558838). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.897) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405671894/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true UNII:3U02EL437C biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0004093 infores:hetionet CHEBI:64028 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0233565 infores:hetionet CHEBI:47381 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0242301 infores:hetionet CAID:CA222190 biolink:causes MONDO:0015152 infores:clingen CAID:CA222190 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PS3_Moderate PM2 The NM_003494.4: c.5509G>A variant in DYSF, which is also known as NM_001130987.2: c.5626G>A p.(Asp1876Asn), is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1837, p.(Asp1837Asn). This variant has been reported in at least five unrelated individuals with features consistent with LGMD (PMID: 36983702, 22194990, 18853459, 11257469), including in a homozygous state in at least one patient without reported familial consanguinity (0.5 pts, PMID: 11257469), confirmed in trans with a pathogenic variant in one patient (NM_003494.4: c.855+1del, 1.0 pt, PMID: 18853459), and in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.6124C>T p.(Arg2042Cys), 0.5 pts, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle (PMID: 22194990, 18853459; PP4_Strong). The variant was also shown to co-segregate with the LGMD phenotype in three affected members of a non-consanguineous Japanese family (PMID: 11257469; PP1 (capped with PP4_Strong)). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.000231 (the upper threshold of the 95% CI of (4/39626 East Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (criterion not met). The computational predictor REVEL gives a score of 0.82, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Asp1837Asn protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222190/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42944 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0038663 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0014544 infores:hetionet CAID:CA117004 biolink:causes MONDO:0011225 infores:clingen CAID:CA117004 MONDO:0011225 PMID: Pathogenic PM2_Supporting, PS3_Moderate, PVS1, PP4_Moderate, PM3 The c.597C>A (p.Tyr199Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).The filtering allele frequency (the upper threshold of the 95% CI of 2/350108 alleles) of the c.597C>A variant in DCLRE1C is 0.00000095 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.This variant frequently occurs among Athabascan-speaking Native Americans, encompassing the Navajo, Apache, and other indigenous groups in North America. PMID 36546626 shows four occurrences in homozygosity (Patient ART001, Patient ART008, Patient ART009, and Patient ART013), reaching the maximum of 1 point. PM3 is met. Of those, Patient ART001 presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met, 0.5 pt + SCID gene panel or exome/genome sequencing conducted 0.5 pt + Navajo or Apache descent 0.25 pt + SCID phenotype corrected by DCLRE1C gene therapy 1 pt + T-B-NK+ lymphocyte subset 1pt. Total is 3.25 points, PP4_Moderate.Additionally, functional assays show activity levels in % of WT activity = Recombination: Mean (SD): 0.00 (1.21) and DNA repair (36h after IR): Mean (SD): 7.46 (19.56). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID: 25917813).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3, PP4, and PS3_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA117004/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3515 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0022346 infores:hetionet CHEBI:46195 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0009676 infores:hetionet CHEBI:15367 biolink:causes HP:0012587 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0473237 infores:hetionet CAID:CA198806 biolink:causes MONDO:0019497 infores:clingen CAID:CA198806 MONDO:0019497 PMID: Pathogenic PS3_Moderate, PM3_Very Strong, PVS1 PM2 The c.1A>G (p.Met1Val) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 550716, 2070085, 371781, 551915). The highest population minor allele frequency of the variant is 0.02% (5/30616) in the South Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). Intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID: 12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID: 26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID: 20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID: 9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023).intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID: 12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID: 26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID: 20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID: 9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA198806/MONDO:0019497/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:1748 biolink:causes MONDO:0014772 infores:monarchinitiative not_provided not_provided HGNC:2917 MONDO:0014772 uuid:c2728c9b-169f-4e8e-80d2-a633450ad53e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA401365192 biolink:causes MONDO:0009290 infores:clingen CAID:CA401365192 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3, PM1, PS3_Supporting PM5 The NM_000152.5:c.1211A>G variant in GAA is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 404 (p.Asp404Gly). It has been reported in two individuals from the same family with Pompe disease: an adult with documentation of deficient GAA and clinical features consistent with LOPD, and a child with documentation of deficient GAA and clinical features of IOPD; both individuals treated enzyme replacement therapy (PMID: 24384324) (PP4_moderate). Both individuals are compound heterozygous for the variant, the adult individual had the variant in trans with c.695+5G>T (phase confirmed) and the child had the variant in trans (phase confirmed) with a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1798C>T (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179940 alleles) in the European (non-Finnish)] population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant alters amino acid Asp404, a residue that crystallography studies have shown to be important in the active site of GAA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). When expressed in HEK293T cells, this variant resulted in normal intracellular amounts of 110 kDa precursor, 95 kDa intermediate, and 76 kDa mature forms of GAA but 12.6% wild type GAA activity in cells and 4.6% in culture media. This suggests that this variant results in a catalytic deficiency but does not impact GAA synthesis and processing. The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 959950 , 2-star review status) with 2 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PM1, PS3_supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401365192/MONDO:0009290/010 2025-04-15 2025-05-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:520985 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0042510 infores:hetionet NCBIGene:259232 biolink:causes MONDO:0024567 infores:monarchinitiative not_provided not_provided HGNC:19082 MONDO:0024567 uuid:a78ae2e7-d080-416b-8ee1-d497496a6bd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3647 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0023052 infores:hetionet CHEBI:53691 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0023530 infores:hetionet CHEBI:63630 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0231528 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0267792 infores:hetionet CHEBI:16586 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C2047937 infores:hetionet CAID:CA913186005 biolink:causes MONDO:0009290 infores:clingen CAID:CA913186005 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM4_Supporting The NM_000152.5:c.1553_1555dup variant in GAA is predicted to cause a change in the length of the protein (p.Asp518_Met519insAsn) due to an in-frame insertion of one amino acid in a non-repeat region (PM4_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. PROVEAN and Mutation Taster predict that this variant will impact the function of GAA (PP3). The is a ClinVar entry for this variant (Variation ID: 932901). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel: PM2_Supporting, PM4_Supporting, PP3.(Classification approved by the ClinGen LD VCEP on May 29, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913186005/MONDO:0009290/010 2023-05-29 2023-05-29 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3387 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0687133 infores:hetionet CHEBI:119573 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0428977 infores:hetionet CHEBI:45409 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0039070 infores:hetionet CHEBI:2453 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0857305 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0178298 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0235082 infores:hetionet CHEBI:9907 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042024 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0235351 infores:hetionet CHEBI:107736 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0026837 infores:hetionet CHEBI:8768 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151827 infores:hetionet CHEBI:85078 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042487 infores:hetionet NCBIGene:29127 biolink:causes MONDO:0030711 infores:monarchinitiative not_provided not_provided HGNC:9804 MONDO:0030711 uuid:f72ff709-cbcc-444c-a313-1beab3a8ad8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68841 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0013404 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011334 infores:hetionet CHEBI:27834 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C1443060 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0549288 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0549288 infores:hetionet CHEBI:65349 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C1384353 infores:hetionet NCBIGene:55690 biolink:causes MONDO:0014006 infores:monarchinitiative not_provided not_provided HGNC:30032 MONDO:0014006 uuid:4ec2bd4f-767c-4f87-8c06-6bf86c9d34dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3039 biolink:causes MONDO:0013512 infores:monarchinitiative not_provided not_provided HGNC:4823 MONDO:0013512 uuid:457663f2-d9fb-44d4-951e-1c0907fb54ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0002965 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0015376 infores:hetionet CHEBI:63598 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0011175 infores:hetionet CAID:CA10568575 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568575 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PP1_Moderate, PP3, PS4 PM2 The c.599A>G (p.Glu200Gly) missense variant has a REVEL score of 0.779 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and v3.1 and therefore, does not meet criteria for rarity in the population. At least 9 patients with mild hemophilia A are reported in literature, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726, 29388750). Three related individuals were reported in Reitter, et al (PMID: 20431853), and two were specifically mentioned to be uncle and a nephew, which counts as 2 meioses. Additionally, authors of the Boylan, et al. paper informed this VCEP that one of the probands had an affected relative who also has this variant, which is counted as 1 meioses (PMID: 25780857). This gives a total of 3 meioses and meeting PP1_Moderate criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PP1_Moderate, PP4_Moderate, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568575/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:50663 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0037199 infores:hetionet CHEBI:31348 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004604 infores:hetionet CAID:CA10549228 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549228 MONDO:0010305 PMID: Benign BS1, BS2, BP4 The NM_005629.4:c.645-14C>T variant in SLC6A8 is and intronic variant that is upstream from the acceptor splice site of intron 3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004174 in the European non-Finnish population which is higher than the ClinGen CCDS VCEP's allele frequency threshold for BS1 (>0.0002), meeting this criterion (BS1). The variant is present in 9 hemizygotes in gnomAD v2.1.1 (BS2). The computational splicing predictors SpliceAI and varSEAK suggest that the variant has no deleterious impact on splicing (BP4). To our knowledge, this variant has not been reported in the literature and results of functional or splicing studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 384841). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549228/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:4672 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0029882 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0021843 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0518015 infores:hetionet CHEBI:6887 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1318520 infores:hetionet CHEBI:8768 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151908 infores:hetionet CHEBI:4659 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0015230 infores:hetionet CHEBI:6076 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0018681 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018418 infores:hetionet CHEBI:10101 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0234233 infores:hetionet CHEBI:9737 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0151904 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C2609183 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2609183 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232431 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0162429 infores:hetionet CHEBI:61033 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0000731 infores:hetionet CHEBI:8805 biolink:causes MONDO:0004892 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0034951 infores:hetionet CHEBI:63610 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C1443060 infores:hetionet CHEBI:18248 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0015672 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020557 infores:hetionet CHEBI:39112 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0151904 infores:hetionet CHEBI:3380 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0015967 infores:hetionet CHEBI:3764 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0237849 infores:hetionet CHEBI:63612 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0424790 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0860945 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0860945 infores:hetionet CHEBI:9763 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0220870 infores:hetionet CHEBI:31401 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0085593 infores:hetionet CHEBI:5864 biolink:causes HP:0030223 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0233651 infores:hetionet CHEBI:520985 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0018681 infores:hetionet CHEBI:3814 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0012833 infores:hetionet CAID:CA229812 biolink:causes MONDO:0009861 infores:clingen CAID:CA229812 MONDO:0009861 PMID:23220018 Pathogenic PVS1, PM2, PP4 The PAH c.842+1G>T variant has been reported at least once in the literature in a 15 month old patient with moderate PKU in the homozygote state (PP4, PMID: 23220018). This variant is absent from 1000G, ESP, and gnomAD databases. This variant disrupts the canonical splice donor site of intron 7 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 7 is present in biologically-relevant transcript. In summary, this variant meets criteria to be pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229812/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49375 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0518015 infores:hetionet CHEBI:145499 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085649 infores:hetionet CHEBI:7514 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0423153 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017574 infores:hetionet CHEBI:93305 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0021368 infores:hetionet CHEBI:8776 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0003862 infores:hetionet CHEBI:5002 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0015967 infores:hetionet CHEBI:50122 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0085605 infores:hetionet CHEBI:8382 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0028754 infores:hetionet CHEBI:8310 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0001925 infores:hetionet CHEBI:5959 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0600228 infores:hetionet CHEBI:9757 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0027497 infores:hetionet CHEBI:84883 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0020458 infores:hetionet NCBIGene:203228 biolink:causes MONDO:0007105 infores:monarchinitiative not_provided not_provided HGNC:28337 MONDO:0007105 uuid:77babda6-04f1-49e1-bcf9-f63ef9d26a94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0014518 infores:hetionet CHEBI:4909 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0917801 infores:hetionet CHEBI:184555 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0687713 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001225 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0029095 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0521491 infores:hetionet CHEBI:71223 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0015672 infores:hetionet NCBIGene:27327 biolink:causes MONDO:0054846 infores:monarchinitiative not_provided not_provided HGNC:11969 MONDO:0054846 uuid:eb70446a-b4ff-47e5-872c-f963a708d1ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020453 infores:hetionet CHEBI:28148 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0003467 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040479 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0221100 infores:hetionet CHEBI:40009 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0013182 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013922 infores:hetionet CHEBI:6067 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003811 infores:hetionet CHEBI:3127 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0038450 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0234215 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0019348 infores:hetionet CAID:CA5950504 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950504 MONDO:0000573 PMID: Uncertain Significance PM1_Supporting BS2, BA1, PS3, BS1, BS3, PM2 The c.909G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Aspartic Acid at amino acid 303 (p.Glu303Asp).The Popmax Filtering Allele Frequency (95% confidence) is 0.0001834 in gnomAD v.4 based on the African/African American population, 14/75040 alleles. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygous has been described in gnomAD v.4, and BS2 is not met.This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2/SCID-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950504/MONDO:0000573/124 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17688 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0010200 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0004238 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0038661 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085681 infores:hetionet CHEBI:17347 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0086168 infores:hetionet CHEBI:15367 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0041657 infores:hetionet CHEBI:3032 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0009806 infores:hetionet CHEBI:31413 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0003467 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0344304 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0344304 infores:hetionet NCBIGene:2273 biolink:causes MONDO:0010401 infores:monarchinitiative not_provided not_provided HGNC:3702 MONDO:0010401 uuid:e9496fc6-c925-41ef-ae79-12406ec24b86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0021400 infores:hetionet CHEBI:48669 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0547030 infores:hetionet CHEBI:49960 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0006277 infores:hetionet CHEBI:473990 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0009450 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0009450 infores:hetionet CHEBI:63577 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0520573 infores:hetionet CAID:CA16620236 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620236 MONDO:0007648 PMID:22020549PMID:22020549PMID:26072394 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.489C>A (p.Cys163Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 26072394). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620236/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA400024919 biolink:causes MONDO:0100326 infores:clingen CAID:CA400024919 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting PS1 The NM_000212.3(ITGB3):c.856G>C (p.Gly286Arg) missense variant has been reported in one homozygous case (PM3_supporting); Case 9 (PMID: 34435350) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0-1% (<25%), as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969 (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM3_supporting, PM2_supporting, PP3. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400024919/MONDO:0100326/011 2025-06-19 2025-06-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8768 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0233407 infores:hetionet CHEBI:31547 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C1443060 infores:hetionet CHEBI:15551 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0021368 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005942 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0035400 infores:hetionet CHEBI:144551 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0232487 infores:hetionet NCBIGene:79639 biolink:causes MONDO:0859226 infores:monarchinitiative not_provided not_provided HGNC:26186 MONDO:0859226 uuid:fa460f68-867d-4149-a028-a6260e6327ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0005684 infores:hetionet CHEBI:38940 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0010200 infores:hetionet CHEBI:9137 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0231528 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0037274 infores:hetionet NCBIGene:54496 biolink:causes MONDO:0014944 infores:monarchinitiative not_provided not_provided HGNC:25557 MONDO:0014944 uuid:8bec83f6-83ab-4781-8b10-7c4778f1dd6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135530 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0012833 infores:hetionet CHEBI:63629 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0040822 infores:hetionet CHEBI:3380 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0003862 infores:hetionet CHEBI:7936 biolink:causes MONDO:0044013 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034040 infores:hetionet NCBIGene:84876 biolink:causes MONDO:0014383 infores:monarchinitiative not_provided not_provided HGNC:25896 MONDO:0014383 uuid:3bd55631-c8e0-4e52-b70c-88476e8ce67b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10110 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0015230 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0033975 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017152 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0854382 infores:hetionet CHEBI:50131 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0034063 infores:hetionet CHEBI:4710 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042963 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0027947 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0521509 infores:hetionet CHEBI:33325 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0017181 infores:hetionet CHEBI:39867 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0016204 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0009806 infores:hetionet CHEBI:3312 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C2242996 infores:hetionet NCBIGene:7138 biolink:causes MONDO:0957281 infores:monarchinitiative not_provided not_provided HGNC:11948 MONDO:0957281 uuid:48d0b94a-7017-4e3e-bbc9-c1e44e089ccf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0018021 infores:hetionet NCBIGene:3860 biolink:causes MONDO:0014346 infores:monarchinitiative not_provided not_provided HGNC:6415 MONDO:0014346 uuid:087863c7-262a-45c7-bac8-fa67d3932a6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0152198 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0392386 infores:hetionet NCBIGene:8898 biolink:causes MONDO:0011066 infores:monarchinitiative not_provided not_provided HGNC:7450 MONDO:0011066 uuid:7834e68a-ce06-4ef7-819c-58145a5644ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2687 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0851341 infores:hetionet CHEBI:2469 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0016204 infores:hetionet CHEBI:9667 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0917801 infores:hetionet CHEBI:63611 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042029 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0031046 infores:hetionet CHEBI:16714 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0032617 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0267792 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013298 infores:hetionet CHEBI:4702 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1761613 infores:hetionet CHEBI:39112 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0232462 infores:hetionet CHEBI:8028 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0033774 infores:hetionet NCBIGene:387119 biolink:causes MONDO:0030031 infores:monarchinitiative not_provided not_provided HGNC:21638 MONDO:0030031 uuid:e1ed1842-9046-4d2d-aa68-1092fe911d26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0549249 infores:hetionet CHEBI:9763 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0043349 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0038814 infores:hetionet CHEBI:45783 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0028081 infores:hetionet CHEBI:63629 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0008350 infores:hetionet CHEBI:10125 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0016867 infores:hetionet CHEBI:3011 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0041657 infores:hetionet CHEBI:9352 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0013378 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005086 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007134 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020456 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0521160 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0521160 infores:hetionet CHEBI:261649 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0085624 infores:hetionet CHEBI:7492 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0029882 infores:hetionet CHEBI:75922 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0234708 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0023067 infores:hetionet CHEBI:4708 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0423791 infores:hetionet CHEBI:50859 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0575081 infores:hetionet NCBIGene:7547 biolink:causes MONDO:0010752 infores:monarchinitiative not_provided not_provided HGNC:12874 MONDO:0010752 uuid:a68d4178-17b9-4437-851a-b78195f8c87d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3U02EL437C biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0558368 infores:hetionet CHEBI:3181 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0235325 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0027947 infores:hetionet CHEBI:167309 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0002792 infores:hetionet CHEBI:8356 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013428 infores:hetionet CHEBI:49668 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0020639 infores:hetionet CHEBI:10127 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018524 infores:hetionet CHEBI:9622 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0233794 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0034150 infores:hetionet UNII:54Z8M50D6Q biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0036104 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0020538 infores:hetionet CHEBI:31980 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0040409 infores:hetionet CHEBI:408174 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0162297 infores:hetionet CHEBI:8863 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011124 infores:hetionet CHEBI:6067 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013404 infores:hetionet CHEBI:9434 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0014591 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0340464 infores:hetionet NCBIGene:1428 biolink:causes MONDO:0014603 infores:monarchinitiative not_provided not_provided HGNC:2418 MONDO:0014603 uuid:79070cac-0c8b-49c7-9963-dbfabcfc9b3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5818 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0221242 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0549373 infores:hetionet CHEBI:82960 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0004093 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0278079 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0027769 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0281981 infores:hetionet CHEBI:3312 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0030554 infores:hetionet CHEBI:3636 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0700590 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0040034 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0005970 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D011023 DB09335_MESH_D011023_2DB00684_MESH_D011023_1DB01044_MESH_D011023_1DB01190_MESH_D011023_1DB00766_MESH_D011023_1DB01332_MESH_D011023_1DB00601_MESH_D011023_1DB00685_MESH_D011023_1DB00218_MESH_D011023_1DB09335_MESH_D011023_1DB02703_MESH_D011023_1DB01165_MESH_D011023_1DB01137_MESH_D011023_1DB00438_MESH_D011023_1DB00479_MESH_D011023_1DB01147_MESH_D011023_1DB00512_MESH_D011023_1DB00415_MESH_D011023_1DB00274_MESH_D011023_1DB01607_MESH_D011023_1DB01059_MESH_D011023_1 CHEBI:17026 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0234215 infores:hetionet CHEBI:5893 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002962 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0267792 infores:hetionet CHEBI:32315 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0019209 infores:hetionet NCBIGene:2706 biolink:causes MONDO:0007422 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0007422 uuid:403811d8-5a42-4f31-a02f-13c22c2ff6d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0542203 infores:hetionet CHEBI:10100 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0085605 infores:hetionet CHEBI:4784 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030554 infores:hetionet CHEBI:194135 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042024 infores:hetionet CHEBI:36704 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0236082 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0014130 infores:hetionet CHEBI:63610 biolink:causes HP:0001622 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0151526 infores:hetionet CHEBI:31859 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0014591 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0018799 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0025061 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0160390 infores:hetionet CHEBI:50648 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0242184 infores:hetionet NCBIGene:84868 biolink:causes MONDO:0019475 infores:monarchinitiative not_provided not_provided HGNC:18437 MONDO:0019475 uuid:695f7ab6-1f84-46e5-b713-30e226dc2a23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0853619 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0019158 infores:hetionet CHEBI:51364 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0041657 infores:hetionet CHEBI:6909 biolink:causes UMLS:C1535975 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1535975 infores:hetionet CHEBI:18248 biolink:causes HP:0034751 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0578736 infores:hetionet CHEBI:31401 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0041657 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0006840 infores:hetionet CHEBI:94686 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0014335 infores:hetionet CHEBI:63681 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0003862 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0855242 infores:hetionet CHEBI:17026 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042133 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0087169 infores:hetionet CHEBI:17026 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0016204 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0029560 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0029560 infores:hetionet CHEBI:5280 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0344232 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019112 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0014742 infores:hetionet CHEBI:94385 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0013395 infores:hetionet CHEBI:2788 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C3665386 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0034065 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549405 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0032961 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0234458 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0152115 infores:hetionet CHEBI:9288 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0023530 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0041912 infores:hetionet CHEBI:4710 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1260880 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0349506 infores:hetionet CHEBI:2618 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0023530 infores:hetionet CHEBI:42355 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0241136 infores:hetionet CHEBI:4445 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0023066 infores:hetionet CHEBI:4903 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0030794 infores:hetionet CHEBI:28864 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C1262144 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0012739 infores:hetionet CHEBI:7577 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0235710 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0851043 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0851043 infores:hetionet NCBIGene:5582 biolink:causes MONDO:0011540 infores:monarchinitiative not_provided not_provided HGNC:9402 MONDO:0011540 uuid:7e3f5a2a-7e60-401d-8c4b-2afacd0ae279 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PR:000011374 biolink:causes GO:0003050 infores:ubergraph knowledge_assertion manual_agent PR:000011374 GO:0003050 CHEBI:584020 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0013144 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235416 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1322281 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0036572 infores:hetionet CHEBI:4953 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0030554 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0863113 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0149931 infores:hetionet CHEBI:6062 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0033774 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0424000 infores:hetionet CHEBI:8774 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0039231 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011991 infores:hetionet CHEBI:63598 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085649 infores:hetionet CAID:CA377781751 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781751 MONDO:0017623 PMID:29752200PMID:29752200 Pathogenic PM6, PM2, PVS1, PS4_Moderate BP7, BP5, BS4, BS3, BS1, BS2, PP1, PP3, PP2, PM5, PM1, PM4, BP2, BP4, BA1, PS1, PS3, PS2 PTEN c.1A>G (p.M1?) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 29752200)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 29752200, 28774669; internal laboratory contributor ClinVar Organization ID: 26957) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781751/MONDO:0017623/003 2019-11-22 2019-12-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7494 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011168 infores:hetionet UMLS:C0017797 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0231528 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020538 infores:hetionet CHEBI:4495 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0014457 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0241310 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0241310 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0679048 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0679048 infores:hetionet CHEBI:6472 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0036830 infores:hetionet NCBIGene:2746 biolink:causes MONDO:0011717 infores:monarchinitiative not_provided not_provided HGNC:4335 MONDO:0011717 uuid:a3526d7d-bd85-4027-897c-7d206176e79b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151763 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0012739 infores:hetionet CHEBI:9086 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0025222 infores:hetionet CHEBI:31397 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0043352 infores:hetionet CHEBI:10127 biolink:causes MONDO:0043994 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0149520 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0413252 infores:hetionet CHEBI:7903 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C1384353 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0040409 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0152008 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0152008 infores:hetionet CHEBI:45599 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0025637 infores:hetionet CHEBI:175901 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0020598 infores:hetionet CHEBI:28177 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0040822 infores:hetionet NCBIGene:3918 biolink:causes MONDO:0030748 infores:monarchinitiative not_provided not_provided HGNC:6493 MONDO:0030748 uuid:72d94cea-7d4b-4f36-ada3-152327f46bba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0016204 infores:hetionet CHEBI:5864 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042510 infores:hetionet CAID:CA410207979 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207979 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, PS4, BP1, BP4, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM3, PM4, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.590T>C (p.Val197Ala) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant resides within a region, 89-204, of RUNX1 that is defined as a critical functional domain by the ClinGen MMVCEP (PMID 31648317) (PM1_Supporting). This missense variant has a REVEL score ≥ 0.88 (0.953). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207979/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:116278 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0020456 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0086132 infores:hetionet GO:0106396 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0150063 CHEBI:49960 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0013378 infores:hetionet CHEBI:2948 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1096250 infores:hetionet CHEBI:4735 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0239937 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0409497 infores:hetionet CHEBI:92712 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0456909 infores:hetionet CHEBI:50742 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0004509 infores:hetionet CHEBI:84050 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0034063 infores:hetionet CHEBI:4888 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0024141 infores:hetionet CHEBI:31949 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0033975 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020649 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037199 infores:hetionet CHEBI:3749 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0040038 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0860803 infores:hetionet CHEBI:63631 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0231807 infores:hetionet CHEBI:50924 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0042963 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0022573 infores:hetionet UMLS:C0145867 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0232461 infores:hetionet CHEBI:9150 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0085605 infores:hetionet CHEBI:168396 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019521 infores:hetionet CHEBI:465284 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0015732 infores:hetionet CHEBI:5123 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0085631 infores:hetionet CHEBI:8874 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0428977 infores:hetionet CHEBI:72296 biolink:causes UMLS:C1697747 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C1697747 infores:hetionet CHEBI:2687 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0235378 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0259799 infores:hetionet CHEBI:8212 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0004093 infores:hetionet CHEBI:42797 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015732 infores:hetionet CAID:CA9091108 biolink:causes MONDO:0021060 infores:clingen CAID:CA9091108 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.45C>T (p.Asn15=) variant in the MAP2K2 gene is 0.0295% (6/8856) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9091108/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8707 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085632 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0423226 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423226 infores:hetionet CHEBI:2549 biolink:causes HP:0002378 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0239842 infores:hetionet CHEBI:4728 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0012797 infores:hetionet CHEBI:8214 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0009763 infores:hetionet GO:2000477 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0001656 CHEBI:9586 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0015230 infores:hetionet CHEBI:41977 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0004134 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0020550 infores:hetionet CHEBI:31401 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0016867 infores:hetionet CHEBI:47781 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0030446 infores:hetionet CHEBI:7577 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0015967 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0948594 infores:hetionet CHEBI:47898 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151905 infores:hetionet NCBIGene:22861 biolink:causes MONDO:0032925 infores:monarchinitiative not_provided not_provided HGNC:14374 MONDO:0032925 uuid:c4c27c4d-a64a-4d95-b904-25fcb23cec7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0677500 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020538 infores:hetionet GO:0090249 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:0090249 GO:0061053 CHEBI:2687 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0743400 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001433 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042251 infores:hetionet CHEBI:50859 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0039231 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0018799 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005016 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011881 infores:hetionet NCBITaxon:5506 biolink:causes MONDO:0016426 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5506 MESH:D060585 DB01167_MESH_D060585_1DB01263_MESH_D060585_1 CHEBI:63617 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0031085 infores:hetionet NCBITaxon:810 biolink:causes MONDO:0021697 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:810 MESH:D002690 DB00254_MESH_D002690_1 CHEBI:188986 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009760 infores:hetionet CHEBI:28864 biolink:causes NCIT:C50524 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0520837 infores:hetionet CHEBI:18248 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0012569 infores:hetionet CHEBI:2904 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0600142 infores:hetionet NCBIGene:57545 biolink:causes MONDO:0012849 infores:monarchinitiative not_provided not_provided HGNC:29253 MONDO:0012849 uuid:cb05a17e-782b-4d89-acd3-7568ff82562e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0023518 infores:hetionet CHEBI:100147 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0011991 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0029408 infores:hetionet CAID:CA410147744 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147744 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1222G>C (p.Gly408Arg) is a missense variant which has a REVEL score < 0.50 (0.289), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147744/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15940 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0030554 infores:hetionet CHEBI:6846 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0042963 infores:hetionet CAID:CA345144656 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144656 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PP4_Moderate BS2, PVS1, BA1, BP1, BP4, BP2, BP3, PS3, PS1, BP7, BS1, BS3, PM3, PM4, PM1, PM5 The variant NM_001100.4:c.1043T>A in ACTA1 is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 348 (p.Leu348Gln). The variant is absent from gnomAD v4.1.0 with adequate coverage (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.976, which is above the threshold necessary to apply PP3. In addition, ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in two probands with congenital myopathy (PS4_Supporting, PMID:25747004, SCV002280810.3). The one proband had hypotonia at birth, end stage limb-girdle dystrophy with diffuse proximal and distal weakness and wasting, and weak axial muscles. Muscle biopsy of this proband showed nemaline rods and electron microscopy showed few zebra bodies and accumulation of actin-like thin filaments (PP4_Moderate, PMID:25747004). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PP4_Moderate, PS4_Supporting, PP2, PP3, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144656/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32315 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0003467 infores:hetionet NCBIGene:2778 biolink:causes MONDO:0012911 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0012911 uuid:de6e8d60-844b-4d96-b42f-19198694f08f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0027651 infores:hetionet CAID:CA410780392 biolink:causes MONDO:0021060 infores:clingen CAID:CA410780392 MONDO:0021060 PMID: Uncertain Significance PM2_Supporting, BP4, PM3_Supporting, PS3_Supporting PP3, BA1, BS1 The c.650A>C variant in LZTR1 is a missense variant predicted to cause substitution of glutamic acid by alanine at amino acid 217 (p.Glu217Ala). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.287, which is below the threshold of 0.3, evidence that does not predict a damaging effect on LZTR1 function (BP4). This variant has been detected in 1 individual with RASopathy. They were homozygous for the variant (0.5 PM3 points, PMID: 29469822) (PM3_Supporting). LZTR1 stability in COS-1 cells showed significantly reduced expression levels compared to wildtype indicating that this variant impacts protein function (PMID:30481304)(PS3_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance with conflicting evidence for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS3_Supporting, PM2_Supporting, PM3_Supporting, BP4. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410780392/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:194135 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013428 infores:hetionet CHEBI:474053 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0151754 infores:hetionet CHEBI:9667 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0009763 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003615 infores:hetionet CHEBI:9123 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0428977 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0030193 infores:hetionet CHEBI:63598 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0271710 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0021359 infores:hetionet CHEBI:453011 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0033774 infores:hetionet CHEBI:51450 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0000731 infores:hetionet CHEBI:6933 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0012833 infores:hetionet CHEBI:9674 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0022346 infores:hetionet CHEBI:55346 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C1519353 infores:hetionet CHEBI:92998 biolink:causes HP:0025088 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0263540 infores:hetionet CHEBI:101278 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0003862 infores:hetionet CHEBI:10124 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0004134 infores:hetionet NCBIGene:2158 biolink:causes MONDO:0010604 infores:monarchinitiative not_provided not_provided HGNC:3551 MONDO:0010604 uuid:fb5890c7-94c3-4f9b-99d5-98abecc6a39b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033117 infores:hetionet CAID:CA349016721 biolink:causes MONDO:0100038 infores:clingen CAID:CA349016721 MONDO:0100038 PMID: Pathogenic PS3, PM6, PS2_Moderate, PM2_Supporting, PS4_Supporting PM1, PM3, PM4, PVS1, PP2, PP3, BP4 "The c.584A>G variant in SCN2A is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 195 (p.Asp195Gly). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 3 individuals with complex neurodevelopmental phenotypes (PMID: 356372276: 2 cases, complex NDD (supp. table 1); PMID: 38651838: 3 cases, epileptic spasms) (PM6), and as a de novo occurrence with confirmed parental relationships in 1 individual with a complex neurodevelopmental phenotype (SCV001444634.3, internal lab contributor) (PS2_moderate). This variant has been reported in 1 additional case meeting ""complex neurodevelopment disorder"" phenotypic criteria (SCV002073223.1) (PS4_supporting). This variant is absent from gnomAD (v4) (PM2_supporting). In patch clamping experiments, voltage dependence of inactivation is shifted by at least 4.1 mV indicating that this variant impacts protein function (PMID: 38651838, see Fig. S6) (PS3). The computational predictor (REVEL) gives a score of 0.99, which is above the threshold of 0.75, evidence that correlates with impact to SCN2A function (no evidence applied). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS3, PM6, PS2_moderate, PM2_supporting, PS4_supporting (ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 2.0.0; approved 8/26/25)." Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349016721/MONDO:0100038/068 2025-08-26 2025-10-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4995 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235086 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0042373 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0235431 infores:hetionet CHEBI:4653 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0002792 infores:hetionet CAID:CA320642815 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642815 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.204C>T (p.Ala68=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.85) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642815/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10110 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0042384 infores:hetionet CHEBI:71417 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0086565 infores:hetionet CHEBI:7824 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1384353 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0009450 infores:hetionet CHEBI:63607 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0038362 infores:hetionet CHEBI:3380 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0038325 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0009450 infores:hetionet CHEBI:7573 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0008031 infores:hetionet CHEBI:6909 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042029 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0314719 infores:hetionet CHEBI:48538 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0033774 infores:hetionet CHEBI:8597 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0024205 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0032285 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0023418 infores:hetionet CHEBI:3286 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0004604 infores:hetionet CHEBI:47519 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0013378 infores:hetionet NCBIGene:63895 biolink:causes MONDO:0007252 infores:monarchinitiative not_provided not_provided HGNC:26270 MONDO:0007252 uuid:ffbd7faa-189b-4ba1-91e0-67f660d37d68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:161680 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0404521 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1167965 infores:hetionet CHEBI:84500 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0476280 infores:hetionet CHEBI:4798 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0000737 infores:hetionet CHEBI:87715 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0020443 infores:hetionet CHEBI:68575 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0027497 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0235025 infores:hetionet CHEBI:3216 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0018681 infores:hetionet CAID:CA220511 biolink:causes MONDO:0001586 infores:clingen CAID:CA220511 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PP4_Moderate, PM2_Supporting The NM_000203.5:c.501C>G (p.Tyr167Ter) variant is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5 out of 14, leading to nonsense-mediated decay in the IDUA gene in which loss-of-function is an established disease mechanism (PVS1; PMID 28676128). An Algerian patient, diagnosed with severe MPS I, has been reported with elevated urine GAGs, IDUA deficiency, and clinical features consistent with the condition (PMID: 27196898) (PP4_Moderate). This patient is homozygous for the variant (PMID: 27196898) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is [8.476e-7] (1/ 1179740 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (< 0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92644). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I, based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 18, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220511/MONDO:0001586/091 2025-03-18 2025-03-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7773 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0030554 infores:hetionet CHEBI:194135 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0037763 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0022660 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0022354 infores:hetionet CHEBI:9943 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020473 infores:hetionet CHEBI:17141 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0011175 infores:hetionet CHEBI:63632 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0033774 infores:hetionet CHEBI:2549 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0003467 infores:hetionet CHEBI:8428 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0016382 infores:hetionet CHEBI:63618 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0026821 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013687 infores:hetionet CHEBI:3757 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0036974 infores:hetionet CHEBI:37924 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0000731 infores:hetionet NCBIGene:695 biolink:causes MONDO:0010421 infores:monarchinitiative not_provided not_provided HGNC:1133 MONDO:0010421 uuid:966dc638-481f-46ed-903b-d723db610b64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0233794 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0001122 infores:hetionet CHEBI:3568 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0857305 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0151735 infores:hetionet NCBIGene:4625 biolink:causes MONDO:0008050 infores:monarchinitiative not_provided not_provided HGNC:7577 MONDO:0008050 uuid:8f80baa4-5760-445f-9499-3ac33b39535d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3213 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0160390 infores:hetionet CHEBI:5778 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0043352 infores:hetionet CAID:CA10014583 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014583 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: No codes met. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014583/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0065374 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030196 infores:hetionet CHEBI:47898 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011175 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0475858 infores:hetionet CHEBI:15365 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0005779 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1096717 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1096717 infores:hetionet CHEBI:15854 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0278061 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0233494 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0595877 infores:hetionet CAID:CA1705479 biolink:causes MONDO:0015152 infores:clingen CAID:CA1705479 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PS3_Moderate PM2, PP3 The NM_003494.4: c.757C>T variant in DYSF, which is also known as NM_001130987.2: c.853C>T p.(Arg285Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 253, p.(Arg253Trp). This variant has been reported in at least 10 individuals with symptoms consistent with LGMD (PMID: 16010686, 18853459, 24803842, 25868377, 26404900, 27666772, 30564623, 30919934, 36983702; LOVD DYSF_000205), including in a homozygous state without reported familial consanguinity in one patient (0.5 pts; PMID: 30919934) and confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 1.0 pt, LOVD Individual #00215315; NM_003494.4: c.2894G>A p.(Trp965Ter), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive proximal muscle weakness and significantly reduced or absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong; PMID: 36983702, 27666772, 25868377). The highest minor allele frequency for this variant in gnomAD v4.1.0 is 0.0001890 in the European (non-Finnish) population (223/1180018 alleles), which is higher than the LGMD VCEP threshold for PM2_Supporting (0.0001) (criterion not met). The computational predictor REVEL gives a score of 0.614, which is below the VCEP's threshold of 0.7 for PP3 (criterion not met). However, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg253Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/08/2025): PM3_Strong, PP4_Strong, PS3_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1705479/MONDO:0015152/180 2025-07-08 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes HP:0003987 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0041601 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085096 infores:hetionet CHEBI:15940 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0032617 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151763 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0027769 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0851341 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0349506 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014869 infores:hetionet CAID:CA16020945 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020945 MONDO:0009861 PMID:24301756 Uncertain Significance PM2, PP4, PP3 PM5 The c.1124A>G (p.Gln375Arg) variant in PAH has been reported in an Iranian patient with mild PKU (PMID: 24301756). This variant is absent in population databases. A deleterious effect is predicted in SIFT, Polyphen-2, and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020945/MONDO:0009861/006 2020-06-19 2020-06-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8764 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020433 infores:hetionet CHEBI:75722 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0239134 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0348024 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0348024 infores:hetionet CHEBI:63681 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0011603 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0042075 infores:hetionet CHEBI:41774 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042998 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0031350 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C2945586 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C2945586 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0233494 infores:hetionet CHEBI:5778 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0004604 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0038362 infores:hetionet UMLS:C0065374 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0024902 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0024117 infores:hetionet CHEBI:3485 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0002878 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0031350 infores:hetionet CHEBI:35778 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1328539 infores:hetionet CHEBI:8327 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0349506 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027769 infores:hetionet CHEBI:94609 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0013378 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0007117 infores:hetionet CHEBI:75984 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0022346 infores:hetionet CHEBI:75984 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0015230 infores:hetionet CHEBI:63637 biolink:causes MONDO:0021036 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0263383 infores:hetionet CHEBI:8869 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0017168 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0022408 infores:hetionet CHEBI:84500 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0040053 infores:hetionet UMLS:C0120107 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0016655 infores:hetionet CHEBI:110423 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0232462 infores:hetionet CAID:CA228357 biolink:causes MONDO:0015631 infores:clingen CAID:CA228357 MONDO:0015631 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3, PM3 PM5 The NM_000552.5(VWF):c.2635G>A variant in VWF is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 879. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0001409 (based on 14/59994 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold (<0.005 for type 2N) for PM2_Supporting. At least 1 patient with this variant displayed mildly prolonged mucocutaneous bleeding, low FVIII activity, decreased VWF:FVIII binding, reduced ability to agglutinate platelets in the presence of ristocetin (VWF:RCo), and reduced VWF expression, which is highly specific for VWD type 2N, despite the reduced HMW multimers (PP4, PMID: 9845532). This patient was compound heterozygous and harbored a second variant (p.Arg1659Ter) in trans that has been classified Pathogenic by the VCEP, (PMID: 9845532, PM3). Factor VIII binding assay performed with the p.Asp879Asn mutant and wild-type recombinant vWF expressed by and purified from HEK293 cells showed dramatically decreased binding, indicating that this variant has a damaging effect on protein function (PMID: 30111575, PMID: 9845532) (PS3). The computational predictor REVEL gives a score of 0.66, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM3, PM2_Supporting, PS3, PP3, PP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228357/MONDO:0015631/090 2024-09-03 2024-09-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:77260 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151904 infores:hetionet CHEBI:17026 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0349790 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0009319 infores:hetionet CHEBI:4672 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0854467 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0020538 infores:hetionet CHEBI:135929 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0025061 infores:hetionet CHEBI:6909 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0333355 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002453 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0206062 infores:hetionet CHEBI:63629 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0001623 infores:hetionet CHEBI:8863 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003467 infores:hetionet CHEBI:84500 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0520887 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0267792 infores:hetionet CHEBI:6539 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0037036 infores:hetionet CHEBI:2682 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235710 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0042109 infores:hetionet CHEBI:7478 biolink:causes UMLS:C1142335 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C1142335 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013395 infores:hetionet CHEBI:63619 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017168 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0853761 infores:hetionet NCBIGene:1376 biolink:causes MONDO:0009704 infores:monarchinitiative not_provided not_provided HGNC:2330 MONDO:0009704 uuid:00e81a82-3056-4c25-bdf8-d4258f6bea74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2010560 infores:hetionet NCBIGene:7280 biolink:causes MONDO:0014337 infores:monarchinitiative not_provided not_provided HGNC:12412 MONDO:0014337 uuid:9809b084-dac9-4e82-8a81-1257b93bfd65 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0033774 infores:hetionet CHEBI:6030 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C2047937 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0277925 infores:hetionet CHEBI:135342 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0039591 infores:hetionet CHEBI:63619 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0014457 infores:hetionet CAID:CA1139532475 biolink:causes MONDO:0007648 infores:clingen CAID:CA1139532475 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM1, PM5, PM4, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2 The c.2526del (p.Ala843LeufsTer3) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and downstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Moderate, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). One family meets the HDGC criteria (PS4_Supporting; Internal lab contributor). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS4_Supporting. This VUS variant is trending to the pathogenic side. The CDH1 VCEP will re-evaluate it, if more evidence emerge in the future. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532475/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:4672 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085661 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1971624 infores:hetionet CHEBI:6128 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0004096 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0001416 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000385 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0497538 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042267 infores:hetionet CHEBI:5383 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0028734 infores:hetionet CHEBI:72564 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0001622 infores:hetionet NCBIGene:3458 biolink:causes MONDO:0033541 infores:monarchinitiative not_provided not_provided HGNC:5438 MONDO:0033541 uuid:269e723f-26fb-4bbc-8ac5-9a1e8310a35a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8060 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0231530 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0028738 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019158 infores:hetionet CHEBI:2549 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020453 infores:hetionet CHEBI:45409 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1142412 infores:hetionet CAID:CA16602292 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602292 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP3, BP2, BP1, BP4, PS4, PS3, PS1, PS2, BP7, BP5, BS1, BS4, BS3, PM5, PM1, PM4, PM3, PM6, PVS1, BS2, PP1, PP2, PP3, PP4 The NM_000527.4(LDLR):c.185C>G (p.Thr62Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602292/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8356 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0041969 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0855242 infores:hetionet CHEBI:51364 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0026961 infores:hetionet CAID:CA214314 biolink:causes MONDO:0015967 infores:clingen CAID:CA214314 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM4_Supporting, PM1_Supporting, PS3_Supporting, PP4_Moderate, PP1 PS4 The c.666_668del variant in the HNF1 homeoboxA gene, HNF1A, results in the inframe deletion of a single lysine at codon 222 of NM_000545.6 (PM4_Supporting). Functional in vitro studies demonstrated that cells with this variant showed severely impaired transactivation activity and DNA binding (significantly below 40%). Furthermore, cells with this variant showed low protein expression levels and impaired nuclear targeting with elevated immunofluorescence signal in the cytoplasm compared to WT HNF1A (PS3_Supporting; Janne Molnes, personal communication). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP. (PM1_Supporting). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsiveness in both and negative antibodies in one) (PP4_Moderate; PMID: 27913849, internal lab contributor). This variant segregated with disease with three informative meioses in a single family with MODY (PP1; internal lab contributor). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 27913849, ClinVar: SCV000053177.2, internal lab contributors). In summary, c.666_668del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PS3_Supporting, PM1_Supporting, PP4_Moderate, PM2_Supporting, PM4_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214314/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA8622980 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622980 MONDO:0100326 PMID: Likely Benign PP3, BA1 The c.557C>T variant in ITGB3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 186. The variant has a high population minor allele frequency in gnomAD v2.1.1 of 0.007131 (178/24960) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024). The computational predictor REVEL gives a score of 0.733, which is above the ClinGen PD VCEP PP3 threshold of >0.7 and predicts a damaging effect on ITGB3 function. It is reported to have an association with lower platelet count in an African American cohorts (PMID: 23103231) but has not been reported in a Glanzmann thrombasthenia patient to our knowledge. In summary, this variant meets the criteria to be classified as a variant of unknown significance - conflicting evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, PP3. (VCEP specifications version 2; date of approval 2/2/2023) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622980/MONDO:0100326/011 2023-02-08 2023-02-15 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true GO:0042310 biolink:causes MONDO:0005044 infores:drugmechdb knowledge_assertion manual_agent GO:0042310 MESH:D006973 DB08822_MESH_D006973_1 CHEBI:41774 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0278134 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0850420 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0267941 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151849 infores:hetionet CHEBI:3219 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0558401 infores:hetionet CHEBI:48273 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0233407 infores:hetionet GO:0048374 biolink:causes GO:0048372 infores:ubergraph knowledge_assertion manual_agent GO:0048374 GO:0048372 CHEBI:2704 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0020437 infores:hetionet CHEBI:59750 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0162835 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0011849 infores:hetionet CAID:CA203388902 biolink:causes MONDO:0011225 infores:clingen CAID:CA203388902 MONDO:0011225 PMID: Uncertain Significance BP7 BA1, BS1, PM2 The c.973-1801T>A (NM_001033855.3) variant in DCLRE1C is an intronic variant which locates in the deep intronic region in the intron 11. It is not predicted to impact splicing by SpliceAI, varSEAK, and NNSplice. BP7 is met.The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004608 (4/8180 alleles) in African/African American population, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C/SCID conditions or in functional studies. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA203388902/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:84500 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0016385 infores:hetionet CAID:CA273106 biolink:causes MONDO:0009861 infores:clingen CAID:CA273106 MONDO:0009861 PMID:8268925PMID:9429153PMID:21820508 Pathogenic PP4_Moderate, PM3_Very Strong, PS3 PM5, PM2, PP3 PAH-specific ACMG/AMP criteria applied: PP4_Moderate: Seen on 3 PKU alleles, BH4 deficiency was ruled out. Upgraded per ClinGen Metabolic WG. (PMID:8268925); PM3_VeryStrong: A403V found with 4 pathogenic variants . Upgraded per ClinGen SVI workgroup. (PMID:9429153); PS3: In vitro A403V mutant protein activity was ~43% wt. (PMID:21820508). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong, PS3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273106/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:188986 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009763 infores:hetionet CAID:CA405680878 biolink:causes MONDO:0018493 infores:clingen CAID:CA405680878 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with methionine at codon 2910 of the RYR1 protein, p.(Tyr2910Met). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.779 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405680878/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:194135 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0234215 infores:hetionet CHEBI:61049 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004604 infores:hetionet CHEBI:8805 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0030305 infores:hetionet CHEBI:6413 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0239377 infores:hetionet CHEBI:140621 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0002994 infores:hetionet CHEBI:127342 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C2363730 infores:hetionet CAID:CA367398657 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398657 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PS4 The c.1166T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 389 (p.(Val389Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19790256). Another missense variant, c.1166T>A p.Val389Asp, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1166T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398657/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:27999 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0013395 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0025061 infores:hetionet CHEBI:63580 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0022281 infores:hetionet CHEBI:31515 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0042963 infores:hetionet CHEBI:9674 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0234518 infores:hetionet NCBIGene:275 biolink:causes MONDO:0958192 infores:monarchinitiative not_provided not_provided HGNC:473 MONDO:0958192 uuid:acb503c1-3ced-47ed-bb56-78d896bd2c98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003864 infores:hetionet CHEBI:3504 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0036974 infores:hetionet CHEBI:6759 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0020649 infores:hetionet NCBIGene:2318 biolink:causes MONDO:0013550 infores:monarchinitiative not_provided not_provided HGNC:3756 MONDO:0013550 uuid:3723b609-f254-4ab9-9f06-5ec464b431ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:367 biolink:causes MONDO:0010384 infores:monarchinitiative not_provided not_provided HGNC:644 MONDO:0010384 uuid:ba042cdb-fa7f-40af-b2df-e59bd5ad6750 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0232461 infores:hetionet CHEBI:6128 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0232726 infores:hetionet CHEBI:63631 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0000731 infores:hetionet GO:0014062 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:0014062 GO:0007267 CHEBI:8768 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0014591 infores:hetionet CHEBI:4907 biolink:causes MONDO:0043731 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0221204 infores:hetionet CHEBI:47781 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C1368065 infores:hetionet CHEBI:3423 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0009421 infores:hetionet CHEBI:52717 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085635 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0018801 infores:hetionet CHEBI:36795 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0851578 infores:hetionet CHEBI:6538 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0085631 infores:hetionet NCBIGene:8462 biolink:causes MONDO:0012513 infores:monarchinitiative not_provided not_provided HGNC:11811 MONDO:0012513 uuid:40f56d88-e309-4f46-bbc1-89d96b716d44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:161680 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0002994 infores:hetionet CHEBI:29688 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0017168 infores:hetionet CHEBI:63635 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020639 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0855242 infores:hetionet CHEBI:6715 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023052 infores:hetionet CHEBI:91834 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0017675 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0029456 infores:hetionet CHEBI:8802 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0028738 infores:hetionet CHEBI:63845 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0002874 infores:hetionet CHEBI:3752 biolink:causes NCIT:C87097 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0032989 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042109 infores:hetionet CHEBI:3534 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0004093 infores:hetionet CHEBI:3082 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0037036 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0233414 infores:hetionet NCBIGene:90 biolink:causes MONDO:0007606 infores:monarchinitiative not_provided not_provided HGNC:171 MONDO:0007606 uuid:75d66004-c103-482e-900f-034d752849dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025061 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0235295 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0011991 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0025874 infores:hetionet CAID:CA386952464 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952464 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PS4, PP3, PP4 The c.41C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 14 (p.(Ala14Val)) of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952464/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0877338 infores:hetionet CAID:CA024272 biolink:causes MONDO:0007783 infores:clingen CAID:CA024272 MONDO:0007783 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with tyrosine at codon 4960 of the RYR1 protein, p.(Phe4960Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with elevated creatine kinase, a second variant of uncertain significance, p.Arg3119His, was also identified in this individual (PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.965) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024272/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:27974 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0004604 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0242656 infores:hetionet CHEBI:64312 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027497 infores:hetionet CHEBI:8774 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0030252 infores:hetionet CHEBI:3001 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0152459 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0262397 infores:hetionet NCBIGene:3350 biolink:causes MONDO:0044660 infores:monarchinitiative not_provided not_provided HGNC:5286 MONDO:0044660 uuid:1f9d2ebd-487d-4b77-a81a-6a2c7aab16ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8080 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0018824 infores:hetionet GO:0014006 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0014006 GO:0007417 CHEBI:94501 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0948594 infores:hetionet CAID:CA10584826 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584826 MONDO:0007750 PMID: Likely Pathogenic PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, PS3, PS4, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.284G>A (p.Cys95Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.918. PM1: Variant meets PM2 and alters one higly conserved Cys residue (Cys95).PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling Simon Broome criteria or with DLCN score >=6, after alternative causes of high cholesterol were excluded, from PMID 28502510 (Bañares et al., 2017). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584826/MONDO:0007750/013 2024-02-23 2025-08-29 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:2202 biolink:causes MONDO:0007471 infores:monarchinitiative not_provided not_provided HGNC:3218 MONDO:0007471 uuid:23f212d2-b68f-472c-adcc-071eb7777ee6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0178298 infores:hetionet CHEBI:5165 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C2937358 infores:hetionet CHEBI:52172 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085635 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0086132 infores:hetionet CHEBI:3181 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0017178 infores:hetionet CHEBI:231594 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0027497 infores:hetionet CHEBI:72292 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0036983 infores:hetionet CHEBI:16469 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2047937 infores:hetionet UMLS:C1738934 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0043144 infores:hetionet CHEBI:7496 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020565 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0549373 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0027947 infores:hetionet CHEBI:37333 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C2830004 infores:hetionet CHEBI:3423 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0012569 infores:hetionet CHEBI:64045 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0007682 infores:hetionet CHEBI:68579 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0014742 infores:hetionet CHEBI:64019 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0002994 infores:hetionet CAID:CA637689884 biolink:causes MONDO:0011071 infores:clingen CAID:CA637689884 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.806-15dup is an intronic variant in intron 7 of the biologically relevant transcript. This variant has not been observed in any population according to gnomAD v3 (PM2_Supporting). The nucleotide and surrounding sequence are not evolutionarily conserved, and the variant is not predicted to affect splicing according to SpliceAI (score 0.01) (BP4, BP7). The variant has not been described in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637689884/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6128 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0027051 infores:hetionet CHEBI:499361 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0035243 infores:hetionet GO:1904542 biolink:causes GO:0010992 infores:ubergraph knowledge_assertion manual_agent GO:1904542 GO:0010992 CHEBI:9725 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0392156 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0234458 infores:hetionet CHEBI:2948 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0206061 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0270810 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0240925 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0240925 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0518015 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0042373 infores:hetionet CHEBI:6402 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0340865 infores:hetionet CHEBI:6909 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0233407 infores:hetionet CHEBI:42944 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0017178 infores:hetionet CHEBI:7865 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0025362 infores:hetionet CAID:CA16620227 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620227 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.7C>T (p.Pro3Ser) is absent from gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is classified as a variant of uncertain significance based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2 _Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620227/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63580 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0039971 infores:hetionet UMLS:C0657912 biolink:causes HP:0002345 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234376 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0085762 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0027765 infores:hetionet NCBIGene:3783 biolink:causes MONDO:0014737 infores:monarchinitiative not_provided not_provided HGNC:6293 MONDO:0014737 uuid:371e6120-c131-4f89-b30e-532cc1b74443 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009763 infores:hetionet CHEBI:135876 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0687713 infores:hetionet CHEBI:7565 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0232462 infores:hetionet CHEBI:16755 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C1443060 infores:hetionet CHEBI:8356 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0687713 infores:hetionet CHEBI:7936 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151827 infores:hetionet CHEBI:64355 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003962 infores:hetionet CAID:CA191858 biolink:causes MONDO:0007648 infores:clingen CAID:CA191858 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2 The c.202delT (p.Tyr68Ilefs*15) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA191858/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf GO:0046530 biolink:causes CL:0000210 infores:ubergraph knowledge_assertion manual_agent GO:0046530 CL:0000210 CHEBI:63627 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0036104 infores:hetionet CHEBI:4562 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0085636 infores:hetionet CHEBI:61049 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085593 infores:hetionet CHEBI:16755 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0206061 infores:hetionet CAID:CA410147225 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147225 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1345C>T (p.Gln449Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147225/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7627 biolink:causes UMLS:C0850569 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0850569 infores:hetionet CHEBI:68478 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0595916 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0852733 infores:hetionet CHEBI:6062 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C2939147 infores:hetionet CHEBI:49713 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0235086 infores:hetionet CHEBI:6413 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0030252 infores:hetionet CAID:CA392343867 biolink:causes MONDO:0007947 infores:clingen CAID:CA392343867 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PM1, PM5 PM6, PVS1, PP1, PP4, BS2, BP1, BP4, BP2, BP3, BA1, PM3, PM4, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4 NM_00138 c.1379G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 460 (p.Cys460Tyr). This variant was found in a proband with bilateral ectopia lentis and mitral valve prolapse (PS4_supporting; PMID: 21932315). This variant has been reported twice in ClinVar as likely pathogenic and once as of uncertain significance (Variation ID: 636640). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). Other variants altering this codon are pathogenic or likely pathogenic (p.Cys460Ser, p.Cys460Trp), supporting the functional importance of this amino acid position (PM5). Computational prediction tools and conservation analysis suggest that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_supporting, PM2_supporting, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392343867/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:61049 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011570 infores:hetionet CHEBI:6950 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151889 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0518015 infores:hetionet CHEBI:7445 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0034069 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042075 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004597 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0034074 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0019158 infores:hetionet NCBIGene:23137 biolink:causes MONDO:0859576 infores:monarchinitiative not_provided not_provided HGNC:20465 MONDO:0859576 uuid:fd4539d0-8e57-4db6-b38a-5f031b14b932 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020517 infores:hetionet CHEBI:31624 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0236075 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0241166 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0241166 infores:hetionet CHEBI:8214 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0236075 infores:hetionet CHEBI:35778 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0235996 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0036572 infores:hetionet CHEBI:132233 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0042963 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034069 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0235431 infores:hetionet CHEBI:50223 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0036974 infores:hetionet CAID:CA8337808 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337808 MONDO:0008723 PMID: Likely Benign BP4, BP7 The c.678C>A (p.Ala226=) variant (NM_000018.3) is a synonymous (silent) variant that is not predicted by NNSplice, MaxEntScan, and SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). This variant is absent from gnomAD v.2.1.1; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337808/MONDO:0008723/021 2025-04-22 2025-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:42797 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013390 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0347390 infores:hetionet CHEBI:92511 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0232849 infores:hetionet CAID:CA6904332 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904332 MONDO:0019497 PMID:18684989 Uncertain Significance PS3_Supporting, PM3 BS1, PP2, PP3, PM2, BA1, BP4 The c.23C>T variant in GJB2 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 8. The filtering allele frequency (the lower threshold of the 95% CI of 75/91084, 1 homozygote) of this variant is 0.06728% in the South Asian chromosomes by gnomAD v4.1.0, which is neither above nor below the thresholds defined by the ClinGen HL EP for autosomal recessive conditions (PM2_Supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function. Dual whole cell voltage clamp and dye transfer assays in HeLa cells demonstrated that even though potassium permeability remains the same in the variant, there is a reduction in cationic and large molecules dye transfer compared to WT (PMID:18684989) (PS3_Supporting). This variant has been detected in at least two individuals with autosomal recessive NSHL. One was compound heterozygous for the variant and a pathogenic variant, c.109G>A (p.Val37Ile), with phase unknown (0.5 PM3 points, PMID: 22384008). One individual was homozygous for the variant (0.5 PM3 points, PMID: 31162818) (PM3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PS3_Supporting (Hearing Loss VCEP specifications version 2; 01/15/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904332/MONDO:0019497/005 2025-01-15 2025-03-18 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:7496 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0851578 infores:hetionet CHEBI:4909 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0002994 infores:hetionet CHEBI:63631 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0015672 infores:hetionet CHEBI:9654 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0009676 infores:hetionet UMLS:C0010592 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0030554 infores:hetionet CHEBI:72564 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0010200 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0019158 infores:hetionet NCBIGene:5745 biolink:causes MONDO:0010803 infores:monarchinitiative not_provided not_provided HGNC:9608 MONDO:0010803 uuid:30033a10-04dd-4c57-872e-4831a2d02298 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49713 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0040264 infores:hetionet CAID:CA915949308 biolink:causes MONDO:0007648 infores:clingen CAID:CA915949308 MONDO:0007648 PMID: Likely Pathogenic PS4_Moderate, PVS1_Strong PP4, PS3 PVS1: The NM_004360.5(CDH1):c.1212del (p.Asn405IlefsTer12) variant in is aframeshift/deletion/ variant [predicted/observed to cause apremature stop codon in 12 leading a premature stop codon is introduced 12 amino acids downstream, leading to a truncated protein.the CDH1 in which loss-of-function is an established disease mechanism (PVS1; PMIDs). aggregation assay in [CELL TYPE]/[NON HUMAN MODEL ORGANISM] showed[DESCRIPTION OF RESULTS] indicating that this variant impacts protein function(PMIDs)(PS3_[STRENGTH]).Significant impairment of cell–cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12 CDH1 compared with cells expressing wild-type CDH1. results suggest that the p.Asn405IlefsX12 mutation of the CDH1 gene contribute to carcinogenesis in patients with FGC.The variant has been reported to segregate with CDH1 in 2 affectedfamily members from one family(ies) (PP1_[STRENGTH]; PMIDs, ClinVar SCVs,Internal lab contributors) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949308/MONDO:0007648/007 2025-05-21 2025-05-21 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:5296 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0009443 infores:hetionet CHEBI:45783 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2363730 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0021845 infores:hetionet NCBIGene:5000 biolink:causes MONDO:0013428 infores:monarchinitiative not_provided not_provided HGNC:8490 MONDO:0013428 uuid:e0bbe05a-1798-4eb9-bd1a-3c39f9c3261e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7601 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0009450 infores:hetionet CHEBI:9943 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014518 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0036572 infores:hetionet CHEBI:37941 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1368065 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0003811 infores:hetionet CHEBI:7514 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0002792 infores:hetionet CHEBI:16714 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0030305 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038358 infores:hetionet NCBIGene:5308 biolink:causes MONDO:0008387 infores:monarchinitiative not_provided not_provided HGNC:9005 MONDO:0008387 uuid:bbe52f2f-29f4-4aa9-a4b5-dadf354487f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8643754 biolink:causes MONDO:0015152 infores:clingen CAID:CA8643754 MONDO:0015152 PMID: Likely Benign BS1 BP4, BP7 The NM_000023.4: c.312+19A>C variant in SGCA is an intronic variant that does not occur in a splice region (+7/-21). The filtering allele frequency for this variant is 0.0009193 for the South Asian population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 94/85460 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.0009 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.19, which is greater than the VCEP threshold of 0.05 (BP4, BP7 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8643754/MONDO:0015152/189 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:45924 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0001824 infores:hetionet CHEBI:50777 biolink:causes MONDO:0000751 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0007855 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151736 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0028259 infores:hetionet CHEBI:6715 biolink:causes HP:0040064 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0239337 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0948594 infores:hetionet NCBIGene:392255 biolink:causes MONDO:0054752 infores:monarchinitiative not_provided not_provided HGNC:4221 MONDO:0054752 uuid:abf6b1c6-cacc-475c-aa6c-51a4ebe4fbd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0853348 infores:hetionet CHEBI:17823 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0002792 infores:hetionet CHEBI:9566 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0040485 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0234215 infores:hetionet CHEBI:5118 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085612 infores:hetionet CHEBI:4975 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0233407 infores:hetionet CHEBI:9434 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0016204 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0595878 infores:hetionet CHEBI:52010 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0020458 infores:hetionet UMLS:C0879264 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004093 infores:hetionet NCBIGene:59 biolink:causes MONDO:0013542 infores:monarchinitiative not_provided not_provided HGNC:130 MONDO:0013542 uuid:231d8a2c-5f87-4a23-815e-4ad06fd7337e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027441 infores:hetionet CHEBI:8890 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020621 infores:hetionet CHEBI:135939 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0344232 infores:hetionet CHEBI:63620 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0004134 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0015397 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0018801 infores:hetionet CHEBI:7865 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0017178 infores:hetionet CHEBI:15367 biolink:causes HP:0001013 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0221252 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040147 infores:hetionet CAID:CA10014474 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014474 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.613+15T>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.18) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014474/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6887 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0041969 infores:hetionet CHEBI:135930 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020625 infores:hetionet UMLS:C0011701 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020488 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0033860 infores:hetionet CHEBI:5864 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0013384 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027769 infores:hetionet CHEBI:6375 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0242429 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018099 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0006266 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021107 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027404 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020437 infores:hetionet CAID:CA1244099 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244099 MONDO:0020367 PMID: Uncertain Significance PP3, PP1, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.1001T>C variant in MYOC is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 334 (p.Leu334Pro). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002891 (1 allele out of 34,592), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.936, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 18385784), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 18385784), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244099/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:291342 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0031350 infores:hetionet CHEBI:30830 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0233407 infores:hetionet CHEBI:2379 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0018524 infores:hetionet CHEBI:136040 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0015672 infores:hetionet NCBIGene:4643 biolink:causes MONDO:0013589 infores:monarchinitiative not_provided not_provided HGNC:7599 MONDO:0013589 uuid:21cc4901-76db-4d71-9e27-4918cf7fcb94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18358 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0016436 infores:hetionet CHEBI:474053 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0002874 infores:hetionet CAID:CA229738 biolink:causes MONDO:0009861 infores:clingen CAID:CA229738 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5 The c.743T>G (p.Leu248Arg) variant in PAH has not been reported in an affected patient to our knowledge. This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229738/MONDO:0009861/006 2020-11-13 2022-03-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:70735 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0013428 infores:hetionet CHEBI:8776 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0019158 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0221165 infores:hetionet CHEBI:51450 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0035243 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0024312 infores:hetionet CHEBI:4708 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020580 infores:hetionet NCBIGene:374654 biolink:causes MONDO:0008708 infores:monarchinitiative not_provided not_provided HGNC:30497 MONDO:0008708 uuid:8c8b6dc4-e4fe-4c29-93ea-5e8deb03f915 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes MONDO:0000918 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0014179 infores:hetionet CHEBI:7514 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0043352 infores:hetionet CHEBI:31949 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0020649 infores:hetionet CHEBI:34911 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0020580 infores:hetionet CHEBI:7476 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085932 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085584 infores:hetionet CHEBI:6062 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151315 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0011827 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013274 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0860210 infores:hetionet CHEBI:135613 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C1565489 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0013378 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020649 infores:hetionet CHEBI:5134 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0019825 infores:hetionet CHEBI:17334 biolink:causes MONDO:0004934 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0031111 infores:hetionet CHEBI:49662 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151786 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0861021 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0861021 infores:hetionet CAID:CA16603574 biolink:causes MONDO:0100084 infores:clingen CAID:CA16603574 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PP1, PM2_Supporting, PP4_Moderate, PS4_Moderate The c.304G>A (NM_001100.4(ACTA1):c.304G>A (p.Glu102Lys)) variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 102 (p.Glu102Lys). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.854, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). This variant has been reported in 4 probands with alpha-actinopathy (PS4_Moderate; SCV000511956, SCV003347757; Invitae & GeneDx Internal Data). At least one patient with this variant displayed muscle biopsy with fiber type disproportion, which is highly specific for alpha-actinopathy (PP4_Moderate; SCV003347757, Invitae internal data). The variant has been reported to segregate with alpha-actinopathy in one affected daughter (PP1; SCV003347757, Invitae internal data). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_supporting, PP2, PP3, PS4_Moderate, PP4_Moderate, PP1 (ClinGen Congenital Myopathies VCEP Specifications Version 2.0, 9/9/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603574/MONDO:0100084/147 2024-09-09 2025-04-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:91541 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0314719 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027339 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0424000 infores:hetionet CHEBI:31199 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0162835 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020877 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0149931 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0314719 infores:hetionet CHEBI:32315 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0022107 infores:hetionet CHEBI:17026 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040038 infores:hetionet CAID:CA2529312623 biolink:causes MONDO:0015967 infores:clingen CAID:CA2529312623 MONDO:0015967 PMID: Likely Pathogenic PS1_Moderate, PP4_Moderate, PP3, PM2_Supporting PS4 The c.679+3A>T variant in the glucokinase gene, GCK, is a noncanonical splice donor site variant in intron 6 of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.87 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, other variants within the same splice donor motif, c.679+5G>A and c.679+5G>C, have been classified as pathogenic by the ClinGen MDEP and c.679+3A>T has a greater predicted deleterious impact by SpliceAI (0.87 vs. 0.26 and 0.43, respectively) (PS1_Moderate). In summary, c.679+3A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS1_Moderate, PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2529312623/MONDO:0015967/086 2025-09-17 2025-09-26 Semidominant inheritance HP:0032113 Supports UMLS:C0011701 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0917801 infores:hetionet CHEBI:94686 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0013390 infores:hetionet CHEBI:71219 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0149745 infores:hetionet CHEBI:64198 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0085624 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1328291 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1328291 infores:hetionet CHEBI:4784 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0034886 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0042109 infores:hetionet CHEBI:82960 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0235710 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0003123 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0851341 infores:hetionet NCBIGene:23312 biolink:causes MONDO:0014497 infores:monarchinitiative not_provided not_provided HGNC:2938 MONDO:0014497 uuid:300f022d-431f-47c6-85b7-c27afc766202 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3213 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0043352 infores:hetionet CHEBI:10650 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0002792 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0004936 infores:hetionet CHEBI:31236 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013384 infores:hetionet CHEBI:9599 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0162285 infores:hetionet CHEBI:4356 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0022660 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0518015 infores:hetionet CHEBI:31859 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0085633 infores:hetionet CHEBI:6741 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151904 infores:hetionet NCBIGene:406987 biolink:causes MONDO:0014747 infores:monarchinitiative not_provided not_provided HGNC:31582 MONDO:0014747 uuid:17123c3f-3d1e-41cf-bd1b-2f3a1aac0638 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0149931 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013595 infores:hetionet CHEBI:5103 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0015230 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0344375 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027947 infores:hetionet CHEBI:8764 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C3665347 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042594 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027339 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0027339 infores:hetionet NCBIGene:1277 biolink:causes MONDO:0030854 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0030854 uuid:75e30c3c-b771-4823-a58e-8f2449d0f671 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50659 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0162557 infores:hetionet CHEBI:73274 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0239935 infores:hetionet CHEBI:2659 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0042487 infores:hetionet CHEBI:34829 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0423602 infores:hetionet CHEBI:40009 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0235031 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0234913 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0009450 infores:hetionet CHEBI:4495 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0423153 infores:hetionet CHEBI:2687 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0020580 infores:hetionet CHEBI:3478 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0004604 infores:hetionet CHEBI:140621 biolink:causes UMLS:C1140716 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C1140716 infores:hetionet CHEBI:10112 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0011603 infores:hetionet CHEBI:480999 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0015967 infores:hetionet CHEBI:28901 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0740394 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0040479 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0006852 infores:hetionet CHEBI:4885 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0013144 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0392176 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030517 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C1096250 infores:hetionet CHEBI:499361 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0018524 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0009806 infores:hetionet CHEBI:31623 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0152459 infores:hetionet CAID:CA024122 biolink:causes MONDO:0007783 infores:clingen CAID:CA024122 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS4, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamine with histidine at codon 474 of the RYR1 protein, p.Gln474His. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.835 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024122/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:31401 biolink:causes HP:0001933 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0854107 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002878 infores:hetionet CHEBI:28748 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151872 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0020651 infores:hetionet CHEBI:5118 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002962 infores:hetionet CHEBI:9398 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0042790 infores:hetionet CHEBI:68554 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0028768 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0852733 infores:hetionet CHEBI:9649 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0522055 infores:hetionet UMLS:C1738934 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233762 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0948873 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0017658 infores:hetionet CHEBI:6640 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0085624 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036454 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151740 infores:hetionet CHEBI:37333 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0030554 infores:hetionet CHEBI:5062 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0026857 infores:hetionet CHEBI:63612 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0004093 infores:hetionet CHEBI:6775 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151632 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0087169 infores:hetionet CHEBI:41977 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0040046 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0040034 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0020651 infores:hetionet CHEBI:36791 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0702166 infores:hetionet CHEBI:7931 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0037763 infores:hetionet CHEBI:32293 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0221436 infores:hetionet CHEBI:465284 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003811 infores:hetionet CHEBI:7465 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0549622 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0344320 infores:hetionet CHEBI:9654 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0494475 infores:hetionet CHEBI:6472 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0235295 infores:hetionet CAID:CA254839 biolink:causes MONDO:0044970 infores:clingen CAID:CA254839 MONDO:0044970 PMID:15870203PMID:8280119PMID:16120315PMID:12729737PMID:9744809PMID:10660592PMID:12527767PMID:7603512 Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4, PP1_Moderate PS2, PM6 The m.3271T>C variant in MT-TL1 gene has been reported in more than 40 affected individuals from 20 kindreds (PS4; PMIDs: 1932147, 8482977, 7993661, 8908402, 9766710, 9427220, 11404119, 11828557, 10214753, 12609508, 16006433, 15794182, 16353243, 18206799, 20972245, 25680467, 33951347). The age of onset ranged from early childhood to the late 30s. This variant has been seen in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; accounts for approximately 10% of cases of MELAS and is the second most common cause) as well as in one individual with myoclonic epilepsy with ragged red fibers (MERRF). Other features seen in affected individual include muscle weakness, exercise intolerance, fatigue, developmental delay, axonal neuropathy, dementia, migraines, seizures, diabetes, growth hormone deficiency, lipoma, sensorineural hearing loss, hypertrophic cardiomyopathy, Wolff-Parkinson-White arrhythmia, optic atrophy, and short stature. Muscle biopsies showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, hypertrophic/atrophic fibers, enlarged mitochondria, abnormal cristae, increased fat droplets, and variable respiratory chain enzyme activities. Heteroplasmy levels were variable but were highest in muscle and urine, and levels were as high as homoplasmic in muscle. This variant segregated with disease in multiple affected members across several families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 9427220, 16006433, 15794182, 18206799, 25680467). There is one report of a de novo occurrence, however technology at the time could have missed low level variants and the tissue(s) tested was not specified (PMID: 11828557). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (78.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Cybrid studies and other assays supported the functional impact of this variant (PS3_moderate; PMIDs: 12527767, 12729737, 15870203, 16120315, 10660592, 9744809, 7603512, 8280119). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254839/MONDO:0044970/015 2023-04-25 2023-05-19 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:49713 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0015672 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0012833 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003708 infores:hetionet CHEBI:5106 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0043144 infores:hetionet CHEBI:49960 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0030193 infores:hetionet CHEBI:8107 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0234233 infores:hetionet CAID:CA5416851 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416851 MONDO:0011225 PMID: Likely Benign BS1 The c.419C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Alanine by Valine at amino acid 140 (p.Ala140Val).The filtering allele frequency (the lower threshold of the 95% CI of 138/75030 alleles) of the c.419C>T variant in DCLRE1C is 0.001589 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00078) for BS1, and therefore meets this criterion (BS1). No homozygotes have been observed in gnomAD. To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416851/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3127 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0231807 infores:hetionet CHEBI:7824 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0004134 infores:hetionet CHEBI:63611 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C3665346 infores:hetionet CHEBI:3756 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233514 infores:hetionet NCBIGene:10370 biolink:causes MONDO:0013748 infores:monarchinitiative not_provided not_provided HGNC:1987 MONDO:0013748 uuid:dc7dc35b-e914-48a8-87ea-ed4e080498ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5296 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0011603 infores:hetionet CHEBI:5118 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013456 infores:hetionet CHEBI:15365 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0085631 infores:hetionet CHEBI:94449 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0041969 infores:hetionet CHEBI:3310 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0004093 infores:hetionet CHEBI:41423 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017086 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035078 infores:hetionet CHEBI:91541 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0004936 infores:hetionet CHEBI:2914 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0009782 infores:hetionet CHEBI:3738 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0002878 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0016436 infores:hetionet GO:1902259 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:1902259 GO:0071805 UMLS:C0010592 biolink:causes HP:0030249 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0014034 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0574067 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0027932 infores:hetionet CHEBI:3175 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0003467 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0151500 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151500 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235901 infores:hetionet CHEBI:9907 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0016204 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004844 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023532 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0011860 infores:hetionet CHEBI:6444 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0009806 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0476089 infores:hetionet CHEBI:7852 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0242528 infores:hetionet CHEBI:63630 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0086439 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0311468 infores:hetionet CHEBI:47781 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0235660 infores:hetionet CHEBI:31348 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0034642 infores:hetionet CHEBI:2675 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0235347 infores:hetionet CAID:CA312282 biolink:causes MONDO:0008723 infores:clingen CAID:CA312282 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.210dup (p.Lys71Ter) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 4/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCAD deficiency. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting, (ACADVL VCEP specifications v2.0; Approved on 03/11/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312282/MONDO:0008723/021 2022-04-06 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:6812 biolink:causes MONDO:0012812 infores:monarchinitiative not_provided not_provided HGNC:11444 MONDO:0012812 uuid:39bf2f85-11a8-48e6-8a6f-7c5ae9121c33 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0080274 infores:hetionet CHEBI:41774 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042963 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013395 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0558348 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0558348 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0030332 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0267596 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018099 infores:hetionet NCBIGene:26175 biolink:causes MONDO:0859156 infores:monarchinitiative not_provided not_provided HGNC:20218 MONDO:0859156 uuid:fe6b4747-3dbb-4cef-8588-3627dd377e75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16914 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0232492 infores:hetionet CHEBI:9137 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020578 infores:hetionet CHEBI:51450 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0016204 infores:hetionet CAID:CA397397502 biolink:causes MONDO:0100438 infores:clingen CAID:CA397397502 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate NM_014336.5(AIPL1):c.172C>A (p.Pro58Thr) is a missense variant replacing the proline at position p.58 with threonine. This variant is present in gnomAD v.4.1.0 with a total frequency of 6.196e-7 with 1 allele /1613990 total alleles, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.800, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 (PP3_Moderate). In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397397502/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:74947 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151905 infores:hetionet CHEBI:231594 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0010200 infores:hetionet CHEBI:50663 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0000737 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0011609 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0009450 infores:hetionet CAID:CA16607552 biolink:causes MONDO:0011132 infores:clingen CAID:CA16607552 MONDO:0011132 PMID:31566583PMID:37419334 Likely Pathogenic PP4, PM2_Supporting, PM1, PP3_Moderate PS3, PM5 The NM_001369369.1(FOXN1):c.962A>G (p.His321Arg) missense variant is located within the well-established DNA binding forkhead domain (amino acids 270-367) at amino acid position 321 (PM1). A deleterious effect is predicted by REVEL with a score of 0.978, above the ≥0.932 threshold for PP3_moderate. This variant was detected heterozygous by exome sequencing in P7 (PMID: 31566583) with T lymphopenia (CD3 32 cell/ul), abnormal hair and abnormal nails (PP4), This variant has a HMAF of 0.000002856 (1/350108 alleles) in the European (non-Finnish) population of gnomADv4.0, below the threshold of <0.00002412 (PM2_supporting). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PP3_moderate, PM1, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607552/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:2549 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0003811 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0009806 infores:hetionet CHEBI:4702 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0020615 infores:hetionet CHEBI:3001 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0151514 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0029408 infores:hetionet CHEBI:4995 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C2047937 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0271240 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0271240 infores:hetionet CHEBI:8774 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1443060 infores:hetionet CHEBI:31709 biolink:causes NCIT:C26921 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0085594 infores:hetionet CAID:CA10549330 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549330 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting BS3 The NM_005629.4:c.808G>A variant in SLC6A8 is a missense variant predicted to cause substitution of a valine for a methionine at amino acid position 270 (p.Val270Met). This variant has been reported in a heterozygous (carrier) female individual in the Exome Variant Server database without further phenotypic information provided (PMID: 25861866); thus, neither BS2 nor PP4 apply. This variant was reported to not alter transporter activity (100% vs wild-type) but experiment did not use physiological creatine concentrations (≤125μM creatine) so BS3 is not met (PMID: 25861866). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.78 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 11704, zero-star review status), with one submitter classifying this variant as pathogenic. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549330/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6640 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C1443060 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0032584 infores:hetionet CHEBI:2549 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020523 infores:hetionet CHEBI:3310 biolink:causes UMLS:C1328540 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C1328540 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151626 infores:hetionet CHEBI:3515 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0017178 infores:hetionet CHEBI:18332 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0027051 infores:hetionet CHEBI:9907 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013428 infores:hetionet CHEBI:7465 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018524 infores:hetionet UMLS:C0065374 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037011 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0236051 infores:hetionet CHEBI:4445 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0085605 infores:hetionet CHEBI:3994 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0344232 infores:hetionet CHEBI:63622 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0162830 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0035455 infores:hetionet CHEBI:75984 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0039231 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013922 infores:hetionet CHEBI:7465 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0000737 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0017178 infores:hetionet CHEBI:3223 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0023530 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0750016 infores:hetionet CHEBI:6437 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0438142 infores:hetionet CHEBI:28901 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0043352 infores:hetionet CHEBI:7822 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0040264 infores:hetionet CAID:CA386959497 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959497 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PM5_Supporting, PP3 PS4, PP4 The c.396G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to aspartic acid at codon 132 (p.(Glu132Asp)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.906, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.394G>A p.(Glu132Lys), has been classified as pathogenic by the ClinGen MDEP but has a higher grantham distance than p.(Glu132Asp) (PM5_Supporting). This variant was identified in 1 individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributors). The MODY probability is unable to be calculated due to a lack of clinical information (internal lab contributors). In summary, c.390G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_supporting, PM1, PP3, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959497/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71229 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0027497 infores:hetionet CHEBI:9599 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0002994 infores:hetionet CHEBI:17630 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0028738 infores:hetionet CHEBI:28177 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0235063 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0034150 infores:hetionet CHEBI:15552 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0015230 infores:hetionet CHEBI:6413 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0917801 infores:hetionet CAID:CA229388 biolink:causes MONDO:0009861 infores:clingen CAID:CA229388 MONDO:0009861 PMID:10408782 Likely Pathogenic PM3, PM2, PP4, PP3 The intronic variant c.1199+5G>T has been reported in two compound heterozygous probands (Akal, 2019) with Asp338Tyr (ClinVar 102468, Pathogenic) and Ala403Val (ClinVar 92731, Pathogenic). This variant is absent from population databases including ExAC, gnomAD, 1000G, and ESP and computational predictors agree that there is alteration of the WT Donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229388/MONDO:0009861/006 2020-09-12 2020-09-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6076 biolink:causes MONDO:0017078 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0014065 infores:hetionet CHEBI:63608 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0030193 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0086543 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235146 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0156353 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0156353 infores:hetionet CAID:CA658824668 biolink:causes MONDO:0007064 infores:clingen CAID:CA658824668 MONDO:0007064 PMID: Pathogenic PP4, PVS1, PM2_Supporting PM3 The c.396dup (p.Val133Serfs*38) (NM_000022.4) variant in ADA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pt) + T-B-NK- lymphocyte subset profile (0.5pt) = 1 point TOTAL, which is highly specific for SCID (PP4_Met, PMID: 21664875). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824668/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0034063 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0025517 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0267596 infores:hetionet NCBIGene:633 biolink:causes MONDO:0010515 infores:monarchinitiative not_provided not_provided HGNC:1044 MONDO:0010515 uuid:acffac31-1489-44a0-82de-48c106f01cd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4995 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0030193 infores:hetionet CAID:CA409106102 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106102 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting PM1 The c.536G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of tryptophan to serine at codon 179 (p.(Trp179Ser)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.881 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Other missense variants at the same residue, c.535T>C (p.Trp179Arg) and c.535T>C (p.Trp179Arg), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.536G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106102/MONDO:0015967/085 2025-08-12 2025-08-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA169506 biolink:causes MONDO:0007648 infores:clingen CAID:CA169506 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.1921C>T p.(Gln641Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_supporting). The variant is present in <1/100,000 alleles in the gnomAD cohort (PM2 _supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_supporting; SCV000187340.5). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_supporting, PS4_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA169506/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:100241 biolink:causes UMLS:C0151588 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151588 infores:hetionet CHEBI:6958 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0042109 infores:hetionet CHEBI:3441 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0003862 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1609512 infores:hetionet NCBIGene:57104 biolink:causes MONDO:0012545 infores:monarchinitiative not_provided not_provided HGNC:30802 MONDO:0012545 uuid:240051b8-602a-4a83-9255-b611773c3188 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA297253 biolink:causes MONDO:0021060 infores:clingen CAID:CA297253 MONDO:0021060 PMID: Uncertain Significance BS2 The c.643T>C (p.Tyr215His) variant in the SOS1 gene is present in 0.014% (5/35434) Latino alleles in gnomAD (BS1 not met). This variant was observed in 9 healthy adult individuals who did not have clinical features of a RASopathy (BS2; SCV000209098.13). In summary, the clinical significance of the p.Tyr215His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297253/MONDO:0021060/004 2019-09-24 2019-12-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6759 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0042109 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0006152 infores:hetionet CHEBI:8430 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0040034 infores:hetionet CHEBI:5790 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0023066 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0175167 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0036454 infores:hetionet CHEBI:7865 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0016382 infores:hetionet CHEBI:5001 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013604 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151828 infores:hetionet CHEBI:65346 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0037199 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0278016 infores:hetionet CHEBI:9943 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0086439 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0041969 infores:hetionet CHEBI:9720 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0234708 infores:hetionet CHEBI:6149 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020461 infores:hetionet CHEBI:38940 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0085593 infores:hetionet CHEBI:3387 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0235063 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085624 infores:hetionet CHEBI:64310 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151904 infores:hetionet NCBIGene:1785 biolink:causes MONDO:0011674 infores:monarchinitiative not_provided not_provided HGNC:2974 MONDO:0011674 uuid:158ab705-71b2-4af2-b557-f7adf584b0f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0852911 infores:hetionet CHEBI:188986 biolink:causes MONDO:0001210 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423224 infores:hetionet CHEBI:8888 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017565 infores:hetionet NCBIGene:1789 biolink:causes MONDO:0009454 infores:monarchinitiative not_provided not_provided HGNC:2979 MONDO:0009454 uuid:cc301aaa-f265-4a90-99de-4a6d534ab98a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151578 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002127 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0041974 infores:hetionet CHEBI:2922 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0017181 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017574 infores:hetionet CHEBI:66899 biolink:causes MONDO:0007769 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0854438 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0235416 infores:hetionet CHEBI:94686 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0259749 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1384666 infores:hetionet CHEBI:6375 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018524 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1608945 infores:hetionet CHEBI:64321 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0009241 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0041912 infores:hetionet UMLS:C0145185 biolink:causes HP:0012101 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0428282 infores:hetionet CHEBI:27777 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0015672 infores:hetionet CHEBI:5613 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0026837 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1096340 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1096340 infores:hetionet CHEBI:32599 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0036974 infores:hetionet CHEBI:16469 biolink:causes MONDO:0016642 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0025286 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0239978 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0018681 infores:hetionet CHEBI:32588 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0032343 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0021843 infores:hetionet CHEBI:50859 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0004134 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0040034 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0278134 infores:hetionet CHEBI:367163 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C2939147 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0036974 infores:hetionet CHEBI:17650 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151692 infores:hetionet CHEBI:63630 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0025289 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0031212 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018674 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0017160 infores:hetionet GO:0006954 biolink:causes MONDO:0005306 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D013167 DB00065_MESH_D013167_1DB07402_MESH_D013167_1DB06674_MESH_D013167_1DB00005_MESH_D013167_1DB00051_MESH_D013167_1DB08904_MESH_D013167_1 CHEBI:10023 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0392171 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0027339 infores:hetionet CAID:CA395136420 biolink:causes MONDO:0700272 infores:clingen CAID:CA395136420 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BS1, BA1 The c.682C>T (p.Gln228Ter) variant in PALB2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 4 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent in the gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA395136420/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:24564 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0023530 infores:hetionet CHEBI:84050 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0011603 infores:hetionet CHEBI:4975 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0004093 infores:hetionet CHEBI:10119 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0023518 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027059 infores:hetionet CHEBI:135530 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0020461 infores:hetionet CHEBI:45716 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0013378 infores:hetionet CHEBI:134745 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0015230 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0005741 infores:hetionet CHEBI:6809 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0039231 infores:hetionet CHEBI:28787 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0020458 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0029408 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019158 infores:hetionet CHEBI:45367 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0008031 infores:hetionet CHEBI:4953 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0035455 infores:hetionet CHEBI:4903 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0392171 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0518015 infores:hetionet CHEBI:27899 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0344232 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0234458 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0575090 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0002994 infores:hetionet CAID:CA347226407 biolink:causes MONDO:0015152 infores:clingen CAID:CA347226407 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.5860G>T p.(Glu1954Ter) variant in DYSF, which is also known as NM_001130987.2: c.5977G>T p.(Glu1993Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 52/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been confirmed in trans with a pathogenic variant in an individual with LGMD (c.857T>A (p.Val286Glu), 1.0 pt, PMID: 33927379) (PM3). This individual displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347226407/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0547030 infores:hetionet CAID:CA120621 biolink:causes MONDO:0044970 infores:clingen CAID:CA120621 MONDO:0044970 PMID:23418307 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP1, PS4, PS2, PM6 The m.15579A>G (p.Y278C) variant in MT-CYB has been reported in one individual with primary mitochondrial disease. This woman had exercise intolerance, epilepsy, intellectual disability, hearing loss, retinal dystrophy, and cataracts (PMID: 11601507). The variant was heteroplasmic in muscle (88%) and leucocytes (15%). The variant was reported as de novo as it was absent in mother’s blood, however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). A dramatic reduction of Complex III activity and Complex III-driven ATP synthesis, enhanced superoxide production, and a perturbation of glutathione homeostasis were seen in a cybrid homoplasmic for this variant (PMID: 23418307; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic or pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214); PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120621/MONDO:0044970/015 2022-07-11 2023-03-13 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5864 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0019158 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018418 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0015397 infores:hetionet CHEBI:8871 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234632 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005020 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0021831 infores:hetionet CHEBI:37924 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151970 infores:hetionet CAID:CA2740089967 biolink:causes MONDO:0008535 infores:clingen CAID:CA2740089967 MONDO:0008535 PMID: Likely Benign PM2_Supporting, BP4, BP5 The NM_001114753.3: c.816+3G>T variant in ENG is an intronic variant located in intron 6. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.03 for donor loss suggesting that the variant has no impact on splicing (BP4). Additionally, this variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; Internal lab contributors). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BP4, BP5, PM2_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA2740089967/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8069 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0221100 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037195 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0018799 infores:hetionet CHEBI:70735 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0014457 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0003864 infores:hetionet CHEBI:6076 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0013144 infores:hetionet CHEBI:17698 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0221203 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0948525 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853123 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853123 infores:hetionet CHEBI:64354 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0043352 infores:hetionet CHEBI:6149 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0003578 infores:hetionet NCBIGene:22845 biolink:causes MONDO:0012556 infores:monarchinitiative not_provided not_provided HGNC:23406 MONDO:0012556 uuid:fce44e95-859d-43ba-ab8d-47d68605e2ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235146 infores:hetionet CHEBI:404903 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0149745 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0021400 infores:hetionet NCBIGene:23328 biolink:causes MONDO:0018657 infores:monarchinitiative not_provided not_provided HGNC:19182 MONDO:0018657 uuid:febafd92-6673-4c49-9083-25b8898ceb46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0853149 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017178 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0037274 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151888 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009319 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0684249 infores:hetionet CHEBI:28901 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0003811 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0520893 infores:hetionet NCBIGene:2055 biolink:causes MONDO:0012391 infores:monarchinitiative not_provided not_provided HGNC:2079 MONDO:0012391 uuid:3bd74c01-0147-4647-a098-14388863eef0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10605085 biolink:causes MONDO:0015152 infores:clingen CAID:CA10605085 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Strong The NM_000070.3: c.2148G>T variant in CAPN3 is a missense variant predicted to cause the substitution of glutamic acid to aspartic acid at codon 716, p.(Glu716Asp). This variant has been reported in at least five individuals with features consistent with LGMD (PMID: 15689361, 32994280, 37526466; LOVD CAPN3_000296), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts; PMID: 15689361, LOVD Individual #00311346), confirmed in trans with a likely pathogenic or pathogenic variant (c.1401_1403del p.(Glu467del), 1.0 pt, PMID: 37526466), and in unknown phase with a pathogenic variant (c.967G>T p.(Glu323Ter), 0.5 pts, PMID: 15689361) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 had both a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 15689361; PP4_Strong). The filtering allele frequency for this variant is 0.000008232 (the upper threshold of the 95% CI of 4/11112002 European (non-Finnish) exome chromosomes in gnomAD v4.1.0), which is less than the LGMD VCEP threshold (0.0001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, evidence which correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605085/MONDO:0015152/187 2025-06-25 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63605 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0041657 infores:hetionet CHEBI:63617 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085932 infores:hetionet CHEBI:175901 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151905 infores:hetionet CHEBI:75984 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0004134 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0549386 infores:hetionet CHEBI:7465 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0013378 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0037274 infores:hetionet CHEBI:70707 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0030554 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0019158 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151763 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0041969 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0518015 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0037199 infores:hetionet CAID:CA226639 biolink:causes MONDO:0010725 infores:clingen CAID:CA226639 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PM4 The NM_000330.4(RS1):c.253_255del variant is an in-frame deletion variant in amino acid 85 not predicted to result in premature protein termination. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant is a short in-frame deletion of 3 base pairs that encode amino acid 85 within a non-repetitive region of RS1 (PM4). This variant has been reported in at least 2 probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PS4_supporting, PMIDs: 10533068, 39462066). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PS4_supporting, and PM4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226639/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:3756 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0242073 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0026848 infores:hetionet CHEBI:8776 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0043144 infores:hetionet CHEBI:50885 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0030305 infores:hetionet CHEBI:3032 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0036572 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0011616 infores:hetionet CHEBI:4974 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0233407 infores:hetionet CHEBI:3175 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0003578 infores:hetionet CHEBI:63624 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0010200 infores:hetionet CHEBI:7476 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151746 infores:hetionet CHEBI:63629 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0030554 infores:hetionet CHEBI:50692 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0687713 infores:hetionet CHEBI:31401 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0015230 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0013395 infores:hetionet CHEBI:5959 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C2939147 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0042109 infores:hetionet CAID:CA367398764 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398764 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS3 The c.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 381 (p.(Met381Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30257192). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30257192, internal lab contributors). At least 5 of these individuals have a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes, with at least 16 informative meioses in 6 families with MODY (PP1_Strong; PMID 30257192, internal lab contributors). In summary, the c.1142T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PP4_Moderate, PS4, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398764/MONDO:0015967/086 2023-07-17 2023-07-17 Semidominant inheritance HP:0032113 Supports CHEBI:28148 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0013378 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C1527407 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0038362 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0010073 infores:hetionet CHEBI:63608 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0234146 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0005976 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:160 MONDO:0005976 CHEBI:140621 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0242528 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0853749 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0853749 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0029408 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0677483 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0677483 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0027726 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0003864 infores:hetionet CHEBI:9316 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0235546 infores:hetionet CHEBI:499361 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C2938875 infores:hetionet CHEBI:9288 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0020615 infores:hetionet CHEBI:32221 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0016204 infores:hetionet GO:1904127 biolink:causes GO:0090245 infores:ubergraph knowledge_assertion manual_agent GO:1904127 GO:0090245 CHEBI:9671 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0018681 infores:hetionet CHEBI:50131 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0424790 infores:hetionet CAID:CA030790 biolink:causes MONDO:0007750 infores:clingen CAID:CA030790 MONDO:0007750 PMID: Benign BA1, BP4, BS2 BP2, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PM2, PVS1, PM6, PP3, PP4, PP1 The NM_000527.5(LDLR):c.941-4G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BA1 - FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1).BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics.BP4 - No REVEL, splicing evaluation needed.Functional data on splicing not available.A) variant located at -20 to +3 bases from canonical acceptor splice siteMES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64.Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0B) variant is intronicC) variant is intronicVariant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA030790/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3175 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0428977 infores:hetionet CHEBI:9150 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0751295 infores:hetionet CHEBI:64312 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151878 infores:hetionet CHEBI:3732 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0022354 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0043352 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0233571 infores:hetionet CHEBI:31705 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0917801 infores:hetionet NCBIGene:5961 biolink:causes MONDO:0024561 infores:monarchinitiative not_provided not_provided HGNC:9942 MONDO:0024561 uuid:25f58728-7cd3-44aa-b81e-9244ba3849c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0311468 infores:hetionet CHEBI:7459 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0030193 infores:hetionet CHEBI:5128 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0033774 infores:hetionet CHEBI:4024 biolink:causes UMLS:C0154933 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0154933 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0006840 infores:hetionet CHEBI:44032 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0016204 infores:hetionet CAID:CA505743509 biolink:causes MONDO:0007750 infores:clingen CAID:CA505743509 MONDO:0007750 PMID: Uncertain Significance BP4, BP7, PM2 PM5, PM1 The NM_000527.5(LDLR):c.666C>T (p.Cys222=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:- PM2: PopMax MAF = 0.000008864 (0.0008864%) in European (non-Finnish) exomes (gnomAD v2.1.1).- BP4: No REVEL, splicing evaluation required. Functional data on splicing not available.B) variant is exonic and at least 50bp downstream from canonical acceptor site and creates GTMES scores: de novo variant = 5.19; canonical donor = 7.67. Ratio de novo variant/canonical donor = 5.19/7.67 = 0.67 --- it is below 0.8Variant is not predicted to alter splicing.- BP7: Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA505743509/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7936 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020651 infores:hetionet NCBITaxon:35793 biolink:causes MONDO:0001154 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:35793 MONDO:0001154 CHEBI:7915 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0085649 infores:hetionet CHEBI:4024 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0017160 infores:hetionet CHEBI:8461 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0011603 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0851341 infores:hetionet CAID:CA397844214 biolink:causes MONDO:0018875 infores:clingen CAID:CA397844214 MONDO:0018875 PMID: Pathogenic PS2, PVS1, PM2_Supporting PS4, PS3, PM1, BS3, PM6, PP4 The NM_000546.6 c.372C>A (p.Cys124Ter) is a TP53 nonsense variant upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1; PMID: 22233476). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with LFS-associated cancers totaling 4 phenotype points (PS2; PMID: 22233476, 32658383). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS2, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397844214/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10127 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0030920 infores:hetionet CHEBI:64045 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0018418 infores:hetionet CHEBI:41423 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0851578 infores:hetionet CHEBI:2379 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0031350 infores:hetionet CHEBI:31205 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C2363731 infores:hetionet CHEBI:16469 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014743 infores:hetionet NCBITaxon:723 biolink:causes MONDO:0005630 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:723 MONDO:0005630 CHEBI:16755 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0037199 infores:hetionet CHEBI:4315 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0085593 infores:hetionet CHEBI:4856 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0428977 infores:hetionet CHEBI:7915 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0012569 infores:hetionet CHEBI:9649 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0004604 infores:hetionet CHEBI:3568 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017168 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003537 infores:hetionet CHEBI:17474 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0030794 infores:hetionet CHEBI:9241 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0014457 infores:hetionet CHEBI:6633 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0005758 infores:hetionet NCBIGene:81027 biolink:causes MONDO:0800047 infores:monarchinitiative not_provided not_provided HGNC:16257 MONDO:0800047 uuid:4515a009-0d91-403e-8f14-785608fc9da6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0017178 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036572 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0014868 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0031117 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0011991 infores:hetionet CHEBI:5147 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0015230 infores:hetionet CHEBI:31485 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0085636 infores:hetionet CHEBI:6759 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0036572 infores:hetionet CHEBI:5893 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020458 infores:hetionet CHEBI:47780 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0338831 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0026764 infores:hetionet CHEBI:45081 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0030554 infores:hetionet CHEBI:38562 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0038325 infores:hetionet CAID:CA412745161 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745161 MONDO:0100437 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM5, PS4, BP4 NM_001034853.2(RPGR):c.389T>C (p.Phe130Ser) is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 130. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives the variant a score of 0.761, which is between the ClinGen X-linked IRD VCEP thresholds of 0.664 to 0.772 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.01 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. At least 1 patient with this variant has been diagnosed with X-linked retinopathy, but phenotype details necessary to meet PP4 or include the patient in PS4_Supporting have not been reported (PMID: 28863407, PMID: 32531858, SCV001162677.1). Another missense variant in the same codon, NM_001034853.2(RPGR):c.389T>G (p.Phe130Cys), has been reported in a patient with X-linked retinopathy (PMID: 8817343). However, the present variant has a lower Grantham score (155) than the comparison variant (205), so that the PM5 code cannot be evaluated. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and PP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745161/MONDO:0100437/106 2025-05-29 2025-05-29 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63791 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0746883 infores:hetionet CHEBI:135342 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0039231 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0022660 infores:hetionet CHEBI:168396 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085632 infores:hetionet CHEBI:6704 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0036572 infores:hetionet CHEBI:64355 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0014742 infores:hetionet CHEBI:2682 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018524 infores:hetionet CHEBI:41423 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0038325 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0234458 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0033975 infores:hetionet CAID:CA343723562 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723562 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.1364C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Lysine at amino acid 455 (p.Thr455Lys). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.938, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 10 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 18067072), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 18067072), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723562/MONDO:0020367/019 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63845 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0409974 infores:hetionet CHEBI:6761 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0034150 infores:hetionet CHEBI:5002 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0020651 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0027765 infores:hetionet CHEBI:8499 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0011991 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0234458 infores:hetionet UMLS:C0120107 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0025323 infores:hetionet CHEBI:100147 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C3263723 infores:hetionet CHEBI:28915 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0025160 infores:hetionet CAID:CA5416902 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416902 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.319G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Valine by Isoleucine at amino acid 107 (p.Val107Ile).The highest population minor allele frequency in gnomAD v4 is 0.0000009500 (2/349990 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416902/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6775 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0008350 infores:hetionet CHEBI:2668 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0004238 infores:hetionet CHEBI:64355 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017675 infores:hetionet CAID:CA410202750 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202750 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.373C>T (p.Pro125Ser) is a missense variant which affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202750/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1139665148 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665148 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PS1, PVS1 The c.1193_1194insGCA; (p.Tyr398delinsTer) variant in ACADVL is a insertion variant predicted to cause an immediate premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The same amino acid change (p.Tyr398Ter), resulting from a different nucleotide change (c.1194C>A), is classified as pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PS1; PMID: 10529389, ClinVar ID: 810875). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665148/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:23765 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0004134 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0038454 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0036572 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0232492 infores:hetionet CHEBI:6538 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0011603 infores:hetionet GO:1904594 biolink:causes GO:0006366 infores:ubergraph knowledge_assertion manual_agent GO:1904594 GO:0006366 CHEBI:28901 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085682 infores:hetionet CHEBI:7443 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0028084 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0553732 infores:hetionet UMLS:C0011701 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0026821 infores:hetionet CHEBI:32221 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0028961 infores:hetionet CHEBI:3223 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0039070 infores:hetionet CHEBI:94609 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0036104 infores:hetionet CHEBI:6413 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042963 infores:hetionet CHEBI:63681 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0231218 infores:hetionet CHEBI:145499 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C3495920 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0025061 infores:hetionet CHEBI:3176 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0235710 infores:hetionet CHEBI:3478 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151872 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0013595 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151736 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0948594 infores:hetionet CHEBI:31547 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0151904 infores:hetionet CHEBI:10124 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0009676 infores:hetionet CHEBI:8024 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151908 infores:hetionet CHEBI:8805 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0002878 infores:hetionet CHEBI:28445 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0270810 infores:hetionet CHEBI:63581 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0151908 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0948089 infores:hetionet CHEBI:32192 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0011603 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0948594 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0005940 infores:hetionet CAID:CA367399922 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399922 MONDO:0015967 PMID: Uncertain Significance PS4_Moderate, PM5_Supporting, PP2, PM2_Supporting PM1, PP3, PP4, BP4 The c.950A>C variant in the glucokinase gene, GCK, causes an amino acid change of histidine to proline at codon 317 (p.(His317Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.392, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to the presence of no more than 1 copy in any subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 29056535, 36400171, 38933241; ClinVar). This variant was identified in individuals with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 29056535, 36400171, 38933241; ClinVar). Another missense variant at the same residue, c.951C>G (p.His317Gln), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.950A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS4_Moderate, PP2, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399922/MONDO:0015967/086 2025-08-29 2025-08-29 Semidominant inheritance HP:0032113 Inconclusive true NCBIGene:6005 biolink:causes MONDO:0019107 infores:monarchinitiative not_provided not_provided HGNC:10006 MONDO:0019107 uuid:7b05823c-b1ee-4e9c-b433-96213a785109 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8228 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0005684 infores:hetionet GO:0085033 biolink:causes GO:0007249 infores:ubergraph knowledge_assertion manual_agent GO:0085033 GO:0007249 CHEBI:100147 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0041834 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0235146 infores:hetionet NCBIGene:1841 biolink:causes MONDO:0859241 infores:monarchinitiative not_provided not_provided HGNC:3061 MONDO:0859241 uuid:ccc61609-2f8d-4071-b8a8-771d0f70f30b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3510 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C2830004 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0032285 infores:hetionet GO:0106088 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0072359 CHEBI:6801 biolink:causes HP:0001993 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0220982 infores:hetionet CHEBI:3638 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0030312 infores:hetionet CHEBI:4495 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0242528 infores:hetionet CHEBI:66901 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0024103 infores:hetionet CHEBI:5778 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0428974 infores:hetionet CHEBI:4798 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0233407 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0151609 infores:hetionet CAID:CA405669526 biolink:causes MONDO:0007783 infores:clingen CAID:CA405669526 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate, PM5_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with valine at codon 2431 of the RYR1 protein, p.(Asp2431Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.952) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405669526/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:4453 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0855242 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0003850 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0080274 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011991 infores:hetionet CHEBI:2955 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0014335 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005892 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0029883 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0232492 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0314719 infores:hetionet CHEBI:8707 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0392684 infores:hetionet CHEBI:63637 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0022603 infores:hetionet CHEBI:52717 biolink:causes MONDO:0018051 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0580181 infores:hetionet CHEBI:63613 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0014457 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1384353 infores:hetionet GO:2000194 biolink:causes GO:0046545 infores:ubergraph knowledge_assertion manual_agent GO:2000194 GO:0046545 CHEBI:10102 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0015402 infores:hetionet UMLS:C0209366 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0027497 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015230 infores:hetionet CHEBI:7936 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0080274 infores:hetionet CHEBI:6909 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1519353 infores:hetionet CHEBI:50156 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C2697368 infores:hetionet CHEBI:3082 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0033774 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0026946 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0085649 infores:hetionet CHEBI:63589 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0035078 infores:hetionet CHEBI:101085 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0003123 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0700572 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0700572 infores:hetionet CHEBI:51860 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0040822 infores:hetionet CHEBI:4814 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0232849 infores:hetionet CHEBI:47612 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0008350 infores:hetionet CHEBI:6847 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0034150 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011551 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0520966 infores:hetionet CHEBI:6339 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C2979982 infores:hetionet CHEBI:135342 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0004093 infores:hetionet NCBIGene:1201 biolink:causes MONDO:0008767 infores:monarchinitiative not_provided not_provided HGNC:2074 MONDO:0008767 uuid:5cf9bc4e-fdbf-46fc-8598-53999d191840 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151889 infores:hetionet CHEBI:28177 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0027497 infores:hetionet CHEBI:5801 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0162835 infores:hetionet CHEBI:8028 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0023380 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011991 infores:hetionet GO:1905304 biolink:causes GO:0055013 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0055013 CAID:CA409108330 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108330 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS4 The c.949C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to valine at codon 317 (p.(Leu317Val)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.793, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 34556497, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; PMID: 34556497, internal lab contributors). In summary, c.949C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108330/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5147 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0003873 infores:hetionet CHEBI:61390 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0015230 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0006826 infores:hetionet NCBIGene:2203 biolink:causes MONDO:0009251 infores:monarchinitiative not_provided not_provided HGNC:3606 MONDO:0009251 uuid:cc325f7a-499f-4248-a6c0-39316f1d4675 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0021177 infores:hetionet CHEBI:8863 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151786 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0027765 infores:hetionet CHEBI:46195 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0015230 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0267792 infores:hetionet CHEBI:3213 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0037763 infores:hetionet CHEBI:37941 biolink:causes MONDO:0024415 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0341245 infores:hetionet CHEBI:16755 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0010692 infores:hetionet NCBIGene:8239 biolink:causes MONDO:0010502 infores:monarchinitiative not_provided not_provided HGNC:12632 MONDO:0010502 uuid:833c4993-e431-4b2f-81a4-fdb3443933ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0340865 infores:hetionet CHEBI:50567 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0042963 infores:hetionet CHEBI:6887 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0237849 infores:hetionet CHEBI:10119 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0009782 infores:hetionet CHEBI:9757 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0022568 infores:hetionet CAID:CA410206795 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206795 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.736A>G (p.Thr246Ala) is a missense variant which has a REVEL score <0.50 (0.165) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206795/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8802 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1141930 infores:hetionet CHEBI:9168 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0024314 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0521490 infores:hetionet CHEBI:5801 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0018784 infores:hetionet CHEBI:8356 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0000731 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0262397 infores:hetionet CHEBI:6078 biolink:causes HP:0003698 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0241237 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0262385 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0026846 infores:hetionet UNII:7F465U79Q1 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0009450 infores:hetionet CAID:CA404080954 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080954 MONDO:0007750 PMID: Uncertain Significance BS3, PM2, PP3 BA1, BP4, BP2, PS3, PS4, PS2, PS1, BS1, BS4, BP7, PM4, PM3, PM1, PM5, PM6, PVS1, BS2, PP1, PP4 The NM_000527.5(LDLR):c.890A>C (p.Asn297Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, BS3, PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.BS3 - Level 1 assays: PMID 28645073:Heterologous cells (CHO-ldlA7), WB, FACS and CLSM assays - result - Normal (91%) expression, binding (97%) and uptake (100%)---- functional study is consistent with no damaging effect (whole cycle is above 90%), so BS3 is Met.PP3 - REVEL = 0.785.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080954/MONDO:0007750/013 2022-02-14 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:127780 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085682 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0011849 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0037199 infores:hetionet CHEBI:63580 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0428977 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002994 infores:hetionet CHEBI:8364 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0231218 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030578 infores:hetionet CHEBI:50173 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0001973 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0019158 infores:hetionet GO:1905063 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905063 GO:0007275 CHEBI:28748 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0521839 infores:hetionet CHEBI:8707 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042998 infores:hetionet CAID:CA9043745 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043745 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4 PM5 The NM_000156.6:c.299G>A variant in GAMT is a missense variant that is predicted to cause the substitution of an arginine by a glutamine at amino acid position 100 (p.Arg100Gln). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003629 (2/55112 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.203 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 2145645). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043745/MONDO:0012999/026 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:54Z8M50D6Q biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0020625 infores:hetionet CHEBI:7577 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0030554 infores:hetionet UMLS:C0065374 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0013428 infores:hetionet CHEBI:6076 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151746 infores:hetionet CHEBI:474180 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0042963 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0009806 infores:hetionet CHEBI:9725 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0026837 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235706 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235706 infores:hetionet CHEBI:31348 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042487 infores:hetionet CHEBI:50729 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C1287298 infores:hetionet CHEBI:15367 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2047937 infores:hetionet CHEBI:50131 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0023380 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0004936 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0041969 infores:hetionet CHEBI:5790 biolink:causes MONDO:1040026 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0220650 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027947 infores:hetionet CHEBI:28177 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C1291078 infores:hetionet CHEBI:175901 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1443060 infores:hetionet CHEBI:7476 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0344232 infores:hetionet CHEBI:9763 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0011124 infores:hetionet CAID:CA16024224 biolink:causes MONDO:0021056 infores:clingen CAID:CA16024224 MONDO:0021056 PMID: Pathogenic PVS1, PS4_Moderate, PM2_Supporting The NM_000038.6(APC):c.1333C>T (p.Gln445Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and is predicted to cause a premature stop codon in exon 11 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 2.0 points (PS4_Moderate, [PMID: 19793053, Ambry Genetics]). The variant is reported in one additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 35418818). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1, PS4_Moderate, PM2_Supporting (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16024224/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31981 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0232461 infores:hetionet CHEBI:6633 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0085624 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0020517 infores:hetionet CAID:CA009864 biolink:causes MONDO:0007356 infores:clingen CAID:CA009864 MONDO:0007356 PMID: Likely Pathogenic PP3_Moderate, PM5, PP1_Moderate, PP4_Moderate, PM2_Supporting The NM_000249.4:c.350C>G variant in MLH1 is a missense variant predicted to cause substitution of Threonin by Arginin at amino acid 117 (p.Thr117Arg). Criteria PM5 is met since p.(Thr117Arg) is a missense change at an amino acid residue where a different missense change was classified by this VCEP as pathogenic on the protein level and not due to aberrant splicing (p.Thr117Met is InSiGHT class 5). The variant is not reported in gnomAD v2.1 and once in gnomAD v4.1 (PM2_supporting). Co-segregation studies showed segragation with disease in pedigree(s) with a combined Bayes Likelihood Ratio >2.08 & ≤4.32 (PP1). The prior probability is 0.948 (PP3_moderate). The variant was detected in 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM5, PM2_SUP, PP1, PP3, PP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA009864/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3973 biolink:causes MONDO:0009384 infores:monarchinitiative not_provided not_provided HGNC:6585 MONDO:0009384 uuid:bd7db8e2-b815-44fa-8f5e-73b9d7359ba4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0023380 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0036572 infores:hetionet CAID:CA10587145 biolink:causes MONDO:0015967 infores:clingen CAID:CA10587145 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 PS4, PP4 The c.1623+3A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 8 of NM_000545.8. Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss, suggesting that the variant has no impact on splicing (BP4). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the number is below the ClinGen MDEP threshold (Clinvar ID: 256598; Internal lab contributors). Also, PP4 cannot be applied because, despite this variant being identified in an individual with diabetes, the MODY probability cannot be calculated as the age at diagnosis is above 35 years (Internal lab contributor). In summary, c.1623+3A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587145/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6076 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0344232 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0521501 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0521501 infores:hetionet CAID:CA415079466 biolink:causes MONDO:0010305 infores:clingen CAID:CA415079466 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_005629.4:c.634G>T (p.Glu212Ter) variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One male patient has been reported with clinical features consistent with creatine transporter deficiency, elvated urine creatine/creatinine ratio (1 point) and brain MRS showing decreased creatine peak (PMID: 29435807) (PP4_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the citeria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific crietria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415079466/MONDO:0010305/027 2023-03-09 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:6923 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0002871 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0041969 infores:hetionet CHEBI:4530 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0033975 infores:hetionet CHEBI:101853 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0542571 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0001824 infores:hetionet CHEBI:681569 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0030554 infores:hetionet CAID:CA2579830381 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830381 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PM1_Supporting The c.-176T>C p.(?) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant in the promoter region of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within a conserved region of the HNF1A/HNF1B binding site in the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.-176T>C p.(?) meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830381/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75998 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0015230 infores:hetionet CAID:CA7143032 biolink:causes MONDO:0019497 infores:clingen CAID:CA7143032 MONDO:0019497 PMID: Benign BA1 The filtering allele frequency (the lower threshold of the 95% CI of 44/24026) of the c.429A>G (p.Pro143=) variant in the COCH gene is 0.14% for African chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA7143032/MONDO:0019497/005 2019-03-25 2019-07-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA3897446 biolink:causes MONDO:0019497 infores:clingen CAID:CA3897446 MONDO:0019497 PMID: Likely Pathogenic PVS1 BS1, BS4, PP1, PM5, PM4, PM1, PM2, PM6, BA1, BP3, PS1, PS4, PS2 The c.2751dup (p.Gln918fs) frameshift variant in MYO6 is predicted to cause a premature stop codon in biologically-relevant exon 26 of 35 total exons, leading to a truncated or absent protein in a gene where loss of function is an established mechanism of autosomal dominant hearing loss (PVS1; PMID: 30192042). The highest minor allele frequency in gnomAD v.2.1.1 was 0.048% (52/109484) of European (non-Finnish) population, but was noted to occur in a low complexity region where variant quality was dubious, so BS1 was not applied. It was observed in 2 probands with moderate sensorineural hearing loss, meeting PS4_Supporting (PMID: 25080041, 33297549). In summary, this variant is likely pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PVS1, PS4_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 7/25/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA3897446/MONDO:0019497/005 2023-07-25 2023-10-05 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:135342 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0009676 infores:hetionet CHEBI:32588 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0000737 infores:hetionet CHEBI:9637 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0030305 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020039 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001164 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003431 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0025209 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0006285 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0836924 infores:hetionet CAID:CA229866 biolink:causes MONDO:0009861 infores:clingen CAID:CA229866 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PM3, PP4 The frameshift variant c.941del (HGVS nomenclature c.940del) occurs in exon 9 of 13 and is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One classical PKU patient has been reported (PMID: 9600453) with this variant in trans with c.1066-11G>A (ClinVar 607, Pathogenic with expert panel review). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229866/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports UNII:R15UI3245N biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0235295 infores:hetionet GO:0045700 biolink:causes GO:0048515 infores:ubergraph knowledge_assertion manual_agent GO:0045700 GO:0048515 CHEBI:50693 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0151636 infores:hetionet CHEBI:4445 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0311468 infores:hetionet CHEBI:6931 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0012569 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0027769 infores:hetionet CHEBI:5134 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0423153 infores:hetionet CHEBI:2904 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0043352 infores:hetionet CHEBI:6061 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0036974 infores:hetionet CHEBI:61058 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0011991 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0851341 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0032285 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009760 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0010399 infores:hetionet CHEBI:16755 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0025222 infores:hetionet CHEBI:8863 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017979 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0027765 infores:hetionet CHEBI:4551 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0423791 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0039971 infores:hetionet UMLS:C1738934 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0007859 infores:hetionet CHEBI:46195 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0014518 infores:hetionet CHEBI:3654 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0030554 infores:hetionet CHEBI:63635 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0917801 infores:hetionet CHEBI:3996 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0151610 infores:hetionet CHEBI:46557 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0030196 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0034530 infores:hetionet CHEBI:63617 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0014457 infores:hetionet CHEBI:3398 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0344232 infores:hetionet CHEBI:3219 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011124 infores:hetionet CAID:CA327916189 biolink:causes MONDO:0100437 infores:clingen CAID:CA327916189 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2218G>T (p.Glu740Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 740 within exon 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 7 years (1 pt), reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with pigment deposits (0.5 pts), optic disc pallor (0.5 pts), cataract, severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327916189/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:10023 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0242528 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151565 infores:hetionet CHEBI:46345 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0027540 infores:hetionet CHEBI:5138 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023380 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0853692 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0233459 infores:hetionet CHEBI:474180 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0029118 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0018674 infores:hetionet CHEBI:8214 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0039231 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151838 infores:hetionet CHEBI:63791 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0542571 infores:hetionet CHEBI:61058 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0027424 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0474381 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1443060 infores:hetionet CHEBI:84883 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0151603 infores:hetionet CHEBI:75722 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030193 infores:hetionet CHEBI:2611 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0080274 infores:hetionet CHEBI:63598 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0231528 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0005741 infores:hetionet CHEBI:31859 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0040435 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014457 infores:hetionet GO:0003312 biolink:causes CL:0002275 infores:ubergraph knowledge_assertion manual_agent GO:0003312 CL:0002275 CHEBI:36791 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234047 infores:hetionet CHEBI:167638 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0042963 infores:hetionet CHEBI:3756 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013456 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0039971 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0851341 infores:hetionet CHEBI:7936 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002792 infores:hetionet CAID:CA255086 biolink:causes MONDO:0010602 infores:clingen CAID:CA255086 MONDO:0010602 PMID: Likely Pathogenic PM5, PM2_Supporting, PP3, PS4_Moderate PP1 The c.980T>C (p.Leu327Pro) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The variant has been reported in two probands with severe hemophilia A meeting phenotypic criteria for F8 in PMID: 8644728 and 26897466. This missense variant has a REVEL score of 0.926 (>0.6). A pathogenic variant, Leu327Val, is reported at the same residue meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PP3, PS4_Moderate, PM2_Supporting, PM5. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255086/MONDO:0010602/071 2024-09-30 2024-10-01 X-linked inheritance HP:0001417 Supports CAID:CA032045 biolink:causes MONDO:0007750 infores:clingen CAID:CA032045 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, PS1, BS1, PM5, PP3 The NM_000527.5(LDLR):c.1088C>T (p.Thr363Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003334 (0.003334%) in Admixed American exomes+genomes (gnomAD v4.1.0).BP4: REVEL=0.289, it is below 0.5, splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby:First AG -- MES score: variant cryptic site= 3.16, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 3.16/2.69=1.175 --- It is above > 1.1. Ratio Var cryptic/Wt canonical= 3.16/13.90=0.227 --- it is NOT above > 0.9.Second AG -- MES score: variant cryptic site= -2.41, wt cryptic site= -3.45, canonical WT site=13.90.Variant not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA032045/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15428 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0085593 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0027769 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013146 infores:hetionet NCBIGene:8737 biolink:causes MONDO:0020849 infores:monarchinitiative not_provided not_provided HGNC:10019 MONDO:0020849 uuid:37c0883e-fb1a-401c-a8d2-df8c45bca736 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0278008 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0022116 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0267596 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0011849 infores:hetionet CHEBI:50841 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0030446 infores:hetionet CHEBI:194135 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038999 infores:hetionet CHEBI:31397 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0042029 infores:hetionet CAID:CA6748843 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748843 MONDO:0009861 PMID: Likely Benign BS1, BP7 PM2 PAH-specific ACMG/AMP criteria applied: BS1: > PAH specific guidelines of AF-0.0002 (0.02%); BP7: No deleterious effect predicted.. In summary this variant meets criteria to be classified as likely benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BP7). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748843/MONDO:0009861/006 2018-08-13 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:367163 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0853034 infores:hetionet NCBIGene:5052 biolink:causes MONDO:0010184 infores:monarchinitiative not_provided not_provided HGNC:9352 MONDO:0010184 uuid:6ef7fa6b-5968-4049-851b-526ad71e1a2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0004833 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0149756 infores:hetionet CHEBI:9649 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151825 infores:hetionet CHEBI:63631 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0026858 infores:hetionet CAID:CA160007 biolink:causes MONDO:0015967 infores:clingen CAID:CA160007 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1 The c.1896A>G variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 632 (p.Ter632=) of NM_000545.8. The computational splicing predictor SpliceAI gives a score of 0.01 for acceptor loss/gain, suggesting that the variant has no impact on splicing (BP4). However, BP7 was not applied for this synonymous variant because phyloP100way suggests conservation with a score >2.0 (2.801). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 0.00000247, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). In summary, c.1896A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA160007/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA512319003 biolink:causes MONDO:0100083 infores:clingen CAID:CA512319003 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.99T>C (p.Asp33=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI predicted acceptor loss of 0.32, which indicates it may impact splicing (BP4/BP7 not applied). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319003/MONDO:0100083/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71940 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0600142 infores:hetionet CHEBI:36791 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0424790 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0009806 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042769 infores:hetionet CHEBI:4670 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0020621 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0549373 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0002871 infores:hetionet NCBIGene:8419 biolink:causes MONDO:0012701 infores:monarchinitiative not_provided not_provided HGNC:1041 MONDO:0012701 uuid:3dec9ee7-1a1b-4fcf-86be-814040246d82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0231218 infores:hetionet CHEBI:8768 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1142412 infores:hetionet CHEBI:45599 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0233407 infores:hetionet CHEBI:4672 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0009676 infores:hetionet UNII:7662KG2R6K biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C2129214 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0948089 infores:hetionet CHEBI:135939 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0042721 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0041909 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0332575 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0234215 infores:hetionet CHEBI:77733 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0016382 infores:hetionet CHEBI:4814 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0151786 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0079043 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0233494 infores:hetionet CHEBI:3561 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C3263723 infores:hetionet CHEBI:27953 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00981 UMLS:C0036104 infores:hetionet CHEBI:134966 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0575081 infores:hetionet CHEBI:7852 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0041657 infores:hetionet CAID:CA8328596 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328596 MONDO:0100438 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3, PS3_Supporting NM_014336.5(AIPL1):c.190G>A (p.Gly64Arg) is a missense variant predicted to replace glycine with arginine at amino acid p.64. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00001921, with 31 / 1614006 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the p.Trp278Ter variant confirmed in trans (VCEP member data, 1 pt) and suspected in trans (PMID:22412862, PMID: 25596619, 0.5 points), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), onset between birth and age ten years (1 pt), nystagmus (1 pt), RPE mottling (0.5 pts), and evidence of cone involvement on ERG (1 pt) which together are specific for AIPL1-related retinopathy (total 4 points, PMID: 22412862, PP4). The computational predictor REVEL gives a score of 0.949, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.93 and predicts a damaging effect on AIPL1 protein function (PP3_Strong). Cells exogenously expressing the variant protein exhibit more than 60% reduction of cGMP levels relative to the wild-type control, which was equivalent to the control lacking AIPL1 (PMID: 28973376, PS3_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3_Strong, PM3, PM2_Supporting, PP4, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328596/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75722 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0021400 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0011991 infores:hetionet CHEBI:27690 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0001824 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0022658 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0040053 infores:hetionet CHEBI:7852 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085593 infores:hetionet CHEBI:27470 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C1443060 infores:hetionet CHEBI:3996 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0235198 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0559031 infores:hetionet CHEBI:182080 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0542571 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0149931 infores:hetionet CHEBI:63584 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0080274 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0021400 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0404521 infores:hetionet CHEBI:28787 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C3665347 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151763 infores:hetionet GO:0060480 biolink:causes CL:1000143 infores:ubergraph knowledge_assertion manual_agent GO:0060480 CL:1000143 CHEBI:91583 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C2047937 infores:hetionet NCBIGene:3737 biolink:causes MONDO:0014607 infores:monarchinitiative not_provided not_provided HGNC:6220 MONDO:0014607 uuid:d257b010-e124-4cd9-86be-22f0e7cb04d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0019348 infores:hetionet CHEBI:7575 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0267792 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0948089 infores:hetionet CHEBI:4356 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0035304 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027651 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042514 infores:hetionet CHEBI:3219 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016382 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0018524 infores:hetionet CHEBI:68478 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0023518 infores:hetionet CHEBI:9137 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151908 infores:hetionet NCBIGene:10142 biolink:causes MONDO:0012738 infores:monarchinitiative not_provided not_provided HGNC:379 MONDO:0012738 uuid:e7ad3ea0-395f-4e00-87b6-52cbd13305f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17026 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0520587 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0020649 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0235146 infores:hetionet CHEBI:3723 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235886 infores:hetionet CHEBI:135193 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0010200 infores:hetionet CHEBI:68647 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0040034 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0042769 infores:hetionet CHEBI:2611 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013456 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0233494 infores:hetionet CHEBI:63605 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0008031 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0521854 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0521854 infores:hetionet CHEBI:74947 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0007859 infores:hetionet UMLS:C0879264 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0428977 infores:hetionet CAID:CA404079930 biolink:causes MONDO:0007750 infores:clingen CAID:CA404079930 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP4, PP1, BS2 The NM_000527.5(LDLR):c.770G>C (p.Arg257Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404079930/MONDO:0007750/013 2022-08-29 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3441 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0546817 infores:hetionet CHEBI:15940 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0037299 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0033771 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0040409 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0580417 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0580417 infores:hetionet CHEBI:8356 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033774 infores:hetionet CAID:CA016679 biolink:causes MONDO:0005045 infores:clingen CAID:CA016679 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PS4_Moderate, PP1_Moderate PM5, PM6, BA1, PP3, PS3, BS1, BS3, BS4, PS1, PS2, BP4 The c.715G>A (p.Asp239Asn) variant in MYH7 has been identified in at least 13 individuals with HCM (PS4_Moderate; Iascone 2007 PMID:17438619; Kaski 2009 PMID:20031618; Garcia-Pavia 2011 PMID:21896538; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ingles 2017 PMID:28408708) and segregated with HCM in 5 affected individuals from 4 families (PP1_Moderate; Iascone 2007 PMID:17438619; Garcia-Pavia 2011 PMID:21896538; LMM ClinVar SCV000059647.6 and pers comm). This variant has been identified in 0.003% (1/34592) of Latino chromosomes but is absent from all other populations in gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PM1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016679/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:50964 biolink:causes MONDO:0021021 infores:monarchinitiative not_provided not_provided HGNC:13771 MONDO:0021021 uuid:5b8e92ad-bfae-422b-8124-62d8a007e09a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37941 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0030252 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013146 infores:hetionet CHEBI:17026 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0000737 infores:hetionet CHEBI:15552 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020437 infores:hetionet CHEBI:4653 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0002962 infores:hetionet GO:1902692 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1902692 GO:0007275 CHEBI:31643 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0151610 infores:hetionet CHEBI:63622 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0023066 infores:hetionet CHEBI:2950 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0003126 infores:hetionet GO:0045064 biolink:causes CL:0000546 infores:ubergraph knowledge_assertion manual_agent GO:0045064 CL:0000546 CHEBI:46295 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0474381 infores:hetionet CHEBI:135736 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C2830004 infores:hetionet CHEBI:135351 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C2830004 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0004936 infores:hetionet CHEBI:3485 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0019080 infores:hetionet CHEBI:63619 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0302809 infores:hetionet CHEBI:28787 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C1328539 infores:hetionet CHEBI:134991 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0039070 infores:hetionet NCBIGene:11222 biolink:causes MONDO:0013811 infores:monarchinitiative not_provided not_provided HGNC:10379 MONDO:0013811 uuid:208a17cd-e07e-435f-ac78-acba8d5bb538 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135920 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0012813 infores:hetionet CHEBI:7476 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020458 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007867 infores:hetionet CHEBI:27504 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0232462 infores:hetionet UBERON:0000992 biolink:causes MONDO:0005602 infores:ubergraph knowledge_assertion manual_agent UBERON:0000992 MONDO:0005602 CHEBI:8768 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0022904 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027765 infores:hetionet CHEBI:8871 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023222 infores:hetionet CAID:CA10385560 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385560 MONDO:0100437 PMID: Benign BP4, BA1 PM2, PM1, BP3 NM_001034853.2(RPGR): c.1059+6G>A an intron 9 variant located six nucleotides after exon 9. This variant is present in gnomAD v4.1.0 at a frequency of 0.0002996 among hemizygous individuals, with 114 variant alleles / 380,467 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385560/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:51450 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C2242588 infores:hetionet NCBIGene:6678 biolink:causes MONDO:0014672 infores:monarchinitiative not_provided not_provided HGNC:11219 MONDO:0014672 uuid:de28b10a-7ee4-4e8f-b1dd-c4b81bd342a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA415079810 biolink:causes MONDO:0010305 infores:clingen CAID:CA415079810 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.676G>T variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/13 (p.Glu226Ter) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been previously reported in one male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 21, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415079810/MONDO:0010305/027 2024-03-21 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:6887 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0039971 infores:hetionet CAID:CA10549611 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549611 MONDO:0010305 PMID: Uncertain Significance BS2, PP3 BS1, BP7, PM2 The NM_005629.4:c.1650C>G variant in SLC6A8 is a synonymous (silent) variant (p.Thr550=). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency (MAF) is 0.00002961 (1/33771 alleles) in the East Asian population. This MAF is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There are 4 hemizygotes across all populations in gnomAD v4.1.0 (3 in the European non-Finnish population, and one in the remaining population) (BS2). The in silico predictor, SpliceAI, predicts gain of a donor splice site one nucleotide upstream (-1); the score is 0.70 (PP3). No RT-PCR studies are available to investigate this prediction. Due to the predicted impact on splicing, although this is a synonymous variant, BP7 is not met. There is a ClinVar entry for this variant (Variation ID: 1139929). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, PP3(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549611/MONDO:0010305/027 2025-03-13 2025-03-14 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:70 biolink:causes MONDO:0013011 infores:monarchinitiative not_provided not_provided HGNC:143 MONDO:0013011 uuid:198b6ada-d316-47e0-a3c8-25b104cd7d88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1112214 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0233414 infores:hetionet CHEBI:50859 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0003467 infores:hetionet CHEBI:2687 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151904 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C2939147 infores:hetionet NCBIGene:374879 biolink:causes MONDO:0859181 infores:monarchinitiative not_provided not_provided HGNC:24750 MONDO:0859181 uuid:8f7bf1a3-bc89-4ae4-9b7e-73de24be13ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70707 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0038661 infores:hetionet CHEBI:31711 biolink:causes UMLS:C1961112 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C1961112 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C2225524 infores:hetionet CHEBI:3286 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C3665347 infores:hetionet CHEBI:31981 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0235660 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0948089 infores:hetionet CHEBI:31236 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235267 infores:hetionet CHEBI:2038 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0025222 infores:hetionet CAID:CA915940809 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940809 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000212.3(ITGB3):c.1616_1617del (p.Phe539TrpfsTer11) is a frameshift variant that causes a premature stop codon at exon 10 and is predicted to undergo nonsense mediated decay (PVS1). The mutation was not found in gnomAD v2.1.1 (PM2_supporting). The variant was found in one homozygous proband reported in the GT database (entry 174). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3_supporting and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940809/MONDO:0100326/011 2023-02-02 2023-02-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ PUBCHEM.COMPOUND:122173801 biolink:causes HP:0033608 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0034079 infores:hetionet CHEBI:6067 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0232849 infores:hetionet CAID:CA367398767 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398767 MONDO:0015967 PMID: Likely Pathogenic PM3_Supporting, PM5, PP2, PP3, PP4, PM2_Supporting PS4 The c.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 381 (p.(Met381Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9459, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant was identified in an individual with neonatal diabetes who was homozygous for this variant (PP4; PM3_Supporting; internal lab contributor). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Lys has an equal or greater Grantham distance (PM5). In summary, c.1142T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4, PM5, PP2, PP3, PM2_Supporting, PM3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398767/MONDO:0015967/086 2023-09-09 2023-09-09 Semidominant inheritance HP:0032113 Supports CHEBI:9139 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042907 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0023895 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002378 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0011649 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0031350 infores:hetionet CHEBI:77260 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0428977 infores:hetionet CHEBI:50275 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0497156 infores:hetionet NCBIGene:9181 biolink:causes MONDO:0056797 infores:monarchinitiative not_provided not_provided HGNC:682 MONDO:0056797 uuid:4ef8257c-90ae-45c3-afe9-949b781986be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4975 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0043246 infores:hetionet CHEBI:5109 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0011603 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042373 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0278080 infores:hetionet CHEBI:5098 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0541799 infores:hetionet CHEBI:47780 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020453 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0037274 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0242350 infores:hetionet CHEBI:6339 biolink:causes HP:0032325 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0333559 infores:hetionet CHEBI:75984 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C1456784 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0231218 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0232459 infores:hetionet NCBIGene:23446 biolink:causes MONDO:0030028 infores:monarchinitiative not_provided not_provided HGNC:18798 MONDO:0030028 uuid:f91b2688-dd04-465d-a218-629994061f14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0013395 infores:hetionet CHEBI:52010 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0001824 infores:hetionet CHEBI:204928 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0011603 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0022650 infores:hetionet CHEBI:16469 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0023903 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0007043 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0007043 uuid:39e71975-c236-4da2-b4ce-386252616ec6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042075 infores:hetionet CHEBI:5779 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0004604 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0007562 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0007562 uuid:83f366c9-4805-4f7d-bd28-d6a4c049dfad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0035309 infores:hetionet CHEBI:499361 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151539 infores:hetionet CHEBI:180905 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0151699 infores:hetionet CHEBI:8863 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0041105 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0000833 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235146 infores:hetionet CHEBI:3761 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0022107 infores:hetionet CAID:CA626379036 biolink:causes MONDO:0100326 infores:clingen CAID:CA626379036 MONDO:0100326 PMID: Likely Pathogenic PM3, PM4, PP4_Moderate, PM2_Supporting NM_000212.3(ITGB3):c.887_901del (p.Asp296_His300del) is an in frame deletion variant predicted to remove 5 amino acid residues (PM4). At least two patients (GT31, GT41 in PMID:19691478) were homozygous for this variant and displayed mucocutaneous bleeding plus impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate, PM3). The highest population minor allele frequency in gnomAD v4.1 is 0.00004392 (4/91076 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM4, PP4_moderate, and PM3. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626379036/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:131405 biolink:causes MONDO:0032862 infores:monarchinitiative not_provided not_provided HGNC:32669 MONDO:0032862 uuid:2bf42e35-19b2-46fd-ad39-4b167f7b7028 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020639 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151736 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151744 infores:hetionet CHEBI:31624 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0002792 infores:hetionet NCBIGene:2678 biolink:causes MONDO:0009285 infores:monarchinitiative not_provided not_provided HGNC:4250 MONDO:0009285 uuid:47d459fc-da39-4921-885b-097e5ffb342f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61058 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0160390 infores:hetionet CHEBI:7466 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0033774 infores:hetionet CHEBI:63620 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0030554 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0041969 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0549373 infores:hetionet CHEBI:46557 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0033774 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0027765 infores:hetionet CAID:CA386965841 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965841 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS3, PM5, PP4 The c.733G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 245 (p.Gly245Arg) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Gly245Arg protein has normal DNA binding but ~55% of transactivation activity and ~55% of nuclear localization compared to wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 28653443). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50% and negative antibodies); however, HNF4A was not tested, and PP4 will not be applied (PMIDs: 19336507, 28653433). Another missense variant, c.734C>T (p.Gly245Val), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.733G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965841/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:231594 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0020517 infores:hetionet CHEBI:44032 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0152198 infores:hetionet CHEBI:63618 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C3665347 infores:hetionet CHEBI:64355 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0041582 infores:hetionet CHEBI:49960 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0040822 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020701 infores:hetionet CHEBI:3752 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0085616 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0027765 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0027051 infores:hetionet CHEBI:16755 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151662 infores:hetionet CHEBI:31348 biolink:causes UMLS:C3665356 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C3665356 infores:hetionet CHEBI:4877 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0278134 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0032285 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0559031 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019360 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042373 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0042109 infores:hetionet CHEBI:31236 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232849 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0015397 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004956 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0936223 infores:hetionet CHEBI:43968 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0020458 infores:hetionet CHEBI:61058 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0022346 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0162429 infores:hetionet CHEBI:31644 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0039231 infores:hetionet CHEBI:101085 biolink:causes HP:0003109 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0948023 infores:hetionet CHEBI:9613 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0012833 infores:hetionet CHEBI:3561 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1510410 infores:hetionet CHEBI:5050 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0013144 infores:hetionet CHEBI:28901 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0024305 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0149931 infores:hetionet CHEBI:92998 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0036830 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009319 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0006266 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0027651 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0020649 infores:hetionet CHEBI:63607 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0011991 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0024295 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D017192 DB11943_MESH_D017192_1DB05659_MESH_D017192_1DB00446_MESH_D017192_1DB06219_MESH_D017192_1 CHEBI:10124 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0574067 infores:hetionet CHEBI:6950 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2830004 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0025061 infores:hetionet NCBIGene:1837 biolink:causes MONDO:0011403 infores:monarchinitiative not_provided not_provided HGNC:3057 MONDO:0011403 uuid:953f27b4-8165-41ff-9b0a-e55b3ec348c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0006852 infores:hetionet CHEBI:9139 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004134 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1258215 infores:hetionet CHEBI:5050 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0015230 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0518015 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0037195 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235169 infores:hetionet CHEBI:18248 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0085631 infores:hetionet CHEBI:10127 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151636 infores:hetionet CHEBI:51141 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0017178 infores:hetionet CHEBI:70746 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0017178 infores:hetionet CHEBI:46295 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C2939147 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001315 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1535893 infores:hetionet CHEBI:64312 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0233407 infores:hetionet CHEBI:83804 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0028084 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0031350 infores:hetionet GO:0010946 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0010946 GO:0019953 CHEBI:6715 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0003862 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0948586 infores:hetionet CHEBI:32139 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0236024 infores:hetionet NCBIGene:79736 biolink:causes MONDO:0957537 infores:monarchinitiative not_provided not_provided HGNC:26223 MONDO:0957537 uuid:f857d18d-b2af-4a01-90d7-1949bdf9ec72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0948594 infores:hetionet CHEBI:75246 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020625 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0518015 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0241705 infores:hetionet CHEBI:7465 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0027424 infores:hetionet CHEBI:67194 biolink:causes GO:0099542 infores:ubergraph knowledge_assertion manual_agent CHEBI:67194 GO:0099542 CHEBI:45951 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0241442 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1384353 infores:hetionet CHEBI:7601 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0011603 infores:hetionet CHEBI:9649 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020757 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0162830 infores:hetionet CHEBI:63622 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0037763 infores:hetionet CHEBI:63621 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0016204 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027947 infores:hetionet CHEBI:100241 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085641 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0162429 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0006849 infores:hetionet CHEBI:45783 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0013404 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0162119 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0027051 infores:hetionet CHEBI:47381 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010034 infores:hetionet GO:0052027 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0052027 GO:0023052 CHEBI:4856 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C3665347 infores:hetionet CHEBI:46081 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151904 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235522 infores:hetionet CHEBI:7903 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C2830004 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0016977 infores:hetionet CHEBI:8404 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0039070 infores:hetionet CHEBI:45327 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C1145670 infores:hetionet CHEBI:51230 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0004095 infores:hetionet CHEBI:2611 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1306341 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0948296 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0235889 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0041969 infores:hetionet CHEBI:9139 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0236000 infores:hetionet CHEBI:9168 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030554 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0699744 infores:hetionet NCBIGene:271 biolink:causes MONDO:0014351 infores:monarchinitiative not_provided not_provided HGNC:469 MONDO:0014351 uuid:29a1d212-4020-43ae-a083-c1dae966a3cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0002871 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027765 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085614 infores:hetionet NCBIGene:1183 biolink:causes MONDO:0010250 infores:monarchinitiative not_provided not_provided HGNC:2022 MONDO:0010250 uuid:eb8ca10c-cd68-4e4c-8c58-415b4b4d3f0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0086439 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0576091 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0576091 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0700184 infores:hetionet CHEBI:16586 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0009676 infores:hetionet CHEBI:68579 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0005758 infores:hetionet CHEBI:9137 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027066 infores:hetionet CHEBI:10023 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0264893 infores:hetionet CHEBI:7476 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0007859 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004096 infores:hetionet CHEBI:94807 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0036974 infores:hetionet CAID:CA275388 biolink:causes MONDO:0100437 infores:clingen CAID:CA275388 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.642_656delinsC (p.Gly215TrpfsTer21) is a frameshift variant that introduces a premature stop codon into exon 7 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least two probands that did not meet the PS4 requirement of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses (PMID: 25556114, PMID: 34985506), so PS4_Supporting could not be met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting and PVS1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA275388/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:3699 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0002170 infores:hetionet UMLS:C0120107 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0036974 infores:hetionet CHEBI:28001 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0234233 infores:hetionet CHEBI:3084 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0036572 infores:hetionet CHEBI:68579 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0037763 infores:hetionet NCBIGene:55343 biolink:causes MONDO:0009953 infores:monarchinitiative not_provided not_provided HGNC:20197 MONDO:0009953 uuid:807401d0-20bb-4ce4-aaca-fc032c378f14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10360837 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360837 MONDO:0010725 PMID: Benign BP4, BA1 PS4, PP1 The NM_000330.4(RS1):c.7C>G variant is a missense variant encoding the substitution of Arginine with Glycine at amino acid 3. This variant is present in gnomAD v.4.1.0 at a frequency of 0.001335 among hemizygous individuals, with 528 variant alleles / 395462 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The computational predictor REVEL gives a score of 0.203, which is below the ClinGen X-linked IRD VCEP threshold of <0.291 and predicts a non-damaging effect on the RS1 function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family; a mother and an affected son. The mother is unaffected, so the PP1 code could not be applied. (PMID: 38317323). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 38317323). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1 and BP4. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360837/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:16796 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0032617 infores:hetionet CHEBI:8871 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020580 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0948089 infores:hetionet GO:0008359 biolink:causes GO:0007351 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0007351 CHEBI:36791 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030794 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C2973529 infores:hetionet GO:1904133 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0060322 CAID:CA916083918 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083918 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1685_1686del (p.His562ArgfsTer20) is a frameshift due to 2-nucleotide deletion in exon 14 of 15 that introduces a premature stop codon after 20 amino acids and is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through an affected mother and son from 1 family (PP1; PMID: 34745198). This variant has been reported in at least 3 apparently unrelated probands (PMID: 30105367, 34985506, 34745198). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083918/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:32020 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0234215 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001245 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085576 infores:hetionet CHEBI:61058 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0042384 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0162429 infores:hetionet CHEBI:2676 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0041969 infores:hetionet CHEBI:6128 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0016204 infores:hetionet CHEBI:44423 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0028960 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0162429 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0027769 infores:hetionet CHEBI:51380 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0014742 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1720798 infores:hetionet CHEBI:61058 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0001824 infores:hetionet CHEBI:2611 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1260880 infores:hetionet NCBIGene:5979 biolink:causes MONDO:0007958 infores:monarchinitiative not_provided not_provided HGNC:9967 MONDO:0007958 uuid:7157914e-2e17-4dd6-8dc6-c8ee39e356a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0234215 infores:hetionet CHEBI:10119 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0014457 infores:hetionet CHEBI:50861 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0018965 infores:hetionet CHEBI:63598 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0152009 infores:hetionet CHEBI:4995 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0852911 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0015230 infores:hetionet CHEBI:5103 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0040264 infores:hetionet CHEBI:6541 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0038999 infores:hetionet CHEBI:94385 biolink:causes MONDO:0042981 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0003507 infores:hetionet CHEBI:7903 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0041657 infores:hetionet CHEBI:3403 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0085593 infores:hetionet CHEBI:94686 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0702166 infores:hetionet CHEBI:167309 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0003467 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0702266 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005095 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0949691 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0011570 infores:hetionet CHEBI:127780 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0080274 infores:hetionet CHEBI:82960 biolink:causes HP:0033136 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0272396 infores:hetionet CHEBI:421707 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0151786 infores:hetionet CHEBI:28148 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0010520 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020550 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0027769 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0029443 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0022408 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009938 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0033246 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020676 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0948089 infores:hetionet CHEBI:9123 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027540 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0040034 infores:hetionet CHEBI:35778 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0232462 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085614 infores:hetionet CHEBI:36704 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0011603 infores:hetionet CHEBI:16755 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0039231 infores:hetionet CHEBI:49662 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0017181 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C2225524 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C1971624 infores:hetionet CHEBI:6402 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151754 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0020456 infores:hetionet CAID:CA2573157347 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157347 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP3, BP1, BP4, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.585del (p.Thr196GlnfsTer15) is a frameshift variant which is predicted to introduce a premature stop codon, resulting in nonsense-mediated mRNA decay and affecting all three isoforms (PVS1). This variant is downstream of c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has not been reported in individuals meeting at least one of the RUNX1 phenotypic criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157347/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0040261 infores:hetionet CHEBI:63598 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0015967 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0030196 infores:hetionet CHEBI:27786 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0040053 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0022354 infores:hetionet CHEBI:74947 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013144 infores:hetionet CHEBI:63791 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0333355 infores:hetionet CHEBI:29007 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0744727 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006444 infores:hetionet NCBIGene:2778 biolink:causes MONDO:0018919 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0018919 uuid:b562bd9f-b835-4608-add4-fc112b764a71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6912 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0036104 infores:hetionet CHEBI:38545 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0027121 infores:hetionet CHEBI:3814 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0003467 infores:hetionet CHEBI:63608 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0015672 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0152006 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0152006 infores:hetionet CHEBI:3286 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0235198 infores:hetionet CAID:CA3054201758 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201758 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.764_765del (p.His255fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98–c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201758/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:18067 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0700590 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001889 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0747102 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0740319 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0740319 infores:hetionet CHEBI:9566 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0026837 infores:hetionet NCBIGene:22808 biolink:causes MONDO:0032786 infores:monarchinitiative not_provided not_provided HGNC:7227 MONDO:0032786 uuid:b0eb953c-de9e-4560-a19b-1987c4090d71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA344713 biolink:causes MONDO:0012996 infores:clingen CAID:CA344713 MONDO:0012996 PMID: Pathogenic PP4_Strong, PM2_Supporting, PVS1_Strong, PM3_Supporting BA1, BS1 The NM_001482.3:c.1111dup (p.Met371AsnfsTer6) variant in GATM is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). This variant has been detected in two siblings with AGAT deficiency who had significantly decreased creatine peak on brain MRS (PMID 20682460) (PP4_Strong). Both individuals were homozygous for the variant, confirmed in trans by parental testing (PMID 20682460) (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA344713/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28593 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0026896 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0948594 infores:hetionet CHEBI:6444 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0002622 infores:hetionet CHEBI:32020 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0015672 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0235678 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0235678 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151613 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0020651 infores:hetionet NCBIGene:10165 biolink:causes MONDO:0011601 infores:monarchinitiative not_provided not_provided HGNC:10983 MONDO:0011601 uuid:bde7d171-f275-45c0-9665-7ad8050dda50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0855242 infores:hetionet CHEBI:194135 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0005778 infores:hetionet CHEBI:3011 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0001824 infores:hetionet CHEBI:44185 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0011603 infores:hetionet CAID:CA16619434 biolink:causes MONDO:0005045 infores:clingen CAID:CA16619434 MONDO:0005045 PMID: Uncertain Significance PM2_Supporting BA1, BS1 NM_000432.4(MYL2):c.376C>G (p.Gln126Glu) - This variant has been reported in association with HCM (PMIDs: 25351510), but is not statistically increased in HCM compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Computational prediction tools are inconclusive about the potential impact of this variant (REVEL score <0.7). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on PM2_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619434/MONDO:0005045/102 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135276 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0267792 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0235876 infores:hetionet CHEBI:3698 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0423791 infores:hetionet NCBIGene:91452 biolink:causes MONDO:0030026 infores:monarchinitiative not_provided not_provided HGNC:23338 MONDO:0030026 uuid:531bc083-6ee2-4085-abe3-ef204dac1351 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70735 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0043352 infores:hetionet CHEBI:6847 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0040034 infores:hetionet CHEBI:8890 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020615 infores:hetionet CHEBI:3082 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0040822 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0687133 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948089 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0026650 infores:hetionet CHEBI:6149 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0003708 infores:hetionet CAID:CA410204318 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204318 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.101C>T (p.Ala34Val) is a missense variant which has a REVEL score < 0.50 (0.414) and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204318/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1167965 infores:hetionet CHEBI:66899 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0423006 infores:hetionet CHEBI:167309 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0043387 infores:hetionet CHEBI:7465 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0151662 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0278079 infores:hetionet CHEBI:61033 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0031542 infores:hetionet CHEBI:45081 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0040822 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0235431 infores:hetionet CHEBI:45863 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011175 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0034150 infores:hetionet CHEBI:31236 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0043352 infores:hetionet NCBIGene:2629 biolink:causes MONDO:0009266 infores:monarchinitiative not_provided not_provided HGNC:4177 MONDO:0009266 uuid:01a77d6c-cc42-4efd-9e42-75dc3b93ac9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585688 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585688 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, BP5, BP7, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1945C>T (p.Pro649Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL = 0.766. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (1 case with probable FH by Simon Broome criteria and 1 case with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca; 1 case with DLCN score >=6 from Meshkov et al 2021, PMID 33418990). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585688/MONDO:0007750/013 2024-10-28 2025-01-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:116278 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0012569 infores:hetionet CAID:CA214206 biolink:causes MONDO:0000572 infores:clingen CAID:CA214206 MONDO:0000572 PMID: Benign BA1 The c.906C>A (NM_000448.3) variant in RAG1 is a missense variant predicted to cause substitution of Aspartic Acid by Glutamic Acid at amino acid 302 (p.Asp302Glu).The filtering allele frequency (the lower threshold of the 95% CI of 1968/24958) of the c.906C>A variant in RAG1 is 0.07684 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214206/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135005 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0235660 infores:hetionet CHEBI:144093 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0023218 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042035 infores:hetionet CHEBI:31932 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0037317 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0234192 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0151773 infores:hetionet CHEBI:9727 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0019214 infores:hetionet CHEBI:10100 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0015967 infores:hetionet CAID:CA134590 biolink:causes MONDO:0021060 infores:clingen CAID:CA134590 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1023-8C>T variant in the MAP2K1 gene is 10.315% (1128/10406) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134590/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3216 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233794 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018801 infores:hetionet CAID:CA010070 biolink:causes MONDO:0005045 infores:clingen CAID:CA010070 MONDO:0005045 PMID: Uncertain Significance PM2, PM1, PS4_Supporting BA1, PP3, PS3, BS1, BS3 The c.1013T>C (p.Val338Ala) variant in MYH7 has been identified in 4 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2; PM1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010070/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31348 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042109 infores:hetionet CHEBI:28901 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0438717 infores:hetionet CHEBI:194135 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0008350 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235416 infores:hetionet CHEBI:10101 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011168 infores:hetionet CHEBI:31348 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0039231 infores:hetionet CHEBI:8430 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0428977 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0029878 infores:hetionet CHEBI:28925 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0022346 infores:hetionet CAID:CA410147680 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147680 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1244A>C (p.Gln415Pro) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147680/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28748 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027813 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002418 infores:hetionet CHEBI:4315 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0023518 infores:hetionet CHEBI:17688 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0038367 infores:hetionet CHEBI:205919 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0234894 infores:hetionet CHEBI:7824 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0003811 infores:hetionet CHEBI:51230 biolink:causes MONDO:0001210 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0014306 infores:hetionet CHEBI:50729 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0344232 infores:hetionet CHEBI:63581 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0235031 infores:hetionet CHEBI:32192 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0023530 infores:hetionet CHEBI:71255 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0038999 infores:hetionet CHEBI:45409 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0037763 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020538 infores:hetionet CAID:CA10647041 biolink:causes MONDO:0012996 infores:clingen CAID:CA10647041 MONDO:0012996 PMID: Benign BA1 The NM_001482.3:c.*940C>T variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1, in a population with >2000 alleles, is 0.8433 (7330/8692 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316200, 1 star review status) with one submitter classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0, ; classification approved June 6, 2022): BA1. Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10647041/MONDO:0012996/025 2022-06-06 2022-10-04 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9434 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0017160 infores:hetionet NCBITaxon:5506 biolink:causes MONDO:0016426 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5506 MONDO:0016426 CHEBI:31547 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0009806 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0267356 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0267356 infores:hetionet CAID:CA398323709 biolink:causes MONDO:0011132 infores:clingen CAID:CA398323709 MONDO:0011132 PMID: Pathogenic PP3, PP4, PP1, PM2_Supporting, PS3_Moderate, PM1, PM3_Supporting, PM5_Supporting The missense variant NM_001369369.1(FOXN1):c.880G>A (p.Val294Ile) is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 294, and thus meets PM1. This variant occurs at the same codon as Val294Leu which has been classified as Likely Pathogenic by the SCID VCEP (PM5_supporting). The variant has a REVEL score of 0.731 which is above the SCID VCEP specified threshold of ≥0.644 to support a deleterious effect of the variant (PP3). A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. The Val294Ile variant had 18% luciferase activity compared to WT which is below the <50% threshold for PS3_moderate(PMID: 37419334). The highest MAF in gnomAD v2.1.1 is 0.000008790 (1/113770 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). Patient P2 (PMID: 30903456) is homozygous for this variant (PM3_supporting), and was diagnosed with T-B+NK+ SCID with absent CD3+ cells and absent TRECs, a poor proliferative response to PHA, athymia, alopecia totalis, and nail dystrophy. The patient was sequenced using a NGS panel of 18 common SCID-related genes and Sanger sequencing for FOXN1. Together this is a highly specific phenotype for FOXN1-related T-cell immunodeficiency, congenital alopecia, and nail dystrophy (PP4). Siblings P1 and P2 (PMID: 30903456) are both affected with T-B+NK+ SCID and homozygous for this variant (PP1), the parents are both heterozygous and do not have any immunodeficiency but have decreased T cell counts and reduced TREC levels compared to age-matched controls. In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PM5_supporting, PP3, PS3_moderate, PM2_supporting, PM3_supporting, PP1, and PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398323709/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:63629 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020651 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0549336 infores:hetionet CHEBI:18258 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0039231 infores:hetionet NCBIGene:3852 biolink:causes MONDO:0030527 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0030527 uuid:ba234ed2-4095-4ec3-bc25-8c2f28b33850 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0242350 infores:hetionet CAID:CA8338295 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338295 MONDO:0008723 PMID: Uncertain Significance PM2, PM5_Supporting PP3, PM1, PM3 The NM_000018.4 c.1838G>A p.(Arg613Gln) in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 613. The highest population minor allele frequency in gnomAD v4.1 is 0.00008017 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.526 which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. This variant does not reside within a region of ACADVL that is defined as a mutational hotspot or critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel.A different aminoacid change at the same position (p.Arg613Trp) has been classified by the ACADVL VCEP group as likely pathogenic (ClinVar ID: 1623) (PM5_Supporting). At least two patients with this variant displayed enzyme levels and/or NBS results, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMIDs:32710939, 30194637). In these reported patients, the variant was reported to occur in individuals who also carried a distinct ACADVL variant not confirmed in trans; however, since none of these variants reached likely pathogenic classification, the ACADVL VCEP could not count these toward PM3 evidence (PMID: 32710939, 30194637). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM5_Supporting, PP4_Moderate (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338295/MONDO:0008723/021 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63620 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1510410 infores:hetionet GO:0141145 biolink:causes GO:0140645 infores:ubergraph knowledge_assertion manual_agent GO:0141145 GO:0140645 CHEBI:408174 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0026821 infores:hetionet CHEBI:474180 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0030554 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0031117 infores:hetionet CHEBI:63613 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0014518 infores:hetionet CHEBI:31401 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0004604 infores:hetionet UMLS:C0657912 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0039070 infores:hetionet CHEBI:161680 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0231528 infores:hetionet CHEBI:34911 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0042963 infores:hetionet CHEBI:3757 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0149725 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001703 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0242225 infores:hetionet CHEBI:135005 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0033687 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0037284 infores:hetionet CHEBI:6759 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0023052 infores:hetionet CHEBI:9907 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C1384353 infores:hetionet CHEBI:31643 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0085628 infores:hetionet CHEBI:142290 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0085649 infores:hetionet CHEBI:63598 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0149725 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0236051 infores:hetionet CAID:CA1396311 biolink:causes MONDO:0019501 infores:clingen CAID:CA1396311 MONDO:0019501 PMID: Likely Pathogenic PP3, PP4, PM5, PM2_Supporting, PM3_Strong The c.2081G>A in USH2A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid 694 (p.Cys694Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002% (2/113290) in the European (non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.92 (PP3). This variant has been detected in at least three probands with Usher syndrome whereby pathogenic or suspected-pathogenic variants were confirmed in trans in two individuals (2.5 PM3_Strong points; PMID:28041643, Invitae Internal Data (SCV001372551.2)). Of the confirmed phase counts, the first harbored the p.Glu767SerfsTer21 variant and second harbored the p.Thr4425Met variant in USH2A (PMID:28041643, Invitae Internal Data). The third individual harbored the p.Cys3267Arg variant but phasing was not confirmed (Invitae Internal Data). At least one proband displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 28041643). Two missense variants, c.2081G>C (p.Cys694Ser) and c.2080T>A (p.Cys694Ser), in the same codon have been classified as likely pathogenic or pathogenic for AR Usher syndrome by two submitters in ClinVar (PM5; ClinVar Variation ID:1217348, 813246). In summary, this variant meets the criteria to be classified as likely pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Strong, PP4, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1396311/MONDO:0019501/005 2023-10-25 2023-11-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:61390 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0004604 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0235360 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235360 infores:hetionet CHEBI:45409 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020453 infores:hetionet CHEBI:63115 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0009782 infores:hetionet CHEBI:5864 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0554976 infores:hetionet CHEBI:4903 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0085633 infores:hetionet CHEBI:8707 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0001807 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0015397 infores:hetionet CHEBI:8888 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151786 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0037199 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0349506 infores:hetionet CHEBI:45783 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0043352 infores:hetionet CAID:CA10581715 biolink:causes MONDO:0100437 infores:clingen CAID:CA10581715 MONDO:0100437 PMID: Uncertain Significance PP3_Strong, PM2_Supporting PP4, PS4 NM_001034853.2(RPGR):c.908G>A (p.Gly303Glu) is a missense variant predicted to cause substitution of glycine with glutamate at amino acid 303. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_strong). The splicing impact predictor SpliceAI gives a score of 0.05 for splice acceptor gain, which is below he ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not predict a damaging impact on splicing. At least one proband harboring this variant exhibits a phenotype consistent with retinitis pigmentosa or rod-cone dystrophy, however, the available details are not sufficient to evaluate specificity for RPGR-related retinopathy (PMID: 27208204). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP3_strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581715/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:45081 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0235431 infores:hetionet CHEBI:10650 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015402 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0851341 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040479 infores:hetionet CHEBI:63638 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013362 infores:hetionet CHEBI:75984 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0023066 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0151828 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151849 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0043251 infores:hetionet GO:0060703 biolink:causes GO:0006259 infores:ubergraph knowledge_assertion manual_agent GO:0060703 GO:0006259 NCBIGene:953 biolink:causes MONDO:0014303 infores:monarchinitiative not_provided not_provided HGNC:3363 MONDO:0014303 uuid:02c1cad4-9eee-4ddb-a0fd-86914e4ff3c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0004936 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0232492 infores:hetionet CHEBI:17026 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0011168 infores:hetionet CHEBI:15640 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0027497 infores:hetionet CHEBI:10650 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0006142 infores:hetionet NCBIGene:55193 biolink:causes MONDO:0007763 infores:monarchinitiative not_provided not_provided HGNC:30064 MONDO:0007763 uuid:62786351-954a-4648-987e-3e6f29f73ca6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0042109 infores:hetionet UMLS:C0004609 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0232849 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0009938 infores:hetionet CHEBI:68534 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0009241 infores:hetionet CHEBI:6541 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0040264 infores:hetionet CHEBI:6067 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0700590 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042075 infores:hetionet CHEBI:17630 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0030554 infores:hetionet CHEBI:3242 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0085593 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0003123 infores:hetionet CHEBI:2618 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0041969 infores:hetionet CHEBI:68534 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0233763 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0002871 infores:hetionet CHEBI:42797 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027066 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0037274 infores:hetionet CHEBI:50885 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0026846 infores:hetionet CHEBI:4798 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0700225 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0023530 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020456 infores:hetionet CHEBI:32192 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0042963 infores:hetionet CAID:CA358484 biolink:causes MONDO:0018875 infores:clingen CAID:CA358484 MONDO:0018875 PMID: Likely Benign BP4, PP1, BS2, PM2_Supporting, PS4_Supporting BA1, BP1, BP2, PS3, PS2, PS1, PM1, PM3, PM5, BP5, BS1, BS3, BS4, PM6, PP2, PP3, PP4 The NM_000546.6: c.85_87AAC variant in TP53 is an AAC deletion at nucleotide positions 88 to 90 predicted to cause an in-frame deletion of asparagine at amino acid 30 (p.Asn30del). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor). This variant has been reported in 2 unrelated probands/families meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal lab contributors). This variant has an allele frequency of 0.0000006197 (1/1613566 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). Computational predictor score (BayesDel = -0.83349) is below the recommended threshold (BayesDel < 0.16), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant is classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PS4_Supporting, PP1, PM2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA358484/MONDO:0018875/009 2025-04-03 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5778 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020458 infores:hetionet CHEBI:94392 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0015672 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085096 infores:hetionet CAID:CA404075778 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075778 MONDO:0007750 PMID: Uncertain Significance PM2 BP1, BP4, BP2, BP3, BA1, PS1, PS4, PS2, PS3, BP5, BP7, BS1, BS4, BS3, PM5, PM3, PM4, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.292G>T (p.Gly98Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075778/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:22930 biolink:causes MONDO:0030376 infores:monarchinitiative not_provided not_provided HGNC:17063 MONDO:0030376 uuid:7fa15e69-1605-4db9-a3ac-c784a1d3d653 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA916084429 biolink:causes MONDO:0009861 infores:clingen CAID:CA916084429 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4_Moderate The p.Ex5del5321 variant is a 5321bp deletion in Exon 5 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to lead to a frameshift at His170, premature protein truncation, and NMD (PVS1). One heterozygote for the deletion is present in gnomAD, corresponding to an allele frequency of 0.000046 (structural variant version, gnomAD SVs v2.1), less than the 0.0002 cutoff for use of PM2 (PM2). It has been previously reported in one patient with PKU (BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate) (PMID: 23942198) in presumed trans with the p.G332R variant (unclassified/VUS).Classification: PathogenicSupporting Criteria: PVS1; PM2; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084429/MONDO:0009861/006 2020-06-05 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports CAID:CA8366085 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366085 MONDO:0100453 PMID: Likely Benign BP4 BS1, PM2 The NM_000180.4(GUCY2D):c.2318T>C (p.Met773Thr) variant is predicted to replace the methionine at position p.773 with threonine. The computational predictor REVEL gives a score of 0.113, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). This variant is present in gnomAD v4.1.0 at a Grpmax allele frequency of 0.0006248, with 783 alleles / 1179072 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0005363, with 865 alleles / 1612966 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366085/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4514 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0542571 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0029134 infores:hetionet CHEBI:6633 biolink:causes UMLS:C0391839 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0391839 infores:hetionet CHEBI:3127 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0028084 infores:hetionet CHEBI:474180 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235431 infores:hetionet CHEBI:9555 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0042963 infores:hetionet CHEBI:9586 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0010200 infores:hetionet CHEBI:584020 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0032227 infores:hetionet CHEBI:5384 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0032617 infores:hetionet CHEBI:5165 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0004604 infores:hetionet CHEBI:2675 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0038362 infores:hetionet CHEBI:15940 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0019158 infores:hetionet CHEBI:4657 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0020458 infores:hetionet CHEBI:3723 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0404521 infores:hetionet NCBIGene:3714 biolink:causes MONDO:0030456 infores:monarchinitiative not_provided not_provided HGNC:6189 MONDO:0030456 uuid:999a1fd2-e5c5-4999-8311-9e733219518a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009782 infores:hetionet CAID:CA658656149 biolink:causes MONDO:0700270 infores:clingen CAID:CA658656149 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, BP4 BA1, BP7, BS1 The ATM c.331+7G>A variant has a GnomAD (v2.1.1) is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In silico splicing predictors (SpliceAI, Donor Loss: 0%, Donor Gain: 0%; NNSplice, no change) predict that this alteration will not have a significant impact on splicing (BP4). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA658656149/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6129 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0948594 infores:hetionet CHEBI:10650 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085593 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0018965 infores:hetionet CHEBI:127342 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C2830004 infores:hetionet CHEBI:3696 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0027497 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0036983 infores:hetionet CHEBI:408174 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0018681 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0031117 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040409 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0340726 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0852733 infores:hetionet NCBIGene:4437 biolink:causes MONDO:0011962 infores:monarchinitiative not_provided not_provided HGNC:7326 MONDO:0011962 uuid:40568904-6bb9-4d36-8778-b8f395e60b8b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA013309 biolink:causes MONDO:0005021 infores:clingen CAID:CA013309 MONDO:0005021 PMID: Uncertain Significance PM2, PP3 PS3, BA1, PM5, PM4, PM1, PM6, PP1, BS1, BS3, BS4, BP4, BP7, BP2, BP5, PS1, PS4, PS2, PVS1 The NM_000257.4(MYH7):c.3020T>C (p.Leu1007Pro) variant has been identified in 1 individual with DCM and 1 individual with a complex cardiac presentation that included DCM (Ambry pers. comm., GeneDx pers. comm.) and segregated with non-compaction cardiomyopathy in 1 affected child (Ambry pers. comm); however, these data are currently insufficient to apply PS4 or establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013309/MONDO:0005021/002 2021-12-09 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3419 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0085631 infores:hetionet CAID:CA410202533 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202533 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, BS3_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP3, BP1, BP4, BP2, PVS1, PM6, BS1, BS4, BP5, BP7, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.475A>G (p.Asn159Asp) is a missense variant affecting one of the residues within the runt homology domain (AA 89-204) (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.88 (0.956) (PP3). Transactivation assays demonstrate normal transactivation at 80.43% (80-115% of wt), suggesting functional similarity to the wild type (BS3_Supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, BS3_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202533/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0522178 infores:hetionet CAID:CA409103809 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103809 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting The c.125G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to valine at codon 42 (p.(Gly42Val)) of NM_175914.5. This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and responsive to sulfonylurea) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the DNA binding domain (codons 37-113 of HNF4A), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.124G>A p.Gly42Arg, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.125G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0 approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103809/MONDO:0015967/085 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8069 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0029442 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0857432 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0857432 infores:hetionet CAID:CA16042720 biolink:causes MONDO:0017623 infores:clingen CAID:CA16042720 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PM6_Strong, PS3_Moderate, PM2_Supporting BS1, BS3, PP4, PM1, BA1, BP1, BP4 NM_000314.8(PTEN):c.140G>A (p.Arg47Lys) meets criteria to be classified as Likely Pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype (internal laboratory contributor).PS3_M: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.357001423.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.903)PM2_P: Absent in the gnomAD cohort. (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042720/MONDO:0017623/003 2023-12-01 2023-12-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5864 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042721 infores:hetionet CAID:CA10650402 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650402 MONDO:0011071 PMID: Benign BA1 PS4, PS3, PS1, BP2, BP4, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 The c.*3977G>A variant in the 3' UTR has an MAF of 0.003831 (0.38%, 12/3132 alleles) in the East Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650402/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9649 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0013595 infores:hetionet CHEBI:10650 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0232462 infores:hetionet CHEBI:2950 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0002792 infores:hetionet CAID:CA658658480 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658480 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.594_595insT p.(Thr199Tyrfs*10) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658480/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7640 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0344232 infores:hetionet CHEBI:7931 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0041657 infores:hetionet CHEBI:50275 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0438142 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0009450 infores:hetionet CHEBI:9555 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0151773 infores:hetionet CHEBI:37924 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0004245 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0003862 infores:hetionet CHEBI:51860 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0021368 infores:hetionet CHEBI:17474 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0024902 infores:hetionet CHEBI:47426 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0011606 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038663 infores:hetionet CHEBI:48538 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0013144 infores:hetionet CHEBI:5280 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C2364111 infores:hetionet CHEBI:135613 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0231835 infores:hetionet CHEBI:15553 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0231218 infores:hetionet GO:0033143 biolink:causes GO:0071383 infores:ubergraph knowledge_assertion manual_agent GO:0033143 GO:0071383 CHEBI:63599 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0232462 infores:hetionet CHEBI:63623 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0000737 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0948525 infores:hetionet CHEBI:127342 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0011124 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0040409 infores:hetionet CHEBI:17347 biolink:causes MONDO:0043243 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0023531 infores:hetionet CHEBI:7825 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0030554 infores:hetionet CHEBI:17688 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0232849 infores:hetionet CHEBI:7443 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0038358 infores:hetionet CHEBI:8776 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0027497 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0232459 infores:hetionet CHEBI:45409 biolink:causes MONDO:0020076 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027022 infores:hetionet CHEBI:4798 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0423791 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0014130 infores:hetionet CHEBI:7798 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0233514 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0178298 infores:hetionet CHEBI:47381 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014457 infores:hetionet UMLS:C0120107 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C1522133 infores:hetionet CHEBI:30659 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C1443060 infores:hetionet CHEBI:64355 biolink:causes HP:0034705 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0234962 infores:hetionet CHEBI:5296 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0036974 infores:hetionet CHEBI:63717 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0003862 infores:hetionet CHEBI:63791 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0041657 infores:hetionet CHEBI:16335 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0030193 infores:hetionet CAID:CA512319072 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319072 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 This variant NM_001754.5(RUNX1):c.600C>T (p.Pro200=) is a synonymous variant. This is a synonymous variant therefore REVEL score cannot be applied but SpliceAI is ≤ 0.20 (0.00) (BP4). The PhyloP score is <2.0 (0.219) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319072/MONDO:0011071/008 2022-01-20 2022-07-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51380 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0042109 infores:hetionet NCBIGene:6843 biolink:causes MONDO:0032675 infores:monarchinitiative not_provided not_provided HGNC:12642 MONDO:0032675 uuid:1f614240-362f-4641-a36d-6ec884ae0fd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42068 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0518015 infores:hetionet CHEBI:51041 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151754 infores:hetionet CHEBI:51450 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0040460 infores:hetionet CHEBI:49662 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002063 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0234215 infores:hetionet NCBITaxon:10279 biolink:causes MONDO:0005855 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10279 MONDO:0005855 CHEBI:30830 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0030554 infores:hetionet CHEBI:4814 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0235490 infores:hetionet CAID:CA172217 biolink:causes MONDO:0019497 infores:clingen CAID:CA172217 MONDO:0019497 PMID:17666888PMID:24158611PMID:26096904PMID:9285800PMID:17666888PMID:24529908PMID:26096904PMID:24158611PMID:9285800PMID:24529908PMID:17666888PMID:24158611PMID:26096904PMID:9285800PMID:17666888PMID:24529908PMID:17666888 Pathogenic PM3_Very Strong, PVS1, BA1 BS4, BS1, BP5, BP7, PP4, PP1, PP3, BS2, PM5, PM1, PM4, PM6, PM2, BP3, BP4, BP2, PS1, PS2, PS4, PS3 The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive nonsyndromic hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 24529908, 26096904, 24158611, 9285800, 17666888). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, BA1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA172217/MONDO:0019497/005 2018-09-19 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63638 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0085631 infores:hetionet NCBIGene:8301 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:15514 MONDO:0018874 uuid:8140e837-4747-46ca-9ca7-7134b6afc820 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5050 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0009450 infores:hetionet GO:0086091 biolink:causes GO:0002027 infores:ubergraph knowledge_assertion manual_agent GO:0086091 GO:0002027 CHEBI:8890 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020440 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0029408 infores:hetionet NCBIGene:79784 biolink:causes MONDO:0013711 infores:monarchinitiative not_provided not_provided HGNC:23212 MONDO:0013711 uuid:a37fc6b5-20ee-421a-ae0c-e29ded3fcbdc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1262144 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0178298 infores:hetionet CAID:CA2621383482 biolink:causes MONDO:0015967 infores:clingen CAID:CA2621383482 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate The c.-284C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant in the promoter region of NM_000545.8. This variant is located within the HNF4A binding site (–c.-276 to c.-288) of the promoter HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and >=3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.-284C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2621383482/MONDO:0015967/017 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:84500 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0003467 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1306341 infores:hetionet CAID:CA1244299 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244299 MONDO:0005338 PMID: Likely Benign BP7, BP4 BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.303A>G variant in MYOC is a synonymous variant (p.Gln101=). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.0004283 (32 alleles out of 74,710), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244299/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0007760 infores:hetionet CHEBI:84500 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085633 infores:hetionet CHEBI:78543 biolink:causes UMLS:C1096252 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1096252 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0152025 infores:hetionet GO:0035490 biolink:causes GO:0006954 infores:ubergraph knowledge_assertion manual_agent GO:0035490 GO:0006954 CAID:CA397723258 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723258 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PP1, PM3_Supporting, PP4_Moderate The c.602A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 201 (p.Tyr201Cys). This variant has been detected in a set of siblings that displayed increased C14:1 on newborn screen and reduced very long chain acyl CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate, PP1; PMID: 17457695, 14517516). These siblings were compound heterozygous for this variant and a likely pathogenic variant confirmed in trans by parental testing (PM3 0.5 points, PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723258/MONDO:0008723/021 2023-11-28 2023-11-28 Autosomal recessive inheritance HP:0000007 Supports GO:2000718 biolink:causes GO:0071962 infores:ubergraph knowledge_assertion manual_agent GO:2000718 GO:0071962 CHEBI:3756 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0085632 infores:hetionet CHEBI:8890 biolink:causes HP:0006579 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0022353 infores:hetionet CHEBI:63607 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0853034 infores:hetionet CHEBI:50859 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013428 infores:hetionet CHEBI:6897 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0013404 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027651 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0403632 infores:hetionet CHEBI:135451 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0011603 infores:hetionet CAID:CA033186 biolink:causes MONDO:0007750 infores:clingen CAID:CA033186 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001088 (0.01088%) in East Asian exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.822.PS4_supporting - Variant meets PM2. Variant identified in 4 unrelated index cases (3 cases with Simon-Broome published in PMID: 9763532; 1 case with DLCN criteria from Robarts Research Institute.PP4 - Variant meets PM2. Variant identified in 4 FH cases (3 cases with Simon-Broome Definite published in PMID: 9763532; 1 case with DLCN criteria = > 6 from Robarts Research Institute. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033186/MONDO:0007750/013 2022-03-07 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7824 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011124 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233794 infores:hetionet NCBIGene:10111 biolink:causes MONDO:0013118 infores:monarchinitiative not_provided not_provided HGNC:9816 MONDO:0013118 uuid:9f5fd713-8153-449b-92a2-5e38cf9dde7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0235032 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1442903 infores:hetionet CHEBI:5893 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0231530 infores:hetionet CHEBI:68478 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1260880 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0027765 infores:hetionet CHEBI:15551 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0344232 infores:hetionet CHEBI:31711 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0232602 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0282193 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0282193 infores:hetionet CAID:CA415086207 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086207 MONDO:0010305 PMID: Uncertain Significance PS3_Supporting, PP4, PP3, PM2_Supporting The NM_005629.4:c.1166A>G variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a tyrosine for a cysteine at amino acid 389 (p.Tyr389Cys). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.909 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.2.0): PS3_Supporting, PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on July 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086207/MONDO:0010305/027 2024-07-11 2025-08-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6541 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0006145 infores:hetionet CHEBI:45327 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0013378 infores:hetionet CHEBI:8776 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0030312 infores:hetionet CHEBI:9448 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0022346 infores:hetionet CHEBI:40303 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0002170 infores:hetionet CHEBI:5001 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0020458 infores:hetionet CHEBI:2948 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0003862 infores:hetionet CHEBI:4024 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0033774 infores:hetionet CHEBI:3082 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C2363730 infores:hetionet CHEBI:9667 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0033774 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232197 infores:hetionet NCBITaxon:10780 biolink:causes MONDO:0025371 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10780 MONDO:0025371 CHEBI:136040 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020625 infores:hetionet CHEBI:64045 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0428977 infores:hetionet CHEBI:6775 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013378 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0017152 infores:hetionet CHEBI:5100 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0020615 infores:hetionet NCBIGene:54936 biolink:causes MONDO:0100095 infores:monarchinitiative not_provided not_provided HGNC:21304 MONDO:0100095 uuid:af414885-d1da-4051-8d41-06ee02d3bdcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0023218 infores:hetionet CHEBI:9137 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0497156 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0035078 infores:hetionet UMLS:C0010592 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C3665347 infores:hetionet CHEBI:45327 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0030554 infores:hetionet NCBITaxon:1654 biolink:causes MONDO:0005631 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1654 MESH:D000196 DB00618_MESH_D000196_1DB00759_MESH_D000196_1DB13092_MESH_D000196_1DB01053_MESH_D000196_1DB00595_MESH_D000196_1DB00254_MESH_D000196_1DB02703_MESH_D000196_1DB01017_MESH_D000196_1 CHEBI:100241 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0948089 infores:hetionet CHEBI:4953 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0232461 infores:hetionet CHEBI:51364 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151905 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013395 infores:hetionet CHEBI:135888 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0038160 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0232910 infores:hetionet CHEBI:87681 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0085649 infores:hetionet CAID:CA412746851 biolink:causes MONDO:0100437 infores:clingen CAID:CA412746851 MONDO:0100437 PMID: Pathogenic PVS1, PS1_Supporting, PM2_Supporting PS4 NM_001034853.2(RPGR):c.28+1G>C is a canonical splice site variant in intron 1 that is predicted to disrupt splicing and induce exon skipping, which is expected to disrupt a critical functional domain in RPGR (PVS1). Another variant at the same position in the donor +1/+2 dinucleotide, NM_001034853.2(RPGR):c.28+1G>A, has previously been classified pathogenic by the X-linked IRD VCEP (PS1_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses (PMID: 30718709), however, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS1_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412746851/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:3478 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0302295 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0162119 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0235416 infores:hetionet CHEBI:135939 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0043352 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0004936 infores:hetionet CHEBI:85078 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0012833 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036130 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151313 infores:hetionet CHEBI:6846 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0019521 infores:hetionet CHEBI:5855 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017979 infores:hetionet CHEBI:6367 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0858635 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0240035 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0001824 infores:hetionet CHEBI:3716 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C2242996 infores:hetionet NCBIGene:25974 biolink:causes MONDO:0010184 infores:monarchinitiative not_provided not_provided HGNC:24525 MONDO:0010184 uuid:b53b3988-c053-4b9a-8859-6d2fe49edda4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0237849 infores:hetionet CHEBI:6541 biolink:causes UMLS:C1142295 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C1142295 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0231441 infores:hetionet CHEBI:3561 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0037287 infores:hetionet CHEBI:691037 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0039446 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0002418 infores:hetionet CHEBI:5098 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C1368065 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020649 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0281981 infores:hetionet CHEBI:144093 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0007859 infores:hetionet CHEBI:6402 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151766 infores:hetionet CHEBI:8768 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0025222 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0234215 infores:hetionet CHEBI:167638 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0409974 infores:hetionet CHEBI:75246 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232487 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0162429 infores:hetionet CHEBI:75722 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0311468 infores:hetionet CAID:CA137387 biolink:causes MONDO:0019501 infores:clingen CAID:CA137387 MONDO:0019501 PMID:19683999PMID:15660226PMID:12075507PMID:15537665PMID:19683999PMID:15660226PMID:12075507PMID:15537665PMID:18273900PMID:16963483PMID:21569298PMID:21738395 Benign BP4, BA1, BS3_Supporting BS4, BS1, BP7, BP5, BS2, PP4, PP1, PP3, PM1, PM5, PM4, PM3, PVS1, PM6, PM2, BP3, BP2, PS2, PS1, PS4, PS3 The filtering allele frequency (the lower threshold of the 95% CI of 3442/23972) of the c.3625A>G (p.Thr1209Ala) variant in the CDH23 gene is 13.15% for African chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). A splicing assay did not show any impact to splicing but BS3 was not applied given no assessment of protein function (PMID:18273900). Computational prediction analysis using the metapredictor tool REVEL did not predict an impact the protein (BP4). Of note, this variant was reported in 3 patients with Usher syndrome (PMID: 15537665, 15660226, 12075507) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BS3_Supporting, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA137387/MONDO:0019501/005 2019-05-28 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3219 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0340464 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0267792 infores:hetionet NCBIGene:267010 biolink:causes MONDO:0011287 infores:monarchinitiative not_provided not_provided HGNC:19380 MONDO:0011287 uuid:a000e857-2638-4d4f-976a-278abb5ed0cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0011606 infores:hetionet NCBIGene:8517 biolink:causes MONDO:0800129 infores:monarchinitiative not_provided not_provided HGNC:5961 MONDO:0800129 uuid:050fe808-44ad-4f2a-929f-59f2cbf5f3e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0038999 infores:hetionet CAID:CA119175 biolink:causes MONDO:0020367 infores:clingen CAID:CA119175 MONDO:0020367 PMID:35196929 Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4_Moderate, PP1_Strong BS1, BS3, BP7, PM6, PM4, PM5, PS1, PS2, BA1, BP4 The c.1440C>A variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), which met PS4_Moderate (≥ 6 probands). In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119175/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:60761 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0151908 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0004096 infores:hetionet CHEBI:6888 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0162834 infores:hetionet CAID:CA8365854 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365854 MONDO:0100453 PMID: Uncertain Significance BP2, PP1, PM2_Supporting PM3, PP3 NM_000180.4(GUCY2D):c.1672G>A (p.Asp558Asn) is a missense variant predicted to replace aspartic acid with asparagine at position p.558. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.00004965, with 80 alleles / 1,611,212 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in an unreported state of zygosity (PMID: 31456290). In the absence of this detail, the PM3 code is not met. This variant has also been reported in a proband with early-onset severe retinal dystrophy in cis with the NM_000180.4(GUCY2D):c.1245del (p.Phe415fs) variant and in trans with the NM_000180.4:c.1956+1G>A variant, both of which have been classified as pathogenic by the ClinGen LCA/eoRD VCEP (PMID: 32865313, BP2). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 32865313, PP1). The computational predictor REVEL gives a score of 0.306, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.04 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP1, and BP2. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365854/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:100241 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0017152 infores:hetionet CHEBI:6375 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0221776 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0853813 infores:hetionet CHEBI:8426 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0018965 infores:hetionet CAID:CA414793545 biolink:causes MONDO:0044970 infores:clingen CAID:CA414793545 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS2, PS3, PS4, PM2, PM6 The m.7746A>G variant in MT-CO2 has been reported in one family to date (haplogroup B) including in an asymptomatic mother, however limited phenotypic details were provided (PMID: 23463613). As this is the only family reported to date, PS4 could not be applied. This variant is present in population databases (Mitomap's 21/59,389 sequences: AF= 0.035%; Helix's 66/195,983 sequences: AF=0.031% including 60 homoplasmic occurrences and an additional six heteroplasmic occurrences across haplogroups A, T, H, D, U, B, K. L3, M, F, I, J L2, and L1; and gnomAD v3.1.2: AF=0.012 % including seven homoplasmic occurrences in addition to two heteroplasmic occurrences in individuals from European, Latino, African, and Askenazi Jewish ancestry). Given the frequency of this variant, it does not meet PM2 criterion. The computational predictor APOGEE gives a consensus rating of benign with a score of 0.43 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that three experts on this panel felt likely benign was a more appropriate classification given the presence in the general population however the majority (five) agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414793545/MONDO:0044970/015 2023-05-22 2024-03-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:45951 biolink:causes UMLS:C0231785 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0231785 infores:hetionet CHEBI:9139 biolink:causes MONDO:0000498 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2242711 infores:hetionet CHEBI:50275 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0019521 infores:hetionet CAID:CA10584732 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584732 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4_Supporting, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.44T>C (p.Leu15Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP4, and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PS3_moderate - Level 2 Assay: PMID:27175606: Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding.LDL binding <70% wild type activity, so PS3_Moderate is met.PS4_supporting - Variant meets PM2 and is identified in - 2 unrelated index cases who fulfill Simon-Broome possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), - 1 case from PMID: 12052488 with LDL-C above 10 mmol/L (DLCN>6), from Sweden.3 cases, so PS4_Supporting is met.PP4 - Variant meets PM2 and is identified in 3 unrelated index cases who fulfill FH clinical criteria (see PS4 for details). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584732/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA10568323 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568323 MONDO:0010602 PMID: Benign BA1 The c.2453C>T (p.Thr818Ile) variant is reported at an MAF of 0.003158 (60/19000 alleles) in the African/African American population in gnomAD v2.1.1, with 18 hemizygotes, meeting BA1 criteria of MAF > 0.000333. It is not reported in patients with Hemophilia A, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568323/MONDO:0010602/071 2024-09-30 2024-10-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:6375 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0010200 infores:hetionet CHEBI:10119 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0740394 infores:hetionet CHEBI:5098 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0018965 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0427008 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0028738 infores:hetionet CHEBI:6128 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0231218 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0037199 infores:hetionet CHEBI:9654 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0155169 infores:hetionet CAID:CA401370634 biolink:causes MONDO:0009290 infores:clingen CAID:CA401370634 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2174G>C variant in GAA is a missense variant that results in the substitution of arginine by proline at amino acid 725 (p.Arg725Pro). This variant has been reported in one patient, in a study from China, diagnosed with infantile onset Pompe disease with <1% GAA activity in fibroblasts (PMID: 18458862) (PP4_Moderate). This patient was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (ClinVar Variation ID: 4029) (PMID: 18458862); the phase is unknown. 0.5 points (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.973 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change at the same amino acid position, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024), has been classified as pathogenic by the LD VCEP (PM5). In addition, c.2174G>A (p.Arg725Gln) (ClinVar Variation ID: 555727) has been identified in an individuals with a positive newborn screen for Pompe disease and is classified as a VUS by the LD VCEP. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0.): PM5, PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, August 31, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401370634/MONDO:0009290/010 2025-08-31 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:28748 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0034063 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0851341 infores:hetionet GO:1902119 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1902119 GO:0051321 CHEBI:9943 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017605 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0009763 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0023067 infores:hetionet CHEBI:63620 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1456784 infores:hetionet CHEBI:32139 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0041657 infores:hetionet CAID:CA160013 biolink:causes MONDO:0015967 infores:clingen CAID:CA160013 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate BP4, PM1, BS1, PM2, PP3 The c.557T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 186 (p.(Ile186Thr)) of transcript NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; [internal lab contributors]). This variant is located in the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280); therefore, PM1_Supporting is not met. The gnomAD PopMax filtering allele frequency of the c.557TC meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/23): PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA160013/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes UMLS:C0151595 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151595 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017152 infores:hetionet CHEBI:134991 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0013404 infores:hetionet NCBIGene:285175 biolink:causes MONDO:0014777 infores:monarchinitiative not_provided not_provided HGNC:26582 MONDO:0014777 uuid:ed676bbd-d6ea-41ee-9b60-6ff6be47d545 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151907 infores:hetionet CHEBI:8776 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0026858 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0521490 infores:hetionet CHEBI:31709 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0030193 infores:hetionet CHEBI:68556 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0020517 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1442903 infores:hetionet CHEBI:135738 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0039231 infores:hetionet CHEBI:6931 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0043387 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0005940 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0231170 infores:hetionet CHEBI:7903 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0002792 infores:hetionet CHEBI:9241 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0234913 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C1510431 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0020649 infores:hetionet CAID:CA5417032 biolink:causes MONDO:0011225 infores:clingen CAID:CA5417032 MONDO:0011225 PMID: Pathogenic PM2_Supporting, PVS1, PM3 PP4 The c.109+1G>T (NM_001033855.3) variant in DCLRE1C occurs within the canonical splice donor site (+1) of intron 1. It is predicted to cause skipping of biologically relevant exon 1/14, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). This prediction is confirmed by RT-PCR analysis (PMID: 25981738).The filtering allele frequency (the upper threshold of the 95% CI of 5/128202 of the c.109+1G>T variant in DCLRE1C is 0.00001128 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least one individual in the literature. Patient 6, PMID: 25981738, is compound heterozygous with 82kb hemizygous deletion involving exons 1–4 of DCLRE1C, at least LP, according to SCID VCEP. 1 point, PM3 is met.In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PVS1, and PM3 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5417032/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3756 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0008489 infores:hetionet CHEBI:45783 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0231218 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0233472 infores:hetionet CHEBI:4027 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0232849 infores:hetionet CHEBI:51860 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0152198 infores:hetionet CHEBI:3216 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0080274 infores:hetionet CHEBI:42820 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0011991 infores:hetionet CHEBI:167638 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0002622 infores:hetionet CHEBI:135930 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0008031 infores:hetionet CHEBI:63638 biolink:causes HP:0001883 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1301937 infores:hetionet CHEBI:71940 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0010200 infores:hetionet CAID:CA355946316 biolink:causes MONDO:0001586 infores:clingen CAID:CA355946316 MONDO:0001586 PMID: Likely Pathogenic PM3_Supporting, PP3_Moderate, PP4_Moderate, PM2_Supporting PS3, PS1, PS2, PM5, BP5, BS3, PM6, BP2, BP4 The NM_000203.5:c.212A>C variant in IDUA is a missense variant that results in the substitution of glutamine by proline at amino acid 71 (p.Gln71Pro). This variant has been reported in the homozygous state in a single patient with a milder phenotype of MPS I (Hurler-Scheie) (PM3_Supporting). In this patient a specific combination of clinical and biochemical evidence diagnostic of MPSI was present (PP4_Moderate). The computational predictor REVEL gives a score of 0.806 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). This variant is absent from gnomAD v4.1.0. (PM2_Supporting).This variant therefore meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM2_Supporting, PM3_Supporting, PP3_Moderate, PP4_Moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, Sept. 15, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355946316/MONDO:0001586/091 2025-09-15 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0235431 infores:hetionet NCBITaxon:28131 biolink:causes MONDO:0006865 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:28131 MESH:D005892 DB00257_MESH_D005892_1 CHEBI:5130 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0234215 infores:hetionet CHEBI:231425 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0013491 infores:hetionet CHEBI:2668 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0039070 infores:hetionet CHEBI:30659 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0948089 infores:hetionet CHEBI:9587 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0020621 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0018799 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151717 infores:hetionet CHEBI:42797 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040264 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0233472 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0854381 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0854381 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0086132 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0018790 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0085593 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0018824 infores:hetionet CHEBI:44185 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018681 infores:hetionet NCBIGene:8701 biolink:causes MONDO:0012748 infores:monarchinitiative not_provided not_provided HGNC:2942 MONDO:0012748 uuid:979aacc7-6851-4eea-9de6-caacf21c1637 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234215 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0011991 infores:hetionet NCBITaxon:37296 biolink:causes MONDO:0005055 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:37296 MONDO:0005055 CHEBI:9570 biolink:causes MONDO:0020547 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0867389 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014863 infores:hetionet CHEBI:51450 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C1384353 infores:hetionet CHEBI:3723 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0221170 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0034065 infores:hetionet CHEBI:77733 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0040822 infores:hetionet NCBIGene:5896 biolink:causes MONDO:0011086 infores:monarchinitiative not_provided not_provided HGNC:9831 MONDO:0011086 uuid:c582185f-9f4f-4242-bf89-65ebcbf6122c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386299735 biolink:causes MONDO:0009861 infores:clingen CAID:CA386299735 MONDO:0009861 PMID: Pathogenic PM3, PVS1, PM2, PP4 This c.442-2A>G variant in PAH was detected in a patient with PKU with the pathogenic variant c.441+3G>C (PMID: 28982351). This variant was absent in population databases. This is a canonical variant in the -2 splice acceptor of intron 4. Exon skipping or use of a cryptic splice site would disrupt reading frame with nonsense mediated decay predicted. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386299735/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9123 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234215 infores:hetionet CAID:CA1707510 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707510 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.5668-7G>A variant in DYSF, which is also known as NM_001130987.2: c.5785-7G>A, occurs in the splice acceptor motif in intron 50. SpliceAI gives a delta score of 0.94 for loss of the canonical acceptor site and of 0.99 for gain of an alternative acceptor 2 bp upstream. RNAseq analysis has shown that this variant disrupts splicing, resulting in the use of the alternate splice acceptor site and insertion of 5 bp of the intron, producing a frameshift and introduction of premature stop codon in exon 52, p.Asp1890ValfsTer78, with nonsense-mediated decay expected (PMID: 36983702; PVS1_RNA). This variant has been reported in at least four patients with signs of LGMD, including in a homozygous state in two unrelated patients without reported familial consanguinity (1.0 pt; PMID: 32400077, LOVD Individual #00300446; PMID: 30564623, LOVD Individual #00220837) and confirmed in trans with a pathogenic variant (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and disease range dysferlin expression in blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). The filtering allele frequency of this variant is 0.000014 in gnomAD v4.1.0 (the upper threshold of the 95% CI of 9/1111596 European (non-Finnish) exome chromosomes) , which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_RNA, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707510/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71255 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0023530 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0004691 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0021294 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0021294 infores:hetionet CHEBI:94807 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0027497 infores:hetionet CHEBI:144093 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0085606 infores:hetionet NCBITaxon:39054 biolink:causes MONDO:0005791 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:39054 MONDO:0005791 CHEBI:31236 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038525 infores:hetionet CHEBI:4653 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0026826 infores:hetionet CAID:CA182757 biolink:causes MONDO:0021060 infores:clingen CAID:CA182757 MONDO:0021060 PMID: Benign BA1, BP7, BP5 The c.1108+9_1108+21del variant is located in intron 10 of the RAF1 gene. This variant has a filtering allele frequency of 0.05951% in the European (non-Finnish) population in gnomAD v2, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1 and therefore meets this criterion (BA1). The variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Additionally, this variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR Lab ID's: 26957, 21766; ClinVar SCV000205113.4, SCV000209007.2). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5, BP7. (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA182757/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7903 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0036416 infores:hetionet CHEBI:31547 biolink:causes UMLS:C1697943 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C1697943 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0233472 infores:hetionet NCBIGene:8504 biolink:causes MONDO:0013948 infores:monarchinitiative not_provided not_provided HGNC:8858 MONDO:0013948 uuid:860d0e35-7e0d-4cd8-ab8a-eb0f10bf6198 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011168 infores:hetionet CHEBI:404903 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0000731 infores:hetionet CHEBI:4792 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0151798 infores:hetionet CAID:CA399805465 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805465 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5(ITGA2B):c.666C>A (p.Phe222Leu) missense variant has been reported in at least one homozygous patient (CC in PMID: 11798398) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate; PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180026 alleles) in the European (non-Finnish) genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805465/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6438 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0005745 infores:hetionet CHEBI:32139 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0012833 infores:hetionet CHEBI:9123 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151878 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0235097 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0235097 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0345904 infores:hetionet CAID:CA251539 biolink:causes MONDO:0009861 infores:clingen CAID:CA251539 MONDO:0009861 PMID:26322415PMID:26322415PMID:16879198PMID:1679030PMID:23430547PMID:17935162 Pathogenic PM3, PP4_Moderate, PP1, PP3, PS3 PM2 The c.143T>C (p.Leu48Ser) variant in PAH has been reported multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26322415, 16879198, 1679030). This variant has a frequency that is higher than the suggested cutoff for PM2 by the PAH VCEP (MAF=0.00026). This variant has 39% residual activity (PS3, PMID: 17935162). This variant was detected in trans with p.G247R (LP, 2 submitters) PM3, PMID: 26322415). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Cosegregation with PKU in 2 siblings for 2 unrelated families was reported ( PMID: 23430547). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3, PP1, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251539/MONDO:0009861/006 2019-04-08 2019-04-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63620 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018801 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0034634 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0034634 infores:hetionet CHEBI:9654 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0023380 infores:hetionet NCBIGene:2956 biolink:causes MONDO:0030841 infores:monarchinitiative not_provided not_provided HGNC:7329 MONDO:0030841 uuid:a4ccf77c-c06a-4b54-b988-643fbeda021e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83531 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0030554 infores:hetionet CHEBI:7494 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0009676 infores:hetionet CHEBI:6909 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0241633 infores:hetionet CHEBI:521033 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0015230 infores:hetionet CAID:CA386965806 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965806 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PP1, PP4 The c.727C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to glutamic acid at codon 243 (p.(Gln243Glu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8659, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 15657605). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 15657605). In summary, c.727C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 1/11/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965806/MONDO:0015967/017 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9667 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0156404 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0034150 infores:hetionet CHEBI:94440 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0004245 infores:hetionet CHEBI:72297 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0000737 infores:hetionet CHEBI:6062 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085631 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0040210 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0040210 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001119 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0025322 infores:hetionet CHEBI:15365 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C1145670 infores:hetionet CHEBI:478164 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0042963 infores:hetionet CHEBI:74947 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085649 infores:hetionet CHEBI:37941 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0015402 infores:hetionet CHEBI:6367 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013604 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0150450 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0694536 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0020517 infores:hetionet CHEBI:145499 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004093 infores:hetionet CHEBI:63589 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0920289 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0015256 infores:hetionet CHEBI:3082 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0024902 infores:hetionet CHEBI:6950 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027066 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0023510 infores:hetionet CHEBI:17076 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0042963 infores:hetionet CHEBI:84500 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0040264 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027947 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151602 infores:hetionet CHEBI:50648 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0029089 infores:hetionet CHEBI:28901 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085932 infores:hetionet CHEBI:9435 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0037763 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0033860 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0342579 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0025061 infores:hetionet CHEBI:10125 biolink:causes HP:0100678 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037301 infores:hetionet CAID:CA404094756 biolink:causes MONDO:0007750 infores:clingen CAID:CA404094756 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, PS3, BS1, BS3 NM_000527.5(LDLR):c.2147A>C (p.Glu716Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.000001695 (0.00017%) in European (non-Finnish) (gnomAD v4.1.0).BP4: REVEL = 0.44. REVEL is below 0.50. Splicing evaluation is required. Functional data on splicing not available. A) not on limits, B) variant does not creates GT or AG, C) There is an AG nearby (and there is no GT nearby). MES scores: variant cryptic score (CACAGAGGCTGCGGCTGCAGTGG) = -2.98, wt cryptic (CACAGAGGCTGAGGCTGCAGTGG) = -10.35, canonical acceptor = 8.76. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404094756/MONDO:0007750/013 2025-03-28 2025-06-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:75722 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0877232 infores:hetionet CHEBI:119486 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C3665386 infores:hetionet CHEBI:6950 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151610 infores:hetionet CHEBI:45783 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0858635 infores:hetionet CHEBI:17347 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0232292 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0152128 infores:hetionet CHEBI:3761 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0234518 infores:hetionet CHEBI:27732 biolink:causes UMLS:C1112470 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1112470 infores:hetionet NCBIGene:5500 biolink:causes MONDO:0054588 infores:monarchinitiative not_provided not_provided HGNC:9282 MONDO:0054588 uuid:7acf30e6-caa1-4d68-8ffe-7cd6361897f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4876 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0085593 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0151664 infores:hetionet CHEBI:145499 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2938875 infores:hetionet CHEBI:61390 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0011991 infores:hetionet NCBIGene:4713 biolink:causes MONDO:0859320 infores:monarchinitiative not_provided not_provided HGNC:7702 MONDO:0859320 uuid:557d4f99-dbca-483b-80f5-a5da544f074c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0162429 infores:hetionet GO:1903859 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0007275 CAID:CA389475129 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475129 MONDO:0100040 PMID: Benign BP5_Strong, BS1, BS2, BP4 The allele frequency of the p.Gly152Ala variant in FOXG1 is 0.008% in Latino sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly152Ala variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2).The p.Gly152Ala variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). Computational analysis prediction tools suggest that the p.Gly152Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gly152Ala variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475129/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0006266 infores:hetionet CHEBI:6367 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0438215 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0520723 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0520723 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0027051 infores:hetionet CHEBI:31625 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0026961 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0155003 infores:hetionet CHEBI:64355 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2010560 infores:hetionet CAID:CA392254706 biolink:causes MONDO:0012996 infores:clingen CAID:CA392254706 MONDO:0012996 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PS3_Supporting PP3, PM3, BP4 The NM_001482.3:c.1238G>A variant in GATM is a missense variant resulting in substitution of arginine by glutamine at amino acid 413 (p.Arg413Gln). One patient with this variant has been reported and has clinical features consistent with AGAT deficiency, as well as absent brain creatine by MRS and reduced plasma GAA (<0.01% normal) (PMID: 23660394 26490222); these features are highly specific for AGAT deficiency (PP4_Strong). This individual is compound heterozygous for this variant and another variant in GATM, c.1237C>T (p.Arg413Trp) that was confirmed to be in trans. Note that the second variant alters the same amino acid as the variant under assessment. The allelic data from this patient will be used in the classification of the second variant, and is not included here to avoid circular logic (PMID: 23660394 26490222). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002228 (1/44890 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.433 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. When expressed in HeLa cells, the variant resulted in 0% wild type AGAT activity (PMID 27233232). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PP4_Strong, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392254706/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2639 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0232459 infores:hetionet CHEBI:10101 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037036 infores:hetionet CHEBI:51380 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0006266 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0012739 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0004936 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0234458 infores:hetionet CHEBI:6935 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0027497 infores:hetionet CHEBI:6775 biolink:causes UMLS:C3665818 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C3665818 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0392025 infores:hetionet CHEBI:135276 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C1443060 infores:hetionet CHEBI:3061 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0003811 infores:hetionet CHEBI:3499 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0595916 infores:hetionet CHEBI:9137 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0015230 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C1384666 infores:hetionet CHEBI:4672 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0014518 infores:hetionet CHEBI:50922 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0022408 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0018939 infores:hetionet CHEBI:167638 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0278106 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026848 infores:hetionet CHEBI:4469 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0012833 infores:hetionet CHEBI:36795 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0016204 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C1328308 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1328308 infores:hetionet CAID:CA367400083 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400083 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.898G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glutamine at codon 300 (p.(Glu300Gln)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes/fasting hyperglycemia with more than 20 informative meioses in multiple families (PP1_Strong; PMID: 8433729, internal lab contributors). This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; PMID: 8433729, internal lab contributors). Additionally, one of these individuals was reported to have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.898G>A (p.Glu300Lys), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PS4, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400083/MONDO:0015967/086 2024-10-13 2024-10-13 Semidominant inheritance HP:0032113 Supports CHEBI:5062 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0033575 infores:hetionet CHEBI:127342 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0232462 infores:hetionet CHEBI:107736 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0392676 infores:hetionet CHEBI:3638 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0003467 infores:hetionet CHEBI:80630 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0037036 infores:hetionet CAID:CA410204028 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204028 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.170C>G (p.Pro57Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204028/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63618 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0029089 infores:hetionet CHEBI:681569 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0018944 infores:hetionet CHEBI:17688 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0702166 infores:hetionet CHEBI:4530 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0018418 infores:hetionet CHEBI:63581 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0235378 infores:hetionet NCBIGene:7021 biolink:causes MONDO:0008209 infores:monarchinitiative not_provided not_provided HGNC:11743 MONDO:0008209 uuid:4fd9760d-7e2f-4dbf-84ab-da3538a7047f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA45511768 biolink:causes MONDO:0800472 infores:clingen CAID:CA45511768 MONDO:0800472 PMID:27243976 Uncertain Significance PP3, PM2_Supporting, PM1, PM3_Supporting PP1, BP4, BA1, PS1, PS3, PS2, PM5, PM4, BP7, BS1, BS4, PVS1 The c.171G>C variant in CYP1B1 is a missense variant predicted to cause substitution of Tryptophan by Cysteine at amino acid 57 (p.Trp57Cys). This missense variant is located in the hinge region, meeting PM1. The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1) = 0.00001339 (1 allele out of 74,690), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.721, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). 1 affected segregation with a CYP1B1-related phenotype has been reported (PMID: 9497261), however the phase was not confirmed in trans, therefore PP1 could not be applied. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) (PMID: 9497261). Total proband points = 0.5, meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM1, PP3, PM2_Supporting, PM3_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA45511768/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4466 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151905 infores:hetionet NCBITaxon:147573 biolink:causes MONDO:0005669 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:147573 MONDO:0005669 CHEBI:52717 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0029132 infores:hetionet CHEBI:135351 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0085639 infores:hetionet CHEBI:44423 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0013604 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0009806 infores:hetionet CAID:CA229786 biolink:causes MONDO:0009861 infores:clingen CAID:CA229786 MONDO:0009861 PMID:11461196 Likely Benign BS3_Supporting, BS1 PM5, PP3 PAH-specific ACMG/AMP criteria applied: BS1: MAF= 0.01815 in 1000G. 2 homozygotes in ExAC, 1 homozygote in 1000G.; BS3_Supporting: Enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. (PMID:11461196). In summary this variant meets criteria to be classified as likely benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS3_Supporting). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229786/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5864 biolink:causes MONDO:0001119 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0025322 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0876973 infores:hetionet CHEBI:3423 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0004093 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085096 infores:hetionet CHEBI:136040 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0000731 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0004096 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0271899 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0271899 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0038454 infores:hetionet CAID:CA913168968 biolink:causes MONDO:0044970 infores:clingen CAID:CA913168968 MONDO:0044970 PMID:12729737PMID:32273537PMID:20471262 Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate, PM5_Supporting PP1, PS2, PM6 The m.3243A>T variant in MT-TL1 has been reported in eight unrelated probands with primary mitochondrial disease. Features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), as well as myoclonic epilepsy, exercise intolerance with rhabdomyolysis, cataracts, sensorineural hearing loss, diabetes, peripheral neuropathy, and ataxia (PMIDs: 9168904, 18203188, 20471262, 23220830, 30210801, 33924034, 25504047; PS4_moderate). In all individuals, the variant was present at heteroplasmy, ranging from 69-99% in muscle and 13-50% in blood. Age of onset varied from six to 29 years old. There are no large families reported in the medical literature to consider for evidence of segregation. There are no de novo occurrences of this variant reported to our knowledge. The m.3243A>T variant is absent in the GenBank dataset and gnomAD3.1.2. There is one heteroplasmic occurrence in 195,893 sequences in the Helix database, however the overall frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 58.8 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.8 (PP3). The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID: 20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID: 12729737). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with likely pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PM5_supporting, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913168968/MONDO:0044970/015 2022-10-10 2023-03-13 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria UNII:2N4O9L084N biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0009450 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0040034 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0403632 infores:hetionet CHEBI:119915 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020598 infores:hetionet CHEBI:3207 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0009782 infores:hetionet CHEBI:64312 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151699 infores:hetionet NCBIGene:8710 biolink:causes MONDO:0014272 infores:monarchinitiative not_provided not_provided HGNC:13902 MONDO:0014272 uuid:78dfcc5d-cae7-4e5a-9ae6-41cc3bc097a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004096 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0857035 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0857035 infores:hetionet NCBIGene:11232 biolink:causes MONDO:0030326 infores:monarchinitiative not_provided not_provided HGNC:9180 MONDO:0030326 uuid:81a8c7c5-840f-451f-a888-8318c8b8a089 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7986 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0013604 infores:hetionet CAID:CA16041899 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041899 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2185del (p.Leu729TrpfsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in three individuals with infantile onset Pompe disease (PMIDs 19588081, 24269976, 28394184)(PP4). One of these individuals is homozygous for the variant (PMID 19588081)(PM3_Supporting); another individual is heterozygous for the variant but a second variant was not found (PMID, 24269976), and one is compound heterozygous for the variant and c.1935C>A (p.Asp645Glu)(PMID 28394184). The allelic data for this latter patient was used in the assessment of p.Asp645Glu and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variant ID 370552; 2 star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041899/MONDO:0009290/010 2021-11-19 2021-11-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:49375 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013922 infores:hetionet CHEBI:6792 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0013378 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0423602 infores:hetionet CAID:CA437911597 biolink:causes MONDO:0001586 infores:clingen CAID:CA437911597 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting PS2, BS4, PP1, PP4 The NM_000203.5:c.65del (p.Pro22ArgfsTer86) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1 out of 14, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with MPS I (severe, Hurler phenotype) on the basis of enzymology (PMID: 11735025; note that older nomenclature, c.153del is used for the variant, presumably referring to NR_110313.1) (insufficient detail to apply PP4). This individual is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.1205G>A (pTrp402Ter) (ClinVar Variation ID: 11908); the phase was not confirmed (PMID: 11735025). Total 0.5 points (PM3_Supporting).The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001537 (1/65052 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 929238). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 23, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA437911597/MONDO:0001586/091 2025-06-23 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50777 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0269189 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0851341 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0948594 infores:hetionet CHEBI:6539 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020672 infores:hetionet CAID:CA386965770 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965770 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PP3 PS4, PP4 The c.721T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to glycine at codon 241 (p.(Cys241Gly)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with disease with 12 informative meioses in three families with MODY (PP1_Strong; PMID: 9032114, PMID: 9867222). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 9032114, 9867222). This variant was identified in individuals with diabetes; however, the calculated MODY probability is <50% and HNF4A was not tested (PMID: 9032114, 9867222). In summary, c.721T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PP3, PM1_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965770/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0014724 infores:hetionet CHEBI:3286 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0011603 infores:hetionet CHEBI:44032 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0033687 infores:hetionet CHEBI:6375 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0023218 infores:hetionet CAID:CA060375 biolink:causes MONDO:0018493 infores:clingen CAID:CA060375 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 4558 of the RYR1 protein, p.(Arg4558Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.79 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA060375/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:2636 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0027497 infores:hetionet NCBIGene:3852 biolink:causes MONDO:0030535 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0030535 uuid:65869376-3595-4f77-b06c-d0d9eff3208a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002874 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0023067 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0427108 infores:hetionet NCBIGene:166379 biolink:causes MONDO:0014440 infores:monarchinitiative not_provided not_provided HGNC:26648 MONDO:0014440 uuid:6bdf8491-f970-4b7b-b95c-72862fa68c4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63618 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0016204 infores:hetionet CHEBI:49662 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0039231 infores:hetionet NCBIGene:2890 biolink:causes MONDO:0030968 infores:monarchinitiative not_provided not_provided HGNC:4571 MONDO:0030968 uuid:8094123c-a03d-4515-9c1b-a1974f943f7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4670 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0018681 infores:hetionet CHEBI:31932 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0040586 infores:hetionet GO:1904653 biolink:causes GO:0030323 infores:ubergraph knowledge_assertion manual_agent GO:1904653 GO:0030323 CHEBI:2914 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0042109 infores:hetionet UMLS:C1738934 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0001807 infores:hetionet UMLS:C0011701 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0043144 infores:hetionet CHEBI:23765 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013456 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004096 infores:hetionet CHEBI:28445 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0030554 infores:hetionet CHEBI:41423 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C3489393 infores:hetionet CHEBI:34911 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0687713 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0476327 infores:hetionet CHEBI:64045 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0085637 infores:hetionet CHEBI:132233 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0004093 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1527311 infores:hetionet CHEBI:3312 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0000833 infores:hetionet NCBIGene:5184 biolink:causes MONDO:0008221 infores:monarchinitiative not_provided not_provided HGNC:8840 MONDO:0008221 uuid:7e81b890-70d1-4c91-ad4f-e1856af6ad7a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0026975 infores:hetionet CHEBI:7822 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0030305 infores:hetionet CHEBI:6897 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0035455 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027769 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0271650 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151505 infores:hetionet CHEBI:63608 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0013604 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151740 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0267792 infores:hetionet CHEBI:16586 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0948594 infores:hetionet GO:1900247 biolink:causes GO:0002181 infores:ubergraph knowledge_assertion manual_agent GO:1900247 GO:0002181 CHEBI:46557 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0000731 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0021364 infores:hetionet CHEBI:7986 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0023530 infores:hetionet CAID:CA2636928 biolink:causes MONDO:0021060 infores:clingen CAID:CA2636928 MONDO:0021060 PMID: Benign BA1 The c.177A>G (p.Gln59=) variant in MRAS is a synonymous variant at position 59. This variant has a filtering allele frequency of 8.578% in the African/African American population in gnomAD v2, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1 (RASopathy VCEP specifications version 1.4; 12/3/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2636928/MONDO:0021060/087 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9570 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0027497 infores:hetionet CHEBI:17823 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0009806 infores:hetionet CHEBI:6532 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0042075 infores:hetionet CHEBI:17334 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0085593 infores:hetionet CHEBI:8776 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0231218 infores:hetionet CHEBI:46195 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0086565 infores:hetionet CHEBI:6904 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0011991 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0232492 infores:hetionet CHEBI:32139 biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C2747793 infores:hetionet CHEBI:41423 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009676 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0019360 infores:hetionet CHEBI:6541 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0004134 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0018802 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0149931 infores:hetionet CHEBI:63611 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0001925 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0018799 infores:hetionet CHEBI:45863 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0206061 infores:hetionet CAID:CA1619848 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619848 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PM5, PP1_Strong, PP3_Strong BA1, BP4, PM1, PM4, PS1, PS2, PS3, BS1, BS4, BP7, PVS1 The c.1168C>A variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Serine at amino acid 390 (p.Arg390Ser). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00003997 (3 alleles out of 75,048), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.967, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699). 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 20664688, ClinVar), which fulfilled PP1_Strong. This variant has been identified in ten individuals with a CYP1B1-related phenotype. Three of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 confirmed in trans, 3 phase unknown) (PMIDs: 14635112, 19234632, 23218183, ClinVar). Two individuals are compound heterozygous for the variant and a variant of uncertain significance (P52L confirmed in trans, R368H) (PMID: 21815720, 38755526). Four individuals are homozygous (assumed consanguineous) for the variant (PMIDs: 20664688, 10655546, ClinVar). Total proband points = 4, meeting PM3_Very Strong. Another missense variant (p.Arg390His, Grantham score = 29, ClinVar ID: 592512) in the same codon has been classified as pathogenic for a CYP1B1-related phenotype by the ClinGen Glaucoma VCEP. CYP1B1:p.Arg390Ser has a higher Grantham score (= 110) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5 to apply. In summary, this variant met the criteria to receive a score of 18 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very Strong, PP1_Strong, PP3_Strong, PM5, PM2_Supporting (combination of PP3 and PM5 is capped at 5 points). Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619848/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50841 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0027849 infores:hetionet CHEBI:3207 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0001623 infores:hetionet CHEBI:52010 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0031117 infores:hetionet GO:0060693 biolink:causes GO:0007431 infores:ubergraph knowledge_assertion manual_agent GO:0060693 GO:0007431 CHEBI:15940 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0011168 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007682 infores:hetionet CHEBI:474053 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0027497 infores:hetionet CHEBI:135930 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0009782 infores:hetionet CHEBI:72564 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0038220 infores:hetionet CHEBI:7824 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0023530 infores:hetionet NCBIGene:9853 biolink:causes MONDO:0030915 infores:monarchinitiative not_provided not_provided HGNC:23625 MONDO:0030915 uuid:8095e8ff-6550-4647-8e9d-36349c865570 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0038362 infores:hetionet CHEBI:4911 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0595916 infores:hetionet CHEBI:27504 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0012833 infores:hetionet CHEBI:9599 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0035455 infores:hetionet CHEBI:4858 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0233471 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0152227 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0243026 infores:hetionet CHEBI:6887 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0236075 infores:hetionet CHEBI:9571 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0013144 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0040034 infores:hetionet CHEBI:68478 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151766 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0040034 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0151773 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009443 infores:hetionet CHEBI:8802 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0033774 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0038362 infores:hetionet CHEBI:15640 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0004093 infores:hetionet CAID:CA213834 biolink:causes MONDO:0015967 infores:clingen CAID:CA213834 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate PM1 The c.704T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 235 (p.(Met235Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.21, which is below the MDEP cutoff (<0.5) (PS3_Moderate; Gloyn et al., 2004 (DOI: 10.1159/000079009)). This variant has been indentified in at least 43 individuals with hyperglycemia (PS4; PMID: 19564454, 30592380; internal lab contributors). Furthermore, this variant segregated with hyperglycemia with at least 11 meioses in multiple families (PP1_Strong; internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; internal lab contributors). Another missense variant at the same residue, c.703A>G (p.Met235Val), has been classified as pathogenic by the ClinGen MDEP and p.Met235Thr has a greater Grantham distance (PM5). In summary, c.704T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS4, PP1_Strong, PS3_Moderate, PP4_Moderate, PM5, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213834/MONDO:0015967/086 2025-09-17 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:31644 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1527344 infores:hetionet CHEBI:37941 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0010200 infores:hetionet UNII:5V9KLZ54CY biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0019080 infores:hetionet CHEBI:119573 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0000729 infores:hetionet CAID:CA512318868 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318868 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.270G>A (p.Val90=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318868/MONDO:0011071/008 2024-09-11 2024-09-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8764 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0021051 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011616 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013447 infores:hetionet CHEBI:64064 biolink:causes UMLS:C1112677 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1112677 infores:hetionet CHEBI:17026 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0028734 infores:hetionet CHEBI:31624 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0028778 infores:hetionet NCBIGene:139886 biolink:causes MONDO:0957919 infores:monarchinitiative not_provided not_provided HGNC:27040 MONDO:0957919 uuid:e3ba120f-f055-42bc-8ea1-b0617ca6d3b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0018524 infores:hetionet CHEBI:37333 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0016382 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0948089 infores:hetionet GO:0061521 biolink:causes CL:0000632 infores:ubergraph knowledge_assertion manual_agent GO:0061521 CL:0000632 UNII:VL0L558GCB biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0085641 infores:hetionet CHEBI:135613 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C1142412 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0233472 infores:hetionet NCBIGene:79188 biolink:causes MONDO:0859235 infores:monarchinitiative not_provided not_provided HGNC:28472 MONDO:0859235 uuid:a214b51b-ee2f-43aa-92e9-7e9c375bb52e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0020580 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0042963 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0005940 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0019158 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0852566 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0852566 infores:hetionet CHEBI:36704 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C3665347 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0221392 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027769 infores:hetionet CHEBI:32315 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0423791 infores:hetionet CHEBI:175901 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0206062 infores:hetionet NCBIGene:4125 biolink:causes MONDO:0009561 infores:monarchinitiative not_provided not_provided HGNC:6826 MONDO:0009561 uuid:7cf2bbf4-07e7-431a-9265-a41840fb711e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16586 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C1443060 infores:hetionet CHEBI:31413 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011168 infores:hetionet CHEBI:63620 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151766 infores:hetionet CHEBI:64028 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C2830004 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0037274 infores:hetionet CHEBI:37924 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1443060 infores:hetionet CHEBI:74947 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C2242996 infores:hetionet CHEBI:71255 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0018418 infores:hetionet CHEBI:31625 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C3665347 infores:hetionet CHEBI:77733 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0015672 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0162429 infores:hetionet NCBITaxon:196 biolink:causes MONDO:0040728 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:196 MONDO:0040728 CHEBI:5130 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017181 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0855242 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1443060 infores:hetionet NCBITaxon:5600 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5600 MONDO:0001867 CHEBI:4672 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0149931 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0006849 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0151664 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0017152 infores:hetionet CHEBI:37941 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151766 infores:hetionet CHEBI:63631 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002962 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042075 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0021053 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0017601 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes NCIT:C26772 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0015668 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020517 infores:hetionet CAID:CA2387272459 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387272459 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-18C>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.16)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387272459/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA10585506 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585506 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP1, BP4, BP3, PS3, PS4, PS1, BP5, BP7, BS1, BS3, BS4, PM4, PM1, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1571T>G (p.Val524Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL = 0.992. PP4: Variant meets PM2 and is identified in 1 case fulfilling Simon Broome criteria for FH in PMID 17142622 (Humphries et al., 2006), UK. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585506/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:40279 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0011849 infores:hetionet CHEBI:3216 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0235086 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0003864 infores:hetionet CHEBI:6076 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020461 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0160390 infores:hetionet NCBIGene:291 biolink:causes MONDO:0012238 infores:monarchinitiative not_provided not_provided HGNC:10990 MONDO:0012238 uuid:7e1a6b61-ffb6-4ea9-bcd0-4b806f107e31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030312 infores:hetionet CHEBI:48131 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C2242996 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0021290 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0021290 infores:hetionet NCBIGene:22934 biolink:causes MONDO:0012073 infores:monarchinitiative not_provided not_provided HGNC:10297 MONDO:0012073 uuid:b0ac6bb2-c27e-468c-b141-647b28e03ef7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18243 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0429098 infores:hetionet CHEBI:9586 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011124 infores:hetionet CHEBI:9139 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042023 infores:hetionet CAID:CA291224896 biolink:causes MONDO:0100326 infores:clingen CAID:CA291224896 MONDO:0100326 PMID:11806996 Pathogenic PP4_Strong, PM3, PP3, PS3_Moderate, PM2_Supporting The NM_000212.3(ITGB3):c.725G>A (p.Arg242Gln) missense variant has a REVEL score of 0.859, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with Arg242Gln (here referred to as Arg216Gln) variant β3 and wild type αIIb showed decreased expression at approximately 20% of WT levels indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate). It is absent from gnomAD v2.1.1 (PM2_Supporting). At least 2 GT patients homozygous for this variant have been reported in PMID: 9215749 and PMID: 19691478 (PM3). And At least one patient (Patient GT4 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and function was pathological. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_moderate, PP4_strong, PM2_supporting, PM3, PP3. (VCEP specifications version 2; date of approval 02/03/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291224896/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:68554 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0575081 infores:hetionet CHEBI:7798 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0013395 infores:hetionet CHEBI:32139 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C2697368 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018418 infores:hetionet CHEBI:7852 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232602 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0003123 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0040034 infores:hetionet CHEBI:63631 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011168 infores:hetionet CHEBI:63635 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0009782 infores:hetionet CHEBI:9613 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0151474 infores:hetionet CHEBI:4024 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0039231 infores:hetionet CHEBI:3242 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0018681 infores:hetionet CHEBI:45783 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0242429 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0854114 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019151 infores:hetionet CHEBI:50663 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0009676 infores:hetionet NCBIGene:28514 biolink:causes MONDO:0032877 infores:monarchinitiative not_provided not_provided HGNC:2908 MONDO:0032877 uuid:a4e1cf7c-7dd6-438f-8fb0-c409fe5087da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013404 infores:hetionet CHEBI:41423 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0025345 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0002622 infores:hetionet CHEBI:4798 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013404 infores:hetionet CHEBI:45783 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151723 infores:hetionet CHEBI:3757 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0038990 infores:hetionet CHEBI:7627 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0000731 infores:hetionet CHEBI:2379 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0233407 infores:hetionet CHEBI:4814 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0023218 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0151773 infores:hetionet CHEBI:8354 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0013144 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0018801 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027947 infores:hetionet CHEBI:46345 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0011071 infores:hetionet CHEBI:68642 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0003811 infores:hetionet CHEBI:63581 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0043352 infores:hetionet CHEBI:6759 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0018794 infores:hetionet CHEBI:31980 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0013378 infores:hetionet NCBIGene:102 biolink:causes MONDO:0014234 infores:monarchinitiative not_provided not_provided HGNC:188 MONDO:0014234 uuid:f24f1fc3-226a-46ce-9583-0c03b97c8c2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151736 infores:hetionet CHEBI:4530 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0018681 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0009450 infores:hetionet CHEBI:3216 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020580 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0917798 infores:hetionet CHEBI:6970 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0039446 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853692 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0413252 infores:hetionet CHEBI:3614 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0234215 infores:hetionet CHEBI:41774 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0271051 infores:hetionet CHEBI:40237 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0003467 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0000737 infores:hetionet CHEBI:209807 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0014518 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0541923 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0541923 infores:hetionet CAID:CA000126 biolink:causes MONDO:0018875 infores:clingen CAID:CA000126 MONDO:0018875 PMID: Likely Benign BP4, BS3, PM2_Supporting BA1, PS1, PS3, PS4, PM5, PM1, BS1, BS4, PM6, PP3, BS2 NM_000546.6(TP53):c.344A>G variant in TP53 is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 115 (p.His115Arg). This variant has an allele frequency of 0.000003101 (5/1612276 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0464; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.2; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000126/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA386952724 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952724 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PM5, PP4 The c.80T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to serine at codon 27 (p.Ile27Ser) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% and PP4 could not be applied (PMID 18003757). Another missense variant, c.80T>C (p.Ile27Thr), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.80T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952724/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44915 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0018524 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0151559 infores:hetionet NCBIGene:999 biolink:causes MONDO:0011962 infores:monarchinitiative not_provided not_provided HGNC:1748 MONDO:0011962 uuid:06cdbd50-782c-40a1-81ea-df306a0cf75a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030552 infores:hetionet CHEBI:7915 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151603 infores:hetionet CHEBI:9599 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0007820 infores:hetionet NCBIGene:7007 biolink:causes MONDO:0011102 infores:monarchinitiative not_provided not_provided HGNC:11720 MONDO:0011102 uuid:ef8825a5-7097-4e17-81cf-3ce755c25e9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020039 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0235283 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0235283 infores:hetionet CHEBI:10100 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0003862 infores:hetionet CHEBI:5778 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0003467 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0015397 infores:hetionet CHEBI:7577 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0151636 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027765 infores:hetionet CHEBI:5132 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0018681 infores:hetionet CAID:CA16608764 biolink:causes MONDO:0010305 infores:clingen CAID:CA16608764 MONDO:0010305 PMID: Benign BA1 The NM_005629.4(SLC6A8):c.87G>C (p.Gly29=) variant in SLC6A8 is a synonymous single nucleotide variant that does not change the amino acid sequence at this position. In gnomAD v2.1.1, the highest population minor allele frequency is 0.005489 (62/11296 alleles) in the European population, with 10 hemizygotes present. The presence of 10 hemizygotes in the gnomAD dataset meets BA1 standalone criteria for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (<10 hemizygotes in population database). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:380589). In summary, this variant meets the criteria to be classified as Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608764/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:8059 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0009806 infores:hetionet CHEBI:8412 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0240735 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017152 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0347950 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0347950 infores:hetionet CHEBI:6413 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0013378 infores:hetionet CHEBI:10127 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009782 infores:hetionet NCBIGene:84265 biolink:causes MONDO:0030992 infores:monarchinitiative not_provided not_provided HGNC:28466 MONDO:0030992 uuid:59c19d2c-5ca7-401a-8594-fd1436229fed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025209 infores:hetionet CHEBI:9449 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0004093 infores:hetionet CHEBI:5855 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0235546 infores:hetionet CHEBI:8059 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0917801 infores:hetionet CHEBI:6715 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025874 infores:hetionet CHEBI:2904 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0007398 infores:hetionet CHEBI:37941 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1456822 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0033117 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0435001 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0435001 infores:hetionet NCBIGene:101929726 biolink:causes MONDO:0100292 infores:monarchinitiative not_provided not_provided HGNC:52391 MONDO:0100292 uuid:52f21ad3-7656-44d4-9031-aad860de8133 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0595930 infores:hetionet CHEBI:9587 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0019158 infores:hetionet CHEBI:6375 biolink:causes HP:0200097 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0853945 infores:hetionet NCBIGene:338657 biolink:causes MONDO:0859329 infores:monarchinitiative not_provided not_provided HGNC:30460 MONDO:0859329 uuid:29355acf-1da6-46dd-874a-0487676eeb44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020538 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0031039 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0281981 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0042075 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018500 infores:hetionet CHEBI:47519 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0002170 infores:hetionet CAID:CA229564 biolink:causes MONDO:0009861 infores:clingen CAID:CA229564 MONDO:0009861 PMID: Uncertain Significance PM2, BP4 VUS: The c.46T>C (p.S16P) variant in PAH has not been reported in the medical literature. It is tolerated by computation predictors: SIFT, Polyphen, MutationTaster, and REVEL=0.567 (BP4). It is however absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary this variant meets the criteria to be classified as uncertain significance. PAH-specific ACMG/AMP criteria applied: BP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229564/MONDO:0009861/006 2019-02-26 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:72292 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0012833 infores:hetionet CHEBI:8888 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0025874 infores:hetionet CHEBI:49668 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0032227 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0178298 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C1956346 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0948594 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0027051 infores:hetionet CHEBI:23765 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085636 infores:hetionet CHEBI:5123 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0022660 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0011168 infores:hetionet CHEBI:39112 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0020461 infores:hetionet CHEBI:9587 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0030193 infores:hetionet CHEBI:8382 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0017979 infores:hetionet CHEBI:4657 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0022354 infores:hetionet CHEBI:253342 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0702166 infores:hetionet CHEBI:8888 biolink:causes HP:0033134 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0549357 infores:hetionet CHEBI:2469 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0004604 infores:hetionet CHEBI:64354 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C2047937 infores:hetionet CHEBI:36791 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015403 infores:hetionet CHEBI:3478 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0001824 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0031350 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0041956 infores:hetionet CHEBI:94686 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0019080 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0030920 infores:hetionet CHEBI:28918 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0917801 infores:hetionet CHEBI:2682 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085682 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0002453 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0023895 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0349506 infores:hetionet CHEBI:9123 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0040822 infores:hetionet UMLS:C0657912 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020458 infores:hetionet CAID:CA9200718 biolink:causes MONDO:0018947 infores:clingen CAID:CA9200718 MONDO:0018947 PMID: Benign BA1, BP4, BP7 BS1, PM2 The variant NM_001005361.3:c.162-6del in DNM2 is an intronic deletion variant. The highest population filtering allele frequency in gnomAD v4.1 is 0.0001715 (15/60000 alleles) in the Admixed American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The c.162-6del variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by theClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA9200718/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50861 biolink:causes UMLS:C0740319 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0740319 infores:hetionet CHEBI:6413 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C1384353 infores:hetionet CHEBI:135935 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0235063 infores:hetionet CHEBI:45951 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0221152 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004690 infores:hetionet CHEBI:31302 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0039231 infores:hetionet NCBIGene:5927 biolink:causes MONDO:0970951 infores:monarchinitiative not_provided not_provided HGNC:9886 MONDO:0970951 uuid:a85b9b68-97ea-4449-b886-c17a1e8c1ff6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512341301 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341301 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This synonymous variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.628)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341301/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:78543 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0042487 infores:hetionet CHEBI:39585 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0015371 infores:hetionet CHEBI:7476 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0080274 infores:hetionet CHEBI:36791 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0575081 infores:hetionet CHEBI:29688 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0235378 infores:hetionet CHEBI:4735 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C1443060 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0700345 infores:hetionet GO:1900211 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900211 GO:0007275 CHEBI:9654 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0004238 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0009450 infores:hetionet CHEBI:125354 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0019080 infores:hetionet CHEBI:8874 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020443 infores:hetionet CHEBI:4646 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0026961 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1527407 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003233 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0270736 infores:hetionet CHEBI:10100 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C1443060 infores:hetionet CHEBI:63611 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003537 infores:hetionet CHEBI:3723 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025874 infores:hetionet NCBIGene:6942 biolink:causes MONDO:0032745 infores:monarchinitiative not_provided not_provided HGNC:11631 MONDO:0032745 uuid:bba4e9ed-0bc3-46c6-a719-68fee6c4a9b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1716 biolink:causes MONDO:0009636 infores:monarchinitiative not_provided not_provided HGNC:2858 MONDO:0009636 uuid:48354ffb-ee01-4061-bdfb-f8022ffbb792 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0854382 infores:hetionet CHEBI:77260 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020598 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0277925 infores:hetionet CHEBI:6367 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042023 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021071 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023055 infores:hetionet CHEBI:3207 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0017178 infores:hetionet CHEBI:31199 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0234894 infores:hetionet CAID:CA2695224143 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224143 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.339_340insGA (p.Thr114GlufsTer16) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BS-40 in PMID: 21699652) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 2; date of approval xx/xx/xxxx). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224143/MONDO:0009276/079 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50729 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0037278 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002968 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0024248 infores:hetionet CHEBI:63598 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235063 infores:hetionet CAID:CA166283 biolink:causes MONDO:0700270 infores:clingen CAID:CA166283 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5_Supporting, PVS1 PM2 The c.790delT (p.Y264Ifs*12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001763 (2/113450 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID: 12815592, 9887333, 26896183, 22213089). In summary, this variant meets the criteria to be classified as a pathogenic variant for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3_strong, PM5_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA166283/MONDO:0700270/020 2024-01-24 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4710 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0600142 infores:hetionet CAID:CA386952188 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952188 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5, PP4_Moderate, PP3 PS4, PP1 The c.16A>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to cysteine at codon 6 (p.(Ser6Cys)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8529, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.16A>G p. Ser6Asn, has been classified as pathogenic by the ClinGen MDEP, and p.Ser6Cys has a greater Grantham distance (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP4_Moderate, PM2_Supporting, PP3, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952188/MONDO:0015967/017 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:23765 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003537 infores:hetionet CHEBI:142290 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C3665386 infores:hetionet CHEBI:144551 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0030196 infores:hetionet CHEBI:53760 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020443 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0948594 infores:hetionet CAID:CA042622 biolink:causes MONDO:0007750 infores:clingen CAID:CA042622 MONDO:0007750 PMID: Pathogenic PS4, PM5, PM3, PP1_Moderate, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM6, PVS1, BS2, PP2 The NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Moderate, PM2, PM3, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH:- 4 unrelated index cases with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia;- at least 1 index case with DLCN probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583646.1), France;- 8 unrelated index cases (7 with DLCN>=6 and 1 SB possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- at least 1 index case with SB criteria for FH (plasma cholesterol of >8.0 mmol/L and family histories of hypercholesterolemia and/or classical clinical stigmata of FH) from PMID 11857755 (Bunn et al., 2002), New Zeland;- 1 index case with SB criteria for FH (grossly increased plasma cholesterol concentration and the presence of xanthomata in childhood and cardiovascular involvement by puberty in the proband, together with hypercholesterolemia in both parents; this index case died at 31years, had cholesterol of 20.7mmol/L and CVD) from PMID 9026534 (Webb et al., 1996), UKso PS4 is met.PP1_moderate - Variant segregates with FH phenotype in 5 informative meiosis from 3 families:- 2 affected family members have the variant, from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA);- 3 affected family members have the variant, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière),so PP1_Moderate is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM3 - variant meets PM2 and was identified in- 1 index case with phenotype of homozygous FH (cholesterol of 20.7mmol/L) and also NM_000527.5(LDLR):c.912C>G (p.Asp304Glu), Likely pathogenic by these guidelines, from PMID 9026534 (Webb et al., 1996), UKso PM3 is metPM5 - 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelinesThere is 1 variant classified as Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.957. It is above 0.75, so PP3 is metPP4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH (see PS4 for details), so PP4 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042622/MONDO:0007750/013 2021-12-30 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:50729 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0232492 infores:hetionet CHEBI:480999 biolink:causes NCIT:C27003 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0184567 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0027051 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0347390 infores:hetionet NCBIGene:2033 biolink:causes MONDO:0020769 infores:monarchinitiative not_provided not_provided HGNC:3373 MONDO:0020769 uuid:58a3f6da-4c01-4fbb-8fc9-c67c234b89d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28487 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0085688 infores:hetionet NCBIGene:5424 biolink:causes MONDO:0014157 infores:monarchinitiative not_provided not_provided HGNC:9175 MONDO:0014157 uuid:a1d2cb2f-8ee8-4f82-ac36-c9623bf93b2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59773 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0231528 infores:hetionet CHEBI:9907 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0206061 infores:hetionet CHEBI:75984 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018989 infores:hetionet CHEBI:7903 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0242528 infores:hetionet CHEBI:6359 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0039971 infores:hetionet CHEBI:9943 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020578 infores:hetionet CHEBI:27432 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0009806 infores:hetionet CHEBI:5147 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004604 infores:hetionet CHEBI:7931 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020580 infores:hetionet CHEBI:231594 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0030794 infores:hetionet CHEBI:2639 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0018834 infores:hetionet CAID:CA10605170 biolink:causes MONDO:0009290 infores:clingen CAID:CA10605170 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting The NM_000152.5:c.1402A>T variant in GAA is a missense variant predicted tocause substitution of isoleucine by phenylalanine at amino acid 468 (p.Ile468Phe). This variant has been identified in at least four unrelated individuals described as having Pompe disease, including two patients with LOPD receiving ERT (PMID: 37701327, 25037089). One of these patients has documented deficiency of GAA in DBS. One individual is part of a cohort of patients with LOPD receiving ERT, although GAA enzyme is not reported (PMID: 37701327). This meets criteria for PP4_moderate. This variant has been reported in compound heterozygosity (phase unknown) in three unrelated patients with the common splice site variant c.-32-13T>G, meeting criteria for PM3. It has also been reported in one individual with confirmed deficient GAA in DBS, muscle, and skin fibroblast with no second variant reported on sequencing or deletion/duplication analysis (PMID: 25037089). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00002 (1/59986 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.747, which meets the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 269826), 1-star review status) with 9 submitters classifying the variant as likely pathogenic (1) and uncertain significance (8). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605170/MONDO:0009290/010 2023-12-19 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3219 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0004134 infores:hetionet CHEBI:50859 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0019080 infores:hetionet CHEBI:8713 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0039231 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0017160 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0525045 infores:hetionet NCBIGene:8915 biolink:causes MONDO:0014491 infores:monarchinitiative not_provided not_provided HGNC:989 MONDO:0014491 uuid:896eb17e-1db5-4e5d-95a0-45c1dee36e4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0009806 infores:hetionet CHEBI:41977 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0522055 infores:hetionet CHEBI:3508 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0023530 infores:hetionet CHEBI:8499 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0857305 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0031350 infores:hetionet UMLS:C1738934 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0423791 infores:hetionet CHEBI:18332 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0009421 infores:hetionet CHEBI:68584 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0043352 infores:hetionet CHEBI:28748 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2242737 infores:hetionet CHEBI:94385 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0042963 infores:hetionet CHEBI:50648 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0026858 infores:hetionet CAID:CA136138 biolink:causes MONDO:0021060 infores:clingen CAID:CA136138 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.3391+7A>G variant in the SOS1 gene is 0.193% (41/16108) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136138/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true UMLS:C0065374 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0456909 infores:hetionet CAID:CA10385663 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385663 MONDO:0100437 PMID: Likely Benign BP4, BS1 NM_001034853.2(RPGR):c.415G>A (p.Glu139Lys) is a missense variant causing substitution of glutamate by lysine at amino acid 139. This variant is present in gnomAD v4.1.0 at a frequency of 0.00003522 among hemizygous individuals, with 14 variant alleles / 397,530 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.076, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.06 for donor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1 and BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385663/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:63577 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1443060 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0029408 infores:hetionet GO:0021936 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0021936 GO:0007275 CHEBI:3757 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0023380 infores:hetionet CHEBI:64045 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0042510 infores:hetionet CHEBI:7915 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014335 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018808 infores:hetionet NCBIGene:100128927 biolink:causes MONDO:0014549 infores:monarchinitiative not_provided not_provided HGNC:32550 MONDO:0014549 uuid:289e0840-7fa2-433b-bab2-41dd79bc8248 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167638 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0234238 infores:hetionet CHEBI:2637 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0028961 infores:hetionet CHEBI:36704 biolink:causes MONDO:0007018 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042996 infores:hetionet CHEBI:37924 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0019521 infores:hetionet NCBIGene:2036 biolink:causes MONDO:0013658 infores:monarchinitiative not_provided not_provided HGNC:3378 MONDO:0013658 uuid:14040f29-20df-4d41-a1c6-c78b01773707 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085628 infores:hetionet CAID:CA336128584 biolink:causes MONDO:0010604 infores:clingen CAID:CA336128584 MONDO:0010604 PMID: Benign BP4, BA1 BP7 The c.88+75A>G variant is reported at an MAF of 0.1727 (1595/9236 alleles) in the Latino population in gnomAD v3 with 580 hemizygotes and 103 homozygotes, meeting BA1 criteria of MAF > 0.0000556. The variant is listed as a polymorphism in the EAHAD database. SpliceAI predicts no impact on splicing, which meets the BP4 criteria. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA336128584/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0178298 infores:hetionet CHEBI:53766 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0027497 infores:hetionet CHEBI:75984 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0011124 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0518015 infores:hetionet CHEBI:78543 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020458 infores:hetionet CHEBI:6904 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0002962 infores:hetionet CHEBI:7809 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0011991 infores:hetionet CHEBI:75998 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0333355 infores:hetionet CHEBI:4702 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0003467 infores:hetionet CHEBI:42944 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0520888 infores:hetionet CAID:CA024225 biolink:causes MONDO:0018493 infores:clingen CAID:CA024225 MONDO:0018493 PMID: Uncertain Significance PS3_Moderate, PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with threonine at codon 4894 of the RYR1 protein, p.Ala4894Thr. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant was reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084), PS4 was not met. Functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:21926372, PMID:33490280). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS3_Moderate, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024225/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:2379 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0008031 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1527411 infores:hetionet CHEBI:51860 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0023218 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0027765 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0009450 infores:hetionet CHEBI:45409 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0376286 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0037199 infores:hetionet CHEBI:8060 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0028738 infores:hetionet CHEBI:10650 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0234233 infores:hetionet CHEBI:41977 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0018524 infores:hetionet CHEBI:499361 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0027497 infores:hetionet CHEBI:94385 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0042029 infores:hetionet CHEBI:474180 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0015672 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0149931 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151664 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0041582 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0013922 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0031212 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042401 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0028960 infores:hetionet CHEBI:2636 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0020649 infores:hetionet CHEBI:9168 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034155 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005039 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0178829 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0262385 infores:hetionet CHEBI:17334 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0003811 infores:hetionet CHEBI:66919 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0267792 infores:hetionet CHEBI:27565 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0030920 infores:hetionet CHEBI:75922 biolink:causes MONDO:0006737 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0013418 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0004604 infores:hetionet CHEBI:44915 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0031542 infores:hetionet CAID:CA410147666 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147666 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1247T>C (p.Phe416Ser) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147666/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47499 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0080274 infores:hetionet CAID:CA10584714 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584714 MONDO:0007750 PMID: Uncertain Significance BS3_Supporting, PM2, PP4 PS4, PP1 The NM_000527.5 (LDLR):c.-36T>G variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP4: Variant meets PM2, and is identified in one index case who fulfils DLCN criteria for probable FH after alternative causes of high cholesterol were excluded, reported in PMID 21538688 (Supplementary Table 2) by De Castro-Oros et al, 2011 from Universidad de Zaragoza, Spain.BS3_Supporting: Level 3 assay performed with luciferase reporter gene assay in HepG2 cells and there was no significant deference observed in gene expression comparing to wild-type construct, reported in PMID 21538688 by De Castro-Oros et al, 2011 from Universidad de Zaragoza, Spain. Level 3 assay performed with luciferase reporter gene assay in HepG2 cells showed 100% expression compared to wild-type, reported in PMID 31395865 by Kircher et al, 2019 from University of Washington, Seattle, USA. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584714/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UMLS:C0004609 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0015397 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040259 infores:hetionet CHEBI:7986 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0000731 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0151623 infores:hetionet CHEBI:6717 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0011606 infores:hetionet CHEBI:47781 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0042510 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0162830 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0442874 infores:hetionet CHEBI:47898 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023218 infores:hetionet CAID:CA658824987 biolink:causes MONDO:0007648 infores:clingen CAID:CA658824987 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1312delA p.(Thr438fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824987/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:5893 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0023380 infores:hetionet CAID:CA002482 biolink:causes MONDO:0018875 infores:clingen CAID:CA002482 MONDO:0018875 PMID: Likely Benign BS3_Supporting, BS2_Supporting, PM2_Supporting BP4, BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BP7, BS1, BS4, PVS1, PM6, PP3, PP1 The NM_000546.6: c.480G>A variant in TP53 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 160 (p.Met160Ile). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). This variant has an allele frequency of 0.000003390 (4/1180050 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, PM2_Supporting. (Bayesian Points: -2; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002482/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:71223 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0004604 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1328337 infores:hetionet CHEBI:9139 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0231528 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009450 infores:hetionet CAID:CA229604 biolink:causes MONDO:0009861 infores:clingen CAID:CA229604 MONDO:0009861 PMID:23842451PMID:9634518PMID:11161839 Pathogenic PM3, PM2, PP4_Moderate, PP3, PS3 The c.521T>C (p.Ile174Thr) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant is absent from ExAC/gnomAD, 1000 Genomes, ESP (PM2). This variant has 1-15% enzyme activity (PS3; PMID: 11161839). This variant was detected in with p.F299C (P/LP, 6 submitters) (PM3; PMID: 23842451). Computational prediction tools and conservation analysis suggest that the variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229604/MONDO:0009861/006 2019-04-08 2019-04-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3387 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011551 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001697 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0476254 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0019348 infores:hetionet CHEBI:9943 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026826 infores:hetionet CHEBI:75722 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040136 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0178298 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011849 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0003864 infores:hetionet CHEBI:17698 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0423791 infores:hetionet CHEBI:7573 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0085649 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0917801 infores:hetionet CHEBI:3723 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0424790 infores:hetionet NCBIGene:56270 biolink:causes MONDO:0060704 infores:monarchinitiative not_provided not_provided HGNC:25072 MONDO:0060704 uuid:c12fb69d-e5d3-4a95-919d-e940ec2c2ea9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40050 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0038325 infores:hetionet CHEBI:6709 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0004093 infores:hetionet CHEBI:7852 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0030232 infores:hetionet CHEBI:63624 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0267797 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0853692 infores:hetionet GO:0098815 biolink:causes GO:0099565 infores:ubergraph knowledge_assertion manual_agent GO:0098815 GO:0099565 CHEBI:3242 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0232431 infores:hetionet CHEBI:17698 biolink:causes UMLS:C0221477 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0221477 infores:hetionet CHEBI:6438 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0013404 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017178 infores:hetionet CHEBI:8888 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034880 infores:hetionet CHEBI:9460 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0234215 infores:hetionet CAID:CA042534 biolink:causes MONDO:0007750 infores:clingen CAID:CA042534 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in:- 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America;- 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China;- 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco;3 unrelated index cases, so PS4_Supporting is met.PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042534/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:180905 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C2830004 infores:hetionet CHEBI:7492 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0023530 infores:hetionet CHEBI:7798 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0085631 infores:hetionet CHEBI:51364 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0016204 infores:hetionet CHEBI:4708 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0424790 infores:hetionet NCBITaxon:1659 biolink:causes MONDO:0005631 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1659 MONDO:0005631 CHEBI:15940 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0042571 infores:hetionet CHEBI:6367 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002994 infores:hetionet CHEBI:31980 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0014457 infores:hetionet CHEBI:27999 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0018834 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151763 infores:hetionet CHEBI:4562 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0006277 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0037199 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0023890 infores:hetionet CHEBI:9137 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0428977 infores:hetionet CHEBI:10110 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0271051 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0033575 infores:hetionet CHEBI:7476 biolink:causes MONDO:0021124 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0021361 infores:hetionet CHEBI:65349 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0344232 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0276680 infores:hetionet NCBIGene:6595 biolink:causes MONDO:0011053 infores:monarchinitiative not_provided not_provided HGNC:11098 MONDO:0011053 uuid:8cc41186-ca26-4668-96b7-28b00ec14873 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51380 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0013144 infores:hetionet CHEBI:28748 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0333355 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0035455 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0424605 infores:hetionet CHEBI:5001 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0006277 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0021053 infores:hetionet CHEBI:30659 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0233494 infores:hetionet NCBITaxon:1648 biolink:causes MONDO:0006752 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1648 MESH:D004887 DB01053_MESH_D004887_1DB09320_MESH_D004887_1 CHEBI:7865 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0687133 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0233494 infores:hetionet GO:0043506 biolink:causes GO:0007254 infores:ubergraph knowledge_assertion manual_agent GO:0043506 GO:0007254 CHEBI:7478 biolink:causes UMLS:C0948521 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0948521 infores:hetionet CHEBI:135939 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0917801 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0349506 infores:hetionet CHEBI:136040 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0018965 infores:hetionet CHEBI:8874 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003578 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0039971 infores:hetionet CHEBI:68554 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C1384353 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232498 infores:hetionet CHEBI:50673 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0002170 infores:hetionet CHEBI:8327 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0030305 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0015734 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0033860 infores:hetionet CHEBI:5138 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0232461 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0032326 infores:hetionet CHEBI:6912 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0027424 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0020649 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0040409 infores:hetionet CAID:CA343772379 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772379 MONDO:0013144 PMID: Uncertain Significance PP3, PM2_Supporting PP4, BP4 The c.1313G>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by methionine at amino acid 438 (p.Arg438Met). The variant is absent from gnomAD v2.1.1, v3.1, v4.0.0 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.82, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PP3, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772379/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71940 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0011606 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0020538 infores:hetionet CHEBI:204928 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0023530 infores:hetionet CHEBI:2675 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0042023 infores:hetionet CHEBI:63621 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0037763 infores:hetionet CHEBI:37924 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151904 infores:hetionet CHEBI:8245 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0239134 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013295 infores:hetionet NCBIGene:23431 biolink:causes MONDO:0008483 infores:monarchinitiative not_provided not_provided HGNC:573 MONDO:0008483 uuid:4e9b9315-2755-48b9-89e5-e3ec8fa2f103 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020473 infores:hetionet CHEBI:64355 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2047937 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0917798 infores:hetionet CHEBI:45783 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011175 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233632 infores:hetionet CAID:CA131013 biolink:causes MONDO:0044970 infores:clingen CAID:CA131013 MONDO:0044970 PMID: Benign BP4, BA1 The m.7476C>T variant in MT-TS1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in 1.310% of individuals in the GenBank dataset (BA1), including in haplogroups J2a (99.7% of individuals) and J2b (98.85% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 1% including in haplogroup J at 20%. If an affected individual is not a member this haplogroup, further evaluation of the variant in that particular individual should be considered. The computational predictor MitoTIP suggests this variant does not impact the function of this tRNA with a score in the 20th percentile, as does HmtVar with a score of 0.1 (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA131013/MONDO:0044970/014 2022-01-10 2022-01-10 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63619 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018099 infores:hetionet CHEBI:31401 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151578 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014863 infores:hetionet CHEBI:2950 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0004238 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017574 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042510 infores:hetionet CHEBI:6717 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C2047937 infores:hetionet CHEBI:3568 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0231528 infores:hetionet NCBIGene:29110 biolink:causes MONDO:0971173 infores:monarchinitiative not_provided not_provided HGNC:11584 MONDO:0971173 uuid:ab56a8fb-0a42-4429-9fe5-8f52367c07bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0041969 infores:hetionet CHEBI:3215 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0340865 infores:hetionet CAID:CA266009 biolink:causes MONDO:0007064 infores:clingen CAID:CA266009 MONDO:0007064 PMID: Benign BA1, BS2_Supporting NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1).This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA266009/MONDO:0007064/114 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63631 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235901 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235431 infores:hetionet CHEBI:63631 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003862 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0042109 infores:hetionet CHEBI:2676 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0235347 infores:hetionet CHEBI:9352 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0015230 infores:hetionet CHEBI:2922 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0011603 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0149931 infores:hetionet CHEBI:59560 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0031350 infores:hetionet CHEBI:10119 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085932 infores:hetionet CHEBI:15765 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0026857 infores:hetionet CHEBI:32020 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0018681 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0009938 infores:hetionet CHEBI:7798 biolink:causes HP:0041055 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0020162 infores:hetionet NCBIGene:1285 biolink:causes MONDO:0957811 infores:monarchinitiative not_provided not_provided HGNC:2204 MONDO:0957811 uuid:1da58359-4e40-4fb9-a750-a5652fc79bae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0232487 infores:hetionet CHEBI:30830 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0003862 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0027813 infores:hetionet CHEBI:50131 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013182 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0001824 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0854495 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0854495 infores:hetionet CHEBI:17303 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0031924 infores:hetionet NCBIGene:55670 biolink:causes MONDO:0013938 infores:monarchinitiative not_provided not_provided HGNC:22965 MONDO:0013938 uuid:2055904b-1a59-44cf-b9e7-dbe4d988a56b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8378 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0033845 infores:hetionet CHEBI:9570 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C1392046 infores:hetionet CHEBI:5123 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0026837 infores:hetionet CAID:CA226510 biolink:causes MONDO:0100368 infores:clingen CAID:CA226510 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting NM_000329.3(RPE65):c.138del (p.Pro47GlnfsTer47) is a frameshift variant that introduces a premature stop codon into exon 3 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 36017377, PM3). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_supporting, and PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226510/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63638 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0231530 infores:hetionet CHEBI:4530 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0338614 infores:hetionet NCBIGene:51371 biolink:causes MONDO:0011169 infores:monarchinitiative not_provided not_provided HGNC:20330 MONDO:0011169 uuid:f39b5b81-f8e8-49b9-89b3-94a5df67e5eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0007642 infores:hetionet CHEBI:9139 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0740394 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0037199 infores:hetionet CHEBI:8871 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027066 infores:hetionet GO:0060278 biolink:causes GO:0007292 infores:ubergraph knowledge_assertion manual_agent GO:0060278 GO:0007292 CHEBI:17026 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0948594 infores:hetionet CAID:CA6748899 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748899 MONDO:0009861 PMID: Uncertain Significance PM5, PM2_Supporting, PP3_Moderate PP4 The c.511G>T (p.Gly171Trp) variant in PAH has not been published to our knowledge. The reference in BioPKU cannot be located. This variant has an extremely low frequency in gnomAD v4.1 (0.000006196). It is predicted deleterious in REVEL=0.921. A different variant at the same amino acid position, c.511G>A (p.Gly171Arg) (VarID:102716) is reported Likely Pathogenic by the Expert Panel. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_moderate, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748899/MONDO:0009861/006 2025-10-12 2025-10-12 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:3239 biolink:causes MONDO:0008513 infores:monarchinitiative not_provided not_provided HGNC:5136 MONDO:0008513 uuid:f13aa92c-668d-4f12-bec3-54a7aefe154c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0156312 infores:hetionet CHEBI:6792 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0008031 infores:hetionet CHEBI:72323 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0002994 infores:hetionet CHEBI:4530 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013144 infores:hetionet CHEBI:421707 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0042963 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042373 infores:hetionet CHEBI:9241 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0037763 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235146 infores:hetionet CAID:CA9870426 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870426 MONDO:0015967 PMID: Benign BA1 The c.1012C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to valine at codon 338 (p.(Leu338Val)) of NM_175914.5. This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00013403, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). In summary, c.1012C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BA1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870426/MONDO:0015967/085 2025-07-16 2025-07-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50729 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0043094 infores:hetionet CHEBI:2208 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0041582 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0008049 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0036454 infores:hetionet CHEBI:3181 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0003811 infores:hetionet CAID:CA10653574 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653574 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BS3, BS4, BP7, BP5, PM2, PM6, PVS1, PM1, PM4, PM5, PM3, BS2, PP2, PP3, PP1, PP4 The c.*107G>A (NM_001754.5) variant is a substitution in the 3'UTR of RUNX1. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v3 is 0.01631% (11/67438 alleles) in the non-Finnish European population, which is higher than the ClinGen Myeloid Malignancy VCEP's threshold of 0.015% (BS1). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653574/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:1457 biolink:causes MONDO:0014893 infores:monarchinitiative not_provided not_provided HGNC:2457 MONDO:0014893 uuid:2a95bbe7-b2e7-4de0-afaa-3432a813ecfb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91541 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0085636 infores:hetionet CAID:CA10602571 biolink:causes MONDO:0011450 infores:clingen CAID:CA10602571 MONDO:0011450 PMID: Pathogenic PVS1, PM5_Strong PM2 The c.5333-36_5406+400del variant in BRCA1 is a large deletion variant. This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). This variant has been previously reported as deletion exon 22 (legacy exon numbering) in PMIDs: 9354803, 18431737, 22544547, and 24065545. Deletion of exon 21 variant is predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (sequence upstream of BRCA1 p.Leu1854 is disrupted) (PVS1 met). The ENIGMA BRCA1/BRCA2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant within BRCA1 exon 23 (PTC occurs before p.I1855) (PM5_Strong (PTC)). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC)). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602571/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50777 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0178298 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0149931 infores:hetionet CHEBI:6887 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0003862 infores:hetionet CHEBI:8772 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042134 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0040034 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027441 infores:hetionet CHEBI:61058 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0239113 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0029408 infores:hetionet CHEBI:9137 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011175 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0948594 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027051 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0005745 infores:hetionet CHEBI:42820 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0085633 infores:hetionet CHEBI:8597 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0015967 infores:hetionet NCBIGene:2706 biolink:causes MONDO:0011103 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0011103 uuid:b7220b1c-d845-4410-83f4-f79dab851273 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0021775 infores:hetionet CHEBI:50859 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0036974 infores:hetionet CHEBI:6367 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085605 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0948873 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0036416 infores:hetionet CAID:CA16043769 biolink:causes MONDO:0015152 infores:clingen CAID:CA16043769 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.5022del p.(Phe1674LeufsTer48) variant in DYSF, which is also known as NM_001130987.2: c.5139del p.(Phe1713LeufsTer48), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 46/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in three individuals with features consistent with limb girdle muscular dystrophy (PMID: 14673575, 36983702, 23406536), including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pts, PMID: 14673575; NM_003494.4: c.6196G>A p.(Ala2066Thr), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant had a clinical suspicion of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 14673575). The filtering allele frequency of this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1112010 European (non-Finnish) chromosomes) , which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043769/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9434 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0085649 infores:hetionet CHEBI:3756 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0036973 infores:hetionet CHEBI:240107 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0234632 infores:hetionet CHEBI:68642 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0013404 infores:hetionet CHEBI:15551 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0236082 infores:hetionet CHEBI:27958 biolink:causes MONDO:0005186 infores:ubergraph knowledge_assertion manual_agent CHEBI:27958 MONDO:0005186 CHEBI:3176 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0031350 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0041912 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0178298 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0029445 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030920 infores:hetionet CHEBI:50275 biolink:causes UMLS:C2242595 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2242595 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030567 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0006826 infores:hetionet CHEBI:23765 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0232461 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0008703 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0008703 uuid:eb4a6441-8f2f-4de3-85e7-b244dbe4acd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2047937 infores:hetionet CHEBI:6067 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018965 infores:hetionet CHEBI:63791 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0856054 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0024115 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0152025 infores:hetionet CHEBI:16714 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0026961 infores:hetionet CAID:CA512318989 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318989 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 The NM_001754.5(RUNX1):c.117C>T (p.Arg39=) is completely absent from all population databases with at least 20x coverage for RUNX1. Since it is a synonymous variant, the REVEL score is not calculable. SpliceAI predicts minimal impact on splicing: Acceptor loss 0.01, Donor loss 0.01, Acceptor gain 0.00, Donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms indicate the site is conserved (PhyloP score 5.67469), and the variant is not the reference nucleotide in any mammals. Bayesian posterior probability is 0.100. In summary, this variant is classified as uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318989/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2666 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085631 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020649 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0151735 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0521634 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0521634 infores:hetionet CHEBI:9599 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0009763 infores:hetionet CHEBI:66919 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0019080 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0012833 infores:hetionet GO:1905939 biolink:causes GO:0045137 infores:ubergraph knowledge_assertion manual_agent GO:1905939 GO:0045137 CHEBI:135929 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0037199 infores:hetionet CHEBI:15854 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0030252 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235818 infores:hetionet CHEBI:5855 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038325 infores:hetionet CHEBI:2948 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0001824 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0175167 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0009319 infores:hetionet CHEBI:6950 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0231528 infores:hetionet CAID:CA226370 biolink:causes MONDO:0100437 infores:clingen CAID:CA226370 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4, PS2 NM_001034853.2(RPGR):c.1573-1G>A is a canonical splice site variant in intron 13 that is predicted to disrupt the reading frame by skipping exon 14, which would disrupt the ORF15 region that has been established as critical to RPGR function (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), second decade onset (1 pt), rod involvement greater than cone (1 pt), myopia (0.5 pts), reduced visual acuity (0.5 pts), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (PMID: 10937588, 5.5 points, PP4). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual. However, the PS2 requirement of some functional vision impairment in affected males by age 30, with decreased or absent cone and/or rod ERG responses was not met (PMID: 30902645). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226370/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:8382 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0233472 infores:hetionet CHEBI:2675 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0043352 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151849 infores:hetionet CHEBI:291342 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0085633 infores:hetionet CHEBI:63618 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0233794 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152029 infores:hetionet CHEBI:127780 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0018524 infores:hetionet CHEBI:47898 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0005758 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0039231 infores:hetionet CHEBI:31524 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0009676 infores:hetionet CAID:CA1139665160 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665160 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 NM_000018.4(ACADVL): c.1730_1733dup (p.Met578Ilefs*15) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 18 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665160/MONDO:0008723/021 2023-03-27 2023-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63631 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0010399 infores:hetionet CHEBI:3011 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0011991 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019348 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0877322 infores:hetionet CHEBI:31705 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0030554 infores:hetionet CHEBI:7986 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0013404 infores:hetionet CHEBI:4911 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0009676 infores:hetionet CHEBI:63624 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0231218 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0034065 infores:hetionet CHEBI:47426 biolink:causes MONDO:0011827 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0013274 infores:hetionet CHEBI:391960 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0038367 infores:hetionet CHEBI:9588 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0026821 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0518015 infores:hetionet CHEBI:7025 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0027497 infores:hetionet NCBIGene:3082 biolink:causes MONDO:0012003 infores:monarchinitiative not_provided not_provided HGNC:4893 MONDO:0012003 uuid:57b074fc-0a27-41ad-8394-d51c524d5ca8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0037383 infores:hetionet CHEBI:7852 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0038999 infores:hetionet CHEBI:40279 biolink:causes HP:0008940 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0476486 infores:hetionet CHEBI:44032 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0035410 infores:hetionet CAID:CA6831654 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831654 MONDO:0015967 PMID: Uncertain Significance PM1_Supporting, PM5_Supporting, PP4 PS4 The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (≤0.00002 allele frequency in the European Non-Finnish population and ≤1 copy in any other subpopulation)(PMIDs 30155490, 18003757, internal lab contributors). Another missense variant, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PP4, PM5_Suppporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831654/MONDO:0015967/017 2022-03-28 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51230 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0009766 infores:hetionet CHEBI:9907 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0007859 infores:hetionet CHEBI:3723 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018926 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0151661 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151661 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0004623 infores:hetionet CHEBI:2687 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0740394 infores:hetionet CHEBI:9939 biolink:causes NCIT:C50611 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0235821 infores:hetionet CHEBI:6761 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0006266 infores:hetionet CHEBI:3757 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0020580 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0162429 infores:hetionet CHEBI:8207 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C3495920 infores:hetionet CHEBI:2639 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0018418 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0010414 infores:hetionet CHEBI:31932 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0035410 infores:hetionet CHEBI:3403 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0151798 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0235750 infores:hetionet NCBIGene:1545 biolink:causes MONDO:0009277 infores:monarchinitiative not_provided not_provided HGNC:2597 MONDO:0009277 uuid:b5b95f29-29b9-453b-a251-f3562be93d3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020672 infores:hetionet CHEBI:3732 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085605 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151849 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020517 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0001623 infores:hetionet CHEBI:3749 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0033774 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0149931 infores:hetionet CHEBI:135920 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0002962 infores:hetionet CHEBI:6128 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0025222 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0595883 infores:hetionet UMLS:C0120107 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0010200 infores:hetionet CAID:CA357240 biolink:causes MONDO:0009861 infores:clingen CAID:CA357240 MONDO:0009861 PMID:25894915PMID:30747360PMID:29316886PMID:29499199PMID:25894915 Likely Pathogenic PM3, PP4_Moderate, PM2 PM5, PP3 The c.1172G>C (p.Ser391Thr) variant in PAH has been reported in at least one individual with MHP (BH4 deficiency excluded, PMID: 30747360, 29499199) in trans with pathogenic variant p.Val399= (PMID: 29316886). This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA357240/MONDO:0009861/006 2020-03-07 2020-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:194135 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0007097 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0043250 infores:hetionet CHEBI:9130 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0001122 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0009450 infores:hetionet CHEBI:50381 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0000737 infores:hetionet CHEBI:27690 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0018939 infores:hetionet NCBIGene:9496 biolink:causes MONDO:0011054 infores:monarchinitiative not_provided not_provided HGNC:11603 MONDO:0011054 uuid:c127bac9-78c4-4c27-becd-cf123e91dba9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0025517 infores:hetionet CHEBI:5779 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0037763 infores:hetionet CAID:CA409108333 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108333 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4 The c.950T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 317 (p.(Leu317Pro)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.924, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%; therefore PP4 will not be applied (internal lab contributors). In summary, c.950T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108333/MONDO:0015967/085 2025-01-16 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:77260 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0043352 infores:hetionet CHEBI:74947 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0206062 infores:hetionet CHEBI:82941 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C2225524 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0403632 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0234215 infores:hetionet CHEBI:17303 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085932 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0314719 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0014130 infores:hetionet CHEBI:31625 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0155169 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0031046 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0002878 infores:hetionet NCBITaxon:574145 biolink:causes MONDO:0024284 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:574145 MONDO:0024284 CHEBI:75179 biolink:causes UMLS:C1096543 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C1096543 infores:hetionet CAID:CA6831851 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831851 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting BP4, PM5, PP4, PP3 The c.866C>A variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to histidine at codon 289 (p.(Pro289His)) of NM_000545.8. This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the South Asian subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant has a REVEL score of 0.569, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of treatment information, and therefore, PP4 will not be applied (internal lab contributors). Two other missense variants at the same residue, c.865C>T (p.Pro289Ser) and c.866C>G (p.Pro289Arg), have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.866C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831851/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:9430ZR8ZAN biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0027441 infores:hetionet CHEBI:8768 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0007859 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020649 infores:hetionet CHEBI:68584 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0085649 infores:hetionet CHEBI:28830 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0002994 infores:hetionet GO:0010965 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0010965 GO:0000278 CHEBI:31413 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0015230 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0021290 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0021290 infores:hetionet CHEBI:8776 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0002994 infores:hetionet CHEBI:31401 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C1368065 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0422974 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0422974 infores:hetionet CHEBI:63605 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020625 infores:hetionet CHEBI:5118 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0424295 infores:hetionet CHEBI:31236 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013378 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0004238 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0021400 infores:hetionet CHEBI:46195 biolink:causes MONDO:0018741 infores:ubergraph knowledge_assertion manual_agent CHEBI:46195 MONDO:0018741 CHEBI:77260 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0040264 infores:hetionet CHEBI:3504 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0149745 infores:hetionet CHEBI:15552 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0232462 infores:hetionet CHEBI:15551 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0011603 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0037274 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0015397 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0234930 infores:hetionet CHEBI:4562 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C1510410 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1527358 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0497201 infores:hetionet CHEBI:584020 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0035357 infores:hetionet NCBIGene:166929 biolink:causes MONDO:0007470 infores:monarchinitiative not_provided not_provided HGNC:28395 MONDO:0007470 uuid:ae357636-9968-4337-93aa-e9d17a2eb256 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0000731 infores:hetionet CHEBI:145499 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0014591 infores:hetionet NCBITaxon:590 biolink:causes MONDO:0000827 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:590 MONDO:0000827 UMLS:C0004609 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1258215 infores:hetionet CHEBI:63630 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0575081 infores:hetionet CHEBI:135930 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C2939147 infores:hetionet CHEBI:8874 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020578 infores:hetionet CHEBI:50173 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0237849 infores:hetionet UNII:T58MSI464G biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0041834 infores:hetionet CHEBI:31932 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0024141 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020649 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040046 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1142172 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1142172 infores:hetionet CHEBI:50156 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0018790 infores:hetionet CHEBI:135736 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0024305 infores:hetionet CHEBI:6437 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0040822 infores:hetionet CHEBI:6970 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0004093 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0017574 infores:hetionet NCBIGene:2260 biolink:causes MONDO:0013074 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0013074 uuid:49dd5f3a-94b9-4cc4-a613-ab0dc143441b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6965 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0236071 infores:hetionet CHEBI:92511 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0162285 infores:hetionet CHEBI:92712 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0338831 infores:hetionet NCBIGene:226 biolink:causes MONDO:0012747 infores:monarchinitiative not_provided not_provided HGNC:414 MONDO:0012747 uuid:02552482-511b-4fe0-9e8d-4b32ba47d2f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7488 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0008031 infores:hetionet CHEBI:31932 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0232462 infores:hetionet CHEBI:4702 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0026896 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0040409 infores:hetionet CHEBI:70735 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0242422 infores:hetionet CHEBI:46557 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0013378 infores:hetionet GO:1903689 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:1903689 GO:0060429 NCBIGene:25915 biolink:causes MONDO:0032623 infores:monarchinitiative not_provided not_provided HGNC:29918 MONDO:0032623 uuid:6c7e103e-2b37-40bf-95b3-4fe4f5c83c2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013395 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0033975 infores:hetionet CHEBI:681569 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0027540 infores:hetionet UMLS:C0657912 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023066 infores:hetionet CHEBI:41423 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0028734 infores:hetionet CHEBI:51450 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0948441 infores:hetionet CAID:CA397725472 biolink:causes MONDO:0008723 infores:clingen CAID:CA397725472 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1605+2T>A (p.?) variant in ACADVL occurs within the canonical splice donor site (+2) of intron 16. It is predicted to cause skipping of biologically-relevant-exon 16/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 09-05-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397725472/MONDO:0008723/021 2022-09-05 2023-06-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4356 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0948807 infores:hetionet CHEBI:48669 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0149871 infores:hetionet CHEBI:64355 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004364 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0581912 infores:hetionet NCBIGene:10479 biolink:causes MONDO:0010278 infores:monarchinitiative not_provided not_provided HGNC:11079 MONDO:0010278 uuid:e20cf977-5524-48ac-bf16-4f201c278e46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46345 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0020649 infores:hetionet CHEBI:9943 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015402 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0036572 infores:hetionet CHEBI:584020 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0039446 infores:hetionet CAID:CA2573051037 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051037 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PP4_Moderate, PVS1 The c.196dupG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 66 (NM_000545.8), adding 30 novel amino acids before encountering a stop codon (p.(Glu66GlyfsTer30)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). Lastly, this variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). In summary, c.196dupG meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051037/MONDO:0015967/017 2022-04-03 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CAID:CA412737551 biolink:causes MONDO:0100437 infores:clingen CAID:CA412737551 MONDO:0100437 PMID: Pathogenic PP4_Moderate, PVS1, PP1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.1572+1G>A is a canonical splice site variant in intron 13 and is predicted to disrupt splicing and induce skipping of exon 13, which is expected to have a deleterious impact on RPGR (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), childhood onset (1 pt), high myopia (1 pt), extinguished electroretinogram responses, photophobia (0.5 pts), visual field constriction (0.5 pts), night blindness (0.5 pts), optic disc pallor (0.5 pts), pigmentary retinopathy (0.5 pts), abnormal color vision (0.5 pts), and reduced visual acuity (0.5 pts), with genotyping by next-generation sequencing identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (9.5 points, PMID: 31456290, PP4_Moderate). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 36445968, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 31456290). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1, PP4_Moderate, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412737551/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:465284 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0014868 infores:hetionet CHEBI:43968 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0014457 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0948089 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0032584 infores:hetionet CAID:CA114115 biolink:causes MONDO:0015628 infores:clingen CAID:CA114115 MONDO:0015628 PMID: Pathogenic PP1_Moderate, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4 BA1, PM5, BS1 NM_000552.5(VWF):c.4883T>C is a missense variant in VWF predicted to cause substitution of isoleucine by threonine at amino acid 1628. The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179884 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for (PM2_Supporting). The computational predictor REVEL gives a score of 0.703, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least sixteen patients with this variant have been diagnosed with VWD Type 2A, of whom nine are documented to have displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (measured by VWF:RCo) low VWF:RCo/ VWF:Ag ratio, and absence of high-molecular weight VWF multimers, which together are highly specific for VWD type 2A (PP4_Moderate, PMID: 28536718, VCEP member-provided data). Thirteen total probands have been described in sufficient detail to establish a phenotype specific to VWD type 2A (PS4_VeryStrong, PMID: 28536718, VCEP member-provided data, PMID: 28971901). The variant has been reported to segregate with VWD type 2A through 6 affected meioses from 1 family and 3 affected meioses in another (PP1_Moderate; PMID: 1673047, PMID: 28971901). Proteolysis assays of an exogenously expressed VWF fragment showed higher susceptibility of the variant protein to ADAMTS13 proteolysis under non-denaturing conditions (PMID: 16221672, PMID: 16322474, PMID: 23110044), indicating that this variant has a damaging effect on protein function (PS3_Supporting). The variant protein exhibited normal multimer distribution (PMID: 16322474) and secretion rate (PMID: 8123844) in vitro. In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3_supporting, PS4, PP1_Moderate, PM2_Supporting, PP3, PP4_Moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114115/MONDO:0015628/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:367163 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014742 infores:hetionet CHEBI:77260 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042023 infores:hetionet CHEBI:110423 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0020523 infores:hetionet UMLS:C1872203 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151908 infores:hetionet CHEBI:28748 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027796 infores:hetionet CHEBI:4046 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0235146 infores:hetionet CHEBI:92769 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0016382 infores:hetionet CHEBI:127342 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0549622 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0017178 infores:hetionet CHEBI:17263 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C2939186 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0851536 infores:hetionet CHEBI:8890 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0085633 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0027813 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0549453 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0549453 infores:hetionet CHEBI:7959 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0011633 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0042401 infores:hetionet CHEBI:17347 biolink:causes HP:0020059 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0427458 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0031117 infores:hetionet CHEBI:9598 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0013395 infores:hetionet CAID:CA380144809 biolink:causes MONDO:0000573 infores:clingen CAID:CA380144809 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.74A>G is a missense variant predicted to cause substitution of Aspartic acid by Glycine at amino acid 25 (p.Asp25Gly). This missense variant is located in the core domain (amino acids 1-383 (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144809/MONDO:0000573/124 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:175901 biolink:causes UMLS:C1609536 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1609536 infores:hetionet CHEBI:5801 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C2830004 infores:hetionet CHEBI:68584 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0009806 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0006826 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0267537 infores:hetionet CHEBI:83804 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013456 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0027707 infores:hetionet CHEBI:31236 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027497 infores:hetionet CHEBI:4856 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0027424 infores:hetionet CHEBI:182080 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0028738 infores:hetionet CHEBI:3312 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0042963 infores:hetionet CHEBI:37924 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151786 infores:hetionet CHEBI:7822 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0009421 infores:hetionet CHEBI:8028 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C1167965 infores:hetionet CHEBI:2675 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0011991 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007117 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0017601 infores:hetionet CHEBI:465284 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0040822 infores:hetionet CAID:CA143472 biolink:causes MONDO:0019501 infores:clingen CAID:CA143472 MONDO:0019501 PMID: Benign BA1 PP2, PP3, PM5, PM1, PM3, PM2, BP1, BP4, PS1, PS4 The c.3902G>T variant in USH2A is a missense variant predicted to cause substitution of glycine by valine at amino acid 1301 (p.Gly1301Val). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (≥0.5%). The computational predictor REVEL gives a score of 0.218, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. While this variant has been reported in several individuals with clinical features of USH2A-related disorders, there are no case-control studies and several affected individuals had an alternate cause of disease identified (PMID:21569298, 25649381, 26927203, 32531858). In summary, this variant meets the criteria to be classified as benign, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BA1, ClinGen Hearing Loss VCEP specifications version 2, 03.20.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143472/MONDO:0019501/005 2024-03-20 2024-04-01 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6838 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0022346 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151740 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0036508 infores:hetionet CHEBI:4814 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0700225 infores:hetionet CHEBI:8874 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019521 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0595878 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0009806 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0021775 infores:hetionet CHEBI:8871 biolink:causes MONDO:0019171 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1141890 infores:hetionet GO:2000589 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:2000589 GO:0001656 UNII:R43D2573WO biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0233794 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0034150 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0011616 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1258215 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0002871 infores:hetionet CHEBI:3647 biolink:causes HP:0002362 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0231688 infores:hetionet NCBIGene:311 biolink:causes MONDO:0027694 infores:monarchinitiative not_provided not_provided HGNC:535 MONDO:0027694 uuid:3c026031-796f-433c-a8fc-dacf627ff68e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0302295 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853710 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853710 infores:hetionet CHEBI:2663 biolink:causes HP:0002926 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0857576 infores:hetionet NCBIGene:5192 biolink:causes MONDO:0013937 infores:monarchinitiative not_provided not_provided HGNC:8851 MONDO:0013937 uuid:5eddbb52-5365-4f41-a30a-4ebb8e20b994 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0004998 infores:hetionet CHEBI:3723 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020580 infores:hetionet CHEBI:17263 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0027769 infores:hetionet CHEBI:80630 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0392156 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0011630 infores:hetionet CHEBI:28001 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0035078 infores:hetionet CHEBI:8768 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0010038 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0079043 infores:hetionet NCBIGene:1785 biolink:causes MONDO:0014149 infores:monarchinitiative not_provided not_provided HGNC:2974 MONDO:0014149 uuid:fdf8def3-d520-4311-b825-7f7cd2393763 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020580 infores:hetionet CHEBI:473990 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0021051 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020507 infores:hetionet CHEBI:63624 biolink:causes MONDO:0006862 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0027073 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0029445 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0006266 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0010709 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0746883 infores:hetionet CHEBI:6715 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151878 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0013595 infores:hetionet CHEBI:41977 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0036974 infores:hetionet CHEBI:5855 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020488 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0018799 infores:hetionet CHEBI:50922 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0030193 infores:hetionet NCBIGene:4210 biolink:causes MONDO:0007601 infores:monarchinitiative not_provided not_provided HGNC:6998 MONDO:0007601 uuid:048d593e-c548-4eab-af3f-92675263959c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0002871 infores:hetionet CHEBI:50275 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085632 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017160 infores:hetionet CAID:CA242620 biolink:causes MONDO:0700270 infores:clingen CAID:CA242620 MONDO:0700270 PMID: Benign BP4, BS1, BP2_Strong BA1, PM2 The ATM c.3925G>A (p.Ala1309Thr) variant has a GnomAD (v2.1.1) filtering allele frequency of 0.1050% (NFE) which is above the ATM BS1 threshold of .05% (BS1). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals without ataxia-telangiectasia (Internal laboratory contributions; BP2_strong). Multiple in silico protein predictors predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA242620/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:37924 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0009806 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0149931 infores:hetionet CHEBI:135285 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0520893 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013295 infores:hetionet CAID:CA023838 biolink:causes MONDO:0007783 infores:clingen CAID:CA023838 MONDO:0007783 PMID:26115329PMID:9334205PMID:26115329PMID:9334205 Pathogenic PM1, PS4_Moderate, PP1_Strong, PP3_Moderate PS3, BS1, BS3, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of cysteine with arginine at codon 35 of the RYR1 protein, p.(Cys35Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:17710899, PMID:20681998, PMID:9066328). Functional studies in HEK293 cells show conflicting data regarding sensitivity to RYR1 agonists, PS3/BS3 were not implemented (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 11 individuals, PP1_Strong (PMID:9066328). A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate, PP1_Strong. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023838/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0687133 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027947 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1720798 infores:hetionet UNII:K2J09EMJ52 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C3665347 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0233494 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020615 infores:hetionet CHEBI:68554 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0001824 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0011570 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002871 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038661 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0853149 infores:hetionet CHEBI:9939 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0542571 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018790 infores:hetionet GO:1905446 biolink:causes GO:0006119 infores:ubergraph knowledge_assertion manual_agent GO:1905446 GO:0006119 CHEBI:8232 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0005940 infores:hetionet CAID:CA915949503 biolink:causes MONDO:0008723 infores:clingen CAID:CA915949503 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1, PP4_Moderate The NM_000018.4(ACADVL):c.552del (p.Ile184fs) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 8/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism ((PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed Newborn Screening and follow-up data, which is highly specific for VLCAD. Specifically, a proband with this variant was identified via newborn screening to have C14:1 uM levels of 2.99 and asserted abnormal plasma acylcarnitine levels (PP4; PMID 24503138). This variant has been detected in at least 1 individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual is a compound heterozygous for the variant and a pathogenic variant (p.V283A) although the variants are not confirmed in trans. Based on ACADVL VCEP specific guidelines, a total of 0.5 points is awarded for criteria PM3 (PMID 24503138). This variant is absent from gnomAD v2.2.1 (PM2_Supporting).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM3_supporting, PS2_supporting.) VCEP classification criteria version 2, 10/15/21. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949503/MONDO:0008723/021 2022-03-14 2022-03-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0162429 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0007194 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0232459 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0549209 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0042109 infores:hetionet CHEBI:39867 biolink:causes MONDO:0019558 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0024138 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0042109 infores:hetionet CHEBI:134991 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C1167965 infores:hetionet CHEBI:7577 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0003862 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0242784 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0242784 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0022660 infores:hetionet CHEBI:75988 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0013604 infores:hetionet CHEBI:23765 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0004093 infores:hetionet CHEBI:4445 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0026837 infores:hetionet CHEBI:142290 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0151907 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0948594 infores:hetionet CHEBI:8863 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0857305 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0007787 infores:hetionet CHEBI:8107 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0162557 infores:hetionet CHEBI:8713 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0231218 infores:hetionet CHEBI:134991 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020598 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0031542 infores:hetionet CAID:CA16020823 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020823 MONDO:0009861 PMID: Uncertain Significance PM3, PP4, PM2_Supporting, PS3_Supporting PP3 The c.587C>A (p.Ser196Tyr) variant in PAH has been reported in one individual with mild hyperphenylalanemia, without exclusion of BH4 deficiency (PMID: 23792259). In this individual, c.587C>A occurred de novo on the paternal allele, with confirmation of paternity. c.842+3G>C was present on the maternal allele (classified as likely pathogenic by PAH VCEP, Variation ID: 102871). In-vitro studies show 21% enzyme activity (PMID: 27620137). This variant is present below the 0.0002 allele frequency threshold for PAH in population databases. Multiple lines of computational evidence yield conflicting predictions regarding the effect of this variant (REVEL=0.542). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4, PM2_supporting, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020823/MONDO:0009861/006 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:51450 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0034063 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0344320 infores:hetionet CHEBI:3286 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0030554 infores:hetionet CHEBI:50692 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0011606 infores:hetionet CHEBI:46081 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0558489 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0232431 infores:hetionet CHEBI:10023 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0032227 infores:hetionet CHEBI:6717 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0040264 infores:hetionet CHEBI:4708 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1306341 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0456909 infores:hetionet NCBITaxon:623 biolink:causes MONDO:0019345 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:623 MESH:D004405 DB01059_MESH_D004405_2DB00537_MESH_D004405_1 CHEBI:2611 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0006145 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1262141 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0019196 infores:hetionet CHEBI:408174 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0012833 infores:hetionet CHEBI:119915 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013447 infores:hetionet CHEBI:5004 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0855329 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0518015 infores:hetionet CHEBI:7476 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002994 infores:hetionet CHEBI:51141 biolink:causes MONDO:0044339 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0158252 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0413252 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0857448 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0003123 infores:hetionet CHEBI:49040 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0016382 infores:hetionet CHEBI:100246 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0003862 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0948586 infores:hetionet CHEBI:83804 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0855333 infores:hetionet CHEBI:367163 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0239981 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0002622 infores:hetionet CHEBI:7492 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0002792 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002418 infores:hetionet CAID:CA200893 biolink:causes MONDO:0009861 infores:clingen CAID:CA200893 MONDO:0009861 PMID: Benign BS2, BS1 BP4 PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA200893/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9654 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0233571 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0262385 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0020651 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0042109 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0973461 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0038362 infores:hetionet CHEBI:4975 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0151878 infores:hetionet CHEBI:8207 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0039070 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0027769 infores:hetionet CHEBI:4735 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0232462 infores:hetionet UNII:R43D2573WO biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0008031 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0948594 infores:hetionet CHEBI:50381 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C2242996 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042109 infores:hetionet NCBIGene:3614 biolink:causes MONDO:0013454 infores:monarchinitiative not_provided not_provided HGNC:6052 MONDO:0013454 uuid:fc6b1e76-8b23-416b-9f4f-7d0b6a7d8c12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0233471 infores:hetionet CHEBI:4046 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0041657 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005147 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011854 infores:hetionet CHEBI:8245 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C1527344 infores:hetionet CHEBI:18248 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0009676 infores:hetionet CHEBI:45652 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C1145670 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002622 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0042134 infores:hetionet CHEBI:7852 biolink:causes HP:0012196 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0008039 infores:hetionet NCBIGene:5073 biolink:causes MONDO:0014612 infores:monarchinitiative not_provided not_provided HGNC:8609 MONDO:0014612 uuid:7388b965-9eca-495f-a79b-02cb8fa055bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0162835 infores:hetionet CHEBI:42797 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C2981158 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042571 infores:hetionet CHEBI:6761 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0001824 infores:hetionet CHEBI:6541 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0003862 infores:hetionet CHEBI:8356 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1527344 infores:hetionet CHEBI:63580 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027424 infores:hetionet CAID:CA229854 biolink:causes MONDO:0009861 infores:clingen CAID:CA229854 MONDO:0009861 PMID:12501224PMID:12501224PMID:18590700 Pathogenic PP4_Moderate, PP3_Strong, PM3, PM5, PM2_Supporting, PS3_Supporting The NM_000277.1(PAH):c.929C>A (p.Ser310Tyr) variant is a missense variant in exon 9/13 in PAH. The variant has been found to result in <1% of wild-type PAH enzyme activity in cDNA and Intinc systems (PMID: 18590700), and has been found to result in high molecular weight aggregates without residual enzyme activity (PMID: 18538294) (PS3_supporting). It has been previously reported in a patient with mild hyperphenylalanemia in trans with p.F55L (Pathogenic/Likely Pathogenic in ClinVar); BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 12501224) (PM3; PP4_Moderate). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.991) (PP3_strong).Classification: PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3; PP4_Moderate; PP3_strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229854/MONDO:0009861/006 2025-10-12 2025-10-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6149 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0023518 infores:hetionet NCBIGene:25871 biolink:causes MONDO:0030019 infores:monarchinitiative not_provided not_provided HGNC:24496 MONDO:0030019 uuid:48b61016-0171-48ce-86d5-aa5dcbd15354 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0031350 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027765 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0022408 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0423602 infores:hetionet CHEBI:63791 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019557 infores:hetionet CHEBI:17347 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0038999 infores:hetionet CHEBI:8024 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0014457 infores:hetionet CAID:CA914658966 biolink:causes MONDO:0011071 infores:clingen CAID:CA914658966 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*3638G>A is a UTR variant which does not meet ant ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA914658966/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3647 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0009806 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0013595 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013295 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0232492 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0948525 infores:hetionet CHEBI:31348 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0236000 infores:hetionet CHEBI:94609 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0027441 infores:hetionet CHEBI:37333 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0687713 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0239488 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030312 infores:hetionet CHEBI:50859 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085593 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0855775 infores:hetionet CHEBI:31401 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151825 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013395 infores:hetionet CHEBI:49713 biolink:causes HP:0030644 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0152192 infores:hetionet CHEBI:65349 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0011991 infores:hetionet CHEBI:3175 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020672 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0001824 infores:hetionet NCBIGene:1027 biolink:causes MONDO:0012552 infores:monarchinitiative not_provided not_provided HGNC:1785 MONDO:0012552 uuid:29e6453d-7a82-4f38-8f30-c45dc22eefcc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0034065 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0012833 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151311 infores:hetionet CHEBI:94440 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0151827 infores:hetionet CAID:CA395137757 biolink:causes MONDO:0700272 infores:clingen CAID:CA395137757 MONDO:0700272 PMID: Uncertain Significance PM2_Supporting, BP1 BS1, PP3, BA1, BP4 The c.338C>T (p.Pro113Leu) variant in PALB2 is a missense variant predicted to cause substitution of proline by leucine at amino acid 113 (p.Pro113Leu). This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM2_Supporting, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA395137757/MONDO:0700272/077 2022-08-31 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6970 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0009763 infores:hetionet CHEBI:6121 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0041834 infores:hetionet CAID:CA007671 biolink:causes MONDO:0100316 infores:clingen CAID:CA007671 MONDO:0100316 PMID:30571187PMID:29021305PMID:29532034PMID:30571187PMID:29021305PMID:29532034 Uncertain Significance PP3 BA1, BP4, PS1, PS3, PS4, BS1, BS3, PM2, PM5, PM1, PP4 NM_000218.3(KCNQ1):c.590C>T is a missense variant predicted to cause replacement of proline with leucine at position 197. This residue is conserved across the 5 human KCNQ paralogues (https://www.cardiodb.org/paralogue_annotation/gene.php?name=KCNQ1) and another missense variant in the same codon, NM_000218.3(KCNQ1):c.589C>T (p.Pro197Ser), has been investigated in connection with long QT syndrome 1 (PMID: 29532034) but has been classified as a variant of uncertain significance for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 is not yet met. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00004576, with 54 / 1179994 in the European non-FInnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant has been reported in the cardiovascular disorder literature, however, the available clinical details are not sufficient for inclusion in PS4, so the PS4_Supporting code is not yet met. The computational predictor REVEL gives a score of 0.965, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant demonstrates 60-70% of wild-type cell surface trafficking by flow cytometry (PMID: 29532034), but 140-150% of wild-type peak current density (PMID: 29532034, PMID: 30571187), which is not compatible with a proposed role as a disease-causing variant for long QT syndrome 1, so the PS3 code is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007671/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44032 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C2047937 infores:hetionet CHEBI:8228 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0151905 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0948089 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005165 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0086692 infores:hetionet CHEBI:188986 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0000737 infores:hetionet CHEBI:474180 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0010200 infores:hetionet CHEBI:2687 biolink:causes HP:0005224 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0267566 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040046 infores:hetionet CHEBI:5165 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013362 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0033775 infores:hetionet CHEBI:40050 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0851578 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0020557 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C1384666 infores:hetionet GO:1900136 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:1900136 GO:0070887 CHEBI:6078 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0162285 infores:hetionet CHEBI:50885 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0151692 infores:hetionet CHEBI:94848 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0009806 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0235146 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0236048 infores:hetionet CHEBI:7476 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013404 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0030312 infores:hetionet CHEBI:15544 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0030848 infores:hetionet CHEBI:2666 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0040264 infores:hetionet CHEBI:4562 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0011603 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0037199 infores:hetionet CHEBI:3561 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0015672 infores:hetionet CHEBI:78543 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0600142 infores:hetionet CHEBI:3219 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0041657 infores:hetionet NCBIGene:30000 biolink:causes MONDO:0859197 infores:monarchinitiative not_provided not_provided HGNC:19998 MONDO:0859197 uuid:97e1eb78-d46d-4f07-8d1a-6dba4c267d0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:5V9KLZ54CY biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0085636 infores:hetionet CHEBI:41879 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020488 infores:hetionet CHEBI:6078 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0004096 infores:hetionet CHEBI:6073 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0023380 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0036572 infores:hetionet CAID:CA367398802 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398802 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP2, PP3, PM2_Supporting PS4, PM1, PP4 The c.1133C>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glycine at codon 378 (p.(Ala378Gly)) of NM_000162.5. This variant has an incomputable Popmax filtering allele frequency in gnomAD 2.1.1 due to only one copy being present, below the PM2_Supporting threshold of Popmax filtering allele frequency ≤ 0.000003 in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The c.1133C>T, p.(Ala378Val) and c.1132G>A, p.(Ala378Thr) variants have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant was identified in two unrelated individuals with a diabetes; however, this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1133C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398802/MONDO:0015967/086 2023-08-07 2023-08-07 Semidominant inheritance HP:0032113 Supports CHEBI:65173 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0018939 infores:hetionet CHEBI:499361 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0033774 infores:hetionet CAID:CA410202501 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202501 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.490G>T (p.Val164Phe) is a missense variant which affects a residue within the Runt Homology Domain (RHD) established by the MM-VCEP for RUNX1 (Val164) (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.959, which is greater than 0.88 (PP3). This variant has been reported in ClinVar; however, no phenotypic data was provided. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202501/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2788 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0423232 infores:hetionet CHEBI:50922 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0549249 infores:hetionet NCBIGene:2187 biolink:causes MONDO:0010351 infores:monarchinitiative not_provided not_provided HGNC:3583 MONDO:0010351 uuid:94e20dec-2ddb-4ecd-902e-627a919c848e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8028 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0027849 infores:hetionet CHEBI:8069 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0009806 infores:hetionet CHEBI:9622 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0042571 infores:hetionet CAID:CA10604244 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604244 MONDO:0015152 PMID: Pathogenic PM3, PM5, PP4_Strong, PP3, PP1, PM2_Supporting PM4, PM6, PVS1, BA1, BP3, BP1, BP4, BP2, PP2, BS2, BP7, BP5, BS1, BS3, BS4, PS3, PS4, PS2, PS1 The NM_000070.3: c.700G>A variant in CAPN3 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 234 (p.Gly234Arg). This variant has been detected in at least four unrelated individuals with LGMD (PMID: 26484845, 32896923, 34720847, 37589857), including confirmed in trans and in unknown phase with a pathogenic variant (c.1746-20C>G, 1.5 pts, PMID: 34720847, 37589857) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 34720847). The variant was also reported to co-segregate with the disease in two affected family members from a single family (PP1; PMID: 37589857). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.93, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.701G>A p.(Gly234Glu), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3, PP4_Strong, PP1, PM2_Supporting, PP3, PM5. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604244/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28148 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0015672 infores:hetionet CHEBI:4453 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0023903 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020538 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0039231 infores:hetionet CHEBI:119573 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0041582 infores:hetionet CHEBI:3441 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0041969 infores:hetionet CHEBI:6067 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018808 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015230 infores:hetionet CHEBI:50777 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0036508 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151824 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0031117 infores:hetionet CHEBI:4784 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0344232 infores:hetionet CHEBI:63580 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0392171 infores:hetionet CHEBI:6067 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235378 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0014742 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0314719 infores:hetionet CHEBI:50922 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C2939147 infores:hetionet CHEBI:63115 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C2242588 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0020615 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040479 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0149931 infores:hetionet CHEBI:6375 biolink:causes NCIT:C3236 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0025568 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0948349 infores:hetionet CHEBI:84050 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0013604 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0151763 infores:hetionet CHEBI:3738 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0085631 infores:hetionet CHEBI:3756 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0080274 infores:hetionet CHEBI:66876 biolink:causes MONDO:0000499 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C1852242 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0004161 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004161 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003811 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0026636 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0232459 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233494 infores:hetionet CAID:CA10585240 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585240 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1004G>T (p.Gly335Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.874. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria of definite FH from PMID: 10735632 (Lombardi MP et al. 2000).so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585240/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:68478 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019572 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085096 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0948089 infores:hetionet CHEBI:85161 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0037036 infores:hetionet CHEBI:17688 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0240557 infores:hetionet CHEBI:7465 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0542571 infores:hetionet CHEBI:7936 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011606 infores:hetionet CHEBI:9738 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2830004 infores:hetionet CHEBI:5118 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0857305 infores:hetionet UMLS:C0879264 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0268000 infores:hetionet CHEBI:144551 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C2363731 infores:hetionet CHEBI:5855 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018681 infores:hetionet CHEBI:76010 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0012833 infores:hetionet CHEBI:8888 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0549249 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0006112 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0006112 infores:hetionet CHEBI:5138 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0015967 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151738 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151738 infores:hetionet CAID:CA019743 biolink:causes MONDO:0005045 infores:clingen CAID:CA019743 MONDO:0005045 PMID:21622575 Pathogenic PS3_Moderate, PM2_Supporting, PP3, PS4_Moderate, PP1_Strong PM5, PM4, PS1, PS2, BP4, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS4, BS3 NM_005159.5(ACTC1): c.301G>A (p.Glu101Lys). This variant has been reported in individuals with HCM and other cardiomyopathies (Olson 2000 PMID: 10966831, Arad 2005 PMID: 16267253, Bookwalter 2006 PMID: 16611632, Monserrat 2007 PMID: 17611253, Monserrat 2007 PMID: 18801786, Klassen 2008 PMID: 18506004, Debold 2010 PMID: 19799913, Walsh 2017 PMID:) and has also been identified in 1 out of 113768 (0.004% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with hypertrophic cardiomyopathy (HCM) compared to controls (OR lower 95% CI>10), therefore, the PS4 criterion has been applied at moderate strength (PS4_Moderate) and the PM2_Supporting criterion has been applied (PM2_Supporting). This variant segregated with disease in numerous affected individuals with HCM from multiple families (PP1_Strong; Monserrat 2007 PMID: 16267253, Olson 2000 PMID: 10966831). A mouse knock-in model for this variant indicates that this variant disrupts the function of ACTC1 and leads to a phenotype consistent with HCM (PS3_Moderate; Song 2011 PMID:21622575). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACTC1-specific ACMG/AMP criteria applied: PP1_Strong, PS4_Moderate, PS3_Moderate, PM2_Supporting, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA019743/MONDO:0005045/101 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17650 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0042963 infores:hetionet CAID:CA120577 biolink:causes MONDO:0044970 infores:clingen CAID:CA120577 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting PP1, PS2, PM6 The m.10010T>C variant in MT-TG has been reported in six unrelated individuals with primary mitochondrial disease. Features in affected individuals include Leigh syndrome (in two individuals), lactic acidosis, hyperCKemia, developmental delay, exercise intolerance, seizures, ataxia, sensorineural hearing loss, and optic atrophy. Muscle biopsies revealed ragged red fibers, COX-deficient fibers, and reduced activities of complexes I, III, and IV. The heteroplasmy levels of the variant in affected individuals ranged from 5.4% in blood to 92% in muscle. In cases that had more than one tissue tested, the heteroplasmy level was consistently and significantly higher in muscle (PS4_moderate; PMIDs: 26469001, 11971101, 16120360, 23847141, 9199564). There are no reported de novo occurrences of this variant to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing in two separate individuals showed higher levels of the variant in COX-negative fibers (97.3% and 91.7%) than in COX-positive fibers (87.2% and 58%) (PS3_supporting, PMIDs: 9199564, 11971101). The computational predictor MitoTIP suggests this variant is pathogenic (82.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120577/MONDO:0044970/015 2022-11-14 2023-01-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:1482 biolink:causes MONDO:0009154 infores:monarchinitiative not_provided not_provided HGNC:2488 MONDO:0009154 uuid:fcef348c-22ee-4611-8fdf-1c7ac0c3fe56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0065374 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0231856 infores:hetionet CAID:CA120807 biolink:causes MONDO:0100437 infores:clingen CAID:CA120807 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2847_2848delinsCT (p.Glu949AspfsTer2) is a variant consisting of two consecutive substitutions in codons 949 and 950 that result in a missense change at amino acid 949 and a premature stop in codon 950 within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 5 affected meioses from 1 family. (PP1_Moderate; PMID: 15914600). This variant has been reported in at least 1 proband meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, with decreased or absent cone and/or rod electroretinogram responses (PMID: 15914600). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA120807/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:28001 biolink:causes MONDO:0018748 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0406650 infores:hetionet CHEBI:79699 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0002994 infores:hetionet CHEBI:40237 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0003862 infores:hetionet CHEBI:35854 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C2973529 infores:hetionet GO:0001959 biolink:causes GO:0071345 infores:ubergraph knowledge_assertion manual_agent GO:0001959 GO:0071345 CHEBI:3219 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0007859 infores:hetionet UMLS:C0004609 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0015672 infores:hetionet CHEBI:3752 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1140680 infores:hetionet CHEBI:63630 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0522153 infores:hetionet CHEBI:9720 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0152032 infores:hetionet CHEBI:75988 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0151773 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0162429 infores:hetionet CHEBI:3216 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0027441 infores:hetionet CAID:CA402998035 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998035 MONDO:0012999 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PP3_Moderate, PM3_Supporting The NM_000156.6:c.160G>C variant in GAMT is predicted to result in the substitution of alanine by proline at amino acid 54 (p.Ala54Pro). Three probands with clinical symptoms consistent with GAMT deficiency have been reported to be homozygous for this variant. One of these individuals had elevated urinary guanidinoacetate, and GAMT enzymatic activity <0.1 nmol/h/mg in lymphoblasts, with full GAMT gene sequencing performed (PMID: 15108290) (PP4_Strong). This individual harbored the variant in cis with two homozygous variants that have been classified as benign by the ClinGen CCDS VCEP, c.626C>T (p.Thr209Met) (ClinVar ID: 21068) and c.459+71G>A (aka c.460-31G>A, ClinVar ID: 21067). For the other two probands, neither biochemical nor MRS data were available (PMID: 38020815, 39006040); therefore, their data was not included for PM3 (total 0.5 points, PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.894 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 2446454). In summary, this variant meets the criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 2.0.0): PP4_Strong, PP3_Moderate, PM2_Supporting, PM3_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 8, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998035/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:66964 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0233494 infores:hetionet CHEBI:50381 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C1443060 infores:hetionet CHEBI:7565 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0015672 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151602 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0006266 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C1443060 infores:hetionet CHEBI:27777 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0016204 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0002170 infores:hetionet CAID:CA16020878 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020878 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4, PM3_Supporting PM5, PS3 The c.870T>G (p.His290Gln) variant in PAH has been reported in one patient with classic PKU (BH4 deficiency not excluded; PP4; PMID: 26210745). It was detected with known pathogenic variant p.R261Q, but parental testing was not reported/performed. This variant is absent from 1000G, ESP, ExAC and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.924. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020878/MONDO:0009861/006 2019-12-02 2021-09-19 Inconclusive true GO:0061924 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0007399 CHEBI:17026 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0085628 infores:hetionet CHEBI:167638 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0022346 infores:hetionet CAID:CA367401977 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401977 MONDO:0015967 PMID: Likely Pathogenic PM5, PP2, PP3, PP4, PS3_Moderate, PM2_Supporting PS4, PM1 The c.437T>G variant in the glucokinase gene, GCK causes an amino acid change of leucine to arginine at codon 210 (p.(Leu146Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.981, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMIDs: 24804978, 29927023). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Leu146Arg variant has a relative activity index (RAI) <0.50 (PS3_Moderate; PMID: 16731834). Another missense variant, c.437T>C p.Leu146Pro, has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Leu146Arg has a greater Grantham distance. (PM5). This variant was identified in three unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 18399931, 24804978, 29927023, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/13/2023): PS3_Moderate, PP2, PM2_Supporting, PP3, PP4, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401977/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Supports NCBIGene:5295 biolink:causes MONDO:0014083 infores:monarchinitiative not_provided not_provided HGNC:8979 MONDO:0014083 uuid:8acdb35c-bd55-43b1-99b2-8a18bc88a764 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0520966 infores:hetionet CHEBI:15367 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0040053 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0002871 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0497365 infores:hetionet CAID:CA002442 biolink:causes MONDO:0018875 infores:clingen CAID:CA002442 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PP3_Moderate, PM1, PP4_Moderate, BS2, PS4_Supporting, PM2_Supporting BA1, BP4, BP2, PS1, PS3, PS2, PM5, BP7, BS1, BS4, PM6, PVS1, PP1 The NM_000546.6: c.523C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cystindine at amino acid 175 (p.Arg175Cys). This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 31119730; Internal lab contributor: Color). This variant has an allele frequency of 0.00003293 (3/91090 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.5443; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors: Ambry). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PM2_Supporting, BS3_Supporting, PM1, PP3_Moderate, BS2_Moderate, PP4_Moderate. (Bayesian Points: 5; VCEP specifications version 2.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002442/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3403 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042963 infores:hetionet CHEBI:8871 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026837 infores:hetionet CAID:CA16616209 biolink:causes MONDO:0007750 infores:clingen CAID:CA16616209 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4, PP1 BA1, BP4, BP2, PS3, PS1, PS2, BP7, BS1, BS3, BS4, PM4, PM5, PM3, PM6, PVS1, BS2 The NM_000527.5(LDLR):c.1175G>A (p.Cys392Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL = 0.966. It is above 0.75.PM1: Variant meets PM2 and is missense in exon 4 and alters Cys392, one of the cysteine residues listed.PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases from different labs (1 case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 1 case with DLCN>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia), after alternative causes of high cholesterol were excluded.PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia: 2 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616209/MONDO:0007750/013 2025-01-31 2025-03-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA000315 biolink:causes MONDO:0018875 infores:clingen CAID:CA000315 MONDO:0018875 PMID: Pathogenic PS3, PS4, PP3_Moderate, PP1_Strong, PM1, PS2_Moderate, PP4_Moderate, PM2_Supporting BP4, BA1, PS1, PM5, BP7, BS3, BS1, PM6, PVS1, BS2 The NM_000546.6 :c.659A>G variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 220 (p.Tyr220Cys). This variant has been reported in 9 unrelated probands and/or families meeting Classic and/or Revised Chompret criteria. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 20028212, 9242456, 19101993, 18307025, 20805372, 21761402, 27714481, 10589545, 10432928, 8118819, ClinVar SCV: SCV000183774.8, Internal lab contributors). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 18307025). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 5 families (PP1_Strong; PMIDs: 20028212, 1910993, 10432928, 8118819, 27714481). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, SCV000183774.8). This variant has an allele frequency of 0.000005932 (7/1179948 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant has 127 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.5625; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PS2_Moderate, PP1_Strong, PM2_Supporting, PS3, PM1, PP3_Moderate, PP4_Moderate (Bayesian Points: 21 points; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000315/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6413 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C2047937 infores:hetionet CAID:CA145784 biolink:causes MONDO:0009290 infores:clingen CAID:CA145784 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.547-4C>G in gnomAD v2.1.1 is 0.7403 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77927) and European Finnish (0.75914) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92485, two star review status), with 6 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145784/MONDO:0009290/010 2020-01-23 2020-05-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:474180 biolink:causes UMLS:C1167945 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1167945 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0026848 infores:hetionet CHEBI:8080 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0002962 infores:hetionet CAID:CA414917900 biolink:causes MONDO:0010602 infores:clingen CAID:CA414917900 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM5, PS4_Supporting, PM2_Supporting, PP3 The c.923C>G (p.Ser308Trp) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3 - PM2_Supporting). This missense variant has a REVEL score of 0.857 (>0.6), meeting criteria for PP3. This variant has been reported in one individual with mild hemophilia A (PMID: 29296726 - PP4_Moderate). Additionally, there is one patient with mild hemophilia A (FVIII:C of 6%) is noted in the internal VCEP data who also has a family history of hemophilia A (PS4_Supporting). Ser308Leu, a variant at the same residue, has been classified as pathogenic by the CFD-VCEP, meeting criteria for PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM5, PS4_Supporting, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414917900/MONDO:0010602/071 2024-12-06 2024-12-06 X-linked inheritance HP:0001417 Supports NCBIGene:9750 biolink:causes MONDO:0014675 infores:monarchinitiative not_provided not_provided HGNC:13872 MONDO:0014675 uuid:c5c09255-036b-406d-8b83-7fc678a5b898 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1457883 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151951 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151951 infores:hetionet CHEBI:63621 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0010200 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027726 infores:hetionet CHEBI:31709 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0040822 infores:hetionet CHEBI:2668 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0030305 infores:hetionet CHEBI:50859 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042023 infores:hetionet CHEBI:61033 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151699 infores:hetionet CHEBI:9943 biolink:causes HP:0025017 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006905 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0314719 infores:hetionet CHEBI:5132 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0007097 infores:hetionet CHEBI:17334 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0036830 infores:hetionet CAID:CA280996 biolink:causes MONDO:0007648 infores:clingen CAID:CA280996 MONDO:0007648 PMID:26182300PMID:10094558PMID:10072428 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BS1, BS3, BS4, BP7, BP5, PM4, PM3, PM1, PM6, BS2, PP2, PP3, PP1, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.59G>A (p.Trp20*) variant is predicted to result in a premature stop codon in exon 2 that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 10072428, 26182300). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA280996/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:63599 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0032285 infores:hetionet CHEBI:8382 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0043094 infores:hetionet UMLS:C0145185 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0010520 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0013428 infores:hetionet CHEBI:52172 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151907 infores:hetionet CHEBI:39585 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C2830004 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0042109 infores:hetionet GO:2000037 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000037 GO:0007275 CAID:CA645509417 biolink:causes MONDO:0100437 infores:clingen CAID:CA645509417 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4, PP1_Strong PP2, PM4, PM5, PS3, PS1, BP1, BP4, BP3, BP7, BS3 NM_001034853.2(RPGR):c.2236_2237del (p.Glu746ArgfsTer23) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), with delayed or milder phenotype in females (1 pt), and rod involvement greater than cone (1 pt), which together are specific for RPGR-related retinopathy (4 points, PP4). This variant has been reported in at least 33 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, or decreased / absent cone and/or rod electroretinogram responses (PMIDs: 20021257, 11950860, 16086276, 17093403, 34745198, 33247286, 33576794, 33090715, 23681342, 31213501, 22807293, 32531858, PS4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from at least 2 families (PP1_strong; PMID: 21857984, 20021257, 11950860, 16086276, 17093403, 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4, PM2_supporting, PP1_strong, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509417/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:10119 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0025874 infores:hetionet CAID:CA16020753 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020753 MONDO:0009861 PMID: Uncertain Significance PM5, PP4_Moderate, PM2_Supporting PM3, PP3 The NM_000277.3(PAH):c.228G>C variant in PAH is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amnio acid 76 (p.Glu76Asp). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PMID: 19394257, PP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 2 different missense variants, p.Glu76Ala and p.Glu76Gly in the same codon have been classified as pathogenic/likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria VCEP: PP4_moderate, PM5, PM2_supporting (Version 2.0, 7/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020753/MONDO:0009861/006 2025-10-12 2025-10-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:204734 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0162835 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013595 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018099 infores:hetionet GO:0048328 biolink:causes GO:0048321 infores:ubergraph knowledge_assertion manual_agent GO:0048328 GO:0048321 CHEBI:135736 biolink:causes MONDO:0008313 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0205990 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018799 infores:hetionet CAID:CA000022 biolink:causes MONDO:0018875 infores:clingen CAID:CA000022 MONDO:0018875 PMID: Pathogenic PS3, PS4, PP1_Moderate, PM2_Supporting BA1, BP4, PS1, PS2, PM5, PM1, BS1, BS2, PP3, PP4 The NM_000546.6: c.1040C>A variant in TP53 is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 347 (p.Ala347Asp). This variant has been reported in 4 unrelated families meeting Classic/Revised Chompret criteria reported in 1 individuals under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 4 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 27496084, Internal lab contributors).The variant has been reported to segregate with LFS-associated cancers in 13 meioses in 1 family (PP1_Moderate; Internal contributor: National Cancer Institute). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 37067901, 12826609, 30224644, 29979965). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PP1_Moderate, PM2_Supporting, PS3. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000022/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15367 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027947 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0035258 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0427008 infores:hetionet CHEBI:15367 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0852911 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0234215 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0242073 infores:hetionet CHEBI:74947 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014394 infores:hetionet CHEBI:119915 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030554 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0014130 infores:hetionet CAID:CA016465 biolink:causes MONDO:0007947 infores:clingen CAID:CA016465 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM2_Supporting, PM1, PS4, PS2 PVS1, PM6, BS2, PP1, BP1, BP4, BP2, BP3, BA1, PM3, PM4, PM5, PS3, PS1, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.6446A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine amino acid 2149 (p.Tyr2149Cys). This variant has been identified in at least 13 individuals with features suggestive of, or consistent with, Marfan syndrome (MFS), including four patients meeting clinical diagnostic criteria for MFS, seven with thoracic aortic aneurysm or dissection (TAAD) with or without additional features of MFS, and two with unspecified clinical suspicion of MFS (PS4, PP4; Johns Hopkins, University of Texas-Houston, LMM, & Invitae internal data; PMIDs: 24793577, 27611364, 37684520, 31098894). The variant was found to be de novo in five of these patients, including three (maternity/paternity assumed) with phenotypes consistent with, but not highly specific to, FBN1, one (maternity/paternity assumed) with TAAD and borderline systemic involvement, and one (maternity/paternity confirmed) with a non-specific and genetically heterogeneous phenotype of TAAD and mitral valve prolapse (PS2; Johns Hopkins & Invitae internal data; PMIDs: 31098894, 37684520). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a conserved residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.900). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS2, PS4, PM1, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA016465/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8888 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018099 infores:hetionet CHEBI:9927 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0004238 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013298 infores:hetionet CHEBI:9139 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0853225 infores:hetionet CHEBI:6715 biolink:causes MONDO:0021003 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0152427 infores:hetionet UBERON:0007005 biolink:causes UBERON:0009881 infores:ubergraph knowledge_assertion manual_agent UBERON:0007005 UBERON:0009881 CHEBI:5855 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0409974 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151736 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0855242 infores:hetionet CHEBI:18332 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0232461 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0031542 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018500 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0002170 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151785 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018801 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0853908 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0149931 infores:hetionet CAID:CA205226 biolink:causes MONDO:0010305 infores:clingen CAID:CA205226 MONDO:0010305 PMID: Likely Benign BS2 PM2, PP3, BP4, PM5 The NM_005629.4:c.1601T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of an isoleucine by a threonine at amino acid position 534 (p.Ile534Thr). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency (MAF) is 0.00001229 (11/894936 alleles, 6 hemizygotes) in the European (Non-Finnish) population. While this MAF is below the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), PM2_Supporting cannot be applied due to the presence of hemizygotes. Overall, there are 7 hemizygotes in gnomAD v4.1.0 (6 in the European non-Finnish population and one in the remaining population) (BS2). The computational predictor REVEL gives a score of 0.474, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 212211). Due to the presence of 7 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2 (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA205226/MONDO:0010305/027 2025-03-13 2025-03-14 X-linked inheritance HP:0001417 Contradicts true CHEBI:72564 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042023 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0429098 infores:hetionet CHEBI:37941 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0009763 infores:hetionet CHEBI:5106 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0004093 infores:hetionet GO:0061294 biolink:causes GO:0061215 infores:ubergraph knowledge_assertion manual_agent GO:0061294 GO:0061215 CHEBI:94848 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0004093 infores:hetionet CHEBI:7478 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0232487 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0024312 infores:hetionet CAID:CA16619907 biolink:causes MONDO:0007113 infores:clingen CAID:CA16619907 MONDO:0007113 PMID: Pathogenic PM6, PP3, PP4, PP1, PM2_Supporting, PS4, PS3_Supporting The c.1576C>T (p.Arg526Cys) variant in the UBE3A gene has been observed in at least 5 individuals with Angelman syndrome (PMID: 10647895, 19213023, 23708187, 25212744; GeneDx: internal database) (PS4). The p.Arg526Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID: 10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID: 23708187) (PP1). The computational predictor REVEL gives a score of 0.866, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3). The p.Arg526Cys variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID: 10647895) (PP4). The p.Arg526Cys variant in UBE3A is absent from gnomAD v4.1 (PM2_Supporting). Protein expression analysis in transfected cell lines has shown that this variant destabilizes the protein, demonstrated by significantly reduced protein levels (PMID: 26255772) (PS3_Supporting). In summary, the p.Arg526Cys variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4, PM6, PP1, PP3, PP4, PM2_supporting, PS3_supporting) (UBE3A specifications version 5.0; curation approved on 2/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619907/MONDO:0007113/037 2025-02-28 2025-03-07 Autosomal dominant inheritance HP:0000006 Supports UNII:5V9KLZ54CY biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0027497 infores:hetionet NCBIGene:100127206 biolink:causes MONDO:0859374 infores:monarchinitiative not_provided not_provided HGNC:33914 MONDO:0859374 uuid:f0f63098-efa9-4964-9acf-7dc9ec1f58c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0042769 infores:hetionet CHEBI:6456 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0019825 infores:hetionet UMLS:C0005740 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0009676 infores:hetionet CHEBI:68579 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C2937358 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0025061 infores:hetionet CHEBI:101278 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0011606 infores:hetionet CHEBI:8430 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0015967 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0948807 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0233632 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0521491 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0042109 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0015393 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0236071 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0043345 infores:hetionet CHEBI:4856 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0008031 infores:hetionet CHEBI:8346 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0014457 infores:hetionet CHEBI:15551 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0039231 infores:hetionet CHEBI:6887 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027424 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0006444 infores:hetionet CHEBI:231425 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C1565489 infores:hetionet CHEBI:3636 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0233571 infores:hetionet GO:0048088 biolink:causes GO:0046661 infores:ubergraph knowledge_assertion manual_agent GO:0048088 GO:0046661 CHEBI:68478 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0030193 infores:hetionet CHEBI:8069 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0085932 infores:hetionet CHEBI:6472 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C1257843 infores:hetionet CHEBI:16796 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C2830004 infores:hetionet CHEBI:6129 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0231530 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0037822 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0235431 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001956 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0343084 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0009319 infores:hetionet CHEBI:4708 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0278106 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0038362 infores:hetionet CHEBI:17026 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0240717 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0403632 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0035204 infores:hetionet CHEBI:3387 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0085932 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011053 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020517 infores:hetionet CHEBI:231594 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0220870 infores:hetionet CHEBI:46557 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C2047937 infores:hetionet CHEBI:63605 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0917801 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0021400 infores:hetionet CHEBI:9599 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0037188 infores:hetionet CHEBI:4356 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0011991 infores:hetionet NCBIGene:92935 biolink:causes MONDO:0014636 infores:monarchinitiative not_provided not_provided HGNC:25133 MONDO:0014636 uuid:1c607199-3c97-4caa-8664-28ec8c7704ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28787 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0231835 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0004623 infores:hetionet CHEBI:70718 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0030252 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0456909 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015734 infores:hetionet CHEBI:6128 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151907 infores:hetionet CHEBI:50378 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0036690 infores:hetionet NCBIGene:8086 biolink:causes MONDO:0009279 infores:monarchinitiative not_provided not_provided HGNC:13666 MONDO:0009279 uuid:770c9e95-6760-4432-8423-8188b55501d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:57462 biolink:causes MONDO:0032673 infores:monarchinitiative not_provided not_provided HGNC:19918 MONDO:0032673 uuid:54a55444-759d-4163-8201-7f3a5b61d29d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3175 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0241057 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0948525 infores:hetionet CHEBI:47426 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0030805 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0016722 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0016722 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020621 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1096460 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1096460 infores:hetionet CHEBI:9566 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C2830004 infores:hetionet CHEBI:17347 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0009782 infores:hetionet CHEBI:39867 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015672 infores:hetionet CHEBI:7476 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0024141 infores:hetionet CHEBI:51860 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0026961 infores:hetionet CHEBI:40279 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0232807 infores:hetionet CAID:CA658658493 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658493 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1679dup p.(Tyr561fs) vvariant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658493/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:31401 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0518015 infores:hetionet CHEBI:46081 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0085593 infores:hetionet CHEBI:116735 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0476273 infores:hetionet CHEBI:3216 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0232602 infores:hetionet GO:0072095 biolink:causes GO:0001657 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0001657 CHEBI:45783 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151827 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0019360 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0542476 infores:hetionet CHEBI:50922 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042510 infores:hetionet CHEBI:44915 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0040822 infores:hetionet NCBIGene:375790 biolink:causes MONDO:0014052 infores:monarchinitiative not_provided not_provided HGNC:329 MONDO:0014052 uuid:cd51185d-c32f-409a-9148-1e32c5d41c43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0409974 infores:hetionet CHEBI:29007 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0017979 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0033777 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0340726 infores:hetionet NCBIGene:5621 biolink:causes MONDO:0005429 infores:ubergraph knowledge_assertion manual_agent HGNC:9449 MONDO:0005429 UNII:UMD7G2653W biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0006384 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042401 infores:hetionet CHEBI:27899 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0027424 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0005741 infores:hetionet CHEBI:45863 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013604 infores:hetionet CHEBI:4975 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0231749 infores:hetionet CHEBI:3213 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0033774 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0041582 infores:hetionet CHEBI:9943 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013378 infores:hetionet CHEBI:50275 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235592 infores:hetionet CHEBI:8869 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0030196 infores:hetionet CHEBI:63638 biolink:causes HP:0000823 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0034012 infores:hetionet CHEBI:28901 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020598 infores:hetionet CHEBI:6067 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0332601 infores:hetionet CHEBI:2549 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1306341 infores:hetionet CHEBI:63621 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0085631 infores:hetionet CAID:CA014956 biolink:causes MONDO:0005045 infores:clingen CAID:CA014956 MONDO:0005045 PMID:19574547PMID:19574547 Uncertain Significance PVS1_Moderate, PS4_Moderate, PM2_Supporting BP5, BS1, BS3, BS4, PP1, PP2, PP3, PM6, PM5, PM4, PM1, BA1, BP2, BP4, PS3, PS2, PS1 NM_000256.3(MYBPC3):c.3811C>T (p.Arg1271Ter) - This variant has been reported in individuals with HCM (LMM data, OMGL data, PMIDs: 19574547, 2339698, 25351510, 27532257, 28254189) and is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, PS4_Moderate criteria has been applied. This variant is present in gnomAD (v2.1.1), but did meet the threshold for PM2_Supporting. This nonsense variant leads to a premature termination codon at position 1271, which is not expected to undergo nonsense mediated decay based on its location and predicted to lead to a truncated protein shortened by 3 amino acids; there is currently no evidence that the last four amino acids in this protein are critical to protein function (PVS1_Moderate). While this variant has been studied in a myectomy sample from an affected individual, this evidence is insufficient to apply PS3 (PMID: 19574547). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, and PVS1_Moderate. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014956/MONDO:0005045/095 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50922 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0404521 infores:hetionet CHEBI:6888 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0039070 infores:hetionet NCBIGene:646960 biolink:causes MONDO:0013293 infores:monarchinitiative not_provided not_provided HGNC:39433 MONDO:0013293 uuid:cfa45b7b-6c1d-4a1e-b47e-2fdc46fc4a1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0178298 infores:hetionet CHEBI:48669 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0162298 infores:hetionet CHEBI:31711 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018790 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0232492 infores:hetionet NCBIGene:10269 biolink:causes MONDO:0800042 infores:monarchinitiative not_provided not_provided HGNC:12877 MONDO:0800042 uuid:26b105f9-072c-4a76-a410-9001386cb74c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151205 infores:hetionet CAID:CA410676273 biolink:causes MONDO:0009276 infores:clingen CAID:CA410676273 MONDO:0009276 PMID: Likely Pathogenic PM3, PP4, PM2_Supporting, PS4_Supporting, PP3_Moderate PP1 NM_000407.5(GP1BB):c.47T>C (p.Leu16Pro) is a missense variant in GP1BB that has been reported in the literature in at least two probands diagnosed with Bernard-Soulier syndrome in the homozygous state (PM3, PMIDs:32419170, 24934643). One of those patients displayed absent expression of GP1bb (CD42) in addition to excessive mucocutaneous bleeding and macrothrombocytopenia (PP4). At least 5 unrelated individuals heterozygous for this variant have been reported with macrothrombocytopenia (<150x10^9 platelets/l and MPV >12) in four publications (PMIDs: 28064200, 36173017, 31793234, 30609015; PS4_supporting). The Grpmax filtering allele frequency in gnomaDv4.1 is 8.200e-7 (based on 4/1141542 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. Additionally, the variant is predicted to have a deleterious effect (REVEL score of 0.886; PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS4_Supporting, PM2_Supporting, PP3_Moderate, PP4, and PM3 (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410676273/MONDO:0009276/082 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50859 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085641 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0178298 infores:hetionet CHEBI:63611 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003467 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019156 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0235260 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235260 infores:hetionet NCBIGene:5352 biolink:causes MONDO:0012217 infores:monarchinitiative not_provided not_provided HGNC:9082 MONDO:0012217 uuid:229a5ca2-237e-4e90-91e7-e17bf7df4f48 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0085649 infores:hetionet GO:2000136 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000136 GO:0007275 CAID:CA120604 biolink:causes MONDO:0044970 infores:clingen CAID:CA120604 MONDO:0044970 PMID:10205264 Likely Pathogenic PP3, PM2_Supporting, PVS1_Strong, PS3_Supporting PP1, PP4, PS4, PS2, PM6 The m.7587T>C (p.M1T) variant in MT-CO2 has been reported in one family with primary mitochondrial disease to date (PMID: 10205264). Affected individuals in this family include a 57-year-old woman with fatigue and unsteady gait and her more severely affected son who was nonambulatory and had cognitive impairment, optic atrophy, pigmentary retinopathy, and distal muscle wasting. The variant was present at 67% heteroplasmy in the muscle of the mother and at 91% in muscle of her affected son. There are no individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1; APOGEE2 score is 0.875), which predicts a damaging effect on gene function (PP3). This initiation codon variant results in a significant truncation of the MT-CO2 protein (PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative (near homoplasmy) than in COX-positive fibers (17–52%; PS3_supporting, PMID: 10205264). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PP3, PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120604/MONDO:0044970/015 2024-03-11 2024-11-19 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:4466 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020621 infores:hetionet CHEBI:119915 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003862 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0040046 infores:hetionet CHEBI:6832 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0022354 infores:hetionet CHEBI:8228 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0041969 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0234215 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0002871 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0948447 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0948447 infores:hetionet CHEBI:63620 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0006384 infores:hetionet CHEBI:4024 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0235267 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0006266 infores:hetionet CHEBI:15544 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0028643 infores:hetionet CHEBI:3504 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0857305 infores:hetionet CAID:CA010431 biolink:causes MONDO:0005045 infores:clingen CAID:CA010431 MONDO:0005045 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM6_Supporting, PM5_Supporting PP2, BA1, BP4, PS1, PS3, BS1, BS3 NM_000432.4(MYL2):c.484G>A (p.Gly162Arg). This variant has been identified in individuals with HCM and other cardiomyopathies (ClinVar Variation ID 164114), including as a presumed de novo occurrence in one of these individuals (PM6_Supporting) and was absent from large population studies (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>5), therefore, the PS4 criterion has been applied at supporting strength (PS4_Supporting) and the PM2_Supporting criterion has also been applied (PM2_Supporting). A different missense variant that meets criteria to be classified as likely pathogenic by this expert panel has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5_Supporting; c.4855G>A, p.Gly162Glu - Variation ID 43479). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Supporting, PM2_Supporting, PM6_Supporting, PP3, PM5_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010431/MONDO:0005045/102 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9332 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0028961 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151970 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019158 infores:hetionet GO:0072307 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:0072307 GO:0001656 CHEBI:3387 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018799 infores:hetionet CHEBI:421707 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0242429 infores:hetionet CHEBI:49375 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0033771 infores:hetionet CHEBI:9123 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014724 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0011615 infores:hetionet CHEBI:3387 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0234708 infores:hetionet CHEBI:5001 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0010200 infores:hetionet CHEBI:38545 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0030193 infores:hetionet CHEBI:8356 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007859 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018802 infores:hetionet CHEBI:9139 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042790 infores:hetionet CHEBI:51141 biolink:causes EFO:1001771 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0013608 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151849 infores:hetionet NCBIGene:7681 biolink:causes MONDO:0014137 infores:monarchinitiative not_provided not_provided HGNC:7114 MONDO:0014137 uuid:287efc83-f3d5-4d4d-aab9-0f9cde94fae9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0221161 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0004238 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0239295 infores:hetionet CHEBI:31397 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0235761 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0021053 infores:hetionet CHEBI:53760 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0028961 infores:hetionet CHEBI:63638 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0917801 infores:hetionet CHEBI:83527 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0040264 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027765 infores:hetionet NCBITaxon:1789 biolink:causes MONDO:0017832 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1789 MONDO:0017832 CHEBI:15940 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0917801 infores:hetionet CHEBI:9571 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0241442 infores:hetionet CAID:CA380140350 biolink:causes MONDO:0000573 infores:clingen CAID:CA380140350 MONDO:0000573 PMID:29772310 Likely Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM1 PM3 The NM_000536.4(RAG2):c.1442A>C variant in RAG2 is a missense variant predicted to cause substitution of histidine by proline at amino acid 481 (p.His481Pro). The variant has been reported in one individual from a consanguineous family with T-B-SCID, zygosity unspecified (PP4, PM3_not met, PMID:12200379). The variant is absent from gnomAD (PM2_Supporting). This variant resides within the PHD domain (amino acids 414-487) of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP (PM1). An in vitro recombination activity assay shows that the relevant activity of the p.H481P variant compared to wildtype RAG2 is 23.8%, which is below the threshold (<25%) established by the SCID VCEP for PS3_Moderate (PMID 29772310). In summary, this variant meets the criteria to be classified as likely pathogenic for SCID based upon the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4, PM2_Supporting, PM1, PS3_Moderate (SCID VCEP specifications version 2) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380140350/MONDO:0000573/124 2025-09-26 2025-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3696 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0021177 infores:hetionet CHEBI:45783 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151205 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0559031 infores:hetionet CHEBI:31413 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0001807 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040435 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0041912 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0687133 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0021843 infores:hetionet CL:0000136 biolink:causes MONDO:0003431 infores:ubergraph knowledge_assertion manual_agent CL:0000136 MONDO:0003431 CHEBI:4702 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0014518 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0518015 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020514 infores:hetionet NCBIGene:3371 biolink:causes MONDO:0014283 infores:monarchinitiative not_provided not_provided HGNC:5318 MONDO:0014283 uuid:f61d27a0-c3a3-4443-b31f-7104909aab7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9288 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0242528 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151763 infores:hetionet CHEBI:2955 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0085631 infores:hetionet CHEBI:6456 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0015230 infores:hetionet CHEBI:36791 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042420 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042769 infores:hetionet CHEBI:15367 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0014236 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0423602 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0007820 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0234458 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027765 infores:hetionet CHEBI:17347 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020621 infores:hetionet CHEBI:135351 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0232462 infores:hetionet CHEBI:10100 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0302809 infores:hetionet CHEBI:68534 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0016655 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0021400 infores:hetionet CHEBI:63580 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C3665347 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0021053 infores:hetionet CHEBI:167638 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0239488 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011630 infores:hetionet CHEBI:100241 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0039070 infores:hetionet CHEBI:64355 biolink:causes UMLS:C3665444 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C3665444 infores:hetionet CHEBI:2904 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0004245 infores:hetionet CHEBI:119573 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085932 infores:hetionet CHEBI:3223 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0041657 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018802 infores:hetionet CHEBI:84500 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0016242 infores:hetionet CHEBI:4466 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0007222 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0234547 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0234547 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0032461 infores:hetionet CHEBI:31711 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0000729 infores:hetionet CHEBI:4858 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0011124 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0014868 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0009319 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151559 infores:hetionet CHEBI:7852 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013144 infores:hetionet CHEBI:41774 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0008031 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0302813 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0302813 infores:hetionet CHEBI:4470 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0020517 infores:hetionet CAID:CA136998 biolink:causes MONDO:0019497 infores:clingen CAID:CA136998 MONDO:0019497 PMID: Benign BA1 BP4 The filtering allele frequency (the lower threshold of the 95% CI of 15730/17934) of the p.Cys1977Arg variant in the MYO15A gene is 86.6% for African chromosomes (including 6913 homozygous observations) by gnomAD v2.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA136998/MONDO:0019497/005 2021-06-16 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:29013 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0332575 infores:hetionet CAID:CA137643 biolink:causes MONDO:0019501 infores:clingen CAID:CA137643 MONDO:0019501 PMID: Uncertain Significance PP3, BS2 BS1, PP4, PM3, PM2 The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID: 25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID: 27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA137643/MONDO:0019501/005 2023-11-15 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:4672 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0020649 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0007137 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0012833 infores:hetionet CHEBI:6538 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0010200 infores:hetionet CHEBI:31709 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0023052 infores:hetionet GO:0042509 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0042509 GO:0023052 CHEBI:171719 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0037274 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0150450 infores:hetionet CHEBI:48131 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0015230 infores:hetionet CHEBI:7956 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0030193 infores:hetionet CHEBI:5118 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2979982 infores:hetionet CHEBI:7865 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0032326 infores:hetionet NCBIGene:585 biolink:causes MONDO:0014433 infores:monarchinitiative not_provided not_provided HGNC:969 MONDO:0014433 uuid:8e7c6649-379d-4419-aa6d-a38d929ca985 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA404098844 biolink:causes MONDO:0007750 infores:clingen CAID:CA404098844 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP4, PS1, BS1, PM5, PVS1, PP3 The NM_000527.5(LDLR): c.2446A>C (p.Lys816Gln) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: This variant is absent from gnomAD (gnomAD v2.1.1) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404098844/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3213 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0026858 infores:hetionet CHEBI:4657 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0015967 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0036454 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0948089 infores:hetionet CAID:CA8315034 biolink:causes MONDO:0009276 infores:clingen CAID:CA8315034 MONDO:0009276 PMID: Pathogenic PP4, PM2_Supporting, PM3_Strong, PVS1_Strong, PS3_Supporting The c.1601_1602del (p.Tyr534CysfsTer82) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it alters a functionally important region, the transmembrane domain (amino acids 532-553), in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient 1 in PMID: 9326230) with this variant had less than 10% expression of GPIba measured by Western blot, which is highly specific for Bernard-Soulier syndrome. The patient also had a severe defect in ristocetin agglutination and a life-long history of excessive bleeding (PP4). This variant has been detected in at least three probands with Bernard-Soulier syndrome. Two of these individuals were homozygous for the variant (PMIDs: 9326229 and 9326230) and one individual was compound heterozygous (confirmed in trans by parental testing) for this variant and the c.165_168del (p.Ser55ArgfsTer12) which was classified as Likely Pathogenic by the VCEP (PMID: 11054083) (PM3_Strong). Surface expression of GP1a measured by flow cytometry in CHO βIX cells transiently co-transfected with the c.1601_1602del variant GP1 and wild type GP1a showed decreased expression at 20% (<25%) WT levels, indicating that this variant impacts protein function (PMID: 9326230)(PS3_supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 0.00002394 (based on 38/1179788 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PM3_Strong, PP4, PM2_Supporting and PS3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8315034/MONDO:0009276/079 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports GO:1903358 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1903358 GO:0010256 CHEBI:15940 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0008350 infores:hetionet CHEBI:5864 biolink:causes HP:0003109 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0948023 infores:hetionet CHEBI:3756 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013428 infores:hetionet CHEBI:6067 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0022107 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0162316 infores:hetionet CAID:CA8365977 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365977 MONDO:0100453 PMID: Uncertain Significance PM2_Supporting PP3 The NM_000180.4(GUCY2D):c.2059C>T (p.His687Tyr) variant is predicted to replace the histidine at position p.687 with tyrosine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00007002, with 113 alleles / 1613828 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.303, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365977/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6438 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0547030 infores:hetionet CHEBI:16796 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0038435 infores:hetionet CHEBI:9943 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2047937 infores:hetionet CAID:CA200780 biolink:causes MONDO:0100437 infores:clingen CAID:CA200780 MONDO:0100437 PMID: Benign BP4_Strong, BA1 BS2 NM_001034853.2(RPGR):c.1274G>A (p.Arg425Lys) is a missense variant predicted to cause substitution of arginine by lysine at amino acid 425. This variant is present in gnomAD v4.1.0 at a frequency of 0.06617 among hemizygous individuals, with 26,057 variant alleles / 393,794 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been observed in more than 15 / 344 individuals with no features or family history of RPGR-related retinopathy, a condition with full penetrance at an early age (PMIDs: 10980543, 11992260). However, it is not clear whether these individuals underwent a complete visual examination, so BS2 was not met. The computational predictor REVEL gives a score of 0.005, which is below the ClinGen X-linked IRD VCEP threshold of <0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.05, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA200780/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true NCBIGene:23418 biolink:causes MONDO:0010818 infores:monarchinitiative not_provided not_provided HGNC:2343 MONDO:0010818 uuid:eeb49de2-6701-431d-affe-352d9e92dd17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0031350 infores:hetionet CHEBI:167638 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0016382 infores:hetionet CHEBI:135935 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C3665347 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0456909 infores:hetionet NCBIGene:2702 biolink:causes MONDO:0013544 infores:monarchinitiative not_provided not_provided HGNC:4279 MONDO:0013544 uuid:17bad345-b3ee-4e70-b375-5624ef3951d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9927 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0036974 infores:hetionet CHEBI:3082 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0043094 infores:hetionet NCBIGene:5557 biolink:causes MONDO:0859276 infores:monarchinitiative not_provided not_provided HGNC:9369 MONDO:0859276 uuid:45260b7c-dd1d-4ee8-957d-22c7ebb03592 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018681 infores:hetionet CAID:CA10587096 biolink:causes MONDO:0017623 infores:clingen CAID:CA10587096 MONDO:0017623 PMID: Likely Benign PM2, BP7, BP4 PVS1, PM6, BP5, BS4, BS3, BS1, PP4, PP1, PP2, PP3, BS2, PM1, PM4, PM5, BA1, BP2, PS2, PS4, PS3, PS1 PTEN c.651C>T (p.V217=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587096/MONDO:0017623/003 2018-07-25 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA241938 biolink:causes MONDO:0015152 infores:clingen CAID:CA241938 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP1, PP3, PM2_Supporting, PS3_Moderate PM4, PM5, PM1, PS1, PS4, PS2, BP1, BP4, BP2, BP3, BA1, BP7, BP5, BS4, BS1, BS3, PVS1, PM6, BS2, PP2 The NM_003494.4: c.1852G>A variant in DYSF, which is also known as NM_001130987.2: c.1906G>A p.(Gly636Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 618 (p.Gly618Arg). This variant has been detected in at least 7 unrelated individuals with LGMD2B. Of those individuals, at least 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.2811-2A>C, 1.0 pt, PMID: 36983702). In addition, three unrelated individuals were homozygous for the variant (1.0 pt, PMID: 26088049, 18853459, 32400077) (PM3_Strong). At least one patient with this variant displayed progressive weakness and reduced dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID: 36983702). The variant was also reported to co-segregate with the disease in one affected family member (PP1; PMID: 12471055). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/21646 alleles) in the European (Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.93, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). Another nucleotide change resulting in the same amino acid change, c.1852G>C p.(Gly618Arg), has been reported in association with LGMD (PMID: 30564623) and classified as pathogenic by the LGMD VCEP. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PP4_Strong, PM3_Strong, PM2_Supporting, PP3, PP1, PS3_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA241938/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50648 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0232849 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877331 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877331 infores:hetionet CHEBI:681850 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0006840 infores:hetionet CHEBI:8863 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027497 infores:hetionet CHEBI:9649 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0438215 infores:hetionet CHEBI:10119 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018843 infores:hetionet CHEBI:68841 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0002792 infores:hetionet CHEBI:75722 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0000731 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011616 infores:hetionet CHEBI:5004 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0003460 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042401 infores:hetionet CHEBI:4909 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0000731 infores:hetionet CAID:CA2740099755 biolink:causes MONDO:0015967 infores:clingen CAID:CA2740099755 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM4_Supporting PM1, PP4 The c.196_198 variant in the HNF1 homeobox A gene, HNF1A, is a 3 base pair insertion resulting in the in-frame addition of 1 amino acid at codon 66 (p.(Glu66dup)) within exon 1 of NM_000545.8. The c.196_198dup variant is predicted to change the length of the protein due to an in-frame insertion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributors). In summary, c.196_198dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0 approved 8/11/2023): PM2_Supporting, PM4_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2740099755/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52717 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0028081 infores:hetionet CAID:CA123228 biolink:causes MONDO:0100326 infores:clingen CAID:CA123228 MONDO:0100326 PMID: Likely Pathogenic PM3, PM5, PP4_Moderate, PP3, PM2_Supporting The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID: 32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123228/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:66901 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0035455 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0442886 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0424790 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027947 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0037274 infores:hetionet CHEBI:49662 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013491 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0497327 infores:hetionet CHEBI:82960 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151904 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0340464 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0234458 infores:hetionet CHEBI:6954 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0151529 infores:hetionet CHEBI:15854 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0232333 infores:hetionet CHEBI:5118 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0152198 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0948089 infores:hetionet CHEBI:94385 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C1142412 infores:hetionet CHEBI:3723 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0853225 infores:hetionet CHEBI:5118 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0023052 infores:hetionet CHEBI:41879 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0002792 infores:hetionet GO:2000458 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:2000458 GO:0070887 CHEBI:8802 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020456 infores:hetionet NCBIGene:23028 biolink:causes MONDO:0014751 infores:monarchinitiative not_provided not_provided HGNC:29079 MONDO:0014751 uuid:c28546d3-92c8-4e3f-8447-1a2ba57db3e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0233494 infores:hetionet CHEBI:4953 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0014742 infores:hetionet CHEBI:63598 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1260880 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0041976 infores:hetionet CHEBI:100246 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0085631 infores:hetionet CHEBI:114785 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0004093 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0549284 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0549284 infores:hetionet CHEBI:6916 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0018524 infores:hetionet CHEBI:6456 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C2939147 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0497156 infores:hetionet CHEBI:70735 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0039070 infores:hetionet CHEBI:63717 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0029442 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0042373 infores:hetionet CHEBI:6970 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0003862 infores:hetionet CHEBI:7465 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0232461 infores:hetionet CHEBI:6904 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0151517 infores:hetionet CHEBI:35854 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0004093 infores:hetionet CHEBI:66876 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C1384353 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151605 infores:hetionet CHEBI:6690 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0002170 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0037274 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0018801 infores:hetionet CHEBI:10110 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0009782 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0028259 infores:hetionet CHEBI:49603 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0006826 infores:hetionet CHEBI:9667 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0002792 infores:hetionet NCBITaxon:12066 biolink:causes MONDO:0005791 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12066 MONDO:0005791 CHEBI:8772 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0003862 infores:hetionet CHEBI:231594 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1368065 infores:hetionet CHEBI:36795 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0424790 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0006444 infores:hetionet CHEBI:171719 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1291078 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0948070 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948070 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0948089 infores:hetionet CHEBI:6076 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0033774 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0018799 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0033975 infores:hetionet NCBIGene:8869 biolink:causes MONDO:0018274 infores:monarchinitiative not_provided not_provided HGNC:10872 MONDO:0018274 uuid:dd339d16-dbfd-4726-83a9-eb4f9d5823e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0012739 infores:hetionet GO:1901673 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:1901673 GO:0140014 CAID:CA323094 biolink:causes MONDO:0019169 infores:clingen CAID:CA323094 MONDO:0019169 PMID:8962591 Pathogenic PM5, PM6_Strong, PP3, PP4, PM2 PM1, PM4, PP1, BA1, PS1, PVS1, BS1 The c.1132C>T (p.R378C) variant in PDHA1 has been reported in multiples males and females with pyruvate dehydrogenase deficiency and is one of the more common pathogenic variants seen in this cohort (PMID: 22896851). It has been seen in at least three individuals with decreased pyruvate dehydrogenase activity (PP4; Patient 6 in PMID: 8962591; Subject M-7 in PMID: 20002461; Subject 35-2 in PMID: 10679936). This variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least 4 unrelated individuals with pyruvate dehydrogenase deficiency [PM6_Strong; utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID: 10679936, subject 35-2; PMID: 20002461, subject M-7; PMID: 21914562, subject AM8; PMID: 21914562, subject AF22]. Of note, to our knowledge, there are no reports of this variant being inherited from a healthy mother, however it is important to note that not all cases reported in the literature had mothers who were tested. This variant is absent from gnomAD v2.1.1 (PM2). Another missense variant at this position [c.1133G>A, p.R378H] has been reported in at least six other probands (PM5; PMIDs: 8032855 - 1 case, 7887409 - 2 cases, 9409363 - 3 cases) and is a known pathogenic variant. The computational predictor REVEL gives a score of 0.907, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM5, PM6_strong, PP3, PP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA323094/MONDO:0019169/014 2021-10-25 2021-10-25 X-linked inheritance HP:0001417 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:5130 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0036974 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0036572 infores:hetionet CHEBI:27786 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0546817 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0042109 infores:hetionet CHEBI:5103 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0085633 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0178298 infores:hetionet CAID:CA226480 biolink:causes MONDO:0100368 infores:clingen CAID:CA226480 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3, PP4, PM2_Supporting NM_000329.3(RPE65):c.1078G>C is a missense variant predicted to replace alanine with proline at position 360. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000001240, with 5 alleles / 1179942 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.1282_1303del (p.Gly428MetfsTer5) or NM_000329.3(RPE65):c.1039C>T (p.Arg347Cys) variants confirmed in trans (PMID: 19431183, PMID: 33952291), both were previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (2 points total, PM3_strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) by next-generation sequencing-based genotyping of a panel of 586 eye disease-associated genes (2 pts), congenital onset (1 pt), reduced central visual acuity (1 pt), extinct ERG responses from rods (0.5 pts) and cones (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (7 pts total, PMID: 33952291, PP4). The computational predictor REVEL gives a score of 0.677, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226480/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63925 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0014518 infores:hetionet CHEBI:49960 biolink:causes UMLS:C1456865 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1456865 infores:hetionet GO:0006954 biolink:causes MONDO:0005011 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003424 DB08904_MESH_D003424_1DB00051_MESH_D003424_1DB00065_MESH_D003424_1DB00108_MESH_D003424_1 UMLS:C0879264 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C1384353 infores:hetionet CHEBI:63624 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0033893 infores:hetionet CHEBI:231594 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0000731 infores:hetionet CHEBI:28748 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014724 infores:hetionet CAID:CA255048 biolink:causes MONDO:0010602 infores:clingen CAID:CA255048 MONDO:0010602 PMID: Likely Benign BS1, BS2 PP3, BP4, BA1, PS4 The NM_000132.4(F8):c.121G>T (p.Gly41Cys) variant is reported at an MAF of 0.0001272 (26/204446 alleles) in the general population in gnomAD v2.1.1, with 9 hemizygotes, meeting BS1 criteria (MAF > 0.0000333). This variant has also been observed in a male with repeated normal FVIII coagulation testing with no family history of bleeding meeting BS2 criteria (PMID:32100410). The variant has been observed in multiple patients in the literature with mild to severe hemophilia A (PMID:19473423, PMID:23020595, PMID:33477601); however, the variant meets BS1 criteria so clinical cases are not applied. Additionally, it was unclear that intron inversion testing was completed in the severe cases. In summary, this variant meets criteria to be classified as benign for hemophilia A. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel (specifications version 1.0.0) for F8: BS1 and BS2. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255048/MONDO:0010602/071 2025-11-07 2025-11-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:6761 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0031256 infores:hetionet CHEBI:261649 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0040264 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0003123 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0036572 infores:hetionet CHEBI:3478 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151662 infores:hetionet CAID:CA399804396 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804396 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PM3, PP3, PP4, BP4 The ITGA2B missense variant NM_000419.5:c.1142C>T replaces the threonine residue with an isoleucine residue (p.Thr381Ile) and is absent from control population databases, including gonmADv4.0 (PM2_supporting). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (GT-71 in PMID: 30792900), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGA2B variant was not identified. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804396/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA10585178 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585178 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, BP2, BA1, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM5, PVS1, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.889A>C (p.Asn297His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 1/24948 = 0.00004 (0.004%) in African/African-American 8692 exomes plus 16256 genomes (gnomAD v2.1.1), so PM2 is Met.PS4_supporting - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585178/MONDO:0007750/013 2022-02-28 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:27834 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0314719 infores:hetionet CHEBI:6775 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151904 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0040034 infores:hetionet CAID:CA367400582 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400582 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP2, PP3, PP4 PM1, PP1 The c.775G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 259 (p.(Ala259Ser)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.744, which is greater than the MDEP VCEP threshold of 0.70 (PP3). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Two other missense variants, c.776C>T p.Ala259Val and c.775G>A p.Ala259Thr, have been interpreted as pathogenic by the ClinGen MDEP, and p.Ala259Ser has a greater Grantham distance than p.Ala259Val and p.Ala259Thr (PM5_Strong). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 30245511). This variant segregated with hyperglycemia/diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 30245511). In summary, c.775G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400582/MONDO:0015967/086 2023-08-12 2023-08-12 Semidominant inheritance HP:0032113 Supports CHEBI:50859 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C2242737 infores:hetionet CHEBI:70735 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0009782 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038358 infores:hetionet CHEBI:7445 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0019572 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0016436 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0155169 infores:hetionet CHEBI:5280 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1510410 infores:hetionet GO:0002306 biolink:causes CL:0000803 infores:ubergraph knowledge_assertion manual_agent GO:0002306 CL:0000803 CHEBI:8356 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1260880 infores:hetionet CHEBI:63638 biolink:causes HP:0008807 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1328407 infores:hetionet CHEBI:71219 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0033771 infores:hetionet CHEBI:39112 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C2047937 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0017178 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0013595 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0035078 infores:hetionet CHEBI:31174 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0085932 infores:hetionet CHEBI:9316 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0036973 infores:hetionet CHEBI:135736 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030193 infores:hetionet CHEBI:27504 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0022661 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011991 infores:hetionet CHEBI:125354 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0021368 infores:hetionet CHEBI:34967 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0030554 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0009450 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0149931 infores:hetionet CHEBI:2704 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0002792 infores:hetionet CHEBI:50729 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0027540 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1384666 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017675 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0009806 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0031350 infores:hetionet CAID:CA913190317 biolink:causes MONDO:0100326 infores:clingen CAID:CA913190317 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The frameshift variant NM_000212.3(ITGB3):c.325del (p.Val109SerfsTer?) is predicted to cause a premature stop codon in biologically-relevant-exon 4/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). The variant is absent from gnomADv4.0.0 (PM2_supporting). The variant has been found in at least one individual with GT, ClinVar entry (SCV000891200.1) by the Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota. The patient is compound heterozygous with variant of uncertain significance NM_000212.3(ITGB3):c.778-2A>G, phasing not confirmed. The patient had bleeding since childhood, abnormal aggregation, and flow cytometry low levels of GPIIb/IIIa. Patient information is consistent with GT but insufficient for PP4. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1 and PM2_supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190317/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UMLS:C0657912 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035304 infores:hetionet CHEBI:94385 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0009676 infores:hetionet CHEBI:51041 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011124 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0032300 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0032300 infores:hetionet CHEBI:8802 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0007166 infores:hetionet CHEBI:3504 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0040460 infores:hetionet CHEBI:3561 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0870082 infores:hetionet CHEBI:7865 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0018524 infores:hetionet CAID:CA320251648 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251648 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.991A>G (p.Ser331Gly) is a missense variant which meets the criteria for BP4. This missense variant has a REVEL score ≤ 0.50 (0.105) and a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251648/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020639 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0345904 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0029408 infores:hetionet GO:1902553 biolink:causes GO:0098869 infores:ubergraph knowledge_assertion manual_agent GO:1902553 GO:0098869 CHEBI:31705 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0020458 infores:hetionet CHEBI:50381 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0030554 infores:hetionet CHEBI:2663 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151904 infores:hetionet CHEBI:9763 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235198 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0521634 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0521634 infores:hetionet CHEBI:8764 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003467 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0178298 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0036508 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030567 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0015230 infores:hetionet CHEBI:49375 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0003811 infores:hetionet CHEBI:94385 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0004604 infores:hetionet CAID:CA199319 biolink:causes MONDO:0010726 infores:clingen CAID:CA199319 MONDO:0010726 PMID: Benign BA1 The allele frequency of the p.Val380Met (NM_004992.3) variant in MECP2 is 0.138% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Val380Met variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199319/MONDO:0010726/016 2021-12-13 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:167309 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0017675 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0006266 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0015397 infores:hetionet CHEBI:8346 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0231218 infores:hetionet CHEBI:681848 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0033774 infores:hetionet CHEBI:51173 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0267792 infores:hetionet NCBIGene:3313 biolink:causes MONDO:0008422 infores:monarchinitiative not_provided not_provided HGNC:5244 MONDO:0008422 uuid:8ca7a526-281a-4d9e-80c9-9e7e5011cfdc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0002962 infores:hetionet CHEBI:32139 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0220983 infores:hetionet CHEBI:39669 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0344232 infores:hetionet CHEBI:68478 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0239571 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0425945 infores:hetionet NCBIGene:5551 biolink:causes MONDO:0011337 infores:monarchinitiative not_provided not_provided HGNC:9360 MONDO:0011337 uuid:d4b4a0c7-f921-4e09-93aa-0f12e22e3cf6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0030193 infores:hetionet CHEBI:367163 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0029118 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0003123 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011127 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027441 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0013395 infores:hetionet CHEBI:135679 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0152227 infores:hetionet CHEBI:43968 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0019080 infores:hetionet CHEBI:9599 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0030193 infores:hetionet NCBIGene:4488 biolink:causes MONDO:0008198 infores:monarchinitiative not_provided not_provided HGNC:7392 MONDO:0008198 uuid:f480f435-03ed-48da-8fbb-d60d3144ae8b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033777 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0032285 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0019158 infores:hetionet CHEBI:75998 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0022603 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0002871 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0007642 infores:hetionet NCBIGene:51308 biolink:causes MONDO:0014282 infores:monarchinitiative not_provided not_provided HGNC:17975 MONDO:0014282 uuid:0784b630-6164-4796-aa97-f36045d2d9da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31644 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042571 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0343869 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0343869 infores:hetionet CHEBI:6532 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0002994 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0019158 infores:hetionet CHEBI:42068 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0036690 infores:hetionet GO:2000702 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0009790 CHEBI:63598 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C3665386 infores:hetionet CHEBI:63115 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0011991 infores:hetionet CHEBI:5790 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0036974 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1262535 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1262535 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0856069 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0856069 infores:hetionet CAID:CA254842 biolink:causes MONDO:0044970 infores:clingen CAID:CA254842 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate PS2, PS3 The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of onset (11 months old to 40s). All cases developed hypertrophic cardiomyopathy. Muscle biopsy revealed COX negative fibers in cardiac tissue and one case had ragged red fibers in skeletal muscle. Heteroplasmy levels were predominantly the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Other affected family members did harbor the variant at 60-100%. Of note, some healthy family members had the variant ranging from 40-100% (PS4_moderate; PMIDs: 10065021, 7646516, 12767666, 12711217, 23847141). This variant segregated with disease in a family with LVH with diffuse hypertrophy as the proband's heteroplasmy was 98% in heart, 85% in muscle, and 95% in blood. His seven affected maternal relatives had heteroplasmy levels ranging from 60-92% in blood. His 12 unaffected relatives available for testing heteroplasmy ranged 50-78% in blood (PP1_moderate, PMID: 1006502). There are no reported de novo occurrences of this variant to our knowledge. There are three occurrences of this variant in Helix dataset (frequency of 0.001%) that includes two homoplasmic and one heteroplasmic individuals. This variant is absent in gnomAD v3.1.2 and in GenBank dataset therefore the frequency is still low enough to meet criteria for PM2_supporting. There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PP1_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254842/MONDO:0044970/015 2022-09-12 2022-10-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:132233 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0011603 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015397 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0152020 infores:hetionet CHEBI:17823 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0549448 infores:hetionet CHEBI:4885 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0018418 infores:hetionet CHEBI:8802 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0036974 infores:hetionet CHEBI:38545 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0030554 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0038454 infores:hetionet CHEBI:6149 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0011168 infores:hetionet CHEBI:52717 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003862 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0032285 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235750 infores:hetionet CHEBI:47898 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013491 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0018939 infores:hetionet CHEBI:5959 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0262988 infores:hetionet CHEBI:10650 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0877359 infores:hetionet CHEBI:61049 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030193 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151436 infores:hetionet CHEBI:68579 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C2047937 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0040034 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0041657 infores:hetionet CHEBI:3441 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0028084 infores:hetionet CHEBI:47381 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0349790 infores:hetionet NCBIGene:9851 biolink:causes MONDO:0030356 infores:monarchinitiative not_provided not_provided HGNC:29110 MONDO:0030356 uuid:310bbd88-bddf-4ed2-b6fd-9fe10e07c69e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0004245 infores:hetionet NCBIGene:1855 biolink:causes MONDO:0014591 infores:monarchinitiative not_provided not_provided HGNC:3084 MONDO:0014591 uuid:47909550-2639-46a4-bf0f-1e248485b086 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA391999297 biolink:causes MONDO:0015152 infores:clingen CAID:CA391999297 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PS2_Supporting, PVS1, PM2_Supporting PS1 The NM_000070.3: c.1194-2A>G variant in CAPN3 occurs within the canonical splice acceptor site of intron 9. This variant is predicted to abolish the consensus splice acceptor site, with a SpliceAI score of 0.99, and strengthen two alternative acceptor sites in exon 10 at +13 and +37 (SpliceAI score 0.66 and 0.36). Skipping of exon 10, which is out of frame, would be expected to disrupt the reading frame, leading to nonsense mediated RNA decay in a gene in which loss of function is an established mechanism of disease. Use of either of the alternative acceptor sites would also be expected to disrupt the reading frame (PVS1). This variant has been detected in one individual with features consistent with LGMD, where it was confirmed in trans with a pathogenic variant (c.1524G>A p.(Glu508=), 1.0 pt, ClinVar SCV001423801.2 internal data communication; PM3). This individual had a clinical diagnosis of muscular dystrophy and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Strong). In this individual, the variant was identified as a de novo occurrence, and parental relationships were confirmed (PS2_Supporting). This variant is not found in gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/09/2025): PVS1, PM3, PP4_Strong, PS2_Supporting, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA391999297/MONDO:0015152/187 2025-10-09 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16755 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0038358 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0007642 infores:hetionet CHEBI:84050 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0041657 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005783 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019064 infores:hetionet CAID:CA005629 biolink:causes MONDO:0100316 infores:clingen CAID:CA005629 MONDO:0100316 PMID: Uncertain Significance BS4_Supporting BP4, PS3, PS4, PS1, BS1, BS3, PM2, PM5, PP3, BS2 NM_000218.3(KCNQ1):c.1343C>T is a missense variant ithat substitutes proline with leucine at codon 448 (p.Pro448Leu). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00005254, with 62 alleles / 1,179,942 total alleles in the European non-Finnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004 so neither criterion is met. This variant has been reported in at least 1 proband affected with long QT syndrome 1, however, the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met (PMID: 23392653, PMID: 19716085, PMID: 25854863). The variant has been observed in a family with long QT syndrome but fails to segregate with the disease phenotype in at least 1 affected member (PMID: 23392653; BS4_Supporting). The computational predictor REVEL gives a score of 0.592, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BS4_Supporting. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA005629/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49040 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0013404 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0035455 infores:hetionet CHEBI:9123 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0917801 infores:hetionet CHEBI:64028 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0085637 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0877153 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003123 infores:hetionet NCBIGene:79827 biolink:causes MONDO:0020718 infores:monarchinitiative not_provided not_provided HGNC:24039 MONDO:0020718 uuid:b2546731-5caf-460d-b701-6fb55cefe4de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C2363731 infores:hetionet CHEBI:32139 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0009806 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0020517 infores:hetionet CHEBI:50648 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011603 infores:hetionet CHEBI:6912 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0085649 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0040034 infores:hetionet CHEBI:9738 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0042963 infores:hetionet CHEBI:63631 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085593 infores:hetionet UMLS:C0011701 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0014591 infores:hetionet CHEBI:77733 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0011603 infores:hetionet CHEBI:64064 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0151686 infores:hetionet CHEBI:28939 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0015230 infores:hetionet CHEBI:107736 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0233477 infores:hetionet NCBIGene:7547 biolink:causes MONDO:0010607 infores:monarchinitiative not_provided not_provided HGNC:12874 MONDO:0010607 uuid:43843b8e-7e1a-4283-be87-99a4fb2b2002 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002453 infores:hetionet CHEBI:66964 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0011991 infores:hetionet CHEBI:3723 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016204 infores:hetionet CHEBI:7577 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0040822 infores:hetionet CHEBI:9654 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0011124 infores:hetionet CAID:CA222224 biolink:causes MONDO:0015152 infores:clingen CAID:CA222224 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.937+1G>A variant in DYSF, which is also known as NM_001130987.2: c.1033+1G>A, occurs within the canonical splice donor site of intron 10 and is predicted to cause skipping of biologically relevant exon 10/55, resulting in a frameshift and premature truncation leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least nine individuals with LGMD (PMID: 16100712, 18853459, 23243261, 27647186, 33560664), including in a homozygous state in three individuals without reported familial consanguinity (1.0 pt, PMID: 23243261, 33560664) and in a compound heterozygous state with a pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 1.0 pt, PMID: 33560664) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed disease progression and had significantly reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 16100712, 18853459, 33560664; PP4_Strong). The filtering allele frequency of this variant is 0.000057966 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 5/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 10/07/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222224/MONDO:0015152/180 2025-10-07 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:404903 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0494475 infores:hetionet CHEBI:9445 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0027497 infores:hetionet CHEBI:8871 biolink:causes HP:0030213 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0233469 infores:hetionet CHEBI:63631 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2364111 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0042373 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0016436 infores:hetionet CHEBI:63624 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0151905 infores:hetionet CHEBI:5613 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0026826 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0006145 infores:hetionet CHEBI:7824 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0917801 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0235290 infores:hetionet CHEBI:145499 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015644 infores:hetionet CHEBI:4995 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0023518 infores:hetionet NCBIGene:4909 biolink:causes MONDO:0013134 infores:monarchinitiative not_provided not_provided HGNC:8024 MONDO:0013134 uuid:9c5b2c4d-76b7-4702-ab8a-5540b1475555 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011991 infores:hetionet CHEBI:45979 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0011603 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0008547 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0008547 uuid:b5ee351b-d7c7-4a62-aa10-9031c8d1d7c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:F64QU97QCR biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0080274 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020517 infores:hetionet CHEBI:16469 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2830004 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0948807 infores:hetionet CHEBI:3752 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0022346 infores:hetionet CHEBI:5106 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0424295 infores:hetionet CHEBI:8774 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0043352 infores:hetionet CHEBI:465284 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085605 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0020523 infores:hetionet CHEBI:85078 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0032617 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0521505 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0521505 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0017178 infores:hetionet CHEBI:2673 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0009676 infores:hetionet CHEBI:30830 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0013404 infores:hetionet CHEBI:3048 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0015967 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235108 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235108 infores:hetionet CHEBI:9168 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0040264 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151919 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151919 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0020517 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0521465 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0034150 infores:hetionet CAID:CA8337902 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337902 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate PM5 The c.896A>T (p.Lys299Met) variant in ACADVL has been reported in the literature in patients with VLCAD deficiency and elevated acylcarnitine (PP4_moderate; PMID: 16982043, 35281659). The variant has also been detected in compound heterozygote with pathogenic variant p.Val283Ala (PM3; PMID: 35281659). Three missense variants (p.Lys299Asn, p.Lys299Arg, p.Lys299Glu; PMIDs: 9973285, 31737040, 33150772) in the same codon have also been reported for VLCAD deficiency. This variant is absent from gnomAD population database v2.1.1(PM2_Supporting) and the computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PP4_moderate, PM3, PM2_Supporting, PP3). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337902/MONDO:0008723/021 2023-06-13 2023-06-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27666 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0235378 infores:hetionet CHEBI:231594 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0020555 infores:hetionet CHEBI:9448 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0015967 infores:hetionet NCBITaxon:5052 biolink:causes MONDO:0005657 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5052 MESH:D001228 DB00681_MESH_D001228_1DB01263_MESH_D001228_1DB06636_MESH_D001228_1 CHEBI:39112 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0017178 infores:hetionet CHEBI:31401 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0002874 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1720775 infores:hetionet NCBIGene:2593 biolink:causes MONDO:0012999 infores:monarchinitiative not_provided not_provided HGNC:4136 MONDO:0012999 uuid:545e4b8b-d6f3-4143-8e78-fc3789ae1537 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0149904 infores:hetionet CHEBI:3478 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0041969 infores:hetionet CHEBI:5784 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C1291078 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151514 infores:hetionet CHEBI:4909 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0151529 infores:hetionet CHEBI:135005 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0043387 infores:hetionet CAID:CA645608317 biolink:causes MONDO:0011071 infores:clingen CAID:CA645608317 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP3, BP2, BP1, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.509-7C>T is an intronic variant which is not predicted by SpliceAI to impact splicing (BP4). Additionally, an evolutionary conservation algorithm predicts the site as not being highly conserved (PhyloP score = 1.55845 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645608317/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28593 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0020651 infores:hetionet CHEBI:17303 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0009676 infores:hetionet CHEBI:7822 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0035078 infores:hetionet CHEBI:3441 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0008031 infores:hetionet CHEBI:5296 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0003862 infores:hetionet CHEBI:3181 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0013144 infores:hetionet CHEBI:6402 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0497156 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0023533 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0476280 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0424295 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0027769 infores:hetionet CHEBI:7581 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0018524 infores:hetionet CHEBI:9907 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0006277 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0234215 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0037274 infores:hetionet CHEBI:6149 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0855775 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0017152 infores:hetionet CHEBI:131512 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0041657 infores:hetionet NCBIGene:79087 biolink:causes MONDO:0011783 infores:monarchinitiative not_provided not_provided HGNC:19358 MONDO:0011783 uuid:32552df4-6b59-4216-b29b-27dd83e012e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030312 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0178298 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0004936 infores:hetionet CHEBI:5855 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0220870 infores:hetionet CHEBI:2948 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0022354 infores:hetionet CHEBI:38562 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0027080 infores:hetionet CHEBI:145499 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151699 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0521591 infores:hetionet CHEBI:3127 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0000768 infores:hetionet CHEBI:10023 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2830004 infores:hetionet CHEBI:63577 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1527344 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151736 infores:hetionet CHEBI:8888 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0423791 infores:hetionet CHEBI:5134 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0043352 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0034634 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034634 infores:hetionet CHEBI:8107 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151786 infores:hetionet CHEBI:16469 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0033771 infores:hetionet CHEBI:6931 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C1260880 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1527407 infores:hetionet NCBIGene:72 biolink:causes MONDO:0020754 infores:monarchinitiative not_provided not_provided HGNC:145 MONDO:0020754 uuid:4d8b5064-dbfb-4548-ae71-8e1068fd034e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59773 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0032461 infores:hetionet CHEBI:8228 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C2047937 infores:hetionet GO:1905005 biolink:causes GO:0003203 infores:ubergraph knowledge_assertion manual_agent GO:1905005 GO:0003203 CHEBI:9635 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0030193 infores:hetionet NCBIGene:6566 biolink:causes MONDO:0009501 infores:monarchinitiative not_provided not_provided HGNC:10922 MONDO:0009501 uuid:ef742a12-6de7-48d9-a401-06a464c363d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA253316 biolink:causes MONDO:0010134 infores:clingen CAID:CA253316 MONDO:0010134 PMID: Likely Pathogenic PS3_Supporting, PP3, PP1, PP4, PM3_Very Strong, BS1_Supporting The c.1003T>C (p.Phe335Leu) variant has been identified in over 20 probands with Hearing loss, 6 of whom had a second pathogenic or suspected pathogenic variant in trans (PM3_VeryStrong; PMIDs: 19509082, 29293505, 25394566, 20668687, 20597900, 19426954, 19204907, 18285825, 17503324, 17357124, 17309986, 15689455, 14679580, 11317356, Laboratory for Molecular Medicine internal data). The variant has been reported to segregate with disease in one affected family member (PP1; PMID: 18285825). Multiple probands presented with hearing loss and enlarged vestibular aqueducts (EVA) which are highly specific to Pendred syndrome (PP4; PMIDs: 14679580, 18285825, 19509082, 25394566, Laboratory for Molecular Medicine internal data). Evidence has been published indicating that the p.Phe335Leu variant may be pathogenic when in trans with a functionally-null or severely hypomorphic variant but not as a mono-allelic variant or in the homozygous state (PMIDs: 19204907, 24051746). The c.1003T>C (p.Phe335Leu) variant was present in 0.203% (76/30612 CI 95%) of South Asian alleles in gnomAD v2.1.1, which is a high enough frequency apply BS1_Supporting. Additionally it was present in 2.1% (27/910 CI 95%) of Amish alleles in gnomAD v3.1 (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for Pendred syndrome outweighs the high allele frequency of the variant in population databases. Therefore, neither BS1_Supporting nor BA1 will contribute to the overall classification. A functional study demonstrates that the p.Phe335Leu variant may impact protein function (PS3_Supporting; PMID: 19204907). Finally, the REVEL computational prediction analysis tool produced a score of 0.828, which is above the threshold necessary to apply PP3. In summary, this variant has been classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PS3_Supporting, PP1, PP3, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA253316/MONDO:0010134/005 2020-08-19 2023-02-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:681850 biolink:causes UMLS:C1112773 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1112773 infores:hetionet CAID:CA891842383 biolink:causes MONDO:0011071 infores:clingen CAID:CA891842383 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP4, BP3, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.777dup (p.Asn260Ter) is a nonsense variant that leads to a loss of function. This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA891842383/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50173 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0015230 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0036454 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009759 infores:hetionet CHEBI:85083 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0002170 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151705 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0004610 infores:hetionet CHEBI:27470 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0006266 infores:hetionet CHEBI:51141 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0020458 infores:hetionet CHEBI:10127 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0035410 infores:hetionet CHEBI:29688 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C2364111 infores:hetionet CHEBI:9667 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0043144 infores:hetionet CHEBI:10125 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0242301 infores:hetionet CHEBI:168396 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019572 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0687707 infores:hetionet CHEBI:63717 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0030193 infores:hetionet GO:0002905 biolink:causes GO:0001782 infores:ubergraph knowledge_assertion manual_agent GO:0002905 GO:0001782 CHEBI:40279 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151578 infores:hetionet CHEBI:9586 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085632 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004238 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0027441 infores:hetionet CHEBI:85083 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0003467 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0314719 infores:hetionet CHEBI:10125 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013604 infores:hetionet CHEBI:85078 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0026946 infores:hetionet CHEBI:44032 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0021368 infores:hetionet CHEBI:6121 biolink:causes UMLS:C0857332 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0857332 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009938 infores:hetionet CHEBI:4551 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0011206 infores:hetionet CHEBI:6633 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C2939465 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0002871 infores:hetionet CHEBI:17263 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0042963 infores:hetionet CHEBI:10650 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085624 infores:hetionet CHEBI:63619 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0264906 infores:hetionet CHEBI:63584 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0085649 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0333641 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0021843 infores:hetionet CHEBI:51041 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042029 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0033975 infores:hetionet CHEBI:15544 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0003578 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0740401 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0740401 infores:hetionet CHEBI:60761 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0023530 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0518015 infores:hetionet CHEBI:3207 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0085633 infores:hetionet CHEBI:42797 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C3489393 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0003123 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002334 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0376545 infores:hetionet CHEBI:64310 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151205 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019372 infores:hetionet GO:0061295 biolink:causes GO:0061228 infores:ubergraph knowledge_assertion manual_agent GO:0061295 GO:0061228 CHEBI:6954 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1306341 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0497247 infores:hetionet CHEBI:6904 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0037317 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0549430 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0549430 infores:hetionet CHEBI:8481 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C2830004 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0005779 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0000833 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0242350 infores:hetionet CHEBI:31397 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0003862 infores:hetionet CHEBI:10110 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0009676 infores:hetionet CHEBI:7443 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002792 infores:hetionet CHEBI:42797 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0428977 infores:hetionet CHEBI:49662 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0012569 infores:hetionet CHEBI:194135 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013491 infores:hetionet CAID:CA16020736 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020736 MONDO:0009861 PMID:25003100PMID:25003100 Uncertain Significance PM3, PM2, PP4 PP3 The c.176A>T (p.Asp59Val) variant in PAH has been reported in an Italian patient with mild PKU (BH4 deficiency not totally excluded) with pathogenic variant p.R261Q (PP4, PM3; PMID: 25003100) This variant is absent from 1000G, ESP, ExAC and gnomAD. computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020736/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31709 biolink:causes MONDO:0010138 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0040156 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0003123 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022568 infores:hetionet CHEBI:50131 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020621 infores:hetionet CHEBI:17347 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0039231 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000723 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0038506 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0027765 infores:hetionet CHEBI:480999 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0575081 infores:hetionet CAID:CA409108073 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108073 MONDO:0015967 PMID: Likely Pathogenic PP3, PM2_Supporting, PM5_Strong PP4, PP1, PM1, BP4, BA1, PS4, BS1 The c.869G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to proline at codon 290 (p.(Arg290Pro)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). Two other missense variants, c.868C>T p.Arg290Cys and c.869G>A p.Arg290His, have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.869G>C meets the criteria to be classified as Likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108073/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4779 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0314719 infores:hetionet CHEBI:63635 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0085612 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0919980 infores:hetionet CHEBI:2704 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151904 infores:hetionet CHEBI:520985 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0041834 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0023067 infores:hetionet CAID:CA10014502 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014502 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.496C>A (p.Arg166=) is a synonymous variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.6 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). Synonymous variant therefore no REVEL score and SpliceAI is ≤ 0.20 (0.14) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014502/MONDO:0100083/008 2022-08-23 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0025323 infores:hetionet CHEBI:8707 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0542571 infores:hetionet CAID:CA802050870 biolink:causes MONDO:0021056 infores:clingen CAID:CA802050870 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting BS2, PP3 "The NM_000038.6(APC):c.136-4A>G variant in APC is an intronic variant which is localized in intron 2. The variant has been reported in 1 individual without a colorectal cancer/polyposis associated phenotype not meeting criteria for BS2 (BS2 not met; internal data Labcorp Genetics (formerly Invitae)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by creating a new acceptor splice site of intron 2 of APC, possibly adding one amino acid (Gln) to exon 3. However, the native acceptor splice site seems not to be affected and the predicted addition of one amino acid would not result in a ""deleterious effect"" (PP3 not met). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023)." InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA802050870/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17474 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042963 infores:hetionet CHEBI:100246 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0035078 infores:hetionet CHEBI:71219 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0030193 infores:hetionet GO:0034094 biolink:causes GO:0051177 infores:ubergraph knowledge_assertion manual_agent GO:0034094 GO:0051177 CAID:CA16608977 biolink:causes MONDO:0010938 infores:clingen CAID:CA16608977 MONDO:0010938 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PP4 BS3, PS3, PM1, BS2 "The c.349C>T (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Arginine by Cysteine at amino acid 117 (p.Arg117Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001755 (1/5698 alleles) in the ""Other"" population; this frequency will not be considered here as the ""Other"" population is characterized on gnomAD as a bottleneck population. The second highest MAF is 0.00003543 (1/28224 alleles) in the South Asia population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, meeting this criterion (PM2_Supporting).No homozygotes have been observed in gnomAD (BS2 is not met).This variant has been described in at least two patients in the literature (PMIDs: 32215810 and 23069490). At least one patient with this variant displayed: *Diagnostic criteria for Leaky SCID 0.5 pts + *Reduced or constitutive cytokine-induced JAK3 tyrosine phosphorylation in patient cells 1 pt + *T-B+NK- lymphocyte subset profile not applied because only IL7R was sequenced, so we can not rule out alternative cause. Total is 1.5 points, PP4_Supporting (PMID: 23069490). The patient is homozygous for this variant (0.5 pts, PM3_Supporting, PMID: 23069490)In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM3_Supporting, and PP4_Supporting (VCEP specifications version 1.0)." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608977/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:27834 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020458 infores:hetionet CHEBI:34829 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0020517 infores:hetionet GO:2000592 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000592 GO:0072001 CHEBI:6741 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0037763 infores:hetionet CHEBI:47499 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0429097 infores:hetionet CHEBI:8455 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0021053 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0036572 infores:hetionet CHEBI:94440 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0232462 infores:hetionet CHEBI:6904 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0009421 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0012833 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0002622 infores:hetionet CHEBI:9123 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0558489 infores:hetionet NCBIGene:26011 biolink:causes MONDO:0014756 infores:monarchinitiative not_provided not_provided HGNC:29945 MONDO:0014756 uuid:540d555f-2e1c-4589-b3e8-a3a43e0db207 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0178415 infores:hetionet CHEBI:3504 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0024312 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0032584 infores:hetionet CHEBI:30830 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0026826 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0037199 infores:hetionet CHEBI:18248 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0034063 infores:hetionet CHEBI:68579 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0041969 infores:hetionet CHEBI:35778 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085641 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1306341 infores:hetionet CHEBI:4672 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0547030 infores:hetionet CAID:CA386969831 biolink:causes MONDO:0015967 infores:clingen CAID:CA386969831 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3, PP4 PS4, PM5, PP1 The c.1295C>T variant in the HNF1 homeobox A] gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 432 (p.(Ser432Phe)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.892, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Two other missense variants, c.1295C>G p.Ser432Cys and c.1295C>A p.Ser432Ter, have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.1295C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 1/11/2023): PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386969831/MONDO:0015967/017 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68554 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0042963 infores:hetionet CHEBI:65346 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0042963 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0021053 infores:hetionet CHEBI:63589 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0233407 infores:hetionet CAID:CA1244262 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244262 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PVS1, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.526del variant in MYOC is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 2 of the frameshift, or amino acid 178 (p.Glu176ArgfsTer2). Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with primary open angle glaucoma is not loss-of-function. The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00003051 (36 alleles out of 1,180,028), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (Souzeau et al, pers. comm.), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244262/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0036690 infores:hetionet NCBIGene:10002 biolink:causes MONDO:0100288 infores:monarchinitiative not_provided not_provided HGNC:7974 MONDO:0100288 uuid:138060bc-8edc-4ef6-9fb6-b6d876db2e89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0687133 infores:hetionet UMLS:C0657912 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0600142 infores:hetionet CHEBI:51364 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0311468 infores:hetionet CAID:CA386493486 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493486 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.994G>A (p.Gly332Arg) variant in PAH is a missense variant predicted to cause substitution of glycine by arginine at amino acid 332. It has been detected in 2 patients with PAH deficiency; one with pathogenic variant c.1162G>A, phase unconfirmed (PMID: 29749107) and the other with pathogenic variant deletion of exon 5 in the PAH gene, phase unconfirmed (PMID: 23942198). This variant has extremely low frequency in gnomAD (MAF=0.00006) in the European (Non-Finnish) population. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PM3, PP3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493486/MONDO:0009861/006 2023-04-01 2023-04-01 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:7040 biolink:causes MONDO:0032601 infores:monarchinitiative not_provided not_provided HGNC:11766 MONDO:0032601 uuid:c9507b97-019e-4b93-b22f-7a11dbb637fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C1456784 infores:hetionet CHEBI:5778 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0017152 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0700184 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0041969 infores:hetionet CHEBI:87681 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0595916 infores:hetionet CHEBI:4325 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0033687 infores:hetionet GO:0061178 biolink:causes GO:0071333 infores:ubergraph knowledge_assertion manual_agent GO:0061178 GO:0071333 CHEBI:50841 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0011168 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151828 infores:hetionet CHEBI:27834 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0014038 infores:hetionet CHEBI:8232 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0038362 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0234215 infores:hetionet CHEBI:64355 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030196 infores:hetionet CHEBI:41879 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0232461 infores:hetionet CHEBI:17026 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0311394 infores:hetionet CHEBI:7956 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0011991 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0018021 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0035455 infores:hetionet CHEBI:16796 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0344315 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0853011 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0853011 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0008035 infores:hetionet CHEBI:6822 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0013144 infores:hetionet CHEBI:3732 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0021051 infores:hetionet CHEBI:39585 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0851578 infores:hetionet NCBIGene:287 biolink:causes MONDO:0010958 infores:monarchinitiative not_provided not_provided HGNC:493 MONDO:0010958 uuid:59e3c9bf-afc0-40f0-b6b4-6b2ab8b2c671 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0004936 infores:hetionet CHEBI:3207 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0344232 infores:hetionet CHEBI:6970 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0041582 infores:hetionet CHEBI:37924 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027424 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020649 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0007642 infores:hetionet CHEBI:10127 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151889 infores:hetionet CHEBI:63619 biolink:causes NCIT:C61050 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0853711 infores:hetionet CHEBI:3082 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0232462 infores:hetionet GO:1904913 biolink:causes GO:0033036 infores:ubergraph knowledge_assertion manual_agent GO:1904913 GO:0033036 CHEBI:3242 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0030552 infores:hetionet CAID:CA969129783 biolink:causes MONDO:0015152 infores:clingen CAID:CA969129783 MONDO:0015152 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000070.3: c.1865_1866del p.(Glu622GlyfsTer9) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in exon 16/24, leading to nonsense-mediated decay in a gene in which loss of function is a known disease mechanism (PVS1). This variant has been reported in at least four individuals with features consistent with LGMD (PMID: 16141003, 16650086, 10330340; LOVD CAPN3_000103), including in unconfirmed phase with a pathogenic variant in one patient (c.1250C>T p.(Thr417Met), 0.5 pts, PMID: 1665008, LOVD Individual #00214386) (PM3_Supporting). It has also been classified as Likely Pathogenic/Pathogenic by multiple submitters in ClinVar (VCV000935255.33). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed severely reduced calpain-3 expression in skeletal muscle as well as progressive limb girdle muscle weakness, which is specific for CAPN3-related LGMD (PMID: 16650086, LOVD Individual #00214386; PP4_Moderate). The filtering allele frequency for this variant is 0.000007 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval of 3/1111832 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/19/2025): PVS1, PM3_Supporting, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA969129783/MONDO:0015152/187 2025-08-19 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports GO:0052078 biolink:causes GO:0140426 infores:ubergraph knowledge_assertion manual_agent GO:0052078 GO:0140426 CHEBI:9137 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011334 infores:hetionet CHEBI:68478 biolink:causes HP:0000869 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0232940 infores:hetionet NCBIGene:5255 biolink:causes MONDO:0010362 infores:monarchinitiative not_provided not_provided HGNC:8925 MONDO:0010362 uuid:c9926ccb-acd4-4e81-91bc-9946b968acf9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011124 infores:hetionet CHEBI:35553 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0006625 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0027765 infores:hetionet CHEBI:4653 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C2830004 infores:hetionet CHEBI:3242 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0041834 infores:hetionet CHEBI:63589 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0006145 infores:hetionet CAID:CA6748732 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748732 MONDO:0009861 PMID:30747360PMID:30459323PMID:26322415PMID:26503515PMID:24401910PMID:31445982PMID:30050108PMID:29316886 Pathogenic PP4_Moderate, PP3, PM3_Very Strong PM2 This c.1174T>A (p.F392I) variant was documented 19 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515, 30459323, 26322415, 30747360). This variant was detected in at least 8 mild hyperphenylalaninemia (MHP) patients and 1 classical PKU patient with a pathogenic variant in trans (PMID: 24401910, 29316886, 30050108, 31445982). This missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease causing (MutationTaster). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM3_very strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748732/MONDO:0009861/006 2019-10-17 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:55164 biolink:causes MONDO:0030958 infores:monarchinitiative not_provided not_provided HGNC:25543 MONDO:0030958 uuid:8c219eff-c7ff-4651-9314-097409379566 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101853 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0041969 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0038454 infores:hetionet CHEBI:6888 biolink:causes MONDO:0009050 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0221406 infores:hetionet CHEBI:8028 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0037763 infores:hetionet CHEBI:6375 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042029 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0542571 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0027813 infores:hetionet CAID:CA6831699 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831699 MONDO:0015967 PMID: Likely Benign BS1, PP3 PM1, PM2, PP4, BS2 The c.257T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to histidine at codon 86 (p.(Leu86His)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8209, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant has a Grpmax Filtering allele frequency in gnomAD 4.1.0 of 0.00005798, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, therefore, PP4 does not apply. While this variant was identified in normoglycemic individuals, none were over the age of 70, so BS2 does not apply. In summary, c.257T>A meets the criteria to be classified as likely benign for monogenic diabetes (posterior probability 0.012). ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP3, BS1 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831699/MONDO:0015967/017 2025-10-28 2025-10-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63681 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0547030 infores:hetionet CHEBI:64355 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0278061 infores:hetionet CHEBI:6073 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0018418 infores:hetionet CHEBI:63681 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0009676 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014544 infores:hetionet CHEBI:64198 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0152227 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0009450 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0151773 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1112341 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1112341 infores:hetionet CHEBI:50742 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0007222 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0001883 infores:hetionet CHEBI:36704 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C2242996 infores:hetionet CHEBI:38545 biolink:causes UMLS:C0281913 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0281913 infores:hetionet CAID:CA1139532533 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139532533 MONDO:0009861 PMID:28982351 Uncertain Significance PM3, PM2, PP4, BP7 This c.912+16T>A (aka IVS8+16T>A) variant in PAH was reported in one patient with mild/moderate PKU, observed in trans with pathogenic variant p.Arg111*. BH4 cofactor deficiency was ruled out, but only urinary pterin analysis was mentioned as a method of exclusion (PMID: 28982351). This intronic variant in absent from controls in population databases. Splicing prediction algorithms predict this variant to be benign. In summary, this variant meets criteria to be classified as Uncertain Significance. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PM3, and BP7. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532533/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8207 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151936 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0037822 infores:hetionet CHEBI:63618 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0018681 infores:hetionet CAID:CA5949991 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949991 MONDO:0000572 PMID: Likely Benign BS1 NM_000448.3(RAG1):c.486T>A is a missense variant predicted to cause substitution of Aspartic Acid by Glutamic Acid at amino acid 162 (p.Asp162Glu). The filtering allele frequency (the upper threshold of the 95% CI of 113/44866 of the c.486T>A variant in RAG1 is 0.002166 for East Asian population, which is higher than the ClinGen SCID VCEP threshold (>0.001951) for BS1, and therefore meets this criterion (BS1). There are no publications for this variant in the literature. As per SCID VCEP specifications 1 Strong criteria is enough to reach Likely Benign classification. In summary, this variant meets the criteria to be classified as Likely Benign variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949991/MONDO:0000572/123 2024-02-07 2024-02-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:114785 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0442874 infores:hetionet CHEBI:8346 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0522055 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0040053 infores:hetionet CHEBI:9570 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0024236 infores:hetionet CHEBI:4466 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0852911 infores:hetionet CAID:CA410677562 biolink:causes MONDO:0009276 infores:clingen CAID:CA410677562 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting PP3, PP4 The c.462G>C (p.Gln154His) variant in GP1BB is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 154 (p.Gln154His). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).At least one BSS patient (BS-9 from PMID: 21699652) is reported in the literature. This patient was not scored because they are reported to be homozygous for the c.462G>C (p.Gln154His) variant in GP1BB, homozygous c.470T>C (p.Leu157Pro) in GP1BB and heterozygous for c.1522T>C (p.Tyr508His) in GP1BA. In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2; date of approval xx/xx/xxxx). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410677562/MONDO:0009276/082 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8802 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0853034 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009946 infores:hetionet CHEBI:15854 biolink:causes HP:0001133 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0235095 infores:hetionet CHEBI:135925 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0338614 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0020649 infores:hetionet CAID:CA343719729 biolink:causes MONDO:0005338 infores:clingen CAID:CA343719729 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS2, PS3, PS1, BA1 The c.116A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 39 (p.Lys39Arg). The highest minor allele frequency of this variant was in the European (non-Finnish)) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008474 (1 allele out of 1,180,044), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.087, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 2 segregations had been reported for primary open angle glaucoma (POAG) (PMID: 23922489), not meeting the ≥ 3 segregations required for PP1. Only 1 proband with POAG had been reported (PMID: 23922489), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343719729/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0032584 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019348 infores:hetionet CHEBI:9086 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1458155 infores:hetionet CHEBI:6797 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0027497 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0036130 infores:hetionet CHEBI:8863 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013428 infores:hetionet CHEBI:17141 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0033845 infores:hetionet CHEBI:42797 biolink:causes HP:0034788 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0232267 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0037199 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151734 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027932 infores:hetionet CAID:CA018611 biolink:causes MONDO:0005835 infores:clingen CAID:CA018611 MONDO:0005835 PMID: Likely Benign BP4, BP7, BS1 BP5 The MSH2 c.1563T>C variant is a synonymous variant, p.(Tyr521=). It is present in GnomAD v2.1.1 (non-cancer dataset) and gnomAD v4.1 within the Maximum Credible Allele Frequency (MCAF) cutoff 0.0001-0.001 (0.01-0.1%). It is not predicted to affect splicing according to predictions from http://priors.hci.utah.edu/PRIORS and SpliceAI. Therefore, this variant is classified as likely benign. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA018611/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8774 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0015967 infores:hetionet CHEBI:3441 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0001925 infores:hetionet NCBIGene:80821 biolink:causes MONDO:0012256 infores:monarchinitiative not_provided not_provided HGNC:19714 MONDO:0012256 uuid:ebe543c7-371e-415b-be87-24d4555419cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0018802 infores:hetionet CHEBI:68478 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0022603 infores:hetionet CHEBI:31859 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151908 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0019112 infores:hetionet NCBIGene:3858 biolink:causes MONDO:0100303 infores:monarchinitiative not_provided not_provided HGNC:6413 MONDO:0100303 uuid:58b9e08f-8e1c-409b-a846-f4c9403e557d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0149745 infores:hetionet CHEBI:8364 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0917801 infores:hetionet CHEBI:3561 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0040128 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0085633 infores:hetionet CHEBI:194135 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002962 infores:hetionet CHEBI:3387 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0012569 infores:hetionet CHEBI:7466 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0002453 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0236051 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0149931 infores:hetionet CHEBI:3757 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1325847 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0858833 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0858833 infores:hetionet NCBITaxon:2 biolink:causes HP:0030049 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D001922 DB00916_MESH_D001922_1 CHEBI:45081 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0877359 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0041948 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0019158 infores:hetionet CHEBI:48273 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0085593 infores:hetionet CHEBI:9328 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0232462 infores:hetionet CHEBI:9137 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0030554 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0036572 infores:hetionet GO:0051394 biolink:causes GO:0038180 infores:ubergraph knowledge_assertion manual_agent GO:0051394 GO:0038180 CHEBI:27777 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0018681 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0178298 infores:hetionet CHEBI:42797 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233407 infores:hetionet CHEBI:64355 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0008031 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018802 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0149931 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020538 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0521616 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0521616 infores:hetionet CHEBI:63717 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0016655 infores:hetionet CHEBI:51230 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0005747 infores:hetionet CAID:CA645294022 biolink:causes MONDO:0015924 infores:clingen CAID:CA645294022 MONDO:0015924 PMID: Pathogenic PM2, PVS1, PS1, PS4 BA1, BS1 The BMPR2 c.418+5G>A variant is a non-canonical splice site (+5) variant located in intron 3. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in four individuals with PAH from the UK, US, or France (PMID: 16429395; the same individuals also included in PMID: 29650961, 29631995, or 18503968) and one individual from Germany (PMID: 21801371) (PS4). In silico prediction indicated likely splice site donor loss (SpliceAI = 0.59) and cDNA analysis demonstrated an inframe deletion, p.Cys84_Ser140del, with loss of 47/99 amino acid residues of the conserved extracellular domain (PMID: 19555857 and 26387786) (PVS1 (RNA)). The variant occurs in the same splice region, and has the same molecular consequence, as an alternate variant classified as pathogenic by the PH VCEP (c.418+3A>T) (PS1). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1(RNA), PS1, PS4, PM2_supporting (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645294022/MONDO:0015924/125 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes UMLS:C0037578 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037578 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0006668 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D003234 DB00684_MESH_D003234_1DB00798_MESH_D003234_1DB02703_MESH_D003234_1DB15566_MESH_D003234_1DB00595_MESH_D003234_1DB06771_MESH_D003234_1DB01044_MESH_D003234_1DB00027_MESH_D003234_1 CHEBI:6076 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0017152 infores:hetionet CHEBI:9720 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0152198 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0497247 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0235416 infores:hetionet CHEBI:4710 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0018932 infores:hetionet CHEBI:119915 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013491 infores:hetionet CHEBI:4858 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0042023 infores:hetionet CHEBI:31980 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0023518 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0027051 infores:hetionet CHEBI:28901 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0003962 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0428895 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0428895 infores:hetionet CAID:CA10587358 biolink:causes MONDO:0011071 infores:clingen CAID:CA10587358 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BA1, BP3, BP1, BP2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PP4, PP2, PP3, PP1, BS2 The c.1275G>A (p.Pro425=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -1.62676 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The variant also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587358/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9123 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235807 infores:hetionet CAID:CA10606721 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606721 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.4408C>T p.(Gln1470Ter) variant in DYSF, which is also known as NM_001130987.2: c.4462C>T p.(Gln1488Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 40/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in two individuals with either suspected or diagnosed LGMD (PMID: 27602406, 33610434, 36983702) in unknown phase with a pathogenic variant (NM_003494.4: c.1517C>G p.(Ser506Ter), 0.5 pts; NM_003494.4: c.6124C>T p.(Arg2042Cys), 0.5 pts) (PM3). Both individuals had absent dysferlin protein expression as well as progressive muscle weakness or clinical diagnosis of LGMD, which is highly specific for DYSF-related LGMD (PMID: 33610434, 36983702; PP4_Strong). The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.00002230 (1/44840 East Asian chromosomes), which is less than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/06/2025): PVS1, PM3, PM2_Supporting, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606721/MONDO:0015152/180 2025-10-06 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10119 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0004134 infores:hetionet CHEBI:50730 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0035455 infores:hetionet CHEBI:64321 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020458 infores:hetionet CHEBI:8080 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0017178 infores:hetionet CHEBI:50922 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0853034 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0242350 infores:hetionet CAID:CA120601 biolink:causes MONDO:0044970 infores:clingen CAID:CA120601 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Moderate, PM6 PP3 The m.9952G>A (p.W249Term) variant in MT-CO3 has been reported in one individual with mitochondrial disease to date, in a 36-year-old woman with encephalopathy, myopathy, exercise-induced myalgia, muscle weakness, and migraines, with onset of symptoms at age 17 years (PMID: 9634511). Muscle biopsy showed reduced COX activity and decreased complex IV activity. The variant was present at 57% heteroplasmy in muscle and was undetectable in blood and skin. The variant was absent in muscle from her mother (PM6; PMID: 9634511). This variant causes a premature stop in the MT-CO3 gene resulting in truncation of 5% of the protein (PVS1_moderate). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in COX negative fibers (56.2%, n=24) than in COX positive fibers (10.1%, n=21), p<0.0002 (PS3_supporting, PMID: 9634511). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6, PVS1_moderate, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120601/MONDO:0044970/015 2024-02-26 2025-06-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:5134 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0149931 infores:hetionet NCBIGene:56652 biolink:causes MONDO:0014504 infores:monarchinitiative not_provided not_provided HGNC:1160 MONDO:0014504 uuid:0cd1ad2c-0d4a-4bf1-926f-134ab6249e05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0006781 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0079487 infores:hetionet CHEBI:6339 biolink:causes HP:0020059 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0427458 infores:hetionet CHEBI:27974 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0014742 infores:hetionet CHEBI:100241 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0033774 infores:hetionet CAID:CA386960865 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960865 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PS4, PP1_Strong The c.526+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1. This variant was identified in 12 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 21242637, internal lab contributors), including an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate, internal lab contributor). This variant segregated with diabetes, with six informative meioses in five families with MODY (PP1_Strong, internal lab collaborators). In summary, c.526+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960865/MONDO:0015967/085 2023-12-02 2023-12-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:167638 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0030554 infores:hetionet CHEBI:36791 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020555 infores:hetionet CHEBI:77733 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0042023 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0427055 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020557 infores:hetionet CHEBI:63637 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0042164 infores:hetionet CHEBI:9288 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0162283 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0002871 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018021 infores:hetionet NCBIGene:6657 biolink:causes MONDO:0008799 infores:monarchinitiative not_provided not_provided HGNC:11195 MONDO:0008799 uuid:91774264-ef7c-4951-8fd3-98ac8bb1ee7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C3263723 infores:hetionet CHEBI:2611 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0002994 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0750016 infores:hetionet CHEBI:36795 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0027066 infores:hetionet CHEBI:4551 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0151517 infores:hetionet CHEBI:9738 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2584688 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0178298 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0011570 infores:hetionet CAID:CA160099 biolink:causes MONDO:0012163 infores:clingen CAID:CA160099 MONDO:0012163 PMID: Pathogenic PP4, PM3_Very Strong, PM2_Supporting PP1, PM5, BS3, PS1, PS3, PS2, PM6 The c.662G>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 221 (p.Ser221Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PMID 17201233: Twin B was diagnosed with SCID and was homozygous for this variant. A fraternal twin A with SCID was also reported, but the genotype of this twin was not reported.PMID 18641513: Three individuals were diagnosed with SCID and were homozygous for this variant.This variant has been detected in 7 individuals with SCID. Four individuals were homozygous for the variant (1pt maximum, PMIDs 17201233, 18641513). Two individuals recorded in the Invitae internal database were heterozygous for this variant and a c.83-2A>T variant. The c.83-2A>T variant is classified as pathogenic following the SCID-VCEP specification. The trans phase was confirmed in one patient but not the other (1.5pt in total). One individual, also from Invitae internal database, was heterozygous for this variant and a c.707-2A>G variant. The c.707-2A>G variant is classified as a pathogenic variant following the SCID-VCEP specification. The trans phase was not confirmed in this patient (0.5pt). 4pt in total, PM3_very strong is met.The individual with this variant and c.707-2A>G variant showed a T-B+NK+ lymphocyte profile, and abnormal newborn TREC result, and a diagnosis of SCID. A comprehensive SCID and CID panel did not identify an alternative cause of the disease. 1.25pt for PP4 and PP4 is met (PP4). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Very strong, PP4. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160099/MONDO:0012163/119 2024-01-23 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0085610 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0022650 infores:hetionet CHEBI:63632 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0030554 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2973529 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0877046 infores:hetionet NCBIGene:3423 biolink:causes MONDO:0010674 infores:monarchinitiative not_provided not_provided HGNC:5389 MONDO:0010674 uuid:94fe94ee-dcb9-4183-97b2-5076626c7726 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0021353 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042138 infores:hetionet NCBIGene:113189 biolink:causes MONDO:0020681 infores:monarchinitiative not_provided not_provided HGNC:24464 MONDO:0020681 uuid:e8ce8773-9ff7-48ce-a336-3ac5457811e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6635 biolink:causes MONDO:0014027 infores:monarchinitiative not_provided not_provided HGNC:11161 MONDO:0014027 uuid:a6765871-799b-4da7-b244-f3dcb50e6b26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0010200 infores:hetionet CHEBI:83527 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0011124 infores:hetionet UMLS:C1738934 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030196 infores:hetionet CHEBI:8764 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042023 infores:hetionet CHEBI:6129 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0033774 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0919980 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0085620 infores:hetionet CHEBI:3175 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0917801 infores:hetionet CHEBI:64355 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0852911 infores:hetionet CHEBI:8356 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013384 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020542 infores:hetionet CHEBI:3504 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0010200 infores:hetionet CHEBI:48947 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0015230 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0036572 infores:hetionet CHEBI:61049 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0028734 infores:hetionet CHEBI:7936 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025874 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0855242 infores:hetionet CAID:CA170464 biolink:causes MONDO:0100039 infores:clingen CAID:CA170464 MONDO:0100039 PMID: Uncertain Significance PP3, PM2_Supporting The p.Leu67Phe variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu67Phe variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Leu67Phe variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PP3). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170464/MONDO:0100039/034 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Inconclusive true UNII:VL0L558GCB biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151699 infores:hetionet CHEBI:4907 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0221201 infores:hetionet CHEBI:31643 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0003467 infores:hetionet CHEBI:36795 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0032617 infores:hetionet CHEBI:9588 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0022354 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0037274 infores:hetionet CHEBI:50924 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C2939186 infores:hetionet NCBIGene:84522 biolink:causes MONDO:0014456 infores:monarchinitiative not_provided not_provided HGNC:26926 MONDO:0014456 uuid:83239de9-2f5b-4f34-9163-67155a3b5d4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0267033 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0267033 infores:hetionet CHEBI:27779 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0006849 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0022660 infores:hetionet CAID:CA118658 biolink:causes MONDO:0018947 infores:clingen CAID:CA118658 MONDO:0018947 PMID: Pathogenic PS4, PP1_Strong, PM5, PS3_Supporting, PM6, PP2, PM2_Supporting BP4, PP3 The c.1105C>T variant in DNM2 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 369 (p.Arg369Trp). The highest population minor allele frequency in gnomAD v4.1 is 0.00001335 (1/74912 alleles) in the African/African American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.683, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. This variant has been reported in at least 11 probands from 6 families meeting phenotypic criteria distal muscular weakness and ptosis, which is highly specific for centronuclear myopathy (PS4; PMIDs: 16227997, 20817456, 22613877, 25492887, 25501959, 28676641). The variant has been reported to segregate with centronuclear myopathy in 5 affected family members from 2 families (PP1_Strong; PMIDs: 16227997, 22613877). Two different missense variants (c.1106G>T, p.Arg369Leu; p.Arg369Gln, c.1106G>A) in the same codon have been classified as likely pathogenic and pathogenic, respectively, for autosomal dominant centronuclear myopathy by the ClinGen Congenital Myopathies VCEP (and autosomal dominant Charcot-Marie-Tooth disease by the ClinGen Charcot-Marie-Tooth disease VCEP) (PM5). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with centronuclear myopathy (PM6; PMIDs: 16227997). A cell culture of human myoblasts from quadriceps showed impaired actin development, indicating that this variant impacts protein function (PMID: 28676641; PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PP1_Strong, PM5, PM6, PM2_Supporting, PP2, PS3_Supporting. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/24) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA118658/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49960 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0041912 infores:hetionet CHEBI:4356 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0010038 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0022660 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0267792 infores:hetionet CHEBI:4856 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0541782 infores:hetionet CHEBI:7577 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013378 infores:hetionet CHEBI:39867 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0424295 infores:hetionet CHEBI:6121 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0012569 infores:hetionet CHEBI:135930 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151905 infores:hetionet CHEBI:9927 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0009782 infores:hetionet CAID:CA340744821 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744821 MONDO:0100368 PMID: Pathogenic PM1, PM3, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting PM5 The NM_000329.3(RPE65):c.938A>G (p.His313Arg) variant is a missense substitution at His313, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281).The computational predictor REVEL gives a score of 0.964 which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 24849605). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 points), absent ERG (0.5 points), nystagmus (0.5 points) and decreased visual acuity (1 point). This patient showed significant improvement in several measures of dark-adapted vision after gene therapy treatment (8 points). Together these are highly specific for RPE65-related recessive retinopathy (10.5 points, PMID: 19854499, PP4_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 35129589). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.292_311del(p.Ile98Hisfs*26) variant suspected in trans (0.5 points) and at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Tyr386 variant suspected in trans (0.5 points) (PMID: 35129589), which were both previously classified pathogenic by the ClinGen LCA/eoRD VCEP. (1.5 total points, PM3).This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.000002280, with 4 alleles/418086 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3_Moderate, PP4_Moderate, PM1, PM3, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744821/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0007222 infores:hetionet CHEBI:7936 biolink:causes HP:0000868 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151639 infores:hetionet CHEBI:41977 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0014868 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0027813 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0392162 infores:hetionet CHEBI:4702 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0010037 infores:hetionet CHEBI:31643 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0423791 infores:hetionet CHEBI:5864 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C3160858 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004623 infores:hetionet CHEBI:5118 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006625 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0013144 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1393815 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1393815 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0003864 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0017178 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0040479 infores:hetionet CHEBI:119486 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0040822 infores:hetionet CHEBI:83531 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0428977 infores:hetionet CAID:CA1251226 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251226 MONDO:0013144 PMID: Likely Benign BP7, BP4 BS1, PM2 The c.1254C>T (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Thr418=). SpliceAI predicts no splicing impact for this variant meeting BP4. The variant is not predicted to cause a splicing impact and the nucleotide is weakly/moderately conserved with a PhyloP score of -1.569 and a PhastCons score of 0.013 meeting BP7 criteria (PhyloP < 0.1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4, BP7. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251226/MONDO:0013144/084 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:59445 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0027497 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038663 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0039621 infores:hetionet CHEBI:2611 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0039231 infores:hetionet CHEBI:4907 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0030312 infores:hetionet CHEBI:6129 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0231218 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0040046 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0855704 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0233472 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0013395 infores:hetionet CHEBI:2948 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0002874 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0037763 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0007787 infores:hetionet CHEBI:71940 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C2830004 infores:hetionet CHEBI:5959 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0034933 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0162429 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0006145 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0853619 infores:hetionet CHEBI:77260 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0019521 infores:hetionet NCBIGene:10002 biolink:causes MONDO:0012625 infores:monarchinitiative not_provided not_provided HGNC:7974 MONDO:0012625 uuid:d6e57d2c-fdc3-4e1b-be96-c8772feb55ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7444 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0038990 infores:hetionet CAID:CA658655953 biolink:causes MONDO:0021056 infores:clingen CAID:CA658655953 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The c.4778del p.(Lys1593Serfs*57) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, Internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655953/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9637 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0012833 infores:hetionet CHEBI:7478 biolink:causes MONDO:0021360 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0030521 infores:hetionet CHEBI:5778 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020625 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0232492 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0234215 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002968 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0024248 infores:hetionet NCBIGene:27089 biolink:causes MONDO:0014065 infores:monarchinitiative not_provided not_provided HGNC:29594 MONDO:0014065 uuid:e99d2d22-0f9e-45ae-b0cd-d6dc1d59884a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0002965 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0033777 infores:hetionet CHEBI:53760 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020903 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0017574 infores:hetionet CAID:CA120427 biolink:causes MONDO:0015152 infores:clingen CAID:CA120427 MONDO:0015152 PMID: Pathogenic PP1_Strong, PM3_Strong, PS3_Supporting, PP3, PP4 PM5, PM4, PM1, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2 The NM_000023.4: c.229C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 77 (p.Arg77Cys). This variant has been detected in at least 12 individuals with symptoms of limb girdle muscular dystrophy. Of those individuals, two were confirmed compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.850C>T, 2 pts, PMID: 12566530, LOVD Individual #0000223892), and at least two were homozygous for the variant (1 pt, PMID: 12566530, 23989969, 7663524, 37628638) (PM3_Strong). The variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in 10 affected family members from five families (PP1_Strong; LOVD Individual #0000223892, PMID: 12566530, 7663524). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PMID: 7663524; PP4) (capped with PP1_Strong). The filtering allele frequency of this variant is 0.0004392 (the lower threshold of the 95% CI of 62/112872 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is lower than the ClinGen LGMD VCEP threshold (>0.0009) for BS1 (BS1, PM2_Supporting not met). In vitro assays have demonstrated this variant disrupts membrane localization of the sarcoglycan protein complex (PMID: 18535179; PS3_Supporting), and the computational predictor REVEL gives a score of 0.95, which exceeds the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3_Strong, PP1_Strong, PP4, PP3, PS3_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA120427/MONDO:0015152/189 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50742 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0010200 infores:hetionet CHEBI:18332 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0030252 infores:hetionet CHEBI:3614 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0020523 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0002871 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027441 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0038362 infores:hetionet NCBIGene:3769 biolink:causes MONDO:0013613 infores:monarchinitiative not_provided not_provided HGNC:6259 MONDO:0013613 uuid:091f9fea-7065-4257-b24a-b55f77998e39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0022107 infores:hetionet CHEBI:16347 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0687713 infores:hetionet CAID:CA397724799 biolink:causes MONDO:0008723 infores:clingen CAID:CA397724799 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL);c.1294G>T(p.Glu432Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724799/MONDO:0008723/021 2023-03-27 2023-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5134 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0032285 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0919715 infores:hetionet CHEBI:17303 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0010520 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019158 infores:hetionet UMLS:C0005740 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0020453 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0006277 infores:hetionet GO:1905715 biolink:causes GO:0031424 infores:ubergraph knowledge_assertion manual_agent GO:1905715 GO:0031424 CHEBI:94385 biolink:causes MONDO:0006716 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0010072 infores:hetionet CHEBI:74947 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C2939186 infores:hetionet NCBITaxon:786 biolink:causes MONDO:0001195 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:786 MESH:D000073605 DB13092_MESH_D000073605_1DB00618_MESH_D000073605_1 CHEBI:109549 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0041912 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2242996 infores:hetionet CHEBI:5004 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0002878 infores:hetionet CHEBI:4910 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0020578 infores:hetionet CAID:CA512318911 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318911 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PVS1, PM6, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.216G>A (p.Arg72=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.43) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318911/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5118 biolink:causes UMLS:C0854381 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0854381 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027441 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0041834 infores:hetionet CHEBI:5132 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0003467 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0242350 infores:hetionet CHEBI:5134 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0271738 infores:hetionet UMLS:C0657912 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026205 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0242350 infores:hetionet CHEBI:63631 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042029 infores:hetionet CHEBI:8212 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0043352 infores:hetionet CAID:CA405670953 biolink:causes MONDO:0018493 infores:clingen CAID:CA405670953 MONDO:0018493 PMID: Likely Pathogenic PP1, PS4_Moderate, PP3_Moderate, PS1_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with leucine at codon 4234 of the RYR1 protein, p.(Val4234Leu); c.12700G>T. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 24013571, The UK (Leeds) MH Unit). This variant segregates with MHS in two families, four meioses, PP1_Supporting (PMID: 24013571). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Another variant at this same nucleotide position, resulting in the same amino acid variation has been classified as pathogenic, PS1_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS1_Moderate, PS4_Moderate, PP1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405670953/MONDO:0018493/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:45409 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0242301 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006285 infores:hetionet CHEBI:6887 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233514 infores:hetionet CHEBI:145499 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015732 infores:hetionet CHEBI:6909 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0404521 infores:hetionet CHEBI:7627 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0027497 infores:hetionet NCBIGene:199223 biolink:causes MONDO:0032744 infores:monarchinitiative not_provided not_provided HGNC:30761 MONDO:0032744 uuid:9ec69353-68de-47d9-a915-14af4125d88b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3499 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0700345 infores:hetionet CHEBI:2682 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019209 infores:hetionet CHEBI:6761 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027765 infores:hetionet CHEBI:8871 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085636 infores:hetionet CHEBI:8455 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0000737 infores:hetionet CHEBI:3219 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0851578 infores:hetionet CHEBI:17026 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C3263723 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0019158 infores:hetionet CHEBI:39867 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015967 infores:hetionet CAID:CA386965487 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965487 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 The c.712A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 238 (p.(Arg238Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.81, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). In summary, c.712A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965487/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8707 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0009806 infores:hetionet CHEBI:46195 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0393593 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0854111 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0854111 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0034882 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0017574 infores:hetionet CHEBI:7581 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0231218 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0235818 infores:hetionet CHEBI:6129 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1456784 infores:hetionet CHEBI:9667 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0018681 infores:hetionet CAID:CA10549671 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549671 MONDO:0010305 PMID: Likely Benign BS2, BP4 BS1, PM2 The NM_005629.4:c.1861C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a serine at amino acid position 621 (p.Pro621Ser). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population allele frequency is 0.00006063 (2/32985 alleles, 2 hemizygotes) in the East Asian population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. Overall across all populations, there are 2 hemizygotes in gnomAD v4.1.0. (BS2). The computational predictor REVEL gives a score of 0.168 suggesting that the variant has no impact on protein function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 373442). In summary, this variant meets criteria to be classified as likely benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549671/MONDO:0010305/027 2025-03-18 2025-03-20 X-linked inheritance HP:0001417 Contradicts true CAID:CA16620230 biolink:causes MONDO:0100488 infores:clingen CAID:CA16620230 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.105G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Glu by Asp at amino acid 35 (p.Glu35Asp). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; Ambry, GeneDx, Invitae). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP (CDH1 VCEP specifications version 3.1): PM2_Supporting, BS2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620230/MONDO:0100488/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:36791 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151998 infores:hetionet CHEBI:63631 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0005747 infores:hetionet CHEBI:9599 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0015230 infores:hetionet CAID:CA255184 biolink:causes MONDO:0010602 infores:clingen CAID:CA255184 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PP1, PS3, PS4 The c.5822A>G (p.Asn1941Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. This missense variant has a REVEL score of 0.943 (>0.6) and meets criteria for PP3. At least 80 probands have been reported in the literature and from internal laboratory data who meet the F8 phenotype criteria meeting thresholds for PS4_Very strong (>8 probands) and PP4_Moderate. Two brothers have been reported with severe hemophilia A, which meets the PP1 criteria (PMID: 15996930). Functional evidence from PMID: 21217077 shows that the variant results in a secretory defect based on barely detectable levels of antigen and activity when expressed in BHK cells, which meets PS3 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PS3, PM2_Supporting, PP1, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255184/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:10119 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020538 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0235893 infores:hetionet CAID:CA16619771 biolink:causes MONDO:0700269 infores:clingen CAID:CA16619771 MONDO:0700269 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.7787G>A variant in BRCA2 is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at amino acid 2596 (p.(Gly2596Glu)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by four calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779848, 39779857, 33293522) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.46, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.02 predicts no impact on splicing (score threshold <0.10) (PP3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619771/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75988 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0009450 infores:hetionet NCBIGene:1487 biolink:causes MONDO:0060666 infores:monarchinitiative not_provided not_provided HGNC:2494 MONDO:0060666 uuid:0fea4cf6-fdb5-4f8b-b79c-00166977a19b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000592 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000592 GO:0007275 CHEBI:92607 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0018524 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0035333 infores:hetionet CHEBI:64312 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0233471 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1263960 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1263960 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014869 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0012833 infores:hetionet NCBIGene:3913 biolink:causes MONDO:0012184 infores:monarchinitiative not_provided not_provided HGNC:6487 MONDO:0012184 uuid:7deed18b-1f76-4ff4-a622-de79d7f8742c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0036508 infores:hetionet CAID:CA6904216 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904216 MONDO:0019497 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PM6, PVS1, BP4, BP1, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The NM_004004.6:c.653G>A variant in GJB2 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 218 (p.Cys218Tyr). The highest minor allele frequency in gnomAD v.2.1.1 is 0.00178% (2/112164) of European (non-Finnish) population which is a low enough frequency to award PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.817 meeting PP3. The variant has been identified in a heterozygous state in one individual with sensorineural hearing loss (PMID: 17666888). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 8/22/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904216/MONDO:0019497/005 2023-08-22 2024-01-10 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3568 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0008350 infores:hetionet CHEBI:6904 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0006266 infores:hetionet CHEBI:144093 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0016655 infores:hetionet CHEBI:3216 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0002792 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085602 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0031350 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0340726 infores:hetionet CHEBI:51860 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0043094 infores:hetionet CAID:CA410149614 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149614 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.941C>G (p.Ser314Cys) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.265) and a spliceAI score <0.2 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149614/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45783 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0003811 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0014130 infores:hetionet CHEBI:28593 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0028961 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0032285 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0015376 infores:hetionet CHEBI:79699 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0017152 infores:hetionet CHEBI:17026 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0039070 infores:hetionet CHEBI:7454 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0020580 infores:hetionet NCBIGene:6418 biolink:causes MONDO:0020847 infores:monarchinitiative not_provided not_provided HGNC:10760 MONDO:0020847 uuid:4def97b1-16a1-46e4-a09f-e342e4254c70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0014534 infores:hetionet CHEBI:8768 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0041834 infores:hetionet CHEBI:35778 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0040460 infores:hetionet CHEBI:10110 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0030305 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0232410 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0232410 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0853149 infores:hetionet UBERON:0006799 biolink:causes MONDO:0002810 infores:ubergraph knowledge_assertion manual_agent UBERON:0006799 MONDO:0002810 CHEBI:3215 biolink:causes MONDO:0005752 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0270629 infores:hetionet CHEBI:41774 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0011603 infores:hetionet CAID:CA418278504 biolink:causes MONDO:0100368 infores:clingen CAID:CA418278504 MONDO:0100368 PMID: Likely Benign BP4, BP7, PM2_Supporting NM_000329.3(RPE65):c.1152C>G (p.Val384=) is a synonymous variant in exon 11. This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The splicing impact predictor SpliceAI gives a score of 0.02 for acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA418278504/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA195350 biolink:causes MONDO:0007648 infores:clingen CAID:CA195350 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PS4_Supporting, PM2_Supporting, PVS1_Strong BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP4, PP1, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1711+2_1711+7delTAAGGG variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000217020.4). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA195350/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:27958 biolink:causes MONDO:0016007 infores:ubergraph knowledge_assertion manual_agent CHEBI:27958 MONDO:0016007 CAID:CA2580616389 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580616389 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.386dup (p.Val130GlyfsTer8) is a frameshift variant which results in an exon deletion that is predicted to undergo nonsense mediated decay(PVS1). This frameshift occurs after c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616389/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45081 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C1565489 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0014868 infores:hetionet CHEBI:3504 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0016204 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027765 infores:hetionet CHEBI:9622 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0009806 infores:hetionet CHEBI:7577 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C1142412 infores:hetionet CHEBI:63630 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011206 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0424000 infores:hetionet CHEBI:52717 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030554 infores:hetionet CHEBI:63607 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0019080 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0031212 infores:hetionet NCBIGene:338 biolink:causes MONDO:0014252 infores:monarchinitiative not_provided not_provided HGNC:603 MONDO:0014252 uuid:4822d8e1-af40-4d67-9f9e-be1bedd4b7c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C2242737 infores:hetionet CHEBI:41977 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0039231 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0040034 infores:hetionet CHEBI:79699 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1608945 infores:hetionet CHEBI:47381 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0340865 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042075 infores:hetionet CHEBI:7956 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0011603 infores:hetionet CHEBI:9434 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0035410 infores:hetionet CHEBI:34967 biolink:causes HP:0025234 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0030508 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0151736 infores:hetionet CAID:CA637745022 biolink:causes MONDO:0011071 infores:clingen CAID:CA637745022 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.509-5C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.86) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637745022/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4551 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0027497 infores:hetionet CHEBI:8707 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020672 infores:hetionet CAID:CA1563057 biolink:causes MONDO:0010986 infores:clingen CAID:CA1563057 MONDO:0010986 PMID: Likely Pathogenic PM5, PM3, PP3, PP4, PM2_Supporting The c.4748G>A variant in OTOF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1583. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16254 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). Another missense variant c.4747C>T (p.R1583C) (PMID:26818607, 31589614, 32747562, 33724713, 34426522, ClinVar Variation ID:402270) in the same codon has been classified as pathogenic/likely pathogenic for autosomal recessive nonsyndromic hearing loss in ClinVar (PM5). At least one patient with this variant and compound heterozygous for the c.2215-1G>C variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for ANSD (PP4, PMID:24001616). This variant has been detected in at least 1 individual with ANSD, who was compound heterozygous for the variant and a pathogenic or likely pathogenic variant were confirmed in trans by family testing (c.2215-1G>C, 1 PM3 point, PMID:24001616). Additional compound heterozygous cases with variants c.5816G>A (p.R1939Q), c.3515G>A (p.R1172Q), and c.2523+1G>T (PMIDs: 24053799, 31095577, 31827501 respectively) were also seen, but excluded from scoring due to less scorable evidence. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PM5, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/21/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1563057/MONDO:0010986/023 2022-08-03 2022-08-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf UMLS:C0011701 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0013395 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0349506 infores:hetionet CHEBI:41879 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0003708 infores:hetionet CHEBI:5856 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0033036 infores:hetionet CHEBI:2663 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0340865 infores:hetionet CHEBI:5855 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0234518 infores:hetionet CHEBI:9943 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011175 infores:hetionet CHEBI:6538 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0013378 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0423602 infores:hetionet CHEBI:50692 biolink:causes MONDO:0043472 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0001231 infores:hetionet CHEBI:74947 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151578 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0857400 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0857400 infores:hetionet CHEBI:36704 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0011606 infores:hetionet CHEBI:31236 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0424489 infores:hetionet CAID:CA1620023 biolink:causes MONDO:0800472 infores:clingen CAID:CA1620023 MONDO:0800472 PMID:19793111PMID:19643970 Uncertain Significance PM2 PP3, PP1, BA1, BP4, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, BP7, PVS1 The c.503G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Glycine by Aspartic Acid at amino acid 168 (p.Gly168Asp). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00003528 (3 alleles out of 85,042), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This missense variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1) and the REVEL score = 0.437, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on CYP1B1 function. A previous study (PMID: 19643970) demonstrated that the 17B estradiol activity levels of the Gly168Asp protein were not below the established threshold for that assay (<20% relative activity compared to background haplotype). This variant was also assessed in PMID: 19793111, however, the thresholds for abnormal impact on protein function in the assays could not be determined. This variant has not been identified as homozygous or compound heterozygous with another variant in CYP1B1, therefore PM3 was not applied. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1620023/MONDO:0800472/104 2025-11-19 2025-11-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3699 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0019158 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0011603 infores:hetionet CAID:CA410150240 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150240 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.833C>T (p.Pro278Leu) is a missense variant which has a REVEL score of 0.491, below the threshold (<0.50) for pathogenicity. The SpliceAI score is 0.1 (threshold <0.20) for acceptor loss, indicating a very low chance this variant impacts splicing (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150240/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6904 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0019158 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0549373 infores:hetionet CHEBI:63681 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0001824 infores:hetionet CHEBI:63589 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0002878 infores:hetionet CHEBI:553473 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0595916 infores:hetionet CHEBI:34967 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0042963 infores:hetionet CHEBI:5383 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0013404 infores:hetionet CHEBI:5959 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0016382 infores:hetionet CHEBI:2955 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0038999 infores:hetionet CHEBI:47780 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233407 infores:hetionet CHEBI:114785 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0042963 infores:hetionet CHEBI:31980 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0151636 infores:hetionet CAID:CA120590 biolink:causes MONDO:0044970 infores:clingen CAID:CA120590 MONDO:0044970 PMID:8687424PMID:8817331PMID:11230176PMID:9915970 Pathogenic PP3, PS3_Moderate, PS4 PP1, PS2, PM6, PM2 The m.1555A>G variant in MT-RNR1 has been reported in more than 65 individuals with primary mitochondrial disease, and the only consistent reported feature in affected individuals was hearing loss (PS4; PMIDs: 7689389, 1613771, 8285309, 8414970, 9111378, 9040738, 9490575, 9831149, 10661905, 12031626, 12920080, 16935512, 20123042, 22317974, 23357420, 24252789, 11870684). Some individuals with this variant have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. Age of onset of hearing loss ranged from infancy (after aminoglycoside exposure) to adulthood. Hearing loss has been reported to be variable, stable in some individuals and progressive in others. Several reports of individuals receiving cochlear implants had good outcomes (PMIDs: 9831149, 16935512, 24252789). While most affected individuals have this variant present at homoplasmy, there have been some reports of heteroplasmic occurrences in those with hearing loss. There are isolated reports of individuals with this variant having other medical concerns, however there is not sufficient evidence currently that this variant was causative of these other concerns. These concerns include chronic progressive external ophthalmoplegia and myopathy (PMID: 11870684), cardiomyopathy (PMIDs: 28104394, 24252789), neural tube defect (PMID: 10661905), hypertension (PMID: 22317974), type 2 diabetes (PMID: 23357420), Parkinson disease (abstract only, Shoffner et al., 1996), autism spectrum disorder and intellectual disability (PMID: 29340697), and Leigh syndrome (PMID: 32867169). There are no de novo occurrences of this variant reported to our knowledge. Many extended families have been reported in the medical literature however the variant was present at homoplasmy in both affected and unaffected family members, thus preventing consideration for PP1. The computational predictor HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Several studies in patient cells (PMIDs: 8817331, 9915970), cybrids (PMIDs: 8687424, 11230176), and single fiber testing (PMID: 9915970) support the functional impact of this variant (PS3_moderate). This variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 15, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120590/MONDO:0044970/015 2022-12-15 2025-11-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA033073 biolink:causes MONDO:0007750 infores:clingen CAID:CA033073 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2 The NM_000527.5(LDLR):c1216C>T (p.Arg406Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3, PS4, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.000097 (0.0097%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.88, which is above the threshold of 0.75. PS3 – Level 1 functional studies: PMID: 2574186; Heterologous cells (CHO), FACS assays - variant results in 60-65% LDLR expression/biosynthesis, LDL binding and LDL internalization compared to wild-type; results meet <70% threshold.PS4 – Variant meets PM2 and is identified in at least 19 unrelated index cases who fulfill clinical criteria for FH (1 case with DLCN criteria from PathWest Laboratory Medicine WA – FH VCEP member lab; 18 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab).PP1_Strong – Variant segregates with phenotype in 31 informative meioses from 15 families in data provided by FH VCEP member labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 11 families: 23 affected with the variant and 1 unaffected without the variant; Laboratory of Genetics and Molecular Cardiology – 4 families: 4 affected with the variant and 3 unaffected without the variant).PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines.2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) – Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033073/MONDO:0007750/013 2022-05-19 2022-05-19 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:77260 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0034150 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0859062 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0859062 infores:hetionet CHEBI:3699 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0026858 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0919936 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0919936 infores:hetionet CHEBI:6129 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0041834 infores:hetionet CHEBI:16469 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0033893 infores:hetionet CHEBI:6775 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085633 infores:hetionet CHEBI:68554 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0085649 infores:hetionet CAID:CA397722486 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722486 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3, BA1, BS1 The c.278-1G>A variant in ACADVL occurs within the canonical splice acceptor site (- 1) of intron 4. It is predicted to cause skipping of biologically-relevant-exon 5/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). The variant has been identified in at least one individual identified by newborn screen or classified as presumptive newborn screen positive for very long chain acyl CoA dehydrogenase (VLCAD) deficiency without evidence or assertion of NBS C14:1 levels, follow-up plasma acylcarnitine levels or reduced enzyme activity; this variant was reported as two alleles with no indication of zygosity (PMID 263853). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL Variant Curation Expert Panel VCEP v2.0; date of approval 2022-02-07). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722486/MONDO:0008723/021 2022-03-08 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4710 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0233571 infores:hetionet NCBIGene:2318 biolink:causes MONDO:0012289 infores:monarchinitiative not_provided not_provided HGNC:3756 MONDO:0012289 uuid:5ee85e0f-de2b-4382-8985-c440be3b6881 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72297 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0019209 infores:hetionet CHEBI:6067 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0035229 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016436 infores:hetionet CHEBI:114785 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0702166 infores:hetionet CHEBI:6129 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0242528 infores:hetionet CHEBI:4672 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1167791 infores:hetionet CHEBI:194135 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014591 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0235639 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151785 infores:hetionet CHEBI:9943 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233471 infores:hetionet CHEBI:63632 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0002170 infores:hetionet CHEBI:6437 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0023380 infores:hetionet CAID:CA008331 biolink:causes MONDO:0100316 infores:clingen CAID:CA008331 MONDO:0100316 PMID:11278406 Likely Pathogenic PM2_Supporting, PS4_Moderate, PS3, PP3, PP4 PM5, PP1 NM_000218.3(KCNQ1):c.817C>T is a missense variant in KCNQ1 that replaces leucine with phenylalanine at codon 273. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.000007627, with 9 alleles / 1180016 total alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is rare and has been reported in at least 5 apparently unrelated probands affected with long QT syndrome 1 (PMID: 8528244, PMID: 25645639, PMID: 27920829, PMID: 24372464, PMID: 37449562, PS4_Moderate). This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds and an exercise-associated event, which together are highly specific for long QT syndrome 1 (PP4, PMID: 24372464). The variant has been reported to segregate with long QT syndrome 1 through the proband and 3 affected family members from one family, however, one member had QTc less than 480 ms and was excluded from counting, so PP1 has not been met (PMID: 28249770). Another missense variant NM_000218.3(KCNQ1):c.817C>G (p.Leu273Val) in the same codon has been observed in relation to Long QT Syndrome, however the PM5 has not been considered to avoid circularity. The computational predictor REVEL gives a score of 0.924, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). This variant has been shown to disrupt KCNQ1 function in at least five experimental assays, including Manual patch-clamp and Experimental/Structural/Functional Simulation (PS3; PMID: 9323054, PMID: 29451064, PMID: 29167462, PMID: 29021305, PMID: 11278406). In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3, PS4_Moderate, PM2_Supporting, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA008331/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CAID:CA023685 biolink:causes MONDO:0007750 infores:clingen CAID:CA023685 MONDO:0007750 PMID: Pathogenic PS4, PS3_Supporting, PVS1, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PM6, PP1, PP2, PP3, BS2 The NM_000527.5(LDLR):c.296C>G (p.Ser99Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met.PS4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019).PM2 - PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PS3_supporting - Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023685/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3508 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0015967 infores:hetionet CHEBI:51860 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0240211 infores:hetionet CHEBI:6916 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0003811 infores:hetionet CHEBI:50131 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0221776 infores:hetionet CHEBI:37333 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C2047937 infores:hetionet CHEBI:50742 biolink:causes NCIT:C50547 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C1704212 infores:hetionet CHEBI:50378 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0020615 infores:hetionet CHEBI:184555 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0035455 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0160390 infores:hetionet CHEBI:5147 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0162285 infores:hetionet CAID:CA405696104 biolink:causes MONDO:0100150 infores:clingen CAID:CA405696104 MONDO:0100150 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000540.3(RYR1):c.10171G>T (p.Glu3391Ter) variant in RYR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 67/106 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000004243 (5/1178340 alleles) in European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤0.00000697) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_P. (Required: ClinGen Congenital Myopathies VCEP specifications version 1; September 9, 2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA405696104/MONDO:0100150/179 2024-09-09 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:101278 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0022650 infores:hetionet CAID:CA913169174 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169174 MONDO:0044970 PMID: Likely Pathogenic PP3, PP1, PM2_Supporting, PS4_Moderate, PS3_Supporting PS2, PM6 The m.3302A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with MELAS and the fourth had myopathy and respiratory failure. The heteroplasmy levels of the variant in affected individuals ranged from 45% to homoplasmic (PS4_moderate; PMIDs: 19370763, 8366098). This variant segregated with disease in one family as the proband and his mother harbored the variant at high heteroplasmy levels (values not provided) in fibroblasts and the variant was homoplasmic in muscle in the proband. An unaffected maternal aunt did not harbor the variant in her white blood cells (PP1; PMID: 8366098). There are no reports of de novo occurrences to our knowledge. Cybrid studies supported the functional impact of this variant as cybrids with the variant present at 98% heteroplasmy had a 6-fold reduction of respiration compared to those with 77% heteroplasmy showing no respiration defect (PS3_supporting; PMID: 17130166). The computational predictor MitoTIP suggests this variant is pathogenic (85.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169174/MONDO:0044970/015 2022-11-14 2023-01-05 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6149 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0178298 infores:hetionet CHEBI:2704 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0003862 infores:hetionet CAID:CA410149697 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149697 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.899C>G (p.Thr300Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149697/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8428 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0009676 infores:hetionet CAID:CA16020765 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020765 MONDO:0009861 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PM5, PM3 The c.317T>C (p.Val106Ala) variant in PAH was reported in a Japanese patient with mild phenylketonuria (BH4 deficiency excluded) (PMID: 21307867). This variant is absent in population databases. The results from in silico predictor [REVEL - 0.656], predict a damaging effect on PAH function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3, PP4-moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020765/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6715 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0392525 infores:hetionet CHEBI:9123 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0037763 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0400823 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1167965 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0027765 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042373 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0162429 infores:hetionet CHEBI:6715 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019829 infores:hetionet UMLS:C0145867 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0003862 infores:hetionet CHEBI:5109 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0027765 infores:hetionet CHEBI:7025 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0011991 infores:hetionet CHEBI:5384 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0018681 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042267 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0041912 infores:hetionet CHEBI:28864 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0595916 infores:hetionet CHEBI:15765 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0278134 infores:hetionet CHEBI:47657 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0030252 infores:hetionet CHEBI:6970 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0151907 infores:hetionet UBERON:0001951 biolink:causes MONDO:0015459 infores:ubergraph knowledge_assertion manual_agent UBERON:0001951 MONDO:0015459 CHEBI:50924 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027765 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0497247 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0269002 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0269002 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0030305 infores:hetionet CHEBI:27974 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C3665386 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027813 infores:hetionet CHEBI:50173 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0010828 infores:hetionet CHEBI:4995 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013604 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0178298 infores:hetionet CHEBI:9599 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0028084 infores:hetionet CHEBI:51041 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0231528 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013395 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0005940 infores:hetionet CHEBI:17026 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0232849 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0017152 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0948978 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0948978 infores:hetionet CHEBI:4710 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0040264 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1456822 infores:hetionet CHEBI:34967 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C1456784 infores:hetionet CHEBI:3219 biolink:causes HP:0040403 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0520594 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0002418 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011053 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0232459 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0019348 infores:hetionet CHEBI:63627 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0020580 infores:hetionet CHEBI:72323 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0020615 infores:hetionet NCBIGene:6005 biolink:causes MONDO:0008493 infores:monarchinitiative not_provided not_provided HGNC:10006 MONDO:0008493 uuid:acabd3cc-9d77-4714-bf54-282697dad5ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6030 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0001824 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0033860 infores:hetionet CHEBI:5893 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0003811 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0033975 infores:hetionet UMLS:C0009315 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0014591 infores:hetionet NCBIGene:23112 biolink:causes MONDO:0030995 infores:monarchinitiative not_provided not_provided HGNC:29190 MONDO:0030995 uuid:328dc719-e129-4536-bedc-180168f8c622 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA390864732 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864732 MONDO:0100216 PMID: Uncertain Significance BP4, PM1_Supporting PVS1, PM2, BA1, BP2, PP3, PP1, PP4, BS2, PM5, PM4, PS1, PS3, PS2, PS4, BP7, BS1, BS3, BS4 The NM_177438.3:c.5404A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1802 (p.Ile1802Val). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000001239 (2/1613990 alleles) with a highest population minor allele frequency of 0.00002670 (2/74908 alleles) in the African/African American population and with multiple alleles present in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.232; MaxEntScan and SpliceAI: no effect on splicing) (BP4). Another missense variant, c.5405T>C (p.Ile1802Thr), in the same codon has been reported (ClinVar Variation ID: 2702708). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER1 VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864732/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64321 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0014724 infores:hetionet CHEBI:100246 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0020458 infores:hetionet CHEBI:9738 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0020580 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0005940 infores:hetionet NCBIGene:4285 biolink:causes MONDO:0014976 infores:monarchinitiative not_provided not_provided HGNC:7104 MONDO:0014976 uuid:d83f0de2-9fcc-4b8f-848f-563062c9b8b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026826 infores:hetionet CHEBI:50156 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0233471 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002170 infores:hetionet CHEBI:61049 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017181 infores:hetionet CHEBI:10102 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0041657 infores:hetionet CHEBI:31236 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0231530 infores:hetionet CHEBI:27470 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0541799 infores:hetionet CAID:CA5950260 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950260 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000448.3(RAG1):c.2442G>T is a missense variant predicted to cause substitution of Glutamic Acid by Aspartic Acid at amino acid 814 (p.Glu814Asp). This missense variant is located in the core domain (amino acids 387-1011) (PM1_Supporting). The filtering allele frequency (the upper threshold of the 95% CI of 3/44724) of the c.2442G>T variant in RAG1 is 0.00001779 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_Supporting,PM2_Supporting(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950260/MONDO:0000572/123 2024-02-26 2024-02-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2663 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151799 infores:hetionet UMLS:C0065374 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030794 infores:hetionet CHEBI:9763 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0016204 infores:hetionet CHEBI:28001 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0085593 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0018939 infores:hetionet CHEBI:6970 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C3263723 infores:hetionet CHEBI:4974 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0858635 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0008325 infores:hetionet CHEBI:16664 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0000737 infores:hetionet CHEBI:45783 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0242184 infores:hetionet GO:0033047 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0033047 GO:0140014 CHEBI:16469 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235955 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0009450 infores:hetionet CHEBI:17334 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C2697368 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0010073 infores:hetionet CHEBI:5778 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042029 infores:hetionet CHEBI:4315 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0013395 infores:hetionet CHEBI:16796 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0016204 infores:hetionet GO:1904323 biolink:causes GO:0002029 infores:ubergraph knowledge_assertion manual_agent GO:1904323 GO:0002029 CHEBI:75922 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0344232 infores:hetionet CHEBI:3441 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151603 infores:hetionet GO:0060159 biolink:causes GO:1903351 infores:ubergraph knowledge_assertion manual_agent GO:0060159 GO:1903351 CHEBI:63607 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0013378 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0035078 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0036454 infores:hetionet CHEBI:6931 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0220870 infores:hetionet NCBIGene:2538 biolink:causes MONDO:0009287 infores:monarchinitiative not_provided not_provided HGNC:4056 MONDO:0009287 uuid:4cc94713-8170-4886-80b2-b6649f3186a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0038450 infores:hetionet CHEBI:6067 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151754 infores:hetionet CHEBI:3568 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0424295 infores:hetionet CHEBI:45081 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0220870 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0031117 infores:hetionet CHEBI:5001 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0023218 infores:hetionet CHEBI:9667 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0263449 infores:hetionet CHEBI:31515 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0233494 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042401 infores:hetionet CHEBI:6456 biolink:causes UMLS:C1868879 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C1868879 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0549373 infores:hetionet CHEBI:9434 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0016382 infores:hetionet CHEBI:9667 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0027813 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0001122 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0021400 infores:hetionet NCBIGene:84173 biolink:causes MONDO:0030549 infores:monarchinitiative not_provided not_provided HGNC:26158 MONDO:0030549 uuid:6dd446f5-23a7-4438-8f73-0f1ab822bfaf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0234913 infores:hetionet CHEBI:48844 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0014742 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0030312 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0042373 infores:hetionet GO:2000121 biolink:causes GO:0071451 infores:ubergraph knowledge_assertion manual_agent GO:2000121 GO:0071451 CHEBI:63617 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151907 infores:hetionet CHEBI:6741 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013404 infores:hetionet CHEBI:7565 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151786 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0031350 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0003123 infores:hetionet CHEBI:6909 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0040264 infores:hetionet CHEBI:3223 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0392156 infores:hetionet CHEBI:3716 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0085636 infores:hetionet CL:0000192 biolink:causes MONDO:0006975 infores:ubergraph knowledge_assertion manual_agent CL:0000192 MONDO:0006975 CHEBI:7823 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0012569 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0007019 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D014848 DB00634_MESH_D014848_1DB06147_MESH_D014848_1DB00259_MESH_D014848_1 CHEBI:7773 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0085593 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0017152 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0007971 infores:hetionet CHEBI:3077 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0392163 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C2697368 infores:hetionet CHEBI:3228 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0036974 infores:hetionet CHEBI:53691 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0271298 infores:hetionet CHEBI:3207 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013404 infores:hetionet CHEBI:4027 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0015967 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042267 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0007222 infores:hetionet CHEBI:15367 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0005758 infores:hetionet CHEBI:61049 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020598 infores:hetionet CHEBI:36795 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0917801 infores:hetionet NCBIGene:4781 biolink:causes MONDO:0032658 infores:monarchinitiative not_provided not_provided HGNC:7785 MONDO:0032658 uuid:e439630f-55e2-45da-af2c-60078282e687 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423232 infores:hetionet CHEBI:48844 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0023052 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151838 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0015230 infores:hetionet CHEBI:31980 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0042963 infores:hetionet CHEBI:3347 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0030252 infores:hetionet CHEBI:44185 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0041956 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0150450 infores:hetionet CHEBI:83804 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0086439 infores:hetionet NCBIGene:5157 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:8805 MONDO:0007256 uuid:c6ff5f9c-c3f0-4177-a86e-a8dcd5291851 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0021053 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0009806 infores:hetionet CHEBI:72296 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0015402 infores:hetionet CHEBI:3504 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0018681 infores:hetionet CHEBI:50859 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085932 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042373 infores:hetionet CAID:CA269519 biolink:causes MONDO:0700272 infores:clingen CAID:CA269519 MONDO:0700272 PMID: Likely Benign BP7, BP4 PM2 The c.212-33A>C variant in PALB2 is an intronic variant. BP7 applies because the threshold for the application of BP7 to deep intronic acceptor site variants is beyond position -21. The computational splicing predictor SpliceAI gives a score of 0.0 for acceptor loss suggesting that the variant has no impact on splicing. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006485 in the non-Finnish European population. (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BP4, BP7) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA269519/MONDO:0700272/077 2023-06-15 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:145499 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020456 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002888 infores:hetionet CHEBI:37941 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018524 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042109 infores:hetionet CHEBI:36795 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0236024 infores:hetionet CHEBI:3044 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0011991 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0032285 infores:hetionet CHEBI:27882 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0030312 infores:hetionet CHEBI:421707 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0877192 infores:hetionet CHEBI:63607 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151766 infores:hetionet CHEBI:48273 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0030469 infores:hetionet CHEBI:8863 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0014236 infores:hetionet CHEBI:6923 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0038362 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0178298 infores:hetionet CHEBI:6754 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0917801 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0020649 infores:hetionet CHEBI:135736 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0547030 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0302295 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0036572 infores:hetionet UNII:7662KG2R6K biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0014724 infores:hetionet CHEBI:8764 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0231218 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0021141 infores:hetionet CHEBI:2659 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0036974 infores:hetionet NCBIGene:3039 biolink:causes MONDO:0054802 infores:monarchinitiative not_provided not_provided HGNC:4823 MONDO:0054802 uuid:0eb613d2-a38a-461f-ad6a-d4d68dceb3c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0003862 infores:hetionet CHEBI:7476 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0008350 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0543467 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002622 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0160390 infores:hetionet CAID:CA024686 biolink:causes MONDO:0007783 infores:clingen CAID:CA024686 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 2348 of the RYR1 protein, p.(Glu2348Gly). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000115, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, The UK (Leeds) MH Investigative Unit)). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.964) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024686/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:175901 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0086565 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013609 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0042109 infores:hetionet CAID:CA399794666 biolink:causes MONDO:0100326 infores:clingen CAID:CA399794666 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting PP3, PP4 The NM_000419.5(ITGA2B):c.2540T>C (p.Leu847Pro) missense variant has been reported homozygous in at least one type I GT patient (FC in PMID: 11798398; PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00001335 (1/74900 alleles) in the African/African-American genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399794666/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA9870416 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870416 MONDO:0015967 PMID: Uncertain Significance PP1_Moderate, PP4, PM1_Supporting PM2, PM4, BA1, PS4, BS1 The c.956_958del variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a 3 base pair deletion resulting in the in-frame deletion of 1 amino acid at codon 319 (p.(Leu319del)) within exon 8 of NM_175914.5. The Grpmax filtering allele frequency of the c.956_958del variant in gnomAD v4.1 is 0.000022, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. The c.956_958del variant is predicted to change the length of the protein due an in-frame deletion of 1 amino acid, but it is within a repeat region of 5 leucines, so PM4_Supporting was not applied. This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and the variant does not meet the PM2_Supporting cutoff (PMID: 21105491, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A and a family history of neonatal hypoglycemia) (PP4_Moderate; PMID: 21105491). This variant segregated with diabetes, with three informative meioses in two families (PP1_Moderate; PMID: 21105491; internal lab contributor). In summary, c.956_958del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PP4_Moderate, PP1_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870416/MONDO:0015967/085 2025-07-25 2025-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9448 biolink:causes MONDO:0041182 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0031736 infores:hetionet CHEBI:9139 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0270996 infores:hetionet CHEBI:4708 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0036974 infores:hetionet CHEBI:478164 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0852911 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0521464 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0521464 infores:hetionet CHEBI:3223 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0393593 infores:hetionet CHEBI:3732 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0035455 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0021400 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0038454 infores:hetionet CHEBI:4728 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0018926 infores:hetionet CHEBI:83527 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0006325 infores:hetionet NCBIGene:1482 biolink:causes MONDO:0016581 infores:monarchinitiative not_provided not_provided HGNC:2488 MONDO:0016581 uuid:4a2c1694-0c2f-4358-b282-b364cd3c6862 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151559 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0019196 infores:hetionet CHEBI:51041 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151766 infores:hetionet CHEBI:8107 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151907 infores:hetionet CHEBI:17303 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020621 infores:hetionet CHEBI:194135 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0547030 infores:hetionet CAID:CA410147802 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147802 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1197C>A (p.Ser399Arg) is a missense variant which has a REVEL score < 0.50 (0.126) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147802/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:26005 biolink:causes MONDO:0014413 infores:monarchinitiative not_provided not_provided HGNC:24564 MONDO:0014413 uuid:8f1f2129-0671-4efe-a199-1da5b86f0137 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2639 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0016204 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0011630 infores:hetionet GO:0043309 biolink:causes GO:0002278 infores:ubergraph knowledge_assertion manual_agent GO:0043309 GO:0002278 CHEBI:16469 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0231528 infores:hetionet UMLS:C1738934 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0016204 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020538 infores:hetionet CAID:CA387460667 biolink:causes MONDO:0019497 infores:clingen CAID:CA387460667 MONDO:0019497 PMID:21112098PMID:21112098 Uncertain Significance PM3, PM2 BS4, BS1, BP5, BP7, BS2, PP1, PP4, PP3, PM5, PM1, PM4, PVS1, PM6, BP3, BP2, BP4, BA1, PS1, PS4, PS2, PS3 The p.Pro225Leu variant in GJB2 is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This variant has been detected in 1 patient with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3; PMID:21112098). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387460667/MONDO:0019497/005 2018-09-20 2019-07-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:82941 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0004093 infores:hetionet CHEBI:3181 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011253 infores:hetionet CHEBI:7903 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0151539 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0026857 infores:hetionet CAID:CA10014482 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014482 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.509-13C>T is an intronic variant which is not predicted to impact splicing (Splice AI score <0.20) (BP4). However, this nucleotide is conserved therefore BP7 is not applied. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014482/MONDO:0011071/008 2024-09-05 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:92607 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0020649 infores:hetionet CAID:CA9870185 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870185 MONDO:0015967 PMID: Benign BA1, BP4, BP5 PP4 The c.224+17dupT variant in the HNF4 homeobox A gene, HNF4A has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0008603, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor gain, suggesting that the variant has no impact on splicing (BP4). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PP4 is not met (internal lab contributors). This variant was also identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.224+17dupT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 11/16/2022): BA1, BP4, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870185/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3441 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0006147 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152029 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036572 infores:hetionet CHEBI:9073 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0012833 infores:hetionet CHEBI:63791 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0025874 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0860603 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0860603 infores:hetionet CHEBI:16755 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042024 infores:hetionet CHEBI:10100 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0011603 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0017178 infores:hetionet CHEBI:32221 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0040264 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0006266 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0008370 infores:hetionet CHEBI:5280 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0271051 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0232409 infores:hetionet CHEBI:53766 biolink:causes MONDO:0019145 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0398625 infores:hetionet CHEBI:131512 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0027497 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1384666 infores:hetionet CHEBI:6775 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002962 infores:hetionet CHEBI:119915 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0039239 infores:hetionet CHEBI:63627 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0028643 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0009324 infores:hetionet CHEBI:4887 biolink:causes MONDO:0003397 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0017567 infores:hetionet CAID:CA400029961 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029961 MONDO:0100326 PMID: Likely Pathogenic PM5, PP4_Moderate, PP3, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.1595G>T (p.Cys532Phe) missense variant has been reported in at least one patient (Case 10 in PMID: 34066320) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.965, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Two different missense variants, Cys532Tyr and Cys532Arg, in the same codon as Cys532Phe, have been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM5, PP3, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029961/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7640 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0085649 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0042109 infores:hetionet CAID:CA10586682 biolink:causes MONDO:0021060 infores:clingen CAID:CA10586682 MONDO:0021060 PMID: Pathogenic PS2_Very Strong, PM2_Supporting, PP2, PS4 The c.146C>G (Pro49Arg) variant in PPP1CB is a missense variant predicted to cause substitution of proline by arginine at amino acid 49. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.438, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 13 probands with features of RASopathy (PS4; PMIDs: 27264673, 27681385, 27868344, 28211982, 30368668, 32476286). This variant has been identified as a de novo occurrence with confirmed parental relationships in 9 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 27264673, 27681385, 27868344). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VS, PS4, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586682/MONDO:0021060/128 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83804 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0030196 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0520540 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0520540 infores:hetionet CHEBI:9738 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0011991 infores:hetionet CHEBI:94609 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0221150 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0018801 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0031099 infores:hetionet CHEBI:93305 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0332575 infores:hetionet CHEBI:4315 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0033845 infores:hetionet CHEBI:3994 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0003578 infores:hetionet CHEBI:134991 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0030196 infores:hetionet CAID:CA229447 biolink:causes MONDO:0009861 infores:clingen CAID:CA229447 MONDO:0009861 PMID:24401910PMID:26322415PMID:24401910PMID:26322415 Uncertain Significance PM3, PP4_Moderate, BS1 PP3 PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4_moderate: Detected in multiple patients with hyperphenylalaninemia, BH4 deficiency excluded (PMID:24401910, 26322415); PM3: Detected in trans with pathogenic variant p.R243Q. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4_moderate, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229447/MONDO:0009861/006 2019-04-08 2019-04-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:71940 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0040264 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0038663 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151752 infores:hetionet CHEBI:2636 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0036974 infores:hetionet CHEBI:119915 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015732 infores:hetionet CHEBI:47780 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1457883 infores:hetionet CHEBI:6541 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020564 infores:hetionet CAID:CA8337936 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337936 MONDO:0008723 PMID: Likely Benign BP4, BS1 PP4, BP2 The c.1077+15C>T variant in ACADVL is an intronic variant which falls downstream of the exon 10 donor splice site. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003767 in the Ashkenazi Jewish population and 0.0033 in the South Asian population which is not higher than the ClinGen ACADVL VCEP threshold (>0.0035) for BS1. However, due to the Ashkenazi Jewish population meeting BS1 while the continental South Asian population is approaching the BS1 threshold, the ACADVL VCEP has applied this criterion (BS1). One individual with this variant did display elevated C14:1 levels on newborn screening; however no values were specified. This same individual was compound heterozygous for this variant and two other variants, though the lack of confirmation in trans disallows this evidence from meeting BP2 (PMID: 27246109; Variants: p.Lys187Glu, c.1678+23 C>T). The results from two in silico splicing predictors (NNSPLICE, SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as likely benign for VLCAD deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL VCEP: BS1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337936/MONDO:0008723/021 2025-01-14 2025-01-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:82960 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0038663 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027947 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015256 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0221706 infores:hetionet CAID:CA10653545 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653545 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS3, PS4, BP4, PVS1, PM6, PM2, BS3, BS4, BS1, BP7, PM4, PM5, PM1, PP3, PP1 The NM_001754.4:c.*4032T>C variant reported at an MAF of 0.096 (9%, 835/8702 alleles) in the African population in gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 25 individuals in gnomAD (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653545/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3437 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0022568 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0235431 infores:hetionet NCBIGene:4009 biolink:causes MONDO:0011074 infores:monarchinitiative not_provided not_provided HGNC:6653 MONDO:0011074 uuid:76e8e11e-27ef-4d83-92f1-b4bcaaae4b6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0020580 infores:hetionet CHEBI:50841 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0022346 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0012833 infores:hetionet CHEBI:6904 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0030193 infores:hetionet CHEBI:6375 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0003467 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0040034 infores:hetionet CHEBI:31236 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019294 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0003864 infores:hetionet CHEBI:39585 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0013384 infores:hetionet CHEBI:9598 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0011991 infores:hetionet CHEBI:3510 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0022107 infores:hetionet CHEBI:63632 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0000737 infores:hetionet CHEBI:7936 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007859 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0014868 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0221100 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028738 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0010692 infores:hetionet CHEBI:4814 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C2830004 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0267792 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0035455 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014868 infores:hetionet CAID:CA355963597 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963597 MONDO:0001586 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PM3, PM5, BP4, PP3, PP1, PP4 The NM_000203.5:c.1226G>A variant in IDUA is a missense variant predicted to cause the substitution of glycine by glutamic acid at amino acid 409 (p.Gly409Glu). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000009841 (11/1117808; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.451 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on the IDUA function. The computational predictor SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 557616). However, to our knowledge, this variant has not been reported in the literature in individuals with MPS1 and the results of functional studies are unavailable. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for MPS1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963597/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8874 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0427008 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0004936 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0039621 infores:hetionet CHEBI:6888 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0030920 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027339 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042134 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0033777 infores:hetionet CHEBI:7443 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0085605 infores:hetionet CHEBI:34967 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0001807 infores:hetionet CHEBI:5130 biolink:causes MONDO:0024335 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0085582 infores:hetionet CHEBI:8228 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0231528 infores:hetionet CAID:CA414441410 biolink:causes MONDO:0010604 infores:clingen CAID:CA414441410 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PVS1 PP1 The NM_000133.4(F9):c.720G>A variant predicts a nonsense change, Trp240Ter, in exon 6 of the F9 gene; NMD is predicted, meeting PVS1 criteria. The variant is absent from gnomAD v2.1.1 and v3, meeting PM2_Supporting criteria. At least 8 severe hemophilia B patients meeting the F9 phenotype criteria have been reported in the literature (PMIDs: 23093250, 18479429, 8091381, 15086324), meeting PS4_Very strong. Inhibitors to factor replacement therapies have been reported (EAHAD database). In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PVS1, PS4_Very strong, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414441410/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports UMLS:C0065374 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0002170 infores:hetionet NCBIGene:5728 biolink:causes MONDO:0008021 infores:monarchinitiative not_provided not_provided HGNC:9588 MONDO:0008021 uuid:a57ddb59-e626-498a-9062-a3c0de060dfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0006266 infores:hetionet CHEBI:8888 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0424295 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020651 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0031039 infores:hetionet CHEBI:4495 biolink:causes HP:0030529 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0438434 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0021400 infores:hetionet CHEBI:17026 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0009763 infores:hetionet GO:0048819 biolink:causes GO:0098773 infores:ubergraph knowledge_assertion manual_agent GO:0048819 GO:0098773 UNII:T58MSI464G biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0021843 infores:hetionet CHEBI:83804 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020580 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022408 infores:hetionet CHEBI:6950 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1510410 infores:hetionet CAID:CA356994 biolink:causes MONDO:0001586 infores:clingen CAID:CA356994 MONDO:0001586 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting PS1, PS2, PM5, PM1, PM4, BP5, BP7, PM6, BP3, PP1, BS2 The NM_000203.5:c.223G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 75, p.(Ala75Thr). This variant has been seen in at least 11 unrelated patients. Six of these patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic, phase not confirmed: c.208C>T (p.Gln70Ter) (PMID: 28752568, 35141277) (ClinVar Variation ID: 11909; 3 patients; max 2 patients counted, 2 x 0.5), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 28752568, 8019563) (3 patients; max 2 patients counted, 2 x 0.5), and 2 individuals are homozygous for the variant (PMID: 11735025, 27146977). In addition, three individuals are compound heterozygous for the variant and either c.895C>T (PMID: 27146977), c.1898C>T (p.Ser633Leu) (PMID: 16438163) or c.1650+1G>T (PMID: 29843745). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Total points = 3 points (PM3_Strong). One of these individuals has specific clinical features (dysostosis multiplex, hepatosplenomegaly, corneal clouding and coarse facial features), with undetectable IDUA enzyme activity compared to Thai controls, and elevated urinary dermatan and heparan sulfate excretion (PMID: 16438163). This is sufficient for use of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74900 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025). Expression of the variant in COS-1 cells resulted in no residual wild type IDUA activity (once background activity subtracted), indicating that this variant may impact protein function (PMID: 7550232)(PS3_Supporting). The computational predictor REVEL gives a score of 0.803 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 222993). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0.): PM3_Strong, PP3_Moderate, PP4_Moderate. PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 4, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA356994/MONDO:0001586/091 2025-05-04 2025-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:474180 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020456 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0277585 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0027765 infores:hetionet CHEBI:4466 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020903 infores:hetionet NCBIGene:63894 biolink:causes MONDO:0013255 infores:monarchinitiative not_provided not_provided HGNC:20347 MONDO:0013255 uuid:83737214-c040-487e-b91f-e25192860007 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10579934 biolink:causes MONDO:0700272 infores:clingen CAID:CA10579934 MONDO:0700272 PMID:31757951PMID:31636395PMID:31586400PMID:24141787PMID:33964450PMID:31757951PMID:31636395PMID:31586400PMID:24141787PMID:33964450 Uncertain Significance BS2_Supporting, PM2_Supporting, BP1 PS3, BS1, BS3, PP3, BP4, BA1 The c.3089C>T variant in PALB2 is a missense variant predicted to cause a substitution of threonine for isoleucine at amino acid 1030 (p.Thr1030Ile). This variant has been observed with another variant in PALB2 that is tentatively classified as likely pathogenic by HBOP VCEP in an individual without Fanconi Anemia (Ambry Genetics). The phase of the variants was not determined. This variant has been tested in multiple protein assays (PMID 33964450, 31636395, 31757951, 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BS2_supporting, PM2_supporting, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10579934/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4511 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0001824 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005552 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0948522 infores:hetionet CHEBI:63115 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0151905 infores:hetionet CHEBI:65346 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0851341 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0013395 infores:hetionet NCBIGene:8092 biolink:causes MONDO:0013271 infores:monarchinitiative not_provided not_provided HGNC:1494 MONDO:0013271 uuid:e3019d06-ec87-4cb1-b6e3-32f42e94d9f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410146659 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146659 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1418A>C (p.Glu473Ala) is a missense variant which has a REVEL score < 0.50 (0.162) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146659/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:93635 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0851578 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0020538 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0549389 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0549389 infores:hetionet CHEBI:31536 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0002994 infores:hetionet CHEBI:94440 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0235146 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0016436 infores:hetionet CHEBI:101278 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0038325 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034063 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0027769 infores:hetionet CHEBI:3723 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019521 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004936 infores:hetionet UMLS:C0657912 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0947912 infores:hetionet CHEBI:9137 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0007859 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0041912 infores:hetionet CHEBI:64312 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0028084 infores:hetionet CAID:CA229420 biolink:causes MONDO:0009861 infores:clingen CAID:CA229420 MONDO:0009861 PMID:23514811PMID:27121329PMID:26503515PMID:27121329 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1262T>C (p.Ile421Thr) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID: 26503515, PMID: 27121329, PMID: 23514811). This variant has low frequency (MAF=0.00001) in gnomAD. This variant was detected with pathogenic variants: R241H (PMID: 27121329); p.Arg408Gln (PMID: 25456745); IVS5-1G＞A, p.Val399= (PMID: 29316886); Ex9_11del (LP PAH VCEP) PMID: 31623983. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_vstrong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229420/MONDO:0009861/006 2021-05-29 2021-05-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8772 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0600142 infores:hetionet CHEBI:17688 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0039070 infores:hetionet CHEBI:9086 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0220870 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C3160741 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0178298 infores:hetionet CHEBI:92607 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0042510 infores:hetionet GO:0106396 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0007399 NCBIGene:4621 biolink:causes MONDO:0008338 infores:monarchinitiative not_provided not_provided HGNC:7573 MONDO:0008338 uuid:b45bca52-eb51-4a53-9ec7-4e69ee834aa0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0016204 infores:hetionet NCBIGene:389856 biolink:causes MONDO:0010510 infores:monarchinitiative not_provided not_provided HGNC:13486 MONDO:0010510 uuid:07784c9a-96b6-4278-9e25-d5596144e833 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C0740411 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0740411 infores:hetionet CHEBI:4858 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0043094 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0003123 infores:hetionet CAID:CA512318849 biolink:causes MONDO:0100083 infores:clingen CAID:CA512318849 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 BP4Multiple lines of computational evidence suggest no impact on gene /gene product. BP4: This synonymous variant has a SpliceAI Δ score < 0.2 and PhyloP100way: 1.191BP7Silent variant predicted with no splice impact. BP7: Evolutionary conservation prediction algorithms predict the site as not being conserved(PhyloP score < 2.0) (BP7).In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteriaapplied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1:BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318849/MONDO:0100083/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:4786 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0085631 infores:hetionet CHEBI:50378 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0151908 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0005741 infores:hetionet CHEBI:7444 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0002622 infores:hetionet CHEBI:16335 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0038990 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0851341 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0019158 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0424605 infores:hetionet CHEBI:8024 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0162830 infores:hetionet UMLS:C0065374 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0235896 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0006145 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0003123 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0023895 infores:hetionet CHEBI:5165 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151830 infores:hetionet CHEBI:72690 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0003467 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017160 infores:hetionet CHEBI:4784 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0040264 infores:hetionet CHEBI:6775 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011603 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014549 infores:hetionet CHEBI:64317 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0020538 infores:hetionet CHEBI:7577 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0043352 infores:hetionet CHEBI:63631 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0023380 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0013922 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0852733 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013404 infores:hetionet CHEBI:3215 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0007166 infores:hetionet CHEBI:125354 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0178298 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151661 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151661 infores:hetionet CHEBI:8212 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0037822 infores:hetionet CHEBI:2914 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0039231 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0234215 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1262013 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0853141 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0853141 infores:hetionet CHEBI:84500 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0023380 infores:hetionet CHEBI:28830 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0022346 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0012833 infores:hetionet UNII:3U02EL437C biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0542346 infores:hetionet NCBIGene:1917 biolink:causes MONDO:0014625 infores:monarchinitiative not_provided not_provided HGNC:3192 MONDO:0014625 uuid:bb2eb524-32b7-46e8-a2a7-57f6bcfc4662 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes HP:0001892 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1458140 infores:hetionet NCBIGene:4624 biolink:causes MONDO:0013198 infores:monarchinitiative not_provided not_provided HGNC:7576 MONDO:0013198 uuid:d3870be2-d3c7-4d5e-b6bc-c799454bdee1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009241 infores:hetionet CAID:CA613324873 biolink:causes MONDO:0100040 infores:clingen CAID:CA613324873 MONDO:0100040 PMID: Benign BA1 PM4, BP3 The highest population minor allele frequency of the p.Glu155del variant in FOXG1 in gnomAD v4.1 is 0.0003552 in the African/African-American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). In summary, the p.Glu155del variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BA1). (FOXG1 Specifications v.4.1; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA613324873/MONDO:0100040/035 2025-06-25 2025-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021053 infores:hetionet CHEBI:50742 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0029124 infores:hetionet CHEBI:4708 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0007820 infores:hetionet CHEBI:10110 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0037763 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0042487 infores:hetionet CHEBI:15365 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0002994 infores:hetionet CHEBI:31932 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042029 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0021053 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0007859 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020649 infores:hetionet CAID:CA386965156 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965156 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PS4_Moderate, PM1_Supporting, PP3 PM5, PP4 The c.683A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to glycine at codon 228 (p.(Glu228Gly)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8659, which is greater than the MDEP threshold of 0.7 (PP3). Additionally, this variant is located within the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.683A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP3, PM1_Supporting, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965156/MONDO:0015967/017 2022-08-05 2022-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA16614941 biolink:causes MONDO:0100488 infores:clingen CAID:CA16614941 MONDO:0100488 PMID: Likely Benign BP7, BS2, BP4 BS1, PM2, PP3, BA1 The c.408A>G (p.Gln136=) variant results in a synonymous change in exon 4 of CDH1. This is a silent variant that occurs at a position that is not highly conserved and for which splicing predictors do not suggest an impact on splicing (BP4, BP7). This variant is absent from the gnomAD population database v3.1.2. This variant was identified in 29 individuals without DGC, LBC, SRC tumours and whose families do not suggest HDGC (BS2; PMID: 30287823, 36436516, and internal laboratory contributors). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as likely benign specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614941/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7465 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0151698 infores:hetionet CAID:CA414447349 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447349 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3 The c.1325G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Glutamate at amino acid 442 (p.Gly442Glu). This variant has been reported in at least 2 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Moderate; PMID: 12604421, 18624698). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Another missense variant c.1234G>A, p.Gly442Arg in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PM5, PS4_Moderate, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447349/MONDO:0010604/080 2024-05-09 2024-05-09 X-linked inheritance HP:0001417 Supports CHEBI:8768 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0851578 infores:hetionet CHEBI:5001 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0002418 infores:hetionet CHEBI:7936 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085631 infores:hetionet CHEBI:53760 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018681 infores:hetionet CHEBI:3223 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013428 infores:hetionet CAID:CA10118733 biolink:causes MONDO:0021060 infores:clingen CAID:CA10118733 MONDO:0021060 PMID: Likely Pathogenic PM3, PM2_Supporting, PS1, PVS1_Moderate BA1, BS1 The NM_006767.4:c.1149+1G>T variant in LZTR1 occurs within the canonical splice donor site (+1) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/21, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008998 (1/111130 alleles) in the European (non-Finnish) population, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, meeting this criterion (PM2_Supporting). A variant causing the same canonical splice site change, resulting from a different nucleotide change c.1149+1G>A, is classified as likely pathogenic for autosomal recessive RASopathy by the ClinGen RASopathy VCEP (PS1). This variant has been detected in 2 individuals with RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and were confirmed in trans by family testing (c.1084C>T (p.Arg362*), c.2062C>T (p.R688C), 1.25 PM3 points, PMIDs: 30859559 and 31182298) (PM3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS1, PVS1_Moderate, PM3, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10118733/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0236000 infores:hetionet CHEBI:30659 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0036572 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0281856 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009763 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0020538 infores:hetionet CHEBI:9137 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0740394 infores:hetionet CHEBI:63635 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0033774 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0948089 infores:hetionet CHEBI:48844 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0231218 infores:hetionet CHEBI:4710 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0700200 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151849 infores:hetionet CHEBI:27363 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01593 UMLS:C0392176 infores:hetionet NCBIGene:51057 biolink:causes MONDO:0009008 infores:monarchinitiative not_provided not_provided HGNC:28027 MONDO:0009008 uuid:43228296-e893-4559-a07b-3edad92b3da4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0008031 infores:hetionet CHEBI:6965 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0392156 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0151898 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151898 infores:hetionet CHEBI:2955 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0030252 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0003123 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0003123 infores:hetionet CAID:CA1139532728 biolink:causes MONDO:0020367 infores:clingen CAID:CA1139532728 MONDO:0020367 PMID:16466712PMID:35196929 Likely Pathogenic PP1_Moderate, PS3_Moderate, PM2_Supporting, PM4_Supporting BP7, BS1, BS3, PM6, PP3, PM5, PS4, PS1, PS2, BA1, BP4 The c.1187_1189dup variant in MYOC is predicted to cause a change in the length of the protein due to an in-frame insertion of 1 amino acid (p.Glu396dup). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. Previous studies (PMIDs: 16466712, 35196929) demonstrated that the Glu396dup protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 5 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PM2_Supporting, PM4_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532728/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports CAID:CA10385669 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385669 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.320A>G (p.Asn107Ser) is a missense variant causing substitution of asparagine by serine at amino acid 107. This variant is present in gnomAD v4.1.0 at a frequency of 0.00005528 among hemizygous individuals, with 22 variant alleles / 398,005 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.197, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X- linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385669/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true NCBIGene:1294 biolink:causes MONDO:0007549 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0007549 uuid:01697f4a-b964-415c-ac9a-3811509bd889 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0030252 infores:hetionet CHEBI:63619 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0040822 infores:hetionet CHEBI:7465 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0086769 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0034150 infores:hetionet NCBIGene:22907 biolink:causes MONDO:0060622 infores:monarchinitiative not_provided not_provided HGNC:16716 MONDO:0060622 uuid:57ea0e55-ecf7-4377-b4fd-562c42f973c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0015967 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0031046 infores:hetionet CAID:CA213966 biolink:causes MONDO:0015967 infores:clingen CAID:CA213966 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.660_662delGCTinsTCAA (p.(Leu221GInfsTer6)) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.660_662delGCTinsTCAA (p.(Leu221GInfsTer6)) meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213966/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32139 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0085681 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151763 infores:hetionet CHEBI:9943 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0392525 infores:hetionet CAID:CA229366 biolink:causes MONDO:0009861 infores:clingen CAID:CA229366 MONDO:0009861 PMID:31623983PMID:27121329PMID:9452061 Pathogenic PM5, PM2, PP4_Moderate, PM3_Strong PP3 This c.1162G>C (p.Val388Leu) variant in PAH was reported in 3 patients with PAH deficiency (PMID: 27121329, 31623983) detected with the likely pathogenic variant p.Pro281Leu and the pathogenic variant p.Arg252Trp. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is a novel missense change at an amino acid residue where a different missense change p.Val388Met determined to be pathogenic has been seen before. This variant is present in Dominican populations at a minor allele frequency of 0.00052 (PAGE study). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229366/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:72297 biolink:causes MONDO:0002569 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0038353 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0031117 infores:hetionet CHEBI:48669 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0042487 infores:hetionet CHEBI:3223 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0700361 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0039446 infores:hetionet CHEBI:68595 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0017178 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0160390 infores:hetionet CHEBI:135920 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0850149 infores:hetionet CHEBI:15367 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013362 infores:hetionet CHEBI:39867 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0011603 infores:hetionet CHEBI:24564 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0151849 infores:hetionet NCBIGene:253959 biolink:causes MONDO:0032921 infores:monarchinitiative not_provided not_provided HGNC:17770 MONDO:0032921 uuid:5cd6c637-f4ac-4c90-968c-f52dec724be6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes UMLS:C0549389 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549389 infores:hetionet CHEBI:8382 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0018524 infores:hetionet CHEBI:85083 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0022107 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007117 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0151673 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151673 infores:hetionet CHEBI:47381 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0241057 infores:hetionet CHEBI:2659 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0039240 infores:hetionet CHEBI:4562 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042963 infores:hetionet CHEBI:27834 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0006277 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0852733 infores:hetionet CHEBI:52717 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0917801 infores:hetionet CHEBI:9168 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C3665347 infores:hetionet CHEBI:31859 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0010200 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0521839 infores:hetionet CHEBI:5855 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020598 infores:hetionet CHEBI:8874 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0033575 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0242350 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001408 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0238309 infores:hetionet CHEBI:8356 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0043094 infores:hetionet CAID:CA242471869 biolink:causes MONDO:0009861 infores:clingen CAID:CA242471869 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting BP7 The NM_000277.3:c.786C>T in PAH is a synonymous (silent) variant (p.Val262=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 883189, 1 star review status) with two submitters classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA242471869/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8310 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0015967 infores:hetionet CHEBI:31236 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011124 infores:hetionet CHEBI:135929 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0000737 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027769 infores:hetionet CHEBI:28148 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020458 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006145 infores:hetionet CHEBI:3393 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0016204 infores:hetionet CAID:CA340925 biolink:causes MONDO:0044970 infores:clingen CAID:CA340925 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1 The m.8361G>A variant in MT-TK has been reported in one individual with primary mitochondrial disease (PMID: 14681892). This individual had seizures onset following febrile illness, ataxia, progressive cognitive and motor regression, sensorimotor neuropathy, and progressive bilateral sensorineural hearing loss. Brain imaging showed cerebral atrophy. Muscle biopsy showed multiple ragged red and COX-negative/SDH-positive fibers. The variant was present at 82% heteroplasmy in muscle, 34% in skin, and 24% in blood. The mother had migraines and the variant present at 1% in blood. The variant was undetectable in blood from the maternal grandmother (who had history of hypertrophic cardiomyopathy) and maternal aunt (who had sudden cardiac death). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). MitoTIP predicts the variant is likely pathogenic (64.8 percentile) and HmtVAR predicts the variant is pathogenic (score of 0.55; PP3). Single fiber testing showed positive correlation between high levels of the variant and COX-negative fibers (PS3_supporting, PMID: 14681892). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340925/MONDO:0044970/015 2024-07-22 2025-10-31 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63618 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C3267047 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0027051 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0029134 infores:hetionet CHEBI:5778 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013491 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024115 infores:hetionet CHEBI:6690 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0234133 infores:hetionet CAID:CA1139665163 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665163 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The c.1896dup (p.Asn633GlnfsTer57) variant in ACADVL is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and extend the protein by 32 amino acids (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. In summary, this variant meets the criteria to be classified as UNCERTAIN SIGNIFICANCE for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 12-29-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665163/MONDO:0008723/021 2023-02-14 2023-02-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6775 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0149931 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0042109 infores:hetionet CHEBI:15367 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0010200 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0267792 infores:hetionet CHEBI:7954 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0701811 infores:hetionet CHEBI:74947 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0917801 infores:hetionet CHEBI:520985 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0235198 infores:hetionet CHEBI:31348 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013456 infores:hetionet CAID:CA229797 biolink:causes MONDO:0009861 infores:clingen CAID:CA229797 MONDO:0009861 PMID:15300621PMID:23932990 Likely Pathogenic PM5, PM2, PP4, PP3 The c.827T>G (p.Met276Arg) variant in PAH is absent from population databases and predicted damaging by in silico models. It is a novel missense change at an amino acid residue where different pathogenic missense changes have been reported (p.Met276Val is LP in ClinVar, p.Met276Lys is LP via PAH EP). It has been reported in individuals with phenylkeonuria in the literature, although a defect in the metabolism of BH4 has not been excluded as a cause for elevated phenylalanine in any of these patients (PMID: 23932990, 15300621). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229797/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports UNII:F64QU97QCR biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C2047937 infores:hetionet CHEBI:6887 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0851578 infores:hetionet CAID:CA119012 biolink:causes MONDO:0800472 infores:clingen CAID:CA119012 MONDO:0800472 PMID: Pathogenic PP1, PM2_Supporting, PM3_Very Strong, PVS1_Moderate PP3, BA1, BP4, PS1, PS3, PS2, PM5, PM1, PM4, BP7, BS1, BS4 The c.2T>C variant in CYP1B1 is an initiation codon variant predicted to cause substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). This initiation codon variant met PVS1_Moderate. The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1) = 0.000005085 (6 alleles out of 1,179,926), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 1 affected segregation with a CYP1B1-related phenotype has been reported (PMID: 21168818), which fulfilled PP1. This variant has been identified in 6 individuals with a CYP1B1-related phenotype. 3 individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) = 3 points (PMIDs: 16735991, 21168818). 1 individual is compound heterozygous for the variant and a variant of uncertain significance (confirmed in trans) = 0.25 points (PMID: 21815720). 2 individuals are homozygous for the variant (1 consanguineous and 1 non-consanguineous) = 0.75 points (PMIDs: 12036985, 24940937). Total proband points = 4, meeting PM3_Very strong. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very-Strong, PVS1_Moderate, PP1, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119012/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0428977 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027339 infores:hetionet NCBIGene:84065 biolink:causes MONDO:0859176 infores:monarchinitiative not_provided not_provided HGNC:25363 MONDO:0859176 uuid:bc538ce0-63a5-4fd1-9782-e3dca2907f85 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0242429 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0035078 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0234222 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0403632 infores:hetionet CHEBI:94686 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0004364 infores:hetionet CAID:CA438057772 biolink:causes MONDO:0001586 infores:clingen CAID:CA438057772 MONDO:0001586 PMID: Pathogenic PM3_Strong, PM4_Supporting, PM1, PP3, PP4, PM2_Supporting PS1, PS3, PM5 "The NM_000203.5(IDUA):c.1045_1047del (p.Asp349del) variant in IDUA is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid in a non-repeat region (p.Asp349del) (PM4_Supporting). This variant removes amino acid Asp349, a residue that has been shown to be important in substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 23959878, 24036510) (PM1). At least 4 probands have been reported with the variant, all with a diagnosis of MPS I and including patients with very low IDUA activity, and elevated urine GAGs (PMID: 36837830) or detailed clinical symptoms consistent with the condition (PMID: 27351199) (PP4). Of those individuals, 2 were compound heterozygous, phase unknown, for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP; either c.713T>A (p.Leu238Gln) (PMID: 27351199, 0.5 points) or c.208C>T (p.Gln70Ter) (PMID: 21394825, 27392569, 0.5 points; cannot confirm that these reports are not the same patient). Two patients are homozygous for the variant (PMID: 21394825, 36837830, 2 x 0.5 points). Total 2 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002229 (1/44872 alleles) in the East Asian population (PM2_Supporting). In silico predictors suggest that the variant impacts the function of the gene product; Mutation Taster predicts that the variant is ""disease-causing"", score for MutPredIndel is 0.789 (>0.5 for deleterious) (PP3). There is a ClinVar entry for this variant (Variation ID: 557885). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_Strong, PM1, PP3, PM2_Supporting, PM4_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA438057772/MONDO:0001586/091 2025-04-07 2025-04-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4356 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0040264 infores:hetionet CHEBI:49960 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151878 infores:hetionet CHEBI:94501 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0035455 infores:hetionet CHEBI:7575 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0428977 infores:hetionet NCBIGene:3110 biolink:causes MONDO:0008305 infores:monarchinitiative not_provided not_provided HGNC:4979 MONDO:0008305 uuid:90c5dd35-da4d-4e0b-9f8d-b3ebe5bb832a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:142290 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0018965 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020649 infores:hetionet CHEBI:4868 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0232487 infores:hetionet CHEBI:74947 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0035455 infores:hetionet CHEBI:7956 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0267792 infores:hetionet CHEBI:9763 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151474 infores:hetionet CHEBI:6887 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0004093 infores:hetionet CHEBI:9288 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0021368 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0543467 infores:hetionet CHEBI:51860 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151889 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0857807 infores:hetionet CHEBI:53691 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0003811 infores:hetionet CHEBI:63608 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1368065 infores:hetionet CAID:CA270591 biolink:causes MONDO:0010726 infores:clingen CAID:CA270591 MONDO:0010726 PMID: Pathogenic PM5, PP4, PS4, PM2_Supporting, PM6_Strong PM1, PP3, BP4 The c.965C>T p.(Pro322Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro322Leu) variant has been observed in at least 5 individuals with Rett syndrome (PMID: 10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PS4, PP4), where it has been reported in as de novo occurrences (biological parentage unconfirmed) in at least 2 individuals (PMID 10814718, 11402105) (PM6_strong). Multiple missense variants have been previously identified within this codon, at least one of which is classified as pathogenic; this indicates that this residue is critical to the function of the protein (PMID 10814719, 16966553, 16225173, 32820509) (PM5). In summary, the c.965C>T p.(Pro322Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PP4, PM5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270591/MONDO:0010726/016 2022-07-05 2022-09-06 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:2549 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0026961 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007642 infores:hetionet CAID:CA512318874 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318874 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.261C>A (p.Gly87=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This synonymous variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.30) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318874/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3506 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0085631 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0854375 infores:hetionet CHEBI:4974 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0014518 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0039971 infores:hetionet CHEBI:4495 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0152025 infores:hetionet CHEBI:5138 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009421 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0037199 infores:hetionet CHEBI:28787 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0700292 infores:hetionet CHEBI:27300 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0030193 infores:hetionet CHEBI:194135 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0019079 infores:hetionet CHEBI:8871 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013428 infores:hetionet CHEBI:2687 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0030312 infores:hetionet CHEBI:119915 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026826 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0085593 infores:hetionet CHEBI:4708 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0036508 infores:hetionet NCBIGene:91137 biolink:causes MONDO:0030260 infores:monarchinitiative not_provided not_provided HGNC:25198 MONDO:0030260 uuid:249f1c5a-c43a-43c9-af03-b736f805d037 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2654 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0042755 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0152027 infores:hetionet CHEBI:9086 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0520966 infores:hetionet CAID:CA025261 biolink:causes MONDO:0700269 infores:clingen CAID:CA025261 MONDO:0700269 PMID: Benign BP5_Stand Alone, BS3, BS1_Supporting, BP4 The c.7759C>T variant in BRCA2 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 2587 (p.Leu2587Phe). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00004512 in the European (non-Finnish) population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.15, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0.04 predicts no impact on splicing (score threshold <0.10) (BP4 met). Reported by four calibrated studies to exhibit protein function similar to benign control variants (PMIDs:38417439, 33293522, 39779857, 39779848) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0022 (based on Cosegregation LR=0.092; Pathology LR=0.675; Family History LR=0.0345), below the thresholds for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID 34597585, 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP4, BS3, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025261/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10650 biolink:causes HP:0002183 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0751466 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0678222 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0023890 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0152029 infores:hetionet CHEBI:617099 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0027765 infores:hetionet CHEBI:36791 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0236075 infores:hetionet CHEBI:5165 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C2047937 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0861111 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0861111 infores:hetionet CHEBI:83804 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0152031 infores:hetionet CHEBI:28748 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0242301 infores:hetionet CHEBI:3181 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042384 infores:hetionet NCBIGene:9928 biolink:causes MONDO:0014552 infores:monarchinitiative not_provided not_provided HGNC:19181 MONDO:0014552 uuid:29b89d33-cfcf-496b-b91e-d40b35a01f7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0035455 infores:hetionet CAID:CA015373 biolink:causes MONDO:0005021 infores:clingen CAID:CA015373 MONDO:0005021 PMID: Uncertain Significance PP3, PM2_Supporting, PP1_Moderate, PS4_Supporting PM6, PM5, PM4, PM1, BA1, PS3, BP3, BS1, BS3, BS4, PS2, PS1, BP5, BP4, BP7, PVS1 The NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln) variant has been identified in 3 individuals with DCM and 2 individuals with HCM (PS4_Supporting; Marston 2015 PMID: 26406308; Minoche 2019 PMID: 29961767; Horvat 2019 PMID: 29892087; GeneDx pers. comm.; Invitae pers. comm). It was also identified in 1 individual with atrial fibrillation (Invitae pers. comm.). This variant has been observed to segregate with DCM in 5 affected relatives of a proband with DCM as well as not segregate with DCM in an affected maternal uncle, although this discrepancy may be explained by the presence of an environmental origin of disease. (PP1_moderate; Minoche 2019 PMID: 29961767; Horvat 2019 PMID: 29892087). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1_Moderate; PM2_Supporting; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015373/MONDO:0005021/002 2022-07-30 2022-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31981 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0004245 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151763 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0036572 infores:hetionet CAID:CA350341605 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341605 MONDO:0015924 PMID: Pathogenic PM2, PVS1, PS4_Supporting BA1, BS1 BMPR2 c.1126G>T (p.Glu376Ter) variant is predicted to cause premature stop at residue 376, in exon 8, and lead to nonsense mediated decay. The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting met) and was identified in two unrelated idiopathic PAH probands (PMID: 26387786 and PMID: 31727138) (PS4_supporting met). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341605/MONDO:0015924/125 2024-09-20 2024-09-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018824 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0232492 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017160 infores:hetionet CAID:CA005312 biolink:causes MONDO:0005045 infores:clingen CAID:CA005312 MONDO:0005045 PMID: Likely Pathogenic PS4_Moderate, PP1_Strong, PM4, PM2_Supporting PS3, BS3, PVS1 NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter). This variant has been reported in individuals with HCM (LMM data, Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 25575096, Brito 2012 PMID: 22857948, Lopes 2013 PMID: 23396983, Bales 2016 PMID: 26936621, Walsh 2017 PMID: 27532257, Mademont-Soler 2017 PMID: 28771489, Ho 2018 PMID: 30297972) and has been identified in been identified in 1 out of 242296 (0.002% FAF 95% CI) of global pan-ethnic chromosomes in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/; v.2.1). This variant is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, PS4_Moderate criterion has been applied. This variant segregated with disease in 7 affected relatives from 6 families (PP1_Strong; Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 20439259, Brito 2012 PMID: 22857948, D. Brito pers comm, GeneDx pers comm; LMM data). This nonsense variant leads to a premature termination codon at position 297. This alteration occurs within the terminal 50 bases of the last exon and is therefore likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 2 amino acids (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PP1_Strong and PM4. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA005312/MONDO:0005045/099 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42797 biolink:causes MONDO:0004866 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0271468 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0234215 infores:hetionet CHEBI:68845 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0033774 infores:hetionet GO:2000977 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:2000977 GO:0060322 CAID:CA10652923 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652923 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*1938C>T is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652923/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA7330808 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330808 MONDO:0100216 PMID: Likely Benign BS3_Supporting, BS2 PVS1, PM2, PM6, BP3, BP1, BP4, BA1, PP2, PP3, PP4, PM1, PM4, PM5, PM3, PS1, PS4, PS3, PS2, BP5, BP7, BS1 The NM_177438.2:c.4740G>T variant in DICER1 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 1580 (p.Gln1580His). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00004585 (74/1614104 alleles) with a highest population minor allele frequency of 0.00006186 (73/1180036 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (BS3_Supporting; Wu 2018, McGill University). The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function; splice predictors MaxEntScan and SpliceAI indicate no impact on splicing (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BS3_Supporting. (Bayesian Points: -5; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330808/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0023530 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0242350 infores:hetionet CHEBI:51230 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0152227 infores:hetionet CAID:CA367401896 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401896 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP2, PP3, PP1, PM2_Supporting The c.465G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to serine at codon 155 (p.(Arg155Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.766, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with three informative meioses in one family (PP1; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.465G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2, PP1, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401896/MONDO:0015967/086 2023-10-03 2023-10-03 Semidominant inheritance HP:0032113 Supports CAID:CA1139771322 biolink:causes MONDO:0007453 infores:clingen CAID:CA1139771322 MONDO:0007453 PMID: Pathogenic PS4_Moderate, PVS1_Strong, PM3, PP4_Moderate, PM2_Supporting PP1 The c.1256del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 419 (NM_000162.5), adding 12 novel amino acids before encountering a stop codon (p.(Phe419SerfsTer12)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 25015100, PMID: 29056535, PMID: 33414663 and internal lab contributors). This variant has been detected in at least two individuals with neonatal diabetes. Of those individuals, two were homozygous. (PM3; PMID: 25015100, PMID: 29056535, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative, and 3 generation dominant family history of diabetes) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.1256del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PS4_Moderate, PM3, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771322/MONDO:0007453/086 2023-06-26 2023-06-26 Semidominant inheritance HP:0032113 Supports CHEBI:5790 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085584 infores:hetionet CHEBI:3723 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235939 infores:hetionet CHEBI:74947 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040038 infores:hetionet CHEBI:31705 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C2939147 infores:hetionet CHEBI:61033 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020580 infores:hetionet CHEBI:9571 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0004044 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0920102 infores:hetionet CHEBI:4798 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0239571 infores:hetionet CAID:CA294385 biolink:causes MONDO:0100488 infores:clingen CAID:CA294385 MONDO:0100488 PMID: Likely Benign BS2 BS1, PM2, BA1 The NM_004360.5(CDH1):c.2020A>T (p.Asn674Tyr) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294385/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA10568007 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568007 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4, PS3 PM5 The c.5303G>A (p.Arg1768His) variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. This missense variant has a REVEL score of 0.819 and meets PP3 criteria (threshold >0.6). At least 7 patients are reported in the literature with mild hemophilia A, meeting F8 phenotype criteria for PP4_Moderate and PS4 (PMID: 29296726, 17222201, 12871415, 21166991, 16972227, 24452774). This variant is known to have discrepant factor VIII levels, with chromogenic (two-stage) being 2-fold lower than one-stage assay levels (EAHAD database, PMID: 32232366). Finally, a COS-1 cell line was used to demonstrate decreased factor VIII activity and antigen levels (PMID: 30997536). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS3, PS4, PM2_Supporting, PP3, PP4_Moderate. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568007/MONDO:0010602/071 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5050 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0042023 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0853813 infores:hetionet CHEBI:64312 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0033774 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0004936 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0029878 infores:hetionet CHEBI:83804 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0424448 infores:hetionet CHEBI:61058 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0030554 infores:hetionet CHEBI:3084 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0232488 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0022904 infores:hetionet CHEBI:5779 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C2830004 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0041969 infores:hetionet CHEBI:28864 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151723 infores:hetionet CAID:CA381933255 biolink:causes MONDO:0700087 infores:clingen CAID:CA381933255 MONDO:0700087 PMID: Uncertain Significance PM3_Supporting, PP3, PP4, PM2_Supporting BS1, BA1 The variant NM_000260.4:c.983T>C in MYO7A is a missense variant predicted to cause substitution of leucine by proline at amino acid 328 (p.Leu328Pro). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant p.Leu328Pro variant was identified by multigene panel testing in a three year old male proband with congenital bilateral profound sensorineural hearing loss and pigmentary retinopathy, delayed motor milestones, blonde fundus, and a diagnosis of Usher Syndrome 1B (PP4, PMID: 32281467). The proband also harbored a likely pathogenic variant NM_000260(MYO7A):c.471-2A>C, however the phase of the variants was not confirmed (0.5 PM3 points, PM3_Supporting; PMID: 32281467). The computational predictor REVEL gives a score of 0.877, which is above the threshold necessary to apply PP3 (PP3). There is a ClinVar entry for this variant (Variation ID: 1308583, one star review status), with one submitter classifying the variant as uncertain significance. In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA381933255/MONDO:0700087/005 2024-12-18 2025-03-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:474180 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1619702 infores:hetionet CHEBI:63612 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0041969 infores:hetionet CAID:CA205044 biolink:causes MONDO:0007113 infores:clingen CAID:CA205044 MONDO:0007113 PMID: Benign BA1 BP7 The allele frequency of the c.1707C>T p.(Tyr569=) variant in UBE3A (NM_130838.2) is 0.15% in the European (non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1707C>T p.(Tyr569=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA205044/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA16615991 biolink:causes MONDO:0007750 infores:clingen CAID:CA16615991 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 The NM_000527.5(LDLR):c.1731G>C (p.Trp577Cys) variant is classified as uncertain significance for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PM5: 5 other missense variant(s) in the same codon, and 1 of them is classified as Pathogenic by these guidelines:- NM_000527.5(LDLR): variant (ClinVar ID 252000)PP3: REVEL = 0.939 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615991/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:167309 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0020517 infores:hetionet CHEBI:4909 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0033774 infores:hetionet CHEBI:5118 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0231530 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0234215 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0518015 infores:hetionet CHEBI:9123 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018965 infores:hetionet CHEBI:3011 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0036974 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0853692 infores:hetionet CHEBI:8081 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0016382 infores:hetionet CHEBI:77260 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0241136 infores:hetionet CHEBI:4511 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151766 infores:hetionet CHEBI:6822 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0162830 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0857361 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0857361 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0021053 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014130 infores:hetionet CHEBI:31348 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022346 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006690 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007274 infores:hetionet CHEBI:71023 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0022281 infores:hetionet CAID:CA383520062 biolink:causes MONDO:0015631 infores:clingen CAID:CA383520062 MONDO:0015631 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3, PM5 PP3, PP1 The NM_000552.5:c.2637C>A variant in VWF is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 879 (p.Asp879Glu). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity and decreased VWF:FVIII binding, which is highly specific for VWD type 2N. (PP4_moderate, PMID 26988807). Additional consistent phenotypes were also reported in the patient including normal VWF:Ag, and normal HMW multimers. This variant has been detected in 1 individual with von Willebrand Disease type 2N. The individual is compound heterozygous for the variant and a pathogenic variant as determined by the ClinGen VWD VCEP, confirmed in trans by the authors (p.Arg854Gln) (PM3, PMID 26988807).This variant is absent from gnomAD v4.1 (PM2_Supporting). Another missense variant c.2635G>A, p.Asp879Asn (PMIDs 9845532, 34298581) in the same codon has been classified as pathogenic for VWD type 2N by the ClinGen VWD VCEP (PM5). Splicing prediction using SpliceAI revealed no expected effects on splicing due to any of these variants. In summary, this variant meets the criteria to be classified as a variant of likely pathogenic for von Willebrand Disease type 2N based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PM3, PM2_Supporting, and PM5. (ClinGen VWD VCEP, VWD type 2N rule specifications v1.0.0; date of approval) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383520062/MONDO:0015631/090 2024-11-05 2024-11-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7492 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0032285 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011991 infores:hetionet NCBIGene:5144 biolink:causes MONDO:0013822 infores:monarchinitiative not_provided not_provided HGNC:8783 MONDO:0013822 uuid:181f62f6-6261-40d6-9903-9290c4b90353 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63638 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0039971 infores:hetionet CHEBI:36795 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0699828 infores:hetionet CHEBI:231594 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0015967 infores:hetionet CHEBI:7822 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0151746 infores:hetionet CHEBI:6062 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042963 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1142011 infores:hetionet CHEBI:9316 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0041834 infores:hetionet CHEBI:4653 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0520966 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0037286 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0948594 infores:hetionet CHEBI:3994 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0012833 infores:hetionet CHEBI:8802 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0232487 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0475858 infores:hetionet CHEBI:72297 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0009782 infores:hetionet CHEBI:30659 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0948594 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0232431 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0574067 infores:hetionet CHEBI:45951 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0151889 infores:hetionet CHEBI:6754 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0009421 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0233494 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0235146 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0042109 infores:hetionet CHEBI:9168 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0546817 infores:hetionet CHEBI:5864 biolink:causes HP:0012587 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0473237 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151735 infores:hetionet CHEBI:37333 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0004093 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0549336 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0015397 infores:hetionet CHEBI:474180 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0237849 infores:hetionet CHEBI:16842 biolink:causes GO:0030164 infores:drugmechdb knowledge_assertion manual_agent MESH:D005557 GO:0030164 DB06799_MESH_D014552_1 CHEBI:63580 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020538 infores:hetionet CHEBI:8774 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0011124 infores:hetionet CHEBI:100246 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0040034 infores:hetionet CHEBI:75722 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009421 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0032961 infores:hetionet CHEBI:10650 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0007859 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038661 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0029928 infores:hetionet CHEBI:127780 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0027497 infores:hetionet CHEBI:5106 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C1260880 infores:hetionet CHEBI:9667 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0702166 infores:hetionet CHEBI:50729 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0036974 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0009938 infores:hetionet CHEBI:8764 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0040822 infores:hetionet CHEBI:3013 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0015230 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0442874 infores:hetionet CHEBI:3699 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0020517 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0948525 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0314719 infores:hetionet CHEBI:17347 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0340865 infores:hetionet CHEBI:253342 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0004093 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0012833 infores:hetionet CHEBI:63791 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0031256 infores:hetionet CHEBI:9241 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0018418 infores:hetionet CAID:CA915940796 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940796 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.2415_2416del (p.Asp805GlufsTer11) frameshift variant in exon 24 is predicted to result in a premature stop codon in biologically-relevant-exon 25 of 30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 10 in PMID:19172520/GT database record 167) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <10%, as measured by flow cytometry. Patient 10 (PMID: 19172520/GT database record 167) is homozygous for this variant (0.5pt; PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940796/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA2697547500 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547500 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.132dup (p.Thr45HisfsTer?) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547500/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6715 biolink:causes MONDO:0019499 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041408 infores:hetionet CHEBI:68595 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0011991 infores:hetionet CHEBI:63589 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0011603 infores:hetionet CHEBI:63605 biolink:causes MONDO:0018979 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0393847 infores:hetionet CHEBI:5847 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0000737 infores:hetionet CHEBI:15365 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0027497 infores:hetionet CHEBI:63629 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013491 infores:hetionet CHEBI:75722 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0010200 infores:hetionet CHEBI:8382 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0338831 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0006266 infores:hetionet CHEBI:8435 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0002994 infores:hetionet CHEBI:61058 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0040034 infores:hetionet CHEBI:3723 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027849 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0025517 infores:hetionet CAID:CA410203838 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203838 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.234G>A (p.Met78Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203838/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2569 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C3665347 infores:hetionet CHEBI:28445 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0023530 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042035 infores:hetionet NCBIGene:5626 biolink:causes MONDO:0009878 infores:monarchinitiative not_provided not_provided HGNC:9455 MONDO:0009878 uuid:698b1649-63cf-4610-bd26-68bb92891b46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0234215 infores:hetionet CHEBI:83527 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0043094 infores:hetionet CHEBI:3387 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009676 infores:hetionet NCBIGene:8942 biolink:causes MONDO:0060555 infores:monarchinitiative not_provided not_provided HGNC:6469 MONDO:0060555 uuid:c64d6443-017f-40c1-99f6-0f8faff34f8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2704 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0021400 infores:hetionet CHEBI:63617 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151836 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0009946 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0041969 infores:hetionet CHEBI:31711 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0009421 infores:hetionet CHEBI:134743 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0349506 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0235290 infores:hetionet CHEBI:4657 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0004245 infores:hetionet NCBIGene:3265 biolink:causes MONDO:0008097 infores:monarchinitiative not_provided not_provided HGNC:5173 MONDO:0008097 uuid:2763abc4-282a-4607-8ded-a07ecbe0ddbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0877153 infores:hetionet CHEBI:135930 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0018681 infores:hetionet CHEBI:3738 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0009806 infores:hetionet NCBIGene:254528 biolink:causes MONDO:0054726 infores:monarchinitiative not_provided not_provided HGNC:28569 MONDO:0054726 uuid:48315b72-7a53-4a47-b6e2-94ab15736429 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:79042 biolink:causes MONDO:0012891 infores:monarchinitiative not_provided not_provided HGNC:15506 MONDO:0012891 uuid:92da8092-1ad4-4d20-a007-5b634da01fb5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0151799 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0497247 infores:hetionet CHEBI:5855 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151578 infores:hetionet CAID:CA293620 biolink:causes MONDO:0010278 infores:clingen CAID:CA293620 MONDO:0010278 PMID: Likely Benign BP7, BS1 The allele frequency of the p.Gly47= variant in SLC9A6 is 0.008% in European (Non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Gly47= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Gly47= variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA293620/MONDO:0010278/016 2022-02-19 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:38940 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0015672 infores:hetionet CHEBI:101278 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1368065 infores:hetionet CHEBI:68558 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0013395 infores:hetionet NCBIGene:11190 biolink:causes MONDO:0020780 infores:monarchinitiative not_provided not_provided HGNC:1859 MONDO:0020780 uuid:4997b1cd-7a29-4f5f-9633-a5103a982a82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10360709 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360709 MONDO:0010725 PMID: Likely Benign PP3_Moderate, BA1 PS4 The NM_000330.4(RS1):c.264G>C variant is a missense variant encoding the substitution of Glutamine with Histidine at amino acid 88. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0002598 among hemizygous individuals, with 103 variant alleles / 396503 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The computational predictor REVEL gives a score of 0.804, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1, PP3_moderate (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360709/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:231594 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0021400 infores:hetionet CAID:CA415084839 biolink:causes MONDO:0010305 infores:clingen CAID:CA415084839 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, PP4_Strong PP3 The NM_005629.4(SLC6A8):c.993C>G variant in SLC6A8 is a missense variant predicted to cause substitution of Asparagine for Lysine at amino acid 331 p.(Asn331Lys). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.665 which is less than the threshold of 0.75 established for in silico predictions, therefore PP3 criteria is not applicable. This variant has not been previously reported in ClinVar, and other variants at p.Asn331 are also not reported there. This variant has been reported in one affected male in the literature with developmental delay, hypotonia, aggressive behavior and seizures who was found to have elevated urine creatine/creatinine ratio and reduced creatine peak by MRS, meeting criteria for PP4_Strong [PMID: 21910234]. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Nov. 8, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415084839/MONDO:0010305/027 2023-11-08 2024-02-11 X-linked inheritance HP:0001417 Inconclusive true CHEBI:9763 biolink:causes UMLS:C0235074 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235074 infores:hetionet CHEBI:188986 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0004093 infores:hetionet CAID:CA017451 biolink:causes MONDO:0007947 infores:clingen CAID:CA017451 MONDO:0007947 PMID: Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong PM5 The NM_00138 c.7892G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2631 (p.Cys2631Tyr). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 42436). This variant has also been identified in at least 2 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 24793577, Invitae ClinVar, internal lab data; PS4_Mod). In one pediatric individual with MFS, this variant found to segregate in an affected sister and was found to be mosaic in the asymptomatic mother (internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.976, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0)). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Moderate, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017451/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:48273 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013604 infores:hetionet CHEBI:17347 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151578 infores:hetionet CHEBI:3996 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0013144 infores:hetionet CHEBI:17303 biolink:causes HP:0031274 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020683 infores:hetionet CHEBI:31623 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0027441 infores:hetionet CHEBI:63589 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0030554 infores:hetionet CHEBI:3504 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0085649 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151717 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0038362 infores:hetionet CAID:CA10585180 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585180 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, PS3, PM5, PP3 The NM_000527.5 (LDLR): c.895G>T (p.Ala299Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025).PP3 not Met: REVEL score = 0.519, which is below the threshold of 0.75. Functional data on splicing is not available, in silico splicing prediction is required. Variant is exonic and at least 50bp downstream from acceptor site and creates GT. MES scores: de novo donor = -2.99, authentic donor = 8.14. De novo score is negative and not used, therefore the variant is not predicted to alter splicing.BP4 not applicable: REVEL score is > 0.5, therefore BP4 is not applicable.PS3 not met: Functional data is not available.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>A (p.Ala299Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585180/MONDO:0007750/013 2022-02-10 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:27786 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0151735 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0150450 infores:hetionet CHEBI:8214 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0026857 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0260662 infores:hetionet CHEBI:204928 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0022346 infores:hetionet CHEBI:63580 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0262662 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0004623 infores:hetionet CHEBI:5893 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0035410 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0034150 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000749 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151463 infores:hetionet CAID:CA229519 biolink:causes MONDO:0009861 infores:clingen CAID:CA229519 MONDO:0009861 PMID: Likely Pathogenic PM2, PVS1 PP4 This canonical PAH variant c.352+1G>A is predicted to result in nonsense mediated decay. This variant was absent in population databases. This variant has been reported in the literature (PMID: 20140859), but is not available for review. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1,PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229519/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:140621 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0041948 infores:hetionet CAID:CA340741969 biolink:causes MONDO:0100368 infores:clingen CAID:CA340741969 MONDO:0100368 PMID: Pathogenic PM3, PM5, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting PM1 The NM_000329.3(RPE65):c.1399C>T (p.Pro467Ser) is predicted to replace the proline at position 467 with serine. The computational predictor REVEL gives a score of 0.929, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Another missense variant in the same codon (p.Pro467Ala) has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP. Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants (PM5). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) and exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 31580392). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.11+5G>A variant confirmed in trans (1 point, PMID: 31580392), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP. A second patient with eoSRD was reported as compound heterozygous with the p.Tyr239Asp variant, previously classified as pathogenic by the LCA/eoRD VCEP, but with no confirmation of phase (0.5 pts, PMID:28224992) (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including poor visual behavior and low-light visual impairment (0.5 pts) beginning in infancy (1 pt) and received a clinical diagnosis of LCA (0.5 pts) at 18 months. No detectable rod (.5 pts) or cone (1 pt) ERG response. The best-corrected visual acuity was 20/150 OU (1 pt), visual field was reduced (1 pt). Subtle whitish pigmentary mottling was observed (0.5 pts) in the retinal periphery of both eyes. OCT of the macula showed attenuation of the ellipsoid zone band (0.5 pts). Patient received RPE65-specific gene therapy treatment and was reported to have markedly improved function in dim lighting and a significantly expanded visual field (2 pts). Together these are specific for RPE65-related recessive retinopathy (total 8.5 points, PMID: 31580392, PP4_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3_moderate, PP4_moderate, PM3, PM5, PM2_Supporting, PS3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340741969/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50173 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235490 infores:hetionet CHEBI:5118 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003862 infores:hetionet CHEBI:45863 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020453 infores:hetionet CAID:CA916083926 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083926 MONDO:0100437 PMID: Pathogenic PVS1, PP4_Moderate, PP1, PM2_Supporting, PS4_Supporting PP3, PS3 NM_001034853.2(RPGR):c.247+5G>A is an intronic variant located in intron 3. The splicing impact predictor SpliceAI gives a score of 0.65 for donor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, while cells expressing a construct harboring the variant splice site generated a smaller mRNA in comparison to the wild-type control, indicating severely defective splicing (PMID: 33467000, PVS1_RNA). The PP3 and PS3_Supporting codes were not met as the evidence has been combined to meet PVS1 instead. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) including a relatively mildly affected female (1 pt), early onset (1 pt), high myopia (1 pt), night blindness (0.5 pts), photophobia (0.5 pts), color vision defect (0.5 pts), visual field constriction (0.5 pts), reduced visual acuity (0.5 pts), and bone spicule pigmentation (0.5 pts), which together are highly specific for RPGR-related retinopathy (8 points, PP4_Moderate). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, in addition to the second apparently unrelated proband previously used for the PP4 code (PMID: 28863407, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through an affected mother and son from 1 family (PP1; PMID: 33467000). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, PM2_Supporting, PP1, and PP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083926/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports GO:0061074 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0061074 GO:0150063 CHEBI:2639 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0027769 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0702166 infores:hetionet CHEBI:9352 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C1368065 infores:hetionet CHEBI:73274 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0162830 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151736 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0235270 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023895 infores:hetionet CHEBI:51364 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0011071 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0853692 infores:hetionet CHEBI:30659 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0003467 infores:hetionet CHEBI:6539 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0002170 infores:hetionet CHEBI:48669 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0019080 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0034063 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0856151 infores:hetionet CHEBI:8772 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0015230 infores:hetionet CHEBI:7476 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C2047937 infores:hetionet CHEBI:3994 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0019158 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151773 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0234215 infores:hetionet NCBIGene:4998 biolink:causes MONDO:0009143 infores:monarchinitiative not_provided not_provided HGNC:8487 MONDO:0009143 uuid:0b626005-392f-4311-9e28-b02ac406f4d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0018681 infores:hetionet CHEBI:9727 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0012569 infores:hetionet CAID:CA005295 biolink:causes MONDO:0021056 infores:clingen CAID:CA005295 MONDO:0021056 PMID: Benign BS2, BP4, BS1, BS3 BP7 The c.1549-13A>T variant in APC is an intronic variant which is located 13 nucleotides upstream of exon 13. This variant has been observed in 10 individuals worth 10 healthy individual points (Ambry internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.003915% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold (0.001%) for BS1, and therefore meets this criterion (BS1). RT-PCR demonstrated no impact of the variant on splicing with evidence of biallelic expression (BS3, Ambry internal data). The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) support that this variant does not affect splicing (BP4). In summary, this variant is classified as Benign for autosomal dominant familial adenomatous polyposis as specified by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP. Criteria applied: BS1, BS2, BS3, BP4 (Specification Version 1.0, date of approval: 10/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA005295/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:84500 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0393761 infores:hetionet CHEBI:127342 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C2363731 infores:hetionet CHEBI:6931 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0009024 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0040053 infores:hetionet CHEBI:35677 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0002792 infores:hetionet CHEBI:144093 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151786 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0919715 infores:hetionet CHEBI:17026 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040460 infores:hetionet CHEBI:367163 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0043094 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0042109 infores:hetionet CHEBI:5779 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0855775 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0034150 infores:hetionet CHEBI:93635 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0030252 infores:hetionet CHEBI:68575 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0011603 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036508 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042769 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020517 infores:hetionet GO:0019057 biolink:causes GO:0006412 infores:ubergraph knowledge_assertion manual_agent GO:0019057 GO:0006412 CHEBI:135939 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0022107 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0542175 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0542175 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0020649 infores:hetionet CAID:CA412353168 biolink:causes MONDO:0100039 infores:clingen CAID:CA412353168 MONDO:0100039 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM1, PS4 The c.592G>C (p.Gly198Arg) variant has been reported in 1 proband meeting the CDKL5 disorder phenotypic spectrum, but not meeting the specificity required for PP4 (PP4_not_met). PS4_Supporting cannot be applied because additional observations are required (CDKL5 registry) (PS4_Supporting_not_met). The computational predictor REVEL gives a score of 0.882, which is above the threshold of 0.75, evidence that correlates with impact to CDKL5 function (PP3). The p.Gly198Arg variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for CDKL5 disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Rett and Angelman-like disorders VCEP: (PP3, PM2_supporting) (CDKL5 specifications version 3.0; 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412353168/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6809 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0018681 infores:hetionet CHEBI:49603 biolink:causes UMLS:C1096403 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C1096403 infores:hetionet CAID:CA010439 biolink:causes MONDO:0005045 infores:clingen CAID:CA010439 MONDO:0005045 PMID: Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PP1_Strong BA1, BP4, PS1, PS3, PS2, BS1, BS3, PM5, PM6 NM_000432.4(MYL2):c.485G>A (p.Gly162Glu). This variant has been identified in individuals with HCM and other cardiomyopathies (ClinVar Variation ID 164114) and segregated with disease in 11 affected relatives from one family (PP1_Strong; Renaudin 2018 PMID: 29549657). It was absent from large population studies (PM2_Supporting; https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>5), therefore, the PS4 criterion has been applied at supporting strength (PS4_Supporting). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Supporting, PM2_Supporting, PP1_Strong, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010439/MONDO:0005045/102 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:114785 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0011603 infores:hetionet CHEBI:10110 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0033774 infores:hetionet CAID:CA172199 biolink:causes MONDO:0100040 infores:clingen CAID:CA172199 MONDO:0100040 PMID: Pathogenic PM1, PP3, PS2_Very Strong, PM2_Supporting The p.Gly267Ser variant in FOXG1 has been reported as a de novo occurrence (biological parenthood confirmed) in at least 2 individuals with FOXG1 disorder (internal database - GeneDx) (PS2_very strong). The p.Gly267Ser variant occurs in the well-characterized Fork-head functional domain of the FOXG1 gene (PM1). The p.Gly267Ser variant in FOXG1 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gly267Ser variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PS2_very strong, PM1, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172199/MONDO:0100040/016 2021-03-24 2021-05-10 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:36795 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1443060 infores:hetionet UMLS:C1738934 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0023380 infores:hetionet CHEBI:45081 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0035410 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0035078 infores:hetionet CAID:CA2573334474 biolink:causes MONDO:0010305 infores:clingen CAID:CA2573334474 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong PP1 "The NM_005629.4:c.635_636del (p.Glu212ValfsTer84) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Twin brothers (not stated if identical or fraternal), have been reported with clinical symptoms consistent with creatine transporter deficiency, ""consistently increased urine creatine/creatinine ratios"", and deficient transporter activity in fibroblasts (with 10 μM D3-creatine) (PMID: 29478817) (PP4_Strong).Their mother (not stated if she is a confirmed heterozygote) has history of ""hyperpyretic epilepsy in childhood, but never displayed learning difficulties and did not receive antiepileptic treatment"". (Insufficent segregations to apply PP1).This variant is not in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP crietria applied, as specified by the Clingen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573334474/MONDO:0010305/027 2023-03-09 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:9137 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0029882 infores:hetionet CHEBI:31711 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0002962 infores:hetionet CHEBI:68554 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0026766 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0041912 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0002418 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0853748 infores:hetionet CAID:CA229610 biolink:causes MONDO:0009861 infores:clingen CAID:CA229610 MONDO:0009861 PMID:8659548PMID:22526846PMID:23842451PMID:16879198PMID:19609714PMID:8659548PMID:22391997PMID:23430918PMID:22513348PMID:26666653 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PP3 The c.529G>C (p.Val177Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate). This variant has an extremely low allele frequency (Pop Max MAF=0.00005 ENF) in gnomAD (PM2). This variant was detected with pathogenic variants: F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported. PMID: 8659548, PMID: 16879198, PMID: 19609714, PMID: 23430918, PMID: 22391997, PMID: 22513348, PMID: 26666653 (PM3_very-strong. Computational prediction tools and conservation analysis do not agree. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229610/MONDO:0009861/006 2019-09-22 2021-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31644 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C2979982 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0009806 infores:hetionet CHEBI:3077 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0014868 infores:hetionet NCBIGene:427 biolink:causes MONDO:0009218 infores:monarchinitiative not_provided not_provided HGNC:735 MONDO:0009218 uuid:136be583-b392-4642-9881-1154d6b0766a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7822 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0700361 infores:hetionet NCBIGene:23512 biolink:causes MONDO:0032916 infores:monarchinitiative not_provided not_provided HGNC:17101 MONDO:0032916 uuid:91dcd7c2-e6a8-40a2-9cd3-a9b2b1254f18 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3508 biolink:causes UMLS:C0854268 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0854268 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0037274 infores:hetionet NCBIGene:3630 biolink:causes MONDO:0013240 infores:monarchinitiative not_provided not_provided HGNC:6081 MONDO:0013240 uuid:a098866b-eff3-462a-80ed-e1520e3823f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes UMLS:C1384489 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1384489 infores:hetionet CAID:CA10014545 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014545 MONDO:0011071 PMID: Benign BP2, BP4, BA1, BP7 PS4, PS3, PS1, PVS1, PM6, PM2, BS4, BS1, BS3, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.351+15A>G variant has a MAF of 0.00809 (0.809%, 524/64,760 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (8) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.34728 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014545/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3647 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0036572 infores:hetionet CHEBI:6897 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0011603 infores:hetionet CHEBI:161680 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0019080 infores:hetionet CHEBI:15553 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0030193 infores:hetionet CHEBI:681569 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0017178 infores:hetionet CHEBI:188986 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013604 infores:hetionet CHEBI:180905 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0242429 infores:hetionet NCBIGene:9782 biolink:causes MONDO:0011632 infores:monarchinitiative not_provided not_provided HGNC:6912 MONDO:0011632 uuid:dab0689c-d0a1-4408-8d53-5ddefe282a29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28915 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0033774 infores:hetionet CHEBI:51173 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0013395 infores:hetionet CHEBI:7824 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018932 infores:hetionet CHEBI:15940 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C1167965 infores:hetionet CHEBI:5103 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0018524 infores:hetionet CHEBI:51041 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0030554 infores:hetionet CHEBI:23765 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C1443060 infores:hetionet CHEBI:93363 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0041834 infores:hetionet CHEBI:45783 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020458 infores:hetionet CHEBI:5088 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0344232 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C1269683 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0036572 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0039971 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0021400 infores:hetionet CHEBI:499361 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0026821 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020676 infores:hetionet GO:1901190 biolink:causes GO:0022613 infores:ubergraph knowledge_assertion manual_agent GO:1901190 GO:0022613 CHEBI:10650 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0149725 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0017160 infores:hetionet CHEBI:17263 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0033774 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020651 infores:hetionet CHEBI:15551 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C1868855 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0948089 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0242350 infores:hetionet CHEBI:68595 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0020621 infores:hetionet CHEBI:2904 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0011603 infores:hetionet CHEBI:7565 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C2697368 infores:hetionet CHEBI:79699 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151699 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0031117 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020649 infores:hetionet CHEBI:27666 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0038367 infores:hetionet CHEBI:18243 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0013404 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0087169 infores:hetionet CHEBI:7825 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0015230 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0267596 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0006266 infores:hetionet CHEBI:5855 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013428 infores:hetionet CAID:CA327915374 biolink:causes MONDO:0100437 infores:clingen CAID:CA327915374 MONDO:0100437 PMID: Benign BP4_Stand Alone, BA1 NM_001034853.2(RPGR):c.2856A>T (p.Glu952Asp) is a missense variant causing substitution of glutamic acid by aspartic acid at amino acid 952. This variant is present in gnomAD v4.1.0 at a frequency of 0.0001313 among hemizygous individuals, with 10 variant alleles / 76,136 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.003, which is below the ClinGen X-linked IRD VCEP threshold of less than or equal to 0.003 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Very-Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Very-Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327915374/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:5613 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0520806 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020456 infores:hetionet CHEBI:7445 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0085688 infores:hetionet CHEBI:5790 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0011168 infores:hetionet CHEBI:78543 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0003862 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0276680 infores:hetionet CHEBI:6129 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0043352 infores:hetionet CHEBI:3506 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0027947 infores:hetionet NCBIGene:50506 biolink:causes MONDO:0011792 infores:monarchinitiative not_provided not_provided HGNC:13273 MONDO:0011792 uuid:181b44c7-013c-4d43-98c0-801eaed90a90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0947999 infores:hetionet CHEBI:63629 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0027497 infores:hetionet CHEBI:3764 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0011603 infores:hetionet CAID:CA637745016 biolink:causes MONDO:0011071 infores:clingen CAID:CA637745016 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS2, PS3, BA1, BP1, BP3, BP2, BP5, BS1, BS4, BS3, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BS2 This c.613+7G>A intronic variant is located at a weakly conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = 1.15676 in GRCh38); it is not predicted to have any splicing impact per SpliceAI (Δ scores ≤ 0.20) (BP7+BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637745016/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA367396876 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396876 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1358C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 453 (p.(Ser453Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes/hyperglycemia; however, PP4 could not be assessed due to lack of clinical information (PMID: 11508276, per author the variant was mistakenly published as Ser452X). In summary, the c.1358C>A variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396876/MONDO:0015967/086 2023-07-29 2023-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:39112 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0919823 infores:hetionet CAID:CA2573054870 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573054870 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1 PP4 The c.-171A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is located within the HNF1A/HNF1B binding region (c.-170 to c.-173 and c.-178 to c.-181) of the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, c.-171A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PM1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573054870/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47499 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0024205 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0027765 infores:hetionet NCBIGene:3172 biolink:causes MONDO:0007452 infores:monarchinitiative not_provided not_provided HGNC:5024 MONDO:0007452 uuid:a890932e-700e-4aa3-a168-b79ae6ee9ce5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233414 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027339 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0020649 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1609512 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004238 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0009806 infores:hetionet CHEBI:4903 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0004093 infores:hetionet CAID:CA518917054 biolink:causes MONDO:0010604 infores:clingen CAID:CA518917054 MONDO:0010604 PMID: Likely Benign PM2_Supporting, BP7, BP4 The c.1107T>A (p.Leu369=) variant is a synonymous variant not predicted to have a splicing impact with a SpliceAI score of 0.00, meeting BP4 criteria (<=0.01) and phylo P score of -0.07, meeting BP7 criteria (<0.01). The variant is absent in males in gnomAD v2 meeting PM2_Supporting. There were no known reported cases of hemophilia B with this variant. In summary, this variant meets the criteria to be classified as likely benign for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP ClinGen Coagulation Factor Deficiency VCEP (version 1.0.0, released 10/5/2023): PM2_Supporting, BP4, BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA518917054/MONDO:0010604/080 2025-06-12 2025-06-25 X-linked inheritance HP:0001417 Contradicts true CHEBI:63638 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233632 infores:hetionet CHEBI:520985 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0006277 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0151436 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233401 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027769 infores:hetionet CHEBI:8888 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0700590 infores:hetionet CHEBI:5855 biolink:causes MONDO:0015742 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0023529 infores:hetionet CHEBI:4659 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0234894 infores:hetionet NCBIGene:1910 biolink:causes MONDO:0010192 infores:monarchinitiative not_provided not_provided HGNC:3180 MONDO:0010192 uuid:29e09243-2cfe-4eff-92fe-62ef5aa70102 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060687 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060687 GO:0007275 CHEBI:31348 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0037299 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1167965 infores:hetionet CHEBI:17650 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0000731 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0026848 infores:hetionet CHEBI:3756 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0015672 infores:hetionet CHEBI:16335 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0264906 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0877365 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0877365 infores:hetionet CHEBI:16586 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0151576 infores:hetionet CHEBI:3242 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0042571 infores:hetionet CHEBI:50777 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0043094 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0235431 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0574067 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0002871 infores:hetionet CAID:CA397723002 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723002 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL): c.480C>G (p.Tyr160Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 7/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature either in a patient with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency or ACADVL associated disease or in functional studies. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. This variant was originally curated November 29, 2021 and the recurated classification was approved by the expert panel on February 27, 2024. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723002/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports CAID:CA404767297 biolink:causes MONDO:0010938 infores:clingen CAID:CA404767297 MONDO:0010938 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP4 BA1, BS1, PS1, PM1, PP1 The NM_000215.4(JAK3):c.2324G>A variant in JAK3 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 775 (p.Arg775His). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000001861, which is lower than the ClinGen SCID VCEP specified PM2_Supporting threshold of <0.000115. Therefore, PM2_supporting is met.This variant has been detected in 6 homozygous individuals with SCID/leaky SCID/Omenn phenotype (PMID 32445296, PMID 31440277, PMID 31589898, PMID 28916186, PMID: 38598033)(0.5 pt each, 3.0 pt). Two additional individuals were reported by Invitae/Labcorp. In one of them the variant was observed in trans with VUS variant p.Ile667del (0.25 pt). In the other case, the variant was observed in trans with VUS variant p.Ala385Ser (0.25 pt). Phasing was determined in both patients and clinically affected status was confirmed. In summary, total PM3 points: 3.5 pt (PM3_strong).This variant has been reported in two patients in ClinVar (Variation ID: 1339536) as pathogenic. In one of them the affected status (patient from PMID: 28916186) was reported as “Omenn syndrome” (PIDTC diagnostic criteria not confirmed). Furthermore, this variant was identified in at least one patient that displayed transplacentally acquired maternal engraftment, diagnosed by QF-PCR (STRs) (PMID: 31440277) in homozygosis, fulfilling the PIDTC 2022 diagnostic criteria for SCID (criterion 4) (0.5 pts). It was detected by ES, ruling out other alternative genetic causes (0.5 pts). (Total PP4 points = 1 pt) (PP4). In summary, this variant meets the criteria to be classified as Likely pathogenic for T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID JAK3 VCEP (PM2_Supporting, PM3_Strong, PP4) (VCEP specifications version 2.1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA404767297/MONDO:0010938/121 2025-10-31 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8412 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0012569 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0002622 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0007785 infores:hetionet CHEBI:135530 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0151908 infores:hetionet NCBIGene:673 biolink:causes MONDO:0013380 infores:monarchinitiative not_provided not_provided HGNC:1097 MONDO:0013380 uuid:42073eb3-e266-49b4-89ff-acfad31423f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9445 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0029408 infores:hetionet CHEBI:8768 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0040822 infores:hetionet CHEBI:10125 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1142135 infores:hetionet CHEBI:9137 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0392156 infores:hetionet CHEBI:15551 biolink:causes MONDO:0007018 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0042996 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027932 infores:hetionet CHEBI:114785 biolink:causes HP:0001937 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0221021 infores:hetionet CHEBI:94609 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0040147 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0221185 infores:hetionet CHEBI:92511 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0041657 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0038661 infores:hetionet CHEBI:6909 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2697368 infores:hetionet CHEBI:144093 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C1320474 infores:hetionet CHEBI:66876 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0178415 infores:hetionet CHEBI:8080 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0233494 infores:hetionet CHEBI:3996 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0278134 infores:hetionet CHEBI:87681 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0009782 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0575090 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0032285 infores:hetionet CHEBI:47499 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0033774 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0009938 infores:hetionet GO:0043922 biolink:causes GO:0019083 infores:ubergraph knowledge_assertion manual_agent GO:0043922 GO:0019083 NCBITaxon:4753 biolink:causes MONDO:0005923 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:4753 MONDO:0005923 CHEBI:168396 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0040264 infores:hetionet CHEBI:47780 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0001925 infores:hetionet CHEBI:38545 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0085605 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0562057 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0562057 infores:hetionet CHEBI:6078 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0014518 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0027765 infores:hetionet CAID:CA013575 biolink:causes MONDO:0005045 infores:clingen CAID:CA013575 MONDO:0005045 PMID: Uncertain Significance PP3, BS1 PM2, PM5, BA1, PS1 NM_000258.3(MYL3):c.170C>A (p.Ala57Asp): This variant has been reported in individuals with HCM in the heterozygous and homozygous state (including PMIDs: 21239446, 23426552, 24111713, 31006259, 33288880), but is not statistically increased in individuals with HCM compared to controls [OR lower 95% CI <5] with respect to autosomal dominant disease. Therefore, the PS4 criterion has not been applied. This variant has been identified in 0.0003 FAF (17/30616) of South Asian chromosomes by gnomAD v2.1.1 (BS1; http://gnomad.broadinstitute.org). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on BS1 and PP3. Evaluation of this variant with respect to autosomal recessive disease was outside the scope of the current specifications. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013575/MONDO:0005045/103 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46345 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0007760 infores:hetionet CHEBI:3077 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015672 infores:hetionet CHEBI:135342 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151830 infores:hetionet CHEBI:31859 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C1322281 infores:hetionet CAID:CA16020963 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020963 MONDO:0009861 PMID: Uncertain Significance PM2, BP7 PP4, BP2 The c.1199+50G>A intronic variant has been reported homozygous in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels with BH4 deficiency excluded. However, this patient is also homozygous for c.441+1G>C (ClinVar 556894, Pathogenic). The c.1199+50G>A variant is present a low frequency in gnomAD with a MAF of 0.000008870 in the South Asian population but it is not highly conserved and is not predicted to have a deleterious effect. Splicing predictors are in consensus that there is no significant impact on splicing signals. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, BP7. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020963/MONDO:0009861/006 2020-09-04 2021-07-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10125 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0039070 infores:hetionet CAID:CA024268 biolink:causes MONDO:0007783 infores:clingen CAID:CA024268 MONDO:0007783 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glycine with valine at codon 4942 of the RYR1 protein, p.(Gly4942Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024268/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8871 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234215 infores:hetionet CAID:CA415076485 biolink:causes MONDO:0010305 infores:clingen CAID:CA415076485 MONDO:0010305 PMID: Uncertain Significance PM2, BP4 The NM_005629.4(SLC6A8):c.145G>C (p.Val49Leu) variant in SLC6A8 is a missense variant predicted to cause substitution of Valine for Leucine at amino acid 49 (p.Val49Leu). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.032 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI does no predict an impact on splicing (BP4). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:658337). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415076485/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CAID:CA645614124 biolink:causes MONDO:0011071 infores:clingen CAID:CA645614124 MONDO:0011071 PMID: Likely Pathogenic PS3, PS2_Supporting, PM2, PS4_Supporting PS1, BP2, BP4, BA1, PVS1, PM6, BP7, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 The M_001754.4:c.968-10C>A variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). RNA studies of the proband (RT-PCR), identified missplicing associated with the germline variant leading to RNA encoding a truncated protein (p.Ala324Leufs*7) (PS3; internal laboratory data). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ supporting; internal laboratory data). There is 1 proband meeting at least one of the RUNX1 phenotypic criteria with confirmed de novo (both maternity and paternity confirmed) occurrence (PS2_ supporting; internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM2, PS4_supporting, PS2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645614124/MONDO:0011071/008 2019-08-18 2020-01-14 Autosomal dominant inheritance HP:0000006 Supports CAID:CA226143 biolink:causes MONDO:0100453 infores:clingen CAID:CA226143 MONDO:0100453 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PP1, PM2_Supporting The NM_000180.4(GUCY2D):c.389del (p.Pro130LeufsTer?) variant is a frameshift variant in exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000002639, with 4 alleles / 1515578 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts), present at birth (1.0 pt), nystagmus (1.0 pt), extinguished ERG (0.5 pt), photophobia (1 pt) and dyschromatopsia (1 pt). That proband also had clinical exome sequencing performed without any additional potential causative variants identified (4 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 9 points, PMID: 37327959, PP4_Moderate). This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 8944027, 10951519). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygotes with variants not yet classified by the LCA/eoRD VCEP and who were not considered for this code. (1 total point, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PP1; PMID: 8944027). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP1, PM3, PP4_Moderate, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226143/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030305 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0018802 infores:hetionet CHEBI:8768 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151936 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018099 infores:hetionet CAID:CA320251539 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251539 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1082C>T (p.Thr361Ile) is a missense variant which has a REVEL score < 0.50 (0.277) and a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251539/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes UMLS:C1096243 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1096243 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0026848 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022568 infores:hetionet NCBIGene:91869 biolink:causes MONDO:0012783 infores:monarchinitiative not_provided not_provided HGNC:30220 MONDO:0012783 uuid:3d8f6bf7-7975-40a0-bf1f-2a88fa1ac48d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9332 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0013404 infores:hetionet CHEBI:5296 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0344232 infores:hetionet CAID:CA913203569 biolink:causes MONDO:0015967 infores:clingen CAID:CA913203569 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4 The c.696dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 233 of NM_000545.8, adding 6 novel amino acids before encountering a stop codon (p.Val233SerfsTer6). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PP4 cannot be applied because the MODY probability cannot be calculated due to lack of family history information, and PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.696dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913203569/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9328 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0542184 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0008325 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0541941 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0027051 infores:hetionet CHEBI:7444 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0018801 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0003123 infores:hetionet CHEBI:3640 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0037763 infores:hetionet CHEBI:3723 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011071 infores:hetionet CHEBI:3312 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0027497 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0424000 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0948594 infores:hetionet CHEBI:28748 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002792 infores:hetionet CHEBI:83531 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0016382 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0026857 infores:hetionet CHEBI:46345 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0002962 infores:hetionet CHEBI:10101 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0033774 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0036130 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0242350 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020517 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0233459 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0855242 infores:hetionet CHEBI:3508 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0042267 infores:hetionet CAID:CA000036 biolink:causes MONDO:0018875 infores:clingen CAID:CA000036 MONDO:0018875 PMID: Benign BP4, BS3, BS2 BA1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, PVS1, PP3, PP1, PP4 The NM_000546.6: c.1096T>G variant in TP53 is a missense variant predicted to cause substitution of serine by alanine at amino acid 366 (p.Ser366Ala). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributors: SCV000214696.6). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.1186; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000036/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3219 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0043144 infores:hetionet CHEBI:465284 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151740 infores:hetionet CHEBI:28748 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0876994 infores:hetionet CHEBI:36791 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009676 infores:hetionet CAID:CA2586966741 biolink:causes MONDO:0100368 infores:clingen CAID:CA2586966741 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting The NM_000329.3(RPE65):c.639dup (p.Ala214SerfsTer20) variant is a frameshift variant that introduces a premature stop codon into exon 6 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the Arg91Trp variant confirmed in trans (1 point, PMIDs: 27422788), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total points, PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, PM2_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586966741/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:116278 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0002994 infores:hetionet NCBIGene:4487 biolink:causes MONDO:0007129 infores:monarchinitiative not_provided not_provided HGNC:7391 MONDO:0007129 uuid:9ef27ca1-00ff-4ade-af56-2760861f45b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0007642 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0155169 infores:hetionet CHEBI:31624 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0522153 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0021053 infores:hetionet CHEBI:63622 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0003811 infores:hetionet CHEBI:29007 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0042109 infores:hetionet CHEBI:8874 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013144 infores:hetionet CHEBI:8346 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0031542 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0038587 infores:hetionet CHEBI:408174 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C3263723 infores:hetionet NCBIGene:2010 biolink:causes MONDO:0100531 infores:monarchinitiative not_provided not_provided HGNC:3331 MONDO:0100531 uuid:5a2a5aa9-b0f4-4dfb-89b6-79e5b08a40da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037763 infores:hetionet CHEBI:490877 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0030305 infores:hetionet NCBIGene:50674 biolink:causes MONDO:0012479 infores:monarchinitiative not_provided not_provided HGNC:13806 MONDO:0012479 uuid:7eb4b1e2-d064-46e5-9c76-b4a196177d05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151908 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0497247 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0017152 infores:hetionet CHEBI:116278 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151579 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027121 infores:hetionet CAID:CA014765 biolink:causes MONDO:0005045 infores:clingen CAID:CA014765 MONDO:0005045 PMID: Uncertain Significance PP3 PM3, PM2, PM4, PM1, PM6, PM5, PP1, BA1, PS3, PP4, BS2, BS1, BS3, BS4, BP3, PS4, PS2, PS1, BP4, BP7, BP5, BP2, PVS1 The c.4283T>C (p.Leu1428Ser) variant in MYH7 has been reported in at least 2 individuals with HCM (Alfares 2015 PMID:25611685; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; LMM per. comm.), but has also been identified in 0.0053% (FAF 95% CI, 12/129150) of non-Finnish European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014765/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:127780 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0392525 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0234458 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0231303 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0234913 infores:hetionet CHEBI:41774 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0014742 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0033975 infores:hetionet CHEBI:119573 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0040822 infores:hetionet CHEBI:47381 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085631 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017574 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004238 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0235416 infores:hetionet NCBIGene:26123 biolink:causes MONDO:0009794 infores:monarchinitiative not_provided not_provided HGNC:24519 MONDO:0009794 uuid:af2ab4d2-5dcc-4007-b1ed-58608a6e4957 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0014457 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0041969 infores:hetionet CHEBI:9622 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0080274 infores:hetionet CHEBI:41774 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0004604 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0746883 infores:hetionet CHEBI:5790 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0027497 infores:hetionet CHEBI:8093 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0022568 infores:hetionet CAID:CA355961254 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961254 MONDO:0001586 PMID: Pathogenic PS1, PVS1_Moderate, PM3, PP4_Moderate, PM2_Supporting "The NM_000203.5:c.386-1G>A variant in IDUA occurs within the canonical splice acceptor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 4 out of 14, resulting in an in-frame deletion of 36 amino acids which represents <10% of the protein (PVS1_Moderate). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, one proband was compound heterozygous for the variant and c.1205G>A p.(Trp402Ter) (ClinVar Variation ID: 11908), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PMID 28752568, 0.5 points). The other two individuals were homozygous for the variant (PMID: 28752568, 1 point) (PM3). These three patients are documented to meet criteria for severe MPS I based on their clinical presentation; one child has confirmed reduced IDUA and ""clinical features"" meeting severe phenotype (PMID: 28752568) (PP4_Moderate). (PP4_Moderate) (PMID 28752568). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). A variant within same splice donor/acceptor ±1,2 dinucleotide, resulting from a different nucleotide change (c.386-2A>G) (Variation ID 222994) is classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (Accession: SCV005619878.1) (PS1). There is a ClinVar entry for this variant (Variation ID: 1458772). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 1.0.0): PS1, PVS1_moderate, PM3, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 19, 2025)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961254/MONDO:0001586/091 2025-05-19 2025-05-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47780 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0035455 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0018799 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0041912 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0006277 infores:hetionet CHEBI:6887 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018790 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0409962 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0409962 infores:hetionet CHEBI:7465 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0020443 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042109 infores:hetionet CHEBI:64317 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0344232 infores:hetionet CHEBI:66919 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0041296 infores:hetionet CHEBI:4910 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C1145670 infores:hetionet CHEBI:4027 biolink:causes MONDO:0009718 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027145 infores:hetionet CHEBI:8869 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0013298 infores:hetionet CHEBI:71272 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0041296 infores:hetionet NCBIGene:4758 biolink:causes MONDO:0009738 infores:monarchinitiative not_provided not_provided HGNC:7758 MONDO:0009738 uuid:cd3dbc32-5e4b-4a1c-b2be-aca9d6eeb3b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91541 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0017605 infores:hetionet CHEBI:8028 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0428977 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027697 infores:hetionet CAID:CA412745724 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745724 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PP1, PM2_Supporting PP3, PS1 NM_001034853.2(RPGR):c.154+1G>A is a canonical splice site variant in intron 2 and is predicted to disrupt splicing and induce skipping of exon 2, which is expected to delete a region that is critical to RPGR function (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), early onset (1 pt), high myopia (1 pt), milder phenotypes in affected females (1 pt), visual field constriction (0.5 pts), night blindness (0.5 pts), visual acuity loss (0.5 pts), and rod involvement greater than code (1 pt), which together are specific for RPGR-related retinopathy (7.5 points, PMID: 14516808, PP4). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family consisting of a mother and two sons (PP1; PMID: 14516808). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, PP4, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745724/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:48669 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0041657 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0036572 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0549209 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020517 infores:hetionet CHEBI:3996 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0152198 infores:hetionet CHEBI:7494 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0428977 infores:hetionet NCBIGene:166785 biolink:causes MONDO:0009613 infores:monarchinitiative not_provided not_provided HGNC:18871 MONDO:0009613 uuid:c928538f-68ab-4094-a25c-d390fd66902e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA269917 biolink:causes MONDO:0019501 infores:clingen CAID:CA269917 MONDO:0019501 PMID: Pathogenic PP4, PM3_Very Strong, PM2_Supporting PP3, BP4 The c.3407G>A variant in USH2A is a missense variant predicted to cause substitution of serine to asparagine at amino acid 1136. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.466 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been reported in at least 6 probands with USH2A-related disorders, including four individuals with autosomal recessive Usher syndrome and two individuals with isolated retinopathy. Of these individuals, the variant was confirmed in trans with a pathogenic variant in two individuals, but phase with a second pathogenic variant was unclear in the remaining 4 individuals (PM3_VeryStrong; PMID: 22135276, 25991456, 27957503, 36011334). Of note, the two individuals with isolated retinopathy harbored the pathogenic p.Cys759Phe variant, which is commonly found in individuals with an isolated retinopathy phenotype (SCV001334331.1). At least one patient with this variant was diagnosed with Usher syndrome (PP4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive USH2A-related disorders including Usher syndrome and isolated retinopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PM3_VeryStrong, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA269917/MONDO:0019501/005 2023-09-26 2023-10-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:6847 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0038325 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0424000 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0006277 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030305 infores:hetionet CHEBI:63115 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0024305 infores:hetionet CHEBI:15552 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020550 infores:hetionet CHEBI:31644 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1320474 infores:hetionet CAID:CA274049 biolink:causes MONDO:0009290 infores:clingen CAID:CA274049 MONDO:0009290 PMID:23884227 Pathogenic PM2, PVS1, PP4 This variant, c.1156C>T (p.Gln386Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. This variant is absent in gnomAD v2.1.1, meeting PM3. A Korean patient with infantile onset Pompe disease, meeting the specifications for PP4, has been reported. This patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg). This in trans data has been used in the assessment of p.Ser619Arg and was not be included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 188858; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274049/MONDO:0009290/010 2020-04-06 2020-05-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6067 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0413252 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0013609 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151882 infores:hetionet CHEBI:7478 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151744 infores:hetionet GO:0045661 biolink:causes GO:0061061 infores:ubergraph knowledge_assertion manual_agent GO:0045661 GO:0061061 CHEBI:8768 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0345904 infores:hetionet CHEBI:59773 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0231218 infores:hetionet CHEBI:31711 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151611 infores:hetionet CHEBI:31547 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0006277 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0236071 infores:hetionet CAID:CA176485 biolink:causes MONDO:0021060 infores:clingen CAID:CA176485 MONDO:0021060 PMID: Likely Benign BP4, BP7 PP3, BA1, BS1, PM2 The c.451-14T>C variant in the KRAS gene is an intronic variant located in intron 6. The filtering allele frequency in gnomAD v4.1.0 is 0.01135% (10/73838 alleles) in the African/African American population (PM2_Supporting/ BS1/ BA1 are not met).This variant is located at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4, BP7 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA176485/MONDO:0021060/044 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:5393 biolink:causes MONDO:0054844 infores:monarchinitiative not_provided not_provided HGNC:9137 MONDO:0054844 uuid:e5ec418d-f951-478c-bde1-6ca68a37055d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410208033 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208033 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The c.567C>G (Tyr189Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 5/8 and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1- phenotypic criteria (PS4_ Supporting; PMID: 31309983). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208033/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51860 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0022107 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0005741 infores:hetionet CHEBI:7476 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0702166 infores:hetionet CHEBI:7476 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C2363730 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0027765 infores:hetionet CHEBI:38940 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0026766 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0022354 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0042373 infores:hetionet CHEBI:50742 biolink:causes UMLS:C1535919 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C1535919 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020456 infores:hetionet CAID:CA367398935 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398935 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PM5_Supporting, PM2, PP2, PP3 PP4 The c.1112G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 371 (p.(Cys371Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 5 informative meioses in a family with diabetes/hyperglycemia (PP1_Strong; internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe)​, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Tyr)(PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GENE-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398935/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports NCBIGene:375387 biolink:causes MONDO:0030033 infores:monarchinitiative not_provided not_provided HGNC:24613 MONDO:0030033 uuid:7d0671d6-42b6-4442-8d64-d52684ea9e52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes MONDO:0015265 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0006272 infores:hetionet GO:0060297 biolink:causes GO:0032989 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0032989 CHEBI:27779 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0014742 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0013395 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0015376 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0011991 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0036572 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0039971 infores:hetionet UMLS:C0657912 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0424295 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0018418 infores:hetionet CHEBI:31184 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0009450 infores:hetionet CHEBI:41774 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0750876 infores:hetionet CHEBI:2950 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0012691 infores:hetionet NCBIGene:84891 biolink:causes MONDO:0975705 infores:monarchinitiative not_provided not_provided HGNC:12997 MONDO:0975705 uuid:b5e0885a-b7ac-41b2-99ef-c732f427c6f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0013595 infores:hetionet CHEBI:83804 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0023530 infores:hetionet CHEBI:68534 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0233794 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0474378 infores:hetionet CHEBI:36791 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0917801 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023533 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0236071 infores:hetionet CHEBI:84500 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0009763 infores:hetionet CHEBI:28748 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0010200 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011991 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0232492 infores:hetionet CHEBI:31547 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0001925 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027947 infores:hetionet CHEBI:63619 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0008031 infores:hetionet CHEBI:4907 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0017152 infores:hetionet CHEBI:17076 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0002994 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0836924 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037822 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0162830 infores:hetionet CHEBI:28177 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0020621 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0037274 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003633 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0334492 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019061 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0241379 infores:hetionet CAID:CA386966305 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966305 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PS4, PM5 The c.806C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to aspartic acid at codon 269 (p.(Ala269Asp)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additonally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.963, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a clinical history highly specific for HNF1A-monogenic diabetes (MPC >50%, negative testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Given that it was only identified in one case, this is below the MDEP VCEP threshold to apply PS4_Moderate. Another missense variant, c.805G>C, p.(Ala269Pro), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.806C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PP3, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966305/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0004936 infores:hetionet CHEBI:82866 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0033774 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0150077 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0150077 infores:hetionet CHEBI:50777 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0687713 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020649 infores:hetionet CHEBI:44185 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235996 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0024115 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0376358 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0948594 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0042267 infores:hetionet GO:1905365 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:1905365 GO:0016192 CHEBI:3723 biolink:causes UMLS:C0027531 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027531 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0018799 infores:hetionet CHEBI:36791 biolink:causes MONDO:0044986 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0024228 infores:hetionet CAID:CA10385310 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385310 MONDO:0100437 PMID: Benign BP4_Strong, BA1 BS2, PS4 NM_001034853.2(RPGR):c.2057T>A (p.Met686Lys) is a missense variant predicted to cause substitution of methionine by lysine at amino acid 686. This variant is present in gnomAD v.4.1.0 at a frequency of 0.002245 among hemizygous individuals, with 874 variant alleles / 389,312 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been observed in at least 3 affected male individuals with features consistent with retinopathy, but was not considered to be the causal variant PMID: 33846575, 24938718). The computational predictor REVEL gives a score of 0.014, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385310/MONDO:0100437/106 2025-08-04 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:44032 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042571 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0234192 infores:hetionet CHEBI:7936 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009676 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0003864 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0019825 infores:hetionet CHEBI:8871 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235309 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0314719 infores:hetionet CHEBI:3127 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0024902 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042373 infores:hetionet CHEBI:4735 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C2047937 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0002871 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019061 infores:hetionet CHEBI:43968 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0011603 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0027765 infores:hetionet CHEBI:6965 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0344232 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0033775 infores:hetionet CHEBI:63617 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0033774 infores:hetionet CHEBI:168396 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151786 infores:hetionet NCBIGene:3795 biolink:causes MONDO:0009252 infores:monarchinitiative not_provided not_provided HGNC:6315 MONDO:0009252 uuid:e2ba67ff-aaaa-45e3-8d9d-62eb7a6f8a13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0032285 infores:hetionet CHEBI:31709 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0009676 infores:hetionet CHEBI:94411 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C2830004 infores:hetionet CHEBI:3219 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085593 infores:hetionet CHEBI:6076 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0041657 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027947 infores:hetionet CAID:CA024313 biolink:causes MONDO:0007783 infores:clingen CAID:CA024313 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PP3_Moderate PM1, PM5, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Leucine at codon 614 of the RYR1 protein, p.(Arg614Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:10051009; PMID:17710899; PMID:10484775 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in seven individuals, PP1_Strong (PMID:9389851; PMID:17710899). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4, PS3_Moderate, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024313/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:116278 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0237849 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0006849 infores:hetionet CL:0000076 biolink:causes MONDO:0024475 infores:ubergraph knowledge_assertion manual_agent CL:0000076 MONDO:0024475 UNII:54Z8M50D6Q biolink:causes MONDO:0001180 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0155111 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0877377 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0877377 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0521591 infores:hetionet CHEBI:4453 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0024902 infores:hetionet CHEBI:8772 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C2979982 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0042373 infores:hetionet CHEBI:473990 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0438215 infores:hetionet CHEBI:8435 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0026837 infores:hetionet CHEBI:47898 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0022638 infores:hetionet CHEBI:61049 biolink:causes MONDO:0013361 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3203356 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001164 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0003431 infores:hetionet CHEBI:7025 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0011606 infores:hetionet CHEBI:36795 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232495 infores:hetionet CHEBI:3176 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0085632 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022650 infores:hetionet CHEBI:8228 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C1443060 infores:hetionet CHEBI:51230 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0022281 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151849 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0025061 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018772 infores:hetionet NCBIGene:56052 biolink:causes MONDO:0012052 infores:monarchinitiative not_provided not_provided HGNC:18294 MONDO:0012052 uuid:2f2b3189-5686-44e3-9ef3-2e00886c9cbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0149745 infores:hetionet GO:0010695 biolink:causes GO:0000070 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0000070 GO:2000345 biolink:causes GO:0001889 infores:ubergraph knowledge_assertion manual_agent GO:2000345 GO:0001889 CHEBI:4784 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0034359 infores:hetionet CHEBI:5801 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0014457 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0687707 infores:hetionet CHEBI:7915 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011124 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0009806 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0043144 infores:hetionet CHEBI:3061 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0004093 infores:hetionet CHEBI:49662 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0008031 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0178298 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235901 infores:hetionet CHEBI:45951 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0014457 infores:hetionet CHEBI:4315 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0003467 infores:hetionet CHEBI:61033 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0033774 infores:hetionet CHEBI:4798 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0004134 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0021843 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0235146 infores:hetionet CHEBI:16469 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151744 infores:hetionet CHEBI:5775 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0013428 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0017160 infores:hetionet NCBIGene:27030 biolink:causes MONDO:0013725 infores:monarchinitiative not_provided not_provided HGNC:7128 MONDO:0013725 uuid:c4f67f57-78af-4706-9ee9-abdb01cd71b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:520985 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0687713 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0041582 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0518015 infores:hetionet NCBIGene:10686 biolink:causes MONDO:0009550 infores:monarchinitiative not_provided not_provided HGNC:2037 MONDO:0009550 uuid:86b336ce-3c11-48db-a5f4-6e8cc06c4550 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2687 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0020649 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002170 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0233414 infores:hetionet CHEBI:3738 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0036572 infores:hetionet CAID:CA9043671 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043671 MONDO:0012999 PMID: Pathogenic PP3, PM2_Supporting, PM3, PP4_Strong, PS3_Supporting, PM5_Supporting The NM_000156.6(GAMT):c.403G>A variant in GAMT is predicted to result in the substitution of aspartate by asparagine at amino acid 135 (p.Asp135Asn). Four probands and one affected sibling have been reported with this variant, all with clinical symptoms consistent with GAMT deficiency, evidence of elevated guanidinoacetate and low creatine in plasma and/or urine, and reduced creatine on brain MRS with guanidinoacetate peak also noted for two patients. In addition, one proband was shown to have deficient GAMT activity in fibroblasts (PMID: 19027335, 19388150, 24071436, 24268530, 24415674) (PP4_Strong). Each of these individuals is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic or likely pathogenic by the ClinGen CCDS VCEP including c.327G>A (2 patients; PMID: 24071436, 24268530, 24415674), c.299dup13 (a.k.a. c.299_311dup) (PMID: 19388150), and c.507_521dup15 (p.Cys169_Ser173dup) (PMID: 19027335)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (2/18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). When the variant was expressed in GAMT-deficient fibroblasts, GAMT enzyme activity was undetectable (PMID: 24415674). The computational predictor REVEL gives a score of 0.856 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another variant at the same amino acid position, c.403G>T (p.Asp135Tyr), has been classified as likely pathogenic by the ClinGen CCDS VCEP (and would be likely pathogenic even without the use of PM5, therefore avoiding circular logic) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 573140). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0); PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 8, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043671/MONDO:0012999/026 2023-06-08 2023-06-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8028 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0039231 infores:hetionet CHEBI:75722 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018681 infores:hetionet CHEBI:35778 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0236024 infores:hetionet NCBIGene:112744 biolink:causes MONDO:0013503 infores:monarchinitiative not_provided not_provided HGNC:16404 MONDO:0013503 uuid:c78da90f-20b1-4d92-83eb-bfe52fbee092 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0278134 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004238 infores:hetionet CHEBI:7575 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0002871 infores:hetionet CHEBI:63635 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0000731 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0039520 infores:hetionet CHEBI:18332 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0156404 infores:hetionet CHEBI:63598 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013456 infores:hetionet CHEBI:4495 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C1258215 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0009450 infores:hetionet CHEBI:6062 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235490 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0041912 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0521839 infores:hetionet CHEBI:32184 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0702166 infores:hetionet CHEBI:8768 biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0220994 infores:hetionet CHEBI:77733 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C3263723 infores:hetionet CHEBI:3219 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009421 infores:hetionet CAID:CA915940788 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940788 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5:c.1599_1600del (p.Ser534ProfsTer) variant in ITGA2B exon 16 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Although in silico tools predict the gain of a splice donor site 3 bp downstream that could lead to reading frame restoration, RT-PCR analysis of this region using RNA from a patient homozygous for the variant (GT-10, PMID: 25539746) confirmed the presence of mRNA with the 2 bp deletion and did not identify evidence of a restored reading frame (personal communication with Dr. Jose Rivera (Servicio de Hematologıa y Oncologıa Medica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacion, Universidad de Murcia)). This variant has been detected in homozygosity in at least one proband with Glanzmann thrombasthenia (GT-10, PMID: 25539746). Total points: 0.5 (PM3_Supporting). This patient (Patient GT-10 in PMID: 25539746) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. (VCEP specifications version 2; date of approval 08/04/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940788/MONDO:0100326/011 2022-08-05 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:10650 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0423153 infores:hetionet CHEBI:28148 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C1321686 infores:hetionet CHEBI:36704 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0038325 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0039971 infores:hetionet CHEBI:28901 biolink:causes MONDO:0020546 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0856825 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0015376 infores:hetionet GO:0045108 biolink:causes GO:0045104 infores:ubergraph knowledge_assertion manual_agent GO:0045108 GO:0045104 CHEBI:145499 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042075 infores:hetionet CHEBI:16755 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C3263723 infores:hetionet CHEBI:85161 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C1096035 infores:hetionet CHEBI:9763 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020433 infores:hetionet CHEBI:231425 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0006145 infores:hetionet CHEBI:28177 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0003811 infores:hetionet CHEBI:135791 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0013604 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085096 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019158 infores:hetionet CHEBI:4708 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0025222 infores:hetionet NCBIGene:4359 biolink:causes MONDO:0008392 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0008392 uuid:d16e30ae-3ed7-4ce5-b4d9-bf55d26303d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027497 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C2047937 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0521492 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521492 infores:hetionet CHEBI:9943 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0542571 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0027765 infores:hetionet CAID:CA314804 biolink:causes MONDO:0012999 infores:clingen CAID:CA314804 MONDO:0012999 PMID: Pathogenic PP3, PP4_Strong, PM2_Supporting, PM3_Very Strong, PS3 The NM_000156.6:c.327G>A (p.Lys109=) variant in GAMT is a synonymous variant that alters the last nucleotide of exon 2. It is one of the most common variants associated with GAMT deficiency, accounting for 31-35% of alleles (PMID: 19027335, 24268530). The variant has been previously reported in at least 30 unrelated GAMT deficiency patients, including among those with elevated urine guanidinoacetate, reduced or absent cerebral creatine peak on MRS (some of whom also have evidence of guanidinoacetate peak on MRS, and GAMT deficiency in fibroblasts (PMIDs: 8651275, 17171576, 19027335, 22019491, 23660394, 24268530, 24766785) (PP4_Strong) including at least 8 homozygotes (PMID: 8651275, 11978605, 19027335, 22019491, 24268530), and in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen CCDS VCEP including c.58dupT (PMID 24766785, confirmed in trans), c.297_c.309dup13 (PMID: 8651275, confirmed in trans; PMID: 19027335), c.522G>A (p.Trp174Ter) (PMID: 17171576, 19027335, 24268530; 3 probands), or c.36_c.37ins26 (PMID: 19027335) as well as c.133T>A (p.Trp45Arg) (PMID 24268530), and c.403G>A (p.Asp135Asn) (PMID 24268530) (PM3_VeryStrong). Additional patients may be reported in the literature but the maximum evidence for PM3_VeryStrong has already been reached. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00039 (34/ 86230 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The c.327G>A variant was shown by RT-PCR and RNA sequencing analysis to result in two abnormal transcripts: in one transcript, the variant resulted in a cryptic splice site in intron 2 and deletion of 146bp, and in the other transcript, the variant resulted in a 44bp insertion leading to altered splicing and skipping of exon 2 (PMID: 8651275) (PS3). It is predicted to alter splicing by SpliceAI (donor loss, score 0.93) and varSEAK (splicing class 5) (PP3). There is a ClinVar entry for this variant (Variation ID: 21065). In summary, this variant meets the criteria to be classified as Pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PM3_VeryStrong, PS3, PP4_Strong, PP3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314804/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CAID:CA399806056 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806056 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The NM_000419.5(ITGA2B):c.409-1G>A splice variant is predicted to result in the skipping of exon 4 of 30, causing a frameshift with a premature stop codon in the next exon which is predicted to result to in NMD. The variant has been reported in at least one GT patient (PMID: 31064749). The highest population minor allele frequency in gnomADv4.0 is 0.000009322 (11/1,180,002 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting and PVS1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806056/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:478164 biolink:causes UMLS:C1112209 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C1112209 infores:hetionet GO:1905132 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1905132 GO:0051321 CHEBI:10101 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0497327 infores:hetionet CHEBI:5613 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0007398 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0948873 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235567 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0162429 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020649 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0152029 infores:hetionet CHEBI:7454 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0344232 infores:hetionet NCBIGene:3329 biolink:causes MONDO:0011532 infores:monarchinitiative not_provided not_provided HGNC:5261 MONDO:0011532 uuid:53ca135e-5202-4f25-9268-0d96a4d392e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020039 infores:hetionet CHEBI:131512 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0021141 infores:hetionet NCBIGene:79846 biolink:causes MONDO:0054728 infores:monarchinitiative not_provided not_provided HGNC:26107 MONDO:0054728 uuid:b79dac92-232d-42b2-b2e2-dd5c0d806429 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0014518 infores:hetionet CHEBI:9598 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0018681 infores:hetionet CHEBI:9137 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0234708 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0852913 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005648 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003504 infores:hetionet CHEBI:63638 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0014518 infores:hetionet CHEBI:45951 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0085612 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1565489 infores:hetionet CHEBI:47780 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085632 infores:hetionet CHEBI:5296 biolink:causes UMLS:C1610056 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C1610056 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151629 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151629 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0853089 infores:hetionet CHEBI:7573 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0033774 infores:hetionet CHEBI:9168 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030193 infores:hetionet CHEBI:8232 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C1320835 infores:hetionet CHEBI:71219 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0013604 infores:hetionet CAID:CA913178873 biolink:causes MONDO:0044970 infores:clingen CAID:CA913178873 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PS4, PS2, PS3, PM6 The m.8299G>A variant in MT-TK has been reported in one individual with primary mitochondrial disease to date (PMID: 22326363), in a 63-year-old man who had progressive dysarthria and ptosis for more than twenty years. He also had low body mass index, external ophthalmoparesis, facial weakness, slight proximal tetraparesis, bilateral sensorineural hearing loss, and bilateral cataract and retinal pigment changes. Brain imaging showed slight cerebellar and cerebral atrophy and some lacunar infarcts in the basal ganglia. He developed sudden respiratory failure but recovered, but a year and a half later developed CO2 retention and died several years later from ventilatory insufficiency. Muscle biopsy showed ragged red fibers, COX-negative fibers, and decreased activities of respiratory chain complexes I and IV. The variant was present at 50% heteroplasmy in muscle and was undetectable in blood. Samples from family members were not available for testing. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (63.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.35 (PP3). There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913178873/MONDO:0044970/015 2024-07-22 2025-08-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:49375 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0206062 infores:hetionet CHEBI:7601 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0002792 infores:hetionet CHEBI:4728 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0016382 infores:hetionet GO:0048906 biolink:causes CL:2000036 infores:ubergraph knowledge_assertion manual_agent GO:0048906 CL:2000036 CHEBI:9434 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0026821 infores:hetionet CHEBI:44915 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0015967 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0232492 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0578687 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0578687 infores:hetionet CHEBI:66901 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0042594 infores:hetionet CHEBI:31932 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0011991 infores:hetionet CHEBI:16467 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0278134 infores:hetionet CHEBI:40303 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0427055 infores:hetionet CHEBI:46557 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151723 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0031542 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2242588 infores:hetionet CHEBI:63638 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0008031 infores:hetionet CAID:CA262046 biolink:causes MONDO:0019497 infores:clingen CAID:CA262046 MONDO:0019497 PMID: Likely Pathogenic PM3, PVS1_Moderate, PP4, PM2_Supporting PM5, PS1, PP3 The c.5193-1G>A variant in OTOF occurs within the canonical splice site (+/- 1,2) of exon 42/47 and is predicted to cause altered splicing. Exon 42 is in frame and exon skipping would result in loss of <10% of the OTOF protein, but LOF variants in this region are rare in the general population (PVS1_Moderate). Another variant affecting this splice acceptor site is classified as pathogenic in ClinVar by 1 laboratory (ClinVar Variation ID 2982202, SCV004642429.1). This variant has been observed in 1/1613896 of the total chromosomes in gnomAD v4, with the highest population minor allele frequency in gnomAD v4 is 0.0016% (1/62502 alleles) in the “Remaining” population, which is lower than the ClinGen Hearing Loss VCEP threshold (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 patients with hearing loss and auditory neuropathy spectrum disorder (ANSD). In both individuals, this variant was observed with a second likely pathogenic variant, but phase was not determined (1 point, PM3, PP4; PMID: 33111345, Partners LMM internal data SCV000065263.6). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1_Moderate, PM3, PP4, PM2_Supporting. (ClinGen Hearing Loss VCEP specifications version 1; 9/24/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA262046/MONDO:0019497/023 2024-09-24 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:51860 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0015672 infores:hetionet CAID:CA006767 biolink:causes MONDO:0100316 infores:clingen CAID:CA006767 MONDO:0100316 PMID: Uncertain Significance PP3 BP4, BA1, PS1, PS3, PS4, PS2, BP5, BS1, BS3, BS4, PM2, PM6, PM5, PM1, PP1, PP4 NM_000218.3(KCNQ1):c.296C>G is a missense variant predicted to cause replacement of proline with arginine at position 99. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001201, with 9/74916 in the African / African-American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant is rare and has been reported in 1 proband affected with heart murmur and sudden infant death during sleep, however, QTc interval is not available and the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met (PMID: 24631775). The computational predictor REVEL gives a score of 0.861, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006767/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4784 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027769 infores:hetionet CHEBI:5165 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0004144 infores:hetionet CHEBI:77733 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0034150 infores:hetionet CHEBI:49960 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0003862 infores:hetionet CHEBI:6950 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013456 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0005940 infores:hetionet CAID:CA8314930 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314930 MONDO:0009276 PMID: Benign BP4, BA1 PM2, PP4, PM3, BS1 The NM_000173.7(GP1BA):c.1232C>T variant in GP1BA is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 411 (p.Pro411Leu). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.007836 (based on 54/5424) in the Middle Eastern population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets BA1. The computational predictor REVEL gives a score of 0.223, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BA function and the SpliceAI score is zero (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4 (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314930/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:94686 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0002792 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030312 infores:hetionet CHEBI:15551 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0016382 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0017160 infores:hetionet CHEBI:6775 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0741494 infores:hetionet CHEBI:6709 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0018681 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002812 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1168225 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0877661 infores:hetionet CHEBI:10125 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0232726 infores:hetionet CHEBI:8346 biolink:causes MONDO:0009718 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0027145 infores:hetionet CHEBI:5138 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1456784 infores:hetionet CHEBI:50156 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C1258215 infores:hetionet CAID:CA350341977 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341977 MONDO:0015924 PMID: Pathogenic PP3, PM2_Supporting, PM1_Supporting, PS4, PS3 BP4, BA1, BS1, BS3 BMPR2 c.1258T>C is a missense variant predicted to cause substitution of cysteine to arginine at amino acid position 420 (p.Cys420Arg). This variant resides within the catalytic kinase domain but is not a known critical residue (PM1_moderate met). The variant is absent in gnomAD databases, meeting PM2_supporting criterion (BA1 and BS1 not met). The REVEL score of 0.934 meets PP3_suporting criteria (>=0.75) (BP4 not met). Functional studies indicated subcellular mislocalization of the mutant protein (PMID: 25688877) and decreased receptor-mediated signaling (PMID: 12045205) (PS3 met). At least five unrelated probands have been reported in the literature (PMID: 11115378, 21801371, 27587546, 32634488, 32966279), meeting the PS4 threshold of >4 probands. Alternative missense variants have been reported in the same location but these variants are pending expert panel curation and PM5 is not scored at this time. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_strong, PS3_strong, PM1_ moderate, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341977/MONDO:0015924/125 2025-01-22 2025-01-22 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:64218 biolink:causes MONDO:0012464 infores:monarchinitiative not_provided not_provided HGNC:10729 MONDO:0012464 uuid:97faed33-3aa7-4ade-9e84-4727c8b275d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5165 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1258215 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0030353 infores:hetionet CHEBI:9654 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0151636 infores:hetionet NCBITaxon:6248 biolink:causes MONDO:0005974 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6248 MESH:D013322 DB00602_MESH_D013322_1 CHEBI:29007 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0085593 infores:hetionet CHEBI:101278 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0085610 infores:hetionet CHEBI:8707 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0014518 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0042109 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0162830 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0001824 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0021843 infores:hetionet UMLS:C0004609 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013384 infores:hetionet CHEBI:3001 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0010200 infores:hetionet CHEBI:6444 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C1306341 infores:hetionet CHEBI:31644 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0231218 infores:hetionet NCBIGene:427 biolink:causes MONDO:0008045 infores:monarchinitiative not_provided not_provided HGNC:735 MONDO:0008045 uuid:77bd96b0-7258-4887-a047-40947f3a9a5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0011701 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0155626 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020437 infores:hetionet CHEBI:134966 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0041969 infores:hetionet CHEBI:65173 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0042024 infores:hetionet CHEBI:231594 biolink:causes UMLS:C1112274 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1112274 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0851341 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036572 infores:hetionet UMLS:C0004609 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013404 infores:hetionet NCBIGene:2064 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:3430 MONDO:0001056 uuid:7ee47bfb-05d7-4c22-822b-95b81ee6bb2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0206062 infores:hetionet CHEBI:136040 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0699828 infores:hetionet CHEBI:59445 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0020625 infores:hetionet CHEBI:87681 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0013404 infores:hetionet CHEBI:100241 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0032617 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020651 infores:hetionet CHEBI:6741 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0235437 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0039971 infores:hetionet CHEBI:408174 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151636 infores:hetionet CHEBI:3485 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0025222 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151736 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151773 infores:hetionet CAID:CA6831796 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831796 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PVS1 PP4 The c.685C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 229 (p.(Arg229Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 34 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29666556, 23517481, 25411618, internal lab contributors). This variant segregated with diabetes, with at least 13 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). In summary, c.685C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831796/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51164 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0917801 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0239295 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0001824 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0454643 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0454643 infores:hetionet CHEBI:39669 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0004093 infores:hetionet CHEBI:8059 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0011991 infores:hetionet CHEBI:490877 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0011991 infores:hetionet CHEBI:4027 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1145670 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0025061 infores:hetionet CHEBI:91834 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0038999 infores:hetionet CHEBI:6847 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0162830 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233485 infores:hetionet CHEBI:5613 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0022346 infores:hetionet NCBIGene:10908 biolink:causes MONDO:0008980 infores:monarchinitiative not_provided not_provided HGNC:16268 MONDO:0008980 uuid:0f751b4a-c26c-442a-8e4a-aecffbf662ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5128 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0030252 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0233472 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0003123 infores:hetionet CHEBI:8888 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C3665386 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0025061 infores:hetionet CHEBI:75998 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020625 infores:hetionet CHEBI:8805 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0003862 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0032285 infores:hetionet CHEBI:5001 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0037763 infores:hetionet CHEBI:42797 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020443 infores:hetionet CHEBI:39585 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042963 infores:hetionet CHEBI:49603 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0042963 infores:hetionet CHEBI:9605 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0018681 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038362 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0007642 infores:hetionet CHEBI:3723 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020578 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0009806 infores:hetionet CHEBI:161680 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0020517 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0086132 infores:hetionet CHEBI:3286 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0037763 infores:hetionet CHEBI:6067 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0162835 infores:hetionet CHEBI:29007 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0151754 infores:hetionet NCBIGene:775 biolink:causes MONDO:0032756 infores:monarchinitiative not_provided not_provided HGNC:1390 MONDO:0032756 uuid:94be08dc-1dbe-4acd-abf7-47024dc3956f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C2830004 infores:hetionet CHEBI:9571 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0233514 infores:hetionet CHEBI:31515 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0013428 infores:hetionet CAID:CA367403885 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403885 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.46-1G>T variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of a portion biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in a single individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). While this individual did have a clinical history suggestive of GCK-hyperglycemia (HbA1C 5.6 – 7.6%), their fasting glucose was above the MDEP cutoff value (5.5-8 mmol/L), and so PP4 does not apply (internal lab contributors). In summary, c.46-1G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403885/MONDO:0015967/086 2025-01-03 2025-01-03 Semidominant inheritance HP:0032113 Supports NCBIGene:2120 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:3495 MONDO:0018874 uuid:a32fe6b9-37b7-426b-8a7e-f47ce11f24bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes UMLS:C0267033 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0267033 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018991 infores:hetionet CAID:CA421823465 biolink:causes MONDO:0013144 infores:clingen CAID:CA421823465 MONDO:0013144 PMID: Likely Benign BP7, PM2_Supporting, BP4 The c.21A>T (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Gly7=). The variant is completely absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 with a good coverage profile across both genomes and exomes in this region meeting PM2_supporting. SpliceAI predicts no splicing impact for this variant meeting BP4. The variant is not predicted to cause a splicing impact and the nucleotide is weakly conserved with a PhyloP100 score of -0.0436063 meeting BP7 criteria (PhyloP < 0.1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4, BP7, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA421823465/MONDO:0013144/084 2024-10-02 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085932 infores:hetionet CHEBI:161680 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0151905 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1262018 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1262018 infores:hetionet CHEBI:465284 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0004604 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0151998 infores:hetionet CHEBI:44915 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0011175 infores:hetionet NCBIGene:2731 biolink:causes MONDO:0958179 infores:monarchinitiative not_provided not_provided HGNC:4313 MONDO:0958179 uuid:71fd82f5-1d49-4d51-9c19-b5ada19dbb3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0018799 infores:hetionet CHEBI:27834 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0702166 infores:hetionet NCBIGene:65260 biolink:causes MONDO:0020770 infores:monarchinitiative not_provided not_provided HGNC:25716 MONDO:0020770 uuid:2c91b053-6748-409d-aa9b-a9b761d2ed1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0045014 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0342892 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0008477 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0008477 uuid:3869d6bf-1fd7-4c4e-a84a-6c0d709786bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0043405 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0043405 GO:0051716 NCBIGene:55750 biolink:causes MONDO:0008922 infores:monarchinitiative not_provided not_provided HGNC:21869 MONDO:0008922 uuid:0dda06fb-618a-4c23-a47d-c936c970f7e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0853149 infores:hetionet CHEBI:8364 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0009806 infores:hetionet GO:0048888 biolink:causes CL:0000851 infores:ubergraph knowledge_assertion manual_agent GO:0048888 CL:0000851 CAID:CA421938925 biolink:causes MONDO:0005338 infores:clingen CAID:CA421938925 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.849G>A variant in MYOC is a synonymous variant (p.Glu283=). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00001099 (1 allele out of 90,988), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (F. Pasutto pers. comm.), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421938925/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27834 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0232462 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0242350 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233571 infores:hetionet NCBIGene:1184 biolink:causes MONDO:0010225 infores:monarchinitiative not_provided not_provided HGNC:2023 MONDO:0010225 uuid:d7920708-0413-442a-82b2-09346c691e66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes UMLS:C2939065 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C2939065 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235280 infores:hetionet CAID:CA415168076 biolink:causes MONDO:0010726 infores:clingen CAID:CA415168076 MONDO:0010726 PMID: Likely Benign BP5, BS2 BS1 The p.Pro361Ser variant in MECP2 (NM_004992.3) is present in 9 XX and 3 XY individual(s) in gnomAD v4.0 (0.001%) (not sufficient to meet BS1 criteria). The p.Pro361Ser variant in the MECP2 gene is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro361Ser variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). In summary, the p.Pro361Ser variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415168076/MONDO:0010726/036 2024-04-18 2024-07-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:16714 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0038587 infores:hetionet CHEBI:7573 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0018681 infores:hetionet CHEBI:71272 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0024312 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0238792 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0238792 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0032285 infores:hetionet NCBIGene:5376 biolink:causes MONDO:0007790 infores:monarchinitiative not_provided not_provided HGNC:9118 MONDO:0007790 uuid:01c64ff2-3f96-4be1-843b-b0d589dd367e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1443060 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0033775 infores:hetionet CHEBI:34911 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0033774 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034063 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0018524 infores:hetionet CHEBI:48390 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0004093 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0039503 infores:hetionet CHEBI:6715 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013390 infores:hetionet CHEBI:4653 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0042963 infores:hetionet CHEBI:4877 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0031046 infores:hetionet CHEBI:9667 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0000731 infores:hetionet CHEBI:17474 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C2979982 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1262064 infores:hetionet CHEBI:4975 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0037763 infores:hetionet CHEBI:42820 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0002871 infores:hetionet CHEBI:17987 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0036508 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0034065 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019348 infores:hetionet NCBIGene:1337 biolink:causes MONDO:0014467 infores:monarchinitiative not_provided not_provided HGNC:2277 MONDO:0014467 uuid:02dc61f3-9b22-43ad-9df9-7386525787a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0035883 biolink:causes CL:0000164 infores:ubergraph knowledge_assertion manual_agent GO:0035883 CL:0000164 CHEBI:31536 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0031117 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1609512 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0042514 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0032326 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1112214 infores:hetionet CHEBI:6437 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0020625 infores:hetionet CHEBI:8869 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0040435 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0264714 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0264714 infores:hetionet CHEBI:9571 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0085602 infores:hetionet CHEBI:3207 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0687713 infores:hetionet CHEBI:3764 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0520893 infores:hetionet CHEBI:2704 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0231218 infores:hetionet CHEBI:4877 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C1504494 infores:hetionet CAID:CA913184909 biolink:causes MONDO:0009290 infores:clingen CAID:CA913184909 MONDO:0009290 PMID: Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong, PM4_Supporting This variant, c.2167_2179delinsTGCGACGTGG, is predicted to result in the in frame deletion of five amino acids (ValAlaArgProLeu) and insertion of another four amino acids in GAA (p.Val723_LeudelinsCysAspValVal), meeting PM4. The variant is absent in gnomAD v2.1.1, meeting PM2. To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and experimental studies are not available. However, there is unpublished clinical laboratory data on two patients with the variant who have deficient GAA activity in dried blood spots, meeting PP4. One is compound heterozygous for the variant and c.-32-13T>G (known pathogenic variant), the other is compound heterozygous for the variant and c.655G>A (p.Gly219Arg) (pathogenic based on assessment by the ClinGen LSD VCEP). In both cases, the variants are confirmed in trans. This data meets PM3_Strong. PROVEAN and Mutation Taster predict that this variant impacts the function of GAA, meeting PP3. There is no entry for this variant in ClinVar. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM2, PM4, PP3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184909/MONDO:0009290/010 2020-04-06 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:68845 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0235416 infores:hetionet CHEBI:8356 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0232462 infores:hetionet CHEBI:51041 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C3665386 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013395 infores:hetionet CHEBI:71219 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0000731 infores:hetionet UMLS:C0005740 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0019080 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002884 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0234458 infores:hetionet CHEBI:31348 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0016204 infores:hetionet CHEBI:7459 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0600142 infores:hetionet CHEBI:84500 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020621 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0007787 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020538 infores:hetionet CAID:CA405667995 biolink:causes MONDO:0007783 infores:clingen CAID:CA405667995 MONDO:0007783 PMID: Likely Benign BS2_Supporting, BP4 PP3, PM5, PM1, PS1, PS4, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 4104 of the RYR1 protein, p.(Gly4104Arg). This variant was not present in a large population database (gnomAD). This variant has been reported in an individual who had a personal or family history of a malignant hyperthermia reaction, however, the caffeine halothane contracture test (CHCT) results for this individual were positive for halothane but not caffeine, PS4 was not implemented (PMID:21455645). This individual had a relative with a negative CHCT test that shared the variant, BS2_Moderate (PMID:21455645). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID: 21118704). A REVEL score <0.5 supports a benign status, BP4. This variant has been classified as Likely Benign. Criteria implemented: BS2_Moderate, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405667995/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3696 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0023518 infores:hetionet CHEBI:15553 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0011175 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0036572 infores:hetionet UNII:3U02EL437C biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0151908 infores:hetionet CHEBI:50885 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0235259 infores:hetionet CHEBI:83804 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0858635 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0232431 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0278080 infores:hetionet CHEBI:9137 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0004093 infores:hetionet CHEBI:3650 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0014742 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020538 infores:hetionet CHEBI:7640 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0006384 infores:hetionet CHEBI:135939 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0600125 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0270810 infores:hetionet CHEBI:65346 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0080274 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0085607 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0085607 infores:hetionet CHEBI:3756 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233795 infores:hetionet CHEBI:9613 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0030312 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0034150 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004936 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151828 infores:hetionet CHEBI:18357 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0497247 infores:hetionet CHEBI:119486 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085633 infores:hetionet CHEBI:3757 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0040264 infores:hetionet CHEBI:17026 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042023 infores:hetionet CHEBI:474180 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0019209 infores:hetionet CHEBI:125354 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0042963 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235032 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018799 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0036572 infores:hetionet CHEBI:7903 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0011603 infores:hetionet CHEBI:47898 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0424790 infores:hetionet CHEBI:584020 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0015230 infores:hetionet CHEBI:63619 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020580 infores:hetionet CHEBI:7820 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0022354 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0041912 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042075 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0030319 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0004936 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0079043 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0267792 infores:hetionet CAID:CA229800 biolink:causes MONDO:0009861 infores:clingen CAID:CA229800 MONDO:0009861 PMID:16601866 Pathogenic PM2, PM5, PP3, PP4, PM3_Strong BP2 The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID: 24350308); c.842+1G>A in 2 patients (PMID: 25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229800/MONDO:0009861/006 2020-06-08 2021-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:29688 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C1443060 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0019158 infores:hetionet CHEBI:8768 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2830004 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040435 infores:hetionet CHEBI:4702 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0014742 infores:hetionet CHEBI:15544 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0013491 infores:hetionet NCBITaxon:10310 biolink:causes MONDO:0004609 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10310 MESH:D006561 DB00787_MESH_D006561_1 CHEBI:8081 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0002962 infores:hetionet CHEBI:47780 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0016204 infores:hetionet CHEBI:135738 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0018681 infores:hetionet CHEBI:51041 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011606 infores:hetionet CHEBI:9449 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0026826 infores:hetionet CAID:CA410203331 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203331 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.351+2T>C is a dinucleotide splice site variant which is predicted to result in exon 4 skipping (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203331/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32020 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0231528 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235315 infores:hetionet CHEBI:7865 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0235063 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030353 infores:hetionet CHEBI:94449 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0013378 infores:hetionet CHEBI:47898 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036974 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0001430 infores:hetionet CHEBI:64019 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0151436 infores:hetionet CHEBI:17688 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0003467 infores:hetionet CHEBI:145499 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0030554 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0007787 infores:hetionet NCBIGene:2395 biolink:causes MONDO:0100340 infores:monarchinitiative not_provided not_provided HGNC:3951 MONDO:0100340 uuid:2b54cbd5-d9d6-4860-a3d7-2e94026f914e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA023533 biolink:causes MONDO:0007750 infores:clingen CAID:CA023533 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195).PS4_supporting - Variant meets PM2. Variant identified in 5 index cases. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023533/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:194135 biolink:causes UMLS:C0410256 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0410256 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0542203 infores:hetionet CHEBI:5790 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0039231 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0009938 infores:hetionet CHEBI:2788 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C3665347 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0332534 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005487 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036337 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0023380 infores:hetionet CHEBI:3764 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0005758 infores:hetionet CHEBI:7986 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0009763 infores:hetionet CHEBI:119915 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0338908 infores:hetionet CHEBI:131512 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0151315 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1269955 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1269955 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0031350 infores:hetionet CHEBI:3723 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018944 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235030 infores:hetionet CHEBI:63620 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042023 infores:hetionet CHEBI:36791 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011124 infores:hetionet CHEBI:27732 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C3263723 infores:hetionet NCBIGene:2673 biolink:causes MONDO:0012518 infores:monarchinitiative not_provided not_provided HGNC:4241 MONDO:0012518 uuid:8ed36fa3-3cfb-4a96-a247-f2da21529b92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C3263723 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0001824 infores:hetionet NCBITaxon:727 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:727 MESH:D001991 DB01165_MESH_D001991_1DB06151_MESH_D001991_1 CHEBI:10125 biolink:causes UMLS:C0034634 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0034634 infores:hetionet CHEBI:92712 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0041834 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0435630 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0435630 infores:hetionet CHEBI:8378 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0042571 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235146 infores:hetionet CHEBI:9448 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0003862 infores:hetionet CAID:CA201118 biolink:causes MONDO:0100453 infores:clingen CAID:CA201118 MONDO:0100453 PMID: Benign BA1, BP4, BS2 The NM_000180.4(GUCY2D):c.2577G>T (p.Pro859=) variant is located at the first base of exon 14 and does not alter the amino acid (proline) at position p.859. The splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04139, with 3871 alleles / 91074 total alleles in the South Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 141 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA201118/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7915 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027497 infores:hetionet CHEBI:36704 biolink:causes NCIT:C54056 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521987 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0178298 infores:hetionet CHEBI:39585 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0700361 infores:hetionet CHEBI:9757 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0026837 infores:hetionet NCBIGene:2707 biolink:causes MONDO:0012976 infores:monarchinitiative not_provided not_provided HGNC:4285 MONDO:0012976 uuid:132109fd-9f47-4697-a626-9315c7157220 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0037299 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020701 infores:hetionet CHEBI:134991 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0009676 infores:hetionet CHEBI:68642 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0235378 infores:hetionet CHEBI:6339 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0018681 infores:hetionet CHEBI:94807 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0541832 infores:hetionet CHEBI:27779 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0027497 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0677500 infores:hetionet CAID:CA2695232631 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695232631 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting PM6, PP3, PP4, BS2, PM5, BP4, BA1, BP7, BS1 NM_001034853.2(RPGR):c.2659_2662del (p.Gly887LysfsTer?) is a frameshift variant due to a 4-nucleotide deletion introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 probands meeting one of the PS4 requirements of a male with some functional visual impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 17325176, PMID: 14564670, PMID: 38219857, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of X-linked retinitis pigmentosa, macular atrophy (1 pt), decreased central vision acuity (0.5 pts), and myopia (0.5 pts), which together are not sufficiently specific to meet the PP4 code for RPGR-related retinopathy (2 points, PMID: 14564670). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695232631/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:31643 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0042109 infores:hetionet CHEBI:70746 biolink:causes UMLS:C2243088 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C2243088 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0023530 infores:hetionet NCBIGene:4625 biolink:causes MONDO:0008647 infores:monarchinitiative not_provided not_provided HGNC:7577 MONDO:0008647 uuid:d52ba3b3-0731-430b-b8a5-b4fbe83253ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1142412 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0001824 infores:hetionet CHEBI:6076 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232487 infores:hetionet CHEBI:135193 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0042963 infores:hetionet CHEBI:6904 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0700590 infores:hetionet UMLS:C0879264 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151904 infores:hetionet CHEBI:31348 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0033046 infores:hetionet CHEBI:6838 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C2830004 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1609512 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0677500 infores:hetionet CHEBI:16347 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0012833 infores:hetionet CHEBI:8356 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023212 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0271308 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0271308 infores:hetionet CHEBI:51860 biolink:causes NCIT:C50526 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0235827 infores:hetionet CHEBI:72564 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0038325 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0042373 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0178298 infores:hetionet CHEBI:28939 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0013604 infores:hetionet CHEBI:4024 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0522224 infores:hetionet CHEBI:6359 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0042963 infores:hetionet CHEBI:5383 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0040822 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0013595 infores:hetionet CHEBI:71255 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0085610 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0861157 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0861157 infores:hetionet CAID:CA10584944 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584944 MONDO:0007750 PMID: Uncertain Significance PM1, PM2, PP3 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, PP1, PP4, BS2 The NM_000527.5(LDLR):c.491T>C (p.Leu164Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.801. PM1: Variant meets PM2 and is a missense in exon 4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584944/MONDO:0007750/013 2024-02-23 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:51173 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0018799 infores:hetionet CHEBI:31236 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085632 infores:hetionet CAID:CA10385255 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385255 MONDO:0100437 PMID: Benign BA1, BP3 NM_001034853.2(RPGR):c.2667_2669del (p.Glu890del) is a short in-frame deletion of 3 base pairs that encode amino acid 890 within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v.4.1.0 at a frequency of 0.1323 among hemizygous individuals, with 6,699 variant alleles / 50,616 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385255/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:16914 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C2830004 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0020517 infores:hetionet CHEBI:42068 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0002871 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0872380 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0872380 infores:hetionet CHEBI:8107 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0033774 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0012833 infores:hetionet CAID:CA410203489 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203489 MONDO:0011071 PMID: Likely Pathogenic PM1, PS3_Moderate, PM2_Supporting, PP3 PS1, PS4, PS2, BP1, BP4, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM5, BS2, PP2, PP4, PP1 This variant affects one of the hotspot residues (residue 107) established by the MM-VCEP for RUNX1 (PM1).The variant exhibits altered function in 2 secondary assays.https://www.embopress.org/doi/epdf/10.1038/sj.emboj.7601568?src=getftrNM001001890.3 c.238C>T p.R80C - Moderate to severe loss of DNA binding and >5 fold decrease in CBFB binding (PS3_moderate).REVEL score is ≥0.88 (0.923) and SpliceAI is ≤0.20 (0.00) (PP3). This variant is completely absent from population databases (gnomad v4.0) with at least 20x coverage for RUNX1 (PM2_supporting).In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PS3_moderate, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203489/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10102 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0038990 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0017152 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0221717 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0178298 infores:hetionet CHEBI:47426 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0162830 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0595879 infores:hetionet CHEBI:9139 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0231919 infores:hetionet CAID:CA401366522 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366522 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3 The NM_000152.5: c.1400T>C variant in GAA is predicted to result in the missense substitution of phenylalanine by serine at amino acid 467 (p.Phe467Ser). This variant has been detected in one patient with a diagnosis of infantile onset Pompe disease (IOPD) with documented deficient GAA activity and on enzyme replacement therapy (Clinical Diagnostic Laboratory) (PP4_Moderate). This variant was confirmed to be in trans with c.2560C>T (p.Arg854Ter), a GAA variant classified as pathogenic by the ClinGen LD VCEP (ClinVar Variation ID: 4034, SCV001371731.1), in one patient with IOPD (Clinical Diagnostic Laboratory) (PM3). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational meta-predictor REVEL has a score of 0.941 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP on Jan 16, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366522/MONDO:0009290/010 2024-01-16 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31705 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0009763 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0029408 infores:hetionet CHEBI:63619 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004144 infores:hetionet CHEBI:45081 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020672 infores:hetionet CHEBI:171719 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0028961 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0267792 infores:hetionet CHEBI:39867 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013390 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009450 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235818 infores:hetionet GO:0010104 biolink:causes GO:0071369 infores:ubergraph knowledge_assertion manual_agent GO:0010104 GO:0071369 CHEBI:31236 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0086769 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151618 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151618 infores:hetionet CHEBI:47519 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0017178 infores:hetionet CHEBI:9599 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1443060 infores:hetionet CHEBI:6710 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0014457 infores:hetionet CHEBI:8874 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018965 infores:hetionet CHEBI:8024 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0020625 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0015376 infores:hetionet CHEBI:68642 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0152031 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014118 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0700184 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0024115 infores:hetionet CHEBI:3082 biolink:causes MONDO:0007122 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0003079 infores:hetionet CHEBI:3048 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0232462 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0006826 infores:hetionet CHEBI:6437 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1384353 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0018939 infores:hetionet CHEBI:7447 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0002994 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0018799 infores:hetionet CHEBI:6437 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0012569 infores:hetionet CHEBI:63612 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0030554 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017160 infores:hetionet CHEBI:10102 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013604 infores:hetionet CAID:CA308085802 biolink:causes MONDO:0018493 infores:clingen CAID:CA308085802 MONDO:0018493 PMID: Uncertain Significance PP1, PS4_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 3806 of the RYR1 protein, p.(Gly3806Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:19191329). No functional studies were identified for this variant. This variant segregates with MHS in 4 individuals, PP1 (PMID:19191329). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308085802/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9137 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0281981 infores:hetionet CHEBI:4974 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0020433 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0235431 infores:hetionet CHEBI:63598 biolink:causes MONDO:0021681 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0036916 infores:hetionet CHEBI:47898 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0476280 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020651 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007114 infores:hetionet UNII:DJJ95FJP1H biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0728899 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0231303 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020517 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0038045 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0038045 infores:hetionet CAID:CA345151718 biolink:causes MONDO:0100084 infores:clingen CAID:CA345151718 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS2 PP1, PP4, BS2, PVS1, PM6, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3 The NM_001100.4 c.37G>A (p.Asp13Asn) variant in ACTA1 is a missense variant predicted to cause a substitution of aspartic acid by asparagine at amino acid 13. ACTA1 is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.763, which is above the threshold for predicting a damaging effect on ACTA1 variants (PP3). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been identified as de novo by trio analysis in one proband with clinical features of congenital myopathy (ARUP Laboratories; SCV001157803.1) (PS2). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: PP2, PP3, PM2_Supporting, PS2; ClinGen Congenital Myopathies VCEP Specifications 2.0.0; 12/9/2024 Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345151718/MONDO:0100084/147 2024-12-09 2025-06-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039621 infores:hetionet CHEBI:7565 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0003862 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020538 infores:hetionet NCBIGene:5361 biolink:causes MONDO:0859260 infores:monarchinitiative not_provided not_provided HGNC:9099 MONDO:0859260 uuid:54be29f1-bb22-41a0-97d3-f0dd3d5fc52f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0029882 infores:hetionet CHEBI:31485 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0015403 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0085584 infores:hetionet CHEBI:6438 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0011991 infores:hetionet CHEBI:6775 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018932 infores:hetionet CHEBI:6931 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0010200 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0011633 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0011633 uuid:47db1d18-c0e1-4db7-bf28-3b37174b2595 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0019270 infores:hetionet CHEBI:3716 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0232462 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0267596 infores:hetionet CHEBI:8455 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0011991 infores:hetionet CHEBI:5778 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0853034 infores:hetionet CHEBI:2955 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151798 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0151705 infores:hetionet CHEBI:9449 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0043352 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0015376 infores:hetionet CHEBI:119915 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1456784 infores:hetionet CHEBI:8774 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0220870 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0086132 infores:hetionet CHEBI:145499 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027497 infores:hetionet CAID:CA915940722 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940722 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The ITGA2B frameshift variant NM_000419.5:c.2459del is expected to introduce a premature termination codon six amino acids downstream (p.Asn820MetfsTer6) in exon 25/30 and the resulting mRNA product is predicted to be susceptible to nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT02, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PP4_moderate, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940722/MONDO:0100326/011 2021-07-08 2021-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:47898 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085631 infores:hetionet CHEBI:135888 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0041834 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1565489 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0235416 infores:hetionet CHEBI:8024 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030252 infores:hetionet CHEBI:45951 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C1258215 infores:hetionet CHEBI:8378 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0027497 infores:hetionet CHEBI:63599 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0007760 infores:hetionet CHEBI:144551 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0030554 infores:hetionet NCBIGene:84705 biolink:causes MONDO:0014525 infores:monarchinitiative not_provided not_provided HGNC:14880 MONDO:0014525 uuid:83a41c62-1dc9-4c50-97a9-bee02926b244 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1142135 infores:hetionet CHEBI:3638 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0917801 infores:hetionet CHEBI:45409 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0018946 infores:hetionet CHEBI:5004 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0231218 infores:hetionet NCBIGene:4907 biolink:causes MONDO:0008895 infores:monarchinitiative not_provided not_provided HGNC:8021 MONDO:0008895 uuid:45bd0807-0b0b-485b-838b-e71b3c515e61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027497 infores:hetionet CHEBI:3504 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0085702 infores:hetionet CHEBI:10127 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0520966 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0000814 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0000814 infores:hetionet NCBIGene:5880 biolink:causes MONDO:0033555 infores:monarchinitiative not_provided not_provided HGNC:9802 MONDO:0033555 uuid:1e673ae0-1a69-48c1-add1-c253348e285c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50131 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151723 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0232124 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0232124 infores:hetionet CHEBI:36791 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0438142 infores:hetionet NCBIGene:2071 biolink:causes MONDO:0014615 infores:monarchinitiative not_provided not_provided HGNC:3435 MONDO:0014615 uuid:78c01412-4f00-4ca5-a0d6-2b129473fb20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA213929 biolink:causes MONDO:0015967 infores:clingen CAID:CA213929 MONDO:0015967 PMID: Likely Benign BS1, BP5 PP3, BP4 The c.361A>G variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of serine to glycine at codon 121 (p.(Ser121Gly)) in NM_175914.5. The Popmax filtering allele frequency of the c.361A>G variant in gnomAD v2.1.1 is 0.00006673, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant has a REVEL score of 0.555, which is between the ClinGen MDEP established cutoffs for PP3 and BS4, predicting neither a damaging nor benign impact on HNF4A function; thus, neither criterion will be applied. This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.361A>G meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BS1, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213929/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47381 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0026821 infores:hetionet CHEBI:28748 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0039231 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042571 infores:hetionet GO:1901207 biolink:causes GO:0035050 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0035050 CHEBI:9605 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0151699 infores:hetionet CHEBI:9139 biolink:causes UMLS:C1504465 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1504465 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042769 infores:hetionet CHEBI:36791 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015402 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0003460 infores:hetionet CHEBI:63618 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0004093 infores:hetionet CHEBI:75998 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0085682 infores:hetionet CHEBI:50305 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0241057 infores:hetionet CHEBI:51137 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0009676 infores:hetionet CHEBI:8435 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0080274 infores:hetionet CHEBI:7575 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0011570 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0004936 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0849796 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0849796 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042514 infores:hetionet NCBIGene:9414 biolink:causes MONDO:0014381 infores:monarchinitiative not_provided not_provided HGNC:11828 MONDO:0014381 uuid:207df5a9-cac6-452c-bbf6-2703a269ea93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3423 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151735 infores:hetionet CHEBI:4903 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0010692 infores:hetionet CHEBI:65173 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0231919 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0027769 infores:hetionet CHEBI:39112 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0011603 infores:hetionet CHEBI:5784 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0020651 infores:hetionet CHEBI:5118 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036974 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006527 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0003028 infores:hetionet CHEBI:3314 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0595862 infores:hetionet CAID:CA172110 biolink:causes MONDO:0018947 infores:clingen CAID:CA172110 MONDO:0018947 PMID: Pathogenic PS3, PS4, PS2, PP2, PP3, PM2_Supporting PM5 The c.1856C>T variant in DNM2 is a missense variant predicted to cause substitution of serine by leucine at amino acid 619. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.936, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen CM VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The variant has been reported in at least four probands with centronuclear myopathy that was confirmed by muscle biopsy, one of which was a de novo occurrence with parental relationships confirmed (PMIDs: PMIDs:17932957, 30208955, 34595679, PS4, PS2). In vitro assays demonstrate that the p.S619L variant increases GTPase activity (PMID: 20700106), indicating that this variant impacts protein function. Additionally, a variant-specific zebrafish model (PMID: 23338057) and a variant-specific mouse model (PMID:32809972) recapitulate patient phenotypes of motor problems, early impaired muscle function and force, and myofiber hypotrophy (PS4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS4, PM2_Supporting, PP2, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA172110/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31536 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0015967 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0920193 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0920193 infores:hetionet CHEBI:31236 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2981158 infores:hetionet CHEBI:46557 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042963 infores:hetionet CHEBI:31644 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151578 infores:hetionet CHEBI:5130 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014236 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042109 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0851341 infores:hetionet CHEBI:5613 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0027947 infores:hetionet CHEBI:6532 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0002792 infores:hetionet CAID:CA320251360 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251360 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, BP1, BP2, BP3, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1221C>T (p.Tyr407=) is a synonymous variant which is not predicted to affect splicing. This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251360/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28925 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0178298 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003366 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1253936 infores:hetionet CHEBI:567361 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0015672 infores:hetionet GO:0039502 biolink:causes GO:0071357 infores:ubergraph knowledge_assertion manual_agent GO:0039502 GO:0071357 CHEBI:3403 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0085616 infores:hetionet CHEBI:4798 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0041657 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0035328 infores:hetionet GO:0033084 biolink:causes GO:0030097 infores:ubergraph knowledge_assertion manual_agent GO:0033084 GO:0030097 NCBITaxon:1980456 biolink:causes MONDO:0017879 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1980456 MONDO:0017879 CHEBI:10127 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0034065 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1145670 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0025061 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0549398 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0549398 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2242737 infores:hetionet CAID:CA10581280 biolink:causes MONDO:0044970 infores:clingen CAID:CA10581280 MONDO:0044970 PMID:26993169PMID:15647368PMID:11406419PMID:18853457 Benign BA1, BP4 PP3, PM2 The m.8932C>T (p.P136S) variant in MT-ATP6 reaches benign stand-alone criteria (BA1) based on overall allele frequency [gnomAD.v3.1: Overall AF is 1.327% (759/56428); in top-level haplogroup L3, AF is 12.89% (731/5669) Mitomap: Overall AF in Mitomap is 0.399% (207/51863; in top-level haplogroup L3, AF is 9.73%. For the individuals in sub-group L3f, the frequency is 81% (205/253)]. Furthermore, this variant is reported in Phylotree as an L3f1b branch marker. There is one reported proband in the medical literature with this variant (PMID: 26993169), however when haplotyped by this curation team using the variants listed in the published report, the proband belonged to haplogroup L3f (haplogroup with which this variant is associated). In silico tools (APOGEE) predict this variant to be neutral (BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. However, if this variant is identified in an individual who is a member of a different haplogroup than described above, consider further evaluation of this variant. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581280/MONDO:0044970/014 2021-05-07 2021-10-22 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:63916 biolink:causes MONDO:0011744 infores:monarchinitiative not_provided not_provided HGNC:17233 MONDO:0011744 uuid:c67659d9-60e5-47f9-a4ad-dbe5c75ab93b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1760428 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0242350 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0021845 infores:hetionet CHEBI:4027 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019080 infores:hetionet NCBIGene:4718 biolink:causes MONDO:0030902 infores:monarchinitiative not_provided not_provided HGNC:7706 MONDO:0030902 uuid:ee0c01aa-4fe0-425e-90ad-d4c2bfaaf2ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48669 biolink:causes HP:0002647 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0340643 infores:hetionet CAID:CA114129 biolink:causes MONDO:0015629 infores:clingen CAID:CA114129 MONDO:0015629 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3, PS4 PP1, PM5 The NM_000552.5(VWF):c.4022G>A (p.Arg1341Gln) variant in VWF has been reported in several dozen vWD type 2B patients. At least one (P8 of PMID: 20118404) has sufficient information reported to meet the PP4_moderate criteria, including mucocutaneous bleeding, positive GOF assay, and loss of HMW multimers. An additional four have been curated for inclusion based on at least a LD-RIPA response (PMIDs: 20118404, 8292729; PS4_strong). In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PS3). The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). This variant is predicted deleterious by REVEL gives a score of 0.792, which is above the ClinGen VWD VCEP threshold of >0.644 (PP3). This variant has been observed segregating in multiple families, however insufficient phenotypic information has been reported on those individuals. In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PP3, and PP4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114129/MONDO:0015629/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42797 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009782 infores:hetionet CHEBI:5384 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0015397 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0948594 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0004238 infores:hetionet CHEBI:50777 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0003862 infores:hetionet CHEBI:47381 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0542571 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0860866 infores:hetionet CHEBI:4672 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0852911 infores:hetionet CHEBI:8890 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0015967 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005940 infores:hetionet CHEBI:499361 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0917801 infores:hetionet CHEBI:6717 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0497156 infores:hetionet CHEBI:78543 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1527344 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042514 infores:hetionet NCBIGene:3827 biolink:causes MONDO:0009234 infores:monarchinitiative not_provided not_provided HGNC:6383 MONDO:0009234 uuid:44cc39a9-d53a-4f59-97e3-7c90b023bda1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0030305 infores:hetionet CHEBI:75246 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0003962 infores:hetionet CHEBI:63616 biolink:causes UMLS:C1557335 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C1557335 infores:hetionet NCBIGene:10806 biolink:causes MONDO:0014444 infores:monarchinitiative not_provided not_provided HGNC:10671 MONDO:0014444 uuid:41d828c1-9767-4765-8c1b-e5896d71598f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65346 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0018801 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0037274 infores:hetionet CHEBI:63580 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035317 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0027497 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0080276 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019087 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0858899 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0858899 infores:hetionet CHEBI:3207 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0520573 infores:hetionet CHEBI:63638 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0338831 infores:hetionet CHEBI:7640 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0011253 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0149931 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0019158 infores:hetionet CAID:CA8603375 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603375 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the intronic variant NM_000419.5(ITGA2B):c.671-15T>C, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant was originally identified by Illumina from a predisposition screen in an ostensibly healthy population. The variant has a minor allele frequency of 0.0001859 (24/129086 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of -0.458 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603375/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9943 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015967 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0020538 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0240417 infores:hetionet CHEBI:4466 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0043144 infores:hetionet CAID:CA070340 biolink:causes MONDO:0018493 infores:clingen CAID:CA070340 MONDO:0018493 PMID: Likely Benign BS2 PP3, PM1, PS4, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of cysteine with serine at codon 2606 of the RYR1 protein, p.(Cys2606Ser). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual had a second variant of uncertain significance in RYR1, p.(Ala1372Val), PS4 was no implemented (PMID:30236257). This variant has been identified in four related individuals with negative IVCT results, BS2_Moderate (PMID:30236257). Functional studies identified for this variant did not fulfill PS3 as defined by the MHS-RYR1 VCEP (PMID:21603587). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.818 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA070340/MONDO:0018493/012 2021-12-21 2021-12-21 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:4882 biolink:causes MONDO:0014401 infores:monarchinitiative not_provided not_provided HGNC:7944 MONDO:0014401 uuid:5b85927f-c63e-4258-ac0e-662417d66c8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020598 infores:hetionet NCBIGene:10484 biolink:causes MONDO:0011911 infores:monarchinitiative not_provided not_provided HGNC:10701 MONDO:0011911 uuid:21b52fe1-b754-4105-bc05-34f55799506e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7823 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016479 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0003864 infores:hetionet CHEBI:49662 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0003578 infores:hetionet CHEBI:9763 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151746 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0857121 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0041956 infores:hetionet CHEBI:10101 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085636 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0030305 infores:hetionet CHEBI:135876 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0008031 infores:hetionet CAID:CA291224999 biolink:causes MONDO:0100326 infores:clingen CAID:CA291224999 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PS3_Moderate, PM3_Strong BS1, PM2, PP3 The NM_000212.3(ITGB3):c.917A>C (p.His306Pro) missense variant has been reported in at least six GT probands, including two homozygotes (Osaka-5 of PMID: 11806996; patient NT of PMID: 9790984) and four compound heterozygotes (PMIDs: 34066320, 15634267, 9790984). Contributing to this classification is patient TK of PMID: 9790984, who is compound heterozygous for the maternal His306Pro variant and the paternal Gly605Ser (classified Likely Pathogenic by the PD-EP) variant. (PM3_Strong). At least three patients (Patients TK, NT, and HJ in PMID:9790984) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 19.9%, 7.5% and15.4% respectively, as measured by flow cytometry. Similarly, surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with His306Pro variant β3 and wild type αIIb showed decreased expression at 25% indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_moderate, PM3_strong, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291224999/MONDO:0100326/011 2024-11-07 2024-11-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4046 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0039231 infores:hetionet CHEBI:8890 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0035229 infores:hetionet CHEBI:64019 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0039070 infores:hetionet NCBIGene:8556 biolink:causes MONDO:0012091 infores:monarchinitiative not_provided not_provided HGNC:1718 MONDO:0012091 uuid:16e80f99-3fb7-49c2-b126-767629fe7491 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5004 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0010692 infores:hetionet CHEBI:8597 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C2830004 infores:hetionet CHEBI:4315 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0206061 infores:hetionet CHEBI:66899 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0234632 infores:hetionet CHEBI:8888 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0035243 infores:hetionet CHEBI:2569 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0009782 infores:hetionet CHEBI:39669 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0042109 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020538 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0015397 infores:hetionet CHEBI:63617 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0025289 infores:hetionet CHEBI:7936 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0024902 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235146 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0003123 infores:hetionet GO:2000093 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:2000093 GO:0001823 CHEBI:94501 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0008031 infores:hetionet CAID:CA280029 biolink:causes MONDO:0021060 infores:clingen CAID:CA280029 MONDO:0021060 PMID:30820351PMID:19206169PMID:23763990PMID:22190897 Pathogenic PS1, PM1, PM6, PM2, PP3, PP2, PS4_Supporting PS2, PS3, PM4, BP7, BP5, BS4, BS3, BS1, BS2, PP1, BP3, BP4, BP1, BP2, BA1 The c.735A>T p.Leu245Phe variant in BRAF has been identified in at least 2 independent occurrences, one of which was de novo, in patients with clinical features of a RASopathy (PM6, PS4_Supporting; Partners LMM, University Magdeburg internal data; GTR Lab IDs: 21766, 506381 PMID: 19206169, 22190897). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, the p.Leu245Phe change has also been reported as a consequence of the c.735A>C variant in BRAF, which has been classified as pathogenic and therefore supports that this residue may be critical to protein function (PS1; ClinVar ID: 40347). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM6, PM1, PM2, PS1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280029/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0235639 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151828 infores:hetionet CHEBI:42944 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0015967 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0178298 infores:hetionet CAID:CA288989 biolink:causes MONDO:0044970 infores:clingen CAID:CA288989 MONDO:0044970 PMID: Uncertain Significance BS2, PM2, BP7 The c.3561 G>C (p.Arg1187=) variant in POLG is present in population databases 1000 genome 0.03%, ExAC at 0.002%, and gnomAD at 0.002% (PM2; observed < 0.05% frequency). Computational prediction tool Revel unavailable given limited data. This variant was observed in homozygotes in 13 cases in gnomAD and 1 case in ExAC (BS2). This variant is a coding synonymous change (BP7). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2, PM2, BP7. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA288989/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:29688 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0151577 infores:hetionet CHEBI:50378 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C1145670 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009326 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002957 infores:hetionet CHEBI:61049 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085624 infores:hetionet CHEBI:6472 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C2242737 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0041969 infores:hetionet CHEBI:39112 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1565489 infores:hetionet CHEBI:127780 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0040822 infores:hetionet CHEBI:63608 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0392699 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0016436 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018939 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0017601 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0160390 infores:hetionet CHEBI:6931 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C2830004 infores:hetionet CHEBI:39867 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0023530 infores:hetionet UMLS:C0120107 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0024902 infores:hetionet CHEBI:8863 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003578 infores:hetionet CHEBI:119486 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0600142 infores:hetionet CHEBI:3181 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0085616 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013781 infores:hetionet CHEBI:4530 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0232487 infores:hetionet CHEBI:7931 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020461 infores:hetionet CHEBI:6950 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011253 infores:hetionet CAID:CA355965360 biolink:causes MONDO:0001586 infores:clingen CAID:CA355965360 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting PP4 The NM_000203.5:c.1750C>T (p.Gln584Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13/14 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Note that although a premature stop codon is predicted to occur in the penultimate exon of the gene, it is upstream from the last 50 bp of the exon, and thus NMD is predicted to occur. When cDNA containing the variant was expressed in COS cells, there was 0% IDUA activity compared to wild type, educed mRNA, and no protein on Western blot (PMID: 12189649) (PVS1). This variant is not in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported in two patients (one Indian, one Taiwanese) with severe MPS I (Hurler syndrome). While no additional data is available for the patient from Taiwan, the Indian patient has clinical features consistent with MPS I and 2.2% IDUA activity in dried blood spot (insufficient data to apply PP4). The Indian individual with MPS I is homozygous for the variant (PMID: 33301762, 0.5 points). The other patient is compound heterozygous for the variant and c.46_57del. The allelic data from this patient has been used in the classification of c.46_57del and is not included here to avoid circular logic. Total points = 0.5 (PM3_Supporting). In summary, the variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PVS1, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355965360/MONDO:0001586/091 2025-05-02 2025-05-06 Autosomal recessive inheritance HP:0000007 Supports PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0011849 infores:hetionet CHEBI:2788 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0035455 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0242350 infores:hetionet CHEBI:8207 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0234632 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1096213 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1096213 infores:hetionet CHEBI:3499 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0014518 infores:hetionet CAID:CA645293999 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293999 MONDO:0015924 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_001204.7(BMPR2):c.240_241insT (p.Lys81Ter) variant is a DNA single thymine base insertion predicted to cause a frameshift, replacing a lysine residue for a stop codon at position 81. The variant is absent from the gnomAD v.2.1.1 controls and v3.0 (PM2_supporting). c.240_241insT was found in a patient with pulmonary arterial hypertension (PMID:20496075). The variant resides in the second exon of BMPR2 and generates a stop codon that is predicted to cause nonsense-mediated decay (PVS1). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PVS1 (VCEP specification version v 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293999/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:144551 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0314719 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0795692 infores:hetionet CAID:CA482430491 biolink:causes MONDO:0015967 infores:clingen CAID:CA482430491 MONDO:0015967 PMID: Likely Benign PM2_Supporting, BP4, BP2, BP7 The c.306C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 102 (p.(Ala102=)) of NM_000545.8. This synonymous variant is not predicted by SpliceAI to impact splicing (BP4; BP7) and is at a nucleotide not predicted to be highly conserved (phyloP100way < 2). Additionally, has been observed in unknown phase with a pathogenic HNF1A variant (BP2; internal lab contributor). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, c.306C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BP2, BP4, BP7, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA482430491/MONDO:0015967/017 2023-08-13 2023-08-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94609 biolink:causes MONDO:0001220 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0020626 infores:hetionet CHEBI:421707 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0151904 infores:hetionet CHEBI:28864 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0423791 infores:hetionet CHEBI:52172 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C3489393 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0860514 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0860514 infores:hetionet CHEBI:5001 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0030554 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0687133 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0017178 infores:hetionet CHEBI:83804 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013362 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042769 infores:hetionet NCBIGene:2153 biolink:causes MONDO:0009210 infores:monarchinitiative not_provided not_provided HGNC:3542 MONDO:0009210 uuid:4dba6246-3021-4cfa-8849-aaf15178c272 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51380 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0003123 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020649 infores:hetionet GO:0061344 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0061344 GO:0007275 CHEBI:7773 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0021053 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0037274 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0221776 infores:hetionet CHEBI:49575 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0026961 infores:hetionet CHEBI:51041 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0007859 infores:hetionet CHEBI:6367 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0019080 infores:hetionet CHEBI:4995 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1457883 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0021053 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0549297 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0549297 infores:hetionet CHEBI:39867 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014553 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0014868 infores:hetionet CHEBI:3082 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0423153 infores:hetionet CAID:CA343718552 biolink:causes MONDO:0005338 infores:clingen CAID:CA343718552 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BS1, BS3, BP7, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.365G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 122 (p.Gly122Val). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00008329 (5 alleles out of 60,032), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.062, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (pers. comm. GeneDX), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343718552/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75988 biolink:causes UMLS:C0280100 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0280100 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0035455 infores:hetionet GO:0090173 biolink:causes GO:0007129 infores:ubergraph knowledge_assertion manual_agent GO:0090173 GO:0007129 CHEBI:2676 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0151565 infores:hetionet CHEBI:8499 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C2363730 infores:hetionet CHEBI:72690 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0017178 infores:hetionet NCBIGene:57178 biolink:causes MONDO:0032855 infores:monarchinitiative not_provided not_provided HGNC:16493 MONDO:0032855 uuid:921e3e6e-243e-4dfc-8d39-81c7ec78136d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0021308 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0153676 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0153676 infores:hetionet CHEBI:27834 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C1306341 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235431 infores:hetionet CHEBI:31397 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0013456 infores:hetionet CHEBI:2618 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0027497 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0178298 infores:hetionet CHEBI:116278 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0038450 infores:hetionet CHEBI:100246 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0020580 infores:hetionet CAID:CA875126776 biolink:causes MONDO:0100437 infores:clingen CAID:CA875126776 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting PM4, PM5, PS1, PS3, BA1, BP4, BS1, BP7 NM_001034853.2(RPGR):c.2252_2255del (p.Lys751ArgfsTer?) is a frameshift variant due to a 4-nucleotide deletion that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4requirements of some functional vision impairment in affected males by age 30, and/or decreased or absent cone and/or rod ERG responses (PMIDs: 17325176, 21857984, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA875126776/MONDO:0100437/106 2025-08-27 2025-08-27 X-linked inheritance HP:0001417 Supports CHEBI:59445 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0020461 infores:hetionet CHEBI:27690 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0278134 infores:hetionet CHEBI:8665 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0235086 infores:hetionet CHEBI:39112 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0032227 infores:hetionet CHEBI:119915 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0241157 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0011991 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0860803 infores:hetionet CHEBI:7822 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0017152 infores:hetionet CHEBI:7443 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0030252 infores:hetionet CAID:CA261568 biolink:causes MONDO:0021060 infores:clingen CAID:CA261568 MONDO:0021060 PMID:29084544 Pathogenic PS4, PM1, PM6, PM2, PP1, PP2 The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID: 29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID: 29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Finally, PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6, PM1, PM2, PP1, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261568/MONDO:0021060/004 2020-06-25 2020-06-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:168396 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018802 infores:hetionet CHEBI:75998 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C1167791 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0018418 infores:hetionet CHEBI:5613 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0549622 infores:hetionet CHEBI:6970 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0027441 infores:hetionet CHEBI:134966 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0018681 infores:hetionet CHEBI:7445 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0011991 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0038363 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0013604 infores:hetionet CAID:CA229457 biolink:causes MONDO:0009861 infores:clingen CAID:CA229457 MONDO:0009861 PMID:18299955PMID:24368688PMID:18299955PMID:24368688 Uncertain Significance PM2, BS2, PP3, BP2 PM5, PP4, BP7 The c.168G>A (p.Glu56=) variant in PAH has been reported as a polymoprhism. It was found in Arab patients’ DNA, including patients and controls (zygosity not reported). (BS2; PMID: 18299955) However, this variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). While it is a synonymous variant, alteration of the WT donor site affecting splicing is suggested by Human Splicing Finder and Alamut (PP3). It was observed in cis with a pathogenic variant, IVS2+1G>A (BP2; PMID: 24368688). In summary, this variant meets criteria to be classified as uncertain significance for PAH due to conflicting evidence. ACMG/AMP criteria applied: BS2, BP2, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229457/MONDO:0009861/006 2019-11-10 2020-01-25 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:1028 biolink:causes MONDO:0013873 infores:monarchinitiative not_provided not_provided HGNC:1786 MONDO:0013873 uuid:455da0ce-66bf-4bf6-92bd-f123d98f21ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes UMLS:C0852932 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0852932 infores:hetionet GO:0030222 biolink:causes CL:0000771 infores:ubergraph knowledge_assertion manual_agent GO:0030222 CL:0000771 CHEBI:49713 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0009421 infores:hetionet CAID:CA10585598 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585598 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP3, PP4 BP4, PS4, PM1 The NM_000527.5(LDLR):c.1750T>C (p.Ser584Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL = 0.86.PS3: Level 1 assays: PMID: 32015373 (Galicia-Garcia et al., 2020): heterologous CHO-ldlA7 cells, cytometry assay, <20% surface LDLR, <10% LDL-LDLR binding, <10% uptake.---- results are below 70% of wild-type, so functional study is consistent with damaging effect.PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling FH criteria (1 case with Dutch Lipid Clinic Network Criteria score ≥ 6 from PMID 19318025 (Alonso et al., 2009), Spain), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585598/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:28915 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0013428 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0026946 infores:hetionet CHEBI:9599 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0034642 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020615 infores:hetionet UMLS:C0657912 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042024 infores:hetionet CHEBI:4907 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0234916 infores:hetionet CHEBI:3286 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0032227 infores:hetionet CHEBI:5790 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151904 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0242350 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1291078 infores:hetionet CHEBI:4702 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0232462 infores:hetionet CHEBI:71219 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0085605 infores:hetionet CAID:CA16616491 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616491 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PS4_Supporting PS3, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5:c.1283dup (p.Leu429fs) is a frameshift variant which is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region is critical to protein function (PVS1_strong). This variant is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; SCV000550167.3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM5_supporting, PM2_supporting, PVS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616491/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64312 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007642 infores:hetionet CHEBI:51860 biolink:causes HP:0011893 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0580531 infores:hetionet CHEBI:17347 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0041582 infores:hetionet CHEBI:391960 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0042963 infores:hetionet CHEBI:9674 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0009676 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0043251 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0031350 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0234458 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0948089 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0015376 infores:hetionet CHEBI:9907 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0009676 infores:hetionet CHEBI:79699 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0687713 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0041969 infores:hetionet CHEBI:194135 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023222 infores:hetionet CHEBI:9123 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014591 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020517 infores:hetionet CHEBI:4953 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0241633 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020456 infores:hetionet CAID:CA008910 biolink:causes MONDO:0100316 infores:clingen CAID:CA008910 MONDO:0100316 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PP3, PM1 BA1, BP4, PS3, BS1, PP1, PM5 NM_000218.3(KCNQ1):c.958C>T is a missense variant predicted to cause substitution of proline by serine at amino acid 320 (p.Pro320Ser). This variant is rare and has been reported in 2 apparently unrelated probands affected with long QT syndrome 1 (PS4_Supporting; PMID: 23392653, PMID: 32383558). This variant is absent in gnomAD v.2.1.1, but present in gnomAD v4.1.0 at a maximum allele frequency of 0.0000008994, with 1 allele / 1,111,812 total alleles in the European Non-Finnish population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is a missense substitution within the pore helix consisting of amino acids 300 to 320, which is a well-characterized functional domain required for the channel function and selectivity filter of KCNQ1 (PMID: 15649981), and has been confirmed to show an absence of likely benign or benign variants listed in gnomAD (PM1). The computational predictor REVEL gives a score of 0.98, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance due to insufficient evidence for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4_Supporting, PM2_Supporting, PM1, PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA008910/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5855 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0231528 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0948296 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0018213 infores:hetionet CHEBI:30830 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C2830004 infores:hetionet CHEBI:10023 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085611 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0521158 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0521158 infores:hetionet CHEBI:50859 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0040264 infores:hetionet CHEBI:7496 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0014591 infores:hetionet CHEBI:17630 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0018681 infores:hetionet CHEBI:40050 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0021655 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0232492 infores:hetionet UMLS:C0004609 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0028734 infores:hetionet NCBIGene:727857 biolink:causes MONDO:0011853 infores:monarchinitiative not_provided not_provided HGNC:35126 MONDO:0011853 uuid:367cfa0b-fcbe-4c5a-8587-f06ee015078e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3814 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0220870 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0009450 infores:hetionet CHEBI:2663 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0547030 infores:hetionet CHEBI:9763 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085631 infores:hetionet CHEBI:9588 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0041349 infores:hetionet CHEBI:9137 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0026826 infores:hetionet CHEBI:63635 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0018524 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0349506 infores:hetionet NCBIGene:1281 biolink:causes MONDO:0007524 infores:monarchinitiative not_provided not_provided HGNC:2201 MONDO:0007524 uuid:c41996fa-0f6c-4ea6-8112-fd86d611dcf3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0036572 infores:hetionet CAID:CA512341359 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341359 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1029C>G (p.Ser343=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.50)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341359/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:178 biolink:causes MONDO:0009291 infores:monarchinitiative not_provided not_provided HGNC:321 MONDO:0009291 uuid:a7bcac28-2849-43c3-b689-27a08411cea7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0013395 infores:hetionet CHEBI:49575 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0085633 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037822 infores:hetionet CHEBI:6402 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151908 infores:hetionet GO:0002361 biolink:causes CL:0000792 infores:ubergraph knowledge_assertion manual_agent GO:0002361 CL:0000792 CHEBI:40050 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0040822 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0948484 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0948484 infores:hetionet CHEBI:7824 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0036974 infores:hetionet CHEBI:231425 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0042075 infores:hetionet CHEBI:473990 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0392386 infores:hetionet NCBIGene:1174 biolink:causes MONDO:0012251 infores:monarchinitiative not_provided not_provided HGNC:559 MONDO:0012251 uuid:c5ff06c4-680e-4635-9637-6e5de645f242 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1902627 biolink:causes GO:0000027 infores:ubergraph knowledge_assertion manual_agent GO:1902627 GO:0000027 CHEBI:6367 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0031256 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0040425 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0521591 infores:hetionet CHEBI:6717 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0085605 infores:hetionet CAID:CA244529794 biolink:causes MONDO:0015967 infores:clingen CAID:CA244529794 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PM1, PM5, PP3, PP4 The c.475C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 159 (p.(Arg159Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.907, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in multiple individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.476G>A, p.(Arg159Gln), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg159Trp has an equal or greater Grantham distance. (PM5). This variant was identified in thirteen unrelated families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; [internal lab contributors; Exeter, BMRC, Paris]). Lastly, this variant segregated with diabetes, with eight informative meioses in five families with MODY (PP1_Strong; [internal lab contributors; Exeter]). In summary, c.475C>T meets the criteria to be classified as pathogneic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PP3, PP4, PM1_Supporting, PM2_Supporting, PM5, PS4, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244529794/MONDO:0015967/017 2021-12-22 2021-12-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5147 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0349790 infores:hetionet CAID:CA8337933 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337933 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4, PM3 The NM_000018.4(ACADVL): c.1076C>T (p.Ala359Val) variant in ACADVL is a missense variant predicted to cause substitution of alanine by valine at amino acid 359 (p.Ala359Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant is reported in the literature in an individual apparently affected with very long-chain acyl-CoA dehydrogenase deficiency, displaying elevated C14:1 carnitine level (1.65 µmol/L) during newborn screening, which is highly specific for VLCAD deficiency (PP4_Supporting, PMID: 27209629). This patient also carried a pathogenic variant c.848T>C (p.V283A) in compound heterozygous fashion (in trans, PM3 score = 1.0, PM3, PMID: 27209629). In addition, this variant has been reported in the literature in 6 patients with an abnormal newborn screen who are apparently heterozygous carriers for the variant (PMIDs: 26385305, 29111448), but this information is insufficient to use toward classification. The computational predictor REVEL gives a score of 0.76, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP3, PM3, PM2_Supporting, PP4_Supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337933/MONDO:0008723/021 2025-04-22 2025-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:48273 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0039231 infores:hetionet CHEBI:6931 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0016655 infores:hetionet GO:1904118 biolink:causes GO:0048568 infores:ubergraph knowledge_assertion manual_agent GO:1904118 GO:0048568 CHEBI:9943 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0149871 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0234215 infores:hetionet NCBITaxon:1513 biolink:causes MONDO:0005526 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1513 MESH:D013742 DB01053_MESH_D013742_1 UNII:3U02EL437C biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0016436 infores:hetionet CHEBI:39669 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0027497 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0032231 infores:hetionet CHEBI:4903 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042023 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0040822 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0947999 infores:hetionet CHEBI:4876 biolink:causes UMLS:C0239182 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0239182 infores:hetionet CHEBI:4046 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0085593 infores:hetionet CHEBI:2453 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0039231 infores:hetionet CHEBI:82960 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020473 infores:hetionet CHEBI:135351 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0038999 infores:hetionet CHEBI:32315 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C2979982 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0852733 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C1384666 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0031542 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0038362 infores:hetionet CHEBI:3242 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0040822 infores:hetionet CHEBI:31348 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020625 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0233472 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0007971 infores:hetionet CHEBI:50922 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085628 infores:hetionet CHEBI:16347 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0010200 infores:hetionet NCBIGene:1290 biolink:causes MONDO:0019568 infores:monarchinitiative not_provided not_provided HGNC:2210 MONDO:0019568 uuid:86baa810-2bec-4c4f-8a45-e4fbe4c4e2f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46295 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0018926 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0342579 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042373 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005376 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0017665 infores:hetionet CHEBI:82960 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0851578 infores:hetionet CHEBI:3696 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0016867 infores:hetionet CHEBI:135351 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0085631 infores:hetionet CHEBI:35854 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C1260880 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0347390 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0151736 infores:hetionet CHEBI:4672 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0013404 infores:hetionet CAID:CA10014581 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014581 MONDO:0011071 PMID:29365323 Likely Benign BP2, BS1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BA1, PVS1, PM2, PM6, BP7, BP5, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.4(RUNX1):c.155T>A (p.Met52Lys) is a missense variant which has a MAF of 0.0007121 (0.071%, 840/1,179,678 alleles, including 1 homozygote) in the European (non-Finnish) subpopulation of the gnomAD v4.1.0 cohort, meeting the threshold for BS1 and BP2. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014581/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0024282 infores:hetionet CAID:CA172173 biolink:causes MONDO:0100040 infores:clingen CAID:CA172173 MONDO:0100040 PMID: Benign BA1 The allele frequency of the p.Leu362= variant in FOXG1 is 0.14% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Leu362= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172173/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135935 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0547030 infores:hetionet CHEBI:116278 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0162830 infores:hetionet CHEBI:36795 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0311468 infores:hetionet GO:0002788 biolink:causes GO:0019732 infores:ubergraph knowledge_assertion manual_agent GO:0002788 GO:0019732 CHEBI:47898 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018965 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0438215 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0857353 infores:hetionet CHEBI:5613 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0041105 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0007222 infores:hetionet CHEBI:31711 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0042487 infores:hetionet CHEBI:42797 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151799 infores:hetionet NCBIGene:4091 biolink:causes MONDO:0013902 infores:monarchinitiative not_provided not_provided HGNC:6772 MONDO:0013902 uuid:0e031232-1f67-4214-b61e-9c3b1010b6c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235266 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0003123 infores:hetionet CHEBI:184555 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0014868 infores:hetionet CHEBI:64321 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C2830004 infores:hetionet CHEBI:7915 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0024902 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0549373 infores:hetionet NCBIGene:695 biolink:causes MONDO:0010615 infores:monarchinitiative not_provided not_provided HGNC:1133 MONDO:0010615 uuid:d12445b8-58a3-4004-b864-88de6cc383d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013604 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0595877 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042035 infores:hetionet CHEBI:79699 biolink:causes MONDO:0011441 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0034931 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0039520 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233472 infores:hetionet CHEBI:171719 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0018790 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015397 infores:hetionet CHEBI:3437 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0012569 infores:hetionet CHEBI:16714 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0855775 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0232849 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0032285 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948586 infores:hetionet CHEBI:3534 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0027707 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0004936 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0233472 infores:hetionet CAID:CA1139666857 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666857 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.-62G>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.16) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.16) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.18) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666857/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7476 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0021053 infores:hetionet CHEBI:6076 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0013604 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0019158 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0151505 infores:hetionet GO:1901722 biolink:causes GO:0001822 infores:ubergraph knowledge_assertion manual_agent GO:1901722 GO:0001822 CHEBI:3756 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0038661 infores:hetionet CHEBI:45327 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0151517 infores:hetionet CHEBI:47519 biolink:causes HP:6000647 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0235014 infores:hetionet CHEBI:91583 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0011603 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000474 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0265122 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1261981 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1261981 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151698 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0011570 infores:hetionet CAID:CA386958889 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958889 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP3, PP4 The c.343G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 115 (p.(Val115Leu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; ClinVar, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.902, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.343G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PS4_Moderate, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958889/MONDO:0015967/017 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:101085 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0001824 infores:hetionet CHEBI:3312 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0011603 infores:hetionet CAID:CA376061278 biolink:causes MONDO:0011225 infores:clingen CAID:CA376061278 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.310G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 104 (p.Glu104Lys).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376061278/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7936 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0026848 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0859062 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0859062 infores:hetionet CHEBI:28830 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C1963951 infores:hetionet CHEBI:31547 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011175 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035854 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0010200 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0400823 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0948089 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020550 infores:hetionet CAID:CA386294521 biolink:causes MONDO:0009861 infores:clingen CAID:CA386294521 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4, PM3_Strong This c.843-1G>A variant in PAH was reported in trans with pathogenic variants p.S70del and p.Arg243Gln in 2 Han Chinese patients with PAH deficiency (PMID: 28982351). This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF=0.000008827). This variant in the -1 splice acceptor site of intron 7 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 strong, PM2, PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386294521/MONDO:0009861/006 2020-12-07 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports UNII:7662KG2R6K biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0017178 infores:hetionet CHEBI:6923 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0014518 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0854425 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0854425 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948349 infores:hetionet CHEBI:499361 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0003862 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0037199 infores:hetionet CHEBI:77260 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0019270 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0013922 infores:hetionet CHEBI:4858 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0235266 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0037199 infores:hetionet CHEBI:63631 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151578 infores:hetionet NCBIGene:6513 biolink:causes MONDO:0012805 infores:monarchinitiative not_provided not_provided HGNC:11005 MONDO:0012805 uuid:7d73257f-06ba-415a-881d-124ddd5e0db9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35854 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0004134 infores:hetionet CHEBI:63631 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014591 infores:hetionet CHEBI:31199 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0085641 infores:hetionet CHEBI:49375 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0015402 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0029882 infores:hetionet CHEBI:75722 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0007859 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0232431 infores:hetionet CHEBI:4702 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0000737 infores:hetionet CHEBI:94449 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0009806 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0151827 infores:hetionet CHEBI:240107 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0151827 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0027769 infores:hetionet CHEBI:119915 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0236075 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0015967 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007642 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004601 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0023223 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0009806 infores:hetionet NCBIGene:5190 biolink:causes MONDO:0013931 infores:monarchinitiative not_provided not_provided HGNC:8859 MONDO:0013931 uuid:3c6bfd43-2d91-4272-99ef-f18123e523eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020473 infores:hetionet CHEBI:47898 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002962 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233632 infores:hetionet CHEBI:49040 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0231528 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0267537 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018801 infores:hetionet CHEBI:4995 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0575081 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0013928 infores:hetionet CHEBI:28748 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0162834 infores:hetionet CHEBI:63599 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0009806 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0011849 infores:hetionet CHEBI:8232 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0002792 infores:hetionet CHEBI:3223 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0234047 infores:hetionet CHEBI:7931 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0017168 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0333641 infores:hetionet CHEBI:79699 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0010200 infores:hetionet CAID:CA10014212 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014212 MONDO:0100083 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1069C>T (p.Pro357Ser) is a missense variant which has a REVEL score < 0.50 (0.27), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014212/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17263 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0235660 infores:hetionet CHEBI:29688 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0014457 infores:hetionet NCBIGene:1259 biolink:causes MONDO:0013405 infores:monarchinitiative not_provided not_provided HGNC:2148 MONDO:0013405 uuid:794e9b8c-d7e6-4738-977c-05b6eb5ad7e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2673 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0004134 infores:hetionet CHEBI:5147 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C2607914 infores:hetionet CHEBI:6923 biolink:causes UMLS:C1328375 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C1328375 infores:hetionet CHEBI:8874 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0542571 infores:hetionet UMLS:C0145185 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0000737 infores:hetionet CHEBI:3223 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0878544 infores:hetionet CHEBI:36795 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0575081 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0234935 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0234935 infores:hetionet CHEBI:8871 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C3160741 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1619712 infores:hetionet CHEBI:144093 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0032227 infores:hetionet CHEBI:6541 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0033774 infores:hetionet NCBIGene:7784 biolink:causes MONDO:0021574 infores:monarchinitiative not_provided not_provided HGNC:13189 MONDO:0021574 uuid:819ff9d6-7b50-4eb3-b6a6-1c38c4adb6d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0836924 infores:hetionet CHEBI:3478 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151905 infores:hetionet CHEBI:167638 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0340865 infores:hetionet CHEBI:4466 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151539 infores:hetionet CHEBI:63612 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0032227 infores:hetionet CHEBI:135005 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0040822 infores:hetionet CHEBI:94686 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0344232 infores:hetionet CHEBI:70707 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C2830004 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0857153 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0857153 infores:hetionet UMLS:C0004609 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0428977 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0015230 infores:hetionet CHEBI:28901 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020433 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0424000 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0236068 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0857361 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0857361 infores:hetionet NCBIGene:8087 biolink:causes MONDO:0032936 infores:monarchinitiative not_provided not_provided HGNC:4023 MONDO:0032936 uuid:7387adb1-006c-450b-be18-ce5d8483fc60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31709 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0036974 infores:hetionet CHEBI:51364 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0030446 infores:hetionet CHEBI:63621 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0009676 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151662 infores:hetionet CAID:CA386960373 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960373 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate PS4, PP1 The c.472A>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 158 (p.Lys158Ter) of NM_000545.8. This variant, located in biologically relevant exon 2 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 16917892). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes. Still, it did not meet the thresholds set for PS4_Moderate by the ClinGen MDEP. However, in one of the identified individuals, the MODY probability was >50% in the presence of negative HNF4A testing and negative autoantibodies (PP4_Moderate, internal lab contributors ). Only 1 informative meiosis was identified in a family, which does not meet the threshold set for PP1 by the ClinGen MDEP. In summary, c.472A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PVS1, PP4_Moderate PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960373/MONDO:0015967/017 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9316 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0026205 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020517 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0006277 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0020649 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0014130 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0427008 infores:hetionet CAID:CA226772 biolink:causes MONDO:0010725 infores:clingen CAID:CA226772 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PP3_Strong NM_000330.4(RS1):c.533G>A (p.Gly178Asp) is a missense variant encoding the substitution of glycine with aspartic acid at amino acid 178. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 9618178, PMID: 11738458, PMID: 31149861, PMID: 12928282, PMID: 31087526, PS4_Moderate). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in two apparently unrelated families, one with affected 3 brothers and the other with two affected brothers (PP1_Strong; PMID: 12928282, PMID: 31087526). The computational predictor REVEL gives a score of 0.989, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PP1_Strong, and PS4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226772/MONDO:0010725/126 2025-09-18 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:585948 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0015672 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0041349 infores:hetionet CHEBI:8713 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0011606 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0333641 infores:hetionet CHEBI:27834 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002874 infores:hetionet CHEBI:36795 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0152032 infores:hetionet CHEBI:6754 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0042963 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1527311 infores:hetionet CHEBI:37924 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0028754 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0021308 infores:hetionet CHEBI:63617 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018794 infores:hetionet CHEBI:10023 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0026766 infores:hetionet CHEBI:7565 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0220981 infores:hetionet CHEBI:2675 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0028643 infores:hetionet CHEBI:8069 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0003578 infores:hetionet CHEBI:7822 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013604 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0021359 infores:hetionet CHEBI:41879 biolink:causes HP:0025560 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0423282 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0850638 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0850638 infores:hetionet CHEBI:724125 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0042109 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017152 infores:hetionet CHEBI:47780 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2047937 infores:hetionet CHEBI:49713 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C1167965 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0009806 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0392197 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0002871 infores:hetionet CHEBI:3650 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0542203 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0020522 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C1443060 infores:hetionet CAID:CA031713 biolink:causes MONDO:0007750 infores:clingen CAID:CA031713 MONDO:0007750 PMID: Uncertain Significance BP4 BA1, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1060+9C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4: No Revel score. The variant does not affect splicing process, the variant is located out of range for all scenarios. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031713/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8802 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0027441 infores:hetionet CHEBI:6078 biolink:causes NCIT:C78440 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0578050 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0858259 infores:hetionet CHEBI:8107 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0023530 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037274 infores:hetionet CHEBI:63598 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1527344 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0518015 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0858678 infores:hetionet NCBIGene:84942 biolink:causes MONDO:0033005 infores:monarchinitiative not_provided not_provided HGNC:25928 MONDO:0033005 uuid:3aa89641-517e-457f-9c29-7fbe1623b39e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0037274 infores:hetionet CHEBI:3499 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0040034 infores:hetionet CHEBI:71219 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1260880 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0009806 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0750016 infores:hetionet CHEBI:231425 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0041657 infores:hetionet CHEBI:7956 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0042963 infores:hetionet CHEBI:8461 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0018524 infores:hetionet CHEBI:617099 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0027947 infores:hetionet CHEBI:50381 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0232462 infores:hetionet CHEBI:5123 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0151818 infores:hetionet CAID:CA1244327 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244327 MONDO:0005338 PMID: Likely Benign BP7, BS1, BP4 BS3, PM2, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.114G>A variant in MYOC is a synonymous variant (p.Arg38=). The highest minor allele frequency of this variant was in the Ashkenazi Jewish genetic ancestry group of gnomAD (v4.1.0) = 0.001148, which met the ≥ 0.001 threshold set for BS1 (34 alleles out of 29,608), meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This synonymous variant meets BP4, so BP7 is met. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma. Additionally, as PM2_Supporting was not met, PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244327/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3732 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0026848 infores:hetionet CHEBI:7852 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0080274 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1096185 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1096185 infores:hetionet CHEBI:4672 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0424790 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001439 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0014583 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595877 infores:hetionet CHEBI:45367 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0004093 infores:hetionet CHEBI:5855 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042963 infores:hetionet CHEBI:23765 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042164 infores:hetionet CHEBI:3698 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0013404 infores:hetionet UMLS:C0879264 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151599 infores:hetionet CAID:CA017349 biolink:causes MONDO:0007947 infores:clingen CAID:CA017349 MONDO:0007947 PMID: Pathogenic PM6, PP2, PM2_Supporting, PM1, PS4, PP1_Strong PP3 The NM_00138 c.7726C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 2576 (p.Arg2576Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband with aortic aneurysm and dissection and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported nine times in ClinVar: five times as pathogenic, three times as likely pathogenic, and once as uncertain significance (Variation ID: 36118). This variant has also been identified in at least 9 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 24161884, 31830381, 33711475, 23278365, 33824467, 37042257, internal lab data; PS4). In three individuals with MFS, this variant was reported to be de novo, without confirmation of parental relationships (internal lab data, Prevention Genetics ClinVar, PM6). In at least 5 families with MFS, the variant was found to segregate with MFS and/or clinical features of MFS in several affected relatives (Internal lab data, Laboratory Corporation of America ClinVar, PP1_Strong). This variant is present in in 1/250782 (0.0004%) of alleles tested in gnomAD but did not pass the quality control criteria in the exome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.686). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_Strong, PM1, PM6, PM2_Sup, PP2, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017349/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9943 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020438 infores:hetionet GO:0003309 biolink:causes CL:0000169 infores:ubergraph knowledge_assertion manual_agent GO:0003309 CL:0000169 CHEBI:63599 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0036508 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0426498 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0426498 infores:hetionet CHEBI:75984 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0039070 infores:hetionet CHEBI:3732 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0038362 infores:hetionet CHEBI:144551 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042023 infores:hetionet CHEBI:8435 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0007398 infores:hetionet CHEBI:16714 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0015672 infores:hetionet CHEBI:8871 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042963 infores:hetionet CHEBI:9927 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C2830004 infores:hetionet CHEBI:15765 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013384 infores:hetionet CHEBI:8093 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0042963 infores:hetionet GO:0002314 biolink:causes CL:0000844 infores:ubergraph knowledge_assertion manual_agent GO:0002314 CL:0000844 CHEBI:3011 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0019158 infores:hetionet CHEBI:209807 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0042267 infores:hetionet CHEBI:2663 biolink:causes MONDO:0015264 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0242770 infores:hetionet CHEBI:31176 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0042963 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0004238 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0542008 infores:hetionet CHEBI:63635 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011124 infores:hetionet CHEBI:499361 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0311468 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0009806 infores:hetionet CHEBI:31981 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0156404 infores:hetionet CHEBI:6904 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0000737 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0017168 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003123 infores:hetionet CHEBI:68478 biolink:causes MONDO:0018177 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017636 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0040034 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0011615 infores:hetionet CAID:CA400028591 biolink:causes MONDO:0100326 infores:clingen CAID:CA400028591 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The ITGB3 nonsense variant NM_000212.3:c.1288C>T (p.Arg430Ter) is expected to introduce an early termination codon and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant was observed in two compound heterozygote individuals presenting with phenotypes specific to GT (GT5 and GT6; PMID: 32237906). This variant occurs at an extremely low frequency in gnomAD (Overall allele frequency: 0.000003979) and is absent from other population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PP4_Moderate Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400028591/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:41879 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0030353 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0836924 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0036572 infores:hetionet CHEBI:32588 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0004245 infores:hetionet CHEBI:3077 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0428977 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0021053 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0033575 infores:hetionet CHEBI:7983 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0041657 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0031046 infores:hetionet CHEBI:27786 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0012833 infores:hetionet CAID:CA409104278 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104278 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM1, PM5, PS2_Moderate PS4 The c.278G>A variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of cystine to histidine at codon 93 (p.(Cys93Tyr)) of NM_175914.5.This variant was identified as a de novo occurrence with unconfirmed parental relationships in one individual with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Moderate; PMID: 30447144). This variant also resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA and is necessary for zinc finger formation which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). In addition, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.958, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A as well as negative diabetes autoantibodies ) (PP4_Moderate; PMID: 30447144, internal lab contributors). Lastly, another missense variant, c.278G>C p., p.Cys106Ser has been interpreted as pathogenic by the ClinGen MDEP, and p.Cys93Tyr has a greater Grantham distance (PM5). In summary, c.278G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0 approved 11/16/2022): PS2_Moderate, PM1, PM2_Supporting, PP3, PP4_Moderate, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104278/MONDO:0015967/085 2023-03-26 2023-03-26 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:6335 biolink:causes MONDO:0007571 infores:monarchinitiative not_provided not_provided HGNC:10597 MONDO:0007571 uuid:151d132b-f6ca-4787-b0e9-5f437a443d57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66899 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0004096 infores:hetionet CAID:CA913178950 biolink:causes MONDO:0044970 infores:clingen CAID:CA913178950 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PM6_Supporting PP3, PP1, PS4, PS3 The m.8319A>G variant in MT-TK has been reported in one individual with primary mitochondrial disease to date (PMID: 23463613; also likely same case reported in PMID: 31965079), in a person with Kearns Sayre syndrome (KSS) with the variant present at 87% in muscle. The variant was undetectable in blood from the healthy mother (PM6_supporting). There are no reports of additional families with this variant segregating with clinical manifestations. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (69.6 percentile) but HmtVAR predicts it to be likely benign with a score of 0.25. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM6_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913178950/MONDO:0044970/015 2024-11-11 2025-05-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:47898 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020580 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151735 infores:hetionet GO:1905780 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:1905780 GO:0006915 CHEBI:18248 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0231528 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020538 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0006840 infores:hetionet CHEBI:17650 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0033845 infores:hetionet CHEBI:45863 biolink:causes HP:0001604 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0751576 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0035455 infores:hetionet CHEBI:2666 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0851578 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020538 infores:hetionet CHEBI:16796 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0021177 infores:hetionet CHEBI:144093 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0311468 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020456 infores:hetionet CHEBI:31638 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0021368 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0041969 infores:hetionet CHEBI:16899 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0004604 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0917798 infores:hetionet CHEBI:147675 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00249 UMLS:C0038999 infores:hetionet GO:0010548 biolink:causes GO:0009657 infores:ubergraph knowledge_assertion manual_agent GO:0010548 GO:0009657 CHEBI:41423 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014518 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877322 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042963 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0027932 infores:hetionet CHEBI:231594 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0702166 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085614 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235315 infores:hetionet CAID:CA242907 biolink:causes MONDO:0019501 infores:clingen CAID:CA242907 MONDO:0019501 PMID: Uncertain Significance BP2 BS1, PP3, PM3, PM2 The c.3527G>A variant in MYO7A is a missense variant predicted to cause substitution of serine by asparagine at amino acid 1176. The highest population minor allele frequency in gnomAD v4.1 is 0.0005863 (44/75046 alleles) in the African/African-American population (PM2_Supporting and BS1_Supporting are not met). The computational predictor REVEL gives a score of 0.638, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function (PP3 not met). The variant has been observed in at least 3 individuals with Usher syndrome type 1. However, in one proband the c.3527G>A variant in the homozygous state was observed with another homozygous pathogenic/likely pathogenic variant in MYO7A (BP2 met; PMID: 26969326). The remaining probands did not have a second pathogenic/likely pathogenic variant in MYO7A identified (PM3 and PP4 not met; PMID: 27344577, 27460420, 31479088). While this variant has also been identified in individuals with hearing loss, they either had no other pathogenic/likely pathogenic variant or an alternate molecular basis for disease was identified (PMID:33297549, LabCorp Genetics (formerly Invitae) internal data ClinVar SCV001418817.4, GeneDx internal data ClinVar SCV000714448.1). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BP2 (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA242907/MONDO:0019501/005 2024-12-18 2025-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:84050 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0020621 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009766 infores:hetionet CHEBI:17303 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085628 infores:hetionet CHEBI:31709 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0041657 infores:hetionet CHEBI:17347 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0004093 infores:hetionet CHEBI:55346 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0852911 infores:hetionet CHEBI:8356 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1510471 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0239293 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0239293 infores:hetionet CHEBI:6954 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0036974 infores:hetionet CHEBI:3699 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0018681 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0857083 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0857083 infores:hetionet CHEBI:6950 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0404521 infores:hetionet CHEBI:35778 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0002994 infores:hetionet CAID:CA410676622 biolink:causes MONDO:0009276 infores:clingen CAID:CA410676622 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting PM3, PP3, PP4, BP4 The c.176A>C variant in GP1BB is a missense variant predicted to cause substitution of Glutamic acid by Alanine at amino acid (p.Glu59Ala). This variant is absent from gnomAD v4.1 (PM2_Supporting). One patient from internal data had a historical diagnosis of Bernard-Soulier Syndrome (BSS) with a history of heavy menstrual bleeding, easy bruising, and macrothrombocytopenia. However, there was normal platelet aggregation and ATP release, inconsistent with BSS. Additionally, there was normal platelet glycoprotein testing with GPIIb of 143%, GPIIIa of 134%, GPIX of 80% and GPIb-alpha of 110%. No additional patients carrying this variant were found in ClinVar or in the literature. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410676622/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0044479 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0044479 GO:0051641 CHEBI:50648 biolink:causes UMLS:C2721737 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2721737 infores:hetionet CHEBI:48273 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0162529 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0040479 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0040034 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042571 infores:hetionet CHEBI:2379 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0701811 infores:hetionet CHEBI:7465 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0085631 infores:hetionet CHEBI:135679 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0013404 infores:hetionet CHEBI:42068 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0027540 infores:hetionet CHEBI:3568 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0001925 infores:hetionet CHEBI:79699 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0037278 infores:hetionet CHEBI:35677 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C1443060 infores:hetionet CHEBI:135566 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0033774 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0948594 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0235290 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011991 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1142135 infores:hetionet CHEBI:63618 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0043094 infores:hetionet CHEBI:102216 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0002792 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0021053 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020651 infores:hetionet CHEBI:553473 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0033774 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0028960 infores:hetionet CHEBI:41774 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0241633 infores:hetionet CHEBI:63622 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0011071 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0029089 infores:hetionet CAID:CA153100 biolink:causes MONDO:0015967 infores:clingen CAID:CA153100 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 BS3 The c.608G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 203 (p.(Arg203His)) of NM_000545.8. This variant segregated with diabetes, in more than 10 families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant was identified in at least 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 23348805, 27913849, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.958, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg203His protein has abnormal nuclear localization below 40% of wildtype, indicating that this variant impacts protein function (PMID: 32910913) (PS3_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID:27913849). In summary, c.608G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS4, PP1_Strong, PM1, PM2_Supporting, PP4_Moderate,PP3, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA153100/MONDO:0015967/017 2022-04-11 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6437 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0267792 infores:hetionet CHEBI:8461 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0009676 infores:hetionet CHEBI:6954 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0030193 infores:hetionet CHEBI:45409 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0023467 infores:hetionet CHEBI:5118 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0948089 infores:hetionet CHEBI:474180 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0235996 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0020437 infores:hetionet CHEBI:31709 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0042963 infores:hetionet CHEBI:7514 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0025061 infores:hetionet NCBIGene:5443 biolink:causes MONDO:0012335 infores:monarchinitiative not_provided not_provided HGNC:9201 MONDO:0012335 uuid:e1618caa-7fe5-433e-8ace-19cb36aa2375 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0018524 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0553548 infores:hetionet CHEBI:94449 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0085636 infores:hetionet CHEBI:3061 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0031350 infores:hetionet CHEBI:5855 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0025323 infores:hetionet CHEBI:27974 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0011991 infores:hetionet CHEBI:92511 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0015967 infores:hetionet CHEBI:28901 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0009676 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1963951 infores:hetionet CHEBI:9150 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0013404 infores:hetionet CHEBI:32293 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0750426 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0019158 infores:hetionet CHEBI:51860 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0162834 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0349506 infores:hetionet CHEBI:31705 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0040264 infores:hetionet CHEBI:87715 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0035317 infores:hetionet CHEBI:37924 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0003467 infores:hetionet CHEBI:472657 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0001824 infores:hetionet CHEBI:70735 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0236075 infores:hetionet CAID:CA229634 biolink:causes MONDO:0009861 infores:clingen CAID:CA229634 MONDO:0009861 PMID:27121329 Pathogenic PM3, PVS1, PP4_Moderate, PM2 The c.586_608del (p.Ser196fs) frameshift variant in PAH is predicted to undergo nonsense-mediated decay. This variant was reported in a Spanish patient with classic PKU in trans with pathogenic variant p.Arg261Gln. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). This variant was also reported in another Spanish patient with moderate PKU and identified with the pathogenic variant p.I65T (PMID 15464430). This variant is absent from gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4 moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229634/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31932 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0030312 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1619702 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042075 infores:hetionet CHEBI:9434 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0424790 infores:hetionet CAID:CA274982 biolink:causes MONDO:0009290 infores:clingen CAID:CA274982 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong PM5 "The NM_000152.5:c. c.1802C>T variant in GAA is a missense variant predicted to cause substitution of serine by leucine at amino acid 601 (p.Ser601Leu). At least eight patients with this variant have been reported to have Pompe disease including three with clinical features consistent with infantile onset Pompe disease and on enzyme replacement therapy (PMID 22538254, 30023291), and one with GAA deficiency reported in the affected range in lymphocytes (PMID 22676651), as well as four patients reported to be diagnosed with the condition (PMID 28394184) (PP4_Moderate). Of note, in one patient, with features of infantile onset Pompe disease and on ERT, the variant was reported to be in cis with pseudodeficiency variants c.1726G>A and c.2065G>A (PMID 22538254). Of these patients, four were compound heterozygous for the variant and a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PMID 22676651, 28394184, 30023291) One patient was homozygous for the variant (PMID 30023291) (PM3_Strong). In addition, three patients were compound heterozygous for the variant and a missense variant (PMID 22538254, 28394184). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD is 0.00064 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0.5% wild type GAA activity in cells and medium, and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe""). This indicates that the variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1802C>G (p.Ser601Trp), in the same codon has been reported in patients with Pompe disease (PMID 17056254, 29422078). However, the data for p.Ser601Leu will be used in the assessment of p.Ser601Trp and therefore PM5 is not met here in order to avoid circular logic (PM5 not met). The is a ClinVar entry for this variant (Variation ID: 194154). In summary, this variant meets the criteria to be classified at pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specification version 2.0): PM3_Strong; PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3.(Classification approved on August 17, 2021)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274982/MONDO:0009290/010 2021-09-07 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:135005 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0013428 infores:hetionet CHEBI:8874 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0023518 infores:hetionet CAID:CA214215 biolink:causes MONDO:0000573 infores:clingen CAID:CA214215 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM1, PM3 The c.1309G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 437 (p.Glu437Lys).The filtering allele frequency (the upper threshold of the 95% CI of 9/63722 alleles) of the c.1309G>A variant in RAG2 is 0.000001910 for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1.The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 0.9% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).The patient presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total is 1 point, PP4 (PMID: 29772310). The same patient is a compound heterozygous for his variant and G35A, a pathogenic variant according to SCID VCEP specifications; 1 point, PM3.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1, PS3_Moderate, PP4, and PM3 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214215/MONDO:0000573/124 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:30830 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011175 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233414 infores:hetionet CHEBI:93635 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0242350 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0575090 infores:hetionet CHEBI:63631 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151603 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0267446 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0267446 infores:hetionet CAID:CA367400776 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400776 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.689G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 230 (p.(Cys230Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 3547291, 30663027, 25306193, internal lab contributors), including an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 35472491, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 8 informative meioses in a 3 families (PP1_Strong; PMID: 35472491, internal lab contributors). In summary, the c.689G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PM1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400776/MONDO:0015967/086 2023-11-22 2023-11-22 Semidominant inheritance HP:0032113 Supports CHEBI:52717 biolink:causes MONDO:0016028 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014804 infores:hetionet CHEBI:4995 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011603 infores:hetionet CHEBI:7773 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C2242737 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0677500 infores:hetionet CHEBI:3568 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085593 infores:hetionet CHEBI:64312 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019080 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0155862 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0178298 infores:hetionet CHEBI:7601 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0015230 infores:hetionet CHEBI:45652 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0231528 infores:hetionet CHEBI:31547 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0034063 infores:hetionet CHEBI:567361 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0221166 infores:hetionet CHEBI:94449 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0039231 infores:hetionet CHEBI:31547 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0004238 infores:hetionet CAID:CA350343048 biolink:causes MONDO:0015924 infores:clingen CAID:CA350343048 MONDO:0015924 PMID: Pathogenic PM2, PVS1, PS4_Moderate BA1, BS1 The NM_001204.7(BMPR2) c.1413+1G>A variant is located in the canonical donor splice site of intron 11, predicted to cause out-of-frame exon skipping and nonsense mediated decay (PVS1). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). The variant has been identified in 4 unrelated probands with pulmonary arterial hypertension (3 reported in ClinVar and 1 from a PH VCEP internal database). No segregation data or mode of inheritance information were available (BS4, PP1, PM6, PS2 not evaluated). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350343048/MONDO:0015924/125 2024-05-07 2024-05-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6916 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0001364 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0004936 infores:hetionet CHEBI:9599 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0013395 infores:hetionet CHEBI:39112 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1384353 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0041912 infores:hetionet CHEBI:5118 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085688 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014130 infores:hetionet CHEBI:4445 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0262662 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0235819 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0235819 infores:hetionet CHEBI:5775 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0039231 infores:hetionet CHEBI:72564 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0015967 infores:hetionet CHEBI:3561 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1527344 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004238 infores:hetionet CHEBI:3749 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0232462 infores:hetionet CHEBI:10101 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0338831 infores:hetionet CHEBI:42797 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019572 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005301 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0026769 infores:hetionet CHEBI:135342 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151744 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0851341 infores:hetionet CHEBI:7465 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0003467 infores:hetionet CHEBI:63580 biolink:causes HP:0020071 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042749 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0038363 infores:hetionet NCBIGene:5162 biolink:causes MONDO:0013580 infores:monarchinitiative not_provided not_provided HGNC:8808 MONDO:0013580 uuid:4c60b538-dbea-40b5-a25f-3bb87e30ab06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0271321 infores:hetionet CHEBI:9727 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0027726 infores:hetionet CHEBI:51860 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0010200 infores:hetionet CHEBI:3723 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017181 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0009450 infores:hetionet CHEBI:6437 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085932 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0152128 infores:hetionet CHEBI:3215 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0220870 infores:hetionet CHEBI:3403 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C3203358 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0027765 infores:hetionet CHEBI:75246 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0026603 infores:hetionet CHEBI:35854 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0010200 infores:hetionet CAID:CA6265757 biolink:causes MONDO:0700270 infores:clingen CAID:CA6265757 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5_Supporting, PVS1 PM2 The c.5692 C>T (p.Arg1898*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 17124347, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003268 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6265757/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:168396 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0152029 infores:hetionet CHEBI:2379 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0235896 infores:hetionet CHEBI:9139 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151786 infores:hetionet CHEBI:47499 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0001807 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020649 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0020517 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0032285 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0009938 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0027765 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0012833 infores:hetionet CHEBI:17688 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0041834 infores:hetionet CHEBI:6950 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0040264 infores:hetionet CHEBI:135876 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0042023 infores:hetionet CHEBI:8207 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0014724 infores:hetionet CHEBI:50861 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0030193 infores:hetionet CHEBI:8768 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0085649 infores:hetionet CHEBI:2904 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0001807 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020649 infores:hetionet CHEBI:8707 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0231218 infores:hetionet CHEBI:2682 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0917801 infores:hetionet CAID:CA412742555 biolink:causes MONDO:0100437 infores:clingen CAID:CA412742555 MONDO:0100437 PMID: Uncertain Significance PP3_Strong, PM2_Supporting PP4, PM5, PS4 NM_001034853.2(RPGR):c.752G>T (p.Gly251Val) is a missense variant that replaces glycine with valine at codon 251. Another missense variant in the same codon, NM_001034853.2(RPGR):c.752G>A (p.Gly251Asp) has been reported in relation to inherited retinal disease (ClinVar Accession: SCV000623951.5), while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (109) than the comparison variant (94), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing. However, the comparison variant has been classified as a variant of uncertain significance for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, so the PM5_Supporting code is not met. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 33576794). PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The proband harboring this variant exhibits a phenotype including onset of visual impairment in the first decade of life (1 pt), reduced or absent electroretinogram responses from rods and cones, and visual field constriction (0.5 pts), which together are not sufficiently specific for RPGR-related retinopathy to meet the PP4 code (1.5 points, PMID: 33576794). In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and PP3_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412742555/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63610 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0032961 infores:hetionet CHEBI:49960 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0009024 infores:hetionet GO:0044509 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0044509 GO:0023052 CHEBI:8212 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0006145 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C1956346 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0232841 infores:hetionet CHEBI:408174 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027424 infores:hetionet CHEBI:7507 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0235259 infores:hetionet CAID:CA7143202 biolink:causes MONDO:0019497 infores:clingen CAID:CA7143202 MONDO:0019497 PMID: Benign BA1 The filtering allele frequency of the c.841G>A (p.Asp281Asn) variant in the COCH gene is 0.5% for African chromosomes by gnomAD (145/24032 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA7143202/MONDO:0019497/005 2019-02-25 2019-07-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true NCBITaxon:6210 biolink:causes MONDO:0044346 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6210 MONDO:0044346 CHEBI:64310 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0162119 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020456 infores:hetionet CAID:CA220346 biolink:causes MONDO:0015152 infores:clingen CAID:CA220346 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting PM5, PM4, PM1, PM6, BA1, BP1, BP4, BP3, BS2, PP2, PP3, BS1, BS3, BP7, BP5, PS1, PS3, PS2, PS4 The NM_000070.3: c.223dup p.(Tyr75LeufsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 1/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least four individuals with LGMD (PMID: 27854218, 30564623; LOVD CAPN3_000537). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788fsTer14), 0.5 pts, LOVD Individual #00220184) (PM3_Supporting), and at least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220346/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3387 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034933 infores:hetionet GO:0042665 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0042665 GO:0009790 CHEBI:75722 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026838 infores:hetionet CAID:CA412370010 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370010 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PP3_Strong, PM5 PM1 NM_000330.4(RS1):c.668G>T (p.Cys223Phe) is a missense variant encoding the substitution of phenylalanine with cysteine at amino acid 223. Another missense variant in the same codon, NM_000330.4(RS1):c.667T>C (p.Cys223Arg), (PMIDs: 34645606, 10533068, 30652005, 33460243, 16361673) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (205) than the comparison variant (180), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.934, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). However, the PP3_Strong code has been met, which is ineligible to be used in combination with the PM1 code at any strength, so the PM1 code was not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, and PM5. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370010/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:3238 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01091 UMLS:C0013378 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017574 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0027765 infores:hetionet NCBIGene:94137 biolink:causes MONDO:0032940 infores:monarchinitiative not_provided not_provided HGNC:15946 MONDO:0032940 uuid:893332b6-8b4f-482a-9b35-3b7bd09f202e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0011168 infores:hetionet CHEBI:3437 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0013604 infores:hetionet CAID:CA145182 biolink:causes MONDO:0800472 infores:clingen CAID:CA145182 MONDO:0800472 PMID:27243976PMID:18470941PMID:19793111PMID:18622259PMID:19234632 Likely Benign PP3_Moderate, BS1 PP1, BA1, BP4, PM3, PM1, PM4, PM5, PS1, PS2, PS3, BP7, BS4, PVS1, PM2 The c.241T>A variant in CYP1B1 is a missense variant predicted to cause substitution of Tyrosine by Asparagine at amino acid 81 (p.Tyr81Asn). The highest minor allele frequency of this variant was in the European (Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.01438, which met the ≥ 0.01 threshold set for BS1 (674 alleles out of 46,866), meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.811, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 18470941) demonstrated that the 17B estradiol activity levels of the Tyr81Asn protein were not below the established threshold for that assay (<20% relative activity compared to background haplotype). This variant was also assessed in PMIDs: 18622259, 19793111, 19234632 & 27243976, however, the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined. As BS1 was met, PM3 did not apply and occurrence of this variant with another CYPB1 variant was not assessed. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BS1, PP3_Moderate Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145182/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8874 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0008350 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0014130 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151773 infores:hetionet CHEBI:47781 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0022346 infores:hetionet CHEBI:5855 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151798 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0003123 infores:hetionet CHEBI:188986 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C3665347 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0041834 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0553732 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011616 infores:hetionet CHEBI:4953 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0016658 infores:hetionet CHEBI:31623 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0085636 infores:hetionet CHEBI:127342 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0699744 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020542 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0699744 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0040034 infores:hetionet CAID:CA410148597 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148597 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BP3, BP2, BP1, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, PM1, BS2, PP4, PP1, PP2, PP3 NM_001754.5(RUNX1):c.1013C>T (p.Ala338Val) is a missense variant has a REVEL score ≤0.50 (0.08) and a SpliceAI score ≤ 0.20 (0.00) (BP4). This variant is not present in population databases (gnomAD v2.1 or v3.1.2) (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148597/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:132233 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0036572 infores:hetionet UMLS:C0657912 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037287 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0008097 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0008097 uuid:c2986583-04e9-4687-9bb7-a93c225145ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8232 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0019158 infores:hetionet CHEBI:4653 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0558489 infores:hetionet CHEBI:3441 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0023530 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004936 infores:hetionet CHEBI:17026 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C2830004 infores:hetionet NCBIGene:57449 biolink:causes MONDO:0012608 infores:monarchinitiative not_provided not_provided HGNC:29105 MONDO:0012608 uuid:63a8a130-a7e4-4557-94bc-d4a2209a8ef8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8499 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0010200 infores:hetionet CHEBI:51164 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0232462 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0022660 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009324 infores:hetionet CHEBI:63599 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0014868 infores:hetionet NCBIGene:1293 biolink:causes MONDO:0958234 infores:monarchinitiative not_provided not_provided HGNC:2213 MONDO:0958234 uuid:9f81bc4b-0491-41d6-ad1f-25a7156a4fa1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA220216 biolink:causes MONDO:0008723 infores:clingen CAID:CA220216 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The NM_000018.4 c.605T>C (p.Leu202Pro) in ACADVL is a missense variant predicted to cause substitution of leucine by proline at amino acid 202 (p. Leu202Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000004 in the general population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in apparently heterozygous fashion in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who also displayed reduced enzyme levels (20% and 26% of wildtype, respectively), which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 23480858, 30194637). At least one individual with this variant was identified by very long chain acyl-CoA dehydrogenase (VLCAD) clinical phenotype, who also carried a pathogenic variant c.848T>C in trans, displaying reduced enzyme levels (4% of wildtype) (PM3 score = 1.0, PM3, PMID: 30194637). The computational predictor REVEL gives a score of 0.953, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220216/MONDO:0008723/021 2024-03-26 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68647 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0019080 infores:hetionet CHEBI:135935 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0027441 infores:hetionet CHEBI:92607 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0020538 infores:hetionet CHEBI:135005 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0016382 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0043241 infores:hetionet CHEBI:47898 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004509 infores:hetionet CHEBI:184555 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0030794 infores:hetionet CHEBI:4903 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1384606 infores:hetionet CHEBI:63605 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0085593 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0857353 infores:hetionet CHEBI:40279 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020580 infores:hetionet CHEBI:585948 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C2939147 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0151436 infores:hetionet CHEBI:31348 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151904 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0085584 infores:hetionet NCBIGene:284439 biolink:causes MONDO:0032736 infores:monarchinitiative not_provided not_provided HGNC:28380 MONDO:0032736 uuid:54cd4810-bbaa-48b8-8fed-c067faca160f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45599 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0033774 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0242354 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0242354 infores:hetionet CHEBI:3219 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0003467 infores:hetionet CHEBI:6804 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0428977 infores:hetionet CHEBI:9566 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0853141 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0853141 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042401 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005530 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0524662 infores:hetionet CHEBI:6413 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C1443060 infores:hetionet CHEBI:75246 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0035455 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1510472 infores:hetionet CHEBI:64028 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0009806 infores:hetionet CHEBI:39112 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0235378 infores:hetionet CHEBI:182080 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0041657 infores:hetionet CHEBI:63598 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151746 infores:hetionet CHEBI:4856 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0027441 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0036572 infores:hetionet CHEBI:101278 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0026821 infores:hetionet CHEBI:3387 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0019572 infores:hetionet UMLS:C0010592 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0740394 infores:hetionet CAID:CA412741594 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741594 MONDO:0100437 PMID: Likely Pathogenic PM5_Supporting, PP3_Strong, PM2_Supporting PS4 NM_001034853.2(RPGR):c.823G>T (p.Gly275Cys) is a missense variant causing substitution of glycine by cysteine at amino acid 275. Another missense variant in the same codon, NM_001034853.2:c.823G>A (p.Gly275Ser) (PMID: 17480003, PMID: 31456290, PMID: 17724181, PMID: 16969763, PMID: 8817343), has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (159) than the comparison variant (56), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands diagnosed with retinitis pigmenosa (PMID: 37217489). However, neither individual meets one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, or decreased or absent electroretinogram responses, so PS4_Supporting was not met. The computational predictor REVEL gives a score of 0.968, which is above the ClinGen X-linked IRD VCEP threshold of ≥0.932 and predicts a damaging effect on RPGR function (PP3_Strong). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PM5_Supporting, and PP3_Strong. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741594/MONDO:0100437/106 2025-09-07 2025-09-08 X-linked inheritance HP:0001417 Supports CHEBI:5801 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0030232 infores:hetionet CAID:CA194486 biolink:causes MONDO:0007648 infores:clingen CAID:CA194486 MONDO:0007648 PMID: Benign BS1, BS2, BP2_Strong BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM1, PM3, PM4, PM5, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BA1, PS3, PS1, PS4, PS2 The c.820G>A (p.Gly274Ser) variant has been observed in >10 (25) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000760786.3, SCV000216659.5 and SCV000520889.4). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer or lobular breast cancer (BP2_Strong; SCV000520889.4). The c.820G>A variant has an allele frequency of 0.001037 (0.1037%, 5/4822 alleles) in the South Asian subpopulation of the gnomAD v.3.1 cohort (BS1). In summary, the clinical significance of this variant is benign, ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong, BS1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA194486/MONDO:0007648/007 2023-08-09 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63631 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017160 infores:hetionet CAID:CA10581648 biolink:causes MONDO:0100368 infores:clingen CAID:CA10581648 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting PP4 The NM_000329.3(RPE65):c.726-2A>C variant occurs at a canonical splice site in intron 7. It is predicted to lead to skipping of a critical exon, resulting in a frameshift, and likely nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000006199, with 1 allele / 91072 alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points), PMID: 27208204). (0.5 total points, PM3_Supporting).In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, PM3_supporting.(VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581648/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:30659 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0027497 infores:hetionet CAID:CA405670033 biolink:causes MONDO:0007783 infores:clingen CAID:CA405670033 MONDO:0007783 PMID: Likely Pathogenic PM5, PM1_Supporting, PS4_Moderate, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 2458 of the RYR1 protein, p.(Arg2458Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:21965348, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg2458His), PM5. A REVEL score >0.85 (0.968) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405670033/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:520985 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0151889 infores:hetionet NCBIGene:388551 biolink:causes MONDO:0032732 infores:monarchinitiative not_provided not_provided HGNC:31948 MONDO:0032732 uuid:177f03cc-3e75-4e17-8024-ab1441ecc0da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8428 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0000737 infores:hetionet CHEBI:10102 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1510410 infores:hetionet CHEBI:5847 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0746883 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0860967 infores:hetionet CHEBI:68606 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0151904 infores:hetionet CHEBI:41977 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0030252 infores:hetionet CHEBI:18332 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0000729 infores:hetionet NCBIGene:259266 biolink:causes MONDO:0012106 infores:monarchinitiative not_provided not_provided HGNC:19048 MONDO:0012106 uuid:e9937ff5-2515-4d6c-bf62-0e7d991f1260 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0178298 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0015397 infores:hetionet CHEBI:9123 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0043349 infores:hetionet CHEBI:6809 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0020517 infores:hetionet CHEBI:70718 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0018681 infores:hetionet CHEBI:5001 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0026821 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151517 infores:hetionet CHEBI:8356 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042420 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013220 infores:hetionet CHEBI:9139 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0026858 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0342579 infores:hetionet CHEBI:63638 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0151611 infores:hetionet CHEBI:6887 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C3665386 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0032285 infores:hetionet CHEBI:2788 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0151827 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0178298 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020437 infores:hetionet CHEBI:480999 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0002962 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0267596 infores:hetionet CHEBI:2379 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C1443060 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0392156 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0314719 infores:hetionet CHEBI:68558 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0025874 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0233479 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0233479 infores:hetionet CHEBI:145499 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151539 infores:hetionet NCBIGene:57570 biolink:causes MONDO:0014684 infores:monarchinitiative not_provided not_provided HGNC:23141 MONDO:0014684 uuid:789496db-29d7-461c-83eb-6ee805ed779d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135530 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0011603 infores:hetionet CHEBI:8499 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0013404 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1096403 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1096403 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0149931 infores:hetionet CHEBI:9168 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085681 infores:hetionet CHEBI:7581 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0022107 infores:hetionet NCBIGene:6772 biolink:causes MONDO:0013599 infores:monarchinitiative not_provided not_provided HGNC:11362 MONDO:0013599 uuid:142eb8b5-37c4-4a39-ad10-006d3f90f45a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0028084 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0040479 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0277925 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0000833 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0003366 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1253936 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0027769 infores:hetionet CAID:CA343726256 biolink:causes MONDO:0005338 infores:clingen CAID:CA343726256 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.757G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 253 (p.Glu253Lys). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.31, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726256/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135935 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0020517 infores:hetionet CHEBI:46557 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0221201 infores:hetionet CHEBI:9599 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C3665386 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042134 infores:hetionet NCBIGene:401138 biolink:causes MONDO:0021547 infores:monarchinitiative not_provided not_provided HGNC:33188 MONDO:0021547 uuid:7889373f-8259-4f2d-91dc-288f7e88da7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0022660 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0549386 infores:hetionet GO:1903729 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1903729 GO:0010256 CHEBI:135361 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0002792 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0235146 infores:hetionet CHEBI:6761 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0020517 infores:hetionet CHEBI:4911 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0041657 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0151763 infores:hetionet CAID:CA6798737 biolink:causes MONDO:0021060 infores:clingen CAID:CA6798737 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1221A>G (p.Gly407=) variant in the PTPN11 gene is 0.115% (27/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6798737/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:15940 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0015397 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1167965 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0847403 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0847403 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0435002 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017601 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0575090 infores:hetionet CHEBI:367163 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0015967 infores:hetionet CHEBI:31638 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0002994 infores:hetionet CHEBI:2038 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0035508 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0037199 infores:hetionet CHEBI:68595 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0020433 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020557 infores:hetionet CHEBI:47612 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0037763 infores:hetionet CHEBI:63598 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0549249 infores:hetionet CHEBI:9738 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0013604 infores:hetionet CHEBI:3485 biolink:causes HP:0001892 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C1458140 infores:hetionet CHEBI:50305 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0037299 infores:hetionet CHEBI:7443 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0020621 infores:hetionet CAID:CA10549426 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549426 MONDO:0010305 PMID: Benign BP4, BA1 The NM_005629.4:c.1141+37G>A variant is in intron 7 of SLC6A8. The highest population minor allele frequency in gnomAD v2.1.1 is 0.1931 (3670/19008 alleles; 952 hemizygotes and 265 homozygotes) in the African/African American population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.002), and therefore meets this criterion (BA1). The computational predictor SpliceAI predicts that the variant has no effect on SLC6A8 splicing (BP4). In summary, this variants meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BA1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 8, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549426/MONDO:0010305/027 2023-06-08 2023-06-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:3398 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0030252 infores:hetionet CHEBI:3082 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0026896 infores:hetionet CHEBI:6078 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0014742 infores:hetionet CHEBI:9435 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0030252 infores:hetionet CHEBI:71940 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0152227 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0037195 infores:hetionet CHEBI:75246 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0015230 infores:hetionet CAID:CA913171966 biolink:causes MONDO:0044970 infores:clingen CAID:CA913171966 MONDO:0044970 PMID:17056256 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting, PM6 PS4 The m.14739G>A variant in MT-TE has been reported in one individual with primary mitochondrial disease (PMID: 17056256). This child had exercise intolerance, muscle weakness, muscle atrophy, developmental delay, and poor appetite with transient weight loss. Muscle biopsy showed ragged red and COX-negative fibers, and irregular mitochondria with tubular structures and focal subsarcolemmal glycogen accumulations. Biochemical investigations in muscle showed elevated activities of citrate synthase, complex II, and the oligomycin-sensitive ATPase in relation to the protein content, and complexes I, III and IV were moderately reduced in relation to citrate synthase activity. The variant was present at 72% heteroplasmy in muscle, 38% in urine sediment, 31% in blood, and 29% in fibroblasts. The variant was not detectable in the mother’s urine and blood, and was undetectable in four maternal aunts and the maternal grandmother (PMID: 17056256). This variant has also been seen in one individual in an internal clinical lab dataset, in a child with speech regression, autism spectrum disorder, hirsutism, and dysmorphic features. The variant was present at 23% in saliva and was not detected in the mother’s saliva sample (PM6). This variant is absent in the Helix dataset, and gnomAD v3.1.2, and there is one occurrence in the MITOMAP GenBank dataset (PM2_supporting). MitoTIP predicts the variant is possible pathogenic (62.1 percentile) and HmtVAR predicts the variant is pathogenic (0.4, PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (86%, range 73–96%; n = 12) than in COX-positive fibers (44%, range 11–79%; n = 12) p<0.0001 (PS3_supporting, PMID: 17056256). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM6, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913171966/MONDO:0044970/015 2024-03-26 2025-10-29 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:64312 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235490 infores:hetionet CHEBI:4445 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0005779 infores:hetionet CHEBI:42355 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0002792 infores:hetionet CHEBI:472657 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0002878 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0853019 infores:hetionet NCBIGene:81607 biolink:causes MONDO:0024565 infores:monarchinitiative not_provided not_provided HGNC:19688 MONDO:0024565 uuid:3fe7bf14-036d-41a3-84bb-357ddecd20b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0086543 infores:hetionet CAID:CA16609628 biolink:causes MONDO:0015152 infores:clingen CAID:CA16609628 MONDO:0015152 PMID:9642272 Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Strong PS3 The NM_000070.3: c.701G>A variant in CAPN3 is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 234 (p.Gly234Glu). This variant has been detected in at least 8 individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, PMID: 27500519, 17994539) and in trans with a likely pathogenic or pathogenic variant in at least one patient (c.1319G>A p.(Arg440Gln), 1.0 pt, PMID: 17994539) (PM3_Strong). At least one patient with this variant displayed a clinical suspicion of limb girdle muscular dystrophy and absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17994539). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609628/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5106 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0242073 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006444 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0003123 infores:hetionet CHEBI:101278 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0917801 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032226 infores:hetionet GO:0032888 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0032888 GO:0000278 CHEBI:51860 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0231528 infores:hetionet CHEBI:6541 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002874 infores:hetionet CHEBI:2675 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C2225524 infores:hetionet CHEBI:63629 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C1306341 infores:hetionet CHEBI:7820 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0151671 infores:hetionet CHEBI:47381 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003811 infores:hetionet CAID:CA16042748 biolink:causes MONDO:0017623 infores:clingen CAID:CA16042748 MONDO:0017623 PMID:25418537PMID:28526761PMID:23886400PMID:28526761PMID:23886400PMID:28526761PMID:23886400PMID:25418537PMID:29785012PMID:29706350PMID:25418537 Pathogenic PM2, PM6, PP2, PP1, PS4_Moderate, PS3 PVS1, BP7, BP5, BS1, BS4, BS3, PP3, BS2, PM5, PM4, PM1, BA1, BP4, BP2, PS1, PS2 PTEN c.320A>T (p.Asp107Val) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type. (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 25418537)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2)PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 28526761, PMID 23886400, internal laboratory contributor SCV000490750.2)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042748/MONDO:0017623/003 2019-06-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9943 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0231530 infores:hetionet CHEBI:480999 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1720798 infores:hetionet CAID:CA012920 biolink:causes MONDO:0005045 infores:clingen CAID:CA012920 MONDO:0005045 PMID: Uncertain Significance PM2, PM1, PP3 BA1, PM5, PS3, PM6, PM4, PP1, BS1, BS3, BS4, PS1, PS4, PS2, BP4, BP2, BP5, BP7, PVS1 The NM_000257.4: c.2714G>C (p.Cys905Ser) variant in MYH7 has been reported in 1 individual with HCM (GeneDx pers. comm.); however this data is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012920/MONDO:0005045/002 2021-09-22 2021-10-01 Inconclusive true CHEBI:6437 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0023895 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005647 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0009663 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0042373 infores:hetionet CHEBI:44915 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0039240 infores:hetionet CHEBI:2659 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0021141 infores:hetionet CHEBI:8404 biolink:causes UMLS:C2939427 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C2939427 infores:hetionet CHEBI:2673 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0039070 infores:hetionet CHEBI:8028 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0013144 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0948715 infores:hetionet CHEBI:94392 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0231170 infores:hetionet NCBIGene:340419 biolink:causes MONDO:0060733 infores:monarchinitiative not_provided not_provided HGNC:28583 MONDO:0060733 uuid:bab0d321-07d9-4e6c-bef9-496e1c0f475a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0020538 infores:hetionet CHEBI:28593 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0039231 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027441 infores:hetionet CHEBI:6128 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0232461 infores:hetionet CHEBI:71940 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0011168 infores:hetionet CHEBI:30830 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0015672 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0012833 infores:hetionet CHEBI:52172 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0032231 infores:hetionet CAID:CA512319073 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319073 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.597G>A (p.Gly199=) is a synonymous variant. REVEL score not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.487268 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319073/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA915940686 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940686 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000419.5:c.2338del (p.Glu780SerfsTer46) variant in ITGA2B exon 23 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 25/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one proband with Glanzmann thrombasthenia. However, it is unclear if the reported proband (GT38, PMID: 19691478) was homozygous for this variant or if a second ITGA2B variant was identified. At least one patient (Patient GT38 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting, PP4_Moderate. (VCEP specifications version 2; date of approval 05/17/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940686/MONDO:0100326/011 2022-05-17 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:31622 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0233407 infores:hetionet CHEBI:49603 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0014591 infores:hetionet CHEBI:6775 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151905 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0003123 infores:hetionet CHEBI:80630 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0021845 infores:hetionet CAID:CA396472215 biolink:causes MONDO:0007648 infores:clingen CAID:CA396472215 MONDO:0007648 PMID: Pathogenic PM2_Supporting, PS2, PVS1_Strong BS1, BS3, BS4, BP7, BP5, PM6, PM5, PM4, PM1, PM3, BS2, PP3, PP2, PP1, PP4, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4 The c.2506G>T (p.Glu836*) variant results in a premature stop codon that leads to a truncated protein. While it is located within the nonsense mediated decay resistance region,it is recognized as the most c-terminal pathogenic variant in CDH1 (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is one known de novo observation with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 29798843). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396472215/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:8382 biolink:causes UMLS:C0235453 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0235453 infores:hetionet CHEBI:27470 biolink:causes UMLS:C0474395 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C1536696 infores:hetionet CHEBI:68558 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0022661 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0920070 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0920070 infores:hetionet CHEBI:92712 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0020625 infores:hetionet CHEBI:6067 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011603 infores:hetionet CHEBI:3219 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232849 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0020538 infores:hetionet CHEBI:2950 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0003467 infores:hetionet GO:0002062 biolink:causes CL:0000138 infores:ubergraph knowledge_assertion manual_agent GO:0002062 CL:0000138 CHEBI:127342 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0040822 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0919980 infores:hetionet CHEBI:49713 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0162283 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0349506 infores:hetionet CHEBI:142290 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0018800 infores:hetionet CHEBI:8214 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0030554 infores:hetionet CHEBI:6067 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0424489 infores:hetionet CHEBI:46295 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0017152 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0162429 infores:hetionet CHEBI:2682 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0038999 infores:hetionet CHEBI:47426 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0013144 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0029882 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235234 infores:hetionet CHEBI:71219 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1527344 infores:hetionet NCBIGene:51703 biolink:causes MONDO:0957253 infores:monarchinitiative not_provided not_provided HGNC:16526 MONDO:0957253 uuid:ac821f52-6a1b-4ece-870b-c6d92c6560b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0476273 infores:hetionet CAID:CA347216158 biolink:causes MONDO:0015152 infores:clingen CAID:CA347216158 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.2894G>A p.(Trp965Ter) variant in DYSF, which is also known as NM_001130987.2: c.2948G>A p.(Trp983Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 27/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least two patients with features consistent with LGMD (PMID: 18853459, 36983702), including confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.757C>T p.(Arg253Trp), 1.0 pt, PMID: 36983702; PM3). At least one individual with this variant and a second DYSF variant displayed progressive proximal muscle weakness and severely reduced dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 18853459, 36983702; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347216158/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7852 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0003578 infores:hetionet CHEBI:5165 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020621 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0037274 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0006277 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0021290 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0021290 infores:hetionet CHEBI:144093 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151539 infores:hetionet CHEBI:72690 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0151825 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004096 infores:hetionet CHEBI:83531 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0600142 infores:hetionet CAID:CA10576290 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576290 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5, PS4_supporting, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.871.It is above 0.75, so PP3 is Met.PM5 - 4 other missense variants in the same codon:- NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.910G>C (p.Asp304His) (ClinVar ID 440612) - VUS by these guidelines- NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines- NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.PS4_supporting - Variant meets PM2 and is identified in at least 2 unrelated index cases: 1 index case who fulfils DLCN>6 criteria for FH from Robarts Research Institute and 1 index case who fulfils Simon Broome criteria for FH from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in at least 2 unrelated index cases as described in PS4, PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576290/MONDO:0007750/013 2022-04-05 2022-04-05 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5790 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020429 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0162429 infores:hetionet CAID:CA9871547 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871547 MONDO:0007064 PMID: Uncertain Significance PM5_Supporting, PM2_Supporting NM_000022.4(ADA):c.715G>A is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 239 (p.Gly239Ser). The filtering allele frequency (the upper threshold of the 95% CI of 9/44902) of the c.715G>Avariant in ADA is 0.00008198 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold 0.0001742 for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Another missense variant [c.716G>A], p.Gly239Asp] in the same codon has been classified as likely pathogenic for SCID by the ClinGen SCID VCEP (PM5_Supporting). Based on the above evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting,PM5_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871547/MONDO:0007064/114 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4027 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0876994 infores:hetionet CHEBI:7822 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0032617 infores:hetionet CHEBI:84500 biolink:causes UMLS:C2363829 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C2363829 infores:hetionet CAID:CA410146714 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146714 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1412G>A (p.Arg471His) is a missense variant which has a REVEL score < 0.50 (0.369) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146714/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135888 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0877661 infores:hetionet CHEBI:71940 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0035328 infores:hetionet CHEBI:63629 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0025222 infores:hetionet CHEBI:7824 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0025874 infores:hetionet NCBIGene:54982 biolink:causes MONDO:0011144 infores:monarchinitiative not_provided not_provided HGNC:2077 MONDO:0011144 uuid:cbb3d0b7-30ae-4959-aa05-db8c20113f3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8093 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0020517 infores:hetionet CHEBI:5855 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0232462 infores:hetionet GO:1902366 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:1902366 GO:0009653 CHEBI:68606 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0004364 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0242350 infores:hetionet CHEBI:9667 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0042571 infores:hetionet CAID:CA320251631 biolink:causes MONDO:0100083 infores:clingen CAID:CA320251631 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 This synonymous variant has a SpliceAI Δ score of 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.008 (< 2)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251631/MONDO:0100083/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5855 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0314719 infores:hetionet CHEBI:134743 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0275524 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019372 infores:hetionet CAID:CA132654 biolink:causes MONDO:0010134 infores:clingen CAID:CA132654 MONDO:0010134 PMID: Likely Benign BS1, PP3 BP5, PP2, PM5, PM1, PM2, BP1, BP4, BA1, PS1, PS4 The filtering allele frequency of the c.1069G>A (p.Ala357Thr) variant in the SLC26A4 gene is 0.46% for African/African American chromosomes by gnomAD v4.1.0 (489/1613848 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL VCEP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.849, which is above the threshold necessary to apply PP3. The HL VCEP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in​ this case as computational scores are error prone, especially when predicting pathogenicity. In summary, the HL VCEP classified this variant as likely benign. (BS1, PP3; Clingen Hearing Loss VCEP Specifications Version 2; 02/19/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132654/MONDO:0010134/005 2025-02-19 2025-03-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:49375 biolink:causes UMLS:C0520863 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0520863 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0234987 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948296 infores:hetionet CHEBI:9288 biolink:causes MONDO:0024677 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0021670 infores:hetionet CHEBI:5959 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C1443060 infores:hetionet CHEBI:31980 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0040460 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0038454 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0020598 infores:hetionet CHEBI:404903 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0575081 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0235955 infores:hetionet CHEBI:23765 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0030312 infores:hetionet CHEBI:64045 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0025345 infores:hetionet CHEBI:50841 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C1262064 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1096340 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1096340 infores:hetionet NCBIGene:196385 biolink:causes MONDO:0030430 infores:monarchinitiative not_provided not_provided HGNC:2941 MONDO:0030430 uuid:6f7e9dfe-f970-46e0-a634-5227d33d3461 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0027769 infores:hetionet GO:0140533 biolink:causes GO:0009616 infores:ubergraph knowledge_assertion manual_agent GO:0140533 GO:0009616 CHEBI:8107 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0017181 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0029134 infores:hetionet CHEBI:3077 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0156404 infores:hetionet CHEBI:6950 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0028084 infores:hetionet CHEBI:31236 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0699828 infores:hetionet CHEBI:4974 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0027497 infores:hetionet CHEBI:9649 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0003467 infores:hetionet CHEBI:188986 biolink:causes UMLS:C3495827 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C3495827 infores:hetionet CAID:CA024566 biolink:causes MONDO:0007783 infores:clingen CAID:CA024566 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with leucine at codon 2117 of the RYR1 protein, p.Val2117Leu. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: MA0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:12709367). An additional individual with a personal history of an MH reaction and a positive CHCT test has been identified through clinical testing at the MH Investigation Unit (MHIU), UHM, Toronto, PS4_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.923) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024566/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63608 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1167965 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0919715 infores:hetionet CHEBI:3561 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0085633 infores:hetionet NCBIGene:721 biolink:causes MONDO:0013720 infores:monarchinitiative not_provided not_provided HGNC:1324 MONDO:0013720 uuid:33b18cd1-7a1f-4f5e-b58a-01ecef03c27d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1112320 infores:hetionet NCBIGene:7552 biolink:causes MONDO:0010430 infores:monarchinitiative not_provided not_provided HGNC:13128 MONDO:0010430 uuid:6a0d92b1-b9f1-486e-9334-d74ef31251c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948349 infores:hetionet CHEBI:6931 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0011206 infores:hetionet CHEBI:31981 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0427086 infores:hetionet NCBITaxon:5759 biolink:causes MONDO:0005644 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5759 MONDO:0005644 CHEBI:8378 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0162835 infores:hetionet CHEBI:31413 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C3665347 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0085096 infores:hetionet CHEBI:49713 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0001925 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0022650 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0042109 infores:hetionet CHEBI:8802 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0003467 infores:hetionet CAID:CA386959373 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959373 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PS4 The c.385C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 129 (p.(Pro129Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting), but was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 9075818, PMID: 15687377). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, the c.385C>A variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959373/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46081 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C1384353 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0853908 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151911 infores:hetionet CHEBI:50924 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0085633 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0022658 infores:hetionet CHEBI:63629 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018790 infores:hetionet CHEBI:8024 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C2047937 infores:hetionet CHEBI:4702 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0235266 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013295 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0012359 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0037274 infores:hetionet CHEBI:28445 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0149745 infores:hetionet CHEBI:18067 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0340865 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0002871 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0003123 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0009806 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020649 infores:hetionet CHEBI:6761 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0013362 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0017168 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003123 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1384353 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0948281 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0948281 infores:hetionet CHEBI:83804 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027497 infores:hetionet CHEBI:82960 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0014742 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042571 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0424605 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042075 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0027765 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0020557 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0853986 infores:hetionet CHEBI:3696 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0043094 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0026946 infores:hetionet CHEBI:64355 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0026827 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0152517 infores:hetionet NCBITaxon:121225 biolink:causes MONDO:0003472 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:121225 MONDO:0003472 NCBIGene:144406 biolink:causes MONDO:0029147 infores:monarchinitiative not_provided not_provided HGNC:28506 MONDO:0029147 uuid:5345d678-8446-459d-89e7-e99855721d9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0687713 infores:hetionet CHEBI:7444 biolink:causes MONDO:0020674 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0232352 infores:hetionet CHEBI:45327 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0004604 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0038814 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0031085 infores:hetionet CHEBI:7581 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0022346 infores:hetionet CAID:CA386972260 biolink:causes MONDO:0015967 infores:clingen CAID:CA386972260 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP4_Moderate, PVS1, PP1 The c.1623+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 8 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 8 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in one family with MODY (PP1; PMID: 12378390). Lastly, this variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 11272211, 30155490; internal lab contributors). In summary, c.1623+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP4_Moderate, PP1, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386972260/MONDO:0015967/017 2022-05-02 2022-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27690 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0018965 infores:hetionet CAID:CA512318835 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318835 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.312G>T (p.Thr104=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.09) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318835/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17650 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0019209 infores:hetionet CAID:CA386958942 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958942 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Moderate, PP4_Moderate, PP3 The c.349A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamic acid at codon 117 (p.(Lys117Glu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with four informative meioses in one family (PP1_Moderate; PMID: 10102714, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to sulphonylureas) (PP4_Moderate; PMID: 10102714, internal lab contributors). In summary, c.349A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP1_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958942/MONDO:0015967/017 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72690 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0877153 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0231303 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0233472 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042401 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0013395 infores:hetionet CHEBI:39867 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0023380 infores:hetionet CHEBI:50648 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0332601 infores:hetionet CHEBI:17347 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0024902 infores:hetionet CHEBI:49662 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0085632 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0522172 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0020649 infores:hetionet CHEBI:3696 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0030193 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0004795 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D010032 DB00803_MESH_D010032_1DB01165_MESH_D010032_1DB00781_MESH_D010032_1 CHEBI:49603 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0015230 infores:hetionet CHEBI:66903 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0013395 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030554 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0029134 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017566 infores:hetionet GO:0044758 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0044758 GO:0007268 CHEBI:6413 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042373 infores:hetionet CAID:CA915940786 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940786 MONDO:0100326 PMID: Uncertain Significance PM4, PM2_Supporting, PM3_Supporting PP4 The c.1005_1013del variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 4 amino acids and insertion of 1 amino acid in a non-repeat region (p.His335_Leu338delinsGln) (PM4). There has been one case of Glanzmann Thrombasthenia associated with this variant reported in the literature. GT patient TGP0218 (PMID: 31064749) is homozygous for this variant 0.5pt (PM3_supporting). Information about the phenotypes of this patient were insufficient to meet group criteria (PP4 not met). This variant was not present in the GT database or the HGMD database. This variant is absent from gnomAD v4.0.0 (PM2_Supporting).In summary, this variant meets the criteria to be classified as variant of unknown significance due to insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM4, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 05/02/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940786/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6715 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027066 infores:hetionet CHEBI:45599 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0027497 infores:hetionet CHEBI:6128 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0043352 infores:hetionet CAID:CA10588918 biolink:causes MONDO:0019501 infores:clingen CAID:CA10588918 MONDO:0019501 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Strong PP3 The c.5516T>A variant in USH2A is a missense variant predicted to cause substitution of valine to glutamate at amino acid position 1839. The variant was absent from gnomAD v2.1.1 and present in 0.001549% (1/64578) of non-Finnish European chromosomes in gnomAD v3 (PM2_Supporting). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been detected in at least 4 individuals (2 with Usher syndrome and 2 with isolated retinitis pigmentosa) (total of 2.5 PM3 points, PM3_Strong). One individual with Usher syndrome was assumed to be compound heterozygous with a pathogenic c.2299del variant, but phase unknown (VCV000002351.78; PMID: 26927203). The other two individuals had retinitis pigmentosa and were assumed compound heterozygous with pathogenic p.(Cys759Phe) variant (VCV000002356.89; PMID: 26927203; PMID: 34203967). One patient displayed both retinal degradation and sensorineural hearing loss, features highly specific for USH2A (PP4). Patients with this variant may present with either Usher syndrome or with isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP4 (VCEP specifications version 2; 10.18.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588918/MONDO:0019501/005 2023-10-18 2024-01-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:5138 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013604 infores:hetionet CHEBI:63630 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085639 infores:hetionet CHEBI:17334 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0015230 infores:hetionet CHEBI:52172 biolink:causes MONDO:0020673 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0264995 infores:hetionet CAID:CA512341328 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341328 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1074G>A (p.Thr358=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.75) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341328/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135935 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0233632 infores:hetionet CHEBI:41977 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0016436 infores:hetionet CHEBI:617099 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0262988 infores:hetionet CHEBI:72564 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0549249 infores:hetionet CHEBI:5613 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0040822 infores:hetionet CHEBI:3638 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0042109 infores:hetionet CHEBI:2379 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C1456822 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0043251 infores:hetionet CHEBI:5165 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1142135 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0023530 infores:hetionet CAID:CA2573159473 biolink:causes MONDO:0010305 infores:clingen CAID:CA2573159473 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_005629.4:c.645-19A>G variant in SLC6A8 is an intronic variant affecting a nucleotide within the consensus splice site of intron 3. To our knowledge, this variant has not been reported in the literature and no functional studies are available. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). SpliceAI predicts no impact on splicing (score <0.2) (BP4). There is a ClinVar entry for this variant (Variation ID: 1562414, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; one submitter: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573159473/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6954 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0015230 infores:hetionet CHEBI:8081 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0008031 infores:hetionet CHEBI:5959 biolink:causes HP:0010742 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0522035 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0021400 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0038362 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0013395 infores:hetionet CAID:CA320603683 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603683 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS2, PS4, PS1, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.705C>T (p.Ala235=) is a synonymous variant not predicted to affect splicing (BP4). However, evolutionary conservation prediction algorithms predict the site as being conserved (PhyloP score: 3.88) and the variant is not the reference nucleotide in one primate and/or three mammal species. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603683/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63622 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0030848 infores:hetionet CHEBI:145499 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0037188 infores:hetionet CHEBI:3048 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C1443060 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151479 infores:hetionet CHEBI:4911 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0041582 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235431 infores:hetionet NCBIGene:4709 biolink:causes MONDO:0032629 infores:monarchinitiative not_provided not_provided HGNC:7698 MONDO:0032629 uuid:ad5711b7-8e7f-4e4c-bc3d-f9c5e471ccda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042571 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0030920 infores:hetionet CHEBI:17630 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0042963 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005854 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0026272 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017675 infores:hetionet CHEBI:3568 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151205 infores:hetionet NCBIGene:374393 biolink:causes MONDO:0014310 infores:monarchinitiative not_provided not_provided HGNC:24200 MONDO:0014310 uuid:3e7c5646-3743-4c69-9156-5096c2a5bd4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0027769 infores:hetionet CHEBI:9137 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151662 infores:hetionet CHEBI:4445 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0027497 infores:hetionet CHEBI:10124 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0232461 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1443060 infores:hetionet CHEBI:135736 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042963 infores:hetionet CHEBI:63627 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0011991 infores:hetionet CHEBI:681569 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0041969 infores:hetionet CHEBI:100147 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0013144 infores:hetionet CHEBI:27786 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0013604 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0018801 infores:hetionet CHEBI:15544 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0002884 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0009806 infores:hetionet CHEBI:52717 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026766 infores:hetionet CHEBI:80630 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C2047937 infores:hetionet CAID:CA10549625 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549625 MONDO:0010305 PMID: Likely Benign BS2 BS1, PM2, PP3, BP4 "The NM_005629.4:c.1714G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 572 (p.Val572Met). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population minor allele frequency MAF) is 0.0000369 (33/894244 alleles, 12 hemizygotes) in the European (Non-Finnish) population. This MAF is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There are 14 hemizygotes in gnomAD v4.1.0. (12 in the European non-Finnish, one in the ""other"" and one in the S. Asian population) (BS2). The computational predictor REVEL gives a score of 0.689, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 449188). Due to the presence of 14 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549625/MONDO:0010305/027 2025-03-13 2025-03-14 X-linked inheritance HP:0001417 Contradicts true CAID:CA2737736947 biolink:causes MONDO:0011071 infores:clingen CAID:CA2737736947 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.352-5T>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.63) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2737736947/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68579 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0919874 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235146 infores:hetionet CHEBI:5280 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0036974 infores:hetionet CHEBI:6931 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0020578 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0042109 infores:hetionet CHEBI:4470 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0033975 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0546343 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0546343 infores:hetionet CHEBI:7936 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0041105 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0152032 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0009806 infores:hetionet CHEBI:17245 biolink:causes GO:0099549 infores:ubergraph knowledge_assertion manual_agent CHEBI:17245 GO:0099549 NCBIGene:6578 biolink:causes MONDO:0008172 infores:monarchinitiative not_provided not_provided HGNC:10955 MONDO:0008172 uuid:5c89ff33-245e-4873-847d-09fcae897b12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4325 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0434437 infores:hetionet CAID:CA16043652 biolink:causes MONDO:0018214 infores:clingen CAID:CA16043652 MONDO:0018214 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3_Moderate, PM5_Supporting PS1, PM1 The c.1709G>A variant in SCN1A is a missense variant predicted to cause substitution of serine by asparagine at amino acid 570 (p.Ser570Asp). The variant has been identified in multiple unrelated individuals meeting criteria for generalized epilepsy with febrile seizures plus or an unspecified epilepsy condition (PS4)(internal lab contributors). This variant was observed in one unaffected parent (internal lab contributors). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.852, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. Additionally, another missense variant in the same codon c.1709G>T, p.S570I in the same codon reaches likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant generalized epilepsy with febrile seizures plus based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; March 26, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043652/MONDO:0018214/067 2024-07-30 2024-11-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4876 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0740394 infores:hetionet CHEBI:5383 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0232462 infores:hetionet CHEBI:2469 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0002871 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234458 infores:hetionet CHEBI:2950 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0151827 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0030552 infores:hetionet CAID:CA10524794 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524794 MONDO:0010278 PMID: Benign BS2, BS1, BP5 PP3, BP4 TThe allele frequency of the p.Lys443Asn variant in SLC9A6 (NM_006359.2) is 0.009% in European (Non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Lys443Asn variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Lys443Asn variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Lys443Asn variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524794/MONDO:0010278/033 2024-02-23 2024-03-31 X-linked inheritance HP:0001417 Contradicts true CHEBI:50122 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0162275 infores:hetionet CHEBI:7773 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C2939147 infores:hetionet CHEBI:92998 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0231528 infores:hetionet CHEBI:8774 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151539 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1442903 infores:hetionet CAID:CA913184710 biolink:causes MONDO:0012999 infores:clingen CAID:CA913184710 MONDO:0012999 PMID: Pathogenic PM2_Supporting, PP4_Strong, PVS1_Strong PM3 The NM_000156.6:c.526dup (p.Glu176GlyfsTer15) variant in GAMT has been previously reported in at least one individual with guanidinoacetate methyltransferase deficiency (PMID: 15108290). This variant is absent in population databases (PM2_Supporting). This variant has been reported in ClinVar (Variation ID: 1409758) and has been interpreted as pathogenic by Invitae. The individual who was previously reported was a compound heterozygote; however, this occurrence was counted for evidence for PM3 for the other variant and thus not used here to prevent circularity in the use of PM3 (PMID: 15108290). This individual showed elevated urinary GAA and partially absent creatine peak and absent GAA peak on brain MRS with full GAMT gene sequencing (PMID: 15108290) (PP4_Strong). The p.Glu176GlyfsTer15 variant is a frameshift variant at amino acid position 176 that is predicted to lead to premature termination 15 amino acids downstream. As the variant results in termination downstream of the last 50 base pairs of the penultimate exon of the GAMT gene, nonsense-mediated decay is not predicted; however, the variant results in removal of >10% of the encoded protein (PVS1_Strong). In summary, this variant meets criteria to be classified as pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PVS1_Strong, PM2_Supporting, PP4_Strong (Richards 2015).(Classification approved by the ClinGen CCDS VCEP on March 23, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184710/MONDO:0012999/026 2023-03-23 2023-03-29 Autosomal recessive inheritance HP:0000007 Supports GO:0061319 biolink:causes CL:0002520 infores:ubergraph knowledge_assertion manual_agent GO:0061319 CL:0002520 CHEBI:47657 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0021400 infores:hetionet CAID:CA165437 biolink:causes MONDO:0100488 infores:clingen CAID:CA165437 MONDO:0100488 PMID: Likely Benign BS2 BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PVS1, PM2, PM6, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The c.1019C>T (p.Thr340Met) missense variant has a frequency of 0.0123% in Africans (2 of 16256 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in ≥10 (14) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000254803.10, SCV000184790.6). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA165437/MONDO:0100488/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7494 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0021400 infores:hetionet CHEBI:85161 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0428977 infores:hetionet CHEBI:7983 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0027497 infores:hetionet CHEBI:4909 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0235063 infores:hetionet NCBIGene:27249 biolink:causes MONDO:0010185 infores:monarchinitiative not_provided not_provided HGNC:25221 MONDO:0010185 uuid:88cf05e2-931e-41d7-9118-9f18e5c7d2ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0021368 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0233494 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0041912 infores:hetionet CHEBI:9448 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0002792 infores:hetionet CHEBI:61049 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2939147 infores:hetionet CHEBI:50173 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0004604 infores:hetionet CHEBI:5120 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0018418 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0853692 infores:hetionet CHEBI:15765 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0700361 infores:hetionet CHEBI:7478 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0086168 infores:hetionet CHEBI:2673 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0027497 infores:hetionet CHEBI:71272 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0042029 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0160390 infores:hetionet NCBIGene:2733 biolink:causes MONDO:0012750 infores:monarchinitiative not_provided not_provided HGNC:4315 MONDO:0012750 uuid:b4379aac-2c8c-419b-9323-01c60d6f2008 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0037763 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011616 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0006852 infores:hetionet CHEBI:61390 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0002170 infores:hetionet CHEBI:2914 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0013404 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0021053 infores:hetionet MONDO:0041752 biolink:causes GO:0042088 infores:mondo not_provided not_provided MONDO:0041752 GO:0042088 infores:monarchinitiativeinfores:phenio urn:uuid:11678e8f-80a9-47c4-b383-8d200aacddfa biolink:Associationbiolink:Entity phenio_edges CAID:CA410206927 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206927 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.674T>G (p.Leu225Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206927/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:2902 biolink:causes MONDO:0030727 infores:monarchinitiative not_provided not_provided HGNC:4584 MONDO:0030727 uuid:6c70c6ff-1ae8-4a31-abca-6f15e8628c7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681850 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0033774 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1510472 infores:hetionet CAID:CA011851 biolink:causes MONDO:0005045 infores:clingen CAID:CA011851 MONDO:0005045 PMID:9829907PMID:27532257PMID:20359594PMID:20359594PMID:1430197PMID:9829907PMID:12707239PMID:16199542PMID:27532257 Pathogenic PP1_Strong, PP3, PM6, PM1, PM5, PM2, BP2, PS4 The c.2167C>T (p.Arg723Cys) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1430197; PMID:27532257; PMID:9829907; PMID:16199542; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). Five of these probands carried additional variants in sarcomere genes (BP2; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:1430197). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:9829907; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). This variant was identified in 2/66738 European chromosomes (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>G p.Arg723Gly - ClinVar Variation ID 42885). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. The benign evidence code BP2 was not considered to be in conflict with this conclusion given that presence of a second variant can be seen in individuals with cardiomyopathy and may contribute to the severity of disease. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PM6; PP3; BP2 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011851/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3499 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0006852 infores:hetionet CHEBI:421707 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0017178 infores:hetionet CHEBI:9352 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0231218 infores:hetionet UMLS:C0009315 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0013362 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0002453 infores:hetionet CHEBI:9123 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003467 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0581912 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017178 infores:hetionet CHEBI:7820 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0022107 infores:hetionet GO:1902490 biolink:causes GO:0007283 infores:ubergraph knowledge_assertion manual_agent GO:1902490 GO:0007283 CHEBI:8869 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0042075 infores:hetionet CHEBI:51041 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0023530 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0031350 infores:hetionet CHEBI:63580 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151744 infores:hetionet CHEBI:4798 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0575081 infores:hetionet CHEBI:44032 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0085593 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0013395 infores:hetionet CHEBI:2904 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0030252 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0426576 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027051 infores:hetionet CAID:CA015125 biolink:causes MONDO:0004994 infores:clingen CAID:CA015125 MONDO:0004994 PMID: Uncertain Significance PM2 BA1, PS3, PM6, PP1, BS1, BS3, BS4, PS4, PS2, BP5, PVS1 The c.457del (p.His153Thrfs*14) variant in MYH7 has been identified in a 6 month old with DCM that also had a second variant in MYH7 (LMM pers comm) as well as 2 cases in the literature without clinical information (Ceyhan-Birsoy 2019 PMID: 30609409; Zimmerman 2010 PMID: 20474083), which is insufficient to apply PS4_Supporting. This variant has been identified in 0.000879% (1/113760) of European (Non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift leading to a truncated or absent protein and the contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood. In summary, due to a lack of evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015125/MONDO:0004994/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9566 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0004936 infores:hetionet NCBIGene:80331 biolink:causes MONDO:0008083 infores:monarchinitiative not_provided not_provided HGNC:16235 MONDO:0008083 uuid:411de738-ce4b-4606-958c-7752b4f4f569 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1142412 infores:hetionet CHEBI:28748 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0001925 infores:hetionet CHEBI:31711 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0232766 infores:hetionet CHEBI:3757 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0003467 infores:hetionet CHEBI:68845 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0085649 infores:hetionet CHEBI:63617 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0030554 infores:hetionet CHEBI:52172 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0237849 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0042109 infores:hetionet NCBIGene:5346 biolink:causes MONDO:0013478 infores:monarchinitiative not_provided not_provided HGNC:9076 MONDO:0013478 uuid:7dbe473f-3cda-4446-a7e9-701596d713c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:788 biolink:causes MONDO:0008918 infores:monarchinitiative not_provided not_provided HGNC:1421 MONDO:0008918 uuid:e9bbf05d-b759-49b5-ac04-b60c94934bdf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9130 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0021053 infores:hetionet CHEBI:3752 biolink:causes NCIT:C78514 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0152149 infores:hetionet NCBIGene:6716 biolink:causes MONDO:0009923 infores:monarchinitiative not_provided not_provided HGNC:11285 MONDO:0009923 uuid:ed2818eb-f28e-4e36-bb71-bfcb3fa8fae8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1585 biolink:causes MONDO:0008751 infores:monarchinitiative not_provided not_provided HGNC:2592 MONDO:0008751 uuid:074eb40b-b8ab-4c67-82b6-8bff42c59e75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085593 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0152227 infores:hetionet CHEBI:9725 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0235660 infores:hetionet CHEBI:5138 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027849 infores:hetionet CHEBI:119915 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0002962 infores:hetionet CHEBI:9139 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014518 infores:hetionet CHEBI:3219 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151611 infores:hetionet CHEBI:27899 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0270612 infores:hetionet CHEBI:8713 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0030252 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0009806 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0001339 infores:hetionet CHEBI:3504 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0006277 infores:hetionet CHEBI:478164 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0595916 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0427008 infores:hetionet CHEBI:184555 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0017152 infores:hetionet CHEBI:135939 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0001807 infores:hetionet CHEBI:63581 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020433 infores:hetionet CHEBI:10125 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0152198 infores:hetionet CHEBI:5790 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0549249 infores:hetionet UNII:Z5N076G8YQ biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0178298 infores:hetionet CHEBI:6792 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0037763 infores:hetionet CHEBI:8888 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0025323 infores:hetionet CHEBI:17474 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0041834 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0033975 infores:hetionet NCBIGene:150274 biolink:causes MONDO:0030436 infores:monarchinitiative not_provided not_provided HGNC:28913 MONDO:0030436 uuid:da08c99f-a7a2-46d4-9c73-0ffc5d718bac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65173 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0086769 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0004936 infores:hetionet CAID:CA294896504 biolink:causes MONDO:0009290 infores:clingen CAID:CA294896504 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000152.5:c.1880C>T variant in GAA is a missense variant predicted to result in substitution of serine by phenylalanine at amino acid 627 (p.Ser627Phe). This variant has been reported in at least three individuals with features consistent with Pompe disease, documented with deficient GAA activity- one within <10% of normal mean in leukocytes (PMID: 29044175) and two individuals with GAA activity below reference range in muscle (PMID:28763149) (PP4_Moderate). Two of these individuals are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, phase known, including c.525delT (ClinVar # VCV000004033.83) (1 points) , c.-32-13T>G (ClinVar # VCV000004027.118) (PMID 28763149) (1 points) (Total 2 points, PM3_strong). In addition, both individuals are heterozygous for c.1642G>T(p.Val548Phe) (ClinVar # VCV000597381.2), which has been classified as likely benign by the ClinGen LD VCEP. In addition, a patient with infantile onset Pompe disease is documented with c.1880C>T (p.Ser627Phe), but no second variant was reported (PMID:29044175). Expression of the variant in HEK293 cells demonstrated loss of GAA activity, and the western blot showed only the 110kDa precursor band suggesting abnormal GAA processing () (PS3_moderate). The computational predictor REVEL gives a score of 0.802 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The variant is absent in gnomAD v4.1.0.(PM2_Supporting). There is a ClinVar entry for this variant (Variant ID:597382). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_strong, PS3_moderate, PP4_moderate, PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, June 3, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294896504/MONDO:0009290/010 2025-06-03 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:45863 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0001418 infores:hetionet CAID:CA386965420 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965420 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 The c.707G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to tyrosine at codon 236 (p.(Cys236Tyr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). In summary, c.707G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965420/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4466 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C2830004 infores:hetionet CHEBI:6538 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0030252 infores:hetionet CHEBI:8871 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085631 infores:hetionet CHEBI:94609 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019209 infores:hetionet CHEBI:2682 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1145670 infores:hetionet GO:1990215 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:1990215 GO:0016192 CHEBI:52717 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2047937 infores:hetionet CHEBI:101278 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151205 infores:hetionet CHEBI:15765 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0042029 infores:hetionet CHEBI:72564 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0231218 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0003123 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0020517 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004239 infores:hetionet CHEBI:45409 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011606 infores:hetionet CHEBI:5790 biolink:causes MONDO:0015129 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0001403 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0004096 infores:hetionet CHEBI:28830 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0027947 infores:hetionet CAID:CA376065993 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065993 MONDO:0011225 PMID: Uncertain Significance PP4, PM2_Supporting, PM3 PP1, PM5 The c.41T>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 14 (p.Ile14Thr).This variant is absent from gnomAD v4 (PM2_Supporting). There is one patient described on ClinVar from Invitae. The patient present: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + SCID gene panel or exome/genome sequencing conducted 0.5pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total 1.5 pts, PP4.Also, the proband is compound heterozygous with c.671del (p.Gly224Glufs*), at least Likely Pathogenic according to SCID VCEP specifications at least. The phase is confirmed = 1 pt = PM3.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4, and PM3. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065993/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9073 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0036974 infores:hetionet CHEBI:28925 biolink:causes MONDO:0021386 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0025063 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151888 infores:hetionet CHEBI:68647 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0017178 infores:hetionet GO:0035495 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:0035495 GO:0016192 NCBIGene:57222 biolink:causes MONDO:0008823 infores:monarchinitiative not_provided not_provided HGNC:29205 MONDO:0008823 uuid:5dc035d5-a9a4-4a8b-8e7b-25dc78a86157 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0019079 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0403632 infores:hetionet CHEBI:50922 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013144 infores:hetionet CHEBI:40237 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0035243 infores:hetionet CHEBI:6931 biolink:causes MONDO:0003040 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0002624 infores:hetionet CHEBI:6759 biolink:causes UMLS:C0456677 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0456677 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0233472 infores:hetionet CHEBI:63630 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013378 infores:hetionet CHEBI:4975 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0151904 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0037274 infores:hetionet CHEBI:59445 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0232487 infores:hetionet CHEBI:36791 biolink:causes MONDO:0015486 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022578 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0037274 infores:hetionet CHEBI:408174 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0392525 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002170 infores:hetionet CHEBI:6931 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0262662 infores:hetionet CHEBI:3347 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0027947 infores:hetionet CHEBI:46195 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0041105 infores:hetionet CHEBI:50275 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0036974 infores:hetionet CHEBI:9150 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0231218 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0877046 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0034530 infores:hetionet CHEBI:553473 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0239113 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0006277 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0233632 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0033975 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0027765 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003864 infores:hetionet CHEBI:4779 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0004095 infores:hetionet CHEBI:64312 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0043094 infores:hetionet CHEBI:46195 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C1096035 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0028738 infores:hetionet CHEBI:6339 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0041834 infores:hetionet CHEBI:47612 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0039520 infores:hetionet CHEBI:50381 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0575081 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0853348 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0042109 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033860 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019112 infores:hetionet CHEBI:49375 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0011168 infores:hetionet CHEBI:5118 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0000737 infores:hetionet CHEBI:46295 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0042963 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0178298 infores:hetionet CHEBI:3223 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C2242996 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020649 infores:hetionet CHEBI:10119 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0025222 infores:hetionet CHEBI:3696 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020625 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0008325 infores:hetionet CHEBI:27432 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0015230 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0032285 infores:hetionet CHEBI:3749 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0004093 infores:hetionet CHEBI:2950 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0013595 infores:hetionet CHEBI:77733 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0235996 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151763 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0948594 infores:hetionet CHEBI:63619 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017565 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0877072 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0877072 infores:hetionet CHEBI:6456 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0027497 infores:hetionet CAID:CA120605 biolink:causes MONDO:0044970 infores:clingen CAID:CA120605 MONDO:0044970 PMID:10486321 Uncertain Significance PP3, PM6_Supporting, PS3_Supporting, PM2 BA1, PS4, BS1 The m.7671T>A (p.M29K) variant in MT-CO2 has been reported in two unrelated individuals with primary mitochondrial disease to date. The first individual was a 14 year old male with proximal myopathy, lactic acidosis, and a five year history of muscle weakness and fatigue. Skeletal muscle biopsies revealed severe COX deficiency, increased SDH staining, and absence of ragged red fibers. Variant heteroplasmy was 90% in muscle and 4.5% - 6% in blood. The second individual was a 48 year old male of European ancestry with mitochondrial myopathy characterized by progressive weakness. Serum creatine kinase levels were elevated and muscle biopsy revealed scattered COX-negative fibers with increased SDH staining. This variant was observed at 52% heteroplasmy, presumably in the muscle sample (PMID: 32800583). Haplogroup information was not reported for both cases precluding consideration for PS4. This variant occurred de novo in one individual (absent in blood from mother; PM6_supporting, PMID: 10486321). Single fiber testing showed higher levels of the variant in COX negative fibers (81%, n=13) than in COX positive fibers (45%, n=4), p<0.01 (PS3_supporting, PMID: 10486321). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.90 and 0.942, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120605/MONDO:0044970/015 2023-11-28 2024-11-26 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:31536 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151905 infores:hetionet CHEBI:4995 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002878 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0267792 infores:hetionet CHEBI:28915 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0042963 infores:hetionet CHEBI:51041 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0036974 infores:hetionet CHEBI:5001 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0030193 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0021359 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0011570 infores:hetionet CHEBI:7494 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0040822 infores:hetionet CAID:CA6832205 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832205 MONDO:0015967 PMID: Benign BS1, BS2, PP4 PS3, PS4, PP1 The c.1849G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to isoleucine at codon 617 (p.(Val617Ile)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003429, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). This variant also was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (internal lab contributors) (BS2). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold, and PM2_Supporting is not met (PMID: 12488962, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 12488962). Transactivation activity (COS-7 cells) was 63% of wildtype, which was between ClinGen MDEP thresholds for PS3_Supporting and BS3_Supporting (PMID: 12488962). In summary, c.1849G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BS1, BS2, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832205/MONDO:0015967/017 2022-05-02 2022-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68606 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0027765 infores:hetionet CHEBI:4672 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0030193 infores:hetionet CHEBI:55346 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0011603 infores:hetionet CHEBI:6792 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0013604 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085096 infores:hetionet CHEBI:45599 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0038999 infores:hetionet CHEBI:8713 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0030305 infores:hetionet CHEBI:2914 biolink:causes MONDO:0006009 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0243010 infores:hetionet CHEBI:31859 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C3665347 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151849 infores:hetionet CHEBI:63619 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0009421 infores:hetionet GO:0106288 biolink:causes GO:0000288 infores:ubergraph knowledge_assertion manual_agent GO:0106288 GO:0000288 CHEBI:45599 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0243026 infores:hetionet CHEBI:17303 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0030193 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011551 infores:hetionet CAID:CA8622881 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622881 MONDO:0100326 PMID: Uncertain Significance BP7, PP4_Moderate, PM2_Supporting, PM3_Supporting The ITGB3 intronic variant NM_000212.3:c.166-14C>A is not predicted by in silico tools to have an impact on splicing and is not highly conserved (BP7). This variant has been observed in homozygosity (PM3_supporting) in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT03, PMID: 16463284). All requirements for PP4_Moderate are met (GT03 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is rare in population databases (1/91018 alleles in the South Asian population in gnomAD v4.1.0; PM2_Supporting). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PP4_Moderate, PM2_Supporting, PM3_Supporting, and BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622881/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:3515 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151849 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0000833 infores:hetionet CAID:CA512341323 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341323 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1077G>C (p.Pro359=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.88) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341323/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0072034 biolink:causes GO:0072087 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0072087 CHEBI:6375 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0600142 infores:hetionet CHEBI:7454 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0428977 infores:hetionet CHEBI:7577 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0232292 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235639 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0041912 infores:hetionet CHEBI:52717 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030196 infores:hetionet CHEBI:5118 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015402 infores:hetionet CHEBI:6717 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0009676 infores:hetionet NCBIGene:170689 biolink:causes MONDO:0957819 infores:monarchinitiative not_provided not_provided HGNC:16305 MONDO:0957819 uuid:01824f2a-9594-4540-a6f4-ecefe4d7100e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0425945 infores:hetionet GO:1903216 biolink:causes GO:0006626 infores:ubergraph knowledge_assertion manual_agent GO:1903216 GO:0006626 CHEBI:391960 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0314719 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0424813 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0424813 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0235901 infores:hetionet GO:1900011 biolink:causes GO:0032870 infores:ubergraph knowledge_assertion manual_agent GO:1900011 GO:0032870 GO:0003339 biolink:causes GO:0072273 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0072273 CHEBI:50859 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0015967 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0041912 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0276680 infores:hetionet CAID:CA010281 biolink:causes MONDO:0005045 infores:clingen CAID:CA010281 MONDO:0005045 PMID: Uncertain Significance PM2, PM1 PP2, PP4, BS2, PM3, PM5, PM6, PM4, PP3, PP1, PS3, BA1, BP1, BP3, BS1, BS3, BS4, PS1, PS2, PS4, BP4, BP5, BP2, PVS1 The c.1148A>G (p.Lys383Arg) variant in MYH7 has been reported in at least 1 individual with HCM (Gruner 2011 PMID: 21511876; Walsh 2017 PMID:27532257); however due to potential overlap in the individuals reported, PS4_Supporting criteria is not met. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficience evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010281/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3699 biolink:causes HP:0001395 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0239946 infores:hetionet CHEBI:5138 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019825 infores:hetionet CHEBI:724125 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0271051 infores:hetionet CHEBI:5138 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0242422 infores:hetionet CHEBI:8356 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018932 infores:hetionet CHEBI:36795 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013378 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0521991 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0521991 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027051 infores:hetionet CHEBI:4710 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0038363 infores:hetionet CHEBI:6437 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0344232 infores:hetionet CHEBI:9398 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0030554 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014742 infores:hetionet CHEBI:17650 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0030486 infores:hetionet CHEBI:8382 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0231528 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0012833 infores:hetionet CHEBI:45924 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0020461 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0019163 infores:hetionet CHEBI:6690 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0241934 infores:hetionet CHEBI:15940 biolink:causes MONDO:0006566 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0022593 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0006145 infores:hetionet NCBIGene:28952 biolink:causes MONDO:0010499 infores:monarchinitiative not_provided not_provided HGNC:28909 MONDO:0010499 uuid:973bf75a-00fd-4c27-908a-66d5ba5a82eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042401 infores:hetionet CHEBI:9587 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0038999 infores:hetionet CHEBI:8069 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0022107 infores:hetionet CHEBI:17650 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0003708 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013395 infores:hetionet CHEBI:9139 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C3665386 infores:hetionet CHEBI:8356 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085593 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0149904 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0001824 infores:hetionet CHEBI:53766 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0025323 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0008035 infores:hetionet CHEBI:3698 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0027497 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0344315 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0037274 infores:hetionet CHEBI:82941 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0033774 infores:hetionet CHEBI:84500 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0554976 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0041912 infores:hetionet CHEBI:63580 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235896 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235146 infores:hetionet CHEBI:45599 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0151539 infores:hetionet NCBIGene:2783 biolink:causes MONDO:0859173 infores:monarchinitiative not_provided not_provided HGNC:4398 MONDO:0859173 uuid:a565f4c4-8888-4aa5-b13f-daa6c569cf6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9150 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0022346 infores:hetionet UMLS:C0010592 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0231218 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0035328 infores:hetionet CHEBI:135920 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0004093 infores:hetionet CHEBI:16335 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0018681 infores:hetionet CHEBI:50648 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0702166 infores:hetionet CHEBI:4814 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0017979 infores:hetionet CHEBI:27958 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0026961 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0028077 infores:hetionet CHEBI:3219 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011168 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0033975 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0243026 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0037274 infores:hetionet CHEBI:2904 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0235996 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151763 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017601 infores:hetionet GO:0106396 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0048699 CHEBI:5118 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0008350 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0037822 infores:hetionet GO:0030855 biolink:causes CL:0000066 infores:ubergraph knowledge_assertion manual_agent GO:0030855 CL:0000066 CAID:CA415080308 biolink:causes MONDO:0010305 infores:clingen CAID:CA415080308 MONDO:0010305 PMID: Uncertain Significance PS3_Supporting, PP3, PP4, PM2_Supporting The NM_005629.4:c.729G>T variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a tryptophan for cysteine at amino acid 243 (p.Trp243Cys). This variant has been previously reported in one male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in undetectable creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.854 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.2.0): PS3_Supporting, PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on July 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415080308/MONDO:0010305/027 2024-07-11 2025-08-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63611 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026826 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0948595 infores:hetionet CAID:CA645369677 biolink:causes MONDO:0007648 infores:clingen CAID:CA645369677 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1746dup p.(Leu583fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369677/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf UNII:G4PX8C4HKV biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0851578 infores:hetionet CHEBI:100241 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151908 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0000833 infores:hetionet CHEBI:132233 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0022107 infores:hetionet NCBIGene:8456 biolink:causes MONDO:0009451 infores:monarchinitiative not_provided not_provided HGNC:12765 MONDO:0009451 uuid:11d4d969-cda5-4470-b690-0fa775ce6384 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10582757 biolink:causes MONDO:0017623 infores:clingen CAID:CA10582757 MONDO:0017623 PMID:29785012PMID:29706350PMID:21194675PMID:28454995PMID:23335809 Pathogenic PVS1, PM2, PS4_Supporting PM6, BS4, BS3, BS1, BP5, BP7, BS2, PP1, PP3, PP2, PM1, PM5, PM4, BP2, BP4, BA1, PS2, PS1 PTEN c.195C>G (p.Y65X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10582757/MONDO:0017623/003 2019-03-05 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042963 infores:hetionet CHEBI:9671 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0004093 infores:hetionet CHEBI:2788 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0162285 infores:hetionet GO:0035914 biolink:causes CL:0000188 infores:ubergraph knowledge_assertion manual_agent GO:0035914 CL:0000188 CHEBI:3534 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0009319 infores:hetionet CAID:CA410676959 biolink:causes MONDO:0009276 infores:clingen CAID:CA410676959 MONDO:0009276 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3_Moderate, PM3_Supporting PM5 NM_000407.5(GP1BB):c.269C>G (p.Pro90Arg) is a missense variant in GP1BB which has been reported in the literature in at least 1 proband in the homozygous state, BSS-15, an indian woman with mucocutaneous bleeding, normal platelet aggregation with agonists (but absent with ristocetin), and 10% platelet expression of GP1bb on flow cytometry (PMID:21699652; PP4_moderate). Additionally, the variant is absent from gnomAD v4.1 and is predicted to have a deleterious effect (REVEL score of 0.853; PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3_Moderate, PP4_moderate, and PM3_supporting. (VCEP specifications version 1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410676959/MONDO:0009276/082 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68584 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0004936 infores:hetionet CHEBI:46557 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0011168 infores:hetionet CHEBI:48390 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0085612 infores:hetionet CHEBI:6754 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0033774 infores:hetionet CAID:CA132727 biolink:causes MONDO:0010134 infores:clingen CAID:CA132727 MONDO:0010134 PMID:11932316PMID:16570074PMID:10700480PMID:16570074PMID:26969326PMID:10700480PMID:16570074PMID:26969326PMID:10700480PMID:27771369PMID:11932316PMID:16570074PMID:26969326PMID:10700480 Pathogenic PP1_Strong, PP3, PP4, PM3_Very Strong, BS3_Supporting, BA1 BP7, BP5, BS1, BS4, BS2, PP2, PM5, PM4, PM1, PVS1, PM2, PM6, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.349C>T variant in SLC26A4 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 117. The filtering allele frequency of the p.Leu117Phe variant is 0.005208 (54/10368 alleles) for Ashkenazi Jewish chromosomes in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). This variant has been identified in patients with EVA, which is a phenotype that was deemed to be highly specific for SLC26A4 by the ClinGen Hearing Loss Expert Panel (LMM) (PP4). The variant has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional study may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence (BS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VS, PP1_S, PP4, PP3, BS3_P (Hearing Loss VCEP specifications version 2; 11/22/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132727/MONDO:0010134/005 2022-11-22 2023-01-25 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63607 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0031542 infores:hetionet CHEBI:31397 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0013404 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0018799 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020538 infores:hetionet CHEBI:119486 biolink:causes MONDO:0019245 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0023794 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0002871 infores:hetionet CHEBI:71415 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0022354 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0037274 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0003864 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0434437 infores:hetionet CAID:CA255129 biolink:causes MONDO:0010602 infores:clingen CAID:CA255129 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PP3, PP1_Strong, PS4, PS2 PM2 The c.1834C>T (p.Arg612Cys) variant is present in 3 hemizygotes in gnomAD v2.1.1, so PM2_Supporting in not met. The REVEL score of 0.88 which meets PP3 criteria (threshold >0.6). Thirty-two patients were reported with mild-moderate hemophilia A in a single publication and over 100 individuals were identified in the My Life Our Future Cohort, meeting F8 phenotype criteria for PP4_Moderate and PS4_Very strong (PMID: 18691168, 29296726). This variant has been associated with mostly mild, but also moderate and severe, hemophilia A with and without inhibitors to factor replacement therapies. This may be in part because the variant has also been associated with discrepant factor VIII activity levels, with chromogenic assays (two-stage) being 2-fold lower than one stage assays (EAHAD database; PMID: 32232366). The variant has been reported to segregate with hemophilia A in greater than 6 meioses across two families (PP1_Strong; PMID: 9292523). This variant has also been found to have at least one de novo occurrence in the mother of a proband, where the proband was found to have the unaffected maternal grandfather's allele via haplotype analysis (PS2; PMID: 9292523). Additionally, this variant has been reported in patients with and without a history of inhibitors to factor replacement products (EAHAD database). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS2, PS4_Very strong, PP1_Strong, PP3 and PP4_Moderate. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255129/MONDO:0010602/071 2024-06-19 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5050 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0020517 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0151785 infores:hetionet CHEBI:68855 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0162429 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037274 infores:hetionet CAID:CA151518 biolink:causes MONDO:0007648 infores:clingen CAID:CA151518 MONDO:0007648 PMID:9537325PMID:9537325 Benign BS2, BP2_Strong BP5, BP7, BS1, BS4, BS3, PM2, PM6, PVS1, PM3, PM5, PM4, PM1, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BA1, PS1, PS3, PS4, PS2 The c.1409C>T (p.Thr470Ile) variant was observed in trans with a known pathogenic CDH1 variant with phase confirmed (BP2_Strong; PMID: 9537325). This variant was also observed in the homozygous state in at least 6 individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; internal laboratory contributors). Additionally, this variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BP2_Strong, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA151518/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7903 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0206062 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0040034 infores:hetionet CAID:CA222203 biolink:causes MONDO:0015152 infores:clingen CAID:CA222203 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP3, PM2_Supporting PS3 The NM_003494.4: c.6124C>T variant in DYSF, which is also known as NM_001130987.2: c.6241C>T p.(Arg2081Cys), is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2042, p.(Arg2042Cys). This variant has been observed in more than 12 patients with limb girdle muscular dystrophy (PMID: 36983702, 25574751, 22194990, 21522182, 18853459, 17698709, 16100712), including confirmed in trans with a likely pathogenic or pathogenic variant in at least two patients (NM_003494.4: c.331C>T p.(Gln111Ter), 1.0 pt, PMID: 36983702; NM_003494.4: c.5768-1G>C, 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF allele displayed progressive limb girdle muscle weakness and severely reduced dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702). The filtering allele frequency for this variant is 0.000064907 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 58/1112004 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed conflicting results for the Arg2042Cys protein, which was classified as functional by 2-A assay but non-functional by immunofluorescence assay (PMID: 35028538; PS3_Moderate not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222203/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63627 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0016204 infores:hetionet NCBIGene:6935 biolink:causes MONDO:0012200 infores:monarchinitiative not_provided not_provided HGNC:11642 MONDO:0012200 uuid:b18c6d5b-2925-457b-a176-252cc747027f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0017178 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0233494 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0007682 infores:hetionet CHEBI:31236 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0241729 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0021053 infores:hetionet CHEBI:63580 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0022107 infores:hetionet CHEBI:66919 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0014591 infores:hetionet CHEBI:9667 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0006840 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0023798 infores:hetionet CHEBI:9332 biolink:causes MONDO:0019170 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0031036 infores:hetionet CHEBI:75922 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0027497 infores:hetionet CHEBI:4953 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0015672 infores:hetionet CHEBI:2549 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0004134 infores:hetionet CHEBI:6456 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0036974 infores:hetionet CHEBI:44185 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1535939 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0234215 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0019348 infores:hetionet CHEBI:4909 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0151746 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020621 infores:hetionet CHEBI:6792 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0042963 infores:hetionet UMLS:C0120107 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0086565 infores:hetionet UMLS:C0010592 biolink:causes EFO:0010670 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0159056 infores:hetionet CHEBI:6076 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0700225 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0021141 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027339 infores:hetionet CHEBI:53760 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020580 infores:hetionet CHEBI:91541 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C1456784 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014742 infores:hetionet NCBIGene:4624 biolink:causes MONDO:0013567 infores:monarchinitiative not_provided not_provided HGNC:7576 MONDO:0013567 uuid:b4197762-ca54-446b-86b2-81a48666b12a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018021 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0026650 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0036572 infores:hetionet CHEBI:50131 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013456 infores:hetionet UNII:7F465U79Q1 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0031542 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0149904 infores:hetionet CHEBI:31981 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0043352 infores:hetionet CAID:CA2580061383 biolink:causes MONDO:0013144 infores:clingen CAID:CA2580061383 MONDO:0013144 PMID: Uncertain Significance PS3_Supporting, PVS1_Moderate, PM2_Supporting, PS4_Supporting The c.1247dup (p.Ser417LysfsTer?) variant in SERPINC1 is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been reported in at least one family meeting an antithrombin activity level of < 0.8 IU/mL and a family history of the disease with reported antithrombin levels (PS4_Supporting; PMID: 38347553). More affected individuals without the details required for scoring were reported in ClinVar (SCV002520629.1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PVS1_moderate, PM2_supporting, PS4_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580061383/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27565 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0162429 infores:hetionet CHEBI:2469 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0022346 infores:hetionet CHEBI:27504 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0034063 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0006145 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027051 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0595930 infores:hetionet CHEBI:7494 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018520 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0162429 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0027769 infores:hetionet CHEBI:32139 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0013378 infores:hetionet CAID:CA10585105 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585105 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 The NM_000527.5(LDLR):c.727T>C (p.Cys243Arg) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.966PM1 - Variant meets PM2 and alters Cys243, one of the cysteine residues listed.PS4_Supporting - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism and PMID: 28502510.PP4 - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism after alternative cause of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585105/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA376059596 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059596 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.564G>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Aspartic Acid at amino acid 188 (p.Glu188Asp).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059596/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA16614163 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614163 MONDO:0100216 PMID: Uncertain Significance BS2_Supporting PM2, PM6, PVS1, BA1, BP1, BP4, BP3, BP2, PP2, PP3, PP1, PM4, PM3, PM1, PM5, PS2, PS4, PS3, PS1, BS1, BS3, BS4, BP5, BP7 The NM_177438.2:c.5038A>G (p.Lys1680Glu) variant in DICER1 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 1680 (p.Lys1680Glu). The total allele frequency in gnomAD v4.1.0 is 0.000003420 (5/1461878 alleles) with highest population minor allele frequencies of 0.00004967 (3/60396 alleles) and 0.000001799 (2/1111996) in a population of undescribed ancestry and the European (non-Finnish) population, respectively (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.697, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab data). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614163/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8764 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085631 infores:hetionet CHEBI:127780 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0037763 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0853760 infores:hetionet CHEBI:3756 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0278106 infores:hetionet CHEBI:16469 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0024902 infores:hetionet CHEBI:41423 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027796 infores:hetionet NCBIGene:6792 biolink:causes MONDO:0010396 infores:monarchinitiative not_provided not_provided HGNC:11411 MONDO:0010396 uuid:f2e0de80-26e5-4735-841f-786b4ba15d76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:8NZ41MIK1O biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0020473 infores:hetionet CHEBI:6413 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0235886 infores:hetionet CHEBI:48669 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0011991 infores:hetionet CHEBI:63613 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0009782 infores:hetionet GO:0060935 biolink:causes CL:0002548 infores:ubergraph knowledge_assertion manual_agent GO:0060935 CL:0002548 CHEBI:15365 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0042963 infores:hetionet CHEBI:5847 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0003862 infores:hetionet CHEBI:63637 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0014743 infores:hetionet CHEBI:3216 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0235198 infores:hetionet CHEBI:68534 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0041969 infores:hetionet CHEBI:8871 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013144 infores:hetionet CHEBI:28177 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0003467 infores:hetionet CHEBI:3242 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0240557 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0233632 infores:hetionet CHEBI:50275 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0344232 infores:hetionet CHEBI:63617 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0242379 infores:hetionet CHEBI:48844 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0015230 infores:hetionet CHEBI:41423 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011606 infores:hetionet GO:0042665 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:0042665 GO:0007369 CHEBI:5130 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0231530 infores:hetionet CHEBI:63630 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0033575 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011991 infores:hetionet CHEBI:145499 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018965 infores:hetionet CHEBI:4909 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0018524 infores:hetionet CHEBI:50730 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0002792 infores:hetionet CHEBI:116278 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0001925 infores:hetionet CHEBI:64312 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004134 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2973529 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0852733 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0340726 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0267596 infores:hetionet CHEBI:474053 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0022354 infores:hetionet CAID:CA406174565 biolink:causes MONDO:0011229 infores:clingen CAID:CA406174565 MONDO:0011229 PMID: Uncertain Significance PM5, PP3, PP4, BP4, PS1 This variant was classified as a variant of uncertain significance as there has not been sufficient evidence to support either a benign or a pathogenic classification. Specifically, this variant has not been reported in the literature in affected or unaffected patients, has no published functional data, and is not present in population databases to assess allele frequency. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA406174565/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:59560 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0017181 infores:hetionet CHEBI:4672 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0311468 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009760 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001244 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042880 infores:hetionet CAID:CA10586302 biolink:causes MONDO:0100038 infores:clingen CAID:CA10586302 MONDO:0100038 PMID:26900580 Pathogenic PM6, PM2_Supporting, PM5_Strong, PS3, PS4, PP3_Moderate The c.5615G>A variant in SCN8A is a missense variant predicted to cause a subtitution of arginine by glutamine at amino acid 1872 (p.Arg1872Gln). This variant has been reported as de novo in at least 3 individuals with unconfirmed parental relationships (PMIDs: 2664715, 28333917, 28387369) (PM6) and at least an additional 8 individuals without informative segregation data available (PMIDs: 25568300, 29655203, 29930392, 32509551, 34395220, 30968951) (PS4). Multiple other amino acid substitutions at the same amino acid position have been previously reported and meet pathogenic per these criteria (p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu) (PM5). Heterologous expression with voltage clamping assay has shown significant hyperpolarizing shift in voltage dependence of activation and significant depolarizing shift of voltage dependence of fast inactivation (PS3). The variant is rare (1 allele) in the population database, gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM6, PM5, PS3, PM2_Supporting (version 1.0; approved 5/23/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586302/MONDO:0100038/070 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6076 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0853692 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023530 infores:hetionet GO:1904444 biolink:causes GO:0060008 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0060008 CHEBI:77260 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0006266 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0233472 infores:hetionet CHEBI:110423 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0027497 infores:hetionet CHEBI:39867 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0423791 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0032285 infores:hetionet NCBIGene:11152 biolink:causes MONDO:0010476 infores:monarchinitiative not_provided not_provided HGNC:28912 MONDO:0010476 uuid:a528507e-8d51-4320-9e94-d12f5805b8ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6933 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0178298 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0016977 infores:hetionet NCBITaxon:55193 biolink:causes MONDO:0011438 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:55193 MESH:D000152 DB00681_MESH_D000152_1 CHEBI:63623 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0030554 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0005779 infores:hetionet CHEBI:135342 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1145670 infores:hetionet CHEBI:2682 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151576 infores:hetionet CHEBI:5818 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C2830004 infores:hetionet CAID:CA229848 biolink:causes MONDO:0009861 infores:clingen CAID:CA229848 MONDO:0009861 PMID:16601866PMID:9634518PMID:8981952PMID:24401910PMID:24350308PMID:22513348PMID:26666653PMID:26322415PMID:24130151PMID:24048906 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229848/MONDO:0009861/006 2020-02-16 2020-02-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52717 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013404 infores:hetionet CHEBI:6067 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151692 infores:hetionet CHEBI:4027 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151747 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0029408 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0278488 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0278488 infores:hetionet CHEBI:53691 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0233715 infores:hetionet CHEBI:87681 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0549249 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0041912 infores:hetionet NCBITaxon:644 biolink:causes MONDO:0005117 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:644 MONDO:0005117 CHEBI:45924 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0030305 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0086543 infores:hetionet CHEBI:63580 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0021368 infores:hetionet NCBIGene:844 biolink:causes MONDO:0014546 infores:monarchinitiative not_provided not_provided HGNC:1512 MONDO:0014546 uuid:b8331058-ba90-4723-ad9d-dc3cc89d24b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0160390 infores:hetionet CHEBI:131512 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0013144 infores:hetionet CHEBI:584020 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0014457 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0156308 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0156308 infores:hetionet CHEBI:28148 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0027497 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0027765 infores:hetionet CHEBI:167638 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0152031 infores:hetionet CHEBI:3699 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0023530 infores:hetionet NCBIGene:132884 biolink:causes MONDO:0009162 infores:monarchinitiative not_provided not_provided HGNC:19747 MONDO:0009162 uuid:56ea72da-5419-4be4-aee5-3651cd7ad060 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2937358 infores:hetionet CHEBI:68478 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0036689 infores:hetionet CHEBI:6887 biolink:causes HP:0001508 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0231246 infores:hetionet CHEBI:55346 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C1384353 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0042109 infores:hetionet CHEBI:48273 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0011603 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0456909 infores:hetionet CHEBI:74947 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0043352 infores:hetionet GO:2000024 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000024 GO:0007275 CHEBI:167638 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0039070 infores:hetionet CHEBI:7936 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013491 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0038362 infores:hetionet CHEBI:4514 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0232462 infores:hetionet CAID:CA16020771 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020771 MONDO:0009861 PMID:26503515 Pathogenic PVS1, PM2, PP4_Moderate This c.353-2A>G (IVS3-2A>G) variant in PAH was reported in two Chinese patients with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from population databases ExAC and gnomAD. This variant in the -2 splice acceptor site of IVS3 results in exon skipping or use of a cryptic splice site. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PVS1_very strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020771/MONDO:0009861/006 2019-10-18 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports UNII:9430ZR8ZAN biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0162429 infores:hetionet GO:0098694 biolink:causes GO:0048488 infores:ubergraph knowledge_assertion manual_agent GO:0098694 GO:0048488 CHEBI:31236 biolink:causes UMLS:C1141884 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1141884 infores:hetionet CHEBI:73275 biolink:causes UMLS:C1112274 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C1112274 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0006826 infores:hetionet CHEBI:48669 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0232487 infores:hetionet CHEBI:85161 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0041834 infores:hetionet CHEBI:4702 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0024141 infores:hetionet CHEBI:9571 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0011603 infores:hetionet CHEBI:38940 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1384353 infores:hetionet CHEBI:180905 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0020621 infores:hetionet CHEBI:9943 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0043387 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0595877 infores:hetionet CHEBI:31236 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0520888 infores:hetionet CHEBI:8382 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0702166 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034359 infores:hetionet CHEBI:9434 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0002994 infores:hetionet CHEBI:8502 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C2242588 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0029882 infores:hetionet CHEBI:15551 biolink:causes EFO:0020915 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0269842 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0013395 infores:hetionet CHEBI:52717 biolink:causes MONDO:0009691 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026948 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0012833 infores:hetionet CHEBI:50131 biolink:causes HP:0033821 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0149726 infores:hetionet CHEBI:31859 biolink:causes HP:0012088 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0278045 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0242350 infores:hetionet CHEBI:27432 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0162429 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0021400 infores:hetionet CHEBI:63619 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2939147 infores:hetionet GO:1905082 biolink:causes GO:0032543 infores:ubergraph knowledge_assertion manual_agent GO:1905082 GO:0032543 CHEBI:2639 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0003862 infores:hetionet NCBIGene:84138 biolink:causes MONDO:0030936 infores:monarchinitiative not_provided not_provided HGNC:25807 MONDO:0030936 uuid:0c655a20-d8f5-4e7d-b442-4bc0c9335ac0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72564 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0033774 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0023895 infores:hetionet CHEBI:8863 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2697368 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0235969 infores:hetionet CHEBI:5001 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0858635 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040586 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0341177 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0341177 infores:hetionet CHEBI:71219 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0018681 infores:hetionet CHEBI:4315 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0017565 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0013404 infores:hetionet CHEBI:5779 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0010200 infores:hetionet CHEBI:63616 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0021845 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0439857 infores:hetionet CAID:CA404080624 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080624 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP3, BP2, PS3, PS4, PS2, PS1, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, BS2, PP1, PP4 The NM_000527.5(LDLR):c.845T>G (p.Phe282Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.975. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080624/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:35778 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0234369 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0025061 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0011991 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0855642 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0855642 infores:hetionet CHEBI:28593 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0547030 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1565489 infores:hetionet NCBIGene:1795 biolink:causes MONDO:0032661 infores:monarchinitiative not_provided not_provided HGNC:2989 MONDO:0032661 uuid:9db9175c-c17f-46d8-800d-c96eb685bd0c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:553473 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C1257843 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0267792 infores:hetionet CHEBI:52717 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0033774 infores:hetionet CHEBI:18248 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0007097 infores:hetionet CHEBI:8356 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018944 infores:hetionet CHEBI:31623 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0010200 infores:hetionet CHEBI:135930 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0017675 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0151735 infores:hetionet CHEBI:4511 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C2047937 infores:hetionet CHEBI:135005 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020443 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0009806 infores:hetionet CHEBI:18258 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0027051 infores:hetionet CHEBI:64019 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0017178 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0002170 infores:hetionet CHEBI:3223 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0041834 infores:hetionet UMLS:C0120107 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0015672 infores:hetionet CHEBI:6076 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0600142 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1384666 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0003123 infores:hetionet CHEBI:72296 biolink:causes HP:0040242 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151702 infores:hetionet CHEBI:7465 biolink:causes NCIT:C74591 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0234925 infores:hetionet NCBIGene:23483 biolink:causes MONDO:0014507 infores:monarchinitiative not_provided not_provided HGNC:20324 MONDO:0014507 uuid:7fb7a763-09a7-4e2c-ad44-fb75b943ba7a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0600142 infores:hetionet CAID:CA000505 biolink:causes MONDO:0018875 infores:clingen CAID:CA000505 MONDO:0018875 PMID: Benign BP4, BS1, BS3, BS2 BP3, BA1, PS3, PS1, PS4, PS2, PM5, PM4, PM1, BS4, BP7, PM2, PVS1, PP3, PP1, PP4 The NM_000546.6 :c.935C>G variant in TP53 is a missense variant predicted to cause substitution of threonine by serine at amino acid 312 (p.Thr312Ser). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000261663, SCV000184232). The filtering allele frequency is 0.0003446 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0123; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS1, BS3, BP4_moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000505/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA512318693 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318693 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PVS1, PM6, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 Evidence Summary: NM_001754.5(RUNX1):c.509-18T>C is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-2.6)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318693/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:134991 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235901 infores:hetionet CHEBI:47898 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0037299 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0017574 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0853149 infores:hetionet NCBIGene:5660 biolink:causes MONDO:0012720 infores:monarchinitiative not_provided not_provided HGNC:9498 MONDO:0012720 uuid:29add403-ce19-440e-bee9-a23f9f74ef9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0021167 infores:hetionet CHEBI:7852 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C3495920 infores:hetionet CHEBI:15366 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB03166 UMLS:C0018965 infores:hetionet CAID:CA10647973 biolink:causes MONDO:0007648 infores:clingen CAID:CA10647973 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM5, PM4, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.*54C>T variant has an allele frequency of 0.18763 (18.76%, 1629/8682 alleles, 147 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10647973/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:41977 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0700590 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0020538 infores:hetionet CAID:CA168422 biolink:causes MONDO:0007648 infores:clingen CAID:CA168422 MONDO:0007648 PMID:31642931PMID:26123647 Benign BS3, BS2, BP2_Strong BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM1, PM3, PM5, PM4, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BA1, PS4, PS3, PS2, PS1 The c.387+5G>A variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329224.7, SCV000288482.5, SCV000186607.5). This variant was also observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; SCV000288482.5). RNA studies demonstrated no abnormal splicing (BS3; PMID: 31642931). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BS3, BP2_Strong. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA168422/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63624 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0027121 infores:hetionet CHEBI:9654 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1096250 infores:hetionet CAID:CA229771 biolink:causes MONDO:0009861 infores:clingen CAID:CA229771 MONDO:0009861 PMID:16256386PMID:19915519PMID:16256386 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The c.801G>C (p.Gln267His) variant in PAH has been reported in 1 Chinese patient with classical PKU. BH4 deficiencies were not assessed. PMID: 16256386, 19915519. It was detected with a known pathogenic variant p.R252Q. PMID: 16256386. It is absent from population databases. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.952. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229771/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135876 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C2364111 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011570 infores:hetionet CHEBI:167638 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0024141 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0017658 infores:hetionet CHEBI:2453 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0023380 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004936 infores:hetionet CHEBI:6375 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0438142 infores:hetionet CHEBI:6775 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C2242737 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0037199 infores:hetionet CHEBI:7575 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0030252 infores:hetionet CHEBI:10125 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042345 infores:hetionet CHEBI:40303 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0002994 infores:hetionet CHEBI:36791 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0221170 infores:hetionet CHEBI:48273 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0014724 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0267792 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0268105 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0268105 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0920108 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0920108 infores:hetionet CAID:CA119132 biolink:causes MONDO:0800406 infores:clingen CAID:CA119132 MONDO:0800406 PMID: Pathogenic PP1_Strong, PS3_Supporting, PP3, PP4, PM3_Very Strong, PS4 BS1, PM2, PS2 The NM_000350.3:c.5882G>A variant in ABCA4 is a missense variant predicted to cause substitution of glycine by glutamine at amino acid 1961 (p.Gly1961Glu). The computational predictor REVEL gives a score of 0.76, which is in the range of 0.644-0.772, evidence that predicts a damaging effect on ABCA4 function (PP3). This variant has been detected in hundreds of individuals with Stargardt disease (PMIDs: 29925512, 33909047). At least seven individuals were homozygous for the variant and at least three were compound heterozygous for the variant and another pathogenic variant in ABCA4, as confirmed in trans by parental testing (PMIDs: 25922843, 33909047; PM3_Very Strong). At least one patient with this variant displayed presence of at least two ABCA4 variants, onset under 18 years of age, macular flecks on imaging, macular atrophy, central scotoma, choriocapillaris atrophy, and severely reduced visual acuity, which is highly specific for ABCA4-related retinopathy (PMID: 22661473; PP4). The variant has been reported to segregate with ABCA4-related retinopathy in affected individuals across at least six families. (PMIDs: 16896346, 19217903, 23769331, 31318848; PP1_Strong). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The odds ratio is 27.8 and the confidence interval is 24.81 to 31.13, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PMID: 35120629; PS4). Measurement of ATPase activity in ABCA4 mutant transfected HEK293 cells showed G1961E exhibiting a reduced basal ATPase activity when inhibited by retinal, an indication of this variant’s impact on protein function (PMID: 11017087; PS3_Supporting). Of note, this variant appears to be associated with a milder phenotype and may have no phenotype if inherited in a homozygous state with no other pathogenic ABCA4 variants (PMID: 38602673). In summary, this variant meets the criteria to be classified as Pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (v.1.0.0): PM3_Very Strong, PP1_Strong, PS4, PP3, PP4, PS3_Supporting. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA119132/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Supports CAID:CA367401662 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401662 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PP4, PM2_Supporting PS4 The c.530A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glycine at codon 177 (p.(Glu177Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Another variant at this same amino acid position, c.531A>T (p.Glu177Asp), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.530A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401662/MONDO:0015967/086 2024-11-16 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:51230 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0005741 infores:hetionet CHEBI:17650 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0002994 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0700184 infores:hetionet CHEBI:167309 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0031542 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0010399 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019372 infores:hetionet CHEBI:45367 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0235996 infores:hetionet CHEBI:16755 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002962 infores:hetionet CHEBI:51041 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002994 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0034150 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0857305 infores:hetionet CHEBI:10650 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2242996 infores:hetionet CHEBI:63613 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0014743 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0040034 infores:hetionet CHEBI:9943 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0451641 infores:hetionet CHEBI:59582 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0152459 infores:hetionet CAID:CA10014524 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014524 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, BS3_Supporting, PS4_Supporting, PP3, PP1 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS1, BS4, PM5, PM4, PM3, PP2, PP4, BS2 The NM_001754.5(RUNX1):c.367G>C (p.Asp123His) is a missense variant. Transactivation assays demonstrating normal transactivation (80-115% of wt) (BS3_Supporting; PMID: 35026845). This variant was found to co-segregate with disease in multiple affected family members, with three or four (4) meioses observed in one family (PP1; PMID: 18723428). This missense variant has a REVEL score ≥ 0.88 (0.943) (PP3). This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 18723428, 35026845). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, PP1, PP3, PM1_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014524/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5134 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0037274 infores:hetionet CHEBI:2637 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0015967 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151734 infores:hetionet CHEBI:27446 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0023052 infores:hetionet CHEBI:36704 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C3263723 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0948610 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948610 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0085096 infores:hetionet CHEBI:10650 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0233715 infores:hetionet NCBIGene:220074 biolink:causes MONDO:0012670 infores:monarchinitiative not_provided not_provided HGNC:25033 MONDO:0012670 uuid:40013e6a-3b0e-46ea-b318-30af355c6a50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0235996 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0919980 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0009763 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014868 infores:hetionet CHEBI:6897 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0233494 infores:hetionet CHEBI:63584 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C2363731 infores:hetionet CHEBI:474180 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0086565 infores:hetionet CHEBI:63610 biolink:causes MONDO:0850046 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013927 infores:hetionet CHEBI:42797 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020453 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0009319 infores:hetionet CHEBI:27732 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0039231 infores:hetionet CHEBI:7931 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C1443060 infores:hetionet CHEBI:8890 biolink:causes HP:0025116 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0015930 infores:hetionet CHEBI:3084 biolink:causes UMLS:C0232693 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0232693 infores:hetionet CHEBI:53760 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0404521 infores:hetionet CHEBI:119915 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231837 infores:hetionet CHEBI:5118 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C3263723 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0948594 infores:hetionet UMLS:C0037663 biolink:causes MONDO:0019933 infores:drugmechdb knowledge_assertion manual_agent MESH:D013006 MESH:D000172 DB00589_MESH_D000172_1 CHEBI:31547 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0042029 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0009319 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0011168 infores:hetionet GO:0002908 biolink:causes GO:0002451 infores:ubergraph knowledge_assertion manual_agent GO:0002908 GO:0002451 CHEBI:63630 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0028734 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0020517 infores:hetionet CHEBI:4868 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0002170 infores:hetionet CHEBI:135530 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0013378 infores:hetionet CHEBI:63925 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0037274 infores:hetionet CHEBI:7936 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0522178 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0029134 infores:hetionet CHEBI:3207 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0235592 infores:hetionet CHEBI:5383 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0235546 infores:hetionet CHEBI:3478 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C1609512 infores:hetionet CHEBI:9943 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042023 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023510 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0042109 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0037274 infores:hetionet CHEBI:8435 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0026205 infores:hetionet NCBIGene:1540 biolink:causes MONDO:0030872 infores:monarchinitiative not_provided not_provided HGNC:2584 MONDO:0030872 uuid:1bf9e5eb-82c2-4fc1-8937-1c72f44712c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0090169 biolink:causes GO:0007059 infores:ubergraph knowledge_assertion manual_agent GO:0090169 GO:0007059 UMLS:C0120107 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0028866 infores:hetionet CHEBI:28748 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1262036 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0042109 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0549373 infores:hetionet CHEBI:6904 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0036974 infores:hetionet CHEBI:68478 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2239176 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0003044 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003044 infores:hetionet CHEBI:4356 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0042075 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0032285 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0221706 infores:hetionet CHEBI:46295 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0014591 infores:hetionet CHEBI:6532 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0232488 infores:hetionet CAID:CA2580617569 biolink:causes MONDO:0010305 infores:clingen CAID:CA2580617569 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.1324del (p.Gln442LysfsTer21) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported a female with intellectual disability, language delays, epilepsy, increased urinary creatine/creatininie ratio and increase plasma creatine level. (PMID: 29478817) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on February 22, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580617569/MONDO:0010305/027 2024-02-22 2024-03-29 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:6367 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0917801 infores:hetionet CHEBI:17474 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1140680 infores:hetionet CHEBI:42944 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C1368065 infores:hetionet CHEBI:4702 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0242429 infores:hetionet CHEBI:46557 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0476280 infores:hetionet GO:2000702 biolink:causes GO:0072080 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0072080 CAID:CA1908888 biolink:causes MONDO:0018958 infores:clingen CAID:CA1908888 MONDO:0018958 PMID: Likely Benign BP4, BP7, BS1 BA1, PM2, PP3 The c.11067C>T is a synonymous (silent) variant (p.Asn3689=) that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0006878 (922/1461502 alleles, 2 homozygotes) in the non-Finnish European population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF ≥ 0.000237) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive congenital myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathy VCEP: BS1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1908888/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63617 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0036508 infores:hetionet CHEBI:15940 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0019079 infores:hetionet CHEBI:2453 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0011175 infores:hetionet CHEBI:15367 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0234233 infores:hetionet CHEBI:64355 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020473 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0020538 infores:hetionet CHEBI:78543 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0013404 infores:hetionet CHEBI:63638 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0014742 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0016382 infores:hetionet CHEBI:84500 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1510410 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0020517 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0015230 infores:hetionet CHEBI:63632 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0010200 infores:hetionet CHEBI:50131 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0239739 infores:hetionet NCBIGene:31 biolink:causes MONDO:0013493 infores:monarchinitiative not_provided not_provided HGNC:84 MONDO:0013493 uuid:41064c99-be26-45ee-9248-3594d7632048 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002874 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0006826 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0003467 infores:hetionet CAID:CA410147476 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147476 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1295G>A (p.Cys432Tyr) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147476/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17688 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0264267 infores:hetionet CHEBI:17987 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0237849 infores:hetionet CHEBI:8863 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0853034 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0232492 infores:hetionet CAID:CA023757 biolink:causes MONDO:0007750 infores:clingen CAID:CA023757 MONDO:0007750 PMID: Uncertain Significance BA1, BP3, BP1, BP4, BP2, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM2, PM6, PP1, PP2, PP3, PP4, BS2 The NM_000527.5(LDLR):c.757C>T (p.Arg253Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (no codes were applied) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023757/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10110 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0020433 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0006266 infores:hetionet CHEBI:71023 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0235267 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0242350 infores:hetionet CHEBI:584020 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0235886 infores:hetionet CHEBI:6916 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0018834 infores:hetionet CHEBI:66876 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0027497 infores:hetionet CHEBI:134990 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0000737 infores:hetionet CHEBI:94440 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0235660 infores:hetionet CHEBI:28487 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0003811 infores:hetionet CAID:CA229559 biolink:causes MONDO:0009861 infores:clingen CAID:CA229559 MONDO:0009861 PMID:9634518PMID:18937047PMID:18937047PMID:26210745PMID:24401910PMID:18937047PMID:23932990 Pathogenic PM2, PP4_Moderate, PP1, PP3, PM3_Strong PS3 The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID: 9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID: 23932990), R111X (PMID: 24401910), IVS4+5G>T c.441+5G>T (PMID: 26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID: 18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229559/MONDO:0009861/006 2019-04-07 2019-04-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3215 biolink:causes UMLS:C1262109 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1262109 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0233472 infores:hetionet CHEBI:46195 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0232487 infores:hetionet CHEBI:85161 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0002170 infores:hetionet CHEBI:84500 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0151934 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0001187 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0001187 uuid:69067528-17b2-4c6f-aee2-1b67ca6ef45a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5103 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0085631 infores:hetionet CAID:CA400021997 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021997 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PP4 The NM_000212.3(ITGB3):c.445T>C (p.Ser149Pro) missense variant has been reported in at least one homozygous patient (PMID:15590407) who displayed mucocutaneous bleeding and impaired aggregation with ADP and collagen but aggregation was not reported for ristocetin. Additionally, flow cytometric analysis showed the presence of normal levels of αIIbβ3 on the patient's platelet surface and the fibrinogen binding study on activated platelets showed normal levels of fibrinogen binding, as such this patient was not considered a confirmed case of Glanzmann thrombasthenia. The variant was not found in gnomAD v4.1 (PM2_supporting). In Silico predictor REVEL gives a score of 0.985, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance, due to insufficient, for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PM2_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021997/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:68556 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0012833 infores:hetionet CHEBI:3534 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0003862 infores:hetionet CHEBI:33325 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0015967 infores:hetionet CHEBI:3614 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0234233 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0919823 infores:hetionet CHEBI:6888 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0019209 infores:hetionet CHEBI:135939 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0017178 infores:hetionet CHEBI:6413 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0236075 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0234192 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0403632 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0267792 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151602 infores:hetionet CAID:CA414443541 biolink:causes MONDO:0010604 infores:clingen CAID:CA414443541 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PP3, PS2_Very Strong PM1 The c.803G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 268 (p.Cys268Tyr). This variant has been previously reported in 4 patients with severe FIX deficiency, including at least 2 probands with de novo occurrence (maternity and paternity confirmed in a carrier female/maternity confirmed in an affected male) (PMID: 30648777; PMID: 30210749; PMID: 34590426), meeting PS4 and PS2_Very strong. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3.1/ gnomAD v4.1.0), meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.989, which is above the threshold of 0.6, evidence that correlates with impact to F9 function, meeting PP3. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS2_Very Strong, PS4, PM2_Supporting, PP3. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414443541/MONDO:0010604/080 2025-10-03 2025-10-07 X-linked inheritance HP:0001417 Supports CAID:CA512318787 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318787 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.363A>G (p.Leu121=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.161) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318787/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0903898 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0235996 infores:hetionet CAID:CA386959501 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959501 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PP3, PP1 PS3, PP4 The c.397G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 133 (p.(Val133Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.974, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v4.1.0 (PM2_Supporting), and was identified in at least five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 10754480, PMID 21170474, PMID 17573900, internal lab contributors). Due to lack of individual level data and/or lack of testing for HNF4A, PP4 could not be applied to any of these cases. This variant segregated with diabetes, with three informative meioses in one family (PP1; PMID 10754480). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 21170474). In summary, the c.397G>A variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PS4_Moderate, PP1, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959501/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports UNII:R43D2573WO biolink:causes MONDO:0005030 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0015934 infores:hetionet CHEBI:63608 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0002878 infores:hetionet CHEBI:63619 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0149745 infores:hetionet CHEBI:4779 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0423153 infores:hetionet CHEBI:9570 biolink:causes MONDO:0006026 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0005686 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1384666 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0221714 infores:hetionet CHEBI:9139 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C3665347 infores:hetionet UNII:3U02EL437C biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0004604 infores:hetionet CHEBI:92998 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1258215 infores:hetionet CHEBI:9434 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0595929 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0037274 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0227791 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0037199 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0010709 infores:hetionet UMLS:C0657912 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020672 infores:hetionet CHEBI:9635 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0040822 infores:hetionet CHEBI:6402 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0085605 infores:hetionet CHEBI:29013 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0027080 infores:hetionet CHEBI:6129 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0221776 infores:hetionet CHEBI:7478 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0162529 infores:hetionet CHEBI:17823 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0015230 infores:hetionet CHEBI:7824 biolink:causes HP:0100507 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0016412 infores:hetionet CHEBI:9757 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C2830004 infores:hetionet CAID:CA410204234 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204234 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.125C>A (p.Pro42Gln) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204234/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68478 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0948586 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0020457 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020457 infores:hetionet CHEBI:29013 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C2129214 infores:hetionet CHEBI:9139 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0041657 infores:hetionet CHEBI:28915 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0151904 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0011991 infores:hetionet CHEBI:135622 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06771 UMLS:C0018681 infores:hetionet CHEBI:135005 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0018965 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007642 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0009443 infores:hetionet CHEBI:39867 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013491 infores:hetionet CHEBI:2038 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0035455 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0026946 infores:hetionet CHEBI:5130 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0221345 infores:hetionet CHEBI:27882 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0024523 infores:hetionet CHEBI:50777 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0232461 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0152128 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0021308 infores:hetionet CHEBI:114785 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0014591 infores:hetionet CHEBI:6775 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0237849 infores:hetionet CHEBI:3312 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0033774 infores:hetionet CHEBI:63629 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018524 infores:hetionet CHEBI:7627 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0025323 infores:hetionet CAID:CA024169 biolink:causes MONDO:0007783 infores:clingen CAID:CA024169 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Methionine with Valine at codon 485 of the RYR1 protein, p.(Met485Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00061, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with central core disease and other myopathies inherited in a recessive pattern. No functional studies were identified for this variant that fulfilled the criteria for functional data as put forth by the ClinGen RYR1 VCEP for MHS (one study tested this variant in myotubes in the presence of other variants (PMID:16940308)). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.551 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024169/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:31547 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0231218 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2225524 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0858678 infores:hetionet CHEBI:94385 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0015967 infores:hetionet CHEBI:63624 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0003862 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0038362 infores:hetionet CHEBI:84500 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0851578 infores:hetionet CHEBI:31236 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0404521 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0152227 infores:hetionet CHEBI:9168 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0024305 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0948586 infores:hetionet NCBIGene:118429 biolink:causes MONDO:0009229 infores:monarchinitiative not_provided not_provided HGNC:21732 MONDO:0009229 uuid:10b98a8a-3320-48d9-99de-ac46891c447d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72690 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0035078 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0277884 infores:hetionet CHEBI:65173 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0242422 infores:hetionet CAID:CA000593 biolink:causes MONDO:0017623 infores:clingen CAID:CA000593 MONDO:0017623 PMID: Likely Benign PM2, BS3, BP4 PVS1, PM6, BP7, BP5, BS1, BS4, PP2, PP3, PP1, PP4, BS2, PM4, PM1, PM3, PM5, BA1, BP1, BP3, BP2, PS3, PS4, PS2, PS1 PTEN c.802-3T>A (IVS7-3T>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populationsBP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000593/MONDO:0017623/003 2025-08-01 2025-10-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3654 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0042384 infores:hetionet CHEBI:8069 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0030193 infores:hetionet CHEBI:194135 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020488 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0015230 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0011053 infores:hetionet CHEBI:8356 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0162285 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0021400 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151735 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232431 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0027947 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0004239 infores:hetionet CHEBI:109549 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0340865 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0700184 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013595 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0232492 infores:hetionet CHEBI:8802 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0006277 infores:hetionet CHEBI:37941 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151746 infores:hetionet CHEBI:5123 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0030312 infores:hetionet CHEBI:3242 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0549249 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0038814 infores:hetionet CHEBI:3561 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0018681 infores:hetionet CHEBI:9571 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0162830 infores:hetionet CHEBI:28148 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0033774 infores:hetionet CHEBI:4911 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0876994 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151505 infores:hetionet CHEBI:7565 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0011603 infores:hetionet CHEBI:32221 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0013428 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0233528 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233528 infores:hetionet CHEBI:5959 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0085612 infores:hetionet CHEBI:3077 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0162835 infores:hetionet CHEBI:66964 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0235146 infores:hetionet CHEBI:63620 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0035305 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0029408 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0034150 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0151849 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027092 infores:hetionet CHEBI:3698 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0011644 infores:hetionet CHEBI:2379 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0018834 infores:hetionet CHEBI:3082 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0857305 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042075 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0860851 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0860851 infores:hetionet CHEBI:6149 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0042029 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0162429 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0853847 infores:hetionet CHEBI:47780 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0851578 infores:hetionet CHEBI:83804 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1320474 infores:hetionet CHEBI:6030 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0022346 infores:hetionet CHEBI:8356 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023903 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0037822 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001265 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036358 infores:hetionet CHEBI:134991 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0085932 infores:hetionet CHEBI:2611 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0002622 infores:hetionet CHEBI:5001 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0438215 infores:hetionet NCBIGene:91647 biolink:causes MONDO:0011421 infores:monarchinitiative not_provided not_provided HGNC:18802 MONDO:0011421 uuid:f40f6aa8-1f19-4ed8-96b9-c152abac9668 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0029878 infores:hetionet CAID:CA16621482 biolink:causes MONDO:0010315 infores:clingen CAID:CA16621482 MONDO:0010315 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting The c.982C>T (p.Arg328Ter) variant in IL2RG is a nonsense variant located in the last exon (8/8). Although it is not predicted to cause nonsense-mediated decay, as it is located in a critical region for protein function, PVS1 is still applied at default strength (PVS1).This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + SCID gene panel or exome (1pt) + XY male sex (0.5 pts), total is 2 points, PP4_Moderate (PMID: 31799703).In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621482/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Supports CHEBI:175901 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0585186 infores:hetionet CHEBI:135876 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C1443060 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1112573 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1112573 infores:hetionet CHEBI:4657 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C1443060 infores:hetionet CHEBI:8871 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C3251821 infores:hetionet CHEBI:134745 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0232492 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0004096 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0003123 infores:hetionet CHEBI:8805 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0011991 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0015230 infores:hetionet CHEBI:9599 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0011603 infores:hetionet CAID:CA229422 biolink:causes MONDO:0009861 infores:clingen CAID:CA229422 MONDO:0009861 PMID:10541324PMID:31737040 Uncertain Significance PP4_Moderate, PM2, PP3 The c.1264G>A (p.Glu422Lys) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded; PP4_Moderate; PMID: 31737040). This variant is absent from population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.96 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229422/MONDO:0009861/006 2020-03-27 2020-03-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4710 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0031117 infores:hetionet CHEBI:45327 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0004245 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006047 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0281361 infores:hetionet CHEBI:261649 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0024115 infores:hetionet CHEBI:3696 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0022346 infores:hetionet CHEBI:3723 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0494475 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232431 infores:hetionet CHEBI:36704 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0392171 infores:hetionet CHEBI:6904 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0037763 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017160 infores:hetionet CHEBI:5138 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085593 infores:hetionet CHEBI:2659 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0340865 infores:hetionet CHEBI:47898 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085669 infores:hetionet GO:0052027 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0052027 GO:0007154 CHEBI:47612 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0031350 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0162429 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0853326 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0853326 infores:hetionet CHEBI:9586 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0232462 infores:hetionet CHEBI:110423 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0239571 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0038587 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0948873 infores:hetionet CHEBI:47657 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0015230 infores:hetionet CAID:CA658798976 biolink:causes MONDO:0009290 infores:clingen CAID:CA658798976 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.342del (p.Lys114AsnfsTer28) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 526523). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798976/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7824 biolink:causes UMLS:C0038045 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038045 infores:hetionet CHEBI:8060 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0043094 infores:hetionet CHEBI:72564 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0003862 infores:hetionet CHEBI:6062 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0003467 infores:hetionet CHEBI:55346 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0006266 infores:hetionet CHEBI:31348 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0000768 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0235431 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0235146 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0520806 infores:hetionet CHEBI:92998 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0013404 infores:hetionet NCBIGene:5915 biolink:causes MONDO:0014229 infores:monarchinitiative not_provided not_provided HGNC:9865 MONDO:0014229 uuid:51c123e9-8dd2-441f-a1c0-caa404fa772a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4653 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0878544 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020651 infores:hetionet CHEBI:47612 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0027121 infores:hetionet CAID:CA410206919 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206919 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP2, PM6, PVS1, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP4, PP1 NM_001754.5(RUNX1):c.677G>C (p.Ser226Thr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206919/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10587144 biolink:causes MONDO:0015967 infores:clingen CAID:CA10587144 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3 BP4, BP7 The c.1548C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 516 (p.(Gly516=)) of NM_000545.8. This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to only one copy in any subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.47 for splice acceptor gain, predicting that the variant impacts the acceptor site of intron 7 of HNF1A (PP3). In summary, c.1548C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587144/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0740394 infores:hetionet CHEBI:48273 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C2830004 infores:hetionet CHEBI:39112 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0151878 infores:hetionet CHEBI:8212 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0012833 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0553548 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0021053 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0919593 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0919593 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0015230 infores:hetionet CHEBI:5128 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0235309 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0162429 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013781 infores:hetionet CHEBI:8455 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0235996 infores:hetionet NCBITaxon:10310 biolink:causes MONDO:0005770 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10310 MESH:D006558 DB00787_MESH_D006558_1DB00577_MESH_D006558_1 CHEBI:9720 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0233794 infores:hetionet UMLS:C1738934 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0700200 infores:hetionet CHEBI:51209 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C1443060 infores:hetionet CHEBI:194135 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151827 infores:hetionet NCBIGene:9949 biolink:causes MONDO:0010516 infores:monarchinitiative not_provided not_provided HGNC:467 MONDO:0010516 uuid:b07e7551-0d56-4291-9f69-e11f7d09359c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0029118 infores:hetionet CHEBI:4779 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0015397 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0259768 infores:hetionet CHEBI:31348 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2939186 infores:hetionet CHEBI:44185 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0549249 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0020517 infores:hetionet CHEBI:135005 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0344232 infores:hetionet CHEBI:3219 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1510410 infores:hetionet CHEBI:8435 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0024141 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0027051 infores:hetionet CHEBI:45979 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0027497 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003864 infores:hetionet CAID:CA386952308 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952308 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 The c.26A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to arginine at codon 9 (p.(Gln9Arg)) of NM_000545.8. This variant is absent from gnomAD v2.1.1(PM2_Supporting). This variant is located within a dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP threshold of 0.70 (PP3). Lastly, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responsive to low-dose sulfonylurea) (PP4_Moderate; internal lab contributor). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PM1_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952308/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3655 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C2830004 infores:hetionet CHEBI:50648 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0010038 infores:hetionet CHEBI:23765 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0022904 infores:hetionet CAID:CA410146486 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146486 MONDO:0011071 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1441T>G (p.Ter481Gly) is a stop-loss variant which results in a protein extension of 52 residues. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (unpublished laboratory data) (PS4_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146486/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10101 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0038220 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0033117 infores:hetionet CHEBI:9137 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C2939447 infores:hetionet CHEBI:65173 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0151683 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0041909 infores:hetionet CHEBI:8428 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0042963 infores:hetionet CHEBI:9398 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C2830004 infores:hetionet CHEBI:92923 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0018681 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0518015 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1443060 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0038454 infores:hetionet CHEBI:6958 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0037763 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1443060 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0006852 infores:hetionet CHEBI:3515 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0038325 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005479 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0546959 infores:hetionet CHEBI:2567 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0011168 infores:hetionet CHEBI:8772 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0027796 infores:hetionet CHEBI:135925 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0043352 infores:hetionet CHEBI:45599 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C1565489 infores:hetionet CHEBI:48947 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0014457 infores:hetionet CHEBI:135738 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C1258215 infores:hetionet CHEBI:64310 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0020580 infores:hetionet CAID:CA124478 biolink:causes MONDO:0015967 infores:clingen CAID:CA124478 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PM5, PM1, PP3 PP4 The c.391C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 131 (p.(R131W)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). and is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.392G>A (p.Arg131Gln) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg131Trp has an equal or greater Grantham distance. (PM5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 44 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9166684, PMID:9075818, PMID:22060211, internal lab contributors). However, the MODY probability is unable to be calculated due to lack of clinical information (PMID:9166684, PMID:9075818, PMID:22060211 internal lab contributors). This variant segregated with disease with 11 informative meioses in six families with MODY (PP1_Strong, internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_Strong, PS4, PM1, PM5, PP3, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124478/MONDO:0015967/017 2021-08-18 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135342 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151905 infores:hetionet CHEBI:6067 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0040053 infores:hetionet CHEBI:49575 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0917801 infores:hetionet CHEBI:421707 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0002170 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0392025 infores:hetionet CHEBI:135530 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0009806 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0011570 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042267 infores:hetionet UMLS:C0145867 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0033774 infores:hetionet CHEBI:8364 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0344232 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0009450 infores:hetionet CHEBI:49040 biolink:causes MONDO:0006591 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0030326 infores:hetionet CHEBI:10125 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1306341 infores:hetionet CHEBI:47898 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013362 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0032461 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0281774 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151717 infores:hetionet CHEBI:31401 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C1320474 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0038363 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0017160 infores:hetionet GO:0035155 biolink:causes GO:0007424 infores:ubergraph knowledge_assertion manual_agent GO:0035155 GO:0007424 CAID:CA10650437 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650437 MONDO:0011071 PMID: Benign BP4, BA1 PS1, PS2, PS3, PS4, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*582del is in an UTR variant. MAF of 0.006923 (0.6923%, 36/5200,) in the East Asian subpopulation of gnomAD cohort v3.1.2 is ≥ 0.0015 (0.15%)(BA1). This UTR variant has a SpliceAI score ≤ 0.20 (Donor Loss 0.01)(BP4). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650437/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27882 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0020517 infores:hetionet CHEBI:9448 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0022354 infores:hetionet CHEBI:101278 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0041969 infores:hetionet CHEBI:180905 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0085631 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0518015 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0178298 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005366 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0524909 infores:hetionet CAID:CA119174 biolink:causes MONDO:0020367 infores:clingen CAID:CA119174 MONDO:0020367 PMID:14688426 Uncertain Significance PS3_Supporting, PP1_Moderate, PM2_Supporting BP7, BS1, BS3, PM6, PP3, PM5, PM4, PS4, PS1, PS2, BA1, BP4 The c.1430T>G variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Serine at amino acid 477 (p.Ile477Ser). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.646, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 10545602) demonstrated that the Ile477Ser protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9328473), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 9328473), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PS3_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119174/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9674 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0085633 infores:hetionet CHEBI:6149 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030252 infores:hetionet CHEBI:30830 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020488 infores:hetionet CHEBI:42797 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030554 infores:hetionet CAID:CA396460000 biolink:causes MONDO:0007648 infores:clingen CAID:CA396460000 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM6, PP1, PP4, PP2, PP3, BS2, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.1051C>T p.(Gln351Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000760845.2). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396460000/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:474180 biolink:causes UMLS:C0949103 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0949103 infores:hetionet CAID:CA390882450 biolink:causes MONDO:0100216 infores:clingen CAID:CA390882450 MONDO:0100216 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PVS1_Moderate PM6, BP4, BP2, BA1, PP3, PP1, PP4, PS3, PS2, BS1, BS3, BS4 The NM_177438.2:c.2257-2A>G variant in DICER1 occurs within the canonical splice acceptor site of intron 14. It is predicted to cause skipping of biologically-relevant exon 15/27, resulting in an in-frame deletion, removing <10% of the protein (PVS1_Moderate). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PM2_Supporting, and PVS1_Moderate. (Bayesian Points: 4; VCEP specifications version 1.3.0; 02/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390882450/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410148131 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148131 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1099G>T (p.Gly367Cys) is a missense variant which is completely absent from gnomAD v2.1.1 with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148131/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:465284 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0542149 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0040034 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0040409 infores:hetionet CHEBI:30830 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0009676 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004390 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0028841 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0025061 infores:hetionet NCBIGene:23095 biolink:causes MONDO:0007308 infores:monarchinitiative not_provided not_provided HGNC:16636 MONDO:0007308 uuid:26b32329-11c1-4dda-a8a7-a9916775bdcc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0542571 infores:hetionet CHEBI:5088 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0016382 infores:hetionet CHEBI:6797 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C2830004 infores:hetionet CAID:CA345132 biolink:causes MONDO:0019497 infores:clingen CAID:CA345132 MONDO:0019497 PMID: Pathogenic PP1_Strong, PP3, PP4, PM3_Very Strong BS1 The c.5098G>C (p.Glu1700Gln) variant in OTOF is a missense variant predicted to cause a substitution of glutamic acid by glutamine at amino acid 1700. The filtering allele frequency (the lower threshold of the 95% CI of 152/44874) of the c.5098G>C (p.Glu1700Gln) is 0.2948% for East Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency the East Asian population, given it is reported as a founder mutation in the Taiwanese population (PMID: 20224275). Therefore, the BS1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.85 which is above the threshold of ≥ 0.7 (PP3). This variant has been detected in at least 18 individuals with autosomal recessive nonsyndromic hearing loss. Eight individuals were homozygous for the variant (PMIDs: 20224275, 35106950). Six individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Glu841Lys, c.4961-1G>A, p.Arg1344*, p.Arg500*; PMID: 28766844). Four individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and confirmed in trans by parental testing (p.Pro1628Thr; PMID: 34692690) (PM3_VeryStrong). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; PMID: 28766844). The variant has been reported to segregate with hearing loss in multiple affected family members from two families (PP1_Strong; PMIDs: 20224275, 34692690). In summary, this variant meets the criteria to be classified as pathogenic for nonsyndromic genetic hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM3_VeryStrong, PP4, PP1_Strong; Version 2; 5/15/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA345132/MONDO:0019497/023 2024-06-28 2024-06-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:3723 biolink:causes UMLS:C0272426 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0272426 infores:hetionet CAID:CA645372549 biolink:causes MONDO:0015967 infores:clingen CAID:CA645372549 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1359del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 454 (NM_000545.8), adding 3 novel amino acids before encountering a stop codon (p.(Ser454AlafsTer3)). This variant, located in biologically-relevant exon 7 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Also, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.1359del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645372549/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9139 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004095 infores:hetionet CHEBI:63620 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1167965 infores:hetionet CHEBI:8461 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0162830 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0016436 infores:hetionet CHEBI:8481 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0016382 infores:hetionet CAID:CA7330980 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330980 MONDO:0100216 PMID: Likely Benign BP4, BS1 PVS1, PM2, BA1, BS2, PP3, PP4, PP1, PM1, PM5, PS3, PS2, PS1, PS4, BS3, BS4 The NM_177438.2:c.3828T>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 1276 (p.Asp1276Glu). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.001374 (88/64032 alleles) in the European (Finnish) population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.09; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BP4. (Bayesian Points: -5; VCEP specifications version 1.4.0, 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330980/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5847 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C1443060 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151479 infores:hetionet CHEBI:8888 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039070 infores:hetionet CAID:CA026270 biolink:causes MONDO:0012933 infores:clingen CAID:CA026270 MONDO:0012933 PMID: Likely Pathogenic PVS1, BS1, BP5_Strong, PM3, PS3, PM5_Strong The c.9699_9702del variant in BRCA2 is a deletion of four nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 15 of the frameshift, or amino acid 3247 (p.Cys3233TrpfsTer15). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0002484 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 7.08E-23 (based on Family History LR=7.08E-23), below the thresholds for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; Ambry internal contributor). Additional published family history analysis also reflects that this variant does not behave like other high risk variants (PMID: 25639900). Frameshift variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (sequence upstream of BRCA2 p.Glu3309 is disrupted) (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 27 (PTC occurs before p.T3310) (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33293522) (PS3 met). This variant has been detected in 1 individual with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least one clinical feature of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, is seen in this individual. The individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed to be in trans. BRCA2:c.9699_9702del has also been detected in multiple individuals with phenotypic features consistent with FA but who did not meet our criteria for applying PM3. Total points equated to 2 (PM3 met; Ambry and Invitae internal contributors, PMID: 25639900). Due to the higher than expected frequency and results of family history analysis, this variant is considered likely pathogenic with suspected reduced penetrance.In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP5_Very strong, PM5_Strong (PTC), PVS1, PS3, PM3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA026270/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50663 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0026858 infores:hetionet CHEBI:66919 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C1384353 infores:hetionet CHEBI:4657 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0013395 infores:hetionet CHEBI:51860 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0014591 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0024299 infores:hetionet CHEBI:17688 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0014591 infores:hetionet CHEBI:80630 biolink:causes UMLS:C1167779 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1167779 infores:hetionet CHEBI:15367 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235896 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042345 infores:hetionet CAID:CA8814832 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814832 MONDO:0009290 PMID: Uncertain Significance PP3 PM2, PP4, PM3, PM5, BS1 The NM_000152.5:c.265C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 89 (p.Arg89Cys). At least 1 proband with this variant had documented GAA deficiency with activity in the affected range in dried blood spot was reported (clinical laboratory data). The patient is heterozygous for the pseudodeficiency variant(s) c.271G>A (p.Asp91Asn) and therefore the GAA activity cannot be used for PP4. The proband is compound heterozygous for the variant and a variant classified as Pathogenic by the ClinGen LSD VCEP, c.307T>G (p.Cys103Gly); the variants are confirmed in trans by parental testing. However, the phase of the pseudodeficiency variant is unknown so PM3 was not applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.001898 (58/30556 alleles) in the South Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). One other missense variant, c.266G>A (p.Arg89His) (ClinVar Variation ID: 283219) has been reported in patients with Pompe disease (PMID: 28196920, 28600779, 25626711, 33202836). However, this variant has been classified as a variant of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 456412; 1 star review status) with one submitter classifying the variant as Likely Pathogenic and 5 as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3.(Classification approved by the ClinGen LSD VCEP on December 20, 2022) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814832/MONDO:0009290/010 2023-01-02 2023-01-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:37924 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0085631 infores:hetionet CHEBI:101278 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0016242 infores:hetionet CHEBI:6375 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0015672 infores:hetionet CHEBI:2666 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0151878 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030312 infores:hetionet CHEBI:42944 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0344232 infores:hetionet CHEBI:8356 biolink:causes HP:5200234 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233657 infores:hetionet CHEBI:51860 biolink:causes HP:0100035 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0751901 infores:hetionet CHEBI:49960 biolink:causes HP:0010310 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0008733 infores:hetionet CHEBI:100241 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0332563 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042267 infores:hetionet NCBIGene:29072 biolink:causes MONDO:0859333 infores:monarchinitiative not_provided not_provided HGNC:18420 MONDO:0859333 uuid:31ff352e-905c-4025-9bb9-9fc970ea767d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA134622 biolink:causes MONDO:0021060 infores:clingen CAID:CA134622 MONDO:0021060 PMID: Benign BP5, BA1 The filtering allele frequency of the c.848C>T (p.Ala283Val) variant in the MAP2K1 gene is 0.052% for African chromosomes by the Exome Aggregation Consortium (10/10366 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data; GTR ID: 21766, 26957; ClinVar SCV000207935.12; SCV000061262.5). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134622/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:84662 biolink:causes MONDO:0012680 infores:monarchinitiative not_provided not_provided HGNC:29450 MONDO:0012680 uuid:78cd3a28-4814-4323-aee1-2f25c394062f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0009450 infores:hetionet NCBIGene:2258 biolink:causes MONDO:0025353 infores:monarchinitiative not_provided not_provided HGNC:3670 MONDO:0025353 uuid:a70949a0-15dd-4757-b532-f720a269ff76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0011603 infores:hetionet GO:0030223 biolink:causes CL:0000775 infores:ubergraph knowledge_assertion manual_agent GO:0030223 CL:0000775 CHEBI:391960 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0574067 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151625 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151514 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0152128 infores:hetionet CAID:CA410147592 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147592 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS1, PS4, BP1, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1264G>A (p.Glu422Lys) is a missense variant in exon 9. This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The REVEL prediction score is 0.12, which is below the threshold for pathogenicity (<0.50), and SpliceAI does not predict an impact on splicing (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147592/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015300 infores:hetionet CHEBI:3387 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151907 infores:hetionet CHEBI:59445 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0009450 infores:hetionet CHEBI:3219 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0917801 infores:hetionet CHEBI:17303 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020440 infores:hetionet CHEBI:43968 biolink:causes HP:0032199 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0580412 infores:hetionet CHEBI:204928 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0231218 infores:hetionet NCBIGene:5274 biolink:causes MONDO:0011412 infores:monarchinitiative not_provided not_provided HGNC:8943 MONDO:0011412 uuid:1f6ef316-533b-4190-809f-f878b081ee3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:175901 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0206061 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0549622 infores:hetionet CHEBI:6367 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013491 infores:hetionet CHEBI:8805 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0008031 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0581912 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0014743 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0031039 infores:hetionet CHEBI:9168 biolink:causes HP:0033670 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0264383 infores:hetionet CHEBI:46295 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0020580 infores:hetionet CHEBI:6923 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0149745 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0235146 infores:hetionet CHEBI:4356 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C1384353 infores:hetionet CHEBI:94385 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0039231 infores:hetionet CAID:CA270538 biolink:causes MONDO:0010726 infores:clingen CAID:CA270538 MONDO:0010726 PMID: Likely Benign BP5, BS2, BP2 PM1, PP4, BP4 The p.Ala287Pro variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Baylor) (BS2). The p.Ala287Pro variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (internal database - GeneDx) (BP2). The p.Ala287Pro variant is found in a patient with an alternate molecular basis of disease (internal database - Baylor) (BP5). The p.Ala287Pro variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.001638% (no criteria met). In summary, the p.Ala287Pro variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270538/MONDO:0010726/016 2021-10-28 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA169542 biolink:causes MONDO:0007648 infores:clingen CAID:CA169542 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM5, PM3, PM4, PM1, PM2, PM6, PVS1, PP4, PP1, PP2, PP3, BS2, BP3, BP1, BP4, PS1, PS2, PS3, PS4 The NM_004360.5(CDH1):c.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA169542/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:94686 biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0278016 infores:hetionet CHEBI:64321 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0085602 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020621 infores:hetionet NCBIGene:2672 biolink:causes MONDO:0013139 infores:monarchinitiative not_provided not_provided HGNC:4237 MONDO:0013139 uuid:261ee8e6-3ff7-4c42-b20c-e944dc3c5e1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042514 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0851341 infores:hetionet GO:0044079 biolink:causes GO:0007269 infores:ubergraph knowledge_assertion manual_agent GO:0044079 GO:0007269 CHEBI:9635 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0040053 infores:hetionet NCBITaxon:1654 biolink:causes MONDO:0005699 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1654 MESH:D000197 DB01053_MESH_D000197_1 CHEBI:7494 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0015230 infores:hetionet CHEBI:9434 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0003862 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0497247 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0030312 infores:hetionet CHEBI:48844 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0149904 infores:hetionet CHEBI:93305 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0241136 infores:hetionet CHEBI:59773 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0019079 infores:hetionet CHEBI:2682 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151723 infores:hetionet CHEBI:49662 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151827 infores:hetionet CAID:CA220158 biolink:causes MONDO:0018997 infores:clingen CAID:CA220158 MONDO:0018997 PMID: Pathogenic PS3, PP1_Strong, PM2, PS2_Very Strong, PP2, PP3 PM6 The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID: 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220158/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3219 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0023067 infores:hetionet CHEBI:83804 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0026858 infores:hetionet CHEBI:83804 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0520966 infores:hetionet CHEBI:63611 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0423791 infores:hetionet CHEBI:404903 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042256 infores:hetionet CHEBI:3219 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0014724 infores:hetionet CHEBI:2038 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0231856 infores:hetionet CHEBI:135342 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0033575 infores:hetionet CHEBI:6958 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0037274 infores:hetionet NCBITaxon:2097 biolink:causes MONDO:0100338 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2097 MESH:D014552 DB00685_MESH_D014552_1 CHEBI:144093 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0035455 infores:hetionet CHEBI:100246 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0240327 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0413252 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151826 infores:hetionet CAID:CA146044 biolink:causes MONDO:0100368 infores:clingen CAID:CA146044 MONDO:0100368 PMID:19431183 Benign BS3_Supporting, BP4, BA1 The NM_000329.3(RPE65):c.963T>G (p.Asn321Lys) missense variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03299, with 1063 alleles / 30614 total alleles in the South Asian population with 29 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least one LCA patient, however the phenotype is not sufficiently specific to RPE65 and no second variant was described in trans, instead two CRB1 variants were identified (PMID: 18055816). The computational predictor REVEL gives a score of 0.215, which is below the ClinGen LCA/eoRD VCEP threshold of <0.3 and predicts no damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). The variant exhibited 127% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it preserves normal protein function (PMID: 19431183, BS3). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS3_Supporting, BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA146044/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:50378 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0006277 infores:hetionet CHEBI:45409 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C2363731 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018799 infores:hetionet NCBIGene:6218 biolink:causes MONDO:0012924 infores:monarchinitiative not_provided not_provided HGNC:10397 MONDO:0012924 uuid:3b8b904d-3b28-41cd-9297-8922cd75b6ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0022346 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0349506 infores:hetionet CHEBI:6062 biolink:causes MONDO:0007197 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0156273 infores:hetionet CHEBI:4784 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0004093 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151883 infores:hetionet NCBIGene:5896 biolink:causes MONDO:0009306 infores:monarchinitiative not_provided not_provided HGNC:9831 MONDO:0009306 uuid:8cbe0ee9-eb8d-41ae-aa53-8c691249d494 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235710 infores:hetionet CAID:CA233007 biolink:causes MONDO:0010726 infores:clingen CAID:CA233007 MONDO:0010726 PMID: Uncertain Significance BP5, PP3, BS2 PM2, BS1, PP4 The highest population minor allele frequency of the p.Arg268Trp variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00002175 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Arg268Trp variant is observed in at least 2 unaffected individuals (PMID 12750821, LabCorp Genetics (formerly Invitae) and GeneDx internal databases) (BS2). The p.Arg268Trp variant is found in a patient with an alternate molecular basis of disease (PMID: 32340510) (BP5). The p.Arg268Trp variant in MECP2 has been reported in male individuals described to have x-linked intellectual disability (PMID: 12750821), in female individuals described to have Rett syndrome (PMID: 18842453), and in unaffected female and male individuals (PMID: 1275082, GeneDx internal data) (PP4_not met). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg268Trp variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, BP5, PP3). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA233007/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:47426 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0546884 infores:hetionet CHEBI:4551 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0232459 infores:hetionet CHEBI:135530 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0042029 infores:hetionet CHEBI:8888 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033774 infores:hetionet CHEBI:28748 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014743 infores:hetionet CHEBI:7447 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0017178 infores:hetionet CHEBI:7507 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0017601 infores:hetionet CHEBI:6375 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C3263723 infores:hetionet CHEBI:3696 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011603 infores:hetionet CHEBI:17549 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0019348 infores:hetionet CAID:CA229873 biolink:causes MONDO:0009861 infores:clingen CAID:CA229873 MONDO:0009861 PMID: Benign BS2, BS3_Supporting, BS1, BP7 PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BP7, BS3_Supporting, BS2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229873/MONDO:0009861/006 2018-07-29 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46081 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0242184 infores:hetionet GO:1901385 biolink:causes GO:0070588 infores:ubergraph knowledge_assertion manual_agent GO:1901385 GO:0070588 CHEBI:80630 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0041364 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0002453 infores:hetionet CHEBI:7983 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0003467 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015256 infores:hetionet CHEBI:73275 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0149871 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030305 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0009763 infores:hetionet CHEBI:59773 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0023052 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0005779 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0011991 infores:hetionet CHEBI:45951 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C2830004 infores:hetionet CHEBI:31644 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0221201 infores:hetionet CHEBI:7601 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0018681 infores:hetionet CHEBI:145499 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020458 infores:hetionet CHEBI:9586 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0004093 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0235032 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020625 infores:hetionet CHEBI:3636 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0012833 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0007835 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0021933 infores:hetionet CHEBI:63613 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0151798 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0853336 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0037274 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234215 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0000833 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007971 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0549622 infores:hetionet CHEBI:5280 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0232462 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0162429 infores:hetionet CHEBI:47780 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0041657 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0041969 infores:hetionet GO:0120194 biolink:causes GO:0009908 infores:ubergraph knowledge_assertion manual_agent GO:0120194 GO:0009908 CHEBI:8764 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0039231 infores:hetionet CHEBI:45081 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0034642 infores:hetionet CHEBI:63621 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151905 infores:hetionet CHEBI:3127 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0010692 infores:hetionet CHEBI:100241 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0035410 infores:hetionet CHEBI:50305 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C2242996 infores:hetionet CHEBI:61049 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085641 infores:hetionet CHEBI:66964 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0018681 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0006849 infores:hetionet CHEBI:6909 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0006277 infores:hetionet CHEBI:6904 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0013378 infores:hetionet CHEBI:31622 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0028084 infores:hetionet CAID:CA341888 biolink:causes MONDO:0044970 infores:clingen CAID:CA341888 MONDO:0044970 PMID: Likely Pathogenic PVS1, PM2 The c.3630dup (p.Gly1211ArgfsTer6) variant in POLG was not in any databases (PM2). This variant results in a frameshift causing a loss of function (PVS1). There are no publications of cases with this variant. In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA341888/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA002212 biolink:causes MONDO:0011450 infores:clingen CAID:CA002212 MONDO:0011450 PMID: Benign BS2, BA1, BP5_Strong, BP1_Strong, BS3 The c.3418A>G variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 1140 (p.Ser1140Gly). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.03171 in the African/African-American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.06, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). This variant has been observed in more than 10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00029 (based on Co-occurrence LR=0.00029), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 16014699). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP1_Strong, BS3, BS2, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002212/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8665 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0013144 infores:hetionet CHEBI:4911 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0151905 infores:hetionet CHEBI:63635 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0023530 infores:hetionet CHEBI:119573 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0035410 infores:hetionet CHEBI:68554 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0041969 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042075 infores:hetionet CHEBI:188986 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0043352 infores:hetionet CHEBI:5893 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0041657 infores:hetionet CHEBI:6690 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0080274 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0014130 infores:hetionet CHEBI:3698 biolink:causes HP:0001920 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0035067 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0442874 infores:hetionet CHEBI:9738 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C1368065 infores:hetionet CHEBI:135285 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0162429 infores:hetionet CAID:CA136129 biolink:causes MONDO:0021060 infores:clingen CAID:CA136129 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.3032A>G (p.Asn1011Ser) variant in the SOS1 gene is 0.26% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (197/66620 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136129/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:32184 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0521495 infores:hetionet CHEBI:64321 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0030252 infores:hetionet CAID:CA891844469 biolink:causes MONDO:0011071 infores:clingen CAID:CA891844469 MONDO:0011071 PMID: Uncertain Significance PM4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.581_586del (p.Lys194_Ile195del) is an in-frame deletion which affects the residue K194 within the Runt Homology Domain (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PM4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844469/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8430 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0039231 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0013144 infores:hetionet NCBIGene:84634 biolink:causes MONDO:0013910 infores:monarchinitiative not_provided not_provided HGNC:4510 MONDO:0013910 uuid:cf68e64a-bc81-4506-87f9-ab722ff30636 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0022408 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0234215 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0434437 infores:hetionet CHEBI:5130 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0085633 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0429029 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0403632 infores:hetionet CHEBI:48669 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0728899 infores:hetionet CHEBI:7936 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014591 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042267 infores:hetionet NCBIGene:6507 biolink:causes MONDO:0012982 infores:monarchinitiative not_provided not_provided HGNC:10941 MONDO:0012982 uuid:ca4190d1-615b-4678-a61a-ec47db53d432 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75246 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0013404 infores:hetionet NCBIGene:27199 biolink:causes MONDO:0958191 infores:monarchinitiative not_provided not_provided HGNC:4531 MONDO:0958191 uuid:d1b5e4d0-51a4-42d3-b758-13e431cfac11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0149745 infores:hetionet CHEBI:82981 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0033774 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0013395 infores:hetionet CHEBI:145499 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0028734 infores:hetionet CHEBI:6367 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1456784 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0233632 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0006826 infores:hetionet CHEBI:7478 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0235086 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0234215 infores:hetionet CAID:CA137913 biolink:causes MONDO:0021060 infores:clingen CAID:CA137913 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1194C>T (p.Thr398=) variant in the MAP2K2 gene is 0.159% (19/7836) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137913/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:92998 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0017178 infores:hetionet CHEBI:3506 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0042963 infores:hetionet CHEBI:5847 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0039240 infores:hetionet CHEBI:8764 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0542571 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0042109 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0858259 infores:hetionet CHEBI:50841 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0027424 infores:hetionet CHEBI:44185 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0033774 infores:hetionet CHEBI:4653 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0026821 infores:hetionet CHEBI:9130 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C1145670 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0234215 infores:hetionet CHEBI:182080 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0547030 infores:hetionet CHEBI:6129 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0039070 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0021053 infores:hetionet CHEBI:9605 biolink:causes HP:0012587 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0473237 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0948525 infores:hetionet CHEBI:32315 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C2830004 infores:hetionet CHEBI:27436 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0156404 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038814 infores:hetionet CHEBI:6129 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030554 infores:hetionet CHEBI:72297 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0014724 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040046 infores:hetionet NCBIGene:4327 biolink:causes MONDO:0012687 infores:monarchinitiative not_provided not_provided HGNC:7165 MONDO:0012687 uuid:a6a5e4c7-5bc7-43a4-9b17-818f3b2787a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10385350 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385350 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.1754-103C>T is an intron 14 variant located 103 nucleotides from exon 15. This variant is present in gnomAD v.4.1.0 at a frequency of 0.07251 among hemizygous individuals, with 25,060 variant alleles / 345,617 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.04, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). The variant is located outside of the splice acceptor region (BP7). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385350/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:5120 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0518015 infores:hetionet CHEBI:63681 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0040264 infores:hetionet CAID:CA396452116 biolink:causes MONDO:0100488 infores:clingen CAID:CA396452116 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.121G>T (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Val by Leu at amino acid 41 (p.Val41Leu). This variant has been observed in Variant seen in >3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; Ambry, GeneDx, Invitae). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396452116/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:135613 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0024117 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0023067 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0234192 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0521509 infores:hetionet CHEBI:3756 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0023530 infores:hetionet CHEBI:63611 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0232461 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0009938 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0518015 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0854113 infores:hetionet CHEBI:51364 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0575081 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0019158 infores:hetionet CHEBI:367163 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0035410 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0017601 infores:hetionet CHEBI:43968 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0003578 infores:hetionet CHEBI:7915 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014724 infores:hetionet CHEBI:92998 biolink:causes UMLS:C3203695 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C3203695 infores:hetionet CHEBI:41774 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042024 infores:hetionet NCBIGene:403 biolink:causes MONDO:0032570 infores:monarchinitiative not_provided not_provided HGNC:694 MONDO:0032570 uuid:ca19ddbc-00ff-43fc-beee-5fa361457635 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0016059 infores:hetionet CHEBI:63611 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0032617 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0031350 infores:hetionet CHEBI:145499 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0575081 infores:hetionet CHEBI:63611 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022281 infores:hetionet CHEBI:74947 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085631 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0018801 infores:hetionet CHEBI:3996 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0231218 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235746 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235746 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0442874 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0015397 infores:hetionet CHEBI:2379 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0234238 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0020538 infores:hetionet CHEBI:10125 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0392171 infores:hetionet CAID:CA399802643 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802643 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, BP4, PM3_Supporting The ITGA2B missense variant NM_000419.5:c.1520C>G replaces the proline residue with an arginine residue (p.Pro507Arg). This variant has been observed in homozygosity (PM3_supporting) in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT43, PMID: 16463284). All requirements for PP4_moderate are met (GT43 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is absent from gnomADv4.1.0 (PM2_supporting). The in silico meta-predictor REVEL score for this variant is 0.224, below the VCEP-established threshold of <0.25 and suggestive of no damaging effect on protein function (BP4). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PP4_Moderate, PM2_Supporting, PM3_Supporting, and BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802643/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:75998 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0003862 infores:hetionet CHEBI:8093 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0030252 infores:hetionet CHEBI:3756 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013362 infores:hetionet CHEBI:114785 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0025222 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0041912 infores:hetionet CHEBI:6717 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0232849 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0015397 infores:hetionet CHEBI:3380 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0014457 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0035078 infores:hetionet CAID:CA261425 biolink:causes MONDO:0010134 infores:clingen CAID:CA261425 MONDO:0010134 PMID: Likely Pathogenic PS3_Supporting, PP4, PM3_Strong BS1, BP4 The c.2145G>T variant in SLC26A4 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 715 (p.Lys715Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06777% (95% CI of 29/30610) in the South Asian population (PM2_supporting, BS1, and BA1 not met). This variant has been observed in 3 probands with hearing loss in trans with another pathogenic or likely pathogenic variant (PM3_Strong; PMID: 26969326, PMID: 32417962, LMM unpublished data SCV000060131.6). At least one proband with this variant presented with clinical features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4; LMM unpublished data SCV000060131.6).This variant has been observed in several other cases where a second variant in SLC26A4 was not found (PMID: 19509082, 19287372, 26188157, 32417962). Functional studies including fluorescence assays and chloride exchange experiments have demonstrated that this variant impacts protein function (PS3_Supporting; PMID: 19509082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 08/22/23: PM3_Strong, PS3_Supporting, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261425/MONDO:0010134/005 2023-08-22 2023-10-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63611 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151828 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0041912 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0234215 infores:hetionet UMLS:C0903898 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0004604 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0027765 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0860866 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0240417 infores:hetionet CHEBI:5384 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0030554 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0027769 infores:hetionet CHEBI:2379 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0028734 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027051 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0232808 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0232808 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0011053 infores:hetionet CAID:CA267669 biolink:causes MONDO:0009861 infores:clingen CAID:CA267669 MONDO:0009861 PMID:26666653PMID:26666653 Uncertain Significance PM2, PP4, PP3, PM3_Supporting PM5 The c.682G>A (p.Glu228Lys) variant in PAH has been reported in 1 individual with classic PKU detected with c.1066-11G>A. (PMID: 26666653). This variant has extremely low frequency in gnomAD. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3-supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267669/MONDO:0009861/006 2020-06-26 2020-06-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6375 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0012569 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005670 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0005681 infores:hetionet CHEBI:39867 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0231218 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0233414 infores:hetionet CHEBI:3756 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0004093 infores:hetionet CHEBI:5959 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042963 infores:hetionet CHEBI:45924 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0043144 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0235234 infores:hetionet NCBIGene:6899 biolink:causes MONDO:0008564 infores:monarchinitiative not_provided not_provided HGNC:11592 MONDO:0008564 uuid:821410ac-1d9c-4f49-ba36-ce6c5d6f9bbf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0027441 infores:hetionet CAID:CA1139533052 biolink:causes MONDO:0021060 infores:clingen CAID:CA1139533052 MONDO:0021060 PMID: Likely Pathogenic PM1, PM2, PP2, PS4_Supporting The c.175_176delinsTT (p.Ala59Phe) in HRAS was absent from gnomAD (PM2; PMID: 29493581). It has been identified in one individual with clinical features of a RASopathy (PS4_Supporting; Otto-von-Guericke University Magdeburg internal data). Furthermore, this variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of HRAS (PM1; PMID 29493581). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the c.175_176delinsTT (p.Ala59Phe) variant is likely pathogenic. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PM1, PM2, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139533052/MONDO:0021060/004 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8060 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0085631 infores:hetionet CHEBI:2611 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020580 infores:hetionet CAID:CA000080 biolink:causes MONDO:0018875 infores:clingen CAID:CA000080 MONDO:0018875 PMID: Likely Benign BP4, BS3, BS2, PM2_Supporting BA1, PS3, PS1, PS4, PS2, PM5, PM1, BS1, BS4, PP3, PP1, PP4 The NM_000546.6: c.245C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 82 (p.Pro82Leu). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal Lab Contributors: SCV000215716.6). This variant has an allele frequency of 0.00003335 (5/59976 alleles) in the Admixed American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0708; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predictor score of [0.01] predicts that the variant has no impact on splicing (score threshold <0.210) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_moderate, PM2_Supporting BS3, BP4, (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000080/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0090049 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0001944 CHEBI:46195 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0015397 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0442874 infores:hetionet CHEBI:30830 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0013390 infores:hetionet CHEBI:5132 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0162830 infores:hetionet CHEBI:65173 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0162316 infores:hetionet CHEBI:15940 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C2830004 infores:hetionet CHEBI:16914 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0038358 infores:hetionet CHEBI:9727 biolink:causes UMLS:C0235905 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0235905 infores:hetionet CAID:CA2499223952 biolink:causes MONDO:0011132 infores:clingen CAID:CA2499223952 MONDO:0011132 PMID:37419334 Likely Pathogenic PS3_Moderate, PM2_Supporting, PVS1_Strong PP4 NM_001369369.1(FOXN1):c.1364_1367del (p.Tyr455CysfsTer?) is a frameshift variant in exon 8 which results in a premature stop codon in the final exon (exon 9) at codon 548. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). This variant is absent from gnomADv2.1.1 (PM2_supporting). It has been reported in one patient and functional analysis was performed in a luciferase reporter construct, which was cotransfected into heterologous cells with an expression vector containing mutant or wild-type FOXN1. This variant had 1.6% luciferase activity compared to wild-type (PMID: 37419334; PS3_Moderate). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_Strong, PS3_Moderate and PM2_Supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499223952/MONDO:0011132/113 2024-07-29 2024-07-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41879 biolink:causes UMLS:C1535948 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1535948 infores:hetionet CHEBI:38940 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0015967 infores:hetionet CHEBI:5004 biolink:causes MONDO:0008599 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0040997 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0029408 infores:hetionet CHEBI:47898 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1535939 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0857121 infores:hetionet CHEBI:15940 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0036974 infores:hetionet CHEBI:132233 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0233477 infores:hetionet CHEBI:567361 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0003811 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0007785 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0877153 infores:hetionet CHEBI:50648 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085932 infores:hetionet CHEBI:8382 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0332601 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0232452 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0232452 infores:hetionet CHEBI:44032 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0038999 infores:hetionet NCBIGene:6331 biolink:causes MONDO:0011377 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0011377 uuid:65e8615e-50e3-4be4-8d88-b39e4a7053af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45285 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0019209 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0162281 infores:hetionet CHEBI:63619 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0024141 infores:hetionet CHEBI:4551 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0262662 infores:hetionet NCBIGene:1545 biolink:causes MONDO:0015016 infores:monarchinitiative not_provided not_provided HGNC:2597 MONDO:0015016 uuid:fd28c7f2-c7e1-4b04-9e5d-2c9f5356ca1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0019112 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0037023 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0235431 infores:hetionet CHEBI:2948 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0023530 infores:hetionet CHEBI:71940 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C2129214 infores:hetionet CHEBI:63925 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0013604 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0029408 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0476273 infores:hetionet UMLS:C1738934 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0003862 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0149931 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0549405 infores:hetionet CHEBI:7478 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0404521 infores:hetionet CAID:CA10584706 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584706 MONDO:0007750 PMID: Uncertain Significance PS3_Supporting, PM2 PS4, BP7, BS4 The NM_000527.4(LDLR):c.-138T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2_Met : This variant is absent from gnomAD (v.2.1.1).PS3_supporting Met: Level 3 Assay: Luciferase Assay + COS cells. The variant T-45C (Hobbs' numbering: -45T>C) is in the proximal Sp1 binding site in repeat 3 of the 42 bp region of the promoter required for steroldependent regulation of transcription. In 1995 Sun et al ( PMID: 8589690) reported that the variant reduced transcriptional activity to approximately 43% of normal in the presence, and 25% in the absence of sterols in the medium (repressing variant). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584706/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:61033 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0000833 infores:hetionet CHEBI:681850 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0917801 infores:hetionet CHEBI:6375 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0025222 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085762 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006145 infores:hetionet CHEBI:63791 biolink:causes MONDO:0018177 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1621958 infores:hetionet CAID:CA1942910 biolink:causes MONDO:0018214 infores:clingen CAID:CA1942910 MONDO:0018214 PMID: Likely Pathogenic PS4, PP3_Moderate, PM5_Supporting BS2, PVS1, PS1, BS1 The NM_001165963.4(SCN1A):c.3629C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 1210 (p.Thr1210Met). The variant has been identified in two probands with consistent phenotypes (Genetic epilepsy with febrile seizures plus) in published literature (PMID:35074891 and PMID:28202706)(PS4). One proband inherited the variant from an unaffected father (PMID:28202706). Another missense variant at the same amino acid position in SCN1A (c.3629C>A, p.Thr1210Lys) has been classified as likely pathogenic for a consistent phenotype (Dravet syndrome)(PM5_supporting). The allele frequency for the variant is 0.002% with 4 alleles in gnomAD V2.1.1 (PM2_supporting and BS1 are not met). The computational predictor REVEL gives a score of 0.841, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant Genetic epilepsy with febrile seizures plus on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM5_supporting, PP3_Moderate. (version 1.0; March 26, 2024) Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1942910/MONDO:0018214/067 2024-04-30 2024-11-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:43968 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0019065 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011053 infores:hetionet NCBIGene:3988 biolink:causes MONDO:0019148 infores:monarchinitiative not_provided not_provided HGNC:6617 MONDO:0019148 uuid:74f15ea0-cc86-49ff-be62-62a5df774539 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA397841387 biolink:causes MONDO:0018875 infores:clingen CAID:CA397841387 MONDO:0018875 PMID: Pathogenic PS3, PM1_Supporting, PP3_Moderate, PS2_Moderate, PM2_Supporting, PS4_Supporting BP4, BA1, PS1, PM5, BS1, BS3, BS4, BP7, PVS1, PP4, PP1, BS2 The NM_000546.6: c.532C>G variant in TP53 is a missense variant predicted to cause substitution of histidine by aspartic acid at amino acid 178 (p.His178Asp). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancers totaling 2 phenotype points (PS2_Moderate; PMID 21345075). This variant has been reported in 2 additional unrelated probands meeting revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; SCV000754561.6, SCV000667198.3). This variant has an allele frequency of 6.195e-7 (1/1614230 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and human cells showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644). This variant has five somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the ClinGen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Computational predictor scores (BayesDel =0.4249); Align GVGD = Class C65) are above recommended thresholds (BayesDel ≥ 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2_Moderate, PS4_Supporting, PM2_Supporting, PS3, PM1_Supporting, PP3_Moderate. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397841387/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5784 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0017979 infores:hetionet CHEBI:8713 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0009782 infores:hetionet CHEBI:175901 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0022661 infores:hetionet CHEBI:92511 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0036974 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085606 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0004936 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018621 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0006145 infores:hetionet CHEBI:63608 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0149514 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0413252 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0003123 infores:hetionet CHEBI:6965 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0855242 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0234192 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0019158 infores:hetionet CAID:CA172179 biolink:causes MONDO:0100040 infores:clingen CAID:CA172179 MONDO:0100040 PMID: Benign BS2, BA1, BP3 The allele frequency of the c.209_235del variant in FOXG1 is 0.17% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions BA1). The p.Gln70_Pro78del variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Gln70_Pro78del variant is an in-frame deletion present in a repetitive region of FOXG1 (BP3). In summary, the p.Gln70_Pro78del variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172179/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:43968 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0001824 infores:hetionet CHEBI:5893 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0038325 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0020651 infores:hetionet CHEBI:50223 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C2830004 infores:hetionet CHEBI:6847 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0011991 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0036572 infores:hetionet CHEBI:18332 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0011991 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0152008 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0152008 infores:hetionet CHEBI:6923 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0011991 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0007642 infores:hetionet CHEBI:50223 biolink:causes UMLS:C1096106 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1096106 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0020538 infores:hetionet CHEBI:47612 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0014518 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0018799 infores:hetionet CHEBI:6887 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027430 infores:hetionet CHEBI:85083 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0027947 infores:hetionet CHEBI:31547 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C2047937 infores:hetionet NCBITaxon:1279 biolink:causes MONDO:0025419 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1279 MESH:D005667 DB00798_MESH_D005667_1 CHEBI:135622 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB06771 UMLS:C1761613 infores:hetionet CHEBI:47781 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0231218 infores:hetionet CHEBI:17474 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0010200 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0026857 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234913 infores:hetionet CHEBI:8499 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0004093 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0020649 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0021843 infores:hetionet CHEBI:5147 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151878 infores:hetionet NCBIGene:2706 biolink:causes MONDO:0007850 infores:monarchinitiative not_provided not_provided HGNC:4284 MONDO:0007850 uuid:b0307d9c-7f26-46f8-a7a2-6c34f4d2f87d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0031117 infores:hetionet CHEBI:51450 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0004093 infores:hetionet CHEBI:168396 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0040822 infores:hetionet CHEBI:53760 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0008350 infores:hetionet CHEBI:3478 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0015230 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020456 infores:hetionet CHEBI:3764 biolink:causes UMLS:C0236083 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0236083 infores:hetionet NCBIGene:5961 biolink:causes MONDO:0011974 infores:monarchinitiative not_provided not_provided HGNC:9942 MONDO:0011974 uuid:9865c0f1-5ab1-4e01-94b2-92dad871129a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3175 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0235267 infores:hetionet CAID:CA6749059 biolink:causes MONDO:0009861 infores:clingen CAID:CA6749059 MONDO:0009861 PMID: Uncertain Significance BP4 PM2, BS1 The NM_000277.3:c.60+9C>T variant in PAH is an intronic variant affecting a nucleotide in intron 1. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002803 (7/24972 alleles) in the African/African American population (none of the population data codes are met). The computational splicing predictor SpliceAI gives a score of 0.01 for donor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 991626, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6749059/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:567361 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0027651 infores:hetionet CHEBI:28487 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0011053 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019360 infores:hetionet CHEBI:8060 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0004093 infores:hetionet CAID:CA410203396 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203396 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.337C>A (p.Pro113Thr) is a missense variant which has a REVEL score ≥ 0.88 (0.966) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203396/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94686 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0002170 infores:hetionet CAID:CA658824402 biolink:causes MONDO:0044970 infores:clingen CAID:CA658824402 MONDO:0044970 PMID:30315213 Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PS3_Supporting, PM6 PP3, PS4 The m.8088delT frameshift variant in MT-CO2 has been reported in one individual with primary mitochondrial disease to date, in a 16-year-old girl with childhood onset exercise intolerance, fatigue, and muscle weakness (PMID: 30315213). Muscle biopsy showed COX deficiency, subsarcolemmal accumulation of mitochondria, and lipid accumulation. Complex IV activity was reduced in muscle (exome sequencing was performed excluding other genetic etiologies, PP4). The variant was present at 96% heteroplasmy in skeletal muscle, 2% in hair follicles, 5% in blood, 6% in fibroblasts, 12% in buccal sample, and 15% in urine. The variant was not detected in her mother’s hair follicles, blood, buccal sample, or urine (PM6; PMID: 30315213). This variant causes a premature stop in the MT-CO2 gene resulting in truncation of 26% of the protein (PVS1_strong). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in COX negative fibers (100%, n=14) than in COX positive fibers (40%, n=14), p<0.05 (PS3_supporting, PMID: 30315213). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PP4, PM6, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824402/MONDO:0044970/015 2024-02-26 2025-06-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8435 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0037274 infores:hetionet CAID:CA409108268 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108268 MONDO:0015967 PMID: Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS4, PM1_Supporting, PP1_Strong BA1, BP4, BS1 The c.932G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 311 (p.(Arg311His)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to absence in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 25414397, 24947580 26059258, 32533152; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies; and family history of LGA/hypoglycemic infant) (PP4_Moderate; PMID: 24947580, internal lab contributors). This variant segregated with diabetes, with 12 informative meioses in 4 families (PP1_Strong; PMIDs: 24947580, 26059258, 32533152, internal lab contributors). Another missense variant, p.(Arg311Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg311His) (PM5_Supporting). In summary, c.932G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting, PS4, PP4_Moderate, PP1_Strong, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108268/MONDO:0015967/085 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:66913 biolink:causes UMLS:C0877128 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0877128 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0853761 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0851341 infores:hetionet CHEBI:3419 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0024031 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0595885 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0595885 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C1268766 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0019348 infores:hetionet CHEBI:7798 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0917801 infores:hetionet CHEBI:53691 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0037383 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085096 infores:hetionet CHEBI:8354 biolink:causes UMLS:C0235957 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0235957 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018418 infores:hetionet CAID:CA515477924 biolink:causes MONDO:0010725 infores:clingen CAID:CA515477924 MONDO:0010725 PMID: Likely Benign PM2_Supporting, BP7, BP4 The NM_000330.4(RS1):c.145C>T variant is a synonymous variant at amino acid 49. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This silent variant c.145C>T causing a synonymous variant at codon 49 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0 for all predictive splice changes which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on splicing (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, BP4, and BP7. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA515477924/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:6950 biolink:causes UMLS:C0151588 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151588 infores:hetionet CHEBI:135342 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C3665347 infores:hetionet CHEBI:3207 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0040409 infores:hetionet CHEBI:15544 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0476273 infores:hetionet CHEBI:7478 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0855333 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0543698 infores:hetionet CHEBI:37924 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020458 infores:hetionet CHEBI:4995 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020598 infores:hetionet NCBIGene:4915 biolink:causes MONDO:0033367 infores:monarchinitiative not_provided not_provided HGNC:8032 MONDO:0033367 uuid:dfdab949-6acc-4d08-a200-06c6e43eaa38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0006145 infores:hetionet CHEBI:9674 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C2047937 infores:hetionet CHEBI:51860 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0162820 infores:hetionet NCBIGene:25913 biolink:causes MONDO:0957263 infores:monarchinitiative not_provided not_provided HGNC:17284 MONDO:0957263 uuid:0f1973c1-880b-45a2-8729-d502ed9e29ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0002874 infores:hetionet CHEBI:140621 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0025061 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0178421 infores:hetionet CHEBI:10125 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0001807 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1619712 infores:hetionet CHEBI:91834 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0004093 infores:hetionet CHEBI:48947 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0040034 infores:hetionet UMLS:C0011701 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0028961 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235431 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0235431 infores:hetionet CHEBI:63617 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085631 infores:hetionet CHEBI:6741 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0018681 infores:hetionet CHEBI:521033 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0020453 infores:hetionet CHEBI:2673 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0003467 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151883 infores:hetionet CHEBI:9586 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0497156 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0015230 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0549385 infores:hetionet NCBIGene:5591 biolink:causes MONDO:0014423 infores:monarchinitiative not_provided not_provided HGNC:9413 MONDO:0014423 uuid:e9c94beb-b77a-49a9-8a83-0df7ec9871a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA166884 biolink:causes MONDO:0007648 infores:clingen CAID:CA166884 MONDO:0007648 PMID:29798843 Uncertain Significance PM2_Supporting, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4 The c.2549_2550delCC (p.Ser850PhefsTer10) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and downstream of codon 836 where the most 3’ pathogenic variant in CDH1 terminates (PVS1_Moderate, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Moderate, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166884/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:101278 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0002622 infores:hetionet CHEBI:28593 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0018681 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151736 infores:hetionet CHEBI:7936 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085623 infores:hetionet CHEBI:75998 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0041969 infores:hetionet CHEBI:42797 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007859 infores:hetionet CAID:CA273356 biolink:causes MONDO:0009861 infores:clingen CAID:CA273356 MONDO:0009861 PMID:8533759PMID:24765287PMID:21871829 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong PM5, PS3 PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD (0.00004065); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.981; PP4_Moderate: L249F was seen 3 times in HPA patients associated with 2 different haplotypes. DHPR defeciency was excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:8533759); PM3_VeryStrong: Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup (PMID:21871829; PMID:24765287). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_VeryStrong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273356/MONDO:0009861/006 2018-08-12 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7445 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0917801 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0020649 infores:hetionet NCBIGene:139285 biolink:causes MONDO:0010310 infores:monarchinitiative not_provided not_provided HGNC:26837 MONDO:0010310 uuid:fd03e78f-8561-4962-807a-d7697e45e599 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0162429 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C1443060 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0278080 infores:hetionet CHEBI:7565 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0004604 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0005940 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0013395 infores:hetionet CAID:CA10014432 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014432 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP5, PVS1, BS1, BS3, BS4, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.613+158C>T is an intronic variant which has a MAF of 0.03363 (3.4%, 595/17690 alleles) in the African subpopulation of the gnomAD v2 cohort, meeting the threshold of ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in an individual or in a population database (gnomAD v2) (BP2). It has a SpliceAI score ≤ 0.20 (0.0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score ≤ 2.0 (-0.58) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014432/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63791 biolink:causes UMLS:C1740832 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1740832 infores:hetionet NCBIGene:10982 biolink:causes MONDO:0014755 infores:monarchinitiative not_provided not_provided HGNC:6891 MONDO:0014755 uuid:3911b31d-9fb9-4da7-9e6d-37574e7d6bcf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0232492 infores:hetionet CHEBI:3698 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0039070 infores:hetionet CHEBI:31236 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0451641 infores:hetionet CHEBI:6375 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0949059 infores:hetionet UMLS:C1738934 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0028081 infores:hetionet CHEBI:681569 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0015230 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0009450 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151828 infores:hetionet CHEBI:6015 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0085605 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019158 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0035455 infores:hetionet NCBIGene:283989 biolink:causes MONDO:0010190 infores:monarchinitiative not_provided not_provided HGNC:27561 MONDO:0010190 uuid:42bff7b9-6b41-44f8-9351-b226e968d289 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C2939147 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0149931 infores:hetionet CHEBI:8214 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0026821 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005657 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004030 infores:hetionet CHEBI:135736 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0239935 infores:hetionet CHEBI:3756 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0010200 infores:hetionet CHEBI:17474 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0016204 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0006849 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0025362 infores:hetionet CHEBI:3423 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0006118 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0020615 infores:hetionet CHEBI:4814 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0085593 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0007642 infores:hetionet CHEBI:36795 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0234047 infores:hetionet NCBIGene:5949 biolink:causes MONDO:0014093 infores:monarchinitiative not_provided not_provided HGNC:9921 MONDO:0014093 uuid:f5c9b3f2-f4d3-45a7-958f-2998eabebb89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7907 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0039231 infores:hetionet CHEBI:36795 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0231530 infores:hetionet CHEBI:82960 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0235198 infores:hetionet GO:0061930 biolink:causes GO:0034101 infores:ubergraph knowledge_assertion manual_agent GO:0061930 GO:0034101 CHEBI:8382 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151970 infores:hetionet GO:0140433 biolink:causes GO:0000212 infores:ubergraph knowledge_assertion manual_agent GO:0140433 GO:0000212 CHEBI:63613 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0038325 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0009763 infores:hetionet CHEBI:3380 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0036830 infores:hetionet CHEBI:51364 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0026837 infores:hetionet CAID:CA10014481 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014481 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.509-12G>T is an intronic variant. This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.76) (BP7). Multiple lines of computational evidence suggest no impact on gene /gene product (SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014481/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:53760 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0007642 infores:hetionet CHEBI:7577 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0232461 infores:hetionet NCBIGene:79188 biolink:causes MONDO:0013677 infores:monarchinitiative not_provided not_provided HGNC:28472 MONDO:0013677 uuid:446b28af-b9bd-44b9-9546-56f293971081 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0023222 infores:hetionet CHEBI:584020 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0013404 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0001416 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037274 infores:hetionet CHEBI:47781 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0152198 infores:hetionet CHEBI:499361 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0035229 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151785 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011849 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0855242 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0037274 infores:hetionet CHEBI:3510 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0015230 infores:hetionet CAID:CA340748268 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748268 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PM5_Supporting, PM2_Supporting PP1 NM_000329.3(RPE65):c.310G>C (p.Gly104Arg) is a missense variant that replaces glycine with arginine at amino acid 104. Another missense variant in the same codon, NM_000329.3(RPE65):c.311G>A (p.Gly104Asp), has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5_Supporting). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 26355662, PMID: 23105016). The variant has been reported to segregate with RP through the proband plus at least 3 similarly affected relatives, with the variant present in the homozygous state (potential PP1_Strong; PMID: 23105016). However, the details on the phenotype was not included and unable for VCEP to confirm if phenotypically in keeping with LCA / eoRP. The computational predictor REVEL gives a score of 0.97, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PM5_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748268/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:171719 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0004093 infores:hetionet CHEBI:50378 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0010038 infores:hetionet CHEBI:31348 biolink:causes HP:0004872 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0267716 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001584 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0028850 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018939 infores:hetionet CHEBI:4735 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0017979 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019054 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0948586 infores:hetionet CHEBI:367163 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0232602 infores:hetionet CHEBI:5118 biolink:causes MONDO:0041526 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0156543 infores:hetionet CHEBI:49375 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0040264 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004601 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0023223 infores:hetionet CHEBI:161680 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0023518 infores:hetionet CHEBI:94449 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0009782 infores:hetionet CHEBI:7627 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0917801 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0948594 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0006444 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020649 infores:hetionet CHEBI:53760 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085633 infores:hetionet CHEBI:100147 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0030353 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0012833 infores:hetionet CHEBI:4735 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0017178 infores:hetionet NCBIGene:10075 biolink:causes MONDO:0010407 infores:monarchinitiative not_provided not_provided HGNC:30892 MONDO:0010407 uuid:e08b8fe6-36f4-40c6-a12d-cf56917f4a0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0003123 infores:hetionet CHEBI:35778 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0037383 infores:hetionet NCBIGene:342035 biolink:causes MONDO:0014965 infores:monarchinitiative not_provided not_provided HGNC:29514 MONDO:0014965 uuid:8a7b1065-3aee-4c9c-80de-4b875ca9a868 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0080274 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020649 infores:hetionet CHEBI:8107 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013144 infores:hetionet CHEBI:4784 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0231528 infores:hetionet CHEBI:8107 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0006384 infores:hetionet CHEBI:100147 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0162298 infores:hetionet CAID:CA512318850 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318850 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS4, BS3, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 The c.294C>G (p.Leu98=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being not highly conserved (PhyloP score = 1.16043 in GRCh38) (BP7). Although the variant is absent from from gnomAD v2 and v3 (PM2_Supporting), it also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318850/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7915 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0000833 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013295 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0006444 infores:hetionet CHEBI:47426 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0151671 infores:hetionet GO:0046782 biolink:causes GO:0019080 infores:ubergraph knowledge_assertion manual_agent GO:0046782 GO:0019080 CHEBI:9139 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151766 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0267792 infores:hetionet CHEBI:28864 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0344232 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020557 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001245 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085576 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0009450 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020437 infores:hetionet CHEBI:64198 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0003467 infores:hetionet CHEBI:9434 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0000737 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020538 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151878 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004096 infores:hetionet CHEBI:15367 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235710 infores:hetionet CHEBI:3756 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0086525 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151826 infores:hetionet CAID:CA7330659 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330659 MONDO:0100216 PMID: Uncertain Significance PM1_Supporting, BS2_Supporting PM2, PM6, BA1, BP4, BP2, PP1, PM5, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.5504A>C variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 1835 (p.Tyr1835Ser). The total allele frequency in gnomAD v4.1.0 is 0.000008054 (13/1614058 alleles) with a highest population minor allele frequency of 0.00001102 (13/1180030 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.676, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors, GTR Lab ID: 50003). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.3.0; 06/24/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330659/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018843 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0235086 infores:hetionet CHEBI:9763 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C1443060 infores:hetionet CHEBI:6149 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151907 infores:hetionet CHEBI:9123 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006384 infores:hetionet CHEBI:41423 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C2979982 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019917 infores:hetionet CHEBI:17076 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0235280 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0031117 infores:hetionet CHEBI:261649 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0877047 infores:hetionet CHEBI:48390 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0687713 infores:hetionet CHEBI:3699 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0428977 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0002871 infores:hetionet CHEBI:4511 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0036974 infores:hetionet CHEBI:7798 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0155169 infores:hetionet CHEBI:68647 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0235378 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0541919 infores:hetionet CHEBI:50378 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0018681 infores:hetionet CHEBI:6067 biolink:causes UMLS:C1611174 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1611174 infores:hetionet CAID:CA410147465 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147465 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP3, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1): c.1297A>G (p.Thr433Ala) is a missense variant which has a REVEL score < 0.50 (0.18) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147465/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8069 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0014518 infores:hetionet CHEBI:10023 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003467 infores:hetionet CAID:CA8815003 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815003 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PP3, PM3, BP4 The NM_000152.5:c.725C>A variant in GAA is a missense variant predicted to cause substitution of Ala by Glu at amino acid 242 (p.Ala242Glu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00028 (7/24910 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.528 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met). It has not been reported in the literature as causative for GAA-related disease, but has been observed in 9 asymptomatic newborn screening cases by a clinical testing laboratory cases. In those cases, the c.1630G>A (p.Val544Met) variant (ClinVar Variation ID; 450358), classified as a variant of uncertain significance by the ClinGen LD VCEP on June 6, 2024), was always present suggesting that the two variants are in cis. There is a ClinVar entry for this variant (Variation ID: 642648). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 21, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815003/MONDO:0009290/010 2024-05-21 2024-09-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:8768 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019372 infores:hetionet CHEBI:39867 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0231528 infores:hetionet CHEBI:31932 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0344232 infores:hetionet CHEBI:71219 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020458 infores:hetionet CHEBI:47657 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0015672 infores:hetionet CHEBI:16469 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C3160741 infores:hetionet CHEBI:8080 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0233477 infores:hetionet CHEBI:91834 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C3263723 infores:hetionet CAID:CA226155 biolink:causes MONDO:0100453 infores:clingen CAID:CA226155 MONDO:0100453 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting The NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met) variant is predicted to replace the threonine at position p.312 with methionine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000005599, with 9 alleles / 1,607,292 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). This variant has been reported in at least 5 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous for the variant. The patient reported in PMID #19959640 has the p.Arg795Trp variant, unclassified by the LCA/eoRD VCEP, suspected in trans (not counted). The patient reported in PMID #26047050 has the p.Arg332Pro variant, currently unclassified, confirmed in trans (0.25 pts). The 2 unrelated patients reported in PMIDs #27375279 and #27422788 both have the p.Leu251Pro variant, currently unclassified, confirmed in trans (0.5 pts). The patient reported in PMID #27375279 has the p.Ser1007Leu variant, currently unclassified, confirmed in trans (0.25 points) (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) before age 1 (1 pt), nystagmus (1 pt), poor vision (1 pt), extinguished rod and cone ERGs (1.5 pts), attenuated vessels (0.5 pts) and no foveal reflex which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 21602930, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PP4, PM3. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226155/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3223 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0235146 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020517 infores:hetionet CAID:CA192317 biolink:causes MONDO:0100488 infores:clingen CAID:CA192317 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting, BP4 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.164-4G>A (NM_004360.5) variant in CDH1 occurs in the splice donor region of intron 2. This variant has been observed in more than 10 individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; Ambry, GeneDx, Invitae). This variant occurs in one in 251,376 alleles in gnomAD 2.1.1 (less than one out of 100,000), within the European Non-Finnish population (one in 113,662 alleles) PM2_Supporting. In silico splice site predictors suggest that this variant does not impact splicing (BP4). However, splicing has not been assessed by in vitro assays. In summary, this variant meets the criteria to be classified as likely benign for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2, BP4. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA192317/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63619 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0026826 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0302295 infores:hetionet CHEBI:10101 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0018834 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0024115 infores:hetionet CHEBI:9435 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0027497 infores:hetionet CHEBI:490877 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0740394 infores:hetionet CAID:CA2499306877 biolink:causes MONDO:0100326 infores:clingen CAID:CA2499306877 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000419.5(ITGA2B):c.188+471_892-70delinsGCCACCCACAGTGCAATCCCACA indel begins in intron 1 where it removes the intron 1 splice acceptor site and deletes through most of intron 9. The expectation is that the intron 1 splice donor will use the next available acceptor site in intron 9 leading to the skipping of exons 2-9 with a frameshift in exon 10 that generates a premature stop codon resulting in NMD. However, patient cDNA indicated use of a cryptic splice acceptor in intron 1 such that exons 2-9 are still removed but there is also retention of portions of introns 1 and 9. The included portion of intron 1 includes an in-frame TAA termination code, 26 triplets downstream of exon 1, which would be expected to result in NMD (PVS1). GT type 1 patient K.W. of PMID: 1702098 is homozygous for this variant (PM2_supporting). This variant is absent from gnomAD SVs v2.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_strong. (VCEP specifications version 2; date of approval 12/21/2021). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499306877/MONDO:0100326/011 2021-12-21 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:80630 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0235896 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0020538 infores:hetionet NCBIGene:2328 biolink:causes MONDO:0018767 infores:monarchinitiative not_provided not_provided HGNC:3771 MONDO:0018767 uuid:7a8f5363-1f50-46e0-b562-68c3b078cb64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0151623 infores:hetionet CHEBI:17026 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0025218 infores:hetionet CAID:CA390864497 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864497 MONDO:0100216 PMID: Uncertain Significance PM1_Supporting PVS1, PM2, PM6, BA1, BP2, BP1, BP4, BP3, PP2, PP3, PP1, PP4, BS2, PM3, PM4, PM5, PS1, PS3, PS2, PS4, BP5, BP7, BS1, BS3, BS4 The NM_177438.2:c.5509A>G variant in DICER1 is a missense variant predicted to cause substitution of Methionine by Valine at amino acid 1837 (p.Met1837Val). The total allele frequency in gnomAD v4.1.0 is 0.000001859 (3/1614072 alleles) with a highest population minor allele frequency of 0.00006683 with multiple alleles present (3/44892 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.594, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_supporting. (Bayesian Points: 1; VCEP specifications version 1.3.0, 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864497/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0033246 infores:hetionet CHEBI:8481 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0011615 infores:hetionet CHEBI:68647 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0017168 infores:hetionet CHEBI:71272 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0033774 infores:hetionet CHEBI:6076 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C2047937 infores:hetionet CHEBI:100241 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151754 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0234458 infores:hetionet CHEBI:71229 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0232487 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0233632 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0574067 infores:hetionet CHEBI:5383 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0151474 infores:hetionet CAID:CA10585371 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585371 MONDO:0007750 PMID: Likely Pathogenic PM3, PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.1243G>C (p.Asp415His) variant is classified as Likely Pathogenic, for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.805. PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling criteria for FH from PMID 11810272 (Fouchier et al., 2001), The Netherlands.PM3: Variant meets PM2 and was identified in an index case with homozygous FH phenotype (LDL-c 893 mg/dL) and LDLR variant (Cys143*) in trans, classified as Pathogenic by these guidelines, from PMID 26894473 (Sanna et al., 2016), Belgium. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585371/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:140621 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0041834 infores:hetionet CHEBI:6715 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0028949 infores:hetionet NCBIGene:3756 biolink:causes MONDO:0024526 infores:monarchinitiative not_provided not_provided HGNC:6250 MONDO:0024526 uuid:e666909f-8949-41a8-9795-c8771842486f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1320474 infores:hetionet CHEBI:45599 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0232462 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0011991 infores:hetionet CHEBI:68558 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C1443060 infores:hetionet CHEBI:63620 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0037299 infores:hetionet CHEBI:52172 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013491 infores:hetionet CAID:CA254237 biolink:causes MONDO:0800472 infores:clingen CAID:CA254237 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM1, PP3_Moderate, PP1_Strong, PS3_Supporting BP4, BA1, PM5, PM4, PS1, PS2, BP7, BS1, BS4, PVS1, PM2 The c.182G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Glycine by Glutamic acid at amino acid 61 (p.Gly61Glu). This missense variant is located in the hinge region, meeting PM1. The highest minor allele frequency of this variant was in the Middle Eastern genetic ancestry group of gnomAD (v4.1.0) = 0.006305 (33 alleles out of 5234), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The REVEL score = 0.795, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 18470941) demonstrated that the Gly61Glu protein had reduced 17B Estradiol Activity levels compared to wild type CYP1B1 protein and another study (PMID: 12807732) demonstrated that the protein had reduced Benzo[a]pyrene Activity levels compared to wild type CYP1B1 protein. Both studies met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. This variant was also assessed in PMIDs: 11740343, 19793111, 19234632, 27243976, however the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 9497261), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in eight individuals with a CYP1B1-related phenotype. Five individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 confirmed in trans and 4 phase unknown). Three individuals are homozygous (2 consanguineous and 1 non-consanguineous) for the variant (PMIDs: 9497261, 12372064, 16490498, 19234632, 22128238, 30270463). Total points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 17 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very strong, PP1_Strong, PM1, PP3_Moderate, PS3_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA254237/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:478164 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0151905 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011616 infores:hetionet CHEBI:142290 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0006277 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0235416 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0031350 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0349506 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0877211 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0877211 infores:hetionet NCBIGene:6597 biolink:causes MONDO:0968980 infores:monarchinitiative not_provided not_provided HGNC:11100 MONDO:0968980 uuid:be3414b9-9b84-421e-9f4f-eda6480bcc5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013404 infores:hetionet CHEBI:9137 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027497 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0156312 infores:hetionet CHEBI:44032 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0004093 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003537 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0018099 infores:hetionet CHEBI:9398 biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0277885 infores:hetionet GO:0042688 biolink:causes CL:0000392 infores:ubergraph knowledge_assertion manual_agent GO:0042688 CL:0000392 CHEBI:68558 biolink:causes MONDO:0004431 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018924 infores:hetionet CHEBI:6717 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0018965 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0024050 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0024050 infores:hetionet CHEBI:45924 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0013384 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042721 infores:hetionet CHEBI:46195 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0004093 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0392176 infores:hetionet CHEBI:2682 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0080274 infores:hetionet CAID:CA512341204 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341204 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1233C>T (p.Ala411=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.37)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341204/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4027 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085932 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0856808 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0856808 infores:hetionet GO:0060998 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:0060998 GO:0048666 CHEBI:499361 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0235431 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033687 infores:hetionet CHEBI:94440 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0015230 infores:hetionet CHEBI:63598 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042023 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004948 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023434 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0037274 infores:hetionet CHEBI:8874 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003862 infores:hetionet CHEBI:116278 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0404521 infores:hetionet CAID:CA293055 biolink:causes MONDO:0000573 infores:clingen CAID:CA293055 MONDO:0000573 PMID: Likely Benign BS2_Supporting, BS1 BA1 The NM_000536.4:c.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID: 28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA293055/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:27777 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0003123 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0021053 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042109 infores:hetionet CHEBI:36791 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011071 infores:hetionet CHEBI:7465 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0026113 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0234215 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0020651 infores:hetionet CHEBI:10102 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085641 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0006266 infores:hetionet CAID:CA16609264 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609264 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate PM1 The c.1361C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glutamic acid at codon 454 (p.(Ala454Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.04, which is below the MDEP cutoff (<0.5) (PMID: 28842611). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 393447, PMIDs: 36257325, 20337973, 16602010, 17204055, internal lab contributors). In summary, c.1361C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS3_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609264/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CHEBI:15940 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0235378 infores:hetionet CHEBI:5383 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0030312 infores:hetionet CHEBI:2704 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C1443060 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0014130 infores:hetionet NCBIGene:9759 biolink:causes MONDO:0859232 infores:monarchinitiative not_provided not_provided HGNC:14063 MONDO:0859232 uuid:8d7a6ad6-fb74-4ba7-8174-ceaddb84fe92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0042665 biolink:causes GO:0001705 infores:ubergraph knowledge_assertion manual_agent GO:0042665 GO:0001705 CHEBI:46195 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0043352 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0027497 infores:hetionet CHEBI:36795 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0242339 infores:hetionet CHEBI:2955 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0852911 infores:hetionet CHEBI:48273 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0014518 infores:hetionet CHEBI:50131 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151766 infores:hetionet CHEBI:3732 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0235378 infores:hetionet CHEBI:9738 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2363730 infores:hetionet CHEBI:5384 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0033774 infores:hetionet CHEBI:44185 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0002874 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0235117 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235117 infores:hetionet CHEBI:48390 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0013395 infores:hetionet CHEBI:85161 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C2830004 infores:hetionet CAID:CA135110 biolink:causes MONDO:0021060 infores:clingen CAID:CA135110 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135110/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3387 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0409974 infores:hetionet CHEBI:5147 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0006277 infores:hetionet CHEBI:5132 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0009676 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0948089 infores:hetionet CHEBI:49713 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0549622 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0424605 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0151436 infores:hetionet CAID:CA034999 biolink:causes MONDO:0007750 infores:clingen CAID:CA034999 MONDO:0007750 PMID: Benign BA1, BP4 BP2, PS4, PS3, PS1, PS2, BP7, BS1, BS3, BS4, PM1, PM4, PM3, PM5, PM2, PM6, PP4, PP1, PP3, BS2 The NM_000527.5(LDLR):c.1586+16G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BA1 - FAF = 0.02014 (2.014%) in African/African American exomes (gnomAD v2.1.1), so BA1 is Met.BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) C) variant is not exonicVariant is not predicted to alter splicing.--- BP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034999/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020538 infores:hetionet CHEBI:4911 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0151799 infores:hetionet CHEBI:135736 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030232 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037199 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0032326 infores:hetionet CHEBI:135622 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06771 UMLS:C0235266 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0014868 infores:hetionet CHEBI:135736 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0242301 infores:hetionet CHEBI:135530 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0033774 infores:hetionet CAID:CA2739267614 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267614 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.551_552insTACCACAGAGCCATCTGTG (p.Gln185ThrfsTer34) is a frameshift variant which terminates 34 amino acids downstream and is predicted to undergo nonsense-mediated decay (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It is a frameshift variant that is downstream of c.98 (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267614/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4514 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0233571 infores:hetionet CHEBI:3614 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0040435 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020649 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0002878 infores:hetionet CHEBI:42797 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0036974 infores:hetionet CAID:CA16602487 biolink:causes MONDO:0011071 infores:clingen CAID:CA16602487 MONDO:0011071 PMID:10508512PMID:19387465PMID:20549580PMID:28513614 Pathogenic PS4, PP1_Strong, PVS1, PM2_Supporting PS1, PS3, PS2, BP3, BP1, BP4, BP2, BA1, BP7, BP5, BS3, BS4, BS1, PM6, PM5, PM1, PM4, PM3, PP2, PP3, PP4, BS2 The NM_001754.4:c.601C>T (p.Arg201Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMIDs: 10508512; 19387465; 20549580; 28513614). The variant was found to co-segregate with disease in multiple affected family members, with 14 meioses observed in across 4 families (PP1_Strong; PMID: 10508512; 19387465; 20549580; 28513614). The variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4, PP1_Strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602487/MONDO:0011071/008 2024-09-04 2024-09-04 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:104454 biolink:causes MONDO:0004662 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:104454 MONDO:0004662 CHEBI:31236 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233471 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0024115 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0030305 infores:hetionet CHEBI:36795 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0542571 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0022904 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0023533 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017566 infores:hetionet CHEBI:15940 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0010200 infores:hetionet CHEBI:75045 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0085649 infores:hetionet CHEBI:46557 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C2363731 infores:hetionet CHEBI:8871 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1519353 infores:hetionet CHEBI:71415 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C1443060 infores:hetionet CHEBI:2955 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0085593 infores:hetionet CHEBI:9674 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233754 infores:hetionet NCBIGene:283489 biolink:causes MONDO:0014699 infores:monarchinitiative not_provided not_provided HGNC:20311 MONDO:0014699 uuid:c844c038-d071-48b1-9668-2a6a5a0629c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA042636 biolink:causes MONDO:0007750 infores:clingen CAID:CA042636 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 PS1, PS3, BS3, PM5, PM3, PP3 The NM_000527.5(LDLR):c.274C>G (p.Gln92Glu) variant is classified as a variant of Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2022.The supporting evidence is as follows: PM2: PopMax MAF = 0.000008790 in European Non-Finnish exomes (gnomAD v2.1.1).BP4: REVEL = 0.49. It is not above 0.75, splicing evaluation needed.Functional data on splicing not available.A) variant is not on limits.B) variant does not create a de-novo AG or GT.The variant is not predicted to alter splicing.PP4: Variant meets PM2 and is identified in 1 case with possible FH by Simon Broome criteria from Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042636/MONDO:0007750/013 2022-10-28 2025-02-07 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:2788 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0015672 infores:hetionet CHEBI:9139 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085298 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002622 infores:hetionet CAID:CA000105 biolink:causes MONDO:0017623 infores:clingen CAID:CA000105 MONDO:0017623 PMID: Likely Benign BP5, BS2_Supporting, BS1 PTEN c.-1026C>A (NC_000010.10:g.89623200C>A) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0056 (0.56%, 173/30,898 alleles) in the gnomAD cohort. (PMID 27535533)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000171228.5)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000171228.5) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000105/MONDO:0017623/003 2016-11-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true UBERON:0001007 biolink:causes MONDO:0024292 infores:ubergraph knowledge_assertion manual_agent UBERON:0001007 MONDO:0024292 CHEBI:205919 biolink:causes UMLS:C0349398 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0349398 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0029927 infores:hetionet CHEBI:4822 biolink:causes MONDO:0020675 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C2004435 infores:hetionet CHEBI:51173 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0344232 infores:hetionet CHEBI:6754 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0041657 infores:hetionet CHEBI:7494 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0009763 infores:hetionet CHEBI:94411 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0043352 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0027769 infores:hetionet CHEBI:6822 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0011991 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002622 infores:hetionet CHEBI:63791 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2363731 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0030305 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0014868 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004096 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0085584 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0017178 infores:hetionet CAID:CA16020719 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020719 MONDO:0009861 PMID:21307867 Uncertain Significance PM2, PP4 PP3, BP4 VUS: The c.47C>A (p.S16Y) variant in PAH was reported in one patient in a PKU cohort without segregation, and evidence of BH4 responsiveness (PP4, PMID: 21307867). This variant is absent from population databases, including 1000 Genomes, gnomAD and ESP. Computations predictors SIFT and Polyphen are conflicting, REVEL=0.569. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020719/MONDO:0009861/006 2019-02-26 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10023 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0036572 infores:hetionet CAID:CA6402355 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402355 MONDO:0019565 PMID: Likely Benign BS1 PP3, BS2, BP4 NM_000552.5(VWF):c.5173C>T is a missense variant that replaces proline with serine at position 1725. TThe Grpmax filtering allele frequency in gnomAD v4.1 is 0.02354 (based on 1836/75022 alleles in the African / African-American population, with 27 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 for BS1. While this variant has been reported in healthy control individuals (PMID: 22197721), BS2 is not being used due to penetrance issues. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402355/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true NCBITaxon:5476 biolink:causes MONDO:0044070 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D058387 DB00196_MESH_D058387_1DB00520_MESH_D058387_3DB01167_MESH_D058387_1 CHEBI:144093 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0013604 infores:hetionet CHEBI:31348 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221245 infores:hetionet CAID:CA10014626 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014626 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS3, BS4, BS1, PM6, PM2, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.97+4T>G is an intronic variant. This intronic variant has a SpliceAI score ≤ 0.20 (0.02 donor gain; 0.01 acceptor gain) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02/0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.640) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014626/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:825 biolink:causes MONDO:0009675 infores:monarchinitiative not_provided not_provided HGNC:1480 MONDO:0009675 uuid:72434424-ef60-4c42-9ba3-38b849ec9692 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027769 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0015230 infores:hetionet CAID:CA405683851 biolink:causes MONDO:0007783 infores:clingen CAID:CA405683851 MONDO:0007783 PMID: Likely Pathogenic PP1, PM5, PS4_Moderate, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 401 of the RYR1 protein, p.Arg401Leu. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). This variant segregates with MHS in four meiosis, PP1 (PMID:30236257). No functional studies were identified for this variant. Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.965) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405683851/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:9605 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0020538 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0002170 infores:hetionet CHEBI:51041 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0542571 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0036454 infores:hetionet CHEBI:7565 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0035455 infores:hetionet CHEBI:3723 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033893 infores:hetionet UMLS:C0011701 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020458 infores:hetionet NCBIGene:171019 biolink:causes MONDO:0859572 infores:monarchinitiative not_provided not_provided HGNC:17111 MONDO:0859572 uuid:0b1b9591-8f0e-4e7d-a432-c078e3d7cd44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C1443060 infores:hetionet CHEBI:4858 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0151827 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0522224 infores:hetionet CHEBI:53691 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0041657 infores:hetionet CHEBI:31485 biolink:causes MONDO:0001439 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0014583 infores:hetionet NCBIGene:8726 biolink:causes MONDO:0060510 infores:monarchinitiative not_provided not_provided HGNC:3188 MONDO:0060510 uuid:35266765-8e75-4518-9b92-a36d2703730a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042109 infores:hetionet CHEBI:209807 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0016382 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0243026 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0031350 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0243026 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151826 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020517 infores:hetionet CHEBI:42797 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003467 infores:hetionet CHEBI:41774 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C3263723 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0241028 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0241028 infores:hetionet CHEBI:41774 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C2979982 infores:hetionet CHEBI:2659 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0232462 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017152 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0007885 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0007885 uuid:49f1db68-6ed2-45c5-8264-e0bcfbbf724c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013428 infores:hetionet CHEBI:9123 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0392156 infores:hetionet CHEBI:8499 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0264906 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0160390 infores:hetionet CAID:CA658683946 biolink:causes MONDO:0007648 infores:clingen CAID:CA658683946 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2 The c.457_460del (p.Lys153Glufs*61) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683946/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:92607 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0018965 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0344315 infores:hetionet CHEBI:31622 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0151786 infores:hetionet CHEBI:31638 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0003467 infores:hetionet CHEBI:5893 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002792 infores:hetionet GO:0046602 biolink:causes GO:0000226 infores:ubergraph knowledge_assertion manual_agent GO:0046602 GO:0000226 CHEBI:5296 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0151773 infores:hetionet CHEBI:63621 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0010520 infores:hetionet CHEBI:553473 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0038325 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0948089 infores:hetionet CHEBI:18332 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0002170 infores:hetionet NCBIGene:9750 biolink:causes MONDO:0011761 infores:monarchinitiative not_provided not_provided HGNC:13872 MONDO:0011761 uuid:214947a5-fdbc-4adf-b9bd-704633afd65a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63616 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0231528 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0743680 infores:hetionet CHEBI:8405 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0000729 infores:hetionet CHEBI:3082 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0242429 infores:hetionet CHEBI:27834 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0004245 infores:hetionet CHEBI:32315 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0043352 infores:hetionet CHEBI:7577 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013491 infores:hetionet CHEBI:4856 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0004144 infores:hetionet CHEBI:50659 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0027497 infores:hetionet CHEBI:2663 biolink:causes MONDO:0003334 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0270922 infores:hetionet CHEBI:50885 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0162834 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0392386 infores:hetionet CAID:CA343722837 biolink:causes MONDO:0020367 infores:clingen CAID:CA343722837 MONDO:0020367 PMID: Uncertain Significance PS3_Supporting, PM5_Supporting, PP3, PM2_Supporting BP7, BS1, BS3, PM6, PP1, PM4, PS1, PS4, PS2, BA1, BP4 The c.1496T>G variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Serine at amino acid 499 (p.Ile499Ser). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.798, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 11004290) demonstrated that the Ile499Ser protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. Only 1 segregation had been reported for juvenile open angle glaucoma (JOAG) (PMID: 11004290), not meeting the ≥ 3 segregations required for PP1. Only 1 proband with JOAG had been reported (PMID: 11004290), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1495A>T, p.Ile499Phe, Grantham score = 21, PMID: 9328473) in the same codon has been classified as likely pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1496T>G, p.Ile499Ser variant has a higher Grantham score (= 142) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343722837/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9588 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0009319 infores:hetionet CHEBI:4702 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0003811 infores:hetionet CHEBI:17141 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0002792 infores:hetionet CAID:CA024896 biolink:causes MONDO:0018493 infores:clingen CAID:CA024896 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PP1_Strong PP3, PM1, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with glycine at codon 2730 of the RYR1 protein, p.(Asp2730Gly). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:19191329). Two ex vivo functional studies, using cells from the same individual, showed an increased sensitivity to RYR1 agonists, however, this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested (PMID:21088110, PMID:19191329). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in 17 individuals, PP1_Strong (PMID:19191329). A REVEL score of 0.722 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP1_Strong. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024896/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:50663 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C2718128 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0014457 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235883 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235883 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020651 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1096444 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1096444 infores:hetionet CHEBI:180905 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0746961 infores:hetionet CHEBI:100241 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151798 infores:hetionet CHEBI:31536 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0085682 infores:hetionet GO:0003400 biolink:causes GO:0006888 infores:ubergraph knowledge_assertion manual_agent GO:0003400 GO:0006888 CHEBI:7514 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0015644 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0160390 infores:hetionet CHEBI:45327 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0428977 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011719 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0238198 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0152486 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0152486 infores:hetionet CHEBI:8107 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0014457 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151826 infores:hetionet CHEBI:8707 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042024 infores:hetionet CHEBI:16796 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0151610 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1096034 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1096034 infores:hetionet CHEBI:5130 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151611 infores:hetionet CHEBI:9130 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0003578 infores:hetionet CHEBI:63589 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0687713 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0233472 infores:hetionet CHEBI:31348 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0700225 infores:hetionet CHEBI:7444 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0547030 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005855 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0026393 infores:hetionet CHEBI:9943 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0404521 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151602 infores:hetionet CHEBI:9168 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085682 infores:hetionet CHEBI:135530 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0002792 infores:hetionet CHEBI:9635 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0239571 infores:hetionet NCBITaxon:302011 biolink:causes MONDO:0024473 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:302011 MONDO:0024473 CHEBI:6801 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1291077 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0549373 infores:hetionet CHEBI:42944 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151878 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0038367 infores:hetionet NCBIGene:6101 biolink:causes MONDO:0008377 infores:monarchinitiative not_provided not_provided HGNC:10263 MONDO:0008377 uuid:363cf370-a70e-4e28-8846-0449f70098c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0852911 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0152027 infores:hetionet CHEBI:50275 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0037763 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0020517 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0434437 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0019112 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0020517 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0007787 infores:hetionet CHEBI:9137 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013378 infores:hetionet CHEBI:3638 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C3665347 infores:hetionet NCBIGene:64919 biolink:causes MONDO:0014981 infores:monarchinitiative not_provided not_provided HGNC:13222 MONDO:0014981 uuid:26c0a6f6-d444-4dc8-ad7b-2dd88c7e5dbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2636 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0011606 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0948595 infores:hetionet GO:0090095 biolink:causes GO:0072186 infores:ubergraph knowledge_assertion manual_agent GO:0090095 GO:0072186 CHEBI:6520 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0038362 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0243065 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0037578 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037578 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0518015 infores:hetionet CHEBI:4027 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027540 infores:hetionet CHEBI:8764 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009676 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0032226 infores:hetionet NCBIGene:23013 biolink:causes MONDO:0859143 infores:monarchinitiative not_provided not_provided HGNC:17575 MONDO:0859143 uuid:f7b9f276-d548-446e-ac28-3549ac98b965 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63627 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C1443060 infores:hetionet CHEBI:3561 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151205 infores:hetionet CHEBI:41879 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0039231 infores:hetionet CHEBI:9086 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085631 infores:hetionet CHEBI:31980 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0497156 infores:hetionet CHEBI:3561 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0025323 infores:hetionet CHEBI:51173 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0855775 infores:hetionet CHEBI:6909 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0004093 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0521839 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0233472 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0041969 infores:hetionet CHEBI:8069 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0085631 infores:hetionet NCBIGene:23096 biolink:causes MONDO:0010656 infores:monarchinitiative not_provided not_provided HGNC:29059 MONDO:0010656 uuid:63eb171e-3494-4f14-8e4f-7cc81a580569 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:24564 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0027497 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039103 infores:hetionet CHEBI:7824 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042790 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0235431 infores:hetionet CAID:CA915940808 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940808 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000212.3:c.1192del (p.Ala398ProfsTer24) variant in ITGB3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/15 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been observed in compound homozygosity in one individual (Patient 3 in PMID: 28748566) in combination with ITGB3 variant c.1639T>G (p.Cys547Gly, trans phase not confirmed). However, this co-occurrence evidence contributed to the classification of c.1639T>G (p.Cys547Gly) and was not used to apply PM3 in the classification of this variant to prevent circularity. This patient (Patient 3 in PMID: 28748566) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting, PP4_Moderate. (VCEP specifications version 2; date of approval 03/15/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940808/MONDO:0100326/011 2022-04-07 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:44185 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013362 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0948586 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0002170 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0162429 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0340464 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0086543 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027651 infores:hetionet CHEBI:3696 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0010038 infores:hetionet NCBIGene:55553 biolink:causes MONDO:0033544 infores:monarchinitiative not_provided not_provided HGNC:16421 MONDO:0033544 uuid:eea5ca87-3b5a-4336-8c55-0509efabe620 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71028 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0178298 infores:hetionet CHEBI:7476 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011168 infores:hetionet CHEBI:50223 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0015967 infores:hetionet CHEBI:43968 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0232462 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151664 infores:hetionet CAID:CA400033092 biolink:causes MONDO:0100326 infores:clingen CAID:CA400033092 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting, BP4 PM3, PP3, PS3 The NM_000212.3(ITGB3):c.2027A>C (p.Lys676Thr) missense variant was detected in a 13-year-old patient with GT based on phenotype (recurrent gum bleeds, easy disability, and history of ecchymotic patches), absent platelet aggregation with ADP, collagen plus reduced aggregation with ristocetin, and absent expression of αIIbβ3 integrin by flow cytometry. This clinical phenotype is specific for GT (PMID: 31777146; PP4_strong). This variant is absent from the gnomAD v2.1.1 database (PM2_Supporting). It has a REVEL score of 0.216 which is lower than the PD VCEP cutoff of <0.25 which predicts a benign impact on protein function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP4_Strong, and BP4 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400033092/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31236 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232602 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0014868 infores:hetionet CHEBI:64312 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0522055 infores:hetionet CHEBI:4657 biolink:causes HP:0012282 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0234918 infores:hetionet CHEBI:37941 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0002792 infores:hetionet CHEBI:7459 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0043387 infores:hetionet NCBITaxon:28845 biolink:causes MONDO:0015260 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:28845 MONDO:0015260 CHEBI:64318 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0231528 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0035309 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0231303 infores:hetionet UMLS:C0010592 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0242528 infores:hetionet CHEBI:6541 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0542571 infores:hetionet CHEBI:50885 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C2586050 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0034065 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0029134 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151436 infores:hetionet CAID:CA367401109 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401109 MONDO:0015967 PMID: Pathogenic PM3, PVS1, PP4_Moderate, PM2_Supporting The c.679+1G>T variant in glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 6 of transcript NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 6 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in an individual with neonatal diabetes in a compound heterozygous state with another variant (c.676G>A) classified as pathogenic by ClinGen MDEP, and these variants were confirmed in trans (internal lab contributors) (PM3). This variant was also identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative, and a 3-generation dominant family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.679+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 02/17/2025): PVS1, PM3, PP4_Moderate, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401109/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports CHEBI:17650 biolink:causes UMLS:C1167675 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C1167675 infores:hetionet CHEBI:94385 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0428977 infores:hetionet CHEBI:50663 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0015967 infores:hetionet CHEBI:82960 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0549249 infores:hetionet CAID:CA136077 biolink:causes MONDO:0021060 infores:clingen CAID:CA136077 MONDO:0021060 PMID: Benign BA1, BP4, BP7, BP5 BS1, PM2, PP3 The c.1230G>A variant in the SOS1 gene is a synonymous (silent) variant (p.Gln410=) at a nucleotide that is not highly conserved and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1. This variant has been identified in patients with an alternate molecular basis for disease (BP5; Partners LMM internal data GTR Lab ID: 21766, ClinVar SCV000062189.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136077/MONDO:0021060/041 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50275 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017152 infores:hetionet CHEBI:3219 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0423791 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020676 infores:hetionet GO:0007317 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0009790 CHEBI:7915 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020443 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019147 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0233494 infores:hetionet CHEBI:27899 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0004093 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0011849 infores:hetionet CHEBI:55346 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0085615 infores:hetionet NCBIGene:973 biolink:causes MONDO:0013288 infores:monarchinitiative not_provided not_provided HGNC:1698 MONDO:0013288 uuid:489bf0cc-bf95-4c8d-9ba5-7394d14e693a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55180 biolink:causes MONDO:0013702 infores:monarchinitiative not_provided not_provided HGNC:30922 MONDO:0013702 uuid:bb41a27e-b505-43aa-a371-fe020138ac62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0973461 infores:hetionet NCBIGene:3763 biolink:causes MONDO:0013572 infores:monarchinitiative not_provided not_provided HGNC:6267 MONDO:0013572 uuid:9aa41c21-5599-481c-a55e-1297b2a6d531 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020473 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0948594 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0012833 infores:hetionet CHEBI:135005 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0014742 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0242350 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085584 infores:hetionet CHEBI:63845 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0085932 infores:hetionet NCBIGene:56983 biolink:causes MONDO:0014307 infores:monarchinitiative not_provided not_provided HGNC:22954 MONDO:0014307 uuid:6c24a6b5-83c1-488c-a4e8-05167abe1356 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0018681 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0042075 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0025061 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0002170 infores:hetionet CAID:CA8603039 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603039 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000419.5:c.1545-1G>A occurs within the canonical splice acceptor site of intron 16. It is predicted to cause skipping of biologically-relevant-exon 16, resulting in a frameshift with a premature stop codon in exon 17/30, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (UPN 5 in PMID: 16879215) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 14.9%, as measured by flow cytometry. UPN 5 is homozygous for this variant (PM3_supporting; PMID: 16879215). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003266 (1/30616alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603039/MONDO:0100326/011 2022-09-20 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:2663 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0020458 infores:hetionet CHEBI:6472 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0042267 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0346989 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0346989 infores:hetionet CAID:CA229440 biolink:causes MONDO:0009861 infores:clingen CAID:CA229440 MONDO:0009861 PMID:10196714 Pathogenic PVS1, PM2, PP4 The c.137delG (p.Gly46Vfs*15) is a frameshift in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 1 individual with PKU (BH4 deficiency not excluded), who carried a second splicing variant (PP4; PMID: 10196714 ). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229440/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10127 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0025323 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0003123 infores:hetionet CHEBI:9763 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C2129214 infores:hetionet CHEBI:100241 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1262036 infores:hetionet CHEBI:3650 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0232459 infores:hetionet CHEBI:4798 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0232462 infores:hetionet CHEBI:31949 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0344320 infores:hetionet CHEBI:8774 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0011606 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0020651 infores:hetionet CHEBI:2453 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0852911 infores:hetionet NCBITaxon:6308 biolink:causes MONDO:0005974 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6308 MONDO:0005974 CHEBI:9674 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0549249 infores:hetionet CHEBI:135530 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0021843 infores:hetionet NCBIGene:63035 biolink:causes MONDO:0026727 infores:monarchinitiative not_provided not_provided HGNC:25657 MONDO:0026727 uuid:b2097a0c-a28c-4d45-88d0-a700d9351fc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0476273 infores:hetionet CHEBI:3504 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0005741 infores:hetionet CHEBI:6437 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0030305 infores:hetionet CHEBI:4315 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0018965 infores:hetionet CHEBI:10023 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042024 infores:hetionet CHEBI:68478 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0152031 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1262013 infores:hetionet CHEBI:7507 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C1325847 infores:hetionet CHEBI:8081 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0018681 infores:hetionet CHEBI:9943 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0025320 infores:hetionet CHEBI:5280 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0085636 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0021053 infores:hetionet CHEBI:6909 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0019521 infores:hetionet CHEBI:15765 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0041969 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0009450 infores:hetionet CHEBI:101278 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0014724 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0042373 infores:hetionet CHEBI:38940 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0005758 infores:hetionet CHEBI:6339 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0011603 infores:hetionet CHEBI:23765 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0032617 infores:hetionet CHEBI:161680 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0000729 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0020517 infores:hetionet CHEBI:119486 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151578 infores:hetionet CHEBI:4856 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0018790 infores:hetionet CHEBI:68606 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0017178 infores:hetionet CHEBI:31644 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0947912 infores:hetionet CHEBI:9445 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0013428 infores:hetionet CHEBI:64355 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0016204 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0004096 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0403632 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C1096670 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C1096670 infores:hetionet CHEBI:63619 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0575081 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030312 infores:hetionet CAID:CA267686 biolink:causes MONDO:0009861 infores:clingen CAID:CA267686 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 The c.913-3C>G variant in PAH is reported Likely Pathogenic in ClinVar (see variant ID 120294) by one laboratory, which states that it was found in a PKU patient but does not provide further information to support their classification. It does not appear to have been reported in the published literature. The variant is a non-canonical splice variant in PAH; it is predicted to result in altered splicing by relevant in-silico predictors, e.g., Human Splicing Finder, dbSNV ADA score 0.9997 (PP3). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267686/MONDO:0009861/006 2019-11-08 2019-11-08 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:476 biolink:causes MONDO:0054833 infores:monarchinitiative not_provided not_provided HGNC:799 MONDO:0054833 uuid:9bd0e462-af7b-4eb3-8de0-edf40890fa18 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000277 biolink:causes MONDO:0017623 infores:clingen CAID:CA000277 MONDO:0017623 PMID:21869887 Uncertain Significance PP2, PM2_Supporting, BS3_Supporting, BP4 PM6, PVS1, BP7, BP5, BS1, BS4, PP3, PP1, PP4, BS2, PM4, PM5, PM1, PM3, BA1, BP3, BP1, BP2, PS1, PS3, PS4, PS2 PTEN c.1061C>T (p.Pro354Leu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score = 0.1615) per Mighell et al. 2018 (PMID: 29706350).BP4: REVEL score < 0.5 (score=0.402)Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 2 benign supporting and 2 pathogenic supporting codes get -1*2 + 1*2 points, total is 0 (VUS). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000277/MONDO:0017623/003 2023-10-11 2023-10-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2663 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040264 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0085610 infores:hetionet CHEBI:50648 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0033845 infores:hetionet CHEBI:77032 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0011603 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019080 infores:hetionet CHEBI:17303 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0014457 infores:hetionet CHEBI:6715 biolink:causes MONDO:0015193 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020305 infores:hetionet CHEBI:49960 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0311468 infores:hetionet CHEBI:10101 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011124 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0042109 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0549405 infores:hetionet NCBIGene:55325 biolink:causes MONDO:0031052 infores:monarchinitiative not_provided not_provided HGNC:25640 MONDO:0031052 uuid:c99a337e-fcf7-4389-bd87-58c14678ea6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3240 biolink:causes MONDO:0013564 infores:monarchinitiative not_provided not_provided HGNC:5141 MONDO:0013564 uuid:0a2824a6-6d4f-4eb4-88d1-a0c07a797c82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0019521 infores:hetionet CHEBI:63618 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C2047937 infores:hetionet CHEBI:71028 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0017178 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0001339 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0235416 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0036572 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0243026 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0031350 infores:hetionet CHEBI:9667 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0042963 infores:hetionet GO:0048374 biolink:causes GO:0048370 infores:ubergraph knowledge_assertion manual_agent GO:0048374 GO:0048370 CHEBI:10119 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0497156 infores:hetionet CHEBI:63613 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0231218 infores:hetionet NCBITaxon:487 biolink:causes MONDO:0005373 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:487 MONDO:0005373 CHEBI:8764 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042024 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0178298 infores:hetionet CAID:CA386295444 biolink:causes MONDO:0009861 infores:clingen CAID:CA386295444 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PM5, PM2_Supporting The c.782G>T (p.Arg261Leu) variant in PAH has been previously reported Pathogenic by one clinical laboratory in ClinVar (see variant ID 576255); the laboratory stated that it was found as an “inherited” allele in 1 Han Chinese proband with PKU (subtype not otherwise specified, no further phenotypic details given). No further information regarding zygosity, familial segregation, and/or functional assays was provided, and no formal classification criteria were given, aside from “case-control” was given in the collection method. The variant results in a substitution of a highly conserved Arg residue with Leucine; the two amino acid residues are physiochemically distinct (basic versus nonpolar side chains) and the substitution is predicted damaging by multiple lines of computational evidence, e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.979) (PP3_Strong). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_Supporting). Other missense changes at this Arg (Arg261) have been previously reported Pathogenic or Likely Pathogenic in ClinVar, e.g., p.Arg261Gln (Pathogenic per internal PAH ClinGen Working Group classification, ClinVar ID 582), as well as p.Arg261Gly and p.Arg261Pro (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PP3_Strong, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386295444/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:404903 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042109 infores:hetionet NCBIGene:506 biolink:causes MONDO:0859302 infores:monarchinitiative not_provided not_provided HGNC:830 MONDO:0859302 uuid:0c119c1a-3ea5-41f5-8adc-1c236fd50945 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0743680 infores:hetionet NCBIGene:7415 biolink:causes MONDO:0014735 infores:monarchinitiative not_provided not_provided HGNC:12666 MONDO:0014735 uuid:e0ce98ac-defc-4c49-81a7-dd9dfafe6b12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1298 biolink:causes MONDO:0010844 infores:monarchinitiative not_provided not_provided HGNC:2218 MONDO:0010844 uuid:0ffdac40-0147-4428-b9dc-337d649a509f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0011615 infores:hetionet CHEBI:6520 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0518015 infores:hetionet NCBIGene:29887 biolink:causes MONDO:0014040 infores:monarchinitiative not_provided not_provided HGNC:14974 MONDO:0014040 uuid:9a088827-ac80-4e28-b3cb-839182338a29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0039231 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0280100 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0280100 infores:hetionet CHEBI:6339 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0020546 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011570 infores:hetionet NCBIGene:189 biolink:causes MONDO:0009823 infores:monarchinitiative not_provided not_provided HGNC:341 MONDO:0009823 uuid:bc3a761b-6168-4fa9-8bd2-ab6194f61f2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0039231 infores:hetionet CHEBI:75998 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0231528 infores:hetionet CHEBI:8802 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0028961 infores:hetionet CHEBI:5864 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0019080 infores:hetionet CAID:CA233931 biolink:causes MONDO:0015152 infores:clingen CAID:CA233931 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PP3, PS3_Moderate, PM2_Supporting The NM_003494.4: c.2790G>C variant in DYSF, which is also known as NM_001130987.2: c.2844G>C p.(Trp948Cys), is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 930, p.(Trp930Cys). This variant has been detected in at least three individuals with LGMD (PMID: 18853459, 36983702, 27602406), including confirmed in trans with a pathogenic variant (NM_003494.4: c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID: 18853459, LOVD Individual #00215573) and in unknown phase with a pathogenic variant (NM_003494.4: c.2643+1G>A, 0.5 pts, PMID: 36983702) (PM3). Although both patients were reported to have additional DYSF variants in unknown phase, these other variants could be classified as likely benign. At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 18853459). This variant is absent from gnomAD v2.1.1, v3.1.2, and v4.1.0 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Trp930Cys protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/06/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA233931/MONDO:0015152/180 2025-03-06 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:30659 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0020615 infores:hetionet CHEBI:47780 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0852911 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0029443 infores:hetionet CHEBI:36795 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0015230 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0267792 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0853692 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0022650 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030312 infores:hetionet NCBIGene:57468 biolink:causes MONDO:0014718 infores:monarchinitiative not_provided not_provided HGNC:13818 MONDO:0014718 uuid:f74db9a2-18cb-4132-9044-779a7318412e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:204928 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0002874 infores:hetionet GO:0021822 biolink:causes GO:0021543 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0021543 CAID:CA015706 biolink:causes MONDO:0005045 infores:clingen CAID:CA015706 MONDO:0005045 PMID: Uncertain Significance PM2, PP3 PM5, PM1, PM6, PP1, BA1, BS1, BS4, PS1, PS4, PS2 The NM_000257.4(MYH7):c.511A>C (p.Asn171His) variant has been identified in 1 individual with HCM (GeneDx pers. comm.), however, this data is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015706/MONDO:0005045/002 2021-11-19 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA145881 biolink:causes MONDO:0001586 infores:clingen CAID:CA145881 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.314G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 105 (p.Arg105Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2431 (22127/91024 alleles; 2838 homozygotes; Grpmax Filtering AF 95% confidence = 0.2404) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92641). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145881/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true NCBITaxon:29461 biolink:causes MONDO:0001190 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:29461 MONDO:0001190 CHEBI:68558 biolink:causes UMLS:C0333291 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0333291 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0178298 infores:hetionet CHEBI:10119 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0542571 infores:hetionet CHEBI:9737 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0040034 infores:hetionet CHEBI:5856 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0030252 infores:hetionet CHEBI:2549 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0039231 infores:hetionet CHEBI:5138 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014724 infores:hetionet CHEBI:64312 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027540 infores:hetionet CHEBI:9139 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0006277 infores:hetionet CHEBI:27777 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0002878 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003811 infores:hetionet CHEBI:5123 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0011168 infores:hetionet CHEBI:7476 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018946 infores:hetionet CHEBI:4672 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0237849 infores:hetionet NCBIGene:55252 biolink:causes MONDO:0014963 infores:monarchinitiative not_provided not_provided HGNC:23805 MONDO:0014963 uuid:de950119-052d-4ea6-a843-afc5b71e7266 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51173 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0011991 infores:hetionet CHEBI:101853 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0852911 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0018799 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0151971 infores:hetionet CHEBI:2639 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0002874 infores:hetionet CHEBI:127780 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0030305 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011570 infores:hetionet CHEBI:8888 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0015732 infores:hetionet NCBIGene:56171 biolink:causes MONDO:0957252 infores:monarchinitiative not_provided not_provided HGNC:18661 MONDO:0957252 uuid:d8eb08fe-cc9e-44cc-b16c-e880e67d4fbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9566 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0162830 infores:hetionet NCBITaxon:1637 biolink:causes MONDO:0005828 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1637 MESH:D008088 DB00199_MESH_D008088_1DB00254_MESH_D008088_1DB00199_MESH_D008088_2DB02703_MESH_D008088_1 CHEBI:63617 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019572 infores:hetionet CHEBI:8764 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0852911 infores:hetionet CHEBI:5441 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0002878 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1306341 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0227791 infores:hetionet CHEBI:4356 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0235896 infores:hetionet CHEBI:144093 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C3665386 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0015663 infores:hetionet CHEBI:47519 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085624 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011551 infores:hetionet NCBIGene:7045 biolink:causes MONDO:0012043 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0012043 uuid:245bb3ea-2ebc-4feb-ae4a-897a3240d973 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:127534 biolink:causes MONDO:0033012 infores:monarchinitiative not_provided not_provided HGNC:4286 MONDO:0033012 uuid:0a007aa4-0a7d-44d0-bf44-8fe0179854b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004998 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0233494 infores:hetionet CHEBI:6402 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030252 infores:hetionet CHEBI:4672 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085669 infores:hetionet CHEBI:4887 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0004093 infores:hetionet CHEBI:4710 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0014457 infores:hetionet CHEBI:53760 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0751295 infores:hetionet CHEBI:10650 biolink:causes HP:0001933 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0854107 infores:hetionet CHEBI:5134 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C1609512 infores:hetionet CHEBI:6128 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0221512 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0151736 infores:hetionet UMLS:C1144403 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0039231 infores:hetionet CHEBI:38940 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C2363731 infores:hetionet CHEBI:63622 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0018834 infores:hetionet CHEBI:47781 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0344232 infores:hetionet CHEBI:27732 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0001122 infores:hetionet CHEBI:10101 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1527344 infores:hetionet NCBIGene:1300 biolink:causes MONDO:0007983 infores:monarchinitiative not_provided not_provided HGNC:2185 MONDO:0007983 uuid:5550dab5-bb4b-4e7a-97b2-c97d36a02632 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135925 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0393761 infores:hetionet UMLS:C0009315 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0034642 infores:hetionet CHEBI:28177 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0032617 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0038358 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0948586 infores:hetionet CAID:CA000039 biolink:causes MONDO:0018875 infores:clingen CAID:CA000039 MONDO:0018875 PMID: Uncertain Significance BP4, BS2_Supporting, PP4, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM1, BS1, BS3, BS4, PM6, PP3, PP1 The NM_000546.6(TP53):c.1102C>T variant in TP53 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 368 (p.His368Tyr). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Ambry). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.2582; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PP4, PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000039/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50859 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0015256 infores:hetionet NCBITaxon:543 biolink:causes MONDO:0019345 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:543 MESH:D004405 DB01015_MESH_D004405_1 CHEBI:45285 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0038002 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020517 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0277884 infores:hetionet CHEBI:8890 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0340865 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0004936 infores:hetionet CHEBI:51141 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0008031 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1287298 infores:hetionet CHEBI:64064 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0002994 infores:hetionet CHEBI:50742 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0085605 infores:hetionet CHEBI:2676 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0018681 infores:hetionet CHEBI:50131 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0023530 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0242350 infores:hetionet CHEBI:77260 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0025345 infores:hetionet CHEBI:52717 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085605 infores:hetionet CHEBI:63580 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235309 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0003123 infores:hetionet CHEBI:474180 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0014457 infores:hetionet CHEBI:7824 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0008031 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1142160 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1142160 infores:hetionet CHEBI:5130 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0004093 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0234215 infores:hetionet CAID:CA114117 biolink:causes MONDO:0015628 infores:clingen CAID:CA114117 MONDO:0015628 PMID:16322474 Pathogenic PS2_Supporting, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS3, PS4_Very Strong PM5 NM_000552.4(VWF):c.4789C>T (p.Arg1597Trp) missense variant has been identified in at least 40 probands reported to have type 2A VWD. This variant has been reported in at least 16 probands meeting PP4 laboratory phenotype criteria. (PS4_VeryStrong; PMIDs: 31939074, 22102197, 26791163, 27214365, 22329792, 14630825, 33807613, 23702511, 25689060, 27766062, 1380739, 16961623, 19277422, 22871923, 23355534). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 11%), low VWF:RCo/VWF:Ag ratio of 0.28, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additionally, a normal RIPA assay was reported for this patient (PP4_moderate, PMID: 25689060 Patient 7). The variant has been reported to segregate with VWD type 2A through >2 affected meioses in at least 2 families (PP1_moderate; PMID: 22329792, 27766062). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 1 individual with VWD type 2A (PS2_supporting; PMID: 27214365). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting), a single allele is present in the European (Finnish) population. ADAMTS susceptibility assay, in 293 EBNA cells and hydrodynamic mouse model, expressing recombinant R1597W VWF showed increased susceptibility indicating that this variant has a damaging effect on protein function and the hydrodynamic model is a strong recapitulation human patients with a multimer profile was skewed toward lower molecular weight multimers, reduced VWF:Ag, and reduced thrombus formation. (PMID: 16322474, 29186156, 22372972)(PS3). The computational predictor CADD gives a PHRED score of 27.4, which is above the ClinGen VWD VCEP threshold of >20 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP1_moderate, PP4_moderate, PS4_VeryStrong, PP3, PM2_supporting, PS2_supporting, PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114117/MONDO:0015628/081 2024-08-13 2024-08-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6933 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0013428 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0040034 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0476414 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0476414 infores:hetionet CHEBI:72323 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0011603 infores:hetionet CHEBI:92712 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0233407 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0349790 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0021053 infores:hetionet CHEBI:63791 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0917801 infores:hetionet CHEBI:3504 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0038325 infores:hetionet CHEBI:91834 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0043352 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0034065 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011551 infores:hetionet CHEBI:7465 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0009782 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0022116 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0026848 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0332575 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0162429 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0574067 infores:hetionet CHEBI:50729 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0038999 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0234192 infores:hetionet CHEBI:71415 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0019158 infores:hetionet CHEBI:5864 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0220981 infores:hetionet CAID:CA315433382 biolink:causes MONDO:0007064 infores:clingen CAID:CA315433382 MONDO:0007064 PMID: Pathogenic PP4, PVS1, PM2_Supporting PM3 The c.976-1G>C (NM_000022.4) variant in ADA occurs within the canonical splice acceptor site of intron 10. It is expected to disrupt RNA splicing, disrupting the reading frame, and is predicted to undergo NMD. (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 9/761480) of the c.976-1G>C variant in ADA is 0.000005560 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.At least one patient with this variant displayed ADA-SCID phenotype corrected by ADA gene therapy (WITHOUT CNV testing performed, 1 pt), which is highly specific for ADA SCID (PP4 is met) PMID 32307643. In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PVS1, PM2_Supporting, and PP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA315433382/MONDO:0007064/114 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51041 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020625 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005173 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0022602 infores:hetionet CHEBI:63635 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C2047937 infores:hetionet CHEBI:119486 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011253 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0152227 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0267596 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042401 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0017160 infores:hetionet CAID:CA397832443 biolink:causes MONDO:0018875 infores:clingen CAID:CA397832443 MONDO:0018875 PMID: Uncertain Significance BP4, PS4, PP1, PP4, PM2_Supporting BA1, PS2, PS1, PS3, PM5, PM1, BS1, BS3, BS4, PP3 The NM_000546.6: c.1039G>A variant in TP53 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 347 (p.Ala347Thr). This variant has been reported in 2 families meeting Classic LFS criteria and 6 unrelated probands meeting Revised Chompret criteria. In addition, this variant was identified in 1 female with HER2+ breast cancer under the age of 40. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 37437600; 33249490, 34906214, Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 3 families (PP1; Internal lab contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors). Based on this evidence, this variant scores 4.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 37437600; 33249490, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.0187547; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met). In summary, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PP1, PP4, BP4_Moderate, PM2_Supporting. (Bayesian Points: 5; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397832443/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0424295 infores:hetionet CHEBI:8768 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0242184 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0040046 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017178 infores:hetionet CAID:CA367400138 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400138 MONDO:0015967 PMID: Uncertain Significance PM1, PM5_Supporting, PP2, PP3, PM2_Supporting, BP2 PP4 The c.883G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 295 (p.(Gly295Arg)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.99, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and this variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies). In this individual the variant was in cis with the variant c.1361C>A p.Ala454Gly, which has been classified as likely pathogenic by the ClinGen MDEP, and thus PP4_Moderate was not applied (BP2). Three other missense variants, c.883G>A p.Gly295Ser, c.884G>A p.Gly295Asp, and c.884G>T p.Gly295Val, have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.883G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, BP2, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400138/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:52172 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0004604 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0677500 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0029882 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011551 infores:hetionet CHEBI:17303 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1260922 infores:hetionet CHEBI:32315 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018681 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0027769 infores:hetionet CHEBI:5138 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011253 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233494 infores:hetionet CHEBI:37924 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0149745 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0006145 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027051 infores:hetionet CHEBI:32192 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0851578 infores:hetionet UBERON:0003072 biolink:causes UBERON:0003073 infores:ubergraph knowledge_assertion manual_agent UBERON:0003072 UBERON:0003073 CHEBI:465284 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0852810 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151826 infores:hetionet CHEBI:8346 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020461 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0948594 infores:hetionet CAID:CA4239423 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239423 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1148C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 383 (p.(Ser383Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 12955723). This variant was identified in another individual with a phenotype suggestive of GCK-hyperglycemia; however, the clinical parameters were not met for PP4 according to ClinGen MDEP VCEP (PhD dissertation by Ovsyannikova [https://iimed.ru/userfiles/models/passages-files/Ovsyannikova_AK_dissertacia.pdf], variant also cited in PMID: 33477506). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 12955723, 33477506, PhD dissertation by Ovsyannikova). In summary, c.1148C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239423/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CAID:CA386299458 biolink:causes MONDO:0009861 infores:clingen CAID:CA386299458 MONDO:0009861 PMID: Uncertain Significance PM2, PM5, PP3 The c.506G>C (p.Arg169Pro) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 446524); no further information is provided. At the time of review, the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent in gnomAD (PM2). Other missense variants at this site are pathogenic/likely pathogenic – p.Arg169Ser (variant ID 932262), p.Arg169His (variant ID 102706), p.Arg169Gly (variant ID 551103), and p.Arg169Cys (variant ID 125436) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386299458/MONDO:0009861/006 2021-03-26 2021-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:87715 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0002871 infores:hetionet CAID:CA915940687 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940687 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000419.5:c.2673_2674dup (p.Ile892LysfsTer19) variant in ITGA2B exon 26 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 27/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one proband with Glanzmann thrombasthenia. This individual (GT70, PMID: 19691478) was compound heterozygous for this variant and an ITGA2B variant provisionally classified as likely pathogenic by the Platelet Disorders VCEP (c.1424_1427dup (p.Ala477GlyfsTer111), phase not confirmed). However, PM3 was not applied because the c.1424_1427dup variant is not sufficiently rare to meet PM2_Supporting. At least one patient (Patient GT70 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting, PP4_Moderate. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940687/MONDO:0100326/011 2022-03-09 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6690 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042035 infores:hetionet CHEBI:8232 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0231528 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042571 infores:hetionet CHEBI:8069 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0011606 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027932 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0004936 infores:hetionet CHEBI:4027 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0033771 infores:hetionet CHEBI:7565 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0236075 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0521839 infores:hetionet CHEBI:94392 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0015230 infores:hetionet CAID:CA320248929 biolink:causes MONDO:0011071 infores:clingen CAID:CA320248929 MONDO:0011071 PMID: Benign BA1 PS4, PS3, PS1, PS2, BP2, BP3, BP1, BP4, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.*3090A>G is a 3' UTR variant. MAF of 0.004228 (0.4228%, 22/5204 alleles) in the East Asian subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320248929/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3756 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009144 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1328375 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1328375 infores:hetionet CHEBI:47898 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018932 infores:hetionet CHEBI:77733 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0037317 infores:hetionet NCBIGene:7415 biolink:causes MONDO:0013501 infores:monarchinitiative not_provided not_provided HGNC:12666 MONDO:0013501 uuid:b1860fae-0812-4085-b912-3f9954d019ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7444 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0004093 infores:hetionet CHEBI:36791 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014457 infores:hetionet CHEBI:3732 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0003126 infores:hetionet CHEBI:91834 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0010200 infores:hetionet CHEBI:9434 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0259749 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015230 infores:hetionet CHEBI:3723 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085633 infores:hetionet CHEBI:15553 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0242184 infores:hetionet CAID:CA658824401 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824401 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP2, BP1, BP4, BP3, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.4(RUNX1):c.690_691delinsAA (p.Leu231Met) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). There are no literature reports of patients with this variant and Familial Platelet Disorder with a predisposition to hematologic malignancies; however, one unpublished proband meeting at least one of the RUNX1 phenotype criteria has been noted (PS4_supporting; SCV000807802.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824401/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4551 biolink:causes UMLS:C0012254 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0012254 infores:hetionet CHEBI:2668 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C1443060 infores:hetionet CHEBI:391960 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0018681 infores:hetionet CHEBI:64354 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0041657 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032131 infores:hetionet CHEBI:3216 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042075 infores:hetionet GO:0048819 biolink:causes GO:0043588 infores:ubergraph knowledge_assertion manual_agent GO:0048819 GO:0043588 CHEBI:8207 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C2979982 infores:hetionet CHEBI:204928 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0687713 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0036572 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0232459 infores:hetionet CAID:CA274102 biolink:causes MONDO:0009290 infores:clingen CAID:CA274102 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Supporting PM5 "The NM_000152.5:c.1942G>A (p.Gly648Ser) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v2.1.1 of 0.00034 (10/29720 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 18 patients with a diagnosis of Pompe disease have been reported with this variant including those with documented deficient GAA activity and/or symptoms consistent with infantile onset Pompe disease and/or on enzyme replacment therapy (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962) (PP4_Moderate). In a study of the Maroon population of French Guiana, 9 out of 15 probands with ""enzymatically confirmed"" infantile onset Pompe disease were compound heterozygous for c.1942G>A (p.Gly648Ser) and c.2560C>T (p.Arg854Ter), a variant which has been classified as pathogenic by the ClinGen LD VCEP. The two variants are assumed to be in trans based on the high carrier frequency of both variants in that population. The carrier frequency of c.1942G>A (p.Gly648Ser) was 1 in 47 (9/425 women tested) (PMID: 29637184). Patients have also been reported who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.2214G>A (p.Trp768Ter) (PMID: 26575883) and c.-32-13T>G (2 patients, PMIDs: 17643989, 25455803, 27193587). In addition, at least 3 patients are homozygous for the variant (PMID: 26497565, 29122469, 29889338, 30214072) (PM3_VeryStrong). Patients compound heterozygous for the variant and c.1076-22T>G (17643989, 25455803), c.2646+2T>A (PMID: 29422078), and c.1099T>C (p.Trp367Arg) (PMID: 31510962) have also been reported. However, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid circular logic. When expressed in SV40_immortalized GAA deficient fibroblasts, the enzyme activity was ""negligible"" (PMID: 9535769), and when expressed in COS cells, the variant resulted in <2% wild type GAA activity (PMID: 19862843) (PS3_Supporting). The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function (PP3). Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID: 188902). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274102/MONDO:0009290/010 2023-07-03 2023-09-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:116278 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0018099 infores:hetionet CHEBI:5778 biolink:causes HP:0010742 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0522035 infores:hetionet CHEBI:6375 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085636 infores:hetionet CHEBI:64354 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020625 infores:hetionet CHEBI:135939 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0037763 infores:hetionet CHEBI:194135 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0026826 infores:hetionet CHEBI:168396 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151746 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013298 infores:hetionet NCBIGene:55800 biolink:causes MONDO:0013146 infores:monarchinitiative not_provided not_provided HGNC:20665 MONDO:0013146 uuid:ecdcd28d-3de3-4951-a350-b9af631cca88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0156312 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0009450 infores:hetionet CHEBI:16914 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0015230 infores:hetionet CHEBI:7465 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0011603 infores:hetionet CHEBI:6822 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0014518 infores:hetionet CHEBI:2611 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0017178 infores:hetionet CHEBI:178699 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0008031 infores:hetionet CHEBI:8764 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151907 infores:hetionet CHEBI:17650 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0221166 infores:hetionet CHEBI:32293 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0013604 infores:hetionet CAID:CA291993 biolink:causes MONDO:0021060 infores:clingen CAID:CA291993 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.546G>A (p.Ala182=) variant in the MAP2K2 gene is 0.083% (7/3952) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA291993/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50223 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0011570 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0031085 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0017160 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0003123 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235490 infores:hetionet CHEBI:87715 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0018681 infores:hetionet CHEBI:63619 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0008370 infores:hetionet NCBIGene:8777 biolink:causes MONDO:0014085 infores:monarchinitiative not_provided not_provided HGNC:7208 MONDO:0014085 uuid:a278c428-b946-4e19-bbb8-98a293234437 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7907 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0332575 infores:hetionet CHEBI:135005 biolink:causes HP:0030155 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0236078 infores:hetionet CHEBI:8502 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0031117 infores:hetionet CHEBI:8378 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0019521 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0004936 infores:hetionet GO:0070382 biolink:causes GO:0006887 infores:ubergraph knowledge_assertion manual_agent GO:0070382 GO:0006887 CHEBI:9086 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0281856 infores:hetionet CHEBI:134966 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0699744 infores:hetionet CHEBI:3216 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0010200 infores:hetionet CHEBI:63599 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0151701 infores:hetionet CHEBI:63618 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0018418 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0009450 infores:hetionet CHEBI:31623 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0018784 infores:hetionet CHEBI:9086 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0039070 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0041969 infores:hetionet CHEBI:68554 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0019209 infores:hetionet NCBIGene:5663 biolink:causes MONDO:0013398 infores:monarchinitiative not_provided not_provided HGNC:9508 MONDO:0013398 uuid:01999340-0d49-4f7d-b710-5242a77c0c7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38545 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0035410 infores:hetionet CHEBI:567361 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0005741 infores:hetionet NCBIGene:9895 biolink:causes MONDO:0014016 infores:monarchinitiative not_provided not_provided HGNC:19957 MONDO:0014016 uuid:4bca2aad-6824-4197-8c59-8c26b3284086 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA9871467 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871467 MONDO:0007064 PMID: Uncertain Significance PM2, BA1, BS1 The c.930G>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Methionine by Isoleucine at amino acid 310 (p.Met310Ile).The filtering allele frequency (the upper threshold of the 95% CI of 37/74916 alleles) of the c.930G>A variant in ADA is 0.0003682 for African/African American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold for BS1 (>0.00161) and BA1 (>0.00721) but higher than the threshold (<0.0001742) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871467/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:713 biolink:causes MONDO:0958187 infores:monarchinitiative not_provided not_provided HGNC:1242 MONDO:0958187 uuid:469b556a-7895-4bbb-9e5c-e92fd6256467 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0542008 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C1384666 infores:hetionet CHEBI:8212 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0231528 infores:hetionet CHEBI:3127 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0003862 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151970 infores:hetionet CHEBI:6912 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0042963 infores:hetionet NCBIGene:9913 biolink:causes MONDO:0700301 infores:monarchinitiative not_provided not_provided HGNC:30632 MONDO:0700301 uuid:0f202e44-2542-4fca-a59f-aa4f1d909321 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135888 biolink:causes MONDO:0004712 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0936250 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0241863 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0332534 infores:hetionet CHEBI:48131 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0019345 infores:hetionet CHEBI:5138 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151315 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006840 infores:hetionet UMLS:C0120107 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0015967 infores:hetionet CHEBI:3515 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0002994 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0858899 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0858899 infores:hetionet CHEBI:7444 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0027497 infores:hetionet CHEBI:5959 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042029 infores:hetionet CAID:CA267653 biolink:causes MONDO:0009861 infores:clingen CAID:CA267653 MONDO:0009861 PMID:18294361PMID:18299955 Pathogenic PVS1, PM2, PP4 BS2, BA1, PS3, BS1 The c.350delC variant in PAH has been previously reported in at least 2 Arab-Israeli probands with classic PKU (PMID: 18299955; PMID: 18294361); BH4 deficiency was not excluded (PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and the Greater Middle East Variome (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267653/MONDO:0009861/006 2018-12-22 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31981 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0232197 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877127 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877127 infores:hetionet CHEBI:9139 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0030554 infores:hetionet CHEBI:63605 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0162834 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0037274 infores:hetionet CHEBI:63630 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0039231 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0948594 infores:hetionet CAID:CA320251669 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251669 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.980T>G (p.Leu327Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251669/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3504 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0687713 infores:hetionet CHEBI:2666 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0027849 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038454 infores:hetionet CHEBI:31174 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0019345 infores:hetionet CHEBI:3215 biolink:causes HP:0025116 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0015930 infores:hetionet CHEBI:2549 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1142412 infores:hetionet CHEBI:7936 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022346 infores:hetionet CHEBI:2922 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0000737 infores:hetionet CHEBI:8107 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C3263723 infores:hetionet CHEBI:31176 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0015967 infores:hetionet CHEBI:3561 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042963 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0948594 infores:hetionet CAID:CA137317 biolink:causes MONDO:0019497 infores:clingen CAID:CA137317 MONDO:0019497 PMID: Benign BA1 BP4 The variant NM_022124.6:c.2263C>T in CDH23 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 755 (p.His755Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.008578 (781/91042 alleles, 11 homozygotes) for the South Asian population, which is higher than the ClinGen Hearing Loss CDH23 threshold (≥0.005) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.211, which meets no codes. This variant was reported in 2 individuals with Usher syndrome and one with Retinitis Pigmentosa, though without any evidence of pathogenicity (PM3 not met; PMIDs: 18429043, 21569298, 30718709). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA137317/MONDO:0019497/005 2024-12-18 2025-03-28 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true UMLS:C0010592 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C3160858 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0151824 infores:hetionet CHEBI:15367 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0700225 infores:hetionet CHEBI:28864 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0855775 infores:hetionet CHEBI:9555 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0038362 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0012833 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0014868 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009319 infores:hetionet CHEBI:27504 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0030312 infores:hetionet CHEBI:7443 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0001925 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0002170 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0037274 infores:hetionet NCBIGene:4810 biolink:causes MONDO:0010544 infores:monarchinitiative not_provided not_provided HGNC:7820 MONDO:0010544 uuid:c9123400-e2e9-4b8a-8f95-5003701c6f08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0314719 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011991 infores:hetionet CHEBI:48131 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0162835 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0027769 infores:hetionet CHEBI:5280 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0018520 infores:hetionet UMLS:C0903898 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0020458 infores:hetionet CHEBI:30830 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0022107 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0434437 infores:hetionet CHEBI:3312 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0017181 infores:hetionet CHEBI:27732 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0012739 infores:hetionet CAID:CA414775553 biolink:causes MONDO:0044970 infores:clingen CAID:CA414775553 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, BP4 PP1, PS4, PS3 The m.4735C>G (p.T89N) variant in MT-ND2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in population databases (PM2_supporting, most recently queried 3/22/2021). In silico tools (APOGEE) predict this variant to be neutral with a score of 0.31 (BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414775553/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:53760 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0027497 infores:hetionet CHEBI:47780 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0232462 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0413252 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0029408 infores:hetionet CHEBI:8871 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0025345 infores:hetionet NCBIGene:9578 biolink:causes MONDO:0859239 infores:monarchinitiative not_provided not_provided HGNC:1738 MONDO:0859239 uuid:b3f09358-5973-40c1-849b-9dd53cdd4b05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0227791 infores:hetionet CHEBI:3478 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0022354 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0018991 infores:hetionet UMLS:C0657912 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151766 infores:hetionet GO:0061132 biolink:causes GO:0061113 infores:ubergraph knowledge_assertion manual_agent GO:0061132 GO:0061113 CHEBI:135888 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C1384353 infores:hetionet CHEBI:46295 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0009782 infores:hetionet CHEBI:47657 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C1443060 infores:hetionet CAID:CA205183 biolink:causes MONDO:0010726 infores:clingen CAID:CA205183 MONDO:0010726 PMID: Likely Benign BS2 BP4, PS4, PM1, PM5, BS1, PP3 The c.748C>T p.Arg250Cys variant in MECP2 (NM_004992.3) is present in 1 XY and 4 XX individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria). The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.Arg250Cys variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools are inconclusive for this variant (criteria not met). Alternative missense variants (p.Arg250Gly and p.Arg250His) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the c.748C>T p.Arg250Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA205183/MONDO:0010726/036 2023-12-06 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:18248 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0851341 infores:hetionet CHEBI:50924 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1260880 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235639 infores:hetionet CHEBI:3084 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C1963818 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0022650 infores:hetionet CHEBI:70746 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0151970 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0027051 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0012833 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0035078 infores:hetionet CHEBI:7789 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0030252 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0020676 infores:hetionet CHEBI:63635 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0239340 infores:hetionet CAID:CA409108243 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108243 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting, PM1_Supporting The c.925C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to serine at codon 309 (p.(Arg309Ser)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.737, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.c.925C>T, p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309Ser (PM5_Supporting). In summary, c.778G>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_supporting, PP3, PM1_supporting, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108243/MONDO:0015967/085 2024-09-26 2024-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7565 biolink:causes HP:0031363 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151190 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020538 infores:hetionet CHEBI:63635 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011606 infores:hetionet CHEBI:34967 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C1384353 infores:hetionet CHEBI:4702 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0013378 infores:hetionet CHEBI:6846 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0009806 infores:hetionet CHEBI:2682 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0030196 infores:hetionet CAID:CA119014 biolink:causes MONDO:0800472 infores:clingen CAID:CA119014 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PP1_Strong, PVS1 PP3, BA1, BP4, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS4, BS1, PM2 The c.171G>A variant in CYP1B1 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Tryptophan at amino acid 57 (p.Trp57Ter). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1) = 0.0005210 (610 alleles out of 1,170,786), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). This nonsense variant was predicted to undergo NMD, meeting PVS1. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 23218701, pers. comm. E. Souzeau), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in five individuals with a CYP1B1-related phenotype. Three of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (all confirmed in trans) and two individuals are homozygous (non-consanguineous) for the variant (PMIDs: 32499604, 23218701, 37788597, 24281366, 30653986). Total points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 20 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Very strong, PP1_Strong. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119014/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CAID:CA402533223 biolink:causes MONDO:0012589 infores:clingen CAID:CA402533223 MONDO:0012589 PMID: Likely Benign BS2 BP4, PM2, BS1, PP3 The highest population minor allele frequency of the p.Met450Val variant in TCF4 in gnomAD v4.1 is 0.00004005 in the African/African American population (not sufficient to meet BS1 criteria). The p.Met450Val variant is observed in at least 2 unaffected individuals (internal database - Ambry Genetics) (BS2). In summary, the p.Met450Val variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2). (TCF4 Specifications v.4.0; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA402533223/MONDO:0012589/032 2025-06-25 2025-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8874 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0235848 infores:hetionet CHEBI:8356 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0428977 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C3160741 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0042373 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0340464 infores:hetionet CHEBI:94440 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0020580 infores:hetionet CHEBI:9588 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0036830 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0002871 infores:hetionet CHEBI:44185 biolink:causes EFO:0011046 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0858970 infores:hetionet CHEBI:209807 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0002792 infores:hetionet CHEBI:8768 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002994 infores:hetionet CHEBI:3561 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0024902 infores:hetionet CL:0000570 biolink:causes MONDO:0015277 infores:ubergraph knowledge_assertion manual_agent CL:0000570 MONDO:0015277 GO:0039502 biolink:causes GO:0045087 infores:ubergraph knowledge_assertion manual_agent GO:0039502 GO:0045087 CHEBI:9168 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020580 infores:hetionet CHEBI:17650 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0018790 infores:hetionet CAID:CA410206811 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206811 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP2, BP3, BA1, PM6, BP5, BP7, BS3, BS1, BS4, PVS1, PM5, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.727C>A (p.Pro243Thr) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.293, and the splice site predictor SpliceAI indicated no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206811/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0233632 infores:hetionet CHEBI:10023 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151578 infores:hetionet CHEBI:194135 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151579 infores:hetionet CHEBI:50122 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0034063 infores:hetionet CHEBI:29007 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0030193 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0851341 infores:hetionet CHEBI:7852 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0032617 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0040822 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0015397 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000945 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042485 infores:hetionet CHEBI:585948 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0030554 infores:hetionet CHEBI:5109 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0017979 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0020456 infores:hetionet CHEBI:8024 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013604 infores:hetionet CAID:CA016808 biolink:causes MONDO:0005045 infores:clingen CAID:CA016808 MONDO:0005045 PMID: Uncertain Significance PM1, PP3, PM2_Supporting, PS4_Supporting PM5, PM6, BA1, PP1, PS3, PP2, PP4, BS2, PM3, BS1, BS3, BS4, BP1, PS1, PS2, BP4, BP2, BP5 The NM_000257.4(MYH7):c.758G>T (p.Gly253Val) variant has been reported in at least 4 individuals with HCM (PS4_Supporting; Ambry pers. comm.; GeneDx pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2_Supporting, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016808/MONDO:0005045/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0090213 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0090213 GO:0007275 CHEBI:135888 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0036689 infores:hetionet CHEBI:65173 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0023380 infores:hetionet CHEBI:182080 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0041582 infores:hetionet CHEBI:31401 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042963 infores:hetionet NCBIGene:1075 biolink:causes MONDO:0009491 infores:monarchinitiative not_provided not_provided HGNC:2528 MONDO:0009491 uuid:d3706e8c-e522-4ebd-a28b-3f203d3e7fed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0025222 infores:hetionet CHEBI:50648 biolink:causes HP:0011032 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2364164 infores:hetionet CHEBI:51173 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0270996 infores:hetionet CAID:CA398324499 biolink:causes MONDO:0011132 infores:clingen CAID:CA398324499 MONDO:0011132 PMID: Likely Pathogenic PM2_Supporting, PM1, PS3, PP3_Moderate PP4 The variant NM_001369369.1(FOXN1):c.965A>G is predicted to cause a asparagine to serine substitution at amino acid position 322. The variant is absent from gnomAD 4.0 (PM2_supporting). The meta predictor REVEL predicts a potential disrupting effect on protein function with a score of 0.947, above the ≥0.932 threshold for PP3_moderate. The missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 322, and thus meets PM1. The variant was found in the heterozygous state in patient 5 from PMID:30809743 who had lymphopenia CD3 1007, CD4 782, reduced NBS TRECs 12 copies/uL. The patient was gene panel sequenced for SCID related genes. Additionally, in an unpublished mouse model, the variant when expressed in mice in the heterozygous state recapitulated features of FOXN1 immunodeficiency including T cell lymphopenia, decreased thymocytes, and a decreased thymic epithelial component. Heterozygous mice had normal FOXN1 protein expression and did not display hair loss (PS3). In summary this variant meets criteria to be classified as Likely Pathogenic for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PP3_moderate, PS3, and PM2_supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398324499/MONDO:0011132/113 2025-07-25 2025-07-25 Semidominant inheritance HP:0032113 Supports CHEBI:391960 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0000737 infores:hetionet CHEBI:7915 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0015967 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0278016 infores:hetionet NCBIGene:3889 biolink:causes MONDO:0033015 infores:monarchinitiative not_provided not_provided HGNC:6460 MONDO:0033015 uuid:8c61fec9-3b31-43ba-8509-3e176dd7a4a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0085681 infores:hetionet CHEBI:16469 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151908 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020517 infores:hetionet NCBIGene:64359 biolink:causes MONDO:0032800 infores:monarchinitiative not_provided not_provided HGNC:18008 MONDO:0032800 uuid:ae404db8-24a8-4952-83a8-a09e6080e4af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:142290 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0009806 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0000731 infores:hetionet CHEBI:27690 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0015967 infores:hetionet CHEBI:8874 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0497156 infores:hetionet CHEBI:8245 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0022116 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042267 infores:hetionet CHEBI:135935 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0085593 infores:hetionet CHEBI:53766 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0005779 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0038587 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085762 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0029882 infores:hetionet CHEBI:136040 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0042963 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0233632 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042514 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0021400 infores:hetionet NCBIGene:9158 biolink:causes MONDO:0014918 infores:monarchinitiative not_provided not_provided HGNC:3705 MONDO:0014918 uuid:3209fdaa-9f6e-4562-8950-b080f08e6bd5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2922 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0948586 infores:hetionet CHEBI:5864 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0876994 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0023895 infores:hetionet CHEBI:78320 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0042487 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0020550 infores:hetionet NCBIGene:5250 biolink:causes MONDO:0012557 infores:monarchinitiative not_provided not_provided HGNC:10989 MONDO:0012557 uuid:2c507f34-eb28-41f0-b869-f518c940fccc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63599 biolink:causes UMLS:C1168174 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C1168174 infores:hetionet UMLS:C0010592 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0009676 infores:hetionet CHEBI:16714 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0042571 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0233494 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0542239 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0542239 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1696943 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1696943 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242379 infores:hetionet CHEBI:9674 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0851578 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0019360 infores:hetionet CHEBI:8356 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040822 infores:hetionet CHEBI:2379 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0036974 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0919909 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0919909 infores:hetionet CHEBI:8874 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0008031 infores:hetionet CHEBI:134936 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0035455 infores:hetionet CHEBI:6472 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0030193 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0011570 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011609 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0085622 infores:hetionet CHEBI:5130 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014518 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0233571 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0031212 infores:hetionet CHEBI:3125 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0026821 infores:hetionet CAID:CA8602943 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602943 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate PM3, BS1, PM2, PP3 The NM_000419.5(ITGA2B):c.1769G>A (p.Arg590Gln) has been reported in one patient with suspected type 3 GT (PMID: 29675921). GT39 of PMID: 29675921 meets the criteria for PP4_moderate; including mucocutaneous bleeding, and impaired aggregation with all agonists except ristocetin. There was reduced function of αIIbβ3 measured by flow cytometry, however 43% PAC-1 binding was not considered sufficient to meet PP4_strong. GT39 is compound heterozygous for Cys857Phe (classified as VUS b the PD VCEP; SCV001809850.1) and Arg590Gln. Based on the evidence available at this time, the variant is classified as uncertain significance. GT-specific criteria applied: PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602943/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63577 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0042769 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0520904 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0520904 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0010709 infores:hetionet CHEBI:36791 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0542571 infores:hetionet CHEBI:68558 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0017178 infores:hetionet CHEBI:50859 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013456 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0027051 infores:hetionet CHEBI:47426 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0392525 infores:hetionet CHEBI:2618 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C1443060 infores:hetionet CHEBI:17549 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C1527311 infores:hetionet CHEBI:31236 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0149871 infores:hetionet CHEBI:75722 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2937350 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0522063 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0013395 infores:hetionet CHEBI:6359 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0020621 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0340952 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0340952 infores:hetionet CHEBI:9720 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0008489 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0018667 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D016724 DB01607_MESH_D016724_1 CHEBI:3216 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0003862 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0233472 infores:hetionet CHEBI:4470 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0027765 infores:hetionet CHEBI:28901 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0041364 infores:hetionet CAID:CA343723671 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723671 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting BP7, BS1, BS3, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BA1, BP4 The c.1342A>C variant in MYOC is a missense variant predicted to cause substitution of Threonine by Proline at amino acid 448 (p.Thr448Pro). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.649, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for primary open angle glaucoma (PMID: 10340788), not meeting the ≥ 3 segregations required for PP1. 3 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 28564705, 15534471, 10340788), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723671/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:2 biolink:causes MONDO:0024295 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D017192 DB02703_MESH_D017192_1DB09042_MESH_D017192_1DB00798_MESH_D017192_1DB04911_MESH_D017192_1 CHEBI:41977 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0019209 infores:hetionet NCBIGene:7259 biolink:causes MONDO:0012124 infores:monarchinitiative not_provided not_provided HGNC:12382 MONDO:0012124 uuid:be5fdc95-1120-43a8-b2c4-de1fb954a5ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019158 infores:hetionet CHEBI:2666 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0028643 infores:hetionet CHEBI:36791 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0270996 infores:hetionet CHEBI:94449 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0001807 infores:hetionet CHEBI:119486 biolink:causes MONDO:0016064 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0008925 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018418 infores:hetionet CHEBI:9086 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0022107 infores:hetionet CHEBI:5132 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0027497 infores:hetionet CHEBI:135686 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0004604 infores:hetionet CHEBI:8024 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0004604 infores:hetionet CHEBI:3172 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0036974 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042514 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0151849 infores:hetionet CHEBI:9168 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018524 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027796 infores:hetionet CHEBI:27834 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0016204 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0003123 infores:hetionet NCBIGene:570 biolink:causes MONDO:0030991 infores:monarchinitiative not_provided not_provided HGNC:932 MONDO:0030991 uuid:f8e49c1e-c458-40d0-acf4-81d7e1a665c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1963951 infores:hetionet CHEBI:8107 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0232726 infores:hetionet CHEBI:9571 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0917801 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0439857 infores:hetionet CHEBI:135925 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0015672 infores:hetionet NCBIGene:3854 biolink:causes MONDO:0014325 infores:monarchinitiative not_provided not_provided HGNC:6444 MONDO:0014325 uuid:374218ef-13cc-4237-a490-b71856e6a586 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55165 biolink:causes MONDO:0009359 infores:monarchinitiative not_provided not_provided HGNC:1161 MONDO:0009359 uuid:ed64d87e-c2b8-4d1d-a016-a3381494a6f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84883 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0919980 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0232459 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0004238 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0178298 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017178 infores:hetionet CHEBI:31184 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0026113 infores:hetionet CHEBI:3181 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0030232 infores:hetionet CAID:CA392339186 biolink:causes MONDO:0007947 infores:clingen CAID:CA392339186 MONDO:0007947 PMID: Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong, PS2_Supporting BP4, PM5, PS1 NM_00138 c.1850G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 617 (p.Cys617Tyr). This variant was found in a proband with ectopia lentis, thoracic aortic aneurysm and dissection, and skeletal features (PP4; Bichat internal data). It has also been reported in the literature in two probands, one meeting revised Ghent criteria for Marfan syndrome and one with EL and a systemic score of 7 (PS4_moderate; PMIDs: 27906200, 33483584). This variant was found to be de novo with confirmation of maternity and paternity in an individual with Marfan syndrome, without specific phenotypic features available (PS2_supporting; deCODE genetics internal data, ClinVar Variation ID: 495563). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys617Arg, p.Cys617Gly, p.Cys617Ser). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PM2_supporting, PS2_supporting, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392339186/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:72564 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020433 infores:hetionet CHEBI:63622 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0015672 infores:hetionet CHEBI:50692 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0001623 infores:hetionet CHEBI:27565 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0016204 infores:hetionet CAID:CA410148460 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148460 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1036C>T (p.Arg346Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). ClinVar has one entry for this variant (Invitae, ClinVar ID 2062797), but the affected status is unknown. To our knowledge, this variant has not been reported in the literature in individuals affected with RUNX1-related conditions. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148460/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:132233 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0014518 infores:hetionet CHEBI:47381 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0016867 infores:hetionet CHEBI:6520 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C3665347 infores:hetionet CHEBI:9150 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0002170 infores:hetionet CHEBI:9086 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151474 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0009319 infores:hetionet CHEBI:7494 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0003467 infores:hetionet CHEBI:72690 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0042075 infores:hetionet CHEBI:7478 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085602 infores:hetionet CHEBI:7577 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0009676 infores:hetionet CHEBI:5088 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0043352 infores:hetionet NCBITaxon:90339 biolink:causes MONDO:0005946 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:90339 MONDO:0005946 CHEBI:127780 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0520966 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0018621 infores:hetionet CHEBI:6916 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0026821 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0836924 infores:hetionet CHEBI:63611 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0041657 infores:hetionet CHEBI:31174 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0029134 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1368065 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0001122 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006145 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0036454 infores:hetionet CHEBI:42797 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013362 infores:hetionet CHEBI:499361 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0018944 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0010346 infores:hetionet CAID:CA073846 biolink:causes MONDO:0100150 infores:clingen CAID:CA073846 MONDO:0100150 PMID: Likely Benign BP7, BS1, BP4 PM2, BA1 The c.985-11del (NM_000540.3(RYR1):c.958-11del) variant in RYR1 is an intronic variant, located in intron 10 and 11 bases upstream of exon 11. The filtering allele frequency (the lower threshold of the 95% CI of 1684/64032 with 32 homozygous observations) of the c.958-11del variant in RYR1 is 0.0001110 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor gain, suggesting that the variant has no impact on splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC genome browser (BP4/BP7). In summary, this variant meets the criteria to be classified as likely benign for RYR1-related myopathies, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (Congenital Myopathies VCEP Specifications Version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA073846/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CHEBI:27796 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0036572 infores:hetionet CHEBI:5864 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0026766 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0031350 infores:hetionet CHEBI:6456 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0085624 infores:hetionet CHEBI:8499 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0023380 infores:hetionet CHEBI:48273 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0026821 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020456 infores:hetionet NCBIGene:8991 biolink:causes MONDO:0029144 infores:monarchinitiative not_provided not_provided HGNC:10719 MONDO:0029144 uuid:463527dd-e926-4fbe-a854-b0503f82623e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7478 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0041834 infores:hetionet NCBIGene:8924 biolink:causes MONDO:0014224 infores:monarchinitiative not_provided not_provided HGNC:4868 MONDO:0014224 uuid:daf1efe0-ea4d-4f6b-bdd6-f9fa7eba6c42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:12059 biolink:causes GO:0002441 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12059 GO:0002441 DB00366_MESH_D003139_1 CHEBI:6067 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0032961 infores:hetionet CHEBI:5118 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042024 infores:hetionet CHEBI:32293 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0030193 infores:hetionet CHEBI:6690 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0041657 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0020517 infores:hetionet CHEBI:2668 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0015672 infores:hetionet CHEBI:8665 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0149514 infores:hetionet CHEBI:41879 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0577559 infores:hetionet NCBIGene:57502 biolink:causes MONDO:0010341 infores:monarchinitiative not_provided not_provided HGNC:14287 MONDO:0010341 uuid:f2224f00-9d49-48e6-a26c-326d274e6a28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011206 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0427008 infores:hetionet CHEBI:47780 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0028961 infores:hetionet CHEBI:2567 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0009450 infores:hetionet NCBITaxon:6282 biolink:causes MONDO:0017137 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6282 MESH:D009855 DB00602_MESH_D009855_1DB00711_MESH_D009855_1DB00602_MESH_D009855_2 CHEBI:46557 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0004239 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0003123 infores:hetionet CHEBI:144093 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0014591 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0155002 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0155002 infores:hetionet CHEBI:3504 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0235896 infores:hetionet CAID:CA2499225877 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225877 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP2, BP3, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5 (RUNX1):c.508+10C>G is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEL score not applicable and SpliceAI is ≤0.20 (0.02) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Bayesian analysis calculates this variant as likely benign. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225877/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3441 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0018790 infores:hetionet CHEBI:29688 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C2697368 infores:hetionet CHEBI:42797 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017565 infores:hetionet CHEBI:135888 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0011606 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0035455 infores:hetionet CHEBI:9720 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0030446 infores:hetionet CHEBI:6367 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027066 infores:hetionet NCBIGene:4864 biolink:causes MONDO:0009757 infores:monarchinitiative not_provided not_provided HGNC:7897 MONDO:0009757 uuid:a35263fd-8437-42c8-8a4f-6fa037006ca5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0033975 infores:hetionet CHEBI:3752 biolink:causes MONDO:0020296 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003855 infores:hetionet CHEBI:46557 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0476281 infores:hetionet CHEBI:131512 biolink:causes HP:0012344 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C1527383 infores:hetionet CHEBI:59560 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0027497 infores:hetionet CHEBI:7931 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0024902 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0011570 infores:hetionet GO:1905024 biolink:causes GO:0060047 infores:ubergraph knowledge_assertion manual_agent GO:1905024 GO:0060047 CHEBI:8774 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0855242 infores:hetionet CHEBI:4888 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0024305 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040046 infores:hetionet CHEBI:47781 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0015230 infores:hetionet CAID:CA340741225 biolink:causes MONDO:0100368 infores:clingen CAID:CA340741225 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1503T>G (p.Tyr501Ter) is a nonsense variant that introduces a premature stop codon into exon 14 of 14 that is predicted not to trigger nonsense-mediated decay but rather to C-terminally truncate the protein product before position p.528, disrupting functionally critical residues required for the active site (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) and has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.825C>A, p.Tyr275Ter variant confirmed in trans (1 point, PMID: 31273949), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pt), extinguished rod ERG responses (0.5 pt), previous exome sequencing that did not provide an alternative explanation for visual impairment (2 pt), symptomatic onset between birth and age five years (1 pt), retinal degeneration with attenuated vessels (0.5 pt), and extinguished cone ERG responses (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 points, PMID: 31273949, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340741225/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:66919 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0015672 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0235146 infores:hetionet NCBIGene:26227 biolink:causes MONDO:0009736 infores:monarchinitiative not_provided not_provided HGNC:8923 MONDO:0009736 uuid:d1cce5d1-83b8-4e9b-b1e5-f60cfd314a5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75045 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0018681 infores:hetionet UMLS:C0657912 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234047 infores:hetionet CHEBI:5123 biolink:causes HP:0000011 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0005697 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006826 infores:hetionet CAID:CA1907493 biolink:causes MONDO:0018958 infores:clingen CAID:CA1907493 MONDO:0018958 PMID: Pathogenic PS3, PM3_Strong, PP1, PP4, PP3 BA1, BP2, BP1, BP4, BP3, PS4, PS2, PS1, PM4, PM1, PM5, BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PP2, BS2 The NM_001164508.2(NEB):c.19944G>A (p.Ser6648=) variant in NEB is a synonymous variant located at the intron exon boundary of exon 129. mRNA characterization of homozygous probands displayed that the variant abolishes the normal donor splice site, shifting towards the use of an alternative (cryptic) splice site in intron 129 which causes a partial intronic retention of 120bp that creates a premature stop codon and shorter polypeptide (PS3) (PMID: 26841830, PMID: 25205138). The computational splicing predictor SpliceAI gives a score of 0.77 for donor loss, predicting splice site disruption (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001659 (1/6026) alleles) in an unspecified ethnic group (no population codes met). This variant has been identified in at least 9 probands in either a homozygous state or with a second likely pathogenic, pathogenic, or rare uncertain variant (PM3_Strong) (PMID 26841830, 36233295, 25205138, 36233295, 37460656, 32222963, 36714460). At least one proband homozygous for the variant had an affected sibling also homozygous for the variant (PP1) (PMID: 37460656). Nemaline rods have been observed in at least one proband identified with the variant (PP4) (PMID: 26841830). In summary, this variant meets the criteria to be classified as pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PS3, PM3_Strong, PP4, PP3, PP1); ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 5/12/2025) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1907493/MONDO:0018958/146 2025-05-12 2025-06-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2618 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0004936 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0040046 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0004936 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0018418 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0006444 infores:hetionet CHEBI:10125 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013404 infores:hetionet CHEBI:46345 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0423153 infores:hetionet NCBIGene:9453 biolink:causes MONDO:0859189 infores:monarchinitiative not_provided not_provided HGNC:4249 MONDO:0859189 uuid:36b8c284-053f-43b0-9a6d-f70d15270bdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0700361 infores:hetionet CHEBI:46195 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0856054 infores:hetionet CHEBI:4909 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0085624 infores:hetionet CHEBI:36791 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039591 infores:hetionet CHEBI:6931 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0015672 infores:hetionet CHEBI:5855 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1291077 infores:hetionet CHEBI:28748 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036980 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040213 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0740409 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0740409 infores:hetionet CHEBI:64355 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011175 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0852909 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0852909 infores:hetionet CHEBI:5613 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C2830004 infores:hetionet CHEBI:17650 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0428977 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0012359 infores:hetionet CHEBI:53760 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0004093 infores:hetionet CHEBI:3752 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0241633 infores:hetionet GO:0035881 biolink:causes CL:0000561 infores:ubergraph knowledge_assertion manual_agent GO:0035881 CL:0000561 CAID:CA410677524 biolink:causes MONDO:0009276 infores:clingen CAID:CA410677524 MONDO:0009276 PMID: Pathogenic PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting, PVS1_Strong The c.443G>A (p.Trp148Ter) variant in GP1BB is a nonsense variant that may cause loss of function of the protein, however, it is predicted to escape nonsense mediated decay and remove 28% of the protein (PVS1_Strong). This variant has been detected in at least 2 unrelated probands with Bernard-Soulier syndrome. One proband was homozygous for the variant (0.5 points, PMID: 12447957). The second proband was compound heterozygous for this variant and a pathogenic or likely pathogenic variant that was confirmed in trans by parental testing (22q11.2 deletion including GP1BB, 1 point, PMID: 23566026, PM3). At least one patient (Patient 1 in PMID: 23566026) with this variant had less than 10% expression of GPIba and GP9 compared to controls. The patient also had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Full gene sequencing of GP1BA, GP1BB, and GP9 were performed as well as del/dup analysis (PP4_Moderate). The Grpmax filtering allele frequency in gnomaDThe Grpmax filtering allele frequency in gnomaDv4.1 is 7.700e-7 (based on 3/1034782 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. Surface expression of GP1BB and GP9 measured by flow cytometry and Western blot in HEK293T cells transiently co-transfected with the NM_000407.5:c.443G>A variant GP1BB and wild type GP1BA/GP9 showed decreased expression at 0% WT levels, indicating that this variant impacts protein function (PMID: 12447957)(PS3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4_Moderate, PM3, PM2_Supporting and PS3_Supporting (VCEP specifications version PILOT). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410677524/MONDO:0009276/082 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8499 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0004245 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0687707 infores:hetionet NCBIGene:2720 biolink:causes MONDO:0009261 infores:monarchinitiative not_provided not_provided HGNC:4298 MONDO:0009261 uuid:2323c6fe-086b-4483-a801-9a7faa49f329 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA118661 biolink:causes MONDO:0018947 infores:clingen CAID:CA118661 MONDO:0018947 PMID: Pathogenic PS4, PS2_Very Strong, PP2, PP3, PS3_Moderate, PM2_Supporting BA1, BS1 The NM_001005361.3:c.1102G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 368 (p.Glu368Lys). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.799, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in at least 6 probands with centronuclear myopathy (PS4; PMIDs: 16227997, 22613877, 25501959, 27159402, 33124102). Of those 6 individuals, the variant was identified as a de novo occurrence with confirmed parental relationships in at least 3 of those individuals with centronuclear myopathy (PS2_VeryStrong; PMIDs: 16227997, 27159402, 33124102). Oligomerization in Sf9 cells showed defective autoinhibition of self-assembly, indicating that this variant impacts protein function (PMID: 26199319). Additionally, GTPase activity in Sf9 cells was between 2–2.5-fold higher than wild-type DNM2 (PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP Specifications Version 1.0; 10/25/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA118661/MONDO:0018947/148 2024-10-25 2025-03-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8863 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027051 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034150 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0860871 infores:hetionet CHEBI:4672 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0030554 infores:hetionet CHEBI:63617 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015402 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0033975 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0040479 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0036572 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0009450 infores:hetionet CHEBI:6838 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0020651 infores:hetionet CHEBI:135736 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C2242737 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0021400 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018621 infores:hetionet CHEBI:31623 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0015967 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002878 infores:hetionet CHEBI:4657 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0013378 infores:hetionet CHEBI:8059 biolink:causes MONDO:0001999 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0152171 infores:hetionet CAID:CA404082719 biolink:causes MONDO:0007750 infores:clingen CAID:CA404082719 MONDO:0007750 PMID:34970301 Likely Pathogenic PS3_Moderate, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS3_moderate - Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake.---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met.PP3 - REVEL = 0.889. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 1 index case from Hu et al. 2021 (PMID: 34970301) with 5.5mmol/L LDL under no medication, and family history of hypercholesterolemia, so Simon-Broome possible is met; so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404082719/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:6307 biolink:causes MONDO:0014793 infores:monarchinitiative not_provided not_provided HGNC:10545 MONDO:0014793 uuid:b62d0b6f-177a-41d6-85db-2183a873e65a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042963 infores:hetionet CHEBI:45367 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0016204 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002332 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037997 infores:hetionet CHEBI:68579 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0030232 infores:hetionet CHEBI:75246 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0030196 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0021053 infores:hetionet CHEBI:82981 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0015230 infores:hetionet NCBIGene:176 biolink:causes MONDO:0013014 infores:monarchinitiative not_provided not_provided HGNC:319 MONDO:0013014 uuid:70ae5123-1343-41e4-9760-33e998f2da47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes UMLS:C0235196 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0235196 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011616 infores:hetionet CHEBI:6339 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0232849 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020538 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0020642 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0311245 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020295 infores:hetionet CHEBI:83804 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011880 infores:hetionet CHEBI:4315 biolink:causes UMLS:C2609073 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C2609073 infores:hetionet CHEBI:2948 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1443060 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0025061 infores:hetionet CHEBI:4653 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0522055 infores:hetionet CHEBI:41423 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0043352 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0851341 infores:hetionet CHEBI:63630 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0007859 infores:hetionet CHEBI:27446 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0002878 infores:hetionet CHEBI:4636 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0043144 infores:hetionet GO:0072094 biolink:causes GO:0003338 infores:ubergraph knowledge_assertion manual_agent GO:0072094 GO:0003338 CAID:CA410203366 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203366 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 BP2, PM3, PP4 NM_001754.5(RUNX1):c.346T>A (p.Phe116Ile) is a missense variant which is found within the runt homology domain but does not occur in an established hotspot residue (PM1_supporting). This variant has a REVEL score ≥ 0.88 (0.98) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203366/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17263 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0020598 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0031117 infores:hetionet CAID:CA227874 biolink:causes MONDO:0100438 infores:clingen CAID:CA227874 MONDO:0100438 PMID: Benign BS2, BA1 PP3, BP4 NM_014336.5(AIPL1):c.268G>C (p.Asp90His) is a missense variant in exon 2 of 6. The variant is predicted to change the amino acid aspartic acid at position p.90 to histidine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.3476, with 15,766 alleles / 44,766 total alleles in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). Additionally, the variant has been found in the homozygous state in 33640 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.612, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 for PP3 and above the threshold of <0.290 for BP4. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which predicts a low or indeterminate impact on splicing. Neither PP3 nor BP4 is met. In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1 and BS2. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227874/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135566 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0010043 infores:hetionet UNII:0RK7M7IABE biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0178298 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151785 infores:hetionet CHEBI:51364 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0234133 infores:hetionet CAID:CA314588 biolink:causes MONDO:0100040 infores:clingen CAID:CA314588 MONDO:0100040 PMID: Benign BA1, BP4 The allele frequency of the p.Gly168Ala variant in FOXG1 is 0.18% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Computational analysis prediction tools suggest that the p.Gly168Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gly168Ala variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314588/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:27565 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0015967 infores:hetionet CAID:CA287019 biolink:causes MONDO:0700270 infores:clingen CAID:CA287019 MONDO:0700270 PMID: Likely Pathogenic PM3_Strong, PS3_Supporting, PP3 PM2 The c.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA287019/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:65173 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0231807 infores:hetionet CHEBI:10101 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1519353 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0085584 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0345904 infores:hetionet CHEBI:46557 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0026858 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002871 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0025061 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004835 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0238124 infores:hetionet CHEBI:63621 biolink:causes MONDO:0024280 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0162323 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0178298 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151605 infores:hetionet CHEBI:131512 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0009676 infores:hetionet CHEBI:48390 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0015230 infores:hetionet CHEBI:253342 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0030193 infores:hetionet CAID:CA398322535 biolink:causes MONDO:0011132 infores:clingen CAID:CA398322535 MONDO:0011132 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The NM_001369369.1(FOXN1):c.699+1G>T intron 4 donor splice site variant is predicted to result in skipping of exon 4 causing an in frame deletion of Gly197 to Gln233, accounting for 5.7% of the protein (PVS1_Moderate). This variant is absent from gnomADv2.1.1 (PM2_supporting). There is one entry for this variant in ClinVar (SCV000766592.5) but it has not been reported in the literature in individuals with FOXN1-related disease. In summary this variant meets criteria to be classified as uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_Moderate and PM2_Supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398322535/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Inconclusive true UNII:DJJ95FJP1H biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0347390 infores:hetionet CHEBI:36791 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020443 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0042109 infores:hetionet CHEBI:63631 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0236024 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0004936 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0332575 infores:hetionet CAID:CA10603793 biolink:causes MONDO:0009290 infores:clingen CAID:CA10603793 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PS3_Supporting "The NM_000152.5:c.853C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 285 (p.Pro285Ser). The highest population minor allele frequency in gnomAD is 0.00009 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. REVEL (in silico meta predictor for missense changes) score = 0.757 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion. At least two patients had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PP4_Moderate). Two individuals with Pompe disease have been reported who are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.2237G>A (p.Trp746Ter)(PMID: 21484825)(0.5 points) or c.1354_1372del19 (PMID: 21550241)(0.5 points), Total 1 point (PM3). This variant results in <5% GAA activity when expressed in COS cells, and was classified as Class C (""less severe"") by Kroos et al, 2012 (PMID:22644586), meeting the ClinGen LSD VCEP criteria for PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 281052, 1 star review status) with 5 submitters, two classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PP3, PM2_supporting, PM3, PS3_supporting." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603793/MONDO:0009290/010 2021-12-02 2021-12-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:61049 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2129214 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0015300 infores:hetionet NCBITaxon:87882 biolink:causes MONDO:0958151 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:87882 MONDO:0958151 CHEBI:7824 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0030312 infores:hetionet CAID:CA412731784 biolink:causes MONDO:0100437 infores:clingen CAID:CA412731784 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.2007G>A (p.Trp669Ter) is a nonsense variant that introduces a premature stop codon at in amino acid 669 and is predicted to cause a truncated protein and to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 28863407, PMID: 35432464, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0: PVS1, PM2_Supporting, and PS4_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412731784/MONDO:0100437/106 2025-07-31 2025-07-31 X-linked inheritance HP:0001417 Supports CHEBI:6775 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151799 infores:hetionet CHEBI:8060 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0039231 infores:hetionet UMLS:C0009315 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0030554 infores:hetionet CAID:CA265916542 biolink:causes MONDO:0100216 infores:clingen CAID:CA265916542 MONDO:0100216 PMID: Uncertain Significance PM2, PM6, BP4, PP3, PM5, PS1, PS3, PS4, PS2, BS3 The NM_177438.2:c.1606C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine acid by cysteine at amino acid 536 (p.Arg536Cys). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000003099 (5/1613336 alleles) with a highest population minor allele frequency of 0.00001339 (1/74696 alleles) in African/African American population and with multiple alleles present in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.659, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function; splice predictors MaxEntScan and SpliceAI indicate no impact on splicing (PP3 and BP4 not met). In summary, since no ACMG/AMP criteria codes can be applied to this variant at this time, this variant is classified as a variant of unknown significance for DICER1-related tumor predisposition. (Bayesian Points: 0; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA265916542/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6804 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0036974 infores:hetionet CHEBI:681569 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0022107 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0948594 infores:hetionet CHEBI:194135 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0338831 infores:hetionet CHEBI:64312 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0687713 infores:hetionet CHEBI:4325 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0027441 infores:hetionet CHEBI:7931 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0220870 infores:hetionet CHEBI:6909 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0392171 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233472 infores:hetionet GO:0030997 biolink:causes GO:0007098 infores:ubergraph knowledge_assertion manual_agent GO:0030997 GO:0007098 CAID:CA274247 biolink:causes MONDO:0009290 infores:clingen CAID:CA274247 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM1, PM2_Supporting, PM3_Strong, PS3_Supporting The NM_000152.5:c.1441T>C variant in GAA is predicted to result in the missense substitution of tryptophan by arginine at amino acid 481 (p.Trp481Arg). The variant has been reported in at least 6 individuals with Pompe disease in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. It was confirmed in trans with c.1326+1G>A (PMIDs: 10189220, 9862843), and was found in unconfirmed phase with c.-32-13T>G (PMID: 14695532, 18757064, 22676651, 27189384, 29556838, 34357340); c.2560C>T (p.Arg854Ter) (PMIDs: 31086307, 35787971), c.1979G>A (p.Arg660His) (PMID: 31086307), and c.2481+102_c.2646+31del (PMID: 26497565, 28657663). Another patient is compound heterozygous for the variant and c.1556T>C (p.Met519Thr) (PMID: 31086307); the allelic data from this patient will be used in the assessment of the other variant and is not included here to avoid circular logic (PM3_Strong). This variant has been reported in individuals with specific phenotypic features of Pompe disease including documented laboratory values revealing GAA deficiency, individuals on enzyme replacement therapy, patients with documented symptoms of infantile onset Pompe disease, and elevated urine Hex4 (PMID: 26497565, 28657663, 31086307, 34357340) (PP4_Moderate). Trp481 is a residue that crystallography studies have shown to be important in the architecture of the active site and substrate binding of GAA; this residues has, therefore, has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). In two independent studies, expression of the variant in COS cells results in <2% GAA activity compared to normal, but also a significant amount of mature GAA protein, suggesting that the variant impacts catalysis rather than protein production or stability (PMID: 14695532, 19862843). The computational predictor REVEL gives a score of 0.967 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: ). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 1, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274247/MONDO:0009290/010 2023-10-01 2023-11-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:135876 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0012833 infores:hetionet CHEBI:41977 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0038002 infores:hetionet CHEBI:4027 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0018681 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004960 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030489 infores:hetionet CHEBI:6073 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0026821 infores:hetionet CHEBI:50131 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0854467 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042401 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0005940 infores:hetionet NCBIGene:5159 biolink:causes MONDO:0014704 infores:monarchinitiative not_provided not_provided HGNC:8804 MONDO:0014704 uuid:5d4d45eb-560a-4128-837c-e6b1ab9883bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1901966 biolink:causes GO:0006879 infores:ubergraph knowledge_assertion manual_agent GO:1901966 GO:0006879 CHEBI:8869 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0030554 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0857122 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0857122 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020517 infores:hetionet NCBIGene:57817 biolink:causes MONDO:0013220 infores:monarchinitiative not_provided not_provided HGNC:15598 MONDO:0013220 uuid:336ca798-74bd-485f-a228-56eae5a9b701 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0008031 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0035455 infores:hetionet CHEBI:38940 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0004093 infores:hetionet CHEBI:17688 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0002792 infores:hetionet CHEBI:5959 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020621 infores:hetionet CHEBI:50859 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151578 infores:hetionet CAID:CA2580611120 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580611120 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 PS4, PP1 The c.682dup variant in the HNF1 homebox A gene, HNF1A, causes a frameshift in the protein at codon 228 (NM_000545.8), adding 11 novel amino acids before encountering a stop codon (p.(Glu228GlyfsTer11)). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:18003757, internal lab contributor). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4Al, and negative antibodies) (PP4; internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.682dup meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580611120/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CAID:CA410204303 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204303 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.107C>G (p.Thr36Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204303/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA512318822 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318822 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.4:c.334del (p.Leu112CysfsTer10) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; from internal laboratory data). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318822/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1145670 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1258215 infores:hetionet CHEBI:168396 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C2047937 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0855223 infores:hetionet CHEBI:9654 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0028643 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0007787 infores:hetionet NCBIGene:56896 biolink:causes MONDO:0030331 infores:monarchinitiative not_provided not_provided HGNC:20637 MONDO:0030331 uuid:85d9df1c-650d-4d8b-af13-759fbb9798e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0017160 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038661 infores:hetionet CHEBI:3504 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0011175 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0235750 infores:hetionet CHEBI:119573 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0041834 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0038362 infores:hetionet CAID:CA009910 biolink:causes MONDO:0005045 infores:clingen CAID:CA009910 MONDO:0005045 PMID: Uncertain Significance PP3 PP2, BP4, PS1, PS4, PM5, PM1, PM2 NM_000432.4(MYL2):c.170G>A (p.Gly57Glu). This variant has been reported in individuals with HCM and other cardiomyopathies (Laboratory for Molecular Medicine (LMM) data, Caleshu 2011 PMID: 21823217, Alfares 2015 PMID: 25611685, Walsh 2017 PMID: 27532257) and has also been identified in 1 out of 34586 (0.01% FAF 95% CI) of Latino chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). This variant is not statistically increased in individuals with HCM compared to controls; [OR lower 95% CI <5]. Therefore, the PS4 criteria has not been applied, and the PM2_Supporting criterion has not been applied either. Additionally, computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA009910/MONDO:0005045/102 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:38940 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0239981 infores:hetionet NCBIGene:5888 biolink:causes MONDO:0013790 infores:monarchinitiative not_provided not_provided HGNC:9817 MONDO:0013790 uuid:5787f6ed-8438-4ac3-871d-0e7cd8bf4ea1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011175 infores:hetionet CAID:CA1442705 biolink:causes MONDO:0100084 infores:clingen CAID:CA1442705 MONDO:0100084 PMID: Likely Benign BP4, BP7 PM2, BA1, BS1 The variant NM_001100.4:c.1104C>T in ACTA1 is a synonymous (silent) variant (p.Gly368=). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.000006150 (13/1180024) in the European (non-Finnish) population(no population codes met). However, SpliceAI predicted no impact on splicing, meeting BP4/BP7 criteria. In summary, the variant meets criteria to be classified as likely benign for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1442705/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0267596 infores:hetionet CHEBI:63631 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232461 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0020538 infores:hetionet CAID:CA472038164 biolink:causes MONDO:0100316 infores:clingen CAID:CA472038164 MONDO:0100316 PMID:29021305PMID:29021305 Likely Benign BP4, BP7 BA1, PS3, PS4, BS1, BS3, BS4, PM2, PM1, BS2, PP3, PP1 NM_000218.3(KCNQ1):c.840G>T (p.Val280=) is a synonymous variant in exon 6. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001610, with 19 alleles out of 1,180,028 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.06 for acceptor gain which is below the ClinGen Potassium Channel Arrhythmia VCEP BP7 threshold of <0.2 and does not strongly predict a splicing defect (BP4). In addition, the conservation tool PhyloP gives this variant a score of 0.275, which is below the Potassium Channel Arrhythmia VCEP BP7 threshold of <2.0 and indicates a low level of evolutionary conservation at this site (BP7). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA472038164/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51364 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0006145 infores:hetionet CHEBI:3738 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0001824 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0017574 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C1565489 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0037199 infores:hetionet CHEBI:17688 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0030193 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0029456 infores:hetionet CHEBI:3223 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085633 infores:hetionet CHEBI:10125 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235267 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1306341 infores:hetionet CHEBI:31401 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151878 infores:hetionet CAID:CA410208239 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208239 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS4, PS2, PS3, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.35C>G (p.Ser12Trp) is a missense variant which is absent from gnomAD v2, v3, and v4.1 (PM2_supporting). This variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.631, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208239/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0392025 infores:hetionet CHEBI:6717 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0003467 infores:hetionet CHEBI:6715 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0016204 infores:hetionet CHEBI:10650 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013456 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0852913 infores:hetionet CHEBI:63638 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C3665386 infores:hetionet CHEBI:45951 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0427086 infores:hetionet CHEBI:3650 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0015230 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0025290 infores:hetionet CHEBI:59750 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0263449 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0009763 infores:hetionet CHEBI:6801 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1291078 infores:hetionet CHEBI:39867 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0005758 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0877398 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0877398 infores:hetionet CAID:CA127306 biolink:causes MONDO:0015152 infores:clingen CAID:CA127306 MONDO:0015152 PMID: Pathogenic PM3, PP3, PP4, PM2_Supporting, PP1_Strong PM5, PVS1, BP7, PS3 The NM_000070.3: c.2306G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid position 769, p.(Arg769Gln). The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID: 14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). It was also observed to segregate with autosomal recessive LGMD in eight affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID: 12461690, 7720071; PP1_Strong). At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 14645990; PP4 (capped with PP1_Strong)). The filtering allele frequency of this variant is 0.000089887 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI predicts the possible loss of an alternate splice donor site due to this variant, with a score of 0.49. However, a minigene assay for this variant demonstrated a largely preserved expression of transcripts with normal splicing (PMID: 32668095). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025). While the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP, result in 9 Bayesian points (PM3, PP1_Strong, PP4, PM2_Supporting, PP3), a classification of Pathogenic was awarded given the strength of the available evidence and the impact of scoring caps on homozygous case data and locus-specific segregation and phenotype evidence. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA127306/MONDO:0015152/187 2025-04-22 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7936 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030252 infores:hetionet CHEBI:8871 biolink:causes NCIT:C78214 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853592 infores:hetionet CAID:CA229635 biolink:causes MONDO:0009861 infores:clingen CAID:CA229635 MONDO:0009861 PMID:9391881 Pathogenic PVS1, PM2, PP4 Pathogenic: The c.58C>T (p.Gln20Ter) is a null variant reported in one patient with classic PKU phenotype (PVS1, PP4, PMID: 9391881). This variant is absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229635/MONDO:0009861/006 2019-02-26 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA913163370 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163370 MONDO:0044970 PMID: Likely Pathogenic PM5_Supporting, PS3_Supporting, PM2_Supporting, PP1, PP3, PS4_Moderate PP4, PS2, PM6 The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID: 15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 24691472). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163370/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA229832 biolink:causes MONDO:0009861 infores:clingen CAID:CA229832 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4 PM5 The c.869A>G (p.His290Arg) variant in PAH has been reported in a Chinese patient PKU (PMID: 15300621) This variant is absent from population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229832/MONDO:0009861/006 2021-03-21 2021-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:94609 biolink:causes MONDO:0018612 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0010308 infores:hetionet CHEBI:45285 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0042109 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0020538 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0853760 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0023067 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0035854 infores:hetionet CHEBI:9725 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0085611 infores:hetionet NCBIGene:57459 biolink:causes MONDO:0014034 infores:monarchinitiative not_provided not_provided HGNC:30778 MONDO:0014034 uuid:1ee27432-0672-4abd-bc3f-e799461f1b09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0852911 infores:hetionet CHEBI:3485 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0006846 infores:hetionet CHEBI:4466 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0030193 infores:hetionet CHEBI:9448 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0027424 infores:hetionet CHEBI:194135 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0392525 infores:hetionet CAID:CA145872 biolink:causes MONDO:0001586 infores:clingen CAID:CA145872 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.1360G>A variant in IDUA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 454 (p.Val454Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.3004 (19925/66322 alleles; 3158 homozygotes; Grpmax Filtering AF 95% confidence = 0.2969) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92630). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145872/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135276 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0042963 infores:hetionet NCBIGene:4597 biolink:causes MONDO:0013868 infores:monarchinitiative not_provided not_provided HGNC:7529 MONDO:0013868 uuid:80558c7a-4c0d-4472-848a-dbf873fc78ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003537 infores:hetionet CHEBI:45979 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0036572 infores:hetionet CHEBI:135736 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0008350 infores:hetionet CHEBI:38562 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0542571 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0948594 infores:hetionet CHEBI:5893 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0016658 infores:hetionet CHEBI:63617 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0687713 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0027707 infores:hetionet CHEBI:50922 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0019270 infores:hetionet CAID:CA396451188 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451188 MONDO:0007648 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM5, PM4, PM1, PM6, PP1, PP4, PP2, PP3, BS2, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.2T>A (p.Met1?) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one proband meeting HDGC clinical criteria (PS4_supporting; Internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2_supporting, PS4_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451188/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA228445 biolink:causes MONDO:0015629 infores:clingen CAID:CA228445 MONDO:0015629 PMID: Pathogenic PP4_Moderate, PM2_Supporting, BP4, PS3, PS4 PM5 The NM_000552.5(VWF):c.3802C>G (p.His1268Asp) variant is a missense variant with a REVEL score of 0.29, which meets the VWD VCEP threshold of less than or equal to 0.29 and does not predict a damaging effect on VWF function (BP4). However, a patient with the H1268D variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of a partial loss of high molecular weight multimers and a significant increase in VWF-GPIb showing gain of function which is highly specific for VWF type 2B. Additionally, the patient developed thrombocytopenia during infectious episodes (PMID: 18805962; PP4_Moderate). There are at least 4 additional type 2B probands with this variant and confirmed increased VWF binding (PMID: 8376405, PMID: 16704443, Christopherson, 2020, SCV002515761.1; PS4). The variant is absent from gnomADv4, thus, meeting PM2_Supporting criterion. RIPA assay demonstrated that the variant demonstrated enhanced responsiveness to rVWF-WT at a low concentration of ristocetin. Furthermore, multimer analysis also showed preferential cleavage of HMWMs (PMID: 26345337). The variant also exhibited increased affinity towards the LBD compared to WT AIM-A1 (PS3). In summary, this variant has been classified as Pathogenic for type 2B Von Willebrand Disease based on the ACMG/AMP criteria applied as specified by the von Willebrand Disease Variant Curation Expert Panel. BP4, PP4_Moderate, PM2_Supporting, PS3, PS4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228445/MONDO:0015629/081 2024-12-03 2024-12-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10023 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0428974 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0178298 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233472 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0013595 infores:hetionet CAID:CA229673 biolink:causes MONDO:0009861 infores:clingen CAID:CA229673 MONDO:0009861 PMID:23514811PMID:8807319PMID:23514811PMID:8807319 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PM5, PP3 The c.649T>G (p.Cys217Gly) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). This variant is absent in population databases. This variant was detected with pathogenic variants: p.P281L (PMID: 8807319), IVS10-11G>A, and p.V245A (PMID: 27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229673/MONDO:0009861/006 2020-07-06 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0033775 infores:hetionet CHEBI:31401 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0232849 infores:hetionet CHEBI:3757 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1443060 infores:hetionet CHEBI:10650 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015468 infores:hetionet CHEBI:5062 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0006277 infores:hetionet CHEBI:72297 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0235378 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0855242 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0027726 infores:hetionet CAID:CA10360607 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360607 MONDO:0010725 PMID: Benign BA1 BP4, PP3 The NM_000330.4(RS1):c.548C>T variant is a missense variant encoding the substitution of Threonine with Isoleucine at amino acid 183. This variant is present in gnomAD v.4.1.0 at a frequency of 0.001272 among hemizygous individuals, with 506 variant alleles / 397702 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The computational predictor REVEL gives a score of 0.554, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 and <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes are not met. In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360607/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:75722 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853986 infores:hetionet CHEBI:66919 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0020443 infores:hetionet CAID:CA386295865 biolink:causes MONDO:0009861 infores:clingen CAID:CA386295865 MONDO:0009861 PMID:30159852 Pathogenic PM3, PVS1, PM2, PP4 This c.707-1G>C (aka IVS6-1G>C) variant in PAH has been observed in one patient with classic PKU, in trans with pathogenic variant c.441+5G>T (PMID: 30159852). This variant is absent from controls in population databases. This variant in the -1 splice acceptor site of intron 6 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay. This variant breaks the splice site in intron 6 according to computational models. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386295865/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47898 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0149745 infores:hetionet CHEBI:3127 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0039070 infores:hetionet CHEBI:31643 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0036974 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0518015 infores:hetionet CHEBI:6916 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0520966 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0031117 infores:hetionet CHEBI:6933 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0085606 infores:hetionet CAID:CA10014582 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014582 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.153G>T (p.Lys51Asn) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014582/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA915944915 biolink:causes MONDO:0015967 infores:clingen CAID:CA915944915 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PVS1, PM2_Supporting The c.1360del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 454 (NM_000162.5), adding 160 novel amino acids before encountering a stop codon (p.(Ala454ArgfsTer160)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). In summary, the c.1360del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915944915/MONDO:0015967/086 2023-06-22 2023-06-22 Semidominant inheritance HP:0032113 Supports UNII:U6XF9NP8HM biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0546817 infores:hetionet CHEBI:5100 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0030554 infores:hetionet CHEBI:9667 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0271650 infores:hetionet CHEBI:17303 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013378 infores:hetionet CHEBI:32315 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0558489 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1392046 infores:hetionet CHEBI:63621 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0520573 infores:hetionet CHEBI:2788 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0011124 infores:hetionet CHEBI:9654 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0032617 infores:hetionet CAID:CA386963576 biolink:causes MONDO:0015967 infores:clingen CAID:CA386963576 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate PS4 The c.544C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 182 (p.(Gln182Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative HNF4A testing, and hepatocellular adenomas) (PP4_Moderate; internal lab contributors). In summary, c.544C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386963576/MONDO:0015967/017 2025-04-17 2025-04-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64318 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0033774 infores:hetionet CHEBI:3061 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0011991 infores:hetionet CHEBI:49603 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0687713 infores:hetionet CHEBI:136040 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0042023 infores:hetionet CHEBI:63630 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0030554 infores:hetionet CHEBI:71272 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0853034 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020649 infores:hetionet NCBITaxon:543 biolink:causes MONDO:0005280 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:543 MESH:D011472 DB01333_MESH_D011472_1 CHEBI:4681 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0010200 infores:hetionet CHEBI:18248 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0002994 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0948089 infores:hetionet CHEBI:8028 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C1321686 infores:hetionet CHEBI:3504 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020625 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151888 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0009450 infores:hetionet CHEBI:16796 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0008031 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013395 infores:hetionet CHEBI:17549 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0267792 infores:hetionet CHEBI:68558 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0033774 infores:hetionet NCBIGene:7399 biolink:causes MONDO:0010169 infores:monarchinitiative not_provided not_provided HGNC:12601 MONDO:0010169 uuid:68f7ad26-d434-4fae-a0b6-c8c06f1b4501 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:520985 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0009676 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0020598 infores:hetionet CHEBI:31485 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0022073 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0161479 infores:hetionet NCBIGene:10667 biolink:causes MONDO:0014882 infores:monarchinitiative not_provided not_provided HGNC:21062 MONDO:0014882 uuid:5ed8ef49-00ee-4829-9e89-140f9c5ee562 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6633 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0220981 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0948594 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1384353 infores:hetionet CHEBI:5613 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0233514 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0234458 infores:hetionet CHEBI:61033 biolink:causes NCIT:C34938 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0032788 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0948873 infores:hetionet CHEBI:27300 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0027497 infores:hetionet CHEBI:617099 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C2363730 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0026946 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0243026 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0006145 infores:hetionet CHEBI:50924 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0010200 infores:hetionet CAID:CA338378687 biolink:causes MONDO:0100283 infores:clingen CAID:CA338378687 MONDO:0100283 PMID: Uncertain Significance BS1, PM2, PM1, PS4 The NM_004958.4:c.3004C>T (p.Arg1002Ter) variant in MTOR is a nonsense variant that is predicted to cause a premature stop codon at exon 19. In gnomAD v4.1.0, this variant has a filtering allele frequency of 0.000028% in the European (non-Finnish) population, and a minor allele frequency of 0.001333% (1/75040) in the African/African American population (PM2_Supporting, BS1, and BS1_Supporting not met). This variant has been reported in 1 tumor sample from a patient with endometriod carcinoma in COSMIC (COSV100816762). However, PS4_Supporting cannot be applied because this variant would need to be observed in at least two tumor samples in order for this criterion to be applied. In summary, this variant meets the criteria to be classified as uncertain significance for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: No Criteria Met (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA338378687/MONDO:0100283/018 2025-06-06 2025-06-30 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true NCBIGene:1478 biolink:causes MONDO:0958200 infores:monarchinitiative not_provided not_provided HGNC:2484 MONDO:0958200 uuid:56b0e411-86d9-4bef-a54c-d9ba71a9f513 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002418 infores:hetionet CHEBI:15367 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0497156 infores:hetionet CHEBI:10125 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235063 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020456 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1142115 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1142115 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0030312 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0022116 infores:hetionet CHEBI:16469 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C3495440 infores:hetionet CHEBI:3698 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0017178 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0005826 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0005826 infores:hetionet GO:0039606 biolink:causes GO:0006413 infores:ubergraph knowledge_assertion manual_agent GO:0039606 GO:0006413 CAID:CA9487981 biolink:causes MONDO:0011229 infores:clingen CAID:CA9487981 MONDO:0011229 PMID: Benign BS2, BA1, BP7 PM5, PS1, PM2, BS1 The allele frequency of the c.6G>A variant in the ETHE1 gene is reported as >16% in gnomAD, including >2,000 homozygotes, which is high enough to be classified as benign based on thresholds defined by the ClinGen ETHE1 Variant Curation Expert Panel (>0.1% in gnomAD- BA1 and BS2). In silico splicing predictors (Splice AI) do not predict a deleterious effect (BP7). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA9487981/MONDO:0011229/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA16020898 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020898 MONDO:0009861 PMID:26322415PMID:24350308 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The NM_000277.3:c.920G>A (p.Gly307Asp) variant is a missense variant in exon 9/13 of PAH. The variant has been reported in confirmed trans with the p.R111* variant (Pathogenic per ClinGen PAH VCEP) in a Chinese patient with mild PKU (plasma Phe 10–20 mg/dl); BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415) (PP4_Moderate). It has also been found in presumed trans in 2 Polish cases: one patient with genotype F55Lfs/G307D with mild PKU and one patient with genotype R408W/G307D with unspecified Phe levels (PMID: 24350308) (PM3_Strong, 2 points total). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.983) (PP3).Classification: Likely PathogenicSupporting Criteria: PM3; PM2; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020898/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA902507 biolink:causes MONDO:0100368 infores:clingen CAID:CA902507 MONDO:0100368 PMID: Likely Benign BP4, BP7, BS1 NM_000329.3(RPE65):c.441A>C (p.Thr147=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.006282, with 142 alleles/19954 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.05 for donor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902507/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:4810 biolink:causes MONDO:0010545 infores:monarchinitiative not_provided not_provided HGNC:7820 MONDO:0010545 uuid:d94048ba-230e-4a74-a9d6-514d3c69fb9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28915 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0030193 infores:hetionet CHEBI:9241 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0038325 infores:hetionet CHEBI:38545 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0028084 infores:hetionet CHEBI:391960 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0016204 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0687707 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0855704 infores:hetionet CHEBI:51450 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0151908 infores:hetionet CHEBI:63584 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0039231 infores:hetionet CHEBI:31536 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0003467 infores:hetionet CAID:CA274073 biolink:causes MONDO:0009290 infores:clingen CAID:CA274073 MONDO:0009290 PMID:25763511 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.766_c.785delinsC (p.Tyr256ArgfsTer6), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding that a patient who is compound heterozygous for this variant and another null variant has no GAA cross-reactive material in cultured skin fibroblasts i.e. CRIM-negative (PMIDs 22252923, 25763511). This patient and one other meet the ClinGen LSD VCEP’s specifications for PP4. The first patient is compound heterozygous for the variant and c.2432delT (p.Leu811fsTer37) (PMID 25763511); the second is compound heterozygous for the variant and c.2014C>T (p.Arg672Trp) (PMID 9535769). The phase of the variants is unknown. In both cases, the in trans data will be used in the assessment of the second variant and was, therefore, not include here for PM3 in order to avoid a circular argument. Another patient has been reported to be compound heterozygous for the variant and c.-32-13T>G but was not included because the residual GAA activity was not reported (PMID 30564623). Finally, two siblings with adult onset Pompe disease have been reported to have the variant but the second variant and residual GAA activity were not provided (PMID 10206684). This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 188880, two star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274073/MONDO:0009290/010 2020-10-06 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:859 biolink:causes MONDO:0012736 infores:monarchinitiative not_provided not_provided HGNC:1529 MONDO:0012736 uuid:0ab77f68-54de-4335-9811-cdf7d4b3c2ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10529706 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529706 MONDO:0010604 PMID: Benign BA1 PS4, PP3, BP4 The c.8G>A (p.Arg3His) variant is reported at an MAF of 0.001469 (28/19065 alleles) in the African/African American population in gnomAD v2.1.1 with 8 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. gnomAD v3.1.1 reports 13 hemizygotes. REVEL score does not meet thresholds for PP3 or BP4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529706/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:3696 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020649 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0948089 infores:hetionet GO:0036305 biolink:causes CL:0000059 infores:ubergraph knowledge_assertion manual_agent GO:0036305 CL:0000059 GO:0006954 biolink:causes MONDO:0006559 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D017497 DB00051_MESH_D017497_1 CHEBI:10110 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0027497 infores:hetionet CHEBI:63619 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0014724 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0034150 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0948089 infores:hetionet GO:2000194 biolink:causes GO:0046660 infores:ubergraph knowledge_assertion manual_agent GO:2000194 GO:0046660 CHEBI:134990 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0015397 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0162429 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000022 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0270327 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0021390 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0031117 infores:hetionet CAID:CA504731736 biolink:causes MONDO:0012999 infores:clingen CAID:CA504731736 MONDO:0012999 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_000156.6:c.39C>A (p.Gly13=) variant in GAMT is a synonymous variant in exon 1. It is absent in gnomAD v2.1.1 (PM2_Supporting); however, this region has low coverage and, therefore, the allele frequency data may not be accurate. It is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant does not appear to have been reported in the published literature. It is noted in ClinVar (Variation ID: 544263). Although this variant may be rare, it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GAMT-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA504731736/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5138 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042023 infores:hetionet CHEBI:63627 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0013404 infores:hetionet NCBIGene:974 biolink:causes MONDO:0012987 infores:monarchinitiative not_provided not_provided HGNC:1699 MONDO:0012987 uuid:6f39ae4e-0d9e-49d1-b7d7-1dd44c61a5b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0019080 infores:hetionet NCBIGene:114548 biolink:causes MONDO:0011776 infores:monarchinitiative not_provided not_provided HGNC:16400 MONDO:0011776 uuid:b27e1664-0a7c-42b6-9468-456c1089d269 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63638 biolink:causes UMLS:C1868998 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1868998 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0235639 infores:hetionet CHEBI:4511 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0041582 infores:hetionet CAID:CA374969537 biolink:causes MONDO:0008535 infores:clingen CAID:CA374969537 MONDO:0008535 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_001114753.3: c.1961C>G variant in ENG is a missense variant predicted to cause substitution of threonine by serine at amino acid 654 (p.Thr654Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.126, which is below the threshold of ≤0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, BP4 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374969537/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63580 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235639 infores:hetionet GO:1900437 biolink:causes GO:0042221 infores:ubergraph knowledge_assertion manual_agent GO:1900437 GO:0042221 CHEBI:3515 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0877322 infores:hetionet CHEBI:8707 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0036974 infores:hetionet CHEBI:3647 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0425945 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011630 infores:hetionet CHEBI:45652 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0003578 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0006849 infores:hetionet CHEBI:47898 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2939147 infores:hetionet CHEBI:5141 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0013395 infores:hetionet CAID:CA2573106198 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573106198 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.490dup variant in the HNF1 Homeobox A gene, HNF1A, causes a frameshift in the protein at codon 164 (NM_000545.8), adding 4 novel amino acids before encountering a stop codon (p.(Asp164Glyfs*4)). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the calculated MODY probability is <50% and HNF1A was not tested (PMID 15928245). In summary, the c.490dup variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied (specification version 1.1.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106198/MONDO:0015967/085 2023-08-13 2023-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10119 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015672 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005989 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0040558 infores:hetionet CAID:CA023955 biolink:causes MONDO:0018493 infores:clingen CAID:CA023955 MONDO:0018493 PMID: Uncertain Significance PM5, PM1_Supporting, PP3_Moderate PS4, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glycine at codon 401 of the RYR1 protein, p.(Arg401Gly). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, this does not meet the criteria for PS4 to be implemented (PMID:16917943). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5. A REVEL score >0.85 (0.865) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386).Criteria implemented: PM1_Supporting, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023955/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA024690 biolink:causes MONDO:0007783 infores:clingen CAID:CA024690 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Alanine with Threonine at codon 2350 of the RYR1 protein, p.(Ala2350Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 19 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 17 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4, (PMID:30236257, PMID:16163667, PMID:11525881, PMID:12434264, and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:11525881). An ex vivo study in myotubes from a single patient also showed increased sensitivity to RYR1 agonists, (PMID:15210166). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 7 individuals PP1_Strong (PMID:11525881, PMID:25960145). A REVEL score >0.85 (0.952) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024690/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:567361 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0034069 infores:hetionet CHEBI:71940 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C3665346 infores:hetionet CHEBI:59773 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0085633 infores:hetionet NCBIGene:407053 biolink:causes MONDO:0013114 infores:monarchinitiative not_provided not_provided HGNC:31648 MONDO:0013114 uuid:90de43ec-b077-4432-a1be-50e02e128f49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151746 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0000924 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0000924 infores:hetionet CHEBI:135935 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0004093 infores:hetionet CHEBI:63791 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0239571 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0042401 infores:hetionet CHEBI:17650 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0025289 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0032584 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0004377 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004377 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042373 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0004238 infores:hetionet CHEBI:3082 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1443060 infores:hetionet CHEBI:7936 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013404 infores:hetionet CHEBI:46081 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0152227 infores:hetionet CHEBI:35778 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085628 infores:hetionet CHEBI:391960 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0149745 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0031117 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0268671 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0268671 infores:hetionet CHEBI:3077 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0085635 infores:hetionet CHEBI:2611 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042023 infores:hetionet CHEBI:4551 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0520887 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013595 infores:hetionet CHEBI:6950 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085932 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032961 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948089 infores:hetionet CHEBI:46295 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0009763 infores:hetionet CHEBI:72564 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0031256 infores:hetionet CHEBI:4710 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013604 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0149931 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0687707 infores:hetionet CAID:CA254834 biolink:causes MONDO:0044970 infores:clingen CAID:CA254834 MONDO:0044970 PMID:16806928PMID:17878308 Uncertain Significance PP3, PS4_Supporting, PM2_Supporting, PS3_Supporting PP1, PP4, PS2, PM6 The m.583G>A variant in MT-TF has been reported in two unrelated individuals with primary mitochondrial disease. The first was a woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) who also had retinal dystrophy, ataxia, and dystonic posturing (PMID: 9771776). The second reported individual had myopathy and retinal dystrophy (PMID 16806928). The variant in the first case was heteroplasmic in the patient’s muscle (58%) but undetectable blood. The variant was also undetectable in the mother's blood. In the second case, the variant was heteroplasmic (79%) in the patient’s muscle but undetectable in other tissues. The ages of onset in the two cases were 12 and 17 years, respectively (PS4_supporting). There are no large families reported in the medical literature to consider for evidence of segregation. The variant was reported de novo in one case report as it was absent in mother’s blood (PMID: 9771776), however the variant was also absent in the proband’s blood, no additional tissues were tested, and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. There are no other reports of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 93.1 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). The m.583G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD3.1.2 (PM2_supporting). A single-fiber study (PMID: 16806928) showed the variant heteroplasmy to be higher in COX-negative fibers (78±22%; n = 11) than in COX-positive fibers (45±16%; n = 15; P < 0.001). An aminoacylation study (PMID: 17878308) showed significant losses in aminoacylation efficiency for this variant (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS3_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254834/MONDO:0044970/015 2022-10-10 2023-03-13 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63620 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085639 infores:hetionet CAID:CA16043377 biolink:causes MONDO:0100062 infores:clingen CAID:CA16043377 MONDO:0100062 PMID:29466837 Pathogenic PM2_Supporting, PS3, PS2_Very Strong, PM6, PM1 BA1, BP4, BS1, PP3 The c.2624T>C variant in SCN3A is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 875 (p.Ile875Thr). The variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) with DEE (PMIDs: 29740860, 29466837) (PS2_Very Strong) and as a de novo occurrance with unconfirmed parental relationship in a least 2 individuals with DEE (PMIDs: 29286531, 28191890) (PM6_Moderate), with additional case evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). Studies have observed that when expressed in mammalian cells in culture, this variant causes a gain-of-function effect on the mutant channels as evidenced by a significant leftward/hyperpolarized shift in the voltage dependence of activation, an increase in the persistent/inactivating current, and a rightward/depolarizing shift in the voltage of inactivation (PS3; PMID: 29466837). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant developmental and epilepstic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_VS, PM6_Moderate, PM2_Supporting, PS3. (Version 1; July 7, 2023). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043377/MONDO:0100062/069 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4814 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0392525 infores:hetionet CHEBI:63611 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0740394 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037274 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0860866 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0027441 infores:hetionet GO:0120074 biolink:causes GO:0003197 infores:ubergraph knowledge_assertion manual_agent GO:0120074 GO:0003197 CHEBI:6437 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0038325 infores:hetionet CHEBI:8310 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C1320835 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0518015 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0039070 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0235431 infores:hetionet GO:0048641 biolink:causes GO:0060538 infores:ubergraph knowledge_assertion manual_agent GO:0048641 GO:0060538 HP:0031377 biolink:causes MONDO:0005447 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D013736 DB00970_MESH_D013736_1 CHEBI:92712 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0043352 infores:hetionet CHEBI:52172 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085681 infores:hetionet NCBITaxon:90370 biolink:causes UMLS:C1443237 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:90370 MESH:D000077299 DB01165_MESH_D000077299_1DB01606_MESH_D000077299_1 CHEBI:2704 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0227791 infores:hetionet CHEBI:5004 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0014518 infores:hetionet CHEBI:499361 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0007222 infores:hetionet CHEBI:8707 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0947912 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027051 infores:hetionet CHEBI:10125 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027796 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0948594 infores:hetionet CHEBI:4903 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0404521 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0024115 infores:hetionet CHEBI:63681 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C1262141 infores:hetionet CHEBI:8863 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151905 infores:hetionet GO:0042093 biolink:causes CL:0000492 infores:ubergraph knowledge_assertion manual_agent GO:0042093 CL:0000492 CHEBI:49575 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020580 infores:hetionet CHEBI:9123 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085593 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0267465 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0267465 infores:hetionet CHEBI:6797 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0233494 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0012739 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0442886 infores:hetionet CHEBI:499361 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0043094 infores:hetionet CHEBI:3387 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151772 infores:hetionet CHEBI:2611 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085593 infores:hetionet CHEBI:9332 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0025637 infores:hetionet CHEBI:2704 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0021368 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0009450 infores:hetionet CHEBI:85083 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0043352 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0548823 infores:hetionet CHEBI:6444 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0015230 infores:hetionet CHEBI:3441 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0232462 infores:hetionet CHEBI:31236 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0000731 infores:hetionet CHEBI:31980 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0004604 infores:hetionet CHEBI:45081 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0043144 infores:hetionet CHEBI:8665 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0018681 infores:hetionet CHEBI:4315 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0041657 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020649 infores:hetionet CHEBI:6887 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C3263723 infores:hetionet CHEBI:7514 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0018681 infores:hetionet CHEBI:8871 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0039070 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0221232 infores:hetionet CHEBI:8499 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0015672 infores:hetionet CHEBI:6715 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C2830004 infores:hetionet CHEBI:584020 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0085649 infores:hetionet CHEBI:6067 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0033845 infores:hetionet CHEBI:7573 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0002962 infores:hetionet CHEBI:119573 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0041657 infores:hetionet CHEBI:5779 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0232487 infores:hetionet CHEBI:6822 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0231218 infores:hetionet CHEBI:6067 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151970 infores:hetionet CHEBI:3312 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0546817 infores:hetionet UNII:R43D2573WO biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0041657 infores:hetionet CAID:CA318501 biolink:causes MONDO:0010278 infores:clingen CAID:CA318501 MONDO:0010278 PMID: Likely Benign BS2, BP5 PM2, BS1 The p.His171Leu variant in SLC9A6 (NM_006359.2) is present in 14 XX and 6 XY individual(s) in gnomAD v4.0 (0.002%) (not sufficient to meet BS1 criteria). The p.His171Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.His171Leu variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). In summary, the p.His171Leu variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA318501/MONDO:0010278/033 2024-04-18 2024-07-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:2914 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0007222 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037199 infores:hetionet CHEBI:9927 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0004604 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0424000 infores:hetionet CHEBI:3125 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0036974 infores:hetionet CHEBI:8597 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C2584688 infores:hetionet CHEBI:10101 biolink:causes HP:0032310 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1282609 infores:hetionet CHEBI:8028 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0011168 infores:hetionet CAID:CA658824775 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824775 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The NM_000152.5:c.437del (p.Met146ArgfsTer7) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.2237G>A (p.Trp746Ter) (PMID 26693141), and the other with c.2481+102_2646+31del (PMID 22658377)(PP4_Moderate, PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 554096, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specification version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824775/MONDO:0009290/010 2021-08-24 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2659 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0020437 infores:hetionet CHEBI:585948 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C2830004 infores:hetionet CHEBI:83531 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0000731 infores:hetionet CHEBI:68606 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0750394 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0474381 infores:hetionet CHEBI:72564 biolink:causes MONDO:0019781 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0004114 infores:hetionet CHEBI:31236 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2979982 infores:hetionet CHEBI:6367 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0026826 infores:hetionet CAID:CA023415 biolink:causes MONDO:0007750 infores:clingen CAID:CA023415 MONDO:0007750 PMID: Uncertain Significance PS4_Moderate, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS3, PS2, PS1, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM5, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN≥6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria ≥6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia.PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023415/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50730 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0037763 infores:hetionet CHEBI:51209 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0009676 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0015734 infores:hetionet CHEBI:9738 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0030554 infores:hetionet CHEBI:94807 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0023518 infores:hetionet CHEBI:127780 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0494475 infores:hetionet NCBIGene:4292 biolink:causes MONDO:0008018 infores:monarchinitiative not_provided not_provided HGNC:7127 MONDO:0008018 uuid:ad02a098-c30e-45ce-beef-284705728f7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5100 biolink:causes UMLS:C0857331 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0857331 infores:hetionet CHEBI:3441 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0039231 infores:hetionet CAID:CA386965798 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965798 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting BP4, PS4, PP3, PP4 The c.725T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 242 (p.(Ile242Thr)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a REVEL score of 0.624, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function. This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in one individual with diabetes; however, this number does not meet the MDEP cutoff for PS4_Moderate, and the MODY probability is unable to be calculated due to lack of clinical information (PMID: 23771925). In summary, c.725T>C meets the criteria to be classified as variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965798/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:231425 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0151872 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042075 infores:hetionet CHEBI:17688 biolink:causes UMLS:C1167842 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1167842 infores:hetionet CHEBI:7915 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1443060 infores:hetionet CHEBI:51230 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0004093 infores:hetionet CHEBI:15940 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0026826 infores:hetionet CHEBI:3814 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0008031 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0243026 infores:hetionet CHEBI:49960 biolink:causes HP:0031370 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151739 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0030312 infores:hetionet UMLS:C0065374 biolink:causes HP:0003365 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0019559 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0009450 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0855775 infores:hetionet CAID:CA023755 biolink:causes MONDO:0007750 infores:clingen CAID:CA023755 MONDO:0007750 PMID: Pathogenic PS4, PM3, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS3, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM6, PVS1, BS2, PP1 The NM_000527.5(LDLR):c.718G>A (p.Glu240Lys) variant is classified as U Pathogenic for Familial Hypercholesterolemia by applying evidence codes PP3, PM2, PS4, PM3, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PP3 - REVEL = 0.865.It is above 0.75, so PP3 is Met.PM2 - PopMax MAF = 0.00005418 (0.005418%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met.PS4 - Variant meets PM2 and is identified in at least 11 unrelated index cases: 2 index cases with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 index case with DLCN>6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 index cases with DLCN>6 from Robarts Research Institute; 2 index cases with DLCN>6 from Color Health, Inc; 2 index cases fulfilling the following criteria: children with a) TC >200 mg/dl or LDL >120 mg/dl and b) presence of primary hypercholesterolemia in 1st degree relatives with autosomal dominant mode of inheritance or c) family history of pCHD or d) presence of xanthomas in proband or in parents, from Greece (PMID: 25463123); at least 1 index case with Simon Broome criteria from China (PMID: 28235710); 1 index case with Definite FH (LDL >13 mmol/l and presence of xanthomas and hypercholesterolemia in both parents) from Italy (PMID: 32977124), so PS4 is Met.PM3 - Variant meets PM2 and is identified in an italian index case with homozygous FH phenotype (LDL>13 mmol/l) with another LDLR variant, in trans (PMID: 32977124). In PMID: 28965616 is identified an italian index case (phenotype not reported) with LDLR variant c.304C>T (p.Gln102*), classified as Pathogenic by these guidelines, but cannot determine if the variants are in trans (PMID: 28965616). Assuming that is the same homozygous index case (same lab), PM3 is Met.PP4 - Variant meets PM2 and is identified in at least 11 unrelated index cases as reported above, so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023755/MONDO:0007750/013 2022-02-14 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:40237 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0026858 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0332575 infores:hetionet CHEBI:7447 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C2047937 infores:hetionet CHEBI:7447 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0001824 infores:hetionet CHEBI:51450 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018790 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0162119 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0036508 infores:hetionet CHEBI:4653 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0030554 infores:hetionet CHEBI:9352 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0013491 infores:hetionet CHEBI:31348 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003467 infores:hetionet CHEBI:51137 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0025061 infores:hetionet CHEBI:6690 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0027424 infores:hetionet CHEBI:15367 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042963 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0948089 infores:hetionet CHEBI:2567 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0231218 infores:hetionet CHEBI:101278 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0039231 infores:hetionet CHEBI:45863 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0026826 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020649 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0015397 infores:hetionet CHEBI:65349 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0015230 infores:hetionet CHEBI:3219 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0260662 infores:hetionet CHEBI:5801 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0162830 infores:hetionet CAID:CA350341879 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341879 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM1 PVS1, BS2, BP4, BA1, BS1 The c.1217T>G (p.Met406Arg) variant is a missense variant located in exon 9 of the BMPR2 gene, predicted to cause substitution of methionine to arginine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating a critical or non-critical amino acid residue (PM1_moderate). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.96 and AlphaMissense is 0.9818 indicating pathogenicity (PP3_supporting). The variant has been reported in four studies based on 2 unrelated probands (PMIDs: 29650961, 33066286, 32581362, and 27537724) (PS4_supporting). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting, PS4_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341879/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6437 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C2830004 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0348801 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0348801 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042373 infores:hetionet CHEBI:6916 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0027947 infores:hetionet CHEBI:46345 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0014591 infores:hetionet CHEBI:31302 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0549249 infores:hetionet CHEBI:63791 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1260880 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0036341 infores:hetionet CAID:CA357950 biolink:causes MONDO:0012163 infores:clingen CAID:CA357950 MONDO:0012163 PMID: Pathogenic PP4, PM2_Supporting, PVS1 BS2 The NM_002185.5(IL7R):c.361dup (p.Ile121AsnfsTer8) frameshift variant in exon 3 creates a premature stop codon in exon 4/5 (upstream of the final 50 nucleotides), which is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in several SCID patients (PMIDs: 35503492, 24759676, 32765500, 28436970, 25046553), at least one of whom was reported with a highly specific phenotype; the diagnosis of SCID was made by criteria of the Primary Immune Deficiency Treatment Consortium in this patient with a T−BlowNK+ (0 CD3+ cells/mm, 300 B cells/mm3, 450 NK cells/mm3) lymphocyte subset profile (PMID: 35503492; PP4). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 9/128422 observed alleles) is 0.00002867 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.00004129) and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PP4. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA357950/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31644 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0037274 infores:hetionet NCBIGene:6557 biolink:causes MONDO:0100344 infores:monarchinitiative not_provided not_provided HGNC:10910 MONDO:0100344 uuid:e8114c14-907f-42e8-a5e7-25de8ec672a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27446 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0015230 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0026857 infores:hetionet CHEBI:49040 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0026821 infores:hetionet CHEBI:64317 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0030252 infores:hetionet CHEBI:31859 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0085631 infores:hetionet CHEBI:119915 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026858 infores:hetionet CAID:CA367403541 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403541 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.110T>G variant in the glucokinase gene,GCK, causes an amino acid change of methionine to arginine at codon 37 (p.(Met37Arg)) of NM_000162.5. This variant segregated with diabetes, with at least four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and an OGTT with minimal increment) (PP4_Moderate; internal lab contributor). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributor, DOI: 10.1055/s-2008-1004713). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.110T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403541/MONDO:0015967/086 2023-08-25 2023-08-25 Semidominant inheritance HP:0032113 Supports CHEBI:3207 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0000833 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0221706 infores:hetionet CAID:CA410777780 biolink:causes MONDO:0021060 infores:clingen CAID:CA410777780 MONDO:0021060 PMID: Uncertain Significance PM2_Supporting, BP4, PM3_Supporting, PS3_Supporting PP3, BA1, BS1 The NM_006767.4:c.1687G>C variant in LZTR1 is a missense variant predicted to cause substitution of glutamic acid by glutamine at amino acid 563 (p.Glu563Gln). The filtering allele frequency (the upper threshold of the 95% CI of 1/30612) of the c.1687G>C variant in LZTR1 is 0.0 for South Asian chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.14, which is below the threshold of 0.3, evidence that does not predict a damaging effect on LZTR1 function (BP4). This variant has been detected in 1 individual with RASopathy. They were homozygous for the variant (0.5 PM3 points, PMID: 29469822) (PM3_Supporting). LZTR1 stability in COS-1 cells showed almost absent expression levels by immunoblotting and relative quatitative analyses indicating that this variant impacts protein function (PMID:30481304)(PS3_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance with conflicting evidence for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS3_Supporting, PM2_Supporting, PM3_Supporting, BP4. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410777780/MONDO:0021060/094 2025-04-23 2025-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9586 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0149931 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0031117 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1145670 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006277 infores:hetionet NCBIGene:9896 biolink:causes MONDO:0008995 infores:monarchinitiative not_provided not_provided HGNC:16873 MONDO:0008995 uuid:760f5adb-c3e0-4e03-a036-a8c8616e19bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5913 biolink:causes MONDO:0014588 infores:monarchinitiative not_provided not_provided HGNC:9863 MONDO:0014588 uuid:89740522-76ac-4f25-a534-3c8c53940ef0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0038362 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0234215 infores:hetionet CHEBI:50742 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0438142 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0349506 infores:hetionet CHEBI:182080 biolink:causes UMLS:C0919567 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0919567 infores:hetionet CHEBI:5130 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0018681 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151734 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0234215 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022575 infores:hetionet GO:1905310 biolink:causes GO:0003151 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0003151 CHEBI:3756 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0404521 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0086543 infores:hetionet CHEBI:7824 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018926 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0155919 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005173 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0022602 infores:hetionet CHEBI:17026 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0547030 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0403632 infores:hetionet CHEBI:3219 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2129214 infores:hetionet CHEBI:45863 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235031 infores:hetionet CHEBI:75998 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0038362 infores:hetionet CHEBI:5801 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0014742 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0855242 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042769 infores:hetionet CHEBI:50885 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0085570 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0178298 infores:hetionet NCBIGene:54820 biolink:causes MONDO:0013527 infores:monarchinitiative not_provided not_provided HGNC:17619 MONDO:0013527 uuid:bc466899-ca71-4b16-b9bf-72692d8624fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63607 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151754 infores:hetionet CAID:CA10639820 biolink:causes MONDO:0100326 infores:clingen CAID:CA10639820 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 After a thorough literature search the missense variant NM_000419.5(ITGA2B):c.230G>A (p.Ser77Asn) has not been found in any individuals with Glanzmann thrombasthenia. The variant is absent from gnomAD (PM2_supporting). The variant was originally identified by Illumina as part of a predisposition screen in an ostensibly healthy population. The computational predictor REVEL gives a score of 0.151, predicting no damaging effect on ITGA2B function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10639820/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8888 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235818 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0030312 infores:hetionet NCBIGene:51099 biolink:causes MONDO:0010155 infores:monarchinitiative not_provided not_provided HGNC:21396 MONDO:0010155 uuid:3b074926-d82c-4878-845d-5edbd84164d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0233472 infores:hetionet CHEBI:5383 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0018681 infores:hetionet CHEBI:36791 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0035243 infores:hetionet CHEBI:5118 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040053 infores:hetionet CHEBI:6909 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0235031 infores:hetionet CHEBI:28748 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0391870 infores:hetionet CHEBI:5778 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0600142 infores:hetionet CHEBI:8354 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0019080 infores:hetionet CHEBI:3423 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0003537 infores:hetionet CAID:CA229611 biolink:causes MONDO:0009861 infores:clingen CAID:CA229611 MONDO:0009861 PMID:10980574 Likely Pathogenic PM5, PM2_Supporting, PP3_Moderate, PS3_Supporting The c.533A>T (p.Glu178Val) variant in PAH has not been reported in the literature/in a patient to our knowledge. This variant is absent in population databases. Computational evidence support a deleterious effect (REVEL= 0.866. Functional studies of this variant have been reported to BioPKU: mutant in vitro expression in COS cells reportedly had 18% enzyme activity as compared to wild type. Another missense change at this amino acid (p.Glu178Gly) is classified as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM5, PP3_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229611/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119486 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0023798 infores:hetionet CHEBI:9086 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0039231 infores:hetionet CAID:CA386952705 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952705 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Moderate, PS2_Supporting, PP3, PP4 PS4 The c.77T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 26 (p.(Leu26Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result <50%) (PS2_Supporting; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, not tested for HNF4A, but individual had hepatocellular adenomas, highly specific for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with four informative meioses in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.77T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3, PS2_Supporting, PP4, PP1_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952705/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA512318633 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318633 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.690G>A (p.Gln230=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318633/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:78320 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0013595 infores:hetionet CHEBI:6754 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0424295 infores:hetionet CHEBI:7640 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0019158 infores:hetionet CHEBI:3723 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027497 infores:hetionet CHEBI:63608 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0042384 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038454 infores:hetionet CHEBI:3223 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0002453 infores:hetionet CHEBI:8228 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C3263723 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0022650 infores:hetionet CAID:CA120615 biolink:causes MONDO:0044970 infores:clingen CAID:CA120615 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PS4 The m.6328C>T (p.S142F) variant in MT-CO1 has been reported in one individual to date with primary mitochondrial disease. This individual had a severe cardioencephalomyopathy resembling mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at >95% heteroplasmy in muscle (PMID: 16284789). P. denitrificans models support a deleterious functional impact of this variant (PS3_supporting; PMID: 16284789). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic and each had a raw score of 0.90 (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120615/MONDO:0044970/015 2023-12-21 2024-11-26 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:94440 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C2364111 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1306341 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0027947 infores:hetionet CHEBI:47499 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0851578 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0033860 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0008325 infores:hetionet CHEBI:5165 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0014591 infores:hetionet CHEBI:465284 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0155365 infores:hetionet CHEBI:2567 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0025320 infores:hetionet CHEBI:3181 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042571 infores:hetionet CHEBI:63618 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0027080 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0037195 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036572 infores:hetionet CHEBI:17650 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0162835 infores:hetionet CHEBI:44423 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0423791 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042075 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0037274 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0015726 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0015726 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0029408 infores:hetionet NCBIGene:7109 biolink:causes MONDO:0859285 infores:monarchinitiative not_provided not_provided HGNC:11868 MONDO:0859285 uuid:d26c75b9-e8b9-4599-9816-00c86630f11b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038814 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0162429 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0235416 infores:hetionet CHEBI:3996 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0042963 infores:hetionet CHEBI:2636 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C2939147 infores:hetionet CHEBI:5118 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0231528 infores:hetionet CHEBI:8212 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0033774 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0949103 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0949103 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0003123 infores:hetionet CHEBI:5001 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0022346 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0027651 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0040034 infores:hetionet CHEBI:194135 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003537 infores:hetionet CHEBI:2955 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011603 infores:hetionet CHEBI:5109 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0037274 infores:hetionet CHEBI:2038 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0037287 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0002871 infores:hetionet CAID:CA341519 biolink:causes MONDO:0008723 infores:clingen CAID:CA341519 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM1, PM3, PP4_Moderate, PS3_Supporting The c.1405C>T variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 469 (p.Arg469Trp). This variant has been detected in at least 5 individuals with clinical signs of very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of these, 2 were heterozygous for the variant without an identified second variant in ACADVL (PMID: 9973285, Olpin SE et al. Int J Neonat Screen. 2017 3(1),2) and 3 individuals were homozygous for the variant (PM3 points = 1.0, PM3, PMID: 9973285). ACADVL activity in one patient's fibroblast cell line was observed at <=20% of normal (PMID: 17999356; PP4_Moderate). Expression of this variant using rACADVL in E. coli showed enzyme activity =< 20% of normal and absence of protein expression indicating that this variant impacts protein function; however, this assay did not use established benign variants as negative controls, and thus only meets criteria to be applied at supporting strength (PS3_Supporting; PMID: 17374501). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PM1; PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 in the EAS population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PS3_Supporting, PM1, PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA341519/MONDO:0008723/021 2024-12-10 2024-12-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes UMLS:C0267925 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0267925 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0302295 infores:hetionet CHEBI:51364 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0023530 infores:hetionet NCBIGene:9289 biolink:causes MONDO:0011738 infores:monarchinitiative not_provided not_provided HGNC:4512 MONDO:0011738 uuid:8047b837-15a6-432d-84fc-a0374dea97f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0338656 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0100338 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D014552 DB01332_MESH_D014552_1DB09050_MESH_D014552_1DB00274_MESH_D014552_1DB01059_MESH_D014552_1DB01140_MESH_D014552_1DB01607_MESH_D014552_1DB00759_MESH_D014552_1DB09335_MESH_D014552_1DB00766_MESH_D014552_1DB00781_MESH_D014552_1DB00355_MESH_D014552_1DB00415_MESH_D014552_1DB00827_MESH_D014552_1DB00447_MESH_D014552_1DB01172_MESH_D014552_1DB00671_MESH_D014552_1DB00467_MESH_D014552_1DB00994_MESH_D014552_1DB00263_MESH_D014552_1DB00578_MESH_D014552_1DB00438_MESH_D014552_1DB00440_MESH_D014552_1DB00978_MESH_D014552_1DB02703_MESH_D014552_1DB00319_MESH_D014552_1DB00551_MESH_D014552_1DB01061_MESH_D014552_1DB01017_MESH_D014552_1DB00828_MESH_D014552_1DB00833_MESH_D014552_1DB01165_MESH_D014552_1DB00948_MESH_D014552_1 CHEBI:10125 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0030252 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004610 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0003467 infores:hetionet CHEBI:18067 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0030193 infores:hetionet CHEBI:42797 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042023 infores:hetionet CHEBI:36795 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0039591 infores:hetionet CHEBI:2469 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0239571 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0162316 infores:hetionet CHEBI:4470 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0013395 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020461 infores:hetionet CHEBI:63630 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0030252 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0232498 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0162429 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0023418 infores:hetionet CHEBI:30659 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0027051 infores:hetionet CHEBI:4995 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014518 infores:hetionet CAID:CA135994 biolink:causes MONDO:0021060 infores:clingen CAID:CA135994 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.520C>T (p.Pro174Ser) variant in the HRAS gene is 0.115% (20/11482) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135994/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0151908 infores:hetionet CHEBI:46345 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0021368 infores:hetionet NCBIGene:777 biolink:causes MONDO:0032657 infores:monarchinitiative not_provided not_provided HGNC:1392 MONDO:0032657 uuid:7f479f2f-2694-4b29-a6fe-121a74968731 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3749 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0012833 infores:hetionet CHEBI:45924 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0014457 infores:hetionet CHEBI:8364 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0039070 infores:hetionet CHEBI:10102 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1306341 infores:hetionet CHEBI:27777 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0023380 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151559 infores:hetionet CHEBI:367163 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0000731 infores:hetionet CHEBI:6775 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0404521 infores:hetionet CHEBI:70746 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0042721 infores:hetionet CHEBI:567361 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004093 infores:hetionet CAID:CA377781872 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781872 MONDO:0017623 PMID: Uncertain Significance PP2, PP3, PP1, PM2_Supporting NM_000314.8(PTEN):c.29G>C (p.Ser10Thr) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Absent in gnomADPP1: Co-segregation with disease in multiple affected family members, with 3 meioses observed. (internal laboratory contributor(s)) PP2: Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.745) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781872/MONDO:0017623/003 2024-02-09 2024-03-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA658795227 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795227 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Strong NM_000152.5:c.379_380del (p.Cys127LeufsTer18) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 patients with Pompe disease and this variant have been reported that meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. Of these patients, the available data includes documentation of laboratory values showing GAA deficiency (PMIDs 18757064, 24245577, 24715333, 30049495, 33162552). Furthermore, one of these patients had documented features consistent with infantile onset Pompe disease (PMID 24715333, 33162552) and another was on enzyme replacement therapy (PMID 30049495)(PP4_Moderate). These patients are all compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.525delT (PMID 24715333, 33162552), “del exon 18” (PMID 9660056), and c.-32-13T>G (PMID 17573812, 17643989, 18757064, 24245577, 33458579; at least two patients). Total 2 points (PM3_Strong). Another patients is compound heterozygous for the variant and c.2104C>T (p.Arg702Cys); phase unconfirmed (PMID 30049495). The in trans data from this patient will be used in the assessment of p.Arg702Cys and was not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 552747, two star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP Specification Version 2.0): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795227/MONDO:0009290/010 2021-08-19 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:100241 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151578 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1619712 infores:hetionet CHEBI:9123 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018944 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0860866 infores:hetionet CHEBI:63623 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C2830004 infores:hetionet NCBIGene:79644 biolink:causes MONDO:0012885 infores:monarchinitiative not_provided not_provided HGNC:25812 MONDO:0012885 uuid:e8f56895-f840-41d4-86ab-84483c0eec92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31397 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0236072 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017601 infores:hetionet CHEBI:144551 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C3665347 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0004238 infores:hetionet CHEBI:3001 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0027424 infores:hetionet CHEBI:52717 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0231528 infores:hetionet CAID:CA587570196 biolink:causes MONDO:0009595 infores:clingen CAID:CA587570196 MONDO:0009595 PMID: Pathogenic PM2_Supporting, PM4, PM3_Strong, PM1_Strong, PP1_Moderate, PP4 The NC_000009.12:g.35658023_35658044dup variant is a 22-base duplication upstream of the transcribed region of the RMRP gene. This variant is also known as NR_003051.4(RMRP):n.-24_-3dup or g.–25_–4dup22TACTACTCTGTGAAGCTGAGAA. It locates between the TATA box (spanning n.-32 to n.-24) and the transcription start site (n.4) (PM1_Strong). It inserts 22 nucleotides that increases the distance between the TATA box and the transcription start site (PM4_Moderate). The Grpmax Filtering allele frequency of this variant is 0.000004890 in gnomAD v4.1.0, which is lower than the SCID-VCEP threshold (<0.0000447) for PM2_Supporting (PM2_Supporting). This variant is reported in trans with the variant g.196C>T (previously curated as pathogenic by the SCID VCEP: NC_000009.12:g.35657823G>A) in four Brazilian patients and is reported in trans with the variant g.97_98dup2(TG) (not curated by the SCID VCEP) in one Brazilian patient (+1.0 points each). The total score is 2.0 meeting this criterion PM3_Strong. (PMID: 32021596). Among these cases, two affected siblings have been described (PP1_Moderate). At least one patient presented with metaphyseal dysplasia (+1.0 points) and hypotrichosis (+0.5 points). PP4 is met. In summary, this variant is classified as pathogenic for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PM1_Strong, PM4_Moderate, PM3_Strong, PP1_Moderate, PP4 (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA587570196/MONDO:0009595/088 2025-10-22 2025-10-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37924 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0575081 infores:hetionet CHEBI:7640 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0024205 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006875 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0028840 infores:hetionet CAID:CA386959775 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959775 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 The c.415C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 139 (p.(Leu139Phe)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent C-peptide over 5 years after T1D diagnosis)(PP4_Moderate; internal lab contributors). Two other missense variants, c.416T>C p.Leu139Pro and c.415C>G p.Leu139Val, have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.415C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959775/MONDO:0015967/017 2024-10-02 2024-10-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32221 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0232493 infores:hetionet NCBIGene:51490 biolink:causes MONDO:0976265 infores:monarchinitiative not_provided not_provided HGNC:26933 MONDO:0976265 uuid:ef032cb0-c398-48df-9681-0b07811368b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35553 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0080276 infores:hetionet CHEBI:681569 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0004093 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151698 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0027609 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036572 infores:hetionet CHEBI:42797 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040434 infores:hetionet CHEBI:3127 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0030848 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1443060 infores:hetionet CHEBI:4784 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030252 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1443060 infores:hetionet CHEBI:50692 biolink:causes HP:6000054 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0026751 infores:hetionet CHEBI:51860 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013456 infores:hetionet CHEBI:3061 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0002962 infores:hetionet CHEBI:31397 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0016658 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0036572 infores:hetionet CHEBI:46195 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0033774 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0267792 infores:hetionet CAID:CA256112 biolink:causes MONDO:0001586 infores:clingen CAID:CA256112 MONDO:0001586 PMID: Pathogenic PP3_Moderate, PS3_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting, PM3_Very Strong The NM_000203.5:c.1598C>G variant in IDUA is a missense variant that is predicted to result in the substitution of proline by arginine at amino acid 533 (p.Pro533Arg). This variant is one of the more common variants identified in patients with mucopolysaccharidosis type 1 (MPS 1). The variant was found in 46 out of 538 patients in the International MPS 1 Registry (PMID: 31194252). It has been identified in patients with MPS 1 from different continents, and it is the most frequent variant in the north African countries (92% of MPS1 alleles in Morocco, 81% in Algeria, and 54% in Tunisia) (reviewed in PMID: 29393969). Of note, the severity of symptoms in individuals with this variant is variable; some homozygous individuals have severe disease while others have attenuated symptoms (PMID: 31194252). At least 50 patients with this variant have been reported including patients with documented laboratory values showing deficient iduronidase activity and detailed features consistent with MPS 1 such as dysmorphic facies, multiple dysostoses, joint stiffness, hepatomegaly, umbilical hernia, hearing loss, cardiovascular disease, and hydrocephalus and/or elevated urine GAGs (2 PP4 criteria met) (PMID: 10738517, 12796790, 1301941). One study provides details on the clinical features, IDUA activity, and GAG values for 9 patients (3 PP4 criteria met, PMID: 27196898) (PP4_Moderate). At least 24 individuals are homozygous for the variant (PMID: 1301941, 10738517, 12203999, 16435195, 24102521, 27196898, 28752568, 31194252, 31298590). At least 12 individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, including at least 8 patients with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (max 2 x 0.5 points), two patients with c.208C>T (p.Gln70Ter) (PMID: 31194252) (ClinVar Variation ID: 11909) (2 x 0.5 points), two apparently unrelated patients with c.1743C>G (p.Tyr581Ter) (ClinVar Variation ID: 550883) (2 x 0.5 points), and at least 24 homozygotes (max 2 x 0.5 points) (PMID: 31194252). 4 PM3 points (PM3_VeryStrong). Many additional individuals have been reported who are compound heterozygous for additional IDUA variants (PMID: 12203999, 12559846, 31194252). Additional evidence is available in the literature but the maximum points for PM3 have been reached (PM3_Very Strong). The variant has been shown to segregate with disease in families, including two families each with two affected children who are homozygous for the variant (PMID: 27196898) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001975 (10/50624 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in CHO cells and tobacco BY-2 cells revealed that the protein is unstable, abnormally processed/trafficked, and has very low, but detectable (<1%), residual activity when compared to wild type (PMID: 12559846, 24036510) (PS3_Supporting). The computational predictor REVEL gives a score of 0.783 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PP3_Moderate). No impact on splicing predicted by SpliceAI. There is a ClinVar entry for this variant (Variant ID: 11910). In summary, this variant meets the criteria to be classified as pathogenic for MPS 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA256112/MONDO:0001586/091 2025-01-03 2025-01-03 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:4141 biolink:causes MONDO:0957221 infores:monarchinitiative not_provided not_provided HGNC:6898 MONDO:0957221 uuid:ed897ebf-853e-476a-8809-2857f5f47734 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:26275 biolink:causes MONDO:0009603 infores:monarchinitiative not_provided not_provided HGNC:4908 MONDO:0009603 uuid:a3994810-e401-4092-b628-a371a5d2df25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0851341 infores:hetionet CHEBI:101853 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0037763 infores:hetionet CHEBI:61049 biolink:causes MONDO:0850420 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0267941 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0574067 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0543698 infores:hetionet NCBIGene:27316 biolink:causes MONDO:0010661 infores:monarchinitiative not_provided not_provided HGNC:9910 MONDO:0010661 uuid:1d7ce357-6504-4fce-95f4-337b7635626e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0039231 infores:hetionet CHEBI:2611 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C2939147 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0018799 infores:hetionet CHEBI:6367 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003862 infores:hetionet CHEBI:6062 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0037299 infores:hetionet CHEBI:6456 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0041834 infores:hetionet UMLS:C0009315 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0242429 infores:hetionet CHEBI:5790 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233471 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0038454 infores:hetionet CHEBI:9637 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0042963 infores:hetionet CHEBI:3286 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0023218 infores:hetionet CHEBI:10650 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0278134 infores:hetionet CAID:CA913163215 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163215 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS2, PS3, PS4, PM6, PM2 The m.1619C>T variant in MT-TV has been reported in one individual in the medical literature, however no clinical details are provided (PMID: 31965079). There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease manifestations. This variant is present in population databases (Mitomap's 3/59,389 sequences: AF=0.005%; Helix's 24/195,983 sequences: AF=0.055%; and gnomAD v3.1.2: AF=0.005% including three homoplasmic occurrences). The computational predictor MitoTIP suggests this variant is benign (15.2 percentile) and HmtVAR (score 0) predicts it to be polymorphic (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163215/MONDO:0044970/015 2023-06-26 2024-07-24 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6076 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0036974 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0264863 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0264863 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042109 infores:hetionet CHEBI:6472 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0948586 infores:hetionet CHEBI:7931 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085641 infores:hetionet CHEBI:64312 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003467 infores:hetionet CAID:CA119183 biolink:causes MONDO:0020367 infores:clingen CAID:CA119183 MONDO:0020367 PMID:16466712PMID:35196929 Likely Benign BS1, BS3_Supporting BP7, PM2, PM6, PP3, PP1, PM4, PM5, PS3, PS4, PS1, PS2, BA1, BP4 The c.144G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 48 (p.Gln48His). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.007937, which met the ≥ 0.001 threshold set for BS1 (243 alleles out of 30,616, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.257, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Gln48His protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of - 6 and to be classified as likely benign (likely benign classification range - 2 to - 6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119183/MONDO:0020367/019 2022-03-06 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9086 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0340464 infores:hetionet CHEBI:8888 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0043352 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0281981 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0558148 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0558148 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0015397 infores:hetionet CHEBI:135736 biolink:causes MONDO:0020076 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027022 infores:hetionet CHEBI:31980 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0001925 infores:hetionet CHEBI:7443 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0085593 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0040409 infores:hetionet CHEBI:63617 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019521 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0152029 infores:hetionet CHEBI:45951 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0080274 infores:hetionet CHEBI:27446 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0014457 infores:hetionet CHEBI:2639 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0027947 infores:hetionet CHEBI:3723 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016867 infores:hetionet CHEBI:91583 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0042510 infores:hetionet GO:0090189 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0060993 CHEBI:6438 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0033774 infores:hetionet CHEBI:7983 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0151763 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1443060 infores:hetionet NCBIGene:1585 biolink:causes MONDO:0012524 infores:monarchinitiative not_provided not_provided HGNC:2592 MONDO:0012524 uuid:92efebd6-e0e0-4625-8dd7-ffffaa36e626 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes UMLS:C1112616 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1112616 infores:hetionet CHEBI:9435 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0221201 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0041912 infores:hetionet CHEBI:66964 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0035455 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0015397 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1368065 infores:hetionet CHEBI:7983 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0009806 infores:hetionet CHEBI:75722 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085932 infores:hetionet CHEBI:27974 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0015230 infores:hetionet CHEBI:63630 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042963 infores:hetionet CHEBI:71219 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151878 infores:hetionet NCBIGene:5002 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:10964 MONDO:0008903 uuid:599dc741-4e81-44a0-abae-c0400bfec598 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152029 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1306341 infores:hetionet CHEBI:6129 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0016199 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151596 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0032285 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0022650 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0518015 infores:hetionet CHEBI:10125 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020433 infores:hetionet CHEBI:4562 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0022904 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020649 infores:hetionet CHEBI:63925 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0349790 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0267792 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0027765 infores:hetionet CHEBI:16469 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042133 infores:hetionet CHEBI:9139 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0162285 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0013604 infores:hetionet CHEBI:63638 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1145670 infores:hetionet CHEBI:168396 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0041296 infores:hetionet CHEBI:50841 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0015230 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0858259 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0031350 infores:hetionet CHEBI:39669 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0020458 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0333641 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0239783 infores:hetionet CHEBI:3242 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0033774 infores:hetionet CHEBI:188986 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0014236 infores:hetionet CHEBI:6456 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0085631 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0856049 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0856049 infores:hetionet NCBIGene:60681 biolink:causes MONDO:0012592 infores:monarchinitiative not_provided not_provided HGNC:18169 MONDO:0012592 uuid:30a6efbc-aa91-4f5d-ac7e-6cd4cb7ca586 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7478 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0036454 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0677500 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0392197 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0008301 infores:hetionet CHEBI:63598 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020625 infores:hetionet CHEBI:2637 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0020649 infores:hetionet CHEBI:49662 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002874 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0036572 infores:hetionet CAID:CA270535 biolink:causes MONDO:0010726 infores:clingen CAID:CA270535 MONDO:0010726 PMID: Likely Pathogenic PM2_Supporting, PS4, PP4 BP4, PM1, PP3 The p.Ala279Val variant in MECP2 (NM_004992.4) has been observed in at least 5 individuals with a clinical phenotype consistent with Rett syndrome (PMID: 15526954, ClinVar, internal database - Invitae) (PS4, PP4). The p.Ala279Val variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ala279Val variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270535/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Supports NCBIGene:1834 biolink:causes MONDO:0007442 infores:monarchinitiative not_provided not_provided HGNC:3054 MONDO:0007442 uuid:e9a9c8c6-f515-4257-9dbf-ec0bd55958bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0000737 infores:hetionet CHEBI:3398 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0040264 infores:hetionet CHEBI:7852 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C3665347 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0030193 infores:hetionet CHEBI:31711 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0003578 infores:hetionet CAID:CA2580098636 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098636 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1363del (p.Ala455fs) is a frameshift variant. This frameshift variant is in a region that is critical to protein function (PVS1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This frameshift variant is downstream c.98 (PM5_supporting). This variant was reported in Clinvar in 2022 by ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, but the affected status of the proband is unknown (Variation ID 1703793).In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098636/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports UNII:15G12L5X8K biolink:causes UMLS:C0595902 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0595902 infores:hetionet CHEBI:142290 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0033774 infores:hetionet CHEBI:119915 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0036973 infores:hetionet CHEBI:9598 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0392171 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0234215 infores:hetionet CHEBI:29007 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0033687 infores:hetionet CHEBI:2618 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0344232 infores:hetionet CHEBI:68595 biolink:causes UMLS:C2609199 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C2609199 infores:hetionet CHEBI:3654 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0012833 infores:hetionet NCBIGene:9563 biolink:causes MONDO:0011503 infores:monarchinitiative not_provided not_provided HGNC:4795 MONDO:0011503 uuid:2e9a66e0-b22c-4638-9d28-8cdbdbe4a522 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C2364111 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0037199 infores:hetionet CHEBI:63611 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0231218 infores:hetionet CHEBI:28915 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0013447 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0152517 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0178298 infores:hetionet CHEBI:7601 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0022107 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151828 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0227791 infores:hetionet CHEBI:5106 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0017675 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0034882 infores:hetionet CHEBI:4708 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0232849 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0038362 infores:hetionet CHEBI:60761 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0001824 infores:hetionet CHEBI:52172 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0917801 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0424230 infores:hetionet CHEBI:52172 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0270996 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0003123 infores:hetionet CHEBI:9613 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0040034 infores:hetionet CHEBI:70746 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0003862 infores:hetionet NCBIGene:8985 biolink:causes MONDO:0012892 infores:monarchinitiative not_provided not_provided HGNC:9083 MONDO:0012892 uuid:86c44096-d2b6-4eee-8523-df94c145b095 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes UMLS:C1262200 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C1262200 infores:hetionet CHEBI:6715 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0043352 infores:hetionet CHEBI:5864 biolink:causes UMLS:C2945586 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C2945586 infores:hetionet CAID:CA000422 biolink:causes MONDO:0017623 infores:clingen CAID:CA000422 MONDO:0017623 PMID:9467011PMID:9259288PMID:10234502PMID:20194734PMID:10866302PMID:29785012PMID:15987703PMID:29706350 Pathogenic PM2, PP2, PM6_Strong, PS4_Supporting, PM1, PS3 PVS1, BS4, BS1, BS3, BP5, BP7, PP1, PP3, BS2, PM4, PM5, BP2, BP4, BA1, PS1, PS2 PTEN c.370T>C (p.Cys124Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 29706350)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000568254.4) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000422/MONDO:0017623/003 2019-06-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63577 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0014724 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0233414 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009806 infores:hetionet CHEBI:3561 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0016658 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0221706 infores:hetionet CHEBI:16469 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151604 infores:hetionet CHEBI:8378 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0340865 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151763 infores:hetionet UMLS:C0145867 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0039070 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0013456 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037822 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009806 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0031350 infores:hetionet CAID:CA16020732 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020732 MONDO:0009861 PMID:24368688PMID:24368688 Likely Pathogenic PM3, PM2, PP4, PVS1_Strong The c.168+1G>T has been reported in compound heterozygote state in 2 patients with PKU (BH4 deficiency not excluded) (PMID: 24368688). The variants in trans include: R111*, and L249F are both confirmed pathogenic (PM3). This variant is absent from population databases (PM2). Null variant (canonical +/- 1 or 2 splice sites) where LOF is a known mechanism of disease, exon skipping preserves reading frame, but the altered region is critical to protein function (14 non-truncating pathogenic variants in the region). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PM3, PP4, PVS1_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020732/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:1959 biolink:causes MONDO:0011890 infores:monarchinitiative not_provided not_provided HGNC:3239 MONDO:0011890 uuid:57faea6b-8cf3-4d87-a83d-596b7dd13f03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9674 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0030193 infores:hetionet CHEBI:51380 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0012569 infores:hetionet CAID:CA2580088947 biolink:causes MONDO:0100216 infores:clingen CAID:CA2580088947 MONDO:0100216 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Supporting, PS3 BP4, BA1, BS1 The NM_177438.3:c.2256+5G>A variant in DICER1 is an intronic variant resulting in an G to A substitution 5 nucleotides downstream from coding exon 14. This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal contributor). This patient was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, Internal contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor). The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS3, PS4_Supporting, PP4, PM2_Supporting, PP3. (Bayesian Points: 8; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580088947/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16586 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0687713 infores:hetionet CAID:CA308104313 biolink:causes MONDO:0007783 infores:clingen CAID:CA308104313 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 2224 of the RYR1 protein, p.(Arg2224His). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported as a variant of uncertain significance (PMID:30155738) and has an entry in ClinVar. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.605 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308104313/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3127 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C3665386 infores:hetionet CHEBI:31981 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0242422 infores:hetionet NCBIGene:5654 biolink:causes MONDO:0014768 infores:monarchinitiative not_provided not_provided HGNC:9476 MONDO:0014768 uuid:cc262e65-0ac9-405c-9db0-b51324ae100a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0518015 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0403632 infores:hetionet CHEBI:28177 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0740394 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0340726 infores:hetionet CHEBI:42820 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0220870 infores:hetionet CHEBI:3223 biolink:causes HP:0001686 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0003564 infores:hetionet CHEBI:91541 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0018681 infores:hetionet GO:0061999 biolink:causes GO:0060485 infores:ubergraph knowledge_assertion manual_agent GO:0061999 GO:0060485 CHEBI:68642 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0009450 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0476414 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0476414 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0520589 infores:hetionet CHEBI:28445 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0015469 infores:hetionet CHEBI:46557 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151827 infores:hetionet CHEBI:63577 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C2047937 infores:hetionet CHEBI:5130 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0040264 infores:hetionet CHEBI:8346 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0002871 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0006849 infores:hetionet CHEBI:17263 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0404521 infores:hetionet CHEBI:63791 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2939186 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0020473 infores:hetionet GO:1904127 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:1904127 GO:0043009 CHEBI:5141 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0036974 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0038362 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0948594 infores:hetionet CHEBI:47657 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C1384353 infores:hetionet CHEBI:8207 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0497156 infores:hetionet CHEBI:3175 biolink:causes UMLS:C1096543 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1096543 infores:hetionet CHEBI:63611 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0547030 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0863093 infores:hetionet CHEBI:6456 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0003578 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0150450 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0278008 infores:hetionet CHEBI:119915 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020625 infores:hetionet CHEBI:408174 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0162285 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0948525 infores:hetionet CHEBI:49662 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0038325 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1536459 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0029408 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007787 infores:hetionet CHEBI:75998 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151905 infores:hetionet CHEBI:9086 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0080274 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042769 infores:hetionet CHEBI:3698 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0041657 infores:hetionet CHEBI:3286 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0013604 infores:hetionet NCBIGene:9992 biolink:causes MONDO:0013370 infores:monarchinitiative not_provided not_provided HGNC:6242 MONDO:0013370 uuid:bf80ce74-0687-4f67-9037-4ec4b9455c59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4657 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0009676 infores:hetionet CHEBI:49960 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0031154 infores:hetionet GO:0072039 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0072039 GO:0007275 CHEBI:8228 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C3665386 infores:hetionet CHEBI:38940 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0237849 infores:hetionet CHEBI:8232 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0003862 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0702266 infores:hetionet CHEBI:8024 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030805 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0233472 infores:hetionet CHEBI:135929 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0004093 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030312 infores:hetionet CHEBI:46557 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0231218 infores:hetionet NCBIGene:400916 biolink:causes MONDO:0014395 infores:monarchinitiative not_provided not_provided HGNC:15559 MONDO:0014395 uuid:4ebb973e-d082-4d00-ad8c-f063a14ed107 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:83700 biolink:causes MONDO:0013394 infores:monarchinitiative not_provided not_provided HGNC:15532 MONDO:0013394 uuid:73762846-fd4a-4491-8f5b-7b4f2b3d8f75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6688 biolink:causes MONDO:0030529 infores:monarchinitiative not_provided not_provided HGNC:11241 MONDO:0030529 uuid:60f0f1b7-afce-47ce-8284-32399fb09032 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0003862 infores:hetionet CHEBI:100241 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003811 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033975 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0342579 infores:hetionet CHEBI:75246 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0002792 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002453 infores:hetionet CHEBI:5147 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0031345 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0234215 infores:hetionet CHEBI:9943 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0028961 infores:hetionet CHEBI:5959 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C2830004 infores:hetionet CHEBI:4702 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0013404 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0020649 infores:hetionet CHEBI:15854 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0547030 infores:hetionet CHEBI:45367 biolink:causes UMLS:C2363980 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C2363980 infores:hetionet CHEBI:5001 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0004604 infores:hetionet CAID:CA278720 biolink:causes MONDO:0019501 infores:clingen CAID:CA278720 MONDO:0019501 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong BP4 The c.977T>A variant in MYO7A is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 326 (p.Leu326Gln). The highest population filtering allele frequency in gnomAD v4.1 is 0.00002995 (7/91056 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.991, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with autosomal recessive Usher syndrome. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (1.5 PM3 points, SCV000199549.4, SCV000589578.6, Laboratory for Molecular Medicine, GeneDx). One individual was homozygous for the variant (0.5 PM3 points, PMID: 18181211) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000199549.4, Laboratory for Molecular Medicine). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278720/MONDO:0019501/005 2024-09-24 2024-09-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:47898 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0003862 infores:hetionet CHEBI:39585 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0427086 infores:hetionet CHEBI:65173 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C2830004 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0001416 infores:hetionet CHEBI:9434 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0015230 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1565489 infores:hetionet CHEBI:31413 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C2981158 infores:hetionet CAID:CA409106019 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106019 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, BP5 The c.500A>C variant in the Hepatocyte nuclear factor 4 alpha, HNF4A, causes an amino acid change of glutamic acid to alanine at codon 167 (p.(Glu167Ala)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.791, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor). In summary, c.500A>C meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PM2_Supporting, PP3, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106019/MONDO:0015967/085 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes UMLS:C0231230 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0231230 infores:hetionet CHEBI:52717 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018524 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009319 infores:hetionet CHEBI:31348 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0162298 infores:hetionet NCBIGene:1123 biolink:causes MONDO:0011444 infores:monarchinitiative not_provided not_provided HGNC:1943 MONDO:0011444 uuid:428ab023-2d5e-4712-b59f-5aa9283bd088 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009450 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0948586 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0013395 infores:hetionet CHEBI:42797 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C3257803 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0267792 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0032285 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0020517 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0013395 infores:hetionet NCBIGene:6660 biolink:causes MONDO:0014778 infores:monarchinitiative not_provided not_provided HGNC:11201 MONDO:0014778 uuid:2807f160-2543-477b-9aee-09edb0eaed03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0178298 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234913 infores:hetionet NCBIGene:9241 biolink:causes MONDO:0012658 infores:monarchinitiative not_provided not_provided HGNC:7866 MONDO:0012658 uuid:2f0b98f3-459e-4243-8f1b-1a4a9f23befd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6597 biolink:causes MONDO:0013821 infores:monarchinitiative not_provided not_provided HGNC:11100 MONDO:0013821 uuid:1aa8b001-8377-4420-a54e-7728c7805f19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0022346 infores:hetionet GO:1901246 biolink:causes GO:0030323 infores:ubergraph knowledge_assertion manual_agent GO:1901246 GO:0030323 CHEBI:5134 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0151686 infores:hetionet CHEBI:9613 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0002878 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0575090 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002622 infores:hetionet CHEBI:75246 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0151603 infores:hetionet UMLS:C0120107 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0231218 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0006145 infores:hetionet NCBIGene:2260 biolink:causes MONDO:0007043 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0007043 uuid:e2783dad-67d4-4190-bc1e-3ae3b07db5eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0021368 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020676 infores:hetionet CHEBI:6916 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0015967 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0178421 infores:hetionet CHEBI:5118 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2047937 infores:hetionet CHEBI:63621 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151786 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0031542 infores:hetionet CHEBI:32184 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0013604 infores:hetionet CHEBI:47499 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C1320835 infores:hetionet CHEBI:45599 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C2242996 infores:hetionet CHEBI:3732 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0018681 infores:hetionet CHEBI:28901 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0019521 infores:hetionet CHEBI:691037 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0033860 infores:hetionet CAID:CA254830 biolink:causes MONDO:0044970 infores:clingen CAID:CA254830 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PP1, PS2, PS4, PM6 The m.5877C>T variant in MT-TY has been reported in one individual with primary mitochondrial disease (PMID: 11594340). This individual had proximal muscle weakness, ptosis, and external ophthalmoplegia onset at age 28 years. She also had episodic diarrhea and atrioventricular block. Muscle biopsy showed ragged red fibers and COX-negative fibers. The variant was present at 73% heteroplasmy in muscle and 0.7% in blood. The variant was present in blood from her mother who had ptosis (heteroplasmy not reported) and in her two healthy children, although they were younger than the proband at the age of symptom onset. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictors are discordant as MitoTIP suggests this variant is benign (24.8 percentile) and HmtVAR predicts it to be pathogenic (0.65). Cybrid studies support the functional impact of this variant as decreased viability and oxygen consumption were associated with higher heteroplasmy levels (PS3_supporting; PMID: 11594340). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254830/MONDO:0044970/015 2024-06-24 2025-04-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:42944 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0023218 infores:hetionet CHEBI:15940 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0038362 infores:hetionet CHEBI:8356 biolink:causes HP:0025234 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030508 infores:hetionet UMLS:C0010592 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235378 infores:hetionet NCBIGene:5297 biolink:causes MONDO:0030669 infores:monarchinitiative not_provided not_provided HGNC:8983 MONDO:0030669 uuid:c10e877a-7758-4e6f-a78a-7ad716303474 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA278732 biolink:causes MONDO:0019501 infores:clingen CAID:CA278732 MONDO:0019501 PMID: Uncertain Significance PP3, PM3 PP4, PM2 The NM_000260.4:c.3827C>T variant in the MYO7A gene is a missense variant predicted to cause substitution of serine to leucine at amino acid 1276 (p.Ser1276Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0078% (1/12706) in African/African American population ( PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 patient with hearing loss in trans with a likely pathogenic variant (PM3; Partners LMM internal data SCV000204707.4). The computational predictor REVEL gives a score of 0.769, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM3, PP3. (VCEP specifications version 2.0.0; Dec 21, 2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278732/MONDO:0019501/005 2023-01-24 2023-02-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:40237 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0040586 infores:hetionet CHEBI:3654 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0011991 infores:hetionet CHEBI:15544 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0043144 infores:hetionet CAID:CA410148524 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148524 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1026C>G (p.Ile342Met) is a missense variant which has a REVEL score < 0.50 (0.016), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148524/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5062 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0242350 infores:hetionet CAID:CA645372267 biolink:causes MONDO:0009861 infores:clingen CAID:CA645372267 MONDO:0009861 PMID:21147011PMID:21147011 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting PM5 The c.835_836delinsTG (p.Pro279Cys) variant in PAH has been reported in 1 individual with hyperphenylalaninemia (BH4 deficiency excluded), detected with pathogenic variant p.R408W (PMID: 21147011). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA645372267/MONDO:0009861/006 2020-11-13 2022-03-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42797 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0162287 infores:hetionet CHEBI:465284 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011168 infores:hetionet CHEBI:10650 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011603 infores:hetionet CHEBI:10101 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1291077 infores:hetionet NCBITaxon:139 biolink:causes MONDO:0019632 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:139 MESH:D008193 DB01112_MESH_D008193_1 CHEBI:50663 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0003811 infores:hetionet CHEBI:231594 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0009782 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233414 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0748726 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0748726 infores:hetionet CHEBI:4822 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0013404 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026636 infores:hetionet CHEBI:114785 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0241157 infores:hetionet UMLS:C1738934 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0034886 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0853714 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0009806 infores:hetionet CHEBI:7931 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0546817 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0032285 infores:hetionet CHEBI:119573 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085682 infores:hetionet CAID:CA915943441 biolink:causes MONDO:0021056 infores:clingen CAID:CA915943441 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 The NM_000038.6(APC):c.156del (p.Gly53GlufsTer17) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 3 in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 0.5 points (PS4 not met; internal data Labcorp Genetics [formerly Invitae]). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1 and PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA915943441/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7447 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0015376 infores:hetionet CHEBI:48669 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0035078 infores:hetionet NCBIGene:26100 biolink:causes MONDO:0032759 infores:monarchinitiative not_provided not_provided HGNC:32225 MONDO:0032759 uuid:b41757c2-2e36-4b9a-a7f7-71c6cc8e8c2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51032 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0009450 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0233494 infores:hetionet CHEBI:119915 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0040822 infores:hetionet CAID:CA020099 biolink:causes MONDO:0008667 infores:clingen CAID:CA020099 MONDO:0008667 PMID: Pathogenic PS4, PM2_Supporting, PP3, PM1, PS3_Supporting, PM6 BS1, BA1 The NM_000551.4(VHL):c.194C>G (p.Ser65Trp) variant in VHL is a missense variant predicted to cause substitution of Ser by Trp at amino acid 65 (p.Ser65Trp).The CIViC database (https://civicdb.org) describes 17 unrelated individuals with clinically diagnosed VHL or cancers in VHL cancer spectrum, many with evidence of VHL in family history. The following PMIDs were used for proband counting (2 unrelated probands or families where noted, all others 1) 28650583(2pt), 17024664, 17392848, 28388566(2pt), 29294023(2pt), 22156657, 23407287, 9829911, 7728151, 18446368, 22357542, 11148816, 21463266, 20518900. In addition, 3 participating laboratories contributed a total of 5 unique subjects. Each subject was evaluated for meeting Danish, Consistent or Nonspecific and a total of 13.5 points was awarded, which constitutes strong evidence. (PS4_Met). A denovo case, 33yo Chinese man presented with Renal Cell Carcinoma, and had a history of urological surgery at the age of 23 years due to an epididymal cyst and an ophthalmologic surgery at 26 years of age for retinal detachment resulting from bilateral retinal angiomatosis. 7 relatives (parents and siblings) were tested for S65W, and it was not identified. The authors do not note confirming maternity/paternity. PMID: 26622630 (PM6_Met). There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (due to a single variant present) (PM2_Supporting). S65W significantly decreases the VHL protein binding to HIF-1alpha, preventing ubiquitination PMID: 15611064 (PS3_Supporting). This variant resides within the VHL beta domain, a key functional domain. It is also defined as a mutational hotspot in Chinese populations (PMID:31620170) (PM1_Met). The computational predictor REVEL gives a score of 0.943, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3_Met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020099/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports GO:0044474 biolink:causes GO:0005245 infores:ubergraph knowledge_assertion manual_agent GO:0044474 GO:0005245 GO:1902510 biolink:causes GO:0097194 infores:ubergraph knowledge_assertion manual_agent GO:1902510 GO:0097194 CHEBI:3207 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0178298 infores:hetionet CHEBI:7931 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0231530 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0029134 infores:hetionet CHEBI:63925 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0235266 infores:hetionet NCBIGene:9049 biolink:causes MONDO:0007052 infores:monarchinitiative not_provided not_provided HGNC:358 MONDO:0007052 uuid:fbbac331-2848-4057-9e5a-734b487c9ee2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0023530 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0948089 infores:hetionet CHEBI:5778 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0026858 infores:hetionet CHEBI:3698 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C1527344 infores:hetionet CHEBI:16469 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027497 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151828 infores:hetionet CHEBI:31401 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0014742 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0019061 infores:hetionet CHEBI:144093 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0015230 infores:hetionet CHEBI:168396 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0000731 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0007787 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015256 infores:hetionet CHEBI:10125 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0542571 infores:hetionet CHEBI:8232 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0424790 infores:hetionet CAID:CA233429 biolink:causes MONDO:0008723 infores:clingen CAID:CA233429 MONDO:0008723 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_000018.4 c.189A>G (p.Lys63=) variant in ACADVL is a synonymous (silent) variant that is not predicted by SpliceSiteFinder, MaxEntScn and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is weakly conserved as shown by phyloP (BP4, BP7). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, although this variant meets PM2_Supporting, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA233429/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4888 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0024299 infores:hetionet CHEBI:116278 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0085932 infores:hetionet CHEBI:2611 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0038325 infores:hetionet NCBIGene:161742 biolink:causes MONDO:0012669 infores:monarchinitiative not_provided not_provided HGNC:20249 MONDO:0012669 uuid:7e034042-6234-48af-b44a-1f53a5f82fee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127780 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0021141 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0006849 infores:hetionet CHEBI:30830 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0233471 infores:hetionet CHEBI:135005 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020625 infores:hetionet CAID:CA399799004 biolink:causes MONDO:0100326 infores:clingen CAID:CA399799004 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5:c.2150T>C variant in ITGA2B is a missense variant predicted to cause substitution of leucine by proline at amino acid 717 (p.Leu717Pro). This variant has been observed in compound heterozygosity in one individual (reported via personal communication with Dr. Jose Rivera, Servicio de Hematologıa y Oncologıa Medica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacion, Universidad de Murcia) in combination with ITGA2B variant c.337C>T (p.Gln113Ter, classified as pathogenic by the Platelet Disorders VCEP, trans phase not confirmed) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry and Western blot, and ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Strong, PM2_Supporting, PM3_Supporting. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399799004/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4511 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C1325847 infores:hetionet CHEBI:391960 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0030193 infores:hetionet CHEBI:7573 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0038990 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0003123 infores:hetionet CHEBI:63584 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0008031 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0151773 infores:hetionet CHEBI:3696 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085682 infores:hetionet CHEBI:8435 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0242429 infores:hetionet CHEBI:29688 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0002792 infores:hetionet NCBIGene:673 biolink:causes MONDO:0007265 infores:monarchinitiative not_provided not_provided HGNC:1097 MONDO:0007265 uuid:8926a27e-9424-4809-9fce-3c4496d0b427 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C2242996 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0006325 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0030312 infores:hetionet CHEBI:3215 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0026205 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0037274 infores:hetionet GO:0010510 biolink:causes GO:0009060 infores:ubergraph knowledge_assertion manual_agent GO:0010510 GO:0009060 CHEBI:59582 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0442886 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0014742 infores:hetionet CHEBI:49960 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0600228 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0269596 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0269596 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0018099 infores:hetionet CHEBI:63638 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0085633 infores:hetionet CHEBI:135451 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C1112525 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0036572 infores:hetionet CHEBI:4784 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151480 infores:hetionet CHEBI:404903 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0014457 infores:hetionet CHEBI:31174 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0033774 infores:hetionet CHEBI:4814 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C1368065 infores:hetionet CHEBI:10119 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0016199 infores:hetionet CHEBI:7822 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0018834 infores:hetionet CHEBI:68478 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0221201 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003850 infores:hetionet CHEBI:31859 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0232461 infores:hetionet CHEBI:32315 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011124 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027441 infores:hetionet CHEBI:6801 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0344232 infores:hetionet CHEBI:6520 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0035078 infores:hetionet NCBIGene:257 biolink:causes MONDO:0007636 infores:monarchinitiative not_provided not_provided HGNC:449 MONDO:0007636 uuid:5ee928f6-c56f-476a-bfbb-6c68a2ca30cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0267596 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0026858 infores:hetionet CHEBI:3219 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233754 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151735 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0233494 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0012833 infores:hetionet CHEBI:31413 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0009676 infores:hetionet NCBIGene:396 biolink:causes MONDO:0014099 infores:monarchinitiative not_provided not_provided HGNC:678 MONDO:0014099 uuid:9283f7e9-80db-4034-90bf-fc021725645c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61058 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C2225524 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0085584 infores:hetionet CHEBI:404903 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0019080 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0233472 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0234215 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0018801 infores:hetionet CHEBI:68841 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0003537 infores:hetionet NCBIGene:6662 biolink:causes MONDO:0014634 infores:monarchinitiative not_provided not_provided HGNC:11204 MONDO:0014634 uuid:f6409f48-d9e0-4cc0-819d-aaa438658e39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:107736 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0023052 infores:hetionet CHEBI:7447 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0038362 infores:hetionet CHEBI:474053 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0151539 infores:hetionet CAID:CA391354119 biolink:causes MONDO:0007113 infores:clingen CAID:CA391354119 MONDO:0007113 PMID: Pathogenic PP4, PVS1, PM2_Supporting PS4 The p.Glu383Ter variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu383Ter variant in UBE3A has been reported in a patient with a clinical phenotype suggestive of Angelman syndrome (PP4). This variant is absent from gnomAD (PM2_supporting). In summary, the p.Glu383Ter variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA391354119/MONDO:0007113/016 2021-03-01 2021-05-05 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:47381 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0948525 infores:hetionet CHEBI:3568 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151836 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0853662 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0853662 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0002871 infores:hetionet CHEBI:8768 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0010200 infores:hetionet CHEBI:116278 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0040264 infores:hetionet CHEBI:8435 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0020456 infores:hetionet CHEBI:4877 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0018099 infores:hetionet NCBIGene:5781 biolink:causes MONDO:0007979 infores:monarchinitiative not_provided not_provided HGNC:9644 MONDO:0007979 uuid:b2d24dbf-d477-4ddd-bb71-d09be520c3e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C2830004 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0020651 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020649 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0851341 infores:hetionet CHEBI:3219 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233407 infores:hetionet CHEBI:9139 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0242184 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0009319 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0006266 infores:hetionet CHEBI:63622 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C2363731 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0020651 infores:hetionet CHEBI:6916 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0020580 infores:hetionet CHEBI:10650 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0221170 infores:hetionet CHEBI:2668 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0028734 infores:hetionet CHEBI:6775 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0023518 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0010709 infores:hetionet CHEBI:64312 biolink:causes NCIT:C78214 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0853592 infores:hetionet CHEBI:48273 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0040409 infores:hetionet CHEBI:15367 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009763 infores:hetionet CHEBI:64355 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0001175 infores:hetionet CHEBI:17076 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0002792 infores:hetionet CAID:CA10014231 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014231 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 This is a synonymous variant, therefore REVEL is not calculable. SpliceAI predicts: Acceptor loss 0.00, donor loss 0.00, acceptor gain 0.00, donor gain 0.00 (BP4). SpliceAI predicts: Acceptor loss 0.00, donor loss 0.00, acceptor gain 0.00, donor gain 0.00. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -2.7502 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014231/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8435 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0150450 infores:hetionet NCBIGene:2068 biolink:causes MONDO:0010212 infores:monarchinitiative not_provided not_provided HGNC:3434 MONDO:0010212 uuid:be1a21c4-4d99-4519-b9db-ade10ac6deb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151578 infores:hetionet CHEBI:9654 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0013604 infores:hetionet CHEBI:28748 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0404521 infores:hetionet CHEBI:8461 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0278134 infores:hetionet CHEBI:5384 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0013604 infores:hetionet CHEBI:9763 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0008031 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151735 infores:hetionet CHEBI:64355 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151577 infores:hetionet CHEBI:17630 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0011991 infores:hetionet CHEBI:48538 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0033117 infores:hetionet CHEBI:9168 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0149745 infores:hetionet CHEBI:75998 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0423791 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C2225524 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011849 infores:hetionet GO:0003357 biolink:causes CL:0008025 infores:ubergraph knowledge_assertion manual_agent GO:0003357 CL:0008025 CHEBI:31623 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0037199 infores:hetionet CHEBI:4784 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020461 infores:hetionet CHEBI:9599 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0029877 infores:hetionet CHEBI:134936 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0010200 infores:hetionet CHEBI:5130 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0001925 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0017605 infores:hetionet CAID:CA229562 biolink:causes MONDO:0009861 infores:clingen CAID:CA229562 MONDO:0009861 PMID:19915519PMID:26322415PMID:26322415PMID:24327145 Pathogenic PP4_Moderate, PM3_Very Strong, PM2_Supporting, PS3_Supporting The c.466G>C (p.Ala156Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 26322415). This variant is absent in population databases. This variant was detected in trans with multiple pathogenic variants: p.H220P (PMID 26322415); c.611A>G (aka EX6-96A>G, PMID: 26600521); p.V5Sfs*33, p.R158W, p.R241C (2 patients), p.R261Q, p.R400T, p.T418P (PMID: 30050108). Functional studies show the PAH A156P mutant produces reduced protein (8.7% of wild type), with a residual enzyme activity of 10.4% (PMID 24327145). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2_supporting, PP4_Moderate, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229562/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5864 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0032617 infores:hetionet CHEBI:6690 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0028084 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042373 infores:hetionet CHEBI:45863 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235266 infores:hetionet CHEBI:27666 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0016382 infores:hetionet CHEBI:6149 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0018965 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0029408 infores:hetionet CHEBI:15544 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0042029 infores:hetionet CHEBI:49575 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011175 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0151505 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0022354 infores:hetionet CHEBI:31199 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0009450 infores:hetionet CHEBI:2676 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0009421 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027441 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042373 infores:hetionet CAID:CA025602 biolink:causes MONDO:0700269 infores:clingen CAID:CA025602 MONDO:0700269 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 BP5, PP4 The c.8362T>C variant in BRCA2 is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 2788 (p.(Trp2788Arg)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by four calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779848, 39779857, 37713444) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.32, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.19 (based on Co-occurrence LR=1.03; Family History LR=1.16), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058, Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025602/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:171719 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011053 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009241 infores:hetionet CAID:CA287476 biolink:causes MONDO:0017623 infores:clingen CAID:CA287476 MONDO:0017623 PMID: Benign BA1 PTEN c.-1311T>C (NC_000010.10:g.89622915T>C) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.0142 (1.42%, 23/1618 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA287476/MONDO:0017623/003 2017-06-02 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA235331 biolink:causes MONDO:0021060 infores:clingen CAID:CA235331 MONDO:0021060 PMID: Pathogenic PM2_Supporting, PM6_Strong, PS3_Moderate, PP2, PP3, PS4 The c.1517A>C (NM_002834.5(PTPN11):c.1517A>C (p.Gln506Pro) variant in PTPN11 is a missense variant predicted to cause substitution of glutamine by proline at amino acid 506 (p.Gln506Pro). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.9, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common. The Z-score for missense variants in PTPN11 in gnomAD v4.1.0 is 4.95 (PP2; PMID: 29493581). This variant has been reported in 7 probands with clinical features of Noonan Syndrome with multiple lentigines (PS4; > 5.0 pts.; CeGaT (SCV001247473) & Ambry Genetics (SCV002708581) internal data, PMIDs: 14961557, 15928039, 20954246, 22528600). More evidence is available in the literature, but the score to apply PS4 at full strength has already been met. This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 4 individuals with Noonan Syndrome with Multiple Lentigines (PM6_strong, 3.5 points; CeGaT internal data (SCV001247473), PMIDs: 14961557, 15928039, 20954246). Enzyme-catalyzed hydrolysis of p-nitrophenyl phosphate analysis in E. Coli indicated reduced catalytic speed for the mutant. A study in HEK293 cells showed that the mutant performed dephosphorylation with greater efficiency and exhibited atypical behavior in ERK pathways. Another analysis in E. Coli showed increased dephosphorylation in the mutant. Each of these three assays indicate that the variant impacts protein function (PS3_moderate; PMIDs: 24935154, 26742426).In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_supporting, PP3, PP2, PS4, PM6_strong, PS3 (Specifications Version 2.3.0; 9/9/2025). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235331/MONDO:0021060/043 2025-09-09 2025-09-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6076 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0162429 infores:hetionet CHEBI:45924 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0027497 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027726 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0020651 infores:hetionet CHEBI:31705 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151746 infores:hetionet CHEBI:3757 biolink:causes UMLS:C1142160 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1142160 infores:hetionet CHEBI:3478 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0423791 infores:hetionet CHEBI:10100 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C2242588 infores:hetionet CHEBI:135935 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0027497 infores:hetionet CHEBI:7956 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0004093 infores:hetionet CHEBI:50861 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0023218 infores:hetionet CHEBI:63619 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085611 infores:hetionet CHEBI:3561 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151692 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0233472 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0020649 infores:hetionet CHEBI:45409 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0006277 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0019158 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0151705 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0340464 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0853141 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0853141 infores:hetionet CHEBI:42355 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0030252 infores:hetionet CHEBI:135005 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C2830004 infores:hetionet CHEBI:8107 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027540 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009319 infores:hetionet GO:0061452 biolink:causes CL:1000001 infores:ubergraph knowledge_assertion manual_agent GO:0061452 CL:1000001 CHEBI:6775 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022658 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0002871 infores:hetionet CHEBI:50922 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0011168 infores:hetionet CHEBI:188986 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423153 infores:hetionet CHEBI:3994 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0040046 infores:hetionet CHEBI:291342 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0043352 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018801 infores:hetionet CHEBI:42944 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0232849 infores:hetionet CHEBI:8356 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023066 infores:hetionet CHEBI:50122 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0341047 infores:hetionet CHEBI:6128 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0013604 infores:hetionet CHEBI:63617 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0039070 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0235146 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020517 infores:hetionet CHEBI:83804 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0852795 infores:hetionet CHEBI:3506 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0687713 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020456 infores:hetionet CHEBI:84050 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0015672 infores:hetionet CHEBI:408174 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0006266 infores:hetionet CAID:CA367402212 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402212 MONDO:0015967 PMID: Pathogenic PS4, PP1_Moderate, PP2, PP3, PP4, PM2_Supporting The c.370G>C variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to histidine at codon 124 (p.(Asp124His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant segregated with hyperglycemia, with three informative meioses in three families (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Taken together, this evidence supports the classification of c.370G>C as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP1_Moderate, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402212/MONDO:0015967/086 2024-03-14 2024-03-14 Semidominant inheritance HP:0032113 Supports CHEBI:63616 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0013604 infores:hetionet CHEBI:28748 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020672 infores:hetionet CHEBI:32315 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0404521 infores:hetionet CHEBI:4903 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0600142 infores:hetionet CHEBI:52172 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0037763 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0151828 infores:hetionet CAID:CA10014287 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014287 MONDO:0011071 PMID: Benign BP4, BA1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS3, BS1, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.824C>T (p.Pro275Leu) is a missense variant which has a minor allele frequency (MAF) of 0.00225 (0.2%, 26/11,566 alleles) in the Latino subpopulation of the ExAC cohort, which is ≥ 0.0015 (0.15%) (BA1). This variant also has a REVEL score < 0.15 (0.146) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014287/MONDO:0011071/008 2025-03-25 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8768 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0086543 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020649 infores:hetionet CHEBI:4909 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0002792 infores:hetionet GO:0060651 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0060651 GO:0035295 CHEBI:41423 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0851341 infores:hetionet CAID:CA251907 biolink:causes MONDO:0008723 infores:clingen CAID:CA251907 MONDO:0008723 PMID:9461620 Likely Pathogenic PM2_Supporting, PP3, PP4, PM3_Strong, PS3_Supporting The c.1372T>C variant is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 458 (p.Phe458Leu). This variant has also been published as Phe418Leu when numbered from the mature peptide. The c.1372T>C variant has been described in at least three individuals diagnosed with very long chain acyl CoA dehydrogenase (VLCAD), with at least two also carrying an additional pathogenic or likely pathogenic ACADVL variant confirmed in trans (PM3_Strong). At least one patient with this variant displayed VLCAD activity 20% of normal, which is highly specific for VLCAD deficiency (PP4; PMID: 9709714). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001759 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Recombinant protein expressing this variant showed reduced VLCAD enzyme activity, indicating that this variant impacts protein function (PS3_Supporting; PMID: 9461620). The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Strong, PP4, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA251907/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4562 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0600142 infores:hetionet CHEBI:4728 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0036572 infores:hetionet CHEBI:2549 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0259749 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0152227 infores:hetionet CHEBI:51380 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0080274 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0036572 infores:hetionet CHEBI:3223 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0151564 infores:hetionet CHEBI:3732 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1167709 infores:hetionet CHEBI:135285 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0020615 infores:hetionet CHEBI:37924 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0003862 infores:hetionet CHEBI:134991 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0575081 infores:hetionet NCBIGene:161582 biolink:causes MONDO:0014203 infores:monarchinitiative not_provided not_provided HGNC:21493 MONDO:0014203 uuid:28cc262e-20f1-4e9c-9cbe-56ff83046ba7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0003467 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0037274 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0277925 infores:hetionet CAID:CA294619 biolink:causes MONDO:0010726 infores:clingen CAID:CA294619 MONDO:0010726 PMID: Likely Benign BP2, BP5, BS2 PM2 The p.His371_His372del variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (PMID: 29961512, internal database - GeneDx) (BS2). The p.His371_His372del variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (internal database - GeneDx) (BP2). The p.His371_His372del variant is found in at least 2 patients with an alternate molecular basis of disease (PMID 29961512, internal database - GeneDx) (BP5). In summary, the p.His371_His372del variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294619/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:7640 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0015967 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0015397 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0687707 infores:hetionet CHEBI:5118 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027540 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003469 infores:hetionet CHEBI:4445 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151827 infores:hetionet CHEBI:7852 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0003467 infores:hetionet CHEBI:8764 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007859 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0032326 infores:hetionet CHEBI:6801 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0042963 infores:hetionet CHEBI:9352 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0014457 infores:hetionet CHEBI:94385 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0011603 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0009806 infores:hetionet CHEBI:27834 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0151746 infores:hetionet CHEBI:49375 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0333355 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0497247 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0007787 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004238 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151740 infores:hetionet CHEBI:8356 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030252 infores:hetionet CHEBI:7852 biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0344375 infores:hetionet CHEBI:9139 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0234708 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151705 infores:hetionet CHEBI:8081 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C1619712 infores:hetionet CHEBI:2904 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0003467 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0851341 infores:hetionet CHEBI:7852 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0016382 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0020649 infores:hetionet CHEBI:38940 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0162835 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0041349 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0740304 infores:hetionet CHEBI:231594 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0242172 infores:hetionet CHEBI:3764 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0403632 infores:hetionet CHEBI:8502 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0549567 infores:hetionet CHEBI:5790 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0026837 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0039971 infores:hetionet NCBIGene:26281 biolink:causes MONDO:0014319 infores:monarchinitiative not_provided not_provided HGNC:3677 MONDO:0014319 uuid:db0772a9-338e-47a0-ad5c-b7db330c7d86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0031350 infores:hetionet CAID:CA626377544 biolink:causes MONDO:0100326 infores:clingen CAID:CA626377544 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PP4 The c.55del variant in ITGB3 is a deletion of 1 nucleotide in exon 1, resulting in a shift of the reading frame and a premature stop signal (p.Ala19Argfs*7). Premature termination codon within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_moderate. This variant occurs at a very low allele frequency overall in gnomAD v4.0.0 of 0.000006374 with a MAF of 0.000002980 (3/1006570) in the non-Finnish European population (PM2_Supporting). The variant has been reported heterozygous in one individual (PMID: 31980526) but has not been reported in any patients with a Glanzmann thrombasthenia phenotype. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate, PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626377544/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9332 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0030312 infores:hetionet CHEBI:78543 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0038362 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0006848 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006848 infores:hetionet CHEBI:134936 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0948873 infores:hetionet GO:1903379 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:1903379 GO:0140014 CHEBI:8888 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014724 infores:hetionet CHEBI:63638 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1368065 infores:hetionet NCBIGene:1146 biolink:causes MONDO:0009926 infores:monarchinitiative not_provided not_provided HGNC:1967 MONDO:0009926 uuid:714acc86-6063-4ca8-988b-c4ef3df045bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0033581 infores:hetionet UNII:3U02EL437C biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0151594 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020649 infores:hetionet NCBIGene:6262 biolink:causes MONDO:0011484 infores:monarchinitiative not_provided not_provided HGNC:10484 MONDO:0011484 uuid:076d203c-f6ad-4c3b-ae3b-35c135bc59e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3398 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0004093 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0015230 infores:hetionet CAID:CA412352120 biolink:causes MONDO:0100039 infores:clingen CAID:CA412352120 MONDO:0100039 PMID: Likely Pathogenic PM5, PP3, PM2_Supporting, PS2 PM1 The p.Ala157Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with clinical features of CDKL5 disorder (internal database - Invitae) (PS2). A pathogenic missense variant (p.Ala157Val) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar - ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel) (PM5). The p.Ala157Pro variant in CDKL5 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ala157Pro variant in CDKL5 is classified as Likely Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PM5, PM2_Supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412352120/MONDO:0100039/034 2023-10-13 2023-12-11 X-linked inheritance HP:0001417 Supports CHEBI:404903 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0851341 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235504 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235504 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0004936 infores:hetionet CHEBI:52172 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0043352 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0543698 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0235853 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0235853 infores:hetionet CHEBI:135939 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0085633 infores:hetionet CHEBI:52172 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042024 infores:hetionet CHEBI:2611 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0156404 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1504376 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1504376 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0595877 infores:hetionet CHEBI:63622 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0030193 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0042769 infores:hetionet CHEBI:7025 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0497365 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0008370 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027765 infores:hetionet CAID:CA410147693 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147693 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS4, PS2, PS3, BP3, BP1, BP2, BA1, BP5, BP7, BS1, BS4, BS3, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1243C>G (p.Gln415Glu) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.322, and the splice site predictor SpliceAI indicated no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147693/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8874 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037036 infores:hetionet CHEBI:51230 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0035455 infores:hetionet GO:0061344 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0061344 GO:0072359 CHEBI:6923 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0027947 infores:hetionet CHEBI:39867 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151599 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0012833 infores:hetionet CHEBI:40237 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0030196 infores:hetionet CHEBI:4710 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0009676 infores:hetionet CHEBI:28787 biolink:causes NCIT:C168262 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0220854 infores:hetionet CAID:CA645294001 biolink:causes MONDO:0015924 infores:clingen CAID:CA645294001 MONDO:0015924 PMID: Likely Pathogenic PS1_Moderate, PM2_Supporting, PVS1_Strong PP3, BP3, BA1, PM4, BS1 The NM_001204.7(BMPR2) c.247+1_247+7del variant is a 7 bp deletion spanning the canonical donor splice site of intron 2. This variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting). It is predicted to cause skipping of biologically relevant exon 2 (171 bp), resulting in an in-frame deletion of amino acids Ala26-Gln82 within the ligand-binding domain, but is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1 so PP3 was not applied to avoid double counting. Another variant affecting this splice site, c.247+6, has been shown by RT-PCR to produce incomplete transcripts (Cogan et. al 2006 PMID:16728714) and was classified as likely pathogenic by the PH VCEP (PS1_moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PS1_moderate, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645294001/MONDO:0015924/125 2025-10-07 2025-10-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:65173 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0014591 infores:hetionet CHEBI:9605 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0015967 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0033860 infores:hetionet CHEBI:17630 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0011603 infores:hetionet CHEBI:38562 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0015967 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0043352 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0030312 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020538 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0152128 infores:hetionet CHEBI:3723 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0392156 infores:hetionet CHEBI:16586 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0042963 infores:hetionet GO:0140165 biolink:causes GO:0038060 infores:ubergraph knowledge_assertion manual_agent GO:0140165 GO:0038060 CHEBI:3175 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0035455 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034063 infores:hetionet CHEBI:8107 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0392156 infores:hetionet CAID:CA277609 biolink:causes MONDO:0015152 infores:clingen CAID:CA277609 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.3112C>T p.(Arg1038Ter) variant in DYSF, which is also known as NM_001130987.2: c.3166C>T p.(Arg1056Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 29/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least five individuals with signs of dysferlinopathy (PMID: 36983702, 23243261, 17698709, 16010686), including confirmed in trans with a likely pathogenic or pathogenic DYSF variant in three patients (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID: 36983702; NM_003494.4: c.4497del p.(Phe1499LeufsTer4), 1.0 pt, PMID: 23243261; NM_003494.4: c.3832C>T p.(Gln1278Ter), 1.0 pt, PMID: 16010686, 7698709). At least one of the patients with this variant and a second presumed diagnostic DYSF allele displayed progressive limb girdle muscle weakness and disease range dysferlin expression in blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702). The filtering allele frequency for this variant is 0.00005974 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval for 57/1111956 European (non-Finnish) chromosomes, which is less than the VCEP threshold of 0.0001 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA277609/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50381 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0026821 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0043241 infores:hetionet CHEBI:9168 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1443060 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0014742 infores:hetionet CHEBI:42797 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151578 infores:hetionet CHEBI:135613 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0003467 infores:hetionet CHEBI:5109 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0027441 infores:hetionet CHEBI:184555 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0221423 infores:hetionet CHEBI:9130 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0242184 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0037199 infores:hetionet CHEBI:50648 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0032227 infores:hetionet CHEBI:3082 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0004245 infores:hetionet CHEBI:5123 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0043352 infores:hetionet CHEBI:107736 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0030252 infores:hetionet CHEBI:6887 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0332563 infores:hetionet CHEBI:4779 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C1761613 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C2973529 infores:hetionet CHEBI:75722 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0149871 infores:hetionet CHEBI:6073 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0015230 infores:hetionet CHEBI:3181 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0041657 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0033860 infores:hetionet CHEBI:31711 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027424 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007222 infores:hetionet CHEBI:3716 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0002994 infores:hetionet CHEBI:31643 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0013378 infores:hetionet CHEBI:31302 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0018790 infores:hetionet CHEBI:63624 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0008031 infores:hetionet CHEBI:31236 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011606 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0039971 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009450 infores:hetionet CHEBI:45599 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0003467 infores:hetionet CAID:CA410203952 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203952 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, BP1, BP2, BS3, PM5, PM3, PP4, PP2, PP3 NM_001754.5(RUNX1):c.193G>A (p.Ala65Thr) is a missense variant which has a REVEL score < 0.50 (0.43) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203952/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA380140600 biolink:causes MONDO:0000573 infores:clingen CAID:CA380140600 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM1, PM3_Supporting The c.1332C>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Isoleucine by Methionine at amino acid 444 (p.Ile444Met).This variant is absent from gnomAD v4 (PM2_Supporting). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1.The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 2.7% (SEM 0.3), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts T-B-NK+ lymphocyte subset profile 0.5 pts, the total is 1 point, PP4 is met (Same patient was reported in PMIDs: 19912631, 29772310, and 32691468). The proband (P32) is homozygous for this variant (0.5 pts; PM3_Supporting; PMID: 29772310).In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PS3_Moderate, PP4 and PM3_Supporting. (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380140600/MONDO:0000573/124 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:168396 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0160390 infores:hetionet CHEBI:42797 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002792 infores:hetionet CHEBI:63611 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026766 infores:hetionet CHEBI:39669 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0917801 infores:hetionet CHEBI:31705 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C1443060 infores:hetionet CHEBI:132233 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C2830004 infores:hetionet CHEBI:4856 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0035455 infores:hetionet CHEBI:6822 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0857305 infores:hetionet CHEBI:9570 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151603 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0003864 infores:hetionet CHEBI:63635 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0019080 infores:hetionet CHEBI:6838 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0013144 infores:hetionet CHEBI:5893 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1368065 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009763 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042514 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0027765 infores:hetionet CHEBI:31711 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0042510 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0267596 infores:hetionet CHEBI:9943 biolink:causes HP:0025388 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040137 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1384489 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1384489 infores:hetionet CHEBI:45716 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0009806 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0349506 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0235710 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0036572 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0027651 infores:hetionet CHEBI:3504 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020615 infores:hetionet CHEBI:61049 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1383860 infores:hetionet CHEBI:178699 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0022660 infores:hetionet CHEBI:31236 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0012691 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027651 infores:hetionet CHEBI:125354 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0026858 infores:hetionet GO:0060281 biolink:causes GO:0009994 infores:ubergraph knowledge_assertion manual_agent GO:0060281 GO:0009994 CHEBI:51209 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0011206 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0033975 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0160390 infores:hetionet CHEBI:6062 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0014724 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0034150 infores:hetionet CHEBI:45327 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0039239 infores:hetionet CHEBI:2659 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0039239 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0027769 infores:hetionet CHEBI:3312 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0232462 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0038454 infores:hetionet CAID:CA1624660 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624660 MONDO:0021060 PMID:22585553 Benign BP5, BS4, BS1, PP2 PS3, PS4, PS2, PS1, PM1, PM4, PM5, BP7, BS3, PM6, PM2, BS2, PP1, PP3, BP3, BP2, BP4, BP1, BA1 The c.1018C>T (p.Pro340Ser) variant in the SOS1 gene has been found not to segregate in a family member of a patient who underwent testing for RASopathies as well as another adult who was unaffected (BS4; GeneDx, Invitae internal data; GTR Lab ID: 26957, 500031; SCV000514724.5, SCV000659124.2). This variant has also been identified in a patient with an alternate molecular basis of disease (BP5; PMID 22585553). The filtering allele frequency of the p.Pro340Ser variant is 0.022% for East Asian exomes in the gnomAD database (20/251276 with 95% CI), which is high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BS1. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624660/MONDO:0021060/004 2019-06-27 2019-06-28 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:2038 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0877303 infores:hetionet CAID:CA9871582 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871582 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4 :c.622G>A is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 208 (p.Gly208Ser). The filtering allele frequency (the upper threshold of the 95% CI of 13/59996) of the c.622G>A variant in ADA is 0.0001715 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871582/MONDO:0007064/114 2024-06-10 2024-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:68575 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C1384353 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006664 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018817 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0520559 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0027769 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0422974 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0422974 infores:hetionet CHEBI:53691 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0085593 infores:hetionet CHEBI:7824 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1306341 infores:hetionet CHEBI:4953 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0235886 infores:hetionet CHEBI:9123 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0033774 infores:hetionet CAID:CA294764 biolink:causes MONDO:0100039 infores:clingen CAID:CA294764 MONDO:0100039 PMID: Benign BA1 The allele frequency of the p.Pro852Leu variant in CDKL5 is 0.031% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro852Leu variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294764/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Contradicts true CHEBI:4466 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0019080 infores:hetionet CHEBI:15367 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0023380 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0012417 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0012417 uuid:e1ad3342-1bfb-4f89-9b75-2462d4996722 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151888 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0424605 infores:hetionet CHEBI:10124 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0011603 infores:hetionet CHEBI:2639 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0547030 infores:hetionet CHEBI:6912 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0014457 infores:hetionet CHEBI:49575 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018790 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0025290 infores:hetionet CHEBI:82866 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0151505 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0242350 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0340726 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0267792 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0851341 infores:hetionet CHEBI:47426 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020598 infores:hetionet NCBIGene:10087 biolink:causes MONDO:0014599 infores:monarchinitiative not_provided not_provided HGNC:2205 MONDO:0014599 uuid:4f1ce13c-e392-4750-a24a-f4e20b828f09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes NCIT:C27003 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0184567 infores:hetionet CHEBI:15367 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085631 infores:hetionet CHEBI:8378 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0231218 infores:hetionet CHEBI:92712 biolink:causes NCIT:C90501 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0553668 infores:hetionet CHEBI:119573 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011124 infores:hetionet CHEBI:253342 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0085636 infores:hetionet CHEBI:75179 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0027497 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0035258 infores:hetionet CHEBI:9352 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0030252 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0034150 infores:hetionet CHEBI:617099 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0022346 infores:hetionet CHEBI:63630 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0015402 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1368065 infores:hetionet NCBIGene:222546 biolink:causes MONDO:0017400 infores:monarchinitiative not_provided not_provided HGNC:21478 MONDO:0017400 uuid:284afafb-4cd6-49e2-8dfc-f39ee5fdaada biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0426576 infores:hetionet CHEBI:8768 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0025323 infores:hetionet CHEBI:17076 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0027497 infores:hetionet CHEBI:48390 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0003811 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009782 infores:hetionet CAID:CA386299637 biolink:causes MONDO:0009861 infores:clingen CAID:CA386299637 MONDO:0009861 PMID:28982351 Pathogenic PVS1, PM2, PP4 This variant c.462C>A (p.Tyr154Ter) in PAH was reported in at least 1 Han Chinese patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 28982351), although a defect in BH4 metabolism was excluded by urinary pterin analysis only. This is a nonsense variant in exon 5 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3'-most exon or the 3'-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386299637/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:473990 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0037274 infores:hetionet CHEBI:2922 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0013378 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0877517 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0020517 infores:hetionet CHEBI:4710 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0043352 infores:hetionet CHEBI:63620 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0016204 infores:hetionet CHEBI:15765 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0233407 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020615 infores:hetionet CHEBI:27834 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0003467 infores:hetionet CHEBI:2668 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0013404 infores:hetionet CHEBI:68841 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0085632 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0015397 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0020651 infores:hetionet CAID:CA415086460 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086460 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS3 The NM_005629.4:c.1206G>A variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (p.Trp402Ter). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PVS1). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086460/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Supports CHEBI:28748 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151773 infores:hetionet NCBIGene:1438 biolink:causes MONDO:0010424 infores:monarchinitiative not_provided not_provided HGNC:2435 MONDO:0010424 uuid:fc7ac4e0-e02e-49c3-b805-1455918708e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35553 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0015371 infores:hetionet CHEBI:46195 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0039231 infores:hetionet CHEBI:2208 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0003862 infores:hetionet CAID:CA2580100385 biolink:causes MONDO:0100039 infores:clingen CAID:CA2580100385 MONDO:0100039 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PVS1 The p.His124GlnfsTer2 variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.His124GlnfsTer2 variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.His124GlnfsTer2 variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 38539105, internal database - Labcorp (formerly Invitae)) (PS4_Supporting). In summary, the p.His124GlnfsTer2 variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_Supporting, PS4_Supporting). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100385/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Supports CHEBI:119915 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0243026 infores:hetionet CHEBI:66876 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0003862 infores:hetionet CHEBI:7936 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085702 infores:hetionet CHEBI:194135 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0206061 infores:hetionet CHEBI:7959 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0040264 infores:hetionet CHEBI:9654 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0033117 infores:hetionet CHEBI:32139 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020488 infores:hetionet CHEBI:63598 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0026821 infores:hetionet CHEBI:46557 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C3665624 infores:hetionet CHEBI:135935 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0917801 infores:hetionet CAID:CA1139665138 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665138 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4(ACADVL):c.421dup (p.Ala141fs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665138/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41423 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014868 infores:hetionet CHEBI:27834 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0016867 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0015397 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0032285 infores:hetionet CHEBI:10125 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002792 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235750 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0259756 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0259756 infores:hetionet CHEBI:6067 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0239571 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0240811 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0240811 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0233494 infores:hetionet CHEBI:134990 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0004604 infores:hetionet CHEBI:3240 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0033774 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0033860 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011991 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0009450 infores:hetionet CHEBI:8080 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0013146 infores:hetionet CHEBI:49662 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0011606 infores:hetionet CHEBI:45327 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0039231 infores:hetionet CHEBI:3387 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0233763 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013595 infores:hetionet CHEBI:31236 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0001925 infores:hetionet CHEBI:50648 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1384353 infores:hetionet CHEBI:17688 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0236075 infores:hetionet CHEBI:31859 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0338831 infores:hetionet CHEBI:28748 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0015967 infores:hetionet CHEBI:5778 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0231528 infores:hetionet CHEBI:178699 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0042345 infores:hetionet CHEBI:17141 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0004134 infores:hetionet CHEBI:75045 biolink:causes UMLS:C1565662 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C1565662 infores:hetionet CHEBI:71940 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0085612 infores:hetionet GO:1901509 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1901509 GO:0007275 NCBIGene:54675 biolink:causes MONDO:0859337 infores:monarchinitiative not_provided not_provided HGNC:16148 MONDO:0859337 uuid:805f5d8f-ccbd-4716-87ed-255a1c76a43a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0015672 infores:hetionet CAID:CA413628043 biolink:causes MONDO:0010315 infores:clingen CAID:CA413628043 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.964C>T (p.Gln322Ter) variant in IL2RG is a nonsense variant located in the last exon (8/8). Although it is not predicted to cause nonsense-mediated decay, as it is located in a critical region for protein function, PVS1 is still applied at default strength (PVS1).This variant is absent from gnomAD v4 (PM2_Supporting). At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts); The total is 1 point, PP4 is met (PMIDs: 33628209 and 9058718).In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413628043/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Supports CHEBI:9637 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0013395 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0853149 infores:hetionet CAID:CA291999 biolink:causes MONDO:0021060 infores:clingen CAID:CA291999 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.825G>A (p.Leu275=) variant in the MAP2K2 gene is 0.142% (14/5968) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA291999/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:61049 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002962 infores:hetionet CHEBI:8028 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0043352 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0234215 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0162830 infores:hetionet CHEBI:50663 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0036974 infores:hetionet CHEBI:44185 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0850149 infores:hetionet CHEBI:5893 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020625 infores:hetionet CHEBI:553473 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0015230 infores:hetionet CHEBI:2636 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0014518 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0549389 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0549389 infores:hetionet CHEBI:10119 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002622 infores:hetionet CHEBI:65346 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0027441 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0518015 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0272891 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0272891 infores:hetionet CHEBI:35778 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0242429 infores:hetionet CHEBI:49668 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0206062 infores:hetionet GO:0097154 biolink:causes CL:0000617 infores:ubergraph knowledge_assertion manual_agent GO:0097154 CL:0000617 CHEBI:7824 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151888 infores:hetionet CHEBI:4445 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0019079 infores:hetionet CHEBI:9150 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0427055 infores:hetionet CHEBI:48538 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0003862 infores:hetionet CHEBI:68579 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0043352 infores:hetionet NCBIGene:92749 biolink:causes MONDO:0014123 infores:monarchinitiative not_provided not_provided HGNC:24245 MONDO:0014123 uuid:abdafdbd-7c58-4930-abce-548b8649dbfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229791 biolink:causes MONDO:0009861 infores:clingen CAID:CA229791 MONDO:0009861 PMID:23514811PMID:23514811 Likely Pathogenic PM5, PM3, PP4_Moderate, PM2, PP3 The c.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID: 23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229791/MONDO:0009861/006 2018-12-09 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9150 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0338656 infores:hetionet CHEBI:10124 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151744 infores:hetionet CHEBI:8080 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0000729 infores:hetionet CAID:CA386966350 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966350 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM5_Strong, PM1, PP3 PP4 The c.811C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 271 (p. (Arg271Trp) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.811C>T (p.Arg271Trp) and c.812G>A (p.Arg271Gln), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg271Gly has a greater Grantham distance than both p.Arg271Trp and p.Arg271Gln (PM5_Strong). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.911, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 was not applied (internal lab contributors). In summary, c.811C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PM5_Strong, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966350/MONDO:0015967/017 2022-04-14 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63627 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0003864 infores:hetionet CHEBI:15765 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0005758 infores:hetionet UMLS:C0004609 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0232488 infores:hetionet CHEBI:4659 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0018681 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1168174 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1168174 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0020649 infores:hetionet CHEBI:16469 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018989 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0852810 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0016655 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0028960 infores:hetionet CHEBI:66876 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0043144 infores:hetionet CHEBI:15552 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0010520 infores:hetionet CHEBI:127780 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0030554 infores:hetionet CAID:CA234977 biolink:causes MONDO:0018997 infores:clingen CAID:CA234977 MONDO:0018997 PMID:17143285PMID:29493581PMID:17143282 Pathogenic PS3, PM1, PM2, PS2_Very Strong, PP2, PP3 The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS3 PS2_VeryStrong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA234977/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:145499 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042109 infores:hetionet CAID:CA023690 biolink:causes MONDO:0007750 infores:clingen CAID:CA023690 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PVS1_Strong, PM3, PP1_Moderate, PM2, PP4 BA1, BP4, BP2, PS1, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM6, PP3, BS2 The NM_000527.5(LDLR):c.313+2T>C variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_moderate, PVS1_strong, PP1_moderate, PS4, PM3, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00002941 (0.002941%) in European (non-Finnish) exomes (gnomAD v3.1.2), so PM2 is Met.PS3_moderate - Level 2 assays: PMID 19026292:Homozygous patient cells, 125I-LDL assays - result - 10% LDLR activity.---- functional study is consistent with damaging effect, so PS3_Moderate is Met.PVS1_strong - Variant is in +2 intronic position, but there are no studies on effect predicted, so give PVS1_Strong to be conservative.PP1_moderate - Variant segregates with FH phenotype in 4 informative meiosis from 2 families: 2 relatives with the phenotype and the variant from Robarts Research Institute, and 2 affected family members with the variant from Germany (PMID: 26036859), so PP1_Moderate is Met.PS4 - Variant meets PM2 and is identified in 19 unrelated index cases from different labs (4 index cases with DLCN>6 from Robarts Research Institute; 4 index cases with DLCN>6 from Color Health, Inc; 1 index case who fulfills the following criteria for FH: i) total cholesterol >= 9.5 mmol/l, ii) triglycerides < 2 mmol/l, iii) presence of tendon xanthomas; or iv) occurrence of hypercholesterolemia or early onset of coronary artery disease in first degree relatives, from The Netherlands (PMID: 7616128); 3 index cases with DLCN>6 (LDL between 7,98 - 9,50 mmol/l and hypercholesterolemia in 1st degree relative) from Germany (PMID: 11462246); 1 index case who fulfills the following criteria for FH: (1) LDL > 95th percentile and triglycerides below 2 mmol/l, and (2) the presence of xanthoma or CHD in the proband or 1st degree relative with type IIa hypercholesterolemia, xanthoma, or CVD, from France (PMID: 12436241); 1 index case with SB criteria for FH (Total cholesterol >290 mg/dL and LDL >200 mg/dL and severe hypercholesterolemia in 1st degree relatives), from Germany (PMID: 14974088); 1 index case with definite FH according to SB criteria from Northern Ireland (PMID: 16159606); 3 index cases fulfilling the following criteria for FH: i) total cholesterol > 8.0 mmol/l and LDL > 6 mmol/l; (ii) premature coronary or vascular disease, or a family history of cardiovascular disorder; and (iii) the presence of tendon xanthoma, from Denmark (PMID: 16542394); 1 index case with definite FH according to SB criteria (total cholesterol = 658 mg/dl and presence of xanthomas, and primary hypercholesterolemia in the probands’ parents or 1st degree relatives), from USA (PMID: 19026292)), so PS4 is Met.PM3 - Variant meets PM2 and is identified in a true homozygous with total cholesterol = 658 mg/dl (PMID: 19026292), so PM3 is Met.PP4 - Variant meets PM2 and is identified in 19 unrelated index cases from different labs as described, so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023690/MONDO:0007750/013 2022-02-14 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0010322 biolink:causes GO:0008299 infores:ubergraph knowledge_assertion manual_agent GO:0010322 GO:0008299 CHEBI:6438 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0014742 infores:hetionet CAID:CA410204328 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204328 MONDO:0011071 PMID: Uncertain Significance PS4_Moderate, PM2_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, BP5, BP7, PVS1, PM6, PM4, PM3, PM1, PM5, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.98-1G>A is a splice acceptor variant which only affects isoform c (PVS1_NA). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27479822, 29932212). In summary, this variant meets the criteria to be classified as a variant of unknown significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PS4_Moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204328/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA312281 biolink:causes MONDO:0008723 infores:clingen CAID:CA312281 MONDO:0008723 PMID:9709714 Likely Pathogenic PM2_Supporting, PM3_Strong, PP4_Moderate, PS3_Supporting PP3 The c.1679-6G>A variant in ACADVL is an intronic variant which creates a novel acceptor site in intron 17, experimentally shown to cause insertion of four nucleotides and causes a frameshift (PS3_Supporting; PMID: 9709714). This variant has been reported in several individuals affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency confirmed in trans to at least one pathogenic variant, presumed in trans to distinct ACADVL variants, and in the homozygous state in at least two individuals (PM3_Strong; PMIDs:23480858, 9709714, 8845838). Fibroblasts derived from one of these individuals showed no detectable VLCAD activity, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID: 234808). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002264 in the Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PS3_Supporting, PM3_Strong, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312281/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52717 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0521465 infores:hetionet CHEBI:3310 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0018965 infores:hetionet CHEBI:15854 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0004093 infores:hetionet CHEBI:28915 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0231528 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042267 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020649 infores:hetionet CAID:CA166465 biolink:causes MONDO:0100488 infores:clingen CAID:CA166465 MONDO:0100488 PMID: Likely Benign BS2 BS1, PM2, PP3, BA1, PS4 The c.2450C>T (p.Ala817Val) variant results in a missense change in the last exon of CDH1. This variant is present at a frequency 3.3x10-5 (5 of 152,172 alleles) in the gnomAD population database v3.1.2. This variant has been observed in 104 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In vitro studies of the A817V variant suggest reduced binding of B-catenin and reduced cell aggregation in a HEK293T cell model (PMID: 33929593). However, evaluation of the use of functional data by the VCEP indicates that functional data currently available for missense variants cannot yet predict the pathogenicity of CDH1 variants, and it is therefore not considered in the classification for any CDH1 missense variant (Lee et al, 2018; PMID: 30311375). As such, published information from in vitro or in vivo assays assessing impact on function for this missense variant has not been considered for variant curation. In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166465/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:42797 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031212 infores:hetionet CHEBI:8455 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0041834 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000088 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034013 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0162429 infores:hetionet CHEBI:8327 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0026821 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011551 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0429098 infores:hetionet CHEBI:8024 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018965 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0010200 infores:hetionet CHEBI:5775 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0018681 infores:hetionet CHEBI:167309 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0233407 infores:hetionet CHEBI:61390 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0232849 infores:hetionet CHEBI:7956 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0236024 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0037274 infores:hetionet GO:0060721 biolink:causes GO:0060712 infores:ubergraph knowledge_assertion manual_agent GO:0060721 GO:0060712 CHEBI:6933 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0023218 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0178298 infores:hetionet CHEBI:135285 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0015672 infores:hetionet CHEBI:135736 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032227 infores:hetionet CAID:CA009520 biolink:causes MONDO:0021056 infores:clingen CAID:CA009520 MONDO:0021056 PMID: Pathogenic PVS1, PS4, PM2_Supporting The NM_000038.6(APC):c.4393_4394del (p.Ser1465TrpfsTer3) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 4 probands meeting 4 phenotype points (PS4_Strong, [PMID: 1316610, 28018803, 29998021, 28782241, 10768871]). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4_Strong and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA009520/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10101 biolink:causes MONDO:0003763 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0236816 infores:hetionet CHEBI:7443 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002874 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0376358 infores:hetionet CHEBI:6970 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0015672 infores:hetionet UMLS:C0657912 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085632 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0344304 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0344304 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0022890 infores:hetionet CAID:CA404077216 biolink:causes MONDO:0007750 infores:clingen CAID:CA404077216 MONDO:0007750 PMID: Likely Pathogenic PM1, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, PP1 The NM_000527.5(LDLR):c.551G>C (p.Cys184Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM1 - Variant meets PM2 and alters Cys184, one of the cysteine residues listed.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.871. It is above 0.75.PP4 - Variant meets PM2 and is identified in 1 index case who fulfills DLCN>=6 criteria for FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France, after alternative causes for high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404077216/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5893 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0039231 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0032285 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0002170 infores:hetionet CHEBI:31859 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0522055 infores:hetionet CHEBI:28918 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0003811 infores:hetionet CHEBI:7852 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0340865 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019158 infores:hetionet CHEBI:182080 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0003123 infores:hetionet CHEBI:50859 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030252 infores:hetionet CHEBI:3534 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0311468 infores:hetionet CHEBI:63635 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0006625 infores:hetionet CHEBI:8776 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0018418 infores:hetionet NCBIGene:3239 biolink:causes MONDO:0007222 infores:monarchinitiative not_provided not_provided HGNC:5136 MONDO:0007222 uuid:84254d44-5ab4-40ee-afa4-efc14a31f6d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135925 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0027497 infores:hetionet CAID:CA000069 biolink:causes MONDO:0018875 infores:clingen CAID:CA000069 MONDO:0018875 PMID: Uncertain Significance PM2_Supporting BA1, BP4, BP2, BP3, PS1, PS3, PS4, PS2, PM5, PM1, PM4, BS1, BS3, BS4, BP7, PVS1, PM6, BS2, PP3, PP1 The NM_000546.6: c.214_215delinsTG variant in TP53 is a deletion/insertion variant predicted to cause substitution of proline by cysteine at amino acid 72 (p.Pro72Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 2.2; 2/6/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000069/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0027339 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0004936 infores:hetionet CHEBI:9757 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0030252 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0010709 infores:hetionet NCBIGene:6495 biolink:causes MONDO:0011519 infores:monarchinitiative not_provided not_provided HGNC:10887 MONDO:0011519 uuid:d99c70f5-f6a0-4572-a11c-f102578d1505 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020458 infores:hetionet CHEBI:4877 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C2697368 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018939 infores:hetionet CHEBI:47780 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085631 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040479 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037023 infores:hetionet NCBIGene:4204 biolink:causes MONDO:0010235 infores:monarchinitiative not_provided not_provided HGNC:6990 MONDO:0010235 uuid:0a9c36fa-df6d-4c29-adfd-2082ac7097cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0237849 infores:hetionet NCBIGene:2890 biolink:causes MONDO:0030964 infores:monarchinitiative not_provided not_provided HGNC:4571 MONDO:0030964 uuid:76df8e77-bee5-4051-beb0-b5560e89cb2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0235259 infores:hetionet CHEBI:10119 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040264 infores:hetionet NCBIGene:190 biolink:causes MONDO:0010264 infores:monarchinitiative not_provided not_provided HGNC:7960 MONDO:0010264 uuid:71509ab4-a9a3-4ae6-9427-5b55c4035482 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:7662KG2R6K biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0236071 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011991 infores:hetionet CHEBI:45863 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234146 infores:hetionet CAID:CA624867876 biolink:causes MONDO:0100453 infores:clingen CAID:CA624867876 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.2595del (p.Lys866ArgfsTer14) is a frameshift variant that introduces a premature stop codon into exon 14 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total frequency of 0.00001921, with 31 alleles / 1614008 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), visual acuity limited to light perception (1 pt) since birth (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), abnormal visually evoked response, absence of medial opacities, and normal-appearing fundus, which together are specific for GUCY2D-related recessive retinopathy (total 5 points, PMID: 29178642, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA624867876/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6887 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0037822 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009443 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0032285 infores:hetionet CAID:CA014062 biolink:causes MONDO:0004994 infores:clingen CAID:CA014062 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3770A>G (p.Asn1257Ser) variant in the MYH7 gene is 0.17% (37/16512) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014062/MONDO:0004994/002 2016-12-16 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10101 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C3665386 infores:hetionet CHEBI:83804 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0232461 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0031542 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013395 infores:hetionet CHEBI:71219 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020580 infores:hetionet CHEBI:553473 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0020580 infores:hetionet CHEBI:15765 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0002962 infores:hetionet CAID:CA134613 biolink:causes MONDO:0021060 infores:clingen CAID:CA134613 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.711G>A (p.Gly237=) variant in the MAP2K1 gene is 1.612% (1130/66724) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134613/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:404903 biolink:causes UMLS:C0239729 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0239729 infores:hetionet CHEBI:50275 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235857 infores:hetionet CHEBI:6402 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0026821 infores:hetionet CHEBI:92923 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0041834 infores:hetionet CHEBI:3723 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039621 infores:hetionet CHEBI:17630 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0242528 infores:hetionet CHEBI:127780 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0392171 infores:hetionet CHEBI:32184 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0151908 infores:hetionet CHEBI:93635 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0021141 infores:hetionet CHEBI:8502 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0206062 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0027765 infores:hetionet CHEBI:119915 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013378 infores:hetionet CHEBI:50648 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0005758 infores:hetionet GO:0007317 biolink:causes GO:0009994 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0009994 CHEBI:63598 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0546817 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0235893 infores:hetionet CHEBI:10101 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0003537 infores:hetionet CHEBI:134990 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0234458 infores:hetionet CHEBI:61033 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0015230 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0022354 infores:hetionet CHEBI:46295 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0042571 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002121 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235880 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0232492 infores:hetionet CHEBI:2453 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151904 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018418 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0342579 infores:hetionet CHEBI:6822 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0018965 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0854193 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0854193 infores:hetionet CHEBI:3215 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0012569 infores:hetionet GO:0060657 biolink:causes GO:0060603 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0060603 CHEBI:92712 biolink:causes HP:0030144 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0232695 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0267792 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0178298 infores:hetionet CHEBI:4784 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020625 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0034150 infores:hetionet CHEBI:167309 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0015967 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0035078 infores:hetionet NCBIGene:55687 biolink:causes MONDO:0013111 infores:monarchinitiative not_provided not_provided HGNC:25481 MONDO:0013111 uuid:2edbd9f1-9476-4e07-9d32-f1681a0b7b22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:73274 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0041969 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0028866 infores:hetionet CHEBI:135351 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0151610 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0269596 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0269596 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017574 infores:hetionet CHEBI:82960 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085602 infores:hetionet CHEBI:9635 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0010038 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042075 infores:hetionet CHEBI:9649 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0010200 infores:hetionet CHEBI:6339 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0404521 infores:hetionet CHEBI:6456 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0220870 infores:hetionet CHEBI:34967 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0020580 infores:hetionet CHEBI:31401 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0002962 infores:hetionet CHEBI:5613 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0917801 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0857353 infores:hetionet CHEBI:167638 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0027424 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0037274 infores:hetionet CHEBI:6846 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0948586 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042373 infores:hetionet HP:0031377 biolink:causes MONDO:0011996 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D015464 DB01005_MESH_D015464_1 CHEBI:45081 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0022660 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0018801 infores:hetionet CHEBI:3219 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0086565 infores:hetionet CHEBI:2636 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0424790 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0015397 infores:hetionet CHEBI:8774 biolink:causes UMLS:C1610056 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1610056 infores:hetionet CAID:CA177561 biolink:causes MONDO:0019497 infores:clingen CAID:CA177561 MONDO:0019497 PMID: Benign BA1, BP4 The filtering allele frequency (the lower threshold of the 95% CI of 232/24628) of the c.1580-6C>T variant in the OTOF gene is 0.843% for African/African-American chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, splice prediction analysis using MaxEntScan and SpliceAI does not suggest an impact to splicing (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA177561/MONDO:0019497/005 2022-05-13 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:65173 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0232487 infores:hetionet CHEBI:3371 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0028961 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0086543 infores:hetionet CHEBI:63616 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0235490 infores:hetionet CHEBI:39867 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013144 infores:hetionet CHEBI:2955 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1510410 infores:hetionet CHEBI:4315 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0241633 infores:hetionet CHEBI:3515 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0014457 infores:hetionet CHEBI:10125 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C3263723 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235890 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1384666 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0267537 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0002622 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1458155 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0234215 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0262985 infores:hetionet CHEBI:39669 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0015672 infores:hetionet CHEBI:8354 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0344232 infores:hetionet CAID:CA16609808 biolink:causes MONDO:0007750 infores:clingen CAID:CA16609808 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.981C>A (p.His327Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in 1 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) (Czechia) with Simon-Broome possible FH, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609808/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3814 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0013395 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0232203 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0232203 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0521464 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0521464 infores:hetionet CHEBI:100241 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011606 infores:hetionet CHEBI:7025 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0043241 infores:hetionet CHEBI:6759 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0027769 infores:hetionet CHEBI:77733 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0023066 infores:hetionet NCBITaxon:188544 biolink:causes MONDO:0017280 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:188544 MONDO:0017280 CHEBI:73274 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0027765 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019158 infores:hetionet CHEBI:5138 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151610 infores:hetionet CHEBI:4653 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0011991 infores:hetionet CAID:CA115292 biolink:causes MONDO:0007064 infores:clingen CAID:CA115292 MONDO:0007064 PMID: Uncertain Significance PP1, PP4_Moderate PM2, PM3, PM5, BS1, PS3 The c.454C>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Leu by Met at amino acid 152.The filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.0006937 for South Asian chromosomes by gnomAD v 2.1.1, which is bigger than the ClinGen SCID VCEP threshold (0.0001742). So, PM2 is not met.The variant has been reported to segregate with SCID in 02 affected members (proband +1) from one family. LOD score: 0.6 = PP1_supporting.At least one patient (P6, PMID: 29744787) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met: 0.5 points, * Reduced ADA enzyme activity in patient cells (see table 2) 1 point, and * Lymphocyte count partially corrected by ADA enzyme replacement therapy: 1 point = TOTAL: 2.5 points, which is highly specific for SCID (PP4_moderate, PMID: 29744787.)In summary, this variant meets the criteria to be classified as VUS for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP1_Supporting, PP4_Moderate (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA115292/MONDO:0007064/114 2024-01-16 2024-01-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:144093 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0033774 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0852908 infores:hetionet CHEBI:53760 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0086439 infores:hetionet CHEBI:6539 biolink:causes NCIT:C50850 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0542127 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0853761 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151605 infores:hetionet UBERON:0003902 biolink:causes UBERON:0005426 infores:ubergraph knowledge_assertion manual_agent UBERON:0003902 UBERON:0005426 CHEBI:16755 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042023 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0029456 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0022660 infores:hetionet CHEBI:8774 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0037763 infores:hetionet NCBIGene:126792 biolink:causes MONDO:0014139 infores:monarchinitiative not_provided not_provided HGNC:17978 MONDO:0014139 uuid:f032bc63-d01c-420f-80bf-1d6c44b504e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28915 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0012833 infores:hetionet NCBIGene:6659 biolink:causes MONDO:0032791 infores:monarchinitiative not_provided not_provided HGNC:11200 MONDO:0032791 uuid:196ba91d-c8ce-4584-bb33-a298aa0799ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1167709 infores:hetionet CHEBI:50648 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1720775 infores:hetionet CHEBI:31401 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0015402 infores:hetionet CHEBI:75722 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013378 infores:hetionet CHEBI:71940 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0030554 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0027769 infores:hetionet CAID:CA399803382 biolink:causes MONDO:0100326 infores:clingen CAID:CA399803382 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The c.1423C>T (p.Gln475Ter) variant is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1; PMID:31980526). At least one patient (Patient 8 in PMID:36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent (<25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_moderate). The same individual was homozygous for the variant and confirmed in trans (0.5 PM3 points, PMID:36672149). Total points: 0.5 (PM3_supporting). This variant is absent from gnomAD v.2.1.1 (PM2_supporting).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3_supporting, PM2_supporting, PP4_moderate. (VCEP specifications version 2; date of approval 02/20/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399803382/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50122 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0014742 infores:hetionet CHEBI:2038 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0029163 infores:hetionet CHEBI:64317 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0012833 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0085762 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027441 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003621 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020651 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0040034 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013238 infores:hetionet CHEBI:17549 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0002871 infores:hetionet CHEBI:6367 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042164 infores:hetionet CHEBI:3561 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1457883 infores:hetionet CHEBI:4046 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0042963 infores:hetionet CHEBI:75984 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C1443060 infores:hetionet CHEBI:41423 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0016204 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0836924 infores:hetionet CHEBI:63681 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0085932 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235639 infores:hetionet CHEBI:31709 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C2939147 infores:hetionet CHEBI:50730 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0027092 infores:hetionet CHEBI:116278 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0349231 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0037199 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0010399 infores:hetionet CHEBI:5118 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151611 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0042109 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1112182 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1112182 infores:hetionet CHEBI:167638 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0015230 infores:hetionet GO:1905100 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:1905100 GO:0023052 CHEBI:46081 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042024 infores:hetionet NCBIGene:27183 biolink:causes MONDO:0035819 infores:monarchinitiative not_provided not_provided HGNC:13488 MONDO:0035819 uuid:5696a4aa-b647-456c-a83f-a416eac90c60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70735 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0149871 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0234215 infores:hetionet CHEBI:5384 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0002874 infores:hetionet NCBIGene:79587 biolink:causes MONDO:0014728 infores:monarchinitiative not_provided not_provided HGNC:25695 MONDO:0014728 uuid:c269a5b0-1289-4339-805b-a7ac744e3392 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:2 biolink:causes MONDO:0006552 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D005499 DB00798_MESH_D005499_1 CHEBI:5893 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013390 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151479 infores:hetionet CHEBI:2948 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1306571 infores:hetionet CHEBI:9123 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020625 infores:hetionet CHEBI:8382 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0025289 infores:hetionet CHEBI:29688 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0003126 infores:hetionet CHEBI:49375 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0853034 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0160390 infores:hetionet CHEBI:28177 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0002170 infores:hetionet CHEBI:10110 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0017565 infores:hetionet CHEBI:63598 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0237849 infores:hetionet CHEBI:5123 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0151576 infores:hetionet CHEBI:134966 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0028949 infores:hetionet CHEBI:9123 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0595929 infores:hetionet CHEBI:53691 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0040053 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0860210 infores:hetionet GO:0072034 biolink:causes GO:0072088 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0072088 NCBIGene:7507 biolink:causes MONDO:0010210 infores:monarchinitiative not_provided not_provided HGNC:12814 MONDO:0010210 uuid:576bf5ea-13fa-4f51-9023-24c463cca37e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA020056 biolink:causes MONDO:0008667 infores:clingen CAID:CA020056 MONDO:0008667 PMID: Benign BA1 PP3 The variant NM_000551.3(VHL):c.154G>A (p.Glu52Lys) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0008611 (78/74388 from African/African American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020056/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:567361 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0026858 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0679429 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0679429 infores:hetionet CHEBI:101278 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151517 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0010692 infores:hetionet CHEBI:144551 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009676 infores:hetionet CHEBI:44915 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0085631 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0043251 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0015663 infores:hetionet CHEBI:5558 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0043352 infores:hetionet CHEBI:10127 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038325 infores:hetionet CHEBI:8412 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0015230 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085762 infores:hetionet CHEBI:135920 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0010200 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0025061 infores:hetionet CHEBI:15553 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042487 infores:hetionet CHEBI:70707 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0086769 infores:hetionet CHEBI:453011 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0015230 infores:hetionet CHEBI:10023 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0917801 infores:hetionet NCBIGene:2674 biolink:causes MONDO:0030822 infores:monarchinitiative not_provided not_provided HGNC:4243 MONDO:0030822 uuid:65540389-a99c-4796-8b90-68f29b4b4d61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042514 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0522224 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1368065 infores:hetionet CHEBI:41423 biolink:causes HP:0041081 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1542178 infores:hetionet CHEBI:5855 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085649 infores:hetionet CHEBI:5856 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0039239 infores:hetionet CHEBI:36791 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085636 infores:hetionet CHEBI:32020 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0027497 infores:hetionet CHEBI:8378 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0700590 infores:hetionet CAID:CA399787972 biolink:causes MONDO:0100326 infores:clingen CAID:CA399787972 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting, PVS1_Strong The NM_000419.5(ITGA2B):c.3061-1G>A occurs within the canonical splice acceptor site of intron 29. It is predicted to cause skipping of biologically-relevant-exon 29, resulting in the in-frame deletion of 39 amino acids (3.7% of the protein) of the transmembrane region, which is considered a critical region by the PD-EP (PVS1_strong). At least one patient (GT31 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). GT31 is compound heterozygous for c.1771dup (classified Pathogenic by the PD-EP) and c.3061-1G>A (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399787972/MONDO:0100326/011 2022-08-05 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:27834 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0036974 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0852810 infores:hetionet CHEBI:63791 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017181 infores:hetionet CHEBI:6715 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1384353 infores:hetionet CAID:CA1139771354 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139771354 MONDO:0015967 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS4, PP4 The c.1295_1297delinsCGGC variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 432 (NM_000162.5), adding 27 novel amino acids before encountering a stop codon (p.(Pro432ArgfsTer27)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of GCK-hyperglycemia, but PP4 could not be evaluated due to insufficient clinical information (PMID 19150152). This variant segregated with diabetes with 3 informative meiosis in this individual's family (PP1; PMID 19150152). In summary, the c.1295_1297delinsGCCG variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771354/MONDO:0015967/086 2023-09-08 2023-09-08 Semidominant inheritance HP:0032113 Supports CHEBI:7907 biolink:causes UMLS:C0235055 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0235055 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0277925 infores:hetionet CHEBI:77260 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0039231 infores:hetionet CHEBI:82960 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0015672 infores:hetionet NCBIGene:4076 biolink:causes MONDO:0968945 infores:monarchinitiative not_provided not_provided HGNC:6743 MONDO:0968945 uuid:ecae9c3b-da12-4e8e-8317-34c36d58b953 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0065374 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0917799 infores:hetionet CHEBI:8874 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0026837 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0549418 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151752 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0018021 infores:hetionet CHEBI:4027 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085692 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030567 infores:hetionet NCBIGene:3508 biolink:causes MONDO:0011436 infores:monarchinitiative not_provided not_provided HGNC:5542 MONDO:0011436 uuid:24902bbb-c6b1-4bb5-9d00-c76fda735536 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009763 infores:hetionet NCBIGene:84976 biolink:causes MONDO:0976262 infores:monarchinitiative not_provided not_provided HGNC:19711 MONDO:0976262 uuid:b797e553-2abc-4bad-a181-5c976234f5ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0003123 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0548823 infores:hetionet CHEBI:17347 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0558489 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0546947 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0546947 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0161679 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0392620 infores:hetionet CHEBI:7852 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0027796 infores:hetionet CHEBI:49375 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151578 infores:hetionet CHEBI:31981 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0026837 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0009938 infores:hetionet GO:0010543 biolink:causes GO:0042060 infores:ubergraph knowledge_assertion manual_agent GO:0010543 GO:0042060 CAID:CA367401747 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401747 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM1, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting The c.503C>A variant in the glucokinase gene, GCK, causes an amino acid change of threonine to asparagine at codon 168 (p.(Thr168Asn)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.879, which is greater than the MDEP VCEP threshold of 0.70 (PP3). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Another missense variant, c.502A>G p.Thr168Ala, has been interpreted as pathogenic by the ClinGen MDEP, and p.Thr168Asn has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.503C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP3, PP2, PM5, PP4_Moderate, PP1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401747/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Supports CHEBI:94449 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0233514 infores:hetionet CHEBI:50729 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151744 infores:hetionet CHEBI:66903 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0020625 infores:hetionet CHEBI:5100 biolink:causes UMLS:C0948168 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0948168 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0006849 infores:hetionet CHEBI:5864 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0036104 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0178298 infores:hetionet CHEBI:47898 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2830004 infores:hetionet NCBIGene:80776 biolink:causes MONDO:0013609 infores:monarchinitiative not_provided not_provided HGNC:28636 MONDO:0013609 uuid:955d775b-24db-4d5c-8516-537ecb8e4c7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1145670 infores:hetionet CHEBI:3504 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0030193 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C2973529 infores:hetionet CHEBI:64312 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009676 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0004936 infores:hetionet CHEBI:2569 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0003811 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151313 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0017152 infores:hetionet CAID:CA320251523 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251523 MONDO:0011071 PMID:34166225 Uncertain Significance PS3, PM2_Supporting PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1093G>C (p.Gly365Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Transactivation assays demonstrate altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) and data from a secondary colony-formation assay demonstrate altered expression (PS3; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PS3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251523/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028961 infores:hetionet CHEBI:50156 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0004245 infores:hetionet CHEBI:6715 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013144 infores:hetionet CHEBI:6904 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0344232 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002622 infores:hetionet NCBIGene:4140 biolink:causes MONDO:0032655 infores:monarchinitiative not_provided not_provided HGNC:6897 MONDO:0032655 uuid:23b5370c-4c34-4cac-aa2d-17d622e43e66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2364111 infores:hetionet CHEBI:63612 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0231528 infores:hetionet CHEBI:63619 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0028643 infores:hetionet CHEBI:681569 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0034063 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020550 infores:hetionet CHEBI:50742 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151905 infores:hetionet CHEBI:63635 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011175 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018099 infores:hetionet CHEBI:7494 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0003862 infores:hetionet CHEBI:6761 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0085932 infores:hetionet CHEBI:4046 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0020458 infores:hetionet CAID:CA041664 biolink:causes MONDO:0007750 infores:clingen CAID:CA041664 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PM1, PM2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM1, PM2, PS3_Moderate, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 February 2022.The supporting evidence is as follows:PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1).PP3: REVEL = 0.759.PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed.PS3_Moderate: PMID:1301956 - Level 2 assay.- study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%.PS4, PP4: Variant meets PM2 and is identified in >15 unrelated index cases fulfilling FH clinical criteria (1 case with possible FH by Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; 2 cases with DLCN score >=6 from Robarts Research Institute, Canada; 2 cases with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, Italy; >10 cases from PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425). PP1: Variant segregates with FH phenotype in at least 2 informative meioses from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, Italy; Laboratory of Genetics and Molecular Cardiology, Brazil): 2 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041664/MONDO:0007750/013 2022-02-25 2025-08-08 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:54903 biolink:causes MONDO:0014928 infores:monarchinitiative not_provided not_provided HGNC:7121 MONDO:0014928 uuid:b483457d-f0b5-48d1-82b7-8a5eacbb6b24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes NCIT:C54356 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151598 infores:hetionet CHEBI:4514 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0012569 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035078 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042109 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0235032 infores:hetionet CHEBI:135791 biolink:causes MONDO:0006564 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0162823 infores:hetionet CHEBI:188986 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0027497 infores:hetionet CHEBI:17474 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0022107 infores:hetionet CAID:CA128828 biolink:causes MONDO:0044970 infores:clingen CAID:CA128828 MONDO:0044970 PMID:19809478 Uncertain Significance PP3, PM2_Supporting, PS3_Moderate PS4 The m.10450A>G variant in MT-TR has been reported in one individual with primary mitochondrial disease (PMID: 19809478). This child had reduced birth weight, length, and head circumference. Shortly after birth, this child was noted to have severe generalized hypotonia, respiratory insufficiency, feeding difficulty, and anemia. By four months old, he had severe psychomotor and growth delay, visual dysfunction, and epilepsy. By eight months, he was noted to have microcephaly, generalized hypotonia and hyporeflexia, no visual contact with surroundings, and intractable epilepsy. By age 4.5 years, he had no acoustic or visual contact, severe intellectual disability, and was tube fed. He had markedly elevated blood and cerebrospinal fluid lactate levels, elevated blood alanine, and increased urinary lactate and Krebs cycle intermediates. Brain imaging showed hypoplastic corpus callosum, abnormal signal in the basal ganglia, and progressive cerebral and cerebellar atrophy. Muscle biopsy showed reduced COX staining, and activities of complexes I, III (muscle only), and IV were reduced in skeletal muscle and/or fibroblasts. There were also reduced levels of fully assembled complexes I, IV and V. Steady state levels of tRNA Arg were reduced in fibroblasts. The variant was present in skeletal muscle at 93% heteroplasmy and in fibroblasts at 92% heteroplasmy. The variant was present in his asymptomatic mother’s fibroblasts at 18% and was undetectable in her blood. This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (69.6 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.65 (PP3). Cybrid studies recapitulated the findings in the patient as they showed reduced in-gel complex I activity and reduced fully assembled complex I, IV, and V; marked reduction in the amount of tRNA Arg; and faster migration of mutant tRNAs in non-denatured conditions (PMID: 19809478; PS3_moderate). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA128828/MONDO:0044970/015 2024-02-26 2025-10-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9139 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0036980 infores:hetionet CHEBI:6933 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0003467 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0520886 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0022660 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0037199 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020649 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024894 infores:hetionet NCBIGene:1493 biolink:causes MONDO:0014493 infores:monarchinitiative not_provided not_provided HGNC:2505 MONDO:0014493 uuid:0bb14f2a-780a-49cd-9ee8-235e7514ef31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15854 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0030312 infores:hetionet NCBIGene:378884 biolink:causes MONDO:0800306 infores:monarchinitiative not_provided not_provided HGNC:21576 MONDO:0800306 uuid:ffc1fc26-d319-4cb6-99c8-a29a787862c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:562 biolink:causes MONDO:0006032 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D003556 DB00537_MESH_D003556_1DB01059_MESH_D003556_1DB01165_MESH_D003556_1 CHEBI:9332 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0595916 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0149904 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0151735 infores:hetionet CHEBI:2704 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0033774 infores:hetionet CHEBI:61049 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011206 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022104 infores:hetionet CHEBI:64045 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0427086 infores:hetionet CHEBI:5138 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1527344 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0006277 infores:hetionet CHEBI:66901 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0027497 infores:hetionet CAID:CA355962355 biolink:causes MONDO:0001586 infores:clingen CAID:CA355962355 MONDO:0001586 PMID:21364962 Likely Pathogenic PP3_Moderate, PM3, PS3_Supporting, PP4, PM2_Supporting PS1, PS2, PM5, PM1, BS4, BP7, BP5, PM6, BP3, BP2, PP1 The NM_000203.5:c.826G>A in IDUA is a missense variant resulting in the substitution of glutamate by lysine at amino acid 276 (p.Glu276Lys). This variant has been reported in at least five probands with MPS I, all with a milder phenotype. In one patient homozygous for this genetic change (PMID 21364962), a highly-specific combination of clinical and biochemical evidence for MPS I has been reported (PMID: 21364962) (PP4). All other probands are also reported to have a confirmed enzymatic diagnosis. This variant has been detected in at least five probands with MPS I in the available literature. There is at least one homozygous patient of Thai ancestry (PMID 21364962), and three Turkish siblings (reported in PMID 23786846, but potentially the same proband as in PMID 21394825), scoring 1 point in total (max for homozygous individuals). Two individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic for MPS I including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (P by LD VCEP, phase unconfirmed, 0.5 points) (PMID: 35141277), and c.494-1G>A (ClinVar Variation ID: 557942) (LP by LD VCEP, phase unconfirmed, 0.25 points) (PMID: 21394825). Another individual is compound heterozygous for the variant and c.250G>C (p.Gly84Arg). The allelic data from the latter patient will be used in the classification of p.Gly84Arg and is not included here to avoid circular logic. Total 1.75 points (PM3). Experimental evidence from a COS-7 cell line, with c.826G>A expressed through site-directed mutagenesis, demonstrated minimal residual enzyme activity (approximately 1%) (PMID 21364962) (PS3_Supporting). The computational predictor REVEL gives a score of 0.833 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 8.522e-7 (1/1173452 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PM3, PP3_Moderate, PP4, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 23, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355962355/MONDO:0001586/091 2025-05-23 2025-05-23 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0231365 infores:hetionet CHEBI:27666 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0027540 infores:hetionet CHEBI:27666 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0013604 infores:hetionet CHEBI:92998 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0030193 infores:hetionet CHEBI:63631 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0522055 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0018799 infores:hetionet CHEBI:5001 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0232461 infores:hetionet CHEBI:567361 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0042029 infores:hetionet CHEBI:8107 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0006277 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002940 infores:hetionet CAID:CA291604 biolink:causes MONDO:0007113 infores:clingen CAID:CA291604 MONDO:0007113 PMID: Benign BP7, BA1, BP4 The allele frequency of the c.558A>T p.(Ala186=) variant in UBE3A (NM_130838.2) is 0.047% in the European (non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.558A>T p.(Ala186=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291604/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:63621 biolink:causes UMLS:C0543392 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0543392 infores:hetionet CAID:CA410203979 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203979 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.185A>G (p.Asp62Gly) is a missense variant which is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). In addition, it has a REVEL score <0.50 (0.418) (BP4). To the best of our knowledge, this variant has not been reported in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203979/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7476 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0021368 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0178298 infores:hetionet CHEBI:8774 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151480 infores:hetionet CHEBI:9123 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151907 infores:hetionet CHEBI:142290 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0917801 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0041912 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0007642 infores:hetionet CHEBI:5790 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0024031 infores:hetionet CHEBI:82941 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0015967 infores:hetionet CAID:CA8459468 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459468 MONDO:0011132 PMID: Likely Benign BP4, BS1 PP4 The variant NM_001369369.1(FOXN1):c.1184C>T is predicted to cause a proline to leucine substitution at amino acid position 395. The variant has a Grpmax allele frequency of 0.002555 based upon the East Asian population in gnomADv4.0, which is greater than 0.00141 and thus meets BS1 criteria. The meta predictor Revel predicts the variant has no deleterious effect on protein function with a score of of 0.249, which is less than 0.290. The variant is also predicted by SpliceAI not to impact splicing (delta = 0.01). The variant was found in the heterozygous state in sample 604 from PMID: 31672859 in a patient who displayed T and B-cell counts within the reference range and TREC values at 0 months of 123.1 uL (PP4 not met). In summary this variant meets criteria to be classified as likely benign for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BS1 and BP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459468/MONDO:0011132/113 2024-10-25 2024-10-25 Semidominant inheritance HP:0032113 Contradicts true CHEBI:3207 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0020522 infores:hetionet CHEBI:83531 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0039070 infores:hetionet CHEBI:5138 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003862 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0178298 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0008903 uuid:3d17da01-fc7b-48ad-8cb2-e6da0e65acd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3403 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0014591 infores:hetionet CHEBI:8346 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0234233 infores:hetionet CHEBI:9352 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0002792 infores:hetionet CHEBI:71219 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151905 infores:hetionet CHEBI:3568 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0004093 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0001824 infores:hetionet CHEBI:46295 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0234708 infores:hetionet CHEBI:63791 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0231807 infores:hetionet CHEBI:5118 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0024141 infores:hetionet CAID:CA562217624 biolink:causes MONDO:0021056 infores:clingen CAID:CA562217624 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting, BS2_Supporting PS4 The NM_000038.6(APC):c.7798_7801del (p.Gln2600ValfsTer15) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/235936 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 0.5 and in 1 proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PS4 not met [Ambry Genetics, GeneDX]). This variant has been observed in a heterozygous state in 3 individuals without a colorectal cancer/polyposis associated phenotype worth 3 healthy individual points in total (BS2_Supporting met; internal data Labcorp Genetics [formerly Invitae] and Ambry Genetics). The HCCP VCEP does not consider it a conflict that BS2_Supporting is fulfilled, as an attenuated polyposis phenotype is known in this region of the gene. In summary, this variant is a Likely Pathogenic variant for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1, PM2_Supporting, BS2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA562217624/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CAID:CA400029324 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029324 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Supporting PM5 The c.1448G>A variant in ITGB3 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 483 (p.Cys483Tyr). This variant was identified in a patient (Patient 11, PMID: 2180491) with GT type 1. This patient had a bleeding phenotype, normal platelet count and morphology, absent or severely diminished platelet aggregation by adenosine diphosphate and other agonists but was normal by ristocetin. Another study (PMID 12152649) sequenced ITGB3 in this patient and identified this variant and demonstrated minimal expression on the cell surface using flow cytometry (PP4_Moderate). This same patient is also reported in PMIDs 28395882 and 3535160. This variant was found in the homozygous state in this GT patient in PMID: 12152649 (PM3_Supporting). COS-7 cells were transfected to express this variant and the wild-type alpha-2-beta-3 surface proteins. Both flow cytometry and immunoblot were used to measure the surface expression of proteins and demonstrated a greatly reduced surface expression, estimated from Figure 3 as 6.5% (PMID: 12152649; PS3_Moderate). This variant has a REVEL score of 0.948 which is above the threshold of 0.7 established by the PD EP (PP3). This variant is not present in the gnomAD database v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PM3_Supporting, PS3_Moderate, PP3 and PM2_Supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029324/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:35778 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042373 infores:hetionet CHEBI:10119 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0855333 infores:hetionet CAID:CA410206837 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206837 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.716G>T (p.Ser239Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206837/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135285 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0042373 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040584 infores:hetionet CHEBI:92998 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0034063 infores:hetionet CAID:CA10014637 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014637 MONDO:0011071 PMID: Likely Benign BP4, BS1, BP7 PS3, PS4, PS2, BA1, PM2, PVS1, PM6, BS3, BS4, PM4, PM1, PP3, PP1 The NM_001754.5(RUNX1):c.59-12C>A variant is intronic and is located upstream to exon 3. The MAF of this variant is 0.00001613. However, in the East Asian subpopulation of the gnomAD v2.1.1 cohort, MAF is 0.0002190 (0.02190%, 4/248018 alleles), which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In addition, splicing algorithms predicted no effect on splicing (SpliceAI score 0.08 < 0.20) (BP4) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP100way (GRCh38/hg38) score 0.368 < 2.0) (BP7). To our knowledge, this variant has not been found in patients with FPD/AML phenotype and no functional studies are available. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014637/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4814 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0085649 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1321686 infores:hetionet CHEBI:37941 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018965 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0340464 infores:hetionet CAID:CA10585356 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585356 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM4, PM2, PP4 BP2, BA1, PS3, PS1, PS2, BS1, BS3, BS4, BP5, PM5, PM1, PM3, PM6, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1207_1209del (p.Phe403del) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM4, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (v2.1.1).PM4: Variant meets PM2 and is an in-frame deletion.PS4_Supporting, PP4: Variant meets PM2 and was identified in at least 5 unrelated index cases who fulfill criteria for FH (4 patients from PMID 22698793 (Tichý et al., 2012) and 1 patient from PMID 11462246 (Nauck et al., 2001), reported as 1205delTCT). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585356/MONDO:0007750/013 2023-01-27 2024-10-07 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0039671 biolink:causes GO:0002323 infores:ubergraph knowledge_assertion manual_agent GO:0039671 GO:0002323 CHEBI:3478 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0028734 infores:hetionet CHEBI:92998 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151766 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042075 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151736 infores:hetionet CHEBI:167638 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C2363730 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0040046 infores:hetionet CHEBI:6715 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0037763 infores:hetionet CHEBI:135679 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0677500 infores:hetionet CAID:CA519344969 biolink:causes MONDO:0010305 infores:clingen CAID:CA519344969 MONDO:0010305 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 The NM_005629.4(SLC6A8):c.1629G>A (p.Glu543=) variant in SLC6A8 is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4). In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP score of -1 (BP7). This variant has been previously reported as a variant of uncertain significance in an individual with suspected SLC6A8 deficiency (no further clinical data provided) (PMID: 20717164); thus PP4 does not apply. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA519344969/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:38940 biolink:causes MONDO:0700051 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0023885 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011991 infores:hetionet CHEBI:52172 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0024312 infores:hetionet CHEBI:8356 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2981158 infores:hetionet CHEBI:17334 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0015967 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0032961 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0162429 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0267596 infores:hetionet CHEBI:8597 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0009676 infores:hetionet CHEBI:29688 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0428977 infores:hetionet CHEBI:8802 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0034642 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0037199 infores:hetionet CHEBI:4798 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0026961 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0033775 infores:hetionet CHEBI:8024 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0032781 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0851341 infores:hetionet CHEBI:15544 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0428977 infores:hetionet CHEBI:2788 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0042420 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0007642 infores:hetionet CHEBI:3647 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0026205 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0232492 infores:hetionet CHEBI:49662 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0034063 infores:hetionet CHEBI:3814 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0009806 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042134 infores:hetionet CHEBI:50648 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151632 infores:hetionet CHEBI:6067 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013456 infores:hetionet CHEBI:48669 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0003811 infores:hetionet CHEBI:9654 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0520966 infores:hetionet CHEBI:125354 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0002792 infores:hetionet CHEBI:4514 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C2364111 infores:hetionet CHEBI:6950 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0022346 infores:hetionet CHEBI:7443 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0042963 infores:hetionet CHEBI:68579 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0035078 infores:hetionet CHEBI:16755 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013404 infores:hetionet CHEBI:8874 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232461 infores:hetionet CHEBI:10650 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015967 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0948586 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0042233 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:C536777 DB01167_MESH_C536777_1DB00196_MESH_C536777_1DB01026_MESH_C536777_1 NCBIGene:1062 biolink:causes MONDO:0014473 infores:monarchinitiative not_provided not_provided HGNC:1856 MONDO:0014473 uuid:0cae8ce9-b05a-461e-92b2-3de9c9d62014 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA120566 biolink:causes MONDO:0044970 infores:clingen CAID:CA120566 MONDO:0044970 PMID:8132749PMID:19631764 Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PS3_Supporting The m.3260A>G variant in MT-TL1 has been reported in five unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 1677065, 8210299, 8941275, 20965148, 24656211). Three individuals had features variably consistent with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; PMIDs: 8941275, 20965148, 24656211) and two individuals had cardiomyopathy and skeletal muscle myopathy (PMIDs: 1677065, 8210299). There are no reported de novo occurrences to our knowledge. This variant segregated with disease in one of the reported families, as five affected family members had heteroplasmy levels ranging from 86% - 90% whereas unaffected family members had heteroplasmy levels ranging from 20% - 78% (PP1_moderate; PMID: 1677065). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (81st percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMIDs: 8132749, 19631764). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120566/MONDO:0044970/015 2023-05-22 2024-07-23 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria NCBITaxon:780 biolink:causes MONDO:0001195 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:780 MONDO:0001195 CHEBI:9352 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0030920 infores:hetionet CHEBI:8768 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C3665386 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0262385 infores:hetionet CHEBI:92712 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0013604 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030305 infores:hetionet CHEBI:44185 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0333355 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0152029 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0035455 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040046 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0042075 infores:hetionet CHEBI:74947 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0016204 infores:hetionet CHEBI:6541 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0010200 infores:hetionet CHEBI:5130 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1142412 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020651 infores:hetionet CHEBI:32599 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0020672 infores:hetionet CHEBI:6822 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0015967 infores:hetionet UMLS:C0004609 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0033774 infores:hetionet NCBIGene:132 biolink:causes MONDO:0100255 infores:monarchinitiative not_provided not_provided HGNC:257 MONDO:0100255 uuid:af0a3333-374d-40ba-b509-9a10690920b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes UMLS:C0152159 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0152159 infores:hetionet CHEBI:31859 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0014742 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0281773 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0281773 infores:hetionet CHEBI:521033 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0855242 infores:hetionet CHEBI:31859 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0037763 infores:hetionet CHEBI:92998 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020437 infores:hetionet CHEBI:80630 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0015230 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0162281 infores:hetionet CAID:CA024656 biolink:causes MONDO:0007783 infores:clingen CAID:CA024656 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with histidine at codon 2283 of the RYR1 protein, p.Asn2283His. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:20681998). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.943) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024656/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6715 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0009450 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0014549 infores:hetionet CHEBI:7575 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0039231 infores:hetionet CAID:CA340747062 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747062 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP1, PP4, PM2_Supporting NM_000329.3(RPE65):c.571A>G (p.Asn191Asp) is a missense variant predicted to replace asparagine with aspartic acid at amino acid p.191. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.000001830, with 6 alleles / 1179954 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.440_441del (p.Thr147ArgfsTer9) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PMID: 40087508, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts, confirmed by clinician communication) before the age of 5 years (1 pt), reduced best-corrected visual acuity (1 pt), nystagmus (1 pt), and decreased electroretinogram responses (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 4 points, PMID: 40087508, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 40087508). The computational predictor REVEL gives a score of 0.935, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747062/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49375 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0033687 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C1384666 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0152227 infores:hetionet CHEBI:52172 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0025222 infores:hetionet CHEBI:31302 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0002792 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020456 infores:hetionet CHEBI:9763 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0025222 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0236071 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0149904 infores:hetionet CHEBI:2663 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0035410 infores:hetionet CAID:CA9043721 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043721 MONDO:0012999 PMID: Uncertain Significance PM2, BP4 The NM_000156.6:c.328-10C>T variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 2. To our knowledge, this variant has not been reported in the literature among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0003385 (10/29542 alleles) in the Ashkenazi Jewish population, followed by 0.0001857 (219/1179100) in the European non-Finnish population, both of which are lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.03 for acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 328349). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043721/MONDO:0012999/026 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5864 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0032584 infores:hetionet CHEBI:73275 biolink:causes HP:0001727 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C1112433 infores:hetionet CHEBI:28748 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0232726 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0151723 infores:hetionet CHEBI:7954 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0476273 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0019158 infores:hetionet GO:1900163 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1900163 GO:0010256 CHEBI:6339 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0018965 infores:hetionet CHEBI:3504 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0162830 infores:hetionet CHEBI:8863 biolink:causes MONDO:0019060 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0005967 infores:hetionet CHEBI:8764 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013404 infores:hetionet CHEBI:28787 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0522224 infores:hetionet NCBIGene:6509 biolink:causes MONDO:0014725 infores:monarchinitiative not_provided not_provided HGNC:10942 MONDO:0014725 uuid:393dbc9c-07cb-4ca0-a9af-af31409448c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135791 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0015230 infores:hetionet CHEBI:92923 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0035854 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0021053 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0031099 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020473 infores:hetionet CHEBI:6015 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0023066 infores:hetionet CHEBI:3223 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0019080 infores:hetionet CHEBI:45783 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0013491 infores:hetionet CHEBI:31236 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003578 infores:hetionet CHEBI:7798 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0017178 infores:hetionet CHEBI:4670 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0020649 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0235324 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0235324 infores:hetionet CHEBI:47898 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151872 infores:hetionet CHEBI:47781 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0002170 infores:hetionet CHEBI:5384 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0003123 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0948586 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011053 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009324 infores:hetionet NCBITaxon:1301 biolink:causes MONDO:0001039 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1301 MESH:D014069 DB01415_MESH_D014069_1DB00833_MESH_D014069_1DB01140_MESH_D014069_1 CHEBI:9571 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0011991 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0264714 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0264714 infores:hetionet UBERON:0000964 biolink:causes UBERON:0005426 infores:ubergraph knowledge_assertion manual_agent UBERON:0000964 UBERON:0005426 CHEBI:135005 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0004936 infores:hetionet CHEBI:49960 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0750394 infores:hetionet CAID:CA5416940 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416940 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.251C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 84 (p.Ser84Cys).The filtering allele frequency (the upper threshold of the 95% CI of 2/74366) of the c.251C>G variant in DCLRE1C is 0.00001005 for African (African American) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD v4.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416940/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:188986 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0234233 infores:hetionet CHEBI:135961 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0013404 infores:hetionet CHEBI:144093 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0013491 infores:hetionet CHEBI:5147 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151671 infores:hetionet CHEBI:94449 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0042510 infores:hetionet CAID:CA23575475 biolink:causes MONDO:0100368 infores:clingen CAID:CA23575475 MONDO:0100368 PMID: Likely Pathogenic PM3, PVS1_Strong, PP4_Moderate, PM2_Supporting BP2, BP3, BA1, PS3, PS1, PM4, PM5, BP7, BS1, BS3, PP3, BS2 NM_000329.3(RPE65):c.246-11A>G is a variant within intron 3 adjacent to exon 4. The splicing impact predictor SpliceAI gives scores of 0.48 for splice acceptor loss and 0.39 for splice acceptor gain, which are above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. RT-PCR of RNA extracted from patient fibroblast-derived iPSCs detected a transcript with cryptic splice site usage introducing a frameshift and a premature termination codon, as well as a smaller amount of wild-type mRNA, consistent with a nearly complete splicing defect and most of the transcript undergoing nonsense-mediated decay (PVS1(RNA)_Strong). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3:c.615_616delCA (p.Ile206Cysfs*27) variant suspected in trans (PMID: 29033008) or the NM_000329.3(RPE65):c.208T>G (p.Phe70Val) variant confirmed in trans (PMID: 33472769, which were previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including abnormal best corrected visual acuity test (1 pt), visual field defect (1 pt), absence of rod response on ERG (0.5 pts), and improvement of FST and rod function following administration of RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (10.5 total points, PMID: 33472769, PP4_Moderate). The variant is present in gnomAD v.2.1.1 at a minor allele frequency of 0.000003988, with 1 allele / 250758 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1(RNA)_Strong, PM2_Supporting, PM3, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA23575475/MONDO:0100368/120 2024-02-01 2024-02-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0948594 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0004096 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0232498 infores:hetionet CHEBI:6061 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0015230 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0035078 infores:hetionet CHEBI:71940 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0085298 infores:hetionet CHEBI:63599 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0028643 infores:hetionet NCBIGene:23312 biolink:causes MONDO:0032858 infores:monarchinitiative not_provided not_provided HGNC:2938 MONDO:0032858 uuid:97e8e7b1-950f-4dbc-aeef-0541df72cffe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4046 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0040264 infores:hetionet CHEBI:6923 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0011603 infores:hetionet CHEBI:6437 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0149725 infores:hetionet CHEBI:18243 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0031924 infores:hetionet CHEBI:10127 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085932 infores:hetionet CHEBI:5001 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0035078 infores:hetionet CHEBI:8863 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0268000 infores:hetionet CHEBI:71028 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0013378 infores:hetionet CHEBI:3082 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C2363731 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232431 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0521634 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0521634 infores:hetionet CHEBI:50648 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0014518 infores:hetionet CHEBI:2038 biolink:causes HP:0005224 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0267566 infores:hetionet CHEBI:18332 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0020615 infores:hetionet CHEBI:7476 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030193 infores:hetionet CHEBI:28748 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2939147 infores:hetionet CHEBI:17650 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0241057 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0020517 infores:hetionet CHEBI:60761 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0028738 infores:hetionet CHEBI:63598 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0016242 infores:hetionet CHEBI:5118 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085649 infores:hetionet CHEBI:3175 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1145670 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011334 infores:hetionet CAID:CA233152 biolink:causes MONDO:0010726 infores:clingen CAID:CA233152 MONDO:0010726 PMID: Pathogenic PP3, PS4, PM6_Strong, PM2_Supporting PS2 The c.378-3C>G variant in MECP2 has been observed in at least 5 individuals with Angelman syndrome (PMID: 15737703, Rettbase, GeneDx internal data) (PS4). It has been reported in at least 2 unconfirmed de novo occurrences in individuals with Rett syndrome (PMID 15737703, 20142466) (PM6_strong). The c.378-3C>G variant in MECP2 is absent from gnomAD (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). In summary, the c.378-3C>G variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA233152/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:7915 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151576 infores:hetionet CHEBI:27690 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0151798 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0021400 infores:hetionet CHEBI:6076 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151723 infores:hetionet CHEBI:10102 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0030554 infores:hetionet CHEBI:3380 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0011606 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0006145 infores:hetionet CHEBI:6775 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009676 infores:hetionet CHEBI:15544 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020443 infores:hetionet CHEBI:3504 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0043094 infores:hetionet CHEBI:3286 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0392171 infores:hetionet CHEBI:132233 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0038990 infores:hetionet CHEBI:35778 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0340865 infores:hetionet CHEBI:51364 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0086439 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002884 infores:hetionet CHEBI:73274 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0002994 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0314719 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0857256 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0857256 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0025061 infores:hetionet CHEBI:94686 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0011603 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0917799 infores:hetionet CHEBI:6923 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0038325 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0003123 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0027051 infores:hetionet CHEBI:17650 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0030920 infores:hetionet CHEBI:50131 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0034642 infores:hetionet CHEBI:28918 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0017178 infores:hetionet CHEBI:3478 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151578 infores:hetionet CHEBI:134745 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0027765 infores:hetionet CHEBI:107736 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0013144 infores:hetionet CHEBI:2922 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0017574 infores:hetionet CHEBI:27882 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0011175 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233472 infores:hetionet CHEBI:135613 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0018794 infores:hetionet CHEBI:6706 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0015672 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0340464 infores:hetionet CHEBI:36791 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151714 infores:hetionet CHEBI:3216 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0004093 infores:hetionet CHEBI:6030 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0233794 infores:hetionet CHEBI:6456 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0152030 infores:hetionet CHEBI:9073 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0018681 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027051 infores:hetionet GO:0010082 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0010082 GO:0007275 CHEBI:44185 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151692 infores:hetionet CHEBI:3223 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0014591 infores:hetionet CHEBI:135736 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014591 infores:hetionet CHEBI:76010 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0497365 infores:hetionet CHEBI:3286 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0001807 infores:hetionet GO:0140886 biolink:causes GO:0071345 infores:ubergraph knowledge_assertion manual_agent GO:0140886 GO:0071345 NCBITaxon:5476 biolink:causes MONDO:0005886 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D002180 DB00196_MESH_D002180_1DB01026_MESH_D002180_1 CHEBI:8713 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0002962 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013595 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014742 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0234215 infores:hetionet CHEBI:63624 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0000731 infores:hetionet NCBIGene:10940 biolink:causes MONDO:0054561 infores:monarchinitiative not_provided not_provided HGNC:30129 MONDO:0054561 uuid:e4ad0a99-0320-40a3-a19b-eaf8b1e51d22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0012833 infores:hetionet CHEBI:6933 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0016382 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0041912 infores:hetionet CHEBI:34385 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0025061 infores:hetionet CAID:CA14860292 biolink:causes MONDO:0011071 infores:clingen CAID:CA14860292 MONDO:0011071 PMID: Benign BP4, BA1, BP7 PS3, PS4, PS2, PS1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.968-134A>G is an intronic variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.5821 (23805/40896 alleles) in African/African American population, which is higher than the ClinGen MMVCEP threshold (0.0015) for BA1, and therefore meets this criterion (BA1). Clinvar has an entry for this variant (Variation ID 1247287). This variant is located in intron 8 and is not predicted by spliceAI to impact splicing (0.0). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP100 (BP4, BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14860292/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:408174 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0086439 infores:hetionet CHEBI:6804 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151888 infores:hetionet CHEBI:465284 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0026826 infores:hetionet CHEBI:6078 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C2830004 infores:hetionet CHEBI:2567 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0037763 infores:hetionet GO:0048328 biolink:causes GO:0048320 infores:ubergraph knowledge_assertion manual_agent GO:0048328 GO:0048320 CHEBI:4887 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0232492 infores:hetionet CL:0000542 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent CL:0000542 GO:0006954 DB00563_MESH_D001171_1DB00563_MESH_D001172_1DB00563_MESH_D011565_1 CAID:CA489885447 biolink:causes MONDO:0015152 infores:clingen CAID:CA489885447 MONDO:0015152 PMID: Pathogenic PM3, PM2, PVS1, PP4 The NM_000070.3: c.1838del p.(Lys613ArgfsTer49) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 17/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three individuals with features of limb girdle muscular dystrophy (PMID: 16607617, 18055493, ClinVar SCV000953543.3 internal data communication), including confirmed in trans with a pathogenic variant (c.1079G>A p.(Trp360Ter), 1.0 pt, ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy or showed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA489885447/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0010592 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0231856 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0022107 infores:hetionet CHEBI:6935 biolink:causes HP:6000377 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C1112565 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011334 infores:hetionet CHEBI:63621 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019214 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0175167 infores:hetionet CHEBI:6950 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2047937 infores:hetionet CHEBI:63925 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0035305 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0030305 infores:hetionet CHEBI:94411 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0233494 infores:hetionet CHEBI:33130 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0042487 infores:hetionet CHEBI:30830 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0001925 infores:hetionet CHEBI:135285 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0595883 infores:hetionet CHEBI:9671 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0151539 infores:hetionet CHEBI:85161 biolink:causes UMLS:C1959622 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C1959622 infores:hetionet CHEBI:72296 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0236178 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0003123 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0021400 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0009806 infores:hetionet CHEBI:77733 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0013404 infores:hetionet CHEBI:8228 biolink:causes UMLS:C1261989 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C1261989 infores:hetionet NCBIGene:2623 biolink:causes MONDO:0010444 infores:monarchinitiative not_provided not_provided HGNC:4170 MONDO:0010444 uuid:ceb8c26e-8060-4d0c-8cc9-2f9fda8f77fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0549373 infores:hetionet CAID:CA512318588 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318588 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.750T>A (p.Arg250=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). No splicing impact or creation of cryptic splice sites is predicted by SSF and MES, and SpliceAI predicts no impact to splicing (score: 0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.842 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 1530364). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318588/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8764 biolink:causes UMLS:C0852925 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0852925 infores:hetionet CHEBI:6775 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0232726 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0009806 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0034359 infores:hetionet CHEBI:27690 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0013395 infores:hetionet CHEBI:31644 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0030252 infores:hetionet CHEBI:63115 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C3160858 infores:hetionet CHEBI:6754 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0231530 infores:hetionet CAID:CA2838140608 biolink:causes MONDO:0015967 infores:clingen CAID:CA2838140608 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP4, PM1, PS4 The c.-173_-172dup variant in the hepatocyte nuclear factor 4-alpha, HNF4A, is a two base pair duplication in the promoter of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is located within the HNF1A/HNF1B binding domain (c.-170 to c.-173 and c.-178 to c.-181) of the HNF4A P2 promoter region, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1); however, it is unclear if a duplication would have the same effect as a nucleotide change. Therefore, PM1 will not be applied. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, c.-173_-172dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2838140608/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8768 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0012833 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027765 infores:hetionet CHEBI:44185 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0014518 infores:hetionet GO:0098694 biolink:causes GO:0036465 infores:ubergraph knowledge_assertion manual_agent GO:0098694 GO:0036465 CHEBI:61049 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038220 infores:hetionet CAID:CA376065632 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065632 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.97C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 33 (p.His33Tyr).The filtering allele frequency (the upper threshold of the 95% CI of 6/761902 alleles) of the c.97C>T variant in DCLRE1C is 0.000002830 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065632/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50275 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0016204 infores:hetionet CHEBI:2704 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0917801 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0042373 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0233494 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0003123 infores:hetionet CAID:CA386952306 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952306 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3, PP4 PP1 The c.26A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to proline at codon 9 (p.(Gln9Pro)) of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Additionally, this variant is located within a dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID: 36257325, internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025: PM2_Supporting, PM1_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952306/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28177 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0042109 infores:hetionet CHEBI:2666 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0022107 infores:hetionet CHEBI:94385 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0012833 infores:hetionet CAID:CA016208 biolink:causes MONDO:0007947 infores:clingen CAID:CA016208 MONDO:0007947 PMID: Uncertain Significance BP2, BS1 PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, PM5, PM1, PM3, PM4, PS1, PS3, PS2, BP5, BP7, BS3, BS4 The NM_000138 c.59A>G, is a missense variant in FBN1 predicted to cause a substitution of a Tyrosine by a Cysteine at amino acid 20 (p.Tyr20Cys). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome, however, a pathogenic splice variant in FBN1 was also identified in cis in this individual (BP2). The variant segregates with the disease in 4 affected family members, who also carry the pathogenic splice variant in FBN1. The variant in FBN1 has been reported 12 times in ClinVar: 3 times as likely benign, 8 times as uncertain significance and once as likely pathogenic (Variation ID: 161245). This variant has been identified in 37 individuals of European non-Finnish origin (MAF: 0.029%) (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA016208/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9637 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0004093 infores:hetionet CHEBI:9649 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0013404 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0948594 infores:hetionet CHEBI:27504 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0010200 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0000833 infores:hetionet CAID:CA8815258 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815258 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Moderate PM5, PS1 The NM_000152.5:c.1316T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 439 (p.Met439Lys). At least 14 patients have been reported with this variant and features consistent with Pompe disease. This includes 7 patients with documented laboratory values showing deficiency of GAA activity, below the reference range for normal activity in leukocytes (PMIDs: 17092519, 21940687, 23884227, 25388776, 28433475, 30360039), some of whom are also reported to have histological features of Pompe disease in muscle (PMID: 20202878, 30894207), and/or documented features of infantile onset Pompe disease including muscle weakness and cardiomyoapthy (PMID: 33344388) and/or on enzyme replacement therapy (PMID: 30894207, 31193175) (PP4_Moderate). Note that pseudodeficiency variants, (p.Gly576Ser and p.Glu689Lys) were confirmed to be absent in at least one of these cases (PMID 28433475). Of these patients, 7 are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.1798C>T (p.Arg600Cys) (PMID: 20202878; phase unknown, 0.5 points), c.2238G>C (p.Trp746Cys) (PMID: 30894207, confirmed in trans, 1 point) (PMID: 25388776, unknown phase, 0.5 points), c.546G>T (PMID: 28433475, unknown phase, 0.5 points), c.2407_2413del (p.Gln803Ter) (PMID: 23884227, unknown phase, 0.5 points), and c.1579_1580del (p.Arg527GlyfsTer3) (PMID: 30360039, phase unknown, 0.5 points), and c.1225dup (PMID: 29869463; phase unknown, 0.25 points); and one patient is homozygous (PMID: 29124014) (0.5 points). Total 4.25 points (PM3_VeryStrong). Additional patients have been reported who are compound heterozygous for the variant and c.796C>T (p.Pro266Ser) (PMID: 17092519, 29044175, 31850350), c.1225dup (PMID: 29869463), and c.1309C>T (p.Arg437Cys) (PMID: 25388776) but the allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. Additional data was not included due to uncertainty about the nomenclature of the second variant (PMIDs: 20202878, 21940687). The highest population minor allele frequency in gnomAD is 0.00038 (6/15644 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells the variant has <2% normal activity and does not show mature GAA protein on western blot (PMID 19862843) (PM3_Moderate). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 371305, 2 star review status) with 3 submitters classifying the variant as pathogenic and 4 as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications version 2): PM3_VeryStrong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815258/MONDO:0009290/010 2022-06-03 2022-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:80630 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0015967 infores:hetionet CHEBI:8888 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0231530 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0008325 infores:hetionet CHEBI:64355 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0002874 infores:hetionet CHEBI:9737 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0015230 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0009938 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0234215 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0002792 infores:hetionet CAID:CA512318845 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318845 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.300C>G (p.Ser100=) is a synonymous variant. In summary, this variant meets the criteria to be classified as likely benign. Therefore, a REVEL score is not calculable. SpliceAI prediction suggests Acceptor loss 0, Donor loss 0, Acceptor gain 0, Donor gain 0. Therefore, there appears to be no effect on splicing (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.302402 < 2.0)(BP7 ). This variant is completely absent from all population databases with at least 20x coverage for RUNX1(PM2_supporting). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318845/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3013 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0687133 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0948089 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003709 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0001818 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0013595 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0009806 infores:hetionet CHEBI:5165 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C2364111 infores:hetionet NCBIGene:7480 biolink:causes MONDO:0009157 infores:monarchinitiative not_provided not_provided HGNC:12775 MONDO:0009157 uuid:07ac24d1-653a-4c5b-bf92-21eb17a070ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0575081 infores:hetionet CHEBI:49960 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0011071 infores:hetionet CHEBI:75984 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0013404 infores:hetionet CHEBI:17347 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0027497 infores:hetionet CHEBI:3441 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235439 infores:hetionet CHEBI:7492 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0013378 infores:hetionet CHEBI:4753 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0677500 infores:hetionet CHEBI:4784 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0917801 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0853662 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0853662 infores:hetionet CAID:CA023765 biolink:causes MONDO:0007750 infores:clingen CAID:CA023765 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PM5_Strong, PP1_Strong, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS1, PS2, BP7, BP5, BS4, BS1, BS3, PM1, PM4, PM3, PM6, PVS1, BS2, PP2, PP3 The NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM5_Strong, PM2, PS3_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis.PP1_strong - variant segregates with phenotype in over 30 informative meiosis in several families from different laboratories.PM5_strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is met.PM2 - PopMax MAF = 0.00007740 (0.008%) in european non-finnish exomes (gnomAD v2.1.1).PS3_moderate - Level 2 assay: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) ---- Overall LDLR activity is below 70% of wild-type activity, so PS3_moderate is Met.PP4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023765/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:472657 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0015230 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014118 infores:hetionet CHEBI:32293 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0004093 infores:hetionet CHEBI:119915 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011168 infores:hetionet CAID:CA350459 biolink:causes MONDO:0700270 infores:clingen CAID:CA350459 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1 PM2 The c.6404_6405insTT (p.Arg2136*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 8 individuals with Ataxia-Telangiectasia (PMIDs: 8659541, 9463314, 21665257). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001357 (16/1178720 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA350459/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports UNII:7662KG2R6K biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0234215 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0857353 infores:hetionet CHEBI:5165 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0003578 infores:hetionet CHEBI:8028 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0041657 infores:hetionet CHEBI:50381 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0030193 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0025061 infores:hetionet CHEBI:6717 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0036974 infores:hetionet CHEBI:9943 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2830004 infores:hetionet CHEBI:10101 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0236075 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0566951 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0566951 infores:hetionet CHEBI:125354 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0000731 infores:hetionet NCBIGene:2324 biolink:causes MONDO:0032913 infores:monarchinitiative not_provided not_provided HGNC:3767 MONDO:0032913 uuid:3315973d-7823-4c54-9418-6ee33e005fdf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018520 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0427008 infores:hetionet GO:2000290 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:2000290 GO:0061053 CHEBI:35778 biolink:causes UMLS:C0542237 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0542237 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0235398 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0235398 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042514 infores:hetionet CHEBI:49040 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151786 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021895 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0039496 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023211 infores:hetionet CHEBI:168396 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C2830004 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0007193 infores:hetionet CHEBI:6950 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0015672 infores:hetionet CHEBI:84500 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0026858 infores:hetionet CHEBI:16664 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0015967 infores:hetionet CHEBI:2208 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0015967 infores:hetionet CAID:CA164768 biolink:causes MONDO:0007648 infores:clingen CAID:CA164768 MONDO:0007648 PMID:18788075PMID:20373070PMID:11968084PMID:26182300 Pathogenic PP1_Moderate, PM5_Supporting, PM2_Supporting, PS4_Moderate, PVS1_Strong BP7, BP5, BS1, BS4, BS3, PM4, PM3, PM1, PM6, BS2, PP2, PP3, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS2, PS3 The c.1565+1G>T variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 26182300, 11968084). The variant was also found to co-segregate with disease in at least two families, with 6 meioses observed (PP1_Moderate; internal laboratory contributors). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Moderate and PP1_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA164768/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:4995 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0008031 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0151511 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151511 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0233494 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0850569 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0850569 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002878 infores:hetionet CHEBI:231594 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0015230 infores:hetionet CHEBI:47519 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0015967 infores:hetionet CHEBI:7824 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013390 infores:hetionet CAID:CA10584703 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584703 MONDO:0007750 PMID: Uncertain Significance PS3_Moderate, PM2 PS4, BP7 The NM_000527.4(LDLR):c.-140C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2_Met : This variant is absent from gnomAD (v2.1.1).PS3_Mderate : Level 3 assay: PMID:21538688, Hep G2 cell, luciferase reporter gene assay. HepG2 transfection experiments resulted in a residual LDLR transcriptional activity of 7%. The authors also performed electrophoresis mobility shift assays (EMSA), with reference to De Castro et al., 2011; PMID 20884100), which assess if a variant alters promoter protein binding properties (rather unspecifically, however). Although, no mention of any validation control or number of repeats in publication source is available, this variant showed a 25% reduction band intensity compared to WT (i.e. some degree of altered binding properties). These results were confirmed by Kircher M et al (PMID: 31395865). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584703/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:64064 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0086543 infores:hetionet CHEBI:42944 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0338656 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151626 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151717 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0521509 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0037199 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234913 infores:hetionet CHEBI:3176 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0022575 infores:hetionet CHEBI:52717 biolink:causes UMLS:C2945586 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2945586 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0152227 infores:hetionet CHEBI:8874 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003537 infores:hetionet CHEBI:87681 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0344232 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009946 infores:hetionet CHEBI:17347 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151905 infores:hetionet CHEBI:68575 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0085649 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018939 infores:hetionet CHEBI:2682 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002994 infores:hetionet CHEBI:45285 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C1443060 infores:hetionet NCBIGene:25930 biolink:causes MONDO:0030046 infores:monarchinitiative not_provided not_provided HGNC:14406 MONDO:0030046 uuid:b84dddb5-4004-4d1a-bca7-a866604d5382 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011175 infores:hetionet CHEBI:46195 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151723 infores:hetionet CHEBI:2618 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0033774 infores:hetionet NCBIGene:1145 biolink:causes MONDO:0011600 infores:monarchinitiative not_provided not_provided HGNC:1966 MONDO:0011600 uuid:8192b60e-6996-4a23-84eb-d71a37d0fc46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0242151 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002311 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0154833 infores:hetionet CAID:CA8338296 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338296 MONDO:0008723 PMID: Likely Benign BP4, PM2, BP7 The c.1839G>A p.(Arg613=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100way (conservation score: 0.95) (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.008134 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting; however, this is not considered conflicting evidence with BP4 and BP7. To our knowledge, this variant has not been reported in the literature in any individuals with autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338296/MONDO:0008723/021 2025-04-22 2025-04-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9086 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0005818 infores:hetionet CHEBI:2567 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0151692 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151849 infores:hetionet CHEBI:8772 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0013922 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0042769 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042373 infores:hetionet CHEBI:46295 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0015230 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013395 infores:hetionet CHEBI:8081 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0221776 infores:hetionet CHEBI:102216 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0039231 infores:hetionet CHEBI:2704 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0014742 infores:hetionet CHEBI:52717 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003467 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020649 infores:hetionet NCBIGene:8722 biolink:causes MONDO:0014147 infores:monarchinitiative not_provided not_provided HGNC:2531 MONDO:0014147 uuid:bb7a0602-e991-465b-8b64-e6a0929aebf7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0041912 infores:hetionet CHEBI:50777 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1305875 infores:hetionet CHEBI:4657 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0039070 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034068 infores:hetionet CHEBI:73274 biolink:causes HP:0002719 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0239998 infores:hetionet CHEBI:7514 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0000729 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020649 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002418 infores:hetionet CHEBI:64310 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085610 infores:hetionet CHEBI:7496 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0011991 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0687133 infores:hetionet CAID:CA1139667435 biolink:causes MONDO:0100437 infores:clingen CAID:CA1139667435 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1926dup (p.Ser643IlefsTer10) is a frameshift variant due to a 1-nucleotide duplication that introduces a premature stop codon after 10 amino acids in exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.0.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 19893586). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) including relatively mildly affected females (1 pt), early onset (1 pt), reduced visual acuity (0.5 pts), visual field constriction (0.5 pts), optic nerve pallor (0.5 pts), and myopia (0.5 pts), which together are specific for RPGR-related retinopathy (6 points, PMID: 19893586, PMID: 10970770, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1_Moderate, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139667435/MONDO:0100437/106 2025-08-04 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:42797 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0025209 infores:hetionet CHEBI:94501 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151905 infores:hetionet CHEBI:3757 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0023218 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0026636 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024299 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0857093 infores:hetionet CHEBI:17650 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0031256 infores:hetionet CHEBI:8356 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0002064 infores:hetionet CHEBI:63599 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C2047937 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042075 infores:hetionet CHEBI:10124 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0003862 infores:hetionet CHEBI:7959 biolink:causes HP:0100678 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0037301 infores:hetionet GO:1905310 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0007507 CHEBI:6754 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C3665347 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0017178 infores:hetionet CHEBI:8871 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0278106 infores:hetionet CAID:CA8622961 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622961 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong PM5, PS3 The NM_000419.5:c.448A>G variant in ITGB3 is a missense variant predicted to cause substitution of methionine by valine at amino acid 150 (p.Met150Val). This variant has been detected in at least 3 probands with Glanzmann thrombasthenia. Two of these individuals were compound heterozygous for this variant and a pathogenic variant and one of those was confirmed to carry the variants in trans by parental testing (c.774_775del (phase not confirmed) and p.Asp145Tyr (phase confirmed)). An additional proband was reported to be homozygous for the variant (personal communication with Dr. Jose Rivera (Servicio de Hematologıa y Oncologıa Medica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacion, Universidad de Murcia)) (PM3_Strong). At least one patient (Patient GT-1, PMID: 25539746) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, αIIbβ3 surface expression was reduced to <25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91082 alleles) in the South Asian population, which is lower than the ClinGen Platelet Disorders VCEP threshold (<0.0001; PM2_Supporting). Furthermore, the computational predictor REVEL gives a score of 0.968, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3_Strong, PP3, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622961/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UMLS:C1738934 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0000731 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0086543 infores:hetionet NCBIGene:716 biolink:causes MONDO:0013419 infores:monarchinitiative not_provided not_provided HGNC:1247 MONDO:0013419 uuid:e682e89e-3445-4394-ac45-6f817fd3f6d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0048334 biolink:causes GO:0001710 infores:ubergraph knowledge_assertion manual_agent GO:0048334 GO:0001710 CHEBI:64045 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0037274 infores:hetionet CHEBI:64045 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0042963 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0236071 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0025061 infores:hetionet CHEBI:75998 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0018932 infores:hetionet CHEBI:63577 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0702166 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0855223 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0033975 infores:hetionet CHEBI:3127 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0002994 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0015397 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0162429 infores:hetionet GO:1902829 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:1902829 GO:0007417 CHEBI:94449 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0017160 infores:hetionet CHEBI:64354 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020621 infores:hetionet CHEBI:45409 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015967 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027424 infores:hetionet CHEBI:3568 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0024141 infores:hetionet CHEBI:3213 biolink:causes MONDO:0006757 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0005398 infores:hetionet NCBIGene:149041 biolink:causes MONDO:0033557 infores:monarchinitiative not_provided not_provided HGNC:29434 MONDO:0033557 uuid:cc045887-0345-4975-bd6b-185f3dd13bb9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013384 infores:hetionet CHEBI:31397 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0015230 infores:hetionet CHEBI:3723 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011253 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151626 infores:hetionet CHEBI:7447 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0151773 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0549475 infores:hetionet CHEBI:161680 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0027424 infores:hetionet CHEBI:32315 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0015967 infores:hetionet CHEBI:3749 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0011991 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C1956346 infores:hetionet CHEBI:63599 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0020580 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1735646 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1735646 infores:hetionet CHEBI:8356 biolink:causes HP:0007378 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017185 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015230 infores:hetionet CHEBI:63598 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002390 infores:hetionet CHEBI:50729 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151904 infores:hetionet CAID:CA7511203 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511203 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000070.3: c.967G>T p.(Glu323Ter) variant in CAPN3, which is also known as p.(Glu323del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in trans with a likely pathogenic or pathogenic variant in an individual with limb girdle muscular dystrophy (c.146G>A p.(Arg49His), 1.0 pt, PMID: 17318636) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 17318636; PP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008802 (1/113610 exome alleles) in the European (non-Finnish) population, which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511203/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029118 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0549493 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0027051 infores:hetionet CHEBI:3561 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0547030 infores:hetionet GO:1900157 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:1900157 GO:0001501 CHEBI:47898 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0021053 infores:hetionet NCBIGene:84572 biolink:causes MONDO:0009652 infores:monarchinitiative not_provided not_provided HGNC:23026 MONDO:0009652 uuid:e0e0806d-455a-437a-82ed-f9d873242394 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512319137 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319137 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.510G>T (p.Gly170=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-0.45) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319137/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8228 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0151744 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0267596 infores:hetionet CHEBI:27958 biolink:causes MONDO:0004456 infores:ubergraph knowledge_assertion manual_agent CHEBI:27958 MONDO:0004456 CHEBI:135342 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0233632 infores:hetionet CHEBI:7865 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0042571 infores:hetionet CHEBI:9316 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C1443060 infores:hetionet CAID:CA286497 biolink:causes MONDO:0009861 infores:clingen CAID:CA286497 MONDO:0009861 PMID:23430918PMID:24368688PMID:24368688 Pathogenic PM2, PP3, PP4, PM3_Very Strong PM5, PM1 The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID: 24368688, 17502162, 3430918). This variant has an extremely low allele frequency (MAF=0.00008) in gnomAD. It was detected with multiple pathogenic variants: p.R408W (in trans, PMID: 24368688); c.1045T>C, c.194T>C (PMID: 17502162); p.F39del, c.47_48delCT (aka c.43_44CT), c.1066-11G>A (PMID: 23430918); p.E280K, p.L348V, p.Y414C (PMID: 31623983). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286497/MONDO:0009861/006 2020-06-05 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:59582 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0011603 infores:hetionet CHEBI:8890 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0438215 infores:hetionet CHEBI:31859 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C2047937 infores:hetionet CHEBI:44915 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0085633 infores:hetionet CHEBI:3752 biolink:causes HP:0001883 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1301937 infores:hetionet UMLS:C0657912 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151825 infores:hetionet CHEBI:10110 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0001122 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0014175 infores:hetionet CHEBI:63791 biolink:causes MONDO:0043994 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149520 infores:hetionet CHEBI:47426 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0740394 infores:hetionet NCBIGene:6774 biolink:causes MONDO:0007818 infores:monarchinitiative not_provided not_provided HGNC:11364 MONDO:0007818 uuid:cbdc41c4-d0d3-482c-99db-5e5ccd14e4cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6078 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0000731 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0033975 infores:hetionet CHEBI:5864 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085615 infores:hetionet NCBIGene:5832 biolink:causes MONDO:0009053 infores:monarchinitiative not_provided not_provided HGNC:9722 MONDO:0009053 uuid:0d1a5173-847f-451d-bc4c-60509c5eabfb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63623 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0595929 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030305 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0009676 infores:hetionet CHEBI:50173 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0023218 infores:hetionet CHEBI:209807 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0242528 infores:hetionet CHEBI:8028 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020505 infores:hetionet CHEBI:38940 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0003811 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0031212 infores:hetionet CHEBI:45924 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0017178 infores:hetionet CHEBI:47499 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C2830004 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151571 infores:hetionet CHEBI:63621 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0025222 infores:hetionet CHEBI:42797 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019825 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0011570 infores:hetionet CHEBI:7476 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151529 infores:hetionet CHEBI:45783 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0549622 infores:hetionet CHEBI:2659 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0018834 infores:hetionet CHEBI:45081 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0002792 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0542351 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0542351 infores:hetionet CHEBI:42797 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0008031 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151717 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027726 infores:hetionet CHEBI:45783 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0013378 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0016436 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0002418 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007177 infores:hetionet CHEBI:3127 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0236075 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004936 infores:hetionet NCBIGene:1292 biolink:causes MONDO:0958235 infores:monarchinitiative not_provided not_provided HGNC:2212 MONDO:0958235 uuid:73668f55-a632-478f-9264-69f06a9aaadf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226547 biolink:causes MONDO:0100368 infores:clingen CAID:CA226547 MONDO:0100368 PMID:16150724 Benign BS3_Supporting, BA1 BP4 NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant exhibited 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (PMID: 16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226547/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA147766 biolink:causes MONDO:0015152 infores:clingen CAID:CA147766 MONDO:0015152 PMID: Benign BA1 PM3, BP4 The NM_003494.4: c.509C>A variant in DYSF, which is also known as NM_001130987.2: c.605C>A p.(Ala202Glu), is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 170 (p.Ala170Glu). The filtering allele frequency of the variant is 0.01467 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 2546/251252), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been identified in individuals with LGMD (e.g., PMID: 16010686, 25135358), its frequency in control populations is high relative to disease prevalence, and additional potentially causative variants were either identified as well or their presence not comprehensively ruled out (PM3 not met). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.22, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147766/MONDO:0015152/180 2025-01-08 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:40050 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C1262113 infores:hetionet CHEBI:77260 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0740394 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1443060 infores:hetionet CHEBI:107736 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0393593 infores:hetionet CHEBI:10650 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0040053 infores:hetionet CHEBI:8707 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0010520 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0018802 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0035455 infores:hetionet CHEBI:231594 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0014742 infores:hetionet GO:0003427 biolink:causes GO:0048705 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0048705 CHEBI:50659 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0002792 infores:hetionet CHEBI:45409 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0242184 infores:hetionet CHEBI:49713 biolink:causes MONDO:0001658 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0221777 infores:hetionet CAID:CA254844 biolink:causes MONDO:0044970 infores:clingen CAID:CA254844 MONDO:0044970 PMID:11171912PMID:11335700 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP1, PS2, PS4, BS4, PM6 The m.4332G>A variant in MT-TQ has been reported in one individual from one family to date (PMID: 11171912), in a man with an atypical presentation of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This individual had hearing loss beginning in his 20s and a stroke-like episode in his 40s. Muscle biopsy showed ragged red fibers and COX-deficient fibers, along with decreased activity of respiratory chain complex IV. The variant was present at 81% in muscle and undetectable in fibroblasts and skin. While the variant was absent in blood from his mother and brother, it was also undetectable in the proband’s blood, therefore it is unclear if this was a de novo variant. There are no large families reported in the medical literature to consider for evidence of segregation. Of note, there is another individual reported with MELAS and this variant, however insufficient clinical details were provided to include this case for consideration for this variant curation (PMID: 20064630). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (81st percentile) as does HmtVar with a score of 0.7 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (mean 99.3% and ranging from 98.8-99.7%, n=13) than in COX-positive fibers (mean 70.5% and ranging from 46.5-94.5%, n=11; p=0.002; PMID: 11335700; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254844/MONDO:0044970/015 2023-01-23 2023-03-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63631 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151907 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0687707 infores:hetionet GO:1902366 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:1902366 GO:0061053 CHEBI:135939 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0234215 infores:hetionet CAID:CA1139666849 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666849 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.351+4C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.53) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666849/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:G4PX8C4HKV biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020443 infores:hetionet CHEBI:31644 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151908 infores:hetionet NCBIGene:134218 biolink:causes MONDO:0014887 infores:monarchinitiative not_provided not_provided HGNC:27030 MONDO:0014887 uuid:c5f7c885-5be9-465e-9db4-3c057976e37e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019348 infores:hetionet CHEBI:63613 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0302809 infores:hetionet CHEBI:9352 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0011603 infores:hetionet CHEBI:5784 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0085631 infores:hetionet CHEBI:9352 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0025290 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0242350 infores:hetionet CHEBI:64312 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0080274 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C1390484 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1390484 infores:hetionet CAID:CA347223040 biolink:causes MONDO:0015152 infores:clingen CAID:CA347223040 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting PP1 The NM_003494.4: c.5503A>G variant in DYSF, which is also known as NM_001130987.2: c.5620A>G p.(Met1874Val), is a missense variant predicted to cause substitution of methionine by valine at amino acid 1835, p.(Met1835Val). This variant is also predicted to disrupt the splice donor site of exon 49 and strengthen an alternative donor site (SpliceAI score of 0.73 and 0.86, respectively). RNAseq analysis has demonstrated use of the cryptic splice site that results in the deletion of 23 bp of exon 49, leading to a frameshift and premature truncation, p.Met1835LeufsTer6, with nonsense mediated decay expected (PMID: 36983702; PVS1_RNA). This variant has been reported in at least two individuals with features consistent with LGMD (PMID: 30564623, 36983702, 32528171; LOVD Individuals #00314263, #00222598), including in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.1639-6T>A, 0.5 pts, PMID: 30564623, 36983702; LOVD Individual #00222598) (PM3_Supporting). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). The same two DYSF variants were identified in one affected family member, but phase was not determined (PMID: 36983702; PP1 not met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/10/2025): PVS1_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347223040/MONDO:0015152/180 2025-06-10 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes HP:0041153 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0159877 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151763 infores:hetionet CHEBI:31981 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0013604 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0947999 infores:hetionet CHEBI:61033 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0009676 infores:hetionet NCBIGene:5782 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:9645 MONDO:0005575 uuid:6f15eb64-fcd0-416f-b75d-799354607139 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0020458 infores:hetionet CHEBI:209807 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0022660 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0497365 infores:hetionet CAID:CA355961899 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961899 MONDO:0001586 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PM2_Supporting The NM_000203.5(IDUA):c.603C>G (p.Tyr201Ter) is a nonsense variant predicted to cause a premature stop codon in exon 6 out of a total of 14 exons, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been detected in at least four probands with MPS I. Of these individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.46_57del (ClinVar Variation ID: 92643) (PMID: 21394825, 33072983, 1 patient 1 x 0.5 points, phase unknown). Two individuals were homozygous for the variant (max 2 x 0.5). (Total 1.5 points, PM3_Moderate). Another patient was compound heterozygous for the variant and c.-14_10del (PMID: 21394825). The allelic data from this patient will be used in the classification of c.-14_10del and is not included here to avoid circular logic. Of these patients, MPS I was confirmed in one newborn female with very low enzyme activity in leucocytes, high excretion of urine heparan sulphate and dermatan sulphate (DS) and clinical features of a severe Hurler phenotype (PMID: 33072983, 33147872, PMID: 32432561), Another patient, a 2.5 year old female of Italian origin had clinical features of a severe form of the disease at 15 days of age, and elevated urinary GAGs (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1 is 0.000000848 (1/1,179,052 alleles) in the European (non-Finnish) population; this is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disease Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4_Moderate, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 7, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961899/MONDO:0001586/091 2025-07-07 2025-07-17 Autosomal recessive inheritance HP:0000007 Supports GO:2000039 biolink:causes GO:0090558 infores:ubergraph knowledge_assertion manual_agent GO:2000039 GO:0090558 NCBIGene:64446 biolink:causes MONDO:0012906 infores:monarchinitiative not_provided not_provided HGNC:18744 MONDO:0012906 uuid:a324944f-3907-4028-947d-f6dae41fb1fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011991 infores:hetionet CAID:CA412731265 biolink:causes MONDO:0100437 infores:clingen CAID:CA412731265 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting PM4, PM5, PS1, BA1, BP3, BP7, BS1 NM_001034853.2(RPGR):c.2176G>T (p.Glu726Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 726 within exon 15 of 15, which disrupts a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 21857984, PMID: 17325176, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412731265/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:48538 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0948594 infores:hetionet CHEBI:7852 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235086 infores:hetionet CHEBI:231594 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0232461 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0021359 infores:hetionet CHEBI:5613 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0021141 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042571 infores:hetionet NCBIGene:2070 biolink:causes MONDO:0011031 infores:monarchinitiative not_provided not_provided HGNC:3522 MONDO:0011031 uuid:db713fe8-2d77-490f-adb5-38ee0acfbd7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0008489 infores:hetionet CHEBI:9445 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0039231 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1269683 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0278080 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0027813 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0857256 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0857256 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0039971 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0863113 infores:hetionet CHEBI:116278 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C2830004 infores:hetionet CHEBI:45863 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030193 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0233494 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011551 infores:hetionet CHEBI:9763 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0014742 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0392197 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0234215 infores:hetionet CHEBI:63618 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0040822 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0595877 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0011616 infores:hetionet CHEBI:50131 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0003962 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0235750 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0236075 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011334 infores:hetionet CHEBI:3508 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0002994 infores:hetionet GO:0046849 biolink:causes MONDO:0005382 infores:drugmechdb knowledge_assertion manual_agent GO:0046849 MESH:D010001 DB01133_MESH_D010001_1 NCBIGene:54967 biolink:causes MONDO:0957202 infores:monarchinitiative not_provided not_provided HGNC:26047 MONDO:0957202 uuid:780c2f20-1886-4817-9a1d-9c5a3f113c89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0162429 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1269955 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1269955 infores:hetionet CHEBI:31859 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0017178 infores:hetionet CHEBI:4856 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0002994 infores:hetionet GO:0060141 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0060141 GO:0009653 GO:0003420 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0007275 CHEBI:10125 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0340865 infores:hetionet CHEBI:7865 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0004144 infores:hetionet CHEBI:94609 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0030554 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0152027 infores:hetionet CHEBI:52717 biolink:causes MONDO:0018689 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023484 infores:hetionet CAID:CA2739267607 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267607 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1014_1033del (p.Leu339ProfsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267607/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72564 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0034530 infores:hetionet CHEBI:70735 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0700225 infores:hetionet CHEBI:125354 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0030554 infores:hetionet CHEBI:17303 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0340865 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042267 infores:hetionet CHEBI:41774 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042133 infores:hetionet NCBITaxon:92251 biolink:causes MONDO:0005998 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:92251 MONDO:0005998 UMLS:C0065374 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0010828 infores:hetionet CHEBI:9907 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C2047937 infores:hetionet CHEBI:4735 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0015967 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020569 infores:hetionet CHEBI:4710 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152115 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0007097 infores:hetionet CHEBI:8776 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0427086 infores:hetionet CHEBI:94609 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0008031 infores:hetionet CAID:CA658683954 biolink:causes MONDO:0007648 infores:clingen CAID:CA658683954 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1443del (p.Asn481fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683954/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:74947 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0521465 infores:hetionet GO:0061100 biolink:causes CL:1000223 infores:ubergraph knowledge_assertion manual_agent GO:0061100 CL:1000223 UNII:R43D2573WO biolink:causes MONDO:0043786 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0036749 infores:hetionet CHEBI:490877 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0162835 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0018802 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0233632 infores:hetionet CHEBI:53760 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0034880 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0007222 infores:hetionet CHEBI:36791 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151825 infores:hetionet CHEBI:64064 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0030232 infores:hetionet CHEBI:9667 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0019572 infores:hetionet CAID:CA410146727 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146727 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1409C>G (p.Ala470Gly) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. This missense variant has a REVEL score <0.5 (0.043)(BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146727/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017601 infores:hetionet CHEBI:7936 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013447 infores:hetionet GO:2001009 biolink:causes GO:0009664 infores:ubergraph knowledge_assertion manual_agent GO:2001009 GO:0009664 CAID:CA16020922 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020922 MONDO:0009861 PMID:23932990 Likely Pathogenic PM5, PM2, PP4_Moderate, PP3 The c.1043T>C (p.Leu348Pro) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded) (PMID: 23932990) This variant is absent from population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.981. Another missense change at the same amino acid is pathogenic: p.Leu348Val Pathogenic by 7 submitters. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020922/MONDO:0009861/006 2020-03-16 2020-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2830004 infores:hetionet CHEBI:10110 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0020453 infores:hetionet CHEBI:64312 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0549249 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0243026 infores:hetionet CHEBI:5384 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0026826 infores:hetionet CHEBI:5130 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0232461 infores:hetionet CHEBI:63617 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0016204 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002884 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0948594 infores:hetionet CHEBI:17347 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0152032 infores:hetionet CHEBI:3219 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006142 infores:hetionet UMLS:C0657912 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011124 infores:hetionet CHEBI:63610 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0017979 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0595861 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0595861 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0740281 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0740281 infores:hetionet CHEBI:63584 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0231528 infores:hetionet NCBIGene:1173 biolink:causes MONDO:0032823 infores:monarchinitiative not_provided not_provided HGNC:564 MONDO:0032823 uuid:d8b957e4-ebae-42ee-9686-0e2fcf45a219 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64045 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0085631 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0010399 infores:hetionet NCBIGene:6913 biolink:causes MONDO:0009845 infores:monarchinitiative not_provided not_provided HGNC:11594 MONDO:0009845 uuid:a5460efe-a5e4-49af-8ac6-a3d0416c4744 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0019080 infores:hetionet CHEBI:75988 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0011991 infores:hetionet CHEBI:63621 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020453 infores:hetionet CHEBI:10100 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0004604 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013595 infores:hetionet CHEBI:5118 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0234022 infores:hetionet CHEBI:4974 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0232487 infores:hetionet GO:1905082 biolink:causes GO:0140053 infores:ubergraph knowledge_assertion manual_agent GO:1905082 GO:0140053 CHEBI:31711 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0030196 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0852733 infores:hetionet CHEBI:6149 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0004093 infores:hetionet CAID:CA294895065 biolink:causes MONDO:0009290 infores:clingen CAID:CA294895065 MONDO:0009290 PMID:21179066 Uncertain Significance PM2_Supporting, PM3_Supporting, PVS1_Moderate PP3, PP4, PS3 The NM_000152.5:c.1626C>G variant is a synonymous (silent) variant in exon 11 of GAA (p.Pro542=). A minigene assay demonstrated that the variant impacts splicing by creating a de novo donor site in exon 11 as well as activating a cryptic acceptor site in exon 12. This results in the deletion of 11 nucleotides from exon 11 and 46 nucleotides from exon 12. A low level of normal transcript was also detected (PMID 21179066). PVS1_moderate was applied because the resulting deletion is predicted to be in frame (57 nucleotides, 29 amino acids deleted; none of which have been designated by the Lysosomal Diseases VCEP as critical residues). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00000254 (3/1179982 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The variant was found homozygous in one patient with late-onset Pompe disease (PM3_supporting); there was insufficient evidence to apply PP4 (PMID 16917947). There is a ClinVar entry for this variant (Variation ID: 430167). In summary, this variant currently meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 26, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294895065/MONDO:0009290/010 2025-06-26 2025-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:42820 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0011603 infores:hetionet CHEBI:47780 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018681 infores:hetionet CAID:CA367399681 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399681 MONDO:0015967 PMID: Pathogenic PS4, PP4_Moderate, PVS1, PM2_Supporting PS1 The c.1019+1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). The nucleotide change c.1019+1G>A was identified in 9 unrelated individuals with hyperglycemia (PS4; PMIDs: 15928245, 28726111, 32533152, 28012402, 36257325, internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). The c.1019+1G>T variant at the same canonical nucleotide and has a similar predicted impact by Splice AI (.96 and .96), but PS1_Supporting cannot be applied because the c.1019+1G>T variant is only likely pathogenic before incorporating information about the G>A variant. In summary, c.1019+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399681/MONDO:0015967/086 2023-11-24 2023-11-24 Semidominant inheritance HP:0032113 Supports CHEBI:27974 biolink:causes UMLS:C0235649 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0235649 infores:hetionet CHEBI:50648 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085633 infores:hetionet CHEBI:49375 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085641 infores:hetionet CHEBI:17303 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0234238 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0022660 infores:hetionet CHEBI:10127 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020621 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002871 infores:hetionet NCBIGene:1353 biolink:causes MONDO:0859520 infores:monarchinitiative not_provided not_provided HGNC:2261 MONDO:0859520 uuid:dd89a400-c986-4e28-9ada-4c1d2972ceb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5123 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0392156 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0243026 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1443060 infores:hetionet CHEBI:87681 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0041657 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0029456 infores:hetionet CHEBI:31932 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0014457 infores:hetionet CHEBI:2904 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0701811 infores:hetionet CHEBI:41423 biolink:causes EFO:0009618 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0272774 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007222 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0011609 infores:hetionet NCBIGene:6654 biolink:causes MONDO:0007609 infores:monarchinitiative not_provided not_provided HGNC:11187 MONDO:0007609 uuid:19732f18-9ae8-4a89-b935-794d119b1390 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0006954 biolink:causes MONDO:0011429 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D001171 DB00051_MESH_D001171_1DB00005_MESH_D001171_1 CHEBI:77260 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0004604 infores:hetionet CHEBI:31711 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151205 infores:hetionet CHEBI:144551 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0002994 infores:hetionet CHEBI:480999 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0231528 infores:hetionet CHEBI:4710 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004604 infores:hetionet CHEBI:47780 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0344232 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0020517 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0231441 infores:hetionet CHEBI:55346 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0085649 infores:hetionet CHEBI:63617 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013604 infores:hetionet CHEBI:194135 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020580 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0438254 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0438254 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0042514 infores:hetionet CHEBI:7494 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011603 infores:hetionet CHEBI:41977 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1262013 infores:hetionet CHEBI:107736 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0268000 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038663 infores:hetionet CHEBI:10124 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0030252 infores:hetionet CHEBI:42797 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0699744 infores:hetionet CHEBI:50861 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0016382 infores:hetionet CHEBI:6950 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0152031 infores:hetionet CHEBI:6121 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0010692 infores:hetionet NCBIGene:58495 biolink:causes MONDO:0007378 infores:monarchinitiative not_provided not_provided HGNC:15804 MONDO:0007378 uuid:a22c7c9e-b8a0-43cd-9664-64722f72da2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0038362 infores:hetionet CHEBI:7577 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0038990 infores:hetionet CHEBI:10125 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003862 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085606 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0041912 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0027051 infores:hetionet CHEBI:6367 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0015967 infores:hetionet NCBIGene:1186 biolink:causes MONDO:0012676 infores:monarchinitiative not_provided not_provided HGNC:2025 MONDO:0012676 uuid:a91cced4-6a96-4f8d-9784-be25be5e8359 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1902746 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:1902746 GO:0043010 CHEBI:51450 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C1145670 infores:hetionet CAID:CA410206870 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206870 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.700A>G (p.Thr234Ala) is a missene variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206870/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6128 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0009319 infores:hetionet CHEBI:63617 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0025874 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0021053 infores:hetionet CAID:CA2697547496 biolink:causes MONDO:0100083 infores:clingen CAID:CA2697547496 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, BP1, BP3, BP2, BA1, PVS1, BP5, BS1, BS3, PM5, PM4, PM1, PM3, PP2, PP3, PP4 NM_001754.5(RUNX1):c.97+10A>C is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant has a SpliceAI ∆ score ≤ 0.20 and PhyloP score <2.0 (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547496/MONDO:0100083/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033774 infores:hetionet CHEBI:16755 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0015230 infores:hetionet CHEBI:10124 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0003811 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0233632 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040425 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002922 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0034212 infores:hetionet CHEBI:31413 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0233471 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023533 infores:hetionet CHEBI:71255 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0013404 infores:hetionet NCBIGene:23607 biolink:causes MONDO:0011917 infores:monarchinitiative not_provided not_provided HGNC:14258 MONDO:0011917 uuid:20624e95-5237-4911-9e68-9fc1abbf76c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0043094 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018939 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005111 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0149678 infores:hetionet CHEBI:3380 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0042963 infores:hetionet CAID:CA376063520 biolink:causes MONDO:0011225 infores:clingen CAID:CA376063520 MONDO:0011225 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_001033855.3:c.180C>A (p.Tyr60Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The highest population minor allele frequency in gnomAD v4 is 0.000001313 (1/761794 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376063520/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63618 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0019158 infores:hetionet CHEBI:61049 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019270 infores:hetionet CHEBI:68478 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020546 infores:hetionet CHEBI:7936 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085611 infores:hetionet CHEBI:48947 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0038325 infores:hetionet CHEBI:82960 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1280433 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002170 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0178298 infores:hetionet CHEBI:5383 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C1306341 infores:hetionet CHEBI:6129 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0234708 infores:hetionet UMLS:C0657912 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003578 infores:hetionet CHEBI:4495 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0012833 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0019158 infores:hetionet CHEBI:2208 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0004509 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0948429 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0948429 infores:hetionet CHEBI:478164 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0038325 infores:hetionet CHEBI:5280 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009676 infores:hetionet CHEBI:9605 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0428977 infores:hetionet CHEBI:7640 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0080274 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0149836 infores:hetionet CHEBI:104011 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0002994 infores:hetionet CHEBI:46557 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0043094 infores:hetionet CHEBI:4995 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0043094 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0004936 infores:hetionet CHEBI:4672 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C3495920 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0948586 infores:hetionet CHEBI:78543 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0043352 infores:hetionet NCBIGene:10297 biolink:causes MONDO:0014951 infores:monarchinitiative not_provided not_provided HGNC:24036 MONDO:0014951 uuid:567b0de1-465f-4c69-bbbc-bde8cab5b452 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:57538 biolink:causes MONDO:0054838 infores:monarchinitiative not_provided not_provided HGNC:17574 MONDO:0054838 uuid:dbb6f264-3082-4d62-83a7-e66815a862c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018944 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0677500 infores:hetionet CHEBI:3387 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0520966 infores:hetionet CHEBI:6062 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0025222 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0038454 infores:hetionet CHEBI:7640 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2363730 infores:hetionet CHEBI:47381 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0302809 infores:hetionet CHEBI:50223 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1384353 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0031117 infores:hetionet CHEBI:100241 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0497156 infores:hetionet CHEBI:31236 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0917801 infores:hetionet CHEBI:10100 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0022346 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030552 infores:hetionet CAID:CA346581171 biolink:causes MONDO:0021060 infores:clingen CAID:CA346581171 MONDO:0021060 PMID: Likely Pathogenic PS4_Supporting, PM2_Supporting, PP2, PS2 The c.166G>C (p.Ala56Pro) variant in PPP1CB is a missense variant predicted to cause substitution of alanine by proline at amino acid 56. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.463, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:27264673). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID: 27264673). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_P, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346581171/MONDO:0021060/128 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135935 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0042023 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232492 infores:hetionet CHEBI:28918 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0034063 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003460 infores:hetionet CHEBI:3181 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0242422 infores:hetionet CHEBI:6062 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0392171 infores:hetionet CHEBI:31980 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0026821 infores:hetionet CHEBI:36791 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019521 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0178298 infores:hetionet CHEBI:6633 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C3544060 infores:hetionet NCBIGene:51204 biolink:causes MONDO:0033638 infores:monarchinitiative not_provided not_provided HGNC:24316 MONDO:0033638 uuid:9808811d-5145-407a-962f-5c50fedf7385 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0036572 infores:hetionet CHEBI:2611 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0025362 infores:hetionet CAID:CA1244034 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244034 MONDO:0020367 PMID: Uncertain Significance PM4_Supporting BP7, BS1, BS3, PM2, PM6, PP1, PP3, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.1357delT variant in MYOC is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 11 of the frameshift, or amino acid 464 (p.Tyr453MetfsTer11). This variant is predicted to cause a deletion of < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.0008013 (20 alleles out of 24,960), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 2 segregations had been reported for primary open angle glaucoma (PMID: 25330346), not meeting the ≥ 3 segregations required for PP1. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM4_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244034/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10124 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1142135 infores:hetionet CHEBI:64354 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0242350 infores:hetionet CHEBI:520985 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020458 infores:hetionet CHEBI:8461 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0857305 infores:hetionet CHEBI:66876 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0236075 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0037822 infores:hetionet CHEBI:4356 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0041969 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0023067 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042373 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0029878 infores:hetionet UMLS:C0023610 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0041834 infores:hetionet CHEBI:68478 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0013428 infores:hetionet CHEBI:4445 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0001339 infores:hetionet CHEBI:7936 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0028961 infores:hetionet CHEBI:10127 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151539 infores:hetionet CAID:CA410204032 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204032 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.170C>T (p.Pro57Leu) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204032/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:5284632 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0236075 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0013395 infores:hetionet CHEBI:63611 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0423153 infores:hetionet CHEBI:7640 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0000737 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0019087 infores:hetionet CHEBI:480999 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0036690 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005648 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0003504 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0012797 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0009319 infores:hetionet CHEBI:3723 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007859 infores:hetionet CHEBI:2682 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0040264 infores:hetionet CHEBI:52717 biolink:causes MONDO:0015288 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019357 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151883 infores:hetionet CHEBI:51137 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0039231 infores:hetionet CHEBI:6128 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0014518 infores:hetionet CHEBI:32588 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0239385 infores:hetionet CHEBI:9571 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0026205 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014868 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0948294 infores:hetionet CHEBI:135876 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0004093 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0003123 infores:hetionet NCBIGene:3758 biolink:causes MONDO:0009424 infores:monarchinitiative not_provided not_provided HGNC:6255 MONDO:0009424 uuid:226ff5d4-d464-4cae-bec6-d056898a7775 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0314719 infores:hetionet GO:0030182 biolink:causes CL:0000540 infores:ubergraph knowledge_assertion manual_agent GO:0030182 CL:0000540 CHEBI:45863 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0021051 infores:hetionet CHEBI:44032 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0085631 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0227791 infores:hetionet CHEBI:44915 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0231528 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0037195 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0035309 infores:hetionet CHEBI:28593 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0393593 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0031046 infores:hetionet CHEBI:3732 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151905 infores:hetionet CHEBI:6897 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0004093 infores:hetionet CHEBI:47612 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0002170 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0687707 infores:hetionet CHEBI:2038 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0004093 infores:hetionet CHEBI:63584 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0030193 infores:hetionet CHEBI:6887 biolink:causes HP:0100035 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0751901 infores:hetionet CAID:CA267644 biolink:causes MONDO:0009861 infores:clingen CAID:CA267644 MONDO:0009861 PMID: Likely Pathogenic PM2_Supporting, PS1, PP3_Moderate PM5 The NM_000277.3(PAH):c.183C>A variant in PAH is a missense variant predicted to cause substitution of asparagine by Lysine at amino acid 61 (p.Asn61Lys). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.815, which is above the threshold of 0.773 but below 0.932, evidence that correlates with moderate impact to PAH function (PP3_Moderate). It is the same amino acid change as a previously established likely pathogenic variant c.183C>G (p.Asn61Lys). (PS1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PP3_moderate, PS1 (Version 2.0, 7/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267644/MONDO:0009861/006 2025-10-17 2025-10-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3756 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020701 infores:hetionet CHEBI:53691 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0030193 infores:hetionet CHEBI:10119 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151578 infores:hetionet CHEBI:50924 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0043352 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0427108 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005670 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0005681 infores:hetionet CHEBI:17987 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0015230 infores:hetionet CHEBI:3181 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0016059 infores:hetionet CHEBI:2637 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0002871 infores:hetionet CAID:CA136123 biolink:causes MONDO:0021060 infores:clingen CAID:CA136123 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2988G>A (p.Pro996=) variant in the SOS1 gene is 0.396% (51/10072) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136123/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5134 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0043144 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0427085 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0427085 infores:hetionet CHEBI:30830 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0549249 infores:hetionet CHEBI:63631 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0038325 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1096448 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1096448 infores:hetionet CHEBI:2687 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0023380 infores:hetionet CHEBI:63623 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0302295 infores:hetionet GO:0035170 biolink:causes CL:0000716 infores:ubergraph knowledge_assertion manual_agent GO:0035170 CL:0000716 CHEBI:31705 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151828 infores:hetionet CHEBI:49375 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0237938 infores:hetionet CHEBI:4710 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020621 infores:hetionet NCBIGene:1559 biolink:causes MONDO:0007390 infores:monarchinitiative not_provided not_provided HGNC:2623 MONDO:0007390 uuid:998e5c95-6bee-42ed-b512-6f0c5e051b02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042023 infores:hetionet CHEBI:7444 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0262662 infores:hetionet CHEBI:68647 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0011991 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0032285 infores:hetionet CHEBI:2567 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0020438 infores:hetionet CHEBI:63613 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0520573 infores:hetionet CHEBI:3380 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0018790 infores:hetionet CAID:CA7511784 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511784 MONDO:0015152 PMID: Likely Benign BP2, BS1 PM3, PM2, PP3, PP4 The NM_000070.3: c.2257G>A variant in CAPN3 is a missense variant predicted to cause a substitution of aspartate by asparagine at position 753, p.(Asp753Asn). The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.002457 (the lower threshold of the 95% CI of 22/6060 Middle Eastern chromosomes), which is greater than the ClinGen LGMD VCEP threshold >0.001 for BS1, meeting this criterion (BS1). The Total population also includes 2 homozygous individuals. While this variant has been reported in patients with features consistent with LGMD (PMID: 38391941, 18854869, 16141003), several individuals had other CAPN3 variants that could explain the phenotype, and the remaining reports did not provide sufficient evidence indicating pathogenicity given the variant's population frequency (PM3, PP4 not met). In one individual, this variant was confirmed in cis with a pathogenic variant (c.1401_1403del p.(Glu467del), PMID 38391941, BP2). The computational predictor REVEL gives a score of 0.649, which is below the LGMD VCEP threshold of ≥0.70 for PP3 (criterion not met). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/28/2025): BS1, BP2. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511784/MONDO:0015152/187 2025-10-28 2025-11-11 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3499 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0002878 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0851341 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027339 infores:hetionet NCBIGene:51341 biolink:causes MONDO:0859231 infores:monarchinitiative not_provided not_provided HGNC:18078 MONDO:0859231 uuid:6af1235f-63fd-4feb-b2d0-2f9cc1d624c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA400023445 biolink:causes MONDO:0100326 infores:clingen CAID:CA400023445 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The ITGB3 missense variant NM_000212.3:c.652C>T replaces the histidine residue with a tyrosine residue (p.His218Tyr). This variant has been observed in homozygosity in one individual (PM3_supporting) with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT17, PMID: 16463284). All requirements for PP4_Moderate are met (GT17 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is absent from population databases, including gnomADv4.1.0 (PM2_supporting), and the in silico meta-predictor REVEL score for this variant is 0.938, exceeding the VCEP-established threshold of ≥0.7 and suggestive of a damaging effect on protein function (PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PP4_moderate, PM2_supporting, PM3_supporting, and PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400023445/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:50131 biolink:causes UMLS:C0241558 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0241558 infores:hetionet NCBIGene:6833 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:59 MONDO:0005148 uuid:caa20914-cc56-47a3-874b-3bb715e937a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:389692 biolink:causes MONDO:0007834 infores:monarchinitiative not_provided not_provided HGNC:23145 MONDO:0007834 uuid:7e57e2d8-ee43-4ee0-8361-d06428aa98df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018799 infores:hetionet CAID:CA203801 biolink:causes MONDO:0018958 infores:clingen CAID:CA203801 MONDO:0018958 PMID: Benign BA1 BP4, BP7, BS1, PM2 The c.18783G>A is a synonymous (silent) variant (p.Gln6261=) that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by the UCSC Genome Browser (BP4, BP7 not met). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.02590 (2413/89448 alleles, 58 homozygotes) in the South Asian population, which is higher than the ClinGen Congenital Myopathies threshold (≥0.00559) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA203801/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3219 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0239739 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0039971 infores:hetionet CHEBI:8665 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0344315 infores:hetionet CHEBI:92712 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0235857 infores:hetionet GO:0060617 biolink:causes GO:0060443 infores:ubergraph knowledge_assertion manual_agent GO:0060617 GO:0060443 CHEBI:168396 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0005779 infores:hetionet CAID:CA397726083 biolink:causes MONDO:0008723 infores:clingen CAID:CA397726083 MONDO:0008723 PMID: Uncertain Significance PVS1_Moderate, PM2 PM3 The c.1878G>A p.(Trp626Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate; PMIDs 9973285, 11590124). This variant has been reported in the literature in individuals undergoing newborn screening (PMIDs: 32778825, 26385305), however, the phenotype or if a second ACADVL variant was detected in trans in these individuals was not reported. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002891 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397726083/MONDO:0008723/021 2025-04-22 2025-04-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:47898 biolink:causes HP:0033113 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0232200 infores:hetionet CHEBI:17263 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0018916 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013595 infores:hetionet CHEBI:3756 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0151205 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020676 infores:hetionet CHEBI:135888 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0702166 infores:hetionet CHEBI:3654 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0740394 infores:hetionet CHEBI:75922 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0423006 infores:hetionet CHEBI:3380 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0344232 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0277925 infores:hetionet CHEBI:28915 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0004096 infores:hetionet GO:0060251 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0060251 GO:0007399 CHEBI:8228 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0008031 infores:hetionet CHEBI:6717 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0042384 infores:hetionet CHEBI:681569 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0476273 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0020514 infores:hetionet CHEBI:63580 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085593 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0948089 infores:hetionet CHEBI:27786 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0011168 infores:hetionet GO:0042665 biolink:causes GO:0007398 infores:ubergraph knowledge_assertion manual_agent GO:0042665 GO:0007398 CHEBI:9674 biolink:causes UMLS:C0683369 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0683369 infores:hetionet NCBIGene:657 biolink:causes MONDO:0017380 infores:monarchinitiative not_provided not_provided HGNC:1076 MONDO:0017380 uuid:4899bcbb-cea5-450d-934d-d03de197996f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:2 biolink:causes UMLS:C0243026 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D018805 DB00916_MESH_D018805_1 CHEBI:63620 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151786 infores:hetionet CHEBI:465284 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0014724 infores:hetionet CHEBI:45951 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C1527311 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0027769 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0232459 infores:hetionet CHEBI:7773 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0038450 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0152227 infores:hetionet CHEBI:6847 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0221185 infores:hetionet NCBIGene:2296 biolink:causes MONDO:0024456 infores:monarchinitiative not_provided not_provided HGNC:3800 MONDO:0024456 uuid:5aabbcff-94ff-4617-8301-b5be3ac6ba41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0004604 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0014868 infores:hetionet CHEBI:7773 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0080274 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024115 infores:hetionet CHEBI:63638 biolink:causes HP:0000371 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0271429 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0032285 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0035455 infores:hetionet NCBITaxon:121226 biolink:causes MONDO:0003471 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:121226 MONDO:0003471 CHEBI:2955 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0392163 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0853700 infores:hetionet CHEBI:4717 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0234428 infores:hetionet CHEBI:16914 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0014868 infores:hetionet CHEBI:6067 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0035410 infores:hetionet CAID:CA1624823 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624823 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.294G>A (p.Lys98=) variant in the SOS1 gene is 0.0284% (9/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624823/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8888 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151889 infores:hetionet NCBIGene:1717 biolink:causes MONDO:0010035 infores:monarchinitiative not_provided not_provided HGNC:2860 MONDO:0010035 uuid:79e0a66a-8626-4938-a967-463db35c2d45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013922 infores:hetionet CHEBI:5855 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1720775 infores:hetionet CHEBI:9599 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0233407 infores:hetionet CHEBI:4887 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C1456784 infores:hetionet CHEBI:7936 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0575081 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0033566 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C1112436 infores:hetionet CHEBI:28901 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1443060 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0392025 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0853026 infores:hetionet CHEBI:91541 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0039231 infores:hetionet CHEBI:35854 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0009676 infores:hetionet NCBIGene:7050 biolink:causes MONDO:0007734 infores:monarchinitiative not_provided not_provided HGNC:11776 MONDO:0007734 uuid:f357fb2a-2756-42b1-8c22-15c9d51ec1a3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0151908 infores:hetionet NCBIGene:1294 biolink:causes MONDO:0007548 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0007548 uuid:507bc4e4-888b-475e-8035-41ed2bc38317 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167638 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0476273 infores:hetionet GO:2000028 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000028 GO:0007275 CHEBI:8207 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0030554 infores:hetionet NCBIGene:112752 biolink:causes MONDO:0036482 infores:monarchinitiative not_provided not_provided HGNC:29669 MONDO:0036482 uuid:cc5656a0-ea82-496d-a179-26e2a2c36686 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16586 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0038454 infores:hetionet CHEBI:101085 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0009946 infores:hetionet GO:1902692 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:1902692 GO:0048699 CHEBI:45409 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0267792 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0403632 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005665 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0376175 infores:hetionet CAID:CA10649411 biolink:causes MONDO:0100326 infores:clingen CAID:CA10649411 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PP3 After a thorough literature search the missense variant NM_000419.5(ITGA2B):c.628G>C (p.Gly210Arg) has not been found in any individuals with Glanzmann thrombasthenia. The variant is absent from gnomAD (PM2_supporting). The variant was originally identified by Illumina as part of a predisposition screen in an ostensibly healthy population. The computational predictor REVEL gives a score of 0.665, which is below the ClinGen PD VCEP PP3 threshold of >0.7 and does not predict a damaging effect on ITGA2B function (PP3 not met). In summary, this variant meets the criteria to be classified as uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10649411/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:107736 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0015967 infores:hetionet CHEBI:41879 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0009763 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0242350 infores:hetionet CHEBI:53760 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0043352 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0595883 infores:hetionet CHEBI:167638 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0085649 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020456 infores:hetionet CHEBI:49662 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0015967 infores:hetionet CHEBI:691037 biolink:causes HP:0025249 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0221228 infores:hetionet CHEBI:46295 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0003862 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0042373 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0948396 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0948396 infores:hetionet CHEBI:9130 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151517 infores:hetionet CHEBI:84050 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0019080 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014742 infores:hetionet CHEBI:2611 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0039070 infores:hetionet CHEBI:75984 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0344232 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0032285 infores:hetionet CHEBI:47381 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0025289 infores:hetionet CHEBI:5790 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235063 infores:hetionet CHEBI:3061 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0392156 infores:hetionet CHEBI:4903 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0019348 infores:hetionet CHEBI:10023 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0234632 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020615 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0004998 infores:hetionet CHEBI:10119 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0242429 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0008325 infores:hetionet CHEBI:6062 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042029 infores:hetionet CHEBI:27899 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0237849 infores:hetionet CHEBI:78543 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1262036 infores:hetionet CHEBI:2038 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C2938875 infores:hetionet CHEBI:5775 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C1443060 infores:hetionet CHEBI:47780 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011168 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0241164 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0155169 infores:hetionet CHEBI:42797 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C3665347 infores:hetionet CHEBI:5893 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0023530 infores:hetionet CHEBI:3814 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0687713 infores:hetionet CHEBI:3647 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0080274 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1504343 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1504343 infores:hetionet CHEBI:7825 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0028259 infores:hetionet CAID:CA229849 biolink:causes MONDO:0009861 infores:clingen CAID:CA229849 MONDO:0009861 PMID:26542770PMID:18590700 Likely Pathogenic PM3, PP4, PM2_Supporting, PP3_Moderate, PS3_Supporting The NM_000277.1(PAH):c.922C>G (p.Leu308Val) variant is a missense variant in exon 9/13 of PAH. The variant has been found to reduce PAH enzymatic activity to 15-19% versus wild type PAH enzyme in transfected COS cells (PMID: 18590700). The variant has been previously reported in confirmed trans with the c.1315+1G>A variant (Pathogenic per ClinGen PAH VCEP) in a patient with mild PKU (plasma Phe 600-900 umol/L); BH4 deficiency does not appear to have been excluded (PMID: 26542770). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP. The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.892).Classification: Likely PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3; PP4; PP3_moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229849/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46195 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0012833 infores:hetionet CHEBI:78543 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020437 infores:hetionet CAID:CA8129820 biolink:causes MONDO:0100488 infores:clingen CAID:CA8129820 MONDO:0100488 PMID: Likely Benign BP7, BS2, PM2_Supporting, BP4 BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.270G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Arg90=) that is not predicted by SpliceAI, varSEAK to impact splicing (BP4, BP7). This variant has been observed in more than 10 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry, GeneDX). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129820/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7915 biolink:causes UMLS:C0542237 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0542237 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030305 infores:hetionet CHEBI:8802 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0017178 infores:hetionet CHEBI:39585 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0232462 infores:hetionet CHEBI:168396 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009676 infores:hetionet CHEBI:64321 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020625 infores:hetionet CHEBI:92923 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C3257803 infores:hetionet CHEBI:6073 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0232487 infores:hetionet CHEBI:7915 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151908 infores:hetionet CHEBI:3082 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0278134 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0855242 infores:hetionet CHEBI:134743 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0948594 infores:hetionet CHEBI:50742 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0600142 infores:hetionet CHEBI:6073 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C3665347 infores:hetionet CHEBI:31524 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0020538 infores:hetionet CAID:CA008443 biolink:causes MONDO:0005835 infores:clingen CAID:CA008443 MONDO:0005835 PMID: Likely Benign BP4, BS4, PM2_Supporting BP5 The MLH1 c.2074T>C variant is predicted as a missense variant, p.(Ser692Pro). Its MAPP+PolyPhen-2 prior probability for pathogenicity is <0.11 (http://priors.hci.utah.edu/PRIORS). It is extremely rare (<1 in 50,000 alleles:0,002%) in gnomAD v2.1.1. non-cancer dataset and gnomAD v4.1. It showed lack of co-segregation with disease with a Bayes likelihood ratio <0.05 (Mayo CCFR). Therefore, this variant is classified as likely benign. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA008443/MONDO:0005835/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6076 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0542571 infores:hetionet CHEBI:49713 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0029221 infores:hetionet CHEBI:9168 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013456 infores:hetionet CAID:CA386967822 biolink:causes MONDO:0015967 infores:clingen CAID:CA386967822 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS1_Supporting, PVS1 PP4 The c.956-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 4 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 5 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). The nucleotide change c.956-1G>C, which is predicted to disrupt the intron splice acceptor site to a similar extent as c.956-1G>A, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID 586798). ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PVS1, PM2_Supporting, PS1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386967822/MONDO:0015967/017 2021-08-24 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8890 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0018790 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027051 infores:hetionet CHEBI:63791 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017565 infores:hetionet CHEBI:50922 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042963 infores:hetionet CHEBI:4909 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0027497 infores:hetionet CHEBI:167309 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0011991 infores:hetionet CAID:CA340938 biolink:causes MONDO:0044970 infores:clingen CAID:CA340938 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting PP1, PM6 The m.10663T>C (p.V65A) variant in MT-ND4L has been reported in at least 28 individuals from eight families, all of whom had Leber Hereditary Optic Neuropathy (LHON) and were haplogroup J and L (PS4_moderate; PMIDs: 29210930, 11935318, 24568867, 22879922, 17003408). There are three reported cases with no family history and, while these variants were assumed to occur de novo, family members were not tested for the variant. Several extended families have been reported in the medical literature (PMID: 24568867) however the variant was homoplasmic and thus prevented consideration for PP1. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are several occurrences in population databases, however some of these are from reported affected individuals (two occurrences in the GenBank dataset however one is from a patient with known mitochondrial disease, one occurrence in the Helix dataset, absent in gnomAD). Although there are several occurrences, the frequency is still low (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 11935318). This variant meets criteria to be classified as uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340938/MONDO:0044970/015 2022-06-13 2022-10-13 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8768 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011053 infores:hetionet CHEBI:6541 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C1443060 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0027769 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0687707 infores:hetionet CHEBI:2682 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0003467 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020676 infores:hetionet CHEBI:4470 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0233494 infores:hetionet CHEBI:7865 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0030252 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020517 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1384666 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013395 infores:hetionet CAID:CA011336 biolink:causes MONDO:0005045 infores:clingen CAID:CA011336 MONDO:0005045 PMID: Likely Benign BS1 BS3, BS4, PP2, PP3, PP1, PM5, PM1, PM2, PM6, BP4, BP2, BA1, PS1, PS3, PS4, PS2 NM_000256.3(MYBPC3):c.1855G>A (p.Glu619Lys). This variant has been described in individuals with HCM and other cardiomyopathies (ClinVar Variation ID: 161303). This variant has also been detected in several genetic ancestry groups in gnomAD v2.1.0 (0.03% Grpmax Filtering AF (95% confidence) in the European population (BS1). This variant is not statistically increased compared to controls (lower 95% CI<5), therefore, the PS4 criterion has not been applied. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner based on BS1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011336/MONDO:0005045/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:91147 biolink:causes MONDO:0800103 infores:monarchinitiative not_provided not_provided HGNC:28396 MONDO:0800103 uuid:366f21b5-a8a9-4d88-b927-3bf3e3abc729 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5106 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0006840 infores:hetionet CHEBI:10101 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0025222 infores:hetionet CAID:CA386960231 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960231 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 The c.458C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 153 (p.(Pro153Leu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (PP4_Moderate; PMID: 23348805, internal lab contributors). In summary, c.458C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960231/MONDO:0015967/017 2024-12-09 2025-04-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45863 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151908 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0036572 infores:hetionet CHEBI:68478 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0239134 infores:hetionet CHEBI:9086 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0232286 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0019158 infores:hetionet CHEBI:6775 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151594 infores:hetionet CHEBI:46345 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0085636 infores:hetionet CHEBI:47898 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0232461 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0231365 infores:hetionet CHEBI:15544 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0042510 infores:hetionet CHEBI:4356 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0086565 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0037274 infores:hetionet CAID:CA367398741 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398741 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PP4, PM2_Supporting The c.1146C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 382 (p.(Cys382Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). In summary, c.1146C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PP4, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398741/MONDO:0015967/086 2023-07-30 2023-07-30 Semidominant inheritance HP:0032113 Supports NCBIGene:79143 biolink:causes MONDO:0014962 infores:monarchinitiative not_provided not_provided HGNC:15505 MONDO:0014962 uuid:4e8f8f9c-57b6-436b-b5d7-0219d919396a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59773 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0013428 infores:hetionet CHEBI:63717 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0151825 infores:hetionet CHEBI:9635 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0013404 infores:hetionet CHEBI:3242 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C3263723 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0022104 infores:hetionet CHEBI:16480 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0018799 infores:hetionet CHEBI:3698 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0015672 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0001824 infores:hetionet CHEBI:3175 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0033774 infores:hetionet CHEBI:30830 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0038362 infores:hetionet CHEBI:6690 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0004245 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002187 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042994 infores:hetionet CHEBI:5790 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0003862 infores:hetionet CHEBI:6375 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020578 infores:hetionet CHEBI:28148 biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C2747793 infores:hetionet CAID:CA208360 biolink:causes MONDO:0010726 infores:clingen CAID:CA208360 MONDO:0010726 PMID: Benign BP7, BS1, BS2 BA1 The allele frequency of the p.Val380= variant in MECP2 is 0.018% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Val380= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Val380= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Val380= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208360/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:100246 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0233494 infores:hetionet CHEBI:6078 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0235266 infores:hetionet GO:0090328 biolink:causes GO:0042221 infores:ubergraph knowledge_assertion manual_agent GO:0090328 GO:0042221 CHEBI:8888 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040409 infores:hetionet CHEBI:135005 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0018524 infores:hetionet CHEBI:7445 biolink:causes NCIT:C87097 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0032989 infores:hetionet CHEBI:64354 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0003123 infores:hetionet CHEBI:6710 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0038362 infores:hetionet CHEBI:94807 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0232462 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0238106 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011991 infores:hetionet CHEBI:45783 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085682 infores:hetionet CAID:CA012239 biolink:causes MONDO:0005045 infores:clingen CAID:CA012239 MONDO:0005045 PMID:27532257PMID:30696458PMID:21959974 Benign PM1, BA1, BS4, BP2 PM2, PM5, PP3, PP1, PS3, BS1, BS3, BP4, PS4 NM_000257.4(MYH7):c.2360G>A (p.Arg787His).This variant has been identified in 0.2% (FAF 95% CI; 200/91078) of South Asian chromosomes, including 1 homozygote, in gnomAD v4.1.0 (BA1; https://gnomad.broadinstitute.org). Additionally, this variant has been identified in multiple affected individuals with other pathogenic variants (BP2; summarized in ClinVar ID: 42900) and was shown not to segregate with disease in 2 affected individuals from 2 families (BS4; Oxford Medical Genetics Laboratory (OMGL)). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Strength; Walsh 2019 PMID: 30696458). This is not considered to be in conflict with BA1 since benign variation within this region was considered during that analysis. In summary, this variant meets criteria to be is classified as benign for hypertrophic cardiomyopathy in an autosomal dominant manner based on BA1, BP2, BS4 and PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012239/MONDO:0005045/002 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8874 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0012813 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0025061 infores:hetionet CHEBI:49713 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C1443060 infores:hetionet CHEBI:3310 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0595862 infores:hetionet CHEBI:404903 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0687713 infores:hetionet CHEBI:480999 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0034063 infores:hetionet CHEBI:8597 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0917801 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0010839 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0010839 uuid:82357dc3-def3-4f19-977b-860fe0997b0b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151602 infores:hetionet CHEBI:2914 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0018790 infores:hetionet CAID:CA2573157371 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157371 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, PM4, PM5, PM1, PP3, PP1 The NM_001754.5(RUNX1):c.806-14C>T variant is intronic and is located upstream to exon 8. This is absent from all population databases, including gnomAD v2.1.1 and v3.1.2, with at least 20x coverage for RUNX1 (PM2_supporting). In addition, splicing algorithms predicted no effect on splicing (SpliceAI score 0.00 < 0.20) (BP4), and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP100way (GRCh38/hg38) score 1.016 < 2.0) (BP7). To our knowledge, this variant has not been found in patients with FPD/AML phenotype, and no functional studies are available. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157371/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009319 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0040128 infores:hetionet CHEBI:4708 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0030554 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0041969 infores:hetionet CHEBI:9763 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0026826 infores:hetionet CHEBI:39585 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0030554 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0403632 infores:hetionet CHEBI:7852 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0003862 infores:hetionet CHEBI:10127 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038220 infores:hetionet CHEBI:8404 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0235031 infores:hetionet CHEBI:5778 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0034933 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0233494 infores:hetionet CAID:CA10586684 biolink:causes MONDO:0021060 infores:clingen CAID:CA10586684 MONDO:0021060 PMID: Pathogenic PM5, PS4_Supporting, PM2_Supporting, PP2, PS2 The c.548A>T (p.Glu183Val) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by valine at amino acid 183. This variant is absent from gnomAD v2 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP2). This variant was observed in a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:27681385). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27681385). The variant occurs at the same amino acid residue as the PPP1CB c.548A>C (p.Glu183Ala) variant, which has been classified as pathogenic by the ClinGen RASOpathy VCEP (PM5). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as likely pathogenic; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy due to the strength of evidence for the PM5 code. In summary, this variant currently meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM5, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586684/MONDO:0021060/128 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports GO:1905557 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:1905557 GO:0000278 CHEBI:42944 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0010200 infores:hetionet CAID:CA295584 biolink:causes MONDO:0008723 infores:clingen CAID:CA295584 MONDO:0008723 PMID:26385305 Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate PM1 The c.538G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 180 (p.Ala180Thr). This variant has been reported in patients affected with very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and elevated C14:1 and reduced VLCAD activity measured in patient lymphocytes (PP4_Moderate, PMID: 26385305, 31844625, 32778825, 30194637). At least one individual was compound heterozygote with a second ACADVL variant, at least one of these variants is confirmed in trans and approved by the ACADVL VCEP as likely pathogenic (PM3, 1 point, PMID: 31844625, 30194637). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 14, 2022 and the recurated classification was approved by the expert panel on April 23, 2023. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA295584/MONDO:0008723/021 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Supports CAID:CA208905 biolink:causes MONDO:0010278 infores:clingen CAID:CA208905 MONDO:0010278 PMID: Benign BA1 The allele frequency of the c.1552-3C>T variant in SLC9A6 is 0.78% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1552-3C>T variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208905/MONDO:0010278/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:8768 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1145670 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020569 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0019348 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0018799 infores:hetionet UMLS:C0657912 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004144 infores:hetionet CHEBI:2663 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0035222 infores:hetionet CHEBI:9674 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0037317 infores:hetionet NCBIGene:2517 biolink:causes MONDO:0009254 infores:monarchinitiative not_provided not_provided HGNC:4006 MONDO:0009254 uuid:edab757c-ae38-4d7f-8ffe-d899b7db7ae9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3647 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0011606 infores:hetionet NCBIGene:5293 biolink:causes MONDO:0013226 infores:monarchinitiative not_provided not_provided HGNC:8977 MONDO:0013226 uuid:41650550-fe2a-406e-ac0e-cbd3ce7c3922 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0042487 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0032584 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034063 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018213 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1368065 infores:hetionet CAID:CA273955 biolink:causes MONDO:0009290 infores:clingen CAID:CA273955 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PS3_Supporting The NM_000152.5: c.1843G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 615 (p.Gly615Arg). At least 7 patients with a diagnosis of Pompe disease have been reported with this variant. Five of these patients are reported to have infantile onset Pompe disease (IOPD) and meet the criteria for PP4_Moderate with <10% GAA activity in cultured fibroblasts and/or GAA activity in the affected range in leukocytes (PMIDs: 15366815, 16860134, 18458862, 25037089), documented symptoms consistent with IOPD, and on enzyme replacement therapy (PMIDs: 16860134, 25037089) (PP4_Moderate). Of the reported patients, three are compound heterozygous, phase unknown, for another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, either c.2238G>A (p.Trp746Ter) (PMID: 16860134) or c.1935C>A (p.Asp645Glu) (PMID: 18458862) (2 patients). Two patients are homozygous for the variant (PMID: 15366815, 25037089) (PM3_Strong). A further two patients are compound heterozygous for the variant and either c.1832G>A (p.Gly611Asp) (PMID: 24269976) or c.1933G>C (p.Asp645His (clinical laboratory data) . The allelic data from these patients will be used in the classification of the other variant and is not included here to avoid circular. Finally, An 4 patients have been reported in the literature but the data was not included because the cDNA change for the variant was not provided, or does not match amino acid change (PMIDs: 10338092, 18607768, 21757382). The highest population minor allele frequency in gnomAD is 0.00022 in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in <2% GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188746, 2 star review status), with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Verions 2.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273955/MONDO:0009290/010 2022-09-06 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:79699 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020517 infores:hetionet CHEBI:6775 biolink:causes MONDO:0021553 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0026976 infores:hetionet CHEBI:3048 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0011168 infores:hetionet CHEBI:5864 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023212 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0033687 infores:hetionet CHEBI:3242 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013456 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0002974 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0002974 uuid:854f233d-d8c7-4075-a2a3-ea4aaa37e2bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0344232 infores:hetionet CHEBI:3387 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0026826 infores:hetionet CHEBI:77260 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014866 infores:hetionet CHEBI:77260 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0231528 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0036572 infores:hetionet CHEBI:15367 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0547030 infores:hetionet CHEBI:8694 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C0004093 infores:hetionet CHEBI:131512 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0687713 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151838 infores:hetionet UNII:U6XF9NP8HM biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0220870 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0015624 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0002871 infores:hetionet CHEBI:32139 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0002792 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0001824 infores:hetionet CHEBI:3757 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037383 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0023530 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0234987 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0234215 infores:hetionet CHEBI:71941 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0002792 infores:hetionet CHEBI:100241 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020488 infores:hetionet CHEBI:29007 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0700590 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0549475 infores:hetionet CHEBI:47898 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009421 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005392 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0036439 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0016508 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0016508 infores:hetionet CHEBI:18248 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C2830004 infores:hetionet CHEBI:6067 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0014236 infores:hetionet CHEBI:16335 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0232487 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0029408 infores:hetionet CHEBI:6888 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0042384 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001119 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025322 infores:hetionet CHEBI:8481 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0036104 infores:hetionet CHEBI:63613 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0239571 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0746883 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1384606 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0004096 infores:hetionet CHEBI:29007 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0014356 infores:hetionet CHEBI:49960 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0549249 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0574067 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0042109 infores:hetionet CHEBI:10119 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0220870 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0002871 infores:hetionet GO:0099149 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0099149 GO:0051641 CHEBI:8356 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029443 infores:hetionet CHEBI:6129 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0542571 infores:hetionet CHEBI:28901 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151904 infores:hetionet CHEBI:135961 biolink:causes UMLS:C1735864 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C1735864 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0235431 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042267 infores:hetionet CHEBI:6715 biolink:causes HP:0033587 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0262666 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0038454 infores:hetionet CHEBI:4911 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0013404 infores:hetionet CHEBI:3347 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0235416 infores:hetionet CHEBI:3242 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0009806 infores:hetionet CHEBI:70735 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0233565 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0475746 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0475746 infores:hetionet CHEBI:17026 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0023218 infores:hetionet CHEBI:3561 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0030554 infores:hetionet CAID:CA723143791 biolink:causes MONDO:0007648 infores:clingen CAID:CA723143791 MONDO:0007648 PMID:9537325PMID:9537325PMID:9537325 Likely Pathogenic PM2_Supporting, PS4_Supporting, PVS1_Strong BS1, BS4, BS3, BP5, BP7, PM6, PM3, PM4, PM1, PM5, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.2265T>A p.(Arg796Profs*11) variant is predicted to result in a premature stop codon that leads to a truncated protein (disrupting the last 87 amino acid residues of the CDH1 protein), and is located within the nonsense-mediated decay resistance region (downstream of aa 795) upstream of c.2506G>T p.(Glu836*) variant (PVS1_strong). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA723143791/MONDO:0007648/007 2024-03-28 2024-03-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA214317 biolink:causes MONDO:0015967 infores:clingen CAID:CA214317 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PP1_Strong, PP4_Moderate, PP3 The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) of NM_000545.8. This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID: 15031772, internal lab contributors) and this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Lastly, the c.670C>T variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.670C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved June 4, 2021): PP1_Strong, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214317/MONDO:0015967/017 2021-12-30 2021-12-30 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:93650 biolink:causes MONDO:0015008 infores:monarchinitiative not_provided not_provided HGNC:14376 MONDO:0015008 uuid:ce8f9ead-54db-4710-ae7c-04f690733a54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0026826 infores:hetionet NCBIGene:4284 biolink:causes MONDO:0014110 infores:monarchinitiative not_provided not_provided HGNC:7103 MONDO:0014110 uuid:6758a736-212d-40a0-bcf6-9a959647d0f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101085 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0022650 infores:hetionet CHEBI:194135 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0016242 infores:hetionet CHEBI:3127 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042963 infores:hetionet CHEBI:135736 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C3665347 infores:hetionet CHEBI:404903 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0008033 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0947999 infores:hetionet CHEBI:9398 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0036974 infores:hetionet NCBIGene:9217 biolink:causes MONDO:0012077 infores:monarchinitiative not_provided not_provided HGNC:12649 MONDO:0012077 uuid:3bd4fdd8-bf81-4e2b-820d-0fe19e4dac0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042133 infores:hetionet CAID:CA512319134 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319134 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.513A>G (p.Lys171=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319134/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4562 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C2047937 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0027051 infores:hetionet CHEBI:63580 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0231218 infores:hetionet CAID:CA10385230 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385230 MONDO:0100437 PMID: Benign BA1, BP3 PS4 NM_001034853.2(RPGR):c.2919_2939dup (p.Glu980_Gly981insGlyGluGluGlyGluGlyGlu) is a short in-frame insertion of 21 base pairs encoding additional residues between amino acids 980 and 981, located within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v4.1.0 at a frequency of 0.03305 among hemizygous individuals, with 4,635 variant alleles / 140,233 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in at least 1 female proband diagnosed with retinitis pigmentosa 3, however, the requirements of functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa are not available, so the proband was not considered for PS4. The variant has also been identified 13 times in an IRD cohort lacking phenotype details for specific cases (PMID: 32679846). The PS4 code cannot be evaluated since the variant has met BA1. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385230/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:15640 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0017178 infores:hetionet CHEBI:3181 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0338614 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0029408 infores:hetionet NCBITaxon:53467 biolink:causes MONDO:0000294 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:53467 MONDO:0000294 CAID:CA16041903 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041903 MONDO:0009290 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000152.5:c.2242G>T (p.Glu748Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant, diagnosed with late onset Pompe disease, has been reported (PMID: 31545528). This individual is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 31545528) (PM3_Supporting). The data are insufficient to apply PP4 based on the specifications of the ClinGen Lysosomal Diseases VCEP. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 370268). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041903/MONDO:0009290/010 2023-04-11 2023-04-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:15367 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0239783 infores:hetionet CHEBI:68647 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0027339 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0424823 infores:hetionet CHEBI:51364 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0392156 infores:hetionet CHEBI:3723 biolink:causes EFO:0009472 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0206504 infores:hetionet CHEBI:31547 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0035078 infores:hetionet CHEBI:17026 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C2979982 infores:hetionet CHEBI:44185 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0016658 infores:hetionet CHEBI:42820 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0018524 infores:hetionet CHEBI:240107 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0085636 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0038814 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003635 infores:hetionet CHEBI:94440 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0003123 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0002871 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231365 infores:hetionet CHEBI:3286 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0043094 infores:hetionet CHEBI:6754 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0015230 infores:hetionet CHEBI:3636 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0027497 infores:hetionet CHEBI:64064 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C2363731 infores:hetionet CHEBI:28593 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0004096 infores:hetionet CHEBI:63608 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0030554 infores:hetionet CHEBI:4495 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0231218 infores:hetionet NCBIGene:29894 biolink:causes MONDO:0032941 infores:monarchinitiative not_provided not_provided HGNC:2324 MONDO:0032941 uuid:4d6fd516-34ea-435c-b825-03c03bd3e732 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0030312 infores:hetionet UMLS:C0011701 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0085631 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0034530 infores:hetionet CHEBI:50378 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0022568 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0392525 infores:hetionet CHEBI:63621 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0037287 infores:hetionet NCBIGene:1496 biolink:causes MONDO:0032578 infores:monarchinitiative not_provided not_provided HGNC:2510 MONDO:0032578 uuid:849a5c3f-9757-4b26-81b2-14c53dcc92af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2695224312 biolink:causes MONDO:0100453 infores:clingen CAID:CA2695224312 MONDO:0100453 PMID: Likely Pathogenic PM4, PM3, PP4_Moderate, PM2_Supporting NM_000180.4(GUCY2D):c.3078_3083dup (p.Ile1027_Leu1028dup) is a short in-frame insertion variant predicted to cause a change in the length of the protein by duplicating residues 1027 and 1028, with at least one of the neighboring base pairs highly conserved with a PhyloP conservation score of 7.80781 (PM4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.726del (p.Ile243SerfsTer3) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 point, PMID: 27375279, PM3). A second proband has been identified as a compound heterozygote with the NM_000180.4(GUCY2D):c.937C>T (p.Arg313Cys) variant confirmed in trans (PMID: 34048777), but has not been curated by the LCA/eoRD VCEP and so is not counted for PM3 (1 total point, PM3) . At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 points) with age of onset at 0.3 years (1 pt), genotyping by exome sequencing with no alternative cause of retinal disease identified (4 pts), poor vision (1 pt), roving nystagmus (1 pt), no light perception, attenuated vessels (0.5 pts), and extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt). Together these are specific for GUCY2D-related recessive retinopathy total of 9.5 points, PMID: 34048777, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3, PM4, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224312/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:48131 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0162830 infores:hetionet CHEBI:231594 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0424489 infores:hetionet CHEBI:61049 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034155 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0520588 infores:hetionet CHEBI:63638 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0423791 infores:hetionet CHEBI:39112 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0085682 infores:hetionet CHEBI:17026 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0004093 infores:hetionet GO:0006954 biolink:causes MONDO:0006608 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D012628 DB00547_MESH_D012628_1DB01130_MESH_D012628_1 CHEBI:44423 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0012833 infores:hetionet NCBITaxon:5811 biolink:causes MONDO:0005989 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5811 MONDO:0005989 CHEBI:43968 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0020517 infores:hetionet CHEBI:45783 biolink:causes HP:0030804 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0546956 infores:hetionet CHEBI:6909 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0030252 infores:hetionet CHEBI:52717 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151827 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005165 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0086692 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0009806 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0160390 infores:hetionet CHEBI:6909 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0751494 infores:hetionet CAID:CA913190364 biolink:causes MONDO:0015967 infores:clingen CAID:CA913190364 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 The c.142delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 48 (NM_000545.8), adding 107 novel amino acids before encountering a stop codon (p.(Glu48SerfsTer107)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (PP4; PMID: 29927023). In summary, c.142delG meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP4 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190364/MONDO:0015967/017 2022-04-02 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6904 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C1456822 infores:hetionet NCBIGene:27445 biolink:causes MONDO:0011948 infores:monarchinitiative not_provided not_provided HGNC:13406 MONDO:0011948 uuid:9d487ca2-c8bc-43a0-be49-b3d2fe230f14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003864 infores:hetionet CHEBI:8597 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0038362 infores:hetionet CAID:CA16041894 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041894 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1567del (p.Ser523ProfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 371433). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041894/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:61049 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018524 infores:hetionet CHEBI:46557 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C2363730 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C2242737 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0004936 infores:hetionet CHEBI:43968 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151723 infores:hetionet NCBIGene:4522 biolink:causes MONDO:0060611 infores:monarchinitiative not_provided not_provided HGNC:7432 MONDO:0060611 uuid:36034d2e-80ad-4381-a95e-cd4ac4f7bf8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA134668 biolink:causes MONDO:0021060 infores:clingen CAID:CA134668 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.48A>G (p.Ala16=) variant in the PTPN11 gene is 0.0284% (9/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134668/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6067 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019825 infores:hetionet CAID:CA226701 biolink:causes MONDO:0010725 infores:clingen CAID:CA226701 MONDO:0010725 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PS3_Supporting BP4, PP3 The NM_000330.4(RS1):c.35T>A variant is a missense variant encoding the substitution of Leucine with Histidine at amino acid 12. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). COS-7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 12417531, PS3_Supporting). The computational predictor REVEL gives a score of 0.633, which is between the ClinGen X-linked IRD VCEP thresholds of 0.664 to 0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, both BP4 and PP3 codes do not apply. This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 9618178, 34822951, 31848469, 32860923, 28348004, 35456481, PS4_supporting). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PS3_supporting, PS4_supporting, and PM2_supporting. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226701/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true UMLS:C0120107 biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0521498 infores:hetionet CHEBI:6741 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0152031 infores:hetionet CHEBI:4903 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1305875 infores:hetionet CHEBI:3757 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0332563 infores:hetionet CHEBI:9720 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0027497 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0242350 infores:hetionet UNII:3U02EL437C biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0022346 infores:hetionet CHEBI:6897 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0020517 infores:hetionet NCBIGene:4191 biolink:causes MONDO:0015025 infores:monarchinitiative not_provided not_provided HGNC:6971 MONDO:0015025 uuid:be08542c-4056-42da-95ae-c8f10cdcb205 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0392525 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020550 infores:hetionet CHEBI:94686 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0008350 infores:hetionet CHEBI:8764 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019521 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011334 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0426576 infores:hetionet CHEBI:52717 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151692 infores:hetionet CHEBI:8356 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151825 infores:hetionet CHEBI:7575 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0151754 infores:hetionet CHEBI:691037 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0009450 infores:hetionet CHEBI:4792 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0020649 infores:hetionet CHEBI:3757 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1260880 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0232492 infores:hetionet CHEBI:6062 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0043352 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0859037 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0859037 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0034150 infores:hetionet NCBIGene:4598 biolink:causes MONDO:0009849 infores:monarchinitiative not_provided not_provided HGNC:7530 MONDO:0009849 uuid:a6670dcb-6e6b-4241-bccb-c9f0fb0ba639 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6954 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0014130 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0344232 infores:hetionet CAID:CA163513 biolink:causes MONDO:0700270 infores:clingen CAID:CA163513 MONDO:0700270 PMID: Benign BA1, BP4, BP2_Strong BS1, BP7, PM2, PP3 The ATM c.2639-17G>T variant has a gnomAD v2.1.1 filtering allele frequency of 6.505% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous state in multiple individuals without biallelic disease (BP2_Strong; GTR Lab ID: 61756). In silico splicing predictors (SpliceAI: AL 0.00/DL 0.00/AG 0.01/DG 0.00; MaxEntScan: +1.92% (wild type = 9.90, variant = 10.09)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA163513/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true NCBITaxon:119088 biolink:causes MONDO:0005745 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:119088 MONDO:0005745 CHEBI:2675 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0009676 infores:hetionet CHEBI:9667 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013390 infores:hetionet CHEBI:6149 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0424790 infores:hetionet CHEBI:5138 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003811 infores:hetionet CHEBI:8093 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0039070 infores:hetionet CHEBI:63608 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0035455 infores:hetionet CHEBI:2663 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042384 infores:hetionet CHEBI:119915 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0007859 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0041969 infores:hetionet CHEBI:10101 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0003862 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002622 infores:hetionet CHEBI:5127 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0263449 infores:hetionet CHEBI:6062 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0034642 infores:hetionet CHEBI:23765 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042029 infores:hetionet CHEBI:9435 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0023218 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1384353 infores:hetionet CHEBI:102216 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0231530 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0032326 infores:hetionet NCBIGene:2987 biolink:causes MONDO:0976132 infores:monarchinitiative not_provided not_provided HGNC:4693 MONDO:0976132 uuid:72e06b15-80bd-4266-93c0-242634f3e506 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151766 infores:hetionet CHEBI:82981 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0015967 infores:hetionet CHEBI:40279 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0027497 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0025061 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0000833 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0022205 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0152081 infores:hetionet CHEBI:30830 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151786 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0003123 infores:hetionet CHEBI:127780 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0019079 infores:hetionet CHEBI:5147 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151907 infores:hetionet CAID:CA199279 biolink:causes MONDO:0100039 infores:clingen CAID:CA199279 MONDO:0100039 PMID: Pathogenic PS3_Supporting, PP4, PM2_Supporting, PM6_Strong, PS4 PP3 The p.Val718Met variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with a CDKL5-related disorder (PMID 18790821, 27599155) (PM6_strong). The p.Val718Met variant has been observed at least 5 individuals with CDKL5-related disorders (PMID 31313283, 18790821, 27599155, GeneDx internal database) (PS4), including in an individual with a clinical phenotype very specific to a CDKL5-related disorder (PMID 27599155) (PP4). Additionally, an in vitro study using a minigene splicing assay showed that splicing is disrupted, resulting in exon 14 being omitted from the transcript (PMID: 29264392) (PS3_supporting). The p.Val718Met variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Val718Met variant in CDKL5 is classified as pathogenic for CDKL5-related disorders based on the ACMG/AMP criteria (PM6_strong, PS4, PP4, PS3_supporting, PM2_supporting). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199279/MONDO:0100039/034 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Supports CHEBI:7573 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0236075 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0008370 infores:hetionet CHEBI:94501 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0023530 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034882 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0428167 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0428167 infores:hetionet CHEBI:617099 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0001824 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0853149 infores:hetionet CHEBI:6887 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0028768 infores:hetionet CHEBI:7915 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151766 infores:hetionet CHEBI:28593 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0221242 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151602 infores:hetionet CHEBI:64355 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085682 infores:hetionet CHEBI:8404 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C3263723 infores:hetionet CHEBI:65173 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0030554 infores:hetionet CHEBI:9168 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1720775 infores:hetionet CHEBI:80630 biolink:causes MONDO:0021117 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0024121 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0007114 infores:hetionet CHEBI:7575 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0426576 infores:hetionet NCBIGene:246243 biolink:causes MONDO:0014656 infores:monarchinitiative not_provided not_provided HGNC:18466 MONDO:0014656 uuid:8fefa08f-3c51-4064-9659-32291f925a5b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA7140642 biolink:causes MONDO:0100040 infores:clingen CAID:CA7140642 MONDO:0100040 PMID: Likely Benign BS2_Supporting, BS1 PM2, PP3, BA1, BP4 The allele frequency of the p.Ser326Asn variant in FOXG1 is 0.023% in South Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ser326Asn variant is observed in at least 1 unaffected individuals (internal database) (BS2_Supporting). In summary, the p.Ser326Asn variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS1, BS2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7140642/MONDO:0100040/035 2023-08-23 2023-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2955 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0035455 infores:hetionet CHEBI:41774 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0023218 infores:hetionet CHEBI:119573 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0036974 infores:hetionet CHEBI:39585 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0028643 infores:hetionet CHEBI:52172 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0235378 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0027769 infores:hetionet GO:0031285 biolink:causes GO:0030587 infores:ubergraph knowledge_assertion manual_agent GO:0031285 GO:0030587 CAID:CA410203871 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203871 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.219C>G (p.Ser73Arg) is a missense variant which has a REVEL score < 0.50 (0.411) and a SpliceAI score ≤ 0.20 (0.03) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203871/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0231528 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0014130 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0235409 infores:hetionet CHEBI:71415 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0042571 infores:hetionet CHEBI:3515 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042256 infores:hetionet CHEBI:6402 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0022346 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235344 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235344 infores:hetionet NCBIGene:9445 biolink:causes MONDO:0014483 infores:monarchinitiative not_provided not_provided HGNC:6174 MONDO:0014483 uuid:eae3adf6-dfa4-473a-a556-f30330d6f24e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0015230 infores:hetionet CHEBI:45367 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0011603 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013295 infores:hetionet CHEBI:52717 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0546817 infores:hetionet CHEBI:453011 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0151827 infores:hetionet CHEBI:50777 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0030794 infores:hetionet CHEBI:231425 biolink:causes UMLS:C2721559 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C2721559 infores:hetionet CHEBI:5790 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0476273 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0017152 infores:hetionet CHEBI:66903 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0030196 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029882 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042373 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015397 infores:hetionet UMLS:C0120107 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013428 infores:hetionet CHEBI:7627 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0013144 infores:hetionet CAID:CA1251411 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251411 MONDO:0013144 PMID: Likely Pathogenic PS4, PS3_Supporting, PP4, BP4 PP3, BA1 The NM_000488.4(SERPINC1):c.439A>G variant predicts a missense change from Threonine to Alanine at position 147. Several patients with AT deficiency are reported with the Thr147Ala variant and meet the phenotype criteria for PS4_Very Strong and PP4. Reduced antithrombin activity was observed when the variant was analyzed by in in-vitro assays (PMID: 32920809) meeting PS3_Supporting. This variant has a frequency of 0.53% (>0.002 at 99.99% CI w/subpopulation of w/min of 5 alleles) in the African American subpopulation, with 143 heterozygous alleles (gnomAD v2.1.1). While this meets the BA1 cut-off set by the Thrombosis VCEP, the variant is excluded from the application from BA1 as it is a founder variant in the African population (PMID: 32920809). This missense variant has a REVEL score of 0.242, which is below the set threshold (>0.3), and meets BP4. However, the Thrombosis VCEP uses the Bayesian point system (PMID: 32720330) in the event of a variant meeting conflicting benign and pathogenic codes. In the case of Thr147Ala, PS4 is met at the very strong level. This give a total of 9 points, which corresponds to a likely pathogenic classification. In summary, the variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_VeryStrong, PP4, PS3_Supporting, BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251411/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45951 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0030312 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0034065 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0149931 infores:hetionet CHEBI:45409 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014518 infores:hetionet CHEBI:144551 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0037036 infores:hetionet CAID:CA267680 biolink:causes MONDO:0009861 infores:clingen CAID:CA267680 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4, PM3_Supporting PM5_Supporting The c.869A>T (p.His290Leu) variant in PAH has been reported in a proband with classic PKU (PMID: 26666653); BH4 deficiency does not appear to have been formally excluded (PP4). It was found with the pathogenic variant c.838G>A (p.Glu280Lys) (PM3_Supporting). The amino acid substitution is predicted damaging by multiple lines of computational evidence (PP3). It is absent from ethnically diverse control databases (PM2). Other missense variants at the site, including p.His290Arg, p.His290Tyr, and p.His290Gln are classified as Likely Pathogenic and Uncertain Significance. Thus, PM5 is not met. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3-supporting, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267680/MONDO:0009861/006 2021-03-26 2021-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7444 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0151602 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0021053 infores:hetionet CHEBI:45863 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0344232 infores:hetionet CHEBI:691037 biolink:causes MONDO:0002922 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0034212 infores:hetionet CAID:CA410202636 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202636 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM4, PM5, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.425C>A (p.Ala142Asp) is a missense variant which has a REVEL score ≥ 0.88 (0.919) (PP3). This variant is found within the Runt Homology Domain, but does not occur at a known hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 29146900). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202636/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75045 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0518015 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1262013 infores:hetionet NCBIGene:23461 biolink:causes MONDO:0007610 infores:monarchinitiative not_provided not_provided HGNC:35 MONDO:0007610 uuid:cc89eb4b-4305-435a-8368-4a2470bbfa84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3647 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0018418 infores:hetionet CHEBI:8356 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0041834 infores:hetionet CHEBI:8346 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C2363730 infores:hetionet CHEBI:6916 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0037763 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0863079 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0863079 infores:hetionet CHEBI:63631 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018524 infores:hetionet CHEBI:8713 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0011991 infores:hetionet CHEBI:50922 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0035455 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020473 infores:hetionet CHEBI:15367 biolink:causes HP:6000956 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0263634 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0549385 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0342257 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0342257 infores:hetionet CHEBI:52172 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0010520 infores:hetionet CHEBI:7903 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0041834 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020649 infores:hetionet CHEBI:3387 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0085593 infores:hetionet CHEBI:188986 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042029 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007971 infores:hetionet CHEBI:36791 biolink:causes HP:0010955 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549253 infores:hetionet CHEBI:46295 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0015402 infores:hetionet NCBIGene:79991 biolink:causes MONDO:0015026 infores:monarchinitiative not_provided not_provided HGNC:26200 MONDO:0015026 uuid:dc7a918b-9008-464d-916e-4c1c2fefa5c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0030305 infores:hetionet CHEBI:40279 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0267940 infores:hetionet CHEBI:7959 biolink:causes MONDO:0007921 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0221348 infores:hetionet CHEBI:7573 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0010200 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0314719 infores:hetionet GO:1902796 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:1902796 GO:0032774 CHEBI:171719 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0000768 infores:hetionet NCBIGene:9533 biolink:causes MONDO:0009558 infores:monarchinitiative not_provided not_provided HGNC:20194 MONDO:0009558 uuid:2d23d25d-35dc-4dc6-b9f9-e7e2a380560b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0043352 infores:hetionet CAID:CA295904 biolink:causes MONDO:0021060 infores:clingen CAID:CA295904 MONDO:0021060 PMID:22899370PMID:26243863PMID:28512244 Pathogenic PS1, PS3, PM1, PM6, PM2, PP3, PP2 PS4, PS2, PM5, PM4, BS4, BS3, BS1, BP7, BP5, PP1, BS2, BP4, BP1, BP3, BP2, BA1 The c.739T>C (p.Phe247Leu) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR Lab ID: 26957; ClinVar SCV000207748.12). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). The c.739T>C variant results in the same amino acid change as the previously established pathogenic c.741T>G (p.Phe247Leu) variant (PS1; ClinVar ID 55793). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PS3, PS1, PM1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA295904/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:145499 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0542571 infores:hetionet CHEBI:7565 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0009782 infores:hetionet CHEBI:63630 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1384353 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0150450 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0004093 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0020538 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0004093 infores:hetionet CHEBI:2682 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020461 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0232492 infores:hetionet CHEBI:10110 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0000768 infores:hetionet CHEBI:3515 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0019080 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0027765 infores:hetionet CHEBI:75722 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0032617 infores:hetionet CHEBI:31623 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0015403 infores:hetionet CAID:CA8815157 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815157 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Very Strong, PVS1_Strong PP3 The NM_000152.5:c.1076-22T>G variant in GAA occurs within intron 6. Experimental studies show that the variant causes skipping of biologically-relevant-exon 6 resulting in an in-frame deletion of amino acids 319-358 (PMIDs 9259196, 10737124). This includes part of the GAA catalytic barrel (amino acids 347-727) (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837) (PVS1_Strong). At least 7 probands have been reported with this variant, at least 5 of them with reported GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PP4_Moderate). Of these individuals, 6 are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including 2 confirmed in trans - c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 9259196), c.1437+1G>A (ClinVar Variation ID: 555864, SCV004227900.1), and 4 with phase unknown - c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902, SCV001371752.2) (PMID: 25455803), c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 22613277), c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113, SCV001371751.1) (PMID: 21484825), and c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 29181627). In addition, two siblings are homozygous for the variant (PMID: 10737124) (PM3_VeryStrong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002658 (3/112848 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370278). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815157/MONDO:0009290/010 2024-02-06 2024-03-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:122553 biolink:causes MONDO:0060640 infores:monarchinitiative not_provided not_provided HGNC:23066 MONDO:0060640 uuid:4bf1ee78-3bae-455c-806a-31cc44917ca5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4351 biolink:causes MONDO:0011257 infores:monarchinitiative not_provided not_provided HGNC:7216 MONDO:0011257 uuid:839e8367-ce0b-4ac3-ab95-3cccf6df7fbf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0016204 infores:hetionet CAID:CA367358007 biolink:causes MONDO:0015967 infores:clingen CAID:CA367358007 MONDO:0015967 PMID: Uncertain Significance PP2 BS1, PM2, PP3, PP4, BP4 The c.40G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glutamine at codon 14 (p.(Glu14Gln)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.603, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.00000443, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.40G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367358007/MONDO:0015967/086 2025-07-16 2025-07-25 Semidominant inheritance HP:0032113 Inconclusive true GO:1902026 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1902026 GO:0007275 CHEBI:135930 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0037763 infores:hetionet CHEBI:168396 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0428977 infores:hetionet CHEBI:28915 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0027769 infores:hetionet CHEBI:3207 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0009763 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0233494 infores:hetionet CHEBI:8707 biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0520886 infores:hetionet CAID:CA410202597 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202597 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS3, PS2, PS1, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.443C>T (p.Thr148Ile) is a missense variant affecting one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant is not present in gnomAD v2.1.1 and v3.1.2 (PM2_supporting), indicating its absence from population databases. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202597/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50378 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0015397 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549356 infores:hetionet CHEBI:37333 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0546817 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0015672 infores:hetionet CHEBI:64354 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C1443060 infores:hetionet CHEBI:41774 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0033774 infores:hetionet CHEBI:63618 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0013404 infores:hetionet CHEBI:52172 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0031256 infores:hetionet CHEBI:116278 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0036974 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0553713 infores:hetionet CHEBI:92998 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0237849 infores:hetionet CHEBI:63623 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0030193 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0020517 infores:hetionet CHEBI:31625 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0042164 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0574067 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040046 infores:hetionet CHEBI:50729 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0206062 infores:hetionet CHEBI:9757 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C1306341 infores:hetionet CHEBI:119915 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017672 infores:hetionet CHEBI:16335 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0162297 infores:hetionet CHEBI:3696 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002064 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0004238 infores:hetionet CHEBI:119915 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235309 infores:hetionet CHEBI:66901 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0037274 infores:hetionet CAID:CA9090826 biolink:causes MONDO:0021060 infores:clingen CAID:CA9090826 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.813C>T (p.Asp271=) variant in the MAP2K2 gene is 0.0045% (1/7096) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9090826/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0013604 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151740 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0032787 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0032787 infores:hetionet GO:0098902 biolink:causes GO:0001508 infores:ubergraph knowledge_assertion manual_agent GO:0098902 GO:0001508 NCBIGene:57152 biolink:causes MONDO:0009552 infores:monarchinitiative not_provided not_provided HGNC:18746 MONDO:0009552 uuid:99f29278-8ceb-436b-835c-c1119303e98c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085649 infores:hetionet CHEBI:5383 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0857305 infores:hetionet CHEBI:79699 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151908 infores:hetionet CHEBI:28001 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0020621 infores:hetionet CHEBI:72296 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151766 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0039971 infores:hetionet CHEBI:167638 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0231218 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0012833 infores:hetionet CHEBI:64355 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151610 infores:hetionet CHEBI:16469 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0022346 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0267596 infores:hetionet CHEBI:63681 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0004245 infores:hetionet CHEBI:36704 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0332563 infores:hetionet NCBIGene:4041 biolink:causes MONDO:0011151 infores:monarchinitiative not_provided not_provided HGNC:6697 MONDO:0011151 uuid:c8010820-fa40-46c9-8b67-9ed06254e63e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3699 biolink:causes UMLS:C0858118 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0858118 infores:hetionet CHEBI:9168 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020473 infores:hetionet GO:0044733 biolink:causes GO:0160128 infores:ubergraph knowledge_assertion manual_agent GO:0044733 GO:0160128 CHEBI:64355 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0005818 infores:hetionet CHEBI:9667 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0043094 infores:hetionet NCBIGene:925 biolink:causes MONDO:0012161 infores:monarchinitiative not_provided not_provided HGNC:1706 MONDO:0012161 uuid:2784983f-a1f3-464d-8682-d42eec598cc8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003537 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C1368065 infores:hetionet CAID:CA114178 biolink:causes MONDO:0015628 infores:clingen CAID:CA114178 MONDO:0015628 PMID: Pathogenic PP4_Moderate, PP1, PM2_Supporting, PS3, PM3 PM6, PP3, BP4, PS2, BP5, BS4, BS3 The NM_000552.4(VWF):c.1583A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 528. This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant has been reported homozygous in two homozygous (PM3) probands meeting the VWD type 2A phenotypic criteria (PP4_moderate, PS4_suporting; PMID: 20335223; 9714529). The variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID: 20335223). There is evidence of defective VWF storage with no response to desmopressin and very little VWF:Ag released after administration. Expression in 293 EBNA cells showed that homozygous N528S-VWF secretion was 7.5% of WT, with a multimer pattern lacking medium and HMWMs (PMID: 20335223 Fig. 4; PS3). Expression in AtT-20 cells showed that the N528S-VWF is not multimerized and is not trafficked to storage granules. In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PP1, PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114178/MONDO:0015628/081 2024-08-13 2024-08-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51032 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0010200 infores:hetionet CHEBI:16335 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0344232 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020615 infores:hetionet CHEBI:520985 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0012569 infores:hetionet CHEBI:71272 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0004093 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0521591 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0019112 infores:hetionet CHEBI:9907 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0019557 infores:hetionet CHEBI:94686 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0032617 infores:hetionet NCBIGene:83959 biolink:causes MONDO:0013204 infores:monarchinitiative not_provided not_provided HGNC:16438 MONDO:0013204 uuid:cdd5c567-ed50-4db2-a34b-0e4d9e81e204 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA343772451 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772451 MONDO:0013144 PMID: Uncertain Significance PM5_Supporting, PP3, PS4_Supporting, PM2_Supporting The c.1301T>G (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by cystenine at amino acid 434 (p.Phe434Cys). This variant has been reported in 1 proband meeting an antithrombin activity level of < 0.8 IU/mL with repeat testing overtime (PS4_Supporting; PMID:1469094). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1302C>A (p.Phe434Leu) (ClinVarID:2202884) in the same codon has been classified as likely pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2, PM5, PS4_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772451/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0007117 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0035258 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0518015 infores:hetionet CHEBI:8871 biolink:causes HP:0040303 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235988 infores:hetionet CHEBI:75722 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2830004 infores:hetionet CHEBI:8772 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0011603 infores:hetionet CHEBI:53691 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0016382 infores:hetionet CAID:CA355945699 biolink:causes MONDO:0001586 infores:clingen CAID:CA355945699 MONDO:0001586 PMID: Likely Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting PS1 The NM_000203.5: c.156C>A variant in IDUA is a missense variant predicted to cause substitution of phenylalanine by Leucine at amino acid 52 (p.Phe52Leu). This variant has been detected in at least one individual with MPS I. This individual is compound heterozygous for the variant and c.1037T>G p.(Leu346Arg), which is classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP (PMID 21480867, phase confirmed in trans, 1 point) (PM3). This individual has documented IDUA deficiency within the affected range (0.2 nmol/h/mg, reference range 27.2-52), increased excretion of urinary dermatan sulfate and heparin sulfate, and clinical features specific to MPS I including hepatosplenomegaly, joint stiffness and airway obstruction (PMID 21480867) (PP4_moderate). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.669 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (PMID: 36413997) (PP3_supporting). Another variant resulting in the same missense change (c.156C>G, p.Phe52Leu) is in ClinVar (Variation ID: 554280) with a low frequency in gnomAD; reported in Abdulelah et al, Iraqi J Pharm Sci, Vol.33(4) 2024). This variant has not yet been classified by the ClinGen LD VCEP. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0.): PM3, PP4_moderate, PP3, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355945699/MONDO:0001586/091 2025-04-07 2025-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9139 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017168 infores:hetionet CHEBI:5118 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0043387 infores:hetionet CHEBI:5959 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0026846 infores:hetionet CHEBI:64312 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0012569 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0021400 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0233485 infores:hetionet CHEBI:16755 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0035455 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0032285 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020649 infores:hetionet CHEBI:404903 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0008031 infores:hetionet CAID:CA008951 biolink:causes MONDO:0021056 infores:clingen CAID:CA008951 MONDO:0021056 PMID: Likely Benign BS2, BP1, BP2, PM2_Supporting The c.420G>C variant in APC is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 140 (p.Glu140Asp). APCis defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in heterozygous state in 67 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). This variant has also been observed in trans with a variant classified as (likely) pathogenic by the HCCP VCEP in an individual with FAP (BP2; Invitae Internal Data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA008951/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17303 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235063 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0003123 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0025061 infores:hetionet CHEBI:28487 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C1761613 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0010709 infores:hetionet CHEBI:55346 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0004238 infores:hetionet CHEBI:4514 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0015230 infores:hetionet CHEBI:9654 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0033774 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002185 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020492 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013595 infores:hetionet CHEBI:39112 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0017152 infores:hetionet CAID:CA355961461 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961461 MONDO:0001586 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The NM_000203.5:c.439C>T (p.Gln147Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4 of 14 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has not been reported in the literature, but has been reported in ClinVar (Variation ID: 984179). This variant is absent from gnomAD v4.1.0. (PM2_Supporting). The ClinGen SVI recommendation for absence/rarity (PM2) suggests that the combination of PVS1 and PM2 should be considered as 'likely pathogenic'. Therefore this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961461/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3216 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1262141 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151717 infores:hetionet CHEBI:38940 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0043352 infores:hetionet CHEBI:47898 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019079 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0015230 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0025202 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0243026 infores:hetionet CHEBI:4814 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C3665347 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0016436 infores:hetionet CHEBI:4798 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0004093 infores:hetionet NCBIGene:5313 biolink:causes MONDO:0009950 infores:monarchinitiative not_provided not_provided HGNC:9020 MONDO:0009950 uuid:d061ec9e-6f6a-41ca-924f-cc776d3ac0ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8815561 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815561 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting, PM3_Strong, PS3_Supporting The NM_000152.5:c.1978C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 660 (p.Arg660Cys). At least 6 patients with clinical features consistent with Pompe disease have been reported with this variant; three with documented laboratory data showing deficiency of GAA in dried blood spot, or lymphocytes and muscle (PMID: 17056254, 31193175, clinical laboratory data), and two reported to have deficient GAA activity and to be on enzyme replacement therapy on enzyme replacement therapy (PMID: 25626711, 29122469, 31904026) (PP4_Moderate). Three of these patients are compound heterozygous, phase unknown, for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, either c.784G>A (p.Glu262Lys) (PMID 31193175), c.1082C>T (p.Pro361Leu) (clinical laboratory data), or c.546G>T (PMID: 29124014) and another patient is homozygous (PMID: 25626711) (PM3_Strong). An additional two patients are compound heterozygous for the variant and [c.1477C>T; c.2221G>A] ([p.Pro493Ser; p.Asp741Asn)] (PMID: 29122469, 31904026), or c.1397T>G (p.Val466Gly) (PMID: 17056254). The allelic data from the latter 2 patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/18006 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant results in <2% normal GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.966 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at this amino acid position, c.1979G>A (p.Arg660His) has been classified as pathogenic by the ClinGen LSD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 558604; 2 star review status) with four submitters classifying the variant as pathogenic, and two as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM5, PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815561/MONDO:0009290/010 2022-03-01 2022-07-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4710 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0149725 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0522224 infores:hetionet CHEBI:9622 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C3665386 infores:hetionet CAID:CA10639817 biolink:causes MONDO:0100326 infores:clingen CAID:CA10639817 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 The c.1014G>A variant is a synonymous (silent) variant (p.Leu338=) that is not predicted by SpliceAI to impact splicing (BP4). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 1.464 (BP7). It was identified as part of a predisposition screen in an ostensibly healthy population and has not been reported in association with Glanzmann Thrombasthenia in the literature. This variant was not reported in the GT database or HGMD. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_supporting, BP4, BP7. (VCEP specifications version 2; date of approval) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10639817/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:92998 biolink:causes MONDO:0009133 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0394006 infores:hetionet CHEBI:31859 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013447 infores:hetionet CHEBI:64198 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0030193 infores:hetionet CAID:CA261565 biolink:causes MONDO:0021060 infores:clingen CAID:CA261565 MONDO:0021060 PMID:23624134PMID:20186801PMID:31560489PMID:26607044PMID:12634870PMID:25862627PMID:15001945 Pathogenic PS4, PM1, PS2_Very Strong, PM2, PP3, PP2 PM5, PP1 The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID: 12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hématologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hématologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID: 26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID: 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261565/MONDO:0021060/004 2019-12-05 2019-12-05 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:101278 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0009763 infores:hetionet CHEBI:6402 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0000768 infores:hetionet CHEBI:3286 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0041657 infores:hetionet CHEBI:74947 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020580 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0021308 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0021053 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1258215 infores:hetionet CHEBI:63631 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151662 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0031350 infores:hetionet CHEBI:110423 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0033687 infores:hetionet CHEBI:75988 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0232462 infores:hetionet CHEBI:135925 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0015967 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0007222 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0677500 infores:hetionet CHEBI:194135 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0032617 infores:hetionet CAID:CA024883 biolink:causes MONDO:0018493 infores:clingen CAID:CA024883 MONDO:0018493 PMID: Likely Pathogenic PS4_Moderate, PP1_Strong PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 2676 of the RYR1 protein, p.(Arg2676Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000259, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted). Two individuals were reported to have a second variant in RYR1 and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, PMID:16163667, PMID:19191329, PMID:25960145, PMID:21157159, Stowell Laboratory personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in more than ten individuals, PP1_Strong (PMID:30236257, PMID:25960145, PMID:14732627). A REVEL score of 0.601 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024883/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ NCBITaxon:5740 biolink:causes MONDO:0001103 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5740 MONDO:0001103 CHEBI:5855 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014518 infores:hetionet CHEBI:46295 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C1384353 infores:hetionet CHEBI:5296 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0042029 infores:hetionet CHEBI:465284 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0023218 infores:hetionet CHEBI:27504 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0011991 infores:hetionet CAID:CA024501 biolink:causes MONDO:0018493 infores:clingen CAID:CA024501 MONDO:0018493 PMID: Uncertain Significance PM1, PS4_Moderate PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 176 of the RYR1 protein, p.(Glu176Lys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0000649, a frequency consistent with pathogenicity for MHS. This variant has been reported in three individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, MH Investigation Unit (MHIU), UHN, Toronto). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.803 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024501/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8890 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0030554 infores:hetionet CAID:CA415173156 biolink:causes MONDO:0010726 infores:clingen CAID:CA415173156 MONDO:0010726 PMID: Benign BS1, BS2 BA1, BP4, PS4, PM1 The highest population minor allele frequency of the NM_004992.4: c.595C>T (p.Pro199Ser) variant in MECP2 in gnomAD v4.1 is 0.0002 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Pro199Ser variant is observed in at least 2 unaffected individuals (internal data, LabCorp Genetics Inc.) (BS2). The p.Pro199Ser variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Pro199Ser variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415173156/MONDO:0010726/036 2025-02-28 2025-03-26 X-linked inheritance HP:0001417 Contradicts true CHEBI:31644 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0028961 infores:hetionet NCBIGene:2260 biolink:causes MONDO:0007844 infores:monarchinitiative not_provided not_provided HGNC:3688 MONDO:0007844 uuid:2519e718-d7db-4155-abbd-a231171d2b0a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5156 biolink:causes MONDO:0011895 infores:monarchinitiative not_provided not_provided HGNC:8803 MONDO:0011895 uuid:a0a6408f-910a-4ecc-bab2-3b2bcc80e797 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75922 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0151601 infores:hetionet CHEBI:63611 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151827 infores:hetionet CHEBI:31624 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0012833 infores:hetionet CHEBI:7478 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042023 infores:hetionet CHEBI:5147 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C3160741 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032290 infores:hetionet CHEBI:9241 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0020555 infores:hetionet CHEBI:48669 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0522251 infores:hetionet CAID:CA902125 biolink:causes MONDO:0100368 infores:clingen CAID:CA902125 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting PM3, PP3, PP4 NM_000329.3:c.1597T>A is a missense variant in RPE65 causing substitution of serine with threonine at position 533. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002596, with 3 alleles / 30608 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.568, which is below the ClinGen LCA / eoRD VCEP threshold of ≥ 0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00 for all change types, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis, however other available phenotypes are not sufficient to evaluate specificity for RPE65-related recessive retinopathy and no second variant has been identified, so PP4 is not met (PMID: 17964524). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 25097241). However, the proband was not counted for PM3_Supporting because the NM_000329.3(RPE65):c.89T>C (p.Val30Ala) variant suspected in trans has not yet been classified for RPE65-related recessive retinopathy and because sufficient phenotype information was not available. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902125/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:194135 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014457 infores:hetionet CHEBI:9555 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0019156 infores:hetionet CHEBI:114785 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C1384353 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0522224 infores:hetionet CHEBI:64355 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0024902 infores:hetionet CHEBI:9086 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0008350 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0036572 infores:hetionet NCBIGene:5191 biolink:causes MONDO:0008972 infores:monarchinitiative not_provided not_provided HGNC:8860 MONDO:0008972 uuid:e5a7e0b6-cd34-47b8-a170-4505ede4778e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0232461 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0302295 infores:hetionet CHEBI:7565 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0010200 infores:hetionet CHEBI:9460 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0231218 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0037199 infores:hetionet CHEBI:3698 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0424790 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025160 infores:hetionet CHEBI:47780 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0917801 infores:hetionet CHEBI:2955 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0030554 infores:hetionet CHEBI:520985 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0023066 infores:hetionet CHEBI:63589 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020473 infores:hetionet CHEBI:38562 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0016382 infores:hetionet GO:0042686 biolink:causes GO:0042684 infores:ubergraph knowledge_assertion manual_agent GO:0042686 GO:0042684 NCBIGene:284656 biolink:causes MONDO:0859527 infores:monarchinitiative not_provided not_provided HGNC:19987 MONDO:0859527 uuid:b841b483-bc22-4631-9089-229fe2a40f7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50885 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0271650 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0234215 infores:hetionet CHEBI:9588 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0015967 infores:hetionet CHEBI:194135 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C2364111 infores:hetionet CHEBI:3371 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0023530 infores:hetionet CHEBI:29688 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0151798 infores:hetionet CHEBI:50275 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0038999 infores:hetionet NCBIGene:1282 biolink:causes MONDO:0008373 infores:monarchinitiative not_provided not_provided HGNC:2202 MONDO:0008373 uuid:f2ca3e17-18db-4caf-90d0-93ce542ee0d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0031046 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0521490 infores:hetionet NCBIGene:3425 biolink:causes MONDO:0011760 infores:monarchinitiative not_provided not_provided HGNC:5391 MONDO:0011760 uuid:c2b18783-6098-4100-b86e-46eb3df1bf95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0232462 infores:hetionet CHEBI:4511 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0017178 infores:hetionet CHEBI:31536 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0030305 infores:hetionet CHEBI:50173 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0018965 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0392386 infores:hetionet CHEBI:28748 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0854467 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001889 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0747102 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1258215 infores:hetionet CHEBI:3757 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0080274 infores:hetionet NCBIGene:1080 biolink:causes MONDO:0009061 infores:monarchinitiative not_provided not_provided HGNC:1884 MONDO:0009061 uuid:5dc7f1d1-eb1f-4edf-a67b-77b9f3cd45b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0039231 infores:hetionet CHEBI:46345 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0234233 infores:hetionet CHEBI:3286 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0018524 infores:hetionet NCBIGene:79809 biolink:causes MONDO:0013441 infores:monarchinitiative not_provided not_provided HGNC:25660 MONDO:0013441 uuid:7c99132d-535c-43bd-bdee-e3e7cb56f941 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011253 infores:hetionet CHEBI:114785 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0011175 infores:hetionet CHEBI:61049 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0026766 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0232197 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011616 infores:hetionet CHEBI:6923 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0019158 infores:hetionet CHEBI:8776 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0018524 infores:hetionet CHEBI:5004 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0018965 infores:hetionet NCBIGene:85365 biolink:causes MONDO:0014543 infores:monarchinitiative not_provided not_provided HGNC:23159 MONDO:0014543 uuid:492c2822-a89c-4a2a-b531-60a20797ca4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0851341 infores:hetionet GO:0033327 biolink:causes CL:0000178 infores:ubergraph knowledge_assertion manual_agent GO:0033327 CL:0000178 CHEBI:71219 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0036974 infores:hetionet GO:1901246 biolink:causes GO:0030324 infores:ubergraph knowledge_assertion manual_agent GO:1901246 GO:0030324 UNII:UMD7G2653W biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042109 infores:hetionet CHEBI:7824 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1760428 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0037199 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0038363 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0853776 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853776 infores:hetionet CAID:CA410206821 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206821 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP4, BP2, BS1, BS3, BS4, BP7, PVS1, PM6, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.723C>G (p.His241Gln) is a missense variant which is entirely absent from all population databases, including gnomAD v2.1.1 and v3.1.2, which provide coverage of at least 20x for the RUNX1 gene at this genomic position (PM2_supporting). Prediction scores cannot be considered, as this missense variant has a REVEL score of 0.633. Additionally, the affected amino acid residue, number 241, falls outside the RHD or residues 89-204. Furthermore, to our knowledge, there is no previous record of this variant, and no other pathogenic or likely pathogenic missense variants affecting the same amino acid residue or resulting in the same residue have been reported. In summary, the clinical significance of this variant is uncertain, and it meets ACMG/AMP criteria as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206821/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8428 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0919715 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0001824 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0042571 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235339 infores:hetionet GO:0061168 biolink:causes GO:0071697 infores:ubergraph knowledge_assertion manual_agent GO:0061168 GO:0071697 CHEBI:3127 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0021775 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0037284 infores:hetionet GO:0141081 biolink:causes GO:0141084 infores:ubergraph knowledge_assertion manual_agent GO:0141081 GO:0141084 CAID:CA343718551 biolink:causes MONDO:0005338 infores:clingen CAID:CA343718551 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.365G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Aspartate at amino acid 122 (p.Gly122Asp). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.036, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma, thus PS4 did not apply. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343718551/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4876 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0036572 infores:hetionet CHEBI:7915 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0025222 infores:hetionet CHEBI:40279 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0917801 infores:hetionet CHEBI:135888 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0018681 infores:hetionet CHEBI:17650 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0013395 infores:hetionet CHEBI:43968 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151904 infores:hetionet CHEBI:4995 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1368065 infores:hetionet CHEBI:3696 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0014591 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0235395 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0235395 infores:hetionet CHEBI:567361 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0017178 infores:hetionet CHEBI:9649 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0032617 infores:hetionet CHEBI:84500 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1260880 infores:hetionet CHEBI:15365 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0220981 infores:hetionet CHEBI:28748 biolink:causes EFO:0010671 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0549124 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0027769 infores:hetionet CHEBI:3647 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0015371 infores:hetionet CHEBI:15365 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0038990 infores:hetionet CHEBI:63612 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0232462 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0235416 infores:hetionet CHEBI:6965 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0023518 infores:hetionet CHEBI:46295 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0851578 infores:hetionet CHEBI:77733 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0013144 infores:hetionet CHEBI:6715 biolink:causes HP:0034967 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0269188 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040409 infores:hetionet UNII:UMD7G2653W biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0595916 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0009450 infores:hetionet CHEBI:8871 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0021177 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0392034 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0392034 infores:hetionet CHEBI:4672 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1140680 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0026946 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0086543 infores:hetionet CHEBI:94385 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0027497 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0042109 infores:hetionet NCBIGene:3850 biolink:causes MONDO:0032904 infores:monarchinitiative not_provided not_provided HGNC:6440 MONDO:0032904 uuid:adf49e72-a408-4429-8f8e-08b389b9d5c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA382556814 biolink:causes MONDO:0700270 infores:clingen CAID:CA382556814 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting BP4, PP3 The c.6880G>A (p.Glu2294Lys) variant in ATM is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 2294 (p.Glu2294Lys). This variant is absent from gnomAD v2.1.1. A computational in silico predictor for this alteration (REVEL: 0.723) is indeterminate. This variant was observed in an individual with Ataxia-Telangiectasia (PMID:26896183). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM2_Supporting, PM3_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382556814/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:133686 biolink:causes MONDO:0014464 infores:monarchinitiative not_provided not_provided HGNC:26404 MONDO:0014464 uuid:cb0932b0-928b-42c0-a928-9401dd8d5171 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0036572 infores:hetionet CHEBI:7936 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0424109 infores:hetionet CHEBI:35854 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0003862 infores:hetionet CHEBI:50777 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0013604 infores:hetionet NCBIGene:5311 biolink:causes MONDO:0013131 infores:monarchinitiative not_provided not_provided HGNC:9009 MONDO:0013131 uuid:9cfb970c-a0d6-48ff-91b4-a8f05c1ba3b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0014591 infores:hetionet CHEBI:2675 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0152227 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0034069 infores:hetionet CHEBI:10119 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022408 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013395 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0877104 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0877104 infores:hetionet CHEBI:5613 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0043352 infores:hetionet CHEBI:421707 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0221773 infores:hetionet CHEBI:87681 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0002622 infores:hetionet CHEBI:63630 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1306341 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0006849 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0011630 infores:hetionet CHEBI:145499 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C3665347 infores:hetionet CHEBI:31536 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0004364 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0011616 infores:hetionet CHEBI:6402 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0011603 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549373 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0011570 infores:hetionet CHEBI:64028 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0013132 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011053 infores:hetionet CHEBI:6030 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0018418 infores:hetionet CAID:CA2697547493 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547493 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.613+12C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547493/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8776 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0002874 infores:hetionet CHEBI:49040 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0010200 infores:hetionet CHEBI:6887 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0858635 infores:hetionet CHEBI:63635 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0151754 infores:hetionet NCBIGene:1185 biolink:causes MONDO:0030947 infores:monarchinitiative not_provided not_provided HGNC:2024 MONDO:0030947 uuid:a627f1e0-45e6-4b8f-8672-f5a736cd2a47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:253342 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0011570 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0233571 infores:hetionet NCBIGene:26160 biolink:causes MONDO:0014284 infores:monarchinitiative not_provided not_provided HGNC:30391 MONDO:0014284 uuid:e8321c22-cd67-4bf8-8b73-1de09e6726fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:51343 biolink:causes MONDO:0859325 infores:monarchinitiative not_provided not_provided HGNC:24824 MONDO:0859325 uuid:7d811ba0-f07b-4ac3-b7f8-d249936466c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0040822 infores:hetionet CHEBI:5613 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0575081 infores:hetionet CHEBI:35553 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0575081 infores:hetionet CHEBI:9571 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0542165 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0039584 infores:hetionet CHEBI:63611 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235660 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020649 infores:hetionet CAID:CA343722794 biolink:causes MONDO:0020367 infores:clingen CAID:CA343722794 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PS3_Moderate, PM2_Supporting BP7, BS1, BS3, PM6, PP3, PM4, PM5, PS4, PS1, PS2, BP4, BA1 The c.1504T>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Proline at amino acid 502 (p.Ser502Pro). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.657, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Ser502Pro protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 6 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 9863594), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9863594), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343722794/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40050 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0011849 infores:hetionet CHEBI:46295 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151905 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0011616 infores:hetionet CHEBI:8707 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085593 infores:hetionet CHEBI:171719 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013144 infores:hetionet CHEBI:28901 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018800 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0162429 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0024117 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0234215 infores:hetionet CHEBI:5959 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0428974 infores:hetionet CHEBI:61058 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0043094 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0162119 infores:hetionet CHEBI:61033 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0085932 infores:hetionet CAID:CA2580610955 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580610955 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.1169del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 290 in NM_000162.5, adding 12 novel amino acids before encountering a stop codon (p.(Ile390ThrfsTer12)). This variant, located in biologically relevant exon 9 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1169del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610955/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:135285 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0042109 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0036572 infores:hetionet CHEBI:63619 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151872 infores:hetionet CHEBI:31236 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0855333 infores:hetionet CHEBI:6931 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0427086 infores:hetionet NCBIGene:291 biolink:causes MONDO:0014175 infores:monarchinitiative not_provided not_provided HGNC:10990 MONDO:0014175 uuid:ac5cb8be-54f3-4e0b-a435-e86d42b84ad7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0559031 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0235416 infores:hetionet CHEBI:6149 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C3160947 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0031117 infores:hetionet CHEBI:49575 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0851578 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0221161 infores:hetionet CHEBI:9434 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013428 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020039 infores:hetionet UniProtKB:A9UF02 biolink:causes MONDO:0011996 infores:drugmechdb knowledge_assertion manual_agent UniProtKB:A9UF02 MESH:D015464 DB04865_MESH_D015464_1 CHEBI:45783 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0022346 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0025061 infores:hetionet CHEBI:465284 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003126 infores:hetionet CHEBI:5893 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0043352 infores:hetionet CHEBI:4672 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0024141 infores:hetionet CHEBI:3757 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0152198 infores:hetionet CAID:CA367401570 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401570 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.559G>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to tyrosine at codon 187 (p.(Asp187Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.922, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 29207974, 17573900). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.559G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401570/MONDO:0015967/086 2024-06-09 2024-06-09 Semidominant inheritance HP:0032113 Supports CHEBI:9599 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0409974 infores:hetionet CHEBI:5138 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085623 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038587 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0026848 infores:hetionet UMLS:C0657912 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023380 infores:hetionet CHEBI:6847 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0262988 infores:hetionet NCBIGene:372 biolink:causes MONDO:0014948 infores:monarchinitiative not_provided not_provided HGNC:649 MONDO:0014948 uuid:6554e1f2-0794-4be4-a5b6-c2d290fd8939 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31644 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0700590 infores:hetionet CAID:CA000424 biolink:causes MONDO:0018875 infores:clingen CAID:CA000424 MONDO:0018875 PMID:21343334PMID:25584008PMID:30224644PMID:12826609PMID:29979965PMID:1562462PMID:25584008PMID:27210295PMID:10435620 Uncertain Significance BS3_Supporting, PP3, PS4_Supporting BA1, BP4, PM1, PM5, BS1 This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). This variant has been reported in 2 probands meeting Chrompret criteria (PS4_Supporting; PMID:25584008, internal laboratory contributor). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.800G>A (p.Arg267Gln) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3, PS4_Supporting, BS3_Supporting. TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000424/MONDO:0018875/009 2020-08-11 2020-08-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45652 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0235086 infores:hetionet CAID:CA409120740 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120740 MONDO:0007064 PMID: Pathogenic PVS1, PM3, PM2_Supporting The c.603C>G (p.Tyr201Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The highest population minor allele frequency in gnomAD v4 is 0.00002992 (1/33422 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. Patient # 46 was found to be heterozygous for c.603C>G (p.Tyr201*) and c.632G>A (p.Arg211His) which is classified as pathogenic for SCID by the ClinGen SCID VCEP (1 pt.) (PMID: 26255240, PM3).In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PM3,PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120740/MONDO:0007064/114 2024-01-24 2024-01-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:145499 biolink:causes UMLS:C0740319 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0740319 infores:hetionet CHEBI:63629 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0037763 infores:hetionet CHEBI:4672 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0242429 infores:hetionet CAID:CA170406 biolink:causes MONDO:0010726 infores:clingen CAID:CA170406 MONDO:0010726 PMID: Pathogenic PM2_Supporting, PS2, PM5_Strong, PP3 BP4, PM1 The p.Lys304Arg variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). The p.Lys304Arg variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Rett syndrome (internal database - GeneDx) (PS2). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar, internal database - GeneDx, internal database - Labcorp Genetics) (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Lys304Arg variant in MECP2 (NM_004992.4) is classified as pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PM2_Supporting, PS2, PM5_Strong, PP3). (MECP2 Specifications v.4.1; curation approved on 06/25/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170406/MONDO:0010726/036 2025-06-25 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:63611 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151786 infores:hetionet CHEBI:2663 biolink:causes UMLS:C2363809 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C2363809 infores:hetionet CHEBI:6888 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0702166 infores:hetionet CHEBI:63613 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0001824 infores:hetionet CHEBI:6931 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0028084 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0002940 infores:hetionet CHEBI:64045 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0011071 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0234215 infores:hetionet CHEBI:8356 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0232849 infores:hetionet CHEBI:71415 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0032227 infores:hetionet CHEBI:6076 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C2363730 infores:hetionet CHEBI:465284 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0022107 infores:hetionet CAID:CA49763127 biolink:causes MONDO:0015152 infores:clingen CAID:CA49763127 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting PS1 The NM_003494.4: c.1053+5G>A variant in DYSF, which is also known as NM_001130987.2: c.1149+5G>A, occurs within the splice donor motif of intron 11. A mini-gene assay has demonstrated that this variant results in skipping of exon 11, causing a frameshift and premature truncation and leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PMID: 25312915; PVS1_RNA). This variant has been observed in at least two individuals with clinical features consistent with LGMD (PMID: 18396043, ClinVar SCV000710095.1 internal data communication), including in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.1668_1669insGTT p.(Leu556_Leu557insVal), 1.0 pt, ClinVar SCV000710095.1 internal data communication; PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (ClinVar SCV000710095.1 internal data communication; PP4_Strong). The filtering allele frequency of this variant is 0.00001859 (the upper threshold of the 95% CI of 13/1111832 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/18/2025): PVS1_RNA, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA49763127/MONDO:0015152/180 2025-06-18 2025-06-18 Autosomal recessive inheritance HP:0000007 Supports CAID:CA16022984 biolink:causes MONDO:0021056 infores:clingen CAID:CA16022984 MONDO:0021056 PMID: Uncertain Significance BP1, PM2_Supporting BS2 The c.754A>G variant in APC is a missense variant predicted to cause substitution of threonine by alanine at amino acid 252 (p.Thr252Ala). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant was observed once in a heterozygous individual with no features of FAP, worth 0.5 healthy individual points (BS2_variable not met). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PM2_Supporting (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16022984/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3176 biolink:causes MONDO:0005085 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0033999 infores:hetionet CHEBI:6775 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151908 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0009806 infores:hetionet NCBIGene:9734 biolink:causes MONDO:0957543 infores:monarchinitiative not_provided not_provided HGNC:14065 MONDO:0957543 uuid:078a7fc4-7996-4e4e-9107-f3e7fd444920 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0233414 infores:hetionet CHEBI:7494 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085633 infores:hetionet CHEBI:119486 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085682 infores:hetionet CAID:CA10576804 biolink:causes MONDO:0019501 infores:clingen CAID:CA10576804 MONDO:0019501 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3 BS1, BS3, BS4, BP7, BP5, PP2, PP1, BS2, PM5, PM4, PM1, PVS1, PM6, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.380A>G (NM_022124.6(CDH23):c.380A>G (p.Asp127Gly)) variant in CDH23 is a missense variant predicted to cause substitution of aspartate by glycine at amino acid 127. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796 which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in one individual with autosomal recessive Usher syndrome. For this individual, they were compound heterozygous for the variant and a pathogenic variant (NM_022124.6(CDH23):c.1949dup (p.Leu651fs) (SCV000271345.2) ) and this individual was confirmed in trans by family testing (1.0 point, PM3; LMM internal data). The patient with the variant had congenital severe-profound hearing loss with vestibular complications and ophthalmology-related issues, features highly specific to Usher syndrome (LMM Internal Data; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP. In summary, this variant is classified as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PM3, PP4 (ClinGen Hearing Loss VCEP Specifications Version 2; 6/27/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576804/MONDO:0019501/005 2023-06-27 2023-06-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:3181 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0037199 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017566 infores:hetionet CHEBI:6954 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0271738 infores:hetionet CHEBI:50924 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0085605 infores:hetionet CHEBI:2682 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018133 infores:hetionet CHEBI:63623 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0085593 infores:hetionet CAID:CA279502031 biolink:causes MONDO:0700272 infores:clingen CAID:CA279502031 MONDO:0700272 PMID: Uncertain Significance PP1, PM2_Supporting, BP1 PS3, PP3 The c.104T>C variant in PALB2 is a missense variant predicted to cause substitution of leucine by proline at amino acid 35 (p.Leu35Pro). This variant is absent in gnomAD v2.1.1. The variant has been reported to segregate with breast cancer in 3 affected family members from one family (PMID: 28319063). This variant is non-functional in multiple protein assays (PMID: 31586400; 31636395; 31757951); however, due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for a autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM2_Supporting, PP1, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA279502031/MONDO:0700272/077 2022-09-15 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6888 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0019521 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0233794 infores:hetionet GO:0075017 biolink:causes GO:0044409 infores:ubergraph knowledge_assertion manual_agent GO:0075017 GO:0044409 CHEBI:63791 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0518015 infores:hetionet CHEBI:101278 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0043352 infores:hetionet CAID:CA10014393 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014393 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-6C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.77) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014393/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6375 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017601 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0221752 infores:hetionet CHEBI:45924 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0042963 infores:hetionet CHEBI:8707 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0392156 infores:hetionet CHEBI:46557 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0022661 infores:hetionet CHEBI:45409 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019080 infores:hetionet GO:0048903 biolink:causes CL:2000034 infores:ubergraph knowledge_assertion manual_agent GO:0048903 CL:2000034 CHEBI:63616 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0948594 infores:hetionet CHEBI:9434 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0522055 infores:hetionet CHEBI:6078 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0023530 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0522224 infores:hetionet CHEBI:7444 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0234518 infores:hetionet CHEBI:32315 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0039231 infores:hetionet CHEBI:10102 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151889 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0039103 infores:hetionet CHEBI:47426 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0080274 infores:hetionet CHEBI:10124 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0027540 infores:hetionet CHEBI:584020 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C2830004 infores:hetionet CHEBI:7601 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0033774 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0000833 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151609 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0040034 infores:hetionet CAID:CA10644605 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644605 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM5, PM3, PM4, PM1, PP2, PP3, PP1, PP4, BS2 This 3' UTR c.*4188G>C variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP = -0.665764 in GRCh38). The variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (European, non-Finnish, subpopulation: 0.03528% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and has not been described in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644605/MONDO:0011071/008 2021-05-26 2022-07-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63584 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0003123 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0025061 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0009763 infores:hetionet CHEBI:71219 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853697 infores:hetionet CHEBI:6958 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0041834 infores:hetionet CHEBI:3387 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034880 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0024115 infores:hetionet CAID:CA392256545 biolink:causes MONDO:0012996 infores:clingen CAID:CA392256545 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4 PM3, PM5, PP3, BA1, BS1 The NM_001482.3:c.1007C>T variant in GATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 366 (p.Thr336Ile). To our knowledge, this variant has not been reported in the literature in any individuals with AGAT deficiency. It has, however, been reported in a family with renal Fanconi syndrome (PMID 29654216). Thie variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.137 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GATM function (PMID: 36413997)(BP4). SpliceAI predicts that the variant has no impact on splicing. Another missense variant c.1006A>G (p.Thr336Ala) in the same codon has also been reported in a family with renal Fanconi syndrome but not AGAT deficiency (PMID 29654216). This variant has not met the criteria to be classified as pathogenic or likely pathogenic for AGAT deficiency by the ClinGen CCDS VCEP (PM5 not met). In summary, the c.1007C>T (p.Thr336Ile) variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 10, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392256545/MONDO:0012996/025 2025-04-10 2025-04-10 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:204 biolink:causes MONDO:0009973 infores:monarchinitiative not_provided not_provided HGNC:362 MONDO:0009973 uuid:cc8287d7-9771-4542-ad72-f7affefb9513 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002871 infores:hetionet CHEBI:135613 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0018681 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0424000 infores:hetionet CAID:CA023515 biolink:causes MONDO:0007750 infores:clingen CAID:CA023515 MONDO:0007750 PMID: Uncertain Significance BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023515/MONDO:0007750/013 2024-10-28 2025-01-20 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:1410 biolink:causes MONDO:0013411 infores:monarchinitiative not_provided not_provided HGNC:2389 MONDO:0013411 uuid:3a03e046-2d80-413a-b95a-a5e84c78a39a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32184 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0033774 infores:hetionet CHEBI:6715 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042256 infores:hetionet CAID:CA2061415 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061415 MONDO:0015924 PMID: Uncertain Significance PM2, PP3, PP1, BA1, BP4, PS1, PS3, PS4, PM5, PM1, BS1, BS3, BS4 The BMPR2 c.1607G>A variant is a missense variant predicted to cause an arginine to histidine substitution at amino acid position 536 (p.(Arg536His)). The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.031% in the African/African American population. Based on these frequency values, the thresholds for BA1 (>1%), BS1 (≥0.1% ) and PM2 (<0.01%) are not met, as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). The REVEL score of 0.608 does not meet the threshold for BP4 (≤0.25) or PP3 (≥ 0.75). Since the amino acid substitution does not occur in a well-established functional domain, PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence. The variant was reported in one patient with PAH in ClinVar, which was not sufficient to apply PS4 (>1 proband). Similarly, functional data is unavailable for this variant, so BS3 and PS3 were not evaluated. In summary, we cannot assign any criteria to this variant. It remains classified as a variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061415/MONDO:0015924/125 2024-05-01 2024-05-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31643 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0041657 infores:hetionet CAID:CA024797 biolink:causes MONDO:0007783 infores:clingen CAID:CA024797 MONDO:0007783 PMID: Likely Pathogenic PP1, PS3_Moderate, PM1, PS4, PP3_Moderate, BS2_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Glycine with Arginine at codon 248 of the RYR1 protein, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024797/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63631 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235198 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011334 infores:hetionet NCBIGene:5314 biolink:causes MONDO:0033004 infores:monarchinitiative not_provided not_provided HGNC:9016 MONDO:0033004 uuid:557f8ec4-95c3-41b5-98ef-2d4331e9d31a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3347 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0010200 infores:hetionet CHEBI:64312 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0035305 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0424000 infores:hetionet CAID:CA412376876 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376876 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000330.4(RS1):c.62G>C (p.Gly21Ala) is a missense variant encoding the substitution of glycine with alanine at amino acid 21. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.541, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of <0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives scores of 0.17 for donor loss and 0.16 for acceptor loss, which are below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and do not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376876/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:9635 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0031117 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1291078 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0233414 infores:hetionet NCBIGene:2161 biolink:causes MONDO:0009315 infores:monarchinitiative not_provided not_provided HGNC:3530 MONDO:0009315 uuid:acf39270-0a1c-45e2-9159-d72d0e1d755f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0024141 infores:hetionet CHEBI:8107 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151636 infores:hetionet CHEBI:45599 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C2939147 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0042571 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0037199 infores:hetionet CAID:CA120629 biolink:causes MONDO:0044970 infores:clingen CAID:CA120629 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS4, PS3 The m.13045A>C (p.M237L) variant in MT-ND5 has been reported in one individual with primary mitochondrial disease to date (PMID: 12509858), in a boy with migraine-like symptoms (dizziness, vomiting, photophobia), clonic seizures that developed into epilepsia partialis continua, bilateral optic atrophy, ophthalmoplegia, ataxia, and cognitive impairment. He also had elevated cerebrospinal fluid lactate (normal lactate in blood) and muscle biopsy showed mildly reduced complex I activity. His brain imaging findings were consistent with Leigh syndrome and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). The variant was present at 82% heteroplasmy in muscle and 13% in blood. The variant was absent in blood from his healthy mother (PM6_supporting). There are several occurrences in population databases (absent in gnomAD v3.1.2 and the Helix dataset; present in one individual in the MITOMAP GenBank sequences, 1/61168, 0.00163%). Although there are several occurrences, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1; score of 0.905 in APOGEE2), which predicts a damaging effect on gene function (PP3). There are no cybrids, supporting single fiber studies, or de novo occurrences reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM6_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120629/MONDO:0044970/015 2023-11-13 2024-08-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6367 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018790 infores:hetionet GO:1901219 biolink:causes GO:0003205 infores:ubergraph knowledge_assertion manual_agent GO:1901219 GO:0003205 CHEBI:6888 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0234894 infores:hetionet GO:0042682 biolink:causes GO:0042675 infores:ubergraph knowledge_assertion manual_agent GO:0042682 GO:0042675 CHEBI:94440 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0036974 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0033038 infores:hetionet CHEBI:6792 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0021400 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0151626 infores:hetionet CHEBI:9448 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0234632 infores:hetionet CHEBI:80630 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0023530 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0863100 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0863100 infores:hetionet CHEBI:72564 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151699 infores:hetionet CHEBI:9570 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0023530 infores:hetionet CHEBI:52172 biolink:causes UMLS:C1262299 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1262299 infores:hetionet CHEBI:4876 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0001339 infores:hetionet CHEBI:168396 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0041657 infores:hetionet CHEBI:10023 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0542571 infores:hetionet CHEBI:119915 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0043094 infores:hetionet CAID:CA367396721 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396721 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1396T>C variant in the glucokinase gene, GCK, is causes an animo acid change at the stop codon of the final exon (10/10), resulting in the addition of 144 amino acids at the end of the protein (p.(Ter466ArgextTer144)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical picture consistent with non-autoimmune/insulin-dependent diabetes, however PS4_moderate cannot be applied because this number is below the MDEP threshold (internal lab contributor). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1396T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396721/MONDO:0015967/086 2023-08-10 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:9139 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0041912 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151888 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0042075 infores:hetionet CHEBI:50131 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0085649 infores:hetionet CHEBI:91834 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0542571 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0021053 infores:hetionet CHEBI:6710 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0019080 infores:hetionet CHEBI:41774 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0311468 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020456 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1142017 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1142017 infores:hetionet CHEBI:9667 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0025289 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1861172 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0854725 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0854725 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0267792 infores:hetionet CHEBI:4814 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0235886 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0006114 infores:hetionet CHEBI:92607 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0023218 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0948594 infores:hetionet CHEBI:85078 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0027497 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0677500 infores:hetionet NCBIGene:4054 biolink:causes MONDO:0011018 infores:monarchinitiative not_provided not_provided HGNC:6716 MONDO:0011018 uuid:eaf5736b-fae4-47eb-a4d7-0186b27c97f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0085593 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015230 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0025061 infores:hetionet CHEBI:64312 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0392171 infores:hetionet CHEBI:28748 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151786 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0037274 infores:hetionet CHEBI:8093 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0011603 infores:hetionet NCBIGene:5498 biolink:causes MONDO:0008297 infores:monarchinitiative not_provided not_provided HGNC:9280 MONDO:0008297 uuid:f83c7abe-4433-404c-ba2e-c96a2663cb16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes UMLS:C0029925 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0029925 infores:hetionet CHEBI:168396 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0232849 infores:hetionet CAID:CA8815361 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815361 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PM5_Supporting The NM_000152.5: c.1537G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 513 (p.Asp513Asn). This variant has been detected in at least five individuals with Pompe disease. One patient of late-onset Pompe disease had documented GAA deficiency as 8.7% of the normal control level of GAA activity (PMID 33301762). Three siblings from one family had documented reduced GAA enzyme activity within the deficient range (clinical laboratory data). Patient(s) with this variant had documented in a Pompe Registry with the onset of symptoms less than 12 years of age (PMID 31342611). (PP4_Moderate). Of those individuals, one individual was homozygous for the variant, and three siblings were compound heterozygous for the variant and the pathogenic c.-32-13T>G variant (PM3 2.0 points, PMID 33301762, clinical laboratory data) (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006533 (2/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact on GAA function (PP3). Another missense variant c.1538A>G (p.Asp513Gly) (PMID 31510962, 33560568; ClinVar Variation ID: 638014) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 960182). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PP4_Moderate, PM3_Strong, PM2_Supporting, PP3, PM5_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815361/MONDO:0009290/010 2023-07-18 2023-07-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2668 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085129 infores:hetionet CHEBI:45599 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0041582 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0518015 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0031117 infores:hetionet CHEBI:132233 biolink:causes MONDO:0003969 infores:ubergraph knowledge_assertion manual_agent CHEBI:2679 MONDO:0003969 CAID:CA10584911 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584911 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PP1_Strong, PM1, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, BS2, PP2 The NM_000527.5(LDLR):c.418G>A (p.Glu140Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 8 informative meioses from 4 families from Instituto Nacional de Saude Doutor Ricardo Jorge and Laboratory of Genetics and Molecular Cardiology, so PP1_Strong is met.PM1 - variant is missense in exon 4 and meets PM2 criteria, so PM1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.965, it is above 0.75, so PP3 is met.PP4 - Variant meets PM2 and was identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.PS4_supporting - variant meets PM2. Identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, PS4_supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584911/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3423 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0948594 infores:hetionet CAID:CA275413 biolink:causes MONDO:0008723 infores:clingen CAID:CA275413 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The NM_000018.4 c.637G>A (p.Ala213Thr) in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 213 (p.Ala213Thr). The highest population minor allele frequency in gnomAD V2.1.1 is 0.00006 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in homozygous fashion in three consanguinity siblings affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, at least one of whom displayed reduced enzyme levels (17% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 1.0, PM3, PMID: 12213615). The computational predictor REVEL gives a score of 0.917, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA275413/MONDO:0008723/021 2024-04-15 2024-04-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5383 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0344232 infores:hetionet CHEBI:3478 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0014742 infores:hetionet CAID:CA16603066 biolink:causes MONDO:0018875 infores:clingen CAID:CA16603066 MONDO:0018875 PMID: Pathogenic PS3, PP3_Moderate, PM1, PM5, PM2_Supporting, PS4_Supporting BP4, BA1, BS1, PP4, BS2 The NM_000546.6: c.523C>G variant in TP53 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 175 (p.Arg175Gly). This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs: 11370630, 25927356). This variant has an allele frequency of 0.000002542 (3/1180042 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.554513; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PM2_Supporting, PM5, PM1, PP3_Moderate, PS3. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603066/MONDO:0018875/009 2024-09-06 2024-09-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6149 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0438142 infores:hetionet CAID:CA409120933 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120933 MONDO:0007064 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.511A>T (p.Lys171Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification.In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (VCEP specifications version 1): PVS1,PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120933/MONDO:0007064/114 2024-05-28 2024-05-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28918 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0237849 infores:hetionet CHEBI:50922 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0040264 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0032285 infores:hetionet CHEBI:31236 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016204 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1608950 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1608950 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C1384606 infores:hetionet CHEBI:8869 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0947912 infores:hetionet CHEBI:63598 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0392163 infores:hetionet CAID:CA8328364 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328364 MONDO:0100438 PMID: Uncertain Significance PP3, PM2_Supporting NM_014336.5(AIPL1):c.868G>C (p.Val290Leu) is a missense variant predicted to replace valine with leucine at amino acid p.290. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00001306, with 21 alleles / 1,607,702 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.712, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function (PP3). The splicing impact predictor SpliceAI gives a score of 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. No published probands harboring the variant have been identified. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328364/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7478 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0043352 infores:hetionet CHEBI:51032 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0027441 infores:hetionet CAID:CA2499224903 biolink:causes MONDO:0008723 infores:clingen CAID:CA2499224903 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1251del (p.Ser418fs) also known as (p.Ser418AlafsTer12) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Additionally, to our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (VCEP specifications version1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499224903/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28918 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0151636 infores:hetionet CHEBI:3752 biolink:causes HP:0011920 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020312 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151547 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0239521 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0239521 infores:hetionet UMLS:C0025241 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C2242996 infores:hetionet CHEBI:10125 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0023380 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0002170 infores:hetionet CAID:CA367401964 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401964 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PM5, PP4 The c.443T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 148 (p.(Phe148Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.442T>A (p.(Phe148Ile)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.443T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401964/MONDO:0015967/086 2023-10-03 2023-10-03 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:6715 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0033845 infores:hetionet NCBIGene:779 biolink:causes MONDO:0042979 infores:monarchinitiative not_provided not_provided HGNC:1397 MONDO:0042979 uuid:f0575f79-e06f-431b-bf00-5989f966a9fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4681 biolink:causes UMLS:C0857175 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0857175 infores:hetionet CHEBI:68534 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0015672 infores:hetionet GO:0110107 biolink:causes GO:0007552 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0007552 CAID:CA16020949 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020949 MONDO:0009861 PMID:22763404PMID:24350308PMID:22763404PMID:24350308 Pathogenic PM3, PM2, PVS1, PP4 The c.1147C>T (p.Gln383Ter) variant in PAH is a nonsense variant predicted to undergo NMD, present in all biologically relevant transcripts, absent from all populations databases. It has been identified in a patient with classic PKU as homozygous, and in trans with a pathogenic variant (R408W), although defect in BH4 metabolism was not excluded in either patient. (PMID: 24350308, 22763404). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020949/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA2580610966 biolink:causes MONDO:0010305 infores:clingen CAID:CA2580610966 MONDO:0010305 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PM4 PS4 The NM_005629.4:c.1592_1639dup133 variant in SLC6A8 is a tandem duplication involving exons 11 and 12 that was experimentally verified via cDNA analysis of patient mRNA to result in a 48 nucleotide insertion between exons 11 and 12, leading to a 16 amino acid insertion in a non-repeat region of the encoded protein (PMID: 24140398) (PM4). This variant has been reported in one male proband with elevated urine creatine/creatinine and reduced creatine peak on brain MRS (PP4_Strong) (PMID: 24140398). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM4, PM2_Supporting, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP, August 10, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610966/MONDO:0010305/027 2023-08-10 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:9943 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0917801 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0919715 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0442886 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0687707 infores:hetionet CHEBI:127780 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0014518 infores:hetionet CHEBI:3738 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0080274 infores:hetionet CHEBI:8871 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0025874 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0037274 infores:hetionet CHEBI:7565 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0030196 infores:hetionet CHEBI:135939 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0013182 infores:hetionet CHEBI:2955 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0033774 infores:hetionet CHEBI:9288 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0085624 infores:hetionet NCBITaxon:55824 biolink:causes MONDO:0001191 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:55824 MONDO:0001191 CHEBI:3127 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0085631 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0860713 infores:hetionet CHEBI:6539 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0018524 infores:hetionet CHEBI:42797 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0086439 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0086543 infores:hetionet CHEBI:114785 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0022575 infores:hetionet CHEBI:63616 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0333355 infores:hetionet NCBIGene:1630 biolink:causes MONDO:0007576 infores:monarchinitiative not_provided not_provided HGNC:2701 MONDO:0007576 uuid:c8eec6ee-3f34-45c6-aea0-bab3ce8d38ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA012160 biolink:causes MONDO:0007947 infores:clingen CAID:CA012160 MONDO:0007947 PMID: Pathogenic PP2, PM2_Supporting, PS4, PM1, PP1_Strong, PS2_Supporting PM6, PVS1, BS2, PP3, PP4, BP2, BP1, BP4, BP3, BA1, PS3, PS1, PM3, PM4, PM5, BP7, BS1, BS4, BS3 NM_00138 c.1453C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 485 (p.Arg484Cys). This variant has been identified in the literature in at least seven probands with features consistent with or suggestive of Marfan syndrome including thoracic aortic aneurysm and dissection (TAAD) with or without additional features (PS4; PMIDs: 16342915, 19293843, 24793577, 30485715). It was found in the homozygous state in two cousins with bilateral ectopia lentis (EL) and additional features of Marfan syndrome; of note, in both instances the variant was inherited from mildly affected or apparently unaffected heterozygous parents (PMID: 17568394). It was identified in trans with a different FBN1 pathogenic variant in three siblings with isolated EL (Bichat internal data); clinical information for the heterozygous parents was not available. The variant has also been identified in the heterozygous state in 5 additional internal probands diagnosed with TAAD with or without systemic features (UZG, Johns Hopkins University, Bichat, & University of Tokyo internal data). It has been found to segregate in the heterozygous state with features of Marfan syndrome in at least 19 individuals among five different families (PP1_strong; PMID: 30485715; Johns Hopkins & Bichat internal data). It has been identified as de novo once with confirmed maternity/paternity in an internal proband with a non-specific phenotype (PS2_supporting; PMID: 19293843; UZG internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis are unclear about the variant’s predicted impact on the protein’s structure or function. The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_strong, PM1, PS2_supporting, PM2_supporting, PP2. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA012160/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:35778 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0233407 infores:hetionet CAID:CA228514 biolink:causes MONDO:0015629 infores:clingen CAID:CA228514 MONDO:0015629 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4, PM5 The NM_000552.5:c.4021C>T variant in VWF is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 1341. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of loss of high molecular weight multimers and an enhanced RIPA assay showing gain of function, which together are highly specific for VWD type 2B. (PP4_moderate, PMID 20118404). VWF antigen/activity ratio was consistent with type 2B which is consistent with VWD type 2B. This variant has been reported in 4 additional probands meeting PP4 laboratory phenotype criteria for VWD 2B (PS4; PMIDs 26456374, 18805962, 9723578). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00006615 (based on 8/60002 alleles in the admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for type 2B (PM2_Supporting). The computational predictor REVEL gives a score of 0.889, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Another missense variant c.4022G>A (p.Arg1341Gln) in the same codon has been classified as pathogenic for VWD 2B by the ClinGen VWD VCEP (PM5). Splicing prediction using SpliceAI revealed no expected effects on splicing due to any of these variants. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant von Willebrand disease 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS4, PM2_Supporting, PP3, PM5 (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228514/MONDO:0015629/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4995 biolink:causes UMLS:C0236003 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0236003 infores:hetionet CHEBI:4562 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0019348 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0006849 infores:hetionet CHEBI:64321 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0006826 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0022408 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0012254 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0012254 infores:hetionet GO:0120222 biolink:causes GO:0001701 infores:ubergraph knowledge_assertion manual_agent GO:0120222 GO:0001701 CHEBI:5103 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0039231 infores:hetionet NCBIGene:4010 biolink:causes MONDO:0008061 infores:monarchinitiative not_provided not_provided HGNC:6654 MONDO:0008061 uuid:84f16552-2f7d-45c4-9670-f116b869f909 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905275 biolink:causes CL:0000247 infores:ubergraph knowledge_assertion manual_agent GO:1905275 CL:0000247 CAID:CA143886 biolink:causes MONDO:0021060 infores:clingen CAID:CA143886 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.1140C>T (p.Ala380=) variant in the MAP2K2 gene is 0.003% (2/796) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA143886/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:54344 biolink:causes MONDO:0033556 infores:monarchinitiative not_provided not_provided HGNC:3007 MONDO:0033556 uuid:ff27ef3f-4e89-4e4a-a24c-fc39510aa244 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31638 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0006852 infores:hetionet CHEBI:40279 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0028643 infores:hetionet CHEBI:8502 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0037299 infores:hetionet CHEBI:2611 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0008031 infores:hetionet NCBIGene:25 biolink:causes MONDO:0060532 infores:monarchinitiative not_provided not_provided HGNC:76 MONDO:0060532 uuid:a9be5abf-2745-4564-bc15-8f9a5a343e3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:521033 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0854382 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0085096 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011991 infores:hetionet CHEBI:93635 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0151596 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0031542 infores:hetionet UNII:T58MSI464G biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0267596 infores:hetionet CHEBI:71415 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0023530 infores:hetionet CHEBI:3655 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0002994 infores:hetionet UMLS:C0657912 biolink:causes HP:0032964 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151582 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0858598 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0235678 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0235678 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0948525 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0242350 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042267 infores:hetionet CHEBI:7492 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0020517 infores:hetionet CHEBI:16899 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1260880 infores:hetionet CHEBI:6339 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0004093 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0022658 infores:hetionet CAID:CA2837589098 biolink:causes MONDO:0015967 infores:clingen CAID:CA2837589098 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 The c.1207del variant in the HNF1A homoeobox A gene, HNF1A, causes a frameshift in the protein at codon 1207 in NM_000545.8, adding 10 novel amino acids before encountering a stop codon (p.(Leu403SerfsTer10)). This variant, located in biologically-relevant exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1207del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0 approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2837589098/MONDO:0015967/017 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63621 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0026858 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0520893 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1141861 infores:hetionet CHEBI:8707 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011168 infores:hetionet CAID:CA512318852 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318852 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5:c.292del p.(Leu98SerfsTer24) variant is a frameshift variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay. All the biologically relevant transcripts are predicted to be affected (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and is a nonsense variant downstream of c.98 (in transcript NM_001754.4) (PM5_supporting). The c.292del variant has been reported in one proband with a diagnosis of clonal cytopenia of undetermined significance (PMID: 33179473). This variant was identified by NGS and had a VAF of 33%. However, its germline origin was not assessed in the study. Therefore, we cannot assess case-study/segregation criteria. In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318852/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15854 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0262988 infores:hetionet CHEBI:5100 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0232462 infores:hetionet CHEBI:4024 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0009766 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0013395 infores:hetionet CHEBI:5134 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0547030 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023067 infores:hetionet CHEBI:4027 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0000768 infores:hetionet NCBITaxon:5598 biolink:causes MONDO:0044083 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5598 MONDO:0044083 CHEBI:6538 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0687133 infores:hetionet CHEBI:2569 biolink:causes UMLS:C0281803 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0281803 infores:hetionet CHEBI:6067 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0233762 infores:hetionet CHEBI:15428 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0547030 infores:hetionet CHEBI:63589 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0035410 infores:hetionet CHEBI:408174 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0037763 infores:hetionet CHEBI:136040 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0022107 infores:hetionet CHEBI:9435 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0039070 infores:hetionet CHEBI:8228 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0231218 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0272753 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0272753 infores:hetionet CHEBI:5165 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011603 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0006266 infores:hetionet CHEBI:61049 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0041582 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0018802 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151436 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0002871 infores:hetionet CAID:CA9307087 biolink:causes MONDO:0100283 infores:clingen CAID:CA9307087 MONDO:0100283 PMID: Likely Benign BP7, BP4 BS1 This NM_005027.4(PIK3R2): c.1629G>A (p.Glu543=) variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as Likely benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BP4, BP7; -2 points (VCEP specifications version 1; Approved: 1/31/2021) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA9307087/MONDO:0100283/018 2022-02-11 2022-02-11 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Contradicts https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:5132 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0262397 infores:hetionet CHEBI:64355 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085593 infores:hetionet CHEBI:15940 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0037763 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002418 infores:hetionet NCBIGene:7072 biolink:causes MONDO:0011466 infores:monarchinitiative not_provided not_provided HGNC:11802 MONDO:0011466 uuid:1bea8959-e99e-4d94-b678-47ccbd4be2af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:81620 biolink:causes MONDO:0013431 infores:monarchinitiative not_provided not_provided HGNC:24576 MONDO:0013431 uuid:3dec79c8-43ad-4c3a-be57-16b3f31318b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135961 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0281981 infores:hetionet CHEBI:7465 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0036508 infores:hetionet CHEBI:2636 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0042963 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162429 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0851341 infores:hetionet GO:0090235 biolink:causes GO:0007049 infores:ubergraph knowledge_assertion manual_agent GO:0090235 GO:0007049 CAID:CA1620059 biolink:causes MONDO:0800472 infores:clingen CAID:CA1620059 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PP3_Moderate, PP1_Moderate BA1, BP4, PM1, PM4, PM5, PS1, PS2, PS3, BP7, BS1, BS4, PVS1 The c.317C>A variant in CYP1B1 is a missense variant predicted to cause substitution of Alanine by Aspartic Acid at amino acid 106 (p.Ala106Asp). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00001717 (1 allele out of 58,242), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.847, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27060699). 2 affected segregations with a CYP1B1-related phenotype and 2 unaffected segregations have been reported (PMIDs: 38450436, 23218701), which fulfilled PP1_Moderate. This variant has been identified in 6 individuals with a CYP1B1-related phenotype. These individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (2 confirmed in trans and 4 with phase unknown) (PMIDs: 25952714, 38450436, 35170016, 23218701, 19234632). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 13 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very-strong, PP1_Moderate, PP3_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1620059/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17630 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0235032 infores:hetionet CHEBI:135451 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0015967 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0948594 infores:hetionet NCBIGene:79228 biolink:causes MONDO:0013362 infores:monarchinitiative not_provided not_provided HGNC:28369 MONDO:0013362 uuid:130341da-85cc-4f49-a044-c8289285d258 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235234 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038814 infores:hetionet CHEBI:49575 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0547030 infores:hetionet CHEBI:91541 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0000737 infores:hetionet GO:0006954 biolink:causes MONDO:0005480 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003877 DB00547_MESH_D003877_1DB01130_MESH_D003877_1 CHEBI:36704 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0009782 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0259799 infores:hetionet CAID:CA120579 biolink:causes MONDO:0044970 infores:clingen CAID:CA120579 MONDO:0044970 PMID:10996779 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PM6 The m.4369dup variant in MT-TQ has been reported in one individual with primary mitochondrial disease (PMID: 10996779; likely this individual is included in PMID: 17560547). This child had chronic progressive external ophthalmoplegia (CPEO), muscle weakness, ptosis, and progressive dysphonia and dysphagia. Muscle biopsy showed COX-deficient ragged red fibers and there was a decrease in steady state levels of COII and ND1. The variant was present at 87% heteroplasmy in limb muscle, 61% in lid elevator muscle, 23% in fibroblasts, and was undetectable in blood. The variant was undetectable in blood from the mother and brother however technology at the time was limited in detecting low heteroplasmy levels. This variant extends the anticodon loop from seven to eight bases. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in COX-negative fibers (82.7 ± 14.73%; n=16) than in COX-positive red fibers (54.1 ± 18.36%; n=17; p<0.001; PS3_supporting, PMID: 10996779). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120579/MONDO:0044970/015 2024-05-28 2025-10-29 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true HP:0031377 biolink:causes MONDO:0005212 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D012208 DB00970_MESH_D012208_1 CHEBI:3534 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0029408 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0012833 infores:hetionet CAID:CA512318615 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318615 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.711G>A (p.Arg237=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.03) (BP4) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318615/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63580 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0549622 infores:hetionet CHEBI:8412 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0017178 infores:hetionet CHEBI:46345 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0023530 infores:hetionet NCBIGene:1540 biolink:causes MONDO:0011512 infores:monarchinitiative not_provided not_provided HGNC:2584 MONDO:0011512 uuid:e9ac6f4a-512a-402c-bf1d-0384c3cd42dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27779 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0015672 infores:hetionet CHEBI:135342 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0338831 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002622 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0012359 infores:hetionet CAID:CA8314782 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314782 MONDO:0009276 PMID: Benign BP4, BA1 The missense variant NM_000173.7(GP1BA):c.482C>T (p.Thr161Met) is associated with the polymorphism HPA-2. Moreover, the Grpmax filtering allele frequency in gnomAD v4.1 is 0.2237 (based on 16982/74950 alleles) in African/African American population, which is significantly higher than the ClinGen PD VCEP threshold (>0.001) for BA1. Additionally, the computational predictor REVEL gives a score of 0.041, which is below the ClinGen PD VCEP threshold of <0.25 predicting no damaging effect on GP1BA function and the SpliceAI score is zero (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314782/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46195 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0030196 infores:hetionet CHEBI:29688 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0149745 infores:hetionet CHEBI:39867 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0004093 infores:hetionet CHEBI:135361 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0152198 infores:hetionet CHEBI:584020 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0220870 infores:hetionet CHEBI:135530 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0013395 infores:hetionet CHEBI:18248 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0030554 infores:hetionet CAID:CA412741117 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741117 MONDO:0100437 PMID: Uncertain Significance PS1_Moderate, PP3, PM2_Supporting PS4 NM_001034853.2(RPGR):c.934G>A (p.Asp312Asn) is a missense variant located in the final nucleotide of exon 8, and encodes the substitution of aspartic acid with asparagine at amino acid 312. The splicing impact predictor SpliceAI gives a score of 0.97 for donor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3). This variant is outside the +/- 1,2 dinucleotide and meets the PP3 code due to predicted splicing disruption and another predicted splicing variant in the same donor site, NM_001034853.2(RPGR):c.934+1G>T (PMID: 14564670), was previously classified as a pathogenic variant for RPGR-related retinopathy by ClinGen X-linked IRD VCEP (PS1_moderate). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 affected proband (PMID: 14564670), however, the number of individuals meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, with decreased or absent cone and/or rod electroretinogram responses, was fewer than the requirement of 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0: PS1_Moderate, PP3, and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741117/MONDO:0100437/106 2025-07-31 2025-07-31 X-linked inheritance HP:0001417 Inconclusive true UNII:Z5N076G8YQ biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0017178 infores:hetionet CHEBI:51137 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0086565 infores:hetionet CHEBI:6690 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011603 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0017178 infores:hetionet CHEBI:37924 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0008031 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1384666 infores:hetionet NCBITaxon:129726 biolink:causes MONDO:0005850 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:129726 MONDO:0005850 CHEBI:30830 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0015230 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027651 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0030922 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0030922 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0853149 infores:hetionet CHEBI:135566 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0344232 infores:hetionet CAID:CA235334 biolink:causes MONDO:0018997 infores:clingen CAID:CA235334 MONDO:0018997 PMID:17603482PMID:29493581PMID:25706034PMID:17603482PMID:22389993PMID:23877478 Pathogenic PS3, PM1, PM2, PP2, PM6_Strong The c.770C>T (p.Ser257Leu) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17603482,22389993, 23877478, 23312806, 25706034). In vitro functional studies provide some evidence that the p.Ser257Leu variant may impact protein function (PS3; PMID 17603482). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235334/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:2549 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013395 infores:hetionet CHEBI:51164 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0032231 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0086525 infores:hetionet NCBIGene:2697 biolink:causes MONDO:0009768 infores:monarchinitiative not_provided not_provided HGNC:4274 MONDO:0009768 uuid:321e68de-c26e-433f-a6ac-c28ebd0cd3db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92511 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0018681 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0013378 infores:hetionet NCBITaxon:5864 biolink:causes MONDO:0005661 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5864 MONDO:0005661 CHEBI:2904 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0021775 infores:hetionet CHEBI:9434 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0027121 infores:hetionet CHEBI:68841 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0009450 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0152128 infores:hetionet CHEBI:125354 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0015672 infores:hetionet CAID:CA1624148 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624148 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.3552T>G (p.Pro1184=) variant in the SOS1 gene is 0.126% (17/8594) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624148/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7640 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0040264 infores:hetionet CHEBI:31709 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0030305 infores:hetionet CHEBI:8776 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0002962 infores:hetionet CHEBI:3172 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C1456784 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151596 infores:hetionet CHEBI:3568 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1167965 infores:hetionet CAID:CA658823289 biolink:causes MONDO:0001586 infores:clingen CAID:CA658823289 MONDO:0001586 PMID: Likely Pathogenic PM4, PM3, PM1, PP3, PM2_Supporting PP4 "The NM_000203.5:c.1073_1093del in IDUA is predicted to cause a change in the length of the protein (p.His358_Thr364del) due to an in-frame deletion of 7 amino acids in a non-repeat region (PM4). This deletion removes Arg363, a residue that has been shown to be important in substrate binding in IDUA and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMIDs: 23959878, 24036510; 24480078, 25459762) (PM1). The variant is predicted to be ""disease-causing"" by MutationTaster, and MutPreIndel gives a score of 0.77463 suggesting that the variant is damaging to IDUA function (PP3). An individual with severe MPS 1 (Hurler syndrome) is reported to be compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS 1, c.1205G>A (p.Trp402Ter); phase confirmed (PMID: 31678774) (insufficient evidence to apply PP4, PM3 applied). The highest population minor allele frequency in gnomAD v4.1.0 is 8.477e-7 (1/1179614 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 557260). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM1, PM3, PM4, PP3 PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658823289/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:23765 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013390 infores:hetionet CHEBI:49662 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0004093 infores:hetionet CHEBI:4514 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0039070 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0234913 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0548823 infores:hetionet NCBIGene:59344 biolink:causes MONDO:0011680 infores:monarchinitiative not_provided not_provided HGNC:13743 MONDO:0011680 uuid:ce0eb447-cfa3-4053-b472-1e73e77f174a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013298 infores:hetionet CHEBI:15367 biolink:causes HP:6000793 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0521172 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0006147 infores:hetionet CAID:CA402996954 biolink:causes MONDO:0012999 infores:clingen CAID:CA402996954 MONDO:0012999 PMID: Pathogenic PP3, PP4_Strong, PM2_Supporting, PS3, PM3_Supporting The NM_000156.6:c.224C>T variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 75 (p.Ala75Val). One patient, with mild intellectual disability, anti-epileptic drug-responsive seizures, and stereotypic movements has been reported with creatine and guanidinoacetate peak absent on MRS, bilateral thalami increased on MRI, and urine guanidinoacetate levels between 1.1 and 12 times above the upper limit of reference range (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (1/15028 alleles) in the African population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). GAMT-deficient fibroblasts transfected with the variant showed <15% wild-type enzyme activity (PMID: 24415674). The computational predictor REVEL gives a score of 0.86 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 544251). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting. Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402996954/MONDO:0012999/026 2023-03-09 2023-03-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63598 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014518 infores:hetionet CHEBI:107736 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0004096 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018621 infores:hetionet CHEBI:63621 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0085593 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0259749 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0003811 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0853813 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0032285 infores:hetionet CHEBI:50275 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0030193 infores:hetionet CHEBI:53691 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0004093 infores:hetionet CAID:CA1707263 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707263 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PP1, PM2_Supporting PM3 The NM_003494.4: c.5044C>T p.(Gln1682Ter) variant in DYSF, which is also known as NM_001130987.2: c.5161C>T p.(Gln1721Ter), is a nonsense variant predicted to cause a premature stop codon in exon 45/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). This variant has been reported in trans with a second presumed diagnostic DYSF variant in an individual with progressive proximal muscle weakness (PMID: 32140910; PP4). This variant has also been shown to co-segregate with autosomal recessive LGMD in one affected family member (PMID: 32140910; PP1). The highest allele frequency for this variant is 0.00001098 in the South Asian population of gnomAD v4.1.0 (1/91086 chromosomes), which is less than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PP4, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707263/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7025 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0030193 infores:hetionet CHEBI:3398 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0022107 infores:hetionet CHEBI:521033 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0006826 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042267 infores:hetionet CHEBI:38562 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C3665347 infores:hetionet NCBITaxon:10299 biolink:causes MONDO:0015288 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10299 MESH:D007635 DB00194_MESH_D007635_1DB00194_MESH_D016849_1DB00249_MESH_D016849_1 CHEBI:50648 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027339 infores:hetionet CHEBI:5893 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0028961 infores:hetionet CHEBI:9434 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0428977 infores:hetionet CHEBI:35854 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0232462 infores:hetionet UNII:T58MSI464G biolink:causes HP:6000377 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C1112565 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234930 infores:hetionet CHEBI:5130 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C3665347 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009763 infores:hetionet CAID:CA220498 biolink:causes MONDO:0001586 infores:clingen CAID:CA220498 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4 PS3, BS1, PM2 The NM_000203.5:c.1205G>A (p.Trp402Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of a total of 14 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Complete loss of IDUA activity was confirmed when the variant was transiently expressed in COS-7 cells (PMID: 11735025) (PVS1). This is the most common variant to be identified in patients with mucopolysaccharidosis type 1 (MPS1) in the United States (45% of alleles), Mexico (29%), Colombia (50%), Brazil (29%), the United Kingdom (45%), the Netherlands (42%), Germany (50%), the Czech Republic and Slovakia (33%), Spain (62%) and Australia (34%) (reviewed in PMID: 29393969). At least 38 homozygotes (PMID: 1301196, 28752568) (max PM3 points = 2 x 0.5 = 1 point for homozygotes), and at least 73 individuals who are compound heterozygous for the variant and a second variant in IDUA, including another well-known pathogenic variant, p.Gln70Ter, have been reported (PMID: 1301941, 11735025, 28752568, 30809705). The allelic evidence from these compound heterozygous patients will be used to support the classification of the other variant and is not included here to avoid circular logic (PM3 based on evidence from homozygotes). Patients are reported with detailed clinical features of MPS I or elevated urine GAGs in addition to documentation of laboratory values showing deficient IDUA activity (PMID: 1301941, 11735025, 30809705) (PP4). A knock in mouse, homozygous for a variant analogous to p.Trp402Ter (mouse Idua Trp392Ter) was reported to have a phenotype that closely correlates with features in humans patients with MPS1 (PMID: 19751987). The highest population minor allele frequency in gnomAD v4.1.0 is 0.001555 (1749/1124730 alleles) in the European non-Finnish population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) and lower than the threshold for BS1 (>0.0025). Therefore, no population codes are met. Additional data is available in the literature but the classification of pathogenic has already been reached. There is a ClinVar entry for this variant (Variation ID: 11908). In summary, this variant is the most frequently reported variant in individuals with MPS1 and meets the criteria to be classified as pathogenic for this disorder. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220498/MONDO:0001586/091 2025-01-03 2025-01-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36795 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0004238 infores:hetionet CHEBI:2663 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040128 infores:hetionet CHEBI:8214 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0022568 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011630 infores:hetionet CHEBI:8382 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1291078 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0221714 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020615 infores:hetionet CHEBI:49713 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0151564 infores:hetionet NCBIGene:10060 biolink:causes MONDO:0012062 infores:monarchinitiative not_provided not_provided HGNC:60 MONDO:0012062 uuid:8298d0f4-8884-438f-832a-d95dd17f6721 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0497156 infores:hetionet CHEBI:5959 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0002792 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0038587 infores:hetionet CHEBI:6847 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0162429 infores:hetionet CHEBI:50859 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011175 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038358 infores:hetionet CHEBI:6402 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0003467 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0006145 infores:hetionet CHEBI:4784 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0085605 infores:hetionet CHEBI:3082 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013378 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0021400 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151966 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151966 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151883 infores:hetionet UMLS:C1738934 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085632 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009763 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0553704 infores:hetionet CHEBI:474180 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0043352 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0340464 infores:hetionet CHEBI:3387 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018524 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0302810 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0302810 infores:hetionet CHEBI:9123 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013378 infores:hetionet CHEBI:18358 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0016689 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0152517 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0242350 infores:hetionet CHEBI:75246 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0041657 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0024115 infores:hetionet CHEBI:3479 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151578 infores:hetionet CHEBI:4975 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0027497 infores:hetionet GO:1900225 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:1900225 GO:0051716 CHEBI:63598 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042510 infores:hetionet CHEBI:3478 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013428 infores:hetionet CHEBI:3181 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0013604 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0001883 infores:hetionet CHEBI:63791 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038990 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042401 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0178298 infores:hetionet CAID:CA386493305 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493305 MONDO:0009861 PMID:31355225 Likely Pathogenic PM3, PP4_Moderate, PM2 PM5, PP3 The c.1102G>A (p.Glu368Lys) variant in PAH has been reported in 1 individual with moderate PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 31355225). This variant has extremely low frequency in gnomAD: MAF=0.00001 (PM2). This variant was detected in trans with pathogenic variant c.1066-11G>A. Parents were also investigated to confirm their carrier status. (PM3). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493305/MONDO:0009861/006 2020-06-26 2020-06-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6129 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0041969 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0031117 infores:hetionet CHEBI:63630 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0026821 infores:hetionet CHEBI:5002 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0009806 infores:hetionet NCBIGene:2651 biolink:causes MONDO:0007289 infores:monarchinitiative not_provided not_provided HGNC:4204 MONDO:0007289 uuid:9de74215-8a6d-4dfd-af9c-23f4a3843f2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4151 biolink:causes MONDO:0859530 infores:monarchinitiative not_provided not_provided HGNC:6915 MONDO:0859530 uuid:1b1ef9f3-a6e7-43f1-abd1-c1a118aa15f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0013491 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0003123 infores:hetionet CHEBI:42797 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0687713 infores:hetionet CHEBI:35778 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0549249 infores:hetionet CHEBI:59560 biolink:causes MONDO:0043797 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0037929 infores:hetionet CHEBI:2379 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0013395 infores:hetionet CHEBI:8874 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0080274 infores:hetionet CHEBI:63619 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0037188 infores:hetionet CHEBI:82866 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0241164 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0013395 infores:hetionet CHEBI:2038 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0032227 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042769 infores:hetionet CHEBI:9586 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0014591 infores:hetionet CAID:CA2499214318 biolink:causes MONDO:0013144 infores:clingen CAID:CA2499214318 MONDO:0013144 PMID: Pathogenic PS4, PM4, PM1, PP1_Moderate, PP4, PM2_Supporting The c.1273_1275del variant in SERPINC1 is predicted to cause a change in the length of the protein (p.Arg425del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4). This variant resides within the critical P1 region of SERPINC1 that allows binding to factor X (PM1). This variant has been reported in four probands meeting an antithrombin activity level of < 0.8 IU/mL and a family history of antithrombin activity levels of < 0.8 IU/mL (PS4; PMID:12591924). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members from two families (PP1_Moderate; PMID:12591924). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis: PM4, PP4, PS4, PM2_Supporting, PM1, PP1_Moderate. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499214318/MONDO:0013144/084 2025-02-21 2025-02-21 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3223 biolink:causes HP:0001816 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0423823 infores:hetionet GO:0014816 biolink:causes CL:0000594 infores:ubergraph knowledge_assertion manual_agent GO:0014816 CL:0000594 CHEBI:9168 biolink:causes MONDO:0100313 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017668 infores:hetionet CHEBI:194135 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030196 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018802 infores:hetionet CHEBI:72297 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0151662 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0027651 infores:hetionet CHEBI:50173 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0232461 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0424000 infores:hetionet CHEBI:3061 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C2830004 infores:hetionet CHEBI:50173 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0043094 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006840 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0006147 infores:hetionet GO:1905024 biolink:causes GO:0086003 infores:ubergraph knowledge_assertion manual_agent GO:1905024 GO:0086003 CHEBI:100246 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0152025 infores:hetionet CHEBI:8707 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C2047937 infores:hetionet CHEBI:8713 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C2830004 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1262113 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014868 infores:hetionet CHEBI:2639 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0030554 infores:hetionet CAID:CA209185 biolink:causes MONDO:0100039 infores:clingen CAID:CA209185 MONDO:0100039 PMID: Benign BS2_Supporting, BP5, BA1, BP4 The allele frequency of the p.Val966Ile variant in CDKL5 is 0.03% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val966Ile variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). Computational analysis prediction tools suggest that the p.Val966Ile variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Val966Ile variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Val966Ile variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA209185/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:8461 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0043352 infores:hetionet CHEBI:3752 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0019294 infores:hetionet CHEBI:75984 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0547030 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002418 infores:hetionet CHEBI:9907 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0028734 infores:hetionet CHEBI:31174 biolink:causes MONDO:0006564 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0162823 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0574067 infores:hetionet CHEBI:520985 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0344232 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042571 infores:hetionet CHEBI:27834 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0017675 infores:hetionet CAID:CA624860719 biolink:causes MONDO:0008723 infores:clingen CAID:CA624860719 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1508del (p.Gly503fs) variant in ACADVL, also known as p.Gly503GlufsTer7, is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 15/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008796 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. (ACADVL VCEP specifications version 1; approved November 8, 2021 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624860719/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63589 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0002622 infores:hetionet CHEBI:4670 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0040034 infores:hetionet NCBIGene:283417 biolink:causes MONDO:0013505 infores:monarchinitiative not_provided not_provided HGNC:19414 MONDO:0013505 uuid:03f08e32-e590-4886-9ca4-bd2d9c6d3b1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0032227 infores:hetionet UNII:R43D2573WO biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0600228 infores:hetionet CHEBI:3380 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0002878 infores:hetionet CHEBI:31547 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C2979982 infores:hetionet CHEBI:6715 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006152 infores:hetionet CHEBI:6121 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0232462 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0012833 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0677500 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0037199 infores:hetionet CHEBI:9566 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0023052 infores:hetionet CHEBI:64354 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0028734 infores:hetionet CHEBI:35854 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0038362 infores:hetionet CAID:CA397722627 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722627 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate The c.342+1G>C variant in ACADVL occurs within the canonical splice donor site of intron 5. It is predicted to cause skipping of biologically-relevant-exon 5, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Moderate). This variant is reported in at least one patient with severe hypoglycemia and postmortem C14:1 measurement of 1.35uM (PP4, PMID: 20107901). In addition, this patient carried the p.Val283Ala mutation. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PP4_Moderate). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722627/MONDO:0008723/021 2022-02-07 2022-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6539 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0029408 infores:hetionet CHEBI:68478 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020625 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002905 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0026884 infores:hetionet CAID:CA020313 biolink:causes MONDO:0008667 infores:clingen CAID:CA020313 MONDO:0008667 PMID: Uncertain Significance PS4_Moderate, BS1, PM1, PP3 PS3, BP4 The variant NM_000551.4(VHL):c.376G>A (p.Asp126Asn) is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at position 126. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00003260 (50/1111878 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). However, this variant fulfills several pathogenic evidence codes as follows. This variant has been reported in 1 proband in literature, a 53yo male with right jugulotympanic paraganglioma (nonspecific = 0.25 points) (PMID: 22566194). This variant has been seen 12 times in testing at Invitae with 3 cases bearing VHL tumors, 3 times at GeneDX with no cases presenting VHL tumors, and 19 times at Ambry with 2 cases including VHL tumors. For the observed cases without VHL spectrum tumors, they either had no personal history of cancer or non-VHL cancers. None were >65yo and lacked VHL-spectrum tumors. In total, the case points calculated are 2.5 points which sums to PS4_Moderate. One HIF-a degradation assay using this variant showed modest / intermediate inability to degrade HIF-a (PMIDs:21454469), but does not meet the criteria for PS3_Supporting. This variant resides within a region of VHL that is defined as a critical functional domain (the Beta Domain) (PM1). The computational predictor REVEL gives a score of 0.716, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). In summary, due to the prevalence of this variant in the gnomAD and numerous cases lacking VHL tumors (though not above the threshold of 65yrs to fulfill the benign criteria) as well as weak/intermediate functional evidence, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020313/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013390 infores:hetionet CHEBI:7852 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020625 infores:hetionet CHEBI:3732 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0030252 infores:hetionet CHEBI:9555 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0010828 infores:hetionet CHEBI:9667 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0027497 infores:hetionet CHEBI:8356 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014866 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020517 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0027769 infores:hetionet CHEBI:61390 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0267792 infores:hetionet NCBIGene:8287 biolink:causes MONDO:0010767 infores:monarchinitiative not_provided not_provided HGNC:12633 MONDO:0010767 uuid:7e6777c1-4408-41b7-9d6e-ff2367aac0d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85083 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0013395 infores:hetionet CHEBI:9649 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042029 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151946 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151946 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0031542 infores:hetionet CHEBI:4708 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0037763 infores:hetionet CHEBI:135736 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1527344 infores:hetionet CHEBI:47780 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022346 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017152 infores:hetionet NCBIGene:5256 biolink:causes MONDO:0010598 infores:monarchinitiative not_provided not_provided HGNC:8926 MONDO:0010598 uuid:45babfba-4a28-4e28-b3ba-dd584bb1b743 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0034880 infores:hetionet CHEBI:6339 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037011 infores:hetionet CHEBI:59773 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0152227 infores:hetionet CHEBI:6067 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0021368 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015230 infores:hetionet CHEBI:119486 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0009782 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1096657 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1096657 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0027769 infores:hetionet CAID:CA377482340 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482340 MONDO:0017623 PMID: Likely Pathogenic PM2, PP1_Moderate, PP2, PP3, PS4_Supporting PTEN c.402G>C (p.Met134Ile) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 23124040, internal laboratory contributor(s) ClinVar Organization ID: 26957)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23124040) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482340/MONDO:0017623/003 2025-08-01 2025-10-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5778 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0392176 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0162287 infores:hetionet CHEBI:681569 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0032227 infores:hetionet CAID:CA007480 biolink:causes MONDO:0100316 infores:clingen CAID:CA007480 MONDO:0100316 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PS3_Moderate, PP3 PP1 NM_000218.3(KCNQ1):c.565G>A (p.Gly189Arg) is a missense variant that causes replacement of glycine with arginine at position 189. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00002228, with 1/44884 in the East Asian population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is rare and has been reported in at least 2 apparently unrelated probands affected with long QT syndrome 1 (PS4_Supporting, PMID: 8528244, PMID: 10220144, PMID: 17470695). The computational predictor REVEL gives a score of 0.967, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.43 for donor loss, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP threshold of >0.5 and does not strongly predict that the variant disrupts the splicing of KCNQ1 (PP3). This variant has been shown to disrupt KCNQ1 function in three experimental assays, including manual patch-clamp, particularly in its impaired activation by treatment with the adenylyl cyclase / protein kinase A activator forskolin, and experimental / structural / functional simulation (PS3_Moderate; PMID: 22456477, PMID: 10376919, PMID: 29021305). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3_Moderate, PS4_Supporting, PM2_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007480/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5384 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0344232 infores:hetionet CHEBI:8212 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0017178 infores:hetionet CHEBI:5775 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0001824 infores:hetionet CAID:CA10014472 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014472 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.613+19G>A is an intronic variant which meets criteria for likely benign classification. It has a SpliceAI score ≤ 0.20 (0.0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.49)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014472/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:404903 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0239571 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0040479 infores:hetionet CHEBI:4798 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1305875 infores:hetionet CHEBI:52717 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020458 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002878 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0009450 infores:hetionet CHEBI:7465 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0040460 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0205204 infores:hetionet NCBIGene:54970 biolink:causes MONDO:0032924 infores:monarchinitiative not_provided not_provided HGNC:23700 MONDO:0032924 uuid:5c17ea50-45de-414d-ab5a-7c57f3d7b0d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes UMLS:C0015929 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0015929 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0033975 infores:hetionet UNII:DJJ95FJP1H biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0549249 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0019158 infores:hetionet CHEBI:46195 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0002792 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0342579 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0036572 infores:hetionet GO:0021889 biolink:causes CL:1001434 infores:ubergraph knowledge_assertion manual_agent GO:0021889 CL:1001434 NCBIGene:2916 biolink:causes MONDO:0009758 infores:monarchinitiative not_provided not_provided HGNC:4598 MONDO:0009758 uuid:95dd59b8-d2dc-49e8-ab28-335ea58c5b6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0948594 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0030332 infores:hetionet CHEBI:110423 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0011168 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232431 infores:hetionet CHEBI:8430 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0011606 infores:hetionet CAID:CA220592 biolink:causes MONDO:0009861 infores:clingen CAID:CA220592 MONDO:0009861 PMID:26666653PMID:26666653PMID:18590700 Pathogenic PM3, PM2, PP4, PP3, PS3 PAH-specific ACMG/AMP criteria applied: PM2: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220592/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6413 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0003864 infores:hetionet CHEBI:36795 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013456 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020456 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020514 infores:hetionet CHEBI:6015 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0019158 infores:hetionet CHEBI:8499 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0011603 infores:hetionet CHEBI:3242 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0012569 infores:hetionet CHEBI:6067 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0549249 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0042109 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0302832 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0302832 infores:hetionet CAID:CA338870 biolink:causes MONDO:0700270 infores:clingen CAID:CA338870 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1 PM2 The c.2413C>T (p.Arg805Ter) variant in ATM is a nonsense variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. The highest minor allele frequency in gnomAD v2.1.1 is 0.0003263 (6/18388) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 26896183, 12815592, 15843990, 16941484, 23807571). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA338870/MONDO:0700270/020 2024-01-24 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40303 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0853034 infores:hetionet CAID:CA213713 biolink:causes MONDO:0015967 infores:clingen CAID:CA213713 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1124C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to phenylalanine at codon 375 (p.(Ser375Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4; ClinVar 36175, internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (fasting glucose 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of hyperglycemia. (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213713/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:3216 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0575081 infores:hetionet CHEBI:15367 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018808 infores:hetionet CHEBI:6887 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0010200 infores:hetionet CHEBI:194135 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0424790 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017160 infores:hetionet CHEBI:6030 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0015967 infores:hetionet CHEBI:31524 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0392676 infores:hetionet CHEBI:4511 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0038362 infores:hetionet CHEBI:161680 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0027497 infores:hetionet CHEBI:85083 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0017178 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0178298 infores:hetionet CHEBI:474180 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0221201 infores:hetionet CHEBI:9168 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151825 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034186 infores:hetionet CHEBI:4445 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0438717 infores:hetionet CHEBI:49575 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0016655 infores:hetionet CHEBI:145499 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0021177 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0002622 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0035078 infores:hetionet CHEBI:10110 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0338831 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042401 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0853811 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0853811 infores:hetionet CHEBI:50841 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0019158 infores:hetionet NCBIGene:197257 biolink:causes MONDO:0009505 infores:monarchinitiative not_provided not_provided HGNC:19708 MONDO:0009505 uuid:6dc4a0b7-8f90-463b-a323-32939d752266 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0033774 infores:hetionet CHEBI:9449 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0003467 infores:hetionet CHEBI:184555 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0023473 infores:hetionet CHEBI:53760 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0240327 infores:hetionet NCBITaxon:1301 biolink:causes MONDO:0002258 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1301 MESH:D010612 DB00833_MESH_D010612_1 CHEBI:93363 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1527411 infores:hetionet CHEBI:27779 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0004093 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0003123 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040034 infores:hetionet NCBIGene:5587 biolink:causes MONDO:0044303 infores:monarchinitiative not_provided not_provided HGNC:9407 MONDO:0044303 uuid:e083d870-8e58-49ce-80ed-7009c20a8cb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0015672 infores:hetionet NCBIGene:4645 biolink:causes MONDO:0030810 infores:monarchinitiative not_provided not_provided HGNC:7603 MONDO:0030810 uuid:07941dcf-0f27-4ce8-9f3c-11e50f5da8ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019360 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0009450 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020676 infores:hetionet CHEBI:6015 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0018790 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0233414 infores:hetionet CHEBI:35854 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C1443060 infores:hetionet CHEBI:6717 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0003811 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0017160 infores:hetionet NCBIGene:1758 biolink:causes MONDO:0009430 infores:monarchinitiative not_provided not_provided HGNC:2932 MONDO:0009430 uuid:879214ea-f941-4b3f-b1e5-93242ecdf40c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037036 infores:hetionet CHEBI:5103 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0600142 infores:hetionet CHEBI:48538 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0030232 infores:hetionet CHEBI:8764 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151942 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014742 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0029456 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0015672 infores:hetionet CHEBI:367163 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020580 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0852733 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0020649 infores:hetionet CHEBI:125354 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0043352 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0015397 infores:hetionet CHEBI:8455 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0011603 infores:hetionet CAID:CA10576272 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576272 MONDO:0007750 PMID: Uncertain Significance PP1_Moderate, PM2, PP4 BP4, PM5, PP3 The NM_000527.5(LDLR):c.251C>T (p.Pro84Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PP1_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1)PP1_Moderate - Variant segregates with FH phenotype in at least 4 informative meiosis from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). In one family 2 family members positive for variant with LDL > 75th percentile, in the other 2 family members negative for variantwith LDL < 50th percentile.PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576272/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10125 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0242350 infores:hetionet CHEBI:28915 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0917801 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0178298 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0549622 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020542 infores:hetionet CHEBI:5280 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0542571 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0023067 infores:hetionet CHEBI:52010 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0086525 infores:hetionet CAID:CA10119380 biolink:causes MONDO:0021060 infores:clingen CAID:CA10119380 MONDO:0021060 PMID: Benign BA1, BP4, BP7 PM2, PP3, BS1 The NM_006767.4:c.2373C>T (p.His791=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v4 is 0.009141 (730/75058 alleles) in African/African American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10119380/MONDO:0021060/094 2024-09-17 2024-09-30 Undetermined mode of inheritance Contradicts true NCBIGene:64856 biolink:causes MONDO:0030977 infores:monarchinitiative not_provided not_provided HGNC:30910 MONDO:0030977 uuid:19f974f9-d805-41a1-a72f-bd329e195b65 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011253 infores:hetionet CHEBI:7824 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0023222 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0041912 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0027947 infores:hetionet CHEBI:8869 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0085649 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235848 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0426576 infores:hetionet CHEBI:5165 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013404 infores:hetionet CHEBI:2955 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0014518 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0152029 infores:hetionet CAID:CA2695195451 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695195451 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, PM4 PP1, PS4 NM_001034853.2(RPGR):c.1071_1073del (p.Gly358del) is an in-frame deletion of 3 nucleotides encoding glycine 358, which is part of the RCC1 domain that is known to have functional importance in RPGR (PM4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent cone and/or rod electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 34745198). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis from 1 family, which is not sufficient to meet the PP1 code (PMID: 34745198). In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM4 and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695195451/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Inconclusive true CHEBI:94686 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0000731 infores:hetionet CHEBI:8428 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0004093 infores:hetionet CHEBI:18243 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0018681 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0012833 infores:hetionet CHEBI:84883 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C1384353 infores:hetionet CHEBI:51364 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020672 infores:hetionet CAID:CA320643161 biolink:causes MONDO:0011071 infores:clingen CAID:CA320643161 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.98-147dup is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1, allowing for application of PM2_Supporting. This is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (0.06). In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100 (0.29) (BP4, BP7). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320643161/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7476 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020517 infores:hetionet CAID:CA1619962 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619962 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM4, PM3_Strong, PM1_Supporting, PP1_Strong PP3, BA1, BP4, PM5, PS3, PS1, PS2, BS1, BS4, BP7, PVS1 The c.806_814del variant in CYP1B1 is predicted to cause a change in the length of the protein due to an in-frame deletion of 3 amino acids (p.Ser269_Phe271del), meeting PM4. This in-frame indel variant is located in the G-helix, meeting PM1_Supporting. The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1) = 0.000002544 (3 alleles out of 1,179,058), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 14729846), which fulfilled PP1_Strong. This variant has been identified in 3 individuals with a CYP1B1-related phenotype. One individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) and two individuals are homozygous (non-consanguineous) for the variant (PMIDs: 15342693, 14635112, 14729846). Total points = 2, meeting PM3_Strong. There were more homozygous cases published than presented here. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PP1_Strong, PM4, PM1_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619962/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44185 biolink:causes MONDO:0019483 infores:ubergraph knowledge_assertion manual_agent CHEBI:44185 MONDO:0019483 CHEBI:135925 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0393760 infores:hetionet CHEBI:37333 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0003811 infores:hetionet CHEBI:3216 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0085631 infores:hetionet UMLS:C0657912 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0340865 infores:hetionet CHEBI:5109 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0038999 infores:hetionet CHEBI:4907 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0000737 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0029221 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0017178 infores:hetionet CHEBI:167309 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C1392046 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0000932 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0000932 infores:hetionet CHEBI:92712 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0033774 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0851578 infores:hetionet CHEBI:3242 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C2830004 infores:hetionet CHEBI:85078 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020615 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0013298 infores:hetionet CHEBI:7581 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0013144 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0017178 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0152006 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0152006 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0022408 infores:hetionet CHEBI:49960 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0917801 infores:hetionet CHEBI:135342 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0015230 infores:hetionet CHEBI:44032 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0239937 infores:hetionet CHEBI:5790 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0232292 infores:hetionet CHEBI:8802 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0085631 infores:hetionet CHEBI:50749 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0020517 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0035455 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0006145 infores:hetionet CHEBI:107736 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0042510 infores:hetionet CHEBI:404903 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0340865 infores:hetionet CHEBI:3011 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0042029 infores:hetionet CHEBI:31859 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013604 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0037052 infores:hetionet GO:1905000 biolink:causes GO:0060048 infores:ubergraph knowledge_assertion manual_agent GO:1905000 GO:0060048 CHEBI:50861 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0428977 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039520 infores:hetionet CAID:CA404099832 biolink:causes MONDO:0007750 infores:clingen CAID:CA404099832 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 The NM_000527.5 (LDLR):c.2530G>A (p.Gly844Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD 2.1.1).PP3: REVEL = 0.875.PM5 not met: One other variant in the same codon: -NM_000527.5:c.2531G>A (Gly844Asp) is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404099832/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5864 biolink:causes UMLS:C0340515 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0340515 infores:hetionet CHEBI:3371 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0022672 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015423 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0521500 infores:hetionet CHEBI:61058 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0030305 infores:hetionet CAID:CA512341139 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341139 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1278G>A (p.Pro426=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v4.0 (PM2_supporting). SpliceAI predicts no impact on splicing (score: 0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -1.5) (BP7). This variant was reported in ClinVar by Invitae, but the affected status of the proband is unknown (Variation ID 1586327). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341139/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8107 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0009782 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020649 infores:hetionet CHEBI:48538 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0700590 infores:hetionet GO:0017081 biolink:causes GO:1902476 infores:ubergraph knowledge_assertion manual_agent GO:0017081 GO:1902476 CHEBI:7496 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0917801 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0234913 infores:hetionet NCBIGene:51574 biolink:causes MONDO:0014031 infores:monarchinitiative not_provided not_provided HGNC:24912 MONDO:0014031 uuid:b17c1822-2013-4e37-bd84-5e1c3cf48b34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040264 infores:hetionet CHEBI:8212 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0042963 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011053 infores:hetionet CHEBI:48273 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0033774 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0007642 infores:hetionet CHEBI:7444 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0476273 infores:hetionet CHEBI:27690 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0002792 infores:hetionet GO:0032887 biolink:causes GO:0098813 infores:ubergraph knowledge_assertion manual_agent GO:0032887 GO:0098813 UMLS:C0004609 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0917798 infores:hetionet CHEBI:47381 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0019080 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0458104 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0458104 infores:hetionet CAID:CA231137 biolink:causes MONDO:0015967 infores:clingen CAID:CA231137 MONDO:0015967 PMID: Pathogenic PS4, PS1, PP1_Strong, PS3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.523G>A variant in the glucokinase gene, GCK causes an amino acid change of Gly to Arg at codon 210 (p.(Gly175Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with diabetes (PS4; PMID: 29944009, 20337973, 26552609, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 4 families with diabetes (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Gly175Arg variant has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657). The nucleotide change c.523G>C, which causes the same amino acid change, has been classified as pathogenic for MODY by the ClinGen MDEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3, PS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA231137/MONDO:0015967/086 2023-07-30 2023-07-30 Semidominant inheritance HP:0032113 Supports CHEBI:7445 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0206062 infores:hetionet CAID:CA386967823 biolink:causes MONDO:0015967 infores:clingen CAID:CA386967823 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP4_Moderate, PVS1 PS1 The c.956-1G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 4 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 5 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). The nucleotide changes c.956-1G>T and c.956-1G>A, which are predicted to disrupt the intron 5 splice acceptor site to a similar extent as c.956-1G>C, have been reported in a patient with diabetes; however, these variants have not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP without the use of PS1. This variant is also absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 31658956, ClinVar ID 617646, internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, sulfonylurea sensitive, and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21: PVS1, PS4, PP4_moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386967823/MONDO:0015967/017 2021-08-24 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47381 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009324 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0221165 infores:hetionet CHEBI:73275 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0600142 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0233632 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0152027 infores:hetionet CHEBI:45081 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0235886 infores:hetionet CHEBI:3032 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0018681 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0263386 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042109 infores:hetionet CHEBI:5141 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0015230 infores:hetionet CHEBI:8707 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0028084 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0243026 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0948525 infores:hetionet CAID:CA120226 biolink:causes MONDO:0015967 infores:clingen CAID:CA120226 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting The 1052T>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of methionine to arginine at codon 351 (p.(Met351Arg)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with four informative meioses in one family (PP1_Moderate; PMID: 17407387). PP4_moderate was met even without MPC or ABCC8 testing because multiple family members are diazoxide-responsive and would have to be a unique ABCC8 situation. (PP4_Moderate; PMID: 17407387). Functional studies demonstrated the p.Met351Arg protein has transactivation below 40% of wildtype but retains the same DNA binding activity as WT HNF4A, indicating that this variant impacts protein function (PMID: 21323639). In summary, c.1052T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS3_supporting, PP1_moderate, PP4_moderate, PM2_supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA120226/MONDO:0015967/085 2024-11-21 2024-11-21 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64355 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0221165 infores:hetionet CHEBI:107736 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0012833 infores:hetionet CAID:CA410148710 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148710 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.996C>G (p.Asp332Glu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). No proband meeting RUNX1 phenotypic criteria has been observed. This missense variant has a REVEL score <0.50 (0.334) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148710/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50692 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0013404 infores:hetionet CHEBI:5383 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0040034 infores:hetionet CHEBI:5130 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0000731 infores:hetionet CHEBI:18067 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0038999 infores:hetionet CHEBI:7983 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0015967 infores:hetionet CHEBI:16899 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1527344 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0281773 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0281773 infores:hetionet CHEBI:83531 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0017152 infores:hetionet CAID:CA401369511 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369511 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PS3_Moderate The NM_000152.5:c.1820G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 607 (p.Gly607Asp). Four probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMID: 29889338, 33301762, 37087815), three with documented deficiency of GAA activity (PMID: 33301762, 37097815) (PP4_Moderate). All of these probands are homozygous this variant. This variant is absent in both gnomAD 2.1.1 and 4.0.0 (PM2_Supporting). Expression of the variant in COS-7 cells resulted 2% wild-type GAA activity in one study (PMID: 14695532) and <2% wild-type GAA activity in a separate study (PMID: 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.872 which is above the threshold predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1819G>T (p.Gly607Cys) (ClinVar Variation ID: 2118057) and c.1819G>A (p.Gly607Ser) (ClinVar Variation ID: 456385), in the same codon have been reported in patients with Pompe disease. However, these variants have not been classified by the ClinGen Lysosomal Diseases VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 932221). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 2, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369511/MONDO:0009290/010 2024-04-02 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5109 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0235874 infores:hetionet CHEBI:3219 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013428 infores:hetionet NCBIGene:6742 biolink:causes MONDO:0008135 infores:monarchinitiative not_provided not_provided HGNC:11317 MONDO:0008135 uuid:3eb36e0f-ca5c-49a1-af1c-fa13747fb1d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0549336 infores:hetionet CHEBI:135925 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0013384 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020676 infores:hetionet CHEBI:5106 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0014742 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0002871 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013295 infores:hetionet CHEBI:17823 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0151714 infores:hetionet CAID:CA386964418 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964418 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5, PP4_Moderate, PP3 The c.619G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to cysteine at codon 207 (p.(Gly207Cys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.923, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributor). Additionally, this variant is located within the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, another missense variant, c.620G>A p.(Gly207Asp) has been interpreted as pathogenic by the ClinGen MDEP and p.Gly207Cys has an equal or greater Grantham distance. (PM5). In summary, c.619G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP3, PP4_moderate, PM1_Supporting, PM2_Supporting, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964418/MONDO:0015967/017 2022-08-04 2022-08-04 Autosomal dominant inheritance HP:0000006 Supports CAID:CA916084427 biolink:causes MONDO:0009861 infores:clingen CAID:CA916084427 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2, PVS1, PM3_Supporting The p.Ex5del1670 (c.442-1377_509+226del1671) is a 1670bp deletion in Exon 5 of PAH, and is predicted to lead to a frameshift at His170, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2). It has been previously reported in one patient with PKU (BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate) (PMID: 23942198) in presumed trans with the p.A313V variant (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting). Classification: Pathogenic Supporting Criteria: PVS1; PM2; PM3_Supporting; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084427/MONDO:0009861/006 2020-06-04 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50859 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0001339 infores:hetionet CHEBI:8404 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0009676 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0175167 infores:hetionet CHEBI:4702 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0041834 infores:hetionet CHEBI:3752 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C3665347 infores:hetionet CHEBI:53760 biolink:causes MONDO:0003040 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002624 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0016385 infores:hetionet CHEBI:63629 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0085633 infores:hetionet CHEBI:66901 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0040264 infores:hetionet CHEBI:6375 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030193 infores:hetionet CHEBI:8863 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0242379 infores:hetionet CHEBI:18332 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0231274 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0032285 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017152 infores:hetionet UMLS:C0004609 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0026838 infores:hetionet GO:2000715 biolink:causes GO:0071961 infores:ubergraph knowledge_assertion manual_agent GO:2000715 GO:0071961 CHEBI:9398 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0004604 infores:hetionet CHEBI:6076 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151766 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0085606 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020649 infores:hetionet CHEBI:27834 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0011603 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C1510472 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0027441 infores:hetionet CHEBI:135925 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C2830004 infores:hetionet CHEBI:7936 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085641 infores:hetionet CHEBI:52172 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020452 infores:hetionet CHEBI:6121 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0231530 infores:hetionet CHEBI:17347 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0029453 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1384666 infores:hetionet CAID:CA386952573 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952573 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS1, PM1_Supporting, PP3 PS4, PM5 The c.58G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 20 (p.(G20R)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). The nucleotide change c.58G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). Two other missense variants, c.59G>A (p.Gly20Glu) and c.59G>C (p.Gly20Ala) do not meet the criteria for likely pathogenic or pathogenic without the supporting evidence of PM5; therefore, PM5 will not be applied. Taken together, the evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PS1, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952573/MONDO:0015967/017 2021-08-18 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:87715 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0021053 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009806 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0235360 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0235360 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0155170 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0155170 infores:hetionet CHEBI:5893 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0003862 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0042075 infores:hetionet CHEBI:4710 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013378 infores:hetionet CHEBI:8764 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002994 infores:hetionet CHEBI:5855 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0424295 infores:hetionet CHEBI:50659 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0011991 infores:hetionet CHEBI:28748 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0008031 infores:hetionet CHEBI:10023 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151723 infores:hetionet CHEBI:3387 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151539 infores:hetionet NCBIGene:9971 biolink:causes MONDO:0014884 infores:monarchinitiative not_provided not_provided HGNC:7967 MONDO:0014884 uuid:89d4a9b6-76a6-444b-b3e0-a094c5b25c89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0025218 infores:hetionet CHEBI:9588 biolink:causes UMLS:C1262535 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C1262535 infores:hetionet CHEBI:119573 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0042029 infores:hetionet CHEBI:12777 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00162 UMLS:C0020517 infores:hetionet CHEBI:36795 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0026961 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0042109 infores:hetionet CHEBI:10102 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0009676 infores:hetionet NCBIGene:6786 biolink:causes MONDO:0013008 infores:monarchinitiative not_provided not_provided HGNC:11386 MONDO:0013008 uuid:6c7d20a3-00a5-40ac-87b3-b4d3eed988cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085593 infores:hetionet CHEBI:3561 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0003467 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042401 infores:hetionet CHEBI:107736 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C2830004 infores:hetionet CHEBI:37924 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151603 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0235234 infores:hetionet CHEBI:63580 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009676 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0036454 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037199 infores:hetionet CHEBI:404903 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009782 infores:hetionet CAID:CA409106025 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106025 MONDO:0015967 PMID: Uncertain Significance PP3, PP4, PP1, PM2_Supporting PM1, PS4 The c.502T>C variant in the Hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of serine to proline at codon 168 (p.( Ser168Pro)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.95, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributor). In summary, c.502T>C meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PM2_Supporting, PP3, PP1, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106025/MONDO:0015967/085 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2379 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0344232 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009946 infores:hetionet CHEBI:31401 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0027796 infores:hetionet UMLS:C0004609 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0012569 infores:hetionet CAID:CA412376877 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376877 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000330.4(RS1):c.62G>A (p.Gly21Glu) is a missense variant encoding the substitution of glycine with glutamate at amino acid 21. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.573, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of <0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives a score of 0.02 for acceptor gain and donor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376877/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance HP:0001417 Inconclusive true CAID:CA401366794 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366794 MONDO:0009290 PMID: Likely Pathogenic PP3, PP4, PM3, PM2_Supporting, PS3_Moderate, PM5_Supporting The NM_000152.5:c.1445C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 482 (p.Pro482Arg). One proband with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID: 31392188) (PP4). This variant has been detected two apparently unrelated probands and one sibling with late onset Pompe disease who were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP, c.-32-13T>G; the phase is unknown (PMID: 24383498, 29122469, 31392188, 31710733, 38313679); 2 x 0.5pt) (PM3). This variant is absent in gnomAD v4.1.0.. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.948 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other missense variants at the same amino acids have been reported in patients with Pompe disease; c.1445C>T (p.Pro482Leu) (ClinVar Variation ID: 982297) has been classified as likely pathogenic by the ClinGen LD VCEP, c.1444C>T (p.Pro482Ser) has not yet been classified by the VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 1067574). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LD VCEP (Specifications Version 2.0.0): PM3, PS3_Moderate, PP3, PP4, PM2_Supporting, PM5_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 28, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366794/MONDO:0009290/010 2025-10-28 2025-10-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UMLS:C0010592 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040264 infores:hetionet CHEBI:29007 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0700225 infores:hetionet CHEBI:8059 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0232462 infores:hetionet CHEBI:3207 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0234233 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0000833 infores:hetionet GO:1905518 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905518 GO:0007275 CHEBI:2682 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0026858 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001539 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035321 infores:hetionet CHEBI:3001 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C1527344 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0007117 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030252 infores:hetionet CHEBI:35854 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0034155 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0041912 infores:hetionet CHEBI:144551 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C2129214 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0040822 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0917798 infores:hetionet CHEBI:63620 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151517 infores:hetionet CHEBI:53691 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0036974 infores:hetionet CHEBI:408174 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C2830004 infores:hetionet CAID:CA320637602 biolink:causes MONDO:0011071 infores:clingen CAID:CA320637602 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+182A>G is an intronic variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. The MAF of 0.01571 in the African subpopulation of the gnomAD v2 cohort allows for application of BA1; the observation of this variant in a homozygous state thrice in the same population allows for the application BP2. This variant has a SpliceAI score of 0, and a PhyloP score of -0.65, allowing for the application of both BP4 and BP7. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320637602/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA350399166 biolink:causes MONDO:0015924 infores:clingen CAID:CA350399166 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PM1 BP4, BA1, PS4, PS1, PM5, BS1 The NM_001204.7(BMPR2):c.140G>A (p.Gly47Asp) variant is a missense variant located within exon 2 of BMPR2, predicted to cause substitution of glycine to an aspartic acid. This variant is located within the conserved extracellular domain of the protein but does not affect a known critical residue (PM1_moderate met). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting met). The REVEL prediction algorithm score is 0.78, which is above the threshold of 0.75 for pathogenicity (PP3_supporting met). The variant has been reported in an individual with PAH associated with congenital heart disease (PMID: 15358693) but not in patients with hereditary or idiopathic PAH (PS4 not met). Alternative alleles at the same nucleotide or amino acid have not been reported (PS1 and PM5 not met). Functional studies have not been reported (PS3 not assessed). Neither segregation or maternity/paternity data are available (PS2, PP1, BS4 not evaluated). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350399166/MONDO:0015924/125 2025-01-22 2025-01-22 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6950 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020557 infores:hetionet CHEBI:4868 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0015230 infores:hetionet CHEBI:50730 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0030305 infores:hetionet CHEBI:182080 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0233407 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0041912 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020538 infores:hetionet CL:0000235 biolink:causes MONDO:0015540 infores:ubergraph knowledge_assertion manual_agent CL:0000235 MONDO:0015540 CHEBI:9398 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0013428 infores:hetionet CHEBI:4995 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0003467 infores:hetionet NCBIGene:352909 biolink:causes MONDO:0011718 infores:monarchinitiative not_provided not_provided HGNC:30492 MONDO:0011718 uuid:d64b19c9-7463-46c5-bc9b-fc58c506bca9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5167 biolink:causes MONDO:0008817 infores:monarchinitiative not_provided not_provided HGNC:3356 MONDO:0008817 uuid:a9f48ba2-a06f-4b1b-b370-69e5ab212a1b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8354 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0039231 infores:hetionet NCBIGene:3735 biolink:causes MONDO:0013338 infores:monarchinitiative not_provided not_provided HGNC:6215 MONDO:0013338 uuid:32f56002-47ec-4420-823f-e24c84cf5a4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45924 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0038362 infores:hetionet CL:0000542 biolink:causes MONDO:0005402 infores:ubergraph knowledge_assertion manual_agent CL:0000542 MONDO:0005402 CHEBI:3996 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0039070 infores:hetionet CHEBI:135342 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0026961 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0018799 infores:hetionet CHEBI:63605 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0333355 infores:hetionet NCBIGene:54084 biolink:causes MONDO:0859339 infores:monarchinitiative not_provided not_provided HGNC:1268 MONDO:0859339 uuid:65842385-d912-4a57-bb3d-e4e01ffd6f8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235567 infores:hetionet CHEBI:17688 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0036104 infores:hetionet CAID:CA16620242 biolink:causes MONDO:0100488 infores:clingen CAID:CA16620242 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM5, PM1, PM3, PM4, PP2, PP3, PP1, PP4, BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS4, PS2 The c.731A>G (p.Asp244Gly) variant results in a non-conservative amino acid substitution in the Cadherin-1 domain. This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD (PM2_supporting) and has been reported in one family meeting IGCLC criteria for HDGC (PMID: 10319582). However, this variant has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished). Functional studies of the p.Asp244Gly variant suggest that this variant may affect the subcellular localization of E-cadherin and regulation of cell adhesion (PMID: 27582386, 28301459). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, PM2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620242/MONDO:0100488/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:64064 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1443060 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0037274 infores:hetionet CAID:CA915943674 biolink:causes MONDO:0013144 infores:clingen CAID:CA915943674 MONDO:0013144 PMID: Pathogenic PP1, PM2_Supporting, PS4_Supporting, PVS1 The c.448dup (p.Gln150ProfsTer27) variant in SERPINC1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3/7 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in one probands meeting an antithrombin activity level of < 0.8 without confirmation of repeated independent samples tested but with a family history of antithrombin activity levels of < 0.8 IU/mL (PS4_Supporting; PMID:28300866). The variant has been reported to segregate with hereditary antithrombin deficiency in two additional affected family members from one family (PP1; PMID:28300866). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PVS1, PM2_Supporting, PS4_Supporting, PP1. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA915943674/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8028 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0080274 infores:hetionet CHEBI:7514 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0011991 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042571 infores:hetionet CHEBI:2639 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0008031 infores:hetionet CHEBI:17650 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0016655 infores:hetionet CHEBI:135530 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0085649 infores:hetionet CHEBI:2676 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0016204 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020517 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0235398 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0235398 infores:hetionet NCBIGene:5277 biolink:causes MONDO:0018346 infores:monarchinitiative not_provided not_provided HGNC:8957 MONDO:0018346 uuid:44a455ba-af11-43e1-80a9-575806667c34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3061 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0231303 infores:hetionet CHEBI:8869 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0232849 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1971624 infores:hetionet CHEBI:10100 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0017178 infores:hetionet CHEBI:3638 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0026848 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0029408 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002378 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011649 infores:hetionet CHEBI:135351 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0233407 infores:hetionet NCBIGene:54765 biolink:causes MONDO:0014938 infores:monarchinitiative not_provided not_provided HGNC:19016 MONDO:0014938 uuid:746443bb-e358-4bb9-a3b1-cb88a08d365a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135925 biolink:causes HP:0012166 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C1696701 infores:hetionet CHEBI:79699 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020598 infores:hetionet CHEBI:27470 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0017178 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0034150 infores:hetionet CHEBI:17688 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0043352 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0038454 infores:hetionet CHEBI:63613 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0040034 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013182 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0008370 infores:hetionet CHEBI:167309 biolink:causes HP:0200123 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0019189 infores:hetionet CHEBI:44185 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0003537 infores:hetionet CHEBI:17303 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0030252 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002884 infores:hetionet CHEBI:4653 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0016382 infores:hetionet CHEBI:8028 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0427086 infores:hetionet CHEBI:63598 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0428977 infores:hetionet UMLS:C0879264 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0036974 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0024894 infores:hetionet CHEBI:31524 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0036974 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0240291 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0240291 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042134 infores:hetionet CHEBI:18248 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C3257803 infores:hetionet NCBIGene:3551 biolink:causes MONDO:0032599 infores:monarchinitiative not_provided not_provided HGNC:5960 MONDO:0032599 uuid:c081310e-b434-4dcf-9d7f-f73388bdbcc7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0853149 infores:hetionet UMLS:C1738934 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0086769 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0041912 infores:hetionet CHEBI:50777 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0011991 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0039520 infores:hetionet CHEBI:9352 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0232462 infores:hetionet CHEBI:53691 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0002792 infores:hetionet GO:1905276 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:1905276 GO:0035295 CHEBI:5138 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0043387 infores:hetionet CAID:CA256123 biolink:causes MONDO:0001586 infores:clingen CAID:CA256123 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PM2_Supporting PP4 The NM_000203.5:c.613_617dup (p.Glu207AlafsTer29) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 8 probands with a diagnosis of MPS I have been reported with the variant. At least 3 individuals with severe MPS I were homozygous for the variant (PMIDs: 8664897, 29620724; PM3). The allelic data for compound heterozygous individuals will be used in the assessment of the second variant and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002011 (9/44746 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PM3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA256123/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0025241 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0003811 infores:hetionet CHEBI:7936 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014848 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1142498 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1142498 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0020649 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0024894 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0851341 infores:hetionet CHEBI:465284 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0424790 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013295 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0948586 infores:hetionet NCBIGene:3640 biolink:causes MONDO:0009047 infores:monarchinitiative not_provided not_provided HGNC:6086 MONDO:0009047 uuid:37821d94-1e23-424c-87dd-941cfd72cd93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0031085 infores:hetionet CHEBI:8356 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085633 infores:hetionet CHEBI:63631 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0700200 infores:hetionet CHEBI:37924 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0085649 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0920195 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0920195 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0392025 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0221392 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0003123 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021259 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033578 infores:hetionet CAID:CA7510845 biolink:causes MONDO:0015152 infores:clingen CAID:CA7510845 MONDO:0015152 PMID: Benign BA1 PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BP1, BP4, BP3, BP2, PP2, PP3, PP1, PP4, BS2, BP7, BP5, BS1, BS3, BS4, PS1, PS3, PS4, PS2 The NM_000070.3: c.73C>T variant in CAPN3 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 25 (p.His25Tyr). The filtering allele frequency of this variant is 0.02825 for African/African American exome chromosomes (the lower threshold of the 95% CI of 530/251040) in gnomAD v2.1.1, which is higher than the LGMD VCEP threshold (≥0.003) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.12, which is above the LGMD VCEP threshold predicting a benign impact on CAPN3 function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7510845/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8356 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0917798 infores:hetionet CHEBI:10119 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085679 infores:hetionet CHEBI:2676 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0014457 infores:hetionet CHEBI:5959 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C2973529 infores:hetionet CHEBI:92712 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0034063 infores:hetionet CHEBI:100241 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C3263723 infores:hetionet CHEBI:135888 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0162834 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0027947 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0015397 infores:hetionet CHEBI:42797 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038990 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0006145 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0006826 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0349506 infores:hetionet CHEBI:3380 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0010200 infores:hetionet CHEBI:93363 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0020458 infores:hetionet NCBIGene:23516 biolink:causes MONDO:0014864 infores:monarchinitiative not_provided not_provided HGNC:20858 MONDO:0014864 uuid:2433f1c0-c76d-4604-a868-1aa13b5a09a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0012318 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007863 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018021 infores:hetionet CHEBI:490877 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0341047 infores:hetionet CHEBI:46195 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0232462 infores:hetionet CHEBI:585948 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0085649 infores:hetionet CAID:CA464450136 biolink:causes MONDO:0009595 infores:clingen CAID:CA464450136 MONDO:0009595 PMID: Uncertain Significance PM2_Supporting, PP4 This variant has been found in gnomAD v4 with an allele frequency of 0.000007990 in the African/ African American population. This variant is below the threshold that the SCID VCEP established to use PM2_Supporting (< 0.0000447). Therefore, this criterion is met: PM2_Supporting.At least one patient (P5, PMID: 16244706) has been described with this variant (also known as g.260C>G). The patient presented with metaphyseal dysplasia (+1.0), immune deficiency phenotype (+0.5), and hematological disease (+0.25), reaching a total of 1.75 points. Therefore PP4 is met at default strength. In summary, this variant is classified as uncertain significance - insufficient evidence for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4 (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA464450136/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8871 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002622 infores:hetionet CHEBI:35778 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0035455 infores:hetionet CHEBI:3223 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0702166 infores:hetionet CHEBI:4024 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0013144 infores:hetionet UMLS:C0657912 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085593 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0020039 infores:hetionet CHEBI:3568 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1510410 infores:hetionet CHEBI:7447 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0027947 infores:hetionet CHEBI:27958 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C1325847 infores:hetionet CHEBI:15940 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151603 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1963951 infores:hetionet CHEBI:60466 biolink:causes GO:0099538 infores:ubergraph knowledge_assertion manual_agent CHEBI:60466 GO:0099538 GO:1903719 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:1903719 GO:0023052 CHEBI:8871 biolink:causes UMLS:C0948050 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948050 infores:hetionet CHEBI:6706 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0012833 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0948048 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0948048 infores:hetionet NCBIGene:83715 biolink:causes MONDO:0032841 infores:monarchinitiative not_provided not_provided HGNC:13281 MONDO:0032841 uuid:4a6780b8-6995-4a41-aa84-5e86cb9410b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5103 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0700590 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0242350 infores:hetionet CHEBI:40303 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0023222 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018939 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0543467 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0232498 infores:hetionet CHEBI:3994 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0013384 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0227791 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0497327 infores:hetionet CHEBI:75722 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030554 infores:hetionet CHEBI:7915 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013428 infores:hetionet CHEBI:391960 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0013604 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0233471 infores:hetionet CHEBI:8890 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0344232 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0034150 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0015397 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1112274 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1112274 infores:hetionet CAID:CA386966053 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966053 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PP4 The c.773T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 258 (p.(Leu258Pro)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is less than 50%, so PP4 does not apply. In summary, c.773T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966053/MONDO:0015967/017 2025-06-27 2025-06-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31709 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0041969 infores:hetionet CHEBI:472657 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0542571 infores:hetionet CHEBI:101853 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0023218 infores:hetionet CHEBI:31236 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233477 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0020649 infores:hetionet CHEBI:18243 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0002962 infores:hetionet CHEBI:31638 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0023530 infores:hetionet NCBIGene:26353 biolink:causes MONDO:0012096 infores:monarchinitiative not_provided not_provided HGNC:30171 MONDO:0012096 uuid:78a40ef6-bd43-4b7e-831d-1c0b9bc03799 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0022658 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0149931 infores:hetionet CHEBI:119915 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018188 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0042075 infores:hetionet CAID:CA175337 biolink:causes MONDO:0021060 infores:clingen CAID:CA175337 MONDO:0021060 PMID: Likely Pathogenic PS4_Moderate, PM2, PM6, PP2, PP3 The c.1595G>A (p.Cys532Tyr) variant in BRAF has been observed in three probands with RASopathies (PS4_Moderate; Laboratory for Molecular Medicine, Hopital Universitaire Robert Debre internal data, ClinVar SCV000197143.4) It has also been seen as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; EGL internal data, ClinVar SCV000112809.8). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Cys532Tyr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM2, PM6, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA175337/MONDO:0021060/004 2020-05-18 2020-07-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6375 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0242350 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002314 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0155145 infores:hetionet CHEBI:10125 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1167965 infores:hetionet CHEBI:31638 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0004604 infores:hetionet UMLS:C0145867 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0036974 infores:hetionet CHEBI:3286 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0232493 infores:hetionet CHEBI:135361 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0027769 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0853760 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0003864 infores:hetionet CHEBI:101085 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0040034 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0521491 infores:hetionet CHEBI:52172 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0017168 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013595 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151838 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027051 infores:hetionet UMLS:C0657912 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026821 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0518015 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020651 infores:hetionet CHEBI:31547 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0151905 infores:hetionet CHEBI:40303 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0014742 infores:hetionet CHEBI:16899 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0013604 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0235431 infores:hetionet CHEBI:9398 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C2047937 infores:hetionet CHEBI:28487 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0013144 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0152198 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020456 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1262170 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1262170 infores:hetionet CAID:CA345151090 biolink:causes MONDO:0100084 infores:clingen CAID:CA345151090 MONDO:0100084 PMID: Uncertain Significance PP2, PP3, PM2_Supporting, PS4_Supporting, BP5 BA1, BP1, BP4, BS1, PM5 The NM_001100.4:c.130G>T variant in ACTA1 is a missense variant predicted to cause substitution of glycine by cysteine at amino acid 44 (p.Gly44Cys). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The REVEL computational prediction analysis tool gives a score of 0.819, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The Z-score in gnomAD v4.1 is 4.53 (PP2). This variant has been reported in at least two probands with neuromuscular features which meets the criteria for PS4_Supporting (Labcorp Genetics, GeneDx, ClinVar: SCV003514647.2, SCV000583187.4). Additionally, this variant was reported in a proband with an alternative cause for disease (a pathogenic variant in RYR1 reported) (BP5, Labcorp Genetics, ClinVar: SCV003514647.2). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PM2_Supporting, PP2, PP3, BP5 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 9/9/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345151090/MONDO:0100084/147 2024-09-09 2025-04-01 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:1901490 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1901490 GO:0072359 CHEBI:28748 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0340726 infores:hetionet CHEBI:3127 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0009782 infores:hetionet CHEBI:5790 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1145670 infores:hetionet CHEBI:3216 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0018834 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004690 infores:hetionet CHEBI:8499 biolink:causes HP:0033660 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0239836 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0037199 infores:hetionet GO:0003292 biolink:causes CL:2000022 infores:ubergraph knowledge_assertion manual_agent GO:0003292 CL:2000022 CAID:CA8314719 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314719 MONDO:0009276 PMID: Benign BA1 PP3, PP4, BS2, BP4, BP5 The missense variant NM_000173.7(GP1BA):c.206C>T (p.Pro69Leu) occurs at a Grpmax filtering allele frequency in gnomAD v4.1 of 0.002916 (based on 3539/1179884 alleles) in the European (non-Finnish) population, (>0.001; BA1). This variant has been reported in at least two families with macrothrombocytopenia or Bernard-Soulier syndrome (PMIDs: 18065693, 25370924) but alternate causes of disease were identified. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 (ClinGen Platelet Disorders VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314719/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:100241 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0015230 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0020517 infores:hetionet CAID:CA337394 biolink:causes MONDO:0005835 infores:clingen CAID:CA337394 MONDO:0005835 PMID:31965077 Likely Pathogenic PP3, PM2_Supporting, PS3 The MSH6 c.1296T>G is a missense variant predicted to cause substitution of Phenylalanine to Leucine at amino acid 432 (p.Phe432Leu). The prior probability for pathogenicity of this missense variant is 0.7 according to hci-priors.hci.utah.edu/PRIORS/ (PP3). Functional odds (CIMRA assay) of 45.743 supports evidence of pathogenicity of the variant (PS3). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PS3, PP3 and PM2_Sup (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA337394/MONDO:0005835/138 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0120107 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042133 infores:hetionet CHEBI:135930 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0162830 infores:hetionet CAID:CA6748704 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748704 MONDO:0009861 PMID:27121329PMID:23500595 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 The c.1259G>T (p.Arg420Met) variant in PAH has been reported in 1 Spanish patient with mild hyperphenylalaninemia (BH4 deficiency excluded) (PP4_Moderate; PMID: 27121329). This variant was detected with p.A403V (Pathogenic in ClinVar, VarID:92731, 18 submitters) (PM3; PMID: 27121329). This variant has a MAF of 0.00002 in population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.835 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748704/MONDO:0009861/006 2020-05-21 2020-05-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:567361 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0151786 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0917798 infores:hetionet CHEBI:6761 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0392676 infores:hetionet CHEBI:5103 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0036104 infores:hetionet CHEBI:4470 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C2830004 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0027051 infores:hetionet CHEBI:32139 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0006266 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0344320 infores:hetionet CHEBI:7931 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0033771 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0032584 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0001824 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0025061 infores:hetionet NCBIGene:5832 biolink:causes MONDO:0014706 infores:monarchinitiative not_provided not_provided HGNC:9722 MONDO:0014706 uuid:699998a6-eacf-4525-82a5-c5ac0fb6cdde biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0270612 infores:hetionet CHEBI:72297 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0853225 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0036454 infores:hetionet CHEBI:6759 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0041834 infores:hetionet CAID:CA10580088 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580088 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.604G>C (p.Val202Leu) variant is absent from gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in the literature. In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580088/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:74947 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002871 infores:hetionet CHEBI:521033 biolink:causes UMLS:C0240520 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0240520 infores:hetionet CHEBI:8069 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0009676 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151596 infores:hetionet NCBIGene:11342 biolink:causes MONDO:0034106 infores:monarchinitiative not_provided not_provided HGNC:10057 MONDO:0034106 uuid:43e1f13c-bbba-4612-b213-a8bc204f4e20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151735 infores:hetionet CHEBI:3506 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0014742 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0036572 infores:hetionet CHEBI:63577 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013428 infores:hetionet CHEBI:15551 biolink:causes HP:0025116 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0015930 infores:hetionet CHEBI:8346 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0234146 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0002453 infores:hetionet CHEBI:3636 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0018681 infores:hetionet CHEBI:7959 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0015230 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0030552 infores:hetionet CAID:CA8328437 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328437 MONDO:0100438 PMID: Benign BP7, BS2, BP4, BA1 NM_014336.5(AIPL1):c.642+48G>A is a variant in intron 4 of 5 where the G at position c.642+48 is replaced with an A. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.4704, with 21338 alleles / 44850 total alleles in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). Additionally, this variant has been found in the homozygous state in 107,303 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). As an intronic variant, NM_014336.5(AIPL1):c.642+48G>A, does not have a REVEL score. The splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328437/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3561 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013378 infores:hetionet CHEBI:5132 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0231218 infores:hetionet CAID:CA7330608 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330608 MONDO:0100216 PMID: Uncertain Significance BP4 PVS1, PM2, BA1, BP2, BS2, PP3, PP1, PP4, PM1, PM4, PM5, PS4, PS3, PS1, PS2, BP7, BS1, BS3, BS4 The NM_177438.3:c.5626G>A variant in DICER1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1876 (p.Gly1876Arg). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001177 (19/1614002 alleles) with a highest population minor allele frequency of 0.0002343 (15/64030 alleles) in European (Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.41; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330608/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64355 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0002170 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011849 infores:hetionet CHEBI:253342 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0032617 infores:hetionet CHEBI:5132 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0009806 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0004936 infores:hetionet CHEBI:75722 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0600142 infores:hetionet CHEBI:35778 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042023 infores:hetionet CHEBI:4670 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0151799 infores:hetionet CHEBI:9654 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0022346 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0005779 infores:hetionet CHEBI:10119 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0030196 infores:hetionet CAID:CA2573102981 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573102981 MONDO:0015967 PMID: Likely Pathogenic PS3_Supporting, PP4_Moderate, PM2_Supporting, PM1 The c.-181G>T p.(?) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the promoter region of HNF1A/HNF1B binding sites, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Functional studies demonstrated the c.-181G>T has transactivation activity below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 38855865). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and a family history of neonatal hypoglycemia and macrosomia) (PP4_Moderate; PMID: 38855865, internal lab contributors). In summary, c.-181G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PP4_Moderate, PM1, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573102981/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Supports CAID:CA396472208 biolink:causes MONDO:0100488 infores:clingen CAID:CA396472208 MONDO:0100488 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2505T>G (p.Tyr835Ter) variant results in a premature translational stop signal upstream of the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) in a region that is not predicted to undergo nonsense-mediated decay (PVS1_Strong, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Strong, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396472208/MONDO:0100488/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:31711 biolink:causes MONDO:0043797 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0037929 infores:hetionet CHEBI:45863 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0007859 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0233472 infores:hetionet CHEBI:9720 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0085610 infores:hetionet CHEBI:7798 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0235267 infores:hetionet CHEBI:63589 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0019209 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0243026 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0019372 infores:hetionet CHEBI:6067 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020672 infores:hetionet CHEBI:17303 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0424790 infores:hetionet CHEBI:3696 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0231530 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0403632 infores:hetionet NCBIGene:2896 biolink:causes MONDO:0011842 infores:monarchinitiative not_provided not_provided HGNC:4601 MONDO:0011842 uuid:0f32e6a1-8980-4300-aab5-06d6a158ed8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0232461 infores:hetionet CHEBI:40303 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0042029 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0031117 infores:hetionet CHEBI:8863 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0025874 infores:hetionet CHEBI:63630 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0040822 infores:hetionet CAID:CA512318634 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318634 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.507A>G (p.Arg169_Gly170=) is a synonymous variant that is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). It alters the last three bases of an exon preceding a splice donor site or the first three bases of an exon following an acceptor splice site, with a predicted decrease in the score of the canonical splice site (measured by both MES and SSF) of at least 75%, regardless of the predicted creation/presence of a putative cryptic splice site (Splice AI score: 0.59) (PP3). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2071711). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318634/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4702 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0155169 infores:hetionet CHEBI:474180 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0852911 infores:hetionet CHEBI:135351 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C3665347 infores:hetionet CHEBI:68595 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0033774 infores:hetionet UMLS:C0011701 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0151904 infores:hetionet CHEBI:6933 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0018834 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0948586 infores:hetionet CHEBI:119915 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1458155 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0235146 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0008370 infores:hetionet CHEBI:567361 biolink:causes UMLS:C1961112 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1961112 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017601 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0006266 infores:hetionet CHEBI:9571 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0009806 infores:hetionet CHEBI:5132 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C1458155 infores:hetionet CAID:CA306130937 biolink:causes MONDO:0010938 infores:clingen CAID:CA306130937 MONDO:0010938 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting PS1, PM5, PM1, BS2 The c.1837C>T (p.Arg613Ter) (NM_000215.4) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The filtering allele frequency (the upper threshold of the 95% CI of 3/113712) of the c.1837C>T variant in JAK3 is 0.000007010 for European (non-Finnish) chromosomes by gnomAD 2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).At least one patient with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), *T-B+NK- lymphocyte subset profile (0.5pt), and *SCID phenotype corrected by JAK3 gene therapy WITHOUT CNV testing performed (1pt), totalizing 2 points, which is highly specific for SCID (PP4_moderate. PMID: 26321643). This variant has been detected in at least one individual with SCID, which is homozygous for the variant (0.5 pt) (PM3_Supporting. PMID: 26321643). One additional patient was found on Clinvar; however, the affected status is unknown.In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PP4_moderate, PM2_supporting and PM3_supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA306130937/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8774 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0003123 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0011609 infores:hetionet CHEBI:168396 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0027497 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0036508 infores:hetionet CHEBI:8768 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0855333 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0039971 infores:hetionet CHEBI:28748 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0392699 infores:hetionet CHEBI:64321 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0017168 infores:hetionet NCBIGene:9276 biolink:causes MONDO:0054716 infores:monarchinitiative not_provided not_provided HGNC:2232 MONDO:0054716 uuid:7d3e8ca7-102e-4d88-9d09-c6a15164fee3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027796 infores:hetionet CHEBI:42944 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151744 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0030920 infores:hetionet CHEBI:35854 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0013404 infores:hetionet CAID:CA7140653 biolink:causes MONDO:0100040 infores:clingen CAID:CA7140653 MONDO:0100040 PMID: Benign PM6, BA1 PM1, BP5, BS2, PP4, BP4 The highest population minor allele frequency of the p.Asn353Ser variant in FOXG1 in gnomAD v4.1 is 0.0003074 in the South Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Asn353Ser variant in FOXG1 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with progressive myoclonic epilepsy (PMID 29933521) (PM6). In summary, this variant meets the criteria to be classified as Benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: BA1, PM6. (FOXG1 Specifications Version 3.0.0; 10/30/2024). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7140653/MONDO:0100040/035 2024-10-30 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8461 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0030193 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151773 infores:hetionet CHEBI:7915 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0028734 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0006145 infores:hetionet CHEBI:3723 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234022 infores:hetionet CHEBI:18248 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0030193 infores:hetionet CHEBI:182080 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0009676 infores:hetionet CHEBI:28748 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019079 infores:hetionet CHEBI:145499 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0231528 infores:hetionet CHEBI:4445 biolink:causes MONDO:0006846 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0020540 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0017675 infores:hetionet CHEBI:8768 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0392525 infores:hetionet CHEBI:3219 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0699744 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0009938 infores:hetionet CAID:CA2580100820 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100820 MONDO:0100437 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PP1 NM_001034853.2(RPGR):c.2997_2998del (p.Glu1000GlyfsTer?) is a frameshift variant due to a two nucleotide deletion and is predicted to cause a premature stop codon after 78 amino acids within exon 15 of 15 and to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) with females showing a milder phenotype (1 pt), electroretinogram responses indicating rod involvement greater than cone involvement (1 pts), onset in the first decade of life (1 pt), reduced visual acuity (0.5 pts), and night blindness (0.5 pts), with genetic testing by next generation sequencing method failing to identify an alternative cause of disease (2 pts), which together are highly specific for RPGR-related retinopathy (8 points, PMID: 30917587, PP4_Moderate). The variant has been reported in at least 1 proband with affected family members (PMID: 30917587), however, the PP1 code was not met as no other affected family member had been genetically tested. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100820/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports UMLS:C0657912 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0010200 infores:hetionet CAID:CA410147212 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147212 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP7, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1347G>C (p.Gln449His) is a missense variant present in heterozygosis in a European (non-Finnish) individual with more than 20x coverage and a MAF of 0.000005807 in gnomAD v2.1.1 and 0.000006588 in gnomAD v3.1.2. In addition, it has a REVEL score <0.50 (0.226) (BP4), but functional studies are not available. Moreover, this variant has not been reported in other probands meeting at least one of the RUNX1-phenotypic criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147212/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2611 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0600142 infores:hetionet CHEBI:59560 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0022107 infores:hetionet CHEBI:65349 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0012833 infores:hetionet GO:0044513 biolink:causes GO:0007186 infores:ubergraph knowledge_assertion manual_agent GO:0044513 GO:0007186 CHEBI:9460 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0042963 infores:hetionet CHEBI:4530 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0700590 infores:hetionet CAID:CA185080 biolink:causes MONDO:0021060 infores:clingen CAID:CA185080 MONDO:0021060 PMID: Uncertain Significance PP2 The c.170C>T (p.Ser57Phe) variant in SHOC2 was present in 0.0055% (5/35376 CI 95%) of Latino alleles in gnomAD v2.1.1 (BS1 not met; PMID: 29493581). It has been identified in healthy individuals without clinical features of a RASopathy, but this information does not meet the current criteria to apply BS2 (Ambry Genetics internal data, Baylor Genetics internal data). The variant is located in SHOC2, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Ser57Phe variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA185080/MONDO:0021060/004 2020-07-23 2020-07-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:135961 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0027051 infores:hetionet NCBITaxon:58839 biolink:causes MONDO:0005743 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:58839 MONDO:0005743 CHEBI:5790 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0017160 infores:hetionet CHEBI:63611 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014591 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0178298 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0234913 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0023418 infores:hetionet CAID:CA2573157366 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157366 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 RUNX1 c.968-5T>G is an intronic variant which is not predicted by in silico tools to impact splicing and is not evolutionarily conserved (BP4, BP7). It is absent from population databases (gnomAD v3) and has not been described in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157366/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8768 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003578 infores:hetionet CHEBI:45951 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0043352 infores:hetionet GO:0060278 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0060278 GO:0019953 CHEBI:45863 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027813 infores:hetionet CHEBI:3814 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0030196 infores:hetionet CHEBI:4903 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0231218 infores:hetionet CHEBI:51230 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0085624 infores:hetionet CHEBI:50859 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085628 infores:hetionet CAID:CA10606091 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606091 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PS3_Moderate, PM2_Supporting The NM_003494.4: c.1861G>A variant in DYSF, which is also known as NM_001130987.2: c.1915G>A (p.Gly639Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 621, p.(Gly621Arg). This variant has been reported in at least four patients with dysferlinopathy (PMID: 16100712, 19528035, 21522182, 36983702), including in trans with a pathogenic variant in at least two individuals (NM_003494.4: c.5509G>A p.(Asp1837Asn), 1.0 pt, PMID: 21522182; NM_003494.4: c.5668-7G>A p.(Lys1889insTrpfsTer56, 1.0 pt, PMID: 16100712) (PM3_Strong). At least one of these patients displayed progressive muscle weakness and absent dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 16100712, 21522182, 36983702) (PP4_Strong). This variant was also shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 36983702; PP1). The highest population alternate allele frequency of this variant is 0.00002236 (1/44722 Admixed American exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly621Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.88, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/03/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606091/MONDO:0015152/180 2025-04-03 2025-06-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0424000 infores:hetionet CHEBI:46345 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0009676 infores:hetionet UMLS:C0065374 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0009676 infores:hetionet CAID:CA16021000 biolink:causes MONDO:0009861 infores:clingen CAID:CA16021000 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4 This variant c.667_674dup (p.Gln226ThrfsTer?) in PAH was documented in a patient with PAH deficiency (>120 μmol/L Phe) in the Czech Republic (PMID: 23357515). This is a frameshift variant in exon 6 out of 13 coding exons, predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16021000/MONDO:0009861/006 2020-11-24 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:408174 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0013378 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0026946 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151883 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0041912 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0027051 infores:hetionet CHEBI:3061 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0085612 infores:hetionet CHEBI:63621 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020488 infores:hetionet CHEBI:8874 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151908 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022408 infores:hetionet CHEBI:45409 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017168 infores:hetionet NCBIGene:93627 biolink:causes MONDO:0014823 infores:monarchinitiative not_provided not_provided HGNC:28261 MONDO:0014823 uuid:197c19b1-cbbd-4ff4-85f7-d4863d65cf20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31302 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0011603 infores:hetionet CHEBI:28748 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151754 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0162429 infores:hetionet CHEBI:6717 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0235996 infores:hetionet CAID:CA070222 biolink:causes MONDO:0018493 infores:clingen CAID:CA070222 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2593 of the RYR1 protein, p.(Arg2593His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000349, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, one individual had a second variant of uncertain significance in RYR1 (p.Arg401Leu) and was not considered for PS4, PS4_Supporting (PMID:17968765, PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.825 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA070222/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3485 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C2973529 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1504452 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1504452 infores:hetionet CHEBI:65173 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C1456784 infores:hetionet CHEBI:74947 biolink:causes MONDO:0019369 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0458219 infores:hetionet CHEBI:2668 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0002170 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042075 infores:hetionet CHEBI:5778 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0018808 infores:hetionet CHEBI:6402 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0001175 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027726 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0004936 infores:hetionet CHEBI:4753 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0231530 infores:hetionet CHEBI:6931 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0042963 infores:hetionet CHEBI:40237 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0858635 infores:hetionet CAID:CA336431 biolink:causes MONDO:0007648 infores:clingen CAID:CA336431 MONDO:0007648 PMID:16061854 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP1, PP2, PP3, PP4, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.1064delT p.(Leu355Terfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 16061854). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA336431/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:5138 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0549249 infores:hetionet CHEBI:50567 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0917801 infores:hetionet CHEBI:7773 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151636 infores:hetionet CHEBI:59560 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0012833 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0006852 infores:hetionet CHEBI:3696 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020453 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0009241 infores:hetionet CHEBI:3228 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0015967 infores:hetionet NCBIGene:5832 biolink:causes MONDO:0014702 infores:monarchinitiative not_provided not_provided HGNC:9722 MONDO:0014702 uuid:a9da7863-89b7-494a-898e-b9f3bff88f80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8623025 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623025 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PP1, PP4, BP2 The p.Arg228His variant on ITGB3 gene is a missense variant that has been reported previously in the context of Glanzmann Thrombasthenia (PMID: 25728920). Multiple in silico tools predict this variant to be deleterious (REVEL score = 0.89; PP3). This variant is rare in large population databases with a MAF of 0.00008008 (6/74924) in the African subpopulation of gnomADv4.1 which is lower than the PD-VCEP threshold of <0.0001 (PM2_supporting). This variant has been reported in homozygosity in two symptomatic siblings who meet diagnostic criteria for GT phenotype (PMID: 25728920). However, the siblings are homozygous for both c.614+1G>T and Arg228His and while this splice variant is Likely Pathogenic an impact of the missense variant can not be excluded so this case has not been considered in the classification of this variant. This variant meets criteria for PP3 and PM2_supporting and is classified as a VUS. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623025/MONDO:0100326/011 2024-09-05 2024-09-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31413 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0010200 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0004936 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0007222 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0024115 infores:hetionet CHEBI:7514 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0028738 infores:hetionet CHEBI:7852 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0030252 infores:hetionet NCBIGene:54084 biolink:causes MONDO:0032584 infores:monarchinitiative not_provided not_provided HGNC:1268 MONDO:0032584 uuid:6e9d718b-1b9f-4467-9219-216a59a379a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0152009 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0009806 infores:hetionet CHEBI:188986 biolink:causes MONDO:0002043 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013592 infores:hetionet CHEBI:27834 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0042164 infores:hetionet CHEBI:135613 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0000731 infores:hetionet CAID:CA401369921 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369921 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1941C>A (p.Cys647Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individual with Pompe disease. However, there is a ClinVar entry for this variant (Variation ID: 663894). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369921/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31236 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1456784 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0234215 infores:hetionet CHEBI:3380 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C1167965 infores:hetionet CHEBI:42944 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0019521 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0009806 infores:hetionet CHEBI:49575 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018524 infores:hetionet CHEBI:3032 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0027424 infores:hetionet CHEBI:17026 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C2047937 infores:hetionet CHEBI:3286 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0235886 infores:hetionet CHEBI:9943 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038990 infores:hetionet CHEBI:68478 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0006142 infores:hetionet CHEBI:404903 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0404521 infores:hetionet CHEBI:8356 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C3665347 infores:hetionet CHEBI:135193 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C1306571 infores:hetionet CHEBI:63618 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0234238 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020649 infores:hetionet CHEBI:61033 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0016204 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235431 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0518015 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0027813 infores:hetionet CHEBI:28925 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0031256 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0162830 infores:hetionet GO:0048814 biolink:causes GO:0048667 infores:ubergraph knowledge_assertion manual_agent GO:0048814 GO:0048667 CHEBI:51380 biolink:causes UMLS:C0541947 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0541947 infores:hetionet CHEBI:10110 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0036974 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0349506 infores:hetionet CHEBI:50173 biolink:causes HP:0002223 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0578682 infores:hetionet NCBIGene:1184 biolink:causes MONDO:0010358 infores:monarchinitiative not_provided not_provided HGNC:2023 MONDO:0010358 uuid:dae6afdb-78b4-4334-b979-45adb26c1b4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:408174 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0520888 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0853946 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0853946 infores:hetionet CHEBI:94807 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0232461 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0858833 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0858833 infores:hetionet CHEBI:8232 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0239571 infores:hetionet CHEBI:3403 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0851578 infores:hetionet CHEBI:53760 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C2979982 infores:hetionet CHEBI:75246 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C2242737 infores:hetionet CHEBI:4470 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0012833 infores:hetionet CHEBI:47780 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018794 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0021843 infores:hetionet CHEBI:74947 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0232461 infores:hetionet CHEBI:39669 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0687713 infores:hetionet CHEBI:5778 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0036974 infores:hetionet GO:0048831 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0048831 GO:0007275 CHEBI:53760 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0019360 infores:hetionet CHEBI:5147 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0023518 infores:hetionet GO:1900260 biolink:causes GO:0001172 infores:ubergraph knowledge_assertion manual_agent GO:1900260 GO:0001172 CHEBI:9435 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0004093 infores:hetionet CHEBI:6067 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0035317 infores:hetionet CAID:CA398324410 biolink:causes MONDO:0011132 infores:clingen CAID:CA398324410 MONDO:0011132 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong The NM_001369369.1(FOXN1):c.928-2A>G variant disrupts the acceptor site of intron 6 and is predicted to cause skipping of exon 7 (11% of the protein) with a frameshift creating a premature stop codon in the final exon (exon 9), which is predicted to escape NMD and truncate the last 16% of the protein. This removes the majority of the forkhead domain in exon 7 and the majority of the transactivation domain in exon 9, both of these domains are critical to protein function (PVS1_Strong). After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_strong, PM2_supporting (specifications v1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398324410/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:63630 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0002871 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0948873 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0038587 infores:hetionet CHEBI:4653 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0023052 infores:hetionet CHEBI:6809 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0017178 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0037274 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151713 infores:hetionet CAID:CA229358 biolink:causes MONDO:0009861 infores:clingen CAID:CA229358 MONDO:0009861 PMID: Uncertain Significance PP4_Moderate, PM2, BP4, PM3_Supporting The NM_000277.3:c.1132A>T (p.Thr378Ser) missense variant has been reported in one mild PKU patient (PMID: 10767174), with compound heterozygous genotype of Thr378Ser with Arg243Gln (ClinVar591; Pathogenic). This variant is absent from 1000G, ESP, and gnomAD databases. It is predicted not to a have damaging effect: SIFT: Tolerated, PolyPhen: Benign, MutationTaster: Polymorphism. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied:PM2, PM3_supporting, PP4_moderate, BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229358/MONDO:0009861/006 2020-05-14 2020-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6958 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0178298 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1328539 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0919936 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0919936 infores:hetionet CAID:CA382541268 biolink:causes MONDO:0700270 infores:clingen CAID:CA382541268 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 PM5 The c.5177+1G>C variant in ATM occurs within the canonical splice donor site of intron 34. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM3_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382541268/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47898 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0314719 infores:hetionet CAID:CA000246 biolink:causes MONDO:0018875 infores:clingen CAID:CA000246 MONDO:0018875 PMID: Likely Benign BS3_Supporting, BS2, PM2_Supporting BP4, BP2, BP3, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM4, BP7, BS1, BS4, PVS1, PM6, PP3, PP1 The NM_000546.6: c.509C>T variant in TP53 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 170 (p.Thr170Met). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). This variant has an allele frequency of 0.00003293 (3/91094 alleles) in the South Asian population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, PM2_Supporting. (Bayesian Points: -2; VCEP specifications version 2.1; 2/6/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000246/MONDO:0018875/009 2025-02-07 2025-02-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:204734 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0026113 infores:hetionet CHEBI:27796 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0037763 infores:hetionet CHEBI:6375 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151786 infores:hetionet CHEBI:15551 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0231528 infores:hetionet CHEBI:3756 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042023 infores:hetionet CAID:CA010240 biolink:causes MONDO:0004994 infores:clingen CAID:CA010240 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1128C>T (p.Asp376=) variant in the MYH7 gene is 37.6% (4016/10404) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010240/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10124 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0497156 infores:hetionet CHEBI:5100 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0014356 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0030312 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151505 infores:hetionet CHEBI:5118 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0340865 infores:hetionet CHEBI:94385 biolink:causes UMLS:C3160769 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C3160769 infores:hetionet CHEBI:4702 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0220981 infores:hetionet CAID:CA275254 biolink:causes MONDO:0015152 infores:clingen CAID:CA275254 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.265C>T p.(Arg89Ter) variant in DYSF, which is also known as NM_001130987.2: c.268C>T (p.Arg90Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least five unrelated individuals with features consistent with LGMD (PMID: 23641709; 18853459; 21173544; 19493611), including in a homozygous state in two patients, one with known familial consanguinity (0.75 pts, PMID: 18853459; 19493611). It has also been observed in unknown phase with a pathogenic variant (NM_003494.4: c.3126G>A p.(Trp1042Ter), 0.5 pts, PMID: 18853459) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 18853459; 19493611; PP4_Strong). The highest population minor allele frequency is 0.00005974 in gnomAD v4.1.0 exomes (2/33480 African/African American chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/16/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA275254/MONDO:0015152/180 2025-04-16 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9150 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0344232 infores:hetionet CHEBI:4885 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0013378 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0005940 infores:hetionet CAID:CA397949792 biolink:causes MONDO:0100453 infores:clingen CAID:CA397949792 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) is a nonsense variant that introduces a premature stop codon into exon 7 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000002479, with 4 alleles /1613362 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), visual impairment (1 pt) noted in the first year of life (1 pt), nondetectable ERG responses from rods (0.5 pts) and cones (1 pt), and high hypermetropia, which together are specific for GUCY2D-related recessive retinopathy (5 pts total, PMID: 29178642, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397949792/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:35553 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0018681 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0393444 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0393444 infores:hetionet CHEBI:31236 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030554 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0019158 infores:hetionet CHEBI:36795 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013428 infores:hetionet CHEBI:6916 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0004245 infores:hetionet CHEBI:408174 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0021368 infores:hetionet CHEBI:4728 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0036974 infores:hetionet CHEBI:4798 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0015967 infores:hetionet CHEBI:31980 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0231218 infores:hetionet CHEBI:127342 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0010200 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0152029 infores:hetionet CHEBI:9654 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0085610 infores:hetionet CHEBI:51450 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0036974 infores:hetionet CHEBI:184555 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0002453 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034063 infores:hetionet CHEBI:50381 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0152025 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0038454 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0595883 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020651 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C0522046 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0522046 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0497247 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0040034 infores:hetionet CHEBI:48273 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0015230 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0006277 infores:hetionet CHEBI:6923 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0042963 infores:hetionet CHEBI:135939 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0038325 infores:hetionet CAID:CA8815234 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815234 MONDO:0009290 PMID:24384324 Pathogenic PP4_Moderate, PP3, PM1, PM2_Supporting, PM3_Strong, PS3_Supporting PM5 The NM_000152.5:c.1210G>A variant in GAA is a missense variant predicted to cause substitution of aspartate by asparagine at amino acid 404 (p.Asp404Asn). At least 9 individuals with Pompe disease have been reported with this variant including individuals with documentation of deficient GAA activity and/or combination of clinical features of IOPD and on enzyme replacement therapy (PMID: 16433701, 22538254, 25687635, 26497565, 29205646) (PP4_Moderate). Four patients with Pompe disease are compound heterozygous for the variant, phase unknown, and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, including c.1064T>C (p.Leu355Pro) (PMIDs 22658377, 23787031, 31193175), c.2481+102_2646+31del (PMID 22538254, 31086307), c.2227C>T (p.Gln743Ter) (PMID 25687635, 29205646), and c.2560C>T (p.Arg854Ter) (PMID 26497565) (0.5 points). In addition, the variant was found in a child in trans with c.2432delT, and his father in trans with c.-32-13T>G (PMID 16433701) (PM3_Strong). The variant has also been reported in compound heterozygosity with c.1445C>T (p.Pro482Leu)(PMID 31086307), c.1979G>A (p.Arg660His) (PMID 31086307), and c.1924G>T (p.Val642Phe) (PMID 29122469). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in a continental population in gnomAD v2.1.1 is 0.00006 (1/15828 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant alters amino acid Asp404, a residue that crystallography studies have shown to be important in the active site of GAA, and therefore has been defined as a critical residue by the ClinGen LSD VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). When expressed in COS or HEK293 cells, this variant resulted in normal intracellular amounts of 110 kDa precursor, 95 kDa intermediate and 76 kDa mature forms of GAA but <2% wild type activity of GAA indicating that this variant may impact protein function (PMID 19862843, 24384324)(PS3_Supporting). The computational predictor REVEL gives a score of 0.869 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Four different missense variants, c.1211A>G (p.Asp404Gly), c.1211A>C (p.Asp404Ala), c.1211A>T (p.Asp404Val), and c.1212C>G (p.Asp404Glu), in the same codon have been reported in patients with Pompe disease (see http://www.pompevariantdatabase.nl/). The data from this variant (c.1210G>A (p.Asp404Asn) will be used to support the classification of the other missense substitutions of Asp404 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 657348, 2 star review status) with five submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP on Sept 21, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815234/MONDO:0009290/010 2022-09-21 2022-10-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3082 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013456 infores:hetionet CAID:CA410202645 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202645 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.421T>C (p.Ser141Pro) is a missense variant which has a REVEL score ≥ 0.88 (0.97) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202645/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6375 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019079 infores:hetionet CHEBI:4672 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0015230 infores:hetionet CHEBI:53760 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0438215 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0037274 infores:hetionet CHEBI:135613 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0041834 infores:hetionet CHEBI:7852 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0231528 infores:hetionet CHEBI:15365 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0011603 infores:hetionet CHEBI:194135 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0026766 infores:hetionet CHEBI:6437 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0231528 infores:hetionet CHEBI:32184 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0151907 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0029882 infores:hetionet CHEBI:6931 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0040822 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0595930 infores:hetionet CAID:CA399805570 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805570 MONDO:0100326 PMID:15543332 Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting PS3 The NM_000419.5(ITGA2B):c.620C>T (p.Thr207Ile) missense variant has been reported in at least one Glanzmann thrombasthenia patient (PMIDs: 21113249, 15543332). Patient OK displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia . Additionally, αIIbβ3 surface expression was reduced to 4%, as measured by flow cytometry, and there was<1% binding to PAC-1. (PP4_strong). Patient OK is homozygous for this variant (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.729 (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM3_supporting, PM2_supporitng, PP3. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805570/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6437 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0001807 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0347390 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0027339 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0030920 infores:hetionet CHEBI:4708 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0549622 infores:hetionet CHEBI:63791 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0029453 infores:hetionet CHEBI:3216 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0152031 infores:hetionet CHEBI:30830 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0043094 infores:hetionet CHEBI:31536 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0423791 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018799 infores:hetionet CHEBI:31397 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0006840 infores:hetionet CHEBI:453011 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0042514 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0010520 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0160390 infores:hetionet CHEBI:79699 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0009782 infores:hetionet CHEBI:5855 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085633 infores:hetionet NCBIGene:30009 biolink:causes MONDO:0008834 infores:monarchinitiative not_provided not_provided HGNC:11599 MONDO:0008834 uuid:186824fb-0969-409b-b3b7-f8970b94e792 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0013604 infores:hetionet CHEBI:48844 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0011606 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0038362 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151313 infores:hetionet CHEBI:46081 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0023530 infores:hetionet CHEBI:6809 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0235146 infores:hetionet CHEBI:9599 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0234632 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0017675 infores:hetionet CHEBI:7478 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0013404 infores:hetionet CHEBI:74947 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0009676 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042075 infores:hetionet CHEBI:77260 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235996 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0029445 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0003460 infores:hetionet CHEBI:6950 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0232849 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019360 infores:hetionet CHEBI:4530 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0003811 infores:hetionet NCBIGene:9997 biolink:causes MONDO:0012154 infores:monarchinitiative not_provided not_provided HGNC:10604 MONDO:0012154 uuid:06206b30-398d-4f28-840e-e3b38845f4da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042075 infores:hetionet CHEBI:45951 biolink:causes HP:0025387 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0751564 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0435002 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0232431 infores:hetionet CHEBI:520985 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0151786 infores:hetionet CHEBI:17076 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0151786 infores:hetionet CHEBI:83804 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027066 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006849 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042769 infores:hetionet NCBIGene:3784 biolink:causes MONDO:0012313 infores:monarchinitiative not_provided not_provided HGNC:6294 MONDO:0012313 uuid:b23ec102-6d75-490f-82c4-8a3ac568993a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0948525 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0026946 infores:hetionet CHEBI:6931 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0162297 infores:hetionet CHEBI:50841 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0009676 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0003123 infores:hetionet CHEBI:9570 biolink:causes MONDO:0012089 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C1504431 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0027765 infores:hetionet CAID:CA10650422 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650422 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS4, PS3, BP4, PM6, PVS1, PM2, BS4, BS3, BS1, BP7, PM5, PM1, PM4, PP1, PP3 The RUNX1 c.*2201dup variant in the 3' UTR has an MAF of 0.02216 (2.2%, 1429/64490 alleles) in the non-Finnish European subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 26 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650422/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9086 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151610 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0851341 infores:hetionet CHEBI:7798 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0497156 infores:hetionet CHEBI:2904 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C1368065 infores:hetionet CHEBI:45863 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027540 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0036572 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0042373 infores:hetionet CHEBI:127780 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0015230 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038358 infores:hetionet GO:0062042 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:0062042 GO:0003007 CHEBI:7465 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0028259 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0580493 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0580493 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0021400 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0235146 infores:hetionet CHEBI:5801 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0687713 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0234215 infores:hetionet CHEBI:83804 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0034155 infores:hetionet UMLS:C0017797 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0687713 infores:hetionet CHEBI:9130 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0026837 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042075 infores:hetionet CHEBI:10023 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085649 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1142412 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0042514 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0162296 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0162296 infores:hetionet CHEBI:64310 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0035222 infores:hetionet CHEBI:63619 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013428 infores:hetionet CHEBI:61049 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0549249 infores:hetionet CHEBI:3478 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0085649 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0033117 infores:hetionet NCBITaxon:623 biolink:causes MONDO:0001517 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:623 MESH:D004403 DB01059_MESH_D004403_1DB00537_MESH_D004403_1 PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0016977 infores:hetionet GO:0043405 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0043405 GO:0007154 UMLS:C0657912 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0021845 infores:hetionet CHEBI:15940 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151907 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0027947 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1608945 infores:hetionet CHEBI:3219 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013390 infores:hetionet CHEBI:15367 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013404 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151544 infores:hetionet CHEBI:63791 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0232462 infores:hetionet NCBIGene:23590 biolink:causes MONDO:0013837 infores:monarchinitiative not_provided not_provided HGNC:17759 MONDO:0013837 uuid:a7ae9b21-df7a-44a8-bab6-6722ac6141ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA392327231 biolink:causes MONDO:0007947 infores:clingen CAID:CA392327231 MONDO:0007947 PMID: Pathogenic PM6, PP4, PP2, PP3, PM2_Supporting, PS4_Moderate, PM1_Strong The NM_00138 c.3290G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1097 (p.Cys1097Tyr). This variant was found in a proband with a neonatal onset of Marfan syndrome (internal data, PP4). This variant has been reported four times in ClinVar: once as pathogenic, twice as likely pathogenic, and once as uncertain significance (Variation ID: 549150). This variant has been reported in the literature in individuals with clinical diagnosis of Marfan syndrome and/or features of Marfan syndrome (PMID 37684520, 29357934, Invitae ClinVar entry, internal data; PS4_Mod), and was observed de novo without parental confirmation in one individual with a highly specific phenotype (PMID 37684520; PM6). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.979, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_moderate, PM6, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392327231/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10101 biolink:causes UMLS:C0574068 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0574068 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0032285 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0041349 infores:hetionet CHEBI:28787 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0018681 infores:hetionet CAID:CA9870423 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870423 MONDO:0015967 PMID: Likely Benign PP3, PM1_Supporting, BP5, BS1 PM2 The c.999C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of isoleucine to methionine at codon 333 (p.(Ile333Met)) of NM_175914.4. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.72, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant occurs within the ligand binding domain of HNF4A (codons 180-220 and 300-350), which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). However, it has a Grpmax Filtering allele frequency in gnomAD v4.1 of 0.00007656, which is greater than or equal to the MDEP threshold for BS1 (0.000033) (BS1). Additionally, it was identified in an individual with an alternate molecular basis for monogenic diabetes (BP5; internal lab contributors). In summary, c.999C>G meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1, BP5, PM1_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870423/MONDO:0015967/085 2025-07-16 2025-07-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63619 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042963 infores:hetionet CHEBI:41879 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0033774 infores:hetionet NCBIGene:199699 biolink:causes MONDO:0976134 infores:monarchinitiative not_provided not_provided HGNC:26780 MONDO:0976134 uuid:bafbc26a-ddd3-4af6-ad32-f23649bc78a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915940376 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940376 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The p.Cys486Alafs*183 variant in exon 10 of ITGB3 gene is predicted to introduce a premature stop codon 183 amino acids downstream and result in NMD. This variant is absent from large population databases including gnomAD. It has been reported previously in compound heterozygous state with another pathogenic variant (p.Arg287Serfs*34) in one proband who meets the ClinGen PD-VCEP criteria for the GT phenotype. The variant meets criteria for PVS1, PP4_moderate, PM3_supporting and PM2_supporting and is classified as pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940376/MONDO:0100326/011 2021-08-17 2021-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA252004 biolink:causes MONDO:0007064 infores:clingen CAID:CA252004 MONDO:0007064 PMID: Pathogenic PM6, PP4_Moderate, PM2_Supporting, PS3_Moderate, PM3_Strong BA1, PM5, BS1, PS1 The c.986C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 329 (p.Ala329Val).The filtering allele frequency (the upper threshold of the 95% CI of 37/74910) of the c.986C>T variant in ADA is 0.0003683 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore do not meet this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.In vitro experiments of ADA activity in E. coli demonstrated a percentage of wild-type (wt) activity ranging from 0.1% to 5.1%, with an average ± standard deviation of 1.2% ± 1.4%. This finding classifies the variant into Group I, suggesting a significant impact on protein function. (PS3_Moderate; PMID 9758612).This variant has been detected in many individuals in the literature. Evaluated here four patients with ADA-SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant: * PMID 8614422, compound heterozygous with p.Gly74Val (at least likely pathogenic according to SCID VCEP specifications, Phase is not confirmed = 0.25pt;* PMID 32307643, compound heterozygous with p.Ser291Leu (at least likely pathogenic according to SCID VCEP specifications. Phase is not confirmed = 0.25pt;* PMID: 8401541, Proband 1 is comp. het. A329V and Q254X (at least likely pathogenic according to SCID VCEP specifications - PM2_Supporting and PVS1) - phase (in trans) confirmed = 1pt; Additionally, 01 individual was homozygous for the variant = 0.5 pts (PMID: 1346349). The total is 2 points, PM3_Strong.Patient from PMID 8614422 presented: * ADA activity in patient RBCs was undetectable (1pt), * Concentration of total deoxyadenosine nucleotides was elevated (2pt). * ADA-SCID phenotypes of the patient were corrected by PEG-ADA supplement (1pt). Total = 4 points, PP4_Moderate. PMID: 8614422.This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 01 individual with ADA-SCID, with phenotype highly specific for the gene (PM6_Moderate, PMID: 1346349).In summary, this variant is classified as Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PS3_Moderate, PM3_Strong, PP4_Moderate, and PM6_Moderate. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA252004/MONDO:0007064/114 2024-02-21 2024-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:78543 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0002962 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0040046 infores:hetionet CHEBI:50275 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0424790 infores:hetionet CHEBI:9586 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0025323 infores:hetionet CHEBI:7915 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014591 infores:hetionet CHEBI:49713 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0549249 infores:hetionet CHEBI:47657 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0042571 infores:hetionet CHEBI:83531 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C2242737 infores:hetionet CHEBI:3127 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0027796 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013604 infores:hetionet CHEBI:16796 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0027339 infores:hetionet CHEBI:3561 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0009763 infores:hetionet NCBIGene:127833 biolink:causes MONDO:0030341 infores:monarchinitiative not_provided not_provided HGNC:11510 MONDO:0030341 uuid:ef49b4b6-c608-4dc8-a087-d7fa45f14a3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020456 infores:hetionet GO:2000807 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:2000807 GO:0051641 CHEBI:28445 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0085605 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0042373 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0004936 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005557 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006705 infores:hetionet CHEBI:3371 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0151763 infores:hetionet NCBIGene:10992 biolink:causes MONDO:0958175 infores:monarchinitiative not_provided not_provided HGNC:10769 MONDO:0958175 uuid:50961801-907b-4854-a34d-a9f1affa5366 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA414910251 biolink:causes MONDO:0010602 infores:clingen CAID:CA414910251 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PP1, PS4 PM5 The NM_000132.4(F8):c.1899G>T (p.Met633Ile) variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.88 (>0.6) meeting PP3. At least 9 individuals with hemophilia A (mix of severities from severe to mild reported) from the literature are reported with the Met633Ile variant (PMID: 29296726, PMID: 19369668, PMID: 9886318 and PMID: 18691168) meeting PS4_Very strong and PP4_Moderate. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very strong, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414910251/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:131512 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0030193 infores:hetionet CAID:CA10576999 biolink:causes MONDO:0021060 infores:clingen CAID:CA10576999 MONDO:0021060 PMID: Pathogenic PS2_Very Strong, PM2, PP2, PS4_Supporting The c.364A>G (p.Asn122Asp) variant in MAP2K1 was absent from gnomAD (PM2). It has been observed in 3 probands with clinical features of a RASopathy, including 1 de novo occurrence with maternity and paternity confirmed and 2 assumed de novo occurrences (PM2_VS; SCV000271240.2; Otto-von-Guericke-Universität Magdeburg internal communication; Invitae internal data, SCV000947966.1). Of these patients, 2 received a clinical diagnosis of either Noonan syndrome or cardiofaciocutaneous syndrome (PS4_Supporting). Of note, this variant was observed in 1 proband without clinical information who inherited it from a parent with unknown clinical status (GeneDx internal data). The c.364A>G (p.Asm122Asp) variant is located in MAP2K1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria (PMID:29493581): PS2_VS, PS4_Supporting, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576999/MONDO:0021060/004 2020-03-16 2020-03-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:17823 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0028734 infores:hetionet GO:0110137 biolink:causes GO:0035218 infores:ubergraph knowledge_assertion manual_agent GO:0110137 GO:0035218 CHEBI:31932 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0022354 infores:hetionet CHEBI:94501 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0009421 infores:hetionet CHEBI:18248 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0040053 infores:hetionet CHEBI:53760 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0000737 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0015397 infores:hetionet CAID:CA229662 biolink:causes MONDO:0009861 infores:clingen CAID:CA229662 MONDO:0009861 PMID:23514811PMID:23514811 Pathogenic PVS1, PM2, PP4_Moderate, PM3_Very Strong PP3, PS3 The c.618C>G (p.Tyr206Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in at least six PKU patients (per abnormal blood Phe levels) (PP4), including in trans with pathogenic variants: with R158Q (pathogenic per PAH VCEP) (PMID: 30829006); homozygous in an Indian case with classic PKU (PMID: 24130151); in trans with the known pathogenic (per PAH VCEP) p.R408W variant (PMID: 9452062); in a Chinese PKU case in trans with the known pathogenic (per PAH VCEP) EX6-96A>G variant (PMID: 16256386); and in two Spanish patients, in trans with the pathogenic (per PAH VCEP) Thr380Met and the p.Ala309Val variants, respectively (PMID: 27121329) (PM3_VeryStrong). It has also been reported Likely Pathogenic by one lab in ClinVar (variation ID 102763). Classification: PathogenicSupporting criteria: PVS1, PM2; PM3_VeryStrong; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229662/MONDO:0009861/006 2020-04-13 2020-04-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50885 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0333641 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0267410 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0267410 infores:hetionet CHEBI:27882 biolink:causes HP:0002486 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0027125 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001828 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0155018 infores:hetionet CHEBI:16796 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0234632 infores:hetionet NCBIGene:128178 biolink:causes MONDO:0013982 infores:monarchinitiative not_provided not_provided HGNC:14341 MONDO:0013982 uuid:56158e10-5d2a-42ec-9d98-009934f73ce4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0392525 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0009806 infores:hetionet CHEBI:39867 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0016658 infores:hetionet CHEBI:71219 biolink:causes HP:0033999 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1321133 infores:hetionet CHEBI:63621 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0877192 infores:hetionet CHEBI:3506 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0040434 infores:hetionet CHEBI:2618 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0011991 infores:hetionet CHEBI:44915 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0039070 infores:hetionet GO:0039657 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0039657 GO:0010467 CHEBI:4975 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0021400 infores:hetionet CHEBI:6067 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0041657 infores:hetionet CHEBI:3698 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0428977 infores:hetionet CAID:CA645530575 biolink:causes MONDO:0015152 infores:clingen CAID:CA645530575 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The NM_003494.4: c.5900del p.(Gly1967AlafsTer6) variant in DYSF, which is also known as NM_001130987.2: c.6017del p.(Gly2006AlafsTer6), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 52/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in unknown phase with a variant classified as at least likely pathogenic in one patient with clinically suspected LGMD (NM_003494.4: c.6196G>A p.(Ala2066Thr), 0.25 pts, PMID: 27066573) (PM3 not met, PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/08/2025): PVS1, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645530575/MONDO:0015152/180 2025-07-08 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:92923 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0007114 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0014549 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0151763 infores:hetionet CHEBI:135005 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0017605 infores:hetionet CHEBI:5296 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0030193 infores:hetionet CHEBI:175901 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0034063 infores:hetionet CHEBI:10127 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0014457 infores:hetionet CHEBI:4708 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0403673 infores:hetionet CHEBI:171719 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0235378 infores:hetionet CHEBI:79699 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0333355 infores:hetionet CHEBI:63717 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0011603 infores:hetionet CHEBI:5130 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C2830004 infores:hetionet CHEBI:134991 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0003467 infores:hetionet CHEBI:63580 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0040822 infores:hetionet CAID:CA409107449 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107449 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM5_Strong PS4 The c.734G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to proline at codon 245 (p.(Arg245Pro)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.9589​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 30730840, internal lab contributors). Two other missense variants, c.733C>T (p.Arg245Cys) and c.734G>A (p.Arg245His), have been interpreted as pathogenic by the ClinGen MDEP and p.Arg245Gly has a greater Grantham distance than p.Arg245His (PM5_Strong). In summary, c.733G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107449/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA10580072 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580072 MONDO:0007648 PMID:30745422 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.124_126delCCCinsT (p.Pro42Serfs*16) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 30745422). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580072/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:50173 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0019158 infores:hetionet CHEBI:119573 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1321898 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0085622 infores:hetionet CHEBI:4798 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0917801 infores:hetionet CHEBI:5296 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0011606 infores:hetionet CHEBI:2549 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0035243 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042267 infores:hetionet CHEBI:6413 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0016655 infores:hetionet CHEBI:10127 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009763 infores:hetionet CHEBI:5138 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023518 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022408 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0031350 infores:hetionet CHEBI:7824 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0015371 infores:hetionet CHEBI:3219 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011206 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0234913 infores:hetionet CHEBI:5130 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0392525 infores:hetionet CHEBI:66919 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0018965 infores:hetionet NCBIGene:11277 biolink:causes MONDO:0012500 infores:monarchinitiative not_provided not_provided HGNC:12269 MONDO:0012500 uuid:2e2ac182-f455-4888-b2c8-098e4c9e55ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0043144 infores:hetionet CHEBI:28918 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0233794 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0006826 infores:hetionet CHEBI:7824 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014335 infores:hetionet CHEBI:51450 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0151766 infores:hetionet CAID:CA915940334 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940334 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 NM_000419.5(ITGA2B):c.1771dup in exon 18 is a frameshift variant predicted to cause p.(p.Asp591GlyfsTer47), with a premature stop codon in exon 19/30 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least two patient (GT31 in PMID: 25728920 and the patient in PMID: 17488698) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting. (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940334/MONDO:0100326/011 2022-08-05 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:404903 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0036690 infores:hetionet CHEBI:8024 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0015967 infores:hetionet CHEBI:50885 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0017979 infores:hetionet CHEBI:3223 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0542571 infores:hetionet CHEBI:6931 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0036104 infores:hetionet CHEBI:8665 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C1443060 infores:hetionet CAID:CA916081961 biolink:causes MONDO:0011071 infores:clingen CAID:CA916081961 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1114_1125dup (p.Gly372_Thr375dup) is an in-frame duplication which does not affect any residues within the Runt Homology Domain (AA 89-204) (PM4 not applied). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081961/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:30830 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011124 infores:hetionet GO:0035477 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0035477 GO:0035295 CHEBI:135530 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0015734 infores:hetionet CHEBI:6015 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0003811 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0221725 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0221725 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0007760 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018099 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0700345 infores:hetionet CHEBI:465284 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151825 infores:hetionet CHEBI:3723 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023518 infores:hetionet CHEBI:51380 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0032617 infores:hetionet CHEBI:8382 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0018800 infores:hetionet CHEBI:9123 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0026837 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0233472 infores:hetionet CHEBI:6931 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0041834 infores:hetionet CHEBI:6931 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233477 infores:hetionet CHEBI:231594 biolink:causes MONDO:0000755 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0032987 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0032584 infores:hetionet CHEBI:9130 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0015967 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0013395 infores:hetionet NCBIGene:254065 biolink:causes MONDO:0010393 infores:monarchinitiative not_provided not_provided HGNC:17342 MONDO:0010393 uuid:835ecb53-c1fa-4a81-a4de-b06f5341d141 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0033687 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020517 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0232492 infores:hetionet CHEBI:3312 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0042487 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0152021 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042401 infores:hetionet CHEBI:6759 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0015967 infores:hetionet CHEBI:182080 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0028259 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0004096 infores:hetionet NCBITaxon:36087 biolink:causes MONDO:0005996 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:36087 MESH:D014257 DB00730_MESH_D014257_1DB00643_MESH_D014257_1 CHEBI:27432 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0017178 infores:hetionet CHEBI:45863 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0010200 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0267792 infores:hetionet CHEBI:31622 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0009676 infores:hetionet CHEBI:27690 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0020621 infores:hetionet CHEBI:31236 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037299 infores:hetionet CHEBI:31348 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0392699 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0232492 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0015230 infores:hetionet CHEBI:51860 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019270 infores:hetionet CHEBI:16899 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C2363731 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0042514 infores:hetionet CHEBI:65346 biolink:causes MONDO:0006679 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0005694 infores:hetionet CHEBI:15551 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0004093 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0855242 infores:hetionet CHEBI:27899 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C2364111 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0267792 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0036454 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0162429 infores:hetionet CHEBI:63620 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0039070 infores:hetionet CHEBI:51450 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0086769 infores:hetionet CHEBI:10127 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0040264 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0151865 infores:hetionet NCBIGene:26834 biolink:causes MONDO:0971172 infores:monarchinitiative not_provided not_provided HGNC:10193 MONDO:0971172 uuid:e6c7e07e-eceb-4637-a18b-b2983e5a2b81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7865 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0039231 infores:hetionet CAID:CA033596 biolink:causes MONDO:0007750 infores:clingen CAID:CA033596 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM3, PM5, PM2, PP3, PP4 PP1 The NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL = 0.951.PM5: 1 other missense variant in the same codon: NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) (ClinVar ID 251792)- Pathogenic by these guidelines.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 unrelated index cases who fulfill criteria for FH: 1 patient with DLCN >=6 from PMID 28458923 (Korneva et al., 2017), Russia; 1 patient with DLCN >=6 from PMID 32423031 (Semenova et al., 2020), Russia; 2 patients with DLCN >=6 from PMID 33418990 (Meshkov et al., 2021), Russia. PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (treated LDL-C > 15.2 mmol/L). This patient also carries the c.2141-954_2390-318del variant, classified as Likely Pathogenic by these guidelines, in trans (PMID 36901902, Nazarenko et al., 2023). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033596/MONDO:0007750/013 2025-01-31 2025-02-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:54539 biolink:causes MONDO:0026721 infores:monarchinitiative not_provided not_provided HGNC:20372 MONDO:0026721 uuid:e8c9e9e9-7281-4d68-b9dd-4f33d6a1ec76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3223 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0242172 infores:hetionet CHEBI:167638 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020615 infores:hetionet CHEBI:31348 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0149871 infores:hetionet CHEBI:8024 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0038990 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0687133 infores:hetionet CHEBI:4717 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0011570 infores:hetionet CHEBI:4708 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0003467 infores:hetionet CHEBI:68478 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0036974 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0006145 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009806 infores:hetionet CHEBI:52717 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004093 infores:hetionet CHEBI:3223 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0559031 infores:hetionet CHEBI:5775 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0085593 infores:hetionet CHEBI:6438 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0023380 infores:hetionet GO:0033132 biolink:causes GO:0046835 infores:ubergraph knowledge_assertion manual_agent GO:0033132 GO:0046835 CAID:CA355963316 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963316 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM5, PM2_Supporting The NM_000203.5:c.1091C>G variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 364 (p.Thr364Arg). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.901 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997; PP3_Moderate). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM2_Supporting, PP3_Moderate, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963316/MONDO:0001586/091 2024-12-05 2025-03-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:75722 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0087169 infores:hetionet CHEBI:71940 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0004093 infores:hetionet CHEBI:31625 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0162285 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0042109 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0948594 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0002792 infores:hetionet CHEBI:45863 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0039239 infores:hetionet CHEBI:5855 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042023 infores:hetionet CHEBI:9332 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C1384353 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0014130 infores:hetionet CHEBI:49960 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0038325 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0854097 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1096460 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1096460 infores:hetionet CHEBI:3398 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0042023 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0234215 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0235194 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0235194 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0031350 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151735 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0520962 infores:hetionet CHEBI:41879 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020555 infores:hetionet CHEBI:194135 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042790 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0851341 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0006849 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0221490 infores:hetionet CHEBI:3534 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0002878 infores:hetionet CHEBI:5118 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0428977 infores:hetionet CHEBI:10119 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1112442 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0861148 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0861148 infores:hetionet CHEBI:3723 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039239 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0018799 infores:hetionet CAID:CA410148169 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148169 MONDO:0011071 PMID: Uncertain Significance PM2 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1090A>T (p.Ile364Phe) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In silico predictions do not support a clearly deleterious effect (SpliceAI score 0.0; REVEL score 0.7, which is below the 0.88 threshold for PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148169/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:1314 biolink:causes MONDO:0001039 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D014069 DB01060_MESH_D014069_1DB00447_MESH_D014069_1DB01416_MESH_D014069_1DB01150_MESH_D014069_1DB00671_MESH_D014069_1DB01333_MESH_D014069_1 CHEBI:45783 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0025222 infores:hetionet CHEBI:478164 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0012833 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0233494 infores:hetionet CHEBI:585948 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0162830 infores:hetionet CHEBI:4974 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0151205 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1306341 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019360 infores:hetionet CHEBI:7852 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C3665386 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0004936 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0003123 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0042109 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003850 infores:hetionet CHEBI:28148 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0006277 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0521592 infores:hetionet NCBIGene:9361 biolink:causes MONDO:0010879 infores:monarchinitiative not_provided not_provided HGNC:9479 MONDO:0010879 uuid:e637619e-0163-450d-a255-27468039f4f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9939 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0026848 infores:hetionet CHEBI:8597 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0013378 infores:hetionet CHEBI:77032 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0006266 infores:hetionet CHEBI:9725 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0004245 infores:hetionet NCBIGene:6899 biolink:causes MONDO:0008644 infores:monarchinitiative not_provided not_provided HGNC:11592 MONDO:0008644 uuid:cd712492-6104-44d4-ae8a-b726f8ab5f93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8499 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0013395 infores:hetionet CHEBI:8207 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0015402 infores:hetionet NCBIGene:50943 biolink:causes MONDO:0010580 infores:monarchinitiative not_provided not_provided HGNC:6106 MONDO:0010580 uuid:cb2643ff-1ff6-459f-bcff-9968b727755c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151746 infores:hetionet CHEBI:37941 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C3263723 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0015230 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0149931 infores:hetionet CHEBI:63607 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0030312 infores:hetionet CHEBI:75984 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0231528 infores:hetionet NCBIGene:7051 biolink:causes MONDO:0009441 infores:monarchinitiative not_provided not_provided HGNC:11777 MONDO:0009441 uuid:8e5f44ed-624f-4f09-ab11-922e55f6d23a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2695232668 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695232668 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2330_2331del (p.Lys777ArgfsTer?) is a frameshift variant due to deletion of 2 nucleotides that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including myopia (0.5 pts), first/second-decade onset of disease (1 pt), family inheritance consistent with X-linked inheritance (2 pts), and night blindness (0.5 pts), which together are specific for RPGR-related retinopathy (4 points, PMID: 20806050, PP4). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 20806050). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1_Moderate, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695232668/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports NCBITaxon:727 biolink:causes MONDO:0000889 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:727 MONDO:0000889 CHEBI:6888 biolink:causes UMLS:C2363949 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C2363949 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0020538 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0413252 infores:hetionet NCBIGene:26580 biolink:causes MONDO:0030860 infores:monarchinitiative not_provided not_provided HGNC:15832 MONDO:0030860 uuid:6a3beb54-e4aa-42ee-803d-b47fdae84ad4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3479 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151904 infores:hetionet CHEBI:3215 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020598 infores:hetionet CHEBI:9137 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003873 infores:hetionet CHEBI:16755 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151904 infores:hetionet CHEBI:8502 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0038002 infores:hetionet CHEBI:7773 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0023052 infores:hetionet CHEBI:3723 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085610 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0020538 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015230 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0857353 infores:hetionet CHEBI:31348 biolink:causes HP:0001395 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0239946 infores:hetionet CHEBI:27565 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0025637 infores:hetionet CHEBI:490877 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0750857 infores:hetionet CHEBI:3756 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C3665347 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0037195 infores:hetionet CHEBI:92998 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151825 infores:hetionet CHEBI:101853 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042963 infores:hetionet CHEBI:6472 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0151883 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0042373 infores:hetionet CAID:CA315435990 biolink:causes MONDO:0007064 infores:clingen CAID:CA315435990 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4:c.608A>C is a missense variant predicted to cause substitution of Glutamic Acid by Alanine at amino acid 203 (p.Glu203Ala).The filtering allele frequency (the upper threshold of the 95% CI of 45/1179982) of the c.608A>C variant in ADA is 0.00002828 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA315435990/MONDO:0007064/114 2024-06-10 2024-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:9430ZR8ZAN biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0009676 infores:hetionet NCBITaxon:730 biolink:causes MONDO:0001797 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:730 MONDO:0001797 CHEBI:3568 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0007117 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042514 infores:hetionet CHEBI:2704 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0015967 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005131 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0302592 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027932 infores:hetionet CHEBI:9605 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0019079 infores:hetionet CHEBI:36704 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0003467 infores:hetionet CHEBI:75722 biolink:causes UMLS:C3203485 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C3203485 infores:hetionet CHEBI:64355 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0917801 infores:hetionet CHEBI:53691 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C1328539 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0023067 infores:hetionet CHEBI:45409 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042029 infores:hetionet GO:0002299 biolink:causes CL:0000797 infores:ubergraph knowledge_assertion manual_agent GO:0002299 CL:0000797 CHEBI:44423 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0231303 infores:hetionet NCBIGene:9487 biolink:causes MONDO:0010221 infores:monarchinitiative not_provided not_provided HGNC:8966 MONDO:0010221 uuid:8b691290-c8f6-4000-8537-9d23ef4d4a39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16664 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0002874 infores:hetionet CHEBI:15367 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004093 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0027497 infores:hetionet CHEBI:41879 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0043094 infores:hetionet NCBIGene:7415 biolink:causes MONDO:0008178 infores:monarchinitiative not_provided not_provided HGNC:12666 MONDO:0008178 uuid:149d47f9-856b-4a42-8eb0-179629ec8bd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029408 infores:hetionet CHEBI:127780 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0700225 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0003864 infores:hetionet CHEBI:188986 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1527344 infores:hetionet CHEBI:171719 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0003537 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0037199 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1565489 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0162429 infores:hetionet CHEBI:50922 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003873 infores:hetionet CHEBI:5004 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0687713 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030567 infores:hetionet CHEBI:63619 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0039231 infores:hetionet CHEBI:8707 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0852911 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1739422 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1739422 infores:hetionet CHEBI:4974 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0016204 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0162429 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0152267 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0018801 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020651 infores:hetionet CHEBI:92923 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0011603 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0267596 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0342579 infores:hetionet CHEBI:8863 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085633 infores:hetionet CHEBI:7577 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0031256 infores:hetionet NCBIGene:2737 biolink:causes MONDO:0008287 infores:monarchinitiative not_provided not_provided HGNC:4319 MONDO:0008287 uuid:57877287-ebd7-4fc6-b043-eacbb9fb04c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4530 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0030312 infores:hetionet CHEBI:63621 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040822 infores:hetionet CHEBI:3423 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0017178 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003864 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0004936 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0021400 infores:hetionet CHEBI:51380 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0428977 infores:hetionet CHEBI:5558 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0002622 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0008325 infores:hetionet CAID:CA658822436 biolink:causes MONDO:0015152 infores:clingen CAID:CA658822436 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.1171_1180+4dup variant in DYSF, which is also known as NM_001130987.2: c.1267_1276+4dup, overlaps the last 10 bases of exon 12 and the splice donor region in intron 13. RNA-Seq analysis has shown that this variant leads to an extension of the splice donor site to the end of the duplication, resulting in a frameshift and premature truncation, p.(Met394SerfsTer10), for which nonsense mediated decay is expected (PMID: 36983702; PVS1_RNA). This variant has been reported in a homozygous state in an individual with suspected LGMD (0.5 pts, PMID: 36983702) (PM3_Supporting). This individual displayed slow progressive muscle weakness and disease range dysferlin expression in blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1_RNA, PP4_Strong, PM2_Supporting, PM3_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658822436/MONDO:0015152/180 2025-02-25 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63598 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018520 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0267596 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0948594 infores:hetionet CHEBI:6062 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0017675 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0235146 infores:hetionet CHEBI:31644 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0025289 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0043250 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0919980 infores:hetionet CHEBI:50885 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C1318520 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0031117 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0403632 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0007642 infores:hetionet NCBIGene:374654 biolink:causes MONDO:0013585 infores:monarchinitiative not_provided not_provided HGNC:30497 MONDO:0013585 uuid:45a9e25c-42c8-4a2d-8f81-114f9bc6cc5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:583 biolink:causes MONDO:0006929 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:583 MONDO:0006929 CHEBI:45367 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0027497 infores:hetionet CHEBI:10119 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085637 infores:hetionet CHEBI:4562 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0231218 infores:hetionet GO:1902490 biolink:causes GO:0048515 infores:ubergraph knowledge_assertion manual_agent GO:1902490 GO:0048515 CHEBI:2675 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0004245 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0031542 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235280 infores:hetionet CHEBI:6950 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0000731 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0848383 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0848383 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0079102 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0595877 infores:hetionet CHEBI:45783 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0206062 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0011615 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038362 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0152029 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0020517 infores:hetionet CHEBI:5165 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0002792 infores:hetionet CHEBI:5847 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0231218 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0948586 infores:hetionet CAID:CA16613454 biolink:causes MONDO:0700270 infores:clingen CAID:CA16613454 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PVS1 BP4, BA1, BS1, PP3 The ATM c.8585-2A>C variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals with Ataxia-Telangiectasia (PM3_Strong; PMID: 23322442, PMID: 29665859). This variant is absent in the gnomAD v2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613454/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44423 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0011991 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020517 infores:hetionet CAID:CA16020827 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020827 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Supporting PS3 The c.604G>A (p.Ala202Thr) variant in PAH has been reported in at least one individual with classic PKU with BH4 deficiency excluded. In this patient it was observed without confirmed phase with c.728G>A (p.Arg243Gln), which is classified as Pathogenic in ClinVar (Variation ID 591). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PM3_Supporting, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020827/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10549409 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549409 MONDO:0010305 PMID: Likely Benign BS2 BS1, PM2, PP3, BP4 "The NM_005629.4:c.1025T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of an isoleucine by a threonine at amino acid position 342 (p.Ile342Thr). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00005812 (52/894699; 14 hemizygotes) in the European non-Finnish population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 16 hemizygotes in gnomAD v4.1.0.; 14 in the European non-Finnish population and 2 in the ""remaining"" population (BS2). The computational predictor REVEL gives a score of 0.64 (PP3), which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 448419). Due to the presence of 16 hemizygotes in gnomAD v4.1.0 in the absence of any evidence for pathogenicity, the consensus of the ClinGen CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2(Classification approved by the ClinGen CCDS VCEP on April 11, 2025)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549409/MONDO:0010305/027 2025-04-11 2025-04-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:49575 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0278134 infores:hetionet CAID:CA396467856 biolink:causes MONDO:0007648 infores:clingen CAID:CA396467856 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2104G>T (p.Glu702Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396467856/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf HP:0031377 biolink:causes MONDO:0021100 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D001943 DB01590_MESH_D001943_1 CHEBI:4672 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0041657 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1306341 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0242350 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0021053 infores:hetionet CAID:CA405677113 biolink:causes MONDO:0007783 infores:clingen CAID:CA405677113 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with serine at codon 178 of the RYR1 protein, p.(Tyr178Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405677113/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7476 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018939 infores:hetionet CHEBI:6520 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0235378 infores:hetionet CHEBI:5118 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0876994 infores:hetionet CAID:CA2697547481 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547481 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.59-43688C>G is a deep intronic variant which may impact splicing (SpliceAI score ≥ 0.38 (0.68 acceptor gain; 0.59 donor gain)) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547481/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9927 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0235431 infores:hetionet CHEBI:2567 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0020598 infores:hetionet CHEBI:30830 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011991 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1565489 infores:hetionet CHEBI:45716 biolink:causes MONDO:0043797 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0037929 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027441 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0234215 infores:hetionet CHEBI:7640 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0000729 infores:hetionet NCBIGene:3155 biolink:causes MONDO:0009520 infores:monarchinitiative not_provided not_provided HGNC:5005 MONDO:0009520 uuid:775c58da-6ba8-462c-b598-9410fc2965aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3640 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0020649 infores:hetionet CHEBI:64312 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0010200 infores:hetionet CHEBI:3568 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023218 infores:hetionet CHEBI:6887 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0021368 infores:hetionet CHEBI:2948 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0085669 infores:hetionet CHEBI:31932 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0030193 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0017160 infores:hetionet CHEBI:4445 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151904 infores:hetionet CHEBI:64045 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0013384 infores:hetionet CHEBI:17026 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0018681 infores:hetionet CHEBI:75998 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0221201 infores:hetionet CHEBI:3181 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0028643 infores:hetionet CHEBI:5864 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085669 infores:hetionet CHEBI:231594 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0021177 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0004936 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0001824 infores:hetionet CHEBI:4953 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0015230 infores:hetionet GO:0061295 biolink:causes GO:0061206 infores:ubergraph knowledge_assertion manual_agent GO:0061295 GO:0061206 CAID:CA658656080 biolink:causes MONDO:0017623 infores:clingen CAID:CA658656080 MONDO:0017623 PMID:28677221PMID:20600018PMID:24778394PMID:28677221 Pathogenic PVS1, PM2, PS4_Supporting PM6, BP5, BP7, BS4, BS3, BS1, BS2, PP1, PP3, PP2, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS1 PTEN c.210-2_211del meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID 28677221). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA658656080/MONDO:0017623/003 2019-11-22 2019-12-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52172 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085682 infores:hetionet NCBIGene:84188 biolink:causes MONDO:0014510 infores:monarchinitiative not_provided not_provided HGNC:26222 MONDO:0014510 uuid:3ad16962-8e74-43d6-b341-08a661158887 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042023 infores:hetionet CHEBI:63617 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0575081 infores:hetionet CHEBI:47381 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0043352 infores:hetionet CHEBI:37941 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0206061 infores:hetionet CHEBI:7822 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0002170 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0847631 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0847631 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0235266 infores:hetionet CHEBI:64312 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0686347 infores:hetionet CHEBI:8802 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0004245 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0948594 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0155169 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0239295 infores:hetionet CHEBI:6402 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0014457 infores:hetionet NCBIGene:79955 biolink:causes MONDO:0033201 infores:monarchinitiative not_provided not_provided HGNC:26257 MONDO:0033201 uuid:2bfcb516-1cae-443c-af33-c02e26d0ed44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5801 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0220870 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0019158 infores:hetionet NCBIGene:3955 biolink:causes MONDO:0012349 infores:monarchinitiative not_provided not_provided HGNC:6560 MONDO:0012349 uuid:1e08abc2-a34b-49f0-afb8-1e8cec5ae17f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0017797 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0027339 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0235146 infores:hetionet CHEBI:45863 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0392676 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0032285 infores:hetionet CHEBI:5847 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0011603 infores:hetionet CHEBI:34967 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0015672 infores:hetionet CAID:CA16020744 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020744 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Supporting The c.196G>A (p.Glu66Lys) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 22921945). This variant is absent in population databases (PM2). This variant was detected with the pathogenic variant p.S349P (PM3_supporting; PMID: 22921945). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020744/MONDO:0009861/006 2022-06-28 2022-06-28 Autosomal recessive inheritance HP:0000007 Supports CAID:CA1585329339 biolink:causes MONDO:0009290 infores:clingen CAID:CA1585329339 MONDO:0009290 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000152.5:c.971dupC (p.Ser325GlufsTer5) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient reported to have infantile-onset Pompe disease is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1802C>T (p.Ser601Leu) (ClinVar Variation ID: 194154; SCV002032130.1); the phase is unconfirmed (PMID: 28394184) (PM3_Supporting). There is insufficient data to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. Initially, the variant was classified a likely pathogenic by the ClinGen Lysosomal Diseases VCEP on August 17, 2021, but it was reclassified as pathogenic on Jan 15, 2024, due to the application of PM3_Supporting. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Feb 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA1585329339/MONDO:0009290/010 2024-03-06 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:188986 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0259799 infores:hetionet CHEBI:40009 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0011603 infores:hetionet CHEBI:46195 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C1142135 infores:hetionet CHEBI:63635 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0031542 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0435002 infores:hetionet CHEBI:4466 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0428977 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0281825 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0281825 infores:hetionet CHEBI:8764 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085932 infores:hetionet CAID:CA10650415 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650415 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.*3297T>C is a UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650415/MONDO:0011071/008 2024-09-11 2024-09-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003850 infores:hetionet CHEBI:8665 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0015644 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0333472 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0333472 infores:hetionet CHEBI:5790 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0001973 infores:hetionet CHEBI:127342 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0344232 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023470 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0271650 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0086543 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0042267 infores:hetionet CHEBI:41774 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0237849 infores:hetionet CHEBI:50841 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0036974 infores:hetionet CHEBI:64312 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015672 infores:hetionet CHEBI:9907 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0026858 infores:hetionet CAID:CA404085992 biolink:causes MONDO:0007750 infores:clingen CAID:CA404085992 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1, PP4 The NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - 2 other missense variants in the same codon:(1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg)- 1 star, Conflicting interpretations of pathogenicity​: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4)- Pathogenic by these guidelines (FH VCEP training Aug 2021)(2) NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) - 0 stars, Pathogenic- Likely pathogenic by these guidelines--- 1 Pathogenic variant in the same codon, so PM5 is met.PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404085992/MONDO:0007750/013 2022-01-28 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9073 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0015230 infores:hetionet CHEBI:145499 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1443060 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0020517 infores:hetionet CHEBI:8874 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0221512 infores:hetionet CHEBI:68647 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020598 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0041912 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0234215 infores:hetionet CHEBI:8069 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0038325 infores:hetionet CHEBI:3568 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029163 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0004238 infores:hetionet CHEBI:28748 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0917801 infores:hetionet CHEBI:7956 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0030252 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0024115 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0042373 infores:hetionet NCBIGene:207 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:391 MONDO:0016419 uuid:b6a11d20-b590-4ee9-85c0-d3a06d3cf37e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C2830004 infores:hetionet CHEBI:8499 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0018790 infores:hetionet CHEBI:37941 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C2010560 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0004936 infores:hetionet UMLS:C0657912 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0031256 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0687707 infores:hetionet CHEBI:134743 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0311468 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0032326 infores:hetionet CHEBI:83527 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0033687 infores:hetionet CHEBI:51209 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0221490 infores:hetionet CAID:CA8337864 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337864 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM4, PM3, PP4_Moderate The NM_000018.4 c.833_835del (p.Lys278del) variant in ACADVL is an in-frame deletion (removes amino acids Lys278) in exon 9/20 that is not predicted to impact splicing (SpliceAI: 0.01). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The c.833_835del variant is predicted to cause a change in the length of the protein (p.Lys278del) due to an in-frame deletion of an amino acid in a non-repeat region (PM4). This variant is reported in the literature in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency in both compound heterozygous and homozygous fashion, with at least one of whom displayed elevated C14:1 carnitine level (1.3 µmol/L) and reduced VLCAD enzyme levels (17% WT control), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 19327992). This patient also carried a pathogenic variant c.1376G>A in trans (PM3 score = 1.0, PM3, PMID: 19327992). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM4, PP4_Moderate, PM3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337864/MONDO:0008723/021 2024-05-16 2024-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8597 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0004245 infores:hetionet CHEBI:37941 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0013404 infores:hetionet CHEBI:474180 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853986 infores:hetionet CHEBI:6067 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0034642 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0475858 infores:hetionet CHEBI:84500 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0231218 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0029408 infores:hetionet CHEBI:17688 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0235198 infores:hetionet CHEBI:49713 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0456909 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0012833 infores:hetionet GO:0048399 biolink:causes GO:0048393 infores:ubergraph knowledge_assertion manual_agent GO:0048399 GO:0048393 PUBCHEM.COMPOUND:45357473 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0015672 infores:hetionet CHEBI:64312 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085649 infores:hetionet CHEBI:28364 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C2363731 infores:hetionet CHEBI:7565 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0009676 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0855242 infores:hetionet CHEBI:87715 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0030196 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1384353 infores:hetionet CHEBI:51380 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0037763 infores:hetionet CHEBI:119915 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085649 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0281774 infores:hetionet CHEBI:5864 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0162283 infores:hetionet CHEBI:8028 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0011071 infores:hetionet CAID:CA2497028946 biolink:causes MONDO:0011132 infores:clingen CAID:CA2497028946 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The variant NM_001369369.1(FOXN1):c.1579_1580del (p.Thr527Ter) is a nonsense variant predicted to cause a premature stop codon (8/9) and escape nonsense mediated decay. The variant is predicted to remove >10% of the FOXN1 protein and truncate the transactivation domain, a domain important to protein function (PVS1_strong). The variant has been found in at least one homozygous patient with FOXN1 SCID (PM3_supporting, P11, PMIDs: 33464451, 31151968). This patient was whole exome sequenced, and displayed phenotypes including alopecia, nail dystrophy, very low T cell number counts for age, impaired proliferative response to PHA, and low CD8+ T cell number relative to age-matched controls (PP4). The variant is absent from gnomADv4.1 (PM2_supporting). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, PP4, PM3_supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup (Pilot, date of approval xx/xx/2024). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497028946/MONDO:0011132/113 2024-09-27 2024-09-27 Semidominant inheritance HP:0032113 Supports GO:0106088 biolink:causes GO:0120077 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0120077 CHEBI:82941 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0021053 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0236065 infores:hetionet CHEBI:7478 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085631 infores:hetionet CHEBI:2668 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0700590 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0878544 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0027769 infores:hetionet CHEBI:92923 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0020555 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0919980 infores:hetionet CHEBI:66899 biolink:causes UMLS:C0863079 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0863079 infores:hetionet CHEBI:17549 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0040034 infores:hetionet CAID:CA229730 biolink:causes MONDO:0009861 infores:clingen CAID:CA229730 MONDO:0009861 PMID:25456745PMID:25456745PMID:16256386 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 PM5 The c.739G>A (p.Gly247Ser) variant in PAH was reported in 1 patient with classical PKU, BH4 deficiency excluded. (PMID: 16256386, 25456745) It was detected with T200Nfs, (pathogenic per PAH VCEP). This variant is absent from ExAC, 1000G, gnomAD, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.981. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229730/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:157657 biolink:causes MONDO:0044308 infores:monarchinitiative not_provided not_provided HGNC:27232 MONDO:0044308 uuid:4274827b-7df0-4f0c-96e5-d7fbbd51003b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63581 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0010200 infores:hetionet CAID:CA399806951 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806951 MONDO:0100326 PMID: Pathogenic PP4_Strong, PP3, PM2_Supporting, PS3, PP1_Strong, PM3_Supporting The NM_000419.5(ITGA2B):c.97A>G (p.Asn33Asp) missense variant has been reported in four homozygous siblings (patients 2, 4, 6, and 9 PMID:21029361; PM3_supporting). All siblings displayed abnormal bleeding and one sibling tested for platelet aggregation demonstrated impaired response to agonists, with a normal response to ristocetin, which is characteristic of GT. Three of the siblings, including the proband, demonstrated absent platelet αIIbβ3 surface expression measured by flow cytometry (PP4_strong, PP1_strong). In Silico predictor revealed a REVEL score of 0.773, predicting a pathogenic effect (PP3). The variant is not found in gnomAD v2.1.1 (PM2_supporting). In BHK cells transfected with the p.Asn33Asp variant, surface expression of αIIbβ3 was absent (PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP1_strong, PP3, PS3, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806951/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3082 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1306341 infores:hetionet CHEBI:5847 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0003811 infores:hetionet CHEBI:9086 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013404 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0038454 infores:hetionet CHEBI:31536 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151786 infores:hetionet CHEBI:4562 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0151786 infores:hetionet UMLS:C0657912 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037384 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004936 infores:hetionet GO:0051941 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0051941 GO:0051641 CHEBI:36795 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020580 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0267792 infores:hetionet CAID:CA210762 biolink:causes MONDO:0013144 infores:clingen CAID:CA210762 MONDO:0013144 PMID: Pathogenic PS4, PM5, PP1_Moderate, PP3, PP4, PM2_Supporting BS1, BA1 The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID: 27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210762/MONDO:0013144/084 2024-08-16 2024-08-21 Autosomal dominant inheritance HP:0000006 Supports CAID:CA255672 biolink:causes MONDO:0018947 infores:clingen CAID:CA255672 MONDO:0018947 PMID: Pathogenic PM2_Supporting, PS4, PVS1 BA1, BS1 The c.670C>T (p.Arg224Ter) variant in MTM1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/15 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 5 probands with X-linked myotubular myopathy (PS4; PMID: 9305655, 10063835, 11552027). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PS4, PM2_Supporting. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA255672/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Supports CHEBI:6128 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0011603 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0027765 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0012833 infores:hetionet CHEBI:15765 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0008031 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151740 infores:hetionet CHEBI:61049 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0267940 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0017178 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234913 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0037274 infores:hetionet CHEBI:75722 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0041657 infores:hetionet CAID:CA8814901 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814901 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP3, PP4, PM3, PS3, PS1 "The NM_000152.5:c.546+5G>T variant occurs in the donor splice region of intron 2 of GAA. RT-PCR of RNA from primary fibroblasts a patient who is compound heterozygous for c.[546+5G>T; 1726G>A] and c.1080C>G (p.Tyr360Ter) revealed a normal-sized fragment containing 2 sequences (one normal and one with a 3-bp insertion) and an aberrantly short fragment containing a deletion of exon 2 (PMID: 34995642, Fig 6). Another study, using minigene analysis, showed that the variant results in almost complete skipping of exon 2 (PMID: 31301153, Fig 3e, f). Consistent with this evidence, the computational predictor SpliceAI predicts loss of the donor splice site (score of 0.42) and gain of a splice donor 3bp downstream of the normal splice donor (score of 0.64). Any transcripts in which exon 2 is skipped would be missing the start codon and signal sequence (https://www.uniprot.org/uniprotkb/P10253/entry). This variant has been found in multiple individuals identified by newborn screening programs in Taiwan and Japan (PMID: 20080426, 21232767, 31076647, 34995642). However, the variant always occurs in cis with pseudodeficiency variants (including c.1726G>A) which could be responsible for the reduced GAA activity observed in these individuals. One patient, who was compound heterozygous for the variant and c.1080C>G (p.Tyr360Ter), was reported to have initial CK elevation, and hypotonia for the first few years of life, but was later described as ""normal"" by the family at age 13 years (PMID: 34995642). Therefore, despite the functional and predictive evidence indicating that this variant impacts splicing, the clinical significance of the variant is unclear. There has been no report of a patient with this variant who is clearly symptomatic for Pompe disease and, therefore, it is unknown if this variant may contribute to late-onset symptoms (neither PP4 nor PM3 were applied). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004978 in the East Asian population which is lower than ClinGen LD VCEP threshold of <0.001 (PM2_supporting). Other variants in the same donor splice site region have various classifications. For example, c.546+5G>A classified by the ClinGen LD VCEP as a variant of uncertain significance (ClinVar SCV004227903.1). Multiple other variants have been reported as pathogenic/likely pathogenic by ClinVar submitters (but not yet classified by the ClinGen LD VCEP) including c.546+2T>C, and c.546+2_+5del, and others in the same region have been classified in ClinVar as benign/Likely benign (not yet classified by the ClinGen LD VCEP) including c.546+4G>C; or VUS (c.546+3G>A). There is ClinVar entry for this variant (Variation ID: 557811). In summary, this variant has been classified as a variant of uncertain significance for Pompe disease by the ClinGen Lysosomal Disorders Variant Curation Expert Panel. Additional data, such as a report of a patient with clear symptoms of Pompe disease, or functional studies in muscle tissue, would be helpful. GAA-Specific ACMG-AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PVS1_Strong, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 5, 2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814901/MONDO:0009290/010 2024-11-05 2024-12-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:50122 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020456 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023533 infores:hetionet CAID:CA645369675 biolink:causes MONDO:0007648 infores:clingen CAID:CA645369675 MONDO:0007648 PMID:26025002 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.603delT p.(Val202Leufs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000580694.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369675/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:3723 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1112442 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0234215 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0033581 infores:hetionet CHEBI:17549 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0237849 infores:hetionet CHEBI:71417 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0015967 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0235706 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0235706 infores:hetionet CHEBI:3213 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0018418 infores:hetionet CHEBI:50156 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0009450 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0006147 infores:hetionet NCBIGene:11284 biolink:causes MONDO:0013254 infores:monarchinitiative not_provided not_provided HGNC:9154 MONDO:0013254 uuid:fa6d33cf-40a3-417e-8124-fa8ac51e4e94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0427086 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0277925 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0152227 infores:hetionet GO:0072008 biolink:causes CL:1000742 infores:ubergraph knowledge_assertion manual_agent GO:0072008 CL:1000742 CHEBI:18248 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0015967 infores:hetionet NCBIGene:2624 biolink:causes MONDO:0013540 infores:monarchinitiative not_provided not_provided HGNC:4171 MONDO:0013540 uuid:e4328d55-a503-4b3c-9676-2a296716d720 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18243 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0425945 infores:hetionet CHEBI:51041 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0021177 infores:hetionet CHEBI:49668 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0011606 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0221269 infores:hetionet CHEBI:3640 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0011603 infores:hetionet CHEBI:63580 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0233471 infores:hetionet CHEBI:83527 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0019087 infores:hetionet GO:0070952 biolink:causes GO:0050830 infores:ubergraph knowledge_assertion manual_agent GO:0070952 GO:0050830 CHEBI:119915 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011175 infores:hetionet CHEBI:84883 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0151904 infores:hetionet CHEBI:15407 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0042963 infores:hetionet CAID:CA9870202 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870202 MONDO:0015967 PMID: Uncertain Significance PP3, PM1_Supporting PM2, PP4, BS1 The c.233G>A variant in the HNF4A gene causes an amino acid change of arginine to glutamine at codon 78 (p.(Arg78Gln)) of NM_175914.5. This variant has a Grpmax filtering allele frequency of 0.00002553 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant is located within the DNA binding domain (codons 37-113) which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.788, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is less than 50%, so PP4 cannot be applied (internal lab contributors). In summary, c.233G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870202/MONDO:0015967/085 2025-08-12 2025-08-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8665 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0013390 infores:hetionet CHEBI:49575 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0041969 infores:hetionet CAID:CA350344424 biolink:causes MONDO:0015924 infores:clingen CAID:CA350344424 MONDO:0015924 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting BA1, BS1 The BMPR2 c.1424C>A variant is a nonsense mutation in the kinase domain (exon 11 of 13). It is predicted to result in nonsense mediated mRNA decay, and therefore meets the criteria for PVS1. It is absent from gnomAD v2.1.1 (all samples), meeting PM2_supporting. There are three reports of this variant in the literature (PMIDs 16429395, 20534176 and 32581362). However, since PMID 16429395 summarized data from multiple countries, including the UK and French populations that were the subject of the later papers, it is not possible to determine if all three probands are independent. Thus conservatively, only counted 2 probands were counted (PS4_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350344424/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9586 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0018520 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0038454 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0948586 infores:hetionet CHEBI:47657 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0267792 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0409974 infores:hetionet CHEBI:36791 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033036 infores:hetionet CHEBI:9137 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0036690 infores:hetionet CHEBI:49603 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C2939419 infores:hetionet CHEBI:52717 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011175 infores:hetionet GO:0048934 biolink:causes CL:2000032 infores:ubergraph knowledge_assertion manual_agent GO:0048934 CL:2000032 CHEBI:6339 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151662 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0012833 infores:hetionet CHEBI:17263 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C2979982 infores:hetionet CAID:CA386958679 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958679 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.327-2A>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 2 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.327-2A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958679/MONDO:0015967/017 2022-04-18 2022-04-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27732 biolink:causes EFO:1001766 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1527348 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0018799 infores:hetionet CHEBI:135935 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0012833 infores:hetionet CHEBI:6375 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0008350 infores:hetionet CHEBI:490877 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0476327 infores:hetionet NCBIGene:79158 biolink:causes MONDO:0018931 infores:monarchinitiative not_provided not_provided HGNC:29670 MONDO:0018931 uuid:b65d65e3-f05e-486c-8f66-cfa290c8d8a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes MONDO:0008542 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0039685 infores:hetionet CHEBI:9137 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027424 infores:hetionet CHEBI:499361 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0009782 infores:hetionet CHEBI:16796 biolink:causes HP:0030142 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0159060 infores:hetionet CHEBI:75045 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0010200 infores:hetionet CHEBI:9434 biolink:causes UMLS:C1868912 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C1868912 infores:hetionet CHEBI:135736 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0239739 infores:hetionet CHEBI:10125 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0040822 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853019 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0234913 infores:hetionet CHEBI:367163 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0036508 infores:hetionet CHEBI:49668 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0232849 infores:hetionet GO:0044741 biolink:causes GO:0019233 infores:ubergraph knowledge_assertion manual_agent GO:0044741 GO:0019233 CHEBI:7465 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0152029 infores:hetionet CHEBI:6717 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0039231 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0234215 infores:hetionet CHEBI:4792 biolink:causes UMLS:C0860711 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0860711 infores:hetionet CHEBI:5123 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0002792 infores:hetionet NCBIGene:124454 biolink:causes MONDO:0013971 infores:monarchinitiative not_provided not_provided HGNC:29419 MONDO:0013971 uuid:490e0fe7-4774-4461-a1f9-2342509eb61b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45979 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0015672 infores:hetionet CHEBI:49603 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0033774 infores:hetionet CAID:CA251543 biolink:causes MONDO:0009861 infores:clingen CAID:CA251543 MONDO:0009861 PMID:9860305PMID:9860305PMID:9860305PMID:9860305 Pathogenic PM3, PM2, PP4, PP3, PS3 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low in ExAC and 1000 genomes (PMID:9860305); PS3: PAH activity in COS cell expression system 15% (PMID:9860305); PM3: Compound het with severe mutation (PMID:9860305); PP3: ; PP4: Reported in patient with classic PKU (PMID:9860305). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3, PP3, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251543/MONDO:0009861/006 2018-08-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA000530 biolink:causes MONDO:0018875 infores:clingen CAID:CA000530 MONDO:0018875 PMID:39060302 Likely Benign BS2_Supporting, BS3, PP3, PM2_Supporting BP4, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PP1, PP4 The NM_000546.6: 997C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 333 (p.Arg333Cys). This variant was observed in an individual with breast cancer in their 20s who also had a VUS in the ATM gene. This variant has also been observed in 44 individuals that did not appear to have LFS across two commercial laboratories (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). This variant has an allele frequency of 0.00001797 (29/1613610alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = 0.237; Align GVGD = Class 35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, PP3. (Bayesian Points: -3; VCEP specifications version 2.2; 2/6/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000530/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3176 biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0854114 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0011570 infores:hetionet CHEBI:681850 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0042029 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027765 infores:hetionet CAID:CA367400477 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400477 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.824G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 275 (p.(Arg275Leu)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.702, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants at this residue, c.823C>T p.(Arg275Cys) and c.823C>G (p.Arg275Gly), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.824G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400477/MONDO:0015967/086 2025-01-10 2025-01-10 Semidominant inheritance HP:0032113 Supports CHEBI:28925 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0023530 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0004936 infores:hetionet CHEBI:2914 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0006114 infores:hetionet CHEBI:9073 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0020517 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0033246 infores:hetionet CHEBI:6822 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0018939 infores:hetionet CHEBI:42068 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0040034 infores:hetionet CHEBI:2659 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0233407 infores:hetionet CL:0000545 biolink:causes GO:0035744 infores:ubergraph knowledge_assertion manual_agent CL:0000545 GO:0035744 CHEBI:63608 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0024299 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0021400 infores:hetionet CHEBI:40303 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0037763 infores:hetionet CAID:CA229406 biolink:causes MONDO:0009861 infores:clingen CAID:CA229406 MONDO:0009861 PMID:18798839 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.1229T>G (p.Phe410Cys) variant in PAH has been detected in two Portuguese patients with moderate PKU (serum Phe = 6.6mg/dL and 15.0mg/dL); BH4 deficiency excluded via urinary pterin analysis (PMID N/A - linked article; PP4_Moderate). This variant was detected with L249F (reported as Pathogenic in ClinVar; VarID:102821; 7 submitters) and R270K (reported as Pathogenic in ClinVar; VarID:102846; 5 submitters) - phase not confirmed - 1.0 points (PMID N/A - linked article; PM3). This variant is absent from population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.99. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229406/MONDO:0009861/006 2020-07-23 2020-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46081 biolink:causes MONDO:0001433 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042251 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0040034 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022568 infores:hetionet CHEBI:3380 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C2364111 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027769 infores:hetionet CHEBI:6916 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0085611 infores:hetionet CHEBI:31236 biolink:causes HP:0002345 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234376 infores:hetionet CHEBI:42797 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0392699 infores:hetionet UNII:9430ZR8ZAN biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0027540 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0034065 infores:hetionet CAID:CA2061553 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061553 MONDO:0015924 PMID: Benign BS3_Supporting, BS1, BS4 PM2, PP3, BS2, BA1, BP4, PM1, PS4 The c.2618G>A variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 873 (p.Arg873Gln). The highest population minor allele frequency in gnomAD v2.2.1 controls is 0.001595 in Other East Asian, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (≥0.001) for BS1 but great than the threshold for BA1 (>05%) (BS1 met). This variant was reported to not segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal PH VCEP member contribution). In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activated BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.1, 1/18/2024): BS4, BS1, BS3_Supporting. Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061553/MONDO:0015924/125 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4903 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0017178 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0034530 infores:hetionet CHEBI:3219 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152030 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0027765 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0231528 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0235431 infores:hetionet CHEBI:3568 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0232286 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151849 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0031039 infores:hetionet CHEBI:63791 biolink:causes HP:0001954 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0277799 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0232492 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0423602 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0022354 infores:hetionet CAID:CA658795297 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795297 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The NM_000152.5(GAA):c.2706del variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Lys903ArgfsTer2). Although the predicted termination codon occurs in the penultimate exon, it is more than 50 base pairs upstream from the 3' end of the exon, and therefore, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is supported by the finding of a patient with this variant who has no GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923) (PVS1). Three patients have been reported with deficient GAA activity in either dried blood spots (in the affected range based on clinical laboratory data) or cultured fibroblasts (<1% normal activity) (personal communication, PMIDs 22252923, 31710733) (PP4_Moderate). One of these patients is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-33-13T>G ( PMID: 31710733), and another is homozygous for the variant (PMID: 22252923, personal communication) (PM3). A patient is compound heterozygous for c.2706del and c.2051C>T (p.Pro684Leu). The alleic data from this patient will be used in the classification of p.Pro684Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 554339, 2 star review status) with 2 submitters reporting the variant as pathogenic and one as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specific by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795297/MONDO:0009290/010 2022-09-06 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5147 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0851578 infores:hetionet CHEBI:50378 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0085636 infores:hetionet CHEBI:47519 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0004509 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0009450 infores:hetionet CHEBI:3756 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0542571 infores:hetionet CHEBI:94686 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1384353 infores:hetionet CAID:CA10119150 biolink:causes MONDO:0021060 infores:clingen CAID:CA10119150 MONDO:0021060 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Strong, PP1_Strong, PS3_Supporting BA1, BS1 The c.1943-256C>T (p.T648fs*36) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17/21 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001557 (2/22704 alleles) in the South Asian population, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 4 individuals with RASopathy. All were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.27dup (p.Gln10Alafs*24), c.1030del (p.Ser344fs), c.2178C>A (p.Tyr726Ter), c.27dupG (p.Gln10Alafs*24), 3.5 PM3 points, PMIDs: 29469822 and 32623905, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics) (PM3_Strong). The variant has been reported to segregate with RASopathy in ≥7 affected meioses from 4 families (PP1_Strong; PMIDs: 29469822 and 32623905, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK indicating that this variant impacts protein function (PMID:32623905)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3_Strong, PP1_Strong, PS3_Supporting, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10119150/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3478 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0438142 infores:hetionet CHEBI:100241 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038999 infores:hetionet NCBIGene:9247 biolink:causes MONDO:0020798 infores:monarchinitiative not_provided not_provided HGNC:4198 MONDO:0020798 uuid:a9f237fd-bd3b-458e-975c-bc1464bc153f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84050 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0010200 infores:hetionet CHEBI:51364 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0043094 infores:hetionet CHEBI:7865 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0856054 infores:hetionet CHEBI:92998 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0011175 infores:hetionet CHEBI:100241 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0162834 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0042373 infores:hetionet CHEBI:2549 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0022346 infores:hetionet CAID:CA512318593 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318593 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PVS1, PM6, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.747T>A (p.Pro249=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (1.17) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318593/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0017797 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0231218 infores:hetionet CHEBI:37941 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0004604 infores:hetionet NCBIGene:113278 biolink:causes MONDO:0100428 infores:monarchinitiative not_provided not_provided HGNC:16187 MONDO:0100428 uuid:b3008b1e-18de-4caf-9ba6-de9a6276f25a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68554 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0687713 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0032285 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1384353 infores:hetionet NCBIGene:7385 biolink:causes MONDO:0014066 infores:monarchinitiative not_provided not_provided HGNC:12586 MONDO:0014066 uuid:f3dd2936-284c-4476-a595-2dad4a16fd7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40303 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0012833 infores:hetionet CAID:CA10014721 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014721 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1):c.58+9A>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -2.6 < 2.0) (BP7). This variant has not been reported in an individual meeting at least one of the RUNX1-phenotypic criteria. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP7, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014721/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3215 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0018799 infores:hetionet CHEBI:681569 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0041364 infores:hetionet CHEBI:8356 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037299 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0003811 infores:hetionet CHEBI:4909 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C1167709 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001875 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014488 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0021053 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0235453 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0235453 infores:hetionet CHEBI:50275 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0040264 infores:hetionet CHEBI:10124 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0852911 infores:hetionet CHEBI:47381 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042023 infores:hetionet CAID:CA355963434 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963434 MONDO:0001586 PMID: Uncertain Significance PM3_Supporting, PP3_Moderate, PM2_Supporting PP4 The NM_000203.5:c.1152G>C variant in IDUA is predicted to result in a missense substitution, p.Lys384Asn. To our knowledge, this variant has not been reported in the literature. To our knowledge, this variant has not been reported in the literature. However, one patient, reported to have MPS1 and elevated urine GAGs, has been identified by a clinical diagnostic laboratory (data is insufficient to meet PP4). This patient is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, p.Gly51Asp; phase not confirmed (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.853 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). The is a ClinVar entry for this variant (Variation ID: 1384361). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PP3_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963434/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3568 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0542571 infores:hetionet CHEBI:50131 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0041834 infores:hetionet CHEBI:28748 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002962 infores:hetionet CHEBI:10127 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085649 infores:hetionet GO:0050872 biolink:causes CL:0000448 infores:ubergraph knowledge_assertion manual_agent GO:0050872 CL:0000448 CHEBI:9943 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0035078 infores:hetionet CHEBI:15940 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151908 infores:hetionet CHEBI:3568 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0004144 infores:hetionet GO:0048708 biolink:causes CL:0000127 infores:ubergraph knowledge_assertion manual_agent GO:0048708 CL:0000127 CHEBI:161680 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0009676 infores:hetionet CHEBI:134991 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0085616 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0014868 infores:hetionet CHEBI:91834 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0000737 infores:hetionet CHEBI:16469 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0332563 infores:hetionet CHEBI:9599 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0022568 infores:hetionet CAID:CA376060024 biolink:causes MONDO:0011225 infores:clingen CAID:CA376060024 MONDO:0011225 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PVS1_Moderate, PP4_Moderate PP3 The c.464+1G>A (NM_001033855.3) variant in DCLRE1C occurs within the canonical splice donor site (+1) of intron 6. It is predicted to cause a in-frame deletion of exon 6, comprising 34 aa (less than 5% of the protein). PVS1_Moderate. At least 4 probands carrying this variant in the homozygous occurrence are reported in the literature (2 points; PMID: 24230999 and 34619682). In addition, unpublished internal data from CeGaT Center for Human Genetics Tuebingen (SCV001249001.34), indicate that three unrelated SCID patients are homozygous for this variant (3 points). Therefore, a total of 5 points are accumulated, meeting the criterion for PM3_Very Strong. At least one patient (P2) with late-onset combined immunodeficiency in the literature shows: Decreased V(D)J recombination WITHOUT other gene testing (1 pt) + T-B-NK+ lymphocyte subset profile (0.5 pts). Increased cellular radiosensitivity WITHOUT other gene testing (0.5 pt) PMID: 21390052 Total is 2 pts, PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001470 (1/68024 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold(<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD v4.1.0.In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Moderate, PM2_Supporting, PP4_Moderate, and PM3_Very Strong. (VCEP specifications version 2.1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376060024/MONDO:0011225/116 2025-11-12 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410147342 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147342 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1328A>G (p.Asn443Ser) is a missense variant which has a REVEL score < 0.50 (0.202) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147342/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:11274 biolink:causes MONDO:0018828 infores:monarchinitiative not_provided not_provided HGNC:12616 MONDO:0018828 uuid:f0441010-8ba3-4511-a9fc-d62e6ba0dacf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0026848 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0017178 infores:hetionet CHEBI:9073 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0041657 infores:hetionet CHEBI:144551 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0013604 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042571 infores:hetionet CHEBI:46195 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151786 infores:hetionet NCBIGene:440 biolink:causes MONDO:0014258 infores:monarchinitiative not_provided not_provided HGNC:753 MONDO:0014258 uuid:79d9cc11-789f-4d9f-8dca-27bb50b7e57a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020991 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020991 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PVS1_Strong, PM3_Supporting The c.1306delT (p.S436Pfs*16) variant in PAH is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one proband with classic PKU, as indexed by abnormal blood Phe levels and in whom BH4 deficiency was said to excluded (PP4_Moderate); it was found in presumed trans with the IVS10-11G>A variant (Pathogenic per ClinGen PAH VCEP) (PMID: 18299955) (0.5 points total; PM3_Supporting). Classification: Likely PathogenicSupporting Criteria: PVS1_Strong, PM2; PP4_Moderate; PM3_Supporting Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020991/MONDO:0009861/006 2020-05-18 2020-05-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:79699 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0003862 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0235416 infores:hetionet CHEBI:7903 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0002994 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002453 infores:hetionet NCBIGene:158326 biolink:causes MONDO:0009560 infores:monarchinitiative not_provided not_provided HGNC:23399 MONDO:0009560 uuid:a46b783b-bf60-43d7-a67b-fd7e59534516 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0018524 infores:hetionet CHEBI:5050 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0018681 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0236068 infores:hetionet NCBIGene:81790 biolink:causes MONDO:0012166 infores:monarchinitiative not_provided not_provided HGNC:25358 MONDO:0012166 uuid:1673e428-d338-43a5-b2ff-2f665af9fa3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0152027 infores:hetionet CHEBI:45783 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0017181 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0281981 infores:hetionet CHEBI:51450 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0235266 infores:hetionet CAID:CA512318935 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318935 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.189C>T (p.Ala63=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318935/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0917801 infores:hetionet CHEBI:5779 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0011175 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0002170 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0178298 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0178298 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0008049 infores:hetionet CAID:CA289257 biolink:causes MONDO:0008723 infores:clingen CAID:CA289257 MONDO:0008723 PMID: Benign BP4, BA1, BP7 PM4, BP3, PVS1 The NM_000018.4(ACADVL):c.693T>A (p.Ser231=) variant is a synonymous (silent) variant that is not predicted by SpliceAI and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP and PhastCons (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2061 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA289257/MONDO:0008723/021 2024-03-26 2024-03-26 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:74947 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014130 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0041909 infores:hetionet CAID:CA10591513 biolink:causes MONDO:0700268 infores:clingen CAID:CA10591513 MONDO:0700268 PMID:30209399PMID:30765603 Uncertain Significance PM2_Supporting, PS3 PP3, BP1, BP4 The c.5003T>C variant in BRCA1 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 1668 (p.Phe1668Ser). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.24, indicating impact on BRCA1 function via protein change is unclear (score range 0.15-0.28). A SpliceAI score of 0.04 predicts no impact on splicing (score threshold ≤0.1) (no bioinformatic code is applied). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234) (PS3 met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_supporting, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10591513/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8869 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0041969 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0314719 infores:hetionet CHEBI:52717 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0278134 infores:hetionet CHEBI:9635 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0008031 infores:hetionet GO:0006954 biolink:causes MONDO:0019558 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D008179 DB01130_MESH_D008179_1DB00547_MESH_D008179_1 CHEBI:70707 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0042963 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0236068 infores:hetionet CAID:CA549264595 biolink:causes MONDO:0001586 infores:clingen CAID:CA549264595 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting PS3, BS3, PP1 The NM_000203.5(IDUA):c.1395del (p.Gly466Alafs*59) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The older of two Japanese sisters was diagnosed with severe MPS I based on clinical symptoms (respiratory disease, coarse facial features, dysostosis multiplex, developmental delay) and absence of IDUA activity in leukocytes. No treatment was available and she died at 1 year 10 month. The younger sister also had reduced IDUA activity in leukocytes but developed few features of MPS I after beginning ERT at 1 month of age and undergoing HSCT at 9 months (PMID: 30755342) (PP4). The younger sister is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP. Parental testing indicated that the variants are in trans (1 point, PM3). Another individual has been reported with IDUA deficiency but normal GAG's and is compound heterozygous for the variant and a variant in IDUA, c.1081G>A (p.Ala361Thr) (ClinVar Variation ID: 92624, SCV005619884.1) that has been classified as benign by the ClinGen LD VCEP (Variation ID: 92624) (PMID: 29801497), and is therefore likely an unaffected heterozygote. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003973 (1/25172 alleles) in the Admixed American population. This is lower than the LD VCEP's threshold for PM2_Supporting (<0.00025), therefore meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 929236. In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA549264595/MONDO:0001586/091 2025-05-02 2025-05-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7565 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0001824 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0853697 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0018799 infores:hetionet GO:0090249 biolink:causes GO:0090245 infores:ubergraph knowledge_assertion manual_agent GO:0090249 GO:0090245 CHEBI:135736 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0152030 infores:hetionet CAID:CA389475390 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475390 MONDO:0100040 PMID: Likely Pathogenic PP3, PM1, PM5, PM2_Supporting The p.Met191Ile variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). The p.Met191Ile variant in FOXG1 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). A pathogenic missense variant (p.Met191Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 26364767, 26993267) (PM5). In summary, the p.Met191Ile variant in FOXG1 is classified as likely pathogenic for a FOXG1-related disorder based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, PM5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475390/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63608 biolink:causes UMLS:C0023070 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0023070 infores:hetionet CHEBI:8069 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C3203358 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085129 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0234215 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0178298 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0032285 infores:hetionet CAID:CA410204213 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204213 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.131C>G (p.Ser44Cys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204213/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135961 biolink:causes NCIT:C98911 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0877225 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0027769 infores:hetionet CHEBI:5123 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0015967 infores:hetionet CHEBI:83531 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0042109 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0041912 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0233494 infores:hetionet NCBIGene:5428 biolink:causes MONDO:0024528 infores:monarchinitiative not_provided not_provided HGNC:9179 MONDO:0024528 uuid:79d4f1de-5dd3-4381-af70-8d4d581464f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10100 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0278134 infores:hetionet CHEBI:36791 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232943 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002957 infores:hetionet CHEBI:63581 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0003862 infores:hetionet CHEBI:9448 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0340865 infores:hetionet CHEBI:2379 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0011991 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0034069 infores:hetionet CHEBI:3175 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0018681 infores:hetionet CHEBI:40279 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020461 infores:hetionet CHEBI:64355 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0025289 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0011991 infores:hetionet CHEBI:31705 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0020580 infores:hetionet CAID:CA410147511 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147511 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1284C>G (p.Ile428Met) is a missense variant which has a REVEL score < 0.50 (0.187), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147511/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31515 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0000729 infores:hetionet CHEBI:7986 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0008031 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1510472 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0002063 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0025061 infores:hetionet CHEBI:64019 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0151904 infores:hetionet CHEBI:7903 biolink:causes UMLS:C3495917 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C3495917 infores:hetionet CHEBI:2682 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0038325 infores:hetionet CHEBI:567361 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0008031 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0027769 infores:hetionet CHEBI:101278 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0344232 infores:hetionet CAID:CA186248 biolink:causes MONDO:0100488 infores:clingen CAID:CA186248 MONDO:0100488 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1009_1010delAG (p.Ser337Phefs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). Two probands meet HDGC phenotype criteria (PS4_Moderate; SCV000212776.4). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA186248/MONDO:0100488/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf GO:1905295 biolink:causes GO:0014034 infores:ubergraph knowledge_assertion manual_agent GO:1905295 GO:0014034 CHEBI:31236 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007787 infores:hetionet CHEBI:135939 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0041657 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0345904 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0040046 infores:hetionet CHEBI:50841 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0027497 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019917 infores:hetionet CHEBI:4636 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0013395 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0006826 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0242350 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042109 infores:hetionet CHEBI:63599 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0006277 infores:hetionet CAID:CA915946630 biolink:causes MONDO:0007947 infores:clingen CAID:CA915946630 MONDO:0007947 PMID: Likely Pathogenic PP1, PP3, PP4, PM2_Supporting, PS4_Moderate, PS2_Supporting PM6, PVS1, BS2, PP2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PM5, PM4, PM1, PM3, BP7, BP5, BS1, BS4, BS3 NM_000138.5 c.7330+3_7330+6del is an intronic variant that removes 4 nucleotides in a splice region. Computational prediction tools strongly suggest that this variant weakens or eliminates use of the canonical donor splice site in intron 58 (PP3). This variant was identified in an internal proband who met the revised Ghent criteria for Marfan syndrome with TAAD and a systemic score of 11 (PP4; University of Tokyo). This variant has been reported in the literature and in ClinVar (Variation ID: 636961) in at least 4 unrelated individuals with clinical suspicion of Marfan syndrome (PS4_moderate; PMID: 19839986, GeneDx, Blueprint Genetics). In one of these cases, the variant was found to be de novo with confirmed parentage in an individual with skeletal features and striae, a non-specific phenotype with high genetic heterogeneity (PS2_supporting; GeneDx). In another family, this variant was found to segregate with features or a diagnosis of Marfan syndrome in 3 affected family members (PP1; GeneDx). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_moderate, PS2_supporting, PM2_supporting, PP1, PP3, PP4). FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946630/MONDO:0007947/022 2023-09-26 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:127342 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0026837 infores:hetionet CHEBI:63577 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0085593 infores:hetionet CHEBI:5165 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0037287 infores:hetionet CAID:CA340749160 biolink:causes MONDO:0100368 infores:clingen CAID:CA340749160 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP1_Moderate, PP4, PM2_Supporting NM_000329.3(RPE65):c.143G>A (p.Gly48Glu) is a missense variant causing substitution of glycine with glutamic acid at position 48. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.859del variant confirmed in trans (PMID: 34492281), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset before age 1 year (1 pt), nystagmus (1 pt), night blindness with onset at age 1 year (0.5 pts), reduced visual fields (1 pt), reduced visual acuity (1 pt), diffuse retinal pigmentation, vascular thinning (0.5 pts), and optic disc pallor (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 total points, PMID: 34492281, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the compound heterozygous state (PP1_Moderate; PMID: 34492281). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting, PM3, PP1_moderate, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340749160/MONDO:0100368/120 2024-02-01 2024-02-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7465 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0241379 infores:hetionet CHEBI:72564 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0009782 infores:hetionet CHEBI:15854 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0015230 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0027051 infores:hetionet CHEBI:31622 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0234518 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0853785 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0853785 infores:hetionet CHEBI:6965 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0543467 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0085628 infores:hetionet CHEBI:7903 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020458 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0039971 infores:hetionet UMLS:C0209366 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0033774 infores:hetionet GO:0044478 biolink:causes GO:0070527 infores:ubergraph knowledge_assertion manual_agent GO:0044478 GO:0070527 CHEBI:46295 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0030252 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0010709 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033975 infores:hetionet CAID:CA367398811 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398811 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1130G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 377 (p.(Arg377Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate: PMIDs: 21348868, 30245511, internal lab contributors). At least two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.(Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Arg377Leu). Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023) : PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398811/MONDO:0015967/086 2023-11-24 2023-11-24 Semidominant inheritance HP:0032113 Supports CHEBI:35778 biolink:causes UMLS:C1096267 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1096267 infores:hetionet CHEBI:31547 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0027497 infores:hetionet CAID:CA034586 biolink:causes MONDO:0007750 infores:clingen CAID:CA034586 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PS4, PP4 The NM_000527.5(LDLR):c.1503G>A (p.Ala501=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF = 0.0002403 (0.02403%) in African/African American population exomes/genomes (gnomAD version). PP3: No REVEL score, splicing evaluation required. Functional data on splicing not available.B). Variant is exonic and at least 50bp upstream from canonical donor site and creates AG MES scores: de novo variant = 9.20; canonical acceptor = 6.76. Ratio de novo variant/canonical acceptor = 9.20/6.76 = 1.36 --- it is above 0.9PP4: variant meets PM2, identified in 1 FH index case from PMID: 20145306 with WHO criteria, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034586/MONDO:0007750/013 2022-08-27 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10124 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020456 infores:hetionet NCBIGene:7273 biolink:causes MONDO:0013412 infores:monarchinitiative not_provided not_provided HGNC:12403 MONDO:0013412 uuid:2d2f9598-48eb-4f74-9690-694a32f236b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0028084 infores:hetionet CHEBI:18248 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0424790 infores:hetionet CHEBI:30659 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0008301 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0160390 infores:hetionet CHEBI:39112 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1145670 infores:hetionet CHEBI:9907 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C3665386 infores:hetionet CHEBI:2618 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0001807 infores:hetionet CHEBI:84500 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0162830 infores:hetionet CHEBI:9130 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0017178 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0002871 infores:hetionet CHEBI:10127 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0004134 infores:hetionet CHEBI:9571 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0002792 infores:hetionet CHEBI:4735 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0231528 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002871 infores:hetionet CHEBI:94609 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0237314 infores:hetionet CHEBI:49375 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0003962 infores:hetionet CHEBI:31638 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0027497 infores:hetionet CHEBI:9086 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011175 infores:hetionet CHEBI:5959 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042384 infores:hetionet CHEBI:3423 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1527311 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0025061 infores:hetionet CHEBI:7601 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0015967 infores:hetionet CAID:CA267684 biolink:causes MONDO:0009861 infores:clingen CAID:CA267684 MONDO:0009861 PMID:12655552PMID:12655552 Pathogenic PM3, PVS1, PM2, PP4 The c.912+2T>C variant in PAH is reported Likely Pathogenic in ClinVar (see variant ID 120292) by one laboratory, which states that it was found in a PKU patient but does not provide further information to support their classification. With respect to the published literature, it has been previously reported in one Croatian proband with “severe” PKU (defined as serum Phe levels >1200); BH4 deficiency does not appear to have been formally excluded (PMID: 12655552) (PP4). The variant was found as a single (heterozygous) variant with the known pathogenic p.R408W allele (see ClinVar variant ID 577) (PM3); phase was confirmed via parental testing. The variant is a null variant (canonical +2 splice site) in a gene where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 8 is present in biologically-relevant transcript (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267684/MONDO:0009861/006 2019-09-29 2019-10-02 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:4978 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:8143 MONDO:0008170 uuid:ee270c11-903c-4d7d-8cbd-5d8182f83b43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0917801 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0037284 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0003123 infores:hetionet CAID:CA337754 biolink:causes MONDO:0700269 infores:clingen CAID:CA337754 MONDO:0700269 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS3 The c.9302T>C variant in BRCA2 is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 3101 (p.(Leu3101Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 38417439, 32444794, 39779857) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.32, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.19 (based on Family History LR=2.19), within the thresholds for supporting evidence towards pathogenicity (LR >2.08 & ≤4.3) (PP4 met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3, PP4). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA337754/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports UNII:R43D2573WO biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0009676 infores:hetionet NCBIGene:1141 biolink:causes MONDO:0011545 infores:monarchinitiative not_provided not_provided HGNC:1962 MONDO:0011545 uuid:ff15a13e-7443-49ae-9fb2-264c75259b61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9332 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0004936 infores:hetionet CHEBI:8107 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0022638 infores:hetionet CHEBI:83804 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0023211 infores:hetionet NCBIGene:25794 biolink:causes MONDO:0011935 infores:monarchinitiative not_provided not_provided HGNC:3960 MONDO:0011935 uuid:a19a4ec8-80fa-42f7-86be-23e8276868df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0030794 infores:hetionet CHEBI:5138 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085649 infores:hetionet CHEBI:9168 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020639 infores:hetionet CHEBI:45599 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0015672 infores:hetionet CHEBI:3219 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0476280 infores:hetionet GO:1904127 biolink:causes GO:0001756 infores:ubergraph knowledge_assertion manual_agent GO:1904127 GO:0001756 CHEBI:42797 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027051 infores:hetionet CHEBI:4814 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0428977 infores:hetionet CHEBI:465284 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0035305 infores:hetionet CHEBI:50131 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0333355 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0040034 infores:hetionet CAID:CA315411486 biolink:causes MONDO:0015967 infores:clingen CAID:CA315411486 MONDO:0015967 PMID: Likely Benign BP4, BS1 The c.826+79C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within intron 7 of NM_175914.5 . The computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that the variant has no impact on splicing (BP4). This variant is not covered in gnomAD v2.1.1 exomes and has a Grpmax Filtering allele frequency of 0.000068 in gnomAD v3.1.2, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033)(BS1). In summary, c.826+79C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA315411486/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:75246 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0009806 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151849 infores:hetionet CHEBI:66876 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0027424 infores:hetionet CHEBI:10110 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0003862 infores:hetionet CAID:CA014888 biolink:causes MONDO:0005045 infores:clingen CAID:CA014888 MONDO:0005045 PMID: Uncertain Significance BP4 BA1, PM2, PM6, PP3, PP1, BS1, BS4, BP7, PS4, PS2 The NM_000257.4(MYH7):c.4354-7C>T variant has been reported in 3 individuals with HCM (Invitae pers. comm; LMM pers. comm.). This variant has also been identified in 0.004% (FAF 95% CI; 4/34362) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). This variant is located in the 3' splice region and computational tools do not predict an impact on splicing, though this information is not predictive enough to rule out pathogenicity (BP4). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): BP4. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014888/MONDO:0005045/002 2021-06-23 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2914 biolink:causes UMLS:C0428886 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0428886 infores:hetionet CHEBI:6359 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0012359 infores:hetionet UMLS:C0657912 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0041105 infores:hetionet CHEBI:8768 biolink:causes NCIT:C50547 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1704212 infores:hetionet NCBIGene:1161 biolink:causes MONDO:0019569 infores:monarchinitiative not_provided not_provided HGNC:3439 MONDO:0019569 uuid:4e15e884-7cd0-4fb3-8e8c-7239114efa79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0877359 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0022904 infores:hetionet CHEBI:2663 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0235896 infores:hetionet CHEBI:2663 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0023211 infores:hetionet CHEBI:28864 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0687713 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0442886 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0948294 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0521508 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0521508 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0031350 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0278079 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151849 infores:hetionet CHEBI:50861 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0030252 infores:hetionet CHEBI:36795 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0393760 infores:hetionet CHEBI:47898 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020488 infores:hetionet CHEBI:94686 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0004604 infores:hetionet CHEBI:50663 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0014518 infores:hetionet CHEBI:7466 biolink:causes UMLS:C0277961 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0277961 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0857257 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0027932 infores:hetionet CHEBI:4710 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030196 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0008370 infores:hetionet GO:1901957 biolink:causes GO:0160062 infores:ubergraph knowledge_assertion manual_agent GO:1901957 GO:0160062 CHEBI:8863 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0162119 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235876 infores:hetionet CHEBI:32192 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0001824 infores:hetionet UNII:8NZ41MIK1O biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0019080 infores:hetionet CAID:CA226554 biolink:causes MONDO:0100368 infores:clingen CAID:CA226554 MONDO:0100368 PMID: Likely Benign BP4, BP7, BS1 NM_000329.3(RPE65):c.48T>C (p.Phe16=) is a synonymous (silent) variant in exon 2. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.001007, with 1250 alleles/1179940 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The REVEL score for this variant is 0, which is below the ClinGen LCA/eoRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPE65 function. Additionally, the splicing impact predictor, SpliceAI, gives a score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226554/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:36704 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0007137 infores:hetionet CAID:CA229640 biolink:causes MONDO:0009861 infores:clingen CAID:CA229640 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 The c.598dup (p.Thr200fs) variant in PAH has been reported in 1 Chinese patient with classic PKU (Phe (>120uM); BH4 deficiency not excluded (PP4). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. (Coding exon number 6 out of 13 coding exons; 6 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229640/MONDO:0009861/006 2021-12-12 2021-12-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10014570 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014570 MONDO:0011071 PMID: Likely Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS3, BS4, BP5, PM2, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.204C>G (p.Ala68=) is a synonymous variant which has a MAF of 0.00017 (0.017%, 5/30230, 30235 alleles) in the South Asian subpopulation of the gnomAD v2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This is a synonymous variant, therefore REVEL is not calculable. On the basis of SpliceAI, the predicted effects on splicing are: Acceptor loss 0.00, donor loss 0.00, acceptor gain 0.00, donor gain 0.00. Therefore, there is no computationally predicted effect on splicing (BP4). On the basis of SpliceAI, the predicted effects on splicing are: Acceptor loss 0.00, donor loss 0.00, acceptor gain 0.00, donor gain 0.00. Therefore, there is no computationally predicted effect on splicing. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.84737 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014570/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42820 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0016436 infores:hetionet CHEBI:6438 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0030252 infores:hetionet CHEBI:2636 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0013404 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0031117 infores:hetionet CHEBI:194135 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042164 infores:hetionet CHEBI:31624 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C3203358 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0034150 infores:hetionet CHEBI:291342 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0522055 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0178298 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042769 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0242350 infores:hetionet CHEBI:28593 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0014742 infores:hetionet CHEBI:253342 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0085624 infores:hetionet CHEBI:31236 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028734 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0155919 infores:hetionet CHEBI:119915 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0232462 infores:hetionet CHEBI:7954 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0004245 infores:hetionet CHEBI:5864 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0086565 infores:hetionet CAID:CA10587105 biolink:causes MONDO:0700270 infores:clingen CAID:CA10587105 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3_Strong BP4, PP3 The c.4397_4398delinsCG variant in ATM is an in-frame deletion of GA and insertion of CG at nucleotide positions 4397 to 4398, which is predicted to cause substitution of arginine by proline at amino acid 1466 (p.Arg1466Pro). This variant has been detected in at least three unrelated individuals with Ataxia-Telangiectasia (PMID: 26896183, Ambry internal data). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002230 (1/44844 alleles) in the East Asian population; while this is higher than the HBOP VCEP threshold (≤0.00001) for PM2_Supporting, it is present in only one allele, meeting this criterion. The computational predictor REVEL gives a score of 0.677, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587105/MONDO:0700270/020 2025-06-19 2025-10-20 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:271 biolink:causes MONDO:0014305 infores:monarchinitiative not_provided not_provided HGNC:469 MONDO:0014305 uuid:d2461962-e38b-451f-a67c-af7a92fa9850 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0857353 infores:hetionet CHEBI:6717 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0039070 infores:hetionet CHEBI:85078 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0015967 infores:hetionet CHEBI:52010 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0235710 infores:hetionet CHEBI:52717 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003962 infores:hetionet CAID:CA10653556 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653556 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*2626A>G variant in the 3' UTR has an MAF of 0.01191 (1.2%, 500/41996 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 2 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653556/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:35854 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0022660 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0019825 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0232431 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0242350 infores:hetionet CAID:CA023877 biolink:causes MONDO:0007783 infores:clingen CAID:CA023877 MONDO:0007783 PMID: Uncertain Significance PM1, PS4_Moderate PP3, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 367 of the RYR1 protein, p.(Arg367Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:21965348, PMID:24433488). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.651 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023877/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:64312 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020580 infores:hetionet CHEBI:63631 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2979982 infores:hetionet CHEBI:6539 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0012833 infores:hetionet CHEBI:9599 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0392163 infores:hetionet CHEBI:63616 biolink:causes HP:0012213 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0853068 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0521161 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0521161 infores:hetionet NCBIGene:368 biolink:causes MONDO:0009925 infores:monarchinitiative not_provided not_provided HGNC:57 MONDO:0009925 uuid:2fc3dde4-236a-45de-ae67-fb33caf98eaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0221245 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0012241 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0012241 infores:hetionet CHEBI:135888 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0237849 infores:hetionet CHEBI:45783 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0031256 infores:hetionet CHEBI:100147 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0033975 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0011849 infores:hetionet CAID:CA658682658 biolink:causes MONDO:0044970 infores:clingen CAID:CA658682658 MONDO:0044970 PMID:12798797 Uncertain Significance PP3, PS4_Supporting, PM2_Supporting, PS3_Supporting PP1, PS2, PM6 The m.3280A>G variant in MT-TL1 has been reported in three unrelated individuals with primary mitochondrial disease. Although there was limited clinical information on some these cases and haplogroups were not provided, the reported cases had similar features and consistent enzymology. The three reported individuals had variable ages of onset, with 1/3 presenting in childhood and 2/3 presenting in their mid-30s. Features included myopathy and ataxia. Heteroplasmy levels were not specified in one individual but the variant was present at 75% in muscle and 23% in blood in one individual and homoplasmic in the other (PS4_supporting; PMIDs: 11335700, 12402350, 12798797). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 15% in blood (PMID: 12798797), however this does not meet criteria to apply PP1_supporting (at least two segregations). Another reported case had a daughter with similar muscle concerns, however there was no mention of testing for the variant in this family member (PMID: 11335700). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in ragged red fibers (78.6 ± 11%; n = 9) than in non-ragged red fibers (10.9 ± 15.9%, n = 9; P < 0:001; PS3_supporting, PMID: 12798797). The computational predictor MitoTIP suggests this variant is pathogenic (82.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP3, PS4_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658682658/MONDO:0044970/015 2022-08-23 2022-09-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:175901 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0002170 infores:hetionet CHEBI:42797 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0026205 infores:hetionet CHEBI:3219 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036830 infores:hetionet CHEBI:6437 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0030193 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0001339 infores:hetionet CHEBI:2948 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0000737 infores:hetionet CHEBI:63622 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0020473 infores:hetionet CHEBI:40279 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020598 infores:hetionet CHEBI:7577 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0039231 infores:hetionet CHEBI:8356 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0025323 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038367 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0021400 infores:hetionet CAID:CA16614180 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614180 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, PM6, BA1, BP3, PM5, PM4, PM1, PS2, PS3, PS1, BP5, BP7, BS1, BS3 The NM_177438.2:c.4412C>T variant in DICER1 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 1471 (p.Pro1471Leu). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors/GTRs). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00001543 (1/64,794 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.04 MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, BS2_Supporting. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614180/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7496 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0013395 infores:hetionet CHEBI:4562 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0014863 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0004238 infores:hetionet CHEBI:84500 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0001339 infores:hetionet CHEBI:3077 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0338656 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0005940 infores:hetionet CHEBI:63577 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0242429 infores:hetionet CHEBI:23765 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0038990 infores:hetionet CHEBI:32315 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0037036 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C2225524 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014130 infores:hetionet CAID:CA016441 biolink:causes MONDO:0005021 infores:clingen CAID:CA016441 MONDO:0005021 PMID:24664454PMID:24664454PMID:27532257PMID:24664454 Likely Pathogenic PM2, PP3, PS4_Moderate, PS2 PM6, PM1, PP1, BA1, PS3, BS1, BS3, BS4, PS1, BP4 The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in at least 6 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID: 24503780; Lamont 2015 PMID: 20301606; Walsh 2017 PMID: 27532257; Wang 2017 PMID: 28855170; Miura 2019 PMID: 30996762). This variant segregated with disease in 2 affected siblings from 1 family (Miura 2019 PMID: 30996762); however this data is currently insufficient to apply PP1. This variant has been confirmed de novo occurrence in 2 of the above reported individuals with additional features of myopathy (PS2; Lamont 2014 PMID24664454). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PS2; PM2; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016441/MONDO:0005021/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6402 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0018681 infores:hetionet CHEBI:5103 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C3665347 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0232841 infores:hetionet CHEBI:135929 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0521465 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1145628 infores:hetionet CHEBI:2668 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0040264 infores:hetionet CHEBI:32315 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020473 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0424000 infores:hetionet CAID:CA015021 biolink:causes MONDO:0007947 infores:clingen CAID:CA015021 MONDO:0007947 PMID: Uncertain Significance PP2, PP3, PS4_Supporting, PM1 PM2, PVS1, PM6, PP4, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PM4, PM5, PM3, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4405C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1469 (p.Arg1469Cys). This variant has been identified in at least two individuals in the literature including one proband with thoracic aortic aneurysm and dissection (TAAD) and one without specific phenotype details available (PS4_supporting; PMIDs: 33824467, 27906200). This variant is present in gnomAD, with a maximum frequency of 0.0066% (1/15268 alleles) in the Admixed American subpopulation (https://gnomad.broadinstitute.org/, v3.1.2); please note that despite this frequency exceeding the threshold for application of BS1 per the VCEP specifications, because of the small total allele count for this subpopulation, the VCEP opted not to apply any population criteria based on this evidence. This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.772). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). However, due to insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_supporting, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA015021/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:16586 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0015230 infores:hetionet NCBIGene:3033 biolink:causes MONDO:0017715 infores:monarchinitiative not_provided not_provided HGNC:4799 MONDO:0017715 uuid:911aa966-d45b-4977-a65f-38654578b06e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0152459 infores:hetionet NCBIGene:1415 biolink:causes MONDO:0011104 infores:monarchinitiative not_provided not_provided HGNC:2398 MONDO:0011104 uuid:c259ea5a-d2f5-412f-a518-80f85a58c130 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16347 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0033774 infores:hetionet NCBIGene:286151 biolink:causes MONDO:0030522 infores:monarchinitiative not_provided not_provided HGNC:28521 MONDO:0030522 uuid:2e0b5c86-f2cb-4020-bf5d-fd6c8664ce1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:79803 biolink:causes MONDO:0013558 infores:monarchinitiative not_provided not_provided HGNC:18817 MONDO:0013558 uuid:b0b54d0d-5739-484b-a750-0c78f15f136a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009676 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0007194 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0029456 infores:hetionet CHEBI:144551 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0015230 infores:hetionet CHEBI:6402 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0035243 infores:hetionet CHEBI:681569 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0238106 infores:hetionet CHEBI:51380 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0233477 infores:hetionet CHEBI:18248 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0278134 infores:hetionet CHEBI:64354 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0030305 infores:hetionet CHEBI:9674 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0008031 infores:hetionet CHEBI:39669 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0036974 infores:hetionet CHEBI:135939 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0027697 infores:hetionet CHEBI:9763 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0038325 infores:hetionet NCBIGene:6103 biolink:causes MONDO:0010566 infores:monarchinitiative not_provided not_provided HGNC:10295 MONDO:0010566 uuid:3d04f066-1978-40b4-98c2-722f59d2a70d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3638 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0028077 infores:hetionet CHEBI:64312 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151827 infores:hetionet CHEBI:42797 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009763 infores:hetionet CHEBI:391960 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C3665347 infores:hetionet CHEBI:240107 biolink:causes UMLS:C1096278 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C1096278 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040409 infores:hetionet CHEBI:50859 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151827 infores:hetionet CAID:CA16619860 biolink:causes MONDO:0100040 infores:clingen CAID:CA16619860 MONDO:0100040 PMID: Benign BS2_Supporting, BP3, BA1 PS3, PS2, PM4, PM1, PM3, BP5, BS1, BS3, BS4, PM2, PM6, PP1, PP4, BP2 The allele frequency of the p.Gln70_Pro78dup variant in FOXG1 is 0.09% in the African sub population in gnomAD v4, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). This variant was observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). Additionally, the p.Gln70_Pro78dup variant is an in-frame duplication present in a repetitive region of FOXG1 (BP3). In summary, the p.Gln70_Pro78dup variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting, BP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619860/MONDO:0100040/035 2023-12-06 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:73274 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042029 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009763 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0162429 infores:hetionet CHEBI:77733 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0085631 infores:hetionet CHEBI:31859 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0231530 infores:hetionet GO:0010717 biolink:causes GO:0060485 infores:ubergraph knowledge_assertion manual_agent GO:0010717 GO:0060485 CHEBI:6792 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0277890 infores:hetionet CHEBI:15940 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0231530 infores:hetionet CHEBI:8327 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0162830 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0008370 infores:hetionet CHEBI:4877 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0687713 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0231856 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0235290 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0019385 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019385 infores:hetionet UBERON:0002384 biolink:causes MONDO:0021054 infores:ubergraph knowledge_assertion manual_agent UBERON:0002384 MONDO:0021054 CHEBI:45783 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0919874 infores:hetionet CHEBI:47612 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0852911 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0152029 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0037822 infores:hetionet CAID:CA410147339 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147339 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1329C>A (p.Asn443Lys) is a missense variant which has a REVEL score < 0.50 (0.14), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147339/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020517 infores:hetionet CAID:CA6909562 biolink:causes MONDO:0015152 infores:clingen CAID:CA6909562 MONDO:0015152 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM3, PM2_Supporting The NM_000231.3: c.87dup p.(Gly30TrpfsTer30) variant in SGCG is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/8, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least seven individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in six (1.0 pt; PMID: 27759885, 18285821, 8923014) (PM3). At least one patient with this variant and a second SGCG variant presented with progressive limb girdle muscle weakness (PP4). The variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in two affected family members from two families (PP1_Moderate; PMID: 27759885). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025)(LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PP1_Moderate, PM2_Supporting, PM3, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6909562/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:64135 biolink:causes MONDO:0014367 infores:monarchinitiative not_provided not_provided HGNC:18873 MONDO:0014367 uuid:36f89f4f-5b0b-409e-921a-4b6e26651f12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0003467 infores:hetionet CHEBI:51860 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085632 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0549478 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0549478 infores:hetionet CHEBI:8707 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0025323 infores:hetionet CHEBI:6413 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0476280 infores:hetionet CHEBI:47780 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0520966 infores:hetionet CAID:CA9871435 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871435 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting BS2, PM5, BS3, PS1, PS3 The c.984T>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 328 (p.Asn328Lys).The highest population minor allele frequency in gnomAD v4 is 0.00004847 (2/41266) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871435/MONDO:0007064/114 2024-02-21 2024-10-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135925 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0014742 infores:hetionet CAID:CA658658175 biolink:causes MONDO:0015967 infores:clingen CAID:CA658658175 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 BA1, BS1 The c. 4delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 2 (NM_000545.6), adding 4 novel amino acids before encountering a stop codon (p.(Val2PhefsTer4)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, the variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658175/MONDO:0015967/017 2022-02-22 2022-02-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:101278 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0442874 infores:hetionet CHEBI:132233 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0011071 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013922 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0575090 infores:hetionet CHEBI:9241 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0023530 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0700345 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151479 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0010037 infores:hetionet CHEBI:63605 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0242698 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0037274 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1565489 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0860871 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018213 infores:hetionet CHEBI:6078 biolink:causes MONDO:0001280 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0008526 infores:hetionet CHEBI:3479 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0014457 infores:hetionet CHEBI:68478 biolink:causes UMLS:C2609269 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2609269 infores:hetionet CHEBI:9654 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0085636 infores:hetionet CHEBI:68534 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0030554 infores:hetionet CHEBI:7852 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085628 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0857980 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0857980 infores:hetionet CHEBI:7773 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151766 infores:hetionet CHEBI:204734 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0030193 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020538 infores:hetionet NCBIGene:7389 biolink:causes MONDO:0008296 infores:monarchinitiative not_provided not_provided HGNC:12591 MONDO:0008296 uuid:7fcb6e5f-d4aa-4b9d-a030-c630c73c0756 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:724125 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0677500 infores:hetionet CAID:CA345145962 biolink:causes MONDO:0100084 infores:clingen CAID:CA345145962 MONDO:0100084 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PP4_Moderate, PS2, PM5 The c.868G>C variant in ACTA1 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 290 (legacy nomenclature: p.Asp288His). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 2 probands , including one with a muscle biopsy containing nemaline rods (PS4_Supporting, PP4_Moderate; PMIDs: 29565416, 28516742). In both individuals, the variant has been identified as a de novo occurrence with confirmed parental relationships (PS2). Another missense variant c.868G>A, p.Asp290Asn (PMIDs: 19562689, 27242277) in the same codon has been classified as pathogenic for AD nemaline myopathy by the ClinGen Congenital Myopathies VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM5, PP4_Moderate, PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 1; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345145962/MONDO:0100084/147 2024-08-27 2024-12-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6933 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0042075 infores:hetionet GO:1905273 biolink:causes GO:1902600 infores:ubergraph knowledge_assertion manual_agent GO:1905273 GO:1902600 CHEBI:42797 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0035410 infores:hetionet CHEBI:52717 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003811 infores:hetionet CHEBI:5383 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0002962 infores:hetionet CHEBI:63599 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0010200 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0276143 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0276143 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0004936 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0018799 infores:hetionet CHEBI:4708 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0231218 infores:hetionet NCBIGene:85478 biolink:causes MONDO:0014215 infores:monarchinitiative not_provided not_provided HGNC:29937 MONDO:0014215 uuid:659d3e0a-993f-4aef-9454-cc908ae98694 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4717 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0036974 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0040034 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0079043 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1384353 infores:hetionet CHEBI:2788 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0039070 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042571 infores:hetionet UNII:VL0L558GCB biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0019080 infores:hetionet CAID:CA024287 biolink:causes MONDO:0007783 infores:clingen CAID:CA024287 MONDO:0007783 PMID: Likely Pathogenic PM5, PM1_Supporting, PS4_Moderate, PP3_Moderate PS3, BS1, BS3, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with cysteine at codon 522 of the RYR1 protein, p.Tyr522Cys. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, one of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, PMID:16244001, PMID:32919876). Studies in HEK293 cells demonstrated a leaky channel and neither PS3 or BS3 were awarded (PMID:26115329, PMID:31841587). Another variant assessed as pathogenic occurs at this codon, p.(Tyr522Ser), PM5. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.949) supports a pathogenic status for this variant, PP3_Moderate. This variant is classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024287/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:7903 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0085682 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0234215 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0558368 infores:hetionet CHEBI:4708 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013144 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0032285 infores:hetionet CHEBI:75984 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0085632 infores:hetionet CHEBI:4784 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0042963 infores:hetionet CHEBI:7956 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0022660 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085096 infores:hetionet CHEBI:2673 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0011603 infores:hetionet NCBIGene:7203 biolink:causes MONDO:0976125 infores:monarchinitiative not_provided not_provided HGNC:1616 MONDO:0976125 uuid:3b6d0a0a-1615-4038-a0fc-ad562ab9f9c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0038362 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151824 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0017574 infores:hetionet CHEBI:64321 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0013604 infores:hetionet CHEBI:3506 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0019080 infores:hetionet CHEBI:16335 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0438716 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0340726 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0853748 infores:hetionet CHEBI:63610 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0008031 infores:hetionet CHEBI:251408 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0029408 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0033975 infores:hetionet CL:0000066 biolink:causes MONDO:0002418 infores:ubergraph knowledge_assertion manual_agent CL:0000066 MONDO:0002418 CHEBI:6539 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0001807 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0235416 infores:hetionet CHEBI:48273 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0003862 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0014544 infores:hetionet CHEBI:5784 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0027497 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020437 infores:hetionet CHEBI:66913 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C1384353 infores:hetionet CHEBI:171719 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0023066 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0042401 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0011991 infores:hetionet CHEBI:3082 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C3665347 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020517 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0018939 infores:hetionet CHEBI:6078 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0004604 infores:hetionet CHEBI:2549 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1145628 infores:hetionet NCBIGene:55697 biolink:causes MONDO:0014889 infores:monarchinitiative not_provided not_provided HGNC:25507 MONDO:0014889 uuid:1dd9f9b7-caad-40d3-ad97-3a770884ac9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0009024 infores:hetionet CAID:CA9043669 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043669 MONDO:0012999 PMID:24415674 Pathogenic PM2_Supporting, PP4_Strong, PM3, PP3_Moderate, PS3_Supporting The NM_000156.6:c.407C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). This variant has been detected in 3 unrelated individuals with GAMT deficiency (PMID: 24415674, PMID: 21140503, ClinVar SCV001428825.1). Of those individuals, two were compound heterozygous for the variant and a pathogenic variant, c.316C>T (p.Q106*) in unknown phase (PMID: 24415674, PMID: 21140503) and 1 was homozygous for the variant (ClinVar SCV001428825.1) (1.5pts total, PM3). One of these individuals had elevated GAA in plasma, deficient GAMT enzyme activity (<5% wild-type enzyme) in fibroblasts, and significantly reduced creatine peak on brain MRS (PMID: 21140503) and one individual had an absent creatine peak with visible GAA peak on brain MRS (PMID: 24415674) (PP4_Strong). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113420 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 544257). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM3, PP3_Moderate, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Oct. 2026, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043669/MONDO:0012999/026 2023-10-26 2023-11-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:55346 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0008031 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0005940 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151601 infores:hetionet CHEBI:4672 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0018834 infores:hetionet CAID:CA320250894 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250894 MONDO:0011071 PMID: Likely Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, PM2, PM6, PVS1, BS4, BP5, PM5, PM4, PM3, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.*263C>G is a UTR variant with a MAF 0.0015 (0.15%) at 0.0006756 (0.06756%, 28/41442,) in the African American subpopulation of gnomAD 3.1.2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 0.00 < 2.0) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250894/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0010592 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0948089 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0020517 infores:hetionet CHEBI:43968 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0027497 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0037274 infores:hetionet CHEBI:63605 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0037763 infores:hetionet CHEBI:5138 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0041105 infores:hetionet NCBIGene:80254 biolink:causes MONDO:0013871 infores:monarchinitiative not_provided not_provided HGNC:25815 MONDO:0013871 uuid:2df38969-04e9-40c3-9ef0-05aca432e35c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085077 infores:hetionet CHEBI:7465 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0235378 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0595877 infores:hetionet CHEBI:68575 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0004096 infores:hetionet CHEBI:9763 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0018681 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009319 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019112 infores:hetionet CHEBI:71417 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0006826 infores:hetionet CAID:CA10585330 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585330 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1153C>G (p.Leu385Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meet PM2. PMID: 20809525 (Marduel et al., 2010), France - 1 case who fulfills Simon-Broome criteria for FH.BP4: REVEL = 0.432. It is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) not on limitsB) it creates a GTscore in MES: de novo donor = 3.09, authentic donor = 7.23. Ratio de novo/authentic is 0.43. It is below 0.8. C) not on limitsVariant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585330/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:30659 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0231274 infores:hetionet NCBIGene:6720 biolink:causes MONDO:0008017 infores:monarchinitiative not_provided not_provided HGNC:11289 MONDO:0008017 uuid:65bb4458-0c52-4e76-90c1-1d36e90649ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512341175 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341175 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1260C>A (p.Gly420=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.00) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341175/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48538 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0015672 infores:hetionet CHEBI:3568 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C2047937 infores:hetionet GO:0031554 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0031554 GO:0010467 CHEBI:47781 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0033975 infores:hetionet CHEBI:5118 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040822 infores:hetionet CHEBI:7465 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0242429 infores:hetionet NCBIGene:83743 biolink:causes MONDO:0976266 infores:monarchinitiative not_provided not_provided HGNC:21270 MONDO:0976266 uuid:904df145-4b64-4470-be22-b45f5323c764 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0032326 infores:hetionet CHEBI:10101 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151539 infores:hetionet GO:0045304 biolink:causes GO:0009294 infores:ubergraph knowledge_assertion manual_agent GO:0045304 GO:0009294 CAID:CA003491 biolink:causes MONDO:0700268 infores:clingen CAID:CA003491 MONDO:0700268 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong PP3, BP1, PS3, BP7, BS3 The c.5332G>A variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic Acid by Asparagine at amino acid 1778 (p.(Asp1778Asn)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant has a SpliceAI score of 0.25, predicting an impact on splicing (score threshold ≥0.2) (PP3 not applied because a PVS1 code is met). Missense variant shown to alter splicing (see PVS1 or BP7 for description), functional data considered only from assays that measure effect via mRNA and protein. Results from one calibrated study with cDNA based design not considered for code application (PMID:38709234). Reported by one calibrated study incorporating mRNA splicing effects to exhibit a partial impact on function, between what was observed for benign and pathogenic control variants (PMID:30209399) (PS3 and BS3 not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 127.1 (based on Pathology LR=0.4; Co-occurrence LR=1.1; Family History LR=287.8), within the thresholds for strong evidence towards pathogenicity (LR >18.7 & ≤350) (PP4_Strong met; PMIDs: 31131967, 31853058, Internal lab contributors). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by skipping of exon 21 (PMID: 25724305, 22505045). Minigene and gel electrophoresis assessment determined that the percent of reference (full-length) and aberrant transcript gel band intensities were 0 % / 100 %, respectively (PMID 25724305). An additional RT-PCR based study demonstrated that the variant impacts splicing by skipping of exon 21 (PMID: 30315757). The percent reference (full-length) and aberrant transcripts produced from the variant allele using non-allele specific semi-quantitative assessment with capillary electrophoresis was determined to be 30 % / 60 %. Final code strength determined by the rubric: PVS1 (RNA). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP4_Strong, PVS1 (RNA)). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003491/MONDO:0700268/092 2025-08-22 2025-08-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50173 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085762 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0004936 infores:hetionet CHEBI:8435 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0004096 infores:hetionet CHEBI:15367 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009421 infores:hetionet CHEBI:2636 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0003811 infores:hetionet CHEBI:8428 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0429097 infores:hetionet CAID:CA015132 biolink:causes MONDO:0004994 infores:clingen CAID:CA015132 MONDO:0004994 PMID: Uncertain Significance PM2 PVS1 The c.4588C>T (p.Arg1530Ter) variant in MYH7 has been identified in 1 individual with DCM who also carried another MYH7 missense variant, and both variants were also identified in the individual's affected sibling (DCM). This nonsense variant was inherited from their unaffected father and the p.Arg143Trp variant was inherited from their unaffected mother (Hershkovitz 2019 PMID:30588760; Partners LMM ClinVar SCV000059574.5). This variant has also been identified in 2 individuals with myopathy (Invitae ClinVar SCV000749836.2; pers. comm.) and 1 adolescent with RCM, who inherited the MYH7 variant from his unaffected father, and was also found to have a de novo truncating TNNI3 variant (Ambry Genetics ClinVar SCV000318079.4; pers. comm.). PS4_Supporting was not applied due to the variability in proband phenotypes and occurrence of additional variants. This variant has been identified in 0.0003% (FAF 95% CI, 2/113694) of European chromosomes in gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1530 leading to a truncated or absent protein. The contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015132/MONDO:0004994/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3568 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023067 infores:hetionet CHEBI:6539 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0004093 infores:hetionet CHEBI:5109 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0015230 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0404521 infores:hetionet CHEBI:31176 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0018681 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0575090 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0017178 infores:hetionet CHEBI:553473 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0001824 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0233494 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0012833 infores:hetionet CHEBI:84050 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0242698 infores:hetionet CHEBI:48390 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0041912 infores:hetionet CHEBI:7936 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004134 infores:hetionet CHEBI:9168 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0025323 infores:hetionet CHEBI:10124 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085616 infores:hetionet CHEBI:3756 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1443060 infores:hetionet CHEBI:6965 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0427086 infores:hetionet CHEBI:50131 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0019080 infores:hetionet CAID:CA032391 biolink:causes MONDO:0007750 infores:clingen CAID:CA032391 MONDO:0007750 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM3, PM2, PVS1, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM6, PP2, PP3, BS2 "The NM_000527.5(LDLR):c.1176C>A (p.Cys392Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PM2, PM3, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is nonsense, causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830), so PVS1 is met.PP1_strong - variant segregates with FH phenotype in:- 7 informative meiosis from 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 4 relatives positive for variant with LDL-C >75th percentile, and 3 relatives negative for variant with LDL-C <50th percentile.- 1 informative meiosis from 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 1 relative positive for variant with LDL-C >75th percentile.- 11 informative meiosis from 1 family from PMID: 8831933 (Langenhoven et al. 1996): 11 relatives are positive for the variant and have LDL-C >75th percentile (9 have >5.0mmol, 2 have 4.6 and 4.3mmol)Segregation was observed in 19 informative meiosis from 3 families, so PP1_Strong is met.PM2 - PopMax MAF = 0.00003267 (0.003%) in South asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PM3 - variant meets PM2 and was identified in 1 index case who also carries NM_000527.5(LDLR):c.1A>T (p.Met1Leu), confirmed in trans, who has LDL 17.3mmol/L from PMID: 8831933 (Langenhoven et al. 1996 Aug 23;125(1):111-9. --- 2nd variant is classified as Pathogenic with these guidelines, so PM3 is met.PS4_moderate - variant meets PM2 and was identified in:- 1 index case who fulfills Simon-Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 1 index case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 4 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada;- 1 Index case (iii-4) with DLCN at least 8 (LDL-C 17.3mmol at 4yo with tendon xanthoma) from PMID: 8831933 (Langenhoven et al. 1996), South Africa; - 1 index case with heterozygous FH per MEDPED criteria from PMID: 11933210 (Salazar et al. 2002), Brazil;- at least 1 index case with definite FH (""definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000]."") from PMID 11810272 (Fouchier et al. 2001), The Netherlands.9 unrelated cases, so PS4_Moderate is met.PP4 - variant meets PM2 and was identified in 9 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is met." Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA032391/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:283310 biolink:causes MONDO:0013984 infores:monarchinitiative not_provided not_provided HGNC:26901 MONDO:0013984 uuid:ad7d493a-b232-427e-b8ef-d2b12bd07973 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51230 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0849918 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0242350 infores:hetionet CHEBI:31236 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0740394 infores:hetionet CHEBI:47780 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151786 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0042029 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151882 infores:hetionet CHEBI:76010 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0033774 infores:hetionet CHEBI:42944 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C2830004 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2973529 infores:hetionet CHEBI:4562 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0003862 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0151826 infores:hetionet CHEBI:9139 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0038990 infores:hetionet CHEBI:75722 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151786 infores:hetionet CHEBI:45783 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0026858 infores:hetionet CHEBI:75722 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014591 infores:hetionet CHEBI:567361 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0038999 infores:hetionet CHEBI:3504 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0085593 infores:hetionet CHEBI:17026 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0015967 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0015397 infores:hetionet CHEBI:114785 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0019572 infores:hetionet CHEBI:17823 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0085631 infores:hetionet CHEBI:7573 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0012833 infores:hetionet CHEBI:15940 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0024902 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0019372 infores:hetionet CHEBI:480999 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0004604 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085096 infores:hetionet CHEBI:36704 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0424790 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0243026 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0030312 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0235270 infores:hetionet CHEBI:6775 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018681 infores:hetionet CHEBI:4024 biolink:causes MONDO:0002307 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0005743 infores:hetionet CHEBI:7931 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085631 infores:hetionet CHEBI:4779 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0037274 infores:hetionet CHEBI:16469 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0043352 infores:hetionet CHEBI:7577 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0035455 infores:hetionet CHEBI:50742 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0947912 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151865 infores:hetionet CHEBI:205919 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0011616 infores:hetionet CHEBI:119486 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020621 infores:hetionet CHEBI:2618 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0011168 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0022904 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C2047937 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0000879 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D002179 DB00257_MESH_D002179_1DB00646_MESH_D002179_1DB01110_MESH_D002179_1 CHEBI:70707 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0086543 infores:hetionet CAID:CA8814885 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814885 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 PP4, PM3, PS3 The NM_000152.5:c.510C>T variant in GAA is a synonymous (silent) variant (p.Asp170=) that is not predicted to impact splicing (BP7, BP4). This variant has been detected in at least 14 individuals with Pompe disease (PMIDs 14695532, 30564623, 30922962, 34405923). However, in all but one individual it was found to co-occur with two additional GAA variants. Additionally, studies have shown that c.510C>T frequently occurs in cis with the c.-32-13T>G variant (pathogenic by the ClinGen Lysosomal Disease VCEP) and is associated with an earlier age of onset and lower GAA enzyme activity in fibroblasts compared to individuals with c.-32-13T>G that do not carry c.510C>T (PMIDs 30922962, 34405923). RT-PCR from patients with c.510C>T and c.-32-13T>G and minigene assays demonstrate that c.510C>T modulates the aberrant splicing caused by c.-32-13T>G, but does not have a significant impact on splicing when it occurs in isolation (PMID 30922962). The highest population minor allele frequency in gnomAD v2.1.1. is 0.00008925 (11/123248 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 280956). While it is uncertain if c.510C>T is causative of disease, there is evidence suggesting that this variant acts as a negative modifying factor when it occurs in cis with c.-32-13T>G. Therefore, this variant is classified as a variant of unknown significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BP4, BP7, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814885/MONDO:0009290/010 2024-03-19 2024-03-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:50841 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0151763 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0021053 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013395 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027092 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0949103 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0949103 infores:hetionet NCBIGene:84061 biolink:causes MONDO:0010455 infores:monarchinitiative not_provided not_provided HGNC:28880 MONDO:0010455 uuid:0be51a8c-370c-4bd9-9531-3edbc0da15e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011168 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0162429 infores:hetionet CHEBI:3568 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0549622 infores:hetionet CHEBI:100246 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151539 infores:hetionet CHEBI:63611 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0013456 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C1442903 infores:hetionet CHEBI:6472 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0017675 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018799 infores:hetionet CHEBI:63631 biolink:causes HP:0004409 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2364082 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0031542 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0020649 infores:hetionet CHEBI:6438 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0041657 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0041969 infores:hetionet NCBIGene:3748 biolink:causes MONDO:0011529 infores:monarchinitiative not_provided not_provided HGNC:6235 MONDO:0011529 uuid:73842eb6-14f8-4cc2-98f7-7e487def6f7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:1280 biolink:causes MONDO:0024313 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D013203 DB00535_MESH_D013203_1DB01326_MESH_D013203_1DB01060_MESH_D013203_1DB00415_MESH_D013203_1DB01333_MESH_D013203_1DB00512_MESH_D013203_1DB00218_MESH_D013203_1DB01066_MESH_D013203_3DB00833_MESH_D013203_1DB01330_MESH_D013203_1DB00567_MESH_D013203_1DB00766_MESH_D013203_1DB06590_MESH_D013203_1DB01147_MESH_D013203_1DB00207_MESH_D013203_1DB02703_MESH_D013203_1DB01044_MESH_D013203_1DB00601_MESH_D013203_1DB01137_MESH_D013203_1DB01606_MESH_D013203_1DB00485_MESH_D013203_1DB01139_MESH_D013203_1DB01607_MESH_D013203_1DB01165_MESH_D013203_1DB01190_MESH_D013203_1DB01627_MESH_D013203_1DB01059_MESH_D013203_1DB13092_MESH_D013203_1DB01416_MESH_D013203_1DB00417_MESH_D013203_1DB09320_MESH_D013203_1DB09324_MESH_D013203_1DB00954_MESH_D013203_1DB01331_MESH_D013203_1DB00319_MESH_D013203_1DB01413_MESH_D013203_1DB00537_MESH_D013203_1DB00438_MESH_D013203_1DB01328_MESH_D013203_1 CHEBI:6888 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0553702 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0042571 infores:hetionet CHEBI:51364 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1443060 infores:hetionet CHEBI:70707 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0020625 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0854381 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0854381 infores:hetionet CHEBI:15553 biolink:causes MONDO:0850046 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0013927 infores:hetionet CHEBI:17334 biolink:causes MONDO:0019632 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0024198 infores:hetionet CHEBI:49713 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0233794 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0271899 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0271899 infores:hetionet NCBIGene:118987 biolink:causes MONDO:0859281 infores:monarchinitiative not_provided not_provided HGNC:26974 MONDO:0859281 uuid:11211675-c503-4e8a-af63-173907d96cb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0015230 infores:hetionet CHEBI:135888 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0040425 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0919980 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0233494 infores:hetionet CHEBI:3752 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0030193 infores:hetionet CHEBI:39669 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0026821 infores:hetionet NCBIGene:3329 biolink:causes MONDO:0012824 infores:monarchinitiative not_provided not_provided HGNC:5261 MONDO:0012824 uuid:e72e3ec0-0542-4e8c-a00c-40afc29215f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042790 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0267792 infores:hetionet GO:0090249 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0090249 GO:0009653 CHEBI:10112 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C2242588 infores:hetionet CHEBI:52172 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151825 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0595930 infores:hetionet CHEBI:142290 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0016059 infores:hetionet CHEBI:44032 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C1145670 infores:hetionet CHEBI:63681 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0851578 infores:hetionet CAID:CA210758 biolink:causes MONDO:0013144 infores:clingen CAID:CA210758 MONDO:0013144 PMID:2615648 Pathogenic PS4, PM1, PP1_Strong, PP3, PP4 BS1, PM5, BS2, PM2 The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210758/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA386492907 biolink:causes MONDO:0009861 infores:clingen CAID:CA386492907 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2, PM3_Very Strong, PVS1_Strong The c.1316-1G>A variant in PAH is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease. It is predicted to result in skipping of coding exon 13, which is a key domain of the enzyme (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in seven Ugyur probands (PMID: 31355225): three homozygotes with mild PKU; one compound heterozygote with classic PKU in trans with the p.R413P variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with classic PKU in trans with the p.R243Q variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with mild PKU in trans with the p.A300S variant (Pathogenic per ClinGen PAH working group); and one compound heterozygote with mild PKU in trans with the p.E182K (Likely Pathogenic per ClinGen PAH working group) variant (PM3_VeryStrong). (In all cases, phase was confirmed by parental testing.) In all cases, BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). It is reported pathogenic in Clinvar (ID 625286) by one lab, for PKU; no further information is given. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386492907/MONDO:0009861/006 2020-06-01 2020-06-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0424790 infores:hetionet CHEBI:17650 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0011603 infores:hetionet CHEBI:41774 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0235309 infores:hetionet CHEBI:63611 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003811 infores:hetionet CAID:CA410149580 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149580 MONDO:0011071 PMID:22318203PMID:18723428PMID:23751892PMID:22318203PMID:27418648PMID:18723428PMID:18723428PMID:22318203 Pathogenic PS4_Moderate, PVS1_Strong, PP1_Strong, PM5_Supporting, PM2_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS4, BS3, BP7, BP5, PM4, PM1, PM3, BS2, PP2, PP3, PP4 The NM_001754.4:c.958C>T (p.Arg320Ter) variant is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 320 - 480) is critical to protein function (PVS1_Strong). This variant was found to co-segregate with disease in multiple affected family members, with more than seven (14) meioses observed across 2 families (PP1_Strong; from internal laboratory data). The variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; from internal laboratory data). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PP1_Strong, PM2_supporting, PS4_Moderate, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149580/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:4771 biolink:causes MONDO:0011789 infores:monarchinitiative not_provided not_provided HGNC:7773 MONDO:0011789 uuid:20fe9910-97b2-4672-8730-36d1c4d0d5ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51137 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0015230 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034067 infores:hetionet CHEBI:83531 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0011253 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151479 infores:hetionet CHEBI:168396 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0438215 infores:hetionet CHEBI:8888 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0010200 infores:hetionet CHEBI:63629 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0041657 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0541879 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0541879 infores:hetionet CHEBI:51860 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0221242 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0038454 infores:hetionet CHEBI:17650 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0235259 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0242350 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0009938 infores:hetionet CHEBI:68534 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0003862 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0027441 infores:hetionet CHEBI:50173 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0033845 infores:hetionet CAID:CA029091 biolink:causes MONDO:0005045 infores:clingen CAID:CA029091 MONDO:0005045 PMID: Uncertain Significance PM2_Supporting, PP2, PP3 BP3, BP2, BP4, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, PP1 The NM_001018005.2(TPM1):c.323C>T (p.Thr108Ile). This variant has not been identified in individuals with cardiomyopathy nor in large population studies (PM2_Supporting; https://gnomad.broadinstitute.org, v.2.1). This missense variant is in a gene that has been determined to have a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2; Walsh et al. 2019 PMID:30696458). Additionally, computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PM2_Supporting, PP2, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA029091/MONDO:0005045/100 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7494 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0022568 infores:hetionet NCBIGene:9354 biolink:causes MONDO:0859207 infores:monarchinitiative not_provided not_provided HGNC:12499 MONDO:0859207 uuid:2bf89ee7-1689-4394-844a-357909223009 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7478 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0032285 infores:hetionet CHEBI:7466 biolink:causes NCIT:C74591 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0234925 infores:hetionet CHEBI:8871 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018944 infores:hetionet CHEBI:6367 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0233477 infores:hetionet CHEBI:7454 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0030554 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0700345 infores:hetionet CAID:CA2637057 biolink:causes MONDO:0021060 infores:clingen CAID:CA2637057 MONDO:0021060 PMID: Benign BA1 The c.528-2del variant in MRAS is a deletion of one base pair in intron 5. This variant has a filtering allele frequency of 0.93 % in the European (non-Finnish) population in gnomAD v2, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1 (RASopathy VCEP specifications version 1.4; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2637057/MONDO:0021060/087 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:52717 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0851578 infores:hetionet CHEBI:3176 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0016204 infores:hetionet CHEBI:7454 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0043352 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030920 infores:hetionet CHEBI:38940 biolink:causes UMLS:C1141926 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1141926 infores:hetionet CHEBI:34911 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C2242996 infores:hetionet CAID:CA410205628 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205628 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.97+1G>T is a splice donor variant which is only predicted to affect isoform c. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (gnomAD v2.1.1 and v3) (PM2_supporting). Variants disrupting this splice site have been reported in two probands with AML (PMID: 33075818). In summary, this variant meets the criteria to be classified as a variant of unknown significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205628/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:72690 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0003862 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0006444 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0178298 infores:hetionet CHEBI:80630 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0231218 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005020 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0021831 infores:hetionet CHEBI:50173 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0232726 infores:hetionet CHEBI:45716 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0023530 infores:hetionet CAID:CA16606083 biolink:causes MONDO:0015967 infores:clingen CAID:CA16606083 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PM1, PVS1, PP4_Moderate The c.511C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 171 (p.(Arg171Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with 13 informative meioses in 5 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 9097962, 10102714, 12530534, 12574234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.511C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PVS1, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606083/MONDO:0015967/017 2022-04-10 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15640 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C1325847 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020437 infores:hetionet CHEBI:64321 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0852911 infores:hetionet CHEBI:10119 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0428977 infores:hetionet NCBIGene:7026 biolink:causes MONDO:0014344 infores:monarchinitiative not_provided not_provided HGNC:7976 MONDO:0014344 uuid:d3bcc402-2c2d-464a-89e1-662026bd97b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042571 infores:hetionet CHEBI:50861 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0002994 infores:hetionet CHEBI:18258 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0003811 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085584 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0042109 infores:hetionet CHEBI:5778 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0041657 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0012359 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029445 infores:hetionet CHEBI:8060 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0036974 infores:hetionet NCBIGene:23414 biolink:causes MONDO:0012431 infores:monarchinitiative not_provided not_provided HGNC:16700 MONDO:0012431 uuid:1dc56158-ba1c-40c5-af39-757462927c8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0041956 infores:hetionet CHEBI:2611 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0004134 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151849 infores:hetionet CHEBI:39669 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0017152 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0032326 infores:hetionet GO:0016247 biolink:causes GO:0055085 infores:ubergraph knowledge_assertion manual_agent GO:0016247 GO:0055085 CHEBI:5778 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0039231 infores:hetionet CAID:CA415077240 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077240 MONDO:0010305 PMID: Pathogenic PM2_Supporting, PP4_Strong, PVS1_Strong PS1 The NM_005629.4:c.263-2A>G variant in SLC6A8 occurs within the canonical splice acceptor site of intron 1. RT-PCR revealed skipping of the first 21 amino acids of exon 2 (r.263_328del; p.Gly88_Glu109) (PMID: 16086185). While this is <10% of the protein length, the region includes Phe107. The variant p.Phe107del is pathogenic based on classification by the ClinGen CCDS VCEP (ClinVar Variation ID: 21448, SCV002600174.1) indicating that Phe107 is an important residue for creatine transporter function. Therefore, PVS1 will be applied at strong rather than moderate (PVS1_Strong). One male patient with this variant has been reported with clinical symptoms consistent with creatine transporter deficiency, elevated urine creatine/creatinine ratio (3.6; controls 0.006–1.2), impaired creatine uptake in fibroblasts, and absence of creatine peak on brain magnetic resonance spectroscopy (PMID: 16086185, 22713831, 2495340) (PP4_Strong). Another variant at the same acceptor splice site dinucleotide, c.263-1G>C has been reported in an affected individual and has a similar impact on splicing as shown by RT-PCR (PMID: 20717164). PS1 will be applied to c.263-1G>C based on the classification of the current variant under assessment (c.263-2A>G); PS1 is, therefore, not applied here to avoid circularity. The variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Another variant at the same acceptor splice site dinucleotide, c.263-1G>C has been reported in an affected individual and has a similar impact on splicing as shown by RT-PCR (PMID: 20717164), There is a ClinVar entry for this variant (Variation ID: 11701). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.2.0): PVS1_Strong, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 12, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077240/MONDO:0010305/027 2024-12-12 2025-08-13 X-linked inheritance HP:0001417 Supports CHEBI:61049 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0239134 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013922 infores:hetionet CHEBI:171719 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0231528 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0018939 infores:hetionet CAID:CA400032481 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032481 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PM5, PM3 The NM_000212.3(ITGB3):c.1757G>T (p.Cys586Phe) missense variant has been reported in at least one patient (Patients HJ in PMID:9790984) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 15.4%, as measured by flow cytometry. The computational predictor REVEL gives a score of 0.944, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180052 alleles) in the European (non-Finnish) genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary this variant meets criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3, PP4_moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032481/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:68579 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0311468 infores:hetionet CHEBI:63638 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0040264 infores:hetionet CHEBI:6539 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0162297 infores:hetionet NCBIGene:112817 biolink:causes MONDO:0013327 infores:monarchinitiative not_provided not_provided HGNC:25155 MONDO:0013327 uuid:66b20284-ae58-4106-b0d1-acb2c92a1fec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:213 biolink:causes MONDO:0014448 infores:monarchinitiative not_provided not_provided HGNC:399 MONDO:0014448 uuid:09e01be7-0d01-4f97-b1dc-0e6ea635001b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853777 infores:hetionet CHEBI:8455 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0038362 infores:hetionet CHEBI:31980 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0344232 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0037274 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0235290 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0851341 infores:hetionet CHEBI:28971 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0857305 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0857353 infores:hetionet CHEBI:8481 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0009806 infores:hetionet CHEBI:74947 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0039231 infores:hetionet CAID:CA410206833 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206833 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.718C>G (p.Pro240Ala) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206833/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:474180 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0030305 infores:hetionet CHEBI:5296 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0041657 infores:hetionet CHEBI:63791 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038160 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0242350 infores:hetionet CHEBI:4551 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C3160741 infores:hetionet CHEBI:367163 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151905 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027813 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0040046 infores:hetionet CHEBI:9943 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0600142 infores:hetionet CHEBI:6149 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0080274 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235966 infores:hetionet CHEBI:5134 biolink:causes MONDO:0024332 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0035457 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0520588 infores:hetionet CHEBI:48538 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0016382 infores:hetionet CHEBI:27470 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0000731 infores:hetionet CAID:CA367401688 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401688 MONDO:0015967 PMID: Pathogenic PS4, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PM1 The c.521C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to leucine at codon 174 (p.(Ser174Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 19790256, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia in 2 informative meiosis 2 families (PP1; internal lab contributors). In summary, c.521C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4, PP1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401688/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports UMLS:C0005740 biolink:causes MONDO:0019203 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0085786 infores:hetionet CHEBI:3423 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0027497 infores:hetionet CHEBI:61390 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0221245 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0015376 infores:hetionet GO:0051394 biolink:causes GO:1990090 infores:ubergraph knowledge_assertion manual_agent GO:0051394 GO:1990090 CHEBI:3647 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0012833 infores:hetionet CHEBI:2682 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0023530 infores:hetionet CHEBI:2668 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0232462 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020649 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0025061 infores:hetionet CAID:CA2579753976 biolink:causes MONDO:0100368 infores:clingen CAID:CA2579753976 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1115del(p.Leu372Ter) is a deletion variant in exon 10 of 14 that introduces a premature stop codon and is predicted to trigger nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including Retinal pigment epithelial mottling (salt-and-pepper appearance of fundus, 0.5 pts), reduction in blood-vessel diameter (0.5 pts), totally extinguished ERG response (0.5 pts for rod, 1 pt for cones), onset before 3 months of age (1 pt), reduced visual acuity (1 pt), and nyctalopia (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 points, PP4). This proband was found to be compound heterozygous, with this variant confirmed in trans with the p.Arg234Ter variant (PMID: 10090910), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3). The variant also segregated with the Leber congenital amaurosis phenotype through at least 1 affected meiosis from the proband's family (PP1; PMID: 10090910). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579753976/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CAID:CA396470822 biolink:causes MONDO:0007648 infores:clingen CAID:CA396470822 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2 The c.2311C>T (p.Gln771Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396470822/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:15367 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004364 infores:hetionet CHEBI:9445 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0040264 infores:hetionet CHEBI:7865 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0013604 infores:hetionet CHEBI:231594 biolink:causes MONDO:0001625 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0010093 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0031117 infores:hetionet CHEBI:567361 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0311468 infores:hetionet CHEBI:3757 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0013456 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0008702 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0008702 uuid:44da7718-c59b-44e5-b3a7-138515639bf2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes UMLS:C0521505 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0521505 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0027651 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0858589 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0858589 infores:hetionet CHEBI:3207 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0003467 infores:hetionet CAID:CA658795288 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795288 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000152.5(GAA):c.2385del (p.Glu795AspfsTer11) variant in GAA is a frameshift variant predicted to cause a premature stop codon in exon 17/20 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). One patient with late-onset Pompe disease has been reported with <1% normal GAA activity in fibroblasts (PMID: 21484825)(PP4_Supporting). This patient is compound heterozygous for the variant and c.2014C>T (p.Arg672Trp). The in trans data from this patient will be used in the assessment of p.Arg672Trp and is not included here in order to avoid circular logic. This variant is not in ClinVar. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCP (Specification Version 2.0): PVS1, PP4_Moderate, PM2_Supporting. (Classification approved on August 17th, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795288/MONDO:0009290/010 2021-08-19 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:47426 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0220981 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0041912 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020433 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0004936 infores:hetionet CHEBI:4798 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C2047937 infores:hetionet CHEBI:116278 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0025345 infores:hetionet CHEBI:6761 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0038362 infores:hetionet CHEBI:7601 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0042384 infores:hetionet CHEBI:7466 biolink:causes UMLS:C3160771 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C3160771 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0035435 infores:hetionet CAID:CA626689324 biolink:causes MONDO:0015152 infores:clingen CAID:CA626689324 MONDO:0015152 PMID: Uncertain Significance PVS1_Moderate, PM2_Supporting BP3, BP2, BP1, BP4, BA1, PM5, PM4, PM1, PS1, PS3, PS2, PS4, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP3 The NM_000023.4: c.1153_1163del p.(Asp385ThrfsTer3) variant in SGCA is expected to cause a frameshift of the last four amino acids of the protein without premature truncation, which may disrupt the function of the protein; however, the resulting transcript is predicted to escape nonsense mediated decay (PVS1_Moderate). The highest population minor allele frequency of this variant is 0.00006 (1/15750 alleles) in the African/African American population in gnomAD v2.1.1, which is less than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant cannot be classified as pathogenic nor benign at this time and remains a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA626689324/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8871 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0041834 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0025061 infores:hetionet CHEBI:65346 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0009450 infores:hetionet CHEBI:16914 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0043094 infores:hetionet CHEBI:31397 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0019825 infores:hetionet CHEBI:3011 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0002878 infores:hetionet CHEBI:3216 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0015644 infores:hetionet CHEBI:5002 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0008031 infores:hetionet CHEBI:50742 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0236075 infores:hetionet NCBIGene:25913 biolink:causes MONDO:0957264 infores:monarchinitiative not_provided not_provided HGNC:17284 MONDO:0957264 uuid:cce65307-2804-4a08-b862-ad3913572e36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92511 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C1761613 infores:hetionet CHEBI:63622 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0001824 infores:hetionet CHEBI:38940 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020598 infores:hetionet CAID:CA397394879 biolink:causes MONDO:0100438 infores:clingen CAID:CA397394879 MONDO:0100438 PMID: Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3_Strong, PS3_Supporting NM_014336.5(AIPL1):c.809G>A (p.Arg270His) is a missense variant predicted to replace arginine with histidine at amino acid p.270. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous (0.5 pts, PMID: 39761966). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) variant either confirmed in trans (1 point, PMID: 33067476) or suspected in trans but lacking confirmation details (0.5 pts, PMID: 21153841), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), photophobia (1 pt), visual acuity limited to hand movements (1 pt), nystagmus (1 pt), mild myopia, extinguished electroretinogram responses from both rods (0.5 pts) and cones (1 pt), and fundus consistent with retinitis pigmentosa with macular atrophy (0.5 pts), which together are specific for AIPL1-related retinopathy (total 5.5 points, PMID: 17724218, PP4). The variant was associated with ~60% PDE6 enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, which was comparable to the negative control lacking AIPL1, indicating that it triggers a severe defect in protein function (PMID: 33067476, PS3_Supporting). The variant also showed severely decreased interaction with HSP90alpha and HSP90beta relative to the wild-type control (PMID: 33067476). The computational predictor REVEL gives a score of 0.940, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.93 and predicts a damaging effect on AIPL1 protein function (PP3_Strong). The splicing impact predictor SpliceAI gives a score of 0.04 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP4, PS3_Supporting, and PP3_Strong. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397394879/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5864 biolink:causes UMLS:C0855335 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0855335 infores:hetionet CHEBI:35677 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0012833 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0001824 infores:hetionet CHEBI:17347 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0236075 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0020649 infores:hetionet CHEBI:75722 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0231528 infores:hetionet NCBIGene:658 biolink:causes MONDO:0014798 infores:monarchinitiative not_provided not_provided HGNC:1077 MONDO:0014798 uuid:f40a746e-c0a0-4dd6-908a-4c47324ecb27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7447 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0030193 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0015397 infores:hetionet CHEBI:7789 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0013144 infores:hetionet CHEBI:51209 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0038990 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0233494 infores:hetionet CHEBI:70746 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018944 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0025061 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0029927 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0015376 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0018099 infores:hetionet CAID:CA001262 biolink:causes MONDO:0011450 infores:clingen CAID:CA001262 MONDO:0011450 PMID:30209399 Pathogenic PP3, PM2_Supporting, PP4_Strong, PS3 The c.191G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 64 (p.Cys64Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.557, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 17239845573264 (based on Cosegregation LR=5300394; Pathology LR=189; Family History LR=17201), above the threshold for Very strong evidence towards pathogenicity (>350) (PP4_Very strong met; PMID: 31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001262/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9123 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0233494 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0267596 infores:hetionet CHEBI:7852 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018965 infores:hetionet CHEBI:3756 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0016382 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0877104 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0877104 infores:hetionet CHEBI:5613 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0015967 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005402 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0023448 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0267792 infores:hetionet CHEBI:5864 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0149871 infores:hetionet CHEBI:367163 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0023380 infores:hetionet CHEBI:10023 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151576 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0028259 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0011991 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0042376 infores:hetionet NCBIGene:23097 biolink:causes MONDO:0030059 infores:monarchinitiative not_provided not_provided HGNC:19338 MONDO:0030059 uuid:3cee6289-ab80-43a6-aa33-d148fbab5ff6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4975 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0007859 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0003085 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D007634 DB00994_MESH_D007634_1DB00626_MESH_D007634_1DB00781_MESH_D007634_1 CHEBI:16796 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0012833 infores:hetionet CHEBI:28445 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0085298 infores:hetionet CHEBI:45081 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C2830004 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0085584 infores:hetionet GO:0045685 biolink:causes GO:0042063 infores:ubergraph knowledge_assertion manual_agent GO:0045685 GO:0042063 UMLS:C0065374 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0031117 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017152 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020456 infores:hetionet CHEBI:7444 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0151636 infores:hetionet CHEBI:51230 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0033774 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0151773 infores:hetionet CHEBI:8207 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151908 infores:hetionet CHEBI:45783 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085932 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0234215 infores:hetionet NCBIGene:348980 biolink:causes MONDO:0014377 infores:monarchinitiative not_provided not_provided HGNC:4845 MONDO:0014377 uuid:201a71f3-a1be-4535-84d7-62aece285497 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0341047 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0234215 infores:hetionet CHEBI:68478 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2717961 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1112320 infores:hetionet CHEBI:7852 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0149871 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0013395 infores:hetionet CHEBI:53760 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0037763 infores:hetionet CAID:CA410203747 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203747 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.268G>A (p.Val90Met) is a missense variant which affects a residue within the Runt Homology Domain (AA 89-204) but does not occur at a hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203747/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63631 biolink:causes UMLS:C0016579 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0016579 infores:hetionet CAID:CA396469962 biolink:causes MONDO:0007648 infores:clingen CAID:CA396469962 MONDO:0007648 PMID:26182300PMID:26182300 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP4, PP3, PP2, PP1, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2 The c.2265T>A (p.Tyr755*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Additionally, this variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 26182300). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396469962/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA228533 biolink:causes MONDO:0015630 infores:clingen CAID:CA228533 MONDO:0015630 PMID: Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PS3, PS4_Moderate PM5, BP5 The NM_000552.4(VWF):c.4105T>A (p.Phe1369Ile) missense variant has been identified in at least three unrelated heterozygous patients (PS4_Moderate), with one of the probands meeting PP4 phenotypic criteria. These phenotypes include normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and reduced binding to platelets in the presence of ristocetin, which together are highly specific for VWD type 2M (PP4_moderate, PMID:9473222). A ristocetin-induced platelet binding assay performed with the F1369I recombinant mutant expressed by COS-7 cells showed ~75% decreased binding indicating that this variant has a damaging effect on protein function (PMID: 9473222; PS3). The computational predictor REVEL gives a score of 0.893, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00004370 (based on 8/91044 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). In summary, the variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP3, PP4_moderate, PM2_supporting, PS4_moderate, and PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228533/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CAID:CA213684 biolink:causes MONDO:0011225 infores:clingen CAID:CA213684 MONDO:0011225 PMID: Benign BA1, BS2_Supporting The NM_001033855.3:c.512C>G variant in DCLRE1C is a missense variant predicted to cause the substitution of proline by arginine at amino acid 171 (p.Pro171Arg). This variant has an allele frequency of 0.19422 in the East Asian population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for DCLRE1C (>0.00346). In addition, this variant is present 1394 adult homozygous individuals in gnomADv2.1.1 (distributed in all gnomAD populations)(BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA213684/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4814 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0003864 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0242350 infores:hetionet CHEBI:31859 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151827 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151735 infores:hetionet CHEBI:6339 biolink:causes HP:0003365 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0019559 infores:hetionet CAID:CA294589 biolink:causes MONDO:0100039 infores:clingen CAID:CA294589 MONDO:0100039 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM1, BP4, PS4 The c.320T>A (p.Val107Asp) variant in CDKL5 has been reported in 1 proband meeting the CDKL5 disorder phenotypic spectrum, but not meeting the specificity required for PP4 (PP4_not_met). PS4_Supporting cannot be applied because additional observations are required (CDKL5 registry, internal database)(PS4_Supporting_not_met). The p.Val107Asp variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.680, which is above the threshold of 0.644, evidence that correlates with impact to CDKL5 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for CDKL5 disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Rett and Angelman-like disorders VCEP: (PM2_supporting, PP3) (CDKL5 specifications version 4.0; 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294589/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:2569 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0860713 infores:hetionet CAID:CA220396 biolink:causes MONDO:0009290 infores:clingen CAID:CA220396 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000152.5:c.2105G>T variant in GAA is a missense variant predicted tocause substitution of arginine by leucine at amino acid 702 (p.Arg702Leu). It has been reported in at least two unrelated patients with infantile-onset Pompe disease with documented GAA deficiency and receiving enzyme replacement therapy, and in one patient identified via newborn screening with deficient confirmatory enzyme in blood and clinical symptoms (Clinical diagnostic laboratory) described has having late-onset Pompe disease, meeting criteria for PP4_moderate (PMID: 26497565, 27344650, 26167453). Of those individuals, a a proband and full sibling were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen LD VCEP, c.2512C>T (p.Gln838Ter) (ClinVar Variation ID: Variation ID: 92479, SCV001371718.1), confirmed in trans by parental testing (PMID: 26167453) (1 point). Another patient was compound heterozygous for the variant and variant classified as pathogenic by the ClinGen LD VCEP, c.1798C>T (p.Arg600Cys) (Variation ID: 640911; SCV002032136.1), phase unknown (PMID: 26497565, 27344650). The variant has also been reported in trans with a pathogenic variant (c.-32-13T>G; ClinVar Variation ID: 4027) in one individual identified on newborn screening with deficient confirmatory GAA and clinical symptoms with deficient confirmatory GAA in DBS (Clinical diagnostic laboratory) (PM3_Strong).It has also been reported in one individual with a positive newborn screen for Pompe disease and deficient confirmatory GAA activity, but no reported phenotype (PMID: 33202836). It is absent from large population databases (gnomAD v2.1.1.) meeting PM2_Supporting. Expression of the variant in COS-7 and HEK293T cells resulted in 0.4% GAA activity in cells and 1.3% in medium and evidence of abnormal GAA synthesis and processing – leading the variant to be classified as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:22644586), meeting PS3_moderate. The computational predictor REVEL gives a score of 0.972 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 92472). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): (PM3_strong, PP4_moderate, PS3_moderate, PM2_supporting, PP3).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220396/MONDO:0009290/010 2024-03-05 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ HP:0031377 biolink:causes MONDO:0005173 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D055623 DB00179_MESH_D055623_1 CHEBI:50275 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0239571 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1096091 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1096091 infores:hetionet CHEBI:474053 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0424295 infores:hetionet CHEBI:8764 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0558489 infores:hetionet CHEBI:41879 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151686 infores:hetionet CHEBI:3568 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0221345 infores:hetionet CHEBI:7565 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0162830 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0029408 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0034150 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0242350 infores:hetionet PR:000012705 biolink:causes GO:0002415 infores:ubergraph knowledge_assertion manual_agent PR:000012705 GO:0002415 CHEBI:9086 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085649 infores:hetionet CHEBI:38562 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0085932 infores:hetionet NCBIGene:51501 biolink:causes MONDO:0014813 infores:monarchinitiative not_provided not_provided HGNC:26938 MONDO:0014813 uuid:57941b49-b11a-4f00-8b68-577525a33164 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135679 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0151827 infores:hetionet NCBIGene:286887 biolink:causes MONDO:0014327 infores:monarchinitiative not_provided not_provided HGNC:20406 MONDO:0014327 uuid:1cad8a9e-8ce5-4980-ac75-6dd3a454cf26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17823 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0085602 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0271650 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0037199 infores:hetionet CHEBI:180905 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0035455 infores:hetionet CHEBI:9763 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0015672 infores:hetionet CHEBI:231594 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0278134 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0948586 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0860866 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0036454 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0010399 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009782 infores:hetionet CHEBI:8871 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151564 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0002884 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0037195 infores:hetionet CHEBI:32192 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0043352 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030353 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0151763 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0015397 infores:hetionet CHEBI:65173 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C3489393 infores:hetionet CHEBI:59582 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0033774 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0267792 infores:hetionet CHEBI:63845 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0005758 infores:hetionet CHEBI:8890 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151905 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0521839 infores:hetionet CAID:CA273297 biolink:causes MONDO:0008723 infores:clingen CAID:CA273297 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1532+1G>A variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 15. It is predicted to cause skipping of biologically-relevant-exon 15/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1 is 0.000008801 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. (ACADVL VCEP specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA273297/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:7157 biolink:causes MONDO:0032573 infores:monarchinitiative not_provided not_provided HGNC:11998 MONDO:0032573 uuid:56550a0b-a917-42c2-a3f6-b322e88c1052 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C3665346 infores:hetionet CHEBI:63631 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085632 infores:hetionet CHEBI:4445 biolink:causes UMLS:C1504379 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1504379 infores:hetionet CHEBI:49375 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0152030 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0020517 infores:hetionet CHEBI:5790 biolink:causes HP:0032149 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1135120 infores:hetionet CHEBI:71417 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0234518 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0878544 infores:hetionet CHEBI:391960 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C1384353 infores:hetionet NCBIGene:89765 biolink:causes MONDO:0014202 infores:monarchinitiative not_provided not_provided HGNC:12371 MONDO:0014202 uuid:c50ceca0-02bb-4baa-a06d-797a56e5c73d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0162429 infores:hetionet CHEBI:47781 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0001824 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151713 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0006852 infores:hetionet CHEBI:135351 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0392699 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020039 infores:hetionet CHEBI:167638 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0011603 infores:hetionet CHEBI:135736 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020488 infores:hetionet CHEBI:144551 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0344232 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040409 infores:hetionet CHEBI:6931 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235546 infores:hetionet NCBIGene:129607 biolink:causes MONDO:0975875 infores:monarchinitiative not_provided not_provided HGNC:27015 MONDO:0975875 uuid:458d40f9-e729-42c8-affa-34996434764a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0015230 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0235146 infores:hetionet CHEBI:6078 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0233471 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0034150 infores:hetionet CHEBI:4909 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0030312 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0002792 infores:hetionet CHEBI:17303 biolink:causes UMLS:C3241936 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C3241936 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027697 infores:hetionet CHEBI:5775 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0002962 infores:hetionet CHEBI:168396 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004144 infores:hetionet CHEBI:9738 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0018524 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0003864 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0013985 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0028738 infores:hetionet CHEBI:51173 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0015230 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0006852 infores:hetionet CHEBI:9398 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0015230 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1291078 infores:hetionet CHEBI:5132 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0002878 infores:hetionet CHEBI:27504 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C2939419 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0023895 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233494 infores:hetionet CHEBI:31643 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0011168 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020517 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005451 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013473 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0854097 infores:hetionet CHEBI:40237 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0232602 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040425 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0521591 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0040046 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1142172 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1142172 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0040264 infores:hetionet CHEBI:8863 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0009782 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0042571 infores:hetionet CHEBI:8764 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006625 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0233494 infores:hetionet CHEBI:92998 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0026858 infores:hetionet CHEBI:3219 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017168 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017675 infores:hetionet CHEBI:75984 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0206062 infores:hetionet CHEBI:47657 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0022660 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0027769 infores:hetionet CAID:CA024784 biolink:causes MONDO:0007783 infores:clingen CAID:CA024784 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PM5, PS4_Moderate, PM1_Supporting, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 2458 of the RYR1 protein, p.(Arg2458Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000008, a frequency consistent with pathogenicity for MHS. This variant has been reported in six unrelated individuals with a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 24433488, 9450902, 10051009, 15731587). Functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 9334205, 27586648). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2458His) PM5. A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024784/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3387 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0015397 infores:hetionet CHEBI:100246 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0037763 infores:hetionet CHEBI:3568 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0024902 infores:hetionet CHEBI:7577 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0151908 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1167965 infores:hetionet CHEBI:50729 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0003811 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0595930 infores:hetionet CHEBI:15552 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0392171 infores:hetionet CHEBI:64355 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0039239 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040053 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042109 infores:hetionet CAID:CA10644641 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644641 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS3, PS4, BP4, PVS1, PM6, PM2, BS3, BS4, BS1, BP7, PM5, PM4, PM1, PP3, PP1 The NM_001754.4:c.*559T>C variant in the 3' UTR has an MAF of 0.1451 (14.5%; 1261/8690 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 415 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644641/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6129 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020461 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0021843 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085682 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0020517 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0341117 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0341117 infores:hetionet CHEBI:48273 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0085635 infores:hetionet NCBIGene:93183 biolink:causes MONDO:0012465 infores:monarchinitiative not_provided not_provided HGNC:18858 MONDO:0012465 uuid:0f27313d-b1aa-4ed3-adfe-304f2edb50a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038663 infores:hetionet CHEBI:3176 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0010034 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0267792 infores:hetionet CAID:CA2573334479 biolink:causes MONDO:0010305 infores:clingen CAID:CA2573334479 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_005629.4:c.859del (p.Asp287MetfsTer21) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A male patient has been reported with clinical features consistent with creatine transporter deficiency in addition to elevated urine creatine/creatinine ratio and low creatine peak on MRS (PMID: 24953403, 26205312 (PP4_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573334479/MONDO:0010305/027 2023-03-09 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:2549 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0220981 infores:hetionet CHEBI:6909 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C3665347 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0857322 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0857322 infores:hetionet CHEBI:9927 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0030554 infores:hetionet CHEBI:34911 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0015230 infores:hetionet CHEBI:8356 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151908 infores:hetionet CHEBI:6970 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0027424 infores:hetionet CHEBI:3698 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0036974 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0595877 infores:hetionet CHEBI:63598 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151539 infores:hetionet CHEBI:16469 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013390 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0024312 infores:hetionet CAID:CA234282 biolink:causes MONDO:0018947 infores:clingen CAID:CA234282 MONDO:0018947 PMID: Uncertain Significance PP3, PM2_Supporting BA1, BP4, PS4, BS1 The c.1169T>A variant in MTM1 is a missense variant predicted to cause substitution of methionine by lysine at amino acid 390. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.948, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications Version 1: 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA234282/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Inconclusive true CHEBI:7852 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1443060 infores:hetionet CHEBI:2549 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0027424 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0009450 infores:hetionet CHEBI:48131 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0237849 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001142 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036093 infores:hetionet CHEBI:47426 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C3665347 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0302870 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0302870 infores:hetionet CHEBI:75988 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0085631 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007222 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0855242 infores:hetionet CHEBI:10124 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0030193 infores:hetionet NCBIGene:25782 biolink:causes MONDO:0013641 infores:monarchinitiative not_provided not_provided HGNC:17168 MONDO:0013641 uuid:8ec63516-7179-4b13-85e4-4deb20487578 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0687133 infores:hetionet GO:0010975 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0010975 GO:0048699 CHEBI:9241 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0042109 infores:hetionet CAID:CA16020814 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020814 MONDO:0009861 PMID: Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Strong, PS3_Supporting PM5 This c.548A>G (p.Glu183Gly) variant in PAH was reported in trans with pathogenic variants p.Arg111* and c.721C>T in 2 patients with PAH deficiency (>120 μmol/L Phe, BH4 deficiency excluded) (PMID: 28982351, 28754886). Residual enzyme activity was 9.1% for p.Glu183Gly compared to the wild-type PAH (PMID: 24327145). Computational evidence for this missense variant is predicted to be damaging (REVEL=0.977). This variant is absent from population databases gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2_supporting, PP4_moderate, PP3_strong, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020814/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9727 biolink:causes UMLS:C0549225 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0549225 infores:hetionet CHEBI:63791 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040822 infores:hetionet CHEBI:135736 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0242184 infores:hetionet CHEBI:71417 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0231528 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0235032 infores:hetionet CHEBI:4356 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0012833 infores:hetionet CAID:CA2466438179 biolink:causes MONDO:0010305 infores:clingen CAID:CA2466438179 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_005629.4:c.1255-35G>A variant in SLC6A8 is an intronic variant affecting a nucleotide within the consensus splice site of intron 8. This variant has been reported as a novel variant in one individual undergoing genetic testing for suspected X-linked intellectual disability (PMID: 15154114), without further specification; thus PP4 does not apply. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictors SpliceAI and varSEAK predict that this variant does not impact splicing (BP4). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4.Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2466438179/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:9288 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0162275 infores:hetionet NCBIGene:6324 biolink:causes MONDO:0011416 infores:monarchinitiative not_provided not_provided HGNC:10586 MONDO:0011416 uuid:596a65b6-a551-4853-9b1c-6aac17c56aa6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0029882 infores:hetionet CHEBI:4907 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0029442 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0162848 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0004245 infores:hetionet CHEBI:110423 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0035078 infores:hetionet CHEBI:31980 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0522055 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0040409 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0424605 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0006840 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011570 infores:hetionet CHEBI:135361 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0042963 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005496 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0740277 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0036416 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0023530 infores:hetionet CHEBI:10650 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1280433 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0023067 infores:hetionet CHEBI:75246 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0015967 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013595 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0403632 infores:hetionet CHEBI:144551 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1443060 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0853619 infores:hetionet CHEBI:553473 biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0521503 infores:hetionet CHEBI:4717 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0020538 infores:hetionet CHEBI:204734 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0038990 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0009241 infores:hetionet CHEBI:8356 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026764 infores:hetionet CHEBI:5138 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017672 infores:hetionet CHEBI:16347 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0231528 infores:hetionet CHEBI:107736 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018681 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0029878 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0027051 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0009806 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0042134 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0162429 infores:hetionet CHEBI:5296 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0947912 infores:hetionet CHEBI:5790 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085649 infores:hetionet UMLS:C0657912 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0423791 infores:hetionet CHEBI:10650 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0242422 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0004936 infores:hetionet GO:0075184 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0075184 GO:0009653 CHEBI:78543 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0920102 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0086565 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151785 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0233472 infores:hetionet CAID:CA415167755 biolink:causes MONDO:0010726 infores:clingen CAID:CA415167755 MONDO:0010726 PMID: Benign BP5, BS1, BS2 BP4, BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BS3, BS4, PM2, PM6, PP3, PP1, PP4 The highest population minor allele frequency of the p.Leu383Phe variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00001789 in African/African-American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0000083) for BS1, and therefore meets this criterion (BS1). The p.Leu383Phe variant is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). This variant is also found in two patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Leu395Phe variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5). (MECP2 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415167755/MONDO:0010726/036 2025-08-27 2025-10-01 X-linked inheritance HP:0001417 Contradicts true CAID:CA396459027 biolink:causes MONDO:0007648 infores:clingen CAID:CA396459027 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong, PS3, PS4_Moderate BS1, BS3, BP5, BS2, BA1, BP2 The CDH1 c.832+1G>A variant is a canonical splice variant in intron 6 predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent from the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in three families meeting IGCLC criteria for HDGC (PS4_Moderate, internal clinical lab data). This variant has also been reported in the literature in families with LBC who do not meet criteria for HDGC (PMID: 36436516, 32489267, 34643667). RNA analysis demonstrated two out-of-frame transcripts, r.754_832del79 p.(V252Efs*4) and r.688_832del145 p.(L230Efs*4) (PS3; internal clinical lab data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS3, PS4_Moderate, PM2_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396459027/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:2948 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0002871 infores:hetionet NCBIGene:2688 biolink:causes MONDO:0013006 infores:monarchinitiative not_provided not_provided HGNC:4261 MONDO:0013006 uuid:ef01d74d-139d-4300-ae95-3dc243ea402a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0027497 infores:hetionet NCBIGene:2639 biolink:causes MONDO:0009281 infores:monarchinitiative not_provided not_provided HGNC:4189 MONDO:0009281 uuid:3b700f69-6b0b-4639-8d92-0fc7c29739bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003862 infores:hetionet CHEBI:63630 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C3263723 infores:hetionet CAID:CA2573106065 biolink:causes MONDO:0007453 infores:clingen CAID:CA2573106065 MONDO:0007453 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1305dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 436 (NM_000162.5), adding 23 novel amino acids before encountering a stop codon (p.(Ile436AspfsTer23)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history consistent with GCK-MODY, but there was insufficient clinical information to evaluate for PP4. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 31704690​, internal lab contributors). In summary, c.1305dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106065/MONDO:0007453/086 2023-11-03 2023-11-03 Semidominant inheritance HP:0032113 Supports UNII:8NZ41MIK1O biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0221423 infores:hetionet CHEBI:2950 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0015230 infores:hetionet NCBIGene:51645 biolink:causes MONDO:0030258 infores:monarchinitiative not_provided not_provided HGNC:9260 MONDO:0030258 uuid:5dfa1c8a-1a65-48c7-908b-905cf7d0c629 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0033774 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0011991 infores:hetionet CHEBI:9674 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0085605 infores:hetionet CAID:CA410147605 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147605 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1261G>T (p.Gly421Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147605/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2675 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0004238 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0700184 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0425946 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0425946 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0015397 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235234 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0027765 infores:hetionet CAID:CA5894328 biolink:causes MONDO:0021060 infores:clingen CAID:CA5894328 MONDO:0021060 PMID: Likely Pathogenic PP3, PS4_Supporting, PS2, PM1, PS3_Supporting BP4, BA1, BS1, PM2 The c.208G>A (p.Ala70Thr) variant in RRAS2 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 70. The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00001084 (2/30538 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.863, which is above the threshold of 0.7, evidence that correlates with impact to RRAS2 function (PP3). This variant resides within the Switch II domain (amino acids 68 – 75), of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). ERK Activation in HEK293T cells showed constitutive promotion of increased ERK phosphorylation indicating that this variant impacts protein function (PMID:31130282)(PS3_Supporting). This variant has been reported in 2 probands with features of RASopathy (PS4_Supporting; PMID:31130282). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:31130282). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM1, PS3_Supporting, PS4_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5894328/MONDO:0021060/127 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4708 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0037199 infores:hetionet CHEBI:9123 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235660 infores:hetionet CHEBI:27899 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0017181 infores:hetionet CHEBI:7476 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0149745 infores:hetionet CHEBI:404903 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C2240374 infores:hetionet CHEBI:8378 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0025289 infores:hetionet GO:1904956 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:1904956 GO:0007417 CHEBI:72297 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0003862 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0235006 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0235006 infores:hetionet CHEBI:2549 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0520887 infores:hetionet GO:0048772 biolink:causes CL:0000571 infores:ubergraph knowledge_assertion manual_agent GO:0048772 CL:0000571 CAID:CA280025 biolink:causes MONDO:0015280 infores:clingen CAID:CA280025 MONDO:0015280 PMID: Pathogenic PS2, PM1, PM6, PM2, PP2, PP3 PS3 The c.730A>C (p.Thr244Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 17551924 and 18042262). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr244Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280025/MONDO:0015280/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:36704 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1527358 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0521591 infores:hetionet CHEBI:45599 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0151578 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042134 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0003123 infores:hetionet CAID:CA10583399 biolink:causes MONDO:0007648 infores:clingen CAID:CA10583399 MONDO:0007648 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting, PS4 BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM1, PM6, PM3, PP3, PP2, PP4, BS2, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2 The c.3G>A (p.Met1Ile) variant causes a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (18726070, 2317870, 20066110) (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; PMID: 28202063, 26182300). This variant has also been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 26182300, 20719348, clinical lab internal data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2_Supporting, PP1_Moderate, PS4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583399/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:4466 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0037822 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027707 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0855242 infores:hetionet CHEBI:66876 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0018965 infores:hetionet CHEBI:94440 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0574002 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0162429 infores:hetionet CHEBI:10023 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0026826 infores:hetionet CHEBI:38940 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151908 infores:hetionet NCBIGene:90167 biolink:causes MONDO:0010693 infores:monarchinitiative not_provided not_provided HGNC:8079 MONDO:0010693 uuid:bb341811-01e6-408f-98df-0e77a657c4e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0022116 infores:hetionet CHEBI:8228 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0234632 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0745528 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0745528 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0039971 infores:hetionet CHEBI:8404 biolink:causes EFO:1001766 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C1527348 infores:hetionet CHEBI:49603 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0235378 infores:hetionet CHEBI:63638 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0004604 infores:hetionet GO:0052151 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:0052151 GO:0006915 CHEBI:50742 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013395 infores:hetionet CHEBI:6633 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0085932 infores:hetionet GO:0060224 biolink:causes GO:0003407 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0003407 CAID:CA232923 biolink:causes MONDO:0010726 infores:clingen CAID:CA232923 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, PM1, BS1, PP3, PP4 The p.Pro393Leu variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Ambry, internal database - Invitae) (BS2). The p.Pro393Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Ambry) (BP5). The highest population minor allele frequency of the p.Pro393Leu variant in MECP2 in gnomAD v4.1 is 0.00002210 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Pro393Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA232923/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:63617 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0002871 infores:hetionet CHEBI:8888 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0575081 infores:hetionet CHEBI:4466 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085649 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0018799 infores:hetionet CAID:CA902549 biolink:causes MONDO:0100368 infores:clingen CAID:CA902549 MONDO:0100368 PMID: Likely Benign BS1 BP4, PM3, PP3, PP4 NM_000329.3(RPE65):c.295G>A is a missense variant causing substitution of valine with isoleucine at position 99. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.002650, with 68 alleles / 19954 total alleles in the East Asian population (with 2 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), peripheral vision loss and (1 pt). However, the proband lacks the second variant required to apply the PP4 code. This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 21602930). However, the probands were not counted for PM3 because they lacked the second variant required to apply the code. The computational predictor REVEL gives a score of 0.517, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902549/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:77733 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0344232 infores:hetionet CHEBI:63577 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0085633 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0041969 infores:hetionet CHEBI:8364 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0027497 infores:hetionet CHEBI:10119 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020598 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0853118 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0853118 infores:hetionet CHEBI:27300 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C1167965 infores:hetionet CHEBI:2682 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002792 infores:hetionet CHEBI:68534 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0041912 infores:hetionet CHEBI:53691 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0022672 infores:hetionet CHEBI:68534 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0917801 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0034063 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0029927 infores:hetionet CAID:CA410147720 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147720 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1234G>C (p.Gly412Arg) is a missense variant which has a REVEL score < 0.50 (0.433) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147720/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41774 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0043094 infores:hetionet CHEBI:7496 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0006266 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0004623 infores:hetionet CHEBI:75984 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C1167965 infores:hetionet CHEBI:3441 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042023 infores:hetionet CHEBI:9927 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0344232 infores:hetionet CHEBI:4356 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0017178 infores:hetionet NCBIGene:392255 biolink:causes MONDO:0013130 infores:monarchinitiative not_provided not_provided HGNC:4221 MONDO:0013130 uuid:29d9f786-b547-4900-9f88-09933d6539b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0036416 infores:hetionet CHEBI:18248 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0232292 infores:hetionet CHEBI:6076 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0040264 infores:hetionet CHEBI:47898 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0024236 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0234215 infores:hetionet CHEBI:46345 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0018681 infores:hetionet CHEBI:681850 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0042075 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038661 infores:hetionet CHEBI:4514 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0027497 infores:hetionet CHEBI:9667 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0015300 infores:hetionet CHEBI:40303 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0042963 infores:hetionet CHEBI:31644 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0015230 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042109 infores:hetionet CHEBI:135930 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027497 infores:hetionet CHEBI:8890 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1145670 infores:hetionet CHEBI:31623 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0043144 infores:hetionet CHEBI:40303 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0003467 infores:hetionet CHEBI:45951 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0232462 infores:hetionet CHEBI:51364 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0686347 infores:hetionet CHEBI:50275 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0032617 infores:hetionet CAID:CA912971829 biolink:causes MONDO:0021060 infores:clingen CAID:CA912971829 MONDO:0021060 PMID: Pathogenic PS3_Moderate, PS4_Supporting, PM2_Supporting, PS2, PM4, PM1 BA1, BS1 The NM_012250.6:c.70_78dup variant is predicted to cause a change in the length of the protein due to an in-frame insertion (duplication) of 3 amino acids in a nonrepeat region (p.Gly24_Gly26dup) (PM4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within the P Loop (amino acids 21 – 28), of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 1 proband with facial dysmorphology typical of NS, macrocephaly, pulmonic stenosis, hemangiomas, mild myopia, and left hearing impairment (PS4_Supporting; PMID:31130285). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with facial dysmorphology typical of NS, macrocephaly, pulmonic stenosis, hemangiomas, mild myopia, and left hearing impairment (PS2; PMID:31130285). Pull-down assays with the Raf-Ras-binding domain (RBD, residues 1–149) of RAF1 in HEK293 cells showed increased binding of activated RAS indicating that this variant impacts protein function (PMID:31130285). Similar results were seen in an immunoblotting assay of the cell lysates expressing WT/variant RRAS2 using anti-phospho-MEK1/2 and phospho-ERK1/2 antibodies. Additionally, Zebrafish embryos injected with variant mRNA showed significantly increased ceratohyal angles, significantly decreased body length, greater head length, and increased incidence of pericardial effusion compared to the uninjected controls (PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS3_Moderate, PM1, PM4, PS4_Supporting, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.1; 5/9/2022) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA912971829/MONDO:0021060/127 2022-05-09 2024-10-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45863 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0026858 infores:hetionet CHEBI:5959 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0041657 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0021053 infores:hetionet CHEBI:9943 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0028084 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0853026 infores:hetionet CAID:CA392324992 biolink:causes MONDO:0007947 infores:clingen CAID:CA392324992 MONDO:0007947 PMID: Likely Pathogenic PM6, PP4, PP2, PP3, PS4_Supporting, PM2_Supporting PM1 The NM_00138 c.3554G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by aspartic acid at amino acid 1185 (p.Gly1185Asp), in a cbEGF-like domain of the protein. This variant was found in a proband who met revised Ghent criteria with a clinical diagnosis of Marfan syndrome (MFS) (PMID 35058154, internal lab data, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 549173). This variant was also found to be de novo in a proband with infantile MFS without confirmation of paternity and maternity (PM6, PS4_Sup; internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.942, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM6, PS4_Sup, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392324992/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7565 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0016382 infores:hetionet CHEBI:4953 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0043094 infores:hetionet CHEBI:3207 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0027424 infores:hetionet CHEBI:7773 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C1619712 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0152128 infores:hetionet CHEBI:43968 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0004093 infores:hetionet NCBIGene:11023 biolink:causes MONDO:0013734 infores:monarchinitiative not_provided not_provided HGNC:12660 MONDO:0013734 uuid:ded5ffe8-15d5-4819-baeb-aa8f18d2286d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231425 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0012833 infores:hetionet CHEBI:3441 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002064 infores:hetionet CHEBI:10127 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151786 infores:hetionet NCBIGene:55145 biolink:causes MONDO:0011264 infores:monarchinitiative not_provided not_provided HGNC:20856 MONDO:0011264 uuid:84f8d5e9-c492-4562-9ea6-32a7ee4672e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0009938 infores:hetionet CHEBI:3216 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C3263723 infores:hetionet CHEBI:91541 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0020649 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013238 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001158 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1704373 infores:hetionet CHEBI:4877 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0011603 infores:hetionet NCBITaxon:5550 biolink:causes UMLS:C0040250 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5550 MESH:D014006 DB00857_MESH_D014006_1DB00525_MESH_D014006_1 CHEBI:8890 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020461 infores:hetionet CHEBI:45327 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0085631 infores:hetionet CAID:CA349036290 biolink:causes MONDO:0100038 infores:clingen CAID:CA349036290 MONDO:0100038 PMID:37578743 Uncertain Significance PP3_Moderate, PM2_Supporting, PS3_Moderate PS1, PM1, PM5 Thec.4614G>T (NM_001040142.2) variant in SCN2A is a missense variant predicted to cause substitution of Methionine by Isoleucine at amino acid 1538 (p.(Met1538Ile)). This variant is absent from population databases (gnomAD v4.1) (PM2_supporting). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3 (PP3_moderate). Functional studies of patch clamping experiments in HEK293T cells, showed that the variant has a depolirized shifted of voltage-dependence of inactivation by 3.1 mV (absolute value) indicating that this variant impacts protein function (PMID: 37578743) (PS3_moderate). In summary, this variant has been classified as variant of uncertain significance on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel Expert Panel: PS3_moderate, PP3_moderate, PM2_supporting (Version 2.0; approved 4/22/25). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349036290/MONDO:0100038/068 2025-04-22 2025-10-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28001 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0011609 infores:hetionet CHEBI:8888 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151836 infores:hetionet CHEBI:50859 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085649 infores:hetionet CAID:CA177671 biolink:causes MONDO:0018997 infores:clingen CAID:CA177671 MONDO:0018997 PMID:11992261PMID:22315187PMID:17020470PMID:23584145PMID:18372317PMID:15987685 Pathogenic PS4, PS3, PS2_Very Strong, PM2, PP2, PP3 The c.417G>C (p.Glu139Asp) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients and at least 5 other independent occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PS4; GeneDx, Baylor, BC Children's internal data; SCV000057396.11, SCV000196664.1, SCV000803709.1; GTR Lab ID: 26957, 1006, 249401 PMID: 22315187, 17020470, 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Glu139Asp variant may impact protein function (PS3; PMID: 23584145, 15987685, 18372317). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the c.417G>C (p.Glu139Asp) variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA177671/MONDO:0018997/004 2017-04-03 2024-08-23 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:28241 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0015230 infores:hetionet NCBIGene:55719 biolink:causes MONDO:0859575 infores:monarchinitiative not_provided not_provided HGNC:17814 MONDO:0859575 uuid:7b821561-c748-4460-9716-8ba6a3411b96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028738 infores:hetionet CHEBI:72690 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0151313 infores:hetionet CHEBI:52172 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151905 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0041969 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042373 infores:hetionet CAID:CA489232958 biolink:causes MONDO:0007113 infores:clingen CAID:CA489232958 MONDO:0007113 PMID: Likely Benign BP4, BP7 BS1 The c.729C>T p.Asn243= variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.003% in the Latino/Admixed American sub population (no criteria met). The silent p.Asn243= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.729C>T p.Asn243= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA489232958/MONDO:0007113/032 2023-06-16 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:71940 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0035078 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235030 infores:hetionet GO:2000870 biolink:causes GO:0042698 infores:ubergraph knowledge_assertion manual_agent GO:2000870 GO:0042698 CHEBI:8435 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0236071 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0020615 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0020456 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0235431 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0010200 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0030920 infores:hetionet CHEBI:134991 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0009806 infores:hetionet GO:0044472 biolink:causes GO:0070588 infores:ubergraph knowledge_assertion manual_agent GO:0044472 GO:0070588 CHEBI:3242 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0011570 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0234913 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0086543 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037199 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0521839 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0855242 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009938 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0149931 infores:hetionet CHEBI:63598 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0542571 infores:hetionet CHEBI:9599 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0151539 infores:hetionet CHEBI:3732 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085612 infores:hetionet CAID:CA10580068 biolink:causes MONDO:0100488 infores:clingen CAID:CA10580068 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.76G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Glu by Gln at amino acid 26 (p.Glu26Gln) in exon 2. This allele is absent from populations in gnomAD V2.1.1 (PM2_Supporting). This variant has been observed in at least three individuals without DGC, SRC tumours and LBC and whose families do not suggest HDGC (BS2_Supporting). This variant was reported in one individual with diffuse gastric cancer at 70 years without a family history of gastric cancer (PMID: 32241597). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580068/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:9445 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0162830 infores:hetionet CHEBI:135451 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0042963 infores:hetionet CHEBI:16469 biolink:causes MONDO:0000751 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007855 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006541 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014527 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0006840 infores:hetionet CHEBI:3752 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0039070 infores:hetionet CAID:CA409105512 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105512 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PS4_Moderate, PP1_Strong The c.352C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 118 (p.(Arg118Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; ClinVar ID:1457657, internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; internal lab contributor). This variant also segregated with diabetes, with four informative meioses in two families (PP1_Strong; internal lab contributors). In summary, c.352C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PVS1, PP1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105512/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4903 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0151998 infores:hetionet CAID:CA229702 biolink:causes MONDO:0009861 infores:clingen CAID:CA229702 MONDO:0009861 PMID:11139255 Likely Benign BP4, BS1 PP4 The c.706+17G>T variant in PAH has been reported in the mother of a patient with PKU (not found in the patient). PMID: 11139255. The MAF for this variant is 0.00269, greater than expected. Multiple splicing predictors suggest no impact (HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. MaxEnt: +15.3 % variation). In summary, this variant meets criteria to be classified as likely benign: BS1, BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229702/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:145499 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0026603 infores:hetionet CHEBI:7573 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0020456 infores:hetionet CAID:CA10604913 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604913 MONDO:0015152 PMID: Pathogenic PM3, PP1_Strong, PVS1, PP4, PM2_Supporting The NM_003494.4: c.3031+2T>C variant in DYSF, which is also known as NM_001130987.2: c.3085+2T>C, occurs within the canonical splice donor site (+/- 1,2) of intron 28. SpliceAI gives a delta score of 0.92 for loss of the canonical donor. RNAseq analysis has demonstrated that this variant causes skipping of exon 28, resulting in a frameshift and premature truncation, p.Asn976AlafsTer46 (PMID: 36983702; PVS1_RNA). This variant has been reported in at least six patients with clinical features consistent with LGMD, including in a homozygous state (0.5 pts) and confirmed in trans with a pathogenic variant (NM_003494.4: c.855+1del, 1.0 pt) (PMID: 26444858, 36983702, 18853459; PM3). At least one individual with this variant and a second DYSF variant had a clinical phenotype considered consistent with LGMD (PMID: 18853459; PP4). In addition, this variant has been shown to co-segregate with autosomal recessive LGMD in at least four family members from three families (PMID: 26444858, 18853459; PP1_Strong). Haplotype analysis of three seemingly unrelated families from Central Switzerland confirmed a founder effect of this variant in that region. The highest population allele frequency of this variant is in gnomAD v4.1.0 is 8.476e-7 (1/1179858 European (non-Finnish) alleles), which is less than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_RNA, PM3, PP4, PP1_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604913/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50131 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0038160 infores:hetionet CHEBI:52717 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2363731 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0232492 infores:hetionet CHEBI:3814 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0042963 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0860210 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011991 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0595877 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0314719 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0031542 infores:hetionet CHEBI:8364 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0043352 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0003864 infores:hetionet UMLS:C0010592 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0221512 infores:hetionet CHEBI:39867 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151747 infores:hetionet CAID:CA143621 biolink:causes MONDO:0019501 infores:clingen CAID:CA143621 MONDO:0019501 PMID: Likely Benign BS1_Supporting, BP4 PP3 The filtering allele frequency of the p.Ala2774Thr variant in the USH2A gene is 0.07463% (931/1179918) of European (non-Finnish) chromosomes in gnomAD v4 (BS1_Supporting). The computational prediction analysis tool REVEL predicted a score of 0.052, which meets the threshold to apply BP4. In summary, this variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1_Supporting, BP4. (ClinGen Hearing Loss VCEP specifications version 2; 03/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143621/MONDO:0019501/005 2025-03-12 2025-03-28 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true NCBIGene:4000 biolink:causes MONDO:0013178 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0013178 uuid:74724a26-1128-4816-a0b2-c473e22f0063 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91583 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C1443060 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0240773 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0240773 infores:hetionet NCBIGene:10056 biolink:causes MONDO:0100215 infores:monarchinitiative not_provided not_provided HGNC:17800 MONDO:0100215 uuid:f33aa4ce-8adc-4d93-b66b-94b674dc75f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151773 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0011974 infores:hetionet CHEBI:6950 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002874 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0031117 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020621 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0031117 infores:hetionet CHEBI:63611 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151632 infores:hetionet CHEBI:2567 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0027497 infores:hetionet CHEBI:8888 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0023380 infores:hetionet CHEBI:82960 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0029453 infores:hetionet CHEBI:63627 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0038325 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0039971 infores:hetionet NCBIGene:285848 biolink:causes MONDO:0014011 infores:monarchinitiative not_provided not_provided HGNC:21246 MONDO:0014011 uuid:e485635e-5769-41d8-b7d1-fd7df7557cd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68579 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0020517 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0035078 infores:hetionet CHEBI:404903 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0744727 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0042109 infores:hetionet CHEBI:51364 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0156404 infores:hetionet CHEBI:499361 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0026858 infores:hetionet CHEBI:2668 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C3665386 infores:hetionet CHEBI:3723 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232462 infores:hetionet CHEBI:5001 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C3263723 infores:hetionet CHEBI:8707 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085631 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0015469 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0039971 infores:hetionet CHEBI:72564 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1384353 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0014868 infores:hetionet CHEBI:28971 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0011991 infores:hetionet CHEBI:114785 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0027697 infores:hetionet CHEBI:6375 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151539 infores:hetionet CHEBI:50648 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151907 infores:hetionet CHEBI:131512 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0016382 infores:hetionet UMLS:C0145185 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0852810 infores:hetionet NCBITaxon:2 biolink:causes UMLS:C0264515 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D000071067 DB01053_MESH_D000071067_1 CHEBI:144551 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0020620 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018418 infores:hetionet CHEBI:2676 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0013378 infores:hetionet CHEBI:15544 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151699 infores:hetionet CHEBI:31932 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0004604 infores:hetionet CAID:CA16619904 biolink:causes MONDO:0007113 infores:clingen CAID:CA16619904 MONDO:0007113 PMID: Likely Pathogenic PVS1_Strong, PP1, PM2_Supporting The c.2065-1G>A variant in UBE3A is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. However, this splice site variant may result in an in-frame loss of the corresponding exon in which pathogenic variants have been observed in affected individuals (PVS1_Strong). The c.2065-1G>A variant in UBE3A is absent from gnomAD (PM2_Supporting). The variant has been reported to segregate in two informative meioses (internal database) (PP1). In summary, the c.2065-1G>A variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1_strong, PM2_supporting, PP1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619904/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:8871 biolink:causes UMLS:C1696700 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1696700 infores:hetionet CAID:CA308104435 biolink:causes MONDO:0007783 infores:clingen CAID:CA308104435 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of histidine with tyrosine at codon 2253 of the RYR1 protein, p.His2253Tyr. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two individuals with a personal or family history of an MH episode, one of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:21965348, PMID:29028638). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.973) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308104435/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3732 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004096 infores:hetionet CHEBI:8327 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0042963 infores:hetionet CHEBI:45081 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0344232 infores:hetionet CAID:CA177354 biolink:causes MONDO:0019497 infores:clingen CAID:CA177354 MONDO:0019497 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PM2, PVS1, PM6, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.2836C>T(NM_004999.4) variant in MYO6 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 946 (p.Arg946Cys).​ The filtering allele frequency of the c.2836C>T variant in the MYO6 gene is 0.12% for South Asian chromosomes by the Genome Aggregation Database v4 (94/63976 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). (ClinGen Hearing Loss VCEP specifications version 2; 12.18.2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA177354/MONDO:0019497/005 2024-12-18 2025-03-28 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:5118 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1306341 infores:hetionet CHEBI:78543 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151908 infores:hetionet CHEBI:7915 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0016204 infores:hetionet CHEBI:37924 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018524 infores:hetionet CHEBI:63611 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0404521 infores:hetionet CHEBI:16347 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0004093 infores:hetionet CAID:CA412351039 biolink:causes MONDO:0100039 infores:clingen CAID:CA412351039 MONDO:0100039 PMID: Likely Pathogenic PM6, PM5, PP3, PM2_Supporting The p.Cys152Arg variant in CDKL5 occurs in the de novo state (biological parentage unconfirmed) in an individual (GeneDx Internal Database) (PM6). The p.Cys152Arg variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). A pathogenic missense variant (p.Cys152Phe) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 15499549; 23651931) (PM5). In summary, the p.Cys152Arg variant in CDKL5 is classified as likely pathogenic for CDKL5-related disorders based on the ACMG/AMP criteria (PM6, PM2_supporting, PP3, PM5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412351039/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Supports CAID:CA512318659 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318659 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.672G>T (p.Arg224=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.16)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318659/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101853 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0853777 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0023895 infores:hetionet CHEBI:9570 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0022346 infores:hetionet CHEBI:49603 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0020433 infores:hetionet CHEBI:2611 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085636 infores:hetionet CHEBI:4672 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0030252 infores:hetionet CHEBI:6129 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0917801 infores:hetionet CHEBI:2379 biolink:causes UMLS:C3665609 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C3665609 infores:hetionet CHEBI:4710 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0349790 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0041912 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0349506 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0456909 infores:hetionet CHEBI:194135 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0019521 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0011630 infores:hetionet CHEBI:3215 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0023066 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0919892 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0919892 infores:hetionet CHEBI:46195 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0015672 infores:hetionet NCBIGene:64207 biolink:causes MONDO:0060759 infores:monarchinitiative not_provided not_provided HGNC:14282 MONDO:0060759 uuid:94ce10f5-910d-4177-acd8-f82739d1d994 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes NCIT:C26921 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085594 infores:hetionet NCBIGene:9241 biolink:causes MONDO:0008484 infores:monarchinitiative not_provided not_provided HGNC:7866 MONDO:0008484 uuid:0f7cdbf5-1869-49a5-b8d0-60e0e4be1f51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0851341 infores:hetionet CHEBI:51164 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0011175 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0019054 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0020517 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013595 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027441 infores:hetionet NCBIGene:2488 biolink:causes MONDO:0009239 infores:monarchinitiative not_provided not_provided HGNC:3964 MONDO:0009239 uuid:19f876c1-54b6-44c8-b366-330723192cfb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9430ZR8ZAN biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0232462 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0242350 infores:hetionet CHEBI:50648 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036974 infores:hetionet CHEBI:47381 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151827 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0574067 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0333516 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0333516 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002965 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0009450 infores:hetionet CHEBI:64321 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0014742 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0233472 infores:hetionet CHEBI:46081 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C1443060 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235874 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0034155 infores:hetionet CHEBI:5864 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002962 infores:hetionet CHEBI:8888 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030196 infores:hetionet CHEBI:9435 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0020625 infores:hetionet CHEBI:18332 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0948089 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0019087 infores:hetionet CHEBI:84050 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0015967 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0434437 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0037199 infores:hetionet CHEBI:180905 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0041657 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036508 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0518015 infores:hetionet CHEBI:2549 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0039070 infores:hetionet UMLS:C0004599 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0001925 infores:hetionet CHEBI:51041 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0497156 infores:hetionet CHEBI:49575 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0037036 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0030319 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1258215 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0032584 infores:hetionet CHEBI:50922 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003467 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0343886 infores:hetionet CHEBI:74947 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0149871 infores:hetionet CHEBI:3723 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0424295 infores:hetionet CHEBI:5138 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019270 infores:hetionet CHEBI:135451 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0546817 infores:hetionet CAID:CA343726245 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726245 MONDO:0020367 PMID:35196929 Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS2_Moderate BP7, BS1, BS3, PM6, PP1, PM5, PM4, PS1, PS4, BA1, BP4 The c.761C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 254 (p.Pro254Leu).This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.925, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 35196929) demonstrated that the Pro254Leu protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. A confirmed de novo proband with juvenile open angle glaucoma was identified (PMID: 27080696), meeting PS2_Moderate. However, as this was the only proband identified, the ≥ 2 probands threshold required to meet PS4_Supporting was not met. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS2_Moderate, PS3_Moderate, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726245/MONDO:0020367/019 2022-03-06 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037763 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0687713 infores:hetionet CHEBI:8802 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020458 infores:hetionet CHEBI:5130 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151746 infores:hetionet CAID:CA2497030226 biolink:causes MONDO:0009861 infores:clingen CAID:CA2497030226 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 PM3 The c.280_283del (p.Ile94SerfsTer4) variant in PAH is a frameshift variant predicted to cause termination at amino acid 98 resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in a patient with classic PKU with likely pathogenic variant p.P281L, phase unconfirmed (PMID: 26210745). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP4, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497030226/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135876 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0426390 infores:hetionet CHEBI:52172 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0687713 infores:hetionet CHEBI:68575 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0231528 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0037822 infores:hetionet CHEBI:8356 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026826 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0235431 infores:hetionet CHEBI:17650 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0021368 infores:hetionet CHEBI:28593 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0876994 infores:hetionet CAID:CA214266 biolink:causes MONDO:0015967 infores:clingen CAID:CA214266 MONDO:0015967 PMID:18811724PMID:18811724 Uncertain Significance PP3, PP4, BS2 BA1, PS4, BS1, PM2 The c.1424C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 475 (p.(Pro475Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.751, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs: 18811724, 23674172, internal lab contributors). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2: internal lab contributors). The frequency of the c.1424C>T variant in gnomAD v2.1.1 falls between the ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.1424C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PP4, BS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214266/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144093 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0032285 infores:hetionet UNII:R43D2573WO biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0037383 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0003864 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085129 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0151849 infores:hetionet CHEBI:47381 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0344232 infores:hetionet CHEBI:36795 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0041657 infores:hetionet CAID:CA404071849 biolink:causes MONDO:0007750 infores:clingen CAID:CA404071849 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP4, PP1 The NM_000527.4(LDLR):c.59G>A (p.Gly20Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.BP4 - REVEL = 0.257. it below 0.50, splicing evaluation required.Functional data on splicing not available.A) not on limitsB) variant is exonic but it does not create GTVariant is predicted to not alter splicing, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404071849/MONDO:0007750/013 2021-12-14 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:499361 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0428977 infores:hetionet CHEBI:135351 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0018681 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0595939 infores:hetionet CHEBI:9566 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0011071 infores:hetionet CHEBI:16347 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0085649 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0028259 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0006852 infores:hetionet CHEBI:8713 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0016204 infores:hetionet CHEBI:17303 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151825 infores:hetionet CAID:CA16022245 biolink:causes MONDO:0021056 infores:clingen CAID:CA16022245 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong BS2 The NM_000038.6(APC):c.422G>A (p.Arg141Lys) variant in APC is a G to non-G change at the last nucleotide of exon 4. It is predicted to cause skipping of exon 4, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (List B; PVS1_Strong). However, exon skipping could not be confirmed by RTPCRSeq data. Even though this could be based on technical limitations, the variant allele was present in 35% of normally spliced reads, so the splicing impact seems to be low (internal data Ambry Genetics). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236810 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). The variant has been reported in three individuals without a colorectal cancer/polyposis associated phenotype (one person fulfills 0.5 points as a “healthy individual,” for the other two not enough information is available; BS2 not met; internal data Ambry Genetics). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1_Strong and PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16022245/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75998 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0004093 infores:hetionet CHEBI:2955 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0438717 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0435002 infores:hetionet CHEBI:78543 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0085649 infores:hetionet CHEBI:45367 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0014457 infores:hetionet CHEBI:75045 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020458 infores:hetionet CHEBI:5383 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0003811 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0009450 infores:hetionet CHEBI:72564 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0000731 infores:hetionet CHEBI:2208 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0026636 infores:hetionet CHEBI:7514 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0009421 infores:hetionet CHEBI:8871 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033774 infores:hetionet CAID:CA380145206 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145206 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.25A>G is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 9 (p.Ser9Gly).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.00003333 (2/60006) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP:PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145206/MONDO:0000573/124 2024-05-07 2024-05-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:72564 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0521839 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0037199 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003123 infores:hetionet CHEBI:63617 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0007859 infores:hetionet CHEBI:6741 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0236075 infores:hetionet CHEBI:45951 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0340865 infores:hetionet CHEBI:4798 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0017672 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0456909 infores:hetionet CHEBI:209807 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0151773 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0233414 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0042109 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0233632 infores:hetionet CHEBI:3219 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038435 infores:hetionet CHEBI:584020 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0151632 infores:hetionet CHEBI:140621 biolink:causes UMLS:C0849916 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0849916 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017601 infores:hetionet CHEBI:9907 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018681 infores:hetionet CHEBI:4784 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0234708 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0700184 infores:hetionet CHEBI:49575 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0392676 infores:hetionet CHEBI:3228 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C2830004 infores:hetionet CAID:CA10014187 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014187 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1301A>G (p.Asn434Ser) is a missense variant which has a REVEL score < 0.50 (0.154) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014187/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA409106718 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106718 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 The c.583-1G>A variant in the hepatocyte nuclear factor4-alpha gene, HNF4A, is predicted to remove a canonical splice acceptor site in intron 5 of NM_175914.5. This variant is predicted to cause skipping of biologically-relevant exon 6 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). In summary, c.583-1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106718/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3077 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0017601 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0011570 infores:hetionet CHEBI:194135 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085631 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003811 infores:hetionet CHEBI:47381 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014236 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0314719 infores:hetionet CHEBI:171719 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0031256 infores:hetionet CHEBI:78320 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0237849 infores:hetionet CHEBI:32293 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0016382 infores:hetionet CHEBI:171719 biolink:causes MONDO:0013361 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C3203356 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0025061 infores:hetionet CHEBI:4798 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0018965 infores:hetionet NCBIGene:1475 biolink:causes MONDO:0011937 infores:monarchinitiative not_provided not_provided HGNC:2481 MONDO:0011937 uuid:d49fd123-71a7-4111-85b0-c9cc4a7c174f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C1145670 infores:hetionet CHEBI:4562 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0015967 infores:hetionet CAID:CA120627 biolink:causes MONDO:0044970 infores:clingen CAID:CA120627 MONDO:0044970 PMID:35715829 Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4, PP1_Moderate The m.14487T>C (p.M63V) variant in MT-ND6 has been reported in at least 37 unrelated individuals with primary mitochondrial disease (PS4; PMIDs: 30741831, 33706792, 34223155, 32162843, 30461153, 30128709, 30095618, 28122886, 28429146, 27338358, 26530508, 23813926, 23463613, 24126373, 23847141, 23010433, 21364701, 21196529, 19062322, 18977334, 17535832, 16044424, 15625630, 15576045, 14595656, 14520668, 14684687, 20019223). Features seen in affected individuals include Leigh syndrome spectrum and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as ataxia, dystonia, epilepsy, optic neuropathy, and ptosis. Heteroplasmy levels were variable in affected individuals as was age of onset (infancy to adulthood). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 14684687,17535832, 20019223, 24126373, 26530508, 28122886). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120627/MONDO:0044970/015 2022-08-08 2023-03-29 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:66903 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0030193 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0041912 infores:hetionet CHEBI:3696 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C1167965 infores:hetionet CHEBI:79699 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0038362 infores:hetionet CHEBI:3048 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0013428 infores:hetionet CAID:CA181309 biolink:causes MONDO:0021060 infores:clingen CAID:CA181309 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.69C>T (p.Thr23=) variant in the MAP2K1 gene is 0.0484% (4/2820) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA181309/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3219 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0034880 infores:hetionet CHEBI:27777 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0011603 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0015726 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0015726 infores:hetionet CHEBI:6062 biolink:causes MONDO:0043310 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0149793 infores:hetionet CHEBI:37333 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0030193 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151585 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151585 infores:hetionet CAID:CA229605 biolink:causes MONDO:0009861 infores:clingen CAID:CA229605 MONDO:0009861 PMID:8659548 Uncertain Significance PM2, PP4, PP3, PM3_Supporting The c.523C>G (p.Pro175Ala) variant in PAH has been reported in a US patient with MHP (PMID: 8659548). It was detected with pathogenic variant p.A104D. This variant is absent from population databases. A deleterious effect is predicted in multiple in silico models. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229605/MONDO:0009861/006 2020-01-30 2020-01-31 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:83804 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011991 infores:hetionet CHEBI:4856 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0520887 infores:hetionet CHEBI:5130 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013491 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0021053 infores:hetionet CHEBI:38940 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0000731 infores:hetionet CHEBI:51041 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0037036 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0235416 infores:hetionet CHEBI:135005 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0011206 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0403632 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151828 infores:hetionet CHEBI:9570 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0162834 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0521839 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023530 infores:hetionet CHEBI:6887 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0030252 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0853149 infores:hetionet CHEBI:9139 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0149725 infores:hetionet CHEBI:4910 biolink:causes HP:0002781 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0740852 infores:hetionet CHEBI:8028 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0340865 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0340464 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0004795 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D010032 DB00994_MESH_D010032_1DB00537_MESH_D010032_1DB00446_MESH_D010032_1DB01059_MESH_D010032_1 CHEBI:119573 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0042109 infores:hetionet NCBIGene:1182 biolink:causes MONDO:0859187 infores:monarchinitiative not_provided not_provided HGNC:2021 MONDO:0859187 uuid:25f0198f-827d-4f4d-8ff2-8b484edd7293 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2173677 infores:hetionet CHEBI:66913 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0015397 infores:hetionet CHEBI:8802 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0006266 infores:hetionet CAID:CA16020859 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020859 MONDO:0009861 PMID:26322415 Pathogenic PM3, PM2, PP4_Moderate, PVS1 The PAH variant c.795C>A (p.Cys265*) is a null variant (stop gain) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD.The PAH variant NM_001354304.2:c.795C>A (p.Cys265Ter) was detected in a Chinese patient with mild PKU (mPKU, Phe levels 10–20 mg/dl). The patient was a compound heterozygote with the pathogenic variant NM_000277.3(PAH):c.782G>A (p.Arg261Gln) (ClinVar ID: 582). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. All mutations identified in patients were confirmed by analyzing parental DNA. (PMID: 26322415)According to gnomAD, the PAH variant c.795C>A (p.Cys265Ter) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.000008798). This variant is absent from the ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PVS1, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020859/MONDO:0009861/006 2020-05-09 2020-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44915 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0948525 infores:hetionet CHEBI:63598 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0026826 infores:hetionet CHEBI:63632 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C1384606 infores:hetionet CHEBI:585948 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0038999 infores:hetionet CHEBI:47898 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014457 infores:hetionet CHEBI:180905 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0015230 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0235146 infores:hetionet CHEBI:45081 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0085595 infores:hetionet CHEBI:7627 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0149871 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018801 infores:hetionet CHEBI:17076 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0011603 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0235969 infores:hetionet CHEBI:32184 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0085649 infores:hetionet CHEBI:6715 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0231218 infores:hetionet CHEBI:48273 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0027441 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0232459 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0595883 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0040264 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0033975 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0010399 infores:hetionet CHEBI:63577 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0043144 infores:hetionet CHEBI:28918 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0012833 infores:hetionet CHEBI:4975 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0004245 infores:hetionet CHEBI:4798 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C3665347 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020517 infores:hetionet CHEBI:16347 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0035455 infores:hetionet CHEBI:61049 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151908 infores:hetionet CHEBI:119486 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0010200 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0004096 infores:hetionet CHEBI:8772 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0151904 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0012833 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151735 infores:hetionet CHEBI:2687 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0027540 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0013395 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0015397 infores:hetionet CHEBI:9586 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0031256 infores:hetionet CHEBI:31536 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C1608945 infores:hetionet CHEBI:3647 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0018790 infores:hetionet CHEBI:41879 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0041657 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003123 infores:hetionet CHEBI:9352 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0039070 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0002170 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0687133 infores:hetionet CHEBI:10119 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0017565 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0281825 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0281825 infores:hetionet CHEBI:39112 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0030193 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0497201 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0041969 infores:hetionet CHEBI:70746 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0011603 infores:hetionet CHEBI:100241 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0234369 infores:hetionet CHEBI:63630 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003467 infores:hetionet NCBITaxon:550 biolink:causes UMLS:C1112209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:550 MESH:D059413 DB09060_MESH_D059413_3DB00303_MESH_D059413_1 CHEBI:8107 biolink:causes MONDO:0000723 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0038506 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0043251 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0005940 infores:hetionet CHEBI:2668 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0011168 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0205204 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0021400 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0332575 infores:hetionet CHEBI:50861 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0232487 infores:hetionet CHEBI:3723 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0302809 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0042373 infores:hetionet CHEBI:8060 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0853034 infores:hetionet CHEBI:32315 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C1504494 infores:hetionet CHEBI:77260 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042847 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013395 infores:hetionet CHEBI:3387 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1291078 infores:hetionet CHEBI:109549 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0948594 infores:hetionet CHEBI:47780 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0232461 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0243026 infores:hetionet CAID:CA298357 biolink:causes MONDO:0700270 infores:clingen CAID:CA298357 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP3 PS3 The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (T (p.Arg771Ter) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The Filtering allele frequency (the upper threshold of the 95% confidence of 16/1111980) is 0.00001439 for European (non-Finnish) chromosomes by gnomeAD v 4.0.0, which is lower than the ClinGen SCID JAK3 VCEP threshold [(<0,000115)] for PM2_Supporting, and therefore meets this criterion (PM2_Supporting)At least one patient with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and *T-B+NK- lymphocyte subset profile (0.5pt), totalizing 1 points, which is highly specific for SCID (PP4) (PMID: 32445296). In addition, this variant has been detected in at least two individuals with SCID, in the homozygous state (PMID: 11668610, 32445296) (total points= 1.0 pt) (PM3). One additional patient was found on Clinvar; however, the affected status is unknown (VCV001459771.4)In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PP4, PM2_supporting and PM3. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA404767321/MONDO:0010938/121 2024-02-21 2024-02-21 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:8754 biolink:causes MONDO:0013002 infores:monarchinitiative not_provided not_provided HGNC:216 MONDO:0013002 uuid:ecd71751-1e34-4fe7-a278-94fccf535abe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16586 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0030193 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0178298 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0178298 infores:hetionet CHEBI:7573 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151908 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0009450 infores:hetionet NCBIGene:8675 biolink:causes MONDO:0011301 infores:monarchinitiative not_provided not_provided HGNC:11431 MONDO:0011301 uuid:f7e6ee2f-a57a-4690-8f75-ae7bdef651c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2588 biolink:causes MONDO:0009659 infores:monarchinitiative not_provided not_provided HGNC:4122 MONDO:0009659 uuid:a3193c37-9595-4ce6-adfa-610a6162380e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA016295 biolink:causes MONDO:0005021 infores:clingen CAID:CA016295 MONDO:0005021 PMID:19412328 Uncertain Significance PM2, PP3, PS4_Moderate PM5, PM1, PM6, PP1, BA1, PS3, PP2, BS1, BS4, BS3, PS1, PS2, BP4 The c.5588G>A (p.Arg1863Gln) variant in MYH7 has been identified in 1 individual with familial DCM (Hershberger 2008 PMID:19412328) and 7 individuals with DCM from clinical testing laboratories (PS4_Moderate; PMID:19412328; Partners LMM ClinVar SCV000059623.5; Invitae ClinVar SCV000818269.1, pers. comm.; Ambry pers. comm.; CHEO ClinVar SCV000901909.1, pers. comm.; GeneDx ClinVar SCV000208646.4, pers. comm.). This variant was also identified in 0.00027% (FAF 95% CI; 2/129158) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016295/MONDO:0005021/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA198797 biolink:causes MONDO:0009290 infores:clingen CAID:CA198797 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM5, PM3, PM2_Supporting PS3 "The NM_000152.5:c.2237G>C variant in GAA is a missense variant predicted to result in the substitution of tryptophan by serine at amino acid 746 (p.Trp746Ser). This variant has been reported in at least 11 patients with late onset Pompe disease (LOPD) (PMID: 18425781, 22081099, 24169249, 28490439, 33344388, 34020684), with two having GAA enzyme activity <10% in muscle (PMID: 22081099) (PP4_Moderate). One Chinese patient with LOPD was compound heterozygous for the variant and a nonsense pathogenic variant c.2237G>A (p.Trp746*) at the same nucleotide; however, this patient has a third variant c.503G>A (p.Arg168Gln) with no phase information (PMID: 24169249), so it's not used for PM3 point counting. Another Chinese patient was compound heterozygous for the variant (maternally inherited) and a pathogenic variant c.1935C>A (p.Asp645Glu) (paternally inherited) (PMID: 33344388); and it's not used for PM3 point counting due to the complex phenotype and the lack other evidence supporting the diagnosis of LOPD. A third Chinese individual heterozygous for the variant, a pathogenic variant c.2662G>T (p.Glu888*), and a third variant c.2647-7G>A was detected by genome sequencing as newborn screening; and it's not used for PM3 point counting due to the lack of phenotype information. Six Italian patients (PMID: 22081099) and one Spanish patient (PMID: 34020684) with LOPD were heterozygous for the variant and c.-32-13T>G pathogenic variant with no phase information (1 point, max for homozygous patients) (PM3). Expression of the variant in COS or HEK293 cells resulted in 2% residual GAA activity in medium and 0.1% normal activity in cells and evidence of abnormal GAA synthesis and processing, leading to a Class B (""potentially less severe"") classification (PMID: 22644586). However, another in vitro study reported the variant as a ""relatively mild mutation"" but also class E ""probably non-pathogenic"" (PMID: 23430493). Functional criteria is not applied due to inconsistent functional classification. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001733 (13/75034) in the African/African American population which is lower than the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP) threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A different missense variant c.2238G>C (p.Trp746Cys) on the same amino acid has been classified as pathogenic by the LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 188484; 2 star review status) with 7 submitters classifying the variant as pathogenic and 5 as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP - Dec. 17, 2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA198797/MONDO:0009290/010 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0085681 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0442874 infores:hetionet CHEBI:50673 biolink:causes MONDO:0018465 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0854359 infores:hetionet CHEBI:52717 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042024 infores:hetionet CHEBI:15854 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0015967 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0852733 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010297 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010297 uuid:da6dd087-1762-4ee5-aa31-2d8d93d0f765 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0239134 infores:hetionet CAID:CA252010 biolink:causes MONDO:0007064 infores:clingen CAID:CA252010 MONDO:0007064 PMID: Likely Pathogenic PM3_Supporting, PVS1_Strong, PM2_Supporting PP4, PS3 The NM_000022.4:c.219-2A>G variant in ADA occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4, resulting in an in-frame deletion (removes amino acids 74-121), and the prediction is confirmed by RT-PCR (PMID 3182793). The variant removes >10% of the protein (48/363 amino acids) and the truncated region is critical to protein function (PMID 3182793) (PVS1_Strong). The variant has been detected in 1 individual with SCID who was homozygous for this variant (PMID 28266921) (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Strong, PM3_Supporting, PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA252010/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007859 infores:hetionet CHEBI:9448 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C1384353 infores:hetionet CAID:CA410202469 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202469 MONDO:0011071 PMID: Likely Pathogenic PM2, PM1, PS4_Supporting, PP3, PP1 PS3, PS1, BA1, BP4, BP2, PM6, PVS1, BS1, BS4, BS3, BP7, PM4, PM5 The NM_001754.4:c.506G>T (p.Arg169Ile) variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in one family (PP1; from internal laboratory data). This missense variant has a REVEL score >0.75 (0.939) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; from internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2, PP1, PP3, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202469/MONDO:0011071/008 2020-01-14 2020-01-14 Autosomal dominant inheritance HP:0000006 Supports CAID:CA229594 biolink:causes MONDO:0009861 infores:clingen CAID:CA229594 MONDO:0009861 PMID: Benign BA1, BP7 The c.510-54G>A variant in PAH has a MAF of 0.4069 in the gnomAD European (Finnish) population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229594/MONDO:0009861/006 2020-03-27 2020-03-27 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:474180 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0042373 infores:hetionet CAID:CA343724796 biolink:causes MONDO:0005338 infores:clingen CAID:CA343724796 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS4, PS1, PS2, BA1, BP4 The c.1079T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 360 (p.Ile360Asn). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00002229 (1 allele out of 44,856), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.635, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The assay in this study (PMID: 14688426), measuring secretion of the Ile360Asn protein, did not meet the OddsPath threshold for PS3_Supporting (> 2.1). Only 1 proband with primary open angle glaucoma had been reported (PMID: 10980537), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724796/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9927 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0041969 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0020456 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0004096 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0235863 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235863 infores:hetionet CHEBI:17688 biolink:causes MONDO:0008575 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0028043 infores:hetionet CHEBI:9139 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0010200 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0025061 infores:hetionet NCBIGene:1786 biolink:causes MONDO:0011397 infores:monarchinitiative not_provided not_provided HGNC:2976 MONDO:0011397 uuid:c7f62164-c32f-4798-8833-942bb3495ed3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9352 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0151872 infores:hetionet CHEBI:7823 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0001824 infores:hetionet CHEBI:70735 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0017178 infores:hetionet CHEBI:132233 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0040822 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0042401 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0854382 infores:hetionet NCBIGene:4927 biolink:causes MONDO:0100104 infores:monarchinitiative not_provided not_provided HGNC:8067 MONDO:0100104 uuid:5c98b3f2-2c00-457b-9a08-32e32d2e61be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003811 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0038363 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0518015 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020550 infores:hetionet CHEBI:18248 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020621 infores:hetionet CHEBI:32293 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0022904 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0948089 infores:hetionet CHEBI:7824 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014457 infores:hetionet CHEBI:59560 biolink:causes MONDO:0016543 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0751436 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011615 infores:hetionet CHEBI:5893 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085932 infores:hetionet CHEBI:40279 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002792 infores:hetionet CHEBI:8665 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0687713 infores:hetionet CAID:CA397723203 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723203 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 The NM_000018.4 c.578G>A (p.Gly193Asp) in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 193 (p. Gly193Asp). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000004 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723203/MONDO:0008723/021 2024-03-26 2024-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:64312 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027092 infores:hetionet CHEBI:7575 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0022346 infores:hetionet CHEBI:6472 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0014356 infores:hetionet NCBIGene:445 biolink:causes MONDO:0008988 infores:monarchinitiative not_provided not_provided HGNC:758 MONDO:0008988 uuid:6d1373c7-d3eb-41d4-b2b0-0375be1ff723 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0393761 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020649 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0700184 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0175167 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0029124 infores:hetionet CAID:CA16020902 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020902 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Supporting The NM_000277.3:c.935G>T (p.Gly312Val) is a missense variant in exon 9/13 of PAH. The variant was found to reduce PAH enzymatic activity to 6-7% of wild-type enzyme activity in transfected cells (PMID: 18590700) (PS3_supporting). The variant has been noted in at least six PKU patients with BH4 deficiency excluded (PP4_Moderate), five of whom harbored it in confirmed trans with a Pathogenic or Likely Pathogenic variant (5 points; PM3_VeryStrong). The variant has been reported as a single heterozygous variant in a Chinese patient with mild PKU; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes and by sequencing of genes in the BH4 cofactor metabolism pathway (PMID: 14722928). It has also been found in confirmed trans with c.913-7A>G (Likely Pathogenic per ClinGen PAH VCEP) in a Chinese patient with classic PKU (plasma Phe ≥ 1200 μmol/L); BH4 deficiency was said to be ruled out (PMID: 24401910). It was found in four Chinese PKU patients (BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes and by sequencing of genes in the BH4 cofactor metabolism pathway) in the following cases: two patients with mild hyperphenylalanemia in confirmed trans with the p.R241C variant (Pathogenic per ClinGen PAH VCEP); one patient with classic PKU in confirmed trans with the p.R413P variant (Pathogenic per ClinGen PAH VCEP); and one patient with mild hyperphenylalanemia in confirmed trans with the p.T372S variant (Likely Pathogenic per ClinGen PAH VCEP) (PMID: 30050108). One heterozygote for the variant is present in gnomAD, corresponding to a global frequency of 0.00000398 and a maximum population frequency of 0.0000544 (East Asian), under the frequency cutoff of 0.0002 for use of PM2 (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.942) (PP3).Classification: PathogenicSupporting Criteria: PM3_VeryStrong; PS3_supporting; PM2_supporting; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020902/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0001824 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0001824 infores:hetionet CAID:CA343719449 biolink:causes MONDO:0020367 infores:clingen CAID:CA343719449 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PM6, PP3, PP1, PM5, PM4, PS4, PS1, PS3, PS2, BA1 The c.169A>G variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Aspartate at amino acid 57 (p.Asn57Asp). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.091, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 11004290), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343719449/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27504 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0235896 infores:hetionet CAID:CA220352 biolink:causes MONDO:0015152 infores:clingen CAID:CA220352 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PP1 PM2 The NM_000070.3: c.550del p.(Thr184ArgfsTer36) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant is one of the most common disease-causing variants in CAPN3 reported in patients with Eastern European and Mediterranean ancestry (PMID: 25900067). It has been detected in at least 36 individuals with LGMD (PMID: 17236769, 17994539, 26404900, 30919934, 31788660, 17702496, 27142102). Of those individuals, at least 11 were compound heterozygous and 18 were homozygous (1.0 pt) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17236769). The variant has also been reported to segregate with LGMD in two affected family members from two families (PP1, capped with PP4_Strong; PMID: 30919934). The filtering allele frequency of the variant is 0.0005368 for European (non-Finnish) exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 48/113726), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4_Strong, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220352/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports PUBCHEM.COMPOUND:122173801 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0010200 infores:hetionet CHEBI:40237 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0392525 infores:hetionet CHEBI:9139 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085624 infores:hetionet CHEBI:17650 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0037278 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C35877 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1112712 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1368065 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017574 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0032285 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0025061 infores:hetionet CAID:CA658655920 biolink:causes MONDO:0021056 infores:clingen CAID:CA658655920 MONDO:0021056 PMID: Likely Pathogenic PP3, PS1, PS4_Moderate, PM2_Supporting The NM_000038.6(APC):c.1312+3A>C variant in APC is an intronic variant, which is located at the 3rd nucleotide in intron 10. This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 points (PS4_Moderate, Ambry Genetics internal data, Tsukanov et al 2017; Russian Journal of Genetics, 2017, Vol. 53, No. 3, pp. 369–375). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from two in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 10 of APC (PP3). Moreover, this variant has similar in silico predictions compared to another noncanonical splicing variant at that same nucleotide position (c.1312+3A>G) (ClinVar ID: 217924), which is classified as pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) (PS1). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS1, PM2_Supporting, PP3, and PS4_Moderate applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655920/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6775 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0522153 infores:hetionet CHEBI:8435 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0033774 infores:hetionet CHEBI:10650 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017181 infores:hetionet CAID:CA386952608 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952608 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate BP4, PS4, PP3 The c.64A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to glycine at codon 22 (p.(Ser22Gly)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant has a REVEL score of 0.598, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant is located within a conserved region of the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for protein function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (Internal lab contributors). In summary, c.64A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952608/MONDO:0015967/017 2025-04-22 2025-04-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8024 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0019345 infores:hetionet CHEBI:4974 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0231528 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0027765 infores:hetionet CHEBI:82960 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0018965 infores:hetionet CHEBI:43968 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0009676 infores:hetionet CHEBI:3312 biolink:causes UMLS:C0522171 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0522171 infores:hetionet CAID:CA404084869 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084869 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP3, PP4, PP1 BA1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PM6, PVS1, BS2 The NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL= 0.907. It is above 0.75, so PP3 is met. PS4_Supporting, PP4: Variant meets PM2. Identified in 3 unrelated cases (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France with possible FH by Simon Broome criteria; 1 case with DLCN score of 6 from Lille University & CHRU Lille, France; 1 case with definite FH by Simon Broome criteria from Centre Hospitalo-Universitaire Xavier Bichat, Paris, France).PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Centre Hospitalo-Universitaire Xavier Bichat, Paris. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084869/MONDO:0007750/013 2025-01-31 2025-03-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:63620 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0235969 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151779 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0009450 infores:hetionet CHEBI:10124 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0947912 infores:hetionet CHEBI:47426 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0030305 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0032961 infores:hetionet CHEBI:6367 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011606 infores:hetionet CHEBI:9763 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0030193 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0152010 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0152010 infores:hetionet CHEBI:3082 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0701811 infores:hetionet CHEBI:3510 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0231170 infores:hetionet CHEBI:8435 biolink:causes HP:0002362 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0231688 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027765 infores:hetionet CHEBI:45863 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0278134 infores:hetionet CHEBI:3752 biolink:causes MONDO:0043762 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0032994 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0037199 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0348024 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0348024 infores:hetionet CHEBI:8356 biolink:causes MONDO:0024487 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0343026 infores:hetionet CHEBI:2611 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0004604 infores:hetionet CHEBI:48390 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0022661 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0032285 infores:hetionet CHEBI:567361 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0015967 infores:hetionet CHEBI:63631 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0019080 infores:hetionet CHEBI:4856 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0232487 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0010692 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0521839 infores:hetionet CHEBI:3732 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013390 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0542203 infores:hetionet UMLS:C0879264 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0027497 infores:hetionet CHEBI:6804 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0018621 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0178298 infores:hetionet GO:1902863 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:1902863 GO:0150063 CHEBI:9571 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0010200 infores:hetionet CHEBI:3996 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C2047937 infores:hetionet CHEBI:4672 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0003811 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0032285 infores:hetionet CHEBI:6717 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013491 infores:hetionet GO:0060685 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0060685 GO:0009790 CHEBI:2379 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C2981158 infores:hetionet CHEBI:5127 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0152459 infores:hetionet CHEBI:3568 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C3665386 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0018839 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0018839 infores:hetionet CHEBI:47781 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0016382 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0011849 infores:hetionet CHEBI:10101 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0014591 infores:hetionet CHEBI:6367 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004134 infores:hetionet CHEBI:32184 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0038999 infores:hetionet GO:0061050 biolink:causes GO:0055007 infores:ubergraph knowledge_assertion manual_agent GO:0061050 GO:0055007 CHEBI:3723 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002884 infores:hetionet CAID:CA512341345 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341345 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1053C>A (p.Gly351=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.0)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341345/MONDO:0011071/008 2024-09-05 2024-09-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9130 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151878 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0027765 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0029878 infores:hetionet CHEBI:2611 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0015967 infores:hetionet UNII:R43D2573WO biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085649 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0027765 infores:hetionet CHEBI:3393 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0040034 infores:hetionet CHEBI:8356 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0010200 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0267792 infores:hetionet CHEBI:8356 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0392156 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0302295 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0541799 infores:hetionet CAID:CA251906 biolink:causes MONDO:0008723 infores:clingen CAID:CA251906 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PM1, PP4_Moderate, PS3_Supporting The NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 382. The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_ Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who was compound heterozygous for the variant and a pathogenic variant confirmed in trans by molecular subcloning (PM3, PMID: 8554073). The reported patient with this variant displayed reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID: 7769092). VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PS3_Supporting, PMID: 8554073). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl CoA dehydrogenase (VLCAD) deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PM3, PP3, PM2_Supporting, PS3_Supporting, PP4_Moderate). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA251906/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4356 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0015967 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0234894 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0005940 infores:hetionet CHEBI:3698 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020580 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0242422 infores:hetionet CHEBI:6149 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0023380 infores:hetionet CHEBI:63791 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0476273 infores:hetionet UMLS:C0657912 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015672 infores:hetionet CHEBI:9943 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0028734 infores:hetionet CHEBI:7492 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0041912 infores:hetionet CHEBI:63631 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0852911 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0042109 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0015397 infores:hetionet CHEBI:6149 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0085649 infores:hetionet CHEBI:10124 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1306341 infores:hetionet CHEBI:53760 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0549249 infores:hetionet CHEBI:8426 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0020517 infores:hetionet CHEBI:9130 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0041349 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0036572 infores:hetionet CHEBI:68478 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0600142 infores:hetionet NCBIGene:55823 biolink:causes MONDO:0030486 infores:monarchinitiative not_provided not_provided HGNC:14583 MONDO:0030486 uuid:9140310d-1d5d-404f-adc7-5e537c4be272 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085593 infores:hetionet CHEBI:8863 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002962 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0332534 infores:hetionet CHEBI:8310 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0004134 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0948089 infores:hetionet CHEBI:51137 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0011603 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025517 infores:hetionet CHEBI:5893 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1142412 infores:hetionet CAID:CA397725955 biolink:causes MONDO:0008723 infores:clingen CAID:CA397725955 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PP4 The c.1818G>A (p.Trp606Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported once as a result of a positive newborn screening for VLCADD (PMID:26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as VUS based on PVS1_Moderate+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397725955/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:92998 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0021400 infores:hetionet CAID:CA412740056 biolink:causes MONDO:0100437 infores:clingen CAID:CA412740056 MONDO:0100437 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PP1 NM_001034853.2(RPGR):c.1077T>A (p.Cys359Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 359 within exon 10 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) with a mildly affected female relative (1 pt), childhood onset (1 pt), high myopia (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), and genotyping by next-generation sequencing panel that did not identify an alternative basis for retinal disease (2 pts) which together are highly specific for RPGR-related retinopathy (8 points, PMID: 30917587, PP4_Moderate). The variant has been reported to segregate with retinal dystrophy through the proband and his carrier mother from 1 family, however, the carrier was reportedly asymptomatic so this was not sufficient to meet the PP1 code (PMID: 30917587). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412740056/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:31705 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0002962 infores:hetionet CHEBI:63584 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0040264 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0004238 infores:hetionet CHEBI:63612 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C1384353 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0035204 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0032326 infores:hetionet CHEBI:30659 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0020550 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0027769 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042769 infores:hetionet CHEBI:175901 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0038990 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0027765 infores:hetionet NCBIGene:2070 biolink:causes MONDO:0011541 infores:monarchinitiative not_provided not_provided HGNC:3522 MONDO:0011541 uuid:09184405-ae28-42df-9d15-1d1e7a4c7c3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0000731 infores:hetionet CHEBI:4027 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0009763 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011991 infores:hetionet CAID:CA171644 biolink:causes MONDO:0100039 infores:clingen CAID:CA171644 MONDO:0100039 PMID:23583054PMID:23583054 Pathogenic PM6, PVS1, PS4_Supporting, PM2_Supporting The p.Tyr171* variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Tyr171* variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 23583054) (PM6. This variant has been observed in at least 1 other individual with CDKL5 disorder (ClinVar) (PS4_Supporting). This variant was absent from gnomAD (PM2_ Supporting). In summary, p.Tyr171* variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_Supporting, PS4_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171644/MONDO:0100039/016 2021-03-09 2021-05-07 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:6933 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0085631 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0025061 infores:hetionet NCBIGene:7277 biolink:causes MONDO:0014531 infores:monarchinitiative not_provided not_provided HGNC:12407 MONDO:0014531 uuid:0f74c6b9-c29d-4a67-9297-8bd8520240f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0014394 infores:hetionet CHEBI:8802 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0004238 infores:hetionet CHEBI:47780 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0010200 infores:hetionet CHEBI:28971 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0340865 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0007787 infores:hetionet CHEBI:63638 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0009763 infores:hetionet CHEBI:8871 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0041657 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151763 infores:hetionet CHEBI:68554 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C2830004 infores:hetionet CAID:CA500261104 biolink:causes MONDO:0100326 infores:clingen CAID:CA500261104 MONDO:0100326 PMID: Pathogenic PM4, PP4_Strong, PP3, PP1, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.3060G>A (p.Lys1020=) synonymous variant disrupts the donor splice site of intron 29/30 of ITGA2B (SpliceAI 0.76; PP3) as confirmed by analysis of patient cDNA, which showed a deletion of exon 29 (PM4; PMID: 21113249). The variant has been reported homozygous in siblings TA and TG, who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <1%, as measured by flow cytometry, and there was <1% binding to PAC-1. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong, PP1, PM3_supporting; PMID: 21113249). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM4, PM3_supporting, PM2_supporitng, PP3. (VCEP specifications version 2; date of approval 05/17/2022). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500261104/MONDO:0100326/011 2022-05-17 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9086 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027066 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0425945 infores:hetionet CHEBI:52717 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015672 infores:hetionet CHEBI:27796 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0020649 infores:hetionet CHEBI:104011 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0020517 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0086543 infores:hetionet CHEBI:70746 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0042029 infores:hetionet CAID:CA421942771 biolink:causes MONDO:0013144 infores:clingen CAID:CA421942771 MONDO:0013144 PMID: Uncertain Significance PS4_Moderate, PP3, PP4, PM2_Supporting The c.1152A>G (NM_000488.3) variant in SERPINC1 is a synonymous variant that is not predicted to cause a substitution (p.Pro384=). The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The results from 2 in silico predictors, Splice AI (donor loss and acceptor gain) and VarSEAK (Class 5 splicing effect), provide evidence that correlates with a splicing impact to SERPINC1 function meeting criteria for PP3. This variant has been reported in 4 individuals with reported antithrombin activity level of < 0.8 IU/mL meeting PP4 and PS4_Moderate criteria (PMID 30975910, 28300866; Internal Thrombosis VCEP data). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP3, PP4, PM2_Supporting, PS4_ Moderate. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA421942771/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5130 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0009676 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0235467 infores:hetionet CHEBI:6690 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0026961 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0178298 infores:hetionet CHEBI:72690 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0030312 infores:hetionet CAID:CA156358 biolink:causes MONDO:0021060 infores:clingen CAID:CA156358 MONDO:0021060 PMID:20949621PMID:17704260PMID:18958496PMID:19020799PMID:20949621PMID:16474405 Pathogenic PP3, PP2, PM2_Supporting, PS3_Moderate, PS4, PM1, PS2_Very Strong BA1, BP4, BP1, BS3, BS1 The c.40G>A variant in the KRAS gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 14 (p.Val14Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.803 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant resides within a region (amino acids 10-17) of KRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 6 individuals with two confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 17704260, 18958496, 19020799, 20949621). In vitro functional studies showed that the p.Val14Ile variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA156358/MONDO:0021060/044 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:168396 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0347390 infores:hetionet CHEBI:51041 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0035455 infores:hetionet CHEBI:3814 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0026821 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0151765 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151765 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040046 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0026848 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152517 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0042109 infores:hetionet CHEBI:3219 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0221776 infores:hetionet CHEBI:71417 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0030353 infores:hetionet CHEBI:29013 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0011603 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085606 infores:hetionet CHEBI:6339 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0030193 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027051 infores:hetionet CAID:CA145874 biolink:causes MONDO:0001586 infores:clingen CAID:CA145874 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.1467C>T variant in IDUA is a synonymous (silent) variant (p.Arg489=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2948 (23904/81086 alleles; 3762 homozygotes; Grpmax Filtering AF 95% confidence = 0.2917) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92632). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disorders Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145874/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4511 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0005940 infores:hetionet CHEBI:45652 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0035078 infores:hetionet CHEBI:3347 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0006277 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020517 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032326 infores:hetionet CHEBI:75275 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0020517 infores:hetionet CHEBI:46345 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0151786 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0019348 infores:hetionet CHEBI:10125 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C2242737 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0032617 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0038362 infores:hetionet NCBIGene:26053 biolink:causes MONDO:0014361 infores:monarchinitiative not_provided not_provided HGNC:14262 MONDO:0014361 uuid:8af6559b-715c-48d1-a807-611a1f29c28a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0039070 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0007869 infores:hetionet CHEBI:39867 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C3251821 infores:hetionet CAID:CA386965868 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965868 MONDO:0015967 PMID:38093550 Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5, PS3_Supporting, PP3, PP4 PS4 The c.737T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to glycine at codon 246 (p.(Val246Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.947, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.736G>T (p.Val246Leu)​ has been interpreted as pathogenic by the ClinGen MDEP, and p.Val246Gly has a greater Grantham distance (PM5). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgement applied given that the individual was diagnosed before age 30 with a non-obese BME, negative genetic testing for HNF4A, and persistent C-peptide for 27 years) (PP4; internal lab contributor). Functional studies demonstrated the p.Val246Gly protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 38093550). In summary, c.737T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM5, PP3, PP4, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965868/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:465284 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C2047937 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0235238 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005530 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0524662 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0025061 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020514 infores:hetionet CHEBI:63598 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0028084 infores:hetionet GO:0090299 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:0090299 GO:0043009 CHEBI:10023 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0160390 infores:hetionet CHEBI:6887 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0852911 infores:hetionet CHEBI:44423 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0015672 infores:hetionet CAID:CA340745897 biolink:causes MONDO:0100368 infores:clingen CAID:CA340745897 MONDO:0100368 PMID: Pathogenic PP4_Moderate, PVS1, PP1, PM2_Supporting, PS1_Supporting PM3 The NM_000329.3(RPE65):c.726-2A>T variant occurs at a canonical splice site in intron 7. It is predicted to lead to skipping of a critical exon, resulting in a frameshift, and likely nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 6.800e-7 , with 3 alleles / 1179940 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with nystagmus (1 pt), myopia, retinal degeneration at 2-years-old (1 pt), sluggish pupillary responses (0.5 pts), extensive atrophic retinal changes, salt and pepper fundus appearance (2 pts), optic disc pallor, and extinguished rod and cone ERG (1.5 pts). Screening by NGS did not reveal any additional variants of interest (2 pts). Together these phenotypes are highly specific for RPE65-related recessive retinopathy (total 8.5 points, PMID: 33308271, PP4_moderate).The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 33308271).This variant is located at the splice acceptor +/-1,2 dinucleotide position and has a comparable Pathogenic variant at the +/-1,2 dinucleotide (NM_000329.3(RPE65):c.726-2A>C).(PS1_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, PP4_moderate, PP1, PS1_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340745897/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410206706 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206706 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS4, PS3, PS2, BA1, BP3, BP2, BP1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.779A>G (p.Asn260Ser) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.208, which is below the threshold of 0.50, and thus does not predict a damaging effect on RUNX1 function; the splice site predictor SpliceAI, with a score of <0.20, also indicates that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as a VUS for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206706/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:171719 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0004096 infores:hetionet CHEBI:4717 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0085593 infores:hetionet CHEBI:3215 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0406834 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0043345 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011849 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0032961 infores:hetionet GO:2000136 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:2000136 GO:0003007 CHEBI:127780 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020580 infores:hetionet NCBIGene:5910 biolink:causes MONDO:0958001 infores:monarchinitiative not_provided not_provided HGNC:9859 MONDO:0958001 uuid:72b63ae1-8f6e-4ef1-b33a-6f54923738a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0002884 infores:hetionet NCBIGene:54768 biolink:causes MONDO:0012088 infores:monarchinitiative not_provided not_provided HGNC:19368 MONDO:0012088 uuid:2a96f464-5a7b-480f-8179-35e6b76d2772 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51364 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0040034 infores:hetionet CHEBI:4953 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0000737 infores:hetionet CHEBI:453011 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0027339 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0521591 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0948089 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0037274 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1167732 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1167732 infores:hetionet CHEBI:231594 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1291077 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0152029 infores:hetionet CHEBI:47780 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020580 infores:hetionet CHEBI:32139 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0002063 infores:hetionet CHEBI:4702 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0235259 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022658 infores:hetionet CHEBI:31236 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026827 infores:hetionet CHEBI:8764 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0033247 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0013395 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0011849 infores:hetionet CHEBI:63612 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0740394 infores:hetionet CHEBI:6797 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0002792 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0005779 infores:hetionet CHEBI:6965 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0549433 infores:hetionet CHEBI:9073 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0009806 infores:hetionet CHEBI:7986 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0015230 infores:hetionet CAID:CA000470 biolink:causes MONDO:0018875 infores:clingen CAID:CA000470 MONDO:0018875 PMID:23894400PMID:26976419PMID:1686725PMID:21343334PMID:12826609PMID:17606709PMID:30224644PMID:26367797 Likely Benign BS3, BS2, PM2_Supporting BP4, BA1, PS1, PS3, PS4, PS2, PM1, PM5, BS1, BS4, PP3, PP1, PP4 The NM_000546.6:c.877G>T variant in TP53 is a missense variant predicted to cause substitution of glycine by tryptophan at amino acid 293 (p.Gly293Trp). This variant has been observed in 4 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors: Ambry, SCV000187101.5). This variant has an allele frequency of 0.00003305 (39/1180036 alleles) in the European (Non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). In summary, TP53 c.877G>T (p.Gly293Trp) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: BS2_Moderate, PM2_Supporting, BS3. (Bayesian Points: -5; VCEP specifications version 2.2, 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000470/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:UMD7G2653W biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0004936 infores:hetionet CHEBI:50131 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0042029 infores:hetionet CHEBI:119915 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1260880 infores:hetionet CAID:CA658824417 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824417 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 This frameshift duplication, located in a critical protein domain of an exon present in all biologically-relevant transcripts, is predicted to undergo NMD (PVS1). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824417/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4469 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0878544 infores:hetionet CAID:CA410208047 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208047 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS4, PS2, PS3, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS4, BS3, PVS1, PM6, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.560C>T (p.Ala187Val) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This missense variant has a REVEL score ≥ 0.88 (0.977) (PP3). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208047/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5441 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020649 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0019360 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0004096 infores:hetionet NCBIGene:857 biolink:causes MONDO:0012923 infores:monarchinitiative not_provided not_provided HGNC:1527 MONDO:0012923 uuid:67039f4f-7d36-484c-8b8f-633866047a3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0016655 infores:hetionet CHEBI:66876 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0006277 infores:hetionet CHEBI:4514 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0009676 infores:hetionet CHEBI:48273 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0000731 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0018799 infores:hetionet CHEBI:17347 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085593 infores:hetionet CHEBI:131512 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0040264 infores:hetionet CHEBI:8874 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0235198 infores:hetionet CHEBI:8871 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0015403 infores:hetionet CHEBI:116278 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151578 infores:hetionet NCBIGene:57158 biolink:causes MONDO:0030366 infores:monarchinitiative not_provided not_provided HGNC:14202 MONDO:0030366 uuid:f2e4273a-30d3-424b-adfe-f8c50cbbdd5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0011168 infores:hetionet CHEBI:18358 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0042109 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0020649 infores:hetionet NCBIGene:1180 biolink:causes MONDO:0009715 infores:monarchinitiative not_provided not_provided HGNC:2019 MONDO:0009715 uuid:cd45f2bf-7c74-466e-833b-37b46416144a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013595 infores:hetionet CAID:CA367403045 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403045 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.232G>C variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to histidine at codon 78 (p.(Asp78His)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 14517956, 28842611, 34440516). One of the individuals harboring this variant had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a three generation family history) (PP4_Moderate; PMID: 34440516). Additonally, this variant segregated with hyperglycemia, with at least 5 informative meioses in a single family (PP1_Strong; PMID: 36257325, internal lab contributors). In summary, c.232G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PP4_Moderate, PP1_Strong). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403045/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:45081 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151578 infores:hetionet CHEBI:49575 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0012569 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037052 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002453 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0852932 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0852932 infores:hetionet CAID:CA410202739 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202739 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS4, PS1, PS3, PS2, BP3, BP1, BP4, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM5, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.378T>G (p.Asp126Glu) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.88, supporting a deleterious effect (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting, PM2_Supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202739/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50131 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1302752 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0018939 infores:hetionet CHEBI:83804 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0039070 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0031350 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0267792 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0003467 infores:hetionet CHEBI:142290 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0231218 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0205204 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003537 infores:hetionet CAID:CA409106107 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106107 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting PS4 The c.537G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of tryptophan to cysteine at codon 179 (p.(Trp179Cys)) of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.892, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 34826540, 37711893). One of these individuals did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; PMID: 37711893). Additionally, this variant segregated with diabetes with four informative meioses in a single family (PP1_Moderate; PMID: 37711893). In summary, c.537G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP1_Moderate, PP4_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106107/MONDO:0015967/085 2025-08-12 2025-08-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA023645 biolink:causes MONDO:0007750 infores:clingen CAID:CA023645 MONDO:0007750 PMID: Benign BA1, BS3_Supporting BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2 NM_000527.5(LDLR):c.2140+5G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.01030 (1.030%) in European non-Finnish exomes (gnomAD v2.1.1). BS3_supporting - Level 3 assay: PMID:19208450 - study on patient's lymphocytes, Northern blot + real-time PCR + FACS used: normal mRNA processing + 108% low-density lipoprotein receptor activity. ---- functional study is consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023645/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3696 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042963 infores:hetionet CHEBI:135961 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0278106 infores:hetionet CHEBI:41977 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0151827 infores:hetionet CAID:CA10539261 biolink:causes MONDO:0018947 infores:clingen CAID:CA10539261 MONDO:0018947 PMID: Benign BA1 PP3, BP4, BS1, PM2 The variant NM_000252.3:c.1454C>T in MTM1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 485 (p.Ala485Val). The filtering allele frequency in gnomAD v4.1.0 is 0.0005657 (35/45691 alleles, 10 hemizygotes) for the Admixed American population, which is higher than the ClinGen congenital myopathy MTM1 threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.221, which is neither above nor below the thresholds predicting a damaging or benign impact on MTM1 function. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10539261/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:145499 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018681 infores:hetionet CHEBI:6741 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0017181 infores:hetionet CHEBI:3650 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0232462 infores:hetionet CHEBI:28445 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0030193 infores:hetionet CHEBI:3061 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0151878 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0036572 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0262397 infores:hetionet CAID:CA10605404 biolink:causes MONDO:0009290 infores:clingen CAID:CA10605404 MONDO:0009290 PMID:22958975PMID:23601496PMID:22958975PMID:19588081PMID:29122469PMID:23601496 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.2501_2502delCA (p.Thr834Argfs) is predicted to result in a frameshift causing a premature termination codon, nonsense medicated decay, and lack of GAA gene product, meeting PVS1. The variant has a highest population minor allele frequency of 0.00005794 in the Latino population, meeting PM2. This variant was found in compound heterozygosity with a known pathogenic variant, c.-32-13T>G, in three patients, who all meet the ClinGen LSD VCEP's PP4 criterion (PMID 22958975). The phase not confirmed in any of these patients. Additional patients with this variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 19588081, 29122469), or the in trans data had been counted towards another variant and therefore were not included here to avoid circular logic (c.1933G>A (p.Asp645Asn), (PMID 23601496). The data meet PP4 and PM3_Supporting. There is a ClinVar entry for this variant (Variant ID: 286229; 2 star review status) with three submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605404/MONDO:0009290/010 2020-05-05 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2659 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0030920 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002635 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0031090 infores:hetionet CHEBI:61058 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0000731 infores:hetionet CHEBI:465284 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085633 infores:hetionet CHEBI:6954 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0018681 infores:hetionet CAID:CA410203973 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203973 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.187G>C (p.Ala63Pro) is a missense variant which has a REVEL score < 0.50 (0.281) and a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203973/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151908 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0026946 infores:hetionet CHEBI:50922 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0278134 infores:hetionet NCBIGene:7399 biolink:causes MONDO:0013436 infores:monarchinitiative not_provided not_provided HGNC:12601 MONDO:0013436 uuid:61fb7d26-e6f6-45af-be4b-88751254cd80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7822 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0002878 infores:hetionet CHEBI:31644 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0003862 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0178298 infores:hetionet CHEBI:3310 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0020437 infores:hetionet CHEBI:9613 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0013395 infores:hetionet NCBIGene:5265 biolink:causes MONDO:0013282 infores:monarchinitiative not_provided not_provided HGNC:8941 MONDO:0013282 uuid:8898036f-e1e9-47d7-9b2b-b2d7c5a8e0e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0853019 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0919715 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0392176 infores:hetionet CHEBI:8871 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085602 infores:hetionet CHEBI:63627 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0018681 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020542 infores:hetionet CHEBI:3172 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0027497 infores:hetionet CHEBI:2704 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0016658 infores:hetionet CHEBI:85161 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C1145670 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002871 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0302295 infores:hetionet CHEBI:6950 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0037036 infores:hetionet CHEBI:45081 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0039070 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0014831 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0014831 uuid:7fdbb387-99b1-41bb-a2fe-0dbf54c1bb75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0267596 infores:hetionet CHEBI:10125 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0028084 infores:hetionet NCBIGene:159686 biolink:causes MONDO:0030868 infores:monarchinitiative not_provided not_provided HGNC:26676 MONDO:0030868 uuid:7b71272a-f3ae-4770-9cc4-ed19c63fb1f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0065374 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0016204 infores:hetionet CHEBI:8028 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0917801 infores:hetionet GO:1900225 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:1900225 GO:0023052 CHEBI:3286 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0006277 infores:hetionet CHEBI:8888 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235198 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0042769 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0020517 infores:hetionet CAID:CA274249 biolink:causes MONDO:0008723 infores:clingen CAID:CA274249 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.887_888del (p.Pro296ArgfsTer17) variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has also been reported in patients with phenotypes suggestive of a fatty acid oxidation defect (PMIDs: 10077518, 32778825). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1+PM2_supporting). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA274249/MONDO:0008723/021 2023-06-13 2023-06-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51032 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0020452 infores:hetionet CHEBI:3207 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0033845 infores:hetionet CHEBI:30659 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0036974 infores:hetionet CHEBI:63619 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0014236 infores:hetionet CHEBI:45979 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0023530 infores:hetionet CHEBI:46345 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0162830 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0038663 infores:hetionet GO:0007317 biolink:causes GO:0048599 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0048599 CAID:CA067440 biolink:causes MONDO:0005835 infores:clingen CAID:CA067440 MONDO:0005835 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS3 The MSH6 c.1282A>G variant is predicted as a missense p.(Lys428Glu) variant. Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.68 & ≤0.81 (http://priors.hci.utah.edu/PRIORS). It is extremely rare in gnomAD v2.1.1 non-cancer dataset and gnomAD v4.1 (<1 in 50,000 alleles: <0,002%). Functional defect was demonstrated by CIMRA assay (Functional Odds for Pathogenicity >18.7; Insight database). It was identified in an individual affected by colon cancer showing MSH6 loss (Insight database). Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA067440/MONDO:0005835/138 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6078 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0234215 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0344315 infores:hetionet CHEBI:3403 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C2830004 infores:hetionet CHEBI:135925 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0026961 infores:hetionet CHEBI:5778 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0010200 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0040479 infores:hetionet CHEBI:3176 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0041969 infores:hetionet CHEBI:9139 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0038325 infores:hetionet CAID:CA16616506 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616506 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1280G>T (p.Arg427Leu) is a missense variant which has a REVEL score < 0.50 (0.473) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616506/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49662 biolink:causes UMLS:C0857035 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0857035 infores:hetionet CHEBI:83804 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0851578 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151602 infores:hetionet CHEBI:63580 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0008031 infores:hetionet NCBIGene:5189 biolink:causes MONDO:0008953 infores:monarchinitiative not_provided not_provided HGNC:8850 MONDO:0008953 uuid:a89aa3d9-89d0-4233-a16c-6e2cf07ea1d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6717 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013428 infores:hetionet CHEBI:5123 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0041834 infores:hetionet CHEBI:32192 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0015672 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0267792 infores:hetionet CAID:CA10647981 biolink:causes MONDO:0007648 infores:clingen CAID:CA10647981 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM5, PM4, PM2, PM6, PVS1, PP4, PP1, PP2, PP3, BS2, BP1, BP4, BP3, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.*1120T>C variant has an allele frequency of 0.21013 (21%, 730/3474 alleles, 79 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10647981/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:8024 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151539 infores:hetionet UMLS:C0657912 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0740394 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007642 infores:hetionet CHEBI:68478 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0022107 infores:hetionet NCBIGene:5111 biolink:causes MONDO:0014399 infores:monarchinitiative not_provided not_provided HGNC:8729 MONDO:0014399 uuid:47dfb220-0ad6-4f0e-ae5e-f26dc11a16f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0028738 infores:hetionet CHEBI:6129 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0012569 infores:hetionet CHEBI:63607 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0022354 infores:hetionet CHEBI:30830 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0036974 infores:hetionet CAID:CA386965309 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965309 MONDO:0015967 PMID:15522234 Likely Pathogenic PM2_Supporting, PS1, PM1_Supporting, PS3_Supporting, PP3 PS4, PP4 The c.697G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 233 (p.(Val233Leu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.892, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Val233Leu protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 15522234). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor). The nucleotide change c.697G>C, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). In summary, c.697G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PS1, PP3, PS3_Supporting, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965309/MONDO:0015967/017 2025-04-25 2025-04-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72564 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151849 infores:hetionet CHEBI:51173 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C1443060 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0149801 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0149801 infores:hetionet CHEBI:7903 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020598 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0234192 infores:hetionet CHEBI:7444 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C1291077 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0042075 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0032961 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0234458 infores:hetionet GO:1902872 biolink:causes GO:0003407 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0003407 NCBIGene:8323 biolink:causes MONDO:0008060 infores:monarchinitiative not_provided not_provided HGNC:4044 MONDO:0008060 uuid:56e449a4-3246-4190-a8ac-567a33088937 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28001 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0428977 infores:hetionet CHEBI:6950 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0026827 infores:hetionet CAID:CA418281644 biolink:causes MONDO:0100368 infores:clingen CAID:CA418281644 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting BP7, PP4 NM_000329.3(RPE65):c.675C>A (p.Ile225=) is a substitution variant in codon 225 of RPE65, which is located in the center of exon 7 and does not alter the encoded amino acid. The splicing impact predictor SpliceAI gives a score of 0.39 for splice acceptor loss and 0.31 for splice donor loss, which are above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. This prediction has been confirmed by a mini-gene splicing assay in which the variant caused a defect in mRNA splicing and exclusion of exon 7 from all transcripts, which is predicted to trigger a frameshift and nonsense-mediated decay of the variant transcript (PMID: 36819107). These in silico and experimental findings have not been used to meet the PP3 and PS3_Supporting codes, but rather combined to meet the PVS1(RNA) code. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.886dup (p.Arg296fs) variants confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 pt, PMID: 36819107, PM3). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1(RNA), PM2_Supporting, PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA418281644/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10608401 biolink:causes MONDO:0013144 infores:clingen CAID:CA10608401 MONDO:0013144 PMID: Uncertain Significance BS1 BP7, BP4 The c.-88G>A (NM_000488.3) variant in SERPINC1 is in the 5' untranslated region (UTR) and changes nucleotide guanine to adenine. The variant is reported at an allele frequency of 0.00004056 with the highest MAF of 0.0003908 (27/69094) in the African/African American population in gnomAD v4.0.0 meeting BS1 (>0.0002). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BS1. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10608401/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144551 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0852908 infores:hetionet CHEBI:3757 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0022107 infores:hetionet GO:0044492 biolink:causes GO:0005248 infores:ubergraph knowledge_assertion manual_agent GO:0044492 GO:0005248 CHEBI:8888 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033975 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0241863 infores:hetionet CHEBI:7936 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0036973 infores:hetionet CHEBI:240107 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C1761613 infores:hetionet CHEBI:391960 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C3665386 infores:hetionet CAID:CA410150424 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150424 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.806-1G>T is a splice site variant which is not predicted to undergo nonsense-mediated decay and will result in exon 8 skipping (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150424/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CL:0000451 biolink:causes GO:0002371 infores:ubergraph knowledge_assertion manual_agent CL:0000451 GO:0002371 CHEBI:41423 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0235431 infores:hetionet CHEBI:8455 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0037274 infores:hetionet GO:2000332 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:2000332 GO:0009653 CHEBI:7936 biolink:causes UMLS:C0233528 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233528 infores:hetionet CHEBI:27504 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0004093 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0409497 infores:hetionet UMLS:C0004609 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013604 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0233472 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002871 infores:hetionet CAID:CA16619073 biolink:causes MONDO:0017623 infores:clingen CAID:CA16619073 MONDO:0017623 PMID: Likely Benign BS1 PVS1, PM6, PM2, BP7, BP5, BS4, BS3, PP2, PP3, PP1, PP4, BS2, PM5, PM4, PM3, PM1, BA1, BP1, BP4, BP3, BP2, PS1, PS4, PS2, PS3 NM_000314.8(PTEN):c.*5T>C meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF in gnomAD for African/African American: 0.00625%. Per ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3, 1 Benign Strong = Likely Benign. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619073/MONDO:0017623/003 2025-06-06 2025-10-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7852 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0043352 infores:hetionet CHEBI:8597 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0018418 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0005586 infores:hetionet CHEBI:16899 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0852911 infores:hetionet CHEBI:131512 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0011991 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041912 infores:hetionet NCBIGene:405753 biolink:causes MONDO:0010137 infores:monarchinitiative not_provided not_provided HGNC:32698 MONDO:0010137 uuid:f305dc2a-c901-4bdb-9569-92dfa94807ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49713 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0003862 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027813 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0009806 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0595882 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595882 infores:hetionet CHEBI:63598 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0206062 infores:hetionet NCBIGene:3594 biolink:causes MONDO:0013955 infores:monarchinitiative not_provided not_provided HGNC:5971 MONDO:0013955 uuid:73bb98b3-9b25-4dd1-9469-2dfeb6d596ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6437 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0948594 infores:hetionet CHEBI:8435 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0232461 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0036508 infores:hetionet CHEBI:178699 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0014866 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0423636 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0423636 infores:hetionet CAID:CA410207939 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207939 MONDO:0011071 PMID: Likely Pathogenic PM5, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP3, BP2, BP1, BP4, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PP4, PP2, PP1, BS2 This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a missense change at the same residue (p.Arg204) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 561253) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5). This missense variant has a REVEL score >0.88 (0.889) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207939/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4911 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0085669 infores:hetionet CHEBI:45081 biolink:causes HP:0001993 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0220982 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0948807 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0003123 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0023067 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0860645 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0860645 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0442874 infores:hetionet CHEBI:37924 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0520573 infores:hetionet CHEBI:9241 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0040034 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0005741 infores:hetionet CHEBI:8214 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0037763 infores:hetionet NCBIGene:1021 biolink:causes MONDO:0014484 infores:monarchinitiative not_provided not_provided HGNC:1777 MONDO:0014484 uuid:923b754c-6a01-416b-8e33-bb97d98be1a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151795 infores:hetionet CHEBI:66919 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0042029 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0012833 infores:hetionet GO:0019233 biolink:causes HP:0012531 infores:drugmechdb knowledge_assertion manual_agent GO:0019233 MESH:D010146 DB00193_MESH_D010146_2DB00281_MESH_D010146_1DB00193_MESH_D010146_1DB06204_MESH_D010146_1 CHEBI:6413 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042075 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0023530 infores:hetionet CHEBI:3437 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0855704 infores:hetionet CHEBI:47426 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0014518 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0009806 infores:hetionet CHEBI:6067 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C3665347 infores:hetionet CHEBI:28748 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0575081 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151838 infores:hetionet CHEBI:10125 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0015230 infores:hetionet CHEBI:4702 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0030554 infores:hetionet CHEBI:94449 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0232849 infores:hetionet CHEBI:10127 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0025222 infores:hetionet CHEBI:18332 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0011168 infores:hetionet CHEBI:9362 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0271298 infores:hetionet CHEBI:68841 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0015230 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0042109 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0027092 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0020538 infores:hetionet NCBIGene:54507 biolink:causes MONDO:0009153 infores:monarchinitiative not_provided not_provided HGNC:19706 MONDO:0009153 uuid:97b6e6c1-6bd5-42b0-a5b6-a03e7a54c29e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:110423 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0042075 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0037274 infores:hetionet CHEBI:6909 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0017178 infores:hetionet CHEBI:6520 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0009938 infores:hetionet CHEBI:68478 biolink:causes UMLS:C2721563 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2721563 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0702109 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0702109 infores:hetionet CHEBI:3506 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0002792 infores:hetionet CHEBI:68579 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0025323 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002871 infores:hetionet CHEBI:5551 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0018681 infores:hetionet CAID:CA645369469 biolink:causes MONDO:0017623 infores:clingen CAID:CA645369469 MONDO:0017623 PMID: Likely Pathogenic PVS1, PM2_Supporting PM6, BP7, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.884_900delinsG (p.Leu295ArgfsTer7) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort (PMID:27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369469/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233794 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0007222 infores:hetionet CHEBI:45863 biolink:causes MONDO:0015474 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0010418 infores:hetionet NCBIGene:745 biolink:causes MONDO:0032653 infores:monarchinitiative not_provided not_provided HGNC:1181 MONDO:0032653 uuid:f6793a45-875d-41be-b2c8-35e0af97c902 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014210 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014210 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1070C>G (p.Pro357Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014210/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47519 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085605 infores:hetionet CHEBI:50841 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0023530 infores:hetionet NCBITaxon:713 biolink:causes MONDO:0006636 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:713 MONDO:0006636 CHEBI:135736 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C2047937 infores:hetionet CHEBI:2611 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013604 infores:hetionet UMLS:C0657912 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013428 infores:hetionet CAID:CA2586969497 biolink:causes MONDO:0015152 infores:clingen CAID:CA2586969497 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_003494.4: c.3790_3797_del p.(Ser1264ValfsTer9) variant in DYSF, which is also known as NM_001130987.2: c.3844_3851del p.(Ser1282ValfsTer9), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 34/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been observed with a second presumed diagnostic DYSF variant in at least one patient with a progressive limb girdle pattern of muscle weakness (PMID: 27647186; 34559919; PP4). This variant is absent from gnomAD v4.1.0 in a region with good sequencing coverage (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/15/2025): PVS1, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586969497/MONDO:0015152/180 2025-07-15 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CAID:CA320251476 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251476 MONDO:0011071 PMID: Uncertain Significance PS3, PS4, PS2, PS1, BA1, BP2, BP1, BP4, BP3, BS1, BS3, BS4, BP7, BP5, PM2, PM6, PVS1, PM3, PM4, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1112T>C (p.Met371Thr) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251476/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45409 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0003467 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151609 infores:hetionet CHEBI:78543 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020453 infores:hetionet CHEBI:75988 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0027947 infores:hetionet CHEBI:27666 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0019156 infores:hetionet CHEBI:291342 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0018524 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0004096 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085393 infores:hetionet NCBIGene:1284 biolink:causes MONDO:0013773 infores:monarchinitiative not_provided not_provided HGNC:2203 MONDO:0013773 uuid:5bef4766-d087-4501-a9cf-7491faf1666a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes UMLS:C0281940 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0281940 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017601 infores:hetionet CAID:CA226064 biolink:causes MONDO:0100453 infores:clingen CAID:CA226064 MONDO:0100453 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PM3 The NM_000180.4(GUCY2D):c.1979G>A (p.Arg660Gln) variant is predicted to replace the arginine at position p.660 with glutamine. The computational predictor REVEL gives a score of 0.655, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function (PP3). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts) as an infant (1 pt). On examination at age 6 years, she had nystagmus (1 pt) with visual acuities of 1/200 (1 pt). Ophthalmoscopy showed attenuated retinal vessels and a granular appearance to the fundus (0.5 pts), Visual field was limited to a central island of function (1 pt). Rod ERGs extinguished (0.5 pts), cone ERGs severely reduced (1 pt). At ages 9 and 10 years, visual acuities had declined to light perception, and there was no measurable visual field by kinetic perimetry. Together these are specific for GUCY2D-related recessive retinopathy. (6.5 points total, PMID: 12623820, PP4). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0003903, with 630 alleles / 1,613,968 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the presumed compound heterozygous state (PMID: 21602930). However, the proband was not counted for this criterion because the other variant, p.Glu103Val, has not yet been classified and was not confirmed to be in trans with p.Arg660Gln (0 pts). PM3_Supporting requires at least 0.5 total points, so this criterion was not met. In summary, this variant meets the criteria to be classified as VUS for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_supporting, PP3, PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226064/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6759 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0038999 infores:hetionet CHEBI:31709 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0007859 infores:hetionet CHEBI:4702 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C2747891 infores:hetionet CHEBI:178699 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0015967 infores:hetionet CHEBI:3127 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0011644 infores:hetionet CHEBI:3084 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0549386 infores:hetionet CHEBI:63620 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0015967 infores:hetionet CHEBI:30830 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0004134 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0002871 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0234913 infores:hetionet CAID:CA410203945 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203945 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.194C>T (p.Ala65Val) is a missense variant which has a REVEL score < 0.50 (0.401) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203945/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2704 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0026826 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042267 infores:hetionet CHEBI:3441 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0037317 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0027051 infores:hetionet CHEBI:71417 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0019087 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0037274 infores:hetionet CHEBI:2208 biolink:causes MONDO:0019474 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C1333984 infores:hetionet NCBIGene:90121 biolink:causes MONDO:0010493 infores:monarchinitiative not_provided not_provided HGNC:25455 MONDO:0010493 uuid:e88e92b1-a76c-4760-85a3-2f3cb8bb3486 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA658799496 biolink:causes MONDO:0021060 infores:clingen CAID:CA658799496 MONDO:0021060 PMID: Pathogenic PVS1, PM3, PM2_Supporting The c.1030del (p.Ser344fs) variant in LZTR1 is a deletion/frameshift variant predicted to cause a premature stop codon 7 amino acids downstream from position 344 in biologically-relevant-exon 10/21 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been detected in 3 individuals with RASopathy. All were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 1 of those were confirmed in trans by whole exome trio analysis (c.1943-256C>T, 1.5 PM3 points, SCV000748478.4, SCV001445973.1, GeneDx, Broad Center for Mendelian Genomics) (PM3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799496/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1443060 infores:hetionet CHEBI:27432 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0013395 infores:hetionet CAID:CA412361050 biolink:causes MONDO:0100039 infores:clingen CAID:CA412361050 MONDO:0100039 PMID: Uncertain Significance BS1, PP4, BP4 The highest population minor allele frequency of the c.1468G>A (p.Gly490Arg) variant in CDKL5 in gnomAD v4.1 is 0.00002 in the Admixed American population (not sufficient to meet BS1 criteria). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.408). In summary, the p.Gly490Arg variant in CDKL5 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria. (CDKL5 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412361050/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:8356 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040261 infores:hetionet CAID:CA410148208 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148208 MONDO:0011071 PMID:34166225 Uncertain Significance BS3_Supporting, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1076C>G (p.Pro359Arg) is a missense variant in which transactivation assays demonstrate normal transactivation (80-115% of wt) (BS3_Supporting; PMID: 34166225). This variant is not present in population databases (gnomAD v2.1 or v3.1.2) (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BS3_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148208/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6402 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042023 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0035078 infores:hetionet CHEBI:4657 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0018794 infores:hetionet CHEBI:5141 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0031350 infores:hetionet CAID:CA9043702 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043702 MONDO:0012999 PMID: Likely Pathogenic PP3, PP4_Strong, PM2_Supporting, PM3_Supporting "The NM_000156.6:c.391+15G>T variant is in intron 3 of GAMT. The computational predictor, SpliceAI, predicts the creation of a new donor splice site 2 bp upstream (score 0.98) indicating that this variants may impact splicing (PP3). This variant has been identified a homozygous individual with clinical features consistent with GAMT deficiency, ""decreased"" GAMT enzyme activity in fibroblasts, elevated GAA and low or low normal creatine in urine, low creatine on brain MRS (PMID: 23234264, 29506905; assumed to be the same patent in both publications) (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003651 (43/1177768 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (ClinVar Variation ID: 544259). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PP3, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 14, 2024)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043702/MONDO:0012999/026 2024-11-14 2025-03-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0234458 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0004936 infores:hetionet CHEBI:9445 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0011991 infores:hetionet CHEBI:63629 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0947912 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038358 infores:hetionet CHEBI:32184 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0041834 infores:hetionet CHEBI:182080 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C1610069 infores:hetionet CHEBI:7494 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0232462 infores:hetionet CHEBI:182080 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C3665347 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0018213 infores:hetionet CHEBI:45863 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011644 infores:hetionet CHEBI:83531 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0002962 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0027051 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0038663 infores:hetionet CHEBI:44423 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0041956 infores:hetionet CAID:CA023512 biolink:causes MONDO:0007750 infores:clingen CAID:CA023512 MONDO:0007750 PMID: Pathogenic PS4, PS3, PP1_Strong, PM3, PM2, PP3, PP4 PM5 The NM_000527.5 (LDLR):c.1474G>A (p.Asp492Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00011 in East Asian population in gnomAD (gnomAD v2.1.1).PP3: REVEL=0.918.PS3: Level 1 assays, heterologous cells (CHO) used for Western blot and flow cytometry, showing diminished LDLR expression, 70% LDL binding and 49% uptake, reported in PMID 32015373 (Galicia-Garcia et al., 2020), Universidad del Pais Vasco, Spain.PS4, PP4: Variant meets PM2 and is identified in at least 43 unrelated index cases fulfilling clinical criteria for FH reported in ClinGen VCI and PubMed: 1 case reported from Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; 1 case from PathWest Laboratory Medicine WA, Australia; 5 cases from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France; 2 cases from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, USA; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, Italy; 1 case from Robarts Research Institute, Canada; 6 cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 11 cases from University Hospital Brno, Czech Republic and PMID 22698793 (Tichý et al., 2012). There are at least 14 index cases fulfilling FH clinical criteria in PMID 9763532, 11737238‚ 12436241‚ 17094996, 17539906‚ 19318025‚ 19446849‚ 20538126‚ 26748104, 28965616, 29353225, 30592178, 32331935, 32977124.PP1_Strong: Variants segregates with FH phenotype in at least 28 informative meiosis in 12 families from different labs (Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; University Hospital Brno, Czech Republic; PathWest Laboratory Medicine WA, Australia; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France): 24 affected family members have the variant and 4 unaffected family members do not have the variant.PM3: 1 index case with HoFH phenotype (17 years female, LDL-C=12.44 mmol/L), also carries pathogenic LDLR p.Gly592Glu, confirmed in trans, reported from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023512/MONDO:0007750/013 2023-11-07 2024-10-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:28864 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0852911 infores:hetionet CHEBI:8774 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0007820 infores:hetionet CHEBI:28864 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0239981 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0040034 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0853619 infores:hetionet NCBIGene:4617 biolink:causes MONDO:0032565 infores:monarchinitiative not_provided not_provided HGNC:7565 MONDO:0032565 uuid:3fc7dd99-81d9-4499-aa6b-83b588d97943 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0403632 infores:hetionet CHEBI:5118 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018790 infores:hetionet CHEBI:44032 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0035508 infores:hetionet NCBIGene:1355 biolink:causes MONDO:0014051 infores:monarchinitiative not_provided not_provided HGNC:2263 MONDO:0014051 uuid:a38acdec-ad40-44f3-938f-6d4a5a6488cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027720 infores:hetionet CHEBI:9635 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0033774 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004936 infores:hetionet CAID:CA10587846 biolink:causes MONDO:0007947 infores:clingen CAID:CA10587846 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1, PM5 The NM_00138 c.2624G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 875 (p.Cys875Tyr). This variant has been reported three times in ClinVar: twice as likely pathogenic and once as uncertain significance (Variation ID: 264089). A different missense variant impacting the same residue, p.Cys875Arg has been previously reported in individuals with clinical features of Marfan syndrome and found to segregate with disease in multiple affected relatives from one family (PMID 19293843, 28973303, internal data; PM5). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a hybrid domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.986, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PM2_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587846/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3723 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002957 infores:hetionet CHEBI:63925 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0042164 infores:hetionet CHEBI:167309 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0031924 infores:hetionet GO:0045688 biolink:causes GO:0009561 infores:ubergraph knowledge_assertion manual_agent GO:0045688 GO:0009561 CHEBI:3082 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0007820 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0027765 infores:hetionet CHEBI:63598 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1510410 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0025061 infores:hetionet CHEBI:3082 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0039070 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042267 infores:hetionet CHEBI:28177 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0233407 infores:hetionet CHEBI:3696 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0026826 infores:hetionet CAID:CA16020910 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020910 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong The c.970-1G>T variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 10 (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in two probands with classic PKU (as defined by abnormal blood Phe levels) (PMID: 27469133); BH4 deficiency does not appear to have been excluded, and there does not appear to be further genotype-level information (PP4). Classification: Likely PathogenicSupporting Criteria: PVS1_Strong; PM2; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020910/MONDO:0009861/006 2020-05-18 2020-05-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:83804 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0392702 infores:hetionet NCBIGene:388389 biolink:causes MONDO:0013854 infores:monarchinitiative not_provided not_provided HGNC:32700 MONDO:0013854 uuid:ac7f820d-c773-46e7-8679-9814b9cb924e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94609 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0011991 infores:hetionet CHEBI:72690 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0015230 infores:hetionet CHEBI:6413 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0043352 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0042373 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0042109 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0919874 infores:hetionet CHEBI:68478 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0030554 infores:hetionet CAID:CA410203388 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203388 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BA1, PM2, PM6, BP5, BS1, BS3, BS4, PM5, PP2, PP3, PP1 NM_001754.5(RUNX1):c.340A>G (p.Ile114Val) is a missense variant which is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203388/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:65173 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0002622 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0035455 infores:hetionet CHEBI:32588 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0032961 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0205204 infores:hetionet CHEBI:184555 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C1096250 infores:hetionet CHEBI:44032 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0009782 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0018524 infores:hetionet GO:0039604 biolink:causes GO:0006412 infores:ubergraph knowledge_assertion manual_agent GO:0039604 GO:0006412 CHEBI:52717 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004936 infores:hetionet NCBIGene:92579 biolink:causes MONDO:0012930 infores:monarchinitiative not_provided not_provided HGNC:24861 MONDO:0012930 uuid:3664edf6-0527-4578-bafa-b89b5b6c31f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2001151 biolink:causes GO:0003091 infores:ubergraph knowledge_assertion manual_agent GO:2001151 GO:0003091 CHEBI:47780 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020578 infores:hetionet CHEBI:8069 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0011206 infores:hetionet CHEBI:28830 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0022660 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0021167 infores:hetionet NCBIGene:285 biolink:causes MONDO:0023662 infores:monarchinitiative not_provided not_provided HGNC:485 MONDO:0023662 uuid:2b29a322-66f4-42ed-8d57-1391f4782510 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151828 infores:hetionet CHEBI:28748 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0700225 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0518015 infores:hetionet CHEBI:3423 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085616 infores:hetionet NCBIGene:6729 biolink:causes MONDO:0032899 infores:monarchinitiative not_provided not_provided HGNC:11301 MONDO:0032899 uuid:e6bbafee-99aa-4f98-bda4-2235942723ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5779 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0011603 infores:hetionet CHEBI:51173 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0018681 infores:hetionet CHEBI:9637 biolink:causes UMLS:C1142175 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C1142175 infores:hetionet CAID:CA413497082 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497082 MONDO:0010315 PMID: Likely Pathogenic PVS1, PM2_Supporting c.216C>A (p.Cys72Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497082/MONDO:0010315/129 2024-01-31 2024-01-31 X-linked inheritance HP:0001417 Supports CHEBI:3215 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020461 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0019158 infores:hetionet CHEBI:231425 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0027497 infores:hetionet CHEBI:6078 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0011991 infores:hetionet CHEBI:63613 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0011603 infores:hetionet CHEBI:31397 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0002994 infores:hetionet CHEBI:83527 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0038325 infores:hetionet CHEBI:4710 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042023 infores:hetionet CHEBI:52172 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0015967 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017152 infores:hetionet NCBIGene:345643 biolink:causes MONDO:0032872 infores:monarchinitiative not_provided not_provided HGNC:40050 MONDO:0032872 uuid:4161474e-2eb0-4e3c-b7dc-8de9b3103a41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0031345 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0854082 infores:hetionet CHEBI:5147 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0017979 infores:hetionet CHEBI:6887 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085633 infores:hetionet CHEBI:84050 biolink:causes UMLS:C1167779 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C1167779 infores:hetionet CHEBI:52010 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0349506 infores:hetionet CHEBI:7931 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0027497 infores:hetionet GO:2000345 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000345 GO:0007275 CHEBI:7865 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0917801 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0026848 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C1565489 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0085632 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038454 infores:hetionet CAID:CA367402690 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402690 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP2, PP3, PP4, PM2_Supporting The c.322T>C variant in the glucokinase gene, GCK, causes an amino acid change of tyrosine to histidine at codon 108 (p.(Tyr108His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, which is [greater than/equal to] the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 14 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 19564454, ClinVar ID: 585918, internal lab contributors), including an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in multiple families (internal lab contributors). In summary, c.322T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402690/MONDO:0015967/086 2023-12-15 2023-12-15 Semidominant inheritance HP:0032113 Supports CHEBI:7494 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0014724 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0152032 infores:hetionet CHEBI:2676 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0038362 infores:hetionet CHEBI:4702 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1456822 infores:hetionet CHEBI:8426 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0151798 infores:hetionet CHEBI:72564 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0027497 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0010709 infores:hetionet CHEBI:63622 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0008031 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0036572 infores:hetionet NCBIGene:715 biolink:causes MONDO:0020684 infores:monarchinitiative not_provided not_provided HGNC:1246 MONDO:0020684 uuid:7cb55c9f-1215-4238-9cd8-732f8a3dfd0e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0016655 infores:hetionet CHEBI:15365 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0235378 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1141930 infores:hetionet CHEBI:63717 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0004093 infores:hetionet CHEBI:48538 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0011991 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0021400 infores:hetionet CHEBI:50859 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1443060 infores:hetionet CHEBI:31980 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0085593 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0020651 infores:hetionet CHEBI:3441 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0085633 infores:hetionet CHEBI:84883 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0231528 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0024117 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0860239 infores:hetionet NCBIGene:80224 biolink:causes MONDO:0032625 infores:monarchinitiative not_provided not_provided HGNC:20278 MONDO:0032625 uuid:ebd00100-c2d6-4f70-9c71-e3359aba2b24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8069 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0027497 infores:hetionet CHEBI:10100 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0028643 infores:hetionet NCBIGene:1760 biolink:causes MONDO:0008056 infores:monarchinitiative not_provided not_provided HGNC:2933 MONDO:0008056 uuid:bfeea93d-1c9c-45e4-a967-dbe4c4a54050 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0232492 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0003811 infores:hetionet CAID:CA10587391 biolink:causes MONDO:0100437 infores:clingen CAID:CA10587391 MONDO:0100437 PMID: Likely Benign BS1 BP4 NM_001034853.2(RPGR):c.1245+6A>G is an intron 10 variant located 6 nucleotides after exon 10. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000005045 among hemizygous individuals, with 2 variant alleles / 396,433 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.14 for donor gain, which is below the ClinGen X-linked IRD VCEP recommended PP3 threshold of >0.2 but above the BP4 threshold of <0.1, so neither PP3 nor BP4 is met. In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587391/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:474053 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0011603 infores:hetionet CHEBI:6067 biolink:causes MONDO:0016467 infores:ubergraph knowledge_assertion manual_agent CHEBI:6067 MONDO:0016467 CHEBI:63621 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0699744 infores:hetionet CHEBI:3216 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0085632 infores:hetionet CAID:CA2654377542 biolink:causes MONDO:0011071 infores:clingen CAID:CA2654377542 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968-11C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.12)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2654377542/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:100241 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004093 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0574741 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0574741 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0233494 infores:hetionet NCBIGene:79693 biolink:causes MONDO:0030476 infores:monarchinitiative not_provided not_provided HGNC:28905 MONDO:0030476 uuid:1f7ae1b7-84a2-4a27-8b58-3a7a57c007dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231594 biolink:causes UMLS:C0853203 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0853203 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0004936 infores:hetionet GO:1902256 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1902256 GO:0072359 CHEBI:64310 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0267792 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0877047 infores:hetionet CAID:CA261403 biolink:causes MONDO:0010134 infores:clingen CAID:CA261403 MONDO:0010134 PMID:9618167PMID:15811013PMID:19017801PMID:9618167PMID:15811013PMID:19017801PMID:23266159PMID:11932316PMID:24007330PMID:15355436PMID:15811013PMID:25394566PMID:27541434PMID:17309986PMID:23638949PMID:28444304PMID:15355436PMID:25372295PMID:25468468PMID:24338212PMID:15811013PMID:19017801PMID:21366435PMID:19786220PMID:24224479PMID:21961810PMID:12676893PMID:24007330PMID:19509082PMID:25394566PMID:27541434PMID:17309986PMID:23638949PMID:28444304PMID:15355436PMID:25372295PMID:25468468PMID:24338212PMID:15811013PMID:19017801PMID:21366435PMID:19786220PMID:24224479PMID:21961810PMID:12676893PMID:24007330PMID:19509082PMID:26763877PMID:15905611PMID:22412181 Pathogenic PP1_Strong, PS3_Supporting, PP4, PP3, PM3_Very Strong, PM2_Supporting BS4, BS1, BP5, BP7, BS2, PM5, PM1, PM4, PVS1, PM6, BP2, BP3, BP4, BA1, PS4, PS2, PS1 This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID: 25372295, 23638949, 25468468, 24338212, 25394566, 19786220, 19017801, 27541434, 21366435, 17309986, 24007330, 24224479, 21961810, 2844304, 19509082, 15811013). The p.Thr410Met variant in SLC26A4 has been reported to segregate in an autosomal recessive pattern with hearing loss in at least 7 family members (PP1_Strong; PMID: 19017801, 9618167, 15811013). Computational prediction tools and conservation analysis suggest that the p.Thr410Met variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA or Mondini malformation (PP4; PMID: 15355436, 15811013). The allele frequency of the p.Thr410Met variant in the SLC26A4 gene is 0.062% (19/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PP1_S, PP3, PS3_P, PM2_P, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261403/MONDO:0010134/005 2018-09-17 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:4876 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0231218 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0009806 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0003864 infores:hetionet CHEBI:35677 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0004093 infores:hetionet CHEBI:10023 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020488 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0006325 infores:hetionet CHEBI:31932 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0015230 infores:hetionet CHEBI:4315 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0268000 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0233472 infores:hetionet UMLS:C0657912 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011603 infores:hetionet NCBIGene:7289 biolink:causes MONDO:0859254 infores:monarchinitiative not_provided not_provided HGNC:12425 MONDO:0859254 uuid:a49ece7b-c168-4e9d-af92-3989f269f2a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA401363871 biolink:causes MONDO:0009290 infores:clingen CAID:CA401363871 MONDO:0009290 PMID:31510962 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.876C>G (p.Tyr292Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product. Therefore, PVS1 can be applied. Functional studies, in which the variant was expressed in COS cells revealed no GAA activity in the cells or medium. However, a faint band representing GAA protein was detectable on Western blot (PMID 31510962). As the experiment was done in an in vitro expression system, it is unclear whether any gene product would be made in vivo. This variant was absent in gnomAD v2.1.1, meeting PM2. Two patients with infantile onset Pompe disease from Thailand have been reported (PMID 31510962). The residual GAA activity was provided for one of them, meeting PP4. This patient is compound heterozygous for the variant and c.1003G>A (p.Gly335Arg). The in trans data from this patient was used in the assessment of p.Gly335Arg and is not included here in order to avoid circular logic. The other patient is homozygous, and both parents were confirmed to be carriers, but the residual GAA activity is not available, and this data will not be included. Therefore, PM3 is currently not met. There is a ClinVar entry for this variant (Variation ID: 637958, 0 star review status) with one submitter (an author of this paper) classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401363871/MONDO:0009290/010 2020-10-05 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2659 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0232493 infores:hetionet CHEBI:47499 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0041657 infores:hetionet NCBIGene:1302 biolink:causes MONDO:0011159 infores:monarchinitiative not_provided not_provided HGNC:2187 MONDO:0011159 uuid:23264655-c189-4ee9-a541-c835c537c781 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2659 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0740394 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0232431 infores:hetionet CAID:CA023697 biolink:causes MONDO:0007750 infores:clingen CAID:CA023697 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM1, PM2, PP1, PP4 BP2, BP4, PS3, BS3, BS4, PM5, PM3, PP3 The NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Moderate, PM1, PM2, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: PopMax MAF = 0.000004496 (0.0004%) in European (non-Finnish) exomes (gnomAD v4.0.0).PM1: Variant meets PM2 and is missense in exon 4.PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; 4 cases with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; 1 case with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia).PP1: Variant segregates with phenotype in 2 informative meiosis in 2 families from different labs (1 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France, and 1 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 2 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023697/MONDO:0007750/013 2024-02-23 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0045700 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0045700 GO:0019953 CHEBI:134966 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0021053 infores:hetionet CHEBI:6801 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0013144 infores:hetionet CAID:CA404086098 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086098 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP2, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM1, PM5, PM4, PM3, PVS1, PM6, PP4, PP1, BS2 The NM_000527.5(LDLR):c.1448G>T (p.Trp483Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.933.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086098/MONDO:0007750/013 2023-04-29 2023-04-29 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:119486 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0035410 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0855242 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0232459 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0854375 infores:hetionet CHEBI:6887 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0040517 infores:hetionet CHEBI:7443 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0013604 infores:hetionet CHEBI:8871 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235198 infores:hetionet CHEBI:5790 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0043387 infores:hetionet CHEBI:16755 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151578 infores:hetionet CHEBI:4702 biolink:causes UMLS:C1112366 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1112366 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151610 infores:hetionet CHEBI:61049 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0043094 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020649 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018099 infores:hetionet CHEBI:45979 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0151579 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0152517 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0442874 infores:hetionet CHEBI:3699 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0085605 infores:hetionet CHEBI:8069 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0242184 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232492 infores:hetionet CHEBI:119915 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233407 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0349506 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0042384 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0027765 infores:hetionet CHEBI:3437 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0917801 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0549475 infores:hetionet CAID:CA013438 biolink:causes MONDO:0013699 infores:clingen CAID:CA013438 MONDO:0013699 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4_Moderate The NM_000535.7: c.989-2A>G p.(?) variant in PMS2 occurs within the canonical splice acceptor site (-2) of intron 9. It is predicted to result in an in-frame exon 10 skipping and the altered region is critical to protein function (PVS1_Strong). RNA studies have confirmed that this variant causes the in-frame skipping of exon 10 (r.989_1144del), resulting in the deletion of the C-terminal ATPase domain (PMID: 23709753, 26247049, 30306255). This variant has been detected in at least 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location. This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1_STR, PM2_SUP, PP4_MOD (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA013438/MONDO:0013699/139 2024-10-17 2024-10-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9328 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0015967 infores:hetionet CHEBI:15551 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0031350 infores:hetionet CAID:CA399806749 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806749 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The c.188+1G>A variant in ITGA2B occurs within the canonical splice donor site of intron 1. It is predicted to introduce a premature stop codon in intron 1, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 36672149). AAt least one patient (Patient 1 in PMID: 36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highlyspecific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, there was absence of GPIIbIIIa platelet surface expression by flow cytometry. This individual, from a consanguineous family, was homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001098 (1/91088 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessiveGlanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting, and PM3_Supportin. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806749/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:37333 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0236075 infores:hetionet NCBIGene:6448 biolink:causes MONDO:0009655 infores:monarchinitiative not_provided not_provided HGNC:10818 MONDO:0009655 uuid:177983a2-6698-4366-b202-3cbc774a1477 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151971 infores:hetionet NCBIGene:51124 biolink:causes MONDO:0031481 infores:monarchinitiative not_provided not_provided HGNC:18550 MONDO:0031481 uuid:b96f7ebe-1141-49b8-9cc5-cd5aa44323f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:283847 biolink:causes MONDO:0030493 infores:monarchinitiative not_provided not_provided HGNC:26675 MONDO:0030493 uuid:118ebb42-6c8d-4a0d-8ef8-e34f5322450e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91541 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0151559 infores:hetionet CHEBI:9738 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0520966 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0518015 infores:hetionet CHEBI:9555 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0232462 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0012833 infores:hetionet CHEBI:70735 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0006145 infores:hetionet CHEBI:3696 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0040264 infores:hetionet CAID:CA8814893 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814893 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PP3, PP4, BP4 The NM_000152.5(GAA):c.545C>G (p.Thr182Arg) variant in GAA has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00010 (11/106436 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The variant has been reported in the literature but not in individuals diagnosed with Pompe disease (PMID: 29149851, 33552729) (PP4 is not met). The computational predictor REVEL gives a score of 0.395, a score which does not clearly predict an impact on GAA function (PMID: 36413997). There is a ClinVar entry for this variant (Variation ID: 499380). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814893/MONDO:0009290/010 2023-05-26 2023-05-26 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:28748 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020615 infores:hetionet CHEBI:44915 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0040264 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0017178 infores:hetionet CHEBI:38562 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0027441 infores:hetionet CHEBI:2567 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0033774 infores:hetionet NCBIGene:5350 biolink:causes MONDO:0013475 infores:monarchinitiative not_provided not_provided HGNC:9080 MONDO:0013475 uuid:e7aeb989-39cb-4e03-b912-b239703d29a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA613324858 biolink:causes MONDO:0100040 infores:clingen CAID:CA613324858 MONDO:0100040 PMID: Benign BP5_Strong, BS2 PM2 The p.Gln70_Pro76del variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Gln70_Pro76del variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). The highest population minor allele frequency of the p.Gln70_Pro76del variant in FOXG1 in gnomAD v4.1 is 0.00005955 in Admixed American population (not sufficient to meet PM2_Supporting criteria). In summary, the p.Gln70_Pro76del variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS2, BP5_Strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA613324858/MONDO:0100040/035 2024-08-30 2024-10-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63616 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0022658 infores:hetionet CHEBI:2618 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0027947 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007745 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017551 infores:hetionet CHEBI:31623 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1519353 infores:hetionet CHEBI:7822 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0038325 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0086543 infores:hetionet CHEBI:92998 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0031154 infores:hetionet CHEBI:134991 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0037199 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0005779 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014130 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0032285 infores:hetionet NCBITaxon:10358 biolink:causes MONDO:0000878 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10358 MESH:D017726 DB00529_MESH_D017726_1 CHEBI:47898 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011991 infores:hetionet CHEBI:5103 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0231218 infores:hetionet CAID:CA10558465 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558465 MONDO:0010726 PMID: Uncertain Significance PM6_Supporting, PVS1, BS1 BA1, PS4, PM2 The p.Glu404Ter variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The highest population minor allele frequency of the p.Glu404Ter variant in MECP2 (NM_004992.4) is 0.0001173 in the East Asian population in gnomAD v4.1, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Glu404Ter variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with seizures (PMID 29655203) (PM6_Supporting). In summary, the p.Glu404Ter variant in MECP2 is classified as variant of uncertain significance based on the ACMG/AMP criteria (BS1, PVS1, PM6_Supporting). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558465/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3757 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0344232 infores:hetionet CHEBI:7494 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085932 infores:hetionet CHEBI:16899 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0546884 infores:hetionet CAID:CA031125 biolink:causes MONDO:0007750 infores:clingen CAID:CA031125 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, PP4, BS2 The NM_000527.4(LDLR):c.1003G>C (p.(Gly335Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2 : PopMax MAF = 0.000008813 (0.0009%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. - PP3 : REVEL = 0.901. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031125/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5384 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0020625 infores:hetionet CHEBI:52717 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151699 infores:hetionet CHEBI:5001 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151786 infores:hetionet CHEBI:9434 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0018681 infores:hetionet CHEBI:4779 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0004936 infores:hetionet CHEBI:15544 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020672 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0024205 infores:hetionet CHEBI:5855 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013491 infores:hetionet CHEBI:135961 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0004093 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0575090 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020538 infores:hetionet CHEBI:71415 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0030554 infores:hetionet CHEBI:6690 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011615 infores:hetionet CAID:CA252000 biolink:causes MONDO:0007064 infores:clingen CAID:CA252000 MONDO:0007064 PMID: Pathogenic PP1_Strong, PP4_Moderate, PM2, PS3_Moderate, PM3_Strong PS1 The NM_000022.4:c.632G>A variant in ADA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 211 (p.Arg211His).The filtering allele frequency (the upper threshold of the 95% CI of 10/35432) of the c.632G>A variant in ADA is 0.0001565 for Latino/Admixed American chromosomes by gnomAD v.2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). Total Expressed ADA Activity in SØ3834 in E. coli showed the values: Mean +- SD = 30.4 +- 35.8 (3.0–134.2)[nmol/h/mg protein] and the following percent of Wild Type (Range) = 0.012 - 0.014 (0.001–0.051), belonging to group I of Arredondo-Vega classification, indicating that this variant impacts protein function (PMID: 9758612, PS3_moderate). This variant has been detected in 22 individuals with SCID. Of those individuals, one was a heterozygous compound with c.95+1G>A (variant classified pathogenic according to the SCID VCEP specifications). The trans phase of the variants was confirmed by parental testing (1pt; PMID 9414266). Four individuals were with this variant, and a variant that has not been curated by the SCID VCEP (p.A179D, PMID 26684479; p.R101Q, PMID 16973956; p.Y201*, PMID 26255240, patient #46; p.L107P, PMID 19179314, patient #2) (0pt - These variants will not be curated now because the pathogenic level was already reached). Seventeen individuals were homozygous for the variant (maximum 1pt; PMID 27129325, 20460637, 26376800, 19179314, 16276484, 9758612). 2pts in total, PM3_Strong is met.At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome (0.5pt) + Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pt) + ADA-SCID phenotype corrected by ADA gene therapy (1pt), in a total of 4.5 points, which is highly specific for SCID (PP4_Moderate; PMID: 9414266). The variant has been reported to segregate with SCID in 4 affected family members from 2 families (LOD score 2.41; PP1_Strong; PMID 20460637, 26376800). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4_Moderate, PM3_Strong, PP1_Strong, PM2_Supporting, PS3_Moderate. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA252000/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50275 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0023222 infores:hetionet CHEBI:9086 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0019270 infores:hetionet CHEBI:72296 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0029163 infores:hetionet GO:0048345 biolink:causes GO:0048340 infores:ubergraph knowledge_assertion manual_agent GO:0048345 GO:0048340 CHEBI:35778 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0039971 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003537 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234987 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0235146 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027765 infores:hetionet CHEBI:6741 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151766 infores:hetionet CHEBI:51141 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0013144 infores:hetionet CHEBI:8212 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0080274 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0855242 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0038454 infores:hetionet CHEBI:4653 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0002994 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020649 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011849 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0853023 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0853023 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1443060 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005723 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085436 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0027339 infores:hetionet CHEBI:28830 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0497156 infores:hetionet CAID:CA2602729 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602729 MONDO:0009276 PMID: Likely Benign BS1, PP4 BP4, PP3, PM3 The c.488C>A variant in GP9 is a missense variant predicted to cause substitution of alanine by asparagine at amino acid 163. At least one homozygous patient, with excessive mucocutaneous bleeding (Case in PMID:24934643), had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). The computational predictor REVEL gives a score of 0.564, which is below the ClinGen PD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on GP9 function. And the computational splicing predictor SpliceAI indicated that the variant has no predicted impact on splicing. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0008153 (based on 74/74086 alleles) in African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0007 for GP9), and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, BS1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602729/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:80630 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0019521 infores:hetionet CHEBI:37924 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0741494 infores:hetionet CAID:CA2261365225 biolink:causes MONDO:0100326 infores:clingen CAID:CA2261365225 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.3001_3010dup (p.Val1004AlafsTer35) variant in ITGA2B is a frameshift variant that may cause loss of function of the protein It is predicted to escape nonsense mediated decay and remove <10% of the protein, however it alters the transmembrane domain at c.2980-3057 (PVS1_Strong). At least one patient (Patient 9 in PMID: 36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, there was absence of GPIIbIIIa platelet surface expression by flow cytometry and ITGA2B and ITGB3 were reported to be sequenced across all exons and intron/exon boundaries (PP4_Strong). This individual, from a consanguineous family, was homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002229 (1/44870 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4_Strong, PM2_Supporting and PM3_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2261365225/MONDO:0100326/011 2025-06-17 2025-06-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4562 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0041912 infores:hetionet CHEBI:2663 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0004134 infores:hetionet CHEBI:8871 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0034642 infores:hetionet CAID:CA915952144 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952144 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, BA1, PS4, PS2, PS3, BS1, PM6, PM2 The m.12241del variant in MT-TS2 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 16/61,168 (0.026%). The frequency in the Helix dataset is 81/195,983 (0.041%) homoplasmic occurrences in addition to 22 heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 53/56,425 (0.094%) and these occurrences are homoplasmic in individuals from various backgrounds. In all three population databases, this variant is seen across individuals from different haplogroups. MitoTIP suggests this variant is benign (37th percentile; BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952144/MONDO:0044970/015 2023-08-22 2024-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:3845 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0018874 uuid:eb19198d-3287-44f6-8ddb-1a83b0f6597a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6078 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0085632 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0242350 infores:hetionet CHEBI:75722 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0025345 infores:hetionet CHEBI:28748 biolink:causes MONDO:0018646 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0008313 infores:hetionet CHEBI:42944 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0015230 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0429098 infores:hetionet CHEBI:35854 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0042963 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011991 infores:hetionet CHEBI:6690 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0206062 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151505 infores:hetionet CHEBI:8080 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0231807 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1096250 infores:hetionet CHEBI:17474 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0002170 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0549373 infores:hetionet CHEBI:8412 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0042963 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C2697368 infores:hetionet CHEBI:27504 biolink:causes HP:0001937 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0221021 infores:hetionet NCBIGene:3781 biolink:causes MONDO:0859225 infores:monarchinitiative not_provided not_provided HGNC:6291 MONDO:0859225 uuid:9531b6b4-bfa3-4b5e-8183-57dbd8278ad8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0746961 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0242350 infores:hetionet CHEBI:61033 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0268000 infores:hetionet CAID:CA10549333 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549333 MONDO:0010305 PMID: Uncertain Significance BS2 BS1, PM2, PP3, BP4 The NM_005629.4:c.820G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 274 (p.Val274Met). This variant has been previously reported in one individual with hypotonia, global developmental delay, and microcephaly, but who was found to have normal urine creatine and guanidinoacetate levels on two separate occasions and a de novo variant in KAT6A as an alternate molecular cause of his symptoms (PMID 27133397) (BS2). In gnomAD v2.1.1, the highest population allele frequency is 0.00015 (14/91767 alleles) in the European (Non-Finnish) population and there are 4 hemizygotes across all populations, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.559, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 4416002). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549333/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:64355 biolink:causes UMLS:C0549259 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549259 infores:hetionet CHEBI:6931 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0040053 infores:hetionet CHEBI:40279 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0856054 infores:hetionet CAID:CA915940256 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940256 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1300del variant results in a frameshift (p.Gln434ArgfsTer9) with a premature stop codon in exon 10/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, Homozygous patient GT42 of PMID: 29675921 who meets the criteria for PP4_strong (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940256/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:101853 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0015230 infores:hetionet CHEBI:7601 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0013395 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0857448 infores:hetionet CHEBI:28177 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0917801 infores:hetionet CHEBI:45285 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0005779 infores:hetionet CHEBI:6149 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0085593 infores:hetionet CHEBI:144551 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0149745 infores:hetionet CHEBI:94449 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0476280 infores:hetionet CHEBI:6015 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0018524 infores:hetionet CHEBI:175901 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0013404 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018021 infores:hetionet CHEBI:40303 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C3263723 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235567 infores:hetionet NCBIGene:338328 biolink:causes MONDO:0014412 infores:monarchinitiative not_provided not_provided HGNC:24945 MONDO:0014412 uuid:f5e3a25c-a967-4c92-8f73-662d46cd36bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0037023 infores:hetionet CAID:CA229879 biolink:causes MONDO:0009861 infores:clingen CAID:CA229879 MONDO:0009861 PMID:30389586PMID:24048906PMID:10947211PMID:26413448PMID:20920871PMID:24368688 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong The c.969+5G>A variant in PAH has been reported in at least 4 individuals with classic PKU (BH4 deficiency excluded) (PP4_moderate; PMID: 24048906). This variant is absent in population databases (PM2). This variant has been detected in the homozygous state and in compound heterozygotes with at least 6 Pathogenic/Likely Pathogenic variants including A300S (ClinVar: 92751, Pathogenic), R176X (ClinVar: 102723, Pathogenic), c.168+5G>C (ClinVar 102606, Pathogenic), and c.913-7A>G (ClinVar: 102894, Likely Pathogenic), c.1066-11G>A (ClinVar: 607, Pathogenic), E280K (ClinVar 580, Pathogenic) (PM3_VeryStrong; PMID: 30159852, PMID:10947211, PMID:24048906, PMID:30389586, PMID:24368688). Computational prediction tools suggest that c.969+5G>A may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229879/MONDO:0009861/006 2019-12-22 2019-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3077 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0271650 infores:hetionet CHEBI:27690 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0016382 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0392162 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013146 infores:hetionet CHEBI:4702 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0006277 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0549389 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0549389 infores:hetionet CHEBI:63632 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C1384353 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035309 infores:hetionet GO:1905915 biolink:causes GO:0090677 infores:ubergraph knowledge_assertion manual_agent GO:1905915 GO:0090677 CHEBI:52717 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0033975 infores:hetionet CHEBI:16347 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0152020 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0521465 infores:hetionet CAID:CA256009 biolink:causes MONDO:0010305 infores:clingen CAID:CA256009 MONDO:0010305 PMID: Pathogenic PM2_Supporting, PP4_Strong, PVS1_Strong, PP1_Strong The NM_005629.4:c.1540C>T (p.Arg514Ter) variant in SLC6A8 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 11/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). A male patient has been reported with almost complete absence of the creatine signal on brain MRS, elevated creatine in urine, and virtually undetectable creatine transport in fibroblasts (PMID: 11326334) (PP4_Strong). The mother, maternal aunt, and maternal grandmother are all heterozygous for the variant and all have evidence of creatine transporter deficiency. The paternal uncle has severe intellectual disability but was unavailable for study (PMID: 11326334) (PP1_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral creatine Deficiencies Variant Curation Expert Panel CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP1_Strong, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA256009/MONDO:0010305/027 2023-10-13 2023-11-08 X-linked inheritance HP:0001417 Supports CHEBI:101278 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0008031 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005113 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2 MONDO:0005113 CHEBI:63629 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013404 infores:hetionet CHEBI:9649 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C2047937 infores:hetionet CHEBI:7443 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1141893 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1141893 infores:hetionet NCBIGene:25942 biolink:causes MONDO:0013256 infores:monarchinitiative not_provided not_provided HGNC:19353 MONDO:0013256 uuid:ee298d4c-92d2-49f2-b26e-2c91e547188c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46295 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0043352 infores:hetionet CHEBI:3752 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0014743 infores:hetionet NCBIGene:5551 biolink:causes MONDO:0015909 infores:monarchinitiative not_provided not_provided HGNC:9360 MONDO:0015909 uuid:3d8cf4dd-9447-4e72-ae19-850ab4a24667 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0004936 infores:hetionet CAID:CA9043739 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043739 MONDO:0012999 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Supporting The NM_000156.6:c.317A>C variant in GAMT is a missense variant that is predicted to result in the substitution of glutamine by proline at amino acid 106 (p.Gln106Pro). The highest population minor allele frequency in gnomAD v4.1.0. is is 0.000040617 (3/73860 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). In HeLa cells, expression of the variant resulted in <15% of wild-type GAMT enzyme activity (PMID: 26003046) (PS3_Supporting). The computational predictor REVEL gives a score of 0.751 which is in the range of 0.644-0.773, evidence that correlates with impact to GAMT function at the supporting level (PP3). To our knowledge, this variant has not been reported in an individual with GAMT deficiency in the published literature. There is a ClinVar entry for this variant (Variation ID: 449690). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043739/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3561 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0542571 infores:hetionet CHEBI:31709 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0023066 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151763 infores:hetionet NCBITaxon:380985 biolink:causes MONDO:0005812 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:380985 MESH:D007251 DB00198_MESH_D007251_1 CAID:CA8602734 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602734 MONDO:0100326 PMID: Uncertain Significance BP4 BS1, PM2, PP3 NM_000419.5(ITGA2B):c.2321G>A (p.Arg774Gln) is a missense variant for which the computational predictor REVEL gives a score of 0.041, below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4), and no splicing effect is predicted by SpliceAI. The highest population minor allele frequency in gnomAD v4.1 is 0.0002271 (268/1180028 alleles) in the European (non-Finnish) genetic ancestry group, which is above than the ClinGen PD VCEP threshold of <0.0001 for PM2_Supporting but below the >0.00158 threshold for BS1. After a thorough literature search, this variant has not been reported in a Glanzmann thrombasthenia patient to our knowledge. ClinVar contains an entry for this variant (Variation ID: 2328709) with multiple VUS submissions (SCV004889457.1, SCV005422410.1, SCV003287488.3), none reporting an affected individual. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602734/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:68478 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019372 infores:hetionet CHEBI:2687 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0854467 infores:hetionet CHEBI:28901 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0242184 infores:hetionet GO:0003400 biolink:causes GO:0051650 infores:ubergraph knowledge_assertion manual_agent GO:0003400 GO:0051650 CHEBI:47898 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0518988 infores:hetionet CHEBI:10110 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0221423 infores:hetionet CHEBI:4445 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0041834 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0021053 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0014544 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151698 infores:hetionet CHEBI:38562 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C2047937 infores:hetionet CHEBI:3207 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0014335 infores:hetionet CHEBI:114785 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0019212 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0022116 infores:hetionet CHEBI:2569 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0017178 infores:hetionet CHEBI:68579 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0015402 infores:hetionet CHEBI:131512 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0037763 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0015256 infores:hetionet CHEBI:3723 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233754 infores:hetionet CAID:CA2499225879 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225879 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, BP1, BP4, BP2, BP3, BA1, BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 The c.713_726del (p.Val238Alafs*18) variant in RUNX1 is a frameshift deletion predicted to cause a premature stop codon in biologically-relevant exon 7/9 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2 and v3 with a mean coverage of at least 20X (PM2_Supporting). Although the variant has not been described in patients, there are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) with sufficient molecular and specific clinical data (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_Supporting, and PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225879/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:6606 biolink:causes MONDO:0010056 infores:monarchinitiative not_provided not_provided HGNC:11117 MONDO:0010056 uuid:562de63f-bc14-4e15-b5c3-beb6fc4f626d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA019161 biolink:causes MONDO:0005835 infores:clingen CAID:CA019161 MONDO:0005835 PMID: Likely Benign BP4, BS3 BA1, BP5, BS1, PM2, BS2 The MSH2 c.1748A>G variant is predicted as a missense variant, p.(Asn583Ser). It has been identified at an MCAF 95% of 0.00934% in gnomAD all non-cancer v2.1.1 and Grpmax AF of 0.007999% in gnomAD v4.1. It is not predicted to affect protein function (Prior_utah (MAPP/PP2 < than 0.11; BP4). The variant did not affect the splicing (pCAS minigene [Pascaline Gaildrat & Stephanie Baert-Desurmont]) and showed proficient function in a calibrated functional assay (PMID 33357406; BS3). The variant was found in a patient with CRC showing MSS/IHC normal (FHCRC CCFR, Insight database). According to the current guidelines, the variant is classified as likely benign. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA019161/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9139 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0003864 infores:hetionet NCBIGene:115286 biolink:causes MONDO:0014775 infores:monarchinitiative not_provided not_provided HGNC:20661 MONDO:0014775 uuid:ee4f8abc-f13e-4198-b65c-d8d569c959f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0015403 infores:hetionet NCBIGene:23250 biolink:causes MONDO:0957279 infores:monarchinitiative not_provided not_provided HGNC:13552 MONDO:0957279 uuid:6100af79-6b34-4a73-b04a-2b8c5993061f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5296 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0006145 infores:hetionet CHEBI:204734 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0036689 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0234192 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0020651 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0027051 infores:hetionet CAID:CA274472 biolink:causes MONDO:0009290 infores:clingen CAID:CA274472 MONDO:0009290 PMID:25455803PMID:27896092PMID:24495340PMID:22538254 Pathogenic PM2, PP4_Moderate, PM3, PVS1_Strong The c.1438-1G>C variant alters the canonical acceptor splice site of intron 9 and is predicted to impact splicing, possibly causing skipping of exon 10 which would result in an in frame deletion that removes ~4% of the primary amino acid sequence, including part of the GAA catalytic barrel (PMIDs 1856189; 22253258; DOI 10.1101/212837). However, in silico splicing predictors indicate the presence of a strong acceptor site 15 nucleotides upstream of the normal site which could be used in the absence of the normal site (Human Splicing Finder score for the normal site is 90.43, and for the upstream site the score is 88.06; MaxEnt Scan score for the normal site is 6.83, and for the upstream site it is 6.94). If the upstream site is used, this would result in the insertion of 5 amino acids and presence of the normal exon 10 sequence. To our knowledge, no functional analysis has been performed to determine the impact of this specific variant. However, the strength of PVS1 has been reduced to PVS1_Strong to recognize impact on the protein suggested by in silico predictors. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00011 in the African population, meeting PM2. Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G, phase unknown. This data meets PM3. Pseudodeficiency variants are known to be absent in the second individual and, therefore, PP4_Moderate can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). There is a ClinVar entry for this variant (Variation ID: 189184, 2 star review status) for which two submitters classify the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1_Strong, PM2, PM3, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274472/MONDO:0009290/010 2020-05-04 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63631 biolink:causes UMLS:C0948856 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0948856 infores:hetionet CHEBI:3403 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042487 infores:hetionet CHEBI:31705 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0003578 infores:hetionet CHEBI:63584 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020621 infores:hetionet CHEBI:6520 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0034069 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0221752 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027769 infores:hetionet CHEBI:3508 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0151474 infores:hetionet CHEBI:7907 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0020517 infores:hetionet CHEBI:9674 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013378 infores:hetionet CHEBI:2567 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0004093 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037274 infores:hetionet CHEBI:50730 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0004096 infores:hetionet CHEBI:7478 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0014868 infores:hetionet CHEBI:4027 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0003962 infores:hetionet CHEBI:63630 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0404521 infores:hetionet CHEBI:63598 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041834 infores:hetionet CHEBI:9352 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0003811 infores:hetionet CHEBI:135961 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0017178 infores:hetionet CHEBI:9555 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0030312 infores:hetionet NCBIGene:3617 biolink:causes MONDO:0014508 infores:monarchinitiative not_provided not_provided HGNC:6055 MONDO:0014508 uuid:a8b3ce19-9a54-4b3e-ba44-4ed112da7a3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085681 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0022660 infores:hetionet CHEBI:7773 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0033774 infores:hetionet CHEBI:521033 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0042109 infores:hetionet NCBIGene:8087 biolink:causes MONDO:0032937 infores:monarchinitiative not_provided not_provided HGNC:4023 MONDO:0032937 uuid:29a0a484-f084-40fb-ad4a-b4231de1dbb7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0600142 infores:hetionet CHEBI:63620 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0206062 infores:hetionet NCBITaxon:4859 biolink:causes MONDO:0000302 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:4859 MONDO:0000302 CHEBI:51860 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C2830004 infores:hetionet CHEBI:31547 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020461 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0522172 infores:hetionet CHEBI:44423 biolink:causes HP:0001896 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0858867 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0233472 infores:hetionet CHEBI:50223 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0000737 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005915 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0040262 infores:hetionet CHEBI:9599 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0041834 infores:hetionet CHEBI:17026 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0404521 infores:hetionet CHEBI:2637 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C1320835 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1274594 infores:hetionet CHEBI:3219 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0702166 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0034150 infores:hetionet CHEBI:5002 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0948089 infores:hetionet CL:0011012 biolink:causes MONDO:0000448 infores:ubergraph knowledge_assertion manual_agent CL:0011012 MONDO:0000448 CHEBI:71255 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0006145 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0023418 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0856148 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0856148 infores:hetionet CHEBI:32192 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0017181 infores:hetionet CHEBI:49040 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0030305 infores:hetionet CHEBI:15428 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0011991 infores:hetionet CHEBI:10650 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013362 infores:hetionet CHEBI:7443 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0016204 infores:hetionet CHEBI:63598 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C2830004 infores:hetionet CAID:CA410206884 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206884 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.691C>A (p.Leu231Met) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206884/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5855 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0235146 infores:hetionet CHEBI:28748 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085631 infores:hetionet GO:2000067 biolink:causes GO:0048364 infores:ubergraph knowledge_assertion manual_agent GO:2000067 GO:0048364 CHEBI:17026 biolink:causes MONDO:0011972 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0085083 infores:hetionet CHEBI:63115 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0151662 infores:hetionet CHEBI:63598 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002994 infores:hetionet CAID:CA410146612 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146612 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1426G>T (p.Val476Leu) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. This missense variant has a REVEL score of 0.502. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146612/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9130 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0262662 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0426576 infores:hetionet NCBIGene:27125 biolink:causes MONDO:0014609 infores:monarchinitiative not_provided not_provided HGNC:17869 MONDO:0014609 uuid:602acc45-0095-4ac1-8f08-6aadda9b7b79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92712 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0020621 infores:hetionet GO:0099145 biolink:causes GO:0098969 infores:ubergraph knowledge_assertion manual_agent GO:0099145 GO:0098969 CHEBI:5801 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0030193 infores:hetionet CHEBI:7824 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0152198 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233471 infores:hetionet CHEBI:8499 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0027947 infores:hetionet CHEBI:50730 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0851578 infores:hetionet CHEBI:4995 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0010200 infores:hetionet CAID:CA10580495 biolink:causes MONDO:0700268 infores:clingen CAID:CA10580495 MONDO:0700268 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3 PP3, BP1, BP4 The c.5200T>A variant in BRCA1 is a missense variant predicted to cause substitution of Phenylalanine by Isoleucine at amino acid 1734 (p.(Phe1734Ile)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.24, indicating impact on BRCA1 function via protein change is unclear (score range 0.15-0.28). A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (no bioinformatic code is applied). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.9 (based on Family History LR=3.9), within the thresholds for supporting evidence towards pathogenicity (LR >2.08 & ≤4.3) (PP4 met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP4). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580495/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3441 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0948089 infores:hetionet CHEBI:50742 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0011606 infores:hetionet CHEBI:3752 biolink:causes MONDO:0008586 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0040588 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0027765 infores:hetionet CHEBI:135351 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0011603 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0239978 infores:hetionet CAID:CA294297 biolink:causes MONDO:0100488 infores:clingen CAID:CA294297 MONDO:0100488 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.214G>A (p.Asp72Asn) missense variant has a maximum subpopulation frequency of 0.048% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 300 probands not meeting HDGC phenotype criteria (BS2; SCV000210893.13, SCV000186096.8, SCV000166549.12). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294297/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:4681 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0003811 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013220 infores:hetionet CAID:CA229534 biolink:causes MONDO:0009861 infores:clingen CAID:CA229534 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 PM3 This c.400C>T (p.Gln134Ter) variant in PAH was detected in a patient with PKU (PMID:17096675). This variant was absent in population databases. This was predicted as a null variant in PAH where LOF is a known mechanism of disease. This is a nonsense variant in exon 4 of 13 coding exons predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1,PM2,PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229534/MONDO:0009861/006 2022-10-14 2022-10-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3756 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0151907 infores:hetionet CHEBI:39585 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0522153 infores:hetionet CHEBI:51173 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0013404 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0036416 infores:hetionet CHEBI:63611 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004604 infores:hetionet CHEBI:27436 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0019080 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151849 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0006849 infores:hetionet CHEBI:31623 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0027497 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0018799 infores:hetionet CHEBI:3082 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0162529 infores:hetionet CHEBI:45285 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0423791 infores:hetionet CHEBI:7447 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C2697368 infores:hetionet CHEBI:474053 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C1257843 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0021400 infores:hetionet CAID:CA2387257481 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387257481 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP3, BP2, BP1, BP4, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.957_959del (p.Ser319del) is an in-frame deletion variant which does not occur within the Runt Homology Domain (AA 89-204) (PM4 not applicable). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387257481/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:3759 biolink:causes MONDO:0012314 infores:monarchinitiative not_provided not_provided HGNC:6263 MONDO:0012314 uuid:af181317-6d43-4be4-95ec-6443f4c7d8d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1278 biolink:causes MONDO:0009804 infores:monarchinitiative not_provided not_provided HGNC:2198 MONDO:0009804 uuid:7182240a-f4c2-4428-be14-d0b82bb5916f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA204685 biolink:causes MONDO:0100040 infores:clingen CAID:CA204685 MONDO:0100040 PMID: Pathogenic PM1, PS2_Very Strong, PS4, PM2_Supporting The p.Asn187Lys variant in FOXG1 has been reported as a de novo occurrence (biological parenthood confirmed) in at least 2 individuals with FOXG1 disorder (PMID 26795593, 28661489) (PS2_very strong). The p.Asn187Lys variant in FOXG1 has been observed in at least 5 other individuals with FOXG1 disorder (PMID 26795593, 25356970, 28661489) (PS4). This variant occurs in the well-characterized Forkhead functional domain of the FOXG1 (PM1). The p.Asn187Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Asn187Lys variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PS2_very strong, PS4, PM1, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA204685/MONDO:0100040/016 2021-03-25 2021-05-10 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:6775 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0021359 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042769 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013146 infores:hetionet CHEBI:42797 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018681 infores:hetionet CHEBI:51209 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0018524 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0521495 infores:hetionet CHEBI:31302 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0042963 infores:hetionet CHEBI:7936 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002390 infores:hetionet CHEBI:37333 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0042963 infores:hetionet NCBIGene:324 biolink:causes MONDO:0021056 infores:monarchinitiative not_provided not_provided HGNC:583 MONDO:0021056 uuid:191622f8-e7b9-4b78-9488-0e1cdf4a4d21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0162830 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0042373 infores:hetionet CAID:CA404084655 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084655 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BA1, PS1, BS1, PM5, PP3 The NM_000527.5(LDLR):c.1189T>C (p.Ser397Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v20210610). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084655/MONDO:0007750/013 2023-06-23 2025-09-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:109549 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C1306341 infores:hetionet CHEBI:135351 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0013384 infores:hetionet CHEBI:15551 biolink:causes HP:0003811 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0410916 infores:hetionet CHEBI:64355 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1619702 infores:hetionet CHEBI:78543 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151825 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018824 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0919620 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0919620 infores:hetionet CHEBI:85083 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0009806 infores:hetionet CHEBI:5106 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0039231 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027707 infores:hetionet CHEBI:8455 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0015967 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0009782 infores:hetionet CHEBI:367163 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1280433 infores:hetionet CHEBI:51230 biolink:causes HP:0500043 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0234665 infores:hetionet CHEBI:2788 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C1443060 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0239729 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0239729 infores:hetionet CAID:CA10653573 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653573 MONDO:0011071 PMID: Benign BA1 PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*264C>T is a 3' UTR variant. MAF 0.006002 (0.6002%, 29/4832) in the South Asian subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653573/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36704 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0006277 infores:hetionet CHEBI:15640 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0023530 infores:hetionet CHEBI:49040 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0006826 infores:hetionet CAID:CA367402580 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402580 MONDO:0015967 PMID: Likely Pathogenic PS2_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1 The c.350G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to valine at codon 117 (p.(Gly117Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 2 hour OGTT increment < 3 mmol/L and negative antibodies) (PP4_Moderate; internal lab contributors), identified as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate, Internal lab contributors). In summary, c.350G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PS2_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402580/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Supports CHEBI:7488 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0423602 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0042963 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0039503 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0022573 infores:hetionet CHEBI:135791 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0263449 infores:hetionet CHEBI:64355 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0221150 infores:hetionet CAID:CA338721 biolink:causes MONDO:0017623 infores:clingen CAID:CA338721 MONDO:0017623 PMID: Benign BA1 PM2, BS1 PTEN c.802-51_802-14del (IVS7-51_IVS7-14del) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.01931 (1.931%, 2747/142,290 alleles) in the global gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA338721/MONDO:0017623/003 2020-03-23 2020-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:59773 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C2047937 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0086543 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015230 infores:hetionet CHEBI:9907 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0019080 infores:hetionet CHEBI:46557 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0007859 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042063 infores:hetionet NCBIGene:84059 biolink:causes MONDO:0011558 infores:monarchinitiative not_provided not_provided HGNC:17416 MONDO:0011558 uuid:ea194b2a-cf20-4569-9919-8c79ae02d843 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151662 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0700345 infores:hetionet CHEBI:85078 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0018681 infores:hetionet GO:2000039 biolink:causes GO:0090626 infores:ubergraph knowledge_assertion manual_agent GO:2000039 GO:0090626 CHEBI:7465 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0235996 infores:hetionet CHEBI:77260 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0234632 infores:hetionet CHEBI:8228 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0547030 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038814 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042514 infores:hetionet CHEBI:9328 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0033774 infores:hetionet CHEBI:5778 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0035410 infores:hetionet CHEBI:63629 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C2239176 infores:hetionet CHEBI:45979 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0520966 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042384 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003123 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0009806 infores:hetionet CHEBI:6339 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013604 infores:hetionet CAID:CA005894 biolink:causes MONDO:0100316 infores:clingen CAID:CA005894 MONDO:0100316 PMID:25705178 Likely Pathogenic PVS1 BP4, PS3, BS1, PM2, PM3, PP3 NM_000218.3(KCNQ1):c.1552C>T (p.Arg518Ter) is a nonsense variant in exon 12 of 16 that introduces a premature stop codon at codon 518 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001737, with 205/1179992 alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 and higher than the PM2_Supporting threshold of <0.00001, so neither criterion is met. This variant has been detected in at least 2 apparently unrelated individuals with Jervell and Lange-Nielsen syndrome who had both a long QT interval and congenital deafness and harbored the variant in the homozygous state (1 pt, PMID: 29922582, PMID: 28438721, PM3), however PM3 is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting). Additional individuals harbored the variant in the compound heterozygous state, some with autosomal recessive long QT syndrome (without congenital deafness) and others with Jervell and Lange-Nielsen syndrome (PMID: 24912595, PMID: 23392653). One individual harbored the variant in the compound heterozygous state, confirmed in trans with the NM_000218.3(KCNQ1):c.1573G>A (p.Ala525Thr) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 24912595). This variant has been shown to disrupt KCNQ1 function in at least four experimental assays, including manual patch-clamp and KCNQ1 mislocalization by immunofluorescence (PMID: 24912595, PMID: 25705178), however, PS3_Supporting is not met since the variant has already met PVS1. In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PVS1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA005894/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17347 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0001807 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0036974 infores:hetionet CHEBI:7931 biolink:causes HP:0012764 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085619 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0027441 infores:hetionet CHEBI:29688 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0028084 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0039971 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0518015 infores:hetionet CAID:CA024110 biolink:causes MONDO:0018493 infores:clingen CAID:CA024110 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with aspartic acid at codon 4733 of the RYR1 protein, p.(Tyr4733Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted.This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 15731587). A functional study using [3H]ryanodine in HEK293 cells showed altered activity of this variant compared to wild-type using but this study did not meet the VCEP criteria for a well-established functional study (PMID:27558158). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.842 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024110/MONDO:0018493/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true UMLS:C0120107 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018681 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0035455 infores:hetionet CHEBI:7565 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0000731 infores:hetionet CHEBI:8356 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013491 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0233494 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0040034 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0085649 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085624 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005900 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030583 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0009443 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042035 infores:hetionet CHEBI:9123 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030252 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0023895 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0005073 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0027960 infores:hetionet CHEBI:2682 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018790 infores:hetionet CHEBI:40279 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0001925 infores:hetionet NCBIGene:4352 biolink:causes MONDO:0011173 infores:monarchinitiative not_provided not_provided HGNC:7217 MONDO:0011173 uuid:8fc7c4ef-a225-46c6-816c-c4da0fa9ffdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151878 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0011644 infores:hetionet CHEBI:8378 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0702166 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0026113 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0151505 infores:hetionet CHEBI:6909 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0002994 infores:hetionet CHEBI:100147 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0151740 infores:hetionet CHEBI:15428 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0040046 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018790 infores:hetionet GO:2000477 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0072210 CHEBI:27899 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151763 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020456 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017181 infores:hetionet CHEBI:63621 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0085669 infores:hetionet CHEBI:45783 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0002792 infores:hetionet CHEBI:41977 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0043352 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0017178 infores:hetionet CHEBI:9943 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0234047 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0233494 infores:hetionet CHEBI:76010 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0042963 infores:hetionet CAID:CA380145372 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145372 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PVS1_Supporting, PM1_Supporting NM_000536.4(RAG2):c.2T>C is a missense variant predicted to cause substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). The next possible initiation codon is at codon 5. This region does not contain known pathogenic/likely pathogenic variants (PVS1_Supporting). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Supporting, PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145372/MONDO:0000573/124 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5384 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C1167965 infores:hetionet CAID:CA245046 biolink:causes MONDO:0015152 infores:clingen CAID:CA245046 MONDO:0015152 PMID: Benign BA1, PP3 PM3, PM2, BS1, PP4 The NM_000023.4: c.320C>T variant in SGCA is a missense variant predicted to cause substitution of alanine by valine at amino acid 170 (p.Ala107Val). The filtering allele frequency of this variant is 0.003138 (the lower threshold of the 95% CI of 71/18394 exome chromosomes) in the East Asian population of gnomAD v2.1.1, which is higher than the ClinGen LGMD VCEP threshold for BA1 (0.002) and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.864, which is above the threshold of 0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BA1, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA245046/MONDO:0015152/189 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:64355 biolink:causes UMLS:C0856095 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0856095 infores:hetionet CHEBI:53760 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085628 infores:hetionet CAID:CA402701458 biolink:causes MONDO:0012589 infores:clingen CAID:CA402701458 MONDO:0012589 PMID:26993267PMID:29322350PMID:26993267PMID:29322350PMID:26993267 Likely Pathogenic PP4, PS4_Moderate, PM6_Strong, PM2_Supporting The p.Ser253Arg variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt–Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PM6_Strong). The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PS4_Moderate). The p.Ser253Arg variant in TCF4 is absent from gnomAD (PM2_Supporting). The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg) (PP4). In summary, the p.Ser253Arg variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA402701458/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:45863 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0039240 infores:hetionet CAID:CA16606476 biolink:causes MONDO:0015967 infores:clingen CAID:CA16606476 MONDO:0015967 PMID: Likely Benign BP4, BP7 BS1, PM2 The c.870C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 290 (p.Pro290=) of NM_000545.8. The computational splicing predictor SpliceAI gives a score of 0.01 for acceptor gain, suggesting that the variant has no impact on splicing and is not highly conserved with a phyloP100 score of -0.658, which is below the ClinGen MDEP cutoff of 2.0 (BP4, BP7). This variant has a Grpmax filtering allele frequency of 0.00000689 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.870C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606476/MONDO:0015967/017 2025-08-29 2025-08-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4876 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0018965 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0035455 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0032584 infores:hetionet CHEBI:75179 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0259799 infores:hetionet CHEBI:42820 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0034150 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0267033 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0267033 infores:hetionet CHEBI:16664 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0151766 infores:hetionet CHEBI:9352 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0151579 infores:hetionet CHEBI:31348 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003962 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0221773 infores:hetionet CHEBI:134966 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0014394 infores:hetionet CHEBI:8107 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011175 infores:hetionet CHEBI:63621 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038325 infores:hetionet CAID:CA10584718 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584718 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PS3, PVS1_Moderate, PP1_Moderate, PM2, PP4 BA1, BP4, BP2, PS2, PS1, BS1, BS3, BS4, BP7, PM4, PM3, PM5, PM6, PP3 The NM_000527.5(LDLR):c.1A>C (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PS3, PS4_Supporting, PP1_Moderate, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - variant is absent from gnomAD (v2.1.1).PVS1_Moderate – variant is predicted to affect the initiation codon.PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: results of 60% cell surface LDLR, 59% LDL binding and 66% LDL uptake, compared to wild-type. Note - Level 3 luciferase reporter assays were also performed: results of 5% luciferase construct activity compared to wild-type. Both studies performed in PMID: 34572405.PS4_Supporting - variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH (4 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab).PP1_Moderate – variant segregates with phenotype in 4 informative meioses in 3 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 3 families: 4 affected relatives with the variant).PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.Note: four other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1A>G (p.Met1Val) – Likely pathogenic by these guidelines.2) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines.3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines.4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584718/MONDO:0007750/013 2022-05-19 2022-05-19 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:63605 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0026858 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0037199 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0022660 infores:hetionet CHEBI:63607 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0344232 infores:hetionet CHEBI:5613 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0040485 infores:hetionet CHEBI:9288 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0015967 infores:hetionet UMLS:C0010592 biolink:causes HP:0031657 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0577822 infores:hetionet CHEBI:473990 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0085605 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0687707 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0392025 infores:hetionet CHEBI:75179 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0020452 infores:hetionet CAID:CA229613 biolink:causes MONDO:0009861 infores:clingen CAID:CA229613 MONDO:0009861 PMID:23430918PMID:23430918 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.929; PP4_Moderate: Detected in 1 PKU patient, primary BH4 deficiency excluded. Upgraded per ClinGen PAH EP. (PMID:23430918); PM3: Detected with c.1066-11G>A (P) (PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229613/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:80630 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151942 infores:hetionet CHEBI:50378 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0011991 infores:hetionet CHEBI:5801 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0549567 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042571 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151824 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0851341 infores:hetionet CAID:CA10606168 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606168 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PP1, PM2_Supporting PM5, PM4, PM1, PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS4, BS1, BS3, PM6, BS2, PP2, PP3 The NM_003494.4: c.2811-2A>C variant in DYSF, which is also known as NM_001130987.2: c.2865-2A>C, occurs within the canonical splice acceptor site of intron 26. It is predicted to cause skipping of biologically relevant exon 27/55, resulting in a frameshift and introduction of a premature truncation codon that is expected to lead to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. RNAseq analysis has shown that this variant results in near-complete elimination of normal splicing, resulting in the production of three alternative transcripts with a frameshift and premature truncation (PMID: 36983702) (PVS1_RNA). This variant has been detected in at least 4 unrelated individuals with dysferlinopathy (PMID: 36983702, 26671124, 33927379, 30564623). Of those individuals, two were homozygous (1.0 pt), one was compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.1852G>A p.Gly618Arg, 1.0 pt), and one carried a variant classified as at least likely pathogenic in unknown phase (c.5529G>A p.Trp1843Ter, 0.25 pts) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702). The variant has also been reported to segregate with LGMD in two affected family members from one family (PMID: 26671124; PP1, capped with PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_RNA, PP4_Strong, PM3_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606168/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31980 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0005779 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0149931 infores:hetionet CHEBI:3175 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0027497 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0403632 infores:hetionet CHEBI:60761 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0002962 infores:hetionet CHEBI:64354 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C2363731 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004967 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023449 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018021 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0037199 infores:hetionet CHEBI:31236 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0423791 infores:hetionet CHEBI:72690 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020437 infores:hetionet NCBITaxon:1824 biolink:causes MONDO:0017776 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1824 MESH:D009617 DB01015_MESH_D009617_1 UMLS:C0010592 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042024 infores:hetionet CHEBI:7494 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C2047937 infores:hetionet CHEBI:63616 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0041834 infores:hetionet CHEBI:5147 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0013378 infores:hetionet CHEBI:8888 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232462 infores:hetionet CAID:CA624860683 biolink:causes MONDO:0008723 infores:clingen CAID:CA624860683 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1, PP4_Moderate The NM_000018.4:c.253dup (p.Asp85Glyfs*19) variant in ACADVL is a one nucleotide duplication that results in a frameshift predicted to cause a premature stop codon in biologically-relevant-exon 5/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a distinct pathogenic (VCV000021025.27; c.848T>C, p.(Val283Ala); not confirmed in trans by parental testing. (PM3 points = 0.5, PMID: 27209629) (PM3_Supporting). At least one patient with this variant displayed >1.0uM C14::1 levels on initial NBS and asserted abnormal levels of plasma acylcarnitine levels at follow-up, which is highly specific for VLCADD (PMID: 27209629) (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001758 in NFE population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM3_Supporting, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 08/11/21). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624860683/MONDO:0008723/021 2022-04-06 2022-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6061 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0085649 infores:hetionet CHEBI:47780 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030252 infores:hetionet CAID:CA355946098 biolink:causes MONDO:0001586 infores:clingen CAID:CA355946098 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5(IDUA):c.178C>T (p.Gln60Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 2 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including skeletal abnormalities and hepatosplenomegaly (PP4). This individual was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909); confirmed in trans by parental testing (PMID: 11735025, 1 pt) PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002228 (1/44874 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 655054). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 16, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355946098/MONDO:0001586/091 2025-06-16 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8874 biolink:causes HP:0000011 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005697 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042109 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151477 infores:hetionet CHEBI:2668 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0005778 infores:hetionet CAID:CA404093661 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093661 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PM5 The NM_000527.5(LDLR):c.2050G>C (p.Ala684Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP3: REVEL score = 0.817. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093661/MONDO:0007750/013 2025-02-20 2025-06-17 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8356 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042345 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0022116 infores:hetionet CHEBI:3215 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0035229 infores:hetionet CHEBI:3223 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0008031 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027441 infores:hetionet CHEBI:49960 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0038160 infores:hetionet CHEBI:3371 biolink:causes UMLS:C0235723 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0235723 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0031350 infores:hetionet CHEBI:63616 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C1384353 infores:hetionet CHEBI:8228 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0085649 infores:hetionet CHEBI:31644 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0039070 infores:hetionet NCBIGene:9837 biolink:causes MONDO:0044725 infores:monarchinitiative not_provided not_provided HGNC:28980 MONDO:0044725 uuid:ccf47c9e-6296-45f1-a672-79ad7468a9d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011616 infores:hetionet CHEBI:2639 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0037763 infores:hetionet CHEBI:473990 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0019158 infores:hetionet CHEBI:8768 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0518988 infores:hetionet NCBIGene:10058 biolink:causes MONDO:0013783 infores:monarchinitiative not_provided not_provided HGNC:47 MONDO:0013783 uuid:f6131537-f9ef-484b-96ff-31325747d974 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0232459 infores:hetionet CHEBI:7822 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0027497 infores:hetionet CHEBI:119573 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0004093 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0040034 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0027765 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0023895 infores:hetionet NCBIGene:8651 biolink:causes MONDO:0800130 infores:monarchinitiative not_provided not_provided HGNC:19383 MONDO:0800130 uuid:1888bf50-d36e-44af-9158-42f4a84b1c51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes UMLS:C0852995 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0852995 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151828 infores:hetionet CHEBI:9654 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0030554 infores:hetionet NCBIGene:25 biolink:causes MONDO:0011996 infores:monarchinitiative not_provided not_provided HGNC:76 MONDO:0011996 uuid:037d3203-2b03-415b-b835-2957a84c5d0a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA376066161 biolink:causes MONDO:0011225 infores:clingen CAID:CA376066161 MONDO:0011225 PMID: Uncertain Significance PP4, PM2_Supporting, PM3_Supporting BS2, PS3, PS1, PM5 The c.17G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Glutamic Acid at amino acid 6 (p.Gly6Glu).This variant is absent from gnomAD v4 (PM2_Supporting).At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + WES (0.5 pts) T-B-NK+ lymphocyte subset profile (0.5 pts); total 1.5 pts, which is highlyspecific for SCID, PP4 is met (PMID: 29051008). The patient is homozygous for this variant (0.5 pts; PM3_Supporting).In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4, and PM3_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376066161/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:75722 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151849 infores:hetionet CHEBI:17698 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0542184 infores:hetionet CHEBI:85078 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0002965 infores:hetionet CAID:CA10581499 biolink:causes MONDO:0015967 infores:clingen CAID:CA10581499 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate PM1 The c.1148C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to leucine at codon 383 (p. (Ser383Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2) This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.831 which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.20, which is below the MDEP cutoff (<0.5) (Matschinsky FM, Magnuson MA (eds): Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front. Diabetes. Basel, Karger, 2004, vol 16, pp 92–109). This variant has been identified in at least 53 unrelated individuals with hyperglycemia and segregated with the phenotype, with 30 informative meioses in 49 families (PS4, PP1_Strong; PMID: 28555465, 30663027, 34462253, 34746319, internal lab contributors). At least of of these patients had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative GAD-65 (PP4_Moderate; PMID: 28555465). In summary, c.1148C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PS4, PP4_Moderate, PP2, PP1_Strong, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581499/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:59750 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0033774 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020437 infores:hetionet CHEBI:2675 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0278134 infores:hetionet CHEBI:7478 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0011124 infores:hetionet CHEBI:5165 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0023218 infores:hetionet CHEBI:32192 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0014742 infores:hetionet NCBIGene:54902 biolink:causes MONDO:0014063 infores:monarchinitiative not_provided not_provided HGNC:26006 MONDO:0014063 uuid:71acca3b-efcc-459f-a030-37a58d907f2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0003467 infores:hetionet CHEBI:3723 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009676 infores:hetionet NCBIGene:64919 biolink:causes MONDO:0060763 infores:monarchinitiative not_provided not_provided HGNC:13222 MONDO:0060763 uuid:3909b804-e68f-49bc-84fc-b1ba2571e119 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA6403841 biolink:causes MONDO:0019565 infores:clingen CAID:CA6403841 MONDO:0019565 PMID: Uncertain Significance BP4 BS1 The NM_000552.5:c.304G>A variant in VWF is a missense variant predicted to cause substitution of valine by methionine at amino acid 102. The computational predictor REVEL gives a score of 0.252, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. The population frequency of this variant is inconclusive of pathogenicity or benignity. There are three ClinVar submissions at the time of this variant classification but a disease assertion or affected status is not specified for any of the submitted cases. No instance of a case carrying this variant being affected by von Willebrand disease could be found in a literature search. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP4. (VWD VCEP specifications v1) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6403841/MONDO:0019565/081 2025-11-04 2025-11-04 Undetermined mode of inheritance Inconclusive true CHEBI:6413 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0022107 infores:hetionet NCBIGene:23265 biolink:causes MONDO:0033658 infores:monarchinitiative not_provided not_provided HGNC:23214 MONDO:0033658 uuid:1e1b04ed-fb4e-44f0-9fab-42e19692d9d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:60761 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0014591 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0026946 infores:hetionet CAID:CA10549367 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549367 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting BS3 The NM_005629.4:c.942C>G variant in SLC6A8 is a missense variant predicted to cause a substitution of a phenylalanine for a leucine at amino acid position 314 (p.Phe314Leu). This variant has been reported in a heterozygous (carrier) female individual in the Exome Variant Server database without further phenotypic information provided (PMID: 25861866); thus, neither BS2 nor PP4 apply. This variant was reported to result in ≥50% of wild-type creatine transporter activity (PMID: 25861866) but experiment did not use physiological creatine concentrations (≤125μM creatine) so BS3 is not met (PMID: 25861866) (BS3_Supporting). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000766 (1/13055 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), and there are no hemizygotes, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.303, which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549367/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:5781 biolink:causes MONDO:0100082 infores:monarchinitiative not_provided not_provided HGNC:9644 MONDO:0100082 uuid:2c8f1914-47e5-4068-94ef-6032b3fe8cd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0600142 infores:hetionet CHEBI:3561 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0085932 infores:hetionet GO:0061322 biolink:causes CL:0002524 infores:ubergraph knowledge_assertion manual_agent GO:0061322 CL:0002524 CAID:CA261666 biolink:causes MONDO:0021060 infores:clingen CAID:CA261666 MONDO:0021060 PMID: Likely Pathogenic PM1, PM6, PM2, PP3, PP2, PS4_Supporting The c.793G>C (p.Gly265Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in one proband diagnosed with a RASopathy (PM6, PS4_Supporting; Laboratory for Molecular Medicine internal data, ClinVar SCV000061628.5). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly265Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM1, PM2, PM6, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261666/MONDO:0021060/004 2020-07-01 2020-07-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4876 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0009676 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0021290 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0021290 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0030353 infores:hetionet CHEBI:50924 biolink:causes UMLS:C1096082 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1096082 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0035078 infores:hetionet NCBIGene:23258 biolink:causes MONDO:0015002 infores:monarchinitiative not_provided not_provided HGNC:19344 MONDO:0015002 uuid:4c2431a7-cc40-466d-bbb5-f1d196018597 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085632 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0007642 infores:hetionet NCBIGene:50939 biolink:causes MONDO:0013314 infores:monarchinitiative not_provided not_provided HGNC:18362 MONDO:0013314 uuid:a5c7b90f-a19f-4980-88f6-713d7b4abac1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:421707 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0014742 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0001364 infores:hetionet CHEBI:10023 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0546817 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0836924 infores:hetionet CHEBI:64354 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020651 infores:hetionet CHEBI:6015 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0085593 infores:hetionet CHEBI:38940 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151701 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0020517 infores:hetionet CHEBI:4046 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0008370 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0178298 infores:hetionet CHEBI:553473 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0518015 infores:hetionet CHEBI:4495 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0162119 infores:hetionet CHEBI:59445 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0546817 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023218 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162830 infores:hetionet CHEBI:167309 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0080274 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0851341 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0007222 infores:hetionet UMLS:C0145185 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0020625 infores:hetionet CHEBI:5130 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151908 infores:hetionet CAID:CA1244289 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244289 MONDO:0005338 PMID:36267417PMID:16466712 Likely Benign BS3_Supporting BP7, BS1, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.376C>T variant in MYOC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 126 (p.Arg126Trp). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.0006165 (37 alleles out of 60,012), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.561, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Arg126Trp protein had similar secretion levels to wild type myocilin protein in these studies (PMIDs: 16466712, 36267417). The assays met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 2 segregations had been reported for primary open angle glaucoma (POAG), not meeting the ≥ 3 segregations required for PP1. Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS3_Moderate Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244289/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:61033 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0085681 infores:hetionet CHEBI:36791 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085633 infores:hetionet CHEBI:134743 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0011603 infores:hetionet CHEBI:5106 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0015403 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0542476 infores:hetionet NCBIGene:2626 biolink:causes MONDO:0014239 infores:monarchinitiative not_provided not_provided HGNC:4173 MONDO:0014239 uuid:bdf1518c-56e5-4b07-87f3-a3d73eb216e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0026636 infores:hetionet CHEBI:64019 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C2830004 infores:hetionet CHEBI:3568 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C3263723 infores:hetionet CHEBI:59773 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0409974 infores:hetionet NCBIGene:10699 biolink:causes MONDO:0013817 infores:monarchinitiative not_provided not_provided HGNC:19012 MONDO:0013817 uuid:eda9b98b-d6f4-442b-bc77-3d2e596b3f51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0002792 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0234215 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0314719 infores:hetionet CHEBI:6149 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0549249 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005366 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0524909 infores:hetionet CHEBI:17474 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0234233 infores:hetionet CHEBI:28939 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0036974 infores:hetionet NCBIGene:7253 biolink:causes MONDO:0010142 infores:monarchinitiative not_provided not_provided HGNC:12373 MONDO:0010142 uuid:99b083d4-b6ba-4d68-a48c-4300c7f8311c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0812387 infores:hetionet CHEBI:127342 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0026961 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0086543 infores:hetionet CHEBI:7983 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0160390 infores:hetionet CAID:CA16611621 biolink:causes MONDO:0021056 infores:clingen CAID:CA16611621 MONDO:0021056 PMID:22987206PMID:15833136PMID:15459959 Likely Pathogenic PS4, PS3_Moderate, PM2_Supporting, PM6_Supporting The NM_000038.6(APC):c.1312+5G>A variant in APC is an intronic variant which is located at the 5th nucleotide in intron 10. This variant has been reported in 16 probands meeting phenotypic criteria, resulting in a total phenotype score of 11.5 points (internal data Labcorp Genetics [formerly Invitae], Ambry Genetics, Peter MacCallum Cancer Centre, Victoria, Australia, PMID: 15459959 and 23159591) (PS4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RNA studies have demonstrated that this variant causes exon 10 skipping (PMID: 22987206, 15459959, 15833136, Ambry internal data) (PS3_Moderate). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with FAP, resulting in a total de novo score of 0.5 (PMID: 15833136) (PM6_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS3_Moderate, PS4, PM2_Supporting, PM6_Supporting (VCEP specifications version 2.1.0; date of approval: 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16611621/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CAID:CA486098749 biolink:causes MONDO:0100040 infores:clingen CAID:CA486098749 MONDO:0100040 PMID: Uncertain Significance PM2, BP4 BP7 The c.699G>T (p.Leu233=) variant in FOXG1 is absent from gnomAD (PM2_supporting). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.699G>T (p.Leu233=) variant in FOXG1 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA486098749/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:36704 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0018099 infores:hetionet CAID:CA012894 biolink:causes MONDO:0005045 infores:clingen CAID:CA012894 MONDO:0005045 PMID: Uncertain Significance PP3, PM1, PM2_Supporting, PS4_Supporting PP1, BA1, PM5, PS3, PM6, PM4, BS1, BS3, BS4, BP4, BP7, BP5, BP2, PS1, PS2, PVS1 The NM_000257.4: c.2707G>A (p.Glu903Lys) variant in MYH7 has been reported in 5 individuals with HCM (PS4_Supporting; Kaski 2009 PMID:20031618; Robyns 2020 PMID:3151393; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012894/MONDO:0005045/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37924 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0877192 infores:hetionet CHEBI:7903 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0015230 infores:hetionet CHEBI:2955 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0043352 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017601 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0013395 infores:hetionet CHEBI:180905 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0000737 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0015397 infores:hetionet CHEBI:119915 biolink:causes NCIT:C27003 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0184567 infores:hetionet CHEBI:4511 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0027066 infores:hetionet CHEBI:7494 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0028961 infores:hetionet CHEBI:63605 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0023530 infores:hetionet CAID:CA229567 biolink:causes MONDO:0009861 infores:clingen CAID:CA229567 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Supporting The c.470G>T (p.Arg157Ile) variant in PAH has been reported in at least one individual with plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND normal urine pterins and normal DHPR activity to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PP4_Moderate, PMID: 28754886). Of those individuals, one was compound heterozygous for the variant and a pathogenic variant in unknown phase (PMID: 28754886, PM3_supporting). This variant is absent in from controls in gnomAD v4.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.968, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2_supporting, PM3_supporting, PP3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229567/MONDO:0009861/006 2025-10-12 2025-10-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:188986 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0022281 infores:hetionet CHEBI:6954 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0023380 infores:hetionet CHEBI:45863 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0024141 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0162119 infores:hetionet CHEBI:59773 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0030193 infores:hetionet CAID:CA10014158 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014158 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*113C>T is a UTR variant. MAF of 0.00362 (0.362%, 123/33968,) in the European (Non-Finnish) subpopulation of gnomAD cohort is ≥ 0.0015 (0.15%)(BA1). This variant is detected in a homozygous state in two individuals in a population database (gnomAD)(BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, and BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014158/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8080 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0039231 infores:hetionet NCBIGene:80207 biolink:causes MONDO:0008133 infores:monarchinitiative not_provided not_provided HGNC:8142 MONDO:0008133 uuid:41072d64-e278-476c-87d2-2c3547620683 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32293 biolink:causes UMLS:C1328519 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C1328519 infores:hetionet CHEBI:64354 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0036974 infores:hetionet CHEBI:28593 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0409974 infores:hetionet CAID:CA023472 biolink:causes MONDO:0007750 infores:clingen CAID:CA023472 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.1381G>A (p.Gly461Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: MAF = 0.0001732 in Admixed American exomes (gnomAD v4.0.0); this is less than 0.0002.BP4: No REVEL score, functional data on splicing is not available. MES: A) not on limits. B) not on limit creating AG; on limit however does not create GT. C) there is a GT nearby: Var cryptic donor/Wt cryptic donor= -12.59/ -14.70= 0.86 ; Var cryptic donor/Wt donor= -12.59/5.46= -2.3, alternative splicing not predicted and REVEL is <0.5, therefore BP4 is met. PP4: One case reported in PMID 36229376 (Tada et al., 2022) fulfilling Japan Atherosclerosis Society criteria for FH. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023472/MONDO:0007750/013 2024-02-23 2025-02-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:61390 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0314719 infores:hetionet CHEBI:15940 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0000737 infores:hetionet CHEBI:50305 biolink:causes UMLS:C1504422 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C1504422 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1608954 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1608954 infores:hetionet CHEBI:63632 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C1145670 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0009450 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0314719 infores:hetionet CHEBI:77260 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0424790 infores:hetionet CHEBI:64312 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0338831 infores:hetionet CHEBI:45863 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0025222 infores:hetionet CHEBI:28748 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151907 infores:hetionet CHEBI:75988 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0003811 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0038663 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0029882 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0836924 infores:hetionet CHEBI:4798 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1368065 infores:hetionet CHEBI:4636 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0042109 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0002871 infores:hetionet CHEBI:4858 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0037763 infores:hetionet CHEBI:4710 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0344232 infores:hetionet CHEBI:45409 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151908 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0233494 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022904 infores:hetionet CHEBI:6456 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0340865 infores:hetionet CHEBI:59773 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0011991 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042769 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948525 infores:hetionet CHEBI:47780 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042963 infores:hetionet CHEBI:7577 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0009763 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151735 infores:hetionet CHEBI:16469 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0234518 infores:hetionet NCBIGene:4292 biolink:causes MONDO:0010159 infores:monarchinitiative not_provided not_provided HGNC:7127 MONDO:0010159 uuid:a3c862c8-0863-42ce-8df0-53908d340eb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3757 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0017178 infores:hetionet CHEBI:17334 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020580 infores:hetionet GO:1904838 biolink:causes GO:0007281 infores:ubergraph knowledge_assertion manual_agent GO:1904838 GO:0007281 CHEBI:68642 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0234215 infores:hetionet CHEBI:63581 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0085605 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011609 infores:hetionet CHEBI:79699 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0085649 infores:hetionet CHEBI:404903 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0014591 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0020649 infores:hetionet CHEBI:31236 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0700200 infores:hetionet CHEBI:10125 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0220870 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0033975 infores:hetionet CHEBI:8707 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011124 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0011991 infores:hetionet CHEBI:231594 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0024902 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0022660 infores:hetionet CHEBI:9137 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C2937350 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0021843 infores:hetionet CHEBI:7915 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0949059 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0235283 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0235283 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020456 infores:hetionet GO:1904389 biolink:causes CL:0000751 infores:ubergraph knowledge_assertion manual_agent GO:1904389 CL:0000751 CHEBI:50648 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027441 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030846 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0917798 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0003123 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027339 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015469 infores:hetionet CHEBI:135920 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0000737 infores:hetionet CHEBI:473990 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0011603 infores:hetionet CHEBI:39585 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0497327 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0028738 infores:hetionet NCBIGene:56159 biolink:causes MONDO:0010647 infores:monarchinitiative not_provided not_provided HGNC:11733 MONDO:0010647 uuid:7ac56c94-cda0-4b8d-aafe-95591e627499 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50729 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0700225 infores:hetionet CHEBI:6761 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C2830004 infores:hetionet CHEBI:3242 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0039070 infores:hetionet CHEBI:3219 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036974 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0855223 infores:hetionet CHEBI:10110 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0000729 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0029878 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0948586 infores:hetionet CHEBI:38940 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0743400 infores:hetionet CAID:CA024515 biolink:causes MONDO:0007783 infores:clingen CAID:CA024515 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024515/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA179550 biolink:causes MONDO:0019501 infores:clingen CAID:CA179550 MONDO:0019501 PMID: Uncertain Significance PM3_Supporting, PP3, BS1_Supporting "The c.6233C>G (p.Pro2078Arg) variant in USH2A was present in 0.4% (lower bound of the 95% CI of 50/10070) of Ashkenazi Jewish alleles in gnomAD v4. However, the next highest population frequency (aside from in the ""remaining"" group in gnomAD) was 0.002458% (29/1179812) of non-Finnish European alleles in gnomAD v4. Because this variant is likely a founder population in the AJ population, BS1 was downgraded to BS1_Supporting. The p.Pro2078Arg variant was detected in one proband with retinitis pigmentosa and the pathogenic variant in USH2A c.12067-2A>G but phase unknown (PM3_Supporting; Hadassah-Hebrew University Medical Center internal data, ClinVar SCV001161352.1, PMID:31456290). It has also been seen in at least 8 probands without a second variant identified in USH2A (Laboratory for Molecular Medicine, Invitae internal data, GeneDx, ClinVar SCV000201902.5, SCV001068267.2, SCV005078111.1). The REVEL computational prediction tool produced a score of 0.702, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PM3_Supporting, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 1.15.2025)." Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA179550/MONDO:0019501/005 2025-01-15 2025-03-18 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:182080 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0039070 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0012833 infores:hetionet CHEBI:127342 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027441 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0178298 infores:hetionet NCBIGene:2798 biolink:causes MONDO:0007794 infores:monarchinitiative not_provided not_provided HGNC:4421 MONDO:0007794 uuid:4efe3b26-388c-400c-b472-1c5a3a6a4735 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8597 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0036572 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0595939 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0022650 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0332534 infores:hetionet CHEBI:499361 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0019348 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0043352 infores:hetionet CHEBI:63623 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0027441 infores:hetionet CHEBI:72292 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0031154 infores:hetionet CHEBI:8768 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020443 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0234215 infores:hetionet CHEBI:9460 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C2047937 infores:hetionet NCBIGene:9499 biolink:causes MONDO:0012215 infores:monarchinitiative not_provided not_provided HGNC:12399 MONDO:0012215 uuid:c93958a4-1c76-4eb1-986c-dfea4f456a94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0002962 infores:hetionet CHEBI:65346 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0011991 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0040034 infores:hetionet CHEBI:79699 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0004093 infores:hetionet CHEBI:50730 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0011603 infores:hetionet CHEBI:101853 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0237849 infores:hetionet CHEBI:17549 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0036508 infores:hetionet NCBIGene:57680 biolink:causes MONDO:0014017 infores:monarchinitiative not_provided not_provided HGNC:20153 MONDO:0014017 uuid:45caf46f-8327-439e-a951-04f26bcaf285 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0233407 infores:hetionet CHEBI:45783 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0004093 infores:hetionet CHEBI:585948 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0042963 infores:hetionet CHEBI:135342 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0009782 infores:hetionet CHEBI:3347 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0019080 infores:hetionet CHEBI:10124 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0438716 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0265935 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0265935 infores:hetionet CHEBI:3561 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020578 infores:hetionet CHEBI:6375 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0040822 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002453 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017675 infores:hetionet CHEBI:3654 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0009806 infores:hetionet CAID:CA415078666 biolink:causes MONDO:0010305 infores:clingen CAID:CA415078666 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_005629.4:c.462G>A p.(Trp154Ter) variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 3/13, and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent in gnomADv2.1.1, meeting criteria for PM2_Supporting, and has not been previously reported in ClinVar. The NM_005629.4:c.462G>A p.(Trp154Ter) variant in SLC6A8 has been reported in a male (patient 5) with severe intellectual disability, speech delay, autism, and epilepsy who was reported to have low/near absent creatine peak on H-MRS, and biochemical evidence of creatine transporter deficiency with a creatine/creatinine ratio of 3.2 (reference range 0.05-1.9) and significantly reduced creatine uptake in fibroblasts (patient 5=4.8uM; reference range 36 +/- 5.1uM)) [Fons, 2009; PMID:19706062], therefore this reported individual meets criteria for PP4_Strong. The NM_005629.4:c.462G>A p.(Trp154Ter) variant in SLC6A8 was also reported in a male proband (patient 1) with psychomotor delay, autism, epilepsy who was reported with absent creatine peak on H-MRS, and biochemical anomalies consistent with creatine transporter deficiency [PMID:21140503], however we cannot exclude the possibility that this patient is the same reported in Fons, 2009 so additional evidence from this patient was not used for curation of this variant. In summary, this variant meets the criteria to be classified as Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, March 23, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415078666/MONDO:0010305/027 2023-03-23 2024-04-10 X-linked inheritance HP:0001417 Supports CHEBI:10650 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009450 infores:hetionet CHEBI:9332 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0004093 infores:hetionet CHEBI:100241 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085612 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0040034 infores:hetionet CHEBI:84883 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0015732 infores:hetionet CHEBI:40279 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1142412 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011551 infores:hetionet CAID:CA024590 biolink:causes MONDO:0007783 infores:clingen CAID:CA024590 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM5, PM1_Supporting, PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Cysteine at codon 2163 of the RYR1 protein, p.(Arg2163Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:10484775, PMID:30236257, PMID:9497245). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9873004). Another variant has been assessed as pathogenic at this codon, p.(Arg2163His), PM5 (PMID:30236257 ). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in over 15 individuals PP1_Strong, (PMID:9497245, PMID:30236257, PMID:10484775). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024590/MONDO:0007783/012 2022-03-14 2022-03-14 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:17347 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085633 infores:hetionet CHEBI:50275 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0233471 infores:hetionet CHEBI:7823 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0344232 infores:hetionet CHEBI:50924 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151905 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0236068 infores:hetionet CHEBI:75722 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030232 infores:hetionet CHEBI:4858 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0151904 infores:hetionet CHEBI:100246 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0018965 infores:hetionet CHEBI:31638 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0030794 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006840 infores:hetionet CHEBI:93635 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0235347 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0000833 infores:hetionet CHEBI:61033 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0236075 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0002792 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0015672 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0011991 infores:hetionet NCBIGene:148345 biolink:causes MONDO:0976135 infores:monarchinitiative not_provided not_provided HGNC:26730 MONDO:0976135 uuid:1a31b4ad-0346-4779-ae7e-82ba9b86eeee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0033860 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0520588 infores:hetionet CHEBI:5801 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0014518 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020456 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030305 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0020651 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0038454 infores:hetionet NCBIGene:3459 biolink:causes MONDO:0008856 infores:monarchinitiative not_provided not_provided HGNC:5439 MONDO:0008856 uuid:f72d2b45-ba14-47af-a830-cbe6c5c46bed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3698 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0027769 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151828 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0033581 infores:hetionet UBERON:0003073 biolink:causes UBERON:0004128 infores:ubergraph knowledge_assertion manual_agent UBERON:0003073 UBERON:0004128 CHEBI:70718 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C1384353 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C1145670 infores:hetionet CHEBI:6078 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0015967 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0677500 infores:hetionet CHEBI:135530 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0002994 infores:hetionet CHEBI:63621 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1280433 infores:hetionet CHEBI:79699 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0000731 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0017152 infores:hetionet CHEBI:3723 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043144 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040034 infores:hetionet CAID:CA2499215129 biolink:causes MONDO:0018958 infores:clingen CAID:CA2499215129 MONDO:0018958 PMID: Uncertain Significance PVS1, PM2_Supporting BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1, PM4, PM1, PM3, PM5, BP7, BP5, BS1, BS3, BS4, PM6, PP2, PP3, PP1, PP4, BS2 The NM_001164508 c.1015del (p.Ala339fs) variant in NEB is a nonsense variant predicted to truncate the protein at amino acid 339 in exon 12 of 183 in NEB. Exon 12 is present in the biologically relevant transcript NM_001164508.2 and loss of function is a known mechanism of disease in NEB (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for Nemaline myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PVS1, PM2_Supporting; ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 8/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499215129/MONDO:0018958/146 2024-08-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10125 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0852911 infores:hetionet CHEBI:79699 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1519353 infores:hetionet NCBIGene:150365 biolink:causes MONDO:0032746 infores:monarchinitiative not_provided not_provided HGNC:28613 MONDO:0032746 uuid:3f85ad23-7d1a-4d75-9b1c-0c6651e3d4f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50122 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0151744 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0948089 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0007117 infores:hetionet NCBIGene:59067 biolink:causes MONDO:0014338 infores:monarchinitiative not_provided not_provided HGNC:6005 MONDO:0014338 uuid:8ed8b43c-e8dc-434b-a671-d576599cf572 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013604 infores:hetionet CAID:CA401366926 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366926 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting, PS3_Supporting PM3 The NM_000152.5:c.1477C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 493 (p.Pro493Ser). This variant has been detected in at least 1 patient reported to have Pompe disease with reported laboratory values demonstrating deficient GAA activity (Duke University; PMID: 31904026, 32518148) (PP4_moderate). This variant has been detected in at least one individual with Pompe disease. This individual was compound heterozygous for the variant, c.1477C>T (p.Pro493Ser), and two other variants: a variant classified as pathogenic by the ClinGen LD VCEP, c.1978C>T (p.Arg660Cys) (ClinVar Variation ID: 558604, SCV002540656.1), and a variant not classified by the by the ClinGen LD VCEP, c.2221G>A (p.Asp741Asn) (ClinVar Variation ID: 571521) (Duke University; PMID: 31904026, 32518148). The c.1477C>T (p.Pro493Ser) variant was confirmed in trans with the c.1978C>T (p.Arg660Cys) and c.2221G>A (p.Asp741Asn). The phase of these variants was confirmed in trans by parental testing (PM3_not met). Another missense variant, c.1478C>T, p.Pro493Leu (ClinVar Variation ID: 379593) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_supporting). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). Residual in vitro enzyme activity for the variant in 2 replicates resulted in a mean of 12.3% wild type GAA activity (within the pathogenic control range of <15%), indicating that this variant may impact protein function (Duke University) (PS3_Supporting). The computational predictor REVEL gives a score of 0.781 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3_met). There is a ClinVar entry for this variant (Variation ID: 2160730; 1 star review status) with one submitter classifying the variant as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_Moderate, PP3_met, PM2_supporting, PM5_supporting, PS3_supporting, PM3_not met). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366926/MONDO:0009290/010 2025-05-06 2025-05-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA3060570773 biolink:causes MONDO:0011071 infores:clingen CAID:CA3060570773 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1200_1205del (p.Pro401_Ser402del) is an in-frame deletion which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3060570773/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63621 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0014130 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085606 infores:hetionet CHEBI:9586 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0022107 infores:hetionet CHEBI:7823 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0687713 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0234215 infores:hetionet CHEBI:132233 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0002994 infores:hetionet CHEBI:37941 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151603 infores:hetionet CAID:CA16606972 biolink:causes MONDO:0100040 infores:clingen CAID:CA16606972 MONDO:0100040 PMID: Benign BP5_Strong, BS2, BP4 BS1 The p.Pro84His variant in FOXG1 is present in 1 individual in gnomAD (0.0039%) (not sufficient to meet BS1 criteria). The p.Pro84His variant is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro84His variant is found in at least 4 patients with an alternate molecular basis of disease (internal database - Invitae; internal database - GeneDx) (BP5_strong). Computational analysis prediction tools suggest that the p.Pro84His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro84His variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS2, BP5_strong, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606972/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6062 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018099 infores:hetionet CHEBI:5384 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0020580 infores:hetionet CHEBI:7565 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151662 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0009319 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0021400 infores:hetionet CAID:CA270369 biolink:causes MONDO:0010726 infores:clingen CAID:CA270369 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PM1, PM6, PS1, PM2_Supporting The c.372G>C (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 10991688) (PM6). The c.372G>C (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>C (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 heterochromatin binding assay and in vitro transcriptional repression assay have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). The c.372G>T variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (internal database - Invitae) (PS1). In summary, the c.372G>C (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PM1, PM6, PM2_supporting, PS3_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270369/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:51041 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085649 infores:hetionet CHEBI:8707 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020473 infores:hetionet CHEBI:28787 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0002965 infores:hetionet CHEBI:8232 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0004093 infores:hetionet CHEBI:15553 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C2047937 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0175167 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020649 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0002871 infores:hetionet CHEBI:63629 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0404521 infores:hetionet CHEBI:2453 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0085649 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0424000 infores:hetionet CAID:CA645369638 biolink:causes MONDO:0007648 infores:clingen CAID:CA645369638 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM6, PM3, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1408del (p.Thr470fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in a family meeting clinical criteria for HDGC (PS4_Supporting; SCV000580711.3). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369638/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:17549 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0030554 infores:hetionet CHEBI:2038 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0015402 infores:hetionet CHEBI:3508 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0014518 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0027765 infores:hetionet CHEBI:168396 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011175 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020649 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006384 infores:hetionet CHEBI:6067 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0010200 infores:hetionet GO:1905939 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905939 GO:0007275 CHEBI:3207 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0687707 infores:hetionet CHEBI:4514 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0004093 infores:hetionet CHEBI:100241 biolink:causes HP:0100716 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085271 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0595877 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151689 infores:hetionet CHEBI:261649 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0232492 infores:hetionet CHEBI:9588 biolink:causes HP:0001923 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0206160 infores:hetionet CHEBI:5855 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0035455 infores:hetionet CHEBI:182080 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0026205 infores:hetionet NCBIGene:4854 biolink:causes MONDO:0007537 infores:monarchinitiative not_provided not_provided HGNC:7883 MONDO:0007537 uuid:a6b902c7-4ac4-461a-aac3-3fc9f6053262 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8430 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0023530 infores:hetionet CHEBI:5778 biolink:causes HP:0003690 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0587246 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011053 infores:hetionet CHEBI:553473 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0404521 infores:hetionet CHEBI:50859 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0080274 infores:hetionet CHEBI:10650 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2363730 infores:hetionet CHEBI:38940 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0036974 infores:hetionet CHEBI:8673 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0002792 infores:hetionet CHEBI:64355 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0039231 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0020437 infores:hetionet CHEBI:3176 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0017178 infores:hetionet CAID:CA213790 biolink:causes MONDO:0015967 infores:clingen CAID:CA213790 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4, PP4 The c.463A>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 156 (p.(Arg155Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.794, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.463A>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213790/MONDO:0015967/086 2024-04-18 2024-04-18 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA398324484 biolink:causes MONDO:0011132 infores:clingen CAID:CA398324484 MONDO:0011132 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PM1, PM3_Supporting, PP3_Moderate, PP4_Moderate PS3 The variant NM_001369369.1(FOXN1):c.958C>T (p.Arg320Trp) has been found in at least 4 individuals with FOXN1 related T cell immunodeficiency (PMIDs: 31566583, 27484032, 31447097, 20978268) in both homozygous and heterozygous states. One individual, where genomic sequencing revealed a homozygous variant, displayed phenotypes including congenital alopecia, nail dystrophy, absent T cells, and no response to PHA. This individual underwent a thymic transplant that corrected the T cell deficiency (PP4_moderate, PM3_supporting). In addition to this individual, three other patients have been described with heterozygous variants resulting in phenotypes including low TRECs and T cell lymphopenia (PS4_supporting). Additionally, the variant is present in one allele in the African/African American population in gnomADv4.0 (1/57226 alleles, MAF 0.00001747 below the PM2 threshold of <0.00002412) (PM2_supporting). The in silico meta predictor REVEL gives a score of 0.94, predicting a deleterious effect (PP3_Moderate). The variant is located within the DNA binding forkhead domain (amino acids 270-367), (PM1). Finally, the variant when expressed into HEK293 cells showed a protein function of 2% compared to wild type in a luciferase assay. In summary this variant meets criteria to be classified as pathogenic for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PP3_moderate, PS4_supporting, PM2_supporting, PM3_supporting, PP4_moderate, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398324484/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:4325 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0161479 infores:hetionet CHEBI:5790 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0018790 infores:hetionet CHEBI:31348 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0014591 infores:hetionet CHEBI:8107 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0004093 infores:hetionet CHEBI:16755 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151603 infores:hetionet CHEBI:4511 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0023052 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0040797 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0040797 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0025319 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0025319 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1609512 infores:hetionet CHEBI:6690 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0037317 infores:hetionet CHEBI:4046 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0232461 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0021308 infores:hetionet CHEBI:94501 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C2047937 infores:hetionet CAID:CA410202578 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202578 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.454A>C (p.Lys152Gln) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score ≥ 0.88 (0.956) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202578/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3127 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2607914 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1269683 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0037199 infores:hetionet CHEBI:48844 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0006840 infores:hetionet CHEBI:8107 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0001925 infores:hetionet CHEBI:134743 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0267792 infores:hetionet NCBIGene:8842 biolink:causes MONDO:0012796 infores:monarchinitiative not_provided not_provided HGNC:9454 MONDO:0012796 uuid:066150b6-dbfb-49f9-83f8-7ae56975d1a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0494475 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0347950 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0347950 infores:hetionet CAID:CA024807 biolink:causes MONDO:0007783 infores:clingen CAID:CA024807 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with leucine at codon 2496 of the RYR1 protein, p.(Pro2496Leu). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00065, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.96) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024807/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9907 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0024115 infores:hetionet CHEBI:6912 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0233407 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0038663 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0031350 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040046 infores:hetionet CAID:CA1939839 biolink:causes MONDO:0100038 infores:clingen CAID:CA1939839 MONDO:0100038 PMID: Benign BA1, BP4 PS1, PS3, BS3, PM2, PM5, PM1, PP2, PP3, PP1, BP1 The c.1571G>A variant in SCN2A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 524 (p.Arg524Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1504% (30/19942 alleles) in Asian population, which is higher than the ClinGen Epilepsy Sodium Channel VCEP threshold (0.01%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.192, evidence that does not predict a damaging effect on SCN2A function (BP4). In summary, this variant meets the criteria to be classified as BENIGN for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 and BP4. (Version 1; approved 6/13/2023) Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1939839/MONDO:0100038/068 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63618 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0278134 infores:hetionet CHEBI:28748 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0340865 infores:hetionet CHEBI:6078 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0020458 infores:hetionet CHEBI:5779 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0018681 infores:hetionet CHEBI:72564 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0034880 infores:hetionet CHEBI:75722 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013384 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0001824 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0020456 infores:hetionet CHEBI:17334 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0021368 infores:hetionet NCBIGene:2132 biolink:causes MONDO:0007586 infores:monarchinitiative not_provided not_provided HGNC:3513 MONDO:0007586 uuid:439e2dc0-b574-4159-bee0-4826f7071512 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0023066 infores:hetionet CHEBI:3479 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0085605 infores:hetionet CHEBI:8081 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0003811 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0522224 infores:hetionet GO:0075210 biolink:causes GO:0141156 infores:ubergraph knowledge_assertion manual_agent GO:0075210 GO:0141156 CHEBI:6832 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0751494 infores:hetionet CHEBI:28593 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0022346 infores:hetionet CHEBI:36704 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030554 infores:hetionet CHEBI:6129 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020625 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0020514 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C1258215 infores:hetionet CHEBI:15765 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0041105 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027813 infores:hetionet CHEBI:63617 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018790 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0037274 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0948031 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0948031 infores:hetionet CAID:CA410202644 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202644 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS4, PS3, PS1, PS2, BA1, BP1, BP4, BP2, BP3, BS3, BS1, BS4, BP7, BP5, PM2, PM6, PVS1, PM3, PM4, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.421T>G (p.Ser141Ala) is a missense variant which has been reported in a mother-son pair with AML (PMID: 32315381 - Supplementary Data/PMID: 28855357 - Supplementary Table 2, and cited by PMID: 32208489 - Supplementary Table 1); however, PS4_supporting cannot be applied because there is >1 allele present in gnomAD (2/282806 alleles in v2 and 2/152176 alleles in v3) and PP1 cannot be applied due to insufficient number of meioses. This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). Biochemical/kinetic studies indicate that this variant has CBFβ-binding comparable to WT, but this assay alone does not meet the requirements for use by the ClinGen Myeloid Malignancy-VCEP. Similarly, the computational predictor REVEL gives a score of 0.851, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. In summary, this variant meets the criteria to be classified as VUS for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy-VCEP: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202644/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0879264 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C2830004 infores:hetionet CAID:CA2573158481 biolink:causes MONDO:0010725 infores:clingen CAID:CA2573158481 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4 The NM_000330.4(RS1):c.131dup variant is a frameshift variant due to one nucleotide duplication introducing a premature stop codon and causing a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). A ClinVar submission has reported a male patient carrying this variant who was diagnosed with retinoschisis, with reported clinical features of abnormal retinal morphology and vasculitis (ClinVar ID 1687568, accession number SCV002521813.1), which meets the PS4 requirement of a male diagnosed with X-linked retinoschisis. However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was unmet. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1 and PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573158481/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:83804 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0702166 infores:hetionet CHEBI:44185 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0025222 infores:hetionet CHEBI:10023 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151827 infores:hetionet NCBIGene:22906 biolink:causes MONDO:0032598 infores:monarchinitiative not_provided not_provided HGNC:29947 MONDO:0032598 uuid:bc2ded68-1ffb-4ae1-a8d9-99ddd6e82e2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C3665624 infores:hetionet CHEBI:50381 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0018681 infores:hetionet CHEBI:44185 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0237849 infores:hetionet CAID:CA126156 biolink:causes MONDO:0009276 infores:clingen CAID:CA126156 MONDO:0009276 PMID:21908432 Likely Pathogenic PM3, PS3_Supporting, PP4, PP1, PM2_Supporting PP3, BP4 The missense variant NM_000407.5(GP1BB):c.397G>C (p.Ala133Pro) has a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00002722 (based on 3/29196 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.00006517; PM2_Supporting). At least one patient (Patient A.K. in PMID: 9116284) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry found the expression of GPIbα, the GPIb/IX complex, and GPIX were remarkably lower than the normal control. which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. The patient is compound heterozygote has been reported with Tyr113Cys (provisionally classified Likely Pathogenic by PD VCEP) and Ala133Pro confirmed in trans from heterozygous parents (PMID: 9116284; PM3). There is segregation of this variant in 1 additional compound heterozygous BSS family member (PMID: 9116284; total 1pt, PP1). In transiently transfected CHO cells HA-GPIbβ was present on the cell surface but GPIX was not (PMID: 21908432). In transiently transfected CHO cells HA-GPIbβ was present on the cell surface around 20% but GPIX was absent (PMID: 21908432; PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_supporting, PM3, PM2_supporting, PP1, PP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA126156/MONDO:0009276/082 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47898 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013182 infores:hetionet CHEBI:5165 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0001925 infores:hetionet CHEBI:28830 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0033774 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0687707 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0021400 infores:hetionet CHEBI:42797 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018524 infores:hetionet CHEBI:68610 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0030196 infores:hetionet CAID:CA658824415 biolink:causes MONDO:0100083 infores:clingen CAID:CA658824415 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP2, BP3, BP1, BP4, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM3, PM4, PM5, PM1, BS2, PP4, PP2, PP1 NC_000021.9:g.34880554_34880573dup is an intronic duplication variant which may impact splicing. This variant has a SpliceAI score ≥ 0.38 (0.47 Donor Gain) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824415/MONDO:0100083/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007642 infores:hetionet CHEBI:134966 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0702166 infores:hetionet CAID:CA037634 biolink:causes MONDO:0007750 infores:clingen CAID:CA037634 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Strong, PM2, PP4 BP4, BP2, BA1, PS3, PS1, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM3, PM1, PVS1, PM6, BS2, PP3 The NM_000527.5(LDLR):c.1975A>C (p.Thr659Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 15 May 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.0001853 (0.01853%) in European (Finnish) exomes (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in 4 unrelated index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID 20809525, Marduel et al. 2010). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France: 6 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037634/MONDO:0007750/013 2023-05-15 2025-02-13 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3215 biolink:causes UMLS:C2939427 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C2939427 infores:hetionet CHEBI:41774 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0027947 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019158 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0040034 infores:hetionet CHEBI:31932 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0001824 infores:hetionet CHEBI:4495 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0023530 infores:hetionet NCBIGene:4358 biolink:causes MONDO:0032728 infores:monarchinitiative not_provided not_provided HGNC:7224 MONDO:0032728 uuid:0b51f304-27fb-4cdc-96cf-b785f15a7d05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:73274 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0700225 infores:hetionet CHEBI:6375 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014724 infores:hetionet CHEBI:47381 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0033247 infores:hetionet CAID:CA410149600 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149600 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS1, PS4, BP1, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.948A>C (p.Glu316Asp) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score < 0.50 (0.107) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149600/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9727 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0001925 infores:hetionet GO:1904133 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0007420 CAID:CA2579830511 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830511 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM1_Supporting PP1 The c.-136A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within the HNF6/OC2 binding site of the promoter (c.-132 to c.-141) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and a personal and family h/o neonatal hypoglycemia) (PP4_Moderate; PMID: 20546279). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 20546279, internal lab contributors). In summary, c.-136A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830511/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63580 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0338831 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0036572 infores:hetionet GO:2000702 biolink:causes GO:0001657 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0001657 CHEBI:7478 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2830004 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0009450 infores:hetionet CHEBI:8364 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0033774 infores:hetionet CHEBI:71415 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0206062 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0919874 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0917798 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0040034 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0022116 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009319 infores:hetionet CHEBI:3723 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0035243 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0015397 infores:hetionet UMLS:C0657912 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0010038 infores:hetionet CHEBI:50131 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1619712 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002871 infores:hetionet CHEBI:7809 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0002994 infores:hetionet CAID:CA376065642 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065642 MONDO:0011225 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM3_Supporting, PM5_Supporting BS2 The c.95C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 32 (p.Ser32Cys).The highest population minor allele frequency in gnomAD v.4 is 0.00002236 (1/44722 alleles) in Latino/Admixed American population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant, c.95C>T; p.Ser32Phe, ClinVar Variation ID: 1438811, in the same codon, has been classified as likely pathogenic for SCID by the ClinGen SCID VCEP (PM5_Supporting).The variant was identified in two patients in the literature (PubMed IDs 25917813, 15242402, and PMID: 35886058. The patient reported in Rosina E et al. presents: Diagnostic criteria for SCID 0.5 pts + SCID gene panel or exome/genome sequencing conducted 0.5pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total is 1.5 points, PP4_Supporting. This same patient is homozygous for the variant: 0.5 pts, PM3_Supporting (PMID: 35886058).Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.4) and DNA repair (36h after IR): Mean (SD): 6.56 (8.73). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID: 25917813).In summary, this variant is classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PM5_Supporting, PP4_Supporting, PM3_Supporting, and PS3_Moderate. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065642/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3207 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0235437 infores:hetionet GO:1903975 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1903975 GO:0007399 CHEBI:9649 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0031350 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0521465 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0425945 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002453 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0014658 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0014658 uuid:6dad22d7-22cc-4c48-8654-39c6452dd9c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681848 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0019521 infores:hetionet CHEBI:85161 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0015230 infores:hetionet CHEBI:49713 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0232292 infores:hetionet CHEBI:8776 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0022354 infores:hetionet CHEBI:3223 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0018524 infores:hetionet CHEBI:42797 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0852911 infores:hetionet CHEBI:75722 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040264 infores:hetionet CHEBI:63620 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0026858 infores:hetionet NCBIGene:6905 biolink:causes MONDO:0009486 infores:monarchinitiative not_provided not_provided HGNC:11582 MONDO:0009486 uuid:4c3e7ac9-6f18-4b04-b34e-67f1e7321211 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA748917401 biolink:causes MONDO:0011071 infores:clingen CAID:CA748917401 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.59-17_59-15del is an intronic variant has a SpliceAI score ≤ 0.20 (0.12) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.12) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.42) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA748917401/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31348 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027059 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0815316 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C2004521 infores:hetionet CHEBI:9445 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0006277 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0024528 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024528 infores:hetionet CHEBI:31643 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0002792 infores:hetionet CHEBI:204928 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0040034 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0236071 infores:hetionet CHEBI:490877 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0232807 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235234 infores:hetionet CHEBI:10124 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0699828 infores:hetionet GO:0090016 biolink:causes GO:0060777 infores:ubergraph knowledge_assertion manual_agent GO:0090016 GO:0060777 CHEBI:8863 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015672 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013595 infores:hetionet CHEBI:17303 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C2047937 infores:hetionet NCBIGene:51750 biolink:causes MONDO:0014613 infores:monarchinitiative not_provided not_provided HGNC:15888 MONDO:0014613 uuid:9d7ca157-1e98-4667-b4fb-2760cf1c4bca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0026826 infores:hetionet CHEBI:3515 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0006277 infores:hetionet CHEBI:38545 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0018418 infores:hetionet CHEBI:87681 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0236075 infores:hetionet CHEBI:44423 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0032343 infores:hetionet CHEBI:51860 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0035455 infores:hetionet CAID:CA412730005 biolink:causes MONDO:0100437 infores:clingen CAID:CA412730005 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2695G>T (p.Glu899Ter) is a nonsense variant that introduces a premature stop in codon 899 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 4 years (1 pt), reduced visual acuity (0.5 pts), decreased electroretinogram responses from rods, mild macular degeneration, pigment deposits (0.5 pts), and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412730005/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:41879 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0016655 infores:hetionet CHEBI:7789 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C1443060 infores:hetionet NCBIGene:2736 biolink:causes MONDO:0014369 infores:monarchinitiative not_provided not_provided HGNC:4318 MONDO:0014369 uuid:dc3981ac-763d-4946-bcb4-2e5546b826c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10110 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0009806 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0037274 infores:hetionet CHEBI:7444 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0235996 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0037023 infores:hetionet CHEBI:32192 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0162830 infores:hetionet NCBIGene:4481 biolink:causes MONDO:0013662 infores:monarchinitiative not_provided not_provided HGNC:7376 MONDO:0013662 uuid:c9cacd5b-b62f-488a-bf50-a02d3d8c2e80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:4786 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0040822 infores:hetionet CHEBI:48669 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0013404 infores:hetionet CHEBI:10124 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0023218 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0521991 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0521991 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0233494 infores:hetionet CAID:CA16020862 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020862 MONDO:0009861 PMID:24401910PMID:24401910PMID:24401910 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS3 PM5 The c.800A>G (p.Gln267Arg) variant in PAH has been reported in 1 individual with Classic PKU (BH4 deficiency excluded) and was detected with G257V which is pathogenic per the ClinGen PAH VCEP (PP4_Moderate, PM3; PMID: 24401910). This variant is absent in population databases (PM2). This variant has 1.1% enzyme activity (PS3; PMID: 24401910). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020862/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47780 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040264 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003468 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0158775 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0243026 infores:hetionet UNII:R43D2573WO biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0010200 infores:hetionet CHEBI:6715 biolink:causes MONDO:0016064 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0008925 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0018418 infores:hetionet GO:0045664 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0045664 GO:0048699 CHEBI:2453 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0015672 infores:hetionet CHEBI:2704 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0017178 infores:hetionet CHEBI:8435 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0152115 infores:hetionet CHEBI:8228 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0018681 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0234215 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020517 infores:hetionet CAID:CA9870393 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870393 MONDO:0015967 PMID: Uncertain Significance PM2, PP3, PP4 The c.844G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to asparagine at codon 282 (p.(Asp282Asn)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (PMID: 27913849). In summary, c.844G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): no criteria met. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870393/MONDO:0015967/085 2024-09-26 2024-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6367 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020580 infores:hetionet CAID:CA2695224150 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224150 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.1012dup (p.Met338AsnfsTer13) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BSS3.01 in PMID: 23402648) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224150/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8888 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0029445 infores:hetionet CHEBI:7444 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0151908 infores:hetionet CHEBI:84500 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0014742 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151971 infores:hetionet CHEBI:48669 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0027497 infores:hetionet CHEBI:9599 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0042571 infores:hetionet CHEBI:8871 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0558489 infores:hetionet CHEBI:64064 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C2047937 infores:hetionet CHEBI:35553 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0042721 infores:hetionet CHEBI:6970 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0687713 infores:hetionet NCBITaxon:11072 biolink:causes MONDO:0019209 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11072 MONDO:0019209 CHEBI:3515 biolink:causes UMLS:C0014718 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0014718 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0243026 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0857353 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019360 infores:hetionet CHEBI:5118 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085684 infores:hetionet CHEBI:6402 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030794 infores:hetionet CHEBI:10102 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151905 infores:hetionet NCBIGene:23418 biolink:causes MONDO:0013453 infores:monarchinitiative not_provided not_provided HGNC:2343 MONDO:0013453 uuid:0d5b1a35-a839-4289-8bf1-7f35696b3c42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63607 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C3665346 infores:hetionet CHEBI:31174 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0011603 infores:hetionet CHEBI:63635 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0085631 infores:hetionet CAID:CA414816070 biolink:causes MONDO:0044970 infores:clingen CAID:CA414816070 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PM6_Strong, PS4_Supporting PS3 The m.13046T>C (p.Met237Thr) variant in MT-ND5 has been reported in three individuals with primary mitochondrial disease (PMIDs: 21850008, 26894521, 34969639; PS4_supporting). Clinical features in affected individuals included Leigh syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), seizures, migraines, optic atrophy, sensorineural hearing loss, and lactic acidosis. The variant was present at heteroplasmy levels between 22-27% in blood, 50-70% in muscle, 52-71% in urine, and 40-83% in fibroblasts. The variant was not detected in each of the three asymptomatic mothers (PMIDs: 21850008, 26894521, 34969639; PM6_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.72 (Min=0, Max=1, PP3). There are no single fiber studies or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_strong, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414816070/MONDO:0044970/015 2024-12-03 2025-11-07 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3723 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033774 infores:hetionet CAID:CA891843862 biolink:causes MONDO:0007648 infores:clingen CAID:CA891843862 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, PP4, PP1, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1170del p.(Asn390fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843862/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:168396 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0006840 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0027765 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018021 infores:hetionet NCBIGene:84667 biolink:causes MONDO:0013366 infores:monarchinitiative not_provided not_provided HGNC:15977 MONDO:0013366 uuid:5e056e5f-3714-449d-a5fb-8e6550748c16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101085 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0233494 infores:hetionet CAID:CA2573157351 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157351 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS4, PS2, PS3, BP2, BP1, BP4, BP3, BA1, PM6, PVS1, BP5, BP7, BS1, BS4, BS3, PM3, PM5, PM4, PM1, BS2, PP4, PP2, PP1 NM_001754.5(RUNX1):c.509-11T>A is an intronic variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant does not have an available REVEL score, but this variant has a SpliceAI score ≥ 0.38 (0.92) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157351/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51380 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0011603 infores:hetionet CHEBI:4717 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0686347 infores:hetionet CHEBI:51364 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1262064 infores:hetionet CHEBI:36791 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038325 infores:hetionet CHEBI:6367 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151474 infores:hetionet CHEBI:9588 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0034150 infores:hetionet NCBIGene:221421 biolink:causes MONDO:0012979 infores:monarchinitiative not_provided not_provided HGNC:21057 MONDO:0012979 uuid:c1d80f80-f60f-42b8-aa01-55464f855f9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0231303 infores:hetionet CHEBI:41879 biolink:causes UMLS:C1963897 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1963897 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029456 infores:hetionet CHEBI:132233 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0013384 infores:hetionet CHEBI:7496 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0151786 infores:hetionet CHEBI:136040 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0016382 infores:hetionet CAID:CA10576303 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576303 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PS3, PM5, PM2, PP4, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1285G>C (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PM5, PP3, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.764. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G=6 from PathWest Laboratory Medicine WA, Australia; 1 case with possible FH by Simon Broome criteria from Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal, PMID 17765246 (Bourbon et al., 2008). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576303/MONDO:0007750/013 2023-03-27 2024-10-04 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5123 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0027849 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0700361 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0034150 infores:hetionet CAID:CA533655724 biolink:causes MONDO:0015152 infores:clingen CAID:CA533655724 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PM2_Supporting PS1, PP4 The NM_003494.4: c.2811-20T>G variant in DYSF, which is also known as NM_001130987.2: c.2865-20T>G, occurs in the splice acceptor motif in intron 26. RNAseq analysis has shown that this variant disrupts splicing, resulting in the use of an alternative splice acceptor site and a frameshift and premature truncation, p.Leu938ArgfsTer3, with nonsense mediated decay expected (PMID: 36983702; PVS1_RNA). These results are consistent with the SpliceAI score of 0.45 for acceptor gain. This variant has been reported in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.2810+1G>A, 1.0 pt) in an individual with absent dysferlin protein expression in skeletal muscle (PMID: 36983702; PM3). The filtering allele frequency for this variant in gnomAD v4.1.0 exomes is 0.000020862 (the upper bound of the 95% confidence interval of 15/1107154 European (non-Finnish) chromosomes), which is less than the LGMD VCEP threshold of 0.0001 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/18/2025): PVS1_RNA, PM3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA533655724/MONDO:0015152/180 2025-06-18 2025-06-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68606 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0178298 infores:hetionet CHEBI:63608 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0231528 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0160390 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0860871 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0007820 infores:hetionet CHEBI:5106 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0003467 infores:hetionet CHEBI:52172 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013428 infores:hetionet CHEBI:33697 biolink:causes GO:0001172 infores:ubergraph knowledge_assertion manual_agent CHEBI:33697 GO:0001172 CHEBI:8499 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0476273 infores:hetionet CAID:CA10652919 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652919 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2217dup is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652919/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA011527 biolink:causes MONDO:0005045 infores:clingen CAID:CA011527 MONDO:0005045 PMID: Uncertain Significance PM1, PP3, PP1, PM2_Supporting PM5, PM4, PM6, BA1, PS3, BS1, BS3, BS4, PS4_Supporting, PS1, PS2, BP4, BP2, BP5, PVS1 The NM_000257.4(MYH7):c.1969A>C (p.Lys657Gln) variant in MYH7 has been reported in at least 1 individual with HCM and segregated with HCM in at least 3 affected relatives (PP1; Hill 2015 PMID:26337809; Walsh 2017 PMID:26337809; LMM pers. comm.). Due to potential overlap in the individuals reported, PS4_Supporting criteria is not met. This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1, PM2_Supporting, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011527/MONDO:0005045/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7903 biolink:causes UMLS:C0262494 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0262494 infores:hetionet CHEBI:2668 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0026821 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0015967 infores:hetionet CHEBI:50156 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0016204 infores:hetionet CAID:CA353528 biolink:causes MONDO:0007648 infores:clingen CAID:CA353528 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP1, PP4, PP2, PP3, BP3, BP2, BP1, BP4, BA1, PS4, PS1, PS3, PS2 The c.1505del (p.Gly502fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA353528/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:4995 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0027726 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0151735 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0574067 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0009450 infores:hetionet CHEBI:8802 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0030554 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0234233 infores:hetionet UMLS:C0004609 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0004093 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0155169 infores:hetionet CHEBI:31176 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0012833 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0855242 infores:hetionet CHEBI:3223 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0037763 infores:hetionet CHEBI:46557 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0018965 infores:hetionet CHEBI:3757 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0010200 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0239385 infores:hetionet CHEBI:63791 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0242301 infores:hetionet CHEBI:391960 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0041969 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0026650 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0877072 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0877072 infores:hetionet CHEBI:6067 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015967 infores:hetionet CHEBI:7476 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0028961 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0042514 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0015397 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1142412 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0521508 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0521508 infores:hetionet CHEBI:8207 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0043387 infores:hetionet CHEBI:63681 biolink:causes MONDO:0000687 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0406458 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0005684 infores:hetionet CHEBI:7492 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C1527344 infores:hetionet CHEBI:27786 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0085631 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0858794 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0858794 infores:hetionet NCBIGene:1893 biolink:causes MONDO:0009530 infores:monarchinitiative not_provided not_provided HGNC:3153 MONDO:0009530 uuid:bfadb840-71d8-451b-9fa1-9e22a1f90ee0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2937358 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0855242 infores:hetionet CHEBI:104011 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C2242996 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0036572 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042373 infores:hetionet GO:1900154 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900154 GO:0007275 CHEBI:4562 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0236075 infores:hetionet GO:0002337 biolink:causes CL:0000820 infores:ubergraph knowledge_assertion manual_agent GO:0002337 CL:0000820 CHEBI:71219 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0740425 infores:hetionet CHEBI:28148 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0022660 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0021400 infores:hetionet NCBIGene:5961 biolink:causes MONDO:0013137 infores:monarchinitiative not_provided not_provided HGNC:9942 MONDO:0013137 uuid:1f527d64-22a2-4090-b1e3-6b94cd7d7a82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6437 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0042571 infores:hetionet CHEBI:61049 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013378 infores:hetionet CHEBI:182080 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0344232 infores:hetionet CHEBI:63613 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0018681 infores:hetionet CAID:CA412736653 biolink:causes MONDO:0100437 infores:clingen CAID:CA412736653 MONDO:0100437 PMID:32788070 Pathogenic PVS1, PP4, PM2_Supporting PP3, PS4, PS3 NM_001034853.2(RPGR):c.1753G>A (p.Glu585Lys) is a missense variant located in the final nucleotide of exon 14, and encodes the substitution of glutamic acid with lysine at amino acid 585. The splicing impact predictor SpliceAI gives a score of 0.52 for donor gain, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. In vitro splicing studies confirm that the variant disrupts splicing of RPGR ORF15 and causes loss of transcript heterogeneity (PMID: 32788070). While these in silico and experimental findings would normally be counted under the PP3 and PS3_Supporting codes, respectively, they have been counted in combination as evidence of a loss-of-function effect (PVS1_RNA). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including onset in first decade of life (1 pt), decreased visual acuity (0.5 pts), night blindness (0.5 pts), severe, diffuse, granular appearance and atrophy of retinal pigment epithelium (0.5 pts), bone-spicule pigmentation (0.5 pts), and arteriolar attenuation in mid-peripheral retina (0.5 pts), with genotyping by previous exome sequencing (2 pts), which together are highly specific for RPGR-related retinopathy (5.5 points, PMID: 32788070, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0: PVS1_RNA, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412736653/MONDO:0100437/106 2025-07-31 2025-07-31 X-linked inheritance HP:0001417 Supports CHEBI:68554 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0231170 infores:hetionet CHEBI:6950 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0025323 infores:hetionet CHEBI:6128 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0017178 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0020517 infores:hetionet CHEBI:9139 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042024 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030312 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0009450 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0021053 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0345904 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0087169 infores:hetionet CHEBI:7465 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0003862 infores:hetionet CHEBI:6759 biolink:causes EFO:1001766 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C1527348 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011609 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0002871 infores:hetionet NCBIGene:4318 biolink:causes MONDO:0013113 infores:monarchinitiative not_provided not_provided HGNC:7176 MONDO:0013113 uuid:0730338e-04b3-4b03-9d2f-148588383ec9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002170 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0022667 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040409 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0162429 infores:hetionet NCBIGene:2752 biolink:causes MONDO:0012393 infores:monarchinitiative not_provided not_provided HGNC:4341 MONDO:0012393 uuid:81c4c755-4227-4acf-a36f-da11485185b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0012833 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0858581 infores:hetionet CHEBI:3207 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0020621 infores:hetionet CHEBI:71255 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0003467 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0027051 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0152965 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0152965 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0267792 infores:hetionet CHEBI:5893 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0009763 infores:hetionet CHEBI:135930 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0043352 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0008170 uuid:907acba5-1262-4fa9-8689-3d5b54efde44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes UMLS:C0231875 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0231875 infores:hetionet CHEBI:50730 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0014591 infores:hetionet CHEBI:50729 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020621 infores:hetionet CHEBI:94848 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0002878 infores:hetionet CHEBI:51173 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0022346 infores:hetionet GO:0048710 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0048710 GO:0007417 CHEBI:5855 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0853149 infores:hetionet CHEBI:7822 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0009763 infores:hetionet CHEBI:63621 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0438717 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0233494 infores:hetionet CHEBI:84500 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0015371 infores:hetionet CHEBI:29688 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0085612 infores:hetionet CHEBI:63611 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0302809 infores:hetionet CHEBI:63610 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0004604 infores:hetionet CAID:CA214270 biolink:causes MONDO:0015967 infores:clingen CAID:CA214270 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1506_1507dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift at codon 503 (NM_000545.8), adding 29 novel amino acids before encountering a stop codon (p.(Tyr503SerfsTer29)). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). In summary, c.1506_1507dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214270/MONDO:0015967/017 2025-04-11 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2675 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0855242 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0948594 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0700184 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013595 infores:hetionet GO:1900193 biolink:causes GO:0048599 infores:ubergraph knowledge_assertion manual_agent GO:1900193 GO:0048599 CHEBI:7824 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0016658 infores:hetionet CHEBI:5558 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0023380 infores:hetionet CHEBI:75045 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0232462 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0003123 infores:hetionet CHEBI:6129 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014457 infores:hetionet CHEBI:5864 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0003862 infores:hetionet CHEBI:3568 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003467 infores:hetionet CHEBI:64028 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0234369 infores:hetionet UMLS:C0657912 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C3665386 infores:hetionet CHEBI:135193 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0030554 infores:hetionet CHEBI:8382 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0024312 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002453 infores:hetionet CHEBI:15854 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0221242 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0234215 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018790 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0178298 infores:hetionet CHEBI:465284 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151599 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0007642 infores:hetionet NCBIGene:29926 biolink:causes MONDO:0014219 infores:monarchinitiative not_provided not_provided HGNC:22923 MONDO:0014219 uuid:5bd31b14-f097-4698-bf05-8f257de02876 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0038325 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0032285 infores:hetionet CHEBI:64310 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0042075 infores:hetionet CHEBI:49713 biolink:causes MONDO:0000469 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0428908 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0018418 infores:hetionet CHEBI:45599 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C1321686 infores:hetionet CHEBI:9566 biolink:causes MONDO:0020575 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0344432 infores:hetionet CHEBI:31705 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0002792 infores:hetionet CHEBI:31348 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0029944 infores:hetionet CAID:CA036811 biolink:causes MONDO:0007750 infores:clingen CAID:CA036811 MONDO:0007750 PMID: Uncertain Significance BP4, BP7, PM2 "NM_000527.5(LDLR):c.1836C>A (p.Ala612=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD v2.1.1).Frequency is higher in ""other"" population exomes and genomes but number of allele is below 10000BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.- Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT.- There is a GT nearby.MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48.Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9Variant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4." Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036811/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:82960 biolink:causes MONDO:0000437 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0007758 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0518988 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0948594 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0521839 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151313 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C1861172 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037284 infores:hetionet CHEBI:30830 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0424295 infores:hetionet CHEBI:28748 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0428977 infores:hetionet NCBIGene:2904 biolink:causes MONDO:0014505 infores:monarchinitiative not_provided not_provided HGNC:4586 MONDO:0014505 uuid:a700c297-0281-41b7-9085-2b61199ba16e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585697 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585697 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4, PP1 BP1, BP4, BP3, BP2, BA1, PS3, PS2, PS1, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM1, PM5, PVS1, PM6, PP2, PP3, BS2 The NM_000527.5(LDLR):c.1960C>T (p.Leu654Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 index cases fulfilling Simon Broome criteria for possible FH criteria, after alternative causes of high cholesterol were excluded, from the Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal.PP1: Variant segregates with FH phenotype in at least 2 informative meioses from 1 family (Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal): 1 affected family member has the variant and 1 unaffected family member does not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585697/MONDO:0007750/013 2024-10-28 2025-01-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50648 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0024115 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0234458 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0949103 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0949103 infores:hetionet CHEBI:9586 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0023218 infores:hetionet CHEBI:5893 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151786 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0031350 infores:hetionet CHEBI:6375 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0041834 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0235467 infores:hetionet CHEBI:3423 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0086439 infores:hetionet CHEBI:7824 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011253 infores:hetionet CAID:CA318538 biolink:causes MONDO:0010278 infores:clingen CAID:CA318538 MONDO:0010278 PMID: Pathogenic PP1_Moderate, PS3, PS2, PM2_Supporting, PS4_Supporting PVS1 The c.430-9_430-5del variant in SLC9A6 occurs in the de novo state (biological parentage confirmed) in an individual with delayed motor milestones and hypotonia (Baylor Genetics internal database)(PS2). RNA study has shown that this variant impacts splicing (PMID 27256868) (PS3). This variant has been reported to segregate in four informative meioses (PMID 27256868)(PP1_moderate). The c.430-9_430-5del variant in SLC9A6 has been observed in 2 unrelated families with Christianson syndrome (PMID 27256868, Baylor Genetics internal database) (PS4_supporting). The c.430-9_430-5del variant in SLC9A6 is absent from gnomAD (PM2_supporting). In summary The c.430-9_430-5del variant in SLC9A6 is classified as pathogenic for Christianson syndrome based on the ACMG/AMP criteria (PS2, PS3, PP1_moderate, PS4_supporting, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA318538/MONDO:0010278/016 2022-02-18 2022-06-30 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:6717 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0009450 infores:hetionet CHEBI:17347 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020443 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0038661 infores:hetionet CHEBI:3223 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0015230 infores:hetionet CHEBI:8461 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0003578 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019158 infores:hetionet CHEBI:3044 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0232462 infores:hetionet GO:0180039 biolink:causes GO:0000749 infores:ubergraph knowledge_assertion manual_agent GO:0180039 GO:0000749 CHEBI:5790 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0009782 infores:hetionet CHEBI:6367 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151908 infores:hetionet CHEBI:144551 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0085633 infores:hetionet UNII:3U02EL437C biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0000729 infores:hetionet CHEBI:135930 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0026821 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0036508 infores:hetionet CHEBI:72297 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0027441 infores:hetionet CHEBI:131512 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0080274 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0521491 infores:hetionet CHEBI:94385 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151942 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0242350 infores:hetionet CHEBI:253342 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0020580 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0038454 infores:hetionet CHEBI:44185 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0002792 infores:hetionet NCBIGene:80704 biolink:causes MONDO:0011841 infores:monarchinitiative not_provided not_provided HGNC:16266 MONDO:0011841 uuid:e00a878e-c505-4ca5-88ec-b36386ef1175 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8805 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0040034 infores:hetionet CHEBI:31932 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C1443060 infores:hetionet GO:0061046 biolink:causes GO:0030324 infores:ubergraph knowledge_assertion manual_agent GO:0061046 GO:0030324 CHEBI:31348 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0017160 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0700613 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0700613 infores:hetionet CHEBI:3223 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0278134 infores:hetionet CHEBI:60761 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0011991 infores:hetionet CHEBI:2788 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0027441 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0037274 infores:hetionet CHEBI:50275 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1510410 infores:hetionet CHEBI:31515 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C2830004 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0033777 infores:hetionet CHEBI:63598 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0001807 infores:hetionet GO:0141072 biolink:causes GO:0033209 infores:ubergraph knowledge_assertion manual_agent GO:0141072 GO:0033209 CHEBI:5864 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030554 infores:hetionet CHEBI:8805 biolink:causes UMLS:C1737211 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C1737211 infores:hetionet CHEBI:72564 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013404 infores:hetionet CHEBI:3723 biolink:causes HP:0010955 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549253 infores:hetionet CHEBI:31547 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0017178 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002871 infores:hetionet CHEBI:70735 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0002962 infores:hetionet CHEBI:85161 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0030193 infores:hetionet CHEBI:7494 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0026821 infores:hetionet CHEBI:8354 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0233571 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013395 infores:hetionet CHEBI:49575 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0037763 infores:hetionet NCBITaxon:12721 biolink:causes MONDO:0005109 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12721 MESH:D015658 DB06414_MESH_D015658_1DB09299_MESH_D015658_1DB08864_MESH_D015658_1DB00300_MESH_D015658_1DB00495_MESH_D015658_1 CHEBI:8764 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004998 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020456 infores:hetionet CHEBI:18358 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0162834 infores:hetionet CHEBI:9435 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0009676 infores:hetionet CHEBI:5558 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0028734 infores:hetionet CHEBI:9943 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0427086 infores:hetionet NCBIGene:9508 biolink:causes MONDO:0032564 infores:monarchinitiative not_provided not_provided HGNC:219 MONDO:0032564 uuid:0b5b74ec-2c1c-47a1-a085-9bdcbe2c8dfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151610 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0687133 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0001824 infores:hetionet CHEBI:94501 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0018681 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0744131 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0744131 infores:hetionet CHEBI:75722 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2979982 infores:hetionet CHEBI:63791 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0242184 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0038362 infores:hetionet CHEBI:474053 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C1443060 infores:hetionet CHEBI:77733 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0002962 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0413252 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0919980 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020542 infores:hetionet CHEBI:73274 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0012833 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0240322 infores:hetionet CHEBI:8884 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0026848 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020651 infores:hetionet CHEBI:38562 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0008031 infores:hetionet CHEBI:6822 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0032617 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027769 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0040046 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0004238 infores:hetionet CHEBI:3636 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0040264 infores:hetionet CHEBI:7627 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0019572 infores:hetionet CHEBI:10102 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0558489 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006846 infores:hetionet CHEBI:17026 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0006152 infores:hetionet CHEBI:31236 biolink:causes HP:6000925 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0032739 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0010709 infores:hetionet CHEBI:144551 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0085649 infores:hetionet NCBIGene:11043 biolink:causes MONDO:0010489 infores:monarchinitiative not_provided not_provided HGNC:7096 MONDO:0010489 uuid:fdc5f341-2031-4ee5-84fd-35ce50d58f15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0022081 infores:hetionet CHEBI:7492 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0031350 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0009319 infores:hetionet CHEBI:2948 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0007114 infores:hetionet CHEBI:134990 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0002994 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0005940 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0034150 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002622 infores:hetionet CAID:CA2580098640 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098640 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1277dup (p.Arg427AlafsTer?) is a duplication that results in a frameshift. This variant is located downstream of c.98 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098640/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7478 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0034150 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0239978 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000827 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036117 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0853784 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0853784 infores:hetionet CHEBI:3568 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015402 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0025061 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0042109 infores:hetionet CHEBI:16914 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0019158 infores:hetionet CHEBI:28241 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C2047937 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0026848 infores:hetionet CHEBI:8884 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0003811 infores:hetionet CAID:CA228498 biolink:causes MONDO:0015629 infores:clingen CAID:CA228498 MONDO:0015629 PMID:11776314PMID:10845912PMID:17087728 Pathogenic PP3, PP4, PM2_Supporting, PS3, PS2_Moderate, PM5 The NM_000552.5(VWF):c.3940G>T (p.Val1314Phe) missense variant has been reported in at least 1 proband with prolonged bleeding time (>20 minutes), decreased binding capacity to GPIb, vWFAg (25 U/dL) associated with the absence of vWFRCo (<5 U/dL) for a ratio of <0.2, and an absence of high molecular weight and intermediate multimers in the plasma. Additional features included decreased levels of VIIIC (30 U/dL) and a total lack of ristocetin platelet aggregation (RIPA) at concentrations of modulator between 0 and 2 mg/mL. His platelet count is around 120 × 10^9/L and decreases to approximately 50 × 10^9/L at the time of bleeding episodes (PP4; PMID: 8298143). As reported by the authors, there is a discrepancy in this patient between an apparent type 2A phenotype and 2B genotype. This discrepancy can be explained as an extremely severe form of type-IIB vWD, where the variant strongly increases the affinity of vWF for platelet GPIb, which might result in plasma in a spontaneous binding of both HMW and intermediate-sized multimers to the platelets. This could explain the thrombocytopenia of the propositus and the clearance of the large and intermediate forms of vWF from the patient’s plasma. The variant was identified as a de novo occurrence in this patient (PS2_moderate; PMIDs: 1419803). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).A GP1b binding assay performed with the recombinant Val1314Phe mutant vWF expressed by COS-7 cells showed spontaneous binding at low doses of ristocetin (PMID: 8298143 and PMID: 8630394), and enhanced binding to platelets in the presence of low-dose ristocetin compared with WT (PMID: 8630394), indicating that this variant has a gain of function effect on the protein (PS3_supporting). Another type 2B variants have been reported at this amino acid residue; Val1314Leu and classified pathogenic by the VWD VCEP (PM5). In summary, the variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS2_moderate, PP3, PP4, PM5, and PM2_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228498/MONDO:0015629/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3739 biolink:causes MONDO:0032656 infores:monarchinitiative not_provided not_provided HGNC:6222 MONDO:0032656 uuid:b5e4719e-61a9-46db-93b4-a3c07446fa16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013395 infores:hetionet CHEBI:51164 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0017178 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0002622 infores:hetionet CHEBI:2453 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0558489 infores:hetionet CHEBI:125354 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0009806 infores:hetionet CHEBI:63632 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0004604 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0033860 infores:hetionet NCBIGene:81704 biolink:causes MONDO:0009478 infores:monarchinitiative not_provided not_provided HGNC:19191 MONDO:0009478 uuid:846ba00f-49a6-43d8-8277-d29338cad7aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0085633 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0349506 infores:hetionet CHEBI:6909 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2242996 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0235818 infores:hetionet CHEBI:3393 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0011603 infores:hetionet CHEBI:50924 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0870082 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011630 infores:hetionet CHEBI:3568 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1274594 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0549373 infores:hetionet CHEBI:6073 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0917801 infores:hetionet CHEBI:6933 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0035328 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0948824 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0948824 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0018500 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011570 infores:hetionet CHEBI:2663 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042963 infores:hetionet CHEBI:567361 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0231807 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096343 infores:hetionet CHEBI:36791 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0600142 infores:hetionet CHEBI:64045 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C1457883 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040435 infores:hetionet NCBIGene:5568 biolink:causes MONDO:0014518 infores:monarchinitiative not_provided not_provided HGNC:9382 MONDO:0014518 uuid:fde14deb-7961-4d29-b485-7cea2041bb69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2580061384 biolink:causes MONDO:0013144 infores:clingen CAID:CA2580061384 MONDO:0013144 PMID: Uncertain Significance BP7, PM2, BP4 The c.1219-8A>G (NM_000488.4) variant in SERPINC1 does not code for protein sequence. SpliceAI predicts no splicing impact for this variant meeting BP4. The variant is not predicted to cause a splicing impact and the nucleotide is weakly/moderately conserved with a PhyloP score of -0.864 and a PhastCons score of 0 meeting BP7 criteria (PhyloP < 0.1). In summary, this variant meets criteria to be classified as variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4, BP7, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580061384/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:59445 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0017181 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002184 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1262760 infores:hetionet NCBIGene:3717 biolink:causes MONDO:0009891 infores:monarchinitiative not_provided not_provided HGNC:6192 MONDO:0009891 uuid:d5633c62-7fd8-4702-a1e3-728c14c8dbc5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0162835 infores:hetionet CHEBI:46295 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C2047937 infores:hetionet CHEBI:135342 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0038990 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0948349 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0221752 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1167965 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0948089 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0011991 infores:hetionet CHEBI:6128 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0034886 infores:hetionet CHEBI:3176 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0030252 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027726 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0029882 infores:hetionet CHEBI:8107 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0016204 infores:hetionet CHEBI:2682 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0542571 infores:hetionet NCBIGene:2733 biolink:causes MONDO:0009670 infores:monarchinitiative not_provided not_provided HGNC:4315 MONDO:0009670 uuid:2ae15621-b7ac-4550-9c45-425cde50af2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92769 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0033774 infores:hetionet CHEBI:10125 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037036 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0012833 infores:hetionet CHEBI:5558 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0004093 infores:hetionet CHEBI:7492 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0013395 infores:hetionet CAID:CA000268 biolink:causes MONDO:0017623 infores:clingen CAID:CA000268 MONDO:0017623 PMID:9425889PMID:9425889PMID:25875300PMID:21828076 Pathogenic PM2, PP2, PS2, PS3 PM6, PVS1, BP5, BP7, BS4, BS3, BS1, BS2, PP1, PP3, PM1, PM4, PM5, BP2, BP4, BA1, PS4, PS1 PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889)PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000268/MONDO:0017623/003 2018-07-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:29007 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0016382 infores:hetionet NCBITaxon:6293 biolink:causes MONDO:0005424 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6293 MESH:D004604 DB00711_MESH_D004604_1 CHEBI:10650 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2363731 infores:hetionet UMLS:C1738934 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0028734 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0020517 infores:hetionet NCBIGene:538 biolink:causes MONDO:0010651 infores:monarchinitiative not_provided not_provided HGNC:869 MONDO:0010651 uuid:d9175eaf-8353-45b4-a4ff-ef4586ed5c07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0038663 infores:hetionet CHEBI:6375 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0040264 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0497365 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0009806 infores:hetionet CHEBI:9587 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0040046 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0027769 infores:hetionet NCBIGene:2335 biolink:causes MONDO:0011165 infores:monarchinitiative not_provided not_provided HGNC:3778 MONDO:0011165 uuid:758c88b7-44f1-4cf2-936e-b058971a5824 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2363731 infores:hetionet CHEBI:75722 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0041834 infores:hetionet CHEBI:17650 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0332601 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0234215 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0032961 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0239340 infores:hetionet NCBIGene:51128 biolink:causes MONDO:0009528 infores:monarchinitiative not_provided not_provided HGNC:10535 MONDO:0009528 uuid:c79cea28-3ec3-44d9-ab39-384d06042d6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C1141949 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1141949 infores:hetionet CHEBI:119486 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027796 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037274 infores:hetionet CHEBI:70746 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0235325 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027947 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0025061 infores:hetionet CHEBI:50173 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0232462 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0009319 infores:hetionet CHEBI:63635 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042023 infores:hetionet CHEBI:9943 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151786 infores:hetionet CHEBI:75984 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0013428 infores:hetionet UMLS:C0004609 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0231528 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0017152 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0005779 infores:hetionet NCBIGene:9071 biolink:causes MONDO:0060564 infores:monarchinitiative not_provided not_provided HGNC:2033 MONDO:0060564 uuid:7be76440-671a-4378-8b3b-e65e17a67ca6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0854097 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0001416 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0700184 infores:hetionet CAID:CA512341268 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341268 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP2, BP1, BP3, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.1152C>T (p.Pro384=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 [1.06]) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341268/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6062 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0008325 infores:hetionet CHEBI:83804 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151905 infores:hetionet CHEBI:8874 biolink:causes EFO:0010670 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0159056 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C3665386 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948353 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948353 infores:hetionet CHEBI:7445 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0009806 infores:hetionet CHEBI:5790 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020437 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022568 infores:hetionet CHEBI:3756 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0015230 infores:hetionet CHEBI:5775 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0042963 infores:hetionet NCBIGene:79875 biolink:causes MONDO:0030731 infores:monarchinitiative not_provided not_provided HGNC:25835 MONDO:0030731 uuid:8b551a79-f640-4aa3-a86f-56369be5d4a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0549433 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0038454 infores:hetionet CAID:CA512341346 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341346 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1050A>G (p.Pro350=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-6.50) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341346/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45783 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0035317 infores:hetionet CHEBI:127780 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151539 infores:hetionet CAID:CA1251471 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251471 MONDO:0013144 PMID: Uncertain Significance BP4 BP7, PM2 The NM_000488.4:c.87C>T variant predicts a synonymous change at position Cys29. SpliceAI predicts no splicing impact. The variant has a total allele MAF = 0.00003593 in gnomAD v4.1, which does not meet the PM2_Supporting cutoff of 0.00002. BP7 was not applied due to the PhyloP score being 0.54, which is above the 0.1 cutoff. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251471/MONDO:0013144/084 2025-02-21 2025-02-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8707 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085637 infores:hetionet CHEBI:9588 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0014742 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027051 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0234215 infores:hetionet CHEBI:6149 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0023066 infores:hetionet CHEBI:65173 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0042023 infores:hetionet CHEBI:4708 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011124 infores:hetionet CAID:CA409103677 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103677 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PP1_Strong The c.62C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, results in a premature termination at codon 21 (p.(Ser21Ter)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to SU) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with 5 meioses in one family (PP1_Strong; PMID:15830177, internal lab contributor). In summary, c.62C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103677/MONDO:0015967/085 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16469 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0149931 infores:hetionet CHEBI:50885 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0030920 infores:hetionet CAID:CA913177648 biolink:causes MONDO:0044970 infores:clingen CAID:CA913177648 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting PP1, PM6 The m.4298G>A variant in MT-TI has been reported in two unrelated adults with primary mitochondrial disease. Chronic progressive external ophthalmoplegia (CPEO) and multiple sclerosis (MS) were seen in one individual (PMID: 9473477) and the second individual had rhabdomyolysis, myoglobinuria, and myalgia after fasting or exercise in addition to muscle weakness and unstable gait (PMID: 16120360). This variant was seen in varying degrees of heteroplasmy in these individuals in muscle, urine, and hair roots by PCR/RFLP, but was not observed in blood (PS4_supporting). Family member testing was performed in one case and the variant was undetectable in the proband’s mother’s blood, however the variant was also undetectable in the proband’s blood precluding confirmation of a de novo occurrence (PMID: 16120360). There are no large families reported in the medical literature to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 63.5 percentile; HmtVAR also predicts it to be pathogenic, scoring in the 75.0 percentile (PP3). The m.4298G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single-fiber testing (PMID: 9473477) showed 78% heteroplasmy in COX-negative fibers and 27% in COX-positive fibers. Aminoacylation assays showed that the capacity for aminoacylation of tRNAs with this variant was virtually nil (<0.1%) and the observed aminoacylation deficiency was rescued by an engineered compensatory variant (PMID: 12655007). This and other results led the authors to propose that the functional defect caused by this mutation is due to fragility of the tRNA structure (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PS3_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913177648/MONDO:0044970/015 2022-12-12 2023-01-25 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2666 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0012833 infores:hetionet CHEBI:7476 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0025874 infores:hetionet CHEBI:6078 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0011603 infores:hetionet NCBIGene:72 biolink:causes MONDO:0030329 infores:monarchinitiative not_provided not_provided HGNC:145 MONDO:0030329 uuid:575360ad-aec0-4d7b-9dc3-98a2314ea07a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0002994 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0012833 infores:hetionet CHEBI:182080 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C1392046 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0001056 uuid:a21a9706-7892-41ac-ab9b-b6496221abcc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0020598 infores:hetionet CHEBI:75984 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0037822 infores:hetionet CHEBI:66913 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0041582 infores:hetionet CHEBI:36791 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233762 infores:hetionet CHEBI:32221 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0011991 infores:hetionet GO:0033668 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:0033668 GO:0006915 CHEBI:4681 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0574067 infores:hetionet CHEBI:17303 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151766 infores:hetionet CAID:CA10608400 biolink:causes MONDO:0013144 infores:clingen CAID:CA10608400 MONDO:0013144 PMID: Likely Benign BP7, BS1, BP4 The c.-57G>A (NM_000488.3) variant in SERPINC1 is in the 5' untranslated region (UTR) and changes nucleotide guanine to adenine. The minor allele frequency in gnomAD v2.1.1 is 0.0002868 (9/31380), which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). SpliceAI predicts no impact on splicing, meeting criteria for BP4. SpliceAI predicts no impact on splicing and PhyloP gives a conservation score of -1.501 which is lower than the ClinGen SERPINC1 threshold (<0.1) for BP7, and therefore meets this criterion (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BP4, BP7. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10608400/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63627 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0520587 infores:hetionet NCBIGene:3949 biolink:causes MONDO:0007750 infores:monarchinitiative not_provided not_provided HGNC:6547 MONDO:0007750 uuid:b63652de-116e-4ac0-8fc8-3b35696e650f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0220983 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0243065 infores:hetionet CHEBI:8428 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0235996 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0008370 infores:hetionet CHEBI:82960 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1456784 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0021167 infores:hetionet CHEBI:3996 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0699828 infores:hetionet CHEBI:7025 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C1325847 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0242350 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042267 infores:hetionet CHEBI:10125 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0004134 infores:hetionet CHEBI:9738 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0031256 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0021053 infores:hetionet CAID:CA041909 biolink:causes MONDO:0008667 infores:clingen CAID:CA041909 MONDO:0008667 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PS4, BS2, BA1 The variant NM_000551.4(VHL):c.610G>T (p.Glu204Ter) is a truncating variant predicted to cause a premature stop codon in biologically-relevant-exon (the third exon). This is not predicted to lead to nonsense mediated decay, although in VHL a loss-of-function is an established disease mechanism. As the role of the region between amino acids (AA205 -213) is overall unknown, this receives PVS1_Moderate per the VHL VCEP PVS1 decision tree (PVS1_Moderate). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00000028 (2/1112000 from European, Non-Finnish Population). PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD (PM2_Supporting). A total of 4 cases between three commercial laboratories did not identify any cases with VHL spectrum tumors, and one case is >= 60yo without VHL spectrum tumors. PS4 is not met, and BS2 is not met. There are no additional reports identified in the literature. In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA041909/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4710 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0022346 infores:hetionet CHEBI:63791 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0023380 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0026826 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0042373 infores:hetionet CHEBI:36791 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0021177 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0948586 infores:hetionet CHEBI:28787 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0038362 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0948594 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0006145 infores:hetionet CHEBI:127342 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0041657 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0006266 infores:hetionet CAID:CA256480 biolink:causes MONDO:0018997 infores:clingen CAID:CA256480 MONDO:0018997 PMID:16921267PMID:20112233PMID:23321623PMID:16474405 Pathogenic PS3, PM1, PM2, PP2, PP3, PM6_Strong PS1 The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6_Strong; PMID 23321623, 20112233, 16921267, 16474405, 22488832, 18247425, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr58Ile variant may impact protein function (PS3; PMID: 23321623, 20949621, 16921267). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PM1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256480/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6754 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0031542 infores:hetionet CHEBI:49375 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0687713 infores:hetionet CHEBI:16469 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0037299 infores:hetionet CHEBI:27690 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0014742 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019917 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0152517 infores:hetionet CHEBI:31932 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020461 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0021843 infores:hetionet CHEBI:31980 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0036974 infores:hetionet GO:0045704 biolink:causes GO:0035272 infores:ubergraph knowledge_assertion manual_agent GO:0045704 GO:0035272 CHEBI:8310 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0012833 infores:hetionet CHEBI:114785 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0021845 infores:hetionet CHEBI:3219 biolink:causes MONDO:0700226 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016470 infores:hetionet NCBIGene:1500 biolink:causes MONDO:0040503 infores:monarchinitiative not_provided not_provided HGNC:2515 MONDO:0040503 uuid:5d20d8e7-6844-428d-9c69-fcadc183be9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C1443060 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0522172 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235893 infores:hetionet CHEBI:68558 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0687713 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0003123 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0015230 infores:hetionet CHEBI:49603 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0151313 infores:hetionet CAID:CA410202476 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202476 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.503G>T (p.Gly168Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score of 0.943, which is ≥ 0.88 (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202476/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5893 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0029408 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004691 infores:hetionet CHEBI:15765 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0012833 infores:hetionet CAID:CA915940766 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940766 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.855dup (p.Val286ArgfsTer43) frameshift variant creates a premature stop codon in biologically-relevant-exon 11/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient FF in PMID:12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 2.9-4.9% of normal, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting. (VCEP specifications version 2; date of approval 01/18/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940766/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:47780 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2364111 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0018801 infores:hetionet CAID:CA3046583529 biolink:causes MONDO:0100326 infores:clingen CAID:CA3046583529 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong The NM_000419.5(ITGA2B):c.2991del (p.Trp998GlyfsTer?) variant causes a frameshift and subsequent stop loss, resulting in alteration of the remaining 42 amino acids followed by the addition of 90 amino acids to the ITGA2B protein. This alters the transmembrane domain of the protein which is considered a critical region for protein function by the Platelet Disorders VCEP (PVS1_strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). The variant has been observed once in the homozygous state but no clinical information is available. In summary, this variant is classified as uncertain significance for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PVS1_Strong, PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA3046583529/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9168 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020437 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024141 infores:hetionet CHEBI:93635 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0002418 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151828 infores:hetionet CHEBI:35854 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0008031 infores:hetionet CHEBI:10125 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C3665347 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0011991 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027651 infores:hetionet CHEBI:6965 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0424295 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0041969 infores:hetionet CHEBI:134966 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0023530 infores:hetionet CHEBI:78320 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0263386 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0235901 infores:hetionet CHEBI:180905 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0040034 infores:hetionet CHEBI:3723 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020453 infores:hetionet CHEBI:6916 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0030920 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0236068 infores:hetionet CAID:CA355966127 biolink:causes MONDO:0001586 infores:clingen CAID:CA355966127 MONDO:0001586 PMID:29282708 Pathogenic PM4, PP4, PM3_Very Strong, PM2_Supporting PS3, PM5 The NM_000203.5:c.1960T>C in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Arg). Sequence analysis of cDNA (by 3'RACE) showed that the variant results in an increase in the length of the protein by 38 amino acids (PMID: 29282708) (PM4). Seven patients have been reported with the variant, including patients with clinical features consistent with MPS 1, and deficient IDUA activity (PMID: 21394825, 29282708) (PP4). Of these patients, five are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, including c.935G>A (p.Trp312Ter), phase unconfirmed (0.5 points) (PMID: 29282708), c.1138C>T (p.Gln380Ter), confirmed in trans (1 point) (PMID: 29282708), 46_57del12, phase not confirmed (0.5 points) (PMID: 21394825), c.208C>T (p.Gln70Ter), phase not confirmed (0.5 points) (PMID: 21394825), and c.266G>A (p.Arg89Gln) (PMID: 29282708), phase not confirmed (0.5 points). Two patients have been reported to be homozygous for the variant (2 x 0.5 points) (PMID: 29282708). Total 4 points (PM3_VeryStrong). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). When expressed in COS-7 cells, the variant resulted in 6% wild type activity, and Western blot pattern was abnormal (PMID: 29282708). The activity the LD VCEP's threshold for PS3_Supporting (<2%) and therefore, PS3_Supporting was not applied. Other IDUA stop loss variants have been reported in patients with MPS 1 including c.1960T>G (p.Ter654Gly) (Tieu et al, 1995, PMID: 7550232), and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762) and c.1962A>T (p.Ter654Cys) (Bach et al, 1993, PMID: 8328452). The classification of c.1960T>C (p.Ter654Arg) will be used in the assessment of those other variants. Therefore, PM5 was not applied here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 960079) In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_VeryStrong, PM1, PM4, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355966127/MONDO:0001586/091 2025-04-07 2025-04-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17650 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151905 infores:hetionet CHEBI:9599 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0009782 infores:hetionet CHEBI:7936 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013390 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007642 infores:hetionet CHEBI:28864 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0033774 infores:hetionet GO:1900217 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900217 GO:0007275 CHEBI:2569 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0033774 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020517 infores:hetionet CHEBI:4708 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0497156 infores:hetionet CAID:CA327925272 biolink:causes MONDO:0100437 infores:clingen CAID:CA327925272 MONDO:0100437 PMID: Benign BA1, BP4, BP7 NM_001034853.2(RPGR):c.1060-203G>A is an intron 9 variant located 203 nucleotides from the boundary with exon 10. This variant is present in gnomAD v4.1.0 at a frequency of 0.02736 among hemizygous individuals, with 994 variant alleles / 34,508 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4, BP7). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327925272/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:50173 biolink:causes MONDO:0005844 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0007933 infores:hetionet CHEBI:49960 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0023380 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0019917 infores:hetionet CHEBI:63627 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0311468 infores:hetionet CAID:CA343720120 biolink:causes MONDO:0005338 infores:clingen CAID:CA343720120 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.31T>C variant in MYOC is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 11 (p.Phe11Leu). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.03, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function.This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343720120/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8665 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0020649 infores:hetionet CHEBI:29007 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0002792 infores:hetionet CHEBI:8207 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0424295 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020514 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0036572 infores:hetionet CHEBI:4974 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0424790 infores:hetionet CHEBI:168396 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0000768 infores:hetionet GO:0045646 biolink:causes GO:0034101 infores:ubergraph knowledge_assertion manual_agent GO:0045646 GO:0034101 CHEBI:9671 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0022346 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0009806 infores:hetionet CHEBI:9123 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0037672 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020649 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004936 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0521495 infores:hetionet CHEBI:47426 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0000731 infores:hetionet CHEBI:5100 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0042571 infores:hetionet CHEBI:3504 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0027497 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0009443 infores:hetionet CHEBI:5855 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0392171 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0518015 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0029882 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020538 infores:hetionet CHEBI:68478 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011603 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1112192 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1112192 infores:hetionet CHEBI:10650 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0019521 infores:hetionet CHEBI:5165 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0022638 infores:hetionet CHEBI:3757 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0018524 infores:hetionet CAID:CA404082671 biolink:causes MONDO:0007750 infores:clingen CAID:CA404082671 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.980A>C (p.His327Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.954PP4 - Variant meet PM2. PMID: 31345425 (Trinder et al., 2019), Canada - 1 case with clinical Dutch Lipid Clinic Network Criteria score ≥ 6. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404082671/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:85078 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0002994 infores:hetionet CHEBI:135736 biolink:causes HP:0040242 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151702 infores:hetionet CHEBI:15551 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0236075 infores:hetionet CAID:CA392320410 biolink:causes MONDO:0007947 infores:clingen CAID:CA392320410 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PS4_Supporting, PM2_Supporting, PM1_Strong PM6, PVS1, PP1, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, PM4, PM5, PM3, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4081T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 1361 (p.Cys1361Arg). This variant has been identified in at least two individuals with clinical diagnoses of Marfan syndrome and in an individual with a clinical suspicion of Marfan syndrome (PP4, PS4_supporting; PMID: 35058154; CHEO internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.920). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_supporting, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392320410/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10101 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0034886 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004238 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0031039 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0851536 infores:hetionet CHEBI:64312 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151539 infores:hetionet CHEBI:7915 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0085633 infores:hetionet CHEBI:28915 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0151798 infores:hetionet UMLS:C0004609 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0018681 infores:hetionet NCBIGene:60529 biolink:causes MONDO:0012309 infores:monarchinitiative not_provided not_provided HGNC:450 MONDO:0012309 uuid:3b4120a5-befb-423d-9ce4-ec16df8d7089 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes UMLS:C0852921 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0852921 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0003123 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019193 infores:hetionet CHEBI:7824 biolink:causes HP:0002926 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0857576 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0281856 infores:hetionet CHEBI:9445 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0340865 infores:hetionet CHEBI:45081 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0231835 infores:hetionet CHEBI:31536 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C1720775 infores:hetionet CHEBI:16480 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0025061 infores:hetionet CHEBI:5118 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1167965 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0233472 infores:hetionet CHEBI:8863 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0019270 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042373 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0549622 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0030554 infores:hetionet NCBIGene:10300 biolink:causes MONDO:0014534 infores:monarchinitiative not_provided not_provided HGNC:6217 MONDO:0014534 uuid:9cf7398f-b58c-4623-9aaf-08cd722714da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1675 biolink:causes MONDO:0013487 infores:monarchinitiative not_provided not_provided HGNC:2771 MONDO:0013487 uuid:aee2eb92-6005-49dc-afe5-06574ca999ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2584 biolink:causes MONDO:0009255 infores:monarchinitiative not_provided not_provided HGNC:4118 MONDO:0009255 uuid:8700c0a4-93c1-4ae8-98a3-c8fc4e907882 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4858 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C1368065 infores:hetionet CAID:CA396463169 biolink:causes MONDO:0007648 infores:clingen CAID:CA396463169 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1480G>T p.(Glu494Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396463169/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:2666 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0027497 infores:hetionet CHEBI:6129 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0011603 infores:hetionet CHEBI:7514 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0009782 infores:hetionet CHEBI:3223 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013404 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002420 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0040188 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0162296 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0162296 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0559031 infores:hetionet CHEBI:75722 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235198 infores:hetionet CHEBI:45327 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0438716 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0003123 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019065 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002726 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0853761 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0851341 infores:hetionet CHEBI:3371 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0020517 infores:hetionet CAID:CA402996122 biolink:causes MONDO:0012999 infores:clingen CAID:CA402996122 MONDO:0012999 PMID: Pathogenic PVS1, PP4_Strong, PM2_Supporting PM3 The NM_000156.6:c.316C>T variant in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients with this variant have been reported with clinical features consistent with GAMT deficiency, elevated guanidinoacetate in urine or plasma, and low or absent creatine peak on brain magnetic resonance spectroscopy (MRS), and one of these patients also had evidence of a guanidinoacetate peak on brain MRS (PMID: 20049533, 24415674, 29506905) (PP4_Strong). Both patients (who have different descriptions) are compound heterozygous for the variant and c.407C>T (p.Thr136Met), phase unknown (PMID 20049533, 24415674, 29506905). The allelic data from these patients will be used in the assessment of p.Thr136Met and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 566624). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_strong, PM2_supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402996122/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63617 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018681 infores:hetionet CHEBI:499361 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0033771 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0041912 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0027765 infores:hetionet NCBIGene:2744 biolink:causes MONDO:0032678 infores:monarchinitiative not_provided not_provided HGNC:4331 MONDO:0032678 uuid:03a14aef-3f1d-47be-8e2e-dc505f13e073 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0013395 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0009450 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042373 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0032584 infores:hetionet CHEBI:85078 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0030196 infores:hetionet CHEBI:70707 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0085631 infores:hetionet CHEBI:28593 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0030252 infores:hetionet CHEBI:142290 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0009782 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0034186 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0836924 infores:hetionet CHEBI:78543 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0011991 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0677500 infores:hetionet CHEBI:45652 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0855775 infores:hetionet CHEBI:8461 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0152032 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151717 infores:hetionet CHEBI:2549 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0022281 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0011609 infores:hetionet CHEBI:9927 biolink:causes MONDO:0019203 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C1279945 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0574067 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1527311 infores:hetionet CAID:CA213828 biolink:causes MONDO:0015967 infores:clingen CAID:CA213828 MONDO:0015967 PMID: Likely Pathogenic PM1, PM5_Supporting, PP2, PP3, PM2_Supporting The c.677T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 226 (p.(Val226Ala)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.822, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Ala (PM5_Supporting). In summary, c.677T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213828/MONDO:0015967/086 2023-10-13 2023-10-13 Semidominant inheritance HP:0032113 Supports CHEBI:144551 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0019825 infores:hetionet CHEBI:63637 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0015967 infores:hetionet CHEBI:64355 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085649 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0013928 infores:hetionet CHEBI:64354 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0014518 infores:hetionet CAID:CA10014567 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014567 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.225C>T (p.Asp75=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014567/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83527 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0015230 infores:hetionet CHEBI:17141 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0023530 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042571 infores:hetionet CHEBI:465284 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0027066 infores:hetionet NCBIGene:894 biolink:causes MONDO:0014408 infores:monarchinitiative not_provided not_provided HGNC:1583 MONDO:0014408 uuid:88113ab4-a42b-4805-af6c-5b4ab83e1a1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8338089 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338089 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The c.1358G>A variant in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 453 (p.Arg453Gln). This variant has been identified in several individuals with a phenotype highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, at least three patients displayed beta oxidation flux of <20% of normal and at least two patients had abnormal newborn screen followed by plasma acylcarnitine analysis consistent with VLCAD deficiency (PP4_Moderate, PMIDs 20060901, 30194637, 33986768). Of those individuals, at least one was presumed compound heterozygous for this variant and a pathogenic ACADVL variant (PMID: 33986768, PM3 0.5 points). At least two individuals were homozygous for the variant (PMID: 30194637, 33986768, PM3 1 point) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.974, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338089/MONDO:0008723/021 2023-09-26 2023-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2618 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0018524 infores:hetionet CHEBI:135961 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0011991 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0162830 infores:hetionet CHEBI:31980 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C2939147 infores:hetionet CHEBI:4315 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0004093 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027769 infores:hetionet CHEBI:84500 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C2830004 infores:hetionet CHEBI:9137 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0022408 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0162830 infores:hetionet CAID:CA7331399 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331399 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, BA1, BP2, PP3, PP1, PP4, BS2, PM1, PM5, PS4, PS1, PS3, PS2, BS1, BS3, BS4 The NM_177438.3:c.1792G>A variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 598 (p.Glu598Lys). The total allele frequency in gnomAD v4.1.0 is 0.000008054 (13/1614038 alleles) with a highest population minor allele frequency of 0.00001102 (13/1180028 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.126; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 10/22/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331399/MONDO:0100216/024 2024-10-22 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50131 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0035243 infores:hetionet CHEBI:3242 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0031350 infores:hetionet CHEBI:75722 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0242429 infores:hetionet CHEBI:3561 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0236075 infores:hetionet CHEBI:3814 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0017178 infores:hetionet CHEBI:6367 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042963 infores:hetionet CHEBI:5280 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0917801 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0000731 infores:hetionet CHEBI:52717 biolink:causes MONDO:0041052 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032768 infores:hetionet CHEBI:135276 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0233477 infores:hetionet CHEBI:7601 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0038990 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0020538 infores:hetionet CHEBI:8772 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0403632 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0948586 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0039503 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0151736 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042373 infores:hetionet CHEBI:46081 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0702166 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025362 infores:hetionet CHEBI:50673 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0019158 infores:hetionet CHEBI:7478 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0040264 infores:hetionet CHEBI:132233 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0037822 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0040034 infores:hetionet CHEBI:9757 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0039231 infores:hetionet CHEBI:8863 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015371 infores:hetionet CHEBI:65346 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0027765 infores:hetionet CHEBI:52172 biolink:causes NCIT:C78280 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0221727 infores:hetionet CHEBI:50156 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0030554 infores:hetionet NCBIGene:7273 biolink:causes MONDO:0011400 infores:monarchinitiative not_provided not_provided HGNC:12403 MONDO:0011400 uuid:e4a868c4-66f6-4b4c-817c-09164e85df3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0344232 infores:hetionet CAID:CA421773580 biolink:causes MONDO:0005338 infores:clingen CAID:CA421773580 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.600A>G variant in MYOC is a synonymous variant (p.Arg200=). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0.06, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421773580/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes UMLS:C0877096 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0877096 infores:hetionet CHEBI:8214 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0011991 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0549373 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0349506 infores:hetionet CHEBI:8356 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1456784 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096091 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096091 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0013395 infores:hetionet CHEBI:5147 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020621 infores:hetionet CHEBI:4659 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0018520 infores:hetionet CHEBI:3011 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0042963 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0740481 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0740481 infores:hetionet CHEBI:3387 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0014457 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0476280 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0149931 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C1443060 infores:hetionet CHEBI:132233 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0162830 infores:hetionet CHEBI:6846 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0033975 infores:hetionet CAID:CA410147637 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147637 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1254G>A (p.Met418Ile) is a missense variant which has a REVEL score < 0.50 (0.209), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147637/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4798 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0596170 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0015376 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002442 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0023976 infores:hetionet CHEBI:32221 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0019080 infores:hetionet CHEBI:474053 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0018834 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0852914 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0852914 infores:hetionet CHEBI:4995 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085632 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0023067 infores:hetionet CHEBI:567361 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0029118 infores:hetionet UMLS:C0657912 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0237849 infores:hetionet CAID:CA512232105 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232105 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1428G>T (p.Val476=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.13) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232105/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63791 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011570 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0002622 infores:hetionet CAID:CA404092833 biolink:causes MONDO:0007750 infores:clingen CAID:CA404092833 MONDO:0007750 PMID: Uncertain Significance PM2, PP4, PP3 BA1, BP2, BP4, PS4, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1907G>T (p.Gly636Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.977.It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 1 index case who fulfills SB criteria for FH [(1) for adults, TC>7.8 mmol/L or LDL>.4.4 mmol/L; (2) for children <16 years old, TC>6.7 mmol/L; (3) patients or their relatives have tendon xanthomas; (4) patients with xanthomas whose TC > 16 mmol/L are diagnosed as homozygous and the others patients are diagnosed as heterozygous] from China (PMID: 24671153), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404092833/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6706 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0016059 infores:hetionet CAID:CA10102341 biolink:causes MONDO:0009276 infores:clingen CAID:CA10102341 MONDO:0009276 PMID: Benign BA1, BP4 The c.389C>T variant in GP1BB is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 130 (p.Pro130Leu). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.004627 (based on 4703/992006 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.092, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BB function and SpliceAI predicts no effect on splicing (delta scores 0.00) (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10102341/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3654 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0042963 infores:hetionet CHEBI:7565 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0234428 infores:hetionet CHEBI:135736 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0040264 infores:hetionet CHEBI:8346 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0032343 infores:hetionet CHEBI:6887 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151907 infores:hetionet NCBITaxon:6249 biolink:causes MONDO:0005656 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6249 MONDO:0005656 UMLS:C0657912 biolink:causes UMLS:C0151834 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151834 infores:hetionet CHEBI:63791 biolink:causes HP:0033724 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0338573 infores:hetionet NCBIGene:10352 biolink:causes MONDO:0030676 infores:monarchinitiative not_provided not_provided HGNC:12730 MONDO:0030676 uuid:4eec4d8a-0d9d-49fc-8935-b527f26083b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0595879 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0015230 infores:hetionet CHEBI:10119 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151662 infores:hetionet CHEBI:5118 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018524 infores:hetionet CHEBI:3723 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039591 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0021053 infores:hetionet NCBIGene:23310 biolink:causes MONDO:0054805 infores:monarchinitiative not_provided not_provided HGNC:28952 MONDO:0054805 uuid:ea17424e-4696-408e-905e-704494649982 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0002871 infores:hetionet CHEBI:31547 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0002965 infores:hetionet CHEBI:84883 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C2173677 infores:hetionet CHEBI:8890 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0080274 infores:hetionet CHEBI:5296 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0009676 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0042109 infores:hetionet CAID:CA2573051051 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051051 MONDO:0015967 PMID: Pathogenic PS3, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting PS4 The c.579+4del variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 5 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.92 for donor loss, predicting that the variant disrupts the donor site of intron 5 of GCK (PP3). There is evidence from RNA studies that this non-canonical splicing variant results in aberrant splicing, indicating that this variant impacts protein function (ClinVar Accession: SCV004037045.1)(PS3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with three informative meioses in two families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.605T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS3, PM2_Supporting, PP3, PP1_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051051/MONDO:0015967/086 2024-04-19 2024-04-19 Semidominant inheritance HP:0032113 Supports CHEBI:40050 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0948594 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0031117 infores:hetionet CHEBI:51380 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0040034 infores:hetionet CHEBI:2682 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151936 infores:hetionet CHEBI:71255 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0015371 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0042109 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0011991 infores:hetionet UMLS:C0065374 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0085636 infores:hetionet CHEBI:61033 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0022107 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0037199 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0849796 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0849796 infores:hetionet CHEBI:7822 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0043352 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0525045 infores:hetionet CAID:CA10653557 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653557 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PM6, PVS1, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001001890.3:c.*2533_*2534TG[10] (or c.*2549_*2550dup) variant in the 3' UTR has an MAF of 0.156 (15.6%, 6456/41366 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 467 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653557/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA512341114 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341114 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1287G>C (p.Leu429=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.87)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341114/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014335 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0013395 infores:hetionet CHEBI:48390 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C2939419 infores:hetionet NCBIGene:165829 biolink:causes MONDO:0957825 infores:monarchinitiative not_provided not_provided HGNC:20844 MONDO:0957825 uuid:8595b9de-e184-4767-8624-5136183cbecc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0151313 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0948594 infores:hetionet CHEBI:8356 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040460 infores:hetionet CHEBI:17688 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0439857 infores:hetionet CHEBI:5118 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013390 infores:hetionet CHEBI:3654 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0040034 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0006277 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0039231 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0314719 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0017152 infores:hetionet CHEBI:8774 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0041657 infores:hetionet CHEBI:8764 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023524 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0015397 infores:hetionet CHEBI:28830 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0034069 infores:hetionet CHEBI:9763 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085593 infores:hetionet UMLS:C0065374 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0085593 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0015230 infores:hetionet CHEBI:5280 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0242429 infores:hetionet NCBIGene:203547 biolink:causes MONDO:0010684 infores:monarchinitiative not_provided not_provided HGNC:22082 MONDO:0010684 uuid:3aa3796d-fb51-469b-aff9-a2a331005250 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:84464 biolink:causes MONDO:0013499 infores:monarchinitiative not_provided not_provided HGNC:23845 MONDO:0013499 uuid:0faa6972-7e6b-488f-9e15-cb0567ee8177 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0014742 infores:hetionet CHEBI:6339 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0028734 infores:hetionet CHEBI:15940 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0002792 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0085584 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0040046 infores:hetionet CHEBI:3732 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0015672 infores:hetionet CHEBI:3756 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0040460 infores:hetionet CHEBI:3479 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0038325 infores:hetionet CHEBI:691037 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0702166 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042109 infores:hetionet CHEBI:9737 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0020598 infores:hetionet CHEBI:39669 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0013404 infores:hetionet CAID:CA399798895 biolink:causes MONDO:0100326 infores:clingen CAID:CA399798895 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting PP3, BP4 Missense variant NM_000419.5(ITGA2B):c.2172G>A (p.Met724Ile) has been identified in at least 2 probands, including GT6 of PMID: 29675921 meeting the criteria for PP4_strong criteria. Patient 440 of the GT database is homozygous for Met724Ile (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3_supporting, PM2_supporting, PP4_strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399798895/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:10650 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0919980 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0018801 infores:hetionet CHEBI:3752 biolink:causes MONDO:0021002 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0039075 infores:hetionet CHEBI:6128 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0042963 infores:hetionet CAID:CA340668 biolink:causes MONDO:0012996 infores:clingen CAID:CA340668 MONDO:0012996 PMID: Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting, PVS1 The NM_001482.3:c.446G>A (p.Trp149Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Three siblings and a cousin with AGAT deficiency are all homozygous for the variant (PM3_Supporting). The proband in this family has total absence of the creatine/phosphocreatine peak on brain MRS, low urine GAA and creatine but normal blood levels; AGAT activity in lymphoblasts <0.3 nmol/hr/mg protein (normal 12.6–23.4)(PP4_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 7302). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA340668/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:253342 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0018681 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005097 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0149782 infores:hetionet CHEBI:4792 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C2242588 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0023530 infores:hetionet CHEBI:31547 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0085649 infores:hetionet CHEBI:135920 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0151908 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0151698 infores:hetionet CHEBI:7936 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019079 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042373 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0476089 infores:hetionet CHEBI:9137 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0010692 infores:hetionet CHEBI:499361 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0000737 infores:hetionet CHEBI:15765 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0004604 infores:hetionet CHEBI:55346 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0009676 infores:hetionet CHEBI:40009 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0009676 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006852 infores:hetionet CHEBI:3568 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014457 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0022081 infores:hetionet CHEBI:4653 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0042510 infores:hetionet UMLS:C0025241 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0042963 infores:hetionet CAID:CA8623019 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623019 MONDO:0100326 PMID: Uncertain Significance BS1, PM2, PP3, PP4, BA1 The c.670G>A variant in ITGB3 is a missense variant predicted tocause substitution of Aspartic Acid by Asparagine at amino acid 224 (p.Asp224Asn). This variant was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. No ACMG/AMP criteria could be applied to this variant. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623019/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA16020934 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020934 MONDO:0009861 PMID:26503515 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1076C>T (p.Ser359Leu) variant in PAH has been reported in multiple individuals with classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.T278I in 2 patients (PMID: 30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020934/MONDO:0009861/006 2020-06-19 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6367 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002874 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0040053 infores:hetionet CHEBI:43968 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0031542 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0595862 infores:hetionet CAID:CA011471 biolink:causes MONDO:0005045 infores:clingen CAID:CA011471 MONDO:0005045 PMID: Uncertain Significance PM2, PS4_Supporting BA1, PP3, PP1, PM5, PM4, PM1, PM6, PS3, BS1, BS4, BS3, PS1, PS2, BP4, BP7, BP5, BP2, PVS1 TThe c.1925C>T (p.Ser642Leu) variant in MYH7 has been identified in 4 individuals with DCM (PS4_Supporting; Daehmlow 2002 PMID:12379228; OMGL pers. comm., Invitae pers. comm., Ambry pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PS4_Supporting Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011471/MONDO:0005045/002 2021-06-16 2021-06-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2453 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0040034 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0152227 infores:hetionet CHEBI:6444 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0033774 infores:hetionet CHEBI:17823 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0151683 infores:hetionet UMLS:C0025241 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0854467 infores:hetionet CHEBI:30830 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020433 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0002792 infores:hetionet CHEBI:15553 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0015230 infores:hetionet CHEBI:49375 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0549567 infores:hetionet CHEBI:3764 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0015230 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151849 infores:hetionet NCBIGene:253738 biolink:causes MONDO:0015021 infores:monarchinitiative not_provided not_provided HGNC:19087 MONDO:0015021 uuid:155bde77-e0a3-4525-9dca-e995fba34c64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C2937358 infores:hetionet CHEBI:7986 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0003811 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0001416 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017160 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007114 infores:hetionet CHEBI:4995 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011071 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0025290 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0233472 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0852733 infores:hetionet CHEBI:63610 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0015967 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0042075 infores:hetionet CHEBI:7443 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0014724 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0004936 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0699744 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0007400 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0007400 uuid:56623da1-d9d2-4a39-8b59-6dbba4c0eba1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:84146 biolink:causes MONDO:0013604 infores:monarchinitiative not_provided not_provided HGNC:29222 MONDO:0013604 uuid:557f0176-6a08-41eb-95d1-fd9eedd73538 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0423153 infores:hetionet NCBIGene:2780 biolink:causes MONDO:0013465 infores:monarchinitiative not_provided not_provided HGNC:4394 MONDO:0013465 uuid:387d71f4-eb90-4951-a51b-c424ee56917c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410781684 biolink:causes MONDO:0021060 infores:clingen CAID:CA410781684 MONDO:0021060 PMID: Pathogenic PVS1, PM2_Supporting, PM3 BA1, BS1 The c.993+1G>A variant in LZTR1 occurs within the canonical splice donor site + 1 of intron 9. It is predicted to cause skipping of biologically-relevant-exon 9/21 (out of frame), resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 1/59454) of the c.993+1G>A variant in LZTR1 is 0 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in 2 individuals with RASopathy. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 1 of those was confirmed in trans by family testing (c.1591G>A (p.D531N) phase unknown, c.1149+1G>A confirmed in trans, 1.25 PM3 points, SCV002107378.4, GeneDx) (PM3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410781684/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7581 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0011991 infores:hetionet CHEBI:3219 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0023380 infores:hetionet CAID:CA229368 biolink:causes MONDO:0009861 infores:clingen CAID:CA229368 MONDO:0009861 PMID:25323746 Pathogenic PVS1, PM2, PP4 The c.1166del (p.Ala389fs) variant in PAH has been detected in 1 patient with PKU, Phe = 1045umol/L; BH4 deficiency not excluded (PMID: 25323746; PP4). This variant is absent from population databases (PM2), and is a variant predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 11 out of 13 coding exons (11 out of total exons) (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229368/MONDO:0009861/006 2020-10-29 2020-10-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9654 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0012797 infores:hetionet CHEBI:3723 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026837 infores:hetionet CAID:CA1244142 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244142 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, PM4 BP7, BS1, BS3, PVS1, PP3, PP1, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.844del variant in MYOC is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 64 of the frameshift, or amino acid 345 (p.Gln282ArgfsTer64). This variant is predicted to involve ≥ 10% of the protein within the conserved olfactomedin domain, meeting PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with primary open angle glaucoma is not loss-of-function. The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00004007 (3 alleles out of 74,876), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (E Souzeau pers. comm.), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Only 1 segregation had been reported for primary open angle glaucoma (E Souzeau pers. comm.), not meeting the ≥ 3 segregations required for PP1. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM4, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244142/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10650 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020569 infores:hetionet CHEBI:7601 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0017178 infores:hetionet CHEBI:7640 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2363731 infores:hetionet CHEBI:490877 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0221512 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030552 infores:hetionet CHEBI:499361 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0004093 infores:hetionet CAID:CA020538 biolink:causes MONDO:0008667 infores:clingen CAID:CA020538 MONDO:0008667 PMID: Benign BA1 The variant NM_000551.3(VHL):c.74C>T (p.Pro25Leu) in VHL is a missense variant occurring prior to the second start site. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.005329 (6211/1141350 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020538/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28901 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0235416 infores:hetionet CAID:CA10014223 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014223 MONDO:0011071 PMID: Benign BA1 PS4, PS3, PS1, BP2, BP4, PVS1, PM6, PM2, BS4, BS1, BS3, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.1005G>T (p.Gln335His) variant has a MAF of 0.00357 (0.357%, 15/4,206 alleles) in the East Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This missense variant has a REVEL score 0.4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014223/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2379 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0021775 infores:hetionet CAID:CA645608283 biolink:causes MONDO:0011071 infores:clingen CAID:CA645608283 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.664dup (p.Ser222fs) is a frameshift variant which affects all biologically relevant isoforms. This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645608283/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63629 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0036572 infores:hetionet CAID:CA401366675 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366675 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PVS1_Strong This variant, c.1437+1G>A, alters the donor splice site of intron 9. Based on RT-PCR results from a patient who is compound heterozygous for the variant, this results in skipping of exon 9, which leads to an in frame deletion of p.Asp443_Lys479del (PMID 22676651), including part of the GAA catalytic barrel (PMID 22253258). Western blot analysis of protein extracted from cultured skin fibroblasts from a patient who is homozygous for the variant revealed that the patient was positive from cross-reactive immunological material, supporting that the variant results in an in-frame consequence (PMID 22252923). Based on these results, PVS1_Strong was applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, meeting PM2_Supporting. Two patients with Pompe disease have been reported who are homozygous for the variant and meet the ClinGen LSD VCEP's PP4 specifications (PMID 22555271, 22252923; personal communication), meeting PM3 and PP4_Moderate. Another patient has been reported with the variant in trans with c.1076-22G>A (PMID 22676651). In trans data from this patient will be used in the assessment of c.1076-22G>A and is not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 555864; two star review status) with five submitters classifying the variant as pathogenic and one submitter classifying as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366675/MONDO:0009290/010 2023-05-16 2023-11-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ HP:0031377 biolink:causes MONDO:0006058 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D009396 DB00970_MESH_D009396_1 CAID:CA211420 biolink:causes MONDO:0008535 infores:clingen CAID:CA211420 MONDO:0008535 PMID: Likely Benign BS3_Supporting, BP2, BS1 PP3 The NM_001114753.3: c.1510G>A variant in ENG is a missense variant predicted to cause substitution of valine by methionine at amino acid 504 (p.Val504Met). The filtering allele frequency (the lower threshold of the 95% CI of 225/24916) of the c.1510G>A variant in ENG is 0.007757 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in trans with the variant c.23T>C, p.Leu8Pro (PMID: 19767588), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in affected family members with HHT. The phase of the variants was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.239, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP2, BS3_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA211420/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9123 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0149745 infores:hetionet CHEBI:44185 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1145670 infores:hetionet CHEBI:6076 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0853034 infores:hetionet CHEBI:94449 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0004245 infores:hetionet CAID:CA2573332224 biolink:causes MONDO:0001586 infores:clingen CAID:CA2573332224 MONDO:0001586 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000203.5:c.1026del (p.Tyr343ThrfsTer4) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 8 (IDUA has 14 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with mucopolysaccharidosis type 1. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573332224/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10127 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C1443060 infores:hetionet CHEBI:6970 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0392171 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0242973 infores:hetionet CHEBI:465284 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0423791 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C1963790 infores:hetionet CHEBI:135005 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0236075 infores:hetionet CHEBI:74947 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1384353 infores:hetionet CHEBI:68478 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0043352 infores:hetionet CHEBI:16469 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0547030 infores:hetionet CHEBI:8888 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1609512 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0018802 infores:hetionet CHEBI:17303 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0231530 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006678 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0005683 infores:hetionet CHEBI:52172 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0852911 infores:hetionet CHEBI:3347 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0041969 infores:hetionet CHEBI:63580 biolink:causes HP:0001147 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0271053 infores:hetionet CHEBI:8707 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C2830004 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020295 infores:hetionet CHEBI:8430 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0007166 infores:hetionet CHEBI:9448 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0858635 infores:hetionet CHEBI:9943 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0302809 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0393615 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0393615 infores:hetionet CHEBI:231594 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0013428 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006145 infores:hetionet CHEBI:45409 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027497 infores:hetionet CHEBI:3723 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0220870 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042769 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0021053 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042571 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0856171 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0856171 infores:hetionet CAID:CA10014572 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014572 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.188C>T (p.Ala63Val) is a missense variant which is present in only 1 individual in gnomAD 2.0 with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.273) and a SpliceAI score ≤0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014572/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:53691 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0574067 infores:hetionet GO:0106396 biolink:causes GO:0001745 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0001745 CAID:CA2695223152 biolink:causes MONDO:0012999 infores:clingen CAID:CA2695223152 MONDO:0012999 PMID: Pathogenic PP4_Strong, PM2_Supporting, PVS1_Strong PM3 The NM_000156.6(GAMT):c.418_419del (p.Ser140GlyfsTer50) variant in GAMT is a frameshift variant predicted to cause a premature stop codon at the end of biologically-relevant-exon 5 of a total of 6 exons. While this variant may not lead to nonsense-mediated decay, the frameshift would result in loss of about 50% of the normal sequence (the frameshift begins at amino acid 140 out of 269 total) including residues in exon 5 that are important in binding guanidinoacetate (Leu171, Thr172, Tyr222) (PMID: 12079381, 15533043) (PVS1_Strong). A Chinese male with clinical features consistent with GAMT deficiency has been reported who has elevated urine guanidinoacetate, low urine creatine, and decreased creatine on brain MRS (PP4_Strong). This individual has been reported to be compound heterozygous for the variant and c.212T>G (p.Met71Arg) (Journal of Clinical Pediatrics, 2024 Vol.42 No.12 1039-1046 (article in Chinese), link to article - https://jcp.xinhuamed.com.cn/EN/10.12372/jcp.2024.24e0300). The allelic data from this patient will be used in the classification of p.Met71Arg and is not included here to avoid circular logic. The variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 3583501). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG-AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Strong, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695223152/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:35854 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0025061 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030332 infores:hetionet CHEBI:4046 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0233494 infores:hetionet CHEBI:63611 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0019079 infores:hetionet CHEBI:28748 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0039070 infores:hetionet CHEBI:3216 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0428977 infores:hetionet CHEBI:3175 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C3665346 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0033975 infores:hetionet CHEBI:2618 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0022107 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0004936 infores:hetionet CHEBI:94392 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0038454 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0042373 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0042109 infores:hetionet CHEBI:109549 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C2830004 infores:hetionet CHEBI:83804 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0043094 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0085649 infores:hetionet CHEBI:4659 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0038435 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0007785 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013609 infores:hetionet CHEBI:8430 biolink:causes UMLS:C1262010 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C1262010 infores:hetionet CHEBI:2948 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0854467 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0031350 infores:hetionet CHEBI:2379 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0023066 infores:hetionet CHEBI:10101 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0018681 infores:hetionet CHEBI:110423 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0221512 infores:hetionet CHEBI:50663 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0018681 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0919823 infores:hetionet CHEBI:61033 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0232462 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013146 infores:hetionet CHEBI:134991 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0017168 infores:hetionet CHEBI:63608 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0476273 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1258215 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009241 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0015397 infores:hetionet CHEBI:617099 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0022354 infores:hetionet CHEBI:92712 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0020615 infores:hetionet CHEBI:584020 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0030554 infores:hetionet CHEBI:94392 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0002792 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0037274 infores:hetionet CHEBI:50729 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0231528 infores:hetionet CHEBI:10023 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085605 infores:hetionet CHEBI:194135 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023518 infores:hetionet GO:0044734 biolink:causes GO:0160128 infores:ubergraph knowledge_assertion manual_agent GO:0044734 GO:0160128 CHEBI:6375 biolink:causes HP:0012743 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0311277 infores:hetionet CHEBI:4702 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0018681 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006277 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003873 infores:hetionet CAID:CA294661 biolink:causes MONDO:0010726 infores:clingen CAID:CA294661 MONDO:0010726 PMID: Benign BA1, BP5_Strong, BS2 PM2 The highest population minor allele frequency of the p.Leu336Val variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.001148 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Leu336Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Leu336Val variant is found in at least 3 patients with an alternate molecular basis of disease (internal database) (BP5_Strong). In summary, the p.Leu336Val variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong). (MECP2 specification v3.0.0; curation approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294661/MONDO:0010726/036 2024-08-30 2024-12-23 X-linked inheritance HP:0001417 Contradicts true CHEBI:3216 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0149931 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034359 infores:hetionet CHEBI:3403 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0034063 infores:hetionet CHEBI:36791 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030196 infores:hetionet CHEBI:9352 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0015967 infores:hetionet CHEBI:7447 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0237849 infores:hetionet CAID:CA011369 biolink:causes MONDO:0021056 infores:clingen CAID:CA011369 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PVS1_Moderate The NM_000038.6(APC):c.645+2T>G variant in APC occurs within the canonical splice donor site of intron 6. It is predicted to result in an in-frame skipping of exon 6 (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in one proband meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, [Ambry Genetics]). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1_Moderate, PS4_Supporting, PM2_Supporting (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA011369/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:3U02EL437C biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0018932 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030578 infores:hetionet CHEBI:6062 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0019080 infores:hetionet CHEBI:9907 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0035455 infores:hetionet CHEBI:3752 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0234632 infores:hetionet CHEBI:10100 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C3263723 infores:hetionet CAID:CA512318963 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318963 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, BP5, BS1, PVS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.147A>G (p.Pro49=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.04) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.32) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318963/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA410208248 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208248 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.30T>A (p.Phe10Leu) is a missense variant which has a REVEL score < 0.50 (0.294), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208248/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10101 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0234238 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007971 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004238 infores:hetionet CHEBI:71940 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0232943 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0008370 infores:hetionet CHEBI:3215 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0438142 infores:hetionet CAID:CA2577490158 biolink:causes MONDO:0011071 infores:clingen CAID:CA2577490158 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BA1, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PP3, PP1 NM_001754.5:c.806-15T>C is an intronic variant occurring in intron 7. This variant is completely absent from all population databases, including gnomAD v2.1.1 and v3.1.2, which have coverage of at least 20x for the RUNX1 gene at this position (PM2_supporting). Additionally, the variant has SpliceAI ∆ scores of ≤ 0.20, with a prediction of 0.04 for the loss of the acceptor splice site and of 0.03 for the loss of the donor splice site, thus indicating a low likelihood of altering splicing (BP4). Evolutionary conservation algorithms also suggest that the site is not conserved, as indicated by a PhyloPway score of 0.647, which is below the threshold of 2.0 (BP7). Furthermore, there is no known previous report of this variant to our knowledge. In summary, this variant meets the criteria to be classified as likely benign according to ACMG/AMP criteria, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7 PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2577490158/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3125 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0011991 infores:hetionet CAID:CA645607320 biolink:causes MONDO:0011071 infores:clingen CAID:CA645607320 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.505dup (p.Arg169LysfsTer?) is a frameshift variant in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). The variant affects the R169 amino acid residue within the RHD (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645607320/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6121 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0003123 infores:hetionet CHEBI:63581 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0019209 infores:hetionet CAID:CA8815079 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815079 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting, PS3_Moderate, PM3_Strong The NM_000152.5:c.871C>T variant in GAA is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 291 (p.Leu291Phe). Five patients with Pompe disease and this variant have been reported, four with characteristics specific for Pompe disease including published laboratory values showing deficient GAA activity and/or on enzyme replacement therapy and/or with documented symptoms consistent with infantile onset Pompe disease (PMID 25526786, 30737479, 31086307, 32849613) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown, including c.716delT (PMID 32849613; 0.5 points), c.1798C>T (p.Arg600Cys)(PMID 26253708; 0.5 points), c.2238G>C (p.Trp746Cys)(PMID 25526786; 0.5 points), and c.2481+102_2646+31del (PMID 31086307; 0.5 points). One patient who is homozygous for the variant, due to uniparental disomy, has also been reported (PMID 30737479; 0.5 points). Total 2.5 points (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006378 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% wild type GAA activity and showed evidence of abnormal synthesis and processing on Western blot (PMID 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.701 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other missense changes, c.872T>C (p.Leu291Pro) and c.872T>A (p.Leu291His), at the same amino acid residue have been reported; c.872T>C (p.Leu291Pro) has been classified as pathogenic based on the specifications of the ClinGen LSD VCEP (CAID: CA401363854)(PM5). The data for this variant, c.871C>T (p.Leu291Phe, will be used in the assessment of p.Leu291His and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID 956209; 1 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM5, PP3, PS3_Moderate, PM3_Strong, PM2_Supporting, PP4_Moderate. (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815079/MONDO:0009290/010 2021-10-26 2021-10-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31623 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0442886 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0423729 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0423729 infores:hetionet CHEBI:6958 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0020649 infores:hetionet CHEBI:7907 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0522224 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151601 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C2225524 infores:hetionet CHEBI:18067 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0020517 infores:hetionet CHEBI:42944 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0030252 infores:hetionet CAID:CA10603804 biolink:causes MONDO:0009861 infores:clingen CAID:CA10603804 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5 PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Predicted deleterious in SIFT, PolyPhen2, Mutation Taster. REVEL=0.952. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603804/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36795 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011606 infores:hetionet CHEBI:3441 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0085649 infores:hetionet CHEBI:8214 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0438717 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0574067 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0027765 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0014130 infores:hetionet CHEBI:61058 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0242422 infores:hetionet NCBIGene:1181 biolink:causes MONDO:0011576 infores:monarchinitiative not_provided not_provided HGNC:2020 MONDO:0011576 uuid:b2a6ee5c-2415-47a5-b2d1-672b2f18e1f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004623 infores:hetionet CAID:CA000123 biolink:causes MONDO:0018875 infores:clingen CAID:CA000123 MONDO:0018875 PMID:33051313 Likely Benign BP4, BS3_Supporting, BS2 BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BP5, BS1, BS4, PM2, PP3, PP1 The NM_000546.6: c.329G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 110 (p.Arg110His). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, BP4. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000123/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15367 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0162830 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0020517 infores:hetionet CHEBI:4315 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0022107 infores:hetionet CHEBI:9599 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0011606 infores:hetionet CHEBI:9086 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0039240 infores:hetionet CHEBI:4325 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0041834 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0234215 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0235874 infores:hetionet CHEBI:41879 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0030554 infores:hetionet CHEBI:63681 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0086769 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0948594 infores:hetionet CHEBI:23765 biolink:causes HP:0005165 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0520878 infores:hetionet CHEBI:101278 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0242422 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0002170 infores:hetionet GO:0080050 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0080050 GO:0061458 CHEBI:9449 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0012833 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0038362 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0004652 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D018410 DB01112_MESH_D018410_1DB01044_MESH_D018410_1DB00254_MESH_D018410_1DB06402_MESH_D018410_1DB00479_MESH_D018410_1DB00207_MESH_D018410_1DB01212_MESH_D018410_1DB01060_MESH_D018410_1DB01331_MESH_D018410_1DB01327_MESH_D018410_1DB01597_MESH_D018410_1DB00199_MESH_D018410_1DB01598_MESH_D018410_1DB00798_MESH_D018410_1DB00493_MESH_D018410_1 CHEBI:204734 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0152459 infores:hetionet CHEBI:134991 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0013378 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0424000 infores:hetionet CAID:CA122854 biolink:causes MONDO:0000573 infores:clingen CAID:CA122854 MONDO:0000573 PMID:17476358 Pathogenic PP4, PP1, PM2_Supporting, PM3, PM1_Supporting, PS3 The c.686G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 229 (p.Arg229Gln). The filtering allele frequency (the upper threshold of the 95% CI of 2/113660) of the c.686G>A variant in RAG2 is 0.000002920 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + T-B-NK+ lymphocyte subset profile (0.5pt) total 1 pt, which is highly specific for SCID (PP4, PMID: 30307608). The variant showed disrupted V(D)J recombination activity at 8.9% of WT-RAG2 (PMID: 29772310). Additionally, an animal model homozygous for the variant recapitulates most phenotypes associated with OS (PMID: 17476358) (PS3). The variant has been reported to segregate with SCID in 02 affected siblings from one family (Proband + one) (PP1_Supporting; PMID: 30307608). Five patients (14–18) were homozygous for the variant (reaching the maximum 1 pt) PM3_Moderate (PMID: 30307608).In summary, this variant meets the criteria to be classified as pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4, PM3_Moderate, PS3, PP1, and PM1_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA122854/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6367 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234458 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0037199 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0853700 infores:hetionet CHEBI:63607 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0014457 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085682 infores:hetionet NCBIGene:85358 biolink:causes MONDO:0011652 infores:monarchinitiative not_provided not_provided HGNC:14294 MONDO:0011652 uuid:74f84cd2-ac35-4f34-ac53-bce0a5c18280 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3764 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0037763 infores:hetionet CHEBI:3757 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0085631 infores:hetionet CHEBI:64312 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1306341 infores:hetionet CHEBI:38545 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0009676 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0235723 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0235723 infores:hetionet CHEBI:50859 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151905 infores:hetionet CHEBI:7025 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0012833 infores:hetionet CHEBI:231594 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0015672 infores:hetionet NCBIGene:10939 biolink:causes MONDO:0033549 infores:monarchinitiative not_provided not_provided HGNC:315 MONDO:0033549 uuid:2dc0be80-c3c9-4e68-9563-c69e4ba97398 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023530 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0020538 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151849 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0027769 infores:hetionet GO:1904130 biolink:causes GO:0001839 infores:ubergraph knowledge_assertion manual_agent GO:1904130 GO:0001839 CHEBI:8871 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C2225524 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042109 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0030578 infores:hetionet CHEBI:47499 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0000729 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0020517 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0021053 infores:hetionet CHEBI:3994 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0009806 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0027765 infores:hetionet CHEBI:6909 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0232493 infores:hetionet CHEBI:8871 biolink:causes HP:0040212 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0343494 infores:hetionet CHEBI:94807 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0015967 infores:hetionet CHEBI:3647 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0002994 infores:hetionet CHEBI:8871 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030554 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001134 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085580 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0233414 infores:hetionet CHEBI:33325 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0016204 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018418 infores:hetionet CHEBI:8869 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C1291077 infores:hetionet CHEBI:9587 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0040034 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0002878 infores:hetionet CHEBI:8502 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0221490 infores:hetionet CHEBI:6539 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0039231 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020621 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0034186 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0347950 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0347950 infores:hetionet CHEBI:78543 biolink:causes EFO:0001425 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0349782 infores:hetionet CHEBI:63623 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0006840 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0152128 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0233472 infores:hetionet CHEBI:64355 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0008033 infores:hetionet CHEBI:49668 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0085605 infores:hetionet CHEBI:567361 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0011603 infores:hetionet CHEBI:9241 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0014518 infores:hetionet CAID:CA2695224153 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224153 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.1465del (p.Glu489AsnfsTer64) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BSS14.01 in PMID: 23995613) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224153/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6715 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0034155 infores:hetionet CAID:CA402998134 biolink:causes MONDO:0012999 infores:clingen CAID:CA402998134 MONDO:0012999 PMID: Likely Pathogenic PP3, PP4_Strong, PM2_Supporting, PM3_Supporting PM5 NM_000156.6(GAMT):c.115A>G (p.Lys39Glu) is a missense variant in the first exon of the GAMT gene. This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.721, which meets the threshold set in Pejaver et al. 2022 (PMID:36413997) for (PP3_Met). The c.115A>G(p.Lys39Glu) variant was identified in a proband alongside the pathogenic variant c.328-2A>G (PMID:3730571). Phase analysis was unclear, meeting the Cerebral Creatine Deficiency Syndromes metric for PM3_Supporting. This same proband is reported with moderate global developmental delay. Dried blood spot analysis measured increased GAA with significantly reduced creatine (2 points), and the patient has a significantly decreased creatine peak via MRS (3 points) (PMID:37305710) (PP4_Strong). In summary, the NM_000156.6(GAMT):c.115A>G (p.Lys39Glu) variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0). PM2_Supporting, PP4_Strong, PP3, PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP on December 14, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402998134/MONDO:0012999/026 2023-12-14 2023-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46557 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0178298 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0039446 infores:hetionet CHEBI:52717 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0743400 infores:hetionet CHEBI:49575 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042963 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0027947 infores:hetionet CHEBI:91541 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0040822 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0037199 infores:hetionet CHEBI:50742 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013404 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0038814 infores:hetionet CHEBI:4717 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0020649 infores:hetionet CHEBI:2673 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0003578 infores:hetionet CHEBI:188986 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0035305 infores:hetionet CHEBI:10124 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0018681 infores:hetionet CHEBI:50275 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042963 infores:hetionet CHEBI:93635 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0392156 infores:hetionet NCBITaxon:485 biolink:causes MONDO:0004277 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:485 MESH:D006069 DB00618_MESH_D006069_1DB01416_MESH_D006069_1DB00948_MESH_D006069_1DB01017_MESH_D006069_1DB00919_MESH_D006069_1DB01165_MESH_D006069_1DB00671_MESH_D006069_1DB00467_MESH_D006069_1DB01332_MESH_D006069_1DB01112_MESH_D006069_1DB00254_MESH_D006069_1DB01602_MESH_D006069_1DB13092_MESH_D006069_1DB00199_MESH_D006069_1DB00365_MESH_D006069_1DB00319_MESH_D006069_1DB01331_MESH_D006069_1DB01059_MESH_D006069_1DB01212_MESH_D006069_1DB02703_MESH_D006069_1DB01212_MESH_D006069_2DB00759_MESH_D006069_1DB00415_MESH_D006069_1 CHEBI:17688 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0004936 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0240515 infores:hetionet CHEBI:50381 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0085593 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0235328 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0235328 infores:hetionet CHEBI:3216 biolink:causes MONDO:0020744 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0264907 infores:hetionet GO:0140886 biolink:causes GO:0140888 infores:ubergraph knowledge_assertion manual_agent GO:0140886 GO:0140888 CHEBI:100241 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022354 infores:hetionet CHEBI:10119 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151576 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0020456 infores:hetionet CHEBI:8764 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0033036 infores:hetionet CAID:CA409106752 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106752 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting The c.590T>C variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 197 (p.(Leu197Pro)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.590T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106752/MONDO:0015967/085 2023-12-25 2023-12-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5790 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020538 infores:hetionet CHEBI:39669 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0011606 infores:hetionet CHEBI:3172 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0151636 infores:hetionet CAID:CA1624337 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624337 MONDO:0021060 PMID: Uncertain Significance BS2 PM1, BP5, PM2, PP2, PP3, BP4, BP2 The c.2728G>C (p.Asp910His) variant in SOS1 is present in 0.009806% of South Asian chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). This variant was observed in 4 healthy adult individuals who did not have clinical features of a RASopathy (BS2; SCV000808073.1). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624337/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:28748 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0010414 infores:hetionet CHEBI:3219 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085649 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0151595 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0151595 infores:hetionet NCBIGene:10345 biolink:causes MONDO:0014191 infores:monarchinitiative not_provided not_provided HGNC:12261 MONDO:0014191 uuid:bd1d428e-d241-4bc4-a165-f91e98527f83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51364 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151818 infores:hetionet CHEBI:240107 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0010034 infores:hetionet CHEBI:68478 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0010200 infores:hetionet CHEBI:85078 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0016658 infores:hetionet UMLS:C0009315 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0015672 infores:hetionet CHEBI:49575 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0232726 infores:hetionet CHEBI:71255 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0011570 infores:hetionet CHEBI:4027 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0026766 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085584 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0403632 infores:hetionet CHEBI:48844 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0027497 infores:hetionet CAID:CA267682 biolink:causes MONDO:0009861 infores:clingen CAID:CA267682 MONDO:0009861 PMID:26666653PMID:26666653 Uncertain Significance PM2, PP3, PP4, PM3_Supporting PM5 The c.887A>G (p.Asp296Gly) variant in PAH has been reported in a proband with classic PKU (PMID: 26666653; PP4). The proband was heterozygous for variant; it was found with the known pathogenic (per ClinGen PAH Working Group – see ClinVar variant ID 577) c.1222C > T (p.Arg408Trp) allele; however, the although paper did say that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing. Thus, PM3 is downgraded to supporting. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent from ethnically diverse control databases (PM2). Another missense at the site, p.Asp296His, has been previously reported (BioPKU PAH0955) heterozygous in a Chinese proband with PKU; no further information appears to be provided in the manuscript or supplementary information regarding phenotype or second variant (PMID: 26503515). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267682/MONDO:0009861/006 2019-07-14 2019-07-14 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:491 biolink:causes MONDO:0030719 infores:monarchinitiative not_provided not_provided HGNC:815 MONDO:0030719 uuid:c76e45c4-e89e-4cbb-ba89-675bf68a3832 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0031256 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027697 infores:hetionet CHEBI:44032 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0026821 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0234215 infores:hetionet CHEBI:7954 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0020458 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006581 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0162423 infores:hetionet CHEBI:9763 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0040822 infores:hetionet CHEBI:51860 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002792 infores:hetionet CAID:CA137975 biolink:causes MONDO:0021060 infores:clingen CAID:CA137975 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.846C>T (p.Pro282=) variant in the MAP2K2 gene is 0.515% (46/6886) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137975/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:17347 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C2047937 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011053 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0006849 infores:hetionet CAID:CA512341241 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341241 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1185G>A (p.Pro395=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-3.50) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341241/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:57728 biolink:causes MONDO:0014579 infores:monarchinitiative not_provided not_provided HGNC:18340 MONDO:0014579 uuid:a14a589d-1765-4f51-8b5e-d8f9fd15409b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75998 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0030578 infores:hetionet GO:1901722 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1901722 GO:0007275 UNII:UMD7G2653W biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0014236 infores:hetionet CHEBI:3478 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151539 infores:hetionet NCBIGene:843 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:1500 MONDO:0001056 uuid:746012ea-c125-4e6c-a665-8d7705d21763 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA658683899 biolink:causes MONDO:0007947 infores:clingen CAID:CA658683899 MONDO:0007947 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PM1, PM4 PVS1, PM6, BS2, PP2, PP3, PP1, PP4, BP2, BP3, BP1, BP4, BA1, PS1, PS3, PS2, PM3, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4407_4409dup is a duplication of 3 nucleotides in FBN1 predicted to cause the duplication of the cysteine residue at amino acid position 1470 (p.Cys1470dup). This variant has been identified in at least two individuals with suspicion for Marfan syndrome including a proband with several systemic features and a proband with tall stature and thoracic aortic aneurysm and dissection (TAAD) (PS4_supporting; GeneDx internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This in-frame insertion introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges (PM1, PM4). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM4, PM2_supporting, PS4_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683899/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:15553 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020621 infores:hetionet CHEBI:3176 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0022568 infores:hetionet CHEBI:3398 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C2830004 infores:hetionet CHEBI:10127 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018681 infores:hetionet GO:0070805 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0070805 GO:0007275 CHEBI:64312 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085932 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004238 infores:hetionet CAID:CA402994004 biolink:causes MONDO:0012999 infores:clingen CAID:CA402994004 MONDO:0012999 PMID: Likely Pathogenic PP3, PM2_Supporting, PM3, PP4_Strong PM5 The NM_000156.6:c.564G>T variant in GAMT is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 188 (p.Met188Ile). This variant has been detected in Chinese individual with elevated guanidinoacetate and low creatine in both serum and urine, and a significantly reduced peak of creatine on brain MRS; full GAMT gene sequencing done (PP4_Strong) (PMID: 28438604). This patient was compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.491dupG. The variants were confirmed to be in trans by parental testing (PMID: 28438604) (1 point) (PM3). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.735 which is in the range of 0.644-0.773, evidence that correlates with impact to GAMT function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 2570636). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PM3, PP3, PM2_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402994004/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3084 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0152227 infores:hetionet CHEBI:63637 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0041834 infores:hetionet CAID:CA016924 biolink:causes MONDO:0007947 infores:clingen CAID:CA016924 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4_Moderate, PP1_Strong PVS1, PM6, BS2, PP4, BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS2, PM5, PM3, PM4, PM1, BP5, BS1, BS3, BS4 NM_00138 c.7003C>T is a missense variant in FBN1 predicted to cause a substitution of an Arginine by Tryptophan at amino acid 2335 (p.Arg2335Trp). This variant was found in a proband with isolated thoracic aortic aneurysm and dissection and segregates with disease in at least 5 affected family members (PP1_strong). It has been reported 2 times in the literature in individuals with ectopia lentis but who did not meet revised Ghent criteria for Marfan syndrome (PMID: 29357934; PMID: 12203992) (PS4_moderate). This variant is not present in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (REVEL: 0.841) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP1_strong, PS4_moderate, PM2_supporting, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA016924/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10650 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0241136 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0267792 infores:hetionet NCBIGene:10491 biolink:causes MONDO:0012536 infores:monarchinitiative not_provided not_provided HGNC:2379 MONDO:0012536 uuid:e302a079-6eeb-47a8-a5c0-060185b1486f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234047 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0543698 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151838 infores:hetionet CHEBI:135925 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0040517 infores:hetionet CHEBI:134990 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0851341 infores:hetionet CHEBI:5118 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011880 infores:hetionet NCBIGene:1299 biolink:causes MONDO:0031047 infores:monarchinitiative not_provided not_provided HGNC:2219 MONDO:0031047 uuid:491e26e1-3648-4f5e-bec6-65c91fa0806e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0010692 infores:hetionet CHEBI:119915 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0851578 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0085682 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042721 infores:hetionet CAID:CA10605281 biolink:causes MONDO:0044970 infores:clingen CAID:CA10605281 MONDO:0044970 PMID: Likely Pathogenic PM2, PVS1 The c.3609_3612dup (p.Gly1205AsnfsTer13) variant in POLG was not in any databases (PM2). This variant results in a frameshift causing a loss of function (PVS1). There are no publications of cases with this variant. In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605281/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria UMLS:C0120107 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0851578 infores:hetionet CHEBI:94501 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0003811 infores:hetionet CHEBI:42944 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0232462 infores:hetionet NCBIGene:63036 biolink:causes MONDO:0032837 infores:monarchinitiative not_provided not_provided HGNC:24609 MONDO:0032837 uuid:f71bfcd6-5718-495f-a492-8238dfd10c25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030794 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151596 infores:hetionet CHEBI:132233 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0277884 infores:hetionet CHEBI:50648 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C3665346 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0549209 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011334 infores:hetionet CHEBI:2682 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1443060 infores:hetionet CHEBI:10102 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C3257803 infores:hetionet CHEBI:68642 biolink:causes UMLS:C2721563 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C2721563 infores:hetionet CHEBI:18358 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0026113 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0022408 infores:hetionet CHEBI:49575 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0010200 infores:hetionet CHEBI:4708 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0232462 infores:hetionet CHEBI:119915 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020639 infores:hetionet CHEBI:50859 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0026826 infores:hetionet CHEBI:167638 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0009676 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0858797 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0011053 infores:hetionet CHEBI:3723 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0156404 infores:hetionet CHEBI:194135 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0022346 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0017152 infores:hetionet CHEBI:3441 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0041657 infores:hetionet CHEBI:7936 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007166 infores:hetionet CHEBI:8764 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0206061 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0341012 infores:hetionet CAID:CA5416771 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416771 MONDO:0011225 PMID: Uncertain Significance BS2, PM2 The c.593C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 198 (p.Pro198Leu).The filtering allele frequency (the upper threshold of the 95% CI of 8/59980) of the c.593C>T variant in DCLRE1C is 0.00006617 for Admixed American chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416771/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:72296 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0013182 infores:hetionet CHEBI:8024 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0039070 infores:hetionet CHEBI:28487 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0042164 infores:hetionet CHEBI:66919 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0004093 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0004936 infores:hetionet CHEBI:28830 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0235025 infores:hetionet CHEBI:8245 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0027769 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0002453 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020615 infores:hetionet UMLS:C0657912 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2830004 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0018799 infores:hetionet CHEBI:87681 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0520966 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0008136 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0008136 uuid:1209a4e4-6675-40a6-b52c-5439d1dd62ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84883 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0086543 infores:hetionet CHEBI:5855 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0010200 infores:hetionet CHEBI:145499 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0023518 infores:hetionet CHEBI:4995 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0549463 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235416 infores:hetionet CHEBI:63581 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1306341 infores:hetionet CHEBI:92712 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C1963818 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011849 infores:hetionet CHEBI:7825 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0041834 infores:hetionet CHEBI:50223 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1510431 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0028866 infores:hetionet CHEBI:3387 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0017672 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0518015 infores:hetionet CHEBI:44032 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0231528 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085633 infores:hetionet CHEBI:7936 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151907 infores:hetionet NCBIGene:30011 biolink:causes MONDO:0010296 infores:monarchinitiative not_provided not_provided HGNC:13867 MONDO:0010296 uuid:f08ae481-b82c-4bad-9785-13bd41e3c3ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50673 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0549567 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2973529 infores:hetionet UMLS:C0017797 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0003862 infores:hetionet CHEBI:10101 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0000737 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006849 infores:hetionet CHEBI:6950 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085632 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0687133 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0853336 infores:hetionet CHEBI:7445 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0028866 infores:hetionet CHEBI:5441 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0162566 infores:hetionet CHEBI:31711 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0010200 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0038362 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0392025 infores:hetionet CHEBI:47426 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1291077 infores:hetionet CHEBI:61058 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0028084 infores:hetionet CHEBI:93305 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0205204 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0029408 infores:hetionet CHEBI:10023 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017565 infores:hetionet CHEBI:10124 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0392156 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011991 infores:hetionet CHEBI:83804 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015230 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020615 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0232409 infores:hetionet CHEBI:28864 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151786 infores:hetionet CHEBI:32888 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0009450 infores:hetionet CHEBI:6532 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0235818 infores:hetionet CHEBI:4717 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0085637 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0020517 infores:hetionet CHEBI:52717 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0242528 infores:hetionet CHEBI:15940 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0003811 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006826 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085605 infores:hetionet CHEBI:63791 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0424790 infores:hetionet CHEBI:63635 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0271051 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0030312 infores:hetionet CAID:CA367397256 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397256 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting PS4, BS1, PP4, BA1, BP4 The c.1268T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 423 (p.(Phe423Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1268T>A, p.Phe423Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe423Ser has a greater Grantham distance (PM5). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 25555642, internal lab contributors). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 25555642, internal lab contributors). In summary, c.1268T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_supporting, PP2, PP3, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397256/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:63622 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C3665347 infores:hetionet CHEBI:8890 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0026821 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0009450 infores:hetionet NCBIGene:6655 biolink:causes MONDO:0014691 infores:monarchinitiative not_provided not_provided HGNC:11188 MONDO:0014691 uuid:810451e6-7158-4bb3-b575-6dc8e6f0314e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004604 infores:hetionet CHEBI:6367 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234535 infores:hetionet CAID:CA367402147 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402147 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PM5_Supporting, PP2, PP3, PM2_Supporting PS4 The c.389T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 130 (p.(Ile130Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). Another missense variant, c.389T>C p.Ile130Thr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.389T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402147/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports GO:0043011 biolink:causes CL:0000782 infores:ubergraph knowledge_assertion manual_agent GO:0043011 CL:0000782 GO:0061382 biolink:causes CL:1000182 infores:ubergraph knowledge_assertion manual_agent GO:0061382 CL:1000182 CHEBI:28593 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0019048 infores:hetionet CHEBI:100147 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C3665347 infores:hetionet CHEBI:72564 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0040435 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0031350 infores:hetionet CHEBI:85161 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0231528 infores:hetionet CHEBI:4514 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0037383 infores:hetionet CAID:CA409107507 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107507 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PP4 The c.763C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to glutamate at codon 255 (p.(Gln255Glu)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (ClinVar ID: 437910). In summary, c.763C>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107507/MONDO:0015967/085 2024-08-30 2024-08-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37924 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0028961 infores:hetionet CHEBI:31644 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C2047937 infores:hetionet CHEBI:63607 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0023530 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0032285 infores:hetionet CHEBI:9123 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030554 infores:hetionet UMLS:C0023610 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0038999 infores:hetionet NCBIGene:26277 biolink:causes MONDO:0009990 infores:monarchinitiative not_provided not_provided HGNC:11824 MONDO:0009990 uuid:12218384-cccb-47c5-8f13-4f673ce4e1bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94686 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1510471 infores:hetionet CHEBI:7478 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151908 infores:hetionet NCBIGene:5054 biolink:causes MONDO:0013227 infores:monarchinitiative not_provided not_provided HGNC:8583 MONDO:0013227 uuid:5c189758-f1ea-469f-886d-c4e539897214 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0007122 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003079 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0042571 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0033975 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235639 infores:hetionet CHEBI:5138 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018790 infores:hetionet CAID:CA347563 biolink:causes MONDO:0015152 infores:clingen CAID:CA347563 MONDO:0015152 PMID: Pathogenic PM4, PP4_Moderate, PP1, PM2_Supporting, PM3_Strong PM5, PM1, PVS1, PM6, BA1, BP3, BP1, BP4, BP2, BS2, PP2, PP3, BP7, BP5, BS1, BS3, BS4, PS1, PS3, PS4, PS2 The NM_000070.3: c.643_663del p.(Ser215_Gly221del) variant in CAPN3 is predicted to cause a change in the length of the protein due to an in-frame deletion of 7 amino acids in a non-repeat region (PM4). This variant has been detected in at least five individuals reported to have autosomal recessive LGMD (PMID: 18055493, 9150160, 22443334; ClinVar SCV000331951.4 internal data communication). In at least one case, the variant was identified in trans with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788fsTer14), 1.0 pt, PMID: 9150160), and in at least three patients, the variant was homozygous (1.0 pt, PMID: 22443334, ClinVar SCV000331951.4 internal data communication) (PM3_Strong). At least one of these patients displayed progressive limb girdle muscle weakness and reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 22443334). The variant was also reported to co-segregate with autosomal recessive disease in one affected family member (PP1; PMID: 9150160). The filtering allele frequency of the c.643_663del variant in CAPN3 is 0.000080464 in the European (non-Finnish) population in gnomAD v2.1.1 (the upper threshold of the 95% CI of 4/113756 exome chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM4, PM3_Strong, PP4_Moderate, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347563/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3568 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0043094 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0015397 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0019193 infores:hetionet CAID:CA410202702 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202702 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.397A>G (p.Met133Val) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202702/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA059076 biolink:causes MONDO:0018493 infores:clingen CAID:CA059076 MONDO:0018493 PMID: Uncertain Significance BP4 PP3, PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with threonine at codon 4185 of the RYR1 protein, p.(Ala4185Thr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000631, a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 21455645, 30236257, 31559918, 27555149). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.402) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA059076/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA1251311 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251311 MONDO:0013144 PMID: Benign BS2, BA1 The c.914C>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by histidine at amino acid 305 (p.Pro305His). The highest population minor allele frequency in gnomAD v2.1.1 is 0.008133 (249/30616 alleles) in the South Asian population, which is higher than the ClinGen SERPINC1 threshold ([>0.002]) for BA1, and therefore meets this criterion (BA1). This variant has been observed in nine individuals, of Indian heritage, with normal normal antithrombin levels, five of which showed normal levels with repeat testing (BS2; PMID: 27161325). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BS2. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251311/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48273 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0236000 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0234215 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0033975 infores:hetionet CHEBI:2636 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0016385 infores:hetionet CHEBI:92712 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0392676 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002871 infores:hetionet CHEBI:404903 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011175 infores:hetionet CHEBI:3441 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C1368065 infores:hetionet CHEBI:9654 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0428977 infores:hetionet CHEBI:84500 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235266 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0020517 infores:hetionet CHEBI:75246 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0042963 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0151596 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0268948 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0268948 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0032227 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0030312 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0151602 infores:hetionet CHEBI:3568 biolink:causes NCIT:C34938 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0032788 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1619702 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0030305 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042401 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0015397 infores:hetionet CHEBI:64355 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013491 infores:hetionet CHEBI:6541 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002878 infores:hetionet CHEBI:4995 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0040822 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0392025 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0022104 infores:hetionet CHEBI:63580 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019825 infores:hetionet CHEBI:3077 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0018524 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0549209 infores:hetionet CAID:CA410202602 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202602 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.442A>G (p.Thr148Ala) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202602/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5132 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C2047937 infores:hetionet CHEBI:6078 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0038325 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005657 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0004030 infores:hetionet CHEBI:3387 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0855775 infores:hetionet CHEBI:3403 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0009450 infores:hetionet CAID:CA490234727 biolink:causes MONDO:0012996 infores:clingen CAID:CA490234727 MONDO:0012996 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_001482.3:c.1227C>T (p.Thr409=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by PhyloP (BP7). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 510409). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GATM-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA490234727/MONDO:0012996/025 2022-10-07 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:18248 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0011991 infores:hetionet CHEBI:53691 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0278134 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0027765 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0041912 infores:hetionet CHEBI:31711 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0004096 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0234215 infores:hetionet CHEBI:8245 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0008031 infores:hetionet CHEBI:135935 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0011570 infores:hetionet CAID:CA115927 biolink:causes MONDO:0700270 infores:clingen CAID:CA115927 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PP1_Strong, PVS1_Strong PM2, PP3 The c.5763-1050A>G variant in ATM is an intronic variant which results in an intronic A>G substitution before coding exon 38 activating a cryptic splice site leading to alternative splicing. The variant has been observed to cause an insertion of 137 nucleotides of intronic sequence at position 5762 and a premature stop codon at position 1930. Some normal splicing has been reported in patients with ATM c.5763-1050A>G, thus, the splice effect is incomplete (PMIDs 8755918, 10330348, 11382771, 15174027, Ambry internal data). This variant has been detected in many individuals with Ataxia-Telangiectasia, some of whom were described as having a mild presentation and/or later age of onset (PMIDs 8755918, 26896183). The variant has also been reported to segregate with Ataxia-Telangiectasia in 6 affected family members from 3 families (PMIDs 8755918, 15174027). The variant has a minor allele frequency in gnomAD v2.1.1 of 0.00003 (PM2_Supporting, BS1, and BA1 are not met). ATM c.5763-1050A>G has been reported as a founder variant in the British Isles (PMID 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Strong (RNA), PM3_Very Strong, PP1_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA115927/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports UNII:G4PX8C4HKV biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009763 infores:hetionet CHEBI:6715 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0000786 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1142011 infores:hetionet CHEBI:8871 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0149741 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0040046 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034063 infores:hetionet CHEBI:724125 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0037278 infores:hetionet CHEBI:32315 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0026961 infores:hetionet CHEBI:3216 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0041969 infores:hetionet CHEBI:9587 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0022354 infores:hetionet CHEBI:6715 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0032708 infores:hetionet CHEBI:74947 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040460 infores:hetionet CAID:CA8970151 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970151 MONDO:0012589 PMID: Likely Pathogenic PM1, PS2, PP1 BA1, PM2, BS1 The p.Gly592Ser variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with a neurodevelopmental disorder (internal database - GeneDx) (PS2). The p.Gly592Ser variant occurs in the well-characterized Basic Helix-Loop-Helix domain (bHLH) (aa 564-617) functional domain of the TCF4 (PM1). The variant has been reported to segregate in three informative meioses (internal database - GeneDx) with limited clinical information provided (PP1). The highest population minor allele frequency of the p.Gly592Ser variant in TCF4 in gnomAD v4.1 is 8.474e-7 (1/1180018 alleles) in European (non-Finnish) population (not sufficient to meet BS1 criteria). Of note, this variant was observed once in gnomAD v4.1. In summary, the p.Gly592Ser variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2, PM1, PP1). (TCF4 specification v.3; approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970151/MONDO:0012589/032 2024-08-30 2024-12-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:472657 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0239113 infores:hetionet CHEBI:64312 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085632 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0020649 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0005940 infores:hetionet CHEBI:3752 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0015967 infores:hetionet CHEBI:50131 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0017672 infores:hetionet CHEBI:2208 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0232462 infores:hetionet UMLS:C0209366 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0011603 infores:hetionet CHEBI:8499 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0012833 infores:hetionet CAID:CA8603557 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603557 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The c.43G>A variant in ITGA2B is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (4/129086 alleles in the European (Non_Finnish) population), which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.367, which is below the ClinGen PD VCEP PP3 threshold of >0.7 and does not predict a damaging effect on ITGA2B function. The computational splicing predictor SpliceAI indicated that the variant has no predicted impact on splicing. To our knowledge, this variant has not been reported in a Glanzmann thrombasthenia patient, and has only been observed by Illumina in a predisposition screen in an ostensibly healthy population. In summary, this variant meets the criteria to be classified as a variant of unknown significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603557/MONDO:0100326/011 2023-02-02 2023-02-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:28445 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0011053 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0442874 infores:hetionet CHEBI:47426 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0022107 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0021843 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0442874 infores:hetionet CAID:CA512232100 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232100 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1437C>T (p.Pro479=) is a synonymous variant that has a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.256331 < 2.0), and the variant is the reference nucleotide in one primate (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232100/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:85161 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0002418 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019360 infores:hetionet CHEBI:3732 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0235287 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0039971 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0005940 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0034150 infores:hetionet CHEBI:8093 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C1096274 infores:hetionet CHEBI:251408 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0011168 infores:hetionet CHEBI:45863 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011606 infores:hetionet CHEBI:28901 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0232462 infores:hetionet CHEBI:51860 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0241934 infores:hetionet CHEBI:10023 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085612 infores:hetionet CHEBI:6950 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1306341 infores:hetionet CHEBI:4814 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0041657 infores:hetionet CHEBI:10650 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0043387 infores:hetionet CHEBI:10119 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0162830 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027051 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151763 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0595883 infores:hetionet CHEBI:6717 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0268000 infores:hetionet CHEBI:63613 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0035410 infores:hetionet CHEBI:47381 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030252 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0029408 infores:hetionet CHEBI:8871 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0016867 infores:hetionet CHEBI:7466 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0020473 infores:hetionet CHEBI:47426 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042023 infores:hetionet CHEBI:75722 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151904 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0007787 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0234215 infores:hetionet CAID:CA200776 biolink:causes MONDO:0015152 infores:clingen CAID:CA200776 MONDO:0015152 PMID: Pathogenic PVS1, PM3, PP4 PM2, PM4 The NM_213599.3: c.989dup (p.Leu330PhefsTer6)) variant in ANO5 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 10/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with progressive limb girdle muscle weakness, where it was confirmed in trans with a likely pathogenic or pathogenic variant (c.304_308del p.(Lys102fs), 1.0 pt, PMID: 27862037) (PM3, PP4). The filtering allele frequency of this variant is 0.000116 (the upper threshold of the 95% CI of 7/113346 European (non-Finnish) exome chromosomes) in gnomAD v2.1.1, which is above the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PM3, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA200776/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:499361 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0043352 infores:hetionet CAID:CA404071705 biolink:causes MONDO:0007750 infores:clingen CAID:CA404071705 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP3, BA1, PS1, PS3, BS1, BS3, PM5, PM4, PVS1, PP3, PP4 The NM_000527.5(LDLR):c.46C>G (p.Leu16Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2:This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met.BP4: REVEL= 0.145, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) not on limitsB) it creates a GTscore in MES: de novo donor = -18.93, authentic donor = 11.08 --- de novo score is <0.8.Variant is not predicted to alter splicing, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404071705/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA386971688 biolink:causes MONDO:0015967 infores:clingen CAID:CA386971688 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate BP4, PM1, PP3 The c.1528G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 510 (p.(Ala510Thr)) of NM_000545.8. This variant has a REVEL score of 0.615, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate, internal lab contributors). In summary, c.1528G>A meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386971688/MONDO:0015967/017 2025-06-20 2025-06-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8428 biolink:causes HP:0010702 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0020455 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1956346 infores:hetionet CHEBI:41879 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0010481 infores:hetionet CHEBI:4876 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0017181 infores:hetionet CHEBI:27899 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0013404 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0015376 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085762 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0027051 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151474 infores:hetionet CHEBI:16586 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0011603 infores:hetionet CAID:CA9870405 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870405 MONDO:0015967 PMID: Likely Benign BP4, BP7 PM2, BS1 The c.906C>T variant in the HNF4 homeobox A gene, HNF4A, is a synonymous variant at codon 302 (p.(Asn302=)) of NM_175914.5.This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0.001 for donor loss, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -2.537, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Grpmax filtering allele frequency of the c.906C>T variant in gnomAD v2.1.1 is 0.000011, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.906C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870405/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA2695231369 biolink:causes MONDO:0010725 infores:clingen CAID:CA2695231369 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PS1_Moderate, PP3 PP4, PP1 The NM_000330.4(RS1):c.78+5G>A variant is an intronic variant in intron 2, located 5 nucleotides after exon 2. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The splicing impact predictor SpliceAI gives a score of 0.64 (Donor Loss), which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3). This variant is outside the +/- 1,2 dinucleotide and meets the PP3 code due to predicted splicing disruption and another predicted splicing variant, NM_000330.4(RS1):c.78+1G>A, was previously classified as a pathogenic variant in the same donor motif for X-linked retinoschisis (PS1_moderate). The variant has been reported to segregate with retinal dystrophy through 1 meiosis in each of two families (PMIDs: 19390641, 34645606). However, the two unrelated families each consist of a carrier mother and an affected son, however, the mothers are asymptomatic and therefore do not meet the PP1 code. At least one proband harboring this variant exhibits a phenotype including X-linked inheritance (Mother was also tested genetically), diagnosis of X-linked retinoschisis before the age of 13 years (required), cecreased central vision acuity, and absence of retinoschisis disease in carrier females, which together are specific for X-linked retinoschisis (PMID: 19390641), however PP4 was not met as this proband was counted for PS4 instead. This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 34645606, 35456481, 19390641, PS4_Moderate). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3, PS1_moderate, and PS4_moderate (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695231369/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:3215 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0413252 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0426576 infores:hetionet CHEBI:31859 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0947912 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0004936 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0234913 infores:hetionet CHEBI:42797 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0558489 infores:hetionet CHEBI:3485 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0033774 infores:hetionet GO:0060222 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0007275 NCBIGene:89910 biolink:causes MONDO:0009485 infores:monarchinitiative not_provided not_provided HGNC:13478 MONDO:0009485 uuid:6eb27b72-a4e9-45f0-b208-ee209f885882 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:Z5N076G8YQ biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0011168 infores:hetionet CAID:CA229600 biolink:causes MONDO:0009861 infores:clingen CAID:CA229600 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4_Moderate, PM3 This c.514C>T (p.Gln172Ter) variant in PAH was detected in multiple patients with PKU with pathogenic variants c.1315+1G>A (PMID:8889590) and p.Ala345Thr (PMID:28754886). This variant was absent in population databases. This was predicted as a null variant in PAH where LOF is a known mechanism of disease. This is a nonsense variant in exon 6 of 13 coding exons predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229600/MONDO:0009861/006 2022-10-14 2022-10-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28830 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C1443060 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0020649 infores:hetionet CHEBI:9613 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0041834 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0160390 infores:hetionet CAID:CA390865100 biolink:causes MONDO:0100216 infores:clingen CAID:CA390865100 MONDO:0100216 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting BP4, BP2, BA1, BS2, PP3, PP1, PP4, PM5, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.5259C>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 1753 (p.Asp1753Glu). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000001239 (2/1614118 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390865100/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0016199 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013395 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0025637 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0022104 infores:hetionet CHEBI:64312 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018524 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0001175 infores:hetionet CHEBI:50859 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0041834 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027430 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0424000 infores:hetionet CAID:CA023675 biolink:causes MONDO:0007750 infores:clingen CAID:CA023675 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS1, PM2, PP3, PP4 PS3 The NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS1, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF = 0.00002 in European (Non-Finnish) in gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.803.PS1: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 5 index cases who fulfil FH diagnostic criteria. Four index cases met DLCN criteria for definite or probable FH: 1 case from Department of Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Denmark, PMID 10532689; 1 case from Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands, PMID 11810272; 1 case from Robarts Research Institute, Canada, PMID 11668627; 1 case submitted to ClinVar from U4M - Lille University & CHRU Lille, France. One proband with LDLC >10mmol/l and xanthoma, reported by Jiang et al, 2016, Department of atherosclerosis, Capital Medical University, China, PMID 27830735. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023675/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:1903541 biolink:causes GO:0097734 infores:ubergraph knowledge_assertion manual_agent GO:1903541 GO:0097734 CHEBI:9738 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0011253 infores:hetionet CHEBI:6539 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0001883 infores:hetionet CHEBI:6149 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0392699 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0242350 infores:hetionet CHEBI:75722 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0036974 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0041969 infores:hetionet CHEBI:6715 biolink:causes MONDO:0008449 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0080178 infores:hetionet CHEBI:9588 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0687713 infores:hetionet CHEBI:188986 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0015230 infores:hetionet CAID:CA043209 biolink:causes MONDO:0007750 infores:clingen CAID:CA043209 MONDO:0007750 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM1, PM3, PM2, PP4 BP2, BP1, BP4, BP3, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PVS1, PM6, BS2, PP2, PP3 The NM_000527.5(LDLR):c.337G>A (p.Glu113Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM1, PM2, PM3, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: PopMax MAF = 0.0001 (0.01%) in South Asian (gnomAD v4.0.0). PM1: Variant meets PM2 and is missense in exon 4.PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 8 unrelated index cases who fulfill criteria for FH (1 case with possible FH by Simon Broome criteria from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with possible FH by Simon Broome criteria and 1 case with DLCN score >=6 from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France; 1 case with possible FH by Simon Broome criteria from PMID 17539906 (Taylor et al., 2007), UK; 1 case with DLCN score >=6 from PMID 16250003 (Fouchier et al., 2005), The Netherlands; 1 case with possible FH by Simon Broome criteria from PMID 10807540 (Wu et al., 2000), USA; 2 cases with definite FH by Simon Broome criteria from PMID 34456049 (Marco-Benedi et al., 2022). PP1_Strong: Variant segregates with FH phenotype in 8 informative meioses in 1 family in PMID: 10807540 (Wu et al., 2000), USA: 7 affected family members have the variant.PM3: Variant meets PM2 and is identified in an index case with a homozygous FH phenotype (10 yo with LDLc= 14.9 mmol/L); variant is in compound heterozygosity with c.2389G>T (p.Val797Leu), which is classified as Likely pathogenic by these guidelines and is in trans, from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France (VCI). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA043209/MONDO:0007750/013 2024-02-23 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7915 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151735 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0015256 infores:hetionet CHEBI:4858 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0001824 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151514 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0155216 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0155216 infores:hetionet CHEBI:4856 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013491 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151773 infores:hetionet CHEBI:15428 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0546817 infores:hetionet CHEBI:80630 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0022346 infores:hetionet NCBIGene:5297 biolink:causes MONDO:0014679 infores:monarchinitiative not_provided not_provided HGNC:8983 MONDO:0014679 uuid:70725924-90ed-4ae3-9775-9e328f327a0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0034063 infores:hetionet NCBIGene:79925 biolink:causes MONDO:0032898 infores:monarchinitiative not_provided not_provided HGNC:26293 MONDO:0032898 uuid:001ae854-abb5-4ac9-a549-e91750afc898 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229318 biolink:causes MONDO:0009861 infores:clingen CAID:CA229318 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PP4 (PAH):c.1065+3A>C is an intronic variant that is predicted to be splice altering in multiple lines of computational evidence. This variant was identified in a patient with an unspecified PKU/HPA phenotype. The variant was not specified to be heterozygous or homozygous (PMID 10394930). This variant is absent in population databases. In summary, this variant has insufficient evidence and is classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2 and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229318/MONDO:0009861/006 2020-07-30 2020-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive true PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0019348 infores:hetionet CHEBI:68554 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0030353 infores:hetionet CHEBI:63115 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0004093 infores:hetionet CHEBI:408174 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0040425 infores:hetionet CHEBI:17303 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0005758 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0027651 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0233632 infores:hetionet CHEBI:3011 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0085649 infores:hetionet CHEBI:9737 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0852911 infores:hetionet CAID:CA3057287117 biolink:causes MONDO:0011071 infores:clingen CAID:CA3057287117 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.222del (p.Asp75fs) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). This frameshift variant is downstream of c.98 and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM5_supporting, PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3057287117/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:74947 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0232462 infores:hetionet CHEBI:8364 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0015967 infores:hetionet CHEBI:29013 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0232493 infores:hetionet CHEBI:5778 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0004238 infores:hetionet CHEBI:75722 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0855775 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013295 infores:hetionet NCBIGene:23581 biolink:causes MONDO:0015018 infores:monarchinitiative not_provided not_provided HGNC:1502 MONDO:0015018 uuid:f7b93136-523e-44c4-8fd8-ac6185daf2b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA029904 biolink:causes MONDO:0007750 infores:clingen CAID:CA029904 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP3, PP1, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, BS2 NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation).PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute).PP3 - REVEL = 0.766.PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA029904/MONDO:0007750/013 2022-01-19 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:735 biolink:causes MONDO:0013445 infores:monarchinitiative not_provided not_provided HGNC:1358 MONDO:0013445 uuid:f45a2ff2-ad2b-4131-95e8-aa594b00b57d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:125354 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0037274 infores:hetionet CHEBI:8871 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003862 infores:hetionet CAID:CA2802126 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802126 MONDO:0001586 PMID:11735025 Likely Pathogenic PP3_Moderate, PM3_Supporting, PS3_Supporting, PP4, PM2_Supporting The NM_000203.5:c.956C>T variant in IDUA is a missense variant predicted to cause substitution of alanine by valine at amino acid 319 (p.Ala319Val). One patient from Pakistan, homozygous for the variant, was diagnosed with attenuated MPS I (described as having Scheie syndrome) and low IDUA activity (PMID: 11735025) (PP4, PM3_supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001673 (1/5976 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When expressed in COS cells, the activity of the variant was indistinguishable from that of untransfected COS cells (PMID: 11735025) (PS3_Supporting). The computational predictor REVEL gives a score of 0.896 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 1683230). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 1.0.0): PP3_Moderate, PP4, PS3_Supporting, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Expert Panel, August 8, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802126/MONDO:0001586/091 2025-08-08 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6775 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151596 infores:hetionet CHEBI:83804 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042024 infores:hetionet CHEBI:10124 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0039070 infores:hetionet CHEBI:94848 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0018681 infores:hetionet CHEBI:52717 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020625 infores:hetionet CHEBI:49575 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0002792 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0031046 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033117 infores:hetionet CHEBI:10650 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003813 infores:hetionet CHEBI:4911 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0002170 infores:hetionet CHEBI:5441 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0036974 infores:hetionet CHEBI:3215 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030554 infores:hetionet CHEBI:94449 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0162297 infores:hetionet CHEBI:127780 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0016382 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0010032 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0010032 infores:hetionet GO:0006954 biolink:causes HP:0003418 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D001416 DB09543_MESH_D001416_1DB01397_MESH_D001416_1 CHEBI:6149 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1258215 infores:hetionet CAID:CA399806969 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806969 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PP4 The NM_000419.5:c.89G>A (p.Trp30Ter) variant in exon 1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/30. NMD is not predicted based on PMID: 21389146 reporting that NMD is not triggered by termination codons within exon 1/ first 100 nucleotides. Therefore, PVS1 is downgraded to PVS1_Moderate. The Trp30Ter nonsense variant has not been reported in patients with GT in the literature, to the best of our knowledge. This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, the significance of this variant for autosomal recessive Glanzmann Thrombasthenia is uncertain based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate, PM2_Supproting. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806969/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:50777 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0392025 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0007117 infores:hetionet CHEBI:17474 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0000731 infores:hetionet CHEBI:36704 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0015672 infores:hetionet CHEBI:6062 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151636 infores:hetionet CAID:CA409120184 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120184 MONDO:0007064 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.763G>T (p.Glu255Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met). The variant is absent in gnomAD v4 (PM2_supporting).There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules,1 very strong and 1 supporting criteria results in a Likely Pathogenic classification. Based on the above evidence, this variant can be classified as likely pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0):PVS1 Met,PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120184/MONDO:0007064/114 2024-02-05 2024-02-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9927 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0020517 infores:hetionet CHEBI:70746 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0041657 infores:hetionet CHEBI:4911 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0232462 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0027769 infores:hetionet CAID:CA2695224281 biolink:causes MONDO:0100453 infores:clingen CAID:CA2695224281 MONDO:0100453 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3 The NM_000180.4(GUCY2D):c.82dup (p.Arg28Profs*291) variant is a frameshift variant that introduces a premature stop codon into exon 2 of 20 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 26027050). However, the proband was not counted for this criterion because p.Arg768Gln, the other variant in trans, has not yet been classified by the LCA/eoRD VCEP. In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224281/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019360 infores:hetionet CHEBI:9123 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0039070 infores:hetionet CHEBI:63611 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1510410 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019196 infores:hetionet CHEBI:3011 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0023530 infores:hetionet CHEBI:31624 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0041657 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0005779 infores:hetionet CHEBI:16914 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0012833 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0162281 infores:hetionet CHEBI:6792 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0020538 infores:hetionet CHEBI:43968 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0017181 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0021053 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011991 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0178298 infores:hetionet CHEBI:6367 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0231218 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0235351 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0032285 infores:hetionet CHEBI:9907 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151905 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0521503 infores:hetionet NCBIGene:10847 biolink:causes MONDO:0007621 infores:monarchinitiative not_provided not_provided HGNC:16974 MONDO:0007621 uuid:8b18bde6-bca3-4281-a115-125af14f2202 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013491 infores:hetionet CHEBI:49668 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0085932 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0002170 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0018799 infores:hetionet CAID:CA227884 biolink:causes MONDO:0100438 infores:clingen CAID:CA227884 MONDO:0100438 PMID: Pathogenic PVS1, PM2_Supporting, PM3, PP1_Moderate NM_014336.5(AIPL1):c.487C>T (p.Gln163Ter) is a nonsense variant that introduces a premature stop codon into exon 4 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (PMIDs: 10873396, 16123401) (1 total point, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative in two independent families, with the variant present in the homozygous state (PP1_Moderate; PMIDs: 10873396, 16123401). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP1_Moderate, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227884/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:35854 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0030554 infores:hetionet CHEBI:44423 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C2830004 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0041969 infores:hetionet CHEBI:30830 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C1384353 infores:hetionet CHEBI:3996 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0013404 infores:hetionet CHEBI:45863 biolink:causes MONDO:0043919 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0206063 infores:hetionet CHEBI:5132 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0018965 infores:hetionet CHEBI:102216 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0424295 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0262397 infores:hetionet CAID:CA013599 biolink:causes MONDO:0005045 infores:clingen CAID:CA013599 MONDO:0005045 PMID: Uncertain Significance PM2, PS4_Moderate PM5, PM4, PM1, PM6, PP3, PP1, BA1, PS3, BS1, BS3, BS4, BP3, PS1, PS2, BP4, BP7, PVS1 The c.3337G>A (p.Ala1113Thr) variant in MYH7 has been identified in 6 individuals with HCM (PS4_Moderate; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013599/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1139667424 biolink:causes MONDO:0100437 infores:clingen CAID:CA1139667424 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PS4 NM_001034853.2(RPGR):c.2457_2460del (p.Glu820ArgfsTer?) is a frameshift variant introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 32679846), however, at least 2 apparently unrelated probands are required to meet PS4_Supporting. The variant has been reported in a family with at least 4 affected individuals, however, only the proband has been genotyped so segregation of the variant cannot be evaluated through the PP1 code (PMID: 32679846). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139667424/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:9622 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0013395 infores:hetionet GO:0006954 biolink:causes HP:0012531 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D010146 DB00945_MESH_D010146_1DB00861_MESH_D010003_1DB07402_MESH_D010003_1DB00991_MESH_D001172_1DB00861_MESH_D010146_1DB00747_MESH_D015863_1DB00939_MESH_D010146_1DB00788_MESH_D010146_1DB00939_MESH_D001172_1DB00939_MESH_D004412_1DB01401_MESH_D010146_1DB07402_MESH_D006073_1DB00749_MESH_D001172_1DB01397_MESH_D020773_1DB00749_MESH_D010003_1DB02266_MESH_D010146_1DB00586_MESH_D004412_1DB01397_MESH_D010146_1DB00939_MESH_D010003_1DB01600_MESH_D010146_1DB00500_MESH_D001171_1DB07477_MESH_D010146_1DB01397_MESH_D004412_1DB00747_MESH_D014605_1DB00861_MESH_D001172_1DB00991_MESH_D010003_1DB00749_MESH_D010146_1DB00788_MESH_D010146_2DB00749_MESH_D001171_1DB00991_MESH_D001171_1DB01050_MESH_D010146_1 CHEBI:8382 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0043251 infores:hetionet CHEBI:2676 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0917801 infores:hetionet CHEBI:63617 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015371 infores:hetionet CHEBI:8378 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0030486 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0027769 infores:hetionet CHEBI:7936 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014457 infores:hetionet CHEBI:119486 biolink:causes MONDO:0000819 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0002902 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0027707 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019360 infores:hetionet CHEBI:75984 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0233471 infores:hetionet CHEBI:135451 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0041582 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0851341 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019360 infores:hetionet CAID:CA16603919 biolink:causes MONDO:0100038 infores:clingen CAID:CA16603919 MONDO:0100038 PMID: Likely Pathogenic PS4_Moderate, PP3_Moderate, PM5_Supporting, PS1_Moderate, PM6, PM2_Supporting PS2, PS3, BS1, PM1, BS2, PP1, BA1, BP2, BP4, BP3 The c.4782G>C variant in SCN2A is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 1594 (p.Trp1594Cys). The variant has been identified in multiple individuals meeting criteria for complex neurodevelopmental disorder (PS4, PM6)(PMID: 34004075, internal lab contributors). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.924, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. The same amino acid change (p.Trp1594Cys), resulting from a different nucleotide change[c.4782G>T](PMID: 35365919, PMID: 23603762) is classified as likely pathogenic for complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP(PS1_Moderate). Additionally, another missense variant in the same codon c.4780T>A, p.Trp1594Arg reaches likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4_Moderate, PM6, PS1_Moderate, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; November 26, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603919/MONDO:0100038/068 2024-11-26 2025-02-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45783 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0746883 infores:hetionet CHEBI:2663 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0231218 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0853402 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0853402 infores:hetionet CHEBI:4877 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0033774 infores:hetionet CHEBI:8212 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0344232 infores:hetionet CHEBI:2950 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0333355 infores:hetionet CHEBI:204734 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0004096 infores:hetionet CHEBI:6078 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0151908 infores:hetionet CHEBI:87715 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0010200 infores:hetionet NCBIGene:94 biolink:causes MONDO:0010880 infores:monarchinitiative not_provided not_provided HGNC:175 MONDO:0010880 uuid:430f469a-acad-4d28-8975-0625e175ba94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:617099 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0700361 infores:hetionet CHEBI:63635 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0009421 infores:hetionet CHEBI:4046 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0043094 infores:hetionet CHEBI:63617 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0023518 infores:hetionet CHEBI:3996 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0038362 infores:hetionet CHEBI:36791 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013604 infores:hetionet CHEBI:3504 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0011603 infores:hetionet CHEBI:4710 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013384 infores:hetionet CHEBI:3219 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0025345 infores:hetionet CAID:CA404095729 biolink:causes MONDO:0007750 infores:clingen CAID:CA404095729 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, PS1, BS1, PM5, PP3 The NM_000527.5(LDLR):c.2291T>G (p.Ile764Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: Variant is absent from gnomAD v4.1.0BP4: REVEL = 0.433, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) not on limits.B) Variant does not create GT.C) There is a GT nearby.MES scores: variant cryptic = -7.17, wt cryptic = -8.16, canonical donor site = 9.06.Cryptic scores are negative, splice site not used. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404095729/MONDO:0007750/013 2025-02-28 2025-04-09 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA229376 biolink:causes MONDO:0009861 infores:clingen CAID:CA229376 MONDO:0009861 PMID:10394930PMID:25894915PMID:28982351 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1194A>G (p.Lys398Lys) variant in PAH has been reported in 1in 2 Chinese patients with moderate/classic PKU and BH4 deficiency excluded. (PMIDs: 25894915, 28982351; PP4_Moderate). Both patients were compound heterozygotes with pathogenic variants R413P and R241C confirmed in trans (PM3_Strong). This variant is present at an extremely low frequency with a MAF of 0.00005438 in the gnomAD East Asian population. (PM2). There is consensus of computational predictors that there is potential alteration of splicing via activation of a cryptic splice site near the end of exon 11.In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PP3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229376/MONDO:0009861/006 2020-09-12 2020-09-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6801 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0231528 infores:hetionet CHEBI:7581 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0026838 infores:hetionet CHEBI:2618 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0013395 infores:hetionet CHEBI:6149 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0406834 infores:hetionet CHEBI:66919 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0026764 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0948594 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0595930 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0013595 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0007222 infores:hetionet CAID:CA410149585 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149585 MONDO:0011071 PMID:34166225 Likely Benign BS3_Supporting, BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.956G>A (p.Ser319Asn) is a missense variant which has been demonstrated to have normal transactivation (80-115% of wt) in transactivation assays (BS3_supporting; PMID: 34166225). This missense variant has a REVEL score < 0.50 (0.127) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149585/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51230 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0010692 infores:hetionet CHEBI:50859 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0423791 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0677658 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0677658 infores:hetionet CHEBI:2682 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0011175 infores:hetionet CHEBI:3696 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151825 infores:hetionet CAID:CA243111 biolink:causes MONDO:0009290 infores:clingen CAID:CA243111 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 PP4 The NM_000152.5:c.615G>A variant in GAA is a synonymous (silent) variant (p.Pro205=) that is not predicted to impact splicing based on the computational splice predictor SpliceAI (BP4). Further, it is not in a position that is highly conserved (BP7). This variant has not been reported in a patient with Pompe disease to our knowledge. The highest population minor allele frequency in gnomAD v4.0. is 0.0004172 (38/91082 alleles) in the South Asian population. This is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (ClinVar Variation ID: 196223). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): BP4, BP7, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 18, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA243111/MONDO:0009290/010 2025-02-18 2025-02-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63621 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020456 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027651 infores:hetionet CHEBI:63589 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C1262113 infores:hetionet CHEBI:63618 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0023530 infores:hetionet CHEBI:499361 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0011168 infores:hetionet CHEBI:23765 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0340865 infores:hetionet CHEBI:72297 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0232726 infores:hetionet CHEBI:35677 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0038325 infores:hetionet CHEBI:9587 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0014457 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0037199 infores:hetionet CHEBI:77260 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1510410 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0233796 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233796 infores:hetionet CHEBI:28939 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0039070 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0031117 infores:hetionet CHEBI:5138 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017168 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0276141 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0276141 infores:hetionet CHEBI:5779 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0020621 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0233472 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0740304 infores:hetionet GO:0140433 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0140433 GO:0019953 CAID:CA16614383 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614383 MONDO:0100216 PMID: Uncertain Significance BS2_Supporting PM2, PM6, BA1, BP4, BP2, PP3, PP1, PM5, PM1, PS1, PS3, PS2, BS1, BS3 The NM_177438.3(DICER1):c.1423A>T variant in DICER1 is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 475 (p.Ser475Cys). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002670 (2/74916 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.568, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 06/25/24). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614383/MONDO:0100216/024 2024-06-25 2024-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3698 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0231218 infores:hetionet CHEBI:40009 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0009421 infores:hetionet CHEBI:31236 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0947912 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0233494 infores:hetionet CAID:CA122775 biolink:causes MONDO:0100038 infores:clingen CAID:CA122775 MONDO:0100038 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP5, BS1, BS3, BS4, PM1, PM5, PM6, BS2, PP3, PP1, BP4, BP2, BA1 The NM_001040142.2(SCN2A):c.3007C>A (p.Leu1003Ile) variant in SCN2A is a missense variant predicted to cause substitution of leucine by isoleucine at amino acid 1003 (p.Leu1003Ile). This variant has been reported in one family meeting phenotypic criteria for Complex Neurodevelopmental Disorder (MONDO:0100038 (PS4_Supporting; PMID 15048894). In this family, the variant was reported to segregate with Complex Neurodevelopmental Disorder (MONDO:0100038) in two meioses (father with two affected children). This does not meet the threshold of three meioses to apply PP1 (PMID 15048894). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Complex Neurodevelopmental Disorder (MONDO:0100038) based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting, PS4_Supporting. (ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0; approved 10/22/2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA122775/MONDO:0100038/068 2024-10-22 2024-12-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA464450591 biolink:causes MONDO:0009595 infores:clingen CAID:CA464450591 MONDO:0009595 PMID: Uncertain Significance PM2_Supporting, PS1_Supporting PP3 The NR_003051.4:n.195G>C variant in RMRP gene (NC_000009.12:g.35657825C>G, ClinVar ID: 1478325) has a highest population minor allele frequency of 0.000002599 (1/384818 alleles) in European (non-Finnish) population in gnomAD v4.1.0, which is lower than the SCID-VCEP threshold (<0.0000447) for PM2_Supporting. No homozygous individual was observed (PM2_Supporting). The variant has not been observed in patient with cartilage-hair hypoplasia. The SNP effect on local RNA secondary structure calculated by RNAsnp is p=0.9352, which is higher than the cutoff (p<0.01) defined by the SCID VCEP (PP3 not met). However, the variant affects the same nucleotide as the NR_003051.4:n.195G>A variant (NC_000009.12:g.35657825C>T, ClinVar ID 928882), which was classified as a likely pathogenic variant by the SCID VCEP (PS1_Supporting). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for cartilage-hair hypoplasia. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PS1_Supporting. (VCEP specifications version 1.0.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA464450591/MONDO:0009595/088 2025-09-10 2025-09-24 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:2629 biolink:causes MONDO:0011945 infores:monarchinitiative not_provided not_provided HGNC:4177 MONDO:0011945 uuid:aa006266-844a-47ce-966a-ca754517aae1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:93986 biolink:causes MONDO:0011184 infores:monarchinitiative not_provided not_provided HGNC:13875 MONDO:0011184 uuid:688e1f19-7fef-42b1-82fa-f8bb77997394 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1320835 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0021141 infores:hetionet CHEBI:3568 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0917801 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0235431 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0027769 infores:hetionet CHEBI:31623 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1260880 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042373 infores:hetionet CHEBI:194135 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0024282 infores:hetionet CHEBI:40279 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0004134 infores:hetionet CHEBI:7852 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020453 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034186 infores:hetionet CHEBI:68554 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0043094 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020619 infores:hetionet CHEBI:18357 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0151795 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0025061 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0042109 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0022408 infores:hetionet CHEBI:3312 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0595862 infores:hetionet CHEBI:3696 biolink:causes NCIT:C26921 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085594 infores:hetionet CHEBI:5790 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1260922 infores:hetionet CAID:CA410206723 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206723 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.772G>T (p.Ala258Ser) is a missense variant which has a REVEL score < 0.50 (0.294), and a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206723/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0948594 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0234215 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0034186 infores:hetionet CHEBI:4653 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0011551 infores:hetionet CHEBI:6149 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0232462 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0015397 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0235969 infores:hetionet CHEBI:47499 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0027066 infores:hetionet CHEBI:6741 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0040264 infores:hetionet CHEBI:5855 biolink:causes HP:0030746 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0240059 infores:hetionet CHEBI:144551 biolink:causes UMLS:C1328308 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1328308 infores:hetionet CHEBI:9137 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1510410 infores:hetionet CHEBI:9763 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C2047937 infores:hetionet CHEBI:9332 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0020625 infores:hetionet CHEBI:63598 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151827 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0004936 infores:hetionet CAID:CA410203375 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203375 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PVS1, PM5, PM4, PM3, PP4, PP2, PP1, BS2 NM_001754.5(RUNX1):c.343G>A (p.Ala115Thr) is a missense variant which has a REVEL score of 0.948 (PP3). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203375/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:107736 biolink:causes MONDO:0005526 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0039614 infores:hetionet CHEBI:94501 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0033774 infores:hetionet CHEBI:49575 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0041834 infores:hetionet CHEBI:5280 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0002792 infores:hetionet NCBITaxon:237561 biolink:causes MONDO:0044070 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D058387 DB00582_MESH_D058387_1DB00362_MESH_D058387_1 CHEBI:75998 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0265031 infores:hetionet CHEBI:7936 biolink:causes HP:0010702 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151669 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0151735 infores:hetionet CHEBI:6706 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0041657 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0033687 infores:hetionet CHEBI:567361 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0027497 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0034882 infores:hetionet CHEBI:8884 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0020517 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0233494 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0021053 infores:hetionet CHEBI:64312 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0035229 infores:hetionet CHEBI:46081 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0020621 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0342882 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0342882 infores:hetionet CHEBI:6129 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0340865 infores:hetionet CHEBI:31711 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0030193 infores:hetionet UMLS:C1738934 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0041657 infores:hetionet CHEBI:8764 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151723 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0314719 infores:hetionet CHEBI:4858 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0036454 infores:hetionet CHEBI:10119 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027080 infores:hetionet CHEBI:4046 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0023530 infores:hetionet NCBIGene:9968 biolink:causes MONDO:0012997 infores:monarchinitiative not_provided not_provided HGNC:11957 MONDO:0012997 uuid:f9cee2f3-a54c-483e-ba91-24dda63d541a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39112 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0010200 infores:hetionet CHEBI:63611 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0019270 infores:hetionet GO:0010081 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0010081 GO:0007275 CHEBI:66913 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0205204 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042075 infores:hetionet CAID:CA410147531 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147531 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1277C>G (p.Pro426Arg) is a missense variant which has a REVEL score < 0.50 (0.254), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147531/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28748 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0033774 infores:hetionet CAID:CA16020788 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020788 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting BP7 The NM_000277.3: c.441+5G>A variant in PAH is an intronic variant that is predicted by SpliceAI to alter splicing (SpliceAI score 0.91, >0.2 cutoff for PP3). c.441+5G>A has a Pop max allele frequency of [8.498e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting. It has been observed in individuals with phenylalanine hydroxylase deficiency in presumed trans (phase confirmed) with other pathogenic variants, including with p.Arg158Gln (ClinVar ID: 587) in one individual (PMID: 18321666) and with p.Val388Met (ClinVar ID 619) in 8 individuals (PMID: 32668217) (PM3_VeryStrong). It has been observed in at least one classic PKU patient with BH4 deficiency excluded (PMID: 18321666; PP4_moderate). In summary, this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3_VeryStrong, PP3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020788/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6690 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0855242 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1971624 infores:hetionet CHEBI:3752 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0018916 infores:hetionet CHEBI:31623 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0235266 infores:hetionet CHEBI:3752 biolink:causes HP:0001537 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0019322 infores:hetionet CHEBI:6887 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013604 infores:hetionet CHEBI:51230 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0003467 infores:hetionet CHEBI:8346 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C2697368 infores:hetionet CHEBI:3723 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013456 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0029408 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0027769 infores:hetionet CAID:CA401365200 biolink:causes MONDO:0009290 infores:clingen CAID:CA401365200 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting The NM_000152.5:c.1216G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 406 (p.Asp406Asn). At least 2 patients with this variant have been reported to have Pompe disease. The patients were siblings from the same family and were both reported to have symptoms consistent with Pompe disease. One of the siblings had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PMID: 31966564, 31439017) (PP4_Moderate). Both siblings were compound heterozygous for the variant and c.1935C>A (p.Asp645Glu), which is classified as pathogenic by the ClinGen LD VCEP, confirmed in trans by parental testing (PMID: 31966564, 31439017) (PM3). This variant has also been reported in one case identified as affected by newborn screening, but GAA enzyme activity and clinical information were not provided (PMID: 23430949). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.81 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 552776). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3, PP3, PP4_Moderate(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, June 17, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401365200/MONDO:0009290/010 2025-06-17 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4469 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0011071 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0037274 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0877035 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0877035 infores:hetionet CHEBI:9943 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023052 infores:hetionet CHEBI:31932 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020621 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0004936 infores:hetionet CHEBI:8863 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151836 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014544 infores:hetionet CHEBI:71223 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0020621 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0032326 infores:hetionet CHEBI:6690 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0028643 infores:hetionet CHEBI:9150 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0033687 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0857370 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0857370 infores:hetionet CHEBI:17263 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0034150 infores:hetionet CHEBI:4027 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0426390 infores:hetionet CHEBI:3181 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027424 infores:hetionet CHEBI:63598 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0234632 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1167965 infores:hetionet CAID:CA012771 biolink:causes MONDO:0005045 infores:clingen CAID:CA012771 MONDO:0005045 PMID: Uncertain Significance PVS1_Moderate, PP1, PS4_Supporting BS1, BS4, BS3, PP2, PP3, PM5, PM1, PM4, PM2, PM6, BP4, BP2, BA1, PS1, PS3, PS2 NM_000256.3(MYBPC3):c.26-2A>G - This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing by multiple in silico tools leading to loss of the canonical splice acceptor site and creation of a cryptic splice acceptor site 6 nucleotides downstream. If used, this cryptic splice site would lead to an in-frame deletion of 2 amino acids. Therefore, PVS1_Moderate has been applied. This variant has been identified in individuals with HCM (LMM data, OMGL data, PMIDs: 15519027, 18957093, 21750094, 22267749, 23674513, 24510615, 27532257) and was identified to be statistically increased in individuals with HCM compared to controls [OR lower 95% CI>5]. Therefore, the PS4_Supporting criterion has been applied. This variant segregated with disease in at least 4 affected individuals from 3 families with HCM (PP1_Supporting; LMM Data) as well as a family with LVNC that did not contribute to the criteria (PMID:29029073). This variant is present in gnomAD (v2.1.1), but did not meet the threshold for PM2_Supporting. In summary, this variant is classified as Uncertain Significance for DCM in an autosomal dominant manner based on PVS1_Moderate, PS4_Supporting, and PP1_Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012771/MONDO:0005045/095 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6067 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0086769 infores:hetionet CHEBI:16335 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C2242996 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0041671 infores:hetionet CHEBI:16467 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0028643 infores:hetionet CHEBI:3082 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0037317 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0235890 infores:hetionet CHEBI:63599 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0740394 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0521491 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0549343 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0549343 infores:hetionet CHEBI:39867 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0542571 infores:hetionet CAID:CA410203416 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203416 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.331A>C (p.Thr111Pro) is a missense variant which has a REVEL score ≥ 0.88 (0.961) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203416/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020542 infores:hetionet CHEBI:8888 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0546817 infores:hetionet CHEBI:17334 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018681 infores:hetionet CAID:CA243345 biolink:causes MONDO:0010726 infores:clingen CAID:CA243345 MONDO:0010726 PMID: Benign BA1, BP4, BP7 The allele frequency of the c.54C>G p.Leu18= variant in MECP2 (NM_004992.1) is 0.042% in the African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Leu18= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.54C>G p.Leu18= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA243345/MONDO:0010726/032 2023-06-15 2023-06-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:5778 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0008031 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0235630 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0235630 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0860803 infores:hetionet CAID:CA340744551 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744551 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting BA1, PM3, BS1 NM_000329.3(RPE65):c.998+1G>A is a non-coding variant that disrupts a canonical splice donor site in intron 9 at the junction with exon 9 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including onset at before the age of 5 years (1 pt), night blindness, reduced visual acuity (1 pt), and extinguished ERG responses from rods (0.5 pts) and cones (1 pt), with exome sequencing-based genotyping that did not provide an alternative explanation for visual impairment (2 pts), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 31273949, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744551/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50275 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0392025 infores:hetionet CHEBI:49040 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0007859 infores:hetionet CAID:CA913190140 biolink:causes MONDO:0008535 infores:clingen CAID:CA913190140 MONDO:0008535 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1 The NM_001114753.3: c.1701del (p.Val568Serfs*5) variant in ENG is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 13 (out of 15) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190140/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15365 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0021400 infores:hetionet CHEBI:45783 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0010828 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0424605 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0159039 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0159039 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0026946 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0549405 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0026848 infores:hetionet CHEBI:6129 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0220981 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042401 infores:hetionet CHEBI:6062 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0015230 infores:hetionet CHEBI:63617 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042024 infores:hetionet CHEBI:48273 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0030252 infores:hetionet CHEBI:9943 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0344232 infores:hetionet CHEBI:5893 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013378 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151904 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0038661 infores:hetionet CAID:CA410205656 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205656 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.92T>C (p.Val31Ala) is a missense variant which has a REVEL score < 0.50 (0.287) and a SpliceAI score ≤ 0.20 (Acceptor Loss 0.02, Donor Loss 0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205656/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:32315 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0040822 infores:hetionet CAID:CA1624132 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624132 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.3658G>A (p.Val1220Met) variant in the SOS1 gene is 0.0328% (10/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624132/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:48844 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0013395 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0022904 infores:hetionet CHEBI:2611 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C3248383 infores:hetionet CAID:CA5416935 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416935 MONDO:0011225 PMID: Uncertain Significance PP4, PM2 The c.265A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Threonine by Alanine at amino acid 89 (p.Thr89Ala).The filtering allele frequency (the upper threshold of the 95% CI of 9/89618) of the c.265A>G variant in DCLRE1C is 0.00005480 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore do not meet this criterion.This variant has been observed in a 14-year-old boy with autoimmune hemolytic anemia. He was severely lymphopenic and had evidence of reduced T and B cell numbers and function, including reduced T cell receptor diversity. Leaky SCID could not be confirmed with the limited evidence reported (PMID: 23701501).In summary, due to insufficient evidence, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416935/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50173 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0205204 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011616 infores:hetionet NCBIGene:23732 biolink:causes MONDO:0014859 infores:monarchinitiative not_provided not_provided HGNC:1362 MONDO:0014859 uuid:f4925ec2-028f-40af-8770-52eff7458a4f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0037274 infores:hetionet CHEBI:8871 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0497156 infores:hetionet CHEBI:8890 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0008031 infores:hetionet CHEBI:28177 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0546817 infores:hetionet CHEBI:50122 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0232461 infores:hetionet CHEBI:44185 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0019080 infores:hetionet NCBIGene:5644 biolink:causes MONDO:0008185 infores:monarchinitiative not_provided not_provided HGNC:9475 MONDO:0008185 uuid:19549f07-74e1-4bcf-8bdd-b9de3c4d1346 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0003862 infores:hetionet CHEBI:3127 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0151786 infores:hetionet CHEBI:51173 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0233514 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0037274 infores:hetionet CHEBI:553473 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0040034 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0497247 infores:hetionet CHEBI:2948 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0021845 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0022660 infores:hetionet CAID:CA294183 biolink:causes MONDO:0700272 infores:clingen CAID:CA294183 MONDO:0700272 PMID: Benign BS2, BP1, BA1 BS3, BP4 The c.3054G>C variant in PALB2 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 1018 (p.Glu1018Asp). The filtering allele frequency in gnomAD v2.1.1 is 0.004 in the East Asian population, which is higher than the ClinGen HBOP threshold (>0.001) for BA1, and therefore meets this criterion. This variant has been observed in a homozygous state and phase unknown with numerous other PALB2 variants that are tentatively classified as likely pathogenic or pathogenic by the HBOP VCEP in individuals without Fanconi Anemia (GeneDx, Ambry Genetics, Invitae). This variant is functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BA1, BP2_Moderate, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA294183/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4909 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0039070 infores:hetionet NCBIGene:5994 biolink:causes MONDO:0971015 infores:monarchinitiative not_provided not_provided HGNC:9988 MONDO:0971015 uuid:c31167c6-264c-441f-a245-d4e410a3d80d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0234632 infores:hetionet CHEBI:8863 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004134 infores:hetionet CAID:CA397844579 biolink:causes MONDO:0018875 infores:clingen CAID:CA397844579 MONDO:0018875 PMID: Likely Pathogenic BP4, PM5_Strong, PS3, PM2 BP2, BA1, PS4, PM1, BS1, BS2, PP3, PP1, PP4 The NM_000546.6: c.328C>G variant in TP53 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 110 (p.Arg110Gly). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). 2 different missense variants (p.Arg110Leu, p.Arg110Pro) (ClinVar Variation IDs: 406597, 233627), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5_Strong). Computational predictor scores (BayesDel = 0.056; Align GVGD Class C15) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, PS3, PM5_Strong, BP4. (Bayesian Points: 8; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397844579/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6067 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009938 infores:hetionet CHEBI:8774 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0948008 infores:hetionet CHEBI:5855 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0700292 infores:hetionet CHEBI:3756 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1527344 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003040 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002624 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0518015 infores:hetionet CHEBI:7465 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0017181 infores:hetionet CHEBI:70735 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0040485 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0234192 infores:hetionet CHEBI:134743 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0162830 infores:hetionet CHEBI:5109 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0026113 infores:hetionet CAID:CA412376053 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376053 MONDO:0010725 PMID:12746437PMID:19849666 Pathogenic PS4_Supporting, PM2_Supporting, PS1, PP3_Moderate, PS3_Supporting, PP4 PM1 The NM_000330.4(RS1):c.176G>C variant is a missense variant encoding the substitution of Cysteine with Serine at position 59 and results in the disruption of the disulfide bridge between amino acids Cys59 and Cys223. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.878, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. A missense variant encoding the same amino acid substitution, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 35982512, 9618178, 17987333, 10450864) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PS1). This variant, p.Cys59Ser, of the RS1 gene, is defined as a critical amino acid residue involved in disulfide bridge formation by the ClinGen X-linked IRD VCEP (PMIDs: 26812435). The PM1_strong code is ineligible to be combined with PP3 at any strength, therefore, the PM1 code was not met. HEK293 or COS7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control. Moreover, exogenously expressed RS1 harboring the variant exhibits aberrant immunofluorescent localization of RS1 to the ER/Golgi relative to the wild-type control. Exogenously expressed RS1 harboring the variant was subjected to co-assembly and successful secretion and exhibits defective oligomerization indicating no formation of octomers (PMID: 12746437, 17525175, 19849666, 22245536, 26812435, PS3_supporting). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 23288992, PP4). This variant has been reported in at least another 2 apparently unrelated probands carrying this variant and diagnosed with X-linked retinoschisis (PMIDs: 35456481, 34645606, PS4_supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_moderate, PS1, PS3_supporting, PS4_supporting, and PP4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376053/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:75722 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040586 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235416 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0042134 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015469 infores:hetionet CHEBI:474180 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020625 infores:hetionet CHEBI:3696 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0010200 infores:hetionet CHEBI:45783 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2129214 infores:hetionet CHEBI:48390 biolink:causes MONDO:0010837 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0221002 infores:hetionet CHEBI:64312 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011603 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085584 infores:hetionet CHEBI:9586 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013362 infores:hetionet CHEBI:36791 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0424295 infores:hetionet CHEBI:30659 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0232461 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1258215 infores:hetionet CHEBI:9448 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0033774 infores:hetionet CHEBI:6067 biolink:causes HP:0001013 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0221252 infores:hetionet NCBIGene:477 biolink:causes MONDO:0007087 infores:monarchinitiative not_provided not_provided HGNC:800 MONDO:0007087 uuid:14ed0d30-ab6d-4cd9-a42b-e813121d9b30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes UMLS:C0857331 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0857331 infores:hetionet CHEBI:6801 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0042847 infores:hetionet CHEBI:724125 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0235266 infores:hetionet CHEBI:10650 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018944 infores:hetionet CHEBI:52717 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085680 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0014742 infores:hetionet CHEBI:17474 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0037763 infores:hetionet CHEBI:40279 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0009676 infores:hetionet CAID:CA405661203 biolink:causes MONDO:0007783 infores:clingen CAID:CA405661203 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with isoleucine at codon 3908 of the RYR1 protein, p.(Asn3908Ile). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:24433488). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.949) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405661203/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:168396 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0005940 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027059 infores:hetionet CHEBI:49040 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151905 infores:hetionet CAID:CA016046 biolink:causes MONDO:0005021 infores:clingen CAID:CA016046 MONDO:0005021 PMID: Uncertain Significance PM2, PP3, PS4_Supporting PS3, BA1, PM5, PM1, PM6, PM4, PP1, BS1, BS3, BS4, BP4, BP2, BP5, BP7, PS1, PS2, PVS1 The NM_000257.4(MYH7):c.5395G>A (p.Glu1799Lys) variant has been identified in at least 5 individuals with DCM, including 1 infant with DCM and LVNC (PS4_Supporting; Mazzarotto 2020 PMID: 3198322; Petrovsky National Research Centre of Surgery - The Federal Agency for Scientific Organizations ClinVar Submission Accession: SCV001445827.; CHEO pers. comm.; GeneDx pers. comm.; OMGL pers. comm.). This variant has also been reported in 2 individuals with LVNC (Takasaki 2018 PMID:30188508; Ambry pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016046/MONDO:0005021/002 2021-12-09 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63925 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0004604 infores:hetionet CHEBI:71255 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0013378 infores:hetionet CHEBI:6538 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0037036 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007194 infores:hetionet CHEBI:31236 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035243 infores:hetionet CHEBI:41774 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0000729 infores:hetionet CAID:CA024665 biolink:causes MONDO:0100150 infores:clingen CAID:CA024665 MONDO:0100150 PMID: Benign BS2, BS1 PP3, PM3 The c.7025A>G (NM_000540.3(RYR1):c.7025A>G (p.Asn2342Ser)) variant in RYR1 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 2342 (p.Asn2342Ser). The highest MAF in gnomAD v4.1.0 is 0.001818 (2145/1180004 alleles) in the European (non-Finnish) population, which is greater than the ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 3 homozygous individuals with no features of RYR1-related myopathy, a condition with full penetrance at an early age (BS2). The computational predictor REVEL gives a score of 0.639, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. The variant is near the end of the exon, but the highest SpliceAI score is 0.04 for donor gain, and the other scores are 0.00, indicating no significant impact to splicing is predicted (no codes met). This variant was found in six probands from five families (two compound heterozygous and three heterozygous cases). However, none of these probands were scored due to the high population allele frequency, and, in specific cases, a potentially causative RYR1 variant on the same allele, a causative variant in another gene, or lack of phenotypic detail/specificity (no codes met; Synnovis Internal Data; PMIDs: 23826317, 31903994, 38982518). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy (undetermined mode of inheritance) based on the ACMG/AMP criteria applied, as specified by theClinGen Congenital Myopathy VCEP: (BS1, BS2; ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 02/10/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024665/MONDO:0100150/150 2025-02-10 2025-04-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63577 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0004364 infores:hetionet CHEBI:8455 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0857093 infores:hetionet CHEBI:45327 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0016382 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0240557 infores:hetionet CAID:CA380151259 biolink:causes MONDO:0000572 infores:clingen CAID:CA380151259 MONDO:0000572 PMID:29772310 Uncertain Significance PP4, PM2_Supporting, PS3_Supporting NM_000448.3(RAG1):c.1088G>A is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 363 (p.Cys363Tyr).The filtering allele frequency (the upper threshold of the 95% CI of 3/44900) of the c.1088G>A variant in RAG1 is 0.00002004 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) Total : 1.5 pts,PP4_met,PMID : 21664875. The recombination activity assay (described in PMID 29772310) showed activity of this variant compared to wildtype RAG1 is 45.3 %, (PS3_supporting) (Dr. Notarangelo lab, internal communication). This variant was found in trans with p.Arg396Cys (not yet curated by SCID VCEP; PMID : 21664875).In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PP4_met,PS3_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380151259/MONDO:0000572/123 2024-03-04 2024-03-04 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:144093 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0600142 infores:hetionet NCBIGene:1687 biolink:causes MONDO:0010973 infores:monarchinitiative not_provided not_provided HGNC:2810 MONDO:0010973 uuid:4851a4b9-3987-44f4-96f9-0d3ae1f51283 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31643 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0039070 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0242073 infores:hetionet GO:0060314 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0060314 GO:0007154 UMLS:C0004609 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0026826 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0948050 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0948050 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0020538 infores:hetionet NCBIGene:219736 biolink:causes MONDO:0012266 infores:monarchinitiative not_provided not_provided HGNC:23508 MONDO:0012266 uuid:e264cf2c-7394-4314-95bf-fb5a920a9918 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017152 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0037274 infores:hetionet CHEBI:119915 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0149745 infores:hetionet CHEBI:49375 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009763 infores:hetionet CHEBI:6717 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002792 infores:hetionet CHEBI:47499 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0013378 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0729552 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0729552 infores:hetionet CHEBI:83804 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0022346 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0002871 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0233472 infores:hetionet CHEBI:31397 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0015672 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0031542 infores:hetionet CHEBI:71219 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151827 infores:hetionet CL:0002258 biolink:causes MONDO:0003806 infores:ubergraph knowledge_assertion manual_agent CL:0002258 MONDO:0003806 CHEBI:5280 biolink:causes MONDO:0002314 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0155145 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0234215 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006574 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0023801 infores:hetionet CHEBI:7822 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0028961 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042401 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0042373 infores:hetionet CHEBI:8805 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0019158 infores:hetionet CHEBI:17026 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0851578 infores:hetionet CHEBI:68579 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0041657 infores:hetionet CHEBI:6710 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0011606 infores:hetionet CAID:CA233131 biolink:causes MONDO:0013144 infores:clingen CAID:CA233131 MONDO:0013144 PMID: Likely Benign BS2_Supporting, BP4 PM5, PM2 The variant is reported at the highest MAF of 0.00004412 (5/113318 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting. This variant has not been reported in the literature in association with autosomal dominant antithrombin III deficiency. The variant is reported in 2 individuals in internal cohort, with 1 reporting normal antithrombin levels meeting BS2_supporting. The variant has a REVEL score of 0.127, which does meet criteria for BP4 (SpliceAI and VarSEAK predicts no impact). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS2_supporting, BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA233131/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3561 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C3665386 infores:hetionet CHEBI:30659 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0233407 infores:hetionet CHEBI:291342 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0085631 infores:hetionet UNII:U6XF9NP8HM biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0948349 infores:hetionet CHEBI:63632 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0015672 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0497327 infores:hetionet NCBIGene:51604 biolink:causes MONDO:0014165 infores:monarchinitiative not_provided not_provided HGNC:14938 MONDO:0014165 uuid:0d60ad45-61c2-4b92-a76e-6e78e1099115 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:472657 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0086565 infores:hetionet CHEBI:6838 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0009806 infores:hetionet CHEBI:3506 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0149512 infores:hetionet CHEBI:9586 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027066 infores:hetionet CHEBI:4710 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0686347 infores:hetionet CAID:CA7435505 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435505 MONDO:0007113 PMID: Likely Benign BP4, BP7, BS1 The allele frequency of the c.1668G>A p.Val556= variant in UBE3A (NM_130838.2) is 0.008% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Val556= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1668G>A p.Val556= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435505/MONDO:0007113/032 2023-06-16 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:1439 biolink:causes MONDO:0013712 infores:monarchinitiative not_provided not_provided HGNC:2436 MONDO:0013712 uuid:14bf31dd-7dc6-4d08-a470-17c767e7b618 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0044479 biolink:causes GO:0002448 infores:ubergraph knowledge_assertion manual_agent GO:0044479 GO:0002448 CHEBI:64355 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0149745 infores:hetionet CHEBI:8863 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020443 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0235290 infores:hetionet CHEBI:83531 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0033774 infores:hetionet CAID:CA356990 biolink:causes MONDO:0001586 infores:clingen CAID:CA356990 MONDO:0001586 PMID: Pathogenic PM3_Strong, PVS1_Strong, PP4_Moderate, PM2_Supporting The NM_000203.5: c.590-7G>A variant in IDUA occurs within the splice acceptor site motif of intron 5. RT-PCR analysis revealed skipping of biologically-relevant-exon 6/14, or, rarely, intron 5 inclusion, resulting mainly in splicing at nt -28 of intron 5, and also a very small amount of normal IDUA mRNA (PMID: 8213840; 9748610) (PVS1_Strong (RNA)). This variant is also reported as IDUA:c. 678-7 G>A in older literature (PMID: 8213840). This variant has been detected in at least 10 individuals with MPS I, all compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, all phase unconfirmed, including c.208C>T (p.Gln70Ter) (PMID: 28752568, ClinVar Variation ID: 11909, 0.5 points), c.1205G>A (p.Trp402Ter) (PMID: 28752568, CinVar Variation ID: 11908, 7 patients, max 2 x 0.5 points), and (c.1029C>G (p.Tyr343Ter) (C;inVar Variation ID: 550474, clinical lab, 0.5 points) (PM3_Strong). Total 2 points (PM3_Strong). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, a significant reduction in urine GAGs upon treatment with enzyme replacement therapy, and clinical features specific to MPS I including arthropathy, corneal involvement, and valvular thickening. (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004241 (50/1178952 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 222996). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_strong, PM3_strong, PP4_moderate, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA356990/MONDO:0001586/091 2024-12-06 2025-06-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50692 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0020538 infores:hetionet CAID:CA015036 biolink:causes MONDO:0004994 infores:clingen CAID:CA015036 MONDO:0004994 PMID: Uncertain Significance PM2, PP3 PM3, PM5, PM1, PM6, PM4, PP1, PS3, BA1, PP4, BS2, BS1, BS3, BS4, BP3, PS1, PS4, PS2, BP4, BP2, BP5, BP7, PVS1 The NM_000257.4(MYH7):c.4499G>A (p.Arg1500Gln) variant has been reported in at least 1 individual with features of ARVC and DCM (Murray 2018 PMID:29709087; Ambry pers. comm), as well as individuals with less specific cardiac features (GeneDx pers. comm.); however these data are insufficient to apply PS4. This variant was identified in 0.0007% (FAF 95% CI; 3/113770) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015036/MONDO:0004994/002 2021-01-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63605 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020580 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0085636 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0232492 infores:hetionet CHEBI:5123 biolink:causes MONDO:1030008 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0026266 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233494 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042109 infores:hetionet CHEBI:7931 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0240327 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0035309 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0178421 infores:hetionet CHEBI:9137 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1306341 infores:hetionet CHEBI:8024 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0404521 infores:hetionet CAID:CA915940253 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940253 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1728del variant results in a frameshift (p.Ser577ProfsTer92) with a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least two probands has been reported with this variant, including GT28 of PMID: 29675921 who meets the criteria for PP4_strong. GT28 is compound heterozygous for c.1728del and Gln298Ter (Classified Pathogenic by the PD-VCEP; PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940253/MONDO:0100326/011 2021-09-14 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:39867 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0040435 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0041349 infores:hetionet CAID:CA232982 biolink:causes MONDO:0010726 infores:clingen CAID:CA232982 MONDO:0010726 PMID: Likely Benign BP7, BS2, BP4 PP4 The c.528C>G (p.Pro176=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). The silent p.Pro176= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Pro176= variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.003275% (no criteria met). In summary, the p.Pro176= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA232982/MONDO:0010726/016 2021-10-28 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:5165 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085584 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151664 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0015397 infores:hetionet CHEBI:6061 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0011606 infores:hetionet CHEBI:36795 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0004093 infores:hetionet CHEBI:66903 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0242528 infores:hetionet CHEBI:9738 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0344232 infores:hetionet CHEBI:6832 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0009676 infores:hetionet CHEBI:15854 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0232493 infores:hetionet CAID:CA136657 biolink:causes MONDO:0021060 infores:clingen CAID:CA136657 MONDO:0021060 PMID: Benign BP5, BA1, BP4 BS1, PM2, PP3, BP2 The c.10A>C variant in the SHOC2 gene is a missense variant predicted to cause substitution of serine by arginine at amino acid 4 (p.Ser4Arg). The highest filtering allele frequency in gnomAD v4.1.0 is 0.2286% (124/59742 alleles) in the Admixed American population and therefore meets this criterion (BA1). The computational predictor tool REVEL gives a score of 0.113 and does not predict a damaging effect on SHOC2 function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766 internal data; ClinVar SCV000209046.7, SCV000062455.5). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136657/MONDO:0021060/038 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:23765 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C1306341 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0001824 infores:hetionet CHEBI:45409 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085641 infores:hetionet CHEBI:8874 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0016867 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1368065 infores:hetionet CHEBI:66901 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0009450 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0854134 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0854134 infores:hetionet CHEBI:135276 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0020458 infores:hetionet CHEBI:404903 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1257843 infores:hetionet CHEBI:5134 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0002792 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0017178 infores:hetionet CHEBI:6888 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0002063 infores:hetionet CHEBI:91583 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0004245 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0038826 infores:hetionet NCBIGene:23328 biolink:causes MONDO:0024524 infores:monarchinitiative not_provided not_provided HGNC:19182 MONDO:0024524 uuid:cc4e8897-2cfc-4b4e-b7e6-b2d7d990a1b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71941 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0018802 infores:hetionet NCBITaxon:6265 biolink:causes MONDO:0005988 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6265 MESH:D014120 DB00730_MESH_D014120_1 CHEBI:4909 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0023533 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0302295 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0021843 infores:hetionet CHEBI:3749 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0022346 infores:hetionet CHEBI:16796 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0015672 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0032326 infores:hetionet CHEBI:3654 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0020437 infores:hetionet CHEBI:9674 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0011551 infores:hetionet CHEBI:4551 biolink:causes UMLS:C0857457 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0857457 infores:hetionet CHEBI:27786 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0020625 infores:hetionet GO:0045314 biolink:causes GO:0001751 infores:ubergraph knowledge_assertion manual_agent GO:0045314 GO:0001751 CHEBI:15367 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015230 infores:hetionet CHEBI:7627 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0018681 infores:hetionet GO:1904441 biolink:causes GO:0030878 infores:ubergraph knowledge_assertion manual_agent GO:1904441 GO:0030878 CHEBI:31859 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013390 infores:hetionet CHEBI:10124 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0014724 infores:hetionet GO:0014061 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:0014061 GO:0007267 CAID:CA1706448 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706448 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PM2_Supporting, PS3_Moderate PP1 The NM_003494.4: c.3113G>A variant in DYSF, which is also known as NM_001130987.2: c.3167G>A (p.Arg1056Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1038, p.(Arg1038Gln). This variant has been detected in at least seven patients with features consistent with LGMD (PMID: 36983702, 26404900, 34559919, 14678801, 30919934, 27854218, 21522182), including in a homozygous state (0.5 pts, PMID: 30919934) and confirmed in trans (NM_003494.4: c.2643+1G>A, 1.0 pt, PMID: 27854218) and in unknown phase (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.25 pts, PMID: 14678801, 26404900; NM_003494.4: c.2077delC p.(His693ThrfsTer4), 0.25 pts, PMID: 21522182) with a variant classified as at least likely pathogenic (PM3_Strong). At least one patient with this variant displayed a clinical suspicion or diagnosis of LGMD and absent or severely reduced dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 14678801, 21522182). The filtering allele frequency of this variant is 0.000056915 (the upper threshold of the 95% CI of 50/1111952 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Gln protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706448/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27300 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0001122 infores:hetionet CHEBI:4046 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0027497 infores:hetionet CHEBI:39867 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0546884 infores:hetionet CHEBI:119486 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C2047937 infores:hetionet CHEBI:6078 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0085593 infores:hetionet CAID:CA16043370 biolink:causes MONDO:0100368 infores:clingen CAID:CA16043370 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PP1, PP4, PM2_Supporting The NM_000329.3(RPE65):c.1338+1G>A variant disrupts a canonical splice site in intron 12 and is predicted to lead to skipping of a critical exon, resulting in a frameshift, and likely nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404AlafsTer4) variant confirmed in trans (0.5 points, PMID 32367544), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_Supporting).The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 32367544). At least one proband harboring this variant was tested by exome sequencing (2.0) and exhibits a phenotype including optic disc pallor (0.5), pigmentary retinopathy with attenuated vessels (0.5), poor pupillary light response (0.5), RPE mottling (0.5), macular atrophy (0.5), and decreased peripheral (1.0) and central vision (1.0) which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 32367544, PP4). This variant is present in gnomAD v.4.1.0 at an allele frequency of 8.478e-7 with 1/1179592 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002. In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP1, PP4, PM3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043370/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0209366 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0009938 infores:hetionet CAID:CA10644626 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644626 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*2594_*2597del is a UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644626/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7956 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0018799 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0038358 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0009324 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0039503 infores:hetionet CHEBI:50648 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1443060 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017178 infores:hetionet CHEBI:4646 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0009763 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0162429 infores:hetionet CHEBI:15428 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0027497 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0002170 infores:hetionet CHEBI:8214 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0006266 infores:hetionet CHEBI:17303 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0312420 infores:hetionet CHEBI:31980 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0700590 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027769 infores:hetionet CHEBI:7478 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0015967 infores:hetionet NCBITaxon:480 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:480 MESH:D001991 DB00447_MESH_D001991_1 CHEBI:2955 biolink:causes MONDO:0002184 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1262760 infores:hetionet CHEBI:70735 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0041657 infores:hetionet CHEBI:7986 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0220870 infores:hetionet CHEBI:9671 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0043352 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0314719 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013395 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0687133 infores:hetionet CHEBI:63607 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0040264 infores:hetionet CHEBI:4470 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0232459 infores:hetionet CHEBI:27882 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0015672 infores:hetionet CHEBI:18332 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0233472 infores:hetionet CAID:CA000653 biolink:causes MONDO:0017623 infores:clingen CAID:CA000653 MONDO:0017623 PMID: Likely Benign BS2_Supporting, BS1 PM2, PM6, PVS1, BP7, BP5, BS3, BS4, PP2, PP3, PP1, PP4, PM3, PM5, PM4, PM1, BA1, BP2, BP1, BP4, BP3, PS1, PS3, PS4, PS2 PTEN c.-975G>A (NC_000010.10:g.89623251G>A) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00127 (0.127%, 11/8660 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (internal laboratory contributor ClinVar Organization ID: 61756) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000653/MONDO:0017623/003 2019-11-22 2019-12-04 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:84314 biolink:causes MONDO:0033045 infores:monarchinitiative not_provided not_provided HGNC:28128 MONDO:0033045 uuid:d927cbf1-b325-4bbb-8cb8-490a142c2f2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2950 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C3665347 infores:hetionet CHEBI:31949 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0018801 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151849 infores:hetionet CHEBI:8874 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0424790 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0267792 infores:hetionet CHEBI:6690 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C1368065 infores:hetionet UBERON:0012429 biolink:causes MONDO:0005170 infores:ubergraph knowledge_assertion manual_agent UBERON:0012429 MONDO:0005170 CHEBI:8069 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0015230 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0575090 infores:hetionet CHEBI:3312 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C1142412 infores:hetionet CHEBI:585948 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0015967 infores:hetionet CAID:CA6748955 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748955 MONDO:0009861 PMID: Pathogenic PVS1, PP4_Moderate, PM2, PM3_Supporting The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID: 24048906) (PM3_Supporting). Classification: PathogenicSupporting Criteria: PVS1, PM2, PM3_Supporting, PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748955/MONDO:0009861/006 2020-04-05 2020-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10119 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0041105 infores:hetionet CHEBI:101853 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0011991 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0017160 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0518015 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151828 infores:hetionet CHEBI:17334 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018790 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0542237 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0542237 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0178298 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0595877 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0553737 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0553737 infores:hetionet CHEBI:50648 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0239340 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011849 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0036572 infores:hetionet CHEBI:8597 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0085631 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027651 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0009938 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0948594 infores:hetionet CHEBI:15854 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0038325 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0026821 infores:hetionet NCBIGene:27349 biolink:causes MONDO:0957935 infores:monarchinitiative not_provided not_provided HGNC:29622 MONDO:0957935 uuid:ebc6913a-2e07-4b31-a168-9fa4e719e7d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0151735 infores:hetionet NCBITaxon:121228 biolink:causes MONDO:0001794 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:121228 MONDO:0001794 CHEBI:75984 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0017181 infores:hetionet CHEBI:74947 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0520966 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031350 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0020649 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0015230 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0009319 infores:hetionet CHEBI:3561 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0016382 infores:hetionet CHEBI:7444 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0037317 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0162429 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0948525 infores:hetionet CHEBI:3696 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042029 infores:hetionet CHEBI:91583 biolink:causes UMLS:C0151859 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0151859 infores:hetionet CHEBI:27436 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0595929 infores:hetionet CHEBI:144093 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0236075 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0234215 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027932 infores:hetionet CHEBI:5280 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0037383 infores:hetionet CHEBI:46295 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0017178 infores:hetionet CHEBI:64310 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0152025 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009319 infores:hetionet CHEBI:92769 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0011603 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0853973 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0853973 infores:hetionet CHEBI:9168 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C3263723 infores:hetionet CHEBI:53691 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0232602 infores:hetionet NCBITaxon:5478 biolink:causes MONDO:0022636 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5478 MONDO:0022636 CHEBI:41879 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0702166 infores:hetionet CHEBI:8764 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151754 infores:hetionet CHEBI:10125 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013362 infores:hetionet CL:0000097 biolink:causes GO:0002553 infores:ubergraph knowledge_assertion manual_agent CL:0000097 GO:0002553 CHEBI:5384 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0020615 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0020473 infores:hetionet CHEBI:68478 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0919924 infores:hetionet CAID:CA16020930 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020930 MONDO:0009861 PMID:26503515 Pathogenic PP4_Moderate, PM2, PVS1 This c.1066-1G>T (IVS10-1G>T) variant in PAH was reported in one Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. This variant in the -1 splice acceptor site results in exon skipping. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020930/MONDO:0009861/006 2019-10-18 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94609 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0497156 infores:hetionet CHEBI:6912 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0037036 infores:hetionet CHEBI:8874 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018946 infores:hetionet CHEBI:17549 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151904 infores:hetionet CHEBI:2914 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0043144 infores:hetionet CHEBI:78543 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0041364 infores:hetionet CHEBI:18248 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C1368065 infores:hetionet CAID:CA10014263 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014263 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS4, PS3, PS2, BA1, BP1, BP7, BS1, BS3, PVS1, PM2, PM6, PM5, PP2, PP3 NM_001754.5(RUNX1):c.950T>G (p.Leu317Arg) is a missense variant which has a highest population minor allele frequency in gnomAD v2 of 0.00002891 (1/34590 alleles) in the non-Finnish European population. This variant has been reported in a patient with AML at a VAF of 15%, but the origin was not confirmed (PMID: 28933735). The computational predictor REVEL gives a score of 0.249, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014263/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28487 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0029124 infores:hetionet CHEBI:5118 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151905 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0877322 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0020538 infores:hetionet CHEBI:127780 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0035455 infores:hetionet CHEBI:3756 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0014457 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0151763 infores:hetionet GO:0070562 biolink:causes GO:0032870 infores:ubergraph knowledge_assertion manual_agent GO:0070562 GO:0032870 UNII:K2J09EMJ52 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0232459 infores:hetionet CHEBI:71219 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C3160858 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0018418 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0009450 infores:hetionet CHEBI:63607 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020621 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0024299 infores:hetionet CHEBI:16586 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0011206 infores:hetionet CHEBI:4717 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0040479 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0038814 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0852733 infores:hetionet CHEBI:9738 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0030312 infores:hetionet UMLS:C0120107 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042963 infores:hetionet CHEBI:194135 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040822 infores:hetionet CAID:CA386952675 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952675 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting BP4, PS4, PP4, PP3 The c.73G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 25 (p.(Ala25Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.684, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested, so PP4 cannot be applied (PMID: 15841481). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15841481, 21224407). In summary, c.73G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952675/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0520888 infores:hetionet CHEBI:499361 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0039239 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0854210 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0854210 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0027339 infores:hetionet CHEBI:82960 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0030193 infores:hetionet CHEBI:7478 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0003811 infores:hetionet CHEBI:15428 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0220870 infores:hetionet CHEBI:4909 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0231218 infores:hetionet CHEBI:3216 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0017178 infores:hetionet CHEBI:3032 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0085631 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0549288 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0549288 infores:hetionet CHEBI:4027 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0428977 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0547030 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0233472 infores:hetionet CHEBI:134966 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0017178 infores:hetionet CHEBI:28593 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0429097 infores:hetionet CHEBI:134991 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0002963 infores:hetionet CAID:CA637749750 biolink:causes MONDO:0011071 infores:clingen CAID:CA637749750 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.58+12C>G is an intronic variant which does not occur in any population in gnomAD v3 (PM2_supporting). It is not predicted to disrupt splicing (SpliceAI score 0.0) (BP4), but it is borderline conserved (PhyloP 2.23), so BP7 does not apply. There are no cases or functional data available in the literature. In summary, the clinical significance of this variant is uncertain due to lack of evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637749750/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6717 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1167965 infores:hetionet CAID:CA1020785 biolink:causes MONDO:0021060 infores:clingen CAID:CA1020785 MONDO:0021060 PMID: Benign BP7, BP4, BA1 BS1, PM2 The c.36T>G (p.Gly12=) variant in NRAS is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0011 (18/10370 alleles) in the Ashkenazi Jewish population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 2.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1020785/MONDO:0021060/039 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49960 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0015397 infores:hetionet CAID:CA10606508 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606508 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3, PP3, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM5, PM1, BS2, PP2, PP1, BP1, BP4, BP2, BP3, BA1, PS4, PS1, PS3, PS2 The NM_000231.3: c.158T>C variant in SGCG is a missense variant predicted to cause substitution of leucine by proline at amino acid 53 (p.Leu53Pro). This variant has been detected in at least three individuals with autosomal recessive limb girdle muscular dystrophy (PMID: 30564623, 18996010), including in a homozygous state in two patients (1.0 pt, PMID: 18996010) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced expression of gamma sarcoglycan protein in skeletal muscle, which is highly specific for SGCG-related LGMD (PP4_Strong; PMID: 18996010). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113696 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LGMD VCEP threshold (≤0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.98, which exceeds the threshold of ≥0.70, evidence that correlates with impact to SGCG function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PP4_Strong, PM3, PM2_supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606508/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:64220 biolink:causes MONDO:0011010 infores:monarchinitiative not_provided not_provided HGNC:30650 MONDO:0011010 uuid:ff52cf0b-d250-454b-89ff-d4bf49f74ba6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0234708 infores:hetionet CHEBI:10101 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020621 infores:hetionet CHEBI:135361 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0000731 infores:hetionet CHEBI:50131 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0040460 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0314719 infores:hetionet CAID:CA024646 biolink:causes MONDO:0007783 infores:clingen CAID:CA024646 MONDO:0007783 PMID: Uncertain Significance PM1, PS4_Moderate PP3, PS3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with lysine at codon 226 of the RYR1 protein, p.(Met226Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:19191329, PMID:24433488, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.841 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024646/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:119573 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1609512 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0746883 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0017152 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042373 infores:hetionet CAID:CA291022 biolink:causes MONDO:0012999 infores:clingen CAID:CA291022 MONDO:0012999 PMID: Benign BS2, BA1, BP4, BP7 The NM_000156.6:c.*11C>T variant is a nucleotide substitution in the 3'UTR of GAMT. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence of the gene product. The highest population minor allele frequency in gnomAD v2.1.1 is 0.05828 (1381/23694 alleles) in the African / African-American population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). Furthermore, the variant has been observed in the homozygous state in 37 individuals out of 134,627 in gnomAD v2.1.1. Given the severity and early onset of the symptoms of GAMT deficiency, this data suggests that the variant does not cause this condition (BS2). It is not predicted to not impact splicing by Splice AI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant is noted in ClinVar (ID 204598). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291022/MONDO:0012999/026 2022-06-06 2024-05-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6640 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0013378 infores:hetionet CHEBI:51860 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0236124 infores:hetionet CHEBI:45409 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0024902 infores:hetionet CHEBI:52172 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0235437 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0006552 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D005499 DB02703_MESH_D005499_1 CHEBI:168396 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003811 infores:hetionet CAID:CA386953145 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953145 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PS1, PS4, PM5, PM1, PP3, PP4 The c.139G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 47 (p.(Gly47Arg)) of NM_000545.8. This variant has a REVEL score of 0.572, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 32741144). The MODY probability is unable to be calculated for this individual due to lack of clinical information (PMID: 32741144). Another missense variant, c.140G>A (p.Gly47Glu) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. The nucleotide change c.139G>C, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.139G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.139G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 6/4/2021): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953145/MONDO:0015967/017 2022-01-19 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5130 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0237849 infores:hetionet CHEBI:404903 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0085628 infores:hetionet NCBIGene:6927 biolink:causes MONDO:0007763 infores:monarchinitiative not_provided not_provided HGNC:11621 MONDO:0007763 uuid:f5b63fc9-5b03-4621-b15b-8ca689e6f8d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020542 infores:hetionet CAID:CA9043720 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043720 MONDO:0012999 PMID: Pathogenic PVS1, PP4_Strong, PM3, PM2_Supporting The NM_000156.6:c.328-1G>A variant in GAMT occurs within the canonical splice acceptor site of intron 2. It is predicted to cause skipping of biologically-relevant-exon 3/6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 patients, all Chinese, with clinical symptoms consistent with GAMT deficiency, and elevated guanidinoacetate (in either urine or blood) have been reported. One of these individuals also had reduced creatine on brain MRS (PP4_Strong). This patient and an affected sibling were homozygous for the variant (Journal of Clinical Pediatrics, 2024 Vol.42 No.12 1039-1046 (article in Chinese), link to article - https://jcp.xinhuamed.com.cn/EN/10.12372/jcp.2024.24e0300; 0.5 points). Another individual was compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.403G>A (p.Asp135Asn) (ClinVar Variation ID: 573140) phase unconfirmed, 0.5 points) (PMID: 37305710) (Total 1 point, PM3). Two additional probands were compound heterozygous and another variant in GAMT, either c.114C>T (p.Gly38=) or c.115 A>G (p.Lys39Glu). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PMID: 37305710). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002883 (34/1179490 alleles) in the European non-Finnish, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 844968). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PP4_Strong, PM3, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043720/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004238 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0013395 infores:hetionet CHEBI:59560 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0010200 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1321686 infores:hetionet CAID:CA409106961 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106961 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PP1, PM5 The c.641C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of serine to phenylalanine at codon 214 (p.(Ser214Phe)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and family history of neonatal hypoglycemia) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). Additionally, a number of other missense variants at this codon (c.640T>G, p.Ser214Ala; c.640T>A, p.Ser214Thr; c.641C>A, p.Ser214Tyr) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.641C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106961/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10124 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0029456 infores:hetionet CHEBI:42068 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0015967 infores:hetionet CHEBI:43968 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0013404 infores:hetionet CHEBI:100147 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0014457 infores:hetionet CHEBI:6710 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0030252 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0038454 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027697 infores:hetionet NCBIGene:440193 biolink:causes MONDO:0014475 infores:monarchinitiative not_provided not_provided HGNC:19967 MONDO:0014475 uuid:b395ba6f-ebe4-47a5-a683-c6987bea03db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1325847 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0015397 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235639 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020580 infores:hetionet CHEBI:132233 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0855242 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0232493 infores:hetionet CHEBI:6754 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C2830004 infores:hetionet CHEBI:31236 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0012569 infores:hetionet CHEBI:465284 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0344232 infores:hetionet CHEBI:72296 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0017565 infores:hetionet CHEBI:84500 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037317 infores:hetionet CHEBI:8871 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0005778 infores:hetionet CHEBI:7494 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0006277 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004936 infores:hetionet CHEBI:8802 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0151517 infores:hetionet CHEBI:2663 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0022661 infores:hetionet CHEBI:45367 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0040034 infores:hetionet CHEBI:2549 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C3263723 infores:hetionet CHEBI:17026 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0236075 infores:hetionet CHEBI:499361 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0221152 infores:hetionet CHEBI:9720 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0018524 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0004604 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0004601 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004601 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0003864 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0033117 infores:hetionet CHEBI:63611 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038325 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0239385 infores:hetionet CHEBI:6965 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0037290 infores:hetionet CAID:CA8459559 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459559 MONDO:0011132 PMID: Benign BA1 PP3, PP4, BP4, BP2, PM3 The variant NM_001369369.1(FOXN1):c.1556T>A is predicted to cause a leucine to glutamine substitution at amino acid position 519. The variant has a Grpmax allele frequency of 0.005940 based upon the gonmADv4.0 African American subpopulation, which is greater than 0.00447 and thus meets BA1 criteria. The meta predictor Revel predicts a score of 0.6, which is less than 0.644 and greater than 0.290, which does not meet BP4 or PP3 criteria. The variant was found in the heterozygous state in P6 from PMID:27484032 who displayed phenotypes such as low TRECs on NBS, severe T cell lymphopenia, and was sequenced via NGS for 46 PIDD genes. Notably this patient did not display phenotypes such as alopecia or nail dystrophy. This patient also carried a pathogenic variant p.Arg320Trp in the heterozygous state, with unknown phasing. In summary this variant meets criteria to be classified as benign for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BA1 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459559/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:135736 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1510431 infores:hetionet CHEBI:3723 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018681 infores:hetionet CHEBI:3403 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042571 infores:hetionet CHEBI:6067 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0041582 infores:hetionet CHEBI:5118 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030554 infores:hetionet CHEBI:2659 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C1291078 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0035078 infores:hetionet CHEBI:50223 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0231528 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0235063 infores:hetionet CHEBI:17549 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0162834 infores:hetionet GO:0052081 biolink:causes GO:0071446 infores:ubergraph knowledge_assertion manual_agent GO:0052081 GO:0071446 CHEBI:567361 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0013604 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013146 infores:hetionet CHEBI:31949 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0234192 infores:hetionet CAID:CA016026 biolink:causes MONDO:0007947 infores:clingen CAID:CA016026 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1_Strong PM5 The NM_00138 c.5747G>A, is a missense variant in FBN1predicted to cause a substitution of a cysteine by tyrosine at amino acid 1916 (p.Cys1916Tyr). This variant was found in a proband diagnosed with Marfan syndrome (PMID 24793577, PP4). This variant has been reported three times in ClinVar: once as pathogenic, once as likely pathogenic, and once as uncertain significance (Variation ID: 42391). This variant is not present in gnomAD(PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.967, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA016026/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:5775 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0008033 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0031350 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027339 infores:hetionet CHEBI:7773 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0043352 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0009806 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020517 infores:hetionet CHEBI:55346 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0311468 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0852995 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0852995 infores:hetionet CHEBI:68584 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0015230 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0086543 infores:hetionet CHEBI:49575 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0041657 infores:hetionet CHEBI:63621 biolink:causes MONDO:0021098 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0205875 infores:hetionet CHEBI:4903 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0043094 infores:hetionet CHEBI:7454 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0036974 infores:hetionet CHEBI:7565 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0234233 infores:hetionet CHEBI:4636 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0004093 infores:hetionet CHEBI:8356 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0231919 infores:hetionet CHEBI:61033 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0017152 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0340464 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0948594 infores:hetionet NCBIGene:7137 biolink:causes MONDO:0007270 infores:monarchinitiative not_provided not_provided HGNC:11947 MONDO:0007270 uuid:35ae8cd8-95aa-44ab-aafb-3a19b6cc5b51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060058 biolink:causes GO:0060443 infores:ubergraph knowledge_assertion manual_agent GO:0060058 GO:0060443 CHEBI:9586 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0040034 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0002170 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0027051 infores:hetionet CHEBI:10023 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0036974 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0012833 infores:hetionet CHEBI:10100 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0038999 infores:hetionet CHEBI:66901 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0027441 infores:hetionet CHEBI:50275 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014518 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0857495 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0857495 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0233494 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018802 infores:hetionet NCBIGene:219844 biolink:causes MONDO:0009365 infores:monarchinitiative not_provided not_provided HGNC:26558 MONDO:0009365 uuid:123a15be-787b-463e-8855-6722545b05a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:521033 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0011124 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0003864 infores:hetionet CHEBI:63635 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0014457 infores:hetionet CHEBI:4681 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0919980 infores:hetionet CHEBI:63618 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0015230 infores:hetionet CHEBI:49575 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011606 infores:hetionet NCBIGene:1491 biolink:causes MONDO:0009058 infores:monarchinitiative not_provided not_provided HGNC:2501 MONDO:0009058 uuid:282b944f-75cc-4673-a133-08813b7bcb54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0233632 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0037199 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0035333 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0039231 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0025061 infores:hetionet CHEBI:4974 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C2973529 infores:hetionet CHEBI:4798 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151786 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0022660 infores:hetionet CHEBI:50673 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0027813 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0231218 infores:hetionet CHEBI:3242 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0031256 infores:hetionet CAID:CA157989 biolink:causes MONDO:0007648 infores:clingen CAID:CA157989 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, BA1, PS3, PS1, PS4, PS2 The c.1225T>C (p. Trp409Arg) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157989/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true NCBIGene:889 biolink:causes MONDO:0020724 infores:monarchinitiative not_provided not_provided HGNC:1573 MONDO:0020724 uuid:d173423a-9fed-4267-8344-9fed00e9f786 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0004604 infores:hetionet CHEBI:50173 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C1443060 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0917798 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0233632 infores:hetionet CHEBI:6775 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151827 infores:hetionet CAID:CA645614125 biolink:causes MONDO:0100083 infores:clingen CAID:CA645614125 MONDO:0100083 PMID: Pathogenic PS4_Moderate, PVS1_Strong, PP1_Strong, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM3, BS2, PP2, PP3, PP4 NM_001754.5(RUNX1):c.967+2_967+5del is a noncoding variant. This variant was found to co-segregate with disease in multiple affected family members, with seven or more (8) meioses observed in one family/across 1 family (PP1_Strong; PMID: 28240786). Skips exon 8 with in frame del270- 323 and D269A deletion in TAD(PVS1_strong). This variant has been reported in two or three probands (X) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 28240786, doi: 10.1093/ajcp/aqz121.026) (PS4_moderate). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_strong, PVS1_strong, PS4_moderate, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645614125/MONDO:0100083/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51860 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0042109 infores:hetionet CHEBI:135876 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0041976 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0029456 infores:hetionet NCBIGene:101060691 biolink:causes MONDO:0032843 infores:monarchinitiative not_provided not_provided HGNC:51204 MONDO:0032843 uuid:c102eff7-0ae9-47c5-9d6e-d4e0d6b4cf6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0035455 infores:hetionet CHEBI:8713 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0043352 infores:hetionet CHEBI:3534 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0023530 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0151626 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0232459 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151464 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151464 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0232487 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0151788 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0151788 infores:hetionet CHEBI:27899 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0006145 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1384606 infores:hetionet CHEBI:22977 biolink:causes MONDO:0043523 infores:ubergraph knowledge_assertion manual_agent CHEBI:22977 MONDO:0043523 CAID:CA10014202 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014202 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1098_1103del p.(Ile366_Gly367del) is an inframe deletion which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014202/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:77733 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0948594 infores:hetionet CHEBI:4551 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0033975 infores:hetionet CAID:CA8338123 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338123 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PP1, PM1, PM3_Supporting, PP4_Moderate PS3 The c.1468G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 490 (p.Ala490Pro), also known as Ala450Pro when numbered from the mature protein. This variant has been detected in at least 5 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 2 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variant, presumed to be in trans (PM3_Supporting, PMID: 26453363, 30194637). This variant has been described in at least 3 unrelated individuals who displayed VLCAD enzyme activity <20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:26453363, 14517516, 30194637). The variant has been reported to segregate with VLCAD deficiency in 2 affected siblings from 1 family (PP1, PMID: 14517516). This variant resides within a region, amino acids 481-516, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PMID: 18227065, 20060901). A substrate specificity assay showed this variant displays abnormal substrate specificity; however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9839948). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel:  PM1, PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338123/MONDO:0008723/021 2023-04-11 2023-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8382 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020517 infores:hetionet CAID:CA410204278 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204278 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.116G>A (p.Arg39His) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204278/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6838 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0033117 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0009806 infores:hetionet CHEBI:15765 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0851578 infores:hetionet CHEBI:15367 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0231218 infores:hetionet CHEBI:4315 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C2363730 infores:hetionet CHEBI:6958 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0042373 infores:hetionet CHEBI:4907 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0013395 infores:hetionet CHEBI:2663 biolink:causes HP:0025388 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040137 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0006840 infores:hetionet GO:0045685 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0045685 GO:0007275 GO:1905132 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1905132 GO:0019953 CHEBI:40303 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0344232 infores:hetionet CAID:CA6402597 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402597 MONDO:0019565 PMID: Uncertain Significance PP4_Moderate, PP3, PP1 PM2, BP2, PS3, PS4, BP5, BS1 NM_000552.5(VWF):c.4130C>T is a missense variant in VWF that replaces alanine with valine at position 1377. At least 1 patient with this variant, in combination with p.Arg1379Cys (ClinVar 100333; Pathogenic VWD type 1) in cis, displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay which together are highly specific for VWD type 2M (PP4_moderate, PMID: 27785872). The p.Ala1377Val and p.Arg1379Cys variants have been reported in cis in 3 additional probands with high mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.6 to 0.7), and decreased GP1b binding assay, but the four patients from Milan show the same short tandem repeats nearby, indicating the possibility of a common ancestor. The proband of Family VIII (PMID: 35452508) has 3 additional type 2M diagnosed individuals, 2 are counted here with VWF Act/ VWF:Ag ratio <=0.42 (the other is 0.75). Each individual is heterozygous for p.A1377V; p.R1379C (PP1). The Grpmax filtering allele frequency of this variant in gnomAD v4.1 is 0.001967 (based on 170/75034 alleles in the African / African-American population), which is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) and higher than the threshold for PM2_Supporting (<0.0001). GP1b-alpha binding assay performed with recombinant VWF expressed by HEK-293 cells showed severely decreased binding when p.Ala1377Val was combined with the p.Arg1379Cys variant, indicating that the combination of these two variants has a damaging effect on protein function. PS3_Supporting was not met because the individual p.Ala1377Val and p.Arg1379Arg mutants showed approximately wild-type binding to GpIb-alpha (PMID: 27785872). The computational predictor REVEL gives a score of 0.805, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PP3, PP1. (Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/12/2024) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402597/MONDO:0019565/090 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31981 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0349506 infores:hetionet CHEBI:145499 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151904 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0878544 infores:hetionet CHEBI:231425 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0231218 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0017178 infores:hetionet CHEBI:63791 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0032227 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0234215 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0221155 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0221155 infores:hetionet NCBIGene:55630 biolink:causes MONDO:0008713 infores:monarchinitiative not_provided not_provided HGNC:17129 MONDO:0008713 uuid:29174903-2a5b-4427-81e7-7f171df9d9ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9605 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0007177 infores:hetionet CHEBI:40237 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0917801 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0345904 infores:hetionet CHEBI:4784 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0002792 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0178298 infores:hetionet CAID:CA10585882 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585882 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 The NM_000527.5(LDLR):c.2547+5G>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 26 April 2023. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: No REVEL, splicing evaluation required.Functional data on splicing not available.A) variant located at -3 to +6 from canonical donor splice site.MES scores: canonical site variant = 3.74; canonical site wt = 11.11.Ratio variant/wt canonical donor: 3.74/11.11 = 0.34 --- it is below 0.8Variant is predicted to alter splicing.PP4: Variant meet PM2 and is identified in 1 index case who fulfils Simon Broome criteria for FH (PMID 20809525, Marduel et al. 2010) after alternative causes of high cholesterol are excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585882/MONDO:0007750/013 2023-04-26 2025-02-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9435 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0424000 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0002871 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018418 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0162820 infores:hetionet CHEBI:9137 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0438215 infores:hetionet CHEBI:3723 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013390 infores:hetionet CHEBI:3561 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0027497 infores:hetionet CHEBI:6912 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0236024 infores:hetionet CHEBI:3568 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0026826 infores:hetionet CHEBI:63617 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0008350 infores:hetionet CHEBI:74947 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0039070 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0006266 infores:hetionet CHEBI:15940 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0004238 infores:hetionet CAID:CA023525 biolink:causes MONDO:0007750 infores:clingen CAID:CA023525 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PM3, PM2, PP3, PP4 BA1, BP1, BP4, PS1, BP5, BS1, BS4, PM1, PM5, PP2 "The NM_000527.5(LDLR): c.1567G>A (p.Val523Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PM3, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003266 (0.003%) in East Asian (gnomAD v2.1.1). PP3: REVEL = 0.917. PS3_Moderate: Functional studies: PMID 1301956 (Hobbs et al., 1992), Level 2 assay using homozygous patients' fibroblasts, 125I-LDL assays - 15-30% LDLR activity (but all cycle was tested) // PMID 9974426 (Bertolini et al., 1999), Level 2 assay using homozygous patient fibroblast, 125I-LDL assays - 25% LDLR activity, (mention of testing LDL binding, internalization, and degradation) // PMID 21865347 (Romano et al., 2011), Level 3 assays using heterozygous patients' Epstein-Barr virus transformed lymphocytes and FACS assays - 30-40% LDLR activity. // PMID 25647241 (Thormaehlen et al., 2015), functional studies using HeLa cells and alternative microscopy assay showed that the LDLR activity is decreased compared to WT and was considered as ""disruptive"" ------ Overall, functional studies (PMID 1301956, 9974426, 21865347) show an activity below 70% of wild-type, consistent with damaging effect and PS3 is met.PS4, PP4: Variant meets PM2 and is identified in at least 22 unrelated cases, 2 fulfilling Simon-Broome criteria (GeneDx) and 20 with DLCN score >=6 (Service de Biochimie et de Biologie Moléculaire, France; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; Robarts Research Institute, Canada). PP1_Strong: variant segregates with FH phenotype in 14 informative meioses in 8 families from different labs (Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology, Brazil; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 11 affected family members have the variant and 3 non-affected family members do not have the variant. PM3: 1 case reported from Service de Biochimie et de Biologie Moléculaire, France (homozygous and LDL-cholesterol 12 mmol/L at 4 years old)." Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023525/MONDO:0007750/013 2023-01-27 2024-10-07 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:4562 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0026821 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0917799 infores:hetionet CAID:CA410203495 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203495 MONDO:0011071 PMID: Likely Pathogenic PM5_Strong, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.318G>T (p.Trp106Cys) is a missense variant, which has a REVEL score ≥ 0.88 (0.949) (PP3). This variant is a missense change at the same residue (p.Trp106) where two or more (2) different missense changes have been previously established as pathogenic variants (ClinVar ID 436617 and ClinVar ID 1045299) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_Supporting, and PM5_Strong Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203495/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9086 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011603 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0520589 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0032285 infores:hetionet CHEBI:9571 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0037036 infores:hetionet CHEBI:6931 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0424295 infores:hetionet CHEBI:3716 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0014742 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0010692 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0017601 infores:hetionet CHEBI:28748 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020598 infores:hetionet CHEBI:7577 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0040264 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0010692 infores:hetionet CHEBI:168396 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0231528 infores:hetionet CHEBI:68584 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0009676 infores:hetionet NCBIGene:1063 biolink:causes MONDO:0009477 infores:monarchinitiative not_provided not_provided HGNC:1857 MONDO:0009477 uuid:9d2a022c-fadd-4eb2-bcd5-ec2980dc68f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003467 infores:hetionet CHEBI:168396 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0023518 infores:hetionet CHEBI:8772 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0236075 infores:hetionet GO:0090369 biolink:causes GO:0006591 infores:ubergraph knowledge_assertion manual_agent GO:0090369 GO:0006591 CHEBI:45081 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0025222 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0031350 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011991 infores:hetionet CHEBI:10100 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0015230 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037278 infores:hetionet CAID:CA8337646 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337646 MONDO:0008723 PMID: Uncertain Significance BP4, BA1, PP4_Moderate PM3, BP2 The c.308A>G variant in ACADVL is a missense variant predicted to cause substitution of lysine by arginine at amino acid 103 (p.Lys103Arg). This variant has been reported in one individual with elevated C14:1 levels, an acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and a positive fatty acid oxidation probe assay, which are highly specific for VLCAD deficiency (PP4; PMID: 27209629). The highest population minor allele frequency in gnomAD v2.1.1 is 1.2% in the African population, which is higher than the ClinGen ACADVL threshold (0.7%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.35, which is below the threshold of 0.5 indicating that the variant does not predict a damaging effect on ACADVL function (BP4). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for VLCAD deficiency, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on April 23, 2024. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337646/MONDO:0008723/021 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA337099441 biolink:causes MONDO:0044970 infores:clingen CAID:CA337099441 MONDO:0044970 PMID: Benign BA1 PP3, BP4 The m.12308A>G variant in MT-TL2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in 12.5% of individuals in the GenBank dataset (BA1) including in haplogroups K (99.5% of individuals) and U (98.9% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 15% including in haplogroups K (99.9% of individuals) and U (99.7% of individuals). If an affected individual is not a member one of these haplogroups, further evaluation of the variant in that particular individual should be considered. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337099441/MONDO:0044970/014 2022-01-10 2022-01-10 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:50859 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1167965 infores:hetionet CHEBI:74947 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013604 infores:hetionet CHEBI:17650 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0152030 infores:hetionet CHEBI:31623 biolink:causes HP:0001103 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0730362 infores:hetionet CHEBI:29688 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C1510410 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0234215 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0426576 infores:hetionet CHEBI:6078 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0012833 infores:hetionet UMLS:C0023610 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0018944 infores:hetionet CHEBI:16899 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0033774 infores:hetionet CHEBI:17026 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0085633 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0038363 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0039971 infores:hetionet CHEBI:144551 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0003811 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0235431 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0041912 infores:hetionet CAID:CA2695201729 biolink:causes MONDO:0010305 infores:clingen CAID:CA2695201729 MONDO:0010305 PMID: Uncertain Significance PP3, PP4, PM2_Supporting The NM_005629.4:c.644+5G>A variant in SLC6A8 is an intronic variant affecting a nucleotide within the donor consensus splice site region of intron 4. The computational predictor SpliceAI predicts that this variant impacts splicing; the score for loss of the donor splice site of intron 4 is 0.98; there is also a predicted gain of a donor site a further 37 base pairs downstream in intron 4 (score = 0.54) (PP3). This variant has been previously reported in one male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695201729/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Inconclusive true CHEBI:41879 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0221166 infores:hetionet NCBIGene:1832 biolink:causes MONDO:0013034 infores:monarchinitiative not_provided not_provided HGNC:3052 MONDO:0013034 uuid:18da42de-cadf-4d28-9da3-85c99c9fc7b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0026827 infores:hetionet NCBIGene:79583 biolink:causes MONDO:0014164 infores:monarchinitiative not_provided not_provided HGNC:37234 MONDO:0014164 uuid:6f3f9cdf-05a9-4bec-9b72-4718c7175d15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4995 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013384 infores:hetionet CHEBI:4911 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0015967 infores:hetionet NCBIGene:2744 biolink:causes MONDO:0032733 infores:monarchinitiative not_provided not_provided HGNC:4331 MONDO:0032733 uuid:419b0cdd-05af-465f-b52e-e946a3c03add biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0033687 infores:hetionet CHEBI:4911 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0014518 infores:hetionet CHEBI:465284 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013404 infores:hetionet CAID:CA386941079 biolink:causes MONDO:0015967 infores:clingen CAID:CA386941079 MONDO:0015967 PMID: Uncertain Significance BS1, PM2, BS2, PP3 The c.1824C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to arginine at codon 608 (p.(Ser608Arg)) of NM_000545.8. While c.1824C>G is absent in the European non-Finnish population in gnomAD v4.1.0, it has 2 copies in the African/African-American subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.666, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in a normoglycemic individual of 45 years old, which is younger than the MDEP-established cutoff (70 years old) for BS2 (internal lab contributors). In summary, c.1824C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): none. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386941079/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7577 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C1443060 infores:hetionet CHEBI:8461 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0038999 infores:hetionet CHEBI:47780 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0242422 infores:hetionet CHEBI:27666 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0004093 infores:hetionet CHEBI:83527 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0234022 infores:hetionet CHEBI:63619 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020443 infores:hetionet CHEBI:8404 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0028643 infores:hetionet CHEBI:82981 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0042109 infores:hetionet CHEBI:7565 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085631 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151966 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151966 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017168 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0012833 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0549475 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0021053 infores:hetionet CAID:CA487845865 biolink:causes MONDO:0100216 infores:clingen CAID:CA487845865 MONDO:0100216 PMID: Uncertain Significance PP3, PM2_Supporting PM6, BA1, BP2, BP4, BS2, PP1, PP4, PM5, PM1, PS2, PS4, PS1, PS3, BS1, BS4, BS3, BP7 The NM_177438.3:c.1020G>T is a synonymous variant (p.Leu340=) that is predicted to impact splicing. The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 and miRNA-Processing Gene VCEP: PM2_Supporting, PP3 (Bayesian Points: 2, VCEP specifications version 1.3.0; 04/23/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA487845865/MONDO:0100216/024 2024-04-23 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0120194 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0120194 GO:0061458 CHEBI:63617 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0234458 infores:hetionet CHEBI:63581 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0003467 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1112214 infores:hetionet NCBIGene:6331 biolink:causes MONDO:0011376 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0011376 uuid:f5ed5820-89bd-428a-ba10-f353ce8c0199 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042373 infores:hetionet CHEBI:63620 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151636 infores:hetionet NCBIGene:4148 biolink:causes MONDO:0011765 infores:monarchinitiative not_provided not_provided HGNC:6909 MONDO:0011765 uuid:b8448036-62b3-48dd-b96e-7bf72deac673 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042373 infores:hetionet CHEBI:194135 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235378 infores:hetionet CHEBI:6888 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0003862 infores:hetionet CHEBI:64355 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0438215 infores:hetionet CHEBI:3380 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0009676 infores:hetionet CHEBI:5441 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0854467 infores:hetionet NCBITaxon:36830 biolink:causes MONDO:0016453 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36830 MONDO:0016453 CHEBI:63631 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0041834 infores:hetionet CHEBI:34967 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0027497 infores:hetionet CHEBI:51141 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0022346 infores:hetionet CHEBI:3380 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0039231 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020538 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0027051 infores:hetionet CHEBI:6912 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0836924 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0948525 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0003123 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0234215 infores:hetionet CHEBI:63621 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043352 infores:hetionet CHEBI:45863 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0002994 infores:hetionet CHEBI:6887 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0033893 infores:hetionet NCBIGene:23092 biolink:causes MONDO:0011908 infores:monarchinitiative not_provided not_provided HGNC:17073 MONDO:0011908 uuid:66d16218-7c7d-4c50-b53d-74e01588bd56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68554 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0030196 infores:hetionet CHEBI:10650 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0699828 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0021359 infores:hetionet CHEBI:8764 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151904 infores:hetionet GO:1903593 biolink:causes GO:0002448 infores:ubergraph knowledge_assertion manual_agent GO:1903593 GO:0002448 CAID:CA353663 biolink:causes MONDO:0007947 infores:clingen CAID:CA353663 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1_Strong NM_00138 c.6820T>C is a missense variant in FBN1 predicted to cause a substitution of cysteine by arginine at amino acid 2274 (p.Cys2274Arg). This variant is not reported in the literature. This variant has been reported twice in ClinVar as Likely pathogenic and once as uncertain significance (Variation ID: 222610). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.0.0). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.992, PP3). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup,PP2, PP3 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA353663/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6073 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0015397 infores:hetionet NCBIGene:554 biolink:causes MONDO:0010581 infores:monarchinitiative not_provided not_provided HGNC:897 MONDO:0010581 uuid:d994c808-7bd3-4c4b-a69f-b53f4a64e80a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C3203358 infores:hetionet CAID:CA410204050 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204050 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.164C>T (p.Ala55Val) is a missense variant that has a REVEL score < 0.50 (0.358) and a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204050/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144093 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011570 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0031085 infores:hetionet CHEBI:16469 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151315 infores:hetionet CHEBI:6149 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151636 infores:hetionet CHEBI:4798 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042790 infores:hetionet CAID:CA16620353 biolink:causes MONDO:0011132 infores:clingen CAID:CA16620353 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PS4_Moderate, PVS1_Strong BP5 The NM_001369369.1(FOXN1):c.1315del (p.Leu439CysfsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). This variant is absent from gnomADv2.1.1 (PM2_supporting). It has been reported heterozygous in three patients (PMID: 31447097 and PMID: 30809743) with low CD3 and CD3+CD8+ T cell counts (PP4, PS4_supporting). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_Supporting, PP4, PS4_moderate as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620353/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:50122 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0032227 infores:hetionet CHEBI:49668 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0003811 infores:hetionet CAID:CA913184734 biolink:causes MONDO:0009290 infores:clingen CAID:CA913184734 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PM3 "The NM_000152.5:c.2585del (p.Gly862GlufsTer25) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 19 (GAA has 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Note that although the premature stop codon is predicted to occur in exon 20, it would still be expected to result in nonsense-mediated decay because it is about 140 bp upstream from the 3' end of exon 19, which is the penultimate exon. One patient from Southern China has been reported with this variant, ""typical clinical features of IOPD presenting in the first few months of life"", and reduced GAA activity. However, insufficient details were provided to apply PP4. This patient is compound heterozygous for c.2585delG and another variant in GAA, c.2815_2816delGT (p.Val939LeufsTer78) (ClinVar Variation ID: 371481, SCV002032119.1) (PMID: 28394184). that has been classified as likely pathogenic by the ClinGen LD VCEP (the classification is likely pathogenic even without the in trans evidence from this patient, therefore avoiding circular logic); the phase is unconfirmed. 0.25 points, PM3 is not met at the current time. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 4, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184734/MONDO:0009290/010 2024-09-04 2024-10-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA415084403 biolink:causes MONDO:0010305 infores:clingen CAID:CA415084403 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.917G>A variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 (p.Trp306Ter) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been previously reported in one male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on Macrh 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415084403/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:8080 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0232459 infores:hetionet CAID:CA415086032 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086032 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_005629.4:c.1142-2A>G variant occurs within the canonical acceptor splice site of intron 7 and is predicted to result in skipping of exon 8 (113 bp) resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). This variant has been reported in an individual who is a participant in the Association for Creatine Deficiencies registry, CreatineINFO. Further clinical and laboratory details are not currently available. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 13, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086032/MONDO:0010305/027 2024-06-13 2024-06-24 X-linked inheritance HP:0001417 Supports CHEBI:17026 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0239571 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0877690 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0877690 infores:hetionet CHEBI:48390 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035302 infores:hetionet NCBIGene:6506 biolink:causes MONDO:0014916 infores:monarchinitiative not_provided not_provided HGNC:10940 MONDO:0014916 uuid:c073ea36-75c2-445f-82ff-06fd59d30667 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0002317 biolink:causes CL:0000786 infores:ubergraph knowledge_assertion manual_agent GO:0002317 CL:0000786 CAID:CA398326766 biolink:causes MONDO:0011132 infores:clingen CAID:CA398326766 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PVS1_Strong The NM_001369369.1(FOXN1):c.1585del (p.Leu529TrpfsTer21) frameshift variant in exon 6 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). Functional analysis was performed in a luciferase reporter construct, which was cotransfected into heterologous cells with an expression vector containing mutant or wild-type FOXN1. This variant had 12.5% luciferase activity compared to wild-type, which is below the <50% threshold for PS3_Moderate (PMID: 37419334). The highest MAF in gnomADv4.0 is 0.00002412 (1/41462 alleles) in the African/African-American population which is below the <=0.00002412 threshold for PM2_supporting. It has been reported heterozygous in one patient (P21 of PMID: 31447097) with low CD3 cells, low CD8 cells, and TRECs below state limit (PP4). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PS3_moderate, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398326766/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:28864 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0031117 infores:hetionet NCBIGene:57082 biolink:causes MONDO:0011437 infores:monarchinitiative not_provided not_provided HGNC:24054 MONDO:0011437 uuid:521f3b2a-91ca-438f-bc19-f9ced4f8d13d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38545 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0002994 infores:hetionet CHEBI:8888 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0000731 infores:hetionet CHEBI:46295 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C3665346 infores:hetionet CHEBI:367163 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0270996 infores:hetionet CHEBI:48844 biolink:causes UMLS:C0264315 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0264315 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0239385 infores:hetionet CAID:CA512341295 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341295 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS2, PS1, PS4, BA1, BP1, BP2, BP3, BP5, BS1, BS3, BS4, PVS1, PM6, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1119G>A (p.Ser373=) is a synonymous variant which is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -0.00400787 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). Although the variant is absent from gnomAD v2 and v3 (PM2_supporting), it also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341295/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50859 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0016204 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0014868 infores:hetionet CHEBI:2208 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0040034 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0235234 infores:hetionet CHEBI:9137 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235710 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0858678 infores:hetionet CHEBI:7573 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C2047937 infores:hetionet CHEBI:404903 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0700292 infores:hetionet CHEBI:8107 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013404 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0392162 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0600142 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0041912 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0155305 infores:hetionet CHEBI:3219 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0003537 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0851341 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0234215 infores:hetionet CAID:CA10653569 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653569 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*1138C>A variant in the 3' UTR has an MAF of 0.05416 (5.4%, 835/15418 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 135 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653569/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64321 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030318 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0235234 infores:hetionet CHEBI:31711 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0009763 infores:hetionet CHEBI:63611 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0036974 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0030305 infores:hetionet CHEBI:15854 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C1291078 infores:hetionet GO:0010725 biolink:causes GO:0060215 infores:ubergraph knowledge_assertion manual_agent GO:0010725 GO:0060215 CHEBI:8768 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013404 infores:hetionet CHEBI:68584 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0027497 infores:hetionet CHEBI:42797 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019521 infores:hetionet CHEBI:9587 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0020517 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233494 infores:hetionet CAID:CA355961724 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961724 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting BS1, BA1 The NM_000203.5:c.540G>A (p.Trp180Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5 out of 14, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 2 patients with MPS I have been reported with this variant. One was compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, but phase was not defined (PMID: 22976768) (0.5 points), and one individual was homozygous for the variant (PMID: 27146977) (0.5 points). (PM3). One of these individuals had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I, including dysostosis multiplex, hepatomegaly, arthropathy, and corneal involvement ( PMID: 27146977) (PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179968 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1321357). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 2, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961724/MONDO:0001586/091 2025-05-02 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:127780 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0022650 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0919874 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0037822 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0041969 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003767 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026265 infores:hetionet CHEBI:6775 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0311468 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0032285 infores:hetionet CHEBI:8888 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235325 infores:hetionet CHEBI:63925 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0006277 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0029408 infores:hetionet CAID:CA114363 biolink:causes MONDO:0009861 infores:clingen CAID:CA114363 MONDO:0009861 PMID:1301200PMID:1301200PMID:18590700PMID:1301200 Likely Pathogenic PP4, PP3, PM3_Strong PM2, PS3 The c.965C>G (p.Ala322Gly) variant in PAH has been reported in 4 individuals with mild hyperphenylalaninemia (BH4 deficiency not excluded). (PP4; PMID: 12501224). This variant has an allele frequency higher than the PAH VCEP PM2 threshold (MAF=0.00044). This variant was detected with p.R408W in 3 individuals (Pathogenic in ClinVar) and with p.R252W in 1 individual (PM3_strong; PMID: 12501224). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM3-strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114363/MONDO:0009861/006 2019-09-27 2019-09-29 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0903898 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0027497 infores:hetionet CHEBI:499361 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0231218 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0031001 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0031001 uuid:8295b5a7-8fff-4921-adae-633dd08d859d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040822 infores:hetionet CAID:CA367401366 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401366 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PM1 The c.608T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 203 (p.(Val203Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and has been identified in at least 15 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; ClinVar ID: 585923, PMIDs: 9075802, 9000695, 8433729, 15841481,19790256). At least one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6%, antibody negative, and three-generation dominant family history of diabetes or hyperglycemia) (PP4_Moderate; PMID 15841481). This variant segregated with diabetes, with at least six informative meioses in five families with MODY (PP1_Strong; PMID:9075802, PMID:16059790). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, functional studies have determined that the c.608C>T variant has decreased catalytic activity as measured by a relative activity index (RAI) < 0.5 (PS3_Moderate; https://doi.org/10.1159/000079009). In summary, c.608C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 3/23/2023): PP1_Strong, PS4, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401366/MONDO:0015967/086 2023-07-31 2023-07-31 Semidominant inheritance HP:0032113 Supports CHEBI:63627 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0041969 infores:hetionet CHEBI:3181 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0012569 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0009938 infores:hetionet CHEBI:8207 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0010200 infores:hetionet CHEBI:8863 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0575081 infores:hetionet CHEBI:9570 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0014335 infores:hetionet CHEBI:71255 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0237849 infores:hetionet UMLS:C0065374 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037317 infores:hetionet CHEBI:9635 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0520966 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0021122 infores:hetionet GO:0099148 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0099148 GO:0007268 CHEBI:135530 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0041969 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0853714 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0019158 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C1861172 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235750 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0021053 infores:hetionet NCBITaxon:813 biolink:causes MONDO:0021697 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:813 MESH:D002690 DB02703_MESH_D002690_1 CHEBI:63791 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013456 infores:hetionet CHEBI:36704 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0004238 infores:hetionet CHEBI:3219 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0028084 infores:hetionet CHEBI:68478 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0426390 infores:hetionet CHEBI:9449 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0151636 infores:hetionet CHEBI:3387 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013404 infores:hetionet CHEBI:4562 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0031350 infores:hetionet GO:1905330 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:1905330 GO:0060429 PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006908 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0032001 infores:hetionet CHEBI:31638 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0917801 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0014175 infores:hetionet CHEBI:72564 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1260926 infores:hetionet CHEBI:15367 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0021368 infores:hetionet CHEBI:9328 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0036830 infores:hetionet CHEBI:31547 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020580 infores:hetionet CHEBI:10119 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020461 infores:hetionet CHEBI:119915 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151907 infores:hetionet CHEBI:63624 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0035410 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0521464 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521464 infores:hetionet CHEBI:9123 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042024 infores:hetionet CHEBI:408174 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0018794 infores:hetionet CHEBI:7581 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0020672 infores:hetionet CHEBI:3223 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0004093 infores:hetionet CHEBI:27834 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0023052 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0015230 infores:hetionet CHEBI:51450 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C2240374 infores:hetionet GO:0043405 biolink:causes GO:0000165 infores:ubergraph knowledge_assertion manual_agent GO:0043405 GO:0000165 CHEBI:2687 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0030554 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0948594 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0040479 infores:hetionet CHEBI:71417 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0009806 infores:hetionet NCBIGene:1301 biolink:causes MONDO:0009226 infores:monarchinitiative not_provided not_provided HGNC:2186 MONDO:0009226 uuid:124282c1-1774-4927-a8ea-537d9c98c310 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3749 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0027497 infores:hetionet CHEBI:404903 biolink:causes EFO:1001753 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0243001 infores:hetionet CHEBI:17698 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0011603 infores:hetionet CAID:CA410147422 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147422 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1): c.1309A>G (p.Thr437Ala) is a missense variant which has a REVEL score < 0.50 (0.154) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147422/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:9927 biolink:causes MONDO:0012231 infores:monarchinitiative not_provided not_provided HGNC:16877 MONDO:0012231 uuid:bb82505d-588c-40c9-b28e-ccad2bf7f701 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034882 infores:hetionet NCBITaxon:5661 biolink:causes MONDO:0011989 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5661 MESH:D007896 DB05630_MESH_D007896_1 CHEBI:40279 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0546817 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0221384 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0221384 infores:hetionet CHEBI:37924 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0023211 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002170 infores:hetionet CHEBI:8776 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0085605 infores:hetionet CHEBI:7852 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0231530 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0040034 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0848309 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0848309 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0541772 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0541772 infores:hetionet CHEBI:2639 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0015230 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1443060 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C3665386 infores:hetionet NCBIGene:126328 biolink:causes MONDO:0032619 infores:monarchinitiative not_provided not_provided HGNC:20371 MONDO:0032619 uuid:fba7fd3a-4c5c-4828-bee8-54f9c992445f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50567 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0162429 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037023 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0344232 infores:hetionet CHEBI:8024 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0917801 infores:hetionet CHEBI:142290 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0003862 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0234215 infores:hetionet CAID:CA2918445 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918445 MONDO:0015152 PMID:22095924 Pathogenic PP1_Moderate, PP4, PP3, PS3_Moderate, PM3_Strong PM2, BS3 The NM_000232.5: c.271C>T variant in SGCB is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 91 p.(Arg91Cys). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy, including in a homozygous state in families from the Plain community (0.5 pts; PMID: 35416532, 9565988) and confirmed in trans with a pathogenic variant in two cases (c.85A>T p.(Arg29Ter), 2.0 pts, PMID: 17994539, 11369190) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed severely reduced expression of β-sarcoglycan in skeletal muscle, which is highly specific for SGCB-related LGMD (PMID: 11369190); however, the presence of potentially diagnostic variants in all of the other three sarcoglycan genes was not ruled out (PP4). The variant has also been reported to segregate with LGMD in at least two affected family members from two nuclear Plain community families (PP1_Moderate; PMID: 9565988). The filtering allele frequency of this variant is 0.0002533 for South Asian exome chromosomes by gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/30614), which is higher than the ClinGen LGMD VCEP threshold (<0.00009) for PM2_Supporting and therefore this criterion is not met. Expression of p.Arg91Cys in β-sarcoglycan in vitro has been shown to disrupt localization of the sarcoglycan complex to the plasma membrane, indicating an impact of the c.271C>T p.(Arg91Cys) variant on protein function (PMID: 37317968) (PS3_Moderate). The computational predictor REVEL gives a score of 0.95, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to SGCB function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PP1_Moderate, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918445/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31174 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0015230 infores:hetionet CHEBI:30830 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0687713 infores:hetionet CHEBI:51364 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0015672 infores:hetionet CHEBI:125354 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0020651 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0018801 infores:hetionet NCBIGene:3762 biolink:causes MONDO:0013359 infores:monarchinitiative not_provided not_provided HGNC:6266 MONDO:0013359 uuid:b138a09c-af62-4b80-b923-ecdfc3ed74a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29013 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0022346 infores:hetionet CHEBI:59560 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0027947 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011849 infores:hetionet CHEBI:3647 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0700075 infores:hetionet NCBIGene:8671 biolink:causes MONDO:0011422 infores:monarchinitiative not_provided not_provided HGNC:11030 MONDO:0011422 uuid:a4aadb38-0900-4a7b-9f3a-e00c8a65ca87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1368065 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0242350 infores:hetionet CHEBI:2659 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0030252 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037195 infores:hetionet CAID:CA512341242 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341242 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1182C>T (p.Gly394=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341242/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45409 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085616 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C1527407 infores:hetionet CHEBI:144551 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0878773 infores:hetionet CHEBI:75998 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0085649 infores:hetionet CHEBI:2704 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0005758 infores:hetionet CHEBI:8805 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0013604 infores:hetionet CHEBI:84500 biolink:causes MONDO:0024361 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0877792 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020517 infores:hetionet CHEBI:180905 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C1443060 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0018799 infores:hetionet CHEBI:6633 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0518015 infores:hetionet CHEBI:4708 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0014591 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151885 infores:hetionet CHEBI:63638 biolink:causes MONDO:0003432 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0038379 infores:hetionet CHEBI:8356 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003962 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0020517 infores:hetionet CHEBI:3510 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0013378 infores:hetionet GO:0036446 biolink:causes CL:0000186 infores:ubergraph knowledge_assertion manual_agent GO:0036446 CL:0000186 CHEBI:6916 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0002622 infores:hetionet CHEBI:29688 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C2129214 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0029408 infores:hetionet CHEBI:9434 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0002792 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0014742 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0152006 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0152006 infores:hetionet CHEBI:16335 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C1145670 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0014868 infores:hetionet CHEBI:5001 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0030252 infores:hetionet CHEBI:16755 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018681 infores:hetionet CHEBI:231594 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0024894 infores:hetionet CHEBI:9139 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0549622 infores:hetionet CHEBI:4027 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0014335 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0041912 infores:hetionet CAID:CA8337554 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337554 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM5, PM4, PS1, BP7 The c.138+1G>A (p.?) (NM_000018.4) variant in ACADVL occurs within the canonical splice acceptor site (+1) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (1/22352 alleles) in SAS population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with this variant in a heterozygous state was positive at NBS or presumed NBS positive; the second allele was not clearly stated (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 11/10/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337554/MONDO:0008723/021 2022-04-06 2022-07-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63589 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0017178 infores:hetionet CHEBI:104011 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0549386 infores:hetionet CHEBI:3215 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0004245 infores:hetionet CHEBI:3380 biolink:causes UMLS:C2712122 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C2712122 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0442886 infores:hetionet CHEBI:31981 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0027497 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1610069 infores:hetionet CHEBI:6541 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0026858 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0020517 infores:hetionet CHEBI:63584 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C1384353 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0349506 infores:hetionet CHEBI:59750 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0009450 infores:hetionet UMLS:C0657912 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026838 infores:hetionet CAID:CA312290 biolink:causes MONDO:0008723 infores:clingen CAID:CA312290 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate The c.343-1G>A variant in ACADVL occurs within the canonical splice acceptor site of intron 5. It is predicted to cause skipping of biologically-relevant-exon 5/6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is reported in at least one patient with abnormal C14:1 (0.4-6.5 uM, 1-365 days), who also carried the pathogenic (p.V283A) variant (PP4_moderate: PMID: 31983732). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PP4_moderate). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312290/MONDO:0008723/021 2021-11-09 2022-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38940 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014130 infores:hetionet CHEBI:36791 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020580 infores:hetionet CAID:CA10360539 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360539 MONDO:0100039 PMID: Benign BP7, BA1 The allele frequency of the p.Ser815= variant in CDKL5 is 0.1% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Ser815= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ser815= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360539/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:71415 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0016059 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020456 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002871 infores:hetionet CAID:CA10549672 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549672 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, PP3, BP4, PM5 The NM_005629.4:c.1861C>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a threonine at amino acid position 621 (p.Pro621Thr). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency is 0.00006063 (2/32985 alleles, 0 hemizygotes) in the East Asian population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.337, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 373452). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549672/MONDO:0010305/027 2025-03-18 2025-03-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:135925 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0040822 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0038358 infores:hetionet CHEBI:9168 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0438215 infores:hetionet CHEBI:6456 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C1443060 infores:hetionet CHEBI:28830 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0232462 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0021053 infores:hetionet CHEBI:8874 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085649 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151773 infores:hetionet CHEBI:16796 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0033117 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042109 infores:hetionet CAID:CA243569 biolink:causes MONDO:0007113 infores:clingen CAID:CA243569 MONDO:0007113 PMID: Likely Benign BS2, BP7, BP5 BS1 The p.Ile324= variant in UBE3A (NM_130838.2) is observed in at least 7 unaffected individuals (internal database - GeneDx) (BS2). The p.Ile324= variant in UBE3A is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The silent p.Ile324= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ile324= variant in UBE3A (NM_130838.2) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA243569/MONDO:0007113/037 2023-12-08 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true GO:1904956 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:1904956 GO:0060322 CHEBI:119915 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0034886 infores:hetionet CHEBI:27786 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0018932 infores:hetionet CHEBI:3534 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0033774 infores:hetionet CHEBI:291342 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0948594 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0948594 infores:hetionet CHEBI:520985 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0520966 infores:hetionet CHEBI:49960 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0015967 infores:hetionet CHEBI:29688 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0042963 infores:hetionet CHEBI:45409 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0030554 infores:hetionet CHEBI:50922 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0041657 infores:hetionet CHEBI:91541 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0032343 infores:hetionet CHEBI:142290 biolink:causes MONDO:0009891 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0032463 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0032285 infores:hetionet CHEBI:7959 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0019080 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0037274 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0007114 infores:hetionet CAID:CA120544 biolink:causes MONDO:0044970 infores:clingen CAID:CA120544 MONDO:0044970 PMID:9792552 Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting, PP1_Moderate BP4, BA1, PS2, BS1, BS3, PM6 The m.12258C>A variant in MT-TS2 gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). Family members of both probands were also affected. The age of onset was in adulthood and ranged from the 20s to 60s. Features seen in affected individuals include diabetes, cataracts, retinitis pigmentosa, hearing loss, and cerebellar ataxia (PMIDs: 9792552, 10090882). This variant segregated with disease in multiple affected members in both families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 10090882, 9792552). There are no reported de novo occurrences of this variant to our knowledge. There is one occurrence in population databases (one occurrence in Mitomap GenBank sequences, absent in gnomAD v3.1.2 and Helix dataset). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (95.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.4 (PP3). Single fiber studies support the functional impact of this variant (PS3_supporting) as the level of variant in COX-positive fibers ranged from 23-71%, while in COX-negative fibers was present at >85% heteroplasmy (PMID: 9792552). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120544/MONDO:0044970/015 2023-03-28 2023-04-03 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:64321 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0221752 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027765 infores:hetionet CHEBI:27666 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0009450 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0857073 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0857073 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042373 infores:hetionet CAID:CA3062640037 biolink:causes MONDO:0700270 infores:clingen CAID:CA3062640037 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.7840_7841insGA (p.Pro2614Argfs*18) variant in ATM is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA3062640037/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38940 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0032227 infores:hetionet CAID:CA314828 biolink:causes MONDO:0012999 infores:clingen CAID:CA314828 MONDO:0012999 PMID: Uncertain Significance PP3, PM2_Supporting The NM_000156.6:c.650C>T variant in GAMT is a missense variant predicted to result in the substitution of proline for leucine at amino acid 217 (p.Pro217Leu). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006674 (5/74922 alleles) in the African African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.773, in the range of 0.644-0.773, evidence that correlates with impact to GAMT function at the supporting level (PMID: 36413997) (PP3). SpliceAI predicts that the variant has no impact on splicing. To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205592). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PP3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314828/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5864 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027059 infores:hetionet CHEBI:31643 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0040264 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0018939 infores:hetionet CHEBI:5801 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0011570 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0858794 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0858794 infores:hetionet CHEBI:50305 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0030554 infores:hetionet CHEBI:5103 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0151636 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0518015 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0740425 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0030305 infores:hetionet CAID:CA255139 biolink:causes MONDO:0010602 infores:clingen CAID:CA255139 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PS3, PS4 The c.2215G>A (p.Glu739Lys) missense variant is absent from males in both gnomAD v2.1.1 and v3.1.1, meeting the PM2_Supporting criteria. The variant has a REVEL score of 0.614 (>0.6), meeting PP3 criteria. At least 13 patients with mild hemophilia A are reported in the literature and internal laboratory data meeting F8 phenotype criteria (PMID: 24452774, 23711237, 21166991, 8547094, 16972227), which meets the PS4_Very strong and PP4_Moderate criteria. This variant has been labeled as an inverse discrepant variant, where the one-stage assays show lower factor VIII levels than the two-stage, or chromogenic, assays (EAHAD database; PMID: 32232366). There were multiple related individuals across 6 different families reported that were genotyped, but their specific relation was not stated, so the PP1 was capped at the moderate weight to be conservative (PMID: 24452774). In-vitro assays in COS-1 cells show FVIII-Glu739Lys results in lower FVIII:C in the mild range, as observed in patients with this variant and hemophilia A (PMID: 30997536). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PS3, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255139/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:15367 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2973529 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003635 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0021141 infores:hetionet CHEBI:6923 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0021053 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1443060 infores:hetionet CHEBI:5123 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0156404 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022081 infores:hetionet CHEBI:134990 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0178298 infores:hetionet CAID:CA658824423 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824423 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS2, PS3, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, BP7, BP5, PM6, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 "The c.171_223del (p.Leu58Profs*62) variant is a frameshift deletion variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). In addition, this variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and was identified in a a 65-year-old female tested due to ""thrombocytopenia with predisposition to AML"" (PS4_supporting; SCV000807767.1). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_supporting, and PM2_supporting." Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824423/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3181 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0178298 infores:hetionet CHEBI:94440 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0018794 infores:hetionet CAID:CA658798978 biolink:causes MONDO:0009290 infores:clingen CAID:CA658798978 MONDO:0009290 PMID:28554557 Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.1153del (p.Arg385AlafsTer7), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP’s specifications for PP4 and who is compound heterozygous for the variant and c.-32-13T>G, phase unknown (28554557). PM3_Supporting is met. There is a ClinVar entry for this variant (Variation ID: 501294, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798978/MONDO:0009290/010 2020-08-31 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5855 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038367 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0948594 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151736 infores:hetionet CHEBI:6933 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0004093 infores:hetionet NCBIGene:51062 biolink:causes MONDO:0013381 infores:monarchinitiative not_provided not_provided HGNC:11231 MONDO:0013381 uuid:638d7723-540e-4211-b4a1-2bffdf6ef7dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0027765 infores:hetionet CHEBI:66964 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0030252 infores:hetionet CHEBI:9123 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0037036 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0040210 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0040210 infores:hetionet CHEBI:64355 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2938875 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0023895 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0004604 infores:hetionet CHEBI:94848 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0086525 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C1261981 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1261981 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0038358 infores:hetionet CHEBI:6375 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013447 infores:hetionet CHEBI:6520 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0009450 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0948089 infores:hetionet CHEBI:180905 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0004238 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1096267 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1096267 infores:hetionet CHEBI:119486 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0016655 infores:hetionet CAID:CA500262444 biolink:causes MONDO:0100326 infores:clingen CAID:CA500262444 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting BP7, PP3, PP4, BP4 The c.2943G>A (p.Gln981=) variant is a synonymous variant that may impact splicing (SpliceAI acceptor loss score of 0.32). It occurs at a nucleotide that is not conserved as shown by phyloP score of 0.42. At least one patient (Patient GT-1 in PMID:37409530, previously reported in https://openscience.ub.uni-mainz.de/bitstream/20.500.12030/5285/1/pillitteri_daniele-funktionelle_u-20201030141153195.pdf) with this variant displayed an ISTH bleeding score of 7. They also were observed to have <1% GPIIb-IIIa receptor occupancy. Because aggregation data for this patient was not shown, PP4 was not met. The individual was homozygous for the variant (PM3_supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of unknown significance due to insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3_supporting, PM2. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500262444/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5103 biolink:causes UMLS:C0700031 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0700031 infores:hetionet CHEBI:9168 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C2047937 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0027769 infores:hetionet CHEBI:4495 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0019080 infores:hetionet CHEBI:3506 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0011606 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0002170 infores:hetionet CHEBI:17474 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0014173 infores:hetionet CHEBI:71272 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0027441 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0456909 infores:hetionet CHEBI:9434 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0040460 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007785 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0242350 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0031212 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0006145 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0314719 infores:hetionet CHEBI:6904 biolink:causes MONDO:0004766 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0038218 infores:hetionet CHEBI:27899 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0042963 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0015376 infores:hetionet CHEBI:50924 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0586553 infores:hetionet CHEBI:7822 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0030312 infores:hetionet UMLS:C0004609 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0233407 infores:hetionet CHEBI:84500 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038002 infores:hetionet CHEBI:7986 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C2830004 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0152128 infores:hetionet CHEBI:68478 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0917801 infores:hetionet NCBIGene:29081 biolink:causes MONDO:0032860 infores:monarchinitiative not_provided not_provided HGNC:25006 MONDO:0032860 uuid:29d9e1bc-36c0-4d15-9641-4a576334b04e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C3248383 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0034150 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042109 infores:hetionet CHEBI:9927 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042963 infores:hetionet CHEBI:3175 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0259799 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0031117 infores:hetionet CHEBI:6715 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151908 infores:hetionet CHEBI:7986 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0025290 infores:hetionet CHEBI:6759 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0013144 infores:hetionet CHEBI:47898 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0038325 infores:hetionet CHEBI:4530 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0040822 infores:hetionet CHEBI:4636 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0162830 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0033975 infores:hetionet CHEBI:3479 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0019080 infores:hetionet CHEBI:2611 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085628 infores:hetionet CHEBI:31413 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0232461 infores:hetionet CHEBI:16714 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0015967 infores:hetionet CHEBI:101853 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0020458 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0036572 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0020649 infores:hetionet CHEBI:5004 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0002874 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0020649 infores:hetionet CAID:CA913178900 biolink:causes MONDO:0044970 infores:clingen CAID:CA913178900 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting PP1, PM6 The m.8306T>C variant in MT-TK has been reported in three individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 22925535, 23847141, 34354612). The first case was reported in 2012 and was a man with onset at 30 years with progressive concerns over time. His medical concerns included muscle weakness, muscle atrophy, cardiac arrhythmia, dysphagia, hearing loss, and insulin resistance. Muscle biopsy showed ragged red fibers and COX-negative fibers, and muscle CT showed bilateral atrophy with fatty replacement. The variant was present at 98% in muscle, 30% in hair roots, 27% in urine, 17% in buccal, and 5% in blood (PMID: 22925535). The other two cases were part of cohort reports with limited clinical details provided (PMIDs: 23847141, 34354612). This variant was reported in additional individuals in one publication (PMID: 29663531) however these cases were excluded from this curation as it was unclear which case(s) had this variant. Furthermore, several cases in this series came from consanguineous families and other nuclear genetic etiologies were not excluded (PMID: 29663531). There are no large families reported in the medical literature to consider for evidence of segregation. While this variant was absent in blood, buccal, hair, and urine from healthy siblings of one proband, the mother was not available for testing to confirm a de novo occurrence (PMID: 22925535). The computational predictor MitoTIP suggests this variant is pathogenic (88.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). This variant is absent in the Genbank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (97.4% +/- 1.2, n=11) than in COX-positive fibers (18.8% +/- 9.2, n+10), p<0.0001 (PS3_supporting, PMID: 22925535). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913178900/MONDO:0044970/015 2022-10-24 2023-01-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3219 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0409497 infores:hetionet CHEBI:119915 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0520966 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0042109 infores:hetionet CHEBI:9720 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0015230 infores:hetionet NCBIGene:129285 biolink:causes MONDO:0859165 infores:monarchinitiative not_provided not_provided HGNC:30595 MONDO:0859165 uuid:7733efc5-3115-4dec-9127-19fc9d623358 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3996 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0038454 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0518015 infores:hetionet CHEBI:4887 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0239937 infores:hetionet CAID:CA279999 biolink:causes MONDO:0015280 infores:clingen CAID:CA279999 MONDO:0015280 PMID: Pathogenic PM5, PM2, PP2, PP3, PM6_Strong, PS4_Supporting The c.388T>C (p.Tyr130His) variant in MAP2K1 has been reported as an unconfirmed de novo occurrence in two probands with clinical features of a RASopathy (PM6_Strong; PMID: 1915617, Ambry Genetics internal data, ClinVar SCV000740998.1). One of these patients had a clinical diagnosis of cardiofaciocutaneous syndrome (PS4_Supporting). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K1 (PM1 not applied; PMID 29493581). Moreover, a different pathogenic missense variant has been previously identified at this codon of MAP2K1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13351). Computational prediction tools and conservation analysis suggest that the p.Tyr130His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM6_Strong, PM5, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279999/MONDO:0015280/004 2020-05-18 2020-07-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8597 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0040822 infores:hetionet CHEBI:107736 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0015672 infores:hetionet CHEBI:64355 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011206 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0242350 infores:hetionet CHEBI:9086 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151766 infores:hetionet CAID:CA346121 biolink:causes MONDO:0015152 infores:clingen CAID:CA346121 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM4, PM2_Supporting, PM3_Very Strong The NM_000070.3: c.598_612del variant in CAPN3 is predicted to cause a change in the length of the protein due to an in-frame deletion of five amino acids in a non-repeat region, p.(Phe200_Leu204del) (PM4). This variant has been detected in at least 24 individuals with LGMD2A (PMID: 23821418, 34720847, 25135358, 34863162, 37688281,16372320, 30564623). At least six patients were compound heterozygous for c.598_612del and a pathogenic variant (c.550del or c.1746-20C>G, 6.0 pts, PMID: 16372320, 23821418, 34720847), and three patients were homozygous (1.0 pt, PMID: 23821418) (PM3_Very Strong). At least one patient with this variant and a second CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression, which is highly consistent with CAPN3-related LGMD (PMID: 16372320; PP4_Strong). The filtering allele frequency (the upper threshold of the 95% CI of 20/1112002 exome chromosomes) is 0.000026 for the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/18/2025): PM4, PM3_Very Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346121/MONDO:0015152/187 2025-03-18 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CAID:CA229621 biolink:causes MONDO:0009861 infores:clingen CAID:CA229621 MONDO:0009861 PMID:9012412PMID:24130151 Pathogenic PM2, PVS1, PP4, PM3_Supporting The c.558_559del (p.Trp187fs) variant in PAH has been reported in 1 Indian PKU patient; Phe = 1240umol/L; BH4 deficiency not excluded (PMID: 24130151; PP4). The variant was detected in the homozygous state, both parents confirmed to be heterozygous (consanguineous) - 0.5 points (PMID: 24130151; PM3_supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 6 out of 13 coding exons; 6 out of total exons) (PVS1). This variant was reported in gnomad with MAF = 0.00016 in South Asian population (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229621/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:3735 biolink:causes MONDO:0013489 infores:monarchinitiative not_provided not_provided HGNC:6215 MONDO:0013489 uuid:09e2b260-f0bc-412c-9abe-a2755bbe80cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0006852 infores:hetionet CHEBI:6067 biolink:causes UMLS:C2721737 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2721737 infores:hetionet CHEBI:51041 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0392525 infores:hetionet GO:0048686 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0048686 GO:0048699 CHEBI:48947 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C1257843 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0456909 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235196 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235196 infores:hetionet CHEBI:6888 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0000737 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0002871 infores:hetionet CHEBI:7798 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0242429 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0442886 infores:hetionet NCBIGene:9338 biolink:causes MONDO:0859085 infores:monarchinitiative not_provided not_provided HGNC:11616 MONDO:0859085 uuid:fa6fd46c-2259-463e-a117-0aff3462a562 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2047937 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151479 infores:hetionet CHEBI:5130 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0004134 infores:hetionet CHEBI:6846 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0233762 infores:hetionet CHEBI:9586 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0947912 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0162429 infores:hetionet CHEBI:15365 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0220870 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0031542 infores:hetionet CHEBI:63589 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0014518 infores:hetionet CAID:CA10549492 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549492 MONDO:0010305 PMID: Likely Benign BS2 BS1, PM2, PP3, PP4, BP4, PM5, PS4 The NM_005629.4:c.1319G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of an arginine by a histidine at amino acid position 440 (p.Arg440His). This variant has been previously reported in one individual with epilepsy and developmental delay without documented evidence of elevated urinary creatine/creatinine or other phenotypic features of creatine transporter deficiency (PMID: 34395220), such that neither PS4 nor PP4 are met. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00003523 (2/56768 alleles; 1 hemizygote) in the South Asian population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 7 hemizygotes in gnomAD v4.1.0.; 6 in the European non-Finnish population and one in the South Asian population (BS2). The computational predictor REVEL gives a score of 0.441 which neither supports a deleterious (>0.75) nor benign impact (<0.2) of the variant on the function of the protein (neither PP3 nor BP4 is met). There is a ClinVar entry for this variant (Variation ID: 372933). Due to the presence of 7 hemizygotes in gnomAD v4.1.0 without any evidence for pathogenicity, the consensus of the ClinGen CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549492/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:63589 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0853692 infores:hetionet CHEBI:36704 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0085641 infores:hetionet CHEBI:49960 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0687713 infores:hetionet NCBIGene:25828 biolink:causes MONDO:0014781 infores:monarchinitiative not_provided not_provided HGNC:17772 MONDO:0014781 uuid:3e6d4a9b-bbfc-4bb0-a342-83b9c4d68173 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0043349 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042514 infores:hetionet CHEBI:8764 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151578 infores:hetionet CHEBI:3207 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0030252 infores:hetionet GO:0003129 biolink:causes GO:0060914 infores:ubergraph knowledge_assertion manual_agent GO:0003129 GO:0060914 CAID:CA414772659 biolink:causes MONDO:0044970 infores:clingen CAID:CA414772659 MONDO:0044970 PMID:18590963PMID:36431069 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting The m.3380G>A (p.R25Q) variant in MT-ND1 has been reported in one individual with primary mitochondrial disease to date, in a 62-year-old woman with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) who also had adult-onset hearing loss (PMID: 18590963). Muscle biopsy showed ragged red fibers. The variant was present at 50% heteroplasmy in skeletal muscle and 5-10% in white blood cells. The variant was absent in blood in her three healthy sons. Single fiber testing in muscle from the proband showed higher levels of the variant in ragged red fibers (61.15%, n=13) than in non-ragged red fibers (29.5%, n=11), p<0.01 (PS3_supporting, PMID: 18590963). Additionally, decreased enzyme activity was seen when this variant was modeled in E. coli (PMID: 36431069). This variant is rare in population databases (MITOMAP: 0.003%, 2/61,883; absent in gnomAD v3.1.2 and Helix; PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (0.65, range 0-1; PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414772659/MONDO:0044970/015 2023-10-23 2025-06-04 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:47381 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013491 infores:hetionet CHEBI:49668 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151701 infores:hetionet CHEBI:48538 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0312420 infores:hetionet CHEBI:31932 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0010200 infores:hetionet CHEBI:7773 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C3665347 infores:hetionet CHEBI:42797 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0234518 infores:hetionet CHEBI:64198 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C1260880 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002878 infores:hetionet CHEBI:65349 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0162285 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0039584 infores:hetionet CHEBI:8772 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0016204 infores:hetionet CHEBI:135791 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0042109 infores:hetionet CHEBI:681569 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0031256 infores:hetionet CHEBI:6717 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0018926 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0027765 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0042373 infores:hetionet CAID:CA166979 biolink:causes MONDO:0700272 infores:clingen CAID:CA166979 MONDO:0700272 PMID: Uncertain Significance BP1 BS1, PM2, BA1 The c.1748T>G (p.Leu583Trp) variant in PALB2 is a missense variant predicted to cause a substitution of leucine by tryptophan at amino acid 583 (p.Leu583Trp). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000044 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA166979/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA658795291 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795291 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM3_Very Strong "The NM_000152.5:c.2481+110_2646+39del variant in GAA, which is also known as c.2481+102_2646+31del and NC_000017.11:g.80117859_80118396del (GRCh38), is a deletion that removes exon 18 in addition to flanking intronic sequences in GAA. The result is an in-frame deletion of 55 amino acids, p.Gly828_Asn882del. In the older literature, this variant has been referred to as ""exon 18 deletion"". When expressed in GAA-deficient fibroblasts, the variant resulted in no increase in GAA activity (Boerkoel et al, 1995; PMID: 7717400). Pulse chase and western blot in fibroblasts from patients with the deletion have shown that GAA precursor protein is made, but is smaller than normal (as expected due to the deletion) and it is not processed to the active form of the enzyme, 76 kDa (PMID: 8884087, 26693141). In addition, studies using brefeldin A indicate that the mutant protein is degraded in the ER and is not secreted or trafficked to the lysosomes (PMID: 8884087) (PVS1). This variant is one of the more common variants identified in patients with Pompe disease, accounting for about 12-15% of alleles in Caucasian patients with infantile onset Pompe disease (PMID: 7945303, 8558570, 8884087, 9950376, 20301438). The Erasmus Medical Center's Pompe database cites 116 patients with this variant (https://www.pompevariantdatabase.nl/). While the level of detail provided is variable in different reports, there are many patients reported with documented deficiency of GAA activity, treated by enzyme replacement therapy, and with clinical features consistent with Pompe disease (for example PMID: 7717400, 8558570, 18285536, 30902109 (PP4_Moderate). Reports of individuals with this variant include patients with infantile onset Pompe disease who are homozygous for the variant (for example, PMID: 8558570 (n=2), 29122469, 30902109; max 0.5 x 2 points); patients with infantile onset Pompe disease who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, for example c.379_380del (PMID: 8558570) (ClinVar Variation ID: 552747,SCV002032110.1), c.437del (PMID: 22658377) (Variation ID: 554096, SCV002032111.1) , c.525del (PMID: 8558570 (n=4), 29122469) (ClinVar Variation ID: 4033, SCV001443331.1), c.2237G>A (p.Trp746Ter) (PMID: 18285536) (ClinVar Variation ID: 280063, SCV001371720.1), and c.2560C>T (p.Arg854Ter) (PMID: 19588081) (ClinVar Variation ID: 4034, SCV001371731.1) (all phase unconfirmed, 0.5 points for each patients with a maximum of 1 point for each second variant = 3 points); and patients with late onset Pompe disease who are compound heterozygous for the variant and c.-32-13T>G, a pathogenic, leaky splice variant that allows a small amount of residual active enzyme to be produced (PMID: 7717400; PMID: 8558570 n=5; PMID: 19588081; PMID: 29122469) (ClinVar Variation ID: 4027, SCV005382543.1). As noted, numerous additional patients have been reported, but the maximum points for PM3 (4 points) has already been reached. Total >4 points (PM3_VeryStrong). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3_VeryStrong, PP4_Moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, August 8, 2025)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795291/MONDO:0009290/010 2025-08-08 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9654 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0233407 infores:hetionet CHEBI:8774 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151746 infores:hetionet CHEBI:8024 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042384 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0541820 infores:hetionet NCBIGene:51649 biolink:causes MONDO:0033534 infores:monarchinitiative not_provided not_provided HGNC:14509 MONDO:0033534 uuid:f72d2cbe-3947-4984-8aab-eff12caff2c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042401 infores:hetionet CHEBI:41774 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0234233 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021400 infores:hetionet CHEBI:75722 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151825 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0015230 infores:hetionet CHEBI:7476 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027796 infores:hetionet CHEBI:63580 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002874 infores:hetionet CHEBI:4530 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0026961 infores:hetionet NCBIGene:10522 biolink:causes MONDO:0014952 infores:monarchinitiative not_provided not_provided HGNC:14677 MONDO:0014952 uuid:42143e14-6d80-4550-bbbb-8eab529df229 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0340865 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0205204 infores:hetionet CHEBI:75922 biolink:causes HP:0400007 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0032519 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0235218 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0235218 infores:hetionet CAID:CA410203877 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203877 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS4, PS2, PS3, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS4, BS3, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.217A>G (p.Ser73Gly) is a missense variant which has a REVEL score < 0.50 (0.335), and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203877/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4046 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0232462 infores:hetionet CHEBI:8707 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013428 infores:hetionet CHEBI:7465 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0036689 infores:hetionet NCBIGene:9129 biolink:causes MONDO:0011075 infores:monarchinitiative not_provided not_provided HGNC:17348 MONDO:0011075 uuid:a919f429-0527-416f-b570-2a387607646b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0149725 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0274714 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0274714 infores:hetionet CHEBI:145499 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0037299 infores:hetionet UMLS:C0657912 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009676 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0042109 infores:hetionet NCBIGene:65057 biolink:causes MONDO:0014690 infores:monarchinitiative not_provided not_provided HGNC:25070 MONDO:0014690 uuid:c72d1230-6c9b-402b-9b95-dc695799b2cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0344232 infores:hetionet CAID:CA7511008 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511008 MONDO:0015152 PMID: Uncertain Significance PP3, PP4, PM3_Strong PM5, PM2, BS2 The NM_000070.3: c.398C>T variant in CAPN3 is a missense variant predicted to cause substitution of alanine by valine at position 133, p.(Ala133Val). This variant has been reported in two unrelated individuals with a clinical diagnosis of LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (c.598_612del p.(Phe200_Leu204del), 1.0 pt x2, PMID: 16141003, LOVD individuals #00214184, #00214185; PM3_Strong, PP4). However, it has also been observed in a homozygous state or in trans with a second presumed diagnostic CAPN3 variant (c.133G>A p.(Ala45Thr), c.1303G>A (p.Glu435Lys)) in three individuals without a clear LGMD phenotype (ClinVar SCV001985435.3, SCV003509679.1 internal data communication). The filtering allele frequency of this variant is 0.0001855 (the upper threshold of the 95% CI of 16/86246 exome chromosomes) in the South Asian population in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Of note, the South Asian population also includes one homozygous individual of unknown age. The computational predictor REVEL gives a score of 0.959, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, while 6 Bayesian points were awarded to this variant based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (PM3_Strong, PP3, PP4), given the conflicting evidence, the VCEP has opted to classify it as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy (LGMD VCEP specifications version 1.0.0; 03/25/2025). Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511008/MONDO:0015152/187 2025-03-25 2025-04-04 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8871 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151878 infores:hetionet CHEBI:4798 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1306341 infores:hetionet CHEBI:127342 biolink:causes UMLS:C2242621 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C2242621 infores:hetionet CAID:CA10014356 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014356 MONDO:0011071 PMID:34166225 Likely Benign BP4, BS3_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.801G>A (p.Met267Ile) is a missense variant which has a REVEL score < 0.50 (0.283) and a SpliceAI score ≤ 0.20 (Acceptor Loss = 0.01) (BP4). Transactivation assays demonstrating normal transactivation (80-115% of wt) (BS3_Supporting; PMID: 34166225). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014356/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0149931 infores:hetionet CHEBI:9168 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0438142 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0521839 infores:hetionet CHEBI:92712 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C2939147 infores:hetionet CAID:CA222800 biolink:causes MONDO:0010726 infores:clingen CAID:CA222800 MONDO:0010726 PMID: Benign BA1 The allele frequency of the c.*14G>A variant in MECP2 (NM_004992) is 0.34% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary the c.*14G>A variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222800/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:4910 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0003811 infores:hetionet CHEBI:31236 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011603 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0020649 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0150450 infores:hetionet CHEBI:499361 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0018965 infores:hetionet NCBIGene:153642 biolink:causes MONDO:0030524 infores:monarchinitiative not_provided not_provided HGNC:25239 MONDO:0030524 uuid:dd711ba1-1e8b-4fbd-ae58-54b39cc170b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0022658 infores:hetionet CHEBI:6741 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0015672 infores:hetionet CHEBI:135351 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0030193 infores:hetionet CHEBI:44915 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0012833 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0037274 infores:hetionet CAID:CA16607985 biolink:causes MONDO:0015967 infores:clingen CAID:CA16607985 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting The c.224+2T>C variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 2 of NM_175914.5. This variant is predicted to cause skipping of biologically-relevant exon 3 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and treated with low-dose sulfonylurea) (PP4; Internal lab contributors). In summary, c.224+2T>C meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607985/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CAID:CA6831958 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831958 MONDO:0015967 PMID: Benign PM5_Supporting, PP4_Moderate, PP3, BA1 PP1, PM1, PS3, PS4, BS3 The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of proline to histidine at codon 379 (p.(Pro379His)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001567, which is greater than the MDEP threshold for BA1 (0.0001)(BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Pro379His protein has transcriptional activity on insulin promoter 62% of WT in RINm5f cells and 78% of WT in HeLA cells (PMID 15883474). While one cell line is greater than the MDEP BS3 cutoff of 75%, one is between the ClinGen MDEP cutoffs for PS3 (<=40%) and BS3, and therefore neither PS3 nor BS3 is applied. This variant was identified in one family and segregated with diabetes with two informative meioses; however, this does not meet the thresholds for PP1 or PS4 set by the ClinGen MDEP (PMIDs: 27236918, 15883474). An individual in this family had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID 15883474). Another missense variant, c.1136C>G (p.Pro379Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379His (PM5_Supporting). In summary, c.1136C>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BA1, PM5_Supporting, PP4_Moderate, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831958/MONDO:0015967/085 2023-12-10 2023-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA206493 biolink:causes MONDO:0010726 infores:clingen CAID:CA206493 MONDO:0010726 PMID: Benign BS1, BS2 The allele frequency of the p.Arg354Cys variant in MECP2 (NM_004992.3) is 0.028% in East Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Arg354Cys variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Arg354Cys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA206493/MONDO:0010726/016 2022-12-09 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA1707668 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707668 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM2_Supporting, PM3_Very Strong PM5, PS3, BS3, PP3 The NM_003494.4: c.6196G>A variant in DYSF, which is also known as NM_001130987.2: c.6313G>A p.(Ala2105Thr), is a missense variant predicted to cause substitution of alanine by threonine at amino acid 2066, p.(Ala2066Thr). This variant has been identified in at least eight individuals with features consistent with LGMD (PMID: 36983702, 21522182, 27066573, 32528171, 32400077, 34559919, 38057384, 35047756, 30028523), including in a homozygous state without reported familial consanguinity in two seemingly unrelated Italian patients (0.5 pts x2, PMID: 30028523, 21522182) and confirmed in trans with a pathogenic variant in two cases (NM_003494.4: c.5022del p.(Phe1674LeufsTer48), 1.0 pt, PMID: 36983702; NM_003494.4: c.4228C>T p.(Gln1410Ter), 1.0 pt, PMID: 35047756). It has also been reported in unconfirmed phase with a pathogenic variant in one case (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 32528171, MYO-SEQ internal data communication) and with a variant independently classified as likely pathogenic in two cases (NM_003494.4: c.5900del p.(Gly1967AlafsTer6), 0.25 pts, PMID: 27066573; NM_003494.4: c.4609del p.(Glu1537LysfsTer5), 0.25 pts, PMID: 34559919, LOVD Individual #00375983) (PM3_Very Strong). At least one patient with this variant had a clinical suspicion of LGMD and severely reduced dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 21522182). The filtering allele frequency of this variant is 0.000015431 (the upper threshold of the 95% CI of 11/1179930 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Ala2066Thr protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538). The computational predictor REVEL gives a score of 0.480 (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Very Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707668/MONDO:0015152/180 2025-07-29 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0521591 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0743680 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001650 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0149523 infores:hetionet CHEBI:135530 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0043352 infores:hetionet CHEBI:9123 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013384 infores:hetionet CHEBI:61390 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0033774 infores:hetionet CHEBI:7581 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0232487 infores:hetionet UNII:R43D2573WO biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0015672 infores:hetionet CHEBI:51141 biolink:causes MONDO:0041775 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C1688637 infores:hetionet CHEBI:8024 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1260880 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0017178 infores:hetionet CHEBI:9763 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020580 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0152198 infores:hetionet CHEBI:68595 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0019112 infores:hetionet CHEBI:9654 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0043094 infores:hetionet CAID:CA398323707 biolink:causes MONDO:0011132 infores:clingen CAID:CA398323707 MONDO:0011132 PMID:37419334 Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PM1 PP4, PS4, PM5 The NM_001369369.1(FOXN1):c.880G>C (p.Val294Leu) missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 294, and thus meets PM1. The variant has a REVEL score of 0.68 which is above the SCID VCEP specified threshold of ≥0.644 to support a deleterious effect of the variant (PP3). The variant is absent from gonmADv2.1.1 (PM2_supporting). A comprehensive literature search, did not identify the variant in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy, however personal communication with Invitae confirmed the variant has been observed in one neonate with low TRECs. A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. This variant had 13.5% luciferase activity compared to WT, which is below the <50% threshold for PS3_moderate (PMID: 37419334). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PM2_supporting, PS3_Moderate, and PP3, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398323707/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:4995 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0231528 infores:hetionet CHEBI:8874 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0039240 infores:hetionet CHEBI:4466 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0039240 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0473120 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0473120 infores:hetionet CHEBI:4514 biolink:causes MONDO:0019369 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0458219 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0041969 infores:hetionet CHEBI:68606 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0041969 infores:hetionet CHEBI:3347 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0008031 infores:hetionet CHEBI:6931 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0424296 infores:hetionet CHEBI:17474 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1510431 infores:hetionet CHEBI:7443 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C2830004 infores:hetionet CHEBI:472657 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0404521 infores:hetionet CHEBI:4995 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0025345 infores:hetionet CHEBI:27786 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0018681 infores:hetionet CHEBI:49040 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0236075 infores:hetionet GO:0003167 biolink:causes CL:0010005 infores:ubergraph knowledge_assertion manual_agent GO:0003167 CL:0010005 CHEBI:63611 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023530 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0178298 infores:hetionet NCBIGene:5593 biolink:causes MONDO:0030487 infores:monarchinitiative not_provided not_provided HGNC:9416 MONDO:0030487 uuid:ee4a4c4e-16bf-41f9-8382-9a0d7db2768d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15365 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C1368065 infores:hetionet CHEBI:17474 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0404521 infores:hetionet CHEBI:9763 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0019079 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0021141 infores:hetionet CHEBI:8356 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0004093 infores:hetionet CHEBI:6520 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0027497 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0027765 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0235032 infores:hetionet CHEBI:3499 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0404521 infores:hetionet CHEBI:3371 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0020621 infores:hetionet NCBIGene:84957 biolink:causes MONDO:0032717 infores:monarchinitiative not_provided not_provided HGNC:13764 MONDO:0032717 uuid:1b34de94-b32c-4880-8f75-fb8a26be52fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8404 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0855775 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0242350 infores:hetionet CHEBI:3478 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0027707 infores:hetionet CHEBI:119915 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0022107 infores:hetionet CHEBI:79699 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0035410 infores:hetionet NCBIGene:6602 biolink:causes MONDO:0032912 infores:monarchinitiative not_provided not_provided HGNC:11106 MONDO:0032912 uuid:4969b041-9136-48bb-9cf8-866afa0a3c9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011991 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0020649 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234922 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234922 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0235431 infores:hetionet CHEBI:4784 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0002962 infores:hetionet NCBIGene:23389 biolink:causes MONDO:0014773 infores:monarchinitiative not_provided not_provided HGNC:22962 MONDO:0014773 uuid:ca2369d9-95cf-48e4-9740-e95b174b2c3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0035854 infores:hetionet CHEBI:3181 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0030662 infores:hetionet CHEBI:2950 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0085631 infores:hetionet CHEBI:50648 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235031 infores:hetionet CHEBI:15367 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0041582 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0948807 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0149904 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0009782 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0012833 infores:hetionet CHEBI:8774 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0037317 infores:hetionet CHEBI:6413 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0020458 infores:hetionet CHEBI:8768 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0404521 infores:hetionet CHEBI:8764 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002962 infores:hetionet CHEBI:6413 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0016658 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0029134 infores:hetionet NCBIGene:6229 biolink:causes MONDO:0012529 infores:monarchinitiative not_provided not_provided HGNC:10411 MONDO:0012529 uuid:b8584ec8-ffc8-444f-be6a-364e0f8a5a89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085632 infores:hetionet CHEBI:3568 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0024282 infores:hetionet CHEBI:16469 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151671 infores:hetionet NCBIGene:79755 biolink:causes MONDO:0012446 infores:monarchinitiative not_provided not_provided HGNC:25843 MONDO:0012446 uuid:ba004932-57a5-4404-90cf-fe540e8fc283 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151763 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0007642 infores:hetionet CHEBI:68584 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0023530 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0021400 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151814 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151814 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0017178 infores:hetionet CAID:CA134953 biolink:causes MONDO:0019497 infores:clingen CAID:CA134953 MONDO:0019497 PMID: Likely Pathogenic PP3, PP1, PM2_Supporting, PM3_Strong The c.227T>C is a missense variant in GJB2 predicted to cause substitution of leucine to proline at amino acid 76. The highest population minor allele frequency in gnomAD v4.1 is 0.0006779% (8/1180042) in the European (non-Finnish) population, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The variant has been detected in 4 probands with hearing loss (3.0 PM3 points). For two of those patients, a pathogenic variant was observed in trans (PMID: 17666888, 19274344), in a third the variant was observed in a homozygous state (ARUP Laboratories internal data, SCV001158697.1), and in the last patient the variant was observed with another pathogenic variant although with unknown phase (Partners LMM internal data, SCV000061486.5) (PM3_Strong). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 19274344). The REVEL computational prediction tool produced a score of 0.976, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel : PM3_Strong, PM2_Supporting, PP1, PP3. (The ClinGen Hearing Loss VCEP Specifications Version 2, 04/17/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA134953/MONDO:0019497/005 2024-04-23 2024-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:68845 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0015230 infores:hetionet CHEBI:16467 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0018965 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0027051 infores:hetionet CHEBI:7823 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0020517 infores:hetionet CHEBI:50859 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0232726 infores:hetionet CHEBI:43968 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0085649 infores:hetionet CAID:CA10549554 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549554 MONDO:0010305 PMID: Uncertain Significance PM2, PP3, BS2, BP4 The NM_005629.4:c.1512G>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a methionine by an isoleucine at amino acid position 504 (p.Met504Ile). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population allele frequency is 0.000006708 (6/894470 alleles, 1 hemizygote) in the European (non-Finnish) population. While this MAF meets the threshold for PM2_Supporting, the criterion is not met due to the presence of a hemizygote. Although a hemizygote is present in gnomAD v4.1.0. this is insufficient for application of BS2 (2 or more hemizygotes required; BS2 not met). The computational predictor REVEL gives a score of 0.349, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 1342107). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549554/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3403 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0231530 infores:hetionet CHEBI:16469 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014173 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0027051 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002170 infores:hetionet CHEBI:71417 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0031256 infores:hetionet CHEBI:94501 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0085610 infores:hetionet CHEBI:8874 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085631 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0036572 infores:hetionet CHEBI:63632 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0012833 infores:hetionet NCBIGene:6182 biolink:causes MONDO:0033533 infores:monarchinitiative not_provided not_provided HGNC:10378 MONDO:0033533 uuid:9e388135-0c2b-415f-84a7-0356790ac2a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0746883 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013395 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0036454 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0043251 infores:hetionet CHEBI:2659 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0031542 infores:hetionet CHEBI:15551 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0004604 infores:hetionet CHEBI:209807 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0030312 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0858524 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0858524 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0234215 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0857322 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0857322 infores:hetionet CHEBI:9622 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0016204 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0521491 infores:hetionet CHEBI:6437 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233514 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0549405 infores:hetionet CHEBI:28748 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018800 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0029191 infores:hetionet CHEBI:4469 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0013404 infores:hetionet CAID:CA397316714 biolink:causes MONDO:0009276 infores:clingen CAID:CA397316714 MONDO:0009276 PMID: Uncertain Significance PP4, PM2_Supporting, BP4, PM3_Supporting The c.463C>G variant in GP1BA is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 155 (p.Leu155Val). At least one patient (Patient 21 in PMID: 28983057) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.290, which is below the ClinGen PD VCEP threshold of <=0.290 and predicts no damaging effect on GP1BA function and the SpliceAI score is zero (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PP4, PM3_Supporting, PM2_Supporting and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397316714/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8356 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0600142 infores:hetionet CHEBI:60761 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0027497 infores:hetionet CHEBI:44185 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0032227 infores:hetionet CHEBI:4909 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0042963 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0232492 infores:hetionet CAID:CA10584778 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584778 MONDO:0007750 PMID: Uncertain Significance PM1, PM2, PP3 BA1, BP4, PS1, BS1, PM5 The NM_000527.5(LDLR):c.188G>A (p.Cys63Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.911. PM1: Variant meets PM2 and alters Cys63, one of the cysteine residues listed. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584778/MONDO:0007750/013 2023-06-23 2025-09-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8874 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007222 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0241266 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0241266 infores:hetionet NCBIGene:6299 biolink:causes MONDO:0054581 infores:monarchinitiative not_provided not_provided HGNC:10524 MONDO:0054581 uuid:7d7e4c2e-8a35-4922-8c8e-e44bb2c8d9f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0553713 infores:hetionet CHEBI:617099 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0014457 infores:hetionet CHEBI:3437 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0006266 infores:hetionet CHEBI:101085 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0042023 infores:hetionet NCBIGene:1311 biolink:causes MONDO:0008322 infores:monarchinitiative not_provided not_provided HGNC:2227 MONDO:0008322 uuid:61d93623-d9f6-4f8d-bc92-23b63b0f61e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA6831682 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831682 MONDO:0015967 PMID: Benign BA1, BP5 BP4, PS3, PM1, BS3, PP3, PP4 The c.185A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 62 (p.(Asn62Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00019, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Furthermore, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). Functional studies demonstrated the p.Asn62Ser protein has 65% transcriptional activity and 70% nuclear localization of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 27899486). This variant has a REVEL score of 0.555, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.185A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BA1, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831682/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA343777896 biolink:causes MONDO:0013144 infores:clingen CAID:CA343777896 MONDO:0013144 PMID: Uncertain Significance PM2, BP4 The c.223G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 75 (p.Ala75Thr). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00001470 (1/68040 alleles) in the European population, which is lower than the ClinGen SERPINC1 threshold ([<0.00002]) for PM2, and therefore meets this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.215, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BP4, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343777896/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9674 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0338831 infores:hetionet CHEBI:28177 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0855775 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0948594 infores:hetionet CHEBI:38545 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0015230 infores:hetionet CHEBI:65346 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0018681 infores:hetionet CHEBI:367163 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0004093 infores:hetionet CHEBI:4784 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C1260880 infores:hetionet UMLS:C0879264 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151766 infores:hetionet CHEBI:8805 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0020456 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0042373 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0948089 infores:hetionet CAID:CA409104106 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104106 MONDO:0015967 PMID: Uncertain Significance PP3, PM1_Supporting PM2, PP4, PS4, BS1 The c.232C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 78 (p.Arg78Trp) of NM_175914.5. This variant has a Grpmax filtering allele frequency of 0.0000069 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the number of cases is less the MDEP threshold for PS4_Moderate and the variant does not meet PM2_Supporting (PMID: 21105941, internal lab contributors). This variant is located within the DNA binding domain (codons 37-113) which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.832, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information and age of diagnosis over 35 (internal lab contributors). In summary, c.232C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104106/MONDO:0015967/085 2025-08-12 2025-08-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6775 biolink:causes UMLS:C0948484 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0948484 infores:hetionet CHEBI:31638 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0010200 infores:hetionet CAID:CA6748669 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748669 MONDO:0009861 PMID:12765842PMID:26210745 Uncertain Significance PP4, BS1 PP3, BP7 The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID: 12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748669/MONDO:0009861/006 2019-09-27 2019-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7936 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020676 infores:hetionet UMLS:C0657912 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085595 infores:hetionet CHEBI:15367 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003962 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0234916 infores:hetionet CHEBI:8212 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0085631 infores:hetionet CHEBI:2636 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0020538 infores:hetionet CHEBI:6931 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0018944 infores:hetionet CHEBI:9649 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0015672 infores:hetionet CHEBI:9943 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151692 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042373 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042769 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0012833 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0948594 infores:hetionet CAID:CA16020891 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020891 MONDO:0009861 PMID:29499199 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 PM5 The c.910C>A (p.Gln304Lys) variant in PAH has been reported in at least one individual with PKU (BH4 deficiency ruled out) (PMID: 29499199, 26503515, 30050108) in trans with pathogenic variant p.R261*. The p.Gln304Lys variant is absent from gnomAD and the ESP population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.973. Another missense change at the same codon has been reported (p.Gln304Arg), however with unknown pathogenicity. Overall, the c.910C>A variant is classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020891/MONDO:0009861/006 2019-12-08 2021-05-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0007971 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0041969 infores:hetionet CHEBI:49040 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0206062 infores:hetionet CHEBI:16469 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007286 infores:hetionet CHEBI:5558 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0036974 infores:hetionet CHEBI:66964 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0011603 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0234215 infores:hetionet CHEBI:72690 biolink:causes MONDO:0001577 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0035235 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0948594 infores:hetionet GO:1905310 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0072359 CHEBI:9137 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085593 infores:hetionet GO:0060251 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060251 GO:0007275 GO:1905273 biolink:causes GO:0015986 infores:ubergraph knowledge_assertion manual_agent GO:1905273 GO:0015986 CHEBI:10101 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0740394 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0853813 infores:hetionet NCBIGene:498 biolink:causes MONDO:0957254 infores:monarchinitiative not_provided not_provided HGNC:823 MONDO:0957254 uuid:8ed6805b-8596-4404-9451-684a0028ec87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31401 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0264893 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0036572 infores:hetionet CHEBI:5128 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0001824 infores:hetionet CHEBI:7915 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018681 infores:hetionet CHEBI:6847 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0018681 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0021053 infores:hetionet CHEBI:2955 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0037278 infores:hetionet CHEBI:4779 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0035455 infores:hetionet CAID:CA91170412 biolink:causes MONDO:0001586 infores:clingen CAID:CA91170412 MONDO:0001586 PMID: Likely Pathogenic PM3, PM5_Supporting, PS3_Supporting, PP3, PM2_Supporting PS1, PS2, PM6, PP1, PP4 The NM_000203.5:c.1487C>T variant in IDUA is a missense variant predicted to cause substitution of proline by leucine at amino acid 496, p.(Pro496Leu). This variant has been reported to account for 0.65% of disease-causing alleles in individuals with MPS I (PMIDs: 28752568, 7550232, 18463126). At least two probands have been reported to be compound heterozygous, phase not confirmed, for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (PMID:18463126, 28752568). Another patient has been reported who is compound heterozygous for the variant and c.223G>A (p.Ala75Thr) (PMID: 7550232). The allelic data for this patient will be used in the classification of p.Ala75Thr and is not included here to avoid circular logic (PM3 applied; insufficient evidence to apply PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000012 (1/80558 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When the variant was expressed in Cos-1 cells, IDUA activity was absent (PMID: 7550232) (PS3_Supporting). Computational predictor tools (REVEL score 0.647) suggest that this variant may be deleterious to IDUA function (PP3). In addition, a different missense variant, c.1487C>G (p.Pro496Arg) [ClinVar Variation ID 496861] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen LD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 551675). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PS3_Supporting, PM2_Supporting, PM3, PM5_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA91170412/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020649 infores:hetionet CHEBI:4784 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0035243 infores:hetionet CHEBI:7986 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0038999 infores:hetionet CHEBI:8888 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151908 infores:hetionet CHEBI:31980 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0039231 infores:hetionet CHEBI:3568 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151907 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0031350 infores:hetionet CHEBI:4858 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0015230 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0852733 infores:hetionet CHEBI:70735 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0162298 infores:hetionet NCBIGene:147007 biolink:causes MONDO:0014790 infores:monarchinitiative not_provided not_provided HGNC:18085 MONDO:0014790 uuid:b9ecf16b-3aee-404b-89cc-9f9d87eb472f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042109 infores:hetionet CHEBI:9445 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0025320 infores:hetionet CAID:CA367396716 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396716 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1398A>G variant in the glucokinase gene, GCK, causes an amino acid change at the stop codon of the final exon (10/10), resulting in the addition of 144 amino acids at the end of the protein (p.(Ter466ArgextTer144)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history consistent with GCK-hyperglycemia, but there was insufficient clinical data to evaluate for PP4 (internal lab contributors). Taken together, this evidence supports the classification of this variant as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: PVS1, PM2_Supporting. (Specification version 1.2.0, approved 6/7/23) Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396716/MONDO:0015967/086 2023-08-10 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:6715 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040264 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0023890 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0162820 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0439857 infores:hetionet NCBITaxon:138 biolink:causes MONDO:0019633 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:138 MESH:D012061 DB00254_MESH_D012061_1DB00595_MESH_D012061_1DB00759_MESH_D012061_1DB01017_MESH_D012061_1DB13092_MESH_D012061_1DB02703_MESH_D012061_1DB00618_MESH_D012061_1 CHEBI:6950 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017675 infores:hetionet CAID:CA157198 biolink:causes MONDO:0700270 infores:clingen CAID:CA157198 MONDO:0700270 PMID: Uncertain Significance PP3, BP2_Strong BA1, BS1, PM2 The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA157198/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50859 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0032617 infores:hetionet CHEBI:80630 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0037763 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0314719 infores:hetionet CHEBI:16469 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0026821 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0151865 infores:hetionet CHEBI:4315 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0019825 infores:hetionet GO:2000733 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0072028 PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0037763 infores:hetionet CHEBI:63607 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0004093 infores:hetionet GO:1903593 biolink:causes GO:0043303 infores:ubergraph knowledge_assertion manual_agent GO:1903593 GO:0043303 CHEBI:3223 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0231218 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0858277 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0858277 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013687 infores:hetionet CHEBI:18358 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0151908 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0043241 infores:hetionet CHEBI:36704 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0235996 infores:hetionet CHEBI:3756 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018834 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042769 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0853692 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0022568 infores:hetionet CHEBI:27899 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0030193 infores:hetionet NCBIGene:25885 biolink:causes MONDO:0014651 infores:monarchinitiative not_provided not_provided HGNC:17264 MONDO:0014651 uuid:e0e93dea-2b11-4e26-83ab-4393a5360424 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8428 biolink:causes HP:0006671 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0030587 infores:hetionet CAID:CA1251296 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251296 MONDO:0013144 PMID: Benign BS2_Supporting, BP7, BA1, BP4 The variant is reported at a popmax FAF of 0.7651 and the highest MAF of 0.7792 (78%; 19440/24948 alleles with 7592 homozygotes) in the African/African-American population in gnomAD v2.1.1, meeting criteria for BA1 (MAF >0.002). The variant is reported in 1 individual with normal antithrombin levels. SpliceAI and VarSeak predict no impact on splicing and PhyloP gives a conservation score of 0.028 (<0.1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BS2_Supporting, BP4, BP7. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251296/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135342 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0011253 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020039 infores:hetionet CHEBI:7447 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0030312 infores:hetionet UMLS:C1738934 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0008031 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235234 infores:hetionet CHEBI:4702 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0004093 infores:hetionet CHEBI:3561 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0231218 infores:hetionet CHEBI:31981 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0043094 infores:hetionet CHEBI:73274 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C1519353 infores:hetionet CHEBI:6897 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0428977 infores:hetionet CHEBI:8212 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0241442 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0332575 infores:hetionet CHEBI:52172 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0023530 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013395 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0013922 infores:hetionet UMLS:C0657912 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022638 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009806 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017178 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0034069 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0242151 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042075 infores:hetionet GO:1903689 biolink:causes GO:0090505 infores:ubergraph knowledge_assertion manual_agent GO:1903689 GO:0090505 CHEBI:84500 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020517 infores:hetionet CHEBI:8327 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0042384 infores:hetionet CAID:CA250636 biolink:causes MONDO:0021060 infores:clingen CAID:CA250636 MONDO:0021060 PMID: Pathogenic PS3, PS2, PM1, PM6, PM2, PP3, PP2, PS4_Supporting PM5 The c.1391G>A (p.Gly464Glu) variant in BRAF has been observed in 2 probands with phenotypes consistent with cardiofaciocutaneous syndrome (PS4_Supporting; LMM internal data, SCV000197160.4; GeneDx internal data, SCV000057209.13). One of these cases was de novo with maternity and paternity confirmed, while the other was de novo without confirmation of maternity or paternity (PS2, PM6). The p.Gly464Glu variant was absent from large population studies (PM2; gnomad.broadinstitute.org). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 25155755). It occurs in the P-loop domain of the protein, which has been identified as an important region for protein function (PM1; 29493581). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein (PP3). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied: PS2, PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA250636/MONDO:0021060/004 2020-03-09 2020-03-09 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8461 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0041657 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0836924 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0032285 infores:hetionet CHEBI:49960 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C3665347 infores:hetionet UNII:U6XF9NP8HM biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0547030 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0012797 infores:hetionet CHEBI:16335 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0220870 infores:hetionet CHEBI:2955 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0004093 infores:hetionet CHEBI:48538 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0041657 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151905 infores:hetionet CHEBI:7443 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0004093 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0234913 infores:hetionet CHEBI:3515 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0232462 infores:hetionet CHEBI:27565 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C1291077 infores:hetionet CHEBI:8764 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020473 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0027765 infores:hetionet CHEBI:37924 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0009676 infores:hetionet CHEBI:119573 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0023066 infores:hetionet CHEBI:84500 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0040460 infores:hetionet CHEBI:42068 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0854467 infores:hetionet CAID:CA170275 biolink:causes MONDO:0010726 infores:clingen CAID:CA170275 MONDO:0010726 PMID: Likely Benign BP5, BS2 PP3, PP4 The c.225G>A (p.Pro75=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The c.225G>A (p.Pro75=) variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the c.225G>A (p.Pro75=) variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170275/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:231594 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0020624 infores:hetionet CHEBI:44915 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0009946 infores:hetionet CHEBI:5141 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0085610 infores:hetionet CAID:CA270173029 biolink:causes MONDO:0012996 infores:clingen CAID:CA270173029 MONDO:0012996 PMID: Benign BA1, BP4 The NM_001482.3:c.288+184_288+195del variant in GATM is an intronic variant which deletes 12 nucleotides in intron 2. The highest population minor allele frequency in gnomAD v2.1.1, in a population with >2000 alleles, is 0.8333 (7205/8646 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 680743). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0: BA1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA270173029/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151828 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0023418 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0855237 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0855237 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0221714 infores:hetionet CHEBI:49668 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0033687 infores:hetionet CAID:CA1670972946 biolink:causes MONDO:0013144 infores:clingen CAID:CA1670972946 MONDO:0013144 PMID: Pathogenic PS2, PP4, PS4_Supporting, PM2_Supporting, PVS1 The c.280_283del (p.Phe94IlefsTer19) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 2/7 and expected to result in nonsense-mediated mRNA decay (PVS1). The variant is absent from gnomADv2.1.1 and v3.1.1 (PM2_Supporting). One proband reported in PMID: 22116592 meets SERPINC1 phenotype criteria with AT activity = 50% and AT antigen = 46% on repeat testing (PS4_Supporting). The variant in this proband is de novo with paternity and maternity confirmed (PS2). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PVS1, PS2, PM2_Supporting, PS4_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1670972946/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6067 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018772 infores:hetionet CHEBI:66919 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0151699 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C2748362 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C2748362 infores:hetionet CHEBI:63620 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018926 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151785 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1141885 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1141885 infores:hetionet CHEBI:5959 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0040822 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020615 infores:hetionet CHEBI:7444 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0022107 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0040586 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0024894 infores:hetionet CHEBI:135876 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0028734 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0877398 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0877398 infores:hetionet CAID:CA376065954 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065954 MONDO:0011225 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Strong PS1, PS3, PM5 The c.47T>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Isoleucine by Tryptophan at amino acid 16 (p.Ile16Thr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting).Activity levels in % of WT activity = Recombination: Mean (SD): 79.67 (0.27) and DNA repair (36h after IR): Mean (SD): 80.11 (18.11). The results are bigger than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is NOT Met (PMID: 25917813).At least one patient with this variant displayed Diagnostic criteria for SCID: 0.5pts + T-B-NK+ lymphocyte subset profile: 0.5 pts + Increased cellular radiosensitivity: 0.5pts = Total 1.5 pts, PP4 met, which is highly specific for SCID (PP4 Met) PMIDs: 15770702 and 25917813.Not reported in the literature, but this variant was identified in one patient at Invitae with a clinical diagnosis of SCID (0.5 pts) + a 207 genes immunodeficiency panel ordered, which included all known SCID genes (0.5 points) + severe T and B cell lymphopenia with normal NK cells (CD3: 13, CD19: 0, CD56: 753), consistent with T-B-NK+ SCID (0.5 pts) = totalizing 1.5 pts, PP4 met.Patient 5 is a compound heterozygous with S119X (Pathogenic according to the SCID VCEP specifications, 1 pt, PM3 Met. PMID: 15770702).Not reported in the literature, but this variant was identified in one patient at Invitae with a clinical diagnosis of SCID. In this patient, the variant co-occurred - in trans - confirmed by parental testing - with DCLRE1C deletion (Exons 1-3), pathogenic according to the SCID VCEP specifications: 1 pt.Total: 1+1: 2 pts, PM3_Strong.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM3_Strong, PM2_supporting, PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065954/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:55012 biolink:causes MONDO:0032738 infores:monarchinitiative not_provided not_provided HGNC:17485 MONDO:0032738 uuid:82fd603d-ee9b-4a83-a569-44f0116fbed6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0029456 infores:hetionet CAID:CA412737582 biolink:causes MONDO:0100437 infores:clingen CAID:CA412737582 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PP4, PS4 NM_001034853.2(RPGR):c.1561C>T (p.Gln521Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 521 within exon 13 of 15 that is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through an affected mother and son from 1 family (PP1; PMID: 34745198). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts) with a female showing milder phenotype, childhood-onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), myopia (0.5 pts), and genetic testing by exome sequencing finding no alternative explanation for retinal disease (2 pts), however no electroretinogram results were reported, so the PP4 code was not met (7.5 points, PMID: 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412737582/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports CHEBI:41977 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0023895 infores:hetionet CHEBI:7496 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0042963 infores:hetionet CHEBI:63608 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0234428 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0241075 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0241075 infores:hetionet CAID:CA2573135907 biolink:causes MONDO:0015152 infores:clingen CAID:CA2573135907 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.5181del p.(Glu1727AspfsTer7) variant in DYSF, which is also known as NM_001130987.2: c.5298del (p.Glu1766AspfsTer7), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 46/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least two individuals with clinical signs of limb girdle muscular dystrophy, including in a homozygous state (0.5 pts, PMID: 29970176) and confirmed in trans with a likely pathogenic or pathogenic variant (c.1668_1669insGTT p.(Leu556_Leu557insVal), 1.0 pt, PMID: 36983702) (PM3). At least one patient with this variant displayed progressive weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702). The highest population minor allele frequency is 0.0000008474 (1/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573135907/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C3665347 infores:hetionet CHEBI:7823 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0233571 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0020443 infores:hetionet CHEBI:42797 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151825 infores:hetionet CHEBI:5098 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0439857 infores:hetionet NCBIGene:1316 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:2235 MONDO:0001056 uuid:5332992f-df35-49b7-bdba-3f9f58f406e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes UMLS:C0855625 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0855625 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0243026 infores:hetionet NCBIGene:125170 biolink:causes MONDO:0033569 infores:monarchinitiative not_provided not_provided HGNC:17920 MONDO:0033569 uuid:106a6ef3-8757-4a28-b12c-a5841ceebd98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes UMLS:C0241832 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0241832 infores:hetionet NCBIGene:2243 biolink:causes MONDO:0014452 infores:monarchinitiative not_provided not_provided HGNC:3661 MONDO:0014452 uuid:5a40fba6-40b2-4b10-b819-38e3cf47de69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0008370 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0039503 infores:hetionet CHEBI:9449 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0008031 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020676 infores:hetionet CHEBI:74947 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014591 infores:hetionet CHEBI:9586 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C3263723 infores:hetionet CHEBI:3655 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0232459 infores:hetionet CHEBI:110423 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0009782 infores:hetionet CHEBI:6887 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0030193 infores:hetionet CHEBI:8874 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085632 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0853149 infores:hetionet CHEBI:7798 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0021051 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0162429 infores:hetionet CAID:CA412744489 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744489 MONDO:0100437 PMID: Pathogenic PP3_Strong, PM2_Supporting, PS4_Moderate, PP1_Strong PVS1, PP4, PM4, PM5, PS1, BA1, BP4, BP3, BP2, BS1, BP7 NM_001034853.2(RPGR):c.592G>A (p.Gly198Arg) is a missense variant encoding the substitution of glycine by arginine at amino acid 198. Another missense variant in the same codon, NM_001034853.2:c.593G>A (p.Gly198Glu) (PMIDs: 18552978, 32821524, 36460718), is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked IRD VCEP specifications, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (125) than the comparison variant (98); however, SpliceAI predicts that c.593G>A (p.Gly198Glu) does not impact splicing, whereas the present variant may impact splicing and may therefore have an additional mechanism for causing disease. Therefore, the PM5 code has not been applied. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 4 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses (PMID: 34985506, PMID: 31456290, personal communication with clinical labs, PS4_Moderate). The variant has also been reported in additional probands with vision abnormalities but insufficient clinical details available to count for the PS4 code (PMID: 31456290, PMID: 32531858). The variant has been reported to segregate with retinal dystrophy through at least 10 affected meioses total from 2 families (PMID: 31456290, PP1_Strong). The computational predictor REVEL gives a score of 0.988, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_Strong). Additionally, the splicing impact predictor SpliceAI gives delta scores of 0.47 and 0.20 for donor loss and donor gain, respectively, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PP1_Strong, PP3_Strong, PS4_Moderate, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744489/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:4903 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0232849 infores:hetionet CHEBI:7465 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0011991 infores:hetionet CHEBI:10023 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002994 infores:hetionet CHEBI:51450 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0149745 infores:hetionet CHEBI:4798 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235996 infores:hetionet CAID:CA512341217 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341217 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS1, PS4, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1218C>T (p.Tyr406=) is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4). However, evolutionary conservation algorithms predict the site as being conserved (PhyloP score = 2.86701 in GRCh38) (BP7 not applied). This variant is absent from gnomAD v2 and v3 (PM2_supporting). In summary, this variant meets the criteria to be classified as a VUS for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341217/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0034882 infores:hetionet CAID:CA175533 biolink:causes MONDO:0019501 infores:clingen CAID:CA175533 MONDO:0019501 PMID: Uncertain Significance BP7, BP5, BS1, BS4, BS3, PP2, PP3, PP4, PP1, BS2, PM1, PM3, PM4, PM5, PM2, PM6, PVS1, BA1, BP1, BP4, BP2, BP3, PS2, PS4, PS3, PS1 The NM_022124.6:c.9566G>A variant in the CDH23 gene is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 3189 (p.Arg3189Gln). This variant has been identified in 1 heterozygous patient with sensorineural hearing loss (Partners LMM internal data, SCV000197429.4). The highest population minor allele frequency of the variant is 0.023% (7/30430) of South Asian alleles in gnomAD v.2.1.1, which does not meet any of the criteria for PM2_P, BA1, and BS1. The REVEL computational prediction analysis tool produced a score of 0.683 which does not meet the criteria for PP3. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: None (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA175533/MONDO:0019501/005 2023-01-18 2023-02-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:9123 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C2242737 infores:hetionet CHEBI:31547 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0026858 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027947 infores:hetionet CHEBI:78543 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0000731 infores:hetionet NCBIGene:124583 biolink:causes MONDO:0054680 infores:monarchinitiative not_provided not_provided HGNC:19721 MONDO:0054680 uuid:b614e216-59ff-4896-82a5-4b5ee8d175d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085615 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0424000 infores:hetionet CHEBI:8364 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0233494 infores:hetionet CAID:CA410204321 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204321 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.100G>A (p.Ala34Thr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.345) and a SpliceAI score ≤0.20 (0.09) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204321/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10603798 biolink:causes MONDO:0015152 infores:clingen CAID:CA10603798 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_000070.3: c.1322del p.(Gly441ValfsTer22) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least six patients with clinical features consistent with LGMD2A (PMID: 15689361, 26501342, 25135358, 17702496, 17236769, 15733273), including in unconfirmed phase with a pathogenic variant in at least three patients (c.2362-2363delinsTCATCT, 0.5 pts, PMID: 15689361; c.550del, 0.5 pts x2, PMID: 17702496, 15733273) (PM3). At least one patient with this variant and a second presumed diagnostic CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 15733273; PP4_Strong). The upper bound of the 95% confidence interval (95% CI) of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000008921 (5/1178404 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/07/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603798/MONDO:0015152/187 2025-10-07 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0025241 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0022346 infores:hetionet CHEBI:135939 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0018681 infores:hetionet CHEBI:31302 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0151786 infores:hetionet CHEBI:35854 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0025323 infores:hetionet CHEBI:3479 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0014742 infores:hetionet CHEBI:6402 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0239571 infores:hetionet CHEBI:2636 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0008031 infores:hetionet CHEBI:8024 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0085593 infores:hetionet CHEBI:68554 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0035222 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0034150 infores:hetionet CHEBI:134966 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0027497 infores:hetionet CHEBI:2682 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235886 infores:hetionet CHEBI:6950 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0040038 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0023067 infores:hetionet CHEBI:63611 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0043094 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0541919 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0039240 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003864 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0392197 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005159 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0600139 infores:hetionet CHEBI:50861 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0014591 infores:hetionet NCBIGene:57187 biolink:causes MONDO:0975826 infores:monarchinitiative not_provided not_provided HGNC:19073 MONDO:0975826 uuid:7c934d23-cf0e-4ce3-96e6-95701ca0ac24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94501 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0267792 infores:hetionet CAID:CA658824400 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824400 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.4:c.719del (p.Pro240fs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). The variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 28659335, 27210295). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824400/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:681848 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0018681 infores:hetionet CAID:CA254258 biolink:causes MONDO:0017623 infores:clingen CAID:CA254258 MONDO:0017623 PMID: Pathogenic PVS1, PM6, PM2, PS4_Supporting PTEN c.40dupA (p.R14Kfs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 10777358)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 10777358) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA254258/MONDO:0017623/003 2018-04-06 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3872 biolink:causes MONDO:0008174 infores:monarchinitiative not_provided not_provided HGNC:6427 MONDO:0008174 uuid:e1cd3640-bddc-46c9-8bb4-c53a73a0f29a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0039231 infores:hetionet CHEBI:7601 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0235996 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0033975 infores:hetionet CHEBI:3640 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0162830 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002615 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0043325 infores:hetionet CHEBI:63605 biolink:causes HP:0007141 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1112256 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000749 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151463 infores:hetionet CHEBI:71219 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0086565 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0000833 infores:hetionet CHEBI:2208 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0006840 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1619712 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0034065 infores:hetionet GO:1904967 biolink:causes GO:0045143 infores:ubergraph knowledge_assertion manual_agent GO:1904967 GO:0045143 CHEBI:10101 biolink:causes UMLS:C0744369 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0744369 infores:hetionet CHEBI:28864 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0004096 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0018802 infores:hetionet CHEBI:71219 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0010200 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0235969 infores:hetionet CHEBI:5138 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020625 infores:hetionet CHEBI:8499 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0035243 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004936 infores:hetionet UMLS:C1738934 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037763 infores:hetionet CHEBI:9137 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013390 infores:hetionet CAID:CA412730514 biolink:causes MONDO:0100437 infores:clingen CAID:CA412730514 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2491G>T (p.Glu831Ter) is a nonsense variant introducing a premature stop in codon 831 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 5 years (1 pt), reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with pigment deposits (0.5 pts), optic disc pallor (0.5 pts), severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412730514/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:8499 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0851341 infores:hetionet CHEBI:8863 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031154 infores:hetionet CHEBI:5613 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C1443060 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1868771 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1868771 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0036572 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0029408 infores:hetionet CHEBI:2611 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0022107 infores:hetionet CHEBI:47499 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0020565 infores:hetionet GO:0075030 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0075030 GO:0009653 CHEBI:5103 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0020578 infores:hetionet CAID:CA002547 biolink:causes MONDO:0018875 infores:clingen CAID:CA002547 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PP3_Moderate, BS2_Supporting, PM2_Supporting BA1, BP4, BP2, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BP5, BS1, BS4, PM6, PP1, PP4 The NM_000546.6:c.461G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 154 (p.Gly154Asp). This variant received a total of 0.5 points in 1 proband. (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal data contributor). This variant has an allele frequency of 0.000001859 (3/1614164 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.2733; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, PM2_supporting, BS3_Supporting, PP3_moderate. (Bayesian Points: 1; VCEP specifications version 2.2; 2/6/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002547/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:9241 biolink:causes MONDO:0008519 infores:monarchinitiative not_provided not_provided HGNC:7866 MONDO:0008519 uuid:80d39a9a-40fa-470e-9a28-5f341bf8f3b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4885 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0033975 infores:hetionet CHEBI:28748 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0028734 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006370 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0152029 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0858794 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0858794 infores:hetionet CHEBI:7577 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0043144 infores:hetionet CHEBI:71219 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151701 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0043352 infores:hetionet NCBIGene:1144 biolink:causes MONDO:0014583 infores:monarchinitiative not_provided not_provided HGNC:1965 MONDO:0014583 uuid:6a57f553-76ef-4583-ba5e-b96b1a08636d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0033975 infores:hetionet CAID:CA410207966 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207966 MONDO:0011071 PMID:26884589PMID:24732596PMID:24732596PMID:26884589PMID:26884589 Likely Pathogenic PM1_Supporting, PS4_Moderate, PM2_Supporting, PP3, PP1 PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM5, PM4, PM3, BS2, PP2, PP4 The NM_001754.4:c.596G>A (p.Gly199Glu) variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 26884589, 25159113, 24732596; internal laboratory data). The variant was found to co-segregate with disease in multiple affected family members, with three meioses observed across 2 families (PP1; PMID: 26884589, 25159113, 24732596; internal laboratory data). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the non-hot-spot residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.956) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PS4_Moderate, PP1, PP3, PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207966/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50859 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151723 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027092 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0149931 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0267792 infores:hetionet CHEBI:7936 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004509 infores:hetionet CHEBI:6456 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0034880 infores:hetionet CHEBI:421707 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0151662 infores:hetionet CHEBI:31397 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0240211 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0677500 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013395 infores:hetionet CHEBI:3723 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042420 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004169 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0376356 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0008370 infores:hetionet CAID:CA512341322 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341322 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1080C>T (p.Val360=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341322/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27899 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C2717961 infores:hetionet CAID:CA409118267 biolink:causes MONDO:0007064 infores:clingen CAID:CA409118267 MONDO:0007064 PMID: Uncertain Significance PVS1_Moderate, PS1_Moderate, PM2_Supporting BS2 The c.1078+2T>C (NM_000022.4) variant in ADA occurs within the canonical splice donor site (+2) of intron 11. It is predicted to cause skipping of biologically relevant exon by SpliceAI (Δ score = Donor Loss = 0.96); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; Variant removes <10% of protein. PVS1_Moderate. This variant is absent from gnomAD v.4 (PM2_Supporting). The intronic change (c.1078+2T>A) is classified as Likely Pathogenic for ADA-SCID by the ClinGen SCID VCEP (PS1_Moderate).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Moderate, PM2_Supporting, and PS1_Modetate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409118267/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2663 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0014457 infores:hetionet CHEBI:10127 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0015967 infores:hetionet CHEBI:5147 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0030252 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027441 infores:hetionet CHEBI:2038 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0600228 infores:hetionet CHEBI:4868 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0040034 infores:hetionet CHEBI:50659 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0206062 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0037268 infores:hetionet CHEBI:119486 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0012569 infores:hetionet CHEBI:3756 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0006277 infores:hetionet CHEBI:6832 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0028738 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0149836 infores:hetionet CHEBI:17303 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011206 infores:hetionet CAID:CA414816093 biolink:causes MONDO:0044970 infores:clingen CAID:CA414816093 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting PP1, PM6 The m.13051G>A (p.G239S) variant in MT-ND5 has been reported in thirteen individuals with primary mitochondrial disease from four kindreds (PS4_moderate; PMIDs: 12736867, 27164671). Age of onset varied from age 18 months to the 40s, and clinical features were consistent with Leber Hereditary Optic Neuropathy (LHON) and Leigh syndrome spectrum disorders, in addition to hearing loss, optic atrophy, retinal dystrophy, ophthalmoplegia, and seizures. Several individuals had elevated lactate levels. The variant was present at or near homoplasmy in all reported individuals, thus precluding consideration for segregation evidence. There are no reports of confirmed de novo occurrences to our knowledge. This variant is absent in the GenBank dataset and gnomAD v3.1.2, however there were three heteroplasmic occurrences in the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.71 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Comprehensive analysis in patient cells showed increased reactive oxygen species and increased mitophagy (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner, although this Expert Panel notes this is a very compelling variant of uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414816093/MONDO:0044970/015 2023-05-23 2024-07-23 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:408174 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0917801 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027769 infores:hetionet CHEBI:142290 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0085593 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0948594 infores:hetionet CHEBI:9943 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151474 infores:hetionet CHEBI:17303 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233477 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0220981 infores:hetionet CHEBI:499361 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0546884 infores:hetionet CAID:CA128829 biolink:causes MONDO:0044970 infores:clingen CAID:CA128829 MONDO:0044970 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting PS3 The m.5816A>G variant in MT-TC has been reported in two unrelated families with primary mitochondrial disease (PS4_supporting; PMIDs: 17724295, 37771542). The first reported family had four affected individuals with variable clinical features including dystonia, seizures, tremor, fatigue, ptosis, pigmentary retinopathy, and optic atrophy. Muscle biopsies in these family members showed mosaic COX deficiency, normal respiratory chain enzyme activities, and decreased steady state levels of mt-tRNA Cys. The variant was homoplasmic in muscle and blood in these individuals (PMID: 17724295). The second family reported had one affected individual, a girl, with dystonia, episodic vomiting, motor regression, tremor, and seizures. Skin fibroblast testing showed reduced basal resting oxygen consumption rate (OCR), ATP production, proton leak, maximal respiration, and reserve capacity OCR. The variant was present in blood and urine but heteroplasmy levels were not reported (PMID: 37771542). The variant was present in additional family members of this second family however phenotypes and heteroplasmy levels were not reported. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (59.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA128829/MONDO:0044970/015 2024-04-23 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5106 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0086543 infores:hetionet CAID:CA267662 biolink:causes MONDO:0009861 infores:clingen CAID:CA267662 MONDO:0009861 PMID:18299955PMID:18299955 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.591G>C (p.Leu197Phe) variant in PAH has been reported in 3 individuals with classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 18299955). This variant is absent in population databases (PM2). This variant was detected with a pathogenic variant (c.168+1G>A) and twice in the homozygous state (PM3). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen2, MutationTaster, REVEL=0.82). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267662/MONDO:0009861/006 2019-05-04 2019-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50924 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0518015 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0002170 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0007785 infores:hetionet UMLS:C0011701 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0013404 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0035078 infores:hetionet CHEBI:50648 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0035410 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0339916 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0233494 infores:hetionet CHEBI:3499 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0042109 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0003123 infores:hetionet CHEBI:180905 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0520888 infores:hetionet CHEBI:2682 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232292 infores:hetionet CHEBI:51137 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0023380 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0007785 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0016436 infores:hetionet CHEBI:39867 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C3665386 infores:hetionet CAID:CA10385660 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385660 MONDO:0100437 PMID: Likely Benign BS1 BP4, BP7 NM_001034853.2(RPGR):c.444A>T (p.Gly148=) is a synonymous variant in codon 148. This variant is present in gnomAD v4.1.0 at a frequency of 0.00002514 among hemizygous individuals, with 10 variant alleles / 397,811 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.14 for donor gain, which falls within the intermediate range above the ClinGen X-linked IRD VCEP recommended BP4 threshold of <0.1 but below the PP3 threshold of >0.2, so neither in silico code was met. In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385660/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:7903 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C2711248 infores:hetionet CHEBI:9763 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0043094 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151828 infores:hetionet CHEBI:28148 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020625 infores:hetionet CHEBI:75988 biolink:causes UMLS:C1963921 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C1963921 infores:hetionet CHEBI:28830 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0030193 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151605 infores:hetionet CHEBI:4511 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0002994 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0853772 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0853772 infores:hetionet CHEBI:5138 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C2937350 infores:hetionet CHEBI:49662 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0042023 infores:hetionet CHEBI:3764 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0010692 infores:hetionet CHEBI:8863 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0022346 infores:hetionet CHEBI:8214 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0036974 infores:hetionet CHEBI:8597 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0033774 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0855242 infores:hetionet CHEBI:4903 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0232461 infores:hetionet CHEBI:6912 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0242422 infores:hetionet CHEBI:3568 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0520888 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0037195 infores:hetionet CHEBI:10119 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0028734 infores:hetionet CHEBI:6375 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0344232 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0276680 infores:hetionet CHEBI:31705 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0015230 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1510472 infores:hetionet CHEBI:63618 biolink:causes UMLS:C1142028 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C1142028 infores:hetionet CHEBI:31176 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0030232 infores:hetionet CHEBI:28593 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0018790 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0409974 infores:hetionet CHEBI:41977 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011570 infores:hetionet CHEBI:63577 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0009676 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0235318 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235318 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0178298 infores:hetionet CHEBI:8874 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009421 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0042373 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0854082 infores:hetionet CHEBI:6367 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018926 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0314719 infores:hetionet CHEBI:6339 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151610 infores:hetionet CHEBI:50692 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0006145 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0233494 infores:hetionet CHEBI:27974 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0476089 infores:hetionet CHEBI:71941 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0340865 infores:hetionet CHEBI:100241 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151636 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2225524 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020621 infores:hetionet CHEBI:63791 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162529 infores:hetionet CHEBI:3127 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0043094 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0022660 infores:hetionet CHEBI:10101 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0013456 infores:hetionet CHEBI:8774 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0085649 infores:hetionet CHEBI:23765 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0031256 infores:hetionet UMLS:C0011701 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233514 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0034065 infores:hetionet CAID:CA226423 biolink:causes MONDO:0100437 infores:clingen CAID:CA226423 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.485_486del (p.Phe162TyrfsTer4) is a frameshift variant due to a 2-nucleotide deletion resulting in a premature stop codon after 4 amino acids within exon 6 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 17325176, PMID: 32795431; PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including onset in the first or second decade of life (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), visual field constriction (0.5 pts), and myopia (0.5 pts), with a family history consistent with X-linked inheritance (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 26197217, PP4). The variant has been reported to segregate with retinal dystrophy through at least 6 affected meioses from 1 family (PP1_Moderate; PMID: 26197217). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, PM2_Supporting, PP1_Moderate, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226423/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:3001 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0014591 infores:hetionet GO:0010668 biolink:causes CL:0000221 infores:ubergraph knowledge_assertion manual_agent GO:0010668 CL:0000221 CHEBI:4868 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0000768 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0403723 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0403723 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0234215 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0162429 infores:hetionet CHEBI:50861 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0025222 infores:hetionet CHEBI:6933 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0030193 infores:hetionet UMLS:C0657912 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023518 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0001430 infores:hetionet CHEBI:63791 biolink:causes MONDO:0019532 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0272118 infores:hetionet CHEBI:9130 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020578 infores:hetionet CHEBI:9654 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0027497 infores:hetionet CHEBI:3242 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0235546 infores:hetionet CHEBI:3761 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0040822 infores:hetionet CHEBI:78543 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0022346 infores:hetionet CHEBI:64317 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0030232 infores:hetionet CHEBI:68478 biolink:causes MONDO:0100193 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0745744 infores:hetionet CHEBI:42797 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0043352 infores:hetionet CHEBI:5088 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0009676 infores:hetionet CHEBI:3310 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0013604 infores:hetionet CHEBI:49668 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0019079 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0178298 infores:hetionet CHEBI:17688 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0041657 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0035333 infores:hetionet CHEBI:5147 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C1262144 infores:hetionet NCBIGene:93426 biolink:causes MONDO:0014844 infores:monarchinitiative not_provided not_provided HGNC:28852 MONDO:0014844 uuid:08973960-f2dc-4864-b8d2-58a9cc26d2b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0039070 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0860155 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0860155 infores:hetionet CHEBI:474053 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0232493 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0007222 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0392162 infores:hetionet CHEBI:63598 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0392525 infores:hetionet CHEBI:63619 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0428977 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0543467 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0277884 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0235063 infores:hetionet CAID:CA386959470 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959470 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PM5, PP3, PP4 The c.395A>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to valine at codon 132 (p.(Glu132Val)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result nearly 50%, negative genetic testing for HNF4A, negative antibodies, and 3 generation family history of diabetes) (PP4; internal lab contributors). Another missense variant, c.394G>A p.Glu132Lys, has been classified as pathogenic by the ClinGen MDEP, and p.Glu132Asp has a greater Grantham distance. In summary, c.395A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1, PM5, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959470/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27796 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0151818 infores:hetionet CHEBI:5118 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002390 infores:hetionet CHEBI:182080 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0036974 infores:hetionet CAID:CA400025655 biolink:causes MONDO:0100326 infores:clingen CAID:CA400025655 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3 The c.961A>C variant in ITGB3 is a missense variant predicted to cause substitution of Methionine by Leucine at amino acid 321 (p.Met321Leu). At least one patient (Patient 3 in PMID: 15748237) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0%, as measured by flow cytometry and Western blot (PP4_Moderate). This patient was homozygous for the variant (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PM3_Supporting and PM2_Supporting (PD-VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400025655/MONDO:0100326/011 2023-09-07 2023-09-08 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:36795 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013362 infores:hetionet NCBIGene:2027 biolink:causes MONDO:0013046 infores:monarchinitiative not_provided not_provided HGNC:3354 MONDO:0013046 uuid:5fea6f4c-cff7-4a62-a290-53b93f715ea3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17263 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0149741 infores:hetionet CHEBI:45599 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0015230 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0015397 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0853028 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0853028 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0233494 infores:hetionet CHEBI:28901 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0235031 infores:hetionet CHEBI:585948 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0009676 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0003123 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0234458 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0241379 infores:hetionet NCBIGene:84131 biolink:causes MONDO:0020778 infores:monarchinitiative not_provided not_provided HGNC:25740 MONDO:0020778 uuid:dbb9873f-31b9-447f-af99-24537885315b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0037274 infores:hetionet NCBIGene:5331 biolink:causes MONDO:0030074 infores:monarchinitiative not_provided not_provided HGNC:9056 MONDO:0030074 uuid:b5f5cb4f-d336-46f3-9bef-e04b0caa438c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8228 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0042571 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0746883 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0302295 infores:hetionet CHEBI:51164 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C1443060 infores:hetionet CHEBI:17688 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0030252 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0011849 infores:hetionet CHEBI:63577 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0149745 infores:hetionet CAID:CA16607615 biolink:causes MONDO:0012589 infores:clingen CAID:CA16607615 MONDO:0012589 PMID:28726809PMID:23033978PMID:28726809PMID:23033978PMID:23033978PMID:28726809 Pathogenic PS3_Supporting, PM1, PP3, PP4, PS2_Very Strong, PM2_Supporting, PS4_Supporting The p.Arg576Gln variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Pitt-Hopkins syndrome (PMID 23033978, 28726809) (PS2_VS, PS4_supporting, PP4). The p.Arg576Gln variant in TCF4 is absent from gnomAD (PM2_supporting). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). The p.Arg576Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg576Gln variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2_VS, PM1, PS4_supporting, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607615/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:63605 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0243026 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0549410 infores:hetionet CHEBI:5855 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018926 infores:hetionet NCBIGene:27102 biolink:causes MONDO:0030036 infores:monarchinitiative not_provided not_provided HGNC:24921 MONDO:0030036 uuid:f59cba6e-bee6-42c7-8111-04f564031224 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0015397 infores:hetionet NCBIGene:56984 biolink:causes MONDO:0030931 infores:monarchinitiative not_provided not_provided HGNC:24929 MONDO:0030931 uuid:e6e5b84b-32f6-4ba5-ab56-e2e05085a303 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0205204 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0948594 infores:hetionet CHEBI:8024 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0022346 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0006145 infores:hetionet CHEBI:180905 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0085682 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027651 infores:hetionet CHEBI:184555 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0267596 infores:hetionet NCBIGene:79147 biolink:causes MONDO:0013157 infores:monarchinitiative not_provided not_provided HGNC:17997 MONDO:0013157 uuid:35d6084f-43c0-4407-baf2-febba0f2b432 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0235710 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0023530 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0023530 infores:hetionet CHEBI:8874 biolink:causes MONDO:0024415 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0341245 infores:hetionet CHEBI:30830 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0232462 infores:hetionet CAID:CA2573051047 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051047 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4 The c.1853_1854delTC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 618 (NM_000545.8), adding 30 novel amino acids before encountering a stop codon (p.(Ile618ArgfsTer30). While this variant, located in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two individuals with autosomal dominant, young-onset diabetes. While both had a calculated MODY probability <50% and were not tested for HNF4A, both had hepatocellular adenomas, which are highly specific to HNF1A-MODY (PP4; PMID: 31166087, internal lab contributors). In summary, c.1853_1854delTC meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1_Strong, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051047/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16021325 biolink:causes MONDO:0021056 infores:clingen CAID:CA16021325 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, BS2_Supporting PVS1 The NM_000038.6(APC):c.1042C>T variant in APC is predicted to cause a premature stop codon (p.R348Ter) located between codon 49 and 2645 in biologically relevant exon 10 (coding exon 9) in a gene in which loss-of-function is an established disease mechanism. However, based on unpublished RNA analyses from Ambry Genetics, the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) does not consider this variant to be applicable to PVS1. The RNA analyses showed that this variant results in an in-frame aberrant transcript lacking part of exon 10 [r.934_1074del (p.V312_Q358del)]. In addition, an increased expression of a naturally occurring alternative transcript (r.934_1236del (p.V312_Q412del), known as “exon 9a”) was observed relative to controls. The predicted premature stop codon (p.R348Ter) was excluded from both the aberrant and naturally occurring transcripts and might provide a rescue mechanism for this nonsense alteration. The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/251004 alleles), which is lower than the HCCP VCEP threshold 0.00001 for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in three families with a polyposis phenotype, resulting in a total phenotype score of 1.5 points (PS4_Supporting, [PMID: 11754114 and 12007223; CanVIG-UK]). On the other hand, this variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth ≥ 6 healthy individual points in total (BS2_Supporting; [Ambry Genetics, Invitae, UK Biobank, 100,000 Genomes Project]). Due to conflicting evidence, this variant is classified as a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS4_Supporting, PM2_Supporting and BS2_Supporting applied (VCEP specifications version 2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16021325/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C1872203 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0002871 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0233414 infores:hetionet CHEBI:9137 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0340865 infores:hetionet CHEBI:367163 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014591 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0851341 infores:hetionet UNII:D27V6190PM biolink:causes HP:0030947 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0860499 infores:hetionet CHEBI:209807 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0151872 infores:hetionet CHEBI:80630 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0575081 infores:hetionet CAID:CA134672 biolink:causes MONDO:0021060 infores:clingen CAID:CA134672 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.526-8C>A variant in the PTPN11 gene is 0.079% (65/66646) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134672/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:49960 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0004936 infores:hetionet CHEBI:32588 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0018790 infores:hetionet CHEBI:367163 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042721 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0041969 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0007785 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011616 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0031212 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0021167 infores:hetionet CHEBI:8107 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0030794 infores:hetionet CHEBI:34385 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0004604 infores:hetionet NCBIGene:7170 biolink:causes MONDO:0800341 infores:monarchinitiative not_provided not_provided HGNC:12012 MONDO:0800341 uuid:38a7bf44-8543-4906-81de-52a8aad2eccd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0231218 infores:hetionet CHEBI:2668 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0002994 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0151849 infores:hetionet NCBIGene:23155 biolink:causes MONDO:0012363 infores:monarchinitiative not_provided not_provided HGNC:29675 MONDO:0012363 uuid:d69c5008-fd61-4ca3-bbb3-69e74d75529e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6073 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0036974 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040425 infores:hetionet CHEBI:47781 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0026961 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0038358 infores:hetionet NCBIGene:23141 biolink:causes MONDO:0014730 infores:monarchinitiative not_provided not_provided HGNC:29101 MONDO:0014730 uuid:aa209261-8ca5-42ea-b7c6-b9753411753d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9460 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0017675 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0036454 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0040479 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004096 infores:hetionet CHEBI:6076 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0016204 infores:hetionet CAID:CA10644629 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644629 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BA1, BP2, BP1, BP3, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM5, PM4, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.*1430C>A is a 3' UTR variant that is not predicted by SpliceAI to impact splicing (BP4). An evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -0.655984 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species. The highest population minor allele frequency (MAF) in gnomAD v4.1 is 0.008143 (370/8596 alleles) in the Ashkenazi Jewish population, but the highest continental population MAF is 0.00008468 (10/118,088 alleles) in the non-Finnish European population, which does not exceed the ClinGen Myeloid Malignancy VCEP threshold (>0.00015) for BS1. The variant has not been reported in the literature. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644629/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:48669 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0004238 infores:hetionet CAID:CA024473 biolink:causes MONDO:0007783 infores:clingen CAID:CA024473 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 165 of the RYR1 protein, p.(Gly165Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).A REVEL score >0.85 (0.957) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024473/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:72690 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020625 infores:hetionet CHEBI:6904 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0235198 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0423273 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0423273 infores:hetionet CHEBI:2788 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0423006 infores:hetionet CHEBI:82866 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0011616 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0015129 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0001403 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0521591 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0018801 infores:hetionet CHEBI:3756 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C2981158 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0403632 infores:hetionet CAID:CA16021002 biolink:causes MONDO:0009861 infores:clingen CAID:CA16021002 MONDO:0009861 PMID:26503515 Uncertain Significance PM2, PP4, PP3 The PAH c.60+5_60+6del variant has been reported once in a PKU case, however without indication of a second in trans variant (PMID: 26503515). This variant is absent from the population database gnomAD and results in deletion of moderately conserved bases in the donor splice site of intron 1. Computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice site. Altogether, there is not enough evidence to classify the c.60+5_60+6del variant with certainty. PAH-specific ACMG/AMP criteria applied: PP4, PP3, PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16021002/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31711 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0000737 infores:hetionet CAID:CA367400569 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400569 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5_Supporting, PP2, PP3, PM2_Supporting, PS3_Moderate PM1 The c.782G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to glutamic acid at codon 261 (p.(Gly261Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in more than 11 unrelated individuals with diabetes/hyperglycemia (PS4; PMID 19358091, 8168652 , internal lab contributors). This variant segregated with diabetes/hyperglycemia with 11 informative meioses in 4 families (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Glu variant has a relative activity index (RAI) of 0, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). Another missense variant, c.781G>A, (p.Gly261Arg), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Gly261Glu​(PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM5_Supporting, PS4, PP1_Strong, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400569/MONDO:0015967/086 2023-08-12 2023-08-12 Semidominant inheritance HP:0032113 Supports CHEBI:6715 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023518 infores:hetionet CHEBI:2618 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0022568 infores:hetionet CAID:CA114123 biolink:causes MONDO:0015629 infores:clingen CAID:CA114123 MONDO:0015629 PMID:20371742 Pathogenic PS2_Supporting, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS3, PS4 PM5 The c.3916C>T (p.Arg1306Trp) variant in VWF has been reported in several dozen vWD type 2B patients (PS4). At least 4 (PMIDs: 1419803, 19740526 and 15041272) have sufficient information reported to meet the PP4_moderate criteria. In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PMID: 20371742). This variant is absent from population databases, including gnomADv4.1 (PM2_supporting). It is predicted deleterious by REVEL which gives a score of 0.769, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant has been observed both de novo (PMID: 1419803; PS2_supporting) and segregating in multiple families (PMID: 15041272 and 1419803; PP1_moderate). In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PS2_supporting, PP1_moderate, PP3, and PP4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114123/MONDO:0015629/081 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:391960 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0015230 infores:hetionet CHEBI:71223 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0004093 infores:hetionet CHEBI:474180 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0016204 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0314719 infores:hetionet CHEBI:145499 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0232462 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0178298 infores:hetionet CHEBI:404903 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0030554 infores:hetionet CHEBI:15640 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0042963 infores:hetionet NCBIGene:58 biolink:causes MONDO:0859523 infores:monarchinitiative not_provided not_provided HGNC:129 MONDO:0859523 uuid:793e35bf-e7c0-4b83-992d-1de092a7bf01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8364 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0035309 infores:hetionet CHEBI:44185 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0232487 infores:hetionet CHEBI:45863 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020598 infores:hetionet CHEBI:3723 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0917801 infores:hetionet CHEBI:7465 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0231218 infores:hetionet CHEBI:49662 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0338614 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0227791 infores:hetionet CHEBI:9150 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0014457 infores:hetionet NCBIGene:55331 biolink:causes MONDO:0044718 infores:monarchinitiative not_provided not_provided HGNC:16066 MONDO:0044718 uuid:ba9098f0-30ef-409e-9f97-b482e9b1d1e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:256297 biolink:causes MONDO:0014406 infores:monarchinitiative not_provided not_provided HGNC:23734 MONDO:0014406 uuid:25609cab-fea0-46ef-b3ce-d25ee374ec08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3510 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0014518 infores:hetionet GO:1903131 biolink:causes CL:0000842 infores:ubergraph knowledge_assertion manual_agent GO:1903131 CL:0000842 CHEBI:50861 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0037199 infores:hetionet CHEBI:68558 biolink:causes UMLS:C3160769 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C3160769 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0009443 infores:hetionet CHEBI:521033 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C2584688 infores:hetionet CHEBI:63791 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0010200 infores:hetionet CHEBI:104011 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C2939147 infores:hetionet CHEBI:3757 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0242429 infores:hetionet CHEBI:9123 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0004093 infores:hetionet CHEBI:52717 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0012569 infores:hetionet CHEBI:50730 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C2973529 infores:hetionet CHEBI:50730 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C1384353 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0856882 infores:hetionet CAID:CA134568 biolink:causes MONDO:0021060 infores:clingen CAID:CA134568 MONDO:0021060 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_002524.5:c.291-8G>A variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008518 (11/129138 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4, BP7. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134568/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:88 biolink:causes MONDO:0012808 infores:monarchinitiative not_provided not_provided HGNC:164 MONDO:0012808 uuid:400db2ab-864b-496f-a686-2a52bc0460f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0004134 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0011630 infores:hetionet CHEBI:39867 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0404521 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0017574 infores:hetionet CHEBI:16899 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0016204 infores:hetionet CHEBI:49713 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020437 infores:hetionet CHEBI:50729 biolink:causes HP:0040088 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0580550 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0947999 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0034150 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0029408 infores:hetionet CHEBI:31205 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0027765 infores:hetionet CHEBI:68478 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0085649 infores:hetionet CAID:CA10014384 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014384 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS3, PS1, PS4, BP2, BA1, PM6, PM2, PVS1, BP7, BS3, BS4, PM1, PM4, PM5, PP3, PP1 The MAF of the synonymous variant, NM_001754.4:c.654C>T (p.Ser218=), is 0.00105 (0.1%, 36/34418 alleles) in the Latino subpopulation of the gnomAD cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This synonymous variant is predicted by SSF and MES to lead to an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014384/MONDO:0011071/008 2019-08-02 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4885 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0013395 infores:hetionet CHEBI:27974 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0000731 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0332534 infores:hetionet CHEBI:161680 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0262662 infores:hetionet CHEBI:85083 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0085593 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0025061 infores:hetionet CHEBI:2673 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0032326 infores:hetionet CHEBI:72564 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0000737 infores:hetionet CHEBI:2675 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0018794 infores:hetionet CHEBI:3757 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0040822 infores:hetionet CHEBI:44915 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020458 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0233472 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0031350 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151514 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0162429 infores:hetionet NCBIGene:7012 biolink:causes MONDO:0007485 infores:monarchinitiative not_provided not_provided HGNC:11727 MONDO:0007485 uuid:666ea592-44f1-4864-8cdb-19d476b2accc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52010 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0002878 infores:hetionet CHEBI:3219 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233565 infores:hetionet CHEBI:64355 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0206062 infores:hetionet CHEBI:64064 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0026821 infores:hetionet CHEBI:5959 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018808 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0427108 infores:hetionet CHEBI:8707 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1456784 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151828 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0027947 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0003864 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027765 infores:hetionet GO:0141127 biolink:causes GO:0032482 infores:ubergraph knowledge_assertion manual_agent GO:0141127 GO:0032482 CHEBI:3752 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0036974 infores:hetionet CHEBI:42797 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151529 infores:hetionet CHEBI:94807 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0020580 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C2363731 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002622 infores:hetionet CHEBI:46195 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0002878 infores:hetionet NCBIGene:991 biolink:causes MONDO:0859521 infores:monarchinitiative not_provided not_provided HGNC:1723 MONDO:0859521 uuid:0eaf62a2-3c35-44cb-bbff-a6564f3dde9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020555 infores:hetionet CHEBI:6413 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0002962 infores:hetionet CHEBI:31859 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0030312 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1527311 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0011991 infores:hetionet CHEBI:5959 biolink:causes NCIT:C78501 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0240464 infores:hetionet CHEBI:135351 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0600142 infores:hetionet CHEBI:50692 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0003467 infores:hetionet CHEBI:145499 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0033774 infores:hetionet NCBIGene:30813 biolink:causes MONDO:0007851 infores:monarchinitiative not_provided not_provided HGNC:12723 MONDO:0007851 uuid:b9a4435e-34da-4fca-ab43-517ecd8a08e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0023895 infores:hetionet CHEBI:63610 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0025323 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0038826 infores:hetionet CHEBI:31622 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0002994 infores:hetionet CHEBI:28748 biolink:causes GO:0006955 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020964 infores:hetionet CHEBI:17549 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C1145670 infores:hetionet CHEBI:45951 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0013144 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0278134 infores:hetionet CHEBI:64318 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0239385 infores:hetionet CHEBI:49603 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0231528 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0085641 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0036572 infores:hetionet CHEBI:2038 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0011175 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0037274 infores:hetionet CHEBI:70735 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0027947 infores:hetionet CHEBI:63581 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0702166 infores:hetionet CHEBI:63791 biolink:causes HP:0005224 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0267566 infores:hetionet CHEBI:7936 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020620 infores:hetionet CHEBI:10125 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020580 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005619 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0041466 infores:hetionet CHEBI:83527 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0006145 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027769 infores:hetionet CHEBI:9168 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C2973529 infores:hetionet CHEBI:194135 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0236075 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2717961 infores:hetionet CHEBI:8869 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0016658 infores:hetionet CHEBI:7983 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C2830004 infores:hetionet CHEBI:8707 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085633 infores:hetionet CHEBI:64310 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0392699 infores:hetionet CAID:CA201366 biolink:causes MONDO:0015152 infores:clingen CAID:CA201366 MONDO:0015152 PMID: Pathogenic PP1_Strong, PVS1, PP4, PM3_Very Strong PS3, PS4, PS2, BS1, BS3, BS4, PM2, PM6, PM1, BS2, BP2, BA1 The NM_213599.3: c.1898+1G>A variant in ANO5 impacts the splice donor site of exon 17, which is out of frame. SpliceAI gives a score of 0.85 for donor loss. RNA analysis has demonstrated that this variant results in skipping of exons 15-17, disrupting the reading frame and introducing a premature truncation codon with nonsense mediated decay expected (PMID: 23041008; PVS1_RNA). Among a selection of the available literature, this variant has been reported in at least 23 unrelated individuals with features consistent with LGMD (PMID: 23041008, 30919934), including in a homozygous state in 8 patients without reported familial consanguinity (1.0 pt; PMID: 30919934). The other fourteen patients were reported as compound heterozygous, with 8 unrelated cases having the pathogenic variant c.191dup p.(Asn64LysfsTer15) confirmed in trans (1.0 pt x8 = 8.0 pts, PMID: 30919934) (PM3_Very Strong). This variant has been shown to co-segregate with autosomal recessive LGMD in at least eight family members from three families (PMID: 30919934; PP1_Strong), and at least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PMID: 30919934; PP4). The highest population minor allele frequency for this variant is 0.0002238 in the Admixed American population of gnomAD v4.1.10 (10/44690 exome chromosomes), which is higher than the VCEP threshold for PM2_Supporting (0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/23/2025): PVS1_RNA, PM3_Very Strong, PP1_Strong, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA201366/MONDO:0015152/188 2025-07-23 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports UMLS:C1738934 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020649 infores:hetionet CHEBI:7443 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0023530 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0011849 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0340865 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0042109 infores:hetionet CHEBI:10023 biolink:causes EFO:1001328 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0016325 infores:hetionet CHEBI:2955 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1257843 infores:hetionet CHEBI:48669 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0026821 infores:hetionet CHEBI:175901 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0231835 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007642 infores:hetionet CHEBI:5120 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0595929 infores:hetionet CHEBI:52717 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0016204 infores:hetionet CAID:CA041752 biolink:causes MONDO:0007750 infores:clingen CAID:CA041752 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP1, PP4 The NM_000527.5(LDLR):c.91G>A (p.Glu31Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes (gnomAD v2.1.1).PP3: REVEL = 0.777. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041752/MONDO:0007750/013 2023-03-24 2025-04-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63619 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0497327 infores:hetionet CHEBI:7986 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0039231 infores:hetionet CHEBI:5693 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00756 UMLS:C0041834 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017605 infores:hetionet CHEBI:17334 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0027497 infores:hetionet CAID:CA358775 biolink:causes MONDO:0007750 infores:clingen CAID:CA358775 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1004G>A (p.Gly335Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001762 (0.001762%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.857. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA358775/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:2000328 biolink:causes GO:0043368 infores:ubergraph knowledge_assertion manual_agent GO:2000328 GO:0043368 CHEBI:205919 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0271738 infores:hetionet CHEBI:31638 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C1609512 infores:hetionet CHEBI:68556 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0015230 infores:hetionet CHEBI:63619 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0023211 infores:hetionet CHEBI:45716 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0027051 infores:hetionet CHEBI:42797 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151936 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022408 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0023530 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027720 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0079043 infores:hetionet CHEBI:8428 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0024141 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020651 infores:hetionet CHEBI:5165 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0039070 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0032285 infores:hetionet CHEBI:66919 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0277884 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0036572 infores:hetionet UNII:3U02EL437C biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0000731 infores:hetionet CHEBI:251408 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0020649 infores:hetionet CHEBI:49040 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0004604 infores:hetionet NCBIGene:64327 biolink:causes MONDO:0008700 infores:monarchinitiative not_provided not_provided HGNC:13243 MONDO:0008700 uuid:a04f6852-a608-46c3-b03a-9d4c77e19b03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0947912 infores:hetionet CHEBI:6541 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030305 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0029408 infores:hetionet CHEBI:31348 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019572 infores:hetionet CHEBI:144093 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0162316 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0008325 infores:hetionet CHEBI:3242 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0037763 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0239375 infores:hetionet CHEBI:71417 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0030554 infores:hetionet CHEBI:17549 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0241157 infores:hetionet CHEBI:75984 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0032617 infores:hetionet UBERON:0010084 biolink:causes UBERON:0009133 infores:ubergraph knowledge_assertion manual_agent UBERON:0010084 UBERON:0009133 CHEBI:6472 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0022346 infores:hetionet CHEBI:3638 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0002792 infores:hetionet CHEBI:367163 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020625 infores:hetionet CHEBI:83531 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0036974 infores:hetionet UMLS:C0657912 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026826 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0235524 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235524 infores:hetionet CAID:CA294896338 biolink:causes MONDO:0009290 infores:clingen CAID:CA294896338 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM5, PM2_Supporting, PS3_Supporting The NM_000152.5:c.1802C>G variant in GAA is a missense variant predicted to cause substitution of serine serine by tryptophan at amino acid 601 (p.Ser601Trp). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008475 (1/1179962 alleles) in the European, non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.964 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). When expressed in COS-7 cells, the variant resulted in <2% wild type activity indicating that this variant may impact protein function (PMID: 19862843) (PS3_supporting). Another missense variant (c.1802C>T, p.Ser601Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (ClinVar Variation ID: 194154; Accession: SCV002032130.1) (PM5). This variant has been detected in at least 11 individuals with Pompe disease. Of those individuals, 9 were compound heterozygous for the variant and the c.-32-13T>G variant (classified as pathogenic by the ClinGen LD VCEP). One individual was compound heterozygous for the variant and the c.1935C>A (p.Asp645Glu) variant (classified as pathogenic by the ClinGen LD VCEP). One individual was compound heterozygous for the variant and c.2800-1G>C (not classified by the ClinGen LD VCEP). Zero individuals were homozygous for the variant. (PM3). At least 3 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, or muscle samples (PMID: 17056254, 22958975, 24158270) and 2 patients were reported to be on enzyme replacement therapy for Pompe disease (PMID: 22081099, 29422078). This meets the criteria for PP4_moderate. There is a ClinVar entry for this variant (Variation ID: 501793). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_moderate, PM3, PM5, PP3, PM2_supporting, PS3_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 20, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294896338/MONDO:0009290/010 2025-05-20 2025-05-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:404903 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0235431 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0948594 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013415 infores:hetionet CHEBI:30659 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0156404 infores:hetionet CHEBI:7903 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0151723 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0948594 infores:hetionet CHEBI:63631 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0423791 infores:hetionet CHEBI:3215 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0023052 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0699893 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019360 infores:hetionet CHEBI:3441 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0027796 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0878544 infores:hetionet CHEBI:7936 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151594 infores:hetionet CHEBI:8871 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0028084 infores:hetionet CAID:CA298941 biolink:causes MONDO:0007648 infores:clingen CAID:CA298941 MONDO:0007648 PMID: Likely Benign BP7, BS2, BP4 BP5, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP2, BP3, BA1, PS1, PS3, PS4, PS2 The c.33G>C (p.Leu11=) variant results in a synonymous amino acid variant within exon 1. This variant is present at an allele frequency of 0.00012 (18/153328) in gnomAD, with a maximum frequency of 0.00026 (16/60398) in the European (Non-Finnish) subpopulation (http://gnomad.broadinstitute.org). The variant has been observed in more than 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2). This variant occurs at a nucleotide that is not highly conserved across species and it is not predicted to alter splicing by multiple splice site predictors (BP7, BP4). Although one predictor suggests alteration of an exonic ESE site, the impact of these events has not been well-characterized experimentally. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4, BP7. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA298941/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:101853 biolink:causes HP:0200097 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0853945 infores:hetionet CHEBI:6935 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0011603 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0151736 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0948594 infores:hetionet CHEBI:15854 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C3665347 infores:hetionet CHEBI:145499 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0016204 infores:hetionet CHEBI:18248 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0043352 infores:hetionet CHEBI:49603 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0267792 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0012833 infores:hetionet CHEBI:92511 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0030193 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0549343 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0549343 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0002897 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:C536773 DB09320_MESH_C536773_1DB01053_MESH_C536773_1 CHEBI:64355 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018800 infores:hetionet UMLS:C0010592 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0024902 infores:hetionet CHEBI:50841 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0234967 infores:hetionet CHEBI:63638 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013604 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0027051 infores:hetionet CHEBI:8776 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0085631 infores:hetionet CHEBI:72564 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0002874 infores:hetionet NCBIGene:92935 biolink:causes MONDO:0012664 infores:monarchinitiative not_provided not_provided HGNC:25133 MONDO:0012664 uuid:13d0a704-96d0-47b2-aff6-eb12212c6e1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0600260 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0013395 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0019158 infores:hetionet CHEBI:194135 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0001807 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0853619 infores:hetionet CHEBI:16899 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0013404 infores:hetionet CHEBI:8461 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0344232 infores:hetionet CAID:CA269554323 biolink:causes MONDO:0007947 infores:clingen CAID:CA269554323 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM2_Supporting, PM1, PS4, PP1_Strong PM6, PVS1, BS2, BA1, BP1, BP4, BP2, BP3, PM5, PM3, PM4, PS1, PS3, PS2, BP5, BP7, BS1, BS3, BS4 The NM_000138 c.4459G>A, is a missense variant in FBN1 predicted to cause a substitution of an Aspartic acid by Asparagine at amino acid 1487 p.(Asp1487Asn). This variant was found in four probands meeting the Ghent criteria (PP4, PS4_strong). The variant segregates with the disease in six affected family members of one proband and three affected family members of another proband (PP1_strong). This variant has been reported three times in ClinVar as likely pathogenic (Variation ID: 549232). It has been reported one time in the literature in a proband with classical Marfan syndrome (PMID: 19293843). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). This variant lies in a critical calcium binding site within a calcium binding EGF domain (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_strong, PM1, PP2, PP3, PP4, PM2_supporting FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA269554323/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3752 biolink:causes MONDO:0016056 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0025958 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0549209 infores:hetionet CHEBI:82981 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0011603 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0080203 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0242350 infores:hetionet CHEBI:28748 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0037763 infores:hetionet CAID:CA1964194540 biolink:causes MONDO:0000573 infores:clingen CAID:CA1964194540 MONDO:0000573 PMID: Pathogenic PP4, PS3_Moderate, PM2_Supporting, PVS1 PM1, PM3 The NM_000536.4:c.829dup variant in RAG2 is a frameshift variant predicted to result in a truncated protein (p.Tyr277Leufs*4). Although this variant is expected to escape nonsense-mediated decay (NMD), it would be expected to disrupt approximately 47% of the RAG2 protein. In addition, this variant would be expected to disrupt/remove the entire PHD domain (amino acids 414-487), which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 15964836). PVS1 met. This variant is absent in gnomAD, which is below the threshold for max filtering allele frequency for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). In an experimental study, this variant demonstrates zero recombination activity, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% wildtype activity) for PS3_Moderate (PMID: 31058115). This variant has been reported in three patients. One patient in a cohort of SCID patients (0.5p) with T-B-NK+ immunophenotype (0.5p) was identified with this variant along with a co-occurring RAG2 p.Phe183Asn variant, though phase was not reported (PMID: 24144642) (1p, PP4). A second patient with a later onset CID-like phenotype was identified with this variant along with a co-occurring RAG2 p.Glu170Gly variant (only one parent tested and was heterozygous for the variant) (PMID: 31058115). The p.Phe183Asn and p.Glu170Gly variants have not yet been classified by the ClinGen SCID VCEP. A third patient with Omenn syndrome was identified with this variant; however, the variant was heterozygous, and a second variant in RAG2 was not identified (PMID: 34851571). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PVS1, PM2_Supporting, PS3_Moderate, and PP4 as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA1964194540/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5959 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0034063 infores:hetionet CHEBI:194135 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020452 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0152227 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0009806 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0020538 infores:hetionet CAID:CA397318012 biolink:causes MONDO:0009276 infores:clingen CAID:CA397318012 MONDO:0009276 PMID: Pathogenic PP4, PP1, PM2_Supporting, PM3_Strong, PM1, PS3_Supporting PP3, BP4, PS1 NM_000173.7(GP1BA):c.673T>A is a missense variant (p.Cys225Ser), which has been reported in at least three probands with Bernard-Soulier syndrome. Two probands are homozygous for this variant, while another proband is compound heterozygous for this variant and a pathogenic frameshift variant c.1454dup (PM3_Strong). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000005530 (based on 2/60024 alleles) in the Admixed American population, this is below <0.0001114 the threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.599, which is below the ClinGen PD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on GP1BA function. At least one patient (Patient M.L. in PMID:7819107) with this variant had aggregation absent for ristocetin but present for all other agonists and flow cytometry with less than 10% expression of GPIBa (PP4). This variant resides at a disulfide bond residue, Cys225, of GP1BA that is defined as a critical functional domain by the ClinGen PD VCEP (PM1). The variant has been reported to segregate with Bernard-Soulier syndrome in one proband (meeting PP4) plus one affected family member both with the compound heterozygous c.1454dup genotype (PMID:11776304). Finally, surface expression of GP1Ba measured by flow cytometry in CHO cells transiently co-transfected with the c.673T>A variant GP1Ba and wild type GP1Ba showed decreased expression at 0% (<25%) WT levels (PS3_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM1, PS3_supporting, PM3_strong, PP4, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397318012/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31709 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0022116 infores:hetionet CHEBI:72564 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1443060 infores:hetionet CHEBI:42944 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0041657 infores:hetionet CAID:CA5253269 biolink:causes MONDO:0008535 infores:clingen CAID:CA5253269 MONDO:0008535 PMID: Uncertain Significance BP5, PS3_Supporting PM2 The NM_001114753.3: c.-9G>A variant is located in the 5' UTR of ENG. Because the variant is located in the 5' UTR, is it not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007942 (76/95698 alleles) in the European (non-Finnish) population. This variant has been observed in patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ACVRL1 variant) (BP5; Internal lab contributors). Expression studies showed this variant causes a small reduction (~18.4%) of endoglin compared to wild type (PS3_Supporting, PMID: 22192717). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS3_Supporting, BP5 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5253269/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:38940 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0586553 infores:hetionet NCBIGene:54808 biolink:causes MONDO:0011814 infores:monarchinitiative not_provided not_provided HGNC:21317 MONDO:0011814 uuid:15aabbba-0806-4c93-9457-9fed5fc93197 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63607 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0017181 infores:hetionet CHEBI:28748 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2830004 infores:hetionet CHEBI:94807 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0000737 infores:hetionet GO:0043313 biolink:causes GO:0002446 infores:ubergraph knowledge_assertion manual_agent GO:0043313 GO:0002446 CHEBI:9654 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0349506 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0231528 infores:hetionet CHEBI:3238 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01091 UMLS:C0677500 infores:hetionet CHEBI:5778 biolink:causes NCIT:C78501 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0240464 infores:hetionet CHEBI:4657 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0008031 infores:hetionet CHEBI:3176 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0042963 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0856554 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0856554 infores:hetionet CAID:CA10584839 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584839 MONDO:0007750 PMID: Likely Pathogenic PM1, PM2, PP4, PP3 BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.311G>T (p.Cys104Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.0.0).PP3: REVEL = 0.882. PM1: Variant meets PM2 and alters Cys104, one of the cysteine residues listed. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH from PMID 16159606 (Graham et al., 2005), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584839/MONDO:0007750/013 2024-02-23 2024-10-07 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3423 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0013604 infores:hetionet CHEBI:7986 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0030252 infores:hetionet NCBIGene:10235 biolink:causes MONDO:0014386 infores:monarchinitiative not_provided not_provided HGNC:9879 MONDO:0014386 uuid:73f8a4d8-9444-4944-a532-75d344364a01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49668 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0011175 infores:hetionet CAID:CA023410 biolink:causes MONDO:0007750 infores:clingen CAID:CA023410 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, PS3, PM5, PM1, PP3 The NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF= 0.00002 (0.002%) in European (Non-Finnish) in genomes+exomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 cases (1 with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 with DLCN score >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case in PMID 33994402 (Huang et al., 2022), Taiwan, and 1 case in PMID 34998859 (Pillai et al., 2022), India, with country-specific FH criteria), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023410/MONDO:0007750/013 2025-01-31 2025-03-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA2586966742 biolink:causes MONDO:0100368 infores:clingen CAID:CA2586966742 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.596dup (p.Asn199LysfsTer?) is a frameshift variant that introduces a premature stop codon into exon 6 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by targeted exome sequencing of 168 retinal genes without identifying an alternative cause of disease (2 pts), onset before age 5 years (1 pt), light staring (1 pt), nystagmus (1 pt), and extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (7 points, PMID: 34830511, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586966742/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17650 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0030193 infores:hetionet CHEBI:75246 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0013456 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0233414 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009806 infores:hetionet CHEBI:63622 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0476273 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003460 infores:hetionet CHEBI:209807 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0700345 infores:hetionet CHEBI:5098 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0017178 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0011991 infores:hetionet CHEBI:61033 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0553692 infores:hetionet CHEBI:231594 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0149741 infores:hetionet CHEBI:7903 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020461 infores:hetionet CHEBI:119915 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0392156 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0235234 infores:hetionet CHEBI:42944 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0917801 infores:hetionet CHEBI:16469 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0268000 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0020538 infores:hetionet CHEBI:30830 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0393760 infores:hetionet CHEBI:44423 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0041834 infores:hetionet CHEBI:8356 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030196 infores:hetionet CHEBI:66964 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0231528 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0016436 infores:hetionet CHEBI:134991 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0040460 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0042373 infores:hetionet CHEBI:6931 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0085633 infores:hetionet CHEBI:38940 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0033774 infores:hetionet CHEBI:3478 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0034359 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0009450 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0018939 infores:hetionet CHEBI:75998 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0006826 infores:hetionet CHEBI:184555 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0013604 infores:hetionet CHEBI:28593 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0085593 infores:hetionet CAID:CA10360543 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360543 MONDO:0100039 PMID: Benign BP7, BS1, BS2 The allele frequency of the p.Pro823= variant in CDKL5 is 0.0088% in African/African American sub population in gnomAD v4, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro823= variant is observed in at least 2 unaffected individuals (GeneDX internal database) (BS2). The silent p.Pro823= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Pro823= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360543/MONDO:0100039/034 2023-12-06 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:9737 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0042963 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030332 infores:hetionet CHEBI:16796 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0020433 infores:hetionet CHEBI:18248 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0600142 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0015230 infores:hetionet NCBITaxon:5693 biolink:causes MONDO:0001444 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5693 MESH:D014355 DB11820_MESH_D014355_1DB11989_MESH_D014355_1 CHEBI:135930 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151539 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0041582 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0002622 infores:hetionet CAID:CA261739 biolink:causes MONDO:0018997 infores:clingen CAID:CA261739 MONDO:0018997 PMID:17143282PMID:23487764PMID:17143282PMID:23487764 Pathogenic PS3, PS2, PS4_Moderate, PM2, PM6, PP2 The c.322G>A (p.Glu108Lys) variant in SOS1 has been reported as confirmed and unconfirmed occurrences in patients with clinical features of a RASopathy (PM6 and PS2; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2). The p.Glu108Lys variant has been identified in several independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data GTR Lab ID: 26957, 21766, 28338; ClinVar SCV000209088.9, SCV000062224.5, SCV000659144.2; PMID: 17143282; 23487764). In vitro functional studies provide some evidence that the p.Glu108Lys variant may impact protein function (PS3; PMID: 17143282, 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS3, PM6, PS4_Moderate, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261739/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ UNII:UMD7G2653W biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2363730 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0410256 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0410256 infores:hetionet CHEBI:74947 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0032227 infores:hetionet CHEBI:50861 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0003467 infores:hetionet UBERON:0034705 biolink:causes MONDO:0021193 infores:ubergraph knowledge_assertion manual_agent UBERON:0034705 MONDO:0021193 CAID:CA386966026 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966026 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PP3 PS4, PP4 The c.770A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to threonine at codon 257 (p.(Asn257Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.879, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and there is not enough clinical information provided to use the MODY probability calculator, so PP4 does not apply either (PMIDs: 16249556, 18838325). However, in one of the families, this variant did segregate with diabetes with five informative meioses (PP1_Strong; PMID: 18838325). In summary, c.770A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966026/MONDO:0015967/017 2024-11-07 2024-11-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83531 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C2047937 infores:hetionet CHEBI:17303 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0036974 infores:hetionet CHEBI:27690 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C1167965 infores:hetionet CHEBI:171719 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0162820 infores:hetionet CHEBI:3568 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0016867 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0033975 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020039 infores:hetionet CHEBI:9460 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0003123 infores:hetionet CHEBI:63621 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0333355 infores:hetionet CHEBI:171719 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011603 infores:hetionet CHEBI:68575 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0041912 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0281981 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0013295 infores:hetionet CAID:CA287439291 biolink:causes MONDO:0008723 infores:clingen CAID:CA287439291 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PP1, PM3, PP4_Moderate The c.1220G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 407 (p.Gly407Ala) and is also known as Gly367Ala in the fully processed protein. This variant has been reported as occurring in trans to a known pathogenic variant in a pair of siblings with positive newborn screens and reduced very long chain acyl-CoA dehydrogenase (VLCAD) activity (PMID: 28755359, PM3, PP1, PP4_moderate). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305, 23798014). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.803, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP1, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287439291/MONDO:0008723/021 2023-02-13 2023-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50742 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0029134 infores:hetionet NCBIGene:150468 biolink:causes MONDO:0010092 infores:monarchinitiative not_provided not_provided HGNC:26877 MONDO:0010092 uuid:4ac64c84-74bb-4176-a51b-f817c651ae58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:76010 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0027947 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027051 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020517 infores:hetionet CHEBI:63598 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0231835 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0007787 infores:hetionet CHEBI:3441 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0428977 infores:hetionet NCBIGene:374462 biolink:causes MONDO:0033260 infores:monarchinitiative not_provided not_provided HGNC:9679 MONDO:0033260 uuid:86054185-f2e1-4ce7-bebe-c145a914784b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0040822 infores:hetionet NCBIGene:10683 biolink:causes MONDO:0020692 infores:monarchinitiative not_provided not_provided HGNC:2909 MONDO:0020692 uuid:b6de3805-f90b-4f21-a527-b1db32dba3bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C2830004 infores:hetionet UMLS:C0145867 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0000737 infores:hetionet CHEBI:8382 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0039231 infores:hetionet CHEBI:72564 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085633 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0234547 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234547 infores:hetionet CHEBI:6715 biolink:causes MONDO:0021163 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0022665 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0149931 infores:hetionet CHEBI:61390 biolink:causes MONDO:0024487 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0343026 infores:hetionet CHEBI:4514 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0003578 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0000833 infores:hetionet CHEBI:6950 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042023 infores:hetionet GO:0048762 biolink:causes CL:0008019 infores:ubergraph knowledge_assertion manual_agent GO:0048762 CL:0008019 CHEBI:3756 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0086132 infores:hetionet CHEBI:8888 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009676 infores:hetionet CHEBI:10102 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0152198 infores:hetionet CHEBI:10124 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0233471 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0162429 infores:hetionet CHEBI:2682 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151701 infores:hetionet CHEBI:4653 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0043352 infores:hetionet CHEBI:8356 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026837 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0034186 infores:hetionet CHEBI:50922 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0039231 infores:hetionet CHEBI:5864 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085682 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0442886 infores:hetionet CHEBI:38940 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0549567 infores:hetionet CHEBI:9667 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0152459 infores:hetionet UMLS:C0657912 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035317 infores:hetionet CAID:CA367400483 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400483 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.821A>C variant in the glucokinase gene, GCK, is a missense variant resulting in an amino acid change of aspartic acid to alanine at codon 274 (p.(Asp274Ala)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in five individuals with hyperglycemia (PS4_Moderate, internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with hyperglycemia, with 4 informative meioses in two families (PP1_Strong; internal lab contributors). In summary, c.821A>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PM2_Supporting, PP1_Strong, PP2, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400483/MONDO:0015967/086 2024-11-04 2024-11-05 Semidominant inheritance HP:0032113 Supports CHEBI:27779 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0001824 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0267792 infores:hetionet CAID:CA2018007655 biolink:causes MONDO:0015967 infores:clingen CAID:CA2018007655 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3 The c.526+4A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to alter the splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss and a score of 0.96 for cryptic donor gain, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative GAD and IA2 antibodies) (PP4_Moderate; internal lab contributors). In summary, c.526+4A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2018007655/MONDO:0015967/017 2025-02-11 2025-02-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020461 infores:hetionet CHEBI:31623 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0035317 infores:hetionet CHEBI:51230 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0043352 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0034063 infores:hetionet CHEBI:36791 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036973 infores:hetionet NCBIGene:100996717 biolink:causes MONDO:0030027 infores:monarchinitiative not_provided not_provided HGNC:53924 MONDO:0030027 uuid:2286c0c5-7685-4cb4-be75-0e9ae6b952ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0036974 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0031350 infores:hetionet CHEBI:145499 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0344232 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0025061 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0751295 infores:hetionet CHEBI:5775 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0278134 infores:hetionet CHEBI:47381 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0232493 infores:hetionet CHEBI:31236 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028754 infores:hetionet CAID:CA16023349 biolink:causes MONDO:0021056 infores:clingen CAID:CA16023349 MONDO:0021056 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PVS1_Strong The NM_000038.6(APC):c.933G>C variant in APC is a G to non-G change at the last nucleotide of exon 9. RNA analysis demonstrated that the variant impacts splicing by an insertion of the first 66 nucleotides of intron 9, resulting in a premature stop codon (r.933_934ins933+1_933+66 p.K311_V312insVTEDYKPWSLMP*) (internal data Ambry Genetics; in Fig. 1B of the ACMG/AMP criteria specification by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP [HCCP VCEP] the variant was evaluated as PVS1_Supporting, but based on the additional RNA data the HCCP VCEP considers PVS1_Strong as applicable for this variant). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 (PS4_Supporting, PMID: 20685668, internal data Labcorp Genetics [formerly Invitae]). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1_Strong, PS4_Supporting, PM2_Supporting applied (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16023349/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41423 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042075 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151601 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0017152 infores:hetionet NCBIGene:6336 biolink:causes MONDO:0014246 infores:monarchinitiative not_provided not_provided HGNC:10582 MONDO:0014246 uuid:43765b4f-1151-4e53-afc9-6172c3b1aac7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA267632 biolink:causes MONDO:0009861 infores:clingen CAID:CA267632 MONDO:0009861 PMID:26666653PMID:26666653 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The c.1180G>T (p.Asp394Tyr) variant in PAH has been reported in 2 French patients with mild PKU, BH4 deficiency not ruled out PMID: 26666653. Detected with pathogenic variants p.T380M and 1066-3C > T, parental analysis not performed. This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267632/MONDO:0009861/006 2020-07-10 2020-07-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2549 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013604 infores:hetionet CHEBI:135005 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0033774 infores:hetionet CHEBI:3223 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C2830004 infores:hetionet CHEBI:36795 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0028961 infores:hetionet CHEBI:50922 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0040822 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0332575 infores:hetionet CHEBI:10102 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0740394 infores:hetionet CHEBI:9288 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0854467 infores:hetionet CHEBI:2704 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0006277 infores:hetionet CHEBI:5138 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0392525 infores:hetionet CHEBI:6809 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0917801 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0178298 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0162830 infores:hetionet CAID:CA397723695 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723695 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3_Supporting, PP4_Moderate, PS3_Supporting The c.790A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 264 (p.Lys264Glu). At least one patient with this variant displayed very long chain acyl-CoA dehydrogenase (VLCAD) activity <20% of normal, which is highly specific for VLCAD (PP4_Moderate, PMID: 17999356). This individual also carried a distinct pathogenic variant, though the variant was not confirmed to be in trans (PMID: 17999356; PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0006 in the East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Transient transfection of this variant into fibroblasts showed reduced very long chain acyl-CoA dehydrogenase (VLCAD) activity indicating that this variant impacts protein function (PMID: 11914034; PS3_Supporting). The computational predictor REVEL gives a score of 0.871, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Supporting, PM2_supporting, PS3_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723695/MONDO:0008723/021 2023-02-14 2023-02-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:175901 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0034069 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0152027 infores:hetionet CHEBI:63619 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151636 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0037822 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0024117 infores:hetionet CHEBI:5613 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042510 infores:hetionet CHEBI:7931 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0014591 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027707 infores:hetionet CHEBI:45863 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151636 infores:hetionet CHEBI:8356 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0001807 infores:hetionet CHEBI:48538 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0013604 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018418 infores:hetionet CHEBI:681848 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0497247 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0015397 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042035 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0079043 infores:hetionet CHEBI:6741 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0003467 infores:hetionet CHEBI:2038 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0020580 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0003864 infores:hetionet CHEBI:63581 biolink:causes UMLS:C1142524 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1142524 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0004936 infores:hetionet UMLS:C0657912 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235198 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0019054 infores:hetionet CHEBI:8888 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020443 infores:hetionet CHEBI:32293 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C1268766 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1320835 infores:hetionet CHEBI:5147 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0392525 infores:hetionet CHEBI:71255 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0039070 infores:hetionet CAID:CA340930 biolink:causes MONDO:0044970 infores:clingen CAID:CA340930 MONDO:0044970 PMID: Uncertain Significance PP3, PS4_Moderate PP1, PS2, PM6, PM2 The m.9804G>A (p.A200T) variant in MT-CO3 has been reported in seven unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 8240356, 17895983, 11339587, 11579587, 30831606). Six cases had Leber Hereditary Optic Neuropathy (LHON; PMIDs: 8240356, 11339587, 11579587, 30831606) and the variant was reported to be homoplasmic in four, heteroplasmic in one (level not provided), and the level was not provided in another. Limited clinical details were available from the seventh case but this child was described as having encephalopathy and the variant present at homoplasmy (PMID: 17895983). There were no reported de novo occurrences and there were no reports of the variant segregating with clinical manifestations in a family. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.296%, 183/61,883; gnomAD v3.1.2: 0.363%, 205/56,420 homoplasmic occurrences in addition to 15 heteroplasmic occurrences; Helix: 0.472%, 926/195,893 homoplasmic occurrences in addition to 30 heteroplasmic occurrences).The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.866 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340930/MONDO:0044970/015 2023-09-26 2025-06-04 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8863 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151735 infores:hetionet CHEBI:47898 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014591 infores:hetionet UMLS:C0120107 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042023 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0152198 infores:hetionet CHEBI:7907 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0041834 infores:hetionet CAID:CA512232179 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232179 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS4, PS2, PS1, PS3, BA1, BP1, BP3, BP2, BP5, BS1, BS4, BS3, PVS1, PM6, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.954C>T (p.Ser318=) is a synonymous variant. This variant has a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.04) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.938)) (BP7). And this variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232179/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8597 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0020538 infores:hetionet CAID:CA198772 biolink:causes MONDO:0009290 infores:clingen CAID:CA198772 MONDO:0009290 PMID: Likely Benign BP4, BS1 The NM_000152.5:c.676C>G variant in GAA is a missense variant predicted to cause substitution of leucine by valine at amino acid 226 (p.Leu226Val). The highest population minor allele frequency of this variant in gnomAD v2.1.1. is 0.006298 (156/24770 alleles) in the African/African American population which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There are ten ClinVar entries for this variant (Variation ID:188476; 2 star review status) with eight submitters classifying the variant as likely benign and two as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 7, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA198772/MONDO:0009290/010 2024-05-07 2024-05-08 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:36791 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235763 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0151472 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151472 infores:hetionet CHEBI:135929 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0018681 infores:hetionet CHEBI:17549 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0085593 infores:hetionet GO:1902722 biolink:causes MONDO:0005804 infores:drugmechdb knowledge_assertion manual_agent GO:1902722 MESH:D006966 DB00248_MESH_D006966_1DB00589_MESH_D000568_1 CHEBI:63613 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0038367 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0037274 infores:hetionet NCBIGene:60675 biolink:causes MONDO:0012528 infores:monarchinitiative not_provided not_provided HGNC:18455 MONDO:0012528 uuid:0568dbeb-faa3-4076-901e-7efff77b9945 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0019079 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0021141 infores:hetionet CHEBI:17347 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0702166 infores:hetionet CHEBI:8028 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0021141 infores:hetionet CAID:CA012222 biolink:causes MONDO:0004994 infores:clingen CAID:CA012222 MONDO:0004994 PMID:29300372 Benign BA1 The filtering allele frequency of the c.2358G>T (p.Thr786=) variant in the MYH7 gene is 0.15% (33/16512) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012222/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:38562 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0002792 infores:hetionet CHEBI:9667 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0332601 infores:hetionet CHEBI:39669 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0018681 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0178298 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0021400 infores:hetionet CHEBI:188986 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0162285 infores:hetionet CHEBI:4511 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0023066 infores:hetionet CHEBI:30830 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020580 infores:hetionet CAID:CA386952583 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952583 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PP1 The c.59G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to alanine at codon 20 (p.(G20A)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.58G>A (p.Gly20Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly20Ala (PM5_Supporting). This variant is absent in gnomAD v4.1.0 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). Taken together, this evidence supports the classification of the c.59G>C variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP4_moderate, PP3, PM1_supporting, PM2_supporting, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952583/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50275 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151970 infores:hetionet CHEBI:16899 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0232602 infores:hetionet CHEBI:8888 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017086 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0856623 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0856623 infores:hetionet CHEBI:40279 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085593 infores:hetionet CAID:CA367401545 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401545 MONDO:0015967 PMID: Likely Pathogenic PS2_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1 The c.567C>G variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to methionine, at codon 189 (p.(Ile189Met)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Another missense variant, c.566T>C, p.Ile189Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile189Met (PM5_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.841, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(PP4_Moderate, internal lab contributors). This occurred in this individual as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; internal lab contributor). While this variant was identified in the individual mentioned above, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. AMCG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3, PS2_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401545/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:6520 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0027651 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030312 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042571 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0042514 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233414 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0522224 infores:hetionet NCBITaxon:12092 biolink:causes MONDO:0005790 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12092 MONDO:0005790 CHEBI:64312 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027441 infores:hetionet CHEBI:7822 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0011991 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0025061 infores:hetionet CHEBI:4995 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085631 infores:hetionet CHEBI:9654 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0018965 infores:hetionet CHEBI:9086 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0001925 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002170 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0017178 infores:hetionet CHEBI:16796 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0043352 infores:hetionet CHEBI:168396 biolink:causes HP:5200424 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0424024 infores:hetionet CHEBI:47499 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0043352 infores:hetionet CHEBI:4315 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0009806 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0040034 infores:hetionet CHEBI:39867 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0018944 infores:hetionet CHEBI:75988 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0008031 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023510 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2225524 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0162429 infores:hetionet CHEBI:17303 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011124 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0234215 infores:hetionet CHEBI:474053 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C1868855 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0948586 infores:hetionet CHEBI:5134 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0027497 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0024115 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0009450 infores:hetionet CHEBI:127780 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151723 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020649 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0021843 infores:hetionet CHEBI:7445 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0011124 infores:hetionet CHEBI:681850 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0017178 infores:hetionet CHEBI:45327 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0085612 infores:hetionet CAID:CA294410 biolink:causes MONDO:0007648 infores:clingen CAID:CA294410 MONDO:0007648 PMID:20921021PMID:20921021PMID:20921021 Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS1, PS2 The c.8C>G (p.Pro3Arg) variant has an allele frequency of 0.00025 (39/155276) in gnomAD and is observed in multiple subpopulations, with a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation (http://gnomad.broadinstitute.org). This variant was observed more than 70 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (BS2; SCV000210891.12, SCV000186617.6). The variant has also been identified in at least 5 individuals with LBC but whose families do not meet HDGC clinical criteria (PMID: 20921021, SCV000210891.12). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. However, localization to the plasma membrane was not affected when the variant was expressed in cells lacking endogenous expression of E-cadherin (PMID: 20921021). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294410/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:8874 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034063 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020550 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0919823 infores:hetionet CHEBI:94449 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0014591 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0403632 infores:hetionet CHEBI:46557 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C2711248 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038367 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0920166 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0920166 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023067 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0027051 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0600327 infores:hetionet CHEBI:3061 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0231528 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030312 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0016655 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042373 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027651 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004936 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027947 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0520563 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0520563 infores:hetionet CAID:CA2582131064 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582131064 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The NM_005629.4(SLC6A8):c.497del (p.Thr166SerfsTer?) variant in SLC6A8 is a frameshift variant predicted to a premature stop codon in biologically-relevant-exon 4/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant was identified in a hemizygous male, his heterozygous mother, and his maternal half sister. The male proband had developmental delay and seizures, normal guanidinoacetate and reduced creatine on blood spot. No urine creatine level, brain creatine level on MRS, or fibroblast creatine uptake studies were reported. There was insufficient evidence to apply PP4 or PP1 The variant is not present in gnomAD v2.1.1 or v4.0. (PM2_Supporting). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0.): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 18, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582131064/MONDO:0010305/027 2024-03-18 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:167638 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020517 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0080203 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0006826 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0541832 infores:hetionet CHEBI:6375 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0232726 infores:hetionet CHEBI:75246 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0008031 infores:hetionet CHEBI:50742 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0011644 infores:hetionet CHEBI:2639 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0019080 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0029408 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0232462 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002933 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029464 infores:hetionet CHEBI:32293 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0085635 infores:hetionet CHEBI:520985 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0231218 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0233697 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0233697 infores:hetionet CHEBI:3723 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0032617 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151517 infores:hetionet CHEBI:16899 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0001122 infores:hetionet CHEBI:5134 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0522251 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0442874 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0030312 infores:hetionet CHEBI:36795 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0039240 infores:hetionet CHEBI:7986 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0232462 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0034150 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0233472 infores:hetionet CHEBI:2675 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0042384 infores:hetionet NCBIGene:778 biolink:causes MONDO:0010335 infores:monarchinitiative not_provided not_provided HGNC:1393 MONDO:0010335 uuid:799d4081-d58b-4a1c-a61b-a26d9a988b21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:421707 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C1262113 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0475858 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020538 infores:hetionet CHEBI:10119 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013456 infores:hetionet CHEBI:52717 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002792 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0002170 infores:hetionet UMLS:C0879264 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0018965 infores:hetionet CHEBI:5775 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0030312 infores:hetionet CHEBI:46345 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0009763 infores:hetionet NCBIGene:4221 biolink:causes MONDO:0007540 infores:monarchinitiative not_provided not_provided HGNC:7010 MONDO:0007540 uuid:496d5c70-598c-4994-8b37-ee56206f8c29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:43968 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0027765 infores:hetionet CHEBI:3752 biolink:causes HP:0011623 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0685707 infores:hetionet CHEBI:6887 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1306341 infores:hetionet CHEBI:45951 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0392676 infores:hetionet CHEBI:8707 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013384 infores:hetionet CAID:CA399805152 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805152 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong, PM3_Supporting PP3 The ITGA2B splice variant NM_000419.5:c.800-2A>G alters a canonical splice acceptor located at the 3' end of intron 7 and the 5' end of exon 8. Although the effect of this splice variant has not been experimentally determined, it is predicted to result in the in frame skipping of exon 8 and loss of 16 amino acids (AA 267-282) from the resulting protein, altering the β propeller domain (spanning AA 32-482) which is critical to protein function (PVS1). This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT27, PMID: 16463284; PM3_supporting). All requirements for PP4_moderate are met (GT27 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Furthermore, this variant is absent from population databases, including gnomADv4.1.0 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PVS1_strong, PP4_moderate, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805152/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5383 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0232461 infores:hetionet CHEBI:31625 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0001622 infores:hetionet CHEBI:63581 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0004604 infores:hetionet CHEBI:94411 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C1443060 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0521591 infores:hetionet CHEBI:45716 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0027947 infores:hetionet CHEBI:7478 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0018524 infores:hetionet CHEBI:8435 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0010200 infores:hetionet CHEBI:6887 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0162820 infores:hetionet NCBIGene:83959 biolink:causes MONDO:0009015 infores:monarchinitiative not_provided not_provided HGNC:16438 MONDO:0009015 uuid:510ae2c0-c367-4baa-9a8c-77a4d72ad9cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0004604 infores:hetionet CHEBI:107736 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0151818 infores:hetionet CHEBI:85161 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0017152 infores:hetionet CHEBI:145499 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0600142 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0242073 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0029134 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013295 infores:hetionet NCBIGene:6487 biolink:causes MONDO:0014003 infores:monarchinitiative not_provided not_provided HGNC:10866 MONDO:0014003 uuid:c38c80bf-4303-4435-8457-f37767b965c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50859 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011053 infores:hetionet CHEBI:2922 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0011606 infores:hetionet CHEBI:3568 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C3160741 infores:hetionet CHEBI:6062 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018681 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0040264 infores:hetionet CHEBI:37333 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C1443060 infores:hetionet CHEBI:135939 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0020458 infores:hetionet CHEBI:8863 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0038990 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0039971 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002957 infores:hetionet CAID:CA171623 biolink:causes MONDO:0100039 infores:clingen CAID:CA171623 MONDO:0100039 PMID: Likely Benign BP5, BS2, BP4 BS1, PM2, PM6, BA1 The p.Thr734Ala variant in CDKL5 is present in 7 female and male individuals in gnomAD (0.003%) (not sufficient to meet BS1 criteria). The p.Thr734Ala variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Thr734Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Thr734Ala variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Thr734Ala variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171623/MONDO:0100039/016 2022-09-01 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7773 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0518015 infores:hetionet CHEBI:32599 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0151559 infores:hetionet CHEBI:68584 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0013404 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233632 infores:hetionet CHEBI:63631 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0005778 infores:hetionet CHEBI:3478 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0231218 infores:hetionet CHEBI:102216 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C1619712 infores:hetionet NCBIGene:54941 biolink:causes MONDO:0014553 infores:monarchinitiative not_provided not_provided HGNC:21150 MONDO:0014553 uuid:e1f9c79b-7a4f-4bc1-a38d-648d8a3bf9bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151746 infores:hetionet CHEBI:32315 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085636 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0011991 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0029134 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0239295 infores:hetionet CHEBI:135876 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0948594 infores:hetionet CHEBI:8346 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0030554 infores:hetionet CHEBI:64064 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0022107 infores:hetionet GO:0033029 biolink:causes GO:0001780 infores:ubergraph knowledge_assertion manual_agent GO:0033029 GO:0001780 CHEBI:3125 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0041657 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0234458 infores:hetionet CHEBI:34829 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0235259 infores:hetionet NCBIGene:23424 biolink:causes MONDO:0013484 infores:monarchinitiative not_provided not_provided HGNC:30831 MONDO:0013484 uuid:5394141d-522f-42c6-848d-260e130f9418 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0000737 infores:hetionet CAID:CA10524682 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524682 MONDO:0010278 PMID: Likely Benign BP4, BS1, BP5, BS2_Supporting The allele frequency of the p.Val193Ile variant in SLC9A6 (NM_006359.2) is 0.008% in South Asian sub population in gnomAD v4, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Val193Ile variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Val193Ile variant is observed in the hemizygous state in at least 1 unaffected individuals (internal database - GeneDx) (BS2_supporting). The p.Val193Ile variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Val193Ile variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4, BS2_supporting, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524682/MONDO:0010278/033 2024-02-23 2024-03-31 X-linked inheritance HP:0001417 Contradicts true CAID:CA285340 biolink:causes MONDO:0019169 infores:clingen CAID:CA285340 MONDO:0019169 PMID: Benign BS2, BA1, BP7 The allele frequency of the c.795A>G variant in the PDHA1 gene is 13.1% in gnomAD, including more than 9,000 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD- BA1; >16 hemizygotes- BS2). Furthermore, splicing predictors (SPLICE AI) do not predict a deleterious effect (BP7). In summary, this synonymous variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA285340/MONDO:0019169/014 2021-05-05 2021-05-06 X-linked inheritance HP:0001417 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:119486 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0853692 infores:hetionet CHEBI:4975 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0037383 infores:hetionet CHEBI:31413 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0017178 infores:hetionet CHEBI:45716 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0011175 infores:hetionet CHEBI:5558 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0022660 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020649 infores:hetionet CHEBI:6706 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0026961 infores:hetionet CHEBI:31397 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0030252 infores:hetionet CAID:CA1310372689 biolink:causes MONDO:0015967 infores:clingen CAID:CA1310372689 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PS2 PP1, PM1, PS4 The c.914dup variant in the HNF4A gene causes a frameshift in the protein at codon 306 (NM_175914.4), adding 2 novel amino acids before encountering a stop codon (p.(Tyr306ValfsTer2)). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 20164212, internal lab contributors). In one of these individuals the variant was identified as a de novo occurence with confirmed parental relationships, and the individual had a clinical history highly specific for HNF4A-monogenic diabetes (neonatal hypoglycemia responsive to diazoxide, negative genetic testing for HNF1A, ABCC8, and KCNJ11, MPC>50%) (PS2, internal lab contributors). The second individual also had a history highly specific for HNF4A-monogenic diabetes (neonatal hypoglycemia responsive to diazoxide, large for gestational age, MPC result >50%, negative genetic testing for ABCC8, HNF1A, and KCNJ11) (PP4_Moderate; PMID: 20164212, internal lab contributors). In this family the variant segregated with diabetes with two informative meioses; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 20164212, internal lab contributors). Taken together, this collective evidence supports the classification of this variant as pathogenic for HNF4A-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PS2, PP4_Moderate PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1310372689/MONDO:0015967/085 2024-12-09 2024-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8871 biolink:causes MONDO:0006373 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0032000 infores:hetionet CHEBI:474180 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0034642 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0003123 infores:hetionet CHEBI:6076 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0000731 infores:hetionet CHEBI:44423 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0233407 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040435 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017160 infores:hetionet CHEBI:167309 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0013144 infores:hetionet CHEBI:16335 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0028643 infores:hetionet CHEBI:66903 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0002453 infores:hetionet CHEBI:6775 biolink:causes HP:6000686 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0241254 infores:hetionet CHEBI:3216 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0010520 infores:hetionet CHEBI:114785 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0018932 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0162529 infores:hetionet CHEBI:46081 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0020443 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0040046 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0006325 infores:hetionet CHEBI:3732 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0016204 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0332575 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0007971 infores:hetionet CHEBI:50818 biolink:causes MONDO:0043283 infores:ubergraph knowledge_assertion manual_agent CHEBI:50818 MONDO:0043283 CHEBI:3223 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0233571 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0233494 infores:hetionet CHEBI:6067 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004604 infores:hetionet NCBIGene:10274 biolink:causes MONDO:0030912 infores:monarchinitiative not_provided not_provided HGNC:11354 MONDO:0030912 uuid:e5e44360-b2bd-4aba-817a-4f18e4fe47de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0340464 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235639 infores:hetionet CAID:CA376059451 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059451 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.634T>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Tyrosine by Asparagine at amino acid 212 (p.Tyr212Asn). This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059451/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63620 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0040046 infores:hetionet CHEBI:9570 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0232849 infores:hetionet CHEBI:39585 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0043094 infores:hetionet NCBIGene:26580 biolink:causes MONDO:0010043 infores:monarchinitiative not_provided not_provided HGNC:15832 MONDO:0010043 uuid:b4162c93-4730-413d-9aad-e27001f7d8ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017168 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0853149 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151571 infores:hetionet CAID:CA380145283 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145283 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.13A>T is a missense variant predicted to cause substitution of Methionine by Leucine at amino acid 5 (p.Met5Leu).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145283/MONDO:0000573/124 2024-04-29 2024-04-29 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:9430ZR8ZAN biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1565489 infores:hetionet CHEBI:3761 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0012569 infores:hetionet CHEBI:64312 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003578 infores:hetionet NCBIGene:64072 biolink:causes MONDO:0011067 infores:monarchinitiative not_provided not_provided HGNC:13733 MONDO:0011067 uuid:3f963644-3ec5-4f99-a0fd-17e70310d682 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0026821 infores:hetionet CHEBI:5296 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C2239176 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0017178 infores:hetionet CHEBI:5165 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0549249 infores:hetionet CAID:CA405667952 biolink:causes MONDO:0007783 infores:clingen CAID:CA405667952 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with glutamine at codon 2359 of the RYR1 protein, p.(Arg2359Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00001, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:24433488, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.873) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405667952/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:5130 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0947912 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0015397 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006849 infores:hetionet CHEBI:8871 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0338831 infores:hetionet CHEBI:107736 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C1443060 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0342579 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0027051 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0948089 infores:hetionet CAID:CA2573150332 biolink:causes MONDO:0100216 infores:clingen CAID:CA2573150332 MONDO:0100216 PMID: Likely Pathogenic PVS1, PM2_Supporting PM6, BA1, BP4, BP2, PP3, PP4, PP1, PM5, PM1, PS4, PS1, PS3, PS2, BS1, BS3, BS4 The NM_177438.2:c.5135dup (p.Leu1712PhefsTer11) variant in DICER1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 24/27 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1, PM2_Supporting. (Bayesian Points: 9; VCEP specifications version 1.3.0; 06/24/2025 DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573150332/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:162514 biolink:causes MONDO:0100296 infores:monarchinitiative not_provided not_provided HGNC:18084 MONDO:0100296 uuid:5e5dd8f2-9bf5-4665-92c5-26bdd17c12b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C2717961 infores:hetionet CHEBI:36795 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0852911 infores:hetionet CHEBI:8356 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0700200 infores:hetionet CHEBI:2663 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0030193 infores:hetionet CHEBI:102216 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0041834 infores:hetionet CHEBI:7627 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0702166 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0740447 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0740447 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0009806 infores:hetionet CHEBI:51450 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0037763 infores:hetionet CAID:CA120805 biolink:causes MONDO:0100437 infores:clingen CAID:CA120805 MONDO:0100437 PMID: Likely Pathogenic PS3_Supporting, PP1_Moderate, PP3_Strong, PP4, PM2_Supporting NM_001034853.2(RPGR):c.517G>C (p.Gly173Arg) is a missense variant encoding the substitution of glycine by arginine at amino acid 173. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) showing a milder phenotype in female family members (1 pt), early-onset (1 pt), rod involvement greater than cone (1 pt), visual field constriction (0.5 pts), night blindness (0.5 pts), myopia (0.5 pts), and reduced visual acuity (0.5 pts), which together are specific for RPGR-related retinopathy (7 points, PMID: 14627685, PP4). The proband also showed systemic phenotypes including episodes of respiratory tract infections, recurrent ear infections, pan-sinusitis, and a mild high frequency hearing loss (PMID: 14627685). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 14627685). The computational predictor REVEL gives a score of 0.972, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.09 for donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. Exogenously expressed RPGR harboring the variant exhibits reduced interaction with RPGRIP1 and RAB8A in yeast-2-hybrid and pulldown experiments (PMID: 20631154, PMID: 23213406, PS3_Supporting). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PP3_Strong, PS3_Supporting, PP1_Moderate, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA120805/MONDO:0100437/106 2025-09-07 2025-09-08 X-linked inheritance HP:0001417 Supports CHEBI:2453 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0002994 infores:hetionet CHEBI:64355 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0232461 infores:hetionet CHEBI:68554 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0022346 infores:hetionet CHEBI:51041 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0740394 infores:hetionet CHEBI:85161 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0015967 infores:hetionet CHEBI:49713 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0151908 infores:hetionet CHEBI:28901 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0854467 infores:hetionet CHEBI:63631 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235996 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0002871 infores:hetionet CHEBI:64355 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0220981 infores:hetionet CHEBI:75045 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0855333 infores:hetionet CAID:CA2573106064 biolink:causes MONDO:0007453 infores:clingen CAID:CA2573106064 MONDO:0007453 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.1307_1319del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 436 (NM_000162.5), adding 174 novel amino acids before encountering a stop codon (p.(Ile436SerfsTer174)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (internal lab contributors). In summary, c.1307_1319del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106064/MONDO:0007453/086 2023-06-20 2023-06-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50122 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020615 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0948594 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0855242 infores:hetionet CAID:CA414898819 biolink:causes MONDO:0010602 infores:clingen CAID:CA414898819 MONDO:0010602 PMID: Likely Benign BP7, BP4 PM2 The c.6429+8606G>C variant has a SpliceAI score that predicts no impact on splicing: Acceptor Loss: 0.00, Donor Loss: 0.01, Acceptor Gain: 0.03, Donor Gain: 0.00 meeting BP4 and BP7, given this variant in intronic. This variant was not present in gnomAD but PM2_Supporting was not applied due to a concern of poor coverage in this region. Other reported variants in gnomAD are downstream of this variant, but application of this rule code would not alter its classification, so the code is not applied out of an abundance of caution. No report of this variant in patients with hemophilia A was identified in the literature. In summary, based on the evidence available at this time, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: BP4, BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414898819/MONDO:0010602/071 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:231425 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0235031 infores:hetionet CHEBI:28864 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0015967 infores:hetionet CHEBI:42944 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0007820 infores:hetionet NCBIGene:2752 biolink:causes MONDO:0970945 infores:monarchinitiative not_provided not_provided HGNC:4341 MONDO:0970945 uuid:7a6cc22e-5de3-4811-8eca-ea625de97d86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1328337 infores:hetionet CHEBI:4681 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0039240 infores:hetionet CHEBI:6801 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0085593 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0041582 infores:hetionet CHEBI:37941 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0023218 infores:hetionet CHEBI:127780 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0039239 infores:hetionet CHEBI:8871 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085615 infores:hetionet CAID:CA060644 biolink:causes MONDO:0007783 infores:clingen CAID:CA060644 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with valine at codon 4640 of the RYR1 protein, p.(Met4640Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (Heytens, 2019). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.911) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA060644/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:283989 biolink:causes MONDO:0009166 infores:monarchinitiative not_provided not_provided HGNC:27561 MONDO:0009166 uuid:7ee56374-f94f-4b47-97f5-1ee5bd8fe1a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C1167965 infores:hetionet CHEBI:8428 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0027497 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0235416 infores:hetionet CHEBI:9570 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0019156 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001208 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0264490 infores:hetionet CHEBI:3757 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0231218 infores:hetionet CHEBI:7931 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0235710 infores:hetionet CHEBI:6904 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0162830 infores:hetionet CAID:CA000478 biolink:causes MONDO:0017623 infores:clingen CAID:CA000478 MONDO:0017623 PMID: Pathogenic PVS1, PM2, PM6_Strong PTEN c.493-2A>G (IVS5-2A>G) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222118.9)PM2: Absent in large sequenced populations. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000478/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51364 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020649 infores:hetionet CHEBI:3638 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0349506 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0700051 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D008100 DB00916_MESH_D008100_1 UNII:R43D2573WO biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0040586 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0267792 infores:hetionet CHEBI:64355 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0032781 infores:hetionet GO:0141145 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:0141145 GO:0044085 UMLS:C0657912 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0086439 infores:hetionet CHEBI:50777 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0006142 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0009806 infores:hetionet CHEBI:135736 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1145670 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0004936 infores:hetionet CAID:CA229439 biolink:causes MONDO:0009861 infores:clingen CAID:CA229439 MONDO:0009861 PMID:7556322PMID:23514811PMID:8829656PMID:8829656PMID:11161839 Pathogenic PP4_Moderate, PM2, PM3_Very Strong, PS3 PP3 The PAH variant c.136G>A (p.Gly46Ser) was detected in four alleles associated with moderate PKU (phenylalanine values of 900-1200 μmol/L). Patients included in the study had serum phenylalanine levels above 150 μmol/L and normal urinary excretion of biopterin and neopterin (PMID: 7556322).The variant c.136G>A (p.Gly46Ser) was documented in trans with seven other PAH pathogenic or likely pathogenic variants in 15 Norwegian patients with mild and classic PKU. Haplotype analysis of index cases and parents was conducted, when necessary siblings were also investigated (PMID: 8829656). PM3_Very Strong (14 points).In vitro, enzyme activity assays demonstrated a residual activity for the PAH variant c.136G>A (p.Gly46Ser) between 26% and 38% compared to the wild type PAH when using the mammalian cell-free transcription-translation system (PMID: 11161839).According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.00015). In silico modeling, predictions are conflicting. According to SIFT this variant is predicted to be tolerated, probably damaging by Polyphen 2-HVAR and disease-causing Automatic by Mutation Taster.In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong, PP4 met_moderate, and PS3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229439/MONDO:0009861/006 2019-12-22 2019-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47381 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0036454 infores:hetionet CHEBI:63611 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009421 infores:hetionet CHEBI:9667 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0006277 infores:hetionet CAID:CA2061282 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061282 MONDO:0015924 PMID: Likely Benign BP4, PM1, BS1 PM2, PP3, BA1, PS4 The BMPR2 missense variant c.1037C>A (p.Thr346Asn) is located in exon eight. This variant has been found with a frequency of 0.00006 in gnomAD version2.1.1 controls, although it is present above 0.1% in Ashkenazi Jewish (0.159%, 16/10,078 total alleles) (BS1_met). The variant is predicted to have no effect on protein function with REVEL score of 0.239, which meets the threshold for BP4 (<0.25). No effect on splicing predicted as SpliceAI score is 0. The missense change is located within the conserved kinase domain but there are no functional data to support the amino acid residue as critical or non-critical (PM1_met with no upgrade). In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, BP4, PM1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061282/MONDO:0015924/125 2024-05-01 2024-05-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6640 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0018524 infores:hetionet GO:2001014 biolink:causes GO:0007519 infores:ubergraph knowledge_assertion manual_agent GO:2001014 GO:0007519 CHEBI:49960 biolink:causes HP:6000377 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1112565 infores:hetionet CHEBI:4530 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0018824 infores:hetionet CAID:CA229475 biolink:causes MONDO:0009861 infores:clingen CAID:CA229475 MONDO:0009861 PMID:8406445 Uncertain Significance PP4_Moderate, PM2, PP3 PM5 The c.190C>A (p.His64Asn) variant in PAH has been reported in a Danish mild PKU patient. Serum Phe levels exceeded 600 umol/L and other causes of hyperphenylalaninemia had been ruled out. It was In cis with p.T63P. PMID: 8406445. The c.190C>A variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229475/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBITaxon:481310 biolink:causes MONDO:0024283 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:481310 MONDO:0024283 CHEBI:3732 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013378 infores:hetionet CHEBI:7986 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0231218 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0039446 infores:hetionet CHEBI:9649 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151480 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0233494 infores:hetionet GO:2001204 biolink:causes GO:0030316 infores:ubergraph knowledge_assertion manual_agent GO:2001204 GO:0030316 CAID:CA226567 biolink:causes MONDO:0100368 infores:clingen CAID:CA226567 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting BA1, PM3, BS1 The RPE65 c.615_616del (p.Ile206fs) variant, previously known as 669delCA, is a frameshift variant that introduces a premature stop codon into exon 6 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 1 patient with this variant exhibited nonrecordable ERG responses from rods (0.5 pts) and cones (1 pt), congenital night blindness (0.5 pts), onset between birth and five years (1 pt), decreased peripheral vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6 pts total, PMID: 11095629, PP4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226567/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports GO:0014016 biolink:causes CL:0000031 infores:ubergraph knowledge_assertion manual_agent GO:0014016 CL:0000031 CHEBI:83531 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0917801 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0022408 infores:hetionet CHEBI:3219 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235378 infores:hetionet CHEBI:72564 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0018979 infores:hetionet CHEBI:50663 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0232462 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0851341 infores:hetionet CAID:CA7624046 biolink:causes MONDO:0021060 infores:clingen CAID:CA7624046 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.896-5T>C variant in the MAP2K1 gene is 0.0328% (10/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7624046/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:0010695 biolink:causes GO:1905047 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:1905047 CHEBI:63631 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030193 infores:hetionet CHEBI:9939 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0003578 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0018799 infores:hetionet CHEBI:16335 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0042023 infores:hetionet CAID:CA235299 biolink:causes MONDO:0021060 infores:clingen CAID:CA235299 MONDO:0021060 PMID:20949621 Pathogenic PP3, PP2, PM2_Supporting, PS4, PS3_Supporting, PM6_Very Strong BA1, BP4, BP1, BS1, BS3 The c.65A>G variant in the KRAS gene is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 22 (p.Glln22Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.749 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in several individuals with clinical features of a RASopathy, with 2 unconfirmed de novo occurrences (PS4, PM6_VeryStrong; GeneDx, Partners LMM, HudsonAlpha Institute for Biotechnology, Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, ARUP Laboratories, Molecular Genetics and Genomics; ClinVar: SCV000207881.10; SCV000198473.4; SCV001870321.1; SCV000678231.1; SCV000604082.1). In vitro functional studies showed that this variant enhanced ERK activation (PS3_Supporting; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM6_VeryStrong, PS4, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235299/MONDO:0021060/044 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Supports CHEBI:453011 biolink:causes HP:0012710 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0027343 infores:hetionet NCBIGene:7123 biolink:causes MONDO:0859568 infores:monarchinitiative not_provided not_provided HGNC:11891 MONDO:0859568 uuid:feb0c3d5-3fcb-4a7c-bf3a-47ee0b6dac6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0030554 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0233571 infores:hetionet CHEBI:80630 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0026821 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0948594 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1696574 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1696574 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0234913 infores:hetionet CHEBI:4911 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0235378 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0021400 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003873 infores:hetionet CAID:CA645509251 biolink:causes MONDO:0007750 infores:clingen CAID:CA645509251 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1, PP4 The NM_000527.4(LDLR):c.-150A>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509251/MONDO:0007750/013 2025-03-28 2025-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA16020780 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020780 MONDO:0009861 PMID:30459323 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.364C>T (p.Pro122Ser) missense variant in PAH was reported in a Spanish patient with Mild HPA. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. This variant was detected in trans with pathogenic variant p.Asp415Asn (PMID 27121329). It was found at extremely low frequency in gnomAD (MAF=0.00003) and predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4 moderate, and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020780/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:691037 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0020555 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0019360 infores:hetionet GO:1904838 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1904838 GO:0019953 NCBIGene:7046 biolink:causes MONDO:0012212 infores:monarchinitiative not_provided not_provided HGNC:11772 MONDO:0012212 uuid:d8a53ccd-8d8b-4a49-a272-2f43af4313a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0012833 infores:hetionet CHEBI:50275 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013428 infores:hetionet CHEBI:50841 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0241442 infores:hetionet CHEBI:8356 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0231530 infores:hetionet CHEBI:3127 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0006277 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0003123 infores:hetionet CHEBI:2955 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0001175 infores:hetionet CHEBI:50729 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0019080 infores:hetionet CHEBI:4514 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0036974 infores:hetionet GO:0110057 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:0110057 GO:0001568 CHEBI:5855 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0302295 infores:hetionet CHEBI:27882 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0027947 infores:hetionet CHEBI:28915 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0015967 infores:hetionet NCBIGene:51360 biolink:causes MONDO:0049223 infores:monarchinitiative not_provided not_provided HGNC:15455 MONDO:0049223 uuid:517379f8-a8de-493c-b88b-90ebe4f91608 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0149745 infores:hetionet CHEBI:64312 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C2830004 infores:hetionet CAID:CA2573320359 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573320359 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PM1_Supporting PM4, PS4 The c.953_958dup variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a 6 base pair insertion resulting in the in-frame addition of 2 amino acids at codon 318 (p.(Leu318_Leu319dup)) within exon 8 of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). While the c.956_958dup variant is predicted to change the length of the protein due to an in-frame insertion of 2 amino acids, it is in a repeat region where the reference sequence contains a tract of 5 leucines and there is a relatively common 4 leucine variant (c.956_958del p.Leu319del, Popmax filtering allele frequency = 0.00011), and PM4 was not applied. This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP. This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes and/or neonatal hypoglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 20164212, internal lab contributors). One of these individuals had a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; PMID: 20164212,internal lab contributors). In summary, c.953_958dup meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573320359/MONDO:0015967/085 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C3665347 infores:hetionet CHEBI:6129 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0242429 infores:hetionet CAID:CA120561 biolink:causes MONDO:0044970 infores:clingen CAID:CA120561 MONDO:0044970 PMID: Likely Pathogenic PP3, PP1, PM2_Supporting, PS4_Moderate, PS3_Supporting PS2, PM6 The m.3256C>T variant in MT-TL1 has been reported in four individuals in the literature and an additional four cases were seen by experts on this panel. Affected individuals had primary mitochondrial disease with variable features including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) phenotype, neurologic involvement (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, seizures, ataxia, myoclonus); neuromuscular involvement (muscle atrophy, progressive myopathy); cardiac involvement (cardiac failure); ophthalmologic involvement (ophthalmoplegia, ptosis, central vision loss); ENT involvement (hearing loss); endocrine involvement (hashimoto thyroiditis, diabetes mellitus); lab abnormalities (elevated blood and CSF lactate and pyruvate); and brain imaging findings (progressive brain atrophy); with heteroplasmy levels in multiple tissues ranging from 8% - 98% (PS4_moderate; PMIDs: 19941338, 10953207, 7804130, 8254046). This variant segregated with disease in a single reported family as the proband’s healthy sister had undetectable levels of variant in blood; the proband’s mother was decreased; and the proband was heteroplasmic for the variant in numerous tissues: 64% (muscle), 8% (white blood cells), 48% (first passage cultured fibroblasts), and 18% (hair roots) (PP1; PMID: 8254046). There are no reports of de novo occurrences of this variant to our knowledge. Ragged red fiber (RRF) analysis in muscle noted only partially impaired COX activity. However, when analyzed for levels of mutant genomes, RRFs were essentially homoplasmic for mutant mtDNAs (range 94-97%). Normal (non-RRFs) had much lower levels of mutant genomes (34-75%). The percentage of mutant mtDNA in total the muscle was 64% (PS3_supporting: PMID: 8254046). This variant is absent from Mitomap's 51,863 sequences (AF=0.00%); Helix's 196,554 sequences (AF=0.00%); and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 93.70%, as does HmtVar with a score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of pathogenic given the overwhelming evidence of pathogenicity (strong single fiber studies, absent in population databases and present in eight individuals with features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PP1, PS3_supporting Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120561/MONDO:0044970/015 2022-08-08 2022-10-13 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:2379 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0033975 infores:hetionet CHEBI:7936 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0002994 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0919625 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0919625 infores:hetionet CHEBI:3441 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0038325 infores:hetionet CHEBI:127342 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0856054 infores:hetionet CHEBI:6832 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C2830004 infores:hetionet CHEBI:17026 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0340865 infores:hetionet CHEBI:48669 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0079102 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020649 infores:hetionet CHEBI:50131 biolink:causes MONDO:0000266 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C2350530 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151882 infores:hetionet CHEBI:10110 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1142412 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0332534 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0235416 infores:hetionet CHEBI:44915 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0085611 infores:hetionet CHEBI:4975 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0085631 infores:hetionet CHEBI:47381 biolink:causes HP:0100583 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0339293 infores:hetionet CHEBI:101278 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0220870 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2711227 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009450 infores:hetionet CHEBI:4445 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1761613 infores:hetionet CHEBI:8874 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0012569 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011616 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023418 infores:hetionet CHEBI:10650 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020546 infores:hetionet CAID:CA412372934 biolink:causes MONDO:0010725 infores:clingen CAID:CA412372934 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PP1_Strong, PP4_Moderate, PP3_Strong The NM_000330.4(RS1):c.227T>A variant is a missense variant encoding the substitution of Valine with Aspartic acid at position 76. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.942, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family (PP1_Strong; PMID: 28060400). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years and showing retinal detachment, which together are highly specific for X-linked retinoschisis (PMID: 28060400, PP4_moderate). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_strong, PP4_moderate, and PP1_strong (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412372934/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports NCBIGene:27247 biolink:causes MONDO:0975796 infores:monarchinitiative not_provided not_provided HGNC:16287 MONDO:0975796 uuid:08c15c88-e4a7-4a78-a3e8-37fa7d1708ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235146 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018939 infores:hetionet CHEBI:5778 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0239377 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0016397 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0026946 infores:hetionet CHEBI:63619 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C3665347 infores:hetionet CHEBI:135005 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0011603 infores:hetionet CHEBI:28939 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0015967 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0236068 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0036454 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002170 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0027651 infores:hetionet CHEBI:42944 biolink:causes MONDO:0004648 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011269 infores:hetionet CHEBI:3286 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0002170 infores:hetionet CAID:CA414908714 biolink:causes MONDO:0010602 infores:clingen CAID:CA414908714 MONDO:0010602 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting The c.5488G>T (p.Glu1830Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 16/26 and expected to result in nonsense-mediated mRNA decay, so PVS1 criteria is met. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3), which meets PM2_Supporting criteria. The c.5488G>T (p.Glu1830Ter) variant is not reported in patients with Hemophilia A in the literature to the best of our knowledge; however 1 patient with severe hemophilia A is reported from internal laboratory data. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PM2_Supporting, PS4_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414908714/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:71219 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0235996 infores:hetionet CHEBI:3638 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0015371 infores:hetionet CHEBI:3614 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0038363 infores:hetionet CHEBI:63605 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0004093 infores:hetionet CHEBI:66964 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0013144 infores:hetionet CHEBI:7852 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011606 infores:hetionet CHEBI:50777 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0002792 infores:hetionet CHEBI:63608 biolink:causes MONDO:0023483 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0158353 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0854097 infores:hetionet CHEBI:10119 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0003467 infores:hetionet CHEBI:64321 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0018681 infores:hetionet CAID:CA16041866 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041866 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID: 9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1,PM2_supporting,PP4). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041866/MONDO:0008723/021 2022-09-20 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CAID:CA367402081 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402081 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting, PS3_Moderate PS4 The c.409C>G variant in the glucokinase gene, GCK, causes an amino acid change of histidine to aspartic acid at codon 137 (p.(His137Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The variant is absent in gnomAD v2.1 and v4.1 (PM2_Supporting). It is predicted to be deleterious by computational evidence, with a REVEL score of 0.747, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.26, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 22761713). Another missense variant at the same codon, c.410A>G, p.(His137Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). The p.His137Asp variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18382660, Internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 18382660). This variant segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; PMID: 18382660, internal lab contributors). In summary, c.409C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS3_Moderate, PP4_Moderate, PM2_supporting, PM5_Supporting, PP1, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402081/MONDO:0015967/086 2025-04-17 2025-04-17 Semidominant inheritance HP:0032113 Supports CHEBI:46295 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0021400 infores:hetionet CAID:CA254851 biolink:causes MONDO:0044970 infores:clingen CAID:CA254851 MONDO:0044970 PMID: Likely Benign BP2, BS1 PP3, PP1, BA1, BP4, PS4, PS2, PS3, PM6, PM2 The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1992 (Leber Hereditary Optic Neuropathy or LHON, PMID: 1322638; hearing loss, PMID: 16500624), however other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at high frequencies in population databases. Furthermore, this variant has been seen in individuals with other well-known pathogenic mitochondrial DNA variants (family with LHON and m.3460G>A, PMID: 7901141; family with hearing loss and m.1555A>G, PMID: 16152638; BP2). The variant was seen at homoplasmy in affected and unaffected family members in several of these publications precluding consideration of segregation evidence. There are no reported de novo occurrences of this variant to our knowledge. Some functional characterization was performed in patient cells, however abnormalities noted were nonspecific and other genetic etiologies were not assessed (PMID: 1322638). This variant is present at considerable frequencies in population databases (BS1). The frequency in the MITOMAP GenBank sequences is 206/59,389 (0.347%; 12/12 individuals in Hg V7, 3/3 individuals in Hg H40b, 4/4 individuals in V7b, 4/4 individuals in W4b, 84/86 individuals in V7a, also seen in individuals from M22b, M38a, H11, HV20, P2, B2e, and others). The frequency in gnomAD v3.1.2 is 302/56,419 (0.535%). Indeed, there are 302 homoplasmic occurrences (seen in all populations except Amish and Middle Eastern, seen across every haplogroup listed; seen in individuals ages 30 years to >80 years) in addition to 10 heteroplasmic occurrences (seen in multiple populations, haplogroups, and heteroplasmy levels). The frequency in the Helix dataset is 775/195,983 (0.395%). Indeed, there are 775 homoplasmic occurrences (seen across many haplogroups) and 24 heteroplasmic occurrences (seen across many haplogroups). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP2. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254851/MONDO:0044970/015 2023-06-26 2023-08-03 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA120564 biolink:causes MONDO:0044970 infores:clingen CAID:CA120564 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PS2_Supporting PS3, PM6 The m.3252A>G variant in MT-TL1 has been reported in five unrelated families with primary mitochondrial disease (PS4_moderate). Some affected individuals had features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and/or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Other manifestations include intellectual disability, pigmentary retinopathy, diabetes, dementia, renal failure, heart block, and hypoparathyroidism; and muscle biopsies showed ragged red fibers and complex I deficiency. Heteroplasmy levels ranged from 18% to greater than 90% in affected individuals (PMID: 8111377; of note, two cases were included in manuscripts without a PMID: Seed et al., 2021, Tan et al., 2023; and two cases were provided by Expert Panel members). The variant segregated with disease manifestations in two families (PP1_moderate). In one, the proband had MELAS and had the variant present at 30% heteroplasmy in blood, 19% in lymphoblasts, and 76% in muscle. The mother had progressive generalized weakness, spastic paraparesis, and dysarthria onset in her 40s and died at 58 years following a stroke-like episode, and was found to have the variant present at 50% heteroplasmy in muscle (PMID: 8111377). In one of the cases provided by an Expert Panel member, the proband had the variant present at >90% heteroplasmy. The less severely affected mother had the variant present at 55% in urine, 40% in buccal, and 18% in blood. The variant was present in the maternal grandmother at 19% in buccal sample, and at lower heteroplasmy levels in a maternal uncle with hearing loss. This variant occurred de novo in one of the reported individuals (absent in blood from mother; PS2_supporting, Tan et al., 2023). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PS2_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120564/MONDO:0044970/015 2024-09-09 2025-04-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:50742 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0000737 infores:hetionet CHEBI:39867 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0037763 infores:hetionet CHEBI:16914 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C3665596 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0086132 infores:hetionet CHEBI:253342 biolink:causes MONDO:0020675 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C2004435 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0948594 infores:hetionet CHEBI:47381 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0152030 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0232492 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0235146 infores:hetionet CHEBI:10125 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0232462 infores:hetionet CHEBI:28748 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0740394 infores:hetionet CHEBI:63622 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0041657 infores:hetionet CHEBI:63620 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085593 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0012833 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020456 infores:hetionet CAID:CA414816540 biolink:causes MONDO:0044970 infores:clingen CAID:CA414816540 MONDO:0044970 PMID: Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4, PM6_Supporting, PP1_Moderate The m.13094T>C (p.V253A) variant in MT-ND5 has been reported in at least 25 individuals with primary mitochondrial disease from 18 families. Affected individuals had variable ages of onset (first months of life to childhood to 20s). Features included Leigh syndrome, MELAS, and LHON. Heteroplasmy levels were variable among tissues and affected individuals, however there are no reports of the variant being homoplasmic to our knowledge (PS4; PMIDs: 29506874, 29479304, 28429146, 23918514, 22577219, 20818383, 18977334; https://www.chop.edu/stories/melas-syndrome-ginas-and-her-familys-story). This variant segregated with disease in multiple families as healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29506874, 29479304). This variant occurred de novo in at least two individuals (PM6_supporting, PMIDs: 23918514, 18977334). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from an individual with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). Cybrid studies show two different classes of function defects (PS3_moderate): (1) complex I/CS activity ratio is highly correlated with the percentage of the variant and loss of ND5 is associated with instability of the membrane arm of Complex I (PMID: 18977334) and (2) autophagy, determined as LC3B-II/Actin levels, was significantly increased in mutant cybrids (PMID: 29479304). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.89 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PP1_moderate, PS3_moderate, PM6_supporting, PS4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414816540/MONDO:0044970/015 2022-07-25 2022-09-02 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:465284 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042075 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0017160 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004095 infores:hetionet CHEBI:31236 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232292 infores:hetionet CHEBI:50924 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027497 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0541819 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0541819 infores:hetionet CHEBI:17688 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0035232 infores:hetionet NCBIGene:1181 biolink:causes MONDO:0014292 infores:monarchinitiative not_provided not_provided HGNC:2020 MONDO:0014292 uuid:72dff675-7e83-4dfb-a973-e30f75ff76ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020580 infores:hetionet CHEBI:42068 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0085593 infores:hetionet CAID:CA340740550 biolink:causes MONDO:0100368 infores:clingen CAID:CA340740550 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4, PM2_Supporting The NM_000329.3(RPE65):c.1590C>A (p.Phe530Leu) variant is a missense variant in RPE65 causing a substitution of phenylalanine with leucine at position p.530. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.888, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the c.200T>G, p.L67R variant confirmed in trans (1 pt) or the c.118G>A p.Gly40Ser variant confirmed in trans (1 pt) (PMIDs: 36729443, 26047050), which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). This variant has also been reported in the compound heterozygous state with the p.Ala507Val and the c.335G>A p.Cys112Tyr, but were not counted for additional points to avoid circularity. At least one proband harboring this variant exhibits a phenotype including severely decreased rod ERG responses (0.5), symptomatic onset between birth and age five years (1), evidence of cone involvement on ERG (1), white/yellow dots on color photography in the context of severe retinal dysfunction (2), previous 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 33952291, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3_Strong, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340740550/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports CAID:CA409105356 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105356 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate, PM1_Supporting, PP1_Strong The c.320C>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to aspartic acid at codon 107 (p.(Ala107Asp)) of NM_175914.5. This variant failed quality control metrics in gnomAD v2.1.1; however, it was absent in gnomAD genomes v3.1 and additional population databases and therefore PM2_Supporting will be applied per guidance of the ClinGen MDEP (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). The variant segregated with diabetes, with at least 7 informative meioses in 3 families (PP1_Strong; internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributor). This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.938, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.320C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PP1_Strong, PP4_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105356/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CAID:CA114372 biolink:causes MONDO:0009861 infores:clingen CAID:CA114372 MONDO:0009861 PMID:9634518PMID:7981714PMID:9298832PMID:7981714PMID:9298832PMID:8088845PMID:11161839 Pathogenic PM5, PP4_Moderate, PM3_Very Strong PM2, PP3, PS3 PAH-specific ACMG/AMP criteria applied: PM5: V245L Pathogenic; PP4_Moderate: Seen in at least 7 MHP patients. Exclusion of a defect in tetrahydrobiopterin metabolism. Upgraded per ClinGen Metabolic Workgroup. (PMID:7981714; PMID:9298832; PMID:9634518); PM3_VeryStrong: V245A detected with IVS-12nt1, R252W, L194P (both P/LP), R408W (Path). Upgraded per ClinGen SVI Workgroup (PMID:7981714; PMID:9298832; PMID:8088845). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM5, PP4_Moderate, PM3_VeryStrong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114372/MONDO:0009861/006 2018-09-28 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6715 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0853117 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0178298 infores:hetionet CHEBI:51041 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0027796 infores:hetionet CHEBI:59750 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0016436 infores:hetionet CHEBI:63580 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042384 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0036572 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0020557 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0032285 infores:hetionet CHEBI:28445 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0026766 infores:hetionet CHEBI:9352 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0036974 infores:hetionet CHEBI:6367 biolink:causes MONDO:0000749 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151463 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0521591 infores:hetionet CHEBI:82960 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0015967 infores:hetionet NCBIGene:199720 biolink:causes MONDO:0030732 infores:monarchinitiative not_provided not_provided HGNC:18869 MONDO:0030732 uuid:a8d57d35-ba1c-4796-963d-7d960cf4be93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0740425 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0262977 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0262977 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0349506 infores:hetionet CHEBI:52010 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0020649 infores:hetionet CHEBI:65349 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0027441 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0948281 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0948281 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0042165 infores:hetionet CHEBI:68478 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0043144 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1611167 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1611167 infores:hetionet CHEBI:3723 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151744 infores:hetionet CHEBI:4551 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C1698480 infores:hetionet CHEBI:41879 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0022568 infores:hetionet CHEBI:44241 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0020538 infores:hetionet CAID:CA2259460 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259460 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.438+8A>T variant in the MAP2K1 gene is 0.075% (19/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259460/MONDO:0021060/004 2018-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:0060762 biolink:causes GO:0060603 infores:ubergraph knowledge_assertion manual_agent GO:0060762 GO:0060603 CHEBI:6149 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0035232 infores:hetionet CAID:CA10014520 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014520 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP7, PVS1, PM2, PM6, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.414A>C (p.Glu138Asp) is a variant which affects a residue within the Runt Homology domain (AA89-294) but does not impact a residue which has been established as a hotspot (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014520/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA340744135 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744135 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000329.3(RPE65):c.1084C>T (p.Gln362Ter) is a nonsense variant that introduces a premature stop codon into exon 10 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 32581362, PM3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744135/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5165 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0031350 infores:hetionet CHEBI:4856 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0041657 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151826 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020651 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0080274 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0424823 infores:hetionet CHEBI:45327 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0085606 infores:hetionet GO:1905651 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:1905651 GO:0035295 NCBIGene:9663 biolink:causes MONDO:0012316 infores:monarchinitiative not_provided not_provided HGNC:14450 MONDO:0012316 uuid:63adfb45-32d0-41e7-a011-d82bc7862d6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0687707 infores:hetionet NCBIGene:55074 biolink:causes MONDO:0008939 infores:monarchinitiative not_provided not_provided HGNC:15822 MONDO:0008939 uuid:9663ec99-bef9-43bc-9732-f631cb00a931 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0043094 infores:hetionet CHEBI:15765 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0040034 infores:hetionet CAID:CA367397015 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397015 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PP4, PM2_Supporting The c.1322C>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Leu)) of NM_000162.5. This variant has a non-calculable Popmax filtering allele frequency, with absence in the gnomAD v2.1.1 European non-Finnish population and one copy in the African/African American subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 28726111). Another missense variant, c.1322C>G p.(Ser441Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Ser441Leu) (PM5_Supporting). In summary, c.1322C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP3, PP2, PP4, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397015/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:71417 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0028084 infores:hetionet CHEBI:204734 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0010200 infores:hetionet CHEBI:77733 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0028949 infores:hetionet CHEBI:10124 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0002418 infores:hetionet CHEBI:63791 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0033774 infores:hetionet CAID:CA913173949 biolink:causes MONDO:0044970 infores:clingen CAID:CA913173949 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PP3, BA1, PS4, PS2, PS3, BS1, BS3, PM6, PM2 The m.15467A>G (p.T241A) variant in MT-CYB was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on March 28, 2023. There are no individuals or families with this variant reported in the medical literature to our knowledge. There are several occurrences in population databases. This variant is present in 0.083% of individuals in GenBank MITOMAP sequences (49/59,389; including multiple individuals from haplogroup T1a), in 0.023% of individuals in gnomAD v3.1.2 (13/56,431; 13 homoplasmic occurrences, seen in individuals from several haplogroups), and in 0.031% of individuals in the Helix dataset (60/195,983; seen in individuals from several haplogroups). In silico tools (APOGEE) predict this variant to be neutral (score of 0.47, BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913173949/MONDO:0044970/015 2023-03-28 2023-03-29 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5165 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C2830004 infores:hetionet CHEBI:43968 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0025222 infores:hetionet CHEBI:39585 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0013378 infores:hetionet CHEBI:31413 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0009806 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0162119 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027765 infores:hetionet CHEBI:681850 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0151723 infores:hetionet CHEBI:8093 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0015230 infores:hetionet CHEBI:45863 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0001339 infores:hetionet CHEBI:10127 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013428 infores:hetionet CHEBI:3640 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0002170 infores:hetionet CHEBI:147675 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00249 UMLS:C0235266 infores:hetionet CHEBI:82960 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0007286 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0008301 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0151905 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0015230 infores:hetionet CHEBI:144093 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042029 infores:hetionet NCBIGene:7157 biolink:causes MONDO:0011775 infores:monarchinitiative not_provided not_provided HGNC:11998 MONDO:0011775 uuid:18da9168-4fbc-4474-8db9-1f2c939f513e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64321 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0043144 infores:hetionet CHEBI:31536 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0162283 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0009319 infores:hetionet CHEBI:3723 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0393761 infores:hetionet CHEBI:474180 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0085593 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004245 infores:hetionet CHEBI:4027 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0919924 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0281981 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015469 infores:hetionet CHEBI:175901 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C2830004 infores:hetionet CAID:CA303154 biolink:causes MONDO:0100135 infores:clingen CAID:CA303154 MONDO:0100135 PMID: Pathogenic PM6_Strong, PM2_Supporting, PS4, PP3_Moderate BA1, BP4, PM1, BS1 The c.2792G>A variant in SCN1A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 931 (p.Arg931His). The variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 2 individual(s) with Dravet syndrome (PMIDs: 28079314, 35072530) (PM6_Strong), and in at least 3 unrelated individuals with Dravet syndrome with unknown inheritance (PMIDs: 21719429, 31031587, 33067208) (PS4), with additional evidence available in the literature. The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6_Strong, PS4, PM2_Supporting, PP3_Moderate. (version 1; approved August 4, 2023). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA303154/MONDO:0100135/067 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49040 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0037199 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0426576 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0027765 infores:hetionet CAID:CA2573051031 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051031 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate The c.42_51delGGCCCTGCTCinsTG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 15 (NM_000545.8), adding 15 novel amino acids before encountering a stop codon (p.(Ala15GlyfsTer15)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.42_51delGGCCCTGCTCinsTG meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051031/MONDO:0015967/017 2022-03-31 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7466 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0011603 infores:hetionet CHEBI:3286 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0232487 infores:hetionet CHEBI:9571 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0220870 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0006145 infores:hetionet CHEBI:8354 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C2830004 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0178298 infores:hetionet CHEBI:32221 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C2830004 infores:hetionet CHEBI:9352 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0017181 infores:hetionet CHEBI:10119 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0009676 infores:hetionet CHEBI:5128 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0039070 infores:hetionet CHEBI:101853 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0018965 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026848 infores:hetionet CHEBI:6402 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030232 infores:hetionet CHEBI:8776 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0023530 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0948586 infores:hetionet CHEBI:6775 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235309 infores:hetionet CHEBI:8093 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0030554 infores:hetionet CHEBI:6846 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0014457 infores:hetionet CHEBI:7915 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0547030 infores:hetionet CHEBI:3757 biolink:causes MONDO:0002801 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0009377 infores:hetionet UMLS:C0145867 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0002962 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0235146 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0018939 infores:hetionet CHEBI:46081 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0424790 infores:hetionet CHEBI:27666 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0002871 infores:hetionet NCBIGene:157855 biolink:causes MONDO:0859352 infores:monarchinitiative not_provided not_provided HGNC:18867 MONDO:0859352 uuid:be84bf2f-90ab-47a3-985e-eebcdcdae985 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:24564 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0036572 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0151738 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151738 infores:hetionet CHEBI:8212 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0085623 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0024115 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0007642 infores:hetionet CHEBI:64317 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0085612 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0018939 infores:hetionet CHEBI:3510 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0042267 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0020538 infores:hetionet CHEBI:180905 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0027497 infores:hetionet CHEBI:59750 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0442886 infores:hetionet CHEBI:75998 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C2937358 infores:hetionet CHEBI:404903 biolink:causes MONDO:0041526 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0156543 infores:hetionet UMLS:C0657912 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0152031 infores:hetionet CHEBI:31624 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0242184 infores:hetionet CHEBI:38562 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0232462 infores:hetionet CAID:CA16020992 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020992 MONDO:0009861 PMID: Uncertain Significance PM2 PM3, PP4, PP3 The c.1312A>G (p.Asn438Asp) variant in PAH is not currently reported in the literature. This variant is absent from population databases (PM2). Computation evidence for this variant is conflicting. It is predicted damaging by SIFT, benign by PolyPhen2, disease causing by MutationTaster, and REVEL = 0.671. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020992/MONDO:0009861/006 2020-04-17 2020-04-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9757 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0013428 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151889 infores:hetionet CHEBI:3207 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0038450 infores:hetionet CHEBI:27786 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0003811 infores:hetionet CHEBI:15765 biolink:causes MONDO:0044843 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013423 infores:hetionet CHEBI:47780 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0221269 infores:hetionet CHEBI:8214 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0004093 infores:hetionet GO:0045113 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:0045113 GO:0010256 CHEBI:5118 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030794 infores:hetionet CHEBI:46295 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151744 infores:hetionet CAID:CA16020988 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020988 MONDO:0009861 PMID:24350308 Pathogenic PVS1, PM2, PP4 PM3 The c.1271T>A (p.Leu424*) variant in PAH meets criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Absent from population databases (1000 Genomes, ExAC). PVS1: Nonsense mutation, causing early termination of exon 12. NMD is predicted to occur. PP4: Patient has classic PKU (PMID:24350308).PM3_Supporting: Found to co-occur with PAH EX5del4232ins268 in one patient with classic PKU, but no additional studies to demonstrate phase of variants. No other PAH variants identified in patient (PMID:24350308). Not predicted to be responsive to BH4 (PMID:24350308) Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020988/MONDO:0009861/006 2020-08-07 2020-08-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8888 biolink:causes UMLS:C1142249 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1142249 infores:hetionet NCBIGene:8842 biolink:causes MONDO:0011957 infores:monarchinitiative not_provided not_provided HGNC:9454 MONDO:0011957 uuid:40ff7c83-e645-4199-946b-38d9a7adb95d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0003467 infores:hetionet CHEBI:7447 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0011991 infores:hetionet CHEBI:180905 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0002962 infores:hetionet CHEBI:4315 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0014742 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0025061 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0006277 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0149931 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0549373 infores:hetionet NCBIGene:56479 biolink:causes MONDO:0030911 infores:monarchinitiative not_provided not_provided HGNC:6299 MONDO:0030911 uuid:6d05ec4b-2e88-482a-b610-cc0070d57706 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:7F465U79Q1 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0546817 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042075 infores:hetionet CHEBI:9907 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0700361 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0333641 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0018802 infores:hetionet CHEBI:29007 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0009450 infores:hetionet CHEBI:135361 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C2830004 infores:hetionet CHEBI:5130 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C2047937 infores:hetionet CAID:CA8328621 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328621 MONDO:0100438 PMID:27268253PMID:32817338 Uncertain Significance PM2_Supporting, PP3_Moderate BS3, BS2, PM3 NM_014336.5(AIPL1):c.112C>T (p.Arg38Cys) is a missense variant resulting in replacement of arginine by cysteine at amino acid p.38. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00002727, with 44 / 1,613,698 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been found in the homozygous state in 1 adult individual in gnomAD version 4.1.0, which is lower than the LCA/eoRD VCEP threshold of ≥3, so BS2_Supporting is not met. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state, however, PM3 was not met because the second AIPL1 variant was not identified (PMID: 17964524). The variant has been identified in another proband from a cohort diagnosed with inherited retinal or optic nerve disorders in an unreported state of zygosity (PMID: 32483926). The computational predictor REVEL gives a score of 0.925, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.08 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The variant exhibited >90% enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, as well as cytoplasmic and nuclear localization similar to the wild-type (PMID: 27268253), however, these assays are not approved to meet BS3_Supporting. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328621/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7936 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0008350 infores:hetionet NCBITaxon:1769 biolink:causes MONDO:0005124 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1769 MONDO:0005124 CHEBI:8069 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0002888 infores:hetionet CHEBI:10125 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0038435 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0424605 infores:hetionet CAID:CA170409 biolink:causes MONDO:0010726 infores:clingen CAID:CA170409 MONDO:0010726 PMID: Benign BP5, BS1, BS2, PP3 "The allele frequency of the p.Thr311Met variant in MECP2 (NM_004992.3) is 0.022% and 0.01% in ""Other"" and South Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Thr311Met variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2) and found in 2 patients with an alternate molecular basis of disease (Baylor Genetics internal database, Invitae internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). As this variant meets 2 strong and 1 supporting benign criteria it can be classified as benign even though in silico predictions meet PP3. In summary, the p.Thr311Met variant in MECP2 is classified as benign for Rett syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5)." Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170409/MONDO:0010726/036 2022-02-18 2024-03-13 X-linked inheritance HP:0001417 Contradicts true CHEBI:28748 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042267 infores:hetionet NCBIGene:1301 biolink:causes MONDO:0011493 infores:monarchinitiative not_provided not_provided HGNC:2186 MONDO:0011493 uuid:5c8f788f-826b-4bda-b57a-64003435a853 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151827 infores:hetionet CHEBI:31705 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0002994 infores:hetionet CHEBI:70746 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0027441 infores:hetionet CHEBI:53760 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013456 infores:hetionet CHEBI:39585 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0016382 infores:hetionet CHEBI:9073 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0002888 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0006266 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0020649 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0013144 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013395 infores:hetionet CHEBI:61033 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0235996 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0239488 infores:hetionet CHEBI:70718 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0014457 infores:hetionet CHEBI:47898 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0034886 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0024305 infores:hetionet CHEBI:8228 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0003862 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0003123 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0025061 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235639 infores:hetionet CHEBI:119915 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0392699 infores:hetionet CHEBI:135930 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0032617 infores:hetionet CHEBI:51137 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0013144 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0235146 infores:hetionet CHEBI:585948 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0011991 infores:hetionet CHEBI:7454 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0016382 infores:hetionet CHEBI:5130 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1510410 infores:hetionet CHEBI:82960 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0011206 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0025362 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0232498 infores:hetionet CHEBI:474180 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004604 infores:hetionet CHEBI:44915 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020473 infores:hetionet CHEBI:51450 biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0277885 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0011053 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0009450 infores:hetionet CHEBI:45783 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0221170 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0521654 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0521654 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0233494 infores:hetionet CHEBI:31711 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0004134 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0013922 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014742 infores:hetionet CHEBI:63581 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0023530 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151773 infores:hetionet CHEBI:408174 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0037317 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0014742 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085584 infores:hetionet GO:0002318 biolink:causes CL:0000839 infores:ubergraph knowledge_assertion manual_agent GO:0002318 CL:0000839 CHEBI:35854 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0039231 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0031117 infores:hetionet CAID:CA2573051038 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051038 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PP1 The c.206delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 69 (NM_000545.8), adding 86 novel amino acids before encountering a stop codon (p.(Gly69AlafsTer86)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 could not be applied (PMID: 18003757, internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.209delG meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051038/MONDO:0015967/017 2022-04-04 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5130 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0152009 infores:hetionet NCBIGene:285590 biolink:causes MONDO:0009579 infores:monarchinitiative not_provided not_provided HGNC:29242 MONDO:0009579 uuid:776a2c7c-cb00-4791-bc3a-6b89408dbe42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151723 infores:hetionet CHEBI:4798 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0017181 infores:hetionet CHEBI:15854 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0004134 infores:hetionet CHEBI:31638 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0017178 infores:hetionet CHEBI:47898 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085682 infores:hetionet CHEBI:5384 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0042963 infores:hetionet NCBIGene:10043 biolink:causes MONDO:0030428 infores:monarchinitiative not_provided not_provided HGNC:11982 MONDO:0030428 uuid:cbd7ad74-7bbc-4cd1-b1db-36c7458f3471 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9435 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0040822 infores:hetionet GO:0140845 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0140845 GO:0010467 CHEBI:63577 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0853692 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0012359 infores:hetionet CHEBI:8080 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0030252 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042769 infores:hetionet CHEBI:8874 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0041657 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0178298 infores:hetionet CAID:CA343723184 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723184 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting BS1, BS3, BP7, PM6, PP1, PM4, PM5, PS3, PS1, PS2, BA1, BP4 The c.1435T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 479 (p.Tyr479His). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.981, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The study reporting functional evidence (PMID: 17615537) demonstrated that the Y479H protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. Only 1 segregation had been reported for open angle glaucoma (ClinVar: SCV001738398.1), not meeting the ≥ 3 segregations required for PP1. 3 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 23922489, 17615537 and ClinVar: SCV001738398.1), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723184/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:391960 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0013395 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0002957 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1306341 infores:hetionet CHEBI:135930 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0038325 infores:hetionet CHEBI:6822 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C2242996 infores:hetionet CHEBI:31174 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0151827 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0031039 infores:hetionet NCBITaxon:83558 biolink:causes MONDO:0025598 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:83558 MESH:D061387 DB01155_MESH_D061387_1DB00218_MESH_D061387_1DB01208_MESH_D061387_1DB00685_MESH_D061387_1DB00207_MESH_D061387_1DB00976_MESH_D061387_1DB09335_MESH_D061387_1DB01165_MESH_D061387_1DB01137_MESH_D061387_1DB01044_MESH_D061387_1 UMLS:C1872203 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0027497 infores:hetionet CHEBI:3441 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002792 infores:hetionet CAID:CA10549373 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549373 MONDO:0010305 PMID: Likely Benign BP7, BS2, BP4 PM2 The NM_005629.4:c.1008C>T variant in SLC6A8 is a synonymous variant (p.Asn336=) with no predicted impact on splicing (all SpliceAI scores <0.1) (PMID: 37352859) (BP4, BP7). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD V4.1.0. the highest population minor allele frequency (MAF) is 0.00001456 (13/892985; 4 hemizygotes) in the European non-Finnish population. While this MAF meets the threshold for PM2_Supporting, the criterion is not met due to the presence of hemizygotes. There are 4 hemizygotes in the European non-Finnish population (BS2). There is a ClinVar entry for this variant (Variation ID: 1138356). In summary, this variant meets criteria to be classified as likely benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549373/MONDO:0010305/027 2025-04-11 2025-04-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:42797 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0039070 infores:hetionet CHEBI:87715 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0031039 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0549209 infores:hetionet CHEBI:75722 biolink:causes HP:0030788 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0021092 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020649 infores:hetionet CHEBI:50729 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0001824 infores:hetionet CHEBI:7915 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1142412 infores:hetionet NCBIGene:401024 biolink:causes MONDO:0029148 infores:monarchinitiative not_provided not_provided HGNC:21675 MONDO:0029148 uuid:b421c7e7-fa43-47e4-a17b-b5b4a99f94ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0032285 infores:hetionet CHEBI:63791 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0036974 infores:hetionet CAID:CA10119038 biolink:causes MONDO:0021060 infores:clingen CAID:CA10119038 MONDO:0021060 PMID: Uncertain Significance BP4 PM2, PP3, BA1, BS1 The NM_006767.4:c.1723G>A variant in LZTR1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 575 (p.Asp575Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002433 (43/128774 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.197, which is below the threshold of 0.3, evidence that does not predict a damaging effect on LZTR1 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10119038/MONDO:0021060/094 2024-12-03 2025-04-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes UMLS:C0849835 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0849835 infores:hetionet CHEBI:31485 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0259799 infores:hetionet CHEBI:53691 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0019080 infores:hetionet CHEBI:46195 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0041948 infores:hetionet CHEBI:3207 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0031345 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011570 infores:hetionet CHEBI:31236 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0010200 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0015230 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0006663 infores:hetionet CHEBI:52172 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0042023 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0019340 infores:hetionet CHEBI:7915 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0000731 infores:hetionet CHEBI:9139 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C3495920 infores:hetionet NCBIGene:2056 biolink:causes MONDO:0033483 infores:monarchinitiative not_provided not_provided HGNC:3415 MONDO:0033483 uuid:9c34843a-20ca-434f-b615-c287cd7d1c39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0086565 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0032326 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0856151 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0687133 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0162429 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014534 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0020517 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0017657 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017657 infores:hetionet CHEBI:6792 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0349790 infores:hetionet CHEBI:9435 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0020458 infores:hetionet CHEBI:7466 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0025061 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0152517 infores:hetionet NCBIGene:9871 biolink:causes MONDO:0014573 infores:monarchinitiative not_provided not_provided HGNC:10706 MONDO:0014573 uuid:3122d998-5072-48ae-bf1f-7bb1b35ababc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2453 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0042075 infores:hetionet UMLS:C1738934 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151827 infores:hetionet CHEBI:7476 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018834 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009324 infores:hetionet CHEBI:27690 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0232462 infores:hetionet CHEBI:9086 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151970 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0027765 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0027765 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0522063 infores:hetionet CHEBI:6062 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0040485 infores:hetionet CHEBI:2567 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0036416 infores:hetionet CAID:CA340741548 biolink:causes MONDO:0100368 infores:clingen CAID:CA340741548 MONDO:0100368 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting "NM_000329.3(RPE65):c.1451-1G>A is a canonical splice variant in intron 13 of RPE65 and is predicted to lead to the skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000004024, with 1 allele / 6096 total alleles in the ""Remaining Individuals"" population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), symptomatic onset between birth and age five years (1 pt), poor pupillary light response (0.5 pts), RPE mottling (0.5 pts), macular atrophy (0.5 pts), decreased central visual acuity (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 31957135, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 2 affected meioses from 1 family, with the variant present in the homozygous state (PP1_Moderate; PMID: 31957135). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP1_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023)." Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340741548/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51041 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002962 infores:hetionet CHEBI:9123 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0236075 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018802 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0521839 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0948586 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0521491 infores:hetionet CHEBI:50841 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0040034 infores:hetionet NCBIGene:6813 biolink:causes MONDO:0013135 infores:monarchinitiative not_provided not_provided HGNC:11445 MONDO:0013135 uuid:5a4b31b4-7a09-4d25-b3b0-c66ed7c6465e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94501 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0002962 infores:hetionet CHEBI:3504 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0085641 infores:hetionet CHEBI:6759 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0428977 infores:hetionet CHEBI:31176 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0013404 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0235416 infores:hetionet CHEBI:4995 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151701 infores:hetionet CHEBI:74947 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0010520 infores:hetionet NCBIGene:2906 biolink:causes MONDO:0014947 infores:monarchinitiative not_provided not_provided HGNC:4588 MONDO:0014947 uuid:41fb841f-27ad-439c-98c3-afbe4e8ae757 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0178298 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0178298 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0007114 infores:hetionet CHEBI:9139 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0028734 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002871 infores:hetionet NCBIGene:1591 biolink:causes MONDO:0020739 infores:monarchinitiative not_provided not_provided HGNC:2602 MONDO:0020739 uuid:b5437b0e-1601-4b13-9630-def73e9c7c4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0240735 infores:hetionet CHEBI:135876 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0042024 infores:hetionet CHEBI:3732 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0040822 infores:hetionet CHEBI:46345 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0151744 infores:hetionet GO:2000977 biolink:causes GO:0021872 infores:ubergraph knowledge_assertion manual_agent GO:2000977 GO:0021872 CHEBI:9086 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151904 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005771 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017677 infores:hetionet CAID:CA392333555 biolink:causes MONDO:0007947 infores:clingen CAID:CA392333555 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PM1_Strong PVS1, PM6, PP1, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, PM4, PM3, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.6662G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2221 (p.Cys2221Tyr). This variant has been reported in three patients, including two with clinical diagnoses of Marfan syndrome and one with ectopia lentis without assessment for additional phenotypes (PP4, PS4_moderate; PMIDs: 26787436, 38190127; Invitae internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.965). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392333555/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:2659 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0033774 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0857386 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0857386 infores:hetionet CHEBI:28748 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151603 infores:hetionet CHEBI:182080 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0012833 infores:hetionet CHEBI:3696 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0220981 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001795 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042548 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877097 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0877097 infores:hetionet CHEBI:3654 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0232487 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0236075 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0022660 infores:hetionet CHEBI:38940 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018944 infores:hetionet CHEBI:82981 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0030193 infores:hetionet CHEBI:4907 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0026636 infores:hetionet CHEBI:8382 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1262113 infores:hetionet CHEBI:3478 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C3665624 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1368065 infores:hetionet CHEBI:53212 biolink:causes MONDO:0025556 infores:ubergraph knowledge_assertion manual_agent CHEBI:53212 MONDO:0025556 CHEBI:64355 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018801 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0030305 infores:hetionet CHEBI:18385 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0002994 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020569 infores:hetionet CAID:CA16602425 biolink:causes MONDO:0021060 infores:clingen CAID:CA16602425 MONDO:0021060 PMID: Pathogenic PS2, PS4_Moderate, PM1, PM2, PP3, PP2 The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Moderate, PM1, PM2, PP2, PP3, RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602425/MONDO:0021060/004 2020-05-18 2020-05-21 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7773 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0036974 infores:hetionet CHEBI:49375 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0030193 infores:hetionet CHEBI:7986 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0011603 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0027051 infores:hetionet CHEBI:87681 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0013428 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0264906 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0004936 infores:hetionet NCBIGene:344658 biolink:causes MONDO:0958326 infores:monarchinitiative not_provided not_provided HGNC:25394 MONDO:0958326 uuid:8fbdcecb-a420-4c19-9e7d-f625ac36a424 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6912 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0151904 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020649 infores:hetionet CHEBI:83531 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0085632 infores:hetionet CHEBI:4315 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0162830 infores:hetionet CHEBI:135342 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0036974 infores:hetionet CHEBI:6954 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0013378 infores:hetionet CHEBI:2639 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0004604 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0399459 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0031046 infores:hetionet CHEBI:3312 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0009450 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0020649 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0878544 infores:hetionet CAID:CA10584719 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584719 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PVS1_Moderate, PM5, PM2, PP4 BA1, BP4, PS3, BP7, BS1, BS3, PM4, PP3 The NM_000527.5(LDLR):c.1A>G (p.Met1Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PM5, PS4_Supporting, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012)The supporting evidence is as follows:PM2 - variant is absent from gnomAD (v2.1.1).PVS1_Moderate – variant is predicted to affect the initiation codon.PS4_Supporting – variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH (3 cases with SB criteria from PMID: 11462246).PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines.2) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines.3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines.4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584719/MONDO:0007750/013 2022-04-22 2022-04-22 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5855 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0041969 infores:hetionet CAID:CA000468 biolink:causes MONDO:0018875 infores:clingen CAID:CA000468 MONDO:0018875 PMID: Benign BP4, BS3, BS2 BA1, BP2, BP3, PS3, PS2, PS4, PS1, PM3, PM4, PM5, PM1, BP5, BP7, BS1, BS4, PVS1, PM2, PP4, PP3, PP1 The NM_000546.6: c.869G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 290 (p.Arg290His). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000187277.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.09; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4 (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000468/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7565 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0030193 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002170 infores:hetionet CHEBI:63589 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0017168 infores:hetionet CHEBI:27732 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0017178 infores:hetionet NCBIGene:291 biolink:causes MONDO:0014959 infores:monarchinitiative not_provided not_provided HGNC:10990 MONDO:0014959 uuid:82c112c1-8e38-40e9-9c3f-3ada7a028cc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45327 biolink:causes UMLS:C0235004 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0235004 infores:hetionet NCBIGene:8540 biolink:causes MONDO:0010823 infores:monarchinitiative not_provided not_provided HGNC:327 MONDO:0010823 uuid:68fe3678-6868-49cc-b18e-9e5b165a13d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA404075695 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075695 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_Strong - 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelinesThere are 3 variants classified as Pathogenic by these guidelines, so PM5_Strong is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.964. It is above 0.75, so PP3 is metPP4 - Variant meets PM2, and was identified in 1 index case with SB criteria for FH (The clinical diagnosis of hoFH was confirmed on the basis of total cholesterol >500 mg/dl at the time of diagnosis, the presence of xanthomas at an early age, and the presence of primary hypercholesterolemia in the probands’ parents or other first degree relatives. This case had total cholesterol 840mg/dl at 3 years of age) from PMID 19026292 (Kolansky et al., 2008), USAso PP4 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075695/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA405663755 biolink:causes MONDO:0018493 infores:clingen CAID:CA405663755 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 2126 of the RYR1 protein, p.(Arg2126Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000018, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:21455645, PMID:24433488). One of these individuals had a second variant of unknown significance identified in RYR1 (p.Gly3938Asp), PS4_Supporting. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.796 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405663755/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:31174 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C2939147 infores:hetionet NCBIGene:8905 biolink:causes MONDO:0010574 infores:monarchinitiative not_provided not_provided HGNC:560 MONDO:0010574 uuid:757203d5-37d1-423a-8f73-628e5f74e062 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA7331487 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331487 MONDO:0100216 PMID: Benign BA1, BP4, BS2 PVS1, PM2, BP2, PP3, PP1, PP4, PM5, PM4, PM1, PS1, PS3, PS2, BP7, BS1, BS3, BS4 The NM_177438.3:c.1381A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 461 (p.Ile461Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.005261 (32/6082 alleles) in the Middle Eastern population, which is higher than the ClinGen DICER1 VCEP threshold (>0.003) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BA1. (Bayesian Points: NA; VCEP specifications version 1.3.0; 06/25/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331487/MONDO:0100216/024 2024-06-25 2024-07-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64312 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0948089 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027051 infores:hetionet CHEBI:6887 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0003811 infores:hetionet CHEBI:119573 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020580 infores:hetionet CHEBI:4702 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0235267 infores:hetionet CHEBI:2659 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0040822 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0021053 infores:hetionet NCBIGene:7390 biolink:causes MONDO:0009902 infores:monarchinitiative not_provided not_provided HGNC:12592 MONDO:0009902 uuid:e8552029-6442-40a4-8ee9-88d0848dc6ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0027441 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0948594 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014863 infores:hetionet CHEBI:4708 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0009676 infores:hetionet CHEBI:4027 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085669 infores:hetionet CHEBI:7773 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0010200 infores:hetionet CHEBI:68610 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0015230 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0574067 infores:hetionet UMLS:C0657912 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032617 infores:hetionet CHEBI:7494 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151766 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0302295 infores:hetionet CHEBI:480999 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0278134 infores:hetionet CHEBI:28971 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0002871 infores:hetionet CHEBI:167309 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0233477 infores:hetionet CHEBI:9599 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0039070 infores:hetionet CHEBI:3127 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0009676 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1321686 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085618 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235315 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0151905 infores:hetionet CHEBI:114785 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0151905 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0009938 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0021308 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0151825 infores:hetionet CHEBI:4672 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1510410 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0017152 infores:hetionet CHEBI:40050 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0027947 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0025061 infores:hetionet CHEBI:4514 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0004044 infores:hetionet CHEBI:15407 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0003467 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0027769 infores:hetionet CAID:CA1139658405 biolink:causes MONDO:0001586 infores:clingen CAID:CA1139658405 MONDO:0001586 PMID: Likely Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting The NM_000203.5:c.1190-10C>A occurs in the region of the acceptor splice site of intron 8 in IDUA. The in silico predictor SpliceAI, suggests that this variant impacts splicing (acceptor loss = 0.72, acceptor gain, 2bp downstream = 0.87) (PP3). If the acceptor splice site is lost and the predicted new acceptor splice site is used, this would result in inclusion of 8 nucleotides into the transcript, frameshift and premature termination (Fig. 6, PMID: 34833038). Four patients have been reported with the variant, all from the same small area in Vietnam but not thought to be related. All have clinical features consistent with MPS1, documented deficiency of IDUA activity in blood spots or leukocytes, and elevated GAGs in urine (PP4_Moderate). Two patients are homozygous for the variant (2 x 0.5 points) (PMID: 34833038). Two patients are compound heterozygous for the variant another variant in IDUA, c.1046A>G (p.Asp349Gly) (PMID: 34833038). The allelic data from the compound heterozygous patients will be used in the classification of p.Asp349Gly and is not included here to avoid circular logic. Total 1 point (PM3). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139658405/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9654 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0687713 infores:hetionet CAID:CA645509536 biolink:causes MONDO:0007648 infores:clingen CAID:CA645509536 MONDO:0007648 PMID:29295527PMID:29131691 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP5, BP7, BS4, BS1, BS3, PM3, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.1612delG p.(Asp538Thrfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 29131691). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509536/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:17650 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0043251 infores:hetionet CHEBI:64355 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0497156 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0010692 infores:hetionet CAID:CA367400571 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400571 MONDO:0015967 PMID: Pathogenic PS1, PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate PM1, PP1 The c.781G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). The nucleotide change c.781G>A, which causes the same amino acid change, has been classified as pathogenic by the ClinGen MDEP (PS1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). In summary, the c.781G>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PS3_Moderate, PS1, PS4_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400571/MONDO:0015967/086 2023-08-12 2023-08-12 Semidominant inheritance HP:0032113 Supports CHEBI:31705 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0011603 infores:hetionet CHEBI:5106 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C1443060 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020538 infores:hetionet CAID:CA314876 biolink:causes MONDO:0012996 infores:clingen CAID:CA314876 MONDO:0012996 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The NM_001482.3: c.778C>T (p.Arg260Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of a total of 9 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0. is 8.474e-7 (1/1180024 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the published literature. However, there is a ClinVar entry for this variant (Variation ID: 205617). The variant has been observed in a child with seizures referred for an epilepsy panel (GeneDx); no second variant in GATM was identified (insufficient evidence for PP4 or PM3). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on May 22, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314876/MONDO:0012996/025 2025-05-22 2025-05-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6804 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0043144 infores:hetionet UMLS:C1738934 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0004093 infores:hetionet CHEBI:6887 biolink:causes HP:0100034 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0751900 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018801 infores:hetionet CAID:CA410148496 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148496 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1031A>T (p.Asp344Val) is a missense variant which has a REVEL score < 0.50 (0.281) and a SpliceAI score ≤ 0.20 (Δ score 0.00) (BP4). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148496/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119573 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0948594 infores:hetionet CHEBI:584020 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0015672 infores:hetionet GO:0140656 biolink:causes GO:0006259 infores:ubergraph knowledge_assertion manual_agent GO:0140656 GO:0006259 CHEBI:6015 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0020456 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0948586 infores:hetionet CAID:CA172101 biolink:causes MONDO:0018947 infores:clingen CAID:CA172101 MONDO:0018947 PMID: Pathogenic PS4, PS2, PP1_Moderate, PS3_Supporting, PP2, PP3, PM2_Supporting BA1, BP1, BP4, BP3, PS1, PM3, PM5, PM4, PM1, BS1, BS3, BS4, BP5, PM6, PP4, BS2 The NM_001005361.3:c.1565G>A variant in DNM2 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 522 (p.Arg522His). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The REVEL computational prediction analysis tool gives a score of 0.892, which is above the threshold necessary to apply PP3. This variant has been reported in at least eight probands with centronuclear myopathy, of which two were identified to be de novo occurrences (PS2, PS4; PMIDs: 20227276, 29105112, 32826616; Baylor Genetics, GeneDx, Athena Diagnostics, ClinVar: SCV000807289.2, SCV000329752.6, SCV000841851.1; VCEP Internal data contributor). Additionally, the variant segregated with disease in 4 family members meeting PP1_Moderate (PMID: 20227276). Live correlative scanning ion conductance microscopy (SICM) and fluorescence confocal microscopy (FCM) showed that the p.Arg522His variant slows down the formation of clathrin-coated pits in skin fibroblasts from patients and in Cos-7 cells expressing corresponding dynamin mutants (PS3_Supporting, PMID: 31017801). In summary, the variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS4, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 4/14/2025 Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA172101/MONDO:0018947/148 2025-04-14 2025-06-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8665 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0020580 infores:hetionet CHEBI:9571 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0011606 infores:hetionet CHEBI:51041 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0404521 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0015230 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C3665347 infores:hetionet CAID:CA290000 biolink:causes MONDO:0007648 infores:clingen CAID:CA290000 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM4, PM5, BS2, PP4, PP1, PP2, PP3, BP3, BP1, BP4, PS2, PS3, PS1, PS4 The NM_004360.5(CDH1):c.324A>G (p.Arg108=) variant has an allele frequency of 0.00769 (0.769%, 192/24966 alleles) in the African subpopulation and one homozygote in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA290000/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5103 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0042109 infores:hetionet CHEBI:3286 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C2004489 infores:hetionet NCBIGene:701 biolink:causes MONDO:0008304 infores:monarchinitiative not_provided not_provided HGNC:1149 MONDO:0008304 uuid:eacd4901-a925-4f3a-9962-65ebd0577411 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7959 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0011609 infores:hetionet CHEBI:4702 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0027497 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0037199 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085660 infores:hetionet CHEBI:10119 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0234022 infores:hetionet CAID:CA10385727 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385727 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.154+14T>C is a non-coding variant in intron 2 that is located outside of the splice donor region (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00 for all splicing events, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a frequency of 0.0004359 among hemizygous individuals, with 29 variant alleles / 66,525 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385727/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:3723 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149836 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0011570 infores:hetionet CAID:CA273111 biolink:causes MONDO:0009861 infores:clingen CAID:CA273111 MONDO:0009861 PMID:11385716PMID:17935162PMID:11385716PMID:24941924 Pathogenic PM2, PP4, PP3, PS3, PM3_Strong The c.508C>G (p.His170Asp) variant in PAH has been reported in 1 patient with hyperphenylalaninemia, and 1 patient with benign persistent hyperphenylalaninemia. (PP4; PMID: 11385716). This variant has an extremely low allele frequency (0.00018) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 43% enzyme activity (PS3; PMID: 17935162). This variant was detected in trans with R261X, c.60+5G>T, c.1315+1G>A (Pathogenic in ClinVar) (PM3_Strong; PMID: 11385716; PMID: 24941924). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM3_Strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273111/MONDO:0009861/006 2018-07-28 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410203383 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203383 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, BA1, BP1, BP4, BP2, BS1, PM5, PM3, PP4, PP2, PP3 NM_001754.5(RUNX1):c.341T>A (p.Ile114Asn) is a missense variant which is found within the runt homology domain but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203383/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3228 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0042963 infores:hetionet CHEBI:2379 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C2047937 infores:hetionet CHEBI:71255 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020456 infores:hetionet CAID:CA410147596 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147596 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1264G>C (p.Glu422Gln) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.089, which is less than 0.50 and a spliceAI score <0.2 (0.0) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147596/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA273108 biolink:causes MONDO:0009861 infores:clingen CAID:CA273108 MONDO:0009861 PMID:21147011PMID:21147011PMID:17935162 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PS3 PM5, PM2 PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. (PMID:21147011); PM3_VeryStrong: Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients. (PMID:21147011); PS3: A300S in vitro PAH activity of 31% (PMID:17935162). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PP4_Moderate, PM3_VeryStrong, PS3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273108/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63635 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0002874 infores:hetionet CHEBI:63598 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023518 infores:hetionet CHEBI:3561 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0438142 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0240035 infores:hetionet CHEBI:63635 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020461 infores:hetionet CHEBI:5558 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0151905 infores:hetionet UNII:R43D2573WO biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0016382 infores:hetionet CHEBI:10102 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0030193 infores:hetionet NCBIGene:617 biolink:causes MONDO:0009872 infores:monarchinitiative not_provided not_provided HGNC:1020 MONDO:0009872 uuid:16e3d6f8-858f-42c5-bb4b-c680518eee8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6954 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0022107 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0149732 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149732 infores:hetionet CHEBI:9137 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0021368 infores:hetionet CHEBI:61049 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0520966 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0018801 infores:hetionet CHEBI:8871 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013132 infores:hetionet CHEBI:421707 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C2363730 infores:hetionet CHEBI:40279 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018926 infores:hetionet CAID:CA10584797 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584797 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, BS3, PP1_Moderate, PM2, PP3, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2 The NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes BS3, PS4_Supporting, PM2, PP1_Moderate, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BS3: Level 1 assays: PMID 25741862: Heterologous cells (CHO), western blot and flow cytometry assays - result: 100% low-density lipoprotein particle receptor biosynthetic process; 90% low-density lipoprotein particle binding; 95% low-density lipoprotein particle clearance. ---- The whole cycle is above 90% of wild-type activity. So, BS3 is met. PS4_Supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille and 1 case with Simon Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). So, PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.898. It is above 0.75, so PP3 is met. PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. So, PP1_Moderate is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from different labs, after alternative causes of high cholesterol were excluded (see PS4 for details). So, PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584797/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31705 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0231218 infores:hetionet CHEBI:63623 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0521839 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C1443060 infores:hetionet CHEBI:83527 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0027497 infores:hetionet CHEBI:17474 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0040038 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151735 infores:hetionet CHEBI:50730 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0699744 infores:hetionet CHEBI:119573 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0231528 infores:hetionet CHEBI:9943 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026961 infores:hetionet CHEBI:35778 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0013144 infores:hetionet CHEBI:9150 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0028866 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0281774 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0521839 infores:hetionet CHEBI:49040 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0030554 infores:hetionet CHEBI:47612 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0042109 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0162119 infores:hetionet CHEBI:2618 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0030252 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0030446 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0041969 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0004936 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0424000 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0021053 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0233414 infores:hetionet CHEBI:3732 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0015967 infores:hetionet CAID:CA226551 biolink:causes MONDO:0100368 infores:clingen CAID:CA226551 MONDO:0100368 PMID: Benign BA1 BP4, BP7 NM_000329.3(RPE65):c.432C>T (p.Tyr144=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.01115, with 852 alleles/75,028 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). Additionally, there are 5 homozygotes in this population in gnomAD. The splicing impact predictor SpliceAI gives a delta score of 0.15 for acceptor gain, which is above the ClinGen LCA / eoRD VCEP threshold of <0.1, so BP4 and BP7 are not met. In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226551/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4710 biolink:causes UMLS:C0004601 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004601 infores:hetionet CAID:CA015001 biolink:causes MONDO:0005045 infores:clingen CAID:CA015001 MONDO:0005045 PMID: Uncertain Significance PM2, PS4_Supporting BA1, PM1, PM5, PM6, PP3, PP1, PS3, BS1, BS3, BS4, BP4, BP2, BP5, PS1, PS2 The NM_000257.4(MYH7):c.4470G>C (p.Glu1490Asp) variant has been reported in 2 individuals with HCM (PS4_Supporting; GeneDx pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v.2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4_Supporting, PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015001/MONDO:0005045/002 2021-09-21 2022-04-27 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:3848 biolink:causes MONDO:0007808 infores:monarchinitiative not_provided not_provided HGNC:6412 MONDO:0007808 uuid:7da04be2-3ec1-4e62-87e8-0c0979e0a779 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0011168 infores:hetionet CAID:CA343724341 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724341 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BS1, BS3, PM6, PP1, PM5, PM4, PS4, PS1, PS3, PS2, BA1, BP4 The c.1196G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Aspartate at amino acid 399 (p.Gly399Asp). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.953, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 17562996), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724341/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:72564 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0018681 infores:hetionet CHEBI:45783 biolink:causes MONDO:0011719 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0238198 infores:hetionet CHEBI:75045 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0085641 infores:hetionet CHEBI:9588 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0020625 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042075 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0233414 infores:hetionet CHEBI:71941 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0017675 infores:hetionet CHEBI:49603 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0027339 infores:hetionet NCBIGene:9739 biolink:causes MONDO:0033630 infores:monarchinitiative not_provided not_provided HGNC:29010 MONDO:0033630 uuid:301e71fc-0749-4410-b680-73f46215c446 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0152027 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011551 infores:hetionet CHEBI:40279 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038999 infores:hetionet CAID:CA8602722 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602722 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 The NM_000419.5(ITGA2B):c.2348+15G>A variant is an intronic variant that is not predicted by SpliceAI to impact splicing (Delta scores <0.03). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -1.96 (BP7). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0003737 (441/1179990 alleles) in the European (non-Finnish) population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. In summary this variant is classified as likely benign for autosomal recessive Glanzmann thrombasthenia, with ACMG criteria applied as specified by the PD VCEP: BP4, BP7 Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602722/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA274281 biolink:causes MONDO:0009290 infores:clingen CAID:CA274281 MONDO:0009290 PMID:25243733PMID:20826098PMID:22237443PMID:30155607PMID:25626711PMID:29181627PMID:24715333PMID:25243733PMID:26873529PMID:29122469PMID:22237443 Pathogenic PM2, PVS1, PP4, PM3_Strong This variant, c.1548G>A (p.Trp516Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 in the European non-Finnish population, meeting the ClinGen LSD VCEP’s threshold for PM2. This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Therefore, PP4 and PM3_Strong can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). There is a ClinVar entry for this variant (Variation ID: 189025, 2 star review status) with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274281/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:6950 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027121 infores:hetionet CHEBI:3347 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0005779 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020651 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0038358 infores:hetionet CHEBI:231425 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0018681 infores:hetionet CHEBI:4903 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C2225524 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023533 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040034 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0022081 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042594 infores:hetionet CHEBI:28787 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0030232 infores:hetionet UMLS:C0145867 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0149514 infores:hetionet CHEBI:2379 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0004093 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0332575 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003937 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0038012 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0242073 infores:hetionet CAID:CA169687 biolink:causes MONDO:0007648 infores:clingen CAID:CA169687 MONDO:0007648 PMID:23709761 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS2, PS3, PS1 The c.1147C>T (p.Gln383Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 23709761). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA169687/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0234215 infores:hetionet CAID:CA2580610964 biolink:causes MONDO:0010305 infores:clingen CAID:CA2580610964 MONDO:0010305 PMID: Pathogenic PP1_Moderate, PS4_Supporting, PM2_Supporting, PP4_Strong, PVS1_Moderate PP3, PS1 The NM_005629.4:c.1495+5G>C variant in SLC6A8 is an intronic variant affecting a nucleotide within the consensus donor splice site of intron 10. RT-PCR of mRNA from fibroblasts from affected brothers who are hemizygous for this variant showed exon skipping, which would be predicted to result in a frameshift, premature termination codon and nonsense-mediated decay. However, because the data was not shown in the publication, PVS1 was reduced to Moderate. This variant has been reported in two brothers with developmental delays, elevated urine creatine/creatinine, deficient creatine uptake in fibroblasts, and reduced creatine peak on brain MRS and was inherited from their mother, who had learning difficulties and impaired language development (PMID: 15690373) (PP4_Strong, PP1), and has also been reported in an unrelated male and his sister, inherited from their mother (PMID: 23660394) (PS4_Supporting). The variant is absent in gnomAD v4.0. (PM2_Supporting). There is no ClinVar entry for this variant. A variant in the same splice region, c.1495+2T>G, has been classified as pathogenic by the ClinGen CCDS VCEP and is predicted, by SpliceAI, to have a similar impact on splicing. However, as the SpliceAI scores are lower for c.1495+5G>C than c.1495+2T>G, PS1 will not be applied (see PMID: 37352859). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_Moderate, PP4_Strong, PS4_Supporting, PP1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on December 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610964/MONDO:0010305/027 2023-12-14 2023-12-14 X-linked inheritance HP:0001417 Supports CHEBI:17650 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0027540 infores:hetionet CAID:CA314832 biolink:causes MONDO:0012999 infores:clingen CAID:CA314832 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_000156.6: c.677C>T variant in GAMT is a missense variant predicted to result in the substitution of proline for leucine at amino acid 226 (p.Pro226Leu). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1179890 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.292 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function. SpliceAI predicts that the variant will have no impact on splicing. To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205594). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314832/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2668 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0009782 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0851341 infores:hetionet CHEBI:59560 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0013395 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0266241 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0266241 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0027339 infores:hetionet CHEBI:2618 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0549249 infores:hetionet CHEBI:17630 biolink:causes UMLS:C3495931 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C3495931 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026113 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0002418 infores:hetionet CHEBI:2704 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0043352 infores:hetionet CHEBI:45979 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0018681 infores:hetionet NCBITaxon:100942 biolink:causes MONDO:0016566 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:100942 MESH:D008118 DB00711_MESH_D008118_1 CHEBI:93363 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0026961 infores:hetionet CHEBI:6741 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151577 infores:hetionet CAID:CA244520729 biolink:causes MONDO:0015967 infores:clingen CAID:CA244520729 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4, PP4 PP3 The c.98C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 33(p.(Pro33Leu)) of NM_000545.8. This variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%,, and response to sulfonylurea) (PP4; internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 6.80e-7, which is below the ClinGen MDEP threshold for PM2_Supporting (≤ 0.000003). Additionally, this variant was identified in eight unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 32238361, internal lab contributors). This variant has a REVEL score of 0.537, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.98C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PS4, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244520729/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52172 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003838 infores:hetionet CHEBI:4909 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0042023 infores:hetionet CAID:CA367401320 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401320 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.622G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 208 (p.(Ala208Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.906, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 individuals with a phenotype suggestive of GCK-hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 18248649, 31595705, 35472491, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (persistent FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate; PMID: 31595705). Two other missense variants, c.623C>T p.Ala208Val and c.622G>A p.Ala208Thr, have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.622G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401320/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:9943 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018944 infores:hetionet CHEBI:6541 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0017152 infores:hetionet CHEBI:85083 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0231807 infores:hetionet CHEBI:617099 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0002994 infores:hetionet CHEBI:8404 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0034880 infores:hetionet CAID:CA10014586 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014586 MONDO:0011071 PMID: Uncertain Significance BP4 PS2, PS4, PS1, PS3, BP3, BP1, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, PM4, PM3, PM1, PM5, BS2, PP2, PP3 The c.143G>A (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of serine by asparagine at amino acid 48 (p.S48N). The highest population minor allele frequency in gnomAD v2 is 0.000009310 (1/107408 alleles) in the non-Finnish European population. The variant of unclear origin has only been reported in an 80yo male with CCUS at a VAF=29.63% (Ferrone, 2022, Postdoctoral Thesis). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014586/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50156 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0522055 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0009450 infores:hetionet CHEBI:132233 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0014742 infores:hetionet CHEBI:3698 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0014591 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151602 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0262428 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0262428 infores:hetionet CHEBI:3387 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0043049 infores:hetionet CHEBI:50305 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0042963 infores:hetionet CHEBI:9588 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0042963 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0040034 infores:hetionet NCBIGene:5931 biolink:causes MONDO:0976123 infores:monarchinitiative not_provided not_provided HGNC:9890 MONDO:0976123 uuid:ec7f8c07-b069-404c-b1b9-9b7f61fc788a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235431 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0948594 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0018099 infores:hetionet NCBIGene:344018 biolink:causes MONDO:0012861 infores:monarchinitiative not_provided not_provided HGNC:24669 MONDO:0012861 uuid:5e5953d6-4917-47bb-8831-949edbde6e8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0034065 infores:hetionet CHEBI:3996 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0030554 infores:hetionet CHEBI:3242 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0085636 infores:hetionet CHEBI:92712 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0017605 infores:hetionet CHEBI:4653 biolink:causes UMLS:C3203457 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C3203457 infores:hetionet CHEBI:60761 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0518015 infores:hetionet CHEBI:63589 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0006266 infores:hetionet CHEBI:240107 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C1096274 infores:hetionet CHEBI:168396 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020625 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0041657 infores:hetionet CHEBI:17474 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0917801 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0278016 infores:hetionet CHEBI:5004 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0038325 infores:hetionet CHEBI:51860 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0231218 infores:hetionet CHEBI:51860 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0332563 infores:hetionet CHEBI:8356 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020578 infores:hetionet CHEBI:5790 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0041834 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0009450 infores:hetionet CHEBI:9398 biolink:causes MONDO:0041775 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C1688637 infores:hetionet CHEBI:50223 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0014868 infores:hetionet CAID:CA2573051300 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051300 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.399_405del variant in the HNF1 Homeobox A gene, HNF1A, causes a frameshift in the protein at codon 134 of NM_000545.8, adding 19 novel amino acids before encountering a stop codon (p.(Val134ProfsTer19)). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant in absent in gnomAD v2.1.1 (PM2_Supporting). In summary, the c.399_405del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051300/MONDO:0015967/017 2022-06-24 2022-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15553 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0013144 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0001824 infores:hetionet CHEBI:3752 biolink:causes MONDO:0000819 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0002902 infores:hetionet GO:2000354 biolink:causes GO:0008585 infores:ubergraph knowledge_assertion manual_agent GO:2000354 GO:0008585 CHEBI:94686 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0853348 infores:hetionet CAID:CA8622982 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622982 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 NM_000212.3(ITGB3):c.567del (p.Tyr190ThrfsTer17) found in a compound heterozygous proband (PMID:28748566) causes a premature stop codon at exon 5 and is predicted to undergo nonsense mediated decay (PVS1). The highest population minor allele frequency in gnomAD v4.1 is 0.000002542 (3/1180010 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1 and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622982/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6067 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0005758 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0917798 infores:hetionet CHEBI:8863 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0006384 infores:hetionet CHEBI:9168 biolink:causes MONDO:0019088 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0432487 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011334 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029124 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020517 infores:hetionet CHEBI:2950 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0030252 infores:hetionet CHEBI:63613 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0003862 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0849796 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0849796 infores:hetionet CHEBI:36791 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0242301 infores:hetionet CHEBI:75984 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0020456 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0034065 infores:hetionet CHEBI:5558 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0393761 infores:hetionet CHEBI:36791 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025222 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151517 infores:hetionet CHEBI:142290 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0028734 infores:hetionet CHEBI:41977 biolink:causes UMLS:C1739418 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1739418 infores:hetionet NCBIGene:9020 biolink:causes MONDO:0957535 infores:monarchinitiative not_provided not_provided HGNC:6853 MONDO:0957535 uuid:bdddb1e5-dd1f-41fb-b488-7cba4c893d46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038160 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0281981 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0235431 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0031046 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0277889 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0277889 infores:hetionet CHEBI:168396 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0267028 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0036572 infores:hetionet CHEBI:8364 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0018418 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0009450 infores:hetionet CHEBI:72564 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011175 infores:hetionet CHEBI:135939 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0009676 infores:hetionet CHEBI:8707 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0231530 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234215 infores:hetionet CAID:CA10529870 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529870 MONDO:0010604 PMID: Benign BP7, BP4, BA1 PM1, PS4 The NM_000133.3:c.1095A>G variant predicts a synonymous change, Ser365=. It is reported at a high frequency of 0.03271 (622/19015 alleles with 172 hemizygotes) in the African subpopulation in gnomAD v2.1.1, meeting the BA1 cut-off of >=0.0000556. The variant is not predicted to impact splicing, and the nucleotide position at which this variant occurs is not highly conserved, meeting the BP4 and BP7 criteria. To the best of our knowledge, the variant has not been reported in male patients with Hemophilia B. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4, BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529870/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:32221 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0030554 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034150 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0518988 infores:hetionet CHEBI:5118 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0558489 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0042401 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0235431 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020461 infores:hetionet CHEBI:7959 biolink:causes MONDO:0019082 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0030805 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0002170 infores:hetionet CHEBI:31236 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151699 infores:hetionet CHEBI:114785 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0030193 infores:hetionet CHEBI:6015 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0020461 infores:hetionet CHEBI:63584 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0041956 infores:hetionet NCBIGene:9791 biolink:causes MONDO:0007892 infores:monarchinitiative not_provided not_provided HGNC:9587 MONDO:0007892 uuid:345e3040-b7ca-4d4b-96dc-de230fc4b87d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011570 infores:hetionet CHEBI:7494 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0035455 infores:hetionet CHEBI:6904 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0043144 infores:hetionet CHEBI:3216 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0476273 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036508 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020538 infores:hetionet NCBITaxon:1402491 biolink:causes MONDO:0005142 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1402491 MONDO:0005142 CHEBI:45716 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0030312 infores:hetionet CHEBI:61049 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0702166 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0018801 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0152128 infores:hetionet CHEBI:31401 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018946 infores:hetionet CHEBI:2618 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0015967 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027651 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0917799 infores:hetionet CHEBI:63115 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0017178 infores:hetionet CHEBI:48538 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0003467 infores:hetionet CHEBI:16755 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0542571 infores:hetionet NCBITaxon:52283 biolink:causes HP:0000989 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:52283 MESH:D011537 DB06770_MESH_D011537_1 CHEBI:6640 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0232462 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017160 infores:hetionet CHEBI:2663 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0086439 infores:hetionet GO:0140433 biolink:causes GO:1990395 infores:ubergraph knowledge_assertion manual_agent GO:0140433 GO:1990395 CHEBI:3568 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0232849 infores:hetionet CHEBI:8207 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0033774 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017574 infores:hetionet CHEBI:63638 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0025362 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0240515 infores:hetionet NCBIGene:136647 biolink:causes MONDO:0021013 infores:monarchinitiative not_provided not_provided HGNC:16002 MONDO:0021013 uuid:da9e7037-3e4c-4345-bddb-1273ac89dd3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0013144 infores:hetionet CHEBI:5855 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0035243 infores:hetionet CHEBI:135736 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0178282 infores:hetionet CHEBI:50305 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0347390 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0858581 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0026946 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0040046 infores:hetionet NCBIGene:51102 biolink:causes MONDO:0957978 infores:monarchinitiative not_provided not_provided HGNC:19691 MONDO:0957978 uuid:58c12ab2-e80c-4450-a7ce-5c797fe736f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004095 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0011991 infores:hetionet NCBIGene:55703 biolink:causes MONDO:0030677 infores:monarchinitiative not_provided not_provided HGNC:30348 MONDO:0030677 uuid:2c171fc2-8831-4178-b1eb-5ea3ba9e7c26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0242528 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0234215 infores:hetionet CHEBI:2549 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0424790 infores:hetionet CHEBI:8888 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0026827 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0860871 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0851341 infores:hetionet CHEBI:27565 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0001824 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0242350 infores:hetionet CHEBI:3756 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0152031 infores:hetionet CHEBI:50648 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0233514 infores:hetionet CHEBI:17347 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0149871 infores:hetionet CHEBI:49575 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0021177 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0235560 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235560 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1291077 infores:hetionet GO:0001964 biolink:causes MONDO:0015648 infores:ubergraph knowledge_assertion manual_agent GO:0001964 MONDO:0015648 NCBIGene:28981 biolink:causes MONDO:0033485 infores:monarchinitiative not_provided not_provided HGNC:14313 MONDO:0033485 uuid:adecf750-60ab-4669-bdee-5e4bd45b8dd2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0234518 infores:hetionet CHEBI:5779 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0013404 infores:hetionet CHEBI:28918 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C2937358 infores:hetionet CHEBI:3176 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423791 infores:hetionet NCBIGene:22909 biolink:causes MONDO:0013898 infores:monarchinitiative not_provided not_provided HGNC:29170 MONDO:0013898 uuid:f1928f13-02dd-47a9-ae37-c14168f225b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151766 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042571 infores:hetionet CHEBI:6690 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0040264 infores:hetionet CHEBI:49960 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0085932 infores:hetionet CHEBI:5790 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0030193 infores:hetionet CHEBI:63589 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0033771 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0001824 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0017601 infores:hetionet CHEBI:171719 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0023646 infores:hetionet CHEBI:30830 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0851578 infores:hetionet UNII:UMD7G2653W biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0019080 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0178298 infores:hetionet NCBIGene:84068 biolink:causes MONDO:0032703 infores:monarchinitiative not_provided not_provided HGNC:23088 MONDO:0032703 uuid:61c3ee9f-7871-48d4-b3bf-719d725c901b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3654 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0022346 infores:hetionet CHEBI:63580 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0233514 infores:hetionet CHEBI:101278 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0085649 infores:hetionet CHEBI:4953 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0007286 infores:hetionet UMLS:C0657912 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022107 infores:hetionet CHEBI:46557 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0011603 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0235889 infores:hetionet CHEBI:135935 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0700200 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0149904 infores:hetionet CHEBI:2904 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0034150 infores:hetionet CAID:CA500435385 biolink:causes MONDO:0100326 infores:clingen CAID:CA500435385 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 The NM_000212.3(ITGB3):c.1764G>C (p.Thr588=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -8.25384 (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006153 (1/16252 alleles) in the African American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Due to conflicting evidence, this variant is classified as likely benign for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BP7, BP4, PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500435385/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA254238 biolink:causes MONDO:0800472 infores:clingen CAID:CA254238 MONDO:0800472 PMID: Likely Pathogenic PP1, PM2_Supporting, PS2_Moderate, PM1_Supporting, PP3_Moderate, PM3_Supporting, PS3_Supporting BA1, BP4, PM4, PM5, PS1, BS1, BS4, BP7, PVS1 The c.1093G>T variant in CYP1B1 is a missense variant predicted to cause substitution of Glycine by Tryptophan at amino acid 365 (p.Gly365Trp). This missense variant is located in the I-helix, meeting PM1_Supporting. The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000007627 (9 alleles out of 1,180,044), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.917, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 12807732) demonstrated that the Gly365Trp protein had reduced Benzo[a]pyrene Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 1 affected segregation with a CYP1B1-related phenotype has been reported (PMID: 9497261), which fulfilled PP1. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is homozygous (non-consanguineous) for this variant (PMID: 9497261). Total proband points = 0.5, meeting PM3_Supporting. One confirmed de novo proband with PCG has been identified (PMID: 9497261). Total de novo points = 1, meeting PS2_Moderate. In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PS2_Moderate, PP3_Moderate, PP1, PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA254238/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0041582 infores:hetionet CHEBI:3515 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0003862 infores:hetionet CHEBI:63610 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0006266 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0004936 infores:hetionet CHEBI:3286 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0042029 infores:hetionet CHEBI:4888 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0231303 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0021775 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0232492 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0035078 infores:hetionet CHEBI:51364 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0032617 infores:hetionet CHEBI:80630 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0020621 infores:hetionet CHEBI:63577 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1260922 infores:hetionet CHEBI:5138 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018965 infores:hetionet CHEBI:101278 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0231528 infores:hetionet CHEBI:144093 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C3665347 infores:hetionet CHEBI:6717 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0018524 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0036454 infores:hetionet CHEBI:50648 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0035229 infores:hetionet CHEBI:44423 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0027497 infores:hetionet CHEBI:145499 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019270 infores:hetionet GO:0031383 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0031383 GO:0048856 CHEBI:4469 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0011603 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013395 infores:hetionet CAID:CA072168 biolink:causes MONDO:0018493 infores:clingen CAID:CA072168 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with proline at codon 2843 of the RYR1 protein, p.(Ser2843Pro). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:21455645). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.761 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA072168/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:52717 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021368 infores:hetionet CHEBI:68610 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0020473 infores:hetionet CHEBI:3387 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C3665624 infores:hetionet CHEBI:92607 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0042514 infores:hetionet CHEBI:17303 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233471 infores:hetionet CHEBI:47898 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151746 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004096 infores:hetionet CHEBI:5801 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0019080 infores:hetionet GO:0035051 biolink:causes CL:0002494 infores:ubergraph knowledge_assertion manual_agent GO:0035051 CL:0002494 CHEBI:188986 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0003864 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020456 infores:hetionet CHEBI:31980 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0438142 infores:hetionet CHEBI:7476 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0392171 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0392197 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030305 infores:hetionet CHEBI:5138 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0039621 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0152229 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0476463 infores:hetionet CHEBI:3380 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C1291078 infores:hetionet CHEBI:42068 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0039239 infores:hetionet CHEBI:16586 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C3257803 infores:hetionet CHEBI:71417 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0000737 infores:hetionet CHEBI:4856 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C1720775 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0042594 infores:hetionet CHEBI:8499 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0018794 infores:hetionet CHEBI:119915 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234632 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0948525 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0085631 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0877613 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0877613 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0027947 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020255 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042963 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0162429 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0233494 infores:hetionet NCBIGene:5745 biolink:causes MONDO:0008970 infores:monarchinitiative not_provided not_provided HGNC:9608 MONDO:0008970 uuid:5c903ea3-f6b8-4d8f-bae0-0422faad9927 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1443060 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0409974 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235901 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0043251 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0020701 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0022660 infores:hetionet CHEBI:39669 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0009806 infores:hetionet CHEBI:3213 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0085584 infores:hetionet CHEBI:9927 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0017178 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0024299 infores:hetionet CHEBI:4784 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0085631 infores:hetionet CHEBI:2569 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0015967 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0422974 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0422974 infores:hetionet CHEBI:15544 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0030794 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0015230 infores:hetionet CHEBI:65173 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0003811 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0234458 infores:hetionet NCBIGene:8260 biolink:causes MONDO:0010457 infores:monarchinitiative not_provided not_provided HGNC:18704 MONDO:0010457 uuid:283ff66c-d4c8-450c-a678-ddd48d28be7d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0853034 infores:hetionet CAID:CA009712 biolink:causes MONDO:0021056 infores:clingen CAID:CA009712 MONDO:0021056 PMID:18199528 Uncertain Significance BS3_Supporting, BP1, PS4 PM2 The c.4732T>G variant in APC is a missense variant predicted to cause the substitution of cysteine by glycine at amino acid position 1578 (p.Cys1578Gly). This variant has been reported in 21 families with FAP worth 9 phenotype points (PS4, Ambry, GeneDX and Invitae internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.0009780% in the non-Finnish European population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel’s (HCCP VCEP) threshold ≤ 0.0008% for PM2_Supporting (PM2_Supporting not met). A luciferase reporter plasmid transiently transfected into SW480 cells is able to suppress beta-catenin-regulated transcription indicating that this variant does not impact protein function (BS3_Supporting; PMID 18199528). APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). Due to conflicting evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PS4, BS3_Supporting, BP1 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA009712/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41879 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0005758 infores:hetionet NCBIGene:6833 biolink:causes MONDO:0012480 infores:monarchinitiative not_provided not_provided HGNC:59 MONDO:0012480 uuid:96ebaa05-42b7-4fe0-8ead-230a7836bfd1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042963 infores:hetionet GO:1900163 biolink:causes GO:0010876 infores:ubergraph knowledge_assertion manual_agent GO:1900163 GO:0010876 CHEBI:61033 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0006285 infores:hetionet CHEBI:8888 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151904 infores:hetionet CHEBI:72564 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0234632 infores:hetionet CHEBI:3640 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0022354 infores:hetionet CHEBI:4653 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0855329 infores:hetionet CHEBI:15854 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0393593 infores:hetionet CHEBI:64064 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037763 infores:hetionet CHEBI:8107 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0019080 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0522063 infores:hetionet CAID:CA418279061 biolink:causes MONDO:0100368 infores:clingen CAID:CA418279061 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1101A>G (p.Arg367=) is a synonymous variant located in the third nucleotide of exon 10. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The splicing impact predictor SpliceAI gives a score of 0.99 for donor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This prediction has been confirmed by a minigene assay showing complete disruption of splicing and production of an alternative transcript with an out-of-frame truncation of 28 base pairs, which is supportive of a damaging effect on protein function (PMID: 28714225). These in silico and experimental findings have not been used to meet the PP3 and PS3_Supporting codes, but rather combined to meet the PVS1(RNA) code. At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), previous 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts), decreased central visual acuity (1 pt), onset between birth and 5 years old (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), RPE mottling (0.5 pts) and macular atrophy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 pts, PMID: 28714225, PMID: 32865313, PP4). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) or NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variants suspected in trans (1 point, PMID: 36909829, 28714225), which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (PM3). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PM3, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA418279061/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53760 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1458155 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0746883 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0029408 infores:hetionet CHEBI:5613 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0018524 infores:hetionet CHEBI:3757 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0027441 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0019158 infores:hetionet CHEBI:3082 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0014236 infores:hetionet CHEBI:4495 biolink:causes HP:0011896 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0038534 infores:hetionet CHEBI:59773 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0039231 infores:hetionet CHEBI:50777 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0016059 infores:hetionet CAID:CA367396861 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396861 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting PM1 The c.1361C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 454 (p.(Ala454Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.916, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4; PMIDs: 34746319, 36257325). Another missense variant, c.1361C>A p.Ala454Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1361C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396861/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CHEBI:5130 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0235146 infores:hetionet CHEBI:5280 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0013428 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0243065 infores:hetionet CHEBI:49375 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085593 infores:hetionet CHEBI:8378 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0002792 infores:hetionet CHEBI:6520 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C2363731 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0025637 infores:hetionet CAID:CA405683844 biolink:causes MONDO:0007783 infores:clingen CAID:CA405683844 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM5, PM1_Supporting PP3, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with serine at codon 401 of the RYR1 protein, p.(Arg401Ser). This variant was not present in a large population database (gnomAD) at the time it was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic that occurs at this codon, p.(Arg401His), PM5. A REVEL score of 0.839 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PM5. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405683844/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6904 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0035455 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0015397 infores:hetionet NCBIGene:10935 biolink:causes MONDO:0859245 infores:monarchinitiative not_provided not_provided HGNC:9354 MONDO:0859245 uuid:f6940e9a-1882-4a05-a417-363c4eba80f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0241618 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0241618 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002622 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0232498 infores:hetionet CAID:CA410148557 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148557 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS1, PS4, BA1, BP2, BP1, BP3, BS1, BS3, BS4, PM6, BP5, BP7, PVS1, PM3, PM5, PM1, PM4, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1019C>T (p.Pro340Leu) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting) but also has not been reported in the literature. The computational predictor REVEL gives a score of 0.255, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148557/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA16609261 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609261 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PP4_Moderate, PP3 PS4, PP1 The c.616T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tryptophan to arginine at codon 206 (p.(Trp206Arg)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.899, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.616T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609261/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4710 biolink:causes MONDO:0003265 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0001546 infores:hetionet CHEBI:7640 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0031256 infores:hetionet CHEBI:3756 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0549249 infores:hetionet CHEBI:15854 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0031256 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020517 infores:hetionet CHEBI:31401 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0003467 infores:hetionet CHEBI:408174 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0220981 infores:hetionet CHEBI:119486 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C3665347 infores:hetionet CHEBI:80630 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0013404 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0549373 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011570 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013395 infores:hetionet CHEBI:4315 biolink:causes MONDO:0004593 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0004767 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0032285 infores:hetionet CHEBI:6741 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0014742 infores:hetionet CHEBI:2673 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C1145670 infores:hetionet CHEBI:2788 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0030232 infores:hetionet CHEBI:6904 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018834 infores:hetionet CHEBI:6950 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C1142135 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006266 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0234458 infores:hetionet CAID:CA2918419 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918419 MONDO:0015152 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_000232.5: c.390G>A p.(Arg130=) variant in SGCB is a synonymous (silent) variant that is not predicted to influence splicing by SpliceAI (score 0.01) (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0005012 (10/19952 alleles) in the East Asian population (PM2_Supporting, BS1, BA1 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918419/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4995 biolink:causes MONDO:0000819 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002902 infores:hetionet UMLS:C0145185 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0027497 infores:hetionet CHEBI:4798 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0005747 infores:hetionet CHEBI:5296 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0232493 infores:hetionet NCBIGene:1832 biolink:causes MONDO:0011581 infores:monarchinitiative not_provided not_provided HGNC:3052 MONDO:0011581 uuid:d289c4ec-0224-4df2-852c-97498e3ff324 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0032227 infores:hetionet CHEBI:4792 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0036572 infores:hetionet CHEBI:45979 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0009676 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0030312 infores:hetionet CHEBI:50777 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0035455 infores:hetionet CHEBI:83527 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0014591 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0020517 infores:hetionet CHEBI:2673 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0151763 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018099 infores:hetionet CHEBI:15367 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0026766 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023518 infores:hetionet CHEBI:5165 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151907 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002170 infores:hetionet CAID:CA2580098623 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098623 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.805+19C>G is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). There is no predicted impact to splice consensus sequence nor the creation of new splice site and nucleotide is not highly conserved PhyloP score <2.0 (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098623/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007398 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0541831 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0541831 infores:hetionet CHEBI:46345 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0030554 infores:hetionet CHEBI:3219 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013404 infores:hetionet CHEBI:49960 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020625 infores:hetionet CHEBI:3650 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0162566 infores:hetionet CHEBI:47780 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2584688 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151734 infores:hetionet CHEBI:7492 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0574067 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042373 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0027339 infores:hetionet CHEBI:7936 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0241934 infores:hetionet CHEBI:44185 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0011606 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027697 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235906 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235906 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0033975 infores:hetionet CHEBI:8890 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042963 infores:hetionet NCBIGene:51008 biolink:causes MONDO:0014807 infores:monarchinitiative not_provided not_provided HGNC:24268 MONDO:0014807 uuid:3060cb6a-1f04-4ea0-85d8-43d77739bf4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3125 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C1321898 infores:hetionet CHEBI:63580 biolink:causes NCIT:C78233 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0853142 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0021053 infores:hetionet CHEBI:37924 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0010200 infores:hetionet CHEBI:7983 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0002994 infores:hetionet CHEBI:724125 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0038999 infores:hetionet CHEBI:32315 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0549249 infores:hetionet CHEBI:55346 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0018681 infores:hetionet NCBIGene:1308 biolink:causes MONDO:0007381 infores:monarchinitiative not_provided not_provided HGNC:2194 MONDO:0007381 uuid:28e1c816-8b22-4c52-a8d8-13f275f41a80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3499 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0027497 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0009938 infores:hetionet CAID:CA2573148473 biolink:causes MONDO:0015628 infores:clingen CAID:CA2573148473 MONDO:0015628 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PS2, PM4 The NM_000552.5(VWF):c.4606_4611del (p.His1536_Val1537del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 2 amino acids in a non-repeat region (PM4). This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 6 IU/dL and VWF:GPIbM 6 IU.dL), low activity/VWF:Ag ratio (0.18), and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID: 30044032). Additional consistent phenotypes were also reported in the patient including a normal platelet count. This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with VWD (PS2; PMID: 30044032). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS2, PM2_Supporting, PM4. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573148473/MONDO:0015628/081 2025-05-06 2025-05-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA398324519 biolink:causes MONDO:0011132 infores:clingen CAID:CA398324519 MONDO:0011132 PMID: Likely Pathogenic PS3_Moderate, PM2_Supporting, PM1, PP3_Moderate PP4 The NM_001369369.1(FOXN1):c.974T>C (p.Leu325Pro) missense variant has been reported in one heterozygous patient (P22), with T cell lymphopenia, however there was insufficient information to determine specificity to FOXN1-related disease (PMID: 31447097). The highest MAF in gnomADv4.0 is 0.000001313 (1/761890 alleles) in the European (non-Finnish) population which is below the <0.00002412 (PM2_supporting). It has a REVEL score of 0.992 (PP3_Moderate). The missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 325 (PM1). A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. The Leu325Pro variant had 2% luciferase activity compared to WT which is below the <50% threshold for PS3_moderate (PMID: 37419334). In summary this variant meets criteria to be classified as likely pathogenic for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PP3_moderate, PS3_moderate, PM2_supporting, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398324519/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CAID:CA011970 biolink:causes MONDO:0005045 infores:clingen CAID:CA011970 MONDO:0005045 PMID:27532257PMID:15856146PMID:17125710PMID:20738943PMID:15856146PMID:17125710PMID:12974739PMID:16630449PMID:16199542PMID:27532257 Pathogenic PM1, PM2, PP1_Moderate, PS4 The c.2207T>C (p.Ile736Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:16630449; PMID:12974739; PMID:16199542; PMID:15856146; PMID:17125710; PMID:20738943; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000199207.4; AGCMC Sydney ClinVar SCV000212631.2). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; PMID:17125710; Partners LMM ClinVar SCV000199207.4). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011970/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8874 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1384353 infores:hetionet CHEBI:10650 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020453 infores:hetionet CAID:CA400028186 biolink:causes MONDO:0100326 infores:clingen CAID:CA400028186 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PVS1_Moderate PP4 The NM_000212.3(ITGB3):c.2T>C (p.Met1Thr) may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. At least one variant (c.31T>C; p.Trp11Arg) has been classified Pathogenic upstream of the next potential in-frame start codon at residue 48 (PVS1_Moderate). Patient 1, of PMID: 31029159, is reported to have a clinical diagnosis of GT and is homozygous for this variant (PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00001576 (1/63468 alleles) in the African/African American genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400028186/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true GO:0039537 biolink:causes GO:0002753 infores:ubergraph knowledge_assertion manual_agent GO:0039537 GO:0002753 CHEBI:9137 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0836924 infores:hetionet CHEBI:5959 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0014591 infores:hetionet CHEBI:5778 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0018965 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015230 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020456 infores:hetionet CHEBI:63627 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C2047937 infores:hetionet CHEBI:27882 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0011991 infores:hetionet CHEBI:28830 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0006826 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009782 infores:hetionet CHEBI:68579 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0687713 infores:hetionet NCBIGene:54840 biolink:causes MONDO:0008842 infores:monarchinitiative not_provided not_provided HGNC:15984 MONDO:0008842 uuid:fdc30428-6683-4fbd-9509-a79ab4b7065d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8069 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0020672 infores:hetionet CHEBI:171719 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1760428 infores:hetionet CHEBI:8869 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0019112 infores:hetionet CHEBI:68554 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0014356 infores:hetionet CHEBI:38562 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0004604 infores:hetionet CAID:CA405668159 biolink:causes MONDO:0007783 infores:clingen CAID:CA405668159 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 2371 of the RYR1 protein, p.(Glu2371Gly). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:24433488). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.891) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405668159/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:39867 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0032285 infores:hetionet CHEBI:6062 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004093 infores:hetionet NCBIGene:6442 biolink:causes MONDO:0011968 infores:monarchinitiative not_provided not_provided HGNC:10805 MONDO:0011968 uuid:5046e0e9-104a-47d2-815b-3f0d58d0caf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16467 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0038990 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0233571 infores:hetionet CHEBI:63608 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0028961 infores:hetionet CHEBI:8805 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0022346 infores:hetionet CHEBI:3716 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0040264 infores:hetionet CHEBI:31536 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0035455 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042267 infores:hetionet GO:2000702 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0060993 CHEBI:31638 biolink:causes UMLS:C0278488 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0278488 infores:hetionet CHEBI:51860 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011071 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0020517 infores:hetionet CAID:CA410206759 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206759 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.755C>A (p.Ser252Tyr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206759/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:724125 biolink:causes UMLS:C0235218 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0235218 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0037274 infores:hetionet CAID:CA386299729 biolink:causes MONDO:0009861 infores:clingen CAID:CA386299729 MONDO:0009861 PMID: Pathogenic PM3, PM2, PVS1, PP4 This c.442-1G>C variant in PAH was reported in trans with pathogenic variant p.Val388Met in 1 Han Chinese patient with PAH deficiency (PMID: 28982351). This variant is absent from population databases gnomAD, 1000 Genomes and ESP. This variant in the -1 splice acceptor site of intron 4 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386299729/MONDO:0009861/006 2020-12-07 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8207 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085649 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0019348 infores:hetionet CHEBI:63621 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0022107 infores:hetionet GO:0085034 biolink:causes GO:0007249 infores:ubergraph knowledge_assertion manual_agent GO:0085034 GO:0007249 CHEBI:7936 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020625 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035854 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027765 infores:hetionet CHEBI:100241 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0028084 infores:hetionet CHEBI:8871 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0231528 infores:hetionet CHEBI:47780 biolink:causes UMLS:C1456329 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1456329 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0021053 infores:hetionet CHEBI:9434 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013456 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0042109 infores:hetionet CHEBI:3423 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0036454 infores:hetionet CHEBI:4636 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0015230 infores:hetionet CAID:CA10014634 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014634 MONDO:0011071 PMID: Benign BA1, BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS3, BS1, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.4(RUNX1):c.65T>A (p.Ile22Lys) is a missense variant which has a MAF of 0.001593 (56/35158 alleles) in the Latino subpopulation in gnomAD v2.1.1, meeting the threshold for BA1. It also has a REVEL score < 0.50 (0.271) and a SpliceAI score ≤ 0.20 (0.04) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014634/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3223 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0026821 infores:hetionet CHEBI:6897 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C3665347 infores:hetionet CHEBI:4995 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085595 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0012833 infores:hetionet CHEBI:63631 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0039070 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027932 infores:hetionet CHEBI:27732 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0151692 infores:hetionet CHEBI:15365 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0020621 infores:hetionet CAID:CA10580157 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580157 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PS4_Moderate, PVS1_Strong BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.2296-2A>G variant is a canonical splice variant predicted to result in a truncated protein (PVS1_strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_moderate; SCV000760771.5). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PS4_moderate, PM2_supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580157/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:84500 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085631 infores:hetionet CHEBI:63618 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0002878 infores:hetionet CHEBI:15552 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0017178 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018991 infores:hetionet CHEBI:10101 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0476273 infores:hetionet CAID:CA8603214 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603214 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PM3, PP3, BP4 The NM_000419.5:c.1157G>A variant in ITGA2B is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 386 (p.Arg386Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006306 (8/126862 alleles) in the European (non Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant was observed by Ilumina as part of a predisposition screen in an ostensibly healthy population but has not been reported in the literature for Glanzmann thrombasthenia. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603214/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:40303 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0232462 infores:hetionet CAID:CA8459420 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459420 MONDO:0011132 PMID: Uncertain Significance PP3, PM2 PP4 The variant NM_001369369.1(FOXN1):c.1021C>T is predicted to cause a arginine to cysteine substitution at amino acid position 341. The variant has a Grpmax allele frequency of 0.00001533 based upon the European (Non-Finnish) population, which is less than 0.0000447 (PM2_supporting). The meta predictor Revel predicts a potential disrupting effect on protein function with a score of 0.741, which is greater than 0.644 and thus meets PP3 criteria. The variant was found in the heterozygous state in sample 536 from PMID: 31672859 in a 9 year old patient who displayed TREC copies/μL of 46.3 and was reportedly exome sequenced for SCID related genes (0.5, PP4 not met). In summary this variant meets criteria to be classified as Variant of Uncertain significance- insufficient evidence for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PP3 and PM2_supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459420/MONDO:0011132/113 2024-10-25 2024-10-25 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:6887 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151849 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020649 infores:hetionet CHEBI:31980 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0031350 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026650 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0004610 infores:hetionet UMLS:C0657912 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0232292 infores:hetionet CHEBI:7956 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0002871 infores:hetionet CHEBI:82960 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0086769 infores:hetionet CHEBI:6538 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0267792 infores:hetionet CHEBI:27504 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0018802 infores:hetionet CHEBI:135530 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C1321686 infores:hetionet CHEBI:45783 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162557 infores:hetionet CHEBI:184555 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018965 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0020517 infores:hetionet NCBIGene:2893 biolink:causes MONDO:0060641 infores:monarchinitiative not_provided not_provided HGNC:4574 MONDO:0060641 uuid:5d620ffc-15a7-4d2d-9638-45e735a29018 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2573051029 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051029 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PP4 The c.-286_-285del variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This region is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50%); however, HNF4A was not tested (internal lab contributors), and therefore PP4 was not applied. In summary, c.-286_-285del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051029/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:465284 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011606 infores:hetionet CHEBI:5280 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0038990 infores:hetionet CHEBI:161680 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0027947 infores:hetionet CHEBI:3216 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0009676 infores:hetionet CHEBI:9674 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0011991 infores:hetionet CHEBI:194135 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085649 infores:hetionet CHEBI:47780 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0740394 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0040034 infores:hetionet CHEBI:94440 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C1306341 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027769 infores:hetionet CHEBI:6030 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0042963 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0021053 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020456 infores:hetionet CHEBI:5959 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0149744 infores:hetionet CAID:CA3054201761 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201761 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP4, BP3, BA1, PM6, BP7, BS1, BS3, BS4, PM3, PM4, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.423_427del (p.Leu144LysfsTer14) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98–c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201761/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0919980 infores:hetionet CHEBI:3485 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0014743 infores:hetionet UMLS:C0010592 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0011124 infores:hetionet GO:0006954 biolink:causes MONDO:0005002 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D029424 DB09076_MESH_D029424_1 CHEBI:31932 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002962 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030305 infores:hetionet CHEBI:71417 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0038362 infores:hetionet CHEBI:134991 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0043352 infores:hetionet CHEBI:31705 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C3665347 infores:hetionet CHEBI:8890 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0039070 infores:hetionet CHEBI:8499 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C3665347 infores:hetionet CHEBI:9150 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0151480 infores:hetionet CHEBI:4657 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0042963 infores:hetionet CHEBI:63637 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0347390 infores:hetionet CHEBI:10127 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0438142 infores:hetionet CHEBI:7822 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0235063 infores:hetionet CHEBI:135935 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0011603 infores:hetionet CHEBI:3749 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0015967 infores:hetionet CHEBI:5280 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0428977 infores:hetionet CHEBI:31348 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2364111 infores:hetionet CHEBI:6367 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0086769 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0086132 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0025061 infores:hetionet CHEBI:52717 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017168 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085606 infores:hetionet CHEBI:473990 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0027947 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0178298 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0040046 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0853619 infores:hetionet CHEBI:188986 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0026858 infores:hetionet CHEBI:27882 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0010043 infores:hetionet CAID:CA399802112 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802112 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting PM3, PP3, BP4 TheNM_000419.5(ITGA2B):c.1742C>A (p.Ala581Asp) missense variant has been reported in at least one patient (Patient PL in PMID:12083483) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0.3-1.4% of normal, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting. (VCEP specifications version 2; date of approval 12/21/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802112/MONDO:0100326/011 2021-12-21 2021-12-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31348 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0005758 infores:hetionet CHEBI:8228 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0853034 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020437 infores:hetionet CAID:CA197127 biolink:causes MONDO:0007648 infores:clingen CAID:CA197127 MONDO:0007648 PMID:28688938PMID:10072428 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS2, PS3, PS1 The c.60G>A (p.Trp20Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 10072428, 28688938). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA197127/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:27882 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0948594 infores:hetionet CHEBI:8382 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0917801 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042373 infores:hetionet CHEBI:490877 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0016204 infores:hetionet CAID:CA10585422 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585422 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Supporting, PP1_Moderate, PM2, PP4 BS4, PP3 The NM_000527.5(LDLR):c.1359-5C>G variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_moderate, PM2, PP4, PS3_supporting, PS4_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PP1_moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo JorgePM2: PopMax MAF = 0.00001766 (0.001766%) in European (non-Finnish) population exomes (gnomAD v2.1.1). PP3: No REVEL, splicing evaluation required. Functional data on splicing not available.A) variant located at -20 to +3 bases from canonical acceptor splice site,MES scores: canonical site variant = 4.09; canonical acceptor wt = 6.76.Ratio variant/wt canonical acceptor: 4.09/6.76 = 0.605 ---- It is below 0.8Variant is predicted to alter splicing.PP4: Variant meets PM2 and is identified in at least 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530), after alternative causes of high cholesterol were excludedPS3_supporting: Level 3 assay: PMID 19411563:Heterozygous patients' lymphocytes, RNA assays - result - Retention of intron 9 (p.Ser453Argfs*2)---- functional study is consistent with damaging effect.PS4_supporting: Variant meets PM2 and is identified in 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585422/MONDO:0007750/013 2022-08-27 2022-12-23 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:1901210 biolink:causes GO:0003205 infores:ubergraph knowledge_assertion manual_agent GO:1901210 GO:0003205 CHEBI:3699 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0151773 infores:hetionet CHEBI:85078 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0011603 infores:hetionet CHEBI:46557 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C1096343 infores:hetionet CHEBI:4466 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0424790 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0878544 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0949059 infores:hetionet CHEBI:521033 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0006145 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0221100 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0027932 infores:hetionet CHEBI:93363 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0014236 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0405479 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0405479 infores:hetionet CHEBI:6970 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0013456 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0037274 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0151849 infores:hetionet CHEBI:63611 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0013404 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0520587 infores:hetionet CHEBI:65349 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0015672 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0677500 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0040046 infores:hetionet CHEBI:8890 biolink:causes UMLS:C1285373 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1285373 infores:hetionet CHEBI:6076 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1384353 infores:hetionet CHEBI:291342 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0013390 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0242350 infores:hetionet CHEBI:63631 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151934 infores:hetionet CHEBI:9599 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018794 infores:hetionet NCBIGene:6328 biolink:causes MONDO:0054776 infores:monarchinitiative not_provided not_provided HGNC:10590 MONDO:0054776 uuid:51642914-4240-47c5-9b41-cedd5186dc50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2694 biolink:causes MONDO:0009852 infores:monarchinitiative not_provided not_provided HGNC:4268 MONDO:0009852 uuid:c2df1be8-3355-40a5-bb89-8d1040925be5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0521839 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0042109 infores:hetionet CAID:CA229573 biolink:causes MONDO:0009861 infores:clingen CAID:CA229573 MONDO:0009861 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PM5, PM3 The c.479A>C (p.Gln160Pro) variant in PAH is reported in a German patient with PAH deficiency (PMID: 12655553); the second allele/genotype was not reported. It is absent from gnomAD. Computational evidence supports a deleterious effect (REVEL=0.668). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229573/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:47898 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0040046 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0020517 infores:hetionet CHEBI:16796 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0000737 infores:hetionet CHEBI:50859 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0687713 infores:hetionet CHEBI:7936 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0700361 infores:hetionet CHEBI:7443 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0043094 infores:hetionet CHEBI:70707 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0234047 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0040046 infores:hetionet CHEBI:2955 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0022107 infores:hetionet CHEBI:104011 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0027497 infores:hetionet CHEBI:101278 biolink:causes UMLS:C2242583 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C2242583 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0009450 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0014175 infores:hetionet CAID:CA512341213 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341213 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1224C>G (p.Gly408=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.50) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341213/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8426 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0002170 infores:hetionet CHEBI:3215 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0016382 infores:hetionet CHEBI:39867 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0031256 infores:hetionet CHEBI:2676 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0022354 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0162830 infores:hetionet GO:1902211 biolink:causes GO:0032870 infores:ubergraph knowledge_assertion manual_agent GO:1902211 GO:0032870 CHEBI:39867 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C3665347 infores:hetionet CHEBI:8107 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0039070 infores:hetionet CHEBI:9667 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0034150 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013447 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0021400 infores:hetionet CHEBI:119915 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0041834 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005300 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C1561643 infores:hetionet CHEBI:5441 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0013604 infores:hetionet CHEBI:53760 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0231218 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0242350 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0025061 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0687707 infores:hetionet CHEBI:9939 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0016382 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0080274 infores:hetionet CAID:CA392446003 biolink:causes MONDO:0007947 infores:clingen CAID:CA392446003 MONDO:0007947 PMID: Likely Pathogenic PM2, PP2, PP3, PS4_Moderate, PM1 PM6, PP1, PP4, BA1, BP4, BP2, PS3, PS2, PM5, BS1, BS3, BS4, BP5 The NM_00138 c.629G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 210 (p.Cys210Tyr). This variant was reported in an individual diagnosed with Marfan syndrome (PMID 33711475), and in an individual with ectopia lentis, pectus carinatum, foot deformity, dural ectasia, and protrusio acetabuli (PMID 31825148) (PS4_Mod). This variant was also found in a 7-year-old male proband with lens luxation, big stature, but a normal cardiac ultrasound, and was inherited from his healthy father, however ophthalmology exams are pending (Internal data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/). The variant in FBN1 has been reported twice in ClinVar as likely pathogenic (Variation ID: 426140). This variant affects a cysteine residue is in the 1st Hybrid domain of protein (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (REVEL: 0.94) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Moderate, PM2_Supportive, PP2, PP3 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392446003/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:194135 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151539 infores:hetionet CHEBI:64064 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0022568 infores:hetionet GO:1903587 biolink:causes GO:0048514 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0048514 CHEBI:61049 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0000731 infores:hetionet CHEBI:31624 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0013404 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0235966 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0037199 infores:hetionet CAID:CA1251493 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251493 MONDO:0013144 PMID: Likely Benign BS1, BP4 The c.29C>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of threonine by asparagine at amino acid 10 (p.Thr10Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003178 (41/129000 alleles) in the European population, which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.141, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BP4 Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251493/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94686 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0004096 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0878773 infores:hetionet CHEBI:5118 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0000731 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0030312 infores:hetionet CHEBI:50729 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020598 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0518015 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037286 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0009144 infores:hetionet CAID:CA2573157355 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157355 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supp, PM2_supp Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157355/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3557 biolink:causes MONDO:0013021 infores:monarchinitiative not_provided not_provided HGNC:6000 MONDO:0013021 uuid:7f484ea8-6dcc-46e8-a06f-fadd1aed23de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0235146 infores:hetionet CHEBI:5127 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0016436 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015397 infores:hetionet CHEBI:45327 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0040264 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0033844 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0033844 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0497327 infores:hetionet NCBIGene:3892 biolink:causes MONDO:0700343 infores:monarchinitiative not_provided not_provided HGNC:6463 MONDO:0700343 uuid:8ab241c5-99e5-4b03-8aaf-ee052b25bc76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232498 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0235648 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0235648 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0027947 infores:hetionet CHEBI:35854 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0085593 infores:hetionet CHEBI:39585 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0011168 infores:hetionet NCBIGene:81555 biolink:causes MONDO:0025690 infores:monarchinitiative not_provided not_provided HGNC:24877 MONDO:0025690 uuid:dcefcf16-098a-44ad-8c09-74e895baedb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94686 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0231528 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0031117 infores:hetionet CHEBI:119915 biolink:causes HP:4000214 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0238844 infores:hetionet CHEBI:4657 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0018790 infores:hetionet CHEBI:8382 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0023518 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017178 infores:hetionet CHEBI:9654 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0019572 infores:hetionet CHEBI:85083 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0004093 infores:hetionet CHEBI:7809 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C1443060 infores:hetionet CHEBI:8214 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0013395 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011630 infores:hetionet CHEBI:2639 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0234708 infores:hetionet CHEBI:68478 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0702166 infores:hetionet CHEBI:50729 biolink:causes HP:0004332 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0427546 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0017178 infores:hetionet CAID:CA10585509 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585509 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PM6, PVS1, BS2, PP2, PP1, PP4 NM_000527.5(LDLR):c.1577C>G (p.Pro526Arg) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.966 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585509/MONDO:0007750/013 2022-01-18 2022-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:60 biolink:causes MONDO:0011500 infores:monarchinitiative not_provided not_provided HGNC:132 MONDO:0011500 uuid:1aa3a7fe-6406-41dc-8f68-f6f9467fe552 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412376034 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376034 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PM1_Strong, PM5 PP3 NM_000330.4(RS1):c.177T>G (p.Cys59Trp) is a missense variant encoding the substitution of cysteine with tryptophan at amino acid 59, which is a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). Another missense variant in the same codon, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 31174210, 10450864, 17987333, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (215) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.724, which is within the ClinGen X-linked IRD VCEP range of 0.772 to 0.644 and predicts a damaging effect on RS1 function. The PM1_strong code is ineligible to be used in combination with the PP3 code, and therefore, this code was not met. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, and PM5. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376034/MONDO:0010725/126 2025-10-03 2025-10-03 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CAID:CA10549443 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549443 MONDO:0010305 PMID: Benign BA1 The NM_005629.4(SLC6A8):c.1162G>A (p.Ala388Thr) variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Alanine at amino acid 338 (p.Ala338Thr). There is a ClinVar entry for this variant (Variation ID:436771). This variant is found with an allele frequency of 0.003854 in gnomADv2.1.1 with 17 hemizygotes present in that population database. Given the presence of >10 hemizygotes in gnomADv2.1.1 and an allele frequency >0.002, the stand alone benign criteria BA1 is applicable for this variant. In summary, this variant meets the criteria to be classified as Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0; ; classification approved Feb 23, 2023): BA1 Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549443/MONDO:0010305/027 2023-02-23 2024-02-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:8430 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0041657 infores:hetionet CHEBI:85078 biolink:causes MONDO:0016264 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0241910 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0037199 infores:hetionet CHEBI:5141 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0000737 infores:hetionet CHEBI:39669 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0547030 infores:hetionet CHEBI:9448 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0085605 infores:hetionet CHEBI:4868 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0854467 infores:hetionet CHEBI:6541 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042029 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0423847 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0423847 infores:hetionet CHEBI:8707 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0009676 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0037274 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0012833 infores:hetionet CHEBI:3756 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0151766 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0151814 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0151814 infores:hetionet CHEBI:2948 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0948441 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0028643 infores:hetionet CHEBI:7494 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020578 infores:hetionet CHEBI:5855 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0349790 infores:hetionet CHEBI:46195 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0235710 infores:hetionet CAID:CA254847 biolink:causes MONDO:0044970 infores:clingen CAID:CA254847 MONDO:0044970 PMID: Likely Pathogenic PS4, PM5_Supporting, PS3_Supporting PP3, PP1, PS2, PM2, PM6 The m.1494C>T variant in the MT-RNR1 gene has been reported in >16 unrelated individuals with primary mitochondrial disease with non-syndromic hearing loss with and without aminoglycoside exposure. All were homoplasmic for the variant with the exception of one case who was heteroplasmic at 85.1% in blood (PS4; PMIDs: 34467602, 20100600, 17084680, 16380089, 17434445, 17698299, 17698030, 30693673, 14681830). Given the homoplasmic nature of this variant, familial segregation cannot be applied for PP1. There are no reports of de novo occurrences to our knowledge. This variant occurs in a highly conserved area and forms U1494-1555A base pair which is in the same position of the C1494-1555G pair created in a well-known pathogenic variant m.1555A>G (PM5_supporting; PMID: 14681830). Cybrid studies support the functional impact of this variant. Compared to control cybrids, there was a decrease in mitochondrial protein synthesis and high concentration of paromomycin in cybrids derived from three symptomatic and two asymptomatic individuals carrying the m.1494C>T variant (PS3_supporting; PMID: 15722487). This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.007%; Helix's 196,554 sequences: AF=0.021%; and gnomAD v3.1.2: AF=0.0023% as this is homoplasmic in 13 individuals and heteroplasmic in one individual). Given the frequency of this variant, it does not meet PM2 criterion. There is limited computational scoring for rRNA variants precluding PP3 criterion. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254847/MONDO:0044970/015 2022-07-11 2022-10-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:61033 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0687713 infores:hetionet CHEBI:3403 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0018681 infores:hetionet CHEBI:2549 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020621 infores:hetionet NCBIGene:25929 biolink:causes MONDO:0859152 infores:monarchinitiative not_provided not_provided HGNC:20043 MONDO:0859152 uuid:15ce992b-c1bb-4473-b3fc-9d65e017d303 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92998 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0242301 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011991 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0027051 infores:hetionet CHEBI:27882 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0002170 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0948595 infores:hetionet CHEBI:50924 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151904 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0042373 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011609 infores:hetionet CHEBI:9622 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0011253 infores:hetionet CAID:CA214324 biolink:causes MONDO:0015967 infores:clingen CAID:CA214324 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PM5 The c.734G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to valine at codon 245 (p.Gly245Val) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative antibodies, and low hsCRP; HNF4A not tested, but low hsCRP is specific to HNF1A vs. HNF4A) (PP4_Moderate; PMID: 30181854). Another missense variant, c.733G>A (p.Gly245Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.734G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214324/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:77260 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027651 infores:hetionet CHEBI:6741 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0015230 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0232492 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0242350 infores:hetionet CHEBI:30659 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0004093 infores:hetionet CHEBI:32139 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0011991 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0021053 infores:hetionet CHEBI:5613 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0234133 infores:hetionet CHEBI:7936 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018965 infores:hetionet CHEBI:36795 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2939147 infores:hetionet CAID:CA222854 biolink:causes MONDO:0100040 infores:clingen CAID:CA222854 MONDO:0100040 PMID: Likely Benign BS2, PM2, BP4 The p.Gln86Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Gln86Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gln86Lys variant in FOXG1 is absent from gnomAD (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: BS2, BP4 (approved 8/25/22). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222854/MONDO:0100040/016 2022-09-01 2022-09-06 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:70735 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0424230 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027947 infores:hetionet CHEBI:145499 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018800 infores:hetionet CHEBI:10650 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0018681 infores:hetionet CHEBI:16469 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0004604 infores:hetionet CAID:CA1938381 biolink:causes MONDO:0100062 infores:clingen CAID:CA1938381 MONDO:0100062 PMID: Benign BA1, PP3_Moderate BP1, BP4, PS4, PS3, PS2, PS1, BP7, BS3, BS4, PM2, PVS1, PM6, PM5, PP1 The c.5584G>T variant in SCN3A is a missense variant predicted to case the substitution of glycine by cysteine at amino acid 1862 (p.Gly1862Cys). The highest population minor allele frequency in gnomAD v.2 is 8.2% (2915/35374 alleles) in the Latino population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.3%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.808 (PP3_Moderate). Although there are both pathogenic and benign types of evidence for this variant, the high frequency of this variant in gnomAD strongly supports a benign classification, and the only evidence in support of pathogenicity is based on a computational predictor that should not override the high population frequency, which precludes this variant from being pathogenic for a rare disease. In summary, this variant meets the criteria to be classified as Benign for autosomal dominant developmental and epileptic encephalopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1; 6/27/2023). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1938381/MONDO:0100062/069 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3504 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0018099 infores:hetionet CHEBI:6073 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0030252 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0003123 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0151888 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0036508 infores:hetionet GO:0061318 biolink:causes CL:0002522 infores:ubergraph knowledge_assertion manual_agent GO:0061318 CL:0002522 CHEBI:9588 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0037763 infores:hetionet CHEBI:51860 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0039240 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0232459 infores:hetionet CAID:CA229633 biolink:causes MONDO:0009861 infores:clingen CAID:CA229633 MONDO:0009861 PMID:9012412PMID:16601866PMID:8533759PMID:7981714PMID:16601866PMID:7981714 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. gnomAD MAF:0.00004.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899; PM3_Strong: Detected in trans with V245A and R261X, both pathogenic (PMID:7981714; PMID:16601866); PP4_Moderate: Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients. (PMID:8533759; PMID:7981714; PMID:9012412; PMID:16601866). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3_Strong, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229633/MONDO:0009861/006 2018-08-13 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15553 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085616 infores:hetionet CAID:CA2739267609 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267609 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, PM6, BP5, BP7, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.656_674del (p.Leu219SerfsTer12) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267609/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28748 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0549567 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0037199 infores:hetionet CAID:CA1706729 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706729 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.3805dup p.(Glu1269GlyfsTer7) variant in DYSF, which is also known as NM_001130987.2: c.3859dup p.(Glu1287GlyfsTer7), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 34/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least two individuals with features of LGMD, including in unknown phase with a pathogenic variant (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 27602406; 36983702; PM3_Supporting). At least one patient with this variant and a second presumed diagnostic variant in DYSF displayed a clinical suspicion of LGMD or progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 27602406; 36983702). The filtering allele frequency of this variant is 0.000020771 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 15/1112008 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/11/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706729/MONDO:0015152/180 2025-04-11 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023533 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0521465 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0022904 infores:hetionet CHEBI:45081 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0038002 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0027707 infores:hetionet CHEBI:5147 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C1527344 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0948594 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0027531 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027531 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0020510 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020510 infores:hetionet CHEBI:4511 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0003862 infores:hetionet CHEBI:52172 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0162285 infores:hetionet CHEBI:45285 biolink:causes HP:0003452 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0151900 infores:hetionet CHEBI:42944 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1368065 infores:hetionet CHEBI:9586 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0520966 infores:hetionet CHEBI:51450 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0744727 infores:hetionet CHEBI:87681 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0036974 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0017601 infores:hetionet CHEBI:51450 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0085649 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0235957 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0235957 infores:hetionet CHEBI:8455 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0267792 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0851341 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042035 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0019112 infores:hetionet CHEBI:7809 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0151904 infores:hetionet CHEBI:78320 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0162834 infores:hetionet NCBIGene:1291 biolink:causes MONDO:0024530 infores:monarchinitiative not_provided not_provided HGNC:2211 MONDO:0024530 uuid:5f33ed0c-e586-4e36-a730-955917160d4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0427008 infores:hetionet CHEBI:63618 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0028643 infores:hetionet CHEBI:38545 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0151736 infores:hetionet CHEBI:9123 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019079 infores:hetionet CHEBI:5778 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0001824 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0029443 infores:hetionet CHEBI:92998 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0023530 infores:hetionet CHEBI:52172 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0268000 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0027769 infores:hetionet CHEBI:5138 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C3665347 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0234987 infores:hetionet CHEBI:9168 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0028961 infores:hetionet CAID:CA412745199 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745199 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.373G>T (p.Glu125Ter) is a nonsense variant that introduces a premature stop in codon 125 within exon 5 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) at age 3 years (1 pt), severely reduced visual acuity (0.5 pts), high myopia (1 pt), markedly reduced electroretinogram responses from rods, widespread retinal pigment epithelium degeneration in the fundus with mid-periphery pigment deposits (0.5 pts), optic disc pallor (0.5 pts), severe macular degeneration, and retinal vessel attenuation, with genotyping by next-generation sequencing of a panel of >300 genes identifying no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (6 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745199/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:9332 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0017178 infores:hetionet CHEBI:18248 biolink:causes UMLS:C1142068 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C1142068 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0007097 infores:hetionet CHEBI:75922 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0010038 infores:hetionet CHEBI:9150 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C3267047 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042571 infores:hetionet CHEBI:4551 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0085614 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0009450 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0595877 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151883 infores:hetionet CHEBI:119486 biolink:causes NCIT:C160411 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0281863 infores:hetionet CHEBI:5098 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0014742 infores:hetionet CHEBI:72690 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0006145 infores:hetionet NCBIGene:3588 biolink:causes MONDO:0012941 infores:monarchinitiative not_provided not_provided HGNC:5965 MONDO:0012941 uuid:6741c445-62e9-4e7f-b3e7-f2d22243479f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31176 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0037383 infores:hetionet CHEBI:47381 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0575081 infores:hetionet CHEBI:4710 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0010200 infores:hetionet CHEBI:35553 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0027497 infores:hetionet GO:0046605 biolink:causes GO:0000226 infores:ubergraph knowledge_assertion manual_agent GO:0046605 GO:0000226 CHEBI:404903 biolink:causes UMLS:C0848648 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0848648 infores:hetionet CHEBI:31348 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011124 infores:hetionet NCBIGene:5896 biolink:causes MONDO:0012359 infores:monarchinitiative not_provided not_provided HGNC:9831 MONDO:0012359 uuid:67f657ed-e217-4d4e-b7f3-febe7e5db697 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0151878 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0004239 infores:hetionet NCBIGene:1311 biolink:causes MONDO:0007561 infores:monarchinitiative not_provided not_provided HGNC:2227 MONDO:0007561 uuid:ffaa56d3-5fa0-42a6-b94f-fc863f1e6bb8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:408174 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0031350 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0008301 infores:hetionet CHEBI:31547 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0008031 infores:hetionet CHEBI:8707 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0016204 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0853946 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0853946 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0521839 infores:hetionet CHEBI:18332 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0015230 infores:hetionet CAID:CA10585508 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585508 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1576C>A (p.Pro526Thr) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.951.PP4 - Variant meets PM2. Identified in 1 FH case with clinical diagnosis of probable heterozygous hypercholesterolemia by DLCN score (DLCN = 8) from PMID 32770674. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585508/MONDO:0007750/013 2022-01-18 2022-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:145499 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235939 infores:hetionet GO:0060222 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0007399 CHEBI:8871 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235763 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0746883 infores:hetionet CHEBI:17987 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0235266 infores:hetionet CHEBI:4466 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0858635 infores:hetionet CHEBI:3561 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0232849 infores:hetionet CHEBI:27786 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0233794 infores:hetionet CHEBI:100147 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0002878 infores:hetionet CHEBI:135342 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0039070 infores:hetionet NCBITaxon:272561 biolink:causes MONDO:0005701 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:272561 MONDO:0005701 CHEBI:4911 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0018681 infores:hetionet CHEBI:4784 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0002994 infores:hetionet CAID:CA025003 biolink:causes MONDO:0007783 infores:clingen CAID:CA025003 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with threonine at codon 3253 of the RYR1 protein, p.(Ile3253Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000201, a frequency consistent with pathogenicity for MHS. This variant has not to our knowledge been reported in any individuals with a personal history of an MH episode or a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.845 supports neither a pathogenic nor a benign status for this variant. This variant has been classified a Variant of Unknown Significance. Criteria implemented: none. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA025003/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:35854 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0019158 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0399459 infores:hetionet CHEBI:27690 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0028643 infores:hetionet CHEBI:9014 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0040264 infores:hetionet NCBIGene:1936 biolink:causes MONDO:0976263 infores:monarchinitiative not_provided not_provided HGNC:3211 MONDO:0976263 uuid:626f876d-44c0-405e-9601-95ec00bda312 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10609269 biolink:causes MONDO:0100084 infores:clingen CAID:CA10609269 MONDO:0100084 PMID: Benign BP4, BA1, BP7 The NM_001100.4:c.-66C>T variant in ACTA1 is a variant which is located in the 5’-UTR. The population filtering allele frequency in gnomAD v4.1.0 is 0.7509 (31375/41396 alleles with 11881 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0025 for AR, ≥0.00000781 for AD) for BA1, and therefore meets this criterion (BA1). The results from the in silico predictor, SpliceAI, suggest that the variant does not impact ACTA1 function and it occurs at a nucleotide that is not conserved as shown by the UCSC Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10609269/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes MONDO:0011962 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007103 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0020538 infores:hetionet CHEBI:71272 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0002994 infores:hetionet CAID:CA902383 biolink:causes MONDO:0100368 infores:clingen CAID:CA902383 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000329.3(RPE65):c.845A>G (p.Asn282Ser) is a missense variant resulting in substitution of asparagine by serine at codon 282. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00009682, with 11 alleles / 113616 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.435, which is above the ClinGen LCA / eoRD VCEP threshold of >0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902383/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8863 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0428977 infores:hetionet CHEBI:2569 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0344232 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019348 infores:hetionet CHEBI:6950 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0234708 infores:hetionet CHEBI:7865 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0027497 infores:hetionet CHEBI:39585 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0016204 infores:hetionet CHEBI:6128 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0002622 infores:hetionet CHEBI:85083 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0012833 infores:hetionet CHEBI:3215 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151904 infores:hetionet CHEBI:724125 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0520893 infores:hetionet CHEBI:46195 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0423791 infores:hetionet CHEBI:40279 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038325 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042510 infores:hetionet CHEBI:64321 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0232462 infores:hetionet CHEBI:3568 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023222 infores:hetionet NCBIGene:2670 biolink:causes MONDO:0008752 infores:monarchinitiative not_provided not_provided HGNC:4235 MONDO:0008752 uuid:0d65c663-3f71-4c3e-991e-3a997fce22a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0012813 infores:hetionet CAID:CA068028 biolink:causes MONDO:0007783 infores:clingen CAID:CA068028 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PP1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with leucine at codon 2102 of the RYR1 protein, p.Val2102Leu. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000018, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this variant was in cis to a second RYR1 variant that has been classified as a variant of uncertain significance (p.Arg1583Cys), for that reason PS4 was not implemented (PMID:23035052). The allele containing both variants segregated with MHS in four individuals in this family, however, since the effect of the two alleles cannot be separated PP1 was not implemented for this variant (PMID:23035052). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.515 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA068028/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:79882 biolink:causes MONDO:0014930 infores:monarchinitiative not_provided not_provided HGNC:20509 MONDO:0014930 uuid:c954dea9-b126-4412-ab5e-3ee480f1bb90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92998 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0017152 infores:hetionet CHEBI:2788 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0019080 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151888 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0020538 infores:hetionet CHEBI:4672 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0026821 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0003864 infores:hetionet CHEBI:9738 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0028643 infores:hetionet CHEBI:8776 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0011168 infores:hetionet CAID:CA042604 biolink:causes MONDO:0007750 infores:clingen CAID:CA042604 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PM5_Strong, PS4_Moderate, PP1_Moderate, PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, BS2 The NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP1_Moderate, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_strong - there are 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines--- There are 2 variants classified as Pathogenic, so PM5_Strong is met.PP1_moderate - Variant segregates with phenotype in 4 informative meiosis from different labs: - 1 unaffected family member does not have the variant, from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation);- 3 informative meiosis from 1 family from PMID 12837857 (Chang et al. 2003): 1 relative has the variant and phenotype (III:1), plus 2 relatives do not have the variant and do not have the phenotype (II:1 and III:2)4 informative meiosis, so PP1_Moderate is met.PM2 - PopMax MAF = 0.0008019 (0.08019%) in East Asian (gnomAD v2.1.1), but this is a founder variant in East Asian populations, so PM2 can be met in this instance.PS3_moderate - Level 2 FS: Chang et al., 2003 (PMID:12837857): Heterologous cells (COS-7), FACS assays - results: 55% LDLR cell surface and uptake. Binding is not studied, so not all cycle is studied (level 2 and not level 1)---- functional study is consistent with damaging effect, activity is below 70% of wild-type, so PS3_Moderate is met.PS4_moderate - variant meets PM2 and was identified in:- 1 index case who fulfills Simon Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 3 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada;- at least 1 index case with DLCN score of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583645.1 in ClinVar), France;- 1 index case who fulfills SB criteria of at least possible FH from PMID 9259195 (Day et al., 1997), UK;- 1 index case who fulfills SB criteria of at least possible FH from PMID 25962062 (Han et al., 2015), Korea;- 2 unrelated index cases who fulfill SB criteria of possible FH (TC>8mmol/L, plus CAD) from PMID 12837857 (Chang et al., 2003), Taiwan, China;9 cases, so PS4_Moderate is met.PP4 - variant meets PM2 and was identified in 9 unrelated index cases from different labs (see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042604/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:77260 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0600142 infores:hetionet CAID:CA229878 biolink:causes MONDO:0009861 infores:clingen CAID:CA229878 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong, PM3_Supporting The PAH variant c.969+1G>A (IVS9+1G>A) is a null variant (donor site) located in exon number 9 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Four null variants in exon 9 of the PAH gene have been reported. This variant is predicted to alter a region that is critical to protein function (13 pathogenic non-nonsense variants in the skipped exon have been reported). Exon skipping is not predicted to disrupt the reading frame. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.968). HSF (-32.06% variation) and MaxEnt (-86.2% variation) agree that this alteration of the WT donor site most probably affects splicing. The PAH variant c.969+1G>A (IVS9+1G>A) was reported with the PAH pathogenic variant c.1222C>T (p.Arg408Trp) (ClinVar ID: 577) in a European patient with classical PKU (serum Phe levels above 1200μmol/L). Cofactor deficiency was excluded by the BH4 test (PMID: 10679941) and in a patient from Iran with classical PKU (serum Phe levels above 1200μmol/L) (PMID: 26413448). This variant is absent in the gnomAD, ExAC, and PAGE population databases. In summary, this variant meets the criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4, and PVS1_Strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229878/MONDO:0009861/006 2020-04-21 2021-02-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42355 biolink:causes MONDO:0001561 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0034194 infores:hetionet CHEBI:4877 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0032285 infores:hetionet CHEBI:3219 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151786 infores:hetionet CHEBI:28901 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0428977 infores:hetionet CHEBI:5118 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0001925 infores:hetionet CHEBI:45716 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0004093 infores:hetionet CHEBI:6375 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011175 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0006266 infores:hetionet CAID:CA10014725 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014725 MONDO:0011071 PMID: Likely Benign BS1 PS4, PS3, PS1, BA1, BP2, BP4, PM6, PM2, PVS1, BS4, BS3, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.54G>T variant that results in a Met18Ile missense change has an MAF of 0.0002403 (0.02%, 6/24966 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This variant meets criteria to be classified as likely benign based on BS1 alone with no contradictory evidence supporting pathogenicity. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014725/MONDO:0011071/008 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Contradicts true PUBCHEM.COMPOUND:657309 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0000737 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0853619 infores:hetionet CAID:CA10585474 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585474 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 PS3 The NM_000527.5 (LDLR):c.1474G>C (p.Asp492His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00002 in Non-Finnish European population in gnomAD (gnomAD v2.1.1).PP3: REVEL=0.993.PM5: Two other missense variants in the same codon: NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn), ClinVar 161285, classified as Pathogenic by these guidelines; NM_000527.5(LDLR):c.1475A>G (p.Asp492Gly), ClinVar 251865, classified as Likely Pathogenic by these guidelines. Therefore PM5 is met.PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for FH diagnosis after alternative causes of high cholesterol were excluded, reported in PMID 10208479 (Heath et al., 1999), from University College London Medical School, UK. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585474/MONDO:0007750/013 2023-11-07 2024-10-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:47381 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020443 infores:hetionet CHEBI:3371 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0438142 infores:hetionet CHEBI:63638 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0009782 infores:hetionet CHEBI:40237 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C1384353 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0020283 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D014605 DB00994_MESH_D014605_1DB00781_MESH_D014605_1DB00634_MESH_D014605_1 CHEBI:3084 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0000729 infores:hetionet CHEBI:251408 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0035232 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0009806 infores:hetionet CHEBI:49662 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0030252 infores:hetionet CHEBI:48131 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0033774 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1258215 infores:hetionet CAID:CA196418 biolink:causes MONDO:0700272 infores:clingen CAID:CA196418 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting The c.2524_2535delinsTCAGA (p.Ala842Serfs*7) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent from gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA196418/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41423 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0003126 infores:hetionet NCBITaxon:6198 biolink:causes MONDO:0005884 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6198 MESH:D009889 DB01058_MESH_D009889_1 CHEBI:31711 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0855329 infores:hetionet CAID:CA415173958 biolink:causes MONDO:0010726 infores:clingen CAID:CA415173958 MONDO:0010726 PMID: Uncertain Significance BS2_Supporting BA1, PS1, PM1, PM5, PM2, BS1 The highest population minor allele frequency of the p.Pro173Thr variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.000002233 in European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro173Thr variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2_Supporting). The p.Pro173Thr variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Pro173Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2_Supporting). (MECP2 specification v3.0.0, curation approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415173958/MONDO:0010726/036 2024-08-30 2024-12-23 X-linked inheritance HP:0001417 Inconclusive true CHEBI:171719 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0085932 infores:hetionet CHEBI:6367 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0851578 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0521839 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234953 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234953 infores:hetionet CHEBI:63605 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0858635 infores:hetionet CHEBI:10127 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0086439 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013595 infores:hetionet CAID:CA16020717 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020717 MONDO:0009861 PMID:21147011 Pathogenic PVS1, PP4_Moderate, PM2_Supporting The c.47_48dup (p.Asp17LeufsTer22) variant in PAH is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is reported on 3 alleles of patients with phenylketonuria, with BH4 deficiency excluded (PP4_moderate, PMID: 21147011). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PP4_moderate, PM2_supporting. (Phenylketonuria VCEP specifications version 1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020717/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9130 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0267792 infores:hetionet CHEBI:8863 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0024312 infores:hetionet CHEBI:41977 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0151636 infores:hetionet CHEBI:6904 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018524 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0027769 infores:hetionet CHEBI:16914 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0677500 infores:hetionet CHEBI:32315 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0233754 infores:hetionet CHEBI:7565 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0235031 infores:hetionet CHEBI:9288 biolink:causes MONDO:0006944 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0238621 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0178298 infores:hetionet CAID:CA229279 biolink:causes MONDO:0009861 infores:clingen CAID:CA229279 MONDO:0009861 PMID:9634518 Pathogenic PVS1, PP4_Moderate, PM2 PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PVS1: Frameshift variant; PP4_Moderate: Reported in patients with PAH deficiency. Bh4 defects excluded. (PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229279/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50924 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0948089 infores:hetionet CHEBI:4653 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0015672 infores:hetionet CHEBI:7936 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007820 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0021843 infores:hetionet CHEBI:2687 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C1287298 infores:hetionet CHEBI:63598 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018524 infores:hetionet CHEBI:135613 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0026858 infores:hetionet CAID:CA000264 biolink:causes MONDO:0018875 infores:clingen CAID:CA000264 MONDO:0018875 PMID: Likely Benign BP4, BS3 BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, BS2, PP3, PP1 The NM_000546.6: c.554G>A variant in TP53 is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 185 (p.Ser185Asn). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.159418; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BP4_Moderate, BS3. (Bayesian Points: -6; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000264/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6532 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0150450 infores:hetionet CHEBI:17026 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1112214 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006145 infores:hetionet CAID:CA413497546 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497546 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.115+2T>C (NM_000206.3) variant in IL2RG occurs within the canonical donor splice site in intron 1. It is expected to disrupt RNA splicing, disrupting the reading frame, and is predicted to undergo NMD. (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient was found in the literature showing: XY male sex (0.5pts) + T-B+NK- lymphocyte subset profile (0.5pt), total 1 point, PP4_Supporting. (PMID: 9058718; Puck JM et al).In summary, this variant meets the criteria to be classified as Pathogenic for SCID based on the ACMG/AMP criteria applied: PVS1, PP4_Supporting, and PM2_Supporting, as specified by the ClinGen SCID VCEP specifications version 1. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497546/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance HP:0001417 Supports CHEBI:3127 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0700590 infores:hetionet CHEBI:144093 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0004604 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0687707 infores:hetionet CHEBI:10127 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0004093 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030312 infores:hetionet CHEBI:47426 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0037763 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042401 infores:hetionet CAID:CA386966297 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966297 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4 The c.805G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 269 (p.(Ala269Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additonally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.947, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD from gnomAD v2.1.1 (PM2_Supporting). This variant has only been detected in one case of diabetes, which is below the MDEP VCEP threshold to apply PS4_Moderate (PMID: 21224407). Additionally, there was no individual level data provided and it was unclear if HNF4A was tested, therefore PP4 will not be applied (PMID: 21224407). Another missense variant, c.806C>A, p.(Ala269Asp), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.805G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966297/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:101278 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042510 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948525 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0031212 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0012813 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0017675 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0030312 infores:hetionet CHEBI:63605 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0040053 infores:hetionet CHEBI:63613 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0002994 infores:hetionet CHEBI:82960 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0016199 infores:hetionet CHEBI:68647 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C1384353 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038358 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0151736 infores:hetionet CHEBI:3723 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0428977 infores:hetionet CHEBI:85083 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0008031 infores:hetionet CHEBI:63629 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C1443060 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0026846 infores:hetionet CHEBI:9086 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0035455 infores:hetionet CHEBI:52717 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0080274 infores:hetionet CHEBI:68595 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0036974 infores:hetionet CHEBI:2950 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0018965 infores:hetionet CHEBI:3752 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0026764 infores:hetionet CHEBI:4466 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020461 infores:hetionet CHEBI:63610 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013404 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0003123 infores:hetionet CHEBI:36791 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0008350 infores:hetionet CHEBI:101853 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0035078 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0039971 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0855242 infores:hetionet CHEBI:100246 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0001925 infores:hetionet CHEBI:5106 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0011603 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0232197 infores:hetionet CHEBI:9737 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0020625 infores:hetionet CHEBI:5613 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0009782 infores:hetionet CHEBI:63681 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0744727 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0033575 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0403632 infores:hetionet NCBIGene:51 biolink:causes MONDO:0030073 infores:monarchinitiative not_provided not_provided HGNC:119 MONDO:0030073 uuid:5ebda685-e39c-40ed-81d9-d8b2024b1913 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65349 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0009806 infores:hetionet CAID:CA229704 biolink:causes MONDO:0009861 infores:clingen CAID:CA229704 MONDO:0009861 PMID: Pathogenic PM3, PM2, PVS1, PP4 This c.707-2A>G variant in PAH was reported in trans with pathogenic variant p.Arg408Trp in 1 Bulgarian patient with PAH deficiency (PMID: 1563085). This variant is absent from population databases gnomAD, 1000 Genomes and ESP. This variant in the -2 splice acceptor site of intron 6 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229704/MONDO:0009861/006 2020-12-07 2021-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7573 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151849 infores:hetionet CHEBI:8428 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0023380 infores:hetionet CHEBI:119486 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1510410 infores:hetionet NCBIGene:22897 biolink:causes MONDO:0013917 infores:monarchinitiative not_provided not_provided HGNC:29182 MONDO:0013917 uuid:716406cc-4059-40f3-8a02-a7abeb4a7b97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5132 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0037274 infores:hetionet CAID:CA8815395 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815395 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000152.5:c.1630G>A variant in GAA is a missense variant predicted to cause substitution of valine by methionine at amino acid 544 (p.Val544Met). This variant has not been reported in the literature in patients with Pompe disease. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00028 (7/ 24886 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.340 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is a ClinVar entry for this variant (Variation ID: 664232; 2 star review status) with two submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM3_supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815395/MONDO:0009290/010 2024-06-06 2024-06-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3756 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018790 infores:hetionet CHEBI:15940 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0241057 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038354 infores:hetionet CAID:CA405667782 biolink:causes MONDO:0007783 infores:clingen CAID:CA405667782 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PM1, PS4_Moderate PP3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with arginine at codon 2345 of the RYR1 protein, p.Ser2345Arg. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:25960145, Valaskova 2013). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:33490280). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.747 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405667782/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:7494 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0007859 infores:hetionet CHEBI:567361 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0232487 infores:hetionet UMLS:C0010592 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0231528 infores:hetionet CHEBI:8107 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013428 infores:hetionet CHEBI:6887 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0006277 infores:hetionet CHEBI:85083 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0011991 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0853619 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0038661 infores:hetionet CHEBI:3419 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0039231 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0010520 infores:hetionet NCBIGene:5830 biolink:causes MONDO:0014743 infores:monarchinitiative not_provided not_provided HGNC:9719 MONDO:0014743 uuid:192afd50-7b1a-4a1a-89a4-f1d17703f64e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32139 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0042109 infores:hetionet CHEBI:92998 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0546817 infores:hetionet CHEBI:4995 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002874 infores:hetionet CHEBI:8707 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0004093 infores:hetionet CHEBI:5280 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C2363730 infores:hetionet CHEBI:50122 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0011991 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C2242737 infores:hetionet NCBIGene:1411 biolink:causes MONDO:0010948 infores:monarchinitiative not_provided not_provided HGNC:2394 MONDO:0010948 uuid:8ab30ae3-7a5e-4f1f-b0ab-19355c7151de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA645294003 biolink:causes MONDO:0015924 infores:clingen CAID:CA645294003 MONDO:0015924 PMID: Likely Pathogenic PVS1, PM2_Supporting BS2, BA1, PS4, BS1 The BMPR2 c. 247+6T>G variant is an intronic variant which is located 6 base pairs upstream of the end of exon 2. Despite being located outside the canonical splice donor site, the variant was shown to lead to a partial loss of exon 2 (PubMed ID16728714). Two alternative splice sites were used. The first cryptic donor site was located 60 base pairs upstream and led to the loss of amino acids 63-82. The second cryptic splice site was located 108 base pairs upstream and led to the loss of amino acids 47-82. Both alternative transcripts resulted in a partial loss of the functionally critical extracellular domain of the BMPR2 receptor, which is located at amino acids 33-131 (PVS1(RNA)). This variant is absent from gnomAD v4.1.0 and GnomAD v2.1.1 (controls) (PM2_supporting). This variant has two entries in ClinVar. One case was not counted as the affected status was “unknown.” The second patient was reported in Cogan et al (PubMed ID16728714) as an obligate carrier from a heritable pulmonary arterial hypertension family (1 known affected PAH proband, PS4 not met). PP1, PS2, PM6 were not assessed due to absence of co-segregation data. Of note, a variant at c.247+5G>A was reported to also result in the loss of the splice donor site and two alternative transcripts, one lacking p.47_82 and the second one missing p.63_82 (PMID: 35346192). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1(RNA), PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645294003/MONDO:0015924/125 2025-10-07 2025-10-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2611 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0009806 infores:hetionet CHEBI:6965 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0080274 infores:hetionet CHEBI:52172 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0005758 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009319 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151826 infores:hetionet CAID:CA645607413 biolink:causes MONDO:0011071 infores:clingen CAID:CA645607413 MONDO:0011071 PMID: Likely Pathogenic PS4_Moderate, PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, BP2, BP3, BP1, BP4, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.356dup (p.Ala120GlyfsTer18) is a frameshift variant which is not predicted to undergo nonsense-mediated decay (NMD), and the truncated/altered region is critical for protein function (PVS1_Strong). This variant is downstream of c.98 (PM5_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in at least two probands meeting RUNX1-phenotypic criteria (PS4_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM5_supporting, PM2_supporting, PS4_Moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645607413/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2611 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0014591 infores:hetionet CAID:CA001412 biolink:causes MONDO:0011450 infores:clingen CAID:CA001412 MONDO:0011450 PMID: Pathogenic PVS1, PP4_Strong, PS3 PM2, BA1, BS1 The c.212+3A>G variant is an intronic variant occurring in intron 4 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. A combination of RT-PCR from patient samples and mini-gene assays demonstrated that the variant impacts splicing by skipping of 22nt from the 3' end of the exon, reported by five studies (PMIDs: 22505045, 11802209, 20215541, 21673748, 24667779). Two of these studies also reported skipping of exon 4 (PMIDs: 20215541, 24667779). Allele-specific expression was reported by one assay on patient-derived material (PMID: 22505045), which showed no WT transcript from the variant allele. This is in agreement with two minigene assays (PMIDs: 21673748, 24667779). One study reported no impact on splicing but no results are shown to assess whether the 22nt skipping event (that is seen in controls at low level) was increased (PMID: 16619214), and therefore, has been excluded from consideration when assessing the splicing impact of this variant. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1615.48 (based on Co-occurrence LR=1.298; Family History LR=1245.06), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 17924331, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PS3, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001412/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9667 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0034063 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0027765 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0011849 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0410256 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0410256 infores:hetionet CHEBI:49662 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0015230 infores:hetionet CHEBI:39867 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0017565 infores:hetionet CHEBI:17698 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0002994 infores:hetionet CHEBI:3761 biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0277885 infores:hetionet CHEBI:2704 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0236075 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0003123 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0020538 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0040046 infores:hetionet NCBIGene:2273 biolink:causes MONDO:0010415 infores:monarchinitiative not_provided not_provided HGNC:3702 MONDO:0010415 uuid:7b3a3b82-c971-4f29-a5aa-26f215e9a836 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92607 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0036572 infores:hetionet CAID:CA254863 biolink:causes MONDO:0044970 infores:clingen CAID:CA254863 MONDO:0044970 PMID:16849371PMID:15466014 Uncertain Significance PP3, PM2_Supporting, PM6_Supporting, PS3_Supporting PP4, PS4 The m.3949T>C (p.Y215H) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features consistent with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at 93% heteroplasmy in muscle, 45% in blood, and 88% in fibroblasts (PMID:15466014). This variant occurred de novo in one individual (absent in blood from mother and two brothers; PM6_supporting, PMID: 15466014). Electron transport chain (ETC) enzyme activity in fibroblasts and muscles was consistent with severe isolated defect of complex I, and levels of assembled complex I was approximately 12% of control; however, nuclear etiologies were not excluded (PMID: 15466014). Studies in E. coli (PMID: 16849371) and cybrids (PMID: 15466014) support the functional impact of this variant and independent studies showed independent deleterious effects of the variant (PS3_supporting). The m.3949GT>C variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup K1a). This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.54 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254863/MONDO:0044970/015 2023-08-22 2024-11-25 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:135005 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0152032 infores:hetionet CHEBI:28918 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0220870 infores:hetionet CHEBI:71941 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0013395 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002311 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0154833 infores:hetionet CHEBI:7627 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0019080 infores:hetionet CHEBI:63630 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0018524 infores:hetionet NCBIGene:8557 biolink:causes MONDO:0011170 infores:monarchinitiative not_provided not_provided HGNC:11610 MONDO:0011170 uuid:cb0b05b7-f68c-47ef-88a0-b6ef85e5ad80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085628 infores:hetionet CHEBI:9725 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0027849 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0442874 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0853700 infores:hetionet CHEBI:4877 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0011606 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0232492 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011570 infores:hetionet NCBIGene:111 biolink:causes MONDO:0800028 infores:monarchinitiative not_provided not_provided HGNC:236 MONDO:0800028 uuid:6746259d-dfc7-45d2-bcdd-671ad67a1dec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6801 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0002962 infores:hetionet CHEBI:7640 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0011991 infores:hetionet CHEBI:9445 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0002792 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0160390 infores:hetionet CHEBI:10101 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0497156 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0021775 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0038663 infores:hetionet CAID:CA024037 biolink:causes MONDO:0007783 infores:clingen CAID:CA024037 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 44 of the RYR1 protein, p.(Arg44His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000066, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257 ). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1, (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024037/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:194135 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030554 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038367 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0033774 infores:hetionet CHEBI:73274 biolink:causes MONDO:0004369 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0021313 infores:hetionet CHEBI:553473 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0002878 infores:hetionet CHEBI:10125 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0030193 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011606 infores:hetionet CHEBI:45599 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0005779 infores:hetionet CHEBI:27504 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0036974 infores:hetionet CAID:CA003905 biolink:causes MONDO:0700268 infores:clingen CAID:CA003905 MONDO:0700268 PMID: Benign BA1, BP1_Strong, BS3 BS2 The c.811G>A variant in BRCA1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 271 (p.Val271Met). The highest non-founder population filter allele frequency in gnomAD v4.1 (read depth ≥20) is 0.001630 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.03, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP1_Strong, BS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003905/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0025345 infores:hetionet CHEBI:4710 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020580 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0743680 infores:hetionet CHEBI:84500 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0151636 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009763 infores:hetionet NCBIGene:170302 biolink:causes MONDO:0010632 infores:monarchinitiative not_provided not_provided HGNC:18060 MONDO:0010632 uuid:acffe483-92b1-4a41-9889-f970e79529f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235901 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009938 infores:hetionet CHEBI:2950 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0340865 infores:hetionet NCBIGene:2642 biolink:causes MONDO:0018582 infores:monarchinitiative not_provided not_provided HGNC:4192 MONDO:0018582 uuid:fec88fcb-4d1e-4102-9100-33f0766a440e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2569 biolink:causes UMLS:C0919572 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0919572 infores:hetionet CHEBI:2618 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0011206 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0009450 infores:hetionet CHEBI:4909 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026848 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0019054 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0852733 infores:hetionet CHEBI:408174 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0023518 infores:hetionet CHEBI:31236 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151539 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017178 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0002170 infores:hetionet CHEBI:2955 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C2830004 infores:hetionet CHEBI:29013 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0016204 infores:hetionet CAID:CA379133956 biolink:causes MONDO:0100316 infores:clingen CAID:CA379133956 MONDO:0100316 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS4, PM5 NM_000218.3(KCNQ1):c.1120C>T is a missense variant in KCNQ1 predicted to replace leucine with phenylalanine at position 374 (p.Leu374Phe). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is rare and has been reported in at least 1 proband potentially affected with long QT syndrome 1, however, the phenotype has not been described in sufficient detail for the PP4 code and the requirement for 2 unrelated probands has not been reached, so the PS4_Supporting code is not yet met (PMID: 29688407). Another missense variant in the same codon, NM_000218.3(KCNQ1):c.1121T>A (p.Leu374His), (PMID: 15840476; PMID: 19716085) has been classified as a VUS for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 cannot be met, although no benign missense variants have been identified in this codon. A missense substitution in the equivalent codon of the paralogue KCNQ2, NM_172107.4(KCNQ2):c.1016T>G (p.Leu339Arg), has been reported in ClinVar in association with benign familial neonatal seizures (Accession: SCV000041606.3). However, this KCNQ2 variant encodes a different amino acid substitution and has not yet been classified by the ClinGen KCNQ Channel Brain Disorders VCEP, so PS1_Moderate is not met. The computational predictor REVEL gives a score of 0.873, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). In summary, this variant meets the criterion to be classified as a variant of uncertain significance for long QT syndrome 1, as specified by the ClinGen Potassium Channel Arrhythmia VCEP; PM2_Supporting, PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA379133956/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA229857 biolink:causes MONDO:0009861 infores:clingen CAID:CA229857 MONDO:0009861 PMID:24350308PMID:24350308 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The NM_000277.1(PAH):c.935G>A (p.Gly312Asp) variant is a missense variant in exon 9/13 of PAH. It has been reported in at least 3 PKU cases in presumed trans with other Pathogenic variants (PM3; 1.5 points total), in two of whom BH4 deficiency was excluded (PP4_Moderate). It has been previously reported in presumed trans with the p.R241C variant (Pathogenic per ClinGen PAH VCEP) in two cases with mild PKU (plasma Phe 600–1200 μmol/L) and BH4 deficiency excluded (PMID: 30459323). It has also been reported in presumed trans with the p. R408W variant (Pathogenic by ClinGen PAH VCEP) in a patient with classic PKU and with undefined BH4 responsiveness. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.958) (PP3).Classification: Likely Pathogenic Supporting Criteria: PM2; PM3; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229857/MONDO:0009861/006 2020-07-27 2020-07-27 Autosomal recessive inheritance HP:0000007 Supports CAID:CA024787 biolink:causes MONDO:0007783 infores:clingen CAID:CA024787 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2458 of the RYR1 protein, p.(Arg2458His). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000054, a frequency consistent with pathogenicity for MHS. This variant has been reported in 26 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 23 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 16163667, 22415532, 9450902, 16732084, 21157159 and others). This variant segregates with MHS in 10 individuals, PP1_Strong (PMID:30236257). Functional studies in HEK293 cells and dyspedic myotubes show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:27586648, 12732639). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.959) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024787/MONDO:0007783/012 2022-01-04 2022-01-04 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:32192 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0011991 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0040435 infores:hetionet CHEBI:3510 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0013428 infores:hetionet CHEBI:8426 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0002871 infores:hetionet CHEBI:8245 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0010200 infores:hetionet CHEBI:8863 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0558489 infores:hetionet CHEBI:50730 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0003467 infores:hetionet CHEBI:64312 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0392525 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0333641 infores:hetionet CHEBI:7492 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0687713 infores:hetionet CHEBI:209807 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0042075 infores:hetionet GO:0090178 biolink:causes GO:0060562 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0060562 CHEBI:135736 biolink:causes HP:0034777 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0241235 infores:hetionet CHEBI:51137 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0428977 infores:hetionet UMLS:C1738934 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085593 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151735 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0013378 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151580 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151580 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0022660 infores:hetionet NCBIGene:10617 biolink:causes MONDO:0013659 infores:monarchinitiative not_provided not_provided HGNC:16950 MONDO:0013659 uuid:66adca69-1a29-485d-91b6-f31bae947b4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0038362 infores:hetionet CHEBI:47381 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151578 infores:hetionet CHEBI:5893 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011606 infores:hetionet CHEBI:5790 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0022408 infores:hetionet CHEBI:4792 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0020461 infores:hetionet NCBIGene:79048 biolink:causes MONDO:0800046 infores:monarchinitiative not_provided not_provided HGNC:30972 MONDO:0800046 uuid:5d499b1a-0ed3-42a1-9d22-a293fce5c999 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51364 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0241705 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0009241 infores:hetionet CHEBI:8093 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0858617 infores:hetionet CHEBI:5062 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0013404 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022650 infores:hetionet CHEBI:75045 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0344232 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0013595 infores:hetionet CHEBI:8502 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0497156 infores:hetionet CHEBI:53760 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011253 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0040034 infores:hetionet CHEBI:30830 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0018524 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015230 infores:hetionet CHEBI:8874 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0424295 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0234373 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0234373 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0021053 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0002871 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009450 infores:hetionet CHEBI:5128 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0037036 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0267792 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002170 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0037274 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0036416 infores:hetionet CHEBI:45863 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0311468 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0877266 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0877266 infores:hetionet CHEBI:8107 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0042024 infores:hetionet CHEBI:92511 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C2242996 infores:hetionet CHEBI:63717 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0001125 infores:hetionet CHEBI:4885 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0012569 infores:hetionet CHEBI:85078 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0002962 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020456 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0920102 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0233571 infores:hetionet CHEBI:27882 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0151786 infores:hetionet CHEBI:3508 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0017178 infores:hetionet CAID:CA214310 biolink:causes MONDO:0015967 infores:clingen CAID:CA214310 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.518_526+37del variant in the HNF1 homeobox A gene, HNF1A, is a 46 base pair deletion that removes a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to: either cause skipping of biologically-relevant exon 2 of 10 or using a cryptic site, both resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.518_526+37del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214310/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0004609 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0547030 infores:hetionet CHEBI:63791 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0428977 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0948296 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0042109 infores:hetionet CHEBI:144551 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0006277 infores:hetionet CHEBI:4907 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0009676 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0019360 infores:hetionet CHEBI:63607 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0010200 infores:hetionet CHEBI:49668 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0033774 infores:hetionet CHEBI:47780 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0039239 infores:hetionet CHEBI:3219 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235996 infores:hetionet CHEBI:8874 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005758 infores:hetionet CHEBI:45783 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162834 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0003864 infores:hetionet CHEBI:61033 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0220870 infores:hetionet CHEBI:8869 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0231528 infores:hetionet CHEBI:45924 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0028084 infores:hetionet CHEBI:63613 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0027947 infores:hetionet CHEBI:63629 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151908 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018801 infores:hetionet CHEBI:3478 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013404 infores:hetionet CHEBI:585948 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0004604 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0025061 infores:hetionet CHEBI:50156 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0020649 infores:hetionet CHEBI:45951 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0030446 infores:hetionet NCBIGene:26040 biolink:causes MONDO:0014482 infores:monarchinitiative not_provided not_provided HGNC:15573 MONDO:0014482 uuid:50fd2627-4e8f-4f32-b9fb-8118d51ad66f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:724125 biolink:causes UMLS:C0241166 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0241166 infores:hetionet CHEBI:75998 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0085593 infores:hetionet CHEBI:37924 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0013378 infores:hetionet CHEBI:100246 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0085612 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0262578 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0262578 infores:hetionet CHEBI:9086 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0392676 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0042109 infores:hetionet CHEBI:3996 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0575081 infores:hetionet CAID:CA229285 biolink:causes MONDO:0009861 infores:clingen CAID:CA229285 MONDO:0009861 PMID:29390883PMID:9634518PMID:26503515PMID:26600521PMID:10980574 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 PM5, PM1 The c.1030G>A (p.Gly344Ser) variant in PAH has been reported in multiple individuals with PKU and mild PKU (BH4 deficiency excluded). (PMID: 26503515, 29390883, 9634518). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Q419R (PMID: 26600521). Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Arg, p.Gly344Val are Likely pathogenic by PAH VCEP). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229285/MONDO:0009861/006 2021-06-11 2021-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:92998 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0019080 infores:hetionet CHEBI:100246 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0002994 infores:hetionet CHEBI:40050 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C2225524 infores:hetionet CHEBI:41879 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0022107 infores:hetionet CHEBI:75246 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0018965 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0162830 infores:hetionet CHEBI:63845 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0013604 infores:hetionet CHEBI:41879 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015403 infores:hetionet CHEBI:2904 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C2830004 infores:hetionet CHEBI:63581 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0016204 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0037274 infores:hetionet CHEBI:119573 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1510410 infores:hetionet CAID:CA410148586 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148586 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1016T>C (p.Leu339Pro) is a missense variant which has a REVEL score < 0.50 (0.387), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148586/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7627 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0025218 infores:hetionet CHEBI:27786 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0038999 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0020538 infores:hetionet CHEBI:8768 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0242379 infores:hetionet CAID:CA023641 biolink:causes MONDO:0007750 infores:clingen CAID:CA023641 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PS4, PS3, BS3, PM5, PP4 The NM_000527.5 (LDLR):c.2126G>A (p.Arg709Lys) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: PopMax MAF=0.000003390 in non-Finnish European exomes+genomes (gnomAD v4.1.0).PP3: REVEL=0.842. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023641/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:41977 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0085593 infores:hetionet CHEBI:50742 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0002878 infores:hetionet NCBIGene:26090 biolink:causes MONDO:0012984 infores:monarchinitiative not_provided not_provided HGNC:15868 MONDO:0012984 uuid:88d6285b-9f6b-403e-8f88-bafd8b3c6180 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0030193 infores:hetionet CHEBI:119486 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0004093 infores:hetionet CHEBI:9943 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0232849 infores:hetionet CHEBI:168396 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0424790 infores:hetionet CHEBI:4636 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0013144 infores:hetionet CAID:CA120217 biolink:causes MONDO:0015967 infores:clingen CAID:CA120217 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, BS3_Supporting, PS4_Moderate PP3, PP1, PM5, BP4 The c.1138G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 380 (p.(Val380Ile)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 2 copies in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 9449683, 23227446, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 9449683). This variant has a REVEL score of 0.344, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. Functional studies demonstrated the p.Val380Ile protein has abnormal nuclear localization/transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 30191603) (BS3_Supporting). Another missense variant, [1139T>G p.(Val380Gly)] has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1138G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4_moderate, PP4, PM2_supporting, BS3_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA120217/MONDO:0015967/085 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63681 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0035204 infores:hetionet CHEBI:3696 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151907 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0948281 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948281 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0427108 infores:hetionet CHEBI:6437 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0439857 infores:hetionet CHEBI:16899 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1443060 infores:hetionet CHEBI:2904 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0027424 infores:hetionet CHEBI:50885 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C1280433 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0020651 infores:hetionet CHEBI:421707 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0231856 infores:hetionet CAID:CA134718 biolink:causes MONDO:0021060 infores:clingen CAID:CA134718 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134718/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:1763 biolink:causes MONDO:0014062 infores:monarchinitiative not_provided not_provided HGNC:2939 MONDO:0014062 uuid:b71f37c8-74cb-45da-b773-121732b7868f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5109 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0333641 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0852879 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0852879 infores:hetionet CHEBI:110423 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0011603 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006981 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0014122 infores:hetionet NCBIGene:286410 biolink:causes MONDO:0060455 infores:monarchinitiative not_provided not_provided HGNC:13554 MONDO:0060455 uuid:10ebdb15-0d57-4ace-afa4-fd5ca888d1fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0855242 infores:hetionet CHEBI:3380 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0041657 infores:hetionet CHEBI:9757 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0009806 infores:hetionet CHEBI:6367 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0019572 infores:hetionet CHEBI:23765 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0080274 infores:hetionet CHEBI:32221 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0041834 infores:hetionet CHEBI:144551 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151830 infores:hetionet CHEBI:3723 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0699828 infores:hetionet CHEBI:50922 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020578 infores:hetionet CHEBI:180905 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0042963 infores:hetionet CHEBI:63632 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0020433 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020456 infores:hetionet CHEBI:6076 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0008031 infores:hetionet NCBIGene:79731 biolink:causes MONDO:0032749 infores:monarchinitiative not_provided not_provided HGNC:26274 MONDO:0032749 uuid:d31e70aa-36e0-4aaf-b5e7-9c3ac98a2861 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0002170 infores:hetionet CHEBI:3423 biolink:causes MONDO:0800133 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0265783 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C2711227 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0036454 infores:hetionet CHEBI:84050 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0027497 infores:hetionet CHEBI:46195 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0023530 infores:hetionet CHEBI:63717 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0008031 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0574067 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011616 infores:hetionet CHEBI:32184 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0015468 infores:hetionet CHEBI:8863 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0233471 infores:hetionet CHEBI:31302 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C1443060 infores:hetionet CHEBI:31236 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018800 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0038362 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0242073 infores:hetionet CHEBI:51141 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0008370 infores:hetionet NCBITaxon:1350 biolink:causes MONDO:1040019 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1350 MONDO:1040019 UMLS:C0005740 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0948594 infores:hetionet CHEBI:66903 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0027765 infores:hetionet CHEBI:30659 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0424295 infores:hetionet CAID:CA305301758 biolink:causes MONDO:0007750 infores:clingen CAID:CA305301758 MONDO:0007750 PMID:35474963 Likely Pathogenic PS4_Supporting, PS3_Supporting, PM2, PP3, PP4, PP1 BP4, BP3, BP2, BA1, PS1, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2 The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305301758/MONDO:0007750/013 2023-11-07 2024-09-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7565 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0015402 infores:hetionet CHEBI:194135 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151878 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0034065 infores:hetionet CAID:CA915952148 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952148 MONDO:0044970 PMID:32158465 Likely Pathogenic PM2_Supporting, PM6_Supporting, PVS1_Strong, PS3_Supporting PP3, BP4, PS4 The m.14513_14514delAT (p.Met54SerfsTer7) variant in MT-ND6 has been reported in one individual to date, in a man with mitochondrial myopathy characterized by adolescent onset exercise intolerance and muscle weakness as well as ptosis, reduced muscle bulk, and lumbar lordosis. Muscle biopsy showed that 13% of muscle fibers were ragged red fibers (RRF) and >75% of fibers showed a complete loss of NDUFB8 immunoreactivity associated with preserved COX-I immunoreactivity (PMID: 32158465). The variant was present at 76% heteroplasmy in skeletal muscle, 10% in urine, and was undetectable in blood and buccal samples. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and urine samples from his healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in a frame shift at position 54 and is predicted to result in loss of >10% protein (PVS1_strong). Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952148/MONDO:0044970/015 2023-12-21 2024-03-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:7822 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0042109 infores:hetionet CHEBI:8060 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0851578 infores:hetionet CHEBI:5959 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0022354 infores:hetionet CHEBI:8874 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151603 infores:hetionet CHEBI:7581 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0013404 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0033975 infores:hetionet CHEBI:7936 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039231 infores:hetionet NCBIGene:54453 biolink:causes MONDO:0013115 infores:monarchinitiative not_provided not_provided HGNC:18750 MONDO:0013115 uuid:058cfe69-50fc-4997-be87-722062c70df4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5004 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0014742 infores:hetionet CHEBI:3393 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0002871 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037199 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0021308 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0178298 infores:hetionet CHEBI:36704 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0036974 infores:hetionet CAID:CA16020738 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020738 MONDO:0009861 PMID:23932990 Uncertain Significance PM2, PP4_Moderate PM5, PP3 The c.184C>G (p.Leu62Val) variant in PAH is reported in a Chinese PAH patient. BH4 deficiency was excluded. (PMID: 23932990) This variant is absent from ExAC, gnomAD, 1000G, and ESP. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020738/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135736 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151904 infores:hetionet CHEBI:4672 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0006142 infores:hetionet CHEBI:63611 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004093 infores:hetionet CHEBI:9566 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0686347 infores:hetionet UMLS:C0011701 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0242429 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0032285 infores:hetionet CHEBI:4877 biolink:causes MONDO:0001703 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0242225 infores:hetionet CHEBI:31302 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0009782 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0233472 infores:hetionet CAID:CA2580098639 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098639 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supp, PM2_supp Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098639/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9927 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0242350 infores:hetionet CHEBI:3568 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0016204 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0025061 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020651 infores:hetionet CAID:CA512341405 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341405 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.969G>A (p.Thr323=) is a synonymous variant which has a SpliceAI score ≥ 0.38 (Acceptor Gain, 0.69) (PP3). This may lead to an aberrant splicing profile, but other evidence is missing for this variant. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341405/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234047 infores:hetionet CAID:CA015510 biolink:causes MONDO:0004994 infores:clingen CAID:CA015510 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4974C>T (p.Asp1658=) variant in the MYH7 gene is 0.36% (53/11558) of Latino chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015510/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135193 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0025061 infores:hetionet CHEBI:47426 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0085680 infores:hetionet CHEBI:61058 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0004093 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005141 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0033817 infores:hetionet CHEBI:63607 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0085593 infores:hetionet CHEBI:5098 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0014743 infores:hetionet NCBIGene:80184 biolink:causes MONDO:0012433 infores:monarchinitiative not_provided not_provided HGNC:29021 MONDO:0012433 uuid:6e2dbe82-60ad-472d-9f90-dd72515cb731 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7931 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042963 infores:hetionet CHEBI:136040 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0011603 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0001339 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0018801 infores:hetionet CAID:CA410202782 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202782 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS2, PS1, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.356T>C (p.Val119Ala) is a missense variant that affects a residue within the Runt Homology Domain (AA 89-204) (PM1_supporting). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting) and has a REVEL score of 0.979 (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202782/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9927 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0019158 infores:hetionet CHEBI:8107 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013456 infores:hetionet CHEBI:17347 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0178415 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0022660 infores:hetionet NCBIGene:871 biolink:causes MONDO:0013459 infores:monarchinitiative not_provided not_provided HGNC:1546 MONDO:0013459 uuid:da72bb36-9825-49df-8d5b-928105782e87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4974 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0015672 infores:hetionet CHEBI:31932 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0036974 infores:hetionet CHEBI:6532 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C1258215 infores:hetionet CHEBI:3699 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0030305 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0549310 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0677500 infores:hetionet CHEBI:194135 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013447 infores:hetionet CHEBI:3312 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0041657 infores:hetionet CHEBI:3640 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0040034 infores:hetionet CAID:CA386960242 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960242 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1_Supporting, PM5_Supporting, PP1_Moderate, PP4, PP3 The c.461T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of methionine to threonine at codon 154 (p.(Met154Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 27083284, internal lab contributors). Additionally, this variant segregated with diabetes with three informative meioses in three families (PP1_Moderate; PMID: 27083284, internal lab contributors). Another missense variant, c.460A>G p.Met154Val, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.461T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PS4_Moderate, PP1_Moderate, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960242/MONDO:0015967/017 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:421707 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0027947 infores:hetionet CHEBI:567361 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0030196 infores:hetionet CAID:CA1244075 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244075 MONDO:0020367 PMID:11004290PMID:10545602PMID:11004290PMID:10545602 Pathogenic PP3, PM2_Supporting, PS4, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS3, PS1, PS2, BP4, BA1 The c.1130C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 377 (p.Thr377Met). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.00006152 (1 allele out of 16 256), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.924, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The studies reporting functional evidence (PMIDs: 11004290, 10545602, 16297911, 16466712) indicated that this variant may impact protein solubility and secretion, however, as the results were conflicting and inconclusive, PS3 was not applied. 47 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 20390039, 11004290, 28564705, 15823921, 12912696), which fulfilled PP1_Strong (≥7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 28564705, 22933836, 11004290, 12868033, 20390039, 14627955, 10196380, 15823921, 12912696), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244075/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41977 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0012833 infores:hetionet CHEBI:209807 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0234233 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0020649 infores:hetionet CAID:CA415166876 biolink:causes MONDO:0010726 infores:clingen CAID:CA415166876 MONDO:0010726 PMID: Likely Benign BS2 BA1, BS1, PM2 The p.Pro403Arg variant in MECP2 (NM_004992.4) is present in 3 XX and 2 XY individual(s) in gnomAD (0.0003564%) (not sufficient to meet BS1 criteria). The p.Pro403Arg variant is observed in 3 unaffected individuals (internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro403Arg variant in MECP2 (NM_004992.4) is classified as likely benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415166876/MONDO:0010726/036 2023-12-06 2024-10-25 X-linked inheritance HP:0001417 Contradicts true CHEBI:8428 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0423791 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0242350 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0002871 infores:hetionet CHEBI:144093 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0085593 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0152029 infores:hetionet CAID:CA512341230 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341230 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP2, BP3, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM1, PM3, PM4, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1200G>A (p.Ser400=) is a synonymous variant that is not predicted to impact splicing. This variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). The SpliceAI score = 0 which is below the threshold for splicing defects (<0.2) and PhyloP100 score = 0.98 which is also below the threshold (<2) meaning the position is not highly conserved (BP7). This variant is not present in gnomAD v2.1.1 or gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341230/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27690 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C2047937 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0042267 infores:hetionet CHEBI:92998 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085593 infores:hetionet CHEBI:52717 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0008350 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0151828 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0314719 infores:hetionet CHEBI:4636 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0009806 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0021053 infores:hetionet CHEBI:6402 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020473 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0029134 infores:hetionet CHEBI:9352 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0027497 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0231303 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853759 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853759 infores:hetionet CHEBI:66901 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0011991 infores:hetionet CHEBI:74947 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0019829 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0497247 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0152517 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0002874 infores:hetionet CHEBI:45924 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0023530 infores:hetionet CAID:CA10584941 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584941 MONDO:0007750 PMID: Uncertain Significance PM1, PM2, PP3 BA1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, PP1, PP4, BS2 The NM_000527.5(LDLR):c.479G>A (p.Cys160Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.936. PM1: Variant meets PM2, is a missense in exon 4, and alters Cys160, one of the cysteine residues listed. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584941/MONDO:0007750/013 2024-02-23 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9123 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0021141 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004835 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0238124 infores:hetionet CHEBI:5106 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0085593 infores:hetionet NCBIGene:7374 biolink:causes MONDO:0011971 infores:monarchinitiative not_provided not_provided HGNC:12572 MONDO:0011971 uuid:6ef5754b-2769-4e01-8c1f-b608c938b967 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0278061 infores:hetionet CHEBI:70707 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0022107 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0853750 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0853750 infores:hetionet CHEBI:75179 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C2930821 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1112525 infores:hetionet CHEBI:49375 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0014591 infores:hetionet CHEBI:5818 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0015230 infores:hetionet CAID:CA020343 biolink:causes MONDO:0008667 infores:clingen CAID:CA020343 MONDO:0008667 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PVS1 The variant NM_000551.4(VHL):c.408del (p.Phe136fs) is a frameshift variant in a biologically relevant exon, altering the sequence starting at amino acid 136 and truncating 25 amino acids downstream. It is predicted to cause nonsense mediated decay (though not proven) and is in a critical domain (first beta domain, 63-155) of the protein (PVS1). Aronoff et al reports 5 affected family members with this variant. Proband III-I meets Danish criteria with pancreatic cyst or tumor, cerebellar haemangioblastoma and first degree member affected (1 point, PS4_Supporting. PMID:29437867). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020343/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49575 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0016658 infores:hetionet CHEBI:107736 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0011206 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0234987 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0022660 infores:hetionet CHEBI:94501 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0232462 infores:hetionet CHEBI:3437 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0020615 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0015397 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0014175 infores:hetionet CAID:CA134715 biolink:causes MONDO:0021060 infores:clingen CAID:CA134715 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1914G>A (p.Thr638=) variant in the RAF1 gene is 0.926% (174/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134715/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA414905047 biolink:causes MONDO:0010602 infores:clingen CAID:CA414905047 MONDO:0010602 PMID: Uncertain Significance PM2_Supporting, BS2, PS4_Moderate PP3 The F8 c.6028T>C (p.Ser2010Pro) variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3). This missense variant has a REVEL score of 0.599 (>0.6), which does not meet the cut off for PP3. At least three individuals with the p.Ser2010Pro variant and severe hemophilia A have been reported in the literature (PMID: 23306409). However, variant was also identified in an unaffected male with a factor VIII level of 90%. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Moderate, PM2_Supporting, BS2. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414905047/MONDO:0010602/071 2024-07-08 2024-07-08 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63629 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0948594 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020456 infores:hetionet CHEBI:16755 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013428 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0009319 infores:hetionet CHEBI:16467 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0151799 infores:hetionet CHEBI:48390 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0011570 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0032961 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0032285 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0031542 infores:hetionet CHEBI:63619 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0005745 infores:hetionet CHEBI:63608 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0001175 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0040034 infores:hetionet NCBIGene:471 biolink:causes MONDO:0012099 infores:monarchinitiative not_provided not_provided HGNC:794 MONDO:0012099 uuid:74bd927b-541a-4137-bf5f-f9da34b5a26a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0010200 infores:hetionet CHEBI:50742 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0019209 infores:hetionet CAID:CA318033 biolink:causes MONDO:0100038 infores:clingen CAID:CA318033 MONDO:0100038 PMID:32400968 Pathogenic PS3, PS4, PM1_Strong, PS2_Moderate, PM2_Supporting PS1, BP5, BS1, BS3, BS4, PM5, PP1, PP4, PP2, PP3, BA1, BP2, BP1, BP4 The c.5317G>A (NM_001040142.2) variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1773 (p.Ala1773Thr). This variant has been reported in 9 probands with complex neurodevelopmental disorder (PMIDs: 34758253, 33000761, 28947817, 29655203, 31440721, 31785789, 34469436, 32400968, 35431799), including as a de novo occurrence with confirmed parental relationships in 2 individual(s) (PMIDs: 31785789, 32400968) and as a de novo occurrence with assumed parental relationships in 2 individuals PMID: 33000761, 35431799). This variant is absent from gnomAD v2.1.1. Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968). This variant resides within a region of SCN2A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as pathogenic for complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS3, PS4, PS2, PM1, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 5/9/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA318033/MONDO:0100038/068 2024-05-07 2024-05-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10023 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085593 infores:hetionet CHEBI:8707 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0008031 infores:hetionet CHEBI:2676 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0238106 infores:hetionet CHEBI:64312 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013604 infores:hetionet CHEBI:9943 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0549249 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011991 infores:hetionet CHEBI:63631 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0162285 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0855237 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0855237 infores:hetionet CHEBI:404903 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0428977 infores:hetionet CHEBI:5138 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002874 infores:hetionet CHEBI:6690 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0233754 infores:hetionet CHEBI:50742 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0149741 infores:hetionet CHEBI:499361 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0026205 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0853619 infores:hetionet CHEBI:31644 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0232462 infores:hetionet CHEBI:28830 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0010692 infores:hetionet CHEBI:63622 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0344232 infores:hetionet CHEBI:7581 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C1306341 infores:hetionet CHEBI:71941 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0040264 infores:hetionet CHEBI:4975 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0151908 infores:hetionet CHEBI:8107 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0016655 infores:hetionet CHEBI:48947 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0040046 infores:hetionet CHEBI:16586 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0036572 infores:hetionet CHEBI:5790 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0428977 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0038814 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0008325 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0003864 infores:hetionet CHEBI:34764 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00663 UMLS:C0033774 infores:hetionet CHEBI:4798 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0085635 infores:hetionet CAID:CA645590904 biolink:causes MONDO:0100438 infores:clingen CAID:CA645590904 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PM3 NM_014336.5(AIPL1):c.1127del (p.Pro376ArgfsTer?) is a frameshift variant that introduces a premature stop codon between positions 338 and 384 of AIPL1 that is predicted not to trigger nonsense-mediated decay but rather to C-terminally truncate part of the protein product that has not yet been functionally characterized (PVS1_Strong). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000002494, with 4 alleles / 1,603,842 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The variant has been reported in one proband with a potentially compatible diagnosis (VCEP member-provided data, Blueprint Genetics) who was compound heterozygous with the NM_014336.5(AIPL1):c.211G>T (p.Val71Phe) suspected in trans, which has been classified as likely pathogenic by the ClinGen LCA/eoRD VCEP. However, the reported phenotype details are not sufficient for inclusion in PM3. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1_Strong and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645590904/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2379 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0151942 infores:hetionet CHEBI:8707 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151578 infores:hetionet CAID:CA1139533026 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139533026 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate BP7 The c.843-6T>C PAH variant has been reported in 1 Northwest Chinese patient with PAH deficiency (Phe ≥ 1200 μmol/L) (PMID: 30747360). A defect in BH4 metabolism was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant is absent from population databases gnomAD, 1000 Genomes and ESP. Splicing prediction algorithms are conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139533026/MONDO:0009861/006 2020-12-09 2021-03-03 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA068565 biolink:causes MONDO:0007783 infores:clingen CAID:CA068565 MONDO:0007783 PMID: Likely Benign PM1, BS1 PP3, PM5, PS1, PS4, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 2224 of the RYR1 protein p.(Arg2224Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00091, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in one individual who has a personal or family history of a malignant hyperthermia reaction, this individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257). The high maf in the SAS population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score 0.728 supports neither a pathogenic or a benign status. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA068565/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6909 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0018524 infores:hetionet CHEBI:28001 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0009782 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0020649 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042594 infores:hetionet CHEBI:8356 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0035410 infores:hetionet CHEBI:7575 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0042963 infores:hetionet NCBIGene:5333 biolink:causes MONDO:0007900 infores:monarchinitiative not_provided not_provided HGNC:9060 MONDO:0007900 uuid:d05b63f6-a820-404a-bb6a-0a603bcde8a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020751 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020751 MONDO:0009861 PMID:26322415PMID:26322415 Likely Pathogenic PM3, PM2, PP4_Moderate PM5, PP3 The c.224A>T (p.Asp75Val) variant in PAH is reported in 1 classic PKU patient. BH4 deficiency was excluded. It was detected in trans with a known pathogenic variant, p.R413P. (PMID: 26322415) This variant is absent from ExAC, gnomAD, 1000G, and ESP.Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020751/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes MONDO:0024633 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0848548 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0343863 infores:hetionet CAID:CA137956 biolink:causes MONDO:0021060 infores:clingen CAID:CA137956 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.603C>T (p.Leu201=) variant in the MAP2K2 gene is 0.191% (18/6102) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137956/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA8602771 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602771 MONDO:0100326 PMID: Uncertain Significance PM5_Supporting BP5, PM2, PP3, PP4 The NM_000419.5(ITGA2B):c.2264G>A (p.Arg755Gln) missense variant has been reported in two related individuals previously (GT35a,b in PMID: 25728920) who additionally had two variants Arg131pro and c.777+1G>A on the ITGB3 gene which have been evaluated to be likely pathogenic and pathogenic respectively by ClinGen Platelet VCEP so the impact of the ITGA2B variant is unclear. The gnomADv2.1.1 allele frequency for the Latino subpopulation is 0.0001903 (6/31522 alleles) which is not <0.01%, therefore PM2_supporting is not met and REVEL score is 0.68, which is below the recommended threshold of >0.70. Another missense change at this residue, Arg755Pro, has been reported previously and assessed to be Likely Pathogenic by ClinGen Platelet Disorder VCEP (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM5_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602771/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5130 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0010200 infores:hetionet CHEBI:78543 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0003811 infores:hetionet CHEBI:3568 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0522055 infores:hetionet CHEBI:4995 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0017086 infores:hetionet CHEBI:7466 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0028949 infores:hetionet CHEBI:8874 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030193 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0006145 infores:hetionet CHEBI:44185 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0031256 infores:hetionet CHEBI:9123 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0424790 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006115 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0005699 infores:hetionet CHEBI:92511 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0235996 infores:hetionet CHEBI:8028 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0017979 infores:hetionet CHEBI:3723 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085632 infores:hetionet CHEBI:31711 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0002792 infores:hetionet CHEBI:72296 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0011603 infores:hetionet CHEBI:7476 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151766 infores:hetionet NCBITaxon:1491 biolink:causes MONDO:0005498 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1491 MONDO:0005498 CHEBI:4356 biolink:causes HP:6000793 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0521172 infores:hetionet CHEBI:10102 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0014724 infores:hetionet CHEBI:9086 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0152031 infores:hetionet CHEBI:4511 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0027497 infores:hetionet CHEBI:474180 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0311468 infores:hetionet CHEBI:50730 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0015672 infores:hetionet CHEBI:60761 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0423791 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0743668 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0743668 infores:hetionet CAID:CA2580098634 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098634 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PM2_Supporting PS1, PS3, PS2, BP4, BP2, BA1, PM6, PVS1, BP7, BS1, BS3, BS4, PM4, PM1, PP3, PP1 The NM_001754.5(RUNX1):c.590_597del change is a frameshift variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay. This variant is predicted to affect all the biologically relevant transcripts (PVS1). In addition, this is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting), and it affects AA downstream of c.98 (in transcript NM_001754.4) (PM5_supporting). Although, this has been found in a single patient in a large cohort of AML cases (PMID: 27137476), its allele frequency and/or germinal origin is unknown. Therefore, we cannot assess case-study/segregation criteria. In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098634/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17303 biolink:causes MONDO:0002127 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0041974 infores:hetionet CHEBI:37941 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019270 infores:hetionet CHEBI:3534 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0002994 infores:hetionet CHEBI:55346 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0917801 infores:hetionet CHEBI:6706 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0232462 infores:hetionet NCBIGene:3704 biolink:causes MONDO:0014719 infores:monarchinitiative not_provided not_provided HGNC:6176 MONDO:0014719 uuid:da16bd2f-50df-4f2a-8890-3c683ae4ce6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40237 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0041969 infores:hetionet CHEBI:63631 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025222 infores:hetionet CHEBI:27899 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0232462 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0002871 infores:hetionet CHEBI:3219 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0392703 infores:hetionet CHEBI:4657 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0162119 infores:hetionet CHEBI:499361 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0235063 infores:hetionet CAID:CA412743002 biolink:causes MONDO:0100437 infores:clingen CAID:CA412743002 MONDO:0100437 PMID: Likely Benign BP4 PM2, BS1 NM_001034853.2(RPGR):c.649C>T (p.Pro217Ser) is a missense variant replacing proline with serine at position 217. This variant is present in gnomAD v4.1.0 at a frequency of 0.000002511 among hemizygous individuals, with 1 variant allele / 398,177 total alleles, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 but lower than the BS1 threshold of >0.000005 and fails to meet either criterion. The computational predictor REVEL gives a score of 0.193, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benigin for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412743002/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true NCBIGene:60561 biolink:causes MONDO:0032844 infores:monarchinitiative not_provided not_provided HGNC:21876 MONDO:0032844 uuid:04fa86ce-43aa-414e-bf2c-57ce413b4610 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:410 biolink:causes MONDO:0009591 infores:monarchinitiative not_provided not_provided HGNC:713 MONDO:0009591 uuid:69c9b1ed-211f-44d8-9ce6-78912ed1bc88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes MONDO:0007972 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0025281 infores:hetionet CHEBI:63618 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0022346 infores:hetionet CHEBI:9763 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0043352 infores:hetionet NCBIGene:4724 biolink:causes MONDO:0100224 infores:monarchinitiative not_provided not_provided HGNC:7711 MONDO:0100224 uuid:49cbb097-dd94-4d57-951b-f6af1d038393 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0234233 infores:hetionet CHEBI:39867 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085593 infores:hetionet CHEBI:27899 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0546817 infores:hetionet CHEBI:6367 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0240211 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0041912 infores:hetionet GO:0060297 biolink:causes GO:0030239 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0030239 CAID:CA343726916 biolink:causes MONDO:0005338 infores:clingen CAID:CA343726916 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.719A>G variant in MYOC is a missense variant predicted to cause substitution of Glutamic acid by Glycine at amino acid 240 (p.Glu240Gly). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000005085 (6 alleles out of 1,180,006), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.205, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726916/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8428 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0429098 infores:hetionet CHEBI:85161 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0009782 infores:hetionet CHEBI:63618 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0026858 infores:hetionet CHEBI:63638 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0030232 infores:hetionet CHEBI:5141 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C2830004 infores:hetionet GO:0072095 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0060993 CHEBI:28262 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01093 UMLS:C0234215 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0948349 infores:hetionet CHEBI:8869 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0016204 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018799 infores:hetionet CHEBI:73274 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0085606 infores:hetionet CAID:CA351754408 biolink:causes MONDO:0008667 infores:clingen CAID:CA351754408 MONDO:0008667 PMID: Uncertain Significance PP3, PM1 PS4, BS1, PM5 The variant NM_000551.3(VHL):c.461C>G (p.Pro154Arg) is a missense variant predicted to cause substitution of Proline by Arginine. This variant is in the nuclear export domain, a critical functional domain of VHL (PM1). The computational predictor REVEL gives a score of 0.942, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). One subject age 40-45 is reported with paraganglioma (0.5 points). Of three commercial laboratories, two report no subjects with this variant. One laboratory reports two women in 60s and 70s with breast cancer (non-VHL related cancers), both having had multi-cancer and common cancer panels run. There is no further detail on phenotype/screening for VHL related phenotypes. Therefore the PS4 code is not met. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00001425 (4/86248 from South Asian Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of >=0.0000156 (0.00156%) for BS1, and therefore does not meet any criterion (BS1, BA1, PM2_Supporting are not met). Three other variants are reported in ClinVar at this position: Pro154Ala, Pro154Ser and Pro154Leu. All have Chuvash polycythemia and VHL as listed conditions. However, only Pro154Leu is reported as Pathogenic. Proline to Leucine is a distance of 98 and Proline to Arginine is a distance of 103 based on Grantham's table (1974). The Arginine substitution has a larger Grantham distance than Leucine. At this time the VHL VCEP has not classified Pro154Leu, and PM5 is not met. In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA351754408/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61058 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0231528 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024312 infores:hetionet NCBIGene:81839 biolink:causes MONDO:0010831 infores:monarchinitiative not_provided not_provided HGNC:15512 MONDO:0010831 uuid:1ac26374-2e42-4f92-a5bc-c3f31e54f817 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3238 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01091 UMLS:C0041834 infores:hetionet CHEBI:44423 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0235996 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0021053 infores:hetionet CAID:CA223027 biolink:causes MONDO:0021060 infores:clingen CAID:CA223027 MONDO:0021060 PMID: Uncertain Significance BS1, PM2, PP2, PP3, BP4, BA1, PS4 The c.-1C>T variant in the SHOC2 gene is an intronic variant located in the 5' UTR, 1 base upstream from the first translated codon. The highest population minor allele frequency in gnomAD v4.1.0 is 0.01172% (7/59740 alleles) in the Latino/Admixed American population. (PM2_Supporting/BS1/BA1 are not met). This variant has been identified in 2 independent occurrences in patients with a clinical features of a RASopathy (PS4 not met; GeneDx, EGL internal data GTR Lab ID's: 26957, 500060; ClinVar SCV000209050.9, SCV000113449.7). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: None (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA223027/MONDO:0021060/038 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6904 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0017086 infores:hetionet CHEBI:50742 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013447 infores:hetionet CHEBI:4710 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C2584688 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0031350 infores:hetionet CHEBI:45716 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0011606 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0241742 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0007787 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0853891 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0853891 infores:hetionet CHEBI:3510 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0011175 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0009319 infores:hetionet CHEBI:47898 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0221776 infores:hetionet CHEBI:5128 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0015230 infores:hetionet CAID:CA014319 biolink:causes MONDO:0007947 infores:clingen CAID:CA014319 MONDO:0007947 PMID: Likely Pathogenic PM6, PP4, PP2, PP3, PS4_Supporting, PM1, PM5 The NM_00138 c.3589G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1197 (p.Asp1197Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was identified in two unrelated pediatric probands with a clinical diagnosis of Marfan syndrome (MFS), and was found to be de novo without confirmation of paternity and maternity (internal lab data, PM6, PP4, PS4_Sup). This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 42339). This variant was found in an individual with thoracic aortic aneurysm and/or dissection (Internal lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3589G>C p.Asp1197His, has previously been previously established as (likely) pathogenic and was reported as de novo in an individual with Marfan syndrome (PMID 19293843, PM5). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.772, PP3). This variant is located in the last nucleotide of the exon. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PM6, PS4_Sup, PM2_Sup, PP2, PP3, PP4. ​ FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA014319/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:100246 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0027707 infores:hetionet CHEBI:28901 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0035455 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0267792 infores:hetionet CHEBI:3568 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030554 infores:hetionet CAID:CA402991093 biolink:causes MONDO:0012999 infores:clingen CAID:CA402991093 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_000156.6:c.571G>A variant in GAMT is a missense variant predicted to cause substitution of a glutamic acid for a lysine at position 191 (p.Glu191Lys). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.624 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.5) impact on GAMT function.. The impact on GAMT function is unclear. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 12, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402991093/MONDO:0012999/026 2023-12-12 2023-12-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7773 biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0521503 infores:hetionet CHEBI:92712 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0018790 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0687133 infores:hetionet CHEBI:5790 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0232462 infores:hetionet CHEBI:92712 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0009763 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0178298 infores:hetionet CAID:CA213792 biolink:causes MONDO:0015967 infores:clingen CAID:CA213792 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PS3, PP1_Strong, PP3, PM2_Supporting The c.483G>A variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 161 (p.(Lys161=)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.85 for donor gain and 0.52 for donor loss, which are greater than the MDEP cutoff of 0.2) (PP3), and there is evidence from RNA studies that this variant results in aberrant splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor). This variant was identified in five unrelated individuals with mildly elevated HbA1c that did not require treatment, and segregated with the phenotype, with four informative meioses in three families (PS4_Moderate, PP1_Strong; PMID: 1956454, Internal lab contributors). In summary, c.483G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 3/23/23): PM2_Supporting, PP3, PS4_Moderate, PP1_Strong, PS3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213792/MONDO:0015967/086 2023-05-26 2023-05-26 Semidominant inheritance HP:0032113 Supports CHEBI:6375 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020580 infores:hetionet UMLS:C0005740 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0231218 infores:hetionet CHEBI:5141 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0011603 infores:hetionet CHEBI:68534 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0018681 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0855242 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0031350 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0751295 infores:hetionet CHEBI:167309 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0003811 infores:hetionet CHEBI:421707 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0034902 infores:hetionet CAID:CA134592 biolink:causes MONDO:0021060 infores:clingen CAID:CA134592 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1137C>T (p.Ile379=) variant in the MAP2K1 gene is 0.175% (26/10406) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134592/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:567361 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0018808 infores:hetionet CHEBI:50275 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0423791 infores:hetionet CHEBI:184555 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0423153 infores:hetionet CHEBI:16347 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C3263723 infores:hetionet CHEBI:50861 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0031350 infores:hetionet CHEBI:5127 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0026113 infores:hetionet CAID:CA199289 biolink:causes MONDO:0100039 infores:clingen CAID:CA199289 MONDO:0100039 PMID:29852413PMID:24564546PMID:21770923PMID:29190809PMID:26482601PMID:29852413PMID:24564546PMID:21770923PMID:29190809 Pathogenic PS2_Very Strong, PS4, PM5_Strong, PM2_Supporting PP3 The p.Arg178Gln variant in CDKL5 has been reported in at least 4 de novo occurrences (biological parentage unconfirmed) in patients with CDKL5 disorder (PMID 26482601, 21770923, 29852413, 29190809, 24564546, 26482601) (PM6_very strong). The variant was present in the mosaic state in one patient, confirming its de novo nature (PMID 26482601) (PS2). The p.Arg178Gln variant in CDKL5 has been reported in at least 7 other individuals with CDKL5 disorder (PMID 26482601, 21770923, 29852413, 29190809, 24564546) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 29100083, 22430159, 19793311, 18809835, 30182498) (PM5_strong). The p.Arg178Gln variant in CDKL5 is absent from gnomAD (PM2_supporting). In summary, the p.Arg178Gln variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4, PM5_strong, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199289/MONDO:0100039/016 2021-03-25 2021-05-10 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:3213 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0014742 infores:hetionet CHEBI:4903 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042029 infores:hetionet CHEBI:31524 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C1443060 infores:hetionet CHEBI:175901 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0237849 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020456 infores:hetionet CAID:CA915941070 biolink:causes MONDO:0700272 infores:clingen CAID:CA915941070 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting The c.2787_2788dup (p.Asn930Ilefs*6) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 8 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent in gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA915941070/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8764 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017086 infores:hetionet CHEBI:66919 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0162429 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039520 infores:hetionet CHEBI:2904 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0008370 infores:hetionet NCBIGene:340990 biolink:causes MONDO:0013985 infores:monarchinitiative not_provided not_provided HGNC:8516 MONDO:0013985 uuid:ace1170d-ed96-4302-a27e-eab04f5efc75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0025061 infores:hetionet CHEBI:2676 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0015230 infores:hetionet UMLS:C1872203 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0033774 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0162429 infores:hetionet CHEBI:64064 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0235710 infores:hetionet CHEBI:31859 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0015967 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019061 infores:hetionet CHEBI:36791 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0024282 infores:hetionet CHEBI:75045 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0033771 infores:hetionet CHEBI:45924 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0041657 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0877334 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0877334 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0333641 infores:hetionet NCBIGene:6262 biolink:causes MONDO:0020745 infores:monarchinitiative not_provided not_provided HGNC:10484 MONDO:0020745 uuid:0ef80c7e-5013-473a-8a3a-cf3610decad8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0029408 infores:hetionet CHEBI:2675 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0344232 infores:hetionet CHEBI:63581 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0018418 infores:hetionet GO:0090183 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:0090183 GO:0072001 GO:1905100 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:1905100 GO:0006915 CHEBI:64355 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0008035 infores:hetionet CHEBI:6715 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0015672 infores:hetionet CAID:CA2580098829 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098829 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 This frameshift variant is in a region that is critical to protein function, and transcript is not expected to undergo NMD (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This frameshift variant is downstream c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098829/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2549 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0426576 infores:hetionet CHEBI:119486 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018524 infores:hetionet CHEBI:3398 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0027497 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0152030 infores:hetionet CHEBI:7915 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C3263723 infores:hetionet CHEBI:194135 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030252 infores:hetionet CHEBI:16714 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0232487 infores:hetionet CHEBI:3723 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004604 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0002792 infores:hetionet CHEBI:65349 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0018681 infores:hetionet CAID:CA10652904 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652904 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 The c.*4238G>T variant in the 3' UTR has an MAF of 0.004815 (0.48%, 311/64584 alleles) in the non-Finish European subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652904/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4974 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0004093 infores:hetionet CHEBI:63580 biolink:causes NCIT:C35105 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0041981 infores:hetionet CHEBI:3996 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0520966 infores:hetionet CHEBI:2675 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0027497 infores:hetionet CAID:CA213711 biolink:causes MONDO:0015967 infores:clingen CAID:CA213711 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1114G>T variant in the glucokinase gene, GCK, results in a premature termination at codon 372 (p.Glu372Ter) of NM_000162.5. While this variant, located in exon 9 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 22335469, ClinVar ID: 36174, internal lab contributor). Two of these individuals had a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 22335469, internal lab contributor). In summary, c.1114G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213711/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:142290 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0007222 infores:hetionet CHEBI:9763 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0231218 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0013428 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0020615 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0019158 infores:hetionet CHEBI:8481 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0152032 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0575090 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0014130 infores:hetionet CHEBI:6438 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C1145670 infores:hetionet CHEBI:9445 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0013404 infores:hetionet CHEBI:6062 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085611 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0948089 infores:hetionet CHEBI:4887 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0037763 infores:hetionet CHEBI:28901 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0014591 infores:hetionet CHEBI:10110 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0041969 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0155003 infores:hetionet CHEBI:472657 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0151754 infores:hetionet CAID:CA410677511 biolink:causes MONDO:0009276 infores:clingen CAID:CA410677511 MONDO:0009276 PMID:16978236 Likely Pathogenic PM3, PM1, PP3, PP4, PM2_Supporting, BS3_Supporting The variant NM_000407.5(GP1BB):c.439T>A (p.Cys147Ser) has been found in at least one individual with Bernard-Soulier syndrome. This patient (PMID:16978236) is compound heterozygous for this variant inherited from the father and c.448del inherited from the mother (PM3). He had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had reduced GP1ba, GPIbb, and GPIX platelet expression and macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. The variant is absent from gnomADv4.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.687, which is above the ClinGen PD VCEP PP3 threshold of >0.644 and predicts a damaging effect on GP1BB function (PP3). This variant resides at a disulfide bond residue, Cys147, of GP1BB that is defined as a critical functional domain by the ClinGen PD VCEP (PM1). However, with stable transfection in CHO cells this variant caused elimination of the GPIbb-GPIba disulfide linkage did not significantly affect GPIb/IX surface expression or the binding of soluble vWF to the GPIb/IX transfected CHO cells (PMID: 16978236; BS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS3_supporting, PP3, PM1, PM2_supporting, PM3 and PP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410677511/MONDO:0009276/082 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5801 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0015967 infores:hetionet CHEBI:50378 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0017160 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0687133 infores:hetionet CHEBI:31547 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0030193 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006384 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0004601 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004601 infores:hetionet CHEBI:32315 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0086439 infores:hetionet UNII:R43D2573WO biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0162297 infores:hetionet NCBIGene:335 biolink:causes MONDO:0971008 infores:monarchinitiative not_provided not_provided HGNC:600 MONDO:0971008 uuid:db1c27c3-4de1-4bad-a145-eb90d5861af8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0429098 infores:hetionet CHEBI:3077 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0019572 infores:hetionet CHEBI:63627 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0013182 infores:hetionet CHEBI:9086 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018524 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003529 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0520575 infores:hetionet CHEBI:8354 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0012833 infores:hetionet CHEBI:188986 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0002962 infores:hetionet CHEBI:8802 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0004144 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0001824 infores:hetionet CHEBI:51380 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0006145 infores:hetionet CHEBI:53691 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0018790 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009760 infores:hetionet CHEBI:51860 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C3665347 infores:hetionet CHEBI:3738 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0040264 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0042075 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0239739 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0476289 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0476289 infores:hetionet CHEBI:3380 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0497156 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030312 infores:hetionet CHEBI:32139 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C1321686 infores:hetionet CHEBI:63584 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0036396 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0234215 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0036572 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0948089 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0349506 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013395 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0948089 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0041969 infores:hetionet CHEBI:16469 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0852911 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1510472 infores:hetionet CHEBI:17347 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0030794 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0435002 infores:hetionet CHEBI:50922 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0018681 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0948089 infores:hetionet CHEBI:231594 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0014743 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0042109 infores:hetionet CHEBI:9139 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0016242 infores:hetionet CHEBI:31980 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0011603 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0020649 infores:hetionet CHEBI:3698 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0014518 infores:hetionet CHEBI:42797 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0024305 infores:hetionet CHEBI:4653 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0231218 infores:hetionet NCBIGene:130557 biolink:causes MONDO:0013328 infores:monarchinitiative not_provided not_provided HGNC:26498 MONDO:0013328 uuid:447d0209-3a9e-451a-999a-f55d20019043 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0004093 infores:hetionet CHEBI:17688 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0018681 infores:hetionet NCBIGene:8878 biolink:causes MONDO:0014945 infores:monarchinitiative not_provided not_provided HGNC:11280 MONDO:0014945 uuid:aed0f3f0-4bbf-4bcb-b1b1-7eaad40000c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0008031 infores:hetionet CHEBI:71940 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0036454 infores:hetionet CHEBI:4953 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0017178 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0018799 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0004238 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0853761 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0025637 infores:hetionet CHEBI:31236 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232462 infores:hetionet CHEBI:15367 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0700590 infores:hetionet CAID:CA352042278 biolink:causes MONDO:0005835 infores:clingen CAID:CA352042278 MONDO:0005835 PMID: Pathogenic PVS1, PP4, PM2_Supporting The (M_000249.4):c.589-2A>C variant in MLH1 occurs within the canonical splice acceptor site (-2) of intron 7. It is predicted to alter the consensus acceptor splice site leading to exon skipping or use of a cryptic splice site disrupting reading frame and predicting to undergo NMD (PVS1). This variant has been detected in at least one CRC MSI-H tumour with loss of MLH1 and PMS2 expression (PP4). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).In summary, this variant meets the criteria to be classified as pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1, PM2_Sup, PP4 (VCEP specifications version 1). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA352042278/MONDO:0005835/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:167638 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0344315 infores:hetionet CHEBI:66903 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0015672 infores:hetionet CAID:CA267222 biolink:causes MONDO:0800472 infores:clingen CAID:CA267222 MONDO:0800472 PMID:27060699 Likely Pathogenic PM2_Supporting, PM1, PM3_Supporting, PP3_Strong PP1, BA1, BP4, PM4, PM5, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.1409G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Cystein by Tyrosine at amino acid 470 (p.Cys470Tyr). This missense variant is located in the L-helix including the haem-binding domain, meeting PM1. The highest minor allele frequency of this variant was in the European (Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00001562 (1 allele out of 64,032), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.955, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699). This variant has been identified in two individuals with a CYP1B1-related phenotype. One of these individuals is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) and one of these is homozygous (consanguineous) for the variant (PMIDs: 20664688, 23218183). Total proband points = 0.75, meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PP3_Strong, PM1, PM2_Supporting, PM3_Supporting (PP3 and PM1 are capped at 4 points). Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA267222/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2618 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0338831 infores:hetionet CHEBI:194135 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0015672 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C1861172 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0027051 infores:hetionet CHEBI:5893 biolink:causes MONDO:0020779 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0008449 infores:hetionet CHEBI:68478 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011175 infores:hetionet CHEBI:209807 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0038325 infores:hetionet CAID:CA384897664 biolink:causes MONDO:0010880 infores:clingen CAID:CA384897664 MONDO:0010880 PMID: Likely Pathogenic PS4, PP3, PM2_Supporting The NM_000020.3: c.137G>C variant in ACVRL1 is a missense variant predicted to cause substitution of cysteine by serine at amino acid 46 (p.Cys46Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 4 probands with a phenotype consistent with HHT (PS4; ClinVar, Internal lab contributors). The computational predictor REVEL gives a score of 0.852, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PM2_Supporting, PP3 (specification version 1.1.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA384897664/MONDO:0010880/135 2024-01-04 2025-03-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63608 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027121 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0018799 infores:hetionet CHEBI:53760 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018965 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0005940 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0242350 infores:hetionet CHEBI:47519 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0036508 infores:hetionet CHEBI:52717 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009676 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009450 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235401 infores:hetionet GO:1905699 biolink:causes GO:0098754 infores:ubergraph knowledge_assertion manual_agent GO:1905699 GO:0098754 CHEBI:3207 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0542571 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0235660 infores:hetionet CHEBI:3752 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1306341 infores:hetionet CAID:CA405688717 biolink:causes MONDO:0018493 infores:clingen CAID:CA405688717 MONDO:0018493 PMID: Uncertain Significance PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts the changing of arginine to a premature stop codon at position 3167 of the RYR1 protein, p.(Arg3167*). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000018, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 not implemented (PMID:26951757). No functional studies were identified for this variant. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: None. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405688717/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7822 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0014742 infores:hetionet CHEBI:5790 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0026827 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0004238 infores:hetionet CHEBI:31711 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0220870 infores:hetionet CHEBI:64312 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0600142 infores:hetionet CHEBI:135566 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0423232 infores:hetionet CHEBI:144551 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0017178 infores:hetionet CHEBI:51450 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0522153 infores:hetionet CHEBI:7496 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0855333 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0038362 infores:hetionet CHEBI:44241 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0019572 infores:hetionet CHEBI:3638 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C1384666 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0042109 infores:hetionet CHEBI:63791 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013604 infores:hetionet CAID:CA6831956 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831956 MONDO:0015967 PMID: Benign BA1, BP2, PP3 PS4 The c.1135C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 379 (p.(Pro379Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001567, which is greater than the MDEP threshold for BA1 (0.0001)(BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has been observed in unknown phase with the variant c.872dup, p.Gly292Argfs*25 (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). This variant was identified in at least 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID 18003757, internal lab contributors). In summary, c.1135C>T meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BA1, BP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831956/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:180905 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0018794 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0037199 infores:hetionet CHEBI:28918 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0020615 infores:hetionet CHEBI:63629 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0231530 infores:hetionet CHEBI:8107 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0423791 infores:hetionet CHEBI:6916 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0233715 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0009806 infores:hetionet CHEBI:31705 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0340865 infores:hetionet CHEBI:9288 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0271650 infores:hetionet CHEBI:2038 biolink:causes UMLS:C1963864 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C1963864 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085606 infores:hetionet CHEBI:68579 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0013604 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0027769 infores:hetionet CHEBI:27974 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0030193 infores:hetionet CHEBI:50692 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0015230 infores:hetionet NCBITaxon:138949 biolink:causes MONDO:0005751 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:138949 MONDO:0005751 CHEBI:28864 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0009676 infores:hetionet CHEBI:45367 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0030554 infores:hetionet CHEBI:5893 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0003467 infores:hetionet CHEBI:9763 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0036508 infores:hetionet CHEBI:2549 biolink:causes HP:0033533 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0085128 infores:hetionet CHEBI:5141 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0012739 infores:hetionet CHEBI:4856 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0015967 infores:hetionet CHEBI:4551 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0011603 infores:hetionet CHEBI:9137 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1142412 infores:hetionet CHEBI:4514 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0152198 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1443060 infores:hetionet CHEBI:28445 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0085684 infores:hetionet CHEBI:63629 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0004604 infores:hetionet CHEBI:8430 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0040264 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020456 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0021053 infores:hetionet CHEBI:77733 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0030193 infores:hetionet CAID:CA8815663 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815663 MONDO:0009290 PMID: Uncertain Significance PP3, PM5, PM2_Supporting PP4 The NM_000152.5:c.2237G>T variant in GAA is a missense variant predicted to cause substitution of tryptophan by leucine at amino acid 746 (p.Trp746Leu). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001102 (7/63508 alleles) in the European Finnish population, which is lower than the ClinGen Lysosomal Diseases threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.832 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.2238G>C, p.Trp746Cys) (ClinVar Variation ID 265160) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). Three additional different missense variants (c.2237G>C, p.Trp746Ser; c.2236T>C, p.Trp746Arg; and c.2236T>G, p.Trp746Gly), in the same codon have been reported in patients with Pompe disease (ClinVar Variation IDs 188484, 499293, 556431). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP. There is a ClinVar entry for this variant (Variation ID: 284776). In summary, there is currently insufficient evidence to determine the pathogenicity of this variant, and it meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM5, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815663/MONDO:0009290/010 2024-12-19 2025-02-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:4514 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0011603 infores:hetionet CHEBI:73274 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0016655 infores:hetionet CHEBI:71417 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0018965 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0314719 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0043145 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043145 infores:hetionet CHEBI:42355 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0000729 infores:hetionet CHEBI:4325 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0151786 infores:hetionet CHEBI:15544 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0023218 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1306577 infores:hetionet CHEBI:7494 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0040264 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151735 infores:hetionet CHEBI:5784 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0040034 infores:hetionet CHEBI:37941 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0040264 infores:hetionet CHEBI:6954 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0025362 infores:hetionet CHEBI:3508 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0006266 infores:hetionet CHEBI:32315 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0014591 infores:hetionet CHEBI:94807 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0004093 infores:hetionet CHEBI:30659 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0011603 infores:hetionet CHEBI:94392 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0234215 infores:hetionet CHEBI:94501 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0085681 infores:hetionet CHEBI:4909 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0302809 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0032285 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004623 infores:hetionet CHEBI:5128 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0575081 infores:hetionet CHEBI:101085 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0015967 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0699893 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0040046 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1963747 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1963747 infores:hetionet NCBIGene:6338 biolink:causes MONDO:0859317 infores:monarchinitiative not_provided not_provided HGNC:10600 MONDO:0859317 uuid:5d4cc8cf-7189-4063-b6f8-41e803c899d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0034880 infores:hetionet CHEBI:42355 biolink:causes MONDO:0021697 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0008149 infores:hetionet CAID:CA10653566 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653566 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*1295G>A is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653566/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71415 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C2242996 infores:hetionet GO:0042491 biolink:causes CL:0000202 infores:ubergraph knowledge_assertion manual_agent GO:0042491 CL:0000202 CHEBI:6965 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0009806 infores:hetionet CHEBI:6539 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0022346 infores:hetionet UMLS:C0209366 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0041834 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020649 infores:hetionet CHEBI:75998 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0234894 infores:hetionet CHEBI:50648 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027424 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0518015 infores:hetionet CHEBI:3310 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0027497 infores:hetionet CHEBI:3175 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0702166 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042035 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019158 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0267596 infores:hetionet CHEBI:144551 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1456784 infores:hetionet CHEBI:50730 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0009782 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0015397 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0178298 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0001418 infores:hetionet CHEBI:51137 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0009782 infores:hetionet CAID:CA913189275 biolink:causes MONDO:0011071 infores:clingen CAID:CA913189275 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PS4_Supporting, PM2_Supporting, PP1 PS3, PS2, PS1, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4 The NM_001754.5(RUNX1):c.1088_1094del (p.Gly363fs) variant is a frameshift variant that is predicted to lead to an elongated RUNX1 protein and that is not predicted to result in nonsense-mediated mRNA decay (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant was found to co-segregate with disease in multiple affected family members, with three or four (4) meioses observed in one family/across 1 family (PP1; PMID: 18723428). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 18723428). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_Supporting, PS4_Supporting and PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189275/MONDO:0011071/008 2022-01-20 2022-06-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31236 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0041582 infores:hetionet CHEBI:31932 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C1384353 infores:hetionet CHEBI:63613 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0030554 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0522570 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0522570 infores:hetionet CHEBI:4909 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C2830004 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017574 infores:hetionet CHEBI:2453 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C2363730 infores:hetionet CHEBI:135736 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0017565 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0037199 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1168174 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1168174 infores:hetionet CHEBI:6888 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018524 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0948594 infores:hetionet CHEBI:28748 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0947912 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009324 infores:hetionet CAID:CA220196 biolink:causes MONDO:0008723 infores:clingen CAID:CA220196 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1389dup (p.Thr464AspfsTer3) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 08-04-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220196/MONDO:0008723/021 2022-08-23 2022-08-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8768 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027707 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0267792 infores:hetionet CHEBI:49668 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0005741 infores:hetionet CHEBI:15428 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0042109 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0497327 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0151313 infores:hetionet CHEBI:31515 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0854082 infores:hetionet CHEBI:7931 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0438237 infores:hetionet CHEBI:6887 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085593 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0178298 infores:hetionet CAID:CA412745347 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745347 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.310+1G>A is a canonical splice site variant in intron 4 and is predicted to induce skipping of exon 4, which is expected to disrupt a critical functional domain in RPGR (PVS1). This variant is absent from hemizygotes in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 24938718, PMID: 32531858, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745347/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:76010 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0021368 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0034186 infores:hetionet GO:0060860 biolink:causes GO:0048437 infores:ubergraph knowledge_assertion manual_agent GO:0060860 GO:0048437 CHEBI:8764 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0008350 infores:hetionet CHEBI:3371 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0235280 infores:hetionet CHEBI:6916 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0043352 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018681 infores:hetionet UMLS:C0145867 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020580 infores:hetionet CHEBI:3176 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0920171 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1306341 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0025517 infores:hetionet CHEBI:4798 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0007286 infores:hetionet CHEBI:31236 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020488 infores:hetionet CHEBI:45783 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030196 infores:hetionet CHEBI:28148 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0039621 infores:hetionet CHEBI:50730 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C1260880 infores:hetionet CHEBI:71941 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0547030 infores:hetionet CHEBI:119573 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1963951 infores:hetionet CHEBI:5106 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0041657 infores:hetionet CHEBI:6375 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0423791 infores:hetionet CHEBI:9720 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0456909 infores:hetionet CHEBI:3723 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085649 infores:hetionet CHEBI:52172 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0030554 infores:hetionet NCBIGene:6777 biolink:causes MONDO:0100211 infores:monarchinitiative not_provided not_provided HGNC:11367 MONDO:0100211 uuid:bb0fee4f-9532-487c-a991-0a4f6db0576a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA170457 biolink:causes MONDO:0100039 infores:clingen CAID:CA170457 MONDO:0100039 PMID: Benign BS2, BA1, BP2 The allele frequency of the p.Ile631Thr variant in CDKL5 is 0.03% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ile631Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ile631Thr variant is observed in the CDKL5 gene where a second pathogenic variant in the same gene is present in the patient (PMID 19793311) (BP2). In summary, the p.Ile631Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170457/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:75722 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0852911 infores:hetionet CHEBI:135530 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0239571 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0877266 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0877266 infores:hetionet CAID:CA397723375 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723375 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM1, PM3_Supporting, PP4_Moderate The NM_000018.4(ACADVL): c.643T>C variant in ACADVL is a missense variant predicted to cause substitution of cystine by arginine at amino acid 215 (p.Cys215Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant is detected in at least one patient in homozygous fashion (PM3 point 0.5, PM3_Supporting, PMID: 25834949). This patient displayed reduced enzyme levels (< 5% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 25834949). This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). The computational predictor REVEL gives a score of 0.951, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723375/MONDO:0008723/021 2023-11-13 2023-11-13 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10586443 biolink:causes MONDO:0100216 infores:clingen CAID:CA10586443 MONDO:0100216 PMID: Uncertain Significance BP4, PS4_Supporting, PM2_Supporting, PS2 BA1, PP3, PP4, PM5, PM1, PS1, PS3, BS1, BS3 The NM_177438.3:c.2236A>G variant in DICER1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 746 (p.Arg746Gly). This variant received a total of 1 phenotype point across 1 proband with pleuropulmonary blastoma, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 26925222). This observation was observed as a de novo occurrence with constitutional mosaicism (PS2; PMIDs:26925222). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.5, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, BP4. (Bayesian Points: 5; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586443/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7478 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020580 infores:hetionet CHEBI:31348 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0520966 infores:hetionet CHEBI:27834 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0231530 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0340726 infores:hetionet NCBIGene:284252 biolink:causes MONDO:0008404 infores:monarchinitiative not_provided not_provided HGNC:18249 MONDO:0008404 uuid:03f4b50b-e3f0-42d7-91a6-fbf981576a1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA481331323 biolink:causes MONDO:0009861 infores:clingen CAID:CA481331323 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, PM3_Supporting, BP7 This c.843T>A (p.Pro281Pro) variant in PAH was detected with the pathogenic variant c.168+5G>C in a patient with PKU (PMID:26413448). This variant was absent in population databases. This is a synonymous variant which is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a variant of unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7, PM3_Supporting, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA481331323/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2663 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0033774 infores:hetionet CAID:CA024034 biolink:causes MONDO:0007783 infores:clingen CAID:CA024034 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PM1, PS4_Moderate, PP3_Moderate BS1, BS3, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of cysteine at codon 44 of the RYR1 protein, p.(Arg44Cys). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:12709367, PMID:24433488). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. For these reasons, this variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024034/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:75722 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027066 infores:hetionet CHEBI:8768 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019270 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0243026 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0019360 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0314719 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0233494 infores:hetionet CHEBI:64312 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0032617 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0100302 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0100302 uuid:d159b449-77bc-4d6f-bdc4-1995aed7e381 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72564 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042267 infores:hetionet CHEBI:6797 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0340865 infores:hetionet CHEBI:71415 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0015230 infores:hetionet NCBIGene:6521 biolink:causes MONDO:0008165 infores:monarchinitiative not_provided not_provided HGNC:11027 MONDO:0008165 uuid:0f89aab0-4e45-4346-ae51-495d8496e68e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085636 infores:hetionet CHEBI:2668 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0428977 infores:hetionet CHEBI:68558 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0019080 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0025061 infores:hetionet NCBIGene:5663 biolink:causes MONDO:0011913 infores:monarchinitiative not_provided not_provided HGNC:9508 MONDO:0011913 uuid:730c8b58-3481-42ec-ba38-db86fa8687a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4822 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0036974 infores:hetionet CHEBI:9398 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C1443060 infores:hetionet CHEBI:119915 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085641 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0024115 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014868 infores:hetionet CHEBI:27796 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0022346 infores:hetionet CAID:CA020075 biolink:causes MONDO:0008667 infores:clingen CAID:CA020075 MONDO:0008667 PMID: Benign BA1 The variant NM_000551.3(VHL):c.183C>G (p.Pro61=) is a silent variant in the first exon of VHL. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001902 (192/89258 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020075/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6149 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0234987 infores:hetionet CHEBI:7822 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0023530 infores:hetionet UMLS:C0004609 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0040822 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0702266 infores:hetionet CHEBI:3216 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0039231 infores:hetionet CHEBI:36791 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0311468 infores:hetionet CHEBI:10125 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0162830 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0022660 infores:hetionet NCBIGene:2300 biolink:causes MONDO:0957928 infores:monarchinitiative not_provided not_provided HGNC:3817 MONDO:0957928 uuid:b70aa496-26ea-4856-8ffa-af334b5f7e2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4636 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0027813 infores:hetionet CHEBI:3752 biolink:causes MONDO:0008167 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0237020 infores:hetionet CHEBI:4514 biolink:causes UMLS:C1522058 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C1522058 infores:hetionet CHEBI:28901 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0009421 infores:hetionet CAID:CA390883127 biolink:causes MONDO:0100216 infores:clingen CAID:CA390883127 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, PVS1, BA1, BP2, BS2, PP3, PP1, PP4, PM5, PM4, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7 The NM_177438.3:c.2051T>C variant in DICER1 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 684 (p.Met684Thr). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000001863 (3/1609982 alleles) with a highest population minor allele frequency of 0.00002672 (2/74840 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.345; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390883127/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:UMD7G2653W biolink:causes UMLS:C0029734 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0029734 infores:hetionet CHEBI:71417 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0270810 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0034150 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0549433 infores:hetionet CAID:CA5689793 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689793 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.1540+8C>A variant in the SHOC2 gene is 0.0459% (8/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689793/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9587 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0023530 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0043037 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042790 infores:hetionet CAID:CA16609272 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609272 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate The c.694dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 232 of NM_000545.8, adding 7 novel amino acids before encountering a stop codon (p.Leu232ProfsTer7). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.694dup meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609272/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8871 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0521839 infores:hetionet CHEBI:68554 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0853697 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0031350 infores:hetionet CHEBI:15940 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0015230 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0029456 infores:hetionet CHEBI:36795 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235996 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0021053 infores:hetionet CHEBI:7936 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151889 infores:hetionet CHEBI:46295 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0018965 infores:hetionet CHEBI:5790 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0344232 infores:hetionet CAID:CA9301631 biolink:causes MONDO:0010938 infores:clingen CAID:CA9301631 MONDO:0010938 PMID: Uncertain Significance PM2_Supporting BA1, BS1, PS1, PM5, BS2 The NM_000215.4(JAK3):c.2291C>T variant in JAK3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 764 (p.Pro764Leu). The filtering allele frequency (the upper threshold of the 95% CI of 3/33008) of the c.2291C>T variant is 0.00002408 for African/African American subpopulation chromosomes by gnomAD v.4.0.0, which is lower than the threshold (<0.000115) defined by the ClinGen Severe Combined immunodeficiency Disease Variant Curation Expert Panel (SCID VCEP) for JAK3 variants (PM2_supporting). One patient was found reported on Clinvar; however, the affected status is unknown (VCV000863482.6). This variant does not meet the criteria to be classified as pathogenic, likely pahogenic, benign or likely benign for T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID JAK3 VCEP (PM2_supporting) ; therefore is classified as a variant of unknown significance (VUS) for this disease. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9301631/MONDO:0010938/121 2024-02-21 2024-02-21 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135005 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0149931 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0497247 infores:hetionet CHEBI:9667 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0004093 infores:hetionet CHEBI:2687 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0021368 infores:hetionet CHEBI:45979 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0002994 infores:hetionet CHEBI:209807 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0008370 infores:hetionet NCBIGene:3851 biolink:causes MONDO:0008676 infores:monarchinitiative not_provided not_provided HGNC:6441 MONDO:0008676 uuid:b007a4cd-9da7-4c24-8008-8c068612fdf4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0234215 infores:hetionet CHEBI:64045 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0012833 infores:hetionet CHEBI:7986 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0037317 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042769 infores:hetionet CHEBI:135361 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C1443060 infores:hetionet GO:0075118 biolink:causes GO:0007186 infores:ubergraph knowledge_assertion manual_agent GO:0075118 GO:0007186 CHEBI:50885 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0085660 infores:hetionet CHEBI:3534 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0042963 infores:hetionet CHEBI:47781 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0018418 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0009917 infores:hetionet CHEBI:85083 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0231528 infores:hetionet CHEBI:9448 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0042571 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017574 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0151313 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1145670 infores:hetionet CHEBI:31625 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0858617 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0016169 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0016169 infores:hetionet CHEBI:6909 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042963 infores:hetionet NCBIGene:51360 biolink:causes MONDO:0010637 infores:monarchinitiative not_provided not_provided HGNC:15455 MONDO:0010637 uuid:71f982db-dfc0-4eee-a19a-57a57413760f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0005747 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0013295 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0234458 infores:hetionet CHEBI:28748 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026640 infores:hetionet CHEBI:7445 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0000731 infores:hetionet CHEBI:3175 biolink:causes HP:0500043 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0234665 infores:hetionet CHEBI:9123 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0010200 infores:hetionet NCBIGene:1536 biolink:causes MONDO:0010600 infores:monarchinitiative not_provided not_provided HGNC:2578 MONDO:0010600 uuid:032d8342-447c-4404-b1d7-0482f15e85c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2704 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0574067 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0435002 infores:hetionet CHEBI:131512 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0042023 infores:hetionet CHEBI:5134 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0263449 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0002170 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0392197 infores:hetionet CHEBI:50859 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0019079 infores:hetionet CHEBI:8435 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0006114 infores:hetionet CHEBI:66901 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0003862 infores:hetionet CHEBI:9123 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0028734 infores:hetionet CHEBI:474180 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0031542 infores:hetionet CHEBI:7956 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0018681 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0020517 infores:hetionet CHEBI:51041 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0025874 infores:hetionet CHEBI:5790 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0010200 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0221706 infores:hetionet CHEBI:50742 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151578 infores:hetionet CHEBI:3380 biolink:causes UMLS:C1390484 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C1390484 infores:hetionet CHEBI:2704 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C1458155 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0243026 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020615 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0009241 infores:hetionet NCBIGene:10233 biolink:causes MONDO:0970999 infores:monarchinitiative not_provided not_provided HGNC:19138 MONDO:0970999 uuid:386333c5-8450-4b2d-877b-ddf5abb9a7af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0574067 infores:hetionet CHEBI:39867 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013362 infores:hetionet NCBIGene:25861 biolink:causes MONDO:0012662 infores:monarchinitiative not_provided not_provided HGNC:16361 MONDO:0012662 uuid:98ff7e4d-031f-4211-9b18-c4f6236c21f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64045 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0023530 infores:hetionet CHEBI:2637 biolink:causes HP:0005101 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0018780 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0012287 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0012287 uuid:29b4ea92-2b09-4bb5-9a8b-31745cb7f29f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0045766 biolink:causes MONDO:0007256 infores:drugmechdb knowledge_assertion manual_agent GO:0045766 MESH:D006528 DB08896_MESH_D006528_1DB00398_MESH_D006528_1 CHEBI:63630 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003850 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0278134 infores:hetionet CHEBI:36791 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028081 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009760 infores:hetionet CHEBI:3175 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0011603 infores:hetionet CHEBI:92712 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0004134 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015376 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0020517 infores:hetionet CAID:CA410203333 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203333 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PVS1, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP4, PP2, PP3, PP1, BS2 The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1). This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 24100448 and 32935436). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_moderate, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203333/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31622 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0020649 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0740401 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0740401 infores:hetionet CHEBI:55346 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0041969 infores:hetionet CHEBI:6933 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0004604 infores:hetionet CHEBI:18067 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0016382 infores:hetionet CAID:CA386960813 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960813 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Moderate, PVS1, PP4_Moderate The c.523C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 175 (p.(Gln175Ter)) of NM_000545.8. This variant, located in biologically relevant exon 2 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; ClinVar, internal lab contributors) and segregated with diabetes with 3 informative meioses in 3 families (PP1_Moderate; internal lab contributors). Furthermore, one of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID, internal lab contributors). In summary, c.523C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting, PS4_Moderate, PP1_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960813/MONDO:0015967/017 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:175901 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151539 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0042401 infores:hetionet CHEBI:8028 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0006114 infores:hetionet CHEBI:49375 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042023 infores:hetionet CHEBI:3011 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0003811 infores:hetionet CHEBI:31174 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0019158 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151596 infores:hetionet CHEBI:50275 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235266 infores:hetionet CHEBI:194135 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C2047937 infores:hetionet CAID:CA2695224138 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224138 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.236dup (p.Asp79GlufsTer2) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however the truncation includes the functionally important transmembrane domain (removes amino acids 532-553) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BSS6.01 in PMID:23995613) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224138/MONDO:0009276/079 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3215 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1320474 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0017160 infores:hetionet CHEBI:4710 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0016436 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0042401 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0521509 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009376 infores:hetionet CAID:CA410149713 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149713 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.891C>A (p.His297Gln) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149713/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5551 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0392525 infores:hetionet CHEBI:7936 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151836 infores:hetionet CHEBI:5106 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0030252 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0162429 infores:hetionet CHEBI:9622 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0043094 infores:hetionet CAID:CA16020840 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020840 MONDO:0009861 PMID:18299955PMID:18299955 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.689T>C (p.Val230Ala) variant in PAH has been reported in multiple individuals with MHP, mild PKU and classical PKU (BH4 deficiency excluded, PMID: 18299955, 29316886, 30747360). This variant is absent in population databases. This variant was detected with multiple pathogenic/likely pathogenic variants: p.V230I, p.A300S, and p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020840/MONDO:0009861/006 2020-08-07 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46081 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0687133 infores:hetionet CHEBI:9927 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0151539 infores:hetionet CHEBI:367163 biolink:causes MONDO:0015474 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0010418 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0152025 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020456 infores:hetionet CHEBI:63612 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0009421 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0262576 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0262576 infores:hetionet CHEBI:10102 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0233471 infores:hetionet CHEBI:16335 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0036454 infores:hetionet CHEBI:15367 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0162835 infores:hetionet CHEBI:8356 biolink:causes MONDO:0043310 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0149793 infores:hetionet CHEBI:3568 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0497156 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0018939 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0852733 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0521591 infores:hetionet CAID:CA390864315 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864315 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, PM6, PVS1, BA1, BP2, PP3, PP1, PP4, BS2, PM4, PM5, PM1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.5552G>A variant in DICER1 is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 1851 (p.Arg1851His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The highest population minor allele frequency in gnomAD v.4 is 000008475 (10/1179966 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.364, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864315/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA009232 biolink:causes MONDO:0013699 infores:clingen CAID:CA009232 MONDO:0013699 PMID: Likely Pathogenic PM2_Supporting, PP4, PVS1_Strong The NM_000535.7:c.1144+1G>A p.(?) variant in PMS2 occurs within the canonical splice donor site (+1) of intron 10. It is predicted to result in an in-frame exon skipping and the altered region is critical to protein function (PVS1_Strong). The variant was detected in one CRC/Endometrial MSI-H tumour using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). This variant is extremely rare (2 in 267958 alleles) in gnomAD using the non cancer dataset and also the gnomAD v4.1 Grpmax AF is 6.856e-7 (PM2_Supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1_STR, PM2_SUP, PP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA009232/MONDO:0013699/139 2024-09-18 2025-08-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:80630 biolink:causes UMLS:C0274702 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0274702 infores:hetionet CHEBI:16586 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0151735 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020517 infores:hetionet CHEBI:3996 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0080274 infores:hetionet CHEBI:64045 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0011570 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0035455 infores:hetionet CHEBI:6437 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009763 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0025061 infores:hetionet CHEBI:8245 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0020649 infores:hetionet CAID:CA000053 biolink:causes MONDO:0018875 infores:clingen CAID:CA000053 MONDO:0018875 PMID: Benign BA1, BP4, BS3, BS2 PS3, PS1, PS4, PS2, PM1, PM5, BS1, BS4, PM2, PP3, PP1, PP4 The NM_000546.6: c.139C>T variant in TP53 is a missense variant predicted to cause substitution of Proline by Serine at amino acid 47 (p.Pro47Ser). The filtering allele frequency of the c.139C>T variant in the TP53 gene is 0.01560 for African/African American population by gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.001) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BA1 (Bayesian Points: N/A; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000053/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:142290 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0232197 infores:hetionet CHEBI:63925 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0020452 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022408 infores:hetionet CHEBI:4995 biolink:causes UMLS:C1456329 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1456329 infores:hetionet CHEBI:135930 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0231528 infores:hetionet CHEBI:6809 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0033975 infores:hetionet CAID:CA008554 biolink:causes MONDO:0100316 infores:clingen CAID:CA008554 MONDO:0100316 PMID: Uncertain Significance PS3, PP3 BA1, PS4, BP5, BS1, PM2, PM1, PM5, PM3 NM_000218.3(KCNQ1):c.898G>A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 300 (p.Ala300Thr). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0003167, with 59996/1613624 in the Admixed American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. The variant is located within the pore helix consisting of amino acids 300 to 320, which is a well-characterized functional domain required for the channel function and selectivity filter of KCNQ1 (PMID: 15649981), and has been confirmed to show an absence of likely benign or benign variants listed in gnomAD. However, this variant is not rare (meeting PM2_Supporting), so it cannot be considered for PM1. This variant has been reported in at least four affected probands with a diagnosis of long QT syndrome, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMIDs: 9641694, 27251404, 28600177, 34165182). This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had both a long QT interval and congenital deafness. This individual was compound heterozygous for the variant and a VUS (c.1066_1071del (p.Gln356_Gln357del)) and not confirmed in trans (PMID: 34165182), so the PM3 code is not met. The computational predictor REVEL gives a score of 0.907, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). This variant has been shown to disrupt KCNQ1 function in two required experimental assays, including automated patch-clamp, mislocalization by immunofluorescence, and structural and functional simulation (PS3; PMIDs: 9641694, 30571187, 11087258,17999538). Please note that the variant has only been observed to cause disease in the homozygous or compound heterozygous state. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3 and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA008554/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15552 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0085631 infores:hetionet CHEBI:15552 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0038002 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0233571 infores:hetionet GO:1901028 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:1901028 GO:0007154 CHEBI:63631 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0231530 infores:hetionet CHEBI:68478 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0030252 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0037195 infores:hetionet CHEBI:144093 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0006277 infores:hetionet CHEBI:724125 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0151827 infores:hetionet CHEBI:3757 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037763 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002878 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005316 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085166 infores:hetionet CHEBI:4657 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0234238 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0025061 infores:hetionet CAID:CA354447789 biolink:causes MONDO:0009276 infores:clingen CAID:CA354447789 MONDO:0009276 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PP1 BS1, PM2 The NM_000174.5(GP9):c.266G>A variant in GPIX is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 89 (p.Cys89Tyr). This variant has been detected in at least 7 probands with Bernard-Soulier syndrome (PM3_Strong). Of those individuals, 2 (PMIDs: 24934643, 28765788) were compound heterozygous for this variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing or other methods (c. 212T>C [p.Phe71Ser], c.182A>G [p.Asn61Ser]. The other 5 probands were homozygous for the variant, with at least 2 of these confirmed in trans (PMIDs: 24934643, 16916536, 8972003). All seven probands are reported to have Japanese ancestry, which points to the likelihood that this variant originated in a common ancestor.At least one patient (Case 1 in PMID:8972003) with this variant had less than 10% expression of GPIba measured by Western blot, which is highly specific for Bernard-Soulier syndrome, in addition to macrothrombocytopenia. This proband received full gene sequencing and del/dup analysis of all BSS genes (PMID: 1577776). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus one affected family member (sister in family 1), both with the homozygous genotype with the c.266G>A variant (PP1; PMID:8972003). Surface expression of GP1a and GP9 measured by flow cytometry in CHO DUK- cells transiently co-transfected with the c.266G>A variant in GP9 and wild type GP1a and GP1b showed absent expression (<25%) WT levels, indicating that this variant impacts protein function (PMID:8972003)(PS3_Supporting). The computational predictor REVEL gives a score of 0.926, which is above the ClinGen PD VCEP threshold of >0.773 and predicts a damaging effect on function (PP3_Moderate).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3_Strong, PP4_Moderate, PP1, PP3_Moderate, PS3_Supporting. (VCEP specifications version 1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA354447789/MONDO:0009276/083 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71415 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C1257843 infores:hetionet NCBIGene:78989 biolink:causes MONDO:0009927 infores:monarchinitiative not_provided not_provided HGNC:17213 MONDO:0009927 uuid:0512137e-a2be-4bad-b588-88f260b967d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27470 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0027497 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0149931 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0948594 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005159 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0600139 infores:hetionet CHEBI:3387 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0030193 infores:hetionet CAID:CA8815292 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815292 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 PP4, PM3 The NM_000152.5:c.1346C>T variant in GAA is a missense variant predicted to cause substitution of serine with leucine at amino acid 449 (p.Ser449Leu). The highest population minor allele frequency in gnomAD v2.1.1. is 0.001177 (36/30594 alleles), including 2 homozygotes, in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. Three patient(s) with this variant had documented GAA deficiency with activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot (PMIDs 33202836, 33301762). However, due to the frequency of homozygotes in gnomAD, PP4 was not applied. The computational predictor REVEL gives a score of 0.307 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is a ClinVar entry for this variant (Variation ID: 714463, 1-star review status) with one submitter classifying as likely benign and one classifying as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PM2_Supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 2, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815292/MONDO:0009290/010 2024-04-02 2024-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:61049 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0553732 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0853714 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0233494 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0232492 infores:hetionet CHEBI:408174 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151315 infores:hetionet CHEBI:64045 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0001824 infores:hetionet NCBIGene:5970 biolink:causes MONDO:0032659 infores:monarchinitiative not_provided not_provided HGNC:9955 MONDO:0032659 uuid:c56fba29-1267-4f8e-b6d9-21e9eb508c36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:121340 biolink:causes MONDO:0013460 infores:monarchinitiative not_provided not_provided HGNC:17321 MONDO:0013460 uuid:be32dc2d-9410-434f-b961-4df0dea10a95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011053 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0021053 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1384666 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2225524 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0152031 infores:hetionet CHEBI:3723 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151825 infores:hetionet CHEBI:47381 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0034152 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162119 infores:hetionet CHEBI:7478 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0018681 infores:hetionet CHEBI:36791 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085649 infores:hetionet CHEBI:5165 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0032290 infores:hetionet CHEBI:6950 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002418 infores:hetionet CHEBI:28748 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038990 infores:hetionet CAID:CA1706298 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706298 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1_Strong, PM2_Supporting PS1 The NM_003494.4: c.2810+1G>A variant in DYSF, which is also known as NM_001130987.2: c.2864+1G>A, occurs within the canonical splice donor site of intron 26. RNAseq analysis has shown that this variant disrupts splicing, resulting in skipping of DYSF exon 26 and a frameshift and premature truncation, p.(Tyr882SerfsTer4), with nonsense mediated decay predicted. Activation of an alternate splice donor site in exon 26 predicted to result in an inframe deletion of 8 amino acids, p.(Trp930_Thr937del), was also observed (PMID: 36983702; PVS1_Strong_RNA). These results are consistent with the SpliceAI predictions for this variant: score of 0.97 for donor loss and 0.57 for donor gain. This variant has been detected in at least four individuals with features of LGMD or absent dysferlin protein expression (PMID: 18853459, 26000923, 36983702, 34559919), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 34559919) and confirmed in trans with a likely pathogenic or pathogenic variant in one individual (NM_003494.4: c.2811-20T>G, 1.0 pt, PMID: 36983702) (PM3). In the two other patients, a second DYSF variant was not identified. At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 34559919; PP4_Strong). The filtering allele frequency of this variant is 0.000009455 (the upper threshold of the 95% CI of 5/111184 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Another nucleotide change at the same position, NM_003494.4: c.2810+1G>C, has also been reported in association with LGMD (PMID: 17994539). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/06/2025): PVS1_Strong_RNA, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706298/MONDO:0015152/180 2025-03-06 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3219 biolink:causes UMLS:C0235162 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235162 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0025061 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0340726 infores:hetionet NCBIGene:3735 biolink:causes MONDO:0030893 infores:monarchinitiative not_provided not_provided HGNC:6215 MONDO:0030893 uuid:ef8c8f62-c521-4787-adc4-d38df00312ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0409974 infores:hetionet CHEBI:63598 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0852911 infores:hetionet CHEBI:5165 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0030554 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0042075 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0037274 infores:hetionet CHEBI:251408 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0004093 infores:hetionet CHEBI:3561 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0004093 infores:hetionet NCBIGene:2653 biolink:causes MONDO:0957382 infores:monarchinitiative not_provided not_provided HGNC:4208 MONDO:0957382 uuid:1d8cda72-d057-4068-b558-17706ffb4c86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66903 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0009782 infores:hetionet CHEBI:10650 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0000731 infores:hetionet CHEBI:31397 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0017178 infores:hetionet CHEBI:520985 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0036974 infores:hetionet CAID:CA16615410 biolink:causes MONDO:0007648 infores:clingen CAID:CA16615410 MONDO:0007648 PMID:26580448PMID:17545690PMID:17545690PMID:15235021PMID:17545690PMID:17545690PMID:17545690PMID:15235021PMID:17545690PMID:26580448PMID:15235021PMID:17545690 Pathogenic PM2_Supporting, PS3, PS4 BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PVS1, PM6, BS2, PP3, PP2, PP1, PP4, BP4, BP1, BP2, BP3, BA1, PS1, PS2 The c.2195G>A variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690 15235021). This variant has also been reported in at least 12 families with HDGC criteria (PS4; PMID: 17545690 15235021 and laboratory internal data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS3, PS4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615410/MONDO:0007648/007 2023-11-27 2023-12-22 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:70746 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0006277 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151529 infores:hetionet GO:0060222 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0150063 CHEBI:47519 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0021053 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042075 infores:hetionet CHEBI:3732 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0038325 infores:hetionet CHEBI:41879 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C3665347 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0857189 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0857189 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0029408 infores:hetionet CHEBI:6741 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0041657 infores:hetionet NCBIGene:5784 biolink:causes MONDO:0013324 infores:monarchinitiative not_provided not_provided HGNC:9647 MONDO:0013324 uuid:a3527ccf-d262-482a-9670-edac8ebf877a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018965 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0003123 infores:hetionet NCBIGene:6017 biolink:causes MONDO:0011839 infores:monarchinitiative not_provided not_provided HGNC:10024 MONDO:0011839 uuid:560f1073-7c9e-4f9f-9647-118575ab312a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0518015 infores:hetionet NCBIGene:29927 biolink:causes MONDO:0014891 infores:monarchinitiative not_provided not_provided HGNC:18276 MONDO:0014891 uuid:98c18e95-fd48-49a0-9d7a-1ccdcff4c54b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA340744560 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744560 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting The NM_000329.3(RPE65):c.997G>C (p.Gly333Arg) variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 33952291). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.1059dupG p.Lys354fs variant confirmed in trans (1 point, PMIDs: 31273949, 21602930), which was previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt), congenital night blindness (0.5 pt), absent decreased rod ERG responses (0.5 pt), evidence of cone involvement on ERG (1 pt), symptomatic onset between birth and age five years (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 31273949 & 21602930, PP4). This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.0001925, with 1 / 5194 total allele in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3, PP3_Moderate, PM2_Supporting, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744560/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10023 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0008350 infores:hetionet CHEBI:28787 biolink:causes UMLS:C2230138 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C2230138 infores:hetionet CAID:CA349767 biolink:causes MONDO:0700270 infores:clingen CAID:CA349767 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1 BA1, BS1, PM2 The c.824del (p.Leu275Ter) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMID: 26896183, 21792198, 9463314, 9887333). The c.824del (p.Leu275Ter) variant in ATM has a minor allele frequency in gnomAD v2.1.1 of 0.000018 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA349767/MONDO:0700270/020 2023-09-05 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:46557 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0002871 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0853714 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0005741 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0948089 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036454 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0013922 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0011616 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002525 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0154251 infores:hetionet CHEBI:2611 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0040264 infores:hetionet CHEBI:2666 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0013604 infores:hetionet CHEBI:63607 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020458 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009938 infores:hetionet CAID:CA006476 biolink:causes MONDO:0100316 infores:clingen CAID:CA006476 MONDO:0100316 PMID:29021305 Uncertain Significance BP4, PS4, PS3, BS1, PM2, PM3, PP3 NM_000218.3(KCNQ1):c.1831G>A is a missense variant that causes replacement of aspartic acid with asparagine at position 611. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1, however, two probands lacked the required phenotype details for inclusion in PS4_Supporting, so this code is not yet met (PMID: 19716085, PMID: 19862833, PMID: 22727609, PMID: 33614747). This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had profound congenital deafness but only a borderline QTc interval of 446 ms, with the variant present in a compound heterozygous state, confirmed in trans with the NM_000218.3:c.546C>A (p.Ser182Arg) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID: 27917693). The computational predictor REVEL gives a score of 0.593, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing. The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID: 29021305), so PS3_Supporting is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: None. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006476/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63637 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0042384 infores:hetionet NCBIGene:164 biolink:causes MONDO:0859196 infores:monarchinitiative not_provided not_provided HGNC:555 MONDO:0859196 uuid:fb6b2170-56ec-457a-82c5-81c9e0298268 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA352060789 biolink:causes MONDO:0007356 infores:clingen CAID:CA352060789 MONDO:0007356 PMID: Likely Pathogenic PVS1_Strong, PP4_Moderate, PM2_Supporting PS3 The NM_000249.4: c.1667G>A variant in MLH1 is a missense variant predicted to cause substitution of Serin by Asparagin at amino acid 556 (p.Ser556Asn).PVS1_STR is met since c.1667G>A is a G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. The variant is not reported in gnomAD v4.1 (PM2_supporting). The variant was detected in 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1_STR, PM2_SUP, PP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA352060789/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17026 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0235955 infores:hetionet NCBIGene:57498 biolink:causes MONDO:0015007 infores:monarchinitiative not_provided not_provided HGNC:29508 MONDO:0015007 uuid:fdd17c87-054f-40d5-be38-99eb4fb8ba15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0039231 infores:hetionet CHEBI:46345 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0013604 infores:hetionet CHEBI:36795 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0022107 infores:hetionet CHEBI:3175 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0022568 infores:hetionet CHEBI:9332 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0041969 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151752 infores:hetionet CHEBI:36791 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018681 infores:hetionet CAID:CA367398804 biolink:causes MONDO:0007453 infores:clingen CAID:CA367398804 MONDO:0007453 PMID: Pathogenic PM5_Strong, PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PP1 The c.1133C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to aspartic acid at codon 378 (p.(Ala378Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5-6 unrelated individuals with hyperglycemia (PS4; internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of diabetes or hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.1133C>T (p.Ala378Val) and c.1132G>A (p.Ala378Thr) have been interpreted as pathogenic by the ClinGen MDEP, and p.Ala378Asp has an greater Grantham distance than p.Ala378Val and p.Ala378Thr (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_moderate, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398804/MONDO:0007453/086 2023-11-22 2023-11-22 Semidominant inheritance HP:0032113 Supports UNII:T58MSI464G biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0151763 infores:hetionet CHEBI:6062 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0522055 infores:hetionet CHEBI:6832 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0002994 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C1510497 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0549373 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0018939 infores:hetionet CHEBI:480999 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0009782 infores:hetionet UMLS:C0004609 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0234518 infores:hetionet CHEBI:49662 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002792 infores:hetionet CHEBI:50223 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0015672 infores:hetionet CHEBI:74947 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011606 infores:hetionet CHEBI:61049 biolink:causes MONDO:0009691 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0026948 infores:hetionet CAID:CA8815512 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815512 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 PP4, PM3 "The NM_000152.5:c.1888+5G>T variant alters the donor splice site consensus sequence of intron 13 in GAA. GAA activity is available for 3 patients with this variant (PMID: 33202836; clinical diagnostic laboratories). Although all of these patients have been reported to have reduced GAA activity, they are all heterozygous for the c.2065G>A (p.Glu689Lys) pseudodeficiency variant. These patients were either identified as ""suspected"" late onset Pompe disease by newborn screen (PMID: 33202836, clinical laboratory), or no further clinical information is available (clinical laboratories). Without confirmation that the variant has been found in a patient with characteristics of Pompe disease, other than reduced GAA activity that could be attributed to pseudodeficiency, PP4 is not met at the current time. All 3 patients with documented GAA deficiency are compound heterozygous for the variant along with c.2065G>A (p.Glu689Lys), and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.-32-13T>G (ClinVar Variation ID: 4027) (with c.510C>T, which is believed to be a modifier, typically occurring in cis with c.-32-13T>G), c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) (PMID: 33202836, clinical laboratory), and c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1). However, because PP4 was not met, and it is unclear if these patients have Pompe disease, PM3 is not met at any weight at the current time. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006 (2/33202 alleles) in the Latino population and, in gnomAD v4.1, the highest population MAF is 0.0004094 (24/58624 alleles) in the Admixed American population both of which are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, results from RNA studies on this variant are not available. SpliceAI indicates that the variant has no significant impact on splicing (donor loss score= 0.04; acceptor gain 126 bp downstream, score 0.11=, donor gain 83 bp downstream, score=0.13) (BP4). There is a ClinVar entry for this variant (Variation ID: 283971). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM2_Supporting, BP4(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815512/MONDO:0009290/010 2024-05-21 2024-05-21 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3504 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0948594 infores:hetionet CHEBI:3441 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0015672 infores:hetionet NCBIGene:91754 biolink:causes MONDO:0014870 infores:monarchinitiative not_provided not_provided HGNC:18591 MONDO:0014870 uuid:e29964cc-9d48-42fe-92af-fcfc5ca57ed3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0086565 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0031117 infores:hetionet NCBIGene:388552 biolink:causes MONDO:0013560 infores:monarchinitiative not_provided not_provided HGNC:20914 MONDO:0013560 uuid:ce2b2559-23a7-4896-8dd8-30a279b8cae0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0006444 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0011609 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0854382 infores:hetionet CHEBI:404903 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0233407 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0429098 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0235431 infores:hetionet NCBIGene:676 biolink:causes MONDO:0054725 infores:monarchinitiative not_provided not_provided HGNC:1105 MONDO:0054725 uuid:38839a83-4c27-4937-b5e8-eb4953476372 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0019158 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003864 infores:hetionet CHEBI:42797 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151827 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0549386 infores:hetionet CHEBI:93635 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0027497 infores:hetionet CHEBI:50730 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0030193 infores:hetionet CHEBI:5118 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0241442 infores:hetionet CHEBI:17549 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0030193 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005915 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040262 infores:hetionet CHEBI:16469 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0024103 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0687133 infores:hetionet CHEBI:6472 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0857305 infores:hetionet CHEBI:5128 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0018524 infores:hetionet CHEBI:47898 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0743400 infores:hetionet CHEBI:92712 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0013144 infores:hetionet CHEBI:2687 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0033687 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0429059 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0429059 infores:hetionet CHEBI:92712 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0032343 infores:hetionet CHEBI:63630 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013428 infores:hetionet CHEBI:36795 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0025222 infores:hetionet CHEBI:23765 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0027497 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0038454 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0205204 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020569 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0009450 infores:hetionet CHEBI:2663 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0919924 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0234215 infores:hetionet CHEBI:2611 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0235198 infores:hetionet CAID:CA410148059 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148059 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BA1, BP4, BP2, BP7, BS1, BS3, BS4, PM6, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1118C>A (p.Ser373Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting), and is not expected to undergo nonsense-mediated decay. Instead, this variant is predicted to result in a truncated protein lacking a portion of the transactivation domain (TAD), inhibitory domain (ID), and the VWRPY motif, crucial for protein function, affecting positions c.917-c.1440 of the coding region (PVS1_Strong). This variant is absent from all population databases, including gnomAD v2.1.1 and v4.0.0, with at least 20x coverage for RUNX1 (PM2_supporting). It has been observed in a single proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 32165484). The patient, a 14-year-old male, presented with malaise, poor appetite, night sweats, and intermittent fever persisting for approximately one month. Clinical findings included thrombocytopenia (27x10^9/L), and a subsequent bone marrow biopsy revealed acute myeloid leukemia (AML). Additionally, this variant has been reported in sample #393 (PMID: 21531982) in a case diagnosed with Philadelphia chromosome–negative myeloproliferative neoplasm, although the germline origin was not studied. In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting, PS4_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148059/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5790 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0041657 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0162429 infores:hetionet CAID:CA342562 biolink:causes MONDO:0019497 infores:clingen CAID:CA342562 MONDO:0019497 PMID: Pathogenic PP1_Strong, PP4, PVS1, PM3_Strong PM2 The c.2122C>T (p.Arg708Ter) variant in OTOF has been reported in reported in at least 11 individuals with autosomal recessive nonsyndromic hearing loss, including 2 probands who were compound heterozygous for a second nonsense variant in OTOF (confirmed in trans in one of these cases) and 9 homozygous probands, and segregated with disease in at least 17 affected family members from 7 families (PM3_Strong, PP1_Strong; PMID: 14635104, 18381613, 26029705, 29434063, 19250381; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6). It has also been identified in 0.0162% (4/24,692) of African/African-American alleles in gnomAD v2 (gnomad.broadinstitute.org). The p.Arg708Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 18/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID: 30192042). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6). In summary, the p.Arg708Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_Strong, PP1_Strong, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA342562/MONDO:0019497/005 2021-03-23 2022-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:221927 biolink:causes MONDO:0013784 infores:monarchinitiative not_provided not_provided HGNC:21701 MONDO:0013784 uuid:a964c761-9c33-446c-9fea-7e28b9cd2e19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0032227 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0030554 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0012833 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014742 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0314719 infores:hetionet CHEBI:63618 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0011603 infores:hetionet CHEBI:50924 biolink:causes MONDO:1040026 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0220650 infores:hetionet NCBIGene:1186 biolink:causes MONDO:0008156 infores:monarchinitiative not_provided not_provided HGNC:2025 MONDO:0008156 uuid:78275e07-39e1-41ee-bbe6-82ed57367b26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1258215 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0178298 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013595 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0022904 infores:hetionet CHEBI:8028 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C2830004 infores:hetionet CHEBI:8774 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027424 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0577730 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0577730 infores:hetionet CHEBI:83804 biolink:causes MONDO:0021040 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0030297 infores:hetionet CHEBI:5134 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0347390 infores:hetionet CAID:CA10585332 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585332 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP2, PS3, PM5, PP3 The NM_000527.5 (LDLR):c.1158C>G (p.Asp386Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent in gnomAD (gnomAD v2.1.1).PP4: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585332/MONDO:0007750/013 2022-03-25 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63621 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043037 infores:hetionet GO:0061888 biolink:causes GO:0014002 infores:ubergraph knowledge_assertion manual_agent GO:0061888 GO:0014002 PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2748540 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0032131 infores:hetionet GO:0005768 biolink:causes GO:0016197 infores:ubergraph knowledge_assertion manual_agent GO:0005768 GO:0016197 CHEBI:100241 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085605 infores:hetionet CHEBI:63618 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0236075 infores:hetionet CHEBI:6904 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0013395 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0008325 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0021141 infores:hetionet CHEBI:7959 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0017675 infores:hetionet CHEBI:8404 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0040822 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0234215 infores:hetionet CHEBI:7956 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0015230 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0027765 infores:hetionet CHEBI:3219 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0237314 infores:hetionet CHEBI:168396 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151942 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0025061 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0413252 infores:hetionet CHEBI:37941 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0003467 infores:hetionet CHEBI:135930 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0033774 infores:hetionet CHEBI:64318 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0428977 infores:hetionet CHEBI:50275 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085593 infores:hetionet CHEBI:209807 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0020649 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0392525 infores:hetionet CHEBI:5864 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023211 infores:hetionet CHEBI:83804 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042029 infores:hetionet CHEBI:6846 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0027769 infores:hetionet CAID:CA010537 biolink:causes MONDO:0005045 infores:clingen CAID:CA010537 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PP3, PP1, PS4_Supporting PP4, PM5, PM6, PM4, BA1, PS3, BS1, BS3, BS4, PS1, PS2, BP4, BP2, BP5, BP7, PVS1 The c.1318G>A (p.Val440Met) variant in MYH7 has been reported in at least 3 individuals with HCM (PS4_Supporting; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Walsh 2017 PMID:27532257; LMM pers comm.; OMGL pers comm.) and 1 individual with RCM (Invitae pers comm.). This variant segregated with HCM in 3 affected relatives from 3 families (PP1; LMM pers comm.; OMGL pers comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PP1; PM2; PM1; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010537/MONDO:0005045/002 2020-08-12 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44185 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0015230 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0521839 infores:hetionet NCBIGene:3839 biolink:causes MONDO:0859309 infores:monarchinitiative not_provided not_provided HGNC:6396 MONDO:0859309 uuid:060324d3-5111-4b12-9832-fae1e95f2af4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135888 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0151505 infores:hetionet CHEBI:72564 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020458 infores:hetionet CHEBI:17334 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0012833 infores:hetionet CHEBI:41423 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0438142 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0032285 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0948521 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0948521 infores:hetionet CAID:CA350341771 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341771 MONDO:0015924 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3, PM1 BS2, BA1, BP4, PS1, PM5, BS1, BS3 The BMPR2 c.1171G>A variant is a missense variant predicted to cause substitution of alanine to threonine at amino acid position 391 (p.(Ala391Thr)). The variant was absent in gnomAD v.4.1.0, so PM2_supporting is met (but not BA1, BS1 nor BS2). Computational predictor REVEL score is 0.86, which is ≥0.75, and AlphaMissense = 0.9729, so PP3 is met and BP4 is not met. This variant is located in the kinase domain (aa 203-504), hence PM1 is met. It does not affect known critical or non-critical amino acids. The variant has been reported in at least two presumably unrelated individuals with IPAH from French (PMID: 18356561) and Spanish cohorts (PMID: 33007923). Another individual with IPAH was reported in Machado et al. (2009) (PMID:19555857) but it was not clear whether it referred to the same individual as in PMID: 18356561, and another report of the French cohort (PMID: 25429696) likely referred to the same individual as in PMID: 18356561. Hence, PS4_supporting was met as the variant was found in >1 PAH patient. PP1, PS2, PM6 were not met due to the absence of co-segregation data. Experimental evidence demonstraed abolished BMPR2-SMAD signaling via a BRE2-Luc vector luciferase assay in murine embryonic endothelial cells that included appropriate controls and replicates (PS3 met). A different missense variant affecting the same amino acid, c.1172C>A p.(Ala391Asp), was reported in an IPAH individual (PMID: 31727138) but was scored as VUS (PM1, PM2_supporting, PM5_supporting, PP3) thus, PM5 was not met. In summary, this variant meets the criteria to be classified as a likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341771/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9571 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0003123 infores:hetionet CHEBI:48273 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0031350 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042514 infores:hetionet CHEBI:3757 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C2047937 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0003123 infores:hetionet CHEBI:3568 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014356 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0403632 infores:hetionet CHEBI:10102 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085593 infores:hetionet CHEBI:16755 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0038990 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027769 infores:hetionet CHEBI:53760 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C2830004 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C1443060 infores:hetionet NCBIGene:3658 biolink:causes MONDO:0032758 infores:monarchinitiative not_provided not_provided HGNC:6115 MONDO:0032758 uuid:5fcf8983-50c6-4285-a0c9-89db467802e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0917801 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0151763 infores:hetionet CHEBI:7565 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0043144 infores:hetionet CHEBI:41423 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0022346 infores:hetionet NCBIGene:22926 biolink:causes MONDO:0014677 infores:monarchinitiative not_provided not_provided HGNC:791 MONDO:0014677 uuid:e23040c5-a581-418d-91f3-ad42d90644d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0518015 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014868 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0595882 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0595882 infores:hetionet CHEBI:2549 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0015967 infores:hetionet CHEBI:10102 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0010692 infores:hetionet GO:0061132 biolink:causes GO:0061130 infores:ubergraph knowledge_assertion manual_agent GO:0061132 GO:0061130 NCBIGene:80736 biolink:causes MONDO:0033259 infores:monarchinitiative not_provided not_provided HGNC:13941 MONDO:0033259 uuid:1d3e10bb-e03a-441c-b1cb-9d8a279b9237 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085605 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0027765 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0267792 infores:hetionet CHEBI:50131 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0030232 infores:hetionet CHEBI:3048 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0038454 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0011603 infores:hetionet CAID:CA399802454 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802454 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PP1, PM2_Supporting, PM3_Supporting The c.1600+1G>A variant in ITGA2B occurs within the canonical splice donor site of intron 16. It is predicted to cause skipping of biologically-relevant-exon 16, resulting in a frameshift with a premature stop codon in exon 18, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This prediction is supported by a SpliceAI Donor Loss score of 0.98. At least two patients (Patients 11 and 12 in PMID: 19172520) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% (from GT database), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. (PP4_moderate). This variant has been reported to segregate with Glanzmann thrombasthenia (confirmed by bleeding phenotype and platelet aggregometry) in the proband plus one affected family member, both with the homozygous genotype with the NM_000419.5(ITGA2B):c.1600+1G>A variant. (PP1; PMID: 19172520). This variant has been detected in the homozygous state in at least 2 probands with Glanzmann thrombasthenia. However, these two individuals are related (PMID: 19172520) and only one affected individual per family can be counted towards PM3. Total points: 0.5 (PM3_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant is not registered in ClinVar. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PP1, PM3_Supporting and PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802454/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5141 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0031542 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032584 infores:hetionet CHEBI:8871 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0600228 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0021845 infores:hetionet CHEBI:127780 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0013604 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0001824 infores:hetionet CHEBI:9725 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0234428 infores:hetionet CHEBI:9943 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0019572 infores:hetionet CHEBI:6832 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0428977 infores:hetionet GO:2000387 biolink:causes GO:0008585 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0008585 CHEBI:63608 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0002622 infores:hetionet CHEBI:8435 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0221152 infores:hetionet CHEBI:4856 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0424790 infores:hetionet CHEBI:4911 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0036690 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0424786 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0424786 infores:hetionet CHEBI:31348 biolink:causes HP:0012764 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085619 infores:hetionet CHEBI:6640 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0042963 infores:hetionet CHEBI:6367 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0086439 infores:hetionet CHEBI:119573 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0011603 infores:hetionet CHEBI:49575 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151786 infores:hetionet CHEBI:7494 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0497156 infores:hetionet CHEBI:31236 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233407 infores:hetionet CHEBI:3568 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011206 infores:hetionet CHEBI:63619 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0043094 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042267 infores:hetionet CHEBI:50305 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0151907 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020557 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085611 infores:hetionet CHEBI:3696 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0520966 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0235431 infores:hetionet CHEBI:8768 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0001925 infores:hetionet CHEBI:6541 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0009763 infores:hetionet CHEBI:63635 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0017152 infores:hetionet CHEBI:9637 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0004238 infores:hetionet NCBIGene:91147 biolink:causes MONDO:0013302 infores:monarchinitiative not_provided not_provided HGNC:28396 MONDO:0013302 uuid:01acabe8-f312-4d22-a3a3-d505ad015176 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0004936 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018790 infores:hetionet CHEBI:3403 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0232493 infores:hetionet CHEBI:65173 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0011253 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0022660 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151589 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151589 infores:hetionet CHEBI:68554 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0002792 infores:hetionet CHEBI:8869 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0015230 infores:hetionet CHEBI:17263 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0012833 infores:hetionet CHEBI:3756 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0549567 infores:hetionet CAID:CA10582615 biolink:causes MONDO:0008535 infores:clingen CAID:CA10582615 MONDO:0008535 PMID: Pathogenic PP3, PP1, PM2_Supporting, PP4_Moderate, PS4, PS3_Supporting The NM_001114753.3: c.447G>C variant in ENG is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 149 (p.Trp149Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent with HHT (PS4; PMID: 9554745, 22022569, 22991266, 32300199, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in 3 affected individuals of a family (4 generations) (PP1; PMID: 10545596). The computational predictor REVEL gives a score of 0.762, which is above the threshold of ≥0.644, evidence that correlates with impact to ENG function (PP3). Additionally, expression studies in endoglin-deficient mice, human umbilical vein endothelial cells (HUVECs) and peripheral blood activated monocytes showed reduced expression of fully processed normal endoglin indicating that this variant impacts protein function (PS3_Supporting; PMID: 10545596, 11343967, 10749981). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PP3, PP4_Moderate, PS4, PS3_Supporting, PP1 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10582615/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135351 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0541798 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0040034 infores:hetionet CAID:CA410147875 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147875 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1172C>A (p.Ala391Glu) is a missense variant which has a REVEL score < 0.50 (0.032), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147875/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:79659 biolink:causes MONDO:0013127 infores:monarchinitiative not_provided not_provided HGNC:2962 MONDO:0013127 uuid:d5433e26-da46-45b8-8104-b873a26c8fa1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17141 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0027769 infores:hetionet CHEBI:205919 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0002170 infores:hetionet NCBIGene:3229 biolink:causes MONDO:0013976 infores:monarchinitiative not_provided not_provided HGNC:5125 MONDO:0013976 uuid:a5ed7d26-afc8-480d-8a5b-6ae6d33c17db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C2242996 infores:hetionet CHEBI:16469 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020598 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C1167732 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C1167732 infores:hetionet CHEBI:7465 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0232292 infores:hetionet CHEBI:7931 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0004096 infores:hetionet CHEBI:63598 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0851578 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0549475 infores:hetionet NCBIGene:55823 biolink:causes MONDO:0014732 infores:monarchinitiative not_provided not_provided HGNC:14583 MONDO:0014732 uuid:d8e8e72f-d90a-461e-a7e5-6f6014dea0f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:9948 biolink:causes MONDO:0007883 infores:monarchinitiative not_provided not_provided HGNC:12754 MONDO:0007883 uuid:79718cb6-bc06-4805-9609-4a4f2794934c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0005940 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006384 infores:hetionet CHEBI:8776 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0338831 infores:hetionet CHEBI:27796 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0020517 infores:hetionet CHEBI:31401 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0740394 infores:hetionet CHEBI:78543 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0344232 infores:hetionet GO:1900032 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900032 GO:0007275 CHEBI:9288 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0235996 infores:hetionet CHEBI:27899 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0032617 infores:hetionet CHEBI:68845 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0004093 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0042109 infores:hetionet CHEBI:2704 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0232462 infores:hetionet CHEBI:9586 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0231528 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0018801 infores:hetionet CAID:CA390869081 biolink:causes MONDO:0100216 infores:clingen CAID:CA390869081 MONDO:0100216 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PVS1, BA1, BP4, BP2, PP1, BS2, PM5, PM4, PM1, PS1, PS3, PS2, PS4, BP7, BS1, BS3, BS4 The NM_177438.3:c.4361A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1454 (p.Asp1454Gly). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with phenotypes of DICER1-related tumor predisposition warranting points application (PS4 not met; Internal lab contributors). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on Wilms tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, Internal contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). While in silico tools do not predict damaging impact of the variant on protein function (REVEL: 0.587), the splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PP3, PP4. (Bayesian Points: 3; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390869081/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0877322 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0155169 infores:hetionet CHEBI:10102 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0042023 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004239 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0852913 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0017601 infores:hetionet CHEBI:17688 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0232487 infores:hetionet CHEBI:9352 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0002994 infores:hetionet CAID:CA915950778 biolink:causes MONDO:0100039 infores:clingen CAID:CA915950778 MONDO:0100039 PMID: Pathogenic PVS1, PS2, PM2_Supporting The p.Tyr941fs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Tyr941fs variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database) (PS2). The p.Tyr941fs variant in CDKL5 is absent from gnomAD (PM2_Supporting). In summary, the p.Tyr941fs variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PS2, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915950778/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:37333 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0031350 infores:hetionet CHEBI:50924 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0239981 infores:hetionet CHEBI:68579 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0017565 infores:hetionet CHEBI:101853 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0033774 infores:hetionet CHEBI:127342 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0037763 infores:hetionet CHEBI:50922 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0542571 infores:hetionet CHEBI:119915 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0549622 infores:hetionet CHEBI:5100 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0027497 infores:hetionet CHEBI:4784 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0013604 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0021053 infores:hetionet CHEBI:92607 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0027765 infores:hetionet CHEBI:5296 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0035455 infores:hetionet CAID:CA376066033 biolink:causes MONDO:0011225 infores:clingen CAID:CA376066033 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2, PS3 The c.34C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Proline by Serine at amino acid 12 (p.Pro12Ser). This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376066033/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:49575 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0575090 infores:hetionet CHEBI:64354 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020538 infores:hetionet CHEBI:9599 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0152030 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042109 infores:hetionet CAID:CA410208234 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208234 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.38A>T (p.Tyr13Phe) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score < 0.50, suggesting a permissive effect (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208234/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:85078 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042023 infores:hetionet CHEBI:36704 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0085631 infores:hetionet CHEBI:52172 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151908 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0267792 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0031117 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0232492 infores:hetionet CHEBI:100241 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022281 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0740425 infores:hetionet CHEBI:175901 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0033774 infores:hetionet CHEBI:4027 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0037763 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0746883 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0036572 infores:hetionet CHEBI:31401 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0206062 infores:hetionet CHEBI:3077 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0002792 infores:hetionet CHEBI:31401 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0001925 infores:hetionet CHEBI:91583 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0017178 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0009450 infores:hetionet CHEBI:5775 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0085631 infores:hetionet CHEBI:9123 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085636 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0234215 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002418 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0004936 infores:hetionet CHEBI:3216 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0542571 infores:hetionet CAID:CA347220902 biolink:causes MONDO:0015152 infores:clingen CAID:CA347220902 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4_Strong, PP3, PM2_Supporting PM5 The NM_003494.4: c.5059T>C variant in DYSF, which is also known as NM_001130987.2: c.5176T>C p.(Ser1726Pro), is a missense variant predicted to cause substitution of serine by proline at amino acid 1687, p.(Ser1687Pro). This variant has been identified in one individual with a diagnosis of LGMD, where it it was confirmed in trans with a variant classified as pathogenic by the LGMD VCEP (c.2643+1G>A, 1.0 pt, PMID: 36983702) (PM3). This patient displayed progressive limb girdle muscle weakness and significantly reduced or absent dysferlin protein expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.8, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/28/2025): PM3, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347220902/MONDO:0015152/180 2025-01-28 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10023 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151735 infores:hetionet CHEBI:63620 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042510 infores:hetionet CHEBI:63611 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0520966 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151826 infores:hetionet CHEBI:4953 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0009676 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0235431 infores:hetionet CHEBI:63611 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020580 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027092 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0038587 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C2225524 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0241266 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0241266 infores:hetionet CHEBI:10101 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1368065 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042267 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0015397 infores:hetionet NCBIGene:284086 biolink:causes MONDO:0971178 infores:monarchinitiative not_provided not_provided HGNC:13387 MONDO:0971178 uuid:d830862f-1325-4a59-be5f-ddffad3810e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0032285 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0016204 infores:hetionet CAID:CA412737713 biolink:causes MONDO:0100437 infores:clingen CAID:CA412737713 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1506+1G>T is a canonical splice site variant in intron 12 that is predicted to disrupt splicing and induce skipping of out-of-frame exon 12, which is expected to introduce a premature stop codon and trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 36835250). This variant has been reported in at least 2 apparently unrelated probands (PMID: 34745198, PMID: 36835250). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, or decreased or absent lectroretinogram responses was fewer than the requirement of at least 2, so PS4_Supporting was not met. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PP1, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412737713/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:66964 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0234215 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0018021 infores:hetionet CAID:CA1244318 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244318 MONDO:0005338 PMID: Likely Benign BP4 BP7, BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.154A>G variant in MYOC is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 52 (p.Ser52Gly). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.0004010 (18 alleles out of 44,888), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.036, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244318/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63580 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0271051 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0009938 infores:hetionet GO:0060224 biolink:causes GO:0060042 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0060042 CHEBI:9086 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0003537 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0013395 infores:hetionet CHEBI:6367 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020453 infores:hetionet CHEBI:63580 biolink:causes MONDO:0018092 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042170 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0948594 infores:hetionet CHEBI:31859 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0009763 infores:hetionet CHEBI:8404 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0002871 infores:hetionet CHEBI:37941 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019079 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0020538 infores:hetionet CHEBI:10112 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0231528 infores:hetionet CHEBI:4877 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0003123 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0178298 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0007787 infores:hetionet CAID:CA410208127 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208127 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BA1, BP4, BP2, PM2, PM6, PVS1, BP7, BS1, BS3, BS4, PM5, PM4, PP3, PP1 NM_001754.5(RUNX1):c.523C>G (p.Leu175Val) is a missense variant which has been found in one individual from gnomAD v2.1.1 (MAF: 0.000003976). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208127/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3011 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0030554 infores:hetionet NCBIGene:1690 biolink:causes MONDO:0011058 infores:monarchinitiative not_provided not_provided HGNC:2180 MONDO:0011058 uuid:a9fb60f5-ad9b-4ae5-abca-c48e78f1c4f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0233407 infores:hetionet CHEBI:4466 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C3665347 infores:hetionet NCBIGene:27152 biolink:causes MONDO:0033375 infores:monarchinitiative not_provided not_provided HGNC:29239 MONDO:0033375 uuid:f0319420-b18a-4b19-bdc5-15e12d7b8e3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0013144 infores:hetionet CHEBI:71940 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0033774 infores:hetionet CHEBI:10102 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151907 infores:hetionet CHEBI:23765 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0038325 infores:hetionet CHEBI:8356 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023380 infores:hetionet CHEBI:100241 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0877055 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0497327 infores:hetionet CHEBI:17334 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020461 infores:hetionet CHEBI:74947 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0549249 infores:hetionet CHEBI:6367 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027497 infores:hetionet CAID:CA036744 biolink:causes MONDO:0007750 infores:clingen CAID:CA036744 MONDO:0007750 PMID: Uncertain Significance BP4, PS4, PM5, PM2, PP3, PP4 The NM_000527.5 (LDLR): c. 1816G>A (p.Ala606Thr) variant is classified as Uncertain significance -insufficient evidence for Familial Hypercholesterolemia as no evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 not Met: PopMax MAF = 0.0002024 in Latino population in gnomAD (gnomAD v2.1.1), and PopMAX MAF = 0.00043 in Latino population in ExAC (ExAC v0.3.1).PP3 not Met: REVEL = 0.725, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. The variant is exonic and located at least 50 bases downstream of authentic acceptor site, but it does not create GT. The variant is not on limit creating de novo acceptor site. Therefore, this variant is not predicted to alter splicing.BP4 not applicable: REVEL score for this variant is not below 0.5, BP4 is not applicable.PP4, PS4 not applicable: Variant did not meet PM2.PM5 not met: There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1817C>A (p.Ala606Asp), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036744/MONDO:0007750/013 2022-05-08 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:27834 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0009676 infores:hetionet CHEBI:68606 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0023787 infores:hetionet CAID:CA170773 biolink:causes MONDO:0015967 infores:clingen CAID:CA170773 MONDO:0015967 PMID: Pathogenic PS2_Very Strong, PP4_Moderate, PP3, PM2_Supporting, PM5, PM1, PS4, PP1_Strong The c.187C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 63 (p.(Arg63Trp) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 24285859, 25819479, 28693455, internal lab contributors). This variant segregated with diabetes, with at least 7 meioses in 4 families (PP1_Strong, PMID: 24285859, 28693455, internal lab contributors). At least 6 individuals have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and Fanconi phenotype) (PP4_Moderate; internal lab contributors). Additionally, this variant was identified as a de novo occurrence with both confirmed and unconfirmed parental relationships in 5 individual(s) with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Very Strong; internal lab contributor, PMID: 24285859, 25819479). This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, another missense variant, c.188G>A (p.Arg63Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg63Trp has a greater Grantham distance (PM5). In summary, c.187C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS2_Very strong, PP1_Strong, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA170773/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:39669 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0013428 infores:hetionet CHEBI:31711 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0751494 infores:hetionet CHEBI:3723 biolink:causes HP:0033842 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0239233 infores:hetionet CHEBI:27777 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0011570 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151735 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151888 infores:hetionet CHEBI:31401 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0039070 infores:hetionet CHEBI:50922 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151827 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0522224 infores:hetionet CHEBI:9123 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011168 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027720 infores:hetionet CHEBI:6128 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0030252 infores:hetionet CHEBI:50885 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0231528 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0235280 infores:hetionet CHEBI:134966 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0027441 infores:hetionet CHEBI:584020 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0042963 infores:hetionet CHEBI:3219 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0149745 infores:hetionet CHEBI:3996 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0344232 infores:hetionet CHEBI:7581 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0027497 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0265031 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0877046 infores:hetionet CHEBI:85078 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0029453 infores:hetionet CHEBI:47381 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0149745 infores:hetionet CAID:CA184631 biolink:causes MONDO:0019501 infores:clingen CAID:CA184631 MONDO:0019501 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PM6, PVS1, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.8177G>A variant in USH2A is a missense variant predicted to cause substitution of glycine to glutamic acid at amino acid 2726. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/111282 alleles) in the European population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.406, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. The variant has been detected in heterozygosity without a second variant in one female proband from the Laboratory of Molecular Medicine with mild to moderate sensorineural hearing loss and other syndromic features (SCV000206052.5). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 9/26/2023) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA184631/MONDO:0019501/005 2023-09-26 2023-10-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:15544 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0030846 infores:hetionet CHEBI:101278 biolink:causes UMLS:C1536074 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C1536074 infores:hetionet CHEBI:8481 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0013144 infores:hetionet CHEBI:8888 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085932 infores:hetionet CHEBI:10125 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0497156 infores:hetionet NCBIGene:2982 biolink:causes MONDO:0014331 infores:monarchinitiative not_provided not_provided HGNC:4685 MONDO:0014331 uuid:19c0a5ea-dca3-4ace-99c4-a18d11c2efc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013595 infores:hetionet CHEBI:5847 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0085605 infores:hetionet CHEBI:6149 biolink:causes MONDO:0001294 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0019937 infores:hetionet CAID:CA512341018 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341018 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1338C>G (p.Leu446=) is a synonymous variant that is not predicted to impact splicing. Since it is a synonymous variant, no REVEL score is applicable, and SpliceAI is ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.004 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341018/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51041 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0392025 infores:hetionet CHEBI:51173 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0085631 infores:hetionet GO:0150011 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:0150011 GO:0030182 CHEBI:9086 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151603 infores:hetionet CHEBI:51209 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0341742 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151883 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0234987 infores:hetionet CHEBI:70746 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0015230 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0234215 infores:hetionet CHEBI:31711 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0015644 infores:hetionet CHEBI:168396 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151723 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0235234 infores:hetionet CHEBI:42944 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003467 infores:hetionet CHEBI:63630 biolink:causes MONDO:0021353 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042138 infores:hetionet CHEBI:10124 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0011175 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0040046 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006266 infores:hetionet CHEBI:50692 biolink:causes MONDO:0000918 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0014179 infores:hetionet CHEBI:31485 biolink:causes UMLS:C1328375 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C1328375 infores:hetionet CAID:CA414914390 biolink:causes MONDO:0010602 infores:clingen CAID:CA414914390 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PS1_Moderate, PM5, PM2_Supporting, PP3, PS4_Moderate PM1 The variant, NM_000132.3(F8):c.1420G>A, predicts a missense change, Gly474Arg, which is not reported in gnomAD v2.1.1 or v3. This variant has been reported in at least three patients with severe or mild-moderate Hemophilia A in the literature (PMID: 9603440, 16972227, 29296726) meeting PS4_Moderate and PP4_Moderate criteria. The variant has a REVEL score of 0.972 (threshold >0.6) meeting criteria for PP3. Another nucleotide change at the same codon, c.1421G>A (p.Gly474Glu) is classified as pathogenic by CFD-VCEP meeting criteria for PM5. In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PM5, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414914390/MONDO:0010602/071 2024-09-30 2024-10-01 X-linked inheritance HP:0001417 Supports NCBIGene:283459 biolink:causes MONDO:0030008 infores:monarchinitiative not_provided not_provided HGNC:25068 MONDO:0030008 uuid:082d8f16-a3f3-4237-9370-5f8bfe174e20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes HP:0025116 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0015930 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0020517 infores:hetionet CHEBI:7494 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0033774 infores:hetionet CHEBI:45979 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0278134 infores:hetionet CHEBI:4975 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0003811 infores:hetionet CHEBI:3127 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0006266 infores:hetionet CHEBI:9130 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0003811 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0012833 infores:hetionet CHEBI:8428 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0028961 infores:hetionet CHEBI:182080 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0042963 infores:hetionet CHEBI:9086 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0022661 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0919980 infores:hetionet CHEBI:8764 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042029 infores:hetionet NCBIGene:93035 biolink:causes MONDO:0968981 infores:monarchinitiative not_provided not_provided HGNC:20313 MONDO:0968981 uuid:6523c2ff-e6da-48f5-b631-dee57ea54aaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0009782 infores:hetionet CHEBI:15367 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013604 infores:hetionet CHEBI:8871 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C2240374 infores:hetionet CHEBI:135005 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0039231 infores:hetionet CAID:CA341869 biolink:causes MONDO:0012996 infores:clingen CAID:CA341869 MONDO:0012996 PMID: Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1 The NM_001482.3:c.484+1G>T variant in GATM occurs within the canonical splice donor site of intron 3. It was shown by RT-PCR to cause skipping of exon 3, resulting in a frameshift, premature termination codon, and nonsense-mediated decay (PMID: 22386973) (PVS1). One individual who is homozygous for the variant has been reported with significantly decreased creatine peak on H1-MRS, nondetectable enzyme activity in cultured lymphoblasts, and low GAA in plasma and low creatine in plasma (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 (1/18394) in the East Asian population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The variant is noted in ClinVar (Variation ID: 21299). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA341869/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:2896 biolink:causes MONDO:0013866 infores:monarchinitiative not_provided not_provided HGNC:4601 MONDO:0013866 uuid:3b4fd180-6235-462b-8548-25426ba9b791 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4735 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0151904 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0149931 infores:hetionet CHEBI:7986 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0917801 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0017152 infores:hetionet CHEBI:2668 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0018681 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235315 infores:hetionet CAID:CA343772388 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772388 MONDO:0013144 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting The c.1312A>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 438 (p.Arg438Gly). The variant is absent from gnomAD v2.1.1, v3.1, v4.0.0 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.752, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant has been reported in a single patient with an antithrombin activity level of 45-53% meeting the SERPINC1-phenotypic criteria (AT level of <0.8 IU/mL) (PS4_Supporting). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PP3, PM2_Supporting, PS4_ Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772388/MONDO:0013144/084 2024-02-19 2024-02-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63638 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0021400 infores:hetionet UMLS:C1709429 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0013404 infores:hetionet CHEBI:8024 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030554 infores:hetionet CHEBI:6367 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003578 infores:hetionet CHEBI:36795 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0035305 infores:hetionet CHEBI:3752 biolink:causes MONDO:0958083 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0041428 infores:hetionet NCBIGene:78995 biolink:causes MONDO:0971176 infores:monarchinitiative not_provided not_provided HGNC:28460 MONDO:0971176 uuid:6eeeb1b1-9985-4c89-a2b3-a79a5556dfbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:161680 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0019158 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151885 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0027651 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0856151 infores:hetionet CHEBI:50742 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0001144 infores:hetionet UMLS:C0004609 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151904 infores:hetionet CHEBI:31236 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1260880 infores:hetionet CHEBI:63631 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014518 infores:hetionet CHEBI:5775 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0232459 infores:hetionet CHEBI:71940 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0017178 infores:hetionet CHEBI:9649 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0428974 infores:hetionet CHEBI:50659 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0267792 infores:hetionet CHEBI:64064 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0424295 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0917799 infores:hetionet CAID:CA658658444 biolink:causes MONDO:0700272 infores:clingen CAID:CA658658444 MONDO:0700272 PMID: Pathogenic PP1_Moderate, PM5_Supporting, PVS1, PM2_Supporting The c.514_517del (p.Ser172fs) variant in PALB2 is a frameshift variant predicted to result in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant was found to co-segregate with disease in multiple affected family members in one family (Invitae). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM2_Supporting, PP1_Moderate) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658444/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4702 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0003862 infores:hetionet NCBIGene:64421 biolink:causes MONDO:0011225 infores:monarchinitiative not_provided not_provided HGNC:17642 MONDO:0011225 uuid:c8b4136f-69c6-4d7b-a77c-23e327996a96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes UMLS:C0239725 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0239725 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0003864 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003813 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0876973 infores:hetionet CHEBI:8874 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0032227 infores:hetionet CHEBI:63638 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0151836 infores:hetionet CHEBI:4798 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042023 infores:hetionet CAID:CA367399714 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399714 MONDO:0015967 PMID: Likely Pathogenic PS4, PP4_Moderate, PP2, PP3, PM2_Supporting PM1, PP1 The c.1010A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 337 (p.(Gln337Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in nine unrelated individuals with hyperglycemia (PS4; PMIDs: 24918535, 36257325, 19790256, and internal lab contributors). Furthermore, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 36257325). In summary, c.1010A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PS4, PP4_Moderate, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399714/MONDO:0015967/086 2025-01-29 2025-01-29 Semidominant inheritance HP:0032113 Supports CHEBI:63115 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0021400 infores:hetionet CHEBI:50659 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0178298 infores:hetionet CHEBI:45081 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0016927 infores:hetionet CHEBI:63611 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0027497 infores:hetionet CHEBI:42797 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013144 infores:hetionet CAID:CA512318619 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318619 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP3, BP1, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PP2, PP3, PP1, PP4 The c.702A>G (p.Thr234=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4). In addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -0.138811 in GRCh38), and the variant is the reference nucleotide in one primate and/or three mammal species. Although the variant is absent from gnomAD v2 and v3 (PM2_Supporting), it has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318619/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48947 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0022354 infores:hetionet UMLS:C0145185 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0236075 infores:hetionet CHEBI:6690 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0018794 infores:hetionet CHEBI:4735 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0595916 infores:hetionet CHEBI:7577 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C2979982 infores:hetionet CHEBI:9654 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0002871 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038362 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0042109 infores:hetionet CHEBI:50693 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0003811 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0424000 infores:hetionet CHEBI:51164 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0085649 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0349506 infores:hetionet CHEBI:188986 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151205 infores:hetionet CHEBI:7852 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0855775 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0042109 infores:hetionet CHEBI:100147 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0008370 infores:hetionet CHEBI:63611 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0015468 infores:hetionet CHEBI:7903 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0039070 infores:hetionet CHEBI:171719 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0026961 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0235351 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0345904 infores:hetionet CHEBI:9288 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0041834 infores:hetionet CHEBI:50673 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0011603 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0242656 infores:hetionet CAID:CA957176 biolink:causes MONDO:0800406 infores:clingen CAID:CA957176 MONDO:0800406 PMID: Likely Benign BP7, PM2_Supporting BP4, PS4 The NM_000350.3:c.5712A>G variant is a synonymous variant (p.Gln1904=). The total minor allele frequency in gnomAD v4.1.0 is 0.00006753 (109/1614110 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting). SpliceAI gives this synonymous variant a delta score of 0.05 for donor gain, which is below the ClinGen ABCA4 VCEP threshold of <0.1 and does not strongly predict a splicing defect. To our knowledge, there is no known conflicting minigene or other functional data available (BP7_Moderate). In summary, this variant meets the criteria to be classified as likely benign for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): BP7_Moderate, PM2_Supporting. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA957176/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9137 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0021843 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0919582 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0919582 infores:hetionet CAID:CA023836 biolink:causes MONDO:0100150 infores:clingen CAID:CA023836 MONDO:0100150 PMID: Pathogenic PS3_Supporting, PP4, PP1, PM3_Very Strong The variant NM_000540.3(RYR1):c.10348-6C>G in RYR1 is an intronic variant located in intron 68. The filtering allele frequency is 0.0003329 (34/75078 alleles, 0 homozygotes) for the African/African American population, which meets no codes. In addition, the SpliceAI Acceptor Loss value is 0.47. The variant was found in compound heterozygosity with variants of uncertain significance, likely pathogenic, or pathogenic variants in 22 patients (PM3_Very Strong; PMIDs: 18253926, 21062345, 20839240, 23553484, 28818389, 30932294, 31069529, 30611313, 34440373, 35627144, 35616356, 36939041). At least 3 patients with this variant displayed ophthalmoparesis and presence of cores on muscle biopsy, which is highly specific for RYR1-related myopathy (PP4; PMID: 20839240). This variant has been observed in at least 11 South African patients with RYR1-related myopathy, suggesting a possible founder variant (PMID: 20839240). The variant has also been reported in cis with the c.14524G>A (p.Val4842Met) variant in 17 of the 22 probands, which is part of a known haplotype and has been reported as a compound heterozygous change in individuals with RYR1-related myopathies (PMIDs: 18253926, 21062345, 20839240, 23553484, 30932294, 30611313, 35627144). The variant has been found to segregate with disease in 4 affected relatives from 2 families (PP1; PMIDs: 18253926, 21062345). Functional studies in patient cells showed that the variant resulted in a loss of splicing of intron 68 and the introduction of a premature stop codon causing the mRNA to undergo NMD (PMIDs: 18253926, 25525159) (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_Very Strong, PP4, PP1, PS3_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2; May 19th, 2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA023836/MONDO:0100150/179 2025-05-19 2025-06-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63631 biolink:causes MONDO:0003038 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234144 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017658 infores:hetionet CAID:CA7330607 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330607 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PVS1, PM6, BP2, BA1, BS2, PP3, PP1, PP4, PM4, PM5, PM1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4 The NM_177438.2:c.5641A>G variant in DICER1 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 1881 (p.Thr1881Ala). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met, Internal lab contributors). This variant has an allele frequency of 0.0000006195 (1/1614186 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.378; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.1.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330607/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31348 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0851341 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0014549 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0004623 infores:hetionet CHEBI:51041 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151836 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0012813 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0006852 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0234215 infores:hetionet CAID:CA410148349 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148349 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1048C>T (p.Pro350Ser) is a missense variant which has a REVEL score < 0.50 (0.338) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148349/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10124 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0152227 infores:hetionet CHEBI:135276 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0085633 infores:hetionet CHEBI:5613 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011603 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0521591 infores:hetionet CHEBI:6402 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0085649 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0015469 infores:hetionet CHEBI:2208 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0042963 infores:hetionet GO:0003250 biolink:causes GO:0003170 infores:ubergraph knowledge_assertion manual_agent GO:0003250 GO:0003170 CHEBI:4027 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0085631 infores:hetionet CHEBI:63612 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0085624 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0034069 infores:hetionet CHEBI:32293 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0031350 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0019054 infores:hetionet CHEBI:8364 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0042963 infores:hetionet NCBIGene:1471 biolink:causes MONDO:0007098 infores:monarchinitiative not_provided not_provided HGNC:2475 MONDO:0007098 uuid:ebb3dfea-65a3-4897-bd59-de8d1bc8b789 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0243026 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0162830 infores:hetionet NCBIGene:10654 biolink:causes MONDO:0008290 infores:monarchinitiative not_provided not_provided HGNC:9141 MONDO:0008290 uuid:cbb5345a-09ed-4970-9218-5682e9dd78cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0033117 infores:hetionet CHEBI:5296 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0042384 infores:hetionet UMLS:C0004609 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0235063 infores:hetionet CAID:CA308109644 biolink:causes MONDO:0007783 infores:clingen CAID:CA308109644 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with glycine at codon 2400 of the RYR1 protein, p.(Asp2400Gly). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000085, a frequency consistent with pathogenicity for MHS. To our knowledge, this variant has not been reported in any individuals with a personal or family history of an MH episode and positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.548 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308109644/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:367163 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0033774 infores:hetionet CHEBI:7466 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0033117 infores:hetionet NCBIGene:53405 biolink:causes MONDO:0014469 infores:monarchinitiative not_provided not_provided HGNC:13517 MONDO:0014469 uuid:25f795a2-9a5b-40ab-a811-1944483e7127 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1904393 biolink:causes GO:0001941 infores:ubergraph knowledge_assertion manual_agent GO:1904393 GO:0001941 CHEBI:135736 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235234 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0235763 infores:hetionet CHEBI:70735 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0013404 infores:hetionet NCBITaxon:85708 biolink:causes MONDO:0025506 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:85708 MONDO:0025506 CAID:CA7331646 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331646 MONDO:0100216 PMID: Uncertain Significance PP3 PM2, PVS1, BP4, BP2, BA1, PP1, PP4, BS2, PM4, PM5, PM1, PS1, PS4, PS2, PS3, BP7, BS1, BS4, BS3 The NM_177438.2:c.527A>T variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 176 (p.Glu176Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179702 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.835) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 02/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331646/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27470 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0231218 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0043246 infores:hetionet CHEBI:3568 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0264267 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085637 infores:hetionet CAID:CA229624 biolink:causes MONDO:0009861 infores:clingen CAID:CA229624 MONDO:0009861 PMID:8268925 Pathogenic PVS1, PP4_Moderate, PM2 PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: Extremely low frequency in gnomAD. MAF=0.00002.; PP4_Moderate: Detected in 3 chromosomes of patients with PAH deficiency. BH4 deficiency ruled out. (PMID:8268925). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229624/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61033 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1720775 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0029134 infores:hetionet CHEBI:4325 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0042571 infores:hetionet CHEBI:9123 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0497156 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0151763 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0029134 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0035243 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013595 infores:hetionet CHEBI:8888 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0740394 infores:hetionet CAID:CA10644610 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644610 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*4140C>T variant in the 3' UTR has an MAF of 0.005246 (0.5%, 16/3050 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644610/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63791 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027947 infores:hetionet NCBIGene:2555 biolink:causes MONDO:0032812 infores:monarchinitiative not_provided not_provided HGNC:4076 MONDO:0032812 uuid:9abff134-19d6-47ec-b96f-aa77ba49063d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63627 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0025323 infores:hetionet CHEBI:7640 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0030312 infores:hetionet CHEBI:474180 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0553706 infores:hetionet CHEBI:4710 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0085593 infores:hetionet CHEBI:51209 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0018681 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0011991 infores:hetionet CHEBI:38940 biolink:causes MONDO:0007243 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0006413 infores:hetionet CAID:CA374983528 biolink:causes MONDO:0008535 infores:clingen CAID:CA374983528 MONDO:0008535 PMID: Likely Pathogenic PM2_Supporting, PP4_Moderate, PS4, PS3_Supporting PP3 The NM_001114753.3: c.662T>C variant in ENG is a missense variant predicted to cause substitution of leucine by proline at amino acid 221 (p.Leu221Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >10 probands with a phenotype consistent with HHT (PS4; PMID: 10545596, 15880681, 17384219, 18498373, 20414677, 22991266, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The computational predictor REVEL gives a score of 0.478, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, protein expression assays in cell lines showed the variant causes reduced endoglin expression (PS3_Supporting; PMID: 10545596). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PP4_Moderate, PS3_Supporting, PM2_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374983528/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CAID:CA410148217 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148217 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1073C>A (p.Thr358Lys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148217/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47612 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0151904 infores:hetionet CHEBI:52717 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019209 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0021400 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0023533 infores:hetionet CHEBI:51860 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C3665386 infores:hetionet CHEBI:7773 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0231218 infores:hetionet CHEBI:2611 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0036974 infores:hetionet CHEBI:6402 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0039231 infores:hetionet CHEBI:51230 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0004096 infores:hetionet CHEBI:4710 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0423153 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0267792 infores:hetionet CHEBI:7507 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0033774 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0037822 infores:hetionet CHEBI:3508 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0836924 infores:hetionet CHEBI:3219 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015371 infores:hetionet CHEBI:5558 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0013144 infores:hetionet CHEBI:72297 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0030196 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0234222 infores:hetionet CHEBI:61033 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0027540 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042267 infores:hetionet CHEBI:91583 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0004093 infores:hetionet CAID:CA2573105963 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573105963 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.1346_1347del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 9 novel amino acids before encountering a premature stop codon (p.(Ala449GlyfsTer9)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes/hyperglycemia; however, PP4 is unable to be evaluated due to lack of clinical information (PMID: 31638168). In summary, the c.1346_1347del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573105963/MONDO:0015967/086 2023-08-26 2023-08-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3181 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0021122 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021240 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0040411 infores:hetionet NCBIGene:7174 biolink:causes MONDO:0030971 infores:monarchinitiative not_provided not_provided HGNC:12016 MONDO:0030971 uuid:567ff74c-0a36-42aa-a2f3-b6b93058ef8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0518015 infores:hetionet CHEBI:8499 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0023066 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0151828 infores:hetionet CHEBI:6456 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0278134 infores:hetionet CHEBI:44032 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151578 infores:hetionet CHEBI:465284 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0035410 infores:hetionet CHEBI:6149 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235063 infores:hetionet CHEBI:68558 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0014591 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0002994 infores:hetionet CHEBI:7496 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0011175 infores:hetionet CHEBI:7601 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0012833 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1266194 infores:hetionet CHEBI:50663 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0004093 infores:hetionet CHEBI:4672 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0221150 infores:hetionet CAID:CA2579830374 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830374 MONDO:0015967 PMID: Pathogenic PP4, PM2_Supporting, PM1, PS4, PP1_Strong The c.-178A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the promoter region of HNF1A/HNF1B binding sites, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 34789499, 39892506; internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator >50% and negative testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with five informative meioses in three families (PP1_Strong; PMID: 39892506, internal lab contributor). In summary, c.-178A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PS4, PP1_Strong, PM1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830374/MONDO:0015967/085 2025-10-13 2025-10-13 Semidominant inheritance HP:0032113 Supports CHEBI:16469 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042256 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0877854 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0877854 infores:hetionet CHEBI:63598 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023052 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0011616 infores:hetionet CHEBI:73274 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0020615 infores:hetionet CHEBI:5855 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085605 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039971 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004623 infores:hetionet CHEBI:50729 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0027947 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0151773 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0012833 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151889 infores:hetionet CHEBI:6367 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0039231 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027769 infores:hetionet CHEBI:50922 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C3251821 infores:hetionet CHEBI:50730 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0004093 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0015376 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0877508 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0877508 infores:hetionet CHEBI:27974 biolink:causes UMLS:C1142383 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1142383 infores:hetionet CHEBI:7601 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0027441 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0005779 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0004096 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021439 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0496901 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0038362 infores:hetionet CHEBI:3011 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0003467 infores:hetionet CAID:CA386966363 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966363 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM5, PM1, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 The c.814C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cystine at codon 272 (p.(Arg272Cys) of transcript, e.g. NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 18003757, 28701371, 25414397, 11719843, 10447526; internal lab contributors). The variant segregated with diabetes, with at least fifteen informative meioses in at least sixteen families with MODY (PP1_Strong; internal lab contributors). Another missense variant, c. 815G>A, p.Arg272His, has been interpreted as pathogenic by the ClinGen MDEP and p.Arg272Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg272Cys protein has DNA binding below 40% of wild type and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 10333057). Lastly, this variant was identified in at least five individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.814C>T, meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PP1_Strong, PM5, PS3_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966363/MONDO:0015967/017 2022-04-15 2022-04-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5004 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0917801 infores:hetionet CHEBI:6149 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0041657 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0549493 infores:hetionet CHEBI:10023 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2047937 infores:hetionet CHEBI:8665 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0151827 infores:hetionet CHEBI:6640 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0036974 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020507 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0549386 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0027765 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0003864 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0013395 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0005779 infores:hetionet CHEBI:8310 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0030554 infores:hetionet CHEBI:175901 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0231528 infores:hetionet CHEBI:10124 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0006266 infores:hetionet CHEBI:31932 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0040460 infores:hetionet CHEBI:27470 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0022107 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0027769 infores:hetionet CAID:CA512318999 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318999 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.4:c.105C>T (p.Ser35=) is a synonymous variant and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4).The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318999/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5132 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0042963 infores:hetionet GO:0061924 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0060322 CAID:CA913178150 biolink:causes MONDO:0044970 infores:clingen CAID:CA913178150 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PS4, PM6 The m.4437C>T variant in MT-TM has been reported in one individual with primary mitochondrial disease to date (PMID: 23463613), in a female with hypotonia, seizures, muscle weakness, hearing loss, and lactic acidosis. The variant was present at homoplasmy in the proband (tissue not specified) and absent in her mother’s blood however no clinical details were provided on the mother. This proband is also likely included in a cohort study (PMID: 31965079). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (67.2 percentile) but HmtVAR predicts it to be neutral with a score of 0.3. There are no cybrid or single-fiber studies reported for this variant however a study showed impaired methylation critical for the recognition of the MT-TM codon during protein synthesis (PS3_supporting, PMID: 27214402). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 14, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913178150/MONDO:0044970/015 2024-10-14 2024-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:119915 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0278079 infores:hetionet CHEBI:16586 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0231528 infores:hetionet CHEBI:51141 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0009782 infores:hetionet CAID:CA320741202 biolink:causes MONDO:0011071 infores:clingen CAID:CA320741202 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.58+264C>T is an intronic variant with a MAF of 0.08337(8.337%, 1286/15426,) in the European subpopulation of gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). This variant is observed in 70 homozygotes in a population database (gnomAD) (BP2). This variant has a SpliceAI score ≤ 0.20 (Donor Loss 0.05) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -1.17 < 2.0 or the variant is the reference nucleotide in one primate (Rhesus) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741202/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA024980 biolink:causes MONDO:0018493 infores:clingen CAID:CA024980 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 3119 of the RYR1 protein, p.(Arg3119His). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000218, a frequency consistent with pathogenicity for MHS. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.711 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024980/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:4714 biolink:causes MONDO:0032635 infores:monarchinitiative not_provided not_provided HGNC:7703 MONDO:0032635 uuid:2d121677-2fba-4945-bf8d-c1ffd9e411ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes UMLS:C0854029 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0854029 infores:hetionet CAID:CA136018 biolink:causes MONDO:0019497 infores:clingen CAID:CA136018 MONDO:0019497 PMID: Benign BA1 PP3, BP4 The filtering allele frequency of the p.Arg317Gly variant in the TECTA gene is 67.5% (16434/24006) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant and autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA136018/MONDO:0019497/005 2018-09-28 2019-07-17 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:64312 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018794 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C1761613 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0233472 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0855618 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0855618 infores:hetionet CAID:CA386966268 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966268 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.802T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to isoleucine at codon 268 (p.(Phe268Ile)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was detected in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; PMID: 32531870). However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32531870). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 32531870). Another missense variant, c.803T>C (p.Phe268Ser), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, the evidence supports the classification of c.802T>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966268/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3504 biolink:causes HP:0032310 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C1282609 infores:hetionet CAID:CA343726305 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726305 MONDO:0020367 PMID: Uncertain Significance PP3, PP1, PM2_Supporting BS1, BS3, BP7, PM6, PM4, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.733T>G variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Glycine at amino acid 245 (p.Cys245Gly). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.917, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 4 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 36543942), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 36543942), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726305/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:D27V6190PM biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0021053 infores:hetionet CHEBI:45863 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019825 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0009806 infores:hetionet CAID:CA127023 biolink:causes MONDO:0019497 infores:clingen CAID:CA127023 MONDO:0019497 PMID:26969326PMID:25999548 Pathogenic PM3_Very Strong, PVS1, BA1, PS4 BP7, BP5, BS1, BS4, BS2, PP3, PP1, PP4, PM5, PM4, PM1, PM2, PM6, BP2, BP4, BP3, PS1, PS3, PS2 The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA127023/MONDO:0019497/005 2018-09-20 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:136040 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0025061 infores:hetionet CHEBI:8107 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0003862 infores:hetionet CHEBI:2663 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0039231 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1262113 infores:hetionet CAID:CA6831693 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831693 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting BP4, PM1, PP3, PP4, PP1 The c.229G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to asparagine at codon 77 (p.(Asp77Asn)) of NM_000545.8. This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.81e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant has a REVEL score of 0.554, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 34496959; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.229G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831693/MONDO:0015967/017 2025-10-27 2025-10-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:38940 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0000833 infores:hetionet CHEBI:3077 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151970 infores:hetionet NCBIGene:80267 biolink:causes MONDO:0030423 infores:monarchinitiative not_provided not_provided HGNC:16787 MONDO:0030423 uuid:1b4944ff-4cad-4bb0-baf3-ce62321bc19b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014518 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0205204 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017605 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009450 infores:hetionet CHEBI:7581 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0042963 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0549209 infores:hetionet CHEBI:28748 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C3665386 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0702166 infores:hetionet CHEBI:44423 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0013428 infores:hetionet CHEBI:50922 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085633 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1167965 infores:hetionet CAID:CA913180175 biolink:causes MONDO:0044970 infores:clingen CAID:CA913180175 MONDO:0044970 PMID:30962064 Uncertain Significance PM2_Supporting, PS4_Supporting, BP4, PS3_Supporting The m.5667G>A variant in MT-TN has been reported in two individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 23847141, 30962064). Minimal clinical details were provided on the first reported individual however this person was reported to have features consistent with mitochondrial disease, ptosis, ragged red fibers, and COX-negative fibers. The variant was present at heteroplasmy but level and tissue were not specified (PMID: 23847141). The second reported individual had chronic progressive external ophthalmoplegia (CPEO). Muscle biopsy showed ragged red fibers, and COX-negative fibers and the activities of complexes I and IV were reduced. The variant was present in vastus lateralis muscle at 19% heteroplasmy and 48% heteroplasmy in extraocular muscles (PMID: 30962064). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). MitoTIP predicts the variant is possible benign (44.6 percentile) and HmtVAR predicts the variant is neutral (score of 0.05, BP4). Single fiber testing of vastus lateralis showed higher levels of the variant in COX-negative fibers (87.8% ± 5.7%, n=30) than in COX-positive fibers (11.0% ± 13%, n=27; p <0.0001; PS3_supporting, PMID: 30962064). This was also seen in extraocular muscles as there were higher levels of the variant in COX-negative fibers (86.0% ± 4.6%, n=20) than in COX-positive fibers (27.1% ± 27.2%, n=28; p < 0.0001). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PS3_supporting, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913180175/MONDO:0044970/015 2024-06-10 2025-10-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63610 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0021390 infores:hetionet CHEBI:5147 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0028734 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042109 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1112537 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1112537 infores:hetionet CAID:CA367398725 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398725 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.1151C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glutamic acid at codon 384 (p.(Ala384Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.96, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMID: 36257325, internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3mmol/L)) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with 7 informative meioses in five families (PP1_Strong; internal lab contributors). In summary, c.1151C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PP1_Strong, PP4_Moderate, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398725/MONDO:0015967/086 2025-06-06 2025-06-06 Semidominant inheritance HP:0032113 Supports UMLS:C0065374 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0025061 infores:hetionet CHEBI:6715 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C3665347 infores:hetionet CHEBI:28177 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0018681 infores:hetionet CHEBI:3756 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0220870 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0852733 infores:hetionet CHEBI:43968 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0010200 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0162830 infores:hetionet CHEBI:64321 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0007222 infores:hetionet CHEBI:45652 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0428977 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027947 infores:hetionet CHEBI:63589 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0028081 infores:hetionet CHEBI:2704 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0162298 infores:hetionet CHEBI:7581 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0033975 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0178298 infores:hetionet CHEBI:8461 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0086525 infores:hetionet CAID:CA412745785 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745785 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PP4, PS4 NM_001034853.2(RPGR):c.126T>G (p.Cys42Trp) is a missense variant encoding the substitution of cysteine with tryptophan at amino acid 42. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 affected proband who did not meet one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 28041643), so the PS4_Supporting code was not met. The computational predictor REVEL gives a score of 0.788, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RPGR function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.01 for donor loss and donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and PP3_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745785/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6822 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0013378 infores:hetionet NCBIGene:1548 biolink:causes MONDO:0007390 infores:monarchinitiative not_provided not_provided HGNC:2610 MONDO:0007390 uuid:a2709943-5f60-493f-abe5-1cb1213e1fbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0032285 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0017160 infores:hetionet CHEBI:3614 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0041834 infores:hetionet CHEBI:8707 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013362 infores:hetionet CHEBI:48538 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0004093 infores:hetionet NCBIGene:8831 biolink:causes MONDO:0012960 infores:monarchinitiative not_provided not_provided HGNC:11497 MONDO:0012960 uuid:f6eaa6ef-c031-49e7-99dd-84c4f47356b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA267651 biolink:causes MONDO:0009861 infores:clingen CAID:CA267651 MONDO:0009861 PMID: Uncertain Significance PM2 PM5, PP3 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC& gnomAD (MAF 0.00018). Absent from 1000G, ESP. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267651/MONDO:0009861/006 2018-09-28 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7443 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0009676 infores:hetionet GO:0070799 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0070799 GO:0061458 CHEBI:49713 biolink:causes UMLS:C0568180 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0568180 infores:hetionet CHEBI:18243 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0429097 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0031350 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0235146 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0042373 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0043094 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0855242 infores:hetionet CHEBI:5147 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0149725 infores:hetionet CAID:CA226515 biolink:causes MONDO:0100368 infores:clingen CAID:CA226515 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting BA1, BS1 NM_000329.3(RPE65):c.1418T>A is a missense variant that substitutes valine with arginine at position 473. This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 9501220, SCV001430890.1). This variant has also been reported in at least 1 probands with early-onset severe retinal dystrophy who was compound heterozygous with the p.Pro363Thr variant confirmed in trans (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one patient harboring the variant exhibits a phenotype including nondetectable ERG responses from rods (0.5 pts) and cones ( 1 pt), nyctalopia (0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), light staring (1 pt), and positive response to RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (13 total points, VCEP member-provided data, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.992, which is above the ClinGen LCA/eoRD VCEP PP3_Mod threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226515/MONDO:0100368/120 2024-01-31 2024-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8356 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009806 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0240564 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0240564 infores:hetionet CHEBI:63611 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0231530 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0022650 infores:hetionet CAID:CA8459411 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459411 MONDO:0011132 PMID: Likely Benign BP4, BP7, BS1 NM_001369369.1(FOXN1):c.930A>G (p.Thr310=) is a synonymous variant. SpliceAI predicts no impact to the splice consensus sequence (delta score 0.00) nor the creation of a new splice site (delta score<=0.01) and the nucleotide is not highly conserved (phyloP score -1.54) (BP4, BP7). The gnomADv2.1.1 PopMax filtering AF is 0.002017 based on 66/24964alleles in the African/African American population, which is above the >0.00141 threshold for BS1. In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BS1, BP4, and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459411/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:3723 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1510472 infores:hetionet CHEBI:68534 biolink:causes HP:0002176 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0037926 infores:hetionet CHEBI:8346 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0004245 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0035309 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0424000 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0019054 infores:hetionet CHEBI:5134 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0039446 infores:hetionet CHEBI:3996 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0036974 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006846 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0042109 infores:hetionet CHEBI:42797 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0025287 infores:hetionet CHEBI:53760 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0520966 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1112369 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1112369 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0018799 infores:hetionet CAID:CA415076214 biolink:causes MONDO:0010305 infores:clingen CAID:CA415076214 MONDO:0010305 PMID: Uncertain Significance BP4 PM2 The NM_005629.4:c.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID: 31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). There is a ClinVar entry for this variant (Variation ID:572616). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415076214/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:7476 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0035455 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0038454 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0020649 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C1956346 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0033777 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0012833 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0020461 infores:hetionet CHEBI:39867 biolink:causes NCIT:C157384 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0438235 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0002888 infores:hetionet CHEBI:75722 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039070 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0349231 infores:hetionet CHEBI:42944 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0028734 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0002871 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0521508 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0521508 infores:hetionet GO:0045592 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:0045592 GO:0048477 CHEBI:38940 biolink:causes MONDO:0000754 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0205929 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017574 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004936 infores:hetionet CHEBI:3387 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0023380 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0017605 infores:hetionet CHEBI:52717 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014335 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C2047937 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037822 infores:hetionet CHEBI:5384 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0030312 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027651 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0085593 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0178298 infores:hetionet CHEBI:37924 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0041657 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027765 infores:hetionet CHEBI:2666 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0004134 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0006145 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0042075 infores:hetionet CAID:CA7624163 biolink:causes MONDO:0021060 infores:clingen CAID:CA7624163 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.1098T>C (p.Ala366=) variant in the MAP2K1 gene is 0.0459% (8/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7624163/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5002 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0018801 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0242350 infores:hetionet CHEBI:3534 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151904 infores:hetionet CHEBI:52717 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018946 infores:hetionet CAID:CA233457 biolink:causes MONDO:0100438 infores:clingen CAID:CA233457 MONDO:0100438 PMID: Benign BS1, BS2, BP4 NM_014336.5(AIPL1):c.1006G>A (p.Ala336Thr) is a missense variant in exon 6 of 6. The variant is predicted to change the amino acid alanine at position p.336 to threonine. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.003394, with 4,110 alleles / 1,179,854 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.00057 (BS1). This variant has been found in the homozygous state in 6 adult individuals in gnomAD which meets the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.209, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.290 and predicts a non-damaging effect on AIPL1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2, and BP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA233457/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA10586683 biolink:causes MONDO:0021060 infores:clingen CAID:CA10586683 MONDO:0021060 PMID: Pathogenic PS2_Very Strong, PM2_Supporting, PS4_Supporting, PP2, BP4 The c.548A>C (p.Glu183Ala) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by alanine at amino acid 183. This variant is absent from gnomAD v2 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP3). The computational predictor REVEL gives a score of 0.283, which is below the threshold of 0.3, does not predict a damaging effect on PPP1CB function (BP4). This variant was observed in a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:30236064). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 30236064, 27681385). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as uncertain significance; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4_Supporting, PM2_Supporting, PP2, BP4. (RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10586683/MONDO:0021060/128 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28901 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0023530 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0040479 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042075 infores:hetionet CHEBI:100241 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0001127 infores:hetionet CHEBI:31547 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C1384353 infores:hetionet CHEBI:3723 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085635 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0423618 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0423618 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0018418 infores:hetionet CHEBI:6076 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011606 infores:hetionet CHEBI:499361 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013362 infores:hetionet CHEBI:42944 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0005779 infores:hetionet CHEBI:7476 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0032708 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0038454 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019158 infores:hetionet CHEBI:63605 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0235025 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013395 infores:hetionet CHEBI:147675 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00249 UMLS:C0005741 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0023533 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0751295 infores:hetionet CHEBI:5147 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027497 infores:hetionet CHEBI:9943 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0232462 infores:hetionet CHEBI:3696 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0852911 infores:hetionet CAID:CA267685 biolink:causes MONDO:0009861 infores:clingen CAID:CA267685 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 The c.912+3A>C variant in PAH has not been reported in the medical literature to the best of our knowledge. This variant is absent from gnomAD and the ESP population databases. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~30%) the canonical donor splice site. Given the absence of clinical information and mRNA functional studies, the significance of the c.912+3A>C variant can not be determined with certainty. PAH-specific ACMG/AMP criteria applied: PP3, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267685/MONDO:0009861/006 2019-11-08 2019-11-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50378 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0009763 infores:hetionet CHEBI:47381 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0233407 infores:hetionet CHEBI:3757 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0040034 infores:hetionet CHEBI:63622 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0234428 infores:hetionet NCBIGene:8795 biolink:causes MONDO:0010150 infores:monarchinitiative not_provided not_provided HGNC:11905 MONDO:0010150 uuid:17357c4c-c826-49a9-89e4-a6324aeeb3cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4885 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0020517 infores:hetionet CHEBI:8665 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0042571 infores:hetionet CHEBI:116278 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0428977 infores:hetionet CHEBI:27796 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0018681 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0041969 infores:hetionet CAID:CA1139664131 biolink:causes MONDO:0044970 infores:clingen CAID:CA1139664131 MONDO:0044970 PMID: Uncertain Significance PM2 The c.*420A>G variant in POLG was absent from databases (PM2). Given the limited data no computational score available. There were no cases in the literature. In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA ACMG/AMP criteria for POLG applied: PM2 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139664131/MONDO:0044970/014 2021-05-06 2021-05-06 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:31638 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0948594 infores:hetionet CHEBI:5855 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0000729 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0041912 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0009241 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085129 infores:hetionet CHEBI:4735 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0221264 infores:hetionet CHEBI:9137 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151578 infores:hetionet NCBIGene:11280 biolink:causes MONDO:0014244 infores:monarchinitiative not_provided not_provided HGNC:10583 MONDO:0014244 uuid:a13a5a46-803e-43c0-a875-948a0eaf9002 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7865 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0549209 infores:hetionet CHEBI:3242 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0014591 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0043345 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0855242 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010233 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010233 uuid:20bc84f2-d07b-4567-a13c-1e07fb725dca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0017605 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0426597 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0426597 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0233408 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0233408 infores:hetionet CAID:CA000260 biolink:causes MONDO:0017623 infores:clingen CAID:CA000260 MONDO:0017623 PMID: Uncertain Significance BP4 PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PP2, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 PTEN c.1027-4C>G (IVS8-4C>G) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000260/MONDO:0017623/003 2023-12-01 2023-12-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:18332 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0015967 infores:hetionet CHEBI:63631 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013456 infores:hetionet CHEBI:4911 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0687713 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0021053 infores:hetionet CHEBI:8093 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0041657 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0973461 infores:hetionet CHEBI:119573 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014724 infores:hetionet UNII:15G12L5X8K biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018944 infores:hetionet CHEBI:2379 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0085593 infores:hetionet CAID:CA278647 biolink:causes MONDO:0700087 infores:clingen CAID:CA278647 MONDO:0700087 PMID: Likely Pathogenic PP4, PP1, PM2_Supporting, PM3_Strong PP3, PM5, BP4 The c.2904G>T variant in MYO7A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 968. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000064 (3/126898 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.563, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. At least one patient with this variant displayed Usher syndrome (PP4, PMID: 33089500). This variant has been detected in at least five individuals with Usher syndrome. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and presumed to be in trans (c.631A>G (p.S211G) and c.3719G>A (p.D1240Q)) and three of those were confirmed in trans by family testing and all of whom had different variants on the other allele (c.224dup (p.D75fs), c.487G>C (p.G163R), c.1189G>A (p.A397T); 2.5 PM3 points, PMID: 25472526, 26969326, 33089500; ClinVar Variation ID: 43325, 43218, 553215) (PM3_Strong). The variant has been reported to segregate with Usher syndrome in three affected family members from one family (PP1; PMID:33089500). Another missense variant, c.2904G>C (p.E968D), in the same codon has been reported in a patient with Usher syndrome (PMID:27460420). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing Loss VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP1, PP4, PM3_S (ClinGen Hearing Loss VCEP specifications version 2; 7/26/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278647/MONDO:0700087/005 2022-08-03 2022-08-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:6904 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0023530 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0040435 infores:hetionet CAID:CA16618472 biolink:causes MONDO:0015967 infores:clingen CAID:CA16618472 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PS3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID: 28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID: 15677479). In summary, c.184G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_strong, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618472/MONDO:0015967/086 2023-08-25 2023-08-25 Semidominant inheritance HP:0032113 Supports CHEBI:50275 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0349506 infores:hetionet CHEBI:9737 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0342579 infores:hetionet CHEBI:100147 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0042109 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020649 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0031350 infores:hetionet CHEBI:6759 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0027497 infores:hetionet CHEBI:8214 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0040822 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0339434 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0339434 infores:hetionet CHEBI:3216 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011124 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0003123 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0542184 infores:hetionet CHEBI:8871 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235710 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0424000 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0006840 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0917799 infores:hetionet CHEBI:8412 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0015672 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0022660 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0234215 infores:hetionet CHEBI:175901 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0030554 infores:hetionet CHEBI:144093 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C2830004 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0917798 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151763 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0011991 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003864 infores:hetionet CHEBI:8888 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151825 infores:hetionet GO:0072124 biolink:causes GO:0072012 infores:ubergraph knowledge_assertion manual_agent GO:0072124 GO:0072012 CHEBI:3219 biolink:causes UMLS:C0521991 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0521991 infores:hetionet CHEBI:31348 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011175 infores:hetionet CHEBI:66919 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0040034 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0234215 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0008370 infores:hetionet CHEBI:4975 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0016512 infores:hetionet CHEBI:135961 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0085593 infores:hetionet CHEBI:50673 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0013144 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0687133 infores:hetionet CHEBI:3732 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085636 infores:hetionet CHEBI:84500 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0858635 infores:hetionet NCBITaxon:1980442 biolink:causes MONDO:0018081 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1980442 MONDO:0018081 NCBITaxon:34504 biolink:causes MONDO:0005895 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:34504 MONDO:0005895 CHEBI:75722 biolink:causes UMLS:C0858765 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0858765 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0015967 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0038454 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0518015 infores:hetionet CHEBI:6128 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0002792 infores:hetionet CAID:CA645607432 biolink:causes MONDO:0011071 infores:clingen CAID:CA645607432 MONDO:0011071 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP2, BP1, BP4, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM5, PM3, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.302TGC[1] (p.Leu102del) is an in-frame deletion variant which is found within the Runt Homology Domain but does not occur at a known hotspot residue (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PM4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645607432/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:85078 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0162429 infores:hetionet CHEBI:3215 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0085649 infores:hetionet CHEBI:10127 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0008031 infores:hetionet CHEBI:45863 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0036974 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0404521 infores:hetionet CHEBI:5864 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0024305 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006444 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020517 infores:hetionet CHEBI:63599 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0149871 infores:hetionet CHEBI:2663 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C3665347 infores:hetionet CHEBI:4445 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0155169 infores:hetionet CHEBI:63607 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151692 infores:hetionet CHEBI:10650 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0004245 infores:hetionet CHEBI:71941 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0040034 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0267596 infores:hetionet CHEBI:28748 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023218 infores:hetionet CHEBI:51209 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0022107 infores:hetionet NCBIGene:729920 biolink:causes MONDO:0014474 infores:monarchinitiative not_provided not_provided HGNC:37276 MONDO:0014474 uuid:6f5e0df8-ac6f-4ee7-8109-a70d4a8bded7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66876 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0392525 infores:hetionet CAID:CA256015 biolink:causes MONDO:0010305 infores:clingen CAID:CA256015 MONDO:0010305 PMID: Likely Pathogenic PS3_Supporting, PP3, PM2_Supporting, PP4_Strong The NM_005629.4:c.1472G>A variant is a missense variant predicted to cause a substitution of a cysteine for a tryptophan at amino acid position 491 (p.Cys491Trp). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 17101918) (PP4_Strong). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts, measured with 25uM creatine (PMID: 22281021) (PS3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.751 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 11704). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA256015/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:100241 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0004604 infores:hetionet NCBIGene:8291 biolink:causes MONDO:0024545 infores:monarchinitiative not_provided not_provided HGNC:3097 MONDO:0024545 uuid:b115e6f4-0e0a-4d4a-80e6-bb6ed241a1cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8338033 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338033 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP4, PP3, PM3_Supporting PM1, PM5, BP2, BP1, PS1, BP7 The c.1183-7A>G variant in ACADVL occurs within splice acceptor site of intron 11. The results from two in silico splicing predictors (MaxEntScn and Human Splicing Finder) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 11 of 20 in ACADVL (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed C14:1-carnitine level at 15.5 micromolar, which is highly specific for VLCAD deficiency (PP4_Supporting, PMID: 31031081). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, and PP4_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338033/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:6491 biolink:causes MONDO:0012989 infores:monarchinitiative not_provided not_provided HGNC:10879 MONDO:0012989 uuid:843bdd38-ae46-4a40-b31a-19e9fefc2766 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0004450 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0265101 infores:hetionet CHEBI:3380 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0340865 infores:hetionet CHEBI:3175 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0013404 infores:hetionet GO:0021892 biolink:causes CL:0010011 infores:ubergraph knowledge_assertion manual_agent GO:0021892 CL:0010011 CHEBI:51860 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019521 infores:hetionet CHEBI:3223 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085631 infores:hetionet CHEBI:4753 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0344232 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026946 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0041912 infores:hetionet CHEBI:4466 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0015230 infores:hetionet UMLS:C0145185 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0008031 infores:hetionet NCBIGene:917 biolink:causes MONDO:0014276 infores:monarchinitiative not_provided not_provided HGNC:1675 MONDO:0014276 uuid:900649c6-d86d-4d9e-bdde-28541be5de34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0600142 infores:hetionet GO:0040028 biolink:causes GO:0002119 infores:ubergraph knowledge_assertion manual_agent GO:0040028 GO:0002119 CHEBI:63791 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0043094 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0025202 infores:hetionet CHEBI:91541 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0013604 infores:hetionet CHEBI:6690 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042963 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020621 infores:hetionet NCBIGene:84231 biolink:causes MONDO:0032572 infores:monarchinitiative not_provided not_provided HGNC:20456 MONDO:0032572 uuid:5100d5b8-6c07-46a8-a4eb-329bdcfffc89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51032 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0574067 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018991 infores:hetionet CHEBI:5001 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0043352 infores:hetionet CHEBI:63589 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0038325 infores:hetionet NCBIGene:60495 biolink:causes MONDO:0009368 infores:monarchinitiative not_provided not_provided HGNC:18374 MONDO:0009368 uuid:119b6bad-6d37-49ab-b918-a9468a4557ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6456 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0003708 infores:hetionet CHEBI:5296 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0030554 infores:hetionet CAID:CA013367 biolink:causes MONDO:0005045 infores:clingen CAID:CA013367 MONDO:0005045 PMID: Uncertain Significance PM2, PP3, PS4_Moderate PM5, PM1, PM6, PP1, BS4, PS1, PS2 The NM_000257.4(MYH7):c.3133C>T (p.Arg1045Cys) variant has been identified in at least 12 individuals with HCM (PS4_Moderate; Olivotto 2008 PMID:18533079; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940; Walsh 2017 PMID: 27532257; Michels 2017 PMID:28005231) and in an additional individual with early-onset DCM that also carried a de novo TNNC1 variant (Hershberger 2008 PMID:19412328; Hershberger 2010 PMID:20215591; Rampersaud 2011 PMID:21483645; Pinto 2011; PMID:21832052). This variant was identified in 0.00152% (FAF 95% CI; 5/129168) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013367/MONDO:0005045/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2955 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0018681 infores:hetionet CHEBI:474180 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0546817 infores:hetionet CHEBI:94440 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0041657 infores:hetionet CHEBI:3219 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0404521 infores:hetionet CHEBI:2788 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0085636 infores:hetionet CAID:CA2573051052 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051052 MONDO:0015967 PMID:18268044 Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS2, PP1_Strong PS4, PS3 The c.225-21A>G variant in the hepatocyte nuclear factor-4-alpha gene, HNF4A, is predicted to disrupt splicing in intron 2 of NM_175914.4. This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture highly specific for HNF4A-MODY (diazoxide-responsive neonatal hypoglycemia and negative testing for KCNJ11 and ABCC8) (PS2; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with at least 4 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors, PMID 18268044). The computational splicing predictor SpliceAI gives a score of 0.74 for acceptor loss, predicting that the variant disrupts the acceptor site of intron 2 of HNF4A (PP3). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and neonatal hypoglycemia responsive to diazoxide) (PP4_Moderate; internal lab contributors). In summary, c.225-21A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS2, PM2_Supporting, PP3, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051052/MONDO:0015967/085 2023-09-01 2023-09-01 Autosomal dominant inheritance HP:0000006 Supports UNII:G4PX8C4HKV biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0011603 infores:hetionet CHEBI:2719 biolink:causes GO:0042310 infores:drugmechdb knowledge_assertion manual_agent MESH:D000804 GO:0042310 DB01340_MESH_D006973_1DB00584_MESH_D006333_1DB00519_MESH_D006973_1DB00542_MESH_D006973_1DB08822_MESH_D006973_1DB09477_MESH_D006973_1DB01197_MESH_D003928_1DB09477_MESH_D006333_1DB00584_MESH_D006973_1DB01348_MESH_D006973_1DB13166_MESH_D006973_1DB01029_MESH_D006973_1DB01197_MESH_D006973_1DB01029_MESH_D003928_1 UMLS:C1738934 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0038363 infores:hetionet CHEBI:53760 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0023218 infores:hetionet CHEBI:46345 biolink:causes HP:0025088 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0263540 infores:hetionet CHEBI:4356 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0013428 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0015423 infores:hetionet NCBIGene:168667 biolink:causes MONDO:0011946 infores:monarchinitiative not_provided not_provided HGNC:24154 MONDO:0011946 uuid:a7b7f401-4fdc-44d8-aad7-f824f7637fc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0024282 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011053 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0003123 infores:hetionet CAID:CA165116 biolink:causes MONDO:0700270 infores:clingen CAID:CA165116 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5_Supporting, PVS1 BS1, PM2 The c.2284_2285del (p.Leu762Valfs*2) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least three unrelated individuals with Ataxia-Telangiectasia (PMID: 26896183). The highest population minor allele frequency in gnomAD v4.1 is 0.00002119 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporing, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA165116/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63791 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007117 infores:hetionet CAID:CA170444 biolink:causes MONDO:0100039 infores:clingen CAID:CA170444 MONDO:0100039 PMID: Pathogenic PM2_Supporting, PVS1, PM6 The c.1311dup variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.1311dup variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with early onset seizures and infantile spasms (PMID 19793311) (PM6). The c.1311dup variant in CDKL5 is absent from gnomAD v2.1.1 (PM2_supporting). In summary, the c.1311dup variant in CDKL5 is classified as pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170444/MONDO:0100039/034 2024-04-18 2024-07-31 X-linked inheritance HP:0001417 Supports CHEBI:42944 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0040822 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034186 infores:hetionet CHEBI:5165 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0947912 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040435 infores:hetionet CAID:CA261418 biolink:causes MONDO:0010134 infores:clingen CAID:CA261418 MONDO:0010134 PMID: Likely Pathogenic PS3_Supporting, PP4, PM2_Supporting, PM3_Strong PP3, PM5 The c.1694G>A variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 565 (p.Cys565Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15418) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold ≤0.00007 (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). Radio isotope assays in Xenopus oocytes and HEK293T cell lines demonstrated that cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin indicating that this variant impacts protein function (PS3_Supporting; PMID: 19204907, 31599023).This variant has been detected in at least 4 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aqueduct (total of 3.5 PM3 points, PM3_Strong). One individual with Pendred syndrome was compound heterozygous with a pathogenic variant p.Q514R (ClinVar ID 43511, PMID: 19204907, 15689455). The second individual was a Pendred syndrome patient compound heterozygous with a pathogenic variant p.L236P (ClinVar ID 4817, PMID: 9618166). The third individual had nonsyndromic hearing loss with enlarged vestibular aqueduct which is highly specific for Pendred syndrome and was compound heterozygous with pathogenic p.H723R (ClinVar ID 4825, PMID: 14508505, PP4). The fourth individual had sensorineural hearing loss and enlarged vestibular aqueduct and was assumed compound heterozygous with pathogenic c.1342-2_1343dupAGTC (p.Leu450Glyfs*19) but phase unknown (Internal data from LMM). In summary, this variant has been classified as likely pathogenic for AR Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PS3_Supporting, PM3_Strong, PP4. (VCEP specifications version 2; 07.19.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261418/MONDO:0010134/005 2023-07-19 2023-10-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:47381 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020580 infores:hetionet CHEBI:45409 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C3203358 infores:hetionet CAID:CA404099252 biolink:causes MONDO:0007750 infores:clingen CAID:CA404099252 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM6, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.2480T>A (p.Val827Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.942 (seen on the website). It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404099252/MONDO:0007750/013 2022-01-28 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63608 biolink:causes MONDO:0024352 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0877203 infores:hetionet CHEBI:71219 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0041834 infores:hetionet CHEBI:6909 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042790 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0687133 infores:hetionet CAID:CA124460 biolink:causes MONDO:0015967 infores:clingen CAID:CA124460 MONDO:0015967 PMID:16562587PMID:18003757PMID:10333057PMID:28701371PMID:10447526PMID:25414397PMID:11719843PMID:15726414PMID:9032114PMID:11393552PMID:15114102PMID:9166684PMID:10585442 Pathogenic PM2_Supporting, PS4, PM1, PP1_Strong, PS3_Supporting, PP3 BP4, BA1, PM5, BS3, BS1 The c.815G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 272 (p.(Arg272His)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31166087, PMID:18003757, PMID:24905847, PMID:31483937, PMID:29439679, PMID:23610083, PMID:21989397, PMID:21395678, PMID:21224407, PMID:15114102, ClinVar ID 14931, internal lab contributors). This variant segregated with diabetes, with 13 informative meioses in multiple families with MODY (PP1_Strong; PMID:15114102, internal lab contributors). Functional studies demonstrated the p.Arg272His protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 16781669). In summary, c.815G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PS4, PM1, PP3, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124460/MONDO:0015967/017 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8428 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0234215 infores:hetionet CHEBI:37333 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0031542 infores:hetionet CHEBI:2453 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0497156 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0027051 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013146 infores:hetionet CHEBI:63635 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0004604 infores:hetionet CHEBI:94501 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0019147 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0027051 infores:hetionet CHEBI:63632 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0020458 infores:hetionet CHEBI:83804 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0686347 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0015397 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0342579 infores:hetionet CHEBI:7822 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C2047937 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0232492 infores:hetionet CHEBI:50131 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151908 infores:hetionet CHEBI:16469 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0017168 infores:hetionet CHEBI:16714 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0042963 infores:hetionet GO:0045501 biolink:causes GO:0007465 infores:ubergraph knowledge_assertion manual_agent GO:0045501 GO:0007465 CAID:CA16020835 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020835 MONDO:0009861 PMID: Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The c.669del (p.Asn223LysfsTer118) variant in PAH is a frameshift variant predicted to cause a premature stop codon in exon 6 leading to nonsense mediated decay. It was reported in a Chinese PKU patient with BH4 deficiency ruled out, in trans with pathogenic variant p.T278N (PMID: 24705691). It is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4_moderate, PM2_supporting, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020835/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31355 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0009450 infores:hetionet CHEBI:7915 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151577 infores:hetionet GO:1902890 biolink:causes GO:0022622 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0022622 CAID:CA10585258 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585258 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3, PP4 PS4, PS3 The NM_000527.5 (LDLR):c.1028G>A (p.Gly343Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PM5_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.959, it is above 0.75.PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France.PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met.PS4 not met: Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France.PS3 not met: Functional data is not available. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585258/MONDO:0007750/013 2023-01-27 2023-04-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:4710 biolink:causes MONDO:0001011 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0006144 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0012833 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0009806 infores:hetionet CAID:CA2739267610 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267610 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.967+11T>G is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score ≤ 0.20 (0.02 donor loss, 0.01 acceptor loss) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.64) (BP7). Multiple lines of computational evidence suggest no impact on gene /gene product (SpliceAI score ≤ 0.20 (0.02 donor loss; 0.01 acceptor loss) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267610/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3485 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0004093 infores:hetionet CHEBI:50648 biolink:causes MONDO:0013592 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0221260 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0009450 infores:hetionet CHEBI:114785 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0221245 infores:hetionet CHEBI:8888 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042023 infores:hetionet CHEBI:50275 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2004489 infores:hetionet CHEBI:8382 biolink:causes HP:0000963 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0423757 infores:hetionet CHEBI:8356 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009676 infores:hetionet CHEBI:8776 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0002170 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0006145 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0518015 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0023418 infores:hetionet CAID:CA658760376 biolink:causes MONDO:0009276 infores:clingen CAID:CA658760376 MONDO:0009276 PMID: Likely Pathogenic PVS1_Strong, PM3_Supporting, PP4, PM2_Supporting The c.119del (p.Gly40AlafsTer43) variant in GP9 is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient BS-4 in PMID: 21699652) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 2; date of approval xx/xx/xxxx). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760376/MONDO:0009276/083 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9123 biolink:causes UMLS:C0265110 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0265110 infores:hetionet CHEBI:3654 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0014457 infores:hetionet CHEBI:4953 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0019080 infores:hetionet CHEBI:52717 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151714 infores:hetionet CHEBI:75998 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020433 infores:hetionet CHEBI:3698 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0004245 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004238 infores:hetionet UMLS:C0011701 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0043094 infores:hetionet CHEBI:31623 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0423006 infores:hetionet CHEBI:251408 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0042023 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0948594 infores:hetionet CHEBI:7903 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0022408 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0858924 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0858924 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0019158 infores:hetionet NCBITaxon:6209 biolink:causes MONDO:0005738 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6209 MONDO:0005738 GO:0045314 biolink:causes GO:0001745 infores:ubergraph knowledge_assertion manual_agent GO:0045314 GO:0001745 CHEBI:681569 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0151825 infores:hetionet CHEBI:28487 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0014591 infores:hetionet CHEBI:84050 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0030554 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0236071 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0042075 infores:hetionet CAID:CA367397060 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397060 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4 The c.1313T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 438 (p.(Phe438Tyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 19564454). Overall, this evidence supports the classification of c.1313T>A as a variant of uncertain significance for monogenic diabetes. CMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/20/2023): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397060/MONDO:0015967/086 2023-06-20 2023-06-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014868 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0241426 infores:hetionet CHEBI:135736 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0476280 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0009806 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0948594 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020456 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0009319 infores:hetionet NCBIGene:123016 biolink:causes MONDO:0014436 infores:monarchinitiative not_provided not_provided HGNC:20087 MONDO:0014436 uuid:d3b80527-6fb7-498b-b7b5-bc3c33575584 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0015397 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0038454 infores:hetionet CHEBI:80630 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0000729 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011615 infores:hetionet CHEBI:15551 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0042963 infores:hetionet CHEBI:23765 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0043352 infores:hetionet CHEBI:47381 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003862 infores:hetionet CAID:CA386492906 biolink:causes MONDO:0009861 infores:clingen CAID:CA386492906 MONDO:0009861 PMID: Likely Pathogenic PM3, PM2, PP4, PVS1_Strong This variant c.1316-1G>C in PAH was detected in a patient with classic PKU with the pathogenic variant p.Arg243Gln (PMID: 28982351). This variant was absent in population databases. This is a canonical variant in the -1 splice acceptor of intron 12; this would alter a region that is critical to protein function with nonsense mediated decay not predicted. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_Strong, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386492906/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9123 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085632 infores:hetionet CAID:CA409105749 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105749 MONDO:0015967 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS4 The c.403C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 135 (p.(Gln135Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in at least three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID:450787, internal lab contributor). Additionally, the variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; internal lab contributor). In summary, c.403C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specidication version 2.0.0, approved 10/11/23): PVS1, PP1,1 PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105749/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:61049 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013395 infores:hetionet CHEBI:47612 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0035410 infores:hetionet CHEBI:6413 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0338908 infores:hetionet NCBIGene:7253 biolink:causes MONDO:0012203 infores:monarchinitiative not_provided not_provided HGNC:12373 MONDO:0012203 uuid:f553213b-8b91-4afc-8ed0-118b716aa483 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8673 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0034068 infores:hetionet CAID:CA025471 biolink:causes MONDO:0012933 infores:clingen CAID:CA025471 MONDO:0012933 PMID: Benign BP5_Strong, BS3, BS2, BA1, BP4 The c.8149G>T variant in BRCA2 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 2717 (p.Ala2717Ser). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met). This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: Internal lab contributors).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BS3, BS2, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025471/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:23524 biolink:causes MONDO:0957397 infores:monarchinitiative not_provided not_provided HGNC:16639 MONDO:0957397 uuid:51f88f42-ce62-485e-8207-282162af3efa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0008031 infores:hetionet CAID:CA177679 biolink:causes MONDO:0021060 infores:clingen CAID:CA177679 MONDO:0021060 PMID: Likely Benign BP4, BP5 The c.935T>C (p.Val312Ala) variant in the RAF1 gene is a missense variant predicted to cause substitution of valine by alanine at amino acid 312. The computational predictor REVEL gives a score of 0.174, which is below the threshold of 0.3 and does not predict a damaging effect on RAF1 function (BP4). Additionally, this variant was identified in a case with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 26957, 21766; ClinVar SCV000200036.4; SCV000209006.12). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4, BP5. (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA177679/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:84690 biolink:causes MONDO:0975843 infores:monarchinitiative not_provided not_provided HGNC:30705 MONDO:0975843 uuid:3a77068d-43b3-42a8-83b8-75d1e8dc402d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151798 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0948089 infores:hetionet CHEBI:39867 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0018794 infores:hetionet CHEBI:75045 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C1384353 infores:hetionet CHEBI:4702 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0007398 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027051 infores:hetionet CHEBI:8863 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0037287 infores:hetionet CHEBI:82960 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0013378 infores:hetionet CHEBI:8890 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013428 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151970 infores:hetionet CHEBI:27953 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00981 UMLS:C0036572 infores:hetionet CAID:CA1251300 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251300 MONDO:0013144 PMID: Benign BS2_Supporting, BA1, BP4 BP7 The c.981A>G (p.Val327=) variant is reported at an Popmax FAF MAF of 0.7471 (19267/24962 alleles) in the African/African-American population in the genomes in gnomAD v2.1.1 with a total of 26873 homozygotes, meeting BA1 criteria of FAF >= 0.002. The variant has been reported in one heterozygous individual with normal AT activity levels (85%) meeting BS2_Supporting criteria. This synonymous variant is not predicted to impact splicing by SpliceAI and VARSEAK meeting BP4 criteria. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BP4, BS2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251300/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:32588 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0546817 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0009450 infores:hetionet NCBIGene:92667 biolink:causes MONDO:0014039 infores:monarchinitiative not_provided not_provided HGNC:16205 MONDO:0014039 uuid:137a1e22-ac5f-4f27-92dc-a6c5f30b1902 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0234458 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0340464 infores:hetionet NCBIGene:80726 biolink:causes MONDO:0859338 infores:monarchinitiative not_provided not_provided HGNC:29350 MONDO:0859338 uuid:35404d45-26c7-4d4f-8c9a-85abcdd2cf33 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0037036 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0518015 infores:hetionet CHEBI:31705 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042510 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020517 infores:hetionet CHEBI:49662 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0917801 infores:hetionet CHEBI:50924 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1527344 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151734 infores:hetionet CHEBI:63623 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0014457 infores:hetionet CHEBI:63791 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019825 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1393815 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1393815 infores:hetionet CHEBI:8356 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0241057 infores:hetionet CHEBI:31622 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C2047937 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0018801 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004238 infores:hetionet CHEBI:8665 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0011253 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0948594 infores:hetionet CAID:CA16611270 biolink:causes MONDO:0008667 infores:clingen CAID:CA16611270 MONDO:0008667 PMID:31337753 Uncertain Significance PM2_Supporting, PP3, PM1, PS3_Supporting PS4 The NM_000551.3(VHL):c.273C>A (p.Phe91Leu) variant in VHL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 91. This variant has been reported in 2 unrelated probands. Dolfus et al reports a VHL subject with (c.263 G>C; p.F91L) from a family in the French VHL Registry, the individual did not have renal involvement. No further phenotypic description is provided. (PMID: 15300849). Gallou et al (PMID:15300849) reports a VHL subject with retinal hemangioblastomas and (c.273 C>G and p.F91L). Olschwang et al (1998) is likely the same subject as Gallou et al and is not included in the proband count. Two of three participating commercial laboratories reports 4 cases with this variant, however none have VHL-related cancers. Given the sparse phenotypic descriptions in the two publications, and the 4 samples lacking VHL phenotypes from commercial laboratories, the ClinGen VHL VCEP does not recommend applying this code. (PS4_NOT_MET). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In Tarade et al, an in vitro pVHL-HIFa binding assay followed by immunoblotting showed the the F91L variant abolished all binding to HIF1a and HIF2a (PMID: 31337753)(PS3_Supporting).This variant resides within a region of VHL that is defined as a critical functional domain (the Beta Domain) (PM1). The computational predictor REVEL gives a score of 0.773, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16611270/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42944 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0026826 infores:hetionet CHEBI:39585 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0546817 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0015230 infores:hetionet CHEBI:7936 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085633 infores:hetionet NCBIGene:6334 biolink:causes MONDO:0013801 infores:monarchinitiative not_provided not_provided HGNC:10596 MONDO:0013801 uuid:38312c0b-05c7-401e-aa5f-69a5778a03c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0013604 infores:hetionet CHEBI:75984 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0030554 infores:hetionet CAID:CA336868 biolink:causes MONDO:0700270 infores:clingen CAID:CA336868 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PM5_Supporting, PVS1 BA1, PS3, BS1 The c.748C>T (p.Arg250*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in numerous individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 12552559, 20840352, 21778326, 22006793, 26896185, 30816533, 31611883). The highest population minor allele frequency in gnomAD v2.1.1 0.00003 (1/34560) which meets the PM2 threshold of n≤1 alleles when sub-population frequency is >0.00001 (PM2_Supporting met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA336868/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:128486 biolink:causes MONDO:0032842 infores:monarchinitiative not_provided not_provided HGNC:16135 MONDO:0032842 uuid:ad7c5d65-6c42-4821-9647-29ef15b0cecb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0035243 infores:hetionet CHEBI:10125 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085635 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0919980 infores:hetionet CHEBI:68579 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0009782 infores:hetionet CHEBI:135736 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027424 infores:hetionet CHEBI:63608 biolink:causes MONDO:0020761 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0006079 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0232459 infores:hetionet CHEBI:23765 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0278134 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0518015 infores:hetionet CHEBI:5098 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0001824 infores:hetionet CHEBI:51164 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C2004489 infores:hetionet CHEBI:6916 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0015672 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0015230 infores:hetionet CHEBI:44915 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0034063 infores:hetionet CAID:CA2387284518 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387284518 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.509-15A>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.49) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387284518/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:681569 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0037199 infores:hetionet CHEBI:7476 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0001925 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0948226 infores:hetionet CHEBI:180905 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0039070 infores:hetionet CHEBI:3219 biolink:causes HP:0041081 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1542178 infores:hetionet CAID:CA16020735 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020735 MONDO:0009861 PMID:26503515 Pathogenic PM2, PVS1, PP4 The c.169_170delGA variant in PAH has been previously reported as a single (heterozygous) mutation in 1 Chinese PKU case (PMID: 26503515; PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020735/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6715 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013922 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0152029 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0278079 infores:hetionet CHEBI:5864 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0080274 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0038362 infores:hetionet NCBIGene:51776 biolink:causes MONDO:0054695 infores:monarchinitiative not_provided not_provided HGNC:17797 MONDO:0054695 uuid:56495e3e-b155-4144-ba10-9ed7f0443bb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9288 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0311468 infores:hetionet CHEBI:4710 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C2830004 infores:hetionet CHEBI:31236 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151671 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0032285 infores:hetionet CHEBI:3387 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0586553 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0019158 infores:hetionet CHEBI:63611 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151636 infores:hetionet CHEBI:8107 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002792 infores:hetionet CHEBI:9123 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232726 infores:hetionet CHEBI:41879 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0011253 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0020538 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020649 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0034882 infores:hetionet CHEBI:63630 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0018681 infores:hetionet NCBIGene:729 biolink:causes MONDO:0012908 infores:monarchinitiative not_provided not_provided HGNC:1339 MONDO:0012908 uuid:bdfa9a56-0b00-4a88-8af3-678493ce681a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0267792 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0006840 infores:hetionet CHEBI:8060 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0231835 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0016977 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0340464 infores:hetionet CHEBI:4466 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0006266 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0002871 infores:hetionet CHEBI:40279 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002878 infores:hetionet CHEBI:5864 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0233762 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017675 infores:hetionet CHEBI:5138 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0206062 infores:hetionet UMLS:C1872203 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0003862 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0031212 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0160390 infores:hetionet CHEBI:45409 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085636 infores:hetionet CHEBI:4315 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0232493 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0349506 infores:hetionet CHEBI:51860 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C2939147 infores:hetionet CHEBI:34385 biolink:causes UMLS:C0856120 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0856120 infores:hetionet CHEBI:4466 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0036983 infores:hetionet UMLS:C0004609 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0000737 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013595 infores:hetionet CAID:CA502179100 biolink:causes MONDO:0009290 infores:clingen CAID:CA502179100 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Moderate, PM3_Supporting PP3, PS3, BP7 The NM_000152.5:c.2040G>A variant in GAA does not result in an amino acid substitution (p.Leu680=) but alters the last nucleotide of exon 14. Sequence analysis of cDNA from a patient who is compound heterozygous for the variant and a missense change in GAA revealed inclusion of intron 14, which is predicted to result in a frameshift and nonsense-mediated decay in some of the transcripts. Quantitative methods were not used in the amplification process, and therefore the proportion of transcripts containing intron 14 is unknown. Consistent with these findings, the in silico predictor, SpliceAI, gives a score of 0.86 for donor loss at the intron 14 donor splice site, suggesting that this variant affects splicing. Based on this data, specifically nonsense-mediated decay but without quantification of the proportion of transcripts in which this occurs, PVS1_Moderate was applied (PMID: 37352859). The variant has been reported in two probands. One proband who had symptoms consistent with infantile onset Pompe disease and undergoing enzyme replacement therapy, was compound heterozygous for the variant and another variant in GAA, phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP, c.1927G>A (p.Gly643Arg) (ClinVar Variation ID: 4023, SCV005089709.1) (PMID 17723315, 23430500) (PP4_Moderate, PM3_Supporting). In addition, two siblings with late onset Pompe disease and cardiomyopathy have been reported with the variant. However, the authors did not state the zygosity of the variant; therefore, this data will not be included (PMID: 37116048). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 984800). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications version 2.0): PVS1_Moderate, PP4_Moderate, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysocomal Diseases Variant Curation Expert Panel on September 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA502179100/MONDO:0009290/010 2024-09-17 2024-09-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3286 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0030662 infores:hetionet CAID:CA386963414 biolink:causes MONDO:0015967 infores:clingen CAID:CA386963414 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PVS1, PP4_Moderate The c.527-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 2 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 3 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 10588527, internal lab contributors). Additionally, this variant was identified in at least 2 individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), including one considered highly specific based on sulfonylurea-responsiveness (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID: 10588527, internal lab contributors). In summary, c.527-1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): PVS1, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386963414/MONDO:0015967/017 2022-04-10 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:584020 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0032617 infores:hetionet CHEBI:63623 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0010200 infores:hetionet CHEBI:70707 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0009782 infores:hetionet CHEBI:39669 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0041657 infores:hetionet CHEBI:36795 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1760428 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0855242 infores:hetionet GO:0019227 biolink:causes HP:0012531 infores:drugmechdb knowledge_assertion manual_agent GO:0019227 MESH:D010146 DB09345_MESH_D010146_1 CHEBI:4910 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C3203358 infores:hetionet CHEBI:10102 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0012569 infores:hetionet CHEBI:51450 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0002962 infores:hetionet GO:0046935 biolink:causes GO:0036092 infores:ubergraph knowledge_assertion manual_agent GO:0046935 GO:0036092 CHEBI:6931 biolink:causes UMLS:C0040210 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0040210 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0027765 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0008350 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0339383 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0339383 infores:hetionet CHEBI:32139 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0013404 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0007971 infores:hetionet NCBIGene:6622 biolink:causes MONDO:0008200 infores:monarchinitiative not_provided not_provided HGNC:11138 MONDO:0008200 uuid:6402393a-76d1-400f-9ffd-a1f18d1453e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes UMLS:C1096176 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1096176 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1760428 infores:hetionet NCBIGene:54802 biolink:causes MONDO:0054742 infores:monarchinitiative not_provided not_provided HGNC:20286 MONDO:0054742 uuid:38e2c39e-971c-43be-ada5-6c3296ebacb4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA5417034 biolink:causes MONDO:0011225 infores:clingen CAID:CA5417034 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.106A>G(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Lysine by Glutamic Acid at amino acid 36 (p.Lys36Glu).The filtering allele frequency (the upper threshold of the 95% CI of 41/1179924) of the c.106A>G variant in DCLRE1C is 0.00002626 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5417034/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:1902890 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0007275 CHEBI:63631 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0520966 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0040435 infores:hetionet GO:2001204 biolink:causes GO:0060348 infores:ubergraph knowledge_assertion manual_agent GO:2001204 GO:0060348 CHEBI:75984 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0043352 infores:hetionet CAID:CA340748185 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748185 MONDO:0100368 PMID: Likely Pathogenic PM1, PP3_Moderate, PM5_Supporting, PM2_Supporting PP4 NM_000329.3(RPE65):c.331C>A is a missense variant encoding a substitution of proline by threonine at codon 111. The variant is located within the membrane-interacting region between amino acids 107 and 125, which is a well-characterized functional domain required for proper localization to the ER membrane (PM1, PMID: 36265895). Another missense variant in the same codon (NM_000329.3(RPE65):c.331C>T (p.Pro111Ser)) has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5_Supporting, PMID: 32347917). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. The computational predictor REVEL gives a score of 0.968, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 for PP3_Moderate and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype of retinal dystrophy, however, sufficient details are not available to establish specificity of phenotype for RPE65-related recessive retinopathy (SCV001240152.1). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRP VCEP: PM1, PM2_Supporting, PM5_Supporting, PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748185/MONDO:0100368/120 2024-01-31 2024-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5801 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0040034 infores:hetionet CHEBI:27786 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0015967 infores:hetionet GO:1902667 biolink:causes GO:0048667 infores:ubergraph knowledge_assertion manual_agent GO:1902667 GO:0048667 CHEBI:50673 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0221490 infores:hetionet CAID:CA8603454 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603454 MONDO:0100326 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3, PM3_Supporting PP4 The missense variant NM_000419.5(ITGA2B):c.475G>A (p.Gly159Ser has been identified in at least one patient UPN 2 (PMID: 16359515; PMID: 16359515) reported to have GT. The patient is homozygous for Gly159Ser (PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.735, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003267 (1/30606 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In HEK 293 cells there was expression on 52% of cells transfected with normal αIIb and β3 and 0% of cells with Gly159Ser were positive. Furthermore, immunoblotting from cell lysates found mature αIIb was seen in the normal αIIbβ3 cells, but there was no detectable mature αIIb in the G159S mutant (PMID: 16359515; PS3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PM2_supporting, PM3_supporting, PS3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603454/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3441 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0030554 infores:hetionet CHEBI:3485 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0014356 infores:hetionet CAID:CA367399038 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399038 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4 The c.1092C>G variant in the GCK gene, glucokinase, causes an amino acid change of cysteine to tryptophan at codon 364 (p.(Cys364Trp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.841, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in a single individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325). In summary, c.1092C>G meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2024): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399038/MONDO:0015967/086 2024-11-16 2024-12-02 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0005740 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0027497 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0235283 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235283 infores:hetionet CAID:CA8815349 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815349 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000152.5:c.1447G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 483 (p.Gly483Arg). At least 7 individuals with this variant have been reported to have Pompe disease. Of these individuals, 3 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, with unknown phase, including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (0.5 points, PMID: 30214072, 33073009), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (0.5 points, PMID: 33073009), and c.32-13T>G (ClinVar Variation ID: 4027) (0.5 points, PMID: 21972175, 29289479). In addition, 2 individuals were homozygous for the variant (2 x 0.5 points. PMID: 36572041, Revvity Omics Clinical Laboratory data) (PM3_Strong). Two more patients have been described with the variant and another variant, either c.-32-17_-32-10delinsT CCCTGCTGAGCCTCCTACA GGCCTCCCGC (PMID: 25687635) or c.569G>A (p.Arg190His) (PMID: 23000108). The allelic data from these patients will be used in the classification the second variant and is not included here to avoid circular logic. At least 4 individuals have GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts / or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 23000108, 36572041, 33073009) (PP4_Moderate). This variant has a minor allele frequency of 0.00010(1/10306) in the African population in gnomAD v2.1.1, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID: 18425781)(PS3_Moderate). The computational predictor REVEL gives a score of 0.822 which is above the thresholds predicting a damaging (>0.7) impact on GAA function and therefore meets this criterion (PS3). There is a ClinVar entry for this variant (Variation ID: 285157). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PS3_moderate, PM2_supporting, PM3_strong, PP3, PP4_moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815349/MONDO:0009290/010 2024-05-07 2024-05-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:68642 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0011071 infores:hetionet CHEBI:114785 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0151908 infores:hetionet CHEBI:4046 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0020649 infores:hetionet CHEBI:7573 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0011124 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0595939 infores:hetionet CHEBI:135930 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0085605 infores:hetionet CHEBI:127780 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0043352 infores:hetionet CHEBI:46345 biolink:causes MONDO:0000437 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0007758 infores:hetionet CHEBI:6030 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0015230 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0042267 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0040435 infores:hetionet CHEBI:17987 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0013604 infores:hetionet CHEBI:8863 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034880 infores:hetionet CHEBI:5790 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0037383 infores:hetionet NCBIGene:3098 biolink:causes MONDO:0044320 infores:monarchinitiative not_provided not_provided HGNC:4922 MONDO:0044320 uuid:92270b87-057b-4166-82d8-8de23220a0dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:34967 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0162429 infores:hetionet NCBIGene:2743 biolink:causes MONDO:0013828 infores:monarchinitiative not_provided not_provided HGNC:4329 MONDO:0013828 uuid:a2a34ba5-750a-4532-bddf-23bb61d92fd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6438 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0012569 infores:hetionet UNII:R43D2573WO biolink:causes HP:6000793 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0521172 infores:hetionet CAID:CA016180 biolink:causes MONDO:0005045 infores:clingen CAID:CA016180 MONDO:0005045 PMID: Uncertain Significance PM2, PP3 PM3, PS3, BA1, PM6, PM1, PM4, PM5, PP1, BS2, PP4, PP2, BS1, BS4, BS3, BP3, BP1, BP2, BP5, BP4, BP7, PS4, PS2, PS1, PVS1 The NM_000257.4(MYH7):c.550A>C (p.Lys184Gln) variant has been identified in at least 4 individuals with LVNC (Miller 2017 PMID:29212898; GeneDx pers. comm.; Invitae pers. comm.), 1 individual with HCM and LVNC (Ambry pers. comm.), 1 individual with HCM who carried another pathogenic variant in MYH7 (GeneDx pers. comm.) and 1 individual with sudden cardiac death. Additionally, this variant has segregated with LVNC in 6 affected relatives from 2 families (GeneDx pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the current evidence is currently insufficient to apply the PS4 or the PP1 criteria for the HCM phenotypes. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes ( Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016180/MONDO:0005045/002 2021-12-01 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:T58MSI464G biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0267792 infores:hetionet CAID:CA229478 biolink:causes MONDO:0009861 infores:clingen CAID:CA229478 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Strong The c.193A>G (p.Ile65Val) variant in PAH has been reported in multiple individuals with mild PKU and mild hyperphenylalaninaemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 12501224). This variant is at extremely low frequency: gnomAD MAF 0.00003 (PM2). This variant was detected with multiple pathogenic variants: p.R261Q, IVS12+1G>A (PMID: 12501224); c.168+5G>C (PMID: 22526846); p.Y386C (PMID: 26210745); p.EX6-96A>G (PMID: 30050108). Multiple lines of computational evidence support a deleterious effect (PP3). Another missense change at the same amino acid residue is pathogenic (p.Ile65Thr). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229478/MONDO:0009861/006 2022-06-28 2022-06-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9139 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0039070 infores:hetionet CAID:CA10014268 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014268 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.926G>A (p.Gly309Asp) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014268/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15553 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0032961 infores:hetionet CHEBI:45409 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0497156 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0403632 infores:hetionet NCBITaxon:550 biolink:causes DOID:50360 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:550 MESH:D004756 DB01059_MESH_D004756_1DB00537_MESH_D004756_1 CHEBI:9649 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0009806 infores:hetionet CAID:CA2697547498 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547498 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.292_334dup (p.Leu112ProfsTer40) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547498/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4466 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0042373 infores:hetionet CHEBI:64312 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018944 infores:hetionet CAID:CA220406 biolink:causes MONDO:0009290 infores:clingen CAID:CA220406 MONDO:0009290 PMID:27142047PMID:23000108PMID:29946513PMID:31676142PMID:24590251PMID:29149851PMID:29422078 Pathogenic PVS1, PM2, PP4, PM3_Very Strong This variant, c.525delT (p.Glu176ArgfsTer45), is one of the most common variants reported in individuals with Pompe disease; over 70 patients are listed in the Erasmus database (http://www.pompevariantdatabase.nl/). It is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of c.525delT in individuals with no GAA cross-reactive immunological material in cultured skin fibroblasts i.e. CRIM-negative (PMID 22252923, 31342611), no detectable increase in GAA activity or GAA protein when cDNA with the variant was expressed in COS cells (PMID 7881422), and low expression of all GAA exons based on qRT-PCR data from a homozygous patient (PMID 25243733). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000188 in the European non-Finnish population, meeting PM2. Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, c.2481+110_2646+39del (exon 18 deletion), c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 (PM3_VeryStrong) was applied. There is a ClinVar entry for this variant (Variation ID: 4033, 2 star review status) with 8 laboratory submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Very Strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220406/MONDO:0009290/010 2020-11-02 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:44032 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0948594 infores:hetionet CHEBI:52717 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0038325 infores:hetionet CHEBI:64312 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042345 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020538 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0020649 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0221161 infores:hetionet CHEBI:15553 biolink:causes MONDO:0020710 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0002631 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0036454 infores:hetionet CAID:CA658798634 biolink:causes MONDO:0100488 infores:clingen CAID:CA658798634 MONDO:0100488 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP4, PP1, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The NM_004360.5:c.2387_2406del (p.Arg796GlnfsTer4) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID: 29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PM5_Supporting, PM2_Supporting. (CDH1 VCEP specifications version 3.1) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798634/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA16621927 biolink:causes MONDO:0015967 infores:clingen CAID:CA16621927 MONDO:0015967 PMID: Pathogenic PS3_Supporting, PP3, PP4, PM2_Supporting, PM1_Supporting, PS4_Moderate, PP1_Strong The c.697G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 233 (p.(Val233Leu)) of NM_000545.8. This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in one family with (PP1_Strong; PMID: 28993341) and the variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.893, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID 28993341). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Val233Leu protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 15522234). Lastly, this variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 12488961, 28993341, 24905847). In summary, c.697G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621927/MONDO:0015967/085 2023-12-18 2023-12-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8382 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020555 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0242350 infores:hetionet CHEBI:16714 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0917801 infores:hetionet CHEBI:63115 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0013595 infores:hetionet CHEBI:5280 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0085649 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0042401 infores:hetionet CHEBI:37941 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0014742 infores:hetionet CHEBI:9586 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020578 infores:hetionet CHEBI:35778 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0547030 infores:hetionet UMLS:C0657912 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0392156 infores:hetionet CHEBI:51860 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1443060 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0040046 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151971 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0001824 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0040046 infores:hetionet CHEBI:421707 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0023380 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151538 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151538 infores:hetionet GO:0010793 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0010793 GO:0010467 CHEBI:52172 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0035258 infores:hetionet CHEBI:9586 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0041657 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0038454 infores:hetionet CHEBI:135342 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0013378 infores:hetionet CHEBI:63630 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020580 infores:hetionet CHEBI:17347 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0267028 infores:hetionet CHEBI:5165 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0268000 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0541919 infores:hetionet CHEBI:51450 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0149514 infores:hetionet CHEBI:75722 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C3495920 infores:hetionet CHEBI:7640 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0039070 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011991 infores:hetionet CAID:CA390866465 biolink:causes MONDO:0100216 infores:clingen CAID:CA390866465 MONDO:0100216 PMID: Uncertain Significance PM2, BP4 PM6, PVS1, BP1, BP3, BP2, BA1, PP2, PP3, PP1, PP4, BS2, PM4, PM1, PM3, PM5, PS3, PS4, PS2, PS1, BP7, BP5, BS1, BS3, BS4 The NM_177438.2:c.4889G>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 1630 (p.Arg1630Leu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.041; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1- related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390866465/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151908 infores:hetionet CAID:CA16020927 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020927 MONDO:0009861 PMID:21147011PMID:12655553 Likely Pathogenic PM2, PP4_Moderate, PM3 PP3 The c.1066-7C>A variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded, PMID: 12655553, 21147011, 21307867). This variant has extremely low frequency in gnomAD (MAF=0.00001). This variant was detected in the homozygous state, with maternity and paternity confirmed (PMID: 12655553); and with pathogenic variant IVS11-2A>G (PMID: 21147011). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020927/MONDO:0009861/006 2020-08-10 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3181 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0237938 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0233472 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0521839 infores:hetionet CHEBI:41879 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0234708 infores:hetionet CHEBI:2569 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0027066 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0085620 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0234215 infores:hetionet CHEBI:8772 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0015967 infores:hetionet UMLS:C0017797 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0033774 infores:hetionet NCBIGene:3953 biolink:causes MONDO:0013992 infores:monarchinitiative not_provided not_provided HGNC:6554 MONDO:0013992 uuid:f9f6cab5-a48e-41fd-b1dd-6e4c769d6939 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45081 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0042384 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0027765 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0948389 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0948389 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0948586 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0026857 infores:hetionet CHEBI:63598 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151936 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0034882 infores:hetionet CHEBI:7865 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0016204 infores:hetionet UMLS:C0879264 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0030252 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011570 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151737 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151737 infores:hetionet CAID:CA023861 biolink:causes MONDO:0700269 infores:clingen CAID:CA023861 MONDO:0700269 PMID: Likely Pathogenic PM2, PVS1 PP3 The c.631+4A>G variant is an intronic variant occurring in intron 7 of the BRCA2 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.71, predicting an impact on splicing (score threshold ≥0.2) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RNAseq, minigene and RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 20455026, 31143303). Preliminary code strength determined by comparison of results to PVS1 decision tree and assessment of mRNA splicing data (PVS1 (RNA) met). The percent reference (full-length, FL) and aberrant transcripts produced from the variant allele using allele specific quantitative assessment with Capillary electrophoresis was determined to be full-length (0%) / exon skipping (100%). Final code strength determined by the rubric: PVS1 (RNA).In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PVS1 (RNA)). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA023861/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:79699 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0017675 infores:hetionet CHEBI:16796 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0011603 infores:hetionet CHEBI:27974 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0006142 infores:hetionet UMLS:C0657912 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0522055 infores:hetionet CHEBI:61058 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0152031 infores:hetionet CHEBI:47381 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010200 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0031256 infores:hetionet CHEBI:3181 biolink:causes MONDO:0043327 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0023182 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0031085 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0009450 infores:hetionet CHEBI:28901 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151798 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0030353 infores:hetionet CHEBI:63580 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0038325 infores:hetionet CHEBI:28748 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0232849 infores:hetionet CHEBI:64317 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0027769 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151849 infores:hetionet CHEBI:51860 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027849 infores:hetionet CHEBI:478164 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0014457 infores:hetionet CHEBI:8382 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0262431 infores:hetionet CHEBI:75998 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0428977 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0010414 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0034069 infores:hetionet NCBIGene:63901 biolink:causes MONDO:0011215 infores:monarchinitiative not_provided not_provided HGNC:24725 MONDO:0011215 uuid:eb006919-a144-4c12-9c8c-166cf9a37976 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0948089 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0027765 infores:hetionet CHEBI:50648 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1145670 infores:hetionet CHEBI:46557 biolink:causes HP:0041166 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0080179 infores:hetionet GO:0061356 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:0061356 GO:0007267 CHEBI:92998 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0037011 infores:hetionet NCBIGene:498 biolink:causes MONDO:0014091 infores:monarchinitiative not_provided not_provided HGNC:823 MONDO:0014091 uuid:bf671dd0-1dd3-4ce7-bf76-56754a9de537 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0017178 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014742 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0006145 infores:hetionet CHEBI:9130 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0041657 infores:hetionet CHEBI:4784 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0423153 infores:hetionet CHEBI:135566 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0022568 infores:hetionet CHEBI:31348 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027066 infores:hetionet CHEBI:3347 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0740394 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020456 infores:hetionet CHEBI:31644 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0030232 infores:hetionet NCBIGene:402381 biolink:causes MONDO:0054666 infores:monarchinitiative not_provided not_provided HGNC:27845 MONDO:0054666 uuid:6a20f5a3-ba86-457b-9df5-50bb3b1a199f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0221100 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0026857 infores:hetionet CHEBI:6801 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0027441 infores:hetionet CHEBI:61049 biolink:causes HP:0005206 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030299 infores:hetionet CHEBI:63631 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0026826 infores:hetionet CHEBI:2639 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0020461 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0858118 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0858118 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0013395 infores:hetionet CHEBI:6472 biolink:causes UMLS:C0578159 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0578159 infores:hetionet CHEBI:43968 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0013428 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1510472 infores:hetionet CHEBI:17823 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0030193 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0344315 infores:hetionet CHEBI:63624 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0026821 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0342579 infores:hetionet CHEBI:87715 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0020473 infores:hetionet CHEBI:167309 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0009806 infores:hetionet CHEBI:3723 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015402 infores:hetionet CHEBI:28915 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0151849 infores:hetionet CAID:CA006221 biolink:causes MONDO:0007356 infores:clingen CAID:CA006221 MONDO:0007356 PMID: Likely Pathogenic PP3_Moderate, PP1_Strong, PM2_Supporting This NM_000249.4:c.1646T>C variant in MLH1 has been reported to segregate with disease in ≥2 families (PP1_strong). The missense variant has a prior probability for pathogenicity >0.81 (MAPP/PP2:0.82) (PP3_moderate). The variant is not reported in gnomAD v2.1.1 (non-cancer) and gnomAD v4.1 datasets (PM2_supporting). Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA006221/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7601 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C1443060 infores:hetionet GO:0072301 biolink:causes GO:0072239 infores:ubergraph knowledge_assertion manual_agent GO:0072301 GO:0072239 NCBIGene:56652 biolink:causes MONDO:0012241 infores:monarchinitiative not_provided not_provided HGNC:1160 MONDO:0012241 uuid:ea03c0cc-a13b-4cb5-9dbc-a92abcc12d4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0039592 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0039592 GO:0000278 CHEBI:31859 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018799 infores:hetionet NCBIGene:7007 biolink:causes MONDO:0011351 infores:monarchinitiative not_provided not_provided HGNC:11720 MONDO:0011351 uuid:34bebf78-1836-466e-a63b-f73ca80c701f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7518 biolink:causes MONDO:0014686 infores:monarchinitiative not_provided not_provided HGNC:12831 MONDO:0014686 uuid:18ab9173-17da-430f-8b0d-c3b58ed134e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes NCIT:C168489 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232285 infores:hetionet CHEBI:520985 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0034880 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0041969 infores:hetionet CHEBI:6129 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1142412 infores:hetionet CHEBI:9737 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0015672 infores:hetionet CHEBI:3752 biolink:causes MONDO:0020673 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0264995 infores:hetionet CHEBI:6715 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C2937358 infores:hetionet CAID:CA10576586 biolink:causes MONDO:0015924 infores:clingen CAID:CA10576586 MONDO:0015924 PMID: Pathogenic PM6, PM2_Supporting, PM1, PS3, PS4 PP3, BS2, BA1, BP4, BS1 The c.901T>C variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of serine by proline at amino acid 301 (p.Ser301Pro). The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting).The variant has been identified in 5 probands, meeting the PH VCEP threshold for PS4 (>4 pro bands; PMIDs 16429395, 18356561, 25917481, 29743074, and PH VCEP internal lab contributors). The variant has been identified as a de novo occurrence in one individual with pulmonary arterial hypertension and unconfirmed parental relationships (PM6; PMID 29743074). Immunostaining in Hela cells transfected with a FLAG-tagged c.901C>T BMPR2 expression construct demonstrated impaired subcellular trafficking of BMPRII (PMID: 25688877) and Western-blot analysis of pulmonary artery smooth muscle cells isolated from a patient with the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID: 19324947), indicating an effect on protein function (PS3). This variant resides in a conserved kinase domain (amino acids 203 – 504) but is not defined as a critical residue by the ClinGen PH VCEP (PM1_moderate). In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.0): PS4, PM6, PM2_Supporting, PS3, PM1_moderate). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576586/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CAID:CA5252632 biolink:causes MONDO:0008535 infores:clingen CAID:CA5252632 MONDO:0008535 PMID: Likely Benign BP4, BP5 PM2, BA1, BS1 The NM_001114753.3: c.1762G>A variant in ENG is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 588 (p.Val588Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003436 (43/125140 alleles) in the non-Finnish European population. The computational predictor REVEL gives a score of 0.043, which is below the threshold of ≤0.1, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). This variant has been observed in a patient with an alternate molecular basis for disease (pathogenic variant identified in ACVRL1) (BP5; internal lab contributors). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BP4, BP5 (specifications version 1.1.0; 09/11/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5252632/MONDO:0008535/136 2024-09-11 2024-09-19 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63638 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0232492 infores:hetionet NCBIGene:7168 biolink:causes MONDO:0007267 infores:monarchinitiative not_provided not_provided HGNC:12010 MONDO:0007267 uuid:952c6c79-912f-4cd6-b203-6309b7adb98d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0029134 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0151602 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0011991 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0030305 infores:hetionet CHEBI:5130 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0032617 infores:hetionet CHEBI:3723 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0241633 infores:hetionet CHEBI:6444 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0037763 infores:hetionet CHEBI:10102 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002994 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0234215 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0518015 infores:hetionet GO:0048686 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:0048686 GO:0048666 CHEBI:68595 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0013595 infores:hetionet CAID:CA386959040 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959040 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS3_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.358A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamic acid at codon 120 (p.(Lys120Glu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This is supported by functional studies that demonstrated the p.Lys120Glu protein has DNA binding and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32017842). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 24698406, PMID: 32741144, internal lab contributor). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 24698406). In summary, the c.358A>G variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 1/22/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959040/MONDO:0015967/017 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17026 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0006277 infores:hetionet CHEBI:31623 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0263449 infores:hetionet CHEBI:61033 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0018681 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037195 infores:hetionet CHEBI:2569 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0025061 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0235660 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0158026 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0158026 infores:hetionet CHEBI:28748 biolink:causes UMLS:C2243088 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2243088 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0025160 infores:hetionet CHEBI:3371 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0595916 infores:hetionet CHEBI:107736 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0235660 infores:hetionet CAID:CA006159 biolink:causes MONDO:0100316 infores:clingen CAID:CA006159 MONDO:0100316 PMID: Likely Benign BA1, PM4 BS4, PM3, PP1 NM_000218.3(KCNQ1):c.160_168dup (p.Pro56_Gly57insIleAlaPro) is an in-frame insertion of nine nucleotides within a non-repeat region of KCNQ1 (PM4). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03002, with 1,854 alleles / 61,766 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 and PS4 codes are not met (PMID: 28438721). This variant has been shown to disrupt KCNQ1 function in only one patch-clamp assay, so experimental evidence is not sufficient to meet PS3_Supporting (PMID 19646991). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1 and PM4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006159/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:53760 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011616 infores:hetionet CAID:CA658799891 biolink:causes MONDO:0010305 infores:clingen CAID:CA658799891 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_005629.4(SLC6A8):c.53_137delinsCCGTGT (p.Lys18fs) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in population databases (PM2_Supporting), and to our current knowledge has not been reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:533702). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799891/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Supports CHEBI:63611 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0947912 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1368065 infores:hetionet CHEBI:9737 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0015967 infores:hetionet CAID:CA359428593 biolink:causes MONDO:0012163 infores:clingen CAID:CA359428593 MONDO:0012163 PMID: Likely Pathogenic PM2_Supporting, PVS1 c.355A>T (p.Lys119Ter)(NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met).The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification.In summary, this variant meets the criteria to be classified as Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met,PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359428593/MONDO:0012163/119 2024-01-30 2024-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64045 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0020456 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0014130 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0038362 infores:hetionet CHEBI:7443 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0014742 infores:hetionet CHEBI:8028 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0013404 infores:hetionet CHEBI:4877 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0234215 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0012833 infores:hetionet CHEBI:66919 biolink:causes UMLS:C0149801 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0149801 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0149931 infores:hetionet CHEBI:43968 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0021368 infores:hetionet CHEBI:71219 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020433 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022650 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0856151 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0221161 infores:hetionet CHEBI:7465 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0858635 infores:hetionet CHEBI:28148 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0151578 infores:hetionet CHEBI:7465 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0234047 infores:hetionet GO:0141069 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0141069 GO:0023052 CHEBI:8871 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0024902 infores:hetionet CHEBI:6633 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0042109 infores:hetionet CHEBI:63622 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0700200 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0948594 infores:hetionet CHEBI:10101 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0476280 infores:hetionet CHEBI:8327 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0221185 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0019158 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0235431 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0242656 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151911 infores:hetionet CHEBI:16469 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0033774 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020437 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0016204 infores:hetionet CHEBI:50777 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0151603 infores:hetionet NCBIGene:146845 biolink:causes MONDO:0030474 infores:monarchinitiative not_provided not_provided HGNC:16053 MONDO:0030474 uuid:cd3ecc15-2282-43b3-99de-35c05c7957f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0025323 infores:hetionet CAID:CA10606688 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606688 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting PM5, PM4, PM1, PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, BS2, PP2, PP3, PP1 The NM_003494.4: c.661C>T p.(Gln221Ter) variant in DYSF, which is also known as NM_001130987.2: c.757C>T p.(Gln253Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in a homozygous state in two patients with LGMD (1.0 pt, ClinVar SCV003309109.1 internal data communication, PMID: 30564623, Jain Foundation Dysferlin Registry internal data communication) (PM3, PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM2_Supporting, PM3, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606688/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:134991 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0035455 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0037274 infores:hetionet CHEBI:3478 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C3263723 infores:hetionet NCBIGene:84660 biolink:causes MONDO:0030718 infores:monarchinitiative not_provided not_provided HGNC:30723 MONDO:0030718 uuid:e09ca155-c718-40a1-ab7e-22602847b99c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1443060 infores:hetionet CHEBI:31413 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0018681 infores:hetionet CAID:CA226488 biolink:causes MONDO:0100368 infores:clingen CAID:CA226488 MONDO:0100368 PMID: Benign BP4, BA1, BP7 NM_000329.3(RPE65):c.1155G>A (p.Thr385=) is a synonymous variant at codon 385. The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01596, with 704 alleles / 41408 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226488/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:34829 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0009763 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005173 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0022602 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0497247 infores:hetionet CHEBI:9123 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042384 infores:hetionet CAID:CA512318641 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318641 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.682C>T (p.Leu228=) is a synonymous variant which has a SpliceAI score of 0.04 and a PhyloP score of 1.87, allowing for the application of both BP4 and BP7. This variant has been detected in population databases, albeit at a low frequency. It has not been featured in functional or case studies. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318641/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0010592 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0043251 infores:hetionet CHEBI:52717 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020461 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151773 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0031117 infores:hetionet CHEBI:8888 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030252 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004001 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0009492 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0302295 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006147 infores:hetionet CHEBI:6073 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0002962 infores:hetionet CHEBI:5959 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0151539 infores:hetionet CHEBI:49375 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0037763 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0855644 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0855644 infores:hetionet CHEBI:64019 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0018681 infores:hetionet CHEBI:28593 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0857305 infores:hetionet CAID:CA248613 biolink:causes MONDO:0011071 infores:clingen CAID:CA248613 MONDO:0011071 PMID:23848403PMID:17290219PMID:11830488PMID:11830488PMID:11830488PMID:11830488 Pathogenic PS3, PP1_Strong, PM5_Supporting, PM1, PM2_Supporting, PS4_Supporting, PP3 PS1, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BS3, BS1, BS4, BP7, BP5, PM4, PM3, PP2, PP4, BS2 Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.328A>G (p.Lys110Glu) variant and data from secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 23848403; 17290219; 11830488). This variant was found to co-segregate with disease in multiple affected family members, with 7 meioses observed in one pedigree (PP1_Strong; PMID: 11830488). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). This variant is a missense change at the same residue (p.K110) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 1518631, 14465) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM1, PM2_supporting, PP3, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248613/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5138 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0853089 infores:hetionet CHEBI:131512 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0234233 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0012833 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235919 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235919 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0162429 infores:hetionet CHEBI:3172 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0011991 infores:hetionet CHEBI:8327 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0015230 infores:hetionet CHEBI:63610 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0424790 infores:hetionet NCBIGene:51692 biolink:causes MONDO:0859250 infores:monarchinitiative not_provided not_provided HGNC:2326 MONDO:0859250 uuid:88708f1f-1d3c-45d3-803a-b98dbb555b5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0002905 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0026884 infores:hetionet CHEBI:4784 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0428977 infores:hetionet CHEBI:75275 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C1322281 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0037274 infores:hetionet NCBIGene:463 biolink:causes MONDO:0700275 infores:monarchinitiative not_provided not_provided HGNC:777 MONDO:0700275 uuid:afa88835-29a8-4421-90af-c80e4cb9d6b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085681 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0232459 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0031117 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0221490 infores:hetionet CHEBI:9332 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0035410 infores:hetionet CHEBI:3642 biolink:causes GO:0090075 infores:drugmechdb knowledge_assertion manual_agent DRUGBANK:DB00856 GO:0090075 DB00856_MESH_D009128_1 CHEBI:32315 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0152128 infores:hetionet CHEBI:119915 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014866 infores:hetionet CHEBI:63627 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0002994 infores:hetionet CHEBI:6541 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0917801 infores:hetionet CHEBI:61049 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0036690 infores:hetionet CHEBI:84883 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0015967 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0003123 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0423602 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0002170 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020538 infores:hetionet CHEBI:5959 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0033575 infores:hetionet CHEBI:18358 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0013395 infores:hetionet CHEBI:94385 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0017178 infores:hetionet CHEBI:3242 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0011168 infores:hetionet CHEBI:135351 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0917801 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0027051 infores:hetionet CHEBI:32192 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0041834 infores:hetionet CAID:CA296066 biolink:causes MONDO:0021060 infores:clingen CAID:CA296066 MONDO:0021060 PMID: Uncertain Significance PP3, PP2 PM1, PM5, PM2, BS2 The c.367C>T (p.Arg123Cys) variant in HRAS was present in 0.008674% (3/34586) of Latino alleles in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been observed in the unaffected parents of probands whose phenotypes were not consistent with RASopathies; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000207857.9; Baylor Genetics internal data). HRAS has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg123Cys variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296066/MONDO:0021060/004 2020-07-23 2020-07-27 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA7330668 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330668 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting PVS1, BA1, BP2, BS2, PP3, PP1, PP4, PM4, PM5, PS1, PS3, PS2, PS4, BS1, BS3, BS4, BP7 The NM_177438.2:c.5382G>C variant in DICER1 is a missense variant predicted to cause substitution of Glutamic Acid by Aspartic Acid at amino acid 1794 (p.Glu1794Asp). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides within the RNase IIIb domain of DICER1 (PM1_Supporting; PMID: 31342592). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.228: MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_supporting, PM2_Supporting, BP4. (Bayesian Points: 1; VCEP specifications version 1.4.0, 08/26/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330668/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:3691 biolink:causes MONDO:0009183 infores:monarchinitiative not_provided not_provided HGNC:6158 MONDO:0009183 uuid:6807eb14-6b39-4cee-b7df-3b48ba3921f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28148 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0040586 infores:hetionet CHEBI:5790 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0011175 infores:hetionet CHEBI:31413 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C1384353 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151735 infores:hetionet CHEBI:27436 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0018418 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017601 infores:hetionet CHEBI:6640 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0013144 infores:hetionet CHEBI:408174 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0149512 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1720798 infores:hetionet CHEBI:8093 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0012833 infores:hetionet CHEBI:3223 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0028734 infores:hetionet CHEBI:100241 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0149745 infores:hetionet CHEBI:8764 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0497156 infores:hetionet CHEBI:3219 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0018681 infores:hetionet CHEBI:408174 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0017979 infores:hetionet CHEBI:7476 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0404521 infores:hetionet CHEBI:3387 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0728899 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0423226 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0423226 infores:hetionet CHEBI:6444 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0000737 infores:hetionet CHEBI:6062 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0520966 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0042109 infores:hetionet CHEBI:3614 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0030554 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0236071 infores:hetionet CHEBI:72564 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0015230 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0016034 infores:hetionet CHEBI:3485 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0017178 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0021843 infores:hetionet CAID:CA10585164 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585164 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, PP2, PP1, BS2 The NM_000527.5(LDLR):c.865T>C (p.Cys289Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM1 - Variant meets PM2 and alters Cys289, one of the cysteine residues listed; PM2 - This variant is absent from gnomAD (gnomAD v4.1.0); PP3 - REVEL = 0.933; PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded; PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case fulfilling Japanese Atherosclerosis Society criteria from PMID: 35929461 (Funabashi et al., 2022), Japan; 1 case fulfilling internationally accepted criteria for FH from PMID: 16314194 (Robles-Osorio et al., 2006), Mexico). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585164/MONDO:0007750/013 2025-01-31 2025-02-27 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:31236 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0521591 infores:hetionet CHEBI:9398 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0010200 infores:hetionet NCBIGene:346171 biolink:causes MONDO:0011073 infores:monarchinitiative not_provided not_provided HGNC:18791 MONDO:0011073 uuid:2767a6fd-e520-494e-b4ab-55474f159a8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013395 infores:hetionet CHEBI:51380 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0002878 infores:hetionet CAID:CA10585700 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585700 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Strong, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, BS2 NM_000527.5(LDLR):c.1965C>G (p.Phe655Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM2, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_strong - Segregation data are published in PMID: 8634338 = 6 informative meiosis.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2. 2 cases fulfilling Simon-Broome criteria published in PMID: 8634338.PS4_supporting - Variant meets PM2. Variant identified in 2 unrelated index cases (2 cases fulfilling Simon-Broome criteria published in PMID: 8634338). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585700/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6339 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017979 infores:hetionet CHEBI:42944 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0035078 infores:hetionet CHEBI:3506 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0036830 infores:hetionet CHEBI:51209 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0012833 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0014742 infores:hetionet CHEBI:39867 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0016867 infores:hetionet CHEBI:71223 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0022661 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0948089 infores:hetionet CAID:CA16039654 biolink:causes MONDO:0021057 infores:clingen CAID:CA16039654 MONDO:0021057 PMID: Uncertain Significance PM2_Supporting BS2, PVS1 The NM_000038.6(APC):c.8446C>T (p.Arg2816Ter) variant in APC is a nonsense variant located downstream of codon 2645, therefore PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in two individuals without a colorectal cancer/polyposis associated phenotype worth 1 healthy individual point in total (BS2 not met; internal data Labcorp Genetics (formerly Invitae) and Ambry). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16039654/MONDO:0021057/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:D27V6190PM biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0235290 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0006826 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007137 infores:hetionet CAID:CA059964 biolink:causes MONDO:0007783 infores:clingen CAID:CA059964 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Proline with Leucine at codon 4501 of the RYR1 protein, p.(Pro4501Leu). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0181, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA059964/MONDO:0007783/012 2021-03-16 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:4514 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0040053 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151779 infores:hetionet CHEBI:4469 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0008031 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0020538 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0235511 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0235511 infores:hetionet CHEBI:50777 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0085633 infores:hetionet CHEBI:63630 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0016655 infores:hetionet CHEBI:6741 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0085932 infores:hetionet CHEBI:65173 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0013404 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151849 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0025061 infores:hetionet NCBIGene:4361 biolink:causes MONDO:0024557 infores:monarchinitiative not_provided not_provided HGNC:7230 MONDO:0024557 uuid:96f8e787-3770-4ffd-96dc-ad1970b4999c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0039971 infores:hetionet CHEBI:100246 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0700345 infores:hetionet CAID:CA10584771 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584771 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BP4, BP3, BA1, PS1, PS3, BS1, BS3, PM5, PM4, PVS1 The NM_000527.5(LDLR):c.169G>A (p.Asp57Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met.PP3: REVEL= 0.791. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 1 case fulfilling WHO criteria published in PMID: 20145306 (Chmara et al., 2010). So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584771/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA10014479 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014479 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.546C>A (p.Asn182Lys) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014479/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6539 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0001824 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0232459 infores:hetionet CHEBI:68647 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0027497 infores:hetionet CHEBI:6717 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0020625 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020456 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0855242 infores:hetionet NCBIGene:23065 biolink:causes MONDO:0014811 infores:monarchinitiative not_provided not_provided HGNC:28957 MONDO:0014811 uuid:3268ef4e-456b-495b-a124-e5236e3bf6f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18358 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0231218 infores:hetionet CHEBI:2639 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0022346 infores:hetionet CHEBI:7903 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0034642 infores:hetionet CAID:CA321113 biolink:causes MONDO:0019169 infores:clingen CAID:CA321113 MONDO:0019169 PMID: Pathogenic PP4, PM6_Supporting, PM2, PVS1 PM4, BS2, BA1, PS2, PS1, BP5, BS1 The c.910C>T; p. R304X variant in the PDHA1 gene is a nonsense mutation resulting in truncation >50bp upstream of the last exon-exon junction in PDHA1 and is predicted to undergo nonsense mediated decay (PVS1). While this mutation occurs in a hotspot domain (aa position R304, phosphorylation loop region), it is predicted to undergo nonsense mediated decay so PM1 was not scored. This variant is absent from population databases (PM2). This variant has been reported once in the literature in an 8-day old patient with neonatal lactic acidosis, microcephaly, hypotonia and psychomotor delay (PMID: 21914562). The variant was not seen in patient’s mother, but maternity was not confirmed (PM6_supporting). Blood pyruvate was significantly elevated at 0.84mM with a lactate/pyruvate ratio of 19, which the PDHA1 Curation Expert Panel agreed was supportive of pathogenicity (PP4). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PVS1, PM2, PM6_supporting, PP4). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 03/10/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA321113/MONDO:0019169/014 2021-04-02 2021-05-06 X-linked inheritance HP:0001417 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA404081052 biolink:causes MONDO:0007750 infores:clingen CAID:CA404081052 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM3, PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP3, PP4, and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype and homozygous for the NM_000527.5(LDLR):c.920A>G (p.Asp307Gly) variant (PMID: 28502510). PP3: REVEL = 0.985. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine). PS4_Supporting: Variant meets PM2 and is identified in at least three index cases who fulfills SB definite criteria for FH after alternative causes of high cholesterol were excluded (PMID: 28502510, M. Arca Lab, Research Lab of Molecular Genetics of Lipid Metabolism, Department of Translational and Precision Medicine). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404081052/MONDO:0007750/013 2023-06-23 2023-07-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:51209 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0278080 infores:hetionet CHEBI:3732 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004364 infores:hetionet CHEBI:100246 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0026826 infores:hetionet CHEBI:64198 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0009763 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0332798 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0332798 infores:hetionet NCBIGene:2560 biolink:causes MONDO:0014942 infores:monarchinitiative not_provided not_provided HGNC:4081 MONDO:0014942 uuid:69eea478-c249-4856-8bb2-68a70bc7ef4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233514 infores:hetionet CHEBI:50131 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151786 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0027765 infores:hetionet NCBIGene:2581 biolink:causes MONDO:0009499 infores:monarchinitiative not_provided not_provided HGNC:4115 MONDO:0009499 uuid:0ec86092-d71a-4154-9107-cf173b0fe5e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA145781 biolink:causes MONDO:0009290 infores:clingen CAID:CA145781 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145781/MONDO:0009290/010 2020-01-21 2020-05-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63791 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040053 infores:hetionet CHEBI:63607 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C1609512 infores:hetionet CHEBI:184555 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0040264 infores:hetionet CHEBI:5120 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0020517 infores:hetionet CHEBI:3699 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0038325 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0007642 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0332575 infores:hetionet GO:0060486 biolink:causes CL:0000158 infores:ubergraph knowledge_assertion manual_agent GO:0060486 CL:0000158 GO:0050936 biolink:causes CL:0000430 infores:ubergraph knowledge_assertion manual_agent GO:0050936 CL:0000430 CAID:CA915940951 biolink:causes MONDO:0007947 infores:clingen CAID:CA915940951 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PM2_Supporting PP2, PP3, BP1, BP4, BP3, BA1, PS3, PS1, PS4, PM4, PM5, BP7, BS1, BS3 NM_00138 c.7383del is a frameshift variant in FBN1 predicted to cause a substitution of a asparagine by a lysine at amino acid position 2461 and a shift in the reading frame, leading to the introduction of a premature stop codon in exon 63; this would result in an absent or disrupted protein (PVS1). This variant was identified in one proband with Marfan syndrome (PP4; Universitair Ziekenhuis Antwerpen). This variant is not present in gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940951/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6061 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0020649 infores:hetionet CHEBI:8802 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0151744 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0037274 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0022893 infores:hetionet CHEBI:18332 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0085633 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0015927 infores:hetionet NCBIGene:3784 biolink:causes MONDO:0011857 infores:monarchinitiative not_provided not_provided HGNC:6294 MONDO:0011857 uuid:e2f1adc3-5498-4bb2-9fb8-fec979771f87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585499 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585499 MONDO:0007750 PMID: Uncertain Significance PM2, PP4, PP1 PS3, PS4, PM5, PP3 The NM_000527.5 (LDLR):c.1552A>G (p. Lys518Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for Definite FH after alternative causes of high cholesterol were excluded, from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation. PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family: 1 affected relative tested positive and 1 unaffected relative tested negative for the variant, reported from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation.PP3 not met: REVEL = 0.593, it is not above 0.75, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing.PS3 not met: Functional data is not available for this variant.PS4 not met: Variant meets PM2 and is identified in less than 2 index case who fulfil FH diagnosis criteria. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1553A>G (p.Lys518Arg) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585499/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:23345 biolink:causes MONDO:0032778 infores:monarchinitiative not_provided not_provided HGNC:17089 MONDO:0032778 uuid:6f9b129b-e056-4e10-a658-4688144b0343 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0340464 infores:hetionet CHEBI:63613 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0011991 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0033975 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0227791 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0035078 infores:hetionet CAID:CA386965322 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965322 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4 The c.700G>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 234 (p.(Glu234Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 15928245). In summary, c.700G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965322/MONDO:0015967/017 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:78543 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020557 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0847033 infores:hetionet CHEBI:6904 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0001824 infores:hetionet NCBIGene:775 biolink:causes MONDO:0012742 infores:monarchinitiative not_provided not_provided HGNC:1390 MONDO:0012742 uuid:48f54c56-2a1c-48c6-b50c-64002c8aa97e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003862 infores:hetionet GO:2000387 biolink:causes GO:0001541 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0001541 CHEBI:3568 biolink:causes UMLS:C0701821 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0701821 infores:hetionet CHEBI:45081 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C3489393 infores:hetionet CHEBI:31859 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0009782 infores:hetionet CHEBI:18248 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0232462 infores:hetionet CHEBI:3699 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0018524 infores:hetionet CHEBI:6909 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0152030 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0001824 infores:hetionet CAID:CA658797748 biolink:causes MONDO:0700270 infores:clingen CAID:CA658797748 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM4, PM3 The c.9145_9146del variant in ATM is predicted to cause a change in the length of the protein (p.Phe3049Profs*13) due to a frameshift of 8 amino acids and an extension of an additional 4 amino acids. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 10817650). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM4, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA658797748/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50275 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0018418 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0036572 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0302295 infores:hetionet CAID:CA137943 biolink:causes MONDO:0021060 infores:clingen CAID:CA137943 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137943/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:31711 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018834 infores:hetionet CHEBI:32588 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0009450 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0021400 infores:hetionet CHEBI:135736 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C2939447 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0032285 infores:hetionet CHEBI:4798 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1142135 infores:hetionet NCBIGene:2512 biolink:causes MONDO:0014274 infores:monarchinitiative not_provided not_provided HGNC:3999 MONDO:0014274 uuid:53de9c26-c6ae-4366-8771-6e5207df5ce9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA9871460 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871460 MONDO:0007064 PMID: Uncertain Significance BS2, PM5 The c.941A>G (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Aspartic Acid by Glycine at amino acid 314( p.Asp314Gly).The highest population minor allele frequency in gnomAD v2.1.1 is 0.0006757 (20/19954 alleles) in the East Asian population. PM2_Supporting (<0.0001742), BS1 (>0.00161), and BA1 (>0.00721) are not met. No homozygotes have been observed in gnomAD.Another missense variant [c.940G>T, p.Asp314Tyr] in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871460/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:80630 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0267537 infores:hetionet CHEBI:4858 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0231530 infores:hetionet CHEBI:45951 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0013404 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0149745 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030312 infores:hetionet CHEBI:6128 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C1142412 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001044 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0014850 infores:hetionet CAID:CA355962032 biolink:causes MONDO:0001586 infores:clingen CAID:CA355962032 MONDO:0001586 PMID: Uncertain Significance PP3, PM2_Supporting PS3, BS3 The NM_000203.5:c.669C>G variant in IDUA is a missense variantpredicted to cause substitution of aspartic acid by glutamic acid at amino acid 223 (p.Asp223Glu). To our knowledge, the results of functional assays have not been reported for this variant and this variant has not been reported in the literature in any individuals with MPS1. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002671 (2/74888 alleles; no homozygotes) in the African / African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.704 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 1968567. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355962032/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:82960 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1760428 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0085762 infores:hetionet CHEBI:2955 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0004096 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0234215 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0018798 infores:hetionet CHEBI:404903 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020672 infores:hetionet CAID:CA512318624 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318624 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS2, PS4, PS1, BP2, BP3, BA1, PM6, PVS1, BS1, BS3, BS4, PM5, PM3, PM4, BS2, PP3, PP1, PP4 The c.699C>T (p.Arg233=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4). In addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -0.0383071 in GRCh38), and the variant is the reference nucleotide in one primate and/or three mammal species. Although the variant is absent from gnomAD v2 and v3 (PM2_Supporting), it has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318624/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:70746 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0006266 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0021845 infores:hetionet CHEBI:63629 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0022346 infores:hetionet CHEBI:64355 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0041657 infores:hetionet CHEBI:2682 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0042963 infores:hetionet UMLS:C0004609 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042024 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0018099 infores:hetionet CHEBI:5790 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0220870 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0013922 infores:hetionet CHEBI:63617 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0043094 infores:hetionet CHEBI:5893 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0558489 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0476414 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0476414 infores:hetionet CHEBI:3479 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0011603 infores:hetionet CHEBI:3423 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0018524 infores:hetionet CHEBI:44185 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0034642 infores:hetionet CHEBI:2955 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011606 infores:hetionet CHEBI:6822 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C2047937 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011551 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018021 infores:hetionet CAID:CA1139665145 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665145 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c.1039del (p.Ala347Profs*6) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity; a second distinct pathogenic or likely pathogenic variant in ACADVL was not reported in this individual (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 07-03-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665145/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16469 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0005741 infores:hetionet NCBIGene:5897 biolink:causes MONDO:0009306 infores:monarchinitiative not_provided not_provided HGNC:9832 MONDO:0009306 uuid:d2173c21-1f05-4e02-8525-15d44c116b4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0152031 infores:hetionet CAID:CA120547 biolink:causes MONDO:0044970 infores:clingen CAID:CA120547 MONDO:0044970 PMID: Pathogenic PM2_Supporting, PS4, PS3_Supporting PP1, PP3, BP4, PS2, PM6 The m.7445A>G variant is located in the MT-TS1 precursor, overlapping with MT-CO1 (Term514Term). This variant has been reported in at least 32 individuals with primary mitochondrial disease, and the only consistent reported feature in affected individuals was hearing loss (PS4; PMIDs: 8019558, 8572257, 9450881, 11069477, 11175301, 15620132, 16092542, 15987292, 23525847, 18537605, 22567359, 21621438, 30035268, 26328603, 29605341, 32169613). Some individuals with this variant have normal hearing, others have hearing loss following aminoglycoside exposure, and others have hearing loss and no known aminoglycoside exposure. The age of onset ranges from infancy to adulthood. The variant is primarily seen in the homoplasmic state however some individuals were reported to have low heteroplasmy levels in blood. Several extended families have been reported in the medical literature however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for segregation evidence of pathogenicity. There are no reports of de novo occurrences in the medical literature to our knowledge however the presence of this variant in individuals from different haplogroups suggests this variant occurred de novo in the ancestors of these individuals of different backgrounds. Of note, another 137 elderly individuals were found to carry this variant in platelets with heteroplasmy levels >2%, and this was reported to significantly correlate with high frequency hearing loss (PMID: 26328603), however these cases were excluded from this curation given the lack of other clinical details. There is one occurrence of this variant in the Mitomap GenBank dataset, however this is from an individual with known mitochondrial disease. This variant is absent in gnomAD v3.1.2. There are six heteroplasmic occurrences in the Helix dataset. Although there are several occurrences, the frequency is still low (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Cybrid studies supported the functional impact of this variant (PS3_supporting). One study showed a 60-70% reduction of steady state ND6 levels and 40-50% reduction of tRNASer (PMID: 15694374). Other cell line studies showed significantly reduced Complex I activity, with lesser reduction in Complex IV (P=0.05; PMID 29934116). Of note, there is one early cell line study that did not demonstrate any bioenergetic impact of this variant (PMID: 9247714). In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the extent of cases with similar phenotypes from different ethnic backgrounds that have been reported, that is further supported by the evidence outlined above. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120547/MONDO:0044970/015 2022-08-08 2023-04-03 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA320637976 biolink:causes MONDO:0011071 infores:clingen CAID:CA320637976 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2, PP3 PS4, BP1, BP4, BP3, PVS1, BP5, BP7, PM3, BS2, PP2, PP4 NM_001754.5(RUNX1):c.431T>C (p.Leu144Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). The variant has a REVEL score ≥ 0.88 (0.97) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_Supporting). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3, PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320637976/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10101 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0014868 infores:hetionet CHEBI:16714 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0152227 infores:hetionet CHEBI:6761 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0039070 infores:hetionet NCBIGene:2138 biolink:causes MONDO:0007236 infores:monarchinitiative not_provided not_provided HGNC:3519 MONDO:0007236 uuid:cdae10fe-70a3-43dc-bc43-6142dfc08d2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0013182 infores:hetionet CHEBI:63608 biolink:causes UMLS:C1388177 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1388177 infores:hetionet NCBIGene:6640 biolink:causes MONDO:0013062 infores:monarchinitiative not_provided not_provided HGNC:11167 MONDO:0013062 uuid:e034a1e1-824f-4a3e-842b-86cbdca06e3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017574 infores:hetionet CHEBI:8764 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013428 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0851341 infores:hetionet CHEBI:9927 biolink:causes MONDO:0800029 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C1800706 infores:hetionet CHEBI:52172 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C2586050 infores:hetionet CHEBI:75988 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0151766 infores:hetionet CHEBI:47898 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0037763 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0029456 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0037199 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2973529 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0034150 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0004936 infores:hetionet CHEBI:7931 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0023052 infores:hetionet CAID:CA410203406 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203406 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.334C>G (p.Leu112Val) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score ≥ 0.88 (0.89) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203406/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63619 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2363730 infores:hetionet CHEBI:68554 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0242301 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0234458 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0149871 infores:hetionet CHEBI:29007 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0085631 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009319 infores:hetionet NCBIGene:5977 biolink:causes MONDO:0054831 infores:monarchinitiative not_provided not_provided HGNC:9964 MONDO:0054831 uuid:ec87bbee-9a8a-4edb-b555-2f2ba0bf8e9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1904266 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:1904266 GO:0070887 CHEBI:144551 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0033774 infores:hetionet CHEBI:46345 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C1262036 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042075 infores:hetionet CAID:CA386965978 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965978 MONDO:0015967 PMID:26431509 Uncertain Significance PM2_Supporting, PM1_Supporting, PS3_Supporting, PP3 PM5, PP1, PP4 The c.761T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to glycine at codon 254 (p.(Leu254Gln)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.931 (PP3), which is greater than or equal to the MDEP threshold of 0.70. Functional studies demonstrated the p.Leu254Gln protein has transactivation below 40% of wildtype (PMID: 26431509; PS3_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 26431509). Additionally, one independent occurrence does not meet the MDEP cutoff for PS4_Moderate. Another missense variant, c.760C>A p.Leu254Met, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.761T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting, PP3, PM1_Supporting, PS3_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965978/MONDO:0015967/017 2022-06-28 2022-06-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:30830 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0035455 infores:hetionet CHEBI:5165 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0917801 infores:hetionet CHEBI:16755 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0017181 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0031039 infores:hetionet CHEBI:31547 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0438142 infores:hetionet CHEBI:7577 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0037763 infores:hetionet CHEBI:39867 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013428 infores:hetionet CHEBI:4887 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C2830004 infores:hetionet CHEBI:231594 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0235660 infores:hetionet CHEBI:31302 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0015672 infores:hetionet NCBIGene:1373 biolink:causes MONDO:0009376 infores:monarchinitiative not_provided not_provided HGNC:2323 MONDO:0009376 uuid:2d0adbad-451c-4807-a89f-9e55922c249c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0281773 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0281773 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042594 infores:hetionet CHEBI:4672 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C2939420 infores:hetionet CHEBI:35854 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0013362 infores:hetionet CAID:CA414917675 biolink:causes MONDO:0010602 infores:clingen CAID:CA414917675 MONDO:0010602 PMID: Uncertain Significance PM5, PS4_Supporting, PM2_Supporting, PP3 The c.980T>G (p.Leu327Arg) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This variant has been reported in one proband with severe hemophilia A, meeting phenotypic criteria for F8 (PS4_Supporting; PMID: 18217193). This missense variant has a REVEL score of 0.916 (>0.6) meeting PP3. A pathogenic variant, Leu327Val, is reported at the same residue meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM2_Supporting, PS4_Supporting, PP3, PM5. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414917675/MONDO:0010602/071 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Inconclusive true CHEBI:31236 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0029408 infores:hetionet CHEBI:94440 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0039070 infores:hetionet CHEBI:37333 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0220870 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042109 infores:hetionet CHEBI:65173 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0002453 infores:hetionet UMLS:C0004609 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1321898 infores:hetionet CHEBI:45863 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042029 infores:hetionet CHEBI:52717 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019270 infores:hetionet CHEBI:6958 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0025061 infores:hetionet CHEBI:114785 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0206062 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151514 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151763 infores:hetionet CHEBI:9725 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0002453 infores:hetionet CHEBI:3219 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2830004 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011615 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0022893 infores:hetionet CHEBI:28593 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0015230 infores:hetionet CHEBI:79699 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011175 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013922 infores:hetionet CHEBI:9654 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0575081 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0030312 infores:hetionet CHEBI:70735 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0004604 infores:hetionet CAID:CA512318594 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318594 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS2, PS4, PS1, PS3, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.744C>T (p.Asn248=) is a synonymous variant predicted by SSF and MES to lead to either an increase or a decrease in the canonical splice site score by no more than 10%, with no putative cryptic splice sites created (BP4). However, evolutionary conservation algorithms predict the site as being moderately conserved (PhyloP score: 2.55) and the variant is not the reference nucleotide in one primate and/or three mammal species. This variant is also absent from population databases (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318594/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6375 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0022346 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009782 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042075 infores:hetionet CHEBI:6888 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0004093 infores:hetionet CHEBI:134991 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0023218 infores:hetionet CHEBI:53760 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1306341 infores:hetionet CHEBI:6715 biolink:causes NCIT:C3887 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0241619 infores:hetionet CHEBI:3011 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0026826 infores:hetionet GO:0060922 biolink:causes CL:1000410 infores:ubergraph knowledge_assertion manual_agent GO:0060922 CL:1000410 CHEBI:7444 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0026896 infores:hetionet CHEBI:3698 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C2047937 infores:hetionet CHEBI:7459 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0085631 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0004936 infores:hetionet CAID:CA314820 biolink:causes MONDO:0012999 infores:clingen CAID:CA314820 MONDO:0012999 PMID: Likely Benign PM2_Supporting, BS3_Supporting, BP4 PM5 The NM_000156.6:c.587C>T variant in GAMT is a missense variant that is predicted to cause the substitution of an alanine by a valine at amino acid position 196 (p.Ala196Val). This variant has been previously reported as a heterozygous variant detected in the context of newborn screening in Dutch newborns (PMID: 26319512). Expression of the variant in GAMT-deficient fibroblasts resulted in similar activity as wild type GAMT indicating that this variant does not impact protein function (PMID: 26319512) (BS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001043 (123/1179840 alleles; no homozygotes) in the European (Non-Finnish) population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.267 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205588). Although there is conflicting evidence, with two benign criteria met (BP4 and BS3_Supporting) and one pathogenic criterion met (PM2_Supporting), the consensus from the ClinGen CCDS VCEP is that this variant is likely benign for GAMT deficiency, based upon the in silico and functional evidence. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BS3_Supporting, BP4 (classification modified to likely benign)(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314820/MONDO:0012999/026 2024-09-11 2025-03-13 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31980 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0236071 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0016436 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042571 infores:hetionet CHEBI:17474 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0086565 infores:hetionet CHEBI:68855 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0151828 infores:hetionet CHEBI:5959 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0151766 infores:hetionet CHEBI:64310 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0041969 infores:hetionet CHEBI:51041 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085702 infores:hetionet CHEBI:52010 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0235198 infores:hetionet CAID:CA343720163 biolink:causes MONDO:0005338 infores:clingen CAID:CA343720163 MONDO:0005338 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting BP7, BS1, BS3, PVS1, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BP4, BA1 The c.24C>A variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Cysteine at amino acid 8 (p.Cys8Ter). Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with juvenile or primary open angle glaucoma (JOAG or POAG) is not loss-of-function. This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 2 probands with JOAG have been reported carrying this variant (PMID: 18385784), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343720163/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64312 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0543467 infores:hetionet CHEBI:64028 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0233794 infores:hetionet CHEBI:31205 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0149745 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0040409 infores:hetionet NCBIGene:546 biolink:causes MONDO:0010328 infores:monarchinitiative not_provided not_provided HGNC:886 MONDO:0010328 uuid:c965d836-8a36-4684-be13-4e8a1a6f8205 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0018681 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0851341 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0151763 infores:hetionet CHEBI:101853 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0016382 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0003123 infores:hetionet CHEBI:31980 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0018790 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0014130 infores:hetionet CHEBI:10127 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011124 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0001125 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0005649 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D001064 DB00319_MESH_D001064_1 CHEBI:85161 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0042373 infores:hetionet CHEBI:8884 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0020538 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0549373 infores:hetionet CHEBI:5118 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018944 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020625 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0042373 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151936 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0009324 infores:hetionet CHEBI:77260 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0852911 infores:hetionet NCBIGene:5376 biolink:causes MONDO:0008087 infores:monarchinitiative not_provided not_provided HGNC:9118 MONDO:0008087 uuid:56274511-3a5f-464a-80f5-1f3df581477e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0027769 infores:hetionet NCBIGene:5336 biolink:causes MONDO:0013766 infores:monarchinitiative not_provided not_provided HGNC:9066 MONDO:0013766 uuid:1a4607da-236a-4807-9960-61aea15231dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0008311 infores:hetionet CHEBI:8863 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018965 infores:hetionet CHEBI:16714 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0033774 infores:hetionet NCBIGene:3977 biolink:causes MONDO:0800043 infores:monarchinitiative not_provided not_provided HGNC:6597 MONDO:0800043 uuid:4489fec4-a7c3-4ba6-a57f-ae57058a8012 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0016436 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0006444 infores:hetionet CHEBI:194135 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085605 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0025061 infores:hetionet CHEBI:135342 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0003537 infores:hetionet CHEBI:3423 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0038999 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0015397 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002418 infores:hetionet CHEBI:28177 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0001925 infores:hetionet CHEBI:9674 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0028084 infores:hetionet CHEBI:38940 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C2717961 infores:hetionet CHEBI:2654 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0744727 infores:hetionet CHEBI:94385 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0017168 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0948594 infores:hetionet CAID:CA382559953 biolink:causes MONDO:0700270 infores:clingen CAID:CA382559953 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PS3_Supporting, PP3 The c.7355T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 2452 (p.Leu2452Pro). This variant has been detected in at least two individuals with Ataxia-Telangiectasia (PMIDs: 19431188, 26896183). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. Western blotting in ATM null cells transfected with cDNA carrying this variant showed inactive phosphorylation of ATM downstream targets as compared to wild-type controls, indicating that this variant impacts protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.914, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Strong, PM2_Supporting, PS3_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382559953/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CAID:CA1624555 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624555 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1770G>A (p.Glu590=) variant in the SOS1 gene is 0.29% (34/8634) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624555/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:5205 biolink:causes MONDO:0009469 infores:monarchinitiative not_provided not_provided HGNC:3706 MONDO:0009469 uuid:49e588ef-f317-4754-802f-a4e1917c8cbe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013428 infores:hetionet CAID:CA8603099 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603099 MONDO:0100326 PMID: Pathogenic PM3, PVS1, PP4_Moderate PM2, PP1 The NM_000419.5:c.1424_1427dup (p.Ala477GlyfsTer111) variant in ITGA2B exon 14 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 18/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least three probands with Glanzmann thrombasthenia. One of those individuals (GT70, PMID: 19691478) was compound heterozygous for this variant and an ITGA2B variant provisionally classified as pathogenic by the Platelet Disorders VCEP (c.2674_2675insGA (p.Ile892ArgfsTer19), phase not confirmed). The other two individuals (GT20, PMID: 19691478 and PMID: 34267460) were homozygous for the variant. At least one patient (Patient GT20 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001960 (6/30616 alleles) in the South Asian population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. Of note, this variant may represent a founder variant, as it was not observed in any other population in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3, PP4_Moderate. (VCEP specifications version 2; date of approval 03/15/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603099/MONDO:0100326/011 2022-03-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:7276 biolink:causes MONDO:0007785 infores:monarchinitiative not_provided not_provided HGNC:12405 MONDO:0007785 uuid:df082333-567d-4551-9685-0624e656b423 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA228441 biolink:causes MONDO:0013304 infores:clingen CAID:CA228441 MONDO:0013304 PMID: Uncertain Significance PP4 PM2, PP3, PP1, BS2, BP2, PS3, PS4, PM5, BP5 The NM_000552.5:c.3797C>A variant in VWF is a missense variant predicted to cause substitution of proline by glutamine at amino acid 1266. Population and in silico predictors were between the pathogenic and benign thresholds for the respective codes. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and no loss of HMW multimers (described as non-selective loss and low intensity but high molecular weight bands are still present), which is specific for VWD type 2M (PP4, PMID 23179108).The majority of reported cases were asserted as VWD type 2M but there were also assertions for type 2B and type 1. No reported case in the literature had a combination of activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced platelet binding. There is conflicting evidence of altered platelet binding phenotype evidenced by in vitro assays showing both enhanced GPIb and decreased GPIb binding (PMIDs 23179108, 30488424). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant VWD type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228441/MONDO:0013304/081 2025-05-06 2025-06-26 Undetermined mode of inheritance Inconclusive true CHEBI:231594 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0028643 infores:hetionet CHEBI:520985 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0085616 infores:hetionet CHEBI:3176 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0037763 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0038587 infores:hetionet CHEBI:8069 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0018681 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0036572 infores:hetionet CHEBI:17141 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0018520 infores:hetionet CHEBI:3207 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0016204 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0015397 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0006826 infores:hetionet CAID:CA10584802 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584802 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 The NM_000527.5(LDLR):c.240C>A (p.Asn80Lys)variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1) BP4 - REVEL = 0.389. It is below 0.50. splicing evaluation required. Functional data not availableA) not on limitsB) does not create AG or GTVariant is not predicted to alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584802/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:107736 biolink:causes UMLS:C0239779 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0239779 infores:hetionet CHEBI:40279 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0231218 infores:hetionet CHEBI:50922 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151610 infores:hetionet CHEBI:63598 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042024 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0006145 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0021167 infores:hetionet CAID:CA410203814 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203814 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, BP1, BP3, BA1, BS1, BS3, BP5, PM3, PM5, PP2, PP4, BS2 NM_001754.5(RUNX1):c.245T>A (p.Leu82Gln) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203814/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004936 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0027765 infores:hetionet CHEBI:32293 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0877359 infores:hetionet CHEBI:6437 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0040460 infores:hetionet CHEBI:49960 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0234632 infores:hetionet CHEBI:48669 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0007682 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0020366 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0020302 infores:hetionet CHEBI:41774 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0206062 infores:hetionet CHEBI:50122 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0002994 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0020517 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0021053 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0011849 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0003123 infores:hetionet CAID:CA16020888 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020888 MONDO:0009861 PMID:20140859 Pathogenic PVS1, PM2, PP4 PM3 The c.901C>T (p.Q301*) variant in PAH has been reported in at least one patient with PKU (PMID: 20140859). This is a nonsense variant that occurs in exon 9 of PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. This variant is absent from population databases, including: 1000 Genomes, ESP, and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020888/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0948594 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0031350 infores:hetionet CAID:CA2387284481 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387284481 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.588del (p.Val197fs) is a frameshift variant. Null variant predicted to undergo NMD and exon is present in biologically relevant transcripts (PVS1, SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Frameshift variant downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387284481/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5280 biolink:causes MONDO:0004926 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0010930 infores:hetionet CHEBI:205919 biolink:causes UMLS:C1142160 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C1142160 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0233494 infores:hetionet CHEBI:4470 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0699828 infores:hetionet CAID:CA5252743 biolink:causes MONDO:0008535 infores:clingen CAID:CA5252743 MONDO:0008535 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS1 The NM_001114753.3: c.1517T>A variant in ENG is a missense variant predicted to cause substitution of leucine by histidine at amino acid 506 (p.Leu506His). This variant has been reported in 2 probands with a phenotype consistent with HHT (PS4_Moderate; Internal lab contributors). The computational predictor REVEL gives a score of 0.88, which is above the threshold of ≥0.644, evidence that correlates with impact to ENG function (PP3). The overall minor allele frequency in gnomAD v2.1.1 is 0.000004 (1/250772 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant, c.1517T>C, p.Leu506Pro (PMID: 24196379, 30073140; ClinVar Variation ID: 1774348), in the same codon has been classified as likely pathogenic for autosomal dominant Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4_Moderate, PP3, PM2_Supporting, PM5 (specifications version 1.1.0; 02/04/2025). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5252743/MONDO:0008535/136 2025-02-04 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17347 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1384353 infores:hetionet CHEBI:5118 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015672 infores:hetionet CHEBI:4814 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0015967 infores:hetionet CHEBI:77260 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042029 infores:hetionet CAID:CA10558461 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558461 MONDO:0010726 PMID: Likely Benign BP5, BS2 PM4, BS1, PM6 The p.Glu394_Pro405del variant in MECP2 (NM_004992.4) is observed in at least 20 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Glu394_Pro405del variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5). The highest population minor allele frequency of the p.Glu394_Pro405del variant in MECP2 in gnomAD v4.1 is 0.00003691 in European (non-Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Glu394_Pro405del variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558461/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:9738 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0018681 infores:hetionet CHEBI:6715 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0018834 infores:hetionet CHEBI:4911 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0237849 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020649 infores:hetionet GO:1904838 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:1904838 GO:0030154 CHEBI:8207 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0027051 infores:hetionet CHEBI:553473 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0002792 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0025061 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015376 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233471 infores:hetionet CHEBI:7936 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020461 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0162848 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0241863 infores:hetionet CHEBI:17076 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0042109 infores:hetionet CHEBI:87681 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0040264 infores:hetionet CHEBI:7824 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1321898 infores:hetionet NCBIGene:5447 biolink:causes MONDO:0013310 infores:monarchinitiative not_provided not_provided HGNC:9208 MONDO:0013310 uuid:3eabd00c-187d-42b3-8dbd-099f33de4730 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151736 infores:hetionet CHEBI:3176 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0013378 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1458155 infores:hetionet CHEBI:100241 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013456 infores:hetionet CHEBI:31348 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151825 infores:hetionet CHEBI:68478 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0041657 infores:hetionet CHEBI:132233 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0038325 infores:hetionet CAID:CA401366477 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366477 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting PM3, PM5 The NM_000152.5:c.1385T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 462 (p.Leu462Pro). The highest population minor allele frequency in gnomAD v4.1.0. is 8.5e-7 (1/1179884 alleles) in the Non-Finnish European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The variant has been reported in an 8 month old male with clinical features consistent with infantile onset Pompe disease and documentation of deficient GAA activity (PMID: 25612604) (PP4_Moderate). This patient is compound heterozygous for the variant and another missense variant that has been classified as likely pathogenic by the ClinGen LD VCEP (PMID: 25612604). Expression of the variant in HEK293 cells (methodology: PMID 36246652) resulted in no GAA activity relative to wild type. Western blot revealed only a precursor (110 kDa) band, evidence of abnormal GAA synthesis and processing (data unpublished) (PS3_moderate). The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 1693548, 3 star review status) with 2 submitters as VUS (1 submitter) or pathogenic (1 submitter). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_supporting, PP4_moderate, PP3, PS3_moderate (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366477/MONDO:0009290/010 2025-06-17 2025-07-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2618 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0234632 infores:hetionet CHEBI:16586 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0041657 infores:hetionet CHEBI:5134 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0019348 infores:hetionet CHEBI:74947 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0341047 infores:hetionet CHEBI:29688 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0033774 infores:hetionet CHEBI:27974 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C3665347 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0025061 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0267596 infores:hetionet CHEBI:8863 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0038450 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0030312 infores:hetionet CHEBI:3127 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0037317 infores:hetionet CHEBI:31638 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C1142412 infores:hetionet CAID:CA16020887 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020887 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.896T>C (p.Phe299Ser) variant in PAH has not been reported in a patient with PKU to our knowledge. It was noted in PMID: 9792411 but the p.Phe299Cys variant is listed as the amino acid change in the table and text, so the actual variant in the patient is unclear. This variant is absent from 1000G, ESP, ExAC and gnomAD and has an extremely low frequency in PAGE (MAF=0.00012). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL. A different pathogenic missense change has been seen at the same amino acid (p.Phe299Cys). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020887/MONDO:0009861/006 2020-02-16 2020-02-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63622 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0026821 infores:hetionet CHEBI:38940 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020461 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0010414 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0521592 infores:hetionet CHEBI:7852 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020429 infores:hetionet CHEBI:4636 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0221490 infores:hetionet CHEBI:31401 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C1443060 infores:hetionet CHEBI:32293 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0039070 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019360 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0024894 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020538 infores:hetionet CHEBI:3207 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0011603 infores:hetionet CHEBI:6367 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011253 infores:hetionet NCBIGene:215 biolink:causes MONDO:0018544 infores:monarchinitiative not_provided not_provided HGNC:61 MONDO:0018544 uuid:2cf77d92-0c4b-4bb9-8d5e-2d3c9aac37ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:87715 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0041969 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0027497 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0234215 infores:hetionet CHEBI:474053 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0009676 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0877046 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005451 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0013473 infores:hetionet CHEBI:3077 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1096274 infores:hetionet CHEBI:2788 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0428977 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1699201 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1699201 infores:hetionet CHEBI:36791 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235198 infores:hetionet CHEBI:27899 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0340865 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002418 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0221706 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0016034 infores:hetionet CHEBI:8502 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0011603 infores:hetionet CHEBI:2637 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C3665346 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0857087 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0857087 infores:hetionet CHEBI:9599 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0476273 infores:hetionet CHEBI:9168 biolink:causes MONDO:0015264 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0242770 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235416 infores:hetionet CAID:CA10014390 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014390 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4_Supporting, BP7, BP5, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP1, PP4 NM_001754.4(RUNX1):c.623A>T (p.Gln208Leu) is a missense variant which has a REVEL score >0.75 (0.848) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014390/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64045 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0042514 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0040479 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0025290 infores:hetionet CHEBI:9316 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0015230 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0263358 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0263358 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0559031 infores:hetionet CHEBI:4702 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0004245 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0007971 infores:hetionet CAID:CA179991 biolink:causes MONDO:0015152 infores:clingen CAID:CA179991 MONDO:0015152 PMID: Benign BA1 BP4 The NM_003494.4: c.3892A>G variant in DYSF, which is also known as NM_001130987.2: c.3946A>G p.(Ile1316Val), is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1298 (p.Ile1298Val). The filtering allele frequency of the variant is 0.006916 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 695/152140), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.12 and the computational predictor REVEL gives a score of 0.42. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA179991/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9123 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0522178 infores:hetionet CHEBI:474180 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0744727 infores:hetionet CHEBI:119915 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0036974 infores:hetionet CAID:CA413497163 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497163 MONDO:0010315 PMID: Pathogenic PM1_Strong, PP4_Moderate, PM5, PS4_Supporting, PM2_Supporting NM_000206.3(IL2RG):c.184T>C is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 62 (p.Cys62Arg). This mutation affects conserved cysteine residue i.e. Cys62 (PM1_strong). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.),T-B+NK- lymphocyte subset profile (0.5 pt.); total : 2.5 pts (PP4_Moderate) (Invitae).Another missense variant [NM_000206.3(IL2RG):c.186T>A (p.Cys62Ter)] in the same codon has been reported (classified as pathogenic by SCID VCEP) (PM5 met).The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (Invitae, PMID: 27484032) (PS4_supporting).In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_strong, PM2_supporting, PP4_Moderate,PM5 met,PS4_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497163/MONDO:0010315/129 2024-06-12 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:8871 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0424448 infores:hetionet CHEBI:4562 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0013395 infores:hetionet CHEBI:16796 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0007859 infores:hetionet CHEBI:205919 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0033774 infores:hetionet CHEBI:3082 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0023380 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013595 infores:hetionet CHEBI:231594 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0023222 infores:hetionet CHEBI:4953 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0019825 infores:hetionet CHEBI:55346 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0033774 infores:hetionet CHEBI:42797 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002994 infores:hetionet CHEBI:3176 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0085631 infores:hetionet CHEBI:2788 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0012833 infores:hetionet CHEBI:50924 biolink:causes HP:0032545 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0159066 infores:hetionet CHEBI:17026 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0000731 infores:hetionet CHEBI:7903 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0013404 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0234916 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1720775 infores:hetionet CHEBI:6413 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0043094 infores:hetionet CHEBI:39112 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0027441 infores:hetionet CHEBI:7823 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0235146 infores:hetionet CHEBI:16469 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0011168 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0027765 infores:hetionet CHEBI:2208 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0002170 infores:hetionet CHEBI:41774 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0003467 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0860866 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0851341 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020473 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0040479 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0020517 infores:hetionet CHEBI:50275 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020433 infores:hetionet CHEBI:6339 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013491 infores:hetionet NCBIGene:57107 biolink:causes MONDO:0013838 infores:monarchinitiative not_provided not_provided HGNC:23041 MONDO:0013838 uuid:d7b86a85-f0fc-4c0a-8c79-2054a5168ac3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009676 infores:hetionet CHEBI:71219 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0854069 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0031350 infores:hetionet CHEBI:2379 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0004245 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0010692 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0027441 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0009806 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0001824 infores:hetionet CHEBI:5132 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0006826 infores:hetionet CAID:CA343776041 biolink:causes MONDO:0013144 infores:clingen CAID:CA343776041 MONDO:0013144 PMID: Likely Pathogenic PVS1_Strong, PM2_Supporting, PS4_Supporting The c.624+1G>A (NM_000488.4) variant in SERPINC1 occurs within the canonical splice donor site (+1) of intron 3. The variant is not predicted to disrupt reading frame, the role of the region is unknown, LoF variants are not common in SERPINC1, the variant is present in transcript NM_000488.4, and is predicted to affect >10% of the protein (15% (71AA in Exon 3/464AA total)) meeting criteria for PVS1_Strong.The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. This variant has been reported in 1 proband with antithrombin activity level of 55 meeting the SERPINC1-phenotypic criteria (AT level of <0.8 IU/mL) (PS4_Supporting; Alhenc-Gelas et al. 2017. PMID: 28300866). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PVS1_Strong, PS4_Supporting, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343776041/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5775 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0022660 infores:hetionet CHEBI:9086 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018834 infores:hetionet CHEBI:6801 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0041834 infores:hetionet CHEBI:6931 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0039231 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0018799 infores:hetionet NCBIGene:8914 biolink:causes MONDO:0031044 infores:monarchinitiative not_provided not_provided HGNC:11813 MONDO:0031044 uuid:3530d028-d4bc-4610-8a68-d4cf6aa10e67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013395 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027769 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C2973529 infores:hetionet CHEBI:63635 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0010200 infores:hetionet CHEBI:47519 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0018681 infores:hetionet CHEBI:39867 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0003467 infores:hetionet CHEBI:53760 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151786 infores:hetionet CAID:CA320251329 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251329 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1310C>G (p.Thr437Ser) is a missense variant that has a REVEL score < 0.50 (0.193) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251329/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63580 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0857305 infores:hetionet CHEBI:3732 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0019209 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0042075 infores:hetionet CHEBI:61033 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0234233 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0948525 infores:hetionet CHEBI:94501 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0013428 infores:hetionet CHEBI:6076 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0018834 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151717 infores:hetionet GO:0050770 biolink:causes GO:0061564 infores:ubergraph knowledge_assertion manual_agent GO:0050770 GO:0061564 CHEBI:4672 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0011644 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0314719 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0162830 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0015397 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0559938 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0559938 infores:hetionet CHEBI:41423 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0001925 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0025061 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0010692 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0243026 infores:hetionet CHEBI:5779 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0012833 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0559546 infores:hetionet CHEBI:6888 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0262431 infores:hetionet CHEBI:4708 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1443060 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0151763 infores:hetionet CHEBI:127342 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0030554 infores:hetionet CHEBI:17347 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151934 infores:hetionet CHEBI:145499 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009676 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0948089 infores:hetionet CHEBI:3654 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0020625 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0178298 infores:hetionet CHEBI:92712 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C2830004 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0151828 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0860803 infores:hetionet CHEBI:10023 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027497 infores:hetionet CHEBI:31524 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0003811 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C2979982 infores:hetionet CHEBI:6339 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0547030 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0518015 infores:hetionet CHEBI:75998 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151662 infores:hetionet CHEBI:116735 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0399459 infores:hetionet CHEBI:45409 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151746 infores:hetionet CHEBI:17630 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0595916 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0700184 infores:hetionet CHEBI:3387 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0004604 infores:hetionet CHEBI:45924 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0015967 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0011972 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085083 infores:hetionet CHEBI:585948 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0040822 infores:hetionet CHEBI:520985 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C1142412 infores:hetionet CHEBI:8874 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0852911 infores:hetionet CHEBI:15854 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042963 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0232492 infores:hetionet CHEBI:45327 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0002792 infores:hetionet CHEBI:3723 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041105 infores:hetionet CHEBI:44185 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018965 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0009806 infores:hetionet CHEBI:63620 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0019270 infores:hetionet CHEBI:367163 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C2240374 infores:hetionet CAID:CA010173 biolink:causes MONDO:0004994 infores:clingen CAID:CA010173 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1095G>A (p.Lys365=) variant in the MYH7 gene is 15.42% (10459/66736) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010173/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9725 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0015967 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0007642 infores:hetionet CHEBI:50378 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0011175 infores:hetionet CHEBI:47781 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0009676 infores:hetionet CHEBI:6950 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151827 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0018939 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151571 infores:hetionet CHEBI:51860 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1760428 infores:hetionet CHEBI:4710 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0041657 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0242073 infores:hetionet CHEBI:63635 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0162830 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0266648 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0266648 infores:hetionet CHEBI:27882 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0027497 infores:hetionet CHEBI:31643 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0013604 infores:hetionet CHEBI:5062 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0018681 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0281981 infores:hetionet CAID:CA402995477 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995477 MONDO:0012999 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS1 "The NM_000156.6:c.391+1G>C variant in GAMT occurs within the canonical splice donor site of intron 3. Both SpliceAI and varSEAK predict the possible use of a cryptic site 7 bp downstream. If this site is used, or if exon 3 is skipped, this variant is predicted to result in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). An adult female with symptoms consistent with GAMT deficiency has been described with ""persistent"" high guanidinoacetate and low creatine in plasma, urine, and dried blood spot, and low creatine on brain MRS (PP4 applied at the supporting level because the data is available in an abstract, not a peer reviewed publication). This individual is is compound heterozygous for the variant and c.327+43G>A (not yet classified by the CCDS VCEP but predicted to disrupt the donor splice site, SpliceAI score 0.7 for donor loss); the allelic data from this patient may be used in the classification of the second variant and is not included here to avoid circular logic. The phase of the variants is unconfirmed (Malays J Pathol 2022; 44(3): 539 – 562, ""Medical Genetics Conference Kuala Lumpur 2022"", Abstract GEN33, Mamat et al). This variant is absent from gnomAD v4.1.0.(PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 664123). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PP4, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on October 8, 2025)." Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995477/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6413 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0004936 infores:hetionet NCBIGene:9722 biolink:causes MONDO:0030895 infores:monarchinitiative not_provided not_provided HGNC:16859 MONDO:0030895 uuid:7a651788-9ba6-4938-bee8-5bb34ad1f90c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0021843 infores:hetionet CHEBI:7936 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085628 infores:hetionet CHEBI:28901 biolink:causes HP:0000823 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0034012 infores:hetionet CHEBI:15553 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085688 infores:hetionet NCBIGene:55072 biolink:causes MONDO:0957981 infores:monarchinitiative not_provided not_provided HGNC:16031 MONDO:0957981 uuid:bfb46d1d-dacc-4a05-bd21-5bcb2c01e42e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0413252 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0007947 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0007947 uuid:0a2fbc4a-9904-42d0-a892-af82be5d6109 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA7542745 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542745 MONDO:0012996 PMID: Benign BA1 The NM_001482.3:c.*27C>G variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000856 (110/128560 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316209). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542745/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3077 biolink:causes HP:0031616 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0423281 infores:hetionet CHEBI:66876 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0232495 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0035078 infores:hetionet CHEBI:75922 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0010037 infores:hetionet CHEBI:5775 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0022346 infores:hetionet CHEBI:6958 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0039231 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0151763 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0020517 infores:hetionet CAID:CA645607409 biolink:causes MONDO:0011071 infores:clingen CAID:CA645607409 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.367dup (p.Asp123fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is downstream of c.98 (PM5_supporting) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645607409/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135920 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0151905 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0851341 infores:hetionet CAID:CA913163445 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163445 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting PS3, PM6 The m.1659T>C variant in MT-TV has been reported in two individuals with primary mitochondrial disease to date (PS4_supporting; PMIDs: 15465092, 38973423). The first case, reported in 2004, had hemiplegia, a movement disorder, learning difficulty, and elevated cerebrospinal fluid lactate level. The variant was present at 98% heteroplasmy in muscle, 98% in lymphocytes, 99% in buccal epithelia, and 99% in urine epithelia. The variant was present at lower heteroplasmy levels in the healthy mother (7% blood, 19% buccal; PMID: 15465092). This variant was also reported in a cohort of individuals with primary mitochondrial disease in 2020 however clinical details were not provided precluding consideration of this case in this curation (PMID: 31965079). Another case was reported in 2024 and this was a man in his 60s with 3-month history of seizures, recurrent encephalopathy, ataxia, and weight loss that was preceded by hemodialysis for end-stage chronic kidney disease and improved over several months. He also had longstanding hearing loss. Brain imaging showed a hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. The variant was present at 91% heteroplasmy in muscle (PMID: 38973423). There are no other families or de novo occurrences of this variant reported to our knowledge. This variant is absent in MITOMAP and gnomAD v3.1.2. There are four occurrences in the Helix dataset. Combining all datasets, this variant is present at 0.00128% (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (65.8 percentile) but HmtVAR predicts it to be neutral with a score of 0.3. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS4_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163445/MONDO:0044970/015 2024-09-09 2025-05-14 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:30659 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0018681 infores:hetionet CHEBI:7903 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0026821 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020039 infores:hetionet CHEBI:9445 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0037822 infores:hetionet CHEBI:16469 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235886 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0518015 infores:hetionet CAID:CA402995925 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995925 MONDO:0012999 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_000156.6:c.328-2A>G variant in GAMT occurs within the canonical splice acceptor site of intron 2. It is predicted to cause skipping of the biologically relevant exon 3/6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant meets PM2_Supporting using the gnomAD v4 dataset. An individual with clinical symptoms consistent with GAMT deficiency, including increased GAA levels in blood and a decreased brain creatine peak via MRS, was reported who was compound heterozygous for this variant and another GAMT variant, c.115A>G (PMID:37305710) (PP4_Strong). PM3 was not applied to the compound heterozygote (c.328-2A>G; c.115A>G(p.Lys39Glu)) in PMID37305710 as the allelic data from this patient will be used in the assessment of c.115A>G(p.Lys39Glu) and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 854099). In summary, this variant meets the criteria to be classified as Pathogenic for GAMT deficiency as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0), PM2_Supporting, PVS1, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on December 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995925/MONDO:0012999/026 2023-12-14 2023-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6062 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027051 infores:hetionet CHEBI:63581 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0030554 infores:hetionet CHEBI:43968 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0085631 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0271650 infores:hetionet CHEBI:2675 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0015672 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0232487 infores:hetionet CHEBI:6741 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030554 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235315 infores:hetionet CHEBI:36791 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151599 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0035455 infores:hetionet CAID:CA290950094 biolink:causes MONDO:0100326 infores:clingen CAID:CA290950094 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The NM_000419.5(ITGA2B):c.1563T>A (p.Cys521Ter) nonsense variant in exon 16/30 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been observed in heterozygosity in an individual with a laboratory phenotype (platelet aggregation and surface expression) consistent with Glanzmann's thrombasthenia (GT), however a second ITGA2B variant was not identified and sufficient bleeding phenotype information to confirm if the individual's phenotype is specific for GT was not provided. This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA290950094/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:145499 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151205 infores:hetionet CAID:CA405676716 biolink:causes MONDO:0007783 infores:clingen CAID:CA405676716 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with aspartic acid at codon 152 of the RYR1 protein, p.(Ala152Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.9) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405676716/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7443 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0234215 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0019112 infores:hetionet CHEBI:4356 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0027497 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0023530 infores:hetionet CHEBI:92769 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0009938 infores:hetionet UMLS:C0120107 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0025874 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151735 infores:hetionet CAID:CA8366093 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366093 MONDO:0100453 PMID: Benign BP4, BA1, BS2 The NM_000180.4(GUCY2D):c.2345T>A (p.Leu782His) variant is predicted to change the leucine at position p.782 to histidine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.3995, with 30227 alleles / 74954 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 17920 adult individuals in gnomAD (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.119, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366093/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:28748 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0021368 infores:hetionet CHEBI:63630 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085632 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0332534 infores:hetionet CAID:CA229394 biolink:causes MONDO:0009861 infores:clingen CAID:CA229394 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PM3_Supporting, PVS1_Strong The NM_000277.3(PAH):c.1200del variant (also reported as c.1200-1del) is a frameshift variant in exon 12 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay, due to the resulting premature stop codon in exon 13, and therefore remove 0.4% of the protein. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong). At least one patient (PMID: 8825461) with this variant had classic PKU with a serum phenylalanine level of 1468 umol/l (PP4). This patient is compound heterozygous for c.11200del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP) without confirmation of phase (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PP4, PM3_supporting, PM2. (PAH VCEP specifications version 1; date of approval xx/xx/xxxx). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229394/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135530 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0687133 infores:hetionet CHEBI:9649 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0744727 infores:hetionet CHEBI:5100 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0018790 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0152025 infores:hetionet CHEBI:70746 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0231807 infores:hetionet CHEBI:15940 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C3665347 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0013985 infores:hetionet CHEBI:2549 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C2830004 infores:hetionet CHEBI:83527 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0015371 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018099 infores:hetionet CHEBI:47781 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C2584688 infores:hetionet CHEBI:681569 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0004604 infores:hetionet CHEBI:5138 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234238 infores:hetionet CHEBI:5801 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0239571 infores:hetionet CHEBI:45409 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015468 infores:hetionet CHEBI:101853 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0917801 infores:hetionet CHEBI:100241 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003467 infores:hetionet CHEBI:2704 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0042998 infores:hetionet CHEBI:6950 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0024902 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0233494 infores:hetionet CHEBI:5138 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0237314 infores:hetionet NCBIGene:2627 biolink:causes MONDO:0013769 infores:monarchinitiative not_provided not_provided HGNC:4174 MONDO:0013769 uuid:fd953bac-0eb3-4f71-97c1-a424815bedbb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15407 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0030193 infores:hetionet CHEBI:73274 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042998 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1167965 infores:hetionet NCBIGene:1053 biolink:causes MONDO:0044207 infores:monarchinitiative not_provided not_provided HGNC:1836 MONDO:0044207 uuid:c424657e-137c-4379-a6e7-a12a38067334 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1963790 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0267792 infores:hetionet CHEBI:8884 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0020649 infores:hetionet CHEBI:5123 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0013144 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0241137 infores:hetionet CHEBI:29007 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0011603 infores:hetionet CHEBI:9130 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0520887 infores:hetionet CHEBI:8884 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0043144 infores:hetionet CHEBI:8802 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0023066 infores:hetionet CHEBI:94686 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0232488 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020456 infores:hetionet CHEBI:465284 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042029 infores:hetionet CHEBI:100241 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232487 infores:hetionet CHEBI:31236 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0600228 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0426576 infores:hetionet CHEBI:8430 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0002792 infores:hetionet CHEBI:27899 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0022660 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0021053 infores:hetionet NCBIGene:23233 biolink:causes MONDO:0032724 infores:monarchinitiative not_provided not_provided HGNC:17085 MONDO:0032724 uuid:5d7c8603-7402-4f19-a7e1-0fc3ef9b6b95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4046 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0040822 infores:hetionet CAID:CA410203493 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203493 MONDO:0011071 PMID: Uncertain Significance PM5_Supporting, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.319C>A (p.Arg107Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.921) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a missense change at the same residue (p.Arg107) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 812740, 1338536) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203493/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16714 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0392703 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0314719 infores:hetionet CHEBI:71940 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C1761613 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0424000 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032326 infores:hetionet CHEBI:135925 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0085631 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020456 infores:hetionet CHEBI:92511 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0233494 infores:hetionet CHEBI:6801 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0040425 infores:hetionet CHEBI:61058 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0027059 infores:hetionet CHEBI:8869 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C1384353 infores:hetionet CHEBI:116278 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0338831 infores:hetionet CHEBI:8888 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019521 infores:hetionet CHEBI:3082 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151205 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011053 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0009806 infores:hetionet CHEBI:3499 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0009319 infores:hetionet CHEBI:3561 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151936 infores:hetionet CHEBI:41423 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018944 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013985 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0002170 infores:hetionet CHEBI:391960 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0035243 infores:hetionet CHEBI:180905 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0236075 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0221717 infores:hetionet NCBITaxon:6334 biolink:causes MONDO:0042458 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6334 MONDO:0042458 CHEBI:8888 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2830004 infores:hetionet CHEBI:51137 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0085631 infores:hetionet CHEBI:36704 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0232726 infores:hetionet CHEBI:94449 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0041834 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235416 infores:hetionet CHEBI:31711 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0031256 infores:hetionet CHEBI:49375 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020621 infores:hetionet CHEBI:3515 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0014742 infores:hetionet CHEBI:63598 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0035229 infores:hetionet CHEBI:72564 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0004134 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0836924 infores:hetionet CHEBI:28864 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0020578 infores:hetionet NCBIGene:1144 biolink:causes MONDO:0014585 infores:monarchinitiative not_provided not_provided HGNC:1965 MONDO:0014585 uuid:c67bf1f1-b205-45c0-9d82-744fba6de2dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8461 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0001824 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0340726 infores:hetionet CAID:CA2573051042 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051042 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4 PP1 The c.1786delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 596 (NM_000545.8), adding 64 novel amino acids before encountering a stop codon (p.(Val596CysfsTer64)). While this variant, located in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1786delG meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1_Strong, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051042/MONDO:0015967/017 2022-07-01 2022-07-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7459 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0030554 infores:hetionet CHEBI:7852 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0019080 infores:hetionet CAID:CA915952197 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952197 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong PP1, PS2, PS3, PM6 The m.3571del (p.Leu89SerfsTer12) variant in MT-ND1 has been reported in one individual with primary mitochondrial disease however case-level details were not provided (PMID: 32652755). This variant results in a truncation of more than 2/3 of the protein (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the effect of this variant would have on the protein structure and function. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952197/MONDO:0044970/015 2024-08-27 2025-08-06 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:63589 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0267792 infores:hetionet CAID:CA10585359 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585359 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1210A>C (p.Thr404Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD v2.1.1PP3: REVEL= 0.93PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite criteria for FH from PMID 8697568, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585359/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50648 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042109 infores:hetionet CHEBI:50885 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0268000 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0008325 infores:hetionet CHEBI:83804 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085593 infores:hetionet CHEBI:7824 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020621 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0032961 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0403632 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0025061 infores:hetionet CHEBI:41977 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C2047937 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0010043 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0392176 infores:hetionet CHEBI:6775 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151610 infores:hetionet CHEBI:681848 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0011991 infores:hetionet CHEBI:681569 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0030193 infores:hetionet CHEBI:52717 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018681 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004690 infores:hetionet CAID:CA280036 biolink:causes MONDO:0015280 infores:clingen CAID:CA280036 MONDO:0015280 PMID:18413255PMID:17981815PMID:23093928PMID:16439621PMID:18042262PMID:17551924 Pathogenic PS3, PM1, PS2_Very Strong, PM2, PP2, PP3 The c.389A>G (p.Tyr130Cys) variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStong; PMID 16439621, 17551924, 18042262). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr130Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PP3, PS3, PM2, PP2, PM1. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280036/MONDO:0015280/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8356 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0038990 infores:hetionet CHEBI:63630 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0016867 infores:hetionet CAID:CA250381 biolink:causes MONDO:0044970 infores:clingen CAID:CA250381 MONDO:0044970 PMID:34045482 Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Supporting, PS3_Supporting PP1, PS2, PM5, PM6 The m.14597A>G (p.I26T) variant in MT-ND6 has been reported in three unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 31669237, 34045482, 26633545). Clinical features in affected individuals include Leber Hereditary Optic Neuropathy (LHON, PMID: 31669237, this 39-year-old man was in haplogroup T2 and heteroplasmy levels were 25% in blood, 76% in skin fibroblasts, and 87% in urine), Leigh syndrome and optic atrophy (PMID: 34045482, this was a Japanese boy with 91% heteroplasmy in skin fibroblasts), and dystonia, dysarthria and prominent perivascular spaces (PMID: 26633545; the heteroplasmy levels in this man were 49% although the tissue was not specified). The variant segregated with clinical features in at least one family (the variant was found at 66% in blood in the sister of the boy with Leigh syndrome and at 17% in his mother’s blood, however blood heteroplasmy was not reported for the proband; PMID: 34045482). The variant was reported to occur de novo in at least one case, however technical details and tissues tested were not provided (PMID: 26633545). This variant is present in population databases (absent in Mitomap GenBank sequences and gnomAD v3.1.2; one heteroplasmic occurrence in the Helix dataset; PM2_supporting). The computation predictor APOGEE predicts this variant to be deleterious (score 0.67 in APOGEE1 and 0.63 in APOGEE2; PP3). Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated. Furthermore, complex I deficiency was noted in skin fibroblasts of an affected individual in whom nuclear DNA etiologies were excluded (PP4, PMID: 26741492). Complex I deficiency was also reported in muscle, however the activity of complex I was reported to be 0% in this tissue, raising concern for the validity of this result. A different amino acid change at this position has been reported (m.14596A>T, p.I26M), however this was classified as a variant of uncertain significance, precluding formal consideration of this as evidence of pathogenicity for the m.14597A>G (p.I26T) variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent biochemical phenotype, compelling functional validation, and that other nearby variants are highly concerning to be causative of primary mitochondrial disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PS4_supporting, PP3, PP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA250381/MONDO:0044970/015 2023-08-14 2024-08-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8888 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040822 infores:hetionet CHEBI:43968 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151662 infores:hetionet CHEBI:8805 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0042384 infores:hetionet CHEBI:71941 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0151539 infores:hetionet CHEBI:291342 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0042029 infores:hetionet CAID:CA16042872 biolink:causes MONDO:0007947 infores:clingen CAID:CA16042872 MONDO:0007947 PMID: Uncertain Significance PM2, PP2, PM5 PM6, PVS1, BS2, PP3, PP1, PP4, BA1, BP1, BP4, BP2, BP3, PS1, PS3, PS4, PS2, PM1, PM3, PM4, BS1, BS3, BS4, BP5, BP7 The NM_000138 c.4466A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at amino position 1489. This variant has not been reported in the literature but has been reported in ClinVar three times as a variant of uncertain significance (Variation ID: 373598). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID: 31227806) the PM1 criterion has not been used. It is not present in gnomAD v2.1.1 nor v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear about the predicted impact of this variant (REVEL = 0.556). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Another missense variant at the same position (p.Asn1489Lys) is classified as likely pathogenic (PM5; PMIDs: 20082464, 26621581; 21542060). Due to the insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM2_supporting, PP2, PM5. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042872/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5778 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0349506 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0234215 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151578 infores:hetionet NCBIGene:57465 biolink:causes MONDO:0009079 infores:monarchinitiative not_provided not_provided HGNC:29203 MONDO:0009079 uuid:388274df-1125-4ee2-ac63-0775afce9826 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0031350 infores:hetionet CHEBI:724125 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0030554 infores:hetionet CHEBI:10124 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0035455 infores:hetionet CHEBI:10119 biolink:causes HP:0004325 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0041667 infores:hetionet NCBIGene:112812 biolink:causes MONDO:0020714 infores:monarchinitiative not_provided not_provided HGNC:30546 MONDO:0020714 uuid:b33c303a-47b6-455d-b47e-c3a431adb144 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7581 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0018939 infores:hetionet CAID:CA5417042 biolink:causes MONDO:0011225 infores:clingen CAID:CA5417042 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting PM5 The c.41T>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Isoleucine by Serine at amino acid 14 (p.Ile14Ser).The highest population minor allele frequency in gnomAD v4 is 0.00004767 (1/20976 alleles) in the Ashkenazi Jewish population. As this is a bottleneck population, and no other alleles have been described there, PM2_Supporting is applied (PM2_Supporting). Allele frequency considering all exomes is 0.000001591, 1/628624 alleles.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5417042/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4798 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020550 infores:hetionet CHEBI:68534 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0027947 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0855242 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0004936 infores:hetionet CHEBI:64312 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1456784 infores:hetionet CHEBI:31981 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0232333 infores:hetionet CHEBI:41423 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0002962 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0233472 infores:hetionet CHEBI:3723 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085624 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0442874 infores:hetionet CHEBI:8435 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0242422 infores:hetionet CAID:CA410206824 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206824 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, PVS1, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.722A>G (p.His241Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206824/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA400030162 biolink:causes MONDO:0100326 infores:clingen CAID:CA400030162 MONDO:0100326 PMID: Uncertain Significance PM5, PP3, PM2_Supporting The NM_000212.3:c.1640G>A variant in ITGB3 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 547 (p.Cys547Tyr). This is a critical cysteine residues for regulation of integrin alphaIIbbeta3 (PMID: 14690453). This variant was reported in the ClinVar Database (ClinVar Variation ID: 850885), but has not yet been reported in the literature in individuals with Glanzmann thrombasthenia. However, another missense variant (c.1639T>G (p.Cys547Gly) in the same codon has been provisionally classified as pathogenic for Glanzmann thrombasthenia by the ClinGen Platelet Disorders VCEP (PM5). The highest population minor allele frequency in gnomAD v4.1 is 0.00001332 (1/75052 alleles) in the African/African-American genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Additionally, the computational predictor REVEL gives a score of 0.973, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM5, PP3. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400030162/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:134990 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0018681 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017178 infores:hetionet CHEBI:38940 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0149725 infores:hetionet CAID:CA512341222 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341222 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS4, BS1, BS3, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1209C>T (p.Tyr403=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341222/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C1738934 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020580 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0010692 infores:hetionet CHEBI:17549 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0702166 infores:hetionet CAID:CA376066117 biolink:causes MONDO:0011225 infores:clingen CAID:CA376066117 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.24G>A(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Methionine by Isoleucine at amino acid 8 (p.Met8Ile).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1c-related conditions or in functional studies.In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376066117/MONDO:0011225/116 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:9839 biolink:causes MONDO:0009341 infores:monarchinitiative not_provided not_provided HGNC:14881 MONDO:0009341 uuid:bb22ae6f-ed25-4284-9c77-77ce1c58fc6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6935 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0009806 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0221185 infores:hetionet CHEBI:8768 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0178415 infores:hetionet CHEBI:8207 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C1320474 infores:hetionet CHEBI:188986 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1761613 infores:hetionet CHEBI:3757 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0042029 infores:hetionet GO:0030548 biolink:causes GO:0099565 infores:ubergraph knowledge_assertion manual_agent GO:0030548 GO:0099565 CHEBI:32139 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0542203 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020676 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0009806 infores:hetionet CHEBI:91583 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0042571 infores:hetionet CHEBI:50922 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0018520 infores:hetionet NCBIGene:10134 biolink:causes MONDO:0010334 infores:monarchinitiative not_provided not_provided HGNC:16695 MONDO:0010334 uuid:8eb5f56c-c989-4047-8f44-1e4bbead44fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0392162 infores:hetionet CHEBI:135935 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0233794 infores:hetionet CHEBI:27446 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0013395 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0855242 infores:hetionet CHEBI:50924 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0333355 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0006849 infores:hetionet CHEBI:36791 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149512 infores:hetionet CHEBI:404903 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018965 infores:hetionet CHEBI:5790 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0268000 infores:hetionet NCBIGene:22827 biolink:causes MONDO:0014263 infores:monarchinitiative not_provided not_provided HGNC:17042 MONDO:0014263 uuid:2961552b-a2c3-41af-950d-862deb31881b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004093 infores:hetionet NCBIGene:6389 biolink:causes MONDO:0013339 infores:monarchinitiative not_provided not_provided HGNC:10680 MONDO:0013339 uuid:a9ee4096-d955-4e23-8d86-a6e0630f958b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0010200 infores:hetionet CHEBI:3732 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1443060 infores:hetionet CHEBI:3286 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C2830004 infores:hetionet CHEBI:32315 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0235195 infores:hetionet CHEBI:68558 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0029163 infores:hetionet CHEBI:32020 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C2047937 infores:hetionet NCBIGene:5648 biolink:causes MONDO:0009770 infores:monarchinitiative not_provided not_provided HGNC:6901 MONDO:0009770 uuid:60e39515-32be-4fdc-b0fa-8704b375e5ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042029 infores:hetionet CHEBI:3568 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013604 infores:hetionet CHEBI:6888 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020488 infores:hetionet CHEBI:15544 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0018790 infores:hetionet CHEBI:474180 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0008031 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027769 infores:hetionet CHEBI:205919 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0017979 infores:hetionet CAID:CA213729 biolink:causes MONDO:0015967 infores:clingen CAID:CA213729 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.1169T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 390 (p.(Ile390Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1169T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213729/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:175901 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0876994 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020456 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002871 infores:hetionet CHEBI:421707 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C2363731 infores:hetionet CHEBI:28787 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0151740 infores:hetionet CHEBI:63599 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0333355 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0521591 infores:hetionet CHEBI:6367 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085633 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0038362 infores:hetionet CHEBI:63577 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0019825 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0030920 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009760 infores:hetionet CHEBI:72292 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0003123 infores:hetionet CHEBI:8430 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0027497 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0018799 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0001824 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0019360 infores:hetionet CHEBI:3478 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0700345 infores:hetionet CHEBI:3699 biolink:causes MONDO:0019127 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0085655 infores:hetionet UMLS:C0010592 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2830004 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0948525 infores:hetionet CHEBI:4784 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0003126 infores:hetionet CAID:CA278075 biolink:causes MONDO:0015924 infores:clingen CAID:CA278075 MONDO:0015924 PMID: Pathogenic PM5_Supporting, PP1, PP3, PM2_Supporting, PS3, PS4, PM1_Strong The BMPR2 c.354T>C variant is a missense variant predicted to cause a cysteine to tryptophan substitution at amino acid position 118 (p.Cys118Trp). The variant is absent from gnomAD exomes v.2.1.1 controls and gnomAD genomes v3.0 (PM2_supporting). More than 4 unrelated pulmonary arterial hypertension probands were identified with this variant (PMID: 10973254, PMID: 32255665, PMID: 33007923, and PMID: 31727138) (PS4). In one multigenerational family, the variant segregated with PAH in at least 3 family members (PMID: 10973254) (PP1). BMPR2 p.Cys118Trp is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID: 9886286, PMID: 12221115, PMID: 12045205, PMID: 16429395) (PM1_strong). Several well-controlled in vitro functional assays provided variant-specific evidence of protein loss of function (PMID: 25688877, PMID: 12221115, and PMID: 32255665) (PS3). In silico prediction (REVEL =0.9279) is consistent with a pathogenic effect for this variant (PP3). Additionally, another variant in the same codon, BMPR2 (NM_001204.7):c.353G>A:(p.Cys118Tyr), was classified as likely pathogenic (PM5_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by theClinGen Pulmonary Hypertension VCEP: PS3, PS4, PM1_strong, PM2_supporting, PM5_supporting, PP3, PP1 (VCEP specification version v 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA278075/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4710 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0038362 infores:hetionet CAID:CA279083 biolink:causes MONDO:0015152 infores:clingen CAID:CA279083 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PS3_Moderate, PM2_Supporting The NM_003494.4: c.5077C>T variant in DYSF, which is also known as NM_001130987.2: c.5194C>T p.(Arg1732Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 1693, p.(Arg1693Trp). This variant has been reported in at least nine individuals from six families with features overlapping LGMD (PMID: 16100712, 23530687, 26088049, 27647186, 27602406, 30919934, 35135626), including in unknown phase with a second pathogenic variant in at least two individuals (NM_003494.4: c.4756C>T p.(Arg1586Ter), 0.5 pts, PMID: 23530687; NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, 27602406) and in a homozygous state without reported consanguinity in two unrelated individuals (1.0 pt, PMID: 16100712, 26088049) (PM3_Strong). At least one patient with this variant and another presumed diagnostic DYSF variant had clinical features of LGMD (Miyoshi myopathy) and absent dysferlin expression in muscle biopsy, which is highly specific for DYSF-related LGMD (PMID: 16100712, 27647186; PP4_Strong). This variant has been observed to co-segregate with autosomal recessive LGMD in two affected family members from three families (PMID: 16100712, 26088049, 30919934; PP1, capped with PP4_Strong). The highest population allele frequency of this variant is 0.00002671 in the African/African American population in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1693Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.74, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/23/2025): PM3_Strong, PP4_Strong, PS3_Moderate, PP3, PM2_Supporting, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279083/MONDO:0015152/180 2025-07-23 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151996 infores:hetionet CHEBI:10110 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0042963 infores:hetionet CHEBI:7789 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C2830004 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0426576 infores:hetionet CHEBI:194135 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151723 infores:hetionet CHEBI:101853 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0427457 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0040034 infores:hetionet CAID:CA229565 biolink:causes MONDO:0009861 infores:clingen CAID:CA229565 MONDO:0009861 PMID: Likely Pathogenic PM3, PP3_Strong, PP4_Moderate, PM2_Supporting The c.470G>A (p.Arg157Lys) variant in PAH has been reported in an individual with classical PKU (BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). (PP4_Moderate; PMID: 16256386, 23932990). This variant is absent from gnomAD v4.1 (PM2_supporting). This variant has been detected in at least two individuals with PAH deficiency. Of those individuals, both were compound heterozygous for the variant and a pathogenic variant and one of those were confirmed in trans by parental testing (PMID: 16256386, 30050108, PM3). The computational predictor REVEL gives a score of 0.946, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2_supporting, PM3, PP3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229565/MONDO:0009861/006 2025-10-12 2025-10-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0019209 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0854113 infores:hetionet CHEBI:9738 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0004134 infores:hetionet CHEBI:116278 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0600228 infores:hetionet CHEBI:209807 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0013404 infores:hetionet CHEBI:68595 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C1384353 infores:hetionet CHEBI:51230 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0162285 infores:hetionet CHEBI:47499 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0017178 infores:hetionet CHEBI:2687 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0030193 infores:hetionet CHEBI:5165 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0032617 infores:hetionet CHEBI:70718 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0041969 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0003123 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0234215 infores:hetionet CHEBI:47781 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0233407 infores:hetionet CHEBI:71223 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0027947 infores:hetionet CHEBI:31624 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0027497 infores:hetionet CHEBI:45409 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0344232 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0020456 infores:hetionet CHEBI:4907 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0948594 infores:hetionet CHEBI:4636 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C1443060 infores:hetionet CHEBI:32315 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0235660 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0020517 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0023646 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042963 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004238 infores:hetionet GO:1902256 biolink:causes GO:0003151 infores:ubergraph knowledge_assertion manual_agent GO:1902256 GO:0003151 CHEBI:63638 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0027066 infores:hetionet CHEBI:9907 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0232493 infores:hetionet CAID:CA10584812 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584812 MONDO:0007750 PMID: Uncertain Significance BP4, PM4, PM2, PP4 PS4, PP3 The NM_000527.5(LDLR):c.257_265del (p.Phe86_Arg88del) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PM4, BP4 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PM4 - Variant meets PM2 and is in frame deletion.BP4 - No REVEL, splicing is needed:A - not on limits.B - not on limitsC - There are 2 AG sites nearby:1- Wild type canonical acceptor: CAATCCTGTCTCTTCTGTAGTGT: 7.07Wild type cryptic acceptor: CAACCGCTGCATTCCTCAGTTCT: -15.64Variant cryptic acceptor: CAACCGCTGCATTCCTCAGTGCG: -13.6cryptic sites have negative scores, so they are not used2- > Wild type canonical acceptor: CAATCCTGTCTCTTCTGTAGTGT: 7.07Wild type cryptic acceptor: CTGGAGGTGCGATGGCCAAGTGG: -7.59Variant cryptic acceptor: TCCTCAGTGCGATGGCCAAGTGG: -4.74 cryptic sites have negative scores, so they are not used There is a GT site nearby:Wild type canonical acceptor: GTCGTAAGT: 9.9Wild type cryptic acceptor: CAGTTCTGG: -3.44Variant cryptic acceptor: CAGTGCGAT: -14.44cryptic sites have negative scores, so they are not usedThe variant does not affect splicing, so BP4 is met..PP4 - Variant meets PM2 and is identified in one index case from PMID 11462246. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584812/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6067 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0001175 infores:hetionet NCBIGene:5837 biolink:causes MONDO:0009293 infores:monarchinitiative not_provided not_provided HGNC:9726 MONDO:0009293 uuid:ef5833e6-2110-4320-b485-9982a68e2c78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0027441 infores:hetionet CHEBI:31932 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0030196 infores:hetionet CHEBI:75246 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0085702 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0392162 infores:hetionet CHEBI:82941 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0018681 infores:hetionet CHEBI:3393 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0013395 infores:hetionet CHEBI:71415 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0004096 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0521491 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002878 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027497 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0236071 infores:hetionet CHEBI:63620 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0035317 infores:hetionet CAID:CA10014480 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014480 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.509-12G>A is a non-coding (intronic) variant. No splicing impact or creation of cryptic splice sites is predicted by SSF and MES. Splice AI predicts no impact on splicing (score: 0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 0.755063 < 2.0) (BP7). This variant was reported in ClinVar in 2023 by Invitae, but the affected status of the proband is unknown (Variation ID 1596540). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP7, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014480/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101853 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0011168 infores:hetionet GO:1903050 biolink:causes GO:0030163 infores:ubergraph knowledge_assertion manual_agent GO:1903050 GO:0030163 CHEBI:74947 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151908 infores:hetionet CAID:CA5950474 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950474 MONDO:0000573 PMID: Likely Benign BP7, BS1 The NM_000536.4:c.1095T>C variant is a synonymous (silent) variant (p.Ser365=) with no predicted splice impact (BP7). This variant has not been reported in the literature in individuals with RAG2-related conditions. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00314 (79/25120) in the Finnish population, which is higher than the ClinGen SCID VCEP's threshold for BS1 (>0.00195). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied BS1 and BP7, as specified by the ClinGen SCID VCEP (VCEP specifications 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950474/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA229667 biolink:causes MONDO:0009861 infores:clingen CAID:CA229667 MONDO:0009861 PMID:26666653PMID:26413448PMID:26666653PMID:26413448 Pathogenic PM3, PVS1, PM2, PP4 The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID: 26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229667/MONDO:0009861/006 2018-12-09 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4653 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0178298 infores:hetionet CHEBI:28148 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0687713 infores:hetionet GO:0061924 biolink:causes GO:0030902 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0030902 CHEBI:6129 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042373 infores:hetionet CAID:CA2918527 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918527 MONDO:0015152 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_000232.5: c.12G>A p.(Ala4=) variant in SGCB is a synonymous (silent) variant that is not predicted to influence splicing by SpliceAI (score 0.01) (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001138 (11/9664 exome alleles) in the East Asian population (PM2_Supporting, BS1, BA1 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918527/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:44915 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0009676 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151883 infores:hetionet CHEBI:17347 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0232461 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0002170 infores:hetionet CHEBI:40303 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C2981158 infores:hetionet CHEBI:31515 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0020649 infores:hetionet CHEBI:23765 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0404521 infores:hetionet CHEBI:17650 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C2047937 infores:hetionet CAID:CA2580098646 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098646 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1238_1240del (p.Ser413del) is an in-frame deletion which does not affect a known functional domain (PM4 not applied). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098646/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0031350 infores:hetionet CHEBI:6129 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151539 infores:hetionet CHEBI:8356 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0393760 infores:hetionet CHEBI:8888 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0023218 infores:hetionet CHEBI:7494 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0027497 infores:hetionet CHEBI:45863 biolink:causes HP:0025088 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0263540 infores:hetionet CHEBI:34829 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0010043 infores:hetionet CHEBI:7936 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0026961 infores:hetionet CHEBI:28918 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0039240 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0340464 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0243026 infores:hetionet CHEBI:87681 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0030305 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0035078 infores:hetionet CHEBI:15552 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0085605 infores:hetionet CHEBI:53760 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0009676 infores:hetionet CHEBI:28593 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0002878 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0034063 infores:hetionet CHEBI:8707 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006384 infores:hetionet CHEBI:4876 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0003123 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027947 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0242973 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0039971 infores:hetionet CHEBI:2687 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0026858 infores:hetionet CHEBI:3398 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0042963 infores:hetionet CHEBI:15765 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0006325 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0948257 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0948257 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020517 infores:hetionet CHEBI:3380 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0002170 infores:hetionet CHEBI:3508 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0006840 infores:hetionet CHEBI:61058 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0023530 infores:hetionet CAID:CA011229 biolink:causes MONDO:0004994 infores:clingen CAID:CA011229 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1767C>T (p.Asn589=) variant in the MYH7 gene is 3.71% (419/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011229/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4636 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0022893 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0036572 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0031542 infores:hetionet CHEBI:10119 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011603 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0011991 infores:hetionet CHEBI:38940 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0026858 infores:hetionet CHEBI:63620 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0041657 infores:hetionet CHEBI:7820 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0156404 infores:hetionet CHEBI:63608 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0014742 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0035078 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0020517 infores:hetionet CAID:CA2739267611 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267611 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.911dup (p.Gly305Trpfs*295) is a frameshift variant in biologically relevant exon 8/9, predicted to alter the C-terminus of the protein, a region critical to protein function (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting). It has been reported in a patient with a myeloid malignancy, although the origin was unclear (PMID: 37102976). Additionally, other nonsense/frameshift variants in exon 8 have been reported as pathogenic/likely pathogenic (PMID: 35764482) (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267611/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9649 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0011570 infores:hetionet CHEBI:5280 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0039231 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0027726 infores:hetionet NCBIGene:117581 biolink:causes MONDO:0008853 infores:monarchinitiative not_provided not_provided HGNC:20670 MONDO:0008853 uuid:6563cc55-5c86-4991-aa42-f1456007d3df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015967 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0267792 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0005940 infores:hetionet UNII:3U02EL437C biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0085641 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0037274 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0037274 infores:hetionet CHEBI:5118 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1112442 infores:hetionet NCBIGene:383 biolink:causes MONDO:0008814 infores:monarchinitiative not_provided not_provided HGNC:663 MONDO:0008814 uuid:6600d1dc-9f96-445e-954c-242280ea7c4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:251408 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0013362 infores:hetionet CAID:CA10578272 biolink:causes MONDO:0007356 infores:clingen CAID:CA10578272 MONDO:0007356 PMID: Uncertain Significance PP4, PM2_Supporting PM5, PP1 The NM_000249.4: c.2041G>C variant in MLH1 is a missense variant predicted to cause substitution of Alanin by Prolin at amino acid 681 (p.Ala681Pro). The variant is not reported in gnomAD (PM2_supporting). The variant was detected in one CRC/Endometrial MSI-H tumour using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM2_SUP, PP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578272/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44423 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0002453 infores:hetionet CHEBI:9720 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0027769 infores:hetionet CHEBI:48273 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013362 infores:hetionet CHEBI:6078 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C1443060 infores:hetionet CHEBI:87681 biolink:causes HP:0004325 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0041667 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0033975 infores:hetionet CAID:CA386965923 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965923 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 The c.749A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to proline at codon 250 (p.Gln250Pro) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.716, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.749A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965923/MONDO:0015967/017 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7986 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0344232 infores:hetionet GO:0110082 biolink:causes GO:0000281 infores:ubergraph knowledge_assertion manual_agent GO:0110082 GO:0000281 CHEBI:5123 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0021177 infores:hetionet CHEBI:6367 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0021177 infores:hetionet CHEBI:6838 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0162830 infores:hetionet CHEBI:68478 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0236000 infores:hetionet CHEBI:83804 biolink:causes MONDO:0011479 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1299624 infores:hetionet CAID:CA029330 biolink:causes MONDO:0007750 infores:clingen CAID:CA029330 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.770G>A (p.Arg257Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00004395 (0.004395%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.BP4 - REVEL = 0.279, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) not on limitsB) does not create GTC) there are no GT nearbyvariant is predicted to not alter splicing, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA029330/MONDO:0007750/013 2022-08-29 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3508 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0027497 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0033575 infores:hetionet CHEBI:45783 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011124 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0004944 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:D009494 DB09320_MESH_D009494_1 CHEBI:50742 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013604 infores:hetionet CHEBI:4717 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0023066 infores:hetionet NCBIGene:1482 biolink:causes MONDO:0008542 infores:monarchinitiative not_provided not_provided HGNC:2488 MONDO:0008542 uuid:dc7eee55-a738-45d6-bb0b-fcb3f8952cba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CL:0000731 biolink:causes MONDO:0024337 infores:ubergraph knowledge_assertion manual_agent CL:0000731 MONDO:0024337 CHEBI:5801 biolink:causes NCIT:C180702 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0312422 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0031350 infores:hetionet CHEBI:66876 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0085649 infores:hetionet CHEBI:3479 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0086565 infores:hetionet NCBIGene:4014 biolink:causes MONDO:0011396 infores:monarchinitiative not_provided not_provided HGNC:6663 MONDO:0011396 uuid:3c419e53-c4a0-447f-890f-ceb09a2b2ca0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235416 infores:hetionet CHEBI:31236 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0032617 infores:hetionet CHEBI:4974 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0004604 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011630 infores:hetionet CHEBI:63630 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085593 infores:hetionet CHEBI:168396 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011206 infores:hetionet CAID:CA167846 biolink:causes MONDO:0007648 infores:clingen CAID:CA167846 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1865A>G (p.Asn622Ser) missense variant has a frequency of 0.000007953 (2 of 251,480) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006152 (1 of 16,256) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >10 (27) individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000166547.6, SCV000329232.7). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA167846/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true GO:0090189 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0001823 CHEBI:63619 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0031256 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0234916 infores:hetionet CHEBI:37924 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0231530 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0520588 infores:hetionet GO:0110073 biolink:causes GO:0002064 infores:ubergraph knowledge_assertion manual_agent GO:0110073 GO:0002064 CHEBI:135361 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0917801 infores:hetionet CHEBI:84500 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013378 infores:hetionet CHEBI:9654 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0040822 infores:hetionet CHEBI:64064 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0023218 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0002884 infores:hetionet CHEBI:188986 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0271321 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0553713 infores:hetionet CHEBI:63632 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0151825 infores:hetionet GO:0045453 biolink:causes MONDO:0005382 infores:drugmechdb knowledge_assertion manual_agent GO:0045453 MESH:D010001 DB00630_MESH_D010001_1 CHEBI:49960 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013609 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085584 infores:hetionet CHEBI:28901 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0004604 infores:hetionet CHEBI:145499 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151766 infores:hetionet CHEBI:5790 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0041948 infores:hetionet CHEBI:50692 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0019080 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151313 infores:hetionet CHEBI:5280 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0003862 infores:hetionet CHEBI:15365 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0002871 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0020649 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0006145 infores:hetionet CHEBI:17303 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0002792 infores:hetionet CHEBI:44032 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0017565 infores:hetionet CHEBI:32139 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0036974 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151838 infores:hetionet CHEBI:119573 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0010200 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0013395 infores:hetionet CHEBI:2453 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0009763 infores:hetionet CHEBI:8871 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0039621 infores:hetionet GO:1905421 biolink:causes GO:0048731 infores:ubergraph knowledge_assertion manual_agent GO:1905421 GO:0048731 CHEBI:37924 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0012833 infores:hetionet CHEBI:9654 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0003537 infores:hetionet CHEBI:63631 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233763 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0031117 infores:hetionet CHEBI:4466 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0027497 infores:hetionet CHEBI:5296 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0027497 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0020538 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0475858 infores:hetionet CAID:CA246980 biolink:causes MONDO:0019501 infores:clingen CAID:CA246980 MONDO:0019501 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, BS2, PP3, PP2, PP1, PP4, PM5, PM4, PM1, PM3, PVS1, PM6, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The variant NM_206933.4:c.14419G>A in USH2A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 4807 (p.Ala4807Thr). The filtering allele frequency (the upper threshold of the 95% CI of 5/30782) of the c.14419G>A variant in USH2A is 0.00006365 for South Asian chromosomes by gnomAD v2.1.1, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 2/21/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA246980/MONDO:0019501/005 2024-02-21 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true UNII:9430ZR8ZAN biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0085593 infores:hetionet CHEBI:3176 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0427457 infores:hetionet CHEBI:92998 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0005758 infores:hetionet CHEBI:4708 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0002962 infores:hetionet CHEBI:63791 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0242528 infores:hetionet CHEBI:31236 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003862 infores:hetionet CHEBI:72292 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0003862 infores:hetionet CHEBI:63630 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0014591 infores:hetionet CHEBI:9720 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C1456784 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0027765 infores:hetionet CHEBI:16755 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018188 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0948594 infores:hetionet CHEBI:49960 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0015732 infores:hetionet CHEBI:77733 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0040264 infores:hetionet GO:1902510 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:1902510 GO:0006915 CHEBI:92998 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0004604 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0178298 infores:hetionet CHEBI:584020 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0231218 infores:hetionet CHEBI:134966 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0085615 infores:hetionet CHEBI:6128 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0039231 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0014431 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0014431 infores:hetionet CHEBI:31236 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151878 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0020649 infores:hetionet CHEBI:50922 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151766 infores:hetionet CHEBI:15553 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0037763 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020621 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0032300 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0032300 infores:hetionet CHEBI:8874 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0021177 infores:hetionet NCBIGene:473 biolink:causes MONDO:0014857 infores:monarchinitiative not_provided not_provided HGNC:9965 MONDO:0014857 uuid:f0ca3b34-dc8d-429b-9b47-43582384616e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16714 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0015397 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0574067 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0013604 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0267792 infores:hetionet CHEBI:15551 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0040822 infores:hetionet CHEBI:72690 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0030193 infores:hetionet CHEBI:18357 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0003811 infores:hetionet CHEBI:8093 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0085631 infores:hetionet CHEBI:4911 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0234909 infores:hetionet NCBIGene:7169 biolink:causes MONDO:0012240 infores:monarchinitiative not_provided not_provided HGNC:12011 MONDO:0012240 uuid:72ab50c0-d74a-42cc-99d5-3b7dcf0adcd1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7454 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0162297 infores:hetionet CHEBI:8232 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0033774 infores:hetionet CHEBI:9943 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151937 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027726 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0015397 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0392176 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0152964 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0152964 infores:hetionet CHEBI:18248 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0037383 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0003123 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151689 infores:hetionet NCBIGene:1490 biolink:causes MONDO:0008881 infores:monarchinitiative not_provided not_provided HGNC:2500 MONDO:0008881 uuid:8b86a40e-55cb-491d-8f56-2f02078d495c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8423030 biolink:causes MONDO:0019497 infores:clingen CAID:CA8423030 MONDO:0019497 PMID: Likely Pathogenic PM3, PVS1 PM2 The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant in biologically relevant exon 2/66 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 210/1179974 alleles (0.0001780 or 0.0178 %) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This variant has been detected in 3 individuals with nonsyndromic hearing loss. For each of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, but phase was not confirmed (p.Lys1003fsTer55, p.Glu209Ter, p.Arg3134Ter; PMIDs: 23208854, 28000701, 31980526; 1.5 pts. PM3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PVS1, PM3; Version 1; 3/20/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8423030/MONDO:0019497/023 2024-03-20 2024-03-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:31348 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003123 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020569 infores:hetionet CHEBI:9130 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0030193 infores:hetionet CHEBI:3011 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C2830004 infores:hetionet NCBIGene:4647 biolink:causes MONDO:0011032 infores:monarchinitiative not_provided not_provided HGNC:7606 MONDO:0011032 uuid:e744ace0-2563-437e-967a-9387d598dde4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0022107 infores:hetionet CHEBI:31932 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0151539 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0038362 infores:hetionet CHEBI:8059 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0042023 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0743668 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0743668 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0009144 infores:hetionet CAID:CA228492 biolink:causes MONDO:0015629 infores:clingen CAID:CA228492 MONDO:0015629 PMID: Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PS3, PS4_Moderate BP2, PM5, BP5 The NM_000552.5(VWF):c.3925A>G (p.Ile1309Val) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.851, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Ile1309Val rVWF resulted in enhanced affinity for the GP1b receptor (PMID: 8621553; PS3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and an assay showing gain of function (enhanced RIPA at 0.3 mg/mL), which together are highly specific for VWD type 2B. (PP4_moderate; PMID: 9308766). This variant has been reported in at least 3 additional type 2B probands with enhanced RIPA reported (PS4_Moderate; PMIDs: 23005922, 18805962, 9198195). The variant has been reported to segregate with VWD type 2B through >2 affected meioses from at least 1 family (PP1; PMID: 18805962). In summary, this variant has been classified as Pathogenic for type 2B Von Willebrand Disease based on the ACMG/AMP criteria applied as specified by the von Willebrand Disease Variant Curation Expert Panel. PM2_supporting, PP3, PS3, PP4_moderate, PS4_moderate, PP1 von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228492/MONDO:0015629/081 2025-02-04 2025-02-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28593 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0852733 infores:hetionet CHEBI:17823 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0030305 infores:hetionet CHEBI:63605 biolink:causes HP:0002495 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1295585 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020517 infores:hetionet CHEBI:7565 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0424790 infores:hetionet CAID:CA645509438 biolink:causes MONDO:0017623 infores:clingen CAID:CA645509438 MONDO:0017623 PMID:21659347PMID:28677221PMID:28677221 Pathogenic PS4_Supporting, PM2_Supporting, PS1, PS3 PVS1, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP3, PP1, PP4, PM5, PM4, PM1, PM3, BP1, BP4, BP3, BP2, BA1, PS2 PTEN c.634+5G>C (IVS6+5G>C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS1: different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant. PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221).PM2_P: Absent in gnomAD (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509438/MONDO:0017623/003 2023-12-01 2023-12-18 Autosomal dominant inheritance HP:0000006 Supports HP:0011104 biolink:causes HP:0000969 infores:drugmechdb knowledge_assertion manual_agent HP:0011104 MESH:D004487 DB00232_MESH_D004487_1 PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0003123 infores:hetionet CHEBI:7601 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0037199 infores:hetionet CHEBI:51209 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0033975 infores:hetionet CHEBI:127342 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0030252 infores:hetionet NCBIGene:64327 biolink:causes MONDO:0008515 infores:monarchinitiative not_provided not_provided HGNC:13243 MONDO:0008515 uuid:b59da91b-7dd9-49be-bf0c-caf403642ee6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6756 biolink:causes MONDO:0859477 infores:monarchinitiative not_provided not_provided HGNC:11335 MONDO:0859477 uuid:59f40a55-bdcc-4373-a8a4-12994abf6d16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C2363731 infores:hetionet CAID:CA308123345 biolink:causes MONDO:0007783 infores:clingen CAID:CA308123345 MONDO:0007783 PMID: Likely Pathogenic PP1, PS4_Supporting, PM1, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with tyrosine at codon 544 of the RYR1 protein, p.Asp544Tyr. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual who had a personal or family history of a malignant hyperthermia reaction, this individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:19191329). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in four individuals, PP1_Supporting (PMID:19191329). A REVEL score >0.85 (0.924) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Supporting, PM1, PP1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308123345/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ GO:2000232 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:2000232 GO:0032774 CHEBI:63618 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0037199 infores:hetionet CHEBI:9943 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2981158 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0040034 infores:hetionet CHEBI:32192 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0004093 infores:hetionet CAID:CA308788 biolink:causes MONDO:0015152 infores:clingen CAID:CA308788 MONDO:0015152 PMID: Uncertain Significance BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP2, PP3, PP1, PP4 The NM_000337.6: c.191T>C variant in SGCD is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 64 (p.Ile64Thr). The highest minor allele frequency of this variant is 0.0001293 in the Admixed American population of gnomAD v2.1.1 (4/30926 exome chromosomes), which is greater than the LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.63 (PP3, BP4 not met). In summary, there is currently insufficient evidence to determine whether this variant is pathogenic or benign and it is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP(LGMD VCEP specifications version 1.0.0; 01/08/2025): no codes applied. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA308788/MONDO:0015152/186 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:182080 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0332534 infores:hetionet CHEBI:35778 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0235266 infores:hetionet CHEBI:6067 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151632 infores:hetionet CHEBI:7507 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0020517 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235874 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0001883 infores:hetionet CHEBI:9150 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C2981158 infores:hetionet CHEBI:8869 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0038358 infores:hetionet CHEBI:6741 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0016204 infores:hetionet CHEBI:27882 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0151905 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151479 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005316 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D016585 DB01190_MESH_D016585_1DB12834_MESH_D016585_1DB00911_MESH_D016585_1DB00916_MESH_D016585_1 CHEBI:53691 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0011603 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233794 infores:hetionet CHEBI:28971 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0011606 infores:hetionet CHEBI:63638 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0012569 infores:hetionet CHEBI:9939 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0015230 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034530 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0026946 infores:hetionet CHEBI:8080 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0085631 infores:hetionet CHEBI:42797 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0162298 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006008 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0751908 infores:hetionet CHEBI:3215 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0004093 infores:hetionet CHEBI:15552 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0013404 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0040034 infores:hetionet CHEBI:28177 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0080274 infores:hetionet CHEBI:6709 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0340865 infores:hetionet CHEBI:8890 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0086439 infores:hetionet CHEBI:8107 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0549249 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0178298 infores:hetionet CHEBI:78543 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0017181 infores:hetionet CHEBI:209807 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0036830 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0034069 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0031350 infores:hetionet CAID:CA5950000 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950000 MONDO:0000572 PMID: Uncertain Significance PP4, PM3, PM2_Supporting PM5, PM1, PS1, PS3, BS3 The c.527G>T (NM_000448.3) variant in RAG1 is a missense variant predicted to cause a substitution of Cysteine by Phenylalanine at amino acid 176 (p.Cys176Phe).The filtering allele frequency (the upper threshold of the 95% CI of 3/128742) of the c.527G>T variant in RAG1 is 0.000002930 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least two individuals with SCID and Leaky SCID who are homozygous for the variant (1 pt, PM3; PMID: 28769923 and 34539671).At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pts) + SCID gene panel (0.5pts) + T-B-NK+ lymphocyte subset profile (0.5 pts), total 1.5 points, PP4 met (PMID: 34539671).In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive SCID based on the ACMG/AMP criteria applied, PM2_Supporting, PM3, and PP4, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950000/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7443 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0017574 infores:hetionet CHEBI:10119 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020625 infores:hetionet CHEBI:9139 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0013404 infores:hetionet NCBIGene:1723 biolink:causes MONDO:0009903 infores:monarchinitiative not_provided not_provided HGNC:2867 MONDO:0009903 uuid:ce33693e-fa76-4b2c-800d-1f65f1c1c18e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014743 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0428886 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0428886 infores:hetionet CHEBI:9613 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0018681 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0234215 infores:hetionet CHEBI:18248 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0018790 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0018939 infores:hetionet NCBIGene:285498 biolink:causes MONDO:0030508 infores:monarchinitiative not_provided not_provided HGNC:27729 MONDO:0030508 uuid:50106bae-eb86-4853-ae2a-a6c2952708a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020538 infores:hetionet CHEBI:4911 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0278134 infores:hetionet CHEBI:64355 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017168 infores:hetionet CAID:CA2017997777 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997777 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1348del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 450 (NM_000162.5), adding 164 novel amino acids before encountering a stop codon (p.(Ala450ProfsTer164)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly consistent with GCK-MODY; however, there was insufficient clinical information to evaluate for PP4. In summary, the c.1348del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997777/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Supports CHEBI:3181 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0023218 infores:hetionet CHEBI:2666 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0020580 infores:hetionet CHEBI:10127 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013362 infores:hetionet CHEBI:94686 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0156404 infores:hetionet CAID:CA10580100 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580100 MONDO:0007648 PMID: Pathogenic PP3, PM2_Supporting, PS3, PS4, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM5, PM1, PM3, BS2, PP2, PP4, PP1, BP4, BP1, BP3, BP2, BA1, PS1, PS2 The c.1008G>A (NM_004360.5) variant in CDH1is a G to non-G variant in the last nucleotide in exon 7. It is predicted to cause a loss of the donor splice site resulting in retention of intron 7 (PVS1_Moderate). This prediction is confirmed by RT-PCR cDNA demonstrating that the variant impacts splicing by producing 4 different alternatively spliced transcripts containing premature termination codons (PTC) caused by the use of cryptic donor splice sites in the intron (PS3, PMID: 8127895). This variant has been reported in 4 probands/families meeting hereditary diffuse gastric cancer genetic testing criteria (PS4; PMIDs 9536098, 27730413, ClinVar SCVs: SCV000275557.6, SCV000760854.3, Internal lab contributors). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The results from 3 in silico splicing predictors (SpliceAI, MaxEntScan, NNsplice) indicate that this variant may affect splicing by disrupting the donor splice site of intron 7 of CDH1 (PP3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4, PP3. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580100/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:50885 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0002453 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1096282 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1096282 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2225524 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0034065 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011570 infores:hetionet CHEBI:6067 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009763 infores:hetionet CHEBI:9241 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0004134 infores:hetionet CHEBI:63619 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018520 infores:hetionet CHEBI:8802 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0039231 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0242350 infores:hetionet CHEBI:4315 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0003862 infores:hetionet CHEBI:2704 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0004093 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0035258 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0021364 infores:hetionet NCBIGene:8647 biolink:causes MONDO:0011559 infores:monarchinitiative not_provided not_provided HGNC:42 MONDO:0011559 uuid:c20a49d8-2dba-4b0d-b1b2-4948824a6529 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0002962 infores:hetionet NCBIGene:54517 biolink:causes MONDO:0032687 infores:monarchinitiative not_provided not_provided HGNC:26033 MONDO:0032687 uuid:6a7ca5ea-c076-4805-9f69-7faef0353a22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0033771 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042267 infores:hetionet CHEBI:4708 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042023 infores:hetionet CHEBI:32139 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0030252 infores:hetionet CHEBI:50275 biolink:causes MONDO:0000702 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0400821 infores:hetionet CHEBI:10119 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040822 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0000731 infores:hetionet CHEBI:6832 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0002622 infores:hetionet CAID:CA915952205 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952205 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP3, PP1, PS2, PS4, PM6 The m.5367_5385del (p.Thr300ProfsTer6) variant in MT-ND2 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on October 14, 2024. There are no individuals with this variant reported in the medical literature to our knowledge. There is one prior report in ClinVar for this variant, however details are not provided precluding consideration of this case for this curation. As such, there are no reported de novo occurrences or large families to consider for evidence of variant segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation of the MT-ND2 protein (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 14, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952205/MONDO:0044970/015 2024-10-14 2024-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:7317 biolink:causes MONDO:0026777 infores:monarchinitiative not_provided not_provided HGNC:12469 MONDO:0026777 uuid:055f5857-3287-49a7-8c03-76a2161947bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0413252 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0025202 infores:hetionet CHEBI:7936 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2047937 infores:hetionet CHEBI:51450 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0014591 infores:hetionet CHEBI:50777 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042023 infores:hetionet CHEBI:63598 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013491 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022650 infores:hetionet NCBIGene:29954 biolink:causes MONDO:0013154 infores:monarchinitiative not_provided not_provided HGNC:19743 MONDO:0013154 uuid:8bd2d097-1b6c-43e0-969f-ff7709c5e179 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6801 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0020649 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0860493 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0860493 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0004096 infores:hetionet CHEBI:64019 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0428977 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085692 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0855620 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0855620 infores:hetionet CHEBI:4710 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0039070 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1167965 infores:hetionet CHEBI:6801 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0750426 infores:hetionet CHEBI:42944 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0852911 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0001824 infores:hetionet CHEBI:63638 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0030196 infores:hetionet CHEBI:17334 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0040046 infores:hetionet CHEBI:85083 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0017168 infores:hetionet GO:1902423 biolink:causes GO:0007080 infores:ubergraph knowledge_assertion manual_agent GO:1902423 GO:0007080 CHEBI:521033 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0242350 infores:hetionet CHEBI:6073 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0344232 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009450 infores:hetionet CHEBI:9907 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002878 infores:hetionet CAID:CA308125185 biolink:causes MONDO:0007783 infores:clingen CAID:CA308125185 MONDO:0007783 PMID: Uncertain Significance PP1, PS4_Supporting, PP3_Moderate BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with proline at codon 612 of the RYR1 protein, p.Ala612Pro. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:22415532). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in 3 individuals, PP1 (PMID:22415532). A REVEL score >0.85 (0.971) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308125185/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:50841 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0392156 infores:hetionet CHEBI:46081 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0004604 infores:hetionet CHEBI:8871 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0851578 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0007787 infores:hetionet CHEBI:6375 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2830004 infores:hetionet CAID:CA624860703 biolink:causes MONDO:0008723 infores:clingen CAID:CA624860703 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1368dup (p.Ile457fs) also known as (p.Ile457HisfsTer6) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001549 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (VCEP specifications version1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624860703/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63577 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C2225524 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0008035 infores:hetionet CHEBI:51041 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0232462 infores:hetionet CAID:CA410147585 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147585 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1265A>T (p.Glu422Val) is a missense variant which has a REVEL score < 0.50 (0.1), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147585/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8093 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0151636 infores:hetionet CHEBI:78543 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0013491 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0231530 infores:hetionet NCBIGene:5146 biolink:causes MONDO:0013129 infores:monarchinitiative not_provided not_provided HGNC:8787 MONDO:0013129 uuid:a787563d-d380-4e0e-a858-fdd430617703 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5100 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0004093 infores:hetionet CHEBI:23765 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0349231 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0743323 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0743323 infores:hetionet CHEBI:50729 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0040425 infores:hetionet GO:2001009 biolink:causes GO:0009832 infores:ubergraph knowledge_assertion manual_agent GO:2001009 GO:0009832 CHEBI:18332 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0018790 infores:hetionet CHEBI:84500 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0036974 infores:hetionet CHEBI:64354 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0917801 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0035455 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085692 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0017152 infores:hetionet CHEBI:45863 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0877359 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0022658 infores:hetionet CAID:CA143304 biolink:causes MONDO:0019501 infores:clingen CAID:CA143304 MONDO:0019501 PMID: Likely Pathogenic PP3, PP1, PM3_Strong PM2 The c.12874A>G variant in USH2A is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 4292 (p.Asn4292Asp). The highest population frequency in gnomAD v4.1.0 is 0.02% (20/86258 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.707, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been identified in at least 6 individuals with apparently isolated retinal dystrophy. One individual was homozygous, one was heterozygous for a second variant of uncertain significance, three had a second pathogenic variant with phase unknown, and one harbored a second pathogenic variant confirmed in trans (2 points, PM3_Strong, PMID: 28041643, 25133751, 37322672, Invitae Internal evidence SCV001403886.5, Blueprint Genetics internal evidence SCV001240918.1). The variant has been reported to segregate with retinal dystrophy in 1 affected family member from 1 family (PP1; PMID: 25133751). Of note, hearing loss was not reported in any of these individuals, indicating that this variant is likely causative for isolated retinal dystrophy and not Usher syndrome. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_Strong, PP1. (Hearing loss VCEP specifications version 2; 05.15.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143304/MONDO:0019501/005 2024-05-15 2024-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:2666 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0020649 infores:hetionet CHEBI:51041 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002418 infores:hetionet NCBIGene:6550 biolink:causes MONDO:0014808 infores:monarchinitiative not_provided not_provided HGNC:11073 MONDO:0014808 uuid:d107bce2-1585-4056-8a2e-548e15079916 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes UMLS:C0520863 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0520863 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0023218 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017160 infores:hetionet CHEBI:167638 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0043387 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0267792 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0242973 infores:hetionet GO:0030219 biolink:causes CL:0000556 infores:ubergraph knowledge_assertion manual_agent GO:0030219 CL:0000556 CHEBI:36795 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0549373 infores:hetionet CHEBI:8869 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0004093 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0040034 infores:hetionet CHEBI:49662 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0019080 infores:hetionet CHEBI:6935 biolink:causes MONDO:0007835 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0021933 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0595883 infores:hetionet CHEBI:7445 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0085633 infores:hetionet CAID:CA2018007654 biolink:causes MONDO:0015967 infores:clingen CAID:CA2018007654 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 BA1, PS4, BS1 The c.526+2del variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant, located in the splice donor for the biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with four informative meioses in two families (PP1_Strong; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.526+2del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2018007654/MONDO:0015967/017 2025-02-11 2025-02-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50777 biolink:causes MONDO:0019623 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0019243 infores:hetionet NCBIGene:4330 biolink:causes MONDO:0032908 infores:monarchinitiative not_provided not_provided HGNC:7180 MONDO:0032908 uuid:c25b6b96-e3ab-4526-9a2e-ce4365c7c31e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75922 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0017178 infores:hetionet CAID:CA10014585 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014585 MONDO:0011071 PMID: Benign BA1, BP2, BP4, BP7 PS4, PS3, PS1, PM6, PM2, PVS1, BS4, BS3, BS1, PM1, PM5, PM4, PP1, PP3 This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least 5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). The variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created, and evolutionary conservation prediction algorithms predict the site as being not highly conserved (PhyloP score: 1.01 [-14.1;6.4]) (BP4; BP7). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014585/MONDO:0011071/008 2021-01-12 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true GO:1905518 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1905518 GO:0007399 CHEBI:135920 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0020517 infores:hetionet CHEBI:3219 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036689 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0042373 infores:hetionet NCBIGene:55898 biolink:causes MONDO:0859164 infores:monarchinitiative not_provided not_provided HGNC:30594 MONDO:0859164 uuid:313e209e-aa05-41c2-8fea-db0b3d483b3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2687 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151723 infores:hetionet CAID:CA024101 biolink:causes MONDO:0018493 infores:clingen CAID:CA024101 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with serine at codon 4684 of the RYR1 protein, p.(Phe4684Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.982) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024101/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:47381 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C2242996 infores:hetionet CHEBI:45783 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0032227 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002332 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0037997 infores:hetionet CHEBI:5296 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C2937358 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0151888 infores:hetionet CHEBI:6904 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0023066 infores:hetionet CHEBI:3756 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0016204 infores:hetionet GO:0030225 biolink:causes CL:0000235 infores:ubergraph knowledge_assertion manual_agent GO:0030225 CL:0000235 CHEBI:5558 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0011603 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0015376 infores:hetionet CHEBI:7478 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151827 infores:hetionet CHEBI:5103 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0344232 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0023533 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0424605 infores:hetionet UMLS:C0879264 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0239981 infores:hetionet NCBIGene:4193 biolink:causes MONDO:0032868 infores:monarchinitiative not_provided not_provided HGNC:6973 MONDO:0032868 uuid:3ec92758-0be7-40d3-a81f-15896e547ab5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5103 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C1527344 infores:hetionet NCBIGene:8314 biolink:causes MONDO:0859230 infores:monarchinitiative not_provided not_provided HGNC:950 MONDO:0859230 uuid:0da8ba14-0495-4bee-be28-16142ea77a91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0001925 infores:hetionet CHEBI:3485 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0002874 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0029408 infores:hetionet CHEBI:6715 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0232461 infores:hetionet NCBIGene:347734 biolink:causes MONDO:0859518 infores:monarchinitiative not_provided not_provided HGNC:16872 MONDO:0859518 uuid:322c8e2a-19fc-4a39-b378-495ef6713e5f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0027051 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0037274 infores:hetionet CHEBI:47780 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0016655 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0000988 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0155540 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0151610 infores:hetionet CHEBI:5847 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0243026 infores:hetionet CHEBI:8024 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033575 infores:hetionet CAID:CA6748962 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748962 MONDO:0009861 PMID: Benign BS2, BP7, BS1 The c.399T>C (p.Asn387=) variant in PAH meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BS1: MAF = 0.00675 which is within the threshold for this expert group. BS7: HSF, Splice AI and TraP predict no significant impact on splicing signals.BS2: Observed in two healthy homozygotes in gnomAd and ExAc. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748962/MONDO:0009861/006 2021-07-25 2021-07-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:68558 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C2979982 infores:hetionet CHEBI:75722 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013491 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0206062 infores:hetionet CHEBI:17303 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232849 infores:hetionet CHEBI:63584 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0009763 infores:hetionet CHEBI:27834 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0040264 infores:hetionet CHEBI:61033 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151905 infores:hetionet CHEBI:92712 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0152032 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0015397 infores:hetionet CHEBI:7931 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0017181 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0267792 infores:hetionet CHEBI:7931 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020443 infores:hetionet CHEBI:367163 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0023787 infores:hetionet CHEBI:66913 biolink:causes UMLS:C1610049 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C1610049 infores:hetionet CHEBI:82981 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0234215 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0917799 infores:hetionet CHEBI:478164 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C1257843 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0016204 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042510 infores:hetionet CHEBI:28901 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0206061 infores:hetionet CHEBI:8776 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0030305 infores:hetionet CHEBI:63612 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0000731 infores:hetionet CHEBI:17474 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0085932 infores:hetionet CHEBI:3175 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0031350 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0232492 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0018418 infores:hetionet CHEBI:7865 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0042963 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0037274 infores:hetionet CHEBI:3479 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0027947 infores:hetionet CHEBI:36704 biolink:causes HP:0030769 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0266453 infores:hetionet CAID:CA10014571 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014571 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.198C>G (p.Ala66=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.23) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014571/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:72564 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0041969 infores:hetionet CHEBI:9449 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0042963 infores:hetionet CHEBI:17026 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0542571 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041976 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001269 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0036412 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030305 infores:hetionet CHEBI:51137 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0151878 infores:hetionet CHEBI:36795 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0858635 infores:hetionet CHEBI:119573 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1167965 infores:hetionet CHEBI:6965 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0549567 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0030353 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0027765 infores:hetionet CHEBI:93363 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0233494 infores:hetionet CHEBI:8346 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0028643 infores:hetionet CAID:CA367398578 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398578 MONDO:0015967 PMID: Likely Pathogenic PS3_Supporting, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1181G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 394 (p.(Arg394Leu)) of transcript NM_000162.5. This variant is absent from gnomAD v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the relative stability index was below the MDEP cutoff of 0.5 (PS3_Supporting; internal lab contributors). Another missense variant at the same amino acid position, c.1181G>C p.Arg394Pro has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1181G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398578/MONDO:0015967/086 2025-04-25 2025-04-25 Semidominant inheritance HP:0032113 Supports CHEBI:9635 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0314719 infores:hetionet CHEBI:63598 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020488 infores:hetionet CL:0000210 biolink:causes MONDO:0024341 infores:ubergraph knowledge_assertion manual_agent CL:0000210 MONDO:0024341 CHEBI:9434 biolink:causes UMLS:C0857189 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0857189 infores:hetionet CHEBI:2704 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0023530 infores:hetionet CHEBI:31236 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0086439 infores:hetionet CHEBI:74947 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0026821 infores:hetionet CHEBI:6375 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013378 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0002258 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D010612 DB00713_MESH_D010612_1DB00254_MESH_D010612_1DB00618_MESH_D010612_1DB01000_MESH_D010612_1DB01053_MESH_D010612_1DB01333_MESH_D010612_1DB13092_MESH_D010612_1DB00595_MESH_D010612_1DB01060_MESH_D010612_1DB01147_MESH_D010612_1DB00954_MESH_D010612_1 CHEBI:31536 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0021655 infores:hetionet CAID:CA320249584 biolink:causes MONDO:0011071 infores:clingen CAID:CA320249584 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2376G>A is a UTR variant which has a MAF of 0.0001765 (0.01765%, 12/67992, 12 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320249584/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5138 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040822 infores:hetionet CHEBI:31236 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0043094 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0018801 infores:hetionet NCBIGene:220 biolink:causes MONDO:0014050 infores:monarchinitiative not_provided not_provided HGNC:409 MONDO:0014050 uuid:96338c68-5a78-438f-99dd-167c98c59a3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70746 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0237938 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0853777 infores:hetionet CHEBI:3216 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0023380 infores:hetionet CHEBI:5130 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0085593 infores:hetionet CHEBI:44915 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0027497 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0235431 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0162848 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0030305 infores:hetionet CHEBI:92998 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0018681 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0232431 infores:hetionet CHEBI:75998 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0023530 infores:hetionet CHEBI:63599 biolink:causes HP:0031189 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0231666 infores:hetionet CHEBI:6067 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0010038 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0027769 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0853023 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0853023 infores:hetionet CHEBI:46557 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151786 infores:hetionet CAID:CA402995151 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995151 MONDO:0012999 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000156.6:c.432G>A variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4 out of 6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been previously reported in one individual with GAMT deficiency (PMID: 36911476). This individual was homozygous for the variant (PM3_Supporting). This individual had significantly decreased creatine peak on brain MRS (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1391239). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 26, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995151/MONDO:0012999/026 2024-04-26 2024-07-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2922 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0002871 infores:hetionet CHEBI:2618 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0086439 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020538 infores:hetionet CHEBI:63607 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C2830004 infores:hetionet CHEBI:63623 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0392171 infores:hetionet CHEBI:131512 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0030252 infores:hetionet CHEBI:51173 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0235063 infores:hetionet CHEBI:188986 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0155169 infores:hetionet CHEBI:63621 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0852911 infores:hetionet UMLS:C0009315 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0037036 infores:hetionet CHEBI:5100 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0040034 infores:hetionet CHEBI:3172 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0033975 infores:hetionet CHEBI:7852 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0039070 infores:hetionet CHEBI:91834 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0020453 infores:hetionet CHEBI:6715 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085605 infores:hetionet CHEBI:9613 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0017178 infores:hetionet CHEBI:465284 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085631 infores:hetionet UMLS:C0065374 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0027424 infores:hetionet CHEBI:6129 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013456 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0340464 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042109 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0243026 infores:hetionet CHEBI:61033 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0001122 infores:hetionet CHEBI:3699 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0032285 infores:hetionet CHEBI:39585 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0041969 infores:hetionet CHEBI:8107 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151889 infores:hetionet CAID:CA410202598 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202598 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.443C>G (p.Thr148Ser) is a missense variant which has a REVEL score < 0.50 (0.466) and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202598/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:34911 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0030554 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1384353 infores:hetionet CHEBI:3077 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0036974 infores:hetionet CHEBI:63608 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0036974 infores:hetionet NCBIGene:9922 biolink:causes MONDO:0032870 infores:monarchinitiative not_provided not_provided HGNC:29112 MONDO:0032870 uuid:72ef4a60-6db2-45c6-b34b-b4c89f5d2540 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6954 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020676 infores:hetionet CHEBI:2379 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0015230 infores:hetionet NCBIGene:493753 biolink:causes MONDO:0014667 infores:monarchinitiative not_provided not_provided HGNC:33848 MONDO:0014667 uuid:ddca35c6-f97f-4fac-90b4-b997675506b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6912 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0042109 infores:hetionet CHEBI:17688 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0392171 infores:hetionet CHEBI:5790 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235195 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0349506 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0403639 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0403639 infores:hetionet UMLS:C0145867 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0016927 infores:hetionet CHEBI:6916 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0028643 infores:hetionet CHEBI:10101 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235266 infores:hetionet CHEBI:8461 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0522224 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0860155 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0860155 infores:hetionet CHEBI:408174 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027497 infores:hetionet CAID:CA248619 biolink:causes MONDO:0011071 infores:clingen CAID:CA248619 MONDO:0011071 PMID:11830488PMID:11830488PMID:11830488 Pathogenic PP1_Strong, PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS3, BS1, BS4, BP7, BP5, PM4, PM1, PM3, PP2, PP3, PP4, BS2 The NM_001754.4:c.861C>A (p.Tyr287Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 11830488). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1_Strong, PM2_supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248619/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27690 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0220981 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020651 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0281774 infores:hetionet CHEBI:42944 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0085649 infores:hetionet CAID:CA16041865 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041865 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.996dup (p.Ala333fs)(NM_000018.3) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one individual with this variant was identified, but this information is insufficient to use toward classification (PMID: 25242572). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041865/MONDO:0008723/021 2024-05-14 2024-05-16 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10580104 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580104 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PP1, PVS1_Strong, PS4, PS3 BS1, BS4, BS3, BP7, BP5, PM2, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS2 The c.1137+1G>A (NM_004360.5) variant in CDH1 occurs within the canonical splice donor site (+/- 1,2) of intron 8. It is predicted to cause a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_strong, PM5_Supporitng). The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the African/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting). The variant has been reported to segregate with diffuse gastric cancer in 3 affected meioses from 1 family that fulfills the clinical HDGC criteria (PP1; PMIDs 10477433). This variant has been reported in 9 probands meeting hereditary diffuse gastric cancer criteria (PS4; PMIDs 26182300, 10477433, ClinVar SCVs SCV000288420.8, SCV000278454.7, Internal lab contributors). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS4, PS3, PM5_Supporting and PP1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580104/MONDO:0007648/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:472657 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0836924 infores:hetionet CHEBI:6950 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085688 infores:hetionet CHEBI:2673 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0020649 infores:hetionet CHEBI:4868 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0018681 infores:hetionet CHEBI:38940 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0242698 infores:hetionet CHEBI:71940 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0002962 infores:hetionet CHEBI:7936 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151539 infores:hetionet NCBIGene:959 biolink:causes MONDO:0010626 infores:monarchinitiative not_provided not_provided HGNC:11935 MONDO:0010626 uuid:82582f20-bd86-4949-b051-6b2e343eb7aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019917 infores:hetionet CHEBI:17347 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0018965 infores:hetionet CHEBI:9398 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C1735601 infores:hetionet CHEBI:3219 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009676 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013295 infores:hetionet NCBIGene:51660 biolink:causes MONDO:0013877 infores:monarchinitiative not_provided not_provided HGNC:21606 MONDO:0013877 uuid:090f0dda-b9e9-4e4f-a47e-944a0275d3bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0041657 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0003123 infores:hetionet CHEBI:6965 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0026837 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0853348 infores:hetionet CAID:CA244534392 biolink:causes MONDO:0015967 infores:clingen CAID:CA244534392 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PP3 PS3, PM1, BS3 The c.1136C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 379 (p.(Pro379Arg)) of NM_000545.8. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative (PP4_Moderate; internal lab contributors). This variant was identified in 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 21170474, PMID: 15657605, internal lab contributors). This variant segregated with diabetes, with at least 4 informative meioses in 3 families with MODY (PP1_Strong; PMID: 15657605, internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PP3, PP4_Moderate, PS4, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244534392/MONDO:0015967/017 2023-08-14 2023-08-14 Autosomal dominant inheritance HP:0000006 Supports CAID:CA10652934 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652934 MONDO:0011071 PMID: Benign BA1, BP4, BP2, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM5, PM1, PM3, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.-89T>C is an intronic variant with a MAF of 0.009027 (0.9027%, 372/41210,) in the African American subpopulation of gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in one individual in gnomAD 3.1.2 African American cohort (BP2). This synonymous variant has a SpliceAI score ≤ 0.20 (Donor/Acceptor Gain 0.12) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.88< 2.0) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652934/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47381 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0152029 infores:hetionet NCBITaxon:6247 biolink:causes MONDO:0005974 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6247 MESH:D013322 DB00730_MESH_D013322_1 CHEBI:127342 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0004604 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0426732 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0547030 infores:hetionet CHEBI:49575 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0036104 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0019158 infores:hetionet CHEBI:8364 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0002170 infores:hetionet CHEBI:27786 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C2047937 infores:hetionet CHEBI:135342 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0037036 infores:hetionet CHEBI:10125 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0040264 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0851341 infores:hetionet CHEBI:8764 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0232462 infores:hetionet CAID:CA059366 biolink:causes MONDO:0017623 infores:clingen CAID:CA059366 MONDO:0017623 PMID: Likely Benign BS1, BP4 PTEN c.165-13_165-10delGTTT (IVS2-13_IVS2-10delGTTT) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0049 (0.49%, 112/22,776 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA059366/MONDO:0017623/003 2016-12-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8890 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0003578 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0025061 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0314719 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0548823 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0041969 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0005779 infores:hetionet CHEBI:6804 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0220870 infores:hetionet CHEBI:52010 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0039231 infores:hetionet NCBIGene:3991 biolink:causes MONDO:0014431 infores:monarchinitiative not_provided not_provided HGNC:6621 MONDO:0014431 uuid:57a09481-b6fd-4f81-a215-a34f3934b537 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4046 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0235710 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0027769 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0006840 infores:hetionet CHEBI:10110 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0014724 infores:hetionet CHEBI:27777 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0004093 infores:hetionet CHEBI:7573 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C1443060 infores:hetionet CHEBI:75722 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0031924 infores:hetionet CHEBI:64310 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0020621 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0332575 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0851341 infores:hetionet CHEBI:9123 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0025345 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151882 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0497365 infores:hetionet CHEBI:119486 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011606 infores:hetionet CHEBI:9123 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151836 infores:hetionet NCBIGene:7222 biolink:causes MONDO:0014626 infores:monarchinitiative not_provided not_provided HGNC:12335 MONDO:0014626 uuid:27f6e6ba-a4d6-4dc3-98a7-0b5502251aef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45716 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0007137 infores:hetionet CHEBI:4710 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0278134 infores:hetionet CAID:CA079715 biolink:causes MONDO:0007783 infores:clingen CAID:CA079715 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 3348 of the RYR1 protein, p.(Arg3348Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000132, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257), PS4_Supporting. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.603 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA079715/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA023437 biolink:causes MONDO:0007750 infores:clingen CAID:CA023437 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4_Moderate, PM2, PP3, PP1, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, BS2 NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate, PP1, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity.PS4_moderate - Variant meets PM2. Variant identified in 8 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria).PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PP3 - REVEL: 0,879. Score is above 0,75.PP4 - Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023437/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7565 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0015397 infores:hetionet CHEBI:100147 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0000737 infores:hetionet CHEBI:18358 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0241136 infores:hetionet UMLS:C0010592 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042023 infores:hetionet CHEBI:7915 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0003862 infores:hetionet CHEBI:7852 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020458 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0042109 infores:hetionet CHEBI:63580 biolink:causes MONDO:0007745 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017551 infores:hetionet CHEBI:7903 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0003467 infores:hetionet CHEBI:2611 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085632 infores:hetionet CHEBI:4710 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0085649 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0021053 infores:hetionet CHEBI:5165 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151786 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0162429 infores:hetionet CHEBI:114785 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0206061 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0042373 infores:hetionet CHEBI:27690 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0022107 infores:hetionet CHEBI:28445 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0019156 infores:hetionet CAID:CA399805578 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805578 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5(ITGA2B):c.617T>A (p.Val206Asp) missense variant was identified in a patient (Patient 2, PMID: 28888044) with severe bleeding. This variant was identified in a patient (Patient 2, PMID 28888044) with a severe bleeding type; common presentations in this cohort included recurrent epistaxis, bleeding in the oral cavity, and easy bruising spontaneously or after trauma. Platelet aggregation was negative for the agonists collagen, ADP, and arachidonic acid but was normal for ristocetin. Flow cytometry to analyze the platelet surface for CD41 and CD61 showed reduced expression in all patients (PP4_Moderate). This variant is absent from the gnomAD database v2.1.1 (PM2_Supporting). TThis variant was confirmed in the homozygous state in the patient. Parents were genotyped and were both heterozygous for this same variant (Patient 2 PMID: 28888044; PM3_supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805578/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8869 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0010200 infores:hetionet CHEBI:50885 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0030353 infores:hetionet CHEBI:6472 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0040046 infores:hetionet CAID:CA16021007 biolink:causes MONDO:0009861 infores:clingen CAID:CA16021007 MONDO:0009861 PMID:21147011PMID:21147011 Pathogenic PM2, PVS1, PP4_Moderate, PM3_Supporting The c.197_204del8 (p.Glu66Alafs*8) variant in PAH has been reported in 1 individual with PAH deficiency (BH4 deficiency excluded, PP4_Moderate; PMID: 21147011). This variant was detected with p.A300S (Pathogenic in ClinVar) (PM3_supporting; PMID: 21147011). It is a frameshift variant predicted to lead to NMD (PVS1). It is absent from gnomAD (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4_Moderate, PM3, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16021007/MONDO:0009861/006 2022-06-28 2022-06-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32221 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0033774 infores:hetionet CHEBI:5130 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0011603 infores:hetionet NCBITaxon:169495 biolink:causes MONDO:0001209 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:169495 MONDO:0001209 CHEBI:37941 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0021845 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0003864 infores:hetionet NCBIGene:801 biolink:causes MONDO:0013966 infores:monarchinitiative not_provided not_provided HGNC:1442 MONDO:0013966 uuid:960094f6-c006-4f04-b796-e36bfcda00a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0009763 infores:hetionet CHEBI:31236 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1704272 infores:hetionet CAID:CA16020919 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020919 MONDO:0009861 PMID:10356314 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The c.1027T>A (p.Tyr343Asn) variant in PAH has been reported in multiple individuals with PKU (PMID: 10356314) detected with pathogenic variants p.R158Q and p.E280K. This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020919/MONDO:0009861/006 2020-06-18 2020-06-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7494 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0234022 infores:hetionet CHEBI:291342 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0011991 infores:hetionet GO:0043304 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0043304 GO:0006955 CHEBI:4856 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0034642 infores:hetionet UNII:T58MSI464G biolink:causes NCIT:C122785 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0333139 infores:hetionet CHEBI:6801 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0018834 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151436 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0027769 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002173 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0273482 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0009450 infores:hetionet CHEBI:3207 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C3665386 infores:hetionet CAID:CA017806 biolink:causes MONDO:0005835 infores:clingen CAID:CA017806 MONDO:0005835 PMID: Likely Benign BP4, BS1 The MSH2 (NM_000251.3):c.1277-16T>C is an intronic variant with no impact on gene or gene product predicted using algorithms (MaxEntScan, NNSplice, SpliceAI) (BP4). The gnomAD filtering allele frequency is 0.00015 and gnomAD v4.1 Grpmax AF is 0.00043, attributing BS1 criteria according to the Maximum Credible Allele Frequency (MCAF) cutoffs for MSH2 (BS1).In summary, this variant meets the criteria to be classified as likely benign for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: BS1 and BP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA017806/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:145499 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0010709 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0857121 infores:hetionet CHEBI:47499 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C2242996 infores:hetionet CHEBI:253342 biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0266813 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0027947 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018772 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0002871 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0948594 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085606 infores:hetionet CHEBI:8871 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011880 infores:hetionet CHEBI:63611 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0232462 infores:hetionet CAID:CA410147539 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147539 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1274C>G (p.Pro425Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147539/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9123 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0855242 infores:hetionet CHEBI:3082 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0043352 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0231230 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0231230 infores:hetionet NCBIGene:8322 biolink:causes MONDO:0007589 infores:monarchinitiative not_provided not_provided HGNC:4042 MONDO:0007589 uuid:ac48cc62-3f8c-404a-bcdf-14c2e4981c9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes HP:0001908 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0178416 infores:hetionet CHEBI:48538 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0038999 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042571 infores:hetionet CHEBI:91541 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0009806 infores:hetionet CHEBI:46195 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0017178 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027947 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0003123 infores:hetionet CHEBI:6073 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0011991 infores:hetionet CHEBI:5893 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C2047937 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0600041 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0600041 infores:hetionet NCBIGene:27161 biolink:causes MONDO:0030897 infores:monarchinitiative not_provided not_provided HGNC:3263 MONDO:0030897 uuid:a9bf172e-b9ca-4d0b-a799-6c7c63c698c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235890 infores:hetionet CAID:CA213739 biolink:causes MONDO:0015967 infores:clingen CAID:CA213739 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM1, PP2, PP3, PP4, PM2_Supporting PS3 The c.1240A>G variant in the glucokinase gene, GCK, causes an amino acid change of lysine to glutamic acid at codon 414 (p.(Lys414Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.9279, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; ClinVar ID 36188, PMID 18411240, internal lab contributors). The variant segregated with diabetes, with 5 informative meioses in three families with MODY (PP1_Strong; internal lab contributors). Additionally, one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). In summary, c.1240A>G meets the criteria to be classified as pathogenic by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PS4, PP4, PM1, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213739/MONDO:0015967/086 2023-06-26 2023-06-26 Semidominant inheritance HP:0032113 Supports CHEBI:51173 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0151766 infores:hetionet CHEBI:94848 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0042963 infores:hetionet UMLS:C0005740 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0018965 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0521839 infores:hetionet CHEBI:10125 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003467 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0024117 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011849 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0086543 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005165 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0086692 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014742 infores:hetionet CHEBI:9150 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0002792 infores:hetionet CHEBI:53691 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0034063 infores:hetionet NCBIGene:60678 biolink:causes MONDO:0976233 infores:monarchinitiative not_provided not_provided HGNC:24614 MONDO:0976233 uuid:911e340f-defa-441f-97d5-dc182101366b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0034882 infores:hetionet CHEBI:7983 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0018524 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0010043 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009763 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0038826 infores:hetionet CAID:CA115378 biolink:causes MONDO:0015152 infores:clingen CAID:CA115378 MONDO:0015152 PMID: Pathogenic PP1_Strong, PVS1, PM3, PP4 BS1, PM2 The NM_213599.3: c.191dup (p.Asn64LysfsTer15) variant in ANO5 is a frameshift variant observed to cause a premature stop codon in biologically relevant exon 5/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1; PMID: 20096397). This variant has been detected in at least 26 individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least eight patients (1.0 pt, PMID: 20096397, 28187523, 30919934; PM3). At least one patient with this variant displayed progressive proximal muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in 4 affected family members from 3 families (PP1_Strong; PMID: 22336395, 20096397, 28187523). The filtering allele frequency of this variant is 0.001770 (the lower threshold of the 95% CI of 139/67894 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (>0.002) for BS1; however, this variant is a frequently observed variant among affected patients and the VCEP opted not to apply this code (BS1 exception). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PP1_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA115378/MONDO:0015152/188 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:101853 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0013395 infores:hetionet CAID:CA1139665159 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665159 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL):c.1723dup (p.Leu575Profs*17) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 18 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665159/MONDO:0008723/021 2023-03-27 2023-03-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75045 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0000737 infores:hetionet CHEBI:77260 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0232462 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0234215 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0035455 infores:hetionet CHEBI:9130 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0010200 infores:hetionet CHEBI:5296 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0011991 infores:hetionet CHEBI:63605 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0013604 infores:hetionet CHEBI:8871 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0022346 infores:hetionet CHEBI:135679 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C2830004 infores:hetionet CHEBI:6076 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0015672 infores:hetionet CAID:CA1244106 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244106 MONDO:0020367 PMID:11004290 Likely Benign BS1, BS3_Supporting BP7, PM2, PM6, PP1, PP3, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.985G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 329 (p.Val329Met). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.002523, which met the ≥ 0.001 threshold set for BS1 (63 alleles out of 24,968, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.466, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 11004290) demonstrated that the Val329Met protein had similar solubility levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244106/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68478 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151539 infores:hetionet CAID:CA015299 biolink:causes MONDO:0004994 infores:clingen CAID:CA015299 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4788G>A (p.Ser1596=) variant in the MYH7 gene is 0.74% (92/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015299/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63621 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023067 infores:hetionet CHEBI:77260 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0003467 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0036983 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0000833 infores:hetionet CHEBI:9763 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0042024 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0267792 infores:hetionet CAID:CA10606426 biolink:causes MONDO:0009290 infores:clingen CAID:CA10606426 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM5, PM2_Supporting The NM_000152.5:c.1082C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 361 (p.Pro361Arg). This variant has been observed in the literature in two cases consistent with late-onset Pompe disease (PMID: 30312517, 32012848) with documented GAA deficiency. Both met PP4 specifications (PP4_Moderate), in compound heterozygosity with the known pathogenic variant c.-32-13T>G, phase not confirmed (PM3). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0000008993 (1/1111956 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.945 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.1082C>T, p.Pro361Leu) (ClinVar Variation ID: 403712) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 289367, 1-star review status) with 2 submitter, classifying this variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PP4_Moderate, PM3, PM2_Supporting, PP3, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606426/MONDO:0009290/010 2023-11-21 2023-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA114166 biolink:causes MONDO:0015631 infores:clingen CAID:CA114166 MONDO:0015631 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3, PS3 The NM_000552.5(VWF):c.2384A>G (p.Tyr795Cys) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 of 2.800e-7 (based on 2/1180036 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.005 for type 2N (PM2_Supporting). The computational predictor REVEL gives a score of 0.688, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least three compound heterozygous VWD type 2N patients have been reported with this variant; two (PMIDs: 33807613, 15461624; PM3) compound heterozygous with R854Q (classified Pathogenic by the VWD VCEP), and one (PMID: 15213842) compound heterozygous with R1566X (not yet been evaluated by the VWD VCEP). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (0.13 IU/ml) and decreased VWF:FVIII binding (<1.5%), which is highly specific for VWD type 2N. (PP4_moderate, PMID:15213842). Factor VIII binding assay performed with theY795C recombinant mutant showed severely impaired binding indicating that this variant has a damaging effect on protein function (PMID: 15213842, 15461624; PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3, PP4_moderate, PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114166/MONDO:0015631/090 2025-01-07 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6367 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0000731 infores:hetionet CHEBI:10650 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085623 infores:hetionet CHEBI:31236 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013491 infores:hetionet CHEBI:68534 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0151786 infores:hetionet CHEBI:7492 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0015672 infores:hetionet CHEBI:7494 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0547030 infores:hetionet CHEBI:36704 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0027424 infores:hetionet CHEBI:17698 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C1761613 infores:hetionet CHEBI:77260 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151603 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C1956346 infores:hetionet CHEBI:2682 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085641 infores:hetionet NCBIGene:203859 biolink:causes MONDO:0013222 infores:monarchinitiative not_provided not_provided HGNC:27337 MONDO:0013222 uuid:44bd725e-ddee-4b00-96a6-c0ec08b2f133 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31643 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0152227 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0854121 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0854121 infores:hetionet CHEBI:5118 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151766 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0023067 infores:hetionet CAID:CA631044684 biolink:causes MONDO:0012999 infores:clingen CAID:CA631044684 MONDO:0012999 PMID:11136556 Likely Pathogenic PM2_Supporting, PM3, PP4_Strong, PS3_Supporting PP3, BP4 The NM_000156.6:c.571-3C>G variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 5. This variant has been detected in one individual with GAMT deficiency, who was compound heterozygous for the variant and a pathogenic variant, with the phase confirmed in trans by family testing (PMID: 11136556) (PM3). This individual had elevated GAA and low creatine in plasma and in urine and absent creatine peak on brain MRS with full GAMT gene sequencing (PMID: 11136556, PMID: 11087795) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/112052 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 939221, 1 star review status) with 2 submitters classifying the variant as a variant of uncertain significance. RT-PCR and northern blot analysis did not show any transcripts with this variant, suggesting that the variant leads to aberrant splicing and impaired transcription (PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PM3, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 13, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631044684/MONDO:0012999/026 2023-04-13 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0065374 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0022408 infores:hetionet CHEBI:8768 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151825 infores:hetionet CHEBI:3084 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0026205 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0011616 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0006266 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017152 infores:hetionet CHEBI:65173 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0002871 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0021390 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017168 infores:hetionet CHEBI:474180 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151904 infores:hetionet CHEBI:9907 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0851578 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011609 infores:hetionet CHEBI:45951 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0011603 infores:hetionet CHEBI:6832 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0917801 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0010692 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017152 infores:hetionet CHEBI:6437 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0239571 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0011603 infores:hetionet CHEBI:71272 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0015672 infores:hetionet CHEBI:465284 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0542571 infores:hetionet CAID:CA119172 biolink:causes MONDO:0020367 infores:clingen CAID:CA119172 MONDO:0020367 PMID:11004290 Pathogenic PS3_Moderate, PM4, PS4, PP1_Strong BS1, BS3, BP7, PM2, PM6, PP3, PM5, PS1, PS2, BA1, BP4 The c.1102C>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamine at amino acid 368 (p.Gln368Ter). This variant is predicted to cause a deletion of ≥ 10% of the protein within the conserved olfactomedin domain, meeting PM4. Although this variant had a minor allele frequency of 0.003344 in the European (Finnish) population of gnomAD (84 alleles out of 25,118), which meets the ≥ 0.001 threshold for BS1, Gln368Ter is exempt from this criterion due to its incomplete penetrance and the presence of a common disease haplotype in all carriers. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. This variant is exempt from the rule which normally does not allow the application of PS4 unless PM2_Supporting is met. 23 probands with juvenile or primary open angle glaucoma (JOAG or POAG) have been reported carrying this variant (PMIDs: 11535458, 11004290, 10815160, 22736945, 11803488, 12189160), which met PS4 (≥ 15 probands). As this variant is exempt from the application of BS1, PP1 has been applied. 52 segregations in 10 families, with JOAG or POAG, have been reported (PMIDs: 11004290, 10815160, 11535458), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). There were many more probands and family studies published than presented here. A previous study (PMID: 16466712) demonstrated that the Gln368Ter protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PM4, PS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119172/MONDO:0020367/019 2022-03-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:77260 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0022107 infores:hetionet CHEBI:50659 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0428977 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0032584 infores:hetionet CHEBI:63791 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030196 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0235639 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0037199 infores:hetionet CHEBI:8888 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019080 infores:hetionet CHEBI:6887 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1384353 infores:hetionet CHEBI:3219 biolink:causes MONDO:0000807 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0577628 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0009450 infores:hetionet CHEBI:7445 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0042963 infores:hetionet CAID:CA000483 biolink:causes MONDO:0018875 infores:clingen CAID:CA000483 MONDO:0018875 PMID: Benign BP4, BS3, BS2 BA1, BP1, BP3, PS3, PS1, PS4, PS2, PM5, PM4, PM1, BP7, BS1, BS4, PVS1, PM2, PP3, PP2, PP1, PP4 The NM_000546.6 :c.892G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 298 (p.Gly298Lys). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; SCV000184859, SCV000260657). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.199; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000483/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5147 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0036689 infores:hetionet CHEBI:194135 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002792 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0041912 infores:hetionet CHEBI:9907 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151603 infores:hetionet CHEBI:6916 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0041657 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0004238 infores:hetionet NCBIGene:65080 biolink:causes MONDO:0014162 infores:monarchinitiative not_provided not_provided HGNC:16650 MONDO:0014162 uuid:4b879156-2c8d-4476-a583-5d6e836662cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:50801 biolink:causes MONDO:0032714 infores:monarchinitiative not_provided not_provided HGNC:6279 MONDO:0032714 uuid:63e4447b-770d-4174-b343-705a00ad0578 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0035410 infores:hetionet CHEBI:93635 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0020651 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027769 infores:hetionet CHEBI:84883 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0949059 infores:hetionet CHEBI:16755 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0040264 infores:hetionet CHEBI:72292 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0003811 infores:hetionet CAID:CA000439 biolink:causes MONDO:0017623 infores:clingen CAID:CA000439 MONDO:0017623 PMID:29706350 Pathogenic PM2, PP2, PS4_Supporting, PM1, PS3 PM6, BS4, BS3, BS1, BP7, BP5, PP1, PP3, BS2, PM4, BP2, BP4, BA1, PS2, PS1 PTEN c.389G>C (p.Arg130Pro) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000185699.6) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000439/MONDO:0017623/003 2019-11-22 2019-12-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119486 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0002994 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0009806 infores:hetionet CHEBI:8382 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0019209 infores:hetionet CHEBI:135351 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0039070 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0038454 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0035305 infores:hetionet CHEBI:50131 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0018944 infores:hetionet CHEBI:31949 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0004093 infores:hetionet CHEBI:17987 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0033774 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0032326 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0043352 infores:hetionet CAID:CA644626142 biolink:causes MONDO:0010278 infores:clingen CAID:CA644626142 MONDO:0010278 PMID: Likely Benign BP4, BS1 The allele frequency of the c.1738-6A>G variant in SLC9A6 (NM_006359.2) is 0.02% in the Other sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.1738-6A>G variant in SLC9A6 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA644626142/MONDO:0010278/033 2023-10-13 2023-12-11 X-linked inheritance HP:0001417 Contradicts true UMLS:C0017797 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0151735 infores:hetionet CHEBI:6950 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0232462 infores:hetionet GO:0052026 biolink:causes GO:0006351 infores:ubergraph knowledge_assertion manual_agent GO:0052026 GO:0006351 UNII:VL0L558GCB biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151905 infores:hetionet CHEBI:184555 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0917801 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0031350 infores:hetionet CHEBI:30830 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027066 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0267953 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0267953 infores:hetionet CAID:CA023747 biolink:causes MONDO:0007750 infores:clingen CAID:CA023747 MONDO:0007750 PMID:2569482 Pathogenic PS3_Moderate, PS4, PP1_Strong, PM1, PM2, PP3, PP4 NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) variant, also known as ‘FH Afrikaner-1’ or ‘FH Maine’, is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PS3_Moderate, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 29 April 2022.The supporting evidence is as follows:PM2: PopMax MAF = 0.00002899 (0.003%) in Latino/Admixed American exomes (gnomAD v2.1.1).PP3: REVEL = 0.864. PM1: Variant meets PM2 and is missense located in exon 4.PS3_Moderate: Level 2 assay PMID 1301956 (Hobbs et al., 1992):Homozygous patient's fibroblasts studied with radiolabeled LDL results in 5-15% LDLR activity. Functional study is consistent with damaging effect.Level 2 assay PMID 2569482 (Leitersdorf et al., 1989):Partial cycle of LDLR studied in CHO Cells. WB after immunoprecipitation of radiolabelled LDLR variant show <50% of WT LDLR expression.PS4, PP4: Variant meets PM2 and is identified in 33 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=2 Robarts Research Institute; n=2 Color Health, Inc.; n=3 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=25 Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA).PP1_Strong: Variant segregates with FH in at least 22 informatives meioses from at least 2 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia): 20 affected family members have the variant and 2 unaffected family members do not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023747/MONDO:0007750/013 2022-04-29 2025-02-13 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6887 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0851341 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038367 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0242461 infores:hetionet CHEBI:5118 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0542571 infores:hetionet CHEBI:51364 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0037036 infores:hetionet CHEBI:71417 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C2830004 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0014742 infores:hetionet CHEBI:32192 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0017178 infores:hetionet NCBIGene:283209 biolink:causes MONDO:0859347 infores:monarchinitiative not_provided not_provided HGNC:20898 MONDO:0859347 uuid:6544f6ae-1f99-4fa5-a2fa-4f549f4dc824 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0036454 infores:hetionet CHEBI:50922 biolink:causes UMLS:C2349423 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C2349423 infores:hetionet CHEBI:28787 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C1443060 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020456 infores:hetionet CHEBI:63619 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0036974 infores:hetionet CAID:CA376061152 biolink:causes MONDO:0011225 infores:clingen CAID:CA376061152 MONDO:0011225 PMID: Pathogenic PP4, PM2_Supporting, PVS1 The c.352G>T (p.Gly118Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).This variant is absent from gnomAD v4 (PM2_Supporting). At least one patient with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and * SCID gene panel or exome/genome sequencing conducted (0.5pt), the total is 1 point, PP4_Supporting (PMID: 37007969). This patient is compound heterozygous with c.328C>G (p.L110V), confirmed in trans (both parents tested); However, this variant has not yet been evaluated by SCID VCEP.In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376061152/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:171719 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0233472 infores:hetionet CHEBI:5775 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0027424 infores:hetionet CHEBI:135736 biolink:causes HP:0003750 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0242979 infores:hetionet CHEBI:64198 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0497247 infores:hetionet CHEBI:9288 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0013604 infores:hetionet CHEBI:44185 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0010200 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0233401 infores:hetionet NCBIGene:4041 biolink:causes MONDO:0007764 infores:monarchinitiative not_provided not_provided HGNC:6697 MONDO:0007764 uuid:91e1d5b3-4cbc-4a68-961f-fe3b98adb8ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0021710 biolink:causes CL:0010010 infores:ubergraph knowledge_assertion manual_agent GO:0021710 CL:0010010 CHEBI:75246 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232492 infores:hetionet CHEBI:16714 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0020672 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0948525 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0267792 infores:hetionet CHEBI:75984 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0015967 infores:hetionet CHEBI:9352 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0547030 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0036454 infores:hetionet CHEBI:7494 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042963 infores:hetionet CAID:CA10644113 biolink:causes MONDO:0007648 infores:clingen CAID:CA10644113 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM2, PM6, PM3, PM1, PM4, PM5, BS2, PP1, PP4, PP2, PP3, BP3, BP1, BP4, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.*410A>T variant has an allele frequency of 0.05129 (5.129%, 443/8638 alleles, 10 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644113/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:119573 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0028738 infores:hetionet CHEBI:50173 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0004093 infores:hetionet CHEBI:3216 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0021368 infores:hetionet CHEBI:27999 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0020625 infores:hetionet CHEBI:253342 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0025345 infores:hetionet GO:0014807 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:0014807 GO:0061053 CHEBI:9943 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0233632 infores:hetionet NCBIGene:57215 biolink:causes MONDO:0975798 infores:monarchinitiative not_provided not_provided HGNC:23194 MONDO:0975798 uuid:e1a2ed61-1761-4970-b5ba-a77fb07ce4c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030446 infores:hetionet CHEBI:4877 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0009676 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011991 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0009806 infores:hetionet CHEBI:421707 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0151905 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1112559 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1112559 infores:hetionet CAID:CA345150851 biolink:causes MONDO:0100084 infores:clingen CAID:CA345150851 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PM6 BP1, BP4, BA1, BS1 The NM_001100.4:c.175G>A variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 59 (p.Glu59Lys). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The REVEL computational prediction analysis tool gives a score of 0.855, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The Z-score in gnomAD v4.1 is 4.53 (PP2). This variant has been reported in at least three probands, of which one was a de novo occurrence with unconfirmed parental relationships (PS4_Supporting, PM6; GeneDx, Harry Perkins Institute Of Medical Research, LabCorp internal data, ClinVar: SCV004040176.2, SCV004041839.1). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM6, PS4_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 9/9/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345150851/MONDO:0100084/147 2024-09-09 2025-04-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3561 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0027769 infores:hetionet CHEBI:3756 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0012569 infores:hetionet CAID:CA16020741 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020741 MONDO:0009861 PMID: Likely Pathogenic PM1, PP4, PM2_Supporting, PS3_Moderate PM3 The NM_000277.3(PAH):c.187_190delinsCCCA (p.Thr63_His64delinsProAsn) variant in PAH has been reported in at least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) without analysis of urine pterins, DHPR activity, or sequencing to exclude defects of BH4 cofactor metabolism (PP4, PMIDs: 8406445, 9634518, 244250308). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). A cell-free transcription-translation system showed 10-13% (<50%) enzyme activity in vitro with >11 benign/pathogenic variant controls, indicating that this variant impacts protein function (PMIDs:11161839, PS3_Moderate). This variant resides within a region that is defined as a mutational hotspot and critical functional domain by the ClinGen PAH Variant Curation Expert Panel (PMID: 11326337; PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria VCEP: PP4, PM2_supporting, PM1, PS3_moderate (Version 2.0, 7/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020741/MONDO:0009861/006 2025-07-18 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6437 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0858635 infores:hetionet CHEBI:5138 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0038325 infores:hetionet CHEBI:47780 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235437 infores:hetionet CHEBI:27504 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0019061 infores:hetionet CHEBI:3175 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0015672 infores:hetionet UMLS:C0004609 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0009676 infores:hetionet CHEBI:45783 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0041834 infores:hetionet CHEBI:3001 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0002792 infores:hetionet CHEBI:63599 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0016059 infores:hetionet CHEBI:521033 biolink:causes MONDO:0018902 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0206669 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0269189 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0012813 infores:hetionet CAID:CA172130 biolink:causes MONDO:0018947 infores:clingen CAID:CA172130 MONDO:0018947 PMID: Benign BP4, BA1, BP7 BS1, PM2 The variant NM_001005361.3:c.2484G>A in DNM2 is a synonymous (silent) variant (p.Pro828=). The filtering allele frequency (the lower threshold of the 95% CI of 2652/74982) of the c.2484G>A variant in DNM2 is 0.03445 for African/African American chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The c.2484G>A (p.Pro828=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA172130/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63638 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0333641 infores:hetionet CHEBI:8346 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0017178 infores:hetionet CHEBI:6067 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0242184 infores:hetionet CHEBI:9130 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0264906 infores:hetionet CHEBI:64312 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0870082 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0029928 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013595 infores:hetionet CHEBI:94385 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C1565489 infores:hetionet CHEBI:10110 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0702166 infores:hetionet UMLS:C0010592 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0004093 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0854388 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0854388 infores:hetionet GO:1902066 biolink:causes GO:0009664 infores:ubergraph knowledge_assertion manual_agent GO:1902066 GO:0009664 CHEBI:9570 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0011603 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0948089 infores:hetionet CHEBI:63612 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0041364 infores:hetionet CHEBI:40050 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0151905 infores:hetionet CHEBI:94449 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C1443060 infores:hetionet CHEBI:9328 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0011991 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0236171 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0236171 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0863113 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0021845 infores:hetionet CHEBI:36791 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149741 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0442874 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0003123 infores:hetionet CHEBI:63618 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0030332 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0030193 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0178298 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0235431 infores:hetionet CHEBI:3723 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023380 infores:hetionet CHEBI:4907 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0018524 infores:hetionet CHEBI:3757 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0008031 infores:hetionet CHEBI:15365 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0004096 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005900 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0030583 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011630 infores:hetionet CHEBI:100246 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0234233 infores:hetionet CHEBI:9635 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0085593 infores:hetionet CHEBI:9139 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0917801 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042267 infores:hetionet CHEBI:2659 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0151636 infores:hetionet CAID:CA011186 biolink:causes MONDO:0005045 infores:clingen CAID:CA011186 MONDO:0005045 PMID:27532257PMID:1552912PMID:10567705PMID:1552912PMID:24093860 Pathogenic PP3, PM1, PM2, PP1_Moderate, PS4 The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011186/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3479 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0033774 infores:hetionet CHEBI:71417 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0030305 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0853746 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0853746 infores:hetionet CHEBI:44185 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235378 infores:hetionet CHEBI:5001 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151766 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0423602 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0037274 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042267 infores:hetionet CHEBI:31625 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0151827 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027947 infores:hetionet CHEBI:27834 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0004134 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1384666 infores:hetionet CHEBI:102216 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0020649 infores:hetionet NCBIGene:3098 biolink:causes MONDO:0032807 infores:monarchinitiative not_provided not_provided HGNC:4922 MONDO:0032807 uuid:51954565-5b15-4f1e-a5c9-6e2e9cde71e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0020649 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0020649 infores:hetionet CHEBI:63599 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0004093 infores:hetionet CHEBI:7466 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0855242 infores:hetionet CHEBI:6710 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0456909 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0595877 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0858678 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017160 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0314719 infores:hetionet GO:1905005 biolink:causes GO:0003197 infores:ubergraph knowledge_assertion manual_agent GO:1905005 GO:0003197 CHEBI:3732 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151878 infores:hetionet NCBIGene:65125 biolink:causes MONDO:0013778 infores:monarchinitiative not_provided not_provided HGNC:14540 MONDO:0013778 uuid:82b4f36a-8639-45bd-8ebd-11650c162cfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0019079 infores:hetionet CHEBI:8060 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0020488 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038814 infores:hetionet CHEBI:6541 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C2830004 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023510 infores:hetionet CHEBI:10101 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0917801 infores:hetionet CHEBI:15551 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0039070 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006840 infores:hetionet CHEBI:8080 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0015672 infores:hetionet CHEBI:74947 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023218 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0267792 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0576995 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0576995 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0014549 infores:hetionet CHEBI:47898 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0162834 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0235431 infores:hetionet CHEBI:421707 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C1145670 infores:hetionet CHEBI:8871 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235592 infores:hetionet CHEBI:3215 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0033036 infores:hetionet NCBIGene:182 biolink:causes MONDO:0008542 infores:monarchinitiative not_provided not_provided HGNC:6188 MONDO:0008542 uuid:902abdef-2b0b-486c-9cc4-c3d65e0c27f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4315 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0040053 infores:hetionet CHEBI:32315 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042024 infores:hetionet CHEBI:71219 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151907 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0332534 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235763 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027813 infores:hetionet CAID:CA6832201 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832201 MONDO:0015967 PMID: Benign BA1, BS3_Supporting PP4 The c.1816G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to serine at codon 606 (p.(Gly606Ser)) of NM_000545.8. This variant has a Grpmax filtering allele frequency of 0.0003196 in gnomAD v4.1.0 exomes, which is above the MDEP cutoff for BA1 (>0.0001) (BA1). Functional studies demonstrated the p.Gly606Ser protein has DNA binding above 75% of wild type and abnormal nuclear localization/transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to insufficient clinical information, and PP4 cannot be applied (PMID: 22432108). In summary, c.1816G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BA1, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832201/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15544 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0006277 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151736 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0242350 infores:hetionet CHEBI:27666 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0014742 infores:hetionet CHEBI:49575 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011253 infores:hetionet CHEBI:49713 biolink:causes UMLS:C1735368 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C1735368 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0423234 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0423234 infores:hetionet CHEBI:15544 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C3665347 infores:hetionet CHEBI:8890 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0003811 infores:hetionet NCBIGene:669 biolink:causes MONDO:0009113 infores:monarchinitiative not_provided not_provided HGNC:1093 MONDO:0009113 uuid:581676fd-0a60-4ebd-b262-6d1b7b9ad4bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49713 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C2830004 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2747793 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0004936 infores:hetionet CHEBI:724125 biolink:causes UMLS:C0852361 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0852361 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151765 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151765 infores:hetionet CAID:CA2580616967 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580616967 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.3308_3309del (p.Tyr1103fs) is a frameshift variant due to a 2-nucleotide deletion introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 36445968, 31645972, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616967/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:3723 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006277 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0042109 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0036220 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0003123 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004239 infores:hetionet CHEBI:17076 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C1565489 infores:hetionet CHEBI:17263 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0027497 infores:hetionet CHEBI:50777 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C2047937 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0025061 infores:hetionet CHEBI:50173 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C1368065 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0038587 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0342579 infores:hetionet CHEBI:204928 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0015230 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004948 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023434 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0234215 infores:hetionet CAID:CA023581 biolink:causes MONDO:0007750 infores:clingen CAID:CA023581 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, BS2 NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 12 index cases.PP1_strong - 10 informative meioses identified by Laboratory of Genetics and Molecular Cardiology.PM2 - PopMax MAF = 0.00001548 (0.0015%) in European non-Finnish (gnomAD v2.1.1). PP3 - REVEL: 0,89. PP4 - Variant meets PM2. Variant identified in 12 index cases fulfilling validated clinical criteria for FH (6 cases with Simon-Broome or DLCN criteria from Ambry Genetics; 2 cases with Simon-Broome from Color laboratory; 3 cases with Simon-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 1 case with Simon-Broome criteria from GeneDx). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023581/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3347 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0011603 infores:hetionet CHEBI:27899 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0003467 infores:hetionet GO:1902890 biolink:causes GO:0080147 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0080147 CHEBI:51364 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0087169 infores:hetionet CAID:CA414446709 biolink:causes MONDO:0010604 infores:clingen CAID:CA414446709 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PP3, PP4_Moderate PM5 The c.1235G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Glutamate at amino acid 412 (p.Gly412Glu). This variant has been reported in at least 8 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_VeryStrong; PMID: 10874302, 29296726, 1680287, 8055323, 12588353). At least one patient with this variant meets the VCEP specification for PP4 (PP4_Moderate, MLOF study). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.981, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414446709/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:75722 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0555120 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0475858 infores:hetionet CHEBI:17823 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0020437 infores:hetionet CHEBI:100241 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C2830004 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0025061 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0595938 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0595938 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0031117 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042075 infores:hetionet CHEBI:31643 biolink:causes UMLS:C0423086 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0423086 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0349506 infores:hetionet NCBIGene:710 biolink:causes MONDO:0007361 infores:monarchinitiative not_provided not_provided HGNC:1228 MONDO:0007361 uuid:bb055760-fcc1-468a-94aa-9093ebd13ceb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0038999 infores:hetionet CHEBI:161680 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C1609512 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0030312 infores:hetionet CHEBI:63624 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0232115 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0232115 infores:hetionet CHEBI:17076 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0042571 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0037274 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0860434 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0860434 infores:hetionet CHEBI:8890 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013384 infores:hetionet CHEBI:82960 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0006142 infores:hetionet CAID:CA10653571 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653571 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS3, PS2, PS4, BP1, BP4, BP3, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This 3' UTR variant has a MAF of 0.028 (2.8%, 243/8618 alleles) in the African/African-American subpopulation of the gnomAD v2.1.1 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 3 homozygotes in gnomAD v2.1.1 (BP2).In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653571/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10119 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042024 infores:hetionet CAID:CA229343 biolink:causes MONDO:0009861 infores:clingen CAID:CA229343 MONDO:0009861 PMID: Pathogenic PVS1, PP4_Moderate, PM2, PM3_Supporting The frameshift variant c.1099del (HGVS nomenclature c.1095del) occurs in exon 11 of 13 and is predicted to result in NMD. The variant is found at an extremely low allele frequency of 0.000003980 overall in gnomAD with a MAF of 0.000008804 (1/113590) in the European population. One classical PKU patient has been reported (PMID: 29176022) with this variant in trans with Arg241Cys (ClinVar 102803, Pathogenic with expert panel review). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229343/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68584 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0009421 infores:hetionet CHEBI:49960 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0013404 infores:hetionet CHEBI:53760 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0025874 infores:hetionet CAID:CA10014262 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014262 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.939_950del (p.Ala315_Ser318del) is an in-frame deletion which does not occur within the Runt Homology Domain (AA 89-204) (PM4 not applied). This variant has a MAF of 0.0001858 (0.01858%, 24/129186, 24 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014262/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0879264 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0853149 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0917798 infores:hetionet CHEBI:17141 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C1443060 infores:hetionet CHEBI:50742 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0015672 infores:hetionet CHEBI:77260 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C3665347 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0853692 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0574067 infores:hetionet CHEBI:7466 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0242301 infores:hetionet CHEBI:63598 biolink:causes UMLS:C2363980 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C2363980 infores:hetionet NCBIGene:7486 biolink:causes MONDO:0010196 infores:monarchinitiative not_provided not_provided HGNC:12791 MONDO:0010196 uuid:904352fd-e756-46f9-b3c2-01db9cf38962 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0034063 infores:hetionet CHEBI:724125 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0205204 infores:hetionet CHEBI:45716 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0002871 infores:hetionet CHEBI:50729 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0085593 infores:hetionet CHEBI:145499 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0152459 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0031350 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026946 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0267792 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0039503 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013491 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0234215 infores:hetionet CHEBI:3127 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0233407 infores:hetionet CHEBI:93363 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0857807 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0006840 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0549475 infores:hetionet CAID:CA386966010 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966010 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.769A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to histidine at codon 257 (p.(Asn257His)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Furthermore, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.905, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another variant at this location, c.770A>C p.(Asn257Thr), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in one unrelated individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, which is below the ClinGen MDEP threshold for PS4_Moderate to be applied (ClinVar: 2758582; internal lab contributors). However, this individual did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; ClinVar ID: 2758582, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.769A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966010/MONDO:0015967/017 2024-11-27 2024-11-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42944 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0151786 infores:hetionet CHEBI:47612 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0014742 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0029408 infores:hetionet CHEBI:9907 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0017181 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0019340 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0267596 infores:hetionet CHEBI:64312 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0278134 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013395 infores:hetionet CHEBI:36704 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0750394 infores:hetionet CAID:CA414773453 biolink:causes MONDO:0044970 infores:clingen CAID:CA414773453 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS2_Moderate PP1, PP4, BA1, PS4, BS1, PM6 The m.3761C>A (p.S152Term) variant causes a premature stop gain in codon 152 of the MT-ND1 gene, which is predicted to remove >10% of the protein (PVS1_strong). This variant has been reported in two individuals. The first individual was a female with late-onset hearing impairment who developed progressive visual loss and headaches during pregnancy at 35, followed by transient left arm weakness, vertigo, sensory disturbances, and fatigue. At 46, she was diagnosed with diabetes mellitus, and began to experience dysarthric speech, reduced muscle strength, and unsteadiness. Heteroplasmy ranged from 12-80% (PMID:32158465). The second individual was an infant male diagnosed with West syndrome who exhibited ventriculomegaly on brain MRI at 7.2 months old and elevated serum lactate levels. Blood heteroplasmy was 81% (PMID:36918699). Haplogroup information was not reported for all cases precluding consideration for PS4. This variant occurred de novo in one individual (absent in blood from mother; PS2_moderate, PMID: 36918699). In the other family, both the mother and maternal grandmother developed hearing impairment in their 40s; however the grandmother was not available for mtDNA testing (PMID:32158465). While nuclear causes of disease were excluded in one proband (PMID:32158465) and biochemical deficiency was shown in another individual (PMID:32158465), there were no cases where nuclear causes of disease and biochemical deficiencies were evaluated in the same individual. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PS2_moderate, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414773453/MONDO:0044970/015 2023-09-26 2024-11-25 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:63681 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0600228 infores:hetionet CHEBI:63580 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003578 infores:hetionet CHEBI:3286 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0018824 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0260662 infores:hetionet CHEBI:2955 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0036830 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C2830004 infores:hetionet GO:1900123 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:1900123 GO:0051716 CAID:CA270574 biolink:causes MONDO:0010726 infores:clingen CAID:CA270574 MONDO:0010726 PMID: Pathogenic PM1, PM5, PP3, PP4, PS4, PM6_Strong, PM2_Supporting The c.905C>T p.(Pro302Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro302Leu) variant has been observed in at least 5 individuals with Rett syndrome or severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756, 16473305, 32472557) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in at least 4 of these individuals (PMID: 10767337, 30377382, 23696494, 11313756) (PM6_very strong). The p.(Pro302Leu) variant occurs in the well-characterized transcriptional repression domain (TRD: aa 302-306) of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID: 10814718, 10814719, 10944854, 17387578, 15737703) (PM5). In summary, the c.905C>T p.(Pro302Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PP3, PP4, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270574/MONDO:0010726/016 2022-06-30 2022-06-30 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:72564 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151854 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1258215 infores:hetionet NCBIGene:9131 biolink:causes MONDO:0010689 infores:monarchinitiative not_provided not_provided HGNC:8768 MONDO:0010689 uuid:28fd9dfb-a569-4140-88a8-6480febdd895 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0090425 biolink:causes CL:0000622 infores:ubergraph knowledge_assertion manual_agent GO:0090425 CL:0000622 CHEBI:135342 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0017178 infores:hetionet CAID:CA6904317 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904317 MONDO:0019497 PMID: Likely Pathogenic PP3, PM3, PM5_Strong PM2, PS3 The c.1101T>C variant in GJB2 is a missense variant predicted to cause substitution of valine by alanine at amino acid 37 (p.Val37Ala). The highest population filtering allele frequency in gnomAD v4 is 0.03% (25/74924 alleles) in the African American population (PM2_Supporting, BA1, and BS1 not met). This variant has been identified in 11 heterozygous individuals who did not harbor a second variant in GJB2 (PMID 21287563, PMID 17666888, PMID 15365987,GeneDx Internal Data, Invitae Internal Data), but has also been detected in 1 patient with hearing loss in trans with a pathogenic variant (1 point, PM3; Partners LMM internal data SCV000967620.2, GeneDx Internal Data, Invitae Internal Data). The REVEL computational prediction analysis tool produced a score of 0.675, which rounded up to 0.7 is above the threshold necessary to apply PP3 (PP3). Two different pathogenic missense variants (p.Val37Ile and p.Val37Phe) have been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5_Strong, p.Val37Ile ClinVar Variation ID 17023, PMID 31160754; p.Val37Phe ClinVar Variation ID:179256 PMID: 37108562). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3, PM5_Strong, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904317/MONDO:0019497/005 2024-04-22 2024-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:63619 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0429098 infores:hetionet CHEBI:2682 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0231528 infores:hetionet CHEBI:63631 biolink:causes EFO:0020909 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0877167 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0242350 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005940 infores:hetionet CHEBI:36791 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151936 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0877690 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877690 infores:hetionet CHEBI:3219 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2937350 infores:hetionet CHEBI:15428 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0004604 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0018939 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0032285 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1096035 infores:hetionet CHEBI:4995 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085633 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1167965 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0233794 infores:hetionet NCBIGene:6097 biolink:causes MONDO:0014710 infores:monarchinitiative not_provided not_provided HGNC:10260 MONDO:0014710 uuid:db1d1abb-6368-4546-bb10-e9635e93a8d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036974 infores:hetionet CHEBI:75988 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0023530 infores:hetionet CHEBI:63581 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0029118 infores:hetionet CHEBI:50841 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0162830 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0948595 infores:hetionet CHEBI:102216 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0013404 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0595930 infores:hetionet CHEBI:37924 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030196 infores:hetionet CHEBI:39867 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0235660 infores:hetionet CHEBI:37941 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0086565 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0948594 infores:hetionet CHEBI:3387 biolink:causes UMLS:C3160771 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C3160771 infores:hetionet CHEBI:77260 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0031256 infores:hetionet CHEBI:5100 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0002874 infores:hetionet CHEBI:10101 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0231218 infores:hetionet CHEBI:6909 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013378 infores:hetionet CHEBI:94848 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0221490 infores:hetionet CHEBI:7601 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0014457 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0151736 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0012254 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0012254 infores:hetionet CHEBI:5778 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013378 infores:hetionet CHEBI:50861 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0031350 infores:hetionet CHEBI:408174 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0011603 infores:hetionet CAID:CA023677 biolink:causes MONDO:0007750 infores:clingen CAID:CA023677 MONDO:0007750 PMID: Uncertain Significance PP3, PP1 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP4, BS2 NM_000527.5(LDLR):c.2479G>A (p.Val827Ile) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - Variant segregates with FH phenotype in 3 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PP3 - REVEL: 0,771. Score is above 0,75. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023677/MONDO:0007750/013 2021-06-22 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8871 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040485 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0042401 infores:hetionet CHEBI:94686 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0022408 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0042109 infores:hetionet CHEBI:31397 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0699744 infores:hetionet CAID:CA9871461 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871461 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting PM5 The c.938G>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 313 (p.Arg313Gln).The filtering allele frequency (the upper threshold of the 95% CI of 2/91080 alleles) of the c.938G>A variant in ADA is 0.000003650 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. No homozygotes have been observed in gnomAD.Another missense variant [c.937C>T, p.Arg313Trp] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871461/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:16796 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0020517 infores:hetionet CAID:CA5950092 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950092 MONDO:0000572 PMID: Uncertain Significance PM2 NM_000448.3(RAG1):c.1064T>C is a missense variant predicted to cause substitution of Methionine by Threonine at amino acid 355 (p.Met355Thr).The highest population minor allele frequency in gnomAD v4 is 0.001815 (11/6062) in Middle Eastern population. (PM2_Supporting, BS1, and BA1 are not met).There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: No criteria met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950092/MONDO:0000572/123 2024-02-12 2024-02-12 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0010592 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0033774 infores:hetionet CAID:CA273289 biolink:causes MONDO:0019501 infores:clingen CAID:CA273289 MONDO:0019501 PMID:22135276PMID:22135276PMID:28041643PMID:15325563PMID:10729113 Pathogenic PP4, PM2, PVS1, PM3_Strong BS4, BS1, BP5, BP7, BS2, PP1, PP3, PM1, PM4, PM5, PM6, BP2, BP3, BP4, BA1, PS2, PS3, PS4, PS1 The c.4510dupA (p.Arg1504LysX26) variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 21/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in 2 patients with hearing loss in trans with 2 different pathogenic variants (PM3_S; PMID:22135276). The allele frequency of the p.Arg1504LysX26 variant in the USH2A gene is 0.003% (3/111138) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with a variant in this gene displayed features of retinitis pigmentosa (PP4; PMID: 22135276). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_S, PM2, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA273289/MONDO:0019501/005 2018-09-10 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf MESH:D012597 biolink:causes MONDO:0005594 infores:drugmechdb knowledge_assertion manual_agent MESH:D012597 HP:0100699 DB06811_MESH_D014648_1 CHEBI:46081 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0013390 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0233494 infores:hetionet NCBIGene:2821 biolink:causes MONDO:0013275 infores:monarchinitiative not_provided not_provided HGNC:4458 MONDO:0013275 uuid:caa8b5cd-9b5f-4076-8940-629fcf8fa094 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2569 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0428977 infores:hetionet CAID:CA229367 biolink:causes MONDO:0009861 infores:clingen CAID:CA229367 MONDO:0009861 PMID:10200057 Pathogenic PVS1, PM2, PP4 The c.1163_1164del (p.Val388fs) variant in PAH has been reported in 1 female patient with classic PKU, Phe = 1210umol/L; BH4 deficiency not excluded (PMID: 10200057; PP4). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 11 out of 13 coding exons (11 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229367/MONDO:0009861/006 2020-10-29 2020-10-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3756 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042029 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0267596 infores:hetionet CHEBI:7936 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030554 infores:hetionet GO:0090173 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0090173 GO:0051321 CHEBI:77260 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1167709 infores:hetionet CHEBI:4717 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0011603 infores:hetionet CHEBI:100241 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025222 infores:hetionet CHEBI:6741 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0020523 infores:hetionet CHEBI:63637 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0013378 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0018681 infores:hetionet NCBIGene:4882 biolink:causes MONDO:0011275 infores:monarchinitiative not_provided not_provided HGNC:7944 MONDO:0011275 uuid:3611535f-6c9e-4f05-ad7c-4c309cbe3181 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0022107 infores:hetionet CHEBI:3347 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0027497 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1392046 infores:hetionet CHEBI:3223 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0004134 infores:hetionet CHEBI:134991 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0026826 infores:hetionet CHEBI:16664 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0019158 infores:hetionet CHEBI:48669 biolink:causes NCIT:C50547 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C1704212 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020676 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1269683 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0034065 infores:hetionet CHEBI:3347 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0518015 infores:hetionet CHEBI:50922 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013404 infores:hetionet CAID:CA410203686 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203686 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.283C>T (p.Pro95Ser) is a missense variant which has a REVEL score ≥ 0.88 (0.951) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203686/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2904 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0006266 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0011053 infores:hetionet CHEBI:15552 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0010200 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0020517 infores:hetionet CHEBI:63681 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0018681 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003615 infores:hetionet CHEBI:3698 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0014742 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0029445 infores:hetionet CHEBI:8455 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0151479 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1141893 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1141893 infores:hetionet CAID:CA322079952 biolink:causes MONDO:0009276 infores:clingen CAID:CA322079952 MONDO:0009276 PMID: Pathogenic PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting, PVS1_Strong The NM_000407.5:c.315del (p.Gly106AlafsTer87) variant in exon 2 of the GP1BB gene is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove 7% of the protein, including the critical transmembrane domain (PVS1_Strong). At least one patient (Proband 1 in PMID:10216092) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry with less than 10% expression of GP9, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Direct sequence analysis of the entire coding region of PCR-amplified GPIba, GPIbb, GPIX, and GPV was performed as well as FISH for deletion analysis, for the patient (PP4_Moderate). This variant has been detected in at least 1 proband with Bernard-Soulier syndrome. This individual was compound heterozygous for this variant and the 22q11.2 deletion including GP1BB (PMID: 10216092; PM3). Surface expression of GP1b and GP9 was measured by flow cytometry in 293T cells transiently co-transfected with the c.315del (p.Gly106AlafsTer87) variant GP1bb and wild type GP1ba and GP9, with no detectable GPIX on the cell surface, indicating that this variant impacts protein function (PMID: 10216092)(PS3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4_Moderate, PM2_supporting, PM3 and PS3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA322079952/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4653 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0008033 infores:hetionet NCBIGene:10282 biolink:causes MONDO:0009682 infores:monarchinitiative not_provided not_provided HGNC:14562 MONDO:0009682 uuid:2dbc1162-b258-4fc0-9dc8-0b3c42eb5c2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151736 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0578454 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0578454 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0242350 infores:hetionet CHEBI:8212 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0857305 infores:hetionet CHEBI:9943 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042963 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011991 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0016436 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0027769 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0011175 infores:hetionet CAID:CA229713 biolink:causes MONDO:0009861 infores:clingen CAID:CA229713 MONDO:0009861 PMID:10527663 Likely Pathogenic PP3_Strong, PM2_Supporting, PM5_Supporting PM1 The c.718T>G (p.Phe240Val) variant in PAH has not been reported in the literature detected in an affected patient to our knowledge. This variant has a Pop Max allele frequency of [0.00001271] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.978. A different likely pathogenic missense change (p.Phe240Ser) has been seen before. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PM5_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229713/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042510 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027813 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0858259 infores:hetionet CHEBI:3738 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0020701 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0041969 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039503 infores:hetionet CHEBI:3647 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0037763 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0020517 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0035854 infores:hetionet CHEBI:7824 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0023380 infores:hetionet CHEBI:6754 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0043352 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0003123 infores:hetionet CHEBI:5280 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0033774 infores:hetionet NCBIGene:4358 biolink:causes MONDO:0009747 infores:monarchinitiative not_provided not_provided HGNC:7224 MONDO:0009747 uuid:06c240f5-f906-4abd-96ae-c56b6ca44f5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45327 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0042510 infores:hetionet CHEBI:61033 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0015967 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0403632 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0042109 infores:hetionet CAID:CA214304 biolink:causes MONDO:0015967 infores:clingen CAID:CA214304 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PP3 The c.441C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to glutamine at codon 147 (p.(His147Gln)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.938, which is greater than the MDEP threshold of 0.70 (PP3). In summary, c.441C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PP3, PM2_Supporting, PM1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214304/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0344232 infores:hetionet CHEBI:68558 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0017565 infores:hetionet CHEBI:51364 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0278106 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0442874 infores:hetionet CHEBI:50924 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0035410 infores:hetionet CHEBI:47898 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0001925 infores:hetionet NCBIGene:54681 biolink:causes MONDO:0032780 infores:monarchinitiative not_provided not_provided HGNC:28858 MONDO:0032780 uuid:1a7b09b4-e333-40e4-ad00-7859dc385d2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020473 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042373 infores:hetionet CAID:CA10603167 biolink:causes MONDO:0017623 infores:clingen CAID:CA10603167 MONDO:0017623 PMID: Pathogenic PM6_Strong, PM2_Supporting, PS3 BS1, PP2, PP3, PM5, BA1, BP1, BP4, PS2 NM_000314.8(PTEN):c.634+5G>A meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6_S: one proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype (PMID:18080326). PS3: assay shows impact on splicing. (PMID:18080326).PM2_P: Absent in large sequenced populations (gnomAD). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603167/MONDO:0017623/003 2023-12-01 2023-12-18 Autosomal dominant inheritance HP:0000006 Supports UNII:15G12L5X8K biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085614 infores:hetionet CHEBI:83804 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0003467 infores:hetionet CAID:CA10524809 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524809 MONDO:0010278 PMID: Benign BS2, BA1, BP5 The highest population minor allele frequency of the p.Ser460= variant in SLC9A6 in gnomAD v4.1 is 0.0004575 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Ser460= variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Ser460= variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Ser460= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524809/MONDO:0010278/033 2024-08-30 2024-11-15 X-linked inheritance HP:0001417 Contradicts true CHEBI:8356 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0162834 infores:hetionet CHEBI:72297 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0000731 infores:hetionet CHEBI:63611 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085605 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0030305 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1696946 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1696946 infores:hetionet CHEBI:473990 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0023890 infores:hetionet CHEBI:5147 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0009763 infores:hetionet CHEBI:4735 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0015230 infores:hetionet NCBIGene:10613 biolink:causes MONDO:0014302 infores:monarchinitiative not_provided not_provided HGNC:16947 MONDO:0014302 uuid:dbb40c98-f77d-40bc-aa77-6bc4370097af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011630 infores:hetionet CHEBI:50692 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C1384353 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011849 infores:hetionet CHEBI:68554 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0232462 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0013595 infores:hetionet CHEBI:16467 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0006114 infores:hetionet CHEBI:408174 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0006277 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0020517 infores:hetionet CHEBI:3441 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002994 infores:hetionet CHEBI:51137 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0424295 infores:hetionet CHEBI:3638 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0162830 infores:hetionet NCBIGene:7439 biolink:causes MONDO:0013175 infores:monarchinitiative not_provided not_provided HGNC:12703 MONDO:0013175 uuid:3b82ddaf-c313-4873-ac82-3f3d3cd3f9e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0149931 infores:hetionet CHEBI:75988 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0040034 infores:hetionet CHEBI:31401 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0231218 infores:hetionet CHEBI:3219 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037763 infores:hetionet CHEBI:63619 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011175 infores:hetionet CHEBI:42820 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0000737 infores:hetionet CAID:CA166072 biolink:causes MONDO:0007648 infores:clingen CAID:CA166072 MONDO:0007648 PMID:26845104 Uncertain Significance BS2_Supporting, PS3_Supporting, PVS1_Moderate BP7, BP5, BS3, BS1, BS4, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2 The c.387+1G>A variant is a canonical splice variant predicted to result in small in-frame amino acid deletions/insertions (PVS1_Moderate). This variant has an allele frequency of 0.00002 in gnomAD (4/245268) and is present with a frequency of 0.00012 (4/33552) in the Latino subpopulation (http://gnomad.broadinstitute.org). RT-PCR analysis demonstrated that this variant results in two additional in-frame transcripts, including a longer transcript with intronic retention of 57 bp and a shorter transcript with a 159 bp deletion (PS3_Supporting; https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20]). This variant has also been reported in at least three individuals not meeting HDGC clinical criteria (BS2_Supporting; https://ascopubs.org/doi/full/10.1200/PO.16.00021, https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20], PMID: 26845104). In summary, this variant is classified as a variant of uncertain significance based on conflicting ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PS3_Supporting, BS2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166072/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63630 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0019521 infores:hetionet CHEBI:61033 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0040586 infores:hetionet CHEBI:119573 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0233407 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0012833 infores:hetionet NCBIGene:950 biolink:causes MONDO:0009699 infores:monarchinitiative not_provided not_provided HGNC:1665 MONDO:0009699 uuid:2d73b178-1eb0-423a-bb36-ff0dfe6abe1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0031117 infores:hetionet CHEBI:7931 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0042029 infores:hetionet CAID:CA229700 biolink:causes MONDO:0009861 infores:clingen CAID:CA229700 MONDO:0009861 PMID:16256386PMID:16256386 Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3_Supporting PM5, PS1 The c.704A>C (p.Gln235Pro) variant in PAH has been reported in a Chinese patient with classical PKU with BH4 deficiency not excluded (PP4), detected in unknown phase with the pathogenic variant c.442-1G>A (ClinVar ID: 594, PMID: 16256386)(PM3_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). A deleterious effect is predicted by REVEL (REVEL score 0.947) (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3_Supporting, PP3_Strong, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229700/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135342 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0232726 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0040264 infores:hetionet NCBIGene:7248 biolink:causes MONDO:0008612 infores:monarchinitiative not_provided not_provided HGNC:12362 MONDO:0008612 uuid:dfb2a142-e94a-4a16-b815-f25b8395d2a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235266 infores:hetionet CHEBI:28001 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0015672 infores:hetionet NCBIGene:6708 biolink:causes MONDO:0009948 infores:monarchinitiative not_provided not_provided HGNC:11272 MONDO:0009948 uuid:6b4a8504-1923-47e2-9858-f2b5e420ade7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9352 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0031117 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0262977 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0262977 infores:hetionet CHEBI:7936 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042963 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0232492 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233494 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0011991 infores:hetionet CHEBI:5138 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1142135 infores:hetionet CHEBI:3380 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0036974 infores:hetionet CHEBI:7565 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0403447 infores:hetionet CHEBI:7465 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0015967 infores:hetionet CHEBI:7640 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0234133 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009450 infores:hetionet CHEBI:8805 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0040435 infores:hetionet NCBIGene:8131 biolink:causes MONDO:0014925 infores:monarchinitiative not_provided not_provided HGNC:14124 MONDO:0014925 uuid:04d3d9bb-2370-4049-b5c8-ce0d1537eac5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C1306341 infores:hetionet CHEBI:51380 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0877055 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0677500 infores:hetionet CHEBI:3732 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085932 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0027051 infores:hetionet CHEBI:5280 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0039070 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0178298 infores:hetionet CHEBI:66876 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0012833 infores:hetionet CHEBI:61033 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1368065 infores:hetionet CHEBI:43968 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0428977 infores:hetionet CHEBI:3312 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0234233 infores:hetionet CHEBI:2687 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0013404 infores:hetionet CHEBI:17698 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0027497 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0034063 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233414 infores:hetionet CHEBI:6931 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0011570 infores:hetionet CHEBI:63620 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027497 infores:hetionet CHEBI:144551 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C3665386 infores:hetionet CHEBI:6887 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0023218 infores:hetionet CHEBI:8356 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0162298 infores:hetionet CHEBI:8232 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151905 infores:hetionet CHEBI:100241 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0234233 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0003123 infores:hetionet CHEBI:4653 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0035455 infores:hetionet CHEBI:8888 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235437 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0232492 infores:hetionet CHEBI:45783 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020625 infores:hetionet CHEBI:5138 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0024902 infores:hetionet CHEBI:72297 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0015672 infores:hetionet CHEBI:2637 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0022660 infores:hetionet CHEBI:10100 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0013395 infores:hetionet NCBIGene:8541 biolink:causes MONDO:1040014 infores:monarchinitiative not_provided not_provided HGNC:9247 MONDO:1040014 uuid:5a8702ce-aacf-438c-8c7c-70b16d93eda6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92511 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0043094 infores:hetionet CHEBI:6761 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0030554 infores:hetionet CHEBI:9123 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018524 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0575090 infores:hetionet CAID:CA179952 biolink:causes MONDO:0800472 infores:clingen CAID:CA179952 MONDO:0800472 PMID: Benign BP4, BA1, BP7 PP3, PP1, PS3, PS1, PS2, PM3, PM1, PM4, PM5, BS1, BS4, BS3, PVS1, PM2 The c.729G>C variant in CYP1B1 is a synonymous variant (p.Val243=). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.2202, which met the ≥ 0.05 threshold set for BA1 (16,524 alleles out of 75,032, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact CYP1B1 function. This synonymous variant is located outside of the first and the last 3 bases of the exon and BP4 is met, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA179952/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7445 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C2979982 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0687133 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0026848 infores:hetionet CHEBI:2659 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0917801 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0005940 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009450 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0021400 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151996 infores:hetionet CAID:CA355965306 biolink:causes MONDO:0001586 infores:clingen CAID:CA355965306 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.1728-1G>C variant in IDUA occurs within the canonical splice acceptor site of intron 12. It is predicted to cause skipping of biologically-relevant exon 13 out of 14, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 3 patients with this variant had documented IDUA deficiency within the affected range and urinary GAG elevation above normal range (PP4; PMID: 31194252). This variant has been detected in at least 2 individuals with MPS I. Of those individuals, both were compound heterozygous for the variant and a pathogenic variant (Q70X; W402X) and neither of those were confirmed in trans (PM3; PMID: 31194252). The highest population minor allele frequency in gnomAD v4.0. is 0.00001612 (19/1178792 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0): PVS1, PP4, PM3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355965306/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8207 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011991 infores:hetionet CAID:CA214079 biolink:causes MONDO:0010938 infores:clingen CAID:CA214079 MONDO:0010938 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM4_Supporting, PM3 PM5, BS2 The NM_000215.4(JAK3):c.1744C>T variant is predicted to cause the Arg582Trp missense substitution, however it has been observed in patient cDNA to cause an in-frame deletion of 213bp (71 amino acids; p.Ser568_Leu638del) due to skipping of exon 13 and 14 (PMID: 9753072). The deleted region contains the NM_000215.4(JAK3):c.1796T>G (p.Val599Gly) variant which has been classified by the SCID VCEP as VUS (PM4_supporting). This variant was identified in at least one T-B+ SCID patient in whom, IL-2-induced JAK3 phosphorylation showed that the JAK3 protein was only marginally activated, and IL-2-induced phosphorylation of STAT5B/A was not detected in BCLs from the patient. This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (PMID: 9753072; PP4_moderate). This patient (PMID: 9753072) was homozygous for the variant and two additional patients are compound heterozygous with second variants confirmed in trans (but not yet classified by the SCID-VCEP so considered VUS), Leu1017Pro (PMID: 33777394) and c.115dup (PMID: 21184155) for three patients in total with this variant (PM3). The highest population allele frequency in gnomAD v2.1.1 is 0.00001239 (1/80718 alleles in the European non-Finnish population), which is lower than the ClinGen SCID VCEP threshold of <0.000115 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3, PM4_supporting, PP4_moderate. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214079/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7492 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0013404 infores:hetionet CHEBI:5050 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0002792 infores:hetionet CHEBI:28901 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0948441 infores:hetionet NCBIGene:1316 biolink:causes MONDO:0700275 infores:monarchinitiative not_provided not_provided HGNC:2235 MONDO:0700275 uuid:6fc8ad36-e9b6-4549-aca0-54276def7f87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8802 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0032227 infores:hetionet CAID:CA16020977 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020977 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4_Moderate, PM3_Strong This c.1242C>A (p.Tyr414Ter) variant in PAH was detected in multiple patients with PKU with the pathogenic variants p.Y204C (PMID: 24705691) and p.Arg241Cys (PMID: 28982351). This variant was absent in population databases. This is a nonsense variant in exon 12 of 13 coding exons predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020977/MONDO:0009861/006 2022-10-14 2022-10-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5959 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013395 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0240449 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0240449 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0948089 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0267792 infores:hetionet CHEBI:64321 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0040046 infores:hetionet NCBIGene:285489 biolink:causes MONDO:0100103 infores:monarchinitiative not_provided not_provided HGNC:26594 MONDO:0100103 uuid:344f3843-3ed1-4e41-b1e3-e2d5e7a6edfc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71229 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0015230 infores:hetionet CHEBI:16347 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0006277 infores:hetionet CHEBI:51860 biolink:causes HP:0033694 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233767 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0021053 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0027765 infores:hetionet CHEBI:40050 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0392525 infores:hetionet GO:1901546 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:1901546 GO:0099504 CHEBI:10102 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0014591 infores:hetionet CHEBI:17650 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C1384353 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017160 infores:hetionet CHEBI:134991 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0028643 infores:hetionet CHEBI:64312 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151632 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0152031 infores:hetionet CHEBI:49713 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0036974 infores:hetionet CHEBI:45979 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0022346 infores:hetionet UMLS:C0065374 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004093 infores:hetionet CAID:CA255007 biolink:causes MONDO:0010602 infores:clingen CAID:CA255007 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PS2_Moderate, PM2_Supporting, PP1, PVS1_Moderate, PS4 The c.6976C>T (p.Arg2326Ter) creates a premature stop codon in exon 26, which is the last exon of the F8 gene. Therefore, protein is not expected to undergo NMD and meets PVS1_Strong. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. More than 20 patients are reported in the literature with severe/moderate hemophilia A, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate. The variant was also reported in two affected brothers and their carrier mother, which meets criteria for PP1 (PMID: 2987704). There is also at least one report of a de novo case where maternity was not confirmed, meeting PS2_Moderate (PMID: 2104741). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PVS1_Strong, PS4_Very strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255007/MONDO:0010602/071 2024-06-19 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:28748 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014868 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0162830 infores:hetionet CAID:CA320637875 biolink:causes MONDO:0011071 infores:clingen CAID:CA320637875 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.455A>G (p.Lys152Arg) is a missense variant affecting one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant has a REVEL score >0.88 (0.912) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320637875/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2704 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0042963 infores:hetionet CHEBI:8356 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033893 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0009806 infores:hetionet CHEBI:17688 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0917801 infores:hetionet CHEBI:9448 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C2242588 infores:hetionet CHEBI:5106 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C3263723 infores:hetionet CAID:CA10014360 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014360 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS4, PS2, PS3, BA1, BP1, BP2, BP3, PVS1, PM2, PM6, BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.768C>T (p.Ser256=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014360/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135613 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0011603 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0020517 infores:hetionet CHEBI:78543 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020598 infores:hetionet NCBIGene:55135 biolink:causes MONDO:0013520 infores:monarchinitiative not_provided not_provided HGNC:25522 MONDO:0013520 uuid:c956e9eb-48cf-4176-a9c4-f74b6ca2ff9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027651 infores:hetionet CHEBI:9667 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0018813 infores:hetionet CHEBI:32192 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0232487 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0033575 infores:hetionet CAID:CA179559 biolink:causes MONDO:0019501 infores:clingen CAID:CA179559 MONDO:0019501 PMID: Uncertain Significance PM3_Supporting, PP4 BP7, BP5, BS1, BS3, BS4, BS2, PP3, PP2, PP1, PM5, PM4, PM1, PVS1, PM2, PM6, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.5039A>G (p.Lys1680Arg) variant in USH2A is a missense variant that replaces lysine with arginine at codon 1680. (Add gnomad information) The REVEL score for this variant is 0.252, which does not meet the threshold for PP3. This variant has been observed in the homozygous state in one individual with a clinical diagnosis of Usher syndrome (PMID: 36909829), meeting PM3_Supporting. The phenotype observed is highly specific for Usher syndrome, meeting PP4. In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Supporting, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA179559/MONDO:0019501/005 2025-05-21 2025-06-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:18358 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0024141 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0018799 infores:hetionet CHEBI:27779 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0020433 infores:hetionet NCBIGene:11133 biolink:causes MONDO:0014289 infores:monarchinitiative not_provided not_provided HGNC:6404 MONDO:0014289 uuid:65fce324-ac97-4985-a1da-86e39d8fd85f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C1096717 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1096717 infores:hetionet CAID:CA512341373 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341373 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS4, PS1, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1014G>A (p.Ala338=) is a synonymous variant that has a SpliceAI score of 0.00 (≤0.20) and no REVEL score applicable. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.33< 2.0). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341373/MONDO:0011071/008 2022-03-17 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42797 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006147 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1609512 infores:hetionet CHEBI:83531 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0000737 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0018621 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020517 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0026848 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0042373 infores:hetionet CHEBI:94449 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0013395 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0007097 infores:hetionet CHEBI:31536 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0033687 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037274 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151849 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0010709 infores:hetionet CHEBI:9086 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1510410 infores:hetionet CHEBI:5383 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0043094 infores:hetionet CAID:CA399807023 biolink:causes MONDO:0100326 infores:clingen CAID:CA399807023 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000419.5:c.59T>G variant in ITGA2B is a missense variant predicted to cause substitution of leucine by arginine at amino acid 20 (p.Leu20Arg). This variant has been observed in homozygosity in one individual (reported via personal communication with Dr. Jose Rivera, Servicio de Hematologıa y Oncologıa Medica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacion, Universidad de Murcia) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry and Western blot, and ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). Furthermore, the computational predictor REVEL gives a score of 0.772, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3_Supporting, PP3, PP4_Strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399807023/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3387 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0030554 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0028077 infores:hetionet CHEBI:48844 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0232493 infores:hetionet CHEBI:5147 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C3263723 infores:hetionet CHEBI:79699 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0206062 infores:hetionet CHEBI:50924 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0002994 infores:hetionet CHEBI:8502 biolink:causes UMLS:C0238874 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0238874 infores:hetionet CHEBI:50861 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0041657 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0948089 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0518015 infores:hetionet CHEBI:78543 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020580 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0860871 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0234936 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0038325 infores:hetionet CHEBI:9674 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0003123 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0011616 infores:hetionet CHEBI:8028 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0085631 infores:hetionet NCBIGene:3394 biolink:causes MONDO:0009194 infores:monarchinitiative not_provided not_provided HGNC:5358 MONDO:0009194 uuid:6e9a69e2-abab-4200-8301-07dc6335ff70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0033575 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151773 infores:hetionet CHEBI:40237 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0004604 infores:hetionet CAID:CA129038 biolink:causes MONDO:0800472 infores:clingen CAID:CA129038 MONDO:0800472 PMID:27243976PMID:17363580PMID:19643970PMID:19234632PMID:19793111 Uncertain Significance PM1, PP3_Moderate, PS3_Supporting PP1, BA1, BP4, PM3, PM4, PM5, PS1, PS2, BP7, BS1, BS4, PVS1, PM2 The c.155C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 52 (p.Pro52Leu). This missense variant is located in the hinge region, meeting PM1. The highest minor allele frequency of this variant, in a genetic ancestry group of at least 2,000 alleles, was in the Ashkenazi Jewish population of gnomAD (v4.1.0) = 0.0008228 (24 alleles out of 29,168), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The REVEL score = 0.91, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 19643970) demonstrated that the Pro52Leu protein had reduced 17B Estradiol Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. This variant was also assessed in PMIDs: 27243976,19234632, 19793111 &17363580, however, the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined. 2 affected individuals carry the Pro52Leu variant (PMID: 21815720) but they also carry two other CYP1B1 variants, so these people are excluded from assessing PM3, as the causative variant cannot be determined. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM1, PP3_Moderate, PS3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA129038/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0072043 biolink:causes GO:0072088 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072088 CHEBI:4672 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0023467 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0277884 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0948089 infores:hetionet CHEBI:8871 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0001807 infores:hetionet CAID:CA409108072 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108072 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4, PP1_Strong PM1, BP4, BA1, BS1 The c.869G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 290 (p.(Arg290His)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Two of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sufonylurea-sensitive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 14 informative meioses in 6 families (PP1_Strong, internal lab contributors). In summary, c.869G>A meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108072/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6367 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1760428 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0162830 infores:hetionet CHEBI:9674 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0039070 infores:hetionet CHEBI:30830 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011551 infores:hetionet NCBIGene:10559 biolink:causes MONDO:0011342 infores:monarchinitiative not_provided not_provided HGNC:11021 MONDO:0011342 uuid:55d43abb-d53c-4ed2-90d3-6f6223293195 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92712 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0000731 infores:hetionet CHEBI:75246 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0016382 infores:hetionet CHEBI:17474 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0026858 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0233494 infores:hetionet CAID:CA414792846 biolink:causes MONDO:0044970 infores:clingen CAID:CA414792846 MONDO:0044970 PMID: Uncertain Significance PM5_Supporting PP3, PS4, PM2 The m.7445A>T (p.*514S) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID: 18639500). This person was Chinese and had severe hearing loss onset at age one year. There was no known precipitating event. The variant was homoplasmic in blood. There was no family history of hearing loss. This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.049%; Helix's 196,554 sequences: AF=0.002%; gnomAD v3.1.2: absent). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414792846/MONDO:0044970/015 2024-07-08 2024-12-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6775 biolink:causes UMLS:C1112762 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1112762 infores:hetionet CHEBI:27446 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0023530 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0242350 infores:hetionet CHEBI:465284 biolink:causes NCIT:C122437 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0740299 infores:hetionet CHEBI:31859 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0003811 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0009938 infores:hetionet CHEBI:6067 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013144 infores:hetionet CHEBI:3044 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0039231 infores:hetionet CHEBI:10101 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1456784 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0948594 infores:hetionet CHEBI:5613 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0027497 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1527311 infores:hetionet CAID:CA410206839 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206839 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.716G>A (p.Ser239Asn) is a missense variant. This missense variant has a REVEL score <0.50 (0.45) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206839/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA024758 biolink:causes MONDO:0007783 infores:clingen CAID:CA024758 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS4, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with aspartic acid at codon 2439 of the RYR1 protein, p.(Glu2439Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge, this variant has not been reported in any individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 not applied (PMID:16835904, unclear MH history). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.734 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024758/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:51137 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0027947 infores:hetionet NCBIGene:22917 biolink:causes MONDO:0014342 infores:monarchinitiative not_provided not_provided HGNC:13187 MONDO:0014342 uuid:e8aefa0a-5da8-4126-9cbb-40398dcf852e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes MONDO:0001294 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0019937 infores:hetionet CAID:CA6831848 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831848 MONDO:0015967 PMID: Pathogenic PP1_Moderate, PVS1, PP4 PS4, PM2 The c.872del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.(Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). Additionally, this variant segregated with diabetes, with at least 30 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.872del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP1_Strong, PP4 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831848/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:367163 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0024299 infores:hetionet CHEBI:6775 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013404 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151734 infores:hetionet CHEBI:42068 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0036974 infores:hetionet CHEBI:65349 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0151662 infores:hetionet CHEBI:5118 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042510 infores:hetionet CHEBI:10650 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0149741 infores:hetionet CHEBI:7466 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0086565 infores:hetionet CHEBI:72296 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0553692 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0151763 infores:hetionet CAID:CA645293835 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293835 MONDO:0015924 PMID: Likely Pathogenic PVS1, PM2_Supporting BP4, BA1, PS4, BS1 The BMPR2 c.1276+4A>G variant is a non-canonical splice site (+4) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with PAH (PMID: 16429395). An in vitro exon trapping assay (including wild-type exon 9, or missense or c.1267+4A>G mutant exon 9) demonstrated exon skipping with the non-canonical splice variant (PMID: 18321866). Further, in silico prediction (SpliceAI = 0.59) indicates the variant will probably impact splicing with loss of the canonical donor site in intron 9. Exon skipping or use of a cryptic splice site would lead to nonsense-mediated decay or disrupt the region encoding the conserved intracellular kinase domain, respectively. Taken together, the data support the application of PVS1 instead of PP3 and PM1 (PMID: 37352859). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293835/MONDO:0015924/125 2025-04-29 2025-04-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:35778 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151605 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0518015 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0746883 infores:hetionet CHEBI:10110 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0022346 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0037274 infores:hetionet CHEBI:63613 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0267797 infores:hetionet CHEBI:8214 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0015230 infores:hetionet NCBIGene:80173 biolink:causes MONDO:0030462 infores:monarchinitiative not_provided not_provided HGNC:21424 MONDO:0030462 uuid:28df604f-0ed8-47bf-9486-24bcee7c790b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0028734 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0020517 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1167677 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1167677 infores:hetionet CHEBI:63598 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0344232 infores:hetionet CAID:CA2802176 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802176 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting PM3, PP4 The NM_000203.5:c.1051G>A variant in IDUA is predicted to result in a missense substitution, p.Ala351Thr. To our knowledge, no patients with this variant have been reported in the literature. However, one patient has been identified by a clinical diagnostic testing laboratory with IDUA activity at the upper end of the affected range; no further details are available (insufficient evidence to apply PP4). This patient is compound heterozygous for the variant and c.1827_1828delinsT (p.Asp610ThrfsTer), a variant that alters the donor splice site of the second to last exon of IDUA (VUS based on classification by the ClinGen Lysosomal Disease VCEP). The variants are likely in trans based on parental testing (insufficient evidence to apply PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006670 (4/59972 alleles; no homozygotes) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.831 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria aplied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PP3_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802176/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8665 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0241137 infores:hetionet CHEBI:101278 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0085633 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0243026 infores:hetionet CHEBI:63616 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0033774 infores:hetionet CHEBI:102216 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C1610069 infores:hetionet CHEBI:2666 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0040822 infores:hetionet CHEBI:3082 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0015967 infores:hetionet NCBIGene:10699 biolink:causes MONDO:0958241 infores:monarchinitiative not_provided not_provided HGNC:19012 MONDO:0958241 uuid:9f4aecfe-6ccb-4c04-a3b4-5073e1023e5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7959 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0017658 infores:hetionet CHEBI:3001 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0027441 infores:hetionet NCBIGene:1001 biolink:causes MONDO:0009155 infores:monarchinitiative not_provided not_provided HGNC:1762 MONDO:0009155 uuid:036bef84-2e1b-40be-879f-f28f18399836 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0271710 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0004936 infores:hetionet CHEBI:8863 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013362 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0314719 infores:hetionet NCBIGene:3021 biolink:causes MONDO:0030607 infores:monarchinitiative not_provided not_provided HGNC:4765 MONDO:0030607 uuid:a6c31d4e-a2f5-4d3c-990c-b80dda2f9aa2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0034150 infores:hetionet CHEBI:85161 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0003811 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0948089 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1561230 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1561230 infores:hetionet CHEBI:2549 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0001807 infores:hetionet CHEBI:94609 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0231218 infores:hetionet CHEBI:6128 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0038362 infores:hetionet CHEBI:9086 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0041105 infores:hetionet CHEBI:7936 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003862 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C3665347 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0863113 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0012833 infores:hetionet CHEBI:6472 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0002792 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0853692 infores:hetionet NCBITaxon:632 biolink:causes MONDO:0019095 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:632 MONDO:0019095 CHEBI:44185 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0020433 infores:hetionet CAID:CA229773 biolink:causes MONDO:0009861 infores:clingen CAID:CA229773 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5 The c.802T>C (p.Tyr268His) variant in PAH has not been reported in the literature to our knowledge. The reference in BioPKU/PAHdb (Eisensmith, 1996) does not include this variant. It is absent from ExAC, 1000G, and ESP, with Extremely low frequency in gnomAD (0.000004063). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.977. . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229773/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15854 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0426576 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0234458 infores:hetionet CHEBI:71415 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0002878 infores:hetionet CHEBI:49668 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0002418 infores:hetionet CAID:CA274422 biolink:causes MONDO:0010134 infores:clingen CAID:CA274422 MONDO:0010134 PMID:15679828PMID:15679828PMID:15679828 Pathogenic PM3_Supporting, PP4, PVS1, PM2 BS4, BS1, BP5, BP7, BS2, PP1, PP3, PM5, PM1, PM4, PM6, BP2, BP4, BP3, BA1, PS1, PS2, PS4, PS3 The p.Ile124Tyrfs variant in SLC26A4 is predicted to cause a premature stop codon in biologically-relevant-exon 4/21 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Ile124fs variant is in 0.003% (1/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with the variant displayed features of enlarged vestibular aqueduct and Mondini malformation which are consistent with Pendred syndrome (PP4; PMID:15679828). This variant has been detected in 2 patients with hearing loss in trans with suspected pathogenic variants (PM3_P, PMID:15679828). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_P. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA274422/MONDO:0010134/005 2018-09-10 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:6904 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0042109 infores:hetionet CHEBI:49375 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042963 infores:hetionet CHEBI:100246 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0018524 infores:hetionet CHEBI:64312 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1443060 infores:hetionet CHEBI:30659 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0036830 infores:hetionet NCBIGene:359948 biolink:causes MONDO:0054691 infores:monarchinitiative not_provided not_provided HGNC:21729 MONDO:0054691 uuid:3a6021a0-6df0-4326-83cb-7cb247487395 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0178298 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0151580 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151580 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085096 infores:hetionet CHEBI:5790 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0003811 infores:hetionet CAID:CA913013630 biolink:causes MONDO:0008723 infores:clingen CAID:CA913013630 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c.307_323dup, p.(Val109Lysfs*14) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity; a second distinct pathogenic or likely pathogenic variant in ACADVL was not reported in this individual (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#2.0; approved 04-25-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA913013630/MONDO:0008723/021 2022-04-26 2022-04-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8356 biolink:causes UMLS:C0032300 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032300 infores:hetionet CHEBI:101278 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0877055 infores:hetionet CAID:CA355962863 biolink:causes MONDO:0001586 infores:clingen CAID:CA355962863 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting PS1, PS3, PM5, BS1, BS3, BA1, BP4 The NM_000203.5(IDUA):c.964G>T variant in IDUA is a missense variant predicted to cause substitution of valine by leucine at amino acid 322 (p.Val322Leu). To our knowledge, this variant has not been reported in the literature in any individuals with MPS1. The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001738 (2/1150642 alleles; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.806 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 905912). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for MPS I due to insufficient evidence and based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM2_Supporting, PP3_Moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355962863/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9137 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0006444 infores:hetionet GO:0046831 biolink:causes GO:0006403 infores:ubergraph knowledge_assertion manual_agent GO:0046831 GO:0006403 CHEBI:64312 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0239978 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0233414 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017178 infores:hetionet CHEBI:9907 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0025222 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0338375 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0338375 infores:hetionet CHEBI:8378 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0027813 infores:hetionet CHEBI:3756 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235063 infores:hetionet CHEBI:49603 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0004604 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042510 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0015397 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009319 infores:hetionet CAID:CA916083902 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083902 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.2403_2406del (p.Glu802GlyfsTer12) is a frameshift variant due to four-nucleotide deletion that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 17325176, 34745198, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083902/MONDO:0100437/106 2025-09-05 2025-11-22 X-linked inheritance HP:0001417 Supports CHEBI:100241 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0034150 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0018799 infores:hetionet UMLS:C0010592 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0595916 infores:hetionet CHEBI:84500 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0023518 infores:hetionet CHEBI:68606 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0043352 infores:hetionet CHEBI:5855 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0039231 infores:hetionet CHEBI:64355 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0034642 infores:hetionet CHEBI:474180 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C2047937 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0853619 infores:hetionet CHEBI:8435 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0040822 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0018621 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0036572 infores:hetionet CHEBI:52717 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011071 infores:hetionet CHEBI:47499 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0009676 infores:hetionet CHEBI:47780 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0575081 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0015672 infores:hetionet CHEBI:10101 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0021368 infores:hetionet CHEBI:63631 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2939186 infores:hetionet CHEBI:6931 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0026205 infores:hetionet CHEBI:31199 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0011616 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0028173 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0235639 infores:hetionet CHEBI:87681 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0018681 infores:hetionet CHEBI:8481 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0015230 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0006147 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0009806 infores:hetionet CHEBI:44032 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030196 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0042109 infores:hetionet CHEBI:9907 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0041657 infores:hetionet NCBITaxon:482538 biolink:causes MONDO:0018769 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:482538 MONDO:0018769 CHEBI:42797 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0023380 infores:hetionet CHEBI:49375 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0237849 infores:hetionet CHEBI:171719 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0393593 infores:hetionet GO:1905770 biolink:causes GO:0048332 infores:ubergraph knowledge_assertion manual_agent GO:1905770 GO:0048332 CHEBI:3077 biolink:causes UMLS:C1608942 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1608942 infores:hetionet CHEBI:7476 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0033247 infores:hetionet CHEBI:39585 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0033117 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0233494 infores:hetionet NCBIGene:2620 biolink:causes MONDO:0971152 infores:monarchinitiative not_provided not_provided HGNC:4167 MONDO:0971152 uuid:a0e8e122-05d4-4565-bd4c-f3f22440643e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0267940 infores:hetionet CHEBI:55346 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0600142 infores:hetionet CHEBI:10110 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0549567 infores:hetionet CHEBI:134990 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0022107 infores:hetionet CHEBI:50841 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0039231 infores:hetionet CHEBI:38940 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0023530 infores:hetionet CHEBI:63608 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0000731 infores:hetionet NCBIGene:8260 biolink:causes MONDO:0010671 infores:monarchinitiative not_provided not_provided HGNC:18704 MONDO:0010671 uuid:0668c7a7-6f1c-425b-88b2-27ab0cfd4d66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA273112 biolink:causes MONDO:0009861 infores:clingen CAID:CA273112 MONDO:0009861 PMID:17935162PMID:23514811PMID:23514811 Pathogenic PM2, PP4_Moderate, PP3, PS3, PM3_Strong PM5 The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 17935162; PMID: 23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID: 23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273112/MONDO:0009861/006 2018-05-24 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA8815119 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815119 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3, PS3 The NM_000152.5:c.971C>T variant in GAA is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 324 (p.Pro324Leu). One patient is reported to be compound heterozygous for the variant and c.794G>A (p.Ser265Asn). However the clinical symptoms were not consistent with Pompe disease. Another patient, with history of muscle weakness, had documented GAA deficiency in leukocytes after immunoprecipitation, 15% of normal mean control level, which does not meet the LD VCEP's threshold for PP4. IN addition, the cDNA changes for the variants in this patient was not provided, and therefore this data was not included (PMID:11071489) (PP4 not met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004014 (1/24914 alleles) in the African /African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.788 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3). When expressed in CHO cells, the variant has activity >2% normal but, because further details are not available regarding the activity of the variant, PS3 was not applied. There is a ClinVar entry for this variant (Variant ID: 431990). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease, based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications version 2.0): PM2_Supporting, PP3.(The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Oct. 4th, 2022. The classification was re-evaluated and re-approved on April 2, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815119/MONDO:0009290/010 2024-04-02 2024-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CAID:CA013030 biolink:causes MONDO:0004994 infores:clingen CAID:CA013030 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.2769C>T (p.Asn923=) variant in the MYH7 gene is 0.22% (47/16512) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013030/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:39112 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0235325 infores:hetionet CHEBI:32293 biolink:causes MONDO:0002516 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0685938 infores:hetionet CHEBI:9123 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0041657 infores:hetionet CHEBI:2704 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0006826 infores:hetionet CHEBI:5856 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0039231 infores:hetionet CHEBI:5855 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0011606 infores:hetionet NCBIGene:51086 biolink:causes MONDO:0014500 infores:monarchinitiative not_provided not_provided HGNC:19661 MONDO:0014500 uuid:b7790024-926c-42d0-9912-cfd0d8937a28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0011991 infores:hetionet CHEBI:9241 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0011991 infores:hetionet CHEBI:7443 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0232462 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151996 infores:hetionet CHEBI:3506 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0424295 infores:hetionet NCBIGene:55388 biolink:causes MONDO:0030266 infores:monarchinitiative not_provided not_provided HGNC:18043 MONDO:0030266 uuid:23f41c1b-2372-4595-a938-87d9e24fe1ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6935 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0017178 infores:hetionet CHEBI:41879 biolink:causes UMLS:C1608942 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1608942 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0021053 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0037274 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0018021 infores:hetionet CHEBI:135005 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0242422 infores:hetionet CAID:CA10636071 biolink:causes MONDO:0012996 infores:clingen CAID:CA10636071 MONDO:0012996 PMID: Benign BA1 The NM_001482.3:c.*734_*735insCA variant inserts two nucleotides in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1, in a population with >2000 alleles, is 0.8397 (7277/8666 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316203). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10636071/MONDO:0012996/025 2022-06-06 2022-10-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4909 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013378 infores:hetionet CHEBI:16796 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0541798 infores:hetionet CHEBI:8356 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017181 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151728 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151728 infores:hetionet CHEBI:5383 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0022346 infores:hetionet CAID:CA393747166 biolink:causes MONDO:0044970 infores:clingen CAID:CA393747166 MONDO:0044970 PMID: Pathogenic PM3, PP4, PM2, PVS1 The c.3643+2 T>C variant in POLG has been reported in trans with other another pathogenic variant Trp784Ser in a child with Alpers syndrome (PM3; PMID: 20691285). This variant was found in 0.00001% allele frequency in gnomAD and no homozygotes reported (PM2). Prediction given it affects a donor splice site causing complete skipping of exon 22 this results in disruptions in mRNA (PVS1; PMID 20691285). In summary, this variant meets criteria to be classified as pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2, PM3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA393747166/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3996 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0087169 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0521591 infores:hetionet CHEBI:8404 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0010520 infores:hetionet NCBIGene:120 biolink:causes MONDO:0014862 infores:monarchinitiative not_provided not_provided HGNC:245 MONDO:0014862 uuid:b435d7ac-4658-4baf-91e7-97c886eb6357 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0030516 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0030182 CHEBI:6149 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020580 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017566 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0020538 infores:hetionet CHEBI:63613 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0149744 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0860453 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0860453 infores:hetionet CHEBI:94807 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0014591 infores:hetionet CHEBI:584020 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0011991 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0006849 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013985 infores:hetionet CHEBI:5855 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014038 infores:hetionet CAID:CA234749 biolink:causes MONDO:0021060 infores:clingen CAID:CA234749 MONDO:0021060 PMID:26817465PMID:11992261PMID:17020470PMID:19352411PMID:22711529PMID:12325025 Pathogenic PS4, PS3, PM1, PM6, PM2, PP3, PP2 The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID: 12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID: 22711529). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA234749/MONDO:0021060/004 2020-02-14 2020-02-18 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9448 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0237849 infores:hetionet CHEBI:6367 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0043094 infores:hetionet CHEBI:17303 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1260880 infores:hetionet CHEBI:8435 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0344232 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0009766 infores:hetionet CHEBI:17630 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C1320835 infores:hetionet CHEBI:9763 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0036974 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0852990 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0852990 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0017152 infores:hetionet CAID:CA367398710 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398710 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP2, PP3, PP4, PM2_Supporting PS4, PP1 The c.1154G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to valine at codon 385 (p.(Gly385Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 10588527, internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 10588527). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with diabetes, but whose clinical picture is not highly specific for GCK-hyperglycemia (PS2_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Another missense variant, c.1153G>A, p.Gly385Arg, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1154G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_supporting, PP4, PM5_supporting, PS2_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398710/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Supports CHEBI:72690 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0013404 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0239295 infores:hetionet CHEBI:50378 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0040434 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853782 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853782 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0151763 infores:hetionet NCBIGene:3483 biolink:causes MONDO:0014420 infores:monarchinitiative not_provided not_provided HGNC:5468 MONDO:0014420 uuid:1c4a25ff-1be3-41b1-ad6b-3a4d03c8775b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:110423 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0235431 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0004093 infores:hetionet CHEBI:253342 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0016436 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0948586 infores:hetionet CHEBI:134990 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0042963 infores:hetionet CHEBI:28901 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018681 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151601 infores:hetionet NCBIGene:221692 biolink:causes MONDO:0032663 infores:monarchinitiative not_provided not_provided HGNC:20990 MONDO:0032663 uuid:4eafea66-3754-4da2-b8ad-f1af4a2d7959 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:553473 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0023530 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0549622 infores:hetionet NCBIGene:29940 biolink:causes MONDO:0014236 infores:monarchinitiative not_provided not_provided HGNC:21144 MONDO:0014236 uuid:e70c8ee9-84f1-4b95-b663-b135c907b5ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0039971 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0149931 infores:hetionet CHEBI:31236 biolink:causes EFO:1001323 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015409 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0851341 infores:hetionet CHEBI:59773 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0023380 infores:hetionet CHEBI:63598 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018834 infores:hetionet CHEBI:31980 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0041657 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C1145670 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0023470 infores:hetionet CHEBI:7465 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0028768 infores:hetionet CHEBI:45863 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151827 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0038661 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0024437 infores:hetionet CAID:CA10585161 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585161 MONDO:0007750 PMID: Uncertain Significance PM2 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.855C>A (p.His285Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2023. The supporting evidence is as follows: PM2: Variant absent from gnomAD (v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585161/MONDO:0007750/013 2023-03-24 2024-12-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:80630 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C3160741 infores:hetionet CHEBI:31981 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0020458 infores:hetionet CHEBI:52172 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018800 infores:hetionet UMLS:C0004599 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00626 UMLS:C0042963 infores:hetionet UMLS:C1709429 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0010200 infores:hetionet NCBIGene:91942 biolink:causes MONDO:0032616 infores:monarchinitiative not_provided not_provided HGNC:28086 MONDO:0032616 uuid:04ca886a-dc7e-4517-b909-f28d0f22a0a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0239134 infores:hetionet CHEBI:6832 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0012569 infores:hetionet CAID:CA345910 biolink:causes MONDO:0044970 infores:clingen CAID:CA345910 MONDO:0044970 PMID: Uncertain Significance PP3, PP1, PM2_Supporting, PS3_Supporting PP4, BP4, BA1, PS1, PS4, PS2, BS1, PM5, PM6 The m.3481G>A (p.E59K) variant in MT-ND1 has been reported in at least two unrelated individuals. The first, an 8-year-old male with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), exhibited muscle weakness, ragged red fibers on muscle biopsy, multiple acute encephalopathic episodes, and rod-cone-type retinal dystrophy. Heteroplasmy ranged from 50%-80% (PMID:17535832). The second individual was a female with severe developmental delay, spastic tetraparesis, joint contractures, type 2 fiber atrophy seen on muscle biopsy, severe visual impairment, and epilepsy with onset at 6 months. She developed hypertrophic cardiomyopathy at 16 years old and died from cardiac insufficiency at 26. Heteroplasmy ranged from 12%-61% (PMID: 18504678). Both individuals had elevated lactate and abnormalities on brain MRI. This variant may have been observed in a third individual with mitochondrial epilepsy; however the full text was unavailable for review (PMID:31665838). Haplogroup information was not reported for all cases precluding consideration for PS4. In the family of the proband with MELAS, the proband exhibited heteroplasmy levels ranging from 50-80% (lymphocytes: 55%). However, unaffected or less severely affected maternal relatives, including the mother, maternal aunt, and maternal cousin (who reported migraines), displayed lower heteroplasmy levels ranging from 15-20% in lymphocytes (PP1, PMID: 17535832). In the other case, the variant was absent in mother’s blood (PMID: 18504678), however the proband's blood was not tested. Complex I deficiency was demonstrated in both probands, however nuclear causes of disease were not excluded (PMIDs: 17535832, 18504678). Cybrid studies demonstrated a strong inverse correlation between heteroplasmy level and Complex I activity (PS3_supporting, PMID: 17535832). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.69 and 0.754, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345910/MONDO:0044970/015 2023-09-26 2024-11-25 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA16020961 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020961 MONDO:0009861 PMID:26542770 Likely Pathogenic PM3, PM2, PP4, PP3 The c.1199+4A>G PAH variant has been reported in 1 Danish patient with classic phenylketonuria (PMID: 26542770) detected with the pathogenic PAH variant c.1315+1G>A. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. It is intronic and multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020961/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022568 infores:hetionet CHEBI:7444 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0012569 infores:hetionet CHEBI:52172 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020443 infores:hetionet CAID:CA412744921 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744921 MONDO:0100437 PMID: Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PP3_Moderate PM6, PM4, PS3, PS4, PS2, BA1, BP4, BP3, BS1, BS3, BS4 NM_001034853.2(RPGR):c.492G>T (p.Trp164Cys) is a missense variant that substitutes tryptophan with cysteine at amino acid 164. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.929, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.08 for donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (lacking male-to-male transmission, 2 pts) with milder phenotypes in females (1 pt), genotyping by a retinal dystrophy panel designed to detect 111 genes identifying no alternative basis for disease (2 pts), night blindness (0.5 pts), reduced best corrected visual acuity (0.5 pts), onset at age 7 years (1 pt), nonrecordable electroretinogram (required), and severe myopia (1 pt), which together are highly specific for RPGR-related retinopathy (8 pts, PMID: 30917587, PP4). The variant has been reported to segregate with retinal dystrophy through an affected mother and son from 1 family (PP1; PMID: 30917587). At least two probands harboring this variant exhibited a phenotype consistent with retinopathy, however, the required phenotypes of reduced electroretinogram responses and/or male loss of visual function before age 30 years could only be confirmed in one case, so PS4_Supporting was not met (PMID: 30718709, PMID: 30917587). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP1, PP3_moderate, and PP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744921/MONDO:0100437/106 2025-05-21 2025-05-23 X-linked inheritance HP:0001417 Supports CAID:CA10567911 biolink:causes MONDO:0010602 infores:clingen CAID:CA10567911 MONDO:0010602 PMID:34242570 Pathogenic PP4, PS4_Very Strong, PS3 PM2, PP3 c.6089G>A (p.Ser2030Asn) is a pathogenic with no predicted deleterious effect due to the REVEL score of .573, just below meeting criteria for PP3 (>=.6) It also has a SpliceAI score of .05, not meeting criteria for PP3 (>=.5).The c.6089G>A (p.Ser2030Asn) variant is present in gnomAD v2 with a MAF of 0.00002729 (5/81740) for the European (non-Finnish) population. There are 3 hemizygotes and 2 homozygotes. It was absent from gnomAD v3 meeting PM2_supporting. There are 13 probands with this variant reported in MLoF with mild hemophilia, meeting PP4. There were 24 probands reported but only 20 met criteria making it PS4_very-strong. Cells were measured by ELISA and chromogenic assays showing a deleterious effect on rFVIII expression, as shown by the reduced but appreciable levels of rFVIII protein (25%–70% of wild-type) and activity (10%–50%), meeting PS3_Moderate. This variant is classified as Pathogenic for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): PS4_Very-strong, PP4, PS3 Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10567911/MONDO:0010602/071 2025-03-10 2025-03-10 X-linked inheritance HP:0001417 Supports CAID:CA298210 biolink:causes MONDO:0700270 infores:clingen CAID:CA298210 MONDO:0700270 PMID: Likely Benign PM2_Supporting, BP4, BP2 The c.76G>C (p.Glu26Gln) variant in ATM is a missense variant predicted to cause substitution of glutamic acid by glutamine at amino acid 26 (p.Glu26Gln). This variant has been observed in the homozygous state in multiple individuals without Ataxia-Telangiectasia (Invitae internal data). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002543 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.164, which is below the threshold of 0.249 and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ATM function. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. In summary, this variant meets criteria to be classified as likely benign for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BP2_Moderate, PM2_Supporting, BP4) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA298210/MONDO:0700270/020 2025-06-11 2025-10-20 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:R43D2573WO biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1443060 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011615 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0040435 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0025160 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0277585 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027813 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0596170 infores:hetionet CHEBI:4453 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0027497 infores:hetionet CHEBI:135679 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0018681 infores:hetionet CHEBI:92998 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0002994 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0852679 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0852679 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0019348 infores:hetionet CHEBI:9398 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0234047 infores:hetionet CHEBI:61058 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0015230 infores:hetionet CHEBI:142290 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0015967 infores:hetionet CHEBI:8888 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2047937 infores:hetionet CHEBI:63611 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C2364111 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0948089 infores:hetionet CHEBI:5296 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0023052 infores:hetionet CHEBI:94807 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0231218 infores:hetionet CHEBI:404903 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C2939147 infores:hetionet CHEBI:59773 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0018681 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0162830 infores:hetionet CHEBI:17334 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0013404 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0027765 infores:hetionet CHEBI:3647 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0392156 infores:hetionet CHEBI:40237 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C2711227 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0442874 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042075 infores:hetionet CHEBI:404903 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0241633 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0009806 infores:hetionet CHEBI:472657 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0018681 infores:hetionet CHEBI:5062 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0006142 infores:hetionet CHEBI:5864 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0018926 infores:hetionet CHEBI:7773 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0012833 infores:hetionet CHEBI:72564 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0338908 infores:hetionet CHEBI:7445 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0278061 infores:hetionet CHEBI:8499 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0233407 infores:hetionet CAID:CA288048 biolink:causes MONDO:0007648 infores:clingen CAID:CA288048 MONDO:0007648 PMID: Benign BS1, BS2 BP5, BP7, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the “Other” subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288048/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:39867 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0006277 infores:hetionet CHEBI:8214 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0033774 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0233632 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0344232 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0344320 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013298 infores:hetionet CHEBI:50859 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013378 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0151828 infores:hetionet CHEBI:4887 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0235198 infores:hetionet CHEBI:5147 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0037763 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0037199 infores:hetionet CHEBI:9139 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151825 infores:hetionet CHEBI:77260 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0010200 infores:hetionet CAID:CA410206747 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206747 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.761A>G (p.Asn254Ser) is a missense variant which has a REVEL score < 0.50 (0.277) and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206747/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6887 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0699744 infores:hetionet CHEBI:68579 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C1443060 infores:hetionet CAID:CA658658479 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658479 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM6, PM3, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.480_486delinsAGAATA p.(Ile161Glufs*54) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000661678.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658479/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf NCBIGene:10984 biolink:causes MONDO:0007534 infores:monarchinitiative not_provided not_provided HGNC:6295 MONDO:0007534 uuid:2dadbe35-c0e8-4d41-b5a1-7351cdc6d275 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4911 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0025061 infores:hetionet CHEBI:52172 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1527344 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0241228 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0241228 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0744403 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0744403 infores:hetionet CHEBI:63584 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042510 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0038454 infores:hetionet CHEBI:73274 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C1609512 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0585186 infores:hetionet CHEBI:107736 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0027497 infores:hetionet CHEBI:8378 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0268000 infores:hetionet CHEBI:50749 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0030193 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0240035 infores:hetionet CAID:CA9091075 biolink:causes MONDO:0021060 infores:clingen CAID:CA9091075 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.225C>T (p.Ile75=) variant in the MAP2K2 gene is 0.08% (20/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9091075/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:28748 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0162835 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0022116 infores:hetionet CHEBI:480999 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0333355 infores:hetionet CHEBI:8764 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C3251821 infores:hetionet CHEBI:59773 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0235266 infores:hetionet CHEBI:53766 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0160390 infores:hetionet CHEBI:2038 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0019080 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0009450 infores:hetionet CHEBI:16586 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0034065 infores:hetionet CHEBI:3387 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013456 infores:hetionet CHEBI:135613 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0020580 infores:hetionet CHEBI:3506 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0038325 infores:hetionet CHEBI:6538 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0015967 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0022650 infores:hetionet CHEBI:41879 biolink:causes HP:0001382 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0022410 infores:hetionet CHEBI:49040 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0018681 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017574 infores:hetionet CHEBI:6690 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0043352 infores:hetionet CHEBI:6950 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011603 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0042075 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235667 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235667 infores:hetionet CHEBI:75722 biolink:causes NCIT:C50431 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0262365 infores:hetionet CHEBI:63581 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0042029 infores:hetionet CHEBI:15854 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0014518 infores:hetionet CHEBI:5165 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0231218 infores:hetionet CHEBI:7443 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0018681 infores:hetionet CHEBI:8888 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013456 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0855242 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0403632 infores:hetionet CHEBI:261649 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0011991 infores:hetionet CHEBI:32315 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0019572 infores:hetionet CHEBI:8346 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0006826 infores:hetionet CHEBI:9137 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151786 infores:hetionet NCBIGene:54714 biolink:causes MONDO:0009875 infores:monarchinitiative not_provided not_provided HGNC:2153 MONDO:0009875 uuid:18980416-2dbc-4d3b-a31a-9bc12f46cfaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0120107 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0041969 infores:hetionet CHEBI:135930 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C1443060 infores:hetionet CHEBI:71219 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0741494 infores:hetionet CHEBI:3207 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0005778 infores:hetionet CHEBI:52010 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0030554 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005790 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019159 infores:hetionet CHEBI:17347 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0040264 infores:hetionet CHEBI:4445 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0546817 infores:hetionet CHEBI:9725 biolink:causes EFO:0020984 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C2939094 infores:hetionet UMLS:C0010592 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0016204 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0021053 infores:hetionet CHEBI:63629 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0687713 infores:hetionet CHEBI:9434 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0014335 infores:hetionet CAID:CA464450338 biolink:causes MONDO:0009595 infores:clingen CAID:CA464450338 MONDO:0009595 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PP4_Moderate The NC_000009.12:g.35657782T>G variant is absent in genomes in gnomAD v4. Therefore this code is applicable: PM2_Supporting.At least one patient with T cell lymphopenia (+0.5 points), metaphyseal dysplasia (+1.0 points), hypotrichosis (+0.5 points) with a total of 2.0 points and therefore this code is applicable: PP4_Moderate. This variant is reported at homozygous state in a proband with CHH phenotype, therefore it meets PM3_Supporting. In summary, this variant is classified as Uncertain Significance - insufficient evidence for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4_Moderate, PM3_Supporting (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA464450338/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6847 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0002792 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011551 infores:hetionet CHEBI:75722 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030196 infores:hetionet CHEBI:63598 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0000731 infores:hetionet CHEBI:6375 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0025345 infores:hetionet CHEBI:5864 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0031256 infores:hetionet CHEBI:18067 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0021053 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0232492 infores:hetionet CHEBI:2038 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151699 infores:hetionet CHEBI:53760 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085631 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0011570 infores:hetionet CHEBI:28148 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0008031 infores:hetionet CHEBI:3082 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0023518 infores:hetionet CHEBI:5864 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0021368 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0152027 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0155626 infores:hetionet CHEBI:49960 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1145670 infores:hetionet CAID:CA137946 biolink:causes MONDO:0021060 infores:clingen CAID:CA137946 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.498C>T (p.Pro166=) variant in the MAP2K2 gene is 0.081% (37/33932) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137946/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:119915 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C3665386 infores:hetionet CHEBI:5134 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0013404 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0856053 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0856053 infores:hetionet CHEBI:3403 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0855775 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011991 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0232431 infores:hetionet CHEBI:3172 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0233472 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019348 infores:hetionet UMLS:C0025241 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0037299 infores:hetionet CHEBI:45327 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0008031 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0435002 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042035 infores:hetionet CHEBI:3638 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0011206 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0015256 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0392025 infores:hetionet CHEBI:51380 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0004093 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0027339 infores:hetionet GO:0060998 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060998 GO:0007275 CHEBI:63616 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0206061 infores:hetionet CHEBI:8382 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151671 infores:hetionet CHEBI:49375 biolink:causes HP:0100310 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0238154 infores:hetionet CHEBI:10119 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022346 infores:hetionet CAID:CA073614 biolink:causes MONDO:0018493 infores:clingen CAID:CA073614 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 316 of the RYR1 protein, p.(Arg316Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000349, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID:31304636). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.793 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA073614/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true PUBCHEM.COMPOUND:3467 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0235063 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0948595 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0340726 infores:hetionet CHEBI:4315 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C1527344 infores:hetionet CHEBI:7931 biolink:causes NCIT:C122529 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0857494 infores:hetionet CHEBI:17698 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0014236 infores:hetionet CHEBI:50275 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085649 infores:hetionet CHEBI:4636 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0002878 infores:hetionet CHEBI:51209 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0039231 infores:hetionet CHEBI:46295 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0018681 infores:hetionet CHEBI:7959 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0085702 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0006266 infores:hetionet CHEBI:63611 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0039240 infores:hetionet CAID:CA213870 biolink:causes MONDO:0015967 infores:clingen CAID:CA213870 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting PS4, PP4 The c.952G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to tryptophan at codon 318 (p.(Gly318Trp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to zero copies in the European non-Finnish subpopulation and 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in a single individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and PP4 cannot be evaluated due to insufficient clinical data (internal lab contributors). Another missense variant, c.952G>A, p.(Gly318Arg) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Gly318Trp) has a greater Grantham distance (PM5). In summary, c.952G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PM5, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213870/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:17026 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0521839 infores:hetionet CHEBI:44032 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0037763 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0007642 infores:hetionet CHEBI:10119 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0026837 infores:hetionet CHEBI:64045 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0003467 infores:hetionet CAID:CA2695201454 biolink:causes MONDO:0011071 infores:clingen CAID:CA2695201454 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.184_187dup (p.Ala63GlyfsTer?) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss of function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is downstream of c.98 (PM5_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695201454/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9566 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0040822 infores:hetionet CHEBI:64312 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004144 infores:hetionet CHEBI:17334 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C2830004 infores:hetionet CHEBI:71219 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0023380 infores:hetionet CHEBI:5118 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003467 infores:hetionet UNII:DJJ95FJP1H biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0151559 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0853754 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0853754 infores:hetionet NCBITaxon:780 biolink:causes MONDO:0001246 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:780 MONDO:0001246 CHEBI:47898 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0014742 infores:hetionet CHEBI:4356 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0340865 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0042373 infores:hetionet NCBIGene:4340 biolink:causes MONDO:0013652 infores:monarchinitiative not_provided not_provided HGNC:7197 MONDO:0013652 uuid:065011d2-f805-4f88-8593-110d111c7b31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29688 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0428974 infores:hetionet CHEBI:15553 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042029 infores:hetionet CHEBI:135876 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C2242737 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0349506 infores:hetionet CHEBI:9674 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0041834 infores:hetionet CHEBI:3175 biolink:causes MONDO:0020366 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020302 infores:hetionet CHEBI:490877 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0085605 infores:hetionet NCBIGene:3816 biolink:causes MONDO:0014415 infores:monarchinitiative not_provided not_provided HGNC:6357 MONDO:0014415 uuid:70902721-6299-4a08-9a2c-a776b0f953f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31401 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0013395 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0585186 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0853847 infores:hetionet CHEBI:63608 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0014553 infores:hetionet CHEBI:4975 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0015967 infores:hetionet CHEBI:144093 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0014457 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0017178 infores:hetionet CHEBI:68584 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0235031 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1619702 infores:hetionet CHEBI:75722 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0152032 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0008325 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0001418 infores:hetionet CHEBI:5100 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0011991 infores:hetionet CHEBI:49713 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0033845 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0277589 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0277589 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0007860 infores:hetionet CHEBI:2379 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0000737 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0034069 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0751295 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0006840 infores:hetionet CHEBI:75722 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004134 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0233494 infores:hetionet CHEBI:31709 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0018681 infores:hetionet CAID:CA10585695 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585695 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, BP2, PS3, PM5, PP3, PP1 The NM_000527.5 (LDLR):c.1957G>T (p.Val653Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases fulfilling criteria for FH (3 cases with DLCN score >=6 from reported in VCI by Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case meeting Simon Broome criteria reported in VCI by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP. Sorbonne Université, Hospital de la Pitié-Salpêtrière, France; 1 case meeting Simon Broome criteria in PMID 14974088 (Dedoussis et al., 2004), from Harokopio University of Athens, Greece). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585695/MONDO:0007750/013 2024-02-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:17650 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0085622 infores:hetionet CHEBI:47781 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0027497 infores:hetionet CHEBI:9667 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013491 infores:hetionet CHEBI:27690 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0020615 infores:hetionet CHEBI:60761 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0023380 infores:hetionet NCBIGene:84665 biolink:causes MONDO:0014100 infores:monarchinitiative not_provided not_provided HGNC:23246 MONDO:0014100 uuid:3ce17063-aafc-4e3d-ba6e-27f067d8b0d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31709 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0033774 infores:hetionet CAID:CA377781994 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781994 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PS2 PM5, PM1, PS3 NM_000314.8(PTEN):c.59G>T (p.Gly20Val) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history (Internal laboratory contributor(s) SCV001393771.3). PS4_P: Proband(s) with phenotype specificity score of 1-1.5 Internal laboratory contributor(s) SCV001393771.3). PM2_Supporting: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score = 0.931. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781994/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3077 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0541820 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0002957 infores:hetionet CHEBI:480999 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0700292 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014868 infores:hetionet CAID:CA343723150 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723150 MONDO:0020367 PMID:16466712PMID:35196929 Likely Pathogenic PP3, PP1, PS3_Moderate, PM2_Supporting, PS1 BP7, BS1, BS3, PM6, PM5, PM4, PS4, PS2, BP4, BA1 The c.1440C>G variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 4 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 18303389), which fulfilled PP1 (3-4 meioses). Only 1 proband with JOAG had been reported (PMID: 18303389), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. The same amino acid change (p.Asn480Lys), resulting from a different nucleotide change (c.1440C>A, ClinVarID: 7951), was classified as pathogenic for JOAG by the ClinGen Glaucoma VCEP. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) (PS1). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS1, PS3_Moderate, PP1, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723150/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40237 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0006277 infores:hetionet CHEBI:31705 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085593 infores:hetionet CAID:CA8643656 biolink:causes MONDO:0015152 infores:clingen CAID:CA8643656 MONDO:0015152 PMID: Benign BP4, BA1, BP7 PM4, PM5, PM1, PM3, BP3, BP1, BP2, PS1, PS3, PS4, PS2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PP2, PP3, PP1, PP4, BS2 The NM_000023.4: c.37+23G>A variant in SGCA is located in intron 1 of 9. The filtering allele frequency of this variant in SGCA is 0.06791 (the lower threshold of the 95% CI of 1625/21638 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is higher than the ClinGen LGMD VCEP threshold (>0.002) for BA1 and therefore meets this criterion (BA1). This variant is not located in a splice region and is not predicted to impact splicing by SpliceAI (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8643656/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31711 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0271298 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0019158 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0026946 infores:hetionet CHEBI:74947 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0231528 infores:hetionet CHEBI:6472 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0600228 infores:hetionet CHEBI:6741 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0041834 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0002871 infores:hetionet CHEBI:7627 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C2979982 infores:hetionet CHEBI:63621 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0035410 infores:hetionet CHEBI:68584 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C2047937 infores:hetionet CAID:CA390864652 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864652 MONDO:0100216 PMID: Uncertain Significance PP3, PM2_Supporting, PM1, PS3_Supporting PM6, PVS1, BA1, BP1, BP4, BP3, BP2, PP2, PP1, PP4, BS2, PM4, PM3, PM5, PS2, PS4, PS1, BP5, BP7, BS1, BS3, BS4 The NM_177438.3:c.5438A>G variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by glycine at amino acid 1813 (p.Glu1813Gly). To our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Glu1813Gly showed that this variant reduces the capacity of the protein to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; PMID: 27036314, 28862265; Wu 2018, McGill University). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.95) (PP3). This variant resides in the p.E1813 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PS3_Supporting, PP3, PM1. (Bayesian Points: 5; VCEP specifications version 1.3.0; 02/25/2025). Although available evidence supports germline pathogenicity of recurrent DICER1 somatic hotspot variants (PMID: 26925222), the clinical significance of this variant in the germline remains uncertain at this time since it has not yet been observed in the germline of an individual with a recognized DICER1 phenotype. DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864652/MONDO:0100216/024 2025-02-25 2025-06-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51041 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0948594 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0853714 infores:hetionet CHEBI:4046 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0022107 infores:hetionet GO:0090192 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0090192 GO:0072006 CAID:CA055122 biolink:causes MONDO:0007947 infores:clingen CAID:CA055122 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP3, PS4_Supporting, PM1 PM2, BA1, BS1 The NM_00138 c.5518C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1840 (p.Arg1840Cys) within a calcium binding EGF-like domain of the protein. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure and this variant may impact disulfide bonding (PM1). This variant was found in a proband who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (PMID 31149040, PP4). This variant has been reported three times in ClinVar: twice as likely pathogenic and once as uncertain significance (Variation ID: 519783). It has been reported in the literature in individuals with clinical features of Marfan syndrome (PMID 25652356, 29357934, 37042257, Internal data, PS4_Sup). This variant is present in 1/35435 (0.003%) of alleles tested from the Admixed American population gnomAD (https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.78, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Sup, PP2, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA055122/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:51137 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C2830004 infores:hetionet CHEBI:5128 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0002792 infores:hetionet CHEBI:36795 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0547030 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C2973529 infores:hetionet CAID:CA314786 biolink:causes MONDO:0012999 infores:clingen CAID:CA314786 MONDO:0012999 PMID: Uncertain Significance PM2, PP3, PM5, BP4, BS1 The NM_000156.6:c.655G>A variant in GAMT is a missense variant that is predicted to cause the substitution of aspartate for asparagine at amino acid 219 (p.Asp219Asn). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004834 (29/59986 alleles) in the Admixed American population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.293 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function. There is a ClinVar entry for this variant (Variation ID: 205569). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): no criteria met. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on April 16, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314786/MONDO:0012999/026 2025-04-16 2025-04-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10102 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0001925 infores:hetionet CHEBI:31981 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0013144 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0160390 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020255 infores:hetionet UMLS:C0017797 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0424790 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0009806 infores:hetionet CHEBI:6367 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013404 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0262397 infores:hetionet CHEBI:31401 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0022346 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0030807 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027769 infores:hetionet CHEBI:73275 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0042373 infores:hetionet CAID:CA10652916 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652916 MONDO:0011071 PMID: Benign BA1 PS4, PS3, PS1, BP2, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*2329A>G variant in the 3' UTR has an MAF of 0.01248 (1.2%, 38/3044 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652916/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63620 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0687133 infores:hetionet CHEBI:6067 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085636 infores:hetionet CHEBI:9586 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151889 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0178298 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0428977 infores:hetionet CHEBI:52717 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020452 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0042373 infores:hetionet CHEBI:144093 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0438215 infores:hetionet CHEBI:5558 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0027497 infores:hetionet CAID:CA10014173 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014173 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP2, BP3, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM3, PM5, PM4, PM1, BS2, PP4, PP1 NM_001754.5(RUNX1):c.1416G>A (p.Leu472=) is a synonymous which variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.50)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014173/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17026 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0344232 infores:hetionet CHEBI:6847 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0026821 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0042373 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0013395 infores:hetionet CHEBI:2675 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0041657 infores:hetionet CHEBI:16796 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0017168 infores:hetionet CHEBI:6073 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0037763 infores:hetionet CAID:CA124453 biolink:causes MONDO:0015967 infores:clingen CAID:CA124453 MONDO:0015967 PMID: Pathogenic PS2_Moderate, PP1_Strong, PVS1 PS4, PM2 The c.872dupC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 292 (NM_000545.8), adding 25 novel amino acids before encountering a stop codon (p.(Gly292ArgfsTer25)). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant segregated with diabetes, with at least 100 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual and unconfirmed parental relationships in another individual with diabetes, but whose clinical picture is suggestive but not highly specific for HNF1A-MODY (MODY probability calculator result >50% but HNF4A not tested) (PS2_Moderate; PMID:9166684, internal lab contributors). The variant is located in a poly-C tract and failed QC in gnomAD v2.1.1 in a manner typical of single base deletions in poly-C tracts in NGS; therefore, PM2_Supporting could not be applied. This variant was identified in at least 200 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because PM2_Supporting cannot be applied (internal lab contributors). In summary, c.872dupC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PS2_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124453/MONDO:0015967/017 2022-04-15 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:10165 biolink:causes MONDO:0011326 infores:monarchinitiative not_provided not_provided HGNC:10983 MONDO:0011326 uuid:0929620b-288a-42b0-893a-a36276a0011c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235025 infores:hetionet CHEBI:2950 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0023067 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0497156 infores:hetionet CHEBI:9123 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011175 infores:hetionet CHEBI:46195 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151904 infores:hetionet CHEBI:53760 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0026826 infores:hetionet CHEBI:4657 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0015672 infores:hetionet CHEBI:50275 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0232849 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151626 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0027765 infores:hetionet NCBIGene:1244 biolink:causes MONDO:0009380 infores:monarchinitiative not_provided not_provided HGNC:53 MONDO:0009380 uuid:a00917da-f4ad-4731-bf91-f9c4112ccaaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6754 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0018524 infores:hetionet CHEBI:63630 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0019080 infores:hetionet NCBIGene:60681 biolink:causes MONDO:0009806 infores:monarchinitiative not_provided not_provided HGNC:18169 MONDO:0009806 uuid:0b438c9a-5fa5-4b7f-aec0-64d1c619c150 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0001175 infores:hetionet NCBIGene:11277 biolink:causes MONDO:0008641 infores:monarchinitiative not_provided not_provided HGNC:12269 MONDO:0008641 uuid:d85aa67a-c446-440e-ad3f-c791229fd54a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0010200 infores:hetionet CHEBI:16899 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0038160 infores:hetionet CHEBI:5050 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0015967 infores:hetionet NCBIGene:7466 biolink:causes MONDO:0013673 infores:monarchinitiative not_provided not_provided HGNC:12762 MONDO:0013673 uuid:7795cab1-f922-48e5-80c8-73cfd54744fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0007859 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0025061 infores:hetionet CHEBI:92712 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0042963 infores:hetionet CHEBI:6402 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C2242996 infores:hetionet CAID:CA367397017 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397017 MONDO:0015967 PMID: Pathogenic PS4, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting The c.1322C>G variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; PMID: 25665835). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ser441Trp has RAI=0.11, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 19884385). This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 27420379, 25665835, 19884385, 17573900, 16965331, 11508276, internal lab contributors). In summary, 1322C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397017/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:31236 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014591 infores:hetionet CHEBI:10101 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011606 infores:hetionet NCBIGene:54658 biolink:causes MONDO:0007745 infores:monarchinitiative not_provided not_provided HGNC:12530 MONDO:0007745 uuid:3f29b082-69ed-4bbd-b40e-a5705859e69b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes UMLS:C0521854 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0521854 infores:hetionet CHEBI:6129 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0035317 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0020517 infores:hetionet CHEBI:4445 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0042963 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0004096 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151601 infores:hetionet CHEBI:51141 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0039070 infores:hetionet CHEBI:8356 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0404521 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0004936 infores:hetionet CHEBI:5118 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0494475 infores:hetionet CHEBI:9571 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0151865 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018500 infores:hetionet NCBIGene:4247 biolink:causes MONDO:0008908 infores:monarchinitiative not_provided not_provided HGNC:7045 MONDO:0008908 uuid:c0868fdf-c683-4d93-9b00-a042195133ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0853761 infores:hetionet CHEBI:7025 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0010200 infores:hetionet CHEBI:6375 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0025323 infores:hetionet UNII:DJJ95FJP1H biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0151735 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0003123 infores:hetionet CHEBI:3647 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0039231 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0030305 infores:hetionet CHEBI:144551 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0080274 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0877232 infores:hetionet CHEBI:63635 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0014724 infores:hetionet CHEBI:9570 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C1443060 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041349 infores:hetionet CHEBI:136040 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0455204 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013395 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0021053 infores:hetionet CHEBI:6437 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1456784 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020295 infores:hetionet CHEBI:116278 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0035243 infores:hetionet CHEBI:5100 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0009676 infores:hetionet CHEBI:49668 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0038325 infores:hetionet CHEBI:36795 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0040822 infores:hetionet CHEBI:37924 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018790 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0235234 infores:hetionet CHEBI:9445 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0008031 infores:hetionet CHEBI:5778 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0026821 infores:hetionet CHEBI:5132 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0033774 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020456 infores:hetionet NCBIGene:340419 biolink:causes MONDO:0060732 infores:monarchinitiative not_provided not_provided HGNC:28583 MONDO:0060732 uuid:98668ac4-256f-44c6-bb70-c433cd36c24d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6622 biolink:causes MONDO:0011562 infores:monarchinitiative not_provided not_provided HGNC:11138 MONDO:0011562 uuid:27642b8d-0eb8-4be4-a1aa-26bb836685ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31709 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0340865 infores:hetionet CAID:CA145737 biolink:causes MONDO:0800472 infores:clingen CAID:CA145737 MONDO:0800472 PMID:19643970PMID:19793111 Likely Benign BP4, BS1 PP3, PP1, BA1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS4, PM2, PVS1 The c.1328C>G variant in CYP1B1 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 443 (p.Ala443Gly). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.04963, which met the ≥ 0.01 threshold set for BS1 (3,723 alleles out of 75,012, meeting the threshold of ≥ 5 of at least 2,000 observed alleles), but not the ≥ 0.05 threshold for BA1. The REVEL score = 0.199, which is within the 0.184-0.290 range for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), suggesting that the variant does not impact CYP1B1 function. A previous study (PMID: 19643970) demonstrated that the 17B estradiol activity levels of the Ala443Gly protein were not below the established threshold for that assay (<20% relative activity compared to background haplotype). This variant was also assessed in PMID: 19793111, however, the threshold for abnormal impact on protein function in the assays could not be determined. In summary, this variant met the criteria to receive a score of -5 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BS1, BP4 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145737/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63631 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0149931 infores:hetionet CHEBI:8764 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010481 infores:hetionet NCBIGene:23030 biolink:causes MONDO:0023657 infores:monarchinitiative not_provided not_provided HGNC:29136 MONDO:0023657 uuid:429c4e84-880b-4147-b787-9562925b533c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5775 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0015967 infores:hetionet CHEBI:7492 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0027424 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042134 infores:hetionet CHEBI:49603 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C1384353 infores:hetionet CHEBI:9587 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0042109 infores:hetionet CHEBI:28925 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0015230 infores:hetionet CHEBI:6367 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0015672 infores:hetionet NCBIGene:6573 biolink:causes MONDO:0011141 infores:monarchinitiative not_provided not_provided HGNC:10937 MONDO:0011141 uuid:cb57a4f0-b8b0-4599-854f-9efb230a9ca4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0038362 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1443060 infores:hetionet CHEBI:135920 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0030252 infores:hetionet CHEBI:567361 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0024312 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0343361 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0343361 infores:hetionet CHEBI:63619 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0037052 infores:hetionet CAID:CA915940582 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940582 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The c.2674del (p.Ile892SerfsTer18) variant in exon 26 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 27 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 13 in PMID: 19172520) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% (from GT database), as measured by flow cytometry (PP4_moderate). This variant has been detected in at least 1 proband with Glanzmann thrombasthenia (Patient 13 in PMID: 19172520). This individual was homozygous for the variant (PMID: 19172520; PM3_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting and PM3_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940582/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50692 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0018681 infores:hetionet CHEBI:44032 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0002962 infores:hetionet CHEBI:49040 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151632 infores:hetionet GO:1902866 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:1902866 GO:0150063 UMLS:C0010592 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1384353 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0021053 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0948818 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0948818 infores:hetionet CHEBI:10119 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2830004 infores:hetionet CHEBI:51041 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0231530 infores:hetionet CHEBI:10119 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0423791 infores:hetionet CHEBI:8435 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0043352 infores:hetionet CHEBI:6539 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0002622 infores:hetionet CHEBI:63791 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162557 infores:hetionet CHEBI:6375 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0235266 infores:hetionet CHEBI:9137 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042510 infores:hetionet NCBIGene:1468 biolink:causes MONDO:0033545 infores:monarchinitiative not_provided not_provided HGNC:10980 MONDO:0033545 uuid:f37f8c56-7418-48c8-b20c-b13d34253a2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes UMLS:C0852879 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0852879 infores:hetionet CHEBI:6539 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0001122 infores:hetionet CHEBI:45081 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0013378 infores:hetionet NCBIGene:2266 biolink:causes MONDO:0014452 infores:monarchinitiative not_provided not_provided HGNC:3694 MONDO:0014452 uuid:75f7bd9e-c42e-4eae-983f-56a5071ed323 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0009782 infores:hetionet CHEBI:144093 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0041657 infores:hetionet CHEBI:28787 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0547030 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0017152 infores:hetionet CHEBI:41423 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0231528 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039584 infores:hetionet CHEBI:6520 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0233407 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0018801 infores:hetionet CHEBI:2682 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C3263723 infores:hetionet CHEBI:119486 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0033774 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0042514 infores:hetionet CAID:CA355961634 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961634 MONDO:0001586 PMID: Likely Pathogenic PVS1_Strong, PM3, PM2_Supporting PS1, PP4 The NM_000203.5:c.494-1G>A variant in IDUA is a canonical splice acceptor variant. This variant is predicted to cause either an in-frame deletion of exon 5 including Glu182 (PVS1), or an activation of a cryptic splice site, leading to a frameshift and premature truncation (p.Arg166ThrfsTer27) (PVS1). The available experimental data do not definitively confirm either of these outcomes, and hence the decision has been made by the ClinGen IDUA VCEP to downgrade the strength of this criterion to PVS1_Strong.The highest population minor allele frequency in gnomAD v4.1.0. is 8.477e-7 (1/1179702 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).This variant has been reported primarily in Turkish patients, with at least five instances in the literature: four times in a homozygous genotype (PM3), and once as part of a compound heterozygous genotype with a variant (c.826G>A) that could be considered likely pathogenic (PMID: 21394825). Segregation studies for these patients were not available in this paper. There is a report of the variant in ClinVar (Variation ID: 557942). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_Strong, PM2_Supporting, PM3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961634/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94609 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0023530 infores:hetionet CHEBI:119915 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C2979982 infores:hetionet CHEBI:3242 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0004134 infores:hetionet CHEBI:188986 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0020443 infores:hetionet UMLS:C0009315 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0003862 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040485 infores:hetionet CHEBI:65349 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0014742 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0233472 infores:hetionet GO:0010975 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0010975 GO:0007275 NCBIGene:5885 biolink:causes MONDO:0013864 infores:monarchinitiative not_provided not_provided HGNC:9811 MONDO:0013864 uuid:444fd119-3c24-49f6-849e-32130c24c30d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0014457 infores:hetionet CHEBI:6375 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085631 infores:hetionet CHEBI:63598 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0008350 infores:hetionet NCBIGene:80184 biolink:causes MONDO:0012723 infores:monarchinitiative not_provided not_provided HGNC:29021 MONDO:0012723 uuid:0c5708c6-d2c9-4a7d-a9bd-4714610f5df9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0033771 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0015230 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0034186 infores:hetionet CHEBI:27834 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C3665386 infores:hetionet CHEBI:45951 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0917801 infores:hetionet CHEBI:7931 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0702166 infores:hetionet CHEBI:3696 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002874 infores:hetionet CHEBI:16469 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0000768 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0034150 infores:hetionet CHEBI:3181 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0018681 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0234913 infores:hetionet CHEBI:367163 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027497 infores:hetionet CHEBI:7798 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0018681 infores:hetionet CHEBI:7443 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C3665347 infores:hetionet CHEBI:7936 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0549249 infores:hetionet NCBIGene:5456 biolink:causes MONDO:0010576 infores:monarchinitiative not_provided not_provided HGNC:9217 MONDO:0010576 uuid:7f8017e9-f574-42a4-8c23-5d898535c4b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0004509 infores:hetionet CHEBI:9241 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0014742 infores:hetionet CHEBI:6413 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0020580 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0037274 infores:hetionet CHEBI:7903 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0013378 infores:hetionet CHEBI:408174 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C3160741 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042109 infores:hetionet CAID:CA5950626 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950626 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.68A>G (p.Asn23Ser) is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 23.This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The filtering allele frequency (the upper threshold of the 95% CI of 11/1180018) of the c.68A>G variant in RAG2 is 0.000004550 for European (Non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950626/MONDO:0000573/124 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:2000090 biolink:causes GO:0061224 infores:ubergraph knowledge_assertion manual_agent GO:2000090 GO:0061224 CHEBI:142290 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0438215 infores:hetionet CHEBI:6472 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0033774 infores:hetionet CAID:CA286788 biolink:causes MONDO:0700270 infores:clingen CAID:CA286788 MONDO:0700270 PMID: Benign BS1, BP2_Strong, PP3 PM3 The c.2932T>C variant in ATM is a missense variant predicted to cause substitution of serine by proline at amino acid 978 (p.Ser978Pro). This variant has been observed with the variant c.8395_8404del (p.F2799Kfs*4) which is classified as pathogenic by the HBOP VCEP (ClinVar SCV005627268.1) in one individual with Ataxia-Telangiectasia and 6 individuals with no features of Ataxia-Telangiectasia (PMID: 26896183, Ambry internal data) (PM3/BP2 points: +2). The phase of the variants was suspected to be in cis by family testing. This variant has also been observed with other pathogenic ATM variants in 21 individuals with no features of Ataxia-Telangiectasia (Ambry internal data) (PM3/BP2 points: -42) (BP2_Strong met, -40 points). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004874 in the South Asian population, which is higher than the ClinGen HBOP VCEP threshold (>0.0005) for BS1, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.87, which is above the threshold of 0.733, evidence that correlates with impact to ATM function (PP3). Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. In summary, this variant meets the criteria to be classified as benign for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BS1, BP2_strong, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA286788/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7986 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0009450 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0021400 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0002871 infores:hetionet CAID:CA410203519 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203519 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM5_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS3, BS1, BS4, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.4(RUNX1):c.314A>C (p.His105Pro) is a missense variant that affects one of the residues (AA 105-204) within the Runt Homology Domain (RHD), though not an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.953 (> 0.75), supporting PP3. Additionally, this variant represents a missense change at the same residue (p.His105) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 666274), meeting PM5_supporting. This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; SCV000807773.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PM5_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203519/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:142290 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0011175 infores:hetionet CHEBI:119915 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0264267 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0332534 infores:hetionet CHEBI:66876 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0917801 infores:hetionet CHEBI:6339 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0009763 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0032326 infores:hetionet CHEBI:29688 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0017152 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853193 infores:hetionet CHEBI:8245 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0033774 infores:hetionet CHEBI:7640 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0086565 infores:hetionet CHEBI:6375 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151723 infores:hetionet CHEBI:6413 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0151825 infores:hetionet CHEBI:367163 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0039070 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0003864 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0037315 infores:hetionet CHEBI:46345 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0018790 infores:hetionet CHEBI:6128 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0027497 infores:hetionet CHEBI:8107 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0008031 infores:hetionet CAID:CA9870374 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870374 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, PP4, PM5, BA1, BP4, BS1 The c.767A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamic acid to alanine at codon 256 (p.(Glu256Ala)) of NM_175914.5. This variant has a REVEL score of 0.641, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the East Asian subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of treatment information (PMID: 28597946). In summary, c.767A>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870374/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085641 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0001824 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0948089 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0037274 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0039971 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0036572 infores:hetionet CHEBI:585948 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0011124 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0152128 infores:hetionet CHEBI:5856 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0012833 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0853761 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0034150 infores:hetionet CHEBI:72690 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0042963 infores:hetionet NCBIGene:6935 biolink:causes MONDO:0013206 infores:monarchinitiative not_provided not_provided HGNC:11642 MONDO:0013206 uuid:0d76dfef-2316-4605-b9c8-3f8711d8b322 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0340865 infores:hetionet CHEBI:10127 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0027066 infores:hetionet CHEBI:473990 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0001125 infores:hetionet CHEBI:32221 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233414 infores:hetionet CHEBI:7496 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0040034 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023530 infores:hetionet CHEBI:9168 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017979 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0340464 infores:hetionet CHEBI:8888 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0242301 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0233494 infores:hetionet CHEBI:3082 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0004095 infores:hetionet CHEBI:44032 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0687713 infores:hetionet CHEBI:2950 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0424295 infores:hetionet CHEBI:102216 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0033774 infores:hetionet CHEBI:63620 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C2010560 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042035 infores:hetionet CHEBI:72297 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0011991 infores:hetionet NCBIGene:10126 biolink:causes MONDO:0014478 infores:monarchinitiative not_provided not_provided HGNC:2955 MONDO:0014478 uuid:c0724f64-cabd-47f3-b91b-e2ea48030c6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085636 infores:hetionet CHEBI:47426 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0023380 infores:hetionet CHEBI:3506 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0011991 infores:hetionet CHEBI:119573 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0031256 infores:hetionet CHEBI:8707 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042029 infores:hetionet CHEBI:15940 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0242301 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0009806 infores:hetionet CHEBI:68478 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0033774 infores:hetionet CHEBI:75984 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0042510 infores:hetionet NCBIGene:2299 biolink:causes MONDO:0010933 infores:monarchinitiative not_provided not_provided HGNC:3815 MONDO:0010933 uuid:2e6c2213-8c3e-4868-bc11-5ad0c21e1879 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4466 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151603 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0456909 infores:hetionet NCBIGene:6121 biolink:causes MONDO:0008765 infores:monarchinitiative not_provided not_provided HGNC:10294 MONDO:0008765 uuid:51ea9aeb-0428-4105-8f8f-e9b53ab12fd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0403632 infores:hetionet CHEBI:30830 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0002418 infores:hetionet CHEBI:6954 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0151686 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151479 infores:hetionet CHEBI:9150 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0015967 infores:hetionet CHEBI:3032 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0028643 infores:hetionet CHEBI:63681 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0038325 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0011991 infores:hetionet CHEBI:52172 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020625 infores:hetionet CHEBI:7575 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0852911 infores:hetionet CHEBI:6061 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0220870 infores:hetionet CHEBI:52717 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0025222 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0020651 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020676 infores:hetionet CHEBI:144093 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C1443060 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0005741 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020538 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0235146 infores:hetionet CHEBI:8764 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014038 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009319 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042571 infores:hetionet CHEBI:3286 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0014591 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0853714 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0857353 infores:hetionet CHEBI:31515 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0013395 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042373 infores:hetionet CHEBI:9435 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0015672 infores:hetionet CHEBI:9667 biolink:causes HP:0001949 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0085570 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004277 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018081 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0162830 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0853662 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0853662 infores:hetionet CAID:CA1619819 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619819 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PP3_Moderate, PP1_Strong, PS3_Supporting BP4, BA1, PS1, PS2, PM5, PM1, PM4, BP7, BS1, BS4, PVS1 The c.1310C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 437 (p.Pro437Leu). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00009328 (7 alleles out of 75,040), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.924 , which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 12807732) demonstrated that the Pro437Leu protein had reduced Benzo[a]pyrene Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. This variant was also assessed in PMID: 27060699, however, the threshold for abnormal impact on protein function in the assays could not be determined. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 9497261, 30662834, 30820150), which fulfilled PP1_Strong. This variant has been identified in 7 individuals with a CYP1B1-related phenotype. 4 individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (2 confirmed in trans and 2 phase unknown) (PMIDs: 38990107, 19528825, 35170016, 30520782). 3 individuals are homozygous for the variant (2 consanguineous and 1 non-consanguineous) (PMIDs: 30662834, 30820150, 9497261). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 16 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very-Strong, PP1_Strong, PP3_Moderate, PM2_Supporting, PS3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619819/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28901 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018965 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0027726 infores:hetionet CHEBI:83531 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0231528 infores:hetionet CHEBI:4798 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C3263723 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0242973 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0006145 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009938 infores:hetionet CHEBI:8069 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0028738 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020514 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0007682 infores:hetionet CHEBI:44185 biolink:causes HP:0001395 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0239946 infores:hetionet CAID:CA1909950 biolink:causes MONDO:0018958 infores:clingen CAID:CA1909950 MONDO:0018958 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting BA1, BP2, BS1 The c.6937C>T (p.Arg2313Ter) variant in NEB is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 52/182 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v.4.1.0 is 0.00001669 (1/59924) in Admixed American which meets the threshold (MAF≤0.0000559) to apply PM2_Supporting. The variant was found in one proband with nemaline myopathy in the literature with a second nonsense variant identified in trans (PM3_Supporting, PMID: 25205138). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PM3_Supporting (Congenital Myopathies VCEP specifications version 1; 09/16/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1909950/MONDO:0018958/146 2024-09-16 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014742 infores:hetionet UMLS:C0657912 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0520966 infores:hetionet CHEBI:15367 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030196 infores:hetionet CAID:CA410202475 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202475 MONDO:0011071 PMID: Likely Pathogenic PM1_Supporting, PS4_Moderate, PM2_Supporting, PP3, PP1 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, BS2 NM_001754.5(RUNX1):c.503G>A (p.Gly168Glu) is a missense variant affecting one of the residues within the Runt Homology Domain (PM1_supporting). This variant has a REVEL score ≥ 0.50 (0.947) (PP3). The SpliceAI score predicts no impact on splicing (score: 0.05, Donor Loss 18bp). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in 2 probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 39375928, internal lab data). This variant has been observed in 3 meioses across 1 family (PMID:39375928) (PP1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting, PS4_supporting, PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202475/MONDO:0011071/008 2025-03-25 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42797 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020569 infores:hetionet CHEBI:5959 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0003862 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0015967 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C1510497 infores:hetionet NCBIGene:5357 biolink:causes MONDO:0032917 infores:monarchinitiative not_provided not_provided HGNC:9090 MONDO:0032917 uuid:16f1dae7-50c9-455e-9b2f-3e01a36c9a4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0023518 infores:hetionet CAID:CA512232206 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232206 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.921C>T (p.Ala307=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.3)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232206/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7915 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017152 infores:hetionet CHEBI:9599 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0020456 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0031046 infores:hetionet CHEBI:64064 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C2363730 infores:hetionet NCBIGene:3636 biolink:causes MONDO:0009785 infores:monarchinitiative not_provided not_provided HGNC:6080 MONDO:0009785 uuid:0d1c3cb3-b079-4f2b-807f-1ecea0155021 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0235431 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0018213 infores:hetionet CHEBI:2668 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0003862 infores:hetionet CHEBI:64321 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0027497 infores:hetionet CHEBI:61049 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027497 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005808 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D003235 DB02703_MESH_D003235_1 CHEBI:63617 biolink:causes MONDO:0004967 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0023449 infores:hetionet CHEBI:38940 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151904 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0039103 infores:hetionet CHEBI:3207 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0702166 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0005940 infores:hetionet CHEBI:42355 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0014518 infores:hetionet CHEBI:8356 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085611 infores:hetionet CHEBI:8764 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003862 infores:hetionet CHEBI:3479 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0026821 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0948089 infores:hetionet CHEBI:50663 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0027947 infores:hetionet CHEBI:63589 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0000731 infores:hetionet CHEBI:2675 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0018681 infores:hetionet CHEBI:5130 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0700361 infores:hetionet CAID:CA2061411 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061411 MONDO:0015924 PMID: Likely Benign BP4, BS1 PM2, PP3, BA1, PS4 The BMPR2 variant c.1587-7_1587-4del is a non-canonical splice site variant on intron 11 predicted to cause deletion of 4 nucleotides. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.173% (4/2314 alleles) in the Ashkenazi Jewish population which meets the threshold for BS1 (≥0.1%). Thus, PM2 (<0.01%) or BA1 (1%) were not met. The computational splicing predictor Splice AI score was 0.10 for acceptor loss suggesting that the variant has no impact on splicing which meets the criteria for BP4. The variant was only found in one proband with idiopathic pulmonary arterial hypertension (PMID: 26387786), hence PS4 was not applied. BS3 and PS3 were not evaluated as no functional data was available for this variant. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, BP4 (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061411/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5004 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0009806 infores:hetionet CHEBI:46081 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0014518 infores:hetionet CHEBI:37941 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0004093 infores:hetionet CHEBI:75045 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0043352 infores:hetionet CHEBI:31932 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0476273 infores:hetionet CAID:CA012535 biolink:causes MONDO:0005045 infores:clingen CAID:CA012535 MONDO:0005045 PMID: Uncertain Significance PP1, PM1, PM2_Supporting, PS4_Supporting PP3, PM5, BA1, PS3, PM6, PM4, BP3, BS1, BS3, BS4, BP4, BP2, BP5, BP7, PS1, PS2, PVS1 The c.2525G>A (p.Ser842Asn) variant in MYH7 has been reported in 4 individuals with HCM (PS4_Supporting; Alfares 2015 PMID:25611685; Walsh 2017 PMID:27532257; CHEO pers. comm.; GeneDx pers. comm.; LMM pers. comm.) and segregated with HCM in 3 affected relatives from 1 family (PP1; GeneDx pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PP1; PM2_Supporting; PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012535/MONDO:0005045/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15854 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042510 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853777 infores:hetionet NCBIGene:6925 biolink:causes MONDO:0012589 infores:monarchinitiative not_provided not_provided HGNC:11634 MONDO:0012589 uuid:fbb81b7e-7782-4397-8a36-6062355b416c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0025289 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0015230 infores:hetionet CHEBI:2955 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0542571 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2697368 infores:hetionet CHEBI:9086 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018681 infores:hetionet CHEBI:40303 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0032533 infores:hetionet NCBIGene:51693 biolink:causes MONDO:0032681 infores:monarchinitiative not_provided not_provided HGNC:30887 MONDO:0032681 uuid:f543cdf0-389f-4410-a71f-547675fedbf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68845 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0011603 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0851341 infores:hetionet CHEBI:50131 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020461 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0020672 infores:hetionet CHEBI:63616 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0002962 infores:hetionet CAID:CA120603 biolink:causes MONDO:0044970 infores:clingen CAID:CA120603 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PS4 The m.9379G>A (p.W58Ter) variant in MT-CO3 has been reported in one individual with primary mitochondrial disease. This individual had childhood onset mitochondrial myopathy and lactic acidosis and harbored the variant at 93% heteroplasmy in muscle; however the variant was not detected in the proband's blood or hair. The variant was also undetectable in blood and hair from the healthy mother and blood from the healthy sister (PMID: 12414820). This variant introduces a premature termination codon in exon 58 out of 261, and is expected to remove 78% of the protein (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120603/MONDO:0044970/015 2024-01-22 2025-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8356 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037672 infores:hetionet CAID:CA404075781 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075781 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP1, BP4, BP3, BP2, PS1, PS4, PS3, PS2, BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.293G>C (p.Gly98Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075781/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6367 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0015468 infores:hetionet CHEBI:7915 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002994 infores:hetionet NCBIGene:10566 biolink:causes MONDO:0957249 infores:monarchinitiative not_provided not_provided HGNC:373 MONDO:0957249 uuid:8c63124c-39bc-47de-a0df-f0595d7bc24f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0028259 infores:hetionet CL:0000542 biolink:causes MONDO:0002052 infores:ubergraph knowledge_assertion manual_agent CL:0000542 MONDO:0002052 CHEBI:63631 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030232 infores:hetionet CHEBI:6931 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0012833 infores:hetionet CHEBI:135935 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0428977 infores:hetionet GO:0039645 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0039645 GO:0000278 UNII:15G12L5X8K biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0234632 infores:hetionet CHEBI:9150 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0013604 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0007124 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0007124 uuid:e40a347c-c213-4179-b096-9c35c24332d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16041885 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041885 MONDO:0009290 PMID:11738358PMID:18505979PMID:25998610 Pathogenic PM2, PVS1, PP4 PM3 This variant, c.573C>A (p.Tyr191Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, meeting PM2. Two patients meeting the ClinGen LSD VCEP's specifications for PP4 have been reported. These patients are compound heterozygous for the variant and either c.2173C>T (p.Arg725Trp) (PMID 18505979), or c.2646+2T>A (PMID 11738358). However, in both cases, the in trans data from these patients will be used in the classification of the other variant and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25998610, 27711114, 30022036). There is a ClinVar entry for this variant (Variation ID: 370276; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041885/MONDO:0009290/010 2020-05-19 2020-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3380 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0011603 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0855242 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0233796 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0233796 infores:hetionet CHEBI:9622 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0030252 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0007177 infores:hetionet CHEBI:64355 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0476280 infores:hetionet CHEBI:27504 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0038362 infores:hetionet CHEBI:66913 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0151827 infores:hetionet CHEBI:31236 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0024902 infores:hetionet CHEBI:145499 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151610 infores:hetionet CHEBI:16335 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0015230 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235639 infores:hetionet CHEBI:50859 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0232461 infores:hetionet CHEBI:83804 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0041657 infores:hetionet CHEBI:63791 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018524 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0029445 infores:hetionet CHEBI:7494 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0030193 infores:hetionet CHEBI:32139 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020461 infores:hetionet CHEBI:9332 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0235996 infores:hetionet CHEBI:3216 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151905 infores:hetionet CHEBI:52717 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0231807 infores:hetionet CHEBI:135351 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0009782 infores:hetionet CHEBI:5383 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0151905 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0948594 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0018799 infores:hetionet NCBIGene:478 biolink:causes MONDO:0030473 infores:monarchinitiative not_provided not_provided HGNC:801 MONDO:0030473 uuid:c90c886e-e67d-4de5-bd77-7bee94abbfb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2573157350 biolink:causes MONDO:0100083 infores:clingen CAID:CA2573157350 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.508+14C>G is an intronic variant which has a SpliceAI ∆ score ≤ 0.20 and a phyloP100 score of 1.617 (BP4, BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157350/MONDO:0100083/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5118 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0549209 infores:hetionet NCBIGene:84071 biolink:causes MONDO:0032748 infores:monarchinitiative not_provided not_provided HGNC:23045 MONDO:0032748 uuid:177870fd-f704-42ac-8c9f-5c496cde191b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0023218 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0020538 infores:hetionet NCBIGene:56947 biolink:causes MONDO:0014905 infores:monarchinitiative not_provided not_provided HGNC:24858 MONDO:0014905 uuid:ea947104-1922-4025-bee9-94155ae39846 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009676 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0264286 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0264286 infores:hetionet CHEBI:75922 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0423153 infores:hetionet CHEBI:50692 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0232462 infores:hetionet CHEBI:45783 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0041582 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0038362 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0025061 infores:hetionet CHEBI:61049 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235710 infores:hetionet CHEBI:5790 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013378 infores:hetionet CHEBI:480999 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0234238 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0038663 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013922 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0521491 infores:hetionet CHEBI:63632 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0232462 infores:hetionet CHEBI:2549 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0004604 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004690 infores:hetionet CHEBI:50659 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0017178 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024312 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0037274 infores:hetionet CHEBI:5106 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0085631 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0006145 infores:hetionet CHEBI:100241 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232495 infores:hetionet CHEBI:45863 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0043352 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0018799 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0948586 infores:hetionet CHEBI:408174 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151671 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0948089 infores:hetionet CHEBI:39585 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0035455 infores:hetionet CHEBI:45863 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018784 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0518015 infores:hetionet CHEBI:71272 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0017178 infores:hetionet CHEBI:44423 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0004093 infores:hetionet CHEBI:51230 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0013395 infores:hetionet NCBIGene:7084 biolink:causes MONDO:0014898 infores:monarchinitiative not_provided not_provided HGNC:11831 MONDO:0014898 uuid:ec99c56c-6b7a-4652-bf68-79995f0d40ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0004044 infores:hetionet CHEBI:9435 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0042571 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009938 infores:hetionet CHEBI:9674 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0547030 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0234215 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0041912 infores:hetionet CHEBI:16335 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0013144 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0006325 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020517 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0278016 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0031542 infores:hetionet CAID:CA410203511 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203511 MONDO:0011071 PMID:22318203PMID:25840971 Likely Pathogenic PM1_Supporting, PS3, PM2_Supporting, PP3 PS1, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS3, BS1, BS4, PM6, PVS1, PM5, PM4, PM3, PP2, PP1, PP4, BS2 The NM_001754.4:c.315C>A (p.His105Gln) variant affects one of the residues (AA 105-204) within the RHD which is not an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) and data from secondary assays demonstrate altered DNA binding and functional consequences in mouse model. (PS3; PMID: 22318203; PMID: 25840971). This missense variant has a REVEL score >0.75 (0.901) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203511/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:585948 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0039070 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0005940 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1368065 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0020557 infores:hetionet CHEBI:47381 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003537 infores:hetionet CHEBI:50729 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020458 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0243026 infores:hetionet CHEBI:63617 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0022346 infores:hetionet CHEBI:28748 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0268000 infores:hetionet CAID:CA367402818 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402818 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM3, PVS1, PP4_Moderate, PM2_Supporting The c.292C>T variant in the glucokinase gene, GCK, results in a premature termination codon at codon 98 (p.(Gln98Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 21518409, 29329106, internal lab contributors). This variant is absent from gnomAD 4.1.0 (PM2_Supporting). This variant has been detected in at least 4 individuals with neonatal diabetes who were homozygous for this variant (PM3; PMID: 21518409, 29329106, internal lab contributors). This variant segregated with diabetes, with at least 14 informative meioses in 5 families (PP1_Strong; PMID: 21518409, 29329106, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8mmol/L and HbA1c 5.6-7.6% and four generations of diabetes/hyperglycemia (PP4_Moderate; internal lab contributors). In summary, c.292C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PVS1, PS4, PM2_Supporting, PM3, PP1_Strong, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402818/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports CHEBI:9907 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C3263723 infores:hetionet CHEBI:31348 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011603 infores:hetionet GO:0098907 biolink:causes GO:0061337 infores:ubergraph knowledge_assertion manual_agent GO:0098907 GO:0061337 CHEBI:7915 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0000737 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0948586 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0021053 infores:hetionet CHEBI:63620 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0699828 infores:hetionet CHEBI:50924 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151744 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0031350 infores:hetionet NCBIGene:10555 biolink:causes MONDO:0012071 infores:monarchinitiative not_provided not_provided HGNC:325 MONDO:0012071 uuid:7b03f770-3839-45d9-9634-319a39e5c441 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16714 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0085631 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011991 infores:hetionet CHEBI:167309 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0011603 infores:hetionet CHEBI:6640 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0013295 infores:hetionet CHEBI:47780 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0341047 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0267792 infores:hetionet CHEBI:2682 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151594 infores:hetionet CHEBI:472657 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0085932 infores:hetionet CHEBI:135930 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0023218 infores:hetionet CHEBI:10124 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0231218 infores:hetionet CAID:CA024439 biolink:causes MONDO:0007783 infores:clingen CAID:CA024439 MONDO:0007783 PMID: Uncertain Significance BP4 PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Lysine with Arginine at codon 1467 of the RYR1 protein, p.(Lys1467Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge, this variant has not been reported in individuals with a personal or family history of an MH episode. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024439/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3638 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0003123 infores:hetionet CHEBI:4027 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0013378 infores:hetionet CHEBI:8890 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151723 infores:hetionet CHEBI:161680 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0011603 infores:hetionet NCBIGene:2535 biolink:causes MONDO:0008123 infores:monarchinitiative not_provided not_provided HGNC:4040 MONDO:0008123 uuid:4a781fab-6363-4520-8122-93ad2ca4aab0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:291342 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0022107 infores:hetionet CHEBI:6456 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0031256 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0019061 infores:hetionet CAID:CA293482 biolink:causes MONDO:0021060 infores:clingen CAID:CA293482 MONDO:0021060 PMID: Benign BP5, BP7, BP4, BA1 BP2 The c.1302C>T (p.Asn434=) variant in the SHOC2 gene has been identified in a patient with an alternate molecular basis for disease (BP5; ClinVar SCV000171633.12). The silent p.Asn434= variant is not predicted by MaxEntScan to impact splicing (BP7, BP4).The filtering allele frequency of the c.1302C>T (p.Asn434=) variant is 0.74% for African chromosomes by the Exome Aggregation Consortium (87/9772 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5, BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA293482/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:0010946 biolink:causes GO:0007131 infores:ubergraph knowledge_assertion manual_agent GO:0010946 GO:0007131 CHEBI:119915 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030252 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0036572 infores:hetionet CAID:CA392337017 biolink:causes MONDO:0007947 infores:clingen CAID:CA392337017 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PM1, PM5 PM6, PVS1, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PS3, PS2, PS1, PM4, PM3, BS1, BS4, BS3, BP7, BP5 NM_000138.5 c.6254G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2085 (p.Cys2085Tyr). This variant was found in a proband with a phenotype that satisfies the revised Ghent criteria for a clinical diagnosis of Marfan syndrome (MFS) (PP4; PMID: 25907466). It has been identified in another individual who meets clinical diagnostic criteria for MFS and one who does not meet diagnostic criteria but has thoracic aortic aneurysm (TAA) and a systemic score of 4 (PS4_moderate; PMID: 29768367; Bichat internal data). It has been reported 2 times in ClinVar as likely pathogenic (1) and of uncertain significance (1) (Variation ID: 547338). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant alters a cysteine in a TGFβ binding-protein-like (TB) domain, in which cysteine residues are believed to form disulfide bridges important for proper protein folding (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3; REVEL = 0.886). A different variant at the same amino acid position (c.6253T>G:p.Cys2085Gly) has been identified in at least two individuals with TAA and ectopia lentis and is classified as pathogenic or likely pathogenic; this further supports the functional importance of this amino acid position (PM5; Invitae internal data). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PP2, PP3, PP4, PM2_supporting, PS4_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392337017/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6129 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0040822 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002871 infores:hetionet CHEBI:3696 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0001623 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0237849 infores:hetionet CHEBI:2955 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151905 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0919593 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0919593 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0267792 infores:hetionet CHEBI:6950 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0009763 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014742 infores:hetionet CHEBI:4551 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0017178 infores:hetionet UMLS:C0657912 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151564 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1142011 infores:hetionet CHEBI:45863 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151744 infores:hetionet CHEBI:3508 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0040822 infores:hetionet GO:0097690 biolink:causes GO:0034755 infores:ubergraph knowledge_assertion manual_agent GO:0097690 GO:0034755 CHEBI:16469 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0005779 infores:hetionet NCBITaxon:36087 biolink:causes MONDO:0005996 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36087 MONDO:0005996 CHEBI:34967 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0178298 infores:hetionet GO:0098820 biolink:causes GO:0099545 infores:ubergraph knowledge_assertion manual_agent GO:0098820 GO:0099545 CHEBI:499361 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0010200 infores:hetionet CHEBI:63577 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0151576 infores:hetionet CHEBI:92998 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0344232 infores:hetionet CHEBI:5280 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1306341 infores:hetionet CHEBI:45327 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0013144 infores:hetionet CHEBI:3011 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0002962 infores:hetionet CHEBI:39867 biolink:causes MONDO:0008487 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0032460 infores:hetionet CHEBI:5790 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1260880 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0009450 infores:hetionet UMLS:C0657912 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020443 infores:hetionet CHEBI:7915 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018524 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0085620 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0687707 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0877035 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0877035 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C2717961 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0019360 infores:hetionet NCBIGene:4615 biolink:causes MONDO:0012839 infores:monarchinitiative not_provided not_provided HGNC:7562 MONDO:0012839 uuid:546ae4cc-20a2-4139-8e81-9672f2b39f6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0014742 infores:hetionet CHEBI:6472 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0001824 infores:hetionet CHEBI:28915 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0404521 infores:hetionet CHEBI:6129 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0043144 infores:hetionet CHEBI:5132 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0232849 infores:hetionet CAID:CA10360416 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360416 MONDO:0100039 PMID: Benign BS1, BP5_Strong, BS2 PM1, PP3, BP4 The allele frequency of the p.Glu590Lys variant in CDKL5 is 0.015% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Additionally, the p.Glu590Lys variant is observed in at least 14 unaffected individuals (internal database - GeneDx) (BS2) and at least 4 patients with an alternate molecular basis of disease (internal database - Invitae, internal database - GeneDx) (BP5_strong). In summary, the p.Glu590Lys variant in CDKL5 is classified as Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BS1, BS2, BP5_Strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360416/MONDO:0100039/016 2023-03-17 2023-03-31 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:9435 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0027769 infores:hetionet CHEBI:499361 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151905 infores:hetionet CHEBI:9763 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0025345 infores:hetionet CHEBI:6741 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0085605 infores:hetionet CHEBI:29007 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0234233 infores:hetionet CHEBI:7478 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0600125 infores:hetionet CAID:CA288022 biolink:causes MONDO:0007648 infores:clingen CAID:CA288022 MONDO:0007648 PMID: Benign BS1, BS2 BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM1, PM3, PM4, PM5, PP2, PP3, PP4, PP1, BP1, BP4, BP2, BP3, BA1, PS1, PS4, PS3, PS2 The c.1223C>T (p.Ala408Val) missense variant has a frequency of 0.114% (>0.1%) in South Asians (35 of 30616 alleles) in the gnomAD v2.1.1 cohort (BS1). This variant has been observed in ≥10 (122) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000260430.7, SCV000186167.6). In summary, the clinical significance of this variant is classified as of benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288022/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA2573054927 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573054927 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.957_958insG (p.Arg320fs) is a frameshift variant which is located within the last 50bp of exon 7, therefore not predicted to undergo nonsense-mediated mRNA decay (PVS1_strong). It is downstream of c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573054927/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6538 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0005758 infores:hetionet CHEBI:3312 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0020461 infores:hetionet CHEBI:92998 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0221245 infores:hetionet CHEBI:38562 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0016204 infores:hetionet CHEBI:2379 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0006266 infores:hetionet CHEBI:2704 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0700361 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007222 infores:hetionet CHEBI:9586 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019079 infores:hetionet CHEBI:6950 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2364111 infores:hetionet CHEBI:9566 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0232462 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0015397 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0027765 infores:hetionet CHEBI:3479 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0852911 infores:hetionet CHEBI:31348 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2242996 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0221165 infores:hetionet CHEBI:3761 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0009676 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0042373 infores:hetionet CHEBI:520985 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0015967 infores:hetionet CHEBI:63623 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0015230 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0030305 infores:hetionet CHEBI:101853 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0013378 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001639 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0041782 infores:hetionet CHEBI:8665 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0233514 infores:hetionet CHEBI:9943 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020461 infores:hetionet CHEBI:7936 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003467 infores:hetionet CHEBI:63630 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085631 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1096387 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1096387 infores:hetionet CAID:CA16041890 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041890 MONDO:0009290 PMID:22980766PMID:17616415PMID:27711114 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1192dup (p.Leu398ProfsTer108), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP’s specifications for PP4 and who is compound heterozygous with c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. The variant has been reported in additional publications but GAA activity was not provided and therefore the data was not included (PMIDs 22980766, 27711114). There is a ClinVar entry for this variant (Variation ID: 370510, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041890/MONDO:0009290/010 2020-09-20 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ GO:1990000 biolink:causes MONDO:0019065 infores:drugmechdb knowledge_assertion manual_agent GO:1990000 MESH:D000686 DB05352_MESH_D000686_1 CHEBI:50648 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0750394 infores:hetionet CHEBI:63598 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0015672 infores:hetionet CHEBI:142290 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0520966 infores:hetionet CHEBI:5893 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1167965 infores:hetionet NCBIGene:1000 biolink:causes MONDO:0030062 infores:monarchinitiative not_provided not_provided HGNC:1759 MONDO:0030062 uuid:0025ce59-2ee0-40bf-848d-c7f909e7b425 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8802 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0392618 infores:hetionet UMLS:C0009315 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0151578 infores:hetionet CHEBI:9139 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0000731 infores:hetionet CHEBI:94686 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0853225 infores:hetionet UMLS:C0009315 biolink:causes HP:0034777 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0241235 infores:hetionet CHEBI:4903 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0236082 infores:hetionet CAID:CA2573051034 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051034 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4 PS4 The c.164_168del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 55 (NM_000545.8), adding 3 novel amino acids before encountering a stop codon (p.(Gly55AlafsTer3)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with diabetes, with 12 informative meioses in two families with MODY (PP1_Strong; PMID: 14598263, internal lab contributor). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, HNF4A not tested but hepatic adenomatosis present) (PP4; internal lab contributor). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 14598263, internal lab contributor). In summary, c.164_169del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051034/MONDO:0015967/017 2022-04-03 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3723 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013595 infores:hetionet CHEBI:7496 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0003467 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0037274 infores:hetionet CHEBI:50663 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0392171 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0024299 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0037822 infores:hetionet CAID:CA2580612120 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612120 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4_Moderate The c.1769-9_1770del variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a splice acceptor site in intron 9 of NM_000545.8. Given the predicted loss of the intron 9 acceptor site, this variant is predicted to result in the loss of exon 10 and to disrupt a significant part of the transactivation domain, a functionally important region of the protein. Even though this truncated transcript is predicted to escape nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease, there is clinical evidence that variants in this region lead to a monogenic diabetes phenotype. (PVS1_Strong; PMID: 23348805). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonyureas) (PP4_Moderate; internal lab contributors). In summary, c.1769-9_1770del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1_Strong, PM2_Supporting, PP4_Moderate). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612120/MONDO:0015967/017 2024-10-13 2024-10-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71940 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0036974 infores:hetionet CHEBI:74947 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0043094 infores:hetionet CHEBI:7825 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0677500 infores:hetionet CAID:CA003888 biolink:causes MONDO:0700268 infores:clingen CAID:CA003888 MONDO:0700268 PMID: Pathogenic PVS1, PM2_Supporting, PS3 PP3 The c.80+4A>T variant is an intronic variant occurring in intron 2 of the BRCA1 gene. This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.66, predicting an impact on splicing (score threshold ≥0.2) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RT-PCRseq demonstrated that the variant impacts splicing by skipping of exon 2 (Ambry internal data). The percent of aberrant transcripts produced was 55%, using a non-allele specific quantitative assessment with sequence analysis. We estimate no full-length transcript is produced by the variant allele. Appropriate code strength determined by comparison of results to PVS1 decision tree, PVS1 (RNA). Reported by one calibrated study incorporating mRNA splicing effects to affect protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PS3, PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003888/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7822 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0018965 infores:hetionet CHEBI:17650 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0041657 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0162429 infores:hetionet CHEBI:18248 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0546817 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0015376 infores:hetionet NCBIGene:6135 biolink:causes MONDO:0012938 infores:monarchinitiative not_provided not_provided HGNC:10301 MONDO:0012938 uuid:364c6c0d-d727-461b-bd41-de8f749eb90b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6015 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0037036 infores:hetionet CHEBI:135613 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0277890 infores:hetionet CHEBI:367163 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085602 infores:hetionet CHEBI:5864 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042963 infores:hetionet CHEBI:5959 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0015967 infores:hetionet CHEBI:63599 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002170 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C1527344 infores:hetionet CHEBI:5106 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C2363730 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038814 infores:hetionet CHEBI:68642 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0013395 infores:hetionet CHEBI:3207 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C2047937 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037286 infores:hetionet CHEBI:9086 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020433 infores:hetionet CHEBI:5893 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0016382 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0027726 infores:hetionet CHEBI:28901 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085669 infores:hetionet CHEBI:51141 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0030252 infores:hetionet CHEBI:3757 biolink:causes HP:0030765 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037320 infores:hetionet CHEBI:7494 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0026961 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013595 infores:hetionet CHEBI:9448 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0547030 infores:hetionet CHEBI:7773 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0340865 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027707 infores:hetionet CHEBI:6950 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0010200 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020456 infores:hetionet CAID:CA10014203 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014203 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BA1, BP1, BP2, BP3, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM3, PM1, PM4, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1098C>T (p.Ile366=) is a synonymous variant therefore no REVEL score and SpliceAI is ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.378488 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014203/MONDO:0011071/008 2022-03-08 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013491 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0038454 infores:hetionet NCBIGene:2138 biolink:causes MONDO:0011258 infores:monarchinitiative not_provided not_provided HGNC:3519 MONDO:0011258 uuid:c28daa72-01e2-46a3-a48a-db8d6891482e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51380 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0855775 infores:hetionet CHEBI:15552 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0231528 infores:hetionet CHEBI:8382 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0428977 infores:hetionet CHEBI:63635 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0028081 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0031350 infores:hetionet CHEBI:521033 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0033774 infores:hetionet CHEBI:46295 biolink:causes MONDO:0020677 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0011057 infores:hetionet CHEBI:75045 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0085932 infores:hetionet CHEBI:3032 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0233763 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0007860 infores:hetionet UMLS:C0011701 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0231528 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0014742 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0043349 infores:hetionet CHEBI:32588 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0009676 infores:hetionet CHEBI:127342 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0030193 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0948594 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0241426 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1096506 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C1096506 infores:hetionet CAID:CA410148693 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148693 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.998C>G (p.Pro333Arg) is a missense variant which has a REVEL score < 0.50 (0.33) and a SpliceAI score ≤ 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148693/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013146 infores:hetionet CHEBI:43968 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0085605 infores:hetionet CHEBI:585948 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0042023 infores:hetionet CHEBI:3172 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0009676 infores:hetionet CAID:CA410207938 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207938 MONDO:0011071 PMID:34166225PMID:27479822PMID:26316320PMID:27112265PMID:19357396PMID:27479822PMID:26316320PMID:27112265PMID:19357396PMID:34166225PMID:27479822PMID:26316320PMID:27112265PMID:19357396 Pathogenic PS4_Moderate, PP1_Strong, PM5_Supporting, PM1, PM2_Supporting, PP3 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PP2, PP4, BS2 The NM_001754.4:c.611G>A (p.Arg204Gln) variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.958) (PP3). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ moderate; PMID: 19357396, PMID: 27112265, PMID: 26316320, PMID: 27479822). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families (PP1_strong; PMID: 19357396, PMID: 27112265, PMID: 26316320, PMID: 27479822). This variant is a missense change at the same residue (p.R204) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 2177591) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_strong, PM1, PM2, PS4_moderate, PP3, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207938/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45081 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0023066 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0233467 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0233467 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027441 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0015393 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0349506 infores:hetionet CHEBI:82866 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0162834 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0227791 infores:hetionet CHEBI:8024 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1322281 infores:hetionet CHEBI:7443 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0003467 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0235146 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0549373 infores:hetionet CHEBI:6149 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0028643 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038663 infores:hetionet CHEBI:49575 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042487 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0233973 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0233973 infores:hetionet CHEBI:2611 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020453 infores:hetionet CHEBI:37924 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0855333 infores:hetionet CHEBI:9586 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085633 infores:hetionet CHEBI:64045 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0026837 infores:hetionet CHEBI:65173 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0231528 infores:hetionet CHEBI:567361 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0038325 infores:hetionet CHEBI:6832 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0022346 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0404445 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0404445 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0948815 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0948815 infores:hetionet CHEBI:77733 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0030446 infores:hetionet CHEBI:5062 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0235969 infores:hetionet CHEBI:29688 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0027497 infores:hetionet CAID:CA180427 biolink:causes MONDO:0015152 infores:clingen CAID:CA180427 MONDO:0015152 PMID: Benign BA1 BP4 The NM_000023.4: c.1120C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 374, p.(Arg374Cys). The filtering allele frequency of this variant for gnomAD v4.1.0 exomes is 0.01775 (the lower threshold of the 95% CI of 63/33478 African/African American chromosomes), which is higher than the ClinGen LGMD VCEP threshold (>0.002) for BA1, and therefore meets this criterion (BA1). This variant is not located in a splice region, and the SpliceAI score is 0, which suggests it does not impact splicing. The computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on SGCA function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180427/MONDO:0015152/189 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7915 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018418 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029928 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0037274 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0549373 infores:hetionet CHEBI:6538 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0031350 infores:hetionet CHEBI:48273 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0007222 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0042769 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0149931 infores:hetionet CHEBI:7476 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0043144 infores:hetionet CHEBI:10119 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0278061 infores:hetionet CHEBI:3213 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0004093 infores:hetionet GO:0035203 biolink:causes GO:0035167 infores:ubergraph knowledge_assertion manual_agent GO:0035203 GO:0035167 CHEBI:5959 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0085633 infores:hetionet NCBIGene:362 biolink:causes MONDO:0010849 infores:monarchinitiative not_provided not_provided HGNC:638 MONDO:0010849 uuid:7f9dea87-6c18-4c23-b859-0dd0c2d05826 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151825 infores:hetionet CHEBI:7852 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0040264 infores:hetionet CHEBI:50859 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0043352 infores:hetionet CHEBI:92712 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0085611 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0409974 infores:hetionet CHEBI:7809 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0033687 infores:hetionet CHEBI:8776 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0018681 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0032285 infores:hetionet CHEBI:3752 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020757 infores:hetionet CHEBI:52172 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0232462 infores:hetionet CHEBI:50924 biolink:causes NCIT:C78341 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0522067 infores:hetionet CHEBI:28487 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0233494 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C2047937 infores:hetionet GO:0090199 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0090199 GO:0007154 CAID:CA913179801 biolink:causes MONDO:0044970 infores:clingen CAID:CA913179801 MONDO:0044970 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting, PM6_Supporting, PS3_Supporting PP1 The m.5540G>A variant in MT-TW has been reported in two unrelated individuals with primary mitochondrial disease. Clinical features in these individuals included encephalomyopathy, ataxia, peripheral neuropathy, dementia, dysarthria, muscle hypotrophy, areflexia, apallesthesia, pes cavus, nystagmus, sensorineural hearing loss, and COX-negative and ragged red fibers. The levels of the variant in affected individuals ranged from 25% in blood to 98% in muscle (PS4_supporting; PMIDs: 31965079, 10762520). This variant was de novo in one individual (PM6_supporting, PMID: 31965079), and family members were not available for testing for the other individual (PMID: 10762520). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (73.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (89%) than in COX positive fibers (43%), p<0.0005 (PS3_supporting, PMID: 10762520). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PM6_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913179801/MONDO:0044970/015 2024-05-13 2025-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA16616271 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616271 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.265C>T (p.Leu89=) is a synonymous variant. The SpliceAI score is ≤0.20 (0) (BP4). It occurs in gnomAD at MAF of 0.00002412 (1 allele), therefore none of the population based criteria can be applied. In summary, the clinical significance of this variant is uncertain due to lack of evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616271/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA267637 biolink:causes MONDO:0009861 infores:clingen CAID:CA267637 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.1240T>C (p.Tyr414His) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 125859); the collection method is stated as “literature only” and no further information is provided. To our knowledge, as of 4/29/19, it has not been reported in the published literature. The variant results in the substitution of a highly conserved Tyrosine residue with Histidine, a physiochemically distinct amino acid (nonpolar versus basic side chains), and the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.969) (PP3). It is present at extremely low frequency in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00001, in the gnomAD/ExAC Non-Finnish European subpopulation, which falls below the 0.0002 allele frequency cutoff for PAH variants (PM2). Another missense variant at this site, p.Tyr414Cys, has been previously reported Pathogenic, including by the ClinGen PAH working group (see ClinVar variant ID 593) (PM5). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267637/MONDO:0009861/006 2019-05-05 2019-05-05 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8888 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0029408 infores:hetionet CHEBI:9943 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151836 infores:hetionet CHEBI:68579 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0231218 infores:hetionet CHEBI:7640 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0004134 infores:hetionet CHEBI:59560 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0002792 infores:hetionet CHEBI:4027 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0423153 infores:hetionet CHEBI:135925 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0015230 infores:hetionet CHEBI:404903 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0542571 infores:hetionet CHEBI:48844 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0221345 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1112353 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1112353 infores:hetionet CHEBI:116278 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0162834 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0542203 infores:hetionet CHEBI:4907 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0011991 infores:hetionet CHEBI:34911 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0041834 infores:hetionet CHEBI:17688 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0004604 infores:hetionet CHEBI:63612 biolink:causes MONDO:0004948 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0023434 infores:hetionet CHEBI:100241 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0010038 infores:hetionet CHEBI:75988 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0010520 infores:hetionet CHEBI:7581 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0032290 infores:hetionet CHEBI:8673 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0020517 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0017178 infores:hetionet CAID:CA2695224154 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224154 MONDO:0009276 PMID: Likely Pathogenic PP4, PP1, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.1592del (p.Leu531ArgfsTer22) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BSS22.01 in PMID: 23995613) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). In addition to this proband, the variant has been reported to segregate with Bernard-Soulier syndrome in one affected family member (Patients BSS22.01 and BSS22.02 from PMID: 23995613), both with the homozygous genotype for the NM_000173.7(GP1BA):c.1592del (p.Leu531ArgfsTer22) variant (PP1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP1, PP4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224154/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5147 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0149514 infores:hetionet GO:1901028 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:1901028 GO:0006915 CHEBI:31980 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0027765 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0242350 infores:hetionet CHEBI:3082 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0004134 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0392025 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017152 infores:hetionet CAID:CA380145022 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145022 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.48G>T is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 16 (p.Gln16His).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145022/MONDO:0000573/124 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4514 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0015397 infores:hetionet NCBIGene:91662 biolink:causes MONDO:0012724 infores:monarchinitiative not_provided not_provided HGNC:22938 MONDO:0012724 uuid:2098e537-1a2a-478b-b33f-dda1f98e00e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0011551 infores:hetionet CAID:CA414896766 biolink:causes MONDO:0010602 infores:clingen CAID:CA414896766 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4 The c.7021G>A (p.Glu2341Lys) missense variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.864 (>0.6) meeting PP3. This variant has been reported in at least five probands in the literature (PMID: 31829478, 21070499, 18691168, 33706050, 16879218) meeting phenotypic criteria for F8 (PP4_Moderate & PS4). In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414896766/MONDO:0010602/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Supports CHEBI:4027 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0340726 infores:hetionet CHEBI:9586 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0039070 infores:hetionet CAID:CA028060 biolink:causes MONDO:0012249 infores:clingen CAID:CA028060 MONDO:0012249 PMID: Uncertain Significance BP4 PM2 The NM_000249.4: c.1270G>A variant in MLH1 is a missense variant predicted to cause substitution of Alanin by Threonin at amino acid 424 (p.Ala424Thr). The prior probability of this variant is 0,10 which fullfills the criteria of BP4 (missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity <0.11 as per http://priors.hci.utah.edu/PRIORS). The Frequency of this variant in gnomAD V4.1.0 Grpmax AF = 0.00005797 (0.005797%), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore PM2_supporting is not met.Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM2_SUP, BP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA028060/MONDO:0012249/115 2025-03-20 2025-03-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4710 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0016658 infores:hetionet CAID:CA271849 biolink:causes MONDO:0010683 infores:clingen CAID:CA271849 MONDO:0010683 PMID: Likely Pathogenic PP4, PM2_Supporting, PS4_Moderate, PM4 PP2, PP3, PP1, BS2, BA1, BP3, BP1, BP4, PS3, PS1, BP7, BS1, BS3, BS4, PVS1, PM1, PM5 The NM_000252.3:c.1792del (p.His598Metfs*23) variant in MTM1 is a frameshift variant in the last exon (exon 15) whose frameshift is predicted to extend the myotubularin protein by 16 amino acids at its C terminus (PM4). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. This variant has been detected in 3 individuals with centronuclear myopathy (PS4_Moderate, PMID:9931531, 31541013, 35729264), one of which was a female adult carrier with moderate MTM1-related myopathy showing distal muscle weakness, assisted ambulation, asymmetric muscle weakness, hemifacial hypoplasia, and differences in hand size which is highly specific for the condition (PP4, PMID:31541013). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM4, PP4, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA271849/MONDO:0010683/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Supports CHEBI:9586 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019270 infores:hetionet CHEBI:2904 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0013144 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0553548 infores:hetionet CHEBI:10124 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085636 infores:hetionet CHEBI:7565 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0039231 infores:hetionet GO:0110061 biolink:causes GO:1904385 infores:ubergraph knowledge_assertion manual_agent GO:0110061 GO:1904385 CHEBI:4453 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0021177 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0013395 infores:hetionet CHEBI:41879 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0029118 infores:hetionet CHEBI:7465 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0920289 infores:hetionet CHEBI:3757 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0041834 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0011991 infores:hetionet GO:1904967 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1904967 GO:0051321 CHEBI:4708 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0026826 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027796 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0020557 infores:hetionet CHEBI:18248 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0085593 infores:hetionet CAID:CA410147474 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147474 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1295G>C (p.Cys432Ser) is a missense variant which is present in only 1 individual in gnomAD 2.0 with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.467) and a Splice AI score <0.20 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147474/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9763 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020517 infores:hetionet CHEBI:50922 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0010200 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0497327 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0020580 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1971624 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151966 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151966 infores:hetionet CHEBI:367163 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085633 infores:hetionet CHEBI:8382 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0004093 infores:hetionet CHEBI:65349 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0006145 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0015376 infores:hetionet CHEBI:66903 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0033774 infores:hetionet CHEBI:135925 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0003467 infores:hetionet CHEBI:64198 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0085631 infores:hetionet CHEBI:31859 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0002622 infores:hetionet CHEBI:75998 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0344232 infores:hetionet CAID:CA9043741 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043741 MONDO:0012999 PMID: Likely Benign BS3_Supporting, BP4 PM2, BS2, PM5 The NM_000156.6:c.314G>A variant in GAMT is a missense variant predicted to cause the substitution of an arginine by a glutamine at amino acid position 105 (p.Arg105Gln). This variant has been previously reported in two individuals in the Exome Variant Server database, both of whom were heterozygous for the variant (PMID: 26003046) but, to our knowledge, it has not been reported among individuals with GAMT deficiency. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002374 (275/1158566 alleles; 1 homozygote) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), but due to the presence of a homozygote, the criterion was not applied. BS2 was not applied here to avoid double counting this evidence. Expression of the variant in HeLa cells resulted in GAMT enzyme activity similar to wild type GAMT (BS3_Supporting). The computational predictor REVEL gives a score of 0.14 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 390894). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BS3_Supporting, BP4.((Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043741/MONDO:0012999/026 2025-03-13 2025-03-14 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA10585613 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585613 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1792A>C (p.Ile598Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meet PM2. PMID: 11810272 (Fouchier et al., 2001), Netherlands - et least 1 case who fulfills validated clinical criteria for FH.BP4 - REVEL: 0.487, it is below 0.50, splicing evaluation required.Functional data on splicing not available.Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons.Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical splicing site of any exons.Scenario B, Acceptor site: The variant is located within the range but does not create de novo AG site.Scenario B, Donor site: The variant is located within range but does not create de novo GT site.Scenario C, Acceptor site: The variant is located at -20 to +3 bases of intraexonic AG but AG is not within the range.Scenario C, Donor site: The variant is not located at -3 to +6 bases of intraexonic GTInterpretation: The variant does not affect splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585613/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:17823 biolink:causes UMLS:C0595876 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0595876 infores:hetionet NCBIGene:90624 biolink:causes MONDO:0014364 infores:monarchinitiative not_provided not_provided HGNC:28072 MONDO:0014364 uuid:42e20267-522e-47dc-b54a-dff1620f0b78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0027769 infores:hetionet CHEBI:59560 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0007222 infores:hetionet CHEBI:4814 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0035078 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0005586 infores:hetionet CHEBI:77260 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002962 infores:hetionet CHEBI:168396 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0028734 infores:hetionet CHEBI:17347 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0086565 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0035204 infores:hetionet CAID:CA10583221 biolink:causes MONDO:0100216 infores:clingen CAID:CA10583221 MONDO:0100216 PMID: Likely Benign BP4, BP2 PM2, PM6, BA1, PP3, PP1, PP4, BS2, PM5, PM1, PS1, PS4, PS2, BS1, BS4 The NM_177438.3:c.1168T>C variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 390 (p.Tyr390His). The total allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1614020 alleles) with a highest population minor allele frequency of 0.000003390 (4/1180016 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been observed in trans with the variant c.5479del, p.Leu1827fs (Internal lab contributors: International PPB Registry, Invitae, Prevention Genetics (all same case)) which is classified as pathogenic by the ClinGen DICER1 VCEP (SCV002540823.1) in an individual with Type II PPB and SLCT. The phase of the variants was confirmed by family testing (BP2). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.16); MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP2, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 08/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583221/MONDO:0100216/024 2024-08-27 2024-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36704 biolink:causes MONDO:0005173 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0022602 infores:hetionet CHEBI:6413 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0085649 infores:hetionet CHEBI:17688 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0006277 infores:hetionet CHEBI:65173 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0278106 infores:hetionet CHEBI:50922 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085624 infores:hetionet CAID:CA367403316 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403316 MONDO:0015967 PMID: Likely Pathogenic PM5, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PP1 The c.170T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 57 (p.(Met57Thr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 22035297; internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). Another missense variant at the same codon, c.171G>A, p.(Met57Ile), has been interpreted as pathogenic by the ClinGen MDEP, and p.(Met57Thr) has a greater Grantham distance (PM5). In summary, c.170T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.1, approved 10/10/2025): PM2_Supporting, PP2, PP3, PP4_Moderate, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403316/MONDO:0015967/086 2025-10-28 2025-10-28 Semidominant inheritance HP:0032113 Supports CHEBI:6532 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0014518 infores:hetionet CHEBI:3764 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0677500 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0339383 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0339383 infores:hetionet CHEBI:4909 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0232493 infores:hetionet CHEBI:50922 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0917801 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085606 infores:hetionet CAID:CA402995480 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995480 MONDO:0012999 PMID:23846910 Likely Pathogenic PP3, PM2_Supporting, PP4_Strong, PS3_Supporting PM3 The NM_000156.6:c.391G>C (p.Gly131Arg) variant in GAMT has been previously reported in one individual with guanidinoacetate methyltransferase deficiency (PMID: 23846910). This variant is absent from population databases (PM2_Supporting). The individual previously reported (PMID: 23846910) was a compound heterozygote for the variant who carried a variant of uncertain significance with unknown phase (c.578A>G (p.Gln193Arg), ClinVar Variation ID: 1328978) in unknown phase. This individual showed an absent creatine peak on brain magnetic resonance spectroscopy and elevated urine GAA with low creatine with full GAMT gene sequencing (PMID: 23846910) (PP4_Strong). This variant alters the last nucleotide of exon 3 of GAMT. The computational splicing predictor SpliceAI gives a score of 0.8 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 of GAMT. This variant was shown to result in abnormal splicing, frameshift, and premature termination based on cDNA analysis of an affected individual (PMID: 23846910). If any protein is made, the variant is predicted to result in a missense, p.Gly131Arg. The computational predictor REVEL gives a score of 0.958 for this missense variant, which is above the threshold of 0.75, evidence that correlates with impact to GAMT function. Therefore, PP3 is met for both the predicted impact on splicing and predicted impact of the missense variant. In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong (Richards 2015).(Classification approved by the ClinGen CCDS VCEP on March 23, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995480/MONDO:0012999/026 2023-03-29 2023-03-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0013609 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0178298 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0474378 infores:hetionet CHEBI:32020 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0004093 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0032285 infores:hetionet CHEBI:66876 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0002965 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0031212 infores:hetionet CAID:CA284654 biolink:causes MONDO:0021060 infores:clingen CAID:CA284654 MONDO:0021060 PMID:28512244 Pathogenic PS3, PS2, PM1, PM2, PM6, PP3, PP2, PS4_Supporting PS1, BP7, BP5, BS4, BS1, BS3, PM5, PM4, PP1, BS2, BP3, BP2, BP4, BP1, BA1 The c.741T>G (p.Phe247Leu) variant in BRAF has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PM6, PS2, PS4_Supporting; GeneDx internal data; GTR Lab ID 26957; SCV000077236.10). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS2, PS3, PM1, PM2, PP2, PP3, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA284654/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:2567 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0042963 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0574067 infores:hetionet CAID:CA017256 biolink:causes MONDO:0007947 infores:clingen CAID:CA017256 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4 PVS1, PM6, BS2, PP4, PP1, BP4, BP3, BP2, BA1, PM1, PM5, PM4, PM3, PS1, PS3, PS2, BP5, BP7, BS1, BS3, BS4 The NM_000138 c.7577A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at position 2526. This variant has been identified in the literature and public and private databases in one proband with a clinical diagnosis of Marfan syndrome and in seven probands with thoracic aortic aneurysm and dissection (TAAD) and/or other features suggestive of Marfan syndrome (PS4; PMID: 17657824, Invitae and GeneDx internal data, ClinVar ID: 200198, UZA internal data). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID: 31227806) the PM1 criterion has not been used. This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3; REVEL = 0.821). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM2_supporting, PP2, PP3). FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017256/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CAID:CA386967815 biolink:causes MONDO:0015967 infores:clingen CAID:CA386967815 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 PS4 The c.956-2A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 4 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 5 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 8945470​, internal lab contributor). This variant segregated with diabetes, with 9 informative meioses in two families with MODY (PP1_Strong; PMID 8945470, internal lab contributor). In summary, c.956-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PP1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386967815/MONDO:0015967/017 2022-08-05 2022-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51364 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C2939147 infores:hetionet CHEBI:41977 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0041834 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009324 infores:hetionet CHEBI:8382 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0237849 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0005940 infores:hetionet CHEBI:4325 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0030305 infores:hetionet CHEBI:135530 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0344232 infores:hetionet CHEBI:5558 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0003467 infores:hetionet CHEBI:40050 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0151766 infores:hetionet CAID:CA9870533 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870533 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, BP4 PM1, PS4 The c.1303G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 435 (p.(Val435Ile)) of NM_175914.5. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.124, which is less than or equal to the MDEP threshold of 0.15 (BP4). This variant has an incomputable gnomAD v2.1.1 GrpmaxPopmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 1 copy each in the East Asian and Admixed American subpopulations, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in two individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.1303G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870533/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40279 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038002 infores:hetionet CHEBI:7931 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C2830004 infores:hetionet CAID:CA658824772 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824772 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.55del (p.Val19CysfsTer24) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 555040. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824772/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA16020954 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020954 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4 PM5 The c.1166C>A variant in PAH has been reported in 1 patient of European ancestry with phenylketonuria (PMID: 10541324). This variant is absent from population databases (PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020954/MONDO:0009861/006 2021-11-21 2021-12-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17347 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0033774 infores:hetionet CHEBI:63617 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011168 infores:hetionet NCBIGene:2516 biolink:causes MONDO:0060489 infores:monarchinitiative not_provided not_provided HGNC:7983 MONDO:0060489 uuid:68441173-98cb-4713-be96-3f4deb5ef12f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9622 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0008031 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0036572 infores:hetionet CHEBI:4710 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0018944 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0020649 infores:hetionet CHEBI:6078 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0232462 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0038454 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027051 infores:hetionet CHEBI:51860 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0032343 infores:hetionet CHEBI:28864 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0042963 infores:hetionet CHEBI:5779 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0017178 infores:hetionet CHEBI:68554 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0030312 infores:hetionet CHEBI:94501 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0038990 infores:hetionet CHEBI:49603 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0002170 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0271899 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0271899 infores:hetionet NCBIGene:79581 biolink:causes MONDO:0013867 infores:monarchinitiative not_provided not_provided HGNC:30224 MONDO:0013867 uuid:c17ae79e-d517-4ee0-a97b-2a98bfc9450e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0040053 infores:hetionet CHEBI:4657 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0042510 infores:hetionet CHEBI:28901 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0333355 infores:hetionet CHEBI:50742 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0011124 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0241164 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0027051 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0033860 infores:hetionet NCBIGene:6523 biolink:causes MONDO:0011731 infores:monarchinitiative not_provided not_provided HGNC:11036 MONDO:0011731 uuid:25e6e534-4e8b-4354-89d5-a3323e0b16d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0031117 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085129 infores:hetionet CHEBI:17303 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0043352 infores:hetionet CHEBI:6437 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0008031 infores:hetionet CHEBI:3216 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011603 infores:hetionet CHEBI:9139 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0039231 infores:hetionet CAID:CA409104280 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104280 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM1, PS2 The c.278G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to serine at codon 93 (p.(Cys93Ser)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with a clinical history highly specific for HNF4A-MODY neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and history of macrosomia in the absence of sufficient maternal hyperglycemia)(PP4_Moderate; PMID: 20164212). This variant was identified as a de novo occurrence with confirmed parental relationships in this individual (PS2; PMID: 20164212). This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA and is necessary for zinc finger formation which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.278G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PS2, PP4_Moderate, PM1, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104280/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6933 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0086565 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0020649 infores:hetionet CHEBI:9398 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C3665347 infores:hetionet CHEBI:2682 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018965 infores:hetionet CHEBI:49960 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020621 infores:hetionet CHEBI:63598 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0687713 infores:hetionet CHEBI:8888 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0149725 infores:hetionet CHEBI:724125 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0085932 infores:hetionet CHEBI:9435 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0004604 infores:hetionet CAID:CA020454 biolink:causes MONDO:0008667 infores:clingen CAID:CA020454 MONDO:0008667 PMID:15574766PMID:19030229 Pathogenic PS4, PM2_Supporting, PM1, PP3, PS3_Supporting, PM6 BP7, BP5, BS1, BS3, PM5, PM4, BS2, PVS1, BA1, BP4, BP3, BP2 The NM_000551.4(VHL):c.500G>A (p.Arg167Gln) variant in VHL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 167. This missense mutation has been identified in at least 19 unrelated individuals with von Hippel-Lindau disease. Mostly VHL Type 2 or 2B phenotypes are noted. However, some publications describe VHL Type 1 as well. PMIDs used: 20846682, 8707293, 9829912, 9829911, 7728151, 12114495, 12624160, 14722919. CIViC EIDs used (https://civicdb.org): 5485, 5354, 5264, 5062, 4913, 5487, 5546, 6118. 2 participating commercial laboratories reported >7 and >20 cases. The number of proband and/or family cases fulfills the criteria for strong evidence (PS4). Multiple publications (PMID: 15574766, PMID: 19030229) support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a (PS3_Supporting). A de novo (and mosaic ~5.5% allele freq in blood and ~34% in a pheochromocytoma at ~80% tumor purity) case was identified in a 16yo with no family history of VHL and fulfilling Danish Criteria for VHL (The 16yo had the following: Hb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule). PMID: 30731206, CIViC evidence ID: EID7714. 1 commercial laboratory reports a de novo case in a child with bilateral retinal hemangiomas in the age range of 10yo (PM6). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Arg167 is one of the germline hotspots outlined by the VHL VCEP, and it is in the Elongin binding domain (PM1). The computational predictor REVEL gives a score of 0.874, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). Per VHL VCEP specifications, this code is applied when the REVEL score is >=0.6. (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020454/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4702 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0042963 infores:hetionet CHEBI:101853 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0238106 infores:hetionet CHEBI:8028 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C2363730 infores:hetionet CAID:CA410147529 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147529 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1277C>T (p.Pro426Leu) is a missense variant which has a REVEL score < 0.50 (0.226), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147529/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63618 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C1443060 infores:hetionet UNII:9YCX42I8IU biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0015734 infores:hetionet CHEBI:3082 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C2047937 infores:hetionet UNII:3U02EL437C biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0014591 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0877097 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0877097 infores:hetionet NCBIGene:224 biolink:causes MONDO:0010031 infores:monarchinitiative not_provided not_provided HGNC:403 MONDO:0010031 uuid:4314d681-b224-4437-991e-7bdaf2df9ae9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020580 infores:hetionet UMLS:C0011701 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0268000 infores:hetionet CHEBI:71941 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0002878 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0686377 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0686377 infores:hetionet CHEBI:499361 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0853697 infores:hetionet CHEBI:6715 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0026858 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0006147 infores:hetionet NCBIGene:6731 biolink:causes MONDO:0013851 infores:monarchinitiative not_provided not_provided HGNC:11303 MONDO:0013851 uuid:0828b683-1d33-429e-9d1d-42a645828f82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002418 infores:hetionet CHEBI:35854 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0043352 infores:hetionet NCBIGene:353 biolink:causes MONDO:0013869 infores:monarchinitiative not_provided not_provided HGNC:626 MONDO:0013869 uuid:562381ec-07a7-4861-b5bc-0a4dde8569a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72296 biolink:causes UMLS:C1696110 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C1696110 infores:hetionet CHEBI:44423 biolink:causes UMLS:C1504383 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1504383 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0267792 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0948525 infores:hetionet NCBIGene:5925 biolink:causes MONDO:0002629 infores:monarchinitiative not_provided not_provided HGNC:9884 MONDO:0002629 uuid:98d59b7b-bc28-4390-8568-3564078d7f71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39112 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0041909 infores:hetionet CHEBI:6775 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0041657 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0041747 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0022660 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0006849 infores:hetionet CHEBI:4708 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0024902 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0004239 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151970 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0013395 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0518015 infores:hetionet CHEBI:66964 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0002622 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0857144 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0857144 infores:hetionet CHEBI:63629 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018926 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0860866 infores:hetionet CHEBI:7824 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0032231 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0234215 infores:hetionet CHEBI:2682 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0740394 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0009806 infores:hetionet CHEBI:45327 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0344232 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0007642 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0233472 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0278079 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0010709 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018799 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0020517 infores:hetionet CAID:CA229515 biolink:causes MONDO:0009861 infores:clingen CAID:CA229515 MONDO:0009861 PMID:9429153PMID:24368688 Pathogenic PM2, PS3, PM3_Strong PP3 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L (P/LP) (PMID:9429153; PMID:24368688). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229515/MONDO:0009861/006 2018-08-07 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51364 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0085631 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0020456 infores:hetionet CHEBI:3398 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0018681 infores:hetionet CHEBI:240107 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0015397 infores:hetionet CHEBI:70735 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0011991 infores:hetionet CHEBI:63589 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0013182 infores:hetionet CAID:CA5416937 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416937 MONDO:0011225 PMID: Uncertain Significance BA1, PM2, BS1 The c.262G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 88 p.Glu88Lys.The filtering allele frequency (the upper threshold of the 95% CI of 90/1164454) of the c.262G>A variant in DCLRE1C is 0.00006702 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD v4.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416937/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:84500 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013362 infores:hetionet CHEBI:161680 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0000737 infores:hetionet CHEBI:499361 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0239937 infores:hetionet CHEBI:9566 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0013604 infores:hetionet CHEBI:31711 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0232292 infores:hetionet CHEBI:9667 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0428977 infores:hetionet GO:2001109 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:2001109 GO:0043010 CHEBI:8764 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022904 infores:hetionet CAID:CA031903 biolink:causes MONDO:0007750 infores:clingen CAID:CA031903 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1070A>G (p.Glu357Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4-supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.000008800 (0.00088%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.984.PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.PS4_supporting - Variant meets PM2 and is identified in 4 index cases (3 cases with Simon-Broome criteria of possible FH in PMID: 34456049 (Marco-Benedí et al., 2022), Spain; 1 case with internationally accepted criteria (Defesche et al, 2000) in PMID: 16250003 (Fouchier et al, 2005), The Netherlands. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031903/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3403 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0085618 infores:hetionet CHEBI:17303 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0043144 infores:hetionet CAID:CA10653561 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653561 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*1823A>C variant in the 3' UTR has an MAF of 0.02230 (2.2%, 68/3050 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653561/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15367 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0231303 infores:hetionet CHEBI:6710 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0042963 infores:hetionet CHEBI:3698 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0086565 infores:hetionet CHEBI:3437 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0039070 infores:hetionet GO:1905304 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0007507 CHEBI:17026 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0011570 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0518015 infores:hetionet NCBIGene:6331 biolink:causes MONDO:0007240 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0007240 uuid:f3c3d517-599f-4309-842a-72d4c21b62d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:404429 biolink:causes MONDO:0005739 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:404429 MONDO:0005739 CHEBI:8207 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013595 infores:hetionet CHEBI:17141 biolink:causes NCIT:C98951 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0231451 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038454 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0851341 infores:hetionet CHEBI:5002 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0233494 infores:hetionet CHEBI:8888 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013428 infores:hetionet CHEBI:2663 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0002874 infores:hetionet CHEBI:50922 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1510410 infores:hetionet CAID:CA1442883 biolink:causes MONDO:0100084 infores:clingen CAID:CA1442883 MONDO:0100084 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.435C>A (p.Tyr145Ter) variant in ACTA1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/7 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism for autosomal recessive nemaline myopathy (PVS1). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.000002480 (4/1179732 alleles) in the European (non-Finnish) population (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_P. (Congenital Myopathies VCEP specifications version 1; 08/07/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1442883/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5001 biolink:causes MONDO:0005311 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0004153 infores:hetionet CAID:CA410203508 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203508 MONDO:0011071 PMID:25840971 Likely Pathogenic PM1_Supporting, PS3, PM2_Supporting, PP3 PS1, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS3, BS1, BS4, BP7, BP5, PM6, PVS1, PM5, PM4, PM3, BS2, PP2, PP1, PP4 The NM_001754.4:c.316T>A (p.Trp106Arg) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) and data from secondary assay demonstrate altered DNA binding (PS3; PMID: 25840971). This missense variant has a REVEL score >0.75 (0.976) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203508/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:231594 biolink:causes UMLS:C0236167 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0236167 infores:hetionet CHEBI:5141 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0220870 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0034065 infores:hetionet CAID:CA367402683 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402683 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PP4 The c.323A>T variant in the glucokinase gene, GCK, causes an amino acid change of tyrosine to phenylalanine at codon 108 (p.(Tyr108Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.849 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.322T>C p.Tyr108His, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Tyr108Phe (PM5_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 15016234). In summary, c.323A>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402683/MONDO:0015967/086 2024-01-18 2024-01-18 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:119573 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1443060 infores:hetionet CHEBI:31236 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0600125 infores:hetionet CHEBI:37333 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0003862 infores:hetionet CHEBI:3508 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0232766 infores:hetionet CHEBI:4798 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0008350 infores:hetionet CHEBI:3732 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0917801 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0002871 infores:hetionet CHEBI:18385 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0036974 infores:hetionet CHEBI:34967 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0013415 infores:hetionet CHEBI:27666 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0019158 infores:hetionet CHEBI:3219 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151908 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0037199 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013395 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0232208 infores:hetionet CHEBI:71255 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0236024 infores:hetionet CHEBI:2663 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0870082 infores:hetionet CHEBI:31413 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0015672 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0521839 infores:hetionet CHEBI:5801 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0547030 infores:hetionet CHEBI:3387 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0085649 infores:hetionet CHEBI:2663 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0015967 infores:hetionet CHEBI:15544 biolink:causes NCIT:C98951 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0231451 infores:hetionet NCBIGene:2214 biolink:causes MONDO:0014313 infores:monarchinitiative not_provided not_provided HGNC:3619 MONDO:0014313 uuid:bd259ebf-e6c6-475c-9413-e0f7f205dd93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0221706 infores:hetionet CHEBI:51450 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0311468 infores:hetionet CHEBI:144551 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1527344 infores:hetionet CHEBI:3757 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0687713 infores:hetionet CHEBI:28593 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0235378 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0014457 infores:hetionet UMLS:C0065374 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0010200 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038454 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002170 infores:hetionet GO:0075188 biolink:causes GO:0044409 infores:ubergraph knowledge_assertion manual_agent GO:0075188 GO:0044409 CHEBI:36791 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0700200 infores:hetionet NCBIGene:7066 biolink:causes MONDO:0957572 infores:monarchinitiative not_provided not_provided HGNC:11795 MONDO:0957572 uuid:ffd85088-f6a1-4901-aaed-cde029a5c0b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018794 infores:hetionet CAID:CA1244345 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244345 MONDO:0005338 PMID:35196929 Likely Benign BS1, BS3_Supporting BP7, PM2, PP3, PP1, PM4, PM5, PS3, PS4, PS1, PS2, BA1, BP4 The c.34G>C variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 12 (p.Gly12Arg). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.006039, which met the ≥ 0.001 threshold set for BS1 (271 alleles out of 44,874), meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.33, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Gly12Arg protein had similar solubility and secretion levels to wild type myocilin protein in this study (PMID: 35196929). The assays met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Although probands with primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1, BS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244345/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3387 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0392702 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0853908 infores:hetionet CHEBI:10650 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2607914 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018213 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0852361 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0852361 infores:hetionet CHEBI:48273 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0392699 infores:hetionet CHEBI:391960 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0547030 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042134 infores:hetionet CHEBI:31547 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0085612 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0518015 infores:hetionet CHEBI:3013 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0034150 infores:hetionet GO:0098906 biolink:causes GO:0086029 infores:ubergraph knowledge_assertion manual_agent GO:0098906 GO:0086029 CHEBI:2904 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018524 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0574002 infores:hetionet CHEBI:7824 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0233471 infores:hetionet CHEBI:5855 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0023530 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0027051 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0235969 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0032961 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0687133 infores:hetionet CHEBI:3219 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026858 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0009938 infores:hetionet CHEBI:84500 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0028081 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0026846 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0231218 infores:hetionet NCBIGene:22880 biolink:causes MONDO:0014736 infores:monarchinitiative not_provided not_provided HGNC:23573 MONDO:0014736 uuid:1489d07c-88c1-48f8-83c7-38bfac212499 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0425945 infores:hetionet CHEBI:63599 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0231528 infores:hetionet CHEBI:7936 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0026821 infores:hetionet CHEBI:16335 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0004604 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0152115 infores:hetionet CHEBI:7852 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C2047937 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0036572 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0006145 infores:hetionet CAID:CA386953303 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953303 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PS2_Moderate, PVS1, PP4_Moderate The c.160C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 54 (p.(Arg54Ter)) of NM_000545.8. This variant, located in biologically relevant exon 1/10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). This variant was identified in 11 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID:21224407, PMID:24905847, PMID:25414397, PMID:26050565, ClinVar ID 805632, internal lab contributors). This variant was identified in an individual with a clinical picture highly specific for HNF1A-MODY (MODY probability calculator >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate, internal lab contributor). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with non-autoimmune diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). This variant segregates with diabetes with 9 informative meioses in 5 families with diabetes (PP1_Strong; PMID:26050565, internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for HNF1A-MODY by the ClinGen MDEP (PVS1, PM2_Supporting, PS4, PP4_Moderate, PP1_Strong, PS2_Moderate). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953303/MONDO:0015967/017 2021-12-28 2021-12-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63637 biolink:causes UMLS:C0014745 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0014745 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0854954 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0854954 infores:hetionet CHEBI:28241 biolink:causes UMLS:C0858924 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0858924 infores:hetionet NCBIGene:158326 biolink:causes MONDO:0013774 infores:monarchinitiative not_provided not_provided HGNC:23399 MONDO:0013774 uuid:168f428b-fd89-4c58-a57c-a669c786825e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0046668 biolink:causes GO:0048592 infores:ubergraph knowledge_assertion manual_agent GO:0046668 GO:0048592 CHEBI:3387 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002170 infores:hetionet CHEBI:7954 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0002170 infores:hetionet CHEBI:36791 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085612 infores:hetionet CHEBI:23765 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0338831 infores:hetionet CHEBI:15428 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0042963 infores:hetionet CHEBI:29688 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0003467 infores:hetionet CHEBI:6640 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0011053 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013781 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0006145 infores:hetionet NCBIGene:85459 biolink:causes MONDO:0958328 infores:monarchinitiative not_provided not_provided HGNC:29366 MONDO:0958328 uuid:3eb820fd-81fe-49e1-ad40-da1db5d54307 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31622 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C1443060 infores:hetionet CHEBI:45652 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0036974 infores:hetionet CHEBI:9086 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0040264 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0018799 infores:hetionet CHEBI:3181 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C2242996 infores:hetionet CHEBI:28593 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0231528 infores:hetionet GO:0060860 biolink:causes GO:0009908 infores:ubergraph knowledge_assertion manual_agent GO:0060860 GO:0009908 CHEBI:135930 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0013404 infores:hetionet CHEBI:100246 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0005758 infores:hetionet CHEBI:367163 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018926 infores:hetionet CHEBI:3242 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0344232 infores:hetionet CHEBI:2950 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0010200 infores:hetionet CHEBI:68478 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0032617 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085584 infores:hetionet NCBIGene:90523 biolink:causes MONDO:0859322 infores:monarchinitiative not_provided not_provided HGNC:21355 MONDO:0859322 uuid:82c8d432-e3a1-403d-b9c1-9cf5cb24022e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0019557 infores:hetionet CHEBI:50648 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0014591 infores:hetionet CHEBI:94449 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0038990 infores:hetionet CAID:CA513686659 biolink:causes MONDO:0009276 infores:clingen CAID:CA513686659 MONDO:0009276 PMID: Likely Benign BP7, PM2_Supporting, BP4 The NM_000407.5(GP1BB):c.15G>A (p.Pro5=) synonymous variant is not predicted by SpliceAI to impact splicing (delta score 0.00; BP4) and the position is not highly conserved (phyloP score -0.56; BP7). The Grpmax filtering allele frequency in gnomaDv4.1 is 8.700e-7 (based on 4/1074086alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. This variant is classified as likely benign for autosomal recessive inheritance of Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PDVCEP: BP7, BP4, PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA513686659/MONDO:0009276/082 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135888 biolink:causes MONDO:0021063 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0007102 infores:hetionet NCBIGene:64412 biolink:causes MONDO:0060556 infores:monarchinitiative not_provided not_provided HGNC:15808 MONDO:0060556 uuid:274e1f09-2f3c-49c3-8fb0-874b1871b669 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0018524 infores:hetionet CHEBI:135193 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0030193 infores:hetionet CHEBI:6916 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0030252 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0042769 infores:hetionet CAID:CA386952516 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952516 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3, PP1 PM5, PP4 The c.49C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 16 (p.(Leu17Val)) of NM_000545.8. This variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP threshold of 0.70 (PP3). This variant segregated with diabetes, with three informative meioses in one family (PP1; internal lab contributors). This variant was reported in one individual with diabetes; however, there was insufficient clinical information to calculate a MODY Probability, and HNF4A was not tested; therefore PP4 will not be applied. Another variant at the same amino acid, c.50T>A (p.Leu17His), was classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952516/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1251221 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251221 MONDO:0013144 PMID: Uncertain Significance BP4 BP7, BS1, PM2 The c.1278G>A (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Ser426=). SpliceAI predicts no splicing impact for this variant which suggests that the variant does not impact SERPINC1 function (BP4). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251221/MONDO:0013144/084 2024-10-02 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0024117 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001882 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0004659 infores:hetionet NCBIGene:123016 biolink:causes MONDO:0013274 infores:monarchinitiative not_provided not_provided HGNC:20087 MONDO:0013274 uuid:79b4683a-7c1d-4da0-a3c8-32a201e60ec2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2788 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0022281 infores:hetionet CHEBI:204928 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0003811 infores:hetionet CAID:CA163616 biolink:causes MONDO:0007648 infores:clingen CAID:CA163616 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM5, PM4, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.1937-13T>C variant has an allele frequency of 0.16607 (16.6%, 4107/24730 alleles, 330 homozygotes) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA163616/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3286 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0006826 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0035078 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020619 infores:hetionet CHEBI:142290 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0037763 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0009319 infores:hetionet CHEBI:100241 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232461 infores:hetionet CHEBI:4753 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0027092 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0033117 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0877096 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0877096 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0948089 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0852995 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0852995 infores:hetionet CHEBI:63621 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151889 infores:hetionet CHEBI:6067 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0239783 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042401 infores:hetionet CAID:CA512232232 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232232 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM6, PVS1, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.894A>G (p.Pro298=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-1.70) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232232/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:408174 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0231528 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0423602 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0037036 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0595877 infores:hetionet CHEBI:35778 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0011603 infores:hetionet CAID:CA222161 biolink:causes MONDO:0015152 infores:clingen CAID:CA222161 MONDO:0015152 PMID: Uncertain Significance PM4, PM3, BP2, PM2_Supporting PP4 The NM_003494.4: c.4060_4062del p.(Ser1354del) variant in DYSF, which is also known as NM_001130987.2: c.4114_4116del p.(Ser1372del), is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (PM4). This variant has been reported in at least eight individuals with features consistent with LGMD (PMID: 33250842, 30827497, 36983702, 30564623; LOVD DYSF_000416). At least one of these patients was reported to carry the c.4060_4062del p.(Ser1354del) variant in trans with NM_003494.4: c.4439A>C p.(Lys1480Thr), which is classified as likely pathogenic by the LGMD VCEP (1.0 pt, LOVD Individuals #00215628, #00215714) (PM3). The c.4060_4062del p.(Ser1354del) variant has also been reported in a homozygous state in one patient with presumed familial consanguinity from the Indian subcontinent (PMID: 33250842). However, among the reported cases, at least six, all of Indian origin, were homozygous for both c.4060_4062del p.(Ser1354del) and c.4439A>C p.(Lys1480Thr), indicating these two variants occur in cis (BP2; PMID: 30564623, 36983702; LOVD Individuals #00219454, #00222227; Jain Foundation Dysferlin Registry internal data communication). The highest minor allele frequency for this variant is 0.00002319 in the South Asian population of gnomAD v4.1.0 exomes (2/86250 chromosomes), which is lower than the LGMD VCEP threshold (0.0001) (PM2_Supporting). In summary, there is currently insufficient evidence to determine whether this variant, when identified without NM_003494.4: c.4439A>C p.(Lys1480Thr) as part of a complex allele, is benign or pathogenic. It is therefore classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025): PM4, PM3, BP2, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222161/MONDO:0015152/180 2025-04-22 2025-05-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17688 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013404 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038454 infores:hetionet CHEBI:7640 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0151878 infores:hetionet CAID:CA270438 biolink:causes MONDO:0010726 infores:clingen CAID:CA270438 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PP3, PP4, PM6, PS4_Moderate, PM5_Strong, PM2_Supporting The p.Thr158Ala variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with preserved speech variant Rett syndrome (PMID 11269512) (PM6). The p.Thr158Ala variant has been observed in 2 other individuals with Rett syndrome (PMID 18842453, 15057977) (PS4_moderate, PP4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18337588, 23270700, 23421866, 10508514, internal database - Invitae) (PM5_strong). The p.Thr158Ala variant in MECP2 is absent from gnomAD (PM2_supporting). Heterochromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr158Ala variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270438/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:68558 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0042075 infores:hetionet CHEBI:3011 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0027947 infores:hetionet CHEBI:17347 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0022107 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0033117 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0014544 infores:hetionet CHEBI:4653 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0004604 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0332534 infores:hetionet CHEBI:64355 biolink:causes HP:0012415 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0476337 infores:hetionet NCBIGene:8792 biolink:causes MONDO:0012859 infores:monarchinitiative not_provided not_provided HGNC:11908 MONDO:0012859 uuid:b7d93ecd-18fe-45ae-bf8e-a3ce18ab5785 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226599 biolink:causes MONDO:0100368 infores:clingen CAID:CA226599 MONDO:0100368 PMID: Likely Pathogenic PM3, PS3_Supporting, PP3, PP4, PP1, PM2_Supporting NM_000329.3(RPE65):c.989G>A (p.Cys330Tyr) is a missense variant resulting in a substitution of cysteine by tyrosine at codon 330. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00000072, with 3 alleles / 1179940 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 15024725, PMID: 32032261). The variant has also been reported in a proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.843_858+7del variant suspected but not confirmed in trans, which was previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (VCEP member-provided data, 0.5 pts), (1.5 total pts, PM3). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), genotyping by next-generation sequencing panel with 176 retina-associated genes that did not provide an alternative explanation for visual impairment (2 pts), decreased central visual acuity (1 pt), and abnormal color vision (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 29332120, PP4). The computational predictor REVEL gives a score of 0.747, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). The variant exhibited 0-2% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16096063, PMID: 16150724, PMID: 24849605. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP4, PP3, PS3_Supporting, PP1, and PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226599/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119915 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0023530 infores:hetionet CAID:CA10118269 biolink:causes MONDO:0021060 infores:clingen CAID:CA10118269 MONDO:0021060 PMID: Uncertain Significance BP4 PM2, PP3, BA1, BS1 The NM_006767.4:c.26G>C variant in LZTR1 is a missense variant predicted to cause substitution of glycine by alanine at amino acid 9 (p.Gly9Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001954 (9/23990 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.093, which is below the threshold of 0.3, evidence that does not predict a damaging effect on LZTR1 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10118269/MONDO:0021060/094 2024-12-03 2025-04-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA336712 biolink:causes MONDO:0007648 infores:clingen CAID:CA336712 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.866C>T (p.Ala289Val) missense variant has a frequency of 0.00002 (6 of 251,472) in gnomAD, with a maximum allele frequency of 0.00010 (3 of 30,616) in the South Asian subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000669016.2, SCV000254833.6). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA336712/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6970 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0442886 infores:hetionet CHEBI:51230 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011124 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1527311 infores:hetionet CHEBI:5864 biolink:causes MONDO:0021163 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0022665 infores:hetionet CHEBI:8426 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0016382 infores:hetionet NCBIGene:341640 biolink:causes MONDO:0007410 infores:monarchinitiative not_provided not_provided HGNC:25396 MONDO:0007410 uuid:70849df5-c885-4459-baf3-16117e118653 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8805 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0013395 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0239978 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020039 infores:hetionet CHEBI:50885 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0020456 infores:hetionet CHEBI:8502 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0013604 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0376297 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0376297 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0043241 infores:hetionet CHEBI:4784 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0700225 infores:hetionet CHEBI:8028 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0242429 infores:hetionet CAID:CA10585154 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585154 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.826T>C (p.Cys276Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2022. The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys276.PM2: This variant is absent from gnomAD v2.1.1.PP3: REVEL = 0.915.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH (3 cases from PMID 10978268 (Bertolini et al. 2000)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585154/MONDO:0007750/013 2022-10-28 2024-12-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8888 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014534 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151559 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020651 infores:hetionet CHEBI:36704 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0002994 infores:hetionet CHEBI:7936 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1320474 infores:hetionet CHEBI:7465 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0008031 infores:hetionet CHEBI:2904 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0231218 infores:hetionet CHEBI:71219 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151744 infores:hetionet CHEBI:6367 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0221776 infores:hetionet CHEBI:31624 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0002962 infores:hetionet CAID:CA8337912 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337912 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 The c.956C>A (p.Ser319Ter)(NM_000018.3) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed NBS and follow-up data, which is highly specific for VLCAD deficiency (PP4_supporting, PMID: 27209629). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_supporting, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337912/MONDO:0008723/021 2024-05-14 2024-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5106 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0242429 infores:hetionet CAID:CA10584919 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584919 MONDO:0007750 PMID: Likely Pathogenic PM1, PS3_Supporting, PM2, PP3 BA1, BP4, BP3, PS1, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM6, BS2, PP1, PP4 The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584919/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6367 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0404521 infores:hetionet CHEBI:421707 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C2047937 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0280100 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0280100 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0234215 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0232492 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0020517 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0021053 infores:hetionet CHEBI:32192 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0027497 infores:hetionet CHEBI:68558 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018418 infores:hetionet CHEBI:50841 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0002170 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016053 infores:hetionet CHEBI:4657 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0013404 infores:hetionet CHEBI:64028 biolink:causes HP:0002317 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0231686 infores:hetionet CAID:CA2580618180 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580618180 MONDO:0015967 PMID: Likely Pathogenic PS3, PP4_Moderate, PP3, PP1, PM2_Supporting PS4 The c.580-9T>G variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 5 of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 31291970, internal lab contributors). At least one of these individuals did have a clinical history highly specific for GCK-hyperglycemia (persistent fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% (≥ 2 HbA1c + ≥ 1 FPG within range) (PP4_Moderate; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.29 for donor gain, predicting that the variant disrupts the donor site of intron 5 of GCK (PP3). Additionally, there is evidence from RNA studies that this non-canonical splicing variant results in aberrant splicing, indicating that this variant impacts protein function (PS3; PMID: 40225161). In summary, c.580-9T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS3, PP4_Moderate, PM2_Supporting, PP1, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580618180/MONDO:0015967/086 2025-10-27 2025-10-28 Semidominant inheritance HP:0032113 Supports NCBIGene:10225 biolink:causes MONDO:0008893 infores:monarchinitiative not_provided not_provided HGNC:16892 MONDO:0008893 uuid:a8e429eb-1ddb-40c7-84c8-59d88ff5d96c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:U6XF9NP8HM biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0015967 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007760 infores:hetionet NCBIGene:4534 biolink:causes MONDO:0010683 infores:monarchinitiative not_provided not_provided HGNC:7448 MONDO:0010683 uuid:2aa8ae39-9f9c-41c8-a3f4-6d896d3cf881 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085636 infores:hetionet CHEBI:47781 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C2242996 infores:hetionet CHEBI:3387 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013384 infores:hetionet CHEBI:41774 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0005758 infores:hetionet CHEBI:3441 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0546884 infores:hetionet CAID:CA10014724 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014724 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BP3, BP2, BP1, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PM1, PM5, PP4, PP2, PP3, PP1 NM_001754.4(RUNX1):c.56G>A (p.Arg19Lys) is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.R19K); note that this variant is in the 5' UTR, c.-161732G>A, of NM_001001890.3. The variant has been reported in a 69-year-old patient with NPM1-mutated, cytogenetically normal AML at a VAF=53% (PMID: 31367767) and in a patient with CMML (PMID: 24030381, Supplementary Table 2); however, germline origin is unclear for these cases. The highest population minor allele frequency in gnomAD v2 is 0.006966% (9/129192 alleles) in the non-Finnish European population, and the variant has also been reported in 1/1358 controls from a study evaluating 57 individuals with cutaneous melanoma and 2 other primaries (PMID: 29641532, Supplementary Table 3). To our knowledge, functional assays have not been reported for this variant, but the computational predictor REVEL gives a score of 0.456, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy-VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014724/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15367 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004623 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0020651 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0232492 infores:hetionet CHEBI:10102 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020433 infores:hetionet CHEBI:16335 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0151517 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0031085 infores:hetionet CHEBI:63581 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0006277 infores:hetionet CHEBI:9570 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151907 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0004936 infores:hetionet CHEBI:4858 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0006152 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0006840 infores:hetionet CHEBI:17474 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C2830004 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0234458 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0403632 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0002871 infores:hetionet CHEBI:8435 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0917801 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002453 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0234215 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020615 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0026857 infores:hetionet CHEBI:51860 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0237849 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0856150 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0856150 infores:hetionet CHEBI:9316 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0020649 infores:hetionet CHEBI:64318 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0042963 infores:hetionet NCBIGene:347688 biolink:causes MONDO:0021573 infores:monarchinitiative not_provided not_provided HGNC:20773 MONDO:0021573 uuid:2542f679-9151-41be-b733-188b90e15f05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0040046 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0009806 infores:hetionet NCBITaxon:42068 biolink:causes MONDO:0019121 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:42068 MONDO:0019121 CHEBI:3398 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0031117 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0018799 infores:hetionet NCBIGene:112476 biolink:causes MONDO:0011178 infores:monarchinitiative not_provided not_provided HGNC:30500 MONDO:0011178 uuid:3e195139-a030-4484-b6ce-7d136dc0124a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0033774 infores:hetionet CHEBI:6754 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0003467 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0011991 infores:hetionet CHEBI:3044 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0027497 infores:hetionet CHEBI:3723 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025323 infores:hetionet CHEBI:4885 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0037036 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235032 infores:hetionet CHEBI:3756 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0002792 infores:hetionet CHEBI:9570 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0004509 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0002878 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026766 infores:hetionet CHEBI:43968 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0687713 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031542 infores:hetionet UMLS:C0657912 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020580 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085393 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020456 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0011609 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020649 infores:hetionet CHEBI:5778 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0027497 infores:hetionet CHEBI:3219 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0541798 infores:hetionet CHEBI:6149 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1145670 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0011053 infores:hetionet CHEBI:71219 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0022346 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014868 infores:hetionet CHEBI:6717 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0009421 infores:hetionet GO:0010058 biolink:causes GO:0022622 infores:ubergraph knowledge_assertion manual_agent GO:0010058 GO:0022622 CHEBI:7825 biolink:causes MONDO:0006540 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0032633 infores:hetionet CHEBI:72690 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0024312 infores:hetionet CHEBI:50749 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0033774 infores:hetionet CHEBI:8888 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151827 infores:hetionet CHEBI:135613 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0600125 infores:hetionet CHEBI:5123 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0085583 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0036508 infores:hetionet CHEBI:6950 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151692 infores:hetionet CHEBI:7496 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0011630 infores:hetionet CHEBI:50648 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0233762 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0032961 infores:hetionet CHEBI:5856 biolink:causes NCIT:C50599 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0700363 infores:hetionet CHEBI:5138 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018524 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0008035 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0852733 infores:hetionet CAID:CA396467508 biolink:causes MONDO:0007648 infores:clingen CAID:CA396467508 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM4, PM1, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1942G>T p.(Glu648Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396467508/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:8461 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0235063 infores:hetionet NCBIGene:27235 biolink:causes MONDO:0011829 infores:monarchinitiative not_provided not_provided HGNC:25223 MONDO:0011829 uuid:57ac8302-09ba-41c0-90be-c941fadc4bd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0002453 infores:hetionet NCBIGene:6559 biolink:causes MONDO:0009904 infores:monarchinitiative not_provided not_provided HGNC:10912 MONDO:0009904 uuid:481cdc3f-edd1-45fc-ba63-e5b161d016c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0235710 infores:hetionet CHEBI:3223 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013144 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0027765 infores:hetionet CHEBI:31644 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0542571 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0007787 infores:hetionet CHEBI:473990 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0275524 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1261167 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1261167 infores:hetionet CHEBI:94501 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0687713 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0151730 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0151730 infores:hetionet CAID:CA213892 biolink:causes MONDO:0015967 infores:clingen CAID:CA213892 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP4, PP3, BP4, PS4 The c.1097C>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to arginine at codon 366 (p.(Pro366Arg)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.222, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to the age of diagnosis over 35 (internal lab contributors). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors). In summary, c.1097C>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213892/MONDO:0015967/085 2024-12-06 2024-12-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9566 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0392156 infores:hetionet CL:0000138 biolink:causes MONDO:0008977 infores:ubergraph knowledge_assertion manual_agent CL:0000138 MONDO:0008977 CHEBI:4702 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0948089 infores:hetionet CHEBI:100147 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0014544 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0699893 infores:hetionet CHEBI:231425 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0032617 infores:hetionet CHEBI:9352 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0023530 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0007269 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0007269 uuid:327d6ecd-44ad-40b2-87ff-94a343996dab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0031350 infores:hetionet CHEBI:188986 biolink:causes MONDO:0015288 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0019357 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020456 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0085096 infores:hetionet CHEBI:7915 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0404521 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0853149 infores:hetionet CHEBI:3534 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0011991 infores:hetionet UMLS:C0120107 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0004604 infores:hetionet CAID:CA343772370 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772370 MONDO:0013144 PMID: Pathogenic PS4, PP1_Moderate, PS3_Supporting, PP3, PP4, PM2_Supporting PM5 The c.1315C>A (p.Pro439Thr) variant is reported at an MAF of (FAF not available), 1/68048 alleles in the non-Finnish European population in gnomAD v3.1.1 and meets criteria for PM2_Supporting (threshold <0.00002). It has a REVEL score of 0.88 and meets criteria for PP3. Several probands can be counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling, meeting PP4 and PS4. Four segregations are counted across two families meeting criteria for PP1_Moderate. Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID: 18480576 revealed decrease in AT secretion, meeting criteria for PS3_Supporting. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Moderate, PP3, PP4, PM2_Supporting, PS3_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772370/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47898 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0005940 infores:hetionet CHEBI:3215 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0024902 infores:hetionet NCBIGene:1296 biolink:causes MONDO:0007637 infores:monarchinitiative not_provided not_provided HGNC:2216 MONDO:0007637 uuid:e84cc0ed-c20d-487d-b2df-ece90e287049 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C1956346 infores:hetionet CHEBI:3647 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0235270 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0403632 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011616 infores:hetionet CHEBI:142290 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013447 infores:hetionet CAID:CA1619868 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619868 MONDO:0800472 PMID:17363580 Pathogenic PM3_Very Strong, PM2_Supporting, PP1_Strong, PVS1 PP3, BA1, BP4, PM4, PM1, PM5, PS3, PS1, PS2, BS1, BS4, BP7 The c.1064_1076del variant in CYP1B1 is a deletion of a 13 consecutive nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 69 of the frameshift (p.Arg355HisfsTer69). The highest minor allele frequency of this variant was in the European (Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0003337 (21 alleles out of 62,940), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This frameshift variant was not predicted to undergo NMD but removes the haem-binding domain (PVS1 met). PS3_Supporting was not applied as the assay reported in PMID:17363580 did not meet the OddsPath threshold (> 2.1). ≥3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 27777502, 25836661), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in 4 individuals with a CYP1B1-related phenotype. These individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) (PMIDs: 21815720, 38990107, 27777502, 25836661). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 21 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3_Very-strong, PP1_Strong, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619868/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8378 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0085932 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0038661 infores:hetionet CHEBI:68647 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0017160 infores:hetionet CHEBI:10023 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018524 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020517 infores:hetionet CHEBI:8863 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0744727 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0009319 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1697542 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1697542 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0010709 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0003864 infores:hetionet CAID:CA8603528 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603528 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting PP3, BP4 The NM_000419.5:c.188G>A variant in ITGA2B is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 63 (Arg63Lys). At least one patient (1yo female proband from Morocco in PMID:12871379) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% (threshold: <25%), as measured by flow cytometry and Western blot. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong, PMID: 12871379). This variant has been detected in homozygosity in at least 1 proband with Glanzmann thrombasthenia. Parents were heterozygous. (0.5pts, PMID: 12871379). Total points: 0.5 (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.000002542 (3/1180026alleles) in the non-Finnish European population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Strong, PM2_Supporting, PM3_Supporting. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603528/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:27834 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0013362 infores:hetionet CHEBI:75275 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0027540 infores:hetionet CAID:CA512318686 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318686 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.648C>G (p.Pro216=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-2.76) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318686/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0162285 infores:hetionet CAID:CA2582343067 biolink:causes MONDO:0700270 infores:clingen CAID:CA2582343067 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PP3 PVS1 The c.7308-14T>G variant in ATM is an intronic variant which is located in intron 49. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183, 30713859). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000001316 in the European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (≤.00001) for PM2_Supporting, meeting this criterion. The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor gain and 0.79 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 49 of ATM. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Strong, PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582343067/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135930 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0040264 infores:hetionet NCBIGene:1374 biolink:causes MONDO:0009705 infores:monarchinitiative not_provided not_provided HGNC:2328 MONDO:0009705 uuid:5d77f56d-5fac-444a-9d75-c250d979b296 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10558 biolink:causes MONDO:0859529 infores:monarchinitiative not_provided not_provided HGNC:11277 MONDO:0859529 uuid:7f55a368-45b1-460c-b924-65cb43ef97db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0013604 infores:hetionet CHEBI:27690 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0151686 infores:hetionet CHEBI:83527 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0018524 infores:hetionet CHEBI:52010 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C1443060 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0405106 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0405106 infores:hetionet CHEBI:68478 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017672 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011991 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0333641 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013395 infores:hetionet CHEBI:46295 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C3263723 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853760 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0031350 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011991 infores:hetionet NCBIGene:145645 biolink:causes MONDO:0030492 infores:monarchinitiative not_provided not_provided HGNC:28520 MONDO:0030492 uuid:220300d8-a2d0-4c96-b8b6-f89ba073664d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7640 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0278134 infores:hetionet CAID:CA013076 biolink:causes MONDO:0005835 infores:clingen CAID:CA013076 MONDO:0005835 PMID:31965077 Likely Pathogenic PP4, PM2_Supporting, PS3 PP3 The MSH6 variant c.3485_3487del is predicted to cause the deletion of alanine residue at codon 1162,p.(Ala1162del). It is absent in gnomAD v2.1.1 non-cancer dataset and gnomAD v4.1. Functional defect was demonstrated by CIMRA assay (functional Odds for Pathogenicity >18.7). It was identified in an individual affected by colon cancer showing MSH6 loss (LOVD). Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA013076/MONDO:0005835/138 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28177 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0027769 infores:hetionet CHEBI:75984 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0041657 infores:hetionet CHEBI:42797 biolink:causes HP:6000087 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1282799 infores:hetionet NCBIGene:4582 biolink:causes MONDO:0020726 infores:monarchinitiative not_provided not_provided HGNC:7508 MONDO:0020726 uuid:a9011ad7-f494-472a-be6d-6afec963ab60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C2830004 infores:hetionet CHEBI:5128 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0027497 infores:hetionet CHEBI:17303 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0004093 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0574067 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003811 infores:hetionet CHEBI:63577 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0000729 infores:hetionet CHEBI:35778 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0423153 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0006663 infores:hetionet CHEBI:8346 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0221150 infores:hetionet UMLS:C1872203 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151904 infores:hetionet CHEBI:31644 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0023218 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0152128 infores:hetionet CHEBI:478164 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0009676 infores:hetionet CAID:CA023683 biolink:causes MONDO:0007750 infores:clingen CAID:CA023683 MONDO:0007750 PMID: Pathogenic PS4, PS3, PP1_Moderate, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS3, BS4, BS1, PM5, PM1, PM4, PM3, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PP1_Moderate, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PS3 - Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met.PS4 - Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs.PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs.PM2 - PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1).PP3 - REVEL = 0.892. PP4 - Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023683/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0075030 biolink:causes GO:0075016 infores:ubergraph knowledge_assertion manual_agent GO:0075030 GO:0075016 CHEBI:75984 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0036572 infores:hetionet CHEBI:9649 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0242528 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0011053 infores:hetionet CHEBI:17347 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0005001 infores:hetionet CAID:CA410206910 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206910 MONDO:0011071 PMID:30990344 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS3, BS1, BS4, BP7, BP5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001001890.2:c.598G>T (p.Glu200Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 30990344). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206910/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:6473 biolink:causes MONDO:0010367 infores:monarchinitiative not_provided not_provided HGNC:10853 MONDO:0010367 uuid:11dab70e-a99c-46b9-a628-c2f05adba83f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0039231 infores:hetionet CAID:CA10604426 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604426 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PP1, PM2_Supporting The NM_003494.4: c.4497del p.(Phe1499LeufsTer4) variant in DYSF, which is also known as NM_001130987.2: c.4614del p.(Phe1538LeufsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 41/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). In the literature, this variant has also been described as c.4870delT. This variant has been detected in at least eight unrelated individuals with limb girdle muscular dystrophy (PMID: 23243261, 12796534, 17070050, 27647186, 26088049, 17614318). Among these individuals, it was identified in a homozygous state in three patients (1.0 pts, PMID: 26088049, 17614318, 12796534) and in trans with a pathogenic variant in at least one patient (c.2643+1G>A, 1.0 pt, PMID: 23243261) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 27647186, 17070050). The variant was also reported to co-segregate with the disease in three affected family members from one family (PMID: 17614318) (PP1, capped with PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604426/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2830004 infores:hetionet CHEBI:6846 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0009676 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020615 infores:hetionet CHEBI:17630 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0024523 infores:hetionet CHEBI:4514 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0030554 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0020649 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0854530 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0854530 infores:hetionet CHEBI:7459 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0236075 infores:hetionet CHEBI:45599 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0344232 infores:hetionet CHEBI:6888 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0700590 infores:hetionet CHEBI:135342 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C2830004 infores:hetionet CAID:CA017544 biolink:causes MONDO:0007947 infores:clingen CAID:CA017544 MONDO:0007947 PMID: Pathogenic PVS1, PM6, PM2_Supporting The NM_00138 c.8080C>T, is a nonsense variant in FBN1 which is predicted to result in a premature stop codon at position 2694, and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with thoracic aortic aneurysm, ectopia lentis, and a systemic score of 10, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). The variant has been identified as a de novo occurrence, without confirmation of paternity and maternity, in one individual with highly specific phenotype and in one individual with a phenotype consistent with the gene but not highly specific (Internal data- Bichat) (PM6). This variant was also found in a proband with ectopia lentis, thoraic aortic aneurysm, and skeletal features, and was found to segregate with the disease in 1 affected family member (internal data, John Hopkins). This variant has been reported 9 times in ClinVaras pathogenic (Variation ID: 163461). At least 20 other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (PMID 17680538, 19293843, 19839986, 24199744, 26787436, 14695540, 18435798, 26133393, internal data, PS4). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4, PM6, PM2_Sup, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA017544/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4046 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0011991 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042514 infores:hetionet CHEBI:8404 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0344232 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0234458 infores:hetionet CHEBI:2038 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009782 infores:hetionet CAID:CA289173 biolink:causes MONDO:0015967 infores:clingen CAID:CA289173 MONDO:0015967 PMID: Benign BA1 PS4, PS3 The c.1522G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 508 (p.(Glu508Lys)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.002884, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). This variant has been found in many unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PMID: 24915262); however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting. Functional studies demonstrated the p.Glu508Lys protein has transactivation activity between 40-80%, which is less severe than typical HNF1A-MODY-causing variants (below 40%) (PMID: 32910913, 27899486). In summary, this variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: BA1 (specification version 1.2, approved 6/5/21). However, this variant is an established risk allele for type 2 diabetes in individuals of Mexican ancestry (PMID: 24915262). These individuals do not respond to treatment with sulfonylureas, unlike individuals with HNF1A-MODY (PMID: 29844095). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA289173/MONDO:0015967/017 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:38562 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0022408 infores:hetionet CHEBI:136040 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0033893 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151613 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042133 infores:hetionet CHEBI:18248 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0003811 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023895 infores:hetionet NCBIGene:1410 biolink:causes MONDO:0013472 infores:monarchinitiative not_provided not_provided HGNC:2389 MONDO:0013472 uuid:498d010a-8127-40ed-afc0-10f24b99057e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9566 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0027849 infores:hetionet GO:0045191 biolink:causes GO:0002381 infores:ubergraph knowledge_assertion manual_agent GO:0045191 GO:0002381 CHEBI:6073 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0033774 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0009241 infores:hetionet CAID:CA355962511 biolink:causes MONDO:0001586 infores:clingen CAID:CA355962511 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5(IDUA):c.895G>T (p.Glu299Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 2 patients with this variant had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PMIDs: 16438163, 27146977) (PP4). Of those individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.223G>A (p.Ala75Thr) (ClinVar Variation ID: 222993); the phase was not confirmed (0.5 points; PMID: 27146977). One individual was homozygous for the variant (ClinVar SCV002562742.2) (0.5 points). Total 1 point (PM3). Another patient was compound heterozygous for the variant and c.164dup (PMID: 16438163). The allelic data for this patient will be used to support the classification of c.164dup and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000023 (2/86636 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 987878). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PP4, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 16, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355962511/MONDO:0001586/091 2025-06-16 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36795 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0003811 infores:hetionet CHEBI:50275 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014724 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0034150 infores:hetionet CHEBI:194135 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0037299 infores:hetionet CHEBI:10119 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151610 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0858217 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0858217 infores:hetionet NCBIGene:3717 biolink:causes MONDO:0007572 infores:monarchinitiative not_provided not_provided HGNC:6192 MONDO:0007572 uuid:3ede2ff2-32d6-4e81-9bf9-b37e224874ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0011701 biolink:causes UMLS:C1168188 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C1168188 infores:hetionet CHEBI:9570 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0852911 infores:hetionet NCBIGene:29775 biolink:causes MONDO:0030484 infores:monarchinitiative not_provided not_provided HGNC:16422 MONDO:0030484 uuid:2b9dec36-5643-4dbe-9bb4-2eb3d7157b43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA024295 biolink:causes MONDO:0007783 infores:clingen CAID:CA024295 MONDO:0007783 PMID: Uncertain Significance PS3_Moderate, PM1 PP3, PS4, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 533 of the RYR1 protein, p.(Arg533His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00044, a frequency consistent with pathogenicity for MHS. This variant has been reported in 3 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257, PMID:16732084). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024295/MONDO:0007783/012 2023-04-10 2023-04-10 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3312 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0011206 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0041912 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002444 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025193 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2718128 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0021845 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0235069 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0235069 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0020649 infores:hetionet CHEBI:4887 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0027497 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0232191 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0232191 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0858814 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0858814 infores:hetionet CHEBI:3757 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0013144 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0002453 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0022667 infores:hetionet CHEBI:7903 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020621 infores:hetionet CHEBI:4027 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0234909 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235639 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0520459 infores:hetionet CAID:CA10385740 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385740 MONDO:0100437 PMID: Likely Benign BP4, BS1 BA1 NM_001034853.2(RPGR):c.30T>A (p.Asp10Glu) is a missense variant causing the substitution of aspartic acid by glutamic acid at amino acid 10. This variant is present in gnomAD v4.1.0 at a frequency of 0.00004056 among hemizygous individuals, with 16 variant alleles / 394,487 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.277, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1 and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385740/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:9763 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0231528 infores:hetionet CHEBI:171719 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0016382 infores:hetionet CHEBI:84500 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0019825 infores:hetionet CHEBI:6887 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038325 infores:hetionet CHEBI:71417 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0009676 infores:hetionet CHEBI:68554 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0151740 infores:hetionet CHEBI:182080 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0235063 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0232197 infores:hetionet CHEBI:3219 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0003862 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0013395 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0267516 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0267516 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0349506 infores:hetionet CHEBI:64019 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0917801 infores:hetionet CHEBI:8863 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0340865 infores:hetionet CHEBI:15765 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0020580 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0426576 infores:hetionet CHEBI:6690 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0151611 infores:hetionet CHEBI:17474 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0340865 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0032326 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022573 infores:hetionet CHEBI:119915 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017181 infores:hetionet CHEBI:48538 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0151735 infores:hetionet NCBIGene:1261 biolink:causes MONDO:0009003 infores:monarchinitiative not_provided not_provided HGNC:2150 MONDO:0009003 uuid:36a848a6-abc2-4d64-aba7-666e149dab1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017181 infores:hetionet CHEBI:17630 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0042571 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0855242 infores:hetionet CHEBI:66919 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0151905 infores:hetionet CHEBI:68606 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0021368 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018802 infores:hetionet CHEBI:3215 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0232462 infores:hetionet CHEBI:6717 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0235063 infores:hetionet CHEBI:17698 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C1443060 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0042571 infores:hetionet CHEBI:6062 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C3665386 infores:hetionet CHEBI:7025 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0038367 infores:hetionet CHEBI:135193 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C2242996 infores:hetionet CHEBI:5790 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085633 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0021775 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0009763 infores:hetionet CHEBI:8232 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0013491 infores:hetionet CHEBI:4659 biolink:causes MONDO:0021718 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0032541 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0002170 infores:hetionet NCBIGene:6834 biolink:causes MONDO:0014733 infores:monarchinitiative not_provided not_provided HGNC:11474 MONDO:0014733 uuid:ed11eaab-0ada-4c3e-8ded-80b4b28e7574 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0003467 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0007642 infores:hetionet CAID:CA10650411 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650411 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*3588G>C is a UTR variant is which completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650411/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6413 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0027651 infores:hetionet CHEBI:3752 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0042907 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007222 infores:hetionet CHEBI:41774 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0456909 infores:hetionet CHEBI:64312 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151766 infores:hetionet CAID:CA003895 biolink:causes MONDO:0011450 infores:clingen CAID:CA003895 MONDO:0011450 PMID: Benign BP7_Strong, BP4, BP5_Strong PM2, BA1, BS1 The c.81-11del variant is an intronic variant occurring in intron 2 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA1 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 21735045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00131 (based on Co-occurrence LR=0.0406; Family History LR=0.0321), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; (PMID: 17924331)).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, BP7_Strong (RNA), BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003895/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true UniProtKB:A9UF02 biolink:causes MONDO:0006115 infores:drugmechdb knowledge_assertion manual_agent UniProtKB:A9UF02 MESH:D001752 DB06616_MESH_D001752_1 CHEBI:8024 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030196 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235901 infores:hetionet CHEBI:8764 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034155 infores:hetionet CHEBI:10650 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085583 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0233494 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151505 infores:hetionet CHEBI:28830 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0015967 infores:hetionet CAID:CA120571 biolink:causes MONDO:0044970 infores:clingen CAID:CA120571 MONDO:0044970 PMID: Uncertain Significance PP1, PS3_Supporting PP3, BP4, PS4, PM2 The m.4284G>A variant in MT-TI has been reported in one family to date (PMID: 11782991). The proband had isolated spastic paraparesis and normal muscle biopsy including normal respiratory chain enzyme activities. The variant was present at 55% muscle, 50% in hair, 40% in urine, 30% in skin, 20% in buccal, and 20% in blood. His mother had truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, and diabetes. Her brain MRI showed cortical and subcortical diffuse atrophy and muscle biopsy showed reduced activities of complex I and complex IV. The variant was present at 80% in muscle, 20% in urine, and 30% in blood. The proband had one brother with a multisystem progressive disorder who ultimately died of cardiomyopathy. His brain imaging showed marked cortical and subcortical atrophy. His muscle biopsy showed reductions in complex I, complex IV, and complex V. The variant was present at 90% in muscle. As this is the only family reported to date, PS4 could not be applied. The proband had another brother who was healthy and had undetectable levels of the variant in blood and urine. Therefore, this variant segregated with disease in multiple affected family members and a healthy family member had undetectable levels of the variant (PP1; PMID: 11782991). In silico predictions are inconsistent as MitoTIP suggests this variant is benign (35th percentile) and HmtVAR predicts it to be deleterious (0.55). This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.003%; Helix's 195,983 sequences: AF=0.001%; and gnomAD v3.1.2: AF=0.007% as this is homoplasmic in four individuals and heteroplasmic in two individual). Given the frequency of this variant, it does not meet PM2 criterion. Cybrid studies showed that the homoplasmic mutant clones had decreases in COX activity and oxygen consumption rates compared to controls (PS3_supporting, PMID: 11782991). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120571/MONDO:0044970/015 2023-11-28 2024-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:180905 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0522055 infores:hetionet CHEBI:5002 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0012833 infores:hetionet CHEBI:4469 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0002994 infores:hetionet CHEBI:9570 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0040264 infores:hetionet CHEBI:68478 biolink:causes HP:0004872 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0267716 infores:hetionet CHEBI:27666 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C1262013 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0497247 infores:hetionet CHEBI:77260 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013378 infores:hetionet CAID:CA915941064 biolink:causes MONDO:0700272 infores:clingen CAID:CA915941064 MONDO:0700272 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting The c.3512del (p.Leu1171CysfsTer20) variant in PALB2 is a frameshift variant predicted to alter a region that is critical to protein function. The C-terminal end of the WD40 domain is substituted by an alternative extended sequence. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1_Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA915941064/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75998 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151723 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0852932 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0852932 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042133 infores:hetionet CHEBI:5001 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0009763 infores:hetionet CHEBI:3441 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011071 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0037199 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1384353 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0151763 infores:hetionet CHEBI:5778 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151662 infores:hetionet CHEBI:84883 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0497156 infores:hetionet CHEBI:8884 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0019521 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027932 infores:hetionet CHEBI:2682 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0428977 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0162429 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0011849 infores:hetionet CHEBI:31236 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039240 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0518015 infores:hetionet CHEBI:16586 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0013604 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004096 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0853760 infores:hetionet CHEBI:75984 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0033774 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0427008 infores:hetionet CHEBI:47780 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0026826 infores:hetionet CHEBI:5118 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0037299 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0004604 infores:hetionet CHEBI:3032 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0020517 infores:hetionet CHEBI:6797 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0023530 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0006145 infores:hetionet CHEBI:2673 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0160390 infores:hetionet CHEBI:7824 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0392525 infores:hetionet CHEBI:63631 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020625 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0267596 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0852566 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0852566 infores:hetionet CHEBI:52010 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0027813 infores:hetionet CHEBI:2618 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0020672 infores:hetionet CHEBI:17303 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0344232 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0019348 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0024355 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D012141 DB01150_MESH_D012141_1 GO:0098828 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0098828 GO:0007268 CHEBI:63631 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0012569 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0013395 infores:hetionet CHEBI:75988 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0042963 infores:hetionet CHEBI:3996 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0001807 infores:hetionet CHEBI:31624 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C1142412 infores:hetionet CHEBI:2569 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0039231 infores:hetionet CHEBI:142290 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0231528 infores:hetionet CHEBI:52717 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0010200 infores:hetionet CHEBI:28901 biolink:causes HP:0003149 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0948643 infores:hetionet CHEBI:5558 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0015672 infores:hetionet CHEBI:46557 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0085593 infores:hetionet CHEBI:50173 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020580 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017152 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0152029 infores:hetionet CHEBI:119486 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235198 infores:hetionet CHEBI:50885 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0040046 infores:hetionet CHEBI:6741 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0232461 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C2711227 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0152025 infores:hetionet CHEBI:28001 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0340865 infores:hetionet GO:1901210 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:1901210 GO:0003007 CHEBI:31401 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0013456 infores:hetionet CHEBI:8874 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151936 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0556385 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0556385 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0018799 infores:hetionet CHEBI:9907 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C1458155 infores:hetionet CHEBI:94449 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0027497 infores:hetionet CHEBI:7465 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018843 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0001824 infores:hetionet CHEBI:10125 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011253 infores:hetionet CHEBI:4717 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0085612 infores:hetionet CHEBI:6633 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0231835 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018666 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0206624 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0475858 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020437 infores:hetionet CHEBI:3219 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151827 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020538 infores:hetionet NCBIGene:5002 biolink:causes MONDO:0009993 infores:monarchinitiative not_provided not_provided HGNC:10964 MONDO:0009993 uuid:cdb3cdc7-3b80-4466-92fe-13449b3117fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes UMLS:C1141938 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1141938 infores:hetionet CHEBI:83804 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235309 infores:hetionet CHEBI:47898 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0542571 infores:hetionet CHEBI:47781 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0033774 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0001824 infores:hetionet CHEBI:585948 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0043352 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002871 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0034063 infores:hetionet CHEBI:142290 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0043352 infores:hetionet GO:1905518 biolink:causes GO:0007416 infores:ubergraph knowledge_assertion manual_agent GO:1905518 GO:0007416 CHEBI:4858 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C1306341 infores:hetionet CHEBI:82866 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0241057 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0029445 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0232452 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0232452 infores:hetionet CHEBI:55346 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151905 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037822 infores:hetionet CHEBI:8802 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018681 infores:hetionet NCBITaxon:779 biolink:causes MONDO:0006780 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:779 MONDO:0006780 CHEBI:16714 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0232462 infores:hetionet CHEBI:7476 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014743 infores:hetionet CAID:CA2695233277 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695233277 MONDO:0100437 PMID:33467000 Pathogenic PVS1, PP4, PM2_Supporting PP3, PP1, PS3 NM_001034853.2(RPGR):c.154+3_154+6del is a non-coding variant that deletes four nucleotides from intron 2. The splicing impact predictor SpliceAI gives delta scores of 0.80 for donor loss and 0.31 for acceptor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. HEK293T cells transfected with a minigene construct harboring the variant produced a transcript of smaller size relative to the wild-type control, confirming the splicing defect (PMID: 33467000). These findings were not used to meet PP3 and PS3_Supporting but rather combined as evidence of null impact on RPGR (PVS1, PMID: 37352859). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), childhood onset (1 pt), night blindness (0.5 pt), photophobia (0.5 pt), color vision defect (0.5), myopia (0.5 pt), visual field constriction (0.5 pt), and pigmentary retinopathy (0.5 pt), which together are specific for RPGR-related retinopathy (6 points, PMID: 33467000, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695233277/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:31236 biolink:causes UMLS:C0151538 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151538 infores:hetionet CHEBI:17347 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0000729 infores:hetionet CHEBI:7492 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0011991 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042571 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033860 infores:hetionet GO:1903072 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:1903072 GO:0023052 CHEBI:4702 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0085636 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002453 infores:hetionet CHEBI:83804 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0002994 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004936 infores:hetionet CHEBI:51450 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0014236 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0032285 infores:hetionet CHEBI:31980 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0085631 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0158281 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0158281 infores:hetionet CHEBI:63621 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0028734 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0042963 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0234458 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0878544 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0036974 infores:hetionet NCBIGene:59 biolink:causes MONDO:0012730 infores:monarchinitiative not_provided not_provided HGNC:130 MONDO:0012730 uuid:62686c67-8bda-4543-ab17-62f067ee6f9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:11234 biolink:causes MONDO:0013557 infores:monarchinitiative not_provided not_provided HGNC:17022 MONDO:0013557 uuid:e9fb28ec-5789-4dd1-aff5-8698faa9eb69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0549385 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0008489 infores:hetionet CHEBI:27899 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0011603 infores:hetionet CHEBI:7494 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0152198 infores:hetionet CHEBI:51364 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151889 infores:hetionet CHEBI:5098 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C2363731 infores:hetionet GO:2000004 biolink:causes GO:0003338 infores:ubergraph knowledge_assertion manual_agent GO:2000004 GO:0003338 CAID:CA255148 biolink:causes MONDO:0010602 infores:clingen CAID:CA255148 MONDO:0010602 PMID: Pathogenic PVS1, PM2_Supporting, PS4 The NM_000132.3(F8):c.4121_4124del (p.Ile1374fs) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay, which meets PVS1. It is reported in at least 7 patients with moderate or severe hemophilia A in the literature reviewed (PMID: 22103590, 20102490, 8307558, 9829908, 17498081, 20028422) meeting PS4_Very strong. There are additional probands with the variant reported in the EAHAD database, recorded from the literature. The variant is absent from gnomAD v2.1.1 and v3, which meets PM2_Supporting. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1, PS4, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255148/MONDO:0010602/071 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:8060 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0231218 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038358 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0037199 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0541799 infores:hetionet CHEBI:28925 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0243065 infores:hetionet CAID:CA8328593 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328593 MONDO:0100438 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Strong, PP3_Moderate, PS3_Supporting NM_014336.5(AIPL1):c.211G>T (p.Val71Phe) is a missense variant resulting in replacement of valine by phenylalanine at amino acid p.71. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000001239, with 2 / 1,614,150 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 15024725, PMID: 20079931, PMID: 20702822, PMID: 26306921). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.216G>A (p.Trp72Ter) variant likely confirmed in trans due to their physical proximity (1 point, PMID: 20702822), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). The variant has been reported in an additional proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.730GAG[1] (p.Glu245del) variant suspected in trans, which has not yet been classified by the ClinGen LCA/eoRD VCEP. At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) received before age 5 years (1 pt), severely reduced central visual acuity (1 pt), kinetic visual field extent (V-4e) undetectable (1 pt), nystagmus (1 pt), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 6 points, PMID: 20702822, PP4). The computational predictor REVEL gives a score of 0.780, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.02 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Co-expression of the variant with PDE6C and Pγ resulted in less than 10% of cGMP hydrolysis activity relative to the wild-type AIPL1 control (PMID: 27268253), while X-ray crystal structures of the wild-type and variant AIPL1 identified an inability of the variant to bind prenyl groups, which are relevant to AIPL1 interaction with the isoprenylated C-terminus of PDE6 (PMID: 28973376)(PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP3_Moderate, PS3_supporting and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328593/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0030232 infores:hetionet CHEBI:3723 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234535 infores:hetionet CHEBI:68558 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0553692 infores:hetionet CHEBI:8364 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0013604 infores:hetionet NCBIGene:146167 biolink:causes MONDO:0012216 infores:monarchinitiative not_provided not_provided HGNC:32434 MONDO:0012216 uuid:02ab04a2-0ee2-42d3-897c-976a1a16add2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7444 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0042963 infores:hetionet CHEBI:65173 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0008350 infores:hetionet CHEBI:72297 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0013491 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0021053 infores:hetionet CHEBI:50841 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0085623 infores:hetionet CAID:CA355961907 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961907 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.606C>A (p.Tyr202Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 6 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, all 3 were compound heterozygous for the variant and a pathogenic variant (c.979G>C p.A327P; c.208C>T p.Q70X; c.1205G>A p.W402X) and none of those were confirmed in trans (PMIDs: 27392569, 22976768, clinical lab; PM3). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex and arthropathy (PMID: 27392569; PP4). The highest population minor allele frequency in gnomAD v4.0 is 0.000005089 (6/1179008 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 552333, 2 star review status) with 5 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 6, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961907/MONDO:0001586/091 2025-01-06 2025-03-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8874 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011334 infores:hetionet CHEBI:136040 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020458 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020456 infores:hetionet CAID:CA410205737 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205737 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS4, PS1, PS2, BA1, BP3, BP2, BP1, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.74T>C (p.Met25Thr) is a missense variant which is absent from gnomAD v2 and v3 (PM2_supporting). However, the highest population minor allele frequency in gnomAD v4.1 is 0.0000008710 (1/1,148,106 alleles) in the non-Finnish European population, which means PM2_supporting is not met. The variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.24, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205737/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68647 biolink:causes UMLS:C0016169 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0016169 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0456909 infores:hetionet CHEBI:6067 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0239340 infores:hetionet CHEBI:8435 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0033117 infores:hetionet CHEBI:5778 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0476273 infores:hetionet NCBIGene:10518 biolink:causes MONDO:0012273 infores:monarchinitiative not_provided not_provided HGNC:24579 MONDO:0012273 uuid:85a003a3-b482-49cd-9d36-b486a9a91ae2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0021368 infores:hetionet CHEBI:94440 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0235198 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0743516 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0743516 infores:hetionet CHEBI:78543 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0011175 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0005741 infores:hetionet CHEBI:7640 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0042510 infores:hetionet GO:0045477 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:0045477 GO:0048477 CHEBI:8764 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0015230 infores:hetionet CHEBI:61033 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0344232 infores:hetionet CHEBI:94385 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151746 infores:hetionet CHEBI:47657 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0003467 infores:hetionet CHEBI:8774 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0026821 infores:hetionet CHEBI:253342 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0015672 infores:hetionet CHEBI:135342 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C2242737 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005770 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019342 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0855242 infores:hetionet CHEBI:10127 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0003578 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0035455 infores:hetionet CHEBI:7575 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0011991 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0233414 infores:hetionet CHEBI:6456 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0428977 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0858259 infores:hetionet CHEBI:499361 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0041969 infores:hetionet CHEBI:9763 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0086439 infores:hetionet CHEBI:94609 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0038999 infores:hetionet CAID:CA199497 biolink:causes MONDO:0010726 infores:clingen CAID:CA199497 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BS1 The highest population minor allele frequency of the c.-146_-138dup variant in MECP2 (NM_004992.4), also known as c.15_23dup (p.Ala6_Ala8dup) in transcript NM_001110792.2, in gnomAD v4.1 is 0.00018 in the Admixed American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The c.-146_-138dup variant is observed in at least 1 unaffected individual (Internal database - Ambry) (BS2_Supporting). In summary, the c.-146_-138dup variant in MECP2 (NM_004992.4) is classified as likely benign based on the ACMG/AMP criteria (BS1, BS2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199497/MONDO:0010726/036 2024-06-25 2024-10-25 X-linked inheritance HP:0001417 Contradicts true CHEBI:51860 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1325847 infores:hetionet CHEBI:16469 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0015403 infores:hetionet CHEBI:8874 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020625 infores:hetionet CHEBI:474180 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0542571 infores:hetionet CHEBI:3504 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0240671 infores:hetionet CHEBI:63791 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038325 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0006145 infores:hetionet CAID:CA402996857 biolink:causes MONDO:0012999 infores:clingen CAID:CA402996857 MONDO:0012999 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PM3, PP3_Moderate PM5 The NM_000156.6:c.233T>A variant in GAMT is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 78 (p.Val78Glu). This variant has been detected in two siblings with GAMT deficiency from one family (PMID: 23660394, PMID: 24268530, PMID: 24071436). The proband showed elevated guanidinoacetate and low creatine in plasma, elevated urine guanidinoacetate, and low creatine peak on brain MRS (PMID: 24071436) (PP4_Strong). These individuals were reported to be compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.299_311dup13 (p.Arg105GfsTer26) (ClinVar Variation ID: 8302); the variants were confirmed to be in trans (PMID: 23660394, PMID: 24268530, PMID: 24071436) (1pt) (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000016 (2/1178172 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.794 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PM3, PP3, PM2_Supporting, (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402996857/MONDO:0012999/026 2025-10-15 2025-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9649 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0016382 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0040034 infores:hetionet CHEBI:35553 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0004093 infores:hetionet CHEBI:36704 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0033687 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0149931 infores:hetionet CHEBI:6437 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0151786 infores:hetionet CHEBI:5384 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0003811 infores:hetionet CHEBI:5959 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0043144 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1956346 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0032285 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0521490 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0392386 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0005940 infores:hetionet CHEBI:3387 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0023218 infores:hetionet CHEBI:100246 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0038325 infores:hetionet CHEBI:44423 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0232462 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017574 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0011609 infores:hetionet CHEBI:64312 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0855329 infores:hetionet CHEBI:15428 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0035455 infores:hetionet CHEBI:41977 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0392171 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0034063 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020569 infores:hetionet CHEBI:41423 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0085605 infores:hetionet CAID:CA2577483681 biolink:causes MONDO:0011071 infores:clingen CAID:CA2577483681 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-13C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.36) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2577483681/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63598 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038663 infores:hetionet CHEBI:47780 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151908 infores:hetionet CHEBI:4469 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0038325 infores:hetionet CHEBI:3181 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0021177 infores:hetionet CAID:CA198776 biolink:causes MONDO:0009290 infores:clingen CAID:CA198776 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA198776/MONDO:0009290/010 2020-01-23 2020-05-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:51450 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018681 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0854679 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0854679 infores:hetionet CAID:CA891843538 biolink:causes MONDO:0009861 infores:clingen CAID:CA891843538 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4 PM3 The c.686dup (p.Asp229fs) variant in PAH is a frameshift variant predicted to cause termination at amino acid 283 resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected as homozygous in a patient with classic PKU (PMID: 28915855). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP4, PVS1 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843538/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9654 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0018524 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0227791 infores:hetionet CHEBI:8863 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0004093 infores:hetionet CAID:CA116586 biolink:causes MONDO:0009290 infores:clingen CAID:CA116586 MONDO:0009290 PMID: Benign BA1, BP4 The NM_000152.5:c.271G>A missense variant in GAA (p.Asp91Asn) has a highest population minor allele frequency in gnomAD v2.1.1 of 0.03291 (4183/127102 alleles; 70 homozygotes) in the European non-Finnish population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.396 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. In addition, the computational splice predictors SpliceAI and varSEAK predict that the variant has no impact on splicing (BP4). This variant is frequently described as a “pseudodeficiency” variant in the literature. It has been identified as the amino acid substitution responsible for the GAA*2 alloenzyme (also known as GAA2) (PMID: 2203258). GAA*2 was identified by its faster migration on starch gel electrophoresis compared to the GAA*1 alloenzyme (PMID: 2688539). In addition, compared to GAA*1, GAA*2 has a 10 fold higher Km for glycogen, but similar Km for maltose and 4-MUG (PMID: 2688539). No differences between the processing of GAA*2 and GAA*1 were noted on Western blot of protein from fibroblasts homozygous for either alloenzyme (PMID: 2688539). Furthermore, comparable amounts of glycogen were found in the lysosomes of the GAA*1 and GAA*2 homozygous cell lines, and there was no evidence of abnormal lysosomal glycogen storage in GAA*2 fibroblasts on electron microscopy (PMID: 2688539). When expressed in SV40-transformed GAA-deficient fibroblasts, c.271G>A (p.Asp91Asn) has similar GAA activity to wild type when 4-MUG is used as the substrate (PMID: 2203258). Studies in cells from patients show a difference in GAA activity depending on the substrate used. In cells from individuals who are homozygous, or compound heterozygous for the variant and a known pathogenic GAA variant, false positives arose when glycogen was used as the substrate in the leukocyte assay, while the expected result was obtained when 4-MUG was used as the substrate in either the leukocyte or fibroblast assays (PMID: 19387865, 33162552). Evidence from the crystal structures of native and recombinant GAA indicate that Asp91 is involved in a sugar binding site, which could explain why this variant binds carbohydrate less effectively (PMID: 29061980; https://www.biorxiv.org/content/10.1101/212837v1 ). In addition, while the computational splice site predictors SpliceAI and varSEAK predict no impact on splicing, a mini-gene assay indicated that the variant results in exon 2 exclusion in about 30% of transcripts (PMID: 31301153). As an explanation for how the biochemical features of this variant result in no clinical features, substrate concentrations are usually far below that required for saturation of the enzyme. A reduction in enzyme activity brought about by decrease in Vmax, or increase in Km, would be compensated for by an increase in substrate concentration, restoring the normal turnover rate and establishing an equilibrium substrate concentration (PMID: 2688539).In patients with Pompe disease, c.271G>A has been found in cis with other variants that have been classified as pathogenic by the ClinGen LSD VCEP, p.Cys103Gly (PMID: 16838077, 33073003) and c.877G>A (p.Gly293Arg) (PMID: 27189384).There is a ClinVar entry for this variant (Variation ID: 4020) with eight submitters classifying the variant as benign, two as likely benign, and two as “other”. In summary, based on the evidence available to date, this variant meets the criteria to be classified as benign for Pompe disease. However, it is important to note that GAA activity may be in the patient range in individuals who are homozygous for the variant, or compound heterozygous for the variant and a pathogenic GAA variant, if glycogen is used as a substrate. Careful evaluation and use of 4-MUG as the substrate is necessary to provide accurate results. Therefore, this variant is classified as “other” to ensure that an explanation for deficient enzyme activity in the context of a clinically benign variant is highlighted. GAA-specific ACMG-AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116586/MONDO:0009290/010 2023-03-03 2023-03-03 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3996 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0018681 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0525045 infores:hetionet CHEBI:8080 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0009806 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0018991 infores:hetionet CHEBI:7577 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0025222 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0034150 infores:hetionet CHEBI:168396 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003467 infores:hetionet CHEBI:18248 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0035455 infores:hetionet CHEBI:9086 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0003467 infores:hetionet CAID:CA386953128 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953128 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3 PP4 The c.137A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to threonine at codon 46 (p.(Lys46Thr)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.764, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and so PP4 cannot be applied (internal lab contributors). In summary, c.137A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953128/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17026 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0043037 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0012833 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0006277 infores:hetionet CHEBI:46295 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0041969 infores:hetionet CAID:CA16024860 biolink:causes MONDO:0021056 infores:clingen CAID:CA16024860 MONDO:0021056 PMID:24599579 Likely Pathogenic PM2_Supporting, PS4_Supporting, PVS1_Strong PS3 The c.1626G>C variant in APC is a G to non-G change at the last nucleotide of exon 13. It is predicted to cause skipping of exon 13, resulting in an in-frame deletion of an exon with sufficient supportive clinical data (r.1549_1626del) (p.A517_Q542del) (PVS1_Strong). This prediction is confirmed by RT-PCR analysis (supplanted by PVS1_Strong; PMID 24599579). This variant was detected in one proband and two other family members, the combined phenotypic point is 1 (PS4_Supporting). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1_Strong, PS4_Supporting and PM2_Supporting. (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16024860/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27504 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C1443060 infores:hetionet CHEBI:74947 biolink:causes MONDO:0020572 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0007462 infores:hetionet CHEBI:6715 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0152031 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0403632 infores:hetionet CHEBI:9137 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020621 infores:hetionet CHEBI:32315 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0917801 infores:hetionet CHEBI:7809 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0038362 infores:hetionet CHEBI:9086 biolink:causes NCIT:C123611 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0178415 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235146 infores:hetionet CHEBI:144551 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009782 infores:hetionet CHEBI:80630 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0018681 infores:hetionet CHEBI:5801 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0232462 infores:hetionet CHEBI:9907 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0011175 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0917799 infores:hetionet CHEBI:42944 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0085631 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0242073 infores:hetionet CHEBI:136040 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0236075 infores:hetionet CHEBI:8863 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0750426 infores:hetionet NCBIGene:10293 biolink:causes MONDO:0014767 infores:monarchinitiative not_provided not_provided HGNC:30764 MONDO:0014767 uuid:79584b9d-8ae9-45d8-80f7-d1a516d80f4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8623516 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623516 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.2328C>T (p.Ala776=), no individuals with Glanzmann thrombasthenia were reported with the variant. The variant was first identified by Illumina in a predisposition screen of an ostensibly healthy population. The variant has a minor allele frequency of 0.001078 (33/30614 alleles) in the South Asian population in gnomAD, which does not meet our threshold criteria for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of .2196 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623516/MONDO:0100326/011 2023-02-02 2023-02-23 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:64045 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0014130 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0003123 infores:hetionet CHEBI:31236 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C3665347 infores:hetionet CHEBI:3994 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0005758 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0852990 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0852990 infores:hetionet CAID:CA8814791 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814791 MONDO:0009290 PMID:22958975PMID:24107549PMID:22676651PMID:22958975PMID:24107549PMID:24269976PMID:29869463PMID:22676651 Pathogenic PM2, PVS1, PP4, PM3_Supporting This nonsense variant, c.118C>T (p.Arg40Ter), is expected to result in a premature termination codon, nonsense mediated decay, and absence of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the South Asian population, meeting PM2. The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975), meeting PM3_Supporting. In addition, a large family has been reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Additional cases with this variant have been reported but were not included because residual enzyme activity was not provided and therefore PP4 could not be assessed. There is a ClinVar entry for this variant (Variation ID: 426593, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814791/MONDO:0009290/010 2020-04-06 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA386966185 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966185 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PP3 PM5 The c.793T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to histidine at codon 265 (p.(Tyr265His)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). The variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Other missense variants at this residue, c.794A>G, p.(Tyr265Cys) and c.794A>C, p.(Tyr265Ser) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.793T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966185/MONDO:0015967/017 2024-10-13 2024-10-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0033771 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0005741 infores:hetionet CAID:CA410147739 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147739 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1225G>A (p.Ala409Thr) is a missense variant which has a REVEL score < 0.50 (0.03) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147739/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31413 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0855775 infores:hetionet CHEBI:8378 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C3665347 infores:hetionet CHEBI:100241 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0547030 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0017574 infores:hetionet CHEBI:29007 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C2129214 infores:hetionet CHEBI:9943 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151754 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0241863 infores:hetionet CHEBI:52172 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0026858 infores:hetionet NCBIGene:140679 biolink:causes MONDO:0958331 infores:monarchinitiative not_provided not_provided HGNC:11018 MONDO:0958331 uuid:722cd154-a0c3-47d8-b1f7-24ad2fbf1b2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:131512 biolink:causes MONDO:0019562 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0036420 infores:hetionet CHEBI:79699 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0221776 infores:hetionet CHEBI:2914 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0043251 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0032584 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0027497 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0595938 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0595938 infores:hetionet CHEBI:50122 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0268000 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0919874 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0003864 infores:hetionet CHEBI:3011 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0006277 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233414 infores:hetionet CHEBI:3696 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0231528 infores:hetionet CHEBI:50922 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003537 infores:hetionet CHEBI:9927 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0003467 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009450 infores:hetionet CHEBI:51141 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C2830004 infores:hetionet CHEBI:5130 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0019080 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0235369 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0029882 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020649 infores:hetionet CHEBI:7852 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151825 infores:hetionet CHEBI:46295 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151701 infores:hetionet CHEBI:31644 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0851578 infores:hetionet CHEBI:3423 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0009676 infores:hetionet CHEBI:15765 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0086525 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037822 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0023066 infores:hetionet CAID:CA343723939 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723939 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting, PM5 BP7, BS1, BS3, PM6, PP1, PM4, PS4, PS1, PS3, PS2, BP4, BA1 The c.1298G>A variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 433 (p.Cys433Tyr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.956, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1297T>C, p.Cys433Arg, Grantham score = 180, ClinVar ID: 7956) in the same codon, has been classified as pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1298G>A, p.Cys433Tyr variant has a higher Grantham score (= 194) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5 to apply. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM5, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723939/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63681 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0030252 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0948089 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1868855 infores:hetionet CHEBI:135736 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0024141 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0233494 infores:hetionet CAID:CA1620046 biolink:causes MONDO:0800472 infores:clingen CAID:CA1620046 MONDO:0800472 PMID:27060699 Uncertain Significance PM2_Supporting PP3, PP1, BA1, BP4, PS3, PS1, PS2, PM1, PM3, PM4, PM5, BP7, BS1, BS4, PVS1 The c.367T>C variant in CYP1B1 is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 123 (p.Phe123Leu). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1) = 0.00003363 (2 alleles out of 59474), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This missense variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1) and the REVEL score = 0.544, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699). This variant has not been identified as homozygous or compound heterozygous with another variant in CYP1B1, therefore PM3 was not applied. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1620046/MONDO:0800472/104 2025-11-19 2025-11-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:35778 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0232292 infores:hetionet CHEBI:8382 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020621 infores:hetionet CHEBI:83804 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0917801 infores:hetionet CHEBI:7824 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0026961 infores:hetionet CHEBI:8356 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0264893 infores:hetionet CAID:CA16020994 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020994 MONDO:0009861 PMID: Pathogenic PM3, PP4_Moderate, PM2, PVS1_Strong The c.1314_1315+4del6 (p.N438fs) variant is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).It is listed in ClinVar (variant ID 555797) as Likely Pathogenic by one lab. It has been reported in the published literature in one case (PMID: 23514811) with abnormal blood Phe and BH4 deficiency formally excluded (PP4_Moderate); in trans with the p.R138Q variant (Pathogenic per PAH VCEP) (PM3). Classification: PathogenicSupporting Criteria: PVS1_Strong; PM2; PM3; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020994/MONDO:0009861/006 2020-05-21 2020-05-21 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0120107 biolink:causes UMLS:C0151995 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151995 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0004936 infores:hetionet NCBIGene:6309 biolink:causes MONDO:0011816 infores:monarchinitiative not_provided not_provided HGNC:10547 MONDO:0011816 uuid:187ee489-aff8-43bd-9fdb-df88d0fb622c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0010200 infores:hetionet CHEBI:9398 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0085593 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151849 infores:hetionet CHEBI:31485 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0234632 infores:hetionet CAID:CA8815500 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815500 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong The NM_000152.5:c.1856G>A variant in GAA is a missense variant predicted to cause substitution of serine by asparagine at amino acid 619 (p.Ser619Asn). At least five probands with symptoms consistent with late-onset-Pompe disease have been reported with this variant (PMIDs 24158270, 16838077, 25052852, 37087815,22194990), two with documented deficiency of GAA activity (PMIDs 24158270, 16838077) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.-32-13T>G (PMID: 25052852). The other three patients are compound heterozygous with unknown phase for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.-32-13T>G, c.1655T>C (p.Leu552Pro) or c.1927G>A (p.Gly643Arg), respectively (PMIDs: 37087815, 16838077, 24158270) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.0 is 0.0001875 (17/90678 alleles) in South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in <5% GAA activity in cells and <5% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 16838077 and 19862843)(PS3_Moderate). The computational predictor REVEL gives a score 0.744 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 370146; 2-star review status) with 10 submitters classifying the variant as pathogenic, and 2 as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815500/MONDO:0009290/010 2025-01-21 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:53766 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C1971624 infores:hetionet CAID:CA16608223 biolink:causes MONDO:0007648 infores:clingen CAID:CA16608223 MONDO:0007648 PMID: Likely Benign BS2, BP4 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BP1, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The c.49-8C>T is an intronic variant in the splice acceptor region of intron 1. This variant has an allele frequency of 0.00001 (2/150178) in gnomAD with a maximum frequency of 0.00003 (2/57282) in the European (Non-Finnish) sub-population. This variant has been reported in at least 12 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000529519.4, SCV000557406.3). This variant is predicted to have no impact on splicing by multiple in silico splice site predictors. HumanSpliceFinder predicts that this variant may create an exonic ESS site, but this effect has not been demonstrated experimentally to our knowledge (BP4). In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608223/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:64355 biolink:causes MONDO:0005141 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0033817 infores:hetionet CHEBI:49668 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151908 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0016977 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0007785 infores:hetionet CHEBI:3082 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0476280 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009450 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0549373 infores:hetionet CHEBI:367163 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019080 infores:hetionet CHEBI:63620 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0028734 infores:hetionet CHEBI:39669 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0038362 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0267792 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0023418 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0541882 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0541882 infores:hetionet CHEBI:175901 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0595916 infores:hetionet CHEBI:44185 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0340865 infores:hetionet CHEBI:45367 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0013378 infores:hetionet CHEBI:5778 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0035455 infores:hetionet UMLS:C0145185 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0237849 infores:hetionet CHEBI:4953 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0024236 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0038454 infores:hetionet UMLS:C0025241 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0016382 infores:hetionet CHEBI:4735 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0020580 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0234930 infores:hetionet NCBIGene:92345 biolink:causes MONDO:0957261 infores:monarchinitiative not_provided not_provided HGNC:25126 MONDO:0957261 uuid:c0df479b-0292-4fe5-99ff-16610efae16f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037822 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0043246 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0442874 infores:hetionet CAID:CA387760324 biolink:causes MONDO:0700269 infores:clingen CAID:CA387760324 MONDO:0700269 PMID: Uncertain Significance PM2_Supporting PVS1 The c.794-2A>G variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 9 of the BRCA2 gene. It is predicted to cause either the in-frame skipping of exon 10 or utilize a cryptic acceptor site 18 bp downstream in exon 10 resulting in an in-frame deletion of 6 amino acids. Neither outcome impacts a region with known protein function and neither is expected to result in nonsense mediated decay. Functional data indicates that a deletion of exon 10 results in a mostly functional protein (>80% activity in an homology directed repair assay and full complementation in a cell viability assay; PMID: 32398771). Based on this, no pathogenic evidence at any strength has been assigned to intron 9 acceptor site variants at the -2 position (PVS1_N/A). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA387760324/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C3665386 infores:hetionet CHEBI:31705 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0032533 infores:hetionet CHEBI:5120 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0340865 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0024507 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0024507 uuid:38e22cab-90d5-4161-a968-900408892363 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410147687 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147687 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM5_Supporting PS3, PS2, PS1, PS4, BA1, BP1, BP4, BP3, BP2, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1243C>T (p.Gln415Ter) is a nonsense variant which is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (nonsense c.917–c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147687/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019112 infores:hetionet CHEBI:136040 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0036974 infores:hetionet CHEBI:6076 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232461 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0521491 infores:hetionet CHEBI:63631 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0231218 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0520546 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0520546 infores:hetionet CHEBI:3756 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0027441 infores:hetionet GO:1900163 biolink:causes GO:0017121 infores:ubergraph knowledge_assertion manual_agent GO:1900163 GO:0017121 CHEBI:119573 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020458 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0086543 infores:hetionet CHEBI:107736 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0424448 infores:hetionet NCBIGene:5449 biolink:causes MONDO:0024464 infores:monarchinitiative not_provided not_provided HGNC:9210 MONDO:0024464 uuid:436fe7e3-3340-4165-8a23-114b9e4636e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410202653 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202653 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1): c.418T>C (p.Tyr140His) is a missense variant within the Runt Homology Domain (AA 89-204) (PM1_supporting). This variant has a REVEL score of 0.96 (PP3). Additionally, this variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202653/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6375 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017160 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0152115 infores:hetionet CHEBI:50742 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0023903 infores:hetionet CHEBI:2948 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0030312 infores:hetionet CHEBI:17026 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0009676 infores:hetionet CHEBI:71415 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0042963 infores:hetionet CHEBI:9445 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0018681 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0006826 infores:hetionet CHEBI:8232 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0027707 infores:hetionet CAID:CA410147431 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147431 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS4, PS1, BP1, BP2, BP3, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM3, PM4, PM1, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1306T>G (p.Ser436Ala) is a missense variant which is absent from gnomAD v2, v3, and v4 (PM2_Supporting) and has not been reported in the literature. The computational predictor REVEL gives a score of 0.133, below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, providing evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147431/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:51062 biolink:causes MONDO:0008437 infores:monarchinitiative not_provided not_provided HGNC:11231 MONDO:0008437 uuid:e6d69e31-2578-4cd7-b582-7e5ea16802ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48844 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0836924 infores:hetionet CHEBI:71028 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0011603 infores:hetionet CHEBI:4657 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0151539 infores:hetionet CHEBI:8435 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0235063 infores:hetionet NCBIGene:1184 biolink:causes MONDO:0010644 infores:monarchinitiative not_provided not_provided HGNC:2023 MONDO:0010644 uuid:3a2c348e-4d67-4a5b-a9b9-d2d4ff0d8e3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31638 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0013395 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0521592 infores:hetionet GO:0030548 biolink:causes GO:0007271 infores:ubergraph knowledge_assertion manual_agent GO:0030548 GO:0007271 CHEBI:480999 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0178298 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1565489 infores:hetionet CHEBI:4975 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0006277 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0006266 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0860801 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0860801 infores:hetionet CHEBI:31199 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0162820 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0011991 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020649 infores:hetionet CHEBI:8327 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C1318520 infores:hetionet NCBIGene:29980 biolink:causes MONDO:0009619 infores:monarchinitiative not_provided not_provided HGNC:2993 MONDO:0009619 uuid:5c62433c-d7c3-4b3d-a8fd-8a2266a38b3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0085611 infores:hetionet CHEBI:49960 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0032290 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0034065 infores:hetionet CHEBI:15640 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0015672 infores:hetionet CHEBI:171719 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0002874 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151517 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0032285 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0575090 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004936 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0518015 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151578 infores:hetionet CHEBI:8245 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0424295 infores:hetionet CHEBI:9168 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0028734 infores:hetionet CHEBI:10650 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009676 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004967 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023449 infores:hetionet MONDO:0100045 biolink:causes NCBIGene:11322 infores:ubergraph knowledge_assertion manual_agent MONDO:0100045 HGNC:18021 CHEBI:17334 biolink:causes UMLS:C0852925 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0852925 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0232431 infores:hetionet CHEBI:30659 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0018790 infores:hetionet CHEBI:49662 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0001122 infores:hetionet CHEBI:49375 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085612 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0042109 infores:hetionet CHEBI:9943 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027066 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0003864 infores:hetionet CHEBI:7824 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0040460 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027441 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0033860 infores:hetionet CHEBI:9939 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0151786 infores:hetionet GO:0044761 biolink:causes GO:0007271 infores:ubergraph knowledge_assertion manual_agent GO:0044761 GO:0007271 CHEBI:27504 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0015230 infores:hetionet CHEBI:135736 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016199 infores:hetionet UNII:D27V6190PM biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0015672 infores:hetionet CHEBI:64312 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011206 infores:hetionet CHEBI:8884 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0011603 infores:hetionet NCBIGene:55172 biolink:causes MONDO:0012918 infores:monarchinitiative not_provided not_provided HGNC:20188 MONDO:0012918 uuid:de3870bc-be5e-4e82-ba18-8fed619fbc91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49603 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0009450 infores:hetionet CHEBI:48273 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0039070 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0042109 infores:hetionet CHEBI:15544 biolink:causes UMLS:C2938970 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2938970 infores:hetionet CHEBI:17650 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0039231 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022104 infores:hetionet CHEBI:63618 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0338656 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0235431 infores:hetionet CHEBI:15765 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0042024 infores:hetionet CL:0000546 biolink:causes GO:0035745 infores:ubergraph knowledge_assertion manual_agent CL:0000546 GO:0035745 CHEBI:15407 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0013428 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0020649 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0040435 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0575090 infores:hetionet CAID:CA350341779 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341779 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PM1 BS2, BP4, BA1, PS4, BS1 The NM_001204.7(BMPR2) c.1175T>C (p.Val392Ala) variant is located in exon 9 of the BMPR2 gene and is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The variant is located in the functionally relevant catalytic kinase domain (PM1_met) but is not a critical or non-critical residue. The variant has been reported in only one individual with IPAH (PMID: 21737554 and 20002458) (PS4 not met). The REVEL score for the variant is 0.954, which is greater than the PH VCEP threshold of >= 0.75, and the AlphaMissense score is 0.9795, indicating pathogenicity (PP3_met). No segregation or parental data were found (PP1 and PS2 not evaluated). No other amino acid change at the same position has been reported for PAH (PS1 and PM5 not evaluated). No functional evidence was found (PS3 not evaluated). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1, PP3 (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341779/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0240671 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0155169 infores:hetionet CHEBI:9137 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0852911 infores:hetionet CHEBI:49960 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0162297 infores:hetionet CHEBI:39585 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0009676 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013395 infores:hetionet CHEBI:261649 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0013604 infores:hetionet CHEBI:6933 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0917801 infores:hetionet CAID:CA387502402 biolink:causes MONDO:0015152 infores:clingen CAID:CA387502402 MONDO:0015152 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM6, BS2, PP2, PP3, PP1, PP4, PM5, PM4, PM1, PM3, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The NM_000231.3: c.66T>A p.(Tyr22Ter) variant in SGCG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/8. However, because the stop codon is located within the first 100 bp, the resulting transcript may escape nonsense mediated decay (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 and 3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA387502402/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17347 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0018790 infores:hetionet CHEBI:5893 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0004093 infores:hetionet CHEBI:42820 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0040034 infores:hetionet CHEBI:68606 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0700225 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0428982 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0428982 infores:hetionet NCBIGene:10013 biolink:causes MONDO:0010463 infores:monarchinitiative not_provided not_provided HGNC:14064 MONDO:0010463 uuid:dabda947-abc4-4969-b7ff-ebb41b6b092d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7865 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0024115 infores:hetionet CHEBI:3647 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C3665347 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0015397 infores:hetionet CHEBI:116735 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0013604 infores:hetionet CHEBI:6367 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1510410 infores:hetionet CHEBI:2618 biolink:causes MONDO:0044037 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0085642 infores:hetionet CHEBI:9738 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0917801 infores:hetionet CHEBI:7476 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0391870 infores:hetionet CHEBI:48538 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C1443060 infores:hetionet CAID:CA16020865 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020865 MONDO:0009861 PMID:18299955PMID:18299955PMID:21307867PMID:18294361 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.813T>G (p.His271Gln) variant in PAH has been reported in 3 individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 1829436, 18299955, 21307867). This variant is absent in population databases (PM2). This variant was detected with IVS10-11G>A, known pathogenic (PM3; PMID: 18299955). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020865/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:72564 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151596 infores:hetionet CHEBI:63623 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0836924 infores:hetionet CHEBI:6456 biolink:causes HP:0001686 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0003564 infores:hetionet CHEBI:41423 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0030554 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235416 infores:hetionet CHEBI:6129 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0038999 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0010823 infores:hetionet CHEBI:6402 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0014591 infores:hetionet CHEBI:64064 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0014591 infores:hetionet CHEBI:6754 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0085633 infores:hetionet CHEBI:15365 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0039231 infores:hetionet CHEBI:71941 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0033687 infores:hetionet CHEBI:231594 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0043094 infores:hetionet CHEBI:474180 biolink:causes NCIT:C78181 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0541802 infores:hetionet CHEBI:68478 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0231807 infores:hetionet CHEBI:31397 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0041582 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0233494 infores:hetionet CAID:CA9043773 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043773 MONDO:0012999 PMID: Benign BA1 PM5 The NM_000156.6:c.182G>A variant in GAMT is a missense variant that is predicted to cause the substitution of a glycine by a glutamate at amino acid position 61 (p.Gly61Glu). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The GrpMax filtering allele frequency (95% confidence) in gnomAD v4.1.0. is 0.01102 in the East Asian population, including 6 homozygotes. This is higher than the ClinGen CCDS VCEP threshold for BA1 (>0.003), meeting this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 328350). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BA1.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043773/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15552 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0011603 infores:hetionet CHEBI:45924 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0041969 infores:hetionet CHEBI:145499 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0040264 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0033774 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0015376 infores:hetionet CHEBI:6909 biolink:causes UMLS:C2609264 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C2609264 infores:hetionet CHEBI:44915 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151740 infores:hetionet CHEBI:3732 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0011603 infores:hetionet CAID:CA415168068 biolink:causes MONDO:0010726 infores:clingen CAID:CA415168068 MONDO:0010726 PMID: Likely Benign BS2 BP4, BS1 The p.Pro362Ser variant in MECP2 (NM_004992.3) is present in 1 XX and 1 XY individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). The p.Pro362Ser variant in MECP2 is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro362Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415168068/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:45924 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0023380 infores:hetionet CHEBI:45409 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017979 infores:hetionet CHEBI:404903 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0041657 infores:hetionet CHEBI:7466 biolink:causes NCIT:C61050 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0853711 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0233494 infores:hetionet CHEBI:6754 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0085631 infores:hetionet CAID:CA410147636 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147636 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP2, BA1, PM6, BP5, BS1, BS3, BS4, PM5, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1254G>C (p.Met418Ile) is a missense variant which has a REVEL score < 0.50 (0.208) and a SpliceAI score ≤ 0.20 (Δ score 0.00) (BP4). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147636/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42068 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0031046 infores:hetionet CHEBI:41774 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0024236 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0227791 infores:hetionet CHEBI:32139 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0003811 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0001824 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0024115 infores:hetionet CHEBI:6754 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0235063 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011053 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0036983 infores:hetionet GO:0005815 biolink:causes GO:0051418 infores:ubergraph knowledge_assertion manual_agent GO:0005815 GO:0051418 NCBIGene:2672 biolink:causes MONDO:0011922 infores:monarchinitiative not_provided not_provided HGNC:4237 MONDO:0011922 uuid:603c255b-c39a-405c-82b3-7a6c0591ce23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0004936 infores:hetionet CHEBI:75722 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0086439 infores:hetionet CHEBI:68610 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0041912 infores:hetionet CAID:CA6798691 biolink:causes MONDO:0021060 infores:clingen CAID:CA6798691 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.951G>A (p.Lys317=) variant in the PTPN11 gene is 0.231% (49/16480) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6798691/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:28901 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0232197 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0009806 infores:hetionet CHEBI:10100 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0009450 infores:hetionet CHEBI:83804 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0231218 infores:hetionet CHEBI:585948 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C1260880 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0015734 infores:hetionet CHEBI:51141 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C1443060 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0853908 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0042109 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0018500 infores:hetionet CHEBI:66901 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0020615 infores:hetionet CHEBI:64019 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0687713 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0241705 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0037274 infores:hetionet CHEBI:6413 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0016382 infores:hetionet CHEBI:16480 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0004144 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027697 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0262985 infores:hetionet CHEBI:45327 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0040822 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009760 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0687133 infores:hetionet CHEBI:9123 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0424295 infores:hetionet CHEBI:6076 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1443060 infores:hetionet CHEBI:7773 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0600228 infores:hetionet CHEBI:85161 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0270996 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235876 infores:hetionet CHEBI:61058 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0428977 infores:hetionet NCBIGene:3630 biolink:causes MONDO:0030089 infores:monarchinitiative not_provided not_provided HGNC:6081 MONDO:0030089 uuid:fac9f780-dd51-49f6-be9d-570049e2d3b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71941 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0036830 infores:hetionet CHEBI:5118 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014356 infores:hetionet CHEBI:3393 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0013378 infores:hetionet CHEBI:42355 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0011991 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035309 infores:hetionet CHEBI:404903 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020458 infores:hetionet CHEBI:4636 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0030554 infores:hetionet CHEBI:7865 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0043352 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0023533 infores:hetionet CAID:CA415086302 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086302 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, PP4_Strong PP1, PP3, BP4 The NM_005629.4:c.1181C>A variant in SLC6A8 is predicted to result in a missense substitution of threonine by lysine at amino acid 394 (p.Thr394Lys). A 5 year old Chinese male, hemizygous for the variant, has been reported with clinical features consistent with creatine tranporter deficiency, elevated creatine/creatinine ratio in urine (value not provided), and decreased creatine peak on brain MRS (PP4_Strong). A brother with similar clinical features, but no biochemical or MRS test results available, is also hemizygous for the variant, while the heterozygous mother is “physically normal” with normal creatine on MRS (insufficient evidence to apply PP1 based on the specifications of the ClinGen CCDS VCEP). The variant is absent in gnomAD v4.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.653 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI predicts that the variant has no impact on splicing. In summary, this variant is of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on May 19, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086302/MONDO:0010305/027 2024-05-19 2024-05-23 X-linked inheritance HP:0001417 Inconclusive true CHEBI:75922 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0235857 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0858520 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0858520 infores:hetionet CHEBI:42797 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027497 infores:hetionet CAID:CA320251351 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251351 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1263C>G (p.Gly421=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.25)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251351/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3423 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0015967 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0007642 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0031350 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0007682 infores:hetionet NCBIGene:6469 biolink:causes MONDO:0007819 infores:monarchinitiative not_provided not_provided HGNC:10848 MONDO:0007819 uuid:7c24d76d-8d0f-4be4-b65d-6612704a7ca9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0004161 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004161 infores:hetionet CHEBI:50922 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0016382 infores:hetionet CHEBI:46345 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0039231 infores:hetionet CHEBI:135613 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0040822 infores:hetionet CHEBI:9763 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0019080 infores:hetionet CHEBI:52717 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0000731 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027051 infores:hetionet CAID:CA367400584 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400584 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.775G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 259 (p.(Ala259Thr)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Another missense variant, c.776C>T, p.Ala259Val, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala259Thr (PM5_Supporting). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 6 families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.775G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Supporting, PS4, PP1_Strong, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400584/MONDO:0015967/086 2023-08-12 2023-08-12 Semidominant inheritance HP:0032113 Supports CHEBI:6717 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0855775 infores:hetionet CHEBI:5103 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0011551 infores:hetionet CHEBI:2611 biolink:causes HP:0002312 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233844 infores:hetionet CHEBI:63616 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0040053 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042373 infores:hetionet CHEBI:3752 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0030554 infores:hetionet CHEBI:4953 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0392171 infores:hetionet CHEBI:9738 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0022346 infores:hetionet CHEBI:28925 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0005758 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233472 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020517 infores:hetionet CHEBI:5062 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0035455 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018099 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0001824 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0234215 infores:hetionet CAID:CA254980 biolink:causes MONDO:0010315 infores:clingen CAID:CA254980 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.186T>A (p.Cys62Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.), Absent CD132 expression (demonstrated by RT-PCR) (1 pt.) total :1.5 pts (PP4) (PMID: 8462096). In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1 Met,PP4,PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA254980/MONDO:0010315/129 2024-02-01 2024-02-01 X-linked inheritance HP:0001417 Supports CHEBI:134991 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0011570 infores:hetionet NCBIGene:63895 biolink:causes MONDO:0014941 infores:monarchinitiative not_provided not_provided HGNC:26270 MONDO:0014941 uuid:3179f5c9-4f07-44f5-b9c6-2e72ecf97086 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020453 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0178298 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0027051 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0342406 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0342406 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0011616 infores:hetionet CHEBI:51364 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0040822 infores:hetionet CHEBI:50922 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0687713 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0080194 infores:hetionet CHEBI:47426 biolink:causes UMLS:C1619727 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1619727 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0948594 infores:hetionet CHEBI:63584 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0231218 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C2712871 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2712871 infores:hetionet CHEBI:8805 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C3665347 infores:hetionet CHEBI:44915 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C2830004 infores:hetionet CHEBI:8776 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0231528 infores:hetionet CHEBI:6538 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0040264 infores:hetionet CHEBI:33325 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0015230 infores:hetionet CAID:CA261734 biolink:causes MONDO:0018997 infores:clingen CAID:CA261734 MONDO:0018997 PMID:17143285PMID:22555271PMID:23673306 Pathogenic PS3, PM1, PM2, PM6, PP2, PP3 PS4 The c.2536G>A (p.Glu846Lys) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261734/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4856 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0015376 infores:hetionet CHEBI:167309 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0020619 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0019158 infores:hetionet CHEBI:135005 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0013378 infores:hetionet CHEBI:28748 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013378 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0042373 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0041969 infores:hetionet CHEBI:5959 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0043094 infores:hetionet CAID:CA011011 biolink:causes MONDO:0005021 infores:clingen CAID:CA011011 MONDO:0005021 PMID:11106718PMID:22949430PMID:2753225PMID:16983074PMID:17351073PMID:23313350PMID:11106718PMID:22949430 Pathogenic PP1_Strong, PM1, PM2, PS3, PP3, PS4_Supporting The c.1594T>C (p.Ser532Pro) variant in MYH7 has been reported in 2 individuals with dilated cardiomyopathy (PS4_Supporting; PMID:11106718; PMID:22949430; Partners LMM ClinVar SCV000199219.4). This variant segregated with disease in >10 affected individuals (PP1_Strong; PMID:11106718; PMID:22949430). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with DCM (PS3; PMID:16983074; PMID:23313350; PMID:17351073 ). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS3; PP1_ Strong; PM1; PM2; PP3; PS4_Supporting Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011011/MONDO:0005021/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5118 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1527407 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0031350 infores:hetionet CHEBI:47519 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0011991 infores:hetionet CAID:CA337526 biolink:causes MONDO:0100488 infores:clingen CAID:CA337526 MONDO:0100488 PMID: Benign BS2, BP2_Strong BS1, PM2, BA1, PS4 The NM_004360.5(CDH1): c.1565C>T (p.Thr522Ile) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 1 individual without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). This variant is known in one family with HDGC criteria (ERN_GENTURIS). In summary, the clinical significance of this variant is classified as benign based on BS2 and BP2_strong. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA337526/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:135920 biolink:causes UMLS:C0859037 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0859037 infores:hetionet CHEBI:32184 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0011603 infores:hetionet CAID:CA023577 biolink:causes MONDO:0007750 infores:clingen CAID:CA023577 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, BS2 NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 239 index cases.PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%.PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023577/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0045691 biolink:causes GO:0009561 infores:ubergraph knowledge_assertion manual_agent GO:0045691 GO:0009561 CHEBI:28148 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0392197 infores:hetionet CHEBI:101853 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0003862 infores:hetionet CHEBI:9927 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0019080 infores:hetionet CHEBI:84500 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0026821 infores:hetionet CHEBI:7936 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004604 infores:hetionet CAID:CA346730170 biolink:causes MONDO:0007356 infores:clingen CAID:CA346730170 MONDO:0007356 PMID: Pathogenic PVS1, PP1, PM2_Supporting BA1, BP1, BP4, BP3, BP2, PS4, PS1, PS3, PS2, BP7, BP5, BS1, BS4, BS3, PM4, PM5, PM1, PM3, PM6, PP2, PP3, BS2 The NM_000251.3:c.366+1G>C variant is in the dinucleotide of canonical donor splice site of exon 2, and predicted by SpliceAI to cause exon 2 skipping leading to a frameshift, p.(Ala72Phefs*9) (PVS1 met). Segregation analysis of pedigree data shows odds of pathogenicity = 3.23 (Australian Colon Cancer Family Registry) (>2.08; PP1 met). The variant is absent in gnomAD v2.1, v3.1 and v4.1 (PM2_Supporting met). Therefore, this variant meets the criteria to be classified as Likely Pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA346730170/MONDO:0007356/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:188986 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0018799 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0549433 infores:hetionet CHEBI:28925 biolink:causes MONDO:0043287 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0038833 infores:hetionet CHEBI:8060 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0012833 infores:hetionet CHEBI:2682 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0011168 infores:hetionet UMLS:C0010592 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0012691 infores:hetionet CHEBI:100241 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0233471 infores:hetionet CHEBI:34967 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0011253 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0025061 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0232492 infores:hetionet CAID:CA256730 biolink:causes MONDO:0100368 infores:clingen CAID:CA256730 MONDO:0100368 PMID: Pathogenic PM3, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting The NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is reported in the literature in a homozygous state in at least two probands affected with Leber congenital amaurosis or early onset severe retinal dystrophy (1 point, PM3, PMID: 9326941, PMID: 26352687). At least one patient harboring the variant exhibited reduced or nondetectable rod ERG (required, 0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), light staring (1 pt), nyctalopia (0.5 pts), and positive response to RPE65 gene therapy (8 pts), which together are specific for RPE65-related recessive retinopathy (13 pts total, VCEP member-provided data, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy in multiple families with at least 3 members (PP1_strong, PMID:9326941, PMID: 26352687). This variant is reported in ClinVar (Variation ID: 13117), and its Popmax Filtering AF in gnomAD v.2.1.1 is 0.00004443 (4/30608 alleles) in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP threshold (<0.0002) (PM2_Supporting). The meta-predictor REVEL gives a score of 0.702, which is above the ClinGen LCA/eoRD VCEP PP3 threshold of >0.644 and predicts a damaging effect on RPE65 function (PP3). An in vitro isomerohydrolase activity assay performed in adenovirus-infected 293A-LRAT cells showed that the p.Pro363Thr mutant exhibits complete loss of 11-cis-retinol production relative to the wild-type RPE65 control, confirming that this variant has a damaging effect on protein function (PMID: 16828753, PS3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP1_Strong, PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA256730/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:83804 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0149871 infores:hetionet CAID:CA415090890 biolink:causes MONDO:0010305 infores:clingen CAID:CA415090890 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting The NM_005629.4: c.1703C>A variant in SLC6A8 is a missense variant predicted to cause substitution of Serine for Tyrosine at amino acid 568 (p.Ser568Tyr). This variant is absent in population databases (PM2_Supporting). The computational predictor REVEL gives a score of 0.9369 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3) To our knowlledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID: 666596). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, PP3.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415090890/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CHEBI:8404 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0235032 infores:hetionet CHEBI:261649 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0013295 infores:hetionet CHEBI:3696 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0030232 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0427008 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235351 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0274435 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0274435 infores:hetionet CHEBI:5165 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0003537 infores:hetionet CHEBI:27882 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0151578 infores:hetionet CHEBI:63638 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0232487 infores:hetionet CHEBI:68534 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0026858 infores:hetionet CHEBI:61049 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151723 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0242350 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020615 infores:hetionet CHEBI:119573 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0558489 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0852911 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0877097 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0877097 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0574067 infores:hetionet CHEBI:61049 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0039070 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007867 infores:hetionet CHEBI:2379 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0236075 infores:hetionet NCBIGene:80324 biolink:causes MONDO:0024553 infores:monarchinitiative not_provided not_provided HGNC:15508 MONDO:0024553 uuid:5068fe32-3d3d-4f9f-8c1c-0687cf2a9836 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA203556 biolink:causes MONDO:0100453 infores:clingen CAID:CA203556 MONDO:0100453 PMID:24616660 Benign BA1, BP4, BS3_Supporting, BS2 PP1 NM_000180.4(GUCY2D):c.1724C>T (p.Pro575Leu) is a missense variant predicted to replace proline with leucine at position p.575. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04850, with 3,738 alleles / 75,008 total alleles in the African / African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 114 adult individuals in gnomAD v.4.1.0, which is higher than the LCA/eoRD VCEP BS2 threshold of greater than or equal to 6 (BS2). The computational predictor REVEL gives a score of 0.229, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.02 for donor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). The variant exhibited ~75% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA/eoRD BS3_Supporting threshold of ≥50% activity, indicating that it largely preserves normal protein function (PMID: 24616660, BS3_Supporting). On the other hand, the variant protein shows enhanced sensitivity to calcium as an inhibitor of stimulation by GCAP1 and GCAP2, however, this mechanism is potentially relevant to the dominant rather than the recessive mode of inheritance, so PS3_Supporting is not met. In summary, this variant meets the criteria to be classified as benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1, BS2, BS3_Supporting, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA203556/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4995 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0023418 infores:hetionet CHEBI:119573 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0520966 infores:hetionet CHEBI:6888 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0002792 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003864 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0853692 infores:hetionet CHEBI:4708 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0231528 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0034642 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0854113 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0029408 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0178298 infores:hetionet CHEBI:5790 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0018681 infores:hetionet CHEBI:3764 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0026821 infores:hetionet CHEBI:6958 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0700292 infores:hetionet CHEBI:8871 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023066 infores:hetionet CHEBI:119486 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235378 infores:hetionet NCBIGene:157680 biolink:causes MONDO:0008999 infores:monarchinitiative not_provided not_provided HGNC:2183 MONDO:0008999 uuid:d9ef76c4-4ae0-4f01-ae4e-4e61e6b8d4f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0027947 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0002994 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0001883 infores:hetionet CHEBI:10124 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0000737 infores:hetionet CAID:CA902588 biolink:causes MONDO:0100368 infores:clingen CAID:CA902588 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) is a nonsense variant that introduces a premature stop codon into exon 3 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least one proband with early-onset severe retinal dystrophy and harboring this variant exhibits a phenotype including onset by age 1 (1 pt), ERG with extinguished responses from rods (0.5 pts) and cones (1 pts), nystagmus ( 1pt), and attenuated retinal blood vessels (0.5 pts), which together are specific for RPE65-related recessive retinopathy (4 points, PMID: 26626312, PP4). The variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00001685, with 7 alleles/129188 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902588/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63791 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011615 infores:hetionet CAID:CA2580098624 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098624 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.351+9C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.53) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098624/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018926 infores:hetionet CHEBI:75722 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026961 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0086543 infores:hetionet CHEBI:9907 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0311468 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0162429 infores:hetionet CHEBI:9571 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0085631 infores:hetionet CHEBI:61049 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027424 infores:hetionet CHEBI:45951 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0017979 infores:hetionet CHEBI:27899 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0039231 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0017152 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0030552 infores:hetionet CHEBI:7822 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0151529 infores:hetionet CHEBI:520985 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0030193 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0040034 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0021167 infores:hetionet CAID:CA645553763 biolink:causes MONDO:0017623 infores:clingen CAID:CA645553763 MONDO:0017623 PMID: Pathogenic PP3, PM2_Supporting, PS3, PS2 PP2, BP4 NM_000314.8(PTEN):c.209+4A>G meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor: SCV001757442.1)PS3: RNA, mini-gene, or other assay shows impact on splicing (Internal laboratory contributor, SCV002725031.1: results in whole exon skipping. Exon 3 in-frame but contains PATH missense variants).PM2_P: Absent in gnomAD (PMID 27535533).PP3: in silico models predict a splicing impact (SpliceAI: strong donor loss=0.71, and strong donor gain=0.65, impact OOF) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645553763/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31401 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C2979982 infores:hetionet CHEBI:42355 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0235266 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0858259 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0027441 infores:hetionet CHEBI:63613 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0004093 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0029882 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0006266 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0036572 infores:hetionet CHEBI:135920 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0080274 infores:hetionet CHEBI:68534 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0027441 infores:hetionet CHEBI:46345 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0027497 infores:hetionet CHEBI:8060 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0015967 infores:hetionet CHEBI:6375 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151683 infores:hetionet CHEBI:8768 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013491 infores:hetionet NCBIGene:137492 biolink:causes MONDO:0013962 infores:monarchinitiative not_provided not_provided HGNC:24928 MONDO:0013962 uuid:adfa9514-ddc9-455c-8bbe-0c95e9d059f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA043768 biolink:causes MONDO:0007750 infores:clingen CAID:CA043768 MONDO:0007750 PMID: Uncertain Significance PM1, PM2 PS4, PP3, PP4 The NM_000527.5(LDLR):c.508G>A (p.Asp170Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1 and PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 4 March 2025. The supporting evidence is as follows: PM1: Variant meets PM2 and is missense in exon 4. PM2: PopMax MAF = 0.00006186 (0.006186%) in European (non-Finnish) exomes (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA043768/MONDO:0007750/013 2025-03-04 2025-03-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:38562 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0003123 infores:hetionet CHEBI:47780 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0267797 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0013456 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0948595 infores:hetionet CHEBI:7936 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151603 infores:hetionet CHEBI:45409 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1328337 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0853761 infores:hetionet CHEBI:7903 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0042164 infores:hetionet NCBIGene:6833 biolink:causes MONDO:0009734 infores:monarchinitiative not_provided not_provided HGNC:59 MONDO:0009734 uuid:6347c514-c660-4174-99e7-93f0dd985dcb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0015397 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0017160 infores:hetionet CHEBI:63580 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0028084 infores:hetionet CAID:CA2573158773 biolink:causes MONDO:0100437 infores:clingen CAID:CA2573158773 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting PP3, BS2, PM4, PM5, PS1, PS3, BP3, BP4, BP7 NM_001034853.2(RPGR):c.2679_2680del (p.Glu894GlyfsTer?) is a frameshift variant due to a 2-nucleotide deletion, introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 28559085, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573158773/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:3219 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042373 infores:hetionet CHEBI:5002 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0235431 infores:hetionet CHEBI:10125 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0007859 infores:hetionet CAID:CA392354459 biolink:causes MONDO:0007947 infores:clingen CAID:CA392354459 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4, PM1_Strong BS2, BA1, BP1, BP4, PS1, PS3, PM5, BS1, BS3 The NM_00138 c.4414T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 1472 (p.Cys1472Arg). This variant was found in a proband with thoracic aortic aneurysm and/or dissection, ectopia lentis, and a systemic score of 7, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent University Hospital) (PP4). This variant has been reported 3 times in ClinVar, once as pathogenic and twice as likely pathogenic (Variation ID: 549229). 6 other probands with a clinical diagnosis of Marfan syndrome or clinical features of Marfan syndrome carry the same variant (PMID 33087052, InvitaeClinVarentry, University of Antwerp ClinVar entry, internal data, PS4). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.979) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1_Strong, PP2, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392354459/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63621 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0007642 infores:hetionet CHEBI:101853 biolink:causes HP:0020059 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0427458 infores:hetionet GO:0060629 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0060629 GO:0051321 CHEBI:5280 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0013456 infores:hetionet CHEBI:77733 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0034063 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0234215 infores:hetionet CHEBI:31705 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0010200 infores:hetionet CHEBI:5959 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0151825 infores:hetionet CHEBI:6832 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0036572 infores:hetionet UMLS:C0065374 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0018681 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0851341 infores:hetionet CHEBI:50885 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0000731 infores:hetionet CHEBI:51041 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0003962 infores:hetionet CHEBI:46195 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0019080 infores:hetionet UMLS:C0145867 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0231530 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0027765 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011570 infores:hetionet CHEBI:168396 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C2363731 infores:hetionet CHEBI:8665 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0235710 infores:hetionet UMLS:C0010592 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0037763 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0233414 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043037 infores:hetionet CHEBI:83531 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0013404 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151698 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0178298 infores:hetionet CHEBI:144551 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0010692 infores:hetionet CHEBI:5118 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0404521 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0521591 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0239150 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0085681 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0271051 infores:hetionet CHEBI:77032 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0042963 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0521465 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019158 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0740481 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0740481 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0854114 infores:hetionet CAID:CA9200851 biolink:causes MONDO:0018947 infores:clingen CAID:CA9200851 MONDO:0018947 PMID: Benign BP4, BA1, BP7 BP1, BP3, PS3, PS1, PM1, PM5, PM4, BS1, BS3, PVS1, PM2, PP2, PP3, PP4 The variant NM_001005361.3:c.654C>T is a synonymous (silent) variant (p.Asp218=) in exon 5/21 of DNM2. The filtering allele frequency (the lower threshold of the 95% CI of 29/1180014) of the c.654C>T variant in DNM2 is 0.00001663 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The c.654C>T (p.Asp218=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA9200851/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15428 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0007222 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0020517 infores:hetionet CHEBI:3216 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0008031 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0040034 infores:hetionet CHEBI:3403 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0027497 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0152025 infores:hetionet CAID:CA367398628 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398628 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PS3_Supporting, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4 The c.1174C>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to serine at codon 392 (p.(Arg392Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.778, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18382660, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; PMID: 18382660). This variant segregated with hyperglycemia, with two informative meioses in two families (PP1; PMID: 18382660, internal lab contributors). Another missense variant, c.1174C>T p.Arg392Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg392Ser (PM5_Supporting). While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the relative stability index was below the MDEP cutoff of 0.5 (PS3_Supporting; PMID: 22761713). In summary, c.1174C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting, PS3_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398628/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Supports CHEBI:18067 biolink:causes HP:0032553 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0232132 infores:hetionet CHEBI:6640 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0011603 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0948586 infores:hetionet CHEBI:63584 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0333355 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0042109 infores:hetionet CHEBI:119915 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027424 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0032285 infores:hetionet CHEBI:8665 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0026205 infores:hetionet CHEBI:4453 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0262397 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0392176 infores:hetionet CHEBI:4672 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0021368 infores:hetionet CHEBI:5558 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0039231 infores:hetionet CHEBI:617099 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0038362 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0041969 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0340464 infores:hetionet CHEBI:5790 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0004604 infores:hetionet CHEBI:9137 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0031256 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0031117 infores:hetionet CHEBI:7954 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0001824 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0023895 infores:hetionet CHEBI:119573 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0030193 infores:hetionet CHEBI:135351 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0041657 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0037274 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0015230 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0575090 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0037274 infores:hetionet CHEBI:2453 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0020621 infores:hetionet CHEBI:2636 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0011603 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0853026 infores:hetionet CHEBI:73274 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042075 infores:hetionet CHEBI:44241 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0001623 infores:hetionet CHEBI:47780 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013404 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0033246 infores:hetionet CHEBI:6888 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0221166 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0026650 infores:hetionet CHEBI:15544 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020580 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0037822 infores:hetionet CAID:CA024894 biolink:causes MONDO:0018493 infores:clingen CAID:CA024894 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with histidine at codon 2730 of the RYR1 protein, p.(Asp2730His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individuals with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, as well, this individual was reported to have a second variant of uncertain significance in RYR1, PS4 was not applied (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.881) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024894/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9943 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0025323 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013295 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011991 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0025061 infores:hetionet CHEBI:3082 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0234632 infores:hetionet CHEBI:50648 biolink:causes HP:0010588 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151628 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0040034 infores:hetionet CHEBI:3506 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0002878 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020473 infores:hetionet CHEBI:50131 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0856054 infores:hetionet CHEBI:9943 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085636 infores:hetionet CHEBI:49668 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0014591 infores:hetionet CHEBI:47898 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151723 infores:hetionet GO:1905780 biolink:causes GO:0097194 infores:ubergraph knowledge_assertion manual_agent GO:1905780 GO:0097194 CAID:CA320741226 biolink:causes MONDO:0011071 infores:clingen CAID:CA320741226 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.58+20G>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.84) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741226/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5138 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0006145 infores:hetionet CHEBI:10124 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0011991 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235347 infores:hetionet CHEBI:7936 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042023 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0040034 infores:hetionet CAID:CA399790170 biolink:causes MONDO:0100326 infores:clingen CAID:CA399790170 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting BS1, BA1 The ITGA2B nonsense variant NM_000419.5:c.2953C>T (p.Gln985Ter) introduces a premature termination codon and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT38, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399790170/MONDO:0100326/011 2021-07-14 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5778 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0162287 infores:hetionet GO:1903680 biolink:causes CL:0002140 infores:ubergraph knowledge_assertion manual_agent GO:1903680 CL:0002140 CHEBI:6375 biolink:causes MONDO:0020108 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002880 infores:hetionet CHEBI:9555 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0022346 infores:hetionet CAID:CA10014525 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014525 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.367G>A (p.Asp123Asn) is a missense variant which is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014525/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50777 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0037199 infores:hetionet CHEBI:18358 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0020517 infores:hetionet CHEBI:31623 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0003862 infores:hetionet CHEBI:7627 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0014742 infores:hetionet CHEBI:31401 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0009763 infores:hetionet CHEBI:135736 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0008033 infores:hetionet CHEBI:4530 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0011603 infores:hetionet CHEBI:79699 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C2939147 infores:hetionet CHEBI:18258 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0020538 infores:hetionet CHEBI:39867 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0040822 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0004610 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0854303 infores:hetionet CHEBI:6149 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151905 infores:hetionet CHEBI:72296 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0019080 infores:hetionet CHEBI:10125 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151632 infores:hetionet CHEBI:9725 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0233571 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0037023 infores:hetionet CHEBI:5856 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0020649 infores:hetionet NCBIGene:50484 biolink:causes MONDO:0010000 infores:monarchinitiative not_provided not_provided HGNC:17296 MONDO:0010000 uuid:b932765c-f7ba-4cd2-9d38-e1bb685f4e07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019209 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0235567 infores:hetionet CHEBI:6761 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0011609 infores:hetionet CHEBI:291342 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0027497 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0427160 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0427160 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0038362 infores:hetionet CHEBI:28001 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0242528 infores:hetionet CHEBI:16755 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002994 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0740399 infores:hetionet CHEBI:7934 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01421 UMLS:C0000737 infores:hetionet CHEBI:82981 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0948594 infores:hetionet CHEBI:5847 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0030193 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0496870 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0496870 infores:hetionet CHEBI:40279 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0023518 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0021053 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0442874 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0442874 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0018799 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040435 infores:hetionet CHEBI:4046 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0011603 infores:hetionet CHEBI:10127 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0001925 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0847033 infores:hetionet NCBIGene:1742 biolink:causes MONDO:0032919 infores:monarchinitiative not_provided not_provided HGNC:2903 MONDO:0032919 uuid:3f7a0fc6-5c09-424d-8e1f-2a9c7339c48f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4657 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0019158 infores:hetionet CHEBI:5864 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0235378 infores:hetionet CHEBI:63620 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085628 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0694536 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0595939 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0948594 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0851341 infores:hetionet CHEBI:3219 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0080274 infores:hetionet CHEBI:44185 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030554 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0002792 infores:hetionet CHEBI:47898 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2242737 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0041912 infores:hetionet CHEBI:71229 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0009450 infores:hetionet CHEBI:77260 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0032617 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0014175 infores:hetionet CHEBI:53760 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0035243 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040435 infores:hetionet CHEBI:45979 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0020580 infores:hetionet CHEBI:8888 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042024 infores:hetionet CAID:CA512341315 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341315 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1089C>T (p.Gly363=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This synonymous variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 1.49391 < 2.0) (BP7). This variant was reported in ClinVar in 2021 by Invitae, but the affected status of the proband is unknown (Variation ID 1486967). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341315/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0657912 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014724 infores:hetionet CHEBI:50131 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0267028 infores:hetionet CHEBI:7956 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0020517 infores:hetionet CHEBI:70735 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0002453 infores:hetionet CAID:CA229711 biolink:causes MONDO:0009861 infores:clingen CAID:CA229711 MONDO:0009861 PMID:31623983PMID:32106880PMID:10394930 Likely Pathogenic PM3, PM2, PP3, PP4 PM5 The c.716G>T (p.Gly239Val) variant in PAH has been reported in 2 individuals with classic PKU (PMID 10394930, 31623983) detected with pathogenic variants p.R408W and IVS10–11g>a (PMID: 32106880). This variant has extremely low frequency in gnomAD (MAF=0.00006). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229711/MONDO:0009861/006 2020-10-23 2020-10-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15552 biolink:causes HP:0012151 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0019123 infores:hetionet CHEBI:64312 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085633 infores:hetionet CHEBI:8207 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020580 infores:hetionet CHEBI:55346 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151766 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0004936 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0004936 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0001824 infores:hetionet CHEBI:7773 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0428977 infores:hetionet CHEBI:6710 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0013604 infores:hetionet UMLS:C0145185 biolink:causes HP:6000500 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0235248 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011053 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0857122 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0857122 infores:hetionet CHEBI:16755 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0687713 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042373 infores:hetionet CHEBI:4708 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1458155 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0031099 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0858598 infores:hetionet CHEBI:50173 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0242301 infores:hetionet CAID:CA2259454 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259454 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1668+4A>G variant in the RAF1 gene is 0.053% (11/11576) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259454/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA340748033 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748033 MONDO:0100368 PMID: Pathogenic PM1, PM3, PP3_Moderate, PP4_Moderate, PP1, PM2_Supporting NM_000329.3(RPE65):c.354G>T (p.Arg118Ser) is a variant that occurs at the first base of exon 5 and potentially impacts the gene at both the protein and RNA levels. At the protein level, this variant is a missense substitution within the membrane-interacting region between amino acids 107 and 125, which is a well-characterized functional domain required for proper localization to the ER membrane (PM1, PMID: 36265895). At the RNA level, the splicing impact predictor SpliceAI gives a score of 0.73, which is above the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This variant is predicted to have the same splicing impact as NM_000329.3(RPE65):c.354-2A>G, a canonical splice variant within the same donor/acceptor motif that was previously classified as pathogenic by the LCA / eoRD VCEP, however, PS1_Moderate was not scored due to mutual exclusivity with the PM1 code. The computational predictor REVEL gives a score of 0.87, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00001333, with 1 allele / 75008 total alleles in the African / African American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1328T>C (p.Val443Ala) variant confirmed in trans, which was previously classified likely pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PMID: 20811047, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis at age 8 months (1 pt), nystagmus (1 pt), sluggish pupils (0.5 pts), night blindness (0.5 pts), abnormal electroretinogram responses from both rods (0.5pts) and cones (1 pt), poor side vision (1 pt), optic nerve pallor (0.5 pts), retinal pigment epithelium mottling (0.5 pts), and significant improvement in visual field sensitivity and visual acuity following Luxterna gene therapy (2 pts), which together are highly specific for RPE65-related recessive retinopathy (total 8.5 points, PMIDs: 20811047, 29869534, 27102010, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 20811047, PP1). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM3, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748033/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:2073 biolink:causes MONDO:0010216 infores:monarchinitiative not_provided not_provided HGNC:3437 MONDO:0010216 uuid:5f942a6a-13ff-4a4c-b3f4-d12aa4cc4ee8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA255197 biolink:causes MONDO:0010602 infores:clingen CAID:CA255197 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4 The c.6046C>T (p.Arg2016Trp) variant is completely absent from gnomAD v2.1.1 and gnomAD v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.822 (>0.6) meeting PP3 criteria. More than 46 probands are reported with the variant and moderate-severe hemophilia A in the literature and internal laboratory data (PMID: 29296726, 20102490, 18387975), meeting F8 phenotype criteria. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been reported in individuals with a history of inhibitor development to factor replacement therapy (EAHAD database). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very Strong, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255197/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:66876 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0020649 infores:hetionet CHEBI:47898 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0231528 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0027932 infores:hetionet CHEBI:4046 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0022346 infores:hetionet CHEBI:6437 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0004093 infores:hetionet CHEBI:63589 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0028084 infores:hetionet CHEBI:36795 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0033774 infores:hetionet CHEBI:8378 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C3263723 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0549433 infores:hetionet CHEBI:3568 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1456784 infores:hetionet CHEBI:49375 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1519353 infores:hetionet CHEBI:8378 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0235259 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0020517 infores:hetionet CHEBI:6129 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C3495920 infores:hetionet CHEBI:119915 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085684 infores:hetionet CHEBI:9570 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0030193 infores:hetionet CHEBI:7476 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042963 infores:hetionet CHEBI:64019 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0178298 infores:hetionet CHEBI:135613 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0039070 infores:hetionet GO:2000702 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0072028 CHEBI:3219 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038325 infores:hetionet CHEBI:10119 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085680 infores:hetionet CAID:CA5949933 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949933 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The NM_000448.3:c.251A>G variant in RAG1 is a missense variant predicted to cause the substitution of Histidine by Arginine at amino acid 249 (p.His84Arg). The Popmax Filtering allele frequency (95% CI) of the c.251A>G variant in RAG1 is 0.01622 in gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1. Therefore, BA1 is met. Additionally, 19 homozygous adults are reported on GnomAD v.4, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949933/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9434 biolink:causes MONDO:0004833 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0149756 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0009450 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005638 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0001816 infores:hetionet CHEBI:39585 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0037036 infores:hetionet UMLS:C0018061 biolink:causes UMLS:C0029967 infores:drugmechdb knowledge_assertion manual_agent UMLS:C0018061 UMLS:C0029967 DB06785_MESH_D010062_1 CHEBI:31623 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0151601 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004239 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0042514 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0014742 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011551 infores:hetionet CHEBI:3757 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C2363730 infores:hetionet CHEBI:3380 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0009917 infores:hetionet CAID:CA222858 biolink:causes MONDO:0100040 infores:clingen CAID:CA222858 MONDO:0100040 PMID: Likely Benign BS2, BP4 BS1, PM2, BA1 The p.Lys157Asn variant in FOXG1 is present in 2 individuals in gnomAD (0.001%) (not sufficient to meet BS1 criteria). The p.Lys157Asn variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Lys157Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Lys157Asn variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222858/MONDO:0100040/016 2022-09-01 2022-09-06 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0474395 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0474395 infores:hetionet CHEBI:39585 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0600142 infores:hetionet CHEBI:16991 biolink:causes GO:0006351 infores:ubergraph knowledge_assertion manual_agent CHEBI:16991 GO:0006351 CAID:CA6197006 biolink:causes MONDO:0019497 infores:clingen CAID:CA6197006 MONDO:0019497 PMID: Uncertain Significance PP3, BS1_Supporting PM3 The c.19G>A (p.Gly7Arg) variant in MYO7A is a missense variant predicted to cause a substitution of glycine by arginine at amino acid 7. The filtering allele frequency (the lower threshold of the 95% CI of 95/74936) of the c.19G>A in MYO7A is 0.1061% for African/African American chromosomes by gnomAD v4.0.0, which is higher than the ClinGen Hearing Loss VCEP threshold (≥0.0007) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). Two probands were compound heterozygous with one confirmed trans with the pathogenic c.6377del, p.Pro2126Leufs*5 variant, and the other one assumed in trans with the pathogenic c.634C>T, p.Arg212Cys variant (ClinVar ID: 802700, internal data from Invitae). However, due to the allele frequency meeting BS1_Supporting criteria, PM3 was not applied. The computational predictor REVEL gives a score of 0.926 which is above the threshold of ≥ 0.7 (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher Syndrome Type 1, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BS1_Supporting, PP3; Version 2; 4/17/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6197006/MONDO:0019497/005 2024-06-28 2024-06-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:49668 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0038358 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0877517 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020649 infores:hetionet CHEBI:48273 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013395 infores:hetionet CHEBI:6149 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0278134 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0025061 infores:hetionet CHEBI:3561 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0085593 infores:hetionet CAID:CA10653552 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653552 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*3138C>G is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653552/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50859 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0027947 infores:hetionet CHEBI:6149 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0004604 infores:hetionet CHEBI:4995 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020458 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0006840 infores:hetionet CHEBI:6067 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0002792 infores:hetionet CHEBI:9727 biolink:causes HP:0001908 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0178416 infores:hetionet CHEBI:167638 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0026821 infores:hetionet CHEBI:135530 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0009782 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0026848 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030920 infores:hetionet CAID:CA345149813 biolink:causes MONDO:0100084 infores:clingen CAID:CA345149813 MONDO:0100084 PMID: Uncertain Significance PP2, PP3 PM2, BA1, BS1 The c.334C>A variant in ACTA1 is a missense variant predicted to cause a substitution of leucine by isoleucine at amino acid position 112. The highest filtering allele frequency in gnomAD v4.1.0 is 0.00001063 (3/74926) in the African/African American population (no population codes met). The computational predictor REVEL gives a score of 0.76, which is above the threshold of 0.7 set by the CM VCEP (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345149813/MONDO:0100084/147 2024-08-27 2024-12-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:127780 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0006840 infores:hetionet CHEBI:31711 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026858 infores:hetionet CAID:CA913189256 biolink:causes MONDO:0100083 infores:clingen CAID:CA913189256 MONDO:0100083 PMID: Pathogenic PS4_Moderate, PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 "The NM_001754.5(RUNX1):c.166_196del (p.Leu56ProfsTer6) variant in RUNX1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 4/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). It has been reported in a proband with thrombocytopenia and MDS/MPN-U and her ""affected"" sister (PMID: 37216690), as well as in 2 additional probands meeting phenotypic criteria for RUNX1 (PMID: 37406166) (PS4_Moderate, PP1 is not met). It has also been reported in a patient with MDS, but variant origin is unclear (cBioPortal.org - Papaemmanuil Lab, 2022). Furthermore, other pathogenic/likely pathogenic frameshift alterations in exon 4 have been reported (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PS4_Moderate, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval)" Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189256/MONDO:0100083/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9927 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0004936 infores:hetionet CAID:CA024939 biolink:causes MONDO:0018493 infores:clingen CAID:CA024939 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 2880 of the RYR1 protein, p.(Glu2880Lys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, one of these individuals had a second variant of uncertain significance in RYR1 (p.Glu3290Lys) and was not counted toward PS4, PS4_Supporting was implemented (PMID:19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024939/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:30830 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0392156 infores:hetionet CHEBI:3216 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0236075 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0574067 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042075 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0392025 infores:hetionet CHEBI:15553 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0018965 infores:hetionet CHEBI:50859 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1306341 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0851341 infores:hetionet CHEBI:4495 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0039231 infores:hetionet CHEBI:499361 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013428 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0002871 infores:hetionet NCBIGene:6683 biolink:causes MONDO:0008438 infores:monarchinitiative not_provided not_provided HGNC:11233 MONDO:0008438 uuid:e4d44000-0604-4c9f-9216-53c3ac2a6e39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0014724 infores:hetionet CHEBI:5004 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0011603 infores:hetionet CHEBI:42797 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030193 infores:hetionet CHEBI:46195 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0235996 infores:hetionet CHEBI:30830 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042023 infores:hetionet CHEBI:404903 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0003811 infores:hetionet CHEBI:2950 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0344232 infores:hetionet CAID:CA279976 biolink:causes MONDO:0015280 infores:clingen CAID:CA279976 MONDO:0015280 PMID: Pathogenic PS3, PM1, PM2, PP2, PP3, PM6_Strong The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6_Strong, PS3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279976/MONDO:0015280/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ GO:0003307 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0003307 GO:0007275 CHEBI:45081 biolink:causes UMLS:C1328552 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C1328552 infores:hetionet CHEBI:47499 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0085633 infores:hetionet CHEBI:41879 biolink:causes HP:0001518 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0024032 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0034065 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0151738 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151738 infores:hetionet GO:0044827 biolink:causes GO:0019079 infores:ubergraph knowledge_assertion manual_agent GO:0044827 GO:0019079 CHEBI:28748 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151970 infores:hetionet CHEBI:3393 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0000729 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0010692 infores:hetionet CHEBI:31348 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042790 infores:hetionet CHEBI:291342 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C1384353 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0028960 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0151623 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0036572 infores:hetionet CHEBI:8212 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0037763 infores:hetionet CHEBI:3996 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0702166 infores:hetionet CHEBI:8107 biolink:causes HP:0012282 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0234918 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0242350 infores:hetionet NCBIGene:4646 biolink:causes MONDO:0011912 infores:monarchinitiative not_provided not_provided HGNC:7605 MONDO:0011912 uuid:11903cea-cbc6-455d-8174-b452d15104d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72297 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0232462 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0856882 infores:hetionet NCBIGene:57511 biolink:causes MONDO:0014131 infores:monarchinitiative not_provided not_provided HGNC:18621 MONDO:0014131 uuid:7dfc07f3-36b3-4c0d-8af2-3be5cd9a7858 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0035078 infores:hetionet NCBIGene:3778 biolink:causes MONDO:0032886 infores:monarchinitiative not_provided not_provided HGNC:6284 MONDO:0032886 uuid:24aa6621-4909-4598-a747-0bf766e90fee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0456909 infores:hetionet CHEBI:45367 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0027121 infores:hetionet CHEBI:8382 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0041582 infores:hetionet CHEBI:31401 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0015967 infores:hetionet CHEBI:4909 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0022107 infores:hetionet UMLS:C0004609 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0023380 infores:hetionet NCBIGene:390594 biolink:causes MONDO:0012237 infores:monarchinitiative not_provided not_provided HGNC:37227 MONDO:0012237 uuid:a6405e45-6e6a-4a4d-9195-06c6c4d9bdb7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042963 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1096250 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1167965 infores:hetionet CHEBI:9316 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0027497 infores:hetionet CHEBI:46195 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0041834 infores:hetionet CHEBI:15367 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0237849 infores:hetionet CHEBI:3380 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0034068 infores:hetionet CHEBI:63611 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0036130 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0040034 infores:hetionet CHEBI:3223 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0015967 infores:hetionet CHEBI:31401 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0012569 infores:hetionet CAID:CA658658476 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658476 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.261delG p.(Arg87Serfs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658476/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:8863 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015734 infores:hetionet CHEBI:91834 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0003862 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006852 infores:hetionet CHEBI:27446 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0042109 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0004096 infores:hetionet NCBIGene:2224 biolink:causes MONDO:0014713 infores:monarchinitiative not_provided not_provided HGNC:3631 MONDO:0014713 uuid:66a64829-ef83-4116-8dc8-e6859c4ac7b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0023067 infores:hetionet CHEBI:39112 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0033771 infores:hetionet CHEBI:59445 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0027540 infores:hetionet GO:0035165 biolink:causes CL:0000715 infores:ubergraph knowledge_assertion manual_agent GO:0035165 CL:0000715 CAID:CA246107 biolink:causes MONDO:0021060 infores:clingen CAID:CA246107 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.698A>G (p.Asn233Ser) variant in the SOS1 gene is 0.0393% (8/10108) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA246107/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:134966 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0009450 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0521845 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0521845 infores:hetionet CHEBI:38940 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0085682 infores:hetionet CHEBI:60761 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C2047937 infores:hetionet NCBIGene:284361 biolink:causes MONDO:0031011 infores:monarchinitiative not_provided not_provided HGNC:27609 MONDO:0031011 uuid:99be56f5-f19a-42be-9c1f-b60fce73a9c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8028 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0023530 infores:hetionet CHEBI:3506 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0022354 infores:hetionet CHEBI:64312 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0023518 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1443060 infores:hetionet CHEBI:6775 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042029 infores:hetionet CHEBI:2675 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0018524 infores:hetionet CHEBI:77260 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0016204 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0034068 infores:hetionet CHEBI:6015 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0011206 infores:hetionet CHEBI:46295 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0042075 infores:hetionet CHEBI:5801 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0242429 infores:hetionet CHEBI:32588 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0429097 infores:hetionet CHEBI:6916 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0011606 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029134 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034065 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0040479 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0009806 infores:hetionet CHEBI:24564 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0232462 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0040435 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0002994 infores:hetionet CHEBI:28177 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0231835 infores:hetionet NCBIGene:9149 biolink:causes MONDO:0014352 infores:monarchinitiative not_provided not_provided HGNC:3092 MONDO:0014352 uuid:e303e1f2-cf30-453a-b64e-83d70ea6715f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0019158 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0033246 infores:hetionet CHEBI:28445 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0015967 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016436 infores:hetionet CHEBI:7959 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0023646 infores:hetionet CHEBI:82960 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0423791 infores:hetionet CHEBI:63589 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0018926 infores:hetionet GO:1905100 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:1905100 GO:0051716 CHEBI:167638 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0002170 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C2225524 infores:hetionet CHEBI:2788 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0011991 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0042109 infores:hetionet CAID:CA16609801 biolink:causes MONDO:0007750 infores:clingen CAID:CA16609801 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 The NM_000527.5(LDLR): NM_000527.4(LDLR):c.-140C>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in one index case who fulfill SB criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609801/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5613 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0080274 infores:hetionet CHEBI:35677 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0000731 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0021308 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0041349 infores:hetionet CAID:CA386959959 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959959 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PM5_Supporting, PP3, PP4 PS4, PP1 The c.429C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to glutamine at codon 143 (p.(His143Gln)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is absent in gnomAD 2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than [or equal to] the MDEP threshold of 0.70 (PP3). Another missense variant, c.427C>T (p.His143Tyr), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.His143Gln (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor); however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 23348805/internal lab contributor). This variant segregated with diabetes with one informative meiosis in this individual's family, however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributor). Taken together, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the by the ClinGen MDEP VCEP (specification version 3.0, approved 6/30/2025): PM1, PP3, PP4, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959959/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports UNII:DJJ95FJP1H biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0004096 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0854082 infores:hetionet CHEBI:9435 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0040034 infores:hetionet GO:1903388 biolink:causes GO:0036465 infores:ubergraph knowledge_assertion manual_agent GO:1903388 GO:0036465 CHEBI:50924 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020676 infores:hetionet CAID:CA145903 biolink:causes MONDO:0015152 infores:clingen CAID:CA145903 MONDO:0015152 PMID: Benign BA1 BS1, BS4, PM2, PM6, PM3, PM5, PP1, PP4, PP3, BS2, BP2, BP4, PS4, PS2, PS1 The NM_000231.3: c.347G>A variant in SGCG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 116, p.(Arg116His). The filtering allele frequency for this variant is 0.1550 in gnomAD v4.1.0 exomes (the lower threshold of the 95% confidence interval of 944/5768 Middle Eastern chromosomes), which is greater than the LGMD VCEP threshold for BA1, meeting this criterion (BA1). This variant was reported in a single heterozygous state in a patient with sarcoglycanopathy who also had a compound heterozygous pair of variants in SGCA that were considered diagnostic (PMID: 18421900). The REVEL score for this variant is 0.375 and the SpliceAI score is 0.01 (BP4, PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/25/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA145903/MONDO:0015152/185 2025-06-25 2025-07-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9588 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0151798 infores:hetionet CHEBI:2955 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151904 infores:hetionet CHEBI:10124 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013390 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0232492 infores:hetionet CHEBI:76607 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0851341 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0553702 infores:hetionet CHEBI:9137 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040435 infores:hetionet CHEBI:10119 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151723 infores:hetionet CHEBI:6916 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0036974 infores:hetionet GO:0044079 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0044079 GO:0007268 CHEBI:3176 biolink:causes EFO:1001322 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0015401 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013395 infores:hetionet CHEBI:4027 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0021368 infores:hetionet CHEBI:7936 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017565 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0027769 infores:hetionet CHEBI:63607 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0040434 infores:hetionet CHEBI:135961 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0085649 infores:hetionet CHEBI:75984 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0009676 infores:hetionet CHEBI:32139 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0015672 infores:hetionet CHEBI:4708 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0494475 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0015376 infores:hetionet CHEBI:17026 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042963 infores:hetionet CHEBI:2675 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0686347 infores:hetionet CHEBI:31711 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018378 infores:hetionet CHEBI:8871 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011124 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0457798 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0457798 infores:hetionet CAID:CA405691060 biolink:causes MONDO:0018493 infores:clingen CAID:CA405691060 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with valine at codon 4928 of the RYR1 protein, p.(Ile4928Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000649, a frequency consistent with pathogenicity for MHS. This variant was reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084), PS4 not met. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score of 0.837 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405691060/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:15367 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0028866 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019158 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0034150 infores:hetionet CHEBI:64312 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0016382 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0035078 infores:hetionet NCBIGene:80705 biolink:causes MONDO:0054730 infores:monarchinitiative not_provided not_provided HGNC:14927 MONDO:0054730 uuid:79833dad-b3cb-4166-8274-699d2e03511a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0851578 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000741 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0221237 infores:hetionet CAID:CA386954959 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954959 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS1_Supporting, PP4_Moderate, PVS1 PS4 The c.326+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 1 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent positive C- peptide) (PP4_Moderate; internal lab contributors). The c.326+1G>A and c.326+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>T has a similar predicted impact on donor loss by Splice AI (0.98) (PS1_Supporting). Lastly, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.326+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1 approved 9/30/21): PVS1, PS1_Supporting, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954959/MONDO:0015967/017 2022-06-10 2022-06-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6067 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027424 infores:hetionet NCBIGene:4038 biolink:causes MONDO:0008931 infores:monarchinitiative not_provided not_provided HGNC:6696 MONDO:0008931 uuid:e1d18211-4193-46d7-8475-a379bb098592 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013595 infores:hetionet NCBIGene:4689 biolink:causes MONDO:0013507 infores:monarchinitiative not_provided not_provided HGNC:7662 MONDO:0013507 uuid:7a27ef3c-b317-4187-84e1-bba33a8035e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034065 infores:hetionet CHEBI:101278 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0404521 infores:hetionet GO:0141072 biolink:causes GO:0071356 infores:ubergraph knowledge_assertion manual_agent GO:0141072 GO:0071356 NCBIGene:9420 biolink:causes MONDO:0010047 infores:monarchinitiative not_provided not_provided HGNC:2652 MONDO:0010047 uuid:53a2b391-be7f-49c7-a6ed-64768426cf36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027720 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0085096 infores:hetionet CHEBI:63622 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0520966 infores:hetionet NCBIGene:415 biolink:causes MONDO:0010555 infores:monarchinitiative not_provided not_provided HGNC:719 MONDO:0010555 uuid:21c203bb-7116-4b4d-b64e-68a975addbab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA023711 biolink:causes MONDO:0007750 infores:clingen CAID:CA023711 MONDO:0007750 PMID: Likely Benign BP4, BP7 BA1, BS1, PM2, PP4 The NM_000527.5(LDLR):c.507C>T (p.Asn169=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows:BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits; B) does not create AG/GT; C) there is an AG nearby. MES scores: variant cryptic = -0.72, wt cryptic = -0.20, canonical acceptor = 8.16. Ratio variant cryptic/wt cryptic: -0.72/-0.20 = 3.6 --- it is above 1.1. Ratio variant cryptic/canonical acceptor: -0.72/8.16 = -0.09 --- it is not above 0.9. Variant is not predicted to alter splicing. PP3 is not met. BP4 is met.BP7: Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023711/MONDO:0007750/013 2025-01-31 2025-02-27 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:36704 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0015403 infores:hetionet CHEBI:50859 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0546884 infores:hetionet CAID:CA226366 biolink:causes MONDO:0100437 infores:clingen CAID:CA226366 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.1507-97T>C is an intron 12 variant located 97 nucleotides from exon 13. This variant is present in gnomAD v4.1.0 at a frequency of 0.09773 among hemizygous individuals, with 4,178 variant alleles / 42,752 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). The variant is located outside of the splice acceptor region (BP7). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226366/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:9086 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0403632 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0242350 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0021053 infores:hetionet CAID:CA8815680 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815680 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong PM5 The NM_000152.5: c.2297A>C variant in GAA is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 766 (p.Tyr766Ser). At least 12 patients with this variant have been reported including 7 with documented GAA deficiency with <1% of normal mean control level of GAA activity in cultured fibroblasts or GAA activity in the affected leukocytes or dried blood spot (PMID: 22538254, 22521436, 31875618, Clinical Laboratory data), one noted to have deficient GAA activity but results were not provided (PMID: 28394184), and two reported to have Pompe disease with no further details (PMID: 26693141). At least three of these patients are receiving enzyme replacement therapy (PMID: 22521436, 22538254, 26693141 29289479, 30214072, 31899940) (PP4_Moderate). Of the reported patients, at least three are homozygous (PMID: 22521436, 22538254, 26693141 29289479, 31899940, Clinical Laboratory data, and seven were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP including c.1309C>T (p.Arg437Cys) (PMID: 22521436), c.-32-13T>G (Clinical Laboratory Data), c.2608C>T (p.Arg870Ter) (Clinical Laboratory Data), c.525delT (PMID: 30214072), all phase unknown, and c.1822C>T (p.Arg608Ter), confirmed in trans by parental testing (PMID: 31875618) (PM3_Very Strong). Two other individuals are compound heterozygous for the variant and either c.1118T>G (p.Leu373Arg) (Clinical Laboratory data) or c.2105G>A (p.Arg702His) (PMID: 28394184) but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005441 (1/18378 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.98 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies for this variant have not been published. Two other missense variants, c.2297A>G (p.Tyr766Cys) and 2296T>A (p.Tyr766Asn), in the same codon have been reported in patients with Pompe disease. The classification of c.2297A>C (p.Tyr766Ser) will be used to apply PM5 for those other variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 420102; 2 star review status) with five submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel: PM3_VeryStrong, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815680/MONDO:0009290/010 2022-06-03 2022-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:167638 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0701811 infores:hetionet GO:2000074 biolink:causes GO:0031018 infores:ubergraph knowledge_assertion manual_agent GO:2000074 GO:0031018 CHEBI:16469 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0554976 infores:hetionet CHEBI:9566 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0013144 infores:hetionet CHEBI:50922 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0009763 infores:hetionet CHEBI:10023 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0033774 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004238 infores:hetionet CHEBI:135566 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0013604 infores:hetionet CHEBI:63616 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0002878 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0151951 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151951 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0858259 infores:hetionet CHEBI:31348 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018926 infores:hetionet CHEBI:171719 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0002994 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235146 infores:hetionet CHEBI:5801 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0877055 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235351 infores:hetionet CHEBI:8207 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0037036 infores:hetionet NCBIGene:547 biolink:causes MONDO:0013634 infores:monarchinitiative not_provided not_provided HGNC:888 MONDO:0013634 uuid:3bd8f5d7-db71-4569-a7fc-69f51018732c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4975 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0013378 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0919986 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0919986 infores:hetionet NCBIGene:551 biolink:causes MONDO:0007450 infores:monarchinitiative not_provided not_provided HGNC:894 MONDO:0007450 uuid:dee878aa-8ad0-450a-850b-4f58b6e8af4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0857305 infores:hetionet NCBIGene:83696 biolink:causes MONDO:0013173 infores:monarchinitiative not_provided not_provided HGNC:30832 MONDO:0013173 uuid:381f1c8c-e11e-45fd-8b95-c43fffbacff1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3996 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0018794 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0014868 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0042373 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0006277 infores:hetionet NCBIGene:54973 biolink:causes MONDO:0957386 infores:monarchinitiative not_provided not_provided HGNC:26052 MONDO:0957386 uuid:ffd904c1-34ed-4793-85ed-21d016c8f269 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6797 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0012833 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011334 infores:hetionet CHEBI:3568 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0004604 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039971 infores:hetionet NCBIGene:2705 biolink:causes MONDO:0010549 infores:monarchinitiative not_provided not_provided HGNC:4283 MONDO:0010549 uuid:c72c00c2-3f40-400e-a9f9-1eebb68bd182 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA233659 biolink:causes MONDO:0100039 infores:clingen CAID:CA233659 MONDO:0100039 PMID: Likely Benign BS2, BP4 RS1 (NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the non-coding 3' region of the main CDKL5 transcript (NM_ 001323289.2). The c.3031 G>A (p.Ala1011Thr) variant in CDKL5 transcript (NM_003159.2) (RS1 c.184+3171C>T) is observed in at least 2 unaffected individuals (GeneDx internal database)(BS2). Computational analysis prediction tools suggest that the c.3031 G>A variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.3031 G>A variant in the alternate CDKL5 transcript (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA233659/MONDO:0100039/034 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Contradicts true CHEBI:36791 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011206 infores:hetionet CHEBI:135930 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0042384 infores:hetionet CHEBI:465284 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151747 infores:hetionet CHEBI:71941 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0017181 infores:hetionet CHEBI:5138 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085932 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0042769 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235431 infores:hetionet CHEBI:7494 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0015967 infores:hetionet CHEBI:45783 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1384353 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0424605 infores:hetionet CHEBI:194135 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1527344 infores:hetionet CHEBI:17688 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0600142 infores:hetionet CHEBI:47780 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2830004 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0851341 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0032285 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0948296 infores:hetionet CHEBI:41879 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0016242 infores:hetionet CHEBI:9943 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0080274 infores:hetionet CHEBI:4953 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0042963 infores:hetionet CAID:CA10568071 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568071 MONDO:0010602 PMID:24108539PMID:21645226 Likely Benign BA1, PS3 PP3, BP4, PS4 The c.4828G>T variant in F8 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 1610 (p.Ala1610Ser) at exon 14 affecting the B domain of the F8 protein. This variant has been reported in 1 patient meeting phenotypic criteria for Hemophilia A. However, PS4_supporting cannot be applied because number of probands must be >=8 since 3 males are seen with this variant in gnomAD v2.1.1 (PMID: 8639447). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0006065 (9/14839 alleles) in East Asian population, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold(>=0.000333) for BA1, and therefore meets this criterion (BA1). 3 males are reported with this variant. The highest MAF in gnomAD v4.1.1 is 0.0002072 (7/33790) in East Asian population, with 2 males reported with this variant, so does not meet BA1 cut-off in gnomAD v4.1.1 as per current rules. One-stage clotting assay in HEK 293T cells showed reduced FVIII:C activity of < 20% of WT but normal FVIII:Ag (approx 60% of WT) indicating that this variant impacts protein function (PMID: 24108539) (PS3). APTT and ELISA in COS-1 and CHO cells showed normal FVIII:C and FVIII:Ag levels (>80% of WT) indicating that this variant does not impact protein function (PMID: 21645226)(BS3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel (version 1.0.0, released 10/5/2023): BA1, PS3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568071/MONDO:0010602/071 2025-05-01 2025-05-01 X-linked inheritance HP:0001417 Contradicts true CAID:CA377482178 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482178 MONDO:0017623 PMID: Pathogenic PM2, PP2, PS4_Supporting, PM5, PS3 BS1, PP1, BA1 PTEN c.319G>T (p.Asp107Tyr) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 10866302, PMID 29706350, PMID 29785012)PM2: Absent in large sequenced populations (PMID 27535533)PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 372481, SCV000930124)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23382303) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482178/MONDO:0017623/003 2021-10-29 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68584 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0003467 infores:hetionet CHEBI:8863 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0231528 infores:hetionet CHEBI:49603 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0017178 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151505 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151828 infores:hetionet CHEBI:17026 biolink:causes MONDO:0011827 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013274 infores:hetionet CHEBI:50742 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0018681 infores:hetionet GO:1900133 biolink:causes GO:0001999 infores:ubergraph knowledge_assertion manual_agent GO:1900133 GO:0001999 CAID:CA902256 biolink:causes MONDO:0100368 infores:clingen CAID:CA902256 MONDO:0100368 PMID: Likely Benign BP4, BP7 BS1 NM_000329.3(RPE65):c.978G>T (p.Val326=) is a silent variant located near the center of exon 11. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0003016, with 15 alleles / 30608 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 and fails to meet this criterion. The splicing impact predictor SpliceAI gives a delta score of 0.01 for splice donor loss and splice donor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902256/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Contradicts true GO:0072043 biolink:causes GO:0072033 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072033 CHEBI:5118 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040034 infores:hetionet CHEBI:144551 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011603 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002519 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0003462 infores:hetionet CHEBI:9907 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0003811 infores:hetionet CHEBI:37941 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0011603 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0022660 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027651 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0040435 infores:hetionet CHEBI:135930 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0022346 infores:hetionet NCBIGene:6391 biolink:causes MONDO:0011740 infores:monarchinitiative not_provided not_provided HGNC:10682 MONDO:0011740 uuid:a780dcc4-4d00-44de-b3c2-85dbdf6755bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10529714 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529714 MONDO:0010604 PMID: Benign BA1 The NM_000133.4:c.51C>T (p.Ile17=) synonymous variant is reported at a high MAF of 0.004462 (125/28017 alleles with 31 hemizygotes) in the Latino population of gnomAD v2.1.1, meeting the BA1 cut-off of >/= 0.0000556. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529714/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:52717 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013362 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0010709 infores:hetionet CHEBI:46557 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0014236 infores:hetionet CHEBI:3216 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011168 infores:hetionet CHEBI:63617 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011603 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0016204 infores:hetionet CHEBI:8707 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0424295 infores:hetionet NCBIGene:83894 biolink:causes MONDO:0032896 infores:monarchinitiative not_provided not_provided HGNC:29936 MONDO:0032896 uuid:e4d7cdf4-8516-4c97-a23a-ea16793fc17b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0009763 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009450 infores:hetionet CHEBI:47381 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085605 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018799 infores:hetionet CHEBI:42944 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003635 infores:hetionet CHEBI:64064 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0038450 infores:hetionet CHEBI:17688 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0014724 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151849 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0948594 infores:hetionet CHEBI:63638 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0023052 infores:hetionet CHEBI:37941 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1112525 infores:hetionet CHEBI:7445 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0546884 infores:hetionet NCBIGene:6605 biolink:causes MONDO:0014838 infores:monarchinitiative not_provided not_provided HGNC:11109 MONDO:0014838 uuid:f3162014-ca8f-4dce-83b6-0bb85534b986 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0948594 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0014130 infores:hetionet CHEBI:7773 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0013144 infores:hetionet CHEBI:35778 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0033774 infores:hetionet CHEBI:15544 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0004604 infores:hetionet CHEBI:5134 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0027441 infores:hetionet CHEBI:35854 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0085631 infores:hetionet CHEBI:64045 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0042267 infores:hetionet CHEBI:63637 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0919980 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0014130 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0549373 infores:hetionet NCBIGene:5521 biolink:causes MONDO:0011439 infores:monarchinitiative not_provided not_provided HGNC:9305 MONDO:0011439 uuid:330d4b17-6ed0-48d1-ad29-55b66a75f85a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27786 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0041969 infores:hetionet CAID:CA500651166 biolink:causes MONDO:0100326 infores:clingen CAID:CA500651166 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The variant NM_000212.3(ITGB3):c.1409dup (p.Asn470LysfsTer2) is a frameshift variant found in exon 10, predicted to cause a premature stop codon in biologically-relevant-exon 10/15 (PVS1). The variant has been detected in at least 1 proband with Glanzmann Thrombasthenia (GT-1, PMID: 23300803). This individual was compound heterozgous for this frameshift variant and likely pathogenic variant NM_000212.3(ITGB3):c.392G>C (p.Arg131Pro) (PM3). Finally, this variant was absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3, PVS1 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500651166/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9943 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0206062 infores:hetionet CHEBI:5779 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0231528 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0243026 infores:hetionet GO:1905651 biolink:causes GO:0060840 infores:ubergraph knowledge_assertion manual_agent GO:1905651 GO:0060840 CHEBI:6339 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0002965 infores:hetionet CHEBI:6062 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0344232 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0403632 infores:hetionet CHEBI:10102 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0000737 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0027726 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0005940 infores:hetionet CHEBI:3176 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0004604 infores:hetionet CAID:CA152660 biolink:causes MONDO:0015152 infores:clingen CAID:CA152660 MONDO:0015152 PMID: Benign BA1, BP4 BP7 The NM_003494.4: c.1284+6G>C variant in DYSF, which is also known as NM_001130987.2: c.1380+6G>C, occurs within the splice donor motif (positions +6 to -3) of intron 13. The Grpmax filtering allele frequency for this variant is 0.02256 in gnomAD v4.1.0 (the lower bound of the 95% CI of 1761/75030 African/African American chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). This variant is also not predicted to significantly affect splicing (non-masked SpliceAI delta score <0.05; BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/14/2025): BA1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA152660/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8207 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0234215 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013395 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014118 infores:hetionet CAID:CA414790267 biolink:causes MONDO:0044970 infores:clingen CAID:CA414790267 MONDO:0044970 PMID:16404693PMID:34072215PMID:16404693PMID:34072215PMID:16404693PMID:34072215 Likely Benign BP4, BP5 PP1, BA1, PS4, PS2, PS3, BS1, PM2, PM6 The m.6951G>A variant in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. Multiple unaffected family members were found to be homoplasmic for this variant in private databases known to this expert panel. In all of these families, the affected individuals had alternate genetic causes determined for their disease (BP5). This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 is 26/56,416 (0.046%) with 26 homoplasmic occurrences and one heteroplasmic occurrence spread over eight top level haplogroups (single letter) with European, Asian, and African ancestry. The frequency in MITOMAP GenBank sequences is 20/59,389 (0.034%) spread over eight top level haplogroups with European, and Asian ancestry. The frequency in the Helix dataset is 75/195,983 (0.038%, all homoplasmic) plus an additional 13 heteroplasmic occurrences, all spread over 17 top level haplogroups with European, Asian, and African ancestry. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). The computational predictor APOGEE gives scores of 0.41 (“neutral”) in APOGEE1 and 0.101 (“likely benign”) in APOGEE2 (Min=0, Max=1), which predict a no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant to date. In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4, BP5. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414790267/MONDO:0044970/015 2023-07-10 2023-08-03 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:81603 biolink:causes MONDO:0100111 infores:monarchinitiative not_provided not_provided HGNC:15579 MONDO:0100111 uuid:57f30cb1-dd5c-4809-8a7a-5eef8ac15faf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3614 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0221776 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0009450 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0004238 infores:hetionet CHEBI:8768 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0015967 infores:hetionet CHEBI:63584 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0043352 infores:hetionet CAID:CA6573017 biolink:causes MONDO:0010880 infores:clingen CAID:CA6573017 MONDO:0010880 PMID: Uncertain Significance PM2, PP3 The NM_000020.3: c.917C>T variant in ACVRL1 is a missense variant predicted to cause substitution of alanine by valine at amino acid 306 (p.Ala306Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001086 (14/128884 alleles) in the European (non-Finnish) population. The computational predictor REVEL gives a score of 0.365, which is neither above nor below the thresholds predicting a damaging or benign impact on ACVRL1 function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: None (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA6573017/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA367401300 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401300 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PP2, PP3, PM2_Supporting PP4 The c.629T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 210 (p.(Met210Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.982, which is greater than the MDEP threshold of 0.70 (PP3). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Met210Thr has Kcat/S0.5<0.5 (PS3_Supporting; PMID: 14517946, DOI:10.1007/s001250051289). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency of due to 0 copies observed in the European non-Finnish population and only 1 copy in another subpopulation (Latino/admixed), thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in 11 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 25555642, 9049484, ClinVar ID: 804852, internal lab contributor). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributor). This variant segregated with diabetes, with 5 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). Taken together, the evidence supports the classification of c.629T>C as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PS4, PS3_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401300/MONDO:0015967/086 2024-01-18 2024-01-18 Semidominant inheritance HP:0032113 Supports GO:0061344 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:0061344 GO:0007507 CHEBI:5790 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0021167 infores:hetionet CHEBI:4027 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0023530 infores:hetionet NCBIGene:811 biolink:causes MONDO:0009692 infores:monarchinitiative not_provided not_provided HGNC:1455 MONDO:0009692 uuid:2352fc63-bf27-4640-b259-16fdf675be0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0948594 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1619712 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0559031 infores:hetionet CHEBI:31236 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2937358 infores:hetionet CHEBI:45409 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C2364111 infores:hetionet CAID:CA6748701 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748701 MONDO:0009861 PMID:28982351PMID:28982351PMID:26503515 Likely Pathogenic PM3, PP4_Moderate, PM2 PP3 The c.1285C>A (p.Gln429Lys) variant in PAH is reported in a patient with mild PKU (Phe level 720). BH4 cofactor deficiency was excluded. It was detected with a known pathogenic variant, EX6-96A>G (VarID 590). (PMID: 26503515, 28982351) This variant has a low frequency in gnomAD and ExAC (MAF=0.00002), and absent in 1000G. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748701/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0008325 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0270458 infores:hetionet CHEBI:6456 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0017574 infores:hetionet CHEBI:3013 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0151436 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0151529 infores:hetionet UMLS:C0120107 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0080274 infores:hetionet CHEBI:75988 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0595916 infores:hetionet CHEBI:82941 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C2129214 infores:hetionet CHEBI:520985 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0042963 infores:hetionet CHEBI:68558 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0017181 infores:hetionet CHEBI:3061 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0042571 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0015397 infores:hetionet CAID:CA346365197 biolink:causes MONDO:0021060 infores:clingen CAID:CA346365197 MONDO:0021060 PMID:17586837PMID:11333268PMID:17586837PMID:11333268PMID:17586837PMID:20673819 Likely Pathogenic PS2, PM2, PP2, PP3, PS4_Supporting PS1, PS3, PM5, PM1, PM4, BP7, BP5, BS3, BS4, BS1, PM6, BS2, PP1, BP3, BP2, BP1, BP4, BA1 The c.1867T>A (p.Phe623Ile) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of Noonan syndrome (PS2; PMID 17586837, 20673819). The p.Phe623Ile variant has also been identified in another independent occurrence in a patient with clinical features of Noonan syndrome (PS4_Supporting; PMID 20673819). This variant was absent from large population studies (PM2; gnomAD; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Phe623Ile variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, two different pathogenic missense variants have been previously reported at this codon of SOS1 (p.Phe623Val and p.Phe623Glu) which may indicate that this residue is critical to the function of the protein, however these variants have not yet met the criteria to be classified as pathogenic (PM5 not met). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346365197/MONDO:0021060/004 2019-02-28 2019-07-15 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63627 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0231528 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0520587 infores:hetionet NCBIGene:6821 biolink:causes MONDO:0010089 infores:monarchinitiative not_provided not_provided HGNC:11460 MONDO:0010089 uuid:0ab87c6b-24f5-4132-ae03-a0dcc1555600 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018524 infores:hetionet CHEBI:585948 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0015230 infores:hetionet CAID:CA350341841 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341841 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, PM1 PM6, PP3, BP4, BA1, PS2, PS4, BS1 The c.1202T>C (p.Leu401Ser) variant is a missense variant harboured inexon 9 of the BMPR2 gene, predicted to cause substitution of leucine toserine encoding the functionally relevant catalytic kinase domain but withoutfunctional evidence indicating either critical or non-critical amino acid residue (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.72, below the PH VCEP threshold of >=0.75 for pathogenicity but above the threshold of <=0.25 for benignity (PP3 and BP4 not met). The variant has been identified in a single individual with hereditary PAH, included in two reports (PMID: 32581362 and PMID: 16429395) (PS4 not met). The variant was paternally inherited (PS2 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_not met (VCEP specification version 1.1.0, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341841/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28148 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0015734 infores:hetionet CAID:CA10585585 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585585 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PS3, PP1_Moderate, PM2, PP3, PP4 The NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PP1_moderate, PM2, PP3, PS4_supporting, PP4, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3: Level 1 assays: PMID 25378237: Heterologous cells, FACS assays -10-15% LDL-LDLR binding; 5% LDL-LDLR uptake; 5% cell surface LDLR---- activity is below 70% of wild-type, so functional study is consistent with damaging effect.PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.937.PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute; 1 case with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation))PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585585/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA10014395 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014395 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-15_614-9dup is an intronic variant in RUNX1 which has not been featured in functional or case studies. Computational and population data have been used to evaluate this variant. The MAF of 0.0003205 (0.03205%, 24/74,884 alleles) in the African/African American subpopulation of gnomAD v4 allows for the application of BS1. This variant has a SpliceAI score of 0.02, allowing for the application of BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014395/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9449 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0020458 infores:hetionet GO:0060224 biolink:causes GO:0060041 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0060041 CHEBI:5959 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0039070 infores:hetionet UMLS:C0657912 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0000737 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040261 infores:hetionet CHEBI:9448 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0003126 infores:hetionet CHEBI:9763 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235086 infores:hetionet CAID:CA512341341 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341341 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1056C>T (p.Ala352=) is a synonymous variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). SpliceAI predicts no impact to splicing (score: 0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.495 (BP7). This variant was reported in ClinVar in 2022 by Invitae but the affected status of the proband is unknown (Variation ID 1577145). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341341/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63598 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0853847 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0042109 infores:hetionet CHEBI:4672 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0014335 infores:hetionet CHEBI:9727 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0232462 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0948525 infores:hetionet CHEBI:50648 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003862 infores:hetionet CHEBI:17347 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0041657 infores:hetionet CHEBI:135566 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0013378 infores:hetionet CHEBI:51450 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0041657 infores:hetionet CHEBI:2549 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0016927 infores:hetionet CHEBI:49375 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0010828 infores:hetionet CHEBI:6339 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0038325 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0020517 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1262013 infores:hetionet NCBIGene:84627 biolink:causes MONDO:0024543 infores:monarchinitiative not_provided not_provided HGNC:23216 MONDO:0024543 uuid:23fd59cd-f091-4e7d-949c-8bb58fe5e0ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28445 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0040034 infores:hetionet NCBIGene:23327 biolink:causes MONDO:0014966 infores:monarchinitiative not_provided not_provided HGNC:7728 MONDO:0014966 uuid:dbe420ff-37ea-4750-9c90-c7e8a3722f34 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA380145381 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145381 MONDO:0000573 PMID: Uncertain Significance PP4, PM2_Supporting, PVS1_Supporting, PM1_Supporting NM_000536.4(RAG2):c.1A>G is a missense variant predicted to cause substitution of Methionine by Valine at amino acid 1 (p.Met1Val). This sequence change affects the initiator methionine of the RAG2 mRNA. The next possible initiation codon is at codon 5. This region does not contain known pathogenic/likely pathogenic variants (PVS1_Supporting). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). Female with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.)& T-B-NK+ lymphocyte subset profile (0.5 pt.) (Total :1.5 pts) (PP4 met) (PMID: 31031743). The patient was found compound heterozygous for c.1A>G; p.M1V and c.1403_1406delATCT (not evaluated by SCID VCEP yet) (PMID: 31031743) (PM3 not evaluated). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Supporting,PM1_supporting, PM2_supporting,PP4 met(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145381/MONDO:0000573/124 2024-06-14 2024-06-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:37333 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0009450 infores:hetionet CHEBI:204928 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0033774 infores:hetionet CHEBI:3757 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0020453 infores:hetionet NCBIGene:10625 biolink:causes MONDO:0033542 infores:monarchinitiative not_provided not_provided HGNC:16951 MONDO:0033542 uuid:316474fa-12b5-439c-9de4-7f898e479f43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:4751 biolink:causes MONDO:0005915 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D014010 DB09321_MESH_D014010_1 CHEBI:6847 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0020517 infores:hetionet CHEBI:74947 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042487 infores:hetionet CHEBI:80630 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151744 infores:hetionet CHEBI:9588 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0015230 infores:hetionet CHEBI:75722 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0023380 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0162429 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0020651 infores:hetionet NCBIGene:6710 biolink:causes MONDO:0000913 infores:monarchinitiative not_provided not_provided HGNC:11274 MONDO:0000913 uuid:6331d112-1860-4862-8226-0e8a3e0934da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0392525 infores:hetionet CHEBI:8412 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0027497 infores:hetionet CAID:CA414791958 biolink:causes MONDO:0044970 infores:clingen CAID:CA414791958 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, BP4 PP3, PS4, PS3 The m.7222A>G (p.Tyr440Cys) variant in MT-CO1 has been reported in two individuals with primary mitochondrial disease (PMIDs: 22632780, 32652755). The first reported individual was a woman in her 60s with an 18 month history of progressive muscle weakness, ptosis, and hyperreflexia. Muscle biopsy showed scattered COX-negative and SDH-positive fibers. The variant was present in muscle at 24% heteroplasmy, in urine sediment at 37% heteroplasmy, and in hair at 5.3% heteroplasmy. The variant was undetectable in blood and buccal mucosa (PMID: 22632780). The second reported individual had peripheral neuropathy, ptosis, and myopathy. The variant was present in muscle at >50% heteroplasmy (PMID: 32652755). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of neutral with a score of 0.41 (Min=0, Max=1, BP4). There are no single fiber studies or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414791958/MONDO:0044970/015 2024-10-28 2025-11-06 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2955 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0009806 infores:hetionet CHEBI:7459 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0018790 infores:hetionet CHEBI:31348 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0015468 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009450 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085606 infores:hetionet CHEBI:3647 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0015967 infores:hetionet CHEBI:3127 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013595 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042373 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0314719 infores:hetionet CHEBI:44915 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0427086 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0022104 infores:hetionet CHEBI:4356 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0018681 infores:hetionet CHEBI:4708 biolink:causes MONDO:0041775 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1688637 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1456863 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1456863 infores:hetionet NCBIGene:64699 biolink:causes MONDO:0010987 infores:monarchinitiative not_provided not_provided HGNC:11877 MONDO:0010987 uuid:d6f6b33d-c143-48f1-84de-ad9137a1a840 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0239978 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042075 infores:hetionet CHEBI:18358 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0409974 infores:hetionet CHEBI:110423 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0022660 infores:hetionet CHEBI:5138 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020578 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0232492 infores:hetionet CHEBI:6838 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0020517 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013447 infores:hetionet CHEBI:3568 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015403 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0024299 infores:hetionet CHEBI:3752 biolink:causes MONDO:0007345 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003492 infores:hetionet CHEBI:27882 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0030446 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0027769 infores:hetionet CHEBI:75722 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0035508 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029408 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0021167 infores:hetionet CHEBI:101278 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0017181 infores:hetionet CHEBI:119915 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0039070 infores:hetionet CHEBI:51450 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0003862 infores:hetionet CHEBI:64355 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151825 infores:hetionet CHEBI:3175 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0036974 infores:hetionet CHEBI:2611 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0041657 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0005741 infores:hetionet CHEBI:8764 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020598 infores:hetionet CHEBI:681569 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0033774 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0001418 infores:hetionet CHEBI:49575 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233754 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027769 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0002878 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013220 infores:hetionet CHEBI:3696 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0035305 infores:hetionet CHEBI:63617 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151827 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030305 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0424823 infores:hetionet NCBIGene:112752 biolink:causes MONDO:0013573 infores:monarchinitiative not_provided not_provided HGNC:29669 MONDO:0013573 uuid:1beba877-97aa-4f87-9ecb-cba8507089bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134966 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0085614 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042345 infores:hetionet CHEBI:84500 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0232462 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0014130 infores:hetionet CHEBI:135876 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0027497 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0270994 infores:hetionet CHEBI:4681 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0004604 infores:hetionet CAID:CA130526 biolink:causes MONDO:0015967 infores:clingen CAID:CA130526 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PS3, PS4, PM1 The c.1015G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 339 (p.(Glu339Lys)) of NM_000545.8. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.963, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 221104275). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (MDEP, PMIDs: 21104275, 34362814). This variant segregated with hyperglycemia, with 4 informative meioses in one family (PP1_Moderate; PMID: 21104275). The 5 individuals with the variant in this family had a clinical history highly specific for GCK-hyperglycemia (all FBG 5.5-8 mmol/L and mean HbA1c 5.6 - 7.6% and antibody-negative)(PP4_Moderate, PMID: 21104275). In summary, c.1015G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA130526/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:45863 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0016242 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1142011 infores:hetionet CHEBI:253342 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0236124 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853760 infores:hetionet CHEBI:40303 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0040822 infores:hetionet NCBIGene:831 biolink:causes MONDO:0014574 infores:monarchinitiative not_provided not_provided HGNC:1515 MONDO:0014574 uuid:8e59acb3-2314-4fc6-a17b-acb4cd808366 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2711227 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027932 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0040264 infores:hetionet CHEBI:63619 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0239739 infores:hetionet CAID:CA8815178 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815178 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PS3_Supporting PM5 The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID: 18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID: 21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) variant meets the criteria to be classified as likely pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815178/MONDO:0009290/010 2022-09-20 2022-12-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:52717 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1443060 infores:hetionet CHEBI:42797 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085633 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0853149 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151602 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0037199 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0027651 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021895 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039496 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0032285 infores:hetionet CHEBI:79699 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1535939 infores:hetionet CHEBI:3814 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0026858 infores:hetionet CHEBI:9398 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0027441 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017168 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006798 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020579 infores:hetionet GO:0061046 biolink:causes GO:0030323 infores:ubergraph knowledge_assertion manual_agent GO:0061046 GO:0030323 CHEBI:92923 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0040435 infores:hetionet NCBIGene:2582 biolink:causes MONDO:0958333 infores:monarchinitiative not_provided not_provided HGNC:4116 MONDO:0958333 uuid:55c94e37-31db-4000-81ca-9f0644382a26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027059 infores:hetionet CHEBI:10650 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030252 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0919883 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0919883 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1565489 infores:hetionet CHEBI:68642 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0016655 infores:hetionet CHEBI:3127 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0009763 infores:hetionet CHEBI:681850 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0085649 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020473 infores:hetionet CAID:CA199300 biolink:causes MONDO:0010726 infores:clingen CAID:CA199300 MONDO:0010726 PMID: Benign BS1, BS2 BA1 The allele frequency of the p.Pro402Leu variant in MECP2 (NM_004992) is 0.011% in European (Non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro402Leu variant is observed in at least 4 unaffected individuals (PMID 12384770) (BS2). In summary the p.Pro402Leu variant in MECP2 is classified as Benign for Rett syndrome disorder based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199300/MONDO:0010726/016 2022-05-11 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA386960641 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960641 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4, PP3 The c.503G>A variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to proline at codon 168 (p.(Arg168Pro)) of NM_000545.8. This variant is located within the DNA binding domains (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.922, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.503G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960641/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8863 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2242588 infores:hetionet CHEBI:6067 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0232487 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0392025 infores:hetionet CHEBI:9328 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0024141 infores:hetionet CAID:CA012515 biolink:causes MONDO:0005201 infores:clingen CAID:CA012515 MONDO:0005201 PMID:27532257PMID:18380764PMID:18380764 Pathogenic PP3, PM1, PM2, PS4_Supporting, PS2 The c.2513C>T (p.Pro838Leu) variant in MYH7 has been reported as a de novo occurrence in two individuals with restrictive cardiomyopathy (PS4_Supporting and PS2: PMID:18380764; Partners LMM ClinVar SCV000059450.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for restrictive cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS2; PM1; PM2; PP3; PS4_ Supporting Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012515/MONDO:0005201/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:2296 biolink:causes MONDO:0011233 infores:monarchinitiative not_provided not_provided HGNC:3800 MONDO:0011233 uuid:e9d0ad20-f0c3-47d9-8802-5fb42af53313 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0008049 infores:hetionet CHEBI:520985 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0043352 infores:hetionet CHEBI:45285 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0003123 infores:hetionet NCBIGene:2692 biolink:causes MONDO:0032567 infores:monarchinitiative not_provided not_provided HGNC:4266 MONDO:0032567 uuid:b57af6ca-29be-4862-8cea-5cfb34be9d1b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1306341 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0017178 infores:hetionet CAID:CA396457818 biolink:causes MONDO:0007648 infores:clingen CAID:CA396457818 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.529C>T (p.Gln177Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000665073.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396457818/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:75922 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0013238 infores:hetionet CHEBI:17303 biolink:causes EFO:0020923 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151821 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235416 infores:hetionet CHEBI:7798 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0231528 infores:hetionet CHEBI:4856 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0004093 infores:hetionet CHEBI:31623 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0042909 infores:hetionet CHEBI:17303 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0016204 infores:hetionet CHEBI:5118 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085593 infores:hetionet CHEBI:51860 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0030554 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019348 infores:hetionet GO:0039646 biolink:causes GO:0045023 infores:ubergraph knowledge_assertion manual_agent GO:0039646 GO:0045023 CHEBI:71415 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0010200 infores:hetionet CHEBI:9215 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0012833 infores:hetionet CHEBI:31980 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0558489 infores:hetionet CHEBI:44185 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0009763 infores:hetionet CAID:CA229814 biolink:causes MONDO:0009861 infores:clingen CAID:CA229814 MONDO:0009861 PMID:8860005PMID:8981952PMID:9521426PMID:23430918 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.; PP4_Moderate: Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism. (PMID:8860005; PMID:8981952); PM3_Strong: Detected in trans with I269L and R408W, known pathogenic variants. (PMID:9521426; PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229814/MONDO:0009861/006 2018-09-11 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63580 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0162529 infores:hetionet CHEBI:8502 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0037290 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0160390 infores:hetionet CHEBI:2955 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0015230 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0036454 infores:hetionet CHEBI:8874 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027497 infores:hetionet CHEBI:9671 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0002888 infores:hetionet CAID:CA280048 biolink:causes MONDO:0010726 infores:clingen CAID:CA280048 MONDO:0010726 PMID: Uncertain Significance BS2, PM2_Supporting PM1, PP4 The p.Lys417Met variant in MECP2 (NM_004992.3) is observed in at least 3 unaffected individuals (PMID 16832102; internal database - GeneDx) (BS2). The p.Lys417Met variant in MECP2 has been reported in a male with early onset encephalopathy (PMID 16832102). The p.Lys417Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Lys417Met variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA280048/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:61049 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0035222 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0541832 infores:hetionet CHEBI:7627 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0033771 infores:hetionet CHEBI:55346 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0032227 infores:hetionet CHEBI:50730 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0033774 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005152 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020635 infores:hetionet NCBIGene:149371 biolink:causes MONDO:0033662 infores:monarchinitiative not_provided not_provided HGNC:24659 MONDO:0033662 uuid:bc9faf16-cf4c-44e5-92fb-773060faddf9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4995 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151849 infores:hetionet CHEBI:3216 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C2047937 infores:hetionet CHEBI:7494 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017605 infores:hetionet CHEBI:10102 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013491 infores:hetionet NCBITaxon:45258 biolink:causes MONDO:0000230 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:45258 MONDO:0000230 CHEBI:9667 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0333641 infores:hetionet CHEBI:48538 biolink:causes UMLS:C0853008 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0853008 infores:hetionet CHEBI:3568 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235592 infores:hetionet CHEBI:135935 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0039231 infores:hetionet CHEBI:27796 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0344232 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0029445 infores:hetionet CHEBI:15365 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0041657 infores:hetionet CHEBI:50673 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0027497 infores:hetionet CHEBI:50275 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085605 infores:hetionet CAID:CA392317779 biolink:causes MONDO:0007947 infores:clingen CAID:CA392317779 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Supporting, PM1, PM5 PVS1, PM6, BS2, PP1, BP1, BP4, BP2, BP3, BA1, PM3, PM4, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4280A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 1427 (p.Tyr1427Cys). This variant has been identified in the literature in an individual with either a suspicion or diagnosis of Marfan syndrome, and by a commercial laboratory in two unrelated individuals with thoracic aortic aneurysm and dissection (TAAD), segregating with TAAD in one similarly affected family member (PS4_supporting; PMID: 21907952, Invitae internal data). It was also identified by a commercial laboratory in an individual with Marfan syndrome including ectopia lentis and a systemic score of 8 (PP4; GeneDx internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & 3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.939). Another variant affecting the same residue (p.Tyr1427Asp) is classified as likely pathogenic, further supporting the functional importance of this amino acid position (PM5; PMID: 17657824). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_supporting, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392317779/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63629 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0009763 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151773 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009782 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0005586 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0006277 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0162848 infores:hetionet CHEBI:45863 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085610 infores:hetionet CHEBI:3568 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0001807 infores:hetionet CHEBI:64355 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013604 infores:hetionet CHEBI:6413 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0027497 infores:hetionet CHEBI:135920 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0033774 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0037274 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005095 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0949691 infores:hetionet CAID:CA356960 biolink:causes MONDO:0021060 infores:clingen CAID:CA356960 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.36C>T (p.Gly12=) variant in the HRAS gene is 0.0461% (8/8626) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA356960/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8404 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C1145670 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034065 infores:hetionet GO:1903684 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:1903684 GO:0060429 CHEBI:63635 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0018681 infores:hetionet CHEBI:72564 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0030554 infores:hetionet CHEBI:3508 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0018524 infores:hetionet CHEBI:119915 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C3203358 infores:hetionet CHEBI:28918 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0008031 infores:hetionet CHEBI:8888 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0008350 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0267792 infores:hetionet NCBIGene:2729 biolink:causes MONDO:0009259 infores:monarchinitiative not_provided not_provided HGNC:4311 MONDO:0009259 uuid:c0870da8-c158-4ec4-a631-49175667e406 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018520 infores:hetionet CHEBI:50173 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151692 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0018681 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015230 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0020517 infores:hetionet CHEBI:7496 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0038990 infores:hetionet CAID:CA229757 biolink:causes MONDO:0009861 infores:clingen CAID:CA229757 MONDO:0009861 PMID:11385716PMID:1682234 Pathogenic PM3, PVS1, PP4 PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4: Detected in 2 unrelated patients (PMID:1682234); PM3: Detected with H170D, pathogenic (PMID:11385716). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229757/MONDO:0009861/006 2018-08-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8499 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C1384353 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0234215 infores:hetionet NCBIGene:285527 biolink:causes MONDO:0975953 infores:monarchinitiative not_provided not_provided HGNC:29127 MONDO:0975953 uuid:f027117a-74ba-40b4-9bca-d3508d0a49b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA231160 biolink:causes MONDO:0015967 infores:clingen CAID:CA231160 MONDO:0015967 PMID: Uncertain Significance PM2 BP4, PP3 The c.1114G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 372 (p.(Ala372Thr)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant has a REVEL score of 0.371, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1114G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA231160/MONDO:0015967/017 2025-04-11 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9398 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0042109 infores:hetionet CHEBI:8081 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0234233 infores:hetionet CAID:CA2739267604 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267604 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1295dup (p.Cys432TrpfsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM5_supporting, PVS1_strong. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267604/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3614 biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0235339 infores:hetionet CAID:CA9870428 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870428 MONDO:0015967 PMID: Likely Benign BS2, BP4, BP7 PM2, BS1 The c.1017C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 339 (p.(Phe339=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -3.055, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c. 1017C>T variant in gnomAD v2.1.1 is 0.00002141, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (PMID: 29026101)(MDEP internal contributor; BS2). In summary, c. 1017C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/22): BS2, BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870428/MONDO:0015967/085 2023-01-12 2023-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5441 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0041834 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0233472 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020538 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0235296 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235296 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0877322 infores:hetionet CHEBI:4953 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0038358 infores:hetionet CAID:CA412376061 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376061 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PM1_Strong, PM5 PP3 NM_000330.4(RS1):c.175T>C (p.Cys59Arg) is a missense variant encoding the substitution of cysteine with arginine at amino acid 59, which is a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). Another missense variant in the same codon, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 31174210, 10450864, 17987333, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (180) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.833, which is within the ClinGen X-linked IRD VCEP range of 0.931 to 0.773, and predicts a damaging effect on RS1 function. PP3 is not met as this code is ineligible to be combined with the PM1_Strong code. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked Retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, and PM5. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376061/MONDO:0010725/126 2025-10-03 2025-10-03 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:63599 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0231218 infores:hetionet CHEBI:28901 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151872 infores:hetionet CAID:CA229313 biolink:causes MONDO:0009861 infores:clingen CAID:CA229313 MONDO:0009861 PMID:10394930 Pathogenic PVS1, PP4, PM2_Supporting The c.1063C>T (p.Gln355Ter) variant in PAH has been reported in a German PKU patient. (PP4; PMID: 10394930). This variant is absent from population databases (PM2_supporting). It is a null variant (nonsense) in exon 10/13 (NMD predicted) in PAH, a gene where loss of function is a known mechanism of disease (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229313/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151636 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233794 infores:hetionet CHEBI:2904 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0233407 infores:hetionet CHEBI:9137 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018965 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009319 infores:hetionet CAID:CA6197628 biolink:causes MONDO:0019501 infores:clingen CAID:CA6197628 MONDO:0019501 PMID: Likely Pathogenic PP1_Strong, PP3, PM3 BS1, PP2, PP4, PM2, BA1, BP1, BP4 The c.1849T>C variant in MYO7A is a missense variant predicted to cause substitution of serine by proline at amino acid 617 (p.Ser617Pro). The highest population minor allele frequency in gnomAD v4 is 0.00009496 (8/84244 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with nonsyndromic hearing loss. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (c.20G>T [p.Gly7Val], c.1258A>T [p.K420*], 2 PM3 points, PMIDs: 30303587, 33187236). One individual was homozygous for the variant (0.5 PM3 points, PMIDs: 27344577, 33671976) (PM3). The variant has been reported to segregate with nonsyndromic hearing loss in 7 affected family members from 3 families (PP1_Strong; PMIDs: 27344577, 30303587, 33187236, 33671976). This variant has also been detected in 1 individual with Usher syndrome, with a second variant c.4838delA (p.Asp1613ValfsTer32) without phase confirmation (PMIDs: 28041643, 32581362). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PM3, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024). As cases have been observed with both nonsyndromic hearing loss and Usher syndrome and genotype-phenotype correlation is currently unclear, individuals should be evaluated for both conditions. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6197628/MONDO:0019501/005 2024-06-28 2024-06-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:6709 biolink:causes MONDO:0013277 infores:monarchinitiative not_provided not_provided HGNC:11273 MONDO:0013277 uuid:c51aad5a-5d33-498b-a062-cea5382b9ea7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9763 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0234458 infores:hetionet CHEBI:60761 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0002170 infores:hetionet CHEBI:367163 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020458 infores:hetionet CHEBI:9448 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0232462 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0012833 infores:hetionet CHEBI:32020 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0021400 infores:hetionet CHEBI:8874 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0028961 infores:hetionet CHEBI:74947 biolink:causes MONDO:0019065 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002726 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0221490 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0006434 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006434 infores:hetionet CHEBI:46295 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C1443060 infores:hetionet CAID:CA10653562 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653562 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*1683_*1684del variant in the 3' UTR has an MAF of 0.006654 (0.67%, 58/8716 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653562/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119573 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020557 infores:hetionet NCBIGene:5422 biolink:causes MONDO:0015601 infores:monarchinitiative not_provided not_provided HGNC:9173 MONDO:0015601 uuid:84cdf929-fb1b-4e58-8274-460dbdfedad1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0546884 infores:hetionet CHEBI:3738 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0002792 infores:hetionet CAID:CA10603819 biolink:causes MONDO:0015152 infores:clingen CAID:CA10603819 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1_Moderate, PP1, PM2_Supporting PM4, PS3 The NM_003494.4: c.4886+1249G>T variant in DYSF, which is also known as NM_001130987.2: c.5003+1249G>T, is a deep intronic variant. SpliceAI gives a score of 0.26 for donor gain and 0.12 for acceptor gain. RNAseq analysis has demonstrated two splice effects of this variant: activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 177 bp intronic sequence and a non-frameshifting insertion of 59 amino acids, p.Lys1646_Met1647ins59; and activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 88 bp of intronic sequence and a frameshift with nonsense mediated decay expected, p.Lys1646AsnfsTer13 (PMID: 36983702; PVS1_Moderate_RNA). This variant has been reported in at least four individuals with features consistent with LGMD (PMID: 26273692, 36983702, 30564623, 25493284), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.1168G>A p.(Asp390Asn), 1.0 pt, PMID: 26273692) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 36983702, 30564623, 25493284; NM_003494.4: c.1834C>T p.(Gln612Ter), 0.5 pts, PMID: 25493284) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF showed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702, 25493284; PP4_Strong). In addition, this variant has been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 30564623, 30564623) (PP1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/23/2025): PVS1_Moderate_RNA, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603819/MONDO:0015152/180 2025-04-23 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:80630 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0162529 infores:hetionet CHEBI:194135 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038450 infores:hetionet CHEBI:8890 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0853034 infores:hetionet CHEBI:681848 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0015967 infores:hetionet CHEBI:3504 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0011606 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0004936 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0042109 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0006145 infores:hetionet CHEBI:7936 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015967 infores:hetionet GO:1901298 biolink:causes GO:0034614 infores:ubergraph knowledge_assertion manual_agent GO:1901298 GO:0034614 CHEBI:7852 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235848 infores:hetionet CHEBI:4562 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0008033 infores:hetionet CHEBI:16796 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0152227 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0518015 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0085631 infores:hetionet CHEBI:135005 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0019158 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0948594 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0029408 infores:hetionet CHEBI:8435 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0393593 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0948594 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0017601 infores:hetionet CHEBI:93363 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0020538 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020433 infores:hetionet CHEBI:9139 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0033774 infores:hetionet CAID:CA350341739 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341739 MONDO:0015924 PMID:34400635 Likely Pathogenic PM5_Supporting, PP3, PM2_Supporting, PM1_Strong BP4, PS1 The NM_001204.7(BMPR2):c.1157A>C (p.Glu386Ala) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). The variant has been reported once in an IPAH subject (PMID: 23675998). The variant is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The REVEL prediction algorithm score is 0.991, AlphaMissense is 0.9832 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Gln, p.Glu386Gly, p.Glu386Lys, p.Glu386Val) have been reported at the same position (PMID: 26387786) (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PP3, PM5_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341739/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CAID:CA286505 biolink:causes MONDO:0009861 infores:clingen CAID:CA286505 MONDO:0009861 PMID:10234516PMID:10234516 Likely Pathogenic PP4_Moderate, PM3_Strong PM2, PP3 PAH-specific ACMG/AMP criteria applied: PP4_Moderate: This variant has been reported in multiple mild hyperphenylalaninaemia (MHP) patients, with BH4 defects excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:10234516); PM3_Strong: Detected with P281L and A403V, both pathogenic variants (PMID:10234516). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286505/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:127342 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0033774 infores:hetionet CHEBI:4470 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0235063 infores:hetionet CAID:CA415077745 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077745 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong, PM6_Supporting PM5 The NM_005629.4:c.342G>C variant in SLC6A8 is predicted to result in the substitution of glutamine by histidine at amino acid 114 (p.Gln114His). The variant has been reported in a male with clinical features consistent with creatine transporter deficiency, markedly elevated urine creatine, and markedly reduced creatine on brain MRS (Association for Creatine Deficiencies registry - CreatineINFO) (PP4_Strong). His mother does not carry the variant; maternity was not confirmed (PM6). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.859 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). Another amino acid change at the same position, c.340C>A (p.Gln114Lys) (ClinVar Variation ID: 561109) has been classified as a VUS by the ClinGen CCDS VCEP. There is a ClinVar entry for this variant (Variation ID: 940774). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine deficiency syndrome. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM6, PP3, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 2, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077745/MONDO:0010305/027 2024-05-02 2024-06-12 X-linked inheritance HP:0001417 Supports CAID:CA512318776 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318776 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.375A>G (p.Pro125=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-3.10) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318776/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36704 biolink:causes UMLS:C0948301 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948301 infores:hetionet CAID:CA399805552 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805552 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000419.5:c.625-1G>A variant in ITGA2B occurs within the canonical splice acceptor site of intron 5. It is predicted to cause skipping of biologically-relevant-exon 6/30, resulting in a frameshift (p.(Ala209Valfs*155) with a premature stop codon in exon 12/30 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT35 of PMID: 29675921 meets the criteria for PP4_strong. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP4_strong. (VCEP specifications version 2; date of approval 09/02/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805552/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51364 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0037822 infores:hetionet CHEBI:4046 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0001824 infores:hetionet CHEBI:8356 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020580 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0040409 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0423232 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0242350 infores:hetionet CHEBI:2668 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042023 infores:hetionet CHEBI:2948 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0014518 infores:hetionet CHEBI:567361 biolink:causes EFO:0010670 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0159056 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0009450 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0002170 infores:hetionet CHEBI:4653 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0000729 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0852711 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0852711 infores:hetionet CHEBI:6950 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011206 infores:hetionet CHEBI:9613 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0004093 infores:hetionet CHEBI:72297 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0235996 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037274 infores:hetionet CHEBI:4877 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0233407 infores:hetionet GO:1903728 biolink:causes CL:0000175 infores:ubergraph knowledge_assertion manual_agent GO:1903728 CL:0000175 CHEBI:41423 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C2830004 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030920 infores:hetionet CHEBI:3223 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0002994 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0012833 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0003123 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0040034 infores:hetionet NCBIGene:3815 biolink:causes MONDO:0019023 infores:monarchinitiative not_provided not_provided HGNC:6342 MONDO:0019023 uuid:f04ad5c6-abeb-46a5-8910-72c0ddb20cd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9720 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0026961 infores:hetionet NCBIGene:80153 biolink:causes MONDO:0014649 infores:monarchinitiative not_provided not_provided HGNC:26114 MONDO:0014649 uuid:13e5a784-c1c5-4550-9beb-b8d5a2f5ea2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10847 biolink:causes MONDO:0859202 infores:monarchinitiative not_provided not_provided HGNC:16974 MONDO:0859202 uuid:ad2aaa5d-959e-4505-b45b-48b81d93ad21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50692 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0231528 infores:hetionet UMLS:C0065374 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0850149 infores:hetionet CHEBI:6710 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0014742 infores:hetionet CHEBI:3207 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0699744 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0029408 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0014130 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020456 infores:hetionet CHEBI:28748 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1519353 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019112 infores:hetionet CHEBI:681850 biolink:causes UMLS:C2721559 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C2721559 infores:hetionet CHEBI:3723 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014591 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0006266 infores:hetionet CHEBI:9139 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0012569 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0018802 infores:hetionet CHEBI:6950 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0080274 infores:hetionet CHEBI:59773 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0014863 infores:hetionet CHEBI:15854 biolink:causes MONDO:0013361 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C3203356 infores:hetionet CHEBI:135736 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015403 infores:hetionet CHEBI:63717 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0030305 infores:hetionet CHEBI:7936 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020580 infores:hetionet CHEBI:42068 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0011603 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0877324 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0877324 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001505 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0019187 infores:hetionet NCBIGene:7545 biolink:causes MONDO:0014705 infores:monarchinitiative not_provided not_provided HGNC:12872 MONDO:0014705 uuid:31e345ba-0ef6-42bc-92d4-e0aa620882da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1145670 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027697 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015300 infores:hetionet NCBIGene:2533 biolink:causes MONDO:0010120 infores:monarchinitiative not_provided not_provided HGNC:4036 MONDO:0010120 uuid:0d7db2f4-9271-43e9-9061-e6e61a926182 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0042487 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0332575 infores:hetionet CHEBI:2654 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0027497 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027765 infores:hetionet CHEBI:43968 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C1258215 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042571 infores:hetionet CHEBI:9445 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C1142412 infores:hetionet NCBIGene:4627 biolink:causes MONDO:0011350 infores:monarchinitiative not_provided not_provided HGNC:7579 MONDO:0011350 uuid:71079734-f9bc-42a2-a20e-fa997e4e56f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2690 biolink:causes MONDO:0011420 infores:monarchinitiative not_provided not_provided HGNC:4263 MONDO:0011420 uuid:52d35db3-8fe5-4c85-adf5-ab604ede6f79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3814 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0000731 infores:hetionet CHEBI:3175 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0014236 infores:hetionet CHEBI:42068 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C1262013 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0549418 infores:hetionet CAID:CA297169 biolink:causes MONDO:0021060 infores:clingen CAID:CA297169 MONDO:0021060 PMID: Likely Benign BS1 BA1 The filtering allele frequency of the c.38A>C (p.Glu13Ala) variant in the SHOC2 gene is 0.0484% (10/11206) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297169/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:92923 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0019360 infores:hetionet CHEBI:8890 biolink:causes UMLS:C1112613 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1112613 infores:hetionet CHEBI:8404 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0006266 infores:hetionet CHEBI:39585 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C1368065 infores:hetionet CHEBI:5001 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0041834 infores:hetionet CHEBI:8874 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0023222 infores:hetionet CHEBI:134991 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0011175 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002871 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151849 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0518015 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C1096355 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0426576 infores:hetionet CHEBI:7445 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0947912 infores:hetionet CHEBI:64355 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004144 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0031212 infores:hetionet CHEBI:8364 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0003862 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0476327 infores:hetionet CHEBI:31236 biolink:causes MONDO:0022792 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009193 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019147 infores:hetionet CAID:CA163819 biolink:causes MONDO:0017623 infores:clingen CAID:CA163819 MONDO:0017623 PMID:21532617PMID:28495237PMID:28821472PMID:28157521PMID:21532617PMID:25669429PMID:21194675PMID:21532617 Likely Benign BS4_Supporting, BP5 PM2, PM6, PVS1, BP7, BS1, BS3, PP2, PP3, PP1, BS2, PM4, PM1, PM3, PM5, BA1, BP1, BP4, BP3, BP2, PS4, PS2, PS3, PS1 PTEN c.-1195del12 (NC_000010.10:g.89623031_89623042delAAGCCGCAGCAA) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS4_P: Lack of segregation in affected members of one family. (Internal laboratory contributor SCV SCV000222146.7)BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributors SCV000222146.7, SCV000183826.5) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA163819/MONDO:0017623/003 2019-03-05 2019-07-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9448 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0003123 infores:hetionet CHEBI:27999 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0030312 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0277589 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0277589 infores:hetionet CHEBI:144093 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0033575 infores:hetionet CHEBI:15765 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0085932 infores:hetionet CAID:CA10014217 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014217 MONDO:0011071 PMID:34166225PMID:34166225 Uncertain Significance BP4, PS4_Supporting PS1, PS3, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1041G>A (p.Met347Ile) is a missense variant which has a REVEL score < 0.50 (0.374) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014217/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4909 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0237849 infores:hetionet GO:1903859 biolink:causes GO:0048812 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0048812 CHEBI:7444 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C2363731 infores:hetionet CHEBI:80630 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0015672 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0919715 infores:hetionet CHEBI:3723 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007820 infores:hetionet CHEBI:45409 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015732 infores:hetionet CHEBI:2038 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009676 infores:hetionet CHEBI:7476 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011606 infores:hetionet CHEBI:31980 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0428977 infores:hetionet CHEBI:7915 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009376 infores:hetionet CHEBI:5118 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018932 infores:hetionet CHEBI:5004 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0019080 infores:hetionet CAID:CA024622 biolink:causes MONDO:0007783 infores:clingen CAID:CA024622 MONDO:0007783 PMID: Pathogenic BS2, PS3_Moderate, PM5, PM1_Supporting, PS4, PP3_Moderate, PP1_Strong BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with methionine at codon 2206 of the RYR1 protein, p.(Thr2206Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918). This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID: 12220451). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5. This variant segregates with MHS in nine individuals, PP1_Strong (PMID: 12059893, 25960145). A REVEL score >0.85 (0.95) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024622/MONDO:0007783/012 2022-03-14 2022-03-14 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:27565 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0023530 infores:hetionet CHEBI:63612 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0014591 infores:hetionet NCBIGene:5155 biolink:causes MONDO:0011789 infores:monarchinitiative not_provided not_provided HGNC:8800 MONDO:0011789 uuid:edad639b-e7aa-47d9-8cc4-16649c716191 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127780 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0221269 infores:hetionet CAID:CA415076138 biolink:causes MONDO:0010305 infores:clingen CAID:CA415076138 MONDO:0010305 PMID: Uncertain Significance BP4 BS3, PM2, PS3, PS4 The NM_005629.4:c.76G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a glycine by an arginine at amino acid position 26 (p.Gly26Arg). This variant has been previously reported in one individual with intellectual disability (PMID:16738945) but without reported biochemical evidence of creatine transporter deficiency, such that neither PP4 nor PS4 is met. In gnomAD v2.1.1, the highest population allele frequency is 0.00007 (2/30107 alleles, 1 hemizygote) in the European (Non-Finnish) population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.079 (BP4). While functional studies have been published for this variant (PMID:17465020, 38070861), they do not meet the specifications required for functional studies by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (transport assays using <125uM creatine in SLC6A8-deficient fibroblasts), such that neither PS3 not BS3 is met. This variant has been reported in an individual in the literature (PMID:16738945), however biochemical evidence of Creatine Transport Deficiency (elevated urine creatine:creatinine) was not obtained for this individual, therefore it does not meet criteria established for PP4. There is a ClinVar entry for this variant (Variation ID: 643295). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on September 23, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415076138/MONDO:0010305/027 2024-09-23 2024-09-23 X-linked inheritance HP:0001417 Inconclusive true CHEBI:4672 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151735 infores:hetionet CHEBI:135736 biolink:causes HP:0040403 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0520594 infores:hetionet CHEBI:92712 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0039231 infores:hetionet CHEBI:16664 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0178298 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0009806 infores:hetionet CHEBI:42797 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030196 infores:hetionet CAID:CA376061249 biolink:causes MONDO:0011225 infores:clingen CAID:CA376061249 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.315G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Aspartic Acid at amino acid 105 (p.Glu105Asp).The filtering allele frequency (the upper threshold of the 95% CI of 2/44874) of the c.315G>C variant in DCLRE1C is 0.000008350 for East Asian chromosomes by gnomAD v4 which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376061249/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:142290 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013404 infores:hetionet UNII:K2J09EMJ52 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0042963 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0574002 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0574002 infores:hetionet CHEBI:8890 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0023518 infores:hetionet CAID:CA512341330 biolink:causes MONDO:0100083 infores:clingen CAID:CA512341330 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 This synonymous variant has a SpliceAI Δ score of 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.008 (< 2)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341330/MONDO:0100083/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0060718 biolink:causes CL:0011101 infores:ubergraph knowledge_assertion manual_agent GO:0060718 CL:0011101 CAID:CA257021 biolink:causes MONDO:0021060 infores:clingen CAID:CA257021 MONDO:0021060 PMID: Pathogenic PS3_Moderate, PS4, PS2_Very Strong, PP3, PP1 BS1, PM2, BP4, BA1 The NM_002524.5:c.179G>A variant in NRAS is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 60 (p.Gly60Glu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006482 (1/15428 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.958, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 13 probands with RASopathy (PS4; PMIDs: 19966803, 26467218, 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). This variant has been identified as a de novo occurrence with confirmed parental relationships in 4 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with RASopathy (PS2_VeryStrong; PMIDs: 19966803 and 28594414, SCV000208921.11, GeneDx, Hôpital Universitaire Robert Debré). The variant has been reported to segregate with RASopathy in 5 affected family members from 3 family(ies (PP1; PMIDs: 19966803, 26467218, 28594414). MEK and ERK activation in COS-7 cells showed increased phophorylation indicating that this variant impacts protein function (PMID: 19966803)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP1, PP3. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA257021/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:64432 biolink:causes MONDO:0033570 infores:monarchinitiative not_provided not_provided HGNC:14511 MONDO:0033570 uuid:dbe9ee0b-c208-4e99-9cd3-2c9002f8308b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0476273 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0042571 infores:hetionet CHEBI:5296 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0026858 infores:hetionet CHEBI:10101 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020461 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0027769 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152517 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0018799 infores:hetionet CHEBI:63630 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C2937358 infores:hetionet CHEBI:23765 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0014518 infores:hetionet CHEBI:6062 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018834 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0854679 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0854679 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0025061 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0021053 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0012797 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009782 infores:hetionet CAID:CA9302185 biolink:causes MONDO:0010938 infores:clingen CAID:CA9302185 MONDO:0010938 PMID: Likely Benign BS1, BS2_Supporting The c.362G>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Arginine by Histidine at amino acid 121 (p.Arg121His).The popmax filtering allele frequency in gnomAD v.4 is 0.0001262 (based on 11/58232 alleles in the Admixed American population), which is higher than the SCID VCEP established threshold of <0.000115 for PM2_Supporting and lower than >0.00447 (BA1 threshold) and 0.001 (BS1 threshold);However, the highest MAF in the Ashkenazi Jewish population is 0.001469 (43/29280 alleles), which is above the SCID VCEP established threshold of >0.00100. As this population is not known to have a higher prevalence of SCID, this is considered to meet BS1. There is a homozygote in gnomAD v.4 in the Ashkenazi Jewish population (43/29280 alleles), BS2_Supporting.To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9302185/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:52172 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003621 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1868843 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1868843 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0027051 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0497247 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0003123 infores:hetionet CHEBI:8768 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0231530 infores:hetionet CHEBI:3286 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0039070 infores:hetionet CHEBI:2208 biolink:causes HP:0003149 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0948643 infores:hetionet CHEBI:38940 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0016199 infores:hetionet CAID:CA386972790 biolink:causes MONDO:0015967 infores:clingen CAID:CA386972790 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting BP4, PS4, PM1, PP3, PP4 The c.1637A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to glycine at codon 546 (p.(Asp546Gly)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.662, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 22432796, internal lab contributors). Furthermore, PP4 is unable to be applied since the calculated MODY probability is <50% or is unable to be calculated due to incomplete clinical data (PMID: 22432796, internal lab contributors). In summary, c.1637A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386972790/MONDO:0015967/017 2024-11-07 2024-11-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17334 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0855223 infores:hetionet CHEBI:7627 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0234233 infores:hetionet CHEBI:7915 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1320474 infores:hetionet CHEBI:9086 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0497156 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003117 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0037650 infores:hetionet CAID:CA10585500 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585500 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, BP4, PM2, PP4 PS3, PM5, PP3 The NM_000527.5 (LDLR):c.1553A>G (p. Lys518Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in ˃1 index case who fulfil criteria for FH diagnosis from 2 labs after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnosis criteria. One index case met MedPed definite FH criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); one index case fulfil Simon Broome criteria for FH, reported by Usifo et al, 2012, British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK (PMID22881376). BP4: REVEL = 0.371, it is below 0.5, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing.PP3 not met: REVEL = 0.371, it is not above 0.75. Alternative splicing is not predicted.PS3 not met: Functional data on splicing is not available.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1552A>G (p.Lys518Glu) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585500/MONDO:0007750/013 2022-08-26 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6888 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0241863 infores:hetionet CHEBI:15553 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0264906 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0007642 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0234215 infores:hetionet CHEBI:4888 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0028738 infores:hetionet CHEBI:61049 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037299 infores:hetionet NCBIGene:29925 biolink:causes MONDO:0014140 infores:monarchinitiative not_provided not_provided HGNC:22932 MONDO:0014140 uuid:1407e624-130d-4158-beb8-fe182b9e11be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0917801 infores:hetionet CHEBI:31236 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027796 infores:hetionet CHEBI:51860 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0033774 infores:hetionet NCBIGene:400569 biolink:causes MONDO:0957225 infores:monarchinitiative not_provided not_provided HGNC:32687 MONDO:0957225 uuid:c70eb1e3-fe3b-4b1e-a9ee-753ecd753c2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0014742 infores:hetionet CHEBI:5959 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0085649 infores:hetionet CHEBI:9445 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0035455 infores:hetionet CHEBI:8024 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037383 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0155002 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0155002 infores:hetionet CHEBI:63638 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0028738 infores:hetionet CHEBI:135193 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0027765 infores:hetionet CHEBI:10124 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0522055 infores:hetionet CAID:CA156430 biolink:causes MONDO:0010726 infores:clingen CAID:CA156430 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PS4 The p.Glu483Ter variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1_Moderate). The p.Glu483Ter variant in MECP2 is absent from gnomAD (PM2_Supporting). This variant was reported in two male siblings with autism who inherited the p.Glu483Ter variant from their unaffected mother (PMID 23352163). In summary, the p.Glu483Ter variant in MECP2 is classified as variant of unknown significance based on the ACMG/AMP criteria (PVS1_Moderate, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA156430/MONDO:0010726/036 2023-08-23 2023-09-15 X-linked inheritance HP:0001417 Inconclusive true CHEBI:50777 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0033774 infores:hetionet CAID:CA377487108 biolink:causes MONDO:0017623 infores:clingen CAID:CA377487108 MONDO:0017623 PMID: Pathogenic PM2, PS3_Supporting, PP2, PS4_Moderate, PS2 PTEN c.1034T>C (p.Leu345Pro) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) ClinVar Organization ID: 26957)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 21659347, internal laboratory contributor(s) ClinVar Organization ID: 26957)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 29785012, PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377487108/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47381 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085932 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0030922 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0030922 infores:hetionet CHEBI:100241 biolink:causes UMLS:C2363980 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C2363980 infores:hetionet CHEBI:50742 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0851578 infores:hetionet GO:0007317 biolink:causes GO:0008358 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0008358 CHEBI:9086 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023518 infores:hetionet CHEBI:6402 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0042384 infores:hetionet CHEBI:7852 biolink:causes EFO:0020923 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151821 infores:hetionet CHEBI:9435 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0085631 infores:hetionet CHEBI:38940 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0011168 infores:hetionet CHEBI:499361 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0014356 infores:hetionet GO:0075193 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0075193 GO:0048856 CHEBI:3478 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0013182 infores:hetionet CHEBI:82960 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0542571 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0476273 infores:hetionet CAID:CA2573153936 biolink:causes MONDO:0100326 infores:clingen CAID:CA2573153936 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The c.2174del (p.Lys725ArgfsTer6) variant in exon 21 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 22 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.0.0 (PM2_Supporting). This variant is reported in one Glanzmann thrombasthenia patient in ClinVar (ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology). However, the phenotypic detail of this patient is not enough to apply PP4 by the PD VCEP. The patient is compound heterozygous with the Likely pathogenic variant NM_000419.5(ITGA2B):c.2169del (p.Met724Ter). No other cases of the variant segregating in GT patients were found in the literature. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting (VCEP specifications version 2; date of approval 04/16/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573153936/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:29688 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0027769 infores:hetionet CHEBI:31348 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019079 infores:hetionet CHEBI:4953 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0232462 infores:hetionet CAID:CA5416841 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416841 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2 The c.457G>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Glycine by Tryptophan at amino acid 153 (p.Gly153Trp).The filtering allele frequency (the upper threshold of the 95% CI of 8/1111862 alleles) of the c.457G>T variant in DCLRE1C is 0.000003100 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416841/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63632 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0042963 infores:hetionet CHEBI:171719 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0023530 infores:hetionet CHEBI:30659 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0015230 infores:hetionet CHEBI:7445 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0025323 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0700184 infores:hetionet CHEBI:64312 biolink:causes MONDO:0042981 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003507 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027932 infores:hetionet CHEBI:9907 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013404 infores:hetionet CAID:CA16602321 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602321 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP3, PP1, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2 The NM_000527.5(LDLR):c.967G>T (p.Gly323Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP1 - variant segregates with the FH phenotype in 2 informative meiosis (1 from each family) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 2 relatives with LDL>75th percentile have the variant, so PP1 is met.PP3 - REVEL = 0.903. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in 4 unrelated index cases who fulfill at least SB Possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so PS4_Supporting is metPP4 - variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical criteria for FH after alternative causes for high cholesterol were excluded (please see PS4 for details), so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602321/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:2379 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0001824 infores:hetionet CHEBI:3380 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030252 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0340726 infores:hetionet CAID:CA229628 biolink:causes MONDO:0009861 infores:clingen CAID:CA229628 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 The c.563G>A (p.Gly188Asp) variant in PAH has been reported in 3 affected individuals (BH4 deficiency excluded). (PP4_Moderate; PMID: 23430918, 26503515, 22526846). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants p.F55fs (parental analysis not reported, PMID: 22526846) and p.R243Q (in trans, PMID: 26322415; PM3). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229628/MONDO:0009861/006 2019-11-18 2021-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2668 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0009806 infores:hetionet CHEBI:6067 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0023052 infores:hetionet CAID:CA658824788 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824788 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.2367dup (p.Pro790ThrfsTer6) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 558571). This variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824788/MONDO:0009290/010 2024-04-05 2024-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA293485 biolink:causes MONDO:0021060 infores:clingen CAID:CA293485 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1423-7C>T variant in the SHOC2 gene is 1.826% (183/8836) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA293485/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:6907 biolink:causes MONDO:0026731 infores:monarchinitiative not_provided not_provided HGNC:11585 MONDO:0026731 uuid:40452f18-6c38-4dcd-9414-7d415a52a98f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020621 infores:hetionet CHEBI:4877 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0497156 infores:hetionet CHEBI:28787 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C1384353 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0014549 infores:hetionet CHEBI:47781 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0232462 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0017574 infores:hetionet CHEBI:8888 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0025222 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0013595 infores:hetionet CHEBI:2038 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0036974 infores:hetionet CHEBI:8024 biolink:causes MONDO:0043786 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0036749 infores:hetionet CHEBI:51364 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0002792 infores:hetionet CHEBI:8207 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C2830004 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0019112 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0856554 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0856554 infores:hetionet CHEBI:36791 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013491 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0853813 infores:hetionet CHEBI:37924 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0085624 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0836924 infores:hetionet CHEBI:16469 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014236 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0038362 infores:hetionet CHEBI:3534 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151872 infores:hetionet CHEBI:6413 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0235266 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0040034 infores:hetionet CHEBI:51450 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020458 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0236141 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0236141 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0160390 infores:hetionet NCBIGene:4953 biolink:causes MONDO:0033642 infores:monarchinitiative not_provided not_provided HGNC:8109 MONDO:0033642 uuid:df2458fa-8eff-4662-90cc-25e47fcebbe6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28939 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0019079 infores:hetionet CAID:CA10558486 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558486 MONDO:0010726 PMID: Likely Benign BS2 BP4, PP3 The p.Pro391Ala variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Invitae and GeneDx) (BS2). The p.Pro391Ala variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro391Ala variant in MECP2 (NM_004992.4) is classified as likely benign for Rett syndrome based on the ACMG/AMP criteria (BS2). (MECP2 specification v.3.0.0, curation approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558486/MONDO:0010726/036 2024-08-30 2024-12-23 X-linked inheritance HP:0001417 Contradicts true CAID:CA314796 biolink:causes MONDO:0012999 infores:clingen CAID:CA314796 MONDO:0012999 PMID: Likely Benign BP4, BS1 The NM_000156.6:c.242C>T variant in GAMT is a missense variant that is predicted to cause the substitution of an alanine by a valine at amino acid position 81 (p.Ala81Val). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The GrpMax filtering allele frequency in gnomAD v4.1.0. is 0.001232 in the E. Asian population, which is higher than the ClinGen CCDS VCEP's threshold for BS1 (>0.001), and therefore meets this criterion. The computational predictor REVEL gives a score of 0.197 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205576). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BS1, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314796/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:16467 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0232462 infores:hetionet CHEBI:66903 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0042963 infores:hetionet NCBIGene:5190 biolink:causes MONDO:0013930 infores:monarchinitiative not_provided not_provided HGNC:8859 MONDO:0013930 uuid:238122ac-29bf-4cca-8abc-f6d28a16eb5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0426576 infores:hetionet CHEBI:7931 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0231528 infores:hetionet CHEBI:4672 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085605 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0022658 infores:hetionet NCBIGene:80216 biolink:causes MONDO:0013999 infores:monarchinitiative not_provided not_provided HGNC:20917 MONDO:0013999 uuid:c95be354-ef57-4f32-8b94-b25426565824 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040034 infores:hetionet CAID:CA377487506 biolink:causes MONDO:0017623 infores:clingen CAID:CA377487506 MONDO:0017623 PMID: Likely Pathogenic PM2_Supporting, PM4, PS1 PTEN c.1212A>C (p.Ter404Cys) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria v3.1.0 (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS1: PTEN c.1212A>T results in the same extension , p.Ter404CysextTer8, and is classified as pathogenic. PM4: the variant causes protein extension PM2_Supporting: the variant is absent in gnomad v2 and v4 PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377487506/MONDO:0017623/003 2025-08-01 2025-10-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3207 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0030554 infores:hetionet CAID:CA024781 biolink:causes MONDO:0007783 infores:clingen CAID:CA024781 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate, BS2_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2454 of the RYR1 protein, p.(Arg2454His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in 34 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted, PS4 (PMID: 30236257, 12059893, 16163667, 24433488, 11575529, 10051009, 10823104, 17081152, 20618998, 21455645, 23460944, 23558838, 25960145). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID: 30236257).Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID: 19191333). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 11 individuals/families PP1_Strong (PMID: 12059893, 10051009). A REVEL score >0.85 (0.923) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024781/MONDO:0007783/012 2021-03-19 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:15765 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0011603 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0025290 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0042373 infores:hetionet GO:0030548 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0030548 GO:0051716 GO:0048328 biolink:causes GO:0048319 infores:ubergraph knowledge_assertion manual_agent GO:0048328 GO:0048319 NCBITaxon:5052 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5052 MESH:D001991 DB00681_MESH_D001991_1 CHEBI:9586 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0018021 infores:hetionet CHEBI:8378 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0019572 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0948765 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0948765 infores:hetionet CHEBI:68606 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0275524 infores:hetionet CHEBI:44032 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C1443060 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0152972 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0152972 infores:hetionet CHEBI:16469 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0156404 infores:hetionet CHEBI:41879 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0085635 infores:hetionet CHEBI:18243 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0242528 infores:hetionet CHEBI:408174 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004096 infores:hetionet CHEBI:8107 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0424295 infores:hetionet CHEBI:31236 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0231218 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0232492 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0234458 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1167965 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0920184 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0920184 infores:hetionet CHEBI:84883 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0018790 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0033777 infores:hetionet UMLS:C0145867 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0041657 infores:hetionet CHEBI:3347 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0231528 infores:hetionet CHEBI:17688 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C2830004 infores:hetionet CHEBI:5790 biolink:causes MONDO:0041052 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0032768 infores:hetionet CHEBI:4710 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004245 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0853011 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0853011 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037278 infores:hetionet CHEBI:4562 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0038999 infores:hetionet CHEBI:59773 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0016204 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0042401 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0852885 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0852885 infores:hetionet NCBIGene:2147 biolink:causes MONDO:0008559 infores:monarchinitiative not_provided not_provided HGNC:3535 MONDO:0008559 uuid:81a4ea80-37ef-4f9a-b18a-92d727221b38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135361 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0042109 infores:hetionet CHEBI:17987 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0041834 infores:hetionet CHEBI:3082 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0037763 infores:hetionet CHEBI:8093 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0033774 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0851341 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042075 infores:hetionet CHEBI:5130 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0031256 infores:hetionet CHEBI:119486 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0003811 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0235431 infores:hetionet CHEBI:3478 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0027497 infores:hetionet CHEBI:8768 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0000731 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018824 infores:hetionet CHEBI:46345 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0041834 infores:hetionet CHEBI:5893 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085610 infores:hetionet CAID:CA10585687 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585687 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP4 BA1, BP4, BP2, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PVS1, PM6, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PS3 - 2 Level 1 assays: PMID 25386756:Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake.PMID 23021490:Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein.---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585687/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5130 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0003467 infores:hetionet CHEBI:50663 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0002792 infores:hetionet CHEBI:9086 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0031256 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0038367 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0026946 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0232492 infores:hetionet CHEBI:39112 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0027497 infores:hetionet CHEBI:61390 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C2718128 infores:hetionet CHEBI:94411 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0857257 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0022660 infores:hetionet CHEBI:75246 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C1167965 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0018799 infores:hetionet CHEBI:51164 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0001807 infores:hetionet CHEBI:31623 biolink:causes HP:0000371 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0271429 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0413252 infores:hetionet CHEBI:490877 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0011603 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0026846 infores:hetionet CHEBI:3757 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0162834 infores:hetionet CHEBI:6633 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0015230 infores:hetionet CHEBI:125354 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0151735 infores:hetionet CHEBI:5864 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0038325 infores:hetionet CHEBI:7573 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0036974 infores:hetionet CHEBI:119573 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0005758 infores:hetionet NCBIGene:4072 biolink:causes MONDO:0013196 infores:monarchinitiative not_provided not_provided HGNC:11529 MONDO:0013196 uuid:653be134-f1f7-4a1a-94d4-9760c2dff0e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000787 biolink:causes GO:0060843 infores:ubergraph knowledge_assertion manual_agent GO:2000787 GO:0060843 CHEBI:9086 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0232849 infores:hetionet NCBIGene:51117 biolink:causes MONDO:0958009 infores:monarchinitiative not_provided not_provided HGNC:19693 MONDO:0958009 uuid:54b1d76c-3110-452d-9242-621865049a0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes UMLS:C0271899 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0271899 infores:hetionet CHEBI:66964 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0004093 infores:hetionet CHEBI:127342 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0234047 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0426576 infores:hetionet CHEBI:9448 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0009782 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0004245 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151735 infores:hetionet CHEBI:50648 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0023380 infores:hetionet CHEBI:6916 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0020538 infores:hetionet CHEBI:5120 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0156404 infores:hetionet CHEBI:68595 biolink:causes NCIT:C35105 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0041981 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0037290 infores:hetionet NCBIGene:4697 biolink:causes MONDO:0033656 infores:monarchinitiative not_provided not_provided HGNC:7687 MONDO:0033656 uuid:54f13f61-b178-4f2e-bd1b-d4b1e461303e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0034065 infores:hetionet CAID:CA135996 biolink:causes MONDO:0021060 infores:clingen CAID:CA135996 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.81T>C (p.His27=) variant in the HRAS gene is 36.7% for African chromosomes by the Exome Aggregation Consortium (3874/10274 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case-level data provided by: SCV000058315; SCV000062146; SCV000196686. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135996/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:75998 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0009450 infores:hetionet CHEBI:8863 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042023 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0155320 infores:hetionet CHEBI:63589 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0231807 infores:hetionet CHEBI:7514 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0018790 infores:hetionet CHEBI:28748 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151714 infores:hetionet CAID:CA10585454 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585454 MONDO:0007750 PMID:31587492 Likely Pathogenic PS4_Supporting, PS3_Moderate, PM5, PM2, PP3, PP4 BA1, BP4, BP3, BP2, PS1, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1444G>C (p.Asp482His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3_Moderate, PM2, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.993. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines;- NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines; - NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) (ClinVar ID 251846) - Likely Pathogenic by these guidelines;There is 1 variant in the same codon classified as Pathogenic by these guidelines. PS3_Moderate: Level 2 assay: PMID 31587492 (Kizhakkedath P et al., 2019) - HEK-293T cells. In immunoblots of the mutants, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 index cases who fulfill Simon Broome criteria for FH (1 case in PMID 11313767 (Heath KE et al., 2001), 1 case in PMID 10559517 (Graham CA et al., 1999)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585454/MONDO:0007750/013 2023-06-23 2024-09-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:45783 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0007177 infores:hetionet CHEBI:64064 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0038999 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0043349 infores:hetionet CHEBI:50729 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0428977 infores:hetionet CHEBI:43968 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0008031 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0878544 infores:hetionet CHEBI:109549 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0027497 infores:hetionet CHEBI:7465 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0041657 infores:hetionet CHEBI:4672 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0011175 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0031117 infores:hetionet CHEBI:4653 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0040822 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004778 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0149881 infores:hetionet CHEBI:72564 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042963 infores:hetionet CHEBI:7915 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017181 infores:hetionet CAID:CA10014206 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014206 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1088G>C (p.Gly363Ala) is a missense variant which is absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.117) (BP4). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2151600). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014206/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:473990 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0020456 infores:hetionet CHEBI:63605 biolink:causes HP:0012533 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0458247 infores:hetionet NCBIGene:2624 biolink:causes MONDO:0013607 infores:monarchinitiative not_provided not_provided HGNC:4171 MONDO:0013607 uuid:5b8f9b13-531b-477f-ac84-a87db387bda2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0001925 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0424605 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0242422 infores:hetionet GO:0052041 biolink:causes GO:0012501 infores:ubergraph knowledge_assertion manual_agent GO:0052041 GO:0012501 CHEBI:5280 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0004093 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0042075 infores:hetionet CHEBI:48273 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0017152 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0574067 infores:hetionet CHEBI:135351 biolink:causes UMLS:C2242575 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C2242575 infores:hetionet CHEBI:27882 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0220981 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0033860 infores:hetionet CAID:CA415086230 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086230 MONDO:0010305 PMID: Pathogenic PP3, PM2_Supporting, PP4_Strong, PP1_Strong PS3, PS4 "The NM_005629.4:c.1169C>T variant in SLC6A8 is a missense variant that is predicted to result in the substitution of proline by leucine at amino acid 390 (p.Pro390Leu). The variant was shown to segregate in a family from a heterozygous mother with mild intellectual disability, to two affected sons and an affected daughter. A clinically unaffected daughter did not carry the variant (PMID: 28065824) (PP1_Strong, PP4_Strong). In addition, two unrelated males with intellectual disability, and an affected brother of one of these individuals, are hemizygous for the variant (PMID: 15154114, 21267006. Fibroblasts from a patient with this variant were shown to be ""deficient in creatine uptake"" (PMID: 17465020), but further details were not provided, other than the patient is unrelated to the patient reported in PMID: 15154114. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). When transiently expressed in SLC6A8-deficient fibroblasts, the variant resulted in reduced creatine transport. However, the study does not meet the specifications of the CCDS VCEP (must be done with <125 mM creatine while the study used 500 uM). The computational predictor REVEL gives a score of 0.942 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP1_Strong, PP4_Strong, PP3, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 11, 2023)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086230/MONDO:0010305/027 2023-05-11 2023-05-25 X-linked inheritance HP:0001417 Supports CHEBI:50381 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0043352 infores:hetionet CHEBI:63624 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0151786 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0413252 infores:hetionet CHEBI:6970 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0015967 infores:hetionet CHEBI:17474 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0018681 infores:hetionet CHEBI:3732 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0404521 infores:hetionet CHEBI:5147 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0033774 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0033975 infores:hetionet NCBIGene:1540 biolink:causes MONDO:0007565 infores:monarchinitiative not_provided not_provided HGNC:2584 MONDO:0007565 uuid:b0880949-f4cc-4f4a-83d9-792506312f6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0038999 infores:hetionet CHEBI:3032 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0015230 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022658 infores:hetionet CHEBI:66903 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0026857 infores:hetionet CHEBI:3640 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C1291078 infores:hetionet CHEBI:23765 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0008031 infores:hetionet CHEBI:5002 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0151744 infores:hetionet CHEBI:5118 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011606 infores:hetionet CHEBI:85161 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0232462 infores:hetionet CHEBI:6741 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0039231 infores:hetionet NCBIGene:55572 biolink:causes MONDO:0032624 infores:monarchinitiative not_provided not_provided HGNC:26927 MONDO:0032624 uuid:c2776418-321f-4a4d-a1e7-0f7fb1bdc7ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027849 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0041912 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042514 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0853149 infores:hetionet CHEBI:68558 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0041657 infores:hetionet CHEBI:175901 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151723 infores:hetionet GO:1903023 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0051321 UNII:8NZ41MIK1O biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0042384 infores:hetionet CAID:CA2740089966 biolink:causes MONDO:0011132 infores:clingen CAID:CA2740089966 MONDO:0011132 PMID:31566583PMID:37419334 Likely Pathogenic PM2_Supporting, PS3_Moderate, PVS1_Strong PP4, PS4 The frameshift variant NM_001369369.1(FOXN1):c.1296del is predicted to cause a premature stop codon in the final exon and escape nonsense mediated decay. The variant truncates the protein by roughly 16% and significantly alters the transactivation domain, a domain important to protein function (PVS1_strong). The variant is absent from gnomAD v4.0 (PM2_supporting). The variant was found in P15 from PMID:31566583 in the heterozygous state. This individual displayed phenotypes such as low T cell counts prior to transplantation and was exome sequenced. However, specific T cell counts were not noted and the type of organ transplantation was not specified (PP4 not met). The variant displayed significantly reduced activity in a two separate luciferase reporter assays 2% and 0.3% from PMIDs: 31566583 and 37419334 respectively, with one of the assays being validated with pathogenic and benign controls (PS3_moderate). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PS3_moderate, and PM2_supporting, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2740089966/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:36704 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0242073 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003635 infores:hetionet CHEBI:15552 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0040822 infores:hetionet CHEBI:7852 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0428977 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0038362 infores:hetionet CHEBI:3568 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0033774 infores:hetionet CHEBI:6067 biolink:causes HP:6000956 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0263634 infores:hetionet CHEBI:16664 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0041969 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019340 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0858797 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0037199 infores:hetionet CHEBI:3723 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0000786 infores:hetionet NCBIGene:23639 biolink:causes MONDO:0013979 infores:monarchinitiative not_provided not_provided HGNC:16725 MONDO:0013979 uuid:f4f95fbc-1df7-4f5f-9fda-1a9a7967482b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94609 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0009676 infores:hetionet NCBIGene:5244 biolink:causes MONDO:0013995 infores:monarchinitiative not_provided not_provided HGNC:45 MONDO:0013995 uuid:d850b598-25c9-4765-943e-7766ebbbfef6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5784 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0042109 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233494 infores:hetionet CHEBI:50922 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0037763 infores:hetionet CHEBI:16899 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0009782 infores:hetionet CAID:CA226350 biolink:causes MONDO:0100437 infores:clingen CAID:CA226350 MONDO:0100437 PMID:23213406PMID:30622176 Uncertain Significance PS3_Supporting, PM2_Supporting, PP3_Moderate PP4, PM5, PS4 NM_001034853.2(RPGR):c.127G>A (p.Gly43Arg) is a missense variant encoding the substitution of glycine with arginine at amino acid 43. Another missense variant in the same codon, NM_001034853.2(RPGR):c.128G>A (p.Gly43Glu) has been reported in association with inherited retinal disease (PMID: 10937588, PMID: 17325176), while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (125) than the comparison variant (98), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing. However, the comparison variant has been classified as a variant of uncertain significance for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, so PM5_Supporting is not met. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/pr decreased or absent electroretinogram responses (PMID: 10937588, PMID: 14564670). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The proband phenotype included diagnosis of X-linked retinitis pigmentosa, high myopia (1), visual field constriction (0.5), and reduced visual acuity (0.5), and reduced electroretinogram responses at both 0.5Hz and 30Hz, which together are not sufficiently specific for RPGR-related retinopathy to meet PP4. The computational predictor REVEL gives a score of 0.925, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.10 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. Exogenously expressed RPGR harboring the variant exhibits reduced interaction with RPGRIP1 in a yeast-2-hybrid system (PMID: 23213406) and reduced interaction with PDE6D, INPP5E, and RPGRIP1L in a co-immunoprecipitation experiment (PMID: 30622176) (PS3_Supporting). In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP3_Moderate, and PS3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226350/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Inconclusive true CHEBI:145499 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151636 infores:hetionet CHEBI:63598 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009676 infores:hetionet CHEBI:38562 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0011603 infores:hetionet GO:2000354 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:2000354 GO:0061458 CAID:CA274311 biolink:causes MONDO:0009290 infores:clingen CAID:CA274311 MONDO:0009290 PMID:22237443PMID:22237443PMID:27408821PMID:20033296PMID:29523196PMID:26873529PMID:18607768 Pathogenic PVS1, PM2, PP4, PM3 This variant, c.1128_1129delGGinsC (p.Trp376Cysfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). There is a ClinVar entry for this variant (Variation ID: 189041, 2 star review status) with 3 submitters classifying the variant and pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274311/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8597 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0235660 infores:hetionet CHEBI:32192 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0018681 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0262397 infores:hetionet CHEBI:16467 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0392386 infores:hetionet CHEBI:474180 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0013378 infores:hetionet CHEBI:43968 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0030193 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0021053 infores:hetionet CHEBI:8776 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0009806 infores:hetionet NCBIGene:221496 biolink:causes MONDO:0859147 infores:monarchinitiative not_provided not_provided HGNC:21244 MONDO:0859147 uuid:fdef43fb-d85b-42ad-bb89-9f1b27ce43e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4636 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0080274 infores:hetionet CHEBI:91834 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0231528 infores:hetionet CHEBI:9137 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0009676 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0155169 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042075 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006938 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0034183 infores:hetionet CHEBI:48273 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0522224 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1142412 infores:hetionet CHEBI:63638 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0085649 infores:hetionet CHEBI:100241 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0021368 infores:hetionet CHEBI:9738 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0002170 infores:hetionet CHEBI:17334 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0277794 infores:hetionet CHEBI:408174 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0034359 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0877406 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0877406 infores:hetionet CAID:CA6748845 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748845 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 The c.757G>A (p.Asp253Asn) variant in PAH has not been reported in the literature to our knowledge. This variant has an extremely low frequency in ExAC and gnomAD (MAF=0.00001). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748845/MONDO:0009861/006 2020-01-26 2020-01-31 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:29013 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0021053 infores:hetionet CHEBI:94385 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0012739 infores:hetionet CHEBI:31709 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0012833 infores:hetionet CHEBI:16899 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0232462 infores:hetionet CHEBI:7573 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0015230 infores:hetionet CHEBI:135920 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0152032 infores:hetionet CHEBI:31949 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0011991 infores:hetionet GO:2000313 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000313 GO:0007275 UNII:R43D2573WO biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011606 infores:hetionet CHEBI:490877 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0003862 infores:hetionet CHEBI:5165 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0042963 infores:hetionet CHEBI:9445 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0015230 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0035078 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0085584 infores:hetionet CHEBI:6950 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042024 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0008049 infores:hetionet CAID:CA367401305 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401305 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP2, PP3, PP4, PM2_Supporting The c.628A>G variant in the glucokinase gene, GCK causes an amino acid change of methionine to valine at codon 210 (p.(Met210Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). Additionally, Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.628A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP ((specification version 1.1.0, approved 3/23/2023): PM5_Strong, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401305/MONDO:0015967/086 2023-05-26 2023-05-26 Semidominant inheritance HP:0032113 Supports CHEBI:51364 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0034880 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151601 infores:hetionet NCBIGene:171546 biolink:causes MONDO:0957309 infores:monarchinitiative not_provided not_provided HGNC:20361 MONDO:0957309 uuid:16e4c1fe-8919-4faa-9471-50e4bcbe7481 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7291 biolink:causes MONDO:0060592 infores:monarchinitiative not_provided not_provided HGNC:12428 MONDO:0060592 uuid:919d35ba-3dd7-4ea8-b054-e5dfc18b685d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0065374 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0344232 infores:hetionet CHEBI:36795 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0033771 infores:hetionet CHEBI:27565 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0302295 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0009676 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0036508 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1443060 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0029408 infores:hetionet CHEBI:5790 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0017168 infores:hetionet CHEBI:10023 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0025874 infores:hetionet CHEBI:3223 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0030252 infores:hetionet CHEBI:3568 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0424790 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151785 infores:hetionet CHEBI:3219 biolink:causes HP:0030223 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233651 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0022672 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151313 infores:hetionet CHEBI:23765 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085605 infores:hetionet CHEBI:135005 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0018681 infores:hetionet CHEBI:6078 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0030193 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0740858 infores:hetionet CHEBI:50742 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151907 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0574067 infores:hetionet CHEBI:10100 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0013604 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0153251 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0153251 infores:hetionet CHEBI:3723 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151786 infores:hetionet CHEBI:5134 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0002994 infores:hetionet CHEBI:51450 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0002994 infores:hetionet NCBIGene:8481 biolink:causes MONDO:0010320 infores:monarchinitiative not_provided not_provided HGNC:2567 MONDO:0010320 uuid:2e438331-246f-498d-8a9b-14eb0a674b64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0018790 infores:hetionet CHEBI:28925 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0002170 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0042267 infores:hetionet CHEBI:74947 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0235660 infores:hetionet NCBIGene:23312 biolink:causes MONDO:0033258 infores:monarchinitiative not_provided not_provided HGNC:2938 MONDO:0033258 uuid:39c6cb92-aa9e-4fd7-8ac3-6c4a04142985 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027765 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007860 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0521839 infores:hetionet CHEBI:34825 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB08933 UMLS:C0007642 infores:hetionet CHEBI:50173 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0152030 infores:hetionet CHEBI:7640 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2047937 infores:hetionet CHEBI:9168 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0857305 infores:hetionet GO:0039524 biolink:causes GO:0006397 infores:ubergraph knowledge_assertion manual_agent GO:0039524 GO:0006397 CHEBI:5784 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0004093 infores:hetionet CHEBI:66903 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0011175 infores:hetionet CHEBI:5801 biolink:causes HP:0001103 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0730362 infores:hetionet CHEBI:4856 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0237849 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0018681 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0002965 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0012833 infores:hetionet CHEBI:5855 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0003467 infores:hetionet CHEBI:9328 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0042963 infores:hetionet CHEBI:4657 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0007166 infores:hetionet CHEBI:5613 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0039231 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042571 infores:hetionet CHEBI:77733 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0424295 infores:hetionet CAID:CA350341737 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341737 MONDO:0015924 PMID: Likely Pathogenic PM5_Supporting, PP3, PM2_Supporting, PM1_Strong The BMPR2 c.1156G>C variant is a missense variant predicted to cause a glutamic acid to glutamine substitution at amino acid position 386. The variant is absent from the gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Only one patient with the variant has been reported (PMID: 26387786), and therefore, PS4 is not met. Glu386Gln is located in the catalytic kinase domain and is known to be an indispensable residue (PM1_strong). Other likely pathogenic missense variants causing a different amino acid change at the same residue have been reported, including Glu386Lys, Glu386Ala, Glu386Val, and Glu386Gly (PM5_supporting). Computational evidence for pathogenicity included a REVEL score of 0.961, which meets the threshold of >0.75 defined by the ClinGen Pulmonary Hypertension VCEP, and AlphaMissense 0.9837 (PP3 met but not BP4). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence. Similarly, functional data is unavailable for this variant, so BS3 and PS3 were not evaluated. In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341737/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2569 biolink:causes UMLS:C0858765 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0858765 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018799 infores:hetionet NCBIGene:124512 biolink:causes MONDO:0014409 infores:monarchinitiative not_provided not_provided HGNC:26988 MONDO:0014409 uuid:f24eec92-8f31-4d2f-be68-607f03296841 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1565489 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0919874 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0003123 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0009450 infores:hetionet CHEBI:4325 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0027497 infores:hetionet CHEBI:50729 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0011071 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0026846 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020456 infores:hetionet CHEBI:31485 biolink:causes MONDO:0016064 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0008925 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0948089 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0242656 infores:hetionet CHEBI:116278 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0014743 infores:hetionet UMLS:C0011701 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0037763 infores:hetionet CHEBI:119573 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0740394 infores:hetionet CHEBI:474053 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0038325 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0033246 infores:hetionet CAID:CA346328326 biolink:causes MONDO:0800472 infores:clingen CAID:CA346328326 MONDO:0800472 PMID:27243976 Uncertain Significance PP3, PM2_Supporting PP1, BP4, BA1, PM5, PM3, PM1, PM4, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.875T>A variant in CYP1B1 is a missense variant predicted to cause substitution of Methionine by Lysine at amino acid 292 (p.Met292Lys). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008487 (1 allele out of 1,178,306), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.702, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assay reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). This variant has been identified in an individual with a CYP1B1-related phenotype (PMID: 17563717). This individual is compound heterozygous for the variant and a variant of uncertain significance (phase unknown = 0 proband points), not meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346328326/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9586 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011616 infores:hetionet CHEBI:15428 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0036572 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0259799 infores:hetionet CHEBI:8356 biolink:causes NCIT:C180702 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0312422 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0019158 infores:hetionet GO:2000709 biolink:causes GO:0051754 infores:ubergraph knowledge_assertion manual_agent GO:2000709 GO:0051754 CHEBI:70707 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0029261 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0549478 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0549478 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0000833 infores:hetionet NCBIGene:5699 biolink:causes MONDO:0030924 infores:monarchinitiative not_provided not_provided HGNC:9538 MONDO:0030924 uuid:64960c76-bf3c-4e64-bab2-962dc7fe4284 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4466 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0042963 infores:hetionet CHEBI:3082 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0005747 infores:hetionet CHEBI:3515 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C1112214 infores:hetionet CAID:CA246512 biolink:causes MONDO:0015152 infores:clingen CAID:CA246512 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3 PM4, PM5, PM1, BP3, BP1, BP4, BP2, BA1, PS1, PS4, PS2, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP3, PP1 The NM_000023.4: c.700G>A variant in SGCA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 234 (p.Asp234Asn). This variant has been detected in at least three individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, ClinVar SCV000769867.5 internal data communication) and in unknown phase with a variant classified as at least likely pathogenic (c.100C>T (p.Arg34Cys), 0.25 pts, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of alpha-sarcoglycan protein in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). The highest minor allele frequency of this variant is 0.0005498 (19/34560 exome chromosomes) in the Admixed American population in gnomAD v2.1.1 (PM2_Supporting, BS1 not met). The computational predictor REVEL gives a score of 0.491 (BP4, PP3 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025)(LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA246512/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports GO:0031554 biolink:causes GO:0006351 infores:ubergraph knowledge_assertion manual_agent GO:0031554 GO:0006351 CHEBI:3176 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0178298 infores:hetionet CHEBI:9445 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0085682 infores:hetionet CAID:CA160246 biolink:causes MONDO:0010938 infores:clingen CAID:CA160246 MONDO:0010938 PMID: Benign BA1, BS2_Supporting The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr).The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1).Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160246/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:47426 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0041349 infores:hetionet CHEBI:42797 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013404 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0019112 infores:hetionet CAID:CA198846 biolink:causes MONDO:0010726 infores:clingen CAID:CA198846 MONDO:0010726 PMID: Pathogenic PVS1, PS2_Very Strong, PS4, PM2_Supporting The p.Pro389* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Pro389* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). This variant has been observed in at least 5 other individuals with Rett syndrome (PMID 26984561, 21982064, 20151026, 19652677, RettBASE) (PS4). The p.Pro389* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro389* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA198846/MONDO:0010726/016 2021-03-24 2021-05-10 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf NCBIGene:5290 biolink:causes MONDO:0014047 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0014047 uuid:2a8dc969-753d-4ffb-b46f-18db1c0651d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0586553 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027765 infores:hetionet CHEBI:7565 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085641 infores:hetionet CHEBI:17650 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0022107 infores:hetionet CHEBI:70718 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0042963 infores:hetionet CHEBI:50693 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0042514 infores:hetionet CHEBI:6741 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0020458 infores:hetionet CHEBI:50173 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0002994 infores:hetionet NCBIGene:164781 biolink:causes MONDO:0957922 infores:monarchinitiative not_provided not_provided HGNC:26383 MONDO:0957922 uuid:ca7b3eaf-cb62-44d2-a730-b6c2881a63c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29013 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0017178 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017574 infores:hetionet CHEBI:8207 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0023066 infores:hetionet CHEBI:6149 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013182 infores:hetionet CHEBI:75722 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232495 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0042109 infores:hetionet NCBIGene:27315 biolink:causes MONDO:0013628 infores:monarchinitiative not_provided not_provided HGNC:17893 MONDO:0013628 uuid:e6fe75ad-1fa6-4b33-a609-e3b721bb49ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002871 infores:hetionet CHEBI:9566 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0700075 infores:hetionet CHEBI:31348 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151907 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0034065 infores:hetionet CHEBI:17303 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0041582 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020651 infores:hetionet CHEBI:5062 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C3263723 infores:hetionet CHEBI:7494 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042345 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1696157 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1696157 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0027947 infores:hetionet CHEBI:41774 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030312 infores:hetionet NCBIGene:6833 biolink:causes MONDO:0009415 infores:monarchinitiative not_provided not_provided HGNC:59 MONDO:0009415 uuid:0a080441-9c94-4f47-85da-f19543a16cf0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:54440 biolink:causes MONDO:0024781 infores:monarchinitiative not_provided not_provided HGNC:15975 MONDO:0024781 uuid:743157cf-9790-47c2-8072-54a35f61f9d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0011603 infores:hetionet CAID:CA658658496 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658496 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM1, PM4, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2029dup (p.Gln677ProfsTer11) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658496/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:36791 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0005940 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0010043 infores:hetionet GO:0061470 biolink:causes CL:0002038 infores:ubergraph knowledge_assertion manual_agent GO:0061470 CL:0002038 CHEBI:3219 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0549249 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0221743 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0221743 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0687133 infores:hetionet CAID:CA10584721 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584721 MONDO:0007750 PMID: Likely Pathogenic PVS1_Moderate, PM5, PM2, PP1, PP4 BA1, PS1, PS3, BP7, BS1, BS3, BS4, PM4 The NM_000527.5(LDLR):c.3G>T (p.Met1Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, PM5, PP1, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PP1- variant segregates with phenotype in 2 informative meioses in 1 family (Centre for Cardiovascular Surgery and Transplantation - 1 family: 2 affected relatives with the variant).PP4 - variant meets PM2 and is identified in 1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PM5 - Three other missense variants at this same codon have been reported, and one is Pathogenic:1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines.2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines.3) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines.Note: One other variant resulting in the same amino acid change at this codon has been reported:1) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. -PS1 is not applicable as such variants must be Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584721/MONDO:0007750/013 2022-01-22 2022-04-22 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6887 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085631 infores:hetionet CHEBI:7798 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0009763 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151736 infores:hetionet NCBIGene:3759 biolink:causes MONDO:0013513 infores:monarchinitiative not_provided not_provided HGNC:6263 MONDO:0013513 uuid:4c49d81e-19e9-49ef-8cc3-ee6d3e27f7e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0034186 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0243026 infores:hetionet CHEBI:92998 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0232462 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151883 infores:hetionet CHEBI:63681 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0035078 infores:hetionet CHEBI:9667 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0004096 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0035078 infores:hetionet CAID:CA039387 biolink:causes MONDO:0007750 infores:clingen CAID:CA039387 MONDO:0007750 PMID: Likely Benign BP4, BS3, PM2, PP4 BA1, PS1, PS4, BS1, BS4, PM5, PP3, PP1, BS2 The NM_000527.5(LDLR):c.2291T>C (p.Ile764Thr) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0001337 (0.01337%) in East Asian exomes + genomes (gnomAD v4.1.0).PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for possible FH from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.BP4: REVEL = 0.352, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) Variant not on limits.B) Does not create GT.C) There is a GT nearby. MES scores: variant cryptic = -5.73, wt cryptic = -8.16, canonical donor site = 9.06. Cryptic scores are negative, splice site not used. Variant is not predicted to alter splicing. BS3: Level 1 assay: PMID 34167030 (Alves et al., 2021): Heterologous cells (CHO), FACS; Result - > Normal cell surface LDLR (105%), LDL-LDLR binding (90%) and uptake (89%). Functional study is consistent with no damaging effect.Level 3 assay: PMID 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays; Result - >100% LDLR expression and >100% LDLR activity. Functional study is consistent with no damaging effect.With the application of BP4 and BS3 and the functional evidence available, consensus was to classify this variant as Likely Benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA039387/MONDO:0007750/013 2025-02-28 2025-04-09 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA024586 biolink:causes MONDO:0007783 infores:clingen CAID:CA024586 MONDO:0007783 PMID: Uncertain Significance PM1 PP3, PS3, PS4, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Glycine with Serine at codon 2160 of the RYR1 protein, p.(Gly2160Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0006, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.635 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024586/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:91541 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0003811 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0026946 infores:hetionet CHEBI:64354 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0162830 infores:hetionet CHEBI:8228 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0006277 infores:hetionet CHEBI:31401 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042345 infores:hetionet CHEBI:31485 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C1096274 infores:hetionet CHEBI:45409 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014591 infores:hetionet CHEBI:6128 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0002994 infores:hetionet UMLS:C0657912 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0016382 infores:hetionet GO:1902026 biolink:causes GO:0051216 infores:ubergraph knowledge_assertion manual_agent GO:1902026 GO:0051216 CHEBI:6710 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0232462 infores:hetionet NCBIGene:1737 biolink:causes MONDO:0009502 infores:monarchinitiative not_provided not_provided HGNC:2896 MONDO:0009502 uuid:6b7c44b6-dd0b-4c10-a515-d5c8576783f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50692 biolink:causes HP:0100718 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0042143 infores:hetionet CHEBI:8028 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0009806 infores:hetionet CHEBI:5128 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0003862 infores:hetionet CHEBI:7476 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0162566 infores:hetionet CHEBI:39112 biolink:causes UMLS:C1412002 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1412002 infores:hetionet CHEBI:2668 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0014742 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0235431 infores:hetionet CAID:CA254853 biolink:causes MONDO:0044970 infores:clingen CAID:CA254853 MONDO:0044970 PMID: Likely Pathogenic PP3, PM6_Strong, PM2_Supporting, PS4_Moderate PP1, PS3 The m.14453G>A (p.A74V) variant in MT-ND6 has been reported in at least 10 individuals with primary mitochondrial disease from 10 families. Affected individuals had onset ranging from the first day of life to adulthood (all but one case had early childhood onset, however); and with features variably consistent with Leigh syndrome and MELAS (PS4_moderate; PMIDs: 34933128, 22947169, 33644659, 32552696, 24642831, 21364701, 11781695). Heteroplasmy levels ranged from 41-83%. There are at least five reports of de novo occurrences of this variant (PM6_strong, score 2.5; PMIDs: 34933128, 33644659, 24642831, 11781695). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 2% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.81 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254853/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3478 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0014518 infores:hetionet CHEBI:63632 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0004093 infores:hetionet CHEBI:3756 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0021177 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0043241 infores:hetionet CHEBI:3756 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0236000 infores:hetionet CHEBI:5779 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0009782 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0233472 infores:hetionet NCBIGene:5015 biolink:causes MONDO:0013518 infores:monarchinitiative not_provided not_provided HGNC:8522 MONDO:0013518 uuid:8ef7a9ff-a8c6-4478-9639-30c19e6a10ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8245 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C2363731 infores:hetionet CHEBI:6375 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0270996 infores:hetionet CAID:CA232809 biolink:causes MONDO:0100453 infores:clingen CAID:CA232809 MONDO:0100453 PMID: Likely Benign BS1, BS2_Supporting BP4, PP3 The NM_000180.4(GUCY2D):c.164C>T (p.Thr55Met) variant is predicted to replace the threonine at position p.55 with methionine. This variant is present in gnomAD v4.1.0 at a Grpmax allele frequency of 0.008088, with 341 alleles / 38476 total alleles in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 3 adult individuals in gnomAD which meets the LCA/eoRD VCEP threshold of ≥3 (gnomAD version 4.1.0; BS2_supporting). In addition, the reported frequency of this variant in the Vietnamese population is 1.5%. (PMID:31180159). The computational predictor REVEL gives a score of 0.409, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on GUCY2D function. Additionally, the splicing impact predictor SpliceAI gives a score of 0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Several papers describing East Asian IRD cohorts (PMIDs: 21602930, 23847139) report the presence of the variant in patients but since this is the population with the highest reported allele frequency these papers were not counted toward PM3. In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA232809/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9637 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0027769 infores:hetionet CHEBI:31236 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020580 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0426576 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0037274 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0020538 infores:hetionet CHEBI:3380 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0035455 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0162429 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0476281 infores:hetionet CHEBI:75045 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020621 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0036508 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042018 infores:hetionet CHEBI:7824 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0424295 infores:hetionet CHEBI:53760 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0030193 infores:hetionet NCBIGene:1286 biolink:causes MONDO:0007709 infores:monarchinitiative not_provided not_provided HGNC:2206 MONDO:0007709 uuid:ce988a98-c060-4ffc-97a2-8e2f7c3b5c00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0687713 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0423602 infores:hetionet CHEBI:47519 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C1443060 infores:hetionet CHEBI:8207 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151766 infores:hetionet CHEBI:135351 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0028768 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0039070 infores:hetionet UBERON:0001981 biolink:causes MONDO:0006255 infores:ubergraph knowledge_assertion manual_agent UBERON:0001981 MONDO:0006255 CHEBI:63612 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0917801 infores:hetionet CHEBI:3393 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0027497 infores:hetionet CHEBI:10650 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0004604 infores:hetionet CAID:CA9870021 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870021 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP1_Strong PM2, PS4, BS1 The c.-12G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the 5' UTR of NM_175914.5. The Grpmax filtering allele frequency of the c.-12G>A variant in gnomAD v4.1.0 is 0.00001030, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in 11 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes with 8 informative meioses in 6 families (PP1_Strong; internal lab contributors). In summary, c.-12G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870021/MONDO:0015967/085 2025-07-25 2025-07-25 Autosomal dominant inheritance HP:0000006 Supports UNII:DJJ95FJP1H biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0413252 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151883 infores:hetionet CHEBI:8060 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0027497 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027540 infores:hetionet CAID:CA5950043 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950043 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The NM_000448.3:c.746A>G variant in RAG1 is a missense variant predicted to cause the substitution of Histidine by Arginine at amino acid 249 (p.His249Arg). The filtering allele frequency (the lower threshold of the 95% CI of 34582/44854) of the c.746A>G variant in RAG1 is 0.7646 for East Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 127763 homozygous adults are reported in gnomAD v.4. BS2_Supporting is Met. In summary, this variant meets the criteria to be classified as Benign for Autosomal Recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950043/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4814 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0036974 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0021775 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0003123 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0025061 infores:hetionet CHEBI:7936 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0423791 infores:hetionet CAID:CA2497028945 biolink:causes MONDO:0011132 infores:clingen CAID:CA2497028945 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PP1 The NM_001369369.1(FOXN1):c.1168del (p.Glu390LysfsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 550. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). The variant is absent from gnomADv4.0 (PM2_Supporting). At least one heterozygous patient has been reported with nail dystrophy, low T cell count for age 1.0x10^9/L, and low TRECs (P8 from PMID: 31447097, PP4). The patient was also described to have recurrent severe infections. This patient's mother, P30 carried the same variant and was noted to have nail dystrophy. In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, and PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497028945/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:5801 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0013604 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0043241 infores:hetionet CHEBI:65173 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0027441 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0028960 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0152027 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0314719 infores:hetionet CHEBI:9674 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C1306341 infores:hetionet CHEBI:367163 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0023530 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0243026 infores:hetionet CHEBI:5778 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151517 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011616 infores:hetionet CHEBI:6541 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0015672 infores:hetionet CHEBI:92923 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0699893 infores:hetionet CHEBI:8776 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0014457 infores:hetionet CHEBI:4911 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0423791 infores:hetionet CHEBI:617099 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C2364111 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0025289 infores:hetionet CHEBI:28177 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0015967 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0232459 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233472 infores:hetionet CHEBI:72564 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C2939419 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0035078 infores:hetionet CHEBI:9943 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0242301 infores:hetionet CHEBI:71028 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C1384353 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0851341 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0005741 infores:hetionet CAID:CA386952580 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952580 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PM5_Supporting, PP3 PP4 The c.59G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to glutamic acid at codon 20 (p.(G20E)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, Another missense variant, c.58G>A (p.Gly20Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly20Glu (PM5_Supporting). This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant was identified in a family with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, and segregated with diabetes with eight informative meioses in one family with MODY (PP1_Strong; PMID: 27323672). At least one individual in this family had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 27323672). Taken together, this evidence supports the classification of c.59G>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP1_strong, PP3, PM1_supporting, PM2_supporting, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952580/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA410208042 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208042 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS3, BS1, BS4, PM5, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.4:c.563C>G (p.Thr188Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score >0.75 (0.922) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208042/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17303 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0948226 infores:hetionet CAID:CA410147485 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147485 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS1, PS2, BP3, BP1, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1292C>T (p.Pro431Leu) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.366, and the splice site predictor SpliceAI indicated no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147485/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6062 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013295 infores:hetionet CHEBI:3738 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0031117 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0011991 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0085096 infores:hetionet CHEBI:9123 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0004604 infores:hetionet CHEBI:8597 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0042023 infores:hetionet CHEBI:39585 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0037011 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0017178 infores:hetionet CHEBI:80630 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0333355 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235847 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235847 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017574 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151505 infores:hetionet CHEBI:51380 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0009676 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0011570 infores:hetionet NCBIGene:2120 biolink:causes MONDO:0014536 infores:monarchinitiative not_provided not_provided HGNC:3495 MONDO:0014536 uuid:ded1c2e3-fa55-48e6-89b5-e7404702a821 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019209 infores:hetionet CHEBI:4814 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0038999 infores:hetionet CHEBI:7936 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0234022 infores:hetionet CHEBI:8356 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037763 infores:hetionet CHEBI:3561 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1167965 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0036572 infores:hetionet CHEBI:6456 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0036973 infores:hetionet NCBITaxon:1301 biolink:causes MONDO:0021680 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1301 MONDO:0021680 CHEBI:9241 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0678222 infores:hetionet CHEBI:135876 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0010692 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0036572 infores:hetionet CHEBI:8874 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0028084 infores:hetionet NCBIGene:6608 biolink:causes MONDO:0011556 infores:monarchinitiative not_provided not_provided HGNC:11119 MONDO:0011556 uuid:16f3bda4-04cc-46a6-a09f-77a7e657372a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C1167965 infores:hetionet CHEBI:6149 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0000737 infores:hetionet NCBIGene:57465 biolink:causes MONDO:0014470 infores:monarchinitiative not_provided not_provided HGNC:29203 MONDO:0014470 uuid:c0b98d47-aef4-4e3f-bbec-4739054078dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037274 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0027765 infores:hetionet CHEBI:724125 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0018681 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1328332 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1328332 infores:hetionet CAID:CA10360368 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360368 MONDO:0100039 PMID: Likely Benign BS2, BP4 BS1, PM2 The p.Lys412Glu variant in CDKL5 is present in 1 XY individual in gnomAD (0.0001707%) (not sufficient to meet BS1 criteria). The p.Lys412Glu variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggests that the p.Lys412Glu variant does not have a deleterious impact (BP4); however this information does not predict clinical significance on its own. In summary, the p.Lys412Glu variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360368/MONDO:0100039/034 2023-08-28 2023-12-08 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:15551 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0020649 infores:hetionet CHEBI:175901 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0031350 infores:hetionet CHEBI:29688 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0009676 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0239978 infores:hetionet CHEBI:49375 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0011603 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0013595 infores:hetionet CHEBI:10101 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037763 infores:hetionet CHEBI:94807 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0085593 infores:hetionet CHEBI:142290 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C2830004 infores:hetionet CHEBI:16469 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0040053 infores:hetionet CHEBI:2788 biolink:causes HP:0030947 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0860499 infores:hetionet NCBIGene:26503 biolink:causes MONDO:0010027 infores:monarchinitiative not_provided not_provided HGNC:10933 MONDO:0010027 uuid:9141d61a-bc44-412b-9ba4-ce89028afad7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2948 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0027497 infores:hetionet CHEBI:8024 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0039231 infores:hetionet CAID:CA000654 biolink:causes MONDO:0017623 infores:clingen CAID:CA000654 MONDO:0017623 PMID:22171747PMID:22171747 Likely Benign BP5, BS1 PVS1, PM6, PM2, BP7, BS4, BS3, PP1, PP3, PP2, BS2, PM5, PM1, PM4, BP2, BP4, BA1, PS1, PS2, PS4, PS3 PTEN c.-975G>C (g.89623251G>C) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.006 (0.6%, 21/3466 alleles) in the European (Finnish) subpopulation and 0.002 (0.2%, 30/14,976) in the European (Non-Finnish) subpopulation of the gnomAD cohort. (PMID 27535533)BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributors SCV000187238.1, SCV000149489.5) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000654/MONDO:0017623/003 2019-06-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5130 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0243026 infores:hetionet CHEBI:6375 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151578 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0042373 infores:hetionet CHEBI:2567 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0012833 infores:hetionet CHEBI:2379 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0042571 infores:hetionet CHEBI:71940 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020458 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0858540 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0858540 infores:hetionet CHEBI:7936 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020578 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0031117 infores:hetionet CHEBI:2663 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0004093 infores:hetionet CHEBI:16467 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0020517 infores:hetionet CAID:CA410203468 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203468 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PM2, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.322T>A (p.Cys108Ser) is a missense variant which has a REVEL score ≥ 0.88 (0.913) (PP3). This missense variant is located within the Runt Homology Domain (AA 89–204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203468/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63620 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C2047937 infores:hetionet GO:0003427 biolink:causes GO:0003424 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0003424 CHEBI:27999 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0542184 infores:hetionet CHEBI:5959 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0003467 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0497247 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0239375 infores:hetionet CHEBI:9654 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0037036 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232492 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0518015 infores:hetionet CHEBI:40050 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0020456 infores:hetionet CHEBI:9943 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0242528 infores:hetionet CHEBI:92712 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0015230 infores:hetionet CHEBI:10101 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0040822 infores:hetionet CHEBI:63613 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0149745 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0521591 infores:hetionet CHEBI:7822 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0042963 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0239385 infores:hetionet CHEBI:2922 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0040034 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0010709 infores:hetionet CHEBI:3561 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0026826 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0423271 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0423271 infores:hetionet CHEBI:465284 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020461 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020517 infores:hetionet CAID:CA226589 biolink:causes MONDO:0100368 infores:clingen CAID:CA226589 MONDO:0100368 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting NM_000329.3(RPE65):c.907A>T (p.Lys303Ter) is a nonsense variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), absence of electroretinogram responses from rods (0.5 pts) and cones, nystagmus (1 pt), loss of color vision (1 pt), severely constricted visual fields (1 pt), optic nerve head pallor (0.5 pts), attenuation of retinal arterioles (0.5 pts) with pigmentary changes, macular atrophy (0.5 pts), and significant improvement of dark-adapted vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (15.5 total pts, PMID: 14962443, PMID: 22323828, PP4_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_supporting, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226589/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes MONDO:0002444 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025193 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0041349 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0423602 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0013428 infores:hetionet CHEBI:3172 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0020651 infores:hetionet CHEBI:31302 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0037763 infores:hetionet CHEBI:7492 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0015967 infores:hetionet CAID:CA16020953 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020953 MONDO:0009861 PMID:23764561PMID:16601866 Pathogenic PM3, PVS1, PP4_Moderate PM2 Variant c.1161C>A (p.Tyr387Ter) in PAH was documented 2 times in European patients with classic phenylketonuria (PMID: 16601866, 23764561)(PP4-moderate). This is a nonsense variant in exon 11 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). This variant was detected in trans with pathogenic variant p.P281L (PMID:16601866, 23764561) (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied:PVS1, PM3, PP4-Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020953/MONDO:0009861/006 2020-05-08 2020-05-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:127780 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0018790 infores:hetionet CHEBI:71272 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0085649 infores:hetionet CHEBI:71417 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0003467 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0027051 infores:hetionet CHEBI:9566 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0011606 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0005952 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1314 MONDO:0005952 CAID:CA073912 biolink:causes MONDO:0018493 infores:clingen CAID:CA073912 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 3212 of the RYR1 protein, p.(Glu3212Gly). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0005609, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.624 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA073912/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:15544 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0037763 infores:hetionet CHEBI:3213 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0020458 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0232459 infores:hetionet CHEBI:63629 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151766 infores:hetionet CHEBI:92998 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0014518 infores:hetionet CAID:CA415083128 biolink:causes MONDO:0010305 infores:clingen CAID:CA415083128 MONDO:0010305 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PP4_Strong, PVS1_Moderate PP1 The NM:_005629.3:c.778-2A>G variant alters acceptor splice site of intron 4 and is predicted to result in skipping of exon 5 with in frame loss of 45 amino acids (less than 10% of protein) (PVS1_moderate). This variant has been reported two unrelated males with intellectual disability, language delay, epilepsy, elevated urine creatine/creatinine ratio and a reduced creatine peak on brain MRS (PMID: 20717164, 37305710) (PP4_strong, PS4_supporting). One of these individuals has a male sibling, hemizygous for the variant, with epilepsy, expressive language difficulties, movement disorder, elevated urine creatine/creatinine ratio and reduced creatine peak on brain MRS. Their mother was heterozygous for the same variant but her phenotypic and biochemical details were not provided (PMID: 20717164) (PP1 not met). The variant is absent in gnomAD v2.1.1. (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_moderate, PP4_strong, PM2_supporting, PS4_supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on Fabruary 22, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415083128/MONDO:0010305/027 2024-02-22 2024-03-29 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:17303 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151908 infores:hetionet CHEBI:8863 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0231218 infores:hetionet CHEBI:6438 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0497365 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0948525 infores:hetionet CAID:CA392261143 biolink:causes MONDO:0012996 infores:clingen CAID:CA392261143 MONDO:0012996 PMID:27233232 Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting, PS3_Supporting PP3, BP4 The NM_001482.3:c.553G>C variant in GATM is a missense variant that is predicted to result in the substitution of alanine by proline at amino acid 185 (p.Ala185Pro). One patient, with one episode of seizure, myopathy, intellectual disability, and abnormal EMG, has been reported with absent creatine on brain MRS, as well as low urine guanidinoacetate, and low plasma guanidinoacetate with low plasma creatine (PMID: 26490222) (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001562 (1/64012 alleles) in the Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion. This allele is the only allele in gnomAD v4.1.0. (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.528 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PP4_Strong, PS3_Supporting, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392261143/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:82960 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0018799 infores:hetionet CAID:CA392336648 biolink:causes MONDO:0007947 infores:clingen CAID:CA392336648 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP1, PP4, PM2_Supporting, PS4_Moderate, PM1_Strong PVS1, PM6, BS2, BA1, BP1, BP4, BP2, BP3, PS3, PS1, PS2, PM3, PM4, PM5, BP7, BP5, BS1, BS4, BS3 NM_000138.5 c.6410G>A is a missense variant in FBN1 predicted to cause a substitution of cysteine by a tyrosine at amino acid 2137 (p.Cys2137Tyr). This variant has been identified in at least five patients with thoracic aortic aneurysm and dissection (TAAD), including two meeting clinical diagnostic criteria for Marfan syndrome (MFS), and in a patient with an unspecified clinical suspicion of Marfan syndrome (PS4_moderate, PP4; University of Texas-Houston & Invitae internal data). The variant was also found to segregate with aortic dilation in two individuals across two families (PP1; University of Texas-Houston & Invitae internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.916). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PP1, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392336648/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:5296 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0027441 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001942 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0270549 infores:hetionet CHEBI:8461 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0009421 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0080203 infores:hetionet NCBITaxon:86056 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:86056 MONDO:0001867 CHEBI:4710 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027424 infores:hetionet CHEBI:74947 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0025874 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0178298 infores:hetionet CHEBI:63598 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0033845 infores:hetionet CHEBI:75722 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011124 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0851341 infores:hetionet CHEBI:50885 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0042571 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0037274 infores:hetionet CHEBI:34385 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0013395 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0031350 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0235146 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0041912 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0003123 infores:hetionet CHEBI:61049 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0340865 infores:hetionet CHEBI:64064 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0043352 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0836924 infores:hetionet CHEBI:6128 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0149745 infores:hetionet CHEBI:2038 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C2939420 infores:hetionet CHEBI:6887 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085298 infores:hetionet CHEBI:6950 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0699828 infores:hetionet CHEBI:50156 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0009676 infores:hetionet CHEBI:7822 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0014724 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0575090 infores:hetionet CHEBI:480999 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0919924 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042373 infores:hetionet CHEBI:51041 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0041657 infores:hetionet CHEBI:27732 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0017181 infores:hetionet CHEBI:6801 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1322281 infores:hetionet CHEBI:72292 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0038454 infores:hetionet CHEBI:63616 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0221150 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0032285 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0150450 infores:hetionet CHEBI:94686 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0003467 infores:hetionet CHEBI:8707 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0338831 infores:hetionet CHEBI:6520 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0040034 infores:hetionet CHEBI:8245 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0085631 infores:hetionet CHEBI:8461 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0009946 infores:hetionet CHEBI:6690 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0162830 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0002170 infores:hetionet CAID:CA8622907 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622907 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting BP7 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.273G>A (p.Glu91=), no individuals with Glanzmann thrombasthenia were reported with the variant. The variant has a minor allele frequency of 0.00006 (2/35438 alleles) in the Latino/Admixed American population in gnomAD, which meets our threshold criteria for PM2_Supporting. In silico predictor SpliceAI revealed that the synonymous mutation is not expected to impact splicing but a PhyloP score of 2.318 shows that the nucleotide position is highly conserved. Due to insufficient evidence, this variant is classified as a variant of unknown significance for Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622907/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true NCBIGene:4593 biolink:causes MONDO:0100101 infores:monarchinitiative not_provided not_provided HGNC:7525 MONDO:0100101 uuid:4b049ae3-8ca7-4b86-91c9-0e0a3a7f7e64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0034882 infores:hetionet CHEBI:3219 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0086769 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151883 infores:hetionet CHEBI:28241 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0011603 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0948594 infores:hetionet CHEBI:8435 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0013384 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0008049 infores:hetionet NCBIGene:4359 biolink:causes MONDO:0011889 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0011889 uuid:ef0f2179-5d06-4729-8c43-ed06cb130ecf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68554 biolink:causes MONDO:0006795 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0020532 infores:hetionet CAID:CA023907 biolink:causes MONDO:0007783 infores:clingen CAID:CA023907 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Glutamine with Glutamic Acid at codon 3756 of the RYR1 protein, p.(Gln3756Glu). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.1085, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023907/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:194135 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0278134 infores:hetionet CHEBI:4784 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0033774 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0037274 infores:hetionet CHEBI:47780 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037672 infores:hetionet CHEBI:3207 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0023518 infores:hetionet CHEBI:3011 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0020461 infores:hetionet CHEBI:2682 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0001122 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151779 infores:hetionet CAID:CA343723639 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723639 MONDO:0020367 PMID:35615698PMID:32818018 Likely Pathogenic PP1_Moderate, PM2_Supporting, PS3 BP7, BS1, BS3, PM6, PP3, PM4, PM5, PS4, PS1, PS2, BP4, BA1 The c.1348A>T variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Tyrosine at amino acid 450 (p.Asn450Tyr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.68, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825), meeting PS3. 9 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 20806035), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 20806035), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 7 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3, PP1_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723639/MONDO:0020367/019 2023-06-01 2023-06-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:84500 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0014130 infores:hetionet CHEBI:119915 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0424489 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027932 infores:hetionet UMLS:C1144403 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0231528 infores:hetionet CHEBI:63637 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0012833 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0006840 infores:hetionet CHEBI:119486 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0016658 infores:hetionet CHEBI:4903 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0030196 infores:hetionet CHEBI:3752 biolink:causes MONDO:0019040 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0008626 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0009806 infores:hetionet CHEBI:28971 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0042963 infores:hetionet CHEBI:85161 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151636 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0948594 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0027765 infores:hetionet CHEBI:7915 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232462 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2225524 infores:hetionet CAID:CA397318622 biolink:causes MONDO:0009276 infores:clingen CAID:CA397318622 MONDO:0009276 PMID: Uncertain Significance PP4, PP1, PM2_Supporting, PM3_Supporting PP3 The c.785T>G variant in GP1BA is a missense variant predicted to cause substitution of Valine by Glycine at amino acid 262 (p.Val262Gly). At least one patient (Patient BSS19.01 in PMID:23995613) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). Additionally, the variant has been reported to segregate in this proband plus 1 additional homozygous BSS affected family member who displays significantly reduced surface expression of GP1BA and giant platelets). 1 pt total (PP1_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM3_Supporting, PP1 and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397318622/MONDO:0009276/079 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:4624 biolink:causes MONDO:0013197 infores:monarchinitiative not_provided not_provided HGNC:7576 MONDO:0013197 uuid:381d2bc7-953f-4cc0-a84f-03045b0f2565 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0018681 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0243026 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0025061 infores:hetionet GO:2000181 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:2000181 GO:0035295 CHEBI:3996 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0033975 infores:hetionet CAID:CA136171 biolink:causes MONDO:0021060 infores:clingen CAID:CA136171 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.570C>T (p.Asp190=) variant in the SOS1 gene is 0.314% (234/66628) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136171/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:66964 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0028084 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0013395 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0003123 infores:hetionet CAID:CA2573102978 biolink:causes MONDO:0007453 infores:clingen CAID:CA2573102978 MONDO:0007453 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting The c.1378del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), adding 154 novel amino acids before encountering a stop codon (p.(Ala460ProfsTer154)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss-of-function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; PMID: 15841481). In summary, c.1378del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573102978/MONDO:0007453/086 2023-06-18 2023-06-18 Semidominant inheritance HP:0032113 Supports CHEBI:9086 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0029878 infores:hetionet CHEBI:63637 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0004604 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0235146 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0027813 infores:hetionet CHEBI:48273 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0235266 infores:hetionet CHEBI:4877 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0042963 infores:hetionet CL:0000125 biolink:causes MONDO:0021042 infores:ubergraph knowledge_assertion manual_agent CL:0000125 MONDO:0021042 NCBIGene:1896 biolink:causes MONDO:0010741 infores:monarchinitiative not_provided not_provided HGNC:3157 MONDO:0010741 uuid:90f75ae1-3888-4fa5-a9ca-5fa92ff9d664 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94501 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020625 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0235050 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235050 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0948873 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0007642 infores:hetionet CHEBI:63115 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0024314 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235818 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0162830 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1565489 infores:hetionet CHEBI:7478 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020458 infores:hetionet CHEBI:6897 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0030252 infores:hetionet CHEBI:421707 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0497156 infores:hetionet GO:2000764 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000764 GO:0007275 CHEBI:10125 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0917801 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0042109 infores:hetionet CHEBI:3756 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0424295 infores:hetionet NCBIGene:527 biolink:causes MONDO:0958196 infores:monarchinitiative not_provided not_provided HGNC:855 MONDO:0958196 uuid:de448cef-fc7d-4893-abd9-49d31ae17042 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0231218 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0022660 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0006145 infores:hetionet CHEBI:142290 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C3665347 infores:hetionet CHEBI:2663 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0015672 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0518015 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0162810 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0162810 infores:hetionet CHEBI:9566 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0018681 infores:hetionet CHEBI:94807 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0020538 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0521626 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0521626 infores:hetionet CHEBI:41977 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0015230 infores:hetionet CHEBI:5100 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0160390 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235290 infores:hetionet CHEBI:63611 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0013428 infores:hetionet CHEBI:46295 biolink:causes MONDO:0000498 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C2242711 infores:hetionet CHEBI:63631 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0026961 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0007785 infores:hetionet CHEBI:63580 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1260880 infores:hetionet CHEBI:3242 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0036974 infores:hetionet CHEBI:84500 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0234233 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001561 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0034194 infores:hetionet CHEBI:9130 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0030305 infores:hetionet NCBIGene:3054 biolink:causes MONDO:0010657 infores:monarchinitiative not_provided not_provided HGNC:4839 MONDO:0010657 uuid:9bd7f636-f428-4067-8b2f-b67afe5b48e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0013378 infores:hetionet GO:1905000 biolink:causes GO:0086026 infores:ubergraph knowledge_assertion manual_agent GO:1905000 GO:0086026 CHEBI:76010 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0234458 infores:hetionet CHEBI:584020 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0026961 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0019054 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0314719 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027947 infores:hetionet CAID:CA8603030 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603030 MONDO:0100326 PMID: Benign BP7, BA1 The NM_000419.5(ITGA2B):c.1600+16G>T variant is an intronic variant that is not predicted by SpliceAI to impact splicing (Delta scores 0.00). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 0.2397 (BP7). The highest population minor allele frequency in gnomAD v4.0.0 is 0.002865 (250/75040alleles) in the African/African-American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1). In summary this variant is classified as Benign for autosomal recessive Glanzmann thrombasthenia, with ACMG criteria applied as specified by the PD VCEP: BA1, BP7 Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603030/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:50729 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0013604 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0037274 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0030305 infores:hetionet CHEBI:28787 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0018520 infores:hetionet CHEBI:63620 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011253 infores:hetionet CHEBI:32192 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0038362 infores:hetionet CHEBI:3314 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0004093 infores:hetionet CHEBI:5551 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0011603 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0019158 infores:hetionet CAID:CA386970422 biolink:causes MONDO:0015967 infores:clingen CAID:CA386970422 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS3, PP3 PVS1, PP4 The c.1501+5G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to impact splicing in intron 7 of NM_000545.8. This variant has a gnomAD 4.1.0 Grpmax Filtering allele frequency of 2.80e-7, which is below the ClinGen MDEP threshold of MDEP threshold of 0.000003 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.64 for donor loss, predicting that the variant disrupts the donor site of intron 7 of HNF1A (PP3). Furthermore, minigene-splicing assay demonstrates that this variant results in abnormal splicing and the in-frame deletion of exon 7 and retention of 42 intronic nucleotides (PS3; Bouvet et al., 2023). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50%, and PP4 cannot be applied (internal lab contributors). In summary, c.1501+5G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PS3, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386970422/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28748 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0034882 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0234975 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0234975 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0029456 infores:hetionet CHEBI:63605 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0151786 infores:hetionet CHEBI:28830 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0206062 infores:hetionet CHEBI:52010 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0012569 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0027051 infores:hetionet NCBIGene:190 biolink:causes MONDO:0010226 infores:monarchinitiative not_provided not_provided HGNC:7960 MONDO:0010226 uuid:4ade1432-ea92-4f37-96d3-cfe7389fc2f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4659 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0278134 infores:hetionet CHEBI:9586 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0009421 infores:hetionet CHEBI:8461 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0013604 infores:hetionet CHEBI:75045 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0014591 infores:hetionet CHEBI:10124 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0010200 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0239376 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0239376 infores:hetionet CHEBI:50742 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0037317 infores:hetionet CHEBI:3215 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030232 infores:hetionet NCBIGene:7401 biolink:causes MONDO:0013610 infores:monarchinitiative not_provided not_provided HGNC:12605 MONDO:0013610 uuid:12282055-c1b6-4db8-aead-1b81497892e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018520 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0029408 infores:hetionet CHEBI:94848 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0043144 infores:hetionet CHEBI:36795 biolink:causes HP:0001103 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0730362 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0022650 infores:hetionet CHEBI:5959 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0026821 infores:hetionet CHEBI:10124 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0022107 infores:hetionet CHEBI:8435 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0023066 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0002871 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0021400 infores:hetionet CHEBI:4495 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0003467 infores:hetionet CHEBI:50924 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0032227 infores:hetionet CHEBI:50378 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0085584 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004238 infores:hetionet CHEBI:78543 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0237849 infores:hetionet CHEBI:101853 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0026896 infores:hetionet CHEBI:3756 biolink:causes HP:0004386 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1535950 infores:hetionet CHEBI:2038 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0034642 infores:hetionet CHEBI:9943 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0008350 infores:hetionet CHEBI:17987 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0521495 infores:hetionet CHEBI:7565 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018790 infores:hetionet UNII:D27V6190PM biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0231919 infores:hetionet CHEBI:520985 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0028084 infores:hetionet CHEBI:8212 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0017566 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0010346 infores:hetionet CHEBI:9605 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0085593 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0010346 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0022904 infores:hetionet CHEBI:4868 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0237849 infores:hetionet CAID:CA269559072 biolink:causes MONDO:0007947 infores:clingen CAID:CA269559072 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP1, PS4_Supporting, PM1 PM2, PM6, PVS1, PP3, BS2, BP1, BP4, BP3, BP2, BA1, PM4, PM5, PM3, PS2, PS1, PS3, BP5, BP7, BS4, BS1, BS3 NM_000138.5(FBN1):c.1390C>T (p.Arg464Cys)NM_00138 c.1390C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 464 (p.Arg464Cys). This variant has been found in two probands including one with bilateral ectopia lentis (EL) and thoracic aortic aneurysm and dissection (TAAD), and one with isolated EL (PP4, PS4_supporting; Invitae & UZG internal data, ClinVar Variation ID: 549013). The variant segregates with features of Marfan syndrome in at least two affected family members (PP1; Invitae internal data). This variant is present in gnomAD v2.1.1 (1/34578 [0.003%] Latino/Admixed American alleles; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis are unclear about the predicted impact of this variant on the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based o the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_supporting, PP1, PP2, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA269559072/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:50861 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0231218 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0233472 infores:hetionet CHEBI:8707 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0000731 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030469 infores:hetionet CHEBI:5296 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0002170 infores:hetionet CHEBI:9649 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0030312 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0042267 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0152029 infores:hetionet CHEBI:9943 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003467 infores:hetionet CAID:CA10585485 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585485 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 PP3 The NM_000527.5(LDLR):c.1504G>T p.(Asp502Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP4: Variant meets PM2 and is identified in one FH case from The Netherlands fulfilling internationally accepted criteria, after alternative causes of high cholesterol were excluded, in PMID 11810272 (Fouchier et al., 2001). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585485/MONDO:0007750/013 2025-02-28 2025-04-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4710 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0575081 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151785 infores:hetionet CHEBI:63611 biolink:causes HP:0046505 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0239833 infores:hetionet CHEBI:8024 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002792 infores:hetionet CHEBI:8802 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0040034 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0038367 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011570 infores:hetionet CHEBI:168396 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007859 infores:hetionet CAID:CA9871679 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871679 MONDO:0007064 PMID: Likely Benign BS2_Supporting, BP7, BS1 The c.402C>T (p.Gly134=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003095 (89/19874 alleles) in African/African American population, which is higher than the ClinGen SCID VCEP threshold (>0.00161) for BS1, and therefore meets this criterion (BS1). In the gnomAD v2.1.1 database, this variant has been observed in 1 homozygous individual with no features of SCID, a condition with full penetrance at an early age. BS2_supporting is met.In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BS1, BP7, and BS2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871679/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:50742 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0033774 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0677500 infores:hetionet CHEBI:8404 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0042963 infores:hetionet CHEBI:92712 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0237314 infores:hetionet CHEBI:9449 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0040822 infores:hetionet CHEBI:47780 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038990 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0243026 infores:hetionet CHEBI:3286 biolink:causes MONDO:0006711 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0031048 infores:hetionet NCBIGene:4038 biolink:causes MONDO:0013679 infores:monarchinitiative not_provided not_provided HGNC:6696 MONDO:0013679 uuid:fe264c02-9e64-48be-9c30-71b3ca2be467 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0345904 infores:hetionet CHEBI:83804 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0023066 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0340464 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0267596 infores:hetionet CHEBI:408174 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004238 infores:hetionet CHEBI:3223 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0428977 infores:hetionet CAID:CA231163 biolink:causes MONDO:0015967 infores:clingen CAID:CA231163 MONDO:0015967 PMID: Uncertain Significance BP4 PM2, PP4, PS3, BS3 The c.1267C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to serine at codon 423 (p.(Pro423Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 22308320). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 15111529 ). In summary, c.1267C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA231163/MONDO:0015967/085 2024-12-12 2024-12-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9763 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0027707 infores:hetionet CHEBI:91541 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0152030 infores:hetionet CHEBI:6950 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0023380 infores:hetionet CHEBI:41423 biolink:causes NCIT:C122437 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0740299 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0234215 infores:hetionet CHEBI:6717 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013447 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0002170 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040261 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003615 infores:hetionet CHEBI:8707 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0043094 infores:hetionet CHEBI:15367 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0001175 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0262397 infores:hetionet NCBIGene:7249 biolink:causes MONDO:0011705 infores:monarchinitiative not_provided not_provided HGNC:12363 MONDO:0011705 uuid:fecd6738-998f-4155-af8f-006a5c90e130 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0879264 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151763 infores:hetionet CHEBI:9654 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0027424 infores:hetionet CHEBI:6931 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0043144 infores:hetionet CHEBI:9586 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019080 infores:hetionet NCBITaxon:777 biolink:causes MONDO:0019186 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:777 MONDO:0019186 CHEBI:135686 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0013395 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027726 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005369 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0007095 infores:hetionet CHEBI:10127 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0423791 infores:hetionet CHEBI:6539 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0428977 infores:hetionet CHEBI:9635 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0149871 infores:hetionet CHEBI:17026 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0003467 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0035309 infores:hetionet CHEBI:184555 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0002418 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0851341 infores:hetionet CHEBI:16586 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0027540 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0795692 infores:hetionet CHEBI:33780 biolink:causes MONDO:0015274 infores:ubergraph knowledge_assertion manual_agent CHEBI:33780 MONDO:0015274 CHEBI:9654 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0011253 infores:hetionet CHEBI:6129 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018944 infores:hetionet NCBIGene:3674 biolink:causes MONDO:0008552 infores:monarchinitiative not_provided not_provided HGNC:6138 MONDO:0008552 uuid:4f491ccb-b9d5-4860-aac2-690ffbcdb017 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0043352 infores:hetionet CAID:CA229466 biolink:causes MONDO:0009861 infores:clingen CAID:CA229466 MONDO:0009861 PMID:10234516PMID:21953985PMID:10234516 Uncertain Significance PM2, PP4_Moderate, PM3_Supporting PP3, PS3 The c.175G>T (p.Asp59Tyr) variant in PAH has been reported in 1 individual with mild hyperphenylalaninaemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 10234516). This variant has is absent in population databases. This variant was detected with A403V (Pathogenic in ClinVar) (PM3_supporting; PMID: 10234516). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229466/MONDO:0009861/006 2021-02-14 2022-06-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45285 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0349506 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0948296 infores:hetionet CHEBI:231425 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0009806 infores:hetionet CHEBI:23765 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0004604 infores:hetionet CHEBI:63599 biolink:causes MONDO:0020108 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002880 infores:hetionet UNII:D27V6190PM biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0004093 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0027441 infores:hetionet CAID:CA9870370 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870370 MONDO:0015967 PMID:15728204PMID:10389854PMID:10606640 Benign PP3, BA1, BS3_Supporting PP4, PM1, PS3 The c.724G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to methionine at codon 242(p.(Val242Met)) of NM_175914.5. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0003423, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.81, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies performed on this variant showed transactivation activity >= 75% of that of wildtype, providing evidence that the variant does not affect HNF4A function (BS3_Supporting; PMIDs: 15728204, 10666040, 10389854). In summary, c.724G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BA1, PP3, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870370/MONDO:0015967/085 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17141 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0020517 infores:hetionet CHEBI:92998 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0231218 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0424000 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1720798 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015469 infores:hetionet CAID:CA1139665149 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665149 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The c.1269+1del variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 12. It is predicted to cause skipping of biologically-relevant-exon 12/20, resulting in an in-frame deletion (removes amino acids 395-423) that is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). To our knowledge, this variant has not been reported in an individual affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. To our knowledge, no functional studies have been performed on this variant. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting (VCEP specifications version1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665149/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3441 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0030552 infores:hetionet CAID:CA16609956 biolink:causes MONDO:0013144 infores:clingen CAID:CA16609956 MONDO:0013144 PMID: Pathogenic PS4, PM4, PP1_Moderate, PP3, PP4, PM2_Supporting The NM_000488.3(SERPINC1):c.1154-14G>A variant is completely absent from gnomAD v2.1.1 and v3.1, meeting criteria for PM2_supporting. More than 20 probands across publications and internal laboratory data meet AT deficiency phenotype criteria and therefore, PS4_Very Strong is applied. 6 segregations across 4 families are counted in the literature (PMIDs: 7981186, 15164384, 7949130, 32686144), so PP1_Moderate is applied. SpliceAI predicts a cryptic acceptor splice site at -2bp with a score of 0.5. At least 2 publications (PMID: 7949130, PMID: 30046692) show experimental evidence of alternative splicing in patients due to the variant and therefore, PP3 is applied. The splicing aberration results in addition of 12bp of intron 4 into exon 5 of SERPINC1, increasing the protein length by 4 amino acids. This region is noted to be important for the folding and polymerization of the protein. Therefore, PM4 is applied. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PM4, PP1_Moderate, PP3, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609956/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:4751 biolink:causes MONDO:0000879 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D002179 DB09321_MESH_D002179_1 CHEBI:10119 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0009763 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0022658 infores:hetionet GO:2000310 biolink:causes GO:0003333 infores:ubergraph knowledge_assertion manual_agent GO:2000310 GO:0003333 CHEBI:135351 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0037199 infores:hetionet CHEBI:63717 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0687713 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0003864 infores:hetionet CHEBI:585948 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0011603 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0178298 infores:hetionet CHEBI:63605 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1527344 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0004936 infores:hetionet NCBIGene:3454 biolink:causes MONDO:0030970 infores:monarchinitiative not_provided not_provided HGNC:5432 MONDO:0030970 uuid:e4dc8493-3940-400a-b39c-f3a4d6f353fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3125 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0020517 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0158350 infores:hetionet CHEBI:44032 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020580 infores:hetionet CAID:CA10014589 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014589 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.138G>T (p.Ala46=) is a synonymous variant. REVEL score not calculable. SpliceAI predicts: Acceptor loss 0.06, Donor loss 0.02, Acceptor gain 0.00, Donor gain 0.00. (BP4) Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.22672 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014589/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48390 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0009806 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0023895 infores:hetionet CHEBI:3756 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0037317 infores:hetionet CHEBI:4911 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0740394 infores:hetionet CHEBI:9168 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018681 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0029408 infores:hetionet CHEBI:9654 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020433 infores:hetionet CHEBI:3647 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0013132 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0026946 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2225524 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0034065 infores:hetionet CHEBI:47898 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0024902 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1269683 infores:hetionet NCBIGene:3172 biolink:causes MONDO:0014458 infores:monarchinitiative not_provided not_provided HGNC:5024 MONDO:0014458 uuid:03022c20-6b54-44f6-8422-33e4817c3ea3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038990 infores:hetionet CHEBI:63610 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0032617 infores:hetionet CHEBI:7494 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018524 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151828 infores:hetionet CHEBI:7465 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0026821 infores:hetionet CHEBI:31980 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0030252 infores:hetionet CHEBI:27834 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C2981158 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030305 infores:hetionet CHEBI:7903 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0035455 infores:hetionet NCBIGene:117531 biolink:causes MONDO:0010967 infores:monarchinitiative not_provided not_provided HGNC:16513 MONDO:0010967 uuid:bb8bf6bf-eae8-491a-a8d4-289a8b8d8bb1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8815179 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815179 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1130del (p.Gly377AlafsTer15) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002354 (3/127432 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting) To our knowledge, this variant has not been reported in a patient with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 497032). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ).GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications version 2.0): PVS1, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815179/MONDO:0009290/010 2023-05-26 2023-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:473990 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0002792 infores:hetionet CHEBI:194135 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085636 infores:hetionet CHEBI:28939 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0013404 infores:hetionet CHEBI:5130 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151786 infores:hetionet NCBIGene:55717 biolink:causes MONDO:0859373 infores:monarchinitiative not_provided not_provided HGNC:13831 MONDO:0859373 uuid:0f109a0b-53ca-4fa2-8018-0362160ccc59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151785 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042373 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151838 infores:hetionet NCBIGene:57096 biolink:causes MONDO:0011987 infores:monarchinitiative not_provided not_provided HGNC:13436 MONDO:0011987 uuid:51f57892-4b20-4c79-b7d9-f8b5c0992188 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020565 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027932 infores:hetionet GO:1902256 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1902256 GO:0007275 CHEBI:7915 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027796 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0034065 infores:hetionet CHEBI:28487 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0428977 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0267792 infores:hetionet CHEBI:6076 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020598 infores:hetionet CHEBI:116735 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0015230 infores:hetionet CHEBI:52172 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151205 infores:hetionet CHEBI:63613 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0004364 infores:hetionet NCBIGene:26284 biolink:causes MONDO:0033047 infores:monarchinitiative not_provided not_provided HGNC:3424 MONDO:0033047 uuid:f6df0d0d-7fc4-4a84-9ff2-f8258d976d03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011570 infores:hetionet CHEBI:31348 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0037763 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0007642 infores:hetionet CAID:CA6831741 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831741 MONDO:0015967 PMID: Uncertain Significance BS3_Supporting, PM1_Supporting, PP3 BA1, PS3, PS4, PM5, BS1, PM2, PP1, PP4 The c.340C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 114 (p.(Arg114Cys)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg114Cys protein has DNA binding above 75% of wild type, normal localization, and transactivation above 75% of wildtype, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 26853433). The Grpmax filtering allele frequency of the c.340C>T variant in gnomAD v2.1.1 is 0.00002596, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs:26853433, 19336507, ClinVar, internal lab contributors). In summary, c.340C>T meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PP3, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831741/MONDO:0015967/017 2025-04-23 2025-04-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8356 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0522172 infores:hetionet CAID:CA380140455 biolink:causes MONDO:0000573 infores:clingen CAID:CA380140455 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PM1, PM3 PM5, PS1 The c.1396C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Leucine by Phenylalanine at amino acid 466 (p.Leu466Phe).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate.One patient from Invitae presents carries this variant in trans with c.1352G>C (p.Gly451Ala) (classified as Likely Pathogenic according to SCID VCEP specifications). The parents were also tested; each was heterozygous for one variant - variants are in trans. 1 point, PM3 is met.The patient carrying this variant presents: T-B-NK+ lymphocyte subset profile 0.5 pts + SCID gene panel or exome/genome sequencing conducted 0.5 pts; + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5 pts; Total is 1.5 points, PP4 is met.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PP4, and PM3 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380140455/MONDO:0000573/124 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:83723 biolink:causes MONDO:0030440 infores:monarchinitiative not_provided not_provided HGNC:25295 MONDO:0030440 uuid:5d00629d-d4c2-46a0-8f81-a133139a334c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085632 infores:hetionet CHEBI:6078 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0027497 infores:hetionet CHEBI:36704 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0424109 infores:hetionet NCBIGene:5468 biolink:causes MONDO:0011448 infores:monarchinitiative not_provided not_provided HGNC:9236 MONDO:0011448 uuid:0c300435-ec8e-47ca-81a1-31f766ce4977 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0559031 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0233494 infores:hetionet CHEBI:16469 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042029 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151838 infores:hetionet CHEBI:75246 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0007859 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0281856 infores:hetionet CHEBI:3568 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011253 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0233472 infores:hetionet CHEBI:7936 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0702166 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0877042 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0877042 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0238201 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0238201 infores:hetionet CHEBI:4027 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020461 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0003123 infores:hetionet CHEBI:5855 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038999 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0031542 infores:hetionet CHEBI:8356 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085636 infores:hetionet CHEBI:45979 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0016382 infores:hetionet CHEBI:8107 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0025289 infores:hetionet CHEBI:15551 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0012833 infores:hetionet CHEBI:61033 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0086565 infores:hetionet CHEBI:5801 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0015230 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0040034 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0016436 infores:hetionet CHEBI:8346 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0497156 infores:hetionet CHEBI:291342 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0233472 infores:hetionet CHEBI:2788 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0027497 infores:hetionet CHEBI:2639 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0017178 infores:hetionet CAID:CA10577537 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577537 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.468G>A (p.Trp156Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577537/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA16618475 biolink:causes MONDO:0015967 infores:clingen CAID:CA16618475 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 1508276, 11079754, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID: 11508276, internal lab contributors). In summary, c.113A>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618475/MONDO:0015967/086 2024-03-19 2024-03-19 Semidominant inheritance HP:0032113 Supports CHEBI:46195 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0004096 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0085584 infores:hetionet CHEBI:46345 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0876994 infores:hetionet CHEBI:51230 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C3665347 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0314719 infores:hetionet CHEBI:142290 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013428 infores:hetionet CHEBI:480999 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0042963 infores:hetionet NCBIGene:91574 biolink:causes MONDO:0014020 infores:monarchinitiative not_provided not_provided HGNC:26784 MONDO:0014020 uuid:2af9671a-4b0c-49f1-851b-91b55943fee2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011168 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0086543 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0043251 infores:hetionet CHEBI:15940 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0035455 infores:hetionet CHEBI:2682 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002064 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0595902 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595902 infores:hetionet CHEBI:9362 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0677500 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0010692 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0948594 infores:hetionet CHEBI:9086 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013428 infores:hetionet CHEBI:585948 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0231528 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0032285 infores:hetionet NCBIGene:116461 biolink:causes MONDO:0014874 infores:monarchinitiative not_provided not_provided HGNC:16791 MONDO:0014874 uuid:81f36965-2cdd-4507-aaf9-944579c34a8b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151601 infores:hetionet CHEBI:92998 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0033774 infores:hetionet CHEBI:50381 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0005779 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014868 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0151849 infores:hetionet CHEBI:46295 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0344232 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014868 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151882 infores:hetionet CHEBI:27786 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0033774 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233401 infores:hetionet UMLS:C1738934 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011168 infores:hetionet CHEBI:63598 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151825 infores:hetionet CAID:CA410204074 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204074 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.160G>C (p.Glu54Gln) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204074/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6339 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0043246 infores:hetionet CHEBI:4445 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0231528 infores:hetionet CHEBI:7954 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0011991 infores:hetionet CAID:CA354151 biolink:causes MONDO:0009861 infores:clingen CAID:CA354151 MONDO:0009861 PMID: Pathogenic PM2, PP4, PM3_Very Strong PP3 This c.320A>G (p.His107Arg) variant in PAH was reported in 22 patients with PAH deficiency (>120 uMol/L Phe), detected in trans in 16 patients with pathogenic variants p.Arg111*, p.Arg400Thr, p.Val399=, p.Val399=, p.Arg241Cys, p.Arg241Cys, p.Arg413Pro, p.Gly257Val, p.His107Arg, p.Arg243Gln, p.His220Pro, p.Arg176*, p.Arg243Gln, p.Arg243Gln, p.Val230Ile, p.Ile65Thr (PMID: 28982351). Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_very-strong, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA354151/MONDO:0009861/006 2020-12-09 2021-01-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8874 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007820 infores:hetionet CHEBI:3479 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C1257843 infores:hetionet CHEBI:135285 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0003862 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0233414 infores:hetionet CHEBI:42944 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020458 infores:hetionet CHEBI:135736 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035455 infores:hetionet CHEBI:8356 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0947912 infores:hetionet CHEBI:45652 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0853875 infores:hetionet CHEBI:9168 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085649 infores:hetionet CHEBI:9445 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0030193 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0006840 infores:hetionet NCBIGene:2895 biolink:causes MONDO:0014530 infores:monarchinitiative not_provided not_provided HGNC:4576 MONDO:0014530 uuid:0b6fa8ff-ff0d-41ed-8d4a-5e99fc2dac01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0033777 infores:hetionet CHEBI:31624 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0006266 infores:hetionet CHEBI:74947 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013384 infores:hetionet CHEBI:84500 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020461 infores:hetionet CHEBI:31302 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0018681 infores:hetionet CHEBI:50648 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0231528 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0948594 infores:hetionet CHEBI:35677 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0042109 infores:hetionet CHEBI:4975 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0013428 infores:hetionet CHEBI:4708 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0043094 infores:hetionet CHEBI:8107 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0037036 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006746 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0553980 infores:hetionet CHEBI:47780 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0016382 infores:hetionet CHEBI:3515 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0221170 infores:hetionet CHEBI:9168 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0549463 infores:hetionet NCBIGene:8878 biolink:causes MONDO:0014940 infores:monarchinitiative not_provided not_provided HGNC:11280 MONDO:0014940 uuid:98185996-7770-4264-ba37-a0ce53629b35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135930 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0002871 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0020517 infores:hetionet CHEBI:44915 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0037036 infores:hetionet NCBIGene:26263 biolink:causes MONDO:0976286 infores:monarchinitiative not_provided not_provided HGNC:13593 MONDO:0976286 uuid:8f5c489c-5dc1-4ded-84db-4f9fad145cc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1384606 infores:hetionet CHEBI:44185 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0022107 infores:hetionet CHEBI:63638 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1142135 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0042514 infores:hetionet CHEBI:70735 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0037763 infores:hetionet CAID:CA10578904 biolink:causes MONDO:0017623 infores:clingen CAID:CA10578904 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PM6_Strong, PM2_Supporting PM5, PS3, PS1 PTEN c.64G>C (p.Asp22His) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_Strong: De novo (parentage not confirmed) in two patients with the disease and no family history (Internal laboratory contributor(s) SCV000577329.3). PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score = 0.965 (>0.7). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578904/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6715 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0032584 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0149931 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0234987 infores:hetionet CHEBI:31932 biolink:causes HP:0012594 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0730345 infores:hetionet CHEBI:7465 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0232462 infores:hetionet CHEBI:4681 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0036974 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0025061 infores:hetionet NCBIGene:25939 biolink:causes MONDO:0013059 infores:monarchinitiative not_provided not_provided HGNC:15925 MONDO:0013059 uuid:9834fe84-980f-48d1-abc0-a43c9823031c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51137 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0235996 infores:hetionet CAID:CA8815026 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815026 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM5_Supporting The NM_000152.5:c.842G>A variant in GAA is a missense variant predicted to cause substitution of Arg by Gln at amino acid 281 (p.Arg281Gln). To our knowledge, this variant has not been reported in the literature in a patient with Pompe disease and the results of functional studies are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00028 (2/7098 alleles) in the Other population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.747 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. Another missense variant (c.841C>T, p.Arg281Trp) (PMID: 23430949, ClinVar Variation ID 283894) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 864108). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_supporting, PP3, PM5_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815026/MONDO:0009290/010 2024-08-06 2024-09-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:6904 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0549249 infores:hetionet CHEBI:8502 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0018681 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0853692 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0233494 infores:hetionet CAID:CA367397114 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397114 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PVS1, PM2_Supporting The c.1302C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 434 (p.(Cys434Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 28726111, PMID 19564454, internal lab contributor). One of these individuals had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID 28726111). Additionally, this variant segregated with diabetes with 5 informative meioses in 2 families with MODY (PP1_Strong; PMID:28726111, internal lab contributor). In summary, the c.1302C>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP1_Strong, PP4_moderate, PS4_moderate, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397114/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:63598 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0036830 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0029456 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0086525 infores:hetionet CHEBI:17347 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0004604 infores:hetionet GO:0010080 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0010080 GO:0007275 CHEBI:4710 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0232462 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013395 infores:hetionet CHEBI:116278 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0004134 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0011991 infores:hetionet CHEBI:47426 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1739363 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027051 infores:hetionet NCBIGene:191 biolink:causes MONDO:0013404 infores:monarchinitiative not_provided not_provided HGNC:343 MONDO:0013404 uuid:aa140190-3871-444e-b431-3a84cb1ac7c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029928 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0687133 infores:hetionet CHEBI:135736 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0026766 infores:hetionet CHEBI:49960 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151692 infores:hetionet CHEBI:2904 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0017178 infores:hetionet CHEBI:3510 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0232459 infores:hetionet CHEBI:31711 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0039070 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020456 infores:hetionet CHEBI:8764 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0025874 infores:hetionet CHEBI:17688 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0037763 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0015732 infores:hetionet CHEBI:681569 biolink:causes UMLS:C1142300 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1142300 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0034882 infores:hetionet CHEBI:7478 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0851578 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0813230 infores:hetionet CAID:CA9871743 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871743 MONDO:0007064 PMID: Likely Benign BP7, BS1 BS2 The c.192G>A (p.Lys64=) variant (NM_000022.4) in ADA is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002796 (67/19946 alleles) in the East Asian population, which is higher than the ClinGen SCID VCEP threshold (>0.00161) for BS1 and therefore meets this criterion (BS1).In summary, this variant is classified as Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BP7 and BS1. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871743/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3510 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0033774 infores:hetionet CHEBI:48947 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0011603 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014742 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0038362 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0038661 infores:hetionet CHEBI:4702 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0085633 infores:hetionet GO:1900206 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900206 GO:0007275 CHEBI:8597 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0233407 infores:hetionet CHEBI:85083 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0027497 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004991 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007120 infores:hetionet GO:0070239 biolink:causes GO:0043029 infores:ubergraph knowledge_assertion manual_agent GO:0070239 GO:0043029 CHEBI:63637 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0855333 infores:hetionet CHEBI:42797 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0577559 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0010709 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0233494 infores:hetionet CHEBI:10102 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0035305 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C1368065 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020676 infores:hetionet CHEBI:5118 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002874 infores:hetionet CHEBI:42797 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020578 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0011991 infores:hetionet CHEBI:5280 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0497156 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0518015 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0034068 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0549373 infores:hetionet CHEBI:8863 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020625 infores:hetionet CHEBI:35854 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0002170 infores:hetionet CHEBI:15544 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0041969 infores:hetionet CHEBI:4903 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0037763 infores:hetionet CHEBI:4514 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0002622 infores:hetionet NCBIGene:22820 biolink:causes MONDO:0975834 infores:monarchinitiative not_provided not_provided HGNC:2236 MONDO:0975834 uuid:ef46ba33-72b1-4f65-928b-658440dfd46c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0038454 infores:hetionet CHEBI:7447 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0015967 infores:hetionet CHEBI:4995 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002792 infores:hetionet CHEBI:38562 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0002994 infores:hetionet CHEBI:6887 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011606 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0948089 infores:hetionet CHEBI:5001 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0002962 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020649 infores:hetionet CHEBI:9586 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0025874 infores:hetionet CHEBI:6690 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0013604 infores:hetionet CHEBI:63621 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015967 infores:hetionet CHEBI:41879 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042909 infores:hetionet CHEBI:6456 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0242429 infores:hetionet CHEBI:5893 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151636 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235416 infores:hetionet CHEBI:46195 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0221201 infores:hetionet CHEBI:27786 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C1096343 infores:hetionet CHEBI:474053 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0311468 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0009450 infores:hetionet GO:0002786 biolink:causes GO:0019731 infores:ubergraph knowledge_assertion manual_agent GO:0002786 GO:0019731 CHEBI:5002 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0340464 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0004570 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0042961 infores:hetionet CHEBI:37924 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030794 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0023533 infores:hetionet CAID:CA16043014 biolink:causes MONDO:0009290 infores:clingen CAID:CA16043014 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.1961C>A (p.Ser654Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individual with Pompe disease. However, there is a ClinVar entry for this variant (Variation ID 372968). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043014/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:94385 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0085932 infores:hetionet CHEBI:291342 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0027441 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0003864 infores:hetionet CHEBI:31348 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151723 infores:hetionet CHEBI:17823 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0014742 infores:hetionet CHEBI:4672 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0232292 infores:hetionet CHEBI:145499 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085593 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0001824 infores:hetionet CHEBI:64028 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0022107 infores:hetionet CHEBI:2663 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0027540 infores:hetionet CHEBI:8768 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011206 infores:hetionet CHEBI:5100 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0015967 infores:hetionet CHEBI:2636 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0035078 infores:hetionet CHEBI:261649 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0015230 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0853761 infores:hetionet CHEBI:6339 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0002994 infores:hetionet NCBIGene:51256 biolink:causes MONDO:0009544 infores:monarchinitiative not_provided not_provided HGNC:21066 MONDO:0009544 uuid:4cc4395f-8f43-417f-9578-016fb10c122a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0232492 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0020517 infores:hetionet CHEBI:27666 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0033246 infores:hetionet CHEBI:7915 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011606 infores:hetionet CHEBI:291342 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0267792 infores:hetionet CHEBI:63618 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C1368065 infores:hetionet CHEBI:3723 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030318 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0860871 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0029134 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0015376 infores:hetionet CHEBI:167309 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0000729 infores:hetionet CHEBI:29007 biolink:causes MONDO:0020108 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0002880 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0023067 infores:hetionet CHEBI:39112 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0030312 infores:hetionet CHEBI:8871 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0010200 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040479 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0043251 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0236141 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0236141 infores:hetionet CHEBI:51041 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0162830 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020517 infores:hetionet CHEBI:7565 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0687713 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0175167 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0018799 infores:hetionet CHEBI:40303 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0022354 infores:hetionet CHEBI:6121 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0027497 infores:hetionet CHEBI:8707 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0423791 infores:hetionet CHEBI:9288 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0030312 infores:hetionet CHEBI:44915 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1320474 infores:hetionet CAID:CA10014475 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014475 MONDO:0011071 PMID: Benign BA1, BP4, BP2, BP7 PS3, PS1, PS4, PM2, PM6, PVS1, BS3, BS1, BS4, PM1, PM4, PM5, PP3, PP1 The NM_001754.4:c.613+8C>T variant has a MAF of 0.00151 (0.151%, 101/66,722 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (15) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.2534 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014475/MONDO:0011071/008 2019-08-06 2019-08-06 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0581912 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0000833 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0038454 infores:hetionet NCBIGene:2801 biolink:causes MONDO:0859375 infores:monarchinitiative not_provided not_provided HGNC:4425 MONDO:0859375 uuid:6d46d1f1-0983-4948-a001-1174964d4c00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0001824 infores:hetionet CHEBI:5384 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0011603 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0242350 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0017160 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0028259 infores:hetionet GO:0036479 biolink:causes GO:0098869 infores:ubergraph knowledge_assertion manual_agent GO:0036479 GO:0098869 CHEBI:94848 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0020649 infores:hetionet CHEBI:6904 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0233794 infores:hetionet CHEBI:7809 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0151596 infores:hetionet CHEBI:4907 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0030554 infores:hetionet CHEBI:102216 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0006266 infores:hetionet NCBIGene:147409 biolink:causes MONDO:0011932 infores:monarchinitiative not_provided not_provided HGNC:21307 MONDO:0011932 uuid:ee00b9fd-f58c-4095-bd00-e01e4a4c108c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0236075 infores:hetionet CHEBI:40237 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C1510410 infores:hetionet CHEBI:3223 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0017178 infores:hetionet CHEBI:85161 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0080274 infores:hetionet CAID:CA226669 biolink:causes MONDO:0010725 infores:clingen CAID:CA226669 MONDO:0010725 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PP3_Strong BS1, PM2 NM_000330.4(RS1):c.305G>A (p.Arg102Gln) is a missense variant encoding the substitution of arginine with glutamine at amino acid 102. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00001261 among hemizygous individuals, with 5 variant alleles / 396,397 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.000002 and BS1 threshold of >0.00002 and fails to meet these criteria. This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 10589241, PMID: 12928282, PMID: 15937075, PMID: 17615541, PMID: 37317958, PS4). The variant has been reported to segregate with retinal dystrophy through >3 meioses in two families (PP1_Strong; PMID: 12928282, PMID: 15937075). HeLa cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 37317958, PS3_Supporting). The computational predictor REVEL gives a score of 0.983, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PS4, PP1_Strong, PP3_Strong, and PS3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226669/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance HP:0001417 Supports CHEBI:194135 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235086 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0006266 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042035 infores:hetionet CHEBI:3510 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0009806 infores:hetionet CHEBI:5778 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0542571 infores:hetionet CHEBI:50131 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0030196 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0439857 infores:hetionet NCBIGene:50651 biolink:causes MONDO:0044322 infores:monarchinitiative not_provided not_provided HGNC:17939 MONDO:0044322 uuid:3f669ccc-8db8-4fec-85e3-e62c954968b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72690 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0040822 infores:hetionet CAID:CA915950042 biolink:causes MONDO:0700268 infores:clingen CAID:CA915950042 MONDO:0700268 PMID: Uncertain Significance PP3, PM2_Supporting PVS1 The c.4484+5G>A variant is an intronic variant occurring in intron 13(14) of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.25, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant is reported to result in aberrant mRNA splicing. RT-PCR of a FFPE sample and capillary electrophoresis analysis of the product demonstrated that the variant impacts splicing by exon skipping (PMID: 32124385). Sample type is potentially not suitable for our analysis standard and difficulty in interpretation of mRNA levels in sample led to final code strength determined by the rubric: PVS1_N/A (RNA). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA915950042/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7915 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0021053 infores:hetionet CHEBI:114785 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0014518 infores:hetionet CHEBI:47781 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0000729 infores:hetionet NCBIGene:64788 biolink:causes MONDO:0009527 infores:monarchinitiative not_provided not_provided HGNC:14154 MONDO:0009527 uuid:75c0a69e-0d82-456c-987a-097471d1fbd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA397724566 biolink:causes MONDO:0008723 infores:clingen CAID:CA397724566 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate PM3 The c.1194C>A (p.Tyr398Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been described in an individual with increased C14:1 acylcarnitine and fibroblasts derived from this individual showed a significantly reduced VLCAD enzyme activity, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMID: 10529389). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724566/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7445 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0003962 infores:hetionet CHEBI:7478 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0032231 infores:hetionet CHEBI:92998 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0011991 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0522224 infores:hetionet CHEBI:7443 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0206062 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030305 infores:hetionet CAID:CA658656806 biolink:causes MONDO:0011071 infores:clingen CAID:CA658656806 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS3, BS1, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.4:c.215_216dup (p.Ser73Glyfs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000638134.1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658656806/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3756 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1167965 infores:hetionet CAID:CA000628 biolink:causes MONDO:0017623 infores:clingen CAID:CA000628 MONDO:0017623 PMID: Benign BA1 PTEN c.-903G>A (NC_000010.10:g.89623323G>A) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.011 (1.1%, 343/30,808 alleles) in the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000628/MONDO:0017623/003 2016-09-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0009806 infores:hetionet CAID:CA220637 biolink:causes MONDO:0017623 infores:clingen CAID:CA220637 MONDO:0017623 PMID: Pathogenic PM2, PP1_Moderate, PM6_Strong, PS4_Supporting, PS3 PTEN c.209+4_209+7delAGTA (IVS3+4_IVS3+7delAGTA) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (Internal laboratory contributor(s))PM2: Absent in large sequenced populations (PMID 27535533).PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (Internal laboratory contributor(s))PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221, internal laboratory contributor(s) SCV000273868.4) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA220637/MONDO:0017623/003 2017-12-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:584020 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0917801 infores:hetionet NCBIGene:80326 biolink:causes MONDO:0007881 infores:monarchinitiative not_provided not_provided HGNC:13829 MONDO:0007881 uuid:98a9a40e-88f8-425f-8be2-ebe9d15b071d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0039231 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0403632 infores:hetionet CHEBI:49713 biolink:causes MONDO:0009718 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0027145 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0151883 infores:hetionet CHEBI:7565 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C2363730 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019360 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0022568 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0005940 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009782 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0015734 infores:hetionet NCBIGene:5879 biolink:causes MONDO:0030913 infores:monarchinitiative not_provided not_provided HGNC:9801 MONDO:0030913 uuid:d2500934-9df0-4896-9c96-8957f9d86ca5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0026205 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0017181 infores:hetionet CHEBI:28925 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0518015 infores:hetionet CHEBI:10124 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085593 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235338 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235338 infores:hetionet CHEBI:4636 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0233494 infores:hetionet CHEBI:51230 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0547030 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0151849 infores:hetionet CHEBI:49668 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151878 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0020649 infores:hetionet CHEBI:291342 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0259749 infores:hetionet CAID:CA345151235 biolink:causes MONDO:0100084 infores:clingen CAID:CA345151235 MONDO:0100084 PMID: Pathogenic PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_Moderate, PS3, PS2 BP4, BA1, BS1, BS3 The NM_001100.4:c.124C>T variant in ACTA1 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 42 (legacy nomenclature: p.His40Tyr). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.72, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In vitro studies demonstrated changes in actin localization and motility (PMID:15226407, 17227580, 27112274). In vivo studies in a mouse model demonstrated impaired function of ACTA1 and limited intrinsic force-generating capacity and maximal tetanic force (PMID:23613869, 23656990)(PS3). This variant has been reported in 4 probands/families with intranuclear rod and/or nemaline myopathies (PS4_Moderate; PMID:10508519, 12921789, 19562689). This variant has occured de novo with confirmed parental relationships in 1 individual and was reported to occur de novo with unconfirmed parental relationships in 1 individual with severe atypical nemaline myopathy with intranuclear nemaline bodies (PS2, PP4_Moderate; PMID:10508519, 19562689). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS3, PS4_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024. Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345151235/MONDO:0100084/147 2024-08-27 2024-12-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5790 biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0016167 infores:hetionet CHEBI:7936 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1458155 infores:hetionet CHEBI:7454 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0085631 infores:hetionet CHEBI:7465 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0042963 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0233494 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549273 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549273 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0034063 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0162429 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151763 infores:hetionet CHEBI:79699 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042029 infores:hetionet CHEBI:27777 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0750876 infores:hetionet CHEBI:31705 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0018790 infores:hetionet CHEBI:7577 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0947912 infores:hetionet CHEBI:3127 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0152169 infores:hetionet CAID:CA1139658985 biolink:causes MONDO:0021056 infores:clingen CAID:CA1139658985 MONDO:0021056 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting The NM_000038.6(APC):c.203del (p.Leu68TyrfsTer2) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 3 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, internal data Invitae, MGZ Medical Genetics Center). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139658985/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3219 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0028081 infores:hetionet CHEBI:10101 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2364111 infores:hetionet CAID:CA915940214 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940214 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting PP1 The c.1230del (p.Tyr411ThrfsTer20) variant in exon 13 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 13 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 9 in PMID: 19172520) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to < 10% of wild type levels, as measured by flow cytometry (according to GT database). However, ITGA2B and ITGB3 were not [reported to be] sequenced across all exons and intron/exon boundaries (PP4_moderate). This variant has been detected in at least 2 probands with Glanzmann thrombasthenia. One of these probands was homozygous for the variant (0.5 points, PMID: 19172520 ). For the other proband carrying the variant, only one mutated allele was detected in the patient's parents (the father's genotype was wild type and the mother carried the c.1230del frameshift mutation) (0 points, PMID: 31404847). Total points: 0.5 (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has also not been registered in ClinVar. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting and PM3_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940214/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7494 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0030554 infores:hetionet CAID:CA10360699 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360699 MONDO:0010725 PMID: Benign BP7, BP4, BA1 The NM_000330.4(RS1):c.326+14G>A variant is an intronic variant at intron 4, located 14 nucleotides after exon 4. This variant is present in gnomAD v4.1.0 at a frequency of 0.0002681 among hemizygous individuals, with 106 variant alleles / 395441 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.01 Acceptor Gain, which is below the ClinGen X- linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This intronic variant does not have an impact at splicing sites according to SpliceAI, which predicts a delta score of 0.01 for Acceptor Gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP7). In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1, BP4, and BP7. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360699/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:6916 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0919924 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0011609 infores:hetionet CHEBI:5441 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0235369 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0009766 infores:hetionet CHEBI:44915 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0001127 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0233472 infores:hetionet CHEBI:46295 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0019080 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0019158 infores:hetionet CHEBI:37924 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042029 infores:hetionet CHEBI:114785 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0919924 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0426576 infores:hetionet CHEBI:7915 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0026826 infores:hetionet NCBITaxon:203691 biolink:causes MONDO:0021839 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:203691 MONDO:0021839 CHEBI:3044 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0020517 infores:hetionet CAID:CA1707525 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707525 MONDO:0015152 PMID: Benign BP4, BA1, BS3, BP7_Strong PM3, PP4 The NM_003494.4: c.5767+6C>T variant in DYSF, which is also known as NM_001130987.2: c.5884+6C>T, occurs within the splice donor motif of exon 51. The Grpmax FAF of this variant is 0.004287 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 216/44886 East Asian alleles), which is greater than the ClinGen LGMD VCEP threshold for BA1 (>0.003), meeting this criterion (BA1). This variant is not predicted to affect splicing (SpliceAI score 0.01) (BP4), and in a mini-gene assay, no effect of this variant on splicing was observed (PMID: 25312915; BP7_Strong_RNA). This variant has been reported with a second DYSF variant in at least two patients with a phenotype consistent with LGMD, but it was not considered a diagnostic finding in either case (PMID: 25591676, 34559919). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/30/2025): BA1, BP4, BP7_Strong_RNA. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707525/MONDO:0015152/180 2025-09-30 2025-10-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:100241 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020452 infores:hetionet NCBIGene:285440 biolink:causes MONDO:0008865 infores:monarchinitiative not_provided not_provided HGNC:23198 MONDO:0008865 uuid:24d4716b-d8e8-48a1-aa02-3e5fa205d1d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233477 infores:hetionet CHEBI:8764 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003537 infores:hetionet GO:1902510 biolink:causes GO:0030262 infores:ubergraph knowledge_assertion manual_agent GO:1902510 GO:0030262 CHEBI:116278 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0009421 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020517 infores:hetionet CHEBI:31536 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C1384353 infores:hetionet CHEBI:3636 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0041657 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0231170 infores:hetionet CHEBI:4659 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0242350 infores:hetionet CHEBI:63616 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0036974 infores:hetionet CHEBI:15940 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0013604 infores:hetionet NCBIGene:24137 biolink:causes MONDO:0010488 infores:monarchinitiative not_provided not_provided HGNC:13339 MONDO:0010488 uuid:98b68f81-d38c-4554-b301-f99b8b9309ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0040822 infores:hetionet CHEBI:68558 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0025222 infores:hetionet CHEBI:9599 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1260880 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0027441 infores:hetionet CAID:CA401367134 biolink:causes MONDO:0009290 infores:clingen CAID:CA401367134 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PS3_Supporting The NM_000152.5:c.1538A>G variant in GAA is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 513 (p.Asp513Gly). This variant has been detected in two individuals with clinical features of Pompe disease. One patient with infantile-onset Pompe disease had documented GAA deficiency with 0%, less than 10% of normal mean control level of GAA activity in leukocytes (PMID 31510962). The other patient had documented deficient GAA enzyme activity, muscle weakness, and cardiomyopathy at 11 months old (clinical laboratory data). (PP4_Moderate). These two individuals were homozygous for the variant (PM3 1.0 point, PMID 31510962, clinical laboratory data) (PM3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS-7 cells resulted in 0.76% wild type GAA activity in cells and 0% in medium (<5%), and evidence of abnormal GAA synthesis and processing on Western blot, leading the variant to be described as Class B “potentially less severe” (Table 4), indicating that this variant may impact protein function (PMID 31510962) (PS3_Supporting). The computational predictor REVEL gives a score of 0.965 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 638014). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401367134/MONDO:0009290/010 2023-07-18 2023-07-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9599 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0232462 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002070 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0018818 infores:hetionet CHEBI:8874 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1704272 infores:hetionet NCBIGene:10991 biolink:causes MONDO:0030881 infores:monarchinitiative not_provided not_provided HGNC:18044 MONDO:0030881 uuid:5fbf8096-9605-41c6-b085-335c9a84e3dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes UMLS:C0948179 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0948179 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0006145 infores:hetionet CHEBI:8502 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0027813 infores:hetionet CAID:CA645373290 biolink:causes MONDO:0100039 infores:clingen CAID:CA645373290 MONDO:0100039 PMID: Uncertain Significance PM2_Supporting, PM4_Supporting The p.Lys432_Tyr433delinsAsn variant in CDKL5 is absent from gnomAD v4.1 (PM2_supporting). The p.Lys432_Tyr433delinsAsn variant causes a change in the length of 1 amino acid in the protein due to an in-frame deletion or insertion in a non-repeat region of CDKL5 (PM4_supporting). In summary, p.Lys432_Tyr433delinsAsn variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PM4_supporting). (CDKL5 Specifications v.5; curation approved on 8/27/25) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA645373290/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:7476 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014518 infores:hetionet CHEBI:49662 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151699 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0080194 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235818 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151479 infores:hetionet CHEBI:15367 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0007859 infores:hetionet CHEBI:7823 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0041657 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0042075 infores:hetionet CHEBI:3175 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0006277 infores:hetionet CHEBI:9599 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0151827 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0007971 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0031350 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0040046 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0521706 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0521706 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1141948 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1141948 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0025202 infores:hetionet CHEBI:9448 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0020580 infores:hetionet CHEBI:4995 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018681 infores:hetionet CHEBI:31705 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0043352 infores:hetionet CHEBI:50841 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0043352 infores:hetionet CHEBI:6715 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0004093 infores:hetionet CAID:CA274152 biolink:causes MONDO:0009861 infores:clingen CAID:CA274152 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong The c.1157A>G (p.Tyr386Cys) variant in PAH has been reported in multiple probands with PKU (BH4 deficiency excluded) (PMID: 16198137; PP4_Moderate). This variant has been detected with c.1315+1G>A, R252W, L311P, R261Q, I65V, Q178G, R158Q (all reported as Pathogenic in ClinVar, 4.0 points total) (PMIDs:24368688, 24941924, 22841515, 16198137, 26210745, 23357515, 18493213; PM3_very-strong). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA274152/MONDO:0009861/006 2021-05-15 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:85083 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0015397 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018802 infores:hetionet CAID:CA343726300 biolink:causes MONDO:0005338 infores:clingen CAID:CA343726300 MONDO:0005338 PMID:21612213PMID:23129764PMID:25524706 Likely Pathogenic PP1_Moderate, PM2_Supporting, PS3_Moderate, PP3_Moderate BP7, BS1, BS3, PM4, PM5, PS4, PS1, PS2, BP4, BA1 The c.736G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 246 (p.Gly246Arg). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008475 (1 allele out of 1,179,938), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.9, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Gly246Arg protein had increased insolubility and instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. This protein has also been assessed in these other studies (PMIDs: 16297911, 27092720), however, the same level of evidence was not met. 6 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 9328473), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 7 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PS3_Moderate, PP1_Moderate, PP3_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726300/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3127 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0234215 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0014549 infores:hetionet CHEBI:50729 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0015230 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0242350 infores:hetionet CHEBI:119573 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0021368 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0020649 infores:hetionet CHEBI:7494 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0035410 infores:hetionet CHEBI:231594 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0231528 infores:hetionet CHEBI:17026 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0234518 infores:hetionet CHEBI:145499 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0036974 infores:hetionet CHEBI:100147 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0027497 infores:hetionet CHEBI:135736 biolink:causes MONDO:0021340 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0021807 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0919939 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0919939 infores:hetionet NCBIGene:7454 biolink:causes MONDO:0010743 infores:monarchinitiative not_provided not_provided HGNC:12731 MONDO:0010743 uuid:a5ec9aba-c05b-46c4-92e2-e40fd199e5a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014394 infores:hetionet CHEBI:68642 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0020443 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013595 infores:hetionet CHEBI:8871 biolink:causes MONDO:0019623 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0019243 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0034150 infores:hetionet CHEBI:8378 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0039231 infores:hetionet CHEBI:7809 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0002792 infores:hetionet NCBITaxon:36830 biolink:causes MONDO:0015803 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36830 MONDO:0015803 CHEBI:31981 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0242350 infores:hetionet CHEBI:135925 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0002792 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011991 infores:hetionet CHEBI:64321 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0019521 infores:hetionet CHEBI:45783 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020461 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001551 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0156339 infores:hetionet CHEBI:553473 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0151754 infores:hetionet CHEBI:7447 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0235378 infores:hetionet CHEBI:31644 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0019079 infores:hetionet CHEBI:44915 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0023518 infores:hetionet CHEBI:71219 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0039070 infores:hetionet NCBIGene:1293 biolink:causes MONDO:0014627 infores:monarchinitiative not_provided not_provided HGNC:2213 MONDO:0014627 uuid:6e20f7f5-4d6d-49ab-83a2-7e04a0b3df0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0043387 infores:hetionet CHEBI:74947 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0024236 infores:hetionet NCBIGene:23395 biolink:causes MONDO:0014869 infores:monarchinitiative not_provided not_provided HGNC:17095 MONDO:0014869 uuid:5851ed6c-50e4-433e-a1d8-254fa4dd9a03 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3239 biolink:causes MONDO:0012544 infores:monarchinitiative not_provided not_provided HGNC:5136 MONDO:0012544 uuid:5bba8efb-956a-4c47-a008-1d7dc92c8acd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0035157 biolink:causes GO:0007424 infores:ubergraph knowledge_assertion manual_agent GO:0035157 GO:0007424 CHEBI:367163 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151691 infores:hetionet CHEBI:10650 biolink:causes HP:5200231 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235013 infores:hetionet CAID:CA229554 biolink:causes MONDO:0009861 infores:clingen CAID:CA229554 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting PM5 The c.452A>G (p.Asp151Gly) variant in PAH is reported in a Spanish patient with phenylketonuria (PMID: 8981952); the second allele/genotype was not reported. It is absent from gnomAD. Multiple lines of computational evidence support a deleterious effect (REVEL=0.98). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229554/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32888 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0036572 infores:hetionet GO:0044479 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:0044479 GO:0006955 CHEBI:10023 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014742 infores:hetionet CHEBI:49662 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0040264 infores:hetionet CHEBI:9654 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0699828 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0851341 infores:hetionet CHEBI:31524 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0018802 infores:hetionet CAID:CA399805484 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805484 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM3, PM2_Supporting PP3, BP4 The NM_000419.5(ITGA2B):c.659A>G (p.Tyr220Cys) has been identified in at least 2 probands, including GT35 of PMID: 29675921 meeting the criteria for PP4_strong criteria. Patient GT35 of PMID: 29675921 is compound heterozygous for Tyr220Cys and c.625-1G>A (classified Pathogenic by the PD-EP) and Patient 436 of the GT database is compound heterozygous for Tyr220Cys and Ala271Gly (classified VUS by the PD-EP), Pt 3 of PMID: 36672149 is homozygous (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003266 (1/30614alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3, PP4_strong. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805484/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA023649 biolink:causes MONDO:0007750 infores:clingen CAID:CA023649 MONDO:0007750 PMID: Benign BP4, BA1 BP2, PS4, PS3, PS1, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PVS1, PM2, PM6, BS2, PP4, PP1, PP3 The NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BA1 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met.BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) variant not on limitsB) does not create AGC) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9--- BP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023649/MONDO:0007750/013 2022-05-24 2022-12-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8107 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0009763 infores:hetionet CHEBI:82960 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151539 infores:hetionet CHEBI:8888 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018800 infores:hetionet CHEBI:3127 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0027497 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0042401 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0016382 infores:hetionet CHEBI:8764 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0702166 infores:hetionet CHEBI:4027 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0013404 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011615 infores:hetionet UMLS:C1872203 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0030196 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0023470 infores:hetionet CAID:CA512341173 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341173 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS4, PS1, PS3, PS2, BA1, BP1, BP2, BP3, PM2, PVS1, PM6, BS1, BS3, BS4, BP5, PM3, PM1, PM4, PM5, BS2, PP2, PP3, PP4, PP1 The c.1260C>G (p.Gly420=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -1.00262 in GRCh38) (BP7). The variant also has not been reported in relevant cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341173/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6759 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0162297 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0015469 infores:hetionet CAID:CA10014722 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014722 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.58+9A>C is an intronic variant not predicted to affect splicing (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.428)) (BP7). In summary, the clinical significance of this variant is Likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014722/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:5V9KLZ54CY biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0002871 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0235074 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235074 infores:hetionet UNII:D27V6190PM biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0026961 infores:hetionet CHEBI:7936 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085605 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023067 infores:hetionet CHEBI:63611 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0000731 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0392386 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018799 infores:hetionet CHEBI:8707 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027066 infores:hetionet CHEBI:2549 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0231528 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0032285 infores:hetionet CHEBI:9635 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C2979982 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034150 infores:hetionet GO:0035171 biolink:causes CL:0000396 infores:ubergraph knowledge_assertion manual_agent GO:0035171 CL:0000396 CHEBI:27690 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0027092 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040259 infores:hetionet CAID:CA182519 biolink:causes MONDO:0019497 infores:clingen CAID:CA182519 MONDO:0019497 PMID: Likely Benign BS1, BP7, BP4 BS4, BP5, BS2, PP4, PP1, PP3, PM5, PM4, PM1, PM3, PM6, PM2, PVS1, BP3, BP2, BA1, PS1, PS3, PS2, PS4 The filtering allele frequency of the c.3492C>T (p.Thr1164=) variant in the TECTA gene is 0.423% for African chromosomes by gnomAD (123/23960) with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The silent p.Thr1164= variant in TECTA is not predicted by MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, BP7, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA182519/MONDO:0019497/005 2019-02-13 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:49375 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0855333 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013146 infores:hetionet CHEBI:4445 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0162297 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0221384 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0221384 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0037274 infores:hetionet CHEBI:37924 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030252 infores:hetionet CHEBI:4792 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0085605 infores:hetionet CHEBI:53691 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C1443060 infores:hetionet CHEBI:84500 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0030193 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233494 infores:hetionet CAID:CA6402670 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402670 MONDO:0019565 PMID: Uncertain Significance PP4, PM2_Supporting, BP4 PP3, PS4 NM_000552.5(VWF):c.3788C>T is a missense variant in VWF predicted to encode substitution of serine by leucine at amino acid 1263. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000008780 (based on 2/91076 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.143, which is below the ClinGen VWD VCEP PP3 threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicates that the variant has no impact on splicing. At least 2 patients with this variant have been reported, only 1 of whom displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio, which together are specific for VWD type 2M (PP4, PMID: 28971901). Both reported patients exhibited low FVIII activity relative to VWF antigen, leading one to be diagnosed with VWD Type 1-2N (PMID: 22315491). This variant is classified as a variant of unknown significance for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4, PM2_Supporting, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402670/MONDO:0019565/090 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2618 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0011253 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0021053 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0018799 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0281981 infores:hetionet CHEBI:48273 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0041657 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0021099 infores:hetionet CHEBI:8874 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0600142 infores:hetionet CHEBI:261649 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0546817 infores:hetionet CAID:CA8815482 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815482 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM1, PS3_Moderate, PM2_Supporting, PM3_Strong PM5 The NM_000152.5:c.1799G>A variant in GAA is a missense variant predicted to result in substitution of arginine by histidine at amino acid 600 (p.Arg600His).This variant has been reported in at least 7 patients including those with symptoms consistent with infantile onset Pompe disease, <10% GAA activity in muscle, and showing improvement on enzyme replacement therapy (PMID: 15121988, 24715333); one patient identified on newborn screen with confirmatory GAA activity testing and showing cardiac hypertrophy and arrythmia on cardiac evaluation (PMID: 33073007), three patients with features consistent with Pompe disease and GAA activity in the laboratory's affected range in dried blood spots or leukocytes (PMID: 2267665, 33741225) (PP4_Moderate). Four patients are compound heterozygous for the variant and another variant in GAA, phase unknown, that has been classified a pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (2 independent probands, PMIDs: 21967859, 2267665), c.2481+110_2646+39del) (2 independent probands, PMID: 15121988, 24715333; PMID: 2267665), and one homozygote (PMID: 33073007) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and another missense change, or c.1465G>A (p.Asp489Asn) (PMID: 22711147) or c.1751A>C (p.His584Pro) (PMID: 33741225). The allelic data from these patients will be used in the assessment of the other missense change and is not included here to avoid circular logic. The amino acid change was reported in additional patients but the cDNA changes were not provided and so the data is not included (PMID: 10338092, 20033296).The highest population minor allele frequency in gnomAD is 0.00003 (1.30606 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).This variant alters the arginine at amino acid 600, a residue that crystallography studies have shown to be important important in the active site architecture and substrate binding of GAA, and therefore has been defined as a critical residue by the ClinGen LSD VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1).This variant results in <2% GAA activity when expressed in COS-7 and HEK 293 cells (PMID: 19862843, 24715333), and was shown to be abnormally processed by Western blot analysis, with production of very little of the active 76 kDa form, when expressed in HEK293 cells (PMID: 24715333). PS3_Moderate is applied based on two separate studies, one showing GAA deficiency and the other showing abnormal GAA processing (PS3_Moderate).The computational predictor REVEL gives a score of 0.967 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).Three additional missense changes in the same codon have been reported in patients with Pompe disease. The classification of p.Arg600His will be used to to support the classification of the other variants c.1798C>T (p.Arg600Cys) (pathogenic based on classification by the ClinGen LSD VCEP), c.1799G>C (p.Arg600Pro) and c.1799G>T (p.Arg600Leu), and is not used here to avoid circular logic.There is a ClinVar entry for this variant (Variation ID: 370130) with 10 submitters classifying the variant as pathogenic and two as likely pathogenic.In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP crteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PM1, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on Oct 18, 2022). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815482/MONDO:0009290/010 2022-10-18 2022-10-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4466 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0855775 infores:hetionet GO:0051797 biolink:causes GO:0098773 infores:ubergraph knowledge_assertion manual_agent GO:0051797 GO:0098773 CHEBI:50173 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0037287 infores:hetionet CHEBI:55346 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151662 infores:hetionet CHEBI:27470 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0002792 infores:hetionet CHEBI:144551 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0014724 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0032787 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0032787 infores:hetionet CHEBI:63580 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004144 infores:hetionet CHEBI:127780 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151786 infores:hetionet CHEBI:68478 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2979982 infores:hetionet CHEBI:3757 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C2830004 infores:hetionet CHEBI:28830 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0040822 infores:hetionet CHEBI:9943 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014743 infores:hetionet CHEBI:125354 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0038002 infores:hetionet CHEBI:84050 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0231528 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0549373 infores:hetionet CHEBI:5864 biolink:causes MONDO:1040026 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0220650 infores:hetionet CHEBI:16480 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0042373 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0015663 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0149931 infores:hetionet CHEBI:5864 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085612 infores:hetionet CHEBI:76010 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0016204 infores:hetionet CHEBI:291342 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0000737 infores:hetionet CHEBI:5001 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0019270 infores:hetionet CAID:CA2697547497 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547497 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.59-16C>T is a intronic variant. PM2_supportingThis variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.422 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). No splicing impact or creation of cryptic splice sites predicted by SSF and MES. Splice AI predicts no impact to splicing (score: 0.03) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547497/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3387 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0234133 infores:hetionet CHEBI:5775 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0013604 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0035258 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0018801 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0087169 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0178298 infores:hetionet CHEBI:64312 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0149745 infores:hetionet CAID:CA238810 biolink:causes MONDO:0100040 infores:clingen CAID:CA238810 MONDO:0100040 PMID: Benign BS1, BP5_Strong, BS2, BP4 The allele frequency of the p.Gln73Pro variant in FOXG1 is 0.027% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gln73Pro variant is observed in at least 50 unaffected individuals (internal database - GeneDx) (BS2). The p.Gln73Pro variant is found in at least 8 individuals with an alternate molecular basis of disease (internal database - Invitae, internal database - GeneDx) (BP5_Strong). Computational analysis prediction tools suggest that the p.Gln73Pro variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gln73Pro variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_Strong, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA238810/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2038 biolink:causes UMLS:C0152965 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0152965 infores:hetionet CHEBI:78543 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0016382 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0596170 infores:hetionet CHEBI:68647 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0015967 infores:hetionet CHEBI:2038 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0018808 infores:hetionet CHEBI:4315 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0086565 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0030552 infores:hetionet CHEBI:7445 biolink:causes MONDO:0001259 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0342405 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004833 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0149756 infores:hetionet CHEBI:68478 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0013604 infores:hetionet CHEBI:8869 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0035455 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020295 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151544 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0013395 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0002871 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0333291 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0333291 infores:hetionet CHEBI:6541 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0231749 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013595 infores:hetionet CHEBI:3223 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0030193 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027441 infores:hetionet CHEBI:63580 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035410 infores:hetionet CHEBI:85161 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C2939147 infores:hetionet CHEBI:4466 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0018681 infores:hetionet CHEBI:32315 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0026821 infores:hetionet CAID:CA312275 biolink:causes MONDO:0008723 infores:clingen CAID:CA312275 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP3, PM1, PM3_Strong, PP4_Moderate PM5 The c.1376G>A variant is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 459 (p.Arg459Gln). This variant has been reported in at least 11 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, with two individuals displaying both reduced VLCAD activity and increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 30194637; PMID: 21429517; PMID: 19327992). In these individuals, the variant was detected three times in the homozygous state plus 1 confirmed in-trans and 5 not confirmed in-trans with the pathogenic variant c.848T>C (PM3_strong; PMID: 30194637; PMID: 21429517). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004646 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant is located in a well-studied dimerization domain which is critical for the protein's dimer interaction (PM1; PMID: 14517516). The computational predictor REVEL gives a score of 0.864, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate; PM3_Strong; PM2_Supporting; PM1; PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312275/MONDO:0008723/021 2022-08-09 2022-08-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:92607 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0030554 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0232492 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0235272 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0235272 infores:hetionet CAID:CA315390550 biolink:causes MONDO:0015967 infores:clingen CAID:CA315390550 MONDO:0015967 PMID: Benign BA1 The c.-121C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the 5' UTR of NM_175914.5. This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.0001435, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). In summary, c.-121C>T meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): BA1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA315390550/MONDO:0015967/085 2025-07-25 2025-07-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36795 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2129214 infores:hetionet CAID:CA255342 biolink:causes MONDO:0010604 infores:clingen CAID:CA255342 MONDO:0010604 PMID:7797466PMID:24759143 Pathogenic PS4, PM1_Strong, PP3, PP4_Moderate PM5, PP1, PS3_Supporting, PM2 The NM_000133.3(F9):c.572G>A predicts a missense change, Arg191His, at the activation residue. This residue is a site for cleavage by FXIa in order to activate FIX and therefore critical for protein function, which meets criteria for PM1_Strong. Over 100 patients meet the F9 phenotype criteria have been reported in the literature (selected PMIDs: 7873393,1972560, 26782891, 27865967, 24375831), meeting PS4_Very strong and PP4_Moderate. The variant has a REVEL score of 0.73 (threshold >0.6), meeting PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PM1_Strong, PP4_Moderate, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255342/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:70718 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0033774 infores:hetionet CHEBI:3082 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0014591 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0178298 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1956346 infores:hetionet NCBIGene:261734 biolink:causes MONDO:0011752 infores:monarchinitiative not_provided not_provided HGNC:19104 MONDO:0011752 uuid:d2eb341b-5866-4537-bc52-a8e9f9398a47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0015967 infores:hetionet CHEBI:9086 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013384 infores:hetionet CHEBI:44185 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085624 infores:hetionet CHEBI:3176 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0015230 infores:hetionet CAID:CA8623144 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623144 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1089C>T (p.Ser363=), no individuals with Glanzmann thrombasthenia were reported with the variant. The variant has a low minor allele frequency of 0.00008673 (3/34592 alleles) in the Latino population in gnomAD, which is less than <0.0001 and thus meets PM2_supporting. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -0.294 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supprorting, BP4, and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623144/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6078 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0015230 infores:hetionet CHEBI:66964 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0687713 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0004936 infores:hetionet CAID:CA226052 biolink:causes MONDO:0100453 infores:clingen CAID:CA226052 MONDO:0100453 PMID: Uncertain Significance PM2_Supporting PM3, PP3 The NM_000180.4(GUCY2D):c.1618C>T (p.Arg540Cys) variant is predicted to replace the arginine at position p.540 with cysteine. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.00005391, with 87 alleles / 1,613,652 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant was reported in individual with LCA but no second variant was identified. It was also seen heterozygously in a patient with a macular dystrophy likely caused by ABCA4 variants (PM3_not met; PMIDs:10951519, 29555955). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226052/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:61049 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0028961 infores:hetionet NCBIGene:71 biolink:causes MONDO:0011480 infores:monarchinitiative not_provided not_provided HGNC:144 MONDO:0011480 uuid:394e1b8c-cce8-4759-b464-394d51c495a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0041969 infores:hetionet CHEBI:10119 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0392676 infores:hetionet CHEBI:4466 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0004245 infores:hetionet CHEBI:44423 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0235896 infores:hetionet CAID:CA645614106 biolink:causes MONDO:0100083 infores:clingen CAID:CA645614106 MONDO:0100083 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 PVS1_strong: Frameshift (+1); c.780-1440 as per VCEP specificationsPM2_supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2).PM5_supporting: Nonsense/frameshift variants that is downstream of c.98 (in transcript NM_001754.4).In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645614106/MONDO:0100083/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:18248 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0036572 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020649 infores:hetionet GO:0014046 biolink:causes NCBIGene:1813 infores:drugmechdb knowledge_assertion manual_agent GO:0014046 UniProtKB:P14416 DB01100_MESH_D005879_1 CHEBI:135876 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0080274 infores:hetionet CHEBI:53760 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0233754 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0020517 infores:hetionet CHEBI:31348 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0162830 infores:hetionet CAID:CA7331394 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331394 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PVS1, PM2, PM6, BP1, BP2, BP3, BA1, PP2, PP3, PP1, PP4, PM5, PM3, PM4, PS1, PS3, PS2, BP5, BP7, BS1, BS3, BS4 The NM_177438.3:c.1802T>C variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 601 (p.Ile601Thr). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000007434 (12/1,614,166 alleles) with a highest population minor allele frequency of 0.00001017 (12/1,179,996 alleles) in European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.033; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331394/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0206062 infores:hetionet CHEBI:61049 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004093 infores:hetionet CHEBI:9241 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0015967 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0162316 infores:hetionet CHEBI:45863 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0004093 infores:hetionet CHEBI:8214 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0016204 infores:hetionet UNII:D27V6190PM biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0547030 infores:hetionet CHEBI:7931 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0003467 infores:hetionet CHEBI:68584 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0042075 infores:hetionet CHEBI:7496 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0004093 infores:hetionet CHEBI:4868 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0027497 infores:hetionet CAID:CA355965290 biolink:causes MONDO:0001586 infores:clingen CAID:CA355965290 MONDO:0001586 PMID: Uncertain Significance PM3_Supporting, PM2_Supporting PP3, PP4 The NM_000203.5:c.1726A>G variant in IDUA is predicted to result in a missense change, p.Lys576Glu. To our knowledge, this variant has not been reported in the literature. One patient, with IDUA activity in the affected range, short stature and GI issues, was reported in a clinical diagnostic laboratory. This patient is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; phase is unconfirmed (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.494 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. Although the variant occurs 2 base pairs upstream from the donor splice junction of exon 12/intron 12, no significant impact on splicing is predicted by SpliceAI (score for donor loss = 0.11). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355965290/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:1905310 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0003007 PUBCHEM.COMPOUND:5284632 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0004093 infores:hetionet CHEBI:63681 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0233794 infores:hetionet CHEBI:474180 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151786 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0585186 infores:hetionet CHEBI:5893 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0032617 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0948089 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020473 infores:hetionet NCBIGene:8431 biolink:causes MONDO:0019182 infores:monarchinitiative not_provided not_provided HGNC:7961 MONDO:0019182 uuid:01ec0dec-f026-4d18-b4bc-6d1a6915e2c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0021400 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0009806 infores:hetionet CHEBI:52717 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0031154 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0028077 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0267596 infores:hetionet CHEBI:7565 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0038325 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0948586 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0521839 infores:hetionet CHEBI:5441 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0023530 infores:hetionet CHEBI:38940 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0085649 infores:hetionet CHEBI:4717 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0392156 infores:hetionet CHEBI:10023 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151786 infores:hetionet GO:0090189 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:0090189 GO:0072028 CHEBI:8871 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0392156 infores:hetionet CHEBI:16796 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0028081 infores:hetionet CHEBI:168396 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0038362 infores:hetionet CHEBI:17303 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0009782 infores:hetionet NCBIGene:200879 biolink:causes MONDO:0011452 infores:monarchinitiative not_provided not_provided HGNC:18483 MONDO:0011452 uuid:503228cc-8c61-4123-85a9-671124d73b72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C3665386 infores:hetionet CAID:CA120543 biolink:causes MONDO:0044970 infores:clingen CAID:CA120543 MONDO:0044970 PMID:18337306 Uncertain Significance PP3, PM2_Supporting, PM6_Supporting, PS3_Supporting PP1, PS4 The m.5545C>T variant in MT-TW has been reported in one individual with primary mitochondrial disease to date, in a boy with hypertrophic cardiomyopathy, hypotonia, lactic acidosis, developmental regression, seizures, slowly progressive chorea, proximal muscle weakness, ataxia, and dysmetria. Brain MRI showed diffuse brain atrophy and bilateral putaminal intensities. Muscle biopsy showed a diffuse reduction in COX activity with normal SDH staining. Respiratory chain enzyme activities in muscle showed reduced complex IV activity (12% of controls). The variant was present at 25% heteroplasmy in muscle, 13% in leukocytes, and 17% in skin fibroblasts (PMID: 18337306). The variant was absent in leukocytes, urine, hair, and buccal sample from his mother (PMID: 18337306; PM6_supporting). There are no other large families reported to consider evidence for segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (31±7%, n = 11) than in COX-positive fibers (3 ± 4%, n = 13), p<0.01 (PS3_supporting, PMID: 18337306). Cybrid studies and translation assay further support the functional effect of this variant (PMID: 18337306). The computational predictor MitoTIP suggests this variant is pathogenic (53 percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120543/MONDO:0044970/015 2024-04-23 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:135935 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0030252 infores:hetionet CHEBI:6076 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0023212 infores:hetionet CHEBI:171719 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0012569 infores:hetionet CHEBI:94807 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0039971 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0178298 infores:hetionet CHEBI:49575 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0001122 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0151478 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151478 infores:hetionet CHEBI:8707 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151904 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0162316 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018099 infores:hetionet CHEBI:17823 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0001925 infores:hetionet CAID:CA274402 biolink:causes MONDO:0009290 infores:clingen CAID:CA274402 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM1, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000152.5:c.1556T>C variant in GAA is a missense variant predicted to cause substitution of methionine by threonine at amino acid 519 (p.Met519Thr). This variant has been detected in at least 4 individuals with Pompe disease. Of those individuals, 3 were compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP, phase unconfirmed, either c.525del (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 14695532), c.1441T>C (p.Trp481Arg) (ClinVar Variation ID: 189007, SCV004227917.1) (PMID: 31086307), or c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu] (ClinVar Variation ID 325781/325782) (Clinical laboratory data); One individual was homozygous for the variant (PMID: 33741225) (PM3_Strong). At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in dried blood spot (PMID: 33741225) and 2 patients were reported to have symptoms consistent with infantile onset Pompe disease (PMID: 14695532) (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30616 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.983 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 resulted in <2% wild type GAA activity with western blot data showing decreased level of mature protein, indicating that this variant may impact protein function (PMIDs: 19862843, 14695532) (PS3_Moderate). This variant alters amino acid M519, a residue that crystallography studies have shown to be important in the active site of GAA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). There is a ClinVar entry for this variant (Variation ID: 189124). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_strong, PP4_moderate, PM1, PS3_moderate, PP3, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274402/MONDO:0009290/010 2024-05-07 2024-05-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5138 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0344232 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151735 infores:hetionet UMLS:C0657912 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0149745 infores:hetionet CHEBI:4876 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0344232 infores:hetionet CAID:CA1707356 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707356 MONDO:0015152 PMID:35028538 Pathogenic PM3, PP4_Strong, PP3, PP1, PS3_Moderate PM2 The NM_003494.4: c.5302C>T variant in DYSF, which is also known as NM_001130987.2: c.5419C>T p.(Arg1807Trp), is a missense variant predicted to cause substitution of arginine to tryptophan at amino acid 1768, p.(Arg1768Trp). This variant has been identified in at least 15 individuals with features consistent with LGMD (PMID: 17698709, 21522182, 25591676, 30564623, 32934002, 34559919; LOVD DYSF_000126), including in a homozygous state in a proband from a family without reported consanguinity (0.5 pts, PMID: 21522182) and confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 1.0 pt, PMID: 17698709) (PM3). This variant was identified in conjunction with another presumed diagnostic DYSF variant in at least one individual with a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 25591676; PP4_Strong). It was also shown to segregate with autosomal recessive LGMD in three affected members from a single family (PMID: 21522182; PP1, capped with PP4_Strong). The filtering allele frequency of this variant is 0.0001734 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/44720 Admixed American chromosomes), which is greater than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1768Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.704, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3, PP4_Strong, PP1, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707356/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50861 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0012833 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151691 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0002871 infores:hetionet CAID:CA340744901 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744901 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4, PM2_Supporting PS1, PM5, PM1, BP7, BS1 The NM_000329.3(RPE65):c.917C>T (p.Thr306Ile) variant is a missense variant in RPE65 causing a substitution of threonine with isoleucine at position 306. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.000005420 with 12 alleles / 1179962 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.962, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 38465142). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with the c.912C>A, p.Y304* variant confirmed in trans, the c.1022T>C p.Leu341Ser variant confirmed in trans, or the c.94G>T p.Gly32Cys variant suspected in trans (2.25 points, PMIDs: 34830511, 34492281, 35129589), which were previously classified pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (2.75 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including severely decreased ERG (0.5 pt), decreased central visual acuity (1 pt), symptomatic onset between birth and age five years (1 pt), congenital night blindness (0.5 pt), salt and pepper pigmentation (0.5 pt), and visual field reduction (1 pt)(4.5 points, PMID: 34492281, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3_Strong, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744901/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9137 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013604 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0009450 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0039231 infores:hetionet CHEBI:7627 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0043094 infores:hetionet CAID:CA410207209 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207209 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.618T>G (p.His206Gln) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207209/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28177 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0011603 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0002871 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0948594 infores:hetionet CHEBI:63584 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0030554 infores:hetionet CHEBI:10650 biolink:causes UMLS:C1142080 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1142080 infores:hetionet CHEBI:68478 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004144 infores:hetionet CAID:CA10640460 biolink:causes MONDO:0008723 infores:clingen CAID:CA10640460 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The NM_000018.4(ACADVL): c.751A>G (p.Ser251Gly) variant is a missense variant predicted to cause substitution of serine by glycine at amino acid 251. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a pathogenic variant and confirmed in trans by parental testing (1.0 PM3 points, PMID: 26937394, PM3_moderate). At least one patient with this variant displayed NBS C14:1 levels ≥ 1.0 μM and follow-up Plasma Acylcarnitine analysis consistent with VLCADD, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 26937394). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.978, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3_moderate, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA10640460/MONDO:0008723/021 2025-02-25 2025-02-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:70746 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018801 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0236068 infores:hetionet NCBIGene:10430 biolink:causes MONDO:0859298 infores:monarchinitiative not_provided not_provided HGNC:30414 MONDO:0859298 uuid:8b06fad0-02e4-4a12-a8dd-42ae0bc366cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0016204 infores:hetionet CHEBI:5109 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0020555 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0438167 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0438167 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0858794 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0858794 infores:hetionet CHEBI:6909 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151908 infores:hetionet CAID:CA10584591 biolink:causes MONDO:0018875 infores:clingen CAID:CA10584591 MONDO:0018875 PMID: Pathogenic PM1_Supporting, PS3, PS4_Moderate, PP3, PP1, PP4, PM2_Supporting BP4, BA1, PS1, PS2, BP7, BS1, BS3, BS4, PVS1, BS2 The NM_000546.6: c.490A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 164 (p.Lys164Glu). This variant has been reported in 2 unrelated families meeting Classic/Revised Chompret criteria. Based on this evidence this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs: 33138793, 38050059). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 38050059). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614174 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5572; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 9 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1, PM2_Supporting, PS3, PP3, PP4, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584591/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45863 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042075 infores:hetionet CHEBI:5130 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0018965 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0948586 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0242350 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017574 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0851341 infores:hetionet UMLS:C0145867 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0233407 infores:hetionet CHEBI:8805 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0086565 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151613 infores:hetionet NCBIGene:5149 biolink:causes MONDO:0012398 infores:monarchinitiative not_provided not_provided HGNC:8790 MONDO:0012398 uuid:41f20ed4-dc50-4d9f-b1d3-587efc42fc4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020517 infores:hetionet CHEBI:65173 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0575081 infores:hetionet UNII:T58MSI464G biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0151766 infores:hetionet CHEBI:8455 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0015230 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1698976 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1698976 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0233472 infores:hetionet CHEBI:6539 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0242184 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0919883 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0919883 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009319 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0020517 infores:hetionet CHEBI:16914 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0013604 infores:hetionet CHEBI:36795 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0024437 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151571 infores:hetionet CAID:CA916084430 biolink:causes MONDO:0009861 infores:clingen CAID:CA916084430 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PVS1, PM2, PM3_Supporting The p.Ex6_7_8del (c.510-735_912+434del) variant is a 4799bp deletion in PAH, a gene where loss of function is a known disease mechanism, and is predicted to lead to a frameshift at Gly171, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2). It has been previously reported in one patient with PKU (BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate) (PMID: 23942198) in presumed trans with the p.F55L variant (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting).Classification: PathogenicSupporting Criteria: PVS1; PM2; PP4_Moderate; PM3_Supporting Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084430/MONDO:0009861/006 2020-06-05 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5779 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0003862 infores:hetionet CHEBI:2663 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0206062 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005747 infores:hetionet CHEBI:7931 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0014724 infores:hetionet NCBIGene:368 biolink:causes MONDO:0013768 infores:monarchinitiative not_provided not_provided HGNC:57 MONDO:0013768 uuid:6f51ab5b-c254-471f-ba1d-54dbc609fa90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0851578 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151810 infores:hetionet CHEBI:80630 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0041582 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0020649 infores:hetionet NCBIGene:5426 biolink:causes MONDO:0014058 infores:monarchinitiative not_provided not_provided HGNC:9177 MONDO:0014058 uuid:e436f128-4111-41f8-8def-cd6791fb14f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020615 infores:hetionet CHEBI:37941 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0553692 infores:hetionet CHEBI:16335 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0043352 infores:hetionet CHEBI:8327 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0740394 infores:hetionet CHEBI:9763 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0035455 infores:hetionet CHEBI:135876 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0020456 infores:hetionet CHEBI:46295 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0027424 infores:hetionet CHEBI:6062 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0010200 infores:hetionet CHEBI:39669 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0013395 infores:hetionet CHEBI:5779 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0085633 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0042571 infores:hetionet CAID:CA256121 biolink:causes MONDO:0001586 infores:clingen CAID:CA256121 MONDO:0001586 PMID:7550232 Likely Pathogenic PM4, PM3, PM5_Supporting, PM2_Supporting PS3, PP4 "The NM_000203.5:c.1960T>G in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Gly), resulting in an increase in the length of the protein (PM1). One patient with ""Hurler-Scheie"" syndrome, who is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909), has been reported. The variants were confirmed to be in trans (PMID: 7550232) (PM3; insufficient evidence to apply PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1179958 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When the variant was expressed in COS cells, the intracellular activity of IDUA was low (negative control 1.3 (U/mg cell protein, wild type 14.5 (U/mg cell protein, variant 2.5 (U/mg cell protein), approximately 10% wild type ( PMID: 7550232). This is higher than the LD VCEP's threshold for IDUA activity for PS3_Supporting (<2%), therefore, PS3 was not applied. Other IDUA stop loss variants have been reported in patients with MPS1. One of these variants, c.1960T>C (p.Ter654Arg) (Bertola et al, PMID: 21394825; Ngiwsara et al, PMID: 29282708), has been classified as likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). The other variants are c.1961A>T (p.Ter654Cys) ((Bach et al, 1993, PMID: 8328452) and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM4, PM3, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA256121/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27899 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0919924 infores:hetionet CHEBI:10124 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0027497 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005086 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0007134 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0018939 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235969 infores:hetionet CHEBI:3508 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C1384353 infores:hetionet NCBIGene:185 biolink:causes MONDO:0009970 infores:monarchinitiative not_provided not_provided HGNC:336 MONDO:0009970 uuid:9ae47c48-5d2b-4b30-ba20-1bb6c05ca7a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027497 infores:hetionet CHEBI:50693 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0020621 infores:hetionet CHEBI:42797 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1368065 infores:hetionet CHEBI:3207 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0271738 infores:hetionet CHEBI:3723 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002874 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0042109 infores:hetionet CHEBI:5118 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0008031 infores:hetionet CHEBI:28445 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0036983 infores:hetionet CAID:CA410206945 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206945 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.670C>T (p.Arg224Trp) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206945/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68478 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0007971 infores:hetionet CHEBI:6538 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0041657 infores:hetionet CHEBI:41423 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0016382 infores:hetionet CAID:CA10588543 biolink:causes MONDO:0015967 infores:clingen CAID:CA10588543 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS3_Moderate, PM1_Supporting, PS4, PP1_Strong, PP4_Moderate, PP3 The c.779C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 260 (p.(Thr260Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 28 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 30760653, 29927023, 30663027, 29207974, 28105082, internal lab contributors). At least two of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, and both were antibody negative and one responded to low dose sulfonylureas) (PP4_Moderate; PMIDs: 30760653, 281505082). This variant segregated with diabetes, with 16 informative meioses in multiple families with MODY (PP1_Strong; PMIDs: 30760653. 28105082, internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Thr260Met protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate; PMID: 32910913). In summary, c.779C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_supporting, PM2_Supporting, PP3, PS4, PP4_Moderate, PP1_Strong, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588543/MONDO:0015967/017 2022-04-14 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CAID:CA398322989 biolink:causes MONDO:0011132 infores:clingen CAID:CA398322989 MONDO:0011132 PMID: Pathogenic PM2_Supporting, PM5_Supporting, PVS1 The NM_001369369.1:c.723C>G variant in FOXN1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/9 leading to nonsense mediated decay (PVS1). The variant is absent in gnomAD v4.1.0 database (PM2_Supporting). A pathogenic variant p.Arg255Ter curated by the SCID VCEP causes premature termination codon in the same exon and downstream to the variant under assessment (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PM5_Supporting. (VCEP specifications version 2.0.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398322989/MONDO:0011132/113 2025-04-25 2025-07-14 Semidominant inheritance HP:0032113 Supports CHEBI:5138 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151754 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0023787 infores:hetionet CHEBI:3738 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0042963 infores:hetionet GO:0070950 biolink:causes GO:0042742 infores:ubergraph knowledge_assertion manual_agent GO:0070950 GO:0042742 CHEBI:17334 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C1325847 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0232208 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017152 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0041969 infores:hetionet CHEBI:7824 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0039070 infores:hetionet CHEBI:36791 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013362 infores:hetionet CHEBI:3215 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0041657 infores:hetionet CHEBI:87681 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0011175 infores:hetionet NCBIGene:545 biolink:causes MONDO:0013806 infores:monarchinitiative not_provided not_provided HGNC:882 MONDO:0013806 uuid:916887e7-436f-40cf-a258-71c8f201ea38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3614 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0040460 infores:hetionet CHEBI:107736 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0040485 infores:hetionet CHEBI:2453 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151905 infores:hetionet CHEBI:6520 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0023380 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0549405 infores:hetionet CHEBI:15940 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0039231 infores:hetionet CHEBI:31711 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0549249 infores:hetionet CHEBI:44032 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C1280433 infores:hetionet CHEBI:64321 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0151905 infores:hetionet NCBIGene:147183 biolink:causes MONDO:0014765 infores:monarchinitiative not_provided not_provided HGNC:30839 MONDO:0014765 uuid:a83e4e3f-da5c-4e59-b9d7-b479996807fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0009763 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0853777 infores:hetionet CHEBI:114785 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0015672 infores:hetionet CHEBI:4453 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0011124 infores:hetionet CHEBI:6541 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0026821 infores:hetionet CAID:CA2802202 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802202 MONDO:0001586 PMID: Pathogenic PP3_Moderate, PP4_Moderate, PM3_Very Strong, PM2_Supporting PM1, PM5 The NM_000203.5:c.1139A>G variant in IDUA is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 380 (p.Gln380Arg). This variant has been detected in at least 34 individuals with MPS I. Of those individuals, 20 were compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic variant for MPS I by the ClinGen LD VCEP, all in unknown phase. The second variant includes c.46_57del (p.Ser16_Ala19del) (PMID: 35141277) (0.5 pt), c.208C>T (p.Gln70Ter)(11 patients, PMID: 24368159, 24875751, 35141277) (max 2 x 0.5 points), c.979G>C p.Ala327Pro (PMID: 28752568) (0.5 pt), c.1205G>A p.Trp402Ter (6 patients, PMID: 28752568, 35141277) (max 2 x 0.5 pts), c.1861C>T (p.Arg621Ter) ((PMID: 11735025) (0.25 pt). Four unrelated individuals are homozygous for the variant PMID: 19396826, 31194252, 35141277) (max 2 x 0.5 pts). Total 4.25 points (PM3_VeryStrong). At least 19 patients with this variant had documented IDUA deficiency within the affected range in leukocytes, and/or urinary GAGs expressed as either total GAGs and/or specific GAG elevation above normal range, and/or clinical features specific to MPS I including dysostosis multiplex, corneal clouding, and hepatosplenomegaly (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.10. is 0.00003112 (36/1156956 alleles) in the NFE population (gnomAD v2.1.1 is 0.00004458 with 3/67302 alleles in the NFE population), which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.872 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 550799). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802202/MONDO:0001586/091 2024-12-06 2025-06-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9907 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0548823 infores:hetionet CHEBI:135342 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0687713 infores:hetionet CHEBI:9674 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013362 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0021400 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006266 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0038002 infores:hetionet CHEBI:44915 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0015672 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0034150 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0020649 infores:hetionet CHEBI:9586 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151908 infores:hetionet UMLS:C0145185 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0546817 infores:hetionet CHEBI:6149 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0007166 infores:hetionet CHEBI:15544 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0027424 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0022660 infores:hetionet CHEBI:31644 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013390 infores:hetionet CHEBI:681569 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0016382 infores:hetionet CAID:CA8603157 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603157 MONDO:0100326 PMID: Benign BA1 PM3, PP3, PP4, BP4 The NM_000419.5(ITGA2B):c.1374C>G (p.Ile458Met) missense variant has been reported in at least one patient (Patient 6 in PMID:19172520/GT database record 163), however it occurs at a high allele frequency with the highest population minor allele frequency in gnomAD v4.0.0 is 0.003502 (319/91084 alleles with 3 homozygotes) in the South Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign, for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603157/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true NCBIGene:3798 biolink:causes MONDO:0011408 infores:monarchinitiative not_provided not_provided HGNC:6323 MONDO:0011408 uuid:847a638b-b4c7-4902-a81b-e4d1bc8dcd39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50730 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0006277 infores:hetionet CHEBI:94501 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0016382 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0036572 infores:hetionet CHEBI:9637 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0242429 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014868 infores:hetionet CHEBI:31485 biolink:causes HP:0031616 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0423281 infores:hetionet CHEBI:3441 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0340865 infores:hetionet NCBIGene:8799 biolink:causes MONDO:0013967 infores:monarchinitiative not_provided not_provided HGNC:8853 MONDO:0013967 uuid:93ca1885-f5d2-4188-b029-cf560bc54f0a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0041969 infores:hetionet CAID:CA637749766 biolink:causes MONDO:0011071 infores:clingen CAID:CA637749766 MONDO:0011071 PMID: Benign BP2, BP4, BA1, BP7 PS3, PS1, PS2, PS4, BP3, BP1, BS1, BS3, BS4, PVS1, PM2, PM6, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 The NM_001754.5(RUNX1):c.-60+52dup variant is a deep intronic variant in a homopolymer region that is not predicted by SpliceAI to impact splicing (BP4). The variant highest minor allele frequency (MAF) is 0.05560 (5.0%, 396/7122 alleles) in the African/African American subpopulation of the gnomAD2.1.1 ( ≥ 0.0015 (0.15%) (BP1)). Additionally, this variant is detected in a homozygous state in 10 individuals in a population database (gnomADv2.1.1) (BP2). This deep intronic variant is not well conserved with a phyloP100way score of 0.9 (BP7 ≤2.0). It has not been reported in individuals meeting at least one of the RUNX1 phenotypic criteria. In summary, the clinical significance of this variant is Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP1, BP2, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637749766/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:547 biolink:causes MONDO:0013656 infores:monarchinitiative not_provided not_provided HGNC:888 MONDO:0013656 uuid:8a074d07-8fe1-4f4c-9448-8d894d1ea1bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0005779 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020538 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0002170 infores:hetionet NCBIGene:388558 biolink:causes MONDO:0975839 infores:monarchinitiative not_provided not_provided HGNC:33230 MONDO:0975839 uuid:3ac6581c-544f-4856-9939-3bec2fa901d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915940374 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940374 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting NM_000419.5(ITGA2B):c.832del (p.Asp278IlefsTer101) frameshift variant in exon 8 is predicted to cause a premature stop codon in biologically-relevant-exon 12/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (GT47 in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting. (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940374/MONDO:0100326/011 2022-08-05 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:408174 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0041969 infores:hetionet CHEBI:7581 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0028643 infores:hetionet CHEBI:5864 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0549249 infores:hetionet CHEBI:84050 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0039070 infores:hetionet CHEBI:63612 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0018681 infores:hetionet CHEBI:31624 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0008031 infores:hetionet CAID:CA410203974 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203974 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.186C>G (p.Asp62Glu) is a missense variant which has a REVEL score < 0.50 (0.31) and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203974/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0061321 biolink:causes CL:0000486 infores:ubergraph knowledge_assertion manual_agent GO:0061321 CL:0000486 CHEBI:4530 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0030252 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0026848 infores:hetionet CHEBI:6375 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0031256 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0008370 infores:hetionet CHEBI:42944 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042024 infores:hetionet CAID:CA2579916736 biolink:causes MONDO:0010305 infores:clingen CAID:CA2579916736 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, PP4_Strong PP3 The NM_005629.4(SLC6A8):c.1016+21_1017-42del variant in SLC6A8 is an intronic deletion of 34 nucleotides within intron 6/12. This variant is also referred to as c.1016+11_1017-52del in literature based on genome build GRCh36. This variant is absent from gnomAD v3.1.2, therefore PM2_Supporting criteria is applicable. The computational predictor SpliceAI gives delta scores of 0.07 (donor loss, -10bp) and acceptor loss 0.01 (acceptor loss, -49bp) which is not highly suggestive of a splicing defect. This variant has not been previously reported in ClinVar, although has been reported in an affected male in the literature with hypotonia, motor delay, speech delay and seizures [PMID:27081545]. This individual was found to have elevated Cr/Crn ratio on two different days with elevated ratio (2.66, 4.56 with reference value <1.5), H-MRS demonstrating marked reduction of the creatine peak in this individual, and creatine uptake assayed in fibroblasts with Cr concentrations of 25 and 500uM, at 25uM the creatine uptake was undetectable and at 500uM creatine uptake was <25% of normal cells. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on August 8, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579916736/MONDO:0010305/027 2023-08-08 2024-06-24 X-linked inheritance HP:0001417 Inconclusive true CHEBI:35778 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0542571 infores:hetionet CHEBI:145499 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085631 infores:hetionet CHEBI:7492 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0011603 infores:hetionet CHEBI:6710 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0015672 infores:hetionet NCBIGene:4359 biolink:causes MONDO:0011903 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0011903 uuid:e64db371-cb94-4efd-b353-4af27d0cd749 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2072 biolink:causes MONDO:0014108 infores:monarchinitiative not_provided not_provided HGNC:3436 MONDO:0014108 uuid:87acf9d5-db16-431c-908a-e600b969eb87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0037036 infores:hetionet CHEBI:51230 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0030193 infores:hetionet CHEBI:6887 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151827 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0518015 infores:hetionet CHEBI:6715 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0015967 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0036572 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0948594 infores:hetionet CHEBI:27666 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0231528 infores:hetionet CHEBI:5141 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0344232 infores:hetionet CHEBI:4702 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0423153 infores:hetionet CHEBI:3310 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0003811 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0234935 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0234935 infores:hetionet CHEBI:65349 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0151754 infores:hetionet CHEBI:2637 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0011053 infores:hetionet CHEBI:8024 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0085605 infores:hetionet NCBIGene:3621 biolink:causes MONDO:0010150 infores:monarchinitiative not_provided not_provided HGNC:6062 MONDO:0010150 uuid:5fad64d6-1655-4bc8-8b55-6aed0f184eaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0023533 infores:hetionet CHEBI:31980 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0033774 infores:hetionet CHEBI:8502 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0042384 infores:hetionet NCBIGene:5894 biolink:causes MONDO:0012691 infores:monarchinitiative not_provided not_provided HGNC:9829 MONDO:0012691 uuid:ba645a68-35e0-4e55-9c54-7ae40673da8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0030554 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0677500 infores:hetionet CHEBI:6965 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0015230 infores:hetionet CHEBI:50223 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0017178 infores:hetionet CAID:CA367398753 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398753 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1144T>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 382 (p.(Cys382Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with 4 informative meioses in a family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). Another missense variant, c.1144T>C (p.Cys382Arg), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys382Gly)(PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Moderate, PS4_Moderate, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398753/MONDO:0015967/086 2023-11-24 2023-11-24 Semidominant inheritance HP:0032113 Supports CHEBI:39585 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0233494 infores:hetionet CAID:CA059460 biolink:causes MONDO:0017623 infores:clingen CAID:CA059460 MONDO:0017623 PMID:28677221PMID:27443514PMID:21659347PMID:25669429PMID:11156385PMID:28677221PMID:29360161PMID:27978560PMID:15589575PMID:25186627PMID:22261759PMID:26976419PMID:22995991PMID:16287957 Benign BS3, BS1 PVS1, PM6, PM2, BS4, BP5, BP7, PP1, PP3, PP2, BS2, PM1, PM4, PM5, BP2, BP4, BA1, PS3, PS2, PS4, PS1 PTEN c.210-7_210-3delCTTTT (IVS3-7_IVS3-3delCTTTT) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00136 (0.14%, 14/10,306 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA059460/MONDO:0017623/003 2019-03-05 2019-07-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2788 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0015397 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037199 infores:hetionet CHEBI:42797 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151754 infores:hetionet CHEBI:75998 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0027947 infores:hetionet CHEBI:3207 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0018681 infores:hetionet CHEBI:231425 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0011880 infores:hetionet NCBIGene:4359 biolink:causes MONDO:0011909 infores:monarchinitiative not_provided not_provided HGNC:7225 MONDO:0011909 uuid:c3de33b1-6f4b-4032-aa5f-4c6ef6b2c94b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0848309 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0848309 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0522165 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0522165 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0541941 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0541941 infores:hetionet CHEBI:6715 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1609512 infores:hetionet CHEBI:6954 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0011991 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0020538 infores:hetionet CHEBI:71255 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0017672 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0011053 infores:hetionet CHEBI:68558 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0013404 infores:hetionet CHEBI:31711 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151744 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151664 infores:hetionet CAID:CA512341391 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341391 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.987G>A (p.Ala329=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.50)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341391/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:9430ZR8ZAN biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151602 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0015376 infores:hetionet CHEBI:16755 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0023530 infores:hetionet CHEBI:4822 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0037763 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0034150 infores:hetionet NCBIGene:4548 biolink:causes MONDO:0009609 infores:monarchinitiative not_provided not_provided HGNC:7468 MONDO:0009609 uuid:85c7ba5f-20b7-40c5-89d2-5badcb13de7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:8195 biolink:causes MONDO:0009367 infores:monarchinitiative not_provided not_provided HGNC:7108 MONDO:0009367 uuid:63942b6f-801e-4f02-8376-1865e84928fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020578 infores:hetionet CHEBI:4856 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0002962 infores:hetionet CHEBI:4887 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0855242 infores:hetionet CHEBI:93305 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0023530 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0233494 infores:hetionet CHEBI:3423 biolink:causes MONDO:0016684 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0334579 infores:hetionet CHEBI:135888 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0035455 infores:hetionet CHEBI:9571 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0686347 infores:hetionet CAID:CA285511 biolink:causes MONDO:0044970 infores:clingen CAID:CA285511 MONDO:0044970 PMID: Benign BS2, BA1 BP4 The c.1984G>A (p.Glu662Lys) variant in POLG has been reported with an allele frequency in the population databases: 0.9 % in gnomAD and in the Latino population at 7% (BA1). It is also seen in the homozygous state in 112 individuals in gnomAD and 42 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA285511/MONDO:0044970/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7601 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0917801 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0013404 infores:hetionet CHEBI:50924 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0011606 infores:hetionet GO:0021822 biolink:causes GO:0030900 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0030900 CHEBI:6367 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151752 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018500 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0497327 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011127 infores:hetionet CHEBI:94449 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0015230 infores:hetionet CHEBI:9571 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0013384 infores:hetionet CAID:CA64042886 biolink:causes MONDO:0015924 infores:clingen CAID:CA64042886 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 BA1, PM1, BS1 The NM_001204.7(BMPR2) c.1698T>A variant is a synonymous (silent) variant (p.Ile566=) that is not predicted by SpliceAI to impact splicing (BP4, BP7). This variant is absent from gnomAD v2.1.1 controls (PM2_supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BP4, BP7, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA64042886/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6950 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2225524 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0267792 infores:hetionet CHEBI:84500 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0497156 infores:hetionet CHEBI:31711 biolink:causes UMLS:C1262195 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C1262195 infores:hetionet NCBIGene:773 biolink:causes MONDO:0020756 infores:monarchinitiative not_provided not_provided HGNC:1388 MONDO:0020756 uuid:667aa851-b0d1-4200-8722-2ee480910883 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0039504 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039504 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0032285 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0009450 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0038362 infores:hetionet CHEBI:35854 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0151905 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0003864 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0005940 infores:hetionet CHEBI:4708 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013378 infores:hetionet CHEBI:9587 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0033774 infores:hetionet CHEBI:6073 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C2363731 infores:hetionet CHEBI:2687 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151539 infores:hetionet CHEBI:82960 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151908 infores:hetionet CHEBI:8069 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0002994 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0020580 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030920 infores:hetionet CHEBI:7565 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0043094 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1384353 infores:hetionet CHEBI:51141 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0041969 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0030446 infores:hetionet CHEBI:92712 biolink:causes MONDO:0008848 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0004331 infores:hetionet CHEBI:94807 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0030193 infores:hetionet CHEBI:32315 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C1306341 infores:hetionet CHEBI:167638 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0344232 infores:hetionet CHEBI:6375 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0236048 infores:hetionet CHEBI:59773 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0008031 infores:hetionet CHEBI:63608 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0040822 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0006764 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D016921 DB00681_MESH_D016921_1 CHEBI:31348 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020456 infores:hetionet UMLS:C0009315 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0010200 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1328337 infores:hetionet CHEBI:49040 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0011991 infores:hetionet CHEBI:64312 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040822 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0149931 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0027497 infores:hetionet CHEBI:50885 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0156404 infores:hetionet CHEBI:31644 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0014236 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0015395 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015395 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0854380 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0854380 infores:hetionet CHEBI:5558 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0042023 infores:hetionet NCBIGene:3178 biolink:causes MONDO:0014179 infores:monarchinitiative not_provided not_provided HGNC:5031 MONDO:0014179 uuid:f2cdda0b-189a-4fea-8b71-d8434ab544ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0475858 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1868855 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0456677 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0456677 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235280 infores:hetionet CHEBI:5558 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0002170 infores:hetionet CHEBI:168396 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0025289 infores:hetionet CHEBI:8802 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0085614 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042134 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0234215 infores:hetionet CHEBI:16469 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0232849 infores:hetionet CHEBI:50742 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0024902 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011849 infores:hetionet CHEBI:35778 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0012569 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0149931 infores:hetionet CHEBI:64028 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C1443060 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0009806 infores:hetionet CHEBI:15854 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0039070 infores:hetionet UMLS:C0657912 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0232726 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C1956346 infores:hetionet CHEBI:46557 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0022081 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003864 infores:hetionet CHEBI:9586 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0242301 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0232459 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017574 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0948089 infores:hetionet CHEBI:119486 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0028754 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0278488 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0278488 infores:hetionet CHEBI:6073 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0004238 infores:hetionet CHEBI:46195 biolink:causes MONDO:0006679 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0005694 infores:hetionet CHEBI:46345 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0242422 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030312 infores:hetionet CHEBI:16796 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0003467 infores:hetionet CHEBI:6887 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027849 infores:hetionet NCBIGene:2232 biolink:causes MONDO:0971174 infores:monarchinitiative not_provided not_provided HGNC:3642 MONDO:0971174 uuid:8c696d65-e041-4d86-9661-53f6e9df0abb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3071 biolink:causes MONDO:0033551 infores:monarchinitiative not_provided not_provided HGNC:4862 MONDO:0033551 uuid:312e86aa-e8b7-435f-97e5-df7f8ccae0ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50223 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0030312 infores:hetionet CHEBI:9943 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0032617 infores:hetionet CAID:CA10014552 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014552 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP2, BP3, BS1, BS3, BS4, BP5, PM2, PVS1, PM6, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.303G>T (p.Val101=) is a synonymous variant. MAF of 0.00671 (0.671%, 167/24878, 167 alleles) in the African subpopulation of the gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). Not a missense variant, therefore, no REVEL score and SpliceAI is ≤0.50 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.4739 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014552/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9398 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C1384353 infores:hetionet CHEBI:75045 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0870082 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0574067 infores:hetionet CHEBI:119915 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0232602 infores:hetionet NCBIGene:7054 biolink:causes MONDO:0011551 infores:monarchinitiative not_provided not_provided HGNC:11782 MONDO:0011551 uuid:4e6a625e-1811-4901-9f1c-3c37b49a286f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151436 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0037199 infores:hetionet CHEBI:15367 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0242184 infores:hetionet CHEBI:8461 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0015230 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018790 infores:hetionet CAID:CA229551 biolink:causes MONDO:0009861 infores:clingen CAID:CA229551 MONDO:0009861 PMID:8535445PMID:10679941PMID:17096675PMID:8659548 Likely Pathogenic PM3, PM2, PP4, PP3 The PAH variant c.442G>A (p.Gly148Ser) has been reported in three individuals with PHA deficiency (Phe levels >120 μM). One patient from the Northeastern region of the US, (PMID: 8659548)(PMID:10429004), one patient from Europe (PMID: 10679941), and one patient from the Campania Region in Southern Italy with mild PKU (Phe between 600 and 1200 μM) (PMID: 17096675). The variant c.442G>A (p.Gly148Ser) was document with the pathogenic variant c.194T>C (p.Ile65Thr)(ClinVar ID: 636), and with the pathogenic variant c.473G>A (p.Arg158Gln)(ClinVar ID: 587) (PMID: 8535445). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the African population (0.00006). In silico modeling predicts that this missense variant is damaging by SIFT, probably damaging by Polyphen 2 and disease causing by Mutation Taster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4 . Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229551/MONDO:0009861/006 2019-12-22 2019-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:85161 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151744 infores:hetionet CHEBI:5165 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0086439 infores:hetionet CHEBI:5864 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0013604 infores:hetionet NCBIGene:8813 biolink:causes MONDO:0012123 infores:monarchinitiative not_provided not_provided HGNC:3005 MONDO:0012123 uuid:86a9015a-f942-413f-b638-bcf5e988f70d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011551 infores:hetionet CHEBI:47612 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0018681 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0549209 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002871 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0023533 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004239 infores:hetionet CHEBI:83527 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0014518 infores:hetionet CHEBI:47780 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0232849 infores:hetionet CHEBI:63621 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0586553 infores:hetionet CHEBI:28148 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0021843 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0030720 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C2945558 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002418 infores:hetionet CHEBI:9137 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C3495920 infores:hetionet CHEBI:3423 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0595916 infores:hetionet CHEBI:10127 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0032617 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151310 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0151310 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0948268 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0948268 infores:hetionet CHEBI:2659 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0002170 infores:hetionet CHEBI:36704 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0023380 infores:hetionet CHEBI:10125 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0016204 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0008325 infores:hetionet CHEBI:47898 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0438717 infores:hetionet CHEBI:7824 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0026826 infores:hetionet CHEBI:63632 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0014591 infores:hetionet CHEBI:10102 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0520966 infores:hetionet CHEBI:6472 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0031154 infores:hetionet CAID:CA2739267619 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267619 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.59-11T>G is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267619/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:9333 biolink:causes MONDO:0012345 infores:monarchinitiative not_provided not_provided HGNC:11781 MONDO:0012345 uuid:14e25ef1-1748-47c6-a8b0-d813eb91fef8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2077 biolink:causes MONDO:0014956 infores:monarchinitiative not_provided not_provided HGNC:3444 MONDO:0014956 uuid:314fac6f-3f00-4ee3-9904-1bb7c2cdb4e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5784 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0011603 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0423791 infores:hetionet CHEBI:9014 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0011991 infores:hetionet CHEBI:205919 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0263449 infores:hetionet CHEBI:45409 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1443060 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0149931 infores:hetionet CAID:CA410676953 biolink:causes MONDO:0009276 infores:clingen CAID:CA410676953 MONDO:0009276 PMID: Likely Pathogenic PP4_Moderate, PM5_Supporting, PP3, PM2_Supporting, PM3_Supporting NM_000407.5(GP1BB):c.268C>T is a missense variant (p.Pro90Ser), which has been reported in one homozygous proband with Bernard-Soulier syndrome. At least one patient (Patient BSS-8 in PMID:25539746) with this variant had aggregation absent for ristocetin and present for all other agonists, and flow cytometry revealed that the GPIbα and GPIX expression was severely reduced (<10% compared to controls), which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes is specific to GP1bb (PP4_moderate). Additionally, the patient had macrothrombocytopenia and excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome. The Grpmax filtering allele frequency in gnomaDv4.1 is 0.000004490 (based on 2/74000 alleles) in the South Asian population, which is below the <0.0000651678 threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.771, which is above the ClinGen PD VCEP PP3 threshold of >0.644 and predicts a damaging effect on GP1BB function (PP3). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome c.269C>G (p.Pro90Arg) (PMID:21699652), it is classified Likely Pathogenic by the PD-VCEP (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PP4_moderate, PM2_supporting, PM5_supporting, and PM3_supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410676953/MONDO:0009276/082 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:144093 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0521839 infores:hetionet CHEBI:45863 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0038325 infores:hetionet CHEBI:9674 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0001807 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0040034 infores:hetionet GO:2000733 biolink:causes GO:0060675 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0060675 CHEBI:3219 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0558368 infores:hetionet CHEBI:3181 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0278134 infores:hetionet CHEBI:6149 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0042510 infores:hetionet CHEBI:194135 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1260880 infores:hetionet CHEBI:31348 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2979982 infores:hetionet CHEBI:3215 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020672 infores:hetionet CAID:CA345144971 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144971 MONDO:0100084 PMID: Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PS2, PM5 PS3 The c.1001C>G variant in ACTA1 is a missense variant predicted to cause a substitution of proline by arginine at amino acid position 334. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.7 set by the CM VCEP (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual and as a de novo occurrence with unconfirmed parental relationships in one individual with alpha-actinopathy (PS4_Supporting, PS2; Invitae internal data; PMID: 19562689,). Another missense variant c.1000C>T, p.Pro334Ser (PMID: 15468086) in the same codon has been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP:PS2, PM5, PS4_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144971/MONDO:0100084/147 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:39867 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014591 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0040034 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0232203 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0232203 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0027765 infores:hetionet CHEBI:7915 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027424 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0031085 infores:hetionet CHEBI:83531 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0015672 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0854100 infores:hetionet CHEBI:50841 biolink:causes HP:0002362 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0231688 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0235169 infores:hetionet CAID:CA2580100794 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100794 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.19_25delinsGGAGCCCGTGGCATGAGGGAG (p.Leu7GlyfsTer?) is a frameshift variant due to a seven-nucleotide deletion combined with a twenty-one-nucleotide insertion that introduces a premature stop codon within exon 1 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been submitted to ClinVar (Accession: SCV002960906.3) but has not been reported in association with an affected proband. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100794/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Supports CHEBI:5441 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0001125 infores:hetionet CAID:CA120617 biolink:causes MONDO:0044970 infores:clingen CAID:CA120617 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Supporting PP1, BP4, PS2, PS4, PM6 The m.14846G>A (p.G34S) variant in MT-CYB has been reported in one individual with primary mitochondrial disease to date (PMID: 10502593), a 52-year-old woman with exercise intolerance since childhood who later developed myalgia and extreme muscle fatigue. The variant was present at 85% heteroplasmy in muscle and was undetectable in blood, myoblasts, and skin fibroblasts. The variant was absent in blood, myoblasts, and skin fibroblasts from her two children. There was not mention of testing in extended maternal family members. There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.73 (Min=0, Max=1; APOGEE2 score is 0.905), which predicts a damaging effect on gene function (PP3). Single fiber testing showed higher levels of the variant in ragged red fibers (91%) than in non-ragged red fibers (17%; PS3_supporting, PMID: 10502593). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120617/MONDO:0044970/015 2024-01-08 2024-11-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5118 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013428 infores:hetionet CHEBI:520985 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0017152 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002871 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0003864 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0232849 infores:hetionet CHEBI:5384 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0009676 infores:hetionet CHEBI:63624 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0877303 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085612 infores:hetionet CHEBI:42068 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0085624 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0017160 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0948594 infores:hetionet UMLS:C0657912 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013404 infores:hetionet CHEBI:134966 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0027947 infores:hetionet CHEBI:37924 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0043352 infores:hetionet CHEBI:7934 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01421 UMLS:C0011991 infores:hetionet CHEBI:5801 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0151786 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0002871 infores:hetionet CHEBI:4315 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0027424 infores:hetionet CHEBI:116278 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0026826 infores:hetionet CHEBI:3504 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0018524 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0032285 infores:hetionet NCBIGene:57697 biolink:causes MONDO:0054732 infores:monarchinitiative not_provided not_provided HGNC:23168 MONDO:0054732 uuid:532f5950-4795-460d-bfbb-44532fa13834 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA024603 biolink:causes MONDO:0007783 infores:clingen CAID:CA024603 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Valine with Methionine at codon 2168 of the RYR1 protein, p.(Val2168Met). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in over 25 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 25 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:11668625; PMID:30236257; PMID:20681998 and others). Functional studies in human myotubes from nine individuals (5 families) showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:15299003). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).This variant segregates with MHS eight individuals PP1_Strong (PMID:12434264, PMID:11575529). A REVEL score >0.85 (0.896)supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024603/MONDO:0007783/012 2022-03-29 2022-03-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63791 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009763 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011630 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0877153 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0853777 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0022660 infores:hetionet CHEBI:6715 biolink:causes DOID:9007 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0038644 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042571 infores:hetionet CHEBI:83804 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0035455 infores:hetionet CAID:CA9870495 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870495 MONDO:0015967 PMID: Benign BS2, BS1 PP3, PP4, PM5, PM1, BP4, PS4 The c.1177G>A in the HNF4A gene causes an amino acid change of glycine to arginine at codon 393 (p.Gly393Arg) of NM_15914.4. The nucleotide change c.1177G>C, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.1177G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0000751, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (internal lab contributor) (BS2). This variant has a REVEL score of 0.451, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on protein function. This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 and lack of clinical information (internal lab contributors). In summary, c.1177G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): BS1, BS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870495/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA147050 biolink:causes MONDO:0100084 infores:clingen CAID:CA147050 MONDO:0100084 PMID: Benign BP4, BA1, BP7 The NM_001100.4:c.809-35del variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The population filtering allele frequency in gnomAD v4.1.0 is 0.2723 (20520/74490 alleles with 2805 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The results from the in silico predictor, SpliceAI, suggest that the variant does not impact ACTA1 function and it occurs at a nucleotide that is not conserved as shown by the UCSC Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA147050/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5790 biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0344375 infores:hetionet CHEBI:63598 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020458 infores:hetionet CHEBI:9448 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0151907 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0853746 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0853746 infores:hetionet CHEBI:5775 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0011603 infores:hetionet NCBIGene:1892 biolink:causes MONDO:0014563 infores:monarchinitiative not_provided not_provided HGNC:3151 MONDO:0014563 uuid:84a57f3d-4630-42ad-9792-7c54f0f60489 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA116604 biolink:causes MONDO:0009290 infores:clingen CAID:CA116604 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PS3_Supporting PP3, PM5 The NM_000152.5:c.1585_1586delinsGT variant in GAA is predicted to cause substitution of serine by valine at amino acid 529 (p.Ser529Val). At least 5 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples or were noted to have deficient GAA activity but results were not provided(PMIDs: 11053688, 17805474, 21984055) (PP4_Moderate). Of those individuals, 2 were compound heterozygous for the variant and a pathogenic variant as classified by the ClinGen Lysosomal Diseases VCEP (PMIDs 17805474, 11053688). Three individuals were homozygous for the variant (PMIDs: 21984055, 11053688) (PM3_Strong). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). This variant results in 14.1% GAA activity when expressed in COS-1 cells by Tsunoda et al, 1996 (PMID 8834250), 10% GAA activity when expressed in SV40 immortalized fibroblasts (TR4912) by Tsujino S et al, 2000 (PMID 11053688), 9.0% wild-type activity in transiently transfected HEK293T cells by Shimada Y et al, 2014 (PMID 25256446), and 14% in transfected COS-7 cells by Flanagan et al, 2009 (PMID: 19862843) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 4026, 0 star review status). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116604/MONDO:0009290/010 2025-06-17 2025-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:240107 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023798 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0014130 infores:hetionet CHEBI:567361 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0333355 infores:hetionet CHEBI:63619 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0015967 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027609 infores:hetionet CHEBI:490877 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C1565489 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0948873 infores:hetionet CHEBI:4885 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0027813 infores:hetionet NCBITaxon:5722 biolink:causes MONDO:0005993 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5722 MONDO:0005993 CHEBI:40279 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020538 infores:hetionet CHEBI:100241 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0019209 infores:hetionet CHEBI:50859 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0033774 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0549239 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549239 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0424230 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0037274 infores:hetionet CHEBI:17303 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0039240 infores:hetionet CHEBI:10125 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235086 infores:hetionet CHEBI:3207 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0151692 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0149931 infores:hetionet CHEBI:27300 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0020438 infores:hetionet GO:1901028 biolink:causes GO:0097190 infores:ubergraph knowledge_assertion manual_agent GO:1901028 GO:0097190 CHEBI:8232 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0011991 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0040822 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0022650 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019158 infores:hetionet CHEBI:135351 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C1443060 infores:hetionet CHEBI:63598 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0311468 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0413252 infores:hetionet CHEBI:7494 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C1320474 infores:hetionet NCBIGene:6524 biolink:causes MONDO:0009297 infores:monarchinitiative not_provided not_provided HGNC:11037 MONDO:0009297 uuid:f9fde342-a5fe-4222-9d90-02ddcd470502 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042963 infores:hetionet CHEBI:94848 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C2830004 infores:hetionet CHEBI:5103 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0033774 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232498 infores:hetionet CHEBI:144093 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0013404 infores:hetionet CHEBI:6717 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1368065 infores:hetionet GO:1904242 biolink:causes GO:0007586 infores:ubergraph knowledge_assertion manual_agent GO:1904242 GO:0007586 UNII:UMD7G2653W biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0002994 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0017178 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0149931 infores:hetionet CHEBI:50922 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C3263723 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0853619 infores:hetionet CAID:CA267630 biolink:causes MONDO:0009861 infores:clingen CAID:CA267630 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 PM3, PP4 The c.1171A>G (p.Ser391Gly) variant in PAH has been reported in at least 1 individual with classic PKU (PMID: 26666653). However, the patient genotype included pathogenic variants c.194 T >C; p.Ile65Thr (ClinVar: 636), c.1169A >G; p.Glu390Gly (ClinVar: 625), and this variant c.1171A >G (p.Ser391Gly) with phasing not confirmed. This variant was absent in population databases (PM2). Computational prediction tools suggest that the c.1171A>G variant may impact the protein (PP3). The alternate missense changes of Ser391Ile (interpreted as Pathogenic by the ClinGen PAH Expert Panel) and Ser391Thr (ClinVar 225136, Likely Pathogenic) have been reported at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267630/MONDO:0009861/006 2020-04-10 2020-04-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA024266 biolink:causes MONDO:0007783 infores:clingen CAID:CA024266 MONDO:0007783 PMID: Uncertain Significance PM1_Supporting, PS4_Moderate, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with threonine at codon 4940 of the RYR1 protein, p.(Ala4940Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been identified in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:15731587, personal communication from VCEP laboratory). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.882) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024266/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:28830 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0013395 infores:hetionet CHEBI:7454 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0233477 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0037274 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0038454 infores:hetionet CHEBI:82960 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0016204 infores:hetionet NCBIGene:5795 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:9673 MONDO:0005575 uuid:4d776fb1-ddad-417d-a561-aa0ae105dd0a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020621 infores:hetionet CHEBI:7773 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0039231 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0019060 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005967 infores:hetionet CHEBI:135285 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0027441 infores:hetionet CHEBI:27899 biolink:causes HP:0032504 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0576702 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0020517 infores:hetionet CHEBI:131512 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0751295 infores:hetionet CHEBI:5384 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0162566 infores:hetionet CHEBI:2904 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0232462 infores:hetionet NCBIGene:2776 biolink:causes MONDO:0008094 infores:monarchinitiative not_provided not_provided HGNC:4390 MONDO:0008094 uuid:12a19957-46fc-46a5-8b38-ba3ab1b556a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060685 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0060685 GO:0061458 CHEBI:68579 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018799 infores:hetionet CHEBI:40303 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0035410 infores:hetionet CHEBI:119915 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0019521 infores:hetionet CHEBI:135961 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0028081 infores:hetionet CHEBI:17263 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0040046 infores:hetionet CHEBI:100241 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027497 infores:hetionet CHEBI:42068 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0004245 infores:hetionet CHEBI:3479 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0002792 infores:hetionet CHEBI:50122 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0012833 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151313 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0332575 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0003621 infores:hetionet CHEBI:9137 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151825 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002884 infores:hetionet CHEBI:68584 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0017178 infores:hetionet CAID:CA9870087 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870087 MONDO:0015967 PMID: Benign BA1 The c.50-4573A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within intron 1 of NM_175914.5. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.00014, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). In summary, c.50-4573A>C meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0 approved 10/11/2023): BA1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870087/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68478 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1258215 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0020542 infores:hetionet CHEBI:36791 biolink:causes MONDO:0019098 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0920163 infores:hetionet CHEBI:38562 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0231218 infores:hetionet CHEBI:44185 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0041364 infores:hetionet CHEBI:63638 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0015967 infores:hetionet CHEBI:75984 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0040034 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235344 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235344 infores:hetionet CAID:CA10644601 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644601 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS3, PS4, BP4, PVS1, PM6, PM2, BS3, BS4, BS1, BP7, PM5, PM1, PM4, PP3, PP1 The c.*4250C>T variant in the 3' UTR has an MAF of 0.002009 (0.2%, 31/15430 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644601/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5613 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0151818 infores:hetionet NCBIGene:91039 biolink:causes MONDO:0957229 infores:monarchinitiative not_provided not_provided HGNC:18648 MONDO:0957229 uuid:28bcdf39-8c7c-4e2c-83dc-3300478f4125 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915940648 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940648 MONDO:0100326 PMID: Pathogenic PM3, PM4, PP4_Moderate, PM2_Supporting, PS3 The NM_000212.3:c.1053_1058del (p.Ile351_Gly353delinsMet) variant in ITGB3 is predicted to cause a change in the length of the protein due to an in-frame substitution of Ile351, Pro352, and Gly353 by a Methionine in a non-repeat region (PM4). Surface expression of β3 measured by flow cytometry (FACS) in CHO cells transiently co-transfected with the c.1053_1058del (p.Ile351_Gly353delinsMet) variant β3 and wild type αII showed decreased expression at 0% (<5%) WT levels, indicating that this variant impacts protein function (PMID: 9226167; PS3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been detected in at least 4 probands with Glanzmann thrombasthenia (3 patients from PMID: 9226167, 1 patient from internal PD VCEP data). These individuals were all homozygous for the variant (PM3). At least one patient (Patient Z from internal PD VCEP data) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM4, PS3, PM2_Supporting, PP4_Moderate and PM3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940648/MONDO:0100326/011 2023-11-02 2023-11-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:119573 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0034882 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0014868 infores:hetionet CAID:CA170346 biolink:causes MONDO:0010726 infores:clingen CAID:CA170346 MONDO:0010726 PMID: Benign BS1, BP5_Strong, BS2 PM1, BP4 The allele frequency of the p.Gly206Ala variant in MECP2 (NM_004992.3) is 0.008% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly206Ala variant in MECP2 is observed in at least 2 unaffected individuals (PMID 17427193, internal database - GeneDx) (BS2). The p.Gly206Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). In summary, the p.Gly206Ala variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170346/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:28864 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C2363731 infores:hetionet CHEBI:408174 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0851578 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020538 infores:hetionet CAID:CA2801880 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801880 MONDO:0001586 PMID: Benign BA1 PS4, PM1, BS2 The NM_000203.5:c.346G>A variant in IDUA is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 116 (p.Gly116Arg). The Grpmax Filtering Allele Frequency (95% confidence) in gnomAD v4.1.0. is 0.008817 in the African / African American population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 712837). In summary, this variant meets the criteria to be classified as benign for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.: BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801880/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:5978 biolink:causes MONDO:0012902 infores:monarchinitiative not_provided not_provided HGNC:9966 MONDO:0012902 uuid:d8c7ba72-1fd0-4ae1-bf03-165217945ace biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0037299 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0034069 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0041969 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085628 infores:hetionet CHEBI:6775 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151662 infores:hetionet CHEBI:35854 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0023530 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0233494 infores:hetionet CHEBI:4798 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0037036 infores:hetionet CAID:CA205543 biolink:causes MONDO:0010278 infores:clingen CAID:CA205543 MONDO:0010278 PMID: Benign BA1 The allele frequency of the c.*12C>T variant in SLC9A6 is 0.05% in Admixed American sub population in gnomAD v4.0, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.*12C>T variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA205543/MONDO:0010278/033 2024-04-18 2024-07-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:50742 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0152198 infores:hetionet NCBIGene:51816 biolink:causes MONDO:0008436 infores:monarchinitiative not_provided not_provided HGNC:1839 MONDO:0008436 uuid:00f832df-6390-4560-9967-66b28f793108 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0043352 infores:hetionet CHEBI:180905 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0003862 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0267792 infores:hetionet NCBIGene:2778 biolink:causes MONDO:0054665 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0054665 uuid:7510f422-2dcc-4457-a312-70e245891265 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0700225 infores:hetionet CHEBI:3478 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C1384353 infores:hetionet GO:1905207 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905207 GO:0007275 CHEBI:9137 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C3665386 infores:hetionet CHEBI:6887 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0043094 infores:hetionet GO:2000074 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:2000074 GO:0060429 CAID:CA10585689 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585689 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, BP5, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1946C>T (p.Pro649Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: PopMax MAF = 8.475e-7 (0.00008475%) in European (non-Finnish) (gnomAD v4.1.0).PP3: REVEL = 0.777.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 index cases who fulfill Simon Broome criteria for FH, after alternative causes of high cholesterol were excluded (1 case from Day et al 1997, PMID 9259195; 1 case from Tosi et al 2007, PMID 17094996). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585689/MONDO:0007750/013 2024-10-28 2025-01-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7954 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0030848 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0020779 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0008449 infores:hetionet CHEBI:41977 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0015967 infores:hetionet CHEBI:135613 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C2047937 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0042571 infores:hetionet CHEBI:36791 biolink:causes UMLS:C3203531 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C3203531 infores:hetionet CHEBI:5778 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013428 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0518015 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0038363 infores:hetionet CHEBI:6847 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0020456 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013298 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0003123 infores:hetionet CHEBI:31625 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0015403 infores:hetionet CAID:CA017055 biolink:causes MONDO:0004994 infores:clingen CAID:CA017055 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.975C>T (p.Asp325=) variant in the MYH7 gene is 2.82% (1920/65662) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA017055/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9137 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0030196 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001956 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0343084 infores:hetionet CHEBI:63630 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1458155 infores:hetionet CHEBI:92712 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0855775 infores:hetionet CHEBI:49040 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0015672 infores:hetionet CHEBI:6804 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0008031 infores:hetionet CAID:CA026350 biolink:causes MONDO:0012933 infores:clingen CAID:CA026350 MONDO:0012933 PMID:29988080 Benign BP5_Strong, BS3, BA1 PVS1, BS2, PS4 The c.9976A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Lysine at amino acid 3326 (p.Lys3326Ter). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18451181, Internal lab contributor).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BS3, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA026350/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6904 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0600142 infores:hetionet CHEBI:10650 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085636 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0019112 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042075 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0011603 infores:hetionet CHEBI:63612 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0522224 infores:hetionet CHEBI:83531 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0003467 infores:hetionet CHEBI:44032 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0344232 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0009806 infores:hetionet CHEBI:5118 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0023518 infores:hetionet CHEBI:75984 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0040264 infores:hetionet CHEBI:51041 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018965 infores:hetionet CHEBI:145499 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004245 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0006840 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0243026 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0919980 infores:hetionet CHEBI:7809 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0003862 infores:hetionet CHEBI:2675 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0021141 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0037274 infores:hetionet NCBIGene:537 biolink:causes MONDO:0010504 infores:monarchinitiative not_provided not_provided HGNC:868 MONDO:0010504 uuid:f8a2a33f-41dc-47f6-adc1-35cf3da1bea6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042267 infores:hetionet NCBIGene:9455 biolink:causes MONDO:0014740 infores:monarchinitiative not_provided not_provided HGNC:17513 MONDO:0014740 uuid:3c6fc87b-6dde-4539-a97c-d00d8febaaea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA023598 biolink:causes MONDO:0007750 infores:clingen CAID:CA023598 MONDO:0007750 PMID: Uncertain Significance PP1 BA1, BP3, BP2, BP1, BP4, PS4, PS3, PS1, PS2, BP5, BP7, BS1, BS4, BS3, PM5, PM1, PM4, PM3, PM2, PM6, PVS1, BS2, PP4, PP2, PP3 The NM_000527.5(LDLR):c.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023598/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8764 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009763 infores:hetionet UMLS:C1872203 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0018681 infores:hetionet UNII:3U02EL437C biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0013378 infores:hetionet CHEBI:63580 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2363730 infores:hetionet CAID:CA7542781 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542781 MONDO:0012996 PMID: Uncertain Significance BP4 BS1, PM2 The NM_001482.3:c.1159+14A>G variant in GATM is an intronic variant in intron 8. The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000085 (11/128906 alleles) in the non-Finnish European population (none of the population data codes are met). To our knowledge, this variant has not been reported in individuals with AGAT deficiency and the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 316210). In summary, this variant meets the criteria to be classified as uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542781/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:141474 biolink:causes UMLS:C0006435 infores:sider not_provided not_provided DRUGBANK:DB00772 UMLS:C0006435 infores:hetionet CHEBI:132233 biolink:causes MONDO:0002420 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0040188 infores:hetionet CHEBI:8768 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0428977 infores:hetionet CHEBI:8461 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0040034 infores:hetionet CHEBI:64321 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0002792 infores:hetionet CAID:CA512318859 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318859 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.282C>T (p.Ser94=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318859/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:1902738 biolink:causes GO:0060351 infores:ubergraph knowledge_assertion manual_agent GO:1902738 GO:0060351 NCBIGene:138050 biolink:causes MONDO:0014687 infores:monarchinitiative not_provided not_provided HGNC:26527 MONDO:0014687 uuid:32e91d1b-733d-4a8c-91b5-22d7a645ec9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020458 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0003834 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C1971624 infores:hetionet CHEBI:6931 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233407 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0521591 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0233528 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0233528 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0518015 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0039503 infores:hetionet CHEBI:51173 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C2830004 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0039231 infores:hetionet CHEBI:38940 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0019065 infores:hetionet CHEBI:3176 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C3665386 infores:hetionet CHEBI:2453 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C2830004 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0267792 infores:hetionet CHEBI:94411 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0020517 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0040034 infores:hetionet CHEBI:8888 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0025345 infores:hetionet CAID:CA8603562 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603562 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, BP4 BS1, PM3, PM2, BP2 The c.10G>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 4. At least one patient (Proband 1 in PMID:18788610) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.001292 58/44900 alleles in the East Asian population, which is below than the ClinGen PD VCEP threshold (>0.00158) for BS1 but above the <0.0001 threshold for PM2_supporting. Furthermore, the computational predictor REVEL gives a score of 0.232, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). In summary, this variant meets the criteria to be classified as Uncertain significance - conflicting evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_moderate, BP4 (VCEP specifications version 2; date of approval 06/06/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603562/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:15854 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0026961 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0858678 infores:hetionet CHEBI:5558 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0034150 infores:hetionet GO:0106088 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0001944 CHEBI:194135 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0600142 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0039446 infores:hetionet CHEBI:3207 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0043144 infores:hetionet NCBIGene:6513 biolink:causes MONDO:0010983 infores:monarchinitiative not_provided not_provided HGNC:11005 MONDO:0010983 uuid:a06dc5c5-f93a-499e-b286-19cc81b5d23f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0033575 infores:hetionet CHEBI:45599 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0003811 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0278008 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013922 infores:hetionet CHEBI:101278 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0232462 infores:hetionet CHEBI:71255 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0232487 infores:hetionet CHEBI:6129 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0428977 infores:hetionet NCBIGene:55775 biolink:causes MONDO:0011801 infores:monarchinitiative not_provided not_provided HGNC:18884 MONDO:0011801 uuid:b2dc5401-ef71-4a43-a442-5ace99e5b19b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C1112320 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020456 infores:hetionet NCBITaxon:286 biolink:causes MONDO:0005141 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:286 MONDO:0005141 CHEBI:7915 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019112 infores:hetionet CHEBI:9123 biolink:causes HP:0003537 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0221333 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0456909 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234987 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0877517 infores:hetionet CHEBI:50648 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0026766 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0392167 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0392167 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0033246 infores:hetionet CHEBI:8214 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0264886 infores:hetionet CHEBI:8107 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0235896 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020557 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0080194 infores:hetionet CHEBI:75722 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235086 infores:hetionet CHEBI:171719 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C3203358 infores:hetionet CHEBI:9241 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0033774 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0948594 infores:hetionet CHEBI:5132 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0002871 infores:hetionet CHEBI:5775 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0497156 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004596 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034072 infores:hetionet CAID:CA226797 biolink:causes MONDO:0010725 infores:clingen CAID:CA226797 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP4_Moderate, PP3_Strong, PP1 The NM_000330.4(RS1):c.589C>T variant is a missense variant encoding the substitution of Arginine with Cystine at amino acid 197. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.99, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through at least 1 meiosis in two unrelated families, each consisting of 2 brothers (PP1; PMID: 29739629, 36377647). Only one family can be counted. At least one 4-year-old proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years and showing detachment, and showing retinal detachment, which together are highly specific for X-linked retinoschisis (PP4_Moderate). This variant has been reported in at least 4 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 34645606, 29739629, 30652005, 34624300, PS4_Moderate). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_strong, PP1, PP4_moderate, and PS4_moderate (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226797/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:49575 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1443060 infores:hetionet CHEBI:52172 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0012569 infores:hetionet CHEBI:6076 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0340865 infores:hetionet CHEBI:74947 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151907 infores:hetionet CAID:CA163797 biolink:causes MONDO:0007648 infores:clingen CAID:CA163797 MONDO:0007648 PMID:19268661PMID:22850631PMID:15173255PMID:19268661PMID:22850631PMID:15173255 Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP3, PP2, PP1, PP4, BS2, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2396C>G (p.Pro799Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA163797/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA16028087 biolink:causes MONDO:0021056 infores:clingen CAID:CA16028087 MONDO:0021056 PMID: Uncertain Significance PS1_Moderate, PM5_Supporting, PM2_Supporting PS4 The c.3084T>G variant in APC is a missense variant predicted to cause the substitution of serine by arginine at codon 1028 (p.Ser1028Arg). Another missense variant c.3084T>A (p.Ser1028Arg) at the same nucleotide position leading to the same amino acid change has been classified as Likely Pathogenic for FAP according to the APC VCEP specifications (PS1_Moderate). Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon leading to a different amino acid change has been classified as Likely Pathogenic for FAP according to the APC VCEP specifications (PM5_Supporting). This variant was identified in 1 proband with polyposis not meeting phenotype criteria (PS4_variable not met; Invitae internal data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In Summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS1_Moderate, PM2_Supporting, PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16028087/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31348 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1112320 infores:hetionet CHEBI:6062 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0016204 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0522245 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0522245 infores:hetionet CHEBI:48844 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0151763 infores:hetionet NCBIGene:57539 biolink:causes MONDO:0013323 infores:monarchinitiative not_provided not_provided HGNC:29250 MONDO:0013323 uuid:37aa1d11-4cba-4343-8cdd-ec89d11ad941 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:421707 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C1971624 infores:hetionet CHEBI:132233 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0085633 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0851341 infores:hetionet CHEBI:171719 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0041948 infores:hetionet CHEBI:9073 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0428977 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0860901 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0860901 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0031350 infores:hetionet CHEBI:2955 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011175 infores:hetionet CHEBI:41879 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0040038 infores:hetionet CHEBI:4814 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0030252 infores:hetionet CHEBI:71219 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0018926 infores:hetionet GO:0051145 biolink:causes CL:0000192 infores:ubergraph knowledge_assertion manual_agent GO:0051145 CL:0000192 CHEBI:5138 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0030193 infores:hetionet CHEBI:9086 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011206 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0027765 infores:hetionet CHEBI:8805 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0235996 infores:hetionet CHEBI:4708 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0000737 infores:hetionet CAID:CA226112 biolink:causes MONDO:0100453 infores:clingen CAID:CA226112 MONDO:0100453 PMID: Likely Pathogenic PM1, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting PM3 NM_000180.4(GUCY2D):c.2983C>T (p.Arg995Trp) is a missense variant that replaces arginine with tryptophan at position p.995, which is located within the active site, a well-characterized functional domain required that binds the GTP substrate and the Mg ion and is required for enzymatic activity (PM1, PMID: 9391039). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000004342, with 7 alleles / 1,612,258 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with either the NM_000180.4:c.2765A>G (p.Tyr922Cys) variant confirmed in trans (PMID: 29844330) or the NM_000180.4(GUCY2D):c.387C>A (p.Asn129Lys) variant suspected in trans (PMID: 10951519). However, the probands were not counted for PM3 to avoid circularity. At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts) with onset at birth (1 pt), inability to follow light or objects, nystagmus (1 pt), normal fundus at birth, RPE mottling (0.5 pts), non-recordable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), severe hyperopia and severe photophobia (1 pt), non-recordable visual field (1 pt) and congenital blindness (1 pt), which together are specific for GUCY2D-related recessive retinopathy (total 7.5 points, PMID: 10951519, PP4). The computational predictor REVEL gives a score of 0.842 which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.02 for splice acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The mutant protein showed significantly compromised binding to RD3 relative to the wild-type control when exogenously expressed in HEK293 cells and analyzed by co-immunoprecipitation and western blotting (PMID: 25477517). The variant also exhibited 0% enzymatic activity in a guanylate cyclase activity assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 11328726, PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM1, PM2_Supporting, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226112/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9599 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0042401 infores:hetionet GO:0048333 biolink:causes CL:0000222 infores:ubergraph knowledge_assertion manual_agent GO:0048333 CL:0000222 CHEBI:2659 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0151799 infores:hetionet CHEBI:27882 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0004093 infores:hetionet CHEBI:36704 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0039070 infores:hetionet CHEBI:63624 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0017178 infores:hetionet NCBIGene:5978 biolink:causes MONDO:0033493 infores:monarchinitiative not_provided not_provided HGNC:9966 MONDO:0033493 uuid:43193dcd-9064-4258-9e20-8ec2e3bfeb77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0947912 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C1720775 infores:hetionet CHEBI:63605 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0220981 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020456 infores:hetionet CHEBI:3723 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011206 infores:hetionet GO:0075054 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0075054 GO:0048856 CHEBI:6715 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042345 infores:hetionet CHEBI:42068 biolink:causes NCIT:C112180 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0239343 infores:hetionet CAID:CA409108070 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108070 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5, PS4, PP1_Strong PM1, BP4 The c.868C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 290 (p.(Arg290Cys)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.92, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 32533152, 21683639, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and a family member with the variant with diazoxide-responsive neonatal hyperinsulinemic hypoglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 20 informative meioses in 8 families (PP1_Strong; internal lab contributors). Another missense variant, c.869G>A p.Arg290His, has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg290Cys has a greater Grantham distance (PM5). In summary, c.868C>T meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PM5, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108070/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:5966 biolink:causes MONDO:0030498 infores:monarchinitiative not_provided not_provided HGNC:9954 MONDO:0030498 uuid:7ff0e702-1bca-49a8-bf58-8bf374608949 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA024221 biolink:causes MONDO:0018493 infores:clingen CAID:CA024221 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 4893 of the RYR1 protein, p.(Arg4893Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds) MH Investigational Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024221/MONDO:0018493/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45951 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0857305 infores:hetionet CAID:CA16020834 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020834 MONDO:0009861 PMID:17096675PMID:18346471PMID:18346471PMID:21820508PMID:18346471 Uncertain Significance PM2, PP3, PP4, PM3_Supporting PM5, PS3 This c.667A>T (p.Asn223Tyr) variant in PAH was reported with pathogenic variant c.165delT in a patient with PAH deficiency (242 μmol/L Phe) (PMID 18346471). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020834/MONDO:0009861/006 2021-01-15 2022-04-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3380 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0151786 infores:hetionet CHEBI:7025 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0043352 infores:hetionet NCBIGene:9325 biolink:causes MONDO:0014806 infores:monarchinitiative not_provided not_provided HGNC:12310 MONDO:0014806 uuid:21f7fe3c-fb38-431f-a708-97b4083f55df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8080 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0015230 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0025061 infores:hetionet CHEBI:8356 biolink:causes HP:0003468 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0158775 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0042514 infores:hetionet CHEBI:78543 biolink:causes UMLS:C1096458 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1096458 infores:hetionet CHEBI:7476 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1142412 infores:hetionet CHEBI:7983 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0233494 infores:hetionet CHEBI:63635 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0002792 infores:hetionet CAID:CA396457187 biolink:causes MONDO:0100488 infores:clingen CAID:CA396457187 MONDO:0100488 PMID: Likely Benign BS2 BP7, BS1, PM1, PM3, PM2, PVS1, PP2, PP3, PP4, BP1, BP4, BP3, BA1, PS1 The NM_004360.5(CDH1):c.221G>A (p.Arg74Gln) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023). CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396457187/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:171719 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011206 infores:hetionet CAID:CA512318705 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318705 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.633T>C (p.Asp211=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.56)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318705/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50742 biolink:causes MONDO:0004139 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0085577 infores:hetionet CAID:CA1037870609 biolink:causes MONDO:0018958 infores:clingen CAID:CA1037870609 MONDO:0018958 PMID: Uncertain Significance PM2_Supporting The variant NM_001164508.2:c.12639+2dup in NEB is a duplication variant. The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has not been noted in any probands in the literature or in ClinVar. In summary, this variant meets the criteria to be classified as uncertain significance for AR nemaline myopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP: PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1037870609/MONDO:0018958/146 2025-01-13 2025-03-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:77260 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042109 infores:hetionet CHEBI:724125 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0041582 infores:hetionet CHEBI:60761 biolink:causes UMLS:C0849913 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0849913 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0020517 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0347390 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C2830004 infores:hetionet CHEBI:31236 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085641 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0019158 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0041912 infores:hetionet CHEBI:6887 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0030554 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042514 infores:hetionet CAID:CA16029995 biolink:causes MONDO:0021056 infores:clingen CAID:CA16029995 MONDO:0021056 PMID: Uncertain Significance BP1, PM2_Supporting The NM_000038.6(APC):c.3950A>G variant in APC is a missense variant predicted to cause substitution of Glutamine by Glycine at amino acid 1317 (p.Glu1317Gly). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The results from multiple in silico splicing predictors support that this variant does not affect splicing. In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PM2_Supporting and BP1 applied (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16029995/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:5631 biolink:causes MONDO:0010533 infores:monarchinitiative not_provided not_provided HGNC:9462 MONDO:0010533 uuid:ea6480e1-1f43-4704-9b9f-0ab3bdacc5cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018965 infores:hetionet CHEBI:44915 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0006266 infores:hetionet NCBIGene:3745 biolink:causes MONDO:0014477 infores:monarchinitiative not_provided not_provided HGNC:6231 MONDO:0014477 uuid:075b139d-f98a-4aa0-8e35-6b1d3e020099 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034886 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151479 infores:hetionet CHEBI:6367 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013384 infores:hetionet CAID:CA658795250 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795250 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3, PM4_Supporting PP3, PS3 The NM_000152.5: c.1320_1322delGAT variant is predicted to cause a change in the length of protein due to an in-frame deletion of one amino acid Met440 in a non-repeat region (PM4_Supporting). This variant has been detected in at least 3 individuals with Pompe disease. All of them were compound heterozygous for the variant and a pathogenic variant (2 cases with c.2238G>C p.Trp746Cys PMIDs: 25526786, 35071497; 1 case with c.2560C>T p.Arg854Ter PMID 28394184. 1.5 total points), meeting PM3. At least 2 patients with this variant had been reported as LOPD, one with documented GAA deficiency with <10% of normal mean control level of GAA activity (PMID: 35071497), one with muscle weakness and need ventilator support (PMID: 25526786), and another patient with this variant had been reported as IOPD (PMID: 28394184) (PP4_moderate). The variant is absent in gnomAD v4.1.0 (PM2_supporting). There is a ClinVar entry for this variant (Variant ID: 526518). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0). Criteria applied: PM2_supporting; PM3, PM4_supporting, PP4_moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 8, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795250/MONDO:0009290/010 2025-10-08 2025-10-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA392336264 biolink:causes MONDO:0007947 infores:clingen CAID:CA392336264 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PP1, PM2_Supporting, PS4, PM1_Strong PM6, PVS1, BS2, BA1, BP1, BP4, BP2, BP3, PS3, PS2, PS1, PM3, PM4, PM5, BS1, BS4, BS3, BP7, BP5 NM_000138.5 c.6419G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2164 (p.Cys2164Tyr). This variant has been identified in at least four individuals meeting clinical diagnostic criteria for Marfan syndrome (MFS) and two individuals with non-specific features suggestive of a connective tissue disorder (PS4, PP4; Bichat & UZG internal data; PMIDs: 31730815, 37558401, 29095814). In one of these individuals, it was found to be de novo; however, phenotype details were not provided and therefore the specificity and consistency of the phenotype with FBN1 cannot be assessed (PMID: 29095814). In another of these families, the variant was found to segregate with disease in two affected family members (PP1; Bichat internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.863). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4, PP1, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392336264/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ UMLS:C0657912 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027441 infores:hetionet CHEBI:6792 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0041657 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0003123 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0948525 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0034359 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0038661 infores:hetionet CHEBI:3761 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C2830004 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151740 infores:hetionet CHEBI:119915 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009676 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0033975 infores:hetionet CHEBI:48273 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0036974 infores:hetionet CHEBI:15551 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0010200 infores:hetionet NCBIGene:593 biolink:causes MONDO:0023691 infores:monarchinitiative not_provided not_provided HGNC:986 MONDO:0023691 uuid:bdfe17ed-9e18-4800-9b97-c4380b7c2f39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0267158 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0267158 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020517 infores:hetionet CHEBI:520985 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0030554 infores:hetionet CHEBI:63610 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0014591 infores:hetionet CHEBI:8356 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0340279 infores:hetionet CHEBI:92998 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0030554 infores:hetionet CHEBI:35854 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0151766 infores:hetionet CHEBI:6062 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0232461 infores:hetionet CHEBI:47381 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C3665347 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0162429 infores:hetionet CHEBI:28177 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0016382 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020615 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1306341 infores:hetionet CHEBI:240107 biolink:causes UMLS:C1142151 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C1142151 infores:hetionet CHEBI:3219 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020443 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042267 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235146 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0013378 infores:hetionet CHEBI:8364 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0232487 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0036572 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0521854 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0521854 infores:hetionet CHEBI:9727 biolink:causes HP:0012047 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0018975 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0007760 infores:hetionet CHEBI:41774 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0018681 infores:hetionet CHEBI:8382 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0232462 infores:hetionet CAID:CA386965452 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965452 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3 The c.710A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to threonine at codon 237 (p.(Asn237Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.888, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.709A>G (p.Asn237Asp), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.710A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965452/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63681 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0009421 infores:hetionet CHEBI:8863 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0232726 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0036572 infores:hetionet CHEBI:7820 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0235431 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0028077 infores:hetionet CAID:CA347224046 biolink:causes MONDO:0015152 infores:clingen CAID:CA347224046 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_003494.4: c.3618C>G p.(Tyr1206Ter) variant in DYSF, which is also known as NM_001130987.2: c.3672C>G p.(Tyr1224Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 33/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two individuals with features of LGMD, including in a homozygous state without reported familial consanguinity in one patient (0.5 pts, PMID: 30564623, LOVD Individual #00219431) and in unknown phase or confirmed in trans with a second presumed diagnostic DYSF variant in at least one patient (NM_003494.4: c.4439A>C p.(Lys1480Thr), PMID: 15827562, 30919934, LOVD Individual #00215274) (PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness (PMID: 30919934; PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/28/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347224046/MONDO:0015152/180 2025-05-28 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6149 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0001122 infores:hetionet CHEBI:2549 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0006266 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019158 infores:hetionet CHEBI:28177 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0020437 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0267596 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0877322 infores:hetionet NCBIGene:6929 biolink:causes MONDO:0014840 infores:monarchinitiative not_provided not_provided HGNC:11633 MONDO:0014840 uuid:82195e9b-c0c6-4fdc-b6a1-017e0d29048f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1527344 infores:hetionet CHEBI:75984 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0917801 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011570 infores:hetionet CAID:CA397723428 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723428 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.668C>G ( p.Ser223Ter)(NM_000018.4) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Suporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723428/MONDO:0008723/021 2023-09-26 2023-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:65349 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0030252 infores:hetionet CHEBI:63599 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0085681 infores:hetionet CAID:CA000456 biolink:causes MONDO:0018875 infores:clingen CAID:CA000456 MONDO:0018875 PMID: Uncertain Significance PP3_Moderate, PM1, BS3, BS2, PM2_Supporting BA1, BP4, BP2, BP3, PS3, PS4, PS2, PM5, PM3, PM4, BP5, BP7, BS1, BS4, PM6, PVS1, PP1, PP4 The NM_000546.6: c.845G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 282 (p.Arg282Leu). This variant has an allele frequency of 0.000003098 (5/1613954 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMIDs: 28975465, 34906214). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.3605; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). In summary this variant meets the criteria to be classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS2_Moderate, PP3_Moderate, PM1, BS3. (Bayesian Points: -1; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000456/MONDO:0018875/009 2025-04-03 2025-06-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:84500 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233632 infores:hetionet CHEBI:64312 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019294 infores:hetionet CHEBI:8382 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0041657 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0178421 infores:hetionet CHEBI:3437 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0009763 infores:hetionet CHEBI:94848 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0011609 infores:hetionet CHEBI:3752 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0030252 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0178421 infores:hetionet CHEBI:16796 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0917801 infores:hetionet CAID:CA182711 biolink:causes MONDO:0019497 infores:clingen CAID:CA182711 MONDO:0019497 PMID: Benign BA1 The filtering allele frequency of the c.1436C>T (p.Pro479Leu) variant in the TECTA gene is 0.63% (219/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA182711/MONDO:0019497/005 2018-09-17 2019-07-17 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:2549 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0019825 infores:hetionet CHEBI:194135 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004144 infores:hetionet CHEBI:18358 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0019348 infores:hetionet CHEBI:28593 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0041657 infores:hetionet CHEBI:47499 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C1368065 infores:hetionet CHEBI:31536 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0221201 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0029408 infores:hetionet CHEBI:8232 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0027497 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004936 infores:hetionet CHEBI:71219 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0235378 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0543698 infores:hetionet CAID:CA8815324 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815324 MONDO:0009290 PMID: Uncertain Significance BP4 PM2, PP3, BS1 The NM_000152.5:c c.1437+19G>A variant in GAA is an intronic variant located in intron 9 of the GAA gene. The computational splicing predictor SpliceAI gives a score of 0 for donor site loss, suggesting that the variant has no impact on splicing (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.002488 (15/6028 alleles) in the Middle Eastern population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), but lower than the threshold for BS1 (<0.005) and therefore does not meet either of these criteria.There is a ClinVar entry for this variant (Variation ID: 515407). In summary, this variant meets the criteria to be classified as uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815324/MONDO:0009290/010 2024-08-06 2024-09-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:9086 biolink:causes UMLS:C0859371 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0859371 infores:hetionet CHEBI:6062 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0017979 infores:hetionet CHEBI:231425 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0002792 infores:hetionet CHEBI:40279 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020433 infores:hetionet CHEBI:10023 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0021051 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0080194 infores:hetionet CHEBI:10650 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0220870 infores:hetionet UMLS:C0004609 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0030554 infores:hetionet CHEBI:10119 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0080274 infores:hetionet CHEBI:31348 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0080274 infores:hetionet NCBIGene:23316 biolink:causes MONDO:0029138 infores:monarchinitiative not_provided not_provided HGNC:19347 MONDO:0029138 uuid:cfc756ff-c35e-4384-aafc-c894bdbb51d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017574 infores:hetionet CHEBI:10650 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0392525 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0243026 infores:hetionet CHEBI:2618 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0013384 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0241742 infores:hetionet CAID:CA356987 biolink:causes MONDO:0001586 infores:clingen CAID:CA356987 MONDO:0001586 PMID:12189649 Likely Pathogenic PM3, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting PM1, PM5 The NM_000203.5(IDUA):c.236C>T variant in IDUA is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 79(p.Ala79Val). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, urinary GAGs elevation above normal range, and clinical features specific to MPS I including hepatosplenomegaly, arthropathy, and corneal involvement (PP4). This variant has been detected in at least 11 individuals with MPS I. Of those individuals, 2were compound heterozygous, phase not confirmed, for the variant and a variant in IDUA that has been classified as likely pathogenic by the ClinGen LD VCEP (variants: c.1882C>T (p.Arg628Ter) (ClinVar Variation ID: 550421), and c.1402+1G>T) (ClinVar Variation ID: 1323099) (2 x 0.25 points = 0.5 points). Another six individuals are compound heterozygous for the variant and a variant in IDUA, either c.536C>G (p.Thr179Arg) (ClinVar Variation ID: 556358), c.589G>A ((p.Val197Ile) (ClinVar Variation ID: 2720835), c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), c.1877G>A (p.Trp626Ter) (ClinVar Variation ID: 928997), or c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927) (PMIDs: 27520059, 21480867). The allelic data from these individuals will be used in the assessment of the second variant. Three individuals were homozygous for the variant (1 point; PMID: 21480867) (PM3). Total 1.5 points (PM3) This variant is absent in gnomAD v4.1.0 (PM2_Supporting). Expression of the variant in CHO-cells resulted in less than 0.1% wild type IDUA activity indicating that this variant may impact protein function (PMID:15300847)(PS3_Supporting). The computational predictor REVEL gives a score of 0.738 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (Pejaver et al.) (PP3). Another missense variant c.235G>A (p.Ala79Thr) in the same codon has not yet been reported in a patient with MPS I. Additionally, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 1458769). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PP4, PM3, PM2_Supporting, PS3_Supporting, PP3(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA356987/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64354 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0013144 infores:hetionet CHEBI:9130 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0035078 infores:hetionet CAID:CA120568 biolink:causes MONDO:0044970 infores:clingen CAID:CA120568 MONDO:0044970 PMID:11723298 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting The m.3274A>G in MT-TL1 has been reported in one individual to date, in a man with a progressive neuropsychiatric disorder and multisystem organ involvement. At 12 years old, he had a decline in school performance. By his late 20s, he experienced acute psychotic symptoms and depression. He also had bilateral hearing loss, gait instability, and bilateral dysdiadokinesis. By his early 30s, he had cataracts, retinal degeneration, muscle weakness, ataxic gait, dysarthria, intention tremor, and dysmetria. Brain MRIs showed progressive cerebral and cerebellar atrophy and T2 hyperintense lesions in the basal ganglia. He had elevated blood and cerebrospinal fluid lactate. Muscle biopsy showed increased central nuclei and ragged red fibers, with reduced complex I activity (53% of lowest norm). The variant was present at 25% in muscle and undetectable in blood (PMID: 11723298). The variant was absent in blood from three healthy maternal family members, but this cannot be considered evidence of de novo status as the variant was also absent in the proband’s blood. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in ragged red fibers (55 ± 26.1%; N=22; mutant mtDNA found in every fiber) than in normal fibers (14 ± 25.7%; N=16; mutant mtDNA found in 7/16 fibers), p<0.001 (PS3_supporting, PMID: 11723298). The computational predictor MitoTIP suggests this variant is pathogenic (77.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120568/MONDO:0044970/015 2024-04-23 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:16469 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0026858 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0015230 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233494 infores:hetionet CAID:CA4239564 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239564 MONDO:0015967 PMID: Benign BS1, BS2, PP2, BP2 PS3, PS4 The c.649G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 217 (p.(Asp217Asn)) of [transcript, e.g. NM_000545.8]. NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00005377, which is greater than the MDEP threshold for BS1 (≥0.0.00004) (BS1). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). Additionally, this variant was identified in an individual with a normal fasting glucose (BS2) (internal lab contributor). This variant has been observed in cis with the variant GCK c.781G>A (p.Gly261Arg) (PMID:22611063), which is classified as pathogenic by the ClinGen MDEP (BP2). Lastly, functional studies suggest that the p.Asp217Asn protein has increased activity (RAI=2.0); however, the thermostability and protein interactions were not analyzed and therefore neither PS3 or BS3 can be applied (PMID 22611063). In summary, c.649G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS1, BS2, BP2, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239564/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Contradicts true CHEBI:17263 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0497247 infores:hetionet CHEBI:7445 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0014591 infores:hetionet CAID:CA000168 biolink:causes MONDO:0018875 infores:clingen CAID:CA000168 MONDO:0018875 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PS4_Supporting BA1, BP1, BP4, BP3, BP2, PS2, PM4, PM1, PM3, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PP2, PP1, BS2 The NM_000546.6: c.413C>T variant in TP53 is a missense variant predicted to cause substitution of alanine by valine at amino acid 138 (p.Ala138Val). This variant has been reported in one proband/family meeting Classic criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 22507745). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors).This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Another missense variant (c.412G>C (p.Ala138Pro)) (ClinVar Variation ID: 12376), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). Computational predictor scores (BayesDel = 0.5174; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3_moderate, PP3, PM2_supporting, PS4_supporting, PP4_moderate, PM5_supporting. (Bayesian Points: 8; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000168/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:283677 biolink:causes MONDO:0030925 infores:monarchinitiative not_provided not_provided HGNC:25065 MONDO:0030925 uuid:c31c9019-f73a-45a6-b794-d68b66770427 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151905 infores:hetionet CHEBI:83531 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0027497 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0027051 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042075 infores:hetionet CHEBI:51380 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C2830004 infores:hetionet CHEBI:63599 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0027497 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011991 infores:hetionet CHEBI:9086 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C2047937 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853958 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853958 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026857 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0017574 infores:hetionet CHEBI:9667 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0019209 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0878544 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0004623 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0013595 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085637 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0027765 infores:hetionet CHEBI:9086 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004604 infores:hetionet CHEBI:9927 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0018681 infores:hetionet CHEBI:6437 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0004604 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0232492 infores:hetionet CHEBI:68534 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C1384353 infores:hetionet UMLS:C0010592 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085631 infores:hetionet CHEBI:28487 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0027769 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0003123 infores:hetionet NCBIGene:2629 biolink:causes MONDO:0009268 infores:monarchinitiative not_provided not_provided HGNC:4177 MONDO:0009268 uuid:bbab0428-8e21-4cbe-b77c-17e46c7ada17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410206743 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206743 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.763C>A (p.His255Asn) is a missense variant which has a REVEL score <0.50 (0.38) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206743/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:11431811 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0030196 infores:hetionet CHEBI:31236 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0041834 infores:hetionet CHEBI:77260 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017979 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0037822 infores:hetionet CHEBI:8107 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0031256 infores:hetionet CHEBI:31401 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0855333 infores:hetionet CHEBI:63624 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C1260880 infores:hetionet CHEBI:45863 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0003467 infores:hetionet CHEBI:63607 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0033774 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042373 infores:hetionet CHEBI:16755 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0011168 infores:hetionet CHEBI:5127 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0011603 infores:hetionet CHEBI:4657 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0232462 infores:hetionet CHEBI:9398 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0011124 infores:hetionet CHEBI:75722 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0038435 infores:hetionet CHEBI:10119 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151766 infores:hetionet CHEBI:74947 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023467 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0151479 infores:hetionet CHEBI:31711 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0036974 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009782 infores:hetionet CHEBI:9123 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015732 infores:hetionet CHEBI:135888 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C2363731 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0029442 infores:hetionet CHEBI:17026 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0235660 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235818 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151828 infores:hetionet CHEBI:9139 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0015402 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0031350 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0025061 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0233571 infores:hetionet CHEBI:3423 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0023530 infores:hetionet CHEBI:31174 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0085624 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0037274 infores:hetionet CHEBI:8774 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0700590 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0847631 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0847631 infores:hetionet CHEBI:75246 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0700590 infores:hetionet CHEBI:261649 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0232493 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0151505 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0020757 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027813 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0023067 infores:hetionet CHEBI:119915 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0542571 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0243026 infores:hetionet CHEBI:5855 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0028961 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0025061 infores:hetionet NCBIGene:3630 biolink:causes MONDO:0014535 infores:monarchinitiative not_provided not_provided HGNC:6081 MONDO:0014535 uuid:8e1d9c08-fcf0-40ce-b4a7-4768b62e4982 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3698 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C3665347 infores:hetionet CHEBI:3219 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0236075 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0549356 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0264909 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0264909 infores:hetionet CHEBI:3398 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0009676 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0339916 infores:hetionet CHEBI:72297 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0005758 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0595883 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0027813 infores:hetionet CHEBI:50859 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151691 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0403632 infores:hetionet CHEBI:17376 biolink:causes MONDO:0009067 infores:drugmechdb knowledge_assertion manual_agent CHEBI:17376 HP:0003131 DB00859_MESH_D003555_2 PUBCHEM.COMPOUND:12162152 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0522055 infores:hetionet CHEBI:64019 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0008031 infores:hetionet CHEBI:2038 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0006277 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002173 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027858 infores:hetionet CHEBI:3219 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026827 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0021122 infores:hetionet CHEBI:10102 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085632 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0036572 infores:hetionet NCBIGene:26074 biolink:causes MONDO:0957301 infores:monarchinitiative not_provided not_provided HGNC:15872 MONDO:0957301 uuid:04d23cd2-b629-481d-848c-b338203a2413 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030552 infores:hetionet CHEBI:31515 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0009806 infores:hetionet NCBIGene:3077 biolink:causes MONDO:0021001 infores:monarchinitiative not_provided not_provided HGNC:4886 MONDO:0021001 uuid:a9c3aab6-ffa4-4c22-aff3-b272f97afeaf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63925 biolink:causes UMLS:C0863090 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0863090 infores:hetionet CHEBI:2636 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0027051 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0041912 infores:hetionet CHEBI:4877 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0344232 infores:hetionet CHEBI:63618 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0015967 infores:hetionet CHEBI:2038 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0333243 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1368065 infores:hetionet CHEBI:70746 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018681 infores:hetionet CHEBI:6078 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0002871 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0233794 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0018801 infores:hetionet CHEBI:27666 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0020598 infores:hetionet CHEBI:36795 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0870082 infores:hetionet CHEBI:32293 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0010200 infores:hetionet CHEBI:50777 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0030196 infores:hetionet NCBIGene:987 biolink:causes MONDO:0013863 infores:monarchinitiative not_provided not_provided HGNC:1742 MONDO:0013863 uuid:3844c86c-666b-47ee-a246-05b25a747444 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0033975 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002070 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0018818 infores:hetionet CHEBI:40279 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0041582 infores:hetionet CHEBI:114785 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0016436 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0017178 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0011570 infores:hetionet CHEBI:7956 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C1443060 infores:hetionet CHEBI:691037 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0016436 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0041969 infores:hetionet CHEBI:29007 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0020517 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006266 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0021053 infores:hetionet CHEBI:36791 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234022 infores:hetionet CHEBI:8863 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0392525 infores:hetionet CHEBI:6030 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0232462 infores:hetionet CAID:CA8815626 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815626 MONDO:0009290 PMID:31228295PMID:22644586 Likely Benign BS3_Supporting, BP4 PM2 The NM_000152.5:c.2152G>A variant in GAA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 718 (p.Val718Ile). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00011 in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting. The highest minor allele frequency in any population is 0.005329 in the Ashkenazi Jewish population. This allele frequency meets the criteria for BS1 (>0.005) but BS1 was not applied because the Ashkenazi Jewish population is not defined as a continental population (PMID: 30311383). When expressed in COS-7 cells, this variant does not result in significantly reduced GAA activity, and the gene product is normally synthesized and/or processed (PMID 22644586, 31228295) (BS3_Supporting). The computational predictor REVEL gives a score of 0.193 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281232) with four submitters classifying the variant as a variant of uncertain significance, four as likely benign and one as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: BP4, BS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815626/MONDO:0009290/010 2024-05-21 2024-05-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:9637 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0011991 infores:hetionet CHEBI:63618 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0000731 infores:hetionet CHEBI:119915 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0024236 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020649 infores:hetionet CHEBI:45367 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0033774 infores:hetionet CHEBI:2618 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0018681 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0522336 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0522336 infores:hetionet CHEBI:5790 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0740394 infores:hetionet UMLS:C0004609 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0043094 infores:hetionet CAID:CA10549374 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549374 MONDO:0010305 PMID: Benign BA1, BP4 The NM_005629.4:c.1016+9C>T variant in SLC6A8 is an intronic variant in the region of the donor splice site of intron 6. The total number of hemizygotes in gnomAD v2.1.1 is 46, meeting the ClinGen CCDS VCEP’s threshold for BA1 (>10 hemizygotes). The highest minor allele frequency is 0.0009212 (European non-Finnish) with 39 hemizygotes in that population (BA1). The computational predictors SpliceAI and varSEAK predict that the variant has no impact in splicing (BP4). There is a ClinVar entry for the variant (Variation ID: 379398). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BA1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549374/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:119915 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0004623 infores:hetionet UMLS:C0145185 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0600142 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085129 infores:hetionet GO:0062042 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0062042 GO:0072359 CHEBI:63791 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0035078 infores:hetionet CHEBI:6690 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0015967 infores:hetionet CHEBI:80630 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0010200 infores:hetionet CHEBI:9667 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0006663 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0267596 infores:hetionet CHEBI:41423 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0549448 infores:hetionet CHEBI:71940 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0041657 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0039070 infores:hetionet CHEBI:6375 biolink:causes MONDO:0021071 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0023055 infores:hetionet CHEBI:9448 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0231218 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0243026 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0015397 infores:hetionet CHEBI:28901 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0013447 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027609 infores:hetionet CHEBI:63622 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0013604 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0152025 infores:hetionet CHEBI:2038 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0026858 infores:hetionet CHEBI:3738 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0011609 infores:hetionet CHEBI:7496 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0022346 infores:hetionet CAID:CA340748250 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748250 MONDO:0100368 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting PM5, PM3, PP4 NM_000329.3(RPE65):c.314C>A is a missense variant causing substitution of threonine with asparagine at position 105. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.917, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in ClinVar in at least 1 proband diagnosed with Leber congenital amaurosis, however, the variant was present in an unknown state of zygosity, so the PM3 code is not met (SCV001425554.1). Another missense variant at the same codon, NM_000329.3(RPE65):c.314C>T (p.Thr105Ile), has previously been reported in relation to early onset severe retinal dystrophy (PMID: 37217489) but has not yet been classified by the ClinGen Leber congenital amaurosis / early onset retinal dystrophy VCEP, so PM5 is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748250/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:75722 biolink:causes MONDO:0004866 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0271468 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0497471 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0497471 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0549284 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0549284 infores:hetionet CHEBI:4877 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0002792 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037023 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0035455 infores:hetionet CHEBI:7496 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0035410 infores:hetionet CHEBI:7936 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235660 infores:hetionet CHEBI:119486 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0423791 infores:hetionet CHEBI:76607 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0235378 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011991 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0021400 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521490 infores:hetionet NCBIGene:11232 biolink:causes MONDO:0032799 infores:monarchinitiative not_provided not_provided HGNC:9180 MONDO:0032799 uuid:a93ef891-ec1e-4181-abff-d3b3e8e0a212 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27974 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0033774 infores:hetionet CHEBI:8768 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0039240 infores:hetionet CHEBI:9398 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0277890 infores:hetionet CHEBI:63624 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0231528 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0948089 infores:hetionet CAID:CA16619140 biolink:causes MONDO:0700270 infores:clingen CAID:CA16619140 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PM3_Supporting The c.2466+5G>C variant in ATM occurs within a splice donor region. It is predicted to cause skipping of biologically-relevant-exon, resulting in an in-frame of frame deletion (removes amino acids 793-822) that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA studies (Ambry internal data). This variant has been identified in at least one individual with Ataxia-Telangiectasia (DOI:10.37897/RJN.2021.2.11). This variant is absent from gnomAD v.4.1.0. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1_Strong[RNA], PM3_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619140/MONDO:0700270/020 2025-11-11 2025-11-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27565 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0017178 infores:hetionet CHEBI:2618 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0028084 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0009938 infores:hetionet GO:0031021 biolink:causes GO:0051415 infores:ubergraph knowledge_assertion manual_agent GO:0031021 GO:0051415 CHEBI:10101 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0232602 infores:hetionet CHEBI:15365 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0001122 infores:hetionet CHEBI:132233 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0018681 infores:hetionet CHEBI:63622 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C1368065 infores:hetionet CHEBI:48844 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0003123 infores:hetionet CHEBI:134745 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0011991 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549405 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0013395 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0012833 infores:hetionet CHEBI:45863 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0032227 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0919980 infores:hetionet CHEBI:9130 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0085682 infores:hetionet CHEBI:4708 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0023218 infores:hetionet NCBIGene:85016 biolink:causes MONDO:0054843 infores:monarchinitiative not_provided not_provided HGNC:28188 MONDO:0054843 uuid:0dac165d-5784-4e19-a659-964098a5007d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3638 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0024437 infores:hetionet CHEBI:80630 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0011606 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0033246 infores:hetionet CHEBI:584020 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0086168 infores:hetionet NCBIGene:51271 biolink:causes MONDO:0032737 infores:monarchinitiative not_provided not_provided HGNC:12461 MONDO:0032737 uuid:13be0ad5-fd49-4264-b22b-1937c52113c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0032285 infores:hetionet CHEBI:45783 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085593 infores:hetionet CHEBI:4514 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0023380 infores:hetionet CHEBI:63608 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0042487 infores:hetionet CHEBI:7824 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151772 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0031350 infores:hetionet CHEBI:63589 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0042571 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0854567 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0854567 infores:hetionet CHEBI:135566 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0020649 infores:hetionet CAID:CA000147 biolink:causes MONDO:0017623 infores:clingen CAID:CA000147 MONDO:0017623 PMID:21828076PMID:29785012PMID:29706350 Uncertain Significance BS3, PM2, PP2 BP7, BP5, BS4, BS1, PVS1, PM6, BS2, PP3, PP1, PP4, PM4, PM5, PM1, PM3, BP3, BP4, BP1, BP2, BA1, PS1, PS3, PS4, PS2 PTEN c.364A>G (p.Ile122Val) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 21828076, 29706350, 29785012) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000147/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94440 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0424790 infores:hetionet CHEBI:101853 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0038362 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151888 infores:hetionet NCBIGene:145258 biolink:causes MONDO:0011227 infores:monarchinitiative not_provided not_provided HGNC:4612 MONDO:0011227 uuid:8d06c26d-4c61-4144-8198-cad581905d70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4470 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0020615 infores:hetionet CAID:CA024299 biolink:causes MONDO:0007783 infores:clingen CAID:CA024299 MONDO:0007783 PMID: Likely Pathogenic PP1, PS3_Moderate, PM1, PS4_Moderate PP3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Tryptophan at codon 552 of the RYR1 protein, p.(Arg552Trp). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in 6 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 5 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, PMID:9138151, PMID:16244001). This variant segregates with MHS in three families, PP1 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.83 supports neither a pathogenic nor a benign status for this variant.implemented: PS4_Moderate, PS3_Moderate, PM1, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024299/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ GO:0048328 biolink:causes GO:0048322 infores:ubergraph knowledge_assertion manual_agent GO:0048328 GO:0048322 CHEBI:36795 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0029261 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0234913 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0233472 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0857153 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0857153 infores:hetionet CHEBI:28748 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0003962 infores:hetionet CAID:CA10639180 biolink:causes MONDO:0015152 infores:clingen CAID:CA10639180 MONDO:0015152 PMID: Benign BP7, BA1, BP4 BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM3, PM4, PM1, PM5, PP2, PP3, PP1, PP4, BS2, BP1, BP2, BP3, PS3, PS1, PS2, PS4 The NM_000231.3: c.*185G>A variant is located in the 3' UTR of SGCG. Because the variant is located in the 3' UTR, it is not expected to alter the amino acid sequence. The filtering allele frequency of the c.*185G>A variant in SGCG is 0.01199 in the African/African American population in gnomAD v2.1.1 (the lower threshold of the 95% CI of 122/8708 genome chromosomes), which is higher than the ClinGen LGMD VCEP threshold (>0.002) for BA1, and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.00 for donor loss and 0.01 for acceptor loss, suggesting that the variant does not impact splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10639180/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8774 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0162429 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031350 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017152 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0585186 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0011849 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235146 infores:hetionet CHEBI:49668 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0015967 infores:hetionet CHEBI:9943 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151610 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0392025 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0429098 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0232492 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004623 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1096668 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1096668 infores:hetionet CHEBI:2682 biolink:causes HP:0032620 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151465 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0040136 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009763 infores:hetionet NCBITaxon:47466 biolink:causes MONDO:0958150 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:47466 MONDO:0958150 CAID:CA337097543 biolink:causes MONDO:0044970 infores:clingen CAID:CA337097543 MONDO:0044970 PMID: Benign BA1, BP7 PP3, BP4 The m.7028C>T (p. A375A) variant in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen at high frequencies in numerous haplogroups and the overall allele frequency in GenBank database (per Mitomap; queried 6/29/2020) is 80.8% (BA1). This is a synonymous variant (BP7). In summary, this variant meets criteria to be classified as benign given its synonymous nature and high frequency in the general population. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP7. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337097543/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7824 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014518 infores:hetionet CHEBI:3077 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020458 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0233485 infores:hetionet CHEBI:3752 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0023518 infores:hetionet CHEBI:24564 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0015672 infores:hetionet CHEBI:71415 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0010520 infores:hetionet NCBIGene:4256 biolink:causes MONDO:0009495 infores:monarchinitiative not_provided not_provided HGNC:7060 MONDO:0009495 uuid:ad55836c-acc7-4a14-80ea-76e5b388cc67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0178298 infores:hetionet CHEBI:114785 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0035222 infores:hetionet CHEBI:28748 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0007859 infores:hetionet CHEBI:8776 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0011253 infores:hetionet CHEBI:2682 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0014591 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009319 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0149504 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0007867 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0012813 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042373 infores:hetionet CHEBI:31485 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0344232 infores:hetionet GO:1901626 biolink:causes GO:0050808 infores:ubergraph knowledge_assertion manual_agent GO:1901626 GO:0050808 CHEBI:3638 biolink:causes MONDO:0019056 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0027868 infores:hetionet CHEBI:231425 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0035410 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948525 infores:hetionet CHEBI:31348 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042963 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0342406 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0342406 infores:hetionet NCBIGene:85440 biolink:causes MONDO:0014371 infores:monarchinitiative not_provided not_provided HGNC:19190 MONDO:0014371 uuid:0fbd9181-fe4a-4d0d-9cf2-87753614d152 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0010200 infores:hetionet CAID:CA114170 biolink:causes MONDO:0019565 infores:clingen CAID:CA114170 MONDO:0019565 PMID: Likely Benign BP5 PM2, PP3, PP4, PP1, PS3, PS4, BS3 The NM_000552.5(VWF):c.3797C>T variant in VWF is a missense variant predicted to cause substitution of proline by leucine at amino acid 1266 (p.Pro1266Leu). The population frequency and in silico pathogenicity predictors of this variant are between the pathogenic and benign thresholds established by the VWD VCEP. This variant has been extensively researched and published in the literature and has been associated with VWD type 2B Malmö/NY. This sub-type of VWD type 2B is characterized by very mild clinical presentation if any, typically no thrombocytopenia and normal multimers. No published case where the variant under consideration was the sole driver of disease had a combination of: activity/antigen ratio <0.7, documented abnormal bleeding phenotype, and enhanced response to ristocetin. This variant has been observed in at least 1 patient with an alternate molecular basis for disease. The patient with VWD type 2, also carried the Arg1315His variant, which has been classified likely pathogenic respectively for VWD type 2M respectively by the VWD VCEP (BP5; PMIDs 16985174). Additionally, carriers of this variant have been documented as being treated with DDAVP without subsequent thrombocytopenia in at least two reports (PMIDs 20305138, 27353798). This observation suggests that the enhanced response to ristocetin data in patients is potentially an artifact and does not represent a biologically relevant increase in binding affinity to GPIb. In summary, this variant meets the criteria to be classified as likely benign for hereditary VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP5. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; May 6th, 2025) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114170/MONDO:0019565/081 2025-05-06 2025-06-26 Undetermined mode of inheritance Contradicts true CHEBI:8871 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0152227 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0031039 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0025061 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042373 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020538 infores:hetionet CHEBI:8461 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0018681 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0155003 infores:hetionet CAID:CA8602942 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602942 MONDO:0100326 PMID: Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Strong PS3 The NM_000419.5(ITGA2B):c.1772A>C (p.Asp591Ala) missense variant has been reported in at least six patients, including at least one patient (P13 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). At least four patients have been reported homozygous for this variant (PMIDs: 34275420, 29385657, ClinVar SCV004013075.1). Two additional compound heterozygous patients have been reported (PMID: 34355501), the first patient had Pro176Ala confirmed in trans (classified Pathogenic by the PD-EP, score 1pt) and the second patient had c.1440-13_1440-1del assumed in trans (PM3_strong).The highest population minor allele frequency in gnomAD v4.0.0 is 0.000005932 (7/1180006alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.755, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_supporting, PM3_strong, PP4_strong and PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602942/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8888 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0392525 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0740304 infores:hetionet CHEBI:34385 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0012833 infores:hetionet CHEBI:8764 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002874 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0034150 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0027726 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011616 infores:hetionet CHEBI:9586 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0016867 infores:hetionet CHEBI:27999 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0000731 infores:hetionet CHEBI:4562 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042267 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0018801 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0014868 infores:hetionet CHEBI:4453 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0014742 infores:hetionet CHEBI:3387 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020672 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0549634 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0549634 infores:hetionet CHEBI:9150 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0917801 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0012833 infores:hetionet CHEBI:84500 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235710 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0856136 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0856136 infores:hetionet CAID:CA10579008 biolink:causes MONDO:0700270 infores:clingen CAID:CA10579008 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5_Supporting, PVS1 The c.1396C>T (p.Gln466*) variant in ATM is a nonsense variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10579008/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10101 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0040460 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0857245 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0857245 infores:hetionet UBERON:0000945 biolink:causes MONDO:0006223 infores:ubergraph knowledge_assertion manual_agent UBERON:0000945 MONDO:0006223 CHEBI:6375 biolink:causes MONDO:0013662 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0004763 infores:hetionet CAID:CA386960405 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960405 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Strong, PP3 The c.475C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 159 (p.(Arg159Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.905, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.476G>A (p.Arg159Gln) and c.475C>T (p.Arg159Trp), have been interpreted as pathogenic by the ClinGen MDEP, and p.(Arg.159Gly) has a greater Grantham distance than both (PM5_Strong). In summary, c.475C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM1_Supporting, PM2_Supporting, PM5_Strong, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960405/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10125 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0041912 infores:hetionet CHEBI:490877 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0021368 infores:hetionet CHEBI:31348 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0036974 infores:hetionet CHEBI:75722 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151578 infores:hetionet CHEBI:8869 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0039070 infores:hetionet CHEBI:65173 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0232461 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0521491 infores:hetionet CHEBI:3698 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0039231 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0542008 infores:hetionet CHEBI:3614 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0521839 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0404521 infores:hetionet CHEBI:8346 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0235266 infores:hetionet CHEBI:3286 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0013384 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0423773 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0027769 infores:hetionet CHEBI:3756 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0030318 infores:hetionet CHEBI:48131 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0677500 infores:hetionet CHEBI:6062 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020580 infores:hetionet CHEBI:4657 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0728899 infores:hetionet CHEBI:6965 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0002453 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0007114 infores:hetionet CHEBI:51380 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0020672 infores:hetionet CHEBI:68478 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0080274 infores:hetionet CHEBI:8346 biolink:causes MONDO:0018612 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0010308 infores:hetionet NCBIGene:1786 biolink:causes MONDO:0013584 infores:monarchinitiative not_provided not_provided HGNC:2976 MONDO:0013584 uuid:c7983f7d-1318-4b71-9666-defbdeef391f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71941 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0034150 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0042109 infores:hetionet CHEBI:45285 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0032708 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0497327 infores:hetionet NCBIGene:84733 biolink:causes MONDO:0013120 infores:monarchinitiative not_provided not_provided HGNC:1552 MONDO:0013120 uuid:093e9924-c88a-4124-a9b3-b7410adac946 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014852 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0948594 infores:hetionet CHEBI:7466 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0030781 infores:hetionet CHEBI:76010 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0178298 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0040034 infores:hetionet CAID:CA6264634 biolink:causes MONDO:0700270 infores:clingen CAID:CA6264634 MONDO:0700270 PMID: Uncertain Significance PM3 BP4, PM2, PP3 The c.590G>A variant in ATM is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 197 (p.Gly197Glu). This variant has been detected in at least two individuals with Ataxia-Telangiectasia (PMID: 18846412, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002288 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.66, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PM3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6264634/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8874 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0039070 infores:hetionet CHEBI:17688 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0085624 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151773 infores:hetionet CHEBI:9073 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0015967 infores:hetionet NCBIGene:84197 biolink:causes MONDO:0014101 infores:monarchinitiative not_provided not_provided HGNC:26267 MONDO:0014101 uuid:521260fa-aa68-4dfa-9266-7372d2cbbf54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes UMLS:C0522042 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0522042 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0001824 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0018674 infores:hetionet CAID:CA228665 biolink:causes MONDO:0015628 infores:clingen CAID:CA228665 MONDO:0015628 PMID: Pathogenic PP1_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting, PS4_Very Strong PP3, PM5 The NM_000552.5:c.4825G>A variant in VWF is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1609. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:RCo, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 31240882). Additional consistent phenotypes were also reported in the patient including a normal platelet count, FVIII activity consistent with VWF antigen (ratio >0.7), and normal RIPA assay. This variant has been reported in 8 additional probands meeting PP4 laboratory phenotype criteria for VWD type 2A (PS4_VeryStrong; PMIDs 28971901, 8348943, 22371917, 35505650 and Versiti Blood Center of Wisconsin private communication). The variant has been reported to segregate with VWD type 2A through ≥2 affected meioses from 2 families (PP1; PMID 22371917 and Versiti Blood Center Wisconsin private communication).The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00000068 (based on 3/1180024 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for type 2A (PM2_Supporting). ADAMTS susceptibility assay performed with the p.Gly1609Arg recombinant mutant vWF expressed by 293 EBNA cells showed increased susceptibility indicating that this variant has a damaging effect on protein function (PMID 16322474)(PS3_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS4_VeryStrong, PP1_Moderate, PM2_Supporting, PS3_Supporting. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228665/MONDO:0015628/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10023 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0003460 infores:hetionet CHEBI:28148 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0546817 infores:hetionet CHEBI:127780 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0011848 infores:hetionet NCBIGene:64135 biolink:causes MONDO:0024535 infores:monarchinitiative not_provided not_provided HGNC:18873 MONDO:0024535 uuid:45b75134-0fd5-4494-bac7-ce25f4bfb517 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412726237 biolink:causes MONDO:0100437 infores:clingen CAID:CA412726237 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, BP4 PP4, PS4 NM_001034853.2(RPGR):c.3423G>T (p.Trp1141Cys) is a missense variant encoding substitution of tryptophan with cysteine at residue 1141. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.2, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant has been reported in at least 1 proband meeting the PS4 requirement of some functional vision impairment in an affected male by age 30 years, with decreased fundus autofluorescence responses (PMID: 32278709). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and BP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412726237/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Inconclusive true CHEBI:32888 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0030193 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0150450 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006852 infores:hetionet CHEBI:45863 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0220870 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235347 infores:hetionet NCBIGene:64240 biolink:causes MONDO:0020748 infores:monarchinitiative not_provided not_provided HGNC:13886 MONDO:0020748 uuid:da05af4a-72a6-4276-a362-ca2ff843fae2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:573 biolink:causes UMLS:C1112209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:573 MESH:D059413 DB00303_MESH_D059413_1DB09060_MESH_D059413_2DB09324_MESH_D059413_1 CHEBI:4911 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0042109 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0011991 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0001122 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0032461 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022408 infores:hetionet CHEBI:17141 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0424295 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042373 infores:hetionet CHEBI:5779 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0558401 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0236068 infores:hetionet CHEBI:15551 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0006266 infores:hetionet CHEBI:49713 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0151786 infores:hetionet CHEBI:28593 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0033774 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002307 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0005743 infores:hetionet CHEBI:7465 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0040822 infores:hetionet CHEBI:94501 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0022346 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0015230 infores:hetionet CHEBI:3696 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151905 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0021108 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D008581 DB01332_MESH_D008581_1DB00199_MESH_D008581_1 CHEBI:3485 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0267797 infores:hetionet CHEBI:92923 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0162285 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151609 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0427008 infores:hetionet CHEBI:63624 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C1443060 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0034150 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0001122 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027769 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0239978 infores:hetionet NCBITaxon:71584 biolink:causes MONDO:0005662 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:71584 MONDO:0005662 CHEBI:63619 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0040213 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0267596 infores:hetionet CHEBI:9727 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0042571 infores:hetionet CHEBI:51860 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0699744 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0851341 infores:hetionet CHEBI:7494 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018681 infores:hetionet CHEBI:63621 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0497156 infores:hetionet CAID:CA137938 biolink:causes MONDO:0021060 infores:clingen CAID:CA137938 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.420C>T (p.Asp140=) variant in the MAP2K2 gene is 0.271% (32/8604) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137938/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:68647 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0267792 infores:hetionet CHEBI:9352 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0009421 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0854303 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151735 infores:hetionet CAID:CA7435619 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435619 MONDO:0007113 PMID: Likely Benign BP4, BS1, BP7 The allele frequency of the c.522A>G p.Ala174= variant in UBE3A (NM_130838.2) is 0.017% in the Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Ala174= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.522A>G p.Ala174= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435619/MONDO:0007113/032 2023-06-15 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94392 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C3665386 infores:hetionet CHEBI:4717 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0150450 infores:hetionet CHEBI:4315 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0015230 infores:hetionet CHEBI:3061 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0027497 infores:hetionet CHEBI:49575 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0424295 infores:hetionet CHEBI:5130 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0038325 infores:hetionet CHEBI:94686 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1519353 infores:hetionet CHEBI:2569 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0085631 infores:hetionet NCBIGene:3612 biolink:causes MONDO:0015020 infores:monarchinitiative not_provided not_provided HGNC:6050 MONDO:0015020 uuid:bb8b7157-4dfe-4bc0-867c-db8ccc4f17ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8093 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0004245 infores:hetionet CHEBI:47780 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235490 infores:hetionet CHEBI:7640 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0034150 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1527407 infores:hetionet CAID:CA270593 biolink:causes MONDO:0010726 infores:clingen CAID:CA270593 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, PM1, BS1, PP3 The p.Leu328Val variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). The p.Leu328Val variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Invitae; internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Leu328Val variant in MECP2 in gnomAD v4.1 is 0.00004283 in European (Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Leu328Val variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270593/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:50173 biolink:causes MONDO:0002185 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020492 infores:hetionet CHEBI:30659 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0039231 infores:hetionet CHEBI:5613 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0018790 infores:hetionet CHEBI:63613 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0877192 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0278008 infores:hetionet CHEBI:31980 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0013404 infores:hetionet CHEBI:3127 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0232849 infores:hetionet CHEBI:5383 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0011991 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085606 infores:hetionet CHEBI:45081 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0018965 infores:hetionet CHEBI:2611 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1384353 infores:hetionet NCBIGene:27072 biolink:causes MONDO:0030312 infores:monarchinitiative not_provided not_provided HGNC:12713 MONDO:0030312 uuid:c7761052-26a7-487d-999d-12006ab4e506 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9613 biolink:causes UMLS:C0232570 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0232570 infores:hetionet CAID:CA343779044 biolink:causes MONDO:0013144 infores:clingen CAID:CA343779044 MONDO:0013144 PMID: Uncertain Significance PM2_Supporting, BP4 The c.31T>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 11 (p.Ser11Thr). The computational predictor REVEL gives a score of 0.107, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008804 (1/113588 alleles) in the European population, which is lower than the ClinGen SERPINC1 threshold ([<0.00002]) for PM2, and therefore meets this criterion (PM2_supporting). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BP4, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343779044/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6538 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0231919 infores:hetionet CHEBI:48947 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0014518 infores:hetionet CHEBI:4657 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0011570 infores:hetionet CAID:CA9043674 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043674 MONDO:0012999 PMID: Likely Benign BS2, BP4, BP7 PM2, BS1 The NM_000156.6:c.396C>A variant in GAMT is a synonymous (silent) variant (p.Ile132=) with no predicted impact on splicing based on the computational predictor, SpliceAI (BP4, BP7). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0006575 (24/10058 alleles; one homozygote) in the Middle Eastern population, which is higher than the PM2_supporting threshold (<0.0004) and lower than the BS1 threshold (>0.001) set by the ClinGen CCDS VCEP (no population codes are met). While the allele frequency in the Ashkenazi Jewish population is higher, at 0.00304 (90/29608), this allele frequency data is not counted because the Ashkenazi Jewish population is not a continental population (see Ghosh et al, 2018, PMID: 30311383). There is a ClinVar entry for this variant (Variation ID: 328348). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043674/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Contradicts true UNII:54Z8M50D6Q biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0020461 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0017574 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0016385 infores:hetionet CHEBI:136040 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020546 infores:hetionet CHEBI:63717 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0267792 infores:hetionet CHEBI:3219 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0032617 infores:hetionet CHEBI:17474 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0033774 infores:hetionet CHEBI:100241 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0311468 infores:hetionet CHEBI:27565 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0011603 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027813 infores:hetionet CHEBI:17303 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0162297 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0234215 infores:hetionet CAID:CA149676 biolink:causes MONDO:0015152 infores:clingen CAID:CA149676 MONDO:0015152 PMID: Benign BP4, BA1 BP7 The NM_213599.3: c.364-8del variant in the ANO5 gene is a single-base deletion located within the extended splice acceptor region (positions -20 to +1) for exon 5. The filtering allele frequency for this variant is 0.4429 in gnomAD v4.1.0 (the lower bound of the 95% CI of 33287/74482 African/African American chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). It is not expected to alter the amino acid sequence and is not predicted to impact splicing (SpliceAI score 0) (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/19/2025): BA1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA149676/MONDO:0015152/188 2025-08-19 2025-09-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:194135 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1609512 infores:hetionet CHEBI:63631 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1260880 infores:hetionet CHEBI:65173 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C1260880 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0037299 infores:hetionet CHEBI:39112 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0854467 infores:hetionet CHEBI:6456 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0025287 infores:hetionet CHEBI:7476 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1458155 infores:hetionet CHEBI:52172 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018926 infores:hetionet CHEBI:231594 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042963 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020456 infores:hetionet CHEBI:7514 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0012833 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0009450 infores:hetionet CHEBI:8077 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0026205 infores:hetionet CHEBI:617099 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0002874 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027441 infores:hetionet CHEBI:6715 biolink:causes HP:0000929 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235942 infores:hetionet CHEBI:83804 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013132 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017152 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038362 infores:hetionet CHEBI:251408 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0700590 infores:hetionet CHEBI:63608 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0015403 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151763 infores:hetionet CHEBI:6935 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0030446 infores:hetionet CHEBI:7789 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0152032 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042131 infores:hetionet CHEBI:48669 biolink:causes MONDO:0018660 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0684275 infores:hetionet CHEBI:15765 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0036974 infores:hetionet CHEBI:3647 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0023530 infores:hetionet CHEBI:49960 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0152169 infores:hetionet CHEBI:63638 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0025345 infores:hetionet CHEBI:77032 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0178298 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0853700 infores:hetionet CHEBI:84500 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0344232 infores:hetionet NCBIGene:4094 biolink:causes MONDO:0010992 infores:monarchinitiative not_provided not_provided HGNC:6776 MONDO:0010992 uuid:6e8f3a74-2cb6-4d15-96fb-fda590b3a03e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5165 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151605 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020649 infores:hetionet CHEBI:9137 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085641 infores:hetionet CHEBI:9123 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0520966 infores:hetionet CHEBI:41774 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0013404 infores:hetionet CHEBI:63631 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C3495440 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0424605 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948296 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0037274 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009450 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002270 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0563238 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0024299 infores:hetionet CHEBI:63608 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0022346 infores:hetionet CHEBI:8802 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0009806 infores:hetionet CHEBI:27834 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0231528 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0030305 infores:hetionet CHEBI:6909 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0036830 infores:hetionet CHEBI:10100 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C2363731 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0014868 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042109 infores:hetionet CHEBI:4551 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0030252 infores:hetionet CHEBI:9635 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0022346 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018799 infores:hetionet CHEBI:6832 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0039070 infores:hetionet CHEBI:17549 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151905 infores:hetionet CHEBI:85078 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C1609512 infores:hetionet CHEBI:5775 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0152227 infores:hetionet CAID:CA233431 biolink:causes MONDO:0008723 infores:clingen CAID:CA233431 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3_Supporting, PP4_Moderate, PM5_Supporting The NM_000018.4 c.637G>C (p.Ala213Pro) in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 213 (p.Ala213Pro). The highest population minor allele frequency in gnomAD V2.1.1 is 0.00018 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in homozygous fashion in an individual affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who displayed markedly reduced enzyme mRNA levels and activity (< 10 % of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 0.5, PM3_Supporting, PMID: 10077518). Another missense variant c.637G>A (p.Ala213Thr) in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3_Supporting, PM5_Supporting, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA233431/MONDO:0008723/021 2024-04-15 2024-04-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:134991 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042023 infores:hetionet CHEBI:8028 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C2363731 infores:hetionet CHEBI:5280 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0085641 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0012817 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0019158 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020649 infores:hetionet CHEBI:94501 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0011603 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0087169 infores:hetionet CHEBI:9123 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0026826 infores:hetionet CHEBI:50173 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011603 infores:hetionet CHEBI:75988 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0854467 infores:hetionet CHEBI:63617 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0040822 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011609 infores:hetionet CHEBI:64064 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0027121 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0085096 infores:hetionet NCBIGene:90417 biolink:causes MONDO:0013226 infores:monarchinitiative not_provided not_provided HGNC:30767 MONDO:0013226 uuid:0b9904b9-c76a-4d1c-a761-af6530414c09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6015 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0235063 infores:hetionet CHEBI:4672 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0039240 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0006840 infores:hetionet CHEBI:31644 biolink:causes MONDO:0015294 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1619692 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085584 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0038362 infores:hetionet CHEBI:3996 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0033774 infores:hetionet CHEBI:83527 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0014742 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043037 infores:hetionet CAID:CA213723 biolink:causes MONDO:0015967 infores:clingen CAID:CA213723 MONDO:0015967 PMID: Pathogenic PS2, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1157T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 286 (p.(Leu386Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified as a de novo occurrence with confirmed parental relationships in 1 individual with a clinical picture highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6 and negative antibodies) (PP4_Moderate, PS2; internal lab contributors). Another missense variant, c.1156C>G, p.(Leu386Val) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Leu386Pro) has a greater Grantham distance (PM5). In summary, c.1157T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS2, PP4_Moderate, PM2_supporting, PP2, PP3, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213723/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:15551 biolink:causes UMLS:C0424535 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0424535 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0042373 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019348 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0022408 infores:hetionet CHEBI:6078 biolink:causes MONDO:0006609 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0221244 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035305 infores:hetionet CHEBI:585948 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0002994 infores:hetionet GO:1903395 biolink:causes GO:0140278 infores:ubergraph knowledge_assertion manual_agent GO:1903395 GO:0140278 CHEBI:46295 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0085624 infores:hetionet CHEBI:49662 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0344232 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0221742 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0016034 infores:hetionet CAID:CA10014168 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014168 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS3, PS4, BP4, PVS1, PM6, PM2, BS3, BS4, BS1, BP7, PM5, PM1, PM4, PP3, PP1 The NM_001754.4:c.*27C>A variant in the 3' UTR has an MAF of 0.4444 (44%, 1352/3042 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 301 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014168/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9139 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2225524 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0548823 infores:hetionet CHEBI:144093 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0009763 infores:hetionet CHEBI:75984 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0162830 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0851341 infores:hetionet CHEBI:114785 biolink:causes MONDO:0015265 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0006272 infores:hetionet CHEBI:4514 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0000737 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0232431 infores:hetionet CHEBI:50729 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0231218 infores:hetionet CHEBI:7466 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0702166 infores:hetionet CAID:CA512232176 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232176 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.958C>A (p.Arg320=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.11) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232176/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8228 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0271051 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0037274 infores:hetionet NCBIGene:284058 biolink:causes MONDO:0012496 infores:monarchinitiative not_provided not_provided HGNC:24565 MONDO:0012496 uuid:a4c19790-5638-4440-add9-600cc1c5e672 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5784 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0001824 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0006266 infores:hetionet NCBITaxon:46684 biolink:causes MONDO:0005655 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:46684 MONDO:0005655 CHEBI:63598 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003123 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022116 infores:hetionet CHEBI:70707 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0003862 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0243026 infores:hetionet CHEBI:28001 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0001824 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0007971 infores:hetionet CHEBI:51041 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0030252 infores:hetionet CHEBI:42944 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0235086 infores:hetionet CHEBI:27974 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0008350 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0038454 infores:hetionet CHEBI:3077 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0035305 infores:hetionet NCBIGene:6555 biolink:causes MONDO:0013214 infores:monarchinitiative not_provided not_provided HGNC:10906 MONDO:0013214 uuid:627b4f8b-81bd-42d0-bb62-0c938712b11e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes MONDO:0005233 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0007131 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020649 infores:hetionet CHEBI:28901 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0042963 infores:hetionet CHEBI:15765 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0040822 infores:hetionet CHEBI:61033 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0030252 infores:hetionet CHEBI:17334 biolink:causes MONDO:0021553 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0026976 infores:hetionet CHEBI:37924 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0085633 infores:hetionet CHEBI:45599 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C1291077 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0700594 infores:hetionet CHEBI:7573 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0041969 infores:hetionet CHEBI:31624 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0015230 infores:hetionet CHEBI:82960 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027424 infores:hetionet CHEBI:3077 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151786 infores:hetionet CHEBI:3561 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013384 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0031350 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0009763 infores:hetionet CHEBI:6539 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0015672 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0020517 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0238807 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0238807 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549622 infores:hetionet CHEBI:9943 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0455769 infores:hetionet CHEBI:71219 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0031154 infores:hetionet CHEBI:5004 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0022346 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0162429 infores:hetionet NCBIGene:4015 biolink:causes MONDO:0014950 infores:monarchinitiative not_provided not_provided HGNC:6664 MONDO:0014950 uuid:e57d45b8-dee5-4d8d-b9d1-c0ede89344da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006325 infores:hetionet CAID:CA386966196 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966196 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PP3 PS4, PM5, PP4 The c.794A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 265 (p.(Tyr265Cys)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold, and PP4 does not apply as the calculated MODY probability is <50% (PMID: 30663027, 36189138). Another missense variant, c.794A>C (p.Tyr265Ser), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.794A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966196/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3506 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0014457 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0027769 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020538 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011053 infores:hetionet CHEBI:63631 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0036974 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0007971 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0032290 infores:hetionet CAID:CA120606 biolink:causes MONDO:0044970 infores:clingen CAID:CA120606 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP3, PS4, PS3 The m.8043_8044del frameshift variant in MT-CO2 has been reported in one individual with primary mitochondrial disease to date, in an infant with severe lactic acidosis who died at 12 days old (PMID: 11471180). Complex IV deficiency was noted in skeletal and cardiac muscle. The variant was present at 20% heteroplasmy in skeletal muscle, 17% in cardiac muscle, 14% in lung tissue, 14% in liver, and 11.5% in skin. The variant was not assessed in proband’s blood and was undetectable in mother’s blood. Of note, nuclear genetic etiologies were not evaluated in this case. This variant causes a premature stop in the MT-CO2 gene resulting in truncation of 33% of the protein (PVS1_strong). This variant is absent in in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. This variant meets criteria to be classified as uncertain significance for primary mitochondrial disease. After extensive discussion, this Expert Panel agreed with this classification given low heteroplasmy levels in the only reported case with a severe phenotype, limited ability of technology used at the time to accurately report heteroplasmy, and because other genetic etiologies were not excluded in the only case reported. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120606/MONDO:0044970/015 2024-01-22 2025-06-12 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8107 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0017566 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006840 infores:hetionet CHEBI:291342 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C1260880 infores:hetionet NCBIGene:529 biolink:causes MONDO:0027462 infores:monarchinitiative not_provided not_provided HGNC:857 MONDO:0027462 uuid:28da9e1c-d347-4585-a110-1a7f82175ea5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002871 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018418 infores:hetionet CHEBI:10127 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013491 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0027051 infores:hetionet CHEBI:9137 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0086565 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020651 infores:hetionet NCBITaxon:772 biolink:causes MONDO:0006924 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:772 MONDO:0006924 CHEBI:119915 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0040264 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0029408 infores:hetionet CAID:CA4239720 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239720 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PS2_Moderate, PP2, PP3, PP4 PS4, PS3, BS1, BS3, PM2, BP4, BA1 The c.106G>T variant in the glucokinase gene,GCK, causes an amino acid change of arginine to tryptophan at codon 36 (p.(Arg36Trp)) of NM_000162.5. While the Popmax filtering allele frequency is 0.000002920 (European non-Finnish population), which is less than the MDEP cutoff for PM2_Supporting, there are two copies of the variant in the African/African American subpopulation; therefore, PM2_Supporting cannot be applied, and PS4 cannot be applied regardless of the number of cases. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.911, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 16965331). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for GCK-MODY (PS2_Moderate; PMID:8168652). This variant segregated with diabetes, with five informative meioses in three families with MODY (PP1_Strong; PMIDs: 17573900, 23433541, 33477506). In summary, c.106C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4, PS2_Moderate, PP1_Strong, Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239720/MONDO:0015967/086 2023-10-10 2023-10-10 Semidominant inheritance HP:0032113 Supports CHEBI:50692 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0026821 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0033860 infores:hetionet UMLS:C1709429 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0015672 infores:hetionet CHEBI:4974 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0003467 infores:hetionet CHEBI:63610 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0006277 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0031046 infores:hetionet CHEBI:45409 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0033247 infores:hetionet CHEBI:6076 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0001623 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027051 infores:hetionet CHEBI:75045 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0009782 infores:hetionet CHEBI:101278 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C3263723 infores:hetionet CAID:CA9043754 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043754 MONDO:0012999 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000156.6:c.261G>A (p.Trp87Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001338 (1/74748 alleles) in the African/African-American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with GAMT deficiency. There is a ClinVar entry for this variant (Variation ID: 849693). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043754/MONDO:0012999/026 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2038 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0041912 infores:hetionet CHEBI:63791 biolink:causes MONDO:0060779 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0341702 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017152 infores:hetionet CHEBI:5138 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234022 infores:hetionet CHEBI:7476 biolink:causes MONDO:0042981 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0003507 infores:hetionet NCBIGene:28982 biolink:causes MONDO:0012177 infores:monarchinitiative not_provided not_provided HGNC:24682 MONDO:0012177 uuid:0709290a-50f7-4538-8ed1-13cc15037db2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9445 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0043352 infores:hetionet NCBIGene:10060 biolink:causes MONDO:0009406 infores:monarchinitiative not_provided not_provided HGNC:60 MONDO:0009406 uuid:842d90cd-3025-4246-96bf-a6f388ce366c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0746883 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0007971 infores:hetionet CHEBI:8890 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0007166 infores:hetionet CHEBI:5959 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0030193 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0153251 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0153251 infores:hetionet CHEBI:5109 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0235259 infores:hetionet CHEBI:7565 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0700590 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0234930 infores:hetionet CHEBI:5123 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0024141 infores:hetionet CAID:CA2579830387 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830387 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP1, PM2_Supporting, PM1_Supporting PS4 The c.-174T>C p.(?) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the promoter region of HNF1A/HNF1B binding sites, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 23348805, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and SU sensitive) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes with 3 informative meioses in a single family (PP1; internal lab contributors). In summary, c.-174T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PM1_Supporting, PM2_Supporting, PP1, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830387/MONDO:0015967/085 2025-10-13 2025-10-13 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:144551 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0853714 infores:hetionet CHEBI:52010 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0015672 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0392197 infores:hetionet CAID:CA2697547487 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547487 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.967+13A>G is an intronic variant that has a SpliceAI score ≤ 0.20 (0.00) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.14) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547487/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8382 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0030486 infores:hetionet CHEBI:48669 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0004093 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027441 infores:hetionet CAID:CA170236 biolink:causes MONDO:0010726 infores:clingen CAID:CA170236 MONDO:0010726 PMID: Benign BS1, BS2 The allele frequency of the p.Ala447Thr (NM_004992.3) variant in MECP2 is 0.02% in East Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala447Thr variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). In summary, the p.Ala447Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170236/MONDO:0010726/016 2021-12-13 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:45081 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0002994 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030312 infores:hetionet CHEBI:135888 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0002994 infores:hetionet CHEBI:50777 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0029927 infores:hetionet CHEBI:4888 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0015967 infores:hetionet CHEBI:5778 biolink:causes HP:0001595 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0157733 infores:hetionet CHEBI:63623 biolink:causes MONDO:0004619 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0025007 infores:hetionet CHEBI:6954 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1291078 infores:hetionet CHEBI:45863 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0023467 infores:hetionet CHEBI:16755 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0037299 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0038454 infores:hetionet CHEBI:29007 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0027497 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0037284 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0020651 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0858797 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0018799 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0004623 infores:hetionet CHEBI:7492 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0034068 infores:hetionet CHEBI:3082 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1384353 infores:hetionet CHEBI:2038 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0206062 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0018799 infores:hetionet CHEBI:9352 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C2973529 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0006826 infores:hetionet CHEBI:65349 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0080274 infores:hetionet CHEBI:5775 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0003862 infores:hetionet CHEBI:4653 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0041657 infores:hetionet CHEBI:47898 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235437 infores:hetionet CHEBI:681850 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0009676 infores:hetionet CHEBI:50693 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0151766 infores:hetionet CHEBI:3504 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0002878 infores:hetionet CAID:CA6748741 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748741 MONDO:0009861 PMID:26503515 Likely Pathogenic PP4_Moderate, PM3_Very Strong PM2, PM5, PP3 The c.1123C>G (p.Gln375Glu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID:26503515). It was detected in trans with pathogenic variants: p.Arg243Gln; p.Arg408Trp; EX6-96A＞G (PMID: 28982351); c.977G>A (p.W326*); p.R413P (PMID: 3005010). This variant has an allele frequency in gnomAD (MAF=0.0003808) that is above the PAH VCEP cutoff for pathogenicity (0.0002). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748741/MONDO:0009861/006 2020-06-22 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6402 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0031350 infores:hetionet CHEBI:4710 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0011603 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0031350 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0149514 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151838 infores:hetionet CHEBI:4876 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0020615 infores:hetionet CHEBI:9139 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014356 infores:hetionet NCBIGene:2110 biolink:causes MONDO:0009282 infores:monarchinitiative not_provided not_provided HGNC:3483 MONDO:0009282 uuid:cabf9741-128b-4db0-aea4-ba5f0421e56b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63115 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0037199 infores:hetionet NCBIGene:83999 biolink:causes MONDO:0044305 infores:monarchinitiative not_provided not_provided HGNC:17550 MONDO:0044305 uuid:e73d117b-15cd-422b-9245-7e0f0f5dce19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9150 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0018681 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0266008 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0266008 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0877338 infores:hetionet CHEBI:4907 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0016658 infores:hetionet UMLS:C0065374 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0239377 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0000265 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D011015 DB01607_MESH_D011015_1DB00948_MESH_D011015_1 CHEBI:36704 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0878544 infores:hetionet CHEBI:4876 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0235416 infores:hetionet CHEBI:15854 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0429097 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0149931 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0521495 infores:hetionet CHEBI:17650 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0033774 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0521503 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0006852 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151479 infores:hetionet CAID:CA294892175 biolink:causes MONDO:0009290 infores:clingen CAID:CA294892175 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting PP3, BP4 The NM_000152.5(GAA):c.1103G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 368 (p.Gly368Asp). This variant has been detected in at least 4 individuals with Pompe disease and deficient GAA activity (PP4_Moderate). Of those individuals, 4 were compound heterozygous for the variant and c.-32-13T>G (ClinVar Variation ID: 4027), a variant that has been classified by the LD VCEP as pathogenic for Pompe disease, c.-32-13T>G; one of those were confirmed in trans by parental/family testing (PMID: 36246652, 33202836, internal lab data) (max 2 patients counted, 1 point for confirmed in trans and 0.5 points for unconfirmed phase, 1.5 points) (PM3)(PMID: 36246652, 33202836, internal lab data). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). Expression of the variant in HEK293 cells resulted in 2.8% wild type GAA activity and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID: 36246652) (PS3_Supporting). The computational predictor REVEL gives a score of 0.647 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 1037598, 1 star review status) with 3 other submitters including 1 classifying the variant as a VUS, 1 as Likely Pathogenic and 1 as Pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PM3, PP4_Moderate, PM2_Supporting, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 2, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294892175/MONDO:0009290/010 2025-08-02 2025-08-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:50922 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0004238 infores:hetionet CHEBI:7852 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085631 infores:hetionet CHEBI:51164 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0009806 infores:hetionet CHEBI:7986 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0232487 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0025061 infores:hetionet CHEBI:78543 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0011606 infores:hetionet NCBIGene:5358 biolink:causes MONDO:0010606 infores:monarchinitiative not_provided not_provided HGNC:9091 MONDO:0010606 uuid:0f7d0550-ad1e-4fb6-b24b-40adb7b3b3bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48131 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0520893 infores:hetionet CHEBI:42944 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0039240 infores:hetionet CHEBI:3403 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0020517 infores:hetionet CHEBI:31000 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0018681 infores:hetionet NCBIGene:7068 biolink:causes MONDO:0008569 infores:monarchinitiative not_provided not_provided HGNC:11799 MONDO:0008569 uuid:497810e5-ed89-42c1-b412-6a10eb7cf322 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15553 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0004093 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0020615 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009938 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015397 infores:hetionet CHEBI:4798 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0003467 infores:hetionet CHEBI:7476 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1306341 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0009806 infores:hetionet CHEBI:71415 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0042384 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0014742 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0031117 infores:hetionet NCBIGene:6496 biolink:causes MONDO:0007999 infores:monarchinitiative not_provided not_provided HGNC:10889 MONDO:0007999 uuid:24e0fc02-ea3e-4244-b84a-d5ba2c183887 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0021053 infores:hetionet CHEBI:421707 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0035078 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0036572 infores:hetionet CHEBI:47781 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0424295 infores:hetionet CHEBI:64321 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0014518 infores:hetionet CHEBI:3393 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0267596 infores:hetionet CHEBI:3172 biolink:causes UMLS:C0265072 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0265072 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0020651 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0009450 infores:hetionet CHEBI:8871 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030193 infores:hetionet CHEBI:3286 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0020458 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0017601 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042109 infores:hetionet NCBIGene:729230 biolink:causes MONDO:0009060 infores:monarchinitiative not_provided not_provided HGNC:1603 MONDO:0009060 uuid:84a8d49f-0406-4cf3-86c9-5e5d03fbf044 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0497156 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0027947 infores:hetionet CHEBI:4717 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0002453 infores:hetionet CHEBI:7809 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0687713 infores:hetionet CAID:CA234222 biolink:causes MONDO:0021060 infores:clingen CAID:CA234222 MONDO:0021060 PMID: Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PM5_Strong, PS2 BP1, BP4, BA1, BS1 The NM_002755.4:c.608A>G variant in MAP2K1 is a missense variant predicted to cause substitution of glutamic acid by glycine at amino acid 203 (p.Glu203Gly). This variant was absent from gnomAD v2.1.1 (PM2_Supporting). The computational prediction tool REVEL gives a score of 0.785, suggesting that this variant may impact the protein (PP3). The p.Glu203Gly variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). Furthermore, four different (likely) pathogenic variants at this residue (Glu203Gln, Glu203Lys, Glu203Val, Glu203Ala) has been identified in several patients with RASopathies (PM5_Strong). This variant has been observed in at least 4 probands with a RASopathy, of which 3 were reported as a de novo occurrence with confirmed parentage (PS2, PS4_Supporting; PMIDs: 35322241, 37600658; GeneDx, ClinVar: SCV003926006.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PM5_Strong, PS4_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 7/8/2025) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA234222/MONDO:0021060/045 2025-07-08 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6375 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0038362 infores:hetionet CHEBI:48273 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0040264 infores:hetionet CHEBI:51041 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0016655 infores:hetionet NCBIGene:1725 biolink:causes MONDO:0032775 infores:monarchinitiative not_provided not_provided HGNC:2869 MONDO:0032775 uuid:3f2799b8-2fa3-430b-914b-f26a03db0754 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1145628 infores:hetionet CHEBI:9352 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0040264 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004096 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013146 infores:hetionet NCBIGene:5530 biolink:causes MONDO:0020630 infores:monarchinitiative not_provided not_provided HGNC:9314 MONDO:0020630 uuid:12efb875-d9d8-43df-8ed7-48ca20b230ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:9255 biolink:causes MONDO:0009843 infores:monarchinitiative not_provided not_provided HGNC:10648 MONDO:0009843 uuid:e108c2ea-d3f5-4bb2-b8ea-11d21cba1b55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0036508 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0403632 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235807 infores:hetionet CHEBI:188986 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0011603 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0243026 infores:hetionet GO:1904341 biolink:causes GO:0014827 infores:ubergraph knowledge_assertion manual_agent GO:1904341 GO:0014827 CHEBI:8871 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0178298 infores:hetionet NCBIGene:55650 biolink:causes MONDO:0009398 infores:monarchinitiative not_provided not_provided HGNC:26031 MONDO:0009398 uuid:47a7ebd3-8f1b-4d9c-9331-1491ed904c3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085393 infores:hetionet CHEBI:10110 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151754 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042373 infores:hetionet CHEBI:367163 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0740394 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0853813 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0027947 infores:hetionet CHEBI:3479 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0040034 infores:hetionet CHEBI:6402 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0019080 infores:hetionet CHEBI:9943 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0035317 infores:hetionet CHEBI:7565 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0027424 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0022650 infores:hetionet CHEBI:6832 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0009763 infores:hetionet CAID:CA410203759 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203759 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.264G>T (p.Glu88Asp) is a missense variant which does not meet any ACMG/AMP codes. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203759/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3478 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0029882 infores:hetionet CHEBI:37924 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0008350 infores:hetionet CHEBI:37941 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0020433 infores:hetionet CAID:CA152952 biolink:causes MONDO:0015967 infores:clingen CAID:CA152952 MONDO:0015967 PMID: Benign BA1 The c.31G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 11 (p.(Ala11Thr)) of NM_000162.5. This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.0225, which is greater than the MDEP threshold for BA1 (>0.0001) (BA1). In summary, c.31G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): BA1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA152952/MONDO:0015967/086 2025-10-28 2025-10-28 Semidominant inheritance HP:0032113 Contradicts true CHEBI:7465 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0344315 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0740425 infores:hetionet CAID:CA130842 biolink:causes MONDO:0021060 infores:clingen CAID:CA130842 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2127+3A>G variant in the BRAF gene is 0.151% (23/10398) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA130842/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7465 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0233414 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0027051 infores:hetionet CHEBI:5123 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0023380 infores:hetionet CHEBI:7565 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014724 infores:hetionet CHEBI:63605 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0236075 infores:hetionet NCBIGene:8772 biolink:causes MONDO:0013408 infores:monarchinitiative not_provided not_provided HGNC:3573 MONDO:0013408 uuid:fc6a678e-6150-4288-a474-244544985773 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8378 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0013491 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0343863 infores:hetionet CHEBI:4708 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0022661 infores:hetionet CHEBI:52717 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235378 infores:hetionet CHEBI:7936 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0149745 infores:hetionet CHEBI:27432 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0019087 infores:hetionet CHEBI:32192 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0151664 infores:hetionet UNII:D27V6190PM biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0000737 infores:hetionet CHEBI:49668 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0038362 infores:hetionet CHEBI:6954 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0234238 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0553731 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0553731 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0233494 infores:hetionet CAID:CA345709 biolink:causes MONDO:0700270 infores:clingen CAID:CA345709 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PM5_Supporting, PVS1 The ATM c.6997dupA (p.Thr2333Nfs*40) variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a compound heterozygous state (presumed) or with a second variant unidentified in four individuals with Ataxia-Telangiectasia (PMID 21459046, 10817650, 9463314, Clinical Laboratory Data: PM3_Strong). Variant is absent in the GnomAD v2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA345709/MONDO:0700270/020 2022-03-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28177 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0232462 infores:hetionet CHEBI:7627 biolink:causes UMLS:C1112274 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C1112274 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0016977 infores:hetionet CHEBI:92923 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0012833 infores:hetionet CHEBI:127342 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0013378 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0022904 infores:hetionet CHEBI:3723 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151934 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0162830 infores:hetionet CHEBI:8081 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0151735 infores:hetionet CHEBI:63613 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0015230 infores:hetionet CHEBI:10119 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085623 infores:hetionet UMLS:C1709429 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0030193 infores:hetionet CHEBI:7936 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020598 infores:hetionet CHEBI:367163 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0028084 infores:hetionet CHEBI:6904 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0003811 infores:hetionet CHEBI:2567 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0015230 infores:hetionet CHEBI:28148 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0039231 infores:hetionet CHEBI:15367 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013144 infores:hetionet CHEBI:92712 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0009421 infores:hetionet CAID:CA8337527 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337527 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 The c.62+18G>A (NM_000018.4) variant in ACADVL is an intronic variant which is located in intron 1 on a weakly conserved nucleotide. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The results from in silico splicing predictors (SpliceSiteFinder and MaxEntScn) support that this variant does not affect splicing (BP4). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337527/MONDO:0008723/021 2023-12-15 2023-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8346 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0085620 infores:hetionet CHEBI:27834 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0013456 infores:hetionet CHEBI:135686 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0020621 infores:hetionet CHEBI:3312 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0012833 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0221392 infores:hetionet CHEBI:110423 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0043144 infores:hetionet CHEBI:5134 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0010481 infores:hetionet NCBIGene:5530 biolink:causes MONDO:0032642 infores:monarchinitiative not_provided not_provided HGNC:9314 MONDO:0032642 uuid:399fa2d6-f032-4f60-9fbe-00c08d4a6a4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235807 infores:hetionet CAID:CA8337769 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337769 MONDO:0008723 PMID: Likely Pathogenic PP3, PM3_Strong, PP4_Moderate, PM2 The NM_000018.4(ACADVL): c.619T>C (p.Ser207Pro) variant is a missense variant predicted to cause substitution of serine by proline at amino acid 207. At least two individuals with this variant displayed a newborn screen consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency as well as follow-up acylcarnitine testing showing increased C14:1 acylcarnitines, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 26927351). This individual was compound heterozygous for this variant and a distinct pathogenic or likely pathogenic variant confirmed in trans by parental testing (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.79, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3_Strong, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337769/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9943 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0016655 infores:hetionet CHEBI:51860 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0041834 infores:hetionet CHEBI:465284 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011124 infores:hetionet CHEBI:4822 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0027051 infores:hetionet CHEBI:17026 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0038999 infores:hetionet CHEBI:45783 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0333355 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0023895 infores:hetionet CHEBI:68575 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0004238 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0005779 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0948349 infores:hetionet NCBIGene:91179 biolink:causes MONDO:0010959 infores:monarchinitiative not_provided not_provided HGNC:19869 MONDO:0010959 uuid:fa098616-f7c5-49f7-a24f-fdefbc60525b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0011127 infores:hetionet CAID:CA8643859 biolink:causes MONDO:0015152 infores:clingen CAID:CA8643859 MONDO:0015152 PMID: Likely Pathogenic PM3_Strong, PM5_Supporting, PP3, PP4 PM4, PM1, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM2, PVS1, PM6, PP2, BS2 The NM_000023.4: c.661C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 221, p.(Arg221Cys). This variant has been identified in at least eight individuals with a clinical suspicion of limb girdle muscular dystrophy (PMID: 35416532, 28403181, 30564623, 32528171, 32875335; LOVD SGCA_000169; John Walton Muscular Dystrophy Research Centre internal data communication; ClinVar SCV000941635.5, SCV005198223.1 internal data communication), including confirmed in trans with the same pathogenic variant in two cases (c.229C>T p.(Arg77Cys), 1.0 pt x2, ClinVar SCV000941635.5, SCV005198223.1 internal data communication) (PP4, PM3_Strong). It has also been reported in a homozygous state in an individual undergoing clinical genome sequencing for suspected rare disease but without phenotype details provided (PMID: 33726816). The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003623 (33/91090 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.787, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In addition, another missense variant at the same codon, c.662G>C p.(Arg221Pro), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/28/2025): PP4, PM3_Strong, PP3, PM5_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8643859/MONDO:0015152/189 2025-10-28 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100147 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0040034 infores:hetionet CHEBI:31348 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1527344 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0043345 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0079043 infores:hetionet CHEBI:18067 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0031542 infores:hetionet CHEBI:63610 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0003862 infores:hetionet CAID:CA6264689 biolink:causes MONDO:0700270 infores:clingen CAID:CA6264689 MONDO:0700270 PMID: Likely Pathogenic PS3_Moderate, PM3_Strong, PP3 PM2 The c.875C>T variant in ATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 292 (p.Pro292Leu). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 18634022, 30549301, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005% (1/19890 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). Experimental studies shows that this variant has impact on ATM kinase activity, protein levels and radiosensitivity was also found to be sensitive (RS<21%) when compared with wild type (PMID:18634022,19431188). The REVEL computational prediction analysis tool predicted a score of 0.752, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_strong, PS3_Moderate, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6264689/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6888 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0015300 infores:hetionet CAID:CA386964742 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964742 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PP4_Moderate, PVS1 PS4 The c.646C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 216 (p.(Gln216Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:23348805, internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with four informative meioses in two families (PP1_Strong; internal lab contributors). In summary, c.646C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP1_Strong, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964742/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2704 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0011168 infores:hetionet CHEBI:64028 biolink:causes UMLS:C1744587 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C1744587 infores:hetionet CHEBI:63638 biolink:causes MONDO:0017427 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0206762 infores:hetionet NCBIGene:1293 biolink:causes MONDO:0958236 infores:monarchinitiative not_provided not_provided HGNC:2213 MONDO:0958236 uuid:0821b0aa-cc08-4554-89a9-6e6190c1660d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0009806 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0948594 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0009450 infores:hetionet CHEBI:7514 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0917801 infores:hetionet CHEBI:8890 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020580 infores:hetionet CHEBI:4636 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0085631 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0029134 infores:hetionet CHEBI:31536 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0687713 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0475858 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0038661 infores:hetionet CHEBI:3510 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0002792 infores:hetionet CHEBI:8707 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037299 infores:hetionet CHEBI:4784 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0004604 infores:hetionet CHEBI:6775 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085077 infores:hetionet CHEBI:8713 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0023052 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009319 infores:hetionet CHEBI:9150 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0151632 infores:hetionet CHEBI:60761 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0009676 infores:hetionet CHEBI:46195 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0520966 infores:hetionet CHEBI:4909 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0041582 infores:hetionet CHEBI:38545 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0948594 infores:hetionet CHEBI:9168 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0558489 infores:hetionet CHEBI:5790 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020580 infores:hetionet CHEBI:4466 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0000731 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0242350 infores:hetionet CHEBI:6792 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0917801 infores:hetionet CHEBI:3242 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C2939147 infores:hetionet CHEBI:38562 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0014457 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0521591 infores:hetionet CAID:CA386959897 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959897 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.425C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to tyrosine at codon 142 (p.(Ser142Tyr)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.425C>T, p.Ser142Phe, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser142Tyr (PM5_Supporting). This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting), and was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, however PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative, C-peptide positive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, [internal lab contributors]). Taken together, this evidence supports a classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.1.0, approved 10/10/2025): PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959897/MONDO:0015967/017 2025-11-18 2025-11-18 Autosomal dominant inheritance HP:0000006 Supports CAID:CA414807568 biolink:causes MONDO:0044970 infores:clingen CAID:CA414807568 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS3, PM2 The m.10931T>C (p.S58P) variant in MT-ND4 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 25, 2023. This variant is included in a manuscript detailing mitochondrial DNA analyses but detailed clinical information is not provided (PMID: 23463613). There are no additional individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.013%, 8/61,883; gnomAD v3.1.2: 0.211%, 119/56,428 homoplasmic occurrences, three heteroplasmic occurrences; Helix: 0.022%, 44/195,893 homoplasmic occurrences). The computational predictor APOGEE1 gives a consensus rating of neutral with a score of 0.43 (Min=0, Max=1; BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414807568/MONDO:0044970/015 2023-04-25 2025-06-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:68478 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011849 infores:hetionet CHEBI:91583 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0687713 infores:hetionet CHEBI:42797 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0025222 infores:hetionet CHEBI:17688 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0085632 infores:hetionet GO:0060657 biolink:causes GO:0060443 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0060443 UMLS:C0145867 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0004093 infores:hetionet CHEBI:2668 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C1368065 infores:hetionet CHEBI:8412 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0085632 infores:hetionet CHEBI:63630 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0162557 infores:hetionet CHEBI:119915 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0600142 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0005741 infores:hetionet CHEBI:31536 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0020621 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235416 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0877584 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0877584 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0233494 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0243026 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0232849 infores:hetionet GO:0010724 biolink:causes GO:0060216 infores:ubergraph knowledge_assertion manual_agent GO:0010724 GO:0060216 CHEBI:49662 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0948692 infores:hetionet CHEBI:4735 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0027497 infores:hetionet CHEBI:15367 biolink:causes MONDO:0022096 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085653 infores:hetionet CHEBI:16899 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0151799 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0017152 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0239885 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0239885 infores:hetionet CAID:CA023798 biolink:causes MONDO:0007750 infores:clingen CAID:CA023798 MONDO:0007750 PMID: Uncertain Significance PP3 BA1, BP1, BP4, BP3, BP2, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM2, PM6, PP2, PP4, PP1, BS2 The NM_000527.5(LDLR):c.967G>A (p.Gly323Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP3 - REVEL = 0.871. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023798/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:46557 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0239150 infores:hetionet CAID:CA201278 biolink:causes MONDO:0010278 infores:clingen CAID:CA201278 MONDO:0010278 PMID: Benign BA1 The allele frequency of the c.*5_*8delinsTT variant (denoted as c.*5_*6del + c.*8 A>T) in SLC9A6 is 0.27% in European (non-Finnish) sub population in gnomAD v4.0, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.*5_*8delinsTT variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA201278/MONDO:0010278/033 2024-04-18 2024-07-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:6888 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0040046 infores:hetionet CHEBI:3175 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0023380 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0042109 infores:hetionet CHEBI:5004 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0033774 infores:hetionet CHEBI:50922 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C2242996 infores:hetionet NCBIGene:5718 biolink:causes MONDO:0054591 infores:monarchinitiative not_provided not_provided HGNC:9557 MONDO:0054591 uuid:19f00c43-c43c-414f-8cfc-c7968feb6f05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0023222 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002871 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0015397 infores:hetionet CAID:CA8602674 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602674 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2, PP4, BA1 The NM_000419.5(ITGA2B):c.2449-11C>T variant is a intronic variant variant that is not predicted by SpliceAI to impact splicing and the nucleotide is only moderately conserved, as shown by phyloP score of 1.044 (BP4, BP7). The highest population minor allele frequency in gnomAD v3.1.2 is 0.0007726 (32/41418 alleles) in the African/African American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting so no allele frequency criteria were met. In addition, no cases of the variant segregating with Glanzmann thrombasthenia were found in the literature. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia with the following ACMG/AMP applied, as specified by the ClinGen PD VCEP: BP4, BP7 (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602674/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8707 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0039231 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0233523 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233523 infores:hetionet CHEBI:39867 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0035455 infores:hetionet CHEBI:7507 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0038238 infores:hetionet CHEBI:9586 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0232461 infores:hetionet CHEBI:3696 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002994 infores:hetionet CHEBI:71272 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0542571 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009450 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0041834 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013395 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853619 infores:hetionet NCBITaxon:5059 biolink:causes MONDO:0005657 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5059 MESH:D001228 DB01167_MESH_D001228_1 NCBIGene:9568 biolink:causes MONDO:0033368 infores:monarchinitiative not_provided not_provided HGNC:4507 MONDO:0033368 uuid:8676cbb5-4625-4d4c-a74e-63b2fa48fc18 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA014162 biolink:causes MONDO:0004994 infores:clingen CAID:CA014162 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3853+7C>T variant in the MYH7 gene is 0.32% (239/66734) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014162/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:1763 biolink:causes MONDO:0970950 infores:monarchinitiative not_provided not_provided HGNC:2939 MONDO:0970950 uuid:7de83a90-8ae9-4209-9292-1e3ea289c206 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0032285 infores:hetionet CHEBI:68584 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0520966 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0849918 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0857807 infores:hetionet CHEBI:4672 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0018681 infores:hetionet CHEBI:31623 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0037278 infores:hetionet GO:0070445 biolink:causes GO:0042063 infores:ubergraph knowledge_assertion manual_agent GO:0070445 GO:0042063 CHEBI:135935 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0162429 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0041349 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0349506 infores:hetionet CHEBI:63618 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0033774 infores:hetionet CHEBI:6359 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0020488 infores:hetionet CHEBI:2948 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0008370 infores:hetionet CAID:CA10644606 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644606 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*4147C>G is a UTR variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.71)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644606/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0243026 infores:hetionet CHEBI:63616 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0039070 infores:hetionet CHEBI:28445 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0456909 infores:hetionet CHEBI:27974 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0700345 infores:hetionet CAID:CA392335055 biolink:causes MONDO:0007947 infores:clingen CAID:CA392335055 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PS4_Supporting, PM2_Supporting, PM1_Strong PVS1, PM6, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PM4, PM3, PM5, PS3, PS1, PS2, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.6541T>C is a missense variant in FBN1 predicted to cause a substitution of cysteine by an arginine at amino acid 2181 (p.Cys2182Arg). It has been identified in one patient meeting clinical diagnostic criteria for Marfan syndrome, including thoracic aortic aneurysm and dissection (TAAD) and systemic involvement, and was found to segregate with TAAD and systemic features in the patient’s sibling (PP4; University of Tokyo). This variant has also been reported in two patients with TAAD, without additional phenotypes noted (PS4_supporting; PMID: 37042257, GeneDx internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/, v2.1.1, 3.1.2, 4.0.0). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.993). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PP2, PP3, PP4, PS4_supporting, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392335055/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:44185 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0600260 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002418 infores:hetionet CHEBI:16755 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0917801 infores:hetionet CAID:CA322080121 biolink:causes MONDO:0009276 infores:clingen CAID:CA322080121 MONDO:0009276 PMID: Benign BP4, BA1 The c.544G>T variant in GP1BB is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 182 (p.Ala182Ser). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.003260 (based on 259/71488alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.149, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BB function and SpliceAI predicts no effect on splicing (delta scores 0.00) (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BA1 and BP4 (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA322080121/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:39585 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0036974 infores:hetionet CHEBI:32221 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0038325 infores:hetionet CHEBI:17650 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0004093 infores:hetionet CHEBI:64317 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0040822 infores:hetionet CHEBI:71941 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0497156 infores:hetionet CHEBI:3647 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0002792 infores:hetionet CHEBI:68584 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C1443060 infores:hetionet CHEBI:46195 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0233477 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020039 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0015397 infores:hetionet CHEBI:63629 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C2047937 infores:hetionet CHEBI:45863 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234632 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013595 infores:hetionet CHEBI:7445 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0013428 infores:hetionet CHEBI:50648 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0022568 infores:hetionet CHEBI:9434 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235996 infores:hetionet CHEBI:41977 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0017152 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0426576 infores:hetionet CHEBI:3082 biolink:causes MONDO:0010138 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0040156 infores:hetionet CAID:CA228457 biolink:causes MONDO:0013304 infores:clingen CAID:CA228457 MONDO:0013304 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PS4_Supporting, PM4 PP1 The NM_000552.5(VWF):c.3831_3833del (p.Asp1277_Leu1278delinsGlu) variant is predicted to cause a change in the length of the protein due to an in-frame loss of 1 amino acid in a non-repeat region (PM4). This variant is absent from gnomAD v4.1 (PM2_Supporting). At least 1 patient (P3F1II1) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 3 IU/dL), low activity/VWF:Ag ratio (0.17), and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID: 16985174). Additional consistent phenotypes were also reported in the patient including FVIII activity consistent with VWF antigen (ratio >0.7). This variant has been reported in at least 1 additional proband meeting PP4 laboratory phenotype criteria (PS4_supporting; PMID: 37732159). The additional patient is reported as VWD type 2M and this variant can not be definitely classified as type 2A, type 2M or type 2A/2M at this time. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal dominant von Willebrand disease type 2 based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM4, PM2_supporting, PP4_moderate, PS4_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228457/MONDO:0013304/081 2025-02-04 2025-02-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2453 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013595 infores:hetionet NCBIGene:5546 biolink:causes MONDO:0003789 infores:monarchinitiative not_provided not_provided HGNC:9343 MONDO:0003789 uuid:fcabc1c9-3829-429c-bf09-64385f6933da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42355 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C1443060 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0014868 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0027709 infores:hetionet CHEBI:75722 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018524 infores:hetionet GO:1903684 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:1903684 GO:0048477 CHEBI:161680 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0231218 infores:hetionet CHEBI:681569 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0030196 infores:hetionet CHEBI:2666 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0033774 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0178421 infores:hetionet CHEBI:6904 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0026821 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0429097 infores:hetionet CHEBI:8356 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037036 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027765 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0013395 infores:hetionet CHEBI:168396 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0031154 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0333355 infores:hetionet CL:0002312 biolink:causes MONDO:0019927 infores:ubergraph knowledge_assertion manual_agent CL:0002312 MONDO:0019927 CHEBI:45367 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0003537 infores:hetionet CHEBI:9123 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085631 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0015395 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0015395 infores:hetionet CAID:CA6264590 biolink:causes MONDO:0700270 infores:clingen CAID:CA6264590 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PVS1_Strong BA1, BS1 The ATM c.332-1G>A variant is predicted to create an NMD-escaping transcript resulting in a loss of part of the HEAT repeat domain (PVS1_strong). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID: 10980530, PM3_strong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6264590/MONDO:0700270/020 2022-11-22 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44185 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0011849 infores:hetionet NCBIGene:2064 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:3430 MONDO:0008170 uuid:2b9e8b12-a2a0-42ac-be1a-b0d1edc9c649 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes UMLS:C0860728 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0860728 infores:hetionet CHEBI:46195 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0001824 infores:hetionet CHEBI:4027 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0014742 infores:hetionet CAID:CA23575009 biolink:causes MONDO:0100368 infores:clingen CAID:CA23575009 MONDO:0100368 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000329.3(RPE65):c.361dup (p.Ser121fs) frameshift variant introduces a premature stop codon in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1). It is reported in the literature in a compound heterozygous state in at least one proband (by whole exome sequencing) who was diagnosed with Leber congenital amaurosis and exhibits infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PMID: 30870047, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA23575009/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4814 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0004134 infores:hetionet NCBIGene:79955 biolink:causes MONDO:0011558 infores:monarchinitiative not_provided not_provided HGNC:26257 MONDO:0011558 uuid:6e350f46-e5a5-477f-8641-0a4c3687f488 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0948594 infores:hetionet CHEBI:49375 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151699 infores:hetionet CHEBI:6375 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018932 infores:hetionet CHEBI:8888 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0851578 infores:hetionet CHEBI:2453 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0022107 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020538 infores:hetionet CHEBI:2682 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0086565 infores:hetionet CHEBI:3242 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0242184 infores:hetionet CAID:CA2573157354 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157354 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-16C>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.87) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157354/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4995 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0042109 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0595877 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0040479 infores:hetionet CHEBI:49662 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0857305 infores:hetionet CHEBI:4708 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0015230 infores:hetionet CHEBI:9943 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0000731 infores:hetionet CHEBI:8673 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0042963 infores:hetionet CHEBI:93305 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0038999 infores:hetionet CHEBI:63605 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0009782 infores:hetionet NCBIGene:538 biolink:causes MONDO:0010338 infores:monarchinitiative not_provided not_provided HGNC:869 MONDO:0010338 uuid:ea95ab2e-b23c-490a-a0b9-788f953fc514 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1167965 infores:hetionet CHEBI:84500 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C2607914 infores:hetionet CAID:CA012732 biolink:causes MONDO:0005045 infores:clingen CAID:CA012732 MONDO:0005045 PMID: Likely Pathogenic PM2, PM5, PP3, PS4 PS3, PM1, PM6, PP1, BS3, BP4, PS1, PS2 The NM_000257.4(MYH7):c.2608C>T (p.Arg870Cys) variant has been reported in >15 individuals with HCM (PS4; Anan 2000 PMID:10862102; Woo 2003 PMID:12975413; Uchiyama 2009 PMID:19149795; Funada 2010 PMID:20975235; Otsuka 2012 PMID:22112859; Fujita 2013 PMID: 24621997; Wang 2014 PMID:25132132; Mademont-Soler 2017 PMID:28771489; Hayashi 2018 PMID:29907873; Mak 2018 PMID:30022097; Inagaki 2018 PMID:30206291; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in 2 affected individual with HCM from 2 families (Otsuka 2011 PMID 22112859; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was identified in 0.0007% (FAF 95% CI; 3/113730) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org/). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257). Additionally, a different pathogenic missense variant has been previously identified at this codon which indicates that this residue may be critical to the function of the protein (PM5; NM_000257.4(MYH7):c.2609G>A (p.Arg870His) - Variation ID 14120). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PM2, PM5, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012732/MONDO:0005045/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports UNII:UMD7G2653W biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0006266 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0234215 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0948070 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0948070 infores:hetionet CAID:CA2061034 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061034 MONDO:0015924 PMID: Likely Benign BS1 PP3, BP4 The BMPR2 c.86A>G missense variant is predicted to cause a substitution of asparagine to serine at amino acid position 29 (p.Asn29Ser) in exon 2 within the signal peptide domain. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.006265 (v4.1.0 is 0.007668) in African/African American population, which is higher than the ClinGen Pulmonary Hypertension VECP threshold ≥0.1% for BS1, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. In summary, the variant meets the criteria to be classified as variant of likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061034/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:41977 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0040034 infores:hetionet CHEBI:7492 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C3665347 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0027947 infores:hetionet NCBIGene:10483 biolink:causes MONDO:0014802 infores:monarchinitiative not_provided not_provided HGNC:10702 MONDO:0014802 uuid:e50d08ea-22b5-4e36-b462-605f2955d2ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0002170 infores:hetionet CHEBI:63584 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0085593 infores:hetionet CHEBI:465284 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0006625 infores:hetionet CHEBI:144551 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0004096 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0162830 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0009806 infores:hetionet UMLS:C0065374 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0015672 infores:hetionet CHEBI:2611 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0042963 infores:hetionet NCBIGene:10112 biolink:causes MONDO:0030330 infores:monarchinitiative not_provided not_provided HGNC:9787 MONDO:0030330 uuid:5381ab23-3292-4012-9a43-84e4ffde729b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:79699 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0032285 infores:hetionet CAID:CA2499225884 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225884 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PM4, PM1, PM3, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.149_158dup (p.Ser53fs) is a frameshift variant that is predicted to undergo nonsense mediated decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Frameshift variant downstream of c.98 (in transcript NM_001754.5) (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225884/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9130 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0013404 infores:hetionet CHEBI:49375 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0344232 infores:hetionet UMLS:C0065374 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0011124 infores:hetionet CHEBI:8890 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0025287 infores:hetionet CHEBI:480999 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0011603 infores:hetionet CHEBI:15940 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0006277 infores:hetionet CAID:CA414447224 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447224 MONDO:0010604 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PM5, PP3 The NM_000133.4:c.1304G> variant in F9 is a missense variant predicted to cause substitution of Cys by Phe at amino acid 435 (p.Cys435Phe). This variant has been reported in 1 proband meeting F9 phenotype criteria (PS4_Supporting; PMID: 19686262). The computational predictor REVEL gives a score of 0.965, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Another missense variant c.1304G>A (p.Cys435Tyr) in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). This variant is absent from gnomAD v2, v3 and v4. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_Supporting, PM2_Supporting, PP3, PM5. (Version 1.0.0, 10/05/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447224/MONDO:0010604/080 2024-05-09 2024-05-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:9654 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0948594 infores:hetionet CHEBI:3508 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0600142 infores:hetionet CHEBI:5855 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018524 infores:hetionet CHEBI:40279 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2364111 infores:hetionet CHEBI:36704 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0027497 infores:hetionet CAID:CA395121845 biolink:causes MONDO:0700272 infores:clingen CAID:CA395121845 MONDO:0700272 PMID:31757951 Uncertain Significance PM2_Supporting, BP1 PS3, BS1, PP3, BP4, BA1 The c.2734T>G variant in PALB2 is a missense variant predicted to cause a substitution of tryptophan by glycine at amino acid 912 (p.Trp912Gly). This variant is absent in the gnomAD v2.1.1 cohort. This variant showed an abnormal read out in multiple protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as VUS for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM2_supporting, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA395121845/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8382 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151905 infores:hetionet CHEBI:2639 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0009421 infores:hetionet CHEBI:31236 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0008350 infores:hetionet CHEBI:3478 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0002994 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0030312 infores:hetionet CHEBI:585948 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0085606 infores:hetionet GO:0080092 biolink:causes GO:0048468 infores:ubergraph knowledge_assertion manual_agent GO:0080092 GO:0048468 CHEBI:39669 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0009676 infores:hetionet CHEBI:70735 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0028084 infores:hetionet CHEBI:68478 biolink:causes NCIT:C50739 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0262627 infores:hetionet UMLS:C0145867 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0030252 infores:hetionet CHEBI:42068 biolink:causes UMLS:C1963921 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C1963921 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018799 infores:hetionet CHEBI:36795 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1321898 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043349 infores:hetionet CHEBI:4466 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0011991 infores:hetionet CHEBI:5134 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0026821 infores:hetionet CHEBI:64355 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0014724 infores:hetionet CAID:CA229291 biolink:causes MONDO:0009861 infores:clingen CAID:CA229291 MONDO:0009861 PMID:15503242PMID:15503242 Likely Pathogenic PM3, PM5, PM2, PP4_Moderate, PP3 PAH-specific ACMG/AMP criteria applied: PM2: Absent from controls in ExaC, 100 Genomes, ESP, and gnomAD; PP3: Deleterious effected predicted by SIFT, Polyphen2, and MutationTaster; PM5: A345S (Variant ID 102484) predicted pathogenic in ClinVar; PP4_Moderate: Found in two individuals with Classic PKU on exon 10.Urinary pterin analysis and dihydropteridine reductase (DHPR) assay were performed t (PMID:15503242); PM3: Found in trans with R243Q (pathogenic in ClinVar). (PMID:15503242). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229291/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015393 infores:hetionet CHEBI:17263 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0011570 infores:hetionet CHEBI:63605 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0011168 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0021053 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0235280 infores:hetionet CAID:CA359430531 biolink:causes MONDO:0012163 infores:clingen CAID:CA359430531 MONDO:0012163 PMID: Pathogenic PP4, PM2_Supporting, PM3, PVS1 The c.538-1G>A (NM_002185.5) variant in IL7R occurs within the canonical splice acceptor site (-1) of intron 4. It is predicted to cause either skipping of biologically relevant exon 5 or use of cryptic splicing site 25 nt upstream (predicted by varSEAK) or 17 nt downstream (predicted by SpliceAI) of the canonical site. In all cases, the variant is predicted to result in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. PVS1 is met.The Popmax filtering allele frequency (the upper threshold of the 95% CI of 2/112934) of the c.538-1G>A variant in IL7R is 0.000002940 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Additionally, no homozygous individuals have been reported.At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + Reduced CD127 expression (1pt) + T-B+NK+ lymphocyte subset profile (0.25pt), which is highly specific for SCID. (Total of 1.75 points, PP4 is met, PMID 9843216). The same patient was compound heterozygous for the variant and p.Trp217Ter, likely pathogenic according to SCID VCEP specifications. The phase of those was confirmed in trans by cloning assay (1pt in total, PM3 is met).In summary, this variant is classified as Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PVS1, PM2_Supporting, PM3, PP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359430531/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100246 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0013395 infores:hetionet CAID:CA120555 biolink:causes MONDO:0044970 infores:clingen CAID:CA120555 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PS3_Supporting PS2, PM6 The m.8363G>A variant in MT-TK has been reported in at least 30 individuals with primary mitochondrial disease from 12 kindreds. Features seen in affected individuals include Leigh syndrome and myoclonic epilepsy with ragged red fibers (MERRF), as well as myopathy, peripheral neuropathy, ataxia, cardiomyopathy, sensorineural hearing loss, ophthalmoplegia, and lipomas. Heteroplasmy levels of this variant in affected individuals is variable, ranging from 40-97% (PS4_moderate; PMIDs: 8651277, 9052804, 10868777, 11108511, 19278689, 18319067, 19370763, 10102446, 16326995, 9932960). This variant segregated with disease in multiple affected family members in multiple families and several healthy family members had lower to undetectable levels (PP1_moderate; PMIDs: 9052804, 10868777, 10102446, 9932960). There are no confirmed de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 94.3 percentile, as does HmtVar with a score of 0.75 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing and cybrid analysis further support the functional impact of this variant (PS3_suporting). Single fiber testing showed the variant was significantly higher in COX-negative ragged red fibers (n = 5; 97.3% ± 2.5) than in normal fibers (n = 5; 89.2 ± 8.3; p < 0.05; PMID: 9932960). Cybrid studies showed that clones with the variant present at homoplasmy had statistically significant decreases in Complex I, ATP synthase, and oxygen consumption (PMIDs: 15554876, 25909222). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3, PP1_moderate, PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120555/MONDO:0044970/015 2023-03-13 2023-03-17 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria UNII:G4PX8C4HKV biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0036572 infores:hetionet CHEBI:63630 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0687713 infores:hetionet CHEBI:7956 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0027765 infores:hetionet CHEBI:63617 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0030252 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011991 infores:hetionet NCBIGene:6519 biolink:causes MONDO:0009067 infores:monarchinitiative not_provided not_provided HGNC:11025 MONDO:0009067 uuid:420a905f-8dcd-41d9-8504-46ec318b28e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0004936 infores:hetionet CHEBI:35553 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0016382 infores:hetionet CHEBI:4858 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C2830004 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0017160 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006384 infores:hetionet CHEBI:64310 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0438717 infores:hetionet CHEBI:9907 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0392171 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0039503 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0233494 infores:hetionet CHEBI:7915 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019080 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042109 infores:hetionet CHEBI:41774 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0016655 infores:hetionet CAID:CA16041879 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041879 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000152.5:c.169C>T (p.Gln57Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 (there are 20 exons in GAA), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One individual with symptoms consistent with late-onset Pompe disease and deficient GAA activity in lymphocytes has been reported who is compound heterozygous for the variant and a missense variant, c,655G>A (p.Gly219Arg), in GAA (PMID 29124014) (PP4_Moderate). The allelic data for this patient will be used in the classification of p.Gly219Arg and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on November 6, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041879/MONDO:0009290/010 2023-11-06 2024-04-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA8814965 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814965 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000152.5:c.692+1G>C variant alters the canonical donor splice site of intron 3 of GAA. It is predicted to cause skipping of biologically-relevant-exon 4 (GAA has 20 exons), resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. A fibroblast cell line derived from a patient who is compound heterozygous for the variant showed reduced GAA enzyme activity via a fluorometric assay using 4-MU. The relative GAA enzyme activity was 3.2% (normal range of GAA activity in fibroblasts is 58.5 +/- 28.1%) (PMID: 19046416). Additionally, RT-PCR analysis performed on cultured fibroblasts from a patient who is compound heterozygous for the variant showed lack of the corresponding mutant transcript, confirming its deleterious effect (PMID: 16917947) (PVS1). At least two patients with findings consistent with Pompe disease have been reported with this variant. Reduced GAA activity was reported for both patients but laboratory values were not provided. One patient, diagnosed with Pompe disease at 5 years of age, showed increased CK levels at 4 years and started ERT at 11 years (PMID: 24395639). The second patient was diagnosed with Pompe disease and presented with clinical features including mild muscular symptoms, mobility problems, weakness and fatigue (PMID: 1691794) (PP4_Moderate). These two patients are compound heterozygous for the variant and another variant in GAA, either c.-32-13T>G (PMID: 16917947) or c.1645G>C (p.G549R) (PMID: 24395639); the phase of the variants is unknown. The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. (PM3_Supporting). In gnomAD v4.1.0, the highest population minor allele frequency is 0.0000008522 (1/1173500 alleles; 0 homozygotes) in the European, (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In gnomAD v2.1.1, the highest population minor allele frequency is 0.000008988 (1/111256 alleles; 0 homozygotes) in the European, (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008522 (1/1173500 alleles; 0 homozygotes) in the European, (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 972793). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 7, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814965/MONDO:0009290/010 2025-01-07 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7773 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0456909 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0008325 infores:hetionet CHEBI:35778 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0034063 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151436 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0494165 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0494165 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0041657 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027813 infores:hetionet CHEBI:6472 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0085932 infores:hetionet CHEBI:8888 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232726 infores:hetionet CHEBI:64354 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0027497 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0948525 infores:hetionet CHEBI:64355 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151205 infores:hetionet CHEBI:5893 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0030554 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0036679 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0036679 infores:hetionet NCBIGene:2318 biolink:causes MONDO:0014883 infores:monarchinitiative not_provided not_provided HGNC:3756 MONDO:0014883 uuid:ef8864bc-b3f8-4d59-a38b-a6b74a964a82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64354 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0027769 infores:hetionet CHEBI:9168 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0036974 infores:hetionet CHEBI:134966 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0028734 infores:hetionet CHEBI:142290 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0232462 infores:hetionet CHEBI:31643 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0542571 infores:hetionet CHEBI:42068 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0687713 infores:hetionet CHEBI:27504 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0002871 infores:hetionet CAID:CA082317 biolink:causes MONDO:0007783 infores:clingen CAID:CA082317 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate, PP1_Moderate PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with methionine at codon 2354 of the RYR1 protein, p.(Val2354Met). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:23558838, PMID:24361844). This variant segregates with MHS in five individuals PP1_Moderate (PMID:24361844). An ex vivo functional study on lymphoblasts from a single family was published for this variant showing a decreased EC50 for 4-CmC, multiple unrelated samples are required to fulfil PS3 (PMID:2461844). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.867) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA082317/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:48273 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0041912 infores:hetionet CHEBI:3286 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0042063 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151883 infores:hetionet CHEBI:48273 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0236024 infores:hetionet CHEBI:63598 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0037299 infores:hetionet CHEBI:50922 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1306341 infores:hetionet CAID:CA415086677 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086677 MONDO:0010305 PMID: Uncertain Significance PS3_Supporting, PM2_Supporting The NM_005629.4:c.1261G>C variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a glycine for an arginine at amino acid position 421 (p.Gly421Arg). This variant has not been reported in the published literature in individuals with creatine transporter deficiency. This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.539 which is neither above the threshold of 0.75 for PP3 nor below the threshold of 0.2 (BP4), such that neither PP3 nor BP4 applies. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086677/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:82716 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0015967 infores:hetionet GO:1905770 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:1905770 GO:0007369 CHEBI:72564 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0024312 infores:hetionet CHEBI:63791 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0024305 infores:hetionet CHEBI:8871 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038450 infores:hetionet CHEBI:3716 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0917801 infores:hetionet CAID:CA16607903 biolink:causes MONDO:0009290 infores:clingen CAID:CA16607903 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM5_Supporting PM3, PS3 The NM_000152.5:c.2316G>T variant in GAA is a missense variant predicted to cause substitution of Tryptophan by Cysteine at amino acid 772 (p.Trp772Cys). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant and this variant has not been reported in the literature in any individuals with Pompe disease. The computational predictor REVEL gives a score of 0.942 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.2314T>C (p.Trp772Arg) (PMID: 31619483, 18757064, ClinVar ID: 552527) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 392862, 2 star review status) with 3 submitters classifying the variant as Uncertain Significance. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3, PM2_Supporting, PM5_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607903/MONDO:0009290/010 2022-09-19 2022-09-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63577 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0011603 infores:hetionet CHEBI:5128 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0018834 infores:hetionet CHEBI:36704 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0497156 infores:hetionet CHEBI:8665 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0232292 infores:hetionet CHEBI:6539 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C3665347 infores:hetionet CHEBI:2682 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0017181 infores:hetionet UMLS:C1709429 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0085649 infores:hetionet CHEBI:8499 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0151942 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0003123 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0860803 infores:hetionet CHEBI:9448 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0030554 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042109 infores:hetionet CHEBI:8028 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0013362 infores:hetionet CHEBI:5801 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0011991 infores:hetionet CHEBI:68584 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0232461 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151313 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0836924 infores:hetionet CHEBI:3219 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0236000 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0178298 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020676 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027769 infores:hetionet CHEBI:6076 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0236075 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027813 infores:hetionet CHEBI:6367 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151827 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020621 infores:hetionet CHEBI:4798 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0085631 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0009806 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0521591 infores:hetionet NCBIGene:112755 biolink:causes MONDO:0014517 infores:monarchinitiative not_provided not_provided HGNC:18539 MONDO:0014517 uuid:694520d8-0375-4d5f-8ef1-2a1318f3074b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31515 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0018418 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0855440 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0855440 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0041912 infores:hetionet NCBIGene:6709 biolink:causes MONDO:0957813 infores:monarchinitiative not_provided not_provided HGNC:11273 MONDO:0957813 uuid:41978378-e200-4b20-8dab-99b17fb62d18 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0086439 infores:hetionet CHEBI:10102 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013362 infores:hetionet CHEBI:87715 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0015402 infores:hetionet CHEBI:31625 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0015230 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0233494 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0015397 infores:hetionet CHEBI:9435 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0036396 infores:hetionet CHEBI:5002 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0428977 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0235620 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0010692 infores:hetionet CAID:CA246543 biolink:causes MONDO:0100453 infores:clingen CAID:CA246543 MONDO:0100453 PMID: Uncertain Significance PM2_Supporting BP4, BS4, PP3 The NM_000180.4(GUCY2D):c.1499C>T (p.Pro500Leu) variant is predicted to change the proline at position p.500 to leucine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0001853, with 299 alleles / 1,613,662 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.598, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant has been observed in the heterozygous state in some but not all affected members of a family with autosomal dominant retinitis pigmentosa. Because the heterozygous state of the variant is not relevant to the disease mode of inheritance, BS4 was not met (PMID: 22277662). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA246543/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:40279 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0035333 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0232197 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234458 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0860239 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0233472 infores:hetionet CHEBI:6402 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0029118 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0004936 infores:hetionet CHEBI:110423 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0020598 infores:hetionet CHEBI:77260 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C3665386 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014742 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0034902 infores:hetionet GO:1903186 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1903186 GO:0019953 CHEBI:63618 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0234233 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040053 infores:hetionet CHEBI:93363 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0004093 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1269683 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235818 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0518015 infores:hetionet CHEBI:5134 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0012833 infores:hetionet NCBIGene:1656 biolink:causes MONDO:0032851 infores:monarchinitiative not_provided not_provided HGNC:2747 MONDO:0032851 uuid:78811896-61d3-41a0-a28f-e9fffba4c036 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:388551 biolink:causes MONDO:0013823 infores:monarchinitiative not_provided not_provided HGNC:31948 MONDO:0013823 uuid:2565f186-751b-4fc1-b85e-a5379c95db5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0027497 infores:hetionet NCBIGene:79947 biolink:causes MONDO:0013468 infores:monarchinitiative not_provided not_provided HGNC:20603 MONDO:0013468 uuid:f596910b-a1f2-45ef-8de1-eb7067df04b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0006145 infores:hetionet CHEBI:3614 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0013378 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0574067 infores:hetionet CAID:CA658795274 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795274 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2136_2137del (p.Phe713ProfsTer23) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 15/20, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A patient with this variant was reported to have deficient GAA activity and to be on enzyme replacement therapy for Pompe disease (PMID: 25614309, 27896092)(PP4). This patient is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-32-13T>G ( PMID: 25614309, 27896092)(PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 556718; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Storage Disorders VCEP (Specification Version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4.(Classification approved on August 17th, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795274/MONDO:0009290/010 2021-08-19 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7565 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0013604 infores:hetionet CHEBI:6887 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0240211 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C2363731 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0521592 infores:hetionet CHEBI:6367 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0024141 infores:hetionet CHEBI:87681 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0041969 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0424740 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0424740 infores:hetionet CHEBI:4858 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0012569 infores:hetionet CHEBI:6897 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0027051 infores:hetionet CAID:CA015397 biolink:causes MONDO:0700269 infores:clingen CAID:CA015397 MONDO:0700269 PMID: Likely Benign BP1_Strong, BP5, BS1_Supporting The c.2471T>C variant in BRCA2 is a missense variant predicted to cause substitution of leucine by serine at amino acid 824 (p.Leu824Ser). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00002053 in the East Asian population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.01, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.30789 (based on Family History LR=0.30789), within the thresholds for supporting benign evidence (LR ≥0.23 & <0.48) (BP5 met; PMIDs 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BS1_Supporting, BP5). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA015397/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31705 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0549249 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0027765 infores:hetionet CHEBI:3125 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0232487 infores:hetionet CHEBI:3756 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0043352 infores:hetionet CHEBI:44423 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0237849 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042075 infores:hetionet NCBIGene:2530 biolink:causes MONDO:0020775 infores:monarchinitiative not_provided not_provided HGNC:4019 MONDO:0020775 uuid:d23aed3b-75f4-40a8-991f-19828c82c875 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C2047937 infores:hetionet NCBIGene:5137 biolink:causes MONDO:0029137 infores:monarchinitiative not_provided not_provided HGNC:8776 MONDO:0029137 uuid:ac85be5e-8d5f-4aa2-a5f2-e46824742438 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA658824381 biolink:causes MONDO:0007947 infores:clingen CAID:CA658824381 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_000138.5 c.8051delinsTT variant in FBN1 is predicted to cause a frameshift resulting in a premature stop codon at position 2704 (p.Gly2684ValfsTer21), leading to an absent or disrupted protein product (PVS1). This variant was found in a pediatric proband with a systemic score of 7 and an aortic root Z-score >3, which is a highly specific phenotype for Marfan syndrome (PP4); this proband also carried another variant in FBN1, p.Tyr20Cys, which was considered a variant of unknown significance (internal data-Ghent University Hospital). This variant has been reported 1 time in ClinVar as a variant of uncertain significance (Variation ID: 549451). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_Supporting, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824381/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8888 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011551 infores:hetionet CHEBI:63598 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0039070 infores:hetionet NCBIGene:81615 biolink:causes MONDO:0859378 infores:monarchinitiative not_provided not_provided HGNC:25380 MONDO:0859378 uuid:9cada281-4576-48da-84ba-433f17fe959d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA7330935 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330935 MONDO:0100216 PMID: Likely Benign BP4, BS2 PM2, BA1, PP3, PM5, PM1, PS1, PS3, BS1, BS3 The NM_177438.3:c.4199A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1400 (p.Asp1400Gly). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory and has been observed in a homozygous state in one healthy individual (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000047 (76/1612760 alleles) with a highest population minor allele frequency of 0.000056 (66/1179824 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.142; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BP4. (Bayesian Points: -5; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330935/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:131512 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0085593 infores:hetionet CHEBI:36795 biolink:causes HP:0031356 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0541798 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002170 infores:hetionet CHEBI:175901 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0042384 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0014868 infores:hetionet CHEBI:2663 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0036104 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0400823 infores:hetionet CHEBI:9460 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0030193 infores:hetionet CHEBI:45863 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013428 infores:hetionet CHEBI:6062 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0600142 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018099 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0043352 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0525045 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0040485 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0017178 infores:hetionet NCBIGene:1785 biolink:causes MONDO:0008048 infores:monarchinitiative not_provided not_provided HGNC:2974 MONDO:0008048 uuid:3cbc0a87-73c1-47f1-bfbd-5f2c0fe6cea6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0424295 infores:hetionet CHEBI:5855 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0595916 infores:hetionet CHEBI:7820 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0027651 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0022650 infores:hetionet CHEBI:36795 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2047937 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0521839 infores:hetionet CHEBI:9599 biolink:causes MONDO:0043786 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0036749 infores:hetionet CHEBI:51230 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C2830004 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0004063 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0004063 infores:hetionet UMLS:C0009315 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0234518 infores:hetionet CHEBI:7577 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0151539 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0010709 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0003123 infores:hetionet CHEBI:38562 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0234233 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0233494 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011053 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006564 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0162823 infores:hetionet CHEBI:51032 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0863093 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0009782 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018802 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1262113 infores:hetionet CHEBI:6067 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0231528 infores:hetionet CHEBI:28901 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0016059 infores:hetionet CHEBI:2666 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0080274 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0278080 infores:hetionet CHEBI:47499 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0021141 infores:hetionet CHEBI:3996 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0003467 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0025517 infores:hetionet NCBIGene:2100 biolink:causes MONDO:0032590 infores:monarchinitiative not_provided not_provided HGNC:3468 MONDO:0032590 uuid:33ba721d-5cf9-4805-85a7-c7f3beb983da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63618 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0040264 infores:hetionet CHEBI:4856 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0037822 infores:hetionet CHEBI:4469 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0013395 infores:hetionet CHEBI:17245 biolink:causes MONDO:0800373 infores:ubergraph knowledge_assertion manual_agent CHEBI:17245 MONDO:0800373 CHEBI:9241 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0017152 infores:hetionet NCBIGene:26154 biolink:causes MONDO:0009443 infores:monarchinitiative not_provided not_provided HGNC:14637 MONDO:0009443 uuid:36fb6700-8375-420e-8137-30553fa81103 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2636 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0340464 infores:hetionet CHEBI:63623 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0033687 infores:hetionet CHEBI:49575 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0237314 infores:hetionet NCBIGene:9152 biolink:causes MONDO:0013827 infores:monarchinitiative not_provided not_provided HGNC:11051 MONDO:0013827 uuid:c534bc24-23bf-41d8-8367-12ad5dbeedd5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0015967 infores:hetionet GO:1901207 biolink:causes GO:0003007 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0003007 CHEBI:16899 biolink:causes UMLS:C1096732 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1096732 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0031350 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0026946 infores:hetionet NCBIGene:6611 biolink:causes MONDO:0010664 infores:monarchinitiative not_provided not_provided HGNC:11123 MONDO:0010664 uuid:8a51b0f5-4fb9-400c-bd1b-7b8af1f447b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3403 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0023218 infores:hetionet CHEBI:75722 biolink:causes MONDO:0020674 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232352 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0020546 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232498 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0019158 infores:hetionet CHEBI:520985 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C3665347 infores:hetionet CHEBI:6067 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0007859 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019158 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0677500 infores:hetionet CHEBI:134743 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0004093 infores:hetionet NCBIGene:2261 biolink:causes MONDO:0012833 infores:monarchinitiative not_provided not_provided HGNC:3690 MONDO:0012833 uuid:5ba7de31-34cb-432d-ad84-5c107ba2d4ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151605 infores:hetionet CAID:CA414798058 biolink:causes MONDO:0044970 infores:clingen CAID:CA414798058 MONDO:0044970 PMID: Uncertain Significance PP3 PP1, PS4, PS2, PS3, PM6, PM2 The m.8783G>A (p.G86E) variant in MT-ATP6 has been reported in one individual with primary mitochondrial disease to date however clinical details are not provided (PMID: 32652755). There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases (0.002%; one homoplasmic occurrence in MITOMAP; one homoplasmic and six heteroplasmic occurrences in gnomAD v3.1.2; four homoplasmic and nine heteroplasmic occurrences in the Helix database). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.59 (Min=0, Max=1; APOGEE2 score is 0.819), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414798058/MONDO:0044970/015 2024-12-09 2025-05-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8378 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0151908 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1608399 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1608399 infores:hetionet CHEBI:8499 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0149725 infores:hetionet CHEBI:51173 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0004134 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0574067 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0549373 infores:hetionet CHEBI:51230 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0035317 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0235146 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0015967 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0235848 infores:hetionet CAID:CA294397 biolink:causes MONDO:0100488 infores:clingen CAID:CA294397 MONDO:0100488 PMID: Likely Benign BS2 BS1, PM2 The NM_004360.5(CDH1):c.2204C>T (p.Ala735Val) is missense variant. The variant has been observed in >10 (188) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; PMID: 26898890; ClinVar: SCVs: SCV000186555.7, SCV000260700.10, SCV000210926.16; internal lab contributors). CDH1-VCEP recommended a variant to reach likely benign classification based on BS2 alone. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294397/MONDO:0100488/007 2024-03-25 2024-03-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:480999 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0017178 infores:hetionet CAID:CA410207187 biolink:causes MONDO:0100083 infores:clingen CAID:CA410207187 MONDO:0100083 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.623A>G (p.Gln208Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207187/MONDO:0100083/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3515 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C2129214 infores:hetionet CHEBI:31625 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0152227 infores:hetionet CHEBI:4995 biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0220994 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0004998 infores:hetionet CHEBI:5138 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0034886 infores:hetionet NCBIGene:4869 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:7910 MONDO:0018874 uuid:438ad79f-0720-4d04-9c7a-47453a1e0975 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92998 biolink:causes MONDO:0005195 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0341503 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0035078 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0574067 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0858259 infores:hetionet CHEBI:77260 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0239571 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0002418 infores:hetionet NCBIGene:55655 biolink:causes MONDO:0957230 infores:monarchinitiative not_provided not_provided HGNC:22948 MONDO:0957230 uuid:683d14b5-b630-4324-9fcc-ded3c087bd25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0549493 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0036983 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151577 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027651 infores:hetionet CHEBI:77260 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0547030 infores:hetionet CAID:CA616115579 biolink:causes MONDO:0100216 infores:clingen CAID:CA616115579 MONDO:0100216 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Moderate PS4 The NM_177438.3:c.2650+5G>A variant in DICER1 is an intronic variant occurring in intron 16. Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an in-frame splicing impact disrupting the RNAse IIIb domain, indicating that this variant impacts protein function (Internal lab contributors; PS3_Moderate). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PS3_Moderate, PP3. (Bayesian Points: 4; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA616115579/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28177 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0022107 infores:hetionet CHEBI:3561 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0149745 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1697542 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1697542 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0344320 infores:hetionet CHEBI:16914 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0011603 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042109 infores:hetionet CAID:CA080431 biolink:causes MONDO:0007783 infores:clingen CAID:CA080431 MONDO:0007783 PMID: Uncertain Significance PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with aspartic acid at codon 3938 of the RYR1 protein, p.(Gly3938Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted). However, a second variant classified as a variant of uncertain significance, p.(Arg2126Gln), was also identified in the proband, PS4 was not implemented (PMID:21455645). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.799 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA080431/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:4814 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C2047937 infores:hetionet CHEBI:47780 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013428 infores:hetionet CHEBI:92998 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0039231 infores:hetionet CHEBI:3242 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0011253 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0037274 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0029928 infores:hetionet CAID:CA412745404 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745404 MONDO:0100437 PMID: Pathogenic PM5_Supporting, PP1_Moderate, PP4_Moderate, PP3_Strong, PM2_Supporting PS4, BA1, BS1 NM_001034853.2(RPGR):c.283G>A (p.Gly95Arg) is a missense variant that replaces glycine with arginine at amino acid 95. Another missense variant in the same codon, NM_001034853.2(RPGR):c.284G>A (p.Gly95Glu) (PMID: 33598457), has been classified as likely pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (125) than the comparison variant (98), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits rod-cone dystrophy (1 pt) with onset during the teens (1 pt), genotyping by next-generation sequencing with a 105-gene panel that did not identify an alternative cause of retinal disease (2 pts), family history consistent with X-linked inheritance (2 pt) with female family members showing milder phenotypes (1 pt), reduced visual acuity (0.5 pts), and fundus mid-peripheral atrophy (0.5 pts), which together are highly specific for RPGR-related retinopathy (8 total pts, PMID: 28488341; PMID: 36882936, PP4_Moderate). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 28488341, PMID: 36882936). The computational predictor REVEL gives a score of 0.972, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.19 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PM5_Supporting, PP1_Moderate, PP3_Strong, and PP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745404/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:9123 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0271710 infores:hetionet NCBIGene:55005 biolink:causes MONDO:0013969 infores:monarchinitiative not_provided not_provided HGNC:21176 MONDO:0013969 uuid:5ccc9971-96d9-4a5a-9d4e-a055bc03885e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151610 infores:hetionet NCBIGene:7080 biolink:causes MONDO:0012593 infores:monarchinitiative not_provided not_provided HGNC:11825 MONDO:0012593 uuid:6d4ef9b3-fbb0-487e-a13a-17de1d076af7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91834 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013491 infores:hetionet CHEBI:47898 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085605 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0027051 infores:hetionet CHEBI:3698 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0004093 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0235431 infores:hetionet CHEBI:2567 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0025222 infores:hetionet CHEBI:27974 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0014173 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0027769 infores:hetionet CHEBI:2666 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0015967 infores:hetionet NCBITaxon:234 biolink:causes MONDO:0005683 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:234 MESH:D002006 DB00254_MESH_D002006_1DB00595_MESH_D002006_1DB01017_MESH_D002006_1DB02703_MESH_D002006_1DB01082_MESH_D002006_1DB00618_MESH_D002006_1DB13092_MESH_D002006_1 CHEBI:51137 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0018801 infores:hetionet CHEBI:31623 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0033774 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0002792 infores:hetionet CHEBI:5779 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0013144 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0019158 infores:hetionet CHEBI:3207 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0008031 infores:hetionet CHEBI:3534 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0022408 infores:hetionet CHEBI:135351 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0004093 infores:hetionet CAID:CA013590 biolink:causes MONDO:0004994 infores:clingen CAID:CA013590 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3337-3dupC variant in the MYH7 gene is 0.23% (146/54400) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013590/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9448 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0020615 infores:hetionet CHEBI:6538 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0541832 infores:hetionet CHEBI:8874 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009782 infores:hetionet CAID:CA10578903 biolink:causes MONDO:0017623 infores:clingen CAID:CA10578903 MONDO:0017623 PMID: Likely Benign BP7, BP4 PTEN c.18A>G (p.L6=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578903/MONDO:0017623/003 2016-10-12 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0065374 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0013447 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0221733 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0221733 infores:hetionet CAID:CA320454 biolink:causes MONDO:0015924 infores:clingen CAID:CA320454 MONDO:0015924 PMID: Uncertain Significance PM2 PP1, BP4, BA1 The BMPR2 c.797G>C variant is a missense variant predicted to cause an arginine to threonine substitution at amino acid 266 (p.Arg266Thr). The variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2 met). The REVEL score is 0.628 and does not meet PP3 (≥0.75) nor BP4 (<0.25) criteria for computational predicted impact on the gene product. Two unrelated idiopathic pulmonary arterial hypertension probands have been reported (PMID: 16429395, PMID: 19555857) but is below the threshold for PP1 (at least three probands). An additional proband with pulmonary arterial hypertension associated with another disease (PMID: 31727138) was not included in the count. Experimental data has not been reported for this variant. In summary, this variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2 (VCEP specifications version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA320454/MONDO:0015924/125 2024-05-02 2024-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9727 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C2830004 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0042029 infores:hetionet CHEBI:70735 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0392156 infores:hetionet CHEBI:9555 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0030781 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0042373 infores:hetionet CHEBI:63621 biolink:causes UMLS:C3665770 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C3665770 infores:hetionet CHEBI:553473 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0014518 infores:hetionet CHEBI:474053 biolink:causes HP:0032004 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0033778 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0079102 infores:hetionet CHEBI:32221 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C1167965 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020456 infores:hetionet CHEBI:6717 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002994 infores:hetionet CHEBI:28445 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0011991 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0041969 infores:hetionet CHEBI:10124 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0000786 infores:hetionet CHEBI:3996 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0687713 infores:hetionet CAID:CA404093668 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093668 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PM5 The NM_000527.5(LDLR):c.2051C>T (p.Ala684Val) variant is classified as Uncertain Significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025.The supporting evidence is as follows: PM2: PopMax MAF=00001667 (0.001667%) in Admixed American exomes+genomes (gnomAD v4.1.0).PP3: REVEL score = 0.787. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093668/MONDO:0007750/013 2025-02-20 2025-06-17 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:1902366 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:1902366 GO:0043009 UMLS:C0005740 biolink:causes MONDO:0043919 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0206063 infores:hetionet CHEBI:31401 biolink:causes HP:0100310 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0238154 infores:hetionet CHEBI:64355 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011168 infores:hetionet CAID:CA338506 biolink:causes MONDO:0018875 infores:clingen CAID:CA338506 MONDO:0018875 PMID:30224644PMID:12826609PMID:30224644PMID:12826609 Likely Benign BP4, BS2_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, PM5, PM1, BS3, BS4, PP1, PP4 The NM_000546.6: c.1136G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 379 (p.Arg379Leu). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). This variant has an allele frequency of 0.000001859 (3/1614000 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Computational predictor scores (BayesDel = -0.0781755; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA338506/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0575090 infores:hetionet CHEBI:2704 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0004604 infores:hetionet CHEBI:7986 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0013144 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0497247 infores:hetionet CHEBI:5384 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0023218 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033860 infores:hetionet NCBIGene:10524 biolink:causes MONDO:0030852 infores:monarchinitiative not_provided not_provided HGNC:5275 MONDO:0030852 uuid:b8fb70a0-7b89-462d-a897-7c312e4c494e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71940 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0009763 infores:hetionet CHEBI:50673 biolink:causes HP:0001325 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0020617 infores:hetionet CAID:CA409108716 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108716 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS2_Moderate, PM1_Supporting PP1, PS4 The c.1033G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 345 (p.(Asp345Tyr)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.913, which is greater than the MDEP threshold of 0.70 (PP3).  This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32670997, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (including neonatal hypoglycemia, large for gestational age, and negative KCNJ11/ABCC8 germline sequencing) (PP4; PMID: 32670997). In summary, c.1033G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP4, PS2_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108716/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA023739 biolink:causes MONDO:0007750 infores:clingen CAID:CA023739 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, BS4, PM1, PM3, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BS1, BS3, BP7, BP5, PM5, PM4, PM6, PVS1, BS2, PP2 NM_000527.5(LDLR): c.662A>G (p.Asp221Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS3_moderate, PS4, PM1, PM2, PM3, PP3, PP4 and BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PP1_strong - Variant segregates with FH phenotype in 92 informative meiosis in at least 37 families from different labs (Robarts Research Institute; Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 55 affected family members have the variant, 37 unaffected family members don’t have the variant.PS3_moderate - PMID: 9974426 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: 8% LDLR activity; PMID: 25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assay: most of mutant LDLR is in ER, LDLR activity decreased compared to WT - considered as disruptive.PS4 - Variant meets PM2. Variant identified in 48 unrelated index cases (2 cases with DLCN≥6 from Robarts Research Institute; 21 cases (13 patients with DLCN≥6, and 8 patients with possible FH (Simon Broome)) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 17 cases with possible/definite FH (Simon-Broome) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with Possible FH (Simon-Broome) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 5 cases with DLCN≥6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with DLCN≥6 from Color Health, Inc.PM1 - Variant meets PM2 and is missense in exon 4.PM2 - PopMax MAF = 0.0001152 (0.01152%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PM3 - Index case from Ambry Genetics has LDL = 750 mg/dl and also LDLR c.2140+1G>T (pathogenic by these guidelines, confirmed to be in trans).PP3 - REVEL = 0.986.PP4 - Variant meets PM2. Identified in 48 FH cases from different labs (for list see PS4) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6 or Simon-Broome possible/definite FH, after alternative causes of high cholesterol were excluded.BS4 - 30 nonsegregations in 12 families (Laboratory of Genetics and Molecular Cardiology, University of São Paulo).Variant has 2 Strong plus 4 Moderate plus 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023739/MONDO:0007750/013 2022-05-30 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA414816476 biolink:causes MONDO:0044970 infores:clingen CAID:CA414816476 MONDO:0044970 PMID:17535832 Uncertain Significance PS3_Supporting PP1, PP3, PS4, PS2, PM6, PM2 The m.13063G>A (p.V243I) variant in MT-ND5 has been reported in two probands with primary mitochondrial disease, however a second nuclear etiology was identified in one of these cases precluding this case from being included in this curation (PMID: 32652755). The case that was included in this curation was a man who was generally healthy until age 32 years when he developed transient vision loss, fluctuating gait instability, slurred speech, and myoclonic jerks. Two years later he had cerebellar and sensory ataxia, dysarthria, and dyspraxia with preserved cognition. Brain MRI showed symmetric signal changes in basal nuclei, thalami, internal capsulae, and brainstem tegmentum. Skeletal muscle biopsy showed ragged red fibers. Complex I activity was decreased in skeletal muscle (46% controls) and skin fibroblasts (28% controls). The variant was present at 80% heteroplasmy in skeletal muscle, 25% in lymphocytes, and 70% in fibroblasts (PMID: 17535832; case also reported in PMIDs: 18332249, 18977334). Lymphocytes from healthy family members were tested and the variant was present in some while being absent in others, precluding consideration for evidence of segregation. There are no de novo occurrences to our knowledge. This variant is present in population databases (0.002%-0.003%; two homoplasmic occurrence in MITOMAP; one homoplasmic and four heteroplasmic occurrences in gnomAD v3.1.2; six heteroplasmic occurrences in the Helix database). In silico prediction tools are conflicting as APOGEE1 predicts a deleterious effect (0.63) and APOGEE2 predicts a neutral effect (0.417). Cybrid studies support the functional impact of this variant as they showed the variant was associated with decreased complex I activity (PS3_supporting; PMID: 17535832). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 7, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414816476/MONDO:0044970/015 2025-01-07 2025-05-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63584 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0746883 infores:hetionet CHEBI:52717 biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0016167 infores:hetionet CHEBI:9137 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0010200 infores:hetionet CHEBI:45924 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0040264 infores:hetionet CHEBI:63638 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0020580 infores:hetionet CHEBI:10650 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0851578 infores:hetionet CHEBI:31485 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0010037 infores:hetionet CHEBI:6715 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041582 infores:hetionet CHEBI:74947 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0013378 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0014742 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0031117 infores:hetionet CHEBI:71219 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0021845 infores:hetionet CHEBI:681848 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0010200 infores:hetionet CHEBI:78543 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0235325 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030305 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0020517 infores:hetionet CHEBI:50859 biolink:causes MONDO:0024291 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0158570 infores:hetionet CHEBI:8768 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0004093 infores:hetionet CHEBI:9943 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003862 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027769 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1565489 infores:hetionet CAID:CA229609 biolink:causes MONDO:0009861 infores:clingen CAID:CA229609 MONDO:0009861 PMID:12501224PMID:23764561PMID:12501224 Pathogenic PM5, PM2, PP4_Moderate, PP3, PM3_Strong The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID: 12501224 It has been detected with known pathogenic variants R408W (PMID: 12501224), and IVS12+1G>A (PMID: 23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229609/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71417 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0917801 infores:hetionet NCBIGene:284 biolink:causes MONDO:0030293 infores:monarchinitiative not_provided not_provided HGNC:484 MONDO:0030293 uuid:eea4ffaf-8ec7-4c26-921c-7d061d009377 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0025874 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0404521 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235890 infores:hetionet CHEBI:31709 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0030554 infores:hetionet CAID:CA120641 biolink:causes MONDO:0044970 infores:clingen CAID:CA120641 MONDO:0044970 PMID: Uncertain Significance PS2_Supporting, PM4, PM2_Supporting PP3, PS4, PS3, PM6 The m.5133_5134delAA variant in MT-ND2 has been reported in one individual from one family (PMID: 12192017), in a male with exercise intolerance, ragged red fibers, and reduced complex I activity. The variant was present at 93% heteroplasmy (PMID:19273755). This variant was reported to have occurred on the paternal mitochondrial DNA as two haplogroups were reportedly present in the proband, one matching his mother’s haplogroup and the other matching his father’s, although the variant was not present in his mother or father (PS2_supporting, PMID: 12192017). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. This 2 base pair deletion starting at amino acid L221 in the MT-ND2 gene results in a stop codon at position 251 (L251Ter). This results in a truncated MT-ND2 gene product (PM4). Of note, this expert panel considered whether this variant should be reviewed for several reasons: (1) analysis of the mitochondrial genome was limited at the time of this report in 2002, raising concern on whether this variant was truly present in the proband or technical artifact; (2) it is possible the variant was present in the nuclear DNA but erroneously assigned to mitochondrial DNA; (3) nuclear DNA etiologies were not assessed in this proband; and (4) there are no other validated occurrences of paternal inheritance of mitochondrial DNA. However, this expert panel elected to review this variant with the current evidence and it meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS2_supporting, PM2_supporting, PM4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120641/MONDO:0044970/014 2023-10-09 2024-03-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:45783 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0040822 infores:hetionet CHEBI:65173 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0023530 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0037274 infores:hetionet CAID:CA6748956 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748956 MONDO:0009861 PMID: Uncertain Significance PM2, BP7, BS1 The NM_000277.3:c.438C>T variant in PAH is a synonymous (silent) variant (p.His146=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002003 (5/24962 alleles) in the African/African American population (none of the population data codes are met). There is a ClinVar entry for this variant (Variation ID: 755030, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): no criteria are met. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748956/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3207 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0004093 infores:hetionet CHEBI:50173 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0750426 infores:hetionet CHEBI:28487 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0018418 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020456 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001225 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0029095 infores:hetionet CHEBI:7824 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042963 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0855242 infores:hetionet CAID:CA314631 biolink:causes MONDO:0100040 infores:clingen CAID:CA314631 MONDO:0100040 PMID: Likely Benign BP5, BS2 The p.Ser349Ala variant in FOXG1 is present in one XX and three XY individuals in gnomAD v2.1.1 (0.001418%) (not sufficient to meet BS1 criteria). The p.Ser349Ala variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ser349Ala variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). In summary, the p.Ser349Ala variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314631/MONDO:0100040/035 2024-04-18 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6128 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151664 infores:hetionet CHEBI:9316 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0011603 infores:hetionet CHEBI:474180 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0031256 infores:hetionet NCBIGene:5873 biolink:causes MONDO:0011872 infores:monarchinitiative not_provided not_provided HGNC:9766 MONDO:0011872 uuid:41f596e3-e9c7-41e1-8d1f-35d58e264d4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0013395 infores:hetionet CHEBI:119573 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0018932 infores:hetionet CHEBI:92998 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0014742 infores:hetionet NCBIGene:7337 biolink:causes MONDO:0007113 infores:monarchinitiative not_provided not_provided HGNC:12496 MONDO:0007113 uuid:11702a51-4cb1-471e-8762-1c1be1dcd74a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018944 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0001056 uuid:927bc4c5-021c-4f5d-a8ba-a3a827ade701 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C2047937 infores:hetionet CAID:CA023564 biolink:causes MONDO:0007750 infores:clingen CAID:CA023564 MONDO:0007750 PMID: Likely Pathogenic PS3_Supporting, PM5, PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS2, BP5, BP7, BS3, BS1, BS4, PM1, PM4, PM3, PVS1, PM6, PP2, PP4, PP1, BS2 NM_000527.5(LDLR):c.1747C>G (p.His583Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008790 (0.0008790%) in European (non-Finnish) (gnomAD v2.1.1). PP3: REVEL = 0.798. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921).PS3_Supporting: Functional studies (PMID 25647241, Thormaehlen et al., 2015) using HeLa-Kyoto cells, LDLR-GFP construct, WB and CLSM assays - results - most of mutant LDLR is in ER, LDLR activity decreased compared to WT - considered as disruptive. Therefore, PS3_Supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023564/MONDO:0007750/013 2023-11-07 2024-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:39112 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1608945 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006574 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0023801 infores:hetionet CHEBI:68478 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004093 infores:hetionet CHEBI:7443 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0011168 infores:hetionet CHEBI:63580 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0423791 infores:hetionet CHEBI:63632 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0018834 infores:hetionet GO:2001074 biolink:causes GO:0001657 infores:ubergraph knowledge_assertion manual_agent GO:2001074 GO:0001657 CAID:CA142894 biolink:causes MONDO:0019497 infores:clingen CAID:CA142894 MONDO:0019497 PMID: Likely Benign BS1 The filtering allele frequency (the lower threshold of the 95% CI of 119/24962) of the c.4582G>A (p.Asp1528Asn) variant in the OTOF gene is 0.407% for African/African-American chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA142894/MONDO:0019497/005 2021-07-27 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true NCBIGene:130589 biolink:causes MONDO:0030105 infores:monarchinitiative not_provided not_provided HGNC:24063 MONDO:0030105 uuid:aafdee4b-9527-42b3-89dd-00c45c6ad687 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA199174 biolink:causes MONDO:0021060 infores:clingen CAID:CA199174 MONDO:0021060 PMID: Pathogenic PS2_Very Strong, PP3, PM2_Supporting, PS4 BS1, BP4, BA1, PS3 The c.519G>A variant in the SHOC2 gene is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 173 (p.Met173Ile). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.768 (PP3). This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and with unconfirmed parental relationships in 1 individual with RASopathy (PS2_VeryStrong; Invitae, GeneDx, Ambry, Genomic Medicine Lab; ClinVar SCV001573982.4, SCV000209055.14, SCV002641556.1, SCV001573024.1). This variant has been reported in more than 5 probands diagnosed with RASopathy (PS4; PMIDs: 25137548, 29907801; Invitae, GeneDx, UCSF Genomic Medicine Lab, LabCorp, Ambry; ClinVar SCV001573982.4, SCV000209055.14, SCV001573024.1, SCV000699327.2, SCV002641556.1). ERK phosphorylation assays showed that this variant decreases the ability of SHOC2 to accelerate ERK1/2 phosphorylation (PS3 not met, PMID: 25137548). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA199174/MONDO:0021060/038 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49668 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0041582 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0011570 infores:hetionet CHEBI:8768 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0008350 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0036454 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0040034 infores:hetionet CHEBI:2549 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020578 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0009319 infores:hetionet CHEBI:9168 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0003862 infores:hetionet CAID:CA380142798 biolink:causes MONDO:0000573 infores:clingen CAID:CA380142798 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM3, PM1_Supporting PP4 The c.501A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Arginine by Serine at amino acid 167 (p.Arg167Ser).The highest population minor allele frequency in gnomAD v4 is 0.0001941 (1/5152 alleles) in the Ashkenazi Jewish population. As this is a known bottleneck population, it will not be considered here for PM2_Supporting. As no other alleles have been reported in other populations, PM2 at the supporting level is applied (Absence in GnomAD). This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.This variant has been detected in one individual with SCID, reported by Invitae in ClinVar. This individual is compound heterozygous for p.Gly95Arg, a likely pathogenic variant according to SCID VCEP specifications. Both parents were tested, and the phase is confirmed: 1 point. PM3_Moderate (Internal lab contributor).No clinical features were described; Not possible to evaluate for PP4.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PM1_Supporting, and PM3_Moderate. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380142798/MONDO:0000573/124 2024-05-14 2024-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:32221 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0020517 infores:hetionet CHEBI:9622 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0085649 infores:hetionet GO:0097029 biolink:causes CL:0000841 infores:ubergraph knowledge_assertion manual_agent GO:0097029 CL:0000841 CHEBI:3207 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0002622 infores:hetionet CHEBI:38940 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014518 infores:hetionet CAID:CA386951959 biolink:causes MONDO:0015967 infores:clingen CAID:CA386951959 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1A>C variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1?) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386951959/MONDO:0015967/017 2022-03-04 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7575 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0012833 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0038358 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0270458 infores:hetionet CHEBI:37941 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0232849 infores:hetionet CHEBI:31932 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0024523 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0302295 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003537 infores:hetionet CHEBI:94385 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0034063 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027932 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0020538 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1696946 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1696946 infores:hetionet CHEBI:16899 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0042571 infores:hetionet CHEBI:31236 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235266 infores:hetionet NCBIGene:9622 biolink:causes MONDO:0008772 infores:monarchinitiative not_provided not_provided HGNC:6365 MONDO:0008772 uuid:a2ffa8b7-e37a-4521-91a9-4637cb9c018c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0948525 infores:hetionet CHEBI:63623 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0011603 infores:hetionet CHEBI:43968 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0014591 infores:hetionet CHEBI:10650 biolink:causes UMLS:C2349423 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2349423 infores:hetionet CHEBI:194135 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0002874 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0413252 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005917 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0032045 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0267596 infores:hetionet CHEBI:9086 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0040822 infores:hetionet CAID:CA003236 biolink:causes MONDO:0700268 infores:clingen CAID:CA003236 MONDO:0700268 PMID: Uncertain Significance PP3, PM2_Supporting PS3, BS3 The c.5096G>C variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Proline at amino acid 1699 (p.(Arg1699Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies with discordant results. Functional effect similar to benign control variants (PMID:38709234) and to pathogenic control variants (PMID:30209399, 35196514) (PS3 and BS3 not met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.43, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold <0.10) (PP3 met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003236/MONDO:0700268/092 2025-08-25 2025-08-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7445 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0032227 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0042401 infores:hetionet CHEBI:134991 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0023067 infores:hetionet CHEBI:32588 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0234518 infores:hetionet CHEBI:64312 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0428977 infores:hetionet CHEBI:6923 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0040460 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015397 infores:hetionet UMLS:C0065374 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0030252 infores:hetionet CHEBI:4046 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0043144 infores:hetionet CHEBI:4530 biolink:causes MONDO:0001999 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0152171 infores:hetionet CAID:CA386965163 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965163 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM5_Strong, PM1_Supporting, PP4_Moderate, PP3 PS4 The c.685C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 229 (p.(Arg229Gly)) of NM_000545.6. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Two of these individuals had a clinical history specific for HNF1A-monogenic diabetes(MODY probability calculator result >50% and negative genetic testing for HNF4A), one of whom also responded to low dose sulfonylurea treatment (PP4_Moderate; internal laboratory contributor). This variant is located within the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Two other missense variants, c.686G>A (p.Arg229Gln) and c.686G>C (p.Arg229Pro), have been classified as pathogenic by the ClinGen MDEP, and p.Arg229Gly has a greater Grantham distance than p.Arg229Gln and p.Arg229Pro (PM5_Strong). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Finally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). In summary, c.685C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): (PP4_Moderate, PM1_Supporting, PM5_Strong, PM2_Supporting, PP3). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965163/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5138 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013384 infores:hetionet GO:1900015 biolink:causes GO:0006954 infores:ubergraph knowledge_assertion manual_agent GO:1900015 GO:0006954 CHEBI:10102 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151786 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0857361 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0857361 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1443060 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0392197 infores:hetionet CHEBI:2379 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0042963 infores:hetionet CAID:CA658824424 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824424 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.4(RUNX1):c.159del (p.Ser53fs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824424/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6472 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0853813 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0031350 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0031212 infores:hetionet CHEBI:48669 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0013395 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0860866 infores:hetionet CHEBI:9667 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0014591 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0233746 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233746 infores:hetionet CHEBI:51380 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0028084 infores:hetionet CHEBI:8764 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0024305 infores:hetionet CHEBI:7443 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0206061 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0392176 infores:hetionet CHEBI:10023 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002792 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0234916 infores:hetionet CHEBI:94449 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0085631 infores:hetionet CAID:CA913182452 biolink:causes MONDO:0044970 infores:clingen CAID:CA913182452 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS4, PS3, PM6 The m.9997T>A variant in MT-TG has been reported in one individual to date, however clinical details were not provided (PMID: 31965079). Similarly, there is no available information on segregation in family members or de novo status. It is possible this individual was reported in a poster abstract submitted by Roggenbuck et al., 2016 (https://www.neurology.org/doi/10.1212/WNL.86.16_supplement.P5.016), but this has not been confirmed. The individual reported with this variant in this abstract was a man with exercise intolerance, myalgia, muscle weakness, ptosis, neuropathy, dilated cardiomyopathy, and renal disease. Respiratory chain enzyme testing on muscle showed low cytochrome c oxidase activity but exact values were not provided. The variant was reported to be present at homoplasmy in the proband and was also reported in other maternal family members with varying clinical features, however details were not provided. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is deleterious (95.2 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913182452/MONDO:0044970/015 2024-07-22 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true UMLS:C0065374 biolink:causes HP:0012764 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0085619 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004936 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0086543 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151736 infores:hetionet CHEBI:64321 biolink:causes HP:0030142 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0159060 infores:hetionet CHEBI:8673 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0023530 infores:hetionet CHEBI:9571 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0085649 infores:hetionet CHEBI:15553 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0041657 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0852879 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0852879 infores:hetionet CHEBI:8378 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C2586050 infores:hetionet CHEBI:3387 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0022346 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0235329 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235329 infores:hetionet CHEBI:167309 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0855775 infores:hetionet CHEBI:50729 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0013404 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0856100 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0856100 infores:hetionet CHEBI:18332 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0233407 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0019112 infores:hetionet NCBITaxon:10298 biolink:causes MONDO:0015288 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10298 MESH:D007635 DB01004_MESH_D007635_1DB00432_MESH_D016849_1 CHEBI:31536 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0016658 infores:hetionet CHEBI:3175 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0152227 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0005779 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0178298 infores:hetionet CHEBI:77733 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0392703 infores:hetionet CHEBI:91834 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0017574 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0392025 infores:hetionet CHEBI:2453 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C2363731 infores:hetionet CHEBI:5106 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0014591 infores:hetionet CHEBI:84500 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0032781 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0018799 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0233571 infores:hetionet CHEBI:28787 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0004245 infores:hetionet CAID:CA296139 biolink:causes MONDO:0021060 infores:clingen CAID:CA296139 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.818A>G (p.Lys273Arg) variant in the MAP2K2 gene is 0.0368% (6/7088) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296139/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:31515 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0038362 infores:hetionet UMLS:C0145867 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0043144 infores:hetionet NCBIGene:142680 biolink:causes MONDO:0009431 infores:monarchinitiative not_provided not_provided HGNC:20305 MONDO:0009431 uuid:507fa19d-6f01-4000-822d-ca01a148225e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0022650 infores:hetionet CHEBI:8207 biolink:causes MONDO:0006843 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0024441 infores:hetionet UMLS:C0657912 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002962 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0012813 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011334 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0858924 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0858924 infores:hetionet CHEBI:44423 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0234233 infores:hetionet CAID:CA409106957 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106957 MONDO:0015967 PMID: Uncertain Significance PP3, PP1, PP4, PM2_Supporting, PM1_Supporting PM5 The c.641C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of serine to tyrosine at codon 214 (p.(Ser214Tyr)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia and large for gestational age, diabetes diagnosed at 13, negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributor). This variant segregated with diabetes, with 3 informative meioses in a single family (PP1; internal lab contributor). Additionally, a number of other missense variants at this codon (c.640T>G, p.Ser214Ala; c.641C>T, p.Ser214Phe; c.640T>A, p.Ser214Thr) have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.641C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106957/MONDO:0015967/085 2024-05-02 2024-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7494 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0009324 infores:hetionet CHEBI:27504 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C2047937 infores:hetionet CHEBI:9435 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0018681 infores:hetionet CHEBI:63581 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C2830004 infores:hetionet CAID:CA16020842 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020842 MONDO:0009861 PMID:26803807 Likely Pathogenic PM2, PS3 PP3 The c.694C>G (p.Gln232Glu) variant in PAH has not been reported in the literature in individuals with PKU. It has been co-expressed with p.E178G and showed 55.0% enzyme activity. PMID: 26803807. BioPKU reports a 42% enzyme activity for this variant (PS3; PMID: 12501224). This variant is absent in population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020842/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47381 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1384353 infores:hetionet CHEBI:7575 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0149871 infores:hetionet CHEBI:135342 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0001925 infores:hetionet CHEBI:3127 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0152030 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0234936 infores:hetionet CHEBI:8435 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0392676 infores:hetionet CAID:CA8814900 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814900 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM3 PP4 The NM_000152.5:c.546+5G>A variant is in intron 2 of GAA. This variant has been detected in one patient with Pompe disease reported to have deficient GAA activity, but results and clinical information were not provided. This variant has also been reported in one individual with a positive newborn screen for Pompe disease and confirmed deficient GAA enzyme in DBS; while this technically meets criteria for PP4_moderate, we cannot apply this evidence code as there has not been a confirmed phenotype in this individual. This individual was compound heterozygous for this variant and the common c.-32-13T>G variant confirmed in trans (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006714 (5/74860 alleles) in the African/African-American subpopulation, which is lower than the ClinGen Lysosomal Disorders VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.57 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). There is another variant at the same location with a different amino acid change (NM_000152.5:c.546+5G>T) classified as a variant of uncertain significance by the ClinGen Lysosomal Disorders VCEP. There is a ClinVar entry for this variant (Variation ID: 2151633, 2 star review status) with two submitters classifying the variant as a uncertain significance. In summary, this variant has been classified as a VUS for Pompe disease by the ClinGen Lysosomal Disorders VCEP. GAA-Specific ACMG-AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814900/MONDO:0009290/010 2023-12-05 2023-12-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:27300 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0242528 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0009450 infores:hetionet CHEBI:85161 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0242184 infores:hetionet CHEBI:72564 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011606 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085617 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0018801 infores:hetionet CHEBI:49575 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0700361 infores:hetionet CHEBI:27834 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0015230 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0149931 infores:hetionet CHEBI:6067 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0043349 infores:hetionet CHEBI:3732 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1257843 infores:hetionet CHEBI:64064 biolink:causes EFO:0003952 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0015970 infores:hetionet CAID:CA409107447 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107447 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PM2, PP3, PS2_Moderate, PS4 PM1 The c.733C>T variant in the hepatocyte nuclear factor-4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 245 (p.(Arg245Cys)) of NM_175914.5. This variant was identified in at least 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab collaborators; PMIDs: 23348805, 31957151, 30026763). This variant is found in only one individual in gnomAD (PM2_Supporting). This variant segregated with diabetes, with at least 4 informative meioses in 2 families with MODY (PP1_Strong; internal lab collaborators). This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Moderate; PMID: 31957151).This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.898, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, antibody negative, and sulfonylurea-responsive) (PP4_Moderate; internal lab collaborators). In summary, c.733C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS4, PM2_Supporting, PP1_Strong, PS2_Moderate, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107447/MONDO:0015967/085 2023-09-15 2023-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17026 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0232462 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0004936 infores:hetionet NCBIGene:3028 biolink:causes MONDO:0010327 infores:monarchinitiative not_provided not_provided HGNC:4800 MONDO:0010327 uuid:f33269a2-bf50-4b87-a2bb-68423ea1c407 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8665 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0026826 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0948586 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0542165 infores:hetionet CHEBI:28593 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0026961 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1263846 infores:hetionet CHEBI:7915 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0600142 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0178298 infores:hetionet CHEBI:42944 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0428977 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0235146 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0027769 infores:hetionet CAID:CA377784410 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784410 MONDO:0017623 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, BS3_Supporting, PS2 PP1 NM_000314.8(PTEN):c.91A>G (p.Asn31Asp) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. [internal laboratory contributor(s)]PS4_P: Proband(s) with phenotype specificity score of 1-1.5. [internal laboratory contributor(s)]PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: in silico REVEL score of 0.966 (>0.7)BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score = 0.549559228) per Mighell et al. 2018 (PMID: 29706350).Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 pathogenic strong, 4 pathogenic supporting and 1 benign supporting codes get (4*1) + (1*4)+ (- 1*1) points = total is 7 (Likely Pathogenic). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784410/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17303 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1145670 infores:hetionet CHEBI:135193 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C1619712 infores:hetionet CHEBI:63621 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023524 infores:hetionet CHEBI:7986 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C2363731 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020517 infores:hetionet CHEBI:3996 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0040264 infores:hetionet UMLS:C0657912 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0262662 infores:hetionet CHEBI:8356 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0554976 infores:hetionet CHEBI:6754 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0026961 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0020615 infores:hetionet CHEBI:5855 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038990 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042075 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0178298 infores:hetionet CHEBI:63631 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027497 infores:hetionet CHEBI:49575 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018681 infores:hetionet NCBIGene:63915 biolink:causes MONDO:0030903 infores:monarchinitiative not_provided not_provided HGNC:18561 MONDO:0030903 uuid:f71e1107-4dce-4b30-88d2-a1f5ed163383 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0027796 infores:hetionet CHEBI:465284 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003962 infores:hetionet CHEBI:16914 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0014742 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018621 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0038587 infores:hetionet CHEBI:87715 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0023530 infores:hetionet CHEBI:63630 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0021177 infores:hetionet CHEBI:135005 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0030252 infores:hetionet CHEBI:38562 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0338656 infores:hetionet CHEBI:3314 biolink:causes UMLS:C3267206 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C3267206 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005160 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003486 infores:hetionet CHEBI:37941 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0000737 infores:hetionet CHEBI:42797 biolink:causes EFO:0009472 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0206504 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0413252 infores:hetionet CHEBI:71229 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0017181 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0008325 infores:hetionet CHEBI:8768 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0231528 infores:hetionet CHEBI:3752 biolink:causes MONDO:0000859 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0080174 infores:hetionet CAID:CA2918420 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918420 MONDO:0015152 PMID: Pathogenic PVS1, PP4_Moderate, PP1_Moderate, PM2_Supporting, PM3_Strong The NM_000232.5: c.377_384dup p.(Gly129delinsGlnTer) variant in SGCB, which is also known as p.(Gly129GlnfsTer2), is a presumed in tandem duplication of nucleotides 377-384, which is predicted to cause a frameshift and introduce a premature stop codon in biologically relevant exon 3/6, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 10 individuals with limb girdle muscular dystrophy, including in a homozygous state in four (1.0 pt) and confirmed in trans with a likely pathogenic or pathogenic variant in two (c.699_702del, 1.0 pt; c.85A>T p.(Arg29Ter), 1.0 pt) (PMID: 25862795, 36077211, 10662809; PM3_Strong). This variant has been reported to segregate with autosomal recessive LGMD in two affected family members from two Italian families (PMID: 25862795; PP1_Moderate). At least one patient with this variant and a second SGCB variant showed a progressive LGMD phenotype and significantly reduced expression of beta-sarcoglycan in skeletal muscle, which is highly specific for SGCB-related LGMD (PP4_Moderate (capped with PP1_Moderate); PMID: 36077211). The highest minor allele frequency of this variant is 0.000008791 in the European (non-Finnish) population in gnomAD v2.1.1 (1/113750 exome chromosomes), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Strong, PP1_Moderate, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918420/MONDO:0015152/184 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042510 infores:hetionet CHEBI:4657 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0020615 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0037274 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0007114 infores:hetionet CHEBI:567361 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0151744 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1384666 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0003123 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0034065 infores:hetionet CHEBI:9137 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0438716 infores:hetionet CHEBI:145499 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085632 infores:hetionet CHEBI:135276 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0033774 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0038362 infores:hetionet CHEBI:36791 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232462 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0006669 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D004697 DB09320_MESH_D004697_1DB00415_MESH_D004697_1DB01139_MESH_D004697_1DB00512_MESH_D004697_1 CHEBI:6402 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0001925 infores:hetionet CHEBI:37924 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151878 infores:hetionet CHEBI:50729 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0041834 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020538 infores:hetionet CHEBI:77733 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0917801 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018801 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0149931 infores:hetionet CHEBI:68478 biolink:causes HP:0034239 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0238457 infores:hetionet CHEBI:15765 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0016382 infores:hetionet CHEBI:4975 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0042023 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027051 infores:hetionet CHEBI:4470 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0015672 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011551 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013395 infores:hetionet CHEBI:32139 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C1291078 infores:hetionet CAID:CA180843 biolink:causes MONDO:0021060 infores:clingen CAID:CA180843 MONDO:0021060 PMID: Benign BP7, BP4, BA1 The c.-204G>C variant in RAF1 is classified as benign because it has been identified in 0.15126% (95% CI of 32/15402) of non-Finnish European chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180843/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:9435 biolink:causes UMLS:C0278126 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0278126 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0032285 infores:hetionet CHEBI:7936 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006384 infores:hetionet CHEBI:47898 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018790 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0149931 infores:hetionet CAID:CA16020797 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020797 MONDO:0009861 PMID:9450897 Uncertain Significance PM5, PM2, PP3 PS3 The c.470G>C (p.Arg157Thr) variant in PAH has not been reported in an affected patient to our knowledge. The reference in BioPKU (Carter KC, 1998) does not include this variant. The p.R157T mutant is listed as having 5% of wt PAH activity in vitro (BioPKU), but this likely corresponds to the p.R157N variant (PMID: 9450897). The p.Arg157Asn variant at the same amino acid is interpreted as pathogenic in ClinVar (VarID 590772). p.Arg157Thr is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen-2, MutationTaster, and REVEL=0.95. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020797/MONDO:0009861/006 2021-02-14 2021-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50861 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0010200 infores:hetionet NCBIGene:55901 biolink:causes MONDO:0032891 infores:monarchinitiative not_provided not_provided HGNC:17754 MONDO:0032891 uuid:4f88dd0a-bfd2-4005-8981-58884f9b5a6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151662 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235567 infores:hetionet CHEBI:63631 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0080274 infores:hetionet CHEBI:45409 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0271738 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0007906 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0007906 uuid:0e7f7ee2-d7f9-479f-bc2b-0ae670f71972 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0018799 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0027769 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0011431 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0011431 uuid:64f0f97b-691e-4832-9174-d540e944cc9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0232492 infores:hetionet CHEBI:7640 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0241934 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0233494 infores:hetionet CHEBI:6640 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0020672 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013395 infores:hetionet CHEBI:135736 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151786 infores:hetionet CHEBI:8776 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C2047937 infores:hetionet CHEBI:47426 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0015230 infores:hetionet CHEBI:4868 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0018790 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004037 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242420 infores:hetionet CAID:CA386959579 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959579 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4 The c.403G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to asparagine at codon 135 (p.(Asp135Asn)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.837, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29207974, internal lab contributors). Additionally. the published case was stated to have antibody negative DM but not to meet classical diagnostic criteria for MODY. In summary, the c.403G>A variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959579/MONDO:0015967/017 2022-07-01 2022-07-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6437 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0018524 infores:hetionet CHEBI:2038 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0021368 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003864 infores:hetionet CHEBI:75984 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0002962 infores:hetionet CHEBI:135342 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1384353 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0549385 infores:hetionet CHEBI:63580 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085633 infores:hetionet CHEBI:100241 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022346 infores:hetionet CHEBI:44032 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0028081 infores:hetionet CHEBI:8378 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0221166 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0027651 infores:hetionet CHEBI:5790 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020578 infores:hetionet CHEBI:205919 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0001622 infores:hetionet CHEBI:8707 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0000737 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0853692 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0854402 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0854402 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0007971 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0162119 infores:hetionet CHEBI:6888 biolink:causes UMLS:C1735864 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C1735864 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0020538 infores:hetionet CHEBI:7581 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0235195 infores:hetionet CHEBI:9674 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0003467 infores:hetionet CHEBI:63577 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0221423 infores:hetionet CHEBI:3127 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0151603 infores:hetionet CHEBI:8024 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0016199 infores:hetionet CHEBI:63629 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0428977 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0553713 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011974 infores:hetionet NCBIGene:2908 biolink:causes MONDO:0014421 infores:monarchinitiative not_provided not_provided HGNC:7978 MONDO:0014421 uuid:a187aacf-f28c-43d7-a681-9126bf9e856f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10464 biolink:causes MONDO:0033311 infores:monarchinitiative not_provided not_provided HGNC:23352 MONDO:0033311 uuid:e08fa154-203e-432a-a832-d9a3781bd68d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0002418 infores:hetionet CHEBI:45979 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0038325 infores:hetionet CHEBI:6541 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0264906 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0151734 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0231303 infores:hetionet CHEBI:3723 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149514 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151883 infores:hetionet CHEBI:31932 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0022346 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0029408 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0233494 infores:hetionet CHEBI:4653 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0494475 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0948089 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0079043 infores:hetionet CHEBI:8871 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0162298 infores:hetionet CHEBI:63607 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0015967 infores:hetionet CHEBI:8707 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037036 infores:hetionet CHEBI:31485 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0014236 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0024299 infores:hetionet CHEBI:3242 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C3203358 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0013395 infores:hetionet CHEBI:10125 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0004095 infores:hetionet CHEBI:6904 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0016204 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001277 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0007773 infores:hetionet CHEBI:5127 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0009450 infores:hetionet CHEBI:3216 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0041834 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0033975 infores:hetionet CHEBI:31397 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0014591 infores:hetionet CHEBI:499361 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0030554 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0741165 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0741165 infores:hetionet CHEBI:9398 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C1260880 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0018500 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0018799 infores:hetionet CHEBI:50275 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C3263723 infores:hetionet CHEBI:63925 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0005741 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042267 infores:hetionet NCBIGene:7424 biolink:causes MONDO:0014393 infores:monarchinitiative not_provided not_provided HGNC:12682 MONDO:0014393 uuid:e5d80857-b7db-41e5-8e00-e2614034ad86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231425 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0149871 infores:hetionet CHEBI:64355 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151636 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033975 infores:hetionet CHEBI:64064 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0030193 infores:hetionet CHEBI:10023 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151671 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0010692 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0235746 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235746 infores:hetionet CHEBI:5004 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0042963 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0699744 infores:hetionet CHEBI:6846 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0085636 infores:hetionet CAID:CA136107 biolink:causes MONDO:0021060 infores:clingen CAID:CA136107 MONDO:0021060 PMID:21387466 Benign BP5, BA1 PS4, PM1, PM2, PP2 The c.2673+14T>C intronic variant in SOS1 is classified as benign because it has been identified in 0.34596% (lower bound of the 95% CI of 481/128770) of non-Finnish European chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant was observed in 1 individual with Noonan syndrome who also carried a pathogenic variant in SHOC2 sufficient to explain their clinical presentation (BP5; SCV000062214.5). ACMG/AMP Criteria applied: BA1, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136107/MONDO:0021060/004 2019-08-27 2019-10-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6904 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0030252 infores:hetionet CHEBI:9907 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0497156 infores:hetionet CHEBI:71272 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0020615 infores:hetionet CHEBI:3125 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0012833 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002325 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040436 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0005779 infores:hetionet CAID:CA391629069 biolink:causes MONDO:0005045 infores:clingen CAID:CA391629069 MONDO:0005045 PMID: Uncertain Significance PM2_Supporting, PP3 PM5, PM4, PM1, PM3, PP1, PS1, PS3, PS4, PS2, BA1, BP3, BP2, PM6, BP7, BP5, BS1, BS3, BS4 The NM_005159.5(ACTC1):c.1034G>T (p.Gly345Val). This variant has not been identified in individuals with cardiomyopathy nor in large population studies (PM2_Supporting; gnomAD, v2.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PM2_Supporting and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA391629069/MONDO:0005045/101 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31348 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0239340 infores:hetionet CHEBI:5106 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0232487 infores:hetionet CAID:CA145880 biolink:causes MONDO:0001586 infores:clingen CAID:CA145880 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.299+6C>T variant in IDUA alters a nucleotide in the region of the donor splice site of intron 2. The filtering allele frequency (the lower threshold of the 95% CI of 14986/1566936) of the c.299+6C>T variant in IDUA is 0.02373 in the Middle Eastern population chromosomes by gnomAD v4.1.0., which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92640). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): BA1(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145880/MONDO:0001586/091 2025-04-21 2025-05-02 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8764 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0037299 infores:hetionet CHEBI:47780 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0015371 infores:hetionet CHEBI:16714 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0026205 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1168034 infores:hetionet CHEBI:6897 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0948594 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007860 infores:hetionet CHEBI:3485 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0035410 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0014863 infores:hetionet CHEBI:78543 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0032227 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0036572 infores:hetionet CHEBI:2637 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0042963 infores:hetionet CHEBI:49713 biolink:causes MONDO:0015263 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C1142166 infores:hetionet CHEBI:63621 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C3263723 infores:hetionet CHEBI:46345 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0020580 infores:hetionet CHEBI:8426 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0011603 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0018799 infores:hetionet CHEBI:5613 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0151564 infores:hetionet CAID:CA124399 biolink:causes MONDO:0012163 infores:clingen CAID:CA124399 MONDO:0012163 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3, PP1_Strong, PS3_Supporting NM_002185.5(IL7R):c.394C>T is a missense variant predicted to cause substitution of Proline by Serine at amino acid 132 (p.Pro132Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002236 (1/44718) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). 3 patients (PMID: 11023514) were found homozygous for this mutation (1 pt.) (PM3_met). 2 patients (Pt. 85 and 86) were found homozygous for this mutation in a consanguineous family (PMID : 35482138). 3 patients with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total : 1.25 pts) (PMID: 11023514,PP4_met). In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R. (PMID: 11023514, PS3_supporting). The variant has been reported to segregate with SCID in 3 affected members from 2 families (PP1_strong).In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PM3_met,PP4_met,PS3_supporting,PP1_strong(VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA124399/MONDO:0012163/119 2024-01-24 2024-01-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9168 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020625 infores:hetionet CHEBI:3011 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0014742 infores:hetionet CHEBI:31401 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0018965 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0022660 infores:hetionet CHEBI:35778 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0036973 infores:hetionet CHEBI:9435 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0750857 infores:hetionet CAID:CA355961295 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961295 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting PM3, PP4 The NM_000203.5:c.395T>C variant in IDUA is a missense variant predicted to cause substitution of leucine by proline at amino acid 132 (p.Leu132Pro). The variant has been reported (PMID:35614200) in a list of variants identified in individuals with features of MPS I. However, no genotype or clinical data were provided (PP4_not met, PM3_not met). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000011 (1/91082 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.927 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). SpliceAI predicts that the variant has no impact on splicing (all scores <0.1). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for MPS I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM2_supporting, PP3_moderate(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, August 4, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961295/MONDO:0001586/091 2025-08-04 2025-09-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA414910923 biolink:causes MONDO:0010602 infores:clingen CAID:CA414910923 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PS4 The c.1814A>G (p.Tyr605Cys) variant is absent from population database gnomAD v2.1.1 and v3.1.2 meeting PM2_Supporting criteria. The missense variant has a REVEL score of 0.957 (>0.6), meeting criteria for PP3. Seven probands with moderate-severe hemophilia A are reported in the literature and internal laboratory data who meet F8 phenotype criteria and criteria for PS4 or PP4_Moderate (PMIDs: 18217193, 21883705, 18691168, 29296726). At least 4 related individuals with this variant were identified in the My Life Our Future Project (PMID: 29296726), meeting criteria for PP1_Moderate. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4, PP4_Moderate, PP1_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414910923/MONDO:0010602/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Supports CHEBI:39867 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0013395 infores:hetionet CAID:CA10644615 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644615 MONDO:0011071 PMID: Likely Benign BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*3277G>T is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEL score is not applicable and SPliceAI is ≤0.20 (0.01) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.68 < 2.0) (BP7). In summary, the clinical significance of this variant is Likely Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644615/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA415077728 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077728 MONDO:0010305 PMID: Uncertain Significance PM5_Supporting, PP3, PP4, PM2_Supporting The NM_005629.4:c.340C>A in SLC6A8 is predicted to result in substitution of glutamine by lysine at amino acid 114 (p.Gln114Lys). One male patient with clinical features and urine creatine results consistent with creatine transporter deficiency has been reported (PMID: 25326635, ClinVar SCV000807540.2, Association for Creatine Deficiencies registry) (PP4). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). This variant is not in gnomAD v2.1.1 or v4.1.0. (PM2_Supporting). Another amino acid change at the same position, c.342G>C (p.Gln114His) (ClinVar Variation ID: 940774) has been classified as likely pathogenic by the ClinGen CCDS VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specification ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version v1.1.0): PP3, PP4, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 13, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077728/MONDO:0010305/027 2024-06-13 2024-06-24 X-linked inheritance HP:0001417 Inconclusive true CHEBI:135935 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C2939147 infores:hetionet CHEBI:45716 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0043352 infores:hetionet CHEBI:45599 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0011168 infores:hetionet GO:1902667 biolink:causes GO:0007409 infores:ubergraph knowledge_assertion manual_agent GO:1902667 GO:0007409 CHEBI:47426 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0039621 infores:hetionet CHEBI:44915 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0013404 infores:hetionet NCBIGene:200931 biolink:causes MONDO:0030360 infores:monarchinitiative not_provided not_provided HGNC:29955 MONDO:0030360 uuid:39c09592-87fb-4187-b633-93b3edc55108 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0012569 infores:hetionet CHEBI:7936 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0041834 infores:hetionet CHEBI:35778 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0040264 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0015376 infores:hetionet CHEBI:17823 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0085636 infores:hetionet CHEBI:6923 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0033774 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0342579 infores:hetionet CHEBI:7936 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034152 infores:hetionet GO:2000495 biolink:causes GO:0048749 infores:ubergraph knowledge_assertion manual_agent GO:2000495 GO:0048749 CHEBI:83531 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0012833 infores:hetionet NCBIGene:6709 biolink:causes MONDO:0957875 infores:monarchinitiative not_provided not_provided HGNC:11273 MONDO:0957875 uuid:da7813a0-d8a1-410a-a64b-c66e39a1dadb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0038454 infores:hetionet CHEBI:63598 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0162297 infores:hetionet CHEBI:142290 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0023218 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0034150 infores:hetionet CHEBI:36791 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0152030 infores:hetionet CHEBI:3011 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0042571 infores:hetionet CHEBI:64354 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0085682 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0270458 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002871 infores:hetionet CHEBI:45863 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0231807 infores:hetionet CHEBI:3347 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0035410 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0026946 infores:hetionet CHEBI:50673 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0015967 infores:hetionet CHEBI:37924 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0030193 infores:hetionet CHEBI:6741 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042963 infores:hetionet CHEBI:168396 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0033774 infores:hetionet CHEBI:7476 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027540 infores:hetionet CHEBI:9571 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0242422 infores:hetionet CHEBI:3175 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0015403 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0427008 infores:hetionet CHEBI:10110 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0019209 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877094 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877094 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1306341 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023470 infores:hetionet CHEBI:82941 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0021368 infores:hetionet CAID:CA034017 biolink:causes MONDO:0007750 infores:clingen CAID:CA034017 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PS4, PM5, PP4 The NM_000527.5 (LDLR):c. 1366C>T (p. Leu456Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1).BP4: REVEL=0.487, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. MES performed:A) Variant is not on limits.B) Variant is on limit but does not crate de novo AG. Variant created GT however is not on limit. C) Variant is on limit and nearby three intra-exonic AGs: cctcctgcctcagcacccAGc/ttt , Var/Wt cryptic score = 0.37/-0.2 = -0.15, it is <1.1; ctcagcacccagc/tttgacAGagc, Var/Wt cryptic score = -3.2/-2.9 = 1.103, it is = 1.1, however both scores are negative; and agcacccagc/tttgacagAGccc, Var/Wt cryptic score = -33.4/-34.48 = 0.97, it is <1.1. MES score for canonical intron 9 acceptor cttctctcctcctgcctcAGcac is 6.76, so none of the Var cryptic scores/Wt score is >0.9. Variant is not predicted to alter splicing and REVEL score is below 0.5, therefore BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034017/MONDO:0007750/013 2023-06-23 2024-10-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4887 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0018681 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0392156 infores:hetionet CHEBI:6809 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0030252 infores:hetionet CHEBI:127342 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0085631 infores:hetionet CHEBI:6456 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0237849 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0160390 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0281856 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0413252 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0040034 infores:hetionet CHEBI:9763 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151539 infores:hetionet CHEBI:63611 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085614 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0005741 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0553731 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0553731 infores:hetionet CHEBI:135005 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0917801 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0031117 infores:hetionet CHEBI:17823 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0232462 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007642 infores:hetionet CHEBI:46195 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0011991 infores:hetionet CHEBI:75922 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0042963 infores:hetionet CHEBI:9654 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020580 infores:hetionet CHEBI:63580 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C3203358 infores:hetionet CHEBI:9398 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0008031 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085637 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0009806 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0267792 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020517 infores:hetionet CHEBI:6359 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0014724 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0233632 infores:hetionet CHEBI:6950 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013428 infores:hetionet CHEBI:31949 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0015672 infores:hetionet CHEBI:68606 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0151691 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027765 infores:hetionet CHEBI:4672 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0024312 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0009450 infores:hetionet GO:1902033 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:1902033 GO:0030154 NCBIGene:23397 biolink:causes MONDO:0054806 infores:monarchinitiative not_provided not_provided HGNC:1112 MONDO:0054806 uuid:b4c679d8-1cd2-4850-b413-36417a0c4eae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0018799 infores:hetionet CHEBI:46295 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0040264 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0853908 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151773 infores:hetionet CHEBI:15367 biolink:causes HP:0010588 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151628 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0032326 infores:hetionet CHEBI:45951 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0270611 infores:hetionet CHEBI:10023 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030193 infores:hetionet CAID:CA16609147 biolink:causes MONDO:0010726 infores:clingen CAID:CA16609147 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, BS2_Supporting The p.Arg471Thr variant in MECP2 (NM_004992.3) is absent from gnomAD v2.1.1 (PM2_supporting). The p.Arg471Thr variant is observed in at least 1 unaffected individuals (GeneDx internal database) (BS2_supporting). In summary, the p.Arg471Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609147/MONDO:0010726/036 2024-04-18 2024-07-01 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:6748 biolink:causes MONDO:0010490 infores:monarchinitiative not_provided not_provided HGNC:11326 MONDO:0010490 uuid:71aca61b-8358-4b5f-ba8d-762fdf8746a3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004093 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0041976 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0030305 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0036508 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027651 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0022568 infores:hetionet CHEBI:136040 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0041969 infores:hetionet CHEBI:31711 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0012833 infores:hetionet CAID:CA279962 biolink:causes MONDO:0015280 infores:clingen CAID:CA279962 MONDO:0015280 PMID: Pathogenic PP3, PS4_Supporting, PM2_Supporting, PP1_Strong, PM1, PS3_Supporting BA1, PM5, BS1 The c.383C>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by glutamine at amino acid 128 (p.Pro128Gln). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928 (PP3). This variant is located in a functional domain supporting pathogenicity (PM1). This variant has been reported to segregate with clinical features of a RASopathy in at least 7 family members of the proband (PS4_Supporting, PP1_Strong; 20358587). ERK phosphorylation assay showed that this variant led to increased ERK phosphorylation compared to wild-type (PS3_P; PMID 20358587). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279962/MONDO:0015280/048 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64355 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151746 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042109 infores:hetionet CHEBI:65173 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0080274 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0033246 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0234913 infores:hetionet CHEBI:63619 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0014591 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042075 infores:hetionet CHEBI:63612 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C2830004 infores:hetionet CHEBI:29688 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0344232 infores:hetionet NCBIGene:200403 biolink:causes MONDO:0014845 infores:monarchinitiative not_provided not_provided HGNC:28385 MONDO:0014845 uuid:9c0d9737-0085-484d-8b2b-47ed13243525 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0232461 infores:hetionet CHEBI:44915 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151636 infores:hetionet CHEBI:80630 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151723 infores:hetionet CHEBI:28445 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0011603 infores:hetionet CHEBI:4562 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0037822 infores:hetionet CHEBI:404903 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027066 infores:hetionet UNII:R43D2573WO biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0232462 infores:hetionet CHEBI:8245 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0028643 infores:hetionet CHEBI:63605 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0428974 infores:hetionet CHEBI:7466 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0013604 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0347390 infores:hetionet CHEBI:10023 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151529 infores:hetionet CHEBI:5134 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C1443060 infores:hetionet CHEBI:5790 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0520966 infores:hetionet CHEBI:4046 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0027424 infores:hetionet GO:0060762 biolink:causes GO:0060443 infores:ubergraph knowledge_assertion manual_agent GO:0060762 GO:0060443 CHEBI:47898 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0021368 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0021843 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0004623 infores:hetionet CHEBI:28901 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0013404 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0853895 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0853895 infores:hetionet CHEBI:7565 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0236124 infores:hetionet CAID:CA409104356 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104356 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS4 The c.297C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of phenylalanine to leucine at codon 99 (p.(Phe99Leu)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:18356407, internal lab contributor). These individuals have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It was also predicted to be deleterious by computational evidence, with a REVEL score of 0.751, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.297C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/23): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104356/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9123 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019270 infores:hetionet CHEBI:27834 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0018790 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020557 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0011053 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0549385 infores:hetionet CHEBI:2914 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0041948 infores:hetionet CHEBI:31705 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0700200 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0332575 infores:hetionet CAID:CA343776693 biolink:causes MONDO:0013144 infores:clingen CAID:CA343776693 MONDO:0013144 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PS4 The c.473T>C variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 158 (p.Leu158Pro). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:28300866). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM2_Supporting, PP4 (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343776693/MONDO:0013144/084 2024-10-28 2024-10-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71415 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C2939465 infores:hetionet CHEBI:18332 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0233494 infores:hetionet CHEBI:50131 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0085593 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020651 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0041657 infores:hetionet CHEBI:135613 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0235710 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005152 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020635 infores:hetionet CHEBI:63631 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020555 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0677500 infores:hetionet CHEBI:28748 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027497 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0851341 infores:hetionet CHEBI:9599 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0003811 infores:hetionet CL:0002138 biolink:causes MONDO:0006282 infores:ubergraph knowledge_assertion manual_agent CL:0002138 MONDO:0006282 CHEBI:6456 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C1527344 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0035455 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020615 infores:hetionet CHEBI:5778 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0016204 infores:hetionet CHEBI:75722 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0424790 infores:hetionet CHEBI:31236 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039239 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0035258 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0149904 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0006325 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011974 infores:hetionet CHEBI:3219 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0162298 infores:hetionet CAID:CA10014733 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014733 MONDO:0011071 PMID: Likely Benign BS1 PS4, PS3, PS1, BP2, BP4, BA1, PM6, PM2, PVS1, BP7, BS4, BS3, PM1, PM4, PM5, PP1, PP3 MAF for NM_001754.4:c.18A>G (p.Ile6Met) variant is 0.00025 (0.02%, 17/66732 Alleles) in the non-Finnish European subpopulation of ExAC database, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Note: The variant is classified as likely benign based on BS1 alone with no contradictory evidence supporting pathogenicity. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014733/MONDO:0011071/008 2019-08-02 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3814 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0852911 infores:hetionet GO:0060128 biolink:causes CL:0000467 infores:ubergraph knowledge_assertion manual_agent GO:0060128 CL:0000467 CHEBI:7640 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0520966 infores:hetionet CHEBI:3752 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0042790 infores:hetionet CHEBI:63611 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C3665347 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0435002 infores:hetionet CHEBI:194135 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0404521 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0029882 infores:hetionet CAID:CA376056127 biolink:causes MONDO:0011225 infores:clingen CAID:CA376056127 MONDO:0011225 PMID: Likely Pathogenic PM2_Supporting, PVS1 PM5 The NM_001033855.3:c.801G>A (p.Trp267Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 10/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1 and PM2_Supporting (VCEP specifications version 2.1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376056127/MONDO:0011225/116 2025-11-04 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:91541 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0235238 infores:hetionet CHEBI:31705 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0018681 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0040479 infores:hetionet CHEBI:50223 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0039070 infores:hetionet CHEBI:10119 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0242301 infores:hetionet UMLS:C0023610 biolink:causes HP:0100879 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0392039 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0042373 infores:hetionet CHEBI:45716 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0015967 infores:hetionet GO:0051611 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0051611 GO:0051641 CHEBI:6804 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0006266 infores:hetionet CHEBI:9674 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0016204 infores:hetionet CHEBI:101278 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0392525 infores:hetionet CHEBI:28748 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151905 infores:hetionet CAID:CA274678 biolink:causes MONDO:0010726 infores:clingen CAID:CA274678 MONDO:0010726 PMID: Pathogenic PP4, PVS1, PM6, PM2_Supporting The c.62+1G>A (NM_001110792.2) variant in MECP2 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.62+1G>A variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 15737703) (PM6, PP4). The c.62+1G>A variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the c.62+1G>A variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6, PP4, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274678/MONDO:0010726/016 2021-12-22 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:75722 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0005741 infores:hetionet CHEBI:50742 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0015230 infores:hetionet CHEBI:6532 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C2830004 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0266998 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0266998 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0027769 infores:hetionet CHEBI:135566 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0031350 infores:hetionet CHEBI:83804 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0037011 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0031117 infores:hetionet CHEBI:127780 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0003862 infores:hetionet CHEBI:50859 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151908 infores:hetionet CHEBI:75988 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0085669 infores:hetionet CHEBI:2659 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0855775 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0004936 infores:hetionet CHEBI:63616 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0206062 infores:hetionet CHEBI:47898 biolink:causes UMLS:C2937222 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2937222 infores:hetionet CAID:CA11154932 biolink:causes MONDO:0015152 infores:clingen CAID:CA11154932 MONDO:0015152 PMID: Benign BA1, BP4, BP7 PM3 The NM_003494.4: c.5668-913C>T variant in DYSF, which is also known as NM_001130987.2: c.5785-913C>T, is located in intron 50 and is not expected to alter the amino acid sequence. This variant was identified in the fibroblasts of a presumably healthy individual (PMID: 31019989; PM3 not met). The filtering allele frequency for this variant in gnomAD v4.1.0 genomes is 0.1166 (the lower bound of the 95% CI of 1854/15294 Admixed American chromosomes), which is higher than the LGMD VCEP threshold for BA1 (0.003), meeting this criterion (BA1). In addition, this variant is not located in a splice region and is not predicted to impact splicing (SpliceAI score 0) (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/23/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA11154932/MONDO:0015152/180 2025-07-23 2025-08-14 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0042109 infores:hetionet CHEBI:8774 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0018681 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0917798 infores:hetionet CHEBI:63637 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0232462 infores:hetionet CHEBI:6076 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0014518 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0014742 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151888 infores:hetionet CHEBI:9571 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0006114 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002170 infores:hetionet CHEBI:16347 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0035078 infores:hetionet CHEBI:63598 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0011168 infores:hetionet CHEBI:53691 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0085616 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0243026 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0475858 infores:hetionet CHEBI:3568 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0010038 infores:hetionet CHEBI:40279 biolink:causes HP:0001923 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0206160 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015397 infores:hetionet CHEBI:100241 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0033771 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0178421 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0004936 infores:hetionet CAID:CA10576608 biolink:causes MONDO:0021060 infores:clingen CAID:CA10576608 MONDO:0021060 PMID: Likely Benign BS1, BP5 The c.124_125delinsAT (p.Ala42Ile) variant in RAF1 is reported in population databases as two contiguous missense variants: c.124G>A and c.125C>T in cis in 27/64,595 (0.03%) European individuals in gnomAD. This meets the cut off set by the ClinGen RASopathy Variant Curation Expert Panel to apply BS1. This variant has been observed in at least 22 individuals (SCV000858114.1, SCV000698121.1, SCV000272341.3, SCV000552093.5, GeneDx internal data). This variant was observed in an individual with an alternate molecular basis for disease (BP5; SCV000698121.1 ). Computational prediction tools and conservation analysis suggest that the p.Ala42Ile variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576608/MONDO:0021060/004 2019-09-24 2019-12-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:2569 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0019521 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018802 infores:hetionet CHEBI:31711 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0004093 infores:hetionet CHEBI:74947 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151315 infores:hetionet CHEBI:42797 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004093 infores:hetionet NCBIGene:25978 biolink:causes MONDO:0010936 infores:monarchinitiative not_provided not_provided HGNC:24537 MONDO:0010936 uuid:975604fb-4de0-49be-bfbb-81469938df59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0002962 infores:hetionet CHEBI:8874 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0016655 infores:hetionet CHEBI:2659 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0011991 infores:hetionet CHEBI:17141 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0015672 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0233494 infores:hetionet NCBIGene:54809 biolink:causes MONDO:0030801 infores:monarchinitiative not_provided not_provided HGNC:1348 MONDO:0030801 uuid:43d916bf-fe20-4f3c-892d-688b2e0a77b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1142135 infores:hetionet CHEBI:474180 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0003467 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002888 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0036508 infores:hetionet CHEBI:2668 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0039231 infores:hetionet CHEBI:84883 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0011168 infores:hetionet CHEBI:6923 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0026821 infores:hetionet CHEBI:45924 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0235896 infores:hetionet CHEBI:48669 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0032617 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0018500 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011551 infores:hetionet CHEBI:3387 biolink:causes MONDO:0006585 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027822 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0031117 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0413252 infores:hetionet CAID:CA197715 biolink:causes MONDO:0007648 infores:clingen CAID:CA197715 MONDO:0007648 PMID:26182300PMID:26182300 Pathogenic PM2_Supporting, PS4, PVS1_Strong BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM5, PM4, PM1, BS2, PP1, PP4, PP3, PP2, BP2, BP4, BP1, BP3, BA1, PS2, PS1, PS3 The c.2430delT (p.Phe810Leufs*6) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 26182300, SCV000261293.4, SCV000218032.4). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA197715/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:421707 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0019209 infores:hetionet CHEBI:17334 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0085631 infores:hetionet CHEBI:119915 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042024 infores:hetionet CHEBI:7476 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0232462 infores:hetionet CHEBI:16899 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0039231 infores:hetionet CAID:CA10585200 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585200 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP1, PP4 The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.787.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585200/MONDO:0007750/013 2022-01-14 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:585948 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C3665347 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0235807 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0006145 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0234936 infores:hetionet CHEBI:27666 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0026766 infores:hetionet CHEBI:44185 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085628 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1096403 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1096403 infores:hetionet CAID:CA343726248 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726248 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BS1, BS3, PM6, PP1, PM5, PM4, PS1, PS4, PS3, PS2, BA1, BP4 The c.760C>A variant in MYOC is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 254 (p.Pro254Thr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.933, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726248/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40303 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0043352 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0016053 infores:hetionet CHEBI:38940 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0001623 infores:hetionet UMLS:C1144403 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0740394 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0235874 infores:hetionet CHEBI:8888 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0010520 infores:hetionet CHEBI:31859 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C1320474 infores:hetionet CAID:CA023759 biolink:causes MONDO:0007750 infores:clingen CAID:CA023759 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP3, BP2, BP1, BP4, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP1, PP4, PP2, PP3, BS2 The NM_000527.5(LDLR):c.770_771delinsAC (p.Arg257His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023759/MONDO:0007750/013 2022-08-26 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA392256442 biolink:causes MONDO:0012996 infores:clingen CAID:CA392256442 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting PM3, PP3, BP4 The NM_001482.3:c.1022C>T variant in GATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 341 (p.Pro341Leu). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.476 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 917496). To our knowledge, this variant has not been reported in an individual with phenotypic features of AGAT deficiency. It has been reported as a single heterozygous variant segregating in a family autosomal dominant renal Fanconi syndrome and kidney failure (PMID: 29654216, 39544690). However, classification with respect to this alternative disorder is outside the scope of this curation. There is a ClinVar entry for this variant (Variation ID: 917496). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on October 8, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392256442/MONDO:0012996/025 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28177 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0017168 infores:hetionet CHEBI:46345 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0152030 infores:hetionet CHEBI:8774 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0013404 infores:hetionet CHEBI:135451 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0027497 infores:hetionet CHEBI:8772 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0037763 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2973529 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0687133 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0014544 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0017178 infores:hetionet CHEBI:17334 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0022408 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232492 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0031542 infores:hetionet CHEBI:74947 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085593 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0006840 infores:hetionet CAID:CA512232276 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232276 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP3, BP2, BP1, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM1, PM5, PP4, PP2, PP3, PP1, BS2 Synonymous variant (no REVEL score applicable) with SpliceAI score ≤ 0.20 (0.01) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.879 (< 2.0)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232276/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:134991 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0009763 infores:hetionet CHEBI:63621 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0039070 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0014868 infores:hetionet CHEBI:16796 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0001807 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0025061 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0039971 infores:hetionet CHEBI:5132 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0012833 infores:hetionet CAID:CA8314813 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314813 MONDO:0009276 PMID: Likely Pathogenic PP4, PP1, PM2_Supporting, PM3, PS3_Supporting PP3 The c.667T>G variant in GP1BA is a missense variant predicted to cause substitution of Tryptophan by Glycine at amino acid 223 (p.Trp223Gly). At least one patient (Patient 2 in PMID:17083647) with this variant had aggregation absent for ristocetin and present for all other agonists as well as absent expression of GPIba measured by Western blot, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome (PP4). The variant has been reported to segregate in this proband plus 1 additional homozygous BSS affected family members (1 point, PP1, PMID: 17083647). This variant has been detected in at least 2 probands with Bernard-Soulier syndrome (PMID: 17083647 and internal lab contributor). These two individuals were both homozygous for the variant (1 point, PM3). Surface expression of GP1ba measured by flow cytometry in BHK cells transiently co-transfected with c.667T>G (p.Trp223Gly) variant GP1BA, and wild type GP1BB and GP9 showed decreased expression at trace WT levels, indicating that this variant impacts protein function (PMID: 17083647)(PS3_supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 7.900e-7 (based on 4/1179888 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP1, PP4, PM2_Supporting and PS3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314813/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3219 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019158 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0029882 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0009450 infores:hetionet CHEBI:7956 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0018524 infores:hetionet CHEBI:46081 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0852911 infores:hetionet CHEBI:78543 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0027441 infores:hetionet CAID:CA16602488 biolink:causes MONDO:0011071 infores:clingen CAID:CA16602488 MONDO:0011071 PMID: Likely Pathogenic PM5_Supporting, PS1_Moderate, PM1, PM2_Supporting, PP3 PS4, PS2, PS3, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, BP7, BP5, PVS1, PM6, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.486G>T (p.Arg162Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3). This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376021, 376022) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>T variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376020) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, PS1_moderate, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602488/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44032 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0019158 infores:hetionet NCBIGene:7026 biolink:causes MONDO:0030049 infores:monarchinitiative not_provided not_provided HGNC:7976 MONDO:0030049 uuid:1433ce54-184c-453f-b034-3cdaaef80b10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44423 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0030193 infores:hetionet CHEBI:102216 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0036974 infores:hetionet CAID:CA8328369 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328369 MONDO:0100438 PMID: Likely Benign BS1 BS2, PP3, BP4 NM_014336.5(AIPL1):c.853G>A (p.Ala285Thr) is a missense variant in exon 6 of 6 that is predicted to replace alanine with threonine at amino acid 285. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.003626, with 300 alleles / 75,042 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.00057 (BS1). The computational predictor REVEL gives a score of 0.422, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 for PP3 and above the threshold of <0.290 for BP4 and does not predict a damaging effect on AIPL1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Neither PP3 nor BP4 is met. In summary, this variant meets the criteria to be classified as likely benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328369/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:52172 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0232492 infores:hetionet CHEBI:52010 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0042963 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0518015 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0679048 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0679048 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0032285 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0392702 infores:hetionet CHEBI:79699 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0030193 infores:hetionet CHEBI:3219 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0547030 infores:hetionet NCBIGene:3199 biolink:causes MONDO:0012854 infores:monarchinitiative not_provided not_provided HGNC:5103 MONDO:0012854 uuid:5e72644e-fb2b-4e55-a0e7-9823c10fa0b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026821 infores:hetionet CHEBI:101278 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0231218 infores:hetionet CHEBI:7575 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0151766 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0233632 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0022354 infores:hetionet CHEBI:79699 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0031256 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0267792 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0333516 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0333516 infores:hetionet CHEBI:49960 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151723 infores:hetionet CHEBI:8435 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0022346 infores:hetionet CHEBI:7444 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0011124 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0860564 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0860564 infores:hetionet NCBIGene:5160 biolink:causes MONDO:0010717 infores:monarchinitiative not_provided not_provided HGNC:8806 MONDO:0010717 uuid:ee92b6c9-7f27-4316-9e38-10a7efdae0f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0013404 infores:hetionet CHEBI:10023 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2363730 infores:hetionet CAID:CA167019 biolink:causes MONDO:0700272 infores:clingen CAID:CA167019 MONDO:0700272 PMID: Likely Pathogenic PM5_Supporting, PVS1 BS1, BS4, PM2, PP1, BA1 The c.3362del (p.Gly1121fs) variant in PALB2 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay; however, it is a truncation of a functionally important region (removes amino acids 1123-1187) in a gene where loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000003979 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA167019/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64355 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0016199 infores:hetionet CHEBI:2663 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0236075 infores:hetionet CHEBI:83804 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0036974 infores:hetionet CHEBI:48669 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0231528 infores:hetionet CHEBI:9086 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C3665347 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0233715 infores:hetionet CHEBI:3723 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019080 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0234215 infores:hetionet CAID:CA16020779 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020779 MONDO:0009861 PMID:26701937 Uncertain Significance PP4_Moderate, PM2, PP3 PM5 The c.362T>C (p.Phe121Ser) variant in PAH is reported in 1 patient with hyperphenylalaninemia. A BH4 metabolism defect was excluded. (PMID: 26701937) This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.977. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020779/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135285 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0851341 infores:hetionet CHEBI:63115 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0023530 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040046 infores:hetionet CAID:CA401366796 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366796 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PM5_Supporting The NM_000152.5:c.1445C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 482 (p.Pro482Leu). At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate). This variant has been detected in at least 6 individuals with Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP. The phase is unconfirmed in all cases. The second variant includes c.1674_1675delTG (ClinVar Variation ID: 1397833) (PMID: 38958145, 0.5 points), c.258dup (ClinVar Variation ID: 282842) (PMID: 31931849, 0.5 points), c.1210G>A (p.Asp404Asn) (ClinVar Variation ID: 657348) (PMID: 31086307, 0.5 points), and c.343C>T (p.Gln115Ter) (ClinVar Variation ID: 188996) (PMID: 17616415, 0.5 points). Two individuals from different geographical areas were homozygous for the variant (2 x 0.5 pt) (PMID: 33741225, 38958145). Total 3 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 8.475e-7 (1/1179992 alleles) in the non-Finnish European population. which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 982297). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LD VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 28, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366796/MONDO:0009290/010 2025-10-28 2025-10-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA8623155 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623155 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PM5, PP4 This intronic variant, NM_000212.3(ITGB3):c.1125+29G>C occurs at an extremely low frequency; the overall allele frequency in gnomAD is 0.000003978 with an MAF of 0.00002891 in the Latino population (PM2_supporting), and to our knowledge, it has not been reported in the literature. The variant is predicted by SpliceAI to have no significant splicing motif alteration detected and the nucleotide is not highly conserved (PhyloP score 0.015; BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, BP4, and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623155/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:15940 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0178298 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0836924 infores:hetionet CHEBI:6456 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0018794 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0031350 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0009450 infores:hetionet CHEBI:15367 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030193 infores:hetionet UMLS:C0145185 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0151795 infores:hetionet CHEBI:17688 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0012833 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0555970 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0555970 infores:hetionet CHEBI:2636 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0234215 infores:hetionet CHEBI:63607 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0015230 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0009806 infores:hetionet CAID:CA024986 biolink:causes MONDO:0007783 infores:clingen CAID:CA024986 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with leucine at codon 316 of the RYR1 protein, p.(Arg316Leu). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0001, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (no test recorded), this does not fulfill PS4 (PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024986/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3371 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0020598 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0233494 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002170 infores:hetionet CHEBI:6015 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C2242588 infores:hetionet CHEBI:7773 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0085605 infores:hetionet CHEBI:5128 biolink:causes UMLS:C3248383 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C3248383 infores:hetionet CHEBI:474053 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0220870 infores:hetionet CHEBI:41977 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0013428 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0011991 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002312 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0029119 infores:hetionet CHEBI:5775 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0231528 infores:hetionet CAID:CA034835 biolink:causes MONDO:0007750 infores:clingen CAID:CA034835 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BA1, BP1, BP4, BP2, PS1, PS3, PS4, PS2, BP5, BS1, BS3, BS4, PM1, PM3, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR): c.1567G>C (p.Val523Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003 in South Asian exomes (gnomAD v2.1.1).PP3: REVEL = 0.904. PM5: There is 1 missense variant in the same codon, NM_000527.5(LDLR):c.1567G>A (p.Val523Met), classified as Pathogenic by these guidelines.PP4: Variant meets PM2 and is identified in 1 patient with possible FH by Simon Broome criteria from PMID 26748104 (Reiman et al., 2016). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034835/MONDO:0007750/013 2024-01-27 2024-10-07 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA199452 biolink:causes MONDO:0010726 infores:clingen CAID:CA199452 MONDO:0010726 PMID: Likely Benign BP5, BS2 The p.Arg478Gln variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Arg478Gln variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). In summary, the p.Arg478Gln variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199452/MONDO:0010726/016 2022-02-18 2022-06-30 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:45081 biolink:causes MONDO:0000878 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0206178 infores:hetionet CHEBI:28971 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0015967 infores:hetionet CHEBI:92923 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0235266 infores:hetionet CHEBI:8768 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0016658 infores:hetionet CHEBI:8772 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0035455 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0151680 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151680 infores:hetionet CHEBI:3175 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1142412 infores:hetionet CHEBI:3650 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0302295 infores:hetionet CAID:CA512341221 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341221 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1212C>T (p.His404=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.87) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341221/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6715 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040034 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003123 infores:hetionet CHEBI:6965 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0011168 infores:hetionet CHEBI:5558 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0231218 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0236023 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0236023 infores:hetionet CHEBI:6775 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085932 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0005976 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:D013587 DB01017_MESH_D013587_1DB13092_MESH_D013587_1DB01053_MESH_D013590_1DB00199_MESH_D013587_1DB00618_MESH_D013587_1DB00759_MESH_D013587_1DB02703_MESH_D013587_1DB09320_MESH_D013587_1DB00595_MESH_D013587_1DB01053_MESH_D013587_1DB00254_MESH_D013587_1DB01053_MESH_D009494_1 CHEBI:2950 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0037383 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0038663 infores:hetionet CHEBI:78543 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0232462 infores:hetionet CHEBI:15544 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0264906 infores:hetionet CHEBI:41774 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1262036 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0232208 infores:hetionet CAID:CA14902411 biolink:causes MONDO:0011071 infores:clingen CAID:CA14902411 MONDO:0011071 PMID: Benign BA1, BP4, BP2, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 Intronic variant with a MAF of 0.06181 (6.2%, 538/8704 alleles) in the African/African-American subpopulation of the gnomAD v2.1.1 cohort (≥ 0.0015 (0.15%)) (BA1). In addition, this variant is reported in 44 homozygotes in gnomAD v2.1.1 (BP2). Splice AI predicts no impact on splicing ≤ 0.20 (score: 0.00-0.06) (BP4). Intronic variants which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved (phyloP100 way (GRCh38/hg38) ≤2.0). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14902411/MONDO:0011071/008 2022-01-20 2022-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:55346 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0031542 infores:hetionet CHEBI:5855 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0232493 infores:hetionet CHEBI:4702 biolink:causes HP:0030947 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0860499 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027441 infores:hetionet CHEBI:8081 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0857353 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0031117 infores:hetionet CHEBI:134966 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C2830004 infores:hetionet CHEBI:2663 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0018681 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151763 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036454 infores:hetionet CHEBI:8404 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0428977 infores:hetionet NCBIGene:51324 biolink:causes MONDO:0009568 infores:monarchinitiative not_provided not_provided HGNC:20373 MONDO:0009568 uuid:885277aa-8aca-450b-aaaf-3c2498828acc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0497365 infores:hetionet CHEBI:8356 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015402 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0032584 infores:hetionet CHEBI:32139 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0000731 infores:hetionet CHEBI:8093 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0235266 infores:hetionet CAID:CA10604123 biolink:causes MONDO:0009290 infores:clingen CAID:CA10604123 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000152.5:c.934del (p.Leu312CysfsTer2) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon in exon 5, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant and deficient GAA activity in dried blood spots has been reported (clinical laboratory data) (PP4_Moderate). This individual is compound heterozygous for the variant and c.1219T>C (p.Tyr407His). The allelic data from this patient will be used in the assessment of p.Tyr407His and is not included here to avoid circular logic. The variant is not in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 282254). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP GAA-specific criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604123/MONDO:0009290/010 2023-06-27 2023-09-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:75998 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0018681 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0027765 infores:hetionet CHEBI:3499 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C1257843 infores:hetionet CHEBI:49662 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0700200 infores:hetionet CHEBI:72690 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020621 infores:hetionet CHEBI:7852 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0035455 infores:hetionet CHEBI:8207 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0009676 infores:hetionet CHEBI:194135 biolink:causes MONDO:0021681 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0036916 infores:hetionet CHEBI:110423 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0006826 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0020649 infores:hetionet CHEBI:47499 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0235857 infores:hetionet CAID:CA367399180 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399180 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.1064T>C variant in the glucokinase gene, GCK, causes an amino acid change of Leucine to Proline at codon 355 (p.(Leu355Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9689, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, as well as in two individuals in ClinVar whose clinical status was not known DOI:10.1055/s-2004-819152, ClinVar ID 804832, internal lab contributor). However, PS4_Moderate cannot be applied because the number of affected individuals is below the ClinGen MDEP threshold. This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, the evidence supports the classification of c.1064T>C as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399180/MONDO:0015967/086 2023-07-18 2023-07-18 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:31981 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0013384 infores:hetionet NCBIGene:23166 biolink:causes MONDO:0958237 infores:monarchinitiative not_provided not_provided HGNC:18628 MONDO:0958237 uuid:6c64b728-612b-46f3-8576-0b2f33cb3083 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31625 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0022073 infores:hetionet CHEBI:17650 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151908 infores:hetionet CHEBI:5790 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0855775 infores:hetionet CHEBI:567361 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0231856 infores:hetionet CHEBI:9328 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151907 infores:hetionet CHEBI:50777 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0013390 infores:hetionet NCBIGene:6337 biolink:causes MONDO:0009917 infores:monarchinitiative not_provided not_provided HGNC:10599 MONDO:0009917 uuid:22aa39be-a9e5-4392-90c1-11ca87414fe6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0038454 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015230 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0017601 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024894 infores:hetionet CHEBI:7640 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0232462 infores:hetionet CHEBI:29013 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0003123 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029191 infores:hetionet CHEBI:6121 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0403632 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0025290 infores:hetionet CHEBI:5775 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0232462 infores:hetionet CHEBI:4822 biolink:causes UMLS:C2720436 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C2720436 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0518015 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0393759 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0393759 infores:hetionet CHEBI:61049 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0476273 infores:hetionet CHEBI:28901 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0019079 infores:hetionet CHEBI:94392 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0040264 infores:hetionet CHEBI:5130 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002792 infores:hetionet NCBIGene:84233 biolink:causes MONDO:0013069 infores:monarchinitiative not_provided not_provided HGNC:25382 MONDO:0013069 uuid:267c807c-86c9-4002-a367-9c52e60fe55a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1727 biolink:causes MONDO:0009606 infores:monarchinitiative not_provided not_provided HGNC:2873 MONDO:0009606 uuid:a2d770f9-6cd3-44a0-96bb-2edfa9c659ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0072182 biolink:causes GO:0072080 infores:ubergraph knowledge_assertion manual_agent GO:0072182 GO:0072080 CHEBI:46081 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C1112442 infores:hetionet CHEBI:49603 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0011175 infores:hetionet CHEBI:31199 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0263449 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0149904 infores:hetionet CHEBI:5959 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0232462 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151763 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0042571 infores:hetionet CHEBI:6149 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C3263723 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042373 infores:hetionet CHEBI:16480 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0235234 infores:hetionet CAID:CA10584698 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584698 MONDO:0007750 PMID: Uncertain Significance PS3_Supporting, PM2, PP4 PS4, PM1, PP3 The NM_000527.4(LDLR):c.-153C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2022. The supporting evidence is as follows: PM2: Variant is absent from gnomAD v2.1.1.PS3_Supporting: Level 3 assay: PMID 31395865 (Kircher et al., 2019), study on heterologous cells (HepG2), luciferase activity 38-42% of wild-type.PP4: Variant meets PM2 and is identified in 1 case meeting Simon Broome criteria for possible FH from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584698/MONDO:0007750/013 2022-10-28 2025-02-07 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4511 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0016204 infores:hetionet CHEBI:7454 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0006266 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0012833 infores:hetionet CHEBI:63581 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0011603 infores:hetionet CHEBI:135736 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0518988 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0235522 infores:hetionet CAID:CA658655961 biolink:causes MONDO:0015967 infores:clingen CAID:CA658655961 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.1155dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 386 in NM_000162.5, adding 72 novel amino acids before encountering a stop codon (p.(Leu386AlafsTer73)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1155dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655961/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:2663 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0030353 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0521839 infores:hetionet CHEBI:47499 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C2047937 infores:hetionet CHEBI:474180 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0004238 infores:hetionet CHEBI:31547 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0018681 infores:hetionet CAID:CA8815665 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815665 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Supporting PM5 The NM_000152.5:c.2238G>C variant in GAA is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 746 (p.Trp746Cys). This variant is one of the most commonly reported variants in patients with late onset Pompe disease from East Asia (PMIDs 21757382, 31076647) and has been reported in more than 30 patients with Pompe disease (PMIDs 7981676, 18458862, 21232767, 21757382, 25093132, 25526786, 27099502, 27692865, 28433475, 29095275, 29120458, 30360039, 30897595). Because the variant often occurs in cis with pseudodeficiency variants, a conservative approach was taken when assessing data for PP4 and PM3. When pseudodeficiency variants were present or not confirmed to be absent, GAA deficiency was not used to apply PP4, and allelic data was not used for PM3 unless there was convincing evidence that the patient has Pompe disease in addition to GAA deficiency and molecular results. At least 7 Chinese patients have been reported to have the variant and were confirmed to not carry either of the pseudodeficiency variants that are common in East Asian populations (c.1726G>A (p.Gly576Ser) and c.2065G>A (p.Glu689Lys))(PMID 25526786). The patients all had documented laboratory values showing deficiency of GAA activity (PP4_Moderate). In addition, at least 4 patients with the variant and one or both pseudodeficiency variants were reported to have clinical features consistent with Pompe disease and improvements on enzyme replacement therapy (PMIDs 21232767, 25093132, 30360039). Of these patients, 8 were compound heterozygous for the variant and a GAA variant classified as pathogenic by the ClinGen LSD VCEP, phase unknown, including c.444C>G (p.Tyr148Ter), phase unknown, (PMID 25093132), c.1356delC (note that nomenclature in the paper is c.1355delC), phase unknown, (ClinVar SCV SCV001443295.1), c.1935C>A (p.Asp645Glu)(three patients, one confirmed in trans)(PMIDs 21232767, 25526786), c.2662G>T (p.Glu888Ter)(2 patients, one confirmed in trans)(ClinVar SCV001371767.1 (PMIDs 21232767, 25526786), and c.241C>T (p.Gln81Ter), phase unknown (ClinVar SCV001443296.1)(PMID 25526786)(PM3_Very Strong). The highest population minor allele frequency in gnomAD is 0.00057 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion (PM2_Supporting). When expressed in cultured cells, this variant has been reported to reduce GAA activity, ranging from 5-29% of the wild type activity (PMIDs 7981676, 21757382, 23430493)(PS3_Supporting). The computational predictor REVEL gives a score of 0.896, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Other missense substitutions at this amino acid position reported in patients with Pompe disease include c.2236T>C (p.Trp746Arg), c.2237G>C (p.Trp746Ser), and c.2237G>T (p.Trp746Leu). The classification for p.Trp746Cys will be used in the assessment of these other variants and therefore PM5 is not met here in order to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 265160; 2 star review status) with 14 submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PP3, PP4_Moderate, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP - Oct. 19, 2021). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815665/MONDO:0009290/010 2021-10-26 2021-10-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3756 biolink:causes UMLS:C0034634 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0034634 infores:hetionet CHEBI:6520 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0242528 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0041912 infores:hetionet CHEBI:4672 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1145670 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0314719 infores:hetionet CAID:CA1244135 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244135 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.865G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic Acid by Asparagine at amino acid 289 (p.Asp289Asn). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1.0) = 0.00004013 (3 alleles out of 74,750), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.428, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma, thus PS4 did not apply. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244135/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3223 biolink:causes HP:0025253 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0008909 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C2363731 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0032290 infores:hetionet CHEBI:10127 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0026826 infores:hetionet CHEBI:9137 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0542571 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0549310 infores:hetionet CHEBI:63616 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0042963 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0013595 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0236082 infores:hetionet NCBIGene:10714 biolink:causes MONDO:0971151 infores:monarchinitiative not_provided not_provided HGNC:20932 MONDO:0971151 uuid:c4c6a76c-02bf-4c1f-b555-4b60a9d0673c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31397 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0027424 infores:hetionet CHEBI:9168 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0032617 infores:hetionet CHEBI:9599 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018681 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0037199 infores:hetionet CHEBI:3752 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0016242 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0012833 infores:hetionet CHEBI:5130 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0018834 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0518015 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0041912 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0149931 infores:hetionet CHEBI:51164 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0028084 infores:hetionet CHEBI:83531 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C3665347 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1269683 infores:hetionet CHEBI:5138 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0232487 infores:hetionet UMLS:C0657912 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007859 infores:hetionet CHEBI:46295 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0007859 infores:hetionet CHEBI:135736 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0851578 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0013395 infores:hetionet CAID:CA367400140 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400140 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.883G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 295 (p.(Gly295Ser)) of NM_000162.5. This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 29510678 and internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and this variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Lastly, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). In summary, c.883G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PS4_Moderate, PP4_Moderate, PM2_Suporting, PP2, PP3, PM1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400140/MONDO:0015967/086 2023-08-11 2023-08-11 Semidominant inheritance HP:0032113 Supports CHEBI:68478 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0031350 infores:hetionet CHEBI:6129 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0002792 infores:hetionet CHEBI:2663 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0851578 infores:hetionet CHEBI:3240 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0038999 infores:hetionet UMLS:C0879264 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0852911 infores:hetionet CHEBI:9907 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0012569 infores:hetionet CHEBI:6367 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0549249 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0006147 infores:hetionet CHEBI:499361 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0002792 infores:hetionet CHEBI:4798 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0008031 infores:hetionet CHEBI:5138 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0034152 infores:hetionet CHEBI:51860 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151827 infores:hetionet CAID:CA10577530 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577530 MONDO:0007648 PMID:11996968PMID:23431106PMID:11996968PMID:23431106 Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.-50C>G variant occurs in the 5'UTR. This variant is absent in the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>G variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID: 23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577530/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:23765 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0009763 infores:hetionet CHEBI:5138 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085636 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0032285 infores:hetionet CHEBI:3478 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0009763 infores:hetionet UMLS:C1738934 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151908 infores:hetionet CHEBI:4822 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0038990 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020538 infores:hetionet NCBIGene:4976 biolink:causes MONDO:0008134 infores:monarchinitiative not_provided not_provided HGNC:8140 MONDO:0008134 uuid:d4fe388a-083d-4797-bf00-b69219b76d35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151576 infores:hetionet CHEBI:3638 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0085631 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027769 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0032961 infores:hetionet CHEBI:46195 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0011606 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015397 infores:hetionet CHEBI:8713 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0034068 infores:hetionet CHEBI:63617 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027066 infores:hetionet CHEBI:182080 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0003578 infores:hetionet CHEBI:71415 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0278134 infores:hetionet CHEBI:7465 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C2697368 infores:hetionet CAID:CA410147256 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147256 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1340C>T (p.Pro447Leu) is a missense variant which has a REVEL score < 0.50 (0.221), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147256/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3568 biolink:causes MONDO:0006011 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042721 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0030312 infores:hetionet CAID:CA10584845 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584845 MONDO:0007750 PMID: Uncertain Significance PS3_Supporting, PM2, PP4 PM3, PP1 The NM_000527.5 (LDLR):c.313+6T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Brome criteria for possible FH after alternative causes of high cholesterol were excluded, reported by Bourbon et al from Unidade de Investigação Cardiovascular, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal (PMID 19411563).PS3_Supporting: Level 3 experiment, heterozygous patients’ lymphocytes were used for RNA assay and exon 3 skipping (p.Leu64_Pro105delinsSer) was observed, reported by Bourbon et al (PMID 19411563). PM3 not met: This variant is identified in an index case with one other variant, LDLR c.1291G>A (p.Ala431Thr), classified as Pathogenic by these guidelines, in trans, reported by Bourbon et al (PMID 19411563).However, patient’s untreated LDL-C is 435mg/dl, which is under 500mg/dl, therefore PM3 is not met.PP1 not met: Variant segregates with FH phenotype in 1 (less than 2) informative meiosis from 1 family who was tested positive for the variant with LDL-C > 75th percentile, reported by Bourbon et al (PMID 19411563). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584845/MONDO:0007750/013 2022-08-26 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:27834 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0541782 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0036220 infores:hetionet CHEBI:5130 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042963 infores:hetionet CHEBI:9332 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0030305 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0019151 infores:hetionet GO:0061050 biolink:causes GO:0061061 infores:ubergraph knowledge_assertion manual_agent GO:0061050 GO:0061061 CHEBI:5790 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0026205 infores:hetionet CHEBI:8107 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0231218 infores:hetionet CHEBI:135888 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0037278 infores:hetionet CAID:CA16041868 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041868 MONDO:0008723 PMID:9973285 Pathogenic PM2_Supporting, PM3_Supporting, PVS1, PP4_Moderate PS3 The NM_000018.4:c.1077+2T>C variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant has been detected in three homozygous siblings with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who inherited the variant from heterozygous parents (PMID:25338548)(PM3_Supporting, points=0.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two patients with this variant displayed elevated C14:1 levels ≥ 1.0 μM and VLCAD enzyme activity <20% of control in proband fibroblast (PMID:25338548, 9973285), which is highly specific for VLCADD (PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM2_supporting,PM3_Supporting, PP4_Moderate. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041868/MONDO:0008723/021 2022-09-29 2022-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37941 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0023530 infores:hetionet GO:0035315 biolink:causes CL:0000855 infores:ubergraph knowledge_assertion manual_agent GO:0035315 CL:0000855 CHEBI:50648 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019348 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0242350 infores:hetionet CHEBI:3638 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0240735 infores:hetionet CHEBI:75722 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0241060 infores:hetionet CHEBI:82960 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0009782 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019340 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0014858 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0005779 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013395 infores:hetionet CHEBI:7822 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0014457 infores:hetionet CAID:CA16020782 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020782 MONDO:0009861 PMID:26503515 Uncertain Significance PP4_Moderate, PM2, PP3 The c.380A>G (p.Glu127Gly) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded) (PP4_Moderate; PMID: 26503515) This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.896. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020782/MONDO:0009861/006 2019-11-17 2019-11-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:94807 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0020517 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0002453 infores:hetionet CHEBI:4911 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0854467 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019193 infores:hetionet CHEBI:3638 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0013384 infores:hetionet CHEBI:10650 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042487 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0042109 infores:hetionet CAID:CA386970356 biolink:causes MONDO:0015967 infores:clingen CAID:CA386970356 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3 PP4 The c.1481C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 494 (p.(Ala494Val)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8439, which is greater the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (internal lab contributor). In summary, the c.1481C>T variant meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 1/11/2023): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386970356/MONDO:0015967/017 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:DJJ95FJP1H biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0040264 infores:hetionet CHEBI:83804 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0006384 infores:hetionet CHEBI:2666 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C2584688 infores:hetionet CHEBI:9725 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0235063 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0162429 infores:hetionet CAID:CA350341979 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341979 MONDO:0015924 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM1, PM5 BP4 BMPR2 c.1259G>A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid position 420 (p.Cys420Tyr). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). A REVEL score of 0.924 meets PP3_supporting (>0.75). This variant resides within the conserved catalytic kinase domain but does not affect a known critical residue (PM1_moderate). The variant has been reported in four unrelated PAH probands (PMID: 15146475, 16429395, 21737554) with additional citations referring back to the same individuals (PMID: 21801371, 32634488, 30578397) (PS4_moderate). A different missense variant at the same amino acid residue, p.Cys420Arg (PMID: 11115378, 21801371) was previously classified by the PH VCEP as pathogenic (PM5_moderate). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_moderate, PM1_moderate, PM5_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341979/MONDO:0015924/125 2025-04-29 2025-04-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7915 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232849 infores:hetionet CHEBI:27504 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0013404 infores:hetionet CHEBI:2682 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085932 infores:hetionet CHEBI:4672 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0037763 infores:hetionet UMLS:C0004609 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013378 infores:hetionet NCBIGene:10659 biolink:causes MONDO:0030453 infores:monarchinitiative not_provided not_provided HGNC:2550 MONDO:0030453 uuid:b7ef3aec-19e7-4086-b13a-e8b7c53ec5d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0948594 infores:hetionet CHEBI:681569 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0015672 infores:hetionet CHEBI:5558 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0022081 infores:hetionet CAID:CA8814744 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814744 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000152.5(GAA):c.-32-5C>T variant in GAA is an intronic variant which is located in intron 1. The computational splicing predictor SpliceAI gives a score of 0.0 for acceptor site loss suggesting that the variant has no impact on splicing (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001851 (1/5402 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 507529). In summary, this variant meets the criteria to be classified as uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 3, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814744/MONDO:0009290/010 2024-09-03 2024-09-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:8890 biolink:causes UMLS:C2747853 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C2747853 infores:hetionet CHEBI:71219 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0008031 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0549622 infores:hetionet CHEBI:6437 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0004096 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0853761 infores:hetionet CHEBI:41977 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0029118 infores:hetionet CHEBI:9667 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0699744 infores:hetionet CHEBI:8404 biolink:causes MONDO:0020673 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0264995 infores:hetionet NCBITaxon:10335 biolink:causes MONDO:0005609 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10335 MESH:D006562 DB00787_MESH_D006562_1DB00426_MESH_D006562_1DB00577_MESH_D006562_1 CAID:CA658824419 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824419 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS4, PS2, PS3, PS1, BA1, BP2, BP1, BP4, BP3, PM6, BS1, BS4, BS3, BP5, BP7, PM1, PM3, PM4, PP1, PP4, PP2, PP3, BS2 The NM_001754.4:c.424dup (p.Ala142fs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported as germ-line in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824419/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31236 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013404 infores:hetionet CHEBI:28748 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0743400 infores:hetionet CHEBI:28864 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0271321 infores:hetionet CAID:CA226572 biolink:causes MONDO:0100368 infores:clingen CAID:CA226572 MONDO:0100368 PMID: Likely Benign BP4, BS1, BP7 The c.644-42del variant in RPE65, is an intronic variant which is present outside of consensus splice sites. The splicing impact predictor SpliceAI gives a delta score of 0.09, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In addition, the PhyloP score was -2.63 which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1, which depicts that the nucleotide is not highly conserved. This intronic variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000827, with 26/24712 in the African/ African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). In summary this variant meets criteria to be classified as Likely Benign for Leber congenital amaurosis (RPE65) based on the ACMG/AMP criteria (codes met: BP4, BP7, BS1). (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226572/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5165 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0080274 infores:hetionet CHEBI:2955 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0344232 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1266194 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0600041 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0600041 infores:hetionet CAID:CA024158 biolink:causes MONDO:0007783 infores:clingen CAID:CA024158 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PS4_Moderate, PM1_Supporting, PP3_Moderate, PP1_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of histidine with tyrosine at codon 4822 of the RYR1 protein, p.(His4833Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 18212565). This variant segregates with MHS in five individuals, PP1_Moderate (PMID: 18212565). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 20461000). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.975) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024158/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:4907 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0002871 infores:hetionet CAID:CA024609 biolink:causes MONDO:0007783 infores:clingen CAID:CA024609 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, PP1, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with phenylalanine at codon 2182 of the RYR1 protein, p.Ile2182Phe. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:12434264). This variant segregates with MHS in three individuals, does not meet PP1 (PMID:12434264). Ex vivo functional studies using cells from a single family were identified for this variant, this does not satisfy PS3 (PMID: 14641996). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.76 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024609/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7445 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0232461 infores:hetionet GO:0006954 biolink:causes HP:0002829 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D018771 DB08797_MESH_D018771_1DB01397_MESH_D018771_1 CHEBI:6923 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0267792 infores:hetionet CHEBI:39585 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0021177 infores:hetionet CAID:CA1139532543 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139532543 MONDO:0009861 PMID:29499199 Uncertain Significance PM2, PP4_Moderate, PP3 This c.706+5G>A variant in PAH was reported in one patient with hyperphenylalaninemia. Tetrahydrobiopterin deficiency was ruled out with urinary pterin analysis and a DHPR activity assay (PMID: 29499199). This variant is absent from population databases. Multiple lines of computation evidence support a deleterious effect. In summary, this variant meets criteria to be classified as Uncertain Significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532543/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3175 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0235266 infores:hetionet CHEBI:7852 biolink:causes UMLS:C2363914 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C2363914 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0022104 infores:hetionet GO:0072043 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0060993 CHEBI:567361 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0042373 infores:hetionet CHEBI:490877 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0015230 infores:hetionet CHEBI:31859 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0086565 infores:hetionet CHEBI:7577 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0016242 infores:hetionet GO:0044473 biolink:causes GO:0005262 infores:ubergraph knowledge_assertion manual_agent GO:0044473 GO:0005262 CHEBI:6402 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0281981 infores:hetionet CHEBI:10101 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0040264 infores:hetionet CHEBI:18358 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0027497 infores:hetionet CHEBI:4672 biolink:causes NCIT:C157384 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0438235 infores:hetionet CHEBI:16755 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0008372 infores:hetionet CHEBI:7577 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0019209 infores:hetionet CAID:CA9302028 biolink:causes MONDO:0010938 infores:clingen CAID:CA9302028 MONDO:0010938 PMID: Likely Benign BS1 PS1, PM5, BS2 The c.938G>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Glycine by Glutamic Acid at amino acid 313 (p.Gly313Glu).The filtering allele frequency (the lower threshold of the 95% CI of 90/30614) of the c.938G>A variant in JAK3 is 0.002449 for South Asian chromosomes by gnomAD v2.1., which is higher than the ClinGen SCID VCEP threshold (>0.001) for BS1, and therefore meets this criterion (BS1). No homozygotes have been observed in gnomAD. (BS2 is not met).To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9302028/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:92607 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0085616 infores:hetionet CHEBI:8871 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027424 infores:hetionet CHEBI:50275 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0231218 infores:hetionet CHEBI:465284 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013604 infores:hetionet CHEBI:119915 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231218 infores:hetionet CHEBI:61058 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0002453 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0003123 infores:hetionet CHEBI:15428 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0001122 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0205204 infores:hetionet CAID:CA10585409 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585409 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0000007200 (0.00007200%) in European (non-Finnish) exomes (gnomAD v4.1.0).PP3: REVEL = 0.961.PS4, PP4: Variant meets PM2 and is identified in at least 14 unrelated index cases who fulfill FH criteria from different labs (5 cases with DLCN score >=6 and 5 cases with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 2 cases with DLCN score >=6 and 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 6 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585409/MONDO:0007750/013 2025-01-31 2025-02-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:135613 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0007787 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042373 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0522063 infores:hetionet CHEBI:9566 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0004096 infores:hetionet CHEBI:119915 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003811 infores:hetionet GO:0120313 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:0120313 GO:0030154 PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0033575 infores:hetionet CAID:CA10567761 biolink:causes MONDO:0010602 infores:clingen CAID:CA10567761 MONDO:0010602 PMID: Benign BA1 PP4, PS4 The c.6724G>A variant in F8 is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 2242 (p.Val2242Met), affecting the first nucleotide in exon 25. The c.6724G>A (p.Val2242Met) variant is reported at an MAF of 0.006735 (100/14847 alleles) in the East Asian population in gnomAD v2.1.1, with 32 hemizygotes, meeting BA1 criteria of MAF >= 0.000333. In summary, this variant is classified as a Benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10567761/MONDO:0010602/071 2024-10-11 2024-10-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:9571 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0020615 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0877055 infores:hetionet CHEBI:7565 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151744 infores:hetionet NCBIGene:1267 biolink:causes MONDO:0033657 infores:monarchinitiative not_provided not_provided HGNC:2158 MONDO:0033657 uuid:5476f162-55ac-412b-a6ae-e1e0fbf444fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3640 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0476273 infores:hetionet CHEBI:6950 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0542571 infores:hetionet CHEBI:4551 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0013395 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0022660 infores:hetionet CHEBI:74947 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151825 infores:hetionet CHEBI:51041 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0004093 infores:hetionet CHEBI:7809 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0042963 infores:hetionet CHEBI:6076 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0877055 infores:hetionet CHEBI:82941 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0023787 infores:hetionet CHEBI:49575 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0017178 infores:hetionet CHEBI:3423 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020452 infores:hetionet CHEBI:478164 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0000737 infores:hetionet CHEBI:135342 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042023 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085096 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0031117 infores:hetionet CHEBI:28748 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017565 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0162830 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0037199 infores:hetionet CHEBI:28364 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0014724 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1368065 infores:hetionet CAID:CA658798354 biolink:causes MONDO:0007947 infores:clingen CAID:CA658798354 MONDO:0007947 PMID: Pathogenic PM6, PP4, PP1, PM2_Supporting, PM4, PS4 PVS1, PP2, PP3, BS2, BP2, BP3, BP1, BP4, BA1, PM3, PM1, PM5, PS2, PS3, PS1, BP5, BP7, BS1, BS4, BS3 NM_000138.5 c.5076_5078del is a deletion of 3 nucleotides in FBN1 predicted to cause the in-frame deletion of arginine at amino acid 1692 (p.Arg1692del) (PM4). This variant has been identified in a patient with thoracic aortic aneurysm and dissection (TAAD), ectopia lentis (EL), and a systemic score ≥ 7, which is a specific phenotype for Marfan syndrome (MFS) (PP4; University of Tokyo internal data). It has been identified in at least 5 other unrelated individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS (PS4; PMIDs: 27146836, 32679894; University of Tokyo & Invitae internal data); in one of these individuals with TAAD, EL, and a systemic score of 10, a phenotype highly specific to FBN1, it was found to be inherited from an apparently mosaic and unaffected parent (PM6; Invitae internal data). This variant has also been identified in at least 4 additional unrelated individuals who do not meet clinical diagnostic criteria but have phenotypes consistent with MFS, including EL or TAAD with or without systemic features (PMIDs: 17657824, 29144511, 33844962; Bichat & Invitae internal data). In two families, the variant was found to segregate with disease in a similarly affected family member (PP1; Bichat & University of Tokyo internal data). It is present in gnomAD in 1 individual of European (non-Finnish) ancestry, with a frequency of 0.00009% (1/1111872 alleles) (PM2_supporting; https://gnomad.broadinstitute.org/, v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM4, PM6, PP1, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798354/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63611 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011570 infores:hetionet CAID:CA003383 biolink:causes MONDO:0700268 infores:clingen CAID:CA003383 MONDO:0700268 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3 The c.5242G>T variant in BRCA1 is a missense variant predicted to cause substitution of Glycine by Cysteine at amino acid 1748 (p.(Gly1748Cys)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.3, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 4.36 (based on Family History LR=4.36), within the thresholds for moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP4_Moderate, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003383/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3752 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0547030 infores:hetionet CHEBI:135939 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0039070 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0854456 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0854456 infores:hetionet CHEBI:184555 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0016204 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017675 infores:hetionet CHEBI:5118 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004604 infores:hetionet CHEBI:3756 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0033774 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0521491 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0022658 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0036454 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0001824 infores:hetionet UMLS:C1738934 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0344232 infores:hetionet CHEBI:7494 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0026826 infores:hetionet CHEBI:29688 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0014869 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0001416 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0001416 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042075 infores:hetionet CHEBI:3698 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0036980 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0042109 infores:hetionet CHEBI:3219 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013456 infores:hetionet CHEBI:8888 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151539 infores:hetionet CHEBI:68579 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0018944 infores:hetionet CAID:CA1707354 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707354 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PP3, PS3_Moderate, PM2_Supporting The NM_003494.4: c.5296G>A variant in DYSF, which is also known as NM_001130987.2: c.5413G>A p.(Glu1805Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 1766, p.(Glu1766Lys). This variant has been identified in at least two unrelated individuals with features consistent with LGMD, including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 29799141) and confirmed in trans with a likely pathogenic or pathogenic variant in another patient (NM_003494.4: c.4090C>T p.(Gln1364Ter), 1.0 pt, PMID: 36983702, 24488599, 27602406) (PM3). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 36983702, 29799141; PP4_Strong). The filtering allele frequency for this variant in in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 9/1180026 European (non-Finnish) chromosomes) is 0.000013309, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting and therefore meets this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Glu1766Lys protein did not reach the cell membrane, indicating a deleterious impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.88, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/28/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707354/MONDO:0015152/180 2025-05-28 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:92923 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0009806 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006444 infores:hetionet CHEBI:50648 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0549249 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0033975 infores:hetionet CAID:CA8623073 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623073 MONDO:0100326 PMID: Benign BP7, BP4, BA1 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.882T>C (p.Pro294=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.2463 (4912/19940 alleles) in gnomAD, found in the East Asian population, which is considerably higher than the expected frequency of the disease (BA1). In Silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing at a nucleotide site that is not highly conserved. In conclusion the criteria BA1, BP4, and BP7 were applied to reach a classification of benign. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623073/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:68534 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0003467 infores:hetionet CHEBI:17474 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0002994 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017152 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0243026 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0020517 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0021775 infores:hetionet CHEBI:7798 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011253 infores:hetionet CHEBI:2666 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0004093 infores:hetionet CHEBI:101278 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0240735 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027765 infores:hetionet CAID:CA376059856 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059856 MONDO:0011225 PMID: Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1 The c.522C>G (p.Tyr174Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).This variant is absent from gnomAD v4 (PM2_Supporting). One patient reported in the literature is homozygous for this variant, 0.5 pts, PM3_Supporting. She is T-B-NK+ (0.5 pts) with diagnosis carried out through SCID gene panel or exome/genome sequencing conducted (0.5 pts), total 1 pt, PP4_Supporting (PMID: 37480474).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059856/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports CAID:CA9043527 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043527 MONDO:0012999 PMID: Uncertain Significance PM2, PP3, BP4, BS1 The NM_000156.6:c.705A>T variant in GAMT is a missense variant that is predicted to cause the substitution of a lysine by an asparagine at amino acid position 235 (p.Lys235Asn). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004016 (18/44822 alleles) in the East Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.342 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function. There is a ClinVar entry for this variant (Variation ID: 2137773). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): no criteria met.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043527/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9566 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0156404 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0151815 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151815 infores:hetionet CHEBI:27436 biolink:causes UMLS:C0151310 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0151310 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0242350 infores:hetionet CHEBI:17303 biolink:causes HP:0030218 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1963933 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0042373 infores:hetionet CHEBI:367163 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0030193 infores:hetionet CHEBI:16714 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0004093 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0012833 infores:hetionet CAID:CA367398311 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398311 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1228G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to cysteine at codon 410 (p.(Gly410Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and OGTT 2 hour increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). Three other missense variants, c.1228G>A p.Gly410Ser, c.1229G>A p.Gly410Asp, and c.1228G>C p.Gly410Arg, have been interpreted as pathogenic by the ClinGen MDEP, and p.Gly410Cys has a greater Grantham distance than p.Gly410Ser, p.Gly410Asp, and p.Gly410Arg (PM5_Strong). In summary, c.1228G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398311/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports NCBIGene:3055 biolink:causes MONDO:0957204 infores:monarchinitiative not_provided not_provided HGNC:4840 MONDO:0957204 uuid:3d4b4bf3-df91-49a5-91e8-8fa50cf1a65a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0021177 infores:hetionet NCBIGene:23636 biolink:causes MONDO:0010080 infores:monarchinitiative not_provided not_provided HGNC:8066 MONDO:0010080 uuid:24e216ef-74b8-41cc-86a8-aea0cde1fc3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0004134 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0009806 infores:hetionet CHEBI:27974 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0025218 infores:hetionet CHEBI:3568 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0236075 infores:hetionet CHEBI:3048 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0042963 infores:hetionet CHEBI:42797 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0877359 infores:hetionet NCBIGene:2324 biolink:causes MONDO:0007919 infores:monarchinitiative not_provided not_provided HGNC:3767 MONDO:0007919 uuid:2bd0f3ee-ee9d-435f-a7cd-dea517190746 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0004245 infores:hetionet UMLS:C1872203 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0595877 infores:hetionet CHEBI:5130 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014335 infores:hetionet CAID:CA15984361 biolink:causes MONDO:0011071 infores:clingen CAID:CA15984361 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.509-281G>T is an intronic variant which has a MAF of 0.8530 (85.3%, 35321/41406, 35321 alleles) in the African/African American subpopulation of the gnomAD 3.1.2 cohort which is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 15115 individuals in a population database (gnomAD 3.1.2) (BP2). This intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.45) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA15984361/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36795 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0043094 infores:hetionet CHEBI:9449 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0917801 infores:hetionet CHEBI:4868 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0423153 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0031350 infores:hetionet NCBIGene:55906 biolink:causes MONDO:0010758 infores:monarchinitiative not_provided not_provided HGNC:24931 MONDO:0010758 uuid:02e11bc2-b043-45b1-9837-50d5f8a4c85a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1139666837 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666837 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1277_1278insCCCCCCCCCCC (p.Arg427ProfsTer?) is an insertion that results in a frameshift. This frameshift variant is located downstream of c.98 (PM5_Supporting). It is not predicted to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.780-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666837/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32221 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0042963 infores:hetionet CHEBI:63608 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0029118 infores:hetionet NCBIGene:999 biolink:causes MONDO:0054740 infores:monarchinitiative not_provided not_provided HGNC:1748 MONDO:0054740 uuid:df8e96f5-ab6d-4331-beb8-3ae81b226f40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0085682 infores:hetionet CHEBI:5778 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0877359 infores:hetionet CHEBI:32315 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042963 infores:hetionet CHEBI:135930 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0344232 infores:hetionet CHEBI:134991 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0004093 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0014742 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0037199 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0011991 infores:hetionet CHEBI:75722 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042963 infores:hetionet CHEBI:6067 biolink:causes HP:0003249 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151281 infores:hetionet CAID:CA10014270 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014270 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: none. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014270/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0270810 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0021775 infores:hetionet NCBIGene:51294 biolink:causes MONDO:0009625 infores:monarchinitiative not_provided not_provided HGNC:8657 MONDO:0009625 uuid:6c1b372f-76d5-4487-9d3d-27c648ef85bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes UMLS:C0860700 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0860700 infores:hetionet CHEBI:6456 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C2363730 infores:hetionet GO:1990216 biolink:causes GO:0006351 infores:ubergraph knowledge_assertion manual_agent GO:1990216 GO:0006351 CHEBI:4708 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0010692 infores:hetionet GO:0060176 biolink:causes GO:0030587 infores:ubergraph knowledge_assertion manual_agent GO:0060176 GO:0030587 CHEBI:40237 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0542571 infores:hetionet CHEBI:4356 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0232487 infores:hetionet CHEBI:75722 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233407 infores:hetionet CHEBI:4907 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0002622 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1956346 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0343886 infores:hetionet CHEBI:10124 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1510410 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0027051 infores:hetionet CHEBI:6847 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0042963 infores:hetionet CHEBI:50305 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0041834 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0031117 infores:hetionet NCBIGene:9231 biolink:causes MONDO:0958205 infores:monarchinitiative not_provided not_provided HGNC:2904 MONDO:0958205 uuid:f385e4b7-18f3-4967-b630-e68e473b54b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1325847 infores:hetionet NCBIGene:26154 biolink:causes MONDO:0011026 infores:monarchinitiative not_provided not_provided HGNC:14637 MONDO:0011026 uuid:5eec2408-d14e-4ffb-8cf3-ba14e1f4a40f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10100 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C2973529 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0027765 infores:hetionet CHEBI:110423 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0042963 infores:hetionet CHEBI:79699 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0024312 infores:hetionet CHEBI:27786 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0013595 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0853954 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0853954 infores:hetionet CHEBI:28901 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0001623 infores:hetionet CHEBI:45924 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0036830 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0009450 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0034150 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0858814 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0858814 infores:hetionet CHEBI:9725 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0917801 infores:hetionet CHEBI:4702 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0152030 infores:hetionet CHEBI:7494 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020580 infores:hetionet CHEBI:31236 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017565 infores:hetionet CHEBI:84883 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0917801 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0020517 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151596 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0004239 infores:hetionet CAID:CA016817 biolink:causes MONDO:0004994 infores:clingen CAID:CA016817 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.77C>T (p.Ala26Val) variant in the MYH7 gene is 0.55% (60/8646) of East Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016817/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:44423 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0030312 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0392025 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0242350 infores:hetionet CHEBI:45716 biolink:causes HP:0000074 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0521619 infores:hetionet CHEBI:31623 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0030332 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002884 infores:hetionet CHEBI:585948 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0231749 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0034063 infores:hetionet CAID:CA357004 biolink:causes MONDO:0008667 infores:clingen CAID:CA357004 MONDO:0008667 PMID: Pathogenic PS4_Moderate, PM2_Supporting, PVS1 The variant NM_000551.3(VHL):c.341-2A>G is a canonical splice site within the 1st intron of the VHL gene, and is predicted to undergo nonsense mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 studies, in cases or families with VHL syndrome or VHL-related cancers. PMIDs: 17661816, 17024664, 27539324, CIViC EIDs (https://civicdb.org): 5748, 5730. Two commercial laboratories report 1 case each, both with a history of VHL-related cancers. One had an additional clinical diagnosis of VHL and a first degree relative with multiple VHL-related cancers in age 30-40yrs who was also VHL positive (PS4_Moderate). Although PP3 was not applied due to use of PVS1, we include the note that multiple splice predictors were used to evaluate the splice site. VarSeak supports the impact of disrupting this canonical splice site (Class 5) and the Splice AI score is 0.93, indicating impact on splicing. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA357004/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50841 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0017601 infores:hetionet NCBIGene:7994 biolink:causes MONDO:0014558 infores:monarchinitiative not_provided not_provided HGNC:13013 MONDO:0014558 uuid:933cd20b-f2a3-4a86-8d5b-fd95588ce1f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0033774 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0236071 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0004936 infores:hetionet CHEBI:94385 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0035229 infores:hetionet CHEBI:84050 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0018681 infores:hetionet CHEBI:5138 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151836 infores:hetionet CHEBI:64312 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040264 infores:hetionet CHEBI:64312 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030196 infores:hetionet CAID:CA10014477 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014477 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS4, PS3, PS1, BP2, PM6, PM2, PVS1, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 The c.552G>T variant predicts a synonymous change, Pro184= and has an MAF of 0.001654 (0.17%, 33/19954 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -8.975 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014477/MONDO:0011071/008 2020-08-24 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:91541 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0013428 infores:hetionet CHEBI:31932 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0231218 infores:hetionet CHEBI:63610 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0000737 infores:hetionet CHEBI:31859 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0027497 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0038367 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0009806 infores:hetionet CAID:CA386973449 biolink:causes MONDO:0015967 infores:clingen CAID:CA386973449 MONDO:0015967 PMID: Likely Pathogenic PS1_Supporting, PM2_Supporting, PVS1_Strong, PS2_Moderate The c.1768+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 9 of NM_000545.8. This variant is predicted to cause an in-frame deletion of biologically-relevant exon 9 of 10, removing more than 10% of an important region of the protein (PVS1_Strong). Additionally, the c.1768+1G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1768+1G>T has a similar or greater predicted impact by Splice AI (0.88 and 0.81) (PS1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PS2_Moderate; internal lab contributors). In summary, c.1768+1G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1_Strong, PS1_Supporting, PM2_Supporting, PS2_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386973449/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:194135 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0227791 infores:hetionet CHEBI:3032 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0549249 infores:hetionet CHEBI:3655 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0013144 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0009450 infores:hetionet CHEBI:5138 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0008031 infores:hetionet CHEBI:41774 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0025320 infores:hetionet CHEBI:6801 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0017178 infores:hetionet CHEBI:2687 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151578 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0917801 infores:hetionet CHEBI:9123 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085641 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0002170 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0851341 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0852733 infores:hetionet CHEBI:92712 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C1112320 infores:hetionet CHEBI:92712 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0149744 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0015672 infores:hetionet CHEBI:38562 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0028866 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0234215 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0034065 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0010200 infores:hetionet CHEBI:51364 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0013428 infores:hetionet CHEBI:93363 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0743680 infores:hetionet CHEBI:31643 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C2242996 infores:hetionet NCBIGene:1536 biolink:causes MONDO:0010389 infores:monarchinitiative not_provided not_provided HGNC:2578 MONDO:0010389 uuid:2ce256d7-a3a3-4e79-bdc5-f738de54c265 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0438717 infores:hetionet CHEBI:5098 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0017672 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0043251 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0021167 infores:hetionet CAID:CA404774961 biolink:causes MONDO:0010938 infores:clingen CAID:CA404774961 MONDO:0010938 PMID: Likely Pathogenic PVS1, PM2_Supporting BA1, BS1, PS1, PM5 The NM_000215.4(JAK3):c.175A>T (p.Lys59Ter) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions, and functional studies have not been found. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1 and PM2_supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA404774961/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2469 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0595916 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0018916 infores:hetionet CHEBI:3219 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037036 infores:hetionet CHEBI:7565 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1368065 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0000833 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0948089 infores:hetionet CHEBI:50648 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0001175 infores:hetionet CHEBI:16796 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0028734 infores:hetionet CHEBI:134743 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0033774 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0853700 infores:hetionet CAID:CA16020810 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020810 MONDO:0009861 PMID:26322415PMID:26322415 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.523C>T (p.Pro175Ser) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded) in trans with pathogenic variant p.R413P (PP4_Moderate, PM3; PMID: 26322415). This variant is absent in population databases (PM2). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020810/MONDO:0009861/006 2019-04-08 2019-04-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0314719 infores:hetionet CAID:CA229297 biolink:causes MONDO:0009861 infores:clingen CAID:CA229297 MONDO:0009861 PMID:11328945PMID:9781015 Pathogenic PVS1, PM2, PP4, PM3_Supporting The c.1043_1053del (p.Leu348fs) variant in PAH has been reported in 1 female patient with classic PKU, serum Phe = 2600 umol/L; BH4 deficiency not excluded (PP4_Moderate). This variant was detected with R408W, reported as Pathogenic in ClinVar, phase not confirmed (0.5 points; PM3_Supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 10 out of 13 coding exons (10 out of total exons) (PVS1), and is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229297/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52717 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0392525 infores:hetionet CHEBI:91834 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0033774 infores:hetionet GO:1901490 biolink:causes GO:0036303 infores:ubergraph knowledge_assertion manual_agent GO:1901490 GO:0036303 CHEBI:53760 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011991 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0006277 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0039503 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042109 infores:hetionet CHEBI:27786 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0011603 infores:hetionet NCBIGene:4640 biolink:causes MONDO:0976268 infores:monarchinitiative not_provided not_provided HGNC:7595 MONDO:0976268 uuid:ee3e5448-6edb-4eaa-b47c-3bfac08cc605 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes UMLS:C0919593 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0919593 infores:hetionet CHEBI:4784 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0026821 infores:hetionet CHEBI:63598 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002874 infores:hetionet CHEBI:3419 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0004604 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0035455 infores:hetionet CHEBI:5778 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0014518 infores:hetionet CHEBI:16755 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013447 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0574067 infores:hetionet CHEBI:8707 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0344232 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1258215 infores:hetionet CHEBI:17347 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0338656 infores:hetionet NCBIGene:57190 biolink:causes MONDO:0011271 infores:monarchinitiative not_provided not_provided HGNC:15999 MONDO:0011271 uuid:e82b28b3-e2a2-49ae-9600-ad623aa156f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135566 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0035455 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0852711 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0852711 infores:hetionet NCBIGene:5723 biolink:causes MONDO:0013531 infores:monarchinitiative not_provided not_provided HGNC:9577 MONDO:0013531 uuid:c4ebf827-333b-47cb-94be-c5cc7180ace8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0920171 infores:hetionet CHEBI:8888 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232495 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0029408 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0267792 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0948525 infores:hetionet CHEBI:17334 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0017086 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0392025 infores:hetionet CHEBI:2567 biolink:causes UMLS:C1442968 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C1442968 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0003123 infores:hetionet CHEBI:6710 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0040264 infores:hetionet CHEBI:28487 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0011124 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020557 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0019158 infores:hetionet CHEBI:2666 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0013384 infores:hetionet CHEBI:63605 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0392525 infores:hetionet CAID:CA4432734 biolink:causes MONDO:0010134 infores:clingen CAID:CA4432734 MONDO:0010134 PMID: Uncertain Significance PP3, PP4, PM5, PM2_Supporting PM3 The c.1262A>G variant in SLC26A4 is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 421 (p.Gln421Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/113084) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). Another missense variant, c.1262A>C (p.Gln421Pro), at the same codon has been classified as likely pathogenic for autosomal recessive Pendred syndrome (PM5; PMID: 17718863, 23918157, 24224479, 28964290). The p.Gln421Arg variant has been reported in five individuals with hearing loss and inner ear abnormalities, which is highly specific for Pendred syndrome (PP4). Two individuals did not have a variant on the second allele identified (PMIDs: 23965030, 14679580). Two individuals were compound heterozygous for the CEVA haplotype, and one individual was compound heterozygous for a variant of uncertain significance, c.284G>A p.Gly95Glu. Phase for these individuals was unknown (0 PM3 points, PMID: 36833263). This variant was re-reviewed on 6.27.2023, and PM2 was downgraded to PM2_Supporting following the most recent specification criteria. Because no contradictory evidence was added, this variant was retained at likely pathogenic for autosomal recessive Pendrome syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM5, PM2_Supporting, PP3, PP4. (VCEP specifications version 2; 06.21.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA4432734/MONDO:0010134/005 2023-06-21 2024-01-10 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6067 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018500 infores:hetionet CHEBI:28901 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0027540 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0002170 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0031350 infores:hetionet CHEBI:7825 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0016436 infores:hetionet CHEBI:9332 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0034152 infores:hetionet CHEBI:16469 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0278134 infores:hetionet CHEBI:8214 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0041657 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005447 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0153594 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004975 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002395 infores:hetionet CHEBI:6062 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C2047937 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1306341 infores:hetionet CHEBI:32315 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151908 infores:hetionet CHEBI:10102 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011124 infores:hetionet CHEBI:2549 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1291077 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0853149 infores:hetionet CHEBI:63620 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0262662 infores:hetionet CHEBI:5280 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0018926 infores:hetionet CHEBI:28939 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0016382 infores:hetionet CHEBI:182080 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0020649 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0518015 infores:hetionet CHEBI:3696 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020598 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026848 infores:hetionet CHEBI:68478 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151692 infores:hetionet CHEBI:59560 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0015230 infores:hetionet UMLS:C0145867 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0232462 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0031542 infores:hetionet NCBIGene:4733 biolink:causes MONDO:0957990 infores:monarchinitiative not_provided not_provided HGNC:3029 MONDO:0957990 uuid:31164dbb-6c65-4ab2-ac7b-535327298e42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0029118 infores:hetionet NCBIGene:93 biolink:causes MONDO:0013403 infores:monarchinitiative not_provided not_provided HGNC:174 MONDO:0013403 uuid:ddcca9cd-f0bf-4375-814b-09d1c79f7c63 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA121125 biolink:causes MONDO:0010604 infores:clingen CAID:CA121125 MONDO:0010604 PMID: Benign BA1, BP4 The c.580A>G (p.Thr194Ala) variant is reported at an MAF of 0.3026 (27985/92495 alleles) in the non-Finnish European population in gnomAD v2.1.1 with 2609 homozygotes and 10667 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. Note that gnomAD v3.1.1 reports a frequency of 0.3041 in the NFE population, with 1859 homozygotes and 4024 hemizygotes. This missense variant has a REVEL score of 0.255 (<0.3) and SpliceAI predicts no impact on splicing, with a score of 0.0, meeting BP4 criteria. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA121125/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:31644 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0040264 infores:hetionet CHEBI:521033 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0029261 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0700184 infores:hetionet CHEBI:135679 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0235267 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0019348 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0030312 infores:hetionet CHEBI:84500 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0149745 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0018418 infores:hetionet CHEBI:63791 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0023467 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0017601 infores:hetionet CHEBI:51173 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0022354 infores:hetionet CHEBI:50131 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0344232 infores:hetionet CHEBI:119915 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0424790 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0039503 infores:hetionet CHEBI:36795 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0338831 infores:hetionet CAID:CA410203987 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203987 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.182C>G (p.Pro61Arg) is a missense variant which is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has a REVEL score < 0.50 (0.316), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203987/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2659 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0080274 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0522224 infores:hetionet CHEBI:7601 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0036830 infores:hetionet CHEBI:7852 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0497156 infores:hetionet MONDO:0034109 biolink:causes NCBIGene:4632 infores:ubergraph knowledge_assertion manual_agent MONDO:0034109 HGNC:7582 NCBIGene:6576 biolink:causes MONDO:0014072 infores:monarchinitiative not_provided not_provided HGNC:10979 MONDO:0014072 uuid:0c525e83-8f61-439b-94f1-39f91fa19255 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:291342 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0010200 infores:hetionet CHEBI:4887 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0000737 infores:hetionet CAID:CA10014182 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014182 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BP1, BP2, BP3, BA1, PM2, PVS1, PM6, BS1, BS3, BP7, PM3, PM4, PM1, PM5, BS2, PP2, PP3, PP4 NM_001754.5(RUNX1):c.1353C>G (p.Asp451Glu) is a missense variant which has a REVEL score of 0.106 and a SpliceAI score indicating no predicted impact on splicing, suggesting no damaging effect on RUNX1 function (BP4). The highest population minor allele frequency in gnomAD v2 is 0.00004406 (1/22696 alleles) in the South Asian population, and the variant has not been reported in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014182/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004245 infores:hetionet CHEBI:3723 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2938875 infores:hetionet NCBIGene:23438 biolink:causes MONDO:0013972 infores:monarchinitiative not_provided not_provided HGNC:4817 MONDO:0013972 uuid:251ac08f-508c-484d-b567-f6b179e7ef5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0002152 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0267988 infores:hetionet NCBIGene:89795 biolink:causes MONDO:0976285 infores:monarchinitiative not_provided not_provided HGNC:15998 MONDO:0976285 uuid:c1d03707-f6ca-418a-b6f3-5390c92e341c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1510410 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0023890 infores:hetionet CHEBI:51450 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0019080 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0018799 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014130 infores:hetionet CHEBI:119573 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1142412 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020437 infores:hetionet CHEBI:31981 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0085631 infores:hetionet CHEBI:135925 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0039231 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0853761 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0027765 infores:hetionet CHEBI:2469 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0267792 infores:hetionet CHEBI:8207 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0004093 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0003864 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013609 infores:hetionet CHEBI:91834 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0231218 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030305 infores:hetionet CAID:CA8328546 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328546 MONDO:0100438 PMID: Uncertain Significance PP3, PM2_Supporting NM_014336.5(AIPL1):c.304C>T (p.Arg102Trp) is a missense variant replacing the arginine at position p.102 with tryptophan. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000021, with 34 alleles / 1613846 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.687, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function (PP3). In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328546/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6690 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011334 infores:hetionet CHEBI:8080 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0042963 infores:hetionet CHEBI:135935 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C1384353 infores:hetionet CHEBI:82981 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0521839 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023533 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151538 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151538 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0151505 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022354 infores:hetionet CHEBI:5103 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0439857 infores:hetionet CHEBI:94686 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0232462 infores:hetionet CHEBI:63616 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0015967 infores:hetionet CHEBI:83804 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0028949 infores:hetionet CAID:CA414443534 biolink:causes MONDO:0010604 infores:clingen CAID:CA414443534 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4, PP3 PM1 The c.802T>C (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 268 (p.Cys268Arg). This variant has been reported in >4 probands with severe FIX deficiency, meeting phenotypic criteria for F9 (PS4 - PMIDs :17014892, 24375831, 15921378). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3/ gnomAD v4.1.0), meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.958, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). A different missense variant causing a change at the same residue (p.Cys268Tyr) has been established as pathogenic for F9 and SpliceAI predicts no impact on splicing (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4 + PM2_supporting + PP3 + PM5. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414443534/MONDO:0010604/080 2025-10-03 2025-10-07 X-linked inheritance HP:0001417 Supports CHEBI:3216 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0547030 infores:hetionet CHEBI:63638 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0038220 infores:hetionet CHEBI:4877 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0543698 infores:hetionet GO:0048928 biolink:causes CL:1000245 infores:ubergraph knowledge_assertion manual_agent GO:0048928 CL:1000245 CAID:CA015028 biolink:causes MONDO:0005045 infores:clingen CAID:CA015028 MONDO:0005045 PMID: Uncertain Significance BP7 BP5, BS1, BS3, BS4, PP2, PP3, PP1, PM2, PM6, PVS1, PM5, PM4, PM1, BA1, BP4, BP2, PS1, PS3, PS4, PS2 NM_000256.3(MYBPC3):c.405A>G (p.Lys135=). This variant has not been reported in the literature in individuals with cardiomyopathy but has been reported by other clinical laboratories in ClinVar (Variation ID 177780). This variant has also been identified in 5 out of 71230 (0.002750% GroupMax FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1; PM2 does not apply; BS1 does not apply). Currently, there is no evidence that this variant is enriched in HCM cases compared to controls (PS4 does not apply). This silent variant occurs in the last three bases of exon 3, which is part of the 5’ splice region. Computational tools do not predict a splicing impact, though this information is not predictive enough to rule out pathogenicity (Splice AI: Donor Loss score 0.27, BP7). Functional studies using a minigene assay did not find that this variant significantly altered splicing compared to reference sequence (Ito 2017 PMID: 28679633), however, this data is currently insufficient to establish functional impact and apply BS4. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on BP7. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015028/MONDO:0005045/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042024 infores:hetionet GO:2000702 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0072006 CAID:CA10014633 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014633 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.77A>C (p.Asn26Thr) is a missense variant which has a REVEL score < 0.50 (0.3) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014633/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15544 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0235969 infores:hetionet CHEBI:520985 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0013378 infores:hetionet CHEBI:4798 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0600142 infores:hetionet CHEBI:31348 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019825 infores:hetionet CHEBI:28901 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0032227 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038363 infores:hetionet NCBIGene:53335 biolink:causes MONDO:0014914 infores:monarchinitiative not_provided not_provided HGNC:13221 MONDO:0014914 uuid:64ae3c97-283f-4c14-97a7-e706e684ed17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA405687465 biolink:causes MONDO:0018493 infores:clingen CAID:CA405687465 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamine with glutamic acid at codon 4837 of the RYR1 protein, p.(Gln4837Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:23558838). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.914) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405687465/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6888 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0018813 infores:hetionet CHEBI:7476 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0476273 infores:hetionet CHEBI:9328 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0340865 infores:hetionet CHEBI:5118 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003578 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0009938 infores:hetionet CAID:CA120562 biolink:causes MONDO:0044970 infores:clingen CAID:CA120562 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4, PP1_Moderate, PS3_Supporting PS2, PM6 The m.3303C>T variant in MT-TL1 has been reported in at least 16 unrelated individuals with primary mitochondrial disease (PS4; 13 individuals were reported in the medical literature, PMIDs: 23847141, 10431114, 32167396, 11768589, 33013660, 20226758, 23258140, 7906985, 31965079; an additional three cases were known to members of this Expert Panel). Many affected individuals had hypertrophic cardiomyopathy and/or skeletal myopathy, as well as exercise intolerance, muscle weakness, lactic acidosis, and failure to thrive. Age of onset varied from infancy to adulthood. Heteroplasmy levels in affected individuals ranged from 58-97% in muscle, 20-80% in blood, and, in one case, was almost homoplasmic in fibroblasts. There are no de novo occurrences of this variant to our knowledge. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMID: 10431114, also seen in cases known to Expert Panel members). Of note, there is a report of this variant in individuals with premature ovarian insufficiency (POI, PMID: 30404982), however this Expert Panel agreed this presentation, when isolated, is not known to be associated with mitochondrial DNA etiologies and it is not clear other organ systems were or were not screened in these cases. Therefore, these cases were not considered as supporting evidence for this variant classification. There is one occurrence in population databases as one individual in the Helix dataset had this variant present at heteroplasmy. Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (92.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing (PMID: 11271374) showed higher levels of the variant in ragged red fibers that were COX-negative (42.4±7.0%) and in ragged red fibers that were COX-positive (58.2±5.8%), and this was significantly higher than levels of the variant in normal appearing fibers (10.7±6.3%; PS3_supporting). Of note, cybrid studies are reported however the generated cybrids include other mitochondrial DNA variants precluding consideration as evidence of pathogenicity of this variant only (PMID: 30404982). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note, however, that some members of this Expert Panel elected to modify the classification to pathogenic given the extent of cases from different ethnic backgrounds that have been reported with overlapping phenotypes that is further supported by the evidence outlined above. The experts were almost evenly divided on the final classification as five experts voted to keep the classification as likely pathogenic and four voted for pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120562/MONDO:0044970/015 2023-01-09 2023-03-31 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3699 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C2242588 infores:hetionet CHEBI:50122 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0040034 infores:hetionet CHEBI:231594 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0010692 infores:hetionet CHEBI:34911 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0278134 infores:hetionet CHEBI:3996 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0002170 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0162429 infores:hetionet CHEBI:78543 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0030554 infores:hetionet CHEBI:8435 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0013132 infores:hetionet CHEBI:10102 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0003578 infores:hetionet CHEBI:10124 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0026826 infores:hetionet CHEBI:9137 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0232849 infores:hetionet CHEBI:82960 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151636 infores:hetionet CHEBI:92998 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0011603 infores:hetionet CHEBI:16335 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0278134 infores:hetionet CHEBI:50861 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0018944 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0347390 infores:hetionet CHEBI:63619 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013378 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0919874 infores:hetionet GO:2000031 biolink:causes GO:0071446 infores:ubergraph knowledge_assertion manual_agent GO:2000031 GO:0071446 CHEBI:39867 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0024282 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0005779 infores:hetionet CHEBI:4798 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0086565 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0027765 infores:hetionet CHEBI:3387 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0004093 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0025061 infores:hetionet CAID:CA410147804 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147804 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS1, PS3, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1196G>A (p.Ser399Asn) is a missense variant with a REVEL score <0.50 (0.053) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (MPN/MDS) (PMID: 32241844) (PS4_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147804/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64312 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1384353 infores:hetionet CHEBI:100241 biolink:causes HP:0030836 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0221785 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011849 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0036572 infores:hetionet NCBIGene:4604 biolink:causes MONDO:0013965 infores:monarchinitiative not_provided not_provided HGNC:7549 MONDO:0013965 uuid:eca742ce-0218-49e2-b2bc-32728b8851ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50922 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0026848 infores:hetionet CHEBI:29013 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0027947 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006277 infores:hetionet UMLS:C0005740 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0034642 infores:hetionet CAID:CA291019 biolink:causes MONDO:0012999 infores:clingen CAID:CA291019 MONDO:0012999 PMID: Benign BS2, BA1, BP4 The NM_000156.6:c.392-7C>T variant in GAMT is a nucleotide substitution in intron 3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00430 (107/24892 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 4 homozygotes in gnomAD v2.1.1 (all in the S Asian population) which, given the early onset and severity of phenotype for GAMT deficiency, supporting that the variant is not associated with GAMT deficiency. Computational evidence from SpliceAI and varSEAK suggests no impact on the gene/gene product (BP4). There is a ClinVar entry for this variant (Variation ID: 137436,). In summary, this variant meets the criteria to be classified as Benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291019/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:231425 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0041969 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0009450 infores:hetionet CHEBI:119486 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0040264 infores:hetionet CHEBI:27470 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0013404 infores:hetionet CHEBI:101278 biolink:causes MONDO:0000469 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0428908 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0424230 infores:hetionet CHEBI:8874 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0231856 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0021845 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028077 infores:hetionet CHEBI:15940 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151691 infores:hetionet CHEBI:3387 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0004245 infores:hetionet CHEBI:3082 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151827 infores:hetionet UMLS:C0657912 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0021177 infores:hetionet CHEBI:17688 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0023218 infores:hetionet CAID:CA10529740 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529740 MONDO:0010604 PMID: Likely Benign BS1, BP4 The c.130C>T; p.Pro44Ser variant has a Grpmax MAF of 0.00005825 in gnomAD v2.1.1 meeting BS1. The variant also has a REVEL score of 0.144 and Splice AI scores: Acceptor Loss: 0.00, Donor Loss: 0.05, Acceptor Gain: 0.00, Donor Gain: 0.00, meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BS1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529740/MONDO:0010604/080 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:17823 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0085632 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0162429 infores:hetionet CHEBI:31709 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0027497 infores:hetionet CHEBI:31623 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0026113 infores:hetionet CAID:CA16020951 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020951 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 PM5, PS3 The c.1154T>C (p.Leu385Pro) variant in PAH has been reported in at least 3 Chinese patients with Phe > 120umol/L (BH4 deficiency excluded) (PP4_Moderate; PMIDs:29499199, 23932990). This variant was detected in the homozygous state in two patients (PM3; PMID:23932990). This variant is absent in population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen, MutationTaster, and REVEL = 0.817 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020951/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:472657 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0027947 infores:hetionet CAID:CA397836496 biolink:causes MONDO:0018875 infores:clingen CAID:CA397836496 MONDO:0018875 PMID: Likely Benign BP4, BS3, PM2_Supporting BA1, BP1, PS3, PS1, PS4, PS2, PM5, PM1, BP5, BS1, BS4, PVS1, PP3, PP2, PP1, PP4, BS2 The NM_000546.6: c.883C>T variant in TP53 is a missense variant predicted to cause substitution of proline by serine at amino acid 295 (p.Pro295Ser). This variant has an allele frequency of 0.000004237 (5/1180042 alleles) in the European non-Finnish population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.2; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397836496/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6715 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042075 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151824 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0038525 infores:hetionet UMLS:C0065374 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0041657 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0040038 infores:hetionet GO:0140884 biolink:causes GO:0071346 infores:ubergraph knowledge_assertion manual_agent GO:0140884 GO:0071346 GO:0072095 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0001823 NCBITaxon:33993 biolink:causes MONDO:0024416 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:33993 MONDO:0024416 CHEBI:63613 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0021053 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0424000 infores:hetionet CAID:CA913169011 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169011 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting, PP1_Moderate PS2, PM6 The m.3255G>A variant in MT-TL1 has been reported in two unrelated families with primary mitochondrial disease to date (PMIDs: 2413483, 12868503). The age of onset was the fifth decade and clinical features included myopathy, lactic acidosis, seizures, pigmentary retinopathy, ptosis, neuropathy, elevated cerebrospinal fluid protein, and ragged red and COX-deficient fibers (PS4_supporting). This variant segregated with clinical manifestations in one of these families as the variant was present in the proband at 53% heteroplasmy in skeletal muscle, 67% in urine sediment, less than 2% in cultured skin fibroblasts, and 22% in blood. The variant was present at less than 2% heteroplasmy in leukocytes from the mother and sister. An additional seven unaffected family members had the variant present at less than 2% in urine and saliva, and the variant was undetectable in another family member (PP1_moderate; PMID: 12868503). There are no individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (75.8 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (94%) than in COX-positive fibers (18%; p<0.0001; PS3_supporting; PMID: 12868503). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169011/MONDO:0044970/015 2024-04-22 2024-11-20 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:66919 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0017181 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0042109 infores:hetionet GO:2001049 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:2001049 GO:0009653 CHEBI:39867 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085649 infores:hetionet CHEBI:3504 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0035455 infores:hetionet CHEBI:27446 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0235996 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0015230 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0040425 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0039621 infores:hetionet CHEBI:5383 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0037822 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015397 infores:hetionet NCBIGene:4297 biolink:causes MONDO:0011518 infores:monarchinitiative not_provided not_provided HGNC:7132 MONDO:0011518 uuid:793dc1b5-7619-4088-af92-a992266ded79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0750394 infores:hetionet NCBITaxon:2104 biolink:causes MONDO:0019377 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2104 MONDO:0019377 CHEBI:7447 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0036830 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0240515 infores:hetionet CHEBI:681848 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0231835 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0006277 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0012833 infores:hetionet CHEBI:10119 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085593 infores:hetionet CAID:CA414799043 biolink:causes MONDO:0044970 infores:clingen CAID:CA414799043 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PP3 PM5, PP4, PP1, BA1, PS4, PS3, PS1, BS2_Supporting, BS1, BS3, PM6 The m.8936T>A (p.L137H) variant in MT-ATP6 has been reported in one family (PMID: 29929013), in a proband with Leigh syndrome and his unaffected mother. Unaffected mother had lower variant heteroplasmy than the proband in blood (8.26% vs 10.92%) and saliva (5.71% vs 8.26%). Family haplogroup is M30d1. There are no reports of de novo occurrence of this variant. This variant is located at the same amino acid position as another variant in ClinVar (m.8936T>C, ClinVar ID: 693028), but that variant is classified as of uncertain significance so cannot be considered evidence for pathogenicity. There are no large families to consider for evidence of segregation. This variant is absent in population databases (PM2_supporting). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP3). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414799043/MONDO:0044970/014 2021-05-07 2021-10-22 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7852 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0031212 infores:hetionet NCBIGene:29927 biolink:causes MONDO:0958013 infores:monarchinitiative not_provided not_provided HGNC:18276 MONDO:0958013 uuid:0707fe09-f365-42b1-a146-5030c612c0f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18243 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0025323 infores:hetionet CHEBI:8774 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C2047937 infores:hetionet CHEBI:42068 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0040038 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0042373 infores:hetionet CHEBI:27786 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0235710 infores:hetionet CHEBI:9435 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0039231 infores:hetionet CHEBI:499361 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0149871 infores:hetionet CHEBI:32020 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0022660 infores:hetionet CHEBI:31709 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0016382 infores:hetionet CHEBI:7627 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0017178 infores:hetionet CAID:CA348209 biolink:causes MONDO:0700270 infores:clingen CAID:CA348209 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PVS1_Strong BA1, BS1 The ATM c.1607+1G>T canonical splice variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1_Strong). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 1712434, 9450906, 19691550, PM3_VeryStrong). This variant has a GnomAD (v2.1.1) allele frequency of 0.0009% (NFE) which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA348209/MONDO:0700270/020 2022-03-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5132 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0011991 infores:hetionet CHEBI:63610 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013428 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0009806 infores:hetionet CAID:CA10602749 biolink:causes MONDO:0100084 infores:clingen CAID:CA10602749 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PS2 PP1, PP4, BS2, PM6, PVS1, BA1, BP3, BP1, BP2, PS3, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3 The variant NM_001100.4:c.442G>C in ACTA1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 148 (p.Gly148Arg). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.979, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Two different missense variants, p.Gly148Ser and p.Gly148Val (Variation IDs: 1364817 and 2582809), in the same codon have been classified as likely pathogenic for alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5 applied to p.Gly148Val). This variant has been reported in 2 probands with alpha-actinopathy, and one of these probands had a de novo occurrence of the variant with parental relationships confirmed (PS4_Supporting, PS2; PMID: 33820833. SCV000330673.6). In summary, this variant meets the criteria to be classified as likely pathogenic for AD alpha-actinopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP (Specification Version 2.0.0): PM2_Supporting, PP3, PP2, PS4_Supporting, PS2 (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 3/10/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602749/MONDO:0100084/147 2025-03-10 2025-04-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6061 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0025637 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005989 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0040558 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027651 infores:hetionet CHEBI:3387 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0085605 infores:hetionet CHEBI:7915 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151830 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0008489 infores:hetionet CHEBI:9943 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2937350 infores:hetionet CHEBI:9555 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0043094 infores:hetionet CAID:CA10385160 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385160 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.3317A>G (p.Lys1106Arg) is a missense variant causing substitution of lysine by arginine at amino acid 1106. This variant is present in gnomAD v4.1.0 at a frequency of 0.00007054 among hemizygous individuals, with 28 variant alleles / 396,946 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.026, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385160/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:46295 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0011603 infores:hetionet CHEBI:10124 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0010520 infores:hetionet NCBIGene:368 biolink:causes MONDO:0008333 infores:monarchinitiative not_provided not_provided HGNC:57 MONDO:0008333 uuid:a07f1528-c6e6-427c-97bd-6b35e974e879 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:83636 biolink:causes MONDO:0014024 infores:monarchinitiative not_provided not_provided HGNC:25443 MONDO:0014024 uuid:c32cfa5b-dcfa-4473-ae8a-d00423343ec7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151883 infores:hetionet CHEBI:36791 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026858 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0423636 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0423636 infores:hetionet NCBIGene:7204 biolink:causes MONDO:0032939 infores:monarchinitiative not_provided not_provided HGNC:12303 MONDO:0032939 uuid:6d657ddd-3a20-420b-ad8e-7a99e2b25fce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31644 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020580 infores:hetionet CHEBI:46557 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0595916 infores:hetionet NCBIGene:84617 biolink:causes MONDO:0060589 infores:monarchinitiative not_provided not_provided HGNC:20776 MONDO:0060589 uuid:da9fb618-635a-4b3f-8c9d-292fd5680d91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5558 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C2981158 infores:hetionet CHEBI:204734 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0039446 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020517 infores:hetionet CHEBI:6931 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0040046 infores:hetionet CHEBI:4708 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0522055 infores:hetionet CHEBI:46195 biolink:causes UMLS:C2609176 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C2609176 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011849 infores:hetionet CHEBI:3561 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0027066 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0034150 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151735 infores:hetionet NCBIGene:7201 biolink:causes MONDO:0032819 infores:monarchinitiative not_provided not_provided HGNC:12299 MONDO:0032819 uuid:8b0d31f1-6953-4e61-a596-27a002807c5f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000004 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:2000004 GO:0072210 CHEBI:8869 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0017675 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0858814 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0858814 infores:hetionet CAID:CA2259744 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259744 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.581+4A>G variant in the RAF1 gene is 0.0375% (34/66642) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259744/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:72690 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020456 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0497247 infores:hetionet CHEBI:8428 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0042384 infores:hetionet CAID:CA014200 biolink:causes MONDO:0004994 infores:clingen CAID:CA014200 MONDO:0004994 PMID: Uncertain Significance PM2, PP3 PM5, PM4, PM1, PM6, BA1, PP1, PS3, BP3, BS1, BS3, BS4, PS1, PS4, PS2, BP4, BP7, BP2, BP5, PVS1 The NM_000257.4(MYH7):c.3883G>A (p.Glu1295Lys) variant has been identified in 1 individual with LVNC, in 1 individual with congestive heart failure and 1 individual with sudden cardiac arrest (GeneDx pers. comm., Invitae pers. comm.); however, due to the nature of the associated phenotypes, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.002% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014200/MONDO:0004994/002 2021-11-19 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9588 biolink:causes UMLS:C0040797 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0040797 infores:hetionet CHEBI:9727 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0024305 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151735 infores:hetionet CHEBI:6444 biolink:causes MONDO:0002285 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0034124 infores:hetionet CAID:CA160129 biolink:causes MONDO:0012163 infores:clingen CAID:CA160129 MONDO:0012163 PMID: Benign BS2_Supporting, BA1 The c.1092T>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause the substitution of Aspartic Acid by Glutamic Acid at amino acid 364 (p.Asp364Glu).The filtering allele frequency (the lower threshold of the 95% CI of 1584/91068 alleles) of the c.1092T>G variant in IL7R is 0.01668 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 35 adult homozygous occurrences are described in gnomAD (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160129/MONDO:0012163/119 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6076 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020621 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003123 infores:hetionet CHEBI:3207 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0007859 infores:hetionet CHEBI:4876 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0018681 infores:hetionet CHEBI:63612 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0270810 infores:hetionet CHEBI:63631 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0547030 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0700345 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0030846 infores:hetionet UMLS:C0004609 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0242184 infores:hetionet NCBIGene:9851 biolink:causes MONDO:0030353 infores:monarchinitiative not_provided not_provided HGNC:29110 MONDO:0030353 uuid:a68e50a9-e970-4694-a45a-dc550fe2e6c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68841 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0043352 infores:hetionet CHEBI:63845 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0020517 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0009782 infores:hetionet CAID:CA404093326 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093326 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS1, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP1, PP2, PP3 The NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PS3: Level 1 assays: PMID 31689621 (Gomez et al., 2019): Heterologous cells (CHO-ldlA7), RT qPCR and 125I-LDL assays - results – normal (100%) LDLR expression and 50% uptake and catabolism -> results are below 70% of wild-type, so functional study is consistent with damaging effect.PP4: Variant meets PM2 and is identified in 1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon (France) with DLCN score ≥ 6, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093326/MONDO:0007750/013 2023-06-23 2025-09-15 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:31536 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0025061 infores:hetionet CHEBI:32293 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0344232 infores:hetionet NCBIGene:9488 biolink:causes MONDO:0032822 infores:monarchinitiative not_provided not_provided HGNC:8959 MONDO:0032822 uuid:be53acee-974e-432e-aa55-defe84a84974 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000444 biolink:causes MONDO:0017623 infores:clingen CAID:CA000444 MONDO:0017623 PMID:25288137PMID:23470840PMID:23335809PMID:32350270PMID:29706350 Pathogenic PM2, PM6, PP2, PS4, PS3 PTEN c.395G>A (p.Gly132Asp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350, PMID 32350270)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s) SCV000279163)PM2: Absent in large sequenced populations (PMID 27535533)PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000444/MONDO:0017623/003 2021-10-29 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49603 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0015672 infores:hetionet CHEBI:7494 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0231528 infores:hetionet CHEBI:6887 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038990 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042373 infores:hetionet CHEBI:9907 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018188 infores:hetionet CHEBI:100241 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151740 infores:hetionet CHEBI:3216 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1260922 infores:hetionet CHEBI:168396 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151636 infores:hetionet CAID:CA397397658 biolink:causes MONDO:0100438 infores:clingen CAID:CA397397658 MONDO:0100438 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting NM_014336.5(AIPL1):c.126T>A (p.Cys42Ter) is a nonsense variant that introduces a premature stop codon into exon 2 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.784G>A (p.Gly262Ser) variant suspected but not confirmed in trans (0.5 points, PMID: 15249368), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with visual acuity limited to hand movements (1 pt), mild maculopathy (0.5 pts), mild optic nerve pallor (0.5 pts), severe pigmentary retinopathy (1 pt), and photoattraction (1 pt), which together are specific for AIPL1-related retinopathy (total 4.5 points, PMID: 15249368, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397397658/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4653 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0018681 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0518015 infores:hetionet CHEBI:50275 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1167709 infores:hetionet CHEBI:50729 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0025323 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0005779 infores:hetionet CHEBI:35854 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0151904 infores:hetionet CHEBI:63608 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0851578 infores:hetionet CHEBI:71255 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0040460 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151828 infores:hetionet CHEBI:16469 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0858635 infores:hetionet CHEBI:8207 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013456 infores:hetionet CHEBI:8059 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0040822 infores:hetionet CHEBI:64064 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0027441 infores:hetionet CHEBI:59773 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0013404 infores:hetionet CHEBI:100241 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0037763 infores:hetionet CAID:CA10014229 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014229 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS2, PS4, PS1, PS3, BP1, BP3, BP2, BA1, BP5, BS4, BS1, BS3, PM6, PM2, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.4(RUNX1):c.981G>C (p.Leu327=) is a synonymous variant is located at a weakly conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = 0.994606 in GRCh38), and the variant is the reference nucleotide in one primate and/or 3 mammals; it is not predicted to have any splicing impact per SpliceAI (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014229/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8707 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030252 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0277589 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0277589 infores:hetionet CHEBI:3994 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0041834 infores:hetionet CHEBI:9328 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0017178 infores:hetionet CHEBI:74947 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0239377 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0877305 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877305 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0042109 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1167965 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0041349 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1971624 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0595939 infores:hetionet CHEBI:5959 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020461 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0007222 infores:hetionet CHEBI:70707 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0017605 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0234215 infores:hetionet CAID:CA415260520 biolink:causes MONDO:0010683 infores:clingen CAID:CA415260520 MONDO:0010683 PMID: Pathogenic PP4, PM2_Supporting, PS4_Moderate, PS2, PVS1_Strong BS2, PP2, PP3, PP1, BP2, BP1, BP4, BP3, BA1, PS3, PS1, BP7, BP5, BS1, BS3, BS4, PM6, PM3, PM1, PM4, PM5 The NM_000252.3:c.1644+1G>A variant in MTM1 occurs within the canonical splice donor site (+1) of intron 14. Although the exact impact of this variant on splicing is unknown, it might cause skipping of biologically-relevant-exon 14/15 resulting in an in-frame deletion and escape nonsense mediated decay, removing <10% of the protein based on computational predictions. However, the C-terminus of MTM1 is a critical region to protein function as specified by the ClinGen Congenital Myopathy VCEP, thus meeting PVS1_Strong. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. This variant has been detected in 3 individuals with myotubular myopathy (PS4_Moderate, PMID:28685322, 33062893, 34366366), one of which has been identified as a de novo occurrence with confirmed parental relationships whose muscle biopsy showed central nuclei, necklace fibers, and atrophy fibers which is highly specific for the disease (PS2, PP4, PMID:28685322). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PS2, PS4_Moderate, PP4, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA415260520/MONDO:0010683/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Supports CHEBI:17650 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0020621 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1168034 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0001339 infores:hetionet CAID:CA019789 biolink:causes MONDO:0700269 infores:clingen CAID:CA019789 MONDO:0700269 PMID: Uncertain Significance PVS1, PM2 The c.425+1G>A variant is an intronic variant within the native donor 1,2 splice site occurring in intron 4 of the BRCA2 gene. It is predicted to cause out-of-frame skipping of exon 4, resulting in a frameshift leading to nonsense mediated decay. All variants at this splice site score very similar with SpliceAI predicting exon 4 skipping, however several variants at this splice site exhibit complex patterns of splicing with only partial prediction of nonsense mediated decay. BRCA2 c.425+2T>C RNA data (RT-PCRseq) shows skipping of exon 4 at 32.55% PSI, with in-frame skipping of exons 4 and 5 at 7.17% PSI. BRCA2:c.425G>A RNA data (RT-PCRseq) shows exon 4 skipping at 36.73% PSI, in-frame skipping of exons 4 and 5 at 13.69% PSI, and out of frame skipping of exons 3 and 4 at 4.05% PSI. Similarly, BRCA2:c.425G>T RNA data (RT-PCRseq) shows exon 4 skipping at 26.85% PSI, skipping of exons 4-5 at 9.63% PSI, and exon 4-7 skipping at 3.84% PSI. Normally spliced transcripts contained nearly 100% WT allele (internal laboratory contributor). Published data also indicates these variants (c.425+2T>C, c.425G>A, c.425G>T) retain partial function and have clinical phenotypes consistent with benign variants (PMID: 33469799; 32398771). Based on this, we have not assigned pathogenic evidence at any strength (PVS1_N/A) to exon 4 donor site variants. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting. In summary, this variant did not meet any criteria and is classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (v1.2). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA019789/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5138 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003460 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0236068 infores:hetionet CHEBI:36704 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0034063 infores:hetionet CHEBI:6931 biolink:causes NCIT:C50526 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235827 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0178298 infores:hetionet NCBIGene:6628 biolink:causes MONDO:0007301 infores:monarchinitiative not_provided not_provided HGNC:11153 MONDO:0007301 uuid:ba0b92d7-2236-41f4-810d-1efdffa125c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0234215 infores:hetionet CAID:CA229373 biolink:causes MONDO:0009861 infores:clingen CAID:CA229373 MONDO:0009861 PMID:9634518PMID:11161839 Pathogenic PP4_Moderate, PP3_Strong, PM2_Supporting, PM3_Strong, PS3_Supporting The NM_000277.3(PAH):c.1183G>C variant is PAH is a missense variant predicted to cause substitution of alanine by proline at amino acid 395 (p.Ala395Pro). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND sequencing of genes in the BH4 cofactor metabolism pathway excluded a defect of BH4 cofactor metabolism, which is highly specific for PAH deficiency (PP4_Moderate, PMIDs: 9634518, 12836060). This variant has been detected in at least 5 individuals with Phenylketonuria. All individuals were compound heterozygous for the variant and distinct pathogenic variants in unknown phase (PM3_strong, PMIDs: 17502162, 12836060, 11999982, 7726156). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001017 in European (non-Finnish), which is lower than the ClinGen PAH Variant Curation Expert Panel threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting). Mutant PAH enzyme activity showed 14-17% enzyme activity in vitro with < 10 benign/pathogenic variant controls, indicating that this variant impacts protein function (PS3_supporting, PMID: 11161839). The computational predictor REVEL gives a score of 0.988, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM3_strong, PM2_supporting, PS3_supporting, PP3_strong. Version 2.0, 7/16/2024. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229373/MONDO:0009861/006 2025-08-15 2025-08-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:68478 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2363731 infores:hetionet CAID:CA026898 biolink:causes MONDO:0021056 infores:clingen CAID:CA026898 MONDO:0021056 PMID: Benign BS2, BP4, BP7, BS1 PP2, PP3, PP4, PP1, PM1, PM3, PM4, PM5, PM2, PM6, PVS1, BA1, BP2, BP3, BP1, PS3, PS1, PS4, PS2, BP5, BS3, BS4 The c.1242C>T (p.Arg414=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (≥ 10) healthy individual points in total (BS2; Ambry internal data). While RT-PCR from internal data demonstrated no impact of the variant on splicing (Ambry Internal Data), transcription assays (not otherwise specified) in the literature demonstrated that the variant impacts splicing by leading to partial exon 10 skipping (p.V313_Q412del) (PMID 20685668). Functional evidence was disregarded in the classification of this variant as they showed conflicting results. The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European (non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.00001) for BS1. In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA026898/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0145185 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0428977 infores:hetionet CAID:CA114176 biolink:causes MONDO:0015631 infores:clingen CAID:CA114176 MONDO:0015631 PMID:12588349 Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3, PS3 The NM_000552.5(VWF):c.3178T>C (p.Cys1060Arg) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.96, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least one homozygote and two compound heterozygotes with R854Q (confirmation of trans phase not reported), which is classified pathogenic by the VWD VCEP (PMID: 12588349; PM3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (FVIII:C 4-10 IU/dL) and absent VWF:FVIII binding, which is highly specific for VWD type 2N. (PP4_moderate, PMID 12406074). Variants in F8 were screened for by sequencing. Site-directed mutagenesis and transient expression in COS-7 cells showed R1060rVWF was completely unable to bind to rFVIII (PMID: 12588349; PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3, PP4_moderate, PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114176/MONDO:0015631/090 2025-02-04 2025-02-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15765 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0002871 infores:hetionet CAID:CA340525 biolink:causes MONDO:0019497 infores:clingen CAID:CA340525 MONDO:0019497 PMID: Pathogenic PP1_Strong, PP4, PM3_Very Strong, PVS1 BS1 The filtering allele frequency (the lower threshold of the 95% CI of 22/34228) of the c.2485C>T (p.Gln829Ter) variant in the OTOF gene is 0.04% for Latino chromosomes in gnomAD v2.1.1, which meets the cutoff to apply BS1_Supporting. However, this variant has been established as a founder variant in the Spanish population and is thought to be causative in 3% of cases of deafness in the Spanish population (BS1_Supporting not applicable; PMID: 27177047). The p.Gln829Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 21/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID: 30192042). The p.Gln829Ter variant has been identified in >50 patients with non-syndromic hearing loss (PM3_VeryStrong; PMIDs: 18381613, 17036997, 16371502, 14635104, 12114484). It has repeatedly been reported to segregate with hearing loss (PP1_Strong; PMIDs: 12114484, 14635104,16371502, 18381613). In addition to hearing loss, at least 24 patients reported to have the p.Gln829Ter variant presented with features of auditory neuropathy spectrum disorder, which is highly specific to OTOF and autosomal recessive hearing loss (PP4; PMIDs:18381613, 17036997, 14635104). In summary, the p.Gln829Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PP1_Strong, PM3_VeryStrong, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA340525/MONDO:0019497/005 2022-05-13 2022-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:162417 biolink:causes MONDO:0009377 infores:monarchinitiative not_provided not_provided HGNC:17996 MONDO:0009377 uuid:49aa7305-ca9d-47b3-bda3-b4228e2d8ce6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40237 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0851341 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0232459 infores:hetionet CHEBI:94385 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0015230 infores:hetionet CHEBI:6822 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0027497 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1328395 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1328395 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0038362 infores:hetionet NCBIGene:128637 biolink:causes MONDO:0014296 infores:monarchinitiative not_provided not_provided HGNC:16133 MONDO:0014296 uuid:5838bf60-bb91-4655-a369-171628332cda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63925 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0021368 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0522224 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027765 infores:hetionet CHEBI:3219 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0338831 infores:hetionet CAID:CA10585385 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585385 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, PS3, PM5, PP3, PP1 The NM_000527.5 (LDLR):c.1284C>G (p.Asn428Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: Variant is absent from gnomAD (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 index cases who fulfill criteria for FH (1 case with total cholesterol >8 mmol/L and family history of hypercholesterolemia or classical clinical stigmata of FH from PMID 11857755 (Bunn et al., 2002), New Zealand; 1 case with total cholesterol >90th percentile and clinical features of FH or family history of early CHD from PMID 11845603 (Vergotine et al., 2001), South Africa; 1 case with DLCN score >=6 from PMID 11810272 (Fouchier et al., 2001), the Netherlands; 1 case with LDL >95th percentile, plus two of: presence of xanthomata, CAD in proband or family history of CAD or high LDL, from PMID 11668640 (Garcia-Garcia et al., 2001) Spain; 1 case with LDLC 6.5 mmol/L, presence of xanthomas, and history of angioplasty or bypass surgery from PMID 11005141 (Khoo et al., 2000), Malaysia. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585385/MONDO:0007750/013 2023-06-23 2024-10-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4514 biolink:causes UMLS:C0269993 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0269993 infores:hetionet CHEBI:168396 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0542571 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0700184 infores:hetionet CHEBI:15854 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C1142412 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0038454 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0039503 infores:hetionet CAID:CA410207064 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207064 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS2, PS1, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.645G>T (p.Lys215Asn) is a missense variant which is absent from both gnomAD v2.1 and gnomAD v3.1.2 (PM2_supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207064/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50885 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0553548 infores:hetionet CHEBI:171719 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0018524 infores:hetionet CHEBI:499361 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013378 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0038525 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017160 infores:hetionet CHEBI:175901 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1720798 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0018991 infores:hetionet CAID:CA512318767 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318767 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.384T>C (p.Thr128=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.77)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318767/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6067 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0017178 infores:hetionet CHEBI:63584 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C2047937 infores:hetionet CHEBI:17474 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0004096 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0031117 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0038454 infores:hetionet CHEBI:31174 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0038814 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0008049 infores:hetionet CHEBI:7444 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0012833 infores:hetionet CHEBI:83527 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0012833 infores:hetionet CHEBI:10110 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151904 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0149931 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0027651 infores:hetionet CHEBI:45863 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0427457 infores:hetionet CAID:CA386952521 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952521 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP1_Moderate, PP3 PS4, PM5, PP4 The c.50T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to histidine at codon 17 (p.(Leu17His)) of NM_000545.6. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP threshold of 0.70 (PP3). This variant was observed in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin deficient diabetes; however, PS4_Moderate cannot be applied because the minimum number of cases is not met (PMID: 21683639, 26479152, internal lab contributor). This variant segregated with diabetes, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 7.900e-7, which is below the ClinGen MDEP threshold for PM2_Supporting (≤ 0.000003) (PM2_Supporting). Another missense variant, c.49C>G (p.Leu17Val), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3, PP1_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952521/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:4436 biolink:causes MONDO:0008018 infores:monarchinitiative not_provided not_provided HGNC:7325 MONDO:0008018 uuid:f81f30be-461f-4e2e-8a4d-6b3028e67668 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5194 biolink:causes MONDO:0013950 infores:monarchinitiative not_provided not_provided HGNC:8855 MONDO:0013950 uuid:e4a98d27-6da3-4d5c-96dd-1106244ea1d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:60761 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0151744 infores:hetionet CHEBI:36704 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0015967 infores:hetionet GO:1902159 biolink:causes GO:0034220 infores:ubergraph knowledge_assertion manual_agent GO:1902159 GO:0034220 CHEBI:50131 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0026636 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0004238 infores:hetionet NCBIGene:128674 biolink:causes MONDO:0009482 infores:monarchinitiative not_provided not_provided HGNC:15836 MONDO:0009482 uuid:9a731452-cea0-4b83-a214-a37e2b4581c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5132 biolink:causes MONDO:0005628 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0242788 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0024115 infores:hetionet CHEBI:6539 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0018794 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0851341 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042109 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0027765 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0042109 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009450 infores:hetionet CHEBI:9316 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0009676 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0034150 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0036454 infores:hetionet CAID:CA10118817 biolink:causes MONDO:0021060 infores:clingen CAID:CA10118817 MONDO:0021060 PMID: Likely Benign BS1 PM2, PP3, BP4, BA1 The NM_006767.4:c.1333G>A variant in LZTR1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 445 (p. Val445Met). The filtering allele frequency (the lower threshold of the 95% CI of 16/35316) of the c.1333G>A variant in LZTR1 is 0.0002680 for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.464, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. In summary, this variant meets the criteria to be classified as likely benign for RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10118817/MONDO:0021060/094 2024-12-03 2025-04-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5138 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0520966 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0004096 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0017152 infores:hetionet CHEBI:135736 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0917801 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0042267 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0020517 infores:hetionet CHEBI:8888 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2173677 infores:hetionet GO:1901207 biolink:causes GO:0048568 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0048568 CHEBI:3387 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0024031 infores:hetionet CHEBI:84500 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0392525 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0000833 infores:hetionet CHEBI:49575 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0003811 infores:hetionet CAID:CA915940266 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940266 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting NM_000419.5(ITGA2B):c.175del (p.Asp59ThrfsTer?) is a frameshift variant that causes a premature stop codon at exon 3 and is predicted to undergo nonsense mediated decay (PVS1). At least one patient homozygous for this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PMID:28078347; PP4_moderate, PM3_supporting). Additionally, αIIbβ3 surface expression was reduced to 3.8%, as measured by flow cytometry. The variant was not found in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PSV1, PM2_supporting, PM3_supporting, PP4_moderate (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940266/MONDO:0100326/011 2023-02-23 2023-02-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:367163 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027121 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030312 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027765 infores:hetionet UNII:R43D2573WO biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0600142 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0267596 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0015469 infores:hetionet CHEBI:9086 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0002962 infores:hetionet CHEBI:31485 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0151827 infores:hetionet CHEBI:499361 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0042963 infores:hetionet CHEBI:8890 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013362 infores:hetionet CHEBI:9613 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0020615 infores:hetionet CHEBI:66876 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0151905 infores:hetionet CHEBI:63632 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0231528 infores:hetionet CHEBI:9599 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0271051 infores:hetionet NCBIGene:2643 biolink:causes MONDO:0007495 infores:monarchinitiative not_provided not_provided HGNC:4193 MONDO:0007495 uuid:baefdfc4-ba97-4840-955f-2bb8627effbc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042963 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151602 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018099 infores:hetionet CHEBI:9086 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0687713 infores:hetionet CHEBI:9649 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0004093 infores:hetionet CAID:CA390864678 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864678 MONDO:0100216 PMID: Uncertain Significance PP3, PM2_Supporting, PM1, PS3_Supporting PM5 The NM_177438.3:c.5428G>C variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 1810 (p.Asp1810His). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant showed that this variant reduces the capacity of the protein to produce 5p and 3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; Wu 2018, McGill University). This variant resides in the p.D1810 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1; PMID: 31342592). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.928) (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS3_Supporting, PM1, PM2_Supporting, PP3. (Bayesian Points: 5; VCEP specifications version 1.3.0; 02/25/2025). Although available evidence supports germline pathogenicity of recurrent DICER1 somatic hotspot variants (PMID: 26925222), the clinical significance of this variant in the germline remains uncertain at this time since it has not yet been observed in the germline of an individual with a recognized DICER1 phenotype. DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864678/MONDO:0100216/024 2025-02-25 2025-06-05 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020580 infores:hetionet CHEBI:27432 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0013378 infores:hetionet CHEBI:7565 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0023530 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038661 infores:hetionet CHEBI:45409 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0018524 infores:hetionet CHEBI:6640 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0038990 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0235032 infores:hetionet CHEBI:45783 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018681 infores:hetionet CHEBI:5778 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0011168 infores:hetionet CHEBI:5893 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011168 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0853692 infores:hetionet CHEBI:6838 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0520806 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0178298 infores:hetionet CAID:CA8459151 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459151 MONDO:0011132 PMID: Uncertain Significance BP4, BS1, BP7, PM2 The NM_001369369.1(FOXN1):c.124-17A>T intron 1 variant occurs at a PopMax filtering AF of 0.00005086 based on 3/15898 alleles in the African/African American population. The SpliceAI delta score for acceptor gain is 0.11. These data are insufficient to apply any criteria resulting in a classification on uncertain significance as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459151/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:3757 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0009450 infores:hetionet CHEBI:3614 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0038367 infores:hetionet CHEBI:31355 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0042487 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0948089 infores:hetionet CHEBI:47780 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0028084 infores:hetionet CHEBI:28748 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0033036 infores:hetionet CHEBI:15854 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0041657 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0024117 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0948089 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0037274 infores:hetionet CHEBI:2682 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027497 infores:hetionet CHEBI:47781 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0014457 infores:hetionet CHEBI:7936 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1456784 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0919671 infores:hetionet CHEBI:83804 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0264886 infores:hetionet CHEBI:45327 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0027424 infores:hetionet CHEBI:3219 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2047937 infores:hetionet CHEBI:4784 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0013404 infores:hetionet CAID:CA410208290 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208290 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.12C>G (p.Asp4Glu) is a missense variant. This missense variant has a REVEL score <0.50 (0.257) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208290/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0021822 biolink:causes GO:0021537 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0021537 CHEBI:2666 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0278134 infores:hetionet CHEBI:3207 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C1384353 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0011570 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1306341 infores:hetionet CAID:CA645608316 biolink:causes MONDO:0011071 infores:clingen CAID:CA645608316 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PP3, PP1 PS3, PS2, PS1, BA1, BP1, BP4, BP2, BP3, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM1, PM3, PM5, PM4, BS2, PP2 NM_001754.5(RUNX1):c.509-3C>G is a splice site variant which has a SpliceAI score of 0.99, exceeding the threshold of 0.38 (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It segregates with disease in three informative meioses in a family enrolled in the RUNX1 Natural History Study (PP1). Additionally, this variant has been reported in one family with well-documented thrombocytopenia and a qualitative platelet defect in the NIH RUNX1 Natural History Study (PS4_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP1, PP3, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645608316/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:5621 biolink:causes MONDO:0007403 infores:monarchinitiative not_provided not_provided HGNC:9449 MONDO:0007403 uuid:2b5441d5-c32f-4324-928d-53c380e3223b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45367 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0017178 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0013395 infores:hetionet CHEBI:91834 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0036974 infores:hetionet CHEBI:3011 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0035455 infores:hetionet NCBIGene:4047 biolink:causes MONDO:0032649 infores:monarchinitiative not_provided not_provided HGNC:6708 MONDO:0032649 uuid:73891ded-9a30-4cb9-a79c-42f424bb8542 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17141 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0030196 infores:hetionet CHEBI:101278 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0002418 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0024312 infores:hetionet CAID:CA409105364 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105364 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM5, PM1_Supporting PP4, PS4 The c.322G>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of valine to phenylalanine at codon 108 (p.(Val108Phe)) of NM_175914.5. This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, it is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.322G>A, p.(Val108Ile), has been interpreted as pathogenic by the ClinGen MDEP, and has a lower Grantham distance than p.(Val108Phe) (PM5). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributors). In summary, c.322G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM1_Supporting, PP3, PM2_Supporting, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105364/MONDO:0015967/085 2024-10-14 2024-10-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:53760 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0086769 infores:hetionet CHEBI:5001 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042963 infores:hetionet CHEBI:49575 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0022346 infores:hetionet CHEBI:5138 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0542571 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0426576 infores:hetionet CHEBI:10110 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0001175 infores:hetionet CHEBI:7465 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C2363730 infores:hetionet CAID:CA181527 biolink:causes MONDO:0021060 infores:clingen CAID:CA181527 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.73C>T (p.Pro25Ser) variant in the SOS1 gene is 0.23% for African chromosomes by the Exome Aggregation Consortium (21/6116 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA181527/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:10124 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C2363731 infores:hetionet CHEBI:567361 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0020458 infores:hetionet CHEBI:50924 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1384353 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027765 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0424000 infores:hetionet CAID:CA10585201 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585201 MONDO:0007750 PMID: Uncertain Significance PM3, PM2, PP4 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM6, PVS1, BS2, PP3, PP1 The NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (plasma cholesterol > 600mg/dL) and LDLR variant NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID: 251517), classified as Likely pathogenic by these guidelines, in trans (PMID: 1301940), so PM3 is Met.PP4 - Variant meets PM2 and is identified in 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID: 1301940), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585201/MONDO:0007750/013 2022-01-17 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9332 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0036830 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040479 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0009782 infores:hetionet CAID:CA96782984 biolink:causes MONDO:0015152 infores:clingen CAID:CA96782984 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP3, PP1, BP3, BP1, BP4, BP2, BA1, PS1, PS3, PS4, PS2, PM4, PM5, PM1, PM3 The NM_000232.5: c.391C>T p.(Arg131Ter) variant in SGCB is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 3/6, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in trans with second presumed diagnostic SGCB variant in one patient with progressive limb girdle muscle weakness and reduced expression of beta-sarcoglycan protein in skeletal muscle; however, the VCEP could not confirm the extent of the reduction (PP4; ClinVar SCV000748307.5 internal data communication). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA96782984/MONDO:0015152/184 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports GO:0120194 biolink:causes GO:0048443 infores:ubergraph knowledge_assertion manual_agent GO:0120194 GO:0048443 CHEBI:6067 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042373 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020624 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041349 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0162119 infores:hetionet CHEBI:5130 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151529 infores:hetionet CHEBI:63717 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0015624 infores:hetionet CAID:CA3055620674 biolink:causes MONDO:0015152 infores:clingen CAID:CA3055620674 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NC_000002.12: g.71479387_71482920del variant is a deletion that encompasses exons 2-3 of DYSF, NM_003494.4: c.89_236del (NM_001130987.2: c.92_239del). Exons 2 and 3 are out of frame, and RNAseq in a carrier of this deletion showed skipping of these exons, resulting in a frameshift expected to lead to premature truncation and nonsense mediated decay, p.Val31SerfsTer71 (PMID: 36983702; PVS1). This variant has been identified in one individual with features consistent with LGMD, where it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 36983702; PM3_Supporting). This individual displayed progressive proximal muscle weakness and absent dysferlin protein expression by blood monocyte assay, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). Similarly sized deletions of these exons are not present in gnomAD SVs v4.1.0 or gnomAD CNVs v4.1.0, but two deletions of DYSF exons 2-3 have been reported in the Database of Genomic Variants (PMID: 24174537) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/17/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3055620674/MONDO:0015152/180 2025-06-17 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports NCBITaxon:810 biolink:causes MONDO:0025598 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:810 MESH:D061387 DB01059_MESH_D061387_1DB00199_MESH_D061387_1 CHEBI:4562 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0020517 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0022408 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020538 infores:hetionet CHEBI:6950 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0037299 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0024115 infores:hetionet UMLS:C0065374 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C2830004 infores:hetionet CHEBI:10102 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0004093 infores:hetionet CHEBI:175901 biolink:causes UMLS:C1142072 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1142072 infores:hetionet CHEBI:49575 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0235198 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034186 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022568 infores:hetionet UMLS:C1872203 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151735 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0232492 infores:hetionet CHEBI:53691 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0027726 infores:hetionet CHEBI:184555 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0085631 infores:hetionet CHEBI:6067 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038325 infores:hetionet CHEBI:70735 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C2830004 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0033975 infores:hetionet CHEBI:2675 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0948089 infores:hetionet UMLS:C1738934 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011175 infores:hetionet CHEBI:10125 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0041657 infores:hetionet CHEBI:36791 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0558489 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1262144 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0013595 infores:hetionet CHEBI:27779 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0041834 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0740401 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0740401 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0031117 infores:hetionet CHEBI:63621 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0029118 infores:hetionet CHEBI:2038 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0013491 infores:hetionet CAID:CA913189268 biolink:causes MONDO:0011071 infores:clingen CAID:CA913189268 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PM5_Supporting, PVS1, PM2_Supporting, PP1 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP4 The NM_001754.5(RUNX1):c.735del (p.Thr246ArgfsTer8) is a frameshift variant in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). At least 2 probands with RUNX1-phenotypic criteria have been reported (PS4_moderate). Cosegregation with disease in multiple affected family members (4 meiosis across 2 families) have been observed (PP1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_moderate, PP1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189268/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:171719 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0232462 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0020456 infores:hetionet CHEBI:92712 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0428977 infores:hetionet CHEBI:4710 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0235198 infores:hetionet CHEBI:8802 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017178 infores:hetionet CHEBI:27899 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0022661 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0009806 infores:hetionet CHEBI:39112 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C1142499 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0015672 infores:hetionet CHEBI:175901 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0010200 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0019158 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0033975 infores:hetionet CAID:CA325653 biolink:causes MONDO:0013144 infores:clingen CAID:CA325653 MONDO:0013144 PMID: Pathogenic PS3, PS4, PP1_Moderate BS1, PP3, BP4 The c.89T>A (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 30 (p.Val30Glu; legacy p.V-3E; also known as the founder variant antithrombin Dublin), so the BS1 code is excluded. This sequence variant has been previously reported in patients with transient antithrombin deficiency, who present with a history of reduced antithrombin activity with at least one reported normal antithrombin activity level (PMID: 27975105; PMID: 27098529; PMID: 34800304) meeting PS4_Very Strong. Large cohort analysis demonstrate carriers of this variant have a 2.3-fold increased risk of thrombosis compared to the general population (PMID: 25772935; PMID: 27098529). Additionally, this variant has been report in at least 4 meioses across 8 families meeting PP1_Moderate. Functional studies performed in mammalian cells demonstrated this variant creates a new signal peptidase cleavage site two amino acids downstream of the normal site, leading to a truncated mature protein missing two amino acids at the N-terminus (PMID: 1977621; PMID: 27098529). The truncated protein has an increased propensity to form intracellular polymers, which hinders antithrombin secretion (PMID: 27098529; PMID: 28229161). Transient environmental factors or other predisposing stress events may exacerbate this polymerization and intracellular retention, contributing to the transient deficiency observed in affected individuals (PMID: 27098529). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4_Very Strong, PP1_moderate, PS3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA325653/MONDO:0013144/084 2025-02-07 2025-02-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50729 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0011630 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0009766 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0876980 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0876980 infores:hetionet CHEBI:3723 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149745 infores:hetionet CHEBI:9649 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020625 infores:hetionet CHEBI:2666 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0014457 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0268732 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0268732 infores:hetionet CHEBI:4710 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0015230 infores:hetionet CHEBI:53760 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0001807 infores:hetionet CHEBI:48390 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0231528 infores:hetionet CHEBI:3994 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0085637 infores:hetionet CHEBI:8888 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034886 infores:hetionet CHEBI:144551 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0039231 infores:hetionet CHEBI:50305 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0041582 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0855242 infores:hetionet CAID:CA412739364 biolink:causes MONDO:0100437 infores:clingen CAID:CA412739364 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PP1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1399C>T (p.Gln467Ter) is a nonsense variant that introduces a premature stop codon in exon 11 of 15 that is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including family history with a delayed or milder phenotype in females (1 pt), night blindness (0.5 pts), severe myopia (1 pt), reduced visual acuity (0.5 pts), optic nerve pallor (0.5 pts), and pigmentary retinopathy (0.5 pts), which together are specific for RPGR-related retinopathy (4 points, PMID: 36276946, PP4). The variant has been reported to segregate with retinal dystrophy through an affected mother and son. (PMID: 36276946, PP1). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP4, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412739364/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:6965 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C1510497 infores:hetionet CHEBI:9599 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0040264 infores:hetionet CHEBI:9588 biolink:causes MONDO:0000704 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0400822 infores:hetionet CAID:CA10558469 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558469 MONDO:0010726 PMID: Benign BP5, BS1, BS2 BP4, BA1, PM2 The highest population minor allele frequency of the p.Pro402Thr variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.0002474 in South Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Pro402Thr variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Pro402Thr variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Pro402Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5). (MECP2 Specification v3.0.0, curation approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558469/MONDO:0010726/036 2024-08-30 2024-12-23 X-linked inheritance HP:0001417 Contradicts true CHEBI:8502 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0022660 infores:hetionet CHEBI:9763 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0013404 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0039503 infores:hetionet NCBIGene:5071 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:8607 MONDO:0008903 uuid:078abefc-bfae-4eca-9d81-80daf7ccc58f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72292 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0027765 infores:hetionet CHEBI:31709 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0030196 infores:hetionet CHEBI:47780 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085636 infores:hetionet CHEBI:2569 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0026837 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0919715 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0687133 infores:hetionet CHEBI:7852 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0017675 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0349506 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0003123 infores:hetionet CHEBI:28148 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0009806 infores:hetionet CAID:CA10584731 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584731 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.44T>A (p.Leu15His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584731/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA10577547 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577547 MONDO:0007648 PMID:29769627PMID:27880784PMID:29769627PMID:23709761PMID:29769627 Pathogenic PP3, PM2_Supporting, PS3, PS4, PP1_Strong BS1, BS4, BS3, BP7, BP5, PM5, PM1, PM3, PM4, PVS1, PM6, BS2, PP2, PP4, BA1, BP4, BP1, BP2, BP3, PS1, PS2 The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP3, PS3, PP1_Strong, PS4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577547/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:45599 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0085681 infores:hetionet CHEBI:6128 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0027707 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0004936 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014549 infores:hetionet CHEBI:15854 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0038990 infores:hetionet NCBIGene:23586 biolink:causes MONDO:0014575 infores:monarchinitiative not_provided not_provided HGNC:19102 MONDO:0014575 uuid:fe51c817-bd01-41ae-a83d-22ddd53431c4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0521491 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0497365 infores:hetionet CHEBI:107736 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0023066 infores:hetionet CHEBI:7936 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023380 infores:hetionet CHEBI:3738 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0221490 infores:hetionet CHEBI:144551 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0236075 infores:hetionet CHEBI:194135 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004134 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0233494 infores:hetionet CHEBI:28487 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0242350 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0152128 infores:hetionet CAID:CA359426693 biolink:causes MONDO:0012163 infores:clingen CAID:CA359426693 MONDO:0012163 PMID: Pathogenic PP1, PM2_Supporting, PP4_Strong, PM3_Strong PM5, PM4, BP7, BS1, PS1, PVS1, BA1 NM_002185.5(IL7R):c.120C>G (p.Phe40Leu) is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 40. The variant is absent in gnomAD v4.1.0 (PM2_supporting). Five patients were detected homozygous for the mutation from unrelated, consanguineous families (+ 2.5 pts; PMID: 31379863) (PM3_Strong). Five patients with SCID (PMID: 31379863) (0.5 pt.): whole exome sequencing conducted (0.5 pt.), reduced CD127 expression and reduced IL-7-induced phosphorylation of STAT5 in patient-derived T-cells (3 pt.), rescue of defective IL-7-receptor-mediated STAT5 phosphorylation by IL-2 or IL-15 induction (4.5 pt.), T-B+NK+ lymphocyte subset profile (0.25 pt.) Total pts : 8.75 (PP4_Strong). A study of 5 patients identified one affected segregation and 4 unaffected segregation in siblings (PMID: 31379863) (PP1).In summary, this variant meets the criteria to be classified as Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4_Strong, PM3_Strong, PP1 (VCEP specifications version 2.1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359426693/MONDO:0012163/119 2025-11-04 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50859 biolink:causes HP:0003146 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151718 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0027051 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151734 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0007097 infores:hetionet CHEBI:31547 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0042963 infores:hetionet CHEBI:75246 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0043352 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0434437 infores:hetionet CHEBI:6754 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0220870 infores:hetionet CHEBI:47381 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151904 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0015397 infores:hetionet CHEBI:135929 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0086565 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0037274 infores:hetionet CHEBI:474180 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0013404 infores:hetionet CHEBI:6690 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C1443060 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0022650 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0235097 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0235097 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015469 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0438142 infores:hetionet CAID:CA116596 biolink:causes MONDO:0009290 infores:clingen CAID:CA116596 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Very Strong "The NM_000152.5:c.1927G>A variant in GAA is predicted to result in the substitution of glycine by arginine at amino acid 643 (p.Gly643Arg). Numerous individuals have been reported with this variant and specific features of Pompe disease including GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay; patients with specific features of infantile onset Pompe disease (including cardiac features and hypotonia_, and on enzyme replacement therapy (PMIDs: 8401535, 17723315, 23430912, 23609349 24158270, 25783438, 26349193, 26497565) (PP4_Moderate). The variant has been reported in patients with Pompe disease who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. In these cases, the second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (at least 10 cases; maximum 2 x 0.5 points; PMID: 16917947, 18607768, 20308911, 23609349, 24158270, 25396301, 25783438, 27862019, 30155607), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1 (2 cases, 2 x 0.5 points) (PMID: 18429042, 23430912), c.1064T>C (p.Leu355Pro) (ClinVar Variation ID: 284093, SCV001371747.2) (0.5 points, PMID: 18429042), c.236_246del (p.Pro79fsTer) (ClinVar Variation ID: 371302, SCV001443298.1 (0.5 points, PMID: 19588081), and c.2662G>T (p.Glu888Ter) (ClinVar Variation ID: 578595, SCV001371767.1 (0.5 points, PMID: 28394184). First cousins have been reported who are compound heterozygous for the variant (inherited from their heterozygous mothers who are sisters) and another pathogenic variant in GAA variant; c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) in one individual, and ""deletion of exon 18"" in the other individual (PMID: 26349193). In each case, the second variant was shown to be inherited from the father. Although the genotypes are different, only one case will be counted from this family, as they are related (1 point, pathogenic variant confirmed in trans). At least 2 cases are homozygous for the variant (max 2 x 0.5 points, PMID: 18429042, 24002816, 26497565, 30023291). Additional cases are compound heterozygous for the variant and either c.2040G>A (PMID: 17723315) or c.2173C>T (p.Arg725Trp) (PMID: 8401535). The in trans data for these patients was used in the classification of the other variant as is not included here to avoid circular logic. Finally, the variant is reported in other cases and publications without sufficient evidence to apply PM3 (PMID:9521422, 17915575, 19862843, 22081099, 29880332) Additional cases may be available in the literature but PM3 is already applied at very strong (>5 points) (PM3_VeryStrong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003667 (4/109080 alleles) in the European non-Finnish population. In gnomAD v4.1, the MAF is 0.00003224 (40/1178798 alleles) in the European non-Finnish population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The activity of this variant, when expressed in COS cells, has been analyzed in several studies (PMIDs: 8401535, 9521422, 19862843) and varies from <2%-6% with 4MUG and ~3% wild type activity in cells with glycogen. Pulse chase analysis showed that the protein is abnormally processed, with most of the protein remaining as precursor (PMID: 8401535) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 4023). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116596/MONDO:0009290/010 2024-06-06 2024-06-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7936 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013781 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151814 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151814 infores:hetionet CHEBI:5959 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C3263723 infores:hetionet CAID:CA367401907 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401907 MONDO:0015967 PMID: Likely Pathogenic PS2_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.461T>G variant in the glucokinase gene, GCK, causes an amino acid change of valine to glycine at codon 154 (p.(Val154Gly)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, whose clinical picture is highly specific for GCK-hyperglycemia (PS2_Moderate; internal lab contributor). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.461T>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS2_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401907/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Supports CHEBI:48273 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0424295 infores:hetionet CHEBI:7640 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0018524 infores:hetionet CHEBI:291342 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0019158 infores:hetionet CHEBI:135888 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0151474 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0948089 infores:hetionet CHEBI:32139 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0027497 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0235431 infores:hetionet CHEBI:4975 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0017672 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0015230 infores:hetionet CHEBI:6904 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0917801 infores:hetionet CHEBI:4702 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0035357 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0038454 infores:hetionet CAID:CA9091060 biolink:causes MONDO:0021060 infores:clingen CAID:CA9091060 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.291C>A (p.Ile97=) variant in the MAP2K2 gene is 0.182% (23/8614) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9091060/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7459 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0027497 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151773 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020598 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0574067 infores:hetionet CAID:CA043947 biolink:causes MONDO:0007750 infores:clingen CAID:CA043947 MONDO:0007750 PMID: Likely Benign BP4, BP7 BA1, BP1, BP3, BP2, PS1, PS3, PS4, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PP2, PP3, PP4, PP1, BS2 The NM_000527.5(LDLR):c.564C>T p.(Tyr188=) variant is classified as Likely benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows:BP4: No REVEL, splicing evaluation needed. Functional data on splicing not available. A) Variant not on limits B) variant is exonic and at least 50 bp downstream from the canonical acceptor site, but it does not create GT. Variant is not predicted to alter splicing.BP7: Variant meets BP4 and is synonymous. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA043947/MONDO:0007750/013 2024-08-30 2024-10-03 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:116278 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0022650 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1384353 infores:hetionet CHEBI:499361 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151904 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0041969 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0178298 infores:hetionet NCBIGene:57020 biolink:causes MONDO:0030864 infores:monarchinitiative not_provided not_provided HGNC:24641 MONDO:0030864 uuid:80fa0d74-a3b3-404a-81ed-a2e2c931a297 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0003862 infores:hetionet CAID:CA350341981 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341981 MONDO:0015924 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PM1, PM5 BA1, BS1 BMPR2 c.1259G>T is a missense variant predicted to cause substitution of cysteine to phenylalanine at amino acid position 420 (p.Cys420Phe). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). A REVEL score of 0.914 meets PP3_supporting (>0.75). The variant resides in the conserved catalytic kinase domain but does not affect a known critical residue (PM1_moderate). The variant has been reported in two unrelated PAH probands, one heritable (PMID: 27453251) and one idiopathic (PMID: 30578397, 32634488) (PS4_supporting). A different missense variant at the same amino acid residue, p.Cys420Arg (PMID: 11115378, 21801371) was classified by the PH VCEP as pathogenic (PM5_moderate). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM5_moderate, PS4_supporting, PM2_supporting, PP3_supporting (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341981/MONDO:0015924/125 2025-04-29 2025-04-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10124 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020578 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0851341 infores:hetionet NCBITaxon:1280 biolink:causes UMLS:C0038166 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D013207 DB06219_MESH_D013207_1DB12924_MESH_D013207_1DB04911_MESH_D013207_1 CHEBI:5855 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0086565 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0677500 infores:hetionet NCBITaxon:33040 biolink:causes MONDO:0000744 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:33040 MESH:D008169 DB01607_MESH_D008169_1 CHEBI:50648 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030193 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020649 infores:hetionet CHEBI:9586 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085583 infores:hetionet CHEBI:83804 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011603 infores:hetionet NCBIGene:5165 biolink:causes MONDO:0010479 infores:monarchinitiative not_provided not_provided HGNC:8811 MONDO:0010479 uuid:cd46cd01-1bf2-4ec4-9c2e-fb0d5443d4b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0013928 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0235431 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0232431 infores:hetionet CHEBI:5855 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0001623 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0034069 infores:hetionet CHEBI:6015 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0086565 infores:hetionet CHEBI:47781 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0040034 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0851341 infores:hetionet CHEBI:37924 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018794 infores:hetionet CHEBI:171719 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1142412 infores:hetionet NCBIGene:3551 biolink:causes MONDO:0014267 infores:monarchinitiative not_provided not_provided HGNC:5960 MONDO:0014267 uuid:bbcd7aed-13ef-4b59-aaf7-3d427a9c1395 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50663 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0006266 infores:hetionet CAID:CA399796017 biolink:causes MONDO:0100326 infores:clingen CAID:CA399796017 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting NM_000419.5(ITGA2B):c.2421G>A (p.Trp807Ter) is a nonsense variant located on exon 24 which is predicted to result in NMD. It is absent from all large population cohorts (gnomAD). This variant has been reported to occur in homozygous state in one proband who meets the diagnostic criteria for the GT phenotype (PMID: 25728920). This variant meets GT specific criteria for PVS1, PP4_moderate, PM2_supporting, and PM3_supporting and is therefore classified as Pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399796017/MONDO:0100326/011 2021-09-03 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:68478 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0152517 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0006266 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0009806 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0020517 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0036572 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0037274 infores:hetionet CHEBI:28001 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0041349 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1527311 infores:hetionet CHEBI:421707 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C1443060 infores:hetionet CAID:CA229477 biolink:causes MONDO:0009861 infores:clingen CAID:CA229477 MONDO:0009861 PMID:23271928 Pathogenic PVS1, PP4_Moderate, PM2 PM3 The frameshift variant c.190del generates a stop codon at residue 72 in exon 3 of 13 and is predicted to undergo NMD. The variant is absent from population databases, including gnomAD. It has been reported heterozygous in at least one PKU patient (PMID: 23271928). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229477/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4653 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0008350 infores:hetionet CHEBI:8764 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0012569 infores:hetionet CHEBI:171719 biolink:causes UMLS:C1879328 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1879328 infores:hetionet CHEBI:119915 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0028081 infores:hetionet CHEBI:63605 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0017152 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0029882 infores:hetionet NCBIGene:140732 biolink:causes MONDO:0014961 infores:monarchinitiative not_provided not_provided HGNC:16252 MONDO:0014961 uuid:3c8b72ea-c941-414f-868a-df0b99780594 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46345 biolink:causes UMLS:C2752009 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C2752009 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0234215 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0022904 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031117 infores:hetionet CHEBI:4672 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0003862 infores:hetionet CHEBI:7514 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0085631 infores:hetionet NCBIGene:8820 biolink:causes MONDO:0008428 infores:monarchinitiative not_provided not_provided HGNC:4877 MONDO:0008428 uuid:dd0dc1e3-5b26-48de-b07e-57ea981a6796 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085639 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0020517 infores:hetionet CHEBI:8404 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0038999 infores:hetionet CHEBI:51860 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151686 infores:hetionet CHEBI:8768 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0009676 infores:hetionet CHEBI:63791 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162298 infores:hetionet CHEBI:6954 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0004093 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0020517 infores:hetionet CHEBI:63791 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042420 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004096 infores:hetionet CHEBI:31623 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0547030 infores:hetionet CHEBI:17026 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0002962 infores:hetionet CHEBI:39867 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0033774 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0036572 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0152227 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0087169 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0087169 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0239150 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0700184 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0036454 infores:hetionet CHEBI:7507 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0038999 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0234913 infores:hetionet CHEBI:47381 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023218 infores:hetionet CHEBI:7824 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151611 infores:hetionet CHEBI:17076 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0030554 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042373 infores:hetionet CHEBI:194135 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003811 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0015734 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0022650 infores:hetionet CAID:CA10585696 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585696 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BP4, PS3, PM5, PP3 The NM_000527.5 (LDLR):c.1958T>G (p.Val653Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases with DLCN score ≥6 (1 case reported in VCI from Centre de Genetique Moleculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP. Sorbonne Université, Hospital de la Pitié-Salpêtrière, France; at least 1 case reported in ClinVar from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585696/MONDO:0007750/013 2024-02-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:205919 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0011253 infores:hetionet CHEBI:6030 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0019158 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0745499 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0745499 infores:hetionet CHEBI:9725 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0428974 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0233472 infores:hetionet CAID:CA229516 biolink:causes MONDO:0009861 infores:clingen CAID:CA229516 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2, PM3 PP3 The c.329C>T (p.Ser110Leu) variant in PAH has been reported in one individual with mild hyperphenylalanemia, in trans to c.842C>T (p.Pro281Leu) (Likely pathogenic by PAH VCEP variation ID: 589) with exclusion of BH4 deficiency (PMID: 16051511, PMID: 12618080). It has also been observed in an additional patient with hyperphenylalanemia without specified exclusion of BH4 deficiency (PMID: 26542770). In-vitro functional studies are unavailable. This variant is absent from population databases. In-silico predictions yield conflicting results regarding the pathogenicity of this variant. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4_moderate, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229516/MONDO:0009861/006 2021-12-16 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5855 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1145670 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151849 infores:hetionet CHEBI:100246 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0033774 infores:hetionet CHEBI:63791 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0687713 infores:hetionet CHEBI:4974 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0018524 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0018799 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0521591 infores:hetionet CHEBI:68575 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0026858 infores:hetionet CHEBI:4798 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0011253 infores:hetionet NCBIGene:10568 biolink:causes MONDO:0009928 infores:monarchinitiative not_provided not_provided HGNC:11020 MONDO:0009928 uuid:2de3356b-ef6e-465f-845f-cdabda014c88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0518988 infores:hetionet CHEBI:47381 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151636 infores:hetionet CHEBI:46557 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020488 infores:hetionet CHEBI:10124 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0043387 infores:hetionet NCBIGene:81788 biolink:causes MONDO:0030338 infores:monarchinitiative not_provided not_provided HGNC:29558 MONDO:0030338 uuid:466e1cc4-aee8-411a-86ab-68a61c514a39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA204367 biolink:causes MONDO:0015967 infores:clingen CAID:CA204367 MONDO:0015967 PMID: Pathogenic PM3_Supporting, PP1_Strong, PM5, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PS4, BS1, BA1 The c.629T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 210 (p.(Met210Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP threshold of 0.70 (PP3), and functional studies suggest that this variant alters glucokinase kinetic parameters, with an RAI less than 0.5 (wild-type QC parameters met including ATP Km between 0.4 and 0.65) (PS3_Moderate; PMIDs: 16731834,14517946). This variant was identified in two unrelated families with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:18399931, 11372010, 27913849, internal lab contributor). At least one individual individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persisting over time) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 10 informative meioses in a family with MODY (PP1_Strong; PMIDs: 18399931, 11372010). This variant has also been detected in at least one family with neonatal diabetes. One individual in this family was homozygous and experienced permanent neonatal diabetes mellitus, and variants were were confirmed in trans (PM3_Supporting; PMIDs:18399931, 11372010). Additionally, another missense variant, c.629T>C (p.Met210Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Met210Lyshas a greater Grantham distance (PM5). In summary, c.629T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PM5, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting, PM3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA204367/MONDO:0015967/086 2023-07-30 2023-07-30 Semidominant inheritance HP:0032113 Supports CAID:CA2802098 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802098 MONDO:0001586 PMID:11172140 Likely Pathogenic PM3_Strong, PP3_Moderate, PP4, PM2_Supporting PS3, PS1, PM1, PM5, PVS1, PP1 The NM_000203.5:c.793G>C variant in IDUA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 265 (p.Gly265Arg). The variant alters the first nucleotide of exon 7. RNA from two patients with this variant, has been analyzed and includes normally spliced transcripts with the p.Gly265Arg substitution (PMID: 15300847). In one of these patients, transcripts with a 33 bp deletion resulting from use of a cryptic splice site (c.793_825del; p.G265_Q275del) were also detected (PMID: 15300847). Because the impact of this variant on splicing appears to vary, PVS1 will not be applied here at any strength. This variant has been detected in at least 10 individuals with MPS I. Of those individuals, 10 were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic or likely pathogenic (variants: c.46_57del, c.1205G>A, c.1487C>G, c.208C>T, and c.979G>C) and none of those were confirmed in trans (PMIDs: 31194252, 30809705, 21394825, 11172140, 35787971) (PM3_Strong). At least 2 patients with this variant had documented deficient IDUA activity in leukocytes, but specific values were not provided, and clinical features consistent with MPS I, including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PMID: 11172140) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001341 (1/74596 alleles) in the African / African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.93 which is above the threshold of 0.773, evidence that correlates with a damaging impact to IDUA function at the moderate level (PP3_Moderate) In addition, SpliceAI give a score of 0.39 for acceptor loss, suggesting that this variant may impact splicing. There is a ClinVar entry for this variant (Variation ID: 638074). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PP3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802098/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0021368 infores:hetionet CHEBI:8430 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0085631 infores:hetionet CHEBI:40009 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0042571 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042109 infores:hetionet CHEBI:4975 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0687713 infores:hetionet CAID:CA3231920 biolink:causes MONDO:0012163 infores:clingen CAID:CA3231920 MONDO:0012163 PMID: Likely Benign BS1 NM_002185.5(IL7R):c.339A>C is a missense variant predicted to cause substitution of Glutamic Acid by Aspartic Acid at amino acid 113 (p.Glu113Asp). The filtering allele frequency (the lower threshold of the 95% CI of 308/75016) of the c.339A>C variant in IL7R is 0.003481 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1).To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1_met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3231920/MONDO:0012163/119 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9654 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C2047937 infores:hetionet CAID:CA024778 biolink:causes MONDO:0007783 infores:clingen CAID:CA024778 MONDO:0007783 PMID: Pathogenic PP1, PS3_Moderate, PM5, PM1_Supporting, PS4_Moderate, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000065. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 10484775, 10612851, 16163667). This variant segregates with MHS in 3 individuals, PP1 (PMI: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg2454His), PM5 (PMID: 26951757). A REVEL score >0.85 (0.913) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024778/MONDO:0007783/012 2022-03-11 2022-07-10 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:9763 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0029408 infores:hetionet CAID:CA222220 biolink:causes MONDO:0015152 infores:clingen CAID:CA222220 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP3, PM2_Supporting, PS3_Moderate PM5, PM4, PM1, PS1, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, PVS1, PP2 The NM_003494.4: c.857T>A variant in DYSF, which is also known as NM_001130987.2: c.953T>A p.(Val318Glu), is a missense variant predicted to cause substitution of valine by glutamic acid at amino acid 318 p.(Val318Glu). This variant has been detected in at least 6 unrelated individuals with dysferlinopathy (PMID: 18832576, 25493284, 27602406, 32528171, 33610434, 33927379, 36983702). Of those individuals, two were compound heterozygous for the variant and a confirmed pathogenic or likely pathogenic variant (c.5860G>T p.Glu1954Ter, 1.0 pt, PMID: 33927379; c.2779del p.Ala927LeufsTer21, 1.0 pt, PMID: 18832576 (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18832576). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113768 alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). RNAseq analysis demonstrated that this variant may result in missplicing in a small percentage of transcripts (PMID: 36983702), but the consequences of this degree of missplicing on protein function are unclear (PVS1_RNA not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.95, which exceeds the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PM3_Strong, PP4_Strong, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222220/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020461 infores:hetionet CAID:CA344828 biolink:causes MONDO:0044970 infores:clingen CAID:CA344828 MONDO:0044970 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, PP3 PM5, PP1, BP4, PS2, PS3, PS1, PM6 The m.3700G>A (p.A132T) variant in MT-ND1 has been reported in 3 individuals with primary mitochondrial disease who had features consistent with Leigh syndrome (1/3) and LHON (2/3; PS4_supporting; PMIDs: 30128709, 22879922, 12150954). There are no reports of de novo occurrences of this variant. There are no reports of testing in family members to date to consider for segregation. There are 3 occurrences of this variant in GenBank dataset, however 2/3 are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is present at <1/50,000 healthy individuals (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA344828/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:36795 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0006145 infores:hetionet CHEBI:5790 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013404 infores:hetionet CHEBI:499361 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0017979 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009782 infores:hetionet UMLS:C0657912 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0231530 infores:hetionet CHEBI:231594 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0404521 infores:hetionet CHEBI:9130 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0855775 infores:hetionet CHEBI:6375 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0026821 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037274 infores:hetionet CHEBI:83804 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015371 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0034069 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0036572 infores:hetionet CHEBI:2659 biolink:causes MONDO:0017988 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0221158 infores:hetionet CHEBI:3561 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0043352 infores:hetionet CHEBI:6775 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C2047937 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002994 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016977 infores:hetionet CHEBI:171719 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0024141 infores:hetionet CAID:CA8338160 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338160 MONDO:0008723 PMID: Likely Benign PM2_Supporting, BP4, BP7 The c.1581G>A variant in ACADVL is a synonymous variant which occurs in exon 16 (out of 20). The results from 2 in silico splicing predictors (SpliceAI, MutationTaster) support that this variant does not affect splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00050 in European (Non-Finnish) population, which is lower than the ClinGen ACADVL Expert Panel threshold (<0.001 (0.1%)) for PM2_Supporting; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2, BP4, BP7 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338160/MONDO:0008723/021 2025-03-25 2025-04-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:10119 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011616 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0235146 infores:hetionet CHEBI:31705 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0542571 infores:hetionet CHEBI:9649 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0020461 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0031117 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0040435 infores:hetionet CAID:CA229468 biolink:causes MONDO:0009861 infores:clingen CAID:CA229468 MONDO:0009861 PMID: Uncertain Significance PM2 PM5, PP3 The c.176A>G (p.Asp59Gly) variant in PAH has not been reported in the literature to our knowledge. A reference from BioPKU/PAHdb is not located (Carducci C, 1999). It is absent from ExAC, gnomAD, 1000G, and ESP. There are conflicting predictions of pathogenicity: SIFT/Polyphen2: benign; MutationTaster: Damaging; REVEL=0.565. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229468/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA010273 biolink:causes MONDO:0005045 infores:clingen CAID:CA010273 MONDO:0005045 PMID: Uncertain Significance PM1, PM2 PM6, PM4, BA1, PP3, PP1, PS3, PP4, BS2, BS1, BS4, BS3, BP3, PS1, PS4, PS2, BP4, BP7, PM5_Supporting, PVS1 The NM_000257.4(MYH7):c.1141G>A (p.Ala381Thr) variant has been identified in 1 neonate with HCM and repolarization abnormalities (LMM pers. comm.); however this case data is insufficient to apply PS4. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010273/MONDO:0005045/002 2021-09-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10014629 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014629 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.97G>A (p.Asp33Asn) is a missense variant has a SpliceAI score ≥ 0.38 (Acceptor Loss: 0.68; Donor Loss: 0.76) and is predicted to impact splicing (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014629/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50275 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0010709 infores:hetionet CHEBI:119486 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0003862 infores:hetionet CHEBI:9288 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0027947 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0267792 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0221490 infores:hetionet CHEBI:5106 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0028643 infores:hetionet CHEBI:71223 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0151766 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0235490 infores:hetionet CHEBI:75045 biolink:causes MONDO:0006591 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0030326 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235032 infores:hetionet CHEBI:499361 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0004604 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0948594 infores:hetionet CAID:CA915940807 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940807 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.812dup variant is a frameshift variant in exon 6 predicted to cause a premature stop codon in exon 6/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 12 in PMID:15748237) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 0%, as measured by flow cytometry. Patient 12 (PMID:15748237) is homozygous for this variant (0.5pt; PM3_Supporting). The variant is absent from gnomAD, PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940807/MONDO:0100326/011 2023-03-21 2023-03-21 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:31236 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232495 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0086543 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0025517 infores:hetionet GO:0099150 biolink:causes GO:0099068 infores:ubergraph knowledge_assertion manual_agent GO:0099150 GO:0099068 CHEBI:94848 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0042023 infores:hetionet NCBIGene:6949 biolink:causes MONDO:0007944 infores:monarchinitiative not_provided not_provided HGNC:11654 MONDO:0007944 uuid:e0059a03-76a9-4fee-92cd-d0bfb19b5f21 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes UMLS:C0158369 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0158369 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0015397 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001339 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0155773 infores:hetionet CHEBI:83804 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0035243 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0018418 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0518015 infores:hetionet CHEBI:3614 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0016658 infores:hetionet CHEBI:50673 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0031542 infores:hetionet CHEBI:8774 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0231528 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018799 infores:hetionet CHEBI:2682 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018681 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0025061 infores:hetionet CHEBI:3479 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0015230 infores:hetionet CHEBI:31236 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0851578 infores:hetionet NCBITaxon:570 biolink:causes MONDO:0030603 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:570 MONDO:0030603 CHEBI:64321 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0042373 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0021400 infores:hetionet CHEBI:15367 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0005778 infores:hetionet CHEBI:7824 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0152031 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1142412 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0240035 infores:hetionet CHEBI:5558 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0344232 infores:hetionet CHEBI:4995 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0027497 infores:hetionet CHEBI:3242 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0034880 infores:hetionet CHEBI:31348 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018932 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019158 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151854 infores:hetionet CHEBI:80630 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0232462 infores:hetionet CHEBI:171719 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0027540 infores:hetionet CHEBI:4551 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0018794 infores:hetionet CHEBI:7601 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0042963 infores:hetionet CHEBI:41774 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020473 infores:hetionet NCBITaxon:115425 biolink:causes MONDO:0005954 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:115425 MONDO:0005954 CHEBI:47426 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0033774 infores:hetionet CHEBI:5118 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011124 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0017675 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0030305 infores:hetionet CHEBI:31174 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0019348 infores:hetionet CHEBI:42355 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0151766 infores:hetionet CHEBI:6633 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0020578 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0851341 infores:hetionet CHEBI:2663 biolink:causes UMLS:C1442835 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1442835 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030305 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0029453 infores:hetionet CHEBI:7478 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0027796 infores:hetionet CHEBI:4657 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0036980 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0037274 infores:hetionet CHEBI:6472 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0038362 infores:hetionet CHEBI:44915 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0042963 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0302295 infores:hetionet CHEBI:29007 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0033774 infores:hetionet CHEBI:45327 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0003811 infores:hetionet CHEBI:31236 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1519353 infores:hetionet CHEBI:6923 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0000737 infores:hetionet CHEBI:63845 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0038325 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042109 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0042075 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0014742 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0034065 infores:hetionet CHEBI:71229 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0042487 infores:hetionet CHEBI:49040 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0003862 infores:hetionet NCBIGene:144535 biolink:causes MONDO:0100607 infores:monarchinitiative not_provided not_provided HGNC:26456 MONDO:0100607 uuid:098d4ee9-daf7-4f91-986a-3fbd5af5ed30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:56980 biolink:causes MONDO:0800455 infores:monarchinitiative not_provided not_provided HGNC:13995 MONDO:0800455 uuid:176e57aa-41a1-44cf-b35c-5c6d75bcf7d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47519 biolink:causes UMLS:C0151689 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151689 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151596 infores:hetionet NCBIGene:27107 biolink:causes MONDO:0032715 infores:monarchinitiative not_provided not_provided HGNC:16740 MONDO:0032715 uuid:c7bdd890-ea04-49b6-ba4e-38503d60f6ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA120619 biolink:causes MONDO:0044970 infores:clingen CAID:CA120619 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong PP3, BP4, PS3, PS4, PS2, PM6 The m.15150G>A (p.W135Ter) variant in MT-CYB has been reported in one individual to date, in an individual with exercise intolerance from childhood (PMID: 11464242). The variant was present at 60% heteroplasmy in skeletal muscle and was undetectable in blood and skin fibroblasts. Complex III activity was reduced in muscle and normal in leukocytes and skin fibroblasts. The variant was undetectable in blood from the healthy mother, however the significance of this is unclear given the variant was also undetectable in blood from the proband. There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (65%) of the MT-CYB protein (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent biochemical phenotype and likely deleterious nature of this truncating variant. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120619/MONDO:0044970/015 2024-01-08 2024-11-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:188986 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013378 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0004096 infores:hetionet CHEBI:87715 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0018965 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0011053 infores:hetionet CHEBI:64354 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0344232 infores:hetionet CHEBI:44032 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0019080 infores:hetionet NCBIGene:7841 biolink:causes MONDO:0011629 infores:monarchinitiative not_provided not_provided HGNC:24862 MONDO:0011629 uuid:152338c5-8036-4c70-b60b-76c4e1febaa4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84050 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0333355 infores:hetionet CHEBI:6375 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0333355 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0581394 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0581394 infores:hetionet CHEBI:15407 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0042510 infores:hetionet CHEBI:6375 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0947912 infores:hetionet CHEBI:15940 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0019080 infores:hetionet CHEBI:63580 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085649 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0302295 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0039971 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0027651 infores:hetionet CHEBI:9566 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0235378 infores:hetionet CHEBI:188986 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0022081 infores:hetionet CHEBI:68642 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0236075 infores:hetionet CHEBI:8888 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039231 infores:hetionet CHEBI:63580 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085632 infores:hetionet CHEBI:74947 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085669 infores:hetionet CHEBI:8768 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003873 infores:hetionet CHEBI:119573 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085636 infores:hetionet CHEBI:2704 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0600142 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015927 infores:hetionet CHEBI:51364 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027424 infores:hetionet CHEBI:46195 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0038325 infores:hetionet CHEBI:2469 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0008031 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0017181 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151472 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151472 infores:hetionet CHEBI:6909 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0032617 infores:hetionet CHEBI:16586 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0035078 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0699885 infores:hetionet CHEBI:9654 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0028081 infores:hetionet CHEBI:2673 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0151735 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0518015 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027765 infores:hetionet CHEBI:8093 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0151744 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0155626 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0854095 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0854095 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0155169 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0234913 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0151735 infores:hetionet NCBIGene:4093 biolink:causes MONDO:0014134 infores:monarchinitiative not_provided not_provided HGNC:6774 MONDO:0014134 uuid:e1966bb7-f652-4ff2-8148-1f9e2054734e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0040264 infores:hetionet CHEBI:68478 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151786 infores:hetionet CHEBI:49575 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0947912 infores:hetionet CAID:CA2602711 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602711 MONDO:0009276 PMID: Likely Benign BP4, BP7 BS1, PM2 The c.423G>A variant is a synonymous (silent) variant (p.Ala141=) that is not predicted by SpliceAI to impact splicing (score <0.2, BP4). In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of -1.8 (<1.5) (BP7). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0001647 (based on 216/1167496alleles) in the European (non-Finnish) population, which is above the ClinGen PD VCEP PM2_supporting threshold (<0.0000329) but below the BS1 threshold (>0.0007).In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7 Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602711/MONDO:0009276/083 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46557 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027441 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042018 infores:hetionet CHEBI:6402 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0023218 infores:hetionet GO:0061168 biolink:causes GO:0001942 infores:ubergraph knowledge_assertion manual_agent GO:0061168 GO:0001942 UNII:9430ZR8ZAN biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0858581 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0025061 infores:hetionet CHEBI:50131 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0032781 infores:hetionet CHEBI:68845 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0027765 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235234 infores:hetionet CHEBI:28445 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C1145670 infores:hetionet GO:1903818 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:1903818 GO:0071805 CHEBI:63624 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0476280 infores:hetionet CHEBI:2453 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029408 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0019158 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0518015 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0013395 infores:hetionet CHEBI:29007 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0340865 infores:hetionet CHEBI:75722 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1456784 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0012833 infores:hetionet CHEBI:17347 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0035455 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0836924 infores:hetionet CHEBI:94449 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0340865 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0861157 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0861157 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1142135 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040046 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0277889 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0277889 infores:hetionet CHEBI:45783 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018834 infores:hetionet CHEBI:3723 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022346 infores:hetionet CAID:CA229737 biolink:causes MONDO:0009861 infores:clingen CAID:CA229737 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4 PM5, PM3 This c.743T>C (p.Leu248Pro) variant in PAH was reported in 1 patient with PAH deficiency (>600 μmol/L Phe, PMID: 8807319). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229737/MONDO:0009861/006 2021-01-25 2022-06-05 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0006954 biolink:causes HP:0012735 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003371 DB01176_MESH_D003371_1DB08936_MESH_D003371_1 CHEBI:6931 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0151636 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022660 infores:hetionet CHEBI:3082 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151905 infores:hetionet CHEBI:116278 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C2047937 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0684249 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233494 infores:hetionet CHEBI:8888 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019825 infores:hetionet CHEBI:17263 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0497327 infores:hetionet CHEBI:9168 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019270 infores:hetionet CHEBI:9667 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0020488 infores:hetionet CHEBI:44032 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0037278 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0855242 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0242350 infores:hetionet NCBIGene:6496 biolink:causes MONDO:0010011 infores:monarchinitiative not_provided not_provided HGNC:10889 MONDO:0010011 uuid:b2c6ac0f-6828-4dbc-8289-1e549b7144dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0003864 infores:hetionet UMLS:C0657912 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242184 infores:hetionet CHEBI:72297 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0231528 infores:hetionet CAID:CA10585641 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585641 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP3, PP4, PP1 BP4, BP3, BP2, BA1, PS1, PS4, PS2, BP7, BS1, BS4, PM5, PM4, PM1, PM3, PM6, BS2 The NM_000527.5(LDLR):c.1840T>A (p.Phe614Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL=0.912. PS3: Level 1 assays: PMID 35568682 (Graça et al., 2022): Heterologous cells (CHO-ldlA7 cells), cytometry assays - results - <60% surface LDLR, <60% LDL-LDLR binding, <60% uptake. ---- results are below 70% of wild-type, so functional study is consistent with damaging effect. PP4: Variant meets PM2 and is identified in 1 case with Possible FH by Simon Broome criteria from Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585641/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:9763 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0232461 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0235818 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0001122 infores:hetionet CHEBI:8346 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0030193 infores:hetionet CHEBI:9332 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0151798 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0019360 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0030312 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151602 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030446 infores:hetionet CHEBI:59773 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0043144 infores:hetionet CHEBI:75922 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0011615 infores:hetionet CHEBI:10650 biolink:causes HP:0034033 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235532 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0003864 infores:hetionet CHEBI:63619 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0264886 infores:hetionet CHEBI:8871 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0035410 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0341012 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0020651 infores:hetionet CHEBI:9448 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0151539 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0000731 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0020517 infores:hetionet CHEBI:127780 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020458 infores:hetionet CHEBI:66876 biolink:causes MONDO:0000498 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C2242711 infores:hetionet NCBIGene:7780 biolink:causes MONDO:0011973 infores:monarchinitiative not_provided not_provided HGNC:11013 MONDO:0011973 uuid:883d6382-a751-4ce3-985f-ec3b42bbc027 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037763 infores:hetionet CHEBI:3312 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0020625 infores:hetionet CHEBI:7822 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0030252 infores:hetionet CHEBI:3638 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0033774 infores:hetionet CHEBI:42355 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0018524 infores:hetionet NCBIGene:2495 biolink:causes MONDO:0014225 infores:monarchinitiative not_provided not_provided HGNC:3976 MONDO:0014225 uuid:06e8907d-a35a-484b-b8c5-c6253bf0721a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0037199 infores:hetionet CHEBI:4702 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0018790 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0034065 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0020517 infores:hetionet CHEBI:7514 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0522224 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0025061 infores:hetionet CHEBI:28177 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0042487 infores:hetionet CHEBI:15354 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00122 UMLS:C0151735 infores:hetionet CHEBI:10100 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0042963 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0006145 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0005778 infores:hetionet CHEBI:87681 biolink:causes MONDO:0024415 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0341245 infores:hetionet CHEBI:180905 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0008031 infores:hetionet CHEBI:4495 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0344232 infores:hetionet CHEBI:3223 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0013378 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0234215 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0259756 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0259756 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0011615 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0033860 infores:hetionet CHEBI:6822 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0002878 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020557 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0002170 infores:hetionet CHEBI:64355 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0006384 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0037274 infores:hetionet CHEBI:8059 biolink:causes UMLS:C0459435 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0459435 infores:hetionet CHEBI:61033 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020621 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0004936 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085584 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0018801 infores:hetionet CHEBI:5864 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0234533 infores:hetionet CHEBI:4710 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0235660 infores:hetionet CHEBI:8356 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024236 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0518015 infores:hetionet CHEBI:50861 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C1096035 infores:hetionet CAID:CA229574 biolink:causes MONDO:0009861 infores:clingen CAID:CA229574 MONDO:0009861 PMID:8535445PMID:8535445 Pathogenic PM3, PVS1, PM2, PP4 PP3 PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PM3, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229574/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7577 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0037199 infores:hetionet CHEBI:28445 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0278134 infores:hetionet CAID:CA10014569 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014569 MONDO:0011071 PMID:12393679PMID:23817177 Benign BS3, BS1 PS4, PS3, PS1, BA1, BP2, BP4, PVS1, PM6, PM2, BS4, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.205G>C variant that results in a Gly69Arg missense change has an MAF of 0.0003133 (0.03%, 6/19148 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Transactivation assays demonstrate normal transactivation as wild-type and normal DNA binding (BS3; PMIDs: 23817177 & 12393679). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014569/MONDO:0011071/008 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:70746 biolink:causes UMLS:C0877398 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0877398 infores:hetionet CAID:CA145865 biolink:causes MONDO:0001586 infores:clingen CAID:CA145865 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.1081G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 361 (p.Ala361Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (27037/90842 alleles; 4256 homozygotes; Grpmax Filtering AF 95% confidence = 0.2947) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92624). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145865/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:39867 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0000729 infores:hetionet CHEBI:32315 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018520 infores:hetionet CHEBI:8863 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003873 infores:hetionet CHEBI:5165 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0004093 infores:hetionet CHEBI:9139 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0008031 infores:hetionet CHEBI:27899 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0030554 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0917798 infores:hetionet CHEBI:107736 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0392156 infores:hetionet CHEBI:17347 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0013428 infores:hetionet CHEBI:490877 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0004093 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0019348 infores:hetionet CHEBI:47898 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0033036 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0023646 infores:hetionet CHEBI:50173 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0037299 infores:hetionet CHEBI:8207 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0231528 infores:hetionet CAID:CA353725 biolink:causes MONDO:0001586 infores:clingen CAID:CA353725 MONDO:0001586 PMID:8328452 Likely Pathogenic PM3_Supporting, PM4, PM5_Supporting, PS3_Supporting, PM2 PP4 "The NM_000203.5:c.1962A>T in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Cys), resulting in an increase in the length of the protein (PM1). The variant was identified in homozygosity in a patient with clinical symptoms consistent with MPS 1 and positive urine spot test for GAGs (PM3_Supporting). IDUA activity was deficient. However, because the patient is also homozygous for a benign ""pseudodeficiency"" variant (c.1225G>C, p.Gly409Arg), there is insufficient data to apply PP4 (PMID: 8328452). When expressed in COS-1 cells, the p.Ter654Cys variant resulted in 2% normal activity (PMID: 8328452) (PS3_Supporting). Three other variants in the stop codon of IDUA have been reported, one of which, c.1960T>C (p.Ter654Arg) (Bertola et al, PMID: 21394825; Ngiwsara et al, PMID: 29282708), has been classified as likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). The other variants are c.1960T>G (p.Ter654Gly) (Tieu et al, 1995, PMID: 7550232), and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762). There is a ClinVar entry for the variant (Variation ID: 242721). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications 1.0.0): PM4, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA353725/MONDO:0001586/091 2024-12-05 2025-03-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44185 biolink:causes HP:0007359 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0751495 infores:hetionet CHEBI:7454 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0011603 infores:hetionet CHEBI:16714 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C2047937 infores:hetionet CHEBI:17549 biolink:causes MONDO:0021042 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0017638 infores:hetionet CHEBI:2469 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151578 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0027051 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151773 infores:hetionet CHEBI:30751 biolink:causes MONDO:0006022 infores:drugmechdb knowledge_assertion manual_agent MESH:C030544 MESH:D000138 DB01213_MESH_D000138_1 CHEBI:2611 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020517 infores:hetionet CHEBI:79699 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0033774 infores:hetionet CHEBI:17650 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0700590 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0006266 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014130 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0009450 infores:hetionet CHEBI:9927 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0035455 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0025061 infores:hetionet CHEBI:6923 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0085593 infores:hetionet CHEBI:47898 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011168 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0034065 infores:hetionet CHEBI:64019 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0015672 infores:hetionet NCBIGene:57716 biolink:causes MONDO:0013959 infores:monarchinitiative not_provided not_provided HGNC:13797 MONDO:0013959 uuid:c690c45a-ca06-4beb-ad17-e7be1a49b3b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0242350 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0015397 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0032285 infores:hetionet CHEBI:52717 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0234233 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0151810 infores:hetionet CHEBI:48669 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0002871 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042035 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0870082 infores:hetionet CHEBI:31236 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020461 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0178298 infores:hetionet CAID:CA512318982 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318982 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.126G>A (p.Pro42=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318982/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3561 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0040034 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162316 infores:hetionet CAID:CA410208078 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208078 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS4, PS2, PS3, BA1, BP3, BP2, BP1, BP4, BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM4, PM3, PM5, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.546C>G (p.Asn182Lys) is a missense variant affecting one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant is located within a critical and well-established functional domain (AA 89-204) of RUNX1. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208078/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50922 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020701 infores:hetionet CHEBI:78543 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0852911 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1861172 infores:hetionet CHEBI:2611 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0011168 infores:hetionet UMLS:C0004609 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0086565 infores:hetionet CHEBI:3561 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1262144 infores:hetionet CHEBI:7459 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0009421 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006285 infores:hetionet CHEBI:194135 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0238106 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0413252 infores:hetionet CHEBI:64354 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0242429 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0005779 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0277925 infores:hetionet CHEBI:10127 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0021051 infores:hetionet GO:1900157 biolink:causes GO:0060348 infores:ubergraph knowledge_assertion manual_agent GO:1900157 GO:0060348 CHEBI:8228 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0025061 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0023895 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0475858 infores:hetionet CHEBI:85083 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0027765 infores:hetionet CHEBI:34764 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00663 UMLS:C0015230 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017178 infores:hetionet CHEBI:182080 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0086565 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0009241 infores:hetionet CAID:CA405667490 biolink:causes MONDO:0018493 infores:clingen CAID:CA405667490 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with leucine at codon 2340 of the RYR1 protein, p.Phe2340Leu. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:25960145). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.789 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405667490/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:43968 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0917801 infores:hetionet CHEBI:31236 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028081 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0038814 infores:hetionet NCBIGene:1778 biolink:causes MONDO:0013644 infores:monarchinitiative not_provided not_provided HGNC:2961 MONDO:0013644 uuid:63fbd195-a85f-454d-8099-f4f656a868f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0008031 infores:hetionet CAID:CA3231862 biolink:causes MONDO:0012163 infores:clingen CAID:CA3231862 MONDO:0012163 PMID: Uncertain Significance PM2_Supporting PM3 NM_002185.5(IL7R):c.212T>C is a missense variant predicted to cause substitution of Phenylalanine by Serine at amino acid 71 (p.Phe71Ser).The filtering allele frequency of the c.212T>C variant in IL7R is 0 by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). One patient (PMID: 23810098) was found heterozygous for F71S & H180P (pre-curated as VUS) (0.25 pt.) (PM3 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3231862/MONDO:0012163/119 2024-06-17 2024-06-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63621 biolink:causes MONDO:0002363 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030354 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0948586 infores:hetionet CHEBI:6754 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0017086 infores:hetionet CHEBI:50692 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0333243 infores:hetionet CAID:CA227892 biolink:causes MONDO:0100438 infores:clingen CAID:CA227892 MONDO:0100438 PMID:27268253 Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3_Moderate, PM3_Supporting, PP1_Moderate, PS3_Supporting NM_014336.5(AIPL1):c.715T>C (p.Cys239Arg) is predicted to replace the cysteine at position p.239 with arginine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (PMID: 15249368) (0.5 total points, PM3_Supporting). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 15249368 and personal communication). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with poor central vision (1 pt) from birth (1 pt), along with severe night blindness (0.5 pts) and pendular nystagmus (1 pt). Full-field electroretinogram responses were non-detectable from both rods (0.5 pts) and cones (1 pt). Visual acuity 20/800 in both eyes at age 17. Fundus examination revealed widespread RPE changes with pigment clumping (0.5 pt), attenuated retinal vessels (1 pt), macular atrophy (0.5 pts) and a pale optic disk (0.5 pts) which together are specific for AIPL1-related retinopathy (total 8 points, PMID: 10873396, PP4_Moderate). The variant protein exhibits less than 10% of wild-type AIPL1 activity in a cGMP hydrolysis assay based on exogenous expression in HEK293T cells (PMID: 27268253, PS3_Supporting). the computational predictor REVEL gives a score of 0.789, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PS3_Supporting, PM3_Supporting, PP1_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227892/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6950 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0497327 infores:hetionet CHEBI:3011 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0015672 infores:hetionet CHEBI:2904 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0039240 infores:hetionet CAID:CA023406 biolink:causes MONDO:0007750 infores:clingen CAID:CA023406 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, BS4, PM5, PM3, PM2, PP3, PP4 The NM_000527.5 (LDLR):c.1027G>A (p.Gly343Ser) variant is classified as Pathogenic (modified) for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong, PM5, PM3, BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMaxMAF=0.00005 in East Asian population from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.929, it is above 0.75.PS3: Level 1 assays: PMID 15100232. Heterologous cells (CHO) were used in WB, FACS and NMR Spectroscopy. The experiments shown <60% cell surface LDLR expression (Fig 5C), and >80% expressed receptor bind and release LDL upon low pH condition (Fig 6B), the amount of LDL bound to the mutant receptor correlates tightly with cell-surface LDLR expression, NMR indicates misfolding defects of the receptor. Functional data is consistent with damaging effect. This study is reported by Boswell et al, 2004, from Department of Biochemistry, Division of Structural Biology, University of Oxford, UK. PP4: Variant meets PM2 and is identified in at least ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded.PS4: Variant meets PM2 and is identified in at least 26 index cases reported in VCI and PubMed. There are 14 unrelated index case reported in VCI who fulfil criteria for FH diagnosis: Twelve cases fulfil DLCN criteria, 7 reported from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France, 1 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 2 from Research Lab of Molecular Genetics of Lipid Metabolism; and 2 from Robarts Research Institute, Canada; two cases fulfil Simon Broome possible criteria, reported from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. Variant is reported in PubMed in at least 12 index cases fulfil criteria for FH diagnosis: 8 cases fulfil DLCN probable/definite FH criteria in PMID 11040093, 11810272, 32977124, 30270055, 27784735; 1 case fulfil Simon Broome possible FH criteria in PMID 26748104; 3 cases fulfil MedPed criteria in PMID 8882879, 27824480. PP1_Strong: Variant segregates with FH phenotype in 18 informative meiosis from 6 families reported from 4 different labs in VCI: 11 affected carries and 7 unaffected non-carriers reported from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Laboratory of Genetics and Molecular Cardiology, and Research Lab of Molecular Genetics of Lipid Metabolism. PM5: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, by these guidelines, therefore PM5 is met.PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (untreated LDL-C > 500mg/dL, or LDL-C > 300 mmol/dL on high-intensive lipid-lowering therapy and the presence of tendon xanthomas before 10 year of age), reported by Sanchez-Hernandez et al, 2016, Universitario Insular Materno Infantil de Gran Canaria, Spain, PMID 27784735. This variant met enough pathogenic criteria toward Pathogenic classification by these guidelines before PM3 code applied.BS4: Variant does not segregate with FH phenotype in total of 6 informative meiosis reported in VCI. Five affected relatives without the variant and had LDL-C>75th percentile, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case each from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Laboratory of Genetics and Molecular Cardiology, and Research Lab of Molecular Genetics of Lipid Metabolism. There is 1 instance reported from 1 laboratory, where an unaffected family member had LDL-C<50th percentile and carries the variant, reported in VCI from Laboratory of Genetics and Molecular Cardiology, GTR LabID 505581.Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes toward Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence code towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023406/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:205919 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0034150 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0162429 infores:hetionet CAID:CA410204065 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204065 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS2, PS4, PS1, BP3, BP1, BP4, BP2, PM6, PVS1, BP5, BP7, BS3, BS4, PM1, PM4, PM3, PM5, PP1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.161A>T (p.Glu54Val) is a missense variant which is completely absent from population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204065/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA512341376 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341376 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1011C>G (p.Pro337=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.62)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341376/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA512318682 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318682 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.474T>C (p.Phe158=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.07) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318682/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15367 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0521495 infores:hetionet CHEBI:3216 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0241157 infores:hetionet CHEBI:73274 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0011175 infores:hetionet CHEBI:135935 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0009806 infores:hetionet NCBIGene:7015 biolink:causes MONDO:0013878 infores:monarchinitiative not_provided not_provided HGNC:11730 MONDO:0013878 uuid:2ed41d47-76a5-4d29-a936-ff406d5634f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:184555 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0234215 infores:hetionet NCBIGene:10584 biolink:causes MONDO:0009554 infores:monarchinitiative not_provided not_provided HGNC:2220 MONDO:0009554 uuid:e44fb647-e1d8-4f10-8fbe-dadbc45df284 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023380 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042514 infores:hetionet CHEBI:64312 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0520966 infores:hetionet CHEBI:63598 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0024282 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0019360 infores:hetionet CHEBI:10101 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0231528 infores:hetionet CHEBI:72564 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0018524 infores:hetionet CAID:CA5689580 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689580 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.363G>A (p.Glu121=) variant in the SHOC2 gene is 0.0384% (8/10350) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689580/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:27999 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0162566 infores:hetionet CHEBI:45924 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0002994 infores:hetionet NCBIGene:6862 biolink:causes MONDO:0014314 infores:monarchinitiative not_provided not_provided HGNC:11515 MONDO:0014314 uuid:e97a921f-e938-4034-bfae-e6b4220868d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235063 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0851341 infores:hetionet CHEBI:16335 biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0520886 infores:hetionet CHEBI:75045 biolink:causes MONDO:0020761 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0006079 infores:hetionet CHEBI:41423 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0007820 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0948089 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0019158 infores:hetionet CHEBI:44032 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0015967 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0005779 infores:hetionet CHEBI:63791 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0029118 infores:hetionet CHEBI:4702 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0043352 infores:hetionet CHEBI:8871 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0744727 infores:hetionet CHEBI:63791 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020443 infores:hetionet CHEBI:31643 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C3257803 infores:hetionet NCBIGene:6885 biolink:causes MONDO:0014935 infores:monarchinitiative not_provided not_provided HGNC:6859 MONDO:0014935 uuid:5c6363f7-8f8b-4599-9ed8-94f5f8e23cde biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2569 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0027497 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0011603 infores:hetionet CHEBI:6970 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0030193 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0003864 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017563 infores:hetionet CHEBI:168396 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0037763 infores:hetionet CHEBI:8871 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151662 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0243026 infores:hetionet CHEBI:5132 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0235660 infores:hetionet CHEBI:9671 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0012833 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0008325 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0009450 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0038454 infores:hetionet CHEBI:171719 biolink:causes HP:0001133 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0235095 infores:hetionet CHEBI:63580 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0040264 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0877338 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042267 infores:hetionet CAID:CA10636633 biolink:causes MONDO:0015967 infores:clingen CAID:CA10636633 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 The c.1768+11C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within intron 9 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, the computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that the variant has no impact on splicing (BP4). In summary, c.1768+11C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM2_Supporting, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10636633/MONDO:0015967/017 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1173563400 biolink:causes MONDO:0100368 infores:clingen CAID:CA1173563400 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting NM_000329.3(RPE65):c.444_445del (p.Glu148AspfsTer8) is a frameshift variant that introduces a premature stop codon into exon 5 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans, which was previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (1 point, VCEP member-provided data, PM3). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1173563400/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3568 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0032227 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0919582 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0919582 infores:hetionet CHEBI:50749 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0030554 infores:hetionet CHEBI:9605 biolink:causes NCIT:C116588 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0877172 infores:hetionet GO:0014725 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0014725 GO:0007275 CHEBI:36795 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0234458 infores:hetionet CHEBI:3752 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0085636 infores:hetionet GO:0003427 biolink:causes GO:0003417 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0003417 CHEBI:64355 biolink:causes MONDO:0002442 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0023976 infores:hetionet CAID:CA132194 biolink:causes MONDO:0019501 infores:clingen CAID:CA132194 MONDO:0019501 PMID: Likely Benign BS1_Supporting, BP2 PP3 The c.1007G>A (p.Arg336His) variant in MYO7A is a missense variant predicted to cause a substitution of arginine by histidine at amino acid 336. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00286 (2854/996858) in the non-Finnish European population, including 4 homozygous individuals, at least two of whom were beyond the average age of onset for MYO7A-related Usher syndrome. This frequency is higher than would be expected for an autosomal recessive condition based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been reported in individuals with nonsyndromic, mild-moderate hearing loss in whom a second variant was not detected (PMID: 23804846) as well as an individual with Usher syndrome but lacking a second variant (PMID: 16470552). A patient with Usher syndrome was homozygous for both p.Arg336His and a likely pathogenic/pathogenic variant (BP2; PMID: 33363762, ClinVar IDs: 551533). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign for both Usher syndrome and nonsyndromic hearing loss. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132194/MONDO:0019501/005 2024-11-20 2025-03-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:45783 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0035410 infores:hetionet CHEBI:27882 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0002871 infores:hetionet CHEBI:45409 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0030252 infores:hetionet CHEBI:10100 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0019079 infores:hetionet CHEBI:7466 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0019825 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0858678 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0004936 infores:hetionet CHEBI:4753 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0152227 infores:hetionet CHEBI:27882 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0038362 infores:hetionet CAID:CA464450288 biolink:causes MONDO:0009595 infores:clingen CAID:CA464450288 MONDO:0009595 PMID: Likely Pathogenic PM2_Supporting, PS1_Supporting, PM3, PP4_Moderate The NC_000009.12:g.35657776T>G is present in a frequency of 0.000006567 Grpmax filtering AF with only 1 allele in 152268, which is below the PM2_Supporting threshold that the SCID VCEP has established, therefore meeting this criterion. Internal data: at least one patient has presented with metaphyseal dysplasia (disproportionate short stature + radiographic evidence) (+1.0), skeletal dysplasia gene panel or WES/WGS conducted with no alternative genetic diagnosis (+1.0) and hypotrichosis (+0.5) reaching a total of 2.5 points. Therefore PP4_Moderate is met.Internal data: this variant has been confirmed in trans with NR_003051.3:n.196C>T (classified Pathogenic by VCEP +1.0) in a proband with the short disproportionate stature, rhizomelic dysplasia, and sparse light hair. Therefore PM3 is met.Finally, this variant (n.244A>C) is located at position 244, which is the same nucleotide that another variant has been classified as Likely Pathogenic in position 244 (n.244A>G), meeting PS1_Supporting. In summary, this variant is classified as Likely Pathogenic for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PS1_Supporting, PM3, PP4_Moderate (SCID VCEP RMRP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA464450288/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47898 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009806 infores:hetionet CHEBI:79699 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0085641 infores:hetionet NCBIGene:3295 biolink:causes MONDO:0009855 infores:monarchinitiative not_provided not_provided HGNC:5213 MONDO:0009855 uuid:771e6d09-68f2-46a2-95be-d0729f30e0aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013604 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1609512 infores:hetionet CHEBI:9586 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0015672 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011570 infores:hetionet CAID:CA136146 biolink:causes MONDO:0021060 infores:clingen CAID:CA136146 MONDO:0021060 PMID: Uncertain Significance PP2 "The filtering allele frequency of the c.3703C>T (p.Pro1235Ser) variant in the SOS1 gene is .016% (1/6134 with 95% CI) of ""Other"" alleles and .0017% (2/113506 with 95% CI) of non-Finnish European alleles in gnomAD (BS1 not met). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Observed cases from laboratories and publications lack sufficient clinical phenotypic information to support or refute pathogenicity (SCV000062232.6; SCV000207254.1; GeneDx internal data; PMID: 27763634) In summary, the clinical significance of the p.Pro1235Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2." RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136146/MONDO:0021060/004 2019-10-07 2019-12-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63925 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0008031 infores:hetionet CHEBI:31236 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020458 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0037274 infores:hetionet NCBIGene:79912 biolink:causes MONDO:0014993 infores:monarchinitiative not_provided not_provided HGNC:26162 MONDO:0014993 uuid:d8b7f22d-5dda-4390-9d92-1cf466636375 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32192 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0178298 infores:hetionet CHEBI:4466 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0520888 infores:hetionet CHEBI:9635 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0015230 infores:hetionet NCBIGene:8295 biolink:causes MONDO:0032760 infores:monarchinitiative not_provided not_provided HGNC:12347 MONDO:0032760 uuid:9fc0dabd-c885-40ae-b875-ce448503f83e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15407 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0015967 infores:hetionet CHEBI:44032 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0085605 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020538 infores:hetionet CAID:CA658822438 biolink:causes MONDO:0015152 infores:clingen CAID:CA658822438 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_003494.4: c.1375dup p.(Met459AsnfsTer15) variant in DYSF, which is also known as c.1471dup p.(Met491AsnfsTer15), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 16/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least 16 unrelated individuals with LGMD (PMID: 27647186, 34559919; LOVD DYSF_000363), including in a homozygous state in two patients from China (0.5 pts, PMID: 34559919) and in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.3137G>A p.(Arg1064His), 0.5 pts, PMID: 27647186, 34559919) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical suspicion of LGMD or progressive limb girdle muscle weakness observed over 6 months (PMID: 27647186, 34559919; PP4). The highest allele frequency for this variant in gnomAD v4.1.0 is 0.00004458 (2/44868 East Asian chromosomes), which is lower than the LGMC VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658822438/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5147 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0031085 infores:hetionet CHEBI:63605 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0231528 infores:hetionet CHEBI:3441 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C3665347 infores:hetionet UMLS:C0657912 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026961 infores:hetionet CHEBI:17698 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0270996 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018801 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0020651 infores:hetionet CHEBI:3347 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0001925 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0015397 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0042373 infores:hetionet CHEBI:2666 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0429097 infores:hetionet CHEBI:3696 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085649 infores:hetionet CHEBI:194135 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0022281 infores:hetionet CHEBI:82960 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0231218 infores:hetionet CHEBI:6954 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0027497 infores:hetionet CHEBI:42944 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0687713 infores:hetionet CHEBI:4356 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0003862 infores:hetionet CHEBI:16469 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0032708 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0241635 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0241635 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020557 infores:hetionet CHEBI:74947 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151799 infores:hetionet GO:0002917 biolink:causes GO:0002451 infores:ubergraph knowledge_assertion manual_agent GO:0002917 GO:0002451 CHEBI:44185 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030578 infores:hetionet CHEBI:31485 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0042164 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0020649 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042267 infores:hetionet CHEBI:87715 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0013404 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0853813 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0178298 infores:hetionet CHEBI:16469 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151907 infores:hetionet CHEBI:6375 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0340865 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0002622 infores:hetionet CHEBI:4708 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085632 infores:hetionet NCBIGene:2057 biolink:causes MONDO:0007572 infores:monarchinitiative not_provided not_provided HGNC:3416 MONDO:0007572 uuid:d4994dae-8dd6-440e-8ae0-5af1eab32d92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0595916 infores:hetionet CAID:CA16020956 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020956 MONDO:0009861 PMID:27121329PMID:8268925PMID:11708866 Pathogenic PM3, PVS1, PP4_Moderate, PM2 The c.1171_1172del (p.Ser391PhefsTer2) variant in PAH has been reported in an individual with Classic PKU (BH4 deficiency excluded). (PMID: 8268925, 11708866, 27121329) in trans with pathogenic variant p.Ser349Pro. It is a frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. This variant has an extremely low allele frequency (MAF=0.000008799) in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate, Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020956/MONDO:0009861/006 2020-06-19 2020-06-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8059 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0085631 infores:hetionet CHEBI:47426 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0002874 infores:hetionet CHEBI:8346 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0015230 infores:hetionet CHEBI:52717 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036980 infores:hetionet CHEBI:52717 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235266 infores:hetionet NCBITaxon:287 biolink:causes UMLS:C1112209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:287 MESH:D059413 DB09060_MESH_D059413_4DB00303_MESH_D059413_1 CHEBI:3398 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0232462 infores:hetionet CHEBI:66901 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0009782 infores:hetionet CHEBI:10650 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0010520 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0267792 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0034150 infores:hetionet NCBIGene:64093 biolink:causes MONDO:0008800 infores:monarchinitiative not_provided not_provided HGNC:20318 MONDO:0008800 uuid:449f95e3-e573-419f-80f2-ff75bc3bf8de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes UMLS:C0264523 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0264523 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1096458 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1096458 infores:hetionet CHEBI:65346 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0041969 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0541832 infores:hetionet CHEBI:31981 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0003811 infores:hetionet CHEBI:7454 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0041657 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023895 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0027765 infores:hetionet NCBIGene:4703 biolink:causes MONDO:0030281 infores:monarchinitiative not_provided not_provided HGNC:7720 MONDO:0030281 uuid:e105b173-42ad-4e67-8b94-dedb1431e844 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2453 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0015230 infores:hetionet CHEBI:71219 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0020546 infores:hetionet CHEBI:3347 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0042963 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0019112 infores:hetionet UMLS:C0004609 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013428 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0344320 infores:hetionet CHEBI:51450 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0040822 infores:hetionet CHEBI:47612 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0917801 infores:hetionet CHEBI:6520 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0016059 infores:hetionet CHEBI:3756 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233471 infores:hetionet CHEBI:9137 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0232461 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0085654 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0085654 infores:hetionet CHEBI:8863 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015967 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0521170 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0521170 infores:hetionet CHEBI:71417 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0700590 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020517 infores:hetionet CHEBI:64310 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151905 infores:hetionet CHEBI:135935 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0020903 infores:hetionet CHEBI:135920 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0011991 infores:hetionet CHEBI:119915 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085635 infores:hetionet CHEBI:2704 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0016655 infores:hetionet CHEBI:6933 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0011603 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0857353 infores:hetionet UMLS:C0657912 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018926 infores:hetionet CHEBI:3219 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017181 infores:hetionet CHEBI:114785 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0036974 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0002026 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5475 MONDO:0002026 CHEBI:64019 biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0155919 infores:hetionet CHEBI:41879 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0332601 infores:hetionet CHEBI:3176 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0022573 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes UMLS:C0877373 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0877373 infores:hetionet CAID:CA6748735 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748735 MONDO:0009861 PMID: Uncertain Significance PM2, BP7, BS1 The NM_000277.3:c.1140G>A variant in PAH is a synonymous (silent) variant (p.Thr380=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004573 (14/30616 alleles) in the South Asian population (none of the population data codes are met). There is a ClinVar entry for this variant (Variation ID: 733267, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): no criteria are met. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748735/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:499361 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0234632 infores:hetionet CHEBI:6846 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0030312 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0239150 infores:hetionet CHEBI:71417 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0042963 infores:hetionet CHEBI:135736 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151908 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0027051 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0152227 infores:hetionet CHEBI:9168 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0039621 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0010399 infores:hetionet CHEBI:10125 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0022408 infores:hetionet CHEBI:3013 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C2973529 infores:hetionet CHEBI:38545 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0151786 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0917801 infores:hetionet CHEBI:6067 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0278134 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0031350 infores:hetionet CHEBI:2950 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0080274 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0233494 infores:hetionet CHEBI:4887 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0023380 infores:hetionet CHEBI:38940 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0017168 infores:hetionet CHEBI:15765 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0026821 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0018799 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0014549 infores:hetionet CHEBI:92712 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0039070 infores:hetionet CHEBI:7492 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0006277 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0687707 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0030920 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0948089 infores:hetionet CHEBI:478164 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0085605 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0007114 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0018799 infores:hetionet CHEBI:9570 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009782 infores:hetionet CHEBI:10650 biolink:causes MONDO:0041526 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0156543 infores:hetionet NCBIGene:126410 biolink:causes MONDO:0011485 infores:monarchinitiative not_provided not_provided HGNC:26820 MONDO:0011485 uuid:3c2e78c5-2667-4dae-b27c-3f9f30aecc12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0015230 infores:hetionet CHEBI:101278 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0162834 infores:hetionet CHEBI:3213 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0700225 infores:hetionet CHEBI:75246 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0000731 infores:hetionet CHEBI:63619 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020625 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0520559 infores:hetionet CHEBI:135005 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0600142 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0023530 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0085620 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013395 infores:hetionet NCBITaxon:319546 biolink:causes MONDO:0024472 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:319546 MONDO:0024472 CHEBI:15367 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0016436 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0037199 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0012833 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1565662 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1565662 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0242350 infores:hetionet CAID:CA185105 biolink:causes MONDO:0019501 infores:clingen CAID:CA185105 MONDO:0019501 PMID: Pathogenic PP1_Strong, PP3, PM3_Very Strong BP5, PP4, PM2 The c.5012G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 1671 (p.Gly1671Asp). The highest population minor allele frequency in gnomAD v4 is 0.04% (51/91074 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.906, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been detected in at least 10 individuals with retinitis pigmentosa or inherited retinal disease. Of those individuals, 9 were homozygous and 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.4251+1G>T, 5 PM3 points, PMID:26667666, 32581362, 33749171, 38219857, PM3_VeryStrong). Internal evidence from one laboratory indicates that this variant has been observed in trans with a likely pathogenic missense variant in an individual with optic neuropathy, night blindness, and sensorineural hearing loss and homozygous in one individual with hearing loss and hyperopia (Personal communication, SCV001789135.4). This suggests that there may be phenotypic variability with some individuals presenting with isolated retinal dystrophy, and some presenting with hearing loss and signs and/or symptoms of retinal dystrophy. Of note, many of these individuals were of South Asian ancestry, consistent with the population evidence from gnomAD (PMID:38219857). The variant has been reported to segregate with inherited retinal disease in 3 affected family members from 2 families (PP1_Strong; PMID: 38219857). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive USH2A-related inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_VeryStrong, PP1_Strong. (ClinGen Hearing Loss VCEP specifications version 2, 02.27.2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA185105/MONDO:0019501/005 2024-02-27 2024-04-01 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:135566 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0423602 infores:hetionet CHEBI:51173 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0600228 infores:hetionet CHEBI:9907 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151578 infores:hetionet CHEBI:5959 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020546 infores:hetionet CHEBI:8327 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0040034 infores:hetionet CHEBI:8802 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0235063 infores:hetionet CAID:CA234034 biolink:causes MONDO:0100040 infores:clingen CAID:CA234034 MONDO:0100040 PMID:35163265 Likely Pathogenic PS4_Moderate, PM1, PS3_Supporting, PM6, PP3, PM2_Supporting PS1, PS2, PM5, PM3, BP5, BS1, BS3, BS4, PP1, PP4, BS2, BA1, BP4, BP2 The p.Gly224Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID: 18571142, 28661489) (PM1). The p.Gly224Ser variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with gross motor delay and infantile spasms (Internal database - GeneDx) (PM6). Functional study has shown that this variant impacts protein function (PMID: 35163265) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Gly224Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting). The p.Gly224Ser variant has been observed in 3 individuals with neurodevelopmental disease (PMID: 30533527, Internal database - GeneDx, Internal database - University of Chicago) (PS4_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic based on ACMG/AMP criteria (PM1, PM6, PS3_supporting, PP3_supporting, PM2_supporting, PS4_moderate). (FOXG1 specification v3.0.0; approved on 12/18/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA234034/MONDO:0100040/035 2024-12-18 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CAID:CA913170013 biolink:causes MONDO:0044970 infores:clingen CAID:CA913170013 MONDO:0044970 PMID:14581685 Uncertain Significance PS4_Supporting, PM2_Supporting, PM6_Supporting, PS3_Supporting PP3, PP1 The m.12294G>A variant in MT-TL2 has been reported in two unrelated individuals with primary mitochondrial disease. These two affected individuals had myopathy and ophthalmoplegia. Age of onset ranged from childhood to teens. Muscle biopsies revealed ragged red fibers, COX-deficient fibers, and combined respiratory chain enzyme activity deficiencies. The variant was identified in muscle in both individuals (one with the variant at 59.8% heteroplasmy and the other at 75% heteroplasmy) and was absent in other tissues tested (blood, urine, buccal, primary myoblasts; PS4_supporting, PMIDs: 14581685, 29052516). There are no large families reported in the medical literature to consider for evidence of segregation. The variant was confirmed to have occurred de novo in one of the reported individuals (absent in healthy mother’s muscle; PMID: 29052516, PM6_supporting). In silico predictors do not agree as the computational predictor MitoTIP suggests this variant is pathogenic (71.4 percentile) and HmtVAR predicts it to be likely polymorphic (0.15). This variant is absent in the Genbank dataset, Helix dataset and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (92.9% ± 7.4, n=10) than in COX-positive fibers (48.3% ± 22.19, n=18, p<0.00001; PS3_supporting, PMID: 14581685). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913170013/MONDO:0044970/015 2022-10-24 2023-01-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:134990 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0033774 infores:hetionet CHEBI:28748 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1260926 infores:hetionet CHEBI:6128 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0004093 infores:hetionet CHEBI:50924 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C2711248 infores:hetionet NCBIGene:83480 biolink:causes MONDO:0014886 infores:monarchinitiative not_provided not_provided HGNC:25461 MONDO:0014886 uuid:c2dc26c8-d6ff-44c5-b197-e6df7b76ac62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0003708 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018799 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0004936 infores:hetionet GO:0045570 biolink:causes GO:0007444 infores:ubergraph knowledge_assertion manual_agent GO:0045570 GO:0007444 CHEBI:681850 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0027765 infores:hetionet CHEBI:4856 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0034063 infores:hetionet CHEBI:28830 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C1287298 infores:hetionet CHEBI:45951 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0024141 infores:hetionet CHEBI:46295 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0039070 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0017178 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0007642 infores:hetionet CHEBI:3207 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0028734 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0004936 infores:hetionet CAID:CA387503468 biolink:causes MONDO:0015152 infores:clingen CAID:CA387503468 MONDO:0015152 PMID: Likely Pathogenic PP1, PP4, PM2_Supporting, PVS1_Moderate, PM3_Supporting BP7, BP5, BS1, BS4, BS3, PM6, BS2, PP2, PP3, PM5, PM4, PM1, BP1, BP4, BP2, BP3, BA1, PS4, PS3, PS2, PS1 The NM_000231.3: c.703-1G>C variant in SGCG occurs within the canonical splice acceptor site (-1) of intron 7. It is predicted to cause skipping of biologically relevant exon 8/8, resulting in an in-frame deletion of less than 10% of the protein (amino acids 235-291) (PVS1_Moderate). This variant has been detected in a homozygous state in at least one patient with signs of limb girdle muscular dystrophy (0.5 pts, ClinVar SCV001200760.3 internal data communication; PM3_Supporting, PP4). The variant has been reported to segregate with autosomal recessive LGMD in one affected family member (PP1; ClinVar SCV001200760.3 internal data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate, PP4, PM3_Supporting, PP1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA387503468/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042963 infores:hetionet CHEBI:9086 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0423791 infores:hetionet CHEBI:2668 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085649 infores:hetionet CAID:CA1139665146 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665146 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1056_1058delinsA, (p.Met352Ilefs*6) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665146/MONDO:0008723/021 2024-12-10 2024-12-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9671 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0040034 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0948594 infores:hetionet CHEBI:5847 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0002170 infores:hetionet CHEBI:63630 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0392525 infores:hetionet CHEBI:2654 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0019572 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0020517 infores:hetionet CHEBI:47519 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0009806 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0005779 infores:hetionet CHEBI:3757 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0549622 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0853021 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0853021 infores:hetionet CHEBI:3127 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013404 infores:hetionet GO:0010080 biolink:causes GO:0009908 infores:ubergraph knowledge_assertion manual_agent GO:0010080 GO:0009908 CHEBI:2453 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0033774 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0518015 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0020514 infores:hetionet CHEBI:8207 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085631 infores:hetionet CHEBI:4702 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0162285 infores:hetionet CHEBI:78320 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0037274 infores:hetionet CAID:CA226965 biolink:causes MONDO:0800406 infores:clingen CAID:CA226965 MONDO:0800406 PMID:33375396 Pathogenic PP3_Moderate, PM3, PS3_Supporting, PM2_Supporting, PS4 The NM_000350.3:c.1957C>T variant in ABCA4 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 653 (p.Arg653Cys). The total minor allele frequency in gnomAD v4.1.0 is 0.00002666 (43/1612644 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.852 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The OR is 139.4 and the CI is 43.93-707.41, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in at least 4 individuals with ABCA4-related retinopathy. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant unconfirmed in trans (c.3386G>T; p.(Arg1129Leu)( PM3; PMID:35119454). ATPase activity in HEK293 cells showed reduction by over 20% compared to wild type indicating that this variant impacts protein function (PS3_Supporting; PMID:33375396). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PS4, PP3_Moderate, PM3, PM2_Supporting, PS3_Supporting. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA226965/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5004 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0240735 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042373 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0010414 infores:hetionet GO:0110137 biolink:causes GO:0002165 infores:ubergraph knowledge_assertion manual_agent GO:0110137 GO:0002165 CHEBI:3723 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2939147 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0852361 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0852361 infores:hetionet CHEBI:28864 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0162285 infores:hetionet CHEBI:18358 biolink:causes HP:0001003 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0036651 infores:hetionet NCBIGene:5172 biolink:causes MONDO:0010134 infores:monarchinitiative not_provided not_provided HGNC:8818 MONDO:0010134 uuid:94bd9265-d2c2-453d-af72-e45354df1ff8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0036974 infores:hetionet NCBIGene:6622 biolink:causes MONDO:0007488 infores:monarchinitiative not_provided not_provided HGNC:11138 MONDO:0007488 uuid:3f60ea72-2345-40ea-9de0-47e11e04b236 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65173 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0037036 infores:hetionet GO:0140166 biolink:causes GO:0001991 infores:ubergraph knowledge_assertion manual_agent GO:0140166 GO:0001991 CHEBI:16755 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0015397 infores:hetionet CHEBI:9139 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0149745 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0424000 infores:hetionet CHEBI:6954 biolink:causes HP:0003537 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0221333 infores:hetionet CHEBI:31236 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021368 infores:hetionet NCBIGene:140628 biolink:causes MONDO:0060663 infores:monarchinitiative not_provided not_provided HGNC:15802 MONDO:0060663 uuid:030f6008-ddc7-42a1-978a-bd175506b37d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018799 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0034882 infores:hetionet CHEBI:41879 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151827 infores:hetionet CHEBI:8378 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0039070 infores:hetionet CHEBI:48669 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0034063 infores:hetionet CHEBI:8871 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0039231 infores:hetionet CHEBI:3127 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0040822 infores:hetionet CAID:CA390886446 biolink:causes MONDO:0100216 infores:clingen CAID:CA390886446 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting BS2, PM1, PM5, PS4 The NM_177438.3:c.1261G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 421 (p.Asp421Asn). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.0000006197 (1/1613812 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.141; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390886446/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0035477 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:0035477 GO:0001568 CHEBI:75722 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011603 infores:hetionet CHEBI:72690 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020433 infores:hetionet CHEBI:9316 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0015967 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0034063 infores:hetionet CAID:CA8970612 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970612 MONDO:0012589 PMID: Uncertain Significance BP4 PS4, PM2, BS1 The highest population minor allele frequency of the p.Thr81Ser variant in TCF4 in gnomAD v4.1 is 0.000027 in the African population (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Thr81Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Thr81Ser variant in TCF4 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970612/MONDO:0012589/032 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94686 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0030305 infores:hetionet CHEBI:2673 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0242184 infores:hetionet GO:1900214 biolink:causes GO:0072205 infores:ubergraph knowledge_assertion manual_agent GO:1900214 GO:0072205 CAID:CA10014190 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014190 MONDO:0011071 PMID: Uncertain Significance PS4, PS3, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM1, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1253T>G (p.Met418Arg) is a variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014190/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135342 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0016199 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233414 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235234 infores:hetionet CAID:CA399807046 biolink:causes MONDO:0100326 infores:clingen CAID:CA399807046 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PVS1_Moderate The NM_000419.5(ITGA2B):c.48G>A (p.Trp16Ter) variant in exon 1 is a nonsense variant in biologically-relevant-exon 1/30. Premature termination codons within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_Moderate. At least one patient (UPN 1 in PMID: 16879215) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 5.6%, as measured by flow cytometry. UPN 1 is homozygous for this variant (PM3_supporting; PMID: 16879215). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399807046/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8707 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0043049 infores:hetionet CHEBI:31236 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0041105 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011127 infores:hetionet CHEBI:92712 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0553721 infores:hetionet CHEBI:9123 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232849 infores:hetionet CHEBI:31205 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0242429 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0014130 infores:hetionet CHEBI:45409 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C2242737 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0011570 infores:hetionet CHEBI:3228 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0003467 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0085584 infores:hetionet CHEBI:7465 biolink:causes MONDO:0043994 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0149520 infores:hetionet CAID:CA115289 biolink:causes MONDO:0007064 infores:clingen CAID:CA115289 MONDO:0007064 PMID: Benign BA1, BS2_Supporting The NM_000022.2:c.22G>A variant in ADA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 8 (p.Asp8Asn). This variant is present at an overall minor allele frequency of 0.05863 (10050/171418 alleles) with the highest population minor allele frequency of 0.1300 (3033/23322) in the South Asian population in gnomAD v2.1.1. This frequency is higher than the ClinGen SCID VCEP's threshold for BA1 (>0.00721); therefore, BA1 is met. This variant has been observed in 434 homozygous individuals in gnomAD, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA115289/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:72292 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0151479 infores:hetionet CHEBI:8378 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0235266 infores:hetionet GO:0060142 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0060142 GO:0048856 CHEBI:9123 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042345 infores:hetionet CAID:CA637689326 biolink:causes MONDO:0011071 infores:clingen CAID:CA637689326 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.*8G>C is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637689326/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0162835 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0008325 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0392176 infores:hetionet CHEBI:7936 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0267940 infores:hetionet CHEBI:6801 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0232462 infores:hetionet CAID:CA16603209 biolink:causes MONDO:0008723 infores:clingen CAID:CA16603209 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP4, PP3, PS3 The c.364A>G (p.Asn122Asp) variant in ACADVL is a missense in exon 6. This variant has been reported as a homozygote in the literature associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID: 34480364). Fatty acid oxidation (FAO) flux assay performed on patient fibroblast homozygous for this variant demonstrated severe reduction of enzyme activity (PS3, PMID: 20060901). In additon, protein production was deficient for this genotype shown by western blot (PMID: 20060901). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.86, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: (PP4,PP3, PS3, PM2_Supporting). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603209/MONDO:0008723/021 2022-05-06 2022-05-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034186 infores:hetionet NCBIGene:85476 biolink:causes MONDO:0012191 infores:monarchinitiative not_provided not_provided HGNC:13780 MONDO:0012191 uuid:e317c53f-0ee7-4673-9de6-cb568334d16a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75998 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0009760 infores:hetionet CHEBI:94440 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0085631 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0853755 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853755 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0242350 infores:hetionet CHEBI:37333 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0036974 infores:hetionet CHEBI:134990 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0003467 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0836924 infores:hetionet CHEBI:6541 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0019158 infores:hetionet CHEBI:15553 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0027497 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040479 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0042514 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0919980 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0010346 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0587054 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0587054 infores:hetionet CHEBI:63635 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0030554 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0232461 infores:hetionet NCBIGene:5293 biolink:causes MONDO:0014222 infores:monarchinitiative not_provided not_provided HGNC:8977 MONDO:0014222 uuid:2881cf5b-48d2-47bc-b334-6837338e3f15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0948594 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0021053 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042075 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0233494 infores:hetionet CHEBI:68845 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0235431 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0027769 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1384353 infores:hetionet CHEBI:110423 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0011991 infores:hetionet CHEBI:2682 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151603 infores:hetionet CHEBI:38940 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0311468 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0427008 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0233414 infores:hetionet CHEBI:182080 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0016382 infores:hetionet CHEBI:46345 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C1619702 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0015230 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0032584 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030662 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0038362 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0221100 infores:hetionet CHEBI:16469 biolink:causes MONDO:0000931 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151622 infores:hetionet CHEBI:5790 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0010520 infores:hetionet CHEBI:6472 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0332534 infores:hetionet CHEBI:91541 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0151786 infores:hetionet CAID:CA226581 biolink:causes MONDO:0100368 infores:clingen CAID:CA226581 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 NM_000329.3(RPE65):c.778_785del (p.Asn260GlnfsTer18) is a frameshift variant that introduces a premature stop codon into exon 8 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) variant suspected but not confirmed in trans (PMID: 11095629). However, the proband was not counted for PM3 in order to avoid circularity. At least one proband harboring this variant exhibits a phenotype including a diagnosis of retinitis pigmentosa with onset of night blindness (0.5 pts) at birth (1 pt), no light perception (1 pt) as an adult, atrophy of the optic disc and retinal pigment epithelium (0.5 pts, PMID: 15288992), and very low autofluorescence (2 pts), which are specific for RPE65-related recessive retinopathy (5 total pts, PMID: 11095629, PMID: 15288992, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226581/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63617 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0032227 infores:hetionet CAID:CA131012 biolink:causes MONDO:0044970 infores:clingen CAID:CA131012 MONDO:0044970 PMID: Uncertain Significance PP1, BP4, PS4, PS3, PS2, PM2, PM6 The m.7471delC variant in MT-TS1 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. This variant is present in population databases (Mitomap's 28/59,389 sequences: AF= 0.047%; Helix's 162/195,983 sequences: AF=0.070% including 137 homoplasmic occurrences in addition to 25 heteroplasmic occurrences, and in haplogroups H, U, T, K, B, D, M, HV, J, A, I, X, T, C, K, M, W, V; and gnomAD v3.1.2: AF=0.053 % including 30 homoplasmic occurrences in addition to five heteroplasmic occurrences). Given the frequency of this variant, it does not meet PM2 criterion. The computational predictor MitoTIP suggests this variant is benign (4.3 percentile) and HmtVAR does not provide a prediction. Given the lack of computational evidence, BP4 cannot be applied. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that three experts on this panel felt likely benign was a more appropriate classification given the presence in the general population however the majority (four) agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): None. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA131012/MONDO:0044970/015 2023-05-22 2024-03-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:205919 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0033860 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027720 infores:hetionet GO:0003307 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0003307 GO:0072359 UMLS:C0879264 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004936 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0021843 infores:hetionet CHEBI:9654 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0021177 infores:hetionet CHEBI:15544 biolink:causes MONDO:0006904 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0345326 infores:hetionet CHEBI:3504 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0013404 infores:hetionet CHEBI:135351 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0017178 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005073 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027962 infores:hetionet CHEBI:9168 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013604 infores:hetionet CHEBI:5613 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0231530 infores:hetionet CHEBI:85078 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0035078 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0026650 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0022904 infores:hetionet CHEBI:49603 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0027947 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0162830 infores:hetionet NCBIGene:1830 biolink:causes MONDO:0030986 infores:monarchinitiative not_provided not_provided HGNC:3050 MONDO:0030986 uuid:94830c7d-c987-464c-a55b-79b026870c88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0025061 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0221714 infores:hetionet CHEBI:5779 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0028081 infores:hetionet CHEBI:9763 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0014457 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0021400 infores:hetionet CHEBI:4876 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0042963 infores:hetionet CHEBI:567361 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0522224 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0948594 infores:hetionet CHEBI:31355 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0015967 infores:hetionet CHEBI:17026 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013604 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0041976 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040479 infores:hetionet CAID:CA073137 biolink:causes MONDO:0100150 infores:clingen CAID:CA073137 MONDO:0100150 PMID: Likely Benign BP7, BS1, BP4 PM2, BA1 The c.9093C>T (p.Ala3031=) variant (NM_000540.3(RYR1):c.9093C>T (p.Ala3031=)) in RYR1 is a synonymous (silent) variant that is not predicted by Splice AI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC genome browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 3/6084) of the c.9093C>T variant in RYR1 is 0.0001414 for Middle Eastern chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for RYR1-related myopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (Congenital Myopathies VCEP Specifications Version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA073137/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CAID:CA1251434 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251434 MONDO:0013144 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PS3, PM5, PM1 The c.363G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of methionine by isoleucine at the highly conserved amino acid 121 (p.Met121Ile, also known as p.Met89Ile), which is located in an alpha-helix secondary structure in the serpin domain. In addition, an amino acid residue in the vicinity forms part of a disulfide bond (residue 127) and another undergoes glycosylation (residue 128). The variant is present in gnomAD v4.1.0 with a Grpmax MAF is <0.00002 (0.0000079), which meets criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.835, which is above the threshold of 0.6, which correlates with a deleterious impact to SERPINC1 function (PP3). One French individual reported with a mean 73% AT cofactor activity and 71% antigen levels, categorized as Type IIPE/Conform (PP4; PMID: 28300866). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel: PM2_supporting, PP3, PP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251434/MONDO:0013144/084 2025-09-19 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7773 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0085631 infores:hetionet UMLS:C0657912 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034886 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0012833 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0004096 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0687133 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1565489 infores:hetionet CHEBI:28748 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0741494 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0038454 infores:hetionet CHEBI:63925 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0086565 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0442886 infores:hetionet CAID:CA500624244 biolink:causes MONDO:0100326 infores:clingen CAID:CA500624244 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.408G>C (p.Val136=) variant is adjacent to the splice donor site of intron 3. The computational splicing predictor SpliceAI gives a score of 0.85 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 (PP3). The predicted result is skipping of exon 3 resulting in a frameshift and a premature stop codon in exon 4 of 30, leading to NMD which is consistent with the fact that αIIb mRNA was undetectable in the patient. One patient (Patient GT5 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and function was pathological. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). GT5 of PMID: 25373348 is compound heterozygous, without confirmation of trans phase reported, for c.408G>C and Ile596Thr (classified Pathogenic by the PD-EP; PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 8.508e-7 (1/1175340 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP3, PM2_supporting, PM3_supporting. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500624244/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8356 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0080274 infores:hetionet CHEBI:5100 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0017181 infores:hetionet CHEBI:5128 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0424295 infores:hetionet CHEBI:2955 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0311468 infores:hetionet CAID:CA658655971 biolink:causes MONDO:0015967 infores:clingen CAID:CA658655971 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting The c.427_428delinsCT variant in the glucokinase gene, GCK, causes an amino acid change of lysine to leucine at codon 143 (p.(Lys143Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a Polyphen result of deleterious and Grantham distance of 107 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.427_428delinsCT meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655971/MONDO:0015967/086 2024-03-22 2024-03-22 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:51141 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C3263723 infores:hetionet CHEBI:50648 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151692 infores:hetionet CHEBI:42797 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085628 infores:hetionet CHEBI:2569 biolink:causes UMLS:C0235524 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0235524 infores:hetionet CHEBI:4798 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0086439 infores:hetionet CHEBI:51450 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0235490 infores:hetionet CHEBI:3314 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0003811 infores:hetionet CHEBI:53766 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0027651 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0017601 infores:hetionet CHEBI:2549 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013404 infores:hetionet CHEBI:15765 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0002994 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0020649 infores:hetionet CHEBI:63580 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004604 infores:hetionet NCBIGene:8312 biolink:causes MONDO:0957832 infores:monarchinitiative not_provided not_provided HGNC:903 MONDO:0957832 uuid:3dda0aaf-0d63-4a08-93a9-b8e4e8964569 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0036130 infores:hetionet NCBIGene:51199 biolink:causes MONDO:0013922 infores:monarchinitiative not_provided not_provided HGNC:14906 MONDO:0013922 uuid:dfca8928-b679-46ee-a66f-0036cc4642f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0010200 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0018099 infores:hetionet CHEBI:10650 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0036974 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0024312 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0836924 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0040264 infores:hetionet CHEBI:63598 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0424295 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0235146 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0340726 infores:hetionet CHEBI:3312 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0006663 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0006266 infores:hetionet CHEBI:18332 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0424295 infores:hetionet CHEBI:31236 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C3263723 infores:hetionet GO:1900225 biolink:causes GO:0006954 infores:ubergraph knowledge_assertion manual_agent GO:1900225 GO:0006954 CHEBI:63621 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0029408 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1609512 infores:hetionet CHEBI:3082 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011124 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026846 infores:hetionet GO:0006954 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D001991 DB00588_MESH_D001991_1DB00901_MESH_D001991_1 CHEBI:27899 biolink:causes UMLS:C0849916 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0849916 infores:hetionet CHEBI:167638 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0036974 infores:hetionet CHEBI:27777 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0002871 infores:hetionet CAID:CA345144203 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144203 MONDO:0100084 PMID: Pathogenic PP2, PP3, PP1, PM2_Supporting, PS4_Moderate, PP4_Strong BP1, BP4, BA1, BS1 The c.1106C>T (p.Pro369Leu) variant in ACTA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 369. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 4 probands with nemaline myopathy, 1 with nemaline rods (PS4_Moderate; PMIDs: 19562689, 26172852; ClinVar SCVs: SCV000589626.2, SCV002287790.1; Internal lab contributors: GeneDx, Invitae). At least one patient with this variant displayed nemaline rods and type 1 fiber predominance, which is highly specific for alpha-actinopathy (PP4_Moderate, PMID: 26172852). The variant has been reported to segregate with autosomal dominant nemaline myopathy in 3 affected family members from 1 family (PP1; ClinVar SCV: SCV000589626.2, Internal lab contributors: GeneDx). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP4_Strong, PS4_Moderate, PM2_Supporting, PP1, PP2, PP3. (Congenital Myopathies VCEP specifications version 2; 08/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144203/MONDO:0100084/147 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50922 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0428977 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0031350 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0267792 infores:hetionet NCBIGene:10456 biolink:causes MONDO:0012548 infores:monarchinitiative not_provided not_provided HGNC:16915 MONDO:0012548 uuid:74916650-571e-49f6-aaa2-f6584df91421 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0853761 infores:hetionet UNII:DJJ95FJP1H biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0085624 infores:hetionet CAID:CA063368 biolink:causes MONDO:0018493 infores:clingen CAID:CA063368 MONDO:0018493 PMID: Uncertain Significance PS3_Moderate, PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with methionine at codon 84 of the RYR1 protein, p.(Thr84Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0003, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257), however, the high MAF in the EAS population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:29344738). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.735 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA063368/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7454 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0003467 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0009450 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0013395 infores:hetionet CHEBI:10124 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0006142 infores:hetionet CHEBI:15552 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0036690 infores:hetionet UMLS:C0017797 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0034886 infores:hetionet CAID:CA386493225 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493225 MONDO:0009861 PMID:22698810 Pathogenic PP4_Moderate, PM2, PM3, PP3, PS3 PM5, PS1 The c.1144T>C (p.Phe382Leu) variant in PAH has been reported in 1 homozygous individual with mild HPA and BH4 deficiency excluded (PP4_Moderate; 0.5 points; PMID: 21147011) and has also been reported in a patient from southern Italy (PMID: 17096675; PMID: 18346471) with mild hyperphenylalanemia (serum Phe 182 umol/L; not specified if BH4 deficiency excluded), who harbored it in presumed trans with the p.R252W variant (Pathogenic in ClinVar by 10 submitters, variation ID 584) (0.5 points) (PM3, 1 point total). This variant was absent in population databases (PM2). Expressed in COS-1 cells, this variant has 18% enzyme activity (PS3; PMID: 22698810). Computational prediction tools suggest that the variant may impact the protein (REVEL = 0.89; PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP4_moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493225/MONDO:0009861/006 2021-02-13 2023-01-28 Autosomal recessive inheritance HP:0000007 Supports GO:1905292 biolink:causes GO:0060485 infores:ubergraph knowledge_assertion manual_agent GO:1905292 GO:0060485 CHEBI:68478 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0877517 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0242350 infores:hetionet CHEBI:8430 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0003708 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027769 infores:hetionet CHEBI:6887 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013404 infores:hetionet CHEBI:63580 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004093 infores:hetionet CAID:CA414434494 biolink:causes MONDO:0010604 infores:clingen CAID:CA414434494 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PP3, PP4_Moderate The F9 c.86C>T (p.Thr29Ile) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.1.1 meeting criteria for PM2_Supporting. This missense variant has a REVEL score of 0.659 (>0.6) meeting criteria for PP3. At least 4 mild hemophilia B patients, including 1 female patient, are reported in the literature (PMID: 29296726) meeting F9 phenotype criteria for PS4_moderate and PP4_moderate. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414434494/MONDO:0010604/080 2024-11-01 2025-03-07 X-linked inheritance HP:0001417 Supports CHEBI:63637 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0151878 infores:hetionet CHEBI:9907 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013447 infores:hetionet CHEBI:63611 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020433 infores:hetionet CAID:CA401369859 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369859 MONDO:0009290 PMID: Likely Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM3_Strong PP3, PM5, BP4 "The NM_000152.5:c.1905C>A variant in GAA is predicted to result in the substitution of asparagine by lysine at amino acid 635 (p.Asn635Lys). The variant has been identified in four probands from Brazil, three of whom were diagnosed with infantile onset Pompe disease (IOPD), with symptoms that included hypotonia, cardiomegaly, and respiratory distress, and death in the first year of life. The fourth patient has late onset Pompe disease (LOPD). No GAA activity was available for any of these indviduals (PMID: 19588081) (PP4). Two of these patients have been reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP; c.2501_2502delCA (p.Thr834Argfs48Ter) in a patient with IOPD, and c.-32-3C>A in a patient with LOPD. The phase was not confirmed. A further two patients are homozygous for the variant (PMID: 19588081)(PM3_Strong). This variant results in 0% GAA activity in cells and 0.1% GAA activity in medium and is abnormally synthesized and processed when expressed in COS-7 or HEK293T cells, and was classified as Class B (""potentially less severe"") by Kroos et al, 2012 (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.61 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v4.0. is 0.00002522 (1/39644 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Another missense variant at the same amino acid position, c.1903A>G (p.Asn635Asp), has been reported in individuals with Pompe disease (PMID: 37087815, Clinical diagnostic laboratory). The evidence from c.1905C>A (p.Asn635Lys) will be used to support the classification of c.1903A>G (p.Asn635Asp) and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 632823). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3, PS3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on November 21, 2023)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369859/MONDO:0009290/010 2023-11-21 2023-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UMLS:C0009315 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0036572 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0002622 infores:hetionet CHEBI:31176 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0020649 infores:hetionet CHEBI:63581 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0086565 infores:hetionet CHEBI:17303 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013404 infores:hetionet CHEBI:3561 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0004604 infores:hetionet CAID:CA343774510 biolink:causes MONDO:0013144 infores:clingen CAID:CA343774510 MONDO:0013144 PMID: Pathogenic PS4, PP1_Strong, PP3, PP4, PM2_Supporting The NM_000488.4(SERPINC1):c.857A>C variant predicts a missense change at position 286, from Glutamine to Proline. The variant has been reported in at least 5 probands with AT deficiency along with multiple segregations in families in the literature (PMID: 28317092, 32862410). This missense variant is completely absent in gnomAD (v2.1.1 and v3.1.1). It has a REVEL score of 0.898 meeting the PP3 code. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_Strong, PS4, PP3, PP4, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343774510/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9086 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0003123 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0750272 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0750272 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0001824 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0032961 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853692 infores:hetionet NCBIGene:3339 biolink:causes MONDO:0100435 infores:monarchinitiative not_provided not_provided HGNC:5273 MONDO:0100435 uuid:4ff8dccf-0915-4e8a-bbff-5ea45eba4922 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101853 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151904 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0162830 infores:hetionet CHEBI:9150 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C1368065 infores:hetionet CHEBI:4356 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0039231 infores:hetionet CHEBI:31236 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0152031 infores:hetionet CHEBI:102216 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0036572 infores:hetionet CAID:CA074227 biolink:causes MONDO:0018493 infores:clingen CAID:CA074227 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 3283 of the RYR1 protein, p.(Arg3283Gln). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000087, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 not implemented (PMID:23558838). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.527 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA074227/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:94686 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0010200 infores:hetionet CHEBI:8356 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235266 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0031046 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235639 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015469 infores:hetionet CHEBI:27882 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0036974 infores:hetionet CHEBI:51137 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0036974 infores:hetionet CHEBI:32315 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002170 infores:hetionet CAID:CA180973 biolink:causes MONDO:0021060 infores:clingen CAID:CA180973 MONDO:0021060 PMID:19506109PMID:26817465PMID:26817465 Pathogenic PS2, PS4, PM2, PP3, PP2 PS1, PS3, PM5, PM4, PM1, BS4, BS3, BS1, BP7, BP5, PM6, BS2, BP3, BP4, BP1, BP2, BA1 The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4, PM2, PP3, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180973/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:75722 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0080276 infores:hetionet CHEBI:2904 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0024141 infores:hetionet CHEBI:84500 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C2938875 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0006145 infores:hetionet CHEBI:7824 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0438717 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0877232 infores:hetionet CHEBI:7466 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0036508 infores:hetionet CHEBI:7565 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0011168 infores:hetionet CHEBI:404903 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0031256 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0017160 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0021053 infores:hetionet CHEBI:37941 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018681 infores:hetionet CHEBI:8093 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0018681 infores:hetionet CHEBI:8077 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C2830004 infores:hetionet CHEBI:135679 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0547030 infores:hetionet UMLS:C0120107 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018965 infores:hetionet CHEBI:50648 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0033774 infores:hetionet CHEBI:37333 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0018681 infores:hetionet CHEBI:584020 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0036572 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0699893 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0020517 infores:hetionet CHEBI:367163 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014724 infores:hetionet NCBIGene:8028 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:16063 MONDO:0018874 uuid:7d8334c6-dc03-4dc0-8a3e-189b80441778 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10100 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0042384 infores:hetionet CHEBI:8107 biolink:causes MONDO:0019170 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0031036 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0851341 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040479 infores:hetionet NCBITaxon:226665 biolink:causes MONDO:0000231 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:226665 MONDO:0000231 CHEBI:23765 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151827 infores:hetionet CAID:CA410148531 biolink:causes MONDO:0100083 infores:clingen CAID:CA410148531 MONDO:0100083 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1024A>G (p.Ile342Val) is a missense variant which has a REVEL score < 0.50 (0.065) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148531/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63623 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0015967 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0023530 infores:hetionet CHEBI:9763 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0026821 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0036835 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0036835 infores:hetionet CAID:CA390864985 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864985 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting BP2, BA1, PP3, PP1, PP4, BS2, PM5, PS3, PS1, PS2, PS4, BS1, BS3, BS4 The NM_177438.2:c.5308G>C variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 1770 (p.Asp1770His). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614160 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.492, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). This variant resides within the RNase IIIb domain of DICER1 (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting. (Bayesian Points: 1, VCEP specifications version 1.4.0, 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864985/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144093 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0086543 infores:hetionet CHEBI:8207 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0004245 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020456 infores:hetionet CAID:CA396464802 biolink:causes MONDO:0007648 infores:clingen CAID:CA396464802 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1569T>A p.(Tyr523Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396464802/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:41423 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0497247 infores:hetionet CHEBI:119486 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0004604 infores:hetionet CHEBI:8107 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027066 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0948594 infores:hetionet CHEBI:6710 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0033774 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0004936 infores:hetionet CHEBI:68584 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0027947 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0020517 infores:hetionet CHEBI:4710 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0012569 infores:hetionet CHEBI:5138 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013378 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020550 infores:hetionet CHEBI:91834 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0012833 infores:hetionet CAID:CA410149642 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149642 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP2, BP1, BP3, BA1, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM5, PM4, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.928A>T (p.Met310Leu) is a missense variant with a REVEL score <0.50 (0.087) and a SpliceAI score ≤ 0.20 (Donor Loss 0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149642/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7824 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151603 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0392176 infores:hetionet CHEBI:4530 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0009806 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0236051 infores:hetionet CHEBI:15407 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0015230 infores:hetionet CAID:CA1139768925 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139768925 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting The nonsense variant c.1176dup (p.Asn393Ter) occurs in exon 11 and is predicted to result in NMD. The variant is absent from population databases. At least one classical PKU patient has been reported (PMID: 20188615) homozygous for this variant. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139768925/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014868 infores:hetionet CHEBI:36791 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0041296 infores:hetionet NCBIGene:6210 biolink:causes MONDO:0032670 infores:monarchinitiative not_provided not_provided HGNC:10389 MONDO:0032670 uuid:42fb2b9a-41fa-42cf-8b7f-44f82f84bb71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0015967 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0023646 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0948594 infores:hetionet CHEBI:93635 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C2830004 infores:hetionet NCBIGene:11020 biolink:causes MONDO:0014447 infores:monarchinitiative not_provided not_provided HGNC:18626 MONDO:0014447 uuid:9bb53b8e-c66f-4582-b416-57a70228fda4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0007222 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027651 infores:hetionet CHEBI:3207 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0003862 infores:hetionet CAID:CA9302036 biolink:causes MONDO:0010938 infores:clingen CAID:CA9302036 MONDO:0010938 PMID: Uncertain Significance PM2_Supporting PM6, BS3, BS4, PS1, PS3, PS2, PM5, PM1, PM3, PP1, PP4, BS2 The c.896T>C (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Valine by Alanine at amino acid 299 (p.Val299Ala).The filtering allele frequency (the upper threshold of the 95% CI of 7/24876) of the c.896T>C variant in JAK3 is 0.00002138 for African/African American chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with JAK3-related conditions. In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting. ( (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9302036/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:47426 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1291078 infores:hetionet CHEBI:41774 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0700345 infores:hetionet CAID:CA10603953 biolink:causes MONDO:0100368 infores:clingen CAID:CA10603953 MONDO:0100368 PMID: Pathogenic PM3_Strong, PM1, PP3_Moderate, PP4, PP1, PM2_Supporting NM_000329.3(RPE65):c.331C>T is a missense variant causing substitution of proline with serine at position 111. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00003249, with 4 alleles / 41440 total alleles in the African/African American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.911, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is located within a well-established functional domain (residues 107-125, PMID: 36265895) required for proper localization of the RPE65 protein to the ER membrane (PM1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5, PMID: 34492281). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.2:c.11+5G>A or NM_000329.2:c.1451G>A (p.Gly484Asp) variants confirmed in trans (2 pts, PMIDs: 34492281), which were previously classified as pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts) with onset before age 1 year (1 pt), reduced ERG responses from rods (0.5 pts) and cones (1 pt), salt and pepper pigmentation of the fundus (0.5 pts), visual fields decreased (1 pt), visual acuity reduced (1 pt), and night blindness (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 points, PMID: 34492281, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PP1; PMID: 34492281). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603953/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:72296 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0025323 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0342579 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0948594 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0011991 infores:hetionet CHEBI:135351 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C1384353 infores:hetionet CHEBI:51041 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085631 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0232452 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232452 infores:hetionet CHEBI:64312 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0700590 infores:hetionet CAID:CA229734 biolink:causes MONDO:0009861 infores:clingen CAID:CA229734 MONDO:0009861 PMID:20920871 Uncertain Significance PM2, PP4, PP3 PM5 The c.740G>A (p.Gly247Asp) variant in PAH was reported in 2 patients with classic PKU. PMID: 20920871. This varant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.975. It has an extremely low frequency in ExAC/gnomAD (MAF 0.00003). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229734/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:18248 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0021368 infores:hetionet CHEBI:84883 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0231218 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0011609 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0795692 infores:hetionet CHEBI:5384 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C2697368 infores:hetionet CAID:CA227880 biolink:causes MONDO:0100438 infores:clingen CAID:CA227880 MONDO:0100438 PMID:27268253 Benign BS2, BA1 BS3, PP3, BP4 NM_014336.5(AIPL1):c.341C>T (p.Thr114Ile) is a missense variant in exon 3 of 6 that is predicted to replace threonine with isoleucine at amino acid p.114. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.05653, with 4,351 alleles / 75,064 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). This variant has been found in the homozygous state in 127 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.469, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 for PP3 and above the threshold of <0.290 for BP4. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which predicts a low or indeterminate impact on splicing. Neither PP3 nor BP4 is met. The variant exhibited >90% enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, as well as cytoplasmic and nuclear localization similar to the wild-type (PMID: 27268253), however, these assays are not approved to meet BS3_Supporting. In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1 and BS2. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227880/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:68595 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0004093 infores:hetionet CHEBI:3506 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0002994 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0750016 infores:hetionet CHEBI:70735 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0007859 infores:hetionet CHEBI:63630 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011175 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0233472 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0042487 infores:hetionet CHEBI:63717 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0151578 infores:hetionet CAID:CA2499222909 biolink:causes MONDO:0015152 infores:clingen CAID:CA2499222909 MONDO:0015152 PMID: Likely Pathogenic PVS1, PM2_Supporting PM5, PM4, PM1, BA1, BP1, BP4, BP3, PP2, PP3, BP7, BP5, BS1, BS3, PS1, PS3 The NM_000070.3: c.219del p.(Leu74PhefsTer53) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/24 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499222909/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6904 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0600260 infores:hetionet CHEBI:3699 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0231218 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0521839 infores:hetionet CHEBI:16914 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0347390 infores:hetionet CHEBI:63616 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0002170 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0162316 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0268732 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0268732 infores:hetionet CHEBI:30830 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020443 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0041969 infores:hetionet CHEBI:50275 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0241136 infores:hetionet CHEBI:71940 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0030252 infores:hetionet CHEBI:472657 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0016204 infores:hetionet CHEBI:15365 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0040034 infores:hetionet CAID:CA229654 biolink:causes MONDO:0009861 infores:clingen CAID:CA229654 MONDO:0009861 PMID:23690520 Pathogenic PVS1, PP4_Moderate, PM2, PM3_Strong The c.612T>G (p.Tyr204Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2). It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): with a Sicilian PKU case with BH4 deficiency excluded (PMID: 8268925) (PP4_Moderate); in a German PKU case (PMID: 10394930); in one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) and 2 additional mild PKU patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811). It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758). Classification: PathogenicSupporting criteria: PVS1, PM2; PM3_Strong; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229654/MONDO:0009861/006 2020-05-08 2020-05-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9927 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0851341 infores:hetionet CHEBI:2453 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0018681 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0021400 infores:hetionet CHEBI:6715 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0021177 infores:hetionet CAID:CA367401327 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401327 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PM1, PP4 The c.620T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to glutamic acid at codon 207 (p.(Val207Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.99, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 19790256). Another missense variant, c.619G>T p.Val207Leu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.620T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401327/MONDO:0015967/086 2025-01-29 2025-01-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:3699 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0015230 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0019158 infores:hetionet CHEBI:144551 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0020580 infores:hetionet CAID:CA292973 biolink:causes MONDO:0021060 infores:clingen CAID:CA292973 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1650G>A (p.Ala550=) variant in the PTPN11 gene is 0.067% (13/11548) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA292973/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:101853 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0232602 infores:hetionet CHEBI:41237 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00676 UMLS:C0085624 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0021400 infores:hetionet CAID:CA1251397 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251397 MONDO:0013144 PMID: Likely Benign BP7, BP4 BS1, PM2 The c.594T>C (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Tyr198=). SpliceAI predicts no splicing impact for this variant meeting BP4. The variant is not predicted to cause a splicing impact and the nucleotide is weakly/moderately conserved with a PhyloP score of 0.025 meeting BP7 criteria (PhyloP < 0.1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BP4, BP7. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251397/MONDO:0013144/084 2024-08-16 2024-08-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3216 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0009782 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0039070 infores:hetionet CHEBI:135736 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0032290 infores:hetionet CHEBI:10124 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0232849 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0009319 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0234458 infores:hetionet CHEBI:7447 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0031542 infores:hetionet CAID:CA198822 biolink:causes MONDO:0010726 infores:clingen CAID:CA198822 MONDO:0010726 PMID: Pathogenic PM1, PP3, PM6, PS4, PM2_Supporting BP4 The p.Leu100Val (NM_004992) variant has been observed in at least 5 other individuals with Rett Syndrome (PMID: 22476991, 16672765, 12966522, 11913567, 11055898, RettBASE) (PS4). The p.Leu100Val variant occurs in the well-characterized Methyl-DNA binding [MBD] functional domain of the MECP2 (PM1). The p.Leu100Val variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Leu100Val variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with mild atypical Rett syndrome (PMID: 12966522)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu100Val variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM1, PM6, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA198822/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:3219 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042035 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0023533 infores:hetionet CHEBI:77260 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0438142 infores:hetionet CHEBI:10127 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0542571 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0232492 infores:hetionet CHEBI:4911 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0017178 infores:hetionet CHEBI:2659 biolink:causes UMLS:C1140716 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C1140716 infores:hetionet NCBIGene:8558 biolink:causes MONDO:0044324 infores:monarchinitiative not_provided not_provided HGNC:1770 MONDO:0044324 uuid:377d29ec-17f9-4e83-a442-d602d89e0e45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0009376 infores:hetionet CHEBI:134936 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0006277 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1096343 infores:hetionet CHEBI:91834 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0037036 infores:hetionet CHEBI:49662 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0030193 infores:hetionet CHEBI:15367 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235309 infores:hetionet CHEBI:7936 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0013428 infores:hetionet CHEBI:84500 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037672 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0033777 infores:hetionet CHEBI:3423 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0042029 infores:hetionet CHEBI:10119 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085649 infores:hetionet CHEBI:9907 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0037317 infores:hetionet CHEBI:144093 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0030554 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038454 infores:hetionet CHEBI:7852 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0022107 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026946 infores:hetionet CHEBI:15765 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0236075 infores:hetionet CHEBI:3207 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0025874 infores:hetionet CHEBI:135736 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015468 infores:hetionet CHEBI:70735 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0151578 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0162429 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0456909 infores:hetionet GO:0035033 biolink:causes GO:0006338 infores:ubergraph knowledge_assertion manual_agent GO:0035033 GO:0006338 CHEBI:9667 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0018790 infores:hetionet CHEBI:167638 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0011991 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0242656 infores:hetionet CHEBI:9086 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042023 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0017178 infores:hetionet CHEBI:46295 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0014869 infores:hetionet CHEBI:53760 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0006277 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0236106 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0236106 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151596 infores:hetionet UMLS:C0120107 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0149871 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0233414 infores:hetionet CHEBI:8884 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0151605 infores:hetionet CHEBI:6759 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0521591 infores:hetionet CHEBI:5864 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0743400 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0027765 infores:hetionet CHEBI:135276 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0027497 infores:hetionet CHEBI:5141 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0030193 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0243026 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0005586 infores:hetionet CHEBI:9168 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0080274 infores:hetionet CAID:CA340942 biolink:causes MONDO:0044970 infores:clingen CAID:CA340942 MONDO:0044970 PMID:35699829 Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS4, PS3 The m.4160T>C (p.L285P) variant in MT-ND1 has been reported in three unrelated individuals to date (PMIDs: 2018041, 22258525, 35699829), however only one case was included in this curation (PMID: 35699829). This individual had Leber Hereditary Optic Neuropathy (LHON) and dystonia, and the variant was present at 80.2% in blood, 90.8% in urine, and 81.7% in buccal. This variant occurred de novo in this individual as it was absent in blood, buccal, and urine samples from his mother and sister (PM6_supporting, PMID: 35699829). One of the other reported families with this variant had LHON however they also had the m.14484T>C variant, one of the three most common variants associated with LHON (PMIDs: 2018041, 29249004), and therefore was not included in this curation. Another individual was reported to have developmental delay, vision involvement, peripheral nervous system involvement, and muscle involvement however the m.4160T>C variant was only present at 11% heteroplasmy (PMID: 22258525). Given the low heteroplasmy, this case was also excluded from this curation. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.89 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are single occurrences in population databases, however these are from reported affected individuals (PM2_supporting). Cybrid studies were performed however were not considered in this curation given the presence of other mitochondrial DNA variants (PMIDs: 35699829, 28455970). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PM6_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340942/MONDO:0044970/015 2024-01-08 2024-04-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6538 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0011570 infores:hetionet CHEBI:50275 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0025222 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1096001 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1096001 infores:hetionet CHEBI:40009 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0036572 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0234913 infores:hetionet CHEBI:3175 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0155169 infores:hetionet CHEBI:44915 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0000729 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0042109 infores:hetionet CHEBI:6715 biolink:causes UMLS:C1096340 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1096340 infores:hetionet CHEBI:8863 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015732 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151970 infores:hetionet CHEBI:75722 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151662 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0004096 infores:hetionet CHEBI:50729 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0522055 infores:hetionet CAID:CA3054205290 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054205290 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.-9_14dup (p.Ser5ArgfsTer22) is a frameshift variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is in an exon that is absent from RUNX1 isoform a and b (c.1-c.97 as per VCEP specifications) (PVS1_NA). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054205290/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8382 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020458 infores:hetionet CHEBI:64355 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0010200 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0032584 infores:hetionet CHEBI:4672 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0549410 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235315 infores:hetionet NCBIGene:7284 biolink:causes MONDO:0012534 infores:monarchinitiative not_provided not_provided HGNC:12420 MONDO:0012534 uuid:4ee8bf3e-e64f-4d0a-86fb-3cb71187df0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16606085 biolink:causes MONDO:0015967 infores:clingen CAID:CA16606085 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM1_Supporting, PS4, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 The c.686G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 229 (p.(Arg229Gln)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies in both and positive C-peptide in one) (PP4_Moderate; PMID: 27913849). The c.686G>A variant was identified in 27 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29927023, 28395978, 27913849, 9032114, 18513305, internal lab contributors). Functional studies demonstrated the p.Arg229Gln protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 12530534, 12574234). Lastly, this variant segregated with diabetes, with at least 17 informative meioses in at more than three families with MODY (PP1_Strong; PMID: 18513305; internal lab contributors). In summary, c.686G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PS3_Supporting, PP1_strong, PS4, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606085/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports UNII:2N4O9L084N biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0314719 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0851647 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0851647 infores:hetionet CHEBI:520985 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0018991 infores:hetionet CHEBI:71940 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0007859 infores:hetionet CHEBI:135342 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0549622 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0009450 infores:hetionet CAID:CA2580098849 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098849 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.806-8C>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.05) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098849/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:48273 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0234192 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0314719 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020456 infores:hetionet CHEBI:9398 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0007859 infores:hetionet CHEBI:63598 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030196 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020649 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0847033 infores:hetionet CHEBI:7476 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C3665347 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C3665386 infores:hetionet CHEBI:45081 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0038325 infores:hetionet CHEBI:7931 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0013404 infores:hetionet CAID:CA401360858 biolink:causes MONDO:0009290 infores:clingen CAID:CA401360858 MONDO:0009290 PMID:31342611PMID:22252923 Pathogenic PM2, PVS1, PP4 This variant, c.352C>T (p.Gln118Ter), is a nonsense variant that is predicted to cause nonsense mediated decay and lack of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in a patient with Pompe disease that meets the ClinGen LSD VCEP’s PP4 specifications (PMID 22252923, personal communication). There is a ClinVar entry for this variant (Variation ID: 553894; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401360858/MONDO:0009290/010 2020-05-19 2020-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:100246 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0009806 infores:hetionet CHEBI:9332 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0002874 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0018799 infores:hetionet CHEBI:5118 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1168034 infores:hetionet NCBIGene:2783 biolink:causes MONDO:0859185 infores:monarchinitiative not_provided not_provided HGNC:4398 MONDO:0859185 uuid:02c013e5-feac-4c11-9a24-73aef41a58aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5159 biolink:causes MONDO:0011150 infores:monarchinitiative not_provided not_provided HGNC:8804 MONDO:0011150 uuid:c67eb6f6-a53e-47b4-9635-c1545d122ead biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0016053 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0042075 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0007628 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0007628 uuid:76e8c5cd-3faa-40cb-95e6-e833d0d135b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0026896 infores:hetionet CHEBI:6933 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0851578 infores:hetionet NCBITaxon:127916 biolink:causes MONDO:0000307 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:127916 MONDO:0000307 CHEBI:8382 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0003467 infores:hetionet CHEBI:63637 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0033774 infores:hetionet CHEBI:5959 biolink:causes NCIT:C50599 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0700363 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0553704 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0235969 infores:hetionet CHEBI:6904 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0039231 infores:hetionet CHEBI:8356 biolink:causes HP:0000011 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0005697 infores:hetionet NCBIGene:339983 biolink:causes MONDO:0013549 infores:monarchinitiative not_provided not_provided HGNC:26742 MONDO:0013549 uuid:e75ba7af-b3ad-4c96-97f6-0e02ff6e1d12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031154 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0024115 infores:hetionet CHEBI:100241 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0039231 infores:hetionet CHEBI:32315 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0028961 infores:hetionet CHEBI:31236 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039070 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0574067 infores:hetionet CHEBI:47381 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0000731 infores:hetionet CHEBI:4325 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0687713 infores:hetionet CAID:CA10014566 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014566 MONDO:0011071 PMID: Uncertain Significance BS3_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.227G>A (p.Arg76His) is a missense variant with a REVEL score ≥ 0.88 (0.92) (PP3). In Koh et al 2013, they measured transcriptional activity by Luciferase reporter assay and showed a subnormal activity (>80% compared to WT) (BS3_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, BS3_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014566/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:6426 biolink:causes MONDO:0957583 infores:monarchinitiative not_provided not_provided HGNC:10780 MONDO:0957583 uuid:adfeb6aa-5d7f-41a8-a7ef-4bdd8dbb62ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3213 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0018939 infores:hetionet CHEBI:9907 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0404521 infores:hetionet CHEBI:8024 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0035455 infores:hetionet CHEBI:40303 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0011633 infores:hetionet CHEBI:61390 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0149745 infores:hetionet CHEBI:8764 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085593 infores:hetionet CHEBI:2379 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0043094 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020039 infores:hetionet CHEBI:5165 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0004134 infores:hetionet CHEBI:6437 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0232462 infores:hetionet GO:1903371 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1903371 GO:0010256 CHEBI:44423 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0027651 infores:hetionet CAID:CA376064481 biolink:causes MONDO:0011225 infores:clingen CAID:CA376064481 MONDO:0011225 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.140T>A (p.Leu47Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376064481/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9571 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0234133 infores:hetionet CHEBI:6822 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0036572 infores:hetionet CAID:CA228706 biolink:causes MONDO:0015630 infores:clingen CAID:CA228706 MONDO:0015630 PMID:20345715PMID:19687512PMID:25051961 Likely Pathogenic PP3, PP4, PM2_Supporting, PS3 PP1, PS4 NM_000552.5(VWF):c.5235G>T is a missense variant in VWF predicted to cause substitution of tryptophan by cysteine at amino acid 1745 in the collagen-binding A3 domain. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/1180040 alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.757, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant was diagnosed with VWD Type 2M and displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of normal high-MW multimer pattern and abnormal collagen binding assay (Reduced VWF:CB / VWF:Ag ratio of 0.3 VWF to both type III and type I collagen), which together are specific for VWD type 2M. (PP4, PMID: 19687512). However, the patient's VWF:RCo was impaired in proportion to the decreased amount of VWF:Ag, so that VWF:RCo / VWF:Ag ratio was 0.9 (approximately normal). A hydrodynamic mouse model expressing p.Trp1745Cys showed decreased expression of the variant (VWF:Ag), but did not test other parameters relevant to the VWD Type 2M phenotype (Figure 4, PMID: 25051961). Collagen binding assay performed with the p.Trp1745Cys recombinant mutant and wild-type vWF expressed by HEK-293 cells showed decreased binding to both Type I and Type III collagens in an ELISA-based format, indicating that this variant has a damaging effect on protein function (PS3; PMID: 19687512, PMID: 20345715, PMID: 25051961). In summary, this variant meets the criteria to be classified as likely pathogenic for von Willebrand disease type 2M. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PP4, PM2_Supporting, PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228706/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3506 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0030312 infores:hetionet CHEBI:45409 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0001925 infores:hetionet CHEBI:135930 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0851578 infores:hetionet CHEBI:8888 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0021177 infores:hetionet CHEBI:6950 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0233407 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0021400 infores:hetionet CHEBI:10124 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0004604 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0948594 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0259749 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009450 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004947 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1292769 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018213 infores:hetionet CHEBI:27690 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0340865 infores:hetionet CHEBI:3423 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0004134 infores:hetionet CHEBI:47781 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0004134 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0854382 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0233472 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0001824 infores:hetionet CHEBI:71940 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0008031 infores:hetionet CHEBI:68478 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0149745 infores:hetionet CHEBI:63577 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0687713 infores:hetionet CHEBI:6015 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0036973 infores:hetionet CHEBI:3499 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0011603 infores:hetionet CHEBI:4672 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0232462 infores:hetionet CHEBI:8024 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0008031 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0152029 infores:hetionet CHEBI:521033 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0002994 infores:hetionet CHEBI:3242 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0027424 infores:hetionet GO:2000356 biolink:causes GO:0072194 infores:ubergraph knowledge_assertion manual_agent GO:2000356 GO:0072194 CHEBI:46295 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0017601 infores:hetionet CAID:CA287434246 biolink:causes MONDO:0008723 infores:clingen CAID:CA287434246 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4(ACADVL):c.192dup (p.Pro65Thrfs*7) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 3/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated November 12, 2021 and the recurated classification was approved by the expert panel on February 27, 2024. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287434246/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9014 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0019080 infores:hetionet CAID:CA658795289 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795289 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3 The NM_000152.5:c.2431dup (p.Leu811ProfsTer73) variant in GAA is a frameshift variant in exon 17 predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in muscle sample (PMID: 10737124) (PP4_moderate). This individual was compound heterozygous for the variant and the common pathogenic IVS1 variant, phase unknown (PM3). Another two individuals have been reported with deficient GAA activity but results were not provided; these individual were described as having cross-reactive immunologic material (CRIM) negative classic infantile-onset Pompe disease (PMID: 27927596, 36572041) and one patient was reported to be on enzyme replacement therapy (PMID: 27927596). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000016 (2/1179844 alleles) in the Non-Finnish European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1322950). Of note, this variant has been described in the literature using historical nomenclature, including c.2432insC (PMID:10737124) and c.2431insC (PMID: 27927596); for the purpose of this summary, current HGVS nomenclature was used. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PVS1, PP4_moderate, PM3, PM2_supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 1, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795289/MONDO:0009290/010 2025-07-01 2025-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8207 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0428977 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0152027 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0000833 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0948089 infores:hetionet CAID:CA255665 biolink:causes MONDO:0018947 infores:clingen CAID:CA255665 MONDO:0018947 PMID:22068590 Pathogenic PP3, PM2_Supporting, PS3, PS4_Moderate, PP1_Strong BA1, BP4, BS1, PM5 The c.205C>T (NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)) variant in MTM1 is a missense variant predicted to cause substitution of Arg by Cys at amino acid 69. The variant was found in at least 3 probands from three families with X-linked centronuclear myopathy (PS4_Moderate; PMIDs: 9285787, 15811014). The variant has been reported to segregate with X-linked centronuclear myopathy in 6 affected individuals from one family (PP1_strong; PMID: 15811014). The variant specific model in mice showed muscle weakness and low myotubularin protein concentrations, indicating that this variant impacts protein function (PS3; PMID: 22068590; Pierson et al., 2012). The computational predictor REVEL gives a score of 0.825, which is above the threshold of 0.7, set by the Congenital Myopathies VCEP, evidence that correlates with impact to MTM1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for x-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: (PS4_Moderate, PP1_Strong, PS3, PP3, PM2_Supporting; Version 1, 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA255665/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:51450 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0028084 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0042109 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0024117 infores:hetionet CHEBI:45599 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0700590 infores:hetionet CHEBI:8768 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0015371 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0149931 infores:hetionet CHEBI:474180 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0018965 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0333650 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0333650 infores:hetionet CHEBI:4514 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0013144 infores:hetionet CHEBI:75722 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0022107 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0005741 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0035078 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029878 infores:hetionet CHEBI:53691 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0002994 infores:hetionet CHEBI:3756 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0032617 infores:hetionet CHEBI:15366 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB03166 UMLS:C0001122 infores:hetionet CHEBI:80630 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0030554 infores:hetionet CHEBI:145499 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0026826 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0042769 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0851341 infores:hetionet CHEBI:15544 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C1142412 infores:hetionet CHEBI:4868 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0003123 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151602 infores:hetionet CHEBI:135193 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0037274 infores:hetionet CHEBI:5893 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0017979 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0042109 infores:hetionet CHEBI:85161 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0340865 infores:hetionet CHEBI:9674 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C1443060 infores:hetionet CHEBI:3011 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0022354 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C1096444 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1096444 infores:hetionet CHEBI:4888 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0011603 infores:hetionet CHEBI:3077 biolink:causes MONDO:0001539 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0035321 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0021053 infores:hetionet CHEBI:6339 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0034642 infores:hetionet CHEBI:261649 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0018681 infores:hetionet CHEBI:119486 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235031 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0239295 infores:hetionet CHEBI:171719 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0028077 infores:hetionet CHEBI:7983 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0027769 infores:hetionet CHEBI:50567 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0004238 infores:hetionet CHEBI:4027 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0206061 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0151773 infores:hetionet CHEBI:63612 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0010200 infores:hetionet NCBIGene:9653 biolink:causes MONDO:0030966 infores:monarchinitiative not_provided not_provided HGNC:5193 MONDO:0030966 uuid:11f0280f-ffe3-437f-ad1a-ab111955183e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0004936 infores:hetionet CHEBI:63631 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0231528 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0022116 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0343863 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0948594 infores:hetionet CHEBI:50861 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0033774 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0018802 infores:hetionet CHEBI:2950 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0011603 infores:hetionet CAID:CA067959 biolink:causes MONDO:0018493 infores:clingen CAID:CA067959 MONDO:0018493 PMID: Uncertain Significance PM1, BP2 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 209 of the RYR1 protein, p.(Glu209Lys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual also carried a pathogenic variant in RYR1 (p.Arg2336His, in cis) which precludes the use of PS4 (PMID:21455645). Additionally, the presence of a pathogenic variant in cis is considered supporting evidence for benign status, BP2. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.711 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, BP2. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA067959/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true UNII:9430ZR8ZAN biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0342579 infores:hetionet CHEBI:85161 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0085593 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0035309 infores:hetionet CHEBI:6402 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013491 infores:hetionet CHEBI:63618 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0018834 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0855242 infores:hetionet CHEBI:144551 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0016199 infores:hetionet CHEBI:5001 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0023530 infores:hetionet GO:0099150 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0099150 GO:0007275 CHEBI:63620 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0039520 infores:hetionet CHEBI:8888 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0917801 infores:hetionet CAID:CA226360 biolink:causes MONDO:0100437 infores:clingen CAID:CA226360 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.141T>G (p.Ser47=) is a synonymous variant in exon 2 of RPGR (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a frequency of 0.0004126 among hemizygous individuals, with 162 variant alleles / 392,654 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226360/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Contradicts true CAID:CA410208104 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208104 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant affects a residue within the Runt Homology domain (AA 89-294) but does not impact a residue which has been established as a hotspot (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208104/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16714 biolink:causes UMLS:C0948429 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0948429 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0549475 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0242350 infores:hetionet GO:0060020 biolink:causes CL:0000644 infores:ubergraph knowledge_assertion manual_agent GO:0060020 CL:0000644 CHEBI:17334 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0003578 infores:hetionet CAID:CA91167249 biolink:causes MONDO:0001586 infores:clingen CAID:CA91167249 MONDO:0001586 PMID: Likely Pathogenic PP3_Moderate, PM3, PP4, PM2_Supporting PS1, PM5, PM1 NM_000203.5:c.539G>C IDUA variant is a missense variant predicted to cause substitution of tryptophan by serine at amino acid 180 (p.Trp180Ser). This variant has been detected in at least four probands with MPS I. Of these individuals, three are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen LD VCEP; all phase unconfirmed. The second variant was either c.46_57del (p.Ser16_Ala19del) (P by LD VCEP, Clinical Lab, 0.5 points), c.1861C>T (p.Arg621Ter) (LP by LD VCEP, Clinical Lab, 0.25 points), or c.1205G>A (p.Trp402Ter) (P by LD VCEP, PMID: 22976768, 25098213, possibly the same patient in both publications, 0.5 points). One individual is homozygous for the variant (Clinical Lab, 0.5 points). Total 1.75 points (PM3). At least one proband had reported deficiency of IDUA enzyme activity, and urinary dermatan and heparan sulfate elevation above normal range (PMID: 25098213; PMID: 22976768, Clinical Lab) (PP4). The highest population minor allele frequency in Genomes gnomAD v4.1.0 is 0.00001666 (1/60010 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2_Supporting). The computational predictor REVEL gives a score of 0.959 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID:1021968). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PM3, PP3_moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA91167249/MONDO:0001586/091 2025-05-07 2025-05-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4636 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0040822 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005073 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027962 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0855242 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0007760 infores:hetionet CHEBI:3640 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0085631 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0233472 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042376 infores:hetionet CHEBI:4466 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C3203358 infores:hetionet CAID:CA8815610 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815610 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5, PM3_Strong, PS3_Supporting The NM_000152.5:c.2105G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 702 (p.Arg702His). At least 3 unrelated patients were noted to have deficient GAA activity but results were not provided (PMID: 26310554, 30897595, 28394184). Two patients are described as having IOPD with clinical symptoms consistent with IOPD reported in one (PMID: 26310554). One patient is described as having juvenile-onset Pompe disease with deficient GAA (value not provided) (PMID: 18211760). Another patient is reported to have deficient GAA and late-onset Pompe disease (PMID: 30897595) (PP4_Moderate). At least one patient is described as having this variant in trans with a variant classified as likely pathogenic by the ClinGen Lysosomal Diseases (LD) VCEP (c.796C>T, p.Pro266Ser; ClinVar Variation ID Variation ID: 556117; SCV002540664.1) (PMID: 18211760). At least two patients have been reported with this variant in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen LD VCEP (c.2297A>C, p.Tyr766Ser, ClinVar Variation ID: Variation ID: 420102, SCV002540647.1, and c.2238G>C, p.Trp746Cys, ClinVar Variation ID: Variation ID: 265160, SCV002032122.1), phase unconfirmed for both (PMID: 28394184 and 30897595) (PM3_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 cells resulted in 5% wild type GAA activity in medium and 13% residual activity in cells with evidence of abnormal synthesizing and processing (PMID: 18425781) leading the variant to be described as Class D “potentially mild” indicating that this variant may impact protein function (PS3_supporting). Another missense variant (c.2105G>T, p.Arg702Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP (ClinVar Variation ID: Variation ID: 92472)(PM5). There is a ClinVar entry for this variant (Variation ID: 426278). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_strong, PM5, PP4_moderate, PM2_supporting, PP3, PS3_supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815610/MONDO:0009290/010 2024-03-05 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9927 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0027947 infores:hetionet CHEBI:9139 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0236075 infores:hetionet CHEBI:135342 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0013428 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042109 infores:hetionet CHEBI:55346 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0002792 infores:hetionet CHEBI:3207 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C2363730 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0155003 infores:hetionet CAID:CA16616504 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616504 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM1, PM5, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1317C>T (p.Ser439=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10%, and no putative cryptic splice sites are created. Additionally, evolutionary conservation algorithms predict the site as not being highly conserved (PhyloP score: -0.44 < 0.1 [-14.1; 6.4]) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616504/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51450 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0026858 infores:hetionet CHEBI:4445 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0020461 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0264309 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0264309 infores:hetionet CHEBI:15367 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151970 infores:hetionet CAID:CA410150356 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150356 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 The NM_001754.4:c.814C>T (p.Gln272Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and is expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The variant has been reported in ClinVar but has not been observed in a proband meeting at least one of the RUNX1-phenotypic criteria. Nonsense variants downstream of c.98 (PM5_supporting) In summary, this variant meets the criteria to be classified as Pathogenic with ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150356/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9943 biolink:causes UMLS:C0553731 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0553731 infores:hetionet CHEBI:119573 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085593 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0015397 infores:hetionet CHEBI:3478 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0860864 infores:hetionet CAID:CA410147809 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147809 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1193C>G (p.Ala398Gly) is a missense variant which has a REVEL score < 0.50 (0.109), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147809/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA386951973 biolink:causes MONDO:0015967 infores:clingen CAID:CA386951973 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate The c.1A>T variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Leu) of transcript NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting and PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386951973/MONDO:0015967/017 2022-03-04 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6931 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0002792 infores:hetionet UMLS:C0657912 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085641 infores:hetionet CHEBI:31705 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085610 infores:hetionet CHEBI:31236 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2363731 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0034063 infores:hetionet CAID:CA376065726 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065726 MONDO:0011225 PMID: Likely Pathogenic PM2_Supporting, PS3_Moderate, PM3_Supporting, PP4_Moderate The c.82G>C(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Alanine by Proline at amino acid 28 (p.Ala28Pro).This variant is absent from gnomAD v4 (PM2_Supporting).At least one patient with this variant displayed Decreased V(D)J recombination 0.5pts + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts. + T−B−NK+ 0.5pts + Increased cellular radiosensitivity 0.5pts. The total is 2 points, which is highly specific for SCID (PP4_Moderate, PMIDs 19953608 and 25917813). The patient is homozygous, 0.5pts. PM3_Supporting.Activity levels in % of WT activity = Recombination: Mean (SD): 3.00(0.15) and DNA repair (36h after IR): Mean (SD): 5.13 (11.95). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level(PMID: 25917813).In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Supporting, and PS3_Moderate. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065726/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:499361 biolink:causes UMLS:C3203457 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C3203457 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0032285 infores:hetionet CHEBI:101278 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C2047937 infores:hetionet CHEBI:9667 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0020555 infores:hetionet GO:1905715 biolink:causes GO:0008544 infores:ubergraph knowledge_assertion manual_agent GO:1905715 GO:0008544 UMLS:C0657912 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151836 infores:hetionet NCBIGene:2688 biolink:causes MONDO:0008250 infores:monarchinitiative not_provided not_provided HGNC:4261 MONDO:0008250 uuid:9d906051-bcb0-48f8-9bf8-4a58d85bd242 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16620222 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620222 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP7, BP5, BS1, BS4, BS3, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2, PS3 The c.-50C>T variant occurs in the 5'UTR. This variant has an allele frequency of 0.00001 (1 in 151,862) in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>T variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID: 23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620222/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:38545 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0030305 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0521490 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022104 infores:hetionet CHEBI:68534 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0085649 infores:hetionet CHEBI:8888 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235086 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009450 infores:hetionet CHEBI:135566 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0152227 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0004936 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0242656 infores:hetionet CHEBI:47426 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0043352 infores:hetionet CAID:CA377485523 biolink:causes MONDO:0017623 infores:clingen CAID:CA377485523 MONDO:0017623 PMID:23335809PMID:23335809PMID:29706350 Likely Pathogenic PM2, PP1_Moderate, PP2, PS3 PM6, PVS1, BS4, BS3, BS1, BP7, BP5, PP3, BS2, PM5, PM1, PM4, BA1, BP2, BP4, PS4, PS2, PS1 PTEN c.830C>G (p.Thr277Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populationsPP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 23335809)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377485523/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:87681 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0700225 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0032961 infores:hetionet CHEBI:7959 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0232462 infores:hetionet CHEBI:17347 biolink:causes UMLS:C3160830 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C3160830 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0518988 infores:hetionet CHEBI:5130 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027497 infores:hetionet UBERON:0000945 biolink:causes MONDO:0008277 infores:ubergraph knowledge_assertion manual_agent UBERON:0000945 MONDO:0008277 CHEBI:681848 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0023530 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0018939 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0042109 infores:hetionet NCBIGene:92840 biolink:causes MONDO:0015013 infores:monarchinitiative not_provided not_provided HGNC:30078 MONDO:0015013 uuid:12c8ef42-0eb7-4608-9ef4-e6297362b071 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6520 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0003123 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0151773 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0013428 infores:hetionet CHEBI:46295 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0041657 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0497247 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0150450 infores:hetionet NCBIGene:11041 biolink:causes MONDO:0014120 infores:monarchinitiative not_provided not_provided HGNC:15685 MONDO:0014120 uuid:fc6e4c67-4eb8-43e5-8c4b-144aea81d211 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0030193 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009806 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0010709 infores:hetionet CHEBI:204734 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0033774 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014534 infores:hetionet NCBIGene:7274 biolink:causes MONDO:0010188 infores:monarchinitiative not_provided not_provided HGNC:12404 MONDO:0010188 uuid:e1087137-a642-4b68-85ca-63ce4b1b64e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0030312 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0151734 infores:hetionet CHEBI:72297 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0853697 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023510 infores:hetionet GO:0098693 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0098693 GO:0051641 CHEBI:4798 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0001925 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0178298 infores:hetionet CHEBI:3696 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0231218 infores:hetionet CHEBI:3506 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0917801 infores:hetionet CHEBI:5864 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0520888 infores:hetionet CHEBI:4868 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0917801 infores:hetionet CHEBI:3082 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1260880 infores:hetionet CHEBI:4909 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0036974 infores:hetionet CHEBI:17474 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0042487 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0242350 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0039971 infores:hetionet CHEBI:5120 biolink:causes MONDO:0005339 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0162311 infores:hetionet CHEBI:3441 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0026821 infores:hetionet CHEBI:84883 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0003811 infores:hetionet CHEBI:3723 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018965 infores:hetionet NCBIGene:55975 biolink:causes MONDO:0014890 infores:monarchinitiative not_provided not_provided HGNC:15646 MONDO:0014890 uuid:c1318001-f1dd-47db-a807-7b838d4104b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5384 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0016382 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0235162 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0235162 infores:hetionet CHEBI:8356 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0005747 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0454643 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0454643 infores:hetionet CHEBI:74947 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038990 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0007785 infores:hetionet CHEBI:4814 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0001925 infores:hetionet CHEBI:3219 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0043094 infores:hetionet CHEBI:2682 biolink:causes MONDO:0016383 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0162283 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1258215 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0002622 infores:hetionet CHEBI:10101 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0518988 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0497365 infores:hetionet NCBIGene:10095 biolink:causes MONDO:0060583 infores:monarchinitiative not_provided not_provided HGNC:704 MONDO:0060583 uuid:834328a9-f056-4fec-b452-c3586f062f91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0262431 infores:hetionet CHEBI:5296 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0162830 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085136 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0278080 infores:hetionet UMLS:C0025241 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151799 infores:hetionet CHEBI:5118 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0268000 infores:hetionet UNII:D27V6190PM biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0013378 infores:hetionet NCBIGene:899 biolink:causes MONDO:0030875 infores:monarchinitiative not_provided not_provided HGNC:1591 MONDO:0030875 uuid:21b8eebe-dc5b-4f24-8a64-4afc6fb239a3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0013362 infores:hetionet CAID:CA198850 biolink:causes MONDO:0010726 infores:clingen CAID:CA198850 MONDO:0010726 PMID: Benign BP5, BS1, BS2, PS4_Supporting "The allele frequency of the p.Pro419Ser variant in MECP2 (NM_004992.3) is 0.02% in ""Other"" sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1) and additionally is present in three male individuals in gnomAD. The p.Pro419Ser variant is observed in at least 7 unaffected individuals (Baylor Genetic internal database, GeneDx internal database, PMID 16225173) (BS2). The p.Pro419Ser variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro419Ser variant has been observed in at least 2 individuals with neurodevelopmental disorders (PMID 32457807, 16225173) (PS4_supporting), however in these studies MECP2 was the only gene sequenced. In summary the p.Pro419Ser variant in MECP2 is classified as benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5) and the PS4_supporting evidence is not considered inconsistent with the final benign classification." Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA198850/MONDO:0010726/016 2022-04-28 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7773 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0547030 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1167965 infores:hetionet CHEBI:194135 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0575081 infores:hetionet CHEBI:10100 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0086565 infores:hetionet CHEBI:47898 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020578 infores:hetionet CAID:CA9871550 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871550 MONDO:0007064 PMID: Likely Pathogenic PP4, PM5_Supporting, PM2_Supporting, PM3_Strong PP1, PM6, BS3, PS1, PS3, PS2 The c.703C>T (NM_000022.4) variant in ADA gene is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 235 (p.Arg235Trp).The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/113770 observed alleles) is 0.000002920 in gnomAD v2.1.1 which is below than SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least 5 individuals with SCID. Of those individuals, 2 were compound heterozygous: Patient #6, W264X, reported by Dalal I et al. (PMID: 21624848, Pathogenic according to the SCID VCEP specifications, confirmed in trans, 1pt) and Patient #26, p.G74D, reported by Chi ZH et al. (PMID: 30290665, Likey Pathogenic according to the SCID VCEP, confirmed in trans, 1 pt). 3 individuals were homozygous for PMIDs: 26255240, 26376800, and 32307643; reaching the limit for homozygous occurrence = 1 pt). Total = 3 pts, PM3_Strong.Evaluating those 5 probands, three of them had PP4 applied at supporting level: * PMID: 30290665: 171 PID-related genes(NGS panel: 0.5pt); T-B-SCID ( SCID gene panel which ruled out alternative causes 0.5pt); SCID diagnostic (0.5pt); Total 1.5pts. * PMID: 26376800: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts, PP4_Met. * PMID: 26255240: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt = TOTAL: 1.5 pts = PP4_Met. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PP4, PM3_Strong, and PM5_supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871550/MONDO:0007064/114 2024-01-16 2024-01-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45716 biolink:causes UMLS:C0851881 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0851881 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0232910 infores:hetionet CHEBI:8869 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0020598 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027765 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0011570 infores:hetionet CHEBI:5141 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0036572 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0021053 infores:hetionet CHEBI:135888 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C2129214 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0267792 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0917798 infores:hetionet CHEBI:7903 biolink:causes UMLS:C1536055 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C1536055 infores:hetionet CHEBI:7822 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0011603 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013395 infores:hetionet CHEBI:3756 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018418 infores:hetionet CHEBI:6073 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0268000 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0039520 infores:hetionet CHEBI:16335 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0042963 infores:hetionet CHEBI:8093 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0039231 infores:hetionet NCBIGene:7490 biolink:causes MONDO:0008679 infores:monarchinitiative not_provided not_provided HGNC:12796 MONDO:0008679 uuid:3f7d5840-531c-4e1a-bd4a-023ba974b0a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0522172 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0029442 infores:hetionet CHEBI:3756 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0030193 infores:hetionet CHEBI:119915 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1320474 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0017152 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0677660 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0677660 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0027339 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027051 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0039520 infores:hetionet CHEBI:17474 biolink:causes UMLS:C2609183 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C2609183 infores:hetionet CHEBI:9434 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0037763 infores:hetionet CHEBI:46081 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0009782 infores:hetionet CHEBI:8060 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0028084 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0858259 infores:hetionet CAID:CA415087505 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087505 MONDO:0010305 PMID: Uncertain Significance PP4, PP3, PM2_Supporting The NM_005629.4:c.1430C>T variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a serine for a leucine at amino acid position 477 (p.Ser477Leu). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 21267006) (PP4). In this report (PMID: 21267006), the variant was said to segregate with disease in the family without further details, including the number of affected individuals, given; thus PP1 does not apply. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.83 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 1303056). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087505/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Inconclusive true CHEBI:85083 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0232462 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0302295 infores:hetionet NCBIGene:22948 biolink:causes MONDO:0009748 infores:monarchinitiative not_provided not_provided HGNC:1618 MONDO:0009748 uuid:107df943-54f9-45a7-ac86-03f4169843d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0027765 infores:hetionet CHEBI:499361 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0038160 infores:hetionet CHEBI:94449 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0015672 infores:hetionet CHEBI:681569 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0311468 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027651 infores:hetionet CHEBI:36791 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085583 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0574067 infores:hetionet UMLS:C0879264 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0033774 infores:hetionet CHEBI:63589 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0004093 infores:hetionet CHEBI:29688 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0026821 infores:hetionet CHEBI:27999 biolink:causes UMLS:C0232570 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0232570 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030305 infores:hetionet CHEBI:10119 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0232461 infores:hetionet CHEBI:71940 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0018681 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0851341 infores:hetionet CHEBI:8356 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151907 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0015376 infores:hetionet NCBIGene:63901 biolink:causes MONDO:0007478 infores:monarchinitiative not_provided not_provided HGNC:24725 MONDO:0007478 uuid:e7146cce-600e-4bbc-9610-eeeeb0fa0f30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042029 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009938 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009763 infores:hetionet CHEBI:47499 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0000737 infores:hetionet CHEBI:51860 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0015230 infores:hetionet CHEBI:8874 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013456 infores:hetionet CHEBI:8214 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0003467 infores:hetionet CHEBI:64312 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0037299 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0015397 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0020538 infores:hetionet CHEBI:4953 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0004604 infores:hetionet NCBIGene:63908 biolink:causes MONDO:0031055 infores:monarchinitiative not_provided not_provided HGNC:15751 MONDO:0031055 uuid:af971825-3660-43b4-88ff-b8218a1c5d6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:8NZ41MIK1O biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0013491 infores:hetionet CHEBI:17347 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0231528 infores:hetionet CHEBI:31236 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151205 infores:hetionet CHEBI:6912 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C1443060 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0152128 infores:hetionet CHEBI:6954 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0040822 infores:hetionet CHEBI:50859 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011124 infores:hetionet CHEBI:68647 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151723 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948352 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948352 infores:hetionet CHEBI:3223 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0036974 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78403 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877027 infores:hetionet CHEBI:16899 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0042075 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0521491 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042267 infores:hetionet CHEBI:5165 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085682 infores:hetionet CAID:CA266005 biolink:causes MONDO:0007064 infores:clingen CAID:CA266005 MONDO:0007064 PMID: Pathogenic PS3_Supporting, PP4_Moderate, PM2_Supporting, PM3_Very Strong PP3 "The NM_000022.4(ADA):c.385G>A (p.Val129Met) variant in exon 5 of ADA is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 129 (p.Val129Met). The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.00000187, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed in gnomAD v4.1.0. (PM2_Supporting). Internal communication with Dr. Michael Hershfield indicated there are records of 2 homozygous patients with a delayed-onset CID phenotype-one cared for in Ottawa Canada and the other in Boston.  Both patients are ADA- deficient and have elevated levels of red cell dAXP. One of these cases may correspond to the patient described in PMID: 32888943, given that the authors are also from Boston (1 point). This variant was also found in the homozygous state in three additional unrelated ADA-deficient probands (3 points; PMID: 31858364, 26255240). In addition, this variant was identified in compound heterozygous state in five unrelated ADA-deficient probands. The accompanying missense ADA variants were Gly140Arg (c.418G>A), Ser291Leu (c.872C>T), His15Asp (c.43C>G) and two variants not specified. The ADA variant Ser291Leu has been classified as likely pathogenic by the SCID expert panel, while the other two are VUS (1.5 points; PMID: 39052144, 32307643, 26376800 ). In total, the evidence sums to 5.5 points, therefore, PM3_very strong is met. 2 patients with delayed onset SCID were reported in PMID: 10200056. Patient ""AR' (homozygous) was tested by sequencing of cDNA, amplified genomic DNA, SSCP of amplified genomic DNA. Increased dAdo nucleotides (dATP or dAXP) was observed in pretreatment erythrocytes (5 pt). Therefore, PP4_Moderate is met The residual enzyme activity for this variant was measured as 0.11+/-0.4% of wild-type. The strength of evidence from cellular models/in vitro studies is dependent upon the level of expressed ADA enzyme activity based on levels defined by Arredondo-Vega et al., 1998 (PMID: 9758612) and meets PS3_Supporting criteria.In summary, this variant meets the criteria to be classified as pathogenic for severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4_Moderate, PM3_Very Strong, PM2_Supporting, and PS3_Supporting (VCEP specifications version 2.1)." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA266005/MONDO:0007064/114 2025-11-20 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6149 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0948594 infores:hetionet CHEBI:3814 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0009782 infores:hetionet CHEBI:63631 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151836 infores:hetionet CAID:CA308102495 biolink:causes MONDO:0007783 infores:clingen CAID:CA308102495 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with glutamic acid at codon 2183 of the RYR1 protein, p.(Gly2183Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:25735680). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.786 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308102495/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8499 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C1262141 infores:hetionet CHEBI:5118 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085616 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0025061 infores:hetionet CHEBI:16586 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0023530 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0549373 infores:hetionet CHEBI:46195 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0026827 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0233632 infores:hetionet CHEBI:92712 biolink:causes MONDO:0000022 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0270327 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221345 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0160390 infores:hetionet CHEBI:4903 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0009782 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0948525 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0042373 infores:hetionet CHEBI:261649 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C2830004 infores:hetionet CHEBI:16664 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0267792 infores:hetionet CHEBI:64355 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0000731 infores:hetionet CHEBI:63630 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0037036 infores:hetionet CHEBI:2469 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0162429 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0242350 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151854 infores:hetionet CHEBI:63619 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017672 infores:hetionet CAID:CA226691 biolink:causes MONDO:0010725 infores:clingen CAID:CA226691 MONDO:0010725 PMID: Benign BP7, BA1, BP4 The NM_000330.4(RS1):c.330T>C variant is a synonymous variant at amino acid 110. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01431 among hemizygous individuals, with 5657 variant alleles / 395399 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This silent variant c.330T>C causing a synonymous variant at codon 110 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for all predictive splice changes which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP7). In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1, BP4, and BP7 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226691/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CAID:CA337448 biolink:causes MONDO:0017623 infores:clingen CAID:CA337448 MONDO:0017623 PMID: Likely Pathogenic PM2, PP2, PS3 BP7, BP5, BS1, BS4, BS3, PVS1, PM6, BS2, PP3, PP1, PP4, PM4, PM3, PM5, PM1, BP3, BP1, BP4, BP2, BA1, PS4, PS2, PS1 PTEN c.422A>C (p.His141Pro) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA337448/MONDO:0017623/003 2020-06-18 2022-09-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8871 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085623 infores:hetionet CHEBI:63791 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235266 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042075 infores:hetionet CHEBI:61049 biolink:causes EFO:0006865 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0150045 infores:hetionet CHEBI:36791 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0338831 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0037274 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0003123 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0858259 infores:hetionet CHEBI:61049 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0947912 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020621 infores:hetionet UMLS:C0005740 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0152459 infores:hetionet CHEBI:77032 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0002792 infores:hetionet CHEBI:9086 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0271710 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0853777 infores:hetionet CHEBI:3561 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0520966 infores:hetionet NCBITaxon:10335 biolink:causes MONDO:0005700 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10335 MESH:D002644 DB00787_MESH_D002644_1DB00577_MESH_D002644_1 NCBIGene:6338 biolink:causes MONDO:0008887 infores:monarchinitiative not_provided not_provided HGNC:10600 MONDO:0008887 uuid:e571bcae-1b55-4553-8d78-4d50e61ef4ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51137 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0030554 infores:hetionet NCBIGene:2548 biolink:causes MONDO:0009290 infores:monarchinitiative not_provided not_provided HGNC:4065 MONDO:0009290 uuid:e68990e5-c2f7-4227-afa6-6ff269bdf946 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:56098 biolink:causes MONDO:0859252 infores:monarchinitiative not_provided not_provided HGNC:8717 MONDO:0859252 uuid:327e2bdb-9a9c-447c-8c39-3d83b6f62e76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91834 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0030193 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0017152 infores:hetionet CHEBI:367163 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0013182 infores:hetionet CHEBI:9943 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1320474 infores:hetionet CHEBI:8093 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0020458 infores:hetionet CHEBI:9434 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0009782 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085622 infores:hetionet CHEBI:9727 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0018681 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0023895 infores:hetionet CHEBI:6801 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0020672 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027339 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0015459 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015459 infores:hetionet UMLS:C0005740 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0015967 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0027651 infores:hetionet CAID:CA658658179 biolink:causes MONDO:0015967 infores:clingen CAID:CA658658179 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM4_Supporting The c.801_802insGGG variant in the HNF1 homeobox A gene, HNF1A, is a 3 base pair insertion resulting in the in-frame addition of 1 amino acid at codon 267 (p.Trp267_Phe268insGly) within exon 4 of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The c.801_802insGGG variant is predicted to change the length of the protein due to an in-frame insertion of a single amino acid in a nonrepeat region (PM4_Supporting). In summary, c.801_802insGGG meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PM4_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658179/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8212 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0151205 infores:hetionet CAID:CA229336 biolink:causes MONDO:0009861 infores:clingen CAID:CA229336 MONDO:0009861 PMID:8659548 Pathogenic PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229336/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119915 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014742 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0030920 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0031350 infores:hetionet NCBIGene:2064 biolink:causes MONDO:0024498 infores:monarchinitiative not_provided not_provided HGNC:3430 MONDO:0024498 uuid:08905b4c-2f8e-44eb-b6c5-89e76fc31490 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA187687 biolink:causes MONDO:0100488 infores:clingen CAID:CA187687 MONDO:0100488 PMID: Likely Benign BP7, BS2, BP4 BS1, BA1, PS4 The c.1170C>T (p.Asn390=) variant results in a synonymous change in exon 9 of CDH1. This is a silent variant that occurs at a position that is not highly conserved and for which splicing predictors do not suggest an impact on splicing (BP4, BP7). This variant is absent from the gnomAD population database v3.1.2. This variant was identified in 70 individuals without DGC, LBC, SRC tumours and whose families do not suggest HDGC (BS2; PMID: 30287823, 36436516, and internal laboratory contributors). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as likely benign specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA187687/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3314 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0085618 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151736 infores:hetionet CAID:CA298974 biolink:causes MONDO:0007648 infores:clingen CAID:CA298974 MONDO:0007648 PMID:26681312 Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2 The c.707C>A (p.Ser236Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA298974/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:6437 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0002418 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151885 infores:hetionet NCBIGene:51475 biolink:causes MONDO:0013963 infores:monarchinitiative not_provided not_provided HGNC:1385 MONDO:0013963 uuid:7d166982-03a5-4857-bf1b-031165369d87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63610 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0011603 infores:hetionet CHEBI:8481 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0018681 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0392618 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0006145 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0233494 infores:hetionet CHEBI:6887 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0014591 infores:hetionet NCBITaxon:4751 biolink:causes MONDO:0002041 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:4751 MONDO:0002041 CHEBI:44185 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0024523 infores:hetionet CHEBI:50859 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042345 infores:hetionet CAID:CA16613026 biolink:causes MONDO:0017623 infores:clingen CAID:CA16613026 MONDO:0017623 PMID:23335809 Pathogenic PM2, PVS1, PS4_Supporting PM6, BS4, BS3, BS1, BP7, BP5, PP1, PP3, PP2, BS2, PM5, PM1, PM4, BA1, BP2, BP4, PS2, PS1, PS3 PTEN c.801+1delG (IVS7+1delG) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populationsPS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613026/MONDO:0017623/003 2020-03-23 2020-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10119 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013428 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0267792 infores:hetionet CHEBI:68554 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0017178 infores:hetionet CHEBI:9605 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0020443 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0029408 infores:hetionet CHEBI:7773 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0393593 infores:hetionet CHEBI:9139 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0038999 infores:hetionet CHEBI:46081 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0877055 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0595862 infores:hetionet CHEBI:63624 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0031350 infores:hetionet CHEBI:53760 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042023 infores:hetionet CHEBI:3568 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040460 infores:hetionet CHEBI:7820 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0740304 infores:hetionet CHEBI:42797 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0438142 infores:hetionet CAID:CA399804688 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804688 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000419.5(ITGA2B):c.998+1G>C occurs within the canonical splice donor site of intron 11. It is predicted to cause skipping of biologically-relevant-exon 11/30, resulting in the p.(Met316Glufs*3) frameshift in exon 12, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). One homozygous patient has been reported with Glanzmann thrombasthenia (PMID: 32581362; PM3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804688/MONDO:0100326/011 2021-09-15 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:188986 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0004604 infores:hetionet NCBIGene:9080 biolink:causes MONDO:0033670 infores:monarchinitiative not_provided not_provided HGNC:2051 MONDO:0033670 uuid:615c7c29-4c93-4a5e-9a5f-07053a7fedbe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7809 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0027707 infores:hetionet CAID:CA1251495 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251495 MONDO:0013144 PMID: Uncertain Significance BP4 BS1, PM2 The c.17T>C (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 6 (p.Ile6Thr). The computational predictor REVEL gives a score of 0.248, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251495/MONDO:0013144/084 2024-10-02 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:5130 biolink:causes MONDO:0012160 infores:monarchinitiative not_provided not_provided HGNC:8754 MONDO:0012160 uuid:cabba448-0fd5-48e7-b418-9c2580f9a2a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50730 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0029882 infores:hetionet CHEBI:8869 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0041657 infores:hetionet CHEBI:3757 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011991 infores:hetionet CHEBI:3614 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0038362 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0013922 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0005940 infores:hetionet CHEBI:135920 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0042075 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0854375 infores:hetionet CAID:CA645369680 biolink:causes MONDO:0007648 infores:clingen CAID:CA645369680 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PS4_Supporting, PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP3, BP1, BP4, BP2, BA1, PS3, PS1, PS2 The c.2490dupG (p.Leu831AlafsTer4) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and upstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in a family meeting HDGC criteria (PS4_Supporting; SCV000580713.3). In summary, the clinical significance of this variant is likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, Supporting, PM2_Supporting CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369680/MONDO:0007648/007 2023-08-30 2023-08-30 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:31236 biolink:causes UMLS:C1112369 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1112369 infores:hetionet CAID:CA120550 biolink:causes MONDO:0044970 infores:clingen CAID:CA120550 MONDO:0044970 PMID:19273760 Uncertain Significance PP3, PM2_Supporting, PM6_Supporting, PS3_Supporting PS4 The m.15967G>A variant in MT-TP has been reported in one individual with primary mitochondrial disease to date (PMID: 19273760). She had adult-onset myoclonic jerks, seizures, myopathy, cerebellar ataxia, hearing loss, cataracts, retinal pigmentary changes, and ragged red fibers on muscle biopsy. Brain imaging showed changes in the cerebral white matter, basal ganglia, and thalami, in addition to cerebral and cerebellar atrophy. This variant occurred de novo in the single reported individual (absent in blood and urine from mother and two healthy sisters; PM6_supporting, PMID: 19273760). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (78.9 percentile) and HmtVAR predicts it to be deleterious with a score of 0.65 (PP3). It should be noted that the low conservation of this variant (35.56% in Mitomap) is misleading due to the absence of this position in many species. Among species with a nucleotide at this position, the conservation is 84%. Single fiber testing showed higher levels of the variant in COX-deficient fibers (98.80%, standard deviation 0.89%) than in COX-positive fibers (31.1%, standard deviation 11.23%; PS3_supporting, PMID: 19273760). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PP3, PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120550/MONDO:0044970/015 2024-05-13 2024-12-04 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA658795275 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795275 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PM3 "The NM_000152.5:c.2161dup (p.Glu721GlyfsTer16) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). One individual with this variant and Pompe disease has been reported in the literature, but the residual GAA activity and second variant were not provided and therefore PP4 cannot be assessed (PMID: 18425781). Another individual with ""p.E721Rfs"", identified by newborn screening had been reported (PMIDs 28196920, 29095812) but the cDNA change was not provided. There is a ClinVar entry for this variant (Variation ID: 550277). This variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024.GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795275/MONDO:0009290/010 2024-04-05 2024-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:57526 biolink:causes MONDO:0010246 infores:monarchinitiative not_provided not_provided HGNC:14270 MONDO:0010246 uuid:c7a525d4-d7cb-4b77-9913-33438dccfc7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009938 infores:hetionet CHEBI:28939 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0340865 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0595900 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595900 infores:hetionet CHEBI:9137 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003862 infores:hetionet CHEBI:45783 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151754 infores:hetionet CHEBI:2549 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0022638 infores:hetionet CHEBI:64312 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042024 infores:hetionet NCBIGene:51013 biolink:causes MONDO:0030261 infores:monarchinitiative not_provided not_provided HGNC:17286 MONDO:0030261 uuid:adbdf799-d92c-4b50-b8cf-27366bf79c2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5962 biolink:causes MONDO:0012602 infores:monarchinitiative not_provided not_provided HGNC:9944 MONDO:0012602 uuid:84b29923-2aee-47b5-810c-1f99d9929a59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0948586 infores:hetionet CHEBI:85083 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0042963 infores:hetionet CHEBI:6931 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0340865 infores:hetionet UMLS:C0009315 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0043144 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0236071 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0852733 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151911 infores:hetionet CHEBI:18332 biolink:causes MONDO:0006809 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0007780 infores:hetionet CHEBI:32315 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0149745 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0015256 infores:hetionet CAID:CA024747 biolink:causes MONDO:0007783 infores:clingen CAID:CA024747 MONDO:0007783 PMID: Pathogenic BS2, PM1, PS4, PS3, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 2434 of the RYR1 protein, p.(Gly2434Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000078, a frequency consistent with pathogenicity for MHS. This variant has been reported in 178 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 174 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted, PS4 (PMID: 30236257, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant has been identified in six individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). p.(Gly2434Arg) knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes, PS3 (PMID:30236258). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 20 individuals, PP1_Strong (PMID: 7849712, 11575529, 12059893, 25960145). A REVEL score >0.85 (0.956) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3, PS4, PM1, PP1_Strong, PP3_Moderate, BS2. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024747/MONDO:0007783/012 2022-07-11 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:68478 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0006145 infores:hetionet CHEBI:142290 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0002390 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0018802 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0036454 infores:hetionet GO:2000733 biolink:causes GO:0016331 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0016331 NCBIGene:23405 biolink:causes MONDO:0007681 infores:monarchinitiative not_provided not_provided HGNC:17098 MONDO:0007681 uuid:d4bb8572-63bf-4286-a7bb-a75a0de63b29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002878 infores:hetionet CHEBI:6801 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0013404 infores:hetionet CHEBI:478164 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0085628 infores:hetionet CHEBI:29007 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0018965 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0002170 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0034882 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0541820 infores:hetionet CAID:CA135641 biolink:causes MONDO:0019497 infores:clingen CAID:CA135641 MONDO:0019497 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BP1, BP3, BP2, PS1, PS3, PS2, PS4 The c.475G>A variant in MYO6 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 159 (p.Glu159Lys).​ The filtering allele frequency of this variant is 0.013% for South Asian chromosomes by the Genome Aggregation Database v4 (18/91064 with 95% CI), which meets no population allele frequency criteria (PM2_Supporting, BS1, and BA1 are not met). However, this variant is also present in 0.8% (257/29596) of Ashkenazi Jewish chromosomes, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). This variant has not been reported in the literature in individuals affected with hearing loss. Therefore, given the lack of contradictory evidence, this variant is classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 01.15.2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA135641/MONDO:0019497/005 2025-01-15 2025-03-28 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:7627 biolink:causes HP:0030248 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0267412 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0872380 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0872380 infores:hetionet NCBIGene:2078 biolink:causes MONDO:0957954 infores:monarchinitiative not_provided not_provided HGNC:3446 MONDO:0957954 uuid:3d3c150f-4693-4e2c-9c31-364e78c943a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3403 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0948594 infores:hetionet CAID:CA8129795 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129795 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.113C>A (p.Thr38Lys) variant results in a non-synonymous amino acid substitution in exon 2 of CDH1. This variant has been observed in at least 10 individuals without DGC, LBC or SRC tumors and whose families do not suggest HDGC (BS2; SCV000637699.3, SCV000275215.5). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129795/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7809 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0020649 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0018799 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0032326 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013595 infores:hetionet CHEBI:41879 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0003811 infores:hetionet CAID:CA10606870 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606870 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Strong The NM_000070.3: c.2290del p.(Asp764ThrfsTer12) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 22/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least three patients with features consistent with LGMD, including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 31671740, LOVD Individual #00416186) and confirmed in trans with a pathogenic variant in two patients (c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 1.0 pt x2, LOVD Individual #00214755; ClinVar SCV002227607.3 personal data communication) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 had a clinical diagnosis of LGMD (LOVD Individual #00214755; PP4). The highest minor allele frequency of this variant is 0.00004472 (2/44722 exome chromosomes) for the Admixed American population in gnomAD v4.1.0, which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/03/2025): PVS1, PM3_Strong, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606870/MONDO:0015152/187 2025-05-03 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94385 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0004238 infores:hetionet CHEBI:32588 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0035232 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0029408 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0018099 infores:hetionet CHEBI:31859 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0011253 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0086543 infores:hetionet CHEBI:3568 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037299 infores:hetionet CHEBI:8378 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0020488 infores:hetionet CHEBI:31932 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0003467 infores:hetionet CHEBI:4911 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1443060 infores:hetionet CAID:CA390864317 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864317 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting BA1, BP1, PP2, PP3, PP4, BS2, PM1, PM3, PM5, PS4, PS1, BS1, BP5 The NM_177438.2:c.5551C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1851 (p.Arg1851Cys). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.416, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 06/24/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864317/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:3460 biolink:causes MONDO:0013953 infores:monarchinitiative not_provided not_provided HGNC:5440 MONDO:0013953 uuid:fb87e019-f31c-40e4-b29f-736ec9ed9d26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018418 infores:hetionet CHEBI:31536 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0016655 infores:hetionet CAID:CA409108445 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108445 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS2, PM1_Supporting PP1, PS4 The c.977C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a missense variant at codon 326 (p.(Thr326Ile)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 16731861, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2; PP4; PMID:16731861). This variant also segregated with diabetes with one informative meiosis in a single family; however, this does not meet the threshold for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.977C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting, PS2, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108445/MONDO:0015967/085 2024-10-24 2024-10-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8774 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027769 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0035078 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0233976 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0233976 infores:hetionet NCBIGene:65109 biolink:causes MONDO:0010398 infores:monarchinitiative not_provided not_provided HGNC:20439 MONDO:0010398 uuid:b0b38570-58c1-44b5-b99d-e2366b7fca97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5004 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0041912 infores:hetionet CHEBI:135679 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0162285 infores:hetionet CHEBI:3568 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018524 infores:hetionet NCBIGene:54676 biolink:causes MONDO:0060711 infores:monarchinitiative not_provided not_provided HGNC:4670 MONDO:0060711 uuid:f77e5c65-8871-4a53-b6d8-4214e84580cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151779 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018801 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1956346 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0037274 infores:hetionet CHEBI:49960 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0011603 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020621 infores:hetionet CHEBI:61390 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0919924 infores:hetionet CHEBI:47426 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0040264 infores:hetionet CHEBI:15407 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0004093 infores:hetionet CHEBI:46195 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0020621 infores:hetionet CHEBI:521033 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0013609 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0042514 infores:hetionet CHEBI:42820 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0043352 infores:hetionet CHEBI:3764 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C1963790 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0002170 infores:hetionet CHEBI:32315 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0233471 infores:hetionet CHEBI:71028 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0438717 infores:hetionet CHEBI:7789 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0042963 infores:hetionet CHEBI:45979 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0012833 infores:hetionet CHEBI:681848 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0549386 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0497327 infores:hetionet CHEBI:4903 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0011124 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0020649 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027651 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0015734 infores:hetionet CHEBI:64019 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0041657 infores:hetionet CHEBI:53760 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0423791 infores:hetionet CHEBI:50378 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0025222 infores:hetionet CHEBI:48273 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0015967 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0030552 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0037199 infores:hetionet GO:2000226 biolink:causes GO:0031018 infores:ubergraph knowledge_assertion manual_agent GO:2000226 GO:0031018 CHEBI:3757 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030196 infores:hetionet CAID:CA399791378 biolink:causes MONDO:0100326 infores:clingen CAID:CA399791378 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PVS1_Moderate PP4 The NM_000419.5(ITGA2B):c.2842-1G>C variant occurs within the canonical splice acceptor site of intron 27. It is predicted to cause skipping of biologically-relevant-exon 28, resulting in an in-frame deletion of 34 amino acids (Arg948_Gln981del), removing 3% of the protein (PVS1_moderate). The study of platelet GPIIb mRNA by RT-PCR confirmed an exon 28 skipping in this patient (PMID: 11798398). GT type I patient MMc (PMID: 11798398) is homozygous for this variant (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399791378/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8107 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2830004 infores:hetionet CHEBI:16664 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0030312 infores:hetionet CL:0000354 biolink:causes MONDO:0006058 infores:ubergraph knowledge_assertion manual_agent CL:0000354 MONDO:0006058 CHEBI:8871 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0542571 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0017178 infores:hetionet CHEBI:3127 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0019209 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020517 infores:hetionet CHEBI:27974 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1140680 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0041912 infores:hetionet CHEBI:3312 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0027540 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0007072 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0007072 uuid:206f775e-6a18-405b-aa83-0e9613d34e62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022346 infores:hetionet CHEBI:9599 biolink:causes HP:0031616 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0423281 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0235431 infores:hetionet CHEBI:4672 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0011603 infores:hetionet CHEBI:5100 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0014518 infores:hetionet CHEBI:6759 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0039231 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0040046 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0038663 infores:hetionet CHEBI:92998 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0003862 infores:hetionet CHEBI:142290 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0428974 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0013687 infores:hetionet GO:0080154 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0080154 GO:0019953 CHEBI:45081 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0002871 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003615 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0006840 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0031039 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0850569 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0850569 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0041976 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018772 infores:hetionet CHEBI:49960 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0232849 infores:hetionet CAID:CA327935288 biolink:causes MONDO:0100437 infores:clingen CAID:CA327935288 MONDO:0100437 PMID: Benign BP4, BA1 PM2 NM_001034853.2(RPGR):c.778+90dup (also referred to as c.778+84dup) is an insertion of 1 nucleotide in intron 7. This variant is present in gnomAD v4.1.0 at a frequency of 0.7216 among hemizygous individuals, with 172,672 variant alleles / 239,288 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327935288/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:4798 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0558489 infores:hetionet CHEBI:8028 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020456 infores:hetionet CHEBI:77733 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C1443060 infores:hetionet CAID:CA409106119 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106119 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4, PM5 The c.539C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a missense variant at codon 180 (p.(Ala180Val)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). Another missense variant p.(Ala180Asp) has been classified as a VUS by the ClinGen MDEP, therefore, PM5 will not be applied. In summary, c.539C>T meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106119/MONDO:0015967/085 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0740394 infores:hetionet CHEBI:473990 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0345904 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0006840 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085617 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0008325 infores:hetionet CHEBI:50173 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017979 infores:hetionet CHEBI:3310 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0000833 infores:hetionet CHEBI:3756 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0151786 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0151740 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019151 infores:hetionet CHEBI:5613 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C3665347 infores:hetionet CHEBI:8356 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2047937 infores:hetionet NCBIGene:374291 biolink:causes MONDO:0032608 infores:monarchinitiative not_provided not_provided HGNC:7714 MONDO:0032608 uuid:2839e1ea-ff60-4447-9f9e-6b20759fc612 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0020517 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0009763 infores:hetionet CHEBI:64317 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0233494 infores:hetionet UMLS:C0065374 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0026858 infores:hetionet CAID:CA414806210 biolink:causes MONDO:0044970 infores:clingen CAID:CA414806210 MONDO:0044970 PMID: Uncertain Significance BP4 PS4, PS3, PM2 The m.10644G>A (p.V59M) variant in MT-ND4L was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 25, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.013%, 8/61,883; gnomAD v3.1.2: 0.025%, 114/56,428 homoplasmic occurrences, one heteroplasmic occurrence; Helix: 0.029%, 56/195,893 homoplasmic occurrences). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.3 (Min=0, Max=1), which predicts a neutral effect on protein function (BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414806210/MONDO:0044970/015 2023-04-25 2025-06-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:42797 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017160 infores:hetionet CHEBI:28971 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0015230 infores:hetionet CAID:CA409105870 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105870 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PVS1_Moderate PM1, PM4 The c.427-1G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is predicted to and has been shown (PMID: 28242437) to remove a canonical splice acceptor site in intron 4 of NM_175914.4. This variant leads to the deletion of 16 amino acids from exon 5 (<10% deletion), which is part of the ligand binding domain (PVS1_Moderate; PMID: 28242437). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID: 28242437). This variant was identified in at least three individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and a personal or family history of persistent neonatal hypoglycemia) (PP4_Moderate; PMID: 28242437). In summary, c.427-1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Moderate, PM2_Supporting, PP1, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105870/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7494 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0518015 infores:hetionet CHEBI:145499 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0014457 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151735 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0020569 infores:hetionet CHEBI:134991 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042963 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0038362 infores:hetionet CHEBI:64045 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0033774 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0233494 infores:hetionet CHEBI:64355 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085631 infores:hetionet CHEBI:15428 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0020625 infores:hetionet CHEBI:66919 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0151825 infores:hetionet CHEBI:27446 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0002792 infores:hetionet CHEBI:2687 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0043094 infores:hetionet CHEBI:2922 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0235996 infores:hetionet CHEBI:8764 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018524 infores:hetionet CAID:CA343723649 biolink:causes MONDO:0005338 infores:clingen CAID:CA343723649 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting BP7, BS1, BS3, PP3, PP1, PM5, PM4, PS4, PS1, PS3, PS2, BP4, BA1 The c.1348A>G variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Aspartic Acid at amino acid 450 (p.Asn450Asp). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00001098 (1 allele out of 91,080), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.605, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant has not yet been identified in a proband diagnosed with juvenile or primary open angle glaucoma, only in a participant with preperimetric primary open angle glaucoma, thus PS4 was not applied. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723649/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50131 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0029163 infores:hetionet CHEBI:49713 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0013144 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0026857 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0038814 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0041912 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0497365 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0497247 infores:hetionet CHEBI:3561 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0033774 infores:hetionet CHEBI:134745 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0232462 infores:hetionet CHEBI:6413 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C2979982 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0262576 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0262576 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002418 infores:hetionet CAID:CA166706 biolink:causes MONDO:0700270 infores:clingen CAID:CA166706 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.1158del p.Lys387Argfs*3 variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 10234507, 26896183, 19147735). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1, PM2_Supporting, PM3, PM5_supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA166706/MONDO:0700270/020 2024-01-24 2025-09-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3732 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0541832 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004238 infores:hetionet NCBITaxon:6183 biolink:causes MONDO:0015254 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6183 MESH:D012552 DB01096_MESH_D012552_1 CHEBI:135276 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0011991 infores:hetionet CHEBI:553473 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0030554 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032285 infores:hetionet CHEBI:9599 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0035243 infores:hetionet NCBIGene:9531 biolink:causes MONDO:0013479 infores:monarchinitiative not_provided not_provided HGNC:939 MONDO:0013479 uuid:c2ff7316-e205-47f7-be19-ceb77a4cd6d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35854 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0019061 infores:hetionet CHEBI:75922 biolink:causes MONDO:0003382 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0015423 infores:hetionet NCBIGene:1959 biolink:causes MONDO:0011527 infores:monarchinitiative not_provided not_provided HGNC:3239 MONDO:0011527 uuid:9cecdb20-e932-4f0a-bac3-dc7a0d951b9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7986 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0014724 infores:hetionet CHEBI:68478 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0000737 infores:hetionet CHEBI:5855 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0085631 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0853748 infores:hetionet NCBIGene:2065 biolink:causes MONDO:8000011 infores:monarchinitiative not_provided not_provided HGNC:3431 MONDO:8000011 uuid:e9be6f78-576d-4ffb-b04a-c249516cc60a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0002871 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0006840 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151613 infores:hetionet CHEBI:101853 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0231528 infores:hetionet CHEBI:8768 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042023 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0016053 infores:hetionet CHEBI:7507 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0235280 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038454 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0020517 infores:hetionet CHEBI:45783 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011606 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0009421 infores:hetionet NCBIGene:7062 biolink:causes MONDO:0014990 infores:monarchinitiative not_provided not_provided HGNC:11791 MONDO:0014990 uuid:b6f42041-b9fe-4b3c-8227-aef840a2de10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9720 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0338656 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0235018 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0235018 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0013395 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027441 infores:hetionet GO:0048378 biolink:causes GO:0048372 infores:ubergraph knowledge_assertion manual_agent GO:0048378 GO:0048372 CHEBI:4728 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0232492 infores:hetionet CHEBI:4710 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030193 infores:hetionet CAID:CA16613125 biolink:causes MONDO:0700270 infores:clingen CAID:CA16613125 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5, PVS1 PM2 The c.3214G>T (p.Glu1072*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 9443866, 26896183, 30579816). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008797 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613125/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17474 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0029134 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0027765 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0332575 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0392386 infores:hetionet CHEBI:8346 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0011991 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0442874 infores:hetionet UNII:7F465U79Q1 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0024115 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0033117 infores:hetionet CHEBI:31859 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0030252 infores:hetionet CHEBI:135686 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0009782 infores:hetionet CHEBI:2636 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0151744 infores:hetionet CHEBI:75722 biolink:causes NCIT:C34791 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853698 infores:hetionet NCBIGene:4729 biolink:causes MONDO:0032612 infores:monarchinitiative not_provided not_provided HGNC:7717 MONDO:0032612 uuid:08dadc91-9831-4157-877c-f6d4f1711082 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0234192 infores:hetionet CHEBI:9139 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0013456 infores:hetionet CHEBI:31859 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C1167965 infores:hetionet CHEBI:31980 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0547030 infores:hetionet CHEBI:5864 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0919924 infores:hetionet UMLS:C0011701 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C1291077 infores:hetionet CHEBI:3380 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0043352 infores:hetionet CHEBI:2704 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0042029 infores:hetionet UMLS:C0657912 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020598 infores:hetionet CHEBI:7865 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0085631 infores:hetionet CHEBI:27786 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0027497 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013220 infores:hetionet CHEBI:204734 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0018681 infores:hetionet CHEBI:68606 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0232462 infores:hetionet CHEBI:63599 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0476273 infores:hetionet CHEBI:8382 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0014236 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015230 infores:hetionet NCBITaxon:5722 biolink:causes MONDO:0002154 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5722 MESH:D014245 DB00911_MESH_D014245_1DB12834_MESH_D014245_1 CHEBI:3181 biolink:causes UMLS:C0424741 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0424741 infores:hetionet NCBIGene:4878 biolink:causes MONDO:0012816 infores:monarchinitiative not_provided not_provided HGNC:7939 MONDO:0012816 uuid:b848f3ba-6394-42e4-95d2-45162134dbad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0242184 infores:hetionet CHEBI:71219 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0025323 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0029442 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0039070 infores:hetionet CHEBI:8356 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033247 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0027765 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235807 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549259 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549259 infores:hetionet UMLS:C0009315 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0008031 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0518015 infores:hetionet CAID:CA386954873 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954873 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM5_Strong, PM1_Supporting, PP1_Strong, PP3 PP4 The c.320T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 107 (p.(Leu107Arg)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v.4.1.0. (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 9166684). This variant segregated with diabetes with 15 informative meioses in this individual's family (PP1_Strong; PMID: 9166684). Two other missense variants at the same residue, c.319C>G (p.Leu107Val) and c.319C>A (p.Leu107Ile), have been interpreted as pathogenic by the ClinGen MDEP, and p.Leu107Arg has greater Grantham distance than p.Leu107Val and p.Leu107Ile (PM5_Strong). In summary, c.320T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP1_Strong, PM5_Strong, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954873/MONDO:0015967/017 2025-07-16 2025-07-25 Autosomal dominant inheritance HP:0000006 Supports UNII:3QJA87N40S biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0149514 infores:hetionet CHEBI:7476 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0006384 infores:hetionet CHEBI:16899 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0231218 infores:hetionet CHEBI:72690 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0206062 infores:hetionet NCBITaxon:36826 biolink:causes MONDO:0016453 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36826 MONDO:0016453 CHEBI:45783 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018801 infores:hetionet CHEBI:161680 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0700345 infores:hetionet CHEBI:15367 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0033845 infores:hetionet CHEBI:51860 biolink:causes UMLS:C3536794 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C3536794 infores:hetionet CHEBI:75045 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0003811 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023218 infores:hetionet CHEBI:68554 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0004238 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0233494 infores:hetionet CHEBI:135791 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0162820 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0851341 infores:hetionet UMLS:C0010592 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019572 infores:hetionet CAID:CA229785 biolink:causes MONDO:0009861 infores:clingen CAID:CA229785 MONDO:0009861 PMID:1671881PMID:24368688PMID:9012412PMID:8533759PMID:24368688 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC and gnomAD (1 allele); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.978; PP4_Moderate: S273F was detected in in Northern Ireland, Belgium/French, Western Scotland, and New South Wales PKU patients. BH4 deficiency was assessed in 1 study. Upgraded per ClinGen Metabolic workgroup. (PMID:1671881; PMID:8533759; PMID:9012412; PMID:24368688); PM3_Strong: Seen with 2 known pathogenic mutations: I65T, R408W. Upgraded based on SVI worgroup recommendations and approved PAH guidelines (PMID:24368688). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229785/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9130 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0013378 infores:hetionet CHEBI:17823 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0006826 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0242350 infores:hetionet CAID:CA410205770 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205770 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.65T>C (p.Ile22Thr) is a missense variant. This variant is present at a MAF of 0.00002915(0.002915%, 1/34310) in the Admixed American population of gnomAD v2.1.1. This missense variant has a REVEL score <0.50 (0.272)(BP4). No probands meeting RUNX1 FPDMM phenotypic criteria have been described with this variant. In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205770/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:8NZ41MIK1O biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0034063 infores:hetionet CHEBI:7903 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0017181 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006852 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0030305 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0022650 infores:hetionet CHEBI:8428 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0409974 infores:hetionet CHEBI:45863 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0206062 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0264886 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1963951 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0221384 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0221384 infores:hetionet CAID:CA010654 biolink:causes MONDO:0005045 infores:clingen CAID:CA010654 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PP3, PS4 PM5, PM4, PM6, PP1, BA1, PS3, BS1, BS3, BS4, PS1, PS2, BP4, BP5, BP2, BP7, PVS1 The c.1370T>C (p.Ile457Thr) variant in MYH7 has been identified in >20 individuals with HCM (PS4_Strong; Waldmüller 2011 PMID: 21750094; Fokstuen 2011 PMID: 21239446; Helms 2016: 27688314; Homburger 2016 PMID: 27247418; Murphy 2016 PMID: 26914223; Ingles 2017 PMID: 28408708; Ross 2017 PMID: 28615295; Viswanathan 2017 PMID: 29121657; Walsh 2017 PMID:27532257; Ko 2018 PMID: 28640247; Centenary Institute Sydney pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OGML pers. comm.). This variant also segregated with HCM in 1 affected relative (GeneDx pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has also been reported in 1 individual with left bundle branch block, 1 individual with sudden cardiac arrest (who carried additional variants in other cardiomyopathy associated genes) and 1 individual with myopathy who also had additional variants in myopathy-associated genes and segregated with myopathy in one affected relative (Ambry pers. comm.; CHEO pers. comm.; Invitae pers. comm.). This variant has also been identified in 0.0009% (1/113764) of European chromosomes by gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant could impact protein function (Adhikari 2019 PMID: 31213605); however, this data is currently insufficient to establish functional impact and apply PS3. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PM2; PM1; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010654/MONDO:0005045/002 2021-09-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:84050 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0162429 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0857807 infores:hetionet CHEBI:8764 biolink:causes MONDO:0010721 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0035288 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0025061 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0022408 infores:hetionet CHEBI:41423 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0013404 infores:hetionet CHEBI:4562 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0392171 infores:hetionet CAID:CA8459444 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459444 MONDO:0011132 PMID: Likely Benign BP4, BP7 BS1, PM2 NM_001369369.1(FOXN1):c.1135+20G>A is an intronic variant. SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (delta scores 0.00) and the nucleotide is not highly conserved (phyloP score -0.235) (BP4, BP7). In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BP4 and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459444/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:15367 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0038362 infores:hetionet CHEBI:8764 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030193 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0001122 infores:hetionet CHEBI:3647 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0025160 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006596 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0162824 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0020517 infores:hetionet CHEBI:37941 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151699 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0242350 infores:hetionet CAID:CA254831 biolink:causes MONDO:0044970 infores:clingen CAID:CA254831 MONDO:0044970 PMID:9673981 Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate PP1, PS2, PM6 The m.5521G>A variant in MT-TW has been reported in four unrelated individuals to date. Ages of onset included childhood (2/4 affected individuals), 20s (1/4 affected individuals), and 50s (1/4 affected individuals). Affected individuals had features including myopathy, seizures, cerebellar ataxia, mood disorders, and eating disorders. Muscle biopsies showed ragged red fibers (RRF) and COX-negative fibers, whereas respiratory chain enzyme deficiencies were variable. Heteroplasmy levels of the variant were not specified in one affected individual, were 98% muscle and undetectable in blood in another affected individual, were homoplasmic in muscle and 87% brain in another affected individual, and were homoplasmic in blood in the last individual (PS4_moderate; PMIDs: 20360171, 23841600, 23847141, 9673981). There are no de novo occurrences of this variant to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (89.7 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative RRF (89.9% +/- 11.76) than in COX-positive fibers (69.35% +/- 26.22), p<0.005 (PS3_supporting, PMID: 9673981). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254831/MONDO:0044970/015 2022-10-03 2022-10-12 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8024 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0041657 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0860433 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038454 infores:hetionet CHEBI:9649 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0740394 infores:hetionet CHEBI:32588 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0003811 infores:hetionet CHEBI:16347 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0013404 infores:hetionet CHEBI:9328 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0027707 infores:hetionet CHEBI:421707 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0151578 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0562057 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0562057 infores:hetionet CHEBI:6887 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0393760 infores:hetionet CHEBI:5128 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C1443060 infores:hetionet CHEBI:7447 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C1325847 infores:hetionet CHEBI:68575 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0151744 infores:hetionet CAID:CA396458165 biolink:causes MONDO:0007648 infores:clingen CAID:CA396458165 MONDO:0007648 PMID: Uncertain Significance BS2_Supporting, PM5_Supporting, PM2_Supporting, PVS1_Strong BS1, BS3, BS4, BP7, BP5, PM6, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.687+2T>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +2 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). The variant has been observed in 6 individuals without DGC, SRC tumors or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting, BS2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396458165/MONDO:0007648/007 2024-02-26 2024-03-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:28901 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020456 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0442874 infores:hetionet CHEBI:51137 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0012569 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0543467 infores:hetionet CHEBI:9943 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017565 infores:hetionet CAID:CA409106086 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106086 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PP1, PM5, PS4 The c.530T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to alanine at codon 177 (p.(Val177Ala)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 27420379, internal lab contributors). Two of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody-negative or SU-sensitive) (PP4_Moderate; PMID: 27420379, internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Another missense variant, c.530T>A p.Val177Asp, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.530T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106086/MONDO:0015967/085 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes UMLS:C0853595 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853595 infores:hetionet CHEBI:47898 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0006846 infores:hetionet CHEBI:50567 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0151636 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011630 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036572 infores:hetionet CHEBI:6887 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0030196 infores:hetionet CHEBI:2704 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0040038 infores:hetionet CHEBI:3478 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0027947 infores:hetionet CHEBI:101085 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0030554 infores:hetionet CHEBI:15367 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011603 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0010692 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0021053 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0041969 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0012739 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0034065 infores:hetionet CAID:CA123230 biolink:causes MONDO:0100326 infores:clingen CAID:CA123230 MONDO:0100326 PMID:8080992 Uncertain Significance PM2_Supporting, PS3 PM3, PP3, PP4 The NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro) missense variant has been reported in at least one Glanzmann thrombasthenia patient (PMID: 1438206). This variant is absent from gnomAD v4.1 (PM2_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in CHO cells transiently co-transfected with the Ser778Pro variant β3 and wild type αIIb showed minimal binding to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 8080992; PS3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PM2_supporitng. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123230/MONDO:0100326/011 2024-11-07 2025-02-27 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:49960 biolink:causes HP:0007141 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1112256 infores:hetionet CHEBI:46557 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0003467 infores:hetionet CHEBI:33130 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0013604 infores:hetionet CHEBI:63616 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151662 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0877440 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0877440 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033575 infores:hetionet CHEBI:3614 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0038999 infores:hetionet CHEBI:136040 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C2584688 infores:hetionet GO:0021936 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:0021936 GO:0060322 CHEBI:2675 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0687713 infores:hetionet CHEBI:28748 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013144 infores:hetionet CHEBI:9139 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0338908 infores:hetionet CAID:CA5950156 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950156 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The NM_000448.3:c.1573C>T variant in RAG1 is a missense variant predicted to cause the substitution of Proline by Serine at amino acid 525 (p.Pro525Ser). The filtering allele frequency (the lower threshold of the 95% CI of 1571/91080) of the c.1573C>T variant in RAG1 is 0.01663 for South Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 24 homozygous adults are reported on gnomAD v.4, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950156/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8059 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0018824 infores:hetionet CHEBI:30659 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0085633 infores:hetionet CHEBI:68478 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0162285 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0549405 infores:hetionet CAID:CA16020863 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020863 MONDO:0009861 PMID:26481238PMID:26481238 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.803A>G (p.Tyr268Cys) variant in PAH has been reported in 1 individual with hyperphenylalaninemia (BH4 deficiency excluded) and was detected with pathogenic variant p.Glu178Gly. (PP4_Moderate, PM3; PMID: 26481238). This variant is absent in population databases (PM2). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020863/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50173 biolink:causes MONDO:0022096 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085653 infores:hetionet GO:0002307 biolink:causes CL:0000795 infores:ubergraph knowledge_assertion manual_agent GO:0002307 CL:0000795 CAID:CA2580098620 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098620 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.351+19T>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.511) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098620/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true UBERON:0006530 biolink:causes MONDO:0008669 infores:ubergraph knowledge_assertion manual_agent UBERON:0006530 MONDO:0008669 CHEBI:17347 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0232492 infores:hetionet CHEBI:44915 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0424296 infores:hetionet CHEBI:23765 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0917801 infores:hetionet NCBIGene:1277 biolink:causes MONDO:0008147 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0008147 uuid:1aaf3e9b-7871-4148-bf2b-3e6ab2c518d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0004604 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009319 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0001125 infores:hetionet CHEBI:64321 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0037383 infores:hetionet CHEBI:8871 biolink:causes UMLS:C3665888 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C3665888 infores:hetionet CHEBI:49662 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0018834 infores:hetionet CHEBI:10101 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0003811 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0403723 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0403723 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0558489 infores:hetionet CHEBI:7789 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0020517 infores:hetionet CHEBI:46557 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0236000 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0010709 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1306341 infores:hetionet CHEBI:2955 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0404521 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0267596 infores:hetionet CHEBI:18385 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0002792 infores:hetionet CHEBI:3696 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0016204 infores:hetionet NCBIGene:7168 biolink:causes MONDO:0012744 infores:monarchinitiative not_provided not_provided HGNC:12010 MONDO:0012744 uuid:a4dc42cb-58a9-42eb-be83-b97b4d64c088 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:178699 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0030193 infores:hetionet CHEBI:51164 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0032227 infores:hetionet CHEBI:7445 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0012833 infores:hetionet CHEBI:41423 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1443060 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0232459 infores:hetionet CHEBI:8764 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085636 infores:hetionet CHEBI:50861 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0232462 infores:hetionet CHEBI:35778 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0428977 infores:hetionet CHEBI:23765 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0264906 infores:hetionet CAID:CA414447351 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447351 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4, PP3 The c.1325G>C (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Alanine at amino acid 442 (p.Gly442Ala). This variant has been reported in at least 4 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Moderate; PMID: 7937052, poster https://www.postersessiononline.eu/173580348_eu/congresos/WFH2018/aula/-M-P_49_WFH2018.pdf, internal laboratory data). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Another missense variant c.1234G>A, p.Gly442Arg in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4, PM5, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447351/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Supports NCBIGene:3145 biolink:causes MONDO:0958226 infores:monarchinitiative not_provided not_provided HGNC:4982 MONDO:0958226 uuid:cdb48ca7-bce2-4e8d-a645-56affede1b90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0029882 infores:hetionet CHEBI:31709 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0040046 infores:hetionet CHEBI:144093 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151904 infores:hetionet CHEBI:3723 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002962 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0032285 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C0948342 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0948342 infores:hetionet CHEBI:253342 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0035243 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0948594 infores:hetionet CHEBI:63621 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043094 infores:hetionet CHEBI:27565 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0011991 infores:hetionet CHEBI:8346 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C3160741 infores:hetionet CHEBI:59773 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0235896 infores:hetionet CHEBI:63589 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0917801 infores:hetionet CHEBI:63631 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018944 infores:hetionet CHEBI:5138 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1368065 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0155943 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0155943 infores:hetionet CAID:CA024017 biolink:causes MONDO:0007783 infores:clingen CAID:CA024017 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Threonine with Methionine at codon 4294 of the RYR1 protein, p.(Thr4294Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0193, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024017/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:61049 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020453 infores:hetionet NCBIGene:6514 biolink:causes MONDO:0009216 infores:monarchinitiative not_provided not_provided HGNC:11006 MONDO:0009216 uuid:5fb33a25-2002-491c-badf-1503f4e2188d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes UMLS:C0340952 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0340952 infores:hetionet CHEBI:144093 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011175 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002418 infores:hetionet NCBIGene:1540 biolink:causes MONDO:0042977 infores:monarchinitiative not_provided not_provided HGNC:2584 MONDO:0042977 uuid:0b843bcd-1359-4629-b7e8-7c7f06623de7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020456 infores:hetionet CHEBI:33130 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0024115 infores:hetionet CHEBI:87681 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0152031 infores:hetionet CHEBI:7959 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0033687 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027813 infores:hetionet CHEBI:8461 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0013384 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0015397 infores:hetionet CAID:CA10644630 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644630 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*1213C>G is an intronic variant which has a SpliceAI of 0.00 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644630/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:584020 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0011603 infores:hetionet CHEBI:8228 biolink:causes MONDO:0004987 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0005695 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0333291 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0333291 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006256 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853879 infores:hetionet CHEBI:75045 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0028081 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0004936 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0038661 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0178298 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0347390 infores:hetionet CHEBI:55346 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0006384 infores:hetionet CHEBI:6923 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C1384353 infores:hetionet CHEBI:63638 biolink:causes HP:0001374 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0019555 infores:hetionet CHEBI:45409 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0235378 infores:hetionet CHEBI:167309 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0026961 infores:hetionet CHEBI:45652 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0042109 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0021400 infores:hetionet CHEBI:9137 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0030794 infores:hetionet CHEBI:6375 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C3489393 infores:hetionet CHEBI:63580 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018790 infores:hetionet CAID:CA023749 biolink:causes MONDO:0007750 infores:clingen CAID:CA023749 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM1, PM2, PP3, PP4 NM_000527.5(LDLR):c.682G>A (p.Glu228Lys) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PS3, PS4, PM1, PM2, PP1_Strong, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001105 (0.01%) in East Asian exomes (gnomAD v2.1.1).PP3 - REVEL = 0.972. It is above 0.75.PM1 - Variant meets PM2 and is missense located in exon 4 .PS3 - Three studies contribute to PS3 attribution. One (PMID: 10978268) report a level 3 assay performed on heterozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (50% LDLR activity). The second reports a level 2 assay perfomed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity).The third is permformed on Heterologous cells (COS-7). FACS, CLSM and WB results in 24% LDLR expression and 21% LDL clearance. LDLR is retained in the ER.PS4 - Variant meets PM2 and is identified in 13 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=1 Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; n=1 Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) or DLCN criteria for FH (n=1 Robarts Research Institute; n=9 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).PP1_Strong - Variant segregate with FH in 10 informatives meiosis (6 relatives positive LDL-C > 75th percentile and 4 relatives negative LDLC < 50th percentile) from 2 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo and in 1 relative positive for variant (LDL-C > 75th percentile) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP4 - Variant meets PM2 and is identified in 13 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=1 Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; n=1 Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) or DLCN criteria for FH (n=1 Robarts Research Institute; n=9 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023749/MONDO:0007750/013 2022-06-21 2022-06-21 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6339 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0003811 infores:hetionet GO:0141159 biolink:causes GO:0090383 infores:ubergraph knowledge_assertion manual_agent GO:0141159 GO:0090383 CHEBI:31624 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0428977 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0085620 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0038661 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014549 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0037274 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0038999 infores:hetionet CHEBI:6444 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0030252 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0178298 infores:hetionet CHEBI:8776 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C2830004 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0005684 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0027651 infores:hetionet CAID:CA114366 biolink:causes MONDO:0009861 infores:clingen CAID:CA114366 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong, PS3_Supporting PM5 The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID: 8098245); p.R261Q (PMID: 21147011); p.S110L (LP by PAH VCEP, PMID: 26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID: 10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114366/MONDO:0009861/006 2022-03-13 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4562 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0948089 infores:hetionet CHEBI:38562 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0032533 infores:hetionet CHEBI:66876 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0033117 infores:hetionet CHEBI:2668 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0019080 infores:hetionet NCBIGene:54800 biolink:causes MONDO:0015006 infores:monarchinitiative not_provided not_provided HGNC:25947 MONDO:0015006 uuid:0808548f-5593-487e-92d0-7b56a379ef25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:F64QU97QCR biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0541832 infores:hetionet CHEBI:49375 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0003467 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042075 infores:hetionet CHEBI:44032 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0015672 infores:hetionet CHEBI:29007 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0231218 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033575 infores:hetionet CHEBI:8356 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037287 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0312414 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0312414 infores:hetionet CHEBI:6541 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0027424 infores:hetionet CHEBI:209807 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0006852 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017675 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0233632 infores:hetionet CHEBI:116278 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1443060 infores:hetionet CHEBI:75246 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0858635 infores:hetionet UMLS:C0023610 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0016204 infores:hetionet NCBIGene:9526 biolink:causes MONDO:0012211 infores:monarchinitiative not_provided not_provided HGNC:7207 MONDO:0012211 uuid:7d5fbbea-0739-4d6d-9853-f5909e1edd1b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0015230 infores:hetionet CHEBI:63630 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1167965 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0020649 infores:hetionet CHEBI:5118 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0242184 infores:hetionet CHEBI:9674 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0035243 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0549433 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0233459 infores:hetionet CHEBI:127780 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085681 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0006266 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0429098 infores:hetionet CHEBI:145499 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0037036 infores:hetionet CHEBI:8707 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013390 infores:hetionet GO:0120194 biolink:causes GO:0048466 infores:ubergraph knowledge_assertion manual_agent GO:0120194 GO:0048466 CHEBI:7931 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085593 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0017160 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0012813 infores:hetionet CHEBI:7798 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0547030 infores:hetionet CHEBI:2904 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0030848 infores:hetionet CHEBI:5147 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0040425 infores:hetionet CHEBI:66964 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0015672 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0010709 infores:hetionet CHEBI:70735 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0002871 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0575090 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0233494 infores:hetionet CHEBI:4702 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0005741 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1258215 infores:hetionet CHEBI:585948 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0003862 infores:hetionet CHEBI:9635 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0012569 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0948089 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0039503 infores:hetionet NCBIGene:440193 biolink:causes MONDO:0009360 infores:monarchinitiative not_provided not_provided HGNC:19967 MONDO:0009360 uuid:38468ba3-734f-4cd1-a2e5-1cbbf88c2fed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0162830 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1384353 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0856049 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0856049 infores:hetionet CHEBI:51230 biolink:causes UMLS:C1112366 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1112366 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151596 infores:hetionet CHEBI:6754 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C1392046 infores:hetionet UMLS:C0025241 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0033774 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0518015 infores:hetionet CHEBI:474053 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0687713 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0029408 infores:hetionet CAID:CA024462 biolink:causes MONDO:0007783 infores:clingen CAID:CA024462 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate PS3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 160 of the RYR1 protein, p.(Glu160Gly). This variant was not present in a large population database (gnomAD) at the time it was interpreted. This variant has been reported in an individual who has a personal or family history of a malignant hyperthermia reaction, this individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.957) supports a pathogenic status for this variant, PP3_Moderate. Using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024462/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45783 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0237849 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0267596 infores:hetionet CHEBI:168396 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085682 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0041912 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013609 infores:hetionet CHEBI:61049 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0404521 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1368065 infores:hetionet CHEBI:63617 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C3665386 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0232459 infores:hetionet CHEBI:4702 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0015967 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0014518 infores:hetionet CHEBI:107736 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0011570 infores:hetionet CHEBI:50729 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020461 infores:hetionet CHEBI:63621 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0026821 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014742 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042075 infores:hetionet CHEBI:465284 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151754 infores:hetionet CHEBI:30659 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0016382 infores:hetionet CHEBI:5558 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0035455 infores:hetionet CHEBI:6912 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0233715 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0948089 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0017675 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0004936 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0014534 infores:hetionet CHEBI:3181 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0031039 infores:hetionet CHEBI:6413 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0392699 infores:hetionet CAID:CA274628 biolink:causes MONDO:0010726 infores:clingen CAID:CA274628 MONDO:0010726 PMID: Likely Pathogenic PS3_Supporting, PM5, PM1, PP3, PM6, PS4_Moderate, PM2_Supporting The p.Phe157Ile variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with a clinical phenotype suggestive of MECP2-related conditions (PMID 16832102) (PM6). The p.Phe157Ile variant in MECP2 has been observed in 2 additional individuals with Rett syndrome (RettBASE) (PS4_moderate). The p.Phe157Ile variant occurs in the well-characterized methyl-DNA binding functional domain of MECP2 (PM1). A pathogenic missense variant (p.Phe157Leu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 19722030, 16225173, 22476991, 30536762, 15675358, ClinVar) (PM5). The p.Phe157Ile variant in MECP2 is absent from gnomAD (PM2_supporting). A MECP2 chromatin binding assay has shown that this variant impacts protein function (PMID 27929079) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Phe157Ile variant in MECP2 is classified as Likely Pathogenic for MECP2-related conditions based on the ACMG/AMP criteria (PM1, PM5, PM6, PS4_moderate, PM2_supporting, PS3_supporting, PP3 ). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274628/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:6759 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0004093 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0729549 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0729549 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0235229 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0235229 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004239 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0018799 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020456 infores:hetionet CHEBI:3423 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0039231 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0023067 infores:hetionet CHEBI:92712 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0231530 infores:hetionet CHEBI:9667 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0024141 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0013395 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151883 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0015230 infores:hetionet CHEBI:50659 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0027765 infores:hetionet CAID:CA276982 biolink:causes MONDO:0012589 infores:clingen CAID:CA276982 MONDO:0012589 PMID:25326637 Pathogenic PVS1, PS2, PM2_Supporting The p.Gly656Argfs*55 variant in TCF4 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gly656Argfs*55 variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Pitt-Hopkins syndrome (PMID 25326637) (PS2). This variant is absent from gnomAD (PM2_supporting). In summary, the p.Gly656Argfs*55 variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PVS1, PS2, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA276982/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA10587839 biolink:causes MONDO:0007947 infores:clingen CAID:CA10587839 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1_Strong PM5 The NM_00138 c.3457T>C, is a missense variant in FBN1 predicted to cause a substitution of a cysteine residue by arginine at amino acid 1153 (p.Cys1153Arg) in a calcium binding EGF-like domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). This variant has been reported two times in ClinVar: once as likely pathogenic, and once as uncertain significance (Variation ID: 263660). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Other missense variants affecting the same residue, including p.Cys1153Ser, Cys1153Phe, and Cys1153Tyr, have been previously reported in individuals with Marfan syndrome (PMID 16222657, 14695540, 24928929, internal data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.944, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587839/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:17650 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0232841 infores:hetionet CHEBI:37924 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0004093 infores:hetionet CHEBI:16755 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0039070 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0235416 infores:hetionet CHEBI:51364 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C2047937 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0020651 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0015469 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0010278 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0017178 infores:hetionet CHEBI:17650 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0240735 infores:hetionet CHEBI:473990 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0030305 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0024115 infores:hetionet CAID:CA10585136 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585136 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5_Strong, PM2, PP3, PP4 BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS2, BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).PM5_Strong - 4 other missense variants in the same codon:- NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines,- NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely pathogenic by these guidelines,- NM_000527.5(LDLR): c.796A>T (p.Asp266Tyr) (ClinVar ID 251456) – Pathogenic by these guidelines,- NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines.There are 3 variants in the same codon classified as Pathogenic by these guidelines;PM2 - This variant is absent from gnomAD (gnomAD v2.1.1);PP3 - REVEL = 0.98;PP4 - Identified in 2 unrelated index cases fulfilling Simon-Broome criteria (published in PMID: 32331935);PS4_Supporting - Variant meets PM2. Identified in 2 unrelated index cases fulfilling Simon-Broome criteria (published in PMID: 32331935); Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585136/MONDO:0007750/013 2021-11-14 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:71415 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0020580 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0314719 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0152128 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0031350 infores:hetionet CHEBI:6775 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0023380 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0855624 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0855624 infores:hetionet CAID:CA314808 biolink:causes MONDO:0012999 infores:clingen CAID:CA314808 MONDO:0012999 PMID: Uncertain Significance PP3, PM2_Supporting BS1 The NM_000156.6:c.575C>T variant in GAMT is a missense variant that is predicted to cause the substitution of a threonine by a methionine at amino acid position 192 (p.Thr192Met). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest continental population minor allele frequency in gnomAD v4.1.0. is 0.0002665 (20/75058 alleles; no homozygotes) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Although the allele frequency in the Ashkenazi Jewish population in gnomAD v4.1.0. is higher at 0.002467 (73/29588 alleles; no homozygotes) (meeting BS1, >0.001) this frequency is not counted because it was found in a non-continental population (Ghosh et al, 2018, PMID: 30311383). The computational predictor REVEL gives a score of 0.677 which is above the threshold of 0.644, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 205582). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, PP3.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314808/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:68584 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0013362 infores:hetionet CHEBI:50777 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0236082 infores:hetionet UMLS:C0065374 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0542571 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1443060 infores:hetionet CHEBI:8774 biolink:causes EFO:0020909 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0877167 infores:hetionet CHEBI:101278 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0030232 infores:hetionet CHEBI:4911 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0026821 infores:hetionet CHEBI:27690 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0036974 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0018991 infores:hetionet GO:1905799 biolink:causes GO:0044782 infores:ubergraph knowledge_assertion manual_agent GO:1905799 GO:0044782 CHEBI:135961 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0231218 infores:hetionet CHEBI:4681 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0042510 infores:hetionet CHEBI:63580 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020453 infores:hetionet CHEBI:31705 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0013404 infores:hetionet CHEBI:8426 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0012833 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0687707 infores:hetionet CHEBI:6715 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006142 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0031117 infores:hetionet CHEBI:18243 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0027497 infores:hetionet CHEBI:8863 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0520966 infores:hetionet CAID:CA320250290 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250290 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*1360C>T is an intronic variant. MAF of 0.001034 (0.10%, 9/8708 alleles) in the African/African-American subpopulation of the gnomAD v2.1.1 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250290/MONDO:0011071/008 2022-06-23 2022-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:168396 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017152 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0235234 infores:hetionet GO:0061924 biolink:causes GO:0021932 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0021932 CHEBI:5118 biolink:causes MONDO:0001164 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003431 infores:hetionet CAID:CA8130238 biolink:causes MONDO:0007648 infores:clingen CAID:CA8130238 MONDO:0007648 PMID: Uncertain Significance PS4_Moderate BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.2281G>A (p.Gly761Arg) variant has an allele frequency of 0.00006 (0.006%, 1/16,256 alleles) in the African gnomAD subpopulation (http://gnomad.broadinstitute.org). The variant has been identified in at least two families that meet HDGC clinical criteria (PS4_Moderate; internal laboratory collaborators). The variant has also been seen in three individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (internal laboratory collaborators); however, BS2 is not applied since more than 30% of reported individuals/family meet HDGC criteria. . In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PS4_Moderate. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8130238/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6887 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0086769 infores:hetionet CHEBI:2549 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0085633 infores:hetionet CAID:CA402997017 biolink:causes MONDO:0012999 infores:clingen CAID:CA402997017 MONDO:0012999 PMID:24415674 Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3, PP3_Moderate, PS3_Supporting PM5 The NM_000156.6:c.220G>C variant in GAMT is predicted to result in a missense substitution of alanine by proline at amino acid 74 (p.Ala74Pro). This variant has been identified in two unrelated probands with clinical features consistent with GAMT deficiency; one with absent creatine peak on MRS, the other with deficient GAMT activity. Both had urine guanidinoacetate levels 1.1 - 12 times above the upper limit of reference range, but specific values for each patient were not provided (PMID: 24415674) (PP4_Moderate). One of these individuals was reported to be compound heterozygous, phase unconfirmed, for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A (ClinVar Variation ID: 21065) (0.5 points) and another patient was homozygous for the variant (0.5 points) (PMID: 24415674) Total 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000033945 (4/1178374 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.930 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM3, PP3_Moderate, PP4_Moderate PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 15, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402997017/MONDO:0012999/026 2025-10-15 2025-10-15 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0065374 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0034063 infores:hetionet CAID:CA036197 biolink:causes MONDO:0007750 infores:clingen CAID:CA036197 MONDO:0007750 PMID: Likely Pathogenic PP1_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2 NM_000527.5(LDLR):c.1721G>A (p.Arg574His) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PP1_strong - PMID: 20018285 - 6 informative meioses in 1 family.PM2 - PopMax MAF = 0.0001129 (0.01129%) in Latino exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.971.PP4 - Variant meets PM2. PMID: 20018285 - 1 case with DLCN > 6. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036197/MONDO:0007750/013 2022-02-13 2022-07-12 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7956 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0027497 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0019158 infores:hetionet CHEBI:27834 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020625 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0679048 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0679048 infores:hetionet CHEBI:28971 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0033774 infores:hetionet CHEBI:7514 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0003811 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0004936 infores:hetionet CHEBI:48669 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0007222 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0042075 infores:hetionet CHEBI:50131 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0151904 infores:hetionet CHEBI:51041 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151772 infores:hetionet UNII:R15UI3245N biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0039231 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0086543 infores:hetionet CHEBI:5120 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0036508 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0008370 infores:hetionet CHEBI:3077 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0152459 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0009806 infores:hetionet CHEBI:15544 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0043352 infores:hetionet CHEBI:585948 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C1142412 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006444 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042373 infores:hetionet CHEBI:50131 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0019079 infores:hetionet CAID:CA014192 biolink:causes MONDO:0004994 infores:clingen CAID:CA014192 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3864C>G (p.Ser1288=) variant in the MYH7 gene is 1.33% (159/10404) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014192/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2663 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0520966 infores:hetionet CHEBI:71417 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0028738 infores:hetionet CHEBI:42944 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011168 infores:hetionet CHEBI:3515 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151872 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0021053 infores:hetionet CHEBI:39669 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0002878 infores:hetionet CHEBI:7465 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0010200 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0020538 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042401 infores:hetionet NCBIGene:3730 biolink:causes MONDO:0010635 infores:monarchinitiative not_provided not_provided HGNC:6211 MONDO:0010635 uuid:09550844-9e0e-43ca-95f6-bd447222c725 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0852911 infores:hetionet CHEBI:9137 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0028084 infores:hetionet CHEBI:51141 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0018681 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0595877 infores:hetionet CHEBI:9150 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0549622 infores:hetionet CHEBI:61049 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0231218 infores:hetionet CAID:CA120613 biolink:causes MONDO:0044970 infores:clingen CAID:CA120613 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS3_Supporting PP3, BP4, PS4, PS2, PM6 The m.5920G>A (p.W6Ter) variant in MT-CO1 has been reported in one individual to date, in a man with childhood onset myopathy, and myoglobinuria first noted in his 20s (case first reported in PMID: 10980727, also reported in PMIDs: 11506394, 11782982). His muscle biopsy showed scattered ragged red fibers (RRF) that stained intensely for SDH but not COX and numerous COX-negative/COX-deficient non-RRF. Immunohistochemistry showed markedly reduced immunostaining with antibodies to COX I and COX II, but normal reaction with antibodies to COX IV and COX VI. He had complex IV deficiency with activity being 32% controls. The variant was present at 61% heteroplasmy in muscle and was absent in blood and fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from his mother and sister, however given it was also absent in the proband’s blood, it is not conclusive the variant arose de novo. There are no additional reported de novo occurrences of this variant to our knowledge. Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in loss of the last 507 amino acids (99% of the protein, PVS1_strong). Single fiber testing showed that the variant was present in all COX-deficient fibers (n=15) and that the mean mutation load in affected fibers was 65% (SD, 32.6%). The variant was only detected in six of 25 COX-positive fibers tested, and the mutational load in COX-positive fibers was 5% (SD, 11.2%; PS3_supporting; PMID: 10980727). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120613/MONDO:0044970/015 2024-01-22 2024-03-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA220580 biolink:causes MONDO:0009861 infores:clingen CAID:CA220580 MONDO:0009861 PMID:27308838 Uncertain Significance PM4, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PM2: Identified a single time in gnomAD (4.06e-06) and absent in ExAC; PM4: p.Ala104_Val106del; PP4: Single patient picked up on NBS with no confirmation studies, no clinical info, no Phe levels, etc. (PMID:27308838). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220580/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:65173 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0013295 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0018939 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235750 infores:hetionet CAID:CA229571 biolink:causes MONDO:0009861 infores:clingen CAID:CA229571 MONDO:0009861 PMID:22330942 Uncertain Significance PM5, PM2, PP3 PM3, PP4 The c.473G>C (p.Arg158Pro) variant in PAH was reported in PMID: 22330942, but was listed as (p.Arg158Gln). Therefore, we are uncertain if the variant is c.473G>C, or p.Arg158Gln. This variant has an extremely low frequency in ExAC and gnomAD (MAF 0.00002). It is predicted deleterious in SIFT, Polyphen2, MutationTaster and REVEL=0.98. Two different pathogenic missense changes at this amino acid have been seen before (R158W, R158Q). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229571/MONDO:0009861/006 2020-02-28 2020-02-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63580 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030353 infores:hetionet CHEBI:4672 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0015967 infores:hetionet CHEBI:83531 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0034886 infores:hetionet NCBIGene:9573 biolink:causes MONDO:0013377 infores:monarchinitiative not_provided not_provided HGNC:4218 MONDO:0013377 uuid:4cd9e96a-bad1-4755-a01a-d7fae0a8711e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0003862 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040479 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0877095 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0877095 infores:hetionet CHEBI:18248 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0036973 infores:hetionet NCBIGene:546 biolink:causes MONDO:0010519 infores:monarchinitiative not_provided not_provided HGNC:886 MONDO:0010519 uuid:ce514079-1287-4299-a75a-5f4d82a53b9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5818 biolink:causes MONDO:0009151 infores:monarchinitiative not_provided not_provided HGNC:9706 MONDO:0009151 uuid:ca4abc69-e8b3-4fc7-b336-965a6f5c43ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0151942 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020649 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0006849 infores:hetionet CHEBI:63612 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0270612 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151736 infores:hetionet CAID:CA374971982 biolink:causes MONDO:0008535 infores:clingen CAID:CA374971982 MONDO:0008535 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4 The NM_001114753.3: c.1807G>A variant in ENG is a missense variant predicted to cause substitution of glycine by arginine at amino acid 603 (p.Gly603Arg). This variant has been reported in 4 probands with a phenotype consistent with Hereditary Hemorrhagic Telangiectasia (PS4, Internal lab contributors, PMID: 20414677). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.876 which is above the threshold of 0.644, evidence that correlates with impact to ENG function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PM2_Supporting, PP3 (specifications version 1.1.0; 11/12/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374971982/MONDO:0008535/136 2024-11-12 2024-11-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5864 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0231218 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0020649 infores:hetionet CHEBI:107736 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0043144 infores:hetionet CHEBI:521033 biolink:causes NCIT:C34437 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0006152 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030552 infores:hetionet CL:0000782 biolink:causes GO:0002372 infores:ubergraph knowledge_assertion manual_agent CL:0000782 GO:0002372 CHEBI:49575 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0037822 infores:hetionet CHEBI:63608 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0041834 infores:hetionet CHEBI:168396 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030252 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151571 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0009806 infores:hetionet NCBIGene:254428 biolink:causes MONDO:0859175 infores:monarchinitiative not_provided not_provided HGNC:19429 MONDO:0859175 uuid:01e3301c-942c-49df-b5e0-47950eed99d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes UMLS:C0853885 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0853885 infores:hetionet CHEBI:194135 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0039070 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0031117 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0017152 infores:hetionet CHEBI:8207 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0233763 infores:hetionet CHEBI:4710 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013390 infores:hetionet CHEBI:68554 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0034152 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020615 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0038362 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1384353 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0522063 infores:hetionet CHEBI:63631 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0575081 infores:hetionet CHEBI:3749 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0015672 infores:hetionet CHEBI:8884 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0003578 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001158 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009595 infores:hetionet CHEBI:3614 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0004604 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0022658 infores:hetionet CHEBI:51137 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0023530 infores:hetionet CHEBI:6375 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0034155 infores:hetionet CHEBI:16914 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0042109 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0001824 infores:hetionet CHEBI:75998 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0014591 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151763 infores:hetionet CHEBI:72297 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C2711227 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151735 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0027769 infores:hetionet NCBIGene:84706 biolink:causes MONDO:0014567 infores:monarchinitiative not_provided not_provided HGNC:18062 MONDO:0014567 uuid:196320b1-9f15-4a6b-8fe3-27de2e4db19c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0919980 infores:hetionet CHEBI:31348 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006625 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0030552 infores:hetionet CHEBI:50861 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0917801 infores:hetionet CHEBI:51041 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0015967 infores:hetionet CHEBI:9168 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019572 infores:hetionet CHEBI:50659 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0034069 infores:hetionet CHEBI:3478 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0010200 infores:hetionet CHEBI:7494 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0231530 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0392618 infores:hetionet CHEBI:15940 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0022354 infores:hetionet CAID:CA16615376 biolink:causes MONDO:0007648 infores:clingen CAID:CA16615376 MONDO:0007648 PMID:31642931PMID:31642931 Likely Pathogenic PM5_Supporting, PS4_Supporting, PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.1008+2T>C variant occurs at the canonical splice donor site of exon 7 and is predicted to result in a truncated or absent protein (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/). In addition, this variant has been identified in one family meeting IGCLC criteria for HDGC (PS4_supporting; SCV000545440.4). Although functional studies have not been reported for this variant, CDH1 c.1008G>T (p.Glu336Asp), affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID: 31642931). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615376/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:2453 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0041912 infores:hetionet CHEBI:9943 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085595 infores:hetionet CHEBI:8028 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0013384 infores:hetionet CHEBI:51173 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011124 infores:hetionet NCBIGene:6878 biolink:causes MONDO:0014931 infores:monarchinitiative not_provided not_provided HGNC:11540 MONDO:0014931 uuid:0b16a94c-c136-494e-8537-562d049e5419 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6761 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0004093 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0392197 infores:hetionet CHEBI:32221 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0041349 infores:hetionet CHEBI:31644 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151878 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0553704 infores:hetionet CAID:CA915949637 biolink:causes MONDO:0011132 infores:clingen CAID:CA915949637 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PVS1 PS3, PS4, PM3 The NM_001369369.1(FOXN1):c.933_936dup (p.Asp313ThrfsTer?) frameshift variant in exon 7, of 9, results in a premature stop codon in exon 8, which is predicted to cause NMD (PVS1). The variant was detected by exome sequencing with Sanger confirmation in one patient (Pt 1) who is compound heterozygous with c.1089_1103del (PMID: 31566583). The patient has normal hair and nails but T-B+NK+ SCID. They had Undetectable TRECs, at 3 months there were low CD3 31 cells/uL (0.5pt), and CD8 3 cells/uL, with NK 188 cells/uL, CD19+ 2159 cells/uL (PP4). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949637/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:3176 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0013395 infores:hetionet NCBIGene:9896 biolink:causes MONDO:0012640 infores:monarchinitiative not_provided not_provided HGNC:16873 MONDO:0012640 uuid:de8dc2e2-b4e1-4e5b-917d-af2c85903439 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0005778 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020651 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0004936 infores:hetionet NCBIGene:112 biolink:causes MONDO:0014570 infores:monarchinitiative not_provided not_provided HGNC:237 MONDO:0014570 uuid:c4451c6c-9082-4eb1-87b5-51bd422a0bb9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges MONDO:0100046 biolink:causes NCBIGene:4016 infores:ubergraph knowledge_assertion manual_agent MONDO:0100046 HGNC:6665 CHEBI:61049 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1306341 infores:hetionet CHEBI:10112 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0404521 infores:hetionet CHEBI:2914 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0002994 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0037274 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0031350 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0877314 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0877314 infores:hetionet CHEBI:16335 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0428977 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0234913 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0001125 infores:hetionet CHEBI:45716 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0149871 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0221201 infores:hetionet GO:0140590 biolink:causes GO:0140546 infores:ubergraph knowledge_assertion manual_agent GO:0140590 GO:0140546 NCBIGene:85015 biolink:causes MONDO:0032794 infores:monarchinitiative not_provided not_provided HGNC:20080 MONDO:0032794 uuid:9fb439c4-224f-4823-998b-f85bf79b1b74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70718 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0020517 infores:hetionet CHEBI:8207 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0023530 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0020649 infores:hetionet CHEBI:63681 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0005758 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042571 infores:hetionet CHEBI:7915 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151662 infores:hetionet CHEBI:5109 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0012833 infores:hetionet CHEBI:45783 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0003467 infores:hetionet CHEBI:41977 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0424790 infores:hetionet CHEBI:91583 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0428977 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0349506 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0013595 infores:hetionet CHEBI:50749 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0520893 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020676 infores:hetionet CHEBI:168396 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0231218 infores:hetionet CAID:CA056681 biolink:causes MONDO:0007783 infores:clingen CAID:CA056681 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate, PM5_Supporting PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 3772 of the RYR1 protein, p.(Arg3772Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000027, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 19191329). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg3772Gln), PM5_Supporting. A REVEL score >0.85 (0.939) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA056681/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3403 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0040264 infores:hetionet CHEBI:68841 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0018681 infores:hetionet CAID:CA409109837 biolink:causes MONDO:0015967 infores:clingen CAID:CA409109837 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS4_Moderate, PP1_Strong, PVS1_Strong PM1 The c.1A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; Internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; Internal lab contributors). In summary, c.1A>G meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PVS1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409109837/MONDO:0015967/085 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8768 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0542571 infores:hetionet CHEBI:68606 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0741494 infores:hetionet CHEBI:40279 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0016382 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0917799 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033975 infores:hetionet CHEBI:131512 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0278134 infores:hetionet CHEBI:75722 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002792 infores:hetionet CHEBI:8404 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0030193 infores:hetionet CHEBI:3640 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0042384 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1510497 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0040046 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0035204 infores:hetionet CHEBI:6375 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014457 infores:hetionet CHEBI:3219 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037672 infores:hetionet CHEBI:10124 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0032617 infores:hetionet NCBIGene:10587 biolink:causes MONDO:0040502 infores:monarchinitiative not_provided not_provided HGNC:18155 MONDO:0040502 uuid:2540b3cc-0a26-43b5-bfc8-5e26c3ce89c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0002962 infores:hetionet CHEBI:231594 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042029 infores:hetionet CHEBI:135736 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019825 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0016204 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0020649 infores:hetionet CAID:CA000293 biolink:causes MONDO:0017623 infores:clingen CAID:CA000293 MONDO:0017623 PMID: Likely Benign BP7, BS1, BP4 PTEN c.1104T>C (p.D368=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0057 (0.57%, 130/22,966 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000293/MONDO:0017623/003 2016-09-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7581 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0018681 infores:hetionet CHEBI:3441 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0017181 infores:hetionet CAID:CA020066 biolink:causes MONDO:0005835 infores:clingen CAID:CA020066 MONDO:0005835 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting BA1, BS1, PP1 The MSH2 (NM_000251.3):c.211G>C variant affects the last G of exon 1. mRNA assays using RNA derived from patient constitutional biological samples indicates that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to a premature stop codon (PVS1). It was identified in 4 CRC/EC tumours showing loss of MSH2/MSH6 expression in >2 families (PP4_strong). It was absent in gnomAD v2.1, v3.1 and v4.1 datasets (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1, PP4_Strong, and PM2_Sup (VCEP specifications version 1). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA020066/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42355 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0520893 infores:hetionet CHEBI:131512 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0085623 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0853760 infores:hetionet CHEBI:5864 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0027497 infores:hetionet CHEBI:5118 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0392525 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020649 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007222 infores:hetionet CHEBI:48273 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0018524 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0037928 infores:hetionet CHEBI:72292 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0948594 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0857257 infores:hetionet CAID:CA380144800 biolink:causes MONDO:0000573 infores:clingen CAID:CA380144800 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.77G>C is a missense variant predicted to cause substitution of Glycine by Alanine at amino acid 26 (p.Gly26Ala).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP:PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144800/MONDO:0000573/124 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7936 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029408 infores:hetionet CHEBI:9757 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0035455 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151601 infores:hetionet CHEBI:2682 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0015402 infores:hetionet CHEBI:36795 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235378 infores:hetionet CHEBI:50378 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0002453 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0025061 infores:hetionet CHEBI:72292 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0011991 infores:hetionet CHEBI:29688 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0039070 infores:hetionet CHEBI:36704 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0080274 infores:hetionet CHEBI:520985 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0005747 infores:hetionet CHEBI:119915 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0039231 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0021053 infores:hetionet CHEBI:50742 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0030305 infores:hetionet CHEBI:63621 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019079 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015256 infores:hetionet CHEBI:7447 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0003862 infores:hetionet CHEBI:3723 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030193 infores:hetionet CHEBI:75988 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0876994 infores:hetionet CAID:CA340744155 biolink:causes MONDO:0100368 infores:clingen CAID:CA340744155 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting PM5, PM3, PP3 NM_000329.3(RPE65):c.1078G>A is a missense variant predicted to replace alanine with threonine at position 360. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 affected proband who harbored the variant in the homozygous state (VCEP member-provided data). This variant has also been reported in at least 1 affected proband who harbored the variant in the compound heterozygous state (VCEP member-provided data) suspected in trans with the NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) variant, which was previously classified likely pathogenic by the ClinGen LCA / eoRD VCEP. However, neither proband was counted for PM3 because sufficient phenotype details were unavailable. Another variant at the same codon, NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro), has not yet been classified for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so PM5 is not yet met. The computational predictor REVEL gives a score of 0.521, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.08 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340744155/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:35553 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0152025 infores:hetionet CHEBI:9123 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0007820 infores:hetionet CHEBI:84500 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1306341 infores:hetionet NCBIGene:4087 biolink:causes MONDO:0030500 infores:monarchinitiative not_provided not_provided HGNC:6768 MONDO:0030500 uuid:1ed1120b-e688-4110-879e-ba2b95a9a1ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007971 infores:hetionet CHEBI:31643 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0027497 infores:hetionet CHEBI:7915 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0424295 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004936 infores:hetionet CHEBI:3654 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0262988 infores:hetionet CHEBI:7865 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0600142 infores:hetionet CHEBI:9654 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0234133 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0037036 infores:hetionet CHEBI:144093 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0019572 infores:hetionet CHEBI:171719 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0020672 infores:hetionet CHEBI:472657 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0042963 infores:hetionet CAID:CA355963315 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963315 MONDO:0001586 PMID: Uncertain Significance PM5, PP3_Moderate, PM2_Supporting The NM_000203.5:c.1091C>A variant in IDUA is a missense variant predicted to cause substitution of threonine by lysine at amino acid 364 (p.Thr364Lys). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I, and no results of functional assays are available. This variant is absent in gnomAD v4.1.0.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997; PP3_Moderate). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM2_Supporting, PP3_Moderate, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963315/MONDO:0001586/091 2024-12-05 2025-03-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4551 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0040034 infores:hetionet CHEBI:8356 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0149871 infores:hetionet CHEBI:74947 biolink:causes MONDO:0009718 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027145 infores:hetionet CHEBI:5778 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042023 infores:hetionet CHEBI:15854 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0002874 infores:hetionet CHEBI:74947 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0036974 infores:hetionet CHEBI:74947 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020757 infores:hetionet CAID:CA348840 biolink:causes MONDO:0007356 infores:clingen CAID:CA348840 MONDO:0007356 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000249.4(MLH1):c.1558+1G>A variant in APC affects a donor splice site in intron 13 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product and loss-of-function variants in MLH1 are known to be pathogenic (PVS1 met). The variant is reported once in gnomAD v4.1 (PM2_supporting met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal-dominant inherited Lynch-syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PVS1 and PM2_supporting applied. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA348840/MONDO:0007356/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CAID:CA410148207 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148207 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1076C>T (p.Pro359Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148207/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0037763 infores:hetionet CAID:CA5689679 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689679 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.886C>T (p.Leu296=) variant in the SHOC2 gene is 0.08% (15/11572) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689679/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:27436 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0340865 infores:hetionet CAID:CA391999585 biolink:causes MONDO:0015152 infores:clingen CAID:CA391999585 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3, PP3, PM2_Supporting PM5, PP1 The NM_000070.3: c.1322G>A variant in CAPN3 is a missense variant expected to result in the substitution of glycine with aspartic acid at amino acid 441, p.(Gly441Asp). This variant has been reported in four individuals with features consistent with LGMD (PMID: 16372320, 37526466, 16650086, 25135358; ClinVar SCV003442816.3 internal data communication), including in a homozygous state without reported familial consanguinity in one patient (0.5 pts; PMID: 16372320, 37526466, 25135358) and in unconfirmed phase with a pathogenic variant in two patients (c.550del p.(Thr184ArgfsTer36), 0.5 pts, ClinVar SCV003442816.3 internal data communication; c.1714C>T p.(Arg572Trp), 0.5 pts, PMID: 16650086) (PM3). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and only trace amounts of calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 16650086). The variant is not found in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/29/2025): PM3, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA391999585/MONDO:0015152/187 2025-10-29 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46081 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0311468 infores:hetionet CHEBI:8060 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C2830004 infores:hetionet CHEBI:2038 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0011168 infores:hetionet CHEBI:119573 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017168 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0009450 infores:hetionet CHEBI:9168 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0026826 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0011991 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033117 infores:hetionet CHEBI:31236 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085612 infores:hetionet CHEBI:231594 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042024 infores:hetionet CHEBI:119486 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0039231 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0002453 infores:hetionet UBERON:0001982 biolink:causes MONDO:0016231 infores:ubergraph knowledge_assertion manual_agent UBERON:0001982 MONDO:0016231 CHEBI:253342 biolink:causes UMLS:C0281825 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0281825 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0041976 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0012359 infores:hetionet CAID:CA025429 biolink:causes MONDO:0700269 infores:clingen CAID:CA025429 MONDO:0700269 PMID: Uncertain Significance PP3, PS3 PM2, BS1, BP5, BP7, PP4, BA1 The c.8059G>T variant in BRCA2 is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 2687 (p.(Val2687Phe)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (Internal lab contributor) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.42 (based on Family History LR=1.42), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025429/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:92712 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0728899 infores:hetionet GO:1905079 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0007417 CHEBI:42797 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020649 infores:hetionet NCBIGene:64805 biolink:causes MONDO:0012354 infores:monarchinitiative not_provided not_provided HGNC:18124 MONDO:0012354 uuid:a7e20bb3-ed7e-46b7-a220-eeb4b9ae7bc0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013595 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018674 infores:hetionet CHEBI:50173 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0231218 infores:hetionet CAID:CA9043635 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043635 MONDO:0012999 PMID: Likely Benign PM2_Supporting, BP4, BS3_Supporting PM5 The NM_000156.6:c.471T>G variant in GAMT is a missense variant predicted to cause the substitution of a phenylalanine for a leucine at amino acid position 157 (p.Phe157Leu). This variant has been identified in two individuals in the Exome Variant Server database without detailed phenotypic information available (PMID: 26003046). The highest population frequency in gnomAD v4.1.0. is 0.00002119 (25/1180010 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in HeLa cells resulted in similar activity versus wild-type GAMT, indicating that this variant does not impact protein function (PMID: 26003046) (BS3_Supporting). The computational predictor REVEL gives a score of 0.259 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 517082). Although there is conflicting evidence, with two benign criteria were met (BP4 and BS3_Supporting) and one pathogenic criterion met (PM2_Supporting), the consensus from the ClinGen CCDS VCEP is that this variant is likely benign for GAMT deficiency, based upon the in silico and functional evidence. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BS3_Supporting, BP4 (classification modified to likely benign)(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 14, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043635/MONDO:0012999/026 2024-11-14 2025-03-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3568 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0870082 infores:hetionet CHEBI:74947 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038325 infores:hetionet NCBITaxon:138 biolink:causes MONDO:0006681 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:138 MONDO:0006681 CHEBI:8214 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0043352 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0178298 infores:hetionet CHEBI:140621 biolink:causes UMLS:C0857370 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0857370 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006840 infores:hetionet CHEBI:7903 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0026636 infores:hetionet CHEBI:87681 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0040822 infores:hetionet CHEBI:3441 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0004245 infores:hetionet GO:0080092 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:0080092 GO:0030154 GO:0070366 biolink:causes GO:0061008 infores:ubergraph knowledge_assertion manual_agent GO:0070366 GO:0061008 CHEBI:101085 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0018681 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0004096 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0009450 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C1565489 infores:hetionet CHEBI:100241 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085631 infores:hetionet CHEBI:2549 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C2939147 infores:hetionet NCBIGene:80000 biolink:causes MONDO:0024520 infores:monarchinitiative not_provided not_provided HGNC:31042 MONDO:0024520 uuid:d926d5d9-f7ce-49aa-8d16-5bb8c8716065 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0022603 infores:hetionet CHEBI:2038 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0013604 infores:hetionet CHEBI:70735 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0003467 infores:hetionet CHEBI:44185 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0014335 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0518015 infores:hetionet CHEBI:17303 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0234518 infores:hetionet CHEBI:4708 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085631 infores:hetionet CAID:CA1139771135 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139771135 MONDO:0011071 PMID:34166225 Pathogenic PM5_Supporting, PVS1, PS3_Moderate, PM2_Supporting PS1, PS4, PS2, BP2, BP1, BP4, BP3, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM3, PM4, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.698del (p.Arg233ProfsTer4) is a variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) (17.93%) (PS3_moderate). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS3_moderate, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771135/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31397 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0018681 infores:hetionet CHEBI:63580 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0043094 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0030305 infores:hetionet CAID:CA981153094 biolink:causes MONDO:0008723 infores:clingen CAID:CA981153094 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4:c.770del (p.Asp257AlafsTer19) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 30194637, 20547398). Additionally, this variant was identified in an individual who reportedly had increased acylcarnities and decreased very long chain acyl-CoA dehydrogenase (VLCAD) activity, but this information was insufficient to use toward classification (PMID: 12682504). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA981153094/MONDO:0008723/021 2023-01-10 2023-01-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6804 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0020649 infores:hetionet NCBIGene:25959 biolink:causes MONDO:0033280 infores:monarchinitiative not_provided not_provided HGNC:29300 MONDO:0033280 uuid:54a1004c-3641-4559-9a0a-111e959ddbe4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C2047937 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0030353 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0520588 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0340464 infores:hetionet CHEBI:167309 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0016658 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020676 infores:hetionet CHEBI:101278 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013456 infores:hetionet CHEBI:9139 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0003862 infores:hetionet NCBITaxon:103826 biolink:causes MONDO:0000299 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:103826 MONDO:0000299 CHEBI:3732 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014868 infores:hetionet CAID:CA145982 biolink:causes MONDO:0009861 infores:clingen CAID:CA145982 MONDO:0009861 PMID: Benign BS2, BP4, BA1 The c.735G>A (p.Val245=) variant in PAH has a MAF of 0.29058 in ExAC (BA1; http://exac.broadinstitute.org) with 6,524 homozygotes (BS2). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP4). In summary, this variant meets criteria to be classified as benign. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA145982/MONDO:0009861/006 2018-04-24 2019-04-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:18248 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0151603 infores:hetionet CAID:CA2061382 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061382 MONDO:0015924 PMID: Likely Benign BP4, BP7 PM2, BA1, BS1 The BMPR2 c.1512T>G;p.(leu504=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.0138% (2/14452 alleles) in the North-Western European population, which is lower than the ClinGen Pulmonary Hypertension VCEP threshold of >0.1% for BS1 and >1% for BA1, but higher than the threshold of <0.01% for PM2 (BS1, BA1 and PM2 are not met). BS2 was not met as the variant was not observed as a homozygous allele in gnomAD v2.1.1 controls. BP4 is met based on the computational predictor, CADD, giving a score of 8.3 which is below the threshold of ≤10.0 for BP4. Due to the absence of segregation data, PP1, PM6 and PS2 could not be evaluated. Due to absence of functional data, BS3 and PS3 could not be evaluated. In summary, the variant meets the criteria to be classified as a likely benign variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BP4, BP7 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061382/MONDO:0015924/125 2024-05-02 2024-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA229369 biolink:causes MONDO:0009861 infores:clingen CAID:CA229369 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PM5, PM2_Supporting PP4 The c.1175T>C (p.Phe392Ser) variant in PAH was reported in one individual with PAH deficiency; however, this report was non-English article that is not accessible and thus cannot be used as case-level evidence at this time (PMID: 22333022). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and is predicted damaging by REVEL = 0.98 (PP3_Strong). A different missense variant at the same position, p.F392I, is reported as pathogenic in ClinVar (VarID: 853581) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM5, PP3_Strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229369/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49960 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020538 infores:hetionet CAID:CA412739725 biolink:causes MONDO:0100437 infores:clingen CAID:CA412739725 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PP1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.1234C>T (p.Arg412Ter) is a nonsense variant that introduces a premature stop codon in exon 10 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance showing no male-to-male transmission (2 pts) and female carriers showing milder symptoms (1 pt), night blindness (0.5 pts), visual acuity reduction (0.5 pts), myopia (0.5 pts), and non-recordable electroretinogram responses, with genotyping by whole exome sequencing panel identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (6.5 points, PMID: 32702353, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 24938718, PMID: 34745198, PMID: 32702353, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from at least 1 family (PP1; PMID: 24938718). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1, PP4, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412739725/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:31348 biolink:causes UMLS:C0856554 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0856554 infores:hetionet CAID:CA7542898 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542898 MONDO:0012996 PMID: Uncertain Significance PP3_Moderate, PS3_Supporting BS1, PM2 The NM_001482.3:c.565C>T variant in GATM is a missense variant that is predicted to result in the substitution of arginine by cysteine at amino acid 189 (p.Arg189Cys). To our knowledge, this variant has not been reported in individuals with AGAT deficiency in the published literature. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006683 (3/44888 alleles) in the East Asian population. This is higher than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), and lower than the threshold for BS1 (Grpmax >0.0001). Therefore, none of the population data codes are met. When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of [0.881] which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 225915). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0.): PS3_Supporting, PP3_Moderate.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542898/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7478 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0037763 infores:hetionet CHEBI:68579 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0008031 infores:hetionet CHEBI:9139 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0242301 infores:hetionet CHEBI:15940 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020580 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0023530 infores:hetionet CAID:CA124454 biolink:causes MONDO:0015967 infores:clingen CAID:CA124454 MONDO:0015967 PMID:10585442PMID:12530534PMID:27899486 Pathogenic PM2_Supporting, PS3_Moderate, PS4, PP1_Strong, PS2_Supporting, PP4, PP3 The c.1340C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 447 (p.(Pro447Leu)) of NM_000545.8. This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY ([MODY probability calculator result <50%/HNF4A not tested) (PS2_Supporting; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro447Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMIDs: 27899486, 12530534, 10585442, 32910913, 32910913). This variant was identified in 11 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with at least 15 informative meioses in families with MODY (PP1_Strong; internal lab contributors), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.1340C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PS4, PP1_Strong, PP3, PP4, PS2_Supporting, PM2_Supporting, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124454/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49960 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0033687 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0033777 infores:hetionet CHEBI:47898 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036980 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0015397 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0010692 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0161479 infores:hetionet CHEBI:63611 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0018524 infores:hetionet CHEBI:2569 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C1619712 infores:hetionet CHEBI:3996 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0086565 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0004239 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042514 infores:hetionet NCBIGene:4792 biolink:causes MONDO:0012806 infores:monarchinitiative not_provided not_provided HGNC:7797 MONDO:0012806 uuid:cb32f235-5780-4535-ae4b-fae7ce2cc553 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0344232 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0162429 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0178298 infores:hetionet CAID:CA356984 biolink:causes MONDO:0001586 infores:clingen CAID:CA356984 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.1029C>A (p.Tyr343Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 8 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes and urinary GAGs expressed as heparan and dermatan sulfate GAG elevation above normal range (PP4; PMID: 35141277). This variant has been detected in at least 2 individuals with MPS I. Of those individuals, both were compound heterozygous for the variant and a pathogenic variant (c.208C>T p (Gln70Ter)) and neither of those were confirmed in trans (PM3; PMID: 35141277). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0): PVS1, PP4, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA356984/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50730 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C3263723 infores:hetionet CHEBI:31302 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0162119 infores:hetionet CHEBI:2704 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0030794 infores:hetionet CHEBI:3647 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0241442 infores:hetionet CHEBI:8764 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0037763 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027697 infores:hetionet CHEBI:7447 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0033687 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0007117 infores:hetionet CHEBI:6954 biolink:causes HP:0001103 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0730362 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0027051 infores:hetionet CAID:CA8815394 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815394 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 The NM_000152.5:c.1629C>T (p.Tyr543=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100 (-0.851) (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004949 (3/6062 alleles; 1 homozygote) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). It has not been reported in any individuals with Pompe disease to our knowledge. There is a ClinVar entry for this variant (Variation ID: 510672). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, BP4, BP7. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 3, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815394/MONDO:0009290/010 2024-09-03 2024-09-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:171719 biolink:causes UMLS:C0302810 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0302810 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0152227 infores:hetionet CAID:CA376061145 biolink:causes MONDO:0011225 infores:clingen CAID:CA376061145 MONDO:0011225 PMID: Likely Pathogenic PS3_Moderate, PM2_Supporting, PM3, PP4_Strong The NM_001033855.3:c.353G>T variant in DCLRE1C is a missense variant predicted to cause substitution of glycine by valine at amino acid 118 (p.Gly118Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001334 (1/74972 alleles) in African/African American population, which is lower than the SCID-VCEP threshold (<0.0001742) for PM2_Supporting. No homozygous individual has been observed (PM2_Supporting). The variant was observed in two patients who were homozygous for this variant (PMIDs 12406895, 19953608). One patient was from a consanguineous family and the consanguinity status of the other family was not known (PM3). One patient (PMID: 12406895) presented with a T-B-NK+ lymphocyte profile. Patient fibroblasts showed increased radiosensitivity (>1 log of decreased cell survival) and decreased V(D)J recombination compared to control cells, and vector-based complementation corrected the decreased V(D)J recombination (PP4_Strong). In addition, the variant also shows significantly decreased activity in both an in vitro DNA repair activity assay and an in vitro V(D)J recombination assay (PMID 25917813) (PS3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3, PP4_Strong, PS3_Moderate. (VCEP specifications version 2.1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376061145/MONDO:0011225/116 2025-11-03 2025-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2666 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0039070 infores:hetionet CHEBI:3732 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0018790 infores:hetionet CHEBI:47381 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0040264 infores:hetionet NCBITaxon:6202 biolink:causes MONDO:0000367 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6202 MONDO:0000367 CHEBI:135005 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0018799 infores:hetionet CHEBI:367163 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085605 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0036572 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0040034 infores:hetionet CAID:CA020131 biolink:causes MONDO:0008667 infores:clingen CAID:CA020131 MONDO:0008667 PMID:21715564 Pathogenic PS4, PM2_Supporting, PM1, PP3, PS3_Supporting, PM6 The variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser) is a missense variant predicted to cause substitution of Asparagine by Serine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 16 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 15.25, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:728151; 23842656; 25952756; 21463266; 25078357; 8634692; 23407287; 8707293; 8730290; 18067796; 12114495; 12202531; 17024664; 28388566; 18446368; 10567493; 29294023; 11850829) This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VHL (PMID:12114495) (PM6). This variant is also seen 4 times in cancerhotspots.org, which meets the criteria of PM1_Supporting, when using somatic data to inform a germline variant curation. However, as the variant resides in the first Beta domain of VHL, a critical functional domain, it meets the full moderate criteria of (PM1). Functional data shows this variant did not alter expression of HIF1a (102% for HIF1α , similar to the truncating control used) and 86% expression for HIF2α (PS3_Supporting; PMID:21715564). The computational predictor REVEL gives a score of 0.767, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020131/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2704 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0010200 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0037199 infores:hetionet CHEBI:64312 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0016655 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0040479 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0041912 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0038454 infores:hetionet CAID:CA024475 biolink:causes MONDO:0007783 infores:clingen CAID:CA024475 MONDO:0007783 PMID: Uncertain Significance PM1, PS4_Moderate PP3, PS3_Moderate, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with asparagine at codon 166 of the RYR1 protein, p.(Asp166Asn). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:12059893, PMID:16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.826 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024475/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10125 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0086439 infores:hetionet CAID:CA8970229 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970229 MONDO:0012589 PMID: Uncertain Significance BS2_Supporting PM1, PS4, BP4, BS1 The highest population minor allele frequency of the p.Met450Thr variant in TCF4 in gnomAD v4.1.0 is 0.00001 in African/African American and European (Non-Finnish) populations (not sufficient to meet BS1 criteria). The p.Met450Thr variant is observed in at least 1 unaffected individual (internal data, LabCorp Genetics Inc.) (BS2_Supporting). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.523). In summary, the p.Met450Thr variant in TCF4 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2_Supporting). (TCF4 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970229/MONDO:0012589/032 2025-02-28 2025-03-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3127 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0340464 infores:hetionet CHEBI:194135 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0015403 infores:hetionet CHEBI:51450 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0855329 infores:hetionet CHEBI:8481 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0553721 infores:hetionet CHEBI:5123 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0686347 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0040034 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0042109 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0003123 infores:hetionet CHEBI:134936 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0013390 infores:hetionet CHEBI:474180 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0017152 infores:hetionet CHEBI:45783 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151686 infores:hetionet CHEBI:681848 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0015644 infores:hetionet CHEBI:50381 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0025345 infores:hetionet CHEBI:4995 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0231218 infores:hetionet CHEBI:10119 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes HP:0032252 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018188 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151477 infores:hetionet CHEBI:7514 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0007222 infores:hetionet CHEBI:17698 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0002874 infores:hetionet CHEBI:77260 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0018524 infores:hetionet CAID:CA387749574 biolink:causes MONDO:0700269 infores:clingen CAID:CA387749574 MONDO:0700269 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.8164A>G variant in BRCA2 is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 2722 (p.(Thr2722Ala)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by four calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779848, 39779857, 37713444) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.4, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA387749574/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports UNII:9430ZR8ZAN biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042963 infores:hetionet CHEBI:6413 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0232461 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0020456 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0151773 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019158 infores:hetionet CHEBI:63620 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085932 infores:hetionet NCBIGene:79443 biolink:causes MONDO:0012395 infores:monarchinitiative not_provided not_provided HGNC:14673 MONDO:0012395 uuid:b4c8c8e4-b3c8-4317-ad0e-b05d1902daae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0438215 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0021053 infores:hetionet CHEBI:45367 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0424605 infores:hetionet CHEBI:9150 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0037317 infores:hetionet CHEBI:3504 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C2129214 infores:hetionet CHEBI:3207 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0151686 infores:hetionet CAID:CA117009 biolink:causes MONDO:0011225 infores:clingen CAID:CA117009 MONDO:0011225 PMID: Uncertain Significance PP1, PP4, PM2_Supporting, PVS1_Supporting BS2, PS3, PM3 The c.2T>C (p.Met1Thr) (NM_001033855.3) is a missense variant predictedto cause the substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). The next possible initiation codon is at codon 8. This region does not contain known pathogenic/likely pathogenic variants, PVS1_Supporting.The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68040 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting).At least one patient was observed in the literature (PMID: 15731174) presenting: * Diagnostic criteria for Omenn syndrome (0.5pt) + * Increased cellular radiosensitivity (0.5pt) = total 1 point, PP4_Supporting. The variant has been reported to segregate with OS in - at least - 02 affected family members (proband + one brother) from one family (PP1_Supporting). The patient also had another affected brother without genomic information (PMID: 15731174).This patient is compound heterozygous with c.103C>G (H35D). Phase is confirmed; Pathogenic according to the SCID VCEP specifications; Not counted here to avoid circularity.Two functional assays were found: PMID: 15731174 shows that the ARTEMIS variant (M1T) resulted in a V(D)J recombination efficiency of 2.1% to 2.7%. This corresponds to a recombination efficiency of between 37% and 48% when compared with the assay with WT-ARTEMIS (Which is higher than our threshold, 25%. In the second reference, the activity levels (in % of WT activity) are Recombination (Mean, SD): 80.41, 4.77 and DNA repair (Mean, SD): 76.04, 6.43. Both exceed the established threshold for PS3 (<25% of wild-type activity). With this, PS3 is not applied at any level of evidence.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: (specification version 1.0): PVS1_Supporting, PM2_Supporting, PP1_Supporting, and PP4_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA117009/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7445 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0025320 infores:hetionet CHEBI:50749 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0237849 infores:hetionet CHEBI:15552 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0242184 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0031117 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027441 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027947 infores:hetionet GO:0003310 biolink:causes CL:0000171 infores:ubergraph knowledge_assertion manual_agent GO:0003310 CL:0000171 CHEBI:47780 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151878 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0750197 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0750197 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0029878 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0020675 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C2004435 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0426576 infores:hetionet CHEBI:6367 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003467 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0413252 infores:hetionet CHEBI:5165 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0027497 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0405479 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0405479 infores:hetionet CHEBI:39669 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0014518 infores:hetionet CHEBI:7915 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0018843 infores:hetionet NCBIGene:3561 biolink:causes MONDO:0010730 infores:monarchinitiative not_provided not_provided HGNC:6010 MONDO:0010730 uuid:4943887a-ee62-4447-8861-8cf5c2e65856 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0852911 infores:hetionet CHEBI:63607 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0041834 infores:hetionet CHEBI:63598 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020452 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042571 infores:hetionet CHEBI:5384 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0020517 infores:hetionet CHEBI:180905 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0003467 infores:hetionet CHEBI:3478 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0404521 infores:hetionet CHEBI:94807 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0035455 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004245 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0029408 infores:hetionet CAID:CA024649 biolink:causes MONDO:0007783 infores:clingen CAID:CA024649 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate PS3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with valine at codon 227 of the RYR1 protein, p.(Asp227Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024649/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:42797 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0012569 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0027769 infores:hetionet CHEBI:3219 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0231530 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0520872 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0520872 infores:hetionet CHEBI:71272 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0016655 infores:hetionet CHEBI:10650 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013384 infores:hetionet CAID:CA165539 biolink:causes MONDO:0700270 infores:clingen CAID:CA165539 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5_Supporting, PVS1 PP3 The c.1355del (p.Thr452AsnfsTer21) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 9463314, 10234507, 26896183). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Supporting, PM2_Supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA165539/MONDO:0700270/020 2023-09-07 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31711 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0013395 infores:hetionet CHEBI:6887 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C2939147 infores:hetionet CHEBI:72564 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C2979982 infores:hetionet CHEBI:83531 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0231218 infores:hetionet CHEBI:49713 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0004134 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0021053 infores:hetionet CHEBI:6640 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0237849 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0853761 infores:hetionet UMLS:C0657912 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0028734 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0027765 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009763 infores:hetionet CHEBI:52717 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0041364 infores:hetionet CHEBI:10650 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1260922 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009450 infores:hetionet CHEBI:63610 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0025345 infores:hetionet CHEBI:63580 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0586553 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0004936 infores:hetionet CHEBI:6520 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C1142499 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232492 infores:hetionet CHEBI:8874 biolink:causes UMLS:C1504422 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1504422 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009782 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0521491 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0002170 infores:hetionet CHEBI:3207 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0041657 infores:hetionet CHEBI:100147 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0012569 infores:hetionet CHEBI:9654 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042571 infores:hetionet CHEBI:6367 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1579838 infores:hetionet CHEBI:3561 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0231530 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0020538 infores:hetionet CHEBI:52172 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0015402 infores:hetionet CHEBI:3698 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0003467 infores:hetionet CHEBI:92923 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0009763 infores:hetionet CHEBI:119486 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0232462 infores:hetionet CHEBI:45409 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0702166 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020651 infores:hetionet CAID:CA410148073 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148073 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BS1, BS3, BS4, BP7, PVS1, PM6, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1114G>A (p.Gly372Ser) is a missense variant which is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.22, which is below the threshold of 0.50 (BP4). Additionally, this variant has been reported in only one proband meeting at least one of the RUNX1-phenotypic criteria, although its germinal origin cannot be confirmed. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148073/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:UMD7G2653W biolink:causes MONDO:0001439 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0014583 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0332575 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0013922 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1609512 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042594 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0549622 infores:hetionet NCBIGene:9419 biolink:causes MONDO:0014347 infores:monarchinitiative not_provided not_provided HGNC:14312 MONDO:0014347 uuid:6523a954-5dfb-4913-a468-5f413e2037f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512341290 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341290 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1125G>A (p.Thr375=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-2.99) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341290/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7445 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0029453 infores:hetionet GO:0035813 biolink:causes GO:0055078 infores:ubergraph knowledge_assertion manual_agent GO:0035813 GO:0055078 CHEBI:8435 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0002878 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0034150 infores:hetionet CHEBI:101278 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042023 infores:hetionet CHEBI:2659 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0015230 infores:hetionet CHEBI:7565 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0019080 infores:hetionet CHEBI:168396 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0039231 infores:hetionet CHEBI:39669 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0018965 infores:hetionet CHEBI:15551 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0030193 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027339 infores:hetionet CHEBI:474053 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0004093 infores:hetionet CAID:CA281000 biolink:causes MONDO:0007648 infores:clingen CAID:CA281000 MONDO:0007648 PMID:16061854PMID:21696387PMID:11419427PMID:16061854PMID:9751616PMID:21696387PMID:16061854PMID:21696387 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS2, PS4, PP1_Strong BP5, BP7, BS1, BS4, BS3, PM1, PM3, PM4, PM6, PP3, PP2, PP4, BS2, BP4, BP1, BP2, BP3, BA1, PS3, PS1 The c.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID: 9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 21696387). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PP1_Strong, PS4, PS2, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA281000/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7459 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0234238 infores:hetionet CHEBI:5004 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0009676 infores:hetionet CHEBI:100246 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0017979 infores:hetionet CHEBI:5864 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0017181 infores:hetionet UNII:UMD7G2653W biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0221201 infores:hetionet CHEBI:3650 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0020625 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0031212 infores:hetionet CHEBI:51860 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0030252 infores:hetionet CHEBI:7959 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0014518 infores:hetionet CAID:CA913175506 biolink:causes MONDO:0044970 infores:clingen CAID:CA913175506 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, BP4, PS4, PS3 The m.578T>C variant in MT-TF has been reported once in a cohort of individuals with primary mitochondrial disease, however clinical details were not provided precluding this case from being considered for this curation (PMID: 31965079). This variant has also been reported in monozygotic twins at low heteroplasmy levels. One twin had multiple sclerosis (MS) and one did not. Of note, MS is not considered a primary mitochondrial disease and the heteroplasmy levels were very low, so these individuals were not included in this curation (PMID: 27119776). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (78.3 percentile) but HmtVAR predicts it to be neutral with a score of 0.05. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note one expert felt likely benign was the more appropriate classification. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913175506/MONDO:0044970/015 2024-08-12 2025-04-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63581 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0795692 infores:hetionet GO:0106088 biolink:causes GO:0048514 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0048514 CHEBI:490877 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0001824 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042267 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0017178 infores:hetionet CHEBI:3716 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0042963 infores:hetionet CHEBI:7478 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0006277 infores:hetionet UMLS:C0011701 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0022107 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020624 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0855242 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0034150 infores:hetionet CHEBI:8212 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0009782 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233414 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0231441 infores:hetionet CHEBI:63631 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042790 infores:hetionet CHEBI:135929 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0030252 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151763 infores:hetionet CHEBI:4672 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0039239 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0002884 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1609512 infores:hetionet CHEBI:3215 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0002994 infores:hetionet CHEBI:7444 biolink:causes MONDO:0043475 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0001396 infores:hetionet CHEBI:135622 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB06771 UMLS:C0022281 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0006849 infores:hetionet CHEBI:3640 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0038325 infores:hetionet CHEBI:5138 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0404521 infores:hetionet CHEBI:194135 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0520966 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0038525 infores:hetionet CHEBI:27999 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0162830 infores:hetionet NCBIGene:5824 biolink:causes MONDO:0013951 infores:monarchinitiative not_provided not_provided HGNC:9713 MONDO:0013951 uuid:aabe8679-c337-4427-ae46-c805bf46c441 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5063 biolink:causes MONDO:0010361 infores:monarchinitiative not_provided not_provided HGNC:8592 MONDO:0010361 uuid:b1273962-7646-4e65-9e94-6fd2d80e5827 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0152031 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002185 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020492 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0034063 infores:hetionet CHEBI:45783 biolink:causes MONDO:0007950 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0024899 infores:hetionet CAID:CA512341271 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341271 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS3, BS4, BS1, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1149G>A (p.Pro383=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.25)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341271/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0065374 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0001824 infores:hetionet CHEBI:68575 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0025061 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027813 infores:hetionet CHEBI:6754 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0027497 infores:hetionet CAID:CA409110090 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110090 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting PP3, PM1, BP4 The c.1127T>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of methionine to arginine at codon 376 (p.(Met376Arg)) of NM_175914.5. This variant has a REVEL score of 0.235, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1127T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110090/MONDO:0015967/085 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7444 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0030848 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0015397 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0040034 infores:hetionet CHEBI:8028 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0030232 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0851341 infores:hetionet CHEBI:5296 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0162429 infores:hetionet CHEBI:8597 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0040034 infores:hetionet CHEBI:63611 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002390 infores:hetionet CHEBI:64312 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027796 infores:hetionet CAID:CA024368 biolink:causes MONDO:0007783 infores:clingen CAID:CA024368 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Alanine with Threonine at codon 933 of the RYR1 protein, p.(Ala933Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00388, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024368/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9570 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0237938 infores:hetionet CHEBI:7466 biolink:causes UMLS:C1142159 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C1142159 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0160390 infores:hetionet CHEBI:46345 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0020757 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0006266 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0233494 infores:hetionet CHEBI:585948 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0033774 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0233632 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0033687 infores:hetionet CAID:CA16608777 biolink:causes MONDO:0012589 infores:clingen CAID:CA16608777 MONDO:0012589 PMID: Uncertain Significance BS2_Supporting, BP5, BP7, PM2_Supporting BA1, BS1 The p.Ser198= variant in TCF4 is absent from gnomAD v4.1 (PM2_Supporting). The p.Ser198= variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2_Supporting). The p.Ser198= variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The silent p.Ser198= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ser198= variant in TCF4 is classified as Uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, BS2_Supporting, BP5, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608777/MONDO:0012589/032 2024-08-30 2024-11-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0024115 infores:hetionet CHEBI:3219 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0424295 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0429098 infores:hetionet CHEBI:2208 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0030305 infores:hetionet CHEBI:28748 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0600142 infores:hetionet CHEBI:3215 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0687713 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037822 infores:hetionet CHEBI:8776 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C1443060 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0029408 infores:hetionet CHEBI:45783 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0852911 infores:hetionet CHEBI:10119 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085631 infores:hetionet CAID:CA346124255 biolink:causes MONDO:0010986 infores:clingen CAID:CA346124255 MONDO:0010986 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.2215-1G>C variant in OTOF occurs within the canonical splice acceptor site (-1) of intron 18. It is predicted to cause skipping of biologically-relevant-exon 19 of 47, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic deafness based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PVS1 and PM2_P (ClinGen Hearing Loss VCEP specifications version 2; 7/21/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA346124255/MONDO:0010986/023 2022-07-21 2022-09-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:3286 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0009676 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037274 infores:hetionet CAID:CA10585399 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585399 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BA1, BP4, BP2, PS1, PS4, PS2, BP7, BS1, BS4, PM4, PM1, PM3, PVS1, PM6, PP4, PP1, BS2 The NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PM5) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.859.It is above 0.75, so PP3 is Met.PM5 - 2 other missense variants in the same codon:- NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) (ClinVar ID: 251784) - VUS by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585399/MONDO:0007750/013 2022-01-17 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50777 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0549622 infores:hetionet CHEBI:8764 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0025289 infores:hetionet CHEBI:49713 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0023518 infores:hetionet CAID:CA10651554 biolink:causes MONDO:0012999 infores:clingen CAID:CA10651554 MONDO:0012999 PMID: Pathogenic PP3, PM2_Supporting, PP4_Strong, PM3_Strong, PS3_Supporting The NM_000156.6:c.133T>A variant in GAMT is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 45 (p.Trp45Arg). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID: 24415674, PMID: 29506905, PMID: 23660394, PMID: 24268530). Of those individuals, one was homozygous for the variant (PMID: 29506905), two were compound heterozygous for the variant and a pathogenic variant, c.327G>A, in trans (phase confirmed by parental testing) (PMID: 24415674, PMID: 23660394), and two were compound heterozygous for the variant and a pathogenic variant, c.327G>A, with phase unknown (PMID: 24268530) (3pts total, PM3_Strong). One of these individuals had an absent creatine peak and present GAA peak on brain MRS and elevated GAA in urine (PMID: 24415674) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in undetectable GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.95 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 328352). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Strong, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10651554/MONDO:0012999/026 2023-11-08 2023-11-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6909 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0750394 infores:hetionet MONDO:0017611 biolink:causes MONDO:0019933 infores:drugmechdb knowledge_assertion manual_agent MESH:D010911 MESH:D000172 DB01200_MESH_D000172_1 CHEBI:28787 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0221242 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0041657 infores:hetionet CHEBI:6359 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0232487 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0018939 infores:hetionet CHEBI:59773 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0162830 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004844 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0023532 infores:hetionet CHEBI:59773 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0030312 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0151601 infores:hetionet CHEBI:4514 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0030193 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018801 infores:hetionet CHEBI:161680 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0002792 infores:hetionet CHEBI:42820 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0009676 infores:hetionet UMLS:C0145867 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0018681 infores:hetionet CHEBI:9667 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0237849 infores:hetionet CHEBI:31644 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0034880 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0518015 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0700345 infores:hetionet CHEBI:15365 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0019080 infores:hetionet NCBIGene:6777 biolink:causes MONDO:0100219 infores:monarchinitiative not_provided not_provided HGNC:11367 MONDO:0100219 uuid:ff00ad27-2ba7-4cd5-9b3e-af6c8de56a4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8673 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0003123 infores:hetionet CHEBI:3441 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0033774 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151795 infores:hetionet CHEBI:5959 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018834 infores:hetionet CHEBI:135961 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0024902 infores:hetionet CHEBI:3423 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0015732 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0018681 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0009241 infores:hetionet CAID:CA280997 biolink:causes MONDO:0007648 infores:clingen CAID:CA280997 MONDO:0007648 PMID:11104024PMID:10477433PMID:11104024PMID:10477433PMID:11104024PMID:10477433 Pathogenic PM5_Supporting, PVS1, PP1, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.70G>T p.(Glu24Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 10477433, 11104024). The variant was also found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; PMID: 10477433, 11104024). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PP1, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA280997/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:135961 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0011124 infores:hetionet CHEBI:3001 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0151686 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0863093 infores:hetionet CHEBI:15553 biolink:causes HP:0001788 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0015944 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0020569 infores:hetionet CHEBI:6402 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0917801 infores:hetionet CHEBI:27882 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0423791 infores:hetionet NCBIGene:9935 biolink:causes MONDO:0014880 infores:monarchinitiative not_provided not_provided HGNC:6408 MONDO:0014880 uuid:55865511-a16d-4d53-8a43-b628909a297c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0001824 infores:hetionet CAID:CA10585615 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585615 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1793T>C (p.Ile598Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specifications version 1.2) on 4 May 2023.The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meet PM2. PMID: 20809525 (Marduel et al., 2010), France – at least 1 case who fulfills internationally accepted criteria for FH, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585615/MONDO:0007750/013 2023-05-04 2025-02-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:38562 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0036974 infores:hetionet CHEBI:65173 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0017168 infores:hetionet CHEBI:50173 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0042998 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0234215 infores:hetionet CHEBI:2639 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0085584 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0008489 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0021053 infores:hetionet CHEBI:8461 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0004096 infores:hetionet CHEBI:9139 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042029 infores:hetionet GO:0045477 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:0045477 GO:0030154 CHEBI:7575 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0016382 infores:hetionet CHEBI:65349 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0009782 infores:hetionet CHEBI:41423 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151578 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0160390 infores:hetionet CHEBI:63620 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0015402 infores:hetionet CHEBI:49668 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0262988 infores:hetionet CHEBI:80630 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0428977 infores:hetionet CHEBI:4911 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0042963 infores:hetionet CHEBI:9654 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0547030 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027769 infores:hetionet CHEBI:7852 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0023066 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0267596 infores:hetionet CHEBI:50922 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0024902 infores:hetionet CHEBI:3510 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0424790 infores:hetionet CHEBI:3723 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042023 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0855242 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0687707 infores:hetionet CHEBI:6775 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018965 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0233472 infores:hetionet NCBIGene:3030 biolink:causes MONDO:0958181 infores:monarchinitiative not_provided not_provided HGNC:4801 MONDO:0958181 uuid:5f25d2c2-7cc0-42a3-8ef2-6005156e6bc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3485 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C2830004 infores:hetionet CHEBI:6904 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0017178 infores:hetionet CHEBI:7852 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085932 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0015230 infores:hetionet CHEBI:8764 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003578 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0022650 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0948594 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020619 infores:hetionet GO:0106214 biolink:causes GO:0048193 infores:ubergraph knowledge_assertion manual_agent GO:0106214 GO:0048193 CHEBI:135276 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0151824 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0948594 infores:hetionet CHEBI:9086 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151744 infores:hetionet CHEBI:9435 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0018524 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0040479 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011849 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0919659 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0919659 infores:hetionet CHEBI:100241 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0036690 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026946 infores:hetionet CHEBI:63630 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0542571 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0015734 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0158350 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0002871 infores:hetionet CHEBI:6367 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0232461 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0020649 infores:hetionet NCBIGene:2055 biolink:causes MONDO:0010830 infores:monarchinitiative not_provided not_provided HGNC:2079 MONDO:0010830 uuid:1cd1b4e2-95d3-4e10-bf30-e40e6b96147a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75246 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0232495 infores:hetionet CHEBI:6887 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C2363731 infores:hetionet CHEBI:46295 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0003467 infores:hetionet CHEBI:9943 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030193 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0037274 infores:hetionet CHEBI:4551 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0018790 infores:hetionet CHEBI:42944 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0231528 infores:hetionet NCBIGene:3918 biolink:causes MONDO:0030749 infores:monarchinitiative not_provided not_provided HGNC:6493 MONDO:0030749 uuid:1e8f0e6f-3977-430d-867a-33541bfd5124 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0022107 infores:hetionet CHEBI:27470 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0015230 infores:hetionet CAID:CA10579274 biolink:causes MONDO:0700270 infores:clingen CAID:CA10579274 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting PP3 The ATM c.7919C>G (p.Thr2640Ser) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico predictors for this alteration (Align GVGD: C55; REVEL: 0.117) are indeterminate. In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA10579274/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2682 biolink:causes UMLS:C0151951 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151951 infores:hetionet CHEBI:6538 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0015230 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0042571 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0151736 infores:hetionet NCBIGene:3690 biolink:causes MONDO:0031009 infores:monarchinitiative not_provided not_provided HGNC:6156 MONDO:0031009 uuid:d2a06196-355f-4924-8d14-dcec9494043b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0879264 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0015672 infores:hetionet CHEBI:9566 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0011603 infores:hetionet CHEBI:7903 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0019080 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020517 infores:hetionet CHEBI:15765 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0424295 infores:hetionet CHEBI:6916 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0014742 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0220870 infores:hetionet CHEBI:50692 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0476089 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1287298 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0242350 infores:hetionet CAID:CA16020906 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020906 MONDO:0009861 PMID:24350308 Uncertain Significance PM2, PP4, PP3, PM3_Supporting The c.968C>T (p.Thr323Ile) variant in PAH meets criteria to be classified as uncertain significance due to insufficient evidence. PAH-specific ACMG/AMP criteria applied: PM2: Absent from population databases (1000 Genomes, ExAC). PP3: Computational prediction tools suggest that the c.968C>T variant is damaging to protein function. Evolutionarily conserved. PP4: Patient has classic PKU (PMID:24350308). PM3_Supporting: Found to co-occur with p.R408W in one patient with classic PKU, but no additional studies to demonstrate phase of variants. No other PAH variants identified in patient (PMID:24350308). Undefined BH4 responsiveness (PMID:24350308). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020906/MONDO:0009861/006 2020-06-25 2020-06-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63580 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004936 infores:hetionet CHEBI:50131 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0018681 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0242350 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0263386 infores:hetionet CHEBI:49575 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0026821 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0021845 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0020538 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022904 infores:hetionet CHEBI:9123 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1142135 infores:hetionet CHEBI:16335 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0040822 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0022354 infores:hetionet CHEBI:3437 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0005745 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0086132 infores:hetionet CHEBI:144551 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0038362 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018939 infores:hetionet CHEBI:52172 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0024902 infores:hetionet CHEBI:10101 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0010520 infores:hetionet NCBIGene:6334 biolink:causes MONDO:0014903 infores:monarchinitiative not_provided not_provided HGNC:10596 MONDO:0014903 uuid:a99c590e-7d8a-462c-b0af-bea410234e30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0162834 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0233472 infores:hetionet CHEBI:7443 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0022354 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042075 infores:hetionet CHEBI:63620 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0232462 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0036416 infores:hetionet CHEBI:5778 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002962 infores:hetionet CHEBI:63612 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0030196 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0548823 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151735 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0541832 infores:hetionet CHEBI:63629 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151798 infores:hetionet GO:0030216 biolink:causes CL:0000312 infores:ubergraph knowledge_assertion manual_agent GO:0030216 CL:0000312 CHEBI:5855 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0036974 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0042571 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0017601 infores:hetionet CHEBI:6339 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0014518 infores:hetionet CHEBI:3176 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0030193 infores:hetionet CHEBI:8805 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0547030 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0020522 infores:hetionet CHEBI:47381 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0028961 infores:hetionet CHEBI:2682 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C3203358 infores:hetionet NCBIGene:2475 biolink:causes MONDO:0014716 infores:monarchinitiative not_provided not_provided HGNC:3942 MONDO:0014716 uuid:a1c78915-2f77-44c2-b40d-3b2ea66a41d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8430 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0018794 infores:hetionet CHEBI:46345 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0018834 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0018790 infores:hetionet CHEBI:404903 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018808 infores:hetionet CAID:CA222127 biolink:causes MONDO:0015152 infores:clingen CAID:CA222127 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.1392dup p.(Asp465ArgfsTer9) variant in DYSF, which is also known as NM_001130987.2: c.1488dup (p.Asp497ArgfsTer9), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 16/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of LGMD (PMID: 27602406, 36983702), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 27602406) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 27602406; NM_003494.4: c.1481-1G>A, 0.5 pts, PMID: 27602406) (PM3). At least one patient with this variant displayed a clinical suspicion of LGMD and severely reduced or absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 27602406, 33610434). The filtering allele frequency of this variant is 0.000012981 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 8/1111992 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222127/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CAID:CA645535219 biolink:causes MONDO:0100283 infores:clingen CAID:CA645535219 MONDO:0100283 PMID: Likely Pathogenic PS2_Moderate, PS3_Moderate, PM2_Supporting, PS4 PM1 The NM_006218.4:c.325GAA[1] (p.Glu110del) variant in PIK3CA is an in-frame deletion of 1 amino acid of the PIK3CA protein. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in a patient with a lymphatic malformation where phosphorylation was increased significantly above controls using patient derived cell lines (PS3_Moderate; PMID:29985963). The variant was also seen in two patients with CLOVES syndrome, two patients with MCAP, two patients with macrodactyly, three patients with facial infiltrating lipomatosis, one patient with facial overgrowth, one patient with hemimegalencephaly and extracerebral segmental overgrowth, one patient with Klippel Trenaunay Syndrome, and in two additional tumor samples from COSMIC (PS4; PMIDs: 29985963, 28151489, 28502725, 29174369, 37452404, 37580112, 34170046). Testing of unaffected and affected tissue showed variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMIDs: 28502725, 28151489). In summary, this variant meets the criteria to be classified as likely pathogenic for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Variant Curation Expert Panel: PM2_Supporting, PS4, PS2_Moderate, PS3_Moderate (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA645535219/MONDO:0100283/018 2025-06-06 2025-06-30 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Supports https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ CHEBI:31623 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1761613 infores:hetionet CHEBI:5138 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0010200 infores:hetionet CHEBI:27504 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0041834 infores:hetionet CHEBI:3510 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0085631 infores:hetionet CHEBI:17549 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0162285 infores:hetionet CHEBI:15367 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0036974 infores:hetionet CHEBI:3757 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0004096 infores:hetionet GO:0045592 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0045592 GO:0019953 CHEBI:66964 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0020458 infores:hetionet CHEBI:6149 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151786 infores:hetionet CHEBI:8107 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1510410 infores:hetionet CAID:CA401363371 biolink:causes MONDO:0009290 infores:clingen CAID:CA401363371 MONDO:0009290 PMID:25026126PMID:23430949 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.763C>T (p.Gln255Ter), is a nonsense variant that is predicted to result in nonsense medicated decay and lack of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in trans with c.670C > T (p.Arg224Trp) in an individual with infantile-onset Pompe disease who meets the ClinGen LSD VCEP’s specifications for PP4 (PMID 25026126). The in trans data from this patient was used in the assessment of p.Arg224Trp, and was not included here in order to avoid circular logic. It was also found in a heterozygote, identified by newborn screening (PMID 23430949). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401363371/MONDO:0009290/010 2020-06-16 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA512341371 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341371 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM5, PM1, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1015C>T (p.Leu339=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341371/MONDO:0011071/008 2025-04-03 2025-04-03 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0065374 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042075 infores:hetionet CHEBI:47519 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C2939147 infores:hetionet CHEBI:35854 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0011603 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0002622 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0002963 infores:hetionet CHEBI:10127 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0392525 infores:hetionet CHEBI:3176 biolink:causes HP:0031616 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423281 infores:hetionet CHEBI:17549 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0041834 infores:hetionet GO:0010695 biolink:causes GO:0000022 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0000022 CHEBI:4672 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0023380 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0011570 infores:hetionet CHEBI:184555 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0424295 infores:hetionet NCBIGene:6017 biolink:causes MONDO:0007639 infores:monarchinitiative not_provided not_provided HGNC:10024 MONDO:0007639 uuid:840aebd4-f335-48e7-8836-0a3bf5058872 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0025320 infores:hetionet CHEBI:3654 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0023530 infores:hetionet NCBITaxon:672 biolink:causes MONDO:0043297 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:672 MONDO:0043297 CHEBI:4792 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0036973 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0085618 infores:hetionet CHEBI:135736 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0231218 infores:hetionet CHEBI:5893 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0026821 infores:hetionet CHEBI:40050 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0016204 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0024115 infores:hetionet CHEBI:3082 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0497156 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0442874 infores:hetionet CHEBI:4027 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0032617 infores:hetionet CHEBI:37941 biolink:causes MONDO:0700226 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0016470 infores:hetionet CHEBI:119573 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0852911 infores:hetionet CHEBI:31348 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0232292 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1527311 infores:hetionet CAID:CA10652929 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652929 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS4, PS2, PS1, PS3, BA1, BP2, BP1, BP4, BP3, BP5, BP7, BS1, BS4, BS3, PM6, PVS1, PM3, PM5, PM4, PM1, PP1, PP2, PP3, PP4, BS2 The NM_001754.4:c.1422G>T (p.Glu474Asp) variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score 0.312. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652929/MONDO:0011071/008 2024-09-11 2024-09-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9448 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0018939 infores:hetionet CHEBI:5280 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C3665347 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0002994 infores:hetionet CAID:CA271794 biolink:causes MONDO:0018947 infores:clingen CAID:CA271794 MONDO:0018947 PMID: Uncertain Significance PP3, PM2_Supporting BA1, BP4, PS4, BS1 The c.137-7T>G variant in MTM1 is located in the 3’ non-canonical splice site of intron 3. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor Splice AI gives a score of 0.55, which is above the threshold of 0.5, suggesting impact on splicing (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications Version 1: 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA271794/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Inconclusive true CHEBI:94686 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0033777 infores:hetionet NCBIGene:2904 biolink:causes MONDO:0013509 infores:monarchinitiative not_provided not_provided HGNC:4586 MONDO:0013509 uuid:49e90cbd-182b-411f-b118-617f6591c99a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018939 infores:hetionet CHEBI:6073 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0041969 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0029882 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0035078 infores:hetionet CHEBI:93635 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0235146 infores:hetionet NCBIGene:675 biolink:causes MONDO:0008679 infores:monarchinitiative not_provided not_provided HGNC:1101 MONDO:0008679 uuid:4bc5e04f-e2be-4724-ba50-dc49d2506c29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9637 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0002994 infores:hetionet CHEBI:9014 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0006266 infores:hetionet CHEBI:31624 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0151907 infores:hetionet CHEBI:7025 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0002792 infores:hetionet CHEBI:145499 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0037763 infores:hetionet CHEBI:17474 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0085633 infores:hetionet CHEBI:6838 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0043094 infores:hetionet CHEBI:63598 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030252 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0919823 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085612 infores:hetionet CHEBI:5138 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027497 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0019158 infores:hetionet CHEBI:38545 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0003862 infores:hetionet NCBIGene:54443 biolink:causes MONDO:0014462 infores:monarchinitiative not_provided not_provided HGNC:14082 MONDO:0014462 uuid:281ad2b2-232f-4822-81f4-948e8b17ca5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151744 infores:hetionet CAID:CA2695237935 biolink:causes MONDO:0010305 infores:clingen CAID:CA2695237935 MONDO:0010305 PMID: Pathogenic PM6, PM2_Supporting, PS4_Supporting, PP4_Strong, PVS1_Moderate The NM_005629.4:c.1392+24_1393-30del variant results in deletion of part of intron 9 of SLC6A8. RT-PCR analysis showed that this variant results in two abnormal splice products (intron 9 retention and skipping of exon 10) (PMID: 20717164) (PVS1_Moderate). This variant has been reported two unrelated males with intellectual disability, language delay, epilepsy, elevated urine creatine/creatinine ratio and a reduced creatine peak on brain MRS (PMID: 20717164, 20501887) (PP4_strong, PS4_supporting). Maternal testing of one proband was negative for the variant (PMID: 20717164) (PM6). The variant is absent in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_moderate, PP4_strong, PM6, PS4_supporting, PM2_supporting.(Classification approved by the ClinGen CCDS VCEP on April 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695237935/MONDO:0010305/027 2024-04-25 2024-06-24 X-linked inheritance HP:0001417 Supports UNII:15G12L5X8K biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0003811 infores:hetionet CHEBI:63791 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019572 infores:hetionet CHEBI:144551 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0002792 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0027765 infores:hetionet CHEBI:6532 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0017178 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0342579 infores:hetionet CAID:CA010349 biolink:causes MONDO:0005045 infores:clingen CAID:CA010349 MONDO:0005045 PMID: Uncertain Significance PP3 PP2, BP1, BA1, PS4, BS1, PM2 NM_000432.4(MYL2):c.428C>T (p.Pro143Leu) - This variant has been reported in individual(s) with HCM (PMIDs: 22958901, 27532257), but is not statistically increased in individuals with HCM compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied. This variant is present in gnomAD (v2.1.1), but did not meet the threshold for PM2. Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010349/MONDO:0005045/102 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51041 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0376286 infores:hetionet CHEBI:63630 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C3495920 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0242350 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006978 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0037998 infores:hetionet CHEBI:63791 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003537 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0009450 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0021845 infores:hetionet CHEBI:134991 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042510 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0033975 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020672 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0034069 infores:hetionet CHEBI:6792 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0340865 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002170 infores:hetionet CHEBI:27882 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0020580 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0149931 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0149931 infores:hetionet NCBIGene:2623 biolink:causes MONDO:0010745 infores:monarchinitiative not_provided not_provided HGNC:4170 MONDO:0010745 uuid:629b178c-0469-49c2-a859-9266a41e8252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060297 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0044085 CHEBI:50131 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0162297 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151849 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0600125 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0243026 infores:hetionet CAID:CA410208062 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208062 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS4, PS2, PS1, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.554A>C (p.Gln185Pro) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score >0.75 (0.977) (PP3). This missense variant is located within the Runt Homology Domain (AA 105-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208062/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA399803746 biolink:causes MONDO:0100326 infores:clingen CAID:CA399803746 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PM3 The c.1252G>T variant in ITGA2B is a missense variant resulting in a substitution of Glycine by Cysteine at codon 418 (p.Gly418Cys). The highest population minor allele frequency in gnomAD v4.0 is 8.996e-7 (1/1111584 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Computational tools support a deleterious effect of the variant on the gene or gene product with REVEL score: 0.72 (PP3). At least one patient (in PMID: 33196509) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). In summary, this variant meets the criteria to be classified as Variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3, PP4_Moderate. (VCEP specifications version 2; date of approval 05/02/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399803746/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:46295 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0027497 infores:hetionet CHEBI:474180 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0333355 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0030305 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0020538 infores:hetionet CAID:CA409108532 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108532 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PS4 The c.994C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, results in a premature termination at codon 332 (p.(Gln332Ter)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PP4 cannot be applied because of limited clinical information (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.994C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108532/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8890 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235063 infores:hetionet CHEBI:49668 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0155169 infores:hetionet CHEBI:63619 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0035455 infores:hetionet CHEBI:2948 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0012833 infores:hetionet CHEBI:194135 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023052 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040046 infores:hetionet CHEBI:15552 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0041657 infores:hetionet CHEBI:28148 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0021845 infores:hetionet CHEBI:68845 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0178298 infores:hetionet NCBIGene:1292 biolink:causes MONDO:0958233 infores:monarchinitiative not_provided not_provided HGNC:2212 MONDO:0958233 uuid:5b6e9c7b-f8dc-40e0-84b9-2a4fd8891278 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA49797983 biolink:causes MONDO:0015152 infores:clingen CAID:CA49797983 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.2071C>T p.(Gln691Ter) variant in DYSF, which is also known as NM_001130987.2: c.2125C>T p.(Gln709Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 22/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in two individuals with LGMD (PMID: 33610434, 36983702), including confirmed in trans in one individual with a pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 1 pt, PMID: 36983702) (PM3). Both individuals had absent dysferlin protein expression, which is highly specific for DYSF-related LGMD, and one individual also displayed progressive muscle weakness (PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000014703 (10/1153648 European (non-Finnish) alleles), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/29/2025): PVS1, PP4_Strong, PM3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA49797983/MONDO:0015152/180 2025-10-29 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7852 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018524 infores:hetionet CHEBI:63608 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0232462 infores:hetionet NCBIGene:7700 biolink:causes MONDO:0014090 infores:monarchinitiative not_provided not_provided HGNC:12926 MONDO:0014090 uuid:a50e49e6-1625-444b-b9d3-9eee50faae7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0025061 infores:hetionet CHEBI:10650 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0586553 infores:hetionet CAID:CA410203419 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203419 MONDO:0011071 PMID:17234761PMID:22649608 Likely Pathogenic PS3, PM1, PM2_Supporting, PP3 PS1, PS4, PS2, BP1, BP4, BP2, BP3, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM3, PM4, PM5, PP2, PP4, PP1, BS2 The c.330G>C (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 110 (p.K110N). This variant involves one of the hotspot residues that is defined as a mutational hotspot by the ClinGen MM-VCEP (PMID: 31648317; PMID: 10404214; PMID: 10620014; PMID: 11257229; PMID: 26010396) (PM1). The variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). The variant has been reported in 4 individuals with AML, but variant origin is unclear (PMID: 10068652; PMID: 27288520; PMID: 31772163; PMID: 32696696) (PS4_Supporting is not met); the somatic variant has been reported in AML (PMID: 29472724), gMDS (PMID: 31772163), and TCGA bladder cancer (COSMIC ID: COSV55875639/cBioPortal) samples. The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488) (PS3). Additional studies of the mutant protein in mouse bone marrow cells showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761). Similarly, the computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.88 (evidence that correlates with impact to RUNX1 function), and the splice site predictor SpliceAI indicated that the variant has no impact on splicing (PP3). In summary, this variant meets the criteria to be classified as a likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PS3, PM1, PM2_Supporting, and PP3. (Version 2; date of approval) Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203419/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5383 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0151436 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0853761 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0233632 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0236071 infores:hetionet CHEBI:10650 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085932 infores:hetionet CHEBI:31711 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0022281 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009450 infores:hetionet CAID:CA10584832 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584832 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM3, PM2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP1, PP3, PP4, PS4_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: This variant is absent from gnomAD (gnomAD v2.1.1)- PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID: 25936346.- PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID: 25936346- PP3: REVEL = 0.93- PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded.- PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID: 25936346) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584832/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6149 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0036572 infores:hetionet CHEBI:31625 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0042165 infores:hetionet CHEBI:91583 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0232462 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151849 infores:hetionet CHEBI:48538 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0042963 infores:hetionet CHEBI:37333 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0015967 infores:hetionet NCBIGene:84700 biolink:causes MONDO:0014689 infores:monarchinitiative not_provided not_provided HGNC:18150 MONDO:0014689 uuid:341ea5bc-4340-47d6-881e-5db2ca2224da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8428 biolink:causes MONDO:0016474 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0263591 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0000833 infores:hetionet CHEBI:6128 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0038325 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0234458 infores:hetionet CHEBI:63612 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0235025 infores:hetionet CHEBI:681850 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0018681 infores:hetionet CHEBI:17026 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0043352 infores:hetionet CHEBI:8713 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0003811 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0235146 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0400823 infores:hetionet CHEBI:8081 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0004093 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151698 infores:hetionet NCBIGene:2258 biolink:causes MONDO:0859086 infores:monarchinitiative not_provided not_provided HGNC:3670 MONDO:0859086 uuid:97a4aa81-7691-44dd-bb8e-78e5f811e2ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C1535849 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C1535849 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0039971 infores:hetionet CHEBI:3738 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0027769 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0029882 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0007787 infores:hetionet CHEBI:45979 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0020456 infores:hetionet CHEBI:7931 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0037299 infores:hetionet CHEBI:10110 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0002994 infores:hetionet CHEBI:63637 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0002792 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027813 infores:hetionet CHEBI:17334 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0151889 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0151585 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0151585 infores:hetionet CHEBI:51860 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018681 infores:hetionet CHEBI:36791 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0029261 infores:hetionet CAID:CA10568266 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568266 MONDO:0010602 PMID: Benign BP4, BA1 PS4 The NM_000132.3:c.2947G>A (p.Val983Ile) variant is reported at a high MAF of 0.00635 (120/18899 alleles with 31 hemizygotes) in the African subpopulation in gnomAD v2.1.1, meeting BA1 cut-off for F8 (>=0.000333). REVEL and SpliceAI scores of 0.194 and 0.01 meeting the BP4 cut-offs of <0.3 and <0.05, respectively. The variant has not been reported in patients with hemophilia A in the literature or Hemophilia databases, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP: BA1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568266/MONDO:0010602/071 2024-02-01 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:119573 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0687713 infores:hetionet CHEBI:6413 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0003467 infores:hetionet CHEBI:135361 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0027497 infores:hetionet CHEBI:75275 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0034065 infores:hetionet CHEBI:3485 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0027497 infores:hetionet CHEBI:8207 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013404 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042373 infores:hetionet CHEBI:9927 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0002170 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0029882 infores:hetionet UMLS:C0145867 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0000731 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0010692 infores:hetionet CHEBI:78543 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0007859 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018418 infores:hetionet CHEBI:4779 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0920171 infores:hetionet CAID:CA915946397 biolink:causes MONDO:0100216 infores:clingen CAID:CA915946397 MONDO:0100216 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Supporting, PS3 BP4, BA1, BS2, PM1, BS1 The NM_177438.2:c.5527+3A>G variant in DICER1 is an intronic variant resulting from a A to G substitution 3 nucleotides downstream from coding exon 25. This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 37248399). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 related tumor predisposition (PP4, PMID: 24481001, PMID: 37248399). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; PMID: 37248399). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PP3, PS3. (Bayesian Points: 8; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946397/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4024 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0009421 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0877232 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0973461 infores:hetionet CHEBI:6541 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0006277 infores:hetionet CHEBI:7915 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0033774 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002367 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0740457 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0085096 infores:hetionet CHEBI:40303 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0003862 infores:hetionet CHEBI:92769 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0018944 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0013395 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0032326 infores:hetionet CHEBI:15367 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085593 infores:hetionet CHEBI:61049 biolink:causes NCIT:C168099 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0476369 infores:hetionet CHEBI:27834 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0013404 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0151763 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0265547 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0265547 infores:hetionet CHEBI:9943 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002962 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0025061 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005657 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004030 infores:hetionet CAID:CA410147721 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147721 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1234G>A (p.Gly412Ser) is a missense variant which has a REVEL score < 0.50 (0.291) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147721/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61049 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004096 infores:hetionet CAID:CA10549177 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549177 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, PP3, BP4 The NM_005629.4:c.283G>A variant in SLC6A8 is a missense variant predicted to cause a substitution of a valine by an isoleucine at amino acid position 95 (p.Val95Ile). This variant has not been reported in the published literature in individuals with creatine transporter deficiency. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00005 (4/78678 alleles, 2 hemizygotes) in the European (Non-Finnish) population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.644, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 449185, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; two submitters: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549177/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:28748 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1325847 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0149931 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0017601 infores:hetionet CHEBI:3504 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0042267 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0009450 infores:hetionet CAID:CA16020807 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020807 MONDO:0009861 PMID:19915519PMID:26503515PMID:23932990 Pathogenic PM2, PVS1, PP4_Moderate This c.510-2A>G (aka IVS5-2A>G) variant in PAH has been observed in at least one patient with PAH deficiency; BH4 deficiency was ruled out (PMID: 26503515, 23932990, and 19915519). The variant is absent from controls in population databases. This variant in the -2 splice acceptor site of intron 5 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay. The variant breaks the splice site in IVS5 according to computational models. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020807/MONDO:0009861/006 2020-10-28 2020-10-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4953 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0041912 infores:hetionet CAID:CA412376054 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376054 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PM1_Strong, PM5, PP4 PP3 The NM_000330.4(RS1):c.176G>A variant is a missense variant encoding the substitution of Cysteine with Tyrosine at amino acid 59 and results in the disruption of the disulfide bridge between Cys59 and Cys223. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant p.Cys59Tyr, of the RS1 gene, is defined as a critical amino acid residue involved in disulfide bridge formation by the ClinGen X-linked IRD VCEP (PMIDs: 26812435, PM1_strong). The computational predictor REVEL gives a score of 0.754, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The PM1_strong code is ineligible to be combined with PP3 at any strength, therefore, the PP3 code was not met. Another missense variant in the same codon, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 31174210, 10450864, 17987333, 9618178) has been classified as likely pathogenic for RS1-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (195) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). At least one proband harboring this variant exhibits a phenotype including the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 32300273, PP4). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 39462066, 30025115, 22245991, 35456481, PS4_Supporting). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PM1_strong, PM5, PS4_supporting, and PP4. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376054/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:3423 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0016059 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019360 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0005940 infores:hetionet CAID:CA367398536 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398536 MONDO:0015967 PMID: Likely Pathogenic PM5, PP2, PP3, PP4, PM2_Supporting PP1 The c.1189C>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 397 (p.(Arg397Glyr)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.817, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two related individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family, however this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918, internal lab contributor). Another missense variant, c.1190G>T p.Arg397Leu, has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Arg397Gly has a greater Grantham distance(PM5). In summary, c.1189C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398536/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Supports CAID:CA913169498 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169498 MONDO:0044970 PMID: Uncertain Significance PP4, PP1, PS4_Supporting, PM2_Supporting PP3, PS3 The m.12148T>C variant in MT-TH has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting: PMIDs: 23463613, 37961166). The first case was a child with developmental delay, optic atrophy, cataracts, hearing loss, and myopathy. The variant was reported to be heteroplasmic in blood but the level was not provided (PMID: 23463613). The variant was undetectable in the proband’s mother’s blood by Sanger sequencing however this technology cannot detect low heteroplasmy levels precluding consideration for a de novo occurrence. The second case had cataracts, retinal dystrophy, hearing loss, cognitive decline, movement disorder, ataxia, and renal involvement. The variant was present at 94% in muscle, 68% in urine, and 35% in blood. Deficiencies of mitochondrial respiratory chain enzyme complexes I and IV were noted in fibroblasts (PP4; PMID: 37961166). The variant was also present in the less severely affected mother with cataracts, hearing loss, and cognitive decline at 10% in urine, 1% in fibroblasts, and 5% in blood. The variant was undetectable in a healthy sibling (PP1; PMID: 37961166). A third case was reported in a cohort study however clinical details were not provided (PMID: 31965079). There is one occurrence of this variant in the MITOMAP GenBank sequences and this variant is absent in the Helix dataset and in gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (74.7 percentile) but HmtVAR predicts it to be neutral with a score of 0.15. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 13, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP4, PP1, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169498/MONDO:0044970/015 2025-01-13 2025-05-21 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8888 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0456909 infores:hetionet CHEBI:15640 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0687713 infores:hetionet CHEBI:119915 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0004604 infores:hetionet CHEBI:9168 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0595916 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0700184 infores:hetionet CHEBI:64312 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0039070 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0025061 infores:hetionet CHEBI:119573 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020598 infores:hetionet CAID:CA345914 biolink:causes MONDO:0044970 infores:clingen CAID:CA345914 MONDO:0044970 PMID:24316278 Likely Pathogenic PS3_Supporting, PM2_Supporting, PP3, PM6_Supporting PM5, PS4, PS1, PVS1 The m.9191T>C (p.L222P) variant in MT-ATP6 has been reported once in the literature (PMID: 16217706, patient 2) in an individual with Leigh syndrome (94% heteroplasmy in muscle and 90% in fibroblasts; only testing done was MT-ATP6 and MT-ATP8 sequencing). This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant occurred de novo in this individual (absent in blood from mother and sister; PM6_supporting, PMID: 16217706). There are no large families reported in the literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Yeast model showed (1) failure to grow on glycerol (indicating at least an 80% reduction in ATP synthase activity/function), (2) 67-85% decrease in oxygen consumption, (3) <10% of control ATP synthesis, and (4) impaired ATPase assembly (PS3_supporting, PMID: 24316278). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given consistent functional evidence of severe deleterious effect and rare nature of the variant, as well as being absent in healthy cohorts even at low heteroplasmy levels. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on January 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM6_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345914/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:64064 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0006277 infores:hetionet CHEBI:51860 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0344232 infores:hetionet CHEBI:10127 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042023 infores:hetionet CHEBI:8863 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042963 infores:hetionet CHEBI:4798 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0014518 infores:hetionet CHEBI:7852 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0004604 infores:hetionet CHEBI:50648 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019214 infores:hetionet CHEBI:3640 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0553548 infores:hetionet CHEBI:63925 biolink:causes MONDO:0005266 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0011884 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0314719 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0233494 infores:hetionet CAID:CA397319701 biolink:causes MONDO:0009276 infores:clingen CAID:CA397319701 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PM3 The NM_000173.7(GP1BA):c.1039G>T (p.Glu347Ter) variant is a nonsense variant in exon 2 of 2, that may cause loss of function of the protein; it is predicted to escape nonsense mediated decay and truncate 47% of the protein (PVS1_Strong). One patient has been reported with this variant (Case I, of PMID: 23414566) and had no aggregation response to ristocetin and decreased thrombin-induced aggregation but normal aggregation with ADP and collagen, additionally GPIbα expression was completely absent on patient platelets, which is highly specific to Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with BSS. This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397319701/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17549 biolink:causes UMLS:C0241166 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0241166 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0575090 infores:hetionet CHEBI:63612 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C2937358 infores:hetionet CHEBI:16586 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0151740 infores:hetionet NCBIGene:9935 biolink:causes MONDO:0008152 infores:monarchinitiative not_provided not_provided HGNC:6408 MONDO:0008152 uuid:0d30b9b7-746b-4e08-8451-3d28b42988ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3403 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0030193 infores:hetionet CHEBI:6375 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027497 infores:hetionet CHEBI:45081 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0013144 infores:hetionet CHEBI:45783 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1321898 infores:hetionet CHEBI:10102 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0003467 infores:hetionet CAID:CA245265 biolink:causes MONDO:0010726 infores:clingen CAID:CA245265 MONDO:0010726 PMID: Benign BA1, BP7, BP5_Strong, BS2 PM2 The highest population minor allele frequency of the p.Pro388= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.0004921 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Pro388= variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Pro388= variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). The silent p.Pro388= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Pro388= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA245265/MONDO:0010726/036 2024-08-30 2024-11-15 X-linked inheritance HP:0001417 Contradicts true CHEBI:4784 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0018790 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0036572 infores:hetionet NCBIGene:79158 biolink:causes MONDO:0009650 infores:monarchinitiative not_provided not_provided HGNC:29670 MONDO:0009650 uuid:90fd2770-751a-46ab-bb85-9b5f40d172be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C2830004 infores:hetionet CHEBI:32293 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0042909 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0553732 infores:hetionet CHEBI:4670 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0013404 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0020517 infores:hetionet GO:0046883 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:0046883 GO:0007267 CHEBI:63607 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0006849 infores:hetionet CHEBI:92712 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0011991 infores:hetionet CHEBI:61049 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3665386 infores:hetionet CHEBI:7773 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0002792 infores:hetionet CHEBI:28148 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0011991 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151849 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0687133 infores:hetionet CAID:CA229840 biolink:causes MONDO:0009861 infores:clingen CAID:CA229840 MONDO:0009861 PMID:16256386PMID:16256386 Pathogenic PVS1, PM2, PM3, PP4 The c.904delT (p.Ser303Profs*38) variant in PAH has been observed in at least one patient with classic PKU (plasma phenylalanine greater than 1200 micromolar) with a known pathogenic variant p.Ser70del (PMID:16256386). This variant is absent in population databases including: 1000 Genomes, ESP, and extremely low in gnomAD. This is a single base pair deletion that creates a frameshift in exon 9 and is predicted to undergo nonsense mediated decay with the truncated region critical to protein function. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229840/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8024 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0009241 infores:hetionet CHEBI:63115 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0012833 infores:hetionet CHEBI:31981 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0014457 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0236080 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0236080 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0037315 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011849 infores:hetionet CHEBI:15765 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0012569 infores:hetionet CHEBI:47780 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085688 infores:hetionet CHEBI:5864 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0014518 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003123 infores:hetionet CHEBI:691037 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0234894 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0031350 infores:hetionet CHEBI:63622 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0036974 infores:hetionet CHEBI:53760 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0015967 infores:hetionet CHEBI:63624 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C1619712 infores:hetionet CHEBI:68642 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0917801 infores:hetionet CHEBI:182080 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0020517 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0948594 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0041969 infores:hetionet CHEBI:231594 biolink:causes HP:0400007 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0032519 infores:hetionet CHEBI:18248 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0016059 infores:hetionet CHEBI:6759 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0151311 infores:hetionet CAID:CA165387 biolink:causes MONDO:0007648 infores:clingen CAID:CA165387 MONDO:0007648 PMID: Benign BS2, BP2_Strong BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BA1, PS1, PS3, PS4, PS2 The c.671G>A (p.Arg224His) missense variant has a frequency of 0. 0.00003189 (8 of 250,850) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00006179 (7 of 113,278) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >50 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000637843.5, SCV000278911.9). This variant was observed in the homozygous state in an individual without DGC, SRC tumors or LBC and whose family does not suggest HDGC (BP2_Strong, internal laboratory contributor). In summary, the clinical significance of this variant is classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA165387/MONDO:0007648/007 2023-08-09 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:4911 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0746883 infores:hetionet CHEBI:3738 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0030554 infores:hetionet CAID:CA199493 biolink:causes MONDO:0010726 infores:clingen CAID:CA199493 MONDO:0010726 PMID: Likely Benign BS1, BP4 The allele frequency of the c.377+18C>G variant (NM_004992.3) in MECP2 is 0.01% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+18C>G variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199493/MONDO:0010726/016 2021-12-22 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:79699 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0852911 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0015786 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0015786 infores:hetionet CAID:CA213765 biolink:causes MONDO:0015967 infores:clingen CAID:CA213765 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PP4_Moderate, PP2, PM2_Supporting PS3, PS4, PP3 The c.146C>A variant in the glucokinase gene, GCK causes an amino acid change of threonine to asparagine at codon 49 (p.(Thr49Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.691, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on GCK function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, this number does not meet the MDEP cutoff for PS4_Moderate (PMID: 30257192, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with 7 informative meioses in 2 families (PP1_Strong; PMID: 30257192, internal lab contributors). Functional studies demonstrated the p.Thr49Asn protein had a relative activity index (RAI) < 0.5; however, the wild-type kinetic parameters didn’t pass the MDEP quality control, and PS3_Moderate could not be applied (PMID: 30257192). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3, approved 8/11/2023): PP1_Strong, PP4_Moderate, PM2_Supporting, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213765/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Supports CHEBI:6754 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0040822 infores:hetionet CHEBI:553473 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0028643 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0518015 infores:hetionet CAID:CA421938581 biolink:causes MONDO:0020367 infores:clingen CAID:CA421938581 MONDO:0020367 PMID: Uncertain Significance BP7, BS1, BS3, PM2, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.1452G>A variant in MYOC is a synonymous variant (p.Lys484=). The gnomAD (v2.1.1) database had poor genotype data for this genomic position and did not represent the population from which the variant has been reported (South Asian). Thus PM2_Supporting was not applied to this variant. Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.90, which did not meet the ≤ 10 threshold for BP4 and a GERP score = 4.88 (threshold <0), not meeting BP7 and indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with JOAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): none Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421938581/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA343720226 biolink:causes MONDO:0005338 infores:clingen CAID:CA343720226 MONDO:0005338 PMID: Uncertain Significance PS4_Supporting, PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BA1 The c.11T>C variant in MYOC is a missense variant predicted to cause substitution of Phenylalanine by Serine at amino acid 4 (p.Phe4Ser). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000002542 (3 alleles out of 1,180,040), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.068, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for primary open angle glaucoma (POAG) (Charlesworth, J. 2006 PhD Thesis), not meeting the ≥ 3 segregations required for PP1. 2 probands with POAG have been reported carrying this variant (PMID: 10196380), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting, PS4_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343720226/MONDO:0005338/019 2025-11-13 2025-11-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA119176 biolink:causes MONDO:0020367 infores:clingen CAID:CA119176 MONDO:0020367 PMID:35196929 Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS1, PS2, BA1, BP4 The c.1099G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 367 (p.Gly367Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.787, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712, 35196929) demonstrated that the Gly367Arg protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 35 segregations in 7 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17304254, 32300215, 12189160, 11815346), which fulfilled PP1_Strong (≥7 meioses in >1 family). 16 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 32300215, 12189160, 11774072, 9345106, 23453510, 12872267, 14627955, 12442283), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119176/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports CAID:CA023801 biolink:causes MONDO:0007750 infores:clingen CAID:CA023801 MONDO:0007750 PMID: Benign BA1, BP2, PP3, PP1, BS2 BP1, BP4, BP3, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS4, BS3, PM5, PM1, PM4, PM3, PM2, PM6, PVS1, PP2, PP4 The NM_000527.5(LDLR):c.970G>A (p.Gly324Ser) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP2, PP1 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). BS2 - Identified in 4 heterozygous non-affected family members from different labs.BP2 - variant identified 1 index case with heterozygous FH phenotype who is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018).PP1 - variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PP3 - REVEL = 0.815.Variant has 1 stand alone, 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Benign, and only 2 Supporting codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023801/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:421707 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0234215 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0877127 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0877127 infores:hetionet CHEBI:49575 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1145670 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0234192 infores:hetionet CHEBI:16469 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0349790 infores:hetionet CHEBI:31711 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0025290 infores:hetionet CAID:CA114125 biolink:causes MONDO:0015629 infores:clingen CAID:CA114125 MONDO:0015629 PMID: Pathogenic PS2_Supporting, PP4_Moderate, PP3, PP1, PM2_Supporting, PS3, PS4_Very Strong PM5 NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys) missense variant is predicted to cause substitution of arginine by cysteine at amino acid 1308. This variant has been reported in at least 30 probands, of which at least 19 reported sufficient phenotypic information to confirm type 2B VWD. (PS4; PMIDs: 18805962, 22077376, 1419803, 2010538, 16246252). Patient 9 of PMID: 2010538, has sufficient information to meet PP4_moerate: lacked HMWM in plasma and had a moderately heightened RIPA (0.6–0.7), as well as low VWF:RCo/VWF:Ag ratio (<0.45), with Platelet-type VWD excluded by mixing experiments to confirm that the defect was in the patient plasma and not in the patient platelets. The variant has been reported to segregate with VWD type 2B through at least 2 affected meioses from 1 family (PP1; PMID: 2010538). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VWD type 2B (PPS2_supporting; PMID: 2010538). This variant is absent from gnomAD v4.1 (PM2_Supporting). GP1bα binding assay in COS-7 cells expressing recombinant VWF, variant alone or together with WT, showed increased binding at low doses of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID: 16246252) (PS3). Similar results have been reported in multiple studies (PMIDs: 26345337, 8630394). The computational predictor REVEL gives a score of 0.673, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3_supporting, PS4_VeryStrong, PM2_supporting, PS2_supporting, PP1, PP3, PP4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114125/MONDO:0015629/081 2024-08-13 2024-08-19 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0010592 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0549463 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0574770 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0574770 infores:hetionet GO:1900133 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:1900133 GO:0007267 CAID:CA002019 biolink:causes MONDO:0011450 infores:clingen CAID:CA002019 MONDO:0011450 PMID: Benign BS2_Supporting, BP1_Strong, BS3, BP5_Strong PM2, BA1, BS1 The c.3082C>T variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 1028 (p.Arg1028Cys). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold < 0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). This variant has been observed in one individual with features considered inconsistent with an FA-associated phenotype, variant is homozygous (total score 1 point) (BS2_Supporting met; PMID: 29435075). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0009 (based on Cosegregation LR=0.131; Pathology LR=0.056; Co-occurrence LR= 1.527; Family History LR= 0.081), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BS3, BS2_Supporting, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002019/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9332 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0041349 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0020517 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0009806 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0040046 infores:hetionet CHEBI:15940 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0022346 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009938 infores:hetionet CHEBI:4814 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0040822 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0085622 infores:hetionet CHEBI:36795 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0028081 infores:hetionet GO:1903859 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0030182 CHEBI:101085 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0392525 infores:hetionet CHEBI:136040 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0151908 infores:hetionet CHEBI:47426 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020625 infores:hetionet CHEBI:41423 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0015967 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0566948 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0566948 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0011849 infores:hetionet CHEBI:2948 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0019829 infores:hetionet CHEBI:2788 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0520966 infores:hetionet CHEBI:68841 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0858797 infores:hetionet NCBIGene:7299 biolink:causes MONDO:0008745 infores:monarchinitiative not_provided not_provided HGNC:12442 MONDO:0008745 uuid:e53de7ad-9305-44b7-b33e-d06b2cb4abff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31174 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0677500 infores:hetionet CHEBI:9123 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027497 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0949070 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0949070 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0033975 infores:hetionet CHEBI:64354 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0237849 infores:hetionet CHEBI:64312 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004093 infores:hetionet NCBIGene:8789 biolink:causes MONDO:0859246 infores:monarchinitiative not_provided not_provided HGNC:3607 MONDO:0859246 uuid:77c07ad1-6d09-464c-8381-535b9f15ac2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0040046 infores:hetionet CHEBI:51173 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0036974 infores:hetionet CHEBI:23765 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0542571 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233472 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0020649 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0018939 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0023533 infores:hetionet GO:1900123 biolink:causes GO:0038092 infores:ubergraph knowledge_assertion manual_agent GO:1900123 GO:0038092 CHEBI:51860 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0029882 infores:hetionet CHEBI:46195 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0002994 infores:hetionet CHEBI:84500 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0032231 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042109 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0578687 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0578687 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0857495 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0857495 infores:hetionet CHEBI:64354 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0740394 infores:hetionet CHEBI:37924 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0917801 infores:hetionet CHEBI:6367 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C2937350 infores:hetionet CHEBI:145499 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085641 infores:hetionet CHEBI:42797 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0016658 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0033975 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0518015 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0033777 infores:hetionet CHEBI:8871 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042023 infores:hetionet NCBIGene:4001 biolink:causes MONDO:0030928 infores:monarchinitiative not_provided not_provided HGNC:6637 MONDO:0030928 uuid:83d35556-8db1-4152-90ec-3ea136a129a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA211309 biolink:causes MONDO:0010726 infores:clingen CAID:CA211309 MONDO:0010726 PMID: Benign BS2, BA1 The allele frequency of the p.Ile125= variant in MECP2 (NM_004992) is 0.394% in South Asian sub population in gnomAD, which is high enough to be classified as Benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ile125= variant is observed in at least 2 unaffected individuals (PMID 11055898, 20479760, RettBASE proband id 4623, 4624) (BS2). In summary, the p.Ile125= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA211309/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:2682 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0392025 infores:hetionet CHEBI:100246 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0038362 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036508 infores:hetionet CHEBI:3387 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0029453 infores:hetionet CAID:CA001720 biolink:causes MONDO:0018875 infores:clingen CAID:CA001720 MONDO:0018875 PMID: Likely Benign PM1_Supporting, BS3, BS2, PP3, PM2_Supporting BP4, BP2, BA1, PS1, PS3, PS4, PS2, PM5, BS1, BS4, PM6, PP1 The NM_000546.6:c.760A>G variant in TP53 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 254 (p.Ile254Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: ClinVar SCV000545356.10). This variant has an allele frequency of 0.000006821 (11/1612700 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.1708; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting, BS3, PP3, PM1_Supporting. (Bayesian Points: -3; VCEP specifications version 2.2; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001720/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6444 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0080274 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0003864 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0403632 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853026 infores:hetionet UMLS:C0017797 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0043352 infores:hetionet CHEBI:28864 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0002994 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0340464 infores:hetionet CHEBI:31980 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0236075 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0041976 infores:hetionet CHEBI:64019 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0006266 infores:hetionet CHEBI:2682 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0549249 infores:hetionet CHEBI:8207 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0014743 infores:hetionet CHEBI:17026 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151825 infores:hetionet CHEBI:49662 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0237849 infores:hetionet CHEBI:63598 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0039240 infores:hetionet CHEBI:6950 biolink:causes HP:0033400 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0000727 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C2979982 infores:hetionet CHEBI:7852 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0016204 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0040034 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0027651 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0009450 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1096195 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1096195 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0740399 infores:hetionet CHEBI:36791 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151766 infores:hetionet CHEBI:8768 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003467 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0348801 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0348801 infores:hetionet UMLS:C0004609 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151818 infores:hetionet CHEBI:28830 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0235378 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0438241 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0438241 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0029443 infores:hetionet CHEBI:51364 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0017178 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0235280 infores:hetionet CHEBI:184555 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0023530 infores:hetionet CHEBI:8772 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0016382 infores:hetionet CHEBI:9445 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0043094 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0413252 infores:hetionet CHEBI:7823 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0156404 infores:hetionet CHEBI:41237 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00676 UMLS:C0152030 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018991 infores:hetionet CHEBI:3082 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011603 infores:hetionet CHEBI:7936 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040822 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0235431 infores:hetionet CHEBI:5790 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0025345 infores:hetionet CHEBI:51230 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0235266 infores:hetionet CAID:CA2580100882 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100882 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2792del (p.Glu931GlyfsTer?) is a frameshift variant due to one nucleotide deletion introducing a premature stop codon after 158 amino acids within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including first/second-decade onset (1 pt), electroretinogram responses showing rod involvement relatively greater than cone involvement (1 pt), and genotyping by next-generation sequencing finding no alternative explanation for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4 total points, PMID: 33372982, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100882/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:6402 biolink:causes MONDO:0011429 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C3495559 infores:hetionet CHEBI:9674 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0004093 infores:hetionet CHEBI:3219 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0039591 infores:hetionet CHEBI:10650 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151636 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002105 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0025162 infores:hetionet CHEBI:82960 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0011615 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0021053 infores:hetionet CHEBI:40279 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1318520 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0162429 infores:hetionet CHEBI:42797 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0026826 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0162429 infores:hetionet NCBIGene:8492 biolink:causes MONDO:0009580 infores:monarchinitiative not_provided not_provided HGNC:9477 MONDO:0009580 uuid:f16e678b-686b-45d8-80ee-df8a4bb59734 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA338402061 biolink:causes MONDO:0100283 infores:clingen CAID:CA338402061 MONDO:0100283 PMID: Likely Pathogenic PS2_Moderate, PP2, PM2_Supporting, PS4_Supporting, PM1_Supporting The NM_004958.4:c.5005G>T variant in MTOR is a missense variant predicted to cause substitution of alanine by serine at amino acid 1669. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations Variant Curation Expert Panel (BM VCEP) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the focal adhesion kinase targeting domain of MTOR that is defined as a critical functional domain by the ClinGen BM VCEP (PM1_Supporting; PMIDs: 23322780, 27482884, 21210909). This variant has been identified in one patient with diffuse cortical dysplasia (PS4_Supporting, PMID: 25599672). In this patient, the variant was present at an alternate allele frequency of 44% in the brain but was not detectable in blood (PS2_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen BM VCEP Panel: PM2_Supporting, PP2, PM1_Supporting, PS4_Supporting, PS2_Moderate (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA338402061/MONDO:0100283/018 2025-06-06 2025-06-30 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Supports https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ CHEBI:10650 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0242429 infores:hetionet CHEBI:5134 biolink:causes UMLS:C1322253 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C1322253 infores:hetionet CHEBI:7852 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0152020 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0235146 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0006849 infores:hetionet CHEBI:31859 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0035455 infores:hetionet CHEBI:63115 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C1384353 infores:hetionet CHEBI:6970 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0033774 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0018939 infores:hetionet NCBIGene:57128 biolink:causes MONDO:0014269 infores:monarchinitiative not_provided not_provided HGNC:21365 MONDO:0014269 uuid:841235a9-e8b6-4c38-b298-adde241a0796 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0262397 infores:hetionet CHEBI:74947 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030252 infores:hetionet CHEBI:7936 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235198 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0855242 infores:hetionet CHEBI:63619 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011168 infores:hetionet CHEBI:6950 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0038325 infores:hetionet CHEBI:168396 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019080 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0011581 infores:hetionet CAID:CA5779327 biolink:causes MONDO:0021060 infores:clingen CAID:CA5779327 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.369C>T (p.Arg123=) variant in the HRAS gene is 0.089% (13/8638) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5779327/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006826 infores:hetionet CHEBI:50173 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011124 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0853760 infores:hetionet CHEBI:168396 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085616 infores:hetionet CHEBI:10124 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0043094 infores:hetionet CHEBI:3216 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0040822 infores:hetionet CHEBI:71023 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0155169 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0042075 infores:hetionet CHEBI:63621 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0156404 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0041969 infores:hetionet NCBIGene:4118 biolink:causes MONDO:0975833 infores:monarchinitiative not_provided not_provided HGNC:6817 MONDO:0975833 uuid:aef3bcdc-cf83-4898-a0f6-9e8066297ac0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0085593 infores:hetionet CHEBI:40279 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0041364 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0036572 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151828 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027813 infores:hetionet CHEBI:8426 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0042023 infores:hetionet CHEBI:7915 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019270 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0007787 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0003123 infores:hetionet CAID:CA023787 biolink:causes MONDO:0007750 infores:clingen CAID:CA023787 MONDO:0007750 PMID: Uncertain Significance PP3 BA1, BP1, BP4, BP3, BP2, PS3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM2, PM6, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.907C>T (p.Arg303Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP3 - REVEL = 0.815. It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023787/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6539 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0549249 infores:hetionet CHEBI:9570 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0003467 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0009806 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0021775 infores:hetionet CHEBI:6954 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0392676 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0020517 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0015397 infores:hetionet CHEBI:5778 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0262988 infores:hetionet CHEBI:9599 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0027441 infores:hetionet CHEBI:6931 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0700200 infores:hetionet CHEBI:3082 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0232461 infores:hetionet CHEBI:4469 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0014742 infores:hetionet GO:0003427 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0060429 CHEBI:144093 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011124 infores:hetionet CHEBI:63635 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013404 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0006325 infores:hetionet CHEBI:2904 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0013404 infores:hetionet CHEBI:9316 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0042024 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0019054 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004059 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0011432 infores:hetionet CHEBI:5050 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0030193 infores:hetionet CHEBI:66901 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C2363731 infores:hetionet CAID:CA402996840 biolink:causes MONDO:0012999 infores:clingen CAID:CA402996840 MONDO:0012999 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong, PM3_Supporting BA1, BS1 The NM_000156.6: c.235C>T (p.Gln79Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one patient with GAMT deficiency. This individual was homozygous for the variant (PMIDs 32606564) (PM3_Supporting). The patient reported with this variant had elevated GAA in plasma and significantly decreased creatine peak (PP4_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct. 12, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402996840/MONDO:0012999/026 2023-10-12 2023-11-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027059 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0349506 infores:hetionet NCBIGene:9493 biolink:causes MONDO:0007109 infores:monarchinitiative not_provided not_provided HGNC:6392 MONDO:0007109 uuid:712154ee-7f8c-482e-8eea-3295ac27e882 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0235234 infores:hetionet GO:0090175 biolink:causes GO:0001738 infores:ubergraph knowledge_assertion manual_agent GO:0090175 GO:0001738 CHEBI:52172 biolink:causes UMLS:C0269268 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0269268 infores:hetionet CAID:CA229762 biolink:causes MONDO:0009861 infores:clingen CAID:CA229762 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5 The c.793T>G (p.Cys265Gly) variant in PAH has not been reported in the literature to our knowledge. Reference in BioPKU/PAHdb does not include a case report for this variant (PMID:9781015). This variant is absent from ExAC, gnomAD, 1000G, and ESP. Multiple lines of computational evidence support a deleterious effect (REVEL=0.822). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229762/MONDO:0009861/006 2022-03-13 2022-04-16 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:51111 biolink:causes MONDO:0030917 infores:monarchinitiative not_provided not_provided HGNC:24283 MONDO:0030917 uuid:d21641bf-8278-4239-8566-4802ec48598b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0349506 infores:hetionet CHEBI:4907 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0423791 infores:hetionet CHEBI:8871 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1527344 infores:hetionet CHEBI:5004 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0013395 infores:hetionet CHEBI:44423 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0700361 infores:hetionet CHEBI:135935 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0025362 infores:hetionet CHEBI:47426 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0426390 infores:hetionet CHEBI:9123 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151908 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0151763 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0033860 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0011616 infores:hetionet CHEBI:135961 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0852911 infores:hetionet CHEBI:141474 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00772 UMLS:C0009763 infores:hetionet CAID:CA254840 biolink:causes MONDO:0044970 infores:clingen CAID:CA254840 MONDO:0044970 PMID:33380464PMID:20550934 Uncertain Significance PS3_Supporting, PM2_Supporting, PP1 PP3, PS4 The m.3249G>A variant in MT-TL1 has been reported in one individual to date, in a man with progressive vision loss, hearing loss, myopathy, and ragged red and COX-negative fibers, whose presentation was reminiscent of Kearns Sayre syndrome (PMID: 11448301). The variant was present at 85% heteroplasmy in skeletal muscle and 45% in leukocytes in the proband, 5% in the blood of the healthy mother, and was undetectable in blood from a healthy sister (PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 39.3%; HmtVAR: 0.45). There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID: 20550934) and RNAseP binding interference (PMID: 33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID: 33380464; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254840/MONDO:0044970/014 2024-04-22 2024-11-20 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:194135 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009319 infores:hetionet CHEBI:144093 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0025222 infores:hetionet CHEBI:50922 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0086439 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0027726 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0009806 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0851341 infores:hetionet CHEBI:465284 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003862 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0012833 infores:hetionet UNII:15G12L5X8K biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0340865 infores:hetionet CHEBI:66903 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0009806 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011053 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0015734 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0037195 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006678 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0005683 infores:hetionet CHEBI:41977 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0040264 infores:hetionet CHEBI:4888 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0014742 infores:hetionet NCBIGene:6329 biolink:causes MONDO:0957265 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0957265 uuid:8e3550fe-35cc-4b2a-8167-9fe8a1bf4ae4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412731233 biolink:causes MONDO:0100437 infores:clingen CAID:CA412731233 MONDO:0100437 PMID: Likely Pathogenic PM2, PVS1 PS4 NM_001034853.2(RPGR):c.2188G>T (p.Gly730Ter) is a nonsense variant introducing a premature stop in codon 730 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa (PMID:23372056), however, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in an affected male by age 30 years, and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412731233/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:2682 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018801 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0032285 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0020649 infores:hetionet CHEBI:29688 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0011603 infores:hetionet CAID:CA261625 biolink:causes MONDO:0021060 infores:clingen CAID:CA261625 MONDO:0021060 PMID: Likely Pathogenic PM1, PM2_Supporting, PS4_Moderate, PS3_Supporting PP3, BP4 The c.768G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by serine at amino acid 256 (p.Arg256Ser). This variant is absent from gnomAD v2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.665, which does not meet PP3 or BP4. This variant is located in the CR2 critical functional domain as defined by the ClinGen RASopathy Expert Panel (PM1). This variant has been reported in 3 individuals with clinical features of Noonan syndrome (PS4_Moderate, PMIDs: 17603483, 22190897, 31292302). In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PMID: 20679480). ERK phosphorylation assay showed that the p.Arg256Ser variant led to significantly increased phosphorylation compared to wild-type (PS3_Supporting; PMID:20679480). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PS3_Supporting, PM2_Supporting (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261625/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0879264 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0237849 infores:hetionet CHEBI:28864 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0011206 infores:hetionet NCBIGene:8884 biolink:causes MONDO:0859255 infores:monarchinitiative not_provided not_provided HGNC:11041 MONDO:0859255 uuid:1b3efb7a-a45e-48ec-a3e8-be399df61eb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:253342 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0022346 infores:hetionet CHEBI:2704 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0035455 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151596 infores:hetionet NCBIGene:27133 biolink:causes MONDO:0957812 infores:monarchinitiative not_provided not_provided HGNC:6254 MONDO:0957812 uuid:4eab8702-be83-4db8-bcd7-3a54f3f9bcf6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0043094 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0231365 infores:hetionet CHEBI:175901 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0392171 infores:hetionet CHEBI:63845 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0030193 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0518015 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0037274 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0702266 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0018834 infores:hetionet NCBIGene:1285 biolink:causes MONDO:0958186 infores:monarchinitiative not_provided not_provided HGNC:2204 MONDO:0958186 uuid:c26411ff-fa72-4c1f-8afb-4995598fd984 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0007222 infores:hetionet CHEBI:61390 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0018681 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0022904 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036689 infores:hetionet CHEBI:16899 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0085593 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0162429 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0010709 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0553713 infores:hetionet CHEBI:93363 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0948595 infores:hetionet CHEBI:17263 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0023218 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0687133 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0392525 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0003864 infores:hetionet CHEBI:6954 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0030554 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042769 infores:hetionet CAID:CA037604 biolink:causes MONDO:0007750 infores:clingen CAID:CA037604 MONDO:0007750 PMID: Uncertain Significance PP1_Strong, BS3, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, BS2 NM_000527.5(LDLR):c.1966C>A (p.His656Asn) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS3, PP1_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS3 - PMID: 32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). ---- functional study is consistent with no damaging effect.PP1_strong - 1 family with 6 informative meiosis is reported by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PM2 - PopMax MAF = 0.00002638 (0.0026%) in European non-Finnish exomes (gnomAD v2.1.1).PP3 - REVEL: 0,905.PP4 - Variant meets PM2. Variant is reported in 1 index case fulfills Simon-Broome criteria. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037604/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50922 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003862 infores:hetionet CHEBI:681569 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0151905 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0391839 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0391839 infores:hetionet CHEBI:94449 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0004238 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0151618 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0151618 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0151559 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0233632 infores:hetionet CHEBI:585948 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0010200 infores:hetionet CAID:CA16022700 biolink:causes MONDO:0021056 infores:clingen CAID:CA16022700 MONDO:0021056 PMID: Uncertain Significance BP1, PS4_Supporting, PM2_Supporting BS2 The NM_000038.6(APC):c.623A>G variant in APC is a missense variant predicted to cause the substitution of glutamine by arginine at amino acid position 208 (p.Gln208Arg). This variant has been reported in 1 family with AFAP worth 1 phenotype point (PS4_Supporting, PMID: 10646887). The variant has been reported in 1 additional individual without a colorectal cancer/polyposis associated phenotype not meeting criteria for BS2 (BS2 not met; [Ambry Genetics]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PS4_Supporting, PM2_Supporting and BP1 (VCEP specifications version 2.1.0; date of approval: 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16022700/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3061 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0010200 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0917799 infores:hetionet CHEBI:28925 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0001824 infores:hetionet CAID:CA9043705 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043705 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 The NM_000156.6:c.372G>A variant in GAMT is a synonymous (silent) variant (p.Leu124=) for which SpliceAI predicts no impact on splicing (all scores <0.1) (BP4, BP7) To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0 is 0.000005933 (7/1179802 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 891607). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043705/MONDO:0012999/026 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:16469 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0037199 infores:hetionet CHEBI:7954 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0242350 infores:hetionet CAID:CA400022111 biolink:causes MONDO:0100326 infores:clingen CAID:CA400022111 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting PM5, PM3, PP3 The NM_000212.3(ITGB3):c.473A>T (p.Gln158Leu) missense variant was detected in a 13yo patient with GT (PMID: 31777146) who has a history of recurrent gum bleeds, easy bruisability, and a history of ecchymotic patches. This patient was born to a non-consanguineous family with no history of bleeding. Lab studies demonstrated mildly prolong PT, normal APPT and TT. Platelet aggregation demonstrated absent aggregation with ADP and collagen and was reduced with ristocetin. Flow cytometry showed an absence of αIIbβ3 integrin and normal levels of GPIb and GPIX receptors which is consistent with. diagnosis of GT (PP4_strong). The Gln158Leu variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP4_Strong (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400022111/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true PUBCHEM.COMPOUND:657309 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0011603 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0026636 infores:hetionet NCBIGene:60 biolink:causes MONDO:0011823 infores:monarchinitiative not_provided not_provided HGNC:132 MONDO:0011823 uuid:9ba33ebf-93d5-46e6-ab85-f8a0b99f3968 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61390 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0037274 infores:hetionet CHEBI:9622 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0233407 infores:hetionet CHEBI:17823 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0020443 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0234215 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020039 infores:hetionet CHEBI:2567 biolink:causes MONDO:0001439 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0014583 infores:hetionet CHEBI:27446 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0022658 infores:hetionet CHEBI:77260 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0002792 infores:hetionet NCBITaxon:11292 biolink:causes MONDO:0019173 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11292 MONDO:0019173 CHEBI:16469 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235889 infores:hetionet CHEBI:28748 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020488 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030305 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027051 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0877047 infores:hetionet CHEBI:6375 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0003811 infores:hetionet CHEBI:465284 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0231218 infores:hetionet CHEBI:474053 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0031542 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030305 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011991 infores:hetionet CHEBI:40237 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0014742 infores:hetionet CHEBI:6149 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0234518 infores:hetionet CHEBI:33325 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0000833 infores:hetionet CAID:CA410149706 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149706 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS3, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS4, BS3, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.893C>T (p.Pro298Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score < 0.50 (0.163) and a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149706/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410147803 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147803 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP3, BP1, BP2, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1196G>C (p.Ser399Thr)is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.048) and a SpliceAI score <0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147803/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:584020 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0030196 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022660 infores:hetionet CHEBI:73274 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0085602 infores:hetionet CHEBI:135005 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0017178 infores:hetionet NCBIGene:5354 biolink:causes MONDO:0010714 infores:monarchinitiative not_provided not_provided HGNC:9086 MONDO:0010714 uuid:c6591e09-a5d3-420f-bce8-3c441e072c91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44032 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0006325 infores:hetionet CHEBI:5098 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0036830 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235283 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235283 infores:hetionet CHEBI:48273 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0015468 infores:hetionet CAID:CA226344 biolink:causes MONDO:0100437 infores:clingen CAID:CA226344 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1120G>T (p.Glu374Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 374 in exon 10 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), electroretinogram responses consistent with retinitis pigmentosa (1 pt), night blindness (0.5 pts), visual field constriction (0.5 pts), and genotyping by next-generation sequencing panel that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 32037395, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226344/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:36791 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235893 infores:hetionet NCBIGene:114803 biolink:causes MONDO:0020856 infores:monarchinitiative not_provided not_provided HGNC:29401 MONDO:0020856 uuid:b9293dd5-ba41-43dc-8fd4-6aa0ce0210f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66876 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0004690 infores:hetionet CHEBI:6062 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085616 infores:hetionet CHEBI:28787 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0033774 infores:hetionet CHEBI:52172 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0232461 infores:hetionet CHEBI:4495 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0018681 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0015230 infores:hetionet CHEBI:48390 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0026821 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013395 infores:hetionet NCBIGene:3178 biolink:causes MONDO:0012410 infores:monarchinitiative not_provided not_provided HGNC:5031 MONDO:0012410 uuid:9b293c5c-f9f6-48b0-a033-28654a0b903c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0232492 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0919569 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0919569 infores:hetionet CHEBI:46195 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0013604 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0851341 infores:hetionet CHEBI:41423 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0232849 infores:hetionet CHEBI:6904 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0033774 infores:hetionet CHEBI:9738 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0021141 infores:hetionet CHEBI:8435 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0009421 infores:hetionet CHEBI:70735 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0016204 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1291078 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0549288 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0549288 infores:hetionet CHEBI:36791 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023222 infores:hetionet CHEBI:4798 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0005758 infores:hetionet CHEBI:44185 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C1384353 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0029927 infores:hetionet CHEBI:3216 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0039070 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0020517 infores:hetionet CHEBI:44185 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0206061 infores:hetionet CHEBI:63584 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0013378 infores:hetionet CHEBI:53760 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0232462 infores:hetionet NCBIGene:117531 biolink:causes MONDO:0011708 infores:monarchinitiative not_provided not_provided HGNC:16513 MONDO:0011708 uuid:ba063721-b818-4c89-a0f4-37312f05e1d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:79029 biolink:causes MONDO:0859206 infores:monarchinitiative not_provided not_provided HGNC:28762 MONDO:0859206 uuid:3f410f45-a44c-4f28-aa36-bf2a64c059b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0575081 infores:hetionet CHEBI:4717 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0026837 infores:hetionet CAID:CA414917674 biolink:causes MONDO:0010602 infores:clingen CAID:CA414917674 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM5, PM2_Supporting, PP3, PP1 The c.980T>A (p.Leu327Gln) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting the PM2_Supporting criteria. The missense variant has a REVEL score of 0.868 (>0.6) meeting PP3. The variant has been reported in a proband with severe hemophilia A in the EAHAD Database genotyped through the My Life Our Future program (PP4_Moderate). This information was confirmed by a VCEP member who also reported a similarly affected nephew also found to harbor this variant meeting PP1 criteria. A pathogenic variant, Leu327Val, is reported at the same residue meeting PM5 criteria meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM5, PP4_Moderate, PP1, PP3, PM2_Supporting Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414917674/MONDO:0010602/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Supports CHEBI:724125 biolink:causes UMLS:C0235050 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0235050 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007642 infores:hetionet NCBITaxon:5551 biolink:causes MONDO:0001628 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5551 MESH:D014009 DB01110_MESH_D014009_1DB09040_MESH_D014009_1DB09041_MESH_D014009_1 NCBIGene:3911 biolink:causes MONDO:0859573 infores:monarchinitiative not_provided not_provided HGNC:6485 MONDO:0859573 uuid:5fadd967-5c7d-43cc-9210-5b2dd27b41d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135361 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0043352 infores:hetionet CHEBI:3561 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0002878 infores:hetionet CHEBI:28593 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0023646 infores:hetionet CHEBI:119573 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0231218 infores:hetionet NCBIGene:649 biolink:causes MONDO:0013924 infores:monarchinitiative not_provided not_provided HGNC:1067 MONDO:0013924 uuid:568c8754-6807-4883-b178-8397b19bf13b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0242301 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0027651 infores:hetionet CHEBI:8356 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0549249 infores:hetionet CHEBI:6437 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0232807 infores:hetionet CHEBI:49375 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013378 infores:hetionet CHEBI:8481 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0152198 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0037286 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0948525 infores:hetionet CHEBI:7025 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0015230 infores:hetionet CHEBI:63616 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0017178 infores:hetionet CHEBI:46081 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0917801 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0021400 infores:hetionet CHEBI:39867 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0851578 infores:hetionet CHEBI:51137 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0013604 infores:hetionet CHEBI:82981 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C2047937 infores:hetionet CHEBI:31625 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0030193 infores:hetionet CHEBI:63580 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151786 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042075 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002363 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0030354 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013182 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0851341 infores:hetionet CHEBI:10125 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011124 infores:hetionet CHEBI:64028 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0023530 infores:hetionet CHEBI:6706 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0042963 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235074 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235074 infores:hetionet NCBIGene:547 biolink:causes MONDO:0012476 infores:monarchinitiative not_provided not_provided HGNC:888 MONDO:0012476 uuid:e2f7e95b-83e5-4ecb-aa2f-8f336a714941 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0162429 infores:hetionet CHEBI:691037 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0263449 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019196 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020542 infores:hetionet CHEBI:4469 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0040822 infores:hetionet CHEBI:251408 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0003811 infores:hetionet CHEBI:51380 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C1096250 infores:hetionet CHEBI:41774 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0027497 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017152 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0948525 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0033860 infores:hetionet CHEBI:18067 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0151828 infores:hetionet NCBIGene:63932 biolink:causes MONDO:0049222 infores:monarchinitiative not_provided not_provided HGNC:26239 MONDO:0049222 uuid:05f39442-5812-4800-acde-f63967a3fb4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64354 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020517 infores:hetionet CHEBI:2682 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0237849 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C3160754 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C3160754 infores:hetionet CHEBI:4975 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0027424 infores:hetionet CAID:CA047113 biolink:causes MONDO:0021056 infores:clingen CAID:CA047113 MONDO:0021056 PMID: Benign BS2, BP1, BS1 BP4 The c.715G>C variant in APC is a missense variant predicted to cause substitution of alanine by proline at amino acid 239 (p.Ala239Pro). This variant has been observed in ≥ 35 heterozygous individuals with no features or family history of FAP, worth ≥ 10 healthy individual points (BS2; Ambry, Invitae internal data). The highest allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 0.0002269 in East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.00001) for BS1 (BS1). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BP1. (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA047113/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7640 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0013395 infores:hetionet CHEBI:17347 biolink:causes MONDO:0003522 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0033949 infores:hetionet CHEBI:15553 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0039231 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0746883 infores:hetionet GO:1903125 biolink:causes GO:0098869 infores:ubergraph knowledge_assertion manual_agent GO:1903125 GO:0098869 CAID:CA401361416 biolink:causes MONDO:0009290 infores:clingen CAID:CA401361416 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The NM_000152.5:c.444C>G (p.Tyr148Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient, with late onset Pompe disease, has been reported who responded to enzyme replacement therapy and had muscle histology consistent with Pompe disease (PMID 25093132)(PP4). This patient is compound heterozygous, phase unknown, for the variant and c.2238G>C (p.Trp746Cys). The allelic data for this patient will be used in the assessment of p.Trp746Cys and is not included here to avoid circular logic. The c.444C>G (p.Tyr148Ter) variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PP4, PM2_Supporting (Approved by the ClinGen LSD VCEP - Oct. 19th, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401361416/MONDO:0009290/010 2021-12-02 2022-11-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UNII:VL0L558GCB biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0042109 infores:hetionet CHEBI:40009 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0018681 infores:hetionet CHEBI:9123 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151827 infores:hetionet GO:0090111 biolink:causes GO:0006888 infores:ubergraph knowledge_assertion manual_agent GO:0090111 GO:0006888 CAID:CA2573157353 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157353 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BA1, PVS1, PM6, BS1, BS3, BS4, PM5, PM4, PM1, PP3 NM_001754.5(RUNX1):c.509-14T>A is an intronic variant which is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, both of which provide at least 20x coverage for the RUNX1 gene at this genomic position (PM2_supporting). Evolutionary conservation algorithms indicate that the site is not conserved (PhyloP100way score of 0.872, < 2.0), supporting BP7. SpliceAI predicts no impact on the splice consensus sequence and no creation of a new splice site, supporting BP4. Furthermore, this variant has not been reported in any patients with RUNX1-related diseases. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157353/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:39867 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0518015 infores:hetionet UNII:D27V6190PM biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0037763 infores:hetionet CHEBI:7445 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0149871 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0025061 infores:hetionet GO:0048742 biolink:causes GO:0060538 infores:ubergraph knowledge_assertion manual_agent GO:0048742 GO:0060538 CHEBI:142290 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0039240 infores:hetionet CHEBI:8024 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0028961 infores:hetionet CAID:CA8603152 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603152 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PP4 The c.1383C>T (p.Asn461=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.913 (BP7 and BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004396 (5/113734 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating with GT were found in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7 and PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603152/MONDO:0100326/011 2023-11-02 2023-11-03 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63681 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0013604 infores:hetionet CHEBI:127780 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0042963 infores:hetionet CHEBI:48844 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0011053 infores:hetionet CHEBI:40237 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0020580 infores:hetionet CHEBI:63629 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0039070 infores:hetionet CHEBI:4356 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0438717 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0235146 infores:hetionet CHEBI:72292 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0040479 infores:hetionet NCBIGene:10297 biolink:causes MONDO:0032866 infores:monarchinitiative not_provided not_provided HGNC:24036 MONDO:0032866 uuid:9c65ea4d-e6c4-41c6-8205-d563dea8c8b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0035317 infores:hetionet GO:0048819 biolink:causes GO:0042633 infores:ubergraph knowledge_assertion manual_agent GO:0048819 GO:0042633 CHEBI:10127 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0030312 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0235194 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235194 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0009806 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013456 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0003864 infores:hetionet NCBIGene:9533 biolink:causes MONDO:0014666 infores:monarchinitiative not_provided not_provided HGNC:20194 MONDO:0014666 uuid:6136e12f-0942-472c-8d6b-26081f7e97e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020598 infores:hetionet CHEBI:2682 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0702166 infores:hetionet CHEBI:50692 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0014518 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0087169 infores:hetionet CHEBI:10119 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085583 infores:hetionet CHEBI:50381 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0002622 infores:hetionet CHEBI:3437 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0011570 infores:hetionet CHEBI:9757 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0013604 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0041969 infores:hetionet CHEBI:63589 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0040034 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0019348 infores:hetionet CHEBI:42944 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0021177 infores:hetionet CHEBI:5383 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0017178 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0020538 infores:hetionet CHEBI:8888 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0522055 infores:hetionet CHEBI:5147 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0003811 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006852 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0877153 infores:hetionet NCBIGene:54805 biolink:causes MONDO:0013480 infores:monarchinitiative not_provided not_provided HGNC:103 MONDO:0013480 uuid:8fbb580d-dbc9-4bc2-82cd-9ea57135e96f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020615 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0013395 infores:hetionet CHEBI:92998 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0009782 infores:hetionet CHEBI:16469 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0002994 infores:hetionet GO:0048709 biolink:causes CL:0000128 infores:ubergraph knowledge_assertion manual_agent GO:0048709 CL:0000128 CHEBI:35778 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0231837 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0015376 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013595 infores:hetionet CHEBI:63618 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0014457 infores:hetionet CHEBI:64321 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0036508 infores:hetionet CHEBI:50924 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0002792 infores:hetionet CHEBI:4027 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0854467 infores:hetionet CHEBI:127342 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0015230 infores:hetionet CHEBI:3756 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0014591 infores:hetionet CHEBI:31348 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0575081 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0520559 infores:hetionet CHEBI:9398 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0013395 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0021053 infores:hetionet CHEBI:3314 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0006663 infores:hetionet CHEBI:64312 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151836 infores:hetionet NCBIGene:2184 biolink:causes MONDO:0010161 infores:monarchinitiative not_provided not_provided HGNC:3579 MONDO:0010161 uuid:7c12499c-319c-4d54-8201-42e603de4e55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C2363731 infores:hetionet CHEBI:2675 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0232462 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0036572 infores:hetionet CHEBI:28901 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0004144 infores:hetionet CHEBI:167638 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0018524 infores:hetionet CHEBI:5296 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C1443060 infores:hetionet CHEBI:83531 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0016204 infores:hetionet CHEBI:145499 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020621 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0235169 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0034069 infores:hetionet CHEBI:64045 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0037763 infores:hetionet CHEBI:16714 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0040822 infores:hetionet CHEBI:38545 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0011603 infores:hetionet CHEBI:136040 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0085631 infores:hetionet NCBIGene:9711 biolink:causes MONDO:0014311 infores:monarchinitiative not_provided not_provided HGNC:28991 MONDO:0014311 uuid:4ace5fa5-5fdd-441b-8294-f9b51cfd4957 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2573157356 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157356 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.58+13T>G is an intronic variant. This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.58) (BP7). Multiple lines of computational evidence suggest no impact on gene /gene product (SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157356/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:23765 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0001925 infores:hetionet CHEBI:63623 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0018681 infores:hetionet CHEBI:64321 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0012833 infores:hetionet CHEBI:36795 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0026858 infores:hetionet CHEBI:9738 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0013144 infores:hetionet CAID:CA626119953 biolink:causes MONDO:0100326 infores:clingen CAID:CA626119953 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PP4 This intronic variant, NM_000419.5(ITGA2B):c.2728-19T>C (p.=) occurs at an extremely low frequency (<1/10,000), with an overall allele frequency in gnomAD of 0.00001377 and an MAF of 0.00003751 (2/53,326 alleles) in the non-Finnish European population (PM2_supporting). To our knowledge, it has not been reported in the literature. The variant is predicted by SpliceAI to have no significant splicing motif alteration detected and the nucleotide is not highly conserved (PhyloP score 0.099; BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting BP4, and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626119953/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9086 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0026848 infores:hetionet CHEBI:7789 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0012833 infores:hetionet CHEBI:9168 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0687713 infores:hetionet CHEBI:5002 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0002962 infores:hetionet CHEBI:7936 biolink:causes MONDO:0021124 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021361 infores:hetionet CHEBI:50859 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020598 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0003123 infores:hetionet CHEBI:6128 biolink:causes MONDO:0010030 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0086981 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0853753 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0853753 infores:hetionet CHEBI:39867 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0038325 infores:hetionet CAID:CA401325518 biolink:causes MONDO:0009290 infores:clingen CAID:CA401325518 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3 The NM_000152.5:c.2467A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 823 (p.Ile823Phe). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002 (2/1179156 alleles) in the European, non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Although this variant has been identified in several individuals with low GAA activity on newborn screen, it not been reported in any symptomatic individuals diagnosed with Pompe disease and, as such, there is insufficient data to apply PM3 and PP4. There is a ClinVar entry for this variant (Variation ID: 456406). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP2, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401325518/MONDO:0009290/010 2025-06-17 2025-07-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:36795 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0023067 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0035078 infores:hetionet CHEBI:5864 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0206061 infores:hetionet CHEBI:4551 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0003467 infores:hetionet CHEBI:50381 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0040822 infores:hetionet CHEBI:9571 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0002878 infores:hetionet CHEBI:2788 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0152227 infores:hetionet CHEBI:15640 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0009676 infores:hetionet CHEBI:41774 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0404521 infores:hetionet CHEBI:64355 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151723 infores:hetionet CHEBI:28748 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151636 infores:hetionet CHEBI:63611 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0002962 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0031039 infores:hetionet CAID:CA10360734 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360734 MONDO:0100039 PMID: Likely Benign BP5, BP4 BS1, PM1, PM2 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2857G>T (p.Ala953Ser) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3137C>A) is present in 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Ala953Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). Additionally, computational analysis prediction tools suggest that the p.Ala953Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala953Ser variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BP5, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360734/MONDO:0100039/034 2023-02-20 2023-06-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:7496 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0424295 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0160390 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0948089 infores:hetionet CHEBI:63580 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042963 infores:hetionet CHEBI:4708 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235490 infores:hetionet CHEBI:63631 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011603 infores:hetionet CHEBI:8890 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020672 infores:hetionet CHEBI:10023 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0039231 infores:hetionet CHEBI:8412 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0009917 infores:hetionet CHEBI:8597 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0030252 infores:hetionet CHEBI:63619 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030193 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0854100 infores:hetionet CHEBI:2453 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0027540 infores:hetionet NCBIGene:2067 biolink:causes MONDO:0012554 infores:monarchinitiative not_provided not_provided HGNC:3433 MONDO:0012554 uuid:495a3eec-7162-4a2c-8f03-7d25708c0005 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:1392 biolink:causes MONDO:0016595 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1392 MESH:C571912 DBDB08902_MESH_C571912_1DB01053_MESH_C571912_1DB05336_MESH_C571912_1DB02703_MESH_C571912_1DB00254_MESH_C571912_1 CHEBI:474053 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0014457 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0158281 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0158281 infores:hetionet CHEBI:7903 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C2047937 infores:hetionet CHEBI:6690 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0041969 infores:hetionet CHEBI:3176 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0040264 infores:hetionet CHEBI:9566 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0024141 infores:hetionet CHEBI:71223 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0000737 infores:hetionet CHEBI:17698 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0014356 infores:hetionet CHEBI:15553 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0036974 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C1258215 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0687707 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C3263723 infores:hetionet CHEBI:31536 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0009782 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151838 infores:hetionet CAID:CA10567779 biolink:causes MONDO:0010602 infores:clingen CAID:CA10567779 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PS4_Very Strong BS1, BS3, BA1 The NM_000132.4(F8):c.6658G>C; p.Ala2220Pro is absent in males in gnomAD database v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.713, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has been reported in at least 17 individuals with mild/moderate hemophilia A (PMID: 18034765 ; 20536985, 10910913, 29296726), meeting the PS4_Very Strong & PP4_Moderate criteria. This variant was found to co-segregate with the disease in multiple affected family members, with 7 meioses observed in one family (PP1_Moderate; PMID: 20536985). This variant has also been associated with incidence of inhibitor development to factor replacement products (PMID: 18034765). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0: PM2_Supporting, PP3, PS4_Very Strong, PP4_Moderate, PP1_Moderate. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10567779/MONDO:0010602/071 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Supports CAID:CA2697547495 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547495 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.695_696del (p.Arg232ProfsTer28) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547495/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0854375 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0039971 infores:hetionet CHEBI:9445 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0085649 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0574067 infores:hetionet UMLS:C0004609 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0016204 infores:hetionet CAID:CA278707 biolink:causes MONDO:0019501 infores:clingen CAID:CA278707 MONDO:0019501 PMID: Pathogenic PP3, PP4, PM2_Supporting, PM3_Very Strong The c.631A>G variant in MYO7A is a missense variant predicted to cause substitution of serine by glycine at amino acid 211 (p.Ser211Gly). The highest population minor allele frequency in gnomAD v4.1.0 is 0.005% (62/1179900 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 7 individuals with clinical features or a diagnosis of Usher syndrome. Of those individuals, 2 were homozygous, and 5 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (4.5 PM3 points, PMID:25472526 and 37466950, Laboratory for Molecular Medicine internal data, SCV000059882.6). At least one patient with this variant displayed congenital profound sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction, which is highly specific for Usher syndrome type 1 (PP4). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PM3_VeryStrong, PP4. ClinGen Hearing Loss VCEP specifications version 2.0.0; 04.17.24. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278707/MONDO:0019501/005 2024-05-01 2024-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:7577 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C1306341 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027609 infores:hetionet CHEBI:68845 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0011991 infores:hetionet CHEBI:3732 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0034152 infores:hetionet CAID:CA915952065 biolink:causes MONDO:0010305 infores:clingen CAID:CA915952065 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_005629.4:c.1394delG (p.Gly465AlafsTer46) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism PVS1). This variant is absent in population databases (PM2_Supporting), and to our current knowledge has not been reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:666588). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1, PM2_Supporting. Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952065/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Supports CAID:CA179945 biolink:causes MONDO:0800472 infores:clingen CAID:CA179945 MONDO:0800472 PMID:11854439PMID:10910054 Benign BA1, BP4 PP1, PP3, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, BP7, PM2, PVS1 The c.1358A>G variant in CYP1B1 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 453 (p.Asn453Ser). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.2284, which met the ≥ 0.05 threshold set for BA1 (20,801 alleles out of 91,086, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.264, which is within the 0.184-0.290 range for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), suggesting that the variant does not impact CYP1B1 function. PS3_Supporting was not applied as the assays reported in PMIDs: 11854439, 10910054 did not meet the OddsPath threshold (> 2.1). In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1, BP4 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA179945/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8707 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0686347 infores:hetionet CHEBI:8863 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018946 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0234913 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0040479 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002418 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C3495442 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C3495442 infores:hetionet CHEBI:6375 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0424295 infores:hetionet CHEBI:10102 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0392525 infores:hetionet CHEBI:47519 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0043352 infores:hetionet CHEBI:7865 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0030446 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017178 infores:hetionet CHEBI:50841 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0043094 infores:hetionet CHEBI:2904 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0004239 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0029456 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0036973 infores:hetionet CHEBI:4562 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C3263723 infores:hetionet CHEBI:9123 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0700590 infores:hetionet CHEBI:15553 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085602 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151883 infores:hetionet CHEBI:45327 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0151636 infores:hetionet CHEBI:16467 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0002792 infores:hetionet CHEBI:50173 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0042384 infores:hetionet CHEBI:9649 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0002994 infores:hetionet CAID:CA414817724 biolink:causes MONDO:0044970 infores:clingen CAID:CA414817724 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS1, PS2, PS3, PS4, PM5, PVS1, PM6 The m.13379A>C (p.H348P) variant in MT-ND5 has been reported in one individual from one family (PMID: 17003408), in a male with LHON. The variant was present at homoplasmy in blood and haplogroup was M1. Although it is reported in this paper that this proband had a family history of poor vision, no details are provided. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.80 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no functional studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414817724/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5118 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0026826 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0007222 infores:hetionet CHEBI:39585 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0700225 infores:hetionet CHEBI:51209 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0220870 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0017675 infores:hetionet CHEBI:92998 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0007859 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011570 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0022408 infores:hetionet CHEBI:64312 biolink:causes MONDO:1030008 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0026266 infores:hetionet CHEBI:5790 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0015230 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0003811 infores:hetionet CHEBI:231594 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0232849 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0333472 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0333472 infores:hetionet NCBIGene:7299 biolink:causes MONDO:0011749 infores:monarchinitiative not_provided not_provided HGNC:12442 MONDO:0011749 uuid:f721a5ac-3489-4373-a756-f9fdc7253284 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0009676 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0854113 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0008093 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0008093 uuid:dc79d40f-3c8c-4701-8dc2-7d09ec9f26f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011053 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151752 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151752 infores:hetionet CHEBI:65349 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0013395 infores:hetionet CHEBI:8863 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1456784 infores:hetionet CHEBI:5784 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0221185 infores:hetionet CHEBI:45081 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020578 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0234987 infores:hetionet CHEBI:8214 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0015672 infores:hetionet CHEBI:8356 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0423153 infores:hetionet CHEBI:135736 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948008 infores:hetionet GO:1901532 biolink:causes GO:0030097 infores:ubergraph knowledge_assertion manual_agent GO:1901532 GO:0030097 CHEBI:5118 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036104 infores:hetionet CHEBI:101278 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0006384 infores:hetionet CHEBI:135935 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0011991 infores:hetionet CHEBI:2704 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151825 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0234913 infores:hetionet CHEBI:7936 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0014518 infores:hetionet CHEBI:2704 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0043094 infores:hetionet CHEBI:8871 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003467 infores:hetionet CAID:CA412376047 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376047 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PM1_Strong, PM5 PP3 NM_000330.4(RS1):c.176G>T (p.Cys59Phe) is a missense variant encoding the substitution of cysteine with phenylalanine at amino acid 59, which is a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). Another missense variant in the same codon, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 31174210, 10450864, 17987333, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (205) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.757, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function. PP3 is not met since this code is ineligible in combination with PM1_Strong. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, and PM5. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376047/MONDO:0010725/126 2025-10-03 2025-10-03 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:83531 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0022107 infores:hetionet CHEBI:68558 biolink:causes HP:0031274 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0020683 infores:hetionet CHEBI:7903 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0042963 infores:hetionet CAID:CA357196 biolink:causes MONDO:0012589 infores:clingen CAID:CA357196 MONDO:0012589 PMID: Uncertain Significance PM5, PM1, PM3, PS1, PS3, PS4, PS2, BP4, BP2, BA1, PM2, PM6, BP5, BS1, BS3, BS4, BS2, PP3, PP1, PP4 The p.His284Tyr variant in TCF4 has been reported in an individual with a neurodevelopmental phenotype (PMID 28554332). The p.His284Tyr variant is present in two XY individuals in gnomAD v4 (0.0003%) (not sufficient to meet BS1 criteria). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.His284Tyr variant in TCF4 is classified as a Variant of Unknown Significance based on the ACMG/AMP criteria (no criteria met). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA357196/MONDO:0012589/032 2023-12-06 2023-12-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31644 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0003811 infores:hetionet CHEBI:83804 biolink:causes NCIT:C122529 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0857494 infores:hetionet CHEBI:3441 biolink:causes HP:0003146 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151718 infores:hetionet CHEBI:65349 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0151904 infores:hetionet CHEBI:521033 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0024902 infores:hetionet CHEBI:39112 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C2242588 infores:hetionet CHEBI:171719 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0009421 infores:hetionet CHEBI:2611 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0043094 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0031046 infores:hetionet CHEBI:63599 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0151579 infores:hetionet CHEBI:5165 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0033774 infores:hetionet CHEBI:63617 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0233471 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0853619 infores:hetionet CHEBI:8776 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0018926 infores:hetionet CHEBI:17347 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151872 infores:hetionet NCBIGene:55186 biolink:causes MONDO:0859362 infores:monarchinitiative not_provided not_provided HGNC:25554 MONDO:0859362 uuid:83902cb5-3922-4296-8901-168cebaa54fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0002792 infores:hetionet CHEBI:231425 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0033774 infores:hetionet UBERON:0019190 biolink:causes MONDO:0004079 infores:ubergraph knowledge_assertion manual_agent UBERON:0019190 MONDO:0004079 CHEBI:64355 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0014868 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0020649 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0015376 infores:hetionet CHEBI:3696 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0242301 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151713 infores:hetionet CHEBI:63635 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0242429 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0018799 infores:hetionet CHEBI:59582 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0015230 infores:hetionet CHEBI:8404 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0003811 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030305 infores:hetionet CHEBI:31623 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0235259 infores:hetionet CHEBI:490877 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0232462 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0026857 infores:hetionet CAID:CA415077156 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077156 MONDO:0010305 PMID: Pathogenic PVS1, PM2, PP4_Strong The NM_005629.4:c.262+1G>T variant occurs within the canonical splice donor of intron 1/12 (exon 1/13) of SLC6A8. It is predicted to cause skipping of biologically-relevant-exon 1/13, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. In silico algorithm SpliceAI predicts a donor loss -1bp from this position (delta score=0.99). This variant has not been previously reported in ClinVar. The c.262+1G>T variant in SLC6A8 has been reported in one individual, a male diagnosed at 1.8y of age (patient 6) with moderate intellectual disability, seizures, autistic features, aggressive and self injurious behaviors. This individual had a urine creatine to creatinine ratio of 14,874 (normal = 6–1200 μmol/mmol creatinine) and a H-MRS showing reduced creatine peak [PMID: 29435807], therefore this reported individual meets criteria for PP4_Strong. In summary, this variant meets the criteria to be classified as Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 29, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077156/MONDO:0010305/027 2024-03-29 2024-03-29 X-linked inheritance HP:0001417 Supports CHEBI:27436 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0018681 infores:hetionet CHEBI:27899 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0023530 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0151735 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0037274 infores:hetionet CHEBI:7986 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0041834 infores:hetionet CHEBI:3752 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0042963 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0221780 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0221780 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020517 infores:hetionet CHEBI:63610 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0041657 infores:hetionet CHEBI:135736 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0023530 infores:hetionet CHEBI:9288 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0030193 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0018681 infores:hetionet GO:1901620 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1901620 GO:0007399 CHEBI:119573 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1306341 infores:hetionet CAID:CA658795276 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795276 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting The NM_000152.5:c.2189+3G>C variant in GAA is located in the donor splice site region of intron 15. At least 2 probands with IOPD and GAA activity in the affected range in dried blood spot have been reported with this variant (Duke Molecular Diagnostic Laboratory; PMIDs: 22252923, 31606152, 33301762) (PP4_Moderate). Of those individuals, one was compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1930_1936dup (p.Val646GlyfsTer93) (ClinVar Variation ID: 1411575) (PMID: 31606152), phase unconfirmed. One individual was homozygous for the variant (PMID: 33301762) (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001345 (1/74366 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor SpliceAI gives a score of 0.46 for loss of the intron 15 donor splice site, and a score of 0.27 for loss of the intron 14 acceptor splice site suggesting possible effect on splicing. While this SpliceAI score does not meet the current SpliceAI threshold (>0.5) of the ClinGen Lysosomal Diseases VCEP, a prediction score of 0.46 for donor loss meets the ClinGen Sequence Variant Interpretation Splicing Subgroup's recommendation to apply PP3 for variants with a SpliceAI score >0.2 (PMID: 37352859). Therefore, PP3 will be applied. (PP3). There is a ClinVar entry for this variant (Variation ID: 1409309). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PM3, PP3, PP4_Moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 2, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795276/MONDO:0009290/010 2025-09-02 2025-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:50841 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0235063 infores:hetionet CAID:CA6266433 biolink:causes MONDO:0700270 infores:clingen CAID:CA6266433 MONDO:0700270 PMID: Likely Benign PM2_Supporting, BP4, BP7 BA1, BS1, PP3 The ATM c.8751C>T (p.Gly2917=) variant has a GnomAD (v2.1.1) allele frequency of 0.000%, which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). It is a synonymous variant (BP7). This variant is not predicted to impact splicing in multiple RNA in silico tools (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6266433/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4858 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0003862 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0017178 infores:hetionet NCBIGene:5624 biolink:causes MONDO:0008316 infores:monarchinitiative not_provided not_provided HGNC:9451 MONDO:0008316 uuid:90a05b23-b75a-47c1-8d81-7b7c0a9bc30c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0234215 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0014868 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1735601 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0037274 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023530 infores:hetionet CHEBI:9352 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0948594 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0006444 infores:hetionet CHEBI:87715 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0018932 infores:hetionet CHEBI:9637 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0030193 infores:hetionet GO:0021936 biolink:causes GO:0030902 infores:ubergraph knowledge_assertion manual_agent GO:0021936 GO:0030902 CHEBI:52172 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020542 infores:hetionet CHEBI:7476 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0010200 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0038814 infores:hetionet CHEBI:3699 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C2830004 infores:hetionet CHEBI:63620 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0023218 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151713 infores:hetionet CHEBI:51860 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0014742 infores:hetionet CAID:CA297267 biolink:causes MONDO:0021060 infores:clingen CAID:CA297267 MONDO:0021060 PMID: Uncertain Significance PM1, PP3, PP2 BS1, BS2 The c.1385T>A (p.Phe462Tyr) variant in SOS1 was present in 0.002891% (1/34590) of Latino alleles in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been identified in at least 1 unaffected parent of a proband with features of a RASopathy; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000209112.10). SOS1 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe462Tyr variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297267/MONDO:0021060/004 2020-07-27 2020-07-27 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:465284 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0015672 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0267596 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0267792 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0239729 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0239729 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0022660 infores:hetionet NCBITaxon:1639 biolink:causes MONDO:0005828 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1639 MONDO:0005828 CHEBI:47381 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085595 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0948586 infores:hetionet NCBIGene:3265 biolink:causes MONDO:0044792 infores:monarchinitiative not_provided not_provided HGNC:5173 MONDO:0044792 uuid:4e4dbe82-6701-49de-a82b-19354d4e27e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018799 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0340464 infores:hetionet CHEBI:16469 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0041657 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0349506 infores:hetionet CHEBI:28915 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0027497 infores:hetionet CHEBI:9139 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0858635 infores:hetionet CHEBI:4903 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0033774 infores:hetionet CHEBI:10102 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0025320 infores:hetionet NCBIGene:3265 biolink:causes MONDO:0001187 infores:monarchinitiative not_provided not_provided HGNC:5173 MONDO:0001187 uuid:7d71686a-7dfa-418d-b5fe-1d4b4c288f99 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:209807 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0019080 infores:hetionet CHEBI:184555 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0011603 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0031117 infores:hetionet CHEBI:71255 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0013384 infores:hetionet NCBIGene:3858 biolink:causes MONDO:0700245 infores:monarchinitiative not_provided not_provided HGNC:6413 MONDO:0700245 uuid:307881af-1acd-4a20-a3be-3612be3eb07a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5132 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0151798 infores:hetionet CHEBI:135566 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0234215 infores:hetionet CHEBI:4356 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0028077 infores:hetionet CAID:CA16620650 biolink:causes MONDO:0100453 infores:clingen CAID:CA16620650 MONDO:0100453 PMID: Uncertain Significance PM1_Supporting, PP3, PM2_Supporting PM3, PP4 The NM_000180.4(GUCY2D):c.2620G>A (p.Glu874Lys) variant is predicted to replace the glutamine at position p.874 with lysine. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000007435, with 12 alleles / 1613964 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.678, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function (PP3). This variant is a missense substitution between amino acids 873 and 951, within the guanylate cyclase catalytic domain which exhibits intolerance to missense variation (PM1_Supporting, PMID: 31704230). One proband harboring this variant exhibits a phenotype including CORD (0.5 pts) with onset at age 3 (1 pt), reduced visual acuity (1 pt), and night blindness (0.5 pts), which are not sufficiently specific for GUCY2D-related recessive retinopathy to meet the PP4 code (total 3 points, PMID: 32821499).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 32821499). However, the proband was not counted for PM3 because the other variant in trans (NM_000180.4(GUCY2D):c.238_252del (p.Ala80_Leu84del)) has not yet been curated so is classified as a VUS (total of 0.25 pts, 0.5 pts is required). In summary, this variant meets the criteria to be classified as a VUS for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM1_Supporting, PP3. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620650/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:47381 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0851341 infores:hetionet CHEBI:63631 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030554 infores:hetionet CHEBI:31174 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0030193 infores:hetionet CHEBI:6413 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0029453 infores:hetionet CHEBI:5134 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0015230 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0042373 infores:hetionet CHEBI:135929 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0034150 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0019158 infores:hetionet CHEBI:3286 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0032231 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1306341 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0009319 infores:hetionet CHEBI:194135 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013362 infores:hetionet CHEBI:3485 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0043352 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0425945 infores:hetionet CAID:CA10558490 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558490 MONDO:0010726 PMID: Uncertain Significance BP3, PM2, BS1, PP4 The c.1148_1159del (p.Leu383_Leu386del) variant in MECP2 (NM_004992.3) is present in 4 female and 1 male individual(s) in gnomAD (0.002578%) (not sufficient to meet BS1 criteria). The p.Leu383_Leu386del variant in MECP2 has been reported in an individual with Rett syndrome; however, no specific phenotype information was provided (PMID 19914908). In summary, the p.Leu383_Leu386del variant in MECP2 is classified as a variant of unknown significance based on the ACMG/AMP criteria (no criteria). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558490/MONDO:0010726/036 2023-08-28 2023-09-15 X-linked inheritance HP:0001417 Inconclusive true CHEBI:8597 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0030446 infores:hetionet CHEBI:2904 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0151904 infores:hetionet CHEBI:8382 biolink:causes MONDO:0020983 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0018813 infores:hetionet CHEBI:50648 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013362 infores:hetionet CHEBI:71219 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0011991 infores:hetionet CHEBI:9588 biolink:causes UMLS:C0858217 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0858217 infores:hetionet CHEBI:231594 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0016204 infores:hetionet CHEBI:63618 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151480 infores:hetionet CHEBI:68647 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0042963 infores:hetionet CHEBI:47519 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0086565 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0026113 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0037199 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0687707 infores:hetionet CHEBI:2675 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0030252 infores:hetionet CHEBI:8713 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0004093 infores:hetionet CHEBI:5118 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0032617 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0227791 infores:hetionet CHEBI:209807 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0020517 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0235639 infores:hetionet NCBIGene:54209 biolink:causes MONDO:0020750 infores:monarchinitiative not_provided not_provided HGNC:17761 MONDO:0020750 uuid:f7644994-74c7-43c8-b16a-6b9c6b84361f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0029132 infores:hetionet CHEBI:31236 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235660 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0149931 infores:hetionet CHEBI:68841 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0687713 infores:hetionet CHEBI:7565 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0025345 infores:hetionet CAID:CA066616 biolink:causes MONDO:0007783 infores:clingen CAID:CA066616 MONDO:0007783 PMID: Uncertain Significance BP4 PP3, PM1, PS4, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with serine at codon 1678 of the RYR1 protein p.(Asn1678Ser). The maximum allele frequency for this variant among the six major gnomAD populations is SAS:0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in one individual who had a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257), this individual was also reported to have a pathogenic variant in RYR1, p.Gly2434Arg, and was not considered for PS4 (personal communication, The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID: 21118704). A REVEL score <0.5 supports a benign status, BP4. Based on using Bayes to combine criteria this variant is assessed to be a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA066616/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7478 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0002792 infores:hetionet CAID:CA6571842 biolink:causes MONDO:0100038 infores:clingen CAID:CA6571842 MONDO:0100038 PMID: Benign BA1 The c.4590G>A variant in SCN8A is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 1530 (p.Met1530Ile). The variant is present in the population database, gnomAD v2.1.1, at a total MAF of 0.003%, with the highest sub-population (South Asian) frequency of 0.02% (BA1). In summary, this variant meets criteria to be classifies as benign for autosomal dominant complex neurodevelopmental disorder by the Epilepsy Sodium Channel VCEP specifications: BA1 (version 1.0; approved 6/27/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA6571842/MONDO:0100038/070 2024-05-07 2024-05-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:77260 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0034359 infores:hetionet CHEBI:5147 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0013604 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0014130 infores:hetionet CHEBI:9586 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0391870 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020676 infores:hetionet CHEBI:63630 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0028961 infores:hetionet CHEBI:63631 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234022 infores:hetionet CHEBI:8884 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0522224 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0267792 infores:hetionet NCBIGene:431705 biolink:causes MONDO:0030490 infores:monarchinitiative not_provided not_provided HGNC:31704 MONDO:0030490 uuid:27b6cabf-29f6-43f5-882f-8b30b3163bcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes UMLS:C0858589 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0858589 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0235416 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013395 infores:hetionet CAID:CA256115 biolink:causes MONDO:0001586 infores:clingen CAID:CA256115 MONDO:0001586 PMID: Likely Pathogenic PM3_Supporting, PVS1_Strong, PP4, PM2_Supporting "The NM_000203.5:c.928C>T (p.Gln310Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR product showed a ""doublet"" with an upper band slightly larger than the normal band (505bp). Part of the mRNA was spliced from intron 5 to include 28nt of intronic sequence, indicating use of a cryptic splice site. This alternative splicing was said to create a frameshift and an open reading frame until exon 9. Since RT-PCR appears to show a near complete proportion of alternatively spliced transcript, the strength of PVS1 was reduced by 1 level to strong (PVS1_Strong; PMID: 8328452). This variant has been detected in at least 1 individual with MPS I. This individual was homozygous for the variant (PMID: 8328452; PM3_Supporting). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex, corneal opacities, hepatosplenomegaly, and arthropathy (PMID: 8328452; PP4). The highest population minor allele frequency in gnomAD v4.0. is 0.0000008630 (1/1158762 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 11915, 0 star review status) with 1 submitter classifying the variant as pathogenic; however this submitter is OMIM. In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1_Strong, PM3_Supporting, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 3, 2025)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA256115/MONDO:0001586/091 2025-03-03 2025-03-12 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:9681 biolink:causes MONDO:0957780 infores:monarchinitiative not_provided not_provided HGNC:18423 MONDO:0957780 uuid:9e08343e-7590-47f7-bc9c-223724927883 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C2939447 infores:hetionet CHEBI:31625 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C1761613 infores:hetionet CHEBI:16914 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C1443060 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002177 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0020459 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042571 infores:hetionet CHEBI:17474 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0085649 infores:hetionet CHEBI:127780 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0007820 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0948594 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019158 infores:hetionet CHEBI:52717 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232849 infores:hetionet CHEBI:6775 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C2363731 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0151824 infores:hetionet CHEBI:520985 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0040822 infores:hetionet CHEBI:7903 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0003862 infores:hetionet CAID:CA512232284 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232284 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.822A>G (p.Gln274=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232284/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7983 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0042963 infores:hetionet CHEBI:4903 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042963 infores:hetionet CHEBI:3223 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020580 infores:hetionet CAID:CA10014473 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014473 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS3, PS2, BA1, BP2, BP3, BP1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM3, PM1, PM4, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.613+18G>C is an intronic variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.48 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). Not a missense variant therefore REVEL score is not applicable and SpliceAI is ≤0.50 (0.00) (BP4). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014473/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0038177 biolink:causes GO:0012501 infores:ubergraph knowledge_assertion manual_agent GO:0038177 GO:0012501 CHEBI:7824 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0004604 infores:hetionet CHEBI:27300 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0006663 infores:hetionet CHEBI:59773 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027497 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0541832 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013404 infores:hetionet CHEBI:4315 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0030794 infores:hetionet CHEBI:37924 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0851578 infores:hetionet CHEBI:15940 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0018681 infores:hetionet CHEBI:3508 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0013378 infores:hetionet CHEBI:16469 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013362 infores:hetionet CHEBI:50275 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0268000 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0034150 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004601 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0023223 infores:hetionet CHEBI:5128 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C2830004 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020175 infores:hetionet CHEBI:3423 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0947912 infores:hetionet CHEBI:4710 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013428 infores:hetionet CHEBI:3423 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0037822 infores:hetionet CHEBI:47499 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011124 infores:hetionet CAID:CA16040650 biolink:causes MONDO:0044970 infores:clingen CAID:CA16040650 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PP3, PS4, PS3, BS1, PM6, PM2 The m.8418T>C (p.L18P) variant in MT-ATP8 has been reported in one individual with primary mitochondrial disease to date (PMID: 28027978), in a man with severe bilateral optic atrophy onset at age 44 years. The variant was present at homoplasmy in lymphocytes and fibroblasts. Family history information was not provided. There are no additional individuals reported with this variant to our knowledge. This variant is rare but present in population databases (Mitomap: 1/61,134; gnomAD v3.1.2: 5/46,432; Helix: 3/195,983) with a combined frequency of 0.00255%, which is slightly higher than the supporting pathogenic cutoff of 0.002% but lower than the frequency of 0.5-0.99% required for evidence of benign status. The computational predictor APOGEE gives a consensus rating of likely benign with a score of 0.175 (Min=0, Max=1), which predicts a neutral effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant although in-silico yeast modeling predicted this variant to destabilize the F0 domain of ATP8 (PMID: 37340059). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16040650/MONDO:0044970/015 2024-11-11 2024-12-11 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5847 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0011175 infores:hetionet CAID:CA10549206 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549206 MONDO:0010305 PMID:25861866 Likely Benign BS2, BP4, BS3_Supporting BS1, PM2 The NM_005629.4:c.557G>A variant in SLC6A8 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 186 (p.Arg186His). The highest population minor allele frequency in gnomAD is 0.00003675 in the European non-Finnish population which meets neither the PM2_Supporting (<0.00002) nor the BS1 (>0.0002) ClinGen CCDS VCEP allele frequency threshold. The variant is present in 2 or more hemizygotes in gnomAD v2.1.1 (BS2). Functional studies show that the variant results in 82% creatine transport of wild type when expressed in HeLa cells (PMID 25861866) (BS3_Supporting). The computational predictor REVEL gives a score of 0.102, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI does not predict any impact of the variant on splicing (BP4). To our knowledge, this variant has not been reported in the literature in any patients with features of creatine transporter deficiency. There is a ClinVar entry for this variant (Variation ID: 516199). In summary, this variant meets the criteria to be classified as likely benign for creatine transporter deficiency. ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2, BS3_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549206/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CAID:CA392448448 biolink:causes MONDO:0007947 infores:clingen CAID:CA392448448 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PM5 PM1 The NM_00138 c.199T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 67 (p.Cys67Arg). This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (Internal data, PP4). This variant has been reported 1 in ClinVar as likely pathogenic and 1 time as uncertain significance (Variantion ID: 1380036). Three other probands with clinical features of Marfan syndrome carry the same variant (PMID 19839986, 33436942, 34281902, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in the fibrillin unique N-terminal (FUN) domain. A different missense variant impacting the same residue, p.Cys67Ser, has previously been established as likely pathogenic, and reported in individuals with clinical features of Marfan syndrome (PMID 27906200, internal data, PM5). Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.883, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM5, PM2_Sup, PP2, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392448448/MONDO:0007947/022 2023-12-21 2023-12-21 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ NCBIGene:5573 biolink:causes MONDO:0012509 infores:monarchinitiative not_provided not_provided HGNC:9388 MONDO:0012509 uuid:8b80af9c-b134-4a6e-bf60-d3405030823c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes UMLS:C1142300 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1142300 infores:hetionet CAID:CA152954 biolink:causes MONDO:0015967 infores:clingen CAID:CA152954 MONDO:0015967 PMID:10525657 Pathogenic PS4, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting, PS3_Moderate The c.544G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 182 (p.(Val182Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting).This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional assays were performed where the MDEP wild type quality control measures were met, and showed that the relative activity Index (RAI) of this variant was 0.02, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 10525657). Furthermore, this variant was identified in at least 12 unrelated individuals with hyperglycemia (PS4; PMID: 8433729, 10754480, 14517956, 25306193, 29510678, 31968686, 34496959, 35737141). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and macrosomia in normoglycemic offspring) (PP4_Moderate; PMID: 34406393). Additionally, this variant segregated with hyperglycemia with 2 informative meioses in 2 families (PP1; PMIDs: 25494859, 29510678). In summary, c.544G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 08/11/2023): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting, PS3_Moderate, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA152954/MONDO:0015967/086 2025-02-07 2025-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:31348 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1142499 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0152128 infores:hetionet CHEBI:9943 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0595929 infores:hetionet CHEBI:7494 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042029 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0162429 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0858600 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0858600 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0021400 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042571 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0034886 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0003864 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0020651 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1112261 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1112261 infores:hetionet CHEBI:45863 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0494475 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0022354 infores:hetionet CHEBI:5118 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0522178 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011570 infores:hetionet CHEBI:7565 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0004134 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0012833 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0011991 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011616 infores:hetionet CHEBI:168396 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C3665386 infores:hetionet CHEBI:10125 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0232849 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0750197 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0750197 infores:hetionet CHEBI:10101 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1306341 infores:hetionet CHEBI:3001 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C2364111 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0948089 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0878544 infores:hetionet CHEBI:50922 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C2830004 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151313 infores:hetionet CHEBI:5775 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0028643 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0027769 infores:hetionet CHEBI:8890 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013144 infores:hetionet CHEBI:8871 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0015967 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0340464 infores:hetionet CAID:CA6748917 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748917 MONDO:0009861 PMID:27121329 Likely Pathogenic PM3, PM5, PP4_Moderate, PM2, PP3 This c.463C>T (p.Arg155Cys) variant in PAH was reported in at least one patient with mild HPA detected in trans with pathogenic variant p.Gly289Arg (PMID: 27121329). A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. Computational evidence supports a deleterious effect. This variant is observed at an amino acid residue where two other pathogenic missense variants have also been observed. This variant is seen at an extremely low frequency in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM5, PM3, PM2, PP4_moderate, and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748917/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA405693438 biolink:causes MONDO:0018493 infores:clingen CAID:CA405693438 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with valine at codon 4990 of the RYR1 protein, p.(Met4990Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:21455645). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score of 0.646 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405693438/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:49575 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151888 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0403632 infores:hetionet CHEBI:7822 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0002792 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0039971 infores:hetionet CHEBI:75722 biolink:causes HP:0020059 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0427458 infores:hetionet CHEBI:63581 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0015967 infores:hetionet CHEBI:9566 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0020458 infores:hetionet CHEBI:6073 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0162830 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0041912 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0038454 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0013295 infores:hetionet CHEBI:44915 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1306341 infores:hetionet CHEBI:63630 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151905 infores:hetionet CHEBI:8356 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042963 infores:hetionet CHEBI:161680 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0022346 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151514 infores:hetionet CHEBI:8874 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030196 infores:hetionet NCBIGene:8318 biolink:causes MONDO:0014894 infores:monarchinitiative not_provided not_provided HGNC:1739 MONDO:0014894 uuid:5de4662d-ecaf-4444-b1ba-2568e373c122 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0027697 infores:hetionet CAID:CA016918 biolink:causes MONDO:0005045 infores:clingen CAID:CA016918 MONDO:0005045 PMID: Uncertain Significance PM1, PP3, PM2_Supporting, PS4_Supporting BS2, PM3, PM5, PM6, BA1, PP1, PS3, BS1, BS3, BS4, PS1, PS2, BP4, BP2, BP5 The NM_000257.4 (MYH7): c.872C>T (p.Ser291Phe) variant has been reported in at least 4 individuals with HCM (PS4_Supporting; Lakdawala 2011 PMID:21943931; Marsiglia 2013 PMID:24093860; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; LMM pers. comm.); however, one of these individuals had early-onset HCM (<25 yo) and also carried a second MYH7 variant that is classified as likely pathogenic by this expert panel (p.Lys847del, LMM pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2_Supporting; PM1; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016918/MONDO:0005045/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63621 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020580 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0858814 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0858814 infores:hetionet CHEBI:47519 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0004093 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0030446 infores:hetionet GO:0006954 biolink:causes MONDO:0011786 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D065631 DB09555_MESH_D065631_1DB01176_MESH_D065631_1DB00719_MESH_D065631_1DB00967_MESH_D065631_1DB00885_MESH_D065631_1DB08936_MESH_D065631_1DB00972_MESH_D065631_1DB00950_MESH_D065631_1DB11591_MESH_D065631_1DB00768_MESH_D065631_1 CHEBI:83804 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235086 infores:hetionet CAID:CA402995388 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995388 MONDO:0012999 PMID: Likely Pathogenic PP3, PM5, PP4_Strong, PM2_Supporting, PM3_Supporting The NM_000156.6:c.403G>T (p.Asp135Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 19027335). This variant was identified in 0.001470% (1/68032) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD) (PM2_Supporting). The patient previously reported was a reported compound heterozygote that carried a pathogenic variant, c.507_521dup15 (p.C169_S173dup; ClinVar Variation ID: 431959), in unknown phase (PM3_Supporting). This individual showed reduced creatine peak on brain magnetic resonance spectroscopy and elevated plasma GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Asp135Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.938) (PP3). A different missense variant at the same amino acid residue, p.Asp135Asn, has been previously reported pathogenic (ClinVar Variation ID: 573140) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM2_Supporting, PM3_Supporting, PM5, PP3, PP4_Strong (Richards 2015).(Classification approved by the ClinGen CCDS VCEP on March 23, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995388/MONDO:0012999/026 2023-03-23 2023-03-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135930 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0003862 infores:hetionet CHEBI:7824 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0033774 infores:hetionet CHEBI:2453 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0004093 infores:hetionet CHEBI:41423 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0026826 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0235293 infores:hetionet CAID:CA409108097 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108097 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM1, PM5 The c.881A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to arginine at codon 294 (p.(Gln294Arg)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, MODY probability cannot be calculated due to lack of clinical information (internal lab contributors). Another missense variant at the same codon, c.881A>C (p.Gln294Pro) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.881A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108097/MONDO:0015967/085 2025-04-07 2025-06-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:77733 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0023380 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0041582 infores:hetionet CHEBI:45783 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018965 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151885 infores:hetionet CHEBI:135342 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0231218 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0037199 infores:hetionet CHEBI:29007 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0151904 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162429 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233477 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019360 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0027765 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020456 infores:hetionet CHEBI:35778 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0020458 infores:hetionet CHEBI:6472 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0404521 infores:hetionet CAID:CA261400 biolink:causes MONDO:0010134 infores:clingen CAID:CA261400 MONDO:0010134 PMID:19204907PMID:19204907 Pathogenic PS3_Supporting, PP4, PP1, PP3, PM2, PM3_Strong The p.Val402Met variant in SLC26A4 was absent from gnomAD v2.1.1 and v3 (PM2). This variant has been detected in 2 probands with hearing loss. For both patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:19204907, Partners LMM unpublished data SCV000060082.6). The variant has been reported to segregate in one affected family member (PP1, PMID:19204907). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, LMM unpublished data SCV000060082.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19204907). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP1, PP3, PP4, PS3_Supporting). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261400/MONDO:0010134/005 2020-02-19 2020-02-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:724125 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0020517 infores:hetionet CHEBI:31524 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0018681 infores:hetionet GO:1903719 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:1903719 GO:0007154 CAID:CA410147622 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147622 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1256T>C (p.Val419Ala) is a missense variant which has a REVEL score < 0.50 (0.082), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147622/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39867 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0000768 infores:hetionet CHEBI:6709 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0013144 infores:hetionet CHEBI:50730 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0034068 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0020538 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0014868 infores:hetionet CAID:CA410148659 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148659 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, BA1, BP1, BP3, BP5, BS1, PM3, PM5, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.1005G>C (p.Gln335His) is a missense variant which has a REVEL score < 0.50 (0.40) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148659/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:127342 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0948594 infores:hetionet CHEBI:2611 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013144 infores:hetionet CHEBI:9086 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0006142 infores:hetionet CAID:CA410147557 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147557 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1271C>A (p.Ser424Ter) is a nonsense variant which is not predicted to undergo NMD; however, the truncated region is critical for protein function (c.917-c.1440 as per VCEP specifications) (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting) and is located downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147557/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17026 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0476089 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005236 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0302314 infores:hetionet UMLS:C0004609 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042963 infores:hetionet CHEBI:6129 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0021177 infores:hetionet CHEBI:27899 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0009782 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0021400 infores:hetionet CHEBI:28748 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017181 infores:hetionet CHEBI:59773 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0151636 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0029408 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0151735 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0836924 infores:hetionet CHEBI:6710 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0687713 infores:hetionet CHEBI:94392 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0150450 infores:hetionet CAID:CA367396996 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396996 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PM2_Supporting PS3, PM1, PP4 The c.1327G>T variant in the glucokinase gene, GCK causes a premature stop codon in the protein at codon 443 (NM_000162.5). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID:19790256). This variant was identified in 4 unrelated individuals with a clinical picture consistent with monogenic diabetes (PS4_Moderate; PMID: 20337973, PMID: 32901087, ClinVar ID 585915), including at least one individual with a clinical history suggestive of GCK-MODY but with insufficient clinical information provided to evaluate for PP4. In summary, c.1327G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396996/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Supports CHEBI:681569 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0027497 infores:hetionet CHEBI:28901 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0030193 infores:hetionet CHEBI:6710 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C1443060 infores:hetionet CHEBI:18358 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0023218 infores:hetionet CAID:CA512318995 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318995 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.111C>T (p.Ser37=) is a synonymous variant. This synonymous variant has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318995/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5134 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0030193 infores:hetionet CHEBI:7478 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0520966 infores:hetionet NCBIGene:51002 biolink:causes MONDO:0033009 infores:monarchinitiative not_provided not_provided HGNC:24259 MONDO:0033009 uuid:b09d5935-f7bc-4b4e-a041-0f1f7f398b59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0014591 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004096 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029443 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038362 infores:hetionet CHEBI:63619 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004245 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0012817 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0021141 infores:hetionet CHEBI:567361 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0235896 infores:hetionet CHEBI:3655 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0541832 infores:hetionet CHEBI:53760 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151610 infores:hetionet CHEBI:51137 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0018790 infores:hetionet CHEBI:52172 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0311468 infores:hetionet CHEBI:6933 biolink:causes UMLS:C0240941 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0240941 infores:hetionet CHEBI:10127 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0023530 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0027765 infores:hetionet CHEBI:28445 biolink:causes EFO:0005632 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C2243080 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0020538 infores:hetionet CHEBI:253342 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027947 infores:hetionet CHEBI:94501 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0002170 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0687133 infores:hetionet CHEBI:3756 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018681 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009324 infores:hetionet CHEBI:28915 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0004604 infores:hetionet CHEBI:50730 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0013604 infores:hetionet CHEBI:9907 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0025323 infores:hetionet CHEBI:194135 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0033845 infores:hetionet CHEBI:45783 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151786 infores:hetionet UMLS:C0009315 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0042963 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0029408 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235893 infores:hetionet NCBIGene:2232 biolink:causes MONDO:0060582 infores:monarchinitiative not_provided not_provided HGNC:3642 MONDO:0060582 uuid:0d616fef-d63d-4d39-88ab-866993e0ce0c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0017797 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0039971 infores:hetionet CHEBI:231594 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C3665386 infores:hetionet CAID:CA147760 biolink:causes MONDO:0015152 infores:clingen CAID:CA147760 MONDO:0015152 PMID: Benign BP4, BA1, BP7 The NM_003494.4: c.4504C>T p.(Leu1502=) variant in DYSF, which is also known as NM_001130987.2: c.4621C>T (p.Leu1541=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.02913 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 198/6022 Middle Eastern chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). In addition, this variant is not predicted to impact splicing (SpliceAI score 0) (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/14/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147760/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:49575 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020523 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0851341 infores:hetionet CHEBI:4027 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0030252 infores:hetionet CHEBI:53760 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0038990 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0149931 infores:hetionet CHEBI:40009 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0020517 infores:hetionet CAID:CA286708 biolink:causes MONDO:0700270 infores:clingen CAID:CA286708 MONDO:0700270 PMID: Benign BP4, BS1, BP2_Strong BA1, PS1, PM2, PP3 The ATM c.1073A>G (p.Asn358Ser) variant has a gnomAD v2.1.1 filtering allele frequency of 0.1523% (African/African-American; exomes) which exceeds the ATM BS1 threshold of 0.05% (BS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 500031, 61756). In silico protein predictors (ALIGN GVGD: Class C0; REVEL: 0.054; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.13/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 10.82, variant = 10.82)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA286708/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50692 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0917801 infores:hetionet CHEBI:9352 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0032227 infores:hetionet CHEBI:119573 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0039621 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003864 infores:hetionet CHEBI:6456 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0013604 infores:hetionet GO:0141081 biolink:causes GO:0006954 infores:ubergraph knowledge_assertion manual_agent GO:0141081 GO:0006954 UBERON:0005356 biolink:causes MONDO:0019614 infores:ubergraph knowledge_assertion manual_agent UBERON:0005356 MONDO:0019614 CHEBI:5959 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0392176 infores:hetionet CHEBI:6710 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0017178 infores:hetionet CHEBI:5558 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0013395 infores:hetionet NCBIGene:10785 biolink:causes MONDO:0032691 infores:monarchinitiative not_provided not_provided HGNC:12756 MONDO:0032691 uuid:a1879826-e425-4f48-856b-6ac15cd83577 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82941 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0011603 infores:hetionet CHEBI:7577 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0027497 infores:hetionet CHEBI:119573 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0008031 infores:hetionet CHEBI:50777 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0010200 infores:hetionet UBERON:0004356 biolink:causes UBERON:0003104 infores:ubergraph knowledge_assertion manual_agent UBERON:0004356 UBERON:0003104 CHEBI:32315 biolink:causes UMLS:C0001969 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0001969 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009450 infores:hetionet CHEBI:7565 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0021368 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004238 infores:hetionet GO:0042682 biolink:causes GO:0001745 infores:ubergraph knowledge_assertion manual_agent GO:0042682 GO:0001745 CHEBI:101853 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0002792 infores:hetionet CHEBI:18059 biolink:causes GO:0099541 infores:ubergraph knowledge_assertion manual_agent CHEBI:18059 GO:0099541 GO:0044477 biolink:causes GO:0030168 infores:ubergraph knowledge_assertion manual_agent GO:0044477 GO:0030168 CHEBI:101853 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0162297 infores:hetionet CHEBI:52717 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023380 infores:hetionet CHEBI:367163 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020461 infores:hetionet CHEBI:28445 biolink:causes HP:0001605 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0042928 infores:hetionet CHEBI:9316 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0018681 infores:hetionet CAID:CA8337660 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337660 MONDO:0008723 PMID: Uncertain Significance BP4 PM2, BS1 The c.342+15G>A variant in ACADVL is an intronic variant in intron 5. The results from MaxEntScn and NNSplice in silico splicing predictors support that this variant does not affect splicing (BP4).The highest population minor allele frequency in gnomAD v2.1.1 is 0.18 in the Latino population. PM2_Supporting, BS1, and BA1 are not met. This variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4. (ACADVL VCEP specifications version 1; approved February 2, 2023) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337660/MONDO:0008723/021 2023-02-28 2023-02-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA10118264 biolink:causes MONDO:0021060 infores:clingen CAID:CA10118264 MONDO:0021060 PMID: Pathogenic PVS1, PM3, PS3_Supporting PM2, BA1, BS1 The c.27dup (p.Gln10fs) variant in LZTR1 is a frameshift variant predicted to cause a premature stop codon 24 amino acids downstream in biologically-relevant-exon 1 (of 21) and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001139 (4/13466 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 individual with RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and which was confirmed in trans by family testing (c.1943-256C>T (p.T648fs*36), 1 PM3 point, PMID: 32623905) (PM3). ERK activation assay in patient-specific cardiomyocytes showed significantly increased levels of phosphorylated ERK supporting the abnormal impact due to loss of LZTR1 function (PMID:32623905)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3, PS3_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10118264/MONDO:0021060/094 2025-04-23 2025-04-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9763 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0033774 infores:hetionet CHEBI:7773 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0011991 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0013395 infores:hetionet CHEBI:45081 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0028081 infores:hetionet CHEBI:76607 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0009450 infores:hetionet CHEBI:9137 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0043094 infores:hetionet GO:2000311 biolink:causes GO:1905039 infores:ubergraph knowledge_assertion manual_agent GO:2000311 GO:1905039 UNII:K2J09EMJ52 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0011603 infores:hetionet CHEBI:6413 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042029 infores:hetionet CHEBI:15553 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0008031 infores:hetionet NCBIGene:1106 biolink:causes MONDO:0014150 infores:monarchinitiative not_provided not_provided HGNC:1917 MONDO:0014150 uuid:e0d13984-f616-4886-9a11-67f71f9d9ca6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46295 biolink:causes MONDO:0000499 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C1852242 infores:hetionet CHEBI:8874 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085593 infores:hetionet CHEBI:5120 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0032461 infores:hetionet CHEBI:4453 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0006145 infores:hetionet CHEBI:5138 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033036 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0233794 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017152 infores:hetionet GO:0060768 biolink:causes GO:0001655 infores:ubergraph knowledge_assertion manual_agent GO:0060768 GO:0001655 CHEBI:6950 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0234458 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0011991 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0497247 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0017152 infores:hetionet CHEBI:45863 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2939186 infores:hetionet CHEBI:50861 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0027497 infores:hetionet CHEBI:27565 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0034150 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0027765 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0042109 infores:hetionet CHEBI:8890 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020639 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0039971 infores:hetionet CHEBI:47519 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0015230 infores:hetionet CHEBI:3614 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0002792 infores:hetionet CHEBI:34385 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0013404 infores:hetionet CHEBI:119915 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037763 infores:hetionet CHEBI:7915 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C1384353 infores:hetionet CHEBI:15367 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018800 infores:hetionet CHEBI:8069 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0009421 infores:hetionet CHEBI:7936 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2979982 infores:hetionet CHEBI:9150 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0040822 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0474378 infores:hetionet CHEBI:7640 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0013378 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0015397 infores:hetionet CHEBI:7476 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085593 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003537 infores:hetionet CHEBI:135276 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0235996 infores:hetionet CHEBI:135961 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0311468 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0149744 infores:hetionet NCBIGene:7045 biolink:causes MONDO:0011185 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0011185 uuid:3ab619c9-498a-4e6c-9820-0be83dbcee9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0032617 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005942 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0035400 infores:hetionet CHEBI:5613 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0392156 infores:hetionet CHEBI:16347 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0007222 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085584 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011849 infores:hetionet CHEBI:16755 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0231218 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0152128 infores:hetionet CHEBI:28787 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0011603 infores:hetionet CHEBI:9241 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0426576 infores:hetionet CHEBI:46557 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0206062 infores:hetionet CHEBI:7931 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0575081 infores:hetionet CHEBI:31980 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0008031 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0412784 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0412784 infores:hetionet CAID:CA1244048 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244048 MONDO:0020367 PMID: Uncertain Significance BP4 BP7, BS1, BS3, PM2, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.1290C>T variant in MYOC is a synonymous variant (p.Phe430=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0006206 (19 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The CADD score (v1.6) = 6.961, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 2.25 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022 pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244048/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0234146 infores:hetionet CHEBI:3696 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0017181 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0004095 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0003123 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009806 infores:hetionet CAID:CA414780655 biolink:causes MONDO:0044970 infores:clingen CAID:CA414780655 MONDO:0044970 PMID: Uncertain Significance BP4 PP3, PP1, BA1, PS4, PS3, BS1, PM2 The m.5558A>G variant in MT-TW was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There are over 100 occurrences in MITOMAP for an overall allele frequency of 0.2%. This does not meet criteria for BA1 or BS1. The computational predictor MitoTIP suggests this variant is possibly benign (31st percentile) and HmtVAR predicts it to be likely polymorphic (0.5, BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414780655/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:51041 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085636 infores:hetionet CHEBI:2379 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0024141 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0333641 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0543698 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0233494 infores:hetionet CHEBI:4562 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0015672 infores:hetionet CHEBI:16469 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0240717 infores:hetionet CHEBI:3387 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0260662 infores:hetionet NCBITaxon:83554 biolink:causes MONDO:0005888 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:83554 MESH:D009956 DB00254_MESH_D009956_1DB00595_MESH_D009956_1DB00759_MESH_D009956_1DB13092_MESH_D009956_1DB02703_MESH_D009956_1DB00618_MESH_D009956_1DB01017_MESH_D009956_1 CHEBI:8707 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235431 infores:hetionet CHEBI:6067 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0017181 infores:hetionet CHEBI:8863 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0232462 infores:hetionet CHEBI:28864 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0014236 infores:hetionet CAID:CA16602989 biolink:causes MONDO:0018875 infores:clingen CAID:CA16602989 MONDO:0018875 PMID: Pathogenic PS3, PM1_Supporting, PP3_Moderate, PP4_Moderate, PM2_Supporting BP4, BA1, PS1, PS4, PS2, PM5, BS1, BS3, BS4, PVS1, PP1, BS2 The NM_000546.6: c.403T>G variant in TP53 is a missense variant predicted to cause substitution of Cysteine by Glycine at amino acid 135 (p.Cys135Gly). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, Internal lab contributors: SCV000664432.4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMID: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5991; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1_Supporting. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602989/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:85161 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151904 infores:hetionet CHEBI:85083 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0018681 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1306600 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1306600 infores:hetionet CHEBI:3756 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0085649 infores:hetionet CHEBI:3215 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0038990 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0041912 infores:hetionet CHEBI:2704 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0013604 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0948594 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030305 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009806 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0032285 infores:hetionet CHEBI:135613 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0030232 infores:hetionet CHEBI:9086 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0404521 infores:hetionet CHEBI:3207 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0152030 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0948595 infores:hetionet CHEBI:64312 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151746 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0235431 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0003864 infores:hetionet CHEBI:43968 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0035078 infores:hetionet CHEBI:17347 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0018681 infores:hetionet CAID:CA000021 biolink:causes MONDO:0018875 infores:clingen CAID:CA000021 MONDO:0018875 PMID: Likely Pathogenic PS3, PP3_Moderate, PM2_Supporting, PS4_Supporting BA1, BP4, BP3, PS1, PS2, PM5, PM4, PM1, BP7, BS1, BS3, BS4, PVS1, PP1, PP4, BS2 The NM_000546.6:c.1031T>C variant in TP53 is a missense variant predicted to cause substitution of leucine by proline at amino acid 344 (p.Leu344Pro). This variant has been reported in 1 proband meeting Classic criteria, and 1 proband meeting revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting PMID: 8649785, 20522432). This variant has an allele frequency of 6.195e-7 (1/1614076 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.4856; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000021/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4445 biolink:causes UMLS:C0015395 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0015395 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0343886 infores:hetionet CHEBI:87681 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0035078 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0003123 infores:hetionet CHEBI:9725 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0011603 infores:hetionet CHEBI:44185 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0016059 infores:hetionet CHEBI:6149 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0003467 infores:hetionet CHEBI:36795 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0002792 infores:hetionet CHEBI:9139 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0232849 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0001122 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027051 infores:hetionet CHEBI:63638 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0037822 infores:hetionet CHEBI:3561 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151662 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0003862 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0026848 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0234458 infores:hetionet CHEBI:17987 biolink:causes UMLS:C0234943 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0234943 infores:hetionet CHEBI:9943 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020580 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0035328 infores:hetionet CHEBI:2038 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0221201 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0003864 infores:hetionet CHEBI:47898 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0876994 infores:hetionet CHEBI:28001 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0041834 infores:hetionet CHEBI:38562 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0162830 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151828 infores:hetionet CHEBI:63621 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0033774 infores:hetionet CHEBI:68647 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C2242588 infores:hetionet CHEBI:135935 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0009676 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0474378 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027769 infores:hetionet CHEBI:7514 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0036104 infores:hetionet CHEBI:52717 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0162298 infores:hetionet CHEBI:5778 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002170 infores:hetionet CHEBI:3732 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0019080 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1443060 infores:hetionet CHEBI:7773 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042023 infores:hetionet CHEBI:7443 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0011603 infores:hetionet CHEBI:17688 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0040435 infores:hetionet CHEBI:7983 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0424295 infores:hetionet CHEBI:28177 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0011606 infores:hetionet CAID:CA415084029 biolink:causes MONDO:0010305 infores:clingen CAID:CA415084029 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting The NM_005629.4:c.874T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of a tyrosine by a histidine at amino acid position 292 (p.Tyr292His). To our knowledge, this variant has not been reported in the literature and no functional studies are available. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.936 (PP3). There is a ClinVar entry for this variant (Variation ID: 1676188, one-star review status), with conflicting interpretations of pathogenicity (one submitter: likely pathogenic; one submitter: uncertain significance). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415084029/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true GO:0043367 biolink:causes CL:0000624 infores:ubergraph knowledge_assertion manual_agent GO:0043367 CL:0000624 CHEBI:100246 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151798 infores:hetionet CAID:CA2830665545 biolink:causes MONDO:0011071 infores:clingen CAID:CA2830665545 MONDO:0011071 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.442_444dup (p.Thr148dup)is an in-frame duplication which occurs in a residue within the Runt Homology Domain, but is not in an established hotspot variant (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2830665545/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA16607631 biolink:causes MONDO:0100040 infores:clingen CAID:CA16607631 MONDO:0100040 PMID: Benign BS1, BS2, BP4 PM2, BA1 The allele frequency of the p.Ala90Ser variant in FOXG1 is 0.01457% in Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala90Ser variant is observed in 10 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ala90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala90Ser variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607631/MONDO:0100040/035 2023-12-06 2023-12-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:61049 biolink:causes UMLS:C0438167 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0438167 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0700345 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005260 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0004352 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0232487 infores:hetionet CHEBI:4466 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0013404 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0233472 infores:hetionet CHEBI:36791 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026821 infores:hetionet CHEBI:8888 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020433 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0000833 infores:hetionet CAID:CA114365 biolink:causes MONDO:0009861 infores:clingen CAID:CA114365 MONDO:0009861 PMID:18299955PMID:18299955PMID:18590700 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS3 PM5 PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA114365/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71219 biolink:causes UMLS:C0151738 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151738 infores:hetionet CHEBI:4907 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0017672 infores:hetionet CAID:CA386493122 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493122 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 The c.1199+2T>G variant in PAH occurs within the canonical splice donor of intron 11. It is predicted to cause skipping of biologically-relevant exon 11, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant may be reported in the literature (PMID: 25863075), but is unavailable for evaluation. Sequence analysis of a PKU mouse model with this variant revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site (PMID: 11161825). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PVS1 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493122/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9586 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1456784 infores:hetionet CHEBI:3127 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0234238 infores:hetionet NCBITaxon:809 biolink:causes MONDO:0020776 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:809 MONDO:0020776 CHEBI:408174 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0007682 infores:hetionet CHEBI:8707 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020621 infores:hetionet NCBIGene:6651 biolink:causes MONDO:0014936 infores:monarchinitiative not_provided not_provided HGNC:11183 MONDO:0014936 uuid:e482fcb3-d99f-477f-875f-20bc382897e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0086543 infores:hetionet CHEBI:9137 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013491 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0027765 infores:hetionet NCBIGene:10083 biolink:causes MONDO:0010171 infores:monarchinitiative not_provided not_provided HGNC:12597 MONDO:0010171 uuid:a3ff5238-d155-4387-8c00-35664f569a20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013378 infores:hetionet NCBIGene:84225 biolink:causes MONDO:0014366 infores:monarchinitiative not_provided not_provided HGNC:20997 MONDO:0014366 uuid:6e7ad04f-9e49-49a9-8fb8-c3a279851f87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5296 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0042571 infores:hetionet CHEBI:6456 biolink:causes EFO:0009510 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0262593 infores:hetionet CHEBI:3207 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0009676 infores:hetionet CHEBI:63611 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0015672 infores:hetionet CHEBI:44915 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020456 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0012833 infores:hetionet CHEBI:59560 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C2363731 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0006145 infores:hetionet CHEBI:36791 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030193 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C2242737 infores:hetionet CAID:CA229280 biolink:causes MONDO:0009861 infores:clingen CAID:CA229280 MONDO:0009861 PMID:27121329PMID:27121329 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.1027T>G (p.Tyr343Asp) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded) detected in trans with p.S349P (PMID: 27121329). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229280/MONDO:0009861/006 2020-06-01 2020-06-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:29007 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0002874 infores:hetionet NCBIGene:2703 biolink:causes MONDO:0007285 infores:monarchinitiative not_provided not_provided HGNC:4281 MONDO:0007285 uuid:5fa0d6ee-d51d-422b-8aae-170e8cde6b4f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1720775 infores:hetionet CHEBI:4909 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0547030 infores:hetionet CHEBI:4909 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0016382 infores:hetionet CHEBI:8356 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0231807 infores:hetionet CHEBI:16714 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0233477 infores:hetionet UBERON:0004801 biolink:causes MONDO:0005131 infores:ubergraph knowledge_assertion manual_agent UBERON:0004801 MONDO:0005131 CHEBI:3228 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0015230 infores:hetionet CHEBI:37924 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C1262113 infores:hetionet CHEBI:63589 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0002994 infores:hetionet CHEBI:49375 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042790 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0037278 infores:hetionet CHEBI:8774 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0030554 infores:hetionet NCBIGene:199857 biolink:causes MONDO:0033619 infores:monarchinitiative not_provided not_provided HGNC:28287 MONDO:0033619 uuid:1f15c283-14b0-47cc-8816-b9ff1926f497 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367402077 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402077 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PP4_Moderate, PP2, PM2_Supporting PS4, PS3, PP3, BP4 The c.410A>G variant in the glucokinase gene, GCK, causes an amino acid change of histidine to arginine at codon 137 (p.(His137Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The variant is absent in gnomAD v2.1 and v4.1 (PM2_Supporting). It has a REVEL score of 0.598, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 10525657, 14517946). This variant was identified in two unrelated cases with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 904948, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). Additionally, this variant segregated with hyperglycemia, with nine informative meioses in a single family (PP1_Strong; PMID: 9049484). In summary, c.410A>G meets the criteria to be classified as a likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PM2_Supporting, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402077/MONDO:0015967/086 2025-04-17 2025-04-17 Semidominant inheritance HP:0032113 Supports CHEBI:63611 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0007642 infores:hetionet NCBIGene:79759 biolink:causes MONDO:0859350 infores:monarchinitiative not_provided not_provided HGNC:25821 MONDO:0859350 uuid:430d7a14-2ddd-4737-ade8-629de3b3c3db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes UMLS:C0948281 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0948281 infores:hetionet CAID:CA180265 biolink:causes MONDO:0009861 infores:clingen CAID:CA180265 MONDO:0009861 PMID: Benign BA1, BP7 PM3, PM2, PP4 This c.1155C>G (p.Leu385=) synonymous variant in PAH is not predicted to have a splice-altering consequence. This variant was present at a high frequency of 0.840256 in 1000 genomes and 0.858145 in ExAC. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA180265/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9086 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018790 infores:hetionet CHEBI:7454 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0012833 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037195 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0002170 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0178298 infores:hetionet CHEBI:9086 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151636 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0037274 infores:hetionet CHEBI:53760 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0040264 infores:hetionet CAID:CA16041895 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041895 MONDO:0009290 PMID:19775921PMID:25741864PMID:19775921 Pathogenic PM2, PVS1, PP4, PM3 This variant, c.1687C>T (p.Gln563Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product. Therefore, PVS1 can be applied. This variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in trans with a frameshift variant in GAA, c.722_723delTT, in an individual who meets the ClinGen LSD VCEP’s specifications for PP4 (PMID 19775921). This data meets PP4 and PM3. Additional patients with this variant have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 25741864). There is a ClinVar entry for this variant (Variation ID: 370357, one star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041895/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63598 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085932 infores:hetionet CAID:CA10585539 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585539 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.1640T>C (p.Leu547Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: MAF=8.477e-7 (0.000085%) in European (non-Finnish) exomes (gnomAD v4.1.0). PP3: REVEL=0.883. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH (1 case with DLCN score >=6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, USA; 2 cases with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585539/MONDO:0007750/013 2024-08-30 2024-10-09 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA414801955 biolink:causes MONDO:0044970 infores:clingen CAID:CA414801955 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate PP1, PS2, PM6 The m.9035T>C (p.L170P) variant in MT-ATP6 has been reported in 10 unrelated individuals with primary mitochondrial disease with shared features of cerebellar ataxia, progressive gait disturbance, sensory neuropathy, and fatigue; several showed developmental delays and learning disabilities (PS4_moderate; five from the literature; PMIDs: 19626676; 22577227; 31187502; an additional five cases with the same clinical presentations as above were submitted to this VCEP from expert panel members, and the expert panel agreed to include these cases). All cases were homoplasmic or near-homoplasmic (94-98%). There are no reported de novo occurrences of this variant to our knowledge. The first case reported with this variant (PMID: 19626676) was a member of a 4-generation, 17-member family with 16 affected maternal family members – the only one unaffected was the son of an affected male. Given this variant typically occurs at homoplasmy, there are no large families with varying heteroplasmy levels to consider for segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies show two different classes of function defects: (1) 85% reduction of F1F0 ATP synthase activity and a resulting 40-50% reduction in ATP output, and (2) an 8-fold higher level of damaging ROS (PS3_moderate; PMID: 19626676). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3, PM2_supporting, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414801955/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:184555 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0031350 infores:hetionet CHEBI:9448 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0002170 infores:hetionet NCBIGene:9414 biolink:causes MONDO:0031446 infores:monarchinitiative not_provided not_provided HGNC:11828 MONDO:0031446 uuid:4afae575-9032-418d-ab28-a6cb6bb2b2c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020929 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020929 MONDO:0009861 PMID:26503515 Pathogenic PVS1, PP4_Moderate, PM2 This c.1066-1G>C (IVS10-1G>C) variant in PAH was reported in one Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. This variant in the -1 splice acceptor site results in exon skipping. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020929/MONDO:0009861/006 2019-10-18 2019-10-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135361 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0233494 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0852913 infores:hetionet CHEBI:63619 biolink:causes HP:0032552 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0235472 infores:hetionet CHEBI:75045 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151904 infores:hetionet CHEBI:3061 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0035455 infores:hetionet CAID:CA397726277 biolink:causes MONDO:0008723 infores:clingen CAID:CA397726277 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP4, PM4 PP3, PM3, PM5 The c.1968A>C variant is predicted to cause a change in the length of the protein due to a stop loss p.(Ter656CysextTer54) (PM4). At least one individual with this variant displayed reduced enzyme assay in leukocytes, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4; PMID 27209629). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM4, PP4, PM2_Supporting (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397726277/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63635 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0003962 infores:hetionet CHEBI:7903 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0030193 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0521495 infores:hetionet CHEBI:8888 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1260880 infores:hetionet NCBIGene:7157 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:11998 MONDO:0016419 uuid:1a42f85b-e6ce-4691-b8a4-c364566f6d0a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0234215 infores:hetionet CHEBI:28487 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0033774 infores:hetionet CAID:CA180743 biolink:causes MONDO:0015280 infores:clingen CAID:CA180743 MONDO:0015280 PMID:25049390PMID:17704260 Pathogenic PS3, PM2, PP2, PP3, PM6_Strong The c.199G>A (p.Asp67Asn) variant in MAP2K1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17704260). In vitro functional studies provide some evidence that the p.Asp67Asn variant may impact protein function (PS3; PMID 25049390). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Asp67Asn variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180743/MONDO:0015280/004 2017-05-09 2020-01-23 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:36791 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026961 infores:hetionet CHEBI:3082 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0233407 infores:hetionet CHEBI:61033 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1291078 infores:hetionet CHEBI:16335 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0004245 infores:hetionet CHEBI:35778 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0015672 infores:hetionet CHEBI:31623 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0151827 infores:hetionet CHEBI:53691 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0015230 infores:hetionet CHEBI:7454 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0023052 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0020538 infores:hetionet CHEBI:10102 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151603 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0948089 infores:hetionet CL:0000731 biolink:causes MONDO:0006350 infores:ubergraph knowledge_assertion manual_agent CL:0000731 MONDO:0006350 CHEBI:4514 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0012833 infores:hetionet CHEBI:10023 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0242301 infores:hetionet CHEBI:2675 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0028084 infores:hetionet CHEBI:291342 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0041912 infores:hetionet CHEBI:480999 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0040053 infores:hetionet NCBITaxon:5036 biolink:causes MONDO:0018312 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5036 MESH:D006660 DB00681_MESH_D006660_1 CHEBI:50777 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0547030 infores:hetionet CAID:CA399799849 biolink:causes MONDO:0100326 infores:clingen CAID:CA399799849 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting PM3, PP3 The NM_000419.5(ITGA2B):c.2051T>G (p.Leu684Arg) missense variant has been reported in at least one Glanzmann thrombasthenia patient (PMID: 21113249). Patient GE displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia . Additionally, αIIbβ3 surface expression was reduced to <1%, as measured by flow cytometry, and there was<1% binding to PAC-1. (PP4_strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporitng. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399799849/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:51164 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0038990 infores:hetionet CHEBI:6846 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0018681 infores:hetionet CHEBI:27834 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002878 infores:hetionet CHEBI:75246 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0231218 infores:hetionet CHEBI:7494 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0027066 infores:hetionet CHEBI:7865 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C2830004 infores:hetionet NCBIGene:56704 biolink:causes MONDO:0975808 infores:monarchinitiative not_provided not_provided HGNC:14201 MONDO:0975808 uuid:de2de593-43b1-4eeb-830b-a76b8d8e31bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0235416 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0023067 infores:hetionet GO:2000025 biolink:causes GO:0009965 infores:ubergraph knowledge_assertion manual_agent GO:2000025 GO:0009965 CHEBI:6402 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0178298 infores:hetionet CHEBI:2922 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0009806 infores:hetionet CHEBI:64064 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0021368 infores:hetionet CAID:CA10102316 biolink:causes MONDO:0009276 infores:clingen CAID:CA10102316 MONDO:0009276 PMID: Uncertain Significance PM3_Supporting, PP3_Moderate PS4, BS1, PM2, PP4 The c.127G>T variant in GP1BB is a missense variant predicted to cause substitution of Glycine by Tryptophan at amino acid 43 (p.Gly43Trp). The computational predictor REVEL gives a score of 0.887, which is above the ClinGen PD VCEP threshold of >0.773 and predicts a damaging effect on function (PP3_Moderate). Patient BSS64 (PMID: 24934643) is reported homozygous (PM3_supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3_Moderate, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10102316/MONDO:0009276/082 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0657912 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042075 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030305 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235351 infores:hetionet CHEBI:9586 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0917801 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C2973529 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030920 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0003123 infores:hetionet CHEBI:5132 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0013604 infores:hetionet CHEBI:5103 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0151610 infores:hetionet CAID:CA16020995 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020995 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM3, PP3, PM2_Supporting The c.1315+5G>C variant in PAH is an intronic variant in intron 12 that is predicted by multiple splicing tools to alter splicing (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). It has been observed in at least 2 moderate or classic PKU patients with BH4 deficiency excluded (PMID: 30747360, PMID: 33980295; PP4_moderate), including 1 case who harbored it in trans (parental genetic analysis reportedly done for all cases) with the known pathogenic variant p.Arg252Gln (ClinVar ID 102824) (PM3_Moderate). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Moderate, PP4_Moderate, PP3_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020995/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16755 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0008031 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0024355 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D012141 DB05659_MESH_D012141_1DB01053_MESH_D012141_1 CHEBI:63589 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0019196 infores:hetionet CHEBI:2668 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0016204 infores:hetionet CAID:CA261617 biolink:causes MONDO:0021060 infores:clingen CAID:CA261617 MONDO:0021060 PMID:29493581 Pathogenic PM1, PP1, PP3, PP2, PM2_Supporting, PM6_Strong, PS4, PM5_Strong, PS3_Supporting The c.775T>A (p.Ser259Thr) variant in the RAF1 gene is a missense variant predicted to cause substitution of serine by threonine at amino acid 259. This variant is absent from gnomAD v2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.753, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function (PP3). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). The variant is also in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10). The variant has also been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Zenker et al. internal data; ClinVar SCV000209017.9). Additionally, it has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338). At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288). In vitro functional studies also provide some evidence that the p.Ser259Thr variant may impact protein function (PS3_Supporting; PMID: 21784453, 20052757). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM5_Strong, PM6_Strong, PS4, PM1, PP1, PP2, PP3, PM2_Supporting, PS3_Supporting. (RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261617/MONDO:0021060/040 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45924 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0009782 infores:hetionet CHEBI:50742 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0023518 infores:hetionet CHEBI:42797 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085636 infores:hetionet CHEBI:32221 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0030920 infores:hetionet CHEBI:5855 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0033247 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0020651 infores:hetionet CAID:CA281520 biolink:causes MONDO:0009861 infores:clingen CAID:CA281520 MONDO:0009861 PMID:11935335PMID:24401910PMID:11935335PMID:24401910PMID:11935335 Likely Pathogenic PM2, PP4, PM3_Strong, PS3_Supporting The c.-4165_-407del3759 deletion in PAH has been reported in 3 unrelated individuals/families with PAH deficiency where it was designated as -4173_-407del. (PMID: 11935335). The -4173_-407del nomenclature was based on the translation initiation site, and corresponds to c.-4165_-407del3759 (based on transcription initiation site). This deletion is absent from gnomAD genomes with good coverage. This variant was detected with pathogenic variants: p.R408Q in 2 unrelated patients; p.E286K in 2 patients (pathogenic by PAH VCEP); and p.E76G in 1 patient (PMID: 24401910). Functional evidence suggests that it diminishes PAH gene expression (retained only 1% of the wild-type CAT activity, PMID: 11935335). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_strong, PS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA281520/MONDO:0009861/006 2020-08-28 2021-02-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:74947 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002170 infores:hetionet CHEBI:8764 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C2047937 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020615 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0234215 infores:hetionet CHEBI:10023 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030554 infores:hetionet CHEBI:47898 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0016867 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027707 infores:hetionet CHEBI:72690 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0151786 infores:hetionet CHEBI:10102 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0497156 infores:hetionet UMLS:C1738934 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0025323 infores:hetionet CHEBI:144551 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018843 infores:hetionet CHEBI:6062 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0003862 infores:hetionet CHEBI:3732 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0013404 infores:hetionet CHEBI:6539 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0085593 infores:hetionet CHEBI:8874 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151827 infores:hetionet CHEBI:75722 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0851578 infores:hetionet CHEBI:8665 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0428977 infores:hetionet CHEBI:5864 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0428977 infores:hetionet CAID:CA2697547490 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547490 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1203del (p.Ser402ProfsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM5_Supporting, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547490/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Supports CAID:CA626684825 biolink:causes MONDO:0100326 infores:clingen CAID:CA626684825 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.225_226del (p.Ala76ProfsTer10) in exon 3 of ITGB3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3/15 and is predicted to lead to nonsense mediated decay (PVS1). GT7 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.3%, as measured by flow cytometry. GT7 (PMID: 32237906) is compound heterozygous for c.225_226del and Arg242Ter (classified Pathogenic by the PD-VCEP; PM3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 (2/18394 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626684825/MONDO:0100326/011 2021-11-09 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UMLS:C0145867 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0036572 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0740425 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004169 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0376356 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0855242 infores:hetionet CHEBI:119915 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0019079 infores:hetionet NCBIGene:58494 biolink:causes MONDO:0032938 infores:monarchinitiative not_provided not_provided HGNC:14686 MONDO:0032938 uuid:95114fdc-65c3-452f-b3d0-5874712b857b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:34829 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0161479 infores:hetionet CHEBI:37924 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0025345 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0017574 infores:hetionet UMLS:C0657912 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011175 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0031039 infores:hetionet CHEBI:2639 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0027497 infores:hetionet CHEBI:41977 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0340865 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027765 infores:hetionet CHEBI:68478 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0035410 infores:hetionet CHEBI:8888 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0600142 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0151736 infores:hetionet CHEBI:70707 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0017178 infores:hetionet CHEBI:8107 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2937358 infores:hetionet CHEBI:6413 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0018681 infores:hetionet CHEBI:44185 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0744727 infores:hetionet CHEBI:9725 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0040822 infores:hetionet CHEBI:52172 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013378 infores:hetionet CAID:CA16020805 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020805 MONDO:0009861 PMID: Likely Pathogenic PM5, PP4_Moderate, PM2_Supporting, PP3_Moderate, PM3_Supporting The c.509A>C variant in PAH is a missense variant predicted to cause substitution of Histidine by Proline at amino acid 170 (p.His170Pro). At least one patient with this variant displayed plasma Phenylalanine 120–600 μmol/L, which is highly specific for PAH deficiency; BH4 deficiency was assessed with dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading (PP4_Moderate; PMID: 26503515, 30050108). This individual was compound heterozygous for the variant and a variant of uncertain significance confirmed in trans by parental testing (p.D296H, Variation ID: 805822, 0.5 pts, PMID: 30050108). The highest population minor allele frequency in gnomAD v4.1 is 0.00001601, which is lower than the ClinGen PAH VCEP threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant [c.508C>G (p.His170Asp)] [ClinVar Variation ID 92744] in the same codon has been classified as pathogenic for PAH deficiency by the ClinGen PAH VCEP (PM5). The computational predictor REVEL gives a SCORE of 0.894, which is between the threshold of 0.773 - 0.932, evidence that correlates with moderate impact to PAH function (PP3_moderate). In summary, this variant meets criteria to be classified as likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_Moderate, PM2_supporting, PM5, PP3_moderate, PM3_supporting. (VCEP specifications version 2.0.0; 01/05/2025) Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020805/MONDO:0009861/006 2025-04-18 2025-04-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51450 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0013491 infores:hetionet CHEBI:180905 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0009676 infores:hetionet CHEBI:51450 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0232849 infores:hetionet CHEBI:63584 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0035078 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0020538 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0409497 infores:hetionet CHEBI:63637 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0004093 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020676 infores:hetionet CHEBI:50693 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C1096343 infores:hetionet CHEBI:9086 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023218 infores:hetionet CHEBI:63584 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0010200 infores:hetionet CHEBI:145499 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0001925 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0178298 infores:hetionet CHEBI:53760 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C2047937 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0227791 infores:hetionet CHEBI:16586 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0340865 infores:hetionet CHEBI:5130 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0028961 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1956346 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020488 infores:hetionet CHEBI:135686 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0009806 infores:hetionet CHEBI:8430 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0039070 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0009443 infores:hetionet CAID:CA213920 biolink:causes MONDO:0015967 infores:clingen CAID:CA213920 MONDO:0015967 PMID: Uncertain Significance BS1 PP4 The c.*4G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A is located in the 3'-UTR of the NM_175914.5. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.000048, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor). In summary, c.*4G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213920/MONDO:0015967/085 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6129 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0039231 infores:hetionet CHEBI:92712 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0549448 infores:hetionet CHEBI:6541 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0001824 infores:hetionet CHEBI:7822 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0042571 infores:hetionet NCBIGene:9780 biolink:causes MONDO:0008689 infores:monarchinitiative not_provided not_provided HGNC:28993 MONDO:0008689 uuid:dc05fbfb-c832-4ed3-89b6-c1ab18216724 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3347 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0022658 infores:hetionet CHEBI:253342 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0016204 infores:hetionet CHEBI:4027 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0476273 infores:hetionet CHEBI:8871 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235086 infores:hetionet CHEBI:171719 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0085631 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0037274 infores:hetionet CHEBI:68595 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0004364 infores:hetionet CHEBI:63638 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0004134 infores:hetionet NCBIGene:4851 biolink:causes MONDO:0024523 infores:monarchinitiative not_provided not_provided HGNC:7881 MONDO:0024523 uuid:5d17eca3-43a5-4158-b864-cbf22cb41b0e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9727 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0003123 infores:hetionet CHEBI:175901 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0852911 infores:hetionet CHEBI:61049 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0162834 infores:hetionet CHEBI:7798 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0003467 infores:hetionet CHEBI:77733 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0036974 infores:hetionet CAID:CA073512 biolink:causes MONDO:0007783 infores:clingen CAID:CA073512 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Alanine with Valine at codon 3118 of the RYR1 protein, p.(Ala3118Val). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0063, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA073512/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:119573 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0005741 infores:hetionet CHEBI:3723 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015371 infores:hetionet CHEBI:49575 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0855775 infores:hetionet CHEBI:71272 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0042963 infores:hetionet CHEBI:8435 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0037763 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004390 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0028841 infores:hetionet CHEBI:3215 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0028643 infores:hetionet CHEBI:31302 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0011253 infores:hetionet CHEBI:47898 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026858 infores:hetionet CHEBI:3175 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0009763 infores:hetionet CHEBI:135736 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085605 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0235639 infores:hetionet CAID:CA244520175 biolink:causes MONDO:0015967 infores:clingen CAID:CA244520175 MONDO:0015967 PMID: Uncertain Significance PM1_Supporting, PP4_Moderate PS4, PM2 The c.-187C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While c.-187C>T is absent in the European non-Finnish population in gnomAD v2.1.1, it has 2 copies in the African subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). Taken together, this criteria supports the classification of c.-187C>T as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PP4_moderate, PM1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244520175/MONDO:0015967/017 2021-08-18 2021-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0231919 infores:hetionet CHEBI:63613 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0002871 infores:hetionet CHEBI:94501 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0023518 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0234215 infores:hetionet CHEBI:63577 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0002994 infores:hetionet CHEBI:50131 biolink:causes HP:4000214 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0238844 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027765 infores:hetionet CHEBI:31515 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0156404 infores:hetionet CHEBI:3568 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0852911 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0233472 infores:hetionet CHEBI:48273 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0003811 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0235063 infores:hetionet CHEBI:6741 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0391870 infores:hetionet CHEBI:50131 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1384353 infores:hetionet CHEBI:63580 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0542571 infores:hetionet CHEBI:17474 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C2939186 infores:hetionet CHEBI:41774 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C3665347 infores:hetionet CHEBI:7903 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0023212 infores:hetionet UMLS:C0009315 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0004093 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0234458 infores:hetionet CHEBI:7577 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0016204 infores:hetionet CAID:CA405690940 biolink:causes MONDO:0018493 infores:clingen CAID:CA405690940 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glutamine at codon 3226 of the RYR1 protein, p.(Glu3226Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual who had a personal or family history of a malignant hyperthermia reaction, this individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.62 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405690940/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7824 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0003467 infores:hetionet CAID:CA367401225 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401225 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PM5 The c.650A>T variant in the GCK gene, glucokinase, causes an amino acid change of aspartic acid to valine at codon 217 (p.(Asp217Val)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant at this same amino acid position, p.Asp217Glu has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.650A>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401225/MONDO:0015967/086 2024-11-16 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:4708 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0162830 infores:hetionet CHEBI:6076 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042023 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0221100 infores:hetionet CHEBI:5778 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0344232 infores:hetionet CHEBI:41977 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0085631 infores:hetionet CHEBI:31348 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0038325 infores:hetionet CHEBI:49713 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0041657 infores:hetionet UMLS:C0010592 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017565 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0006266 infores:hetionet NCBIGene:10093 biolink:causes MONDO:0859324 infores:monarchinitiative not_provided not_provided HGNC:707 MONDO:0859324 uuid:2a57161a-49d5-48be-aa55-bfff2b976c2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013415 infores:hetionet CAID:CA2573051296 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051296 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 PP1 The c.535dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 179 in NM_000545.8), adding nine novel amino acids before encountering a stop codon (p.(His179ProfsTer9)). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.535dup meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051296/MONDO:0015967/017 2025-03-05 2025-04-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes UMLS:C0280100 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0280100 infores:hetionet CHEBI:42944 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0231218 infores:hetionet CAID:CA320251355 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251355 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1262G>C (p.Gly421Ala) is a missense variant which has a REVEL score < 0.50 (0.347), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251355/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37333 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0235890 infores:hetionet CHEBI:15367 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0232849 infores:hetionet CHEBI:9215 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0042109 infores:hetionet NCBIGene:5294 biolink:causes MONDO:0030717 infores:monarchinitiative not_provided not_provided HGNC:8978 MONDO:0030717 uuid:d980fe6e-bbee-4170-990f-8e2baba3c926 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7954 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0011570 infores:hetionet CHEBI:49662 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0232487 infores:hetionet CHEBI:63632 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0015230 infores:hetionet CHEBI:15367 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0241057 infores:hetionet CHEBI:63580 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0231528 infores:hetionet CHEBI:4975 biolink:causes MONDO:0004619 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0025007 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0006285 infores:hetionet CHEBI:63635 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042963 infores:hetionet CHEBI:64028 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0020672 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0006840 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042571 infores:hetionet CHEBI:31302 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0344232 infores:hetionet CHEBI:119915 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011124 infores:hetionet CHEBI:31980 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0004238 infores:hetionet CHEBI:6931 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0028738 infores:hetionet CHEBI:66919 biolink:causes MONDO:0004369 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0021313 infores:hetionet CHEBI:182080 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0917801 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0042109 infores:hetionet CHEBI:3176 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0004095 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0178298 infores:hetionet CHEBI:16480 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0036974 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0152128 infores:hetionet CAID:CA386952237 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952237 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PVS1 PP4 The c.19C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 7 (p.(Gln7Ter)) of NM_000545.8. This variant is located in exon 1 of 10, and is therefore predicted to result in nonsense mediated decay of a biologically relevant transcript in a gene in which loss of function is an established disease mechanism (PVS1; PMID 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 9097962, internal lab contributors). These cases were not tested for HNF4A; therefore, PP4 was not met. Lastly, this variant segregated with diabetes with at least ten informative meioses in three families with MODY (PP1_Strong; PMID 9097962; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PS4_Moderate, PP1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952237/MONDO:0015967/017 2022-03-18 2022-03-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3387 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0038663 infores:hetionet CHEBI:135939 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0033774 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0018799 infores:hetionet CHEBI:567361 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0549249 infores:hetionet CAID:CA410202611 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202611 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS2, PS3, PS4, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.437A>T (p.Asn146Ile) is a missense variant affecting one of the residues within the Runt Homology Domain, but not a known hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202611/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27899 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0002170 infores:hetionet CHEBI:4551 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0042963 infores:hetionet CHEBI:46295 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0085612 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042075 infores:hetionet GO:0106396 biolink:causes GO:0048749 infores:ubergraph knowledge_assertion manual_agent GO:0106396 GO:0048749 CHEBI:7627 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0000729 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0948815 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0948815 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0018799 infores:hetionet CHEBI:9943 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038325 infores:hetionet CHEBI:8888 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013404 infores:hetionet CHEBI:367163 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0232461 infores:hetionet CHEBI:68554 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0030193 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0025061 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151505 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0850060 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0850060 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0233494 infores:hetionet CHEBI:3127 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0231218 infores:hetionet GO:0044542 biolink:causes GO:0031639 infores:ubergraph knowledge_assertion manual_agent GO:0044542 GO:0031639 CHEBI:9725 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C1096355 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0019340 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0242350 infores:hetionet CHEBI:49960 biolink:causes UMLS:C1608397 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1608397 infores:hetionet CHEBI:171719 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0857177 infores:hetionet CHEBI:6076 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0242429 infores:hetionet GO:2000477 biolink:causes GO:0072224 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0072224 CHEBI:4975 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0542571 infores:hetionet CHEBI:52717 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023518 infores:hetionet CHEBI:47780 biolink:causes UMLS:C1290864 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1290864 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0011991 infores:hetionet CAID:CA502402192 biolink:causes MONDO:0009290 infores:clingen CAID:CA502402192 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.258del (p.Asn87ThrfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID:551592). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA502402192/MONDO:0009290/010 2024-04-05 2024-04-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:83531 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0234215 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0027051 infores:hetionet CHEBI:83531 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0009676 infores:hetionet CHEBI:9613 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0015230 infores:hetionet NCBIGene:3781 biolink:causes MONDO:0030538 infores:monarchinitiative not_provided not_provided HGNC:6291 MONDO:0030538 uuid:ebaba877-bd67-4df6-857e-f872338e6dc0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151825 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020295 infores:hetionet UMLS:C0004609 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0030252 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0233459 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0017160 infores:hetionet CHEBI:4953 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0016655 infores:hetionet CHEBI:10102 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0080274 infores:hetionet CHEBI:8207 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011168 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1306341 infores:hetionet CAID:CA10585363 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585363 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1223A>C (p.Glu408Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.914. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 1 index case with DLCN score of probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583810.1), France, so PP4 is met.PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases with SB criteria for FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), France, so PS4_Supporting is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585363/MONDO:0007750/013 2021-12-16 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4784 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0043352 infores:hetionet CHEBI:9570 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0041834 infores:hetionet CHEBI:36791 biolink:causes HP:0005165 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0520878 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0836924 infores:hetionet CHEBI:6402 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1384353 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009806 infores:hetionet CHEBI:3508 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0237849 infores:hetionet CHEBI:41423 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0023218 infores:hetionet CHEBI:5132 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0917801 infores:hetionet CHEBI:2567 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0002170 infores:hetionet CHEBI:64355 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0149871 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0162429 infores:hetionet NCBIGene:4311 biolink:causes MONDO:0014867 infores:monarchinitiative not_provided not_provided HGNC:7154 MONDO:0014867 uuid:fa2180d5-9b88-4369-9cc4-b08d2aef8b7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0021053 infores:hetionet CHEBI:7823 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0549249 infores:hetionet CHEBI:48273 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0037763 infores:hetionet CAID:CA192745504 biolink:causes MONDO:0009595 infores:clingen CAID:CA192745504 MONDO:0009595 PMID: Uncertain Significance PM2 This variant has been found in gnomAD v4.1.0 with an allele frequency of 0.0001355 in the European (non-Finnish) population and has a gnomAD v4.1.0 Grpmax filtering AF of 0.0001038. This frequency is above the threshold the SCID VCEP established to use PM2_Supporting (<0.0000447). The variant has not been described in patients with cartilage-hair hypoplasia or in trans with any other RMRP variant. In summary, this variant is classified as Variant of Uncertain Significance - insufficient evidence. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA192745504/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA519344994 biolink:causes MONDO:0010305 infores:clingen CAID:CA519344994 MONDO:0010305 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 "The NM_005629.4:c.1425C>T variant in SLC6A8 is a synonymous (silent) variant (p.Tyr475=). SpliceAI predicts no impact on splicing (score <0.1). Although the nucleotide is somewhat conserved (PhyloP score 1.482), recent guidance indicates that ""conservation has limited predictive power to detect non-splice disrupting variants "" (PMID: 37352859) (BP4, BP7). To our knowledge, this variant has not been reported in the literature and no functional studies are available. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001117 (1/895070 alleles; 0 homozygotes) in the European non-Finnish population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.00002), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1336429). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4, BP7, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 9, 2025)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA519344994/MONDO:0010305/027 2025-01-09 2025-01-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:8364 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0015672 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0007785 infores:hetionet CHEBI:50275 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0017168 infores:hetionet CHEBI:71023 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0235266 infores:hetionet CHEBI:5098 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0234215 infores:hetionet CHEBI:8245 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C2363730 infores:hetionet CHEBI:63638 biolink:causes MONDO:0024519 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1619700 infores:hetionet CHEBI:5001 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0522055 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0020649 infores:hetionet CHEBI:9168 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042029 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0948594 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034067 infores:hetionet CHEBI:7465 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0085593 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007156 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0574960 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0040046 infores:hetionet CHEBI:9241 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0020517 infores:hetionet CHEBI:16469 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0232495 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0001824 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0701836 infores:hetionet CHEBI:3757 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011603 infores:hetionet CHEBI:17474 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0004604 infores:hetionet CHEBI:8356 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0231528 infores:hetionet CHEBI:3207 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0036974 infores:hetionet CHEBI:63598 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085593 infores:hetionet CHEBI:71272 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0040034 infores:hetionet CHEBI:52010 biolink:causes HP:0001908 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0178416 infores:hetionet CHEBI:63622 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0037317 infores:hetionet CHEBI:32020 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0009806 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0017152 infores:hetionet CHEBI:47499 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C1384353 infores:hetionet CHEBI:6904 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0015967 infores:hetionet UMLS:C0065374 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0043144 infores:hetionet CHEBI:51450 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020580 infores:hetionet CHEBI:15544 biolink:causes MONDO:0008867 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0005411 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0041976 infores:hetionet NCBIGene:2902 biolink:causes MONDO:0060629 infores:monarchinitiative not_provided not_provided HGNC:4584 MONDO:0060629 uuid:1eb93914-6e60-4fd9-b517-cedd994e0654 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006145 infores:hetionet CAID:CA226850 biolink:causes MONDO:0010725 infores:clingen CAID:CA226850 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1 The NM_000330.4(RS1):c.68C>A variant is a nonsense variant in amino acid 23, which results in a premature stop codon and causes a truncated protein. This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PS4_supporting, PMIDs: 9618178, 35456481). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PS4_supporting, and PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226850/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:4027 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0236075 infores:hetionet CAID:CA409108858 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108858 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PS1 The c.1063G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is predicted to cause an amino acid change of glycine to arginine at codon 355 (p.(Gly355Arg) in transcript NM_175914.5. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.565, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. However, the computational splicing predictor SpliceAI gives a score of 0.66 for donor loss, predicting that this variant, located in the last nucleotide of exon 8, disrupts the donor site for intron 8 of HNF4A (PP3 met for splicing predictor). The nucleotide change c.1063G>C, which causes the same amino acid change and is also located in the last nucleotide of exon 8, is predicted to disrupt the donor site for intron 8 of HNF4A with a higher prediction value for donor loss by SpliceAI (0.94) in comparison to c.1063G>C (0.66), and the c.1063G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.1063G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108858/MONDO:0015967/085 2024-12-06 2024-12-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71272 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0009450 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0267792 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0858635 infores:hetionet CHEBI:63612 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0031256 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0029408 infores:hetionet CHEBI:9943 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0455204 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0011849 infores:hetionet CHEBI:10102 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151827 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0041969 infores:hetionet CHEBI:31709 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C2830004 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0233494 infores:hetionet CHEBI:63620 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0023066 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0595930 infores:hetionet CHEBI:3561 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0424295 infores:hetionet CHEBI:8346 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0033774 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0175167 infores:hetionet CHEBI:8863 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2242737 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0021400 infores:hetionet CHEBI:8107 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085631 infores:hetionet CHEBI:31348 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085611 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020517 infores:hetionet CAID:CA2695216038 biolink:causes MONDO:0015628 infores:clingen CAID:CA2695216038 MONDO:0015628 PMID:22479377 Pathogenic PP4_Moderate, PP1, PM2_Supporting, PS3, PM4 The NM_000552.5(VWF):c.4586_4591del (p.Asp1529_Val1530del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 2 amino acids in a non-repeat region (PM4). It is absent from gnomADv4.1 (PM2_supporting). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of very low VWF activity (6.2 U/dL), low activity/VWF:Ag ratio (0.30), and loss of high molecular weight multimers, which is highly specific for VWD type 2A. (PP4_Moderate, PMID: 22479377). Additional consistent phenotypes were also reported in the patient including, FVIII activity consistent with VWF antigen (ratio >0.7), and a RIPA assay. It segregates with VWD type 2A through 4 affected meioses from this family (PP1; PMID:22479377). Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers, indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3). In summary, this variant classifies as Pathogenic based on ACMG criteria as specified by the VWD VCEP: PM4, PM2_supporting, PP4_Moderate, PP1, and PS3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695216038/MONDO:0015628/081 2024-11-05 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4708 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042035 infores:hetionet CHEBI:8430 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0018790 infores:hetionet CHEBI:8455 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0042963 infores:hetionet NCBITaxon:6333 biolink:causes MONDO:0019444 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6333 MESH:D014235 DB00959_MESH_D014235_1DB01380_MESH_D014235_1DB00620_MESH_D014235_1DB00635_MESH_D014235_1DB00741_MESH_D014235_1DB00443_MESH_D014235_1 CHEBI:31174 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0151883 infores:hetionet NCBIGene:51608 biolink:causes MONDO:0859356 infores:monarchinitiative not_provided not_provided HGNC:21690 MONDO:0859356 uuid:cbaf1885-3de4-4ebd-935c-9a07046168c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0011603 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0271240 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0271240 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0232492 infores:hetionet NCBIGene:8738 biolink:causes MONDO:0013785 infores:monarchinitiative not_provided not_provided HGNC:2340 MONDO:0013785 uuid:041d7bef-5a3b-4e90-a9e5-390036908845 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0040409 infores:hetionet CHEBI:9086 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042024 infores:hetionet CHEBI:50275 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0022346 infores:hetionet NCBIGene:164656 biolink:causes MONDO:0008788 infores:monarchinitiative not_provided not_provided HGNC:16517 MONDO:0008788 uuid:57163fbe-2002-409c-9fd4-af5cd4a49401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0026205 infores:hetionet GO:0044499 biolink:causes GO:0042310 infores:ubergraph knowledge_assertion manual_agent GO:0044499 GO:0042310 CHEBI:7798 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0542571 infores:hetionet CHEBI:8888 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235490 infores:hetionet CHEBI:45979 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0008370 infores:hetionet CHEBI:4814 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0015672 infores:hetionet CHEBI:2687 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0015672 infores:hetionet CHEBI:6062 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027424 infores:hetionet CHEBI:7465 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0149871 infores:hetionet CHEBI:3485 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0036974 infores:hetionet CHEBI:37941 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018944 infores:hetionet CHEBI:94501 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0002871 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235818 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0039584 infores:hetionet GO:1902872 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0043010 CHEBI:8107 biolink:causes HP:0003487 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0034935 infores:hetionet UBERON:0004823 biolink:causes MONDO:0003210 infores:ubergraph knowledge_assertion manual_agent UBERON:0004823 MONDO:0003210 CHEBI:16899 biolink:causes UMLS:C1740793 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1740793 infores:hetionet CAID:CA10604398 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604398 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP3, PM3_Very Strong, PM2_Supporting The NM_000070.3: c.2105C>T variant in CAPN3 is a missense variant expected to result in the substitution of alanine with valine at amino acid 702, p.(Ala702Val). This variant has been detected in at least 11 individuals with features consistent with LGMD (PMID: 19556129; 31937337; 35741838; 16141003; 27066573; 16650086; ClinVar SCV001218172.5 internal data communication). Five seemingly unrelated patients were homozygous, with familial consanguinity reported in four (0.25 pts x4, 0.5 pts x1, capped at 1.0 pt). Two patients had a likely pathogenic or pathogenic CAPN3 variant confirmed in trans (c.1993-1G>A, 1.0 pt, ClinVar SCV001218172.5 internal data communication; c.1981del p.(Gln660_Ile661insTer), 1.0 pt, PMID: 19556129), and two patients had a pathogenic variant in unknown phase (c.2120A>G (p.Asp707Gly), 0.5 pts, PMID: 27066573; c.2362_2363delinsTCATCT (p.Arg788SerfsTer14), 0.5 pts, PMID: 35741838) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 19556129) (PP4_Strong). The filtering allele frequency of this variant is 0.000011828 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval of 7/1111640 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604398/MONDO:0015152/187 2025-05-14 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6541 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0003469 infores:hetionet CHEBI:2682 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020578 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0018621 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0006840 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0948594 infores:hetionet CHEBI:5801 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0002871 infores:hetionet CHEBI:44423 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0235378 infores:hetionet CHEBI:17076 biolink:causes HP:0002540 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0560046 infores:hetionet CHEBI:28364 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0033774 infores:hetionet CHEBI:63624 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0015230 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0687133 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0011991 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0025061 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0854114 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0017566 infores:hetionet CHEBI:3441 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151904 infores:hetionet CHEBI:43968 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0011991 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0042401 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0234215 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0021400 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853117 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0340464 infores:hetionet CHEBI:83804 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0014236 infores:hetionet CHEBI:6367 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0152198 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0020538 infores:hetionet CHEBI:39112 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0027947 infores:hetionet CHEBI:52717 biolink:causes MONDO:0010947 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0856761 infores:hetionet CHEBI:77733 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0870082 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1168034 infores:hetionet CHEBI:79699 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0015672 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0037274 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0009806 infores:hetionet CHEBI:17303 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085631 infores:hetionet CHEBI:44915 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0030196 infores:hetionet CHEBI:49960 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0033774 infores:hetionet CHEBI:3756 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0241057 infores:hetionet CAID:CA1139666850 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666850 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1):c.270dup (p.Arg91AlafsTer47) variant in RUNX1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). The variant has been reported in a 78yo female with AML, but variant origin is unclear (PMID: 37680325); it has also been reported in 1/3219 patients referred for clinical diagnostic testing who underwent WGS, but phenotype and germline origin are unspecified (PMID: 33726816) (PS4_Supporting is not met). However, other pathogenic/likely pathogenic frameshift alterations in exons 4 or 5 have been reported (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval) Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666850/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA386958785 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958785 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PP4 The c.332A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to glycine at codon 111 (p.(Asp111Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% and HNF4A was not tested (internal lab contributors). In summary, c.332A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PM_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958785/MONDO:0015967/017 2024-01-28 2024-01-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0029408 infores:hetionet CHEBI:63717 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0004604 infores:hetionet NCBIGene:9786 biolink:causes MONDO:0014688 infores:monarchinitiative not_provided not_provided HGNC:19960 MONDO:0014688 uuid:22003f9a-4079-4388-8de9-84293c94fc30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64064 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0851578 infores:hetionet NCBIGene:1733 biolink:causes MONDO:0030839 infores:monarchinitiative not_provided not_provided HGNC:2883 MONDO:0030839 uuid:c069a88d-c0d3-4bcb-8852-f7ac54ddacf7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6295 biolink:causes MONDO:0859367 infores:monarchinitiative not_provided not_provided HGNC:10521 MONDO:0859367 uuid:bdce0cae-4b3d-4ff4-8bb7-3e98595f22e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235351 infores:hetionet CHEBI:6717 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0019080 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0038661 infores:hetionet CHEBI:48273 biolink:causes UMLS:C2349423 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C2349423 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0278080 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0020538 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0002170 infores:hetionet CHEBI:8888 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151754 infores:hetionet CAID:CA390879466 biolink:causes MONDO:0100216 infores:clingen CAID:CA390879466 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting BA1, BS2, PP3, PM5, PM1, PS4, BS1 The NM_177438.3:c.2774A>G variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by glycine at amino acid 925 (p.Glu925Gly). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.225; MaxEntScan and SpliceAI: no effect on splicing) (BP4). Another missense variant, c.2773G>A (p.Glu925Lys), in the same codon has been reported (ClinVar Variation ID: 941599). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER1 VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 01/07/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390879466/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0032617 infores:hetionet CHEBI:4445 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151636 infores:hetionet CHEBI:3814 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0030920 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0021053 infores:hetionet CHEBI:42068 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0014868 infores:hetionet CHEBI:84500 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0232461 infores:hetionet CHEBI:6129 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1096274 infores:hetionet CHEBI:66964 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0151836 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0267537 infores:hetionet CHEBI:30830 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0947912 infores:hetionet CAID:CA399804480 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804480 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.1096C>T (p.Arg366Ter) nonsense variant in biologically-relevant-exon 12/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient CT in PMID: 12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Patient CT of PMID: 12083483 is homozygous for the Arg366Ter nonsense variant (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 01/18/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804480/MONDO:0100326/011 2022-04-07 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:194135 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017181 infores:hetionet CHEBI:50922 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0852911 infores:hetionet CHEBI:6761 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0030252 infores:hetionet CHEBI:3387 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0235660 infores:hetionet CHEBI:4798 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0234428 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0000731 infores:hetionet CHEBI:31705 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085631 infores:hetionet GO:0075030 biolink:causes GO:0044409 infores:ubergraph knowledge_assertion manual_agent GO:0075030 GO:0044409 CHEBI:5130 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1328337 infores:hetionet CAID:CA279966 biolink:causes MONDO:0015280 infores:clingen CAID:CA279966 MONDO:0015280 PMID: Likely Pathogenic PP3, PP2, PM2_Supporting, PS3_Moderate, PM1, PS4_Moderate, PM6_Supporting BP4, BA1, BS1 The c.158T>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 53 (p.Phe53Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.938 (PP3). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). Furthermore, the variant is in a location, analogous to MEK2 F57 residue, that has been defined by the ClinGen RASopathy Expert Panel functional domain of MAP2K1 (PM1). This variant has been reported in the literature in 4 individuals with clinical features of RASopathy with 1 unconfirmed de novo occurrence (PS4_Moderate, PM6_Supporting; PMIDs: 16439621, 18039235, 21062266, 30141192). ERK/MAPK phosphorylation assays showed that this variant led to significantly increased phosphorylation compared to wildtype (PS3_Moderate; PMID: 16439621, 17981815). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PM1, PM2_Supporting, PM6_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279966/MONDO:0015280/045 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CAID:CA404039368 biolink:causes MONDO:0018947 infores:clingen CAID:CA404039368 MONDO:0018947 PMID: Likely Pathogenic PM5, PP2, PP3, PM2_Supporting, PS4_Supporting BA1, BP4, BS1 The variant NM_001005361.3:c.1564C>T in DNM2 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 522 (p.Arg522Cys). The highest population minor allele frequency in gnomAD v4.1.0 is 8.526e-7 (1/1172834 alleles) in non-Finnish European which meets PM2_Supporting. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The REVEL computational prediction analysis tool produced a score of 0.746, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). Two different missense variants, p.Arg522His and p.Arg522Leu (ClinVar IDs: 158514 and 373110), in the same codon have been classified as (likely) pathogenic on ClinVar, of which p.Arg522His has been classified as pathogenic for centronuclear myopathy by the ClinGen Congenital Myopathies VCEP (PM5). This variant has been reported in one proband with centronuclear myopathy who presented with predominantly distal muscle weakness, ptosis, ophthalmoplegia/ paresis, facial weakness, weak deep tendon reflexes, stepping gait, central nuclei, fiber hypotrophy, and Type 1 fiber predominance (0.25pts, PS4_Supporting; PMID: 22396310). In summary, the variant meets criteria to be classified as likely pathogenic for centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM5, PS4_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; September 8th, 2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA404039368/MONDO:0018947/148 2025-09-08 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CAID:CA409107542 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107542 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate The c.778G>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to tyrosine at codon 260 (p.(Asp260Tyr)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.778G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4_moderate, PP1_moderate, PP4_moderate, PM2_supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107542/MONDO:0015967/085 2024-09-26 2024-09-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3650 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0020175 infores:hetionet CHEBI:10125 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151905 infores:hetionet CHEBI:6375 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0233471 infores:hetionet CHEBI:2682 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151907 infores:hetionet NCBIGene:4281 biolink:causes MONDO:0010222 infores:monarchinitiative not_provided not_provided HGNC:7095 MONDO:0010222 uuid:e4bdc9d4-da83-4594-87cd-0fcb96439b19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0022650 infores:hetionet CHEBI:6067 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038999 infores:hetionet UMLS:C0879264 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0013404 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027726 infores:hetionet CAID:CA8815197 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815197 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PS3_Moderate PP4, PM5, PM3 The NM_000152.5:c.1190C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 397 (p.Pro397Leu). One patient with a diagnosis of Pompe disease has been reported with this variant, but GAA activity and clinical details were not available (PMID: 30155607). This patient is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1781G>A (p.Arg594His) (PMID: 30155607). The variant was also found in heterozygosity in individuals identified by newborn screening who also carried pseudodeficiency variants (PMID: 31076647, 34922579). Although this variant has been reported multiple times, there is currently insufficient evidence to apply either PM3 or PP4. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001865 (22/1111896 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 456370). In summary, this variant currently meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on criteria specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PS3_Moderate, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815197/MONDO:0009290/010 2025-05-06 2025-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63611 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0852913 infores:hetionet CAID:CA229649 biolink:causes MONDO:0009861 infores:clingen CAID:CA229649 MONDO:0009861 PMID: Uncertain Significance BS1 PP3 The c.609C>T (p.Cys203=) variant in PAH has not been reported in a patient with PAH deficiency to our knowledge. This variant has a MAF that is too high (0.00473 in gnomAD). A deleterious effect is predicted using HSF, IIEs from Zhang et al, Fas-ESS hexamers, and NNSplice, but Splice AI predicts a benign effect (0). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229649/MONDO:0009861/006 2020-10-23 2020-10-23 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:10516 biolink:causes MONDO:0030689 infores:monarchinitiative not_provided not_provided HGNC:3602 MONDO:0030689 uuid:29f78fbd-d78d-47b0-ba23-6af2f9aa9aa0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16664 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0027497 infores:hetionet CHEBI:4814 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0015230 infores:hetionet CHEBI:3181 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0220870 infores:hetionet CHEBI:46081 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0016204 infores:hetionet CHEBI:45409 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0040822 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0574067 infores:hetionet GO:0061924 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0007417 CAID:CA030745 biolink:causes MONDO:0007750 infores:clingen CAID:CA030745 MONDO:0007750 PMID: Benign BA1, BP4 BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.941-39C>T variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1: FAF=0.005249 (0.5249%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So BA1 is met.BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA030745/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:16755 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013295 infores:hetionet CAID:CA6748885 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748885 MONDO:0009861 PMID:26503515 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 The c.668A>T (p.Asn223Ile) variant in PAH has been reported in 2 individuals with PKU and MHP (BH4 deficiency excluded). (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.0001307). This variant was detected with in trans with p.Y166* (PMID: 30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748885/MONDO:0009861/006 2020-06-01 2021-10-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011175 infores:hetionet CAID:CA347217077 biolink:causes MONDO:0015152 infores:clingen CAID:CA347217077 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.3126G>A p.(Trp1042Ter) variant in DYSF, which is also known as NM_001130987.2: c.3180G>A p.(Trp1060Ter) or p.(Trp1060del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 29/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two unrelated individuals with clinical signs of LGMD (PMID: 18853459, ClinVar SCV002762694.1 internal data communication), including confirmed in trans with a pathogenic variant (c.855+1del, 1.0 pt, PMID: 18853459) (PM3). At least one individual with the variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347217077/MONDO:0015152/180 2025-01-08 2025-04-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:65349 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0009450 infores:hetionet CHEBI:142290 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0497156 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0497201 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0233472 infores:hetionet CHEBI:44185 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085593 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0948089 infores:hetionet CAID:CA91170263 biolink:causes MONDO:0001586 infores:clingen CAID:CA91170263 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting The NM_000203.5:c.1403-1G>T variant in IDUA occurs within the canonical splice acceptor site of intron 9. It is predicted to cause skipping of biologically-relevant-exon 10 out of 14, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been detected in at least 2 individuals reported with severe MPS I. Of those individuals, both were compound heterozygous, unknown phase, for the variant and NM_000203.5(IDUA):c.1198C>T (p.Gln400Ter) (Variation ID: 1683229), which has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, meeting PM3_Supporting. (PMID: 31194252.) The highest population minor allele frequency in gnomAD v4.1.0 is 0.000007943 (9/1133112 alleles) in the European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold (<0.00025) for meeting PM2_Supporting criterion. There is a ClinVar entry for this variant (Variation ID: 652306). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PM3_supporting, PM2_supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 2, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA91170263/MONDO:0001586/091 2025-06-02 2025-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3534 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0011603 infores:hetionet CHEBI:6444 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0031212 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0042571 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0948089 infores:hetionet CHEBI:76010 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0311468 infores:hetionet CHEBI:66901 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0011603 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0021053 infores:hetionet CHEBI:71028 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0428977 infores:hetionet CHEBI:6904 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0242429 infores:hetionet CHEBI:75998 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0043352 infores:hetionet CHEBI:49960 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0242301 infores:hetionet CHEBI:5134 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0025320 infores:hetionet CHEBI:2904 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0041657 infores:hetionet UMLS:C0657912 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151827 infores:hetionet CAID:CA2580083090 biolink:causes MONDO:0700270 infores:clingen CAID:CA2580083090 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.6136del (p.Leu2046*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been identified in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580083090/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119486 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0016204 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0424790 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0032584 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0162429 infores:hetionet CHEBI:31643 biolink:causes MONDO:0015294 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C1619692 infores:hetionet CHEBI:51141 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0014518 infores:hetionet CHEBI:9757 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0018681 infores:hetionet CHEBI:64310 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0027497 infores:hetionet CHEBI:47780 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022107 infores:hetionet CHEBI:28445 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0042963 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0162429 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0854382 infores:hetionet CAID:CA8328673 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328673 MONDO:0100438 PMID: Likely Benign BP7, PM2_Supporting, BP4 NM_014336.5(AIPL1):c.51G>A (p.Leu17=) is a synonymous variant in exon 1 of 6 that is not close to the exon-intron boundaries. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00002292, with 37 alleles / 1,614,098 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328673/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7443 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002170 infores:hetionet CAID:CA8129781 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129781 MONDO:0007648 PMID: Likely Benign BS2_Supporting, BP4 BP7, BP5, BS1, BS3, BS4, PM1, PM3, PM4, PM5, PVS1, PM2, PM6, PP1, PP4, PP2, PP3, BP2, BP1, BP3, BA1, PS3, PS4, PS1, PS2 The c.48+5C>T variant was observed in at least 3 families without a personal and/or family history of diffuse gastric cancer, lobular breast cancer or a signet ring cell tumor (BP2_Supporting; internal data). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). Therefore, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_Supporting, BP4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129781/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true GO:0060622 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0060622 GO:0019953 CHEBI:116278 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0009763 infores:hetionet CHEBI:8232 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0020433 infores:hetionet CHEBI:7465 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1306341 infores:hetionet CHEBI:17688 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0019521 infores:hetionet CAID:CA7511545 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511545 MONDO:0015152 PMID: Likely Benign BP4, BP7, BS1 PM3 The NM_000070.3: c.1800+21C>T variant in CAPN3 is an intronic variant that does not occur in a splice region (+7/-21). The filtering allele frequency for this variant is 0.002152 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2461/1105660 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.01, which is less than the VCEP threshold of 0.05 (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511545/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:28939 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0178298 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020651 infores:hetionet CHEBI:9649 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018524 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042514 infores:hetionet CHEBI:6909 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0009763 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0020517 infores:hetionet NCBIGene:444 biolink:causes MONDO:0011106 infores:monarchinitiative not_provided not_provided HGNC:757 MONDO:0011106 uuid:99202c2d-7be9-4370-b029-9273ede79fdf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149512 infores:hetionet CHEBI:167638 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0020458 infores:hetionet GO:0061105 biolink:causes GO:0062094 infores:ubergraph knowledge_assertion manual_agent GO:0061105 GO:0062094 CHEBI:9649 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0232462 infores:hetionet CHEBI:8214 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0039070 infores:hetionet CHEBI:161680 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0015230 infores:hetionet CHEBI:5855 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042384 infores:hetionet CHEBI:50131 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0000731 infores:hetionet CHEBI:31981 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0013404 infores:hetionet CHEBI:47780 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0000737 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0518015 infores:hetionet CHEBI:8890 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0085593 infores:hetionet CHEBI:681569 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0231835 infores:hetionet CHEBI:63599 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C1167791 infores:hetionet CHEBI:4728 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0027497 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151602 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020538 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038525 infores:hetionet CHEBI:6128 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0001824 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014742 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0427055 infores:hetionet GO:0080092 biolink:causes GO:0009856 infores:ubergraph knowledge_assertion manual_agent GO:0080092 GO:0009856 CHEBI:71219 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0004093 infores:hetionet CHEBI:4653 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0085612 infores:hetionet CHEBI:31859 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013144 infores:hetionet CHEBI:64310 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0235378 infores:hetionet CHEBI:135876 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0002871 infores:hetionet CHEBI:17334 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0014457 infores:hetionet CHEBI:6801 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0476273 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020514 infores:hetionet CAID:CA024620 biolink:causes MONDO:0007783 infores:clingen CAID:CA024620 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4_Moderate, PP3_Moderate, PP1_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with arginine at codon 2206 of the RYR1 protein, p.(Thr2206Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 10484775, 30236257, 16244001). This variant segregates with MHS in six individuals, PP1_Moderate (PMID: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 16163667). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.968) supports a pathogenic status for this variant, PP3_Moderate. 75e1f85c-b5bd-4e59-83c6-5d22ed39b50e75e1f85c-b5bd-4e59-83c6-5d22ed39b50eRYR1NC_000019.10g.38543551A>GNM_000540.2(RYR1):c.11798A>G|p.Tyr3933CysMONDOMONDO:0007783Likely Benign2022-01-04assertion-criteriaAutosomal dominant inheritancehttps://erepo.clinicalgenome.org/evrepo/ui/interpretation/75e1f85c-b5bd-4e59-83c6-5d22ed39b50eThis pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of tyrosine with cysteine at codon 3933 of the RYR1 protein, p.(Tyr3933Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.001332, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 25958340, 20681998, 23558838, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.983) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is classified as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024620/MONDO:0007783/012 2022-01-04 2022-01-04 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ NCBIGene:5286 biolink:causes MONDO:0034145 infores:monarchinitiative not_provided not_provided HGNC:8971 MONDO:0034145 uuid:02fcf89f-5885-4a99-bb03-6463632918f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6339 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0015397 infores:hetionet CHEBI:142290 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0041657 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033860 infores:hetionet NCBIGene:10806 biolink:causes MONDO:0013326 infores:monarchinitiative not_provided not_provided HGNC:10671 MONDO:0013326 uuid:da3abb97-ff03-47b8-85a3-e43a76967c25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0010399 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0392171 infores:hetionet CHEBI:6375 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0376286 infores:hetionet CHEBI:79699 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0004604 infores:hetionet CAID:CA10585595 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585595 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS4, PS2, BP5, BP7, BS3, BS1, PM1, PM4, PM3, PM6, PVS1, PP2, PP1 NM_000527.5(LDLR):c.1748A>G (p.His583Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.819. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921).PP4: Variant meets PM2 and is identified in at least 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic (PMID 22698793, Tichý et al., 2012). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585595/MONDO:0007750/013 2023-11-07 2024-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6402 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0027651 infores:hetionet CHEBI:6954 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C1443060 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232197 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0039971 infores:hetionet CHEBI:6359 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0241379 infores:hetionet CHEBI:3175 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020443 infores:hetionet CHEBI:63612 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0043144 infores:hetionet NCBIGene:3073 biolink:causes MONDO:0010100 infores:monarchinitiative not_provided not_provided HGNC:4878 MONDO:0010100 uuid:75825dd9-0e01-497a-990a-68f4dc6173f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014868 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0240520 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0240520 infores:hetionet CHEBI:68478 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0740394 infores:hetionet CHEBI:15940 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0852795 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0233632 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0033581 infores:hetionet CAID:CA2018007672 biolink:causes MONDO:0015967 infores:clingen CAID:CA2018007672 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 The c.1261del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 421 (NM_000162.5), adding 10 novel amino acids before encountering a stop codon (p.(Glu421SerfsTer10)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with non-autoimmune or non-absolute/near-absolute insulin-deficient diabetes/hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 16965331). However, the clinical history for this individual is highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 16965331). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023: PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2018007672/MONDO:0015967/086 2023-06-26 2023-06-26 Semidominant inheritance HP:0032113 Supports CHEBI:41423 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0029408 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011053 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0039971 infores:hetionet CHEBI:8768 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0035410 infores:hetionet CHEBI:51860 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011175 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0027813 infores:hetionet CHEBI:5132 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0600142 infores:hetionet CHEBI:65173 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0043094 infores:hetionet CHEBI:6933 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0013404 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0019112 infores:hetionet CHEBI:3127 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0003811 infores:hetionet CHEBI:16335 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0030554 infores:hetionet CAID:CA5416508 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416508 MONDO:0011225 PMID: Benign BA1, BS2_Supporting NM_001033855.3(DCLRE1C):c.1284A>C is a missense variant predicted to cause substitution of Lysine by Asparagine at amino acid 428 (p.Lys428Asn).The filtering allele frequency (the lower threshold of the 95% CI of 501/75018) of the c.1284A>C variant in DCLRE1C is 0.005719 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, 2 homozygous adults are reported in gnomAD v.4 in the same population. BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416508/MONDO:0011225/116 2024-02-05 2024-02-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63717 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0948594 infores:hetionet CHEBI:10023 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0428977 infores:hetionet CHEBI:39669 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C2973529 infores:hetionet CHEBI:6792 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0038362 infores:hetionet CHEBI:144093 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0043352 infores:hetionet CHEBI:167309 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0037763 infores:hetionet CHEBI:47381 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0037287 infores:hetionet CHEBI:37333 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0033774 infores:hetionet CHEBI:404903 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0015672 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0853714 infores:hetionet CHEBI:68610 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0010200 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0521991 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0521991 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0349506 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020651 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0521845 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0521845 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0014868 infores:hetionet CHEBI:4315 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0040822 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0340726 infores:hetionet CHEBI:3127 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0032617 infores:hetionet CHEBI:94686 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0149725 infores:hetionet CAID:CA010465 biolink:causes MONDO:0005045 infores:clingen CAID:CA010465 MONDO:0005045 PMID: Uncertain Significance PM1, PP3, PM2_Supporting, PS4_Supporting BS2, PP4, PP2, BA1, PM5, PM6, PM3, PM4, PP1, PS3, BS1, BS3, BS4, BP1, BP3, PS1, PS2, BP2, BP5, BP4, BP7, PVS1 The c.1273G>A (p.Gly425Arg) variant in MYH7 has been identified in at least 3 individuals with HCM, the majority of whom are of Chinese ancestry (PS4_Supporting; Song 2005 PMID:15563892; Wang 2009 PMID:19586842; Homburger 2016 PMID:27247418; Mak 2018 PMID:29497013). This variant segregated with disease in 2 relatives with HCM from 1 family (Wang 2009 PMID:19586842); however this data is currently insufficient to apply PP1. This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM2_Supporting; PM1; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010465/MONDO:0005045/002 2022-07-30 2022-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9599 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0008031 infores:hetionet CHEBI:94848 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0917801 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1720798 infores:hetionet CHEBI:3011 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0040034 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0948089 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020517 infores:hetionet CHEBI:8890 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0039231 infores:hetionet CHEBI:7476 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0231218 infores:hetionet CHEBI:6931 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0017178 infores:hetionet CHEBI:135930 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C2363731 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0036572 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0267596 infores:hetionet CAID:CA206151 biolink:causes MONDO:0007113 infores:clingen CAID:CA206151 MONDO:0007113 PMID: Benign BA1, BP5 BS2 The allele frequency of The p.Lys679Thr variant in UBE3A (NM_130838.2) is 0.03187% in European (non-Finnish) sub population in gnomAD v4, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Lys679Thr variant is found in a patient with an alternate molecular basis of disease (internal database - Baylor) (BP5). In summary, the p.Lys679Thr variant in UBE3A (NM_130838.2) is classified as benign based on the ACMG/AMP criteria (BA1, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA206151/MONDO:0007113/037 2023-12-06 2023-12-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:32315 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0006277 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0042075 infores:hetionet GO:0021822 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0007420 CHEBI:3380 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0020625 infores:hetionet CAID:CA10585851 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585851 MONDO:0007750 PMID: Likely Pathogenic PM2, PVS1 BA1, BS1 NM_000527.5(LDLR):c.2397_2412del (p.Val800fs) variant is classified as Likely Pathogenic, for Familial Hypercholesterolemia by applying evidence code PM2 and PVS1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: This variant is absent from gnomAD (gnomAD v2.1.1).. PSV1: Deletion of 16 bp causing an out-of-frame consequence (Exon 17) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585851/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:50648 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020453 infores:hetionet NCBIGene:3914 biolink:causes MONDO:0007094 infores:monarchinitiative not_provided not_provided HGNC:6490 MONDO:0007094 uuid:cba44f5d-d589-4c5e-bd89-d8754016b8e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3698 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0600142 infores:hetionet CAID:CA229753 biolink:causes MONDO:0009861 infores:clingen CAID:CA229753 MONDO:0009861 PMID:26503515PMID:9575658PMID:26322415 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong PM5, PS3 The c.770G>T (p.Gly257Val) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 26503515). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.R408Q, p.Ser70del (PMID: 26322415); p.R111X (PMID: 14722928); p.Arg261Gln (PMID: 17502162); c.1068C>A (p.Y356*, PMID: 25894915); p.Arg252Trp, p.Arg243Gln, p.His107Arg, p.Leu255Ser (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229753/MONDO:0009861/006 2020-11-14 2022-03-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63580 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C3665386 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0020538 infores:hetionet CHEBI:50924 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0206061 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0005940 infores:hetionet CHEBI:135193 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0677500 infores:hetionet CHEBI:79699 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0149745 infores:hetionet CAID:CA1139665924 biolink:causes MONDO:0009290 infores:clingen CAID:CA1139665924 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 "The NM_000152.5:c.1579del (p.Arg527GlyfsTer51) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 12 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant was identified by newborn screening in Taiwan, with a predicted severe/classical phenotype, with confirmatory GAA deficiency ""defined as lymphocyte GAA activity <3% of the normal mean"", and absence of the pseudodeficiency variant c.1726G>A. The patient was reported to be on enzyme replacement therapy based on an ""unrecorded indication"" (PMID: 34995642) (PP4_Moderate). This patient is compound heterozygous for the variant and c.1222A>G (p.Met408Val) (ClinVar Variation ID: 371235); the variants are confirmed to be in trans (PMID: 34995642). The allelic data from this patient has been used in the classification of p.Met408Val and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2024)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665924/MONDO:0009290/010 2024-04-15 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:16755 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013390 infores:hetionet CHEBI:7936 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151798 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0241266 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0241266 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151605 infores:hetionet CHEBI:32293 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0036974 infores:hetionet CHEBI:5165 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0023530 infores:hetionet CHEBI:51041 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042345 infores:hetionet CHEBI:3181 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0039231 infores:hetionet CHEBI:63613 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0026636 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0853149 infores:hetionet CHEBI:6375 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0558489 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0013395 infores:hetionet CHEBI:5558 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0043094 infores:hetionet CHEBI:31859 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0085649 infores:hetionet NCBIGene:1441 biolink:causes MONDO:0014865 infores:monarchinitiative not_provided not_provided HGNC:2439 MONDO:0014865 uuid:5d1cedd0-dfc2-422b-9b4a-8840d62fc35d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes UMLS:C0392618 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0392618 infores:hetionet CHEBI:31236 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085649 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151849 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0233414 infores:hetionet CHEBI:91541 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C1443060 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0235467 infores:hetionet CAID:CA041174 biolink:causes MONDO:0007750 infores:clingen CAID:CA041174 MONDO:0007750 PMID: Uncertain Significance BP4 PM2, PP4 The NM_000527.5(LDLR):c.2548-19G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 May 2025.The supporting evidence is as follows: BP4: No REVEL score, splicing evaluation required. Not on splicing limits and no published functional data on splicing found, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041174/MONDO:0007750/013 2025-05-09 2025-10-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6690 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0001807 infores:hetionet CHEBI:7575 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0220870 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0018799 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0033117 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0025202 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0025061 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0267792 infores:hetionet NCBIGene:3549 biolink:causes MONDO:0007215 infores:monarchinitiative not_provided not_provided HGNC:5956 MONDO:0007215 uuid:6068811f-ef81-495e-abdd-1fdfefbc71e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0152227 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0549386 infores:hetionet CHEBI:5613 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0001824 infores:hetionet CHEBI:68610 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0017178 infores:hetionet CHEBI:7822 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0040822 infores:hetionet CHEBI:84050 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0030312 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042075 infores:hetionet CAID:CA10014163 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014163 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.*44C>G is a 3' UTR variant. MAF of 0.01 (1.31%, 885/67420 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 4 homozygotes in gnomAD v3.1.2 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014163/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15367 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085636 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0018099 infores:hetionet GO:0090078 biolink:causes CL:0000892 infores:ubergraph knowledge_assertion manual_agent GO:0090078 CL:0000892 CHEBI:6950 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0009319 infores:hetionet CHEBI:31638 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0151662 infores:hetionet CHEBI:16469 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019080 infores:hetionet CHEBI:28748 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0012569 infores:hetionet CHEBI:6149 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0344232 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018099 infores:hetionet CHEBI:41774 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0015230 infores:hetionet GO:2000794 biolink:causes GO:0060428 infores:ubergraph knowledge_assertion manual_agent GO:2000794 GO:0060428 CHEBI:3213 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0020649 infores:hetionet CHEBI:4822 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0085612 infores:hetionet CHEBI:36704 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0237849 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0877468 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0877468 infores:hetionet NCBIGene:1718 biolink:causes MONDO:0011217 infores:monarchinitiative not_provided not_provided HGNC:2859 MONDO:0011217 uuid:78100547-0feb-44a5-ad6d-ca4860f84f90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8232 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0036974 infores:hetionet CHEBI:72564 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1527311 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0042571 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0036572 infores:hetionet CHEBI:79699 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042023 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0012797 infores:hetionet CHEBI:82941 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0011991 infores:hetionet CHEBI:50730 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0030252 infores:hetionet NCBIGene:8291 biolink:causes MONDO:0009676 infores:monarchinitiative not_provided not_provided HGNC:3097 MONDO:0009676 uuid:6b525049-ce44-496d-a203-3623ac3d0a9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59773 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0014457 infores:hetionet CAID:CA396458057 biolink:causes MONDO:0007648 infores:clingen CAID:CA396458057 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP4, PP3, PP2, PP1, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2 The c.635G>T (p.Gly212Val) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000661629.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396458057/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:15553 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0036572 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0021053 infores:hetionet CHEBI:2950 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C3665386 infores:hetionet CHEBI:2950 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0017160 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042514 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0271650 infores:hetionet CHEBI:42797 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0015672 infores:hetionet CHEBI:50859 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020625 infores:hetionet CHEBI:50173 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030554 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0020649 infores:hetionet CHEBI:167309 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0038990 infores:hetionet CHEBI:72564 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0542571 infores:hetionet CAID:CA2579830356 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830356 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting PP1, PM1, PS4 The c.-183T>C variant in the hepatic nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant in the promoter region of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.-183T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830356/MONDO:0015967/085 2024-01-28 2024-01-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA343724698 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724698 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting BS1, BS3, BP7, PM6, PP1, PM4, PM5, PS1, PS2, PS4, PS3, BA1, BP4 The c.1107C>G variant in MYOC is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 369 (p.Phe369Leu). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.825, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 2 segregations had been reported for juvenile open angle glaucoma (JOAG, PMID: 35389460), not meeting the ≥ 3 segregations required for PP1. Only 1 proband with JOAG had been reported (PMID: 35389460), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724698/MONDO:0020367/019 2023-04-04 2023-04-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50730 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0022346 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0041976 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0025061 infores:hetionet CHEBI:6076 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020580 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0160390 infores:hetionet CHEBI:6062 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0015967 infores:hetionet CAID:CA041918 biolink:causes MONDO:0007750 infores:clingen CAID:CA041918 MONDO:0007750 PMID: Uncertain Significance BS3, PM2, PP4 BA1, BP1, BP4, BP2, BP3, PS3, PS4, PS2, PS1, BP5, BP7, BS1, BS4, PM1, PM3, PM4, PM5, PM6, PVS1, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (BS3, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS3 - Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- whole cycle is above 90% of wild-type activity, so BS3 is Met.PM2 - PopMax MAF = 0.0001307 (0.013%) in South Asian exomes (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in at least 1 FH case from Laboratory of Genetics and Molecular Cardiology who fulfill Simon-Broome criteria. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041918/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA10585082 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585082 MONDO:0007750 PMID: Likely Benign BP4, BP7, PM2 BA1, BP3, BP2, PS3, PS4, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.690C>T (p.Asn230=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4, and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence codes towards Pathogenic, so we are confident in classifying this variant as Likely benign.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). So, PM2 is met. BP4: No REVEL found. Splicing evaluation required.Functional data on splicing not available.A) not on limitsB) does not create GTC) no GT nearbyVariant is not predicted to alter splicing. So, BP4 is met. BP7: Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585082/MONDO:0007750/013 2025-01-31 2025-03-09 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6715 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0030196 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0025637 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020538 infores:hetionet CHEBI:3371 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0035078 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0243026 infores:hetionet GO:2000345 biolink:causes GO:0072576 infores:ubergraph knowledge_assertion manual_agent GO:2000345 GO:0072576 CHEBI:31236 biolink:causes UMLS:C1536916 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1536916 infores:hetionet CHEBI:168396 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018520 infores:hetionet CHEBI:50841 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0033774 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0919714 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0919714 infores:hetionet CHEBI:17474 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1291077 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0015397 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1971624 infores:hetionet CHEBI:135930 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0028734 infores:hetionet CHEBI:79699 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0019348 infores:hetionet CHEBI:9720 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0012833 infores:hetionet CHEBI:28939 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0017178 infores:hetionet NCBIGene:23086 biolink:causes MONDO:0014014 infores:monarchinitiative not_provided not_provided HGNC:30578 MONDO:0014014 uuid:f957bb5c-7ec2-44a6-9358-bd58aa888006 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0947999 infores:hetionet CHEBI:5118 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085605 infores:hetionet CHEBI:421707 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0038325 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0021400 infores:hetionet CHEBI:2038 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0028081 infores:hetionet CHEBI:4356 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0456909 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0013395 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0267596 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031117 infores:hetionet CHEBI:4469 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0040517 infores:hetionet CHEBI:119915 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C3495920 infores:hetionet CHEBI:4822 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0043049 infores:hetionet CHEBI:40237 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0344232 infores:hetionet CAID:CA145892 biolink:causes MONDO:0001586 infores:clingen CAID:CA145892 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.942G>C variant in IDUA is a synonymous (silent) variant (p.Ala314=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2937 in the South Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92650). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145892/MONDO:0001586/091 2025-01-02 2025-01-02 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:1959 biolink:causes MONDO:0007790 infores:monarchinitiative not_provided not_provided HGNC:3239 MONDO:0007790 uuid:b5653f00-d228-4b79-b068-f544186c989c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0037763 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031039 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0020456 infores:hetionet CAID:CA404041406 biolink:causes MONDO:0018947 infores:clingen CAID:CA404041406 MONDO:0018947 PMID: Likely Pathogenic PS4, PS3_Supporting, PP1_Moderate, PP2, PM2_Supporting The c.1948G>A (NM_001005361.3(DNM2):c.1948G>A (p.Glu650Lys)) variant in DNM2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 650. This variant has been reported in 7 probands from 3 families all meeting phenotypic criteria and six having ptosis (PS4; PMIDs: 19623537, 24465259, 31655408). The variant has been reported to segregate with centronuclear myopathy in 4 affected individuals from one family (PP1_Moderate; PMID: 19623537). This variant is absent from gnomAD v4.1 (PM2_Supporting). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). An in-vitro cell culture in muscle cells showed increased GTPase activity indicating that this variant impacts protein function (PMID: 26199319, PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by theClinGen Congenital Myopathies VCEP: PS4, PP1_Moderate, PP2, PM2_Supporting, PS3_Supporting. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA404041406/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3696 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011206 infores:hetionet CHEBI:37924 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0018681 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0242350 infores:hetionet CHEBI:18332 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0151786 infores:hetionet CAID:CA412740347 biolink:causes MONDO:0100437 infores:clingen CAID:CA412740347 MONDO:0100437 PMID: Uncertain Significance PP3, PM2_Supporting NM_001034853.2(RPGR):c.968G>A (p.Arg323His) is a missense variant encoding substitution of arginine with histidine at amino acid 323. The variant is present in ClinVar but has not yet been reported in published probands. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002553 among hemizygous individuals, with 1 variant allele / 391,742 total alleles, which is lower than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 (PM2_Supporting). The computational predictor REVEL gives a score of 0.693, which is between the ClinGen X-linked IRD VCEP threshold of 0644 to 0.773 and predicts a damaging effect on RPGR function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict disruption of RPGR splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting and PP3_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412740347/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Inconclusive true CHEBI:63580 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015672 infores:hetionet CHEBI:5138 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011168 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0025061 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0041912 infores:hetionet CHEBI:6067 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0231919 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0036572 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0036341 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0314719 infores:hetionet CHEBI:7789 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0026961 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011991 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1963818 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1963818 infores:hetionet CHEBI:94440 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0030252 infores:hetionet CHEBI:29688 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0030252 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020569 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0278134 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0020517 infores:hetionet CHEBI:6456 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0018681 infores:hetionet CHEBI:3387 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027796 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0877517 infores:hetionet CAID:CA415090808 biolink:causes MONDO:0010305 infores:clingen CAID:CA415090808 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 The NM_005629.4:c.1667G>A (p.Trp556Ter) variant in SLC6A8 is is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 12/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Although the variant is in the penultimate exon of the gene, it is upstream of last 50bp. Therefore, nonsense-mediated decay is not predicted to occur (PVS1). This variant has been reported in two male probands, from different countries, with the diagnosis of creatine transporter deficiency (PMID: 22281021, 34050321). For one of these individuals, the diagnosis was confirmed by elevated creatine to creatinine ratio in urine and the variant was identified by exome sequencing (PMID: 34050321) (PP4). Therefore is insufficient evidence to apply PS4 for the second individual. The variant is absent in gnomAD v4.0. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on December 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415090808/MONDO:0010305/027 2023-12-14 2023-12-14 X-linked inheritance HP:0001417 Supports CHEBI:8356 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0149931 infores:hetionet GO:1904967 biolink:causes GO:0043060 infores:ubergraph knowledge_assertion manual_agent GO:1904967 GO:0043060 CHEBI:63611 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0012569 infores:hetionet CHEBI:41977 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0232461 infores:hetionet CHEBI:10125 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011168 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0029408 infores:hetionet NCBIGene:55526 biolink:causes MONDO:0008774 infores:monarchinitiative not_provided not_provided HGNC:23537 MONDO:0008774 uuid:bcbc93fe-38fa-4c42-a7bc-c859653bf76f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0151825 infores:hetionet NCBIGene:727 biolink:causes MONDO:0012295 infores:monarchinitiative not_provided not_provided HGNC:1331 MONDO:0012295 uuid:ef4c61af-ac60-47ce-869b-8bd8399b1c39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA012022 biolink:causes MONDO:0005045 infores:clingen CAID:CA012022 MONDO:0005045 PMID:27532257PMID:15856146PMID:8533830PMID:27532257 Pathogenic PP3, PM1, PM5, PM2, PP1_Moderate, PS4 The c.2221G>T (p.Gly741Trp) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID: 8533830; PMID:15856146; PMID:27532257; Partners LMM ClinVar SCV000203910.4; AGCMC Sydney ClinVar SCV000212638.1). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; AGCMC Sydney ClinVar SCV000212638.1). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>C p.Gly741Arg - Variation ID 14098). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PP1_Moderate; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012022/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:37941 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042029 infores:hetionet CAID:CA220590 biolink:causes MONDO:0009861 infores:clingen CAID:CA220590 MONDO:0009861 PMID:24401910PMID:9298832PMID:24401910PMID:24401910PMID:9298832 Pathogenic PP4_Moderate, PM2, PP3, PS3, PM3_Strong The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220590/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27666 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0041582 infores:hetionet CAID:CA024581 biolink:causes MONDO:0018493 infores:clingen CAID:CA024581 MONDO:0018493 PMID: Uncertain Significance PP1, BS2, PM1, PS4_Moderate, BS3_Supporting PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with methionine at codon 214 of the RYR1 protein, p.(Thr214Met). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00017, a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) PS4_Moderate (PMID:30236257). This variant has been reported in a fifth individual with a second variant in RYR1 classified as Likely Pathogenic (p.Glu2348del), this individual was not counted toward PS4 (PMID:27857962), the mother of this individual shared the p.Thr214Met variant and was MHN by IVCT, BS2_Moderate. Functional studies in HEK293 cells do not show a significant increase in sensitivity to RYR1 agonists, BS3_Supporting (PMID:27857962). This variant segregates with MHS in three individuals, PP1 (PMID:25658027, PMID:30236257). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.533 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: PS4_Moderate, PM1, PP1, BS2_Moderate, BS3_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024581/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:3094 biolink:causes MONDO:0007646 infores:monarchinitiative not_provided not_provided HGNC:4912 MONDO:0007646 uuid:5f8819b2-e038-4f40-b20e-9f8cc7068d62 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27999 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0001824 infores:hetionet CHEBI:29013 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0011991 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151740 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0234987 infores:hetionet CHEBI:15552 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0018965 infores:hetionet NCBIGene:2313 biolink:causes MONDO:0054577 infores:monarchinitiative not_provided not_provided HGNC:3749 MONDO:0054577 uuid:4a28d9f8-4ac5-4505-8abe-aa7db3c51b1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135929 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0020651 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022658 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042109 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0518015 infores:hetionet CHEBI:63616 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0011168 infores:hetionet CHEBI:101085 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0220981 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0020517 infores:hetionet CAID:CA202241 biolink:causes MONDO:0100437 infores:clingen CAID:CA202241 MONDO:0100437 PMID: Benign BA1 PP3, BP4 NM_001034853.2(RPGR):c.223A>G (p.Ile75Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 75. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01338 among hemizygous individuals, with 5304 variant alleles / 396,459 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.000005 (BA1). The computational predictor REVEL gives a score of 0.218, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives a delta score of 0.12 for acceptor gain, which falls in the intermediate range above the ClinGen X-linked IRD VCEP recommended BP4 threshold of <0.1 but lower than the PP3 threshold of >0.2, so neither in silico code is met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA202241/MONDO:0100437/106 2025-08-04 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:3996 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0015230 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151717 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0178421 infores:hetionet CHEBI:3996 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0016204 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037274 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0011849 infores:hetionet CHEBI:3314 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0018790 infores:hetionet CHEBI:261649 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C1384666 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0857353 infores:hetionet CHEBI:15854 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0876994 infores:hetionet CHEBI:31644 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1142412 infores:hetionet GO:1905796 biolink:causes GO:0044782 infores:ubergraph knowledge_assertion manual_agent GO:1905796 GO:0044782 CHEBI:6847 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0027497 infores:hetionet CHEBI:4024 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0042401 infores:hetionet CHEBI:71223 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0232462 infores:hetionet CHEBI:8768 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0043352 infores:hetionet CHEBI:45863 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085649 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027339 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0860871 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0559031 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0020517 infores:hetionet CHEBI:37924 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0231274 infores:hetionet CHEBI:64045 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0027849 infores:hetionet CAID:CA410202557 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202557 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.463G>A (p.Val155Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202557/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41423 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020625 infores:hetionet CHEBI:261649 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0237849 infores:hetionet CHEBI:480999 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1384353 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0589616 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0589616 infores:hetionet CHEBI:28864 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0002792 infores:hetionet CAID:CA145894 biolink:causes MONDO:0001586 infores:clingen CAID:CA145894 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.99T>G variant in IDUA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 33 (p.His33Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.9605 (65474/68164 alleles; 31451 homozygotes; Grpmax Filtering AF 95% confidence = 0.9544) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92651). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145894/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63580 biolink:causes UMLS:C2609174 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2609174 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022354 infores:hetionet NCBIGene:3273 biolink:causes MONDO:0013143 infores:monarchinitiative not_provided not_provided HGNC:5181 MONDO:0013143 uuid:b662e7e5-c85e-4595-9dd2-84d35abbc027 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes UMLS:C0520729 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0520729 infores:hetionet CHEBI:135613 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0027497 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0004096 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027441 infores:hetionet CHEBI:7445 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0206061 infores:hetionet CHEBI:6916 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0428974 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0541832 infores:hetionet CHEBI:6367 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018965 infores:hetionet CHEBI:2637 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0001925 infores:hetionet CHEBI:8863 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0000731 infores:hetionet CHEBI:50730 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0011615 infores:hetionet CHEBI:3419 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0039070 infores:hetionet CHEBI:31644 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085614 infores:hetionet CHEBI:68478 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151908 infores:hetionet CHEBI:50673 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0003862 infores:hetionet CHEBI:3485 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0011606 infores:hetionet CHEBI:8863 biolink:causes HP:6000070 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151684 infores:hetionet CAID:CA229327 biolink:causes MONDO:0009861 infores:clingen CAID:CA229327 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4_Moderate PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF:0.00006.; PP4_Moderate: seen in classic and mild PKU patients. BH4 deficiency excluded.. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229327/MONDO:0009861/006 2018-08-07 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75045 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C2937358 infores:hetionet CL:0002187 biolink:causes MONDO:0005341 infores:ubergraph knowledge_assertion manual_agent CL:0002187 MONDO:0005341 CHEBI:408174 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0149514 infores:hetionet CAID:CA255115 biolink:causes MONDO:0010602 infores:clingen CAID:CA255115 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4 The c.1649G>A (p.Arg550His) variant is absent from males in gnomAD v2.1.1. It is reported in heterozygotes at a frequency of 0.00002442 (2/81904 alleles) in the non-Finnish European population. At least 35 male individuals with mild hemophilia A are found in the literature and internal laboratory data with the Arg550His variant. More cases are available in the literature (EAHAD reports 64 patients), however >8 probands have been counted towards PS4_VeryStrong and one for PP4_moderate. This variant is associated with discrepant factor VIII activity levels with some individuals having normal levels on one-stage assays and levels in the mild hemophilia range on a chromogenic, or two-stage, assay (CDC Champs/EAHAD databases). Some individuals have been reported to have a history of inhibitor formation to factor replacement products (CDC Champs/EAHAD databases). The c.1649G>A (p.Arg550His) missense variant has a REVEL score of 0.78 (>0.6). Other variants at the same residue, Arg550Cys, Arg550Gly, Arg550Leu and Arg550Pro have been reported, but evidence from these variant curations has not been used in classifying the Arg550His variant. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_VeryStrong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255115/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:6078 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0009760 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011053 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151735 infores:hetionet CAID:CA397725976 biolink:causes MONDO:0008723 infores:clingen CAID:CA397725976 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 The c.1827+1G>A (NM_000018.4) variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 19. It is predicted to cause skipping of biologically-relevant-exon 19/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed a positive newborn screen followed by reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 30194637). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397725976/MONDO:0008723/021 2024-04-09 2024-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31348 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0021368 infores:hetionet CHEBI:31236 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235198 infores:hetionet CHEBI:3371 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0151698 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0227791 infores:hetionet CHEBI:135285 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0019158 infores:hetionet CHEBI:135342 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1384606 infores:hetionet CHEBI:9434 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0232462 infores:hetionet CHEBI:5130 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013428 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0036572 infores:hetionet CAID:CA16609804 biolink:causes MONDO:0007750 infores:clingen CAID:CA16609804 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP4 BP4, PP3 The NM_000527.5(LDLR):c.510C>A (p.Asp170Glu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 March 2025. The supporting evidence is as follows:PM2: PopMax MAF = 0.00002664 (0.002664%) in African/African American exomes (gnomAD v4.1.0).PM1: Variant meets PM2 and is missense in exon 4.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill Simon Broome criteria for possible FH (1 case from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case meeting Simon Broome criteria for possible FH in PMID 27824480 (Gabčová et al., 2017)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609804/MONDO:0007750/013 2025-03-09 2025-03-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3219 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016397 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2363731 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0020456 infores:hetionet NCBIGene:79784 biolink:causes MONDO:0010915 infores:monarchinitiative not_provided not_provided HGNC:23212 MONDO:0010915 uuid:402782e0-2de5-43e3-b6cb-8f49afc438b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45951 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0023530 infores:hetionet CHEBI:8356 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018926 infores:hetionet CHEBI:9448 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0017178 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020621 infores:hetionet CHEBI:9654 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0600125 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0015230 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0178298 infores:hetionet CHEBI:16347 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0002871 infores:hetionet CHEBI:5118 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0423791 infores:hetionet CHEBI:7494 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0030794 infores:hetionet CHEBI:17698 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0017675 infores:hetionet CHEBI:7936 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151905 infores:hetionet CHEBI:4708 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0917801 infores:hetionet CHEBI:6375 biolink:causes MONDO:0000702 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0400821 infores:hetionet CHEBI:6690 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0000729 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151971 infores:hetionet CAID:CA012936 biolink:causes MONDO:0005045 infores:clingen CAID:CA012936 MONDO:0005045 PMID:15528230PMID:12081993PMID:27532257PMID:16267253PMID:15528230PMID:24510615PMID:12081993PMID:27532257 Pathogenic PP1_Strong, PM1, PM2, PS4 The c.2717A>G (p.Asp906Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:12081993; PMID:15528230; PMID:16267253; PMID:24510615; Partners LMM ClinVar SCV000059468.5). This variant segregated with disease in 10 affected individuals (PP1_Strong; PMID:12081993; PMID:15528230). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012936/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68845 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0017178 infores:hetionet CHEBI:5959 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018681 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1145628 infores:hetionet CHEBI:53760 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0027796 infores:hetionet CHEBI:32888 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0002170 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019360 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0019158 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0018802 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020649 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0392025 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0277925 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009806 infores:hetionet CHEBI:6129 biolink:causes NCIT:C34938 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0032788 infores:hetionet CHEBI:5855 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0016204 infores:hetionet CHEBI:60761 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0013922 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0011849 infores:hetionet CAID:CA229656 biolink:causes MONDO:0009861 infores:clingen CAID:CA229656 MONDO:0009861 PMID:27121329PMID:27121329 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.613G>A (p.Glu205Lys) variant in PAH has been reported in 2 individuals with mild-moderate and classic PKU, in trans with pathogenic variant p.Arg243* in both patients (PMID: 27121329). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229656/MONDO:0009861/006 2020-06-01 2020-06-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0022107 infores:hetionet CHEBI:553473 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0151872 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027441 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0014549 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021400 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009376 infores:hetionet CHEBI:6129 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0019080 infores:hetionet CHEBI:15940 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151610 infores:hetionet CHEBI:8802 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0013604 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042035 infores:hetionet CHEBI:5613 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0002453 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0232409 infores:hetionet GO:2000172 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000172 GO:0007275 CHEBI:4710 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0015397 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0276908 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0276908 infores:hetionet CAID:CA412379054 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379054 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000330.4(RS1):c.37C>A (p.Leu13Ile) is a missense variant encoding the substitution of leucine with isoleucine at position 13. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.474, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of <0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379054/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true UMLS:C0065374 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0017152 infores:hetionet CHEBI:6076 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C2973529 infores:hetionet UMLS:C0903898 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0030252 infores:hetionet CAID:CA10014195 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014195 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1171G>C (p.Ala391Pro) is a missense variant which has a REVEL score < 0.50 (0.103), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014195/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:66901 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0008033 infores:hetionet CHEBI:7931 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020598 infores:hetionet CAID:CA320248519 biolink:causes MONDO:0011071 infores:clingen CAID:CA320248519 MONDO:0011071 PMID: Likely Benign BS1 BP1, BP4, BP3, BP5, BP7, PM3, PM1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.*3582G>A is a 3' UTR variant, which has an MAF of 0.01297 (0.1297%, 23/17732 alleles) in the Admixed American subpopulation of the gnomAD v4.1.0 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320248519/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63617 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018802 infores:hetionet CHEBI:134743 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0009806 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0687707 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151544 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0151505 infores:hetionet CAID:CA5689600 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689600 MONDO:0021060 PMID: Benign BS4, BS2, BP4 PS4, PM1, BS1, PP1, PP2, BA1 The c.610A>G (p.Ile204Val) variant in SHOC2 is present in 0.01241% (16/128978) of non-Finnish European alleles in gnomAD. This variant was observed in 3 unaffected individuals as well as several individuals with varying clinical presentations lacking clear associations with a RASopathy (BS2; Invitae internal data, SCV000289856.3; Institut Universitaire d'Hématologie internal data). It was absent from the symptomatic sister of 1 proband with Noonan syndrome who carried this variant (BS4; Institut Universitaire d'Hématologie internal data). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the p.Ile204Val variant meets criteria to be classified as benign for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP Criteria applied (PMID:29493581): BS2, BS4, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689600/MONDO:0021060/004 2020-01-13 2020-01-13 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:28177 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0232493 infores:hetionet CHEBI:61049 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0270612 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0021053 infores:hetionet CHEBI:8871 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0012569 infores:hetionet CAID:CA916083903 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083903 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2340del (p.Ala781ArgfsTer?) is a frameshift variant due to a 1-nucleotide deletion introducing a premature stop codon after 34 amino acids within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 4 apparently unrelated probands (PMID: 14564670, PMID: 34985506, PMID: 23372056, PMID: 31953110, PMID: 21857984). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. The variant has been reported to segregate through at least 3 meioses in one family (PP1_moderate; PMID: 21857984). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083903/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports GO:1905210 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:1905210 GO:0070887 CAID:CA658658494 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658494 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP4, PP1, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1948_1949dup p.(Ile651fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658494/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:61049 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0014742 infores:hetionet CHEBI:42820 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0015967 infores:hetionet CHEBI:10101 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151970 infores:hetionet GO:0055021 biolink:causes GO:0048738 infores:ubergraph knowledge_assertion manual_agent GO:0055021 GO:0048738 CHEBI:53691 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0858797 infores:hetionet CHEBI:3127 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0162529 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0233494 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006947 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0020545 infores:hetionet CHEBI:5296 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0015230 infores:hetionet CHEBI:29688 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0017675 infores:hetionet CAID:CA5416773 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416773 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting PM5 The c.587G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Glutamine at amino acid 196 (p.Arg196Gln).The filtering allele frequency (the upper threshold of the 95% CI of 34/1180044 alleles) of the c.587G>A variant in DCLRE1C is 0.00002074 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416773/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:54931 biolink:causes MONDO:0014856 infores:monarchinitiative not_provided not_provided HGNC:26022 MONDO:0014856 uuid:c7d803f5-f1dd-45f3-8e00-86fbb200ffa2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59582 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0263449 infores:hetionet CHEBI:68478 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0030196 infores:hetionet CHEBI:9328 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0000737 infores:hetionet NCBIGene:51506 biolink:causes MONDO:0060752 infores:monarchinitiative not_provided not_provided HGNC:26941 MONDO:0060752 uuid:7928065c-1480-46f3-9fdf-45a93250474a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63613 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0235996 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0234215 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0522224 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042769 infores:hetionet CHEBI:39585 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0917801 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027932 infores:hetionet NCBIGene:25778 biolink:causes MONDO:0010046 infores:monarchinitiative not_provided not_provided HGNC:29043 MONDO:0010046 uuid:e7d0cf46-5b55-443f-8b63-5dea2facad72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68595 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0085649 infores:hetionet CHEBI:31643 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0023052 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030552 infores:hetionet CHEBI:92712 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0151636 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0032300 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0032300 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013395 infores:hetionet UMLS:C0065374 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0023052 infores:hetionet CHEBI:134991 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0041657 infores:hetionet CHEBI:9215 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0917801 infores:hetionet CHEBI:41879 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0035305 infores:hetionet CHEBI:2453 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0424790 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0039971 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0858318 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0858318 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002170 infores:hetionet CHEBI:63621 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018524 infores:hetionet CHEBI:135342 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0035455 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013395 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0026650 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020615 infores:hetionet CHEBI:31644 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0025222 infores:hetionet CHEBI:7931 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C1384353 infores:hetionet CHEBI:4511 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0231530 infores:hetionet CHEBI:3347 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020458 infores:hetionet CHEBI:17650 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151686 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002170 infores:hetionet CHEBI:31705 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042571 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0019061 infores:hetionet CHEBI:71255 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0242422 infores:hetionet CHEBI:31236 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030318 infores:hetionet NCBIGene:91 biolink:causes MONDO:0015278 infores:monarchinitiative not_provided not_provided HGNC:172 MONDO:0015278 uuid:e2e50759-9e71-4265-a2bf-3b0722aa9b7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027765 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235169 infores:hetionet CHEBI:3082 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0920171 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030319 infores:hetionet CHEBI:100241 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0239571 infores:hetionet CHEBI:6437 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C2363730 infores:hetionet NCBIGene:207 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:391 MONDO:0008170 uuid:a4a1b0d4-bdfe-4ccc-b8e5-a6c3cda1f277 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82941 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0029445 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0877661 infores:hetionet CHEBI:8768 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2937358 infores:hetionet CHEBI:39867 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085932 infores:hetionet CHEBI:15640 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0011603 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0021400 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0009324 infores:hetionet CHEBI:3698 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0009763 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033575 infores:hetionet CAID:CA658658781 biolink:causes MONDO:0007750 infores:clingen CAID:CA658658781 MONDO:0007750 PMID: Uncertain Significance BP4 BP1, BP3, BP2, BA1, PS4, PS2, PS3, PS1, BP7, BP5, BS1, BS4, BS3, PM4, PM3, PM1, PM5, PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.2231_2232delinsAG (p.Arg744Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows: BP4 - No REVEL, splicing evaluation needed.Functional studies are not availableA) variant not on limits.B) variant is exonic and at least 50bp downstream from the canonical acceptor site and creates de novo AG site.MES scores: de novo variant = -3.1; canonical acceptor = 8.76.Ratio de novo variant/canonical acceptor =-3.1/8.76 = -0.35 -> it is below 0.8. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658781/MONDO:0007750/013 2022-05-27 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4909 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0518015 infores:hetionet CHEBI:68575 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0010200 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0558368 infores:hetionet NCBITaxon:11320 biolink:causes MONDO:0005812 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:11320 MESH:D007251 DB03843_MESH_D007251_1DB11888_MESH_D007251_1DB00558_MESH_D007251_1 CHEBI:49662 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0032326 infores:hetionet CHEBI:31980 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0002994 infores:hetionet CHEBI:8028 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0004096 infores:hetionet CHEBI:9927 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0011991 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004936 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0006826 infores:hetionet CAID:CA014215 biolink:causes MONDO:0007947 infores:clingen CAID:CA014215 MONDO:0007947 PMID: Benign BP2, BA1, BP5 PM2, PP2, PP3, PP1, BP1, BP4, PS1, PS3, PS4, PM5, PM1, BS1, BS3 The NM_00138 c.3509G>A, is a missense variant in FBN1 predicted to cause a substitution of an arginine acid by histidine at amino acid 1170 (p.Arg1170His). This variant has been previously reported in several apparently unrelated individuals with Marfan syndrome (PMID 26787436, internal data), incomplete Marfan syndrome, including with skeletal features and/or mitral valve prolapse (PMID 7870075, 9837823, 17418587, 17627385, 17657824), in individuals with isolated thoracic aortic aneurysm and/or dissection (internal data) and in other phenotypes like arterial dissection and venous bleeding (internal data). This variant was found to segregate with disease in seven affected individuals with incomplete Marfan syndrome from three families (PMID 7870075, 9837823, internal data). This variant has been found to co-occur with different pathogenic variants in FBN1 (BP2), TGFBR1, and TGFRB2 (BP5) (internal data). This variant has been identified in 286 individuals of European non-Finnish origin (MAF: 0.2%) (BA1; https://gnomad.broadinstitute.org/, version 2.1.1). The variant in FBN1 has been reported 21 times in ClinVar: 16 times as likely benign and 5 times as uncertain significance (Variation ID: 16451). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.502). Functional studies, including in-vitro splicing analysis, found that this variant had no impact on splicing (PMID 21895641, 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1, BP2, BP5. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA014215/MONDO:0007947/022 2023-02-01 2023-02-01 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50742 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020565 infores:hetionet CHEBI:135888 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0011603 infores:hetionet CAID:CA377784475 biolink:causes MONDO:0017623 infores:clingen CAID:CA377784475 MONDO:0017623 PMID: Likely Pathogenic PP1, PP2, PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate NM_000314.8(PTEN):c.106G>A (p.Gly36Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.69 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_M: Probands with phenotype specificity score of 2-3.5 (PMID: 32442409, internal laboratory contributor: SCV002061526.2).PM2_P: Absent in gnomAD.PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (internal laboratory contributor: SCV002061526.2).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.995). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377784475/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:39585 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0015230 infores:hetionet CHEBI:8871 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020433 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0025362 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0595878 infores:hetionet CHEBI:10023 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0035222 infores:hetionet NCBIGene:54014 biolink:causes MONDO:0957396 infores:monarchinitiative not_provided not_provided HGNC:12760 MONDO:0957396 uuid:58735530-3057-466f-a53b-2c9e107ae359 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3061 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0030252 infores:hetionet NCBIGene:23322 biolink:causes MONDO:0030862 infores:monarchinitiative not_provided not_provided HGNC:29168 MONDO:0030862 uuid:770a4bb6-d95f-44d3-9ae3-2a07e4ce6f59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15854 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0012739 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0044872 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013363 infores:hetionet CHEBI:116278 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0231218 infores:hetionet CHEBI:2682 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0035229 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0700184 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0232459 infores:hetionet CHEBI:76010 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0017178 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023530 infores:hetionet NCBIGene:27086 biolink:causes MONDO:0013352 infores:monarchinitiative not_provided not_provided HGNC:3823 MONDO:0013352 uuid:fa991e65-0aea-4185-8630-bfd20a456eff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0038999 infores:hetionet NCBIGene:116085 biolink:causes MONDO:0020728 infores:monarchinitiative not_provided not_provided HGNC:17989 MONDO:0020728 uuid:396d663c-b514-4f9f-9a20-8b601c62e1fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0392702 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0150450 infores:hetionet CHEBI:9737 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0311468 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0853705 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0853705 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005173 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022602 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0003864 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0020651 infores:hetionet CHEBI:63611 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0031154 infores:hetionet CHEBI:10102 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0037672 infores:hetionet CHEBI:3723 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030196 infores:hetionet CHEBI:404903 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013404 infores:hetionet CAID:CA409104248 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104248 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS2_Moderate, PM1 PS4 The c.270C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to tryptophan at codon 90 (p.(Cys90Trp)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors). One of these individuals had a clinical picture consistent with HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative diabetes antibodies), and this variant was detected as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate, PP4_Moderate; internal lab contributors). In summary, c.270C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PP4_Moderate, PM2_Supporting, PM1, PS2_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104248/MONDO:0015967/085 2024-11-26 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6128 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0041834 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0160390 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0013415 infores:hetionet CHEBI:8890 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0041834 infores:hetionet CHEBI:75984 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0085636 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0853026 infores:hetionet CHEBI:3504 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0235266 infores:hetionet CHEBI:27899 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0038362 infores:hetionet GO:0045823 biolink:causes HP:0001649 infores:drugmechdb knowledge_assertion manual_agent GO:0045823 MESH:D013610 DB12212_MESH_D013610_1 CHEBI:4907 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0038325 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0037274 infores:hetionet CHEBI:63611 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0037763 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009806 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002871 infores:hetionet NCBIGene:5664 biolink:causes MONDO:0011743 infores:monarchinitiative not_provided not_provided HGNC:9509 MONDO:0011743 uuid:f6794197-2850-43f9-a59b-bc1e61976cdf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020676 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042373 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020456 infores:hetionet CHEBI:83531 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0009806 infores:hetionet CHEBI:520985 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0231528 infores:hetionet CHEBI:44032 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151908 infores:hetionet CAID:CA410203336 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203336 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, BS2, PP1, PP2, PP3, PP4 The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27931139). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203336/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6717 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0038325 infores:hetionet CHEBI:8404 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0220870 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0795692 infores:hetionet CHEBI:16469 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0030794 infores:hetionet CHEBI:107736 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0009676 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0012833 infores:hetionet CHEBI:8888 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011206 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0003123 infores:hetionet CHEBI:15940 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0002994 infores:hetionet CHEBI:6456 biolink:causes UMLS:C2939427 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C2939427 infores:hetionet CHEBI:3814 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0014724 infores:hetionet CHEBI:135613 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0020458 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0018799 infores:hetionet CHEBI:9667 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C2047937 infores:hetionet CAID:CA2573054928 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573054928 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.830del (p.Pro277fs) is a frameshift variant predicted to undergo NMD (PVS1 CNV tree). This variant is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573054928/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3723 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1443060 infores:hetionet CHEBI:4877 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C2047937 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0553702 infores:hetionet CHEBI:68554 biolink:causes HP:0002493 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C1504405 infores:hetionet CHEBI:63619 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2047937 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0005940 infores:hetionet CHEBI:2922 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0011991 infores:hetionet CHEBI:9605 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0020517 infores:hetionet CHEBI:64045 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0027947 infores:hetionet CAID:CA10014272 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014272 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS4, BS3, BP5, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.900G>A (p.Thr300=) is a synonymous variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP score -2.86554 ≤2.0) meeting BP7. This variant is a synonymous variant therefore no REVEL score is applicable and SpliceAI is ≤0.20 (0.00) (BP4). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014272/MONDO:0011071/008 2022-04-08 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0657912 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0162848 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0005741 infores:hetionet CHEBI:63620 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0025222 infores:hetionet CHEBI:63612 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0029118 infores:hetionet CHEBI:8871 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0403673 infores:hetionet CHEBI:64355 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011124 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0019158 infores:hetionet CHEBI:2549 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0023067 infores:hetionet CHEBI:34385 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0008031 infores:hetionet CHEBI:6339 biolink:causes UMLS:C1868912 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1868912 infores:hetionet CHEBI:66964 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0004134 infores:hetionet CHEBI:7454 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0037763 infores:hetionet CHEBI:9150 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0016382 infores:hetionet CHEBI:32588 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0016204 infores:hetionet NCBIGene:7293 biolink:causes MONDO:0014268 infores:monarchinitiative not_provided not_provided HGNC:11918 MONDO:0014268 uuid:dec9697d-d8ce-4092-a2ca-d7fd642eb007 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:51241 biolink:causes MONDO:0859160 infores:monarchinitiative not_provided not_provided HGNC:20213 MONDO:0859160 uuid:ecc13ba2-7be8-41c1-82db-f7af923c57da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:421707 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0018213 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018801 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020651 infores:hetionet CHEBI:9130 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0162285 infores:hetionet CHEBI:47780 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C3665347 infores:hetionet CHEBI:8888 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033036 infores:hetionet CHEBI:3756 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0022107 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1112214 infores:hetionet CAID:CA915940605 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940605 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.2031_2041del in exon 13/15 is a frameshift variant creating p.(Asp677Glufs*4), where it is predicted to cause a premature stop codon and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This is thought to be a founder variant in the Iraqi-Jewish population and has been identified in at least 12 patients from 9 kindreds (PMID: 2014236). At least two patients (Patients 2 and 4 in PMID: 30078718) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent as measured by flow cytometry. Patient 2 is homozygous for the variant (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 01/18/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940605/MONDO:0100326/011 2022-04-07 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UNII:5V9KLZ54CY biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0234215 infores:hetionet CHEBI:87715 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0015230 infores:hetionet CHEBI:47499 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0085631 infores:hetionet CHEBI:7565 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0009421 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0020538 infores:hetionet CHEBI:28901 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018926 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0235295 infores:hetionet CAID:CA10014290 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014290 MONDO:0011071 PMID: Benign BP4, BA1 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This missense variant has been published in Taiwanese patients with CEBPA double-mutated, cytogenetically normal-AML (PMID: 29773598), pediatric T-ALL (PMID: 30280491), and ovarian cancer (PMID: 31761620), although germline origin was unknown for these cases. However, the variant has an MAF of 0.1854% (37/19952 alleles) in the East Asian subpopulation of the gnomAD cohort, which is ≥ 0.0015 (0.15%) (BA1). It also has a REVEL score <0.50 (0.326) and SpliceAI does not predict (Δ scores ≤ 0.20) a significant impact on the canonical splice sites or the creation of putative cryptic splice sites (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014290/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6456 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0161479 infores:hetionet CHEBI:51041 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0014868 infores:hetionet CHEBI:6958 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0006266 infores:hetionet CHEBI:8327 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0011991 infores:hetionet CHEBI:499361 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0009763 infores:hetionet CHEBI:8764 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0242528 infores:hetionet CHEBI:50841 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0427086 infores:hetionet CAID:CA2580616387 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580616387 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-25_614-16dup is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616387/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6067 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0547030 infores:hetionet CAID:CA013589 biolink:causes MONDO:0005045 infores:clingen CAID:CA013589 MONDO:0005045 PMID: Uncertain Significance PP3, PP1 PM2, PM1, BA1, PS4, BS1 NM_000258.3(MYL3):c.170C>G (p.Ala57Gly) - This variant has been reported in individuals with HCM (PMIDs: 11174330, 20641121, 31513939, 32380161, 324928950), but is not statistically increased in individuals with HCM compared to controls [OR lower 95% CI <5] with respect to autosomal dominant disease. Therefore, the PS4 criterion has not been applied. This variant is present in gnomAD (v2.1.1), but did not meet the threshold for PM2 or BS1. This variant segregated with HCM in 4 affected individuals from 1 family (PP1; PMID:20641121). Functional studies have been reported, but are insufficient to apply PS3 (PMID: 21885653, 22131351, 23748425, 29914921). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on PP1 and PP3. Evaluation of this variant with respect to autosomal recessive disease was outside the scope of the current specifications. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013589/MONDO:0005045/103 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0060723 biolink:causes GO:0001890 infores:ubergraph knowledge_assertion manual_agent GO:0060723 GO:0001890 CHEBI:50378 biolink:causes HP:0030249 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0014034 infores:hetionet NCBIGene:9992 biolink:causes MONDO:0012677 infores:monarchinitiative not_provided not_provided HGNC:6242 MONDO:0012677 uuid:03482d85-cb4b-4c38-a28d-48c8fabe7a05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45081 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0036572 infores:hetionet NCBIGene:50846 biolink:causes MONDO:0011766 infores:monarchinitiative not_provided not_provided HGNC:2865 MONDO:0011766 uuid:fc672d9e-d3ce-43c3-8bc9-9bb07c1226a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:5052 biolink:causes MONDO:0005961 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5052 MESH:D012852 DB00681_MESH_D012852_1 CHEBI:68534 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0027765 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0007760 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0233494 infores:hetionet CHEBI:135935 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0013404 infores:hetionet CHEBI:9763 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0002962 infores:hetionet CHEBI:53766 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0019080 infores:hetionet CHEBI:3207 biolink:causes MONDO:0015943 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0008728 infores:hetionet CHEBI:37924 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0033774 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020437 infores:hetionet CHEBI:32293 biolink:causes UMLS:C1697883 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C1697883 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151661 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151661 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0004936 infores:hetionet CHEBI:2955 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0085932 infores:hetionet CHEBI:127780 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0023530 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042401 infores:hetionet CAID:CA512341276 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341276 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BS1, BS3, BS4, PVS1, PM6, PM4, PM5, PM1, PP3, PP1 The variant NM_001754.5(RUNX1):c.1143G>A (p.Leu381=) is a synonymous change. It is not present in any population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). Furthermore, the variant has a SpliceAI score of ≤ 0.20 (SpliceAI AG: 0.01), indicating a low likelihood of affecting splicing. Evolutionary conservation prediction algorithms suggest that the site is not conserved (PhyloP score 0.342 < 2.0) or that the variant is the reference nucleotide in only one primate and/or three mammal species (BP7). Additionally, there is no previous report of this variant. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341276/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA251004 biolink:causes MONDO:0700272 infores:clingen CAID:CA251004 MONDO:0700272 PMID:31757951 Pathogenic PS4, PM5_Supporting, PVS1 PS3, BS1, PM2, PP3 The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID: 21285249, 23448497). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID: 27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PS4, PM5_Supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA251004/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8888 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018520 infores:hetionet CHEBI:4822 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0018524 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0344320 infores:hetionet CHEBI:17650 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0017160 infores:hetionet CHEBI:6801 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0020458 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0002965 infores:hetionet NCBIGene:79753 biolink:causes MONDO:0013787 infores:monarchinitiative not_provided not_provided HGNC:30587 MONDO:0013787 uuid:210ba14b-4a91-4744-958c-b031869afbaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0006266 infores:hetionet CHEBI:567361 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0014742 infores:hetionet CHEBI:45863 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0476273 infores:hetionet CHEBI:134966 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0015230 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0027651 infores:hetionet CAID:CA312294 biolink:causes MONDO:0008723 infores:clingen CAID:CA312294 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PM4, PP4_Moderate The NM_000018.4 c.507_527del (p.Met169_Gly175del) variant in ACADVL is an in-frame deletion (removes amino acids Met169_Gly175) in exon7/20 that is not predicted to impact splicing (SpliceAI: 0.0200). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0001 in Middle Eastern population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The c.507_527del variant is predicted to cause a change in the length of the protein (p. Met169_Gly175del) due to an in-frame deletion of seven amino acids in a non-repeat region (PM4). This variant is reported in the literature in two individuals affected with very long-chain acyl-CoA dehydrogenase deficiency in a heterozygous fashion, who displayed elevated C14:1 carnitine level (0.8 and 1.14 µmol/L, respectively) during newborn screening and reduced VLCAD enzyme levels in the latter one of them, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 31031081). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM4, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312294/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:52717 biolink:causes MONDO:0005828 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023860 infores:hetionet CHEBI:51041 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C1456784 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0403632 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017178 infores:hetionet CHEBI:68478 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0476273 infores:hetionet CHEBI:92998 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0006266 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006277 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0034065 infores:hetionet NCBIGene:10881 biolink:causes MONDO:0957593 infores:monarchinitiative not_provided not_provided HGNC:161 MONDO:0957593 uuid:48f12b67-4d8a-498e-8612-47143e283027 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0011615 infores:hetionet CHEBI:28593 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042510 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0340726 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0030312 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018798 infores:hetionet CAID:CA16619068 biolink:causes MONDO:0017623 infores:clingen CAID:CA16619068 MONDO:0017623 PMID: Likely Pathogenic PM6, PP2, PP3, PS4_Supporting, PM2_Supporting, PS3_Moderate PVS1, BS1, BS3, BS4, BP7, BP5, BS2, PP1, PP4, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS2 NM_000314.8(PTEN):c.947T>C (p.Leu316Pro) meets criteria to be classified as Likely Pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. ( internal laboratory contributor: SCV000565874.4)PS3_M: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.74442367.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.77)PS4_P: Proband with phenotype specificity score of 2-3.5. (PMID:30311381, internal laboratory contributor: SCV000565874.4) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619068/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5109 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0041834 infores:hetionet CHEBI:47781 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0003811 infores:hetionet NCBIGene:23746 biolink:causes MONDO:0011458 infores:monarchinitiative not_provided not_provided HGNC:359 MONDO:0011458 uuid:7a415947-1983-4fee-aef5-61b3b95290b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000007 biolink:causes MONDO:0018875 infores:clingen CAID:CA000007 MONDO:0018875 PMID: Uncertain Significance PS4, BS3, PP1_Moderate, BS2, PM2_Supporting BA1, BP4, PS3, PS1, PS2, PM5, PM1, BS1, BS4, PP4, PP3 The NM_000546.6: c.1000G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 334 (p.Gly334Arg). This variant has been reported in 11 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 23580068, 25584008, 32675277, Internal lab contributors: SCV000216886.6, SCV000545272.7). The variant has been reported to segregate with LFS-associated cancers in 5 meioses in 3 families (PP1_Moderate; PMIDs: 32675277, Internal contributor). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributors: SCV000545272.9). This variant has an allele frequency of 0.000002543 (3/1179822 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported as a putative low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277). At this time, the TP53 VCEP cannot curate variants for low-penetrance designation. In summary, this variant is classified as a variant of unknown significance for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PS4, PP1_Moderate, PM2_supporting. (Bayesian Points: -1; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000007/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8212 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0036974 infores:hetionet CHEBI:4907 biolink:causes UMLS:C0334040 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0334040 infores:hetionet CHEBI:4798 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0014591 infores:hetionet CHEBI:36791 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016204 infores:hetionet CHEBI:478164 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0030193 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042571 infores:hetionet CHEBI:63580 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020433 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026857 infores:hetionet CHEBI:92712 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0005741 infores:hetionet CHEBI:9588 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0030312 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0032461 infores:hetionet CHEBI:3215 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C3160741 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0022660 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0018939 infores:hetionet NCBITaxon:37816 biolink:causes MONDO:0000232 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:37816 MONDO:0000232 CHEBI:9123 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1443060 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1956346 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0042571 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005249 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D011014 DB01328_MESH_D011014_1DB00274_MESH_D011014_1DB01332_MESH_D011014_1DB13092_MESH_D011014_1DB01333_MESH_D011014_1DB01139_MESH_D011014_1DB00456_MESH_D011014_1DB00595_MESH_D011014_1DB00618_MESH_D011014_1DB00954_MESH_D011014_1DB01326_MESH_D011014_1 UMLS:C0009315 biolink:causes NCIT:C50524 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0520837 infores:hetionet CHEBI:94440 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0020538 infores:hetionet CHEBI:45783 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2047937 infores:hetionet NCBIGene:6785 biolink:causes MONDO:0007574 infores:monarchinitiative not_provided not_provided HGNC:14415 MONDO:0007574 uuid:ebfb91a4-0f79-4181-8dad-fbfd1bb8cba6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6847 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0003123 infores:hetionet CHEBI:28787 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0600142 infores:hetionet CHEBI:63580 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0026858 infores:hetionet CHEBI:6532 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0012359 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0234215 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0429029 infores:hetionet NCBIGene:5193 biolink:causes MONDO:0013927 infores:monarchinitiative not_provided not_provided HGNC:8854 MONDO:0013927 uuid:7612e523-d171-43bf-9640-cabdb9a1b4ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1384353 infores:hetionet CHEBI:521033 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0403673 infores:hetionet CHEBI:681848 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0016382 infores:hetionet NCBIGene:57679 biolink:causes MONDO:0011663 infores:monarchinitiative not_provided not_provided HGNC:443 MONDO:0011663 uuid:55b81ab2-003f-42f4-9c47-4ec7e797c6d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042769 infores:hetionet CHEBI:83804 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0428977 infores:hetionet CHEBI:6076 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0022346 infores:hetionet CAID:CA214292 biolink:causes MONDO:0015967 infores:clingen CAID:CA214292 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 The c.1A>G variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Val) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): PVS1, PM2_Supporting, PP4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214292/MONDO:0015967/017 2022-03-04 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:43968 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0178298 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020538 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020517 infores:hetionet CHEBI:135736 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0558401 infores:hetionet CHEBI:3749 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0232849 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151849 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0175167 infores:hetionet CHEBI:15407 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0235146 infores:hetionet CHEBI:2682 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0242184 infores:hetionet CHEBI:91834 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0085624 infores:hetionet CHEBI:70707 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0040822 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042109 infores:hetionet CHEBI:136040 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0011991 infores:hetionet CAID:CA386959674 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959674 MONDO:0015967 PMID:18003757 Uncertain Significance PM2_Supporting, PM1_Supporting, PP3, PP4 PS4 The c.410C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to serine at codon 137 (p.(Thr137Ser)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757, internal lab contributors). However, one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). Taken together, this variant meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0, approved 6/30/2025): PP3, PP4, PM1_Supporting, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959674/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:1904259 biolink:causes GO:0032989 infores:ubergraph knowledge_assertion manual_agent GO:1904259 GO:0032989 CAID:CA241824 biolink:causes MONDO:0007113 infores:clingen CAID:CA241824 MONDO:0007113 PMID: Uncertain Significance PP3, PM2_Supporting The c.3-14_3-7del variant in UBE3A is absent from gnomAD (PM2_supporting). Splice prediction analysis using multiple computational tools suggests a possible impact to splicing (PP3). In summary, the c.3-14_3-7del variant in UBE3A is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA241824/MONDO:0007113/016 2021-05-18 2021-05-18 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:28830 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0011615 infores:hetionet CAID:CA2580098682 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098682 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-20C>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.44) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098682/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA273607 biolink:causes MONDO:0021060 infores:clingen CAID:CA273607 MONDO:0021060 PMID: Likely Pathogenic PM1, PM6, PM2, PP2, PS4_Supporting The c.175_176delinsCT (p.Ala59Leu) in HRAS was absent from gnomAD (PM2; PMID: 29493581). It has been identified as a de novo occurrence (parentage unconfirmed) in 1 individual with clinical features of a RASopathy (PM6, PS4_Supporting; SCV000205760.4, PMID: 26918529). Furthermore, the p.Ala59Leu variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of HRAS (PM1; PMID 29493581). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PM1, PM2, PM6, PS4_Supporting. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA273607/MONDO:0021060/004 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:2569 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C1141861 infores:hetionet CHEBI:75722 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085635 infores:hetionet CHEBI:8093 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0027497 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085096 infores:hetionet CHEBI:2904 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0011991 infores:hetionet CAID:CA482164157 biolink:causes MONDO:0015967 infores:clingen CAID:CA482164157 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM4_Supporting, PP4 The c.676_678del variant in the HNF1 homeobox A gene, HNF1A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 226 (p.(Lys226del)) within exon 3 of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). The c.676_678del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Lastly, this variant was identified in an individual with a clinical history specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.676_678del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PM1_Supporting, PM2_Supporting, PM4_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA482164157/MONDO:0015967/017 2025-10-28 2025-10-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63630 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0233472 infores:hetionet CAID:CA294768 biolink:causes MONDO:0100039 infores:clingen CAID:CA294768 MONDO:0100039 PMID: Likely Benign BS2, BP4 BS1, PM2, BA1 RS1 (NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the non-coding 3' region of the main CDKL5 transcript (NM_ 001323289.2). The c.2739 G>C (p.Gln913His) variant in CDKL5 transcript (NM_003159.3) (RS1 c.326+1159 C>G) is observed in at least 2 unaffected individuals (GeneDx and Invitae internal databases) (BS2). Computational analysis prediction tools suggest that the c.2739 G>C variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2739 G>C variant in the alternate CDKL5 transcript (NM_003159.3) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294768/MONDO:0100039/034 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Contradicts true CHEBI:70718 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0438717 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0034882 infores:hetionet CAID:CA512232141 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232141 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1371C>A (p.Gly457=) is a synonymous variant. In summary, this variant meets criteria to be classified as likely benign. REVEL score not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.120819 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232141/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15552 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0039231 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042109 infores:hetionet CHEBI:188986 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0015672 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0233459 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085681 infores:hetionet CAID:CA16618069 biolink:causes MONDO:0021056 infores:clingen CAID:CA16618069 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PM2_Supporting, PS3_Moderate The c.835-8A>G variant in APC is an intronic variant 8 nucleotides upstream of the splice acceptor site for exon 9. The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 8 of APC (PP3). RNA data from carrier blood demonstrated aberrant splicing leading to a frameshift (PS3_Moderate; PMID 20649969; PMID 21779980). This alteration was identified in multiple individuals with a personal and/or family history consistent with familial adenomatous polyposis (PS4_Moderate; PMID 20649969, PMID 21779988; Ambry and GeneDx Internal Data). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_Moderate; PS4_Moderate; PM2_Supporting, PP3 (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618069/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8378 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0518015 infores:hetionet NCBIGene:4286 biolink:causes MONDO:0007077 infores:monarchinitiative not_provided not_provided HGNC:7105 MONDO:0007077 uuid:282b8da3-2da0-463d-9f81-e69cf0a12d63 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7581 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0020517 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0043250 infores:hetionet CHEBI:724125 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0007117 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0007642 infores:hetionet GO:0045664 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0045664 GO:0007399 CHEBI:3207 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013378 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013595 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0237326 infores:hetionet CHEBI:50859 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020639 infores:hetionet CHEBI:8707 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0522055 infores:hetionet CHEBI:17334 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0232487 infores:hetionet CHEBI:87681 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0015230 infores:hetionet CHEBI:16467 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0750876 infores:hetionet GO:2000018 biolink:causes GO:0046661 infores:ubergraph knowledge_assertion manual_agent GO:2000018 GO:0046661 CHEBI:47780 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0025061 infores:hetionet CAID:CA410677679 biolink:causes MONDO:0009276 infores:clingen CAID:CA410677679 MONDO:0009276 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PM3, PP1 The NM_000407.5:c.524T>C variant in GP1BB is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 175. At least one patient (Patient K3 in PMID: 28064200, also referred to in BRIDGE database as TG0767 or RVV000000P) with this variant had an abnormal aggregation response to ristocetin but normal response to ADP, Collagen, Arachidonic Acid, and Epinephrine, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had reduced expression of GPIb (with CD42b marker), macrothrombocytopenia, and mild bleeding (i.e., menorrhagia) which is consistent with Bernard-Soulier syndrome (PP4). The computational predictor REVEL gives a score of 0.713, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). The Grpmax filtering allele frequency in gnomaDv4.1 is 0.00004474 (based on 63/1124544 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PP3 and PM2_Supporting (VCEP specifications v1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410677679/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6775 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0919715 infores:hetionet NCBITaxon:746128 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:746128 GO:0006954 DB00860_MESH_D001229_1 CHEBI:50841 biolink:causes HP:0030187 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0701824 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0020517 infores:hetionet CHEBI:7496 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020473 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235416 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042109 infores:hetionet CHEBI:3441 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0271650 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042075 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031542 infores:hetionet NCBITaxon:5722 biolink:causes MONDO:0030705 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5722 MONDO:0030705 CHEBI:474180 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0221752 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0003123 infores:hetionet CAID:CA038311 biolink:causes MONDO:0007750 infores:clingen CAID:CA038311 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP1, PP4 PS4, PM5 The NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.01337% in East Asian exomes/genomes (gnomAD v4.1.0).PP3: REVEL score = 0.807.PP4: 1 case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France.PP1: Variant segregates with FH phenotype in 2 informative meioses from 1 family (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France): 1 affected family member has the variant and 1 non-affected family member does not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038311/MONDO:0007750/013 2025-02-20 2025-06-17 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63577 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0233472 infores:hetionet CHEBI:7565 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0036974 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0424813 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0424813 infores:hetionet CHEBI:50922 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0232462 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0020517 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0542008 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0029882 infores:hetionet CAID:CA024099 biolink:causes MONDO:0018493 infores:clingen CAID:CA024099 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with serine at codon 4668 of the RYR1 protein, p.(Pro4668Ser). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00000799, a frequency consistent with pathogenicity for MHS. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction. This individual did not have a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 11928716), as well this individual had a second RYR1 variant, p.(Leu4838Val), that is classified as Likely Pathogenic, PS4 was not implemented. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024099/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8888 biolink:causes HP:0003468 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0158775 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0027769 infores:hetionet CAID:CA136165 biolink:causes MONDO:0018997 infores:clingen CAID:CA136165 MONDO:0018997 PMID:26918529PMID:26918529 Pathogenic PS4_Moderate, PS2, PM2, PP2, PP3 PS3, PS1, BS3, BS4, BS1, BP7, BP5, PM1, PM4, PM5, PM6, PP1, BS2, BA1, BP3, BP2, BP1, BP4 The c.512T>G (p.Val171Gly) variant has been identified in a patient with clinical features of a RASopathy in a de novo occurance (PS2; Ambry Genetics internal data, GTR ID: 61756, ClinVar SCV000742607.1) This variant has also been identified in two other independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate PMID: 26918529, Partners LMM, Invitae internal data; GTR ID: 21766, 500031 ClinVar SCV000062241.5, SCV000553263.2). Of note, a different likely pathogenic missense variant (p.Val171Ala) has been previously identified at this codon of SOS1 (PM5 not met; ClinVar 45373). The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2). Computational prediction tools and conservation analysis suggest that the p.Val171Gly variant may impact the protein (PP3). Of note, the variant occurs at the second nucleotide of exon 5 (in-frame) but no functional evidence has indicated that the variant would cause skipping of the exon. The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Moderate, PM2, PP3, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136165/MONDO:0018997/004 2019-02-28 2020-03-12 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9622 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0015672 infores:hetionet CHEBI:63617 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0004245 infores:hetionet CHEBI:64045 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0040822 infores:hetionet CHEBI:3752 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0016204 infores:hetionet CHEBI:63681 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C1456784 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0015397 infores:hetionet CHEBI:45863 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0033774 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0234972 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0234972 infores:hetionet CHEBI:8364 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0004093 infores:hetionet NCBIGene:19 biolink:causes MONDO:0008783 infores:monarchinitiative not_provided not_provided HGNC:29 MONDO:0008783 uuid:2507f310-95ab-40be-bf35-710ff9d4d5ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66876 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0020615 infores:hetionet GO:0140885 biolink:causes GO:0038196 infores:ubergraph knowledge_assertion manual_agent GO:0140885 GO:0038196 CHEBI:4903 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C2047937 infores:hetionet CHEBI:39867 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232487 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0542184 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0426576 infores:hetionet CAID:CA294630 biolink:causes MONDO:0007113 infores:clingen CAID:CA294630 MONDO:0007113 PMID:29655203 Likely Pathogenic PP1_Moderate, PP3, PP4, PM2_Supporting, PS4_Supporting The p.Leu835Phe variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Leu835Phe variant has been observed in at least 1 other affected individual (PMID 29655203) (PS4_Supporting). The variant has been reported to segregate in three informative meioses (PP1_moderate). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu835Phe variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PP4). In summary, the p.Leu835Phe variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PS4_supporting, PP1_moderate, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294630/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:42797 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0025345 infores:hetionet CHEBI:7936 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015402 infores:hetionet CHEBI:7986 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0037036 infores:hetionet CHEBI:8346 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0013362 infores:hetionet CHEBI:32315 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0233795 infores:hetionet CHEBI:32315 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013182 infores:hetionet NCBIGene:9325 biolink:causes MONDO:0014896 infores:monarchinitiative not_provided not_provided HGNC:12310 MONDO:0014896 uuid:75201d9f-0aa2-44b7-b6c3-f86edf8c90ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63608 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1956346 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0314719 infores:hetionet CHEBI:42797 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151474 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019156 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085584 infores:hetionet CHEBI:7954 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0242429 infores:hetionet CHEBI:4495 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0220870 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0442874 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0004239 infores:hetionet CHEBI:3441 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0085610 infores:hetionet CHEBI:3698 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0023052 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233794 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0042401 infores:hetionet CHEBI:6715 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027540 infores:hetionet CHEBI:4909 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0014868 infores:hetionet CHEBI:15551 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0041657 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0004936 infores:hetionet CHEBI:4903 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0015230 infores:hetionet CHEBI:119486 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027497 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0036572 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0948765 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0948765 infores:hetionet CHEBI:8428 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0231528 infores:hetionet CHEBI:175901 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C2939420 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0474381 infores:hetionet CAID:CA251532 biolink:causes MONDO:0009861 infores:clingen CAID:CA251532 MONDO:0009861 PMID:1975559 Pathogenic PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.; PP4: G272X found on one allele of a patient with classic PKU (PMID:1975559). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251532/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA129023 biolink:causes MONDO:0005338 infores:clingen CAID:CA129023 MONDO:0005338 PMID: Likely Pathogenic PS3_Moderate, PM2_Supporting, PS4_Supporting, PP1_Strong BP7, BS1, BS3, PP3, PM4, PM5, PS1, PS2, BP4, BA1 The c.1430T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 477 (p.Ile477Asn). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.534, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Ile477Asn protein had increased insolubility, instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 20334347, 21612213, 23129764, 36267417). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. This protein has also been assessed in these other studies (PMIDs: 10545602, 11004290, 16297911, 27092720), however, the same level of evidence was not met. 34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 3 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666, ARVO Abstract), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP1_Strong, PS3_Moderate, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA129023/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5280 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0040264 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015734 infores:hetionet NCBIGene:84153 biolink:causes MONDO:0012471 infores:monarchinitiative not_provided not_provided HGNC:24116 MONDO:0012471 uuid:692add68-68e2-4727-82bf-70ee5fb45afb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235146 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0847033 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018801 infores:hetionet CAID:CA410149667 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149667 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.914G>T (p.Gly305Val) is a missense variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. It is not present in any population databases with sufficient coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score of 0, allowing for the application of BP4. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149667/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6438 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0241863 infores:hetionet CAID:CA201617 biolink:causes MONDO:0021060 infores:clingen CAID:CA201617 MONDO:0021060 PMID: Benign BA1, BP4, BS2_Supporting, BP5, BS4 The c.119G>A variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by histidine at amino acid 40 (p.Arg40His). The filtering allele frequency of this variant is 0.5265% for Admixed American chromosomes in gnomAD v4, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). The computational predictor REVEL gives a score of 0.281, which is below the threshold of 0.3 and does not predict a damaging effect on RAF1 function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease and did not segregate with disease in affected family members (BP5, BS4; GeneDx internal data; GTR ID: 26957; SCV000171283.11). Additionally this variant was identified in multiple healthy individuals (BS2_P, Eurofins, SCV000227278.5; Illumina, SCV000440638.3; Ambry Genetics, SCV000736788.4). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BS4, BS2_supporting, BP4, BP5 (Specification Version 2.1, 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA201617/MONDO:0021060/040 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:8425 biolink:causes MONDO:0013170 infores:monarchinitiative not_provided not_provided HGNC:6717 MONDO:0013170 uuid:c5bdec61-ebc8-48a6-8773-865d11f37c23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63622 biolink:causes MONDO:0020575 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0344432 infores:hetionet CHEBI:119486 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0041834 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0020538 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0027765 infores:hetionet CHEBI:9738 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0015230 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0917798 infores:hetionet CHEBI:15552 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0019080 infores:hetionet CHEBI:6149 biolink:causes EFO:0009510 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0262593 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020676 infores:hetionet CHEBI:50742 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0014743 infores:hetionet CHEBI:50648 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085593 infores:hetionet CHEBI:8461 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0085637 infores:hetionet CHEBI:3732 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0033774 infores:hetionet CHEBI:63599 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0031542 infores:hetionet CHEBI:50673 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0033774 infores:hetionet CHEBI:63608 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0004093 infores:hetionet CHEBI:16469 biolink:causes UMLS:C2607896 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2607896 infores:hetionet CAID:CA320250528 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250528 MONDO:0011071 PMID: Benign BA1 PS1, PS3, PS2, PS4, BP1, BP4, BP2, BP3, PM2, PVS1, PM6, BS1, BS4, BS3, BP5, BP7, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*940G>A is a 3' UTR variant. MAF of 0.002277(0.2277%, 11/4830, 152154 alleles) in the South Asian subpopulation of the gnomad v3.1.2 is cohort is ≥ 0.0015 (0.15%). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250528/MONDO:0011071/008 2022-01-20 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0020517 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021308 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020039 infores:hetionet CAID:CA392254708 biolink:causes MONDO:0012996 infores:clingen CAID:CA392254708 MONDO:0012996 PMID:27233232 Likely Pathogenic PM3, PP4_Strong, PM2_Supporting, PS3_Supporting, PM5_Supporting PP3, BP4 The NM_001482.3:c.1237C>T variant in GATM is a missense variant predicted to cause the substitution of an arginine by a tryptophan at amino acid position 413 (p.Arg413Trp). This variant has been detected in one individual with AGAT deficiency who had low guanidinoacetate in plasma and low to low-normal creatine in plasma, as well as significantly decreased creatine peak on brain MRS (PMID 26490222) (PP4_Strong). This individual was compound heterozygous for the variant and a likely pathogenic variant (p.Arg413Gln, ClinVar ID: 2446451), and the variants were confirmed in trans by parental testing (PMID 23660394) (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in HeLa cells resulted in 0% wild type AGAT activity (PMID: 27233232), indicating that this variant may impact protein function (PS3_Supporting). The computational predictor REVEL gives a score of 0.585 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function.Another missense variant c.1238G>A, (p.Arg413Gln) (PMID: 23660394, 26490222, 27233232) in the same codon has been classified as likely pathogenic for AGAT deficiency by the ClinGen CCDS VCEP (ClinVar ID: 2446451) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 598112). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM3, PM2_Supporting, PS3_Supporting, PM5_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392254708/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63618 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0014518 infores:hetionet CHEBI:75045 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0015967 infores:hetionet NCBIGene:4524 biolink:causes MONDO:0009353 infores:monarchinitiative not_provided not_provided HGNC:7436 MONDO:0009353 uuid:f1d56e3c-958f-4d99-bfe6-d1015367c083 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042023 infores:hetionet CHEBI:39669 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0033687 infores:hetionet CAID:CA412745605 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745605 MONDO:0100437 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PP4, PM5, PS4 NM_001034853.2(RPGR):c.198G>C (p.Gln66His) is a missense variant in RPGR predicted to cause substitution of glutamine with histidine at amino acid 66. At least one proband harboring this variant has received a diagnosis retinal dystrophy (ClinVar submission SCV001239432.1), however, the available phenotype details were not sufficient to evaluate specificity for RPGR-related retinopathy. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.853, which is between the ClinGen X-linked IRD VCEP thresholds of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). Another known missense variant in the same codon, NM_001034853.2:c.197A>G (p.Gln66Arg), has been reported in association with retinal dystrophy (PMID: 28838317) but has a higher Grantham score than this variant, so PM5 has not been considered. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and PP3_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745605/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Inconclusive true CHEBI:119486 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0030193 infores:hetionet CHEBI:3504 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0004093 infores:hetionet NCBIGene:779 biolink:causes MONDO:0859514 infores:monarchinitiative not_provided not_provided HGNC:1397 MONDO:0859514 uuid:924ac74d-59e0-4b78-93e7-42263f0914a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72564 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0040046 infores:hetionet CAID:CA512318576 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318576 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.765C>T (p.His255=) is a synonymous variant. This variant has a spliceAI score >0.2 (0.03) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318576/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135920 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0027497 infores:hetionet CHEBI:51380 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0221242 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0034065 infores:hetionet CHEBI:61049 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151786 infores:hetionet CHEBI:45409 biolink:causes MONDO:0010602 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019069 infores:hetionet CHEBI:68647 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0041969 infores:hetionet NCBIGene:668 biolink:causes MONDO:0012169 infores:monarchinitiative not_provided not_provided HGNC:1092 MONDO:0012169 uuid:77220fc9-c9df-4ca1-811c-90326f0420ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0438717 infores:hetionet CHEBI:8863 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0010200 infores:hetionet CHEBI:8069 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0039070 infores:hetionet CAID:CA229865 biolink:causes MONDO:0009861 infores:clingen CAID:CA229865 MONDO:0009861 PMID: Pathogenic PM5, PM3, PP4_Moderate, PM2, PS3 PP3 The c.940C>T (p.Pro314Ser) variant in PAH is absent in population databases, and is in the same codon as two previously described Pathogenic/Likely pathogenic variants (p.Pro314His and p.Pro314Thr). It has been found in trans with a pathogenic variant (p.R408W) in a patient with PAH deficiency (BH4 defects excluded, PMID: 12501224). Functional studies showed it has 26% enzyme activity compared to wild type controls. PMID: 18590700. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229865/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3216 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0043144 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040147 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0013395 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0043251 infores:hetionet CHEBI:94686 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0015967 infores:hetionet GO:2000387 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0061458 CHEBI:36704 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0852733 infores:hetionet CHEBI:4995 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0016382 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0031542 infores:hetionet CHEBI:7956 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0019345 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0029882 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0042023 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853149 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042267 infores:hetionet GO:0141079 biolink:causes GO:0006954 infores:ubergraph knowledge_assertion manual_agent GO:0141079 GO:0006954 CHEBI:15367 biolink:causes HP:0001595 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0157733 infores:hetionet CAID:CA8337984 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337984 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000018.4(ACADVL):c.1182+17C>A variant in ACADVL is an intronic variant which is located in intron 11. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (< 0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The results from two in silico splicing predictors (SpliceSiteFinder-like and NNSPLICE) support that this variant does not affect splicing (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive very long chain acyl CoA dehydrogenase (VLCAD) deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, BP4. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337984/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7492 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0234913 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0015397 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0234215 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0853149 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0233494 infores:hetionet CHEBI:31638 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0019080 infores:hetionet CHEBI:49713 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0234518 infores:hetionet CHEBI:490877 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0002170 infores:hetionet CAID:CA176353 biolink:causes MONDO:0009026 infores:clingen CAID:CA176353 MONDO:0009026 PMID:29493581 Likely Pathogenic PS4_Moderate, PM1, PP1, PP3, PM2_Supporting BS1, PP2, BA1, BP4 The c.175G>A variant in the HRAS gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 59 (p.Ala59Thr). This variant was absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.755 supporting deleterious impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000198374.4, SCV000950586.1). Moreover, this variant has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM2_Supporting, PP1, PP3 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA176353/MONDO:0009026/046 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119915 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0004936 infores:hetionet CHEBI:36791 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030318 infores:hetionet CHEBI:6541 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0152031 infores:hetionet CHEBI:5130 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1443060 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042373 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0041969 infores:hetionet CHEBI:41977 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0235896 infores:hetionet CHEBI:38562 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0085649 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0025061 infores:hetionet CHEBI:5790 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0030252 infores:hetionet CHEBI:31547 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0036974 infores:hetionet CHEBI:584020 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0151539 infores:hetionet CHEBI:23765 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0392525 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038454 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0007137 infores:hetionet CHEBI:31174 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0036572 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0277884 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0424000 infores:hetionet CAID:CA7330653 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330653 MONDO:0100216 PMID: Uncertain Significance PP3, PM1_Supporting, BS2_Supporting PVS1, PM2, BP4, BA1, PP2, PS4, PS3, BS1, BS3 The NM_177438.3:c.5524A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1842 (p.Ile1842Val). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors, GTR Lab ID: 500031 and 61756). The highest population minor allele frequency in gnomAD v 4.1.0 is 0.000008474 (10/1180038 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3, PM1_Supporting, BS2_Supporting (Bayesian Points: 1; VCEP specifications version 1.3.0; 06/24/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330653/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135566 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0205204 infores:hetionet CHEBI:64045 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009938 infores:hetionet CHEBI:17026 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0043349 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027765 infores:hetionet CHEBI:8774 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0010200 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0027769 infores:hetionet UMLS:C0120107 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0030554 infores:hetionet CHEBI:31644 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0687713 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0234913 infores:hetionet CHEBI:4903 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0702166 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027765 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0018799 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0031117 infores:hetionet CHEBI:31981 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0241442 infores:hetionet CHEBI:92511 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0560024 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0007222 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005942 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0035400 infores:hetionet CAID:CA343724770 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724770 MONDO:0020367 PMID: Likely Pathogenic PP1_Moderate, PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS1, PS2, BP4, BA1 The c.1087G>A variant in MYOC is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 363 (p.Ala363Thr). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.905, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Ala363Thr protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 5 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 18334962, 16491872), which fulfilled PP1_Moderate (5-6 meioses). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 15534471, 18334962), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 7 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724770/MONDO:0020367/019 2022-03-08 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:367163 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014130 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0234193 infores:hetionet CHEBI:8382 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151611 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0151736 infores:hetionet CHEBI:7959 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0011606 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002352 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007107 infores:hetionet NCBIGene:64208 biolink:causes MONDO:0030014 infores:monarchinitiative not_provided not_provided HGNC:17649 MONDO:0030014 uuid:2336a8ea-130f-4825-8a08-11c733b17f78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0497156 infores:hetionet GO:0031383 biolink:causes GO:0000747 infores:ubergraph knowledge_assertion manual_agent GO:0031383 GO:0000747 CHEBI:44241 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0017178 infores:hetionet CHEBI:3510 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0002874 infores:hetionet CHEBI:168396 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0024314 infores:hetionet CHEBI:71219 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0033687 infores:hetionet CHEBI:50663 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0011991 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0032285 infores:hetionet CHEBI:7983 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0004134 infores:hetionet CAID:CA401368920 biolink:causes MONDO:0009290 infores:clingen CAID:CA401368920 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting, PM5_Supporting The NM_000152.5:c.1670T>G variant in GAA is a missense variant predicted to cause substitution of isoleucine by serine at amino acid 557 (p.Ile557Ser). One patient with clinically asymptomatic Pompe disease, persistent elevated creatine kinase, abnormal muscle MRI, and <10% normal mean GAA activity in muscle has been reported (PMID 26474166) (PP4_Moderate). This patient is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 31342611) (PM3_Supporting). The variant is not in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.746 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant in the same codon, c.1669A>T (p.Ile557Phe) (ClinVar Variation ID: 558634; PMID 23884227), has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no ClinVar entry for NM_000152.5:c.1670T>G (p.Ile557Ser). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM5, PP4_Moderate, PM3_Supporting, PP3, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401368920/MONDO:0009290/010 2022-05-16 2022-05-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8024 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151609 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232431 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034150 infores:hetionet NCBIGene:124093 biolink:causes MONDO:0013890 infores:monarchinitiative not_provided not_provided HGNC:14153 MONDO:0013890 uuid:ab467c04-89f8-477a-85f8-8df94c61bf4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0423791 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0856882 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0018799 infores:hetionet CHEBI:45599 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0234233 infores:hetionet NCBIGene:6327 biolink:causes MONDO:0014156 infores:monarchinitiative not_provided not_provided HGNC:10589 MONDO:0014156 uuid:c87ce2a2-4ffa-4cd2-983b-a78e0f1749e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4315 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0027497 infores:hetionet CHEBI:10102 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085606 infores:hetionet CHEBI:8378 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C2047937 infores:hetionet CHEBI:63607 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0238106 infores:hetionet CHEBI:72297 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0231530 infores:hetionet CHEBI:8888 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151610 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0029408 infores:hetionet CAID:CA396467238 biolink:causes MONDO:0007648 infores:clingen CAID:CA396467238 MONDO:0007648 PMID:17955726PMID:17955726 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP4, PP3, PP2, PP1, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2 The c.1913G>A (p.Trp638*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 17955726). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396467238/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:2208 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0006145 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235876 infores:hetionet CHEBI:119915 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233763 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C1443060 infores:hetionet NCBIGene:80856 biolink:causes MONDO:0060761 infores:monarchinitiative not_provided not_provided HGNC:21610 MONDO:0060761 uuid:f089221f-48bd-4166-80b3-63f9980c487b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1269683 infores:hetionet CHEBI:6717 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0025222 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0029456 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0152029 infores:hetionet CHEBI:63630 biolink:causes MONDO:0042981 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003507 infores:hetionet CHEBI:7494 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0235660 infores:hetionet CHEBI:100241 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085636 infores:hetionet CHEBI:421707 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0011991 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0235431 infores:hetionet GO:0044068 biolink:causes GO:0009987 infores:ubergraph knowledge_assertion manual_agent GO:0044068 GO:0009987 NCBIGene:399 biolink:causes MONDO:0032666 infores:monarchinitiative not_provided not_provided HGNC:686 MONDO:0032666 uuid:a8c8f36a-1791-4d50-baf9-3f8242297ddd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0023218 infores:hetionet CHEBI:3403 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0015230 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0549444 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0549444 infores:hetionet CHEBI:6754 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0009806 infores:hetionet CHEBI:48947 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0002792 infores:hetionet CHEBI:17650 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0019521 infores:hetionet CHEBI:3172 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0234233 infores:hetionet CAID:CA122872 biolink:causes MONDO:0000573 infores:clingen CAID:CA122872 MONDO:0000573 PMID:18463379 Pathogenic PP4, PM2_Supporting, PM1, PM3, PP1_Strong, PS3_Supporting BS2 The NM_000536.4:c.1352G>C variant in RAG2 is a missense variant predicted to cause the substitution of glycine by alanine at amino acid 451 (p.Gly451Ala). The variant has been identified in at least 8 individuals. Three individuals described by Dr. Jolan were homozygous for this variant (reaching the maximum of 1 pt for homozygous occurrence). One individual with Omenn Syndrome was heterozygous for this variant and a p.R229Q variant, which is classified as pathogenic according to the SCID VCEP specifications. The trans phase was not confirmed (0.5 points, PMID 32655540). One individual with CID was heterozygous for this variant, and p.M459L, a likely pathogenic variant classified by the SCID VCEP. The trans phase was not confirmed (0.25pt, PMID 26457731). Three other individuals were heterozygous for this variant and a VUS (p.I210T, PMID 31334206; p.G32E, PMID 26457731; p.T77N, PMID 18463379, 24331380, 26457731, 29772310). 1.75 points in total, PM3 is met.These three homozygous individuals described by Dr. Jolan are from the same family: 3 affected segregations, LOD score 1.81, PP1_Strong. The filtering allele frequency (the upper threshold of the 95% CI of 9/129174 alleles) of this variant in gnomAD v.2.1.1 is 0.00003418 for European (non-Finnish) chromosomes, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting)This variant resides within the PHD domain region, amino acids 414-487, of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP (PM1). In one study (PMID 29772310), a recombination activity assay shows that the relevant activity of the p.G451A variant to wildtype RAG2 is 66.3%, which is higher than the SCID VCEP threshold (<60%) for PS3_supporting. However, in two other studies (PMID 18463379, 24331380), the relevant activity of the variant is shown to be 30% and 27.6%, respectively, which falls in the SCID VCEP threshold (>25% and <60%) for PS3_supporting (PS3_Supporting). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + SCID gene panel or exome/genome sequencing conducted 0.5pts; the total is 1 point, PP4 is met (PMID: 32655540).In summary, this variant meets the criteria to be classified as Pathogenic for SCID due to recombinase activating gene 2 deficiency. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM3, PM2_Supporting, PM1, PS3_Supporting, PP4, and PP1_Strong. (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA122872/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50777 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0023533 infores:hetionet NCBIGene:16 biolink:causes MONDO:0030634 infores:monarchinitiative not_provided not_provided HGNC:20 MONDO:0030634 uuid:fb2dd342-7ec7-445f-a811-05cf31d0c91e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA409120875 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120875 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4 :c.539T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 180 (p.Ile180Thr).The filtering allele frequency (the upper threshold of the 95% CI of 6/91086) of the c.539T>C variant in ADA is 0.00002995 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as Variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120875/MONDO:0007064/114 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6520 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0456909 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0178298 infores:hetionet CHEBI:23765 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003873 infores:hetionet NCBITaxon:12089 biolink:causes MONDO:0005634 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12089 MONDO:0005634 CHEBI:63621 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0041657 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0438167 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0438167 infores:hetionet CAID:CA404075655 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075655 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BA1, BP1, BP4, BP2, BP3, PS1, PS3, PS2, BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PVS1, PM6, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.259T>C (p.Trp87Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - 1 other missense variant in the same codon:- NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) - Pathogenic by expert panel in ClinVar,so PM5 is met.PP3 - REVEL = 0.891. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075655/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3423 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085584 infores:hetionet CHEBI:3223 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0699828 infores:hetionet CHEBI:7492 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0027497 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0853619 infores:hetionet CHEBI:5120 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0003467 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0574067 infores:hetionet CHEBI:465284 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0000768 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020538 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0403632 infores:hetionet CHEBI:3650 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0033247 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0036572 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013595 infores:hetionet CHEBI:49040 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0043352 infores:hetionet CAID:CA220193 biolink:causes MONDO:0008723 infores:clingen CAID:CA220193 MONDO:0008723 PMID: Pathogenic PP3, PM1, PM3_Strong, PM2, PP4_Moderate BP4 The c.1322G>A (p.Gly441Asp) variant in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 441. At least two individuals with this variant displayed VLCAD enzyme activity <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 25834949). The variant has been described in the homozygous state in at least 4 affected individuals, confirmed in trans to a pathogenic variant in at least one individual, and in at least one individual with a distinct pathogenic variant without determination of phase of the variants (PM3_Strong; PMIDs: 1648817, 17999356, 24305961, 30194637, 32061778). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion. This variant occurs adjacent to the FAD binding pocket and is located on a loop that contributes to dimer formation (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220193/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6822 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0042963 infores:hetionet CHEBI:144551 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C2830004 infores:hetionet CHEBI:17303 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233763 infores:hetionet CHEBI:3814 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0017181 infores:hetionet CHEBI:80630 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0011603 infores:hetionet CAID:CA658795253 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795253 MONDO:0009290 PMID:22252923PMID:24269976PMID:25526786 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.1356del (p.Ser454AlafsTer23), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay and lack of gene product, meeting PVS1. This variant is absent in gnomAD v2.1.1, meeting PM2. One patient has been reported who is compound heterozygous for the variant and c.2238G>C (p.Trp746Cys) (PMID 25526786). Note that in other studies, c.2238G>C (p.Trp746Cys) has been found in cis with the pseudodeficiency variants p.Gly576Ser or p.Glu689Lys. However, no details on the presence of pseudodeficiency variants was provided for this case, and PP4 is met based on the specifications of the ClinGen LSD VCEP. The in trans data from this patient has been used in the assessment of p.Trp746Cys and was not included here in order to avoid a circular argument. At least one other patient, with infantile onset Pompe disease, has been reported but either the GAA activity was not provided, or the second variant is not known, and therefore this data was not included (PMID 22252923, 24269976). There is no entry for this variant in ClinVar. In summary, this variant is pathogenic for Pompe disease based on the specifications of the ClinGen LSD VCEP. ACMG/AMP criteria met: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795253/MONDO:0009290/010 2020-06-16 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:52717 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017181 infores:hetionet GO:0061104 biolink:causes CL:1000426 infores:ubergraph knowledge_assertion manual_agent GO:0061104 CL:1000426 NCBITaxon:10310 biolink:causes MONDO:0012521 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10310 MESH:D020803 DB00787_MESH_D020803_1 CHEBI:75722 biolink:causes UMLS:C0232452 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232452 infores:hetionet CHEBI:2673 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C1443060 infores:hetionet CHEBI:3011 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0023052 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0038358 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0042373 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0023418 infores:hetionet CHEBI:180905 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0542571 infores:hetionet CAID:CA2695232559 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695232559 MONDO:0100437 PMID: Likely Pathogenic PP1, PM2_Supporting, PS4_Supporting, PVS1_Strong NM_001034853.2(RPGR):c.3399del (p.Pro1134HisfsTer18) is a frameshift variant due to a 1-nucleotide deletion introducing a premature stop codon within exon 15 of 15, causing truncation of less than 10% of the RPGR protein within a domain of unknown function (PVS1_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 31645972, PMID: 35806195, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through an affected mother and son (PP1; PMID: 31645972). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1_Strong, PM2_Supporting, PP1, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695232559/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:6950 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0004093 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0015397 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0595877 infores:hetionet CHEBI:15552 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0917801 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0029882 infores:hetionet CAID:CA279947 biolink:causes MONDO:0015967 infores:clingen CAID:CA279947 MONDO:0015967 PMID: Likely Pathogenic PM3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PP1 The c.1030G>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to tyrosine at codon 344 (p.(Asp344Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 27016322, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2H increment < 3 mmol/L and negative antibodies) (PP4_Moderate; PMID: 27016322). This variant has been detected in the homozygous state in 1 individual with permanent neonatal diabetes (PM3_Supporting; internal lab contributors). This variant segregated with hyperglycemia with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 27016322). In summary, c.1165G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_supporting, PP2, PP3, PM3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA279947/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:473990 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0018965 infores:hetionet CHEBI:2682 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0392699 infores:hetionet CAID:CA512341111 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341111 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1290G>T (p.Pro430=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.25)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341111/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9168 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0032461 infores:hetionet CAID:CA410147867 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147867 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1175A>G (p.Gln392Arg) is a missense variant which is present at a MAF of 0.00003853 (0.003853%, 1/25956) in the Admixed American population of gnomAD v2.1. This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. It has a REVEL score < 0.50 (0.197) and a SpliceAI score ≤ 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147867/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0015469 infores:hetionet CHEBI:404903 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042029 infores:hetionet CHEBI:5801 biolink:causes UMLS:C3160840 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C3160840 infores:hetionet NCBIGene:84148 biolink:causes MONDO:0033547 infores:monarchinitiative not_provided not_provided HGNC:17933 MONDO:0033547 uuid:45769c68-61f5-4822-899d-1865ade6901b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0027540 infores:hetionet CHEBI:6909 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042023 infores:hetionet CHEBI:4974 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0030252 infores:hetionet NCBITaxon:5036 biolink:causes MONDO:0018312 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5036 MONDO:0018312 CHEBI:5088 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0027497 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0178298 infores:hetionet CHEBI:5098 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0023530 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017658 infores:hetionet NCBIGene:6530 biolink:causes MONDO:0011479 infores:monarchinitiative not_provided not_provided HGNC:11048 MONDO:0011479 uuid:bbc026dd-a15b-44d5-973a-c0d9ecb1e121 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA891843628 biolink:causes MONDO:0700272 infores:clingen CAID:CA891843628 MONDO:0700272 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting The c.532del (p.Glu178fs) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 4 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843628/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:60761 biolink:causes UMLS:C0340613 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0340613 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151698 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C1368065 infores:hetionet CHEBI:4974 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0033774 infores:hetionet CHEBI:75722 biolink:causes NCIT:C3887 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0241619 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0027947 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004619 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0025007 infores:hetionet CHEBI:2668 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0008031 infores:hetionet CHEBI:6832 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0042109 infores:hetionet CHEBI:8764 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018681 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0917801 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0746883 infores:hetionet CHEBI:2567 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0020437 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0241863 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0037274 infores:hetionet CHEBI:5050 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C2830004 infores:hetionet CHEBI:4995 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018790 infores:hetionet CHEBI:17823 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C2830004 infores:hetionet CHEBI:3504 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0018965 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0948594 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0037822 infores:hetionet GO:0061046 biolink:causes GO:0060562 infores:ubergraph knowledge_assertion manual_agent GO:0061046 GO:0060562 CHEBI:8378 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0262431 infores:hetionet CHEBI:9445 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0086525 infores:hetionet CHEBI:9123 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1167965 infores:hetionet CHEBI:205919 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0041834 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0018939 infores:hetionet CHEBI:119486 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0014743 infores:hetionet CHEBI:3647 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0020615 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0002888 infores:hetionet CHEBI:94609 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0004093 infores:hetionet CAID:CA2259466 biolink:causes MONDO:0021060 infores:clingen CAID:CA2259466 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1587G>A (p.Ser529=) variant in the RAF1 gene is 0.052% (10/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2259466/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3698 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0003811 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011551 infores:hetionet CHEBI:36791 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0393761 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085682 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0012833 infores:hetionet CHEBI:9139 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0019270 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027813 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0233472 infores:hetionet CHEBI:6015 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0022346 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0233494 infores:hetionet CHEBI:2948 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0019080 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0424000 infores:hetionet CHEBI:4995 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013404 infores:hetionet CHEBI:7447 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0038999 infores:hetionet NCBIGene:100996717 biolink:causes MONDO:0023671 infores:monarchinitiative not_provided not_provided HGNC:53924 MONDO:0023671 uuid:1795e9a9-2a6c-487b-8977-ac7a6d315b29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0041582 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233632 infores:hetionet CHEBI:31536 biolink:causes HP:0003249 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151281 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013395 infores:hetionet CHEBI:27882 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0151576 infores:hetionet CHEBI:71219 biolink:causes HP:0033279 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0341318 infores:hetionet CHEBI:5002 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0039231 infores:hetionet CHEBI:2611 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0549249 infores:hetionet CAID:CA213704 biolink:causes MONDO:0015967 infores:clingen CAID:CA213704 MONDO:0015967 PMID: Pathogenic PVS1, PM2_Supporting, PS1_Supporting PS4 The c.1020-1G>C variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in deletion of >10% of a protein encoded by a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18248649). The c.1020G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1020G>C has a similar predicted impact by Splice AI (0.99 and 0.99 for Acceptor Loss) (PS1_Supporting). In summary, c.1020-1G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0; approved 8/11/2023): PVS1, PM2_Supporting, PS1_Supporting.  Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213704/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CHEBI:77260 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0236048 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0877211 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0877211 infores:hetionet CHEBI:681569 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0595916 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035078 infores:hetionet CHEBI:145499 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042029 infores:hetionet CHEBI:9570 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0004134 infores:hetionet CHEBI:44915 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020578 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0008370 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0595862 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0595862 infores:hetionet CHEBI:9674 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233794 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0003123 infores:hetionet CHEBI:42797 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017979 infores:hetionet CHEBI:7852 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0017565 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0027697 infores:hetionet CHEBI:9763 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0009763 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0541820 infores:hetionet CHEBI:3561 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0003862 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0006840 infores:hetionet CHEBI:5100 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0011603 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0020517 infores:hetionet CHEBI:8888 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014457 infores:hetionet CHEBI:92712 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0030446 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0340464 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0553704 infores:hetionet CHEBI:15367 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0232766 infores:hetionet CHEBI:32315 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0025323 infores:hetionet CHEBI:119915 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032617 infores:hetionet CHEBI:171719 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0022107 infores:hetionet CHEBI:3732 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1384353 infores:hetionet CHEBI:134991 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0600142 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0234913 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005366 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0524909 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0038454 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027769 infores:hetionet CHEBI:184555 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0027497 infores:hetionet CHEBI:9599 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1456822 infores:hetionet CHEBI:5790 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013428 infores:hetionet CHEBI:45409 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0311468 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0014742 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0015397 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020649 infores:hetionet UMLS:C0009315 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C2830004 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0233401 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0234192 infores:hetionet CHEBI:6931 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0233795 infores:hetionet CHEBI:51173 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0917801 infores:hetionet CHEBI:6367 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1443060 infores:hetionet CHEBI:63620 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003862 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0241705 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0011991 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0020538 infores:hetionet CAID:CA149410 biolink:causes MONDO:0007113 infores:clingen CAID:CA149410 MONDO:0007113 PMID: Benign BA1 BP7 The allele frequency of the c.313T>C p.(Leu105=) variant in UBE3A (NM_130838.2) is 7.5% in African/African-American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.313T>C p.(Leu105=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA149410/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:6741 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027497 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0012739 infores:hetionet CHEBI:6067 biolink:causes HP:0033832 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0332579 infores:hetionet NCBIGene:55340 biolink:causes MONDO:0030397 infores:monarchinitiative not_provided not_provided HGNC:18005 MONDO:0030397 uuid:ee31eabc-8385-4381-a49c-6e2081fc226e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1442845 biolink:causes MONDO:0100084 infores:clingen CAID:CA1442845 MONDO:0100084 PMID:17187373 Pathogenic PM3, PS3_Supporting, PVS1, PP4_Moderate BA1, BS1, PM2 The NM_001100.4:c.541del (p.Asp181fs) variant in ACTA1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 4/7 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population filtering allele frequency in gnomAD v4.1 is 0.0002402 (29/91056 alleles) in the South Asian population (this variant is excluded from the application of BA1/BS1 by the ClinGen Congenital Myopathies VCEP as it is a well established pathogenic variant). This variant has been detected in 6 individuals with nemaline myopathy. All of these individuals were homozygous for the variant (PMID: 17187373, GeneDx, SCV000568673.4) (PM3). Multiple patients with this variant displayed zebra bodies, which is highly specific for nemaline myopathy (PP4, PMID: 17187373). Western blot analysis of the muscle biopsy in one of the patients showed complete absence of α-skeletal muscle actin, whereas they had high levels of α-cardiac actin when compared with control subjects indicating that this variant impacts protein expression (PMID: 17187373) (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM3, PS3_Supporting, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1442845/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50861 biolink:causes UMLS:C0577598 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0577598 infores:hetionet CHEBI:10023 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013456 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0038362 infores:hetionet CHEBI:101278 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0016204 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013295 infores:hetionet CAID:CA387747333 biolink:causes MONDO:0700269 infores:clingen CAID:CA387747333 MONDO:0700269 PMID: Uncertain Significance PS3 PM2, BP5, PP3, PP4 The c.7970A>C variant in BRCA2 is a missense variant predicted to cause substitution of lysine by threonine at amino acid 2657 (p.(Lys2657Thr)). This BRCA2 missense variant is within a key functional domain. The computational predictor BayesDel (noAF) gives a score of 0.27, indicating that impact on BRCA2 function via protein change is unclear (score range 0.18-0.30) and the SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1) (no bioinformatic code is applied). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMID: 38417439, 39779857, 39779848). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.49 (based on Family History LR=1.49), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (PMID: 31853058). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA387747333/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7443 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0035078 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0836924 infores:hetionet CHEBI:8888 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0032533 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0004238 infores:hetionet CHEBI:28787 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0236075 infores:hetionet NCBIGene:4337 biolink:causes MONDO:0009643 infores:monarchinitiative not_provided not_provided HGNC:7190 MONDO:0009643 uuid:cabf32a2-524f-426c-9f5d-8900f946e17c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68556 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0027765 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0028077 infores:hetionet NCBIGene:27068 biolink:causes MONDO:0014973 infores:monarchinitiative not_provided not_provided HGNC:28883 MONDO:0014973 uuid:00421f72-17ef-4f6f-8e63-60ef94054a3f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000070 biolink:causes MONDO:0018875 infores:clingen CAID:CA000070 MONDO:0018875 PMID: Likely Benign BP4, BS2 BP1, BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BS1, BS3, BS4, PM2, PM6, PP2, PP3, PP1, PP4 The NM_000546.6: c.214C>G variant in TP53 is a missense variant predicted to cause substitution of proline by alanine at amino acid 72 (p.Pro72Ala).This is a polymorphic residue (alternate nomenclature: p.Arg72). This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.215412; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.2; 2/6/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000070/MONDO:0018875/009 2025-02-06 2025-02-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:724125 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0015397 infores:hetionet CHEBI:3506 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0027497 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0242461 infores:hetionet CHEBI:51041 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0030193 infores:hetionet CHEBI:46295 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0002792 infores:hetionet CHEBI:421707 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0232462 infores:hetionet CHEBI:10101 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0015967 infores:hetionet CHEBI:64321 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0026205 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0018802 infores:hetionet UNII:3U02EL437C biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0025874 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0002622 infores:hetionet CAID:CA8338049 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338049 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM3_Supporting, PVS1_Moderate, PP4_Moderate The c.1269+1G>A variant in ACADVL, also published as IVS12+1G>A, occurs within the canonical splice donor site (+/- 1,2) of intron 12. It is predicted to cause skipping of biologically-relevant-exon 12/20, resulting in an in-frame deletion (removes amino acids 395-423) that is predicted to escape nonsense mediated decay (PVS1_Moderate). This variant has been described without an additional ACADVL variant in 3 individuals identified by newborn screen, identified in an unknown phase to a variant of uncertain significance in two individuals, and has also been identified occurring in the homozygous state in an individual identified by newborn screen (PM3_Supporting, PMIDs: 32793418, 30194637, 25834949, 21932095, 21531094). The individual who carried the c.1269+1G>A variant in the homozygous state also displayed reduced VLCAD enzyme activity, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMID: 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM3_Supporting, PP4_Moderate, PM2_Supporting (VCEP specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338049/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2453 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013604 infores:hetionet CHEBI:4909 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0043352 infores:hetionet CAID:CA2497030023 biolink:causes MONDO:0015967 infores:clingen CAID:CA2497030023 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PVS1, PP4_Moderate The c.404del variant in the HNF1 Homeobox A gene, HMF1A, causes a frameshift in the protein at codon 135 (NM_000545.8), adding 20 novel amino acids before encountering a stop codon (p.(Asp135ValfsTer20)). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 9 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30269055, internal lab contributors). At least one of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate; PMID 30269055, internal lab contributor). This variant also segregated with diabetes, with at least 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributor). In summary, the c.404del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497030023/MONDO:0015967/017 2022-07-01 2022-07-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4046 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0013144 infores:hetionet CHEBI:6339 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C3665347 infores:hetionet CHEBI:4027 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0235378 infores:hetionet CHEBI:41977 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0009676 infores:hetionet CHEBI:8382 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0016382 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151773 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0002871 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023067 infores:hetionet CHEBI:8869 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0003811 infores:hetionet CHEBI:27777 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0233494 infores:hetionet CHEBI:8356 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018524 infores:hetionet CHEBI:7581 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0036974 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0151773 infores:hetionet CHEBI:75246 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0151904 infores:hetionet CHEBI:2682 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0855775 infores:hetionet CHEBI:31236 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042345 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0018099 infores:hetionet CHEBI:63584 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0004604 infores:hetionet CHEBI:5280 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0018524 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0518015 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0541766 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0541766 infores:hetionet CAID:CA902337 biolink:causes MONDO:0100368 infores:clingen CAID:CA902337 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting BP4, PP3, PP4 NM_000329.3(RPE65):c.975T>G is a missense variant causing substitution of isoleucine with methionine at position 325. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00004116, with 9 alleles / 113694 total alleles in the European non-Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.46, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant has not yet been reported in published cases or affected individuals in ClinVar. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902337/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:27732 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C2004489 infores:hetionet CHEBI:3698 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0042023 infores:hetionet CHEBI:135361 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0235238 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0151849 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0852913 infores:hetionet GO:2000794 biolink:causes GO:0030323 infores:ubergraph knowledge_assertion manual_agent GO:2000794 GO:0030323 CAID:CA7542752 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542752 MONDO:0012996 PMID:27233232 Benign BA1, BS3_Supporting PP3, BP4 The NM_001482.3:c.1244G>A variant in GATM is a missense variant predicted to cause the substitution of an arginine by a glutamine at amino acid position 415 (p.Arg415Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000915 (28/30616 alleles) in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in 39% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.201 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 225921). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BS3_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542752/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7903 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0029408 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0149931 infores:hetionet CHEBI:119915 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151936 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0427008 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0036130 infores:hetionet CHEBI:9649 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0014457 infores:hetionet CHEBI:27786 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0042487 infores:hetionet GO:0048819 biolink:causes GO:0001942 infores:ubergraph knowledge_assertion manual_agent GO:0048819 GO:0001942 CHEBI:253342 biolink:causes MONDO:0007835 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0021933 infores:hetionet GO:0042386 biolink:causes CL:0000387 infores:ubergraph knowledge_assertion manual_agent GO:0042386 CL:0000387 CHEBI:47381 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027765 infores:hetionet CAID:CA343774795 biolink:causes MONDO:0013144 infores:clingen CAID:CA343774795 MONDO:0013144 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1 The c.778A>T, p.Lys260* (NM_000488.3) in SERPINC1 is a nonsense variant predicted to cause a premature stop codon at codon 260 in biologically-relevant exon 5/7 that leads to nonsense mediated decay (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 1 proband with antithrombin activity level of 48 meeting the SERPINC1-phenotypic criteria (AT level of <0.8 IU/mL, no repeat testing) (PS4_Supporting; Internal lab contributors). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PVS1, PM2_Supporting, PS4_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343774795/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44032 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151904 infores:hetionet CHEBI:15940 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0002170 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0013395 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0521490 infores:hetionet CHEBI:52172 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C2363731 infores:hetionet CHEBI:6809 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0338614 infores:hetionet CHEBI:7931 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0014236 infores:hetionet CHEBI:404903 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0032227 infores:hetionet CHEBI:4511 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0036572 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0948586 infores:hetionet CHEBI:135888 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0699744 infores:hetionet CHEBI:7915 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0008031 infores:hetionet CHEBI:8426 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0232462 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0520589 infores:hetionet CHEBI:2038 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0030232 infores:hetionet CHEBI:51860 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0234967 infores:hetionet CHEBI:3698 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020461 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0043246 infores:hetionet CHEBI:50131 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0235710 infores:hetionet CHEBI:7936 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023066 infores:hetionet CAID:CA410149618 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149618 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP2, BP1, BP3, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM3, PM4, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.938T>C (p.Leu313Pro) is a missense variant which has a REVEL score < 0.50 (0.171) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149618/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68642 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C1384353 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0018799 infores:hetionet CHEBI:63581 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0023787 infores:hetionet CHEBI:8805 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0340865 infores:hetionet CHEBI:29688 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0030554 infores:hetionet CHEBI:34829 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0151692 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0041834 infores:hetionet GO:0055007 biolink:causes CL:0000746 infores:ubergraph knowledge_assertion manual_agent GO:0055007 CL:0000746 CHEBI:45783 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0687713 infores:hetionet CHEBI:2668 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085631 infores:hetionet CHEBI:70707 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0232462 infores:hetionet CHEBI:2663 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0004245 infores:hetionet CHEBI:51860 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0392156 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0233632 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0009443 infores:hetionet CHEBI:8707 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0003467 infores:hetionet CHEBI:94449 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C2830004 infores:hetionet CHEBI:4702 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1443060 infores:hetionet NCBIGene:10616 biolink:causes MONDO:0014389 infores:monarchinitiative not_provided not_provided HGNC:15864 MONDO:0014389 uuid:d13a5351-46ec-4907-b0d5-7feee6d0e689 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042109 infores:hetionet CHEBI:75984 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C1527344 infores:hetionet CHEBI:119486 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0043352 infores:hetionet CHEBI:63631 biolink:causes HP:0002312 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233844 infores:hetionet CHEBI:10101 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2047937 infores:hetionet CHEBI:6456 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0549249 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0014742 infores:hetionet CHEBI:5118 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151907 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0677500 infores:hetionet CHEBI:291342 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0235996 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0034067 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0012813 infores:hetionet GO:1902071 biolink:causes GO:0071456 infores:ubergraph knowledge_assertion manual_agent GO:1902071 GO:0071456 CHEBI:36791 biolink:causes MONDO:0001266 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014733 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0000879 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D002179 DB00681_MESH_D002179_1 CHEBI:8107 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0015376 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0854100 infores:hetionet CHEBI:474053 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0014742 infores:hetionet NCBITaxon:813 biolink:causes MONDO:0000918 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:813 MESH:D004716 DB00685_MESH_D004716_1DB01330_MESH_D004716_1DB00355_MESH_D004716_1DB00438_MESH_D004716_1 CHEBI:31932 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0041657 infores:hetionet CHEBI:6444 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C3665386 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0521839 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0041912 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0948594 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0233414 infores:hetionet NCBIGene:8379 biolink:causes MONDO:0700275 infores:monarchinitiative not_provided not_provided HGNC:6762 MONDO:0700275 uuid:b363f20c-8f9e-42fa-8c62-0eb9be2a4957 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0024902 infores:hetionet CHEBI:61049 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2586050 infores:hetionet CHEBI:39867 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0019080 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0333355 infores:hetionet CHEBI:5118 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0520966 infores:hetionet UNII:3QJA87N40S biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0151578 infores:hetionet CHEBI:3568 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0232461 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0542203 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0152227 infores:hetionet CHEBI:50692 biolink:causes MONDO:0002817 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0750887 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151885 infores:hetionet CHEBI:31236 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0023380 infores:hetionet CHEBI:135935 biolink:causes HP:0011713 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0023211 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151888 infores:hetionet CHEBI:63638 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0010200 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0032285 infores:hetionet CHEBI:8364 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0030252 infores:hetionet CHEBI:45367 biolink:causes MONDO:0021678 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0085423 infores:hetionet CHEBI:9654 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0012569 infores:hetionet CHEBI:7478 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151636 infores:hetionet GO:2000733 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0060993 CHEBI:63612 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0035410 infores:hetionet NCBIGene:64241 biolink:causes MONDO:0020747 infores:monarchinitiative not_provided not_provided HGNC:13887 MONDO:0020747 uuid:35525af1-c1fe-4e65-8912-3093711b40d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3508 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0853813 infores:hetionet CHEBI:47519 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0340865 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0236151 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0236151 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001556 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041972 infores:hetionet CHEBI:3219 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0029261 infores:hetionet CHEBI:3219 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026961 infores:hetionet CHEBI:39669 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0030252 infores:hetionet CHEBI:3756 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013144 infores:hetionet CHEBI:101278 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0239340 infores:hetionet CHEBI:144093 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0004093 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0004096 infores:hetionet CHEBI:2950 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0851578 infores:hetionet NCBIGene:2779 biolink:causes MONDO:0014614 infores:monarchinitiative not_provided not_provided HGNC:4393 MONDO:0014614 uuid:3e9415b3-acbe-4dc1-a2ed-98a22c53b5de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0019474 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1333984 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0017152 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0011991 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0854113 infores:hetionet CHEBI:8863 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0427457 infores:hetionet CAID:CA023769 biolink:causes MONDO:0007750 infores:clingen CAID:CA023769 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4, PP1 BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, PM5, PM4, PM1, PM3, PM6, PVS1, PP3, BS2 The NM_000527.5(LDLR):c.811G>A (p.Val271Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP4, and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1). BP4: REVEL=0.33. It is below 0.5, splicing evaluation required.Functional data on splicing not available.A) not on limits.B) does not create GT.C) there is no GT nearby.Variant is not predicted to alter splicing. PP1: Variant segregates with FH phenotype in 3 informative meioses in 1 family from PMID 26036859 (Brænne I et al., 2016). 2 affected family members have the variant. PP4: Variant meets PM2 and is identified in 1 index case with DLCN score >=6 from PMID 26036859 (Brænne I et al., 2016: LDL-C 286 mg/dl and a history of premature CAD, DLCN=7). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023769/MONDO:0007750/013 2023-06-23 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3647 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0030446 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0010692 infores:hetionet CHEBI:36704 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0231528 infores:hetionet CHEBI:5165 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0017181 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0151773 infores:hetionet CAID:CA343723135 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723135 MONDO:0020367 PMID: Likely Pathogenic PP3, PP1, PS3_Moderate, PS4_Supporting, PM2_Supporting BP7, BS1, BS3, PM6, PM5, PM4, PS1, PS2, BA1, BP4 The c.1442C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 481 (p.Pro481Leu). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.72, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Pro481Leu protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 3 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 12189160), which fulfilled PP1 (3-4 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 10196380, 12189160), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP1, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723135/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports GO:1902746 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:1902746 GO:0150063 CHEBI:7936 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003469 infores:hetionet CHEBI:6912 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0043352 infores:hetionet CAID:CA9302108 biolink:causes MONDO:0010938 infores:clingen CAID:CA9302108 MONDO:0010938 PMID: Likely Benign BS1, BS2_Supporting "NM_000215.4(JAK3):c.649G>A (p.Val217Met) occurs at a very low allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.00001607 (based on 4/99752 alleles in the non-Finnish European population) which is below the SCID VCEP established threshold of <0.000115 for PM2_Supporting; However, the highest MAF in the Ashkenazi Jewish population is 0.002786 (26/9332 alleles) which is above the SCID VCEP established threshold of >0.00100. Considering that this population does not have a higher disease prevalence, it is determined to meet BS1. Furthermore, a 01 homozygous individual from the ""Other"" population satisfies the BS2_Supporting criteria.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting (VCEP specifications version 1.0)." Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9302108/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA10602909 biolink:causes MONDO:0021056 infores:clingen CAID:CA10602909 MONDO:0021056 PMID:19196998 Likely Pathogenic PP3, PS3, PS4_Supporting, PM2_Supporting The NM_000038.6(APC):c.531+5G>C variant in APC is an intronic variant which is located at the 5th nucleotide in intron 5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 1 point (PMID: 19196998, 20223039, 12010888; the first two references refer to the same German family) (PS4_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). RNA studies have demonstrated that this variant causes exon 5 deletion (c.531+5G>C; r.423_531del; p.Arg144Serfs*8; PMID: 19196998) (PS3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3, PS4_Supporting, PM2_Supporting and PP3 (VCEP specifications version 2.1.0; date of approval: 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10602909/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:465284 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1260880 infores:hetionet CHEBI:9086 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1320474 infores:hetionet NCBIGene:9731 biolink:causes MONDO:0031031 infores:monarchinitiative not_provided not_provided HGNC:24866 MONDO:0031031 uuid:65ee1809-f675-43f3-b41f-81781dda535e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004245 infores:hetionet CHEBI:8232 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C1257843 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0038814 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014130 infores:hetionet GO:1900206 biolink:causes GO:0039019 infores:ubergraph knowledge_assertion manual_agent GO:1900206 GO:0039019 CHEBI:50381 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0027765 infores:hetionet CAID:CA011960 biolink:causes MONDO:0007947 infores:clingen CAID:CA011960 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP3, PM2_Supporting, PS4_Moderate PM1 The NM_00138 c.1147G>A is a missense variant in FBN1 predicted to cause a substitution of a glutamic acid by lysine at amino acid 383 (p.Glu383Lys). This variant was found in a proband with a systemic score >7 and thoracic aortic aneurysm and/or dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 11700157, internal lab data, PP4). This variant has been reported four times in ClinVar: once as pathogenic, once as likely pathogenic, and twice as uncertain significance (Variation ID: 200177). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant has been reported in the literature in at least three individuals with clinical features of MFS and/or thoracic aortic aneurysm and dissection (PS4_Mod; PMID 19159394, Invitae ClinVar entry, internal lab data) and in an individual with left iliac aneurysm (GeneDx internal lab data). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.702). This variant is located in the last nucleotide of exon 9. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM2_Sup, PP2, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA011960/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:10023 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085584 infores:hetionet CHEBI:71229 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0031542 infores:hetionet CHEBI:6832 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0043251 infores:hetionet CHEBI:2379 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0007398 infores:hetionet GO:1903297 biolink:causes GO:0071456 infores:ubergraph knowledge_assertion manual_agent GO:1903297 GO:0071456 CHEBI:8713 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0015672 infores:hetionet CHEBI:17263 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0476089 infores:hetionet CAID:CA267658 biolink:causes MONDO:0009861 infores:clingen CAID:CA267658 MONDO:0009861 PMID:26666653PMID:26666653 Likely Pathogenic PM3, PM2, PP3, PP4 The c.547_548delGAinsTT PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). It was detected in trans with the pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608). This variant is absent from 1000G, ESP, and gnomAD databases. It is predicted deleterious in multiple in silico models. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267658/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10110 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0085595 infores:hetionet CHEBI:9139 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2047937 infores:hetionet CHEBI:16714 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0003467 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0018799 infores:hetionet CHEBI:3757 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0423791 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0948594 infores:hetionet CHEBI:48538 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0027441 infores:hetionet CHEBI:65349 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0034150 infores:hetionet CHEBI:64355 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040434 infores:hetionet CHEBI:6822 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0027092 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0005940 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0021053 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0021680 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D013290 DB00976_MESH_D013290_1DB00601_MESH_D013290_1DB01326_MESH_D013290_1DB01369_MESH_D013290_1DB01060_MESH_D013290_1DB01059_MESH_D013290_1DB09320_MESH_D013290_1DB00438_MESH_D013290_1DB01328_MESH_D013290_1DB00207_MESH_D013290_1DB06590_MESH_D013290_1DB01764_MESH_D013290_1DB01137_MESH_D013290_1DB01330_MESH_D013290_1DB01139_MESH_D013290_1DB00833_MESH_D013290_1DB01332_MESH_D013290_1DB00537_MESH_D013290_1DB00218_MESH_D013290_1DB01190_MESH_D013290_1DB00954_MESH_D013290_1DB01066_MESH_D013290_3DB01331_MESH_D013290_1DB00567_MESH_D013290_1DB01053_MESH_D013290_1DB01165_MESH_D013290_1DB01413_MESH_D013290_1DB00417_MESH_D013290_1DB01333_MESH_D013290_1DB01212_MESH_D013290_1DB01627_MESH_D013290_1 NCBIGene:3852 biolink:causes MONDO:0030489 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0030489 uuid:0b950b0c-ba63-4991-a241-fc5ad6adbb61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085635 infores:hetionet CHEBI:231594 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0025874 infores:hetionet CHEBI:10124 biolink:causes MONDO:0009861 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0031485 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0004936 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0856150 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0856150 infores:hetionet CHEBI:9622 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0948594 infores:hetionet CHEBI:3314 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0549249 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0016977 infores:hetionet UMLS:C0120107 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0232462 infores:hetionet CHEBI:3699 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0040034 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0162281 infores:hetionet CHEBI:45285 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0020517 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0234987 infores:hetionet CAID:CA16020907 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020907 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4, PM3_Supporting The c.969+6T>C variant in PAH is absent from population databases (PM2). It has been observed in at least one mild PKU patient (PMID: 24941924; PP4). The patient is compound heterozygous with pathogenic variant c.1066‐11G>A (ClinVar 607; PM3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020907/MONDO:0009861/006 2020-07-09 2022-06-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6149 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0007859 infores:hetionet CHEBI:15854 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0019048 infores:hetionet NCBIGene:27241 biolink:causes MONDO:0014437 infores:monarchinitiative not_provided not_provided HGNC:30000 MONDO:0014437 uuid:5d56ed9c-10a9-46db-a841-60d121959fc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8459596 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459596 MONDO:0011132 PMID:37419334 Likely Benign BP4, BS1 BS3 The NM_001369369.1(FOXN1):c.1664C>T (p.Ala555Val) missense variant has a gnomADv2.1.1 PopMax filtering AF of 0.003187 based on 77/19952alleles in the East Asian population, which is above the >0.00141 threshold for BS1. No deleterious effect is predicted with a REVEL score of 0.197 meeting the threshold of <0.290 for BP4. Additionally, no splicing effect is predicted by SpliceAI (delta score 0.00). After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1, BP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459596/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:51041 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0013378 infores:hetionet CAID:CA8130277 biolink:causes MONDO:0007648 infores:clingen CAID:CA8130277 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.2439+22C>T has a frequency of 0.00096 in gnomAD (271 of 280,840), with a maximum subpopulation frequency of 0.01029 (255 of 24,778) in the African population and includes one homozygote (BA1; http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets criteria to be classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8130277/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:47381 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0010346 infores:hetionet CHEBI:6887 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0152030 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042373 infores:hetionet CHEBI:36795 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0030252 infores:hetionet CHEBI:119573 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151474 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0029408 infores:hetionet CHEBI:3423 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0011603 infores:hetionet CHEBI:31236 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0025222 infores:hetionet CHEBI:9613 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0232459 infores:hetionet CHEBI:18248 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0700590 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011849 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0040479 infores:hetionet CHEBI:3077 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0042384 infores:hetionet NCBIGene:2954 biolink:causes MONDO:0060527 infores:monarchinitiative not_provided not_provided HGNC:4643 MONDO:0060527 uuid:6ba2c851-e895-43b4-a1e6-e6fd7624db82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3U02EL437C biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0877098 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004238 infores:hetionet CHEBI:7936 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038325 infores:hetionet CHEBI:27882 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0086565 infores:hetionet CHEBI:39867 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0700361 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0023067 infores:hetionet CHEBI:3749 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0497156 infores:hetionet CHEBI:3398 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0040822 infores:hetionet CHEBI:110423 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0002994 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0878773 infores:hetionet CHEBI:135193 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0235063 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0037274 infores:hetionet CHEBI:31625 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0086543 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151888 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0003123 infores:hetionet UMLS:C0879264 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0018681 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0575805 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0575805 infores:hetionet CHEBI:18243 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0039231 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0016397 infores:hetionet CHEBI:28901 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1142412 infores:hetionet CAID:CA399790478 biolink:causes MONDO:0100326 infores:clingen CAID:CA399790478 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3, BP4, PS3 The NM_000419.5:c.2933G>T (p.Gly978Val) variant in ITGA2B is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 978 (p.Gly978Val). At least one patient (Patient GT-1 in PMIDs 22837472 and 30934104) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, αIIbβ3 surface expression was reduced to 0%, as measured by flow cytometry. This individual was compound heterozygous for this variant and the NM_000419.5(ITGA2B):c.2994G>A (p.Trp998Ter) variant, which was classified as Pathogenic by the PD VCEP. The phase of the variants in this proband is unknown (PMID: 22837472, PM3_Supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399790478/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:4027 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0231218 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0009450 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0017574 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042594 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006277 infores:hetionet CAID:CA16620635 biolink:causes MONDO:0018875 infores:clingen CAID:CA16620635 MONDO:0018875 PMID:29979965PMID:30224644PMID:12826609 Likely Benign PP3_Moderate, BS2_Supporting, BS3, PM2_Supporting BP4, BP2, BA1, PS1, PS3, PS2, PM1, BS1, BS4, PM6, PP1 The NM_000546.6: c.353C>T variant in TP53 is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 118 (p.Thr118Ile). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; ClinVar SCVs: SCV000664386.6). This variant has an allele frequency of 0.0000006203 (1/1612196 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.3466; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, PP3_Moderate. (Bayesian Points: -2; VCEP specifications version 2.3). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620635/MONDO:0018875/009 2025-03-04 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28445 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0013428 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0021053 infores:hetionet CAID:CA6403580 biolink:causes MONDO:0019565 infores:clingen CAID:CA6403580 MONDO:0019565 PMID: Likely Benign BS1 BP4 The NM_000552.5:c.1037C>T variant in VWF is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 346. The variant has been reported in the literature in individuals associated with control or unaffected cohorts. In a single report of a case with asserted VWD type 1, the laboratory phenotype was not consistent with VWD. The variant was also reported to LOVD but no additional details were in the record. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01275 (based on 1008/75020 alleles in the African/African American population, including 10 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 for BS1. In summary, this variant meets the criteria to be classified as likely benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1. ( Required: add VCEP specifications version#; date of approval) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6403580/MONDO:0019565/081 2025-11-04 2025-11-04 Undetermined mode of inheritance Contradicts true CHEBI:6950 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0031256 infores:hetionet CHEBI:17650 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151937 infores:hetionet CHEBI:8874 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151836 infores:hetionet CHEBI:2569 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0547030 infores:hetionet NCBIGene:463 biolink:causes MONDO:0010847 infores:monarchinitiative not_provided not_provided HGNC:777 MONDO:0010847 uuid:6b6d563a-b894-4c4a-a550-2b32837a64e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0232462 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0001339 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027765 infores:hetionet CHEBI:7660 biolink:causes UMLS:C0023775 infores:drugmechdb knowledge_assertion manual_agent MESH:D009761 UMLS:C0023775 DB00646_MESH_D002180_1DB00646_MESH_D002179_1DB00646_MESH_D002181_1 CHEBI:49575 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0740399 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0031542 infores:hetionet CAID:CA412741475 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741475 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.851C>G (p.Ser284Ter) is a nonsense variant that introduces a premature stop in codon 284 within exon 8 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1pts), night blindness (0.5 pts), reduced visual acuity (0.5 pts), pigment deposits (0.5 pts), optic disc pallor (0.5 pts), and genotyping by next-generation sequencing with a panel of 483 genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741475/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:50275 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014869 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0002928 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0002928 infores:hetionet CHEBI:17263 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0013604 infores:hetionet CHEBI:6704 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0025323 infores:hetionet CAID:CA383503778 biolink:causes MONDO:0015630 infores:clingen CAID:CA383503778 MONDO:0015630 PMID: Likely Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate The NM_000552.5(VWF):c.4225G>T variant in VWF is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 1409. This variant has been reported in at least 3 apparently unrelated probands exhibiting a VWD Type 2M phenotype (PMID: 28971901 and PMID: 19404524, PS4_Moderate). The two probands of PMID: 28971901, exhibit excessive mucocutaneous bleeding as well as a laboratory phenotype of normal multimers, low VWF:RCo/VWF:Ag ratio and low collagen binding, which together are specific for VWD type 2M (PP4_Moderate). Low FVIII activity, an inconsistent phenotype, was also reported in these patients. The variant has been reported to segregate with VWD type 2M through at least 2 affected meioses from 2 different families (PP1_Moderate; PMID: 28971901). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The computational splicing predictor SpliceAI indicates that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP1_Moderate, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383503778/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports GO:0010946 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0010946 GO:0051321 GO:0060644 biolink:causes CL:0002327 infores:ubergraph knowledge_assertion manual_agent GO:0060644 CL:0002327 CHEBI:63598 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0860866 infores:hetionet CHEBI:46345 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0235266 infores:hetionet CHEBI:188986 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0013182 infores:hetionet NCBIGene:10585 biolink:causes MONDO:0012248 infores:monarchinitiative not_provided not_provided HGNC:9202 MONDO:0012248 uuid:1f11fc7f-1049-4663-8bf1-694625aa9189 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0740394 infores:hetionet CHEBI:4315 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0037763 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020538 infores:hetionet CHEBI:9943 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0036974 infores:hetionet CHEBI:7565 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0038450 infores:hetionet NCBIGene:91754 biolink:causes MONDO:0014873 infores:monarchinitiative not_provided not_provided HGNC:18591 MONDO:0014873 uuid:17c2bb86-3e8c-4f07-8929-baac6c8c7686 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019209 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0235620 infores:hetionet CHEBI:10110 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0042023 infores:hetionet CHEBI:8382 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0424295 infores:hetionet CHEBI:71417 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0043352 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0235416 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0259768 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0035508 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0038587 infores:hetionet CAID:CA658798681 biolink:causes MONDO:0009276 infores:clingen CAID:CA658798681 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3, PS3_Supporting PP1 The c.104del (p.Lys35ArgfsTer4) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient GA in PMID: 8950770) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). They also had thrombocytopenia, giant platelets, and life-long severe bleeding, including recurrent bruising and prolonged bleeding time. This variant has been detected in at least 2 probands with Bernard-Soulier syndrome (PMID: 8950770 and 36507135). These individuals were both homozygous for the variant (PM3). Surface expression of GP1A measured by flow cytometry in mouse L cells transiently co-transfected with c.104del (p.Lys35ArgfsTer4) variant GP1A and wild type GP1B-GP9 showed undetectable expression at 0% WT levels, indicating that this variant impacts protein function (PMID: 8950770, PS3_supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 3.000e-7 (based on 2/1179868 alleles) in the European non Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting, PM3, and PS3_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798681/MONDO:0009276/079 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5132 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0033246 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0022658 infores:hetionet CHEBI:2904 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0023212 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0037274 infores:hetionet CAID:CA410147570 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147570 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, BA1, BP1, BP3, BP2, BP5, BS1, BS3, PM3, PM5, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.1268G>A (p.Arg423His) is a missense variant which has a REVEL score < 0.50 (0.445) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147570/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47780 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0267792 infores:hetionet CAID:CA10014176 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014176 MONDO:0011071 PMID: Benign BA1, BP4 PS4, PS3, PS1, BP2, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.1396A>T variant that results in a Met466Leu missense change has an MAF of 0.001761 (0.1%, 23/13058 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort, which is >0.0015 (0.15%) (BA1). This missense variant has a REVEL score <0.15 (0.149) and SSF and MES predict no effect on splicing (BP4). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014176/MONDO:0011071/008 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:71415 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0009676 infores:hetionet CAID:CA658824780 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824780 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.766_767insC (p.Tyr256SerfsTer74) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in a patient with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 550104. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf )GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824780/MONDO:0009290/010 2023-05-26 2023-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ GO:0021914 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0021914 GO:0007399 CHEBI:40279 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0011603 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0009241 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0235416 infores:hetionet CHEBI:37941 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019065 infores:hetionet CHEBI:71941 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0042029 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0019360 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0027813 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0232492 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0497365 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0017178 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0034186 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0037274 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009760 infores:hetionet CHEBI:2904 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0015230 infores:hetionet CAID:CA10360460 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360460 MONDO:0100039 PMID: Likely Benign BP5, BS2 BS1, PM2, BP4, BA1 The p.Leu703Val variant in CDKL5 is present in 1 female individual in gnomAD (0.0005%) (not sufficient to meet BS1 criteria). The p.Leu703Val variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Leu703Val variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Leu703Val variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360460/MONDO:0100039/034 2023-08-28 2023-09-14 X-linked inheritance HP:0001417 Contradicts true CHEBI:31199 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0016436 infores:hetionet CHEBI:134991 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0004604 infores:hetionet CHEBI:8356 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0028734 infores:hetionet CHEBI:7577 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0085649 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0027051 infores:hetionet CHEBI:17650 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151970 infores:hetionet CHEBI:3723 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0438142 infores:hetionet CHEBI:50729 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151539 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0687133 infores:hetionet CAID:CA409118977 biolink:causes MONDO:0007064 infores:clingen CAID:CA409118977 MONDO:0007064 PMID: Uncertain Significance PM2, BA1, PM5, BS1 The c.902A>G (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 301 (p.Lys301Arg).The highest population minor allele frequency in gnomAD v4 is 0.0002240 (1/4464 alleles) in the Middle Eastern population. As this is a known gnomAD bottleneck population, and additionally has a higher SCID prevalence, we are excluding this population from this analysis. The second highest MAF is 0.00002423 (1/41270 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting and, therefore, meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Also, no homozygous was reported (BS2 Not Met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409118977/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4653 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0039971 infores:hetionet CAID:CA259739 biolink:causes MONDO:0044970 infores:clingen CAID:CA259739 MONDO:0044970 PMID: Likely Benign BA1 PP3, BP4, PS4, PS2, PS3, BS1, PM6, PM2 The m.5814T>C variant in MT-TC was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1996. However, other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at very high frequencies in population databases, especially in individuals in haplogroup L2. The variant was first reported in individuals with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS, PMID: 8829635); progressive external ophthalmoplegia and encephalopathy (PMID: 9185178); hypertrophic cardiomyopathy, myopathy, and lactic acidosis (PMID: 11453453); exercise intolerance and ragged red fibers (PMID: 11335700); and severe encephalopathy (PMID: 17241783). The variant was present at >90% heteroplasmy to homoplasmy in all severely affected individuals. The variant was present at variable levels in family members of affected individuals, ranging from 8% to homoplasmy (PMIDs: 9185178, 11335700, 17241783). There are no reported de novo occurrences of the variant to our knowledge. Single fiber testing was performed however there was wide variability in the heteroplasmy level in normal and abnormal muscle fibers, as well as overlap in the heteroplasmy levels among normal and abnormal muscle fibers (PMID: 8829635). This variant is present at high frequencies in population databases (BA1). The frequency in the MITOMAP GenBank sequences is 215/59,389 (0.362%) including in 132/133 individuals from haplogroup L2b and also seen in individuals from haplogroups R0, N, H4a, B4a, and others. The frequency in gnomAD v3.1.2 is 779/56,413 (1.377%) including 777 homoplasmic occurrences (seen across populations and haplogroups, highest in African/African Americans and L2) and two heteroplasmic occurrences, and seen in individuals across age groups. The frequency in Helix is 519/195,983 (0.255%) including 500 homoplasmic occurrences (seen across haplogroups, highest in L2) and 19 heteroplasmic occurrences. The computational predictor MitoTIP suggests this variant is benign (38.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.75. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This variant is associated with haplogroup L2 and therefore would not be associated with primary mitochondrial disease in individuals from this haplogroup. While this variant is seen across haplogroups, the effects of this variant in other haplogroups is not as well-defined. Furthermore, while single fiber testing showed differences in mean heteroplasmy levels in normal and abnormal muscle fibers, this did not provide definitive evidence of pathogenicity. However, taken together, this expert panel elected to modify the classification to likely benign. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA259739/MONDO:0044970/015 2023-06-26 2023-08-03 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6717 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0014356 infores:hetionet CHEBI:28864 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0019079 infores:hetionet CHEBI:61390 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0162429 infores:hetionet CAID:CA10014549 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014549 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP1, BP2, BP3, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM3, PM1, PM4, PM5, PP2, PP3, PP4, PP1, BS2 Synonymous variant (no REVEL score applicable) with SpliceAI score ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.160 (< 2.0)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014549/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50742 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C3665347 infores:hetionet CHEBI:51173 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0009676 infores:hetionet CHEBI:64312 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042023 infores:hetionet CHEBI:68558 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0015230 infores:hetionet CHEBI:6904 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0007398 infores:hetionet CHEBI:48273 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0236075 infores:hetionet CHEBI:6456 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0012833 infores:hetionet CHEBI:63577 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0002792 infores:hetionet CHEBI:135925 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0002994 infores:hetionet CHEBI:84050 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0162834 infores:hetionet CAID:CA229699 biolink:causes MONDO:0009861 infores:clingen CAID:CA229699 MONDO:0009861 PMID:9012412PMID:24705691PMID:24705691 Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Strong The c.699C>A (p.Phe233Leu) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded), detected in trans with pathogenic variants: p.S70del (PMID: 24705691); p.Ala403Val, p.Arg243Gln (PMID: 23500595). This variant is absent in population databases. Computational prediction tools and conservation analysis support a deleterious effect. Another variant at the same amino acid (p.F233I) is interpreted as pathogenic by the ClinGen PAH VCEP. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229699/MONDO:0009861/006 2020-11-09 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410203818 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203818 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.242T>C (p.Val81Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 1024911). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203818/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:70735 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0027765 infores:hetionet CHEBI:64354 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C1318520 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0917798 infores:hetionet CHEBI:116278 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0007820 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1258215 infores:hetionet CHEBI:60761 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0085636 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235890 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0235818 infores:hetionet CHEBI:68534 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0006277 infores:hetionet CHEBI:135925 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0878544 infores:hetionet CHEBI:3696 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013428 infores:hetionet GO:0006954 biolink:causes MONDO:0002400 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D013585 DB01397_MESH_D013585_1 NCBIGene:57169 biolink:causes MONDO:0030491 infores:monarchinitiative not_provided not_provided HGNC:29271 MONDO:0030491 uuid:ea01275e-1d55-42fa-9cc1-51aa96aa625d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020598 infores:hetionet CHEBI:38545 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0035455 infores:hetionet CHEBI:75722 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232462 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0008325 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023530 infores:hetionet CHEBI:82941 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0015230 infores:hetionet CAID:CA226545 biolink:causes MONDO:0100368 infores:clingen CAID:CA226545 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a nonsense variant that introduces a premature stop codon into exon 5 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002191, with 9 alleles / 24480 total alleles in the African/African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226545/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports UNII:9430ZR8ZAN biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0022660 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0149931 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0162429 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042075 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1145628 infores:hetionet CHEBI:4909 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0006277 infores:hetionet CHEBI:45081 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0699744 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0152027 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005520 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0035579 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0521839 infores:hetionet NCBITaxon:4890 biolink:causes MONDO:0001628 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:4890 MONDO:0001628 CHEBI:3752 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0085633 infores:hetionet CHEBI:10102 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0018681 infores:hetionet CAID:CA2573133615 biolink:causes MONDO:0100062 infores:clingen CAID:CA2573133615 MONDO:0100062 PMID: Pathogenic PM2_Supporting, PVS1, PS2_Moderate The c.585_586del (p.Phe195LeufsTer?) variant in SCN3A frameshift variant predicted to cause nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been identified as de novo with confirmed parental relationships in at least one individual with a consistent phenotype (PS2_Moderate, internal data (Invitae)). The variant is absent from the population database, gnomAD v2.1.1. (PM2_Supporting). In summary, this variant has been classified as pathogenic for autosomal dominant developmental and epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by the Epilepsy Sodium Channel VCEP: PVS1, PS2_Moderate, PM2_Supporting (version 1.0; approved 12/11/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573133615/MONDO:0100062/069 2024-05-07 2024-05-07 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3082 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0235198 infores:hetionet CHEBI:45951 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0424448 infores:hetionet CHEBI:15367 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0010520 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020615 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0233494 infores:hetionet CHEBI:6129 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0028961 infores:hetionet CAID:CA16613246 biolink:causes MONDO:0017623 infores:clingen CAID:CA16613246 MONDO:0017623 PMID:23399955PMID:23335809PMID:27531073PMID:27829222PMID:10866302PMID:17942903PMID:21828076PMID:29706350PMID:31006514 Pathogenic PM6, PM2, PP2, PS4, PS3 PVS1, BS4, BS3, BS1, BP7, BP5, PP1, PP3, BS2, PM4, PM1, PM5, BP2, BP4, BA1, PS2, PS1 PTEN c.464A>G (p.Tyr155Cys) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076, 10866302, 29706350)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 23399955, internal laboratory contributors SCV000579967.3, ClinVar Organization ID: 19864)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613246/MONDO:0017623/003 2019-11-22 2019-12-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3756 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0040409 infores:hetionet CHEBI:4877 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0235896 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0080203 infores:hetionet CHEBI:27834 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0030554 infores:hetionet CHEBI:3215 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151636 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0006019 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:D015001 DB00595_MESH_D015001_1DB01053_MESH_D015001_1DB00618_MESH_D015001_1DB01017_MESH_D015001_1DB00759_MESH_D015001_1DB13092_MESH_D015001_1DB02703_MESH_D015001_1DB09320_MESH_D015001_1DB00254_MESH_D015001_1 CHEBI:75045 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0042909 infores:hetionet CHEBI:36791 biolink:causes HP:0003978 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0034628 infores:hetionet CHEBI:41977 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0030193 infores:hetionet CHEBI:28748 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085624 infores:hetionet NCBIGene:3394 biolink:causes MONDO:0013957 infores:monarchinitiative not_provided not_provided HGNC:5358 MONDO:0013957 uuid:eb960e69-e0fb-43f9-8f21-772c6a2c6709 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:520985 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0917801 infores:hetionet CHEBI:51364 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0013384 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0178298 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0342579 infores:hetionet CHEBI:4779 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0235266 infores:hetionet CHEBI:64354 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0042963 infores:hetionet CHEBI:71219 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0006145 infores:hetionet CHEBI:28939 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C1306341 infores:hetionet CHEBI:6904 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0026858 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042373 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0038454 infores:hetionet CAID:CA367400174 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400174 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting PS4, PM1, PP4 The c.875T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 292 (p.(Leu292Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (no fasting glucose data) (internal lab contributors). In summary, c.875T>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400174/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA638054527 biolink:causes MONDO:0100083 infores:clingen CAID:CA638054527 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 BP4: This intronic variant has a SpliceAI Δ score 0< 0.2BP7: Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score < 2.0 (BP7).In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteriaapplied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1:BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054527/MONDO:0100083/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:75722 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232461 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0232208 infores:hetionet UMLS:C0004609 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0004604 infores:hetionet CAID:CA645584081 biolink:causes MONDO:0009861 infores:clingen CAID:CA645584081 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate, PP3 The c.969+4A>T PAH variant has been reported in 1 Northwest Chinese patient with PAH deficiency (Phe ≥ 1200 μmol/L) (PMID: 30747360). A defect in BH4 metabolism was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant is absent from population databases gnomAD, 1000 Genomes and ESP. Splicing prediction algorithms predict this variant to be probably damaging. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA645584081/MONDO:0009861/006 2020-12-11 2021-03-03 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36791 biolink:causes NCIT:C92849 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0240802 infores:hetionet CHEBI:10650 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0497156 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0033687 infores:hetionet CHEBI:7824 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085649 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013447 infores:hetionet CHEBI:2666 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0020458 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0040264 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0347390 infores:hetionet UMLS:C1738934 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0013428 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011849 infores:hetionet CHEBI:4995 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0233471 infores:hetionet UMLS:C0004609 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0575081 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0021400 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0948594 infores:hetionet CHEBI:28901 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151578 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020649 infores:hetionet CAID:CA9204959 biolink:causes MONDO:0007750 infores:clingen CAID:CA9204959 MONDO:0007750 PMID: Uncertain Significance BP4 BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.2389+14G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023.The supporting evidence is as follows:BP4: No REVEL, splicing evaluation is required.Functional data on splicing not available.A) not within limitsB) does not create GT C) not within limitsVariant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA9204959/MONDO:0007750/013 2023-03-27 2024-10-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10119 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040435 infores:hetionet CHEBI:5779 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0020458 infores:hetionet CHEBI:50729 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151662 infores:hetionet CHEBI:478164 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0023530 infores:hetionet CHEBI:3215 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0036974 infores:hetionet CAID:CA415085444 biolink:causes MONDO:0010305 infores:clingen CAID:CA415085444 MONDO:0010305 PMID: Uncertain Significance BP7, PM2_Supporting, BP4 The NM_005629.4:c.1068C>T variant in SLC6A8 is a synonymous (silent) variant (p.Gly356=). To our knowledge, this variant has not been reported in the literature and no functional studies are available. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). SpliceAI predicts no impact on splicing (score <0.2) and the nucleotide is poorly conserved (PhyloP score -0.67) (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 804100). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415085444/MONDO:0010305/027 2025-01-07 2025-01-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:2379 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0015672 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0232431 infores:hetionet CHEBI:17347 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0040038 infores:hetionet CHEBI:39585 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0041657 infores:hetionet CHEBI:45652 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0026826 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233632 infores:hetionet CHEBI:92712 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0151908 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0017160 infores:hetionet CHEBI:167309 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0151878 infores:hetionet CHEBI:142290 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0235378 infores:hetionet CHEBI:50777 biolink:causes MONDO:0000755 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0032987 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0314719 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0002871 infores:hetionet CHEBI:31401 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151699 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0392025 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009319 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0340464 infores:hetionet CHEBI:28748 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020461 infores:hetionet CHEBI:17650 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0338656 infores:hetionet CHEBI:2636 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0015230 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0541865 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0541865 infores:hetionet CHEBI:3423 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151799 infores:hetionet CAID:CA024145 biolink:causes MONDO:0018493 infores:clingen CAID:CA024145 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with tryptophan at codon 4820 of the RYR1 protein, p.(Gly4820Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (.918) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024145/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:49603 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0025061 infores:hetionet CHEBI:84050 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0235378 infores:hetionet CHEBI:9637 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0017181 infores:hetionet CHEBI:9555 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0948441 infores:hetionet CHEBI:63619 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0016204 infores:hetionet CHEBI:3048 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0011603 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0024437 infores:hetionet CHEBI:18358 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0015967 infores:hetionet CHEBI:80630 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C1142412 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0233494 infores:hetionet CHEBI:9907 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0030193 infores:hetionet CHEBI:51860 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0392676 infores:hetionet CHEBI:4445 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0234632 infores:hetionet CHEBI:3504 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0028734 infores:hetionet GO:0044493 biolink:causes GO:0005248 infores:ubergraph knowledge_assertion manual_agent GO:0044493 GO:0005248 CHEBI:5130 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017574 infores:hetionet CAID:CA7511300 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511300 MONDO:0015152 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong PM2, BP7, PS3 The NM_000070.3: c.1250C>T variant in CAPN3 is a missense variant predicted to cause the substitution of threonine by methionine at codon 417, p.(Thr417Met). Across a selection of the available literature, this variant has been detected in at least seven individuals with features consistent with LGMD (PMID: 19556129, 27447704, 16650086, 37526466), including in a homozygous state in two patients without reported familial consanguinity (1.0 pt, PMID: 37526466) and confirmed in trans with a pathogenic variant in at least three patients (c.550del p.(Thr184ArgfsTer36) x2, 2.0 pts, PMID: 27447704, 37526466; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 1.0 pt, PMID: 16650086) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 16650086; PP4_Moderate). The filtering allele frequency of this variant is 0.0001353 (the upper threshold of the 95% CI of 130/1111468 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.90, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). A minigene assay showed the variant does not affect splicing (PMID: 32668095), consistent with the SpliceAI score of 0.02. In vitro evidence indicates that the p.Thr417Met amino acid change results in accelerated autoproteolysis, rendering the enzyme inactive prematurely (PMID: 19226146). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/03/2025): PM3_Very Strong, PP4_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511300/MONDO:0015152/187 2025-05-03 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:585948 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0008031 infores:hetionet CHEBI:8713 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0001824 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0853619 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006266 infores:hetionet CHEBI:41879 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0232462 infores:hetionet CHEBI:168396 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011603 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0008035 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0235639 infores:hetionet UMLS:C1738934 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0231807 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0002871 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020295 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0221776 infores:hetionet CHEBI:8888 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0001807 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0004096 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0549475 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0392106 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0392106 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020651 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0020517 infores:hetionet CHEBI:27777 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0040822 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151735 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151626 infores:hetionet CHEBI:7936 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085583 infores:hetionet CHEBI:6076 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0036830 infores:hetionet CAID:CA412745655 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745655 MONDO:0100437 PMID: Likely Pathogenic PP3_Strong, PP4, PP1, PM2_Supporting PP2, BS2, PM5, PM1, PS3, PS4, BP1, BP4, BA1, BS1, BS3, BS4 NM_001034853.2(RPGR):c.178G>A (p.Gly60Ser) is a predicted missense variant that replaces glycine with serine at amino acid 60. Another missense variant in the same codon, NM_001034853.2(RPGR):c.179G>T (p.Gly60Val), has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. However, the present variant has a lower Grantham’s distance (56) than the comparison variant (109), so the PM5_Supporting code is not met. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of rod-cone dystrophy with childhood onset (1 pt), electroretinogram confirmation of rod involvement greater than cone (1pt), genotyping by next-generation sequencing using a 105-gene panel that did not identify an alternative cause of retinal disease (2 pts), family history consistent with X-linked inheritance (2 pts), night blindness (0.5 pts), and photophobia (0.5 pts), which together are specific for RPGR-related retinopathy (7 points, PMID: 28341476, https://c.peervoice.com/programs/505204504/downloads/PV_transcript_CHS_EN.pdf, PP4). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 28341476). The computational predictor REVEL gives a score of 0.944, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_Strong). Also, the computational splicing predictor SpliceAI gives delta scores of 0.35 for acceptor loss and 0.33 for donor loss, which are above the ClinGen X-linked IRD VCEP threshold of >0.2 and predict a damaging impact on splicing. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP4, PP1, and PP3_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745655/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:45409 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0010692 infores:hetionet CAID:CA120182 biolink:causes MONDO:0015967 infores:clingen CAID:CA120182 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Moderate, PP1_Strong The c.763C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 255 (p.(Gln255Ter)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and located in biologically relevant exon 7 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 8945471, 22060211, internal lab contributors). This variant was segregated with diabetes, with at least 33 informative meioses in three families (PP1_Strong; PMID: 8945471, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.763C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PS4_moderate, PP1_strong, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA120182/MONDO:0015967/085 2024-08-30 2024-08-30 Autosomal dominant inheritance HP:0000006 Supports CAID:CA232789 biolink:causes MONDO:0015152 infores:clingen CAID:CA232789 MONDO:0015152 PMID: Pathogenic PM3_Strong, PP1_Strong, PP3, PP4, PM2_Supporting PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM5, PM1, PP2, BS2, BP3, BP1, BP4, BP2, BA1 The NM_213599.3: c.2018A>G variant in ANO5 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 673 (p.Tyr673Cys). This variant has been detected in at least 6 individuals with autosomal recessive limb-girdle muscular dystrophy. Of those individuals, five had another pathogenic or likely pathogenic variant, with three confirmed in trans by parental testing (c.191dup x2, 2 pts, PMIDs: 21820307, 21186264) and two phase unknown (c.191dup, 0.5 pts, ClinVar SCV001371267.12 internal data communication; c.989dup, 0.5 pts, PMID: 23606453). One individual was homozygous for the variant (0.5 pts, ClinVar SCV000767092.3 internal data communication) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PP4; PMD: 21820307). The variant has been reported to segregate with the LGMD phenotype in four affected family members from two families (PP1_Strong; PMID: 21186264, 23670307). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15424 alleles) in the European (non-Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.88, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Strong, PP1_Strong, PP4, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA232789/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:145499 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0022904 infores:hetionet CAID:CA381946913 biolink:causes MONDO:0019501 infores:clingen CAID:CA381946913 MONDO:0019501 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong The p.Asn1182Lys variant in MYO7A is a missense variant predicted to cause substitution of asparagine to lysine at amino acid 1182. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.833 which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own (PP3). This variant has been detected in at least four probands with AR Usher syndrome. Two patients were homozygous for the variant, while the other two were compound heterozygous with a pathogenic or likely pathogenic variant; however only one was confirmed trans (c.721C>T (p.Arg241Cys), 2.0 PM3_Strong points, PMID:27460420, 28041643, 31479088, Invitae Internal Data (SCV001211338.4)). At least one patient with a variant identified in this gene displayed sensorineural hearing loss and retinitis pigmentosa, features consistent with Usher syndrome (PP4). The variant has been reported to segregate with AR Usher syndrome in 1 affected family member from 1 family (PP1; PMID: 31479088). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Strong, PP1, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA381946913/MONDO:0019501/005 2023-06-27 2023-10-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:3181 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0026821 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0236071 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0000918 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D004716 DB01598_MESH_D004716_1DB00916_MESH_D004716_1DB01212_MESH_D004716_1DB01597_MESH_D004716_1DB01331_MESH_D004716_1 CHEBI:3723 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042024 infores:hetionet NCBIGene:1767 biolink:causes MONDO:0012085 infores:monarchinitiative not_provided not_provided HGNC:2950 MONDO:0012085 uuid:b7f28f37-ba10-4fda-a2d0-3c70b4816035 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27974 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0002792 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C2973529 infores:hetionet CAID:CA405665125 biolink:causes MONDO:0007783 infores:clingen CAID:CA405665125 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with phenylalanine at codon 4039 of the RYR1 protein, p.(Ile4039Phe). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.621 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405665125/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10119 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0016204 infores:hetionet CHEBI:77032 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0017178 infores:hetionet CHEBI:31348 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549567 infores:hetionet CAID:CA254160 biolink:causes MONDO:0012589 infores:clingen CAID:CA254160 MONDO:0012589 PMID:17436254PMID:17436254PMID:17436254 Pathogenic PS3_Supporting, PM1, PP3, PP4, PM6_Strong, PS4_Supporting, PM2_Supporting The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA254160/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:9435 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0013404 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013922 infores:hetionet CHEBI:45924 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0018524 infores:hetionet CHEBI:4470 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0004936 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151883 infores:hetionet CAID:CA10385258 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385258 MONDO:0100437 PMID: Benign BP3, BA1 PM2 NM_001034853.2(RPGR):c.2606_2632dup (p.Glu869_Glu877dup) is a short in-frame insertion of 27 base pairs that encode additional residues between amino acids 869 and 877 within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v4.1.0 at a frequency of 0.0003639 among hemizygous individuals, with 75 variant alleles / 206,093 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385258/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:31644 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0438215 infores:hetionet CHEBI:6073 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0011603 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0162429 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0178298 infores:hetionet CHEBI:6690 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0022346 infores:hetionet CAID:CA915950964 biolink:causes MONDO:0100437 infores:clingen CAID:CA915950964 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2790_2791del (p.Glu931GlyfsTer?) is a frameshift variant due to 2-nucleotide deletion introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 10 affected meioses from 1 family (PP1_Moderate; PMID: 32679846). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915950964/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:45863 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0919980 infores:hetionet CHEBI:5098 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0542184 infores:hetionet CAID:CA350341728 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341728 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM1 BP4, BA1, PM5, PS1, BS1 The c.1151C>T (p.Ala384Val) variant is a missense variant located in exon 9 of the BMPR2 gene, predicted to cause substitution of alanine to valine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating critical or non-critical (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.917, AlphaMissense is 0.9915 indicating pathogenicity (PP3_met). The variant has been reported in one Japanese individual (PMID: 23675998) and one Chinese individual (PMID: 30578397, PMID: 32634488) with idiopathic PAH (PS4_supporting). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341728/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9586 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0003864 infores:hetionet NCBIGene:170302 biolink:causes MONDO:0010654 infores:monarchinitiative not_provided not_provided HGNC:18060 MONDO:0010654 uuid:bc82bc0e-4316-4199-86a7-7526f1bac54b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C2047937 infores:hetionet CAID:CA399804780 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804780 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000419.5(ITGA2B):c.957T>A (p.Tyr319Ter) variant in exon 11/30 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient GT12 in PMID:25373348) with this variant (compound heterozygous with c.2326_2331dup) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting. (VCEP specifications version 2; date of approval 05/17/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804780/MONDO:0100326/011 2022-05-17 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6128 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0013404 infores:hetionet CHEBI:50777 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0013428 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C3284 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0028778 infores:hetionet CHEBI:66876 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0231528 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0549373 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0234916 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0234930 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0677500 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1262091 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1262091 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151883 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0700345 infores:hetionet CHEBI:8212 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0015732 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0178298 infores:hetionet CAID:CA16020979 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020979 MONDO:0009861 PMID:21890392PMID:21890392 Pathogenic PM2, PM5, PP3, PP4, PM3_Strong The c.1244A>T (p.Asp415Val) variant in PAH has been reported in 2 individuals with PKU, detected in trans with pathogenic variants c.1066-11G>A and c.47_48delCT (PMID: 21890392). This variant is absent in population databases. Computational prediction tools and conservation analysis support a deleterious effect. Another missense variant at the same amino acid is interpreted as pathogenic (p.Asp415Asn) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020979/MONDO:0009861/006 2020-11-09 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7573 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0023530 infores:hetionet CHEBI:10125 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C3665386 infores:hetionet CHEBI:64045 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0015672 infores:hetionet CHEBI:101853 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0011603 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0008370 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0002170 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006809 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0007780 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0086543 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0003123 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005030 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0015934 infores:hetionet NCBIGene:1824 biolink:causes MONDO:0012506 infores:monarchinitiative not_provided not_provided HGNC:3036 MONDO:0012506 uuid:c0a1b7e1-9c82-4d0a-9b05-096f035361e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0005758 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0877211 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0877211 infores:hetionet CHEBI:3749 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0018681 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0011609 infores:hetionet CHEBI:3757 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C2225524 infores:hetionet CHEBI:5138 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0003578 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151717 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0027497 infores:hetionet CHEBI:6128 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0232462 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009326 infores:hetionet CHEBI:36704 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030201 infores:hetionet CAID:CA024489 biolink:causes MONDO:0018493 infores:clingen CAID:CA024489 MONDO:0018493 PMID: Uncertain Significance PM1 PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a deletion of aspartic acid at codon 17 of the RYR1 protein, p.(Asp17del). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024489/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:119573 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0019209 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009319 infores:hetionet NCBIGene:60386 biolink:causes MONDO:0011790 infores:monarchinitiative not_provided not_provided HGNC:14409 MONDO:0011790 uuid:2b2982be-4594-47db-8225-ffddd37013a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0855242 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0040034 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0684249 infores:hetionet CHEBI:49603 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0018681 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0151571 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151571 infores:hetionet CHEBI:42820 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0003123 infores:hetionet CAID:CA1251327 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251327 MONDO:0013144 PMID: Uncertain Significance PM5, PP3 PS4, BS1, PM2 The NM_000488.4:c.858G>C variant, which predicts a Gln286His missense change is reported at POPMAX FAF of 0.0001666 in the African/African American population in gnomAD v3.1.2, but does not meet BS1 cut-off of >=0.0002. The variant has a REVEL score of 0.697 and meets PP3 cut-off of >0.6. It is not reported in individuals with AT deficiency in the literature, to the best of our knowledge. It is reported in dbSNP (rs139463995). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPiNC1: PP3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251327/MONDO:0013144/084 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0032285 infores:hetionet CHEBI:5118 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011175 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0877092 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0877092 infores:hetionet CAID:CA229705 biolink:causes MONDO:0009861 infores:clingen CAID:CA229705 MONDO:0009861 PMID:1363786PMID:11295882PMID:1363786 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The c.712A>C (p.Thr238Pro) variant in PAH has been reported in 2 individuals with PKU, detected with pathogenic variants p.R408W (PMID: 1363786) and p.R158Q (PMID: 11295882). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229705/MONDO:0009861/006 2020-10-23 2020-10-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38562 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0035410 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0750151 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0750151 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0232459 infores:hetionet CHEBI:9725 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0014457 infores:hetionet CHEBI:585948 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0039231 infores:hetionet CHEBI:94392 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0038362 infores:hetionet NCBIGene:23443 biolink:causes MONDO:0014248 infores:monarchinitiative not_provided not_provided HGNC:11023 MONDO:0014248 uuid:f2c9dedb-1259-4d5e-878c-f31cb1f58646 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3172 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0085633 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0858259 infores:hetionet CHEBI:9130 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0042963 infores:hetionet CHEBI:8024 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0014742 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0234193 infores:hetionet CHEBI:46195 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0699828 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0002170 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020437 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0019572 infores:hetionet NCBIGene:84668 biolink:causes MONDO:0012514 infores:monarchinitiative not_provided not_provided HGNC:24587 MONDO:0012514 uuid:c10ec40e-c04a-42ec-8fbc-5defdf14b7bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151971 infores:hetionet CHEBI:8214 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0011570 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027765 infores:hetionet CHEBI:17549 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0027497 infores:hetionet CHEBI:3011 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0009806 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0236068 infores:hetionet CHEBI:50838 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0004936 infores:hetionet GO:0042682 biolink:causes GO:0042676 infores:ubergraph knowledge_assertion manual_agent GO:0042682 GO:0042676 CHEBI:2208 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0028960 infores:hetionet CHEBI:100241 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020458 infores:hetionet CAID:CA180870 biolink:causes MONDO:0021060 infores:clingen CAID:CA180870 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.893C>T (p.Pro298Leu) variant in the MAP2K2 gene is 0.953% (68/5776) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180870/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:47898 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036983 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1384666 infores:hetionet CHEBI:6741 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042384 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0233494 infores:hetionet CHEBI:6520 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0015967 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1321686 infores:hetionet CHEBI:7478 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0026837 infores:hetionet CHEBI:2611 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0311468 infores:hetionet CAID:CA269989 biolink:causes MONDO:0044970 infores:clingen CAID:CA269989 MONDO:0044970 PMID: Benign BA1, BP4 The m.15326A>G (p.T194A) variant in MT-CYB was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen at high frequencies in numerous haplogroups and the overall allele frequency in GenBank database (per Mitomap; queried 6/29/2020) is 98.7% (BA1). Additionally, the computational predictor APOGEE gives a consensus rating of neutral with a low pathogenicity predictor score, 0.4 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA269989/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:7920 biolink:causes MONDO:0030673 infores:monarchinitiative not_provided not_provided HGNC:13921 MONDO:0030673 uuid:be1652d2-fdf7-4f58-b583-d78a9dc7018c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10908 biolink:causes MONDO:0009514 infores:monarchinitiative not_provided not_provided HGNC:16268 MONDO:0009514 uuid:dc4bc32c-b8c5-4022-9d7c-e8f3553c9091 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1624273 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624273 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.3072C>T (p.Leu1024=) variant in the SOS1 gene is 0.075% (19/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624273/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:324 biolink:causes MONDO:0007608 infores:monarchinitiative not_provided not_provided HGNC:583 MONDO:0007608 uuid:0108b8d9-3c85-427d-8dec-2bbe63a03a4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0008350 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0009760 infores:hetionet CHEBI:9727 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0011603 infores:hetionet CHEBI:50922 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0018926 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0039437 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0039437 infores:hetionet CAID:CA16603236 biolink:causes MONDO:0015967 infores:clingen CAID:CA16603236 MONDO:0015967 PMID: Likely Pathogenic PS1, PM5_Supporting, PP2, PP3, PP4, PM2_Supporting PM1 The c.171G>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 57 (p.(Met57Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 34440516). The nucleotide change c.171G>A, which results in the same amino acid change, has been classified as pathogenic for GCK-hyperglycemia by the ClinGen MDEP (PS1). Another missense variant at the same codon, c.170T>G (p.Met57Arg), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.171G>T p.(Met57Ile) meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PM5_Supporting, PP2, PP3, PP4, PS1). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603236/MONDO:0015967/086 2024-10-31 2025-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:135736 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0004239 infores:hetionet NCBIGene:152926 biolink:causes MONDO:0014057 infores:monarchinitiative not_provided not_provided HGNC:25415 MONDO:0014057 uuid:9737cd2f-cd8f-45fa-ba80-be6271f9ac0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0001807 infores:hetionet CHEBI:188986 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0040264 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0018681 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0234458 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0003123 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0039971 infores:hetionet CHEBI:85083 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0085631 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0541887 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0541887 infores:hetionet CHEBI:10100 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0040034 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0041912 infores:hetionet CHEBI:34829 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0042769 infores:hetionet GO:0110073 biolink:causes GO:0030855 infores:ubergraph knowledge_assertion manual_agent GO:0110073 GO:0030855 CHEBI:7494 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0520966 infores:hetionet CHEBI:9654 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0344232 infores:hetionet CHEBI:31401 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151603 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0518015 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0037274 infores:hetionet CHEBI:17688 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0231218 infores:hetionet CHEBI:8863 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011253 infores:hetionet NCBIGene:22884 biolink:causes MONDO:0032850 infores:monarchinitiative not_provided not_provided HGNC:31406 MONDO:0032850 uuid:2ad4d2bb-9cd5-410c-8404-7ea2d428ac83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0037928 infores:hetionet CAID:CA229409 biolink:causes MONDO:0009861 infores:clingen CAID:CA229409 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 The NM_000277.3(PAH):c.1232C>A (p.Ser411Ter) variant in exon 12 of PAH is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 12/13 and is predicted to lead to nonsense mediated decay (PVS1). This variant is absent from gnomAD v2.1.1 (PM2). The variant has been reported in one patient in PMID: 17935162 however additional phenotype and genotype information was not specified. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2. (PAH VCEP specifications version 1) Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229409/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0040053 infores:hetionet CHEBI:5103 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0013146 infores:hetionet CHEBI:47657 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0035243 infores:hetionet CHEBI:36704 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0013604 infores:hetionet CHEBI:9123 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017181 infores:hetionet CHEBI:404903 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018944 infores:hetionet CHEBI:8024 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027497 infores:hetionet CAID:CA5950635 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950635 MONDO:0000573 PMID: Uncertain Significance PM1_Supporting PM2 NM_000536.4(RAG2):c.14T>A is a missense variant predicted to cause substitution of Methionine by Lysine at amino acid 5 (p.Met5Lys). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.0003307 (389/1176246) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950635/MONDO:0000573/124 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63617 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0002622 infores:hetionet CHEBI:9137 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085631 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0003811 infores:hetionet CHEBI:7575 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0013604 infores:hetionet CHEBI:45863 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0041364 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0037199 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0032584 infores:hetionet NCBIGene:6691 biolink:causes MONDO:0054733 infores:monarchinitiative not_provided not_provided HGNC:11245 MONDO:0054733 uuid:07650177-e904-4647-8604-aa570c44f69d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030794 infores:hetionet CHEBI:45367 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0948594 infores:hetionet CHEBI:3441 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0030193 infores:hetionet CHEBI:70735 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0013390 infores:hetionet CHEBI:28939 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0013456 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0003123 infores:hetionet NCBIGene:171546 biolink:causes MONDO:0957308 infores:monarchinitiative not_provided not_provided HGNC:20361 MONDO:0957308 uuid:07e4417c-a365-41cc-b6e7-b84bef739aa7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0018932 infores:hetionet CHEBI:31643 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0234215 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0267596 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042571 infores:hetionet CHEBI:63619 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0043352 infores:hetionet CHEBI:5165 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0004096 infores:hetionet NCBIGene:4901 biolink:causes MONDO:0013402 infores:monarchinitiative not_provided not_provided HGNC:8002 MONDO:0013402 uuid:c3985ab8-db48-40d6-95a2-2bedb625a9f8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0232910 infores:hetionet CHEBI:188986 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1384353 infores:hetionet CHEBI:3242 biolink:causes GO:0090075 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0026836 infores:hetionet CHEBI:49662 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0236075 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0011175 infores:hetionet CHEBI:7809 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0011603 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0033975 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0235416 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0476089 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0042384 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0002170 infores:hetionet NCBIGene:57520 biolink:causes MONDO:0014995 infores:monarchinitiative not_provided not_provided HGNC:29853 MONDO:0014995 uuid:b89f73ea-a729-4624-9e79-0ba36393d390 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50859 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020453 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0017601 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0026766 infores:hetionet CHEBI:6847 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0392176 infores:hetionet CAID:CA6264503 biolink:causes MONDO:0700270 infores:clingen CAID:CA6264503 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5, PVS1 PM2 The c.67C>T (p.Arg23*) variant in ATM is a nonsense variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in 4 at least individuals with Ataxia-Telangiectasia (PMID: 26896183, 35260754, 36439585). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000098 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6264503/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9449 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0026821 infores:hetionet CHEBI:6062 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0917801 infores:hetionet CHEBI:3696 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0917801 infores:hetionet CHEBI:4708 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151908 infores:hetionet NCBIGene:2322 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:3765 MONDO:0018874 uuid:b3d34850-ca1a-4423-a347-ae1e99386e81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:51010 biolink:causes MONDO:0013853 infores:monarchinitiative not_provided not_provided HGNC:17944 MONDO:0013853 uuid:ad72c4dc-04d5-429a-8c97-f1d625ffae74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0042109 infores:hetionet CHEBI:63638 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013384 infores:hetionet CHEBI:404903 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0026858 infores:hetionet CHEBI:2914 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0700292 infores:hetionet CHEBI:92511 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0011603 infores:hetionet CHEBI:50924 biolink:causes MONDO:0043919 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0206063 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221776 infores:hetionet CHEBI:3698 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0041948 infores:hetionet CHEBI:6444 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0917801 infores:hetionet CHEBI:167309 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0235063 infores:hetionet CHEBI:78543 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0031256 infores:hetionet CHEBI:4903 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0149741 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005551 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0852875 infores:hetionet CHEBI:3423 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1443060 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0015397 infores:hetionet CHEBI:50275 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1443060 infores:hetionet CHEBI:10650 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042963 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0852977 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0852977 infores:hetionet CHEBI:119915 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0015672 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0021053 infores:hetionet CHEBI:47898 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0043352 infores:hetionet CHEBI:15552 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0016382 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0851341 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0162429 infores:hetionet CAID:CA396451176 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451176 MONDO:0007648 PMID: Pathogenic PVS1, PP1, PS4_Supporting, PM2_Supporting BP5, BP7, BS4, BS3, BS1, PM6, PM1, PM3, PM5, PM4, BS2, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS3, PS2, PS1 The c.1A>G (p.Met1Val) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one proband meeting HDGC clinical criteria (PS4_supporting; SCV000760810.2). This variant was also found to co-segregate with disease in multiple affected family members (PP1; SCV000760810.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_supporting, PM2_supporting, PP1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451176/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:36791 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0392699 infores:hetionet CHEBI:8232 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0020621 infores:hetionet CHEBI:4702 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0013395 infores:hetionet CHEBI:64354 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0086525 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0232498 infores:hetionet CHEBI:45924 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0000737 infores:hetionet CHEBI:231594 biolink:causes UMLS:C1112353 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C1112353 infores:hetionet CHEBI:6809 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0013395 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0015663 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042373 infores:hetionet CHEBI:77260 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013390 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0040409 infores:hetionet CHEBI:52172 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0008033 infores:hetionet CHEBI:3215 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0006266 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235639 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0149931 infores:hetionet CHEBI:32315 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013404 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0012833 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005783 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0019064 infores:hetionet CAID:CA367397094 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397094 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP1, PP2, PP3, PM2_Supporting PM1 The c.1306A>T variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to phenylalanine at codon 436 (p.(Ile436Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8259, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). Three of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributor). Additionally, another missense variant, c.1307T>A (p.Ile436Asn), has been classified as likely pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile436Phe (PM5_Supporting). Taken together, this evidence supports the classification of c.1306A>T as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4_Moderate, PP1, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397094/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:63925 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0022568 infores:hetionet CHEBI:50381 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0547030 infores:hetionet CHEBI:64312 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020443 infores:hetionet CHEBI:135613 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0017178 infores:hetionet CHEBI:50659 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0234913 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151826 infores:hetionet NCBIGene:8566 biolink:causes MONDO:0032792 infores:monarchinitiative not_provided not_provided HGNC:8819 MONDO:0032792 uuid:7a3c4129-0320-4df8-afe7-6a17e4801b12 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8346 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0234215 infores:hetionet NCBIGene:268 biolink:causes MONDO:0009857 infores:monarchinitiative not_provided not_provided HGNC:464 MONDO:0009857 uuid:58af4aaf-4204-4f53-9269-6aa58745fad7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3125 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0009319 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0034065 infores:hetionet CAID:CA229717 biolink:causes MONDO:0009861 infores:clingen CAID:CA229717 MONDO:0009861 PMID:30459323PMID:26322415 Pathogenic PM2, PVS1, PP4_Moderate, PM3_Very Strong The PAH variant c.722del (p.Arg241fs) is a null variant (frameshift indel) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease: 98 pathogenic null variants were reported in ClinVar for this gene, across 13 different exons, of which 11 variants were found on exon 7. The mRNA transcript is predicted to undergo NMD.The PAH variant c.722del (p.Arg241fs) was detected in four Chinese patients with classic PKU (Phe levels >20 mg/dl) and one Chinese patient with mild PKU (Phe levels 10–20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415).The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PMID: 26322415). The variant c.722del (p.Arg241fs) was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612)(PMID: 30459323). PM3_Very Strong (6.75).The variant c.722del (p.Arg241fs) is absent from the gnomAD, and ExAC population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong (6.75), PVS1, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229717/MONDO:0009861/006 2020-05-09 2020-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38940 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0013604 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0015376 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0235293 infores:hetionet CAID:CA10014172 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014172 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1434G>A (p.Arg478=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.25)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014172/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63618 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0027497 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0006826 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0553732 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0948594 infores:hetionet CHEBI:15367 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0036973 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0036572 infores:hetionet CHEBI:63623 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0241705 infores:hetionet CAID:CA8459206 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459206 MONDO:0011132 PMID: Likely Benign BP4, BS1 PM5, BS3 The NM_001369369.1(FOXN1):c.362C>T (p.Ala121Val) missense variant has a popmax filtering allele frequency in gnomADv2.1.1 is 0.002556 (based on 93/30402 alleles) in the South Asian population, this is above the SCID VCEP specified threshold of >0.00141 (BS1). The REVEL score of 0.207 is below the SCID VCEP specified threshold of <0.290 and does not predict a damaging effect (BP4). After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria, as specified by the ClinGen SCID VCEP: BS1, BP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459206/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:34380 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00600 UMLS:C1325847 infores:hetionet CHEBI:7936 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0231530 infores:hetionet CHEBI:41977 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0025289 infores:hetionet CHEBI:7465 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0002965 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038663 infores:hetionet CHEBI:47780 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0043387 infores:hetionet GO:2000121 biolink:causes GO:0097237 infores:ubergraph knowledge_assertion manual_agent GO:2000121 GO:0097237 CHEBI:38940 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0032285 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020676 infores:hetionet NCBIGene:10750 biolink:causes MONDO:0032761 infores:monarchinitiative not_provided not_provided HGNC:4562 MONDO:0032761 uuid:523c169b-0037-4f1f-9613-8eba0ba9db53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0021400 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0948594 infores:hetionet NCBIGene:79600 biolink:causes MONDO:0013608 infores:monarchinitiative not_provided not_provided HGNC:26113 MONDO:0013608 uuid:da904679-6b6f-4063-b268-cd7191131067 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1443060 infores:hetionet CHEBI:63620 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0549622 infores:hetionet CHEBI:63617 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0030794 infores:hetionet CAID:CA396451339 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451339 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS3, PS2, PS1 The c.26C>A (p.Ser9Ter) variant is predicted to result in a premature stop codon in exon 1 that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Two families meet HDGC phenotypic criteria (PS4_moderate; SCV000947495.1 and internal contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_supporting, PS4_moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451339/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf NCBIGene:10815 biolink:causes MONDO:0033372 infores:monarchinitiative not_provided not_provided HGNC:2309 MONDO:0033372 uuid:76667490-5c49-47e1-b52d-046bbe4eaccd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:2 biolink:causes MONDO:0004768 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D007637 DB02703_MESH_D007637_1DB00684_MESH_D007637_1 CHEBI:3011 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0011124 infores:hetionet CHEBI:8768 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011168 infores:hetionet NCBIGene:84314 biolink:causes MONDO:0033044 infores:monarchinitiative not_provided not_provided HGNC:28128 MONDO:0033044 uuid:cb8c958d-28bc-412a-83af-1b6c7f0305e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7454 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0278134 infores:hetionet CHEBI:4779 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0015230 infores:hetionet NCBIGene:51116 biolink:causes MONDO:0054781 infores:monarchinitiative not_provided not_provided HGNC:14495 MONDO:0054781 uuid:f181b1d6-b3e1-41ac-a538-392e603d89ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31515 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0043352 infores:hetionet CHEBI:8890 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0004144 infores:hetionet CHEBI:27899 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0002878 infores:hetionet CHEBI:10100 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0019158 infores:hetionet CHEBI:205919 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0235266 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0003123 infores:hetionet CHEBI:167638 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C1320835 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0036572 infores:hetionet CHEBI:3077 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020452 infores:hetionet CAID:CA002009 biolink:causes MONDO:0011450 infores:clingen CAID:CA002009 MONDO:0011450 PMID:30219179 Benign PM2_Supporting, BP1_Strong, BS3, BP5_Strong The c.305C>G variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 102 (p.Ala102Gly). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.00, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30219179) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.015 (based on Co-occurrence LR=1.177; Family History LR=0.0127), below the threshold for strong benign evidence (LR <0.05) (BP5_Strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP1_Strong, BS3, BP5_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002009/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:145499 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019158 infores:hetionet CHEBI:5959 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0041969 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018021 infores:hetionet CAID:CA410207940 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207940 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM5_Supporting, PVS1, PM2_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, BP7, BP5, PM6, PM4, PM1, PM3, PP2, PP3, PP4, BS2 The c.610C>T (Arg204Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 5/8 and expected to result in nonsense-mediated mRNA decay (PVS1). It is completely absent from gnomAD v2.1.1 and v3 with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in three probands meeting at least one of the RUNX1- phenotypic criteria (PS4_Moderate; PMID: 32165484, 10508512, 26492932). It was also found to co-segregate with disease in multiple affected family members, with eight meioses observed in across 3 families (PP1_Strong; PMID: 10508512, 26492932 , 32165484). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1_strong, PS4_moderate, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207940/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47499 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0017601 infores:hetionet CHEBI:51450 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0015672 infores:hetionet CAID:CA134671 biolink:causes MONDO:0021060 infores:clingen CAID:CA134671 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.525+12G>C variant in the PTPN11 gene is 1.4% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (969/66644 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case level data available: SCV000057399.8; SCV000061311.5; SCV000248623.2; SCV000206755.1; SCV000207666.1. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134671/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:17347 biolink:causes UMLS:C0877144 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877144 infores:hetionet CHEBI:17823 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0151825 infores:hetionet CHEBI:9907 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0023218 infores:hetionet NCBIGene:6573 biolink:causes MONDO:0957955 infores:monarchinitiative not_provided not_provided HGNC:10937 MONDO:0957955 uuid:9b2b3d04-b95a-4fcc-a914-462e4476e8ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70746 biolink:causes UMLS:C0040797 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0040797 infores:hetionet CHEBI:135876 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0152030 infores:hetionet CHEBI:136040 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0011124 infores:hetionet CHEBI:6541 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0023530 infores:hetionet CHEBI:94609 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C2363731 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1956346 infores:hetionet CHEBI:6923 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0011616 infores:hetionet CHEBI:7601 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0003467 infores:hetionet GO:0021870 biolink:causes CL:0000695 infores:ubergraph knowledge_assertion manual_agent GO:0021870 CL:0000695 CHEBI:7852 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042514 infores:hetionet CHEBI:83527 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0699828 infores:hetionet CAID:CA2579916788 biolink:causes MONDO:0010305 infores:clingen CAID:CA2579916788 MONDO:0010305 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PM4 The NM_005629.4(SLC6A8):c.1079_1081del variant in SLC6A8 is a deletion of three nucleotides within exon 7/13 and is predicted to lead to the in frame deletion of a single amino acid, p.(Phe360del). This variant is absent from gnomAD v3.1.2, therefore PM2_Supporting criteria is applicable. The NM_005629.4(SLC6A8):c.1079_1081del variant is predicted to cause a change in the length of the protein (p.Phe360del) due to an in-frame deletion of 1 amino acid in a non-repeat region (PM4). The NM_005629.4(SLC6A8):c.1079_1081del (p.Phe360del) variant was identified in two siblings with profound intellectual disability, epilepsy, severe speech delay, and one of two siblings with microcephaly [PMID:20049533]. These individuals were both found to have reduced creatine peak on H-MRS, and elevated creatine/creatinine levels in urine, 3.0 in sib 1 and 2.6 in sib 2, meeting criteria for PP4_Strong. This variant has been reported in additional publications, however we cannot exclude that the individuals reported in those publications are independent of the siblings reported above [PMID:19706062, 19319661] so they were not included as evidence for this curation. In summary, the NM_005629.4(SLC6A8):c.1079_1081del, p.(Phe360del) variant meets the criteria to be classified as a Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, PM4, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on November 9, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579916788/MONDO:0010305/027 2023-11-09 2024-02-11 X-linked inheritance HP:0001417 Supports CHEBI:2549 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0011991 infores:hetionet CHEBI:5118 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019521 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0006849 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0025061 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0018099 infores:hetionet CHEBI:48273 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0017178 infores:hetionet CAID:CA4239437 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239437 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP4_Moderate, PVS1, PM2_Supporting PP1 The c.1072C>T variant in the glucokinase gene, GCK, results in a premature termination at codon 358 (p.(Arg358Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 38928025, internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.1072C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PVS1, PS4_Moderate, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239437/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports CHEBI:46557 biolink:causes UMLS:C3160754 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C3160754 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0851341 infores:hetionet CHEBI:6067 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2830004 infores:hetionet CHEBI:75722 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2240374 infores:hetionet CAID:CA343777356 biolink:causes MONDO:0013144 infores:clingen CAID:CA343777356 MONDO:0013144 PMID:38474138 Uncertain Significance PS3_Supporting, PP3, PM2_Supporting PS4, PM5, PP4 The c.362T>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of methionine by threonine at the highly conserved amino acid 121 (p.Met121Arg, also known as p.Met89Arg in the literature per older nomenclature), which is located in an alpha-helix secondary structure in the serpin domain. In addition, an amino acid residue in the vicinity forms part of a disulfide bond (residue 127) and another undergoes glycosylation (residue 128). The variant is absent from gnomAD v4.1.0 (PM2_supporting). The computational predictor REVEL gives a score of 0.943, which is above the threshold of 0.6, which correlates with a deleterious impact to SERPINC1 function (PP3). In-vitro testing of transfected HEK293 cells demonstrated by Western blot analysis, a high AT protein expression in the p.Met121Arg cell lysates but low protein expression in the media, consistent with a secretion defect (PS3_supporting; PMID: 38474138). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel: PS3_supporting, PM2_Supporting, PP3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343777356/MONDO:0013144/084 2025-09-19 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4027 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0332575 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0015967 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0018021 infores:hetionet CAID:CA658821614 biolink:causes MONDO:0009595 infores:clingen CAID:CA658821614 MONDO:0009595 PMID: Uncertain Significance PM2_Supporting, PM1_Strong PM4 The variant NC_000009.12:g.35658033_35658035dup is absent in population databases such as gnomAD v4. PM2_Supporting This variant creates an extension of 3 nucleotides, increasing the distance between the TATA box (spanning n.-32 to n.-24) and the transcription start site (n.1) PM1_Strong. However, the insertion is only 3 nucleotides and therefore this criterion is not met. The variant has not been described in patients with cartilage-hair hypoplasia or in trans with any other RMRP variantIn summary, this variant is classified as Uncertain significance: PM2_Supporting, PM1_Strong. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA658821614/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8024 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C3665386 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0009766 infores:hetionet CAID:CA1706889 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706889 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4_Strong, PP3 PM5, BS3, PM2 The NM_003494.4: c.4024C>T variant in DYSF, which is also known as NM_001130987.2: c.4078C>T p.(Arg1360Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 1342, p.(Arg1342Trp). This variant has been identified in at least five individuals with features of LGMD (PMID: 36983702, 21522182, 22616201, Jain Foundation Dysferlin Registry internal data communication, ClinVar SCV003223254.2 internal data communication), including confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.2706dup p.(Lys903GlnfsTer4), 1.0 pt, PMID: 22616201, 21522182) and in unknown phase with a pathogenic variant (NM_003494.4: c.1053+1G>C, 0.5 pts, Jain Foundation Dysferlin Registry internal data communication) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had progressive limb girdle muscle weakness or a clinical suspicion of LGMD and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 21522182, Jain Foundation Dysferlin Registry internal data communication; PP4_Strong). The highest population minor allele frequency for this variant is 0.0002782 (24/86254 exome chromosomes) in the South Asian population in gnomAD v4.1.0, which is greater than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Arg1342Trp protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538). The computational predictor REVEL gives a score of 0.79, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PM3, PP4_Strong, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706889/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15553 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C1443060 infores:hetionet GO:0048895 biolink:causes CL:1000050 infores:ubergraph knowledge_assertion manual_agent GO:0048895 CL:1000050 CHEBI:3242 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0085631 infores:hetionet CHEBI:119915 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018790 infores:hetionet CHEBI:101278 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0004093 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0037274 infores:hetionet CHEBI:145499 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0032231 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013395 infores:hetionet CHEBI:9674 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0151786 infores:hetionet CHEBI:490877 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0037023 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151505 infores:hetionet CHEBI:32221 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0025874 infores:hetionet CHEBI:194135 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023218 infores:hetionet CHEBI:45863 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0002792 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0522224 infores:hetionet CAID:CA6401422 biolink:causes MONDO:0019565 infores:clingen CAID:CA6401422 MONDO:0019565 PMID: Likely Benign BP4, BS1 PP3, BS2, BA1 NM_000552.5(VWF):c.7997C>T is a missense variant that substitutes threonine for methionine at position 2666. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.06826 (based on 5238/74998 alleles in the African/African American population) which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). While this variant has been observed in healthy control individuals (PMID: 22197721), BS2 is not being used due to penetrance issues. The computational predictor REVEL gives a score of 0.027, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as likely benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6401422/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true CHEBI:3698 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020651 infores:hetionet CAID:CA16605802 biolink:causes MONDO:0015967 infores:clingen CAID:CA16605802 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4, PP2, PP3, PM2_Supporting The c.1099G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 367 (p.(Val367Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with diabetes/hyperglycemia (PS4; PMID 27256595, 31968686, 9049484, internal lab contributors). This variant segregated with diabetes with 4 informative meioses in 3 families with diabetes/hyperglycemia (PP1_Strong; PMID 27256595, 9049484, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID 27256595 ). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PS4, PP4, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16605802/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:9139 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0152029 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0855977 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0855977 infores:hetionet CHEBI:2038 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C2939419 infores:hetionet CHEBI:4887 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0006145 infores:hetionet CHEBI:10101 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0232493 infores:hetionet CHEBI:480999 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0020580 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0008196 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0008196 uuid:4484138a-dbe1-4ca2-9dae-69a185eab2b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0001561 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0034194 infores:hetionet CHEBI:8665 biolink:causes GO:0030432 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0031133 infores:hetionet CHEBI:7478 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0011603 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235467 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0032285 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0267792 infores:hetionet CHEBI:31624 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0013595 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0948586 infores:hetionet CHEBI:4717 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0006266 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0235218 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0235218 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0009450 infores:hetionet CAID:CA376063513 biolink:causes MONDO:0011225 infores:clingen CAID:CA376063513 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.181T>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 61 (p.Cys61Arg).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376063513/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3568 biolink:causes MONDO:0000931 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151622 infores:hetionet CHEBI:50922 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0002962 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0011974 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0521481 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0521481 infores:hetionet CHEBI:119486 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085605 infores:hetionet CHEBI:42797 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027429 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020649 infores:hetionet CHEBI:63619 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0023530 infores:hetionet CHEBI:9586 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0015967 infores:hetionet CHEBI:31622 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0427108 infores:hetionet CHEBI:49575 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013384 infores:hetionet CAID:CA410147908 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147908 MONDO:0011071 PMID:20846103PMID:20846103PMID:20846103PMID:20846103 Likely Pathogenic PVS1_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting PS1, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS3, BS4, BS1, PM6, PM4, PM1, PM5, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.4:c.1163C>A (p.Ser388Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Transactivation assays demonstrate enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 20846103). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 20846103). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS3_Supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147908/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51450 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0267792 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0032584 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0004926 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D003607 DB02703_MESH_D003607_1DB00798_MESH_D003607_1 CHEBI:71255 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0854082 infores:hetionet CHEBI:50692 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0004093 infores:hetionet CHEBI:46295 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0547030 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0039520 infores:hetionet CAID:CA8815477 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815477 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PS3_Moderate, PM2_Supporting PM5 "The NM_000152.5:c.1781G>A variant in GAA is a missense variant predicted to result in substitution of arginine by histidine at amino acid 594 (p.Arg594His). At least 7 patients with this variant have been reported including two with documented laboratory values showing deficiency of GAA activity (Clinical Diagnostic Laboratory, PMID 33073003) (meeting PP4_Moderate), two on enzyme replacement therapy (meeting PP4 (PMID: 27711114, 30022036), and additional patients reported to have Pompe disease (PMID: 24444888, 25526786, 25998610, 27711114, 30022036, 30155607 ) or identified by newborn screen (PMID: 26889246) (PP4_Moderate). Four probands are compound heterozygous for another variant in GAA that has been classified by the ClinGen Lysosomal Storage Disorders VCEP as pathogenic or likely pathogenic for Pompe disease, including c.1735G>A (p.Glu579Lys) (Clinical Diagnostic Laboratory), 0.5 points; c.-32-13T>G, phase unknown (PMID: 27711114, 30022036), 0.5 points; c.1935C>A (p.Asp645Glu), phase unknown (PMID: 24444888) 0.5 points; c.1194+5G>A, phase unknown (2 patients, could be related) (PMID: 25998610, 27711114, 30022036), 0.25 points. Total 1.75 points (PM3). In addition, three patients are compound heterozygous for the variant and another variant in GAA including c.1194+3G>C (Clinical Diagnostic Laboratory, PMID: 33073003), c.1190C>T (p.Pro397Leu) (PMID: 30155607), c.1562A>T (p.Glu521Val) (PMID: 25526786). The allelic data for these patients will be used in the classification of the other variant and is not included here to avoid circular logic. When expressed in COS cells, this variant was classified as Class B (""potentially less severe"") by Kroos et al, 2012 (PMID: 22644586). This includes 0.1% GAA activity in cells and 1.4% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate). The computational predictor REVEL gives a score of 0.927 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest population minor allele frequency in a continental population in gnomAD v2.1.1 is 0.000009 (1/111938 alleles) in the European (Non-Finnish) population; the highest population minor allele frequency in any population is 0.0001 in Ashkenzi Jewish (1/9994). This is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant, c.1781G>C (p.Arg594Pro), at the same position has been reported in individuals with Pompe disease. The classification of c.1781G>A (p.Arg594His) will be used to support the classification of p.Arg594Pro. Therefore, to avoid circular logic, PM5 was not applied. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP on December 16, 2022)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815477/MONDO:0009290/010 2022-12-16 2022-12-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:94440 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0011168 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0038663 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0008035 infores:hetionet CHEBI:6076 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232493 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0028738 infores:hetionet CHEBI:31184 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0151514 infores:hetionet CHEBI:4495 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0030193 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042373 infores:hetionet CHEBI:47381 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0000729 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0549209 infores:hetionet CHEBI:3441 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0035455 infores:hetionet CAID:CA8314972 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314972 MONDO:0009276 PMID: Benign BP4, BA1, BP7 The NM_000173.7(GP1BA):c.1311A>G (p.Pro437=) synonymous variant occurs at a Grpmax filtering allele frequency of 0.8560 (based 186885/217504 alleles in the European non-Finnish population) in gnomADv4.1, which is higher than the ClinGen PD VCEP threshold (>0.001) for BA1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing (delta score 0.00) and a PhyloP score of 0.011 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314972/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA336249727 biolink:causes MONDO:0010278 infores:clingen CAID:CA336249727 MONDO:0010278 PMID: Likely Benign BP4, BP5, BP7, BS1 The allele frequency of the c.1704C>T (p.Ile568=) variant in SLC9A6 (NM_006359.2) is 0.008% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ile568= variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The silent p.Ile568= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the p.Ile568= variant in SLC9A6 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP5, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA336249727/MONDO:0010278/033 2023-10-13 2023-12-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:63617 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0740394 infores:hetionet CHEBI:27779 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0015230 infores:hetionet CAID:CA512341087 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341087 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM6, PVS1, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1302C>T (p.Asn434=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (1.61) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341087/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16469 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0025323 infores:hetionet CHEBI:63580 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018808 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0038454 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0863084 infores:hetionet CHEBI:4562 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0039231 infores:hetionet CHEBI:3478 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0025345 infores:hetionet CHEBI:119915 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030193 infores:hetionet UMLS:C0010592 biolink:causes HP:0001937 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0221021 infores:hetionet CHEBI:8673 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0014518 infores:hetionet CHEBI:7931 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0018681 infores:hetionet CHEBI:50275 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2047937 infores:hetionet NCBIGene:8988 biolink:causes MONDO:0013243 infores:monarchinitiative not_provided not_provided HGNC:5248 MONDO:0013243 uuid:2ec6dcf6-cf60-4a67-8c3e-ce743138b775 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151937 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1971624 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0079102 infores:hetionet CHEBI:63608 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0015967 infores:hetionet CAID:CA410147644 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147644 MONDO:0011071 PMID: Benign BP4, BA1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1252A>T (p.Met418Leu) is a missense variant that has a MAF of 0.005069 (0.5%, 119/23476 alleles) in the East Asian subpopulation of the gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). This missense variant has a REVEL score < 0.50 (0.219) and a SpliceAI score ≤ 0.20 (0.0) (BP4).In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147644/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36791 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C3665347 infores:hetionet CAID:CA367401223 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401223 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PS1 The c.651C>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to glutamic acid at codon 217 (p.(Asp217Glu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.805, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36257325, internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). The nucleotide change c.651C>G, which causes the same amino acid change, has been reported in an individual with monogenic diabetes; however, the c.651C>G variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.651C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4_moderate, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401223/MONDO:0015967/086 2024-11-16 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:9137 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0518988 infores:hetionet CHEBI:75922 biolink:causes MONDO:0016175 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0010495 infores:hetionet CHEBI:60761 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0002792 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0684249 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0589616 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0589616 infores:hetionet NCBIGene:161725 biolink:causes MONDO:0968979 infores:monarchinitiative not_provided not_provided HGNC:20718 MONDO:0968979 uuid:cc4b58f4-e6a0-4e09-bc08-b78171ef8d40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0233494 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042790 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0017601 infores:hetionet CHEBI:7465 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0085762 infores:hetionet CHEBI:32139 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0022660 infores:hetionet CHEBI:45863 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0017168 infores:hetionet CHEBI:161680 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0038362 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0020039 infores:hetionet CHEBI:51860 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0162830 infores:hetionet CHEBI:15765 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0030196 infores:hetionet CHEBI:45081 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0003811 infores:hetionet CAID:CA16609267 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609267 MONDO:0015967 PMID: Pathogenic PS4, PM5_Supporting, PP2, PP3, PP1, PS3_Moderate, PM2_Supporting PM1 The c.1016A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glycine at codon 339 (p.(Glu339Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; ClinVar: 393450, PMIDs: 18399931, 16731834, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 1 family (PP1; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.06, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 16731834). Another missense variant, c.1015G>A p.Glu339Lys, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1016A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PS3_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609267/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:3403 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0151827 infores:hetionet CHEBI:2682 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0010520 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0004096 infores:hetionet CHEBI:8499 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0001824 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020517 infores:hetionet CHEBI:31643 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0043144 infores:hetionet CAID:CA135140 biolink:causes MONDO:0021060 infores:clingen CAID:CA135140 MONDO:0021060 PMID: Likely Pathogenic PM1, PM2, PP3, PP2, PS4_Supporting PS2, PS1, PS3, PM4, PM5, BP7, BP5, BS3, BS1, BS4, PM6, BS2, PP1, BP3, BP2, BP4, BP1, BA1 The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135140/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9352 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0008350 infores:hetionet CHEBI:3242 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0021177 infores:hetionet CHEBI:114785 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0231528 infores:hetionet CHEBI:5441 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0017178 infores:hetionet CHEBI:5775 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0423153 infores:hetionet CHEBI:27690 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0018681 infores:hetionet CHEBI:2549 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0009782 infores:hetionet CHEBI:8024 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0013378 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233494 infores:hetionet CHEBI:75246 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0037763 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0314719 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0031350 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0031046 infores:hetionet CHEBI:9667 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0010481 infores:hetionet UMLS:C0657912 biolink:causes HP:0001482 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151811 infores:hetionet CHEBI:45327 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C1096250 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0302295 infores:hetionet CAID:CA275275 biolink:causes MONDO:0015152 infores:clingen CAID:CA275275 MONDO:0015152 PMID: Benign BA1 BP4 The NM_003494.4: c.4820T>C variant in DYSF, which is also known as NM_001130987.2: c.4937T>C p.(Ile1646Thr), is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 1607 (p.Ile1607Thr). The filtering allele frequency of the variant is 0.01198 for South Asian exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 742/251478), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.19 and the computational predictor REVEL gives a score of 0.36. Both of these scores are neither above nor below the thresholds predicting a damaging or benign impact (BP4/PP3 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA275275/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8356 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020546 infores:hetionet NCBIGene:3020 biolink:causes MONDO:0030606 infores:monarchinitiative not_provided not_provided HGNC:4764 MONDO:0030606 uuid:6ffa8e33-05b2-46fb-93e5-5f67778115dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA913190424 biolink:causes MONDO:0100437 infores:clingen CAID:CA913190424 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting, PS4_Supporting PP3, BS2, PM1, PM4, PS3, BP2, BP4, BP3, BA1, BP7, BS1, BS4 NM_001034853.2(RPGR):c.2505_2506del (p.Glu836ArgfsTer?) is a frameshift variant due to a deletion of 2 nucleotides, introducing a premature stop codon in exon 15 of 15 after 241 amino acids that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years (data shared by personal communication, PMID: 37446072, PMID: 14564670, PS4_Moderate). The variant has been reported to segregate in the hemizygous state with retinal dystrophy through 2 affected half brothers, with the shared mother noted to have poor night vision and untested but considered an obligate carrier of the variant (data shared by personal communication, PP1). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Moderate, PM2_Supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190424/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:8481 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0026961 infores:hetionet CHEBI:8412 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0015397 infores:hetionet CHEBI:5004 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C1443060 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011551 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0003460 infores:hetionet CHEBI:9123 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0000731 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0233494 infores:hetionet CHEBI:3696 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C3263723 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233459 infores:hetionet CHEBI:32315 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0220870 infores:hetionet UMLS:C0065374 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0022346 infores:hetionet CHEBI:4708 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0012569 infores:hetionet CHEBI:9727 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C1268766 infores:hetionet CHEBI:681569 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0038160 infores:hetionet CHEBI:17650 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0016658 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0028960 infores:hetionet CHEBI:6367 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002962 infores:hetionet GO:0001865 biolink:causes CL:0000814 infores:ubergraph knowledge_assertion manual_agent GO:0001865 CL:0000814 NCBITaxon:5052 biolink:causes MONDO:0005657 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5052 MONDO:0005657 CHEBI:50131 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0027441 infores:hetionet CHEBI:473990 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0004093 infores:hetionet CHEBI:32139 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0151539 infores:hetionet CHEBI:45409 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0012569 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0011570 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0041349 infores:hetionet CHEBI:135876 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C1142412 infores:hetionet CHEBI:70735 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0003811 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020437 infores:hetionet CHEBI:3207 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0043094 infores:hetionet CHEBI:8888 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042029 infores:hetionet CHEBI:127342 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0700200 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0521839 infores:hetionet CHEBI:71417 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0036974 infores:hetionet CHEBI:51450 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0023380 infores:hetionet CHEBI:10127 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0220981 infores:hetionet CAID:CA024744 biolink:causes MONDO:0007783 infores:clingen CAID:CA024744 MONDO:0007783 PMID: Likely Pathogenic PP1, PS3_Moderate, PM1_Supporting, PS4_Moderate, PP3_Moderate, PM5_Supporting BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with tyrosine at codon 2431 of the RYR1 protein, p.(Asp2431Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, PMID:30115273). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:30115273). Another variant assessed as likely pathogenic occurs at this codon, p.(Asp2431Asn), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:30236257). A REVEL score >0.85 (0.964) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024744/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:53760 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151888 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0854100 infores:hetionet NCBIGene:402 biolink:causes MONDO:0033644 infores:monarchinitiative not_provided not_provided HGNC:693 MONDO:0033644 uuid:80d42aad-aa25-4e86-b934-8e847964c77f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5779 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0476281 infores:hetionet CHEBI:4876 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0011991 infores:hetionet CHEBI:33130 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0020625 infores:hetionet CHEBI:15552 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0030312 infores:hetionet CHEBI:144551 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0017168 infores:hetionet CHEBI:4909 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0085593 infores:hetionet CHEBI:135920 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0542571 infores:hetionet CHEBI:94392 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0744727 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0234936 infores:hetionet CHEBI:68584 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0152169 infores:hetionet CHEBI:34380 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00600 UMLS:C0152030 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014130 infores:hetionet CHEBI:101278 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0026826 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0034069 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0012833 infores:hetionet CHEBI:6067 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036690 infores:hetionet CHEBI:75988 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0018681 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C3665386 infores:hetionet CHEBI:5775 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0152031 infores:hetionet CHEBI:4911 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0015672 infores:hetionet CHEBI:31199 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0033774 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0948594 infores:hetionet CAID:CA7963442 biolink:causes MONDO:0700272 infores:clingen CAID:CA7963442 MONDO:0700272 PMID:31586400 Uncertain Significance BP1 BS3, PM2 The c.3049G>A (p.Ala1017Thr) variant in PALB2 is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 1017 (p.Ala1017Thr). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00003 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in a protein assay (PMID: 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA7963442/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50742 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C3665386 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020621 infores:hetionet CHEBI:5138 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0004245 infores:hetionet CHEBI:44423 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0085593 infores:hetionet CHEBI:119486 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0004364 infores:hetionet CHEBI:64312 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013378 infores:hetionet CHEBI:55346 biolink:causes NCIT:C54356 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151598 infores:hetionet CHEBI:3650 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0040034 infores:hetionet CHEBI:7936 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0438142 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0010692 infores:hetionet CAID:CA229674 biolink:causes MONDO:0009861 infores:clingen CAID:CA229674 MONDO:0009861 PMID:21307867 Uncertain Significance PM2, PP4_Moderate, PP3 PM5 The c.650G>A (p.Cys217Tyr) variant in PAH was reported in 1 Japanese PKU patient. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. (PMID: 21307867). This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.982. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229674/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:84883 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0039070 infores:hetionet CHEBI:119486 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0004134 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0235431 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042571 infores:hetionet CHEBI:6375 biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0266813 infores:hetionet CHEBI:75998 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0033774 infores:hetionet CAID:CA410147696 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147696 MONDO:0011071 PMID: Pathogenic PS4, PVS1_Strong, PM5_Supporting, PM2_Supporting, PP1 PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter) is a nonsense variant which is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong, PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PMID: 33560381, 37680325, 37458302, 37738626) (PS4). It was also found to co-segregate with disease in multiple affected family members, with three meioses observed across two families (PP1; PMID: 37680325, 37458302). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM5_supporting, PM2_supporting, PP1, PS4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147696/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3996 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0041657 infores:hetionet CHEBI:6887 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0031256 infores:hetionet CHEBI:51450 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0043144 infores:hetionet CHEBI:3749 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0017181 infores:hetionet CHEBI:6792 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0004096 infores:hetionet CHEBI:47381 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020578 infores:hetionet CHEBI:8764 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023066 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009806 infores:hetionet CHEBI:6775 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0003873 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013395 infores:hetionet CHEBI:31236 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033046 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0033687 infores:hetionet CHEBI:2637 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0027497 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019348 infores:hetionet CAID:CA637740591 biolink:causes MONDO:0011071 infores:clingen CAID:CA637740591 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.59-10G>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.11) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -1.023 < 2.0) or the variant is the reference nucleotide in one primate (BP7). This variant has not been reported in an individual meeting at least one of the RUNX1-phenotypic criteria. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP7, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA637740591/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6909 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0235266 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0027769 infores:hetionet NCBIGene:2558 biolink:causes MONDO:0032813 infores:monarchinitiative not_provided not_provided HGNC:4079 MONDO:0032813 uuid:40f21098-6421-48f5-8f73-5059f1bb5ae0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31623 biolink:causes HP:0011886 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0020581 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020456 infores:hetionet CHEBI:119915 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017565 infores:hetionet CHEBI:63638 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0858635 infores:hetionet CHEBI:63580 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0547030 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151474 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005152 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0020635 infores:hetionet CHEBI:64064 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0234233 infores:hetionet UMLS:C0120107 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0344232 infores:hetionet CAID:CA915952147 biolink:causes MONDO:0044970 infores:clingen CAID:CA915952147 MONDO:0044970 PMID: Likely Pathogenic PM6_Supporting, PVS1_Strong PP3, BP4, PS4, PS2, PS3, PM2 The m.12425del (p.N30TfsX7) variant in MT-ND5 has been reported in one individual to date, in a girl with mitochondrial myopathy and renal failure. In childhood, she was found to have impaired growth, mild metabolic acidosis, and elevated creatinine. After several years, her renal function declined, and she had daily vomiting and weight loss. Additionally, she had exercise intolerance and mild pigmentary retinopathy. She had received a donor kidney at the time of report and did well. She had persistently elevated blood lactate (5.1-5.9 mmol/L, normal 0.7-2.1). A renal biopsy showed glomerulocystic disease with significant atrophy and fibrosis. A muscle biopsy showed mild variation in fiber size with occasional atrophic, angulated fibers but no evidence of inflammatory changes and mild increase in lipid content. COX and SDH histochemistry revealed moderately increased enzyme activities in subsarcolemmal areas, subsarcolemmal mitochondrial accumulation, reduced complex I activity (with normal complex II+III and complex IV activities) and reduced fully assembled complex I. The variant was present at 85% heteroplasmy in muscle, 14% in blood, 19% in urine, and 22% in buccal sample (PMID: 20018511). As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and urine samples from her healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.007%; Helix's 196,554 sequences: AF=0.0005%; and gnomAD v3.1.2: AF=0.016% as this is heteroplasmic in 4 individuals). Given the frequency of this variant, it does not meet PM2 criterion. This variant results in a frameshift in codon 30, introducing a premature stop codon which predicts a truncation of the MT-ND5 protein from its full-length of 604 amino acids to 35 amino acids (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given biochemical evidence in the proband’s muscle is consistent with the predicted effect of this variant and because the variant is present at low heteroplasmy levels in the sequences in gnomAD v3.1.2. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952147/MONDO:0044970/015 2023-11-28 2024-03-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:84500 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0002994 infores:hetionet CHEBI:4995 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235198 infores:hetionet CAID:CA340769 biolink:causes MONDO:0012999 infores:clingen CAID:CA340769 MONDO:0012999 PMID: Pathogenic PP3, PP4_Strong, PM3_Strong, PS3_Supporting PM2, PP1, PM5 The NM_000156.6:c.59G>C variant in GAMT is a missense variant predicted to cause substitution of tryptophan by serine at amino acid 20 (p.Trp20Ser). This variant has been detected in at least 9 unrelated individuals with GAMT deficiency (PMID: 15651030, PMID: 16855203, PMID: 15108290). Of those individuals, one was compound heterozygous for the variant and a pathogenic variant, c.521G>A (p.Trp174*, in trans (PMID: 16855203) and eight individuals were homozygous for the variant (PMID: 15651030, PMID: 16855203, PMID: 15108290) (2 points total) (PM3_Strong). These individuals showed elevated plasma GAA and urine GAA (PMID: 15651030, PMID: 16855203, PMID: 15108290), three also showed deficient (<5% wild-type) GAMT enzyme activity in lymphoblasts (PMID: 15651030), and one also showed deficient (<5% wild-type) GAMT enzyme activity in fibroblasts and reduced creatine signal on brain MRS (PMID: 16855203, PMID: 21140503) (PP4_Strong). Expression of the variant in HeLa cells resulted in 3% wild type GAMT activity indicating that this variant may impact protein function (PMID: 17336114)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (3/27420 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004); however, as this variant is covered in <50% of individuals in gnomAD v2.1.1, allele frequency estimates may not be reliable and thus PM2_Supporting is not met. The computational predictor REVEL gives a score of 0.94 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 8303, 2 star review status) with 9 submitters classifying the variant as pathogenic and 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM3_Strong, PP3, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA340769/MONDO:0012999/026 2023-05-25 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8713 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0022660 infores:hetionet CAID:CA263244 biolink:causes MONDO:0012996 infores:clingen CAID:CA263244 MONDO:0012996 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PM3_Supporting, PS3_Supporting PP3, BP4 The NM_001482.3:c.608A>C variant in GATM is a missense variant that is predicted to result in substitution of tyrosine by serine at amino acid 203 (p.Tyr203Ser). This variant has been previously reported in two siblings (PMID: 23770102), both of whom showed significantly decreased creatine peak on H1-MRS and low GAA in plasma and low creatine in plasma (PP4_Strong). Both siblings were homozygous for the variant and their parents, who were first cousins, were confirmed to be heterozygous (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). When expressed in HeLa cells, the variant had 0% of wild-type GATM activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.64 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 55921). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PP4_Strong, PS3_Supporting, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA263244/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50841 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0013384 infores:hetionet CHEBI:2663 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0032227 infores:hetionet CHEBI:171719 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0009676 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032781 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0221745 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0221745 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0015230 infores:hetionet CAID:CA226697 biolink:causes MONDO:0010725 infores:clingen CAID:CA226697 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3_Moderate, PS3_Supporting The NM_000330.4(RS1):c.337C>T variant is a missense variant encoding the substitution of Leucine with Phenylalanine at amino acid 113. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.874, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.02 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 30040949, 16361673, PS3_Supporting). This variant has been reported in at least 5 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 11738458, 34645606, 34822951, 28348004, 9618178, 39462066, https://doi.org/10.1134/S1022795421070139, PS4). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_moderate, PS3_supporting, PS4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226697/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:10127 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085637 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042075 infores:hetionet CHEBI:3082 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0235266 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0031350 infores:hetionet CHEBI:453011 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0521495 infores:hetionet CHEBI:7822 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0039070 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0004623 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0040046 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0162429 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0152154 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0152154 infores:hetionet NCBIGene:27030 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:7128 MONDO:0005575 uuid:33859fc6-06af-4c6d-b03e-fbf3b291119f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50381 biolink:causes UMLS:C0235018 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0235018 infores:hetionet CHEBI:100241 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022661 infores:hetionet CHEBI:6897 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0027497 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042769 infores:hetionet CHEBI:7865 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0011175 infores:hetionet CAID:CA343773664 biolink:causes MONDO:0013144 infores:clingen CAID:CA343773664 MONDO:0013144 PMID: Likely Pathogenic PS4, PP3, PM2_Supporting PM5 The c.1058C>T variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 353 (p.Pro353Leu). This variant has been reported in at least five probands meeting an antithrombin activity level of < 0.8 IU/mL, probands without a family history with reported AT activity levels or repeat testing were only awarded half a point (4 points; PS4; PMIDs:28300866, 25522812, 21264449). The computational predictor REVEL gives a score of 0.991, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP3, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343773664/MONDO:0013144/084 2025-10-17 2025-10-21 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9086 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0851578 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020557 infores:hetionet CHEBI:3479 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0020517 infores:hetionet CHEBI:188986 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0033575 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0031117 infores:hetionet CHEBI:63577 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0700590 infores:hetionet NCBIGene:6899 biolink:causes MONDO:0008542 infores:monarchinitiative not_provided not_provided HGNC:11592 MONDO:0008542 uuid:591e42d4-dfda-4ac4-bf1c-74930e8b2506 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027339 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151838 infores:hetionet CHEBI:52717 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026764 infores:hetionet CHEBI:47898 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017979 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0860967 infores:hetionet GO:0045465 biolink:causes CL:0000709 infores:ubergraph knowledge_assertion manual_agent GO:0045465 CL:0000709 CHEBI:4681 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0030554 infores:hetionet CHEBI:135005 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0041969 infores:hetionet CHEBI:38940 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0033771 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0020649 infores:hetionet CHEBI:31644 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0236024 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0017601 infores:hetionet CHEBI:2663 biolink:causes HP:0007141 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C1112256 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002871 infores:hetionet CHEBI:131512 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0039231 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020676 infores:hetionet CHEBI:3749 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0151907 infores:hetionet CHEBI:167309 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0000737 infores:hetionet CHEBI:134991 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0151744 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2939147 infores:hetionet CHEBI:119573 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0016204 infores:hetionet GO:0070306 biolink:causes CL:0011004 infores:ubergraph knowledge_assertion manual_agent GO:0070306 CL:0011004 NCBIGene:79641 biolink:causes MONDO:0009185 infores:monarchinitiative not_provided not_provided HGNC:29478 MONDO:0009185 uuid:cc3c3795-e739-4cb3-b9c8-087136829b76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1761613 infores:hetionet CHEBI:3314 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0232462 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020456 infores:hetionet CHEBI:3310 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0020488 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0029408 infores:hetionet CHEBI:4445 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1384353 infores:hetionet CHEBI:8354 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0021368 infores:hetionet CHEBI:63621 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0728899 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0231528 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015230 infores:hetionet CHEBI:75722 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0149514 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549209 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0018802 infores:hetionet CHEBI:50173 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C2364111 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0006840 infores:hetionet CHEBI:15765 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0015672 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0018799 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0232333 infores:hetionet CHEBI:9927 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0151786 infores:hetionet CHEBI:4024 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0004134 infores:hetionet CHEBI:6888 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0041657 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1112470 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1112470 infores:hetionet CHEBI:8874 biolink:causes MONDO:0043475 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0001396 infores:hetionet CHEBI:7903 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0028754 infores:hetionet CHEBI:80630 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C3263723 infores:hetionet CHEBI:101853 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0004093 infores:hetionet CHEBI:253342 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0151905 infores:hetionet NCBIGene:6595 biolink:causes MONDO:0859139 infores:monarchinitiative not_provided not_provided HGNC:11098 MONDO:0859139 uuid:f2d76ba0-04c7-40da-a229-2709ea550837 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42068 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0020517 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035455 infores:hetionet GO:0106088 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0035295 CHEBI:63629 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0043352 infores:hetionet CHEBI:134991 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020453 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0025061 infores:hetionet CHEBI:132233 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C3263723 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0015230 infores:hetionet CHEBI:3732 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0009676 infores:hetionet CHEBI:520985 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C1510410 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0851341 infores:hetionet CHEBI:8888 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037299 infores:hetionet CHEBI:28925 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0004509 infores:hetionet NCBIGene:81575 biolink:causes MONDO:0958229 infores:monarchinitiative not_provided not_provided HGNC:25268 MONDO:0958229 uuid:5da33f7d-e3c3-47cf-acab-3fb3a5f1180b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63616 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0042075 infores:hetionet CHEBI:5004 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0013404 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0006147 infores:hetionet CHEBI:4708 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0026821 infores:hetionet CHEBI:31401 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0085649 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0162529 infores:hetionet CHEBI:6950 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0268000 infores:hetionet CHEBI:9588 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0011603 infores:hetionet CHEBI:47657 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0035455 infores:hetionet CHEBI:6775 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151577 infores:hetionet CAID:CA410202463 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202463 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PVS1, PM2_Supporting PS2, PS1, PS3, BA1, BP1, BP4, BP2, BP3, PM6, BP7, BP5, BS4, BS1, BS3, PM3, PM4, PM5, PM1, PP2, PP3, PP1, PP4, BS2 The c.508+1G>A variant has not been reported in gnomAD (v2 and v3) (PM2_supporting) or in case reports. It is predicted to result in the use of a cryptic site 23nt upstream of 5' splice site. This is predicted to lead to a frameshift and a premature termination codon leading to loss of function to the protein. SpliceAI delta score =1. (PVS1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 29632235, SCV001161868.1, 2 (Patient ID :A001099, A001100) PMID: 29632235). This variant was found to co-segregate with disease in affected family members, with two meioses observed in one family (PMID: 29632235). The maternal grandmother and great uncle had history of AML but have not been screened for the RUNX1 variant so cannot be included. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_Moderate, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202463/MONDO:0011071/008 2022-08-31 2023-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63589 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0553692 infores:hetionet CHEBI:4735 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0037383 infores:hetionet CHEBI:50730 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0020580 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0033777 infores:hetionet CHEBI:61049 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0016867 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0863113 infores:hetionet CHEBI:45327 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0030193 infores:hetionet CHEBI:17303 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0231218 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0948089 infores:hetionet CHEBI:2922 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0033687 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0009806 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0549356 infores:hetionet CHEBI:5130 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0404521 infores:hetionet CHEBI:6741 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0003811 infores:hetionet CHEBI:44032 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0040822 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0036572 infores:hetionet CHEBI:6456 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0003467 infores:hetionet CHEBI:9586 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0149745 infores:hetionet CHEBI:41977 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0026826 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005654 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003950 infores:hetionet CHEBI:70718 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0041834 infores:hetionet CAID:CA2695237858 biolink:causes MONDO:0010305 infores:clingen CAID:CA2695237858 MONDO:0010305 PMID: Pathogenic PM6, PVS1, PS1_Supporting, PM2_Supporting, PP4_Strong The NM_005629.4:c.262_262+1delinsTT variant (a.k.a. NC_000023.11:g.153688836_153688837delinsTT) alters the donor splice site of intron 1, replacing the last nucleotide of exon 1 and first nucleotide of intron 1 with TT. SpliceAI predicts that the donor splice site will be obliterated (Score for donor loss = 0.99). To our knowledge, no RNA studies are available to indicate the impact of the variant on splicing. However, an out of frame consequence is predicted (PVS1). A male patient with clinical features consistent with creatine transporter deficiency has been reported with brain MRS showing virtual absence of the creatine peak, and a significantly elevated urine creatine/creatinine ratio. The variant was reported to be de novo (Abstract 278-P, PMID: 18677552) (PP4_Strong, PM6). The variant is absent in gnomAD v2.1.1. and v4.1.0 (PM2_Supporting). Another variant at the same donor splice site dinucleotide, c.262+1G>T (ClinVar Variation ID: 3066445, SCV004809059.1) has been classified as pathogenic by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel which allows PS1_Supporting to be applied (PMID: 37352859) (PS1_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM6, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 9, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695237858/MONDO:0010305/027 2025-01-09 2025-01-09 X-linked inheritance HP:0001417 Supports CHEBI:42068 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0027059 infores:hetionet NCBIGene:104 biolink:causes MONDO:0030025 infores:monarchinitiative not_provided not_provided HGNC:226 MONDO:0030025 uuid:e1e3151c-55d7-409c-9499-2b63ca7fb1ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UBERON:0002515 biolink:causes MONDO:0002359 infores:ubergraph knowledge_assertion manual_agent UBERON:0002515 MONDO:0002359 CHEBI:64355 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0015230 infores:hetionet CHEBI:3485 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0016204 infores:hetionet CHEBI:9667 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0085633 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0041349 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0302810 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0302810 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0413252 infores:hetionet CAID:CA410149725 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149725 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, BP1, BP3, BP2, PM6, BS1, BS3, BS4, PM5, PM4, PM3, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.886G>A (p.Val296Met) is a missense variant which has a REVEL score < 0.50 (0.141) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149725/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8107 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020039 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0014742 infores:hetionet CHEBI:41977 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0019521 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018799 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0031117 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0227791 infores:hetionet CHEBI:44241 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0750394 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0849916 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0849916 infores:hetionet CHEBI:45285 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0042963 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0041349 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0232492 infores:hetionet CHEBI:64064 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C2607914 infores:hetionet CHEBI:50859 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0002962 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1443060 infores:hetionet GO:0034776 biolink:causes MONDO:0006004 infores:drugmechdb knowledge_assertion manual_agent GO:0034776 MESH:D012223 DB08799_MESH_D012223_1 CHEBI:3127 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0277925 infores:hetionet CHEBI:6931 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0003467 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151763 infores:hetionet CHEBI:8081 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0687713 infores:hetionet CHEBI:135005 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0035410 infores:hetionet CHEBI:77260 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235886 infores:hetionet CHEBI:85161 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151878 infores:hetionet CHEBI:3732 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0041969 infores:hetionet CHEBI:4562 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0011991 infores:hetionet NCBIGene:128869 biolink:causes MONDO:0032824 infores:monarchinitiative not_provided not_provided HGNC:15791 MONDO:0032824 uuid:e8249d28-dce3-4ab5-bbdf-07f746cbb484 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6754 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0003460 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0678222 infores:hetionet CHEBI:6067 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0003467 infores:hetionet CHEBI:45863 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0239783 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001011 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0006144 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0033975 infores:hetionet CHEBI:5138 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011175 infores:hetionet CHEBI:71255 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0039239 infores:hetionet CHEBI:167309 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0917801 infores:hetionet CHEBI:50841 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0424448 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0017152 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020538 infores:hetionet CHEBI:63611 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0917801 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0241166 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0241166 infores:hetionet CHEBI:2636 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0277890 infores:hetionet CHEBI:92712 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0011206 infores:hetionet CHEBI:5118 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0686347 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020615 infores:hetionet CHEBI:5778 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0043094 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0023533 infores:hetionet CHEBI:27690 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0162830 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0029408 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0948525 infores:hetionet CHEBI:6129 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013404 infores:hetionet CHEBI:7865 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0231837 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0017160 infores:hetionet CHEBI:68579 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0042963 infores:hetionet CAID:CA346327121 biolink:causes MONDO:0800472 infores:clingen CAID:CA346327121 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM1, PM3_Strong, PP3_Moderate, PP1_Moderate BA1, BP4, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4, PVS1 The c.1454C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Serine by Phenylalanine at amino acid 485 (p.Ser485Phe). This missense variant is located in the L-helix including the haem-binding domain, meeting PM1. This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.873, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699). 2 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 24001018), which fulfilled PP1_Moderate. This variant has been identified in 5 individuals with a CYP1B1-related phenotype. 1 of these individuals is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) and 4 are homozygous (assumed consanguineous) (PMIDs: 23218183, 21306220, 24001018). Total proband points = 2 meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 11 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PM1, PP1_Moderate, PP3_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346327121/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:85083 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0267792 infores:hetionet CHEBI:45924 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0221242 infores:hetionet CAID:CA377482110 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482110 MONDO:0017623 PMID: Likely Pathogenic PM6, PP2, PP3, PS3_Moderate, PM2_Supporting BP5, BP7, BS1, BS3, BS4, BS2, PP4, PP1, PM5, PM1, PM3, PM4, BP1, BP4, BP2, BP3, BA1, PS1, PS4, PS2 PTEN c.287C>T (p.Pro96Leu) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3_Moderate: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.48 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350).PM2_Supporting: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history (internal laboratory contributor SCV000616840.3).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.933). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482110/MONDO:0017623/003 2024-04-05 2024-04-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:35778 biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0521498 infores:hetionet CHEBI:45924 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0003467 infores:hetionet NCBIGene:7490 biolink:causes MONDO:0012164 infores:monarchinitiative not_provided not_provided HGNC:12796 MONDO:0012164 uuid:3f85fc0c-c8fa-44d9-90bf-18c877fb5042 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0039503 infores:hetionet CHEBI:3732 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0000737 infores:hetionet CHEBI:5134 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0235761 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0344357 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0344357 infores:hetionet CHEBI:2379 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0151517 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0149931 infores:hetionet CHEBI:100241 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038325 infores:hetionet UMLS:C0009315 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0013404 infores:hetionet CHEBI:7865 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0344232 infores:hetionet CHEBI:8499 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0220870 infores:hetionet CAID:CA000046 biolink:causes MONDO:0018875 infores:clingen CAID:CA000046 MONDO:0018875 PMID: Likely Benign BP4, BS2, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS3, BS4, PM6, PP3, PP1, PP4 The NM_000546.6: c.1150A>G variant in TP53 is a missense variant predicted to cause substitution of methionine by valine at amino acid 384 (p.Met384Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: Invitae). Computational predictor scores (BayesDel = -0.073; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). This variant has an allele frequency of 0.00001780 (21/1179926 alleles) in the Europen (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BP4_Moderate, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 2.0; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000046/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17026 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0018916 infores:hetionet CHEBI:7601 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0011606 infores:hetionet CAID:CA367402001 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402001 MONDO:0015967 PMID: Uncertain Significance BS2, PP2, PM2_Supporting PP3, BP4 The c.429G>T variant in the glucokinase gene, GCK, causes an amino acid change of lysine to asparagine at codon 143 (p.(Lys143Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with normal fasting glucose (BS2; PMID: 23799006, internal lab contributors). In summary, c.449T>C meets the criteria to be classified as Uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PM2_Supporting, PP2, BS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402001/MONDO:0015967/086 2024-03-22 2024-03-22 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:2618 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0547030 infores:hetionet CHEBI:4551 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0340464 infores:hetionet CHEBI:27504 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0002170 infores:hetionet CHEBI:6715 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019825 infores:hetionet CHEBI:2639 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0013395 infores:hetionet GO:0140196 biolink:causes GO:0003015 infores:ubergraph knowledge_assertion manual_agent GO:0140196 GO:0003015 CHEBI:63621 biolink:causes UMLS:C0236053 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0236053 infores:hetionet CHEBI:10110 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0004364 infores:hetionet CHEBI:44423 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0015967 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0042373 infores:hetionet CHEBI:5118 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013404 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0948594 infores:hetionet CHEBI:4445 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0037036 infores:hetionet CAID:CA229419 biolink:causes MONDO:0009861 infores:clingen CAID:CA229419 MONDO:0009861 PMID:9380432PMID:9781015PMID:9380432PMID:11461190PMID:21953985 Likely Pathogenic PM3, PM2, PP4, PS3 PP3 The c.125A>T (p.Lys42Ile) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency not assessed/reported). (PP4; PMID: 9380432; 9781015). This variant is absent in population databases (PM2). This variant was detected with p.E280K (Pathogenic in ClinVar) (PM3). This variant has 12% enzyme activity in vitro (PS3; PMID: 21953985). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PP4, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229419/MONDO:0009861/006 2019-04-07 2019-04-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31932 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0015672 infores:hetionet GO:0008283 biolink:causes MONDO:0016586 infores:drugmechdb knowledge_assertion manual_agent GO:0008283 MESH:D034721 DB00619_MESH_D034721_1 CHEBI:3756 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011175 infores:hetionet CHEBI:6715 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0600142 infores:hetionet CHEBI:3996 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0015371 infores:hetionet CAID:CA9870289 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870289 MONDO:0015967 PMID: Uncertain Significance PP4 PM2, PP3, PM1, BP4, BS1 The c.481A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to glycine at codon 161 (p.(Ser161Gly)) of NM_175914.5. The Grpmax filtering allele frequency of the c.481A>G variant in gnomAD v2.1.1 is 0.00001121, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in an individual with a clinical history of HNF4A-MODY (diagnosed over 35 years old but clinical judgment applied due to multiple hypoglycemic episodes on sulfonylurea and negative genetic testing for HNF1A) (PP4; internal lab contributor). Additionally, this variant has a REVEL score of 0.347, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.481A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870289/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68554 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0038358 infores:hetionet CHEBI:83527 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0234047 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0029882 infores:hetionet NCBIGene:27031 biolink:causes MONDO:0011456 infores:monarchinitiative not_provided not_provided HGNC:7907 MONDO:0011456 uuid:bd3ae1f6-be25-49d7-a611-ac1c5a1a5f7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367398754 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398754 MONDO:0015967 PMID: Pathogenic PS4, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1144T>C variant in the glucokinase gene, GCK, causes an amino acid change of Cys to Arg at codon 382 (p.(Cys382Arg)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1144T>G p.Cys382Gly, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:24804978, Zubkova N.A et al, World J PM. 2017;1(1):40-48. https://doi.org/10.14341/WJPM9298, internal lab contributors). In summary, c.1144T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5_Supporting, PP4_Moderate, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398754/MONDO:0015967/086 2023-07-16 2023-07-16 Semidominant inheritance HP:0032113 Supports CAID:CA213680 biolink:causes MONDO:0011225 infores:clingen CAID:CA213680 MONDO:0011225 PMID:25917813 Benign BA1, BS2_Supporting PS3 The c.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg).The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting).Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA213680/MONDO:0011225/116 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6741 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013604 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0037199 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0009443 infores:hetionet CHEBI:94686 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0030193 infores:hetionet CAID:CA533253809 biolink:causes MONDO:0015152 infores:clingen CAID:CA533253809 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.799_800del p.(Phe267LeufsTer5) variant in DYSF, which is also known as NM_001130987.2: c.895_896del p.(Phe299LeufsTer5), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 8/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least seven patients with suspected LGMD or dysferlinopathy (PMID: 18853459, 25591676, 27647186, 30107846), including in a homozygous state in at least one individual with no known familial consanguinity (0.5 pts, PMID: 27647186; PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 18853459; PP4_Strong). The highest minor allele frequency for this variant is 0.00002519 in the East Asian population in gnomAD v4.1.0 (1/39700 exome chromosomes), which is lower than the ClinGen LGMD VCEP threshold (0.0001) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/28/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA533253809/MONDO:0015152/180 2025-05-28 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10014208 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014208 MONDO:0011071 PMID: Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1086G>T (p.Ser362=) is a synonymous variant. AF 0.0006271 (0.06271%)( 10/15946 in East Asian subpopulation in gnomAD v2.1.1.) is 0.015% between 0.15% (BS1). REVEL score not calculable as this is a synonymous variant. SpliceAI predicts the following: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.503315 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014208/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2611 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0232431 infores:hetionet CHEBI:100241 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014236 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009938 infores:hetionet NCBIGene:9842 biolink:causes MONDO:0020848 infores:monarchinitiative not_provided not_provided HGNC:29017 MONDO:0020848 uuid:f8bf7124-b3b9-42d5-a4d5-e5ac5d6d1bde biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0025874 infores:hetionet CHEBI:8207 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0015967 infores:hetionet CHEBI:52172 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0007859 infores:hetionet NCBIGene:540 biolink:causes MONDO:0010200 infores:monarchinitiative not_provided not_provided HGNC:870 MONDO:0010200 uuid:619c0953-5793-4040-bc75-d1ce546714a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:367163 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0851341 infores:hetionet CHEBI:6933 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0031924 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0042109 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0020517 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0041912 infores:hetionet CHEBI:5138 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0080274 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027796 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0002418 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1861172 infores:hetionet NCBIGene:57639 biolink:causes MONDO:0971002 infores:monarchinitiative not_provided not_provided HGNC:29296 MONDO:0971002 uuid:374ab7ac-3a8d-482a-b1d7-07d3846c0f15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40303 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0002878 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0026857 infores:hetionet CHEBI:9943 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009676 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0029134 infores:hetionet NCBIGene:1297 biolink:causes MONDO:0013590 infores:monarchinitiative not_provided not_provided HGNC:2217 MONDO:0013590 uuid:18a6d6c5-e823-4f08-b630-056c376e15ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229371 biolink:causes MONDO:0009861 infores:clingen CAID:CA229371 MONDO:0009861 PMID:8889590PMID:21147011PMID:8889590 Likely Pathogenic PP4_Moderate, PM2, PM3, PP3 PM5 The c.1180G>C (p.Asp394His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8889590, 21147011, 31355225 ). This variant is absent in population databases. This variant was detected with pathogenic variants IVS10-11G>A (PMID: 8889590); IVS11nt1g>c (IVS11+1G>C, PMID: 10947211). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229371/MONDO:0009861/006 2020-08-17 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:93363 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C2830004 infores:hetionet NCBIGene:2160 biolink:causes MONDO:0012897 infores:monarchinitiative not_provided not_provided HGNC:3529 MONDO:0012897 uuid:b0bcf797-849b-4d1f-b55a-192fc0fed23d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47499 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0004936 infores:hetionet CHEBI:3380 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0033774 infores:hetionet CHEBI:34385 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0040822 infores:hetionet UMLS:C0005740 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0235896 infores:hetionet CHEBI:8481 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0000731 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0332575 infores:hetionet CHEBI:119915 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0030196 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0029445 infores:hetionet CAID:CA347525 biolink:causes MONDO:0015152 infores:clingen CAID:CA347525 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PP3, PM3_Strong PM2 The NM_000070.3: c.1319G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid 440 (p.Arg440Gln). This variant has been detected in at least 12 individuals with a clinical diagnosis or suspicion of limb girdle muscular dystrophy (PMID: 20694146, 18055493, 17994539, 18334579, 18854869, 15689361, 19048948, 21984748; Washington University internal clinic data communication), including confirmed in trans with a pathogenic variant (c.550del, 1.0 pt, PMID: 17994539), and in unknown phase with a likely pathogenic or pathogenic variant in three cases (c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts, PMID: 21984748; c.633G>C p.(Lys211Asn), 0.5 pts, PMID: 18334579, 20694146, 18055493) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18055493, 20694146, 18854869, 19048948). The filtering allele frequency of the variant is 0.0004336 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 7/30318), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.79, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4_Strong, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347525/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4798 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0021368 infores:hetionet CHEBI:50648 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0546817 infores:hetionet CHEBI:6375 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0542571 infores:hetionet CHEBI:8499 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0030554 infores:hetionet CHEBI:3478 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0033774 infores:hetionet CHEBI:61049 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029453 infores:hetionet CHEBI:36791 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C3263723 infores:hetionet CHEBI:7865 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0023052 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0036341 infores:hetionet CHEBI:3723 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151836 infores:hetionet NCBIGene:5015 biolink:causes MONDO:0012413 infores:monarchinitiative not_provided not_provided HGNC:8522 MONDO:0012413 uuid:c2f225b4-6b5a-442f-a684-b313f1087b6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410206649 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206649 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.803A>G (p.Gln268Arg) is a missense variant that is not present in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has a REVEL score < 0.50 (0.468), and a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206649/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63607 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0013395 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0232462 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0234215 infores:hetionet CHEBI:3534 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0267792 infores:hetionet CHEBI:8597 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0014457 infores:hetionet CHEBI:3001 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0011603 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0235660 infores:hetionet CHEBI:38940 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0221201 infores:hetionet CHEBI:4445 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0267792 infores:hetionet CHEBI:61033 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0018790 infores:hetionet CAID:CA160225 biolink:causes MONDO:0010938 infores:clingen CAID:CA160225 MONDO:0010938 PMID: Benign BA1, BS2_Supporting NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile).The filtering allele frequency (the lower threshold of the 95% CI of 12957/1180016) of the c.2164G>A variant in JAK3 is 0.01082 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Additionally, 120 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and B2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160225/MONDO:0010938/121 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA226376 biolink:causes MONDO:0100437 infores:clingen CAID:CA226376 MONDO:0100437 PMID:23213406 Likely Pathogenic PP1_Moderate, PS3_Supporting, PP3_Strong, PP4, PM2_Supporting PVS1, PM6, BS2, PP2, PM5, PM4, PM3, PM1, PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP7, BP5 NM_001034853.2(RPGR):c.179G>T (p.Gly60Val) is a missense variant that replaces glycine with valine at amino acid 60. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts) with delayed or milder phenotype in females (1 pt), visual field reduction (0.5 pts), central vision problem (0.5 pts) since 6 years of age (1 pt), poor night vision (0.5 pts), pigmentary retinopathy (0.5 pts), and nondetectable electroretinogram responses, which together are specific for RPGR-related retinopathy (6 points, PMID: 9855162, PP4). This variant has been reported in other publications, however, the ability to conclude that the probands described are unrelated was not successful (PMIDs: 28559085, 10937588, 34985506, 9399904, 9855162). The variant has been reported to segregate with retinal dystrophy through at least 4 meioses from at least 1 family (PP1_moderate; PMID: [9855162]). The computational predictor REVEL gives a score of 0.98, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.19 for acceptor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. Exogenously expressed RPGR harboring the variant exhibits reduced interaction with RPGRIP1 in a yeast-2-hybrid experiment (PMID: 23213406, 23213406, PS3_supporting). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PP1_moderate, PP3_strong, PS3_supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226376/MONDO:0100437/106 2025-05-21 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:63631 biolink:causes HP:0007359 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0751495 infores:hetionet GO:0031931 biolink:causes GO:0038202 infores:ubergraph knowledge_assertion manual_agent GO:0031931 GO:0038202 CHEBI:32184 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0853714 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C1258215 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027441 infores:hetionet MONDO:0041751 biolink:causes GO:0042092 infores:mondo not_provided not_provided MONDO:0041751 GO:0042092 infores:monarchinitiativeinfores:phenio urn:uuid:594e4d65-b4f1-42c9-a99a-aae489821963 biolink:Associationbiolink:Entity phenio_edges CHEBI:6775 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006266 infores:hetionet CHEBI:3756 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0004604 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0155365 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011570 infores:hetionet CHEBI:16899 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0038362 infores:hetionet CHEBI:91541 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0011334 infores:hetionet CAID:CA399792888 biolink:causes MONDO:0100326 infores:clingen CAID:CA399792888 MONDO:0100326 PMID: Pathogenic PM3, PVS1, PP4_Moderate, PM2_Supporting NM_000419.5(ITGA2B):c.2702C>A (p.Ser901Ter) found in three unrelated homozygous probands from Tunisia (PMID:30325339; PM3) causes a premature stop codon at exon 26 and is predicted to undergo nonsense mediated decay (PVS1). At least one patient with this variant displayed abnormal bleeding and an impaired response to agonists, with a normal response to ristocetin, which is characteristic of Glanzmann thrombasthenia (PMID:30325339; PP4_moderate). The variant was not found in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP4_moderate, and PM3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399792888/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:63638 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233494 infores:hetionet CHEBI:8356 biolink:causes HP:0001537 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019322 infores:hetionet CHEBI:6717 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0340865 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018790 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037274 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007787 infores:hetionet CHEBI:47898 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0040053 infores:hetionet CHEBI:480999 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0085605 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0010709 infores:hetionet NCBIGene:84515 biolink:causes MONDO:0044776 infores:monarchinitiative not_provided not_provided HGNC:16147 MONDO:0044776 uuid:3fbab062-0a29-4811-bf7d-e4444ef95f73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2950 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0392171 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0010709 infores:hetionet CHEBI:63619 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011124 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0948594 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0012833 infores:hetionet NCBIGene:6444 biolink:causes MONDO:0011028 infores:monarchinitiative not_provided not_provided HGNC:10807 MONDO:0011028 uuid:3342fad4-30db-482d-86cb-9e27d1c387a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA340747151 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747151 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting BP4, BA1, PS2, BS1, PM6, PP1 NM_000329.3(RPE65):c.536C>T is a missense variant causing substitution of alanine by valine at position 179. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, VCEP member-provided data, PM3). At least one proband harboring this variant exhibits a phenotype including symptomatic onset between birth and age 5 years (1 pt), genotyping by retinal dystrophy next generation sequencing panel that did not provide an alternative explanation for visual impairment (2 pts), depressed ERG responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), nyctalopia, decreased central visual acuity (1 pt), fundus atrophy (0.5 pts), optic nerve pallor (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), RPE mottling (0.5 pts), decreased peripheral vision (1 pt), and significant positive response to Luxturna (8 pts), which together are specific for RPE65-related recessive retinopathy (16.5 total points, VCEP member-provided data, PP4_Moderate). The computational predictor REVEL gives the variant a score of 0.996, which is above the ClinGen LCA / eoRD VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting, PM3, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747151/MONDO:0100368/120 2024-02-01 2024-02-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45951 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0575081 infores:hetionet CHEBI:240107 biolink:causes HP:0000559 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0349702 infores:hetionet CHEBI:70718 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0035078 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018799 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0857448 infores:hetionet CHEBI:63584 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0151905 infores:hetionet CHEBI:83804 biolink:causes HP:0002533 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0231471 infores:hetionet CHEBI:3752 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0015672 infores:hetionet CHEBI:77260 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0023222 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0267792 infores:hetionet CHEBI:9123 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0855333 infores:hetionet CHEBI:101853 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C3665624 infores:hetionet CHEBI:5002 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0011991 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0086543 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0025061 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0006849 infores:hetionet CAID:CA229372 biolink:causes MONDO:0009861 infores:clingen CAID:CA229372 MONDO:0009861 PMID:8268925PMID:8830172 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 PM5 The c.1181A>C (p.Asp394Ala) variant in PAH has been reported in multiple Sicilian individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8268925). This variant is absent in population databases. This variant was detected with pathogenic variants: p.R261Q (PMID: 8830172); IVS4+5G>T (PMID: 21837404). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229372/MONDO:0009861/006 2020-08-17 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5147 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0002962 infores:hetionet CAID:CA410147998 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147998 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, BP4, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1135A>G (p.Thr379Ala) is a missense variant which is located outside of the Runt Homology Domain and is completely absent from all general population databases in gnomAD v3 (PM2_Supporting). It has not been reported in the literature, and functional evidence is not available. Although the REVEL score is high, it does not meet the ≥ 0.88 threshold for applying PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147998/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6402 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0009319 infores:hetionet CHEBI:68556 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0002792 infores:hetionet CAID:CA10567784 biolink:causes MONDO:0010602 infores:clingen CAID:CA10567784 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM5, PP3, PS4 PM2, BS1 The NM_000132.4(F8):c.6623A>G (p.Gln2208Arg) is a missense variant. The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3_Supporting). This variant has been reported in 4 probands with mild hemophilia A This variant was reported in 2 patients with mild hemophilia A with FVIII:C = 23% and FVIII:C=34%. VWD was excluded. (PMID: 26879396; PMID 27734074). This variant was reported in 1 patient with mild hemophilia A with FVIII:C = 23%. VWD was ruled out (PMID: 27734074). Reported in 1 patient with mild hemophilia A with FVIII:C = 34%. VWD is excluded. Another missense variant c.6622C>G (p.Gln2208Glu) is present at the same codon and has been classified as pathogenic by CFD VCEP. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PM5, PP3, PS4_Strong. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10567784/MONDO:0010602/071 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Supports CHEBI:3380 biolink:causes MONDO:0011827 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0013274 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011849 infores:hetionet CHEBI:3228 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0428977 infores:hetionet CHEBI:63620 biolink:causes MONDO:0044872 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013363 infores:hetionet CAID:CA913189165 biolink:causes MONDO:0015967 infores:clingen CAID:CA913189165 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PP4_Moderate, PP3, PM2_Supporting PS4 The c.1019+5G>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with hyperglycemia, with four informative meioses in two families (PP1_Strong; PMIDs: 19564454, 31604004). The computational splicing predictor SpliceAI gives a score of 0.63 for donor gain and 0.50 for donor loss, predicting that the variant disrupts the donor site of intron 8 of GCK (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; PMID: 31604004). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 19564454, 31604004). In summary, c.1019+5G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP1_Strong, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189165/MONDO:0015967/086 2023-11-24 2023-11-24 Semidominant inheritance HP:0032113 Supports CHEBI:92511 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0027497 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0038826 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0038358 infores:hetionet CHEBI:38562 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0040822 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0002871 infores:hetionet CHEBI:9738 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0080274 infores:hetionet CHEBI:50924 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0024312 infores:hetionet NCBIGene:6690 biolink:causes MONDO:0008185 infores:monarchinitiative not_provided not_provided HGNC:11244 MONDO:0008185 uuid:a864df1b-7568-4b0f-8095-154baa8c60ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA335750 biolink:causes MONDO:0013144 infores:clingen CAID:CA335750 MONDO:0013144 PMID: Likely Benign BS1, BP4 The NM_000488.4(SERPINC1):c.1154-5T>C variant is an intronic change that has a frequency of 0.03% in South Asians with 11 alleles (gnomAD v2.1.1). No splicing disruption prediction is noted per SpliceAI and varSEAK, but the nucleotide may be moderately conserved. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA335750/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6931 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C3665347 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003123 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0435002 infores:hetionet CHEBI:31711 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0040822 infores:hetionet CHEBI:94686 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0232461 infores:hetionet CHEBI:9599 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0036974 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151970 infores:hetionet CHEBI:5801 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0032708 infores:hetionet CHEBI:6073 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0016382 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0948594 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0032708 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0232492 infores:hetionet CAID:CA916083898 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083898 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting PP4 NM_001034853.2(RPGR):c.2516_2520del (p.Glu839GlyfsTer?) is a frameshift variant due to a 5-nucleotide deletion in exon 15 of 15 that introduces a premature stop codon and is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 23681342, PMID: 10937588, PMID: 17325176, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083898/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports UNII:7662KG2R6K biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0043094 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0037199 infores:hetionet CHEBI:37924 biolink:causes UMLS:C3203690 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C3203690 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017152 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0037199 infores:hetionet CHEBI:16480 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0012833 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0014868 infores:hetionet CHEBI:8774 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0036974 infores:hetionet CHEBI:15544 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0231837 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0234215 infores:hetionet CHEBI:9599 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0041657 infores:hetionet GO:0021531 biolink:causes CL:1000073 infores:ubergraph knowledge_assertion manual_agent GO:0021531 CL:1000073 NCBIGene:2516 biolink:causes MONDO:0013066 infores:monarchinitiative not_provided not_provided HGNC:7983 MONDO:0013066 uuid:b243e120-bdff-4ece-ab1d-d6954221619a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0015967 infores:hetionet NCBIGene:57466 biolink:causes MONDO:0957787 infores:monarchinitiative not_provided not_provided HGNC:19304 MONDO:0957787 uuid:1c40e9ff-1d29-4207-969f-f438be028587 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA376059636 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059636 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2 The c.554G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Glutamic Acidat amino acid 185 (p.Gly185Glu).The filtering allele frequency (the upper threshold of the 95% CI of 3/74902 alleles) of the c.554G>A variant in DCLRE1C is 0.00001064 for African/African American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059636/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:1650 biolink:causes MONDO:0013789 infores:monarchinitiative not_provided not_provided HGNC:2728 MONDO:0013789 uuid:16438d2c-18f4-4c0f-a16e-a20f105daf69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31644 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020598 infores:hetionet CHEBI:4784 biolink:causes HP:0030839 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0231749 infores:hetionet CAID:CA172206 biolink:causes MONDO:0019497 infores:clingen CAID:CA172206 MONDO:0019497 PMID:31160754PMID:14694360PMID:10903123PMID:31160754PMID:31160754PMID:14694360PMID:10903123PMID:31160754PMID:31160754PMID:31160754PMID:31160754PMID:31160754PMID:10556284PMID:15033936PMID:27884957PMID:16849369PMID:12189493PMID:16300957PMID:31160754 Pathogenic PP3, PP1, PM3_Very Strong, PS4 BP5, BP7, BS1, BS4, BS2, PP4, PM4, PM1, PM5, PM6, PM2, PVS1, BP3, BP4, BP2, BA1, PS2, PS3, PS1 The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA172206/MONDO:0019497/005 2019-06-24 2019-06-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:51164 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0242151 infores:hetionet CAID:CA512319128 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319128 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.522T>C (p.Thr174=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0, -1.92) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319128/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10023 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0231218 infores:hetionet CHEBI:64321 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0033771 infores:hetionet CHEBI:36791 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033893 infores:hetionet CHEBI:51173 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0042963 infores:hetionet CL:0000646 biolink:causes MONDO:0020799 infores:ubergraph knowledge_assertion manual_agent CL:0000646 MONDO:0020799 NCBIGene:51067 biolink:causes MONDO:0013307 infores:monarchinitiative not_provided not_provided HGNC:24249 MONDO:0013307 uuid:60fea594-7268-4d31-902b-27aa37d89747 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3510 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0003537 infores:hetionet CHEBI:3001 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0020555 infores:hetionet CHEBI:7824 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0423791 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0003123 infores:hetionet CHEBI:74947 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040264 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0037274 infores:hetionet CHEBI:75922 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0155169 infores:hetionet CHEBI:28864 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0311468 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0039503 infores:hetionet CHEBI:10125 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009676 infores:hetionet NCBIGene:84172 biolink:causes MONDO:0030067 infores:monarchinitiative not_provided not_provided HGNC:20454 MONDO:0030067 uuid:77d4b99e-84ef-4d5b-990a-7f6485298f44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0038358 infores:hetionet CHEBI:474053 biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0344375 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030552 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0033975 infores:hetionet CHEBI:8707 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040264 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0442874 infores:hetionet CHEBI:6067 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0333355 infores:hetionet CHEBI:404903 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0040434 infores:hetionet CHEBI:16469 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0040264 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0037274 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0742007 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0742007 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0027609 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023067 infores:hetionet CAID:CA414447219 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447219 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PP3, PP1, PP4 PM1 The NM_000133.4:c.1304G>A variant in F9 is a missense variant predicted to cause substitution of Cys by Tyr at amino acid 435 (p.Cys435Tyr). This variant has been reported in 9 probands meeting F9 phenotype criteria (PS4_Very Strong, PP4; PMIDs: s: 8091381, 10698280, 29296726, 22103590, 21118338, 8217825, 7482402). The variant has been reported to segregate with hemophilia B in 2 affected family members from 1 family (PP1; PMID: 21118338). The computational predictor REVEL gives a score of 0.943, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). This variant is absent from gnomAD v2, v3 and v4. In summary, this variant meets the criteria to be classified as pathogenic for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_Very Strong, PM2_Supporting, PP4, PP3, PP1. (Version 1.0.0, 10/05/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447219/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:3223 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0042023 infores:hetionet CHEBI:8874 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232726 infores:hetionet CHEBI:2567 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0009806 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0549493 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0042109 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0012833 infores:hetionet CHEBI:8764 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027497 infores:hetionet CHEBI:63791 biolink:causes HP:0041159 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0035522 infores:hetionet CHEBI:63589 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0041657 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151736 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0021053 infores:hetionet CHEBI:8768 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0344232 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0041912 infores:hetionet CHEBI:5050 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0043352 infores:hetionet CHEBI:2687 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0333355 infores:hetionet CHEBI:3387 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0428977 infores:hetionet CHEBI:3510 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0000737 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0677500 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0038363 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085584 infores:hetionet CHEBI:91541 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0020458 infores:hetionet CHEBI:291342 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0014591 infores:hetionet CHEBI:8874 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0520966 infores:hetionet CHEBI:50275 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151908 infores:hetionet NCBIGene:6809 biolink:causes MONDO:0030335 infores:monarchinitiative not_provided not_provided HGNC:11438 MONDO:0030335 uuid:7a194980-0cb4-47c8-94e4-4d7f92307905 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0012739 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0027765 infores:hetionet CHEBI:50861 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0043144 infores:hetionet CHEBI:4511 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0948586 infores:hetionet CHEBI:2950 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0016382 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0035078 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0559031 infores:hetionet CHEBI:36795 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0520966 infores:hetionet CHEBI:43968 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0020615 infores:hetionet CAID:CA220206 biolink:causes MONDO:0008723 infores:clingen CAID:CA220206 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 PM3 The NM_000018.4(ACADVL): c.343del (p.Glu115Lysfs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant, however it has been reported in the literature in at least four individuals with VLCADD (PP4: PMID: 7479827, 31031081, 32778825). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PP4.) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220206/MONDO:0008723/021 2021-11-09 2022-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135888 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0041912 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0018802 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0041969 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0009763 infores:hetionet CHEBI:3215 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0549249 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018790 infores:hetionet NCBIGene:6554 biolink:causes MONDO:0031003 infores:monarchinitiative not_provided not_provided HGNC:10905 MONDO:0031003 uuid:fe9e8bb9-8c65-4cda-8ee1-725863dd23cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1262113 infores:hetionet CHEBI:31932 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C3263723 infores:hetionet CHEBI:6717 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0033774 infores:hetionet CHEBI:100241 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0026826 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0162281 infores:hetionet CHEBI:47519 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0232462 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018802 infores:hetionet CAID:CA367401681 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401681 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PP4, PM2_Supporting The c.524G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to alanine at codon 175 (p.(Gly175Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.523G>A p.Gly175Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly175Ala (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 19002431). In summary, c.524G>C meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM5_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401681/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:7465 biolink:causes UMLS:C0235162 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0235162 infores:hetionet CHEBI:39867 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151529 infores:hetionet CHEBI:6375 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0391870 infores:hetionet CAID:CA410147011 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147011 MONDO:0011071 PMID: Uncertain Significance BP4 PS4, PS3, PS2, PS1, BP2, BP1, BP3, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1379G>A (p.Ser460Asn) is a missense variant which has a REVEL score ≤0.50 (0.218) and a SpliceAI ≤0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147011/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:4722 biolink:causes MONDO:0032613 infores:monarchinitiative not_provided not_provided HGNC:7710 MONDO:0032613 uuid:5778894f-25cc-49d9-a4f0-e5a764c51694 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6717 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0040034 infores:hetionet CHEBI:3479 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0011991 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013395 infores:hetionet CHEBI:63845 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C1761613 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0427108 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0160390 infores:hetionet NCBIGene:3659 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:6116 MONDO:0008903 uuid:a6f60989-4efc-4968-8c11-496f077dcae1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:391960 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0039231 infores:hetionet CAID:CA136094 biolink:causes MONDO:0021060 infores:clingen CAID:CA136094 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2122G>A (p.Ala708Thr) variant in the SOS1 gene is 5.13% for Latino chromosomes by the Exome Aggregation Consortium (633/11554 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136094/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:51164 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0031039 infores:hetionet CHEBI:46557 biolink:causes UMLS:C3495917 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C3495917 infores:hetionet CHEBI:7825 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0011616 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0032326 infores:hetionet UMLS:C0017797 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0085593 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005030 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0015934 infores:hetionet CHEBI:134990 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0542571 infores:hetionet CHEBI:4822 biolink:causes HP:0031944 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0264545 infores:hetionet CHEBI:18358 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0017178 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020538 infores:hetionet CHEBI:68579 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0406834 infores:hetionet CHEBI:75722 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1260880 infores:hetionet CHEBI:465284 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151908 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0948525 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0014544 infores:hetionet NCBIGene:80222 biolink:causes MONDO:0014398 infores:monarchinitiative not_provided not_provided HGNC:30740 MONDO:0014398 uuid:9ac3a9e7-c3f5-44f8-803c-d99fa96d28ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2704 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C2939186 infores:hetionet CHEBI:43968 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0022346 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0006840 infores:hetionet CAID:CA351736 biolink:causes MONDO:0021060 infores:clingen CAID:CA351736 MONDO:0021060 PMID:20679480 Uncertain Significance PS3, PM1, PM2, PP2 PS4, PM5, PP3 The c.779C>T (p.Thr260Ile) variant in RAF1 was absent from large population databases (PM2; gnomad.broadinstitute.org). It occurs in the CR2 domain of the protein, which has been identified as a region important for protein function (PM1, 29493581). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 20679480). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 17603483; Blueprint Genetics internal data, SCV000264163.2; Invitae internal data, SCV000824563.1; Ambry internal data, SCV000740058.2; GeneDx internal data, SCV000582743.4). Although criteria suggest that this variant is likely pathogenic given its location and in vitro functional studies, the lack of clear clinical presentations of a RASopathy phenotype supports that this variant is of uncertain significance at this time. RASopathy-specific ACMG/AMP criteria applied: PS3, PM1, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA351736/MONDO:0021060/004 2020-03-09 2020-03-09 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7931 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0005758 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0013604 infores:hetionet CHEBI:50275 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1142412 infores:hetionet CHEBI:3636 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0018790 infores:hetionet CHEBI:4027 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C3665347 infores:hetionet CHEBI:8707 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235660 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0038362 infores:hetionet CHEBI:63580 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013604 infores:hetionet CAID:CA214261 biolink:causes MONDO:0015967 infores:clingen CAID:CA214261 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4 PS4 The c.130delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids before encountering a stop codon (p.(Leu44TrpfsTer111)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID: 15305805). This variant segregated with diabetes, with at least five informative meioses in two families with MODY (PP1_Strong; PMIDs: 15305805 and 12453976). This variant was Identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15305805 and 12453976). In summary, c.130delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214261/MONDO:0015967/017 2022-04-02 2022-04-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31348 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006266 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151828 infores:hetionet CHEBI:17650 biolink:causes MONDO:0019801 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151467 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0040034 infores:hetionet CHEBI:44032 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0438142 infores:hetionet NCBIGene:1000 biolink:causes MONDO:0859261 infores:monarchinitiative not_provided not_provided HGNC:1759 MONDO:0859261 uuid:b2bac36d-94fa-4f5f-bd3e-10f3fa2a6493 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0085649 infores:hetionet CHEBI:6761 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0011606 infores:hetionet CAID:CA255162 biolink:causes MONDO:0010602 infores:clingen CAID:CA255162 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4 The NM_000132.4(F8):c.5399G>A (p.Arg1800His) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.1.2, meeting the PM2_Supporting criteria. More than 17 individuals in the literature and 40 in the internal laboratory data are observed with hemophilia A ranging from mild to severe carrying the Arg1800His variant. More cases are available in the literature (EAHAD database reports 76 individuals); however, the threshold for PS4_VeryStrong (>8) and PP4_Moderate have been reached. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been associated with inhibitor development to factor replacement therapy (CDC CHAMPS/EAHAD databases). The c.5399G>A (p.Arg1800His) missense variant has a REVEL score of 0.96 (>0.6), which meets the PP3 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255162/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5847 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C2047937 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017574 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0159028 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0159028 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0025061 infores:hetionet CHEBI:31638 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0030196 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0242350 infores:hetionet CHEBI:49040 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0042963 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0025061 infores:hetionet UMLS:C0657912 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037036 infores:hetionet CHEBI:63584 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0023530 infores:hetionet CHEBI:28864 biolink:causes UMLS:C3495950 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C3495950 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042109 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0015397 infores:hetionet CHEBI:27786 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0042075 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007971 infores:hetionet CHEBI:8207 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0040053 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0001622 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0019360 infores:hetionet CHEBI:50922 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C3665347 infores:hetionet CHEBI:30659 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0232602 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0037199 infores:hetionet CHEBI:2469 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0010200 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0234215 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0948525 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027651 infores:hetionet CHEBI:63631 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017565 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002622 infores:hetionet CHEBI:94411 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0009676 infores:hetionet CHEBI:51141 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C1735601 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233494 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0264906 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0021843 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0853149 infores:hetionet CHEBI:9943 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018520 infores:hetionet CHEBI:3219 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0043387 infores:hetionet CHEBI:31859 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0002994 infores:hetionet CAID:CA367398584 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398584 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1 The c.1180C>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to serine at codon 394 (p.(Arg394Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.773, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 28323911, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 2 hour OGTT increment < 3 mmol/L and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1181G>C p.Arg394Pro has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1180C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398584/MONDO:0015967/086 2025-04-21 2025-04-23 Semidominant inheritance HP:0032113 Supports CHEBI:7773 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0015672 infores:hetionet CHEBI:50648 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0311468 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0026946 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0027947 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001741 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020502 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0002418 infores:hetionet CHEBI:39867 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0518988 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0014032 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0014032 uuid:6c3a5272-5df0-405f-b69a-b57996737511 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91834 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C2242996 infores:hetionet CAID:CA2573157349 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157349 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.508+20T>C is an intronic variant in intron 5 of the biologically relevant transcript. This variant has not been observed in any population according to gnomAD v3 (PM2_Supporting). The nucleotide is not evolutionarily conserved (PhyloP 0.045), and the variant is not predicted to affect splicing according to SpliceAI (score 0.01) (BP4, BP7). The variant has not been described in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157349/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA748900124 biolink:causes MONDO:0011071 infores:clingen CAID:CA748900124 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.*1967G>A is a non-coding variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This is a non-coding variant; therefore, no REVEL score is applicable. The SpliceAI score is ≤ 0.20 (0) and the PhyloP score is < 0.1 (-0.2) (BP4, BP7). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA748900124/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119486 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0031117 infores:hetionet GO:0003427 biolink:causes GO:0003419 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0003419 UMLS:C0209366 biolink:causes MONDO:0002070 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0018818 infores:hetionet CHEBI:2208 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0151798 infores:hetionet GO:0048089 biolink:causes GO:0046660 infores:ubergraph knowledge_assertion manual_agent GO:0048089 GO:0046660 CHEBI:51137 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0040264 infores:hetionet CHEBI:3756 biolink:causes HP:0001686 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0003564 infores:hetionet CHEBI:135920 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0016204 infores:hetionet CAID:CA415090844 biolink:causes MONDO:0010305 infores:clingen CAID:CA415090844 MONDO:0010305 PMID: Likely Pathogenic PP1_Moderate, PP3, PM2_Supporting, PP4_Strong The NM_005629.4:c.1681G>C variant in SLC6A8 is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 561 (p.Gly561Arg). This variant has been reported in three brothers with developmental delays, seizures, and elevated urine creatine/creatinine and was inherited from their mother (PP1_Moderate); in addition to elevated urine creatine/creatinine, the proband also had significantly reduced creatine peak on brain magnetic resonance spectroscopy (PP4_Strong) (PMID: 24045174). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP1_Moderate, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on Oct. 16, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415090844/MONDO:0010305/027 2023-10-13 2023-11-08 X-linked inheritance HP:0001417 Supports CHEBI:135791 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0011603 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0853813 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0235416 infores:hetionet NCBIGene:146206 biolink:causes MONDO:0029134 infores:monarchinitiative not_provided not_provided HGNC:27089 MONDO:0029134 uuid:f725b1d8-2fab-49ff-812f-33209a2b104d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0022568 infores:hetionet CHEBI:5106 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C2047937 infores:hetionet CHEBI:6541 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0018681 infores:hetionet CHEBI:8597 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0392676 infores:hetionet CHEBI:64354 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0004093 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0029408 infores:hetionet CHEBI:9674 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0020517 infores:hetionet CHEBI:6904 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0003862 infores:hetionet CHEBI:31643 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0035455 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0032961 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0008311 infores:hetionet CHEBI:4798 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0085605 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040479 infores:hetionet CHEBI:135613 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0549249 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151505 infores:hetionet CHEBI:87715 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0013491 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0162429 infores:hetionet CHEBI:3506 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0012833 infores:hetionet CHEBI:15553 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0031256 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0037274 infores:hetionet CHEBI:8772 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0948594 infores:hetionet CHEBI:10101 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0344232 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0687133 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0027765 infores:hetionet CAID:CA120593 biolink:causes MONDO:0044970 infores:clingen CAID:CA120593 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PP1, PS4, PS2, PS1, PM6 The m.8529G>A variant (resulting in p.Trp55X in MT-ATP8 and p.M1M in MT-ATP6) has been reported in one individual with primary mitochondrial disease (PMID: 17953552). This is a male with hypertrophic cardiomyopathy, gross motor delay, exercise intolerance, dysarthria, ataxia, ophthalmoplegia, and elevated cerebrospinal fluid lactate. The variant was present at homoplasmy in muscle and fibroblasts. Although not included in this curation given additional details are not available, we are aware of one additional case by personal communication with ataxia and spastic paraplegia. There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex V activity (PS3_supporting, PMID: 17954552). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120593/MONDO:0044970/015 2024-08-12 2025-04-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:17334 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0018939 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0027769 infores:hetionet CHEBI:144551 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0235266 infores:hetionet CHEBI:135361 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0009676 infores:hetionet CHEBI:9123 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0005758 infores:hetionet CHEBI:72297 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0027424 infores:hetionet CHEBI:71417 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0015672 infores:hetionet CHEBI:31348 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2363731 infores:hetionet CHEBI:42797 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006142 infores:hetionet CHEBI:63632 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0031350 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151763 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0549373 infores:hetionet CAID:CA194225 biolink:causes MONDO:0700270 infores:clingen CAID:CA194225 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM5_Supporting, PVS1 BA1, BS1, PM2 The c.8395_8404del (p.Phe2799Lysfs*4) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 7 individuals with Ataxia-Telangiectasia (PMID: 9792409, 9887333, 10817650, 12815592, 19147735, 21833744, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000026 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_supporting, PM3_Very Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA194225/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3219 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0600142 infores:hetionet CHEBI:4876 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0001824 infores:hetionet CHEBI:10101 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151315 infores:hetionet CHEBI:135342 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020443 infores:hetionet CHEBI:7931 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0013447 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0241950 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0241950 infores:hetionet CHEBI:16469 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009763 infores:hetionet GO:0044542 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0044542 GO:0010467 CHEBI:42944 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0034150 infores:hetionet CHEBI:135530 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0013428 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0234215 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0018802 infores:hetionet CHEBI:64355 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0038002 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0040034 infores:hetionet CHEBI:71219 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0030554 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1442903 infores:hetionet CHEBI:144551 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C2047937 infores:hetionet CHEBI:144093 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151766 infores:hetionet CHEBI:3347 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0002871 infores:hetionet CHEBI:3387 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0016658 infores:hetionet CHEBI:27899 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0085669 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0456909 infores:hetionet CHEBI:140621 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0018790 infores:hetionet CHEBI:36791 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043094 infores:hetionet CAID:CA403385475 biolink:causes MONDO:0021060 infores:clingen CAID:CA403385475 MONDO:0021060 PMID: Uncertain Significance PP2, BP4 PM5, PM1, PM2, BS2 The c.842G>A (p.Arg281Gln) variant in MAP2K2 was present in 0.007324% (1/13654) of Latino chromosomes in gnomAD v3. It was observed in one healthy adult male who did not have features of a RASopathy (BS2 not met; Baylor internal data). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PP2, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA403385475/MONDO:0021060/004 2020-03-19 2020-03-23 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3207 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0040435 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0042109 infores:hetionet UNII:K2J09EMJ52 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0022346 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1760428 infores:hetionet CHEBI:52172 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151970 infores:hetionet CHEBI:75722 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042024 infores:hetionet CHEBI:30830 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0003578 infores:hetionet NCBIGene:200373 biolink:causes MONDO:0010220 infores:monarchinitiative not_provided not_provided HGNC:33720 MONDO:0010220 uuid:068e60fa-07d2-49ca-8b4d-371df8e5ccb1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50838 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0037274 infores:hetionet CHEBI:3387 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0026961 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004754 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0034888 infores:hetionet CHEBI:168396 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0010481 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0011570 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0001824 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018099 infores:hetionet CHEBI:499361 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0030794 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0009450 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0009450 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0574067 infores:hetionet CHEBI:51450 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0085605 infores:hetionet CHEBI:39585 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C1527344 infores:hetionet CHEBI:15765 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013604 infores:hetionet NCBIGene:84342 biolink:causes MONDO:0012635 infores:monarchinitiative not_provided not_provided HGNC:18623 MONDO:0012635 uuid:ebe8bcb6-bcc2-4ad0-ba82-5543cc4263ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512341068 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341068 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1311C>G (p.Thr437=) is s synonymous variant. Computation evidence is not calculable for the effect of this SYNONYMOUS variant on protein function. The REVEL score is not calculable. Splice AI predicts a 0.00 score for acceptor loss, donor loss, acceptor gain, and donor gain(BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.62398 < 2.0)(BP7). This synonymous variant is absent from all examined population databases with at least 20x coverage for RUNX1(PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341068/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:101278 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0034150 infores:hetionet CHEBI:2636 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0549386 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018772 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0004239 infores:hetionet CHEBI:7936 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034880 infores:hetionet NCBIGene:25939 biolink:causes MONDO:0013739 infores:monarchinitiative not_provided not_provided HGNC:15925 MONDO:0013739 uuid:b2d75b25-ed10-4ead-8a4b-54c978816379 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50692 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C2979982 infores:hetionet CHEBI:6933 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0085593 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0162830 infores:hetionet CHEBI:31638 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0015672 infores:hetionet CHEBI:63632 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C1443060 infores:hetionet UNII:DJJ95FJP1H biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0677500 infores:hetionet CHEBI:584020 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0004093 infores:hetionet CHEBI:75998 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0239981 infores:hetionet CHEBI:61033 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0013404 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006266 infores:hetionet CHEBI:171719 biolink:causes MONDO:0003656 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0019048 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0035078 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0239150 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0018129 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018129 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0518015 infores:hetionet CAID:CA16043531 biolink:causes MONDO:0100326 infores:clingen CAID:CA16043531 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 "The c.1699C>T (p.Gln567Ter) variant in exon 11 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 11/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Glanzmann Patient, ""HEMOSTAZA SKOZI KLINIČNE PRIMERE"", August 2022) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% (<25%), as measured by flow cytometry (PP4_moderate). This individual is compound heterozygous for this variant and likely pathogenic variant c.749A>G (p.Asp250Gly). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate and PM2_Supporting (VCEP specifications version 2)." Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043531/MONDO:0100326/011 2023-04-06 2023-04-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50648 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2242996 infores:hetionet CHEBI:3423 biolink:causes EFO:0008501 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0334044 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0030824 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030824 infores:hetionet CHEBI:7852 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0031924 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0948594 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011334 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0340464 infores:hetionet CHEBI:39867 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0019521 infores:hetionet CHEBI:4814 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0016867 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0020517 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042131 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0042109 infores:hetionet NCBIGene:27152 biolink:causes MONDO:0044328 infores:monarchinitiative not_provided not_provided HGNC:29239 MONDO:0044328 uuid:ec52fa11-3a17-4497-99a0-acbdefc1d126 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA391355426 biolink:causes MONDO:0007113 infores:clingen CAID:CA391355426 MONDO:0007113 PMID: Pathogenic PP4, PVS1, PM2_Supporting PS4 The p.Ser189Ter variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Ser189Ter variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PP4). This variant is absent from gnomAD (PM2_supporting). In summary, the p.Ser189Ter variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA391355426/MONDO:0007113/016 2021-03-01 2021-05-07 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf UMLS:C0011701 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0150450 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0700345 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0314719 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0700594 infores:hetionet NCBITaxon:29171 biolink:causes MONDO:0005730 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:29171 MONDO:0005730 CHEBI:49668 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0034882 infores:hetionet CHEBI:9654 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0042024 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042790 infores:hetionet CHEBI:2567 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0002994 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020538 infores:hetionet CHEBI:9586 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1306341 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0002453 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0026846 infores:hetionet CHEBI:114785 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0234909 infores:hetionet CHEBI:10127 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020625 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0948089 infores:hetionet CHEBI:8871 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C3665386 infores:hetionet CAID:CA913191112 biolink:causes MONDO:0019497 infores:clingen CAID:CA913191112 MONDO:0019497 PMID: Pathogenic PP1_Strong, PM3, PM2_Supporting, PVS1 The c.1171_1177dup (p.Tyr393fs) variant in the MYO15A gene was absent from gnomAD with adequate coverage of the region (PM2_Supporting). This variant is a proposed founder variant in Oman and has been detected in 8 probands with hearing loss in the homozygous state (PM3; PMID: 27734841). This variant has been reported to segregate with hearing loss in at least 3 family members (PP1_Strong; PMID: 27734841). The p.Tyr393fs variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 2/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP1_Strong, PM3, PVS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA913191112/MONDO:0019497/005 2021-09-28 2022-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:3478 biolink:causes UMLS:C0030824 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0030824 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085606 infores:hetionet CHEBI:7496 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0018681 infores:hetionet CHEBI:4325 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0344232 infores:hetionet CHEBI:9654 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0008370 infores:hetionet CHEBI:2666 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C1368065 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0349506 infores:hetionet CHEBI:42797 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0041834 infores:hetionet CHEBI:9123 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013604 infores:hetionet CHEBI:168396 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030794 infores:hetionet CAID:CA913190432 biolink:causes MONDO:0010305 infores:clingen CAID:CA913190432 MONDO:0010305 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PP4 The NM_005629.4:c.626_627del (p.Pro209ArgfsTer87) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was identified by clinical exome sequencing in one male proband with developmental delay and seizures, and his similarly affected brother. (PMID 32434645). While these clinical features are consistent with a diagnosis of creatine transporter deficiency, more data to support this diagnosis, such as elevated urine creatine and reduced creatine on brain magnetic resonance spectroscopy, are not available (PP4 is not met). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 635461). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190432/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Supports CHEBI:50378 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0032708 infores:hetionet CHEBI:45327 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0010200 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009782 infores:hetionet CHEBI:5103 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0015672 infores:hetionet CHEBI:8888 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0149514 infores:hetionet CHEBI:7445 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0600142 infores:hetionet CHEBI:36791 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003467 infores:hetionet CHEBI:8764 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0547030 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027765 infores:hetionet CHEBI:4856 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0021368 infores:hetionet CHEBI:6933 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0027497 infores:hetionet CHEBI:31643 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0428977 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151849 infores:hetionet CHEBI:7476 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0000731 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2711248 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0740304 infores:hetionet CHEBI:38940 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1608945 infores:hetionet GO:0022603 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0022603 GO:0048856 CHEBI:3001 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C1260880 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0027051 infores:hetionet CHEBI:63598 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085633 infores:hetionet CHEBI:9586 biolink:causes NCIT:C127841 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0476427 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0227791 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0030312 infores:hetionet CHEBI:102216 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0687713 infores:hetionet CHEBI:41423 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151827 infores:hetionet CHEBI:38562 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0917801 infores:hetionet CHEBI:9215 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0002792 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0014591 infores:hetionet CHEBI:6690 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0016382 infores:hetionet CHEBI:40279 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0242528 infores:hetionet CHEBI:3485 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0687713 infores:hetionet CHEBI:52172 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1608945 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151596 infores:hetionet CHEBI:50673 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C2364111 infores:hetionet NCBIGene:7273 biolink:causes MONDO:0012127 infores:monarchinitiative not_provided not_provided HGNC:12403 MONDO:0012127 uuid:0c297adc-45e2-420a-8dad-58e7da4259bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C3665386 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003864 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0852810 infores:hetionet CHEBI:3757 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0242184 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0152128 infores:hetionet CHEBI:9939 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0340865 infores:hetionet CHEBI:71219 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151662 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0849918 infores:hetionet CHEBI:2668 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0033774 infores:hetionet CHEBI:45951 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0027497 infores:hetionet CHEBI:6741 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042790 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011849 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0038661 infores:hetionet CHEBI:10101 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151827 infores:hetionet CHEBI:4953 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0013404 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0234215 infores:hetionet CHEBI:7581 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0036104 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020255 infores:hetionet CHEBI:50729 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0025345 infores:hetionet CHEBI:8764 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0000731 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006277 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029456 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0019917 infores:hetionet CHEBI:9586 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042023 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0033975 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019054 infores:hetionet CHEBI:6715 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0232849 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0542165 infores:hetionet CHEBI:64045 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0015371 infores:hetionet CHEBI:6931 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0085593 infores:hetionet CAID:CA023658 biolink:causes MONDO:0007750 infores:clingen CAID:CA023658 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BA1, BP3, BP2, BP1, BP4, PS3, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PVS1, PM6, PP1, PP2, PP3, BS2 The NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001002 (0.010%) in South Asian exomes (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in 2 FH cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch Lipid Clinic score ≥ 6. PS4_supporting - Variant meets PM2. Variant identified in at least 4 unrelated index cases with Simon-Broome criteria for FH or Dutch Lipid Clinic score equal or above 6 from different labs. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023658/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3286 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0855242 infores:hetionet CAID:CA345666 biolink:causes MONDO:0007648 infores:clingen CAID:CA345666 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM1, PM5, PM4, PM3, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, PS4 The NM_004360.5(CDH1):c.2053G>A (p.Val685Met) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000665065.2, SCV000278915.9, SCV000260925.4). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA345666/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:16469 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0241136 infores:hetionet GO:0060998 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0060998 GO:0007399 CHEBI:68558 biolink:causes UMLS:C0852361 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0852361 infores:hetionet CHEBI:3127 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0428977 infores:hetionet CHEBI:9435 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0041657 infores:hetionet CHEBI:8884 biolink:causes UMLS:C0042380 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0042380 infores:hetionet CHEBI:4653 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0013404 infores:hetionet CHEBI:3764 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0042023 infores:hetionet CHEBI:4856 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0008033 infores:hetionet CHEBI:4858 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C3665347 infores:hetionet CHEBI:49575 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0034886 infores:hetionet CHEBI:101085 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0004093 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0086543 infores:hetionet CHEBI:27999 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0302295 infores:hetionet CHEBI:66899 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0009766 infores:hetionet CHEBI:42068 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0000729 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0852566 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0852566 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0042514 infores:hetionet CHEBI:188986 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0085635 infores:hetionet CHEBI:8107 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0234518 infores:hetionet CHEBI:8364 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0039231 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019340 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003864 infores:hetionet CHEBI:4681 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0018794 infores:hetionet CHEBI:31401 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151539 infores:hetionet CHEBI:3638 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0040034 infores:hetionet CHEBI:45783 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0036974 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0022658 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0855242 infores:hetionet GO:0045688 biolink:causes GO:0009553 infores:ubergraph knowledge_assertion manual_agent GO:0045688 GO:0009553 CHEBI:9667 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0042384 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040034 infores:hetionet NCBIGene:29895 biolink:causes MONDO:0030847 infores:monarchinitiative not_provided not_provided HGNC:29824 MONDO:0030847 uuid:d51dca25-89aa-4f61-b6fd-237fdfca8529 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8232 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0014742 infores:hetionet CAID:CA013294 biolink:causes MONDO:0004994 infores:clingen CAID:CA013294 MONDO:0004994 PMID: Uncertain Significance PM2 PS3, BA1, PM1, PM6, PM5, PP3, PP1, BS1, BS3, BS4, BP4, BP2, BP5, PS4, PS2, PS1 The NM_000257.4(MYH7):c.29G>C (p.Gly10Ala) variant has been reported in the homozygous state in 1 infant with a complex cardiac presentation that included DCM and HCM (GeneDx pers. comm.) ; however, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.002% (FAF 95% CI; 5/113546) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013294/MONDO:0004994/002 2021-03-25 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6710 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0036830 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0033975 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235889 infores:hetionet CHEBI:194135 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0546817 infores:hetionet CHEBI:50223 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1443060 infores:hetionet CAID:CA412740096 biolink:causes MONDO:0100437 infores:clingen CAID:CA412740096 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PS4 NM_001034853.2(RPGR):c.1060-1G>A is a canonical splice site variant in intron 9 that is predicted to disrupt splicing and induce skipping of exon 10, which is expected to disrupt a critical functional domain in RPGR (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 34745198). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. At least one proband harboring this variant exhibits a phenotype including childhood onset (1 pts), night blindness (0.5 pts), reduced visual acuity (0.5 pts), and genetic testing by whole exome sequencing with a 126-gene panel that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4 points), however, electroretinogram responses were not reported so the PP4 code could not be met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412740096/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports NCBIGene:590 biolink:causes MONDO:0015270 infores:monarchinitiative not_provided not_provided HGNC:983 MONDO:0015270 uuid:69ef8053-53a7-455c-a1be-7517942c7b09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2739267615 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267615 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.508_508+10del is a canonical splice variant which leads to loss of the donor site at c.508 (SpliceAI score for donor loss = 1.0), resulting in skipping of exon 5 and a frameshift, or use of a cryptic splice donor site also resulting in a frameshift (score for donor gain = 0.62) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267615/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16020847 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020847 MONDO:0009861 PMID:23842451PMID:26503515PMID:23842451 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.712A>G (p.Thr238Ala) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 23842451, 26503515). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant p.P281L (PM3; PMID: 23842451). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020847/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7627 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0002792 infores:hetionet NCBIGene:9742 biolink:causes MONDO:0976269 infores:monarchinitiative not_provided not_provided HGNC:29077 MONDO:0976269 uuid:0899851e-afe1-4ce1-a279-47481b8cffa7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8364 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0948594 infores:hetionet NCBIGene:10892 biolink:causes MONDO:0014197 infores:monarchinitiative not_provided not_provided HGNC:6819 MONDO:0014197 uuid:30f90ae6-454a-40d0-82f5-6847168ef539 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018946 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0002871 infores:hetionet CHEBI:7824 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0016204 infores:hetionet CHEBI:10119 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0392156 infores:hetionet CHEBI:404903 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0014335 infores:hetionet CHEBI:5147 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0085649 infores:hetionet CHEBI:44032 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0002792 infores:hetionet CHEBI:8080 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0011603 infores:hetionet NCBIGene:6873 biolink:causes MONDO:0014273 infores:monarchinitiative not_provided not_provided HGNC:11536 MONDO:0014273 uuid:d5f83941-f9e5-4498-9658-6e42f9fd10cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82941 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0948089 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0340464 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0235744 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0235744 infores:hetionet CHEBI:8597 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0030312 infores:hetionet CAID:CA409120803 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120803 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4(ADA):c.572G>A is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 191 (p.Ser191Asn). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as Variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120803/MONDO:0007064/114 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBITaxon:2 biolink:causes MONDO:0000744 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D008169 DB01053_MESH_D008169_1DB01331_MESH_D008169_1 CHEBI:27666 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0011991 infores:hetionet CHEBI:135736 biolink:causes MONDO:0000945 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042485 infores:hetionet CHEBI:17026 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1963790 infores:hetionet CHEBI:7824 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0404521 infores:hetionet CAID:CA000207 biolink:causes MONDO:0017623 infores:clingen CAID:CA000207 MONDO:0017623 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PM6_Strong, PS4_Supporting NM_000314.8(PTEN):c.830C>T (p.Thr277Ile) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID:25549896 and internal laboratory contributor).PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score=0.988)PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 25549896). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000207/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0010592 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0243026 infores:hetionet CHEBI:51860 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233407 infores:hetionet CHEBI:80630 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0002962 infores:hetionet NCBIGene:23111 biolink:causes MONDO:0010156 infores:monarchinitiative not_provided not_provided HGNC:18514 MONDO:0010156 uuid:5374246b-6078-4c99-b277-e0517298756e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5779 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0001824 infores:hetionet CHEBI:135930 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151205 infores:hetionet CHEBI:73274 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0041657 infores:hetionet CHEBI:2567 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0000737 infores:hetionet CHEBI:64312 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020488 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0549373 infores:hetionet CAID:CA16020925 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020925 MONDO:0009861 PMID: Uncertain Significance PM3, PM2, PP4 PP3 (PAH):c.1066-13T>G is an intronic variant with conflicting in silico evidence in splicing impact. This variant was documented in a patient with moderate PKU in trans with pathogenic variant p.R243Q (PMID 24705691). This variant is absent from population databases. In summary, this variant has insufficient evidence and is classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020925/MONDO:0009861/006 2020-07-25 2020-07-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36791 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0010200 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002622 infores:hetionet NCBIGene:2521 biolink:causes MONDO:0013888 infores:monarchinitiative not_provided not_provided HGNC:4010 MONDO:0013888 uuid:0f7761cb-ff63-4eec-b84a-4ad078a2dd47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013390 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0232910 infores:hetionet CHEBI:16755 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0085649 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0031046 infores:hetionet CHEBI:3749 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0021843 infores:hetionet GO:0060046 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0060046 GO:0019953 CHEBI:473990 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0027497 infores:hetionet CAID:CA397955568 biolink:causes MONDO:0100453 infores:clingen CAID:CA397955568 MONDO:0100453 PMID:25477517 Likely Pathogenic PM3, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.3056A>C (p.His1019Pro) is a missense variant that replaces histidine with proline at position p.1019. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000001241, with 2 alleles / 1,611,736 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 total point, PMID: 10951519, PMID: 32783370, PM3). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts) with onset at birth (1 pt), inability to follow light or objects, nystagmus (1 pt), normal fundus at birth, RPE mottling (0.5 pts), non-recordable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), severe hyperopia and severe photophobia (1 pt), non-recordable visual field (1 pt) and congenital blindness (1 pt), which together are specific for GUCY2D-related recessive retinopathy (total 7.5 points, PMID: 10951519, PP4). The computational predictor REVEL gives a score of 0.932 which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The mutant protein showed significantly compromised binding to RD3 relative to the wild-type control when exogenously expressed in HEK293 cells and analyzed by co-immunoprecipitation and western blotting (PMID: 25477517). The variant also exhibited 0% enzymatic activity in a guanylate cyclase activity assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 11328726, PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397955568/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:40009 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0015230 infores:hetionet CHEBI:7496 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0041834 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151854 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0403632 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0020517 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0520540 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0520540 infores:hetionet CHEBI:91583 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0003811 infores:hetionet NCBITaxon:53436 biolink:causes MONDO:0007000 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:53436 MESH:D014211 DB01053_MESH_D014211_1 CHEBI:10650 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0237849 infores:hetionet GO:0062041 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:0062041 GO:0007127 CAID:CA000506 biolink:causes MONDO:0018875 infores:clingen CAID:CA000506 MONDO:0018875 PMID:29979965 Likely Benign BP4, BS3, PM2_Supporting BP2, BA1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, BS2, PP3, PP1, PP4 The NM_000546.6: c.943T>A variant in TP53 is a missense variant predicted to cause substitution of Serine by Threonine at amino acid 315 (p.Ser315Thr). This variant has an allele frequency of 0.000001239 (2/1614066 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0544455; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BP4_Moderate, BS3. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000506/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47781 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0011124 infores:hetionet CHEBI:8874 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011124 infores:hetionet CHEBI:4876 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C2047937 infores:hetionet CHEBI:41977 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0424295 infores:hetionet CHEBI:3215 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0018794 infores:hetionet CHEBI:5790 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0080274 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0948594 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0438142 infores:hetionet CHEBI:27974 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0012833 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0011849 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1274594 infores:hetionet CHEBI:8404 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0036974 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0152198 infores:hetionet GO:1905356 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:1905356 GO:0032774 CAID:CA000134 biolink:causes MONDO:0018875 infores:clingen CAID:CA000134 MONDO:0018875 PMID: Likely Benign BP4, BS3_Supporting, BS2_Supporting, PM2_Supporting BP2, BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, PP3, PP1, PP4 The NM_000546.6: c.364G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 122 (p.Val122Met). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor: Invitae). This variant has an allele frequency of 0.000001695 (2/1180034 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor score (BayesDel = 0.134118) is below the recommended threshold (BayesDel < 0.16), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000134/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16469 biolink:causes UMLS:C0521845 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0521845 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0442874 infores:hetionet NCBIGene:65062 biolink:causes MONDO:0013745 infores:monarchinitiative not_provided not_provided HGNC:14432 MONDO:0013745 uuid:44401f6a-b735-43c2-82d5-e523b9f6e2e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50223 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C2047937 infores:hetionet CHEBI:4953 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0917801 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0038362 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0178298 infores:hetionet CHEBI:6472 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0086565 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151623 infores:hetionet CHEBI:6067 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020877 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014534 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0151505 infores:hetionet CHEBI:9637 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0023530 infores:hetionet CHEBI:6339 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0232462 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011570 infores:hetionet CHEBI:7824 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018965 infores:hetionet CHEBI:4315 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0438215 infores:hetionet CHEBI:36795 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0030554 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0497365 infores:hetionet CHEBI:8665 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0042963 infores:hetionet CAID:CA320642905 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642905 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.177C>T (p.Gly59=) is a synonymous variant. Not REVEL score because synonymous variant and SpliceAI is ≤0.20 (0.00) meeting BP4. Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP 1.22672 < 2.0)meeting BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642905/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2788 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0231528 infores:hetionet CHEBI:45863 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151905 infores:hetionet CHEBI:92607 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0037763 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151849 infores:hetionet CHEBI:8874 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011603 infores:hetionet CAID:CA014123 biolink:causes MONDO:0021056 infores:clingen CAID:CA014123 MONDO:0021056 PMID: Benign BS2, BA1, BP1 The c.7862C>G variant in APC is a missense variant predicted to cause the substitution of Serine by Cysteine at amino acid position 2621 (p.Ser2621Cys). This variant has been observed in more than 10 heterozygous individuals over the age of 50 with no features of FAP, worth more than 10 healthy individual points (BS2; Ambry internal data). APC is defined by the ClinGen APC VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.5021% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold of 0.1% for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BA1, BS2, and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA014123/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:22873 biolink:causes MONDO:0030844 infores:monarchinitiative not_provided not_provided HGNC:20908 MONDO:0030844 uuid:32f644c2-c0bc-44a2-ad12-ba740ac8282c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:391960 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0027497 infores:hetionet CHEBI:6076 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0040822 infores:hetionet CHEBI:47426 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0026821 infores:hetionet CHEBI:3176 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0151205 infores:hetionet NCBIGene:6938 biolink:causes MONDO:0014128 infores:monarchinitiative not_provided not_provided HGNC:11623 MONDO:0014128 uuid:b80c6d89-dd71-4f39-ab74-3f004eefe0ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0160390 infores:hetionet CHEBI:50777 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0015967 infores:hetionet CHEBI:8356 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0520966 infores:hetionet CHEBI:3001 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0037199 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0333244 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0333244 infores:hetionet CHEBI:42944 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0004093 infores:hetionet CHEBI:2666 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0085631 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0041976 infores:hetionet CHEBI:7798 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0687713 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0011616 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0021053 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0011053 infores:hetionet CHEBI:45652 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0035410 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020621 infores:hetionet CHEBI:47519 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0267792 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0740330 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0740330 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085932 infores:hetionet CHEBI:7824 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0687713 infores:hetionet CHEBI:617099 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0002170 infores:hetionet CHEBI:7565 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0023222 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020569 infores:hetionet CHEBI:31397 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0004093 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1328308 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1328308 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0542184 infores:hetionet CHEBI:6887 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1443060 infores:hetionet CHEBI:135566 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0018681 infores:hetionet CHEBI:48131 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0341012 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853761 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0004245 infores:hetionet CHEBI:64312 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0001807 infores:hetionet CHEBI:4356 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0151747 infores:hetionet CHEBI:9398 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0278106 infores:hetionet CHEBI:5050 biolink:causes MONDO:0024332 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0035457 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0021053 infores:hetionet CHEBI:63580 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009421 infores:hetionet NCBIGene:9294 biolink:causes MONDO:0012485 infores:monarchinitiative not_provided not_provided HGNC:3169 MONDO:0012485 uuid:8ef022e6-6bd9-437e-b971-eed9a483b0d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31174 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0011615 infores:hetionet CHEBI:4681 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0085612 infores:hetionet CHEBI:63681 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0264886 infores:hetionet CHEBI:5893 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0035455 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0021053 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0160390 infores:hetionet CHEBI:3423 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C3665347 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0033975 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020538 infores:hetionet CHEBI:42944 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0012813 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0021053 infores:hetionet CAID:CA000523 biolink:causes MONDO:0017623 infores:clingen CAID:CA000523 MONDO:0017623 PMID:25669429PMID:16773562 Likely Benign BS1, BP4 PVS1, PM6, PM2, BS4, BS3, BP5, BP7, PP1, PP3, PP2, BS2, PM5, PM1, PM4, BP2, BA1, PS1, PS4, PS2, PS3 PTEN c.579G>A (p.Leu193=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00125 (0.125%, 13/10,360 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000523/MONDO:0017623/003 2019-11-22 2019-12-04 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:58499 biolink:causes MONDO:0032836 infores:monarchinitiative not_provided not_provided HGNC:21684 MONDO:0032836 uuid:d4e59dda-73e4-47c5-bd37-083224c68db5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:9213 biolink:causes MONDO:0014628 infores:monarchinitiative not_provided not_provided HGNC:12827 MONDO:0014628 uuid:931daf70-d319-4f58-8a12-97b6392eae60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0917801 infores:hetionet CHEBI:8713 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0039070 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020649 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0243026 infores:hetionet CHEBI:5141 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0020649 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0235431 infores:hetionet CAID:CA386960233 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960233 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP4_Moderate, PP3 PP1 The c.460A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of methionine to valine at codon 154 (p.(Met154Val)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.974, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in six unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 23348805, 34440499, internal lab contributors). Furthermore, one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative diabetes antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.460A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960233/MONDO:0015967/017 2025-01-02 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75988 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0002878 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C2047937 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0040046 infores:hetionet CHEBI:7809 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0027497 infores:hetionet CHEBI:45409 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0026821 infores:hetionet CHEBI:3312 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0009676 infores:hetionet CHEBI:27899 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0040822 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0162119 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0086543 infores:hetionet CHEBI:7445 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0009763 infores:hetionet CHEBI:28748 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014591 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040479 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0032285 infores:hetionet CHEBI:17474 biolink:causes MONDO:0003054 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0281784 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020295 infores:hetionet CHEBI:2567 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0013395 infores:hetionet CHEBI:8871 biolink:causes MONDO:0019338 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0036202 infores:hetionet CAID:CA1706854 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706854 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PS3_Moderate PM2 The NM_003494.4: c.4003G>A variant in DYSF, which is also known as NM_001130987.2: c.4057G>A (p.Glu1353Lys), is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 1335, p.(Glu1335Lys). This variant has been reported in at least six patients with dysferlinopathy (PMID: 14678801, 17070050, 21522182, 22194990, 33613410, 36983702), including in a homozygous state in at least one individual without known familial consanguinity (0.5 pt; PMID 17070050, 22194990) and confirmed in trans with a likely pathogenic or pathogenic variant in two individuals (c.1639-6T>A p.(Gly547AlafsTer24), 1 pt, PMID: 36983702; c.2875C>T p.(Arg959Trp), 1 pt, PMID: 14678801) (PM3_Strong). At least one of the patients with a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 17070050, 21522182, 22194990, 33613410, 36983702) (PP4_Strong). This variant has also been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 14678801; PP1). The highest minor allele frequency is 0.0001309 (2/15284 genome alleles) in the Admixed American population of gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Glu1335Lys protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706854/MONDO:0015152/180 2025-02-25 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45599 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0392176 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022904 infores:hetionet CHEBI:4735 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0003123 infores:hetionet CHEBI:63577 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0029118 infores:hetionet NCBIGene:8367 biolink:causes MONDO:0030993 infores:monarchinitiative not_provided not_provided HGNC:4790 MONDO:0030993 uuid:e86408a0-3ac4-494f-b0da-6244d52eee81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16480 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0151701 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0037199 infores:hetionet CHEBI:15765 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013404 infores:hetionet CHEBI:77260 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0149745 infores:hetionet CHEBI:63589 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0009782 infores:hetionet CHEBI:10650 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0086168 infores:hetionet CHEBI:39112 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0151662 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1971624 infores:hetionet CHEBI:46345 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0002622 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0428886 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0428886 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0851341 infores:hetionet CHEBI:70746 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0040053 infores:hetionet CHEBI:9130 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0086565 infores:hetionet NCBIGene:50515 biolink:causes MONDO:0032574 infores:monarchinitiative not_provided not_provided HGNC:17422 MONDO:0032574 uuid:c53c8701-33fe-4b7b-9eb8-5cfabfc9b990 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1565489 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0014130 infores:hetionet CHEBI:2453 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0085593 infores:hetionet CHEBI:6690 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0040822 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0234458 infores:hetionet CHEBI:31174 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0152030 infores:hetionet CHEBI:7915 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C2047937 infores:hetionet CAID:CA1139666839 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666839 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968-7C>A is an intronic variant which has a Splice AI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.24)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666839/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63619 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0000731 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0013595 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011053 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0006913 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D008586 DB00415_MESH_D008586_1DB01212_MESH_D008586_1DB01053_MESH_D008586_1 CHEBI:68554 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0011991 infores:hetionet CHEBI:3696 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C2047937 infores:hetionet NCBIGene:132158 biolink:causes MONDO:0009070 infores:monarchinitiative not_provided not_provided HGNC:24247 MONDO:0009070 uuid:29867f44-e406-423e-b339-48c18275045a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0039240 infores:hetionet CHEBI:6715 biolink:causes MONDO:0008294 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0162565 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0036572 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0859229 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0859229 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0026946 infores:hetionet CHEBI:50173 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0042029 infores:hetionet CHEBI:4911 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0030193 infores:hetionet CHEBI:63622 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0013144 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0040435 infores:hetionet CHEBI:8863 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0003862 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0013395 infores:hetionet CHEBI:72690 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0042029 infores:hetionet CAID:CA024154 biolink:causes MONDO:0007783 infores:clingen CAID:CA024154 MONDO:0007783 PMID: Pathogenic PM1_Supporting, PS4, PS3, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with isoleucine at codon 4826 of the RYR1 protein, p.(Thr4826Ile). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 10888602, 16163667, 18564801, 25960145). This variant segregates with MHS in seven families, PP1_Strong ( PMID: 30236257). Two studies using a knock-in mouse model support pathogenicity of this variant. One study demonstrated a malignant hyperthermia reaction in response to agonist (PMID: 22131268). The other ex vivo study showed increased response to agonist with increased calcium release (PMID: 22139840), PS3_Strong. Studies in dyspedic myotubes also show increased sensitivity to RYR1 agonists (PMID: 12732639, 15347586). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.977) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024154/MONDO:0007783/012 2021-03-22 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63623 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0000729 infores:hetionet CAID:CA10014292 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014292 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP2, BP3, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.806-20A>C is an intronic variant which meets criteria for likely benign classification. SpliceAI does not predict any significant splicing impact (Δ scores ≤ 0.20) (BP4). The variant is located at a nucleotide that is not highly conserved, with a PhyloP score of 0.755606 (BP7), and the variant allele matches the reference nucleotide in one primate and/or three mammal species. In summary, this variant meets criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014292/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49375 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0855242 infores:hetionet CHEBI:2453 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0234238 infores:hetionet CHEBI:10650 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0028643 infores:hetionet CHEBI:7640 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0014457 infores:hetionet CHEBI:6754 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C1142412 infores:hetionet CHEBI:3048 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0039231 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0007971 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0015927 infores:hetionet CHEBI:8346 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0019080 infores:hetionet CHEBI:4728 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0020649 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0029408 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0541923 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0541923 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0948586 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0973461 infores:hetionet UNII:UMD7G2653W biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0026858 infores:hetionet CHEBI:27504 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0018681 infores:hetionet CHEBI:15407 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0232462 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0038454 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0017675 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0030807 infores:hetionet CHEBI:63616 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0030193 infores:hetionet CHEBI:2453 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0034155 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0002170 infores:hetionet CHEBI:4710 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013456 infores:hetionet GO:1901301 biolink:causes GO:0006888 infores:ubergraph knowledge_assertion manual_agent GO:1901301 GO:0006888 CHEBI:63632 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0030552 infores:hetionet CHEBI:3001 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0018681 infores:hetionet CHEBI:45285 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C2047937 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0036572 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005638 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0001816 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0036572 infores:hetionet NCBIGene:6338 biolink:causes MONDO:0020607 infores:monarchinitiative not_provided not_provided HGNC:10600 MONDO:0020607 uuid:bba2dd72-baa3-4cb3-b24c-b2875bc469fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0037274 infores:hetionet CHEBI:68558 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0700225 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0021400 infores:hetionet CHEBI:100241 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0231530 infores:hetionet CHEBI:291342 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0917801 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0042075 infores:hetionet CHEBI:3510 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0043352 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0860209 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0860209 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0020443 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1443060 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0162429 infores:hetionet CHEBI:9635 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0917801 infores:hetionet NCBIGene:10194 biolink:causes MONDO:0011921 infores:monarchinitiative not_provided not_provided HGNC:10669 MONDO:0011921 uuid:296df094-e07b-46aa-b120-516b506e86c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151578 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0851341 infores:hetionet CHEBI:68606 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0520573 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1112192 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1112192 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0002792 infores:hetionet NCBIGene:4968 biolink:causes MONDO:0007763 infores:monarchinitiative not_provided not_provided HGNC:8125 MONDO:0007763 uuid:f8b25243-45d5-431d-9923-93911b6841e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes HP:0001595 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0157733 infores:hetionet CAID:CA267639 biolink:causes MONDO:0009861 infores:clingen CAID:CA267639 MONDO:0009861 PMID:26666653PMID:26666653 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The c.164T>C (p.Phe55Ser) variant in PAH is reported in 1 French patient with classic PKU. BH4 deficiency was not assessed. It was detected with a known pathogenic variant c.1066-11G>A (PMID: 26666653). This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.96. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267639/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports GO:0039635 biolink:causes GO:0009273 infores:ubergraph knowledge_assertion manual_agent GO:0039635 GO:0009273 NCBIGene:157657 biolink:causes MONDO:0013786 infores:monarchinitiative not_provided not_provided HGNC:27232 MONDO:0013786 uuid:8a24d60b-974f-41a6-b2ec-38614531f13d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0595877 infores:hetionet CAID:CA386959427 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959427 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PM5_Supporting, PP3, PP1 The c.390G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to histidine at codon 130 (p.(Gln130His)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was segregated with diabetes, with three informative meioses in one family (PP1; PMID: 16834925). Another missense variant, c.388C>G p.Gln130Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.390G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_supporting, PM1, PP3, PP1, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959427/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4856 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0036572 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0003864 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0267596 infores:hetionet CHEBI:9241 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C1443060 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0021400 infores:hetionet CHEBI:50131 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1619702 infores:hetionet CHEBI:8069 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0018524 infores:hetionet CHEBI:8707 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0038325 infores:hetionet CHEBI:473990 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0687713 infores:hetionet CHEBI:4636 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0011609 infores:hetionet CAID:CA337098000 biolink:causes MONDO:0044970 infores:clingen CAID:CA337098000 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP1, PP3, PS2, PS4, PS3, PM6 The m.8719G>A (p.G65Term) variant in MT-ATP8 has been reported in one individual with primary mitochondrial disease to date (PMID: 23463613). Detailed clinical and family histories were not provided however this proband was described as having myopathy and the variant present at >99% heteroplasmy in muscle determined by Sanger sequencing. There are no additional individuals reported with this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation of the MT-ATP6 protein (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337098000/MONDO:0044970/015 2024-11-11 2024-12-11 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true GO:0060657 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0007275 UNII:15G12L5X8K biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0015397 infores:hetionet CHEBI:63598 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0033774 infores:hetionet CHEBI:38940 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014724 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005866 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0026916 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0860603 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0860603 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0424000 infores:hetionet CHEBI:2922 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0206062 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0013395 infores:hetionet CHEBI:8093 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0036974 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0426576 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C1861172 infores:hetionet CHEBI:2676 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0002994 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0026821 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0853149 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0855242 infores:hetionet CHEBI:42944 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042963 infores:hetionet CHEBI:7798 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0027497 infores:hetionet UNII:9YCX42I8IU biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C1321686 infores:hetionet CHEBI:61049 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017168 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0004623 infores:hetionet CHEBI:194135 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085612 infores:hetionet CAID:CA5416824 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416824 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.475A>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Isoleucine by Phenylalanine at amino acid 159 (p.Ile159Phe).The filtering allele frequency (the upper threshold of the 95% CI of 34/1179098 alleles) of the c.475A>T variant in DCLRE1C is 0.00002075 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416824/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:49040 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0002792 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0015376 infores:hetionet CHEBI:8888 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018524 infores:hetionet CHEBI:49375 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0235896 infores:hetionet CHEBI:5130 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151594 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0013595 infores:hetionet CHEBI:63629 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0015672 infores:hetionet CAID:CA343771985 biolink:causes MONDO:0013144 infores:clingen CAID:CA343771985 MONDO:0013144 PMID: Uncertain Significance PM4, PM2_Supporting PP3 The c.1393T>C variant is predicted to cause a change in the length of the protein (p.Ter465Gln) due to being a stop-loss variant in a non-repeat region (PM4). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM4, PM2_Supporting. ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; 2/21/25. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343771985/MONDO:0013144/084 2025-02-21 2025-02-21 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:5V9KLZ54CY biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0028738 infores:hetionet CHEBI:63638 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013390 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043251 infores:hetionet CHEBI:194135 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0015967 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0025061 infores:hetionet CHEBI:404903 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0235896 infores:hetionet CAID:CA334794 biolink:causes MONDO:0700270 infores:clingen CAID:CA334794 MONDO:0700270 PMID: Pathogenic PM3, PM5_Supporting, PVS1 PM2 The c.8307G>A (p.Trp2769*) variant in ATM is a nonsense variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 8845835, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 0.00005 in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_supporting, PM3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA334794/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:6575 biolink:causes MONDO:0024538 infores:monarchinitiative not_provided not_provided HGNC:10947 MONDO:0024538 uuid:bba026ef-731d-41ec-bb4d-6d4413abe1b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0947912 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0021605 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0021605 infores:hetionet CHEBI:31348 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549410 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0006277 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014130 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0151478 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151478 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0035078 infores:hetionet CAID:CA413497169 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497169 MONDO:0010315 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.181C>T (p.Gln61Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant is absent in gnomAD v4 (PM2_supporting). This variant is reported in a patient in PMID: 35874699 with no details provided. The patient doesn't meet PP4 criteria.In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497169/MONDO:0010315/129 2024-06-12 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:31355 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00958 UMLS:C0546817 infores:hetionet CAID:CA380144964 biolink:causes MONDO:0000572 infores:clingen CAID:CA380144964 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting PS3 The NM_000448.3:c.17C>T variant in RAG1 is a missense variant predicted to cause a substitution of proline by leucine at amino acid 6 (p.Pro6Leu). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV003314204.1). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144964/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15365 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0039971 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0853813 infores:hetionet GO:0001928 biolink:causes GO:0006904 infores:ubergraph knowledge_assertion manual_agent GO:0001928 GO:0006904 CHEBI:41423 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1305875 infores:hetionet CHEBI:17141 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0085631 infores:hetionet CHEBI:2038 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0018965 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011334 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0001824 infores:hetionet CHEBI:8382 biolink:causes UMLS:C2363722 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C2363722 infores:hetionet CHEBI:15765 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0017672 infores:hetionet CHEBI:47381 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151905 infores:hetionet CHEBI:167309 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0234238 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0549373 infores:hetionet CHEBI:63637 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0010200 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042514 infores:hetionet CHEBI:6367 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151905 infores:hetionet CHEBI:4907 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0003862 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1384353 infores:hetionet CAID:CA2802455 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802455 MONDO:0001586 PMID: Pathogenic PVS1_Moderate, PP4, PM3_Very Strong, PM2_Supporting PS3, BS3 The NM_000203.5:c.1855C>T (p.Arg619Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed. (PVS1_Moderate; PMID: 24480078). At least 4 patients with this variant had documented IDUA deficiency within the affected range in leukocytes or plasma, and clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PP4). This variant has been detected in at least 12 individuals with MPS I. Of those individuals, 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (Variants: 1163C>G (p.Thr388Arg), 1598C>G (p.Pro533Arg), 1205G>A (p.Trp402Ter), 386-2A>G, 208C>T (p.Gln70Ter)) and none of those were confirmed in trans (PMIDs: 28752568, 11735025). 6 individuals were homozygous for the variant (PMID: 28752568, PMID: 27146977) (PM3_very strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002881 (34/1179960 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 280976, 2 star review status) with 6 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_very strong, PVS1_moderate, PP4, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802455/MONDO:0001586/091 2024-12-06 2025-06-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:681569 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0235416 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0041912 infores:hetionet CHEBI:46557 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0085631 infores:hetionet CHEBI:66964 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0233715 infores:hetionet CHEBI:5558 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0917801 infores:hetionet CHEBI:119915 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0494475 infores:hetionet CHEBI:2611 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0012569 infores:hetionet CHEBI:3698 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0042963 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0413252 infores:hetionet CHEBI:63611 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151905 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0162429 infores:hetionet CHEBI:9738 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0034150 infores:hetionet CHEBI:39867 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C2047937 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0242350 infores:hetionet CHEBI:4710 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0008031 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235280 infores:hetionet CHEBI:64064 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0013456 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002885 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014752 infores:hetionet CAID:CA072871 biolink:causes MONDO:0100150 infores:clingen CAID:CA072871 MONDO:0100150 PMID: Pathogenic PS3_Supporting, PP3, PP1, PM2_Supporting, PM3_Very Strong BP7, BP5, BS3, BS4, PVS1, PM6, BS2, PP2, PP4, BP1, BP4, BP2, BP3, PM5, PM4, PM1, PS1, PS2, PS4 The NM_000540.3:c.8888T>C variant in RYR1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 2963 (p.Leu2963Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1179858 alleles) in the European (non-Finnish) population (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.841, which is above the threshold necessary to apply PP3. This variant has been reported in five probands with RYR1-related myopathy (PM3_VeryStrong). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.6721C>T(p.Arg2241Ter), c.14416A>G(p.Asn4806Asp), c.46-1G>A, ) and three of those were confirmed in trans (PMIDs:24951453, 27234031; SCV003761249.1; VCEP internal data). One individual was homozygous for the variant (PMIDs:23826317). The variant has been reported to segregate in one affected sibling from a family (PP1, PMID: 24951453). Western blot analysis of a deltoid muscle extract revealed a strong reduction of the RYR1 protein level by 37% in patient cells compared to a healthy age-matched control, supporting that the variant reduced protein expression (PS3_Supporting, PMID:23826317). In summary, the variant meets the criteria to be classified as Pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA072871/MONDO:0100150/179 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6076 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0160390 infores:hetionet CHEBI:8597 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0028734 infores:hetionet CHEBI:7443 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0038362 infores:hetionet NCBIGene:23384 biolink:causes MONDO:0800025 infores:monarchinitiative not_provided not_provided HGNC:29022 MONDO:0800025 uuid:0f418eaf-39db-4874-ad19-7165450273d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0018799 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1456863 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1456863 infores:hetionet CHEBI:52172 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0242301 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009319 infores:hetionet CHEBI:31515 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0024902 infores:hetionet CHEBI:8888 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0242528 infores:hetionet CHEBI:474180 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0233407 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0009450 infores:hetionet CHEBI:7986 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0037274 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006609 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0221244 infores:hetionet UMLS:C0120107 biolink:causes EFO:0008008 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0574785 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0009806 infores:hetionet NCBIGene:94005 biolink:causes MONDO:0029140 infores:monarchinitiative not_provided not_provided HGNC:14937 MONDO:0029140 uuid:b8b263b9-d588-4fc4-9b2e-2111c0516aa5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:291342 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0012833 infores:hetionet CHEBI:4514 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0917801 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0029456 infores:hetionet CHEBI:45783 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151904 infores:hetionet CHEBI:75722 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013428 infores:hetionet GO:1904933 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1904933 GO:0007275 CAID:CA229793 biolink:causes MONDO:0009861 infores:clingen CAID:CA229793 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Very Strong This c.824 C>T (p.Pro275Leu) variant in PAH was reported in individuals affected with PAH deficiency in trans with various pathogenic variants: IVS4-1G>A (PMID 26600521); p.His170Gln (PMID 28982351,26600521); p.Arg241Cys (PMID 26600521); p.Lys42del (PMID 27243974); and p.Tyr414Cys (without phasing, PMID 12501224). This variant was absent in population databases. Two pathogenic variants are found in the same codon (p.Pro275Ser and p.Pro275Arg). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very strong, PM2, PM5, PP3, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229793/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3314 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0000833 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0595885 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595885 infores:hetionet CHEBI:46195 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0027066 infores:hetionet CHEBI:17334 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C1443060 infores:hetionet NCBIGene:617 biolink:causes MONDO:0011308 infores:monarchinitiative not_provided not_provided HGNC:1020 MONDO:0011308 uuid:9d5ac6fa-8b58-4f60-a9e6-1f769e2f3688 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51380 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0013404 infores:hetionet CHEBI:6931 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0011603 infores:hetionet CAID:CA382536948 biolink:causes MONDO:0700270 infores:clingen CAID:CA382536948 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3, PP3 The c.4850T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1617 (p.Leu1617Pro). This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID 26896183). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008475 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.901, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382536948/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:92923 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0027497 infores:hetionet CAID:CA023792 biolink:causes MONDO:0007750 infores:clingen CAID:CA023792 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PM3, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PVS1, PM6, BS2 The NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3_moderate, PS4, PP1_strong, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.883.It is above 0.75, so PP3 is Met.PS3_moderate - 2 Level 2 assays performed by different labs:PMID 2088165:Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity.PMID 6438436:Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity.2 Level 3 assays performed by different labs:PMID 4061492:Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activityPMID 6438436:Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met.PS4 - Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID: 21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID: 23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID: 12436241), so PS4 is Met.PP1_strong - Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met.PM3 - Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met.PP4 - Variant meets PM2 and is identified in at least 14 unrelated index cases as described in PS4, PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023792/MONDO:0007750/013 2021-12-17 2022-04-05 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:10119 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0008031 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0032285 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042109 infores:hetionet CHEBI:23765 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0003811 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0032285 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0013595 infores:hetionet CHEBI:8356 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151205 infores:hetionet CHEBI:8764 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0016204 infores:hetionet CHEBI:31709 biolink:causes UMLS:C3241936 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C3241936 infores:hetionet CHEBI:17026 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151907 infores:hetionet UMLS:C0657912 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0231919 infores:hetionet CHEBI:27300 biolink:causes HP:0004934 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0342649 infores:hetionet CHEBI:75984 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C2364111 infores:hetionet CHEBI:64312 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085605 infores:hetionet CHEBI:127780 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0023510 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0033777 infores:hetionet CHEBI:28148 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0025637 infores:hetionet CHEBI:94686 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0002994 infores:hetionet CAID:CA003746 biolink:causes MONDO:0011450 infores:clingen CAID:CA003746 MONDO:0011450 PMID: Benign BP7_Strong, BA1, BP5_Strong The c.591C>T variant in BRCA1 is a synonymous variant (p.Cys197=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.001402 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing or an increase of in-frame naturally occurring splice isoforms with production of wildtype transcripts (PMIDs: 19892845, 22505045, 24607278, 23239986), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.33E-16 (based on Pathology LR=1.33E-16), below the threshold for very strong benign evidence (LR <0.00285) (BP5_Very strong met; ENIGMA internal contributor).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP7_Strong (RNA), BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003746/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3219 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030232 infores:hetionet CHEBI:8455 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0004936 infores:hetionet CHEBI:3515 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151539 infores:hetionet CHEBI:5050 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0033975 infores:hetionet CHEBI:31536 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0232807 infores:hetionet CHEBI:18243 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0003467 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0042109 infores:hetionet CHEBI:61049 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030252 infores:hetionet CHEBI:6062 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0428974 infores:hetionet CAID:CA512319045 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319045 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.69T>G (p.Leu23=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.04) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319045/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15551 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0000737 infores:hetionet CHEBI:119486 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0220870 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0007642 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0007642 infores:hetionet CHEBI:49040 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0030193 infores:hetionet CHEBI:135613 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0344232 infores:hetionet CHEBI:3127 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235660 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0020651 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0853692 infores:hetionet CHEBI:7476 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0740394 infores:hetionet CHEBI:68647 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151904 infores:hetionet CHEBI:2567 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0041834 infores:hetionet CHEBI:8435 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0020615 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0002170 infores:hetionet CHEBI:17303 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0549249 infores:hetionet CHEBI:85083 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0015967 infores:hetionet CHEBI:8207 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0011606 infores:hetionet CHEBI:5106 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0000731 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0041912 infores:hetionet CHEBI:4672 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0035455 infores:hetionet CAID:CA16040595 biolink:causes MONDO:0018875 infores:clingen CAID:CA16040595 MONDO:0018875 PMID: Pathogenic PS3, PM1, PP4_Moderate, PM2_Supporting, PS4_Supporting BP4, BA1, PS2, PS1, PM5, BS1, BS3, BS4, PVS1, PP3, PP1, BS2 The NM_000546.6: c.641A>G variant in TP53 is a missense variant predicted to cause substitution of histidine by arginine at amino acid 214 (p.His214Arg). This variant has been reported in 2 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 20522432; Internal lab contributor: SCV000581129.5). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000581129.5). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant has 35 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PM1. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16040595/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7915 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002792 infores:hetionet CHEBI:16755 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0011175 infores:hetionet CHEBI:18243 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0015376 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0031212 infores:hetionet CAID:CA384904367 biolink:causes MONDO:0100038 infores:clingen CAID:CA384904367 MONDO:0100038 PMID: Likely Pathogenic PM2_Supporting, PS2, PP3_Moderate, PM6_Supporting PM5, PM1 The c.3953A>G variant in SCN8A is a missense variant predicted to cause substitution of asparagine by serine at amino acid 1318 (p.Asn1318Ser). This variant has been reported as de novo with confirmed parental relationships in 2 individuals (PMID: 30968951, 31672125) and de novo with unconfirmed parental relationships in 1 individual (PMID: 35230384) with consistent phenotypes (PS2, PM6_Supporting). A novel missense variant at the same position in the paralogous gene, SCN1A (p.Asn1338Thr) has been reported as pathogenic, however, two novel missense variants are required to meet PM5_Supporting so this criterion was not applied. This variant is absent from the population database, gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.832, which is above the threshold of 0.773, evidence that correlates with a strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2, PM6_Supporting, PM2_Supporting, PP3_Moderate (version 1.0; approved 5/23/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA384904367/MONDO:0100038/070 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3223 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0242350 infores:hetionet CHEBI:8869 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0009763 infores:hetionet CHEBI:47780 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0392676 infores:hetionet CAID:CA915942047 biolink:causes MONDO:0100084 infores:clingen CAID:CA915942047 MONDO:0100084 PMID: Pathogenic PM2_Supporting, PM3, PVS1 PS4 The NM_001100.4:c.217dup (p.Ile73fs*11) variant in ACTA1 is a frameshift variant that is expected to result in nonsense-mediated mRNA decay and is present in biologically-relevant transcripts (PVS1). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). There is no published data on this variant, however Invitae has reported the variant in one proband, who presented with hypotonia (SCV001201868.3). In addition, this proband carried the variant of interest in trans with a second ACTA1 variant c.782A>T (p.Glu261Val) that has been classified as pathogenic at Invitae (PM3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PVS1, PM2_Supporting, PM3 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA915942047/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42944 biolink:causes UMLS:C0024050 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0024050 infores:hetionet CHEBI:63638 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0015230 infores:hetionet CHEBI:32139 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0278134 infores:hetionet CHEBI:75984 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0009421 infores:hetionet CHEBI:28148 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0149514 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0011206 infores:hetionet CHEBI:16714 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0041657 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0521839 infores:hetionet CHEBI:28364 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0003862 infores:hetionet CHEBI:45599 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0236024 infores:hetionet CHEBI:63617 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0014591 infores:hetionet NCBIGene:199713 biolink:causes MONDO:0009273 infores:monarchinitiative not_provided not_provided HGNC:22947 MONDO:0009273 uuid:9ed987a7-0f6c-4a1f-b142-147cfddb4b20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007222 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0000833 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0028081 infores:hetionet CHEBI:10650 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026858 infores:hetionet CHEBI:7514 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0004936 infores:hetionet CHEBI:127780 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0023218 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0009806 infores:hetionet CHEBI:4681 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0040479 infores:hetionet CAID:CA913163112 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163112 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS4, PS2, PS3, PM6 The m.10408T>C variant in MT-TR has been reported in one individual with primary mitochondrial disease to date however clinical details were not provided (PMID: 31965079). There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (64.3 percentile; PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163112/MONDO:0044970/015 2024-12-09 2025-05-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:48131 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0151505 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0017178 infores:hetionet CHEBI:8871 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040264 infores:hetionet CHEBI:7454 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0040822 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0948594 infores:hetionet CHEBI:8768 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0037287 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0948594 infores:hetionet CHEBI:51364 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0162830 infores:hetionet CHEBI:119915 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233477 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0235819 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0235819 infores:hetionet CHEBI:8776 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0001824 infores:hetionet UMLS:C0657912 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017565 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0595883 infores:hetionet CAID:CA021744 biolink:causes MONDO:0005045 infores:clingen CAID:CA021744 MONDO:0005045 PMID: Likely Pathogenic PM1, BP4, PS4_Moderate, PP1_Strong PM5, BS1, BS3, PM2, PP2, PP3, BA1, PS1, PS3 The NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln). This variant has been reported in individuals with HCM and other cardiomyopathies (Laboratory for Molecular Medicine (LMM) data, Oxford Medical Genomics Laboratory (OMGL) data, Sen-Chowdhry 2016 PMID 27681577, Mouton 2015 PMID 25940119, Ramachandran 2013 PMID 23967088, Rani 2012 PMID 22876777, Gruner 2011 PMID 21511876, Bos 2006 PMID 16352453, Ingles 2005 PMID 16199542, Cheng 2005 PMID 15992656, Doolan 2005 PMID 15698845, Mogensen 2004 PMID 15607392, Van Driest 2003 PMID 12860912) and has also been identified in 6 out of 113172 (0.09% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR, lower 95% CI>10), therefore, the PS4 criterion has been applied at moderate strength (PS4_Moderate) and the PM2_Supporting criterion has not been applied. In one of the individuals with HCM, the variant was identified in the homozygous state, and at least 2 individuals carried a second MYH7 variant that is classified as pathogenic by this expert panel (p.Arg1712Gln, Gruner 2011 PMID 21511876; LMM pers. comm.). This variant also segregated with HCM in at least 7 affected relatives from at least 2 families (PP1_Strong; Mogensen 2004 PMID 15607392; LMM pers. comm.). However, this variant was also present in several unaffected relatives, many of whom were older than 50, suggesting reduced penetrance or a milder role (Mogensen 2004 PMID 15607392, LMM data). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1; Walsh 2019 PMID:30696458). In vitro functional studies provide some evidence that this variant could impact protein function (Doolan 2005 PMID: 15698845); however, this data is currently insufficient to establish functional impact and apply PS3. Additionally, computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4; REVEL score <0.4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PP1_Strong, PM1, and BP4. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA021744/MONDO:0005045/098 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50173 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0858617 infores:hetionet CHEBI:8874 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C2173677 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0029456 infores:hetionet CHEBI:71941 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0009806 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0235969 infores:hetionet CHEBI:7445 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0015230 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235234 infores:hetionet CHEBI:46195 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0041969 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020651 infores:hetionet CHEBI:27999 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0033774 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0442886 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004691 infores:hetionet CHEBI:31709 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C1443060 infores:hetionet CHEBI:63621 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0033771 infores:hetionet NCBIGene:6768 biolink:causes MONDO:0011218 infores:monarchinitiative not_provided not_provided HGNC:11344 MONDO:0011218 uuid:0ba5f6b5-dee6-491c-9a71-eb95bb240826 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009319 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015230 infores:hetionet CHEBI:3127 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0030193 infores:hetionet CHEBI:4885 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0015230 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0023533 infores:hetionet CHEBI:8597 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0015230 infores:hetionet CHEBI:76010 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0021053 infores:hetionet CAID:CA504731636 biolink:causes MONDO:0012999 infores:clingen CAID:CA504731636 MONDO:0012999 PMID: Likely Pathogenic PP3, PP4_Strong, PM3, PM2_Supporting The NM_000156.6:c.114C>T (p.Gly38=) variant in GAMT is a synonymous (silent) variant. The computational splicing predictor SpliceAI gives a score of 0.98 for donor gain, predicting that the variant activates a cryptic splice site within exon 1 of GAMT (PP3). This variant has been reported in an individual with GAMT deficiency (PMID: 37305710). This individual was compound heterozygous for this variant and a variant that has been classified as likely pathogenic variant by the ClinGen CCDS VCEP, c.328-1G>A (ClinVar ID 844968), and confirmed in trans by parental testing (PMID: 37305710). This individual had elevated guanidinoacetate levels in plasma and significantly decreased creatine peak on brain MRS (PP4_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1305363). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, PM3, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on April 26, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA504731636/MONDO:0012999/026 2024-04-26 2024-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15765 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0231303 infores:hetionet CHEBI:51860 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0162835 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0948594 infores:hetionet CHEBI:499361 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C2830004 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020676 infores:hetionet CAID:CA9201616 biolink:causes MONDO:0018947 infores:clingen CAID:CA9201616 MONDO:0018947 PMID: Benign BP4, BA1 PP2 The c.2414C>T variant in DNM2 is a missense variant predicted to cause substitution of serine by leucine at amino acid 805 (p.Ser805Leu). The highest population filtering allele frequency in gnomAD v4.1 is 0.00008863 (9/59994 alleles) for the Admixed American population, which is higher than the ClinGen congenital myopathy DNM2 threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.009, which is below the threshold of 0.15, evidence that does not predict a damaging effect on DNM2 function (BP4). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2, not applied for this variant due to high allele frequency). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA9201616/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6367 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0427108 infores:hetionet NCBIGene:3930 biolink:causes MONDO:0013276 infores:monarchinitiative not_provided not_provided HGNC:6518 MONDO:0013276 uuid:2b9521a2-0a4e-4568-9a38-85d32a9a15c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9725 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0030232 infores:hetionet CAID:CA291046 biolink:causes MONDO:0012996 infores:clingen CAID:CA291046 MONDO:0012996 PMID: Benign BP4, BA1 PP3, PM2 The NM_001482.3:c.69+13C>T variant in GATM is an intronic variant located in intron 8. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00151 (88/58242 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 137454). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BP4.(Classification approved by the ClinGen CCDS VCEP on January 25, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291046/MONDO:0012996/025 2023-01-25 2023-01-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8232 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151529 infores:hetionet CHEBI:473990 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0700225 infores:hetionet CHEBI:5098 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0018681 infores:hetionet CHEBI:49713 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0013378 infores:hetionet CHEBI:8768 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2979982 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0011127 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0018802 infores:hetionet CHEBI:136040 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0039591 infores:hetionet GO:0090178 biolink:causes GO:0001841 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0001841 CHEBI:3387 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0004936 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0332575 infores:hetionet CHEBI:8107 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0041657 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0015230 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149931 infores:hetionet CAID:CA10443824 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443824 MONDO:0010315 PMID: Uncertain Significance PM1, PM2, BS2 The c.739G>A (NM_000206.3) variant in IL2RG is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 247 (p.Gly247Arg).The filtering allele frequency (the upper threshold of the 95% CI of 3/841874 alleles) of the c.739G>A variant in IL2RG is 0.00000095 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000124) for PM2_Supporting. However, there is 01 hemizygote reported in gnomAD in the South Asian population; Therefore, PM2_Supporting is not met.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/IL2RG-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443824/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6375 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0349506 infores:hetionet CHEBI:3508 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0014457 infores:hetionet CHEBI:6801 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0036974 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0004096 infores:hetionet CHEBI:7822 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0010692 infores:hetionet CHEBI:15365 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0032617 infores:hetionet CHEBI:35854 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0002874 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027051 infores:hetionet CHEBI:52172 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020453 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0027813 infores:hetionet CHEBI:5130 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0015967 infores:hetionet CHEBI:135930 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0858635 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0162429 infores:hetionet CHEBI:5383 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0085932 infores:hetionet CHEBI:49662 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0023530 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0014742 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009938 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0037315 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0026857 infores:hetionet CHEBI:4779 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0039231 infores:hetionet CHEBI:63635 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0009676 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020615 infores:hetionet CHEBI:100246 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0011606 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040046 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0027769 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0026821 infores:hetionet CHEBI:3127 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013456 infores:hetionet CHEBI:28445 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0021141 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0577115 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0577115 infores:hetionet CHEBI:4975 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0004604 infores:hetionet NCBIGene:140803 biolink:causes MONDO:0011176 infores:monarchinitiative not_provided not_provided HGNC:17995 MONDO:0011176 uuid:04ef6b47-35a3-4cc6-9eb0-5d4092b4d921 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0948594 infores:hetionet CHEBI:5001 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0740394 infores:hetionet CAID:CA386960365 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960365 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PM5_Supporting, PP4_Moderate, PP3 The c.472A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamate at codon 158 (p.(Lys158Glu)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.978, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another variant affecting this same amino acid, c.474G>T (p.Lys158Asn), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.472A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PM1, PM2_Supporting, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960365/MONDO:0015967/017 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA5416971 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416971 MONDO:0011225 PMID: Benign BA1 The c.227G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Arginine by Threonine at amino acid 76 p.Arg76Thr.The filtering allele frequency (the lower threshold of the 95% CI of 713/24912) of the c.227G>C variant in DCLRE1C is 0.02613 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, there have been descriptions of 11 homozygous individuals.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416971/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3647 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0013144 infores:hetionet CHEBI:61049 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0426390 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0031117 infores:hetionet CHEBI:42797 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085631 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0054550 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0054550 uuid:402a437b-022e-48fb-8b8d-a477a2f94422 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0008031 infores:hetionet CHEBI:68478 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020473 infores:hetionet CHEBI:8802 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0030201 infores:hetionet CHEBI:6073 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0041657 infores:hetionet CHEBI:65349 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0035455 infores:hetionet CHEBI:45863 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009676 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011991 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0017160 infores:hetionet CHEBI:49662 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0009421 infores:hetionet CHEBI:136040 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0015967 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0027947 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0017160 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020649 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013395 infores:hetionet CHEBI:41879 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042384 infores:hetionet CHEBI:3219 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0036396 infores:hetionet CHEBI:171719 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042345 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0002871 infores:hetionet CHEBI:8426 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0239739 infores:hetionet NCBIGene:2271 biolink:causes MONDO:0011730 infores:monarchinitiative not_provided not_provided HGNC:3700 MONDO:0011730 uuid:09b2f5cd-4ef9-4664-9b44-57949a37d91e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA402994573 biolink:causes MONDO:0012999 infores:clingen CAID:CA402994573 MONDO:0012999 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong, PM3_Supporting, PS3_Supporting The NM_000156.6:c.497T>C variant in GAMT is a missense variant predicted to cause substitution of leucine by proline at amino acid 166 (p.Leu166Pro). This variant has been detected in one individual with GAMT deficiency, who was homozygous for the variant (0.5pts, PM3_Supporting) (PMID: 24268530, PMID: 17466557, PMID: 17186272). This individual had elevated GAA and low creatine in urine, absent creatine peak on brain MRS, and deficient (<5% normal) GAMT activity in cultured fibroblasts with full GAMT gene sequencing (PMID: 24268530, PMID: 17466557, PMID: 17186272) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113320 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient human fibroblast cell line resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.953 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 1312506, 1 star review status) with 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP4_Strong, PP3.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402994573/MONDO:0012999/026 2023-05-25 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37333 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0015230 infores:hetionet CHEBI:45409 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1306341 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0036572 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0025061 infores:hetionet CHEBI:2567 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0014866 infores:hetionet CAID:CA252233 biolink:causes MONDO:0019501 infores:clingen CAID:CA252233 MONDO:0019501 PMID:25261458PMID:25823529PMID:26764160PMID:25262649 Pathogenic PP1_Strong, BS1, PP4, PP3, PS4, PM3_Strong BP5, BP7, BS4, BS2, PM1, PM4, PM5, PVS1, PM6, PM2, BP2, BP3, BP4, BA1, PS2, PS3, PS1 The p.Cys759Phe variant in USH2A has been reported in 10 individuals with a clinical diagnosis of Usher Syndrome type II who were all confirmed compound heterozygous with a second pathogenic variant on the remaining allele (PMIDs: 16098008, 24944099, 29912909) (PM3_Strong). Note that scoring for PM3 was downgraded from PM3_VeryStrong to PM3_Strong since this variant has an allele frequency that meets criteria for BS1 (see below). Co-segregation with Usher II was demonstrated collectively in 2 affected and 13 unaffected siblings (LOD score: 2.23). When including all families affected with Usher II or an atypical Usher presentation (retinitis pigmentosa (RP) with some form of hearing loss), co-segregation can be identified in three affected and 26 unaffected siblings total (LOD score: 4.45) (PMID: 29912909) (PP1_Strong). When considering those patients who present with isolated RP, the variant segregated in an additional 15 affected and 32 unaffected siblings (LOD score: 12.43) (PMIDs:10775529, 12525556, 21151602, 29912909). The filtering allele frequency (the lower threshold of the 95% CI of 72/35410) of the p.Cys759Phe variant in the Latino population in gnomAD is 0.17% and it has also been observed at the filtering allele frequency (the lower threshold of the 95% CI of 17/2536) of 0.43% across several Spanish or Latino populations published in the literature (PMIDs: 12525556, 12112664, 25262649, 26764160, 25261458, 25823529; BS1). Although this allele frequency meets the threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants, other studies suggest it may still be associated with Usher syndrome, albeit with potentially reduced penetrance. The variant is statistically enriched in cohorts of Usher (2.00% (54/2704) in Usher patients compared to 0.67% (17/2536) as the highest and most ethnically matched published Spanish and Latino control populations; Fisher’s exact p value <0.0001) and RP patients (1.87% (109/5828) in RP patients compared to 0.71% in published Spanish and Latino controls; Chi-Square p value <0.0001) (PMIDs: 12525556, 12112664, 25262649, 26764160, 25261458, 25823529, 10909849, 12112664, 14970843, 15325563, 16098008, 17405132, 18273898, 19683999, 22004887, 21738395, 24944099, 25375654, 28041643, 29588463, 21151602, 25097241, 23591405, 25910913, 25649381, 29283788, 22135276, 22334370) (PS4). The association with Usher syndrome is particularly clear when paired with a predicted loss-of-function or other pathogenic variant compared to homozygous individuals who are more at risk to develop non-syndromic RP (PMIDs: 29912909 and 25375654). There may also be evidence of reduced penetrance for both hearing loss and RP as two homozygous individuals were documented to have no evidence of any phenotype through their 6th decade (PMIDs: 16098008, 12525556). The PP4 rule has also been applied to this variant given the combination of hearing loss and RP that is seen in these patients and that most patients were screened for other Usher genes. Lastly, computational prediction tools and conservation analysis suggest that the p.Cys759Phe variant may impact the protein (REVEL: 0.902), and an analysis using the homologous mouse laminin gamma 1 chain concluded that this variant is likely to disrupt disulfide bonding with the cysteine at position 747 (PMID: 10909849) (PP3). In summary, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for Usher Syndrome outweighs its higher than expected allele frequency in population databases and other general population cohorts. Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome (ACMG codes applied: BS1, PS4, PM3_Strong, PP1_Strong, PP4, and PP3). Please note that patients with this variant may present with either Usher syndrome or with isolated RP. Isolated RP presentations are more common when the variant is seen in homozygosity as opposed to combined with a distinct pathogenic USH2A variant. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA252233/MONDO:0019501/005 2019-07-28 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:68841 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0030193 infores:hetionet CHEBI:80630 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0026205 infores:hetionet CHEBI:8081 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0030920 infores:hetionet CHEBI:47898 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027540 infores:hetionet CHEBI:9943 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1167709 infores:hetionet CAID:CA410150422 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150422 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PVS1_Strong, PM2_Supporting, PS3_Moderate, PP1 PS1, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP4, PP2, PP3 NM_001754.5(RUNX1):c.806-1G>A is a canonical splice site mutation predicted to disrupt exon 8 acceptor splice site recognition. According to the SpliceAI prediction, the acceptor loss is 0.98 at -1 bp, and the acceptor gain is 0.53 at -8 bp. This variant is predicted to result in exon 8 skipping, causing an in-frame deletion of Δ270-323 and D269A (GAT-GCG), leading to a deletion in TAD (PVS1_Strong and PS3_Moderate). Additionally, the variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in 2 families in the RUNX1 Natural History Study, with 3 documented segregations in total (PS4_Moderate, PP1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting, PS3_Moderate, PS4_Moderate, PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150422/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports GO:2000807 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:2000807 GO:0099504 CAID:CA913188994 biolink:causes MONDO:0007750 infores:clingen CAID:CA913188994 MONDO:0007750 PMID: Uncertain Significance BP4, PM5, PM2 PS1, PS4, PS3, BS3, PP3 The NM_000527.5(LDLR):c.1413_1414delinsGA (p.Asp472Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v4.1.0); PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (ClinVar ID 183116) -Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines; BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create AG. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA913188994/MONDO:0007750/013 2025-01-31 2025-02-27 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6367 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0575081 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003123 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0314719 infores:hetionet CHEBI:205919 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C1368065 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0031046 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0042790 infores:hetionet CHEBI:47381 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0025222 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005316 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085166 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0006604 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D012393 DB00684_MESH_D012393_1DB00916_MESH_D012393_1DB02703_MESH_D012393_1 CHEBI:41977 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0948089 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0014130 infores:hetionet CHEBI:6367 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0687713 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0009450 infores:hetionet CHEBI:9727 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0027497 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151735 infores:hetionet UMLS:C0011701 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0018524 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0027651 infores:hetionet CHEBI:36791 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151872 infores:hetionet CHEBI:9738 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0231218 infores:hetionet CHEBI:6923 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0040435 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0029408 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0027769 infores:hetionet CHEBI:30659 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0027769 infores:hetionet CHEBI:7514 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0178298 infores:hetionet CAID:CA1139532590 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139532590 MONDO:0009861 PMID:28754886 Likely Pathogenic PM4, PP4_Moderate, PM2, PM3_Supporting This c.543_545del (p.Glu182del) variant in PAH was reported in a patient with moderate PKU. BH4 enzyme deficiency was ruled out by analysis of urinary pterins and DHPR activity. This variant is observed with pathogenic variant c.611A>G, phase is unknown (PMID: 28754886). The variant is absent from controls in population databases. This in-frame deletion changes the protein length in a non-repeat region. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM4, PP4_moderate, and PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532590/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015230 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0041912 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0027765 infores:hetionet NCBIGene:55210 biolink:causes MONDO:0032931 infores:monarchinitiative not_provided not_provided HGNC:25567 MONDO:0032931 uuid:fa5a24e0-1d48-4376-a5d1-829fd4cc9500 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0033036 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0023530 infores:hetionet CHEBI:47426 biolink:causes MONDO:0044751 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0401151 infores:hetionet CHEBI:5855 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019825 infores:hetionet CHEBI:3172 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0013404 infores:hetionet UMLS:C0657912 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0270996 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0521839 infores:hetionet CHEBI:7915 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040264 infores:hetionet CHEBI:9123 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C2830004 infores:hetionet CHEBI:8874 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006625 infores:hetionet CHEBI:31623 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0030193 infores:hetionet CHEBI:63589 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0151908 infores:hetionet CHEBI:7573 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0043352 infores:hetionet CHEBI:100241 biolink:causes HP:6000076 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0152002 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0010709 infores:hetionet CAID:CA119182 biolink:causes MONDO:0020367 infores:clingen CAID:CA119182 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3 BP7, BS1, BS3, PM2, PM6, PM5, PM4, PS4, PS1, PS3, PS2, BA1, BP4 The c.1196G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 399 (p.Gly399Val). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.0001156 (4 alleles out of 34,592), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.968, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 10 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 11774072), which fulfilled PP1_Moderate (5-6 meioses). Although a proband with JOAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119182/MONDO:0020367/019 2022-12-14 2022-12-14 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042769 infores:hetionet CHEBI:135613 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0425591 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0001824 infores:hetionet GO:2000431 biolink:causes GO:0061640 infores:ubergraph knowledge_assertion manual_agent GO:2000431 GO:0061640 CHEBI:31711 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0003123 infores:hetionet CHEBI:182080 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0014549 infores:hetionet CHEBI:119915 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0023380 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042109 infores:hetionet GO:0031630 biolink:causes GO:0016079 infores:ubergraph knowledge_assertion manual_agent GO:0031630 GO:0016079 NCBIGene:54532 biolink:causes MONDO:0030503 infores:monarchinitiative not_provided not_provided HGNC:29255 MONDO:0030503 uuid:83a3a868-64a7-4732-ac51-88e867663ff9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0009676 infores:hetionet CHEBI:68554 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C1142135 infores:hetionet CHEBI:135935 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0006145 infores:hetionet CHEBI:10110 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0268000 infores:hetionet CAID:CA206547 biolink:causes MONDO:0015967 infores:clingen CAID:CA206547 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.370G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 124 (p.(Asp124Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.817, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and one copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 14 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 22773699, internal lab contributors). This variant was identified in a at least three individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in five families (PP1_Strong; internal lab contributors). In summary, c.379G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA206547/MONDO:0015967/086 2023-11-02 2023-11-02 Semidominant inheritance HP:0032113 Supports CHEBI:63635 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013456 infores:hetionet CHEBI:9435 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C2364111 infores:hetionet CHEBI:85161 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0030232 infores:hetionet CHEBI:18332 biolink:causes MONDO:0015469 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0010278 infores:hetionet CHEBI:45409 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019209 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009319 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0438173 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0438173 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0024115 infores:hetionet CHEBI:44423 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0019080 infores:hetionet CHEBI:2675 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0039231 infores:hetionet CHEBI:28148 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0151529 infores:hetionet CAID:CA355965141 biolink:causes MONDO:0001586 infores:clingen CAID:CA355965141 MONDO:0001586 PMID: Likely Pathogenic PM3_Strong, PVS1_Moderate, PP4_Moderate, PM2_Supporting PS1, PM4, BP7, BP5, BS3, BS4, PM6, BP1, BP4, BP3, BP2, PP2, PP3, PP1, BS2 The NM_000203.5:c.1650+1G>T variant in IDUA is a canonical splice donor variant. This variant is predicted to cause in-frame loss of exon 11 (42 amino acids; 6.4% of total protein length)(PVS1_Moderate). Whilst this is a GC donor splice site (in comparison to typical GT dinucleotide), in silico predictors indicate that loss of the donor site is highly likely (Splice AI delta score 0.83). This variant has been reported in four patients of Tunisian heritage in a single paper (PMID: 29843745), all of whom meet three phenotypic specificity criteria: 1) evidence of heparan and dermatan sulfate bands on gel electrophoresis, 2) undetectable/low IDUA enzyme activity, 3) 'Organomegaly' and 'Bone Involvement' as specific clinical features. This is sufficient diagnostic specificity to apply PP4_Moderate. One of these patients is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.223G>A (p.Ala75Thr) (ClinVar Variation ID: 222993); the variants were confirmed to be in trans (1 point). Two patients were homozygous for the variant (2 x 0.5 points). Another patient is compound heterozygous for the variant and c.1664G>A (p.Arg555His). The allelic data from this patient will be used in the classification of p.Arg555His and is not included here to avoid circular logic. Total PM3 points = 2 points (PM3_Strong). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). Three other splice variants (c.1650+1G>A, c.1650+2C>G and c.1650+5G>A) in the same region have been reported. The classification of the variant under assessment, c.1650+1G>T will be used to support the classification of these other variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 1323092). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PM3_Strong, PVS1_Moderate, PP4_Moderate, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 4, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355965141/MONDO:0001586/091 2025-05-04 2025-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5128 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0018681 infores:hetionet CHEBI:64321 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0546884 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0546947 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0546947 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020621 infores:hetionet NCBITaxon:1763 biolink:causes MONDO:0019146 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1763 MONDO:0019146 CAID:CA235339 biolink:causes MONDO:0021060 infores:clingen CAID:CA235339 MONDO:0021060 PMID: Likely Benign BP7, BP4 BS2 The c.1113T>C (p.Asp371=) is present in 7/1113684 European alleles (MAF 2.88e-05, 95% CI) gnomAD v2.1.1. Sixteen apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time (BS2 not met; SCV000515669.4). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Computational prediction tools and conservation analysis suggest that the p.Asp371= variant does not impact the protein (BP4). In summary, the clinical significance of the p.Asp371= variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP7, BP4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235339/MONDO:0021060/004 2020-03-09 2020-04-01 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:16914 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0220870 infores:hetionet CHEBI:68845 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0009782 infores:hetionet CHEBI:10119 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1519353 infores:hetionet CHEBI:27882 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0035410 infores:hetionet CHEBI:6541 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030554 infores:hetionet CAID:CA226585 biolink:causes MONDO:0100368 infores:clingen CAID:CA226585 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting BP4, PM5 NM_000329.3(RPE65):c.859G>T (p.Val287Phe) is both a missense variant, changing the valine at position 287 to phenylalanine, and a possible splicing variant, located at the first nucleotide of exon 9. SpliceAI's highest score is for Acceptor Loss, at 0.07, predicting a non-deleterious effect on splicing. The computational predictor REVEL has a score of 0.887, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.774 and predicts a damaging effect on RPE65 function (PP3_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts) and significant improvement after gene therapy treatment (8 pts), which together are highly specific for RPE65-related recessive retinopathy (8.5 points, PMID: 21911650 , PP4_Moderate). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 18722466, 21911650). (1.0 total points, PM3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3_moderate, PM2_supporting, PP4_moderate, PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226585/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:171719 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0344232 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0877098 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235146 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0004936 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0948525 infores:hetionet CHEBI:8245 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0043094 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0009450 infores:hetionet CHEBI:2549 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0027441 infores:hetionet UMLS:C0004609 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0011175 infores:hetionet NCBIGene:4436 biolink:causes MONDO:0030840 infores:monarchinitiative not_provided not_provided HGNC:7325 MONDO:0030840 uuid:2b027f49-4733-46c6-bc94-8f972183209c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0003811 infores:hetionet CHEBI:28971 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0002792 infores:hetionet CHEBI:2469 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0018965 infores:hetionet CHEBI:168396 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0232495 infores:hetionet CHEBI:9123 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009676 infores:hetionet CHEBI:8888 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020903 infores:hetionet CHEBI:10102 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0016204 infores:hetionet CHEBI:8863 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0311468 infores:hetionet CHEBI:15765 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0033774 infores:hetionet CHEBI:47898 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023467 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1861172 infores:hetionet CHEBI:3387 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0017675 infores:hetionet CHEBI:6437 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0043094 infores:hetionet CAID:CA16020767 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020767 MONDO:0009861 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The c.338_341del (p.Lys113ArgfsTer81) variant in PAH is a frameshift predicted to cause a premature stop codon in exon 3 leading to nonsense mediated decay exon. It was reported in a Japanese PKU patient with BH4 deficiency ruled out (PMID: 21307867). It is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020767/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63624 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0015967 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0011991 infores:hetionet NCBIGene:6095 biolink:causes MONDO:0060745 infores:monarchinitiative not_provided not_provided HGNC:10258 MONDO:0060745 uuid:20535f44-eb43-4890-839c-dd4210a10142 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0854082 infores:hetionet CHEBI:9241 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0035078 infores:hetionet CHEBI:724125 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0332563 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0003123 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0276684 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0276684 infores:hetionet CHEBI:10023 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011206 infores:hetionet CHEBI:94440 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0085649 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018991 infores:hetionet CAID:CA386960246 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960246 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3 The c.461T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of methionine to arginine at codon 154 (p.(Met154Arg)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.978, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Two other missense variants, c.460A>G p.(Met154Val) and c.461T>C p.(Met154Thr) have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.461T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960246/MONDO:0015967/017 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63630 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003862 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0009450 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0242656 infores:hetionet CHEBI:8107 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0232493 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0029408 infores:hetionet CHEBI:2687 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0003811 infores:hetionet NCBIGene:79718 biolink:causes MONDO:0014842 infores:monarchinitiative not_provided not_provided HGNC:29529 MONDO:0014842 uuid:f49d8db8-a556-4269-9b50-5a83c1ec3c16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0424295 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0040034 infores:hetionet CHEBI:135736 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0149725 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0032584 infores:hetionet NCBIGene:4023 biolink:causes MONDO:0009387 infores:monarchinitiative not_provided not_provided HGNC:6677 MONDO:0009387 uuid:19094438-38fc-4a65-b02e-1429c3f5811e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C3665386 infores:hetionet CHEBI:10127 biolink:causes MONDO:0020674 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0232352 infores:hetionet CAID:CA386960147 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960147 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PS1, PS4, PM5, PP1 The c.450G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to asparagine at codon 150 (p.(Lys150Asn)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additonally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.883, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). Furthermore, in one of these families, this variant segregated with diabetes with a single informative meiosis; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Another missense variant at this residue, p.(Lys150Glu) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Additionally, another nucleotide change at this location resulting in the same amino acid change, c.450G>T p.(Lys150Asn), has been classified as a VUS by the ClinGen MDEP; therefore, PS1 will not be applied. In summary, c.450G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PM1_Supporting, PP3, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960147/MONDO:0015967/017 2024-10-13 2024-10-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6759 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0025287 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0035078 infores:hetionet NCBIGene:57379 biolink:causes MONDO:0011528 infores:monarchinitiative not_provided not_provided HGNC:13203 MONDO:0011528 uuid:4ae0772a-500f-43a8-998c-71f0e33b6dbd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0029443 infores:hetionet CL:0000785 biolink:causes MONDO:0004949 infores:ubergraph knowledge_assertion manual_agent CL:0000785 MONDO:0004949 CHEBI:3127 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0030554 infores:hetionet NCBIGene:84466 biolink:causes MONDO:0013731 infores:monarchinitiative not_provided not_provided HGNC:29634 MONDO:0013731 uuid:6ba3fe2c-7d32-4f6e-a4c6-b3a285ed13d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0235146 infores:hetionet CHEBI:28915 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0852911 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0022650 infores:hetionet CHEBI:29013 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0000737 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0413252 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0013395 infores:hetionet CHEBI:48273 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013378 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031085 infores:hetionet CHEBI:8707 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0026837 infores:hetionet CAID:CA409120799 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120799 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4:c.574A>G is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 192 (p.Ser192Gly). The filtering allele frequency (the upper threshold of the 95% CI of 17/1179900) of the c.574A>G variant in ADA is 0.000008100 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120799/MONDO:0007064/114 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8863 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020651 infores:hetionet CHEBI:63598 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151872 infores:hetionet CHEBI:6375 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0024902 infores:hetionet NCBITaxon:5855 biolink:causes MONDO:0005921 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5855 MESH:D016780 DB12975_MESH_D016780_2DB00608_MESH_D016780_1DB01218_MESH_D016780_1DB01087_MESH_D016780_1DB09274_MESH_D016780_1DB12975_MESH_D016780_1DB00358_MESH_D016780_1DB01611_MESH_D016780_1 CHEBI:71941 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0014742 infores:hetionet CHEBI:36795 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1291078 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0424605 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C1527405 infores:hetionet CAID:CA180933 biolink:causes MONDO:0021060 infores:clingen CAID:CA180933 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.927A>T (p.Ala309=) variant in the MAP2K1 gene is 1.307% (156/10406) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180933/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8207 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0023218 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0015397 infores:hetionet CHEBI:64310 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0015230 infores:hetionet CHEBI:15367 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0016382 infores:hetionet CHEBI:31401 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151610 infores:hetionet CHEBI:8888 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003862 infores:hetionet CHEBI:51860 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0012569 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0242350 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235919 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235919 infores:hetionet CAID:CA229666 biolink:causes MONDO:0009861 infores:clingen CAID:CA229666 MONDO:0009861 PMID:11708866PMID:21147011PMID:11708866PMID:21147011PMID:11708866 Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong PM5, PS3 The c.631C>A (p.Pro211Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 11708866, 21147011, 1619813). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: IVS10-11G>A (4 patients, PMID: 21147011); p.R261Q in 2 unrelated patients (PMID: 11708866); p.R408W (PMID: 9429153); p.G272X (PMID: 16198137). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229666/MONDO:0009861/006 2020-07-02 2021-07-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9435 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C2697368 infores:hetionet CHEBI:71255 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0002994 infores:hetionet NCBIGene:2617 biolink:causes MONDO:0015353 infores:monarchinitiative not_provided not_provided HGNC:4162 MONDO:0015353 uuid:c838fd94-cab7-4163-aee3-b245321d3a0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51173 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0017181 infores:hetionet CHEBI:6339 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0016204 infores:hetionet CHEBI:7581 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0751295 infores:hetionet CHEBI:6456 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0002994 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042401 infores:hetionet CHEBI:38545 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0031350 infores:hetionet CHEBI:30659 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0009421 infores:hetionet NCBIGene:1822 biolink:causes MONDO:0007435 infores:monarchinitiative not_provided not_provided HGNC:3033 MONDO:0007435 uuid:ddd34190-dd3e-4c37-8145-ee7c638c4c72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9430ZR8ZAN biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0236024 infores:hetionet CHEBI:63791 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0231218 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009324 infores:hetionet NCBIGene:8312 biolink:causes MONDO:0011928 infores:monarchinitiative not_provided not_provided HGNC:903 MONDO:0011928 uuid:417178f3-868f-4dfe-aee2-3b1072b30e76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:180905 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0020651 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0009450 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0040034 infores:hetionet CAID:CA10529708 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529708 MONDO:0010604 PMID: Benign BS2, BA1 PS4, BP4 NM_000133.3:c.19A>T variant results in a missense change in the signal peptide. This variant is reported at a frequency of 0.001643 (152/92537 alleles with 57 hemizygotes) in the non-Finnish European population in gnomAD v2.1.1, meeting the BA1 cut-off of >= 0.0000556. At least 2 individuals with the variant and normal FIX levels from the literature and internal laboratory data are reported (PMID: 29296726) meeting the BS2 criterion. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BS2. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529708/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:5138 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014394 infores:hetionet CAID:CA292853 biolink:causes MONDO:0044970 infores:clingen CAID:CA292853 MONDO:0044970 PMID: Uncertain Significance PM2 BS2 The c.3482-14 T>C variant in POLG is observed in population databases ExAC at 0.00007% and gnomAD 0.0005% (PM2; observed < 0.05% frequency). Computational prediction tool Revel not available given intronic variant. This variant has not been seen in homozygotes or published in the literature. In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA292853/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6897 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0085636 infores:hetionet CHEBI:6950 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0041582 infores:hetionet CHEBI:474053 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0039070 infores:hetionet CAID:CA10585298 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585298 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM3, PP1_Moderate, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS3, BS1, BS3, BS4, PM5 The NM_000527.5(LDLR):c.1090T>C (p.Cys364Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys364, one of the highly conserved cysteine residues listed. PM2: PopMax MAF=0.00001666 (0.001666%) in Admixed American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.984. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases (1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy; 1 case with modified Simon-Broome criteria from PMID 23064986 (Ahmad et al., 2012), USA). PP1_Moderate: Variant segregates with FH phenotype in 5 informative meiosis from 2 families from different labs (Laboratory of Genetics and Molecular Cardiology, Brazil and Research Lab of Molecular Genetics of Lipid Metabolism, Italy): 3 affected family members have the variant and 2 unaffected family members do not have the variant.PM3: Variant meets PM2 and is identified in at least 1 clinically diagnosed HoFH, homozygous for the variant (PMID 37119068; PMID 27940769). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585298/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6801 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0009450 infores:hetionet CHEBI:5693 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00756 UMLS:C0349506 infores:hetionet CHEBI:40279 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0423791 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235416 infores:hetionet CHEBI:27777 biolink:causes UMLS:C0542247 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0542247 infores:hetionet CHEBI:44915 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0042510 infores:hetionet UMLS:C0657912 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0231528 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0542184 infores:hetionet CAID:CA16020883 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020883 MONDO:0009861 PMID:15503242PMID:15503242PMID:17924342PMID:16253218 Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting The c.877T>A (p.Leu293Met) variant in PAH has been reported in 1 individual with classical PKU (BH4 deficiency excluded, detected with pathogenic variant IVS4-1G>A (PMID: 15503242). This variant is absent in population databases. Computational evidence support a deleterious effect (REVEL=0.742). In vitro PAH activity of L293M mutant is 41% of wild type (PMID: 16253218). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2_supporting, PM3_supporting, PS3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020883/MONDO:0009861/006 2024-09-06 2025-08-02 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:112476 biolink:causes MONDO:0011593 infores:monarchinitiative not_provided not_provided HGNC:30500 MONDO:0011593 uuid:cd9d521c-e704-42a8-bfd9-5b22c332d09c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0231528 infores:hetionet GO:0007317 biolink:causes GO:0007315 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0007315 CHEBI:5893 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0022408 infores:hetionet CHEBI:520985 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0003467 infores:hetionet CHEBI:16796 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0015230 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235032 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0029445 infores:hetionet CHEBI:7465 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1519353 infores:hetionet NCBIGene:28957 biolink:causes MONDO:0033537 infores:monarchinitiative not_provided not_provided HGNC:14513 MONDO:0033537 uuid:e24fce83-a42e-460b-9b80-e443b4aad8a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68579 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0518015 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0013395 infores:hetionet CHEBI:7573 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0002170 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0039971 infores:hetionet CHEBI:63681 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0085631 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0042109 infores:hetionet CHEBI:9667 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0234708 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0560024 infores:hetionet CHEBI:50173 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0040264 infores:hetionet CHEBI:499361 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0019521 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0020039 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0020456 infores:hetionet CHEBI:63620 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013390 infores:hetionet CHEBI:135566 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0010037 infores:hetionet CHEBI:45863 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020580 infores:hetionet NCBIGene:55151 biolink:causes MONDO:0014029 infores:monarchinitiative not_provided not_provided HGNC:25535 MONDO:0014029 uuid:2f41d185-749c-4a45-af82-e2e4be9381db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4530 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0233494 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0004936 infores:hetionet CHEBI:8802 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0002871 infores:hetionet CHEBI:3347 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0003467 infores:hetionet CHEBI:3723 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0231530 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0424000 infores:hetionet CHEBI:8863 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018926 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0031117 infores:hetionet CHEBI:4653 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C1291078 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0030252 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0033975 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0948594 infores:hetionet CHEBI:9130 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C3203358 infores:hetionet CHEBI:63598 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020580 infores:hetionet CHEBI:36795 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0023530 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0032285 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0025061 infores:hetionet GO:0043921 biolink:causes GO:0019080 infores:ubergraph knowledge_assertion manual_agent GO:0043921 GO:0019080 CHEBI:9588 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0000731 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2830004 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017160 infores:hetionet CHEBI:3752 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C2239176 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0038363 infores:hetionet CAID:CA412395150 biolink:causes MONDO:0019169 infores:clingen CAID:CA412395150 MONDO:0019169 PMID: Uncertain Significance PP3, PM2 PM1, PP4, BS2, BA1, BP4, PS2, PM6, BS1 The c.839T>G; p.I280S variant in the PDHA1 gene is a novel missense mutation that has not been reported in population databases (PM2). One patient with an episodic gait disorder, speech delay, cognitive delay, elevated serum and CSF lactate and brain MRI findings consistent with Leigh syndrome has been reported in the literature with this variant (PMID: 20691944). This variant was also seen in his reportedly unaffected mother and two uncles with dystonia, which was insufficient to meet criteria of 4 or more segregations for PP1 per ClinGen SVI. Serum pyruvate levels were normal for this patient and no other biochemical studies were performed. In silico meta-predictors indicate a deleterious effect (PP3). In summary, this variant meets criteria to be classified as a variant of uncertain significance of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM2, PP3). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA412395150/MONDO:0019169/014 2021-04-02 2021-05-06 X-linked inheritance HP:0001417 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:37924 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151908 infores:hetionet CHEBI:135935 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0086769 infores:hetionet CHEBI:261649 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0014868 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0021400 infores:hetionet CHEBI:17141 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0028084 infores:hetionet CHEBI:6801 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0020580 infores:hetionet CHEBI:85078 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0017178 infores:hetionet CHEBI:42797 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0947912 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042063 infores:hetionet CHEBI:63619 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C1443060 infores:hetionet CHEBI:5280 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1443060 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0037763 infores:hetionet CHEBI:520985 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0009763 infores:hetionet CHEBI:4876 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0011168 infores:hetionet CHEBI:63616 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0003862 infores:hetionet CHEBI:7514 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0037036 infores:hetionet CHEBI:3638 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0429097 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0038454 infores:hetionet CHEBI:474180 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0239571 infores:hetionet CHEBI:31401 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0004096 infores:hetionet CHEBI:4511 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0043144 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0012833 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0015256 infores:hetionet NCBIGene:7283 biolink:causes MONDO:0014171 infores:monarchinitiative not_provided not_provided HGNC:12417 MONDO:0014171 uuid:0d203a54-0554-4a71-a712-dcd6b4c71d27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0040046 infores:hetionet CHEBI:63589 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0043352 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0003123 infores:hetionet CHEBI:4953 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0039503 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151888 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0234913 infores:hetionet CHEBI:75998 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151699 infores:hetionet CHEBI:17303 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0035455 infores:hetionet CHEBI:36795 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0030193 infores:hetionet CHEBI:161680 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0151636 infores:hetionet CHEBI:231425 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C1167965 infores:hetionet CHEBI:63610 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C1368065 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0019348 infores:hetionet CAID:CA214003 biolink:causes MONDO:0015967 infores:clingen CAID:CA214003 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS2_Moderate, PM1_Supporting, PS4 The c.931C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 311 (p.(Arg311Cys)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID: 28862987, internal lab contributors). One of these 2 cases was a a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID: 28862987). In summary, c.931C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0 approved 10/11/2023): PS4, PP4_Moderate, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214003/MONDO:0015967/085 2024-07-28 2024-07-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135920 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0344232 infores:hetionet CHEBI:31622 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0234215 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0017152 infores:hetionet CHEBI:63622 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0036980 infores:hetionet CHEBI:3647 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0041657 infores:hetionet CHEBI:51141 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0011991 infores:hetionet CHEBI:51860 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013144 infores:hetionet CAID:CA386967824 biolink:causes MONDO:0015967 infores:clingen CAID:CA386967824 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS1_Supporting, PVS1 PS4, PP4, PP1 The c.956-1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 4 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 5 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). The c.956-1G>C variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.956-1G>T has a similar or greater predicted impact by Splice AI (0.95 and 1.0) (PS1_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 19150152). This individual had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 19150152). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID 19150152). ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PVS1, PM2_Supporting, PS1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386967824/MONDO:0015967/017 2021-08-24 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2611 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0037274 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1276146 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1276146 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235032 infores:hetionet CHEBI:100241 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151905 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020517 infores:hetionet CHEBI:46295 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0006145 infores:hetionet CHEBI:3419 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0022107 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0333641 infores:hetionet CHEBI:9123 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0233471 infores:hetionet CL:0000767 biolink:causes GO:0002557 infores:ubergraph knowledge_assertion manual_agent CL:0000767 GO:0002557 CHEBI:51364 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0917801 infores:hetionet CHEBI:9123 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0340865 infores:hetionet CHEBI:63717 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0410256 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0410256 infores:hetionet CHEBI:39669 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0042963 infores:hetionet CHEBI:45599 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0042487 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0008325 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0033687 infores:hetionet NCBIGene:58497 biolink:causes MONDO:0060490 infores:monarchinitiative not_provided not_provided HGNC:13420 MONDO:0060490 uuid:e09f602f-9c5f-4fbb-b0fa-56d6e7c1c6a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6741 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1443060 infores:hetionet CHEBI:2668 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0549622 infores:hetionet CHEBI:5106 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0392703 infores:hetionet CHEBI:50841 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0085631 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0030305 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0026846 infores:hetionet CHEBI:5106 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0271738 infores:hetionet CHEBI:9599 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0043352 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1443060 infores:hetionet CHEBI:4856 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0043144 infores:hetionet CHEBI:367163 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0852911 infores:hetionet CHEBI:231594 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042345 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1321686 infores:hetionet CAID:CA8459140 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459140 MONDO:0011132 PMID: Likely Benign BP4, BP7 BS1, PM2 NM_001369369.1(FOXN1):c.114C>T (p.Ala38=) is a synonymous variant. SpliceAI predicts no impact to the splice consensus sequence (delta score 0.00) nor the creation of a new splice site (delta score<=0.08) and the nucleotide is not highly conserved (phyloP score -0.92) (BP4, BP7). In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BP4 and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459140/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:9139 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0242379 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0087169 infores:hetionet CHEBI:391960 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0038990 infores:hetionet CHEBI:46195 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0085641 infores:hetionet CHEBI:75722 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042023 infores:hetionet CHEBI:5002 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0027497 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0024312 infores:hetionet CHEBI:188986 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0231919 infores:hetionet CHEBI:100246 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0042384 infores:hetionet CHEBI:40237 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0014869 infores:hetionet CHEBI:8871 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C2047937 infores:hetionet CHEBI:47499 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0085612 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0027765 infores:hetionet UBERON:0004670 biolink:causes MONDO:0003266 infores:ubergraph knowledge_assertion manual_agent UBERON:0004670 MONDO:0003266 CHEBI:39112 biolink:causes MONDO:0024352 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0877203 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0009806 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009450 infores:hetionet CHEBI:17347 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1527344 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0314719 infores:hetionet CHEBI:3479 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0002878 infores:hetionet CHEBI:47657 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0151662 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0852733 infores:hetionet CHEBI:4909 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0423791 infores:hetionet CHEBI:9445 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0020621 infores:hetionet CHEBI:36791 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0010520 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0687133 infores:hetionet CHEBI:6444 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0018790 infores:hetionet CHEBI:3732 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C3665347 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0009676 infores:hetionet CHEBI:63622 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0242429 infores:hetionet CHEBI:8707 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037672 infores:hetionet CHEBI:44032 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0152169 infores:hetionet NCBIGene:2159 biolink:causes MONDO:0009212 infores:monarchinitiative not_provided not_provided HGNC:3528 MONDO:0009212 uuid:7385bd7d-61ae-4192-8efb-65b2ccb08f1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905770 biolink:causes GO:0001707 infores:ubergraph knowledge_assertion manual_agent GO:1905770 GO:0001707 NCBIGene:1757 biolink:causes MONDO:0010008 infores:monarchinitiative not_provided not_provided HGNC:10536 MONDO:0010008 uuid:db8daf67-a8c5-46f1-899f-9367d8856dcd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0392176 infores:hetionet CHEBI:6916 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0008031 infores:hetionet CHEBI:119915 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0423791 infores:hetionet CHEBI:78543 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0030312 infores:hetionet CHEBI:2668 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0018418 infores:hetionet CAID:CA415091332 biolink:causes MONDO:0010305 infores:clingen CAID:CA415091332 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, PP3, PM5, BP4 The NM_005629.4:c.1901T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by an alanine at amino acid position 634 (p.Val634Ala). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00005341 (3/56170 alleles; 1 hemizygote) in the African/African American population. This MAF is higher than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.00002) and lower than the threshold for BS1 (>0.0002). Therefore, no population codes are met. The computational predictor REVEL gives a score of 0.336, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 567526). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415091332/MONDO:0010305/027 2025-03-18 2025-03-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:50692 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0020649 infores:hetionet CHEBI:681569 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0009782 infores:hetionet UBERON:0001199 biolink:causes MONDO:0006221 infores:ubergraph knowledge_assertion manual_agent UBERON:0001199 MONDO:0006221 CHEBI:50885 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0086543 infores:hetionet CHEBI:7577 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0231528 infores:hetionet CHEBI:51450 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020615 infores:hetionet CHEBI:63619 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0497156 infores:hetionet CHEBI:7822 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0232462 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0011551 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020615 infores:hetionet CHEBI:5855 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1320474 infores:hetionet CHEBI:35854 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C3263723 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0032285 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002453 infores:hetionet CHEBI:63631 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0040822 infores:hetionet CHEBI:553473 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0278134 infores:hetionet CHEBI:8874 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006277 infores:hetionet CHEBI:6367 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234428 infores:hetionet CHEBI:127780 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0011168 infores:hetionet CHEBI:28901 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0009782 infores:hetionet NCBIGene:9968 biolink:causes MONDO:0010477 infores:monarchinitiative not_provided not_provided HGNC:11957 MONDO:0010477 uuid:785c823b-0688-4487-9d7a-0013db8ab686 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0000731 infores:hetionet CHEBI:4046 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0027769 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003537 infores:hetionet CHEBI:15365 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0020615 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C3665473 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235198 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011991 infores:hetionet CHEBI:63632 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0423791 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0042109 infores:hetionet CAID:CA390863714 biolink:causes MONDO:0100216 infores:clingen CAID:CA390863714 MONDO:0100216 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PM6, BP1, BP4, BP2, BP3, BA1, PP2, PP3, PP4, PP1, BS2, PM5, PM3, PM4, PM1, PS1, PS3, PS4, PS2, BP5, BP7, BS1, BS3, BS4 The NM_177438.2:c.5622C>A (p.Tyr1874Ter) variant in DICER1 is a nonsense variant that may cause loss of function of the protein; however, it is predicted to escape nonsense-mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has an allele frequency of 0.0000006196 (1/1614038 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1_Moderate, PM2_Supporting. (Bayesian Points: 3; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390863714/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8774 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0030305 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0034065 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0522351 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0522351 infores:hetionet NCBIGene:3643 biolink:causes MONDO:0009517 infores:monarchinitiative not_provided not_provided HGNC:6091 MONDO:0009517 uuid:46d2c6b2-01b3-4618-96c1-c7c1d3226b07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0030252 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0040479 infores:hetionet CHEBI:5138 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151766 infores:hetionet CAID:CA000656 biolink:causes MONDO:0017623 infores:clingen CAID:CA000656 MONDO:0017623 PMID: Pathogenic PM2, PVS1, PS4_Supporting PTEN c.987_990delTAAA (p.N329KfsX14) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 10232405) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000656/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0145867 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0236024 infores:hetionet CHEBI:31644 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C1260880 infores:hetionet NCBIGene:5236 biolink:causes MONDO:0013968 infores:monarchinitiative not_provided not_provided HGNC:8905 MONDO:0013968 uuid:e692285d-f212-47fc-82f1-11ae15c69b27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0424295 infores:hetionet NCBIGene:2719 biolink:causes MONDO:0008679 infores:monarchinitiative not_provided not_provided HGNC:4451 MONDO:0008679 uuid:8ba47481-9bb3-43bc-a5dc-d4fd3dae00be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0016382 infores:hetionet CHEBI:94609 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0039231 infores:hetionet CHEBI:261649 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0009676 infores:hetionet CHEBI:135935 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0151904 infores:hetionet CHEBI:15551 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0019521 infores:hetionet CHEBI:46195 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0017605 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0017152 infores:hetionet CHEBI:63627 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0015230 infores:hetionet CHEBI:63613 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0041582 infores:hetionet CAID:CA9870228 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870228 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP3, PP4, BS4 PM2, PM1, PS4, BS1 The c.341G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 114 (p.(Arg114Gln)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.869, which is greater than the MDEP VCEP threshold of 0.70 (PP3).The Popmax filtering allele frequency of the c.341G>A variant in gnomAD v2.1.1 is 0.000029, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4, internal lab contributors). This variant does not segregate with diabetes in one family (BS4; internal lab contributors). Another missense variant, c.340C>T p.Arg114Trp, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.341G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS4, PP3, PP4, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870228/MONDO:0015967/085 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6062 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027497 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0235351 infores:hetionet CAID:CA213771 biolink:causes MONDO:0015967 infores:clingen CAID:CA213771 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.214G>A variant in the glucokinase gene, GCK causes an amino acid change of glycine to arginine at codon 72 (p.(Gly72Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copies in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 48 unrelated individuals with diabetes/hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 23 informative meioses in multiple families (PP1_Strong; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km was between 0.4-0.65, the p.Gly72Arg had a relative activity index (RAI) > 0.5 and a relative stability index (RSI) <=0.5 (PS3_Supporting; PMID: 25015100). In summary, c.214G>A meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213771/MONDO:0015967/086 2023-08-13 2023-08-13 Semidominant inheritance HP:0032113 Supports CHEBI:404903 biolink:causes MONDO:0024388 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009062 infores:hetionet NCBIGene:9997 biolink:causes MONDO:0011451 infores:monarchinitiative not_provided not_provided HGNC:10604 MONDO:0011451 uuid:49dbe2f6-6d5e-4379-b914-140f70f193cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0027813 infores:hetionet CHEBI:53760 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018520 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0003864 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0235807 infores:hetionet CHEBI:135930 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151786 infores:hetionet CHEBI:5118 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0025222 infores:hetionet CHEBI:63629 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013604 infores:hetionet NCBIGene:146227 biolink:causes MONDO:0007296 infores:monarchinitiative not_provided not_provided HGNC:24160 MONDO:0007296 uuid:bc4c767f-4b98-4bec-9831-ab3b5f424c42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2138 biolink:causes MONDO:0024532 infores:monarchinitiative not_provided not_provided HGNC:3519 MONDO:0024532 uuid:dd3b070e-bff5-4248-994b-96209e478012 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8028 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0151818 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0031350 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0086543 infores:hetionet UMLS:C0017797 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0086565 infores:hetionet CHEBI:5109 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0016436 infores:hetionet CHEBI:8207 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0404521 infores:hetionet CHEBI:100241 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0002994 infores:hetionet CHEBI:404903 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0023222 infores:hetionet CHEBI:480999 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0232462 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0018802 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0178298 infores:hetionet CHEBI:16899 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0162298 infores:hetionet CHEBI:7496 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0021368 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0267792 infores:hetionet UNII:F64QU97QCR biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0220870 infores:hetionet CHEBI:8081 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0236000 infores:hetionet CHEBI:63610 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0015672 infores:hetionet CHEBI:6129 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0547030 infores:hetionet CHEBI:50381 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0023222 infores:hetionet CHEBI:135285 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0237849 infores:hetionet CHEBI:51209 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C1704272 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0860967 infores:hetionet CHEBI:6367 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0080274 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151735 infores:hetionet CHEBI:3314 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0011206 infores:hetionet CHEBI:5383 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0041657 infores:hetionet CHEBI:8461 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0013395 infores:hetionet CHEBI:3499 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0031542 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0012833 infores:hetionet CHEBI:3175 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0043352 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019112 infores:hetionet CHEBI:91541 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0041969 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0011053 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0026846 infores:hetionet CHEBI:63599 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002390 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0031117 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0032285 infores:hetionet CHEBI:3219 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0033774 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0003123 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0035078 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0040046 infores:hetionet CHEBI:8871 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0686347 infores:hetionet CHEBI:184555 biolink:causes MONDO:0018301 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0282488 infores:hetionet CHEBI:4903 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0040460 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0549373 infores:hetionet CHEBI:3561 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0221242 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0024115 infores:hetionet CHEBI:10650 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0040460 infores:hetionet CHEBI:6062 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C2830004 infores:hetionet CHEBI:47780 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1167965 infores:hetionet GO:0090104 biolink:causes CL:0005019 infores:ubergraph knowledge_assertion manual_agent GO:0090104 CL:0005019 CHEBI:6950 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0005779 infores:hetionet UMLS:C1872203 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0004093 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0021400 infores:hetionet CHEBI:132233 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0013390 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0017563 infores:hetionet CHEBI:27432 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0011603 infores:hetionet CHEBI:3568 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039231 infores:hetionet NCBIGene:2074 biolink:causes MONDO:0019570 infores:monarchinitiative not_provided not_provided HGNC:3438 MONDO:0019570 uuid:767b3cb4-d28f-4d3c-8306-534169303a57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35854 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0030193 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018099 infores:hetionet CHEBI:7956 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C2973529 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0242073 infores:hetionet CHEBI:91834 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0011991 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042769 infores:hetionet NCBIGene:9227 biolink:causes MONDO:0013231 infores:monarchinitiative not_provided not_provided HGNC:6685 MONDO:0013231 uuid:4eb06a3b-4ebc-4fc3-8f79-124e2b244b9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151907 infores:hetionet CHEBI:4708 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0015967 infores:hetionet CHEBI:8430 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0012833 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020538 infores:hetionet CHEBI:70718 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0011991 infores:hetionet CHEBI:45409 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0029089 infores:hetionet CHEBI:7773 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0041834 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020649 infores:hetionet CHEBI:7915 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0085631 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018418 infores:hetionet CHEBI:63584 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0009676 infores:hetionet CHEBI:5441 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0009676 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0027769 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0004239 infores:hetionet CHEBI:7936 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011168 infores:hetionet CHEBI:61049 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007286 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029878 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0855242 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002453 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948586 infores:hetionet CHEBI:45783 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0239981 infores:hetionet CHEBI:2636 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0003578 infores:hetionet CHEBI:2668 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0231528 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0023646 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027709 infores:hetionet CHEBI:27899 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C2939419 infores:hetionet NCBIGene:1184 biolink:causes MONDO:0010687 infores:monarchinitiative not_provided not_provided HGNC:2023 MONDO:0010687 uuid:35cc0532-a5a2-4d87-bbce-2fafc054b276 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040264 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1519353 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0040034 infores:hetionet CHEBI:85161 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0039239 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0917805 infores:hetionet CAID:CA030486 biolink:causes MONDO:0007750 infores:clingen CAID:CA030486 MONDO:0007750 PMID: Benign BP4, BA1 BP1, BP2, BP3, PS1, PS3, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PVS1, PM2, PM6, BS2, PP2, PP3, PP4, PP1 The NM_000527.5(LDLR): c.940+9C>T variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: BA1: FAF = 0.02650 (2.650%) in African/African American exomes+genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) and C) variant is not exonic.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA030486/MONDO:0007750/013 2024-08-30 2024-10-03 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5128 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0220870 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235416 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003864 infores:hetionet CHEBI:8435 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0020649 infores:hetionet CAID:CA2580616050 biolink:causes MONDO:0001586 infores:clingen CAID:CA2580616050 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting PS1, PM1 The NM_000203.5(IDUA):c.1587_1588dup (p.Leu530Argfs*31) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 12 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least two MPS1 patients with this variant have been reported. One had documented IDUA deficiency within the affected range in leukocytes, elevated urinary GAGs, and clinical features consistent with MPS I (PMID: 21639919, 22074387) (PP4). Of these patients, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908), but it was not confirmed in trans (0.5 points, PMID:25098213). One individual was homozygous for the variant (0.5 points, PMID:21639919 ). Total: 1 point (PM3). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2203498). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616050/MONDO:0001586/091 2024-12-05 2025-03-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:74947 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0428977 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042267 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0919874 infores:hetionet CHEBI:8435 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0151889 infores:hetionet CHEBI:3219 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038990 infores:hetionet CHEBI:4636 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0013428 infores:hetionet CHEBI:63631 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0086769 infores:hetionet CAID:CA043710 biolink:causes MONDO:0007750 infores:clingen CAID:CA043710 MONDO:0007750 PMID: Likely Benign BP4, BP7, BS1 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP2, PP3, PP4, PP1 The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA043710/MONDO:0007750/013 2024-08-30 2024-10-09 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA059160 biolink:causes MONDO:0017623 infores:clingen CAID:CA059160 MONDO:0017623 PMID: Uncertain Significance PP2, PM2_Supporting, BP4 PVS1, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP3, PP1, PP4, PM4, PM5, PM1, PM3, BP3, BP1, BP2, BA1, PS1, PS3, PS4, PS2 PTEN c.1093G>A (p.Val365Ile) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BP4: REVEL score < 0.5 (score=0.441)Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 2 pathogenic supporting codes get -1 + (1*2) points; total is 1 (VUS). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA059160/MONDO:0017623/003 2023-12-01 2023-12-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:132233 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0242350 infores:hetionet CHEBI:8802 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0013428 infores:hetionet CAID:CA177674 biolink:causes MONDO:0021060 infores:clingen CAID:CA177674 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.925A>G (p.Ile309Val) variant in the PTPN11 gene is 0.04% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (46/66736 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA177674/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:119486 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0574067 infores:hetionet NCBIGene:1376 biolink:causes MONDO:0010914 infores:monarchinitiative not_provided not_provided HGNC:2330 MONDO:0010914 uuid:2348a244-a461-46dc-b083-ba7fcd9c2bfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1262113 infores:hetionet CHEBI:8455 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0018524 infores:hetionet CHEBI:40303 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0008031 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0027765 infores:hetionet CAID:CA340741972 biolink:causes MONDO:0100368 infores:clingen CAID:CA340741972 MONDO:0100368 PMID:31580392 Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4, PP1, PM2_Supporting BS1 NM_000329.3(RPE65):c.1399C>G is a missense variant causing substitution of proline by alanine at position 467. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00001898, with 2 alleles / 18384 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.998+1G>A or NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) variants confirmed in trans (PMID: 31273949, PMID: 30996589), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including grey-white fundus albipunctatus‐like changes (2 pts), genotyping by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), night blindness with onset before age 5 years (1 pt), extinguished rod ERG responses (0.5 pts), and severely reduced cone ERG responses (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 total points, PMID: 31273949, PP4). Two other probands also meet the PP4 criteria including extinguished ERG, night blindness with onset in early childhood as well as additional consistent features such as white dot deposits in the mid-peripheral retina, and reduced visual acuity (PP4; PMID: 31273949). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative in 2 different families, with the variant present in the compound heterozygous state (PP1; PMID: 31273949). The computational predictor REVEL gives a score of 0.891, which is above the ClinGen LCA/eoRD VCEP threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 31580392). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340741972/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4911 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0029134 infores:hetionet CHEBI:10102 biolink:causes MONDO:0100345 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0022951 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0442874 infores:hetionet CHEBI:145499 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0043094 infores:hetionet CHEBI:6438 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0003811 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001277 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0007773 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0852792 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0852792 infores:hetionet CAID:CA345151305 biolink:causes MONDO:0100084 infores:clingen CAID:CA345151305 MONDO:0100084 PMID: Pathogenic PP2, PP3, PM2_Supporting, PM5_Strong, PS2 BP4, BA1, PS1, PS4, BS1 The NM_001100.4(ACTA1):c.109G>T variant in ACTA1 is a missense variant predicted to cause substitution of valine by leucine at amino acid 37 (legacy nomenclature: p.Val35Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.881, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Three other variants occur at the same residue (c.110T>C (p.V37A); c.110T>G (p.V37G)) with c.109G>C (p.V37L) occurring at the same nucleotide (PM5_Strong). This variant has occurred de novo in one individual with nemaline myopathy, hypotonia, respiratory distress, and cardiac arrest (PS2; PMID:28973083, Baylor Genetics, SCV000807332.1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM5_Strong, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345151305/MONDO:0100084/147 2024-08-27 2024-12-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8346 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0009450 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0031117 infores:hetionet CHEBI:7496 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0015967 infores:hetionet CHEBI:31623 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0271051 infores:hetionet CHEBI:2682 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085624 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0595930 infores:hetionet CHEBI:10102 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085631 infores:hetionet CHEBI:2618 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0151766 infores:hetionet CHEBI:5383 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0600142 infores:hetionet CHEBI:55346 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C1443060 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0013395 infores:hetionet GO:1903406 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:1903406 GO:0071805 CHEBI:135939 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0085614 infores:hetionet CHEBI:6149 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0004245 infores:hetionet CHEBI:9720 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C2830004 infores:hetionet CHEBI:41879 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0026896 infores:hetionet CHEBI:453011 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0018681 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0035309 infores:hetionet CHEBI:6838 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0687133 infores:hetionet CHEBI:45285 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0231218 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0005741 infores:hetionet CHEBI:100246 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0039503 infores:hetionet CHEBI:63577 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0851578 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235082 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0852810 infores:hetionet CAID:CA16020789 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020789 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Supporting, PM5_Supporting The c.442G>C (p.Gly148Arg) variant in PAH is a missense variant that is predicted damaging by REVEL (REVEL score 0.947) (PP3_Strong). It is absent from gnomAD v2.1.1 (PM2_Supporting). It has been reported in at least 1 Chinese patient with PAH deficiency with BH4 deficiency excluded (PMID: 26503515, 30050108) (PP4_Moderate), and has been reported in unknown phase with the pathogenic variant p.Arg243Gln (ClinVar ID: 591) (PM3_Supporting). Multiple different missense variants at the same site have been reported likely pathogenic in ClinVar, including c.443G>A (p.Gly148Asp) (ClinVar ID: 872837), c.443G>T (p.Gly148Val) (ClinVar ID: 552657), c.442G>A (p.Gly148Ser) (ClinVar ID: 102680) (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM5_Supporting, PP4_Moderate, PP3_Strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020789/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63577 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020429 infores:hetionet UMLS:C0004609 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151934 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0877661 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0001824 infores:hetionet CHEBI:116278 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013378 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0234458 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0042109 infores:hetionet CHEBI:41879 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1761613 infores:hetionet CHEBI:2659 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0011603 infores:hetionet CHEBI:167309 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0009676 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0037199 infores:hetionet CHEBI:31515 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0541919 infores:hetionet CHEBI:27834 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C3257803 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0427160 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0427160 infores:hetionet CAID:CA10014327 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014327 MONDO:0011071 PMID: Benign BA1, BP4, BP2, BP7 PS1, PS3, PS2, PS4, BP1, BP3, PM2, PM6, PVS1, BS1, BS3, PM5, PM4, PM3, PP2, PP3, PP4, BS2 The c.805+186C>T variant is a deep intronic variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being weakly conserved (PhyloP score = 0.0621969 in GRCh38) (BP7). The variant's highest population minor allele frequency in gnomAD v2 is 0.06817 (1055/15476 alleles) in the African/African American population, which is higher than the ClinGen Myeloid Malignancy threshold (>0.0015) for BA1; in addition, this allele count includes 43 homozygotes, and there are no reports of probands with homozygous pathogenic variants plus RUNX1-deficient mice are embryonic lethal (BP2). The variant may have been reported in the germline of a patient with MDS/MPN-U and other syndromic features related to a MECOM alteration (underwent WES trio analysis), but the carrier status of another family member was unpublished (PMID: 29097497); otherwise, the variant has not been reported in germline cases (PMID: 24211365) or functionally evaluated in the literature. In summary, this variant meets the criteria to be classified as benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BA1, BP2, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014327/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48273 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0011053 infores:hetionet NCBIGene:9094 biolink:causes MONDO:0957240 infores:monarchinitiative not_provided not_provided HGNC:12565 MONDO:0957240 uuid:3481f9fd-2ec0-43bc-a245-fe462dc3bee3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0042571 infores:hetionet CHEBI:4784 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0042023 infores:hetionet CHEBI:6078 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0235592 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0178298 infores:hetionet CHEBI:31711 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026838 infores:hetionet CHEBI:681848 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0036572 infores:hetionet CHEBI:7852 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0005758 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0267792 infores:hetionet NCBIGene:60 biolink:causes MONDO:0957564 infores:monarchinitiative not_provided not_provided HGNC:132 MONDO:0957564 uuid:10632aea-e962-4450-ab63-75b0d36e3332 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes UMLS:C0264734 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0264734 infores:hetionet CHEBI:49575 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0003862 infores:hetionet CHEBI:35778 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0010520 infores:hetionet CHEBI:9352 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0042963 infores:hetionet CHEBI:209807 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C1609512 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0023530 infores:hetionet CHEBI:5864 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1519353 infores:hetionet CAID:CA024596 biolink:causes MONDO:0007783 infores:clingen CAID:CA024596 MONDO:0007783 PMID: Likely Pathogenic PP1, PM5, PM1_Supporting, PS4_Moderate, PP3_Moderate BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with proline at codon 2163 of the RYR1 protein, p.Arg2163Pro. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:10757649, PMID:20681998, PMID:24433488, PMID:31559918). This variant segregates with MHS in five individuals, PP1 (PMID:10757649). No functional studies were identified for this variant. Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5. A REVEL score >0.85 (0.947) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024596/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:404903 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1527344 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020538 infores:hetionet CHEBI:30830 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151905 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0858833 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0858833 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151479 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0009806 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0018213 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0012833 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0042035 infores:hetionet CHEBI:3387 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0005758 infores:hetionet CHEBI:36795 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0234022 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007137 infores:hetionet CHEBI:17650 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0017178 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020456 infores:hetionet CHEBI:567361 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0003467 infores:hetionet CHEBI:31711 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0547030 infores:hetionet CHEBI:75722 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085593 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0155003 infores:hetionet CAID:CA512232117 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232117 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1413C>G (p.Arg471=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.49)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232117/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:68558 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0009782 infores:hetionet CHEBI:2682 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0019080 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018099 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019360 infores:hetionet CHEBI:34911 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0015967 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001548 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019147 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0151735 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0151661 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151661 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0521839 infores:hetionet CHEBI:5147 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0043352 infores:hetionet NCBIGene:9445 biolink:causes MONDO:0007297 infores:monarchinitiative not_provided not_provided HGNC:6174 MONDO:0007297 uuid:6dc29f21-825c-46db-a8e3-e7f5890f593b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2666 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C2047937 infores:hetionet CHEBI:23765 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0035455 infores:hetionet CHEBI:100241 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0423791 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151664 infores:hetionet CHEBI:44185 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0231218 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0079102 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0020649 infores:hetionet CAID:CA031387 biolink:causes MONDO:0007750 infores:clingen CAID:CA031387 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM2, PVS1, PP4 PS3, BS4 The NM_000527.5 (LDLR):c.1048C>T(p.Arg350Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4, PP1_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1).PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830).PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4: Variant meets PM2 and is identified in 23 unrelated index cases fulfil clinical criteria for FH. Ten cases fulfil Simon Broome FH criteria (5 cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; 3 cases from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, PMID 22698793; 1 case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 1 case from Division of Cardiology, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (PMID 20538126)). Thirteen cases fulfil DLCN criteria (10 cases from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; 1 case each from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain (PMID 19318025); Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland (PMID 9654205); GeneDx).PP1_Strong: Variant segregates with FH phenotype in 20 informative meiosis from at least 11 families. Fifteen affected relatives tested positive for the variant from at least 6 families from 4 different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation; GeneDx; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Five unaffected relatives tested negative for the variant from 5 families (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031387/MONDO:0007750/013 2022-03-25 2022-04-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8597 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0028084 infores:hetionet CHEBI:6367 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0008031 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0948594 infores:hetionet CHEBI:3561 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0030193 infores:hetionet CHEBI:41879 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0547030 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0019163 infores:hetionet CHEBI:5138 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017181 infores:hetionet CHEBI:4672 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0002962 infores:hetionet NCBIGene:4210 biolink:causes MONDO:0011959 infores:monarchinitiative not_provided not_provided HGNC:6998 MONDO:0011959 uuid:617907e6-4f25-4f7c-99e3-24fa04b228a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0541832 infores:hetionet CAID:CA177689 biolink:causes MONDO:0021060 infores:clingen CAID:CA177689 MONDO:0021060 PMID: Benign BP7, BP5, BA1, BP4 The c.-339_-338delAG variant in RAF1 is classified as benign because it has been identified in 0.33579% (95% CI of 63/15050) of non-Finnish European alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). This variant was identified in 4 individuals with Noonan syndrome who carried additional pathogenic variants in PTPN11 sufficient to explain their clinical presentations (BP5). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA177689/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3380 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0853760 infores:hetionet UMLS:C0657912 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151315 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0012833 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0541881 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0541881 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0429098 infores:hetionet CHEBI:66919 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0016204 infores:hetionet NCBIGene:6775 biolink:causes MONDO:0957497 infores:monarchinitiative not_provided not_provided HGNC:11365 MONDO:0957497 uuid:cb825993-ad87-472c-b3d2-32e47663cd4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4000 biolink:causes MONDO:0030781 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0030781 uuid:d9162a89-6ca0-49dc-b2ba-ed675d3cb50e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3510 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0018965 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151479 infores:hetionet CHEBI:119915 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0035229 infores:hetionet CHEBI:35677 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0015672 infores:hetionet CHEBI:68575 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0851341 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0027726 infores:hetionet CHEBI:3752 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0000731 infores:hetionet CHEBI:64355 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0740394 infores:hetionet CHEBI:135961 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0232462 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0014868 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0853619 infores:hetionet CHEBI:45081 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0000737 infores:hetionet CHEBI:10110 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0027121 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0243026 infores:hetionet CHEBI:6846 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0015230 infores:hetionet CHEBI:48947 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0332534 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020456 infores:hetionet CHEBI:5778 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0149744 infores:hetionet CHEBI:85078 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0242339 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151559 infores:hetionet CHEBI:8077 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0004093 infores:hetionet CAID:CA320251627 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251627 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1004A>G (p.Gln335Arg) is a missense variant which has a REVEL score < 0.50 (0.37) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251627/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5383 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0541900 infores:hetionet UBERON:0001765 biolink:causes MONDO:0002488 infores:ubergraph knowledge_assertion manual_agent UBERON:0001765 MONDO:0002488 CHEBI:94686 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0151824 infores:hetionet CHEBI:8869 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0042029 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0004238 infores:hetionet CHEBI:10110 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151907 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0521591 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C50599 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0700363 infores:hetionet CHEBI:17347 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0010200 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0001125 infores:hetionet CHEBI:32315 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0575081 infores:hetionet CHEBI:28864 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0038362 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0541799 infores:hetionet CHEBI:64321 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0234632 infores:hetionet CHEBI:6801 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0030196 infores:hetionet NCBIGene:6334 biolink:causes MONDO:0013680 infores:monarchinitiative not_provided not_provided HGNC:10596 MONDO:0013680 uuid:90a60911-5664-432b-9750-64e48697ace3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3698 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0030193 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0019158 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0233632 infores:hetionet NCBITaxon:149546 biolink:causes MONDO:0001262 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:149546 MONDO:0001262 CHEBI:8232 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151904 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0857751 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0857751 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0580493 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0580493 infores:hetionet CHEBI:6520 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0030312 infores:hetionet CHEBI:5296 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0009782 infores:hetionet CHEBI:17474 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0040053 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0585186 infores:hetionet CHEBI:40050 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0232487 infores:hetionet CHEBI:10124 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0242429 infores:hetionet CAID:CA10585341 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585341 MONDO:0007750 PMID:21511053 Likely Pathogenic PS4_Supporting, PM3, PP1_Moderate, PM2, PP3, PP4 BS3, PM5 The NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PM3, PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP3: REVEL=0.774, which is above threshold of 0.75, met PP3, splicing prediction is not required by these guidelines. However, this variant is located at the end of exon 8 within canonical donor motif, and is predicted to affect donor site splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23; Variant canonical donor motif: TGAGTGAGC, MES: 3.38. Var/Wt ratio = 0.47 (<0.8), also met PP3.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index case who fulfil DLCN criteria for FH diagnosis, one case reported by Koivisto et al, 1995, University of Helsinki, Finland; PMID 7573037; one case reported from Robarts Research Institute, Canada.PM3: This variant meets PM2, and is identified in a HoFH index case (LDLC 14.9 mmol/l at age of 3yrs) and LDLR:c.16_17insTTCCT:p.W6fs (ClinVarID 369864), classified as Pathogenic by these guidelines. Two variants are confirmed in trans, reported from Robarts Research Institute, Canada. PP1_Moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from two families. Three affected family members tested positive for the variant from one family, reported from Robarts Research Institute, Canada. At least 1 co-segregation with hypercholesterolemia was observed from one family, reported by Koivisto et al, 1995, University of Helsinki, Finland; PMID 7573037.BS3 not met: Level 1 assays of whole LDLR cycle performed in LDLR-/- fibroblasts (549T cells) infected with recombinant retroviruses expressing WT LDLR and the variant. Assay results shown cells expressing G396S had no effect on lipoprotein uptake and no defects in receptor distribution, lipoprotein binding, or acid-dependent release, reported by Zhao and Michaely, 2011, Department of Cell Biology at the University of Texas Southwestern Medical Center, US, PMID 21511053. The functional study is not consistent with damaging effect. The experiments did not include splicing mechanism, variant affecting splicing process would not be validated in this study. PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg), (ClinVarID 870321), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585341/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0061001 biolink:causes GO:0016358 infores:ubergraph knowledge_assertion manual_agent GO:0061001 GO:0016358 CHEBI:7931 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085681 infores:hetionet CHEBI:7773 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0018681 infores:hetionet NCBIGene:60684 biolink:causes MONDO:0014144 infores:monarchinitiative not_provided not_provided HGNC:25751 MONDO:0014144 uuid:0f11ae45-7b80-4fac-bef4-bc0b8c6a3f98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0031350 infores:hetionet CAID:CA410148592 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148592 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1015C>G (p.Leu339Val) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.13) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148592/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA915940777 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940777 MONDO:0100326 PMID: Pathogenic PM3, PM2, PVS1 PP4, PP1 The c.189-319_236del variant in ITGA2B is an intronic variant which occurs within the canonical splice acceptor site of intron 1. It is predicted to cause skipping of biologically-relevant-exon 2, resulting in a frameshift with a premature stop codon in exon 3/15, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 31029159). This variant has been detected in at least 2 probands with Glanzmann thrombasthenia. 2 probands were homozygous for the variant (1PM3 point, PMIDs: 31029159). Total points: 1 (PM3_Moderate). This variant is absent from gnomAD SVs v4 (PM2_Supporting).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3, PM2. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940777/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9434 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C1384353 infores:hetionet CHEBI:17549 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0019080 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0005779 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0162820 infores:hetionet NCBIGene:6886 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:11556 MONDO:0013108 uuid:3a285848-f496-4de9-835b-74c0abf01ab6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0019372 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0036572 infores:hetionet CAID:CA6402593 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402593 MONDO:0019565 PMID: Benign BP4, BA1, BP5 BS2, BP2, BS3 The missense variant NM_000552.5(VWF):c.4141A>G (p.Thr1381Ala) is common in the general population with a Grpmax filtering allele frequency of 0.8925 (based on 67313/74942 alleles in the African/African American population) in gnomAD v4.1 (BA1). Several probands have been reported (PMID: 30817071, PMID: 30762591) with Thr1381Ala in cis or trans with additional vWF variants, including the type 2B Arg1308Cys variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP; BP5). and therefore meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4, BP5 (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; 08/12/2024). von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402593/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true CHEBI:10124 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042963 infores:hetionet CHEBI:63616 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0015672 infores:hetionet CHEBI:31705 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0009676 infores:hetionet NCBIGene:3074 biolink:causes MONDO:0010006 infores:monarchinitiative not_provided not_provided HGNC:4879 MONDO:0010006 uuid:ff38ce09-be05-45af-827e-b5500aa97ddc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042384 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0162830 infores:hetionet CHEBI:40050 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0014742 infores:hetionet CHEBI:7581 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0013395 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011616 infores:hetionet CAID:CA16020808 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020808 MONDO:0009861 PMID: Pathogenic PM3, PVS1, PM2, PP4 The c.510-1G>A variant in PAH is a canonical splice acceptor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was detected in a patient with classic PKU in an Australian cohort with the pathogenic variant c.1066-11G>A (PMID 24368688). 2 patients in a Chinese Han PKU cohort were identified with c.510-1G>A in trans with pathogenic variant p.Arg241Cys and VUS p.Ile421Thr. (PMID 28982351). This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020808/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32315 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0948594 infores:hetionet CAID:CA404074852 biolink:causes MONDO:0007750 infores:clingen CAID:CA404074852 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1, PP4 NM_000527.5(LDLR):c.139G>T (p.Asp47Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.962 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404074852/MONDO:0007750/013 2022-03-30 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6402 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013378 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0860988 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0860988 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0040046 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0034150 infores:hetionet CHEBI:145499 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015967 infores:hetionet CHEBI:31236 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0344232 infores:hetionet CHEBI:63631 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013132 infores:hetionet CHEBI:63717 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C1565489 infores:hetionet NCBIGene:7132 biolink:causes MONDO:0007727 infores:monarchinitiative not_provided not_provided HGNC:11916 MONDO:0007727 uuid:4d44526e-fbe3-48c7-bbb1-e96c7780e4e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2469 biolink:causes UMLS:C0392390 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0392390 infores:hetionet CHEBI:2663 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0541782 infores:hetionet CHEBI:92712 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0002962 infores:hetionet UMLS:C0657912 biolink:causes HP:0012232 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151879 infores:hetionet CHEBI:5801 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0038325 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0019212 infores:hetionet CHEBI:32184 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0021099 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0036220 infores:hetionet CHEBI:2682 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0003811 infores:hetionet CHEBI:3636 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C2830004 infores:hetionet CHEBI:52717 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020578 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0028738 infores:hetionet CHEBI:47780 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030232 infores:hetionet CHEBI:10119 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C3263723 infores:hetionet CHEBI:50859 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C2047937 infores:hetionet NCBIGene:2131 biolink:causes MONDO:0008977 infores:monarchinitiative not_provided not_provided HGNC:3512 MONDO:0008977 uuid:0ad62bab-3c06-4d8b-828b-1cd9ef7df342 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0857305 infores:hetionet CHEBI:49713 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0032617 infores:hetionet CAID:CA410147855 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147855 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS4, PS3, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1178G>A (p.Gly393Glu) is a missense variant which has a REVEL score < 0.50 (0.029), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147855/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521591 infores:hetionet CHEBI:45409 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0558489 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0037274 infores:hetionet CHEBI:31644 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0035455 infores:hetionet CHEBI:28593 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0020458 infores:hetionet CHEBI:70735 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0023380 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029445 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0518015 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0919593 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0919593 infores:hetionet CAID:CA397723954 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723954 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 PP4, PM5, PM1, PM3_Supporting, PS3 The c.910G>A variant in ACADVL is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 304 (p.Ala304Thr). This variant has been reported in the literature in one individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency with reduced VLCAD activity and beta oxidation flux, but at levels that do not currently meet the ACADVL Variant Curation Expert Panel specifications for PP4 (PMID: 17999356). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723954/MONDO:0008723/021 2022-07-28 2022-07-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31711 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0700590 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0264714 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0264714 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0234215 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002871 infores:hetionet CHEBI:31638 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0700345 infores:hetionet CHEBI:45951 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0151818 infores:hetionet CHEBI:474180 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0858635 infores:hetionet UMLS:C1738934 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0232487 infores:hetionet CHEBI:144551 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018681 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000879 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006846 infores:hetionet CHEBI:125354 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0003862 infores:hetionet CHEBI:4953 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0040038 infores:hetionet CHEBI:114785 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0015967 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948594 infores:hetionet CHEBI:46195 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0030252 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0002886 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0019193 infores:hetionet CAID:CA255329 biolink:causes MONDO:0010604 infores:clingen CAID:CA255329 MONDO:0010604 PMID: Pathogenic PM1, PS4, PP3, PP1, PP4_Moderate BS1, PM5, PM2 The c.316G>A (p.Gly106Ser) variant affects one of the functional domains (aa 93-129; EGF-like 1 domain) in the F9 protein, meeting the PM1 criteria. This missense variant has a REVEL score of 0.905(>0.6), meeting the PP3 criteria. It is reported at an MAF of 0.00002441 (5/204867 alleles) in the overall population in gnomAD v2.1.1, with 3 hemizygotes; however BS1 criteria of MAF >=0.0000278 is not met. Over 60 patients with mild and moderate hemophilia B are reported in the literature meeting PS4_Very strong and PP4_Moderate criteria (PMID: 22103590, 29296726). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PM1, PP4_Moderate, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255329/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:4710 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0221490 infores:hetionet CHEBI:36791 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0404521 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040409 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0042267 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0032285 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0025061 infores:hetionet CHEBI:42797 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013491 infores:hetionet GO:0010965 biolink:causes GO:0000070 infores:ubergraph knowledge_assertion manual_agent GO:0010965 GO:0000070 UNII:9430ZR8ZAN biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0030794 infores:hetionet CHEBI:39585 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0027497 infores:hetionet CHEBI:10101 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0028081 infores:hetionet CHEBI:135961 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0152031 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0036572 infores:hetionet CHEBI:63607 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C3263723 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151951 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151951 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007642 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0948089 infores:hetionet CHEBI:8776 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0033774 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0948594 infores:hetionet CHEBI:63631 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030252 infores:hetionet CHEBI:7798 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0002871 infores:hetionet CHEBI:6888 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151937 infores:hetionet CHEBI:31980 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0015672 infores:hetionet CHEBI:7465 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1262141 infores:hetionet CHEBI:36791 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085610 infores:hetionet CHEBI:37333 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0031212 infores:hetionet CHEBI:9168 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0206062 infores:hetionet CHEBI:4728 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0085631 infores:hetionet CHEBI:44423 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0037299 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0001122 infores:hetionet CHEBI:6538 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0009806 infores:hetionet CHEBI:4562 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042023 infores:hetionet CHEBI:36795 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0920289 infores:hetionet CHEBI:8060 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C1443060 infores:hetionet CHEBI:48273 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0019825 infores:hetionet CAID:CA355963534 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963534 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_000203.5:c.1198C>T (p.Gln400Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 9 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 3 patients with this variant had documented IDUA deficiency within the affected range in leukocytes and urinary GAG elevation above normal range (PP4; PMIDs: 31194252, 11735025). This variant has been detected in at least 1 individual with MPS I. This individual was compound heterozygous for the variant and a pathogenic variant (c.590-7G>A) that was not confirmed in trans (PM3_Supporting; PMID: 11735025). The highest population minor allele frequency in gnomAD v4.0 is 0.000005417 (6/1107690 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PP4, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963534/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports UNII:5V9KLZ54CY biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0028643 infores:hetionet CHEBI:9168 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0702166 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0034186 infores:hetionet CHEBI:3011 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0151539 infores:hetionet CHEBI:3996 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C2004489 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0025061 infores:hetionet CHEBI:3176 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0085636 infores:hetionet CHEBI:31711 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0015230 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0027765 infores:hetionet CHEBI:49575 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0004604 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0009450 infores:hetionet CHEBI:2654 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0033774 infores:hetionet CHEBI:3504 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0043352 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0023530 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027947 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0002622 infores:hetionet CHEBI:6965 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0085623 infores:hetionet CHEBI:47781 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0000737 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009450 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0024115 infores:hetionet CHEBI:6073 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0042510 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004574 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C1527330 infores:hetionet CHEBI:2453 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0034063 infores:hetionet CHEBI:5138 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011206 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027121 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0005779 infores:hetionet CHEBI:44423 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0151799 infores:hetionet CHEBI:6438 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0027497 infores:hetionet CHEBI:36791 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0522178 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0235431 infores:hetionet CHEBI:32020 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0042109 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0859023 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0859023 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038362 infores:hetionet NCBIGene:93166 biolink:causes MONDO:0024266 infores:monarchinitiative not_provided not_provided HGNC:9350 MONDO:0024266 uuid:71affc88-1770-46b7-be32-7c34e3be6fac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0007859 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0162287 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0233794 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0004880 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0016807 infores:hetionet CHEBI:28748 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011175 infores:hetionet CHEBI:178699 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0032227 infores:hetionet CHEBI:3640 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0011606 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042514 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0234518 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0948586 infores:hetionet CHEBI:6437 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013390 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0040479 infores:hetionet CHEBI:84500 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C3665347 infores:hetionet CHEBI:8356 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1519353 infores:hetionet CHEBI:7852 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0013604 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0009450 infores:hetionet CHEBI:6754 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0018681 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0027769 infores:hetionet CHEBI:8310 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0948525 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0042769 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0233494 infores:hetionet UMLS:C1738934 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009676 infores:hetionet CHEBI:3723 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235490 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0027769 infores:hetionet CHEBI:142290 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0151908 infores:hetionet CHEBI:6413 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0231218 infores:hetionet CHEBI:8228 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0043094 infores:hetionet CHEBI:4027 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0035410 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0086543 infores:hetionet CHEBI:27504 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0085624 infores:hetionet CHEBI:50275 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151578 infores:hetionet CHEBI:85161 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0235996 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151559 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0237849 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0178298 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0018799 infores:hetionet NCBIGene:26276 biolink:causes MONDO:0031040 infores:monarchinitiative not_provided not_provided HGNC:12712 MONDO:0031040 uuid:88456675-d544-477e-940f-481925ee320d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0021400 infores:hetionet CHEBI:61058 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0011124 infores:hetionet CHEBI:38940 biolink:causes HP:0025079 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0238334 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0015256 infores:hetionet CHEBI:42797 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020580 infores:hetionet CAID:CA2496602227 biolink:causes MONDO:0015967 infores:clingen CAID:CA2496602227 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1358_*127del168insT variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 453 (NM_000162.5), adding 25 novel amino acids before encountering a stop codon (p.(S453LfsX25)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 could not be evaluated due to lack of clinical information (internal lab contributor). PS4_Moderate also cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). In summary, c.1358_*127del168insT meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2496602227/MONDO:0015967/086 2023-06-20 2023-06-20 Semidominant inheritance HP:0032113 Supports CAID:CA213703 biolink:causes MONDO:0015967 infores:clingen CAID:CA213703 MONDO:0015967 PMID: Likely Pathogenic PP1_Strong, PP4_Moderate, PP3, PM2_Supporting PS4 The c.1020-10C>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.95 for acceptor loss, predicting that the variant disrupts the acceptor site of intron 8 of GCK (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, three-generation, dominant family history of diabetes or hyperglycemia, and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1020-10C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213703/MONDO:0015967/086 2024-02-02 2024-02-02 Semidominant inheritance HP:0032113 Supports CHEBI:253342 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0011615 infores:hetionet CHEBI:92607 biolink:causes GO:0070471 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0042130 infores:hetionet NCBIGene:283652 biolink:causes MONDO:0018264 infores:monarchinitiative not_provided not_provided HGNC:20611 MONDO:0018264 uuid:055a512a-48f3-4c3e-afcd-8677443a5063 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31623 biolink:causes UMLS:C0456495 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0456495 infores:hetionet CHEBI:7956 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0042109 infores:hetionet CHEBI:6916 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0011603 infores:hetionet CHEBI:3223 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020458 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027813 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0233494 infores:hetionet CHEBI:5134 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0235259 infores:hetionet CHEBI:52717 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040264 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004095 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0079731 infores:hetionet CHEBI:7476 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0010038 infores:hetionet CHEBI:4024 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0042165 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0232459 infores:hetionet CHEBI:48844 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C1443060 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0002170 infores:hetionet CHEBI:16469 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0232461 infores:hetionet CHEBI:7820 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0156312 infores:hetionet CHEBI:3636 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0039070 infores:hetionet CHEBI:64045 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0004093 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0242350 infores:hetionet NCBIGene:10236 biolink:causes MONDO:0859297 infores:monarchinitiative not_provided not_provided HGNC:5047 MONDO:0859297 uuid:030c130a-b070-4594-8fd8-50b126d990b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013595 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0012739 infores:hetionet CHEBI:31644 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013491 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0345904 infores:hetionet CHEBI:29013 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0035410 infores:hetionet CHEBI:3732 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0027497 infores:hetionet CHEBI:9763 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151205 infores:hetionet CHEBI:31348 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013362 infores:hetionet CHEBI:100241 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1510410 infores:hetionet CAID:CA024388 biolink:causes MONDO:0007783 infores:clingen CAID:CA024388 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 1043 of the RYR1 protein, p.Arg1043Cys. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual also had a second RYR1 variant classified as pathogenic p.Arg2336His (PMID:19191329). Both the presence of a pathogenic RYR1 variant and the high MAF in the AMR population in gnomAD preclude the use of PS4. No functional studies were identified for this variant. A REVEL score >0.85 (0.936) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024388/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:50859 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0008325 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006781 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0079487 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042514 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0877365 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0877365 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0011616 infores:hetionet CHEBI:50922 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0040435 infores:hetionet CHEBI:38940 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0740394 infores:hetionet CHEBI:167638 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0002994 infores:hetionet CHEBI:127780 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0004604 infores:hetionet CHEBI:37333 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0259749 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085682 infores:hetionet CHEBI:63611 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014457 infores:hetionet CHEBI:44032 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0497156 infores:hetionet CAID:CA410203500 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203500 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.318G>A (p.Trp106Ter) is a nonsense variant which is predicted to undergo nonsense-mediated decay (as per the modified RUNX1 PVS1 decision tree) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). It is a nonsense variant that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 34233450). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203500/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63791 biolink:causes UMLS:C0740304 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0740304 infores:hetionet CHEBI:6367 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0009421 infores:hetionet CHEBI:63630 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027066 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0340726 infores:hetionet CHEBI:15765 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0011253 infores:hetionet CHEBI:48538 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0018681 infores:hetionet NCBIGene:81887 biolink:causes MONDO:0010665 infores:monarchinitiative not_provided not_provided HGNC:25726 MONDO:0010665 uuid:a3072054-1b77-489b-9045-4869f130357d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0033774 infores:hetionet CHEBI:45409 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013491 infores:hetionet CHEBI:9398 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0178298 infores:hetionet CAID:CA273892 biolink:causes MONDO:0009290 infores:clingen CAID:CA273892 MONDO:0009290 PMID:25139343PMID:16860134PMID:30155607PMID:18429042PMID:27927596PMID:23601496PMID:29122469PMID:9535769PMID:30105547PMID:26497565PMID:25455803PMID:15145338PMID:19862843PMID:17723315PMID:9535769PMID:15145338 Pathogenic PM2, PP3, PP4, PM5, PM3_Strong, PS3 This variant, c.1933G>A (p.Asp645Asn), is a missense change which has been reported in least 11 individuals with deficient GAA activity meeting the ClinGen LSD VCEP's specifications for PP4 (PMIDs 9535769, 15145338, 16860134, 17723315, 23601496, 25139343, 26497565). Five of these individuals are homozygous for the variant have been reported to have infantile onset Pompe disease (PMIDs 16860134, 25139343, 26497565). This variant was also found in two patients who meet PP4 specifications, in compound heterozygosity, phase not confirmed, with a unique pathogenic variant in GAA, either c.2501_2502del or c.2242dup (PMIDs 9535769, 23601496). Based on data from homozygous and compound heterozygous patients, PM3_Strong is met. Additional compound heterozygous cases have been reported but the in trans data has been used in the assessment of the second variant and therefore is not included here in order to avoid circular logic (PMIDs 15145338, 17723315, 26497565). Other cases were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 18429042, 25455803, 27927596, 29122469, 30105547, 30155607). The highest population minor allele frequency in gnomAD is 0.00007 in the African population, meeting PM2. When expressed in GAA-deficient fibroblasts and COS cells, this variant results in virtually no GAA activity (PMIDs 9535769, 15145338), meeting PS3. The score for the in silico meta-predictor, REVEL, is 0.868 suggesting that the variant impacts the function of GAA, meeting PP3. Three other amino acid changes have been reported in patients with Pompe disease at the same amino acid position (c.1933G>C (p.Asp645His), c.1933G>T (p.Asp645Tyr), c.1935C>A (p.Asp645Glu). At least one of these variants, c.1935C>A (p.Asp645Glu), is pathogenic, meeting PM5. In summary, this variant meets the criteria to be specified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PM5, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273892/MONDO:0009290/010 2020-05-28 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4784 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020651 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0028173 infores:hetionet NCBIGene:7043 biolink:causes MONDO:0014262 infores:monarchinitiative not_provided not_provided HGNC:11769 MONDO:0014262 uuid:fe33a62c-3b74-4578-932c-328742b9dd6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6331 biolink:causes MONDO:0011001 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0011001 uuid:2d97b962-da7a-403b-8ced-f4ad4f331e51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3U02EL437C biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0521491 infores:hetionet CHEBI:15940 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0016382 infores:hetionet CHEBI:27999 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0018681 infores:hetionet CHEBI:9086 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0007820 infores:hetionet CHEBI:63581 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0001125 infores:hetionet CHEBI:51164 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0043094 infores:hetionet CAID:CA2581463496 biolink:causes MONDO:0100437 infores:clingen CAID:CA2581463496 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting PP4, PS4 NM_001034853.2(RPGR):c.27del (p.Asp10IlefsTer?) is a frameshift variant due to 1-nucleotide deletion introducing a premature stop codon within exon 1 of 15 that is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses (PMID: 30105367, PMID: 29528978). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts) with relatively mild female phenotypes (1 pt), reduced visual acuity (0.5 pts), abnormal fundus autofluorescence imaging, bone spicule pigmentation of the retina (0.5 pts), and optic disc pallor (0.5 pts), however, the PP4 code was not met due to the unreported age of onset (4.5 total points, PMID: 29528978). The variant has been reported to segregate with retinal dystrophy through at least 12 affected meioses from 1 family (PP1_Moderate; PMID: 30105367, PMID: 29528978). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2581463496/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CAID:CA414802017 biolink:causes MONDO:0044970 infores:clingen CAID:CA414802017 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PS4, PS3 The m.9049G>A (p.Gly175Ter) variant in MT-ATP6 has been reported in one individual with primary mitochondrial disease to date, in a person with ataxia, peripheral neuropathy, and myopathy (PMID: 32652755). The variant was present at 21% heteroplasmy in blood. This variant results in a truncation of 23% of the protein (PVS1_strong). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414802017/MONDO:0044970/015 2024-12-03 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9434 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C3665386 infores:hetionet CHEBI:3568 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235086 infores:hetionet CHEBI:6954 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0018418 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0037274 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0027769 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005106 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0023798 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027441 infores:hetionet NCBIGene:3746 biolink:causes MONDO:0014521 infores:monarchinitiative not_provided not_provided HGNC:6233 MONDO:0014521 uuid:bd908141-26d2-4eee-af84-e8eb20057cc4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27436 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0518015 infores:hetionet CHEBI:4702 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0011124 infores:hetionet NCBIGene:7343 biolink:causes MONDO:0044701 infores:monarchinitiative not_provided not_provided HGNC:12511 MONDO:0044701 uuid:2e36c708-e2a4-4582-8e1f-7149669f65bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034150 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0858797 infores:hetionet CHEBI:7581 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233477 infores:hetionet CAID:CA10549563 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549563 MONDO:0010305 PMID: Likely Benign BS2, BP4 BS1, PM2 "The NM_005629.4:c.1570T>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a serine by a threonine at amino acid position 524 (p.Ser524Thr). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0.., the highest population allele frequency is 0.0001737 (150/863464 alleles, 47 hemizygotes) in the European non-Finnish population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 50 hemizygotes in gnomAD v4.1.0.; 47 in the European non-Finnish population, 2 in the ""remaining"" population, and one in the African/African American population (BS2). The computational predictor REVEL gives a score of 0.191 suggesting that the variant has no impact on the function of the gene product, and SpliceAI predicts that the variant has no impact on splicing. (BP4). There is a ClinVar entry for this variant (Variation ID: 410223). Due to the presence of 50 hemizygotes in gnomAD v4.1.0 in the absence of any evidence for pathogenicity, the consensus of the ClinGen CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549563/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:16467 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0015230 infores:hetionet CHEBI:119573 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0423791 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004245 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151479 infores:hetionet CHEBI:3403 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0036974 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0243026 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0856882 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020538 infores:hetionet CHEBI:194135 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017979 infores:hetionet CHEBI:8871 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0232462 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006444 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0036572 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0701836 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0701836 infores:hetionet CHEBI:76010 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0235431 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0026946 infores:hetionet CHEBI:5165 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0085636 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0151559 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151576 infores:hetionet CHEBI:135738 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0853692 infores:hetionet CHEBI:8863 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002874 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0178298 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0581912 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0011991 infores:hetionet CHEBI:6933 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0039231 infores:hetionet CHEBI:65349 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0392525 infores:hetionet CAID:CA645369682 biolink:causes MONDO:0007648 infores:clingen CAID:CA645369682 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM6, PP4, PP1, PP2, PP3, BS2, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.1131delC p.(Thr378fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000580700.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369682/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA2499225872 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225872 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS2, PS3, PS4, BA1, BP3, BP1, BP2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PP2, PP3, PP4, PP1, BS2 The c.968-9G>A intronic variant is not predicted by SpliceAI to impact splicing (BP4). In addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -4.74743 in GRCh38), and the variant is the reference nucleotide in one primate and/or three mammal species. Although the variant is absent from gnomAD v2 and v3 (PM2_Supporting), it has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225872/MONDO:0011071/008 2022-06-30 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8863 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0038362 infores:hetionet CHEBI:240107 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0392163 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0853750 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853750 infores:hetionet CHEBI:91541 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0009676 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0877517 infores:hetionet NCBIGene:26509 biolink:causes MONDO:0025713 infores:monarchinitiative not_provided not_provided HGNC:3656 MONDO:0025713 uuid:b7231ee2-5065-4f94-8140-1b4c42339e74 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0001385 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0155320 infores:hetionet CHEBI:16469 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0085631 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0404572 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0429468 infores:hetionet CHEBI:9086 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085681 infores:hetionet CAID:CA913187388 biolink:causes MONDO:0009290 infores:clingen CAID:CA913187388 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PS1_Supporting, PM2_Supporting, PM3_Supporting PS3 The NM_000152.5:c.1551+3_1551+6del variant in GAA removes four nucleotides in the donor splice region of intron 10. RT-PCR from muscle from a patient who is compound heterozygous for the variant and c.2238G>C (p.Trp746Cys), indicates that the variant results in skipping of exon 10 (PMID: 25526786), causing an in frame deletion that removes part of the GAA catalytic barrel, including two residues, Trp481 and Trp516, which are part of the active site of the enzyme (PMID 1856189; PMID 22253258; Deming et al, 2017; DOI 10.1101/212837) (PVS1). This patient is Chinese, with clinical features consistent with late-onset Pompe disease and documented deficient GAA activity in lymphocytes (PMID: 25526786) (PP4_Moderate). The second variant in this patient, c.2238G>C (p.Trp746Cys) (ClinVar Variation ID: 265160 has been classified as pathogenic by the ClinGen LD VCEP; the phase is unknown (0.5 points, PMID: 25526786) (PM3_Supporting). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). Additional variants in the same splice region have been classified as pathogenic by the ClinGen LD VCEP including c.1551+1G>A (ClinVar Variation ID: 1065143), c.1551+1G>C (ClinVar Variation ID: 554983), and c.1551+1G>T (ClinVar Variation ID: 555986) (PS1_Supporting; PMID: 37352859). In summary, this variant meets the criteria to be classified a pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0.0): PVS1, PP4_Moderate, PS1_Supporting, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases variant Curation Expert Panel on May 20, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913187388/MONDO:0009290/010 2025-05-20 2025-05-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:480999 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0021141 infores:hetionet CHEBI:5779 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0033774 infores:hetionet CAID:CA10650410 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650410 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*3721A>T variant in the 3' UTR has an MAF of 0.001757 (0.18%, 24/13660 alleles) in the Latino subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 8 Amish individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650410/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63610 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0032285 infores:hetionet CHEBI:4469 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0038990 infores:hetionet NCBIGene:8243 biolink:causes MONDO:0010370 infores:monarchinitiative not_provided not_provided HGNC:11111 MONDO:0010370 uuid:813d7226-6c37-4734-9546-b1d1153a4288 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40237 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0042109 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0027441 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0005741 infores:hetionet CHEBI:167309 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0041834 infores:hetionet CHEBI:7494 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013404 infores:hetionet NCBIGene:126792 biolink:causes MONDO:0010075 infores:monarchinitiative not_provided not_provided HGNC:17978 MONDO:0010075 uuid:8e80f1d3-7237-46ad-9c3d-322d29d40455 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042384 infores:hetionet CHEBI:17987 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0521490 infores:hetionet CHEBI:4975 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0014742 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0234192 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0541799 infores:hetionet CHEBI:6375 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011606 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0243026 infores:hetionet NCBIGene:3593 biolink:causes MONDO:0013954 infores:monarchinitiative not_provided not_provided HGNC:5970 MONDO:0013954 uuid:3f42d9e9-17cb-4d0d-a3af-9114dc0914a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151539 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042769 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0520589 infores:hetionet CHEBI:3508 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0040034 infores:hetionet CHEBI:7573 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0035455 infores:hetionet CHEBI:41774 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030794 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0034634 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0034634 infores:hetionet CHEBI:6076 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0085682 infores:hetionet CHEBI:39585 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0037763 infores:hetionet CHEBI:71417 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0039070 infores:hetionet CHEBI:46195 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0034063 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151735 infores:hetionet CHEBI:10127 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0000737 infores:hetionet CAID:CA454863224 biolink:causes MONDO:0015967 infores:clingen CAID:CA454863224 MONDO:0015967 PMID: Likely Benign BP7, BP4 BS1, PM2 The c.1155G>A variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 385 (p.(Gly385=)) of NM_000162.5. The Grpmax filtering allele frequency of the c.1155G>A variant in gnomAD 4.1.0 is 0.00001064, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This synonymous variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0.00, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.317, which is below the MDEP cutoff of 2.0) (BP4, BP7). In summary, c.1155G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA454863224/MONDO:0015967/086 2025-06-02 2025-06-27 Semidominant inheritance HP:0032113 Contradicts true CHEBI:6775 biolink:causes MONDO:0043479 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0001486 infores:hetionet CHEBI:79699 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0221201 infores:hetionet GO:0070587 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0070587 GO:0009790 CAID:CA206184 biolink:causes MONDO:0010726 infores:clingen CAID:CA206184 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BS1 BP4 The allele frequency of the p.Pro399Ser variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro399Ser variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Pro399Ser variant in MECP2 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA206184/MONDO:0010726/016 2022-12-09 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:85161 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0033036 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0013395 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0855242 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0877014 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0877014 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0178298 infores:hetionet CHEBI:8346 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0017181 infores:hetionet CHEBI:473990 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0023530 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0006849 infores:hetionet CHEBI:8888 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1456784 infores:hetionet CHEBI:77260 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085649 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0001339 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005350 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0162871 infores:hetionet CAID:CA16613238 biolink:causes MONDO:0017623 infores:clingen CAID:CA16613238 MONDO:0017623 PMID:29785012PMID:29706350PMID:29706633 Likely Pathogenic PP2, PP3, PM6_Strong, PS3_Moderate, PM2_Supporting PVS1, BP7, BP5, BS1, BS3, BS4, PP4, PP1, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS2 NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_S: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history in a proband(s) with phenotype specificity score of 1-1.5 (PMID: 24375884).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.648 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM2_P: Absent in large sequenced populations (PMID: 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant = 0.991) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613238/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0145867 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1291078 infores:hetionet CHEBI:31980 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0030554 infores:hetionet NCBIGene:8195 biolink:causes MONDO:0011523 infores:monarchinitiative not_provided not_provided HGNC:7108 MONDO:0011523 uuid:8d629b35-18ea-4fed-a375-6289970335a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0019080 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018418 infores:hetionet CHEBI:3749 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0221264 infores:hetionet CHEBI:72292 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0027497 infores:hetionet CHEBI:6367 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0041657 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0036572 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0857121 infores:hetionet CHEBI:6801 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1565489 infores:hetionet CHEBI:63607 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0001125 infores:hetionet CHEBI:63620 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0700345 infores:hetionet NCBIGene:5396 biolink:causes MONDO:0008740 infores:monarchinitiative not_provided not_provided HGNC:9142 MONDO:0008740 uuid:c7a06753-5eee-4288-8090-2d7de8895a75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4735 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0018681 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027765 infores:hetionet CHEBI:10023 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0852911 infores:hetionet CHEBI:3219 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232461 infores:hetionet CHEBI:2676 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0002878 infores:hetionet CHEBI:8871 biolink:causes HP:0002486 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027125 infores:hetionet CHEBI:17987 biolink:causes UMLS:C1696574 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C1696574 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0403632 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027765 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521495 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017178 infores:hetionet CHEBI:8080 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0338614 infores:hetionet CHEBI:63599 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0013428 infores:hetionet CHEBI:5050 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0015672 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0021843 infores:hetionet CHEBI:50648 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018800 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0021400 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235295 infores:hetionet CHEBI:5130 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014591 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0007642 infores:hetionet CAID:CA135587 biolink:causes MONDO:0019497 infores:clingen CAID:CA135587 MONDO:0019497 PMID:27068579 Benign PP3, BA1 BP7, PP4, PM4, PM5, PM2, PVS1, BP3, BP4, PS4, PS1 The filtering allele frequency of the p.Ala342Val variant in the MYO6 gene is 0.21% for European (non-Finnish) chromosomes by gnomAD (304/129090 with 95% CI), and one homozygous European (Finnish) individual, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). The REVEL computational prediction analysis tool produced a score of 0.905, however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, the HL EP classified this variant as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA135587/MONDO:0019497/005 2019-03-25 2019-07-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA410206792 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206792 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.737C>G (p.Thr246Arg) is a missense variant which has a REVEL score < 0.50 (0.478) and a SpliceAI score ≤ 0.20 (Acceptor Loss 0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206792/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50122 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0015672 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013595 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0024894 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0027709 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0549493 infores:hetionet CHEBI:6916 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0030554 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020651 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0040034 infores:hetionet CHEBI:63619 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0338831 infores:hetionet CHEBI:74947 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0018790 infores:hetionet CHEBI:4708 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0008370 infores:hetionet CAID:CA8365564 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365564 MONDO:0100453 PMID: Likely Pathogenic PP3_Moderate, PM3_Supporting, PS3_Supporting, PP4, PM2_Supporting PM5 NM_000180.4(GUCY2D):c.743C>G (p.Ser248Trp) is a missense variant predicted to replace serine with tryptophan at position p.248 in the RetGC-1 protein. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000001240, with 2 alleles / 1,612,844 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.3224+1G>C variant suspected in trans (0.5 points, PMID: 23035049), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (0.5 total points, PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), decreased central visual acuity (1 pt) with onset in the first year of life (1 pt), nystagmus (1 pt), decreased peripheral vision (1 pt), retinal vessel attenuation with granularity of peripheral fundus (0.5 pts), outer nuclear layer thickness on OCT within normal limits (1 pt), poor pupillary light response (0.5 pts), and undetectable electroretinogram responses from rods (0.5 pts). and cones (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 23035049, PP4). The computational predictor REVEL gives a score of 0.878, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). Gucy2e-knockout mouse retinas injected with an adeno-associated virus-packaged GUCY2D construct encoding the p.Ser248Trp variant showed mRNA levels similar to the wild-type control but dramatically reduced protein levels and essentially no cGMP production, indicating that it triggers a severe defect in protein function (PMID: 27881908, PS3_Supporting). Another missense variant in the same codon (NM_000180.4(GUCY2D):c.743C>T (p.Ser248Leu)) has been reported in association with GUCY2D-related recessive retinopathy (PMID: 26957854). However, the variant has not yet been classified by the LCA/eoRD VCEP, so the PM5 code is not met. In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3_Supporting, PP4, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365564/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5613 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0037036 infores:hetionet NCBITaxon:562 biolink:causes UMLS:C1112209 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D059413 DB00537_MESH_D059413_1DB00303_MESH_D059413_1DB09335_MESH_D059413_1DB00319_MESH_D059413_1DB00218_MESH_D059413_1DB01165_MESH_D059413_1DB01607_MESH_D059413_1DB01330_MESH_D059413_1DB00415_MESH_D059413_1DB09060_MESH_D059413_1DB00685_MESH_D059413_1DB01172_MESH_D059413_1DB00438_MESH_D059413_1DB09050_MESH_D059413_1DB00560_MESH_D059413_1DB01059_MESH_D059413_1 CHEBI:231594 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0019348 infores:hetionet CHEBI:37924 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0231528 infores:hetionet CHEBI:10119 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0086769 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042345 infores:hetionet CHEBI:32139 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0015230 infores:hetionet CHEBI:8461 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0041834 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034880 infores:hetionet CHEBI:46195 biolink:causes MONDO:0001817 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0154946 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0029882 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0262397 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020580 infores:hetionet CHEBI:63632 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0038362 infores:hetionet CHEBI:72690 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C1443060 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0039503 infores:hetionet NCBITaxon:446 biolink:causes MONDO:0005823 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:446 MONDO:0005823 CHEBI:9637 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0040034 infores:hetionet CHEBI:63638 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0036454 infores:hetionet CHEBI:5165 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0392156 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0948349 infores:hetionet CHEBI:28148 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0004093 infores:hetionet CHEBI:4445 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0012833 infores:hetionet CHEBI:9635 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0600142 infores:hetionet CAID:CA2017997770 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997770 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP1, PP4 The c.1331dup variant in the GCK gene causes a frameshift in the protein at codon 445 (NM_000162.5), adding 14 novel amino acids before encountering a stop codon (p.(Ser445GlnfsTer14)). While this variant, located in exon 10/10, is predicted to result in a premature stop codon that is predicted to escape nonsense mediated decay, it is a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a clinical picture consistent with monogenic diabetes; however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributor). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant segregated with disease with one informative meiosis in a family with MODY; however, this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, c.1331dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997770/MONDO:0015967/086 2023-07-30 2023-07-30 Semidominant inheritance HP:0032113 Supports CHEBI:9435 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0003578 infores:hetionet CHEBI:31624 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0232602 infores:hetionet CHEBI:63605 biolink:causes UMLS:C1262106 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1262106 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027339 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0005779 infores:hetionet CHEBI:27974 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0027497 infores:hetionet CHEBI:116278 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0021845 infores:hetionet CHEBI:9757 biolink:causes UMLS:C0235048 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0235048 infores:hetionet GO:0048713 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0048713 GO:0007417 CHEBI:63619 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0541782 infores:hetionet CAID:CA10585149 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585149 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PP1_Moderate, PS3_Supporting, PM2, PVS1, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, BS2, PP2, PP3 The NM_000527.5(LDLR):c.818-2A>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Moderate, PM2, PP4, PS3_Supporting and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is in +2 AG splice site and has been proven to result in retention of 10 nt of intron5, which lead to out of frame consequence: p.Val273Glufs*31, so PVS1 is met.PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - 3 relatives with the phenotype have the variant and 2 relatives without phenotype do not have the variant. PP1_Moderate is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - variant meets PM2. Identified in 3 unrelated index cases who fulfill SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PP4 is metPS3_supporting - Level 3 FS: Medeiros et al., 2010 (PMID 20828696) - Htz patients' lymphocytes, RNA assays - results: Retention of 10 nt of intron5 (p.Val273Glufs*31) --- an aberrant transcript was identified, so PS3_Supporting is metPS4_supporting - variant meets PM2. Identified in 3 unrelated index cases who fulfill SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PS4_Supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585149/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:135613 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0018799 infores:hetionet CAID:CA392260686 biolink:causes MONDO:0012996 infores:clingen CAID:CA392260686 MONDO:0012996 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1, PP4_Moderate The NM_001482.3:c.629G>A (p.Trp210Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4/9, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It is absent in gnomAD v2.1.1. (PM2_Supporting). The variant has been reported in 3 siblings with undetectable guanidinoacetate in urine, and undetectable guanidinoacetate with low creatine in plasma (PMID: 26490222) (PP4_Moderate), all homozygous for the variant (PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Moderate, PM2_Supporting; PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP on January 24, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392260686/MONDO:0012996/025 2023-01-24 2023-01-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010709 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0022660 infores:hetionet CHEBI:71272 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0242339 infores:hetionet CAID:CA414912841 biolink:causes MONDO:0010602 infores:clingen CAID:CA414912841 MONDO:0010602 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3, PP1, PS4_Moderate The c.1468A>G variant in F8 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 490 (p.Arg490Gly). There a My Life Our Future proband with mild hemophilia A associated with this variant, meeting phenotypic criteria for F8 (PP4_Moderate, PMID: 29296726, PMID: 35770352). This proband has at least 2 affected male relatives with mild hemophilia A meeting PP1 (PMID: 29296726). This variant has been reported in 3 additional probands meeting phenotypic criteria for hemophilia A meeting PS4_Moderate (PMIDs: 10404764, 18691168, & internal laboratory data). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1.0 meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.887, which is above the threshold of >=0.6, evidence that correlates with impact to F8 function meeting PP3. In summary, this variant meets the criteria to be classified as likely pathogenic for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): PP4_Moderate, PP1, PS4_Moderate PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414912841/MONDO:0010602/071 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Supports CAID:CA1139771069 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139771069 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BS2 This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PM5_supporting, PVS1 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771069/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3387 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0341742 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0007682 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0241863 infores:hetionet CHEBI:74947 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023518 infores:hetionet CHEBI:8378 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0041657 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0018799 infores:hetionet CAID:CA415077715 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077715 MONDO:0010305 PMID:23644449 Uncertain Significance PS3_Supporting, PP4, PP3, PM2_Supporting The NM_005629.4:c.338G>A variant in SLC6A8 is a missense variant that is predicted to result in the substitution of glycine by aspartate at amino acid 113 (p.Gly113Asp). This variant has been previously reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in undetectable creatine transport activity, with 25uM creatine, when expressed in SLC6A8 deficient fibroblasts (PMID: 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077715/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:2317 biolink:causes MONDO:0007167 infores:monarchinitiative not_provided not_provided HGNC:3755 MONDO:0007167 uuid:708cd4bb-33c4-4753-98b1-87ab9109170b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0027051 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0028259 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C1971624 infores:hetionet CHEBI:100241 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014518 infores:hetionet CHEBI:35778 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C3495920 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0024894 infores:hetionet CHEBI:63580 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0043352 infores:hetionet CHEBI:9086 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0036974 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0022354 infores:hetionet CHEBI:9139 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151744 infores:hetionet CHEBI:28939 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0038450 infores:hetionet CHEBI:92607 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0002962 infores:hetionet CHEBI:135276 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0042075 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0853714 infores:hetionet CHEBI:63610 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0700590 infores:hetionet CHEBI:8212 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0020625 infores:hetionet CHEBI:7601 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0010200 infores:hetionet CHEBI:127780 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020621 infores:hetionet CHEBI:31643 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0000737 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018802 infores:hetionet CAID:CA169895 biolink:causes MONDO:0100488 infores:clingen CAID:CA169895 MONDO:0100488 PMID: Likely Benign BS2 BP5, BS1, BS4, PP3, PP1, BP2, BA1, PS4 The c.1136C>T (p.Thr379Met) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 2 of 152,226 alleles in the gnomAD population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA169895/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:31236 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006145 infores:hetionet CHEBI:9654 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0220870 infores:hetionet CHEBI:9907 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0033774 infores:hetionet CHEBI:47898 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0740394 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0162316 infores:hetionet CHEBI:8069 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0014742 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0009450 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085584 infores:hetionet CHEBI:8772 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0234233 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0851341 infores:hetionet CHEBI:6367 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020578 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0037274 infores:hetionet CHEBI:10023 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151746 infores:hetionet CHEBI:8874 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042420 infores:hetionet CHEBI:50922 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020672 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1142135 infores:hetionet CHEBI:31644 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013404 infores:hetionet CHEBI:17823 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0013378 infores:hetionet CHEBI:37924 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011175 infores:hetionet CHEBI:93635 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0038990 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0009806 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0149931 infores:hetionet UNII:3U02EL437C biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0041834 infores:hetionet GO:0003420 biolink:causes GO:0003417 infores:ubergraph knowledge_assertion manual_agent GO:0003420 GO:0003417 NCBIGene:843 biolink:causes MONDO:0011383 infores:monarchinitiative not_provided not_provided HGNC:1500 MONDO:0011383 uuid:2631df08-9b2e-4850-99b2-4686483e9921 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011334 infores:hetionet CHEBI:94449 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0015967 infores:hetionet CHEBI:50859 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0231528 infores:hetionet CHEBI:50692 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0236075 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0006444 infores:hetionet CHEBI:8768 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151723 infores:hetionet CAID:CA254841 biolink:causes MONDO:0044970 infores:clingen CAID:CA254841 MONDO:0044970 PMID: Uncertain Significance PS3_Moderate, PS4_Moderate PP3, PP1, BA1, BP4, BS1, PM2 The m.4295A>G variant in MT-TI has been reported in at least four families from different ethnic groups with features of primary mitochondrial disease including deafness, hearing loss, and cardiomyopathy (PMIDs: 18177739, 22241583, 33398350, 34991096, 8889580; PS4_moderate). Of note, other isolated phenotypes have been reported including essential hypertension and autism spectrum disorder, but these are outside the scope of this curation (PMIDs: 11406419, 19778529, 19043581). This variant is seen in the general population (<0.5% in three large population databases: Mitomap - 112/61168, gnomAD v3.1.2 - 167/56431, and Helix - 923/195983). Notably, these occurrences are almost exclusively in haplogroup (hg) K (110/112 in specifically K1a in Mitomap; 166/167 in hg K in gnomAD, 911/923 in K in Helix) and these three databases combined reported only 15 individuals from non-K haplogroups (H, I, R, X, J, U, and V). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly benign (0.44) but HmtVAR predicts it to be pathogenic (0.75). Of note, this variant is 100% conserved among 45 species ranging from Drosophila to Homo sapiens in the extraordinarily conserved anticodon loop of tRNA Isoleucine. Cybrid studies showed multiple deleterious biochemical impacts of the variant in a Chinese family from haplogroup D4j (PMID: 33398350). Other studies showed this variant reduces the efficiency with which tRNAIle can be processed by 3′-tRNase (PMID: 18177739). An in-vitro system utilizing plasmids with tRNAIle inserts showed that this variant reduces the tRNase Z reaction 10.3-fold (PMID: 12655007). On the basis of these strong, independent, and consistent functional studies, this Expert Panel elected to give higher weight to this line of evidence (PS3_moderate). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note there was much discussion of the possible differing roles of this variant in haplogroups K1a (protective or tolerated) and D4j (damaging), however the VCEP elected to keep the classification of this variant as uncertain significance (four of 11 experts felt likely benign was the more appropriate classification). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254841/MONDO:0044970/015 2023-12-11 2025-03-12 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:15544 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0035078 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0178298 infores:hetionet CHEBI:9757 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0033975 infores:hetionet GO:0030516 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0048666 CHEBI:39585 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0039070 infores:hetionet CHEBI:3013 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0032617 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0036572 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0220983 infores:hetionet CHEBI:6775 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0025222 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0032961 infores:hetionet CHEBI:3996 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0027497 infores:hetionet NCBIGene:3718 biolink:causes MONDO:0010938 infores:monarchinitiative not_provided not_provided HGNC:6193 MONDO:0010938 uuid:ae5a9102-dbb6-4c87-9d70-7476b355d9f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5002 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:10964 MONDO:0016419 uuid:32e24a58-0b10-4372-a066-b173284a0af1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3U02EL437C biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0014868 infores:hetionet CAID:CA121527 biolink:causes MONDO:0100039 infores:clingen CAID:CA121527 MONDO:0100039 PMID: Uncertain Significance PM6, PS4_Supporting, PM2_Supporting BS3, PM1, PM5, PP3, PS3, PS1 The p.Cys291Tyr variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with severe early-onset encephalopathy (PMID 18809835) (PM6). The p.Cys291Tyr variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Cys291Tyr variant has been observed in at least 1 other individual with CDKL5-related disorder (PMID 18809835, PMID 25657822) (PS4_Supporting). In summary, the p.Cys291Tyr variant in CDKL5 is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM6, PM2_Supporting, PS4_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121527/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:63619 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0015397 infores:hetionet CHEBI:3814 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0232459 infores:hetionet CHEBI:92712 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0080274 infores:hetionet CAID:CA386493436 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493436 MONDO:0009861 PMID: Likely Pathogenic PM2, PM3, PP3, PP4 PM5 This c.1023 G>C (p.Lys341Asn) variant in PAH was seen in a patient with mPKU in trans with the pathogenic variant p.Ala434Asp (PMID: 28982351). This variant was found at a very low frequency in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493436/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:3875 biolink:causes MONDO:0007329 infores:monarchinitiative not_provided not_provided HGNC:6430 MONDO:0007329 uuid:00e3d35a-f436-4e46-aba8-f6b23f958fb5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0178298 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013609 infores:hetionet CHEBI:52010 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0036572 infores:hetionet NCBITaxon:1392 biolink:causes MONDO:0005119 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1392 MONDO:0005119 GO:0060687 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0060687 GO:0061458 CHEBI:8382 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0023380 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0162830 infores:hetionet NCBITaxon:480418 biolink:causes MONDO:0005124 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:480418 MESH:D007918 DB00250_MESH_D007918_2 CHEBI:48131 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0022073 infores:hetionet CHEBI:6775 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0041834 infores:hetionet CHEBI:17650 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0239295 infores:hetionet CHEBI:2549 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0001125 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040409 infores:hetionet CHEBI:8404 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C2830004 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0015469 infores:hetionet CHEBI:5801 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0302809 infores:hetionet CAID:CA409104394 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104394 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS2, PM1_Supporting The c.309G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of methionine to isoleucine at codon 103 (p.Met103Ile)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with a clinical history highly specific for HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and macrosomia in the absence of sufficient maternal hyperglycemia)(PP4_Moderate; PMID:20164212). It was also identified as a de novo occurrence with confirmed parental relationships in this individual with a clinical picture highly specific for HNF4A-MODY (PS2; PMID:20164212). This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.945, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.309G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PS2, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104394/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31705 biolink:causes UMLS:C3241936 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C3241936 infores:hetionet NCBIGene:57731 biolink:causes MONDO:0060496 infores:monarchinitiative not_provided not_provided HGNC:14896 MONDO:0060496 uuid:f8e4b1c9-7c3a-45c7-9aff-e0fc8b1a66ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0410256 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0410256 infores:hetionet GO:0090210 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0090210 GO:0007275 UMLS:C1738934 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0038160 infores:hetionet CHEBI:6539 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0040034 infores:hetionet CHEBI:2904 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0008031 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1443060 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0553704 infores:hetionet CHEBI:10650 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042510 infores:hetionet CHEBI:63791 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2129214 infores:hetionet CHEBI:3286 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C1145670 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0027947 infores:hetionet CHEBI:31859 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C2129214 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0041969 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085637 infores:hetionet CHEBI:3996 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0235660 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0010692 infores:hetionet CHEBI:50841 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0020580 infores:hetionet CHEBI:4495 biolink:causes HP:0001993 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0220982 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042514 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0033975 infores:hetionet CHEBI:9637 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0518015 infores:hetionet CHEBI:46557 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0017168 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0948525 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0853692 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0000731 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0575090 infores:hetionet CHEBI:31949 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0012569 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0687133 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042109 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0302810 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0302810 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009759 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0006145 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0235567 infores:hetionet CHEBI:2675 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0232461 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0235889 infores:hetionet CHEBI:10650 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042023 infores:hetionet CHEBI:29013 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0003811 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0012833 infores:hetionet CHEBI:10125 biolink:causes UMLS:C1868980 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1868980 infores:hetionet CHEBI:31932 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0023530 infores:hetionet CHEBI:7494 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0149745 infores:hetionet CHEBI:35778 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0013404 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0019340 infores:hetionet CHEBI:7986 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0018834 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0878544 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0003123 infores:hetionet CHEBI:7959 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0262988 infores:hetionet CHEBI:63624 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C2129214 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0271412 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0271412 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0007222 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0699893 infores:hetionet NCBIGene:51095 biolink:causes MONDO:0014487 infores:monarchinitiative not_provided not_provided HGNC:17341 MONDO:0014487 uuid:63b620bd-6913-4a8b-bdcb-31173f92169f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0011609 infores:hetionet CHEBI:8597 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0023530 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0920184 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0920184 infores:hetionet CHEBI:17474 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0006826 infores:hetionet NCBIGene:6023 biolink:causes MONDO:0009595 infores:monarchinitiative not_provided not_provided HGNC:10031 MONDO:0009595 uuid:e86fbd95-7f84-473f-a6c0-0128dfb5a79e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0034642 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0877338 infores:hetionet CHEBI:17141 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0023380 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0178298 infores:hetionet CHEBI:30659 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0003811 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0038454 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0518015 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0027765 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0424605 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0475858 infores:hetionet CHEBI:63616 biolink:causes UMLS:C1167745 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C1167745 infores:hetionet CHEBI:35854 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0549249 infores:hetionet NCBIGene:10019 biolink:causes MONDO:0007572 infores:monarchinitiative not_provided not_provided HGNC:29605 MONDO:0007572 uuid:eee8c75a-133d-47c4-8859-dd8739bcbcef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020437 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0030305 infores:hetionet CHEBI:9137 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0025345 infores:hetionet CHEBI:3534 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0037274 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0456909 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0040034 infores:hetionet CAID:CA273416 biolink:causes MONDO:0015280 infores:clingen CAID:CA273416 MONDO:0015280 PMID:20949621PMID:20949621PMID:16474404 Pathogenic PS3, PM1, PM2, PP2, PP3, PM6_Strong The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621). In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM2, PM1, PP3, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA273416/MONDO:0015280/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:9599 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0016059 infores:hetionet CHEBI:45285 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0235416 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234913 infores:hetionet CHEBI:5847 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0009806 infores:hetionet CHEBI:4784 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0036974 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0521839 infores:hetionet CHEBI:3077 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1443060 infores:hetionet NCBIGene:5335 biolink:causes MONDO:0957790 infores:monarchinitiative not_provided not_provided HGNC:9065 MONDO:0957790 uuid:44539086-2af9-42ed-953c-6232658df9cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7986 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0020517 infores:hetionet CHEBI:8356 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020443 infores:hetionet CHEBI:63638 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0702166 infores:hetionet CHEBI:3207 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042023 infores:hetionet CHEBI:29007 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0424295 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0178298 infores:hetionet CHEBI:49375 biolink:causes MONDO:0013577 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0398370 infores:hetionet CHEBI:4562 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C3665386 infores:hetionet CHEBI:63791 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0221245 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019212 infores:hetionet CHEBI:63627 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0031117 infores:hetionet CHEBI:8863 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0232487 infores:hetionet CHEBI:4858 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0004604 infores:hetionet CHEBI:31348 biolink:causes NCIT:C78341 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0522067 infores:hetionet GO:0061168 biolink:causes GO:0098773 infores:ubergraph knowledge_assertion manual_agent GO:0061168 GO:0098773 CHEBI:28364 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0019087 infores:hetionet CHEBI:64198 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C2242996 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0863093 infores:hetionet CAID:CA409103850 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103850 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting, PM1 PP4 The c.146A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of histidine to proline at codon 49 (p.(His49Pro)) of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, therefore, PP4 cannot be applied (PMID: 29927023). Another missense variant at the same residue, c.145C>T (p.His49Tyr), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.His49Pro (PM5_Supporting). In summary, c.146A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PM5_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103850/MONDO:0015967/085 2025-09-17 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10125 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085624 infores:hetionet CHEBI:47519 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0270996 infores:hetionet CAID:CA891844264 biolink:causes MONDO:0008723 infores:clingen CAID:CA891844264 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL):c.809del (p.Pro270GlnfsTer6) variant in ACADVL is a frameshift variant predicted cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Suporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844264/MONDO:0008723/021 2023-09-26 2023-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16469 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018965 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0007787 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0012833 infores:hetionet UMLS:C0011701 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0000731 infores:hetionet CAID:CA175346 biolink:causes MONDO:0021060 infores:clingen CAID:CA175346 MONDO:0021060 PMID: Likely Benign BP7, BP5 The c.111G>A (p.Ser37=) variant in BRAF is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data, GTR ID's: SCV000197179.4, SCV000512270.5). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP7, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA175346/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA10014563 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014563 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.249C>G (p.Ala83=) is a synonymous variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP 0.324528 is <2.0) meeting BP7. This variant is a synonymous variant therefore no REVEL score is applicable and Splice is ≤0.20 (0.00) meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP7 and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014563/MONDO:0011071/008 2022-02-14 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA16620225 biolink:causes MONDO:0007648 infores:clingen CAID:CA16620225 MONDO:0007648 PMID: Uncertain Significance BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.-45C>T variant does not meet any criteria codes. In summary, this variant meets criteria to be classified as a variant of uncertain significance based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): None. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620225/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5855 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151883 infores:hetionet CHEBI:59773 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0015967 infores:hetionet CHEBI:7986 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0040822 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0014868 infores:hetionet CHEBI:52717 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0600228 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042769 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0037023 infores:hetionet CHEBI:63617 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0006277 infores:hetionet CHEBI:32588 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0234215 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0160390 infores:hetionet CHEBI:5004 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0233407 infores:hetionet CHEBI:35553 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0036974 infores:hetionet CHEBI:36791 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1260880 infores:hetionet CHEBI:3181 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0015672 infores:hetionet CHEBI:2682 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235378 infores:hetionet CHEBI:10101 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0232849 infores:hetionet CHEBI:63629 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020473 infores:hetionet CHEBI:5118 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0740394 infores:hetionet CHEBI:3175 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020564 infores:hetionet CHEBI:7852 biolink:causes MONDO:0041052 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0032768 infores:hetionet CHEBI:5118 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011603 infores:hetionet NCBIGene:1282 biolink:causes MONDO:0008289 infores:monarchinitiative not_provided not_provided HGNC:2202 MONDO:0008289 uuid:e68631e8-01f4-4976-80da-fce07652be84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0009676 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151735 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0853149 infores:hetionet NCBIGene:6094 biolink:causes MONDO:0011974 infores:monarchinitiative not_provided not_provided HGNC:10254 MONDO:0011974 uuid:ec2226ed-2109-461e-82f0-c658bf2a5092 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0140136 biolink:causes GO:0050877 infores:ubergraph knowledge_assertion manual_agent GO:0140136 GO:0050877 CHEBI:44032 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0037199 infores:hetionet CHEBI:94440 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0013395 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0267792 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0032285 infores:hetionet CHEBI:5130 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013604 infores:hetionet CHEBI:10650 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0040822 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0149931 infores:hetionet CHEBI:167309 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0015230 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027651 infores:hetionet CHEBI:2682 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232807 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0521839 infores:hetionet CAID:CA512318683 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318683 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.651G>C (p.Gly217=) is a synonymous variant. This is a synonymous variant with no REVEL score available and a SpliceAI score is ≤0.50 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.06724 ≤ 2.0) (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AP criteria applied, as specified for Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318683/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:70735 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0032961 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0020039 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233414 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0027441 infores:hetionet CHEBI:8764 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002792 infores:hetionet CHEBI:64064 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0015403 infores:hetionet CHEBI:7852 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0000729 infores:hetionet CHEBI:182080 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0220870 infores:hetionet CAID:CA10604325 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604325 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting PM5, PM4, PM1, PS1, PS3, BA1, BP1, BP4, BP3, BP7, BS1, BS3, PP2, PP3 The NM_003494.4: c.3504dup p.(Lys1169GlnfsTer6) variant in DYSF, which is also known as NM_001130987.2: c.3558dup p.(Lys1187GlnfsTer6), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 32/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three individuals with LGMD (PMID: 20544924, 21522182; ClinVar SCV003761541.2), including confirmed in trans with a pathogenic variant (c.855+1del, 1.0 pt, PMID: 20544924) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 21522182). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604325/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2904 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0002622 infores:hetionet CHEBI:52717 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019521 infores:hetionet CHEBI:8435 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0003578 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0344232 infores:hetionet CHEBI:6754 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0030232 infores:hetionet CHEBI:32315 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C1443060 infores:hetionet GO:1903224 biolink:causes GO:0007492 infores:ubergraph knowledge_assertion manual_agent GO:1903224 GO:0007492 CHEBI:6073 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0018799 infores:hetionet CHEBI:9667 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0409974 infores:hetionet NCBIGene:23568 biolink:causes MONDO:0014186 infores:monarchinitiative not_provided not_provided HGNC:17146 MONDO:0014186 uuid:143fa525-9859-4543-bd4a-b9901b5034c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28148 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0243026 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0555120 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151605 infores:hetionet CHEBI:7824 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C3665347 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0231528 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014742 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0040435 infores:hetionet CHEBI:2453 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0231218 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1167965 infores:hetionet CHEBI:18248 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0030196 infores:hetionet CHEBI:63581 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0000737 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0002170 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0694547 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0694547 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020649 infores:hetionet CHEBI:2950 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0033774 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0042514 infores:hetionet CHEBI:2567 biolink:causes HP:0033331 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0001349 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0221706 infores:hetionet CAID:CA274414 biolink:causes MONDO:0009290 infores:clingen CAID:CA274414 MONDO:0009290 PMID:12897283 Pathogenic PVS1, PM2, PP4, PM3 This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274414/MONDO:0009290/010 2020-02-14 2020-05-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UMLS:C0120107 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0036572 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1168034 infores:hetionet CHEBI:3347 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0235431 infores:hetionet CHEBI:37924 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0043144 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020649 infores:hetionet CAID:CA170272 biolink:causes MONDO:0010726 infores:clingen CAID:CA170272 MONDO:0010726 PMID: Benign BA1 PM1, BP4 The allele frequency of the p.Pro75Leu variant in MECP2 (NM_004992.3) is 0.038% in the Other sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro75Leu variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170272/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:61390 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0041969 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002886 infores:hetionet NCBIGene:5981 biolink:causes MONDO:0044720 infores:monarchinitiative not_provided not_provided HGNC:9969 MONDO:0044720 uuid:2ff22f29-3461-4830-9289-137f032b804d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:65173 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0040822 infores:hetionet CHEBI:6887 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0857305 infores:hetionet CAID:CA8338130 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338130 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM4, PM1, PM3, PP4_Moderate, PP1_Moderate The c.1500_1502del variant is predicted to cause a change in the length of the protein (p.Leu502del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4). This variant has been detected in six individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, one was assumed compound heterozygous for the variant and a distinct pathogenic variant, p.Val243Ala; parental confirmation was not provided (PM3 points=0.5, PMID: 30194637, ClinVar Variation ID: 21025). Five individuals were homozygous for the variant (PM3 points = 1.0 max, PMIDs: 26385305, 27943070, 24765510, 32793418) (Total PM3 points = 1.5; PM3). At least one patient with this variant displayed VLCAD enzyme activity <= 20% of normal which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMIDs: 30194637, 27943070, 32793418). This variant resides within a region, amino acids 481-516: Membrane binding, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 18227065, 20060901) (PM1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008795 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM1, PM4, PM2_Supporting. (ClinGen ACADVL VCEP specifications version#1.0; approved 12-13-22) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338130/MONDO:0008723/021 2022-12-13 2022-12-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:144551 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0004604 infores:hetionet CHEBI:15940 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0870082 infores:hetionet CHEBI:32139 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0013604 infores:hetionet CHEBI:63616 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0041969 infores:hetionet CHEBI:44185 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0020458 infores:hetionet CHEBI:3696 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0028734 infores:hetionet CHEBI:9637 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0008031 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151889 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027720 infores:hetionet CAID:CA16043285 biolink:causes MONDO:0010315 infores:clingen CAID:CA16043285 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_000206.3(IL2RG):c.43C>T (p.Gln15Ter) nonsense variant occurs in exon 1 of 8 and, therefore, may result in NMD (PVS1). Male (0.5pt) X-SCID patient with T-B+NK+ subset (ALC of 66/mm3 with 3% CD3+, 39% CD19+, and 36% CD56+); Diagnostic criteria for SCID met (very low CD3+ T cells and this variant is Likely Pathogenic without considering PP4) 0.5pt. Total is 1pt; PP4 met (PMID: 18615703). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PP4. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043285/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:5784 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0349506 infores:hetionet CHEBI:5088 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0014457 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235639 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0030193 infores:hetionet CAID:CA000211 biolink:causes MONDO:0017623 infores:clingen CAID:CA000211 MONDO:0017623 PMID:29785012PMID:29706350PMID:29785012PMID:29706350PMID:29945567 Uncertain Significance PP2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 NM_000314.8(PTEN):c.841C>G (p.Pro281Ala) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000211/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39585 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0005758 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0746883 infores:hetionet CHEBI:6887 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C2047937 infores:hetionet CHEBI:209807 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0041969 infores:hetionet CHEBI:68579 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0040460 infores:hetionet CHEBI:478164 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0030554 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0024299 infores:hetionet CHEBI:7565 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0040264 infores:hetionet CHEBI:9332 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0002994 infores:hetionet CHEBI:5100 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0019158 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0042373 infores:hetionet CHEBI:4887 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0232462 infores:hetionet CHEBI:63577 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0043352 infores:hetionet CHEBI:3534 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0027497 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0271308 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0271308 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0178298 infores:hetionet CHEBI:7773 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0242184 infores:hetionet CHEBI:45783 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0008031 infores:hetionet CHEBI:63620 biolink:causes UMLS:C1306600 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1306600 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0009450 infores:hetionet CHEBI:66903 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0002170 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0034150 infores:hetionet GO:0021895 biolink:causes CL:0010012 infores:ubergraph knowledge_assertion manual_agent GO:0021895 CL:0010012 CHEBI:8059 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0497247 infores:hetionet NCBIGene:6708 biolink:causes MONDO:0010053 infores:monarchinitiative not_provided not_provided HGNC:11272 MONDO:0010053 uuid:12c4e0c8-32ea-4da4-bb71-56e2836a23e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135613 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0004093 infores:hetionet CHEBI:94807 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0015230 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0004936 infores:hetionet CAID:CA915946357 biolink:causes MONDO:0100216 infores:clingen CAID:CA915946357 MONDO:0100216 PMID: Likely Pathogenic PP4, PM2_Supporting, PS4_Supporting, PM4, PS3_Supporting PVS1, BP2, BP4, BA1, BS2, PP1, PP3, PM5, PM1, PS2, PS1, BP7, BS1, BS3, BS4 The NM_177438.3:c.5225_5227del variant is predicted to cause a change in the length of the protein (p.Asn1742del) due to an in-frame deletion of one amino acid in a non-repeat region within the RNase IIIb domain (PM4). This variant received a total of 1 phenotype point in a single proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 31067372). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 31067372). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant p.Asn1742del showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; PMID: 31067372). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM4, PS4_Supporting, PP4, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946357/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7447 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0234215 infores:hetionet CHEBI:63791 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0044903 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026987 infores:hetionet CHEBI:5801 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0028084 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0392162 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0152227 infores:hetionet CHEBI:50859 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0438142 infores:hetionet CHEBI:135566 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0151601 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0403632 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0042514 infores:hetionet CHEBI:6402 biolink:causes NCIT:C54056 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0521987 infores:hetionet CHEBI:3387 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0036974 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019112 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0239978 infores:hetionet CHEBI:6030 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0002874 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0026821 infores:hetionet CHEBI:32192 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0025222 infores:hetionet CHEBI:3723 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025222 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0027765 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0857448 infores:hetionet CHEBI:6909 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0237849 infores:hetionet CAID:CA367401686 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401686 MONDO:0015967 PMID: Pathogenic PS1, PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.523G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 175 (p.(Gly175Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs:21978167, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with at least six informative meioses in two families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; PMIDs:21978167). The nucleotide change c.523G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). In summary, c.523G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting, PP2, PP3, PS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401686/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Supports CHEBI:7936 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011849 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0497247 infores:hetionet CHEBI:37941 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0034155 infores:hetionet CHEBI:3723 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0008350 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0853800 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0853800 infores:hetionet CHEBI:8430 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0001122 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0027769 infores:hetionet CHEBI:6797 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0013144 infores:hetionet CAID:CA405687674 biolink:causes MONDO:0100150 infores:clingen CAID:CA405687674 MONDO:0100150 PMID: Likely Pathogenic PP3, PM1, PM2_Supporting, PS4_Moderate The NM_000540.3:c.14551C>G variant in RYR1 is a missense variant predicted to cause substitution of leucine by valine at amino acid 4851 (p. Leu4851Val). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant resides within the pore/transmembrane region, amino acids 4800-4950, of RYR1 that is defined as a critical functional domain by the ClinGen Congenital Myopathies VCEP (PM1). This variant has been reported in 1 proband meeting presence of central cores in muscle biopsy and characteristic muscle imaging. The patient had delayed motor milestones and was seen by a neurologist at ~70yo for progressive proximal muscle weakness and normal CK. The biopsy showed “Dusty central cores” and Type 1 fiber predominance. Muscle MRI imaging is compatible with RYR1-related disease, including sparing of rectus femoris muscle (0.5pts, PS4_Moderate; Internal VCEP contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM1, PM2_Supporting, PP3. (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; September 15th, 2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA405687674/MONDO:0100150/150 2025-09-15 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6717 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0014457 infores:hetionet CHEBI:66876 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0042963 infores:hetionet CHEBI:51041 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0010200 infores:hetionet CHEBI:50858 biolink:causes MONDO:0024651 infores:ubergraph knowledge_assertion manual_agent CHEBI:50858 MONDO:0024651 CHEBI:30830 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0403632 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0014742 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0948089 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0403632 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0040034 infores:hetionet CAID:CA367398737 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398737 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting The c.1147T>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to proline at codon 383 (p. (Ser383Pro)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2) This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.804 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1148C>T (p.Ser383Leu), has been interpreted as pathogenic by the ClinGen MDEP, but has a greater Grantham distance than p.Ser383Pro (PM5_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 36257325, 30663027, internal lab contributors). In summary, c.1147T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PP2, PM5_Supporting, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398737/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CHEBI:144551 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0000731 infores:hetionet CAID:CA130372 biolink:causes MONDO:0044970 infores:clingen CAID:CA130372 MONDO:0044970 PMID: Likely Pathogenic PS3_Moderate, PM2_Supporting, PS4_Moderate PP3, PP1, BP4, PS2, PM6 The m.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy. There was limited testing in family members precluding considering of segregation evidence. There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time. There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65). Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotypes in affected individuals and strong functional evidence showing impaired modification of the tRNA. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA130372/MONDO:0044970/015 2023-06-26 2024-07-24 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8024 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0007859 infores:hetionet CHEBI:110423 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0013395 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0030920 infores:hetionet CAID:CA412369187 biolink:causes MONDO:0100039 infores:clingen CAID:CA412369187 MONDO:0100039 PMID: Pathogenic PS2_Very Strong, PVS1, PM2_Supporting The p.Arg948Ter variant in CDKL5 is absent from gnomAD (PM2_Supporting). The p.Arg948Ter variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with features of CDKL5-associated disorder (PMID 32366967; internal database) (PS2_Very Strong). The p.Arg948Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1). In summary, the p.Arg948Ter variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PM2_Supporting, PS2_Very Strong, PVS1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412369187/MONDO:0100039/016 2022-09-01 2022-09-06 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:9434 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0035078 infores:hetionet CHEBI:48273 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0042023 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0442874 infores:hetionet NCBIGene:4720 biolink:causes MONDO:0032611 infores:monarchinitiative not_provided not_provided HGNC:7708 MONDO:0032611 uuid:cfa4948b-3821-4c1c-aece-049b54070adb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0037274 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0041969 infores:hetionet CHEBI:100241 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0031256 infores:hetionet CHEBI:5130 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020461 infores:hetionet CHEBI:31643 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0003578 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151785 infores:hetionet CHEBI:50131 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020433 infores:hetionet CHEBI:6970 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0271738 infores:hetionet CHEBI:44185 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013378 infores:hetionet CAID:CA320741227 biolink:causes MONDO:0011071 infores:clingen CAID:CA320741227 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.20T>C (p.Phe7Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741227/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63619 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018681 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0009319 infores:hetionet CAID:CA025994 biolink:causes MONDO:0012933 infores:clingen CAID:CA025994 MONDO:0012933 PMID: Pathogenic PVS1, PP4_Strong PM2, BS1, BA1 The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID: 17924331, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025994/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50305 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0178298 infores:hetionet CHEBI:4708 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0004134 infores:hetionet CHEBI:135342 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0037822 infores:hetionet CHEBI:8874 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020580 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0042373 infores:hetionet CHEBI:135351 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0042963 infores:hetionet CHEBI:7478 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0030252 infores:hetionet CHEBI:38562 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0010200 infores:hetionet CHEBI:51364 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0014457 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151849 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0687707 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0038587 infores:hetionet CHEBI:3223 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0917801 infores:hetionet CHEBI:47381 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013428 infores:hetionet CHEBI:63681 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0022107 infores:hetionet CAID:CA228555 biolink:causes MONDO:0015630 infores:clingen CAID:CA228555 MONDO:0015630 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4_Very Strong PP1, PM5 The NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys) missense variant has been reported in a proband displaying excessive mucocutaneous bleeding as well as laboratory phenotypes of low VWF:RCo/VWF:Ag ratio (0.67), abnormal collagen binding assay, and normal high molecular weight multimer pattern, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 28083987). Although the patient's multimer pattern did not lack high-molecular weight forms, it was visibly smeared, similar to those associated with the p.Arg1315Cys and p.Arg1374Cys variants (PMID: 26988807). This variant has been reported in at least 10 additional probands meeting PP4 laboratory phenotype criteria for type 2M VWD (PS4_VS; PMID: 17000885, PMID: 26988807, PMID: 35452508, PMID: 34758185, Internal Laboratory Contributors). The computational predictor REVEL gives a score of 0.712, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Grpmax allele frequency in gnomAD v4.1 is 0.00005281 (8/74886 alleles) in the African/African American population, which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). In summary, the variant meets the criteria to be classified as Pathogenic for von Willebrand disease Type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Very Strong, PP4_Moderate, PP3, and PM2_Supporting. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228555/MONDO:0015630/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8871 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0019079 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033581 infores:hetionet CHEBI:63791 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085631 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0027769 infores:hetionet CHEBI:70746 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C2937358 infores:hetionet CHEBI:3510 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0036572 infores:hetionet CHEBI:6437 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013456 infores:hetionet CHEBI:2682 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0030554 infores:hetionet CHEBI:5855 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0039239 infores:hetionet CHEBI:53691 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0015967 infores:hetionet CHEBI:4877 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0028643 infores:hetionet CHEBI:47499 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0152198 infores:hetionet CHEBI:92712 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0030252 infores:hetionet CHEBI:499361 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0040822 infores:hetionet CHEBI:41977 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0003467 infores:hetionet CHEBI:7496 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0017178 infores:hetionet CHEBI:136040 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0035410 infores:hetionet GO:2000006 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:2000006 GO:0001656 CHEBI:6715 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041969 infores:hetionet CHEBI:31397 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0858635 infores:hetionet CHEBI:9570 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0549567 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0233494 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0948089 infores:hetionet CHEBI:44185 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0344232 infores:hetionet CHEBI:10102 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0024282 infores:hetionet CHEBI:100246 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0040822 infores:hetionet CHEBI:6715 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0428977 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0040046 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0036572 infores:hetionet CHEBI:79699 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0013604 infores:hetionet CHEBI:8764 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C3495920 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0009806 infores:hetionet CHEBI:41879 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0018800 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0027497 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0087169 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0013922 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0027769 infores:hetionet NCBIGene:2050 biolink:causes MONDO:0020785 infores:monarchinitiative not_provided not_provided HGNC:3395 MONDO:0020785 uuid:0787b54e-55bf-4f22-9fd7-ee6c37e67f78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2948 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0024305 infores:hetionet CHEBI:27974 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0042133 infores:hetionet NCBITaxon:11234 biolink:causes MONDO:0009835 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11234 MONDO:0009835 CHEBI:50648 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0423791 infores:hetionet NCBIGene:730 biolink:causes MONDO:0012412 infores:monarchinitiative not_provided not_provided HGNC:1346 MONDO:0012412 uuid:ebf9d2ec-dc3f-40d1-a905-4b16c50c59a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18385 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0085631 infores:hetionet CHEBI:71219 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0033774 infores:hetionet CHEBI:3176 biolink:causes UMLS:C3665818 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C3665818 infores:hetionet CHEBI:3757 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0522055 infores:hetionet CHEBI:63638 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0004095 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009241 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0037199 infores:hetionet CHEBI:2659 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0038220 infores:hetionet CHEBI:8869 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0004096 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C1510410 infores:hetionet CHEBI:110423 biolink:causes MONDO:0006964 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0020503 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0948525 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018991 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0032285 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0038661 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0035309 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042267 infores:hetionet CHEBI:28864 biolink:causes MONDO:0000816 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0524620 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0032961 infores:hetionet CHEBI:61033 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0005778 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0012833 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0029408 infores:hetionet CHEBI:35854 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C2830004 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0233494 infores:hetionet CHEBI:367163 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019521 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0020651 infores:hetionet CHEBI:31348 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0476273 infores:hetionet CHEBI:8107 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020458 infores:hetionet CHEBI:40303 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0028259 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0227791 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0042109 infores:hetionet CHEBI:94609 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0010200 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0234458 infores:hetionet CHEBI:8673 biolink:causes MONDO:0001989 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0155964 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0004238 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0423773 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0852908 infores:hetionet CAID:CA314826 biolink:causes MONDO:0012999 infores:clingen CAID:CA314826 MONDO:0012999 PMID: Likely Pathogenic PP4_Strong, PM2_Supporting, PVS1_Moderate The NM_000156.6:c.1A>G (p.Met1Val) variant in GAMT may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Moderate). This variant is reported in an individual with elevated GAA and low creatine in plasma, elevated guanidinoacetate in urine, and diminished creatine peak on magnetic resonance spectroscopy (GAA not reported) (CreatineInfo, Association for Creatine Deficiencies registry). The variant is also reported in one individual with epilepsy and/or neurodevelopmental delay without reported biochemical evidence of GAMT deficiency (PMID: 29655203; unknown if these cases may be the same individual) (PP4_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 9.588e-7 (1/1042950 alleles; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205591). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Moderate, PM2_Supporting, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314826/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0549567 infores:hetionet CAID:CA344825 biolink:causes MONDO:0044970 infores:clingen CAID:CA344825 MONDO:0044970 PMID: Likely Pathogenic PP1_Moderate, PM2_Supporting, PP3, PS4_Moderate PS2, PS3, PM6 The m.14568C>T (p.G36S) variant in MT-ND6 has been reported in eight individuals from seven families, all of whom had LHON (PS4_moderate; PMIDs: 10447650, 19319978, 12324878, 22879922, 9177303). There are no reports of de novo occurrences to our knowledge. This variant segregated with disease in one family with LHON (affected individuals: proband and brother with heteroplasmy levels ranging from 60-90%; unaffected individuals: mother and maternal aunt with lower heteroplasmy levels; PP1_moderate; PMID: 22879922). There are several occurrences in population databases, however some of these are from reported affected individuals. Although there are several occurrences, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA344825/MONDO:0044970/014 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3215 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0023380 infores:hetionet NCBIGene:5618 biolink:causes MONDO:0014250 infores:monarchinitiative not_provided not_provided HGNC:9446 MONDO:0014250 uuid:225720a4-4f78-4d4e-a5af-262dd8086a23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0030196 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C1443060 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0037195 infores:hetionet CHEBI:46195 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0000731 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0456909 infores:hetionet CHEBI:7627 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0162830 infores:hetionet CAID:CA038513 biolink:causes MONDO:0007750 infores:clingen CAID:CA038513 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PS4, PS3, PM5, PP4 The NM_000527.5 (LDLR):c.2089G>A (p.Ala697Thr) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: PopMax MAF=0.00002196 in South Asian exomes (gnomAD v4.1.0).PP3: REVEL=0.815. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038513/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:82960 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017178 infores:hetionet CHEBI:45716 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0033687 infores:hetionet CHEBI:5132 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0020456 infores:hetionet CHEBI:3048 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0233494 infores:hetionet CHEBI:9123 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C3665386 infores:hetionet CHEBI:63630 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027796 infores:hetionet CHEBI:7822 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0011606 infores:hetionet CHEBI:691037 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0152459 infores:hetionet CHEBI:9130 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151798 infores:hetionet CAID:CA10585373 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585373 MONDO:0007750 PMID: Uncertain Significance PM3, PM2, PP3 PM5 The NM_000527.5(LDLR):c.1244A>T (p.Asp415Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.929. PM3: 1 case reported in PMID 36325061 (Du et al., 2022), China, who was homozygous and presented with an untreated LDL-C ≥13 mmol/L or a treated LDL-C ≥8 mmol/L and either cutaneous or tendon xanthomas before the age of 10 years. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585373/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5778 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0427008 infores:hetionet CAID:CA170355 biolink:causes MONDO:0010726 infores:clingen CAID:CA170355 MONDO:0010726 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting PM1, PP3, PP4 The p.Gln227Glu variant in MECP2 (NM_004992.3) has been reported in an individual with clinical features of MECP2-related conditions (PMID 17383248). The p.Gln227Glu variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Gln227Glu variant is observed in at least 1 unaffected male (internal database - Invitae) (BS2_supporting). In summary, the p.Gln227Glu variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170355/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:51860 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0012833 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1565489 infores:hetionet CHEBI:50648 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0239571 infores:hetionet CHEBI:135530 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0042963 infores:hetionet CHEBI:9123 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0012569 infores:hetionet NCBIGene:7965 biolink:causes MONDO:0054817 infores:monarchinitiative not_provided not_provided HGNC:20609 MONDO:0054817 uuid:be943f5d-1345-4852-ba14-6707f6c06251 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0037195 infores:hetionet CHEBI:64355 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0039240 infores:hetionet GO:0072106 biolink:causes GO:0072080 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0072080 CHEBI:31348 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027339 infores:hetionet CHEBI:63621 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0851578 infores:hetionet NCBIGene:1736 biolink:causes MONDO:0010584 infores:monarchinitiative not_provided not_provided HGNC:2890 MONDO:0010584 uuid:afb6314c-21e4-4118-94ed-0891884a4c54 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013404 infores:hetionet NCBIGene:7225 biolink:causes MONDO:0011390 infores:monarchinitiative not_provided not_provided HGNC:12338 MONDO:0011390 uuid:9b7e9c34-deca-4ed4-8e43-739da547de99 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0015672 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0574067 infores:hetionet CHEBI:3479 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0038826 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0020456 infores:hetionet CHEBI:5001 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0035410 infores:hetionet CAID:CA410203376 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203376 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.342C>G (p.Ile114Met) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203376/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7915 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0031350 infores:hetionet CHEBI:71219 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0025222 infores:hetionet CHEBI:3215 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0085631 infores:hetionet CHEBI:49375 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C3665624 infores:hetionet CHEBI:3764 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0152030 infores:hetionet CAID:CA397723872 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723872 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting, PP4_Moderate The NM_000018.4(ACADVL): c.877C>T variant in ACADVL is a missense variant predicted to cause substitution of histamine by tyrosine at amino acid 293 (p.His293Tyr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been co-detected with a p.Gly441Asp pathogenic variant in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency with unknown phase confirmation (PM3 point 0.5, PM3_Supporting, PMIDs: 25834949). This patient also displayed reduced enzyme levels (< 20 % of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 25834949). The computational predictor REVEL gives a score of 0.494, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723872/MONDO:0008723/021 2023-11-13 2023-11-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9943 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029134 infores:hetionet CHEBI:64354 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0016204 infores:hetionet CAID:CA000586 biolink:causes MONDO:0017623 infores:clingen CAID:CA000586 MONDO:0017623 PMID: Likely Pathogenic PM2, PVS1 PM6, BS4, BS3, BS1, BP7, BP5, PP3, PP2, PP1, BS2, PM5, PM1, PM4, BA1, BP2, BP4, PS4, PS2, PS1, PS3 PTEN 80-1G>C (IVS1-1G>C) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000586/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135876 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0085649 infores:hetionet CAID:CA915940223 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940223 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000419.5(ITGA2B):c.1899del (p.Cys633TrpfsTer17) found in a homozygous proband (PMID:31029159; PM3_supporting) causes a premature stop codon at exon 20 and is predicted to undergo nonsense mediated decay (PVS1). The variant was not found in gnomAD v2.1.1 (PM2_supporting). In conclusion the criteria PSV1, PM2_supporting, and PM3_supporting, were applied to reach a score of pathogenic. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940223/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7915 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0162848 infores:hetionet CHEBI:4356 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0700225 infores:hetionet CHEBI:7956 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0030554 infores:hetionet CHEBI:6759 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0020538 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0031046 infores:hetionet CHEBI:2675 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0026961 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0005741 infores:hetionet CHEBI:9599 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0428977 infores:hetionet CAID:CA10360777 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360777 MONDO:0100039 PMID: Benign BP4, BA1 PM1 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequencing of the c.3059C>A (p.Thr1020Lys) variant in CDKL5 transcript (NM_003159.2) (RS1 c.184+3143G>T) is 0.033% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Additionally, computational analysis prediction tools suggest that the p.Thr1020Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Thr1020Lys variant in CDKL5 (NM_003159.2) is classified as Benign according to ACMG/AMP criteria (BA1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360777/MONDO:0100039/034 2023-02-20 2023-06-19 X-linked inheritance HP:0001417 Contradicts true CHEBI:44185 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0206062 infores:hetionet NCBIGene:6872 biolink:causes MONDO:0010747 infores:monarchinitiative not_provided not_provided HGNC:11535 MONDO:0010747 uuid:56446ea7-c121-418c-81fa-a50df23f9280 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0002237 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007078 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0034359 infores:hetionet CHEBI:8802 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0085593 infores:hetionet CHEBI:63607 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151904 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0015376 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0022408 infores:hetionet CHEBI:5062 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0029261 infores:hetionet CHEBI:6887 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011206 infores:hetionet CHEBI:3048 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0344232 infores:hetionet CHEBI:4466 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0023518 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0426576 infores:hetionet CAID:CA386960844 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960844 MONDO:0015967 PMID: Pathogenic PVS1, PM2_Supporting, PS1_Supporting PP1, PP4 The c.526+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The HNF1A(NM_000545.8):c.526+1G>A and c.526+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>T has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33bp 65%) (PS1_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information.  This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP.  In summary, c.526+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PS1_Supporting, PM2_Supporting.     Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960844/MONDO:0015967/085 2023-12-02 2023-12-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7494 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0687713 infores:hetionet CHEBI:31401 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0008350 infores:hetionet CHEBI:51860 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0030312 infores:hetionet CHEBI:63620 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0080274 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0855331 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0855331 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0015397 infores:hetionet NCBIGene:26229 biolink:causes MONDO:0009511 infores:monarchinitiative not_provided not_provided HGNC:923 MONDO:0009511 uuid:9e89b501-3694-4d35-b6ec-d27f38afd43a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020458 infores:hetionet CHEBI:63621 biolink:causes MONDO:0006536 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0221032 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020649 infores:hetionet CHEBI:31711 biolink:causes UMLS:C1394290 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C1394290 infores:hetionet NCBIGene:9420 biolink:causes MONDO:0013439 infores:monarchinitiative not_provided not_provided HGNC:2652 MONDO:0013439 uuid:86509cd1-e458-460f-95c1-c073fab5fc6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:151254 biolink:causes MONDO:0030721 infores:monarchinitiative not_provided not_provided HGNC:14438 MONDO:0030721 uuid:68b7e9a8-48a2-4b7c-8e78-bd960d4ddd3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0549450 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0549450 infores:hetionet CHEBI:17026 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0033774 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0919671 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0035078 infores:hetionet CHEBI:3441 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0017979 infores:hetionet CHEBI:135451 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0234233 infores:hetionet CHEBI:6367 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0233471 infores:hetionet CHEBI:10101 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0035455 infores:hetionet CHEBI:7476 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014724 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0021775 infores:hetionet CHEBI:4466 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0043352 infores:hetionet CHEBI:3752 biolink:causes MONDO:0017611 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0032019 infores:hetionet CHEBI:34829 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0344232 infores:hetionet CHEBI:3207 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0851578 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0025517 infores:hetionet CAID:CA410204137 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204137 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.145C>T (p.Pro49Ser) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score < 0.50 (0.425) and a SpliceAI score ≤ 0.20 (0.05) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204137/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4325 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0040264 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0234215 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0007860 infores:hetionet CHEBI:4453 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0043094 infores:hetionet CHEBI:3749 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0234894 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0037763 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0518015 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0259768 infores:hetionet CHEBI:2666 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0028084 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0423729 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0423729 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037822 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0032461 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0002453 infores:hetionet CAID:CA2573157358 biolink:causes MONDO:0100083 infores:clingen CAID:CA2573157358 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.46_47del (p.Cys16LeufsTer13) is a frameshift variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). PVS1 was not applied because this variant is not present in all biologically relevant isoforms. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157358/MONDO:0100083/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:861 biolink:causes MONDO:0100083 infores:monarchinitiative not_provided not_provided HGNC:10471 MONDO:0100083 uuid:0bd0a1d7-a36f-4ce2-83e6-d503e294eb17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0085631 infores:hetionet CHEBI:23765 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0019521 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0221161 infores:hetionet CHEBI:7823 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0015967 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0034150 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0004592 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D007169 DB00410_MESH_D007169_1DB01112_MESH_D007169_1 CAID:CA410204316 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204316 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.101C>G (p.Ala34Gly) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. This missense variant has a REVEL score <0.5 (0.407)(BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204316/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16899 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0027441 infores:hetionet CHEBI:8802 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0151636 infores:hetionet CHEBI:73275 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0553692 infores:hetionet CHEBI:50223 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0010200 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0041969 infores:hetionet CHEBI:3996 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0039231 infores:hetionet CHEBI:52010 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0344232 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0149745 infores:hetionet CAID:CA410148443 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148443 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1039A>G (p.Met347Val) is a missense variant which has a REVEL score < 0.50 (0.332) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148443/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47780 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042029 infores:hetionet CAID:CA396451240 biolink:causes MONDO:0007648 infores:clingen CAID:CA396451240 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM6, BS2, PP4, PP1, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS3, PS2, PS4, PS1 The c.11G>A (p.Trp4Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451240/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:52717 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0243065 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0043352 infores:hetionet CHEBI:8404 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0278134 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0038663 infores:hetionet CHEBI:6367 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0016204 infores:hetionet CHEBI:7445 biolink:causes MONDO:0006373 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0032000 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0235431 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853336 infores:hetionet CHEBI:53760 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002792 infores:hetionet CHEBI:63611 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0013604 infores:hetionet NCBIGene:975 biolink:causes MONDO:0013286 infores:monarchinitiative not_provided not_provided HGNC:1701 MONDO:0013286 uuid:f5e8130c-bcb7-4d36-ad86-8f50acd961a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0009450 infores:hetionet NCBIGene:5961 biolink:causes MONDO:0008210 infores:monarchinitiative not_provided not_provided HGNC:9942 MONDO:0008210 uuid:7a633b70-d0c5-4e85-9315-008b24c2e526 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0030193 infores:hetionet CHEBI:45783 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0376358 infores:hetionet UMLS:C0657912 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0520887 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0025517 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0011615 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021204 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0271441 infores:hetionet CHEBI:5801 biolink:causes MONDO:0003004 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0024437 infores:hetionet CHEBI:6847 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0023530 infores:hetionet CAID:CA10385260 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385260 MONDO:0100437 PMID: Benign BA1, BP3 NM_001034853.2(RPGR):c.2606_2620del (p.Glu869_Glu873del) is a short in-frame deletion of 15 nucleotides that encode amino acids 869–873 within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v4.1.0 at a frequency of 0.007397 among hemizygous individuals, with 1,400 variant alleles / 189,256 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385260/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:7627 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C3665346 infores:hetionet CHEBI:3699 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0014742 infores:hetionet CAID:CA409106746 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106746 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting The c.589C>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to methionine at codon 197 (p.(Leu197Met)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9029, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.589C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106746/MONDO:0015967/085 2023-12-25 2023-12-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41423 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042267 infores:hetionet CHEBI:45409 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011168 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0009450 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0162830 infores:hetionet CHEBI:9654 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0221170 infores:hetionet CHEBI:72564 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C3665386 infores:hetionet CHEBI:421707 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0013604 infores:hetionet CHEBI:32315 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C3263723 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0854303 infores:hetionet CHEBI:3994 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0008489 infores:hetionet CHEBI:29007 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0036572 infores:hetionet CAID:CA10584584 biolink:causes MONDO:0018875 infores:clingen CAID:CA10584584 MONDO:0018875 PMID: Likely Benign BP4, BS3, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, BS2, PP3, PP1, PP4 The NM_000546.5:c.1136G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 379 (p.Arg379His). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has a BayesDel score ≤ -0.008 and Align GVGD (Zebrafish) is Class C0 (BP4_moderate). This variant has an allele frequency of 0.00002671 (2/74876 alleles) in the African/African American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_supporting, BP4_moderate, BS3. (Bayesian Points: -5; VCEP specifications version 2.0, Date of Approval: 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584584/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:5965 biolink:causes MONDO:0957266 infores:monarchinitiative not_provided not_provided HGNC:9948 MONDO:0957266 uuid:01cc4887-8b55-4724-ae7f-54ca5f5a3936 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10112 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0851578 infores:hetionet GO:1902442 biolink:causes GO:0070266 infores:ubergraph knowledge_assertion manual_agent GO:1902442 GO:0070266 CHEBI:8888 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0028084 infores:hetionet CHEBI:161680 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0858635 infores:hetionet CHEBI:3219 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020580 infores:hetionet CAID:CA265898357 biolink:causes MONDO:0100216 infores:clingen CAID:CA265898357 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, BA1, BS2, PM1, PM5, PS4, BS1 The NM_177438.3:c.4357A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1453 (p.Ile1453Val). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001550 (25/1613406 alleles) with a highest population minor allele frequency of 0.0001337 (6/44888 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.316; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA265898357/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63115 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0024299 infores:hetionet CHEBI:7444 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0006266 infores:hetionet CAID:CA349036828 biolink:causes MONDO:0100038 infores:clingen CAID:CA349036828 MONDO:0100038 PMID: Likely Pathogenic PP3_Moderate, PS2_Moderate, PM2, PM6 The c.4780T>A variant in SCN2A is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 1594 (p.Trp1594Arg). The variant has been identified in multiple individuals meeting criteria for complex neurodevelopmental disorder (PM6)(PMID: 34004075, 28256214, 28135719, internal lab contributors). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. Additionally, two other missense variants in the same codon c.4782G>C, p.Trp1594Cys and c.4782G>T, p.Trp1594Cys also reach likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; November 26, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349036828/MONDO:0100038/068 2024-11-26 2025-02-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52172 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020621 infores:hetionet CHEBI:75922 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0152227 infores:hetionet CHEBI:63618 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0231218 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0151491 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151491 infores:hetionet CHEBI:8772 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0231528 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042571 infores:hetionet CHEBI:16914 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0013395 infores:hetionet CHEBI:109549 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0231528 infores:hetionet CHEBI:47657 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0018681 infores:hetionet CHEBI:8597 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0003811 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042373 infores:hetionet CHEBI:9725 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0150450 infores:hetionet CHEBI:41879 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0392163 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0032326 infores:hetionet CHEBI:36791 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233763 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0518015 infores:hetionet CHEBI:4974 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0022346 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0858259 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0003123 infores:hetionet CAID:CA385227782 biolink:causes MONDO:0100038 infores:clingen CAID:CA385227782 MONDO:0100038 PMID: Likely Pathogenic PM1, PS2_Moderate, PM2_Supporting, PS4_Supporting, PP3_Moderate, PM6_Supporting PM5 The c.1201T>C variant in SCN8A is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 401 (p.Tyr401His). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with Complex Neurodevelopmental Disorder (PM6_supporting; PMID 30171078) and identified as a de novo with confirmed parental relationships in 1 individual with Complex Neurodevelopmental Disorder (PS2_moderate; internal case at Labcorp (formerly Invitae)). This variant has been reported in 1 additional case with Complex Neurodevelopmental Disorder (PS4_supporting; internal case at Ambry). This variant is absent from gnomAD v4.1.0 (PM2_supporting) and resides within a region of SCN8A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). The computational predictor REVEL gives a score of 0.971, which is above the threshold of 0.773, evidence that correlates with impact to SCN8A function (PP3_moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM1, PM6_supporting, PS2_moderate, PS4_supporting, PP3_moderate, PM2_supporting. (Version 2.0.0; approved 9/23/2025). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA385227782/MONDO:0100038/070 2025-09-23 2025-10-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5296 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0030305 infores:hetionet CHEBI:63612 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0438717 infores:hetionet CHEBI:17026 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0029927 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0476281 infores:hetionet CHEBI:50131 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0014591 infores:hetionet CHEBI:66913 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0009763 infores:hetionet UMLS:C0145185 biolink:causes EFO:0020915 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0269842 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0034063 infores:hetionet CHEBI:2675 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0022346 infores:hetionet CHEBI:27666 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0151686 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013395 infores:hetionet UMLS:C0004609 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0036974 infores:hetionet CHEBI:46295 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0035328 infores:hetionet CHEBI:72297 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0002962 infores:hetionet CAID:CA415173087 biolink:causes MONDO:0010726 infores:clingen CAID:CA415173087 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, BS1 The highest population minor allele frequency of the p.Ala202Gly variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00004246 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ala202Gly variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ala202Gly variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). In summary, the p.Ala202Gly variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). (MECP2 Specifications v.4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415173087/MONDO:0010726/036 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Contradicts true CAID:CA135122 biolink:causes MONDO:0021060 infores:clingen CAID:CA135122 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2235A>G (p.Leu745=) variant in the BRAF gene is 1.11% (113/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135122/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8665 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0037763 infores:hetionet CAID:CA902539 biolink:causes MONDO:0100368 infores:clingen CAID:CA902539 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000329.3(RPE65):c.353+7G>A is a non-coding variant in intron 4 near the junction with exon 4. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001415, with 6 alleles / 18394 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The splicing impact predictor SpliceAI gives a score of 0.14 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended PP3 threshold of ≥0.2 and higher than the BP4 threshold of <0.1 and does not strongly predict an impact on splicing, so neither in silico predictor code is met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902539/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28148 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0002792 infores:hetionet CHEBI:9907 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013491 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0037274 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004245 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0413252 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0549493 infores:hetionet CHEBI:36791 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037287 infores:hetionet CHEBI:164200 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08604 UMLS:C0020517 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011616 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0855223 infores:hetionet CHEBI:10100 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0002994 infores:hetionet CHEBI:168396 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019079 infores:hetionet CHEBI:63607 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0003578 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0020517 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0677500 infores:hetionet CHEBI:64317 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0020649 infores:hetionet CAID:CA414892027 biolink:causes MONDO:0010602 infores:clingen CAID:CA414892027 MONDO:0010602 PMID: Uncertain Significance PM2_Supporting, BP4 PS4 The c.4148C>G (p.Ala1383Gly) variant is completely absent in gnomAD v2.1.1, v3, and v4 (PM2_Supporting). It has a REVEL score of 0.299 (<0.3) and meets criteria for BP4. This variant is not reported in patients with hemophilia A in the literature, to the best of our knowledge. A female individual with this variant from internal laboratory data is reported, but does not meet F8-phenotype criteria. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PM2_Supporting, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414892027/MONDO:0010602/071 2024-09-30 2024-10-01 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:79644 biolink:causes MONDO:0012991 infores:monarchinitiative not_provided not_provided HGNC:25812 MONDO:0012991 uuid:a35db51b-f70e-43b3-a3e7-513bf091d388 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0152517 infores:hetionet CHEBI:9130 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0085611 infores:hetionet CHEBI:49668 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0006384 infores:hetionet NCBIGene:9897 biolink:causes MONDO:0011339 infores:monarchinitiative not_provided not_provided HGNC:28984 MONDO:0011339 uuid:61b59a52-cc7a-41ba-8ea5-33b0889ac890 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0040034 infores:hetionet CHEBI:6129 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1167965 infores:hetionet CAID:CA340944 biolink:causes MONDO:0044970 infores:clingen CAID:CA340944 MONDO:0044970 PMID: Uncertain Significance PP3, BA1, PS4, PS3_Supporting PP1, PS2, PM6 "The m.3394T>C (p.Y30H) variant in MT-ND1 has been reported in 157 individuals with phenotypes consistent with primary mitochondrial disease, including Leber Hereditary Optic Neuropathy (LHON) and diabetes. This variant was present in 2.1% of 1,741 individuals in one cohort of LHON, and is thought to increase penetrance and occurrence of optic neuropathy in families when present with the well-known pathogenic variant, m.11778G>A (PMID: 30597069). The m.3394T>C variant is widely considered a secondary ""helper"" variant, not a variant associated with primary mitochondrial disease. However, of the 157 cases reported to date, the m.3394T>C variant has been reported without an accompanying primary mitochondrial disease-associated variant in 31 LHON families, two individuals with diabetes, and one individual with hypertrophic cardiomyopathy (PS4). Although outside the scope of this curation, this variant also been shown to be adaptive for high-altitude Tibetans where multiple independent origins of m.3394T>C have been documented (PMID: 22517755). The variant is present in 100% in Tibetan-associated haplogroups M9a (349/349) and M9b (4/4) in MITOMAP. In a study of type 2 diabetes mellitus in Han Chinese, this variant was found with significantly higher frequency in affected individuals (23.6%) than in the controls (2.0%; PMID: 18679013). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.76 (Min=0, Max=1; APOGEE2 score is 0.582), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that this variant can either be deleterious or beneficial depending on haplogroup and environmental context. The variant reduces both complex I activity and NADH-linked respiration especially when on non-M9 haplogroups. In Asia, this variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, this variant is enriched on the M9 background in Tibet. When present on the M9 background, this variant is associated with a complex I activity that is equal to or higher than that of the wild type sequence on other haplotype backgrounds (B4c and F1; PMID: 22517755). In a cybrid study of East Asian metabolic syndrome (PMID: 29997041), complex I activity of the cells with this variant had lower complex I activity than cells with the wild type sequence, and that these lower complex I levels correlated with increased risk for metabolic phenotypes. Addition of this variant further reduced the complex I activity on cybrids of B4c, F1, and M9 haplogroup backgrounds (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3, PS3_supporting, PS4." Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340944/MONDO:0044970/015 2023-09-11 2025-03-12 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8890 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235030 infores:hetionet CHEBI:27666 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0002874 infores:hetionet CHEBI:3347 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0011991 infores:hetionet NCBIGene:2176 biolink:causes MONDO:0009213 infores:monarchinitiative not_provided not_provided HGNC:3584 MONDO:0009213 uuid:647a7ea9-e593-4764-b927-d9a3ed7dc63c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0024440 infores:hetionet CHEBI:5778 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002994 infores:hetionet NCBIGene:65125 biolink:causes MONDO:0024309 infores:monarchinitiative not_provided not_provided HGNC:14540 MONDO:0024309 uuid:00d01156-a327-4981-93b0-9dca2804ee9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:83879 biolink:causes MONDO:0014828 infores:monarchinitiative not_provided not_provided HGNC:14628 MONDO:0014828 uuid:2c58de54-baf6-4445-80dd-2d13003ba6ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2695231613 biolink:causes MONDO:0010725 infores:clingen CAID:CA2695231613 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4 The NM_000330.4(RS1):c.26del variant is a frameshift variant due to the deletion of 1 nucleotide introducing a premature stop codon after 117 amino acids and causing a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family (PP1_Strong; PMID: 17615541). At least one proband harboring this variant exhibits a phenotype including appearance of retinoschisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 17615541, PP4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PM2_supporting, PP4, and PP1_strong (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695231613/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:17688 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0021400 infores:hetionet CHEBI:5790 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0231528 infores:hetionet CHEBI:144551 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0041657 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0853074 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0853074 infores:hetionet CHEBI:63620 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0015732 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0853149 infores:hetionet CAID:CA399794416 biolink:causes MONDO:0100326 infores:clingen CAID:CA399794416 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PM5, PP4 The NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg) missense variant is predicted deleterious with a REVEL score of 0.741 (PP3). The highest population minor allele frequency in gnomAD v4.0 is 0.000007875 (6/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). It reported in one patient stated to have a disease of platelet function (PMID: 31064749) but information was insufficient or inconsistent to apply any evidence for this patient. Cys857Arg occurs at the same amino acid residue as Cys857Phe which is also classified by the PD-VCEP as VUS. In summary, based on the evidence available at this time, the variant is classified as uncertain significance. GT-specific criteria applied: PM2_supporting and PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399794416/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6775 biolink:causes UMLS:C1112626 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1112626 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0020517 infores:hetionet CHEBI:29688 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0086565 infores:hetionet CAID:CA386963431 biolink:causes MONDO:0015967 infores:clingen CAID:CA386963431 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3 PM1, PM5 The c.528G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to histidine at codon 176 (p.(Gln176His)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.718, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributor). Another missense variant, c.527A>C p.Gln176Pro, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.528G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386963431/MONDO:0015967/017 2025-04-23 2025-04-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10650 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0311394 infores:hetionet CAID:CA8315005 biolink:causes MONDO:0009276 infores:clingen CAID:CA8315005 MONDO:0009276 PMID: Pathogenic PM2, PP4, PM3_Strong, PVS1_Strong PP1 The c.1480del (p.Thr494ProfsTer59) variant in GP1BA is a frameshift variant in exon 2 of 2, that may cause loss of function of the protein; it is predicted to escape nonsense mediated decay and remove 15% of the protein (PVS1_Strong). At least four Bernard-Soulier syndrome patients have been reported with this variant (PM3_Strong); two are homozygous (PMIDs: 9628437, 8772211; 1pt) and two are compound heterozygous with Glu347Ter and c.1454dup variants respectively (PMID: 23414566, 9241731). Case I, of PMID: 23414566, had no aggregation response to ristocetin and decreased thrombin-induced aggregation but normal aggregation with ADP and collagen, additionally GPIbα expression was completely absent on patient platelets, which is highly specific to Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with BSS. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00004345 (5/44886 alleles) in the East Asian population and is below the <0.0001114 threshold for PM2_Supporting. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM3_Strong, PVS1_Strong, PM2_Supporting (ClinGen Platelet Disorders VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8315005/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6129 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151746 infores:hetionet CHEBI:63629 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0001127 infores:hetionet CHEBI:28925 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0009450 infores:hetionet CHEBI:75988 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0002170 infores:hetionet CHEBI:15544 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0039070 infores:hetionet CHEBI:28748 biolink:causes NCIT:C112180 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0239343 infores:hetionet NCBIGene:4763 biolink:causes MONDO:0008078 infores:monarchinitiative not_provided not_provided HGNC:7765 MONDO:0008078 uuid:956c86bb-56d4-4a6d-8c9c-685751d96fc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0428977 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0151828 infores:hetionet CHEBI:31932 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C1318520 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0344232 infores:hetionet CHEBI:231594 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0156404 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0036508 infores:hetionet CHEBI:50885 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0014868 infores:hetionet UMLS:C1738934 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0740394 infores:hetionet CHEBI:68642 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0017178 infores:hetionet CHEBI:16469 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0011124 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0026857 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0027765 infores:hetionet GO:0072257 biolink:causes CL:1000123 infores:ubergraph knowledge_assertion manual_agent GO:0072257 CL:1000123 CHEBI:74947 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0033860 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0919980 infores:hetionet NCBIGene:1384 biolink:causes MONDO:0054764 infores:monarchinitiative not_provided not_provided HGNC:2342 MONDO:0054764 uuid:2d12983b-67de-47be-b561-43d949d83c95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853034 infores:hetionet CHEBI:75984 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0030193 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0740399 infores:hetionet CHEBI:135920 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0002994 infores:hetionet CHEBI:92511 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0040034 infores:hetionet CHEBI:6931 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235195 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0012813 infores:hetionet CHEBI:2569 biolink:causes UMLS:C0919569 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0919569 infores:hetionet CHEBI:65173 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0043352 infores:hetionet CHEBI:35677 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0006266 infores:hetionet CAID:CA2499225756 biolink:causes MONDO:0015967 infores:clingen CAID:CA2499225756 MONDO:0015967 PMID: Pathogenic PS3_Supporting, PP4, PM2_Supporting, PM1, PS4, PP1_Strong The c.-181G>A variant in the HNF4 homeobox A gene, HNF4A, is a single nucleotide variant within the P2 promotor region of NM_175914.5. A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the protein has transactivation activity below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 32910913; PMID: 12235114; PMID: 38855865). This variant was identified in nine unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 12235114, 38855865; internal lab contributors). This variant is located within the HNF1A binding site of the HNF4A promoter, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant segregated with diabetes, with at least 10 informative meioses in five families (PP1_Strong; PMID: 12235114, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors) In summary, c.-181G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 4.0.0, approved 10/10/2025): PS3_Supporting, PS4, PM1, PM2_Supporting, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225756/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:465284 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1384353 infores:hetionet NCBIGene:55806 biolink:causes MONDO:0008847 infores:monarchinitiative not_provided not_provided HGNC:5172 MONDO:0008847 uuid:f776c868-6979-42ca-9381-d29e12f10d24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63581 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0022650 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0011860 infores:hetionet CHEBI:3752 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0033774 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0043251 infores:hetionet CHEBI:6888 biolink:causes HP:0000963 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0423757 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0002874 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005181 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0162292 infores:hetionet CHEBI:27974 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0025323 infores:hetionet CHEBI:3568 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0008031 infores:hetionet CHEBI:7447 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0151596 infores:hetionet CHEBI:45716 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0017181 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042373 infores:hetionet CHEBI:4315 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0040034 infores:hetionet CHEBI:8499 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0041834 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0522224 infores:hetionet CHEBI:9599 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0547030 infores:hetionet CHEBI:42797 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C2979982 infores:hetionet CHEBI:4551 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0085632 infores:hetionet CAID:CA316750 biolink:causes MONDO:0044970 infores:clingen CAID:CA316750 MONDO:0044970 PMID: Uncertain Significance PM2, BP5 BP4 The c.3293 G>C (p.Ser1098Thr) variant in POLG is observed at an allele frequency of 0.003% in gnomAD (PM2). There is no prediction tool evidence available. This variant was found in a proband of Chinese ancestry with congenital cataracts who harbored a pathogenic variant in the PITX3 gene (BP5; PMID 30894134). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, BP5. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA316750/MONDO:0044970/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA000251 biolink:causes MONDO:0018875 infores:clingen CAID:CA000251 MONDO:0018875 PMID: Pathogenic PS4_Moderate, PS3, PM1, PP1_Moderate, PP3, PM2_Supporting BA1, BP4, PS1, PM5, BS1, BS3, BS4, PP4, BS2 The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000251/MONDO:0018875/009 2024-09-06 2024-09-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7565 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0542571 infores:hetionet CHEBI:15940 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0877359 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0235639 infores:hetionet CHEBI:15544 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0004093 infores:hetionet CAID:CA10652049 biolink:causes MONDO:0011229 infores:clingen CAID:CA10652049 MONDO:0011229 PMID: Benign BS2, BA1 PM5, PM3, PP3, PP1, PP4, BP4, BP2, PS1, PS3, PS4, BP5, BS3, BS4 The filtering allele frequency of the c.55G>T variant in the ETHE1 gene is >0.7% by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Mito Variant Curation Expert Panel (BA1) Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652049/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:71417 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0349506 infores:hetionet CHEBI:72564 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0004093 infores:hetionet CHEBI:27300 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0948525 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0259749 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860871 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0541879 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0541879 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0349506 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0403645 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0403645 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0042571 infores:hetionet CHEBI:37333 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C2939147 infores:hetionet CHEBI:2549 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0023218 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0030193 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0029408 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0543698 infores:hetionet GO:1903056 biolink:causes GO:0033059 infores:ubergraph knowledge_assertion manual_agent GO:1903056 GO:0033059 CAID:CA315408883 biolink:causes MONDO:0015967 infores:clingen CAID:CA315408883 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting PP3, PP1, PM1, BP4, PS4 The c.461T>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of isoleucine to serine at codon 154 (p.(Ile154Ser)) of NM_175914.4. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 31291970, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; PMID: 31291970, internal lab contributors). This variant segregated with diabetes with a single informative meioses in one family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant has a REVEL score of 0.667, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.461T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA315408883/MONDO:0015967/085 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4798 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0041105 infores:hetionet CHEBI:28939 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0031350 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0025061 infores:hetionet CHEBI:4681 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0085620 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0233488 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233488 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0232431 infores:hetionet CHEBI:63630 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011124 infores:hetionet CHEBI:94392 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0085593 infores:hetionet CHEBI:8871 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0750876 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0234215 infores:hetionet CHEBI:10101 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0003467 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035357 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004936 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0002871 infores:hetionet CHEBI:49575 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0234518 infores:hetionet CHEBI:50659 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0162830 infores:hetionet GO:0043854 biolink:causes GO:0030551 infores:ubergraph knowledge_assertion manual_agent GO:0043854 GO:0030551 CHEBI:94501 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0149931 infores:hetionet CHEBI:3207 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0027497 infores:hetionet CAID:CA367401376 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401376 MONDO:0015967 PMID: Pathogenic PS4, PM5, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). Another missense variant, c.605T>C p.Met202Thr has been interpreted as pathogenic by the ClinGen MDEP, and p.Met202Arg has an equal or greater Grantham distance (PM5). In summary, c.605T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PS4, PP4_Moderate, PP1_Moderate, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401376/MONDO:0015967/086 2024-04-19 2024-04-19 Semidominant inheritance HP:0032113 Supports CHEBI:32293 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0042345 infores:hetionet CHEBI:28971 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C1368065 infores:hetionet CHEBI:5280 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151908 infores:hetionet CHEBI:5383 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0042963 infores:hetionet NCBIGene:29980 biolink:causes MONDO:0060533 infores:monarchinitiative not_provided not_provided HGNC:2993 MONDO:0060533 uuid:2fd26738-e110-4564-bc9a-e034752d2263 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0021141 infores:hetionet CHEBI:4975 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0008031 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0235146 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0520559 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0162429 infores:hetionet CHEBI:4953 biolink:causes MONDO:0004701 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0156369 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0232459 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0302295 infores:hetionet CHEBI:2904 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0857305 infores:hetionet CHEBI:4911 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0011603 infores:hetionet CHEBI:4511 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0948594 infores:hetionet NCBIGene:116150 biolink:causes MONDO:0030921 infores:monarchinitiative not_provided not_provided HGNC:21042 MONDO:0030921 uuid:c6dbc3b0-a9e5-456d-a4d2-ee5835d28fcf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes UMLS:C0234373 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0234373 infores:hetionet CHEBI:8805 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0004604 infores:hetionet CHEBI:10101 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0700590 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020538 infores:hetionet CHEBI:71255 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0004093 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0162429 infores:hetionet CAID:CA414434363 biolink:causes MONDO:0010604 infores:clingen CAID:CA414434363 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3 The c.59T>C; p.Leu20Ser variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. The missense variant has a REVEL score of 0.636 (>0.6) meeting PP3. At least 5 patients with moderate-severe hemophilia B are reported in the literature (PMID: 32875744, 25251685, 27109384, 15921378, and 10874302), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414434363/MONDO:0010604/080 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Supports CHEBI:37924 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0025061 infores:hetionet CHEBI:3387 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0008031 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0022081 infores:hetionet CHEBI:42820 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0242528 infores:hetionet CHEBI:27565 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0002878 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017601 infores:hetionet CHEBI:9586 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0034186 infores:hetionet CHEBI:135566 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0314719 infores:hetionet CAID:CA031460 biolink:causes MONDO:0007750 infores:clingen CAID:CA031460 MONDO:0007750 PMID: Benign BA1, BP2, BP4, BS2 BP1, BP3, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PM2, PM6, PVS1, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1060+10G>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1).BS2 - observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University).BP2 - Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L).BP4 - no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031460/MONDO:0007750/013 2021-06-23 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:39867 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0040264 infores:hetionet CHEBI:7447 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0027707 infores:hetionet CHEBI:3699 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0016204 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1527358 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0015397 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030312 infores:hetionet UNII:F64QU97QCR biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0547030 infores:hetionet CHEBI:135935 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0746961 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C2973529 infores:hetionet CHEBI:51164 biolink:causes UMLS:C0877090 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0877090 infores:hetionet CAID:CA294887189 biolink:causes MONDO:0009290 infores:clingen CAID:CA294887189 MONDO:0009290 PMID:17056254PMID:25681614PMID:19588081 Pathogenic PM2, PVS1, PP4, PM3 This variant, c.377G>A (p.Trp126Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Five individuals with Pompe disease and residual GAA activity meeting PP4 specifications have been reported with this variant (PMIDs 17056254, 25681614). One of these individuals is compound heterozygous for the variant and c.236_246del (p.Pro79ArgfsX13); as the mother is heterozygous for the variant, it is likely that the variants are in trans (PMID 17056254). Another individual is the proband in a family of three siblings with late onset Pompe disease who are all compound heterozygous for the variant and c.-32-13T>G. In addition, two Brazilian siblings are compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) but this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Finally, an individual with infantile onset Pompe disease appeared to be homozygous for the variant (PMID 17056254). While the mother was heterozygous, the father was neither confirmed to be a carrier, nor appeared to have a deletion. Non-paternity was not ruled out. This data will not be included because the nature of the second variant is unclear. This in trans data meets PM3. An additional case has been reported but was not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 19588081). The variant is absent in gnomAD v2.1.1, meeting PM2. There is no ClinVar entry for this variant. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG-AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294887189/MONDO:0009290/010 2020-04-20 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3504 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0039070 infores:hetionet CHEBI:7577 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0004134 infores:hetionet CHEBI:38940 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0687713 infores:hetionet NCBIGene:1909 biolink:causes MONDO:0014608 infores:monarchinitiative not_provided not_provided HGNC:3179 MONDO:0014608 uuid:93685df3-4f19-4733-83eb-6e466c4008ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8060 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0030554 infores:hetionet CHEBI:63619 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011603 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0040046 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0002878 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0021400 infores:hetionet CHEBI:47657 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0011603 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0040409 infores:hetionet CHEBI:50648 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013144 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038587 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0022650 infores:hetionet CAID:CA390885499 biolink:causes MONDO:0100216 infores:clingen CAID:CA390885499 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, BA1, BS2, PM1, PM5, PS4, BS1 The NM_177438.3:c.1472A>G variant in DICER1 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 491 (p.Asn491Ser). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000001 (2/1614122 alleles) across gnomAD v4.1.0 with a highest population minor allele frequency of 1179964 (2/74786 alleles) in Non-Finnish European population and with multiple alleles present in the Non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.089; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390885499/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9448 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0151763 infores:hetionet CHEBI:180905 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0028734 infores:hetionet CHEBI:7915 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151723 infores:hetionet CHEBI:8871 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002994 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0040259 infores:hetionet CHEBI:52010 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0040822 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0018621 infores:hetionet CHEBI:45979 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0344232 infores:hetionet CHEBI:4636 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011053 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0041912 infores:hetionet CHEBI:47898 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0700225 infores:hetionet CHEBI:5118 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015732 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151849 infores:hetionet CHEBI:9398 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0018681 infores:hetionet CHEBI:68642 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0085682 infores:hetionet CHEBI:15552 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0016204 infores:hetionet CHEBI:119573 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0700225 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0037274 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0011570 infores:hetionet CHEBI:4995 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018965 infores:hetionet CHEBI:9571 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0018418 infores:hetionet CHEBI:3716 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0038325 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C2939147 infores:hetionet CHEBI:4562 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0037763 infores:hetionet CHEBI:31981 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0085623 infores:hetionet CAID:CA7330848 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330848 MONDO:0100216 PMID: Uncertain Significance BP4, BS2_Supporting PVS1, PM2, PM6, BP1, BP3, BP2, BA1, PP2, PP3, PP4, PP1, PM5, PM4, PM1, PM3, PS1, PS3, PS2, PS4, BP7, BP5, BS1, BS3, BS4 The NM_177438.2:c.4423A>G variant in DICER1 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 1475 (p.Thr1475Ala). This variant was observed in a proband with medulloepithelioma, type unspecified (PS4 not met; Internal lab contributor). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0003287 (2/6084 alleles) in the Middle Eastern population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.058; MaxEntScan and SpliceAI: no effect on splicing) (BP4). Though this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied (BS2_Supporting, BP4), the ClinGen DICER1 VCEP has decided to override classification to Uncertain Significance due to the potential observation of ciliary body medulloepithelioma (a high-specificity phenotype) in a proband with limited available clinical data. (Bayesian Points: -2; VCEP specifications version 1.3.0; 02/27/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330848/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41879 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0175167 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0021368 infores:hetionet CHEBI:23765 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C3495920 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0009450 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0234458 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0019825 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0031212 infores:hetionet CHEBI:8888 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1868855 infores:hetionet CHEBI:6539 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0855775 infores:hetionet CHEBI:75722 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0917801 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0919980 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0853761 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017675 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0085622 infores:hetionet CAID:CA229606 biolink:causes MONDO:0009861 infores:clingen CAID:CA229606 MONDO:0009861 PMID:26210745PMID:30459323PMID:27121329PMID:10234516 Pathogenic PM5, PP4_Moderate, PM2, PM3_Strong PP3 This c.527G>A (p.Arg176Gln) variant in PAH was reported in at least two patients with PAH deficiency (PMID: 30459323, 26210745, and 27121329) and detected with pathogenic variants p.Val388Met, p.Arg158Gln, and Arg243Gln (PMID: 27121329,10234516, and 30459323). This variant has extremely low frequency in gnomAD (MAF=0.00007). One other missense variant at this amino acid residue is determined to be pathogenic in ClinVar: p.Arg176Leu by nine submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific AMCG/AMP criteria applied: PM3_strong, PM2, PM5, and PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229606/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36704 biolink:causes UMLS:C1142459 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1142459 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0235329 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235329 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006145 infores:hetionet CHEBI:72564 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013378 infores:hetionet CHEBI:9332 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0235896 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020517 infores:hetionet CHEBI:5165 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020461 infores:hetionet CHEBI:6129 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0085628 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0233632 infores:hetionet CHEBI:17474 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0023218 infores:hetionet CHEBI:4470 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0027497 infores:hetionet CHEBI:7565 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0022346 infores:hetionet CHEBI:44185 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085605 infores:hetionet CAID:CA163551 biolink:causes MONDO:0007648 infores:clingen CAID:CA163551 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS4, BS1, BS3, PM3, PM4, PM1, PM5, PVS1, PM2, PM6, BS2, PP1, PP4, PP2, PP3, BP3, BP1, BP4, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.48+5C>G variant has an allele frequency of 0.11584 (11.584%, 1670/14416 alleles, 98 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA163551/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:114785 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0033687 infores:hetionet CHEBI:63608 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027424 infores:hetionet CHEBI:3127 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0033774 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0040034 infores:hetionet CHEBI:6128 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0086565 infores:hetionet CHEBI:4445 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0035410 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020621 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0442874 infores:hetionet CHEBI:46557 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0043352 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0239293 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0239293 infores:hetionet CAID:CA16020968 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020968 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate, PP3 PM5, PM3 The c.1204T>A (p.Phe402Ile) variant in PAH has been detected in 1 Japanese patient with mild HPA, BH4 deficiency excluded (PMID: 21307867). This variant is absent from population databases (PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.946 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4_M. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020968/MONDO:0009861/006 2021-05-15 2021-09-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4672 biolink:causes UMLS:C0497364 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0497364 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0233494 infores:hetionet CHEBI:9671 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0015230 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0004096 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026848 infores:hetionet CHEBI:145499 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0518988 infores:hetionet CHEBI:28148 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0151539 infores:hetionet NCBIGene:4920 biolink:causes MONDO:0009999 infores:monarchinitiative not_provided not_provided HGNC:10257 MONDO:0009999 uuid:3da55199-0fc7-47cc-85c2-1c2a0bfce17b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0860866 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0002884 infores:hetionet CHEBI:70707 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0549622 infores:hetionet CHEBI:9086 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0028084 infores:hetionet CHEBI:68575 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0008031 infores:hetionet CHEBI:37941 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0740394 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0233494 infores:hetionet CAID:CA308078035 biolink:causes MONDO:0018493 infores:clingen CAID:CA308078035 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 1223 of the RYR1 protein, p.(Glu1223Lys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000259, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), this individual also had a pathogenic variant in RYR1 (p.Gly2434Arg), PS4 was not implemented (PMID:30236257, personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.831 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: None. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308078035/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3082 biolink:causes UMLS:C0497201 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0497201 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0349506 infores:hetionet CAID:CA409103851 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103851 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting, PM1 PP4 The c.146A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of histidine to arginine at codon 49 (p.(His49Arg)) of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, therefore, PP4 cannot be applied (PMID: 25555642). Another missense variant at the same residue, c.145C>T (p.His49Tyr), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.His49Arg (PM5_Supporting). In summary, c.146A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PM5_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103851/MONDO:0015967/085 2025-09-17 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50648 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0006840 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0439857 infores:hetionet CHEBI:8874 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0041834 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0392386 infores:hetionet NCBIGene:210 biolink:causes MONDO:0013000 infores:monarchinitiative not_provided not_provided HGNC:395 MONDO:0013000 uuid:34a4a400-3706-456c-af31-8bbe20d7fe8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0392386 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0040479 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0746883 infores:hetionet CHEBI:2663 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0006826 infores:hetionet CHEBI:8378 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0022408 infores:hetionet CAID:CA222176 biolink:causes MONDO:0015152 infores:clingen CAID:CA222176 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP3, PM3_Very Strong PM5, PS1, PS3, BA1, BP4, BS1, BS3, PVS1, PM2 The NM_003494.4: c.4794G>T variant in DYSF, which is also known as NM_001130987.2: c.4911G>T (p.Lys1637Asn), is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 1598, p.(Lys1598Asn). This variant affects the last residue in exon 45 and is predicted to disrupt the consensus splice donor site (SpliceAI delta score 0.33) and strengthen an alternative splice site in the intron (SpliceAI delta score 0.63) (PP3). RNAseq analysis has demonstrated that this variant has a leaky splice effect, resulting in skipping of exon 43 and an inframe deletion, p.Gly1547_Lys1598del, in a subset of transcripts (PMID: 36983702). This variant has been detected in nine individuals with features consistent with LGMD (PMID: 33144682; 33610434; 30564623; 36983702; 27195159; ClinVar SCV005360734.1 internal data communication; LOVD DYSF_000170), including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.4756C>T, p.(Arg1586Ter), 1.0 pt, LOVD Individual #00215321; NM_003494.4: c.6124C>T p.(Arg2042Cys), 1.0 pt, ClinVar SCV005360734.1 internal data communication). In at least four patients, it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 36983702); (NM_003494.4: c.6124C>T p.(Arg2042Cys), 0.5 pts x2, PMID: 36983702; PMID: 30564623; LOVD Individual #00220316); (NM_003494.4: c.755C>T p.(Thr252Met), 0.5 pts, PMID: 30564623; LOVD Individual #00219977) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF displayed a progressive limb girdle pattern of weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID: 27195159). The filtering allele frequency of this variant is 0.0002 for gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 201/1112000 European (non-Finnish) chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (criterion not met). The Lys1598Asn protein was classified as functional in both 2A and ICC assays of dysferlin membrane localization (PMID: 35028538), and the REVEL score is 0.387. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PP3, PM3_Very Strong, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222176/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018378 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0349506 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0018799 infores:hetionet CHEBI:5784 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C1318520 infores:hetionet CAID:CA1620123 biolink:causes MONDO:0800472 infores:clingen CAID:CA1620123 MONDO:0800472 PMID: Likely Benign BP4 PP3, PP1, BA1, PS3, PS1, PS2, PM3, PM1, PM4, PM5, BP7, BS1, BS4, PVS1, PM2 The c.35C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Proline by Lysine at amino acid 12 (p.Pro12Leu). The highest minor allele frequency of this variant was in the African/African American genetic ancestry group of gnomAD (v4.1) = 0.003997 (300 alleles out of 75060), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The REVEL score = 0.063, which is within the 0.017-0.183 range for BP4_Moderate and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), suggesting that the variant does not impact CYP1B1 function. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in an individual with a CYP1B1-related phenotype, however BP4 is met, therefore PM3 was not assessed. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BP4_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1620123/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3223 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0855329 infores:hetionet CHEBI:6078 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0019158 infores:hetionet CAID:CA533258221 biolink:causes MONDO:0015152 infores:clingen CAID:CA533258221 MONDO:0015152 PMID: Pathogenic PM4, PP4_Strong, PM3_Strong, PM2_Supporting The NM_003494.4: c.1668_1669insGTT p.(Leu556_Leu557insVal) variant in DYSF, which is also known as NM_001130987.2: c.1722_1723insGTT (p.Leu574_Leu575insVal), is predicted to cause a change in the length of the protein due to an in-frame insertion of one amino acid in a non-repeat region (PM4). This variant has been observed in trans with a likely pathogenic or pathogenic variant in at least two individuals with LGMD (c.5181del p.(Glu1727AspfsTer7), 1.0 pt, PMID: 36983702; c.1053+5G>A, 1.0 pt, ClinVar SCV000710095.1 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 36983702, ClinVar SCV000710095.1 internal data communication; PP4_Strong). The filtering allele frequency of this variant is 0.00000824 (the upper threshold of the 95% CI of 4/1110874 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PM4, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA533258221/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17347 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0311468 infores:hetionet CHEBI:94392 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0020651 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0006840 infores:hetionet CHEBI:3423 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0948441 infores:hetionet CHEBI:7640 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0038362 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151888 infores:hetionet CHEBI:5864 biolink:causes MONDO:0019514 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0019156 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0233472 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0015376 infores:hetionet GO:0032417 biolink:causes GO:1902600 infores:ubergraph knowledge_assertion manual_agent GO:0032417 GO:1902600 CHEBI:45652 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0041105 infores:hetionet CHEBI:127342 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0036974 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009806 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0162830 infores:hetionet CHEBI:9139 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042345 infores:hetionet CHEBI:47898 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0018681 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0017152 infores:hetionet CHEBI:3698 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0700590 infores:hetionet CHEBI:34829 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0022073 infores:hetionet CHEBI:5132 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0022346 infores:hetionet CHEBI:8207 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0035305 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037822 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0677500 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0021775 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0235369 infores:hetionet CHEBI:63629 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0235378 infores:hetionet CHEBI:37941 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0025323 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C1510472 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018939 infores:hetionet CAID:CA410207192 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207192 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS4, PS3, PS2, BA1, BP1, BP4, BP2, BP3, PM6, BS1, BS3, BS4, BP7, BP5, PM1, PM3, PM4, BS2, PP4, PP2, PP3, PP1 The NM_001754.5:c.622C>T (p.Gln208Ter) variant in RUNX1 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant exon 7/9 that leads to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (PVS1, PM5_supporting). This variant is absent from gnomAD v2 and v3 with at least 20 coverage (PM2_Supporting). Although variant has not been confirmed in the germline of patients, it has been reported in a 16yo female with heavy menorrhagia and a storage pool disorder whose father reported bleeding symptoms (PMID: 31064749). Note that the variant (unclear origin) has also been reported in a patient with MDS (PMID: 33520721) and acquired in 2 patients with AML (PMID: 19808697 and 21339757). In summary, this variant is classified as pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_supporting, PM5_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207192/MONDO:0011071/008 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6887 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233472 infores:hetionet CHEBI:7915 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0149745 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0041948 infores:hetionet CHEBI:31981 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0022354 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0267792 infores:hetionet CHEBI:44423 biolink:causes MONDO:0001366 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1260402 infores:hetionet CHEBI:31401 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0086565 infores:hetionet GO:0046626 biolink:causes GO:0032869 infores:ubergraph knowledge_assertion manual_agent GO:0046626 GO:0032869 CHEBI:17549 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C2939147 infores:hetionet CHEBI:77733 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C3665347 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0087169 infores:hetionet CHEBI:7931 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C2047937 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038826 infores:hetionet CHEBI:6375 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0236075 infores:hetionet CHEBI:9434 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0151786 infores:hetionet CHEBI:31236 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233565 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0040046 infores:hetionet CHEBI:3011 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0013604 infores:hetionet CHEBI:50663 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0010200 infores:hetionet CHEBI:74947 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0041657 infores:hetionet CAID:CA10653563 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653563 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The RUNX1 c.*1466G>A variant in the 3' UTR has an MAF of 0.01193 (1.2%, 163/13658 alleles) in the Latino subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 5 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653563/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28001 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0917801 infores:hetionet CHEBI:31547 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0041969 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042109 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151785 infores:hetionet NCBIGene:10203 biolink:causes MONDO:0032907 infores:monarchinitiative not_provided not_provided HGNC:16709 MONDO:0032907 uuid:89c09dc5-96e0-417b-b09e-71e9a2099236 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28148 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0233407 infores:hetionet CHEBI:15553 biolink:causes HP:0025116 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0015930 infores:hetionet CAID:CA410148358 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148358 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1046A>G (p.Tyr349Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148358/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63635 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027066 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0021053 infores:hetionet CHEBI:63577 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0002874 infores:hetionet CHEBI:75722 biolink:causes MONDO:0044986 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0024228 infores:hetionet CHEBI:3207 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0003126 infores:hetionet NCBIGene:55640 biolink:causes MONDO:0009168 infores:monarchinitiative not_provided not_provided HGNC:20105 MONDO:0009168 uuid:55c9e3da-8bcb-4a39-b524-ce6635a7d2e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1394188 biolink:causes MONDO:0019501 infores:clingen CAID:CA1394188 MONDO:0019501 PMID: Uncertain Significance PM3_Supporting, PP4, PM2_Supporting BS1, PP3, PM5, BP4, BA1 The NM_206933.2:c.9885T>G variant in the USH2A gene is a missense variant predicted to cause the substitution of cysteine by tryptophan at amino acid 3295 (p.Cys3295Trp). The minor allele frequency of this variant in gnomAD v.4.1.0 is 0.004004% (3/74928) in the African American population meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.569, which doesn’t meet either of the thresholds necessary to apply PP3/BP4. This variant has been detected with another pathogenic variant in one patient with Usher syndrome (PM3_Supporting; PMIDs: 30796641, 37446072). The phenotype observed was highly specific for Usher syndrome in the proband (PP4, PMIDs: 30796641, 37446072). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PM3_Supporting, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 6/18/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1394188/MONDO:0019501/005 2025-06-18 2025-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:134991 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0042790 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017574 infores:hetionet CHEBI:77733 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0151786 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0549447 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0549447 infores:hetionet UNII:3U02EL437C biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0016199 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0001824 infores:hetionet CHEBI:3568 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0575081 infores:hetionet GO:1905100 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:1905100 GO:0007154 CHEBI:119486 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C2129214 infores:hetionet CHEBI:9943 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040136 infores:hetionet CHEBI:7494 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0080274 infores:hetionet CHEBI:73274 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0004093 infores:hetionet CHEBI:94501 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0917801 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0027441 infores:hetionet CAID:CA386952412 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952412 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3 PP4 The c.35T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 12 (p.(Leu12Pro)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). Additionally, this variant is located within the dimerization domain of HNF1A (codons 1-32), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history suggestive of HNF1A-monogenic diabetes (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 28395978). Lastly, other missense variants at this same codon, c.34C>G, (p.Leu12Val) and c.34C>T (p.Leu12Phe), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952412/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:127780 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0033774 infores:hetionet CHEBI:73274 biolink:causes MONDO:0006904 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0345326 infores:hetionet CAID:CA10588622 biolink:causes MONDO:0007648 infores:clingen CAID:CA10588622 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PS3_Supporting, PM2_Supporting, PS4_Supporting, PVS1_Strong BS1, BS3, BS4, BP7, BP5, PM6, PM1, PM4, PM3, BS2, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS2 The c.1320+1G>C variant occurs at the canonical splice donor site of exon 9 (PVS1_strong, PM5_supporting). This variant is absent from populations in gnomAD (PM2_supporting; http://gnomad.broadinstitute.org). Splicing analysis in vitro has shown that the C allele results in skipping of exon 9, producing an abnormal in-frame transcript (PS3_supporting; PMID: 8033105, 28301459). Furthermore, this variant has been observed in at least one family meeting IGCLC criteria for HDGC (PS4_supporting; SCV000322628.7). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_supporting, PS3_supporting, PS4_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588622/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:6129 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018524 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019348 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0027769 infores:hetionet CHEBI:28901 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C2717961 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0018939 infores:hetionet CHEBI:52717 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0476273 infores:hetionet CHEBI:75922 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0022281 infores:hetionet CHEBI:472657 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0014518 infores:hetionet CAID:CA7435453 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435453 MONDO:0007113 PMID: Likely Benign BP4, BP7, BS1 The allele frequency of the c.1905A>G p.Leu635= variant in UBE3A (NM_130838.2) is 0.01% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Leu635= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1905A>G p.Leu635= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435453/MONDO:0007113/032 2023-06-16 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6067 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0041834 infores:hetionet GO:1900136 biolink:causes GO:0009605 infores:ubergraph knowledge_assertion manual_agent GO:1900136 GO:0009605 CHEBI:2922 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0025222 infores:hetionet CHEBI:63610 biolink:causes HP:0100718 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0042143 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0015230 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0029134 infores:hetionet CHEBI:8212 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0040822 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0541819 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0541819 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007787 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151735 infores:hetionet CHEBI:7936 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2937350 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0423791 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0011974 infores:hetionet CHEBI:3403 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0003467 infores:hetionet CHEBI:16664 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0001824 infores:hetionet CAID:CA2802300 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802300 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM3, PP4 PS3, BS1, BS3, PM2 "The NM_000203.5:c.1577T>C variant in IDUA is a missense variant predicted to cause substitution of leucine by proline at amino acid 526 (p.Leu526Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0005078 (42/82710 alleles) in the South Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), and lower than the threshold for BS1 (>0.0025). Therefore, none of the population data codes are met. At least 12 individuals have been reported with biallelic variants in IDUA (not including pseudodeficiency variants). Eight of those individuals were identified by a newborn screen, all with low IDUA activity, but all with normal total GAGs, and either normal or mildly elevated dermatan and heparan sulfate; two of these individuals were described as having an attenuated phenotype based on clinical evaluation, and others as suspected or undetermined diagnosis (30442156, 30093709, 32432561, 33072983, 33147872, 35787971, 37516270, Greenwood Genetic Center). At least 3 other individuals have been reported to have symptoms consistent with MPS I (22976768, 26260077, 31194252, 37181073). One individual with the variant has been reported with an extremely attenuated phenotype (PMID: 37181073). This individual, who is compound heterozygous for the variant and c.228T>A (p.Tyr76Ter), confirmed in trans by parental testing (1 point for PM3), was diagnosed with MPS I at age 38 years. She presented with valvular disease, retinopathy, short stature, dysostosis multiplex, and coarse facial features, and had deficient IDUA activity and elevated urine and serum dermatan and heparan sulfate (elevations were mild) (PP4 met based on clinical symptoms and IDUA deficiency). Another patient, reported to be on ERT and to have skeletal features of MPS I (PMID: 26260077, 31194252; may be the same patient in both papers) is compound heterozygous for the variant and c.1205G>A (p.Trp402Ter) (PMID: 26260077, 3119425) in unknown phase (0.5 points for PM3). Data from another patient, compound heterozygous for the variant and p.Gln70Ter, were not included due to lack of GAG levels, and the presence of a pseudodeficiency variant (PMID: 22976768; personal communication). Total 1.5 points (PM3) However, 27-year-old female, who is compound heterozygous for p.Leu526Pro and c.1205G>A (p.Tyr402Ter), confirmed in trans, has no clinical features of MPS I based on detailed physical exam. Although she has elevated NRE marker UA-HNAc(1S), the elevation is not of the degree observed in affected individuals (PMID: 39702574). Similarly, a 7-month-old with the same genotype also has elevated NRE marker UA-HNAc(1S), but not in the range typically associated with MPS I (PMID: 39702574) (Total 1.5 points, PM3). PP4 was applied based on the reported features of MPS I in some patients. The computational predictor REVEL gives a score of 0.774 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). When the variant was expressed in IDUA knock-out HEK293 cells, the relative specific activity (activity of IDUA/amount of IDUA protein) was 15% of wild type activity (3 times higher than the activity of the ""pseudodeficiency"" variant, p.Ala79Thr, which is clinically benign). However, the p.Leu526Pro IDUA protein exhibits impaired proteolytic processing on Western blot, and evidence of aggregation of native gel electrophoresis. Based on the relatively high activity, but abnormalities in processing and aggregation, neither PS3 nor BS3 is met. There is a ClinVar entry for this variant (Variation ID: 567566). In summary, currently, the clinical impact of p.Leu526Pro is unclear (variant of uncertain significance), particularly given the reports of some patients with a diagnosis of MPS I, and others with normal total GAG levels and reports of only mild elevations of dermatan and heparan sulfate (PMID: 39702574, Greenwood Genetic Center). This could suggest that the variant has reduced penetrance; however additional data is required to fully understand the clinical impact of this variant. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PM3, PP3_Moderate, PP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 21, 2025)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802300/MONDO:0001586/091 2025-04-21 2025-08-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:92998 biolink:causes UMLS:C1112210 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1112210 infores:hetionet CHEBI:9398 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0006145 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0006266 infores:hetionet CHEBI:8863 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020672 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0006849 infores:hetionet CHEBI:134991 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C3665386 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0851341 infores:hetionet CAID:CA186535 biolink:causes MONDO:0100488 infores:clingen CAID:CA186535 MONDO:0100488 PMID: Likely Benign BP7, BS2, BP4 BS1, PM1, PM3, PVS1, PM2, PP2, PP4, BA1, BP1, BP3, PS1, PS4 The NM_004360.5:c.1500C>T (p.Gly500=) variant results in a synonymous amino acid variant within exon 10. This variant is present at an allele frequency of 0.00002828 (8/282862) in gnomAD v2.1.1, with a maximum frequency of 0.0003508 (7/19954) in the East Asian subpopulation. The variant has been observed in more than 10 (97) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2). This variant occurs at a nucleotide that is not predicted to alter splicing or protein function by multiple in silico predictors (BP7, BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4, BP7. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA186535/MONDO:0100488/007 2023-08-28 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:47781 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0341047 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0004936 infores:hetionet CHEBI:63627 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0033774 infores:hetionet CHEBI:8871 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0041105 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011334 infores:hetionet NCBIGene:2710 biolink:causes MONDO:0010613 infores:monarchinitiative not_provided not_provided HGNC:4289 MONDO:0010613 uuid:c413ba1c-b8a9-4c91-811a-c73df7ae2111 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0085641 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0546817 infores:hetionet CHEBI:6741 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0011606 infores:hetionet CHEBI:15367 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042023 infores:hetionet CHEBI:194135 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0428977 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0025061 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0006840 infores:hetionet CHEBI:6931 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0851578 infores:hetionet CHEBI:2687 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0878544 infores:hetionet CHEBI:367163 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0013428 infores:hetionet CHEBI:3696 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0026205 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0521498 infores:hetionet CHEBI:63638 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0027497 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0427008 infores:hetionet CAID:CA222172 biolink:causes MONDO:0015152 infores:clingen CAID:CA222172 MONDO:0015152 PMID:35028538 Benign BA1 PM3, BP4, BS3, PP3 The NM_003494.4: c.4742G>A variant in DYSF, which is also known as NM_001130987.2: c.4859G>A (p.Arg1620His), is a missense variant predicted to cause substitution of arginine to histidine at amino acid 1581, p.(Arg1581His). The filtering allele frequency of this variant is 0.005130 (the lower threshold of the 95% CI of 256/44880 chromosomes) in the East Asian population of gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold >0.003 for BA1, meeting this criterion (BA1). While this variant has been identified in individuals with suspected LGMD (e.g., PMID: 25868377, 30107846, 30564623, 36983702, 36319958), in at least one individual two other presumed diagnostic DYSF variants were reported (LOVD Individual #00221717), and in several others a second presumed diagnostic DYSF variant was not identified. (PM3 not met) Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Arg1581His protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met). The computational predictor REVEL gives a score of 0.686 (PP3 and BP4 not met). In summary, this variant is classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/30/2025): BA1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222172/MONDO:0015152/180 2025-10-30 2025-11-11 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2663 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0018021 infores:hetionet CHEBI:2038 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0476280 infores:hetionet UMLS:C0023610 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0027497 infores:hetionet CHEBI:3242 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013404 infores:hetionet CHEBI:50922 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0233471 infores:hetionet CHEBI:10124 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0232462 infores:hetionet UMLS:C0009315 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0595916 infores:hetionet CHEBI:8764 biolink:causes NCIT:C54356 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151598 infores:hetionet CHEBI:9434 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0023218 infores:hetionet CHEBI:101278 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018418 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038362 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0037023 infores:hetionet CHEBI:585948 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0542571 infores:hetionet CHEBI:47426 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0038999 infores:hetionet CHEBI:135736 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015732 infores:hetionet CHEBI:6437 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013144 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0855675 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0855675 infores:hetionet CAID:CA386954965 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954965 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS1_Supporting, PP1_Strong, PVS1, PP4 PS4 The c.326+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 1 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant segregated with diabetes, with five informative meioses in one family with MODY (PP1_Strong; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributors). Lastly, the c.326+1G>T and c.326+1G>C variants at the same canonical nucleotides have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>A has a similar predicted impact on donor loss by Splice AI (0.98) (PS1_Supporting). In summary, c.326+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21):PVS1, PP1_Strong, PP4, PS1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954965/MONDO:0015967/017 2022-06-10 2022-06-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:175901 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0030193 infores:hetionet CHEBI:6078 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C3665346 infores:hetionet CHEBI:5050 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0014591 infores:hetionet CHEBI:4911 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0085593 infores:hetionet CHEBI:10125 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0344232 infores:hetionet CAID:CA16020974 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020974 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The c.1232C>G (p.Ser411Ter) variant in PAH is a nonsense variant in exon 12 of 13 predicted to lead to nonsense mediated decay. It was reported in a Brazilian patient with classic PKU, detected with pathogenic variant p.V388M (PMID: 11139255). This variant is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2_supporting, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020974/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2788 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0948294 infores:hetionet CHEBI:3371 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0040264 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0015230 infores:hetionet CHEBI:16914 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0027497 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0042109 infores:hetionet NCBIGene:1387 biolink:causes MONDO:0020763 infores:monarchinitiative not_provided not_provided HGNC:2348 MONDO:0020763 uuid:04ded24a-bd75-46aa-8fff-6a6a37bbfa13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA286499 biolink:causes MONDO:0009861 infores:clingen CAID:CA286499 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 BA1, PS3, BS1 The c.212G>A (p.Arg71His) variant in PAH has been reported in multiple individual with PAH deficiency with BH4 deficiency excluded (PP4_Moderate; PMID: 10495930, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variant p.R408W (PM3). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286499/MONDO:0009861/006 2019-09-29 2019-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44185 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018799 infores:hetionet CHEBI:47898 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020458 infores:hetionet CHEBI:3534 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0019080 infores:hetionet CHEBI:31236 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0007286 infores:hetionet CHEBI:3655 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0015230 infores:hetionet CHEBI:8772 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0035328 infores:hetionet CHEBI:6149 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0151904 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020651 infores:hetionet CHEBI:10101 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151636 infores:hetionet CHEBI:5103 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0233477 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0281981 infores:hetionet CHEBI:3181 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0002418 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0029408 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1619712 infores:hetionet CHEBI:27974 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C2937358 infores:hetionet CAID:CA10014256 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014256 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.967+15A>G is an intronic variant with a SpliceAI score of 0.02, which is ≤ 0.20 (BP4). Additionally, evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score of 0.17, which is ≤ 2.0 (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014256/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:32315 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020621 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0521839 infores:hetionet UNII:R43D2573WO biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0008033 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0429098 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0087169 infores:hetionet CHEBI:6532 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0234215 infores:hetionet CHEBI:7581 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0038990 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0332534 infores:hetionet CHEBI:9086 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0237314 infores:hetionet CHEBI:3515 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0013144 infores:hetionet CAID:CA45506175 biolink:causes MONDO:0800472 infores:clingen CAID:CA45506175 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PP3_Moderate, PP1_Strong BA1, BP4, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4, PVS1 The c.1331G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 444 (p.Arg444Gln). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00006682 (3 alleles out of 44,896), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.828, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 27508083, 35087999), which fulfilled PP1_Strong. This variant has been identified in 6 individuals with a CYP1B1-related phenotype. 4 individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (3 confirmed in trans and 1 phase unknown) (PMIDs: 17718864, 21850185, 35087999). 2 individuals are homozygous (consanguineous) for the variant (PMIDs: 11239867, 27508083). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 15 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very-Strong, PP1_Strong, PP3_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA45506175/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports GO:0071895 biolink:causes CL:0000060 infores:ubergraph knowledge_assertion manual_agent GO:0071895 CL:0000060 CHEBI:8382 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0002063 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0040034 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0009319 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0011991 infores:hetionet CHEBI:6538 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0007222 infores:hetionet CAID:CA512318567 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318567 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.777T>C (p.Phe259=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318567/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA376064484 biolink:causes MONDO:0011225 infores:clingen CAID:CA376064484 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BA1, BS1 The c.137C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 46 (p.Thr46Ile).The filtering allele frequency (the upper threshold of the 95% CI of 3/39670) of the c.137C>T variant in DCLRE1C is 0.00002005 for East Asian chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376064484/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7478 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2939147 infores:hetionet CHEBI:3314 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C2242996 infores:hetionet CHEBI:63618 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0014236 infores:hetionet CHEBI:135736 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0026858 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235969 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0277925 infores:hetionet CHEBI:8764 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0428977 infores:hetionet CHEBI:63681 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0232462 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0034065 infores:hetionet GO:1903379 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:1903379 GO:0000278 CHEBI:7492 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0235567 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005266 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011884 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0234215 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0332575 infores:hetionet NCBIGene:10664 biolink:causes MONDO:0014213 infores:monarchinitiative not_provided not_provided HGNC:13723 MONDO:0014213 uuid:a363f6f5-6a9f-436c-b2e6-9b9366fa2c89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0037299 infores:hetionet CAID:CA2573153942 biolink:causes MONDO:0100326 infores:clingen CAID:CA2573153942 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 NM_000419.5(ITGA2B):c.138dup (p.Gly47TrpfsTer?) is a frameshift variant in exon 2 resulting in a premature stop codon in exon 3, of 30, which is predicted to cause NMD (PVS1). This variant is absent from population databases including gnomADv4.0 (PM2_supporting). One homozygous patient has reported with lab results consistent with type I Glanzmann Thrombasthenia (ClinVar SCV002515513.1; PM3_supporting). In summary this variant is classified as Pathogenic for Glanzmann thrombasthenia, meeting PD-VCEP specified criteria for GT: PVS1, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573153942/MONDO:0100326/011 2023-12-19 2023-12-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:66964 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C2047937 infores:hetionet CHEBI:93363 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0013144 infores:hetionet CHEBI:17347 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0019080 infores:hetionet NCBIGene:6772 biolink:causes MONDO:0013956 infores:monarchinitiative not_provided not_provided HGNC:11362 MONDO:0013956 uuid:c190d35a-500c-4630-8249-e9ca23bc3dd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004936 infores:hetionet CAID:CA229668 biolink:causes MONDO:0009861 infores:clingen CAID:CA229668 MONDO:0009861 PMID:9781015PMID:27620137 Likely Pathogenic PM2, PM3, PP3, PP4, PS3_Supporting PM5 The c.635T>C (p.Leu212Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9781015) detected with pathogenic variants: p.R408W (PMID: 17502162); p.R158Q (PMID: 23430918); c.1066-11G>A (PMID: 26666653). This variant is absent in population databases. In vitro residual activity of the p.L212P mutant enzyme is 17% of wild type, and it also showed reduced protein expression. Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229668/MONDO:0009861/006 2021-07-17 2021-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53760 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1504494 infores:hetionet CHEBI:75998 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C1262036 infores:hetionet CHEBI:63637 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0003862 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0019360 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0029408 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0376297 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0376297 infores:hetionet CHEBI:63584 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0003811 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0162429 infores:hetionet CHEBI:3752 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0004604 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001150 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0020255 infores:hetionet CHEBI:3312 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0020437 infores:hetionet CHEBI:2379 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0009676 infores:hetionet CHEBI:50275 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151905 infores:hetionet CHEBI:100246 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0013362 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0521839 infores:hetionet CHEBI:3510 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0013404 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0233494 infores:hetionet CHEBI:8707 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011603 infores:hetionet CHEBI:61049 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021368 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0031350 infores:hetionet NCBIGene:11107 biolink:causes MONDO:0013605 infores:monarchinitiative not_provided not_provided HGNC:9349 MONDO:0013605 uuid:cefff752-cad6-4494-822c-091dea9d0f4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020473 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0027441 infores:hetionet CHEBI:8364 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0013144 infores:hetionet CHEBI:8428 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0027947 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020651 infores:hetionet CHEBI:78543 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0033771 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0855242 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0549373 infores:hetionet CAID:CA386304246 biolink:causes MONDO:0009861 infores:clingen CAID:CA386304246 MONDO:0009861 PMID: Uncertain Significance PM5, PP4_Moderate, PM2_Supporting PP3 The NM_000277.3(PAH):c.182A>G (p.Asn61Ser)variant in PAH is a missense variant predicted to cause substitution of asparagine by serine at amino acid 61 (p.Asn61Ser). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND normal urine pterins and DHPR activity to exclude a defect of BH4 cofactor metabolism, which is highly specific for Phenylketonuria (PP4_Moderate; PMID:29499199). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 2 different missense variants c.181A>G (p.Asn61Asp) and c.183C>A (p.Asn61Lys) in the same codon have been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria VCEP: PP4_moderate, PM2_supporting, PM5 (Version 2.0, 7/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386304246/MONDO:0009861/006 2025-07-18 2025-07-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63681 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0041834 infores:hetionet GO:0060782 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060782 GO:0007275 CHEBI:31236 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015806 infores:hetionet CAID:CA350399040 biolink:causes MONDO:0015924 infores:clingen CAID:CA350399040 MONDO:0015924 PMID:25688877PMID:9886286 Pathogenic PM5_Supporting, PP3, PM2_Supporting, PS4_Supporting, PS3, PM1_Strong PS1 The NM_001204.7(BMPR2) c.100T>C variant is a missense variant predicted to cause a cysteine to arginine substitution at amino acid position 34 (p.Cys34Arg). The variant is absent from gnomAD v.2.1.1 and v4.1 (PM2_supporting) and has been reported in two unrelated PAH probands (PMID: 29650961) (PS4_supporting). The variant is located within the extracellular ligand-binding domain and p.Cys34 is a critical residue for protein function (PM1_strong). Two additional likely pathogenic variants, c.101G>T (p.Cys34Phe) and c.102T>G (p.Cys34Trp) have been reported at the same residue (PMID: 27453251, PMID: 30578397) (PM5_supporting). HeLa cells transfected with a BMPR2 p.C34R construct demonstrated that the mutant protein is mislocalized in the cell and does not reach the plasma membrane, with some retention in the ER/Golgi (PMID: 25688877) (PS3). In silico prediction (REVEL = 0.939) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version v 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350399040/MONDO:0015924/125 2024-09-20 2024-09-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7444 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0428977 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0017160 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020039 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0232492 infores:hetionet CHEBI:3223 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C1112320 infores:hetionet NCBIGene:9377 biolink:causes MONDO:0033655 infores:monarchinitiative not_provided not_provided HGNC:2267 MONDO:0033655 uuid:5a460fdb-37c0-404f-996b-5d1f579ddad8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8327 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0011603 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0948779 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0948779 infores:hetionet CHEBI:46195 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0455769 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0152227 infores:hetionet CHEBI:63612 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0003862 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0020538 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0340726 infores:hetionet CAID:CA320603743 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603743 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP3, BP1, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM1, PM5, PM3, PP4, PP1, PP2, BS2 NM_001754.5(RUNX1):c.614-9C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603743/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7936 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020433 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0025061 infores:hetionet CHEBI:42944 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C3665347 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0026848 infores:hetionet CHEBI:9362 biolink:causes HP:0001892 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C1458140 infores:hetionet CHEBI:135342 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0007859 infores:hetionet CHEBI:135935 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0010200 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0020039 infores:hetionet NCBITaxon:210 biolink:causes MONDO:0004247 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:210 MESH:D010437 DB02701_MESH_D010437_1DB09221_MESH_D010437_1 CHEBI:8871 biolink:causes UMLS:C0857980 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0857980 infores:hetionet CHEBI:3508 biolink:causes NCIT:C122443 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0239113 infores:hetionet CHEBI:3077 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0234708 infores:hetionet CHEBI:34967 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0003467 infores:hetionet CHEBI:15552 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0002792 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0018418 infores:hetionet CHEBI:253342 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0231218 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0242648 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0242648 infores:hetionet CHEBI:70735 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0011603 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0162627 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0085606 infores:hetionet CHEBI:3696 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0008031 infores:hetionet UNII:VL0L558GCB biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0021368 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0033975 infores:hetionet CHEBI:77260 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1384353 infores:hetionet CHEBI:50729 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0595916 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151698 infores:hetionet CHEBI:75722 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026205 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0079043 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0003467 infores:hetionet CAID:CA213751 biolink:causes MONDO:0015967 infores:clingen CAID:CA213751 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PS3_Supporting, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1307T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 436 (p.(Ile436Asn)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID 17204055, PMID 20337973, PMID 22493702, internal lab contributors). At least 2 of these individuals have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies +/- 2 hour oral glucose tolerance test increment <3 mmol/L) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). Another missense variant, c.1306A>T p.Ile436Phe has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). While the RAI of this variant was 0.975, this variant results in decreased inhibition by GKRP (PS3_Supporting; PMID: 22493702). In summary, this evidence supports the classification of c.1307T>A as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PP4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213751/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:6076 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151539 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0027651 infores:hetionet CHEBI:70707 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0011991 infores:hetionet CHEBI:4530 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0700361 infores:hetionet CHEBI:42944 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0025222 infores:hetionet CHEBI:50173 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020555 infores:hetionet CHEBI:31302 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0855775 infores:hetionet CHEBI:45409 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0007859 infores:hetionet CHEBI:2663 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0002962 infores:hetionet CHEBI:29007 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C1257843 infores:hetionet CHEBI:63925 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C1761613 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0856150 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0856150 infores:hetionet CHEBI:5128 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0004134 infores:hetionet CHEBI:73275 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0178298 infores:hetionet UMLS:C0017797 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0015967 infores:hetionet CHEBI:51860 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1318520 infores:hetionet CHEBI:9763 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0012569 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0035435 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0017160 infores:hetionet CHEBI:4903 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0033046 infores:hetionet CHEBI:8378 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0271650 infores:hetionet CHEBI:8346 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0015967 infores:hetionet CHEBI:48131 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0020517 infores:hetionet CHEBI:7494 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0004245 infores:hetionet CHEBI:131512 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0012833 infores:hetionet GO:0002320 biolink:causes CL:0000838 infores:ubergraph knowledge_assertion manual_agent GO:0002320 CL:0000838 CHEBI:31932 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0687713 infores:hetionet CHEBI:261649 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0031542 infores:hetionet CHEBI:15551 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0021053 infores:hetionet CAID:CA523301794 biolink:causes MONDO:0100368 infores:clingen CAID:CA523301794 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PM2_Supporting NM_000329.3(RPE65):c.440_441del (p.Thr147ArgfsTer9) is a frameshift variant that introduces a premature stop codon into exon 5 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.000008030, with 16 alleles / 1,180,016 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 17724218) and in an LCA patient who was compound heterozygous with the p.Asp483del variant confirmed in trans (0.25 points, PMID: 9033008) which has not been classified by the ClinGen LCA / eoRD VCEP. (0.75 pts, PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PM3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA523301794/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CAID:CA367399044 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399044 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PP4, PM2_Supporting PS4, PM5 The c.1091G>T variant in the GCK gene, glucokinase, causes an amino acid change of cysteine to phenylalanine at codon 364 (p.(Cys364Phe)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 33450726, internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4, internal lab contributors). Another missense variant at this same amino acid position, p.(Cys364Trp) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1091G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399044/MONDO:0015967/086 2024-11-16 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA10644642 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644642 MONDO:0011071 PMID: Benign BA1 PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*429T>C is a 3' UTR variant. MAF 0.003527 (0.35%), 17/4820 alleles) in the South Asian subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644642/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9907 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0007222 infores:hetionet CAID:CA915952603 biolink:causes MONDO:0011071 infores:clingen CAID:CA915952603 MONDO:0011071 PMID: Likely Pathogenic PS4_Moderate, PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1035_1036dup (p.Arg346fs) is a frameshift variant which is not predicted to undergo nonsense-mediated mRNA decay (PVS1_strong). This variant is downstream of c.98 (PM5_supporting). It is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_moderate; PMID: 28933735, Appendix A Table 1, and unpublished data from the RUNX1 Natural History Cohort). In summary, this variant is classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PS4_moderate, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952603/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CAID:CA367400147 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400147 MONDO:0015967 PMID: Pathogenic PS4, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PM1 The c.881G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 294 (p.(Gly294Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.793, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 35737141, internal lab contributors). Additonally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with 2 informative meioses in 2 families (PP1; internal lab contributors). In summary, c.881G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PM2_Supporting, PP1, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400147/MONDO:0015967/086 2025-01-16 2025-01-29 Semidominant inheritance HP:0032113 Supports CHEBI:17334 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0013491 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0040147 infores:hetionet CHEBI:6741 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0025290 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0030312 infores:hetionet CHEBI:31401 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042029 infores:hetionet CHEBI:5098 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0002871 infores:hetionet CHEBI:4702 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0012569 infores:hetionet CHEBI:9943 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0234022 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0036454 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0267792 infores:hetionet CHEBI:28593 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C3665347 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0349506 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0234215 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0235763 infores:hetionet CHEBI:100241 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C2242737 infores:hetionet CHEBI:6801 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0013456 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0152010 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0152010 infores:hetionet CHEBI:10023 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0040264 infores:hetionet CAID:CA658798685 biolink:causes MONDO:0008723 infores:clingen CAID:CA658798685 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL): c.864del (p.Phe288Leufs*65) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Suporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798685/MONDO:0008723/021 2023-09-26 2023-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31348 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027947 infores:hetionet CAID:CA166228 biolink:causes MONDO:0700270 infores:clingen CAID:CA166228 MONDO:0700270 PMID:18634022 Uncertain Significance PM2_Supporting, PM3, PS3_Supporting, PP3 The c.5858C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1953 (p.Thr1953Ile). This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 18634022, 26896183). This variant is absent from gnomAD v2.1.1. Additionally, experimental studies showed that this variant impacts ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_supporting, PS3_supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA166228/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:48538 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0013384 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027339 infores:hetionet CHEBI:74947 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151942 infores:hetionet CHEBI:63613 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0027540 infores:hetionet CAID:CA398321249 biolink:causes MONDO:0011132 infores:clingen CAID:CA398321249 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PVS1 PS4, PM3 NM_001369369.1(FOXN1):c.340C>T (p.Arg114Ter) is a nonsense variant predicted to cause a premature stop codon (3/9) and lead to nonsense mediated decay in a disease that is loss of function (PVS1). The variant has been found in at least one homozygous patient with FOXN1 deficiency (PMID: 33464451, PM3_supporting). This patient displayed phenotypes including alopecia, nail dystrophy, absent lymphocyte proliferation to PHA, and very low CD4+CD31+CD45RA+ (PP4). The patient also had received a thymus transplant. The GrpMax in gnomADv4.1 is 0.000002920 (based on 8/1179484 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4, as specified by the ClinGen SCID VCEP. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398321249/MONDO:0011132/113 2024-09-27 2024-09-27 Semidominant inheritance HP:0032113 Supports CHEBI:63632 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0018790 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0042134 infores:hetionet CHEBI:119486 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0006625 infores:hetionet CAID:CA16615415 biolink:causes MONDO:0007648 infores:clingen CAID:CA16615415 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS4, BS3, PM6, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS2, PS3, PS4 The c.2324delG (p.Gly775Alafs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615415/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:50673 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C2830004 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0007222 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0042109 infores:hetionet NCBITaxon:1280 biolink:causes MONDO:0011438 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D000152 DB02703_MESH_D000152_1 CHEBI:51230 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0271321 infores:hetionet CAID:CA2582343066 biolink:causes MONDO:0700270 infores:clingen CAID:CA2582343066 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5, PVS1 The c.8491_8497del (p.Phe2831Thrfs*24) variant in ATM is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.2.1.1. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_ Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582343066/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28748 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0037287 infores:hetionet CHEBI:15553 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042024 infores:hetionet CHEBI:8888 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0028734 infores:hetionet CHEBI:40050 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0029118 infores:hetionet CHEBI:17688 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0235710 infores:hetionet CHEBI:194135 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0344232 infores:hetionet CHEBI:3061 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0011603 infores:hetionet NCBIGene:7138 biolink:causes MONDO:0957284 infores:monarchinitiative not_provided not_provided HGNC:11948 MONDO:0957284 uuid:32463321-5938-4352-936a-4e2a8ad4338c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3398 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0917801 infores:hetionet CHEBI:63621 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0003467 infores:hetionet CHEBI:5778 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0011124 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0013220 infores:hetionet CHEBI:6931 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0039070 infores:hetionet CHEBI:8802 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0233477 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042109 infores:hetionet CHEBI:68556 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0011603 infores:hetionet CHEBI:6640 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0013604 infores:hetionet CHEBI:8356 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037383 infores:hetionet CHEBI:8024 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0006277 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0019340 infores:hetionet CHEBI:7478 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C1167965 infores:hetionet CHEBI:50131 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0852911 infores:hetionet CHEBI:64354 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0038325 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018418 infores:hetionet CHEBI:8069 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0424295 infores:hetionet CHEBI:29688 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0008370 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037822 infores:hetionet NCBIGene:3662 biolink:causes MONDO:0976229 infores:monarchinitiative not_provided not_provided HGNC:6119 MONDO:0976229 uuid:ef561e73-4e40-48f0-be0f-d875093a6b1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2904 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0009806 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034882 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0270994 infores:hetionet CHEBI:127780 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0018681 infores:hetionet CHEBI:35854 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0014742 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019158 infores:hetionet CHEBI:36791 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030252 infores:hetionet CHEBI:63598 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C2242996 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0010073 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006325 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017178 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040046 infores:hetionet CHEBI:8327 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C1291078 infores:hetionet CHEBI:94440 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0010200 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0155169 infores:hetionet CHEBI:3207 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0002994 infores:hetionet CHEBI:68647 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0232462 infores:hetionet CHEBI:63717 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C2711227 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0003460 infores:hetionet CHEBI:3723 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0241060 infores:hetionet CHEBI:68845 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0015672 infores:hetionet CHEBI:9316 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0235063 infores:hetionet CHEBI:6923 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0030193 infores:hetionet CHEBI:2904 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0023222 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0014457 infores:hetionet CHEBI:3387 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0233407 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0349506 infores:hetionet CHEBI:7465 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0006277 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020676 infores:hetionet CHEBI:50922 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0851578 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0233414 infores:hetionet CHEBI:9288 biolink:causes MONDO:0060779 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0341702 infores:hetionet CHEBI:64064 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037011 infores:hetionet CHEBI:15407 biolink:causes UMLS:C0242453 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0242453 infores:hetionet CHEBI:17650 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0040046 infores:hetionet CHEBI:2636 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0016382 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0034063 infores:hetionet CHEBI:91834 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0019080 infores:hetionet NCBIGene:54345 biolink:causes MONDO:0011914 infores:monarchinitiative not_provided not_provided HGNC:11194 MONDO:0011914 uuid:330c2031-e6ba-4149-ab03-9d966f3a0bf3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0344232 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0035854 infores:hetionet CHEBI:7986 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0152227 infores:hetionet CHEBI:6931 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C1145670 infores:hetionet CHEBI:3647 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0424448 infores:hetionet CHEBI:78543 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0031039 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0036572 infores:hetionet CHEBI:116278 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0037763 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0235146 infores:hetionet UMLS:C0120107 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0740394 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027796 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0919671 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0239295 infores:hetionet CHEBI:42355 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0042963 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002170 infores:hetionet NCBIGene:9244 biolink:causes MONDO:0010091 infores:monarchinitiative not_provided not_provided HGNC:2364 MONDO:0010091 uuid:fa260f9e-3da7-4f7a-a643-e45a923bff5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35677 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0009676 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0032584 infores:hetionet CHEBI:63581 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0009782 infores:hetionet CHEBI:7445 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0043094 infores:hetionet CAID:CA320251499 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251499 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1100G>A (p.Gly367Asp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251499/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:46557 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0239340 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1619702 infores:hetionet CHEBI:9555 biolink:causes UMLS:C0020510 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0020510 infores:hetionet CAID:CA8815129 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815129 MONDO:0009290 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3 The NM_000152.5(GAA):c.1019A>G variant in GAA is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 340 (p.Tyr340Cys). This variant has been detected in at least 4 individuals with Pompe disease and at least 2 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (internal lab data). Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 1 was confirmed in trans by parental testing, including c.-32-13T>G (1 patient, internal lab data, confirmed in trans), c.2560C>T; p.Arg854* (1 patient, internal lab data, phase unknown), and c.1292_1295dup p.(Gln433Alafs *74) (1 patient, PMID: 32802993, phase unknown and no follow up to NBS). In addition, one patient is compound heterozygous for the variant and c.1725C>T (p.Tyr575Tyr) (internal lab data), which is not classified as P/LP and one patient was compound heterozygous for the variant and c.2432delT (p.Leu811Argfs*37) (internal lab data, confirmed in trans), but enzyme testing was in the carrier range (PM3 and PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (28/282466 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.752 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 289356, 2 star review status) with 7 submitters classifying the variant as a variant of uncertain significance. In summary, while this variant meets the criteria to be classified as likely pathogenic for Pompe disease, the GAA VCEP does not believe there is insufficient phenotypic evidence to support this classification at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VAriant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen Lysosomal Diseases VCEP, August 1st, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815129/MONDO:0009290/010 2023-08-01 2023-09-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:9123 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013144 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0677500 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002285 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0034124 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0948594 infores:hetionet UMLS:C0025241 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0149745 infores:hetionet CHEBI:64312 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0030232 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151541 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151541 infores:hetionet CHEBI:31413 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011206 infores:hetionet NCBIGene:80067 biolink:causes MONDO:0009419 infores:monarchinitiative not_provided not_provided HGNC:25784 MONDO:0009419 uuid:e2b11277-f27a-4273-b87b-2a47368d117e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:54872 biolink:causes MONDO:0014832 infores:monarchinitiative not_provided not_provided HGNC:25985 MONDO:0014832 uuid:4244485c-dafd-494d-96a4-21f6f6deebc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002622 infores:hetionet CHEBI:49662 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0027497 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0040046 infores:hetionet CAID:CA10590104 biolink:causes MONDO:0044970 infores:clingen CAID:CA10590104 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, BP4, PS4 PP1, PS2, PS3, PM6 The m.14692A>G variant in MT-TE has been reported in four people with primary mitochondrial disease to date (PMIDs: 27519417, 32169613; PS4_supporting). Affected individuals had maternally inherited diabetes and deafness (MIDD). The variant was homoplasmic in blood in three individuals and heteroplasmy level was not reported in the fourth. The variant was homoplasmic in affected and unaffected family members. There are no reported de novo occurrences. Additional associations with this variant have been reported but are outside the scope of this curation, including as a modifier of Leber Hereditary Optic Neuropathy, LHON (PMID: 8728098), and associated with tic disorders (PMID: 33289513), hypertension (PMID: 27544295), and dilated cardiomyopathy (PMID: 34991096). There are several occurrences in population databases (MITOMAP’s GenBank sequences - 0.040%; gnomAD v3.1.2 - 0.002%, Helix dataset - 0.009%). Although there are several occurrences, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is benign (2.4 percentile) and HmtVAR predicts it to be tolerated with a score of 0.1 (BP4). While there are no cybrids or single fiber studies reported on this variant, additional studies support a deleterious effect of this variant including those showing aberrant tRNA modification and conformation, decreased amount of tRNAGlu and decreased steady state levels of tRNAGlu, decreased mitochondrial protein amounts with those with higher proportion of glutamic acid residues having lower levels; and reductions (in the range of 56-72% of controls) in basal oxygen consumption rate (OCR), ATP-linked OCR, proton leak OCR, maximal OCR, reserve capacity, and non-mitochondrial OCR (PMID: 27519417). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 7, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10590104/MONDO:0044970/015 2025-01-07 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:28901 biolink:causes UMLS:C0541887 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0541887 infores:hetionet CHEBI:6715 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0036974 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0009782 infores:hetionet CHEBI:7903 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020488 infores:hetionet CHEBI:8214 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0017178 infores:hetionet CHEBI:16469 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0687713 infores:hetionet CHEBI:8888 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151905 infores:hetionet CHEBI:75988 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0085593 infores:hetionet CHEBI:7514 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0033774 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151763 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0037274 infores:hetionet CAID:CA5416774 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416774 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.586C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Tryptophan at amino acid 196 (p.Arg196Trp).The filtering allele frequency (the upper threshold of the 95% CI of 4/59978 alleles) of the c.586C>T variant in DCLRE1C is 0.00002256 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416774/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:2N4O9L084N biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0700590 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0020651 infores:hetionet CHEBI:8232 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0031542 infores:hetionet CHEBI:32315 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0438215 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0007194 infores:hetionet CHEBI:51380 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0001824 infores:hetionet CAID:CA160228 biolink:causes MONDO:0010938 infores:clingen CAID:CA160228 MONDO:0010938 PMID: Uncertain Significance PM2_Supporting BA1, BS1, PM5 The NM_000215.4(JAK3):c.2324G>A variant in JAK3 is a missense variant predicted to cause substitution of arginine by cysteineat amino acid 775 (p.Arg775Cys). The filtering allele frequency (the upper threshold of the 95% CI of 55/1113096) of the c.2323C>T variant in JAK3 is 0.00003886 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID JAK3 VCEP threshold (<0.000115) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160228/MONDO:0010938/121 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45409 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022081 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235218 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235218 infores:hetionet CHEBI:47499 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0235660 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0014130 infores:hetionet CHEBI:474180 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020580 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0030920 infores:hetionet CHEBI:63617 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0031256 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0242350 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0162429 infores:hetionet CHEBI:40279 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0027066 infores:hetionet NCBIGene:439 biolink:causes MONDO:0859358 infores:monarchinitiative not_provided not_provided HGNC:752 MONDO:0859358 uuid:d002467f-550a-4044-9591-a7a830205224 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512232133 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232133 MONDO:0011071 PMID: Uncertain Significance PS4_Moderate, BP4, BP7, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1389C>T (p.Pro463=) is a synonymous variant which has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27106701). This synonymous variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.50) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_moderate, BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232133/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63599 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0232459 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0852967 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0852967 infores:hetionet CAID:CA367400486 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400486 MONDO:0015967 PMID: Likely Pathogenic PM5, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.820G>T variant in the glucokinase gene, GCK, is a missense variant resulting in an amino acid change of aspartic acid to tyrosine at codon 274 (p.(Asp274Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.99, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with hyperglycemia with four informative meioses in a single family (PP1_Moderate, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies). (PP4_Moderate; internal lab contributors). Another missense variant at the same amino acid, c.820G>A p.(Asp274Ala), has been classified as pathogenic by the ClinGen MDEP and p.Asp274Tyr has a larger Grantham distance (PM5). In summary, c.820G>T variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP1_Moderate, PP4_Moderate, PM2_Supporting, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400486/MONDO:0015967/086 2024-11-04 2024-11-05 Semidominant inheritance HP:0032113 Supports CHEBI:4995 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151480 infores:hetionet CHEBI:7852 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018681 infores:hetionet CHEBI:28487 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0042963 infores:hetionet CHEBI:6520 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0029124 infores:hetionet CHEBI:145499 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004144 infores:hetionet NCBIGene:3040 biolink:causes MONDO:0013512 infores:monarchinitiative not_provided not_provided HGNC:4824 MONDO:0013512 uuid:0709b8dd-d544-4d24-8dad-773e41244122 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4754 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01127 UMLS:C0085624 infores:hetionet CHEBI:9460 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0013604 infores:hetionet CHEBI:44185 biolink:causes HP:0200123 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0019189 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0030312 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0151596 infores:hetionet CHEBI:4953 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0008031 infores:hetionet CHEBI:8888 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002994 infores:hetionet CHEBI:16714 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0080274 infores:hetionet CHEBI:28864 biolink:causes HP:0001686 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0003564 infores:hetionet CAID:CA658658486 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658486 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP7, BP5, BS4, BS1, BS3, PM4, PM1, PM3, PM6, PP1, PP4, PP3, PP2, BS2, BP3, BP4, BP1, BP2, BA1, PS1, PS3, PS2 The c.1085delT (p.Val362Glyfs*31) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000669065.1). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658486/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:8707 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0232461 infores:hetionet UMLS:C0011701 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0010200 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0919715 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0425945 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019360 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0018524 infores:hetionet CHEBI:6375 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014518 infores:hetionet CHEBI:92712 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0022575 infores:hetionet HP:0001950 biolink:causes MONDO:0006625 infores:drugmechdb knowledge_assertion manual_agent HP:0001950 MESH:D000532 DB00819_MESH_D000532_1 CHEBI:205919 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0858797 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0003123 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0023067 infores:hetionet CHEBI:32599 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0035232 infores:hetionet CHEBI:8107 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0162830 infores:hetionet CHEBI:9599 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0242429 infores:hetionet CAID:CA16020923 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020923 MONDO:0009861 PMID: Likely Pathogenic PM2, PVS1 PP4 The frameshift variant c.1057del (p.Glu353AsnfsTer47) in exon 10 creates a premature stop codon in exon 11 which is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One typical PKU patient has been reported (PMID: 8069318) which BioPKU reports affiliated with this variant however the actual variant is c.1055del, so no patients have been reported with this variant. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1 and PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020923/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports UNII:3U02EL437C biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0853813 infores:hetionet CHEBI:32315 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0232462 infores:hetionet CHEBI:74947 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0423791 infores:hetionet CHEBI:6359 biolink:causes UMLS:C0235395 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0235395 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0518015 infores:hetionet CHEBI:47381 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022107 infores:hetionet CHEBI:3127 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0023212 infores:hetionet CAID:CA214291 biolink:causes MONDO:0015967 infores:clingen CAID:CA214291 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 The c.1768+65dup variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within intron 9 of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss, suggesting that the variant has no impact on splicing (BP4). In summary, c.1768+65dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214291/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0011551 infores:hetionet CHEBI:3994 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0549249 infores:hetionet CHEBI:5134 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0152459 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0521492 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0521492 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020517 infores:hetionet CHEBI:45924 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C1257843 infores:hetionet CHEBI:6149 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030486 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020651 infores:hetionet NCBIGene:23250 biolink:causes MONDO:0030724 infores:monarchinitiative not_provided not_provided HGNC:13552 MONDO:0030724 uuid:3314ad91-8ea2-48f5-85ca-ea3433579c9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030193 infores:hetionet CHEBI:83804 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0338831 infores:hetionet CHEBI:10023 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0009676 infores:hetionet GO:0044551 biolink:causes GO:0042311 infores:ubergraph knowledge_assertion manual_agent GO:0044551 GO:0042311 CHEBI:119915 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151505 infores:hetionet CHEBI:9907 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0011168 infores:hetionet CAID:CA9870529 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870529 MONDO:0015967 PMID: Likely Benign PP4, BP4, BP7, BS1 The c.1293C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 431 (p.(Val431=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.754, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006015, which is greater than the MDEP threshold for BS1 (greater than 0.000033) (BS1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; Internal lab contributor). In summary, c. 1293C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BS1, BP4, BP7, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870529/MONDO:0015967/085 2023-01-12 2023-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0065374 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0015230 infores:hetionet CHEBI:64310 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0542571 infores:hetionet CHEBI:9137 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0004134 infores:hetionet CHEBI:64312 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0856054 infores:hetionet CAID:CA386960529 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960529 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Moderate, PVS1, PP4 PS4 The c.494G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 165 (p.(Trp165Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Furthermore, this variant segregated with diabetes, with three informative meioses, in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability estimated between 39-59% based on available clinical information, sulfonylurea-sensitive, and negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.494G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Moderate, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960529/MONDO:0015967/017 2022-06-10 2022-06-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2663 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0235270 infores:hetionet CAID:CA051349 biolink:causes MONDO:0007947 infores:clingen CAID:CA051349 MONDO:0007947 PMID: Likely Benign BP2, BS4 PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM3, PM4, BP5, BP7, BS1, BS3 NM_00138 c.3689T>C is a missense variant in FBN1 predicted to cause a substitution of a Methionine by Threonine at amino acid 1230 p.(Met1230Thr). This variant was identified in an internal proband with ectopia lentis and thoracic aortic aneurysm and dissection, however a pathogenic frameshift variant in FBN1 was also identified in the proband (BP2) and was considered to explain the phenotype. Furthermore this variant does not segregate with disease in an affected family member (BS4). . This variant has been previously reported in ClinVar as of uncertain significance (Variation ID: 263789). This variant has been identified in 0.0018% of individuals of European origin (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS4, BP2 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA051349/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:70735 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0235660 infores:hetionet CHEBI:132233 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0011570 infores:hetionet NCBIGene:9662 biolink:causes MONDO:0013849 infores:monarchinitiative not_provided not_provided HGNC:29086 MONDO:0013849 uuid:c1be7516-b8fd-4264-a153-021e7b4c6015 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0007222 infores:hetionet CHEBI:473990 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0019212 infores:hetionet CHEBI:6438 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0039070 infores:hetionet CHEBI:3207 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0497156 infores:hetionet CHEBI:3756 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0013390 infores:hetionet CHEBI:6822 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0017178 infores:hetionet CHEBI:52717 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232461 infores:hetionet CHEBI:101278 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042384 infores:hetionet CHEBI:47381 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013390 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0015376 infores:hetionet CHEBI:7476 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151825 infores:hetionet NCBIGene:4148 biolink:causes MONDO:0012108 infores:monarchinitiative not_provided not_provided HGNC:6909 MONDO:0012108 uuid:55e92246-7fe2-4bc1-85c6-aa4c452b0b8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes UMLS:C0221780 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0221780 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0162429 infores:hetionet NCBIGene:50484 biolink:causes MONDO:0013117 infores:monarchinitiative not_provided not_provided HGNC:17296 MONDO:0013117 uuid:29e31d4f-8b96-4fed-aad4-0260ce356e81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0004936 infores:hetionet CHEBI:52172 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0852795 infores:hetionet NCBIGene:8912 biolink:causes MONDO:0014875 infores:monarchinitiative not_provided not_provided HGNC:1395 MONDO:0014875 uuid:b15b2718-213b-40ed-a669-2a736ab0232a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0020517 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0349506 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0302295 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0178298 infores:hetionet CHEBI:135935 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0549249 infores:hetionet CHEBI:7443 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0162830 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0016436 infores:hetionet CAID:CA409121739 biolink:causes MONDO:0007064 infores:clingen CAID:CA409121739 MONDO:0007064 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The NM_000022.4(ADA):c.201C>G (p.Tyr67Ter) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 3/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in ClinVar without patient information; however, it has not been reported in the literature to our knowledge. In summary, this variant meets the criteria to be classified as Likely Pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1 and PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409121739/MONDO:0007064/114 2024-01-16 2024-01-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018801 infores:hetionet CAID:CA010043 biolink:causes MONDO:0004994 infores:clingen CAID:CA010043 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.1002C>T (p.Asn334=) variant in the MYH7 gene is 4.12% (463/10398) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010043/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3756 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0518015 infores:hetionet CHEBI:10650 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0699744 infores:hetionet CHEBI:7507 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0002792 infores:hetionet CHEBI:49603 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0013404 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0267792 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0037274 infores:hetionet CHEBI:3219 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085631 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0039971 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0857353 infores:hetionet CAID:CA386958912 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958912 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP1_Moderate, PP3 BP4, PS4, PP4 The c.346G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 116 (p.(Ala116Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.968, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in three unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributors). This variant segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). Another missense variant, c.347C>T (p.Ala116Val), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala116Thr (PM5_Supporting). In summary, c.346G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP1_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958912/MONDO:0015967/017 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38940 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0162834 infores:hetionet CHEBI:28445 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0522224 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0520962 infores:hetionet CHEBI:2567 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0017152 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0836924 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0948089 infores:hetionet CHEBI:3757 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0013604 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0032285 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0029408 infores:hetionet CHEBI:34967 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0018681 infores:hetionet CHEBI:42944 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0018524 infores:hetionet CAID:CA8328353 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328353 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting PP3 NM_014336.5(AIPL1):c.931C>T (p.Arg311Cys) is a missense variant replacing arginine with cysteine at amino acid p.311. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000004349, with 7 alleles / 1,609,436 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.519, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on AIPL1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. No published probands harboring the variant have been identified. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328353/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63577 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0232462 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0025061 infores:hetionet CHEBI:2904 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0541782 infores:hetionet CAID:CA2695202143 biolink:causes MONDO:0700270 infores:clingen CAID:CA2695202143 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5_Supporting, PVS1 The c.480_484del p.Gln161Thrfs*22 variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 10234507, 26896183). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM3_supporting, PM5_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202143/MONDO:0700270/020 2024-02-26 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:132233 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0232492 infores:hetionet CAID:CA177366 biolink:causes MONDO:0019501 infores:clingen CAID:CA177366 MONDO:0019501 PMID: Likely Pathogenic PP4, PP3, PM3, PM5 BS1, PM2, BA1 The c.397C>A variant in MYO7A is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 133 (p.His133Asn). The filtering allele frequency in gnomAD v4 is 0.01079% (147/1179888) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met). This variant has been reported as compound heterozygous, phase unknown, with a pathogenic variant in three individuals. One individual had a phenotype of Usher syndrome, one individual had congenital, severe to profound hearing loss, and one individual had inherited retinal disease (PM3, PP4; PMID: 36011334, 26969326, 38219857). Two additional individuals with clinical features of Usher syndrome harbored the variant phase unknown with another variant of uncertain significance (PMID: 37466950, SCV001218757.5). The computational predictor REVEL gives a score of 0.937, which is above the threshold necessary to apply PP3 (PP3). Another missense variant, c.397C>T p.His133Tyr, in the same codon has been classified as pathogenic for Usher syndrome by the ClinGen Hearing Loss VCEP (PM5; ClinVar Variation ID: 43228). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4, PP3, PM5. (ClinGen Hearing Loss VCEP specifications version 2; 03/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA177366/MONDO:0019501/005 2025-03-12 2025-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:2668 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C1510410 infores:hetionet CHEBI:82716 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0234233 infores:hetionet CHEBI:51209 biolink:causes UMLS:C0242453 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0242453 infores:hetionet NCBIGene:6795 biolink:causes MONDO:0009461 infores:monarchinitiative not_provided not_provided HGNC:11391 MONDO:0009461 uuid:7fb42c4f-4034-4608-82e7-440d38d7595a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0001175 infores:hetionet CAID:CA512341312 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341312 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1):c.1092C>T (p.Ile364=) synonymous variant in RUNX1 has a reported MAF of Allele frequency 0.00001 (1/88634) in non-Finnish Europeans, and does not meet criteria for BA1, BS2, or PM2_Supporting. REVEL score is not calculable, as this is a synonymous variant. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.245646 < 2.0). In summary, this variant is classified as Likely Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341312/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7494 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0039971 infores:hetionet CHEBI:63115 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0018790 infores:hetionet CHEBI:5613 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0024902 infores:hetionet CHEBI:2668 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0022346 infores:hetionet CHEBI:4798 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C1527344 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0012833 infores:hetionet CHEBI:47780 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027066 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039971 infores:hetionet CHEBI:61049 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0233407 infores:hetionet CHEBI:63620 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020580 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0020649 infores:hetionet CHEBI:101278 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0041657 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020517 infores:hetionet CHEBI:51450 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0011175 infores:hetionet CHEBI:52010 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0027424 infores:hetionet CHEBI:51230 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0020443 infores:hetionet CAID:CA382516273 biolink:causes MONDO:0700270 infores:clingen CAID:CA382516273 MONDO:0700270 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PM3 PM5, PP3 The c.3284G>C (p.Arg1095Thr) variant in ATM is a missense variant occurring in last base pair of exon 21. It is predicted to cause skipping of biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism variant. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMIDs: 10980530, 37787810). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1_Strong, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382516273/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6359 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0011175 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013985 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020615 infores:hetionet CHEBI:421707 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0043144 infores:hetionet CHEBI:8707 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030196 infores:hetionet CHEBI:3568 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017181 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0948594 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0002871 infores:hetionet CAID:CA121707 biolink:causes MONDO:0010726 infores:clingen CAID:CA121707 MONDO:0010726 PMID: Benign BS1, BS2 PP3 The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly428Ser variant is observed in at least 2 unaffected individuals (PMID: 11238684, PMID: 12161600) (BS2). In summary the p.Gly428Ser variant in MECP2 is classified as Benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121707/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:408174 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0013604 infores:hetionet CHEBI:39867 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0235996 infores:hetionet CHEBI:4551 biolink:causes MONDO:0005479 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0546959 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235969 infores:hetionet CHEBI:8890 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0000731 infores:hetionet NCBIGene:3039 biolink:causes MONDO:0020835 infores:monarchinitiative not_provided not_provided HGNC:4823 MONDO:0020835 uuid:a22eedf7-29c8-43c2-9dc2-00837cbd9e67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0347390 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0023530 infores:hetionet CHEBI:28445 biolink:causes HP:0033400 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0000727 infores:hetionet CHEBI:68478 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020580 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0018099 infores:hetionet UNII:54Z8M50D6Q biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0221490 infores:hetionet CHEBI:9738 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0242429 infores:hetionet NCBIGene:487 biolink:causes MONDO:0010977 infores:monarchinitiative not_provided not_provided HGNC:811 MONDO:0010977 uuid:717612ce-5d5f-4761-b5ad-455c206ae2be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0019054 infores:hetionet NCBIGene:930 biolink:causes MONDO:0013283 infores:monarchinitiative not_provided not_provided HGNC:1633 MONDO:0013283 uuid:40c466af-69e4-424a-9a54-43846ae5a2f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410206771 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206771 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.748C>T (p.Arg250Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206771/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2639 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0003123 infores:hetionet CHEBI:135613 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0030196 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0006840 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0032285 infores:hetionet CAID:CA386960575 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960575 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.498C>G variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 166 (p.(Tyr166Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.498C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023: PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960575/MONDO:0015967/017 2025-01-17 2025-01-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72297 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0042963 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0001824 infores:hetionet CHEBI:4027 biolink:causes MONDO:0044919 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0153618 infores:hetionet CAID:CA1394924 biolink:causes MONDO:0019501 infores:clingen CAID:CA1394924 MONDO:0019501 PMID: Likely Benign BP7, BP4, BS1_Supporting The filtering allele frequency (the lower threshold of the 95% CI of 57/19928 of the c.7167C>T (p.Ser2389=) variant in the USH2A gene is 0.22% for East Asian chromosomes by gnomAD v2.1.1, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The silent c.7167C>T variant in USH2A is not predicted by the computational prediction analysis using MaxEntScan to impact splicing (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_P, BP4,BP7. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1394924/MONDO:0019501/005 2020-05-26 2020-05-26 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3732 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0034886 infores:hetionet CHEBI:135736 biolink:causes NCIT:C92849 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0240802 infores:hetionet UMLS:C0025241 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0030193 infores:hetionet UNII:R43D2573WO biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013378 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0027651 infores:hetionet CHEBI:4672 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0043352 infores:hetionet CAID:CA170197 biolink:causes MONDO:0010726 infores:clingen CAID:CA170197 MONDO:0010726 PMID: Benign BP5, BS2, BA1, BP4 The allele frequency of the p.Glu394Lys variant in MECP2 is 0.035% in East Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Glu394Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Glu394Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Glu394Lys variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Glu394Lys variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170197/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:168396 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0027651 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1096340 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1096340 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014549 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0005114 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D011008 DB01627_MESH_D011008_1DB02703_MESH_D011008_1 CHEBI:4784 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0021141 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0013395 infores:hetionet CHEBI:145499 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0004604 infores:hetionet CHEBI:3757 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0033774 infores:hetionet CHEBI:7496 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0149745 infores:hetionet CHEBI:3752 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0019065 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0948349 infores:hetionet CHEBI:27834 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0024103 infores:hetionet CHEBI:5864 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0344232 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0018801 infores:hetionet CHEBI:31638 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0236075 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0017160 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0002871 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0234458 infores:hetionet NCBIGene:3187 biolink:causes MONDO:0859301 infores:monarchinitiative not_provided not_provided HGNC:5041 MONDO:0859301 uuid:36254596-03b6-4a8d-bc25-64e758304cda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0041582 infores:hetionet NCBIGene:4308 biolink:causes MONDO:0013183 infores:monarchinitiative not_provided not_provided HGNC:7146 MONDO:0013183 uuid:91676eaa-6f05-4abe-8f82-86144dfead2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0236082 infores:hetionet CHEBI:63621 biolink:causes UMLS:C2939130 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2939130 infores:hetionet CHEBI:3371 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0030193 infores:hetionet CHEBI:8428 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0003862 infores:hetionet CHEBI:45081 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0042963 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0548823 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005383 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030319 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234987 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0086543 infores:hetionet CHEBI:4551 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0344232 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0017152 infores:hetionet CAID:CA412361753 biolink:causes MONDO:0100039 infores:clingen CAID:CA412361753 MONDO:0100039 PMID: Likely Benign BS1, BS2_Supporting PM1, PP3, BP4, PS4 The allele frequency of the p.Pro527Ser variant in CDKL5 is 0.017% in African sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro527Ser variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro527Ser variant in CDKL5 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412361753/MONDO:0100039/034 2023-02-20 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:51860 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0424295 infores:hetionet NCBIGene:51412 biolink:causes MONDO:0032768 infores:monarchinitiative not_provided not_provided HGNC:160 MONDO:0032768 uuid:9c7cd58c-4093-4e98-830b-f5333fa7a65d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151786 infores:hetionet CHEBI:134991 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0039231 infores:hetionet CAID:CA389475173 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475173 MONDO:0100040 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting, BP4 BS1 The p.Ala159Thr variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). The p.Ala159Thr variant is observed in at least 1 unaffected individual (internal database - Labcorp Genetics) (BS2_Supporting). The computational predictor REVEL gives a score of 0.218, which is below the threshold of 0.290, evidence that does not predict a damaging effect on FOXG1 function (BP4). In summary, the p.Ala159Thr variant in FOXG1 is classified as variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BS2_Supporting, BP4). (FOXG1 Specifications v.4.1; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475173/MONDO:0100040/035 2025-06-25 2025-06-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17026 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0037274 infores:hetionet CHEBI:16714 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0042075 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0038363 infores:hetionet CHEBI:3647 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0013384 infores:hetionet CHEBI:32588 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0728899 infores:hetionet CHEBI:135285 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0012833 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0542184 infores:hetionet CAID:CA376062327 biolink:causes MONDO:0011225 infores:clingen CAID:CA376062327 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.276G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 92 (p.Gln92His).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376062327/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45367 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0238106 infores:hetionet CAID:CA8129833 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129833 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM5, PM4, PM6, PVS1, PP1, PP2, PP3, PP4, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.363C>A variant is <1/50,000 alleles (0.002%, 2/113,262 alleles) in the non-Finnish European gnomAD subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). No additional evidence met criteria for consideration. Therefore, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129833/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:52717 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009938 infores:hetionet CHEBI:68647 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C1527344 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0917799 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027765 infores:hetionet CHEBI:6129 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0085631 infores:hetionet CHEBI:31302 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0001807 infores:hetionet CAID:CA16610570 biolink:causes MONDO:0015924 infores:clingen CAID:CA16610570 MONDO:0015924 PMID:7768349PMID:30809644PMID:18321866PMID:25688877 Uncertain Significance PM2, PP3, BP4, PS1, PM1, PM5, BS1, BS3 The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.0001105 (1/9046 alleles) in East Asian population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The computational predictor REVEL gives a score of 0.662, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. The variant does not affect protein localization to the plasma membrane (PMID: 25688877) or cell viability (PMID: 30809644). A single luciferase assay demonstrated comparable canonical transcriptional activity to wild-type (PMID: 18321866). However, the lack of effect on canonical signaling in one assay without replication in an independent assay, did not provide conclusive evidence for non-criticality (BS3 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: No criteria scored. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA16610570/MONDO:0015924/125 2025-09-19 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3077 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0268000 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006285 infores:hetionet CHEBI:5130 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0037299 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0740409 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0740409 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011570 infores:hetionet GO:0043300 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0043300 GO:0051641 UMLS:C1872203 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0085649 infores:hetionet CHEBI:204928 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0002792 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151698 infores:hetionet CHEBI:68478 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0344232 infores:hetionet CAID:CA10014446 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014446 MONDO:0011071 PMID: Benign BP4, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.613+108G>A is a noncoding (intronic) variant. This variant has a MAF of 0.00244 (0.244%, 646/265052, 547 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort, which is ≥ 0.0015 (0.15%) (BA1). No splicing impact or creation of cryptic splice sites is predicted by SSF and MES. SpliceAI predicts no impact to splicing (score: 0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.18222 < 2.0) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014446/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:46557 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020621 infores:hetionet CHEBI:83804 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015967 infores:hetionet CHEBI:10650 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0340865 infores:hetionet CHEBI:45863 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0162834 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0037199 infores:hetionet CHEBI:8888 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0233471 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0038587 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0235431 infores:hetionet CHEBI:5864 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C2047937 infores:hetionet CAID:CA199769 biolink:causes MONDO:0044970 infores:clingen CAID:CA199769 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting, PP1_Moderate, PS2_Moderate PP4, PM6 The m.8969G>A (p.S148N) variant in MT-ATP6 has been reported in at least five individuals from four families in the literature with features including nephrotic syndrome, developmental delay, seizures, stroke-like episodes, muscle weakness, brain atrophy, agenesis of the corpus callosum, hearing loss, Wolff-Parkinson-White syndrome, increased fasting level of glucose, liver steatosis, and failure to thrive, with heteroplasmy levels ranging from 61-96% (PS4_moderate; PMIDs: 25037980, 29350304, 27812026, 27450679). Additionally, this expert panel knew of two local families with affected individuals with this variant that the expert panel agreed to include. The variant was de novo in two of the four families reported in the literature (PS2_moderate; PMIDs: 25037980, 27450679). This variant segregated with disease in multiple affected members in one family and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29350304). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMID: 27812026). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.57 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS2_moderate, PP1_moderate, PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA199769/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:2663 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0018790 infores:hetionet GO:1905079 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0007420 CHEBI:64321 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0152027 infores:hetionet CHEBI:31711 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C2939147 infores:hetionet CHEBI:4735 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0152227 infores:hetionet CHEBI:6367 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0558489 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0018799 infores:hetionet CHEBI:119573 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0025874 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0235234 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0243026 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0456909 infores:hetionet CHEBI:63631 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085623 infores:hetionet CHEBI:3219 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040435 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0013395 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018799 infores:hetionet NCBIGene:3643 biolink:causes MONDO:0009874 infores:monarchinitiative not_provided not_provided HGNC:6091 MONDO:0009874 uuid:9e969334-35d7-4853-bd00-1a08bf9ce5d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0009763 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0004936 infores:hetionet CAID:CA8328516 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328516 MONDO:0100438 PMID: Pathogenic PVS1, PM2_Supporting, PM3 NM_014336.5(AIPL1):c.421C>T (p.Gln141Ter) is a nonsense variant that introduces a premature stop codon into exon 3 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000002482, with 4 / 1611860 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID:31630094, PM3). This variant has also been reported in at least 4 probands with early-onset severe retinal dystrophy who were compound heterozygous with the p.Asp51Gly, p.Glu304Ter, or p.Lys214Asn variants confirmed in trans (PMID:31630094). These variants have not yet been classified by the ClinGen LCA/eoRD VCEP so were not counted for PM3. In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, and PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328516/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15854 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0948594 infores:hetionet CHEBI:50131 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0038002 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0004134 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0010692 infores:hetionet CHEBI:51141 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C1268766 infores:hetionet CHEBI:47780 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C2937358 infores:hetionet CHEBI:31536 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0917801 infores:hetionet CAID:CA228314 biolink:causes MONDO:0015631 infores:clingen CAID:CA228314 MONDO:0015631 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, BP4, PM3, PS3 PP1, PM5 The c.2278C>T variant in VWF is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 760 (p.Arg760Cys). This variant lies 4 amino acids before the cleavage site for pro-VWF. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity and decreased VWF:FVIII binding 0f 0.23, which is highly specific for VWD type 2N. (PP4_moderate, PMID: 12393698). This individual was compound heterozygous (confirmed in trans by parental testing) for this variant and the p.R854Q variant which was classified as pathogenic by the VCEP (1 PM3 points, PM3). Factor VIII binding assay performed with the p.Arg760Cys recombinant mutant and wt vWF expressed by FUR4BHK cells showed absent binding indicating that this variant has a damaging effect on protein function (PMID: 12393698 )(PS3). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000007410 (based on 2/60034 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.005 for type 2N VWD (PM2_Supporting). The computational predictor REVEL gives a score of 0.219, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function. Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive von Willebrand disease type 2N based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PM2_Supporting, PM3, PS3, and BP4 (VCEP specifications version 1.0.0; date of approval). von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228314/MONDO:0015631/090 2025-01-07 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports UNII:15G12L5X8K biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1145670 infores:hetionet GO:2000702 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0001823 CHEBI:63618 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0015672 infores:hetionet NCBIGene:7227 biolink:causes MONDO:0008596 infores:monarchinitiative not_provided not_provided HGNC:12340 MONDO:0008596 uuid:66c4a287-a5b3-4f4e-992c-8ae9d213b889 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040409 infores:hetionet CHEBI:5790 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0033774 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009241 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0006145 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013395 infores:hetionet CHEBI:8802 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1565489 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042401 infores:hetionet CHEBI:50730 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0040425 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003117 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0037650 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0549369 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0549369 infores:hetionet CHEBI:9943 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2979982 infores:hetionet CHEBI:48844 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0232492 infores:hetionet CHEBI:72297 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C2830004 infores:hetionet CHEBI:64312 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085628 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0269936 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C1331543 infores:hetionet CHEBI:7852 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1260880 infores:hetionet CHEBI:48273 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0016382 infores:hetionet CHEBI:135736 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0040586 infores:hetionet CHEBI:465284 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151577 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020517 infores:hetionet CHEBI:6950 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011175 infores:hetionet CHEBI:51230 biolink:causes HP:6000420 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0234655 infores:hetionet CHEBI:17303 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0015967 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0854134 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0854134 infores:hetionet CHEBI:2038 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C1384353 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0033575 infores:hetionet CHEBI:9943 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0025222 infores:hetionet CHEBI:231594 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0036974 infores:hetionet CAID:CA401365023 biolink:causes MONDO:0009290 infores:clingen CAID:CA401365023 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000152.5:c.1134C>G (p.Tyr378Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 7/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients with this variant have been reported with Pompe disease, both treated with enzyme replacement therapy (PMID: 29181627, 31392188) (PP4). One of these individuals is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G (PMID: 31392188). The second patient is compound heterozygous for the variant and c.1478C>T (p.Pro493Leu) (PMID: 29181627); the allelic data for this patient will be used in the classification of p.Pro493Leu and was not included here to avoid circular logic (PM3_Supporting). This variant was absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 595469). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PVS1, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401365023/MONDO:0009290/010 2023-07-03 2023-09-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UNII:3QJA87N40S biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0040586 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0022408 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009806 infores:hetionet CAID:CA6748984 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748984 MONDO:0009861 PMID:17502162PMID:17502162PMID:24368688 Uncertain Significance PP4, PM2_Supporting, PM3_Supporting, PP3_Moderate PM5 The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID: 17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID: 17502162) and a likely pathogenic variant p.Y154F (PMID: 24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748984/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4672 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0004134 infores:hetionet CHEBI:3508 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0021368 infores:hetionet CHEBI:9588 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0151594 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0027051 infores:hetionet CHEBI:63620 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085633 infores:hetionet CHEBI:47898 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0549410 infores:hetionet CHEBI:50729 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0232493 infores:hetionet CHEBI:5134 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C1527344 infores:hetionet CHEBI:3814 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0037195 infores:hetionet CHEBI:6128 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0035455 infores:hetionet CHEBI:7443 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0000768 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0012797 infores:hetionet CHEBI:5558 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0003862 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0086543 infores:hetionet CHEBI:3216 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0028643 infores:hetionet CHEBI:45409 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0080274 infores:hetionet CAID:CA410205749 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205749 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, BA1, BP1, BP3, BP2, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.71G>A (p.Gly24Glu) is a missense variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score < 0.50 (0.328) and a SpliceAI score ≤ 0.20 (0.12) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205749/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:38940 biolink:causes MONDO:0024643 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C3241958 infores:hetionet CHEBI:6931 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0549249 infores:hetionet GO:0090178 biolink:causes GO:0016331 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0016331 CHEBI:4995 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151904 infores:hetionet CHEBI:2704 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0008031 infores:hetionet CHEBI:4445 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0010043 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002418 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0003537 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1328337 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0018799 infores:hetionet CHEBI:84500 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011124 infores:hetionet CHEBI:17650 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0232462 infores:hetionet CAID:CA512318853 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318853 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1):c.291C>T (p.Phe97=) variant is reported at a MAF of 0.00005 (0.005%, 1/21626 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort, and does not meet thresholds for BA1, BS1, or PM2. The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. REVEL score is not calculable for a synonymous variant; SpiceAI predicts: Acceptor loss 0.02, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.74248< 2.0) In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318853/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:74947 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0033687 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0426576 infores:hetionet GO:1900225 biolink:causes GO:0141084 infores:ubergraph knowledge_assertion manual_agent GO:1900225 GO:0141084 CHEBI:63637 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0009806 infores:hetionet NCBIGene:1302 biolink:causes MONDO:0044206 infores:monarchinitiative not_provided not_provided HGNC:2187 MONDO:0044206 uuid:4afcc91d-79f3-41fd-92a7-d0cc3d5872ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49040 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0019158 infores:hetionet CAID:CA177281 biolink:causes MONDO:0019497 infores:clingen CAID:CA177281 MONDO:0019497 PMID: Likely Benign BS1 The filtering allele frequency (the lower threshold of the 95% CI of 41/10294) of the c.9998G>A (p.Arg3333Gln) variant in the MYO15A gene is 0.302% for Ashkenazi Jewish chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA177281/MONDO:0019497/005 2021-07-22 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:31348 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0086769 infores:hetionet CHEBI:3215 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0025290 infores:hetionet CHEBI:4356 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0003811 infores:hetionet CHEBI:145499 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2830004 infores:hetionet CHEBI:391960 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0002994 infores:hetionet CHEBI:28864 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0423006 infores:hetionet CHEBI:7445 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0029089 infores:hetionet CHEBI:27446 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0011606 infores:hetionet CHEBI:3640 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0027497 infores:hetionet CHEBI:6375 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013456 infores:hetionet CHEBI:135613 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0013378 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0854725 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0854725 infores:hetionet CHEBI:27958 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0027769 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0042109 infores:hetionet CHEBI:27777 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0042963 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0574067 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0012833 infores:hetionet CHEBI:63607 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0151603 infores:hetionet CHEBI:3732 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004604 infores:hetionet CHEBI:50663 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0234215 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009806 infores:hetionet CHEBI:5001 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0039231 infores:hetionet CHEBI:5138 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0947912 infores:hetionet CHEBI:6375 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0016658 infores:hetionet CHEBI:9943 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0242184 infores:hetionet NCBIGene:492 biolink:causes MONDO:0010547 infores:monarchinitiative not_provided not_provided HGNC:816 MONDO:0010547 uuid:cd3333ad-0226-4e60-baf9-d8100d2d71c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0233794 infores:hetionet CHEBI:50131 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0027497 infores:hetionet CHEBI:71417 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0002170 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0022650 infores:hetionet NCBIGene:34 biolink:causes MONDO:0008721 infores:monarchinitiative not_provided not_provided HGNC:89 MONDO:0008721 uuid:4efb5081-ea83-47f2-bb7a-cf94def18aeb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA380144505 biolink:causes MONDO:0000573 infores:clingen CAID:CA380144505 MONDO:0000573 PMID: Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1 The NM_000536.4:c.130G>T variant in RAG2 is a nonsense variant predicted to result in a truncated protein (p.Gly44*). Although this variant is expected to escape nonsense mediated decay (NMD), it would be expected to disrupt approximately 91% of the total RAG2 protein (would remove 484 / 528 amino acids). In addition, it would remove the entire PHD domain (amino acids 414-487), which is defined by the SCID VCEP as a region critical to RAG2 protein function (PMID: 15964836). Therefore PVS1 is met. This variant has an allele frequency of 0.000008792 in the European (non-Finnish) population in gnomAD, which is below the threshold for max filtering allele frequency for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant has not been reported in individuals with SCID in a peer-reviewed publication; however, it has been reported in an infant with typical SCID in a pre-print research article by Alizadeh et al (DOI: https://doi.org/10.21203/rs.3.rs-1728908/v1). The was identified via WES (0.5p) in an infant with T-NK+ typical SCID (0.5p) from a consanguineous family with a family history of SCID (0.5p) meeting the ClinGen SCID VCEP's criteria for PP4 (1.5p). The variant was homozygous in the affected infant and heterozygous in the parents (0.5p, PM3_supporting). In addition, a different frameshift variant (NM_000536.4:c.829dup p.Tyr277Leufs*4) that occurs downstream of this variant has been classified as LP by the ClinGen SCID VCEP. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PVS1, PM2_Supporting, PP4, and PM3_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144505/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6413 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0023380 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0023530 infores:hetionet CHEBI:71417 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0040034 infores:hetionet CAID:CA386973446 biolink:causes MONDO:0015967 infores:clingen CAID:CA386973446 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS1_Supporting, PVS1_Strong, PP4_Moderate The c.1768+1G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 9 of NM_000545.8. This variant is predicted to cause an in-frame deletion of biologically-relevant exon 9 of 10, removing more than 10% of an important region of the protein (PVS1_Strong). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). The c.1768+1G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1768+1G>C has a similar or greater predicted impact by Splice AI (0.98 and 0.81) (PS1_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.1768+1G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1_Strong, PM2_Supporting, PS1_Supporting, PP4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386973446/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45599 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0006266 infores:hetionet CHEBI:43968 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0018524 infores:hetionet CHEBI:68478 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0039231 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0162429 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0036572 infores:hetionet CHEBI:15765 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0016204 infores:hetionet CHEBI:42797 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085932 infores:hetionet CHEBI:194135 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0423791 infores:hetionet CHEBI:63617 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0014724 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030807 infores:hetionet UMLS:C0025241 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0039231 infores:hetionet CAID:CA024617 biolink:causes MONDO:0018493 infores:clingen CAID:CA024617 MONDO:0018493 PMID: Likely Pathogenic PP1, PM1, PS4_Moderate PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of histidine with glutamine at codon 2204 of the RYR1 protein, p.(His2204Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; five of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in two meioses PP1 (The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.739 supports neither a pathogenic nor a benign status for this variant. This variant was initially reported to segregate with positive IVCT status in five individuals meeting PP1_Moderate and contributing to a classification of Likely Pathogenic. After review it was determined that an IVCT positive/genotype negative individual in one of the families demonstrating segregation removed that family from consideration (3 meioses) for PP1. The remaining two meisoses would not meet PP1 based on RYR1 specified ACMG rules for variant interpretation. However, the RYR1-MHS VCEP has decided to leave the variant classification at Likely Pathogenic. It it should be noted that this is based on expert opinion and not a strict adherence to the RYR1 specified ACMG rules for variant interpretation. Criteria implemented: PS4_Moderate, PM1, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024617/MONDO:0018493/012 2023-12-15 2023-12-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:5893 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0010200 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0041912 infores:hetionet CAID:CA119177 biolink:causes MONDO:0020367 infores:clingen CAID:CA119177 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3, PM2_Supporting, PS4_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS3, PS1, PS2, BP4, BA1 The c.1010A>G variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 337 (p.Gln337Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.743, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 6 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 34923728, 9361308), which fulfilled PP1_Moderate (≥5 meioses). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 34923728, 32300215, 9361308), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119177/MONDO:0020367/019 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:29688 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0858635 infores:hetionet CHEBI:94449 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0392676 infores:hetionet CHEBI:63632 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0023530 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0221161 infores:hetionet CHEBI:119915 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C2939147 infores:hetionet CAID:CA345034 biolink:causes MONDO:0010305 infores:clingen CAID:CA345034 MONDO:0010305 PMID: Likely Pathogenic PM6, PP3, PM2_Supporting, PS4_Supporting, PP4_Strong PP1, PS3 The NM_005629.4:c.1631C>T in SLC6A8 is a missense variant predicted to cause substitution of Proline with Leucine (p.Pro544Leu) at amino acid 544 in the 12th of 13 exons. This variant is absent from gnomAD v2.1.1, (PM2_Supporting). The computational predictor REVEL gives a score of 0.784 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). This variant was reported in a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. Urine analysis showed an increased creatine/creatinine ratio (1.83; n.v. 0.03–0.92) with normal guanidinoacetate/creatinine ratio (0.024; n.v. 0.023–0.214) (1 point). Brain MRI with angiography and perfusion study was normal, while 1H-MRS revealed a consistent decrease in the creatine peak (Fig. 2) (3 points). Full sequencing of the SLC6A8 gene was reported. (PMID:17553121) (PP4_Strong). This variant was reported in a proband with an increased urine creatine/creatinine ratio of 2.0 (normal range 0.017–0.72), the proband’s brother also was affected and had elevated urine ratios and was hemizygous for the variant, while their mother was heterozygous for the same variant (PMID: 15690373). (PS4_Supporting). A female proband presented with learning disabilities, seizures and significantly reduced creatine by 1 H-MRS (fig. 1). The patient had normal urine creatine/creatinine ratio (0.38 mmol/mmol). Molecular genetic testing identified the heterozygous variant SLC6A8 (c.1631C>T, p.(Pro544Leu)). Segregation analysis including both parents revealed that the variant was de novo in the patient (PMID: 37708665) (PM6). This variant was assessed for co-segregation evidence (PP1) and functional evidence (PS3), but in both cases did not meet the specifications (PP1_Not Met, PS3_Not Met). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0). PM2_Supporting, PP3, PP4_Strong, PS4_Supporting, PM6.(Classification approved by the ClinGen CCDS VCEP on Oct. 26, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA345034/MONDO:0010305/027 2023-10-26 2023-11-08 X-linked inheritance HP:0001417 Supports CHEBI:28148 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0006285 infores:hetionet CAID:CA343725060 biolink:causes MONDO:0020367 infores:clingen CAID:CA343725060 MONDO:0020367 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS3, PS1, PS2, BA1, BP4 The c.1021T>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Proline at amino acid 341 (p.Ser341Pro). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.821, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 12 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17867509, 24825108, 33214997, 25777973), which fulfilled PP1_Strong (≥ 7 meioses in >1 family). 8 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9510647, 24825108, 25777973, 33214997, 17867509, ClinVar: Invitae), which met PS4_Moderate (≥ 6 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PP3, PS4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725060/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8802 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0342579 infores:hetionet CHEBI:10119 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151754 infores:hetionet CHEBI:5138 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0917801 infores:hetionet CHEBI:3614 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0037023 infores:hetionet CHEBI:64355 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042023 infores:hetionet CHEBI:51041 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0039070 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018991 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037274 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0042373 infores:hetionet CHEBI:9445 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0015967 infores:hetionet CHEBI:125354 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0041657 infores:hetionet NCBIGene:10157 biolink:causes MONDO:0009388 infores:monarchinitiative not_provided not_provided HGNC:17366 MONDO:0009388 uuid:a97e972e-46e8-449a-893a-e7a3ae336add biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0041969 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020517 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020651 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0233494 infores:hetionet CHEBI:52172 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151723 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0030920 infores:hetionet NCBIGene:388962 biolink:causes MONDO:0013675 infores:monarchinitiative not_provided not_provided HGNC:24415 MONDO:0013675 uuid:09076dfa-a57e-437b-88e5-e36748bb653d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63599 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0085393 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0017178 infores:hetionet CHEBI:119915 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0021368 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0018939 infores:hetionet CHEBI:6706 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0039070 infores:hetionet CHEBI:8069 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0042109 infores:hetionet CHEBI:4710 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0036974 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0332575 infores:hetionet CHEBI:63580 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0234233 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0750426 infores:hetionet CHEBI:31624 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0027424 infores:hetionet CHEBI:7640 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0003811 infores:hetionet CHEBI:45863 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0017672 infores:hetionet CHEBI:135920 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0559031 infores:hetionet CHEBI:29688 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C1384353 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1142412 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0014742 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0687133 infores:hetionet CHEBI:119573 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C2242996 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0025061 infores:hetionet CHEBI:2453 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0162830 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0027765 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0574067 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0034068 infores:hetionet CHEBI:144551 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0235857 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0022672 infores:hetionet GO:1904347 biolink:causes GO:0014827 infores:ubergraph knowledge_assertion manual_agent GO:1904347 GO:0014827 CHEBI:119573 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0004604 infores:hetionet CHEBI:6715 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0038999 infores:hetionet NCBIGene:22859 biolink:causes MONDO:0859292 infores:monarchinitiative not_provided not_provided HGNC:20973 MONDO:0859292 uuid:0fa8249d-299b-46ca-91b3-aaf13895c6b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042109 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020676 infores:hetionet CHEBI:31413 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0002871 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0003123 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0037199 infores:hetionet CHEBI:3387 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151786 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0234215 infores:hetionet CHEBI:3213 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0035078 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0041912 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0855242 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011570 infores:hetionet CHEBI:83531 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0028084 infores:hetionet CHEBI:6954 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0017178 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0030312 infores:hetionet CHEBI:8502 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0040034 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006615 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038986 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0162429 infores:hetionet CAID:CA240279 biolink:causes MONDO:0015152 infores:clingen CAID:CA240279 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PP3, PS3_Moderate, PM2_Supporting The NM_003494.4: c.1343T>C variant in DYSF, which is also known as NM_001130987.2: c.1439T>C p.(Leu480Pro), is a missense variant predicted to cause substitution of leucine by proline at amino acid 448, p.(Leu448Pro). This variant has been reported in at least five patients with suspected LGMD (PMID: 23519732, 27602406, 30564623), including in unknown phase with a pathogenic variant in two individuals (NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19), 0.5 pts, PMID: 23519732; NM_003494.4: c.3444_3445delinsAA p.(Tyr1148Ter), 0.5 pts, PMID: 27602406) (PM3). At least one of these patients displayed progressive muscle weakness and reduced or absent dysferlin expression in muscle biopsy, which is highly specific for DYSF-related LGMD (PMID: 23519732, 27602406) (PP4_Strong). The filtering allele frequency of this variant is 0.000025627 (the upper bound of the 95% CI of 21/1180016 European (non-Finnish) chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu448Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.76, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/14/2025): PM3, PP4_Strong, PS3_Moderate, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA240279/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9649 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042963 infores:hetionet CHEBI:3996 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C1504494 infores:hetionet CHEBI:63608 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018843 infores:hetionet CHEBI:68534 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0018965 infores:hetionet CHEBI:4798 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0039070 infores:hetionet CHEBI:490877 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0001125 infores:hetionet CHEBI:74947 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151766 infores:hetionet CAID:CA645509160 biolink:causes MONDO:0021056 infores:clingen CAID:CA645509160 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 The c.1240del (p.Arg414Alafs*40)) variant in APC is a frameshift variant located between codon 49 and 2645 predicted to cause a premature stop codon in exon 10 in a gene in which loss-of-function is an established disease mechanism (PVS1). It is listed once each in ClinVar and the APC InSiGHT LOVD (https://www.lovd.nl/APC), without informative clinical or phenotypic data. The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1 and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509160/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:80630 biolink:causes MONDO:0002105 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0025162 infores:hetionet CAID:CA10585115 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585115 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BP4, BA1, PS1, PS3, PS4, BP7, BS1, BS3, PM5, PM1, PM4, PVS1, BS2 The NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID: 20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585115/MONDO:0007750/013 2022-04-22 2022-04-22 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA347221658 biolink:causes MONDO:0015152 infores:clingen CAID:CA347221658 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3_Supporting, PP3, PM2_Supporting PM5, PS3, BP7 The NM_003494.4: c.5341G>A variant in DYSF, which is also known as NM_001130987.2: c.5458G>A p.(Gly1820Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1781, p.(Gly1781Arg). This variant affects the first nucleotide of exon 48, but SpliceAI gives a score of only 0.23 for acceptor loss and RNAseq analysis indicates the variant does not affect splicing (PMID: 36983702). This variant has been reported in unknown phase with a pathogenic variant in one individual with progressive proximal muscle weakness, dystrophic signs on muscle biopsy, and absent dysferlin protein expression by blood monocyte assay (NM_003494.4: c.3137G>A p.(Arg1064His), 0.5 pts, PMID: 36983702) (PM3_Supporting, PP4_Strong). The highest population allele frequency of this variant is 0.0000008 (1/1179880 alleles) in the European (non-Finnish) population of gnomAD v4.1.0, which is less than the LGMD VCEP threshold (PM2_Supporting). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347221658/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:4705 biolink:causes MONDO:0032626 infores:monarchinitiative not_provided not_provided HGNC:7684 MONDO:0032626 uuid:aa3f884d-a100-4660-838a-3b8ac47d4175 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45951 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0033774 infores:hetionet CAID:CA10647042 biolink:causes MONDO:0012996 infores:clingen CAID:CA10647042 MONDO:0012996 PMID: Benign BA1 The NM_001482.3:c.*600A>G variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1, in a continental population with >2000 alleles, is 0.2934 (2554/8704 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316206). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10647042/MONDO:0012996/025 2022-06-06 2022-10-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:64317 biolink:causes UMLS:C0542052 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0542052 infores:hetionet NCBIGene:55717 biolink:causes MONDO:0013926 infores:monarchinitiative not_provided not_provided HGNC:13831 MONDO:0013926 uuid:86620409-b808-4860-9a20-b1b231a55468 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27300 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0022661 infores:hetionet CHEBI:83527 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0039070 infores:hetionet CAID:CA16602179 biolink:causes MONDO:0008667 infores:clingen CAID:CA16602179 MONDO:0008667 PMID: Pathogenic PS4_Moderate, PM2_Supporting, PVS1 The variant NM_000551.3(VHL):c.208G>T (p.Glu70Ter) variant in VHL is a truncating variant. This variant causes a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The variant has been reported in 6 unrelated probands and/or families meeting either VHL Type 1 or affected with VHL-related cancers. CIViC Evidence IDs (https://civicdb.org): 9266,5361,5445,5035,6059,8209 and PMIDs: 18446368, 8707293, 20660572, 9829911, 7728151, 11148816. (PS4_Moderate)There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (due to a single variant present) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602179/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135736 biolink:causes UMLS:C0852909 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0852909 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0018621 infores:hetionet CHEBI:8871 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0028643 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0948594 infores:hetionet CHEBI:29007 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C2939147 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0034150 infores:hetionet CHEBI:5893 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0040264 infores:hetionet CAID:CA404079636 biolink:causes MONDO:0007750 infores:clingen CAID:CA404079636 MONDO:0007750 PMID: Uncertain Significance PM2 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP3, PP1, PP4, BS2 The NM_000527.5(LDLR):c.731C>G (p.Ser244Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: No exome data available for this variant in gnomAD v2.1.1. Genome and exome data were available for the neighboring variant, 19-11217264-G-A(GRCh37). The c.731C>G (p.Ser244Cys) variant was present in 1/15432 European (non-Finnish) genomes. The 19-11217264-G-A(GRCh37) variant was tested in 113760 alles from European (non-Finnish) exomes. Final adjusted allele frequency: 1/( 15432+ 113760) = 0.0007740417%. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404079636/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8863 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030252 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029456 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0543467 infores:hetionet NCBIGene:9440 biolink:causes MONDO:0013351 infores:monarchinitiative not_provided not_provided HGNC:2375 MONDO:0013351 uuid:2b796317-d86e-4273-b62e-8f6f36a42c39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6437 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0018674 infores:hetionet CHEBI:3223 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0234238 infores:hetionet CHEBI:27796 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00662 UMLS:C0233407 infores:hetionet CHEBI:37924 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0013491 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235290 infores:hetionet CHEBI:3647 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0013404 infores:hetionet CHEBI:75984 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0042963 infores:hetionet CHEBI:4909 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0018926 infores:hetionet CHEBI:8863 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0242301 infores:hetionet NCBIGene:55163 biolink:causes MONDO:0012407 infores:monarchinitiative not_provided not_provided HGNC:30260 MONDO:0012407 uuid:8fc6e9d9-20a3-4974-85ee-facd8d16b29a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9014 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0518015 infores:hetionet CHEBI:3732 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0017152 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0302295 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017601 infores:hetionet CHEBI:72564 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0392171 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0004936 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0014544 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0007222 infores:hetionet CHEBI:17474 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0013604 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0243026 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235522 infores:hetionet CHEBI:45081 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0013404 infores:hetionet CHEBI:9637 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0041657 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001461 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040252 infores:hetionet CAID:CA320644105 biolink:causes MONDO:0011071 infores:clingen CAID:CA320644105 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.98-1410dup is an intronic variant with a MAF of 0.09615 (9.615%, 30/312, 30 alleles) in the Middle Eastern subpopulation of the gnomAD 3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state 25 times in population database gnomAD 3.1.2. (BP2). This intronic variant has a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.03) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.53) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320644105/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9943 biolink:causes MONDO:0000945 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042485 infores:hetionet CAID:CA1139666834 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666834 MONDO:0011071 PMID: Uncertain Significance BP1, BP4, PM2, BP7, BS1, PP4, PP2, PP3 NM_001754.5(RUNX1):c.*463C>T is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666834/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31236 biolink:causes UMLS:C1611167 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1611167 infores:hetionet CAID:CA012698 biolink:causes MONDO:0005045 infores:clingen CAID:CA012698 MONDO:0005045 PMID:27532257 Likely Pathogenic PM2, PM1, PP3, PS4_Moderate PM5, PP1, PS3, BS3, PS1, BP4 The NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro) variant has been identified in at least 13 probands with HCM (PM4_Moderate; Millat 2010 PMID:20624503; Millat 2010 PMID:20800588; Walsh 2017 PMID: 27532257; Ambry pers. comm., GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.). Additionally, this variant was reported in a patient with suspected RCM/HCM as well as arrhythmia, who also carried the pathogenic NM_000257.4(MYH7):c.2167C>T p.(Arg723Cys) variant. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM4_Moderate, PM2, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012698/MONDO:0005045/002 2021-09-28 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020649 infores:hetionet CHEBI:9123 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1457883 infores:hetionet CHEBI:116278 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0600142 infores:hetionet CHEBI:31980 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0085624 infores:hetionet GO:0005816 biolink:causes GO:0051417 infores:ubergraph knowledge_assertion manual_agent GO:0005816 GO:0051417 CHEBI:63621 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0314719 infores:hetionet CHEBI:6076 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042963 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0235194 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235194 infores:hetionet CHEBI:49603 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0010200 infores:hetionet NCBIGene:51025 biolink:causes MONDO:0013223 infores:monarchinitiative not_provided not_provided HGNC:29679 MONDO:0013223 uuid:36d9d5ab-2020-4507-9622-00bd3c98e5ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0031814 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0392185 infores:hetionet CAID:CA180753 biolink:causes MONDO:0021060 infores:clingen CAID:CA180753 MONDO:0021060 PMID: Pathogenic PM2_Supporting, PM5_Strong, PS4_Moderate, PS2_Very Strong BS1, BA1, BP4, PP3, PM1 The NM_002524.5:c.34G>A variant in NRAS is a missense variant predicted to cause substitution of glycine by serine at amino acid 12 (p.Gly12Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.612, which is neither above nor below the thresholds predicting a damaging or benign impact on NRAS function. This variant occurs at an amino acid residue defined by the ClinGen RASopathy VCEP as an amino acid residue where ≥2 different [likely] pathogenic residues changes at the same codon have been observed in ≥5 probands (PM5_Strong). This variant has been reported in 4 probands with RASopathy (PS4_Moderate; PMIDs: 26918529, 28098151, 28594414, SCV00028917.11, GeneDx). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with RASopathy (PS2_VeryStrong; PMIDs: 28098151 and 28594414, SCV000208917.11, GeneDx). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PM5_Strong, PS4_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180753/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7824 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0231218 infores:hetionet CHEBI:8890 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0231530 infores:hetionet HP:0031377 biolink:causes MONDO:0011382 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D000755 DB01005_MESH_D000755_1 CHEBI:6541 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0037763 infores:hetionet CAID:CA16606897 biolink:causes MONDO:0007113 infores:clingen CAID:CA16606897 MONDO:0007113 PMID: Likely Benign BS2, PM2_Supporting, BP4, BP7 The c.1560C>T p.Ile520= variant in UBE3A (NM_130838.2) is absent from gnomAD v4.1 (PM2_Supporting). However, the p.Ile520= variant is observed in at least 4 unaffected individuals (GeneDx internal database) (BS2). The silent p.Ile520= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: BS2, BP4, BP7. (UBE3A Specification v5.0; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606897/MONDO:0007113/037 2025-05-07 2025-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0145867 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0005778 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0038363 infores:hetionet GO:1901028 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:1901028 GO:0023052 CAID:CA157966 biolink:causes MONDO:0007648 infores:clingen CAID:CA157966 MONDO:0007648 PMID:23197654PMID:26182300PMID:24728327PMID:25980754PMID:23197654 Benign BA1 BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM3, PM4, PM1, PP3, PP2, PP4, PP1, BS2, BP4, BP1, BP2, BP3, PS3, PS1, PS4, PS2 The c.2413G>A (p.Asp805Asn) variant has an allele frequency of 0.00207 (0.21%, 21/10,148 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157966/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:47426 biolink:causes MONDO:0006541 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0014527 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042075 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0235146 infores:hetionet CHEBI:17688 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0019825 infores:hetionet GO:1902119 biolink:causes GO:0000212 infores:ubergraph knowledge_assertion manual_agent GO:1902119 GO:0000212 CHEBI:17026 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0023895 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0006266 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0006444 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0005779 infores:hetionet CHEBI:3127 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0011124 infores:hetionet CAID:CA055885 biolink:causes MONDO:0007783 infores:clingen CAID:CA055885 MONDO:0007783 PMID: Uncertain Significance PP1, PS4_Supporting PP3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with methionine at codon 3711 of the RYR1 protein, p.(Thr3711Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual who had a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). This family presented with four informative meiosis, (PMID:30236257, The UK (Leeds) MH Unit), PP1. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.637 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA055885/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63608 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0033687 infores:hetionet CHEBI:61390 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0015672 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0040034 infores:hetionet CAID:CA390866574 biolink:causes MONDO:0100216 infores:clingen CAID:CA390866574 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PM6, BP2, PP3, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS3 The NM_177438.2:c.4874C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 1625 (p.Ser1625Phe). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.1; SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1- related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390866574/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9130 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0340464 infores:hetionet CHEBI:6640 biolink:causes NCIT:C113708 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0266813 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0234215 infores:hetionet CHEBI:100241 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0917801 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C2711227 infores:hetionet CHEBI:10023 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2363731 infores:hetionet CHEBI:65349 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0038454 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0031542 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0028738 infores:hetionet CHEBI:6067 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0476273 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0087169 infores:hetionet CAID:CA163776 biolink:causes MONDO:0007648 infores:clingen CAID:CA163776 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.604G>A (p.Val202Ile) variant has an allele frequency of 0.00354 (0.35%, 109/30,772 alleles) in the South Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA163776/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5864 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0022660 infores:hetionet CHEBI:2666 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0341047 infores:hetionet CHEBI:9123 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0575081 infores:hetionet CHEBI:87681 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0015672 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006852 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235146 infores:hetionet CHEBI:27779 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C1443060 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0234458 infores:hetionet CAID:CA6832104 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832104 MONDO:0015967 PMID: Likely Benign BS3_Supporting, BS1, PP3 PS4 The c.1544C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to lysine at codon 515 (p.(Thr515Lys)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0000358, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). PS4 therefore cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:2992702). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.7659, which is greater than the MDEP VCEP threshold of 0.70 (PP3). However, functional studies demonstrated the p.Thr515Lys protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). In summary, c.1544C>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BS1, BS3_Supporting, PP3). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832104/MONDO:0015967/017 2022-02-08 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:92923 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0004604 infores:hetionet UMLS:C0657912 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015402 infores:hetionet CHEBI:68558 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0476281 infores:hetionet CHEBI:119915 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042023 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0021053 infores:hetionet CHEBI:45951 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0011071 infores:hetionet CAID:CA401359822 biolink:causes MONDO:0009290 infores:clingen CAID:CA401359822 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.4G>T (p.Gly2Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in individuals with Pompe disease in the literature and functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 560377). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401359822/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UMLS:C0065374 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0028961 infores:hetionet CHEBI:68478 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042029 infores:hetionet CHEBI:16714 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0015230 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0039231 infores:hetionet NCBIGene:710 biolink:causes MONDO:0033946 infores:monarchinitiative not_provided not_provided HGNC:1228 MONDO:0033946 uuid:c56443f1-9109-49f8-a628-0da21ced2ee0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412376221 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376221 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PVS1, PP4 The NM_000330.4(RS1):c.149G>A variant is a nonsense variant in amino acid 50, which results in a premature stop codon and causes a truncated protein. This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis ( PMID: 16272055, PP4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PP4, and PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376221/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:64310 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0032285 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009763 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C1565489 infores:hetionet CHEBI:7577 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013428 infores:hetionet CHEBI:6887 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0042963 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016397 infores:hetionet CAID:CA1139532918 biolink:causes MONDO:0015152 infores:clingen CAID:CA1139532918 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1 PM2 The NM_003494.4: c.3373del p.(Glu1125LysfsTer9) variant in DYSF, which is also known as NM_001130987.2: c.3427del p.(Glu1143LysfsTer9), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 31/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 12 patients with features of LGMD, including in the homozygous state in at least eight individuals (1.0 pt; PMID: 32400077; 26088049; 2324326; 12410383; LOVD DYSF_000024; PM3). It appears to be particularly common among Japanese patients with a Miyoshi myopathy phenotype. At least one of the patients homozygous for this variant displayed absent dysferlin protein expression in skeletal muscle in addition to a clinical diagnosis of LGMD, which is highly specific for DYSF-related LGMD (PMID: 12410383; PP4_Strong). The filtering allele frequency of this variant is 0.00023 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 4/39700 East Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PVS1, PM3, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532918/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CAID:CA229404 biolink:causes MONDO:0009861 infores:clingen CAID:CA229404 MONDO:0009861 PMID:1312992PMID:9860305PMID:9860305PMID:14722928PMID:1312992 Pathogenic PP4_Moderate, PP3, PS3, PM3_Strong PM2 PAH-specific ACMG/AMP criteria applied: PM3_Strong: In trans with R408W, IVS4-1G>A, R241C (ClinGen, P) (PMID:1312992; PMID:14722928); PP3: ; PS3: Mutant enzyme activity of 46% in BioPKU (PMID:9860305); PP4_Moderate: ~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown (PMID:9860305; PMID:1312992). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM3_Strong, PP3, PS3, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229404/MONDO:0009861/006 2018-08-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports GO:0090178 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0043009 CHEBI:17026 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C3665347 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0042373 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0029408 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0162429 infores:hetionet CHEBI:9123 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003862 infores:hetionet CHEBI:10125 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0033774 infores:hetionet CAID:CA10606113 biolink:causes MONDO:0009290 infores:clingen CAID:CA10606113 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3 The NM_000152.5:c.736del (p.Leu246PhefsTer22) variant in GAA is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). One patient with limb girdle muscular dystrophy was reported to be compound heterozygous for c.736delC and another variant in GAA that has been classified by the ClinGen LD VCEP as pathogenic, c.546G>A; the phase is unknown. However, because no aditional information is available to support the diagnosis of Pompe disease, such as GAA deficiency, there is insufficient evidence to apply PM3 at this time. . There is a ClinVar entry for this variant (Variation ID: 288505. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606113/MONDO:0009290/010 2023-07-18 2023-07-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:61049 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0039971 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0948089 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0853776 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0853776 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0267792 infores:hetionet CHEBI:6715 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023066 infores:hetionet CHEBI:38562 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0853034 infores:hetionet CHEBI:3756 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0016655 infores:hetionet CAID:CA16616270 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616270 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS3, BS1, BS4, BP7, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.4(RUNX1):c.351+1G>C variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616270/MONDO:0011071/008 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Supports GO:1905539 biolink:causes GO:0099536 infores:ubergraph knowledge_assertion manual_agent GO:1905539 GO:0099536 CHEBI:49662 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0267380 infores:hetionet CHEBI:7478 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0030554 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235969 infores:hetionet CHEBI:49713 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0016204 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0853714 infores:hetionet CAID:CA913190952 biolink:causes MONDO:0008723 infores:clingen CAID:CA913190952 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1317dup (p.Met440fs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 13/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant has been reported as a result of a positive newborn screening for VLCADD (PMID:26385305). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190952/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41423 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0022660 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006716 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0010072 infores:hetionet CHEBI:3215 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0018965 infores:hetionet CHEBI:87681 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C1443060 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0549475 infores:hetionet CAID:CA415087966 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087966 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong PM6 "The NM_005629.4:c.1495+2T>G variant in SLC6A8 occurs within the canonical splice donor site of intron 10. This variant is predicted to abolish splicing at the intron 10 donor splice site. To our knowledge, the results of no RNA studies are available to indicate the impact of this variant on splicing. One possibility if the exon 10 is skipped. However, the in silico splice predictor, SpliceAI, predicts use of a cryptic splice site 26 base pairs upstream from the normal donor splice site (SpliceAI score for donor gain = 0.8). If used, the last 26 bp of exon 10 would be lost. In either case, a shift in the reading frame resulting in a premature termination codon and nonsense-mediated decay is predicted (PVS1). A female with neurological symptoms, heterozygous for the variant, has been reported with a ""severe drop"" in cerebral creatine levels on magnetic resonance spectroscopy, consistently elevated urine creatine/creatinine ratios and reduced creatine transporter in cultured fibroblasts (PMID: 29478817) (PP4_Strong). The variant is absent in gnomAD v4.0. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on December 14, 2023)." Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087966/MONDO:0010305/027 2023-12-14 2023-12-14 X-linked inheritance HP:0001417 Supports CHEBI:6128 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0015672 infores:hetionet CHEBI:63589 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0027497 infores:hetionet CHEBI:7565 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0005758 infores:hetionet CHEBI:3219 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0039231 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0857256 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0857256 infores:hetionet GO:0042509 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0042509 GO:0051716 CHEBI:119573 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0043251 infores:hetionet CHEBI:75045 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0015672 infores:hetionet CHEBI:171719 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0028084 infores:hetionet CHEBI:6792 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0013144 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006444 infores:hetionet CAID:CA16040652 biolink:causes MONDO:0044970 infores:clingen CAID:CA16040652 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PS3 The m.9237G>A (p.Val11Met) variant in MT-CO3 has been reported in one individual with primary mitochondrial disease (PMID: 28027978). This individual had mitochondrial encephalopathy, epilepsy, and developmental delay. The heteroplasmy level was not reported. This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.54 (Min=0, Max=1) however APOGEE2 gives a score of 0.458 consistent with uncertain significance. There are no single fiber studies or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16040652/MONDO:0044970/015 2024-12-03 2025-11-07 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true GO:0060685 biolink:causes GO:0001655 infores:ubergraph knowledge_assertion manual_agent GO:0060685 GO:0001655 CHEBI:7822 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C1368065 infores:hetionet CHEBI:53760 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0018524 infores:hetionet GO:0003427 biolink:causes GO:0003416 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0003416 UNII:F64QU97QCR biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0004093 infores:hetionet CHEBI:9168 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0023518 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004238 infores:hetionet CHEBI:45716 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0041956 infores:hetionet CHEBI:6402 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013404 infores:hetionet CHEBI:27504 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0919924 infores:hetionet CHEBI:50648 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018681 infores:hetionet CHEBI:71415 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0016204 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018801 infores:hetionet CHEBI:63617 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C3263723 infores:hetionet CHEBI:27882 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0018681 infores:hetionet CHEBI:8890 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020598 infores:hetionet CHEBI:9907 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018800 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0017160 infores:hetionet NCBIGene:113278 biolink:causes MONDO:0024537 infores:monarchinitiative not_provided not_provided HGNC:16187 MONDO:0024537 uuid:d7d92550-1012-49bd-9d76-578b096a80fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes UMLS:C0541819 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0541819 infores:hetionet CHEBI:47499 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011991 infores:hetionet CHEBI:3732 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0311468 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0021308 infores:hetionet CHEBI:9014 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0027497 infores:hetionet CHEBI:28864 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0085682 infores:hetionet CHEBI:168396 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0858635 infores:hetionet CHEBI:6935 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0426576 infores:hetionet CHEBI:36795 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085635 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0233523 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233523 infores:hetionet CHEBI:2549 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0016382 infores:hetionet CAID:CA007509 biolink:causes MONDO:0021056 infores:clingen CAID:CA007509 MONDO:0021056 PMID: Benign BA1, BP1 PP3, PM2, BP4, BS1 The c.2476T>G variant in APC is a missense variant predicted to cause a substitution of leucine by valine at amino acid position 826 (p.Leu826Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1576% in the non-cancer African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). Additionally, APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel as a gene for which primarily truncating variants are known to cause disease (BP1). Multiple lines of computational evidence suggest no splicing impact. In summary, this variant meets the criteria to be classified as Benign for FAP. ACMG/AMP criteria applied, as specified by the ClinGen/InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel: BA1, BP1 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA007509/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:39585 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0312420 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0281856 infores:hetionet NCBITaxon:55193 biolink:causes MONDO:0006608 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:55193 MESH:D012628 DB01026_MESH_D012628_1DB00257_MESH_D012628_1DB00634_MESH_D012628_1DB01188_MESH_D012628_1 CHEBI:8426 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0042963 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0027765 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0019158 infores:hetionet CHEBI:171719 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0041657 infores:hetionet CHEBI:31623 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0039446 infores:hetionet CHEBI:61049 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019572 infores:hetionet CHEBI:6887 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0007859 infores:hetionet CAID:CA179542 biolink:causes MONDO:0019501 infores:clingen CAID:CA179542 MONDO:0019501 PMID: Uncertain Significance PM3_Supporting, BS1, PP4 PP3, BP4 The c.6730G>A (p.Val2244Met) variant in USH2A is a missense variant predicted to cause a substitution of valine by methionine at amino acid 2244. The filtering allele frequency (the lower threshold of the 95% CI of 312/91082) of the c.6730G>A (p.Val2244Met) is 0.3112% for South Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least one individual with Usher syndrome. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Leu4567Profs*16; PMID: 27460420) (PM3_Supporting). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4; PMID: 27460420). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BS1, PM3_Supporting, PP4; Version 2; 5/15/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA179542/MONDO:0019501/005 2024-06-28 2024-06-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:10650 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0234632 infores:hetionet CHEBI:9241 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0042384 infores:hetionet CHEBI:31236 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151576 infores:hetionet CHEBI:28901 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0008031 infores:hetionet CHEBI:10102 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0025222 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0027813 infores:hetionet CAID:CA015902 biolink:causes MONDO:0005045 infores:clingen CAID:CA015902 MONDO:0005045 PMID: Uncertain Significance PM2, PP3, PS4_Supporting BA1, PM5, PM1, PS3, PM6, PP1, BS1, BS3, BS4, PS1, PS2, BP4, BP5 The c.5305C>A (p.Leu1769Met) variant in MYH7 has been reported in 5 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease (PS4_Supporting; Girolami 2006 PMID:16858239; Santos 2012 PMID:22429680; GeneDx pers. comm.), as well as in 1 individual with DCM (Stanford Center for Inherited Cardiovascular Disease, ClinVar SCV000280363.1), and 3 individuals with other cardiac phenotypes (1 with syncope and VT, 1 with unspecified cardiomyopathy, and 1 with dysplastic pulmonary valve and stenosis; GeneDx pers. comm.; Mayo Clinic Laboratories pers. comm.). This variant was identified in 0.002% (FAF 95% CI; 6/129192) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015902/MONDO:0005045/002 2021-08-25 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:29007 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0392197 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0025061 infores:hetionet CHEBI:8774 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0040264 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0853149 infores:hetionet CHEBI:51164 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0277925 infores:hetionet GO:0110026 biolink:causes GO:0031297 infores:ubergraph knowledge_assertion manual_agent GO:0110026 GO:0031297 CHEBI:100241 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0518015 infores:hetionet CHEBI:71417 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0085669 infores:hetionet CAID:CA320251604 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251604 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS2, PS4, PS3, BP2, BP1, BP3, BA1, BP5, BS1, BS4, BS3, PM6, PVS1, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1011C>T (p.Pro337=) is a synonymous variant which is absent from gnomAD (PM2_supporting). This variant does not have a REVEL score, and SpliceAI ≤ 0.20 and is not conserved (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251604/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50922 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0029882 infores:hetionet CHEBI:2687 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0042373 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0005779 infores:hetionet CHEBI:9288 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0006826 infores:hetionet CHEBI:3219 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017979 infores:hetionet CHEBI:9599 biolink:causes MONDO:0002311 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0154833 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0240840 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0240840 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002871 infores:hetionet CHEBI:8435 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C2363731 infores:hetionet CHEBI:8764 biolink:causes HP:0032620 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151465 infores:hetionet CHEBI:9570 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0004093 infores:hetionet CAID:CA123249 biolink:causes MONDO:0100326 infores:clingen CAID:CA123249 MONDO:0100326 PMID: Pathogenic PM3, PS3_Supporting, PP4_Moderate, PM2_Supporting, PVS1_Strong NM_000212.2(ITGB3):c.1924G>T (p.Glu642Ter) in exon 12 of 15 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR analysis in the proband of PMID: 9845537 found that, instead, a shortened transcript was produced (in similar quantities to the normal allele) with in-frame skipping of exons 11 and 12 (reported by authors as exons 10 and 11, using alternate numbering), resulting in removal of 14% of the protein (PVS1_strong). CHO cells were transiently cotransfected with the plasmid pcDNA3-GPIIb and either WT or mutant pcDNA3-GPIIIa with this variant. To investigate the surface exposure of GPIIb-IIIa, intact cells were labeled with biotin, and the GPIIb-IIIa complexes were immunoprecipitated with anti-GPIIb (M3) or anti-GPIIIa (P37) MoAbs. No biotin-labeled products were found in cells cotransfected with normal GPIIb and mutant GPIIIa. Additionally, to examine the intracellular presence of GPIIb and/or GPIIIa as either monomers or heterodimers, total cell lysates were labeled with biotin, and GPIIb, GPIIIa, or GPIIb-IIIa complexes were immunoprecipitated. Unlike in extracts from cells coexpressing normal subunits, heterodimers failed to immunoprecipitate using a complex-specific MoAb, suggesting that the mutant ΔGPIIIa does not complex with GPIIb. Pulse-chase experiments further verified that the mutant ΔGPIIIa does not complex to GPIIb (PMID: 9845537; PS3_supporting). This variant has been detected homozygous in at least 2 probands with Glanzmann thrombasthenia (PMIDs: 14985172, 9845537; PM3). At least one patient (Patient II.1 in PMID: 14985172) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry and Western blot. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PS3_supporting, PP4_moderate, PM3, PM2_supporitng. (VCEP specifications version 2; date of approval 12/21/21). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123249/MONDO:0100326/011 2021-12-21 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3001 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0013390 infores:hetionet CHEBI:4514 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0037822 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0015397 infores:hetionet CHEBI:5106 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0151686 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0013395 infores:hetionet CHEBI:45652 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0039231 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0409497 infores:hetionet CHEBI:6541 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002962 infores:hetionet CHEBI:55346 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151904 infores:hetionet CHEBI:92712 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0424295 infores:hetionet CHEBI:3223 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0220870 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030305 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0017658 infores:hetionet CHEBI:5004 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0015672 infores:hetionet CHEBI:42068 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0002170 infores:hetionet CHEBI:17303 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013144 infores:hetionet CHEBI:6715 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0033046 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042571 infores:hetionet NCBIGene:84059 biolink:causes MONDO:0011443 infores:monarchinitiative not_provided not_provided HGNC:17416 MONDO:0011443 uuid:4b2fbfe5-cd45-47d8-8b65-f3d351bfb97d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:5V9KLZ54CY biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0011570 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027769 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0948594 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0852810 infores:hetionet CHEBI:5130 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017565 infores:hetionet CHEBI:6923 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0018681 infores:hetionet CAID:CA212170 biolink:causes MONDO:0007783 infores:clingen CAID:CA212170 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Cysteine at codon 1667 of the RYR1 protein, p.(Arg1667Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0051, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA212170/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63717 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C1167965 infores:hetionet CHEBI:5103 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0040822 infores:hetionet CAID:CA409103848 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103848 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PM1, PS2 PS4 The c.145C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of histidine to tyrosine at codon 49 (p.(His49Tyr)) of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in two individuals with unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes and one with hyperinsulinemic hypoglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 31595705, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative diabetes autoantibodies, and sulfonyurea sensitive) (PP4_Moderate; internal lab contributors). Additionally, this variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF4A-MODY (hyperinsulinemic hypoglycemia and negative genetic testing for ABCC8 and KCNJ11) (PS2; internal lab contributors). This variant segregated with diabetes, with two informative meioses in two families (PP1; PMID: 31595705, internal lab contributors). In summary, c.145C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PS2, PM1, PP4_Moderate, PM2_Supporting, PP1, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103848/MONDO:0015967/085 2025-09-15 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7822 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0019158 infores:hetionet CHEBI:3216 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233407 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151763 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0439857 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0233414 infores:hetionet CAID:CA410147814 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147814 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS2, PS1, PS4, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1191A>T (p.Gln397His) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.323, and the splice site predictor SpliceAI indicated no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147814/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:480999 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030554 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235416 infores:hetionet CHEBI:42797 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0233471 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0233528 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233528 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027697 infores:hetionet CHEBI:9763 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0004604 infores:hetionet CHEBI:2038 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C2129214 infores:hetionet CHEBI:6367 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0037299 infores:hetionet CHEBI:3242 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0233754 infores:hetionet CHEBI:231594 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0030193 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0267792 infores:hetionet CHEBI:43968 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0014742 infores:hetionet CHEBI:3568 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003578 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0040409 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0042769 infores:hetionet CHEBI:3437 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0235266 infores:hetionet CHEBI:41423 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014457 infores:hetionet CHEBI:125354 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0521592 infores:hetionet CHEBI:9130 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0428977 infores:hetionet CHEBI:3242 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0003467 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0851341 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0020437 infores:hetionet CAID:CA401359799 biolink:causes MONDO:0009290 infores:clingen CAID:CA401359799 MONDO:0009290 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The NM_000152.5:c.1A>T (p.Met1?) variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence. The next in-frame methionine is at position 122; if used, the gene product would be missing the signal sequence (PMID 22252923). When expressed in HEK293T cells, a very low level of an approximately 85 kD protein was seen on Western blot, suggesting the use of a downstream ATG in this in vitro system but there was no detectable GAA activity in the cells (PMID 22644586). There is also evidence that this variant may result in skipping of exon 2 in about 40-50% of transcripts when compared to wild type (PMID: 31301153). Based on the specifications of the ClinGen LD VCEP, PVS1_Strong was applied. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in a patient with clinical features consistent with late onset Pompe disease on enzyme replacement therapy (PP4). This patient is compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.-32-13T>G (ClinVar Variation ID: 4027) (PMID 27711114, 30022036) (PP4, PM3_Supporting). Of note, additional initiator codon variants, including c.1A>G, c.2T>C, and c.3G>A, have been reported in patients with Pompe disease (see http://www.pompevariantdatabase.nl/). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401359799/MONDO:0009290/010 2024-09-17 2024-09-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:82960 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0232462 infores:hetionet CHEBI:473990 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0267792 infores:hetionet CAID:CA915940958 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940958 MONDO:0100326 PMID: Likely Pathogenic PM4, PP4_Moderate, PM2_Supporting, PM3_Supporting This c.2187_2203delinsTCATTGGCTCA (p.Ile730_Leu735delinsHisTrpLeuIle) variant is predicted to cause a change in the length of the protein due to an in-frame indel, substituting six amino acid residues (Ile, Leu, Leu, Ile, Gly, Leu) by four different amino acids (His, Gly, Leu, Ile) in a non-repeat region (PM4). At least one patient (Patient GT20 in PMID:16463284) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This individual was homozygous for the variant (0.5 points, PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PM4, PM2_Supporting, PM3_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940958/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:47519 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0009782 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0002871 infores:hetionet CHEBI:3127 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0004245 infores:hetionet CHEBI:9649 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0014591 infores:hetionet CHEBI:135935 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0235086 infores:hetionet CHEBI:75722 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0149512 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0010200 infores:hetionet CHEBI:47499 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0151766 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0684249 infores:hetionet CHEBI:3756 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0037036 infores:hetionet CHEBI:48390 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0010200 infores:hetionet CHEBI:6710 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0917801 infores:hetionet CHEBI:9352 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0014591 infores:hetionet CHEBI:5118 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020453 infores:hetionet CHEBI:66903 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0852911 infores:hetionet CHEBI:59560 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C1145670 infores:hetionet CHEBI:30659 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0233472 infores:hetionet CHEBI:64019 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0036974 infores:hetionet CHEBI:31547 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0015967 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0855242 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0022650 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020615 infores:hetionet CHEBI:45367 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0042164 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0042109 infores:hetionet CHEBI:51230 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0031350 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0038663 infores:hetionet GO:0090095 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:0090095 GO:0001656 CHEBI:70735 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0575081 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0344315 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0235431 infores:hetionet CHEBI:79699 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0015402 infores:hetionet CHEBI:27999 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0541900 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011609 infores:hetionet CHEBI:119915 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018524 infores:hetionet CHEBI:7601 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0687713 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0278080 infores:hetionet CHEBI:8802 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0013384 infores:hetionet CHEBI:9123 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235490 infores:hetionet NCBIGene:5925 biolink:causes MONDO:0018160 infores:monarchinitiative not_provided not_provided HGNC:9884 MONDO:0018160 uuid:e0f44e76-d79e-42cb-b60d-69acb02cbe20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0022408 infores:hetionet CHEBI:50730 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0026821 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020039 infores:hetionet CHEBI:100246 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C2830004 infores:hetionet CHEBI:17474 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1609512 infores:hetionet CHEBI:5118 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004093 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020039 infores:hetionet CHEBI:3636 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0042963 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0239295 infores:hetionet CHEBI:18248 biolink:causes HP:0008940 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0476486 infores:hetionet CHEBI:17474 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0030193 infores:hetionet CAID:CA024696 biolink:causes MONDO:0007783 infores:clingen CAID:CA024696 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate, PM5_Supporting BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 2362 of the RYR1 protein, p.(Glu2362Gly). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:24433488). No functional studies were identified for this variant. Another variant assessed as likely pathogenic occurs at this codon, p.(Glu2362Lys), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.944) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024696/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10119 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0016867 infores:hetionet GO:1905024 biolink:causes GO:0060048 infores:ubergraph knowledge_assertion manual_agent GO:1905024 GO:0060048 CHEBI:6640 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0015230 infores:hetionet CHEBI:63612 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020598 infores:hetionet NCBIGene:3574 biolink:causes MONDO:0032667 infores:monarchinitiative not_provided not_provided HGNC:6023 MONDO:0032667 uuid:ff5c257c-f0ef-439b-bdbf-ef88bc9296fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020517 infores:hetionet CHEBI:107736 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0004245 infores:hetionet CHEBI:45863 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1527344 infores:hetionet CAID:CA16020755 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020755 MONDO:0009861 PMID:26503515 Uncertain Significance PP4_Moderate, PM2, PP3 The c.233A>T (p.Glu78Val) variant in PAH has been reported in a patient with PAH deficiency (BH4 deficiency excluded) (PP4_Moderate; PMID: 26503515) This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.824. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020755/MONDO:0009861/006 2019-11-10 2019-11-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7478 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085616 infores:hetionet CHEBI:2663 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0011124 infores:hetionet CAID:CA1139771066 biolink:causes MONDO:0100083 infores:clingen CAID:CA1139771066 MONDO:0100083 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 PVS1: frameshift variant (-1) between c.98-758.PM2_supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1.PS4_Supporting: This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 34166225).This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteriaapplied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1:PVS1, PM2_supporting, PS4_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771066/MONDO:0100083/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8232 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0852911 infores:hetionet CHEBI:3219 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0004093 infores:hetionet CHEBI:74947 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004093 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0030252 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0743668 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0743668 infores:hetionet CHEBI:63635 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0085593 infores:hetionet CAID:CA400029776 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029776 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.1552C>T (p.Gln518Ter) nonsense variant creates a premature termination codon in exon 10 of 15 and is predicted to cause NMD (PVS1). At least one compound heterozygous patient (DOI: 10.26502/acmcr.96550268) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, flow cytometry decreased expression of CD41 (αIIbβ3) at 44% WT levels. The highest population minor allele frequency in gnomAD v4.1 is 0.00003393 (1/29474 alleles) in the Ashkenazi Jewish genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting,PP4_Moderate. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029776/MONDO:0100326/011 2025-03-06 2025-03-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0017152 infores:hetionet CHEBI:7478 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042510 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0348024 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0348024 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0042109 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0021400 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0020517 infores:hetionet CHEBI:5959 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C3665347 infores:hetionet CHEBI:47519 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0231218 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0332534 infores:hetionet CHEBI:253342 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C2004489 infores:hetionet CHEBI:490877 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0030554 infores:hetionet CHEBI:10102 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0947912 infores:hetionet CHEBI:135736 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037299 infores:hetionet NCBIGene:116369 biolink:causes MONDO:0011720 infores:monarchinitiative not_provided not_provided HGNC:14468 MONDO:0011720 uuid:611f192f-7d77-455c-a6b3-901e643f0a97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042594 infores:hetionet CHEBI:15940 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0080274 infores:hetionet CHEBI:5118 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014591 infores:hetionet CHEBI:31401 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0003862 infores:hetionet CAID:CA410149640 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149640 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.928A>C (p.Met310Leu) is a missense variant which has a REVEL score < 0.50 (0.087), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149640/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4027 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0003811 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0026946 infores:hetionet CAID:CA640955042 biolink:causes MONDO:0100437 infores:clingen CAID:CA640955042 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Moderate, PP1_Strong PP4 NM_001034853.2(RPGR):c.3027_3028del (p.Glu1010GlyfsTer?) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent among hemizygous individuals in gnomAD v.4.1.0 (PM2_supporting). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years or decreased/absent cone and/or rod electroretinogram responses (PMIDs: 31816670, 32000842, 34745198, PS4_moderate). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), previous genotyping by whole exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), and night blindness (0.5 pts), which together are specific for RPGR-related etinopathy (4.5 points), however, PP4 has not been met as this proband was previously counted for PS4_Moderate. The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 2 families (PP1_strong; PMID: 34745198). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, PP1, and PP4. (date of approval 05/16/2025). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_moderate, PM2_supporting, and PP1_strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA640955042/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:4784 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0015967 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0392025 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0007642 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0042109 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0549622 infores:hetionet CHEBI:567361 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0013491 infores:hetionet CHEBI:35854 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0231528 infores:hetionet CHEBI:465284 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151539 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0002453 infores:hetionet CHEBI:7798 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0003811 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1609512 infores:hetionet CHEBI:36791 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0004604 infores:hetionet CHEBI:7824 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0017565 infores:hetionet CHEBI:6129 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027497 infores:hetionet CHEBI:6367 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0037036 infores:hetionet CHEBI:9737 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0002871 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0033975 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0034065 infores:hetionet CAID:CA213731 biolink:causes MONDO:0015967 infores:clingen CAID:CA213731 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PM2_Supporting The c.1169T>C variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to threonine at codon 390 (p.(Ile390Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.878, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.1169T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213731/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:80630 biolink:causes UMLS:C0857117 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0857117 infores:hetionet CHEBI:135939 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0011991 infores:hetionet CAID:CA191131 biolink:causes MONDO:0700270 infores:clingen CAID:CA191131 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.3349C>T (p.Gln1117*) variant in ATM is a nonsense variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA191131/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10101 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0037274 infores:hetionet NCBIGene:1794 biolink:causes MONDO:0014637 infores:monarchinitiative not_provided not_provided HGNC:2988 MONDO:0014637 uuid:cb3a092c-d027-40e3-a4b4-e90ed113fbc0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0038663 infores:hetionet NCBIGene:9688 biolink:causes MONDO:0014817 infores:monarchinitiative not_provided not_provided HGNC:28958 MONDO:0014817 uuid:9fa2bef0-5b8f-412a-a5be-88d7bc138b3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes UMLS:C0151981 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151981 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0948594 infores:hetionet CHEBI:31236 biolink:causes HP:0000298 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0424448 infores:hetionet GO:1900157 biolink:causes GO:0070977 infores:ubergraph knowledge_assertion manual_agent GO:1900157 GO:0070977 CHEBI:4798 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0036974 infores:hetionet CHEBI:6846 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0344232 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020437 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0018991 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0032285 infores:hetionet NCBIGene:80204 biolink:causes MONDO:0060760 infores:monarchinitiative not_provided not_provided HGNC:13590 MONDO:0060760 uuid:e56c22e8-f47b-421d-aa21-5321acb17dd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0004093 infores:hetionet CHEBI:31932 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C1260880 infores:hetionet CHEBI:51173 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0019557 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0027769 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0038826 infores:hetionet NCBIGene:153241 biolink:causes MONDO:0014577 infores:monarchinitiative not_provided not_provided HGNC:26690 MONDO:0014577 uuid:468345de-4bbc-4f58-b0c9-d25f2139cbda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0140885 biolink:causes GO:0071358 infores:ubergraph knowledge_assertion manual_agent GO:0140885 GO:0071358 CHEBI:17026 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0010200 infores:hetionet CHEBI:50742 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C1527411 infores:hetionet CHEBI:63621 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004134 infores:hetionet NCBIGene:9657 biolink:causes MONDO:0012225 infores:monarchinitiative not_provided not_provided HGNC:28949 MONDO:0012225 uuid:11cce91b-69b8-4296-a80f-3ec23f27674f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020433 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0699744 infores:hetionet CHEBI:64355 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019080 infores:hetionet CHEBI:188986 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0423006 infores:hetionet CHEBI:6822 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0003123 infores:hetionet CHEBI:9727 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0700361 infores:hetionet CHEBI:45783 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018946 infores:hetionet CHEBI:32293 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0009763 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0162119 infores:hetionet CHEBI:15428 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0039231 infores:hetionet NCBIGene:201163 biolink:causes MONDO:0007763 infores:monarchinitiative not_provided not_provided HGNC:27310 MONDO:0007763 uuid:65ccb014-fbb7-4f03-a994-0c66c46d0d14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060843 biolink:causes CL:0002543 infores:ubergraph knowledge_assertion manual_agent GO:0060843 CL:0002543 CHEBI:31348 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0234909 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011334 infores:hetionet CHEBI:46195 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151889 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151824 infores:hetionet CHEBI:2569 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0340865 infores:hetionet NCBIGene:4763 biolink:causes MONDO:0011908 infores:monarchinitiative not_provided not_provided HGNC:7765 MONDO:0011908 uuid:15383a67-5bd6-40d5-8db8-6b4c0e3411c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10110 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0038325 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042109 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0015397 infores:hetionet CAID:CA392342805 biolink:causes MONDO:0007947 infores:clingen CAID:CA392342805 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PM1_Strong PVS1, PM6, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PM5, PM4, PM3, BP5, BP7, BS1, BS3, BS4 NM_000138.5(FBN1):c.1481G>C (p.Cys494Ser)NM_00138 c.1481G>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by serine at amino acid 494 (p.Cys494Ser). This variant was found in two probands, one with isolated thoracic aortic aneurysm and dissection (TAAD) and one with TAAD and systemic features of Marfan syndrome (PS4_supporting; PMID: 32209317; UZG internal data). This variant has been reported twice in ClinVar as likely pathogenic and once as of uncertain significance (Variation ID: 502478). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys494Tyr, p.Cys494Trp, p.Cys494Phe). Computational prediction tools and conservation analysis strongly support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_supporting, PP2, PP3, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392342805/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63635 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0040822 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0267792 infores:hetionet CHEBI:92712 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0085631 infores:hetionet CHEBI:40279 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0009763 infores:hetionet CHEBI:50861 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0231528 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042109 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0026636 infores:hetionet CAID:CA347510 biolink:causes MONDO:0015152 infores:clingen CAID:CA347510 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4 PM2, PS1 The NM_000070.3: c.499-1G>A variant in CAPN3 occurs within the canonical splice acceptor site for exon 4 and is predicted to abolish the acceptor site, with a SpliceAI score of 0.77. Skipping of exon 4, which is out of frame, is expected to lead to a frameshift, premature truncation, and nonsense mediated RNA decay in a gene in which loss of function is an established mechanism of disease (PVS1). This variant has been reported in at least six individuals with features consistent with LGMD (PMID: 18055493, 16650086, 16650086, 19556129; ClinVar SCV001395475.6 internal data communication), including in a homozygous state without reported familial consanguinity in one patient (0.5 pts, ClinVar SCV001395475.6 internal data communication) and confirmed in trans with a likely pathogenic or pathogenic variant in one patient (c.1468C>T (p.Arg490Trp), 1.0 pt, ClinVar SCV001395475.6 internal data communication) (PM3). At least one individual with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PMID: 18055493, 16650086; ClinVar SCV001395475.6 internal data communication) (PP4). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.0002351 (the upper bound of the 95% CI of 5/44722 Admixed American chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/14/2025): PVS1, PM3, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347510/MONDO:0015152/187 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA348719 biolink:causes MONDO:0700270 infores:clingen CAID:CA348719 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3 BP4, PP3 The c.8520G>C variant in ATM is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 2840 (p.Leu2840Phe). This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183, 22649200). This variant is absent from gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.464, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA348719/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1251479 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251479 MONDO:0013144 PMID: Benign BS2, BA1 The NM_000488.4:c.42-18C>T variant is reported at a popmax FAF of 0.0771 and the highest MAF of 0.08248 (8%; 1996/24200 alleles with 85 homozygotes) in the African/African American population in gnomAD v2.1.1, meeting criteria for BA1 (MAF >0.002). The variant is reported in 2 individuals with normal antithrombin levels. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BS2. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251479/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA012805 biolink:causes MONDO:0021056 infores:clingen CAID:CA012805 MONDO:0021056 PMID: Benign BS2, BP4, BA1, BP7 PP1, PP4, PM3, PM1, PM6, BP2, PS3, PS4, PS2, BP5, BS3, BS4 The c.705A>G (p.Leu235=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant has been observed 3 (≥ 2) times in homozygous state in gnomAD 2.1.1 (BS2). The highest population minor allele frequency in the non-cancer population of gnomAD v2.1.1 is 0.004669 in the Finnish population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (>0.001) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BS2, BP4, and BP7 (Specification Version 1.0; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA012805/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42797 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042594 infores:hetionet CHEBI:6402 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0344232 infores:hetionet CHEBI:63619 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0233715 infores:hetionet CAID:CA2573157345 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157345 MONDO:0011071 PMID:33692461PMID:34166225PMID:33692461PMID:34166225 Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.613+14C>G is an intronic variant. This variant is absent from gnomAD v2.1.1 (mean depth of coverage > 60) and from gnomAD v3.1.1 (mean depth of coverage 30) (PM2_Supporting). It is not predicted by SpliceAI to impact splicing (≤0.20). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP100 (0.09) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157345/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:421707 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0009782 infores:hetionet CHEBI:24564 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0002871 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0018939 infores:hetionet CHEBI:7852 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0040822 infores:hetionet CAID:CA124457 biolink:causes MONDO:0015967 infores:clingen CAID:CA124457 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS3_Supporting, PP1_Moderate, PP3 PS4, PM5, PP4 The c.395A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 122 (p.(Tyr122Cys)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and PP4 cannot be applied due to lack of clinical information (PMID: 9097962, internal lab contributors). The variant segregated with diabetes with four informative meioses in one family (PP1_Moderate; PMID: 9097962). Additionally, functional studies demonstrated the p.Tyr122Cys protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, PMID: 10585442). Another missense variant, c.364T>C (p.Tyr122His) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Taken together, this evidence supports the classification of c.365A>G as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0): PP1_moderate. PP3, PM1_supporting, PM2_supporting, PS3_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124457/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3764 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0000737 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0033581 infores:hetionet CHEBI:135791 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0009450 infores:hetionet CHEBI:64064 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0003467 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027769 infores:hetionet CHEBI:2682 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0023222 infores:hetionet CHEBI:4876 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0015230 infores:hetionet CHEBI:63577 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0039070 infores:hetionet CHEBI:4868 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0019825 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0520559 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0520559 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0149904 infores:hetionet CAID:CA262054 biolink:causes MONDO:0019501 infores:clingen CAID:CA262054 MONDO:0019501 PMID:15241801PMID:24160897PMID:10729113PMID:17405132PMID:22135276PMID:25521520PMID:15241801PMID:24160897PMID:10729113PMID:17405132PMID:22135276PMID:25521520PMID:15241801PMID:24160897PMID:17405132PMID:10729113PMID:22135276PMID:25521520PMID:15241801PMID:24160897PMID:26969326PMID:22135276PMID:15241801PMID:24160897PMID:26969326PMID:22135276 Pathogenic PP1_Strong, PP3, PP4, PM3_Very Strong, PM2_Supporting BP7, BP5, BS4, BS1, BS2, PM4, PM1, PM5, PVS1, PM6, BP3, BP4, BP2, BA1, PS3, PS1, PS2, PS4 The allele frequency of the p.Asn346His variant in the USH2A gene is 0.016% (20/126318) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The p.Asn346His variant in USH2A has been reported to segregate with hearing loss in at least 7 families including 13 family members (PP1_S; 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15241801, 24160897, 22135276, 26969326). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). Computational prediction tools and conservation analysis suggest that the p.Asn346His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP1_S, PM3_VS, PP4, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA262054/MONDO:0019501/005 2018-09-14 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:168396 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151872 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0948824 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0948824 infores:hetionet NCBIGene:1991 biolink:causes MONDO:0008090 infores:monarchinitiative not_provided not_provided HGNC:3309 MONDO:0008090 uuid:a1a64cc1-fab0-44d7-9994-0008395a887d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42820 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0233472 infores:hetionet GO:0002304 biolink:causes CL:0000801 infores:ubergraph knowledge_assertion manual_agent GO:0002304 CL:0000801 CHEBI:63580 biolink:causes HP:0001923 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0206160 infores:hetionet CHEBI:4995 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0017565 infores:hetionet CHEBI:17026 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0575081 infores:hetionet CHEBI:9123 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009421 infores:hetionet CHEBI:32293 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0026858 infores:hetionet NCBIGene:51284 biolink:causes MONDO:0026767 infores:monarchinitiative not_provided not_provided HGNC:15631 MONDO:0026767 uuid:343b540c-1348-4a43-9a97-684f80eb71d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1321686 infores:hetionet CHEBI:68556 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0018681 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005746 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0086227 infores:hetionet CHEBI:70746 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0151904 infores:hetionet CHEBI:32020 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0011991 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0162429 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0234458 infores:hetionet CHEBI:4681 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0004245 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0018681 infores:hetionet CHEBI:6832 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0011603 infores:hetionet CHEBI:4466 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0039239 infores:hetionet CAID:CA308113474 biolink:causes MONDO:0018493 infores:clingen CAID:CA308113474 MONDO:0018493 PMID: Likely Pathogenic PS4_Moderate, PP3_Moderate, PP1_Strong PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with 2627 at codon leucine of the RYR1 protein, p.(Val2627Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000065, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (The UK (Leeds) MH Unit). This variant segregates with MHS in seven individuals, PP1_Strong (The UK (Leeds) MH Unit). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.894) supports a pathogenic, PP3_Moderate. This variant has been classified as Likey Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308113474/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:4469 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0036572 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020437 infores:hetionet CHEBI:68647 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0004093 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0004936 infores:hetionet CHEBI:8327 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0034150 infores:hetionet CHEBI:6935 biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0919671 infores:hetionet NCBIGene:317719 biolink:causes MONDO:0014037 infores:monarchinitiative not_provided not_provided HGNC:18829 MONDO:0014037 uuid:223400c2-cbb1-46f1-8cd8-f3f6e60bf2c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6923 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0002792 infores:hetionet CAID:CA220149 biolink:causes MONDO:0021060 infores:clingen CAID:CA220149 MONDO:0021060 PMID: Pathogenic PM2_Supporting, PS3_Moderate, PP2, PP3, PP1, PM1, PS4, PM6 The c.836A>G (NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys))variant in PTPN11 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 279 (p.Tyr279Cys). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.973, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common. The Z-score for missense variants in PTPN11 in gnomAD v4.1.0 is 4.95 (PP2; PMID: 29493581). This variant resides in a region (amino acids 278-281) of PTPN11 that is defined as a mutational hotspot and/or critical functional domain by the ClinGen RASopathy VCEP (PM1; PMID 29493581). This variant has been observed in 10 probands with clinical features of Noonan Syndrome with multiple lentigines (PS4, 7.0 pts.; PMIDs: 14634749, 15520399, 24401936, 24775816, 28483241). The variant was identified as a de novo occurrence with unconfirmed parental relationships in the father of an affected family (PM6, 1.0 pts.; PMID: 24401936). The variant segregated with disease in his 4 affected children (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_supporting, PP3, PP2, PM1, PS4, PM6, PP1 (Specifications Version 2.3.0; 9/9/2025). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220149/MONDO:0021060/043 2025-09-09 2025-09-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7936 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042345 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0241558 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0241558 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0233472 infores:hetionet CHEBI:478164 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0027066 infores:hetionet CHEBI:135005 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0338831 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0040034 infores:hetionet CHEBI:51173 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0220981 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C1510472 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042109 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020550 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004095 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0002453 infores:hetionet CHEBI:92511 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0314719 infores:hetionet CHEBI:3423 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0011849 infores:hetionet CHEBI:10125 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0010200 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0744221 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0744221 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001752 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013240 infores:hetionet CAID:CA9487866 biolink:causes MONDO:0011229 infores:clingen CAID:CA9487866 MONDO:0011229 PMID: Benign BS2, BA1, BP7 PM5, PM1, PM3, PP3, PP4, PP1, BP4, BP2, PS1, PS3, PS4, PS2, PM2, PM6, BP5, BS3, BS4 The filtering allele frequency of the c.378G>A variant in the ETHE1 gene is >0.2% by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Mito Variant Curation Expert Panel (BA1) Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA9487866/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2666 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0235198 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011053 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002622 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0014549 infores:hetionet CHEBI:2682 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0852911 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0041909 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0033975 infores:hetionet CHEBI:50173 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0231528 infores:hetionet CHEBI:75722 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019079 infores:hetionet CHEBI:37333 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0600142 infores:hetionet CHEBI:31643 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0010520 infores:hetionet CHEBI:6715 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0852911 infores:hetionet CHEBI:4975 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C2830004 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0011570 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0042109 infores:hetionet CHEBI:6541 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0233794 infores:hetionet CHEBI:9137 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013447 infores:hetionet CAID:CA10524885 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524885 MONDO:0010278 PMID: Likely Benign BP4, BP7, BS1 The allele frequency of the c.1971G>A (p.Pro657=) variant in SLC9A6 (NM_006359.2) is 0.015% in African/African-American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Pro657= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the p.Pro657= variant in SLC9A6 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524885/MONDO:0010278/033 2023-10-13 2023-12-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:4784 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0017675 infores:hetionet CHEBI:41977 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0036508 infores:hetionet CHEBI:31348 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085616 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0150450 infores:hetionet CHEBI:7447 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0000737 infores:hetionet CHEBI:6375 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085593 infores:hetionet CHEBI:84050 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0151904 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235025 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020538 infores:hetionet NCBIGene:10092 biolink:causes MONDO:0957920 infores:monarchinitiative not_provided not_provided HGNC:708 MONDO:0957920 uuid:3286972e-776f-42f2-9c3d-509aad500188 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3286 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0086439 infores:hetionet CHEBI:3398 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0020649 infores:hetionet NCBIGene:5307 biolink:causes MONDO:0007342 infores:monarchinitiative not_provided not_provided HGNC:9004 MONDO:0007342 uuid:78fccf84-9562-473a-8d6b-ee7e53bac4d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27834 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0042769 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0242350 infores:hetionet NCBIGene:3815 biolink:causes MONDO:0008244 infores:monarchinitiative not_provided not_provided HGNC:6342 MONDO:0008244 uuid:f8f44d2e-5b96-4944-8ad8-5c5c932691cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151786 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0595877 infores:hetionet CAID:CA031354 biolink:causes MONDO:0007750 infores:clingen CAID:CA031354 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PP1_Moderate, PM3, PVS1, PM2, PP4 PS3 The NM_000527.5 (LDLR):c.1045C>T (p.Gln349Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4_Supporting, PM3, PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF = 0.00006 in South Asian population in gnomAD (gnomAD v2.1.1).PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830).PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting: Variant meets PM2, and is identified in 3 unrelated index cases: 1 case fulfil Simon Broome possible FH criteria (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case fulfil DLCN criteria (Robarts Research Institute, Canada); 1 case met criteria of total and LDL-C levels over the 95th percentile corrected for age and sex, plus two of: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative and hypercholesterolemic children in the family (Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain, PMID 11668640).PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C: 11.1mmol/l at age of 5 yr.) and is homozygous for the variant (Robarts Research Institute, Canada). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meiosis from 2 families from 2 research labs. One affected relative tested positive for the variant from one family (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Three affected relative tested positive for the variant from another family (Robarts Research Institute, Canada). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA031354/MONDO:0007750/013 2022-04-25 2022-04-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:31348 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0004093 infores:hetionet CHEBI:171719 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0004134 infores:hetionet CHEBI:3723 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026826 infores:hetionet CHEBI:94392 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0851578 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019348 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0036454 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0009806 infores:hetionet GO:1902803 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1902803 GO:0051641 NCBIGene:2707 biolink:causes MONDO:0009076 infores:monarchinitiative not_provided not_provided HGNC:4285 MONDO:0009076 uuid:e0693ebb-1e47-4e0a-b979-5376f69d6383 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6538 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C2830004 infores:hetionet CHEBI:367163 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0917801 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020538 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0235032 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0858786 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0858786 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037274 infores:hetionet CHEBI:45783 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0041364 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0151786 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0234458 infores:hetionet CHEBI:10023 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017675 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017152 infores:hetionet CHEBI:17650 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0002792 infores:hetionet CAID:CA003718 biolink:causes MONDO:0700268 infores:clingen CAID:CA003718 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP4, BP5 The c.5561T>C variant in BRCA1 is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 1854 (p.(Leu1854Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.41, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.15 (based on Co-occurrence LR=1.07; Family History LR=1.07), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003718/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31711 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151601 infores:hetionet UMLS:C0010592 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0020458 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0023533 infores:hetionet CHEBI:6912 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0004093 infores:hetionet NCBIGene:731 biolink:causes MONDO:0013422 infores:monarchinitiative not_provided not_provided HGNC:1352 MONDO:0013422 uuid:f2cc7fb2-efac-4abb-9962-8e68aaddf48a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0002170 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017605 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0020538 infores:hetionet NCBIGene:55033 biolink:causes MONDO:0013800 infores:monarchinitiative not_provided not_provided HGNC:18625 MONDO:0013800 uuid:b08b646e-6b77-4225-80e1-286c009f7fc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1443060 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0270934 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0270934 infores:hetionet UMLS:C0004609 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0085593 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002922 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0034212 infores:hetionet CHEBI:52717 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014591 infores:hetionet CHEBI:4708 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0019270 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0427008 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0039503 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0518015 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0016034 infores:hetionet CHEBI:3001 biolink:causes UMLS:C0919659 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0919659 infores:hetionet CHEBI:2379 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C2363730 infores:hetionet CAID:CA312285 biolink:causes MONDO:0008723 infores:clingen CAID:CA312285 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP4, PM4, PM3_Supporting The NM_000018.4 c.889_891del (p.Glu297del) variant in ACADVL is an in-frame deletion (removes amino acids Glu297) in exon 10/20 that is not predicted to impact splicing (SpliceAI: 0.08). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The c.889_891del variant is predicted to cause a change in the length of the protein (p.Glu297del) due to an in-frame deletion of an amino acid in a non-repeat region (PM4). This variant is reported in the literature in an individual affected with confirmed very long-chain acyl-CoA dehydrogenase deficiency displaying elevated C14:1 carnitine level (2.64 µmol/L), which is highly specific for VLCAD deficiency. This patient also carries a likely pathogenic variant ACADVL c.1246G>T with unknown phase (PP4_Moderate, PM3_Supporting, PMID: 25456746). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM4, PP4_Moderate, PM3_Supporting, PM2_Supporting, (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312285/MONDO:0008723/021 2024-09-24 2024-10-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0277925 infores:hetionet CHEBI:45409 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0033774 infores:hetionet CHEBI:5801 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0151907 infores:hetionet CHEBI:4911 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0700590 infores:hetionet CHEBI:6413 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0013604 infores:hetionet CHEBI:520985 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0017168 infores:hetionet CHEBI:47780 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037317 infores:hetionet CAID:CA386959120 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959120 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3 PP4 The c.364T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to histidine at codon 122 (p.(Tyr122His)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Another missense variant at the same codon, c.365A>G p.Tyr122Cys, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50%, and therefore, PP4 does not apply (internal lab contributors). In summary, c.364T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959120/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15765 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0034150 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025061 infores:hetionet CHEBI:30830 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0014591 infores:hetionet CHEBI:7445 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0027497 infores:hetionet CHEBI:28593 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0011606 infores:hetionet CAID:CA512318875 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318875 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.261C>T (p.Gly87=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.08) (BP4). This variant has a SpliceAI score ≤ 0.20 and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.605)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318875/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6538 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0948594 infores:hetionet CHEBI:92998 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0019294 infores:hetionet CAID:CA5949977 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949977 MONDO:0000572 PMID: Pathogenic PM2_Supporting, PM3, PVS1 PP4, PS3 The nonsense variant NM_000448.3(RAG1):c.424C>T (p.Arg142Ter) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense-mediated decay but does truncate 86% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). The popmax allele frequency is 0.00004007 (1/24954 alleles) in the African/African American population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). This variant has been reported in at least seven patients with atypical SCID or Omenn syndrome (PMIDs: 30877075, 33225392, 30307608, 25849362, 20109747, 24290284, 17075247) however in all cases there is insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). This variant has been reported homozygous in at least two Omenn syndrome patients (PMIDs: 33225392, 30307608; 1pt; PM3). Five additional atypical SCID or Omenn syndrome cases have been reported compound heterozygous for this variant (PMIDs: 30877075, 25849362, 20109747, 24290284, 17075247). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Arg142Ter was 9.0% of wild type +/- 4.0 (PMID: 24290284). However, because no patient has been identified meeting the PP4 criteria PS3 is not applied at any strength. In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM3 and PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949977/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:56945 biolink:causes MONDO:0020857 infores:monarchinitiative not_provided not_provided HGNC:14508 MONDO:0020857 uuid:a14755e8-d5d9-4445-92ce-33ad98c77728 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3699 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0002874 infores:hetionet CHEBI:9086 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0600104 infores:hetionet GO:0060685 biolink:causes GO:0060512 infores:ubergraph knowledge_assertion manual_agent GO:0060685 GO:0060512 PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0333641 infores:hetionet CHEBI:6775 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0232495 infores:hetionet CHEBI:101853 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0404521 infores:hetionet GO:2000006 biolink:causes GO:0072273 infores:ubergraph knowledge_assertion manual_agent GO:2000006 GO:0072273 CHEBI:9445 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0004238 infores:hetionet GO:0090049 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0072359 CAID:CA7330936 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330936 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, BP2, BA1, PP3, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.4189T>C variant in DICER1 is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 1397 (p.Trp1397Arg). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002462 (1/40622 alleles) in African/African American population (PM2_Supporting, BS1, and BA1 are not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors: 61756, 500031). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.207; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as likely benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_supporting; BP4. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330936/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51450 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0015230 infores:hetionet CHEBI:681848 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0023066 infores:hetionet GO:0075198 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0075198 GO:0048856 CHEBI:50131 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0037199 infores:hetionet NCBIGene:8074 biolink:causes MONDO:0008660 infores:monarchinitiative not_provided not_provided HGNC:3680 MONDO:0008660 uuid:4329d861-0bbe-417f-8af6-1d069bf598f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0018799 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0242350 infores:hetionet CHEBI:3011 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0033774 infores:hetionet CAID:CA413495887 biolink:causes MONDO:0010315 infores:clingen CAID:CA413495887 MONDO:0010315 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting The c.720G>A (p.Trp240Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts) + SCID phenotype corrected by IL2RG gene therapy WITHOUT CNV testing reported (1 pt). Total is 2 points, PP4_Moderate.In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413495887/MONDO:0010315/129 2024-06-13 2024-06-13 X-linked inheritance HP:0001417 Supports CAID:CA1624896 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624896 MONDO:0021060 PMID: Likely Benign BP7, BP4 PS4, BP5, PM2 The c.39A>G (p.Glu13Glu) variant in SOS1 is classified as likely benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing (BP4, BP7). It has been identified in 0.004165% (5/120058) of non-Finnish European chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). This variant was observed in several individuals with varying clinical presentations that lacked clear associations with a RASopathy. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624896/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:34967 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0037199 infores:hetionet CHEBI:63632 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0011991 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0037199 infores:hetionet CHEBI:41879 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0858617 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0001824 infores:hetionet CHEBI:63612 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0027796 infores:hetionet CHEBI:3510 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0011974 infores:hetionet CHEBI:50131 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0011991 infores:hetionet CHEBI:31547 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011991 infores:hetionet CHEBI:84050 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0085649 infores:hetionet CHEBI:3994 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0221242 infores:hetionet NCBIGene:5663 biolink:causes MONDO:0013371 infores:monarchinitiative not_provided not_provided HGNC:9508 MONDO:0013371 uuid:1aef3c45-e77d-4c5e-bdaa-0d53e9e85f61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5088 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0027769 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0687133 infores:hetionet CHEBI:4653 biolink:causes UMLS:C1540600 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C1540600 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0236071 infores:hetionet CHEBI:3638 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0237849 infores:hetionet CHEBI:2948 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0206062 infores:hetionet NCBIGene:5727 biolink:causes MONDO:0012562 infores:monarchinitiative not_provided not_provided HGNC:9585 MONDO:0012562 uuid:e27674a2-37f2-4ab1-8dff-9809d74bedd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10717 biolink:causes MONDO:0013551 infores:monarchinitiative not_provided not_provided HGNC:572 MONDO:0013551 uuid:05969946-9ba3-448a-874d-ab0eb348cae9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94609 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0560024 infores:hetionet CHEBI:135613 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0917801 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013395 infores:hetionet CHEBI:53691 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0009763 infores:hetionet CHEBI:127780 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0030252 infores:hetionet CHEBI:15367 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0149745 infores:hetionet CHEBI:61390 biolink:causes HP:0031446 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0399461 infores:hetionet NCBIGene:57728 biolink:causes MONDO:0013718 infores:monarchinitiative not_provided not_provided HGNC:18340 MONDO:0013718 uuid:ee70d3c4-c66d-4ded-992e-ed1d331717ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9727 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0011606 infores:hetionet CHEBI:4659 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0020580 infores:hetionet CAID:CA000368 biolink:causes MONDO:0017623 infores:clingen CAID:CA000368 MONDO:0017623 PMID: Likely Benign BS1, BP7, BP4 PTEN c.254-39G>T (IVS4-39G>T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0064 (0.64%, 112/17,490 alleles) in the South Asian subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is intronic and at or beyond +7/-21, nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000368/MONDO:0017623/003 2016-12-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:134991 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0236075 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0012833 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0233632 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0948396 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0948396 infores:hetionet CHEBI:2618 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0312420 infores:hetionet CHEBI:17263 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C3495440 infores:hetionet GO:0035155 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0035155 GO:0007275 CHEBI:75246 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0178298 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0004936 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0235822 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235822 infores:hetionet CHEBI:7936 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0404521 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0233417 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0233417 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0003864 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0020517 infores:hetionet CHEBI:47499 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0520966 infores:hetionet CHEBI:47898 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026640 infores:hetionet CHEBI:145499 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0019572 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0235431 infores:hetionet CHEBI:135961 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0236075 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002187 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042994 infores:hetionet CHEBI:94392 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0004093 infores:hetionet CHEBI:3647 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0917801 infores:hetionet CHEBI:41423 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0034886 infores:hetionet GO:0003427 biolink:causes GO:0001738 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0001738 CHEBI:41774 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0234632 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0033860 infores:hetionet NCBIGene:7508 biolink:causes MONDO:0010211 infores:monarchinitiative not_provided not_provided HGNC:12816 MONDO:0010211 uuid:e12a85ad-dc11-47b5-ad24-51eb3c48aa1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9738 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0009676 infores:hetionet CHEBI:8228 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0023218 infores:hetionet CHEBI:6912 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0015672 infores:hetionet CHEBI:3207 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0006277 infores:hetionet CHEBI:50924 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0040038 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0012833 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0236075 infores:hetionet CAID:CA337220546 biolink:causes MONDO:0010305 infores:clingen CAID:CA337220546 MONDO:0010305 PMID:38070861PMID:25861866 Uncertain Significance PM2_Supporting, BP4 PS3 The NM_005629.4:c.1654G>T variant in SLC6A8 is a missense variant predicted to cause substitution of a leucine for a valine at amino acid position 552 (p.Val552Leu).This variant is absent in gnomAD v2.1.1. (PM2_Supporting), and has a REVEL score of 0.193 which suggest no impact to protein function (BP4). DesRoches et al. evaluated the p.Val552Leu variant for creatine uptake in HeLa cells transiently transfected with the missense variant, this assay measured a reduction of 35% of wild-type, which does not meet the threshold or assay conditions for PS3 as set by the Cerebral Creatine Deficiency VCEP (PMID:25861866). Ferrada et al. followed up the DesRoches study with a creatine uptake assay based on the electrogenicity of the SLC6A8 transport function, where the p.Val552Leu variant was assessed to have a ratio of variant efficacy to wild-type efficacy of 0.87, and was assessed as being wild-type by the publication (Table S3 and 2)(PMID:38070861). Neither publication chose to assay the variant based on its presence in an affected individual (PS3 Not Met). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0), PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on February 22, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA337220546/MONDO:0010305/027 2024-02-22 2024-03-25 X-linked inheritance HP:0001417 Inconclusive true CHEBI:28241 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0235195 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0039971 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004238 infores:hetionet CHEBI:28787 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0020578 infores:hetionet CHEBI:9555 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0038002 infores:hetionet CAID:CA16614307 biolink:causes MONDO:0100216 infores:clingen CAID:CA16614307 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, PVS1, BP3, BP2, BA1, PP3, PP1, PP4, PM5, PM4, PM1, PM3, PS1, PS3, PS4, BP7, BS1, BS3, BS4 NM_177438.3(DICER1):c.4283T>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by lysine at amino acid 1428 (p.Met1802Lys). This variant received a total of 0.5 phenotype points in a single proband (PS4 not met; Internal lab contributors SCV001509541.1). This variant has also been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors SCV001509541.1, SCV001444307.1). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.00008606 (3/34860 alleles) in Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.115; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614307/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA392335589 biolink:causes MONDO:0007947 infores:clingen CAID:CA392335589 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1_Strong PS4, PM5 The NM_00138 c.2287T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 763 (p.Cys763Arg). This variant has been reported 3 times in ClinVar, twice as likely pathogenic and once as uncertain significance (Variation ID: 519758). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.979) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup, PP2, PP3 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392335589/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:32221 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0344232 infores:hetionet CHEBI:38940 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151905 infores:hetionet GO:1903388 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:1903388 GO:0099504 CHEBI:251408 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0233514 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0080203 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0009806 infores:hetionet CHEBI:6897 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0027769 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020517 infores:hetionet CHEBI:9137 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0522055 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0037195 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0037274 infores:hetionet CHEBI:34385 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0017178 infores:hetionet CAID:CA386965264 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965264 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP1 BP4, PS3, PS4, PP3 The c.694C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 232 (p.(Leu232Val)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.688, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 1 family (PP1; internal lab contributors). Another missense variant, c.695T>C p.Leu232Pro, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.694C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP1, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965264/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49960 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0010692 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0023418 infores:hetionet CHEBI:29688 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0032617 infores:hetionet CAID:CA229361 biolink:causes MONDO:0009861 infores:clingen CAID:CA229361 MONDO:0009861 PMID: Likely Pathogenic PM2, PM5, PP3, PP4, PM3_Supporting The c.1156T>G (p.Tyr386Asp) variant in PAH has been reported in 1 female, Italian patient - type of PKU not specified, serum Phe = 822umol/L; BH4 responsiveness was not specified (PMID: 23430918; PP4). This variant has been detected with R158Q - reported as pathogenic in ClinVar (VarID:587), 14 submitters, phase unknown - 0.5 points (PMID: 23430918; PM3_Supporting). Another missense change at the same amino is pathogenic (p.Tyr386Cys). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.977 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3, PP4, PM3_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229361/MONDO:0009861/006 2022-06-24 2022-06-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5134 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0029453 infores:hetionet CHEBI:171719 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0019080 infores:hetionet CHEBI:36704 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0000737 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0014868 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0005779 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0006444 infores:hetionet CHEBI:50730 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C1760428 infores:hetionet CHEBI:31413 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C1145670 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018991 infores:hetionet CHEBI:32315 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0038999 infores:hetionet CHEBI:2379 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C3665347 infores:hetionet CHEBI:27777 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C1565489 infores:hetionet CHEBI:51164 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0030252 infores:hetionet CHEBI:10102 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085610 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0036572 infores:hetionet CHEBI:82981 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0085593 infores:hetionet CHEBI:3756 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0018524 infores:hetionet CHEBI:28445 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0032617 infores:hetionet CAID:CA413497107 biolink:causes MONDO:0010315 infores:clingen CAID:CA413497107 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.207C>A (p.Tyr69Ter)(NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.); total: 1 pt. (PP4) (PMID: 19398866).In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1,PM2_supporting,PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413497107/MONDO:0010315/129 2024-02-01 2024-02-01 X-linked inheritance HP:0001417 Supports CHEBI:28901 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0013428 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0267055 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0267055 infores:hetionet CHEBI:63717 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0035410 infores:hetionet CHEBI:4814 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0917801 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011334 infores:hetionet CHEBI:63637 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0018681 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0235431 infores:hetionet CHEBI:135530 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0600260 infores:hetionet CHEBI:74947 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0009763 infores:hetionet CHEBI:3640 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0392176 infores:hetionet CHEBI:68606 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0013415 infores:hetionet CHEBI:42797 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C2047937 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042373 infores:hetionet CHEBI:64064 biolink:causes MONDO:0700226 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0016470 infores:hetionet CHEBI:61049 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085612 infores:hetionet GO:1901249 biolink:causes GO:0060481 infores:ubergraph knowledge_assertion manual_agent GO:1901249 GO:0060481 CHEBI:6067 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011849 infores:hetionet CHEBI:2673 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0020517 infores:hetionet CHEBI:68845 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0037763 infores:hetionet CHEBI:4877 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0038325 infores:hetionet CHEBI:205919 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0037274 infores:hetionet CHEBI:4046 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0003123 infores:hetionet NCBITaxon:813 biolink:causes MONDO:0001249 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:813 MESH:D014141 DB00254_MESH_D014141_1DB00263_MESH_D014141_1DB01017_MESH_D014141_1DB02703_MESH_D014141_1DB09093_MESH_D014141_1DB00595_MESH_D014141_1DB13092_MESH_D014141_1DB00634_MESH_D014141_1DB00618_MESH_D014141_1DB00759_MESH_D014141_1 CHEBI:68478 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017178 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0011991 infores:hetionet CHEBI:40237 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0037011 infores:hetionet CHEBI:107736 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0085623 infores:hetionet CHEBI:5959 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0231218 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0948594 infores:hetionet CHEBI:4995 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C2830004 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0281913 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0281913 infores:hetionet CHEBI:8107 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0003537 infores:hetionet CHEBI:4798 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0005779 infores:hetionet NCBIGene:54885 biolink:causes MONDO:0026726 infores:monarchinitiative not_provided not_provided HGNC:24715 MONDO:0026726 uuid:0ea3fe97-3bba-48df-9e24-a9f82dba9437 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135930 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0242429 infores:hetionet CHEBI:37333 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0003467 infores:hetionet CAID:CA312257 biolink:causes MONDO:0008723 infores:clingen CAID:CA312257 MONDO:0008723 PMID:17999356 Uncertain Significance PM2_Supporting, PP3, PM3_Supporting, PP4_Moderate PM1, PM5, PS1, PS3 The c.881G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 294 (p.Gly294Glu). At least two patients with this variant displayed low very long chain acyl-CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8739957, 12208138). This variant has been detected in at least three patients with clinically diagnosed VLCAD deficiency. Two of these individuals were compound heterozygous for this variant and a likely pathogenic variant, neither confirmed to be in trans (PM3_Supporting; PMID: 25737446,17999356). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL VCEP threshold (0.001) for PM2_supporting, meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.75, evidence that correlates with impact to VLCAD function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_moderate, PM2_supporting, PM3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). This variant was originally curated April 12, 2022 and the recurated classification was approved by the expert panel on March 28, 2023. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312257/MONDO:0008723/021 2023-03-28 2023-03-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63622 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0233407 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0022650 infores:hetionet NCBIGene:4053 biolink:causes MONDO:0013899 infores:monarchinitiative not_provided not_provided HGNC:6715 MONDO:0013899 uuid:d9e3d17c-1b4a-4006-a3cc-6cf8fd092a30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135679 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0010200 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0235416 infores:hetionet CAID:CA340940 biolink:causes MONDO:0044970 infores:clingen CAID:CA340940 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PS4 The m.5244G>A (p.G259S) variant in MT-ND2 has been reported in one family (PMID: 1634041) with Leber Hereditary Optic Neuropathy (LHON), however individuals in this family also harbored other mitochondrial DNA variants also associated with LHON, making the association of this variant to the primary mitochondrial disease features in these individuals unclear. Furthermore, to our knowledge, nuclear genetic testing was not performed. There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (77 percentile, PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340940/MONDO:0044970/015 2023-10-09 2023-11-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:31236 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0040034 infores:hetionet CAID:CA023828 biolink:causes MONDO:0007783 infores:clingen CAID:CA023828 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PS4_Moderate, PS1, PM1_Supporting, PP3_Moderate, PP1_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Glycine with Arginine at codon 341 of the RYR1 protein, p.(Gly341Arg), c.1021G>C. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, four of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:12059893, PMID:16163667, PMID:30236257 ). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:12059893, PMID:12411788). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Gly341Arg, c.1021G>A), PS1. This variant segregates with MHS in two individuals (PMID:12059893). A REVEL score >0.85 (0.876) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP3_Moderate.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023828/MONDO:0007783/012 2022-03-14 2022-03-14 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:53760 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042109 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0852733 infores:hetionet NCBIGene:10383 biolink:causes MONDO:0060650 infores:monarchinitiative not_provided not_provided HGNC:20771 MONDO:0060650 uuid:af6380cb-6d4f-4a62-9f36-3a91a6afebf3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0012833 infores:hetionet CHEBI:4702 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0344232 infores:hetionet CHEBI:8382 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0344232 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005386 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1306889 infores:hetionet CHEBI:3515 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0013404 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0272426 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0272426 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0041671 infores:hetionet CHEBI:31644 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0014724 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0442874 infores:hetionet CHEBI:15552 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0039070 infores:hetionet GO:1904136 biolink:causes GO:0030903 infores:ubergraph knowledge_assertion manual_agent GO:1904136 GO:0030903 CHEBI:18248 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0002792 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0027051 infores:hetionet CHEBI:3175 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0542571 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0687707 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0333641 infores:hetionet CHEBI:6950 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0009676 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0948594 infores:hetionet CHEBI:17026 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0008031 infores:hetionet CHEBI:9150 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0037763 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0853697 infores:hetionet CHEBI:31623 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0162820 infores:hetionet CHEBI:3286 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0022408 infores:hetionet CHEBI:5801 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0030312 infores:hetionet CAID:CA024662 biolink:causes MONDO:0007783 infores:clingen CAID:CA024662 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4, PP1_Strong, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2336 of the RYR1 protein, p.(Arg2336His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 26 individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 19191329, 24433488, 21455645, 23460944, 23558838, 23736090, 31559918). This variant segregates with IVCT status in over 10 individuals (PMID: 30236257, 19191329, 24433488). Functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.903) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024662/MONDO:0007783/012 2022-07-10 2022-07-10 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:36791 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017601 infores:hetionet NCBIGene:84196 biolink:causes MONDO:0859366 infores:monarchinitiative not_provided not_provided HGNC:18533 MONDO:0859366 uuid:89c55e57-0750-46ca-bde0-9480231939f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA119171 biolink:causes MONDO:0020367 infores:clingen CAID:CA119171 MONDO:0020367 PMID:15069026PMID:11004290PMID:19234343 Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS1, PS2, BP4, BA1 The c.1109C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 370 (p.Pro370Leu). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.89, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Pro370Leu protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (≥7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119171/MONDO:0020367/019 2022-03-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:77733 biolink:causes MONDO:0008848 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0004331 infores:hetionet CAID:CA010191 biolink:causes MONDO:0021056 infores:clingen CAID:CA010191 MONDO:0021056 PMID: Likely Pathogenic PP3, PS1_Moderate, PS4_Moderate, PM2_Supporting The NM_000038.6(APC):c.531+5G>A variant in APC is an intronic variant which consists of a G>A nucleotide substitution at the +5 position of intron 5 of the APC gene. The results from in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 3 probands meeting 2 phenotype points (PS4_Moderate; PMID: 21813337, GeneDX internal cases). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 25980754, 26681312, Ambry internal case). This variant has similar in silico predictions compared to another splicing variant at that same nucleotide position (c.531+5G>C) (PMID: 12010888, 20223039, 19196998, ClinVar ID 279681), which has been classified as likely pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS1_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA010191/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41774 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0029408 infores:hetionet CAID:CA399805008 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805008 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5(ITGA2B):c.859G>C (p.Gly287Arg) missense variant has been reported in at least one patient (Patient 5 in PMID:19172520/GT database record 162) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <10%, as measured by flow cytometry. Patient 5 (PMID: 19172520/GT database record 162) is homozygous for this variant (0.5pt; PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PM2_Supporting, PM3_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805008/MONDO:0100326/011 2022-12-01 2022-12-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:474180 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0085624 infores:hetionet CHEBI:5128 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0023530 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0948089 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0037274 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233414 infores:hetionet NCBIGene:3767 biolink:causes MONDO:0014589 infores:monarchinitiative not_provided not_provided HGNC:6257 MONDO:0014589 uuid:46958ed6-46a5-4fdd-a660-5e27cc4c2ac8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3638 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0017178 infores:hetionet CAID:CA266818 biolink:causes MONDO:0012589 infores:clingen CAID:CA266818 MONDO:0012589 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The p.Trp362Ter variant in TCF4 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a TCF4 where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the TCF4 is pathogenic (PVS1). The p.Trp362Ter variant in TCF4 is absent from gnomAD (PM2_Supporting). In summary, the p.Trp362Ter variant in TCF4 is classified as likely pathogenic based on the ACMG/AMP criteria (PVS1, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA266818/MONDO:0012589/016 2021-04-02 2021-04-19 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:6775 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0032285 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0013395 infores:hetionet CHEBI:47519 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0231528 infores:hetionet CHEBI:49575 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0085593 infores:hetionet CHEBI:50922 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0033774 infores:hetionet NCBIGene:54567 biolink:causes MONDO:0014703 infores:monarchinitiative not_provided not_provided HGNC:2910 MONDO:0014703 uuid:728d0854-3aeb-424f-9e83-9e1afe443c8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0007859 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028768 infores:hetionet CHEBI:8874 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1167965 infores:hetionet CAID:CA251530 biolink:causes MONDO:0009861 infores:clingen CAID:CA251530 MONDO:0009861 PMID:23500595PMID:10479481PMID:24368688PMID:23500595PMID:19036622PMID:2014036 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PS3 PM2, PS2 PAH-specific ACMG/AMP criteria applied: PS3: R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type. (PMID:2014036; PMID:19036622); PP3: tools predict damaging ; PP4_Moderate: BH4 testing showed responsive in a pt, pretreatment 1065uM (PMID:23500595); PM3_VeryStrong: in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter. (PMID:23500595; PMID:10479481; PMID:24368688). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PP3, PP4_Moderate, PM3_VeryStrong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251530/MONDO:0009861/006 2018-08-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0234535 infores:hetionet CHEBI:64310 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0027947 infores:hetionet CHEBI:9667 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0015967 infores:hetionet CHEBI:6931 biolink:causes UMLS:C1701474 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C1701474 infores:hetionet CHEBI:32599 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0038990 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0948594 infores:hetionet CHEBI:6402 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0700590 infores:hetionet CHEBI:5551 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0042963 infores:hetionet CHEBI:2955 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0231528 infores:hetionet CHEBI:9449 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037195 infores:hetionet CAID:CA343725043 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725043 MONDO:0005338 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting BP7, BS1, BS3, PP1, PM4, PM5, PS3, PS1, PS2, BP4, BA1 The c.1025G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 342 (p.Arg342Lys). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v4.1.0) = 0.0000008474 (1 allele out of 1,180,018), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.649, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 2 probands with primary open angle glaucoma have been reported carrying this variant (PMID: 12362081), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725043/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2573320431 biolink:causes MONDO:0044970 infores:clingen CAID:CA2573320431 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting PP1, PS3, PM6 The m.3273del variant in MT-TL1 has been reported in two unrelated individuals (PS4_supporting; PMIDs: 7854527, 30701423). The first reported case (PMID: 7854527) was a man with encephalomyopathy and cerebral and basal ganglia calcifications. He also had seizures, hearing loss, cataracts, glaucoma, retinitis pigmentosa, hyperactivity, hypogonadism, renal failure, and neurologic decline in adulthood. He had elevated cerebrospinal fluid (CSF) protein and serum lactate, and muscle biopsy showed ragged red fibers and paracrystalline inclusions. The variant was present at 65% heteroplasmy in muscle. The second reported case (PMID: 30701423) was a woman who was generally healthy until age 20 years when she developed diabetes. She then went on to have hearing loss, cognitive impairment, bilateral cataracts, and retinal dystrophy. She also had basal ganglia calcifications and cerebellar atrophy. She had elevated CSF lactate. Muscle biopsy was unrevealing. The variant as described as present in muscle but the heteroplasmy level was not provided. The variant was reported to be absent in blood from the mother in the first reported case however heteroplasmy level in blood was not determined for the proband, precluding consideration for de novo status. There are no other reports of large families with this variant segregating with disease manifestations. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (85.7 percentile; PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as of uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573320431/MONDO:0044970/015 2023-05-23 2024-07-23 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4453 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0042109 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004892 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0034951 infores:hetionet CHEBI:6367 biolink:causes HP:0034773 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0422980 infores:hetionet CHEBI:30659 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0003862 infores:hetionet CHEBI:474180 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0428977 infores:hetionet CAID:CA397722480 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722480 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 PP3, PM3, PS3 The c.277+1G>A variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 4. It is predicted to cause skipping of biologically-relevant-exon 4/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in at least 2 individuals with a newborn screen consistent with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, one was compound heterozygous for the variant and an additional variant not yet curated by the ACADVL VCEP, c.1376G>A (PMID: 30194637). In this individual, the residual VLCAD activity in lymphocytes was 7% (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PP4_moderate. (VCEP specifications v2.0, approved on 09/16/2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722480/MONDO:0008723/021 2022-04-26 2022-04-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3561 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0036974 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0039971 infores:hetionet CHEBI:87681 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0010200 infores:hetionet CHEBI:291342 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0423791 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0042487 infores:hetionet CHEBI:28901 biolink:causes UMLS:C1407280 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1407280 infores:hetionet CHEBI:9586 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0003467 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020538 infores:hetionet CHEBI:3756 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042790 infores:hetionet CHEBI:10124 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151786 infores:hetionet CHEBI:31711 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0038999 infores:hetionet CAID:CA229769 biolink:causes MONDO:0009861 infores:clingen CAID:CA229769 MONDO:0009861 PMID:26600521PMID:16256386PMID:26600521PMID:16256386PMID:9450897PMID:7914195 Pathogenic PM3, PM2, PP4, PP3, PS3 PM5 The c.799C>G (p.Gln267Glu) variant in PAH was reported in 2 Chinese PKU patients. BH4 deficiencies not completely ruled out. (PMID: 26600521) This variant was detected with known pathogenic variants p.R111X (PMID: 16256386), and D101N (not in ClinVar, PMID: 26600521). It is absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.935. This variant was expressed in e. coli using a rat Q267E mutant. It has 11% activity of wt. based on duplicate determinations of a single clone. (PMID: 7914195). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229769/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63617 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0030305 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0152027 infores:hetionet CHEBI:66964 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0948594 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0858751 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0858751 infores:hetionet CAID:CA10650429 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650429 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*917del is a 3' UTR variant with a MAF in the African American subpopulation which is higher than expected for this disorder (0.039%). There is no computational or functional evidence to support a deleterious impact on the protein function. So far, the variant has not been described in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650429/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10023 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020517 infores:hetionet CHEBI:135613 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0085610 infores:hetionet CHEBI:585948 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0235439 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0037199 infores:hetionet CHEBI:9586 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1443060 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0024115 infores:hetionet NCBIGene:4633 biolink:causes MONDO:0012112 infores:monarchinitiative not_provided not_provided HGNC:7583 MONDO:0012112 uuid:9035e4bc-f60f-4605-a04d-c33f580aba24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:U6XF9NP8HM biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0220994 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003615 infores:hetionet CHEBI:71940 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0035455 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0236051 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0178298 infores:hetionet CHEBI:71415 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0011991 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0009806 infores:hetionet NCBIGene:93587 biolink:causes MONDO:0000208 infores:monarchinitiative not_provided not_provided HGNC:28403 MONDO:0000208 uuid:9e5a1264-4395-4b51-a2ba-b214191fea5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:93363 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0151827 infores:hetionet CHEBI:135530 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0017178 infores:hetionet CHEBI:38562 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0014724 infores:hetionet CHEBI:3723 biolink:causes NCIT:C92849 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0240802 infores:hetionet CHEBI:16469 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0241729 infores:hetionet CHEBI:9586 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042029 infores:hetionet CHEBI:2788 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0344232 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0009450 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0392197 infores:hetionet NCBIGene:7187 biolink:causes MONDO:0976228 infores:monarchinitiative not_provided not_provided HGNC:12033 MONDO:0976228 uuid:c8b026fd-24e0-4dbe-976a-ba4d95c8051e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0231528 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0232492 infores:hetionet CHEBI:4995 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151754 infores:hetionet CHEBI:8764 biolink:causes EFO:0005632 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C2243080 infores:hetionet CHEBI:42355 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0042571 infores:hetionet CAID:CA3050533369 biolink:causes MONDO:0015152 infores:clingen CAID:CA3050533369 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1 PM2 The NC_000002.12: g.71679006_71679285del (GRCh38) variant is a deletion that encompasses exon 52 of the DYSF gene, NM_003494.4: c.5768_5946del. Exon 52 is out of frame, and RNAseq analysis in an individuals heterozygous for this deletion demonstrated skipping of exon 52 or skipping of exons 52 and 53, both leading to a frameshift and premature truncation, p.Ser1924GlnfsTer13 and p.Ser1924AlafsTer16, respectively (PMID: 36983702; PVS1). This variant has been reported in unconfirmed phase with a stop-gained variant in an individual with suspected LGMD (NM_003494.4: c.1834C>T p.(Gln612Ter), PMID: 36983702). In addition, two similar deletions of exon 52 with slightly different breakends have been reported confirmed in trans in individuals with features consistent with LGMD (NM_003494.4: c.2875C>T p.(Arg959Trp), 1.0 pt; c.1663C>T p.(Arg555Trp), 1.0 pt; PMID: 36983702) (PM3_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency of a similar deletion of DYSF exon 52 is 0.0001779 (5/59088 European (non-Finnish) genome chromosomes) in gnomAD SVs v4.1.0, which is greater than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/29/2025): PVS1, PM3_Strong, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3050533369/MONDO:0015152/180 2025-10-29 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6339 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0002792 infores:hetionet CHEBI:94609 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C1443060 infores:hetionet CHEBI:145499 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018524 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029878 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020621 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233494 infores:hetionet CHEBI:94609 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0006826 infores:hetionet NCBIGene:7360 biolink:causes MONDO:0032895 infores:monarchinitiative not_provided not_provided HGNC:12527 MONDO:0032895 uuid:5f983c5f-c2d4-4b0a-9954-eff6613be80d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0006145 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235890 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235890 infores:hetionet UMLS:C1872203 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0852913 infores:hetionet CAID:CA590769 biolink:causes MONDO:0100283 infores:clingen CAID:CA590769 MONDO:0100283 PMID: Uncertain Significance PP2 BS1, PM2 The NM_004958.4:c.1249A>G variant in the MTOR gene is a missense variant predicted to cause substitution of methionine by valine at amino acid 417. In gnomAD v4.1.0, this variant has a filtering allele frequency of 0.001567% in the European (non-Finnish) population and a minor allele frequency of 0.002288% (27/1180014), also in the European (non-Finnish) population (PM2_Supporting, BS1, and BS1_Supporting not met). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations Variant Curation Expert Panel (BM VCEP) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as uncertain significance for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen BM VCEP: PP2 (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA590769/MONDO:0100283/018 2025-06-06 2025-06-30 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:23765 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0149931 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0005940 infores:hetionet CHEBI:52717 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0268000 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151996 infores:hetionet CHEBI:9599 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0151942 infores:hetionet CHEBI:7459 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0031924 infores:hetionet CHEBI:44032 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0232462 infores:hetionet CHEBI:7492 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0008031 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0422974 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0422974 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0549383 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0549383 infores:hetionet CHEBI:63630 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0006277 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0034065 infores:hetionet CHEBI:45081 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0009676 infores:hetionet CHEBI:9654 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0231530 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0018965 infores:hetionet CHEBI:5959 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0151576 infores:hetionet CHEBI:6759 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0085631 infores:hetionet CHEBI:28748 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2047937 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0262385 infores:hetionet CHEBI:68534 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0948594 infores:hetionet CHEBI:6715 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0043094 infores:hetionet CHEBI:3738 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0040034 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0149931 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0856151 infores:hetionet CHEBI:29013 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0008370 infores:hetionet CHEBI:49662 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002878 infores:hetionet CHEBI:5801 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0522224 infores:hetionet CHEBI:10023 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013404 infores:hetionet CHEBI:63608 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0016204 infores:hetionet CHEBI:7824 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018681 infores:hetionet CAID:CA410148791 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148791 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS4, PS3, PS1, BP2, BA1, PM6, PM2, PVS1, BS4, BS3, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.985G>A variant that results in a Ala329Thr missense change has an MAF of 0.0002825 (0.02%, 9/21854 alleles) in the Latino subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score <0.15 (0.067) and splicing tools predict no splicing impact (BP4). The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148791/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037036 infores:hetionet CHEBI:75246 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C1443060 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0040034 infores:hetionet CHEBI:9637 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0011175 infores:hetionet CHEBI:8776 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0428977 infores:hetionet CHEBI:4027 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0043094 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014868 infores:hetionet CHEBI:4653 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C2047937 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0919715 infores:hetionet CAID:CA1251448 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251448 MONDO:0013144 PMID: Uncertain Significance BS1 PS4, PP3, BP4 The c.233G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 78 (p.Arg78Gln). The variant is reported at an allele frequency of 0.00003889 With the highest MAF of 0.0002540 (9/35440) in the South Asian population in gnomAD v2.1.1 meeting BS1 (>0.0002). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BS1. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251448/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47780 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0028738 infores:hetionet CHEBI:68558 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0006826 infores:hetionet CHEBI:6909 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0014724 infores:hetionet CHEBI:31644 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0278134 infores:hetionet UNII:R43D2573WO biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0744727 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0266998 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0266998 infores:hetionet CHEBI:6413 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0220870 infores:hetionet CHEBI:16469 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020453 infores:hetionet CHEBI:8863 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017178 infores:hetionet CHEBI:9168 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151723 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0027765 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1258215 infores:hetionet CHEBI:9445 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0041657 infores:hetionet CAID:CA314578 biolink:causes MONDO:0100040 infores:clingen CAID:CA314578 MONDO:0100040 PMID: Benign BP5_Strong, BS2, BA1, BP4 The highest population minor allele frequency of the p.Pro82Gln variant in FOXG1 in gnomAD v2.1.1 is 0.00087 in the African/African American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Pro82Gln variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Pro82Gln variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). Computational analysis prediction tools suggest that the p.Pro82Gln variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro82Gln variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong, BP4). (FOXG1 specification v.3; approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314578/MONDO:0100040/035 2024-08-30 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:3339 biolink:causes MONDO:0009140 infores:monarchinitiative not_provided not_provided HGNC:5273 MONDO:0009140 uuid:ee925f16-b199-48ff-ad04-d0f01ed5864e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0040822 infores:hetionet CHEBI:8428 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0428977 infores:hetionet CHEBI:135961 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0344232 infores:hetionet CHEBI:61049 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232461 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0031085 infores:hetionet CHEBI:101278 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151579 infores:hetionet CHEBI:28001 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0016204 infores:hetionet CHEBI:681569 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0024312 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0400839 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0400839 infores:hetionet CHEBI:2453 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0040822 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0035078 infores:hetionet CHEBI:6062 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0032617 infores:hetionet CHEBI:78543 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0000737 infores:hetionet CHEBI:2955 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0423791 infores:hetionet CHEBI:6887 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0085641 infores:hetionet CHEBI:135876 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0234215 infores:hetionet CAID:CA024460 biolink:causes MONDO:0007783 infores:clingen CAID:CA024460 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PM1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with leucine at codon 1592 of the RYR1 protein, p.Pro1592Leu. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000015, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, a second variant of uncertain significance (p.Arg533His) was also identified in this individual. Both variants were homozygous, PS4 was not implemented (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.927) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024460/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:2676 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0085631 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0277885 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0243026 infores:hetionet CHEBI:64354 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0023530 infores:hetionet CHEBI:584020 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0426576 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018790 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0236072 infores:hetionet CHEBI:63617 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151830 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0860207 infores:hetionet NCBIGene:4763 biolink:causes MONDO:0018975 infores:monarchinitiative not_provided not_provided HGNC:7765 MONDO:0018975 uuid:bfe0f2a6-abc7-4117-807f-68f6bb0993ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15551 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0015230 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0030824 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030824 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0521170 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0521170 infores:hetionet CHEBI:66876 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0004093 infores:hetionet CHEBI:6759 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0080274 infores:hetionet CHEBI:17303 biolink:causes HP:0012196 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0008039 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0002957 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0009782 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0032131 infores:hetionet CAID:CA16603354 biolink:causes MONDO:0044970 infores:clingen CAID:CA16603354 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, BA1, PS4, PS3, PS2, BS1, PM2, PM6 The m.15848A>G (p.T368A) variant in MT-CYB was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at varying frequencies in population databases. The frequency in the MITOMAP GenBank sequences in 38/59,389 (0.064%) spread over 13 top level (single letter) haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences of this variant in the Helix dataset in 98/195,983 (0.050%), in addition to 10 heteroplasmic occurrences, spread over 15 top level haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences in gnomAD v3.1.2 is 217/56,429 (0.385%) in addition to two heteroplasmic occurrences, spread over 13 top level haplogroups with European, Asian, and African ancestry. The overall frequency is notably higher in this database than in MITOMAP and Helix, with 185 of the gnomAD sequences categorized as Latin American and all in top level haplogroup A. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). The computational predictor APOGEE gives scores of 0.33 (“neutral”) in APOGEE1 and 0.0087 (“benign”) in APOGEE2 (Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603354/MONDO:0044970/015 2023-07-10 2023-08-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6339 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0009782 infores:hetionet CHEBI:3216 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1384353 infores:hetionet CHEBI:7865 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0020458 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151849 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0003864 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0021053 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0042109 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020651 infores:hetionet CHEBI:64310 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0012569 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0948089 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0344315 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0549405 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0011849 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1565489 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0020651 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030807 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0151865 infores:hetionet CHEBI:6067 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0028643 infores:hetionet CHEBI:5118 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151827 infores:hetionet CHEBI:42820 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0232462 infores:hetionet CHEBI:9139 biolink:causes MONDO:0100431 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0338480 infores:hetionet CHEBI:50692 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0030193 infores:hetionet CHEBI:3561 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0040822 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027051 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0442856 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0442856 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0853692 infores:hetionet CHEBI:8764 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151603 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0877661 infores:hetionet CHEBI:15544 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0700225 infores:hetionet CHEBI:45924 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0011603 infores:hetionet CHEBI:9137 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0699828 infores:hetionet CHEBI:6067 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0700225 infores:hetionet CHEBI:6801 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0011991 infores:hetionet CHEBI:9398 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0015672 infores:hetionet CHEBI:3568 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1306341 infores:hetionet CHEBI:3175 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0235063 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0162287 infores:hetionet UNII:R15UI3245N biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0008031 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0013395 infores:hetionet CHEBI:8888 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020580 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017160 infores:hetionet CHEBI:6367 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0016382 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0000833 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006852 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001910 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0028817 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0178298 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0027697 infores:hetionet CHEBI:194135 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0010200 infores:hetionet CHEBI:4672 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151908 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0277941 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0277941 infores:hetionet CHEBI:41423 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042029 infores:hetionet NCBIGene:1738 biolink:causes MONDO:0009529 infores:monarchinitiative not_provided not_provided HGNC:2898 MONDO:0009529 uuid:0be8fda1-4bdc-4b19-8db3-f2610ecd7c69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61390 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0009782 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027765 infores:hetionet CHEBI:41774 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0854069 infores:hetionet CAID:CA234129 biolink:causes MONDO:0001586 infores:clingen CAID:CA234129 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.1614del (p.His539ThrfsTer21) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 4 individuals with MPS I, with documented IDUA deficiency within the affected range in leukocytes (PMID: 8213840, 15300847, 19396826, 35141277) and/or clinical features specific to MPS I including short stature, joint stiffness, progressive developmental decline, severe hepatosplenomegaly, systolic murmur, mitral valve defects, umbilical hernia, hirsutism, large tongue, corneal clouding (PMID: 15300847, 19396826) (PP4). Of these individuals, at least 3 were compound heterozygous for the variant and another variant in IDUA, phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 8213840, 15300847, 35141277, 2 or 3 patients; max 2 x 0.5 points), and c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 25614311, 0.5 points). Another patient is compound heterozygous for the variant and c.1650+5G>A (PMID: 19396826). The allelic data from this patient will be used in the classification of c.1650+5G>A and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001741 (2/1148676 alleles) in the NFE population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 167191). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Moderate, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA234129/MONDO:0001586/091 2024-12-05 2025-03-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27899 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0011175 infores:hetionet CHEBI:5004 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0013428 infores:hetionet CHEBI:45081 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0010828 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0541799 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0424230 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0151849 infores:hetionet CHEBI:31624 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0013604 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0020649 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0021053 infores:hetionet CHEBI:15552 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0026858 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1145670 infores:hetionet CAID:CA181005 biolink:causes MONDO:0021060 infores:clingen CAID:CA181005 MONDO:0021060 PMID: Benign BP7, BP5, BP4, BA1 The c.-267G>A variant was identified in the RAF1 gene. The filtering allele frequency for the c.-267G>A is 6.32% for African chromosomes in gnomAD (68/8706 with 95% CI) (https://gnomad.broadinstitute.org/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). The variant has also been identified in a patient with an alternate molecular basis for disease (BP5; Laboratory for Molecular Medicine internal data). In summary, the c.-267G>A variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA181005/MONDO:0021060/004 2019-07-25 2019-12-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:45285 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0162830 infores:hetionet CHEBI:31980 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0043144 infores:hetionet CHEBI:63605 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0151744 infores:hetionet CAID:CA222185 biolink:causes MONDO:0015152 infores:clingen CAID:CA222185 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PS1_Supporting, PM2_Supporting PM3 The NM_003494.4: c.5429+1G>T variant in DYSF, which is also known as NM_001130987.2: c.5546+1G>T, occurs within the splice donor site (+/- 1,2 dinucleotide) of exon 48. SpliceAI gives a score of 0.8 for loss of the donor site, and RNAseq analysis has demonstrated that this variant causes skipping of exon 48, resulting in a frameshift and premature truncation, p.Gly1781ValfsTer17 (PMID: 36983702; PVS1_RNA). This variant has been identified in trans with a likely pathogenic variant in a patient with a clinical diagnosis of LGMD (NM_003494.4: c.5057+5G>T, 0.25 pts, PMID: 36983702, 33610434) (PP4; PM3_Supporting not met). This variant is absent from gnomAD v4.1.0 and v2.1.1 (PM2_Supporting). Another variant affecting the same donor splice motif, NM_003494.4: c.5429G>A, which has a similar SpliceAI prediction score and has been experimentally demonstrated to also cause skipping of exon 48, has been classified as Pathogenic by the LGMD VCEP (PS1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_RNA, PP4, PM2_Supporting, PS1_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222185/MONDO:0015152/180 2025-07-29 2025-08-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6402 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0162429 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0262397 infores:hetionet CHEBI:16467 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0027429 infores:hetionet CHEBI:6904 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0007820 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0021400 infores:hetionet GO:0098694 biolink:causes GO:0048489 infores:ubergraph knowledge_assertion manual_agent GO:0098694 GO:0048489 CHEBI:40279 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0013395 infores:hetionet CHEBI:10125 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235710 infores:hetionet CHEBI:63617 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0040264 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020557 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0009319 infores:hetionet CAID:CA2573054925 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573054925 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1142_1145dup (p.Pro383AlafsTer?) is a duplication variant that results in a frameshift in the last exon. This variant is located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting), is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which is critical for protein function (PVS1_Strong). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573054925/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42068 biolink:causes UMLS:C0392196 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0392196 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027769 infores:hetionet CHEBI:8356 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0086168 infores:hetionet CHEBI:63607 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0917801 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0031350 infores:hetionet CHEBI:9943 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004093 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0231365 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0038814 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0035078 infores:hetionet NCBIGene:6444 biolink:causes MONDO:0011702 infores:monarchinitiative not_provided not_provided HGNC:10807 MONDO:0011702 uuid:50649693-7e8c-48d8-8ec8-4ab508aeaa0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8378 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C1761613 infores:hetionet CHEBI:119915 biolink:causes HP:0200097 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0853945 infores:hetionet CHEBI:41977 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0231528 infores:hetionet CHEBI:17347 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0042963 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0011991 infores:hetionet CHEBI:65173 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0007398 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0178298 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042514 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0857483 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0857483 infores:hetionet CHEBI:8212 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0002453 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027651 infores:hetionet CHEBI:72323 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0162557 infores:hetionet CHEBI:63618 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0042384 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0234215 infores:hetionet CHEBI:584020 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C2047937 infores:hetionet CHEBI:47612 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0017152 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002170 infores:hetionet CAID:CA658795243 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795243 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PVS1_Strong PS3 The NM_000152.5:c.1194+5G>A variant is a nucleotide substitution in the donor splice region of intron 7 in GAA. RT-PCR of RNA from the peripheral blood cells of a patient with Pompe disease who is homozygous for the variant revealed that the major impact of this variant on splicing is the skipping of exon 7, which would result in a frameshift. In addition, intron 7 and intron 8 were retained in some transcripts, and the level of GAA mRNA in general was reduced, likely due to nonsense-mediated decay (Fig 2, PMID: 30770309); qPCR indicates expression ∼15% of normal splicing of exon 7 compared with the healthy control. The in silico predictor, SpliceAI also predicts loss of the donor splice site (score = 0.59 ) and loss of the acceptor splice site of exon 7 (score = 0.64) (PVS1_Strong). Three patients with a diagnosis of Pompe disease have been described with this variant, all with late-onset Pompe disease. Residual GAA activity levels were available for one of these patients (PMID: 30770309), and the other two patients were reported to be on enzyme replacement therapy (PMID: 27711114; possible overlap with patients in PMIDs: 25998610, 31378569) (PP4_Moderate). One patient is homozygous for the variant (PMID: 30770309) (PM3_Supporting). Two patients are compound heterozygous for the variant and c.1781G>A (p.Arg594His), phase unknown (PMID: 27711114). The data from these two patients was used in the classification of p.Arg594His and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001650 (1/6062 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).The is a ClinVar entry for this variant (Variation ID: 930445).In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Diseases VCEP (Specifications Version 2.0.0): PVS1_Strong, PP4_Moderate, PM2_Supporting PM3_Supporting.(Classification approved by the ClinGen Lysosomal Storage Diseases Variant Curation Expert Panel on August 5, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795243/MONDO:0009290/010 2025-08-05 2025-08-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8461 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0039231 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151838 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0005940 infores:hetionet CHEBI:17688 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1306341 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041912 infores:hetionet CHEBI:45367 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0036974 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0028866 infores:hetionet CHEBI:47780 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0428977 infores:hetionet CHEBI:4708 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0040822 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0877042 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0877042 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0034882 infores:hetionet CHEBI:681848 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0042514 infores:hetionet CHEBI:4702 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0022073 infores:hetionet NCBIGene:55624 biolink:causes MONDO:0009667 infores:monarchinitiative not_provided not_provided HGNC:19139 MONDO:0009667 uuid:f9598157-15c6-46bd-9470-e58002ab11b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45924 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0235996 infores:hetionet UMLS:C1144403 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0011603 infores:hetionet CHEBI:30830 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0018965 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0151773 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0152029 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0877664 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0877664 infores:hetionet CHEBI:4672 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027796 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0232492 infores:hetionet CHEBI:46557 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0232462 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0003864 infores:hetionet CHEBI:15553 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0013428 infores:hetionet CHEBI:9316 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C2830004 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020517 infores:hetionet CHEBI:4653 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0004093 infores:hetionet CHEBI:7627 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0042755 infores:hetionet CAID:CA10360748 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360748 MONDO:0100039 PMID: Likely Benign BS1, BP4 RS1 (NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.2933T>G (p.Leu978Arg) variant in the CDKL5 transcript (NM_003159.2) (RS1 c.185-3213A>C) is 0.01184% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Leu978Arg variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Leu978Arg variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360748/MONDO:0100039/016 2023-02-20 2023-12-08 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:408174 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0522224 infores:hetionet CHEBI:3286 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0013395 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0274702 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0274702 infores:hetionet CHEBI:16347 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0030517 infores:hetionet CHEBI:8028 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0234238 infores:hetionet CHEBI:51173 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C3665347 infores:hetionet CHEBI:34967 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0004093 infores:hetionet CAID:CA10014261 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014261 MONDO:0011071 PMID:30478137PMID:23753029PMID:27577878PMID:28933735 Benign BA1, BP4 PS3, PS1, PS4, BP2, PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PM4, PM5, PM1, PP1, PP3 This missense variant is present in gnomAD (v2) at an allele frequency 0.6377% >0.15% with 226 out of 35438 alleles in Latino subpopulation (BA1). Additionally, this missense variant has a REVEL score <0.15 (0.093), and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014261/MONDO:0011071/008 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119915 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0233632 infores:hetionet CHEBI:209807 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0404521 infores:hetionet CHEBI:107736 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0600228 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0750466 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0750466 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151735 infores:hetionet CHEBI:15854 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0034155 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0025061 infores:hetionet CHEBI:2687 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0011991 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0030193 infores:hetionet NCBIGene:6223 biolink:causes MONDO:0007110 infores:monarchinitiative not_provided not_provided HGNC:10402 MONDO:0007110 uuid:5a90abbf-26e4-4d4b-b5df-b5d3fc1d4336 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA116601 biolink:causes MONDO:0009290 infores:clingen CAID:CA116601 MONDO:0009290 PMID:7717400 Likely Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting, PM3_Supporting, PS3_Supporting "The NM_000152.5:c.896T>G variant in GAA is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 299 (p.Leu299Arg). This variant has been detected in 1 individual with Pompe disease. This individual was compound heterozygous for the variant and a pathogenic variant, an exon 18 deletion previously assessed by the ClinGen LSD VCEP (PMID:7603531,7717400) (PM3_Supporting). The patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts, but exact values for the patient's GAA activity and laboratory control values for GAA activity were not provided and PP4 could not be applied (PMID:7717400). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity, indicating that this variant may impact protein function (PMID:19862843), meeting criteria for PS3_Supporting. Expression of the variant in TR4219 cells in a separate study resulted in ""complete loss of GAA activity"" (PMID:7717400). REVEL Score = 0.93 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 4025, 1 star review status) with 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PM5, PP3, PM2_Supporting, PM3_Supporting, PS3_Supporting." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116601/MONDO:0009290/010 2022-05-11 2022-05-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:28177 biolink:causes MONDO:0005479 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0546959 infores:hetionet CHEBI:47381 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013144 infores:hetionet CHEBI:36795 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0014724 infores:hetionet CHEBI:474180 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0232462 infores:hetionet CHEBI:9943 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033774 infores:hetionet CHEBI:3716 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0015230 infores:hetionet CHEBI:16796 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0043094 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012701 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0426636 infores:hetionet CHEBI:10110 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0023530 infores:hetionet UMLS:C0010592 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0018681 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0151436 infores:hetionet NCBIGene:477 biolink:causes MONDO:0011232 infores:monarchinitiative not_provided not_provided HGNC:800 MONDO:0011232 uuid:21956831-68c6-4abf-9dc0-fc3fd1a0065e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:U6XF9NP8HM biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0030193 infores:hetionet CHEBI:63635 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0155365 infores:hetionet CHEBI:7852 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0220870 infores:hetionet CHEBI:72296 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0017181 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0232459 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0277934 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0277934 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0349506 infores:hetionet CHEBI:31236 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0750426 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0426649 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0426649 infores:hetionet CHEBI:52172 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040264 infores:hetionet CHEBI:63623 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0232462 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0518015 infores:hetionet GO:0061183 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:0061183 GO:0061053 PUBCHEM.COMPOUND:122173801 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0267797 infores:hetionet CHEBI:9137 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085633 infores:hetionet CAID:CA226534 biolink:causes MONDO:0100368 infores:clingen CAID:CA226534 MONDO:0100368 PMID: Likely Pathogenic PM3, PM1, PP4_Moderate, PP3, PM2_Supporting PM5 NM_000329.3(RPE65):c.272G>C (p.Arg91Pro) is a missense variant predicted to replace arginine with proline at amino acid p.91. This residue is a well-characterized functional site that forms a salt bridge with glutamate 127 that is reportedly required for correct positioning of membrane-binding elements that mediate localization to the ER membrane (PMID: 19805034, PM1). Another missense variant in the same codon, NM_000329.3(RPE65):c.272G>A (p.Arg91Gln), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP. However, splicing prediction using SpliceAI indicated a likely splicing defect due to NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) (score of 0.21 for acceptor loss) that was not predicted for the present variant (with a score of 0.12 for acceptor gain), so the PM5 code was not met. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.430T>G (p.Tyr144Asp) variant confirmed in trans (1 point, PMID: 17724218) which was previously classified likely pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PM3). The variant has also been reported in a second proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.65T>C (p.Leu22Pro) variant suspected in trans (PMID: 32865313), which was not included in the PM3 code. At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), light-gazing (1 pt), visual acuity limited to light perception (1 pt), nystagmus (1 pt), extinguished ERG responses from both rods (0.5 pts) and cones (1 pt), salt-and-pepper fundus (0.5 pts) with macular atrophy (0.5 pts), and absence of fundus autofluorescence (2 pts), which together are highly specific for RPE65-related recessive retinopathy (total 8 points, PMID: 17724218, PP4_Moderate). The computational predictor REVEL gives a score of 0.766, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). The splicing impact predictor SpliceAI gives a score of 0.12 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM1, PM2_Supporting, PM3, PP3, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226534/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:54949 biolink:causes MONDO:0011121 infores:monarchinitiative not_provided not_provided HGNC:26034 MONDO:0011121 uuid:bb73ced7-ed28-47bf-8eca-9b76b37c1b6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31622 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0004134 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0036572 infores:hetionet CHEBI:7601 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0023052 infores:hetionet NCBIGene:9321 biolink:causes MONDO:0008701 infores:monarchinitiative not_provided not_provided HGNC:12305 MONDO:0008701 uuid:96e31139-e9d3-44ef-83f2-e9c783ce321e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0013384 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0021167 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002311 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0154833 infores:hetionet CAID:CA10443890 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443890 MONDO:0010315 PMID: Likely Benign BS2 PM2 NM_000206.3(IL2RG):c.311A>T is a missense variant predicted to cause substitution of Histidine by Leucine at amino acid 104 (p.His104Leu).The filtering allele frequency (the upper threshold of the 95% CI of 35/893746 alleles) of the c.311A>T variant in IL2RG is 0.00002843 for European (Non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000124 ) for PM2_Supporting. However, as hemizygotes were observed, PM2 is not met. Eleven adult hemizygous occurrences are described in gnomAD (BS2_Strong).In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2_Strong (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443890/MONDO:0010315/129 2024-04-03 2024-04-03 X-linked inheritance HP:0001417 Contradicts true CHEBI:17026 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0023222 infores:hetionet CHEBI:4975 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0041657 infores:hetionet NCBIGene:170302 biolink:causes MONDO:0010317 infores:monarchinitiative not_provided not_provided HGNC:18060 MONDO:0010317 uuid:36ef561b-c1e1-4233-a879-36ca623d6ca3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0027765 infores:hetionet CHEBI:71255 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C1522133 infores:hetionet CHEBI:135791 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0016436 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0149976 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0149976 infores:hetionet CHEBI:8212 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0152030 infores:hetionet CHEBI:7820 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0917801 infores:hetionet CAID:CA10014591 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014591 MONDO:0011071 PMID: Uncertain Significance PS4, PS3, PS1, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.110G>T (p.Ser37Ile) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014591/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6149 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0232431 infores:hetionet CHEBI:5778 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0037763 infores:hetionet CAID:CA5950267 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950267 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The NM_000448.3:c.2459A>G variant in RAG1 is a missense variant predicted to cause the substitution of Lysine by Arginine at amino acid 820 (p.Lys820Arg). The filtering allele frequency (the lower threshold of the 95% CI of 26338/44862) of the c.2459A>G variant in RAG1 is 0.5818 for East Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 22786 homozygous adults are reported on gnomAD v.4, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950267/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:17303 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0855775 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0549373 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006626 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011882 infores:hetionet CHEBI:4911 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0002792 infores:hetionet CHEBI:63611 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0428977 infores:hetionet CHEBI:31705 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0023218 infores:hetionet CHEBI:3499 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0042963 infores:hetionet CHEBI:145499 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0852911 infores:hetionet CHEBI:77260 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151610 infores:hetionet CAID:CA011148 biolink:causes MONDO:0005021 infores:clingen CAID:CA011148 MONDO:0005021 PMID: Uncertain Significance PM2, PP1, PS4_Supporting PM5, PM4, PM1, PM6, PP3, BA1, PS3, BP3, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 The c.1700G>A (p.Arg567His) variant in MYH7 has been identified in 3 individuals with DCM, 1 of whom also had an additional variant in another DCM-associated gene (PS4_Supporting; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; GeneDx pers. comm., LMM pers. comm.) and segregated with disease in 3 affected relatives with DCM from 1 family (PP1; LMM pers. comm.). Additionally, this variant has also been reported in an individual with neuropathy and unspecified heart disease who also had an additional variant in a gene that could account for the clinical features observed (Invitae pers. comm.). This variant has been identified in 0.003% (1/30616) of South Asian chromosomes (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1; PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011148/MONDO:0005021/002 2021-09-27 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3696 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085096 infores:hetionet CHEBI:63637 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0011603 infores:hetionet CHEBI:465284 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0011175 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0004936 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0011991 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151951 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151951 infores:hetionet CHEBI:3286 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0085616 infores:hetionet CHEBI:8890 biolink:causes MONDO:0006650 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0221069 infores:hetionet CHEBI:6759 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0030554 infores:hetionet CHEBI:8081 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0025061 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0032285 infores:hetionet CHEBI:3614 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0041582 infores:hetionet CAID:CA16041880 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041880 MONDO:0009290 PMID:30022036PMID:32125626PMID:30778879PMID:23825616PMID:29143201PMID:22980766PMID:26913919PMID:30371346PMID:17056254PMID:22194990PMID:25998610PMID:19588081 Pathogenic PVS1, PM2, PP4, PM3 This variant, c.236_246del (p.Pro79ArgfsTer13), has been reported in multiple patients with Pompe disease. For two of these patients, residual GAA activity is reported and meets the ClinGen LSD VCEP's specifications for PP4 (PMID 17056254, 30778879). Both of these patients are compound heterozygous for the variant and a unique pathogenic variant; one with c.377G>A (p.Trp126Ter), in trans (PMID 17056254), and the other with c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). This data meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). There is a ClinVar entry for this variant (Variation ID: 371302, 1 star review status) with 1 submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041880/MONDO:0009290/010 2020-06-16 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:44915 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020461 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0032961 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027441 infores:hetionet CHEBI:68606 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0595930 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011991 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0031350 infores:hetionet CHEBI:82960 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0009676 infores:hetionet CHEBI:75179 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0314719 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0948594 infores:hetionet CHEBI:45081 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0000786 infores:hetionet CHEBI:50648 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0740394 infores:hetionet CHEBI:8207 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151699 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0011570 infores:hetionet CHEBI:2914 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0006266 infores:hetionet CHEBI:3127 biolink:causes MONDO:0021945 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0260662 infores:hetionet NCBIGene:9474 biolink:causes MONDO:0033115 infores:monarchinitiative not_provided not_provided HGNC:589 MONDO:0033115 uuid:a12e58c3-ce5d-49e5-8a6b-8e9b6b510066 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C2830004 infores:hetionet CHEBI:61033 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0041657 infores:hetionet CHEBI:135939 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0040822 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0019054 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0151763 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0021167 infores:hetionet CHEBI:63598 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0236075 infores:hetionet CHEBI:4909 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0149745 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0948089 infores:hetionet CHEBI:68478 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0236075 infores:hetionet CHEBI:6846 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0014742 infores:hetionet NCBIGene:64423 biolink:causes MONDO:0013758 infores:monarchinitiative not_provided not_provided HGNC:23791 MONDO:0013758 uuid:8dfdaf81-036d-45b8-bcd1-b20e6e3ccd65 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1024 biolink:causes MONDO:0032897 infores:monarchinitiative not_provided not_provided HGNC:1779 MONDO:0032897 uuid:80900bdd-d4bb-4112-8eb7-9996f54485dc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0039503 infores:hetionet CHEBI:4702 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1142412 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013609 infores:hetionet CAID:CA10646088 biolink:causes MONDO:0012996 infores:clingen CAID:CA10646088 MONDO:0012996 PMID: Benign BA1 The NM_001482.3:c.*847G>A variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.01493 (130/8702 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316202). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10646088/MONDO:0012996/025 2022-06-06 2022-10-05 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA069583 biolink:causes MONDO:0007783 infores:clingen CAID:CA069583 MONDO:0007783 PMID: Uncertain Significance PP3_Moderate PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Proline with Leucine at codon 2462 of the RYR1 protein, p.(Pro2462Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA069583/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7936 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0005586 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020517 infores:hetionet CHEBI:6375 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0013604 infores:hetionet CHEBI:100246 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0001824 infores:hetionet CHEBI:45599 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0020580 infores:hetionet CHEBI:9674 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C3665347 infores:hetionet NCBIGene:2059 biolink:causes MONDO:0014428 infores:monarchinitiative not_provided not_provided HGNC:3420 MONDO:0014428 uuid:0478f20c-5820-49ea-8814-dfd8ffcd7c25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042029 infores:hetionet CHEBI:9566 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C1443060 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235876 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009450 infores:hetionet CHEBI:7903 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C1443060 infores:hetionet CHEBI:5138 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0025323 infores:hetionet CHEBI:8024 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0026821 infores:hetionet CHEBI:63617 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0043352 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0007354 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0007354 uuid:88062b11-8656-404c-8858-884d645fed59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0425481 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0425481 infores:hetionet CHEBI:7986 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0267792 infores:hetionet CHEBI:73274 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0027497 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0855242 infores:hetionet CHEBI:63619 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0022346 infores:hetionet CAID:CA8815236 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815236 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting PP3, BP4 The NM_000152.5:c.1222A>G variant in GAA is predicted to result in the substitution of methionine by valine at amino acid 408 (p.Met408Val). Four patients have been reported with this variant; three with infantile onset Pompe disease and documented values showing GAA deficiency, at least two of them treated with enzyme replacement therapy (PMID: 11738358, 26497565, 34995642). Another patient has later onset symptoms with reduction of urine Glc4 on enzyme replacement therapy (PMID: 21687968) (PP4_Moderate). One individual is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.1579del, confirmed in trans (PMID: 34995642) (ClinVar Variation ID: 952947). Another patient is homozygous for the variant (PMID: 26497565). Two patients are compound heterozygous for the variant and either c.1000G>A (p.Gly334Ser) (PMID: 21687968) or c.1408_1410del (PMID: 11738358); the allelic data for these two patients will be used in the classification of the other variant and is not included here to avoid circular logic (PM3). When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111716 alleles) in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 26, 2020. Since then, the data for this variant have been re-evaluated. The classification of likely pathogenic was reapproved on May 6, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815236/MONDO:0009290/010 2024-05-06 2024-05-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3508 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0002878 infores:hetionet CHEBI:182080 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0013404 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0019158 infores:hetionet CHEBI:27690 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0020625 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0392176 infores:hetionet CHEBI:71415 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0014742 infores:hetionet CHEBI:75722 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0017181 infores:hetionet CHEBI:7954 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0233472 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0027813 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151828 infores:hetionet CHEBI:6128 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C2047937 infores:hetionet CAID:CA915940901 biolink:causes MONDO:0008723 infores:clingen CAID:CA915940901 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PP4, PM3, PS3_Supporting PM4, PM1 The c.879-8T>A variant in ACADVL is an intronic variant which occurs in intron 9. The variant has been reported twice in the literature in one individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency displaying increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4; PMID: 19208414; PMID: 20668464). In this same proband, the variant was detected confirmed in-trans with the pathogenic variant c.848T>C (PM3; PMID: 19208414). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.64 for acceptor loss and 0.98 for acceptor gain, predicting that the variant disrupts the acceptor splice site of intron 9 of ACADVL (PP3). RNA sequencing in patient-derived cells demonstrated the presence of alternately spliced transcripts in a proband and the VCEP considered PM4 for an in-frame insertion of two amino acids, but this information is incomplete (PS3_supporting; PMID: 19208414). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM3, PM2_Supporting, PP3, PS3_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940901/MONDO:0008723/021 2023-04-25 2023-04-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6888 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0178298 infores:hetionet CHEBI:50922 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020429 infores:hetionet CHEBI:45367 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0042963 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027441 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1096509 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1096509 infores:hetionet CHEBI:63580 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035243 infores:hetionet CHEBI:109549 biolink:causes UMLS:C0751249 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0751249 infores:hetionet CHEBI:28864 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0149725 infores:hetionet CHEBI:3698 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0030252 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0235416 infores:hetionet CHEBI:7577 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C2047937 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0014130 infores:hetionet CHEBI:61058 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0042963 infores:hetionet CHEBI:28445 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0041364 infores:hetionet CHEBI:63598 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0019080 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0021053 infores:hetionet GO:0003427 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:0003427 GO:0001501 CHEBI:478164 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0856882 infores:hetionet NCBIGene:57697 biolink:causes MONDO:0054862 infores:monarchinitiative not_provided not_provided HGNC:23168 MONDO:0054862 uuid:50706671-ca6c-41e1-9192-2ce62c163789 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0542101 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0003123 infores:hetionet CHEBI:6822 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0018681 infores:hetionet CHEBI:4469 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0855242 infores:hetionet CHEBI:45599 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0005778 infores:hetionet NCBIGene:650 biolink:causes MONDO:0007216 infores:monarchinitiative not_provided not_provided HGNC:1069 MONDO:0007216 uuid:a97a692d-0ec9-4274-8523-3e17af9c7cd5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0034150 infores:hetionet CHEBI:9649 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0428977 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151313 infores:hetionet CHEBI:8356 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152169 infores:hetionet CHEBI:39867 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002874 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0151735 infores:hetionet CAID:CA6402756 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402756 MONDO:0019565 PMID:28544236 Benign PP3, BA1 PP4, BS2, BS3 NM_000552.5(VWF):c.3485C>T is a missense variant that replaces proline with leucine at position 1162. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.2036 (based on 7087/34136 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). Heterologous expression of the variant protein revealed similarities to the wild-type VWF control in secretion, collagen binding, GPIb binding, and multimerization (PMID: 28544236). The computational predictor REVEL gives a score of 0.677, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402756/MONDO:0019565/090 2024-08-12 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:135193 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0178298 infores:hetionet CHEBI:49040 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0338656 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0424230 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0021843 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151773 infores:hetionet CHEBI:134991 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0040822 infores:hetionet NCBIGene:1294 biolink:causes MONDO:0011398 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0011398 uuid:f0104e34-a98e-4716-bc49-50c995bcbc2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042075 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0030312 infores:hetionet CHEBI:5050 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0013404 infores:hetionet CAID:CA340934 biolink:causes MONDO:0044970 infores:clingen CAID:CA340934 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM5 PP1, PS2, PS3, PM6 The m.14482C>A (p.M64I) variant in MT-ND6 has been reported in at least five unrelated individuals with LHON (PS4_moderate; PMIDs: 19319978, 12112086, 11931086, 12150954). Ages of onset varied from 10-29-years-old. All affected individuals had the variant present at homoplasmy. There are no reports of de novo occurrences to our knowledge. Several extended families have been reported in the medical literature (PMIDs: 11931086, 12112086) however family member testing was not performed or the variant was homoplasmic and thus prevented consideration for PP1. There are two occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant – m.14484T>C (p.M64V, PM5). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PM5, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340934/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:681850 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0004936 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0677500 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0027932 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151849 infores:hetionet CHEBI:17823 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0003467 infores:hetionet CHEBI:42068 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0011991 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0035078 infores:hetionet CHEBI:50275 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0026821 infores:hetionet CHEBI:28748 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0030252 infores:hetionet CHEBI:17303 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C3665347 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0020649 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020649 infores:hetionet CHEBI:10110 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0019825 infores:hetionet CAID:CA405688428 biolink:causes MONDO:0018493 infores:clingen CAID:CA405688428 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with valine at codon 487 of the RYR1 protein, p.(Leu487Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.668 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405688428/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:2379 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0025061 infores:hetionet CAID:CA10653576 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653576 MONDO:0011071 PMID: Likely Benign BS1 PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BS3, BS4, BP7, BP5, PM2, PM6, PVS1, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP4, PP1 The c.*68G>T (NM_001754.5) variant is a substitution in the 3'UTR of RUNX1. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2 is 0.02214% (5/22584 alleles) in the non-Finnish European population, which is higher than the ClinGen Myeloid Malignancy VCEP's threshold of 0.015% (BS1). In summary, this variant is classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria, as specified by the ClinGen Myeloid Malignancy VCEP: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653576/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA16614169 biolink:causes MONDO:0010880 infores:clingen CAID:CA16614169 MONDO:0010880 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting The NM_000020.3: c.1217G>A (p.Trp406Ter) variant in ACVRL1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8 (out of 10) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614169/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:47381 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018520 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0349506 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0006145 infores:hetionet CHEBI:2704 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0025320 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151726 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151726 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0027765 infores:hetionet CHEBI:9086 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0015402 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0024117 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011609 infores:hetionet CHEBI:168396 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003578 infores:hetionet CHEBI:18248 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0028643 infores:hetionet GO:0045314 biolink:causes GO:0048749 infores:ubergraph knowledge_assertion manual_agent GO:0045314 GO:0048749 CHEBI:691037 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0271738 infores:hetionet CHEBI:72564 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011603 infores:hetionet GO:1905024 biolink:causes GO:0008015 infores:ubergraph knowledge_assertion manual_agent GO:1905024 GO:0008015 CHEBI:8874 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151889 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020651 infores:hetionet CHEBI:175901 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0031256 infores:hetionet CHEBI:9571 biolink:causes GO:0030432 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0031133 infores:hetionet CHEBI:53760 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0278134 infores:hetionet NCBIGene:2131 biolink:causes MONDO:0007585 infores:monarchinitiative not_provided not_provided HGNC:3512 MONDO:0007585 uuid:13b6a351-b981-4fc0-8c94-a97a50599a59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0003811 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0021845 infores:hetionet CHEBI:31623 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0013456 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0235266 infores:hetionet CHEBI:7444 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0017152 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0340952 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0340952 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0024117 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151824 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020517 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0235431 infores:hetionet CHEBI:367163 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0030252 infores:hetionet CHEBI:15367 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0004604 infores:hetionet CHEBI:92511 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0232461 infores:hetionet CHEBI:94392 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0033774 infores:hetionet CHEBI:8310 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0040046 infores:hetionet CHEBI:7956 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0004936 infores:hetionet CHEBI:27690 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0013378 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0332534 infores:hetionet CHEBI:5855 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0012569 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0017152 infores:hetionet CHEBI:50173 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151827 infores:hetionet CHEBI:63598 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0032227 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0031046 infores:hetionet CHEBI:4868 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0040264 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0024299 infores:hetionet NCBIGene:1660 biolink:causes MONDO:0975838 infores:monarchinitiative not_provided not_provided HGNC:2750 MONDO:0975838 uuid:705a3d23-c680-4223-8e96-361d8523e0bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135276 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0020649 infores:hetionet CHEBI:27834 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002170 infores:hetionet CAID:CA1139667841 biolink:causes MONDO:0010305 infores:clingen CAID:CA1139667841 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting, PM4 The NM_005629.4:c.467_469del variant in SLC6A8 is a deletion of 3 nucleotides within exon 3/13 of the SLC6A8 gene and is predicted to lead to an in-frame deletion of 1 amino acid (p.Phe156del) (PM4). This variant has been previously reported (PMID: 22281021); however, no data, including zygosity and/or phenotypic features, regarding the individual/s with this variant is provided. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The in silico predictors MutPredIndel and MutationTaster predict that the variant impacts SLC6A8 function (PP3) There is a ClinVar entry for this variant (Variation ID: 941841, 1 star review status), with one submitter classifying it as a variant of uncertain significance and one submitter classifying it as likely pathogenic. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM4, PP3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 25, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139667841/MONDO:0010305/027 2024-06-25 2024-06-25 X-linked inheritance HP:0001417 Inconclusive true CHEBI:567361 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0031542 infores:hetionet CHEBI:9137 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017675 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0948525 infores:hetionet CHEBI:44032 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042029 infores:hetionet CHEBI:5864 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0232462 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0235234 infores:hetionet CHEBI:63717 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0231528 infores:hetionet CAID:CA8337546 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337546 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 The c.109C>T variant in ACADVL is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 37 (p.Arg37Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.316, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, BP4. (ACADVL VCEP specifications version 1; approved February 28, 2023) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337546/MONDO:0008723/021 2023-02-28 2023-02-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6128 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0011606 infores:hetionet NCBIGene:2348 biolink:causes MONDO:0013110 infores:monarchinitiative not_provided not_provided HGNC:3791 MONDO:0013110 uuid:e30dad5a-674e-4aab-a9e2-04a03da278bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0011168 infores:hetionet CHEBI:3698 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C2830004 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042769 infores:hetionet CHEBI:61049 biolink:causes MONDO:0003038 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0234144 infores:hetionet CHEBI:27306 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00165 UMLS:C2830004 infores:hetionet CHEBI:50922 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0018524 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002418 infores:hetionet CHEBI:8802 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0042024 infores:hetionet CHEBI:8890 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0001122 infores:hetionet GO:1901193 biolink:causes GO:0022613 infores:ubergraph knowledge_assertion manual_agent GO:1901193 GO:0022613 CHEBI:9588 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0016204 infores:hetionet CHEBI:4445 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0020621 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0022116 infores:hetionet CAID:CA149414 biolink:causes MONDO:0007113 infores:clingen CAID:CA149414 MONDO:0007113 PMID: Benign BP7, BA1, BP4 The allele frequency of the c.417A>T p.(Ala139=) variant in UBE3A (NM_130838.2) is 9.85% in African/African-American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.417A>T p.(Ala139=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA149414/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA213988 biolink:causes MONDO:0015967 infores:clingen CAID:CA213988 MONDO:0015967 PMID: Benign PP4, BA1 The c.826+30dup variant in the HNF4 homeobox A gene, HNF4A, is a single nucleotide insertion within intron 7 of NM_175914.5. This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8, KCNJ11, HNF1A, GLUD1, and HADH) (PP4; internal lab contributors). However, this variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005686, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). In summary, c.826+30dup meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BA1, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213988/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16469 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C3263723 infores:hetionet CHEBI:80630 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0030193 infores:hetionet CHEBI:4646 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0030193 infores:hetionet CHEBI:61058 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0014457 infores:hetionet CHEBI:45409 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0006625 infores:hetionet CHEBI:64354 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0262988 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0413252 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0518015 infores:hetionet CHEBI:48844 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0016204 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0022658 infores:hetionet CHEBI:6539 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0002884 infores:hetionet CHEBI:4469 biolink:causes HP:0100034 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0751900 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0019158 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0178298 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0233794 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0043250 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0020517 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018799 infores:hetionet CHEBI:25154 biolink:causes MONDO:0017638 infores:ubergraph knowledge_assertion manual_agent CHEBI:25154 MONDO:0017638 CHEBI:127342 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0039239 infores:hetionet CHEBI:53760 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0000768 infores:hetionet CHEBI:5558 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0015230 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235416 infores:hetionet CHEBI:3403 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0004093 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0332575 infores:hetionet GO:0090210 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0090210 GO:0007399 PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0018802 infores:hetionet CHEBI:5165 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C2242996 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0221706 infores:hetionet CHEBI:8871 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0233471 infores:hetionet CHEBI:135005 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0038325 infores:hetionet CHEBI:31413 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0040034 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0009450 infores:hetionet CHEBI:5959 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0232461 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0233472 infores:hetionet CHEBI:36791 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002962 infores:hetionet CAID:CA10591261 biolink:causes MONDO:0700268 infores:clingen CAID:CA10591261 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP1 The c.5140G>T variant in BRCA1 is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 1714 (p.(Val1714Phe)). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.50, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.00 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Cosegregation analysis of one family carrying this variant has a Bayes Score of 1.85 and provided no evidence (Internal lab contributor). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PM2_Supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10591261/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6950 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0948089 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0233472 infores:hetionet CHEBI:8356 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039070 infores:hetionet CAID:CA410148080 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148080 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1113G>A (p.Met371Ile) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148080/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1139771060 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139771060 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS2, PS1, PS4, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BS2 This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+)/nonsense c.98-c.779 as per VCEP specifications) (PVS1). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771060/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6375 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018520 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026650 infores:hetionet CHEBI:8888 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1510410 infores:hetionet CHEBI:94449 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0232602 infores:hetionet CHEBI:136040 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0151766 infores:hetionet CHEBI:10023 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011606 infores:hetionet CHEBI:39867 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232766 infores:hetionet CHEBI:2038 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0013428 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042131 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0235324 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0235324 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085096 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0948594 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0012833 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0948089 infores:hetionet CHEBI:474180 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0013604 infores:hetionet CHEBI:2663 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0687713 infores:hetionet CHEBI:50173 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085593 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0019151 infores:hetionet CHEBI:9587 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0014518 infores:hetionet CHEBI:7494 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042023 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0019348 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0740858 infores:hetionet CHEBI:27834 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0019080 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0235050 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0235050 infores:hetionet CAID:CA915940477 biolink:causes MONDO:0010305 infores:clingen CAID:CA915940477 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_005629.4:c.878_879del (p.Leu293GlnfsTer3) variant in SLC6A8 is a frameshift variant that is predicted to cause a premature stop codon in biologically-relevant-exon 5/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One male patient with this variant has been reported with clinical features consistent with creatine transporter deficiency (absent speech, intellectual disability, seizures), elevated creatine/creatinine ratio in urine, undetectable creatine uptake in fibroblasts (with 25 μmol/L creatine), and creatine and phosphocreatine peaks severely reduced in the white matter (PMIDs: 16601898, 17825809, 18925426, 19706062, 19955008 (PP4_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, August 8, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940477/MONDO:0010305/027 2023-08-08 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:9086 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0016204 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0014724 infores:hetionet CHEBI:55346 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020461 infores:hetionet CHEBI:7824 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085593 infores:hetionet CHEBI:9332 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0038362 infores:hetionet CHEBI:10119 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0392684 infores:hetionet CHEBI:7798 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011603 infores:hetionet CHEBI:10023 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151905 infores:hetionet CAID:CA253312 biolink:causes MONDO:0010134 infores:clingen CAID:CA253312 MONDO:0010134 PMID:12788906PMID:12788906PMID:11932316PMID:23273637PMID:12788906PMID:18285825PMID:21551164PMID:23965030PMID:23273637PMID:16570074PMID:15689455PMID:12788906PMID:24224479PMID:17503324PMID:20597900PMID:18285825PMID:21551164PMID:23965030PMID:23273637PMID:16570074PMID:15689455PMID:12788906PMID:24224479PMID:17503324PMID:20597900PMID:25999548PMID:23336812PMID:26683941 Pathogenic PP1_Moderate, PS3_Supporting, PP4, PP3, PM3_Very Strong, PM2_Supporting, PS4 BP5, BP7, BS4, BS1, BS2, PM1, PM4, PM5, PVS1, PM6, BP2, BP3, BP4, BA1, PS2, PS1 The p.Val138Phe variant in SLC26A4 has been detected in over 4 patients with Pendred syndrome or hearing loss with enlarged vestibular aqueducts who harbored a pathogenic or suspected pathogenic variant in trans with p.Val138Phe (PM3_VS; PMID: 17503324, 15689455, 20597900, 18285825, 23965030, 24224479, 21551164, 23273637, 12788906, 16570074). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 25999548, 23336812, 26683941). The p.Val138Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID: 12788906). The allele frequency of the p.Val138Phe variant in the SLC26A4 gene is 0.03% (38/126540) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). Computational prediction tools and conservation analysis suggest that the p.Val138Phe variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA and/or Mondini malformation which are consistent with Pendred syndrome (PP4; PMID: 12788906, 23273637). A functional study performed in HeLa and human embryonic kidney cell lines demonstrated that pendrin harboring the p.Val138Phe variant did not localize to the cell membrane. However, there was no effect on iodide efflux (PS3_P; PMID: 11932316). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome/EVA based on the ACMG/AMP criteria applied: PM3_VS, PS4, PP1_M, PM2_Supporting, PP3, PP4, PS3_P. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA253312/MONDO:0010134/005 2018-09-19 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:65250 biolink:causes MONDO:0010176 infores:monarchinitiative not_provided not_provided HGNC:25801 MONDO:0010176 uuid:c0990814-7fde-4f35-8049-babd47ee5217 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035229 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0856151 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0042769 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001265 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036358 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0027765 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0001623 infores:hetionet CAID:CA357779 biolink:causes MONDO:0017623 infores:clingen CAID:CA357779 MONDO:0017623 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PM6_Strong, PM5 PS4 PTEN c.408T>G (p.Cys136Trp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_S: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history (internal laboratory contributor(s) SCV003926429.1).PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 189406, SCV000840468.3).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.54 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350).PP3: REVEL score > 0.7 (score of this variant = 0.954).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PM2_P: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA357779/MONDO:0017623/003 2025-04-04 2025-06-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7936 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0376358 infores:hetionet CHEBI:75045 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151908 infores:hetionet CAID:CA916081959 biolink:causes MONDO:0011071 infores:clingen CAID:CA916081959 MONDO:0011071 PMID: Uncertain Significance BS1, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.59-6T>C is a splicing variant which may impact splicing. These changes are only predicted to impact isoform C. MAF of 0.000207 (0.021%, 1/4834, 1 allele) in the South Asian subpopulation of the gnomAD 3.1.2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This intronic variant has a SpliceAI score ≥ 0.38 (Acceptor Loss = 0.49, Donor Loss = 0.45) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081959/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63631 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020507 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042109 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0233494 infores:hetionet CHEBI:47780 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151907 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0948594 infores:hetionet CHEBI:3181 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0232493 infores:hetionet CAID:CA343724569 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724569 MONDO:0020367 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting, PS3_Moderate BS1, BS3, BP7, PM6, PP1, PM4, PS1, PS4, PS2, BA1, BP4 The c.1139A>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glycine at amino acid 380 (p.Asp380Gly). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.964, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (John Hulleman pers. comm., using method described in PMID: 35196929) demonstrated that the Asp380Gly protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. Only 1 proband with JOAG (Juvenile open angle glaucoma) had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1139A>G, p.Asp380Gly variant has a higher Grantham score (= 94) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS3_Moderate, PP3, PM2_Supporting, PM5_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724569/MONDO:0020367/019 2022-03-08 2022-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17347 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0005758 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235746 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235746 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0221745 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0221745 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020517 infores:hetionet CHEBI:3223 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0427086 infores:hetionet CHEBI:45863 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0086439 infores:hetionet CHEBI:49375 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013604 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0008049 infores:hetionet NCBIGene:3753 biolink:causes MONDO:0012871 infores:monarchinitiative not_provided not_provided HGNC:6240 MONDO:0012871 uuid:0c1d64dc-f16a-421f-ac50-1a8931a41a85 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009241 infores:hetionet CHEBI:6888 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C1384353 infores:hetionet CAID:CA024293 biolink:causes MONDO:0007783 infores:clingen CAID:CA024293 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PS4_Supporting, PM1, PP1_Strong, PP3_Moderate BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Cysteine at codon 533 of the RYR1 protein, p.(Arg533Cys). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:12709367). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 8 individuals PP1_Strong (PMID:12709367). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Supporting, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024293/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:49375 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0038525 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0016382 infores:hetionet CHEBI:10119 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0002962 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018021 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0948586 infores:hetionet CHEBI:6832 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0231527 infores:hetionet CHEBI:71940 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0025874 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0740858 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0151904 infores:hetionet CHEBI:75998 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0013378 infores:hetionet CHEBI:28445 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0854467 infores:hetionet CAID:CA024853 biolink:causes MONDO:0018493 infores:clingen CAID:CA024853 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with isoleucine at codon 2596 of the RYR1 protein, p.(Thr2596Ile). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000145, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 not implemented (PMID:16917943). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.822 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024853/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA341585 biolink:causes MONDO:0015967 infores:clingen CAID:CA341585 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM3_Supporting, PM5, PP2, PP3, PP4, PM2_Supporting PM1 The variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 378 (p.(Ala378Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 9 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 14578306, 25935773, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (internal lab contributors). It has also been detected in an individual with neonatal diabetes who was homozygous for this variant and had antibody-negative diabetes (PM3_Supporting, PMID: 14578306). This variant also segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; internal lab contributors). Additionally, another missense variant, c.1132G>A (p.Ala378Thr) has been interpreted as pathogenic by the ClinGen MDEP and p.Ala378Val has a greater Grantham distance (PM5). In summary, c.1133C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PP4, PS4, PM5, PP2, PP3, PM2_Supporting, PM3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA341585/MONDO:0015967/086 2023-08-08 2023-08-08 Semidominant inheritance HP:0032113 Supports CHEBI:82960 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1720775 infores:hetionet CAID:CA16602347 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602347 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, PS3, PM5, PP3 The NM_000527.5 (LDLR):c.2125A>G (p.Arg709Gly) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: PopMax MAF=0.000004237 in non-Finnish European exomes (gnomAD v4.1.0).PP4: Variant meets PM2, and is identified in one index case with DLCN score >=6 after alternative causes of high cholesterol were excluded, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602347/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA041712 biolink:causes MONDO:0007750 infores:clingen CAID:CA041712 MONDO:0007750 PMID: Uncertain Significance BP4 PS4, PM1, PM5, PM2, PP4 The NM_000527.5(LDLR):c.82G>A (p.Glu28Lys) variant is classified as a variant of uncertain significance for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows: BP4_Met : REVEL = 0.306. It is below 0.50.splicing evaluation is required.A) not on limitsB) does not create AGC) there is a AG nearbyThe variant does not alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA041712/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50275 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0009782 infores:hetionet CHEBI:47781 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0018524 infores:hetionet CHEBI:51364 biolink:causes MONDO:0004258 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0033948 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0160390 infores:hetionet CAID:CA348611 biolink:causes MONDO:0012933 infores:clingen CAID:CA348611 MONDO:0012933 PMID: Likely Pathogenic PP4_Moderate, PVS1_Moderate, PM3 PM2, BS1, BA1 The c.632-3C>G variant is an intronic variant occurring in intron 7 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by creating a new acceptor splice site, resulting in retention of 2bp from intron 7, which leads to a frameshift and generates a premature stop codon (PMIDs: 30883759, 32123317, 22505045). Reduced expression of aberrant transcript reported by one assay suggesting potential incomplete expression of the aberrant transcript (Ambry internal contributor). Appropriate code strength determined by comparison of results to PVS1 decision tree PVS1 (RNA) was downgraded to PVS1_Moderate (RNA). This variant has been detected in 2 siblings with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, are seen in these individuals. Both siblings were homozygous for the variant. Total points equated to 2 (PM3 met; PMID: 25381700). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 12.477 (based on Pathology LR=1.07; Co-occurrence LR=1.0498; Family History LR=11.107), within the thresholds for Moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Moderate (RNA), PM3, PP4_Moderate). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA348611/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235086 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0008370 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0080203 infores:hetionet CHEBI:53760 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0008031 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0413252 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0677500 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0006145 infores:hetionet CHEBI:16347 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0030193 infores:hetionet CHEBI:2611 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C1527344 infores:hetionet CHEBI:5790 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233407 infores:hetionet CHEBI:72296 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0852911 infores:hetionet NCBIGene:55505 biolink:causes MONDO:0009136 infores:monarchinitiative not_provided not_provided HGNC:14378 MONDO:0009136 uuid:789ffecb-f66f-4498-ada3-7554316e6673 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0178298 infores:hetionet UMLS:C1872203 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0015672 infores:hetionet CHEBI:36791 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002874 infores:hetionet CHEBI:7573 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0232462 infores:hetionet CHEBI:404903 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018932 infores:hetionet CHEBI:132233 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0000737 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0549373 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0042109 infores:hetionet CHEBI:4325 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0022667 infores:hetionet CHEBI:17303 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0008031 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0521591 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0040034 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0263355 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0263355 infores:hetionet CHEBI:75988 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0039231 infores:hetionet NCBIGene:1837 biolink:causes MONDO:0975830 infores:monarchinitiative not_provided not_provided HGNC:3057 MONDO:0975830 uuid:bcc2f305-20de-47a4-8418-85952b669897 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0231528 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038663 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0233414 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020542 infores:hetionet CHEBI:47780 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0242184 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0221392 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0221185 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042134 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0001364 infores:hetionet CHEBI:31644 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0009806 infores:hetionet NCBIGene:10677 biolink:causes MONDO:0032826 infores:monarchinitiative not_provided not_provided HGNC:14188 MONDO:0032826 uuid:c7b2a9fb-9f68-4181-88ce-6a1cd13a364d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2379 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0013604 infores:hetionet CHEBI:4868 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0151908 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0017601 infores:hetionet CAID:CA10642200 biolink:causes MONDO:0007750 infores:clingen CAID:CA10642200 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 PS4 The NM_000527.5(LDLR):c.2389+7G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001501 (0.015%) in Admixed American exomes/genomes (gnomAD v4.1.0). BP4: No REVEL score, splicing evaluation required. Not on splicing limits and no published functional data on splicing found, so BP4 is met.PP4: Variant meets PM2 and is identified in at least 1 index case (1 case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10642200/MONDO:0007750/013 2025-02-20 2025-06-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:0048395 biolink:causes GO:0048391 infores:ubergraph knowledge_assertion manual_agent GO:0048395 GO:0048391 CHEBI:6067 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0039446 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0014869 infores:hetionet CAID:CA023783 biolink:causes MONDO:0007750 infores:clingen CAID:CA023783 MONDO:0007750 PMID: Pathogenic PS4_Moderate, PP1_Strong, PS3_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS4, BS1, BS3, PM5, PM1, PM4, PM3, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR):c.862G>A (p.Glu288Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM2, PS4_Moderate, PP3, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 13 informative meiosis in at least 6 families from different labs.PM2 - PopMax MAF = 0.0001960 (0.0196%) in South Asian exomes (gnomAD v2.1.1).PS4_moderate - Variant meets PM2. Variant identified in at least 7 unrelated index cases with Simon-Broome criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL = 0.85. PP4 - Variant meets PM2. Identified in 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PS3_supporting - Level 3 assays: PMID 21990180: Htz Patient lymphocytes, FACS assays - results - normal (90%) cell surface LDLR, 50% LDL-LDLR binding and 45% LDL uptake ---- results are below 85% of wild-type activity, so PS3_supporting is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023783/MONDO:0007750/013 2021-06-08 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:94686 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0006266 infores:hetionet CHEBI:91834 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0030252 infores:hetionet CHEBI:8890 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C2242737 infores:hetionet CHEBI:6413 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0002994 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0242656 infores:hetionet CAID:CA10385227 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385227 MONDO:0100437 PMID: Benign BA1, BP3 BS2, BP2 NM_001034853.2(RPGR):c.2976_2990del (p.Glu993_Glu997del) is an in-frame deletion variant of 15 nucleotides encoding amino acids 993-997 and is located within a low complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (PMID: 11992260, BP3). This variant is present in gnomAD v4.1.0 at a frequency of 0.0007266 among hemizygous individuals, with 126 variant alleles / 173,417 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported to be present in 0.8% of the affected patients carrying another variant found to be the cause of disease (PMID: 11992260), however, BP2 is considered not applicable for RPGR. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385227/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:7445 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0011570 infores:hetionet CHEBI:77260 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020433 infores:hetionet CHEBI:31236 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0423006 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0235416 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0008370 infores:hetionet CHEBI:681569 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0149745 infores:hetionet CHEBI:7459 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0042510 infores:hetionet CHEBI:231425 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0017181 infores:hetionet CHEBI:50173 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0702166 infores:hetionet CHEBI:48669 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0038999 infores:hetionet CHEBI:2379 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0017178 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151838 infores:hetionet CHEBI:28748 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020580 infores:hetionet CHEBI:27436 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0002792 infores:hetionet CHEBI:75246 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011175 infores:hetionet CHEBI:144551 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151578 infores:hetionet CHEBI:37333 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0042487 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0549428 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0549428 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0042109 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C1861172 infores:hetionet CHEBI:63611 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0033893 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0340726 infores:hetionet CHEBI:31709 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0003862 infores:hetionet GO:0010975 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:0010975 GO:0048666 UNII:G4PX8C4HKV biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0042267 infores:hetionet CHEBI:3176 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0085129 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0002871 infores:hetionet CHEBI:367163 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014518 infores:hetionet CHEBI:61049 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003862 infores:hetionet CHEBI:50673 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0030554 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0853777 infores:hetionet CAID:CA2697547482 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547482 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.58+5_58+7del is an intronic variant which may impact splicing. This variant has a SpliceAI score ≥ 0.38 (Donor Loss - 0.85) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547482/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6640 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0042109 infores:hetionet CHEBI:135285 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0041912 infores:hetionet CHEBI:3387 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0003467 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0232459 infores:hetionet NCBITaxon:5498 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5498 MONDO:0001867 CHEBI:10119 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0854082 infores:hetionet CHEBI:75722 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003467 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0267537 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0267537 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038367 infores:hetionet CAID:CA2739267616 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267616 MONDO:0011071 PMID: Pathogenic PM1_Supporting, PVS1, PM5, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.411dup (p.Glu138Ter) is a nonsense variant which is predicted to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). It is downstream of c.98 (PM5_Supporting) and impacts amino acid 138, which is located within the Runt Homology Domain (RHD) but does not occur in an established hotspot residue (PM1_Supporting). Clinical and functional data are not available for this variant. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting, PM5_Supporting, PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267616/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0080274 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0042109 infores:hetionet CAID:CA6265193 biolink:causes MONDO:0700270 infores:clingen CAID:CA6265193 MONDO:0700270 PMID: Pathogenic PM3_Strong, PVS1 PM5, PM2 The c.3078-1G>A variant in ATM occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 20. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in gnomAD v2.1.1 is (0. 0.0018%) (2/113536 alleles) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 10234507). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1, PM3_Strong). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6265193/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3077 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0041296 infores:hetionet CHEBI:31348 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0015672 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0020649 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0038661 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151559 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0435002 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001265 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0036358 infores:hetionet CHEBI:144093 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0235896 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0026848 infores:hetionet CHEBI:4315 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0030305 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020676 infores:hetionet CHEBI:8707 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0030554 infores:hetionet CHEBI:17334 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020578 infores:hetionet CHEBI:9241 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0009676 infores:hetionet CHEBI:5613 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0232462 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0018965 infores:hetionet CHEBI:50673 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0037290 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0178298 infores:hetionet CHEBI:16914 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0085624 infores:hetionet CHEBI:63631 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085605 infores:hetionet CHEBI:50223 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0011991 infores:hetionet CAID:CA374978902 biolink:causes MONDO:0008535 infores:clingen CAID:CA374978902 MONDO:0008535 PMID: Pathogenic PP1, PM1, PM2_Supporting, PP4_Moderate, PS4, PS3_Supporting The NM_001114753.3: c.1145G>A variant in ENG is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 382 (p.Cys382Tyr). This variant alters amino acid C382 of ENG that is defined as a critical residue (previously reported to be likely pathogenic or pathogenic) by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1; PMID: 17786384). This variant has been reported in more than 4 probands with a phenotype consistent with HHT (PS4; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; PMID: 30763665). The variant has been reported to segregate with HHT in 3 affected family members from a single family (PP1; PMID: 30763665, Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.56, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. Functional assays showed the variant protein to have reduced protein expression in CHO-K1 cells, indicating that this variant impacts protein function (PS3_Supporting, PMID: 30763665). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4, PM1, PP4_Moderate, PM2_Supporting, PS3_Supporting, PP1 (specifications version 1.1.0; 02/04/2025). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374978902/MONDO:0008535/136 2025-02-04 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CAID:CA229641 biolink:causes MONDO:0009861 infores:clingen CAID:CA229641 MONDO:0009861 PMID:10679941PMID:10679941 Uncertain Significance PM2, PP4, PM3_Supporting PP3 VUS:The c.59A>T (p.Q20L) variant was detected in trans with a known pathogenic variant (c.1315+1G>A) in a patient with hyperphenylalaninemia (parental testing not reported) (PP4, PM3-supporting; PMID: 10679941). This variant is absent from population databases including, gnomAD, ESP, and 1000 Genomes (PM2). Computation predictors on protein structure and function indicate conflicting results (SIFT: tolerated, Polyphen: Benign, MutationTaster: Disease causing, REVEL=0.582). In summary this variant meets the criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3-supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229641/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6759 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0233494 infores:hetionet CHEBI:4672 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0022346 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0151814 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151814 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0521591 infores:hetionet CAID:CA404083133 biolink:causes MONDO:0007750 infores:clingen CAID:CA404083133 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1069G>C (p.Glu357Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.935. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404083133/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:17263 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0032708 infores:hetionet CHEBI:59773 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0013378 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0042109 infores:hetionet CHEBI:3215 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0002792 infores:hetionet CHEBI:64355 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019345 infores:hetionet NCBIGene:1145 biolink:causes MONDO:0014586 infores:monarchinitiative not_provided not_provided HGNC:1966 MONDO:0014586 uuid:af9b74d1-ec67-4305-9374-399333e9f130 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027813 infores:hetionet CHEBI:8364 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0027769 infores:hetionet CHEBI:6801 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0001122 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0079102 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0025202 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0012088 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0278045 infores:hetionet CHEBI:3176 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0011603 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0003123 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0856880 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0856880 infores:hetionet GO:0106104 biolink:causes GO:0050808 infores:ubergraph knowledge_assertion manual_agent GO:0106104 GO:0050808 CHEBI:50885 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0011615 infores:hetionet NCBIGene:79989 biolink:causes MONDO:0859191 infores:monarchinitiative not_provided not_provided HGNC:21882 MONDO:0859191 uuid:aed9fda1-0a16-4c90-ac98-491fab6a6ec5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8713 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0017181 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004652 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0004626 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011630 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0234215 infores:hetionet CHEBI:134991 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0023222 infores:hetionet CHEBI:42797 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151907 infores:hetionet CHEBI:63598 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0015403 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0162848 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0853692 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0038661 infores:hetionet CHEBI:47381 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C3263723 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0006277 infores:hetionet GO:0006954 biolink:causes MONDO:0005324 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D006255 DB01069_MESH_D006255_1DB08936_MESH_D006255_1DB00719_MESH_D006255_1DB01176_MESH_D006255_1DB00967_MESH_D006255_1DB00950_MESH_D006255_1DB00972_MESH_D006255_1DB00768_MESH_D006255_1 CHEBI:16469 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0476089 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0005741 infores:hetionet CHEBI:3181 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0023380 infores:hetionet CHEBI:3650 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0687133 infores:hetionet CHEBI:41423 biolink:causes HP:0002140 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0948008 infores:hetionet CHEBI:6931 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0151786 infores:hetionet CHEBI:6797 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0011603 infores:hetionet CHEBI:2668 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042963 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027651 infores:hetionet CHEBI:167309 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0034063 infores:hetionet CHEBI:51173 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0428977 infores:hetionet CHEBI:9635 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0018681 infores:hetionet CHEBI:63632 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0085669 infores:hetionet CHEBI:31547 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0392171 infores:hetionet CHEBI:59773 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C1368065 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0349506 infores:hetionet CHEBI:63611 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0340865 infores:hetionet NCBIGene:11261 biolink:causes MONDO:0032753 infores:monarchinitiative not_provided not_provided HGNC:17433 MONDO:0032753 uuid:a9bd67c6-f461-4f8e-966d-4f63b62f2ef1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72564 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0015397 infores:hetionet NCBIGene:55636 biolink:causes MONDO:0012880 infores:monarchinitiative not_provided not_provided HGNC:20626 MONDO:0012880 uuid:707a8ec2-0e58-46da-b88f-9536e174d528 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0086565 infores:hetionet CHEBI:63598 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0005778 infores:hetionet UMLS:C0023610 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0036974 infores:hetionet CHEBI:9649 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0002962 infores:hetionet CHEBI:64064 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1260880 infores:hetionet CHEBI:9014 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0042571 infores:hetionet CHEBI:17303 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0234233 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0032285 infores:hetionet CAID:CA2387272448 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387272448 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-5A>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387272448/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA229263 biolink:causes MONDO:0009861 infores:clingen CAID:CA229263 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3_Supporting PM5 The c.1001G>C (p.Cys334Ser) variant in PAH has been reported in 2 patients with mild PKU/HPA. (BH4 deficiency not ruled out. PMID: 8632937, 10693064). It was detected with pathogenic variant p.F299C (unknown phase). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.976. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229263/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51209 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0428977 infores:hetionet CAID:CA367398738 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398738 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PM2, PP4_Moderate, PP2, PP3 The c.1147T>A variant in the glucokinase gene, GCK, causes an amino acid change of serine to threonine at codon 383 (p. (Ser383Thr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2) This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.73 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1148C>T (p.Ser383Leu), has been interpreted as pathogenic by the ClinGen MDEP, but has a greater Grantham distance than p.Ser383Thr (PM5_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 28726111, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID:28726111). In summary, c.1147T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP3, PP2, PM5_Supporting, PM2_Supporting, PP4_Moderate, PS4_Moderate Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398738/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:134991 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0027051 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009938 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0038587 infores:hetionet CHEBI:63617 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020672 infores:hetionet CHEBI:3756 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0021368 infores:hetionet CHEBI:8356 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1510410 infores:hetionet CHEBI:50838 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0024902 infores:hetionet CHEBI:63618 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151786 infores:hetionet CAID:CA1619762 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619762 MONDO:0800472 PMID: Likely Pathogenic PM2_Supporting, PM3_Strong, PM4, PP1_Moderate PP3, BP4, BA1, PS3, PS1, PS2, PM1, PM5, BP7, BS1, BS4, PVS1 The c.1536_1541del variant in CYP1B1 is predicted to cause a change in the length of the protein due to an in-frame deletion of 2 amino acids (p.Pro513_Lys514del), meeting PM4. The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00003474 (41 alleles out of 1,180,044), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. 2 affected segregations with a CYP1B1-related phenotype have been reported (ANZRAG database [E. Souzeau pers. comm.]), which fulfilled PP1_Moderate. This variant has been identified in 4 individuals with a CYP1B1-related phenotype. 3 of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 confirmed in trans, Baylor Genetics pers. comm. and 2 with phase unknown, PMID: 19234632) and 1 compound heterozygous with a variant of uncertain significance (ANZRAG [E. Souzeau pers. comm.]). Total proband points = 2.25, meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PP1_Moderate, PM4, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619762/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17823 biolink:causes MONDO:0005890 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0029405 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0221269 infores:hetionet CHEBI:27436 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0855242 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233571 infores:hetionet CHEBI:28177 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0020456 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0948525 infores:hetionet CHEBI:127342 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0023380 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0856137 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0856137 infores:hetionet CHEBI:48273 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0002994 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006026 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0005686 infores:hetionet CHEBI:404903 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0040822 infores:hetionet CHEBI:68845 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0853034 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235567 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0259756 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0259756 infores:hetionet CHEBI:72296 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0406834 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0032285 infores:hetionet GO:1902943 biolink:causes GO:1902476 infores:ubergraph knowledge_assertion manual_agent GO:1902943 GO:1902476 CAID:CA16616940 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616940 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1294T>C (p.Cys432Arg) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616940/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085096 infores:hetionet CHEBI:2666 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0030252 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0345904 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151849 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002332 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0037997 infores:hetionet NCBIGene:5139 biolink:causes MONDO:0007211 infores:monarchinitiative not_provided not_provided HGNC:8778 MONDO:0007211 uuid:e9fd3073-5052-4a39-a30a-0c098e6fc6f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3654 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0003811 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0234987 infores:hetionet CHEBI:18248 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0010520 infores:hetionet CHEBI:6838 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0160390 infores:hetionet CHEBI:6754 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0233407 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0005940 infores:hetionet CHEBI:50275 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0700590 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0149931 infores:hetionet CHEBI:3568 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0025323 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0574067 infores:hetionet CHEBI:9328 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151579 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0750272 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0750272 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0233414 infores:hetionet CHEBI:31348 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0017168 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022904 infores:hetionet CHEBI:5118 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042023 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0002884 infores:hetionet CHEBI:5864 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0014394 infores:hetionet CHEBI:45599 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0039621 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0018799 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027651 infores:hetionet CHEBI:8435 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0149871 infores:hetionet NCBIGene:201294 biolink:causes MONDO:0012146 infores:monarchinitiative not_provided not_provided HGNC:23147 MONDO:0012146 uuid:7caf9cb8-bdd7-4479-85d4-e9b70d1cf9a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3084 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C1328539 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0948594 infores:hetionet CHEBI:63608 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0035410 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0032231 infores:hetionet CHEBI:9763 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0235490 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0021053 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0027769 infores:hetionet CAID:CA270366 biolink:causes MONDO:0010726 infores:clingen CAID:CA270366 MONDO:0010726 PMID: Pathogenic PM1, PP3, PP4, PS2, PM2_Supporting, PS4_Supporting The p.Val122Met variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 17089071) (PP4). The p.Val122Met variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in this individual. It is also reported in the mosaic state in a male patient with clinical features of Rett syndrome (PMID 28837158, internal database - GeneDx) and therefore confirmed to be de novo (PS2, PS4_supporting). The p.Val122Met variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val122Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Val122Met variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PM1, PS4_supporting, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270366/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf NCBIGene:5376 biolink:causes MONDO:0008392 infores:monarchinitiative not_provided not_provided HGNC:9118 MONDO:0008392 uuid:56b39c49-cca9-4b72-aa90-74fe2660d610 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA405687229 biolink:causes MONDO:0018493 infores:clingen CAID:CA405687229 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting PP3, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 4820 of the RYR1 protein, p.(Gly4820Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 23267001). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of .835 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405687229/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10023 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030305 infores:hetionet CHEBI:6067 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085077 infores:hetionet CHEBI:8768 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0017181 infores:hetionet CHEBI:480999 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0236000 infores:hetionet CHEBI:51364 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0013144 infores:hetionet CHEBI:4653 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0006266 infores:hetionet CHEBI:3647 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0542165 infores:hetionet CHEBI:41879 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0156404 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0020517 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0521839 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0234215 infores:hetionet CHEBI:9137 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020461 infores:hetionet CHEBI:6717 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0033687 infores:hetionet CHEBI:31981 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0004096 infores:hetionet CHEBI:41774 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0028643 infores:hetionet CHEBI:4798 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151744 infores:hetionet CHEBI:10127 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C1142135 infores:hetionet CHEBI:3380 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0917801 infores:hetionet CHEBI:41423 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0423791 infores:hetionet CHEBI:2948 biolink:causes HP:0012133 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0542035 infores:hetionet CAID:CA410147701 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147701 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, BA1, BP1, BP4, BP3, BP2, PM2, BS1, BS3, PM4, PM3, PM5, BS2, PP2, PP3, PP4 NM_001754.5(RUNX1):c.1241A>G (p.Tyr414Cys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147701/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9139 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0036454 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0344315 infores:hetionet CHEBI:9763 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0014724 infores:hetionet CHEBI:8597 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C1443060 infores:hetionet CAID:CA16621223 biolink:causes MONDO:0010305 infores:clingen CAID:CA16621223 MONDO:0010305 PMID: Uncertain Significance PP3, PM2_Supporting, PS1_Supporting PS2 The NM_005629.4:c.912G>C in SLC6A8 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 304 (p.Gln304His). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.749 (>0.75 provides evidence that correlates with impact to SLC6A8 function). The computational splicing predictors SpliceAI and varSEAK predict that the variant may disrupt the donor splice site of intron 5 (PP3). Another variant at this position, c.912G>A (p.Gln304=), which has been reported in a patient with creatine transporter deficiency and may disrupt normal splicing of SLC6A8 (PMIDs: 17101918, 23660394, 29478817) has been classified as likely pathogenic by the ClinGen CCDS VCEP. Comparison of the in silico predictions for c.912G>A (p.Gln304=) and c.912G>C (p.Gln304His) suggest that c.912G>A (p.Gln304=) is less damaging to splicing than c.912G>C (p.Gln304His) (PS1_Supporting). To our knowledge, c.912G>C (p.Gln304His) has not been reported in the literature and results of functional and splicing studies are unavailable. However, there is a ClinVar entry for this variant (Variation ID: 420991); follow up with the lab did not provide sufficient evidence to apply additional criteria. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP3, PM2_Supporting, PS1_Supporting.(Classification approved by the ClinGen CCDS VCEP, Jan 12, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621223/MONDO:0010305/027 2023-08-24 2023-08-24 X-linked inheritance HP:0001417 Inconclusive true CHEBI:5280 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0235146 infores:hetionet NCBIGene:4212 biolink:causes MONDO:0010970 infores:monarchinitiative not_provided not_provided HGNC:7001 MONDO:0010970 uuid:09b8fa60-3c80-4ef9-8be9-b797ce325ed8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006826 infores:hetionet CHEBI:27834 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0023530 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0042075 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0033975 infores:hetionet CHEBI:188986 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0036454 infores:hetionet NCBIGene:657 biolink:causes MONDO:0012405 infores:monarchinitiative not_provided not_provided HGNC:1076 MONDO:0012405 uuid:417526c6-da32-47b4-bef8-59a0dd57a2ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23765 biolink:causes MONDO:0013500 infores:monarchinitiative not_provided not_provided HGNC:5985 MONDO:0013500 uuid:9d2514de-5e9f-47ab-99cd-2751ce6f9364 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235431 infores:hetionet CHEBI:63612 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0027947 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0342579 infores:hetionet CAID:CA8337602 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337602 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 BP7 The c.216C>T (p.Ser72=) variant (NM_000018.4) is a synonymous (silent) variant. BP7 was not applied because the nucleotide is conserved, as shown by PhastCons. The results from 3 in silico splicing predictors (SpliceAI, NNsplice, MaxEntScan) support that this variant does not affect splicing (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001471 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337602/MONDO:0008723/021 2023-12-12 2023-12-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8888 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0015230 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0241705 infores:hetionet CHEBI:7447 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0040046 infores:hetionet CHEBI:31302 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0004134 infores:hetionet CHEBI:408174 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0039231 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0027765 infores:hetionet CHEBI:135930 biolink:causes MONDO:0043786 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0036749 infores:hetionet CHEBI:3238 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01091 UMLS:C0011616 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0595877 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853026 infores:hetionet CAID:CA8815025 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815025 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong PM5, PS3 The NM_000152.5:c.841C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 281 (p.Arg281Trp). This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID: 36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID: 31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID: 33202836), as well as in five individuals reported to have later-onset disease (PMID: 22081099, 33073009) (PP4_Moderate). Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID: 36299500, phase unknown) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID: 33202836; phase unknown) (ClinVar Variation ID: 4027) (PM3_Strong). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2_Supporting. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894). This variant meets the criteria to the classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2019. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 8, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815025/MONDO:0009290/010 2024-04-08 2024-04-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA208420 biolink:causes MONDO:0015967 infores:clingen CAID:CA208420 MONDO:0015967 PMID: Benign BP5, PP2, BA1 PS3, PS4, PP3 The c.835G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glutamine at codon 279 (p.(Glu279Gln)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.001404, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). This variant was identified in at least 4 unrelated individuals with hyperglycemia; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID 8446612, PMID 24097065, PMID 30245511, internal lab contributors). This variant was identified in an individual with an alternate molecular basis for disease (BP5; PMID: 36400171). This variant has a REVEL score of 0.698, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. While functional studies exploring the effect of this mutation on the gene have been assessed, these studies do not meet the criteria set forth by the MDEP for application of PS3 or BS3 (PMID: 8446612). In summary, c.835G>C meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): BA1, BP5, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA208420/MONDO:0015967/086 2025-10-03 2025-10-03 Semidominant inheritance HP:0032113 Contradicts true CAID:CA913188120 biolink:causes MONDO:0021056 infores:clingen CAID:CA913188120 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting BS2, PVS1 The c.32dup (p.Gln12Alafs*3) variant in APC is a duplication variant which inserts 1 nucleotide in the first coding exon of the APC gene, creating a frameshift and premature translation stop signal. Since the frameshift and the premature truncation codon occurs upstream of codon 49, PVS1 does not apply according to the APC-specific modifications of the PVS1 decision tree (PVS1 not met). The variant is not reported in gnomAD v2.1.1 (PM2_supporting). This variant has been observed in heterozygous state in 3 healthy unrelated adult individuals worth 1.5 healthy individual points in total (BS2_variable not met; Invitae and GeneDX internal data). In summary, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PM2_Supporting (VCEP specifications version 1; date of approval 12/12/22). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA913188120/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2922 biolink:causes UMLS:C0151624 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0151624 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0035309 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0025061 infores:hetionet CHEBI:127780 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0917801 infores:hetionet CHEBI:3077 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C3263723 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002177 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020459 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0275378 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0275378 infores:hetionet CHEBI:7936 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151904 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0341012 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0003123 infores:hetionet CHEBI:10125 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003811 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0521501 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0521501 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0877661 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0009938 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0521507 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0521507 infores:hetionet CAID:CA000487 biolink:causes MONDO:0017623 infores:clingen CAID:CA000487 MONDO:0017623 PMID:23160955PMID:28250423PMID:23160955PMID:28250423PMID:23160955 Likely Pathogenic PM6, PP3, PP2, PM1, PM2_Supporting PVS1, BP7, BP5, BS1, BS3, BS4, PP1, PP4, BS2, PM5, PM4, PM3, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2, PS4 PTEN c.500C>A (p.Thr167Asn) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2_Supporting: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID:23160955)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score=0.751). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000487/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63598 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0007097 infores:hetionet CAID:CA143431 biolink:causes MONDO:0019501 infores:clingen CAID:CA143431 MONDO:0019501 PMID: Likely Benign BP4, BS1_Supporting PP3, PM3, PM2, BA1 The allele frequency of the c.1966G>A (p.Asp656Asn) variant in USH2A is 0.09251% (1246/1613836 CI 95%) of European (Non Finnish) alleles in gnomAD v4, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). The variant has been identified in 3 probands with hearing loss and 2 probands with Usher syndrome (SCV000065500.6; PMID: 16963483); however an alternate cause of hearing loss in other genes was identified in 3 probands (SCV000065500.6), and a second variant in USH2A was not identified in the other two probands (SCV000065500.6; PMID: 16963483). Finally, in the last proband, another likely benign variant was identified with phasing unknown (SCV000065500.6). Altogether, this evidence does not meet the criteria set to apply PM3_Supporting. Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, the c.1966G>A (p.Asp656Asn) variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143431/MONDO:0019501/005 2025-06-18 2025-06-30 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CAID:CA170424 biolink:causes MONDO:0010726 infores:clingen CAID:CA170424 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, BS2_Supporting, PP4 BP4, PM1, PP3 The NM_004992.4:c.992A>G (p.Lys331Arg) variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 21212452) (PP4) and in at least 1 unaffected individual (PMID: 21212452) (BS2_Supporting). The p.Lys331Arg variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.459). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Rett syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Rett and Angelman-like disorders VCEP (BS2_Supporting, PM2_Supporting, PP4) (MECP2 Specifications v3.0; curation approved on 2/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170424/MONDO:0010726/036 2025-02-28 2025-03-26 X-linked inheritance HP:0001417 Inconclusive true UNII:9430ZR8ZAN biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0243026 infores:hetionet CHEBI:70735 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0151564 infores:hetionet CHEBI:63630 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0008350 infores:hetionet GO:0006954 biolink:causes HP:0000989 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D011537 DB01620_MESH_D011537_1DB01246_MESH_D011537_1DB00420_MESH_D011537_1 PUBCHEM.COMPOUND:657309 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0042963 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0240873 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0240873 infores:hetionet CHEBI:7444 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C2363730 infores:hetionet CAID:CA023930 biolink:causes MONDO:0007783 infores:clingen CAID:CA023930 MONDO:0007783 PMID: Uncertain Significance PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with methionine at codon 3916 of the RYR1 protein, p.(Ile3916Met). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, a second variant classified as pathogenic was identified in trans in this individual, PS4 was not implemented (PMID:16163667). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.765 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023930/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:47898 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C2939419 infores:hetionet CHEBI:465284 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0039231 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0030578 infores:hetionet CHEBI:8435 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0151564 infores:hetionet CHEBI:2654 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0018021 infores:hetionet CHEBI:5123 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0033774 infores:hetionet CHEBI:3696 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0007820 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0003864 infores:hetionet NCBIGene:3931 biolink:causes MONDO:0007620 infores:monarchinitiative not_provided not_provided HGNC:6522 MONDO:0007620 uuid:47d84713-4ddf-4c6b-94b7-d8cb12ad6d78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0017168 infores:hetionet CHEBI:134966 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0006277 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0037199 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0039231 infores:hetionet CHEBI:4551 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0042510 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0031117 infores:hetionet CHEBI:132233 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0039231 infores:hetionet CHEBI:4784 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0008031 infores:hetionet CHEBI:71219 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0149871 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018799 infores:hetionet UMLS:C0145867 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020488 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0042109 infores:hetionet NCBIGene:24145 biolink:causes MONDO:0032810 infores:monarchinitiative not_provided not_provided HGNC:8599 MONDO:0032810 uuid:f68051f3-ecea-48da-bd28-23b750030b27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85161 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0011991 infores:hetionet CHEBI:8802 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0233407 infores:hetionet CHEBI:253342 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1167965 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0029882 infores:hetionet CHEBI:5778 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0278134 infores:hetionet CHEBI:18357 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0015376 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002569 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038353 infores:hetionet CHEBI:8802 biolink:causes UMLS:C1328332 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1328332 infores:hetionet CHEBI:4702 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C2830004 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0033975 infores:hetionet GO:0070366 biolink:causes GO:0001889 infores:ubergraph knowledge_assertion manual_agent GO:0070366 GO:0001889 CHEBI:5778 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0033774 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014742 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0042109 infores:hetionet CHEBI:49040 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0017178 infores:hetionet CAID:CA8328472 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328472 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting PP3, BP4 NM_014336.5(AIPL1):c.559C>T (p.Arg187Trp) is a missense variant replacing the arginine at position p.187 with tryptophan. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000068, with 11 alleles / 1,614,074 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.631, which is above the ClinGen LCA/eoRD VCEP threshold of <0.290 for BP4 and below the threshold of ≥0.644 for PP3 so neither code is applicable. No published probands harboring the variant have been identified. In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328472/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6887 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002170 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2973529 infores:hetionet NCBIGene:3756 biolink:causes MONDO:0012735 infores:monarchinitiative not_provided not_provided HGNC:6250 MONDO:0012735 uuid:cc5cc533-3967-4835-8130-2830713a09c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0009450 infores:hetionet CAID:CA355945969 biolink:causes MONDO:0001586 infores:clingen CAID:CA355945969 MONDO:0001586 PMID: Pathogenic PM3, PP1_Moderate, PVS1, PP4, PM2_Supporting The NM_000203.5:c.164dup (p.Leu56fs) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_very strong). This variant is also referred to as c.252insC in the literature due to the use of a different transcript (ClinVar Variation ID: 855487). This variant has been detected in at least 5 individuals with MPS1, including one set of monozygotic twins. Of those individuals, 3 are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP including c.1395delC p.(Gly466AlafsTer59) (ClinVar Variation ID: 929236) (proband and affected sibling, confirmed in trans, 1 point) (PMID: 30755342) and c.1205G>A p.(Trp402Ter) (ClinVar Variation ID: 11908) (1 patient, phase not confirmed, 0.5 points) (PMID: 7550242), Total 1.5 points (PM3). This variant has also been reported in monozygotic twins with attenuated MPS1 in the compound heterozygous state with the variant and c.1209C>A p.(Thr374Asn), also referred to as c.1121C>A in the literature due to the use of different transcript (PMID: 21176924). Notably, the paper does not clearly state the reference transcript, and the allelic data for these patients will be used to support the classification of c.1209C>A and is not included here in order to avoid circular logic. One patient with this variant in the compound heterozygous state with c.1395delC has been reported with a clinical diagnosis of Hurler syndrome, presenting with reduced IDUA enzyme activity (<0.8nmol/mg protein/hr, reference 28.8-89.8), mild dysostosis multiplex, and mild cardiac valvular disease. This patient received ERT at 34 days of age until 8 months of age and HSCT at 9 months of age. Their sibling, also compound heterozygous for this variant and c.1395delC had undetectable IDUA enzyme activity, dysostosis multiplex, coarse facies, and chronic pulmonary dysfunction. ERT was not available at the time of diagnosis and they died at 1 year 10 months of age of a respiratory infection (PMID 30755342)(PP4_moderate, PP1_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000245 (11/44,856 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 855487). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP1_moderate, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 16, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355945969/MONDO:0001586/091 2025-06-16 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:4488 biolink:causes MONDO:0011481 infores:monarchinitiative not_provided not_provided HGNC:7392 MONDO:0011481 uuid:bad288bd-69f0-4485-a83f-12146a68e8e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA023949 biolink:causes MONDO:0007783 infores:clingen CAID:CA023949 MONDO:0007783 PMID: Uncertain Significance PS4_Moderate, PP3_Moderate PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tryptophan with arginine at codon 3985 of the RYR1 protein, p.(Trp3985Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:18719443, PMID:23558838). An ex vivo assay using muscle cells from mutation positive relatives showed an increased sensitivity to RYR1 agonists, this did not meet PS3 which requires multiple unrelated samples to be tested (PMID:18719443). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.941) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023949/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:51860 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018799 infores:hetionet CHEBI:9725 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0003811 infores:hetionet NCBIGene:8294 biolink:causes MONDO:0031000 infores:monarchinitiative not_provided not_provided HGNC:4793 MONDO:0031000 uuid:95045e7b-2cfe-421f-9211-c42d5cc7dfe2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0442874 infores:hetionet CHEBI:681850 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0041834 infores:hetionet CHEBI:8863 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0041657 infores:hetionet CHEBI:52172 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040822 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235416 infores:hetionet CHEBI:94392 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0003862 infores:hetionet NCBIGene:4052 biolink:causes MONDO:0030337 infores:monarchinitiative not_provided not_provided HGNC:6714 MONDO:0030337 uuid:c6d62a7a-cf31-4672-b738-ad78293a3d76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6741 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0020433 infores:hetionet CHEBI:48947 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0011991 infores:hetionet CHEBI:6741 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013378 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0043037 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042267 infores:hetionet CHEBI:6149 biolink:causes UMLS:C1737224 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1737224 infores:hetionet CHEBI:131512 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0042963 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0029442 infores:hetionet CHEBI:77260 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0000737 infores:hetionet CHEBI:63622 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0547030 infores:hetionet NCBIGene:2690 biolink:causes MONDO:0009877 infores:monarchinitiative not_provided not_provided HGNC:4263 MONDO:0009877 uuid:8cca1fc6-5402-412d-8007-666a431075cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0029878 infores:hetionet CHEBI:7865 biolink:causes HP:0012532 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0150055 infores:hetionet CHEBI:53691 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0423153 infores:hetionet GO:0097086 biolink:causes CL:0002639 infores:ubergraph knowledge_assertion manual_agent GO:0097086 CL:0002639 CHEBI:3207 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0020538 infores:hetionet CHEBI:17347 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0043094 infores:hetionet CHEBI:119915 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013428 infores:hetionet CHEBI:42068 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0006384 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0037199 infores:hetionet CHEBI:50838 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C2981158 infores:hetionet CAID:CA386493446 biolink:causes MONDO:0009861 infores:clingen CAID:CA386493446 MONDO:0009861 PMID: Likely Pathogenic PM2, PM3, PP3, PP4 PM5 This c.1016 C>T (p.Ser339Phe) variant was detected in a patient with mPKU in trans with the pathogenic variant p. Ex6-96A>G (PMID: 28982351). This variant was absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386493446/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3048 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0020517 infores:hetionet CAID:CA346329435 biolink:causes MONDO:0800472 infores:clingen CAID:CA346329435 MONDO:0800472 PMID:17893647PMID:27243976 Likely Pathogenic PP3, PM2_Supporting, PM3, PP1_Strong, PM5_Supporting BA1, BP4, PS1, PS3, PS2, PM1, PM4, BP7, BS1, BS4, PVS1 The c.349C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 117 (p.Arg117Trp). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.726, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) (PMID: 27243976, 17893647) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 17893647), which fulfilled PP1_Strong. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) (PMID: 17893647). Total proband points = 1, meeting PM3. Another missense variant (p.Arg117Gln, Grantham score = 43, ClinVar ID: 2500809) in the same codon has been classified as likely pathogenic for a CYP1B1-related phenotype by the ClinGen Glaucoma VCEP. CYP1B1:p.Arg117Trp has a higher Grantham score (= 101) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PP1_Strong, PM3, PM5_Supporting, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346329435/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3698 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0023530 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0020651 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0038454 infores:hetionet CHEBI:83804 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085612 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0236174 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0236174 infores:hetionet CHEBI:74947 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004245 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017601 infores:hetionet CHEBI:3561 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0014591 infores:hetionet CAID:CA410147027 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147027 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1377C>G (p.His459Gln) is a missense variant which has a REVEL score < 0.50 (0.317) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147027/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2668 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0041657 infores:hetionet CHEBI:48390 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0948594 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0031046 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0032285 infores:hetionet CHEBI:92998 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0039070 infores:hetionet CHEBI:52010 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0020538 infores:hetionet CHEBI:31302 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0040822 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0151664 infores:hetionet CHEBI:31709 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0038999 infores:hetionet CHEBI:6539 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0836924 infores:hetionet CHEBI:6931 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0003578 infores:hetionet CHEBI:6339 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013404 infores:hetionet CHEBI:4636 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0085593 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0027707 infores:hetionet CHEBI:17334 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0151436 infores:hetionet CHEBI:5130 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0022346 infores:hetionet CHEBI:28918 biolink:causes MONDO:0005767 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0017105 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0009443 infores:hetionet CHEBI:17347 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0376358 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0917801 infores:hetionet CHEBI:9150 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0853034 infores:hetionet CHEBI:32293 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C2047937 infores:hetionet GO:2000300 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:2000300 GO:0099504 CHEBI:8080 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0013604 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0853692 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0242350 infores:hetionet NCBIGene:611 biolink:causes MONDO:0008610 infores:monarchinitiative not_provided not_provided HGNC:1012 MONDO:0008610 uuid:5393c28e-fbab-408e-a23a-b414528d189d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C2047937 infores:hetionet CHEBI:4858 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0239377 infores:hetionet CHEBI:4868 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0013922 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0031117 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0427008 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0042109 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0149931 infores:hetionet CHEBI:75988 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0857353 infores:hetionet CHEBI:4858 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0151908 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0020649 infores:hetionet UMLS:C0023610 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0042963 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0221395 infores:hetionet CHEBI:72296 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C2979982 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1619712 infores:hetionet CHEBI:5855 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0242528 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0011570 infores:hetionet CHEBI:9288 biolink:causes MONDO:0009217 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0151638 infores:hetionet CHEBI:31932 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042384 infores:hetionet CHEBI:63612 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0025362 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006615 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0038986 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019348 infores:hetionet CHEBI:68554 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0004093 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151514 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0855242 infores:hetionet CHEBI:8214 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0018524 infores:hetionet CHEBI:175901 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0085649 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0847033 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0847033 infores:hetionet CHEBI:82960 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0042963 infores:hetionet CHEBI:101085 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0042963 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0013604 infores:hetionet CHEBI:7494 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042024 infores:hetionet NCBIGene:10516 biolink:causes MONDO:0012145 infores:monarchinitiative not_provided not_provided HGNC:3602 MONDO:0012145 uuid:280b814b-b836-458b-b22a-8bf9deb832ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018843 infores:hetionet CHEBI:16347 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0947912 infores:hetionet CHEBI:71219 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0232462 infores:hetionet GO:2000084 biolink:causes GO:0061206 infores:ubergraph knowledge_assertion manual_agent GO:2000084 GO:0061206 CHEBI:7798 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0011206 infores:hetionet NCBITaxon:1809 biolink:causes MONDO:0000327 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1809 MONDO:0000327 CHEBI:8327 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0020517 infores:hetionet CHEBI:9352 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0015672 infores:hetionet CHEBI:83804 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0007820 infores:hetionet CHEBI:6741 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0021845 infores:hetionet CHEBI:50859 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0003811 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0011570 infores:hetionet NCBIGene:5950 biolink:causes MONDO:0014635 infores:monarchinitiative not_provided not_provided HGNC:9922 MONDO:0014635 uuid:6bb752c2-03d8-447b-96f5-b236b07f74e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0042510 infores:hetionet CHEBI:51137 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0043094 infores:hetionet NCBIGene:100151683 biolink:causes MONDO:0014722 infores:monarchinitiative not_provided not_provided HGNC:34016 MONDO:0014722 uuid:63680abc-e233-4bbc-ba49-e4bf0204b20f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1142412 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0019112 infores:hetionet CHEBI:17698 biolink:causes UMLS:C0853040 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0853040 infores:hetionet CHEBI:7823 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0085628 infores:hetionet CHEBI:251408 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0042963 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C2830004 infores:hetionet CHEBI:4974 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0023530 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0033844 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0033844 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0235863 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235863 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0235290 infores:hetionet CHEBI:5864 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0151747 infores:hetionet CHEBI:63629 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0031256 infores:hetionet GO:1904318 biolink:causes GO:0060073 infores:ubergraph knowledge_assertion manual_agent GO:1904318 GO:0060073 CHEBI:3387 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0024299 infores:hetionet NCBIGene:51729 biolink:causes MONDO:0030987 infores:monarchinitiative not_provided not_provided HGNC:16461 MONDO:0030987 uuid:b3c99e87-bfb8-4649-80b8-672d472d9e44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135361 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0857257 infores:hetionet CHEBI:45863 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0231856 infores:hetionet CHEBI:6838 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C1442826 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0042109 infores:hetionet CHEBI:5864 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042023 infores:hetionet CHEBI:74947 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038220 infores:hetionet CAID:CA390887653 biolink:causes MONDO:0100216 infores:clingen CAID:CA390887653 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting BP2, BA1, PP3, PP1, PP4, BS2, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.3(DICER1):c.818A>C variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by alanine at amino acid 273 (p.Glu273Ala). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.185; MaxEntScan and SpliceAI: no effect on splicing) (BP4). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 02/27/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390887653/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:72564 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0520966 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235290 infores:hetionet CAID:CA213762 biolink:causes MONDO:0015967 infores:clingen CAID:CA213762 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4, PP1 The c.1372_1373del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 458 (NM_000162.6), adding 75 novel amino acids before encountering a stop codon (p.(Lys458GlufsTer75)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). Additionally, this variant is absent in gnomAD v.2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes, however PS4 cannot be applied because this number is below the MDEP threshold (internal lab contributors). This variant was identified in a case consistent with GCK-hyperglycemia but there was insufficient clinical information to evaluate for PP4 (internal lab contributors). This variant segregated with disease with one informative meiosis in a family with MODY, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID 27236918) (internal lab contributors). In summary, c.1372_1373del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213762/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Supports NCBIGene:254528 biolink:causes MONDO:0958035 infores:monarchinitiative not_provided not_provided HGNC:28569 MONDO:0958035 uuid:97648c6b-6535-4e05-aeb7-58453bf00d01 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0014868 infores:hetionet CHEBI:4046 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0080274 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0042109 infores:hetionet CHEBI:2611 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0039239 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015230 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235522 infores:hetionet CHEBI:45924 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0917801 infores:hetionet CHEBI:8354 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0027497 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0013595 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0002170 infores:hetionet CHEBI:9907 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0438717 infores:hetionet CHEBI:68554 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0162830 infores:hetionet CHEBI:8024 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018926 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0234215 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0853692 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003265 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0001546 infores:hetionet CHEBI:188986 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151907 infores:hetionet CHEBI:37941 biolink:causes MONDO:0010602 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019069 infores:hetionet CHEBI:44423 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0151578 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027813 infores:hetionet CHEBI:499361 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020672 infores:hetionet CHEBI:52172 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0022346 infores:hetionet CHEBI:8871 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014591 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0041349 infores:hetionet CHEBI:135566 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0855704 infores:hetionet CHEBI:4657 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0040034 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0013182 infores:hetionet CAID:CA10585869 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585869 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP3, PP4 PS3 The NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PM5) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.93.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnostic criteria. One index case fulfil criteria of TC > 8mmol/l and strong family history of CAD, Laurie et al, 2004, Canterbury Health Laboratories, New Zealand, PMID: 15556094. One index case with DLCN score ≥6, Meshkov et al, 2021, National Medical Research Center for Therapy and Preventive Medicine, Russia, PMID: 33418990.PM5: Two other missense variants in the same codon: NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines, therefore PM5 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585869/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:151648 biolink:causes MONDO:0014528 infores:monarchinitiative not_provided not_provided HGNC:25088 MONDO:0014528 uuid:56363f38-22d1-4cf9-a5f2-4d8a802c3951 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10100 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0005758 infores:hetionet CHEBI:7640 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0009676 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034186 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0002871 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0021400 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0854082 infores:hetionet CAID:CA270166553 biolink:causes MONDO:0012996 infores:clingen CAID:CA270166553 MONDO:0012996 PMID:27233232 Uncertain Significance PM2_Supporting, BP4, PS3_Supporting The NM_001482.3:c.1037C>T variant in GATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 346 (p.Pro346Leu). To our knowledge, this variant has not been reported in the literature in any individuals with AGAT deficiency. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002545 (3/1178764 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). Expression of the variant in HeLa cells resulted in <10% wild type AGAT activity indicating that this variant may impact protein function (PMID 27233232)(PS3_Supporting). The computational predictor REVEL gives a score of 0.237 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (PMID: 36413997), and SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, PS3_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA270166553/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36795 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0029408 infores:hetionet CHEBI:36795 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0026821 infores:hetionet CAID:CA512341226 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341226 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1203C>G (p.Pro401=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-4.12) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341226/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2704 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0232461 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0234913 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0042134 infores:hetionet CHEBI:47612 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0027497 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0029456 infores:hetionet CHEBI:45863 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0262662 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0413252 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005741 infores:hetionet UNII:T58MSI464G biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0687713 infores:hetionet CHEBI:53760 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085688 infores:hetionet CHEBI:119486 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0033687 infores:hetionet CHEBI:3723 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0086439 infores:hetionet CHEBI:5790 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020625 infores:hetionet CHEBI:15428 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0012833 infores:hetionet CHEBI:52172 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0235266 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C2047937 infores:hetionet CHEBI:46557 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027497 infores:hetionet CHEBI:27882 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0858635 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042571 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1142412 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235969 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0522251 infores:hetionet CHEBI:9137 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0019270 infores:hetionet CHEBI:46345 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0015230 infores:hetionet CHEBI:49575 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C2830004 infores:hetionet CHEBI:35854 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0542571 infores:hetionet CHEBI:31536 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0035078 infores:hetionet CHEBI:53760 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0542571 infores:hetionet CHEBI:83531 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0013428 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029928 infores:hetionet CHEBI:3510 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0027947 infores:hetionet CHEBI:28864 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0233407 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0267792 infores:hetionet NCBIGene:5339 biolink:causes MONDO:0012807 infores:monarchinitiative not_provided not_provided HGNC:9069 MONDO:0012807 uuid:14b27fd9-af43-4ffb-a895-7d59b6dc47b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63605 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0023380 infores:hetionet UMLS:C0009315 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0027497 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0233494 infores:hetionet CHEBI:144093 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151905 infores:hetionet CAID:CA347208953 biolink:causes MONDO:0015152 infores:clingen CAID:CA347208953 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The NM_003494.4: c.2212C>T p.(Gln738Ter) variant in DYSF, which is also known as NM_001130987.2: c.2266C>T p.(Gln756Ter), is a nonsense variant predicted to cause a premature stop codon in exon 23/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). This variant has been reported in a homozygous state in an individual with known familial consanguinity who displayed features of LGMD including proximal muscle weakness (0.25 pts, PMID: 39548682, LOVD individual #00391981) (PP4; PM3_Supporting not met). The highest allele frequency for this variant is 0.0000008474 in the European (non-Finnish) population of gnomAD v4.1.0 (1/1180024 chromosomes), which is less than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/23/2025): PVS1, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347208953/MONDO:0015152/180 2025-07-23 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63631 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235086 infores:hetionet CHEBI:127780 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151854 infores:hetionet CHEBI:6715 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0030554 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0042109 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0006852 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1698400 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1698400 infores:hetionet CHEBI:9654 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0151827 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0267596 infores:hetionet CAID:CA000114 biolink:causes MONDO:0018875 infores:clingen CAID:CA000114 MONDO:0018875 PMID:11733960 Likely Benign BS3_Supporting, BP4, BS2, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PP3, PP4, PP1 The NM_000546.6: c.322G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 108 (p.Gly108Ser). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; internal lab contributors). This variant received a total of 0.5 points across 1 proband (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000005932 (7/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0347; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting, BS3_Supporting, BP4. (Bayesian Points: -3; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000114/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0145185 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0162429 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0086543 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0037274 infores:hetionet CAID:CA5923496 biolink:causes MONDO:0015152 infores:clingen CAID:CA5923496 MONDO:0015152 PMID: Likely Benign BS1, BP4 BP7 The NM_213599.3: c.2236-21_2236-17del variant in ANO5 is an intronic deletion. The filtering allele frequency for this variant is 0.001514 for the African/African American population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 59/31020 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0, which is less than the VCEP threshold of 0.05 (BP4). Because this variant occurs in a splice region (+7/-21), BP7 is not applicable. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5923496/MONDO:0015152/188 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5384 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0000737 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0541832 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0274702 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0274702 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0029445 infores:hetionet CAID:CA226374 biolink:causes MONDO:0100437 infores:clingen CAID:CA226374 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1747G>T (p.Glu583Ter) is a nonsense variant introducing a premature stop in codon 583 within exon 14 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 14564670, PMID: 17325176). However, the PS4_Supporting code requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226374/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:17347 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0003864 infores:hetionet CAID:CA902270 biolink:causes MONDO:0100368 infores:clingen CAID:CA902270 MONDO:0100368 PMID: Uncertain Significance BP4, PM2_Supporting PM3 NM_000329.3(RPE65):c.1129-5C>T is an intronic variant -5 from exon 11 and has only been reported once to date in published literature. There is no computational predictor REVEL score for the variant NM_000329.3(RPE65):c.1129-5C>T. The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4 met). This variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00003454, with 11 alleles/127858 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_supporting threshold of <0.0002 (PM2_Supporting). A published report (PMID:35569774) described a proband with recessive RP (proband P7) heterozygous for the c.1129-5C>T variant but failed to find any additional variants in RPE65. (PM3_not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for RPE65-related recessive retinopathy due to insufficient evidence based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP with a total combined score of 0: BP4, PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902270/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4995 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0042963 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0024299 infores:hetionet CHEBI:42355 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0022346 infores:hetionet CHEBI:6067 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235896 infores:hetionet CHEBI:6015 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0085612 infores:hetionet CAID:CA6832097 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832097 MONDO:0015967 PMID: Uncertain Significance BS1, PP1_Moderate, PP3, PP4 PS4, PS3, BS3, BS2 The c.1513C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to asparagine at codon 505 (p.(His505Asn)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.7549, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.His505Asn protein has transactivation 54% of wildtype and nuclear localization 64% of WT; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 27899486). This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00003748, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). This variant was identified in at least 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31595705, PMID: 29207974, internal lab contributor). One of these individuals has a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID: 31595705). Additionally, the variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; PMID: 31595705, internal lab contributor). This variant has also been identified in multiple normoglycemic individuals, however they are under age 70 and therefore BS2 cannot be applied (PMID: 27899486, internal lab contributor). In summary, the c.1513C>A variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1, PP1_Moderate, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832097/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151205 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0424000 infores:hetionet CHEBI:39867 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020672 infores:hetionet CHEBI:75246 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020615 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0027769 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0795692 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0013395 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0342579 infores:hetionet CAID:CA10014218 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014218 MONDO:0011071 PMID: Uncertain Significance PS3, PS2, PS1, PS4, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1034C>G (p.Pro345Arg) is a missense variant. The variant is present in gnomAD v.4.1.0. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014218/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6887 biolink:causes UMLS:C0232288 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0232288 infores:hetionet CHEBI:84500 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0002962 infores:hetionet CHEBI:63631 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0851578 infores:hetionet CAID:CA135978 biolink:causes MONDO:0021060 infores:clingen CAID:CA135978 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.357C>T (p.Asp119=) variant in the HRAS gene is 0.129% (102/66416) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135978/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:1028 biolink:causes MONDO:0007534 infores:monarchinitiative not_provided not_provided HGNC:1786 MONDO:0007534 uuid:13c5edfa-3b0c-40cf-af92-aef0a0784f6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127780 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0004134 infores:hetionet CHEBI:6067 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0016199 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0948525 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0036572 infores:hetionet CHEBI:3716 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0040034 infores:hetionet CHEBI:3228 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0085631 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0034063 infores:hetionet CAID:CA314590 biolink:causes MONDO:0100040 infores:clingen CAID:CA314590 MONDO:0100040 PMID: Benign BP5_Strong, BS2, BA1 PM1 The allele frequency of the p.Pro198= variant in FOXG1 is 0.04% in African sub population in gnomAD v2.1.1, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Pro198= variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro198= variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx internal database) (BP5_strong). The p.Pro198= variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene; however, as this is a synonymous change, there would be no affect on the amino acid sequence of the functional domain (PM1 not met). In summary, the p.Pro198= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314590/MONDO:0100040/035 2024-04-18 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0010592 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0030193 infores:hetionet CHEBI:94501 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0003862 infores:hetionet CHEBI:50378 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0040034 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151773 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0238106 infores:hetionet NCBITaxon:2060905 biolink:causes MONDO:0000239 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2060905 MONDO:0000239 CHEBI:31981 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C2242588 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0006840 infores:hetionet CHEBI:75922 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0022081 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0038814 infores:hetionet CHEBI:3213 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0027497 infores:hetionet NCBIGene:790955 biolink:causes MONDO:0014496 infores:monarchinitiative not_provided not_provided HGNC:34399 MONDO:0014496 uuid:75d60091-4b34-4f27-98d7-fb1fb1d21201 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:93305 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0041834 infores:hetionet CHEBI:3698 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0542571 infores:hetionet CHEBI:6062 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0035243 infores:hetionet CHEBI:9352 biolink:causes MONDO:0004835 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0238124 infores:hetionet CHEBI:478164 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0013378 infores:hetionet CHEBI:63617 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027497 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0020649 infores:hetionet CHEBI:10023 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0392156 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0456909 infores:hetionet CHEBI:7936 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038220 infores:hetionet CHEBI:94449 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0026961 infores:hetionet CHEBI:8024 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1456822 infores:hetionet CHEBI:3716 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0687713 infores:hetionet CHEBI:9139 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2830004 infores:hetionet CHEBI:51450 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0015967 infores:hetionet CHEBI:3757 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0018418 infores:hetionet CHEBI:3387 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162275 infores:hetionet CHEBI:4909 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0014457 infores:hetionet NCBIGene:1282 biolink:causes MONDO:0032814 infores:monarchinitiative not_provided not_provided HGNC:2202 MONDO:0032814 uuid:0f6e85f7-4641-41e4-8a73-c19a639ef178 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64198 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0037036 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0037199 infores:hetionet CHEBI:63621 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004093 infores:hetionet CHEBI:125354 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0004936 infores:hetionet CHEBI:48844 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0040264 infores:hetionet GO:0006954 biolink:causes MONDO:0006814 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D007500 DB00253_MESH_D007500_1 CHEBI:135888 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0016436 infores:hetionet NCBIGene:6323 biolink:causes MONDO:0011461 infores:monarchinitiative not_provided not_provided HGNC:10585 MONDO:0011461 uuid:f1520fa8-c549-4bae-a67a-21d6f147d258 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0030193 infores:hetionet CHEBI:31711 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0010520 infores:hetionet CHEBI:4672 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0008031 infores:hetionet CHEBI:2379 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0003467 infores:hetionet CHEBI:50659 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0042384 infores:hetionet CHEBI:5384 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0232462 infores:hetionet CAID:CA350341741 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341741 MONDO:0015924 PMID: Likely Pathogenic PM5_Supporting, PP3, PM2_Supporting, PM1_Strong PP1, BP4 The c.1157A>T (p.Glu386Val) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The variant has been reported once in an FPAH subject (PMID: 18364108) (PS4 not met). The REVEL prediction algorithm score is 0.99, the AlphaMissense score is 0.996 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Ala/Gln/Gly/Lys) have been reported at the same position (PMIDs: 18503968, 21801371, 23675998 and 26387786) (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341741/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CAID:CA229830 biolink:causes MONDO:0009861 infores:clingen CAID:CA229830 MONDO:0009861 PMID:23514811PMID:22921945 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS1 The c.865G>C (p.Gly289Arg) variant in PAH is absent from population databases and predicted deleterious with in silico prediction software. This is the same amnio acid change as a previously established pathogenic variant (c.865G>A; p.Gly289Arg). It has been identified in trans with a pathogenic variant (R155C, curated by the PAH EP), and a defect in BH4 metabolism was excluded (PMID: 22921945). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS1, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229830/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:42944 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0086543 infores:hetionet CHEBI:31705 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0012569 infores:hetionet CHEBI:5864 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0151686 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0027441 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0854144 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0854144 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0020517 infores:hetionet CHEBI:6062 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235198 infores:hetionet CAID:CA410148836 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148836 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.968-2A>G is a splice site variant which is predicted to cause an acceptor loss. This change affects 33% of the remaining protein and is not predicted to impact NMD (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148836/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50730 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0004936 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0018213 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042401 infores:hetionet CHEBI:499361 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0013404 infores:hetionet CHEBI:31622 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0033975 infores:hetionet CHEBI:6690 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0520966 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0152128 infores:hetionet CHEBI:16899 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0006277 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0032584 infores:hetionet CHEBI:63607 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0017152 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1096036 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096036 infores:hetionet CHEBI:64355 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0234146 infores:hetionet CHEBI:49040 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0030196 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0028077 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011849 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0030305 infores:hetionet NCBIGene:478 biolink:causes MONDO:0011038 infores:monarchinitiative not_provided not_provided HGNC:801 MONDO:0011038 uuid:2cb1b631-23c7-428f-9714-d33b0b180117 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0277890 infores:hetionet CAID:CA135067 biolink:causes MONDO:0021060 infores:clingen CAID:CA135067 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1332G>A (p.Arg444=) variant in the BRAF gene is 0.077% (64/66708) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135067/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8768 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042109 infores:hetionet CHEBI:7852 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0039231 infores:hetionet CHEBI:94501 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0019521 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0017574 infores:hetionet CHEBI:17026 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151671 infores:hetionet CHEBI:9763 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0232462 infores:hetionet CHEBI:5118 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0004144 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013395 infores:hetionet CHEBI:3082 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0423006 infores:hetionet CHEBI:71255 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0002792 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0162429 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0233459 infores:hetionet CHEBI:3994 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0233407 infores:hetionet CHEBI:7798 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0004093 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0023533 infores:hetionet CHEBI:43968 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0002792 infores:hetionet CHEBI:567361 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1443060 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0027441 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0006145 infores:hetionet CHEBI:6801 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C2697368 infores:hetionet CHEBI:10102 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0004604 infores:hetionet UMLS:C0657912 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1510410 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0033975 infores:hetionet CHEBI:63613 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C2047937 infores:hetionet CHEBI:16467 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0011603 infores:hetionet CHEBI:474053 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0151872 infores:hetionet UMLS:C1738934 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085636 infores:hetionet CHEBI:8207 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0008350 infores:hetionet CHEBI:8499 biolink:causes MONDO:0002465 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0006271 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0006823 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0022735 infores:hetionet CHEBI:465284 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0162830 infores:hetionet CAID:CA415169023 biolink:causes MONDO:0010726 infores:clingen CAID:CA415169023 MONDO:0010726 PMID: Pathogenic PM2_Supporting, PM5_Strong, PS2 BP4, PP3 The p.Lys304Asn variant in MECP2 (NM_004992.3) is absent from gnomAD v2 (PM2_supporting). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID: 23770565, PMID: 16077736, PMID: 16473305, RettBASE) (PM5_strong). The p.Lys304Asn variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Rett syndrome (internal database - Invitae) (PS2). In summary, the p.Lys304Asn variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM2_supporting, PM5_strong, PS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415169023/MONDO:0010726/036 2024-02-23 2024-06-27 X-linked inheritance HP:0001417 Supports CHEBI:53766 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0237849 infores:hetionet CHEBI:145499 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003862 infores:hetionet CAID:CA658658495 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658495 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS4, BS1, BS3, PM3, PM4, PM1, PM6, BS2, PP4, PP1, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1948_1949del p.(Ile650fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658495/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:43968 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0042267 infores:hetionet CHEBI:9434 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0025222 infores:hetionet CHEBI:5141 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0151734 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0021843 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0178298 infores:hetionet CHEBI:6715 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0917801 infores:hetionet CHEBI:8805 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0178298 infores:hetionet CAID:CA074266 biolink:causes MONDO:0100150 infores:clingen CAID:CA074266 MONDO:0100150 PMID: Uncertain Significance PP3, BP4, BA1, BS1, PM2 The c.9874C>T variant in RYR1 is a missense variant predicted to cause substitution of proline by serine at amino acid 3292 (p.Pro3292Ser). The filtering allele frequency (the lower threshold of the 95% CI of 10/126442) of the c.9874C>T variant in RYR1 is 0.00004204 for European (non-Finnish) chromosomes by gnomAD v4.1 (BA1, BS1, PM2 not met). The computational predictor REVEL gives a score of 0.346, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. In summary, this variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: None. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA074266/MONDO:0100150/150 2024-08-27 2025-01-03 Undetermined mode of inheritance Inconclusive true UNII:UMD7G2653W biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0036416 infores:hetionet CHEBI:82960 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0022661 infores:hetionet CHEBI:6413 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0030193 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0857121 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022408 infores:hetionet CHEBI:39585 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0020580 infores:hetionet CHEBI:31536 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0085932 infores:hetionet CHEBI:64312 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0234632 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0149931 infores:hetionet CHEBI:44423 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C2047937 infores:hetionet CHEBI:567361 biolink:causes HP:0032061 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0745091 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0029408 infores:hetionet CHEBI:9649 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0023530 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1096106 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1096106 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235032 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0242350 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0332534 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0746883 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002420 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0040188 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0152029 infores:hetionet CHEBI:16664 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0162557 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038367 infores:hetionet CAID:CA2580101804 biolink:causes MONDO:0010305 infores:clingen CAID:CA2580101804 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong, PS4_Moderate, PS2 The NM_005629.4:c.1519_1543del (p.Ile507LeufsTer5) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in a male proband with elevated urine creatine/creatinine and reduced creatine peak on brain MRS (PP4_Strong) and was found to be a de novo variant in this individual (PS2) (PMID: 23534590). This variant has also been reported in two additional unrelated male probands (PMID: 21660517, PMID: 23234264) (PS4_Moderate). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1703957). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PS2, PS4_Moderate, PM2_Supporting, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP: August 10, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580101804/MONDO:0010305/027 2023-08-10 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:64045 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0011991 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0019158 infores:hetionet CHEBI:8502 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0151436 infores:hetionet CHEBI:31348 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0030196 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0855242 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0854193 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0854193 infores:hetionet CHEBI:72292 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0009782 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0033975 infores:hetionet CHEBI:45863 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0026821 infores:hetionet CHEBI:4975 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0038325 infores:hetionet CHEBI:6367 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0236075 infores:hetionet CAID:CA386959510 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959510 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3, PP4 PP1 The c.397G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 133 (p.(Val133Leu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.947, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v4.1.0 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). Another missense variant, c.397G>A (p.Val133Met), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.397G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP3, PP4, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959510/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8863 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0025637 infores:hetionet CHEBI:50567 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0340464 infores:hetionet CHEBI:5775 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0035357 infores:hetionet CHEBI:7476 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C2363731 infores:hetionet CHEBI:5847 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0035078 infores:hetionet CHEBI:10112 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C1443060 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0003864 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0000833 infores:hetionet GO:2000039 biolink:causes GO:0010026 infores:ubergraph knowledge_assertion manual_agent GO:2000039 GO:0010026 CHEBI:63580 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235939 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0007787 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017566 infores:hetionet CHEBI:28748 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042023 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0038358 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0022650 infores:hetionet CHEBI:3506 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0030193 infores:hetionet CHEBI:84500 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233407 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0041912 infores:hetionet CHEBI:27899 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0009763 infores:hetionet CAID:CA2580610837 biolink:causes MONDO:0700270 infores:clingen CAID:CA2580610837 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.5366del (p.Leu1789Argfs*4) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.4.1.0. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610837/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28901 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0011606 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151602 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0018802 infores:hetionet CHEBI:45951 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0004096 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0855242 infores:hetionet CHEBI:61033 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0021843 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0948333 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0948333 infores:hetionet CHEBI:51860 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013604 infores:hetionet CHEBI:6640 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0030193 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0235818 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0003123 infores:hetionet CHEBI:31623 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0016436 infores:hetionet CHEBI:6061 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0428977 infores:hetionet CHEBI:31711 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0023052 infores:hetionet CHEBI:3423 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0003467 infores:hetionet NCBIGene:9675 biolink:causes MONDO:0957531 infores:monarchinitiative not_provided not_provided HGNC:29029 MONDO:0957531 uuid:071741f6-8de5-412d-ba4a-7c365b5c5925 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905557 biolink:causes GO:0006998 infores:ubergraph knowledge_assertion manual_agent GO:1905557 GO:0006998 CHEBI:135736 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151878 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0020517 infores:hetionet CHEBI:3504 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C1306341 infores:hetionet CHEBI:9587 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0019080 infores:hetionet CHEBI:4907 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0023218 infores:hetionet CHEBI:71219 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0221201 infores:hetionet CHEBI:291342 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0015967 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0018799 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0235234 infores:hetionet CHEBI:3723 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2979982 infores:hetionet CHEBI:84500 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042023 infores:hetionet NCBIGene:5663 biolink:causes MONDO:0010857 infores:monarchinitiative not_provided not_provided HGNC:9508 MONDO:0010857 uuid:f73dfa76-0ad6-4143-a15c-f79adc7d7481 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5280 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0423791 infores:hetionet CHEBI:17303 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0001973 infores:hetionet NCBIGene:50964 biolink:causes MONDO:0010016 infores:monarchinitiative not_provided not_provided HGNC:13771 MONDO:0010016 uuid:307848f9-f00f-462b-a94b-579cacb28c4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0700361 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0340726 infores:hetionet CHEBI:63580 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0033247 infores:hetionet CHEBI:8884 biolink:causes UMLS:C1258192 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C1258192 infores:hetionet CHEBI:31859 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0004096 infores:hetionet CAID:CA16028084 biolink:causes MONDO:0021056 infores:clingen CAID:CA16028084 MONDO:0021056 PMID: Likely Pathogenic PM5_Supporting, PP1_Moderate, PS4_Moderate, PM2_Supporting The NM_000038.6:c.3083G>A variant in APC is a missense variant predicted to cause the substitution of serine to asparagine at amino acid position 1028 (p.Ser1028Asn). This variant has been reported in 4 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate; internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one individual with colorectal cancer in the family history (internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). This variant has been reported to segregate with FAP in 5 meioses in 2 families (PP1_Moderate; internal data Ambry Genetics and Peter MacCallum Cancer Centre, Victoria, Australia). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants (c.3084T>A and c.3083G>T) in the same codon leading to a different amino acid change at this position (p.Ser1028Arg; p.Ser1028Ile) have been classified as Likely Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS4_Moderate, PP1_Moderate, PM2_Supporting and PM5_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16028084/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports GO:1903132 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:1903132 GO:0035295 CHEBI:17698 biolink:causes UMLS:C0270276 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0270276 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151883 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0149931 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0233472 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0019348 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0027765 infores:hetionet CHEBI:47381 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0687713 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0002871 infores:hetionet CHEBI:68841 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0012833 infores:hetionet CHEBI:23765 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002622 infores:hetionet CHEBI:45951 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0007398 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0004691 infores:hetionet CHEBI:50223 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0041657 infores:hetionet CHEBI:27446 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0302295 infores:hetionet CHEBI:31625 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0009763 infores:hetionet CHEBI:3640 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0017979 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151740 infores:hetionet CHEBI:68478 biolink:causes MONDO:0009421 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151721 infores:hetionet CHEBI:63621 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0003862 infores:hetionet CAID:CA415075865 biolink:causes MONDO:0010305 infores:clingen CAID:CA415075865 MONDO:0010305 PMID:17465020 Uncertain Significance PM2_Supporting, BP4 BS3, PP4 The NM_005629.4:c.11A>G variant in SLC6A8 is predicted to result in the missense substitution of lysine by arginine at amino acid 4 (p.Lys4Arg). The variant has been reported in a 15 year old hemizygous male with intellectual disability. Results of urine creatine level, creatine level on brain MRS, and creatine uptake studies are not available. There is insufficient evidence to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). When the variant was expressed in SLC6A8-deficient fibroblasts and creatine uptake was measured, the variant was reported to be non-pathogenic (Table 2). Compared to empty vector, expression of the variant increased creatine transport about 5 times, and expression of wild type SLC6A8 increased creatine transport about 6 times. However, because the assay was performed with 500uM creatine, and not <125uM (as required by the ClinGen CCDS VCEP), BS3 is not met. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.2, evidence that does not predict a damaging effect on SLC6A8 function (BP4). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes applied, as specified by the ClinGen CCDS VCEP: PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on January 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415075865/MONDO:0010305/027 2024-01-11 2024-03-25 X-linked inheritance HP:0001417 Inconclusive true CHEBI:91583 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0027765 infores:hetionet CHEBI:4024 biolink:causes HP:0011484 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0152253 infores:hetionet CHEBI:64019 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0020443 infores:hetionet CHEBI:135930 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0036974 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0020517 infores:hetionet CHEBI:9570 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151539 infores:hetionet CHEBI:4975 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0018965 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0162119 infores:hetionet CHEBI:8245 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0687713 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0011603 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0852990 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0852990 infores:hetionet CHEBI:4657 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0012569 infores:hetionet CHEBI:2569 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0018790 infores:hetionet CHEBI:51364 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151766 infores:hetionet CHEBI:3561 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0025222 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0403632 infores:hetionet CHEBI:3756 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C1142135 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011991 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0687133 infores:hetionet CHEBI:38940 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0030196 infores:hetionet NCBIGene:4488 biolink:causes MONDO:0008197 infores:monarchinitiative not_provided not_provided HGNC:7392 MONDO:0008197 uuid:6a4c0830-b6fd-42f5-aff0-cdbf6fb24ef7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9073 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C1306341 infores:hetionet CHEBI:50729 biolink:causes UMLS:C2363980 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C2363980 infores:hetionet CHEBI:49662 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0002994 infores:hetionet CHEBI:63632 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C2939419 infores:hetionet CHEBI:3732 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0008031 infores:hetionet CHEBI:49662 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C2047937 infores:hetionet UMLS:C0009315 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0040264 infores:hetionet NCBIGene:9987 biolink:causes MONDO:0012193 infores:monarchinitiative not_provided not_provided HGNC:5037 MONDO:0012193 uuid:4f313bb2-42cc-4d9c-93c7-f4ed45970f06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1443060 infores:hetionet CAID:CA6327349 biolink:causes MONDO:0019497 infores:clingen CAID:CA6327349 MONDO:0019497 PMID:31163360 Pathogenic PM3_Supporting, PM2_Supporting, PVS1 BP5 The c.4085G>A (p.Trp1362Ter) nonsense variant in TECTA is predicted to cause a premature stop codon in biologically-relevant exon 11 of 23 total exons, leading to a truncated or absent protein in a gene in which loss of function is an established mechanism of autosomal recessive nonsyndromic hearing loss (PVS1; PMID: 30192042). This variant is present in 0.01121% (14/124864) of non-Finnish European chromosomes in gnomAD v2 (PM2_Supporting). It has been observed in at least two probands presenting with nonsyndromic hearing loss (PMID: 31163360; LMM internal data SCV000711208.2). One individual harbored another nonsense variant in TECTA, which was suspected to be pathogenic (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6327349/MONDO:0019497/005 2020-01-21 2020-01-22 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf GO:0014725 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:0014725 GO:0043010 CHEBI:6909 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1963790 infores:hetionet NCBIGene:83932 biolink:causes MONDO:0014527 infores:monarchinitiative not_provided not_provided HGNC:25356 MONDO:0014527 uuid:637f2d49-30db-498a-aadb-238ee478dc25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0022408 infores:hetionet CAID:CA1589161 biolink:causes MONDO:0021060 infores:clingen CAID:CA1589161 MONDO:0021060 PMID: Benign BA1 The c.53-9G>A variant in PPP1CB is an intronic splicing variant located in intron 1 of PPP1CB. The filtering allele frequency in gnomAD v2 is 0.5284% in the African American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1. (RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1589161/MONDO:0021060/128 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42820 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0031256 infores:hetionet CAID:CA631301069 biolink:causes MONDO:0012999 infores:clingen CAID:CA631301069 MONDO:0012999 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000156.6:c.91_92insCACGG (Asp31AlafsTer13) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 1 out of a total of 6 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005621 (2/35578 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with GAMT deficiency. There is a ClinVar entry for this variant (Variation ID: 939992). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on October 7, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631301069/MONDO:0012999/026 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013456 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022904 infores:hetionet CHEBI:474180 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0027424 infores:hetionet CHEBI:18067 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0012833 infores:hetionet CHEBI:5296 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0151766 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0855242 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0009806 infores:hetionet CAID:CA10385246 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385246 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.2808A>T (p.Glu936Asp) is a missense variant causing substitution of glutamic acid by aspartic acid at amino acid 936. This variant is present in gnomAD v4.1.0 at a frequency of 0.0003934 among hemizygous individuals, with 35 variant alleles / 88,973 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.064, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385246/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:9445 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0232462 infores:hetionet NCBIGene:6840 biolink:causes MONDO:0033620 infores:monarchinitiative not_provided not_provided HGNC:11480 MONDO:0033620 uuid:bd32373c-f7eb-4cba-8851-2d61a1f02d92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0243026 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0029882 infores:hetionet CHEBI:9725 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0686347 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0086543 infores:hetionet CHEBI:408174 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0010200 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0037274 infores:hetionet CHEBI:9168 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0595929 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0232492 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0234894 infores:hetionet NCBIGene:1111 biolink:causes MONDO:0957961 infores:monarchinitiative not_provided not_provided HGNC:1925 MONDO:0957961 uuid:e07c15b4-0c8b-45a0-8073-a2423e899839 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018681 infores:hetionet CHEBI:63617 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0542571 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0014549 infores:hetionet CHEBI:64064 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0151825 infores:hetionet CHEBI:39867 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0016655 infores:hetionet CHEBI:8871 biolink:causes MONDO:0020439 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0016522 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0853149 infores:hetionet NCBIGene:1503 biolink:causes MONDO:0014391 infores:monarchinitiative not_provided not_provided HGNC:2519 MONDO:0014391 uuid:6d86a70d-7b34-44cc-9bac-7c3237afffad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0332534 infores:hetionet CHEBI:40279 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0015967 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0233414 infores:hetionet CHEBI:32293 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C3665347 infores:hetionet CHEBI:75045 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0235325 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0027769 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0004096 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0231528 infores:hetionet CHEBI:50673 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C1320835 infores:hetionet NCBIGene:51750 biolink:causes MONDO:0014076 infores:monarchinitiative not_provided not_provided HGNC:15888 MONDO:0014076 uuid:2bdda30d-9ac1-4d70-8ad2-10fdb324cda0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0518015 infores:hetionet CHEBI:6375 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020625 infores:hetionet CHEBI:291342 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0311468 infores:hetionet GO:0046668 biolink:causes GO:0048468 infores:ubergraph knowledge_assertion manual_agent GO:0046668 GO:0048468 CHEBI:94609 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0037023 infores:hetionet CHEBI:63618 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151905 infores:hetionet CHEBI:7824 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0232461 infores:hetionet CHEBI:15552 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0011991 infores:hetionet CHEBI:50663 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0019080 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0233494 infores:hetionet CAID:CA16616762 biolink:causes MONDO:0021060 infores:clingen CAID:CA16616762 MONDO:0021060 PMID:21387466PMID:29625050 Likely Pathogenic PS4_Moderate, PM1_Strong, PP3, PP2 PS2, PS1, PS3, PM5, PM4, BS3, BS4, BS1, BP7, BP5, PM6, PM2, BS2, PP1, BP3, BP2, BP4, BP1, BA1 The c.1655G>T (p.Arg552Met) variant has been identified in at least 3 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx internal data; GTR Lab IDs 26957; SCV000565586.5 PMID: 21387466). his AA residue has been specified as a hotspot for variation. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Met variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616762/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:135005 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0549418 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0227791 infores:hetionet CHEBI:50692 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0231218 infores:hetionet NCBIGene:80308 biolink:causes MONDO:0009703 infores:monarchinitiative not_provided not_provided HGNC:24671 MONDO:0009703 uuid:5f4067fb-d29a-4b6b-9446-b1c1f62b00ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0015230 infores:hetionet CAID:CA023615 biolink:causes MONDO:0007750 infores:clingen CAID:CA023615 MONDO:0007750 PMID: Uncertain Significance PM2 PS1, BS3, PM5, PM1, PP3 The NM_000527.5(LDLR):c.1954A>G (p.Met652Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow:PM2_Met : Allele frequency is 0.00002 in European (Non-Finnish) subpopulation (>129178 alleles tested) in GnomAD (gnomAD v2.1.1). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023615/MONDO:0007750/013 2022-12-23 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UMLS:C0145185 biolink:causes UMLS:C1412000 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C1412000 infores:hetionet CHEBI:71219 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0019061 infores:hetionet CHEBI:5001 biolink:causes MONDO:0024647 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0451641 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0027769 infores:hetionet CHEBI:135961 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C1096355 infores:hetionet CHEBI:3387 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0085631 infores:hetionet CHEBI:5001 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0311468 infores:hetionet NCBITaxon:727 biolink:causes GO:0042710 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:727 GO:0042710 DB06151_MESH_D001991_1 CHEBI:16714 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0000729 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020461 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0027769 infores:hetionet CHEBI:50922 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0423791 infores:hetionet NCBIGene:64388 biolink:causes MONDO:0014999 infores:monarchinitiative not_provided not_provided HGNC:17655 MONDO:0014999 uuid:a74e6ea9-ec39-4146-b120-8b45b64e7d4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0024282 infores:hetionet CHEBI:45979 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0013395 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0852913 infores:hetionet CHEBI:32315 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0019270 infores:hetionet CHEBI:63630 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085583 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0009450 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0003864 infores:hetionet CAID:CA405694199 biolink:causes MONDO:0018493 infores:clingen CAID:CA405694199 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tryptophan with cysteine at codon 5020 of the RYR1 protein, p.(Trp5020Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:25960145). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.892) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405694199/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBITaxon:186817 biolink:causes MONDO:0006923 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:186817 MONDO:0006923 CAID:CA658820706 biolink:causes MONDO:0009276 infores:clingen CAID:CA658820706 MONDO:0009276 PMID:10928479 Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PM4, PP1_Moderate, PS3_Supporting The c.584_586del (p.Leu195del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (PM4). At least one patient (Patient H.S. in PMID: 7873390) with this variant had aggregation absent for ristocetin and present for all other agonists. Flow cytometry assays found reduced surface expression of GP1BA on the proband's platelets and Western blot analysis found that GP1BA expression was absent in the patient. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). The variant has been reported to segregate in the proband plus 2 additional homozygous BSS affected siblings (PMID: 7873390, 2 points, PP1_Moderate). Surface expression of GP1a measured by flow cytometry in CHO cells transiently co-transfected with p.Leu195del variant GPIb-IX complexes and wild type GPIb-IX complexes showed decreased expression at 20% (<25%) WT levels, indicating that this variant impacts protein function (PMID: 10928479 )(PS3_supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_Supporting, PP1_Moderate, PM4, PP4, PM2_Supporting and PM3_Supporting (VCEP specifications version 1.0.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658820706/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:32184 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0152030 infores:hetionet NCBIGene:1719 biolink:causes MONDO:0013456 infores:monarchinitiative not_provided not_provided HGNC:2861 MONDO:0013456 uuid:252a15f7-7f33-47a3-a1ea-8780a3fb5454 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6909 biolink:causes MONDO:0032607 infores:monarchinitiative not_provided not_provided HGNC:11597 MONDO:0032607 uuid:bd9e91d3-a90d-473f-9e9f-2798bc39adfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges HGNC:5716 biolink:causes MONDO:0013576 infores:monarchinitiative not_provided not_provided HGNC:5716 MONDO:0013576 uuid:ad65486b-796b-4d61-ab35-fdd9004d9d9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3380 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0233494 infores:hetionet CHEBI:35778 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085624 infores:hetionet CHEBI:31644 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0018524 infores:hetionet CHEBI:145499 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013491 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0948525 infores:hetionet CHEBI:5103 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0235546 infores:hetionet CHEBI:72564 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1368065 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0004096 infores:hetionet CHEBI:51380 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0027441 infores:hetionet CHEBI:51141 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0004604 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0085762 infores:hetionet CHEBI:38940 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0041364 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0029456 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0743525 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0743525 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011609 infores:hetionet CAID:CA025129 biolink:causes MONDO:0012933 infores:clingen CAID:CA025129 MONDO:0012933 PMID: Benign BP5_Strong, BS1, BP7_Strong, BP4 The c.7521A>G variant in BRCA2 is a synonymous variant (p.Pro2507=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003057 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 24489791), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.01 (based on Cosegregation LR=0.01), within the thresholds for Strong benign evidence (LR ≥0.00285 & <0.05) (BP5_Strong met; PMID: 24489791).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP4, BP7_Strong (RNA), BP5_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025129/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5106 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0015230 infores:hetionet CHEBI:3219 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0877303 infores:hetionet CHEBI:10102 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0027796 infores:hetionet CAID:CA160243 biolink:causes MONDO:0010938 infores:clingen CAID:CA160243 MONDO:0010938 PMID: Benign BA1 NM_000215.4(JAK3):c.3268G>A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1090 (p.Ala1090Thr). The filtering allele frequency (the lower threshold of the 95% CI of 373/75020) of the c.3268G>A variant in JAK3 is 0.004556 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160243/MONDO:0010938/121 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:490877 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0020456 infores:hetionet NCBIGene:4919 biolink:causes MONDO:0033200 infores:monarchinitiative not_provided not_provided HGNC:10256 MONDO:0033200 uuid:c7c07c68-be61-4e34-bf1d-3b1cfdbf01f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5130 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0023518 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0003123 infores:hetionet CHEBI:9637 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0242350 infores:hetionet CHEBI:499361 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0023380 infores:hetionet CHEBI:52717 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042847 infores:hetionet CHEBI:31536 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C1328337 infores:hetionet CAID:CA2918272 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918272 MONDO:0015152 PMID: Benign PP3, BA1 The NM_000232.5: c.799C>T variant in SGCB is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 267 (p.Arg267Cys). The filtering allele frequency of this variant is 0.01396 in the South Asian population in gnomAD v2.1.1 (the lower threshold of the 95% CI of 462/30614 exome chromosomes), which is higher than the LGMD VCEP threshold (>0.002) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.75, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the predictive pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BA1, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918272/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6887 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013447 infores:hetionet CHEBI:9599 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0085649 infores:hetionet CHEBI:5118 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020578 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0006826 infores:hetionet NCBIGene:63929 biolink:causes MONDO:0013163 infores:monarchinitiative not_provided not_provided HGNC:28052 MONDO:0013163 uuid:1c1814ba-67f4-45d8-a0a9-3b8d5342041e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0010200 infores:hetionet CHEBI:8871 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009676 infores:hetionet CHEBI:3228 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C1443060 infores:hetionet CHEBI:45409 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020473 infores:hetionet CHEBI:7773 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0016204 infores:hetionet CHEBI:63613 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0027497 infores:hetionet CHEBI:8707 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013378 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0020615 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0243026 infores:hetionet CHEBI:9139 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1761613 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0027765 infores:hetionet CHEBI:38545 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0018681 infores:hetionet NCBIGene:29960 biolink:causes MONDO:0032815 infores:monarchinitiative not_provided not_provided HGNC:16352 MONDO:0032815 uuid:616a959a-3b79-42fa-9183-bdb735fefc79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes UMLS:C0919714 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0919714 infores:hetionet CAID:CA412745793 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745793 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PS4 NM_001034853.2(RPGR):c.122C>G (p.Ser41Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 41 in exon 2 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis from 1 family, but details are not sufficient to meet the PP1 code (PMID: 16969763). This variant has been reported in at least 2 apparently unrelated probands (PMIDs: 34745198, 16969763). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent ERG responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745793/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:31236 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151603 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0152025 infores:hetionet CHEBI:63613 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C2225524 infores:hetionet CHEBI:31932 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0262988 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0040034 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151662 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151735 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038814 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0858635 infores:hetionet CHEBI:135929 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0151602 infores:hetionet CHEBI:70718 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0002792 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0234215 infores:hetionet CHEBI:3749 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0014335 infores:hetionet CHEBI:4903 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0235660 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020538 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0694536 infores:hetionet CAID:CA115928 biolink:causes MONDO:0700270 infores:clingen CAID:CA115928 MONDO:0700270 PMID: Likely Pathogenic PM3_Strong, PS3_Supporting, PP3 BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS2, BP5, BP7, BS1, BS4, BS3, PM1, PM4, PM5, PVS1, PM2, PM6, PP2, PP1, PP4, BS2 The c.8480T>G variant in ATM is a missense variant predicted to cause the substitution of phenylalanine by cysteine at amino acid 2827 (p.Phe2827Cys). This variant has been detected in at least one individual with Ataxia-Telangiectasia, who was described having a mild presentation (PMIDs: 8755918, 9000145, 9463314, 15928302, 19431188, 25040471, 30549301). The highest population minor allele frequency in gnomAD v4.1 is 0.00002196 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). Stable transfection of ATM-based cDNA constructs in an ATM-null lymphoblastoid cell line showed slightly decreased levels of kinase activity (caused by protein instability) indicating that this variant impacts protein function (PMID 19431188). The computational predictor, REVEL, gives a score of 0.889, which is above the threshold of 0.7333, evidence that correlates with impact on ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PS3_Supporting, PM3_Strong, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA115928/MONDO:0700270/020 2025-06-19 2025-07-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31348 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151664 infores:hetionet CAID:CA367398252 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398252 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PP1, PM2_Supporting PP4 The c.1240A>T variant in the glucokinase gene, GCK, results in a premature termination at codon 414 (p.(Lys414Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributors). There was insufficient clinical information on these individuals to evaluate for PP4 (internal lab contributors). In summary, c.1240A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP4_Moderate, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398252/MONDO:0015967/086 2023-09-08 2023-09-08 Semidominant inheritance HP:0032113 Supports CHEBI:63638 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0004936 infores:hetionet CAID:CA8459214 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459214 MONDO:0011132 PMID: Likely Benign BA1 PP3, PP4, BP4 The variant NM_001369369.1(FOXN1):c.382C>T (p.Arg128Trp) is predicted to cause an arginine to tryptophan substitution at amino acid position 128. The variant has a Grpmax allele frequency of 0.005950 based upon the gnomADv4.0 African American subpopulation, which is greater than 0.00447 and thus meets BA1 criteria. The meta predictor Revel predicts a score of 0.616, which is less than 0.644 and greater than 0.290, which does not meet BP4 or PP3 criteria. The variant was found in the heterozygous state in sample 336 from PMID: 31672859 who displayed isolated phenotypes such as low TRECs and low CD4+ count (PP4 not met). In summary this variant meets criteria to be classified as benign for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BA1 as specified by the ClinGen SCID VCEP FOXN1 subgroup, however the ClinGen SCID VCEP has modified the classification to Likely Benign due to the suspicious patient and the remaining possibility that the variant could be associated with isolated immunologic phenotypes such as low TRECs. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459214/MONDO:0011132/113 2024-10-25 2024-10-25 Semidominant inheritance HP:0032113 Contradicts true CHEBI:116278 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0233632 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0232492 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0017601 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C1956346 infores:hetionet CAID:CA233621 biolink:causes MONDO:0015152 infores:clingen CAID:CA233621 MONDO:0015152 PMID:9642272PMID:14578192 Pathogenic PP4_Moderate, PP3, PM3_Very Strong PM2, PS3 The NM_000070.3: c.1468C>T variant in CAPN3 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 490 (p.Arg490Trp). This variant has been detected in at least 18 individuals with limb girdle muscular dystrophy (PMID: 18055493, 10330340, 25214167, 25135358, 26632398, 12461690, 17994539), including in a homozygous state in at least two cases (1.0 pt; PMID: 18055493), confirmed in trans with a pathogenic variant in one case (c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 17994539), and in unknown phase with a pathogenic variant in four cases c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 25135358; c.2279dup p.(Asn760LysfsTer5), 0.5 pts, PMID: 18055493; c.2242C>T p.(Arg748Ter), 0.5 pts, PMID: 25214167) (PM3_Very Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 17994539). The highest population minor allele frequency of this variant is 0.0004598 (4/8700 genome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.84, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA233621/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31623 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0020555 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0037278 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549453 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549453 infores:hetionet CHEBI:2914 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0015230 infores:hetionet CHEBI:167309 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0038587 infores:hetionet CHEBI:7465 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0162298 infores:hetionet CHEBI:36791 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025345 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0948089 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0017152 infores:hetionet GO:1905651 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:1905651 GO:0001944 CHEBI:8356 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040409 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0858678 infores:hetionet NCBIGene:2736 biolink:causes MONDO:0012563 infores:monarchinitiative not_provided not_provided HGNC:4318 MONDO:0012563 uuid:e15c5e83-2bb0-4e91-a31e-fdef448ab7ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8346 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0037036 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0948089 infores:hetionet GO:1904536 biolink:causes GO:0120109 infores:ubergraph knowledge_assertion manual_agent GO:1904536 GO:0120109 NCBIGene:2074 biolink:causes MONDO:0010217 infores:monarchinitiative not_provided not_provided HGNC:3438 MONDO:0010217 uuid:25416bfd-eab1-480d-9d5b-9f12673d23a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151904 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027769 infores:hetionet CHEBI:8888 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0001925 infores:hetionet CHEBI:16899 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C1384353 infores:hetionet CHEBI:51141 biolink:causes UMLS:C2242582 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C2242582 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0021053 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0040034 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0277884 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0277884 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0162429 infores:hetionet CHEBI:8665 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0233763 infores:hetionet CHEBI:3423 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C3263723 infores:hetionet CHEBI:10023 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0341047 infores:hetionet CHEBI:8874 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0392676 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0003123 infores:hetionet CHEBI:10101 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0239739 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1609512 infores:hetionet CHEBI:6149 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0011991 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0037822 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0042029 infores:hetionet CAID:CA631044817 biolink:causes MONDO:0012999 infores:clingen CAID:CA631044817 MONDO:0012999 PMID: Benign BS2, BA1 The NM_000156.6:c.182-265_182-228del variant in GAMT is a 48bp in-frame deletion in an intronic region. The highest population minor allele frequency in gnomAD v2.1.1 is 0.09413 (690/7330 alleles) in the African / African American population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 37 homozygotes for the variant (all African) in gnomAD v2.1.1 which, given the early onset and severity of the phenotype, supports that this variant is not associated with GAMT deficiency (BS2). This variant does not appear to have been reported in the published literature, but is noted in ClinVar (Variation ID: 674232). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BS2.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631044817/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:41423 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0521839 infores:hetionet CHEBI:4974 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0542571 infores:hetionet CAID:CA10014564 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014564 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BP1, BP4, BP2, BP3, BA1, BP7, BP5, BS1, BS4, BS3, PM2, PM6, PVS1, PM3, PM1, PM4, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.238_243del (p.Glu80_Val81del) is an in-frame deletion which does not affect any residues within the Runt Homology Domain (AA 89-204) (PM4 not applied). This variant has not been found in patients meeting the RUNX1 phenotypic criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014564/MONDO:0011071/008 2024-09-24 2024-09-24 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0048395 biolink:causes GO:0048392 infores:ubergraph knowledge_assertion manual_agent GO:0048395 GO:0048392 GO:0010590 biolink:causes GO:0051301 infores:ubergraph knowledge_assertion manual_agent GO:0010590 GO:0051301 CHEBI:31184 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0011603 infores:hetionet CHEBI:681850 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0043352 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0006444 infores:hetionet CHEBI:50173 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085636 infores:hetionet CHEBI:7494 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085606 infores:hetionet CHEBI:7936 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018926 infores:hetionet CAID:CA1139666832 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666832 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*1293A>G is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666832/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:145499 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020578 infores:hetionet NCBIGene:343035 biolink:causes MONDO:0012525 infores:monarchinitiative not_provided not_provided HGNC:19689 MONDO:0012525 uuid:9b7ad6b1-52b7-4a79-9191-e735d4cc68d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16796 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0013395 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0027769 infores:hetionet GO:0099148 biolink:causes GO:0007269 infores:ubergraph knowledge_assertion manual_agent GO:0099148 GO:0007269 CHEBI:37941 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0016204 infores:hetionet CHEBI:6904 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0040264 infores:hetionet CAID:CA13674149 biolink:causes MONDO:0009861 infores:clingen CAID:CA13674149 MONDO:0009861 PMID:24048906 Benign BA1, BP7 BP2 The c.509+101A>C variant in PAH has a MAF of 0.2325 in the gnomAD European (Non-Finnish) population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA13674149/MONDO:0009861/006 2020-09-12 2020-09-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:47780 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0340865 infores:hetionet CHEBI:8597 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0002170 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0234215 infores:hetionet NCBIGene:90268 biolink:causes MONDO:0700338 infores:monarchinitiative not_provided not_provided HGNC:25118 MONDO:0700338 uuid:d80e4a3f-f6bd-4e49-a477-c965fcfe0fc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4551 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0687713 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027651 infores:hetionet CAID:CA023802 biolink:causes MONDO:0007750 infores:clingen CAID:CA023802 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM2, PVS1, PP4 NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PVS1, PS3, PS4, PP1_Strong, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 25 March 2022.The supporting evidence is as follows:PM2 - PopMax MAF = 0.00001759 (0.002%) in European non-Finnish exomes (gnomAD v2.1.1).PVS1 - Variant leads to stop at codon 33, amino-terminal of amino acid 830.PS3 - Two studies contribute to PS3 attribution. One (PMID:2088165) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay performed on Heterologous cells (CHO-ldlA7). FACS, CLSM and WB results in 10% expression, binding and uptake of LDLR which is retained in the ER.PS4 - Variant meets PM2 and is identified in at least 10 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). 8 cases fulfil SB possible criteria and 14 fulfil DLCN >= 6 criteria.PP1_Strong- Variant segregates with phenotype in >6 informative meioses in >1 family [data from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière]: 14 affected family members have the variant.PP4 - Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023802/MONDO:0007750/013 2022-03-25 2024-12-02 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:82941 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0853692 infores:hetionet CHEBI:9328 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0018681 infores:hetionet CAID:CA415169171 biolink:causes MONDO:0010726 infores:clingen CAID:CA415169171 MONDO:0010726 PMID: Uncertain Significance PM2_Supporting, PS2 BP4, PS4, PP3 The p.Leu301Val variant in MECP2 (NM_004992.4) has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Rett syndrome (PMID: 36619507) (PS2). The p.Leu301Val variant in MECP2 (NM_004992.4) is absent from gnomAD v2.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, p.Leu301Val variant in MECP2 (NM_004992.4) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PS2, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415169171/MONDO:0010726/036 2024-06-25 2024-12-19 X-linked inheritance HP:0001417 Inconclusive true CHEBI:50648 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0241136 infores:hetionet CHEBI:63630 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0018790 infores:hetionet NCBIGene:53616 biolink:causes MONDO:0033370 infores:monarchinitiative not_provided not_provided HGNC:201 MONDO:0033370 uuid:a60ee7a8-e942-4655-88df-95a4da9780af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1167965 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0042401 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235467 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C3665347 infores:hetionet NCBIGene:7490 biolink:causes MONDO:0009733 infores:monarchinitiative not_provided not_provided HGNC:12796 MONDO:0009733 uuid:339f243d-6ac7-4261-acd3-a93b5d11c79d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3647 biolink:causes UMLS:C0267516 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0267516 infores:hetionet CHEBI:5613 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0547030 infores:hetionet CHEBI:3215 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0003708 infores:hetionet NCBIGene:5172 biolink:causes MONDO:0010933 infores:monarchinitiative not_provided not_provided HGNC:8818 MONDO:0010933 uuid:c191d4a0-758a-4edf-938c-aa8cc52a9a72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020542 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0855242 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0234215 infores:hetionet CHEBI:72297 biolink:causes UMLS:C1456329 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C1456329 infores:hetionet CAID:CA023773 biolink:causes MONDO:0007750 infores:clingen CAID:CA023773 MONDO:0007750 PMID: Pathogenic PS4, PM3, PM2, PVS1, PP1, PP4 PS3, BS4, PM1 The NM_000527.5(LDLR):c.828C>A (p.Cys276Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PM3, PP1, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:-PVS1: Variant is predicted to result in a stop codon at amino acid 276, which is amino-terminal of amino acid 830.-PS4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID: 32977124, homozygous FH; 1 cases with SB possible FH from PMID: 26036859, and 1 case with FH by MedPed criteria from PMID 21310417).-PM2: This variant is absent from gnomAD (gnomAD v2.1.1).-PM3: Variant identified as homozygous state in an index case with homozygous FH phenotype from PMID: 32977124.-PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).-PP4: Variant meets PM2 and is identified in 12 unrelated index cases (3 cases with Simon-Broome criteria of possible FH and 6 cases with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with DLCN>=6 from PMID: 32977124, homozygous FH; 1 cases with SB possible FH from PMID: 26036859, and 1 case with FH by MedPed criteria from PMID 21310417), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023773/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ NCBIGene:5130 biolink:causes MONDO:0958023 infores:monarchinitiative not_provided not_provided HGNC:8754 MONDO:0958023 uuid:cd820c22-5231-4c0f-8521-abeffe7290fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6444 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0085631 infores:hetionet CHEBI:53760 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0030252 infores:hetionet CHEBI:31705 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0700361 infores:hetionet CHEBI:66899 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0086543 infores:hetionet CHEBI:39867 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020580 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0011991 infores:hetionet CHEBI:28901 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0040053 infores:hetionet CHEBI:64312 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0025345 infores:hetionet CHEBI:40050 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C2129214 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0024115 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151736 infores:hetionet CHEBI:6887 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027497 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0010692 infores:hetionet CHEBI:63631 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0338656 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0038362 infores:hetionet CHEBI:50859 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0009676 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0011991 infores:hetionet CHEBI:6775 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0030252 infores:hetionet CHEBI:68558 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018926 infores:hetionet CHEBI:10650 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0240735 infores:hetionet NCBIGene:1298 biolink:causes MONDO:0013666 infores:monarchinitiative not_provided not_provided HGNC:2218 MONDO:0013666 uuid:aaec3e8b-a3e0-4734-b439-f653a7b4c42a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0003467 infores:hetionet CHEBI:6715 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0086565 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0032285 infores:hetionet CHEBI:63630 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0022107 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0015230 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009443 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0155709 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0155709 infores:hetionet CAID:CA512341050 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341050 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1320G>A (p.Ala440=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.628)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341050/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:144093 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042024 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0017178 infores:hetionet CHEBI:6933 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0030554 infores:hetionet CHEBI:8869 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0232495 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0549310 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1096250 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085096 infores:hetionet GO:0010969 biolink:causes GO:0000749 infores:ubergraph knowledge_assertion manual_agent GO:0010969 GO:0000749 CHEBI:37924 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C2047937 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0025061 infores:hetionet GO:1902869 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:1902869 GO:0150063 CHEBI:37924 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0699744 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0302295 infores:hetionet CHEBI:478164 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0151872 infores:hetionet CHEBI:2666 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0030312 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0853813 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151602 infores:hetionet CHEBI:3387 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013144 infores:hetionet CHEBI:83531 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0085631 infores:hetionet CHEBI:6456 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0234233 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007785 infores:hetionet CHEBI:6690 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0037036 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0003123 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0553698 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0553698 infores:hetionet NCBIGene:3852 biolink:causes MONDO:0030525 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0030525 uuid:aa307752-79d0-442f-bf63-003531a007b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151908 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007785 infores:hetionet CHEBI:2453 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0031542 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0006145 infores:hetionet CHEBI:144093 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0034882 infores:hetionet CHEBI:94501 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0009782 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0015967 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0029882 infores:hetionet CHEBI:3654 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0008372 infores:hetionet UMLS:C0004609 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0240735 infores:hetionet NCBIGene:51362 biolink:causes MONDO:0030259 infores:monarchinitiative not_provided not_provided HGNC:17350 MONDO:0030259 uuid:f6ca50fc-9d20-4023-89a6-596b82262ec6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037274 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0029408 infores:hetionet GO:1903072 biolink:causes GO:0097191 infores:ubergraph knowledge_assertion manual_agent GO:1903072 GO:0097191 CHEBI:6076 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0687133 infores:hetionet CHEBI:52717 biolink:causes HP:0012417 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085383 infores:hetionet CHEBI:7581 biolink:causes MONDO:0003040 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0002624 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0012833 infores:hetionet CHEBI:135930 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0015967 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0853926 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0853926 infores:hetionet CHEBI:135342 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0234022 infores:hetionet CHEBI:47780 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0004093 infores:hetionet UMLS:C0065374 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042963 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0178298 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002418 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0025202 infores:hetionet CHEBI:39112 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0311468 infores:hetionet CHEBI:4903 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0547030 infores:hetionet CHEBI:50841 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0001824 infores:hetionet CHEBI:2569 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0014591 infores:hetionet NCBIGene:7276 biolink:causes MONDO:0020730 infores:monarchinitiative not_provided not_provided HGNC:12405 MONDO:0020730 uuid:023efb28-524a-4f9a-b966-9a177b5cab46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0001973 infores:hetionet CHEBI:9907 biolink:causes HP:0033608 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0034079 infores:hetionet CHEBI:59773 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C3257803 infores:hetionet CHEBI:119915 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085631 infores:hetionet CHEBI:7627 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C2225524 infores:hetionet NCBIGene:5308 biolink:causes MONDO:0008386 infores:monarchinitiative not_provided not_provided HGNC:9005 MONDO:0008386 uuid:58c92ae6-a33b-423a-8076-179d8fb8b45e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7773 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0042963 infores:hetionet NCBIGene:207 biolink:causes MONDO:0008318 infores:monarchinitiative not_provided not_provided HGNC:391 MONDO:0008318 uuid:717a5517-c00d-488a-96eb-052fbfef65bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0009450 infores:hetionet CHEBI:63631 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0016204 infores:hetionet CHEBI:3814 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C2129214 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002418 infores:hetionet CHEBI:6339 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013378 infores:hetionet CHEBI:5118 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085632 infores:hetionet CAID:CA229599 biolink:causes MONDO:0009861 infores:clingen CAID:CA229599 MONDO:0009861 PMID:7833954PMID:9634518PMID:7833954PMID:29653233PMID:10479481 Likely Pathogenic PP4_Moderate, PM2_Supporting, PM3_Supporting, PP3_Moderate, PS3_Supporting The c.512G>C (p.Gly171Ala) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 7833954, 9634518); detected with IVSl0nt546 (aka c.1066-11G>A PMID: 7833954). This variant is absent in population databases (PM2_supporting). This variant produces 27% enzyme activity as compared to wild type PAH (PMID: 10479481) Computational evidence supports a damaging effect (REVEL=0.947). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PP4_Moderate, PM2_supporting, PP3_moderatePM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229599/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6775 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002874 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019348 infores:hetionet CHEBI:63845 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0151798 infores:hetionet CHEBI:84500 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0040128 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0948089 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0241863 infores:hetionet CHEBI:63618 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0012569 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0877095 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0877095 infores:hetionet GO:1902956 biolink:causes GO:0006119 infores:ubergraph knowledge_assertion manual_agent GO:1902956 GO:0006119 CHEBI:499361 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0600142 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0162830 infores:hetionet CHEBI:8364 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0086543 infores:hetionet CHEBI:6761 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0042963 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0015695 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0700031 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0700031 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007097 infores:hetionet CHEBI:8874 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0392171 infores:hetionet CAID:CA386959398 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959398 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PP4_Moderate, PVS1 The c.388C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 130 (p.(Gln130Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in seven unrelated (though part of a population isolate and likely having a common ancestor) individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was segregated with diabetes, with eight informative meioses in four families with MODY (PP1_Strong; internal lab contributors). This variant was identified in at least 3 individuals with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >75%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.388C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_supporting, PS4_moderate, PP1_strong, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959398/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA3060570772 biolink:causes MONDO:0011071 infores:clingen CAID:CA3060570772 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PP1_Moderate, PM5_Supporting, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.1413_1415delinsG (p.Leu472fs) is a frameshift variant which is not predicted to undergo nonsense-mediated decay, and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong, PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It was found to co-segregate with disease in multiple affected family members, with six meioses observed in one family (PP1_moderate; PMID: 24353905). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 24353905). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PP1_moderate, PM2_supporting, PM5_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3060570772/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6715 biolink:causes MONDO:0000819 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002902 infores:hetionet NCBIGene:9368 biolink:causes MONDO:0012851 infores:monarchinitiative not_provided not_provided HGNC:11075 MONDO:0012851 uuid:62e61eb5-c98e-4328-9fc6-fdac89198fb7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8412 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0037274 infores:hetionet CHEBI:7494 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0037036 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0235055 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0235055 infores:hetionet UNII:3U02EL437C biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0011603 infores:hetionet CHEBI:3127 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0242429 infores:hetionet CHEBI:5959 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0549622 infores:hetionet CHEBI:3996 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0542571 infores:hetionet CHEBI:50131 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0015967 infores:hetionet CHEBI:127342 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0085633 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0032584 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0242350 infores:hetionet CHEBI:16469 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0085593 infores:hetionet CHEBI:6904 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0018790 infores:hetionet CHEBI:68584 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0086439 infores:hetionet CHEBI:9927 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0036830 infores:hetionet CHEBI:29688 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0012569 infores:hetionet CHEBI:79699 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1384353 infores:hetionet CHEBI:8212 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0011991 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0853692 infores:hetionet CHEBI:5050 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C1456784 infores:hetionet CHEBI:50861 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0011603 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0010709 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235874 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0236082 infores:hetionet CHEBI:6413 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0014518 infores:hetionet CAID:CA186532 biolink:causes MONDO:0007648 infores:clingen CAID:CA186532 MONDO:0007648 PMID:24204729 Likely Benign BP7, BS2, BP4 BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The c.1416C>T variant has been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4), and the nucleotide is not conserved (BP7). Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4, BP7. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA186532/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7581 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0026821 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0027765 infores:hetionet CHEBI:28593 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0002874 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003864 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0243026 infores:hetionet CHEBI:42820 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0234369 infores:hetionet CHEBI:63631 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085633 infores:hetionet CAID:CA7511779 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511779 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4_Moderate PM2 The NM_000070.3: c.2242C>T p.(Arg748Ter) variant in CAPN3, which is also known as p.(Arg748del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID: 17157502) (PVS1). This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID: 25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal clinic data communication). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID: 12461690, 17157502) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 16971480). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511779/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0010592 biolink:causes HP:0004372 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0234428 infores:hetionet NCBIGene:6324 biolink:causes MONDO:0013015 infores:monarchinitiative not_provided not_provided HGNC:10586 MONDO:0013015 uuid:1da6eb8b-70ae-4b86-87a5-d20fe677570b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231425 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0012739 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1510472 infores:hetionet CHEBI:6129 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0018834 infores:hetionet CHEBI:3478 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0004096 infores:hetionet CHEBI:28787 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0018794 infores:hetionet CHEBI:75722 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0740394 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0027769 infores:hetionet CHEBI:17688 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0085631 infores:hetionet CAID:CA318256 biolink:causes MONDO:0100038 infores:clingen CAID:CA318256 MONDO:0100038 PMID: Likely Pathogenic PM6, PS2_Moderate, PM1, PM2_Supporting, PP3_Moderate PVS1, PM5, PM4, BS2, BP4, BP3, BP2, BA1, PS1, PS3, BP7, BP5, BS1, BS3 The NM_001330260.2:c.2534C>T variant in SCN8A is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 845 (p.Ser845Phe). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 2 individuals, all of whom meet criteria for a complex neurodevelopmental disorder (PS2_Moderate, PM6_Moderate; PMID 37853563, 29655203, internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, which is above the threshold of 0.773, evidence that correlates with impact to SCN8A function (PP3_Moderate). This variant resides within a region, amino acids 844-852, of SCN8A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2_Moderate, PM1, PP3_Moderate, PM2_Supporting, PM6_Moderate. (ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 2.0.0, approved 1/7/2025). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA318256/MONDO:0100038/070 2025-09-23 2025-09-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15367 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0005779 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020649 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0030332 infores:hetionet CHEBI:408174 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0085631 infores:hetionet CHEBI:16469 biolink:causes HP:0100878 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151994 infores:hetionet CHEBI:3510 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C1257843 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0007760 infores:hetionet CHEBI:168396 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004134 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0314719 infores:hetionet CHEBI:63925 biolink:causes MONDO:0015288 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0019357 infores:hetionet CAID:CA401367166 biolink:causes MONDO:0009290 infores:clingen CAID:CA401367166 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting The NM_000152.5:c.1551+1G>A variant alters the canonical donor splice site of intron 10 of GAA. RT-PCR and sequencing using cells from an individual who is compound heterozygous for this variant show that the predominant effect is skipping of exon 10 (GAA has 20 exons). Additionally, an immunoblot from a patient homozygous for this variant showed a specific band at ~105.8 kD, which is consistent with the size of the 110 kD precursor GAA protein minus 4.2 kD, caused by an in-frame skip of exon 10 (PMID: 25243733, 29428273). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID: 29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 5 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 5 patients and was deficient (<10% residual activity) (PMID: 29428273, 21550241, 27189384, 37542277) (PP4_Moderate). At least one patient is homozygous for the variant, 0.5 points (PMID: 29428273). One patient is compound heterozygous for the variant and c.1561G>A, p.E521K (PMID: 37542277, pathogenic by ClinGen LD VCEP, phase unknown), 0.5 points. Two patients are compound heterozygous for the variant and GAA variant c.-32-3C>G (PMID: 27189384). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1 and gnomAD v4.1.0 (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>C, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). One of these variants, c.1551+1G>C, has been classified as Pathogenic by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 1065143). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401367166/MONDO:0009290/010 2025-01-21 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:47612 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0042075 infores:hetionet CHEBI:50648 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0004093 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020621 infores:hetionet CHEBI:8207 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042029 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042109 infores:hetionet CHEBI:465284 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0014457 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002622 infores:hetionet CHEBI:16469 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2939186 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0011849 infores:hetionet CHEBI:50122 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0020473 infores:hetionet CHEBI:82941 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0015672 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0004623 infores:hetionet CHEBI:10650 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0032343 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0037199 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0039971 infores:hetionet CAID:CA2573332225 biolink:causes MONDO:0001586 infores:clingen CAID:CA2573332225 MONDO:0001586 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000203.5:c.1082del (p.Ala361GlyfsTer79) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in exon 9 out of 14 total exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v4.1.0. To our knowledge, this variant has not been reported in the literature in any individuals with mucopolysaccharidosis type 1. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573332225/MONDO:0001586/091 2025-01-03 2025-01-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28748 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041657 infores:hetionet CHEBI:585948 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0549622 infores:hetionet CHEBI:63631 biolink:causes MONDO:0007426 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2607947 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040479 infores:hetionet CHEBI:7983 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0428977 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0010709 infores:hetionet CHEBI:4903 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0002170 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235416 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0038358 infores:hetionet CHEBI:7789 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0392176 infores:hetionet CHEBI:4911 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1142520 infores:hetionet CHEBI:8863 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002994 infores:hetionet CHEBI:3723 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151827 infores:hetionet CHEBI:6413 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0000737 infores:hetionet CHEBI:63610 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C1167965 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0037274 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0027765 infores:hetionet CHEBI:3387 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0015230 infores:hetionet CAID:CA346859 biolink:causes MONDO:0015152 infores:clingen CAID:CA346859 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Strong, PP1_Strong The NM_000070.3: c.1981del p.(Ile661Ter) variant in CAPN3, which is also known as p.(Gln660_Ile661insTer), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 17/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 11 patients with features consistent with LGMD (PMID: 30919934, 37526466, 19556129, 18337726, 18055493; LOVD CAPN3_000104), including confirmed in trans with a pathogenic variant in one individual (c.550del p.(Thr184Argfs36), 1.0 pt, PMID: 37526466), in unknown phase with a pathogenic variant in another individual (c.1838del p.(Lys613ArgfsTer49), 0.5 pts, PMID: 18055493), and in a homozygous state in an individual without reported familial consanguinity (0.5 pts, PMID: 18055493) (PM3_Strong). This variant has also been reported to co-segregate with autosomal recessive LGMD in four affected family members from two families (PMID: 30919934; PP1_Strong). In addition, at least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and severely reduced or absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18337726, 19556129) (PP4, capped with PP1_Strong). The filtering allele frequency of this variant is 0.000061919 (the upper threshold of the 95% CI of 55/1111948 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/14/2025): PVS1, PM3_Strong, PP1_Strong, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346859/MONDO:0015152/187 2025-05-14 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7865 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0000731 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0234215 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0162429 infores:hetionet CAID:CA024331 biolink:causes MONDO:0007783 infores:clingen CAID:CA024331 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, PS4, PS3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Aspartic acid with Asparagine at codon 708 of the RYR1 protein, p.(Asp708Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0007, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with congenital myopathies inherited in an autosomal recessive pattern. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.726 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024331/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA380144678 biolink:causes MONDO:0000573 infores:clingen CAID:CA380144678 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.95G>T is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 32 (p.Gly32Val).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144678/MONDO:0000573/124 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:64355 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0039070 infores:hetionet CHEBI:47499 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0235347 infores:hetionet CAID:CA410203831 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203831 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.236T>C (p.Val79Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1:: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203831/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8863 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0009676 infores:hetionet CHEBI:253342 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C3263723 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0007682 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0004093 infores:hetionet CHEBI:28445 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0020580 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0031117 infores:hetionet CL:0000166 biolink:causes MONDO:0006076 infores:ubergraph knowledge_assertion manual_agent UBERON:0001236 MONDO:0006076 CAID:CA2695217482 biolink:causes MONDO:0015967 infores:clingen CAID:CA2695217482 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PVS1 PS4, PP1 The c.68_69del variant in the HNF1A/ HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 23 in NM_000545.8, adding 9 novel amino acids before encountering a stop codon (p.(Lys23ArgfsTer9)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21224407, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with 1 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.68_69 meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695217482/MONDO:0015967/017 2024-08-30 2024-08-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31949 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0033774 infores:hetionet CHEBI:7773 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0038325 infores:hetionet CHEBI:47898 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0438215 infores:hetionet CHEBI:2904 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0020458 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0021400 infores:hetionet CAID:CA497925710 biolink:causes MONDO:0018875 infores:clingen CAID:CA497925710 MONDO:0018875 PMID: Likely Benign BP4, BP7, PM2_Supporting BP1, BP3, BP2, BA1, PS3, PS4, PS2, PM4, PM3, PM1, BP5, BS1, BS3, BS4, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The c.414C>T (p.Ala138=) variant is a synonymous (silent) variant outside of the core splice motif, and BP4 code is met for splicing prediction (BP4, BP7). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). This variant has an allele frequency of 6.195e-7 (1/1614158 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant (PS3/BS3 not met). The computational splicing predictor SpliceAI gives a score of [0.01], predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (BP4). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BP4, BP7, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA497925710/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5138 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0235660 infores:hetionet CHEBI:50131 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0032227 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0549475 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1442903 infores:hetionet NCBITaxon:2697049 biolink:causes MONDO:0100163 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2697049 MONDO:0100163 CHEBI:16899 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0702166 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0235032 infores:hetionet CHEBI:72564 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020453 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0015397 infores:hetionet NCBIGene:9636 biolink:causes MONDO:0014502 infores:monarchinitiative not_provided not_provided HGNC:4053 MONDO:0014502 uuid:a5202499-c52f-4a16-9260-65bf1f91110a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9241 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C1320835 infores:hetionet CHEBI:64310 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0013404 infores:hetionet CHEBI:75998 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020458 infores:hetionet CHEBI:291342 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0232462 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0948594 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0020538 infores:hetionet CHEBI:408174 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0009806 infores:hetionet CAID:CA8423796 biolink:causes MONDO:0019497 infores:clingen CAID:CA8423796 MONDO:0019497 PMID: Pathogenic PP1_Strong, PP3, PM3_Strong PM2 The allele frequency of the c.4198G>A (p.Val1400Met) variant in the MYO15A gene is 0.01980% (7/35356) of African/African-American chromosomes by gnomAD. This variant has been reported to segregate with hearing loss in at least 3 separate families (PP1_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). This variant has been detected in 10 probands with nonsyndromic hearing loss. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, in 1 a rare variant of unknown significance was observed in trans, and in 7 the variant was observed in the homozygous state (PM3_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). Additionally, the REVEL computational prediction analysis tool produced a score of 0.891, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8423796/MONDO:0019497/005 2021-07-27 2022-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:9613 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0853026 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0015397 infores:hetionet CHEBI:91541 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0151908 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000827 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036117 infores:hetionet CHEBI:5864 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0018524 infores:hetionet CHEBI:135530 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0018681 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018418 infores:hetionet CHEBI:18248 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0042963 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0009450 infores:hetionet CHEBI:31949 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0234458 infores:hetionet CHEBI:49713 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0009024 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0700184 infores:hetionet CHEBI:37924 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0947912 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0036572 infores:hetionet CAID:CA145885 biolink:causes MONDO:0001586 infores:clingen CAID:CA145885 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.543T>C variant in IDUA is a synonymous (silent) variant (p.Asn181=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2950 in the South Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92645). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145885/MONDO:0001586/091 2025-01-02 2025-01-02 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:657309 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0037036 infores:hetionet CHEBI:7915 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042963 infores:hetionet CHEBI:6402 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0007859 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0009763 infores:hetionet CHEBI:49713 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0011848 infores:hetionet CHEBI:17334 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0497156 infores:hetionet CHEBI:3996 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0008031 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020651 infores:hetionet CHEBI:45367 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0267792 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1306341 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0014534 infores:hetionet CHEBI:31623 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0085635 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0017574 infores:hetionet CHEBI:4495 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0011991 infores:hetionet CHEBI:8713 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0700590 infores:hetionet CHEBI:9073 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0424295 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151735 infores:hetionet CHEBI:39585 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0233794 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006277 infores:hetionet CHEBI:8597 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0009806 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0438243 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0438243 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0006145 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0027765 infores:hetionet CHEBI:135939 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0428977 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0236082 infores:hetionet NCBIGene:4089 biolink:causes MONDO:0007688 infores:monarchinitiative not_provided not_provided HGNC:6770 MONDO:0007688 uuid:90455c74-fae2-471d-86ec-e818fa55d43f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0015397 infores:hetionet CHEBI:9168 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C3160741 infores:hetionet CHEBI:51041 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0004604 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042109 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0004936 infores:hetionet CHEBI:63580 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009917 infores:hetionet UMLS:C0120107 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0021177 infores:hetionet CHEBI:144551 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0018965 infores:hetionet CHEBI:4659 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0028643 infores:hetionet CAID:CA402528512 biolink:causes MONDO:0012589 infores:clingen CAID:CA402528512 MONDO:0012589 PMID: Likely Pathogenic PM1, PS2, PM2_Supporting, PP3 The p.Thr606Ile variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with global developmental delay, epilepsy, ventriculomegaly, and dysmorphic facial features (PMID 34580403) (PS2). The p.Thr606Ile variant occurs in the well-characterized Basic Helix-Loop-Helix functional domain of the TCF4 gene (PM1). The p.Thr606Ile variant in TCF4 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr606Ile variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2, PM1, PM2_supporting, PP3). (TCF4 Specifications v4.0; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA402528512/MONDO:0012589/032 2025-05-07 2025-06-30 Autosomal dominant inheritance HP:0000006 Supports CAID:CA410148474 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148474 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1034C>A (p.Pro345His) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148474/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63584 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0010692 infores:hetionet CHEBI:7956 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0013378 infores:hetionet CHEBI:6402 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0003811 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0948594 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0038362 infores:hetionet NCBIGene:673 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:1097 MONDO:0005575 uuid:864a41b5-64e9-4732-a686-ce4605ffa713 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3437 biolink:causes MONDO:0002307 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0005743 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0013395 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0004239 infores:hetionet CHEBI:40279 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2242996 infores:hetionet CHEBI:8888 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085632 infores:hetionet CHEBI:46295 biolink:causes UMLS:C2609264 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C2609264 infores:hetionet GO:0061190 biolink:causes GO:0061053 infores:ubergraph knowledge_assertion manual_agent GO:0061190 GO:0061053 CHEBI:10125 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0043352 infores:hetionet CHEBI:3756 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0026826 infores:hetionet CHEBI:35778 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0010200 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0851341 infores:hetionet CAID:CA8337704 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337704 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4 The c.476A>G (p.Gln159Arg) variant in ACADVL is a missense in exon 6. This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID: 9973285). The highest population minor allele frequency in gnomAD is 0.00003 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.90, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). There is however insufficient experimental or case data identified in the literature for this variant and is therefore classified as a VUS. (ACADVL-specific ACMG/AMP criteria applied: PP4; PM2_supporting; PP3). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337704/MONDO:0008723/021 2022-09-20 2022-09-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:367163 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0852733 infores:hetionet CHEBI:8435 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C2830004 infores:hetionet CHEBI:17688 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0030232 infores:hetionet CHEBI:48844 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0034150 infores:hetionet CHEBI:135876 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C2047937 infores:hetionet CHEBI:6717 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0042075 infores:hetionet CHEBI:3127 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0004093 infores:hetionet CHEBI:63617 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0015732 infores:hetionet CHEBI:72297 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0027497 infores:hetionet CHEBI:16914 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0018524 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0021364 infores:hetionet CHEBI:15765 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0041657 infores:hetionet CHEBI:6067 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0700361 infores:hetionet CHEBI:9586 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0231530 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0038362 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0030552 infores:hetionet NCBIGene:547 biolink:causes MONDO:0971149 infores:monarchinitiative not_provided not_provided HGNC:888 MONDO:0971149 uuid:261245ed-b54c-46b4-ab4d-3b01c87532f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0162429 infores:hetionet CAID:CA226576 biolink:causes MONDO:0100368 infores:clingen CAID:CA226576 MONDO:0100368 PMID: Likely Pathogenic PM3, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting BA1, BS1 NM_000329.3(RPE65):c.65T>C is a missense variant causing substitution of leucine with proline at position 22. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002137, with 2 alleles / 16214 total alleles in the African/African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including onset in infancy (1 pt), nyctalopia since childhood (0.5 pts), diagnosis based on a 300-gene testing panel that did not provide an alternative explanation for visual impairment (2 pts), non-detectable rod ERG response (0.5 pts), reduced cone ERG response (1 pt), reduced visual acuity (1 pt), light-seeking behavior (1 pt), retinal vessel attenuation (0.5 pts), optic nerve pallor (0.5 pts), and pigment clumping (0.5 pts), which together are highly specific for RPE65-related recessive retinopathy (8 total points, VCEP member-provided data, PP4_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PMID: 28127548, VCEP member-provided data). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.1067dup (p.Asn356fs) or NM_000329.3(RPE65):c.10C>T (p.Gln4Ter) variants suspected in trans (1 pt, PMID: 35129589), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total pts, PM3). The computational predictor REVEL gives a score of 0.711, which is above the ClinGen LCA / eoRD VCEP PP3 threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). The variant exhibited 2.8-13.5% enzymatic activity in retinoid isomerase assays relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 18599565, PMID: 24849605, PMID: 26427455). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3, PP3, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226576/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Supports UNII:DJJ95FJP1H biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0013378 infores:hetionet CHEBI:5856 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0020651 infores:hetionet CHEBI:16796 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0018520 infores:hetionet CHEBI:47426 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0041834 infores:hetionet CHEBI:28001 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0151746 infores:hetionet CHEBI:41879 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0016658 infores:hetionet CHEBI:8382 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0234708 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0015397 infores:hetionet CHEBI:18243 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0017086 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0518015 infores:hetionet GO:0075135 biolink:causes GO:0019722 infores:ubergraph knowledge_assertion manual_agent GO:0075135 GO:0019722 CHEBI:6067 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0034063 infores:hetionet CHEBI:3176 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0012569 infores:hetionet NCBIGene:5340 biolink:causes MONDO:0025712 infores:monarchinitiative not_provided not_provided HGNC:9071 MONDO:0025712 uuid:804f2abb-3331-4576-9981-9416fc605bb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17026 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151905 infores:hetionet CHEBI:3485 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0423791 infores:hetionet CHEBI:72690 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0085649 infores:hetionet CAID:CA007870 biolink:causes MONDO:0100316 infores:clingen CAID:CA007870 MONDO:0100316 PMID:21451124PMID:11087258PMID:19590188PMID:29021305PMID:22456477 Likely Pathogenic PS4, PS3, PP3 BA1, BS1, BS3, PVS1, PM2, PM1 NM_000218.3(KCNQ1):c.674C>T is a missense variant predicted to cause a substitution of serine with leucine at amino acid 225 (p.Ser225Leu). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001098, with 1 allele / 91,080 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant has been reported in at least 11 unrelated individuals with LQTS (PS4; PMID: 22885918, 19841300, 17470695, 15840476, 10973849, 15466642, 9927399). Functional studies have been performed on this variant and meet criteria for PS3 with 1 RNA observation and 4 electrophysiology study observations all demonstrating a damaging effect on the protein function (PS3; PMID: 29021305, 22456477, 21451124, 19590188, 11087258). Multiple lines of computational evidence (REVEL score 0.873) suggest this variant is likely to be disruptive (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3, PS4, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA007870/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9139 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151717 infores:hetionet CHEBI:367163 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085631 infores:hetionet NCBIGene:56160 biolink:causes MONDO:0014984 infores:monarchinitiative not_provided not_provided HGNC:7677 MONDO:0014984 uuid:d6138d56-8853-442b-8235-78709deede97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5100 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0018681 infores:hetionet CHEBI:68642 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0011991 infores:hetionet CHEBI:8871 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0035243 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0032285 infores:hetionet CHEBI:51380 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0423153 infores:hetionet NCBIGene:55750 biolink:causes MONDO:0013859 infores:monarchinitiative not_provided not_provided HGNC:21869 MONDO:0013859 uuid:307851b2-595b-416a-ab57-7e215d99d3fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0002453 infores:hetionet CHEBI:42355 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0234233 infores:hetionet CHEBI:17347 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0003467 infores:hetionet CHEBI:3504 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0018944 infores:hetionet UNII:T58MSI464G biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0011991 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0005940 infores:hetionet CAID:CA010464 biolink:causes MONDO:0005045 infores:clingen CAID:CA010464 MONDO:0005045 PMID: Likely Pathogenic PP1_Strong, PM1, PS4_Moderate BS1, BS3, PP2, PP3, PM2, BP4, BA1, PS1, PS3 The NM_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln). This variant has been reported in individuals with HCM and other cardiomyopathies (ClinVar Variation ID: 164113) and has also been identified in 5 out of 112974 (0.009% FAF 95% CI) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>10), therefore, the PS4 criterion has been applied at moderate strength (PS4_Moderate) and the PM2_Supporting criterion has not been applied. This variant segregated with disease in >7 affected individuals with HCM from at least 4 families (PP1_Strong; Maron 2011 PMID: 21185001, Agarwal 2015 PMID: 26271555, Mattos 2016 Year PMID: 27737317, Ross 2017 PMID: 28615295). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Strength; Walsh 2019 PMID: 30696458). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (REVEL score <0.7). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PP1_Strong and PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010464/MONDO:0005045/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17823 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0332575 infores:hetionet CHEBI:4814 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0032617 infores:hetionet CHEBI:585948 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0020517 infores:hetionet CHEBI:63630 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0008325 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C1258215 infores:hetionet CHEBI:92712 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0027092 infores:hetionet CHEBI:6887 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0522224 infores:hetionet CAID:CA213717 biolink:causes MONDO:0015967 infores:clingen CAID:CA213717 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM3, PP2, PP3, PP4, PM2_Supporting PS3 The c.1136C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 379 (p.(Ala379Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; PMID 30592380, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 30592389) (PP4; internal lab contributors). This variant has been detected in one individual with neonatal diabetes. This individual was compound heterozygous for the variant and a pathogenic variant and was confirmed in trans by parental/family testing (PM3; PMID 30592380). Functional studies demonstrated the p.Ala379Glu protein has RAI<0.5; however, the wild-type kinetic parameters didn’t pass the quality control, and the PS3 cannot be applied (PMID: 30592380). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4, PM3, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213717/MONDO:0015967/086 2023-07-17 2023-07-17 Semidominant inheritance HP:0032113 Supports CHEBI:135285 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0040822 infores:hetionet CHEBI:4469 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0015230 infores:hetionet NCBIGene:5631 biolink:causes MONDO:0010395 infores:monarchinitiative not_provided not_provided HGNC:9462 MONDO:0010395 uuid:395d29f4-49de-48c8-bd68-f6e9c096e7a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0007869 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0234215 infores:hetionet CHEBI:41774 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0013378 infores:hetionet CHEBI:63637 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0424790 infores:hetionet CHEBI:119915 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0010200 infores:hetionet CHEBI:50275 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0001925 infores:hetionet CHEBI:2682 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C2830004 infores:hetionet CHEBI:408174 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0011991 infores:hetionet CHEBI:31401 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0404521 infores:hetionet CHEBI:64310 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0042963 infores:hetionet CHEBI:63621 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0025345 infores:hetionet CHEBI:4315 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0030554 infores:hetionet NCBIGene:203859 biolink:causes MONDO:0008151 infores:monarchinitiative not_provided not_provided HGNC:27337 MONDO:0008151 uuid:339325d4-3cbe-4334-bf0d-175f6a896371 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51032 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0235266 infores:hetionet CHEBI:6710 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0035078 infores:hetionet NCBIGene:7431 biolink:causes MONDO:0007286 infores:monarchinitiative not_provided not_provided HGNC:12692 MONDO:0007286 uuid:e0c6ff2c-fd6d-4fc7-ac35-8f6cde654701 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0231218 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020701 infores:hetionet CHEBI:50223 biolink:causes UMLS:C1868855 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1868855 infores:hetionet CHEBI:91541 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0015230 infores:hetionet NCBIGene:27178 biolink:causes MONDO:0030314 infores:monarchinitiative not_provided not_provided HGNC:15563 MONDO:0030314 uuid:690da24d-bed3-477c-a464-64b651eb40ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45081 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0948349 infores:hetionet CHEBI:32315 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151907 infores:hetionet CHEBI:75722 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004604 infores:hetionet CHEBI:6128 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0085661 infores:hetionet NCBIGene:60 biolink:causes MONDO:0009470 infores:monarchinitiative not_provided not_provided HGNC:132 MONDO:0009470 uuid:c62daae1-1c58-412e-bdf4-49f7647f3425 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127342 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0003467 infores:hetionet CHEBI:3242 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0004604 infores:hetionet CHEBI:5864 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0235266 infores:hetionet CHEBI:17334 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0042963 infores:hetionet CHEBI:184555 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0042963 infores:hetionet CHEBI:29688 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0232462 infores:hetionet CHEBI:59560 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0858635 infores:hetionet UMLS:C0004609 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0085631 infores:hetionet CHEBI:10110 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0041834 infores:hetionet CHEBI:9667 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C2363731 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0235266 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0677500 infores:hetionet CHEBI:4814 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0042023 infores:hetionet CHEBI:44915 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0011603 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0015230 infores:hetionet CHEBI:5779 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0085649 infores:hetionet CHEBI:50275 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0011603 infores:hetionet CHEBI:474053 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0019080 infores:hetionet NCBIGene:5277 biolink:causes MONDO:0010438 infores:monarchinitiative not_provided not_provided HGNC:8957 MONDO:0010438 uuid:145876d2-bf56-4a0e-9534-d410ed90cd95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042075 infores:hetionet CHEBI:3215 biolink:causes EFO:0009510 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0262593 infores:hetionet CHEBI:8707 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027849 infores:hetionet CHEBI:3814 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0038999 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0235818 infores:hetionet CHEBI:15365 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0003862 infores:hetionet CHEBI:119915 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0744727 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0005940 infores:hetionet CHEBI:38940 biolink:causes MONDO:0018824 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0085652 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0038454 infores:hetionet NCBIGene:3972 biolink:causes MONDO:0009223 infores:monarchinitiative not_provided not_provided HGNC:6584 MONDO:0009223 uuid:1d0fc907-098f-4864-974a-cb16c7d8f73d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043241 infores:hetionet CHEBI:16899 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0040046 infores:hetionet CHEBI:7577 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0423791 infores:hetionet CHEBI:134743 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0015230 infores:hetionet GO:1904967 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:1904967 GO:0007127 CHEBI:6367 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085636 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020649 infores:hetionet GO:1902026 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:1902026 GO:0001501 CHEBI:6339 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0235431 infores:hetionet CHEBI:8871 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0149725 infores:hetionet CHEBI:42797 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0232849 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0018799 infores:hetionet CHEBI:135285 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0011991 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0033975 infores:hetionet CHEBI:77260 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151578 infores:hetionet CHEBI:8428 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0002878 infores:hetionet CHEBI:10100 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0042109 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042571 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0221490 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0040435 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0006145 infores:hetionet CHEBI:3485 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C1258215 infores:hetionet CHEBI:15367 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0231528 infores:hetionet GO:0006954 biolink:causes MONDO:0010481 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D000799 DB01246_MESH_D000799_1 CHEBI:17376 biolink:causes HP:0033067 infores:drugmechdb knowledge_assertion manual_agent CHEBI:17376 HP:0033067 DB06823_MESH_D003555_1 CHEBI:2663 biolink:causes UMLS:C0581386 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0581386 infores:hetionet CHEBI:7565 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0016204 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0013221 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013221 infores:hetionet CHEBI:51450 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0268000 infores:hetionet CHEBI:71028 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0700590 infores:hetionet CHEBI:63616 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0038325 infores:hetionet CHEBI:9139 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035243 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151662 infores:hetionet CHEBI:2687 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0022346 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235763 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020538 infores:hetionet CHEBI:4911 biolink:causes EFO:0011051 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0920103 infores:hetionet CHEBI:6909 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1167965 infores:hetionet CHEBI:37924 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C2363731 infores:hetionet CHEBI:6339 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0043352 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0241950 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0241950 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0155626 infores:hetionet CHEBI:31547 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0151578 infores:hetionet CHEBI:204928 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0042963 infores:hetionet CHEBI:28787 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0234535 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0521591 infores:hetionet NCBIGene:55770 biolink:causes MONDO:0859141 infores:monarchinitiative not_provided not_provided HGNC:24968 MONDO:0859141 uuid:b3b84d24-b635-405b-aacf-81310b4127de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0152227 infores:hetionet CHEBI:63612 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0042963 infores:hetionet CHEBI:36791 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027066 infores:hetionet CHEBI:404903 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013378 infores:hetionet CHEBI:44241 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0027497 infores:hetionet CHEBI:5778 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0040460 infores:hetionet CHEBI:3181 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0235896 infores:hetionet CHEBI:8228 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0522055 infores:hetionet CHEBI:5864 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0232766 infores:hetionet CHEBI:5001 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0010692 infores:hetionet NCBIGene:375298 biolink:causes MONDO:0012024 infores:monarchinitiative not_provided not_provided HGNC:21699 MONDO:0012024 uuid:ad564aa9-208e-4515-ae9e-6db37f985172 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0033975 infores:hetionet CAID:CA400024376 biolink:causes MONDO:0100326 infores:clingen CAID:CA400024376 MONDO:0100326 PMID: Pathogenic PM2, PVS1, PM3_Supporting PP4 The ITGB3 variant c.792G>A (p.Trp264Ter) is a nonsense variant causing a premature stop codon in exon 6/15, and is predicted to undergo nonsense mediated decay (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005782 (2/34590 alleles) in the Latino population, which meets threshold for PM2_supporting. At least one homozygous patient (Patient II-2 in PMID:24357714) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists with no αIIbβ3 surface expression as measured by flow cytometry (PM3_supporting). This patient was also diagnosed with primary ciliary dyskinesia. In summary, based on the available evidence at this time, the c.792G>A variant is classified Pathogenic. GT-specific criteria applied: PM3_supporting, PM2_Supporting, PVS1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400024376/MONDO:0100326/011 2023-02-02 2023-02-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51173 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0015397 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042267 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017675 infores:hetionet CAID:CA114137 biolink:causes MONDO:0015631 infores:clingen CAID:CA114137 MONDO:0015631 PMID:28581694 Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3, PS3, PP1_Moderate BP2 The NM_000552.5:c.2446C>T variant in VWF is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 816. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00009000 (based on 10/59984 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.005 (PM2_Supporting). At least 8 patients with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (1.3% or 9.8%) and decreased VWF:FVIII binding (0.00 to 0.1), which is highly specific for VWD type 2N (PMID: 28536718, PMID: 1832934, PMID: 28971901), (PP4_Moderate). Five individuals were homozygous for the variant (PM3) and three were compound heterozygous (PMID: 28536718, PMID: 28971901, PMID: 1832934). The variant has been reported to segregate with VWD type 2N in a proband plus two affected family members (PP1_moderate; PMID: 1832934). A hydrodynamic mouse model showed prolonged bleeding time, reduced factor VIII stability, and impaired binding of factor VIII to VWF, indicating that this variant has a damaging effect on protein function (PMID: 28581694)(PS3). The computational predictor REVEL gives a score of 0.756, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM3, PP1_Moderate, PP3, PP4_Moderate, PS3, PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114137/MONDO:0015631/090 2024-07-09 2024-08-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3219 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0021400 infores:hetionet CHEBI:44185 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004093 infores:hetionet CHEBI:6710 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0518015 infores:hetionet CAID:CA000093 biolink:causes MONDO:0018875 infores:clingen CAID:CA000093 MONDO:0018875 PMID: Benign BP4, BS3, BS2, PM2_Supporting BA1, PS1, PS4, PS2, PM5, PM1, BS1, BS4, PP3, PP1, PP4 The NM_000546.6: c.28G>A variant in TP53 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 10 (p.Val10Ile). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributors: SCV000184102.7). This variant has an allele frequency of .000021066 (34/1613962 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0961; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000093/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA6402069 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402069 MONDO:0019565 PMID: Uncertain Significance PM2, PP4, BP4, PM3, BS1 NM_000552.5:c.6104G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 2035. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.003657 (based on 186/44882 alleles in the East Asian population, with 2 homozygotes), which is between the ClinGen VWD VCEP thresholds for BS1 (>0.01) and PM2_Supporting (<0.0001), failing to meet either criterion. This variant has been reported in the heterozygous state in at least one patient with a mildly abnormal bleeding score and reduced quantity of von Willebrand factor, which together are consistent with but not highly specific for VWD Type 1 (PMID: 28536718). This variant also has been reported in at least 1 individual with VWD Type 3, who was compound heterozygous for the variant in trans with the NM_000552.5(VWF):c.3365C>T (p.Thr1122Met) variant. PM3 was not considered due to the absence of phenotype details to confirm the diagnosis (PMID: 34490048). The computation predictor REVEL gives a score of 0.071, which is below the ClinGen VWD VCEP BP4 threshold of <0.290 and does not predict a damaging effect on VWF function. However, the computational splicing predictor SpliceAI gives the variant a delta score of 0.13 for splice donor gain, indicating an inconclusive impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the absence of any ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402069/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Inconclusive true CHEBI:51164 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0010200 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0160390 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1112182 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1112182 infores:hetionet CAID:CA286904 biolink:causes MONDO:0700270 infores:clingen CAID:CA286904 MONDO:0700270 PMID: Likely Benign PS3, BP2_Strong BP4, BS1, PM2, PP3 The c.5821G>C (p.Val1941Leu) variant in ATM is a missense variant predicted to cause substitution of valine by leucine at amino acid 1941 (p.Val1941Leu). This variant has been observed in the homozygous state or phase unknown with a pathogenic variant in multiple individuals without Ataxia-Telangiectasia (Invitae internal data). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0003843 the Remaining population (PM2_Supporting, BS1, and BA1 are not met). ATM kinase activity assay in ATM-null lymphoblastoid cell line showed reduced kinase activity of ATM and its downstream targets indicating that this variant may impact protein function (PMID: 19431188). The computational predictor REVEL gives a score of 0.548, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. In summary, this variant meets criteria to be classified as likely benign for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BP2_Strong, PS3_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA286904/MONDO:0700270/020 2025-06-11 2025-07-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA410146982 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146982 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1382A>G (p.Asn461Ser) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146982/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C1738934 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042963 infores:hetionet CHEBI:4469 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0027051 infores:hetionet CHEBI:64064 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0004093 infores:hetionet CHEBI:17698 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0017178 infores:hetionet CHEBI:28901 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C1096274 infores:hetionet CHEBI:9168 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013404 infores:hetionet GO:0048378 biolink:causes GO:0048371 infores:ubergraph knowledge_assertion manual_agent GO:0048378 GO:0048371 CHEBI:5441 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0030554 infores:hetionet CHEBI:47381 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0162285 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0025061 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007642 infores:hetionet GO:0009913 biolink:causes CL:0000362 infores:ubergraph knowledge_assertion manual_agent GO:0009913 CL:0000362 CHEBI:7936 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027121 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0281913 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0281913 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0015230 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0032285 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011991 infores:hetionet CHEBI:50729 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0221512 infores:hetionet CHEBI:6909 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0234632 infores:hetionet CHEBI:38562 biolink:causes UMLS:C1142028 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C1142028 infores:hetionet CHEBI:8874 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0231528 infores:hetionet CHEBI:71417 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0876994 infores:hetionet NCBITaxon:5597 biolink:causes MONDO:0001215 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5597 MONDO:0001215 CHEBI:48669 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0012833 infores:hetionet UMLS:C0065374 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0242528 infores:hetionet CHEBI:135736 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037383 infores:hetionet CAID:CA229686 biolink:causes MONDO:0009861 infores:clingen CAID:CA229686 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM5, PP3 The c.673C>G (p.Pro225Ala) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded, PMID: 29499199). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Another missense change at the same amino acid, p.Pro225Thr, is interpreted as pathogenic by multiple submitters in ClinVar (variation ID 102779). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229686/MONDO:0009861/006 2021-02-14 2021-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37924 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0037274 infores:hetionet CHEBI:15367 biolink:causes HP:0011032 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2364164 infores:hetionet CHEBI:72690 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0030794 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013595 infores:hetionet GO:2000248 biolink:causes GO:0007405 infores:ubergraph knowledge_assertion manual_agent GO:2000248 GO:0007405 NCBIGene:55733 biolink:causes MONDO:0010814 infores:monarchinitiative not_provided not_provided HGNC:18270 MONDO:0010814 uuid:7099c4fa-0159-4768-ae21-f611241f987d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0005779 infores:hetionet CHEBI:27786 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0002994 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0522224 infores:hetionet CAID:CA409106952 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106952 MONDO:0015967 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PM1_Supporting PP1, PM5 The c.640T>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to alanine at codon 214 (p.(Ser214Ala)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide or hyperinsulinemic hypoglycemia and negative genetic testing for ABCC8 and KCNJ11) (PP4; internal lab contributor). This variant segregated with diabetes with at least one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). Additionally, a number of other missense variants at this codon (c.640T>A, p.Ser214Thr; c.641C>T, p.Ser214Phe; c.641C>A, p.Ser214Tyr) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.640T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PP4, PM1_Supporting, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106952/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135736 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0475858 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039503 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0001339 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0017160 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0851341 infores:hetionet CAID:CA2580098637 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098637 MONDO:0011071 PMID: Pathogenic PM1_Supporting, PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM3, BS2, PP2, PP3, PP1, PP4 The NM_001754.5(RUNX1):c.285del (p.Asn96ThrfsTer26) is a frameshift variant in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). This variant affects one of the amino acid residues between 89-204 within the RHD (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM1_supporting, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098637/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:102216 biolink:causes UMLS:C1392046 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C1392046 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009760 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0001824 infores:hetionet CHEBI:8863 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002792 infores:hetionet CHEBI:5098 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0014457 infores:hetionet CHEBI:42944 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0006277 infores:hetionet CHEBI:7959 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0750857 infores:hetionet GO:0141083 biolink:causes GO:1903409 infores:ubergraph knowledge_assertion manual_agent GO:0141083 GO:1903409 CHEBI:2639 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0948594 infores:hetionet CHEBI:31709 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0011991 infores:hetionet CHEBI:93635 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0424295 infores:hetionet CHEBI:168396 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0015967 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0004623 infores:hetionet CHEBI:5778 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0023222 infores:hetionet CHEBI:2611 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0030252 infores:hetionet CHEBI:7478 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0015644 infores:hetionet CHEBI:5280 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0026826 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0002871 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0011849 infores:hetionet CHEBI:77733 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0231303 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0032285 infores:hetionet CHEBI:5118 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0235198 infores:hetionet CHEBI:75722 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026821 infores:hetionet CHEBI:10101 biolink:causes HP:0032106 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0240962 infores:hetionet CAID:CA137906 biolink:causes MONDO:0021060 infores:clingen CAID:CA137906 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1020C>T (p.Pro340=) variant in the MAP2K2 gene is 0.262% (29/7910) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137906/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:15854 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0037274 infores:hetionet CHEBI:6715 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0024902 infores:hetionet CHEBI:8890 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0006266 infores:hetionet UBERON:0007195 biolink:causes MONDO:0002631 infores:ubergraph knowledge_assertion manual_agent UBERON:0007195 MONDO:0002631 CHEBI:63635 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0004093 infores:hetionet GO:0051147 biolink:causes GO:0061061 infores:ubergraph knowledge_assertion manual_agent GO:0051147 GO:0061061 CHEBI:40237 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0015672 infores:hetionet UMLS:C0657912 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0221170 infores:hetionet CHEBI:23765 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013491 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0240925 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0240925 infores:hetionet CHEBI:5141 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0232462 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0031542 infores:hetionet CHEBI:63607 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C1167965 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235295 infores:hetionet CHEBI:50131 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0858635 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005900 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030583 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0042373 infores:hetionet CHEBI:5790 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0086769 infores:hetionet CHEBI:63629 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042510 infores:hetionet CHEBI:75722 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0236075 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0041969 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0002258 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D010612 DB00415_MESH_D010612_1DB09320_MESH_D010612_1DB00759_MESH_D010612_1DB02703_MESH_D010612_1DB00671_MESH_D010612_1DB01416_MESH_D010612_1DB01017_MESH_D010612_1DB00417_MESH_D010612_1DB01602_MESH_D010612_1 CHEBI:8481 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0009676 infores:hetionet CHEBI:64310 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151662 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0243026 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001823 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0037052 infores:hetionet UMLS:C0010592 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0028084 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0034065 infores:hetionet CHEBI:119573 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0235198 infores:hetionet CHEBI:145499 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0404521 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0008370 infores:hetionet CHEBI:18248 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020456 infores:hetionet CHEBI:50924 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0040264 infores:hetionet CHEBI:66899 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0042029 infores:hetionet CHEBI:10023 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013390 infores:hetionet CHEBI:7601 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0035455 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0036572 infores:hetionet CHEBI:18248 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0023218 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0015230 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0029408 infores:hetionet CHEBI:63620 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0023052 infores:hetionet CHEBI:75045 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151662 infores:hetionet CAID:CA2061559 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061559 MONDO:0015924 PMID: Likely Benign BS1 PM2, PP3, BS2, BP4, BA1, PM1, PS4 The BMPR2 c.2656C>T variant is a missense variant predicted to cause an arginine to cysteine substitution at amino acid position 886. The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.1130% (11/9738 alleles) in the African/African American population. The population evidence available meets the threshold for BS1 (≥0.1%), but not for BA1 (>5%) or PM2 (<0.01%) as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.485 indicating that neither BP4 or PP3 were met since the threshold specified by the PH-VCEP is <0.25 and >0.75, respectively. The amino acid substitution occurs in the c-terminal domain, which is not a well-established functional domain, so PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. BS3 and PS3 were not evaluated due to the lack of functional data for this variant. In summary, the variant meets the criteria to be classified as likely benign (LB) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061559/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:681569 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0009319 infores:hetionet CHEBI:49040 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0011633 infores:hetionet CHEBI:3347 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0853692 infores:hetionet CHEBI:5893 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C2830004 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0231365 infores:hetionet CHEBI:8597 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0020651 infores:hetionet CHEBI:41423 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0392171 infores:hetionet CHEBI:17549 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0423791 infores:hetionet CHEBI:70746 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0014591 infores:hetionet CAID:CA346329433 biolink:causes MONDO:0800472 infores:clingen CAID:CA346329433 MONDO:0800472 PMID:27243976 Likely Pathogenic PP3, PM2_Supporting, PM5, PM3 PP1, BA1, BP4, PM1, PM4, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.350G>C variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Proline at amino acid 117 (p.Arg117Pro). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00002258 (1 allele out of 44,296), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.76, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27243976). This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) (PMID: 17157584). Total proband points = 1, meeting PM3. Two other missense variants (p.Arg117Trp, Grantham score = 101, ClinVar ID: 813356 and p.Arg117Gln, Grantham score = 43, ClinVar ID: 2500809) in the same codon have been classified as likely pathogenic for a CYP1B1-related phenotype by the ClinGen Glaucoma VCEP. CYP1B1:p.Arg117Pro has a higher Grantham score (= 103) than the previously classified amino acid changes, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5 to apply. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3, PM5, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346329433/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50922 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085637 infores:hetionet CHEBI:55346 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0002994 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0020456 infores:hetionet NCBIGene:51569 biolink:causes MONDO:0033486 infores:monarchinitiative not_provided not_provided HGNC:20597 MONDO:0033486 uuid:20bb32f1-053f-4622-9b7c-a9494e35646a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8364 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0042023 infores:hetionet CHEBI:7575 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0026821 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0031350 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0030785 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0030785 infores:hetionet CHEBI:5855 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018965 infores:hetionet CHEBI:9943 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013384 infores:hetionet NCBIGene:6045 biolink:causes MONDO:0859171 infores:monarchinitiative not_provided not_provided HGNC:10061 MONDO:0859171 uuid:f09aa4d5-5de3-4cea-ac5b-76fe46727c6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085393 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0160390 infores:hetionet CHEBI:6532 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0000731 infores:hetionet CHEBI:71415 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0206061 infores:hetionet CHEBI:72690 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0027441 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0021053 infores:hetionet CHEBI:50861 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0013404 infores:hetionet CAID:CA10580073 biolink:causes MONDO:0100488 infores:clingen CAID:CA10580073 MONDO:0100488 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.125C>T (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of Pro by Leu at amino acid 42 (p.Pro42Leu). This variant has been observed in more than 10 heterozygous individuals with no DGC, SRC tumours and whose families do not suggest HDGC (BS2; GeneDx, Invitae, Color). In summary, the CDH1 VCEP classified the variant as likely benign for DGLBCS based on BS2 alone based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580073/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6950 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151905 infores:hetionet NCBIGene:8878 biolink:causes MONDO:0008176 infores:monarchinitiative not_provided not_provided HGNC:11280 MONDO:0008176 uuid:693f29b9-6dbf-476a-b566-6471177bfc41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0155626 infores:hetionet NCBIGene:2317 biolink:causes MONDO:0007208 infores:monarchinitiative not_provided not_provided HGNC:3755 MONDO:0007208 uuid:94c1ef38-282d-474a-881f-76370e3b8dd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0026946 infores:hetionet CHEBI:63608 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011603 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0442874 infores:hetionet CAID:CA410147245 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147245 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1342A>T (p.Asn448Tyr) is a missense variant which has a REVEL score < 0.50 (0.164) and no splicing effect predicted (SpliceAI < 0.2) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147245/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9332 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0036572 infores:hetionet CHEBI:17263 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0003862 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0687133 infores:hetionet CHEBI:50305 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0406834 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003615 infores:hetionet CHEBI:3398 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0015672 infores:hetionet CHEBI:8871 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023052 infores:hetionet CHEBI:7444 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0232462 infores:hetionet NCBIGene:816 biolink:causes MONDO:0030920 infores:monarchinitiative not_provided not_provided HGNC:1461 MONDO:0030920 uuid:11398772-4458-4192-8fb0-cf5a221724c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0947912 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0037274 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0520587 infores:hetionet CHEBI:161680 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0012569 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0235431 infores:hetionet CHEBI:6538 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0030193 infores:hetionet CHEBI:29007 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0030554 infores:hetionet CAID:CA512341309 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341309 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1095C>A (p.Gly365=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341309/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:478164 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0151849 infores:hetionet CHEBI:3011 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0002792 infores:hetionet CHEBI:94449 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0030232 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0002418 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0233494 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0860803 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0151606 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151606 infores:hetionet CHEBI:8485 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0677500 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1368065 infores:hetionet CAID:CA2697547492 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547492 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.805+1_805+2dup is a splice-site variant which is predicted to cause a donor loss at the c.805 donor site (SpliceAI donor loss = 0.96) (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547492/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39585 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0015672 infores:hetionet CHEBI:32315 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011603 infores:hetionet CHEBI:51380 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0026205 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0020517 infores:hetionet NCBIGene:10907 biolink:causes MONDO:0012064 infores:monarchinitiative not_provided not_provided HGNC:30551 MONDO:0012064 uuid:826fda4f-7c0e-47e7-8994-a438bd2297a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474053 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0015230 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020598 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0038367 infores:hetionet CHEBI:9123 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020453 infores:hetionet CHEBI:37941 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0085649 infores:hetionet CHEBI:7581 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C1504494 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0006147 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0235763 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0018099 infores:hetionet GO:0010807 biolink:causes GO:0016079 infores:ubergraph knowledge_assertion manual_agent GO:0010807 GO:0016079 CHEBI:37941 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0033774 infores:hetionet CHEBI:41423 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151904 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0270274 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0270274 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0476089 infores:hetionet CHEBI:16755 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0700361 infores:hetionet CHEBI:135736 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085641 infores:hetionet CHEBI:10023 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0038325 infores:hetionet CAID:CA915941307 biolink:causes MONDO:0100368 infores:clingen CAID:CA915941307 MONDO:0100368 PMID: Likely Pathogenic PM4_Supporting, PM3_Strong, PP1, PP4, PM2_Supporting NM_000329.3(RPE65):c.991_993dup is an in-frame insertion variant encoding a duplication of tryptophan 331. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to cause a change in the length of the protein due to an in-frame insertion encoding 1 amino acid in a non-repeat region, with at least one of the neighboring base pairs highly conserved with a PhyloP conservation score of 7.47347 (PM4_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), visual loss (1 pt) before the age of 5 years (1 pt), nystagmus (1 pt), undetectable or significantly reduced electroretinogram responses from rods (0.5 pts) and cones (1 pt), optic disc pallor (0.5 pt), and retinal pigment epithelium mottling (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 total pts, PMID: 20683928, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 20683928). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant (suspected in trans, VCEP member-provided data), the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant (suspected in trans, PMID: 32032261), or the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant (confirmed in trans, PMID: 20683928), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state in one family member and in the compound heterozygous state in the other (PP1; PMID: 20683928). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PM4_Supporting, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915941307/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7822 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0085605 infores:hetionet CHEBI:15551 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0043144 infores:hetionet CHEBI:5147 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C3665386 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0233472 infores:hetionet CHEBI:31205 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0030554 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0013295 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1306577 infores:hetionet CAID:CA1244086 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244086 MONDO:0020367 PMID:16466712 Likely Benign BS1, BS3_Supporting BP7, PM2, PM6, PP1, PP3, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.1058C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 353 (p.Thr353Ile). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.009122, which met the ≥ 0.001 threshold set for BS1 (182 alleles out of 19,952, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.316, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Thr353Ile protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244086/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0852911 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0040034 infores:hetionet CHEBI:36791 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0030232 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0080203 infores:hetionet GO:0045691 biolink:causes GO:0009553 infores:ubergraph knowledge_assertion manual_agent GO:0045691 GO:0009553 CHEBI:7444 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0030554 infores:hetionet CHEBI:168396 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0917801 infores:hetionet CHEBI:63630 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013384 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0018799 infores:hetionet CHEBI:27436 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0005779 infores:hetionet CAID:CA1139666836 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666836 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*260C>A is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666836/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA8815163 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815163 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong PM5 The NM_000152.5:c.1082C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 361 (p.Pro361Leu). This variant has been reported in at least 13 individuals with clinical symptoms consistent with Pompe disease including 6 individuals with documented laboratory values showing deficiency of GAA activity below normal range in leukocytes or <1% activity in fibroblasts or another tissue, many of whom were also reported to be showing improvement on enzyme replacement therapy and/or had specific features reported for infantile onset Pompe disease including cardiomyopathy and motor delay (PMID: 21484825, 25139343, 25526786, 26497565, 27344650, 31439017, 31915562) and another patient with features specific for infantile onset Pompe disease, on enzyme replacement therapy (PMID: 30023291). Pseudodeficiency variants, c.1726G>A and c.2065G>A, were reported to be absent in at least one of these patients (PMID: 25526786) (PP4_Moderate). Of the patients reported with this variant, four are compound heterozygous for the variant and another variant in GAA classified as pathogenic by the ClinGen LSD VCEP including c.784G>A (p.Glu262Lys) (PMID: 31915562; confirmed in trans by parental DNA testing) and c.1933G>A (p.Asp645Asn) (PMID: 26497565, 27344650; phase unknown), c.1935C>A (p.Asp645Glu) (PMID: 31439017; phase unknown), and c.2238G>C (p.Trp746Cys) (PMID: 35123860; phase unknown). In addition, two homozygotes have been reported (PMID: 30023291, 31931849), one of whom was identified by next generation sequencing panel for limb girdle muscle weakness, and not counted due to no report of follow up enzyme studies to confirm diagnosis of Pompe disease (PMID: 31931849) (PM3_Strong). Additional patients have been reported with the variant in compound heterozygosity with another variant including c.503G>C (p.Arg168Pro) (PMID: 25526786), c.953T>C (p.Met318Thr) (PMID: 25139343), c.1309C>T (p.Arg437Cys) (PMID: 12601120, 27692865), c.1432G>A (p.Gly478Arg) (PMID: 25213570), c.1979G>A (p.Arg660His) (PMID: 21484825), and c.1551+1G>C (PMID: 16917947). In these cases, the allelic data will be used in the assessment of the second variant and was not applied to PM3 here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells and GAA deficient fibroblasts, this variant resulted in <4% wild type GAA activity in three different studies (PMID: 12601120, 19862843, 22644586) and showed evidence of abnormal synthesis and processing on Western blot (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at the same codon, c.1082C>A (p.Pro361Arg) has been reported (PMID: 31076647). The classification of p.Pro163Leu will be used in the assessment of p.Pro361Arg and, therefore, PM5 is not applied here. There is a ClinVar entry for this variant (Variation ID: 403712, 2 star review status) with four submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815163/MONDO:0009290/010 2022-06-03 2022-06-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7627 biolink:causes EFO:0010671 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0549124 infores:hetionet CHEBI:253342 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1096250 infores:hetionet CHEBI:18067 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0013404 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521491 infores:hetionet CHEBI:50275 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085631 infores:hetionet CHEBI:3423 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0000737 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0006145 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0234215 infores:hetionet CHEBI:68478 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0035222 infores:hetionet CHEBI:31623 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0041834 infores:hetionet CHEBI:63598 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0271298 infores:hetionet CHEBI:31547 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0040264 infores:hetionet CHEBI:39585 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0011603 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042790 infores:hetionet GO:0050931 biolink:causes CL:0000147 infores:ubergraph knowledge_assertion manual_agent GO:0050931 CL:0000147 CHEBI:8871 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0852733 infores:hetionet NCBIGene:2592 biolink:causes MONDO:0009258 infores:monarchinitiative not_provided not_provided HGNC:4135 MONDO:0009258 uuid:9763a06e-7a6a-446c-8e3c-4af36fbfc1e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA214301 biolink:causes MONDO:0015967 infores:clingen CAID:CA214301 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM4_Supporting, PM1_Supporting, PP1_Strong, PP4_Moderate PS4 The c.375_377dup variant in the HNF1 homeobox A gene, HNF1A, is a 3 base pair insertion resulting in the in-frame addition of 1 amino acid at codon 125 (p.Gln125dup) within exon 2 of NM_000545.8. The c.375_377dup variant is predicted to change the length of the protein due to an in-frame insertion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is also located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 8 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). In summary, c.375_377dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM4_Supporting, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214301/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9150 biolink:causes UMLS:C1142028 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C1142028 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0574067 infores:hetionet CHEBI:6888 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151786 infores:hetionet CHEBI:71219 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0860864 infores:hetionet CHEBI:231594 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0013390 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0242350 infores:hetionet CHEBI:10650 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085635 infores:hetionet CHEBI:10127 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151908 infores:hetionet CAID:CA320653 biolink:causes MONDO:0019169 infores:clingen CAID:CA320653 MONDO:0019169 PMID: Likely Pathogenic PP3, PP4, PM2, PM6 BA1, BS1 The c.214C>T (p.R72C) variant in PDHA1 has been reported in multiples males with pyruvate dehydrogenase deficiency with phenotypes ranging from childhood onset Leigh syndrome spectrum (PMID: 8664900) to living into adulthood with ataxia, neuropathy, and dystonia (PMID: 21914562). We did not come across any affected female case reports in this extensive literature review. This variant has been reported to be inherited from a healthy mother (PMID: 10679936; case 3-4) and there have been several de novo case reports, as well. Indeed, this variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least three unrelated individuals with pyruvate dehydrogenase deficiency [PM6; Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID: 10679936, case 3-2; PMID: 10679936, case 3-3; PMID: 21914562, case AM23]. Additionally, this variant has been seen in at least one other individual with documented decreased pyruvate dehydrogenase activity (PP4; Patient 3 in PMID: 15384102 had Leigh syndrome and decreased total PDH complex activity (in native and DCA-activated states) in fibroblast cell line (<3rd percentile of controls). This variant is absent from gnomAD v2.1.1 (PM2). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM6, PP3, PP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA320653/MONDO:0019169/014 2021-10-25 2021-10-25 X-linked inheritance HP:0001417 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:49375 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0006266 infores:hetionet CHEBI:5855 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013144 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018621 infores:hetionet CHEBI:52717 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026821 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151311 infores:hetionet CHEBI:9123 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0022408 infores:hetionet CAID:CA16613005 biolink:causes MONDO:0017623 infores:clingen CAID:CA16613005 MONDO:0017623 PMID: Uncertain Significance PM2, BP4 BS1, PP2, BP1, BA1 PTEN c.253+4G>A (IVS4+4G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populationsBP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613005/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0023610 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0009938 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0031350 infores:hetionet CHEBI:31705 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C3665386 infores:hetionet CHEBI:50841 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0028643 infores:hetionet CHEBI:5613 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0023518 infores:hetionet CHEBI:17688 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0232292 infores:hetionet CHEBI:10124 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0040822 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0340464 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011849 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0011849 infores:hetionet NCBITaxon:562 biolink:causes DOID:50360 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D004756 DB00218_MESH_D004756_1 CHEBI:6741 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0002962 infores:hetionet CHEBI:50922 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0232461 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0162429 infores:hetionet CHEBI:101278 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0022408 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0036572 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004260 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030925 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0011609 infores:hetionet CHEBI:3044 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0232459 infores:hetionet CAID:CA229844 biolink:causes MONDO:0009861 infores:clingen CAID:CA229844 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting The c.911A>G (p.Gln304Arg) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8632937, 22841515, 30747360). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant p.R252W (PM3_supporting). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229844/MONDO:0009861/006 2019-12-14 2021-05-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135925 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0917801 infores:hetionet CHEBI:10124 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0338831 infores:hetionet CHEBI:48273 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0002962 infores:hetionet CHEBI:3393 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0011991 infores:hetionet CAID:CA396465476 biolink:causes MONDO:0007648 infores:clingen CAID:CA396465476 MONDO:0007648 PMID:28152038 Likely Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS2, PS3 The c.1711+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is absent in the gnomAD cohort. (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +1 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). Therefore, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396465476/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA405696830 biolink:causes MONDO:0007783 infores:clingen CAID:CA405696830 MONDO:0007783 PMID: Uncertain Significance PS4_Moderate PP3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of asparagine with aspartic acid at codon 3418 of the RYR1 protein, p.(Asn3418Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.535 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405696830/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:135736 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151905 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0234369 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C2242576 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C2242576 infores:hetionet CAID:CA2499225886 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225886 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.98-3dup is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225886/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7465 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0231530 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0149931 infores:hetionet CHEBI:6909 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0024902 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1443060 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0039503 infores:hetionet CAID:CA512319218 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319218 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.12C>T (p.Asp4=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.09) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.09) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.62)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319218/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51450 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0027497 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0243026 infores:hetionet CHEBI:2682 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0039070 infores:hetionet CHEBI:7986 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C1291077 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151998 infores:hetionet CHEBI:8232 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0030193 infores:hetionet CAID:CA367400637 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400637 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting The c.749G>C variant in the glucokinase gene, GCK, causes an amino acid change of arginine to proline at codon 250 (p.(Arg250Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.748C>T p.Arg250Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg250Pro (PM5_Supporting). In summary, c.749G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400637/MONDO:0015967/086 2024-02-02 2024-02-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:5296 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0002994 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0020565 infores:hetionet CHEBI:8346 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0233471 infores:hetionet CHEBI:64312 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0740394 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0018681 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0004096 infores:hetionet CHEBI:16796 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0020598 infores:hetionet CHEBI:63635 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0030196 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0034634 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0034634 infores:hetionet NCBITaxon:6259 biolink:causes MONDO:0000297 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6259 MONDO:0000297 CHEBI:7986 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0004604 infores:hetionet CHEBI:7936 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0152032 infores:hetionet CHEBI:50156 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0429097 infores:hetionet CHEBI:75984 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0541782 infores:hetionet CHEBI:36791 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235086 infores:hetionet CHEBI:194135 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0030193 infores:hetionet CHEBI:499361 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0700225 infores:hetionet CHEBI:3077 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0917801 infores:hetionet CHEBI:61049 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085631 infores:hetionet CHEBI:8356 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013404 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0043352 infores:hetionet CHEBI:7476 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030554 infores:hetionet CHEBI:184555 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0011991 infores:hetionet CHEBI:7824 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0600142 infores:hetionet CHEBI:7959 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0151632 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0241863 infores:hetionet NCBIGene:55037 biolink:causes MONDO:0033631 infores:monarchinitiative not_provided not_provided HGNC:24717 MONDO:0033631 uuid:8b9b0cbb-a154-48e3-98ae-d7b8099ee2ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020461 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030353 infores:hetionet CHEBI:3387 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018965 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0042075 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0423602 infores:hetionet CHEBI:5128 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0043352 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0041747 infores:hetionet CHEBI:84500 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0026826 infores:hetionet CHEBI:3213 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0020621 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0333641 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0033975 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0027765 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0003123 infores:hetionet NCBIGene:5625 biolink:causes MONDO:0009400 infores:monarchinitiative not_provided not_provided HGNC:9453 MONDO:0009400 uuid:b52b3a3c-73cd-42e5-a09d-df9f56feb6ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017574 infores:hetionet CHEBI:41423 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0040435 infores:hetionet CHEBI:2567 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1321686 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0037928 infores:hetionet CHEBI:39867 biolink:causes HP:0011900 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0553681 infores:hetionet CHEBI:8346 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0042963 infores:hetionet CHEBI:5001 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C3665386 infores:hetionet CHEBI:9123 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085637 infores:hetionet UNII:3QJA87N40S biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0005778 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0004096 infores:hetionet CHEBI:8207 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085932 infores:hetionet CHEBI:4856 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0022107 infores:hetionet CHEBI:63622 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0011991 infores:hetionet CHEBI:32315 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042029 infores:hetionet CHEBI:4856 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0151799 infores:hetionet CHEBI:65173 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0268000 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0235896 infores:hetionet NCBIGene:138050 biolink:causes MONDO:0009657 infores:monarchinitiative not_provided not_provided HGNC:26527 MONDO:0009657 uuid:39f8c5a5-d0ec-4aae-bc63-5a08738d931e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91541 biolink:causes UMLS:C1112366 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C1112366 infores:hetionet CHEBI:28001 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0033774 infores:hetionet CAID:CA437912662 biolink:causes MONDO:0001586 infores:clingen CAID:CA437912662 MONDO:0001586 PMID: Uncertain Significance BP7, BP4, PM2_Supporting The NM_000203.5:c.216C>G (p.Leu72=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing and the variant is not in the first nucleotide or last three nucleotides of an exon (econ 2) (BP7). The computational splicing predictor SpliceAI gives a score of 0.01 for donor gain suggesting that the variant has no impact on splicing (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001334 (1/74938 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 754391). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Variant Curation Expert Panel (Specifications Version 1.0.0): BP4, BP7, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA437912662/MONDO:0001586/091 2025-05-02 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:48273 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0019521 infores:hetionet CHEBI:3757 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0231919 infores:hetionet CHEBI:404903 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018790 infores:hetionet CHEBI:10125 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0039231 infores:hetionet CHEBI:135930 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0030807 infores:hetionet CHEBI:91541 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0011603 infores:hetionet CHEBI:40279 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2981158 infores:hetionet CHEBI:45652 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0022660 infores:hetionet CHEBI:50742 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042963 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0035078 infores:hetionet GO:0060314 biolink:causes GO:0019722 infores:ubergraph knowledge_assertion manual_agent GO:0060314 GO:0019722 CHEBI:7025 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0518015 infores:hetionet CAID:CA386951978 biolink:causes MONDO:0015967 infores:clingen CAID:CA386951978 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PVS1 PP4, PP1 The c.2T>C variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1?) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 18003757, PMID: 23348805, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 was not applied (internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.2T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2, approved 8/4/2022): PVS1, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386951978/MONDO:0015967/017 2022-08-26 2022-08-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75984 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0042571 infores:hetionet CHEBI:28830 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0740394 infores:hetionet CHEBI:59445 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0042963 infores:hetionet CHEBI:71415 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0002874 infores:hetionet CHEBI:84500 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0003862 infores:hetionet CHEBI:116278 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0023518 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0392025 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004431 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0018924 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0344232 infores:hetionet CHEBI:3176 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0392163 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0017601 infores:hetionet CHEBI:7852 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0233477 infores:hetionet CAID:CA000401 biolink:causes MONDO:0017623 infores:clingen CAID:CA000401 MONDO:0017623 PMID:11476841PMID:29785012PMID:29706350 Likely Pathogenic PM2, PP2, PS3, PS4_Moderate BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PP3, PP1, PP4, BS2, PM4, PM1, PM3, PM5, BA1, BP4, BP1, BP3, BP2, PS2, PS1 PTEN c.331T>C (p.Trp111Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29785012, 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) ClinVar Organization ID: 61756, ClinVar Organization ID: 19864)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000401/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8212 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0004936 infores:hetionet CHEBI:9241 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C2225524 infores:hetionet CHEBI:7936 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0392156 infores:hetionet CHEBI:6375 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0016655 infores:hetionet CHEBI:6904 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0234238 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0021053 infores:hetionet CHEBI:107736 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0004238 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0042109 infores:hetionet CAID:CA9870361 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870361 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM5, PS4 The c.691C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 231 (p.(Arg231Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.927, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). Another missense variant, c.692G>A (p.Arg231Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg231Trp has a greater grantham distance (PM5). In summary, c.691C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PM5, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870361/MONDO:0015967/085 2024-05-10 2024-05-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:127342 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0851578 infores:hetionet CHEBI:50729 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0008031 infores:hetionet CHEBI:145499 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0040822 infores:hetionet CHEBI:8597 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0030318 infores:hetionet GO:0060222 biolink:causes GO:0048593 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0048593 CHEBI:44032 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042963 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017675 infores:hetionet CHEBI:63598 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0026896 infores:hetionet CHEBI:8871 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014236 infores:hetionet CHEBI:15765 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0013378 infores:hetionet CAID:CA121519 biolink:causes MONDO:0100039 infores:clingen CAID:CA121519 MONDO:0100039 PMID: Pathogenic PP4, PM2_Supporting, PM6, PVS1 The p.Gln834Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln834Ter variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.Gln834Ter variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of CDKL5 disorder (PMID: 16813600) (PP4). The p.Gln834Ter variant in CDKL5 occurs in the de novo state (biological parentage unconfirmed) in this individual (PM6). In summary, the p.Gln834Ter variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_Supporting, PP4, PM6). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121519/MONDO:0100039/034 2024-10-30 2024-12-04 X-linked inheritance HP:0001417 Supports CHEBI:6472 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0015967 infores:hetionet NCBIGene:5825 biolink:causes MONDO:0014564 infores:monarchinitiative not_provided not_provided HGNC:67 MONDO:0014564 uuid:fd0e068c-ccc3-416a-8b35-d3b8ddae5d0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0015672 infores:hetionet CHEBI:15367 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0022568 infores:hetionet CHEBI:68647 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C1608945 infores:hetionet CHEBI:63599 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0003811 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0029882 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009763 infores:hetionet CAID:CA410203606 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203606 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.298T>A (p.Ser100Thr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203606/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28864 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0031350 infores:hetionet CAID:CA401363854 biolink:causes MONDO:0009290 infores:clingen CAID:CA401363854 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Strong PM5 The NM_000152.5:c.872T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 291 (p.Leu291Pro). At least 5 patients have been reported with this variant and features consistent with Pompe disease, including documented laboratory values showing deficiency GAA activity and/or treated with enzyme replacement therapy, and/or features consistent with infantile onset Pompe disease meeting specifications of the ClinGen LSD VCEP for PP4_Moderate (PMID 17151339, 18458862, 22353292, 22658377, 24243590, 25213570, 31193175). Additional patients have also been reported (PMID 18425781, 18458862, 29095275). Four patients are compound heterozygous for the variant and GAA variant classified as pathogenic by the ClinGen LSD VCEP, phase unknown, including c.1411_1414del (PMID 24243590; ClinVar SCV001443324.1), c.1798C>T (p.Arg600Cys)(PMID 18458862, 22353292, 25213570; 2 patients), and c.1935C>A (p.Asp645Glu)(PMID 29095275), and at least 2 patients are homozygous for the variant (PMID 16857770, 17151339, 18458862, 22658377, 31193175)(PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). When expressed in COS cells, this variant had 0.7% wild type GAA activity in cells and showed evidence of abnormal synthesis and processing on Western blot (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.908 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other variants have been identified at the same amino acid position, c.871C>T (p.Leu291Phe) and c.872T>A (p.Leu291His). The data from this variant, c.872T>C (p.Leu291Pro), will be used in the classification of p.Leu291Phe and p.Leu291His and is not included here to avoid circular logic. There is no entry for this variant in ClinVar. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PS3_Moderate, PM3_Strong, PM2_Supporting, PP3, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401363854/MONDO:0009290/010 2021-12-02 2021-12-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:119915 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0022904 infores:hetionet CHEBI:8356 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020453 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151883 infores:hetionet CHEBI:63620 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0017181 infores:hetionet CHEBI:41774 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0235378 infores:hetionet CHEBI:3485 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0404521 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0042075 infores:hetionet CHEBI:6413 biolink:causes EFO:0801084 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0596240 infores:hetionet CHEBI:2569 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0041834 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009760 infores:hetionet CHEBI:75722 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0043352 infores:hetionet CHEBI:71255 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0035410 infores:hetionet CHEBI:47780 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0423791 infores:hetionet CHEBI:5778 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0232493 infores:hetionet CHEBI:9674 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0037763 infores:hetionet CHEBI:9943 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0392171 infores:hetionet CHEBI:3127 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0085633 infores:hetionet CAID:CA145883 biolink:causes MONDO:0001586 infores:clingen CAID:CA145883 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.352C>T variant in IDUA is a synonymous (silent) variant (p.Leu118=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2517 (296774/1178988 alleles; 37458 homozygotes) in the European non-Finnish population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92642). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145883/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3994 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0030554 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0002792 infores:hetionet CAID:CA645372415 biolink:causes MONDO:0021056 infores:clingen CAID:CA645372415 MONDO:0021056 PMID: Likely Pathogenic PP3, PM2, PS4_Moderate, PS3_Moderate The NM_000038.6(APC):c.835-7T>G variant in APC is an intronic variant in intron 8. This variant has been reported in 3 families meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate, PMID: 18433509, internal data Labcorp Genetics (formerly Invitae)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEnt) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 8 and creating a cryptic acceptor splice site (PP3). RT-PCR sequencing of cDNA demonstrated that the variant impacts splicing by insertion of the last six bases of intron 8 between exon 8 and 9, the second inserted codon is a stop codon. However, relative quantitation of full-length normal transcript versus mutant was not performed (PS3_Moderate, PMID 18433509). In summary, this variant is a Likely Pathogenic variant for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS4_Moderate, PS3_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA645372415/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28830 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0027497 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0851341 infores:hetionet CHEBI:31980 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0009763 infores:hetionet NCBIGene:846 biolink:causes MONDO:0011013 infores:monarchinitiative not_provided not_provided HGNC:1514 MONDO:0011013 uuid:9391655d-500f-4d90-9324-2ba525435b04 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017574 infores:hetionet CAID:CA033871 biolink:causes MONDO:0007750 infores:clingen CAID:CA033871 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 PS4 The NM_000527.5(LDLR):c.1358+7G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 20 February 2025. The supporting evidence is as follows:PM2: PopMax MAF = 0.0001201 (0.012%) in African/African American exomes/genomes (gnomAD v4.1.0). BP4: No REVEL score, splicing evaluation required. Not on splicing limits and no published functional data on splicing found, so BP4 is met.PP4: Variant meets PM2 and is identified in at least 1 index case (1 case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA033871/MONDO:0007750/013 2025-02-20 2025-06-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:51450 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0040264 infores:hetionet CAID:CA269618 biolink:causes MONDO:0700272 infores:clingen CAID:CA269618 MONDO:0700272 PMID: Likely Pathogenic PM3, PVS1 PS1, BS1, PM2, PP3, BP4, BA1 The c.3350+4A>G variant in PALB2 is an intronic variant proximal to the exon 12 canonical splice donor site. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000008796 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This intronic variant is proximal to the exon 12 canonical splice donor site. RNA analysis demonstrated that the variant impacts splicing, generating two abnormal products: r.3202_ 3350del149, in which exon 12 is skipped, and r.3350insGCAG, which utilizes a cryptic splice donor site, both of which result in translational frameshifts. The resulting mRNA products are not expected to be susceptible to nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region (PMID: 17200671, additional information in Reinhard Kalb dissertation (urn:nbn:de:bvb:20-opus-25823)). This variant has been detected in an individual with Fanconi Anemia that is compound heterozygous for this variant and a pathogenic variant confirmed in trans by parental testing (PALB2 c.2393_2394insCT (p.Thr799fs), PMID: 17200671). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA269618/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:171719 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0018681 infores:hetionet CHEBI:4702 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0014591 infores:hetionet CHEBI:15640 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0013404 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0027769 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0277585 infores:hetionet CHEBI:32221 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0018965 infores:hetionet CHEBI:6339 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0036974 infores:hetionet CAID:CA024095 biolink:causes MONDO:0018493 infores:clingen CAID:CA024095 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PM6_Supporting PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with proline at codon 4665 of the RYR1 protein, p.(Leu4665Pro), c.13994_13995delTCinsCT. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported as de novo in one individual with a personal history of a malignant hyperthermia reaction. This individual did not have a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 17483490), PS4 was not met, PM6_supporting was implemented. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). No REVEL score was available for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM6_Supporting, PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024095/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63598 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0206061 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0746883 infores:hetionet CHEBI:119915 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0022346 infores:hetionet CHEBI:7443 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0392525 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0014742 infores:hetionet CHEBI:145499 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009763 infores:hetionet CHEBI:9599 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0011124 infores:hetionet CHEBI:9434 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042029 infores:hetionet CHEBI:32588 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0019080 infores:hetionet CHEBI:145499 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0008031 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0037199 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0233571 infores:hetionet CHEBI:8382 biolink:causes MONDO:0018616 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0730328 infores:hetionet CHEBI:30659 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0040822 infores:hetionet CHEBI:10023 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031256 infores:hetionet CHEBI:3441 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0152031 infores:hetionet CHEBI:9599 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018500 infores:hetionet CHEBI:16714 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0036974 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0270994 infores:hetionet NCBIGene:2103 biolink:causes MONDO:0012060 infores:monarchinitiative not_provided not_provided HGNC:3473 MONDO:0012060 uuid:c26b1b6a-a5cc-4af8-a95d-f562376d494a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51164 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0020651 infores:hetionet CHEBI:9168 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0014591 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0029443 infores:hetionet CHEBI:45599 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0008031 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0854029 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0854029 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013928 infores:hetionet CHEBI:6062 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0033575 infores:hetionet CHEBI:27690 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0085631 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002136 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0155177 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0162429 infores:hetionet CHEBI:10023 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0035243 infores:hetionet CHEBI:3749 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0019209 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0743680 infores:hetionet NCBIGene:79738 biolink:causes MONDO:0014438 infores:monarchinitiative not_provided not_provided HGNC:26291 MONDO:0014438 uuid:85f820ed-dd49-4eea-adf6-0272ab5598b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:472657 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0015967 infores:hetionet CHEBI:29688 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0018524 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0520588 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042373 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0429098 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0037822 infores:hetionet CHEBI:31711 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0542571 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0035309 infores:hetionet CHEBI:10100 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0423798 infores:hetionet CHEBI:31515 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0003811 infores:hetionet CHEBI:2453 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0042164 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0948586 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0009938 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0005779 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0042109 infores:hetionet CHEBI:15551 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0027497 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0032285 infores:hetionet CHEBI:4453 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0042963 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042514 infores:hetionet CHEBI:7915 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0016658 infores:hetionet GO:1901190 biolink:causes GO:0006412 infores:ubergraph knowledge_assertion manual_agent GO:1901190 GO:0006412 CHEBI:63635 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0002170 infores:hetionet CHEBI:63577 biolink:causes HP:0200123 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0019189 infores:hetionet CAID:CA16602353 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602353 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP1, PP4 The NM_000527.5(LDLR):c.2479G>T (p.Val827Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.86. It is above 0.75, so PP3 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602353/MONDO:0007750/013 2022-01-28 2022-07-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31623 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0011991 infores:hetionet CHEBI:6129 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0002994 infores:hetionet CHEBI:4953 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0015967 infores:hetionet CAID:CA8603374 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603374 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 BS1, PP4, BA1 The c.671-13C>T variant in ITGA2B is an intronic variant which located in intron 6. The variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 0.328102 (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006666 (4/60004 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however no cases of the variant segregating in GT patients were found in the literature. Due to conflicting evidence, this variant is classified as likely benign for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BP4, BP7 and PM2_Supporting (VCEP specifications version 2.1.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603374/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:28915 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0016204 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0518015 infores:hetionet CHEBI:6538 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0522153 infores:hetionet CHEBI:50692 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0020621 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042018 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042133 infores:hetionet GO:2000359 biolink:causes GO:0007338 infores:ubergraph knowledge_assertion manual_agent GO:2000359 GO:0007338 CHEBI:4856 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0033774 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0259749 infores:hetionet CHEBI:15765 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0019080 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0029456 infores:hetionet CHEBI:49713 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0004093 infores:hetionet CHEBI:3082 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0235490 infores:hetionet CAID:CA2580100792 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100792 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PM2_Supporting NM_001034853.2(RPGR):c.3316_3319del (p.Lys1106GlnfsTer24) is a frameshift variant due to a 4-nucleotide deletion introducing a premature stop codon in exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 7 affected meioses from 1 family diagnosed with cone-rod dystrophy (PP1_Moderate; PMID: 12859409). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100792/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:68647 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0085682 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0010709 infores:hetionet CHEBI:63631 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0043094 infores:hetionet CAID:CA220584 biolink:causes MONDO:0009861 infores:clingen CAID:CA220584 MONDO:0009861 PMID:9012412PMID:10679941PMID:26666653PMID:24368688PMID:26666653 Likely Pathogenic PP4_Moderate, PM2, PM3_Strong PP3 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220584/MONDO:0009861/006 2018-08-28 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0033777 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020676 infores:hetionet CAID:CA2739267605 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267605 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1271_1272insTCTC (p.Pro425LeufsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267605/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:18258 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0020649 infores:hetionet CHEBI:6792 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0030252 infores:hetionet CHEBI:8354 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0020578 infores:hetionet CHEBI:68579 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0015672 infores:hetionet NCBIGene:4604 biolink:causes MONDO:0032797 infores:monarchinitiative not_provided not_provided HGNC:7549 MONDO:0032797 uuid:d3ceefa3-d0ec-40bc-b3f2-71b97633f629 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63610 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0037763 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0277919 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0277919 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0948429 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0948429 infores:hetionet NCBIGene:1778 biolink:causes MONDO:0008026 infores:monarchinitiative not_provided not_provided HGNC:2961 MONDO:0008026 uuid:c55aaa9a-e51d-4943-a044-329a84436336 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0027497 infores:hetionet NCBIGene:7137 biolink:causes MONDO:0012746 infores:monarchinitiative not_provided not_provided HGNC:11947 MONDO:0012746 uuid:6fe9a053-abea-49d7-ba39-aeb97e730e2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94848 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0344232 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0858678 infores:hetionet CHEBI:168396 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151539 infores:hetionet CHEBI:188986 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0020555 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0853336 infores:hetionet NCBIGene:387 biolink:causes MONDO:0032884 infores:monarchinitiative not_provided not_provided HGNC:667 MONDO:0032884 uuid:c4fea82c-c539-48e5-8ad2-afd376591171 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72292 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0232462 infores:hetionet CAID:CA10524597 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524597 MONDO:0010278 PMID: Uncertain Significance BS4_Supporting, BP4, PS2, PM2_Supporting The p.Gly46Asp variant in SLC9A6 has been reported in the mosaic state in a male patient with clinical features of Christianson syndrome (internal database) and therefore confirmed to be de novo (PS2). However the variant is not present in one affected family member with autism and developmental delays (BS4_supporting).The p.Gly46Asp variant in SLC9A6 is absent from gnomAD (PM2_supporting). Computational analysis prediction tools suggests that the p.G46D variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Gly46Asp variant in SLC9A6 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PS2, PM2_supporting, BS4_supporting, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524597/MONDO:0010278/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA916084367 biolink:causes MONDO:0008723 infores:clingen CAID:CA916084367 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3, PVS1, PP4_Moderate, PS3_Supporting The c.1606-3_1606-2del variant in ACADVL is a variant that causes a deletion in the canonical splice acceptor site of intron 17. RNA studies in patient cells carrying this variant show that this variant causes use of a cryptic acceptor and deletion of 4 nucleotides of the transcript (P3_Supporting; PMID: 11914034). This is predicted to result in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been reported in trans to a pathogenic variant in an affected individual (PM3; PMID: 11914034). In cells derived from this individual, VLCAD enzyme activity was less than 20% of controls, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting, PS3_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084367/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports UNII:VL0L558GCB biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0030193 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0428977 infores:hetionet CHEBI:2567 biolink:causes MONDO:0019019 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0029434 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0151737 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151737 infores:hetionet CHEBI:6909 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1443060 infores:hetionet CHEBI:31981 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0027849 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0005779 infores:hetionet CHEBI:8207 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0025874 infores:hetionet CHEBI:31622 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0013144 infores:hetionet CHEBI:8435 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0700075 infores:hetionet CHEBI:64321 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0009782 infores:hetionet CAID:CA119892 biolink:causes MONDO:0011132 infores:clingen CAID:CA119892 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PM3, PP1_Strong, PVS1 The NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter) nonsense variant occurs in exon 5 of 9 and is predicted to result in non-sense mediated decay (PVS1). The highest MAF in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). At least one patient (PMID: 10206641) is described with congenital alopecia, nail dystrophy, and very low T cell number which is highly specific to FOXN1 deficiency (PP4). This individual had an affected siblings, also homozygous for the variant, as reported in PMID: 10206641. Additionally PMID: 31447097 reports another 14 heterozygous relatives with nail dystrophy belonging to same extended family (estimated LOD score 4.82; PP1_Strong). At least two additional unrelated patients have been reported, these three unrelated patients are all homozygous (PMIDs: 28636882, 20978268, 10206641; PM3). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4, PP1_strong, PM3 as specified by the ClinGen SCID VCEP FOXN1 subgroup (specifications v1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA119892/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:4868 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0027051 infores:hetionet CHEBI:31711 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0011603 infores:hetionet CHEBI:76607 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0235527 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0015734 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0032584 infores:hetionet CHEBI:9434 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0338908 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0029445 infores:hetionet CHEBI:10124 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0023052 infores:hetionet CHEBI:8768 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003962 infores:hetionet NCBIGene:4338 biolink:causes MONDO:0009644 infores:monarchinitiative not_provided not_provided HGNC:7193 MONDO:0009644 uuid:bc0b82c5-46ce-48a5-8474-657dffbd4e70 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0522224 infores:hetionet GO:1900154 biolink:causes GO:0061430 infores:ubergraph knowledge_assertion manual_agent GO:1900154 GO:0061430 CHEBI:84050 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0013378 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0021167 infores:hetionet CHEBI:8707 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151662 infores:hetionet CHEBI:7478 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0011991 infores:hetionet CHEBI:51164 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0015672 infores:hetionet CHEBI:63629 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0038990 infores:hetionet GO:1903421 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1903421 GO:0051641 UNII:UMD7G2653W biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0027796 infores:hetionet CHEBI:8207 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C1262144 infores:hetionet CHEBI:135736 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0151636 infores:hetionet CAID:CA512341219 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341219 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS2, PS3, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM5, PM1, PM3, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1215G>A (p.Leu405=) is a synonymous variant which is located at a non-conserved nucleotide per an evolutionary conservation algorithm (PhyloP score = -0.00400787 in GRCh38); it is not predicted to have any splicing impact per SpliceAI (BP7, BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341219/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151798 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0036572 infores:hetionet CHEBI:5130 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0041657 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0027947 infores:hetionet CHEBI:3638 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C1443060 infores:hetionet CHEBI:2682 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0423791 infores:hetionet CHEBI:6887 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233471 infores:hetionet CAID:CA8623267 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623267 MONDO:0100326 PMID: Uncertain Significance BS1, PM2, PP3, BP4 The variant NM_000212.3:c.1459C>T is a missense variant causing a substitution of arginine for cysteine at amino acid position 487. The highest population minor allele frequency for this variant in gnomAD v 2.1.1 is 0.0001002 (2/19952 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. Additionally, the computational predictor REVEL gives a score of .44, which is above the ClinGen PD VCEP threshold of <0.25 for BP4, but below the ClinGen PD VCEP PP3 threshold of >0.7. The variant was identified in a predispositional screen of a healthy population by Illumina, and has not been associated with any individuals with Glanzmann thrombasthenia thus far in the scientific literature. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623267/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA10014510 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014510 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.461A>G (p.Gln154Arg) is a missense variant which affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). This missense variant has a REVEL score ≥ 0.88 (0.938) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014510/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0061320 biolink:causes CL:0000474 infores:ubergraph knowledge_assertion manual_agent GO:0061320 CL:0000474 CHEBI:50131 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0003467 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0042571 infores:hetionet UMLS:C0017797 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0004093 infores:hetionet CHEBI:47499 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0014457 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0853149 infores:hetionet CHEBI:63611 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026858 infores:hetionet CHEBI:135925 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0020458 infores:hetionet CHEBI:3181 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011991 infores:hetionet NCBITaxon:6264 biolink:causes MONDO:0005988 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6264 MONDO:0005988 CHEBI:6775 biolink:causes HP:0004743 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0238304 infores:hetionet CHEBI:46295 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0041834 infores:hetionet UNII:D27V6190PM biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0043094 infores:hetionet NCBIGene:56915 biolink:causes MONDO:0859200 infores:monarchinitiative not_provided not_provided HGNC:24662 MONDO:0859200 uuid:9e8ea453-05c2-434c-9da8-36836195b898 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:35789 biolink:causes MONDO:0000331 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:35789 MONDO:0000331 CHEBI:7476 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0003811 infores:hetionet CAID:CA16020981 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020981 MONDO:0009861 PMID: Likely Pathogenic PM2, PM3, PP3, PP4 PM5, PS3, BS3 The c.1247C>A (p.Pro416Gln) variant in PAH has been reported in 2 patients with mild PKU (PP4; PMID: 27413125, 31623983). This variant has been detected with pathogenic variants: p.I306V (PMID: 23430547) and c.664_665del (PMID: 17502162) (PM3). This variant has an extremely low frequency in gnomAD (MAF=0.000008792, PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.986 (PP3). This variant was shown to retain enzyme activity, but unfolds at a faster rate than WT (PMID: 18937047). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020981/MONDO:0009861/006 2021-03-12 2021-03-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:18357 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0242151 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0858259 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003864 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232492 infores:hetionet CHEBI:50924 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0023530 infores:hetionet CHEBI:17303 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C2830004 infores:hetionet NCBIGene:80000 biolink:causes MONDO:0030998 infores:monarchinitiative not_provided not_provided HGNC:31042 MONDO:0030998 uuid:4585e708-bb9e-4b9e-963a-266b94f2bd60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0041834 infores:hetionet CHEBI:44915 biolink:causes HP:0002781 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0740852 infores:hetionet CHEBI:17026 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0233407 infores:hetionet CHEBI:7496 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0003862 infores:hetionet CHEBI:2469 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0040034 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0015695 infores:hetionet CHEBI:6801 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0002965 infores:hetionet GO:1902058 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1902058 GO:0019953 UNII:54Z8M50D6Q biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0235266 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0020651 infores:hetionet CHEBI:6888 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0025289 infores:hetionet CAID:CA401366671 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366671 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3 PS1 The NM_000152.5:c.1437G>C (p.Lys479Asn) variant in GAA alters the last nucleotide of exon 9. The computational predictor SpliceAI predicts that this variant may impact splicing (score for loss of the intron 10 donor splice site = 0.37; possible donor gain 175 bp downstream) (PP3). The computational predictor REVEL gives a score of 0.608 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Three probands have been reported with the variant, all with infantile onset Pompe disease and documented values showing GAA activity in the affected range. One of the patients was on enzyme replacement therapy (PMID: 18458862, 31510962, 32711049) (PP4_Moderate). Two probands are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (ClinVar Variation ID: 4029; SCV002032138.1) (PMID: 18458862, 32711049, 2 x 0.5 points) (PM3). Another proband is compound heterozygous for the variant, confirmed in trans with c.1327-2A>G (PMID: 31510962). The allelic data from this patient will be used in the assessment of the splicing variant and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Other variants of the same splice region have been reported in patients with Pompe disease including c.1437+1G>A (likely pathogenic based on classification by the ClinGen LD VCEP); and c.1437+2T>C (pathogenic based on classification by the ClinGen LD VCEP). However, the SpliceAI score for donor loss is lower than for these other variants, and therefore PS1 was not applied at any strength (see Table 2, PMID: 37352859). There is a ClinVar entry for the variant (Variation ID: 3241647). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366671/MONDO:0009290/010 2024-09-17 2024-09-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8871 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0152029 infores:hetionet CHEBI:7959 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0149745 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0235409 infores:hetionet CAID:CA229290 biolink:causes MONDO:0009861 infores:clingen CAID:CA229290 MONDO:0009861 PMID:10679941 Uncertain Significance PM2, PP3, PP4, PM3_Supporting PM5, PP1 The c.1031G>T (p.Gly344Val) variant in PAH has been reported in 2 siblings with classic PKU, detected with pathogenic variant p.R243Q. (PMID: 10679941). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Ser and p.Gly344Arg are likely pathogenic by PAH VCEP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229290/MONDO:0009861/006 2021-06-11 2021-06-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:83804 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0033774 infores:hetionet CHEBI:50922 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020546 infores:hetionet CAID:CA10585453 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585453 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP4, BA1, PS1, BS1, PM5 The NM_000527.5(LDLR):c.1441G>A (p.Val481Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0000008475 (0.00008475%) in European (non-Finnish) exomes + genomes (gnomAD v4.1.0).PP3: REVEL = 0.83. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585453/MONDO:0007750/013 2025-02-28 2025-04-10 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15367 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003123 infores:hetionet CHEBI:36795 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0853034 infores:hetionet CAID:CA227897 biolink:causes MONDO:0100438 infores:clingen CAID:CA227897 MONDO:0100438 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting PP3, PS3 NM_014336.5(AIPL1):c.784G>A (p.Gly262Ser) is an apparent missense variant predicted to result in replacement of glycine with serine at codon 262 but which is also located in the final nucleotide of exon 5 of 6. The splicing impact predictor SpliceAI gives a score of 0.72 for donor gain, which is above the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. A minigene assay indicates that the variant abolishes the production of normal length splice products and instead results in cryptic splice usage and either complete skipping of exon 5 or skipping of the last 40 bp of exon 5. These computational and experimental data have not been used to meet PP3 and PS3_Supporting but rather combined to indicate a null impact on AIPL1 (PVS1(RNA)). A number of publications studying this variant as an exogenously expressed missense change p.Gly262Ser have shown functional activity comparable to the wild-type control (PMID: 15347646 , PMID: 18408180, PMID: 27268253), however BS3_Supporting has not been applied as the variant appears to impact AIPL1 functionally through a splicing defect rather than a missense mechanism. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00007188, with 116 alleles / 1,613,738 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) variant suspected but not confirmed in trans (0.5 points, PMID: 10873396), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with visual acuity limited to hand movements (1 pt), mild maculopathy (0.5 pts), mild optic nerve pallor (0.5 pts), moderate-to-severe pigmentary retinopathy (1 pt), and photoattraction (1 pt), which together are specific for AIPL1-related retinopathy (total 4.5 points, PMID: 15249368, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1(RNA), PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025), Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227897/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:66901 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0027765 infores:hetionet CHEBI:94449 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0424489 infores:hetionet CHEBI:4995 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0030252 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0026946 infores:hetionet NCBIGene:51434 biolink:causes MONDO:0859220 infores:monarchinitiative not_provided not_provided HGNC:17380 MONDO:0859220 uuid:7332ba21-7c42-4007-8099-87076b9753d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0235431 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0232197 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0152025 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0037284 infores:hetionet CHEBI:4027 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0018965 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0413252 infores:hetionet CHEBI:4822 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0085616 infores:hetionet CAID:CA312807 biolink:causes MONDO:0009861 infores:clingen CAID:CA312807 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 PP4 c.2T>C (p.Met1Thr) is a null PAH variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has an extremely low frequency in ExAC, ESP, gnomAD. However, it has not been reported in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA312807/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports NCBITaxon:1747 biolink:causes MONDO:0011438 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1747 MESH:D000152 DB00199_MESH_D000152_1DB12447_MESH_D000152_1DB01017_MESH_D000152_1DB12924_MESH_D000152_1DB00634_MESH_D000152_1DB00250_MESH_D000152_1DB00548_MESH_D000152_2DB00257_MESH_D000152_3DB00759_MESH_D000152_1 CHEBI:100241 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151692 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0012359 infores:hetionet CHEBI:3508 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0033774 infores:hetionet CHEBI:31709 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C3160741 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0009806 infores:hetionet CHEBI:6538 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0231528 infores:hetionet CHEBI:36704 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0917801 infores:hetionet CHEBI:47612 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C1368065 infores:hetionet CAID:CA2580616968 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580616968 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.1582_1585del (p.Thr528fs) is a 4-bp deletion variant in exon 14 of 15, which results in a frameshift and premature stop codon after 4 amino acids and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retiniopathy (PMIDs: 33372982, 14564670, PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616968/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Supports UMLS:C0004609 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0009806 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0013985 infores:hetionet CHEBI:7789 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0085631 infores:hetionet NCBIGene:80184 biolink:causes MONDO:0012626 infores:monarchinitiative not_provided not_provided HGNC:29021 MONDO:0012626 uuid:c7f4cbbf-9d2a-4954-bba1-69f1d682a58a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA160117 biolink:causes MONDO:0012163 infores:clingen CAID:CA160117 MONDO:0012163 PMID: Likely Benign BS2_Supporting, BS1 The c.1231A>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 411 (p.Thr411Ala).The filtering allele frequency (the lower threshold of the 95% CI of 329/24950) of the c.1231A>G variant in IL7R is 0.01172 in exomes (4 homozygous reported) and 0.01126 in genomes (1 homozygous reported) for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1). Five (05) adult homozygous individuals with this variant are present in gnomAD v2.1.1 (African/African American)(BS2_Supporting). The variant has not been identified in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160117/MONDO:0012163/119 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3698 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0003862 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0011849 infores:hetionet CHEBI:75722 biolink:causes HP:0005537 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1096368 infores:hetionet CHEBI:6838 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0080274 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0042075 infores:hetionet CAID:CA399805683 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805683 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The c.575-2A>T variant in ITGA2B occurs within the canonical splice acceptor site of intron 4. It is predicted to result in a frameshift of 46 amino acids with a premature stop codon in exon 7, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 2 in PMID: 36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, there was only 1% αIIb platelet surface expression by flow cytometry. This individual, from a consanguineous family, was homozygous for the variant (PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting and PM3_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805683/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:10650 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0037199 infores:hetionet CHEBI:5959 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0002994 infores:hetionet CHEBI:53760 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0019521 infores:hetionet NCBIGene:55027 biolink:causes MONDO:0031071 infores:monarchinitiative not_provided not_provided HGNC:26087 MONDO:0031071 uuid:3ecf4cfa-07dc-488d-90d4-032f0a3ad9bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0036508 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0022660 infores:hetionet CHEBI:9168 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0002994 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0152029 infores:hetionet CHEBI:17026 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0040822 infores:hetionet CHEBI:44185 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0232462 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0034186 infores:hetionet CHEBI:4910 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0030193 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0574067 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0013395 infores:hetionet CHEBI:16914 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0232462 infores:hetionet CHEBI:4702 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0013428 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1142412 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0027651 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0162281 infores:hetionet CHEBI:3752 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0438717 infores:hetionet CHEBI:8107 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0428977 infores:hetionet CHEBI:9448 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0026821 infores:hetionet CAID:CA5416704 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416704 MONDO:0011225 PMID: Benign BA1, BS2_Supporting The c.728A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 243 (p.His243Arg).The filtering allele frequency (the lower threshold of the 95% CI of 13221/60002) of the c.728A>G variant in DCLRE1C is 0.2249 for Admixed American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, 23214 adult homozygous have been reported (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416704/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:61049 biolink:causes UMLS:C0858346 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0858346 infores:hetionet UNII:R43D2573WO biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0340865 infores:hetionet CHEBI:8502 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0003862 infores:hetionet CHEBI:4027 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0035222 infores:hetionet NCBIGene:84978 biolink:causes MONDO:0859305 infores:monarchinitiative not_provided not_provided HGNC:28214 MONDO:0859305 uuid:30724737-dd6f-42de-a57b-e2bc818c24e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes UMLS:C0948779 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0948779 infores:hetionet CHEBI:15407 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0013404 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0014130 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0262397 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0855242 infores:hetionet CHEBI:63577 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0027497 infores:hetionet CHEBI:82716 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0031542 infores:hetionet CHEBI:8212 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C2981158 infores:hetionet CHEBI:6717 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0235266 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0033975 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0025061 infores:hetionet CHEBI:15854 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0919715 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0231230 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0231230 infores:hetionet CAID:CA343774114 biolink:causes MONDO:0013144 infores:clingen CAID:CA343774114 MONDO:0013144 PMID: Pathogenic PS4, PP3, PP4, PM2_Supporting The NM_000488.4(SERPINC1):c.953C>T variant predicts a Pro318Leu missense change. It is absent from gnomAD v2.1.1 and v3.1.2, meeting criteria for PM2_Supporting. It has a REVEL score of 0.956 and meets PP3 (threshold >0.6). At least 2 probands with AT deficiency (and repeat sampling) are reported in the literature (PP4) and 8 probands with AT deficiency and a positive family history are noted from internal VCEP data, meeting criteria for PS4_Very Strong. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP3, PP4, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343774114/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71255 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020538 infores:hetionet CHEBI:38562 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0151786 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0235876 infores:hetionet NCBIGene:3178 biolink:causes MONDO:0014181 infores:monarchinitiative not_provided not_provided HGNC:5031 MONDO:0014181 uuid:b575be2b-069d-4078-925a-2c5daadc560c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:34967 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0033774 infores:hetionet CHEBI:499361 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0042023 infores:hetionet NCBIGene:64218 biolink:causes MONDO:0012463 infores:monarchinitiative not_provided not_provided HGNC:10729 MONDO:0012463 uuid:1d7f103e-434a-4e76-8928-9493f5b3e72a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474053 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0013395 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0041912 infores:hetionet CAID:CA2424845361 biolink:causes MONDO:0100437 infores:clingen CAID:CA2424845361 MONDO:0100437 PMID:33467000 Likely Pathogenic PVS1, PS1_Supporting PM2, PP3, PP4, PS3, PS4, BS1 NM_001034853.2(RPGR):c.1573-12A>G is a non-coding variant in intron 13 that is located outside the +/- 1,2 dinucleotide but is part of the same splice acceptor motif and has the same predicted impact on splice acceptor loss as another variant, NM_001034853.2(RPGR):c.1573-1G>A, that was previously classified as pathogenic by the X-linked IRD VCEP (PS1_Supporting). The splicing impact predictor SpliceAI gives delta scores of 0.77 for acceptor loss, 0.51 for acceptor gain, and 0.30 for donor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. HEK293T cells expressing minigene constructs harboring the variant produced a band of smaller size in comparison to the wild-type control (PMID: 33467000). This disrupted splicing and induced skipping of exon 14 is expected to be deleterious to RPGR function (PVS1). This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002271 among hemizygous individuals, with 1 variant allele / 880,809 total allele, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.0000005 and fails to meet this criterion. At least one male proband harboring this variant exhibits a phenotype that includes visual field constriction (0.5 pts), photophobia (0.5 pts), night blindness (0.5 pts), decreased central visual acuity (0.5 pts), and bone spicule pigmentation (0.5 pts), with genotyping by whole exome sequencing that did not identify an alternative basis for retinal disease (2 pts), and scotopic and photopic electroretinograms showing residual photopic responses. However, the onset was reportedly after age 40 years, so the phenotype is not sufficiently specific for RPGR-related retinopathy to meet PP4 (4.5 points, PMID: 33467000). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PS1_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2424845361/MONDO:0100437/106 2025-10-06 2025-10-06 X-linked inheritance HP:0001417 Supports NCBIGene:3703 biolink:causes MONDO:0014270 infores:monarchinitiative not_provided not_provided HGNC:6172 MONDO:0014270 uuid:be660cdd-47d9-4088-ba89-1e0993dc143a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7496 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0037763 infores:hetionet CAID:CA7176746 biolink:causes MONDO:0021060 infores:clingen CAID:CA7176746 MONDO:0021060 PMID: Uncertain Significance BP4 BA1, BS1, PM2 The c.3584C>T (NM_006939.4(SOS2):c.3584C>T (p.Ala1195Val)) variant in SOS2 is a missense variant predicted to cause substitution of alanine by valine at amino acid 1195. The filtering allele frequency in gnomAD v2.1.1 is 0.003446 % (no population codes met). The computational predictor REVEL gives a score of 0.183 which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7176746/MONDO:0021060/042 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0004609 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C1456784 infores:hetionet CHEBI:5790 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0700200 infores:hetionet CHEBI:6715 biolink:causes MONDO:0016755 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0027830 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0038362 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0235966 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0009806 infores:hetionet NCBIGene:8989 biolink:causes MONDO:0014021 infores:monarchinitiative not_provided not_provided HGNC:497 MONDO:0014021 uuid:084cf86a-1f7a-482d-98d1-40a0e05795a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes MONDO:0005316 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0085166 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0020538 infores:hetionet CHEBI:408174 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C1458155 infores:hetionet CHEBI:31536 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0030193 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0851341 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0019112 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0948089 infores:hetionet CHEBI:2676 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0040434 infores:hetionet CHEBI:28445 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0011175 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0852733 infores:hetionet CHEBI:5855 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0041657 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0858797 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0235496 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0235496 infores:hetionet CHEBI:50924 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0015967 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0030193 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0042373 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042514 infores:hetionet CHEBI:9635 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0023380 infores:hetionet CHEBI:7820 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0014534 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151763 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0235431 infores:hetionet CHEBI:7577 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0035305 infores:hetionet CAID:CA145984 biolink:causes MONDO:0009861 infores:clingen CAID:CA145984 MONDO:0009861 PMID: Benign BA1 BP4 PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.49022 in ExAC. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA145984/MONDO:0009861/006 2019-02-26 2019-04-06 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:46081 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0232462 infores:hetionet CHEBI:135939 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0014518 infores:hetionet CHEBI:114785 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0085593 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1384353 infores:hetionet NCBIGene:8882 biolink:causes MONDO:0859146 infores:monarchinitiative not_provided not_provided HGNC:13051 MONDO:0859146 uuid:637e6d50-e652-4552-af75-c4afe3c11000 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0948594 infores:hetionet CHEBI:3032 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0020580 infores:hetionet NCBIGene:6566 biolink:causes MONDO:0014490 infores:monarchinitiative not_provided not_provided HGNC:10922 MONDO:0014490 uuid:71023906-ecf3-40f9-9de5-28c70bd47978 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0162297 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C2939147 infores:hetionet NCBIGene:23405 biolink:causes MONDO:0018445 infores:monarchinitiative not_provided not_provided HGNC:17098 MONDO:0018445 uuid:3d4d6df2-a076-42bc-9f24-c8e26e800b69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82981 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0000737 infores:hetionet CHEBI:6076 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0085649 infores:hetionet CHEBI:7601 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0019158 infores:hetionet NCBIGene:54456 biolink:causes MONDO:0030818 infores:monarchinitiative not_provided not_provided HGNC:7201 MONDO:0030818 uuid:0277bb8b-e736-4182-82e2-a428e267c6e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018965 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0038354 infores:hetionet GO:0002300 biolink:causes CL:0000796 infores:ubergraph knowledge_assertion manual_agent GO:0002300 CL:0000796 CHEBI:75722 biolink:causes EFO:0011023 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0006107 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0018099 infores:hetionet CAID:CA2580100908 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100908 MONDO:0100437 PMID: Uncertain Significance PS1_Moderate, PP3, PM2_Supporting PS4 NM_001034853.2(RPGR):c.154+5G>A is a non-coding variant in intron 2. The splicing impact predictor SpliceAI gives delta scores of 0.96 for donor loss and 0.49 for acceptor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing (PP3). Another variant in the same donor motif with the same predicted splicing impact, NM_001034853.2(RPGR):c.154G>A (p.Gly52Arg), was previously classified as pathogenic for RPGR-related retinopathy by the X-linked IRD VCEP (PS1_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband (PMID: 38927562). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses, was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PS1_Moderate, and PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100908/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance (primarily recessive with milder female expression) Inconclusive true UNII:G4PX8C4HKV biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0151539 infores:hetionet CHEBI:28445 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0020625 infores:hetionet CHEBI:3814 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0018681 infores:hetionet CAID:CA229479 biolink:causes MONDO:0009861 infores:clingen CAID:CA229479 MONDO:0009861 PMID:9521426PMID:9521426 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.194T>A (p.Ile65Asn) variant was identified in a patient with classic PKU. BH4 deficiency was ruled out. (PMID: 9521426). It was detected in trans with known pathogenic mutation c.143T>C (p.L48S). It has an extremely low frequency in PAGE (0.00026); and is absent from ExAC, 1000 Genomes, gnomAD. Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229479/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:194135 biolink:causes UMLS:C0860801 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0860801 infores:hetionet CHEBI:10100 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0018939 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0029408 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2939147 infores:hetionet CHEBI:6933 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0080274 infores:hetionet CHEBI:4995 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151772 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0011615 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0855242 infores:hetionet CHEBI:44032 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0002994 infores:hetionet CHEBI:75045 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0042029 infores:hetionet CAID:CA397319477 biolink:causes MONDO:0009276 infores:clingen CAID:CA397319477 MONDO:0009276 PMID:26133172 Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong, PS3_Supporting The c.987G>A (p.Trp329Ter) variant in GP1BA is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient 1 in PMID: 26133172) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had macrothrombocytopenia which is consistent with Bernard-Soulier syndrome (PP4). This variant has been detected in at least 1 proband with Bernard-Soulier syndrome (Case 1 in PMID: 26133172). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). Surface expression of GP1a and GP9 measured by flow cytometry and Western blot in CHO cells transiently co-transfected with c.987G>A (p.Trp329Ter) variant GP1a and wild type GP1b, and GP9 showed decreased expression at 1% WT levels, indicating that this variant impacts protein function (PMID: 26133172, PS3_supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is absent (based on 1/1179858 alleles) in the European (non Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporintg, PS3_Supporting, and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397319477/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:107736 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0023530 infores:hetionet CHEBI:6129 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0032617 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0019158 infores:hetionet CHEBI:92607 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0013404 infores:hetionet NCBIGene:7490 biolink:causes MONDO:0007635 infores:monarchinitiative not_provided not_provided HGNC:12796 MONDO:0007635 uuid:e89859ec-4644-497f-8702-54a0870bf2ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0017178 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0024117 infores:hetionet CAID:CA410147727 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147727 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1231G>A (p.Ala411Thr) is a missense variant which has a REVEL score < 0.50 (0.103) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147727/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7573 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0234215 infores:hetionet CHEBI:135005 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0085649 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0021400 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0022081 infores:hetionet CHEBI:28177 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0085631 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0852913 infores:hetionet CHEBI:3082 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151746 infores:hetionet CHEBI:6444 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0012569 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0027651 infores:hetionet NCBIGene:2625 biolink:causes MONDO:0007797 infores:monarchinitiative not_provided not_provided HGNC:4172 MONDO:0007797 uuid:e461ba7f-ff87-472a-b715-434f9b5653f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0151773 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C1443060 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1959622 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1959622 infores:hetionet CHEBI:9448 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0038325 infores:hetionet UMLS:C0879264 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0546817 infores:hetionet CHEBI:48273 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0085631 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151849 infores:hetionet CHEBI:51164 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0039231 infores:hetionet CHEBI:50648 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235378 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027769 infores:hetionet CHEBI:17698 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0001824 infores:hetionet NCBIGene:79709 biolink:causes MONDO:0100105 infores:monarchinitiative not_provided not_provided HGNC:26182 MONDO:0100105 uuid:d4cf9006-0e2c-40a0-a8b2-fa83a56e3a4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085932 infores:hetionet CHEBI:66876 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0039231 infores:hetionet CHEBI:63617 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151636 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0750194 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0750194 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0553737 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0553737 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1442826 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0497327 infores:hetionet CHEBI:63611 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014236 infores:hetionet CAID:CA410150242 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150242 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.833C>G (p.Pro278Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150242/MONDO:0011071/008 2025-07-11 2025-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63621 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015397 infores:hetionet CHEBI:490877 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0231528 infores:hetionet CHEBI:34967 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0043352 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042018 infores:hetionet NCBIGene:84340 biolink:causes MONDO:0032726 infores:monarchinitiative not_provided not_provided HGNC:29682 MONDO:0032726 uuid:2e7316ff-423e-4555-a835-2a6ebaa5d07d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0042963 infores:hetionet CAID:CA410202624 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202624 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.431T>A (p.Leu144Gln) is a missense variant affecting one of the residues within the Runt Homology Domain, but not a known hotspot residue (PM1_supporting). This variant has a REVEL score ≥ 0.88 (0.985) (PP3). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202624/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0041912 infores:hetionet CHEBI:51450 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0026821 infores:hetionet CHEBI:9168 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151746 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0233494 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0162429 infores:hetionet CHEBI:6904 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C3665347 infores:hetionet CHEBI:3534 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0009782 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0009450 infores:hetionet CHEBI:47898 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030554 infores:hetionet CHEBI:2569 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0011603 infores:hetionet CHEBI:10023 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0242429 infores:hetionet UMLS:C0011701 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0004093 infores:hetionet CHEBI:6950 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0023530 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0521510 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0521510 infores:hetionet CHEBI:9014 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0027697 infores:hetionet CHEBI:68575 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0006266 infores:hetionet CHEBI:35677 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0011991 infores:hetionet NCBIGene:92211 biolink:causes MONDO:0013348 infores:monarchinitiative not_provided not_provided HGNC:14550 MONDO:0013348 uuid:4dd07ea6-09f4-4236-97be-30a1bbb8f891 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40050 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0027051 infores:hetionet UMLS:C1709429 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0151699 infores:hetionet CHEBI:94807 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0917801 infores:hetionet CHEBI:31644 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0344232 infores:hetionet CAID:CA226596 biolink:causes MONDO:0100368 infores:clingen CAID:CA226596 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting This is a frameshift variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg124Ter variant confirmed in trans (1 point, PMID: 9501220), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3).This variant has an allele frequency of 0.0001148 (1/8712) in the African/African-American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) for this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226596/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6062 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027769 infores:hetionet CHEBI:87681 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0687713 infores:hetionet CHEBI:27777 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C2047937 infores:hetionet CHEBI:94411 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0030252 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0919866 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0919866 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0153690 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0153690 infores:hetionet GO:0046828 biolink:causes GO:0006403 infores:ubergraph knowledge_assertion manual_agent GO:0046828 GO:0006403 CHEBI:63621 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C2607914 infores:hetionet CHEBI:2636 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0020598 infores:hetionet CHEBI:75045 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151905 infores:hetionet CHEBI:367163 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0520573 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0034065 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017160 infores:hetionet CAID:CA410146734 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146734 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS2, PM6, BP7 NM_001754.5(RUNX1):c.1408G>A (p.Ala470Thr) is a missense variant which has a REVEL score < 0.50 (0.067) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146734/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16755 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0178298 infores:hetionet CHEBI:6067 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0032227 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0029882 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0012833 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0332534 infores:hetionet CAID:CA320741302 biolink:causes MONDO:0011071 infores:clingen CAID:CA320741302 MONDO:0011071 PMID: Uncertain Significance BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NC_000021.9:g.35049406del is a noncoding variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.88 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant was reported in ClinVar in 2019 by GeneDX but the affected status of the proband is unknown (Variation ID 1290150). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741302/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA229751 biolink:causes MONDO:0009861 infores:clingen CAID:CA229751 MONDO:0009861 PMID:10693064PMID:26666653PMID:26666653 Likely Pathogenic PP3_Strong, PM5, PP4, PM2_Supporting, PM3_Supporting PM1 The c.770G>A variant in PAH is a missense variant predicted to cause substitution of Glycine by Aspartic acid at amino acid 257 (p.Gly257Asp). At least one patient with this variant displayed plasma Phenylalanine > 1200 μmol/L, which is highly specific for PAH deficiency; BH4 deficiency was not reported to be ruled out (PP4, PMID: 10693064, 26666653). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.995, which is above the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_strong). Another missense variant c.770G>T, (p.Gly257Val) [ClinVar Variation ID102830] in the same codon has been classified as pathogenic for PAH deficiency by the ClinGen PAH VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4, PM2_supporting, PP3_strong, PM5. (PAH VCEP specifications version 2.0.0; 01/03/2025). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229751/MONDO:0009861/006 2025-04-18 2025-04-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8597 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0003467 infores:hetionet CAID:CA2499215929 biolink:causes MONDO:0800472 infores:clingen CAID:CA2499215929 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3, PP1_Moderate, PS3_Supporting, PVS1 PP3, BP4, BA1, PM1, PM4, PM5, PS1, PS2, BP7, BS1, BS4 The c.434_443del variant in CYP1B1 is a deletion of ten consecutive nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 4 of the frameshift (p.Arg145ProfsTer4). The highest minor allele frequency of this variant was in the Middle Eastern genetic ancestry group of gnomAD (v4.1.0) = 0.0003358 (2 alleles out of 5956), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This frameshift variant was predicted to undergo NMD, meeting PVS1. A previous study (PMID: 12807732) demonstrated that the Arg145ProfsTer4 protein had reduced Benzo[a]pyrene Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 2 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 23767995), which fulfilled PP1_Moderate. This variant has been identified in four individuals with a CYP1B1-related phenotype. One individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) and three individuals are homozygous (consanguineous) (PMIDs: 22128238, 10655546, 16735994, 23767995). Total proband points = 1.25, meeting PM3. In summary, this variant met the criteria to receive a score of 14 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM3, PP1_Moderate, PS3_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499215929/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9150 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0003862 infores:hetionet CHEBI:18248 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0003862 infores:hetionet CHEBI:144093 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0542571 infores:hetionet CHEBI:92998 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0016204 infores:hetionet CHEBI:2611 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013428 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0748052 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0748052 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018099 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0001824 infores:hetionet CHEBI:18332 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0000737 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0033975 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0042109 infores:hetionet CHEBI:32139 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0030554 infores:hetionet CHEBI:59750 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0151514 infores:hetionet CHEBI:2948 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0231528 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C2939147 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0549297 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0549297 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0860239 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0027947 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0392168 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0392168 infores:hetionet NCBIGene:2591 biolink:causes MONDO:0100252 infores:monarchinitiative not_provided not_provided HGNC:4125 MONDO:0100252 uuid:8bca2114-7567-4ab5-a2ae-dd831da42d7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39112 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0702166 infores:hetionet CHEBI:63617 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085623 infores:hetionet CHEBI:168396 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013428 infores:hetionet CHEBI:7986 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0851578 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0022661 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0012359 infores:hetionet CHEBI:46557 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020598 infores:hetionet CHEBI:92712 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0002622 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0019112 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0235002 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235002 infores:hetionet CHEBI:4024 biolink:causes MONDO:0006918 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0042167 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0003123 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0027051 infores:hetionet CHEBI:6775 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033771 infores:hetionet CAID:CA16041896 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041896 MONDO:0009290 PMID:24976573 Pathogenic PVS1, PM2, PP4, PM3_Supporting This variant, c.1824_1828dup (p.Ala610AspfsTer88), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. A patient with infantile onset Pompe disease, meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported who is homozygous for the variant (PMID 24976573). This data meets PM3_Supporting. There is a ClinVar entry for this variant (Variation ID: 370866, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041896/MONDO:0009290/010 2020-10-29 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA512318974 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318974 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, PVS1, PM6, BP7, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.135C>G (p.Thr45=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318974/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6149 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0033771 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0150450 infores:hetionet CHEBI:39867 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0027497 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0029408 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0919980 infores:hetionet CHEBI:3423 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0032290 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0011616 infores:hetionet CHEBI:408174 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0009782 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0302295 infores:hetionet CHEBI:70707 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0013395 infores:hetionet CHEBI:135888 biolink:causes MONDO:0004612 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0019623 infores:hetionet CHEBI:144093 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0231528 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004238 infores:hetionet CHEBI:41977 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0017181 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0035078 infores:hetionet NCBIGene:2177 biolink:causes MONDO:0009214 infores:monarchinitiative not_provided not_provided HGNC:3585 MONDO:0009214 uuid:60c23a03-6727-434d-9e89-36dfa06d2307 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5893 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0004096 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0036572 infores:hetionet UBERON:0001811 biolink:causes MONDO:0003453 infores:ubergraph knowledge_assertion manual_agent UBERON:0001811 MONDO:0003453 CHEBI:8869 biolink:causes MONDO:0007721 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C3489393 infores:hetionet CHEBI:6954 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0013144 infores:hetionet CAID:CA7542760 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542760 MONDO:0012996 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_001482.3:c.1170C>G (p.Thr390=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by PhyloP (BP7). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 513891). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GATM-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542760/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6520 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0235030 infores:hetionet CHEBI:27690 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0004134 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151723 infores:hetionet CHEBI:6375 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002792 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0021400 infores:hetionet CHEBI:8694 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01589 UMLS:C2830004 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0009450 infores:hetionet NCBITaxon:39824 biolink:causes MONDO:0005777 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:39824 MONDO:0005777 CHEBI:7936 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0522224 infores:hetionet CHEBI:17347 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0015672 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0424000 infores:hetionet CHEBI:100246 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0015672 infores:hetionet CHEBI:10124 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151594 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023530 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1956346 infores:hetionet CHEBI:421707 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0877359 infores:hetionet CHEBI:145499 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011603 infores:hetionet CHEBI:5790 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0030554 infores:hetionet CHEBI:92923 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0549567 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0002792 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0036572 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018799 infores:hetionet NCBIGene:64376 biolink:causes MONDO:0030867 infores:monarchinitiative not_provided not_provided HGNC:14283 MONDO:0030867 uuid:97d45ba6-12b7-4b9b-ba46-98eb374ec970 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386954870 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954870 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PM5_Supporting, PP4_Moderate, PP3 PS4 The c.319C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 107 (p.(Leu107Val)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is predicted to be deleterious by computational evidence, with a REVEL score of 0.8209, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with diabetes with four informative meioses in two families (PP1_Strong; internal lab contributors). One of the individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative HNF4A testing, and antibody negative) (PP4_Moderate; internal lab contributor). Additionally, another missense variant, c.319C>A (p.Leu107Ile), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.319C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 8/18/21): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954870/MONDO:0015967/017 2021-09-10 2021-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6375 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1368065 infores:hetionet CAID:CA412729246 biolink:causes MONDO:0100437 infores:clingen CAID:CA412729246 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.3001G>T (p.Glu1001Ter) is a nonsense variant that introduces a premature stop in codon 1001 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 5 years (1 pt), reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing pigment deposits (0.5 pts), visual field constriction (0.5 pts), optic disc pallor (0.5 pts), severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5.5 points, PMID: 36276946, PP4). The variant has been reported to segregate with retinal dystrophy through at least 5 affected meioses from 1 family (PP1_Moderate; PMID: 36276946). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1_Moderate, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412729246/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:68647 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0160390 infores:hetionet CHEBI:100147 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0038325 infores:hetionet CHEBI:7459 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0013404 infores:hetionet GO:2000084 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:2000084 GO:0001823 NCBIGene:5479 biolink:causes MONDO:0009805 infores:monarchinitiative not_provided not_provided HGNC:9255 MONDO:0009805 uuid:f98e60d7-00e0-44ae-9913-f84fe0ecf9af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0004093 infores:hetionet CHEBI:50730 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0231528 infores:hetionet HP:0031377 biolink:causes MONDO:0010029 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D014402 DB01590_MESH_D014402_1 CHEBI:499361 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0085593 infores:hetionet CHEBI:45327 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0039070 infores:hetionet CHEBI:8093 biolink:causes EFO:1001323 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0015409 infores:hetionet NCBIGene:2065 biolink:causes MONDO:0011868 infores:monarchinitiative not_provided not_provided HGNC:3431 MONDO:0011868 uuid:2db55d71-13f2-4314-8d90-190b197b3eb2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410204129 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204129 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.148G>C (p.Gly50Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204129/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31644 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151594 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0033687 infores:hetionet CHEBI:83804 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0018681 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017160 infores:hetionet CAID:CA226484 biolink:causes MONDO:0100368 infores:clingen CAID:CA226484 MONDO:0100368 PMID: Pathogenic PP3_Moderate, PP1, PM3_Very Strong, PM2_Supporting PP4 NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) is a missense variant that replaces the tyrosine at position 368 with histidine. It has been reported in the literature in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 12960219, PMID: 25257057). The variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A, c.292_311del p.Ile98Hisfs*26, or p.Arg44Ter variant confirmed in trans (3 points, PMIDs: 11786058, PMID: 34492281). All of these variants were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (4 total points, PM3_VeryStrong). The variant has also been reported to segregate with childhood-onset severe retinal dystrophy through at least 1 affected meiosis from 1 family (PP1; PMID:11786058). The variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.00009488, with 19/129116 in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_VeryStrong, PP1, PM2_Supporting, PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226484/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2038 biolink:causes UMLS:C0920166 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0920166 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0031350 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018799 infores:hetionet CHEBI:17303 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0000731 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1720775 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0575090 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0018799 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040435 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0020517 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0160390 infores:hetionet CHEBI:7824 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0149745 infores:hetionet CHEBI:8455 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0025061 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0005940 infores:hetionet CHEBI:391960 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C3263723 infores:hetionet GO:1903132 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1903132 GO:0007275 CHEBI:52717 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021400 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0021099 infores:hetionet NCBIGene:91754 biolink:causes MONDO:0013660 infores:monarchinitiative not_provided not_provided HGNC:18591 MONDO:0013660 uuid:6af1c5aa-6d03-4a8c-b37f-d96b73d3d420 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA397954276 biolink:causes MONDO:0100453 infores:clingen CAID:CA397954276 MONDO:0100453 PMID: Likely Pathogenic PM3, PM1_Supporting, PP3_Moderate, PM2_Supporting NM_000180.4(GUCY2D):c.2765A>G (p.Tyr922Cys) is a missense variant that replaces tyrosine with cysteine at position p.922, which is located within the guanylate cyclase catalytic domain that exhibits intolerance to missense variation (PM1_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state confirmed in trans with the NM_000180.4(GUCY2D):c.2983C>T (p.Arg995Trp) variant, which was previously classified as likely pathogenic by the ClinGen LCA/eoRD VCEP (1 pt, PMID: 29844330, PM3). The computational predictor REVEL gives a score of 0.946 which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.03 for splice donor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM1_Supporting, PM3, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397954276/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CAID:CA913012619 biolink:causes MONDO:0100326 infores:clingen CAID:CA913012619 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting NM_000212.3(ITGB3):c.2068_2069del (p.Val690ArgfsTer7) in exon 13 of ITGB3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 13/15 and is predicted to lead to nonsense mediated decay (PVS1). Homozygous patient PJ displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <1%, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong, PM3_supporting; PMID: 21113249). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA913012619/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:47499 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011615 infores:hetionet CHEBI:84050 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0026858 infores:hetionet GO:0060946 biolink:causes CL:0010006 infores:ubergraph knowledge_assertion manual_agent GO:0060946 CL:0010006 UNII:G4PX8C4HKV biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0042963 infores:hetionet CHEBI:9757 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0006266 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0020517 infores:hetionet CHEBI:63617 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C2937358 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0005940 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0585186 infores:hetionet CHEBI:34385 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0549373 infores:hetionet CHEBI:5132 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0025637 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0020649 infores:hetionet NCBIGene:91252 biolink:causes MONDO:0012873 infores:monarchinitiative not_provided not_provided HGNC:20859 MONDO:0012873 uuid:e0d059d1-eb97-4c03-8dfc-b075f47896a3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0917801 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030446 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0267596 infores:hetionet CHEBI:31547 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0740394 infores:hetionet CHEBI:37333 biolink:causes MONDO:0015294 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C1619692 infores:hetionet CHEBI:9763 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0039231 infores:hetionet CHEBI:9139 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0003467 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0595885 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0595885 infores:hetionet NCBITaxon:6204 biolink:causes UMLS:C0338437 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6204 MESH:D020019 DB00518_MESH_D020019_1 CHEBI:45863 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0522055 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151735 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0259768 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020676 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0267792 infores:hetionet CHEBI:40279 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0043094 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0027726 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016385 infores:hetionet CHEBI:4753 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0022081 infores:hetionet CHEBI:10102 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0022107 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042510 infores:hetionet CHEBI:10110 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0014742 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0376288 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0376288 infores:hetionet UBERON:0000084 biolink:causes UBERON:0003220 infores:ubergraph knowledge_assertion manual_agent UBERON:0000084 UBERON:0003220 CHEBI:7494 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0022573 infores:hetionet CAID:CA000290 biolink:causes MONDO:0017623 infores:clingen CAID:CA000290 MONDO:0017623 PMID: Uncertain Significance PM2 PTEN c.*10del (NC_000010.10:g.89725239delT) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000290/MONDO:0017623/003 2021-10-29 2021-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10110 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0027769 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0233794 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0235290 infores:hetionet CHEBI:188986 biolink:causes HP:0011896 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0038534 infores:hetionet CHEBI:31711 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0235710 infores:hetionet CHEBI:3640 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0026821 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0035455 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0409497 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0409497 infores:hetionet UMLS:C0657912 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030196 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0521591 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233472 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0020649 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005032 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0151468 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033687 infores:hetionet GO:2001222 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:2001222 GO:0048699 CHEBI:3732 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0574067 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0026946 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0030554 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005111 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0149678 infores:hetionet CHEBI:5132 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0011124 infores:hetionet CHEBI:51141 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0007222 infores:hetionet CHEBI:6339 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0018524 infores:hetionet CHEBI:132233 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0085631 infores:hetionet CHEBI:10124 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0009763 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020621 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0231530 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0242073 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151735 infores:hetionet CHEBI:47499 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0026961 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0948807 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0031046 infores:hetionet CHEBI:8863 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2937358 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018802 infores:hetionet CHEBI:68478 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0003467 infores:hetionet CHEBI:50924 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0013378 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0948594 infores:hetionet CHEBI:3228 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0009676 infores:hetionet CAID:CA8603453 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603453 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the synonymous variant NM_000419.5(ITGA2B):c.487T>C (p.Leu163=), no individuals with Glanzmann thrombasthenia were reported with the variant. The variant has a minor allele frequency of 0.00068 (24/35340) in the Latino population in gnomAD, which does not meet our threshold criteria for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -1.245 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603453/MONDO:0100326/011 2023-01-17 2023-02-15 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:2950 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0235761 infores:hetionet CHEBI:9605 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0038999 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0002170 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0853348 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853348 infores:hetionet CHEBI:101853 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0744727 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0022660 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151736 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0151828 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0037199 infores:hetionet CHEBI:10127 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0080274 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0549386 infores:hetionet CHEBI:9086 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0242379 infores:hetionet NCBIGene:56616 biolink:causes MONDO:0013593 infores:monarchinitiative not_provided not_provided HGNC:21528 MONDO:0013593 uuid:0fa2d9f2-24b7-42b2-8203-cdf5b7f1930c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0039514 biolink:causes GO:0007259 infores:ubergraph knowledge_assertion manual_agent GO:0039514 GO:0007259 CHEBI:63635 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011991 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005280 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D011472 DB00578_MESH_D011472_1 CAID:CA024070 biolink:causes MONDO:0018493 infores:clingen CAID:CA024070 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with leucine at codon 4587 of the RYR1 protein, p.(Pro4587Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000069, a frequency consistent with pathogenicity for MHS. This variant has been reported in a mutation report as occurring in MH without supporting evidence (PMID: 16521288). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.785 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024070/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3504 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0520962 infores:hetionet CHEBI:5384 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0035455 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0234215 infores:hetionet UNII:K2J09EMJ52 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0022650 infores:hetionet CHEBI:40009 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0013144 infores:hetionet CHEBI:5778 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0740394 infores:hetionet NCBIGene:2254 biolink:causes MONDO:0013064 infores:monarchinitiative not_provided not_provided HGNC:3687 MONDO:0013064 uuid:52ac0333-1c71-4fe0-aef6-fd838c54b529 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0018802 infores:hetionet CHEBI:125354 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0017178 infores:hetionet NCBIGene:28960 biolink:causes MONDO:0014648 infores:monarchinitiative not_provided not_provided HGNC:29812 MONDO:0014648 uuid:39d0cabd-0ddb-4ef1-b7f3-48a618e3e174 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA228500 biolink:causes MONDO:0015629 infores:clingen CAID:CA228500 MONDO:0015629 PMID: Pathogenic PS2_Supporting, PP4_Moderate, PP3, PM2_Supporting, PS3, PM5 The NM_000552.5(VWF):c.3941T>A (p.Val1314Asp) missense variant has been reported in one patient, Family 1 patient II:1 (PMID: 11325649) who displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and a high affinity of plasma vWF for ristocetin-dependent platelet receptor was confirmed at 0.4mg/m showing gain of function, which together are highly specific for VWD type 2B (PP4_moderate). The patient was also reported to have thrombocytopenia (9,600-80,000 platelets/μL) and a VWF antigen/activity ratio of 0.25, consistent with type 2B. The variant was identified de novo with parental relationships not fully confirmed (PS2_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.761, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Platelet binding assay performed with the V1314D recombinant vWF expressed by HEK293 cells showed binding in the absence of ristocetin under rheological shear flow, enhanced relative to wild-type indicating that this variant has a gain of function effect on the protein (PMID: 31628947; PS3). Another type 2B variants have been reported at this amino acid residue Val1314Leu and classified pathogenic by the VWD VCEP (PM5). In summary, the variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3_supporting, PS2_supporting, PP3, PP4_moderate, PM5 and PM2_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228500/MONDO:0015629/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6715 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0702166 infores:hetionet CHEBI:9943 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023218 infores:hetionet CHEBI:6933 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0235996 infores:hetionet CAID:CA122880 biolink:causes MONDO:0000572 infores:clingen CAID:CA122880 MONDO:0000572 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.2814T>G (p.Tyr938Ter) (NM_000448.3) variant in RAG1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. However, it is predicted to truncate part of the core region (between aa 387-1011) critical to the function of the protein (PVS1 Met).The variant is absent in gnomAD v4 (PM2_supporting). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PVS1 Met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA122880/MONDO:0000572/123 2024-03-04 2024-03-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:465284 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0022354 infores:hetionet CHEBI:63580 biolink:causes EFO:0009625 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015468 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0232452 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232452 infores:hetionet CHEBI:31413 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0085632 infores:hetionet CHEBI:8890 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0040264 infores:hetionet CHEBI:5383 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0014742 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0042373 infores:hetionet CHEBI:82716 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0027497 infores:hetionet CHEBI:29688 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0085605 infores:hetionet CHEBI:10124 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0026827 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0392386 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0009319 infores:hetionet CHEBI:7496 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020433 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0687133 infores:hetionet CHEBI:100246 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0022107 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0003123 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0438215 infores:hetionet CHEBI:7575 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0392386 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235416 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0011053 infores:hetionet CAID:CA023728 biolink:causes MONDO:0007750 infores:clingen CAID:CA023728 MONDO:0007750 PMID: Benign BS3, BS4, PP1_Moderate, BS2 BA1, BP3, BP2, BP1, BP4, PS3, PS1, PS4, PS2, BP7, BP5, BS1, PM5, PM1, PM4, PM3, PM2, PM6, PVS1, PP2, PP3, PP4 The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database.BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met.BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy.Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023728/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15544 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0012833 infores:hetionet CHEBI:2663 biolink:causes MONDO:0000437 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0007758 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0036341 infores:hetionet CHEBI:31859 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013384 infores:hetionet CHEBI:17688 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C2242996 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0239385 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027441 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0239779 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0239779 infores:hetionet CHEBI:65346 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0017178 infores:hetionet CAID:CA367403838 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403838 MONDO:0015967 PMID: Uncertain Significance PP2, PM2_Supporting PP3, BP4 The c.54G>T variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to histidine at codon 18 (p.(Gln18His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.683, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. In summary, c.54G>T meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PP2, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403838/MONDO:0015967/086 2025-01-03 2025-01-03 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:474053 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0033774 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027769 infores:hetionet CHEBI:6887 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011991 infores:hetionet NCBIGene:7476 biolink:causes MONDO:0009232 infores:monarchinitiative not_provided not_provided HGNC:12786 MONDO:0009232 uuid:6f97618f-a6ee-4f8f-83c8-15a8e540d4e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71255 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0036341 infores:hetionet CHEBI:5147 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0013404 infores:hetionet CHEBI:31638 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0009806 infores:hetionet NCBITaxon:59201 biolink:causes MONDO:0018626 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:59201 MESH:D010284 DB00415_MESH_D010284_1DB00446_MESH_D010284_1 CHEBI:50841 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0349506 infores:hetionet NCBIGene:10908 biolink:causes MONDO:0010152 infores:monarchinitiative not_provided not_provided HGNC:16268 MONDO:0010152 uuid:a0952ff1-e2a4-43c4-a0c2-131fcb3dc868 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0031099 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013378 infores:hetionet CHEBI:7443 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0017181 infores:hetionet CAID:CA024770 biolink:causes MONDO:0007783 infores:clingen CAID:CA024770 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PM1, PS4_Moderate, PP1_Moderate PP3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 2452 of the RYR1 protein, p.(Arg2452Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 30236257, 10823104, 12059893, 24433488). This variant segregates with MHS in five families/individuals, PP1_Moderate (PMID:30236257, 10823104, 12059893, 25086907). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 25086907). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.828 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024770/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:17026 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0009782 infores:hetionet CHEBI:71255 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0340865 infores:hetionet CHEBI:82960 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0041834 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0851341 infores:hetionet CHEBI:9720 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0027849 infores:hetionet CAID:CA2023554331 biolink:causes MONDO:0015967 infores:clingen CAID:CA2023554331 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4, PP1 The c.427del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 143 (NM_000545.8), adding 12 novel amino acids before encountering a stop codon (p.(His143ThrfsTer12)). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 18003757, internal lab contributor). Additionally, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757). This variant segregated with diabetes with two informative meioses in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2023554331/MONDO:0015967/017 2021-10-29 2021-11-19 Autosomal dominant inheritance HP:0000006 Supports CAID:CA213981 biolink:causes MONDO:0015967 infores:clingen CAID:CA213981 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, PP4, PS4 The c.768G>C variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of glutamate to aspartate at codon 256 (p.(Glu256Asp)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant has a REVEL score of 0.364, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, c.768G>C meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213981/MONDO:0015967/085 2024-09-26 2024-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:1182 biolink:causes MONDO:0859188 infores:monarchinitiative not_provided not_provided HGNC:2021 MONDO:0859188 uuid:a7389ec3-a9d3-431c-a791-6bfb49a6d5d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0007177 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0162316 infores:hetionet CHEBI:8428 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0232462 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0003123 infores:hetionet UMLS:C0010592 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0028081 infores:hetionet CHEBI:92607 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0040264 infores:hetionet CHEBI:31348 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0311394 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0849916 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0849916 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0234215 infores:hetionet CHEBI:135888 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0011991 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0003864 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0015397 infores:hetionet CHEBI:9435 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0020672 infores:hetionet CHEBI:2955 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0085641 infores:hetionet CHEBI:474053 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0015967 infores:hetionet CHEBI:71219 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0231528 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0235032 infores:hetionet CHEBI:10110 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0035455 infores:hetionet CHEBI:46557 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0028643 infores:hetionet CHEBI:50648 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0231835 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0677500 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0021400 infores:hetionet CAID:CA410147139 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147139 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS4, PS3, BA1, BP1, BP3, BP2, BS1, BS4, BS3, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1362G>T (p.Glu454Asp) is a missense variant which is completely absent from gnomAD 2.0 with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.164) and a Splice AI score <0.20 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147139/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8707 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017601 infores:hetionet NCBIGene:4695 biolink:causes MONDO:0032618 infores:monarchinitiative not_provided not_provided HGNC:7685 MONDO:0032618 uuid:a664253c-5ef2-42aa-a0b9-5714b0c40220 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042571 infores:hetionet CHEBI:37924 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0438142 infores:hetionet CHEBI:7852 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020578 infores:hetionet CHEBI:3568 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015967 infores:hetionet CHEBI:49603 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0151905 infores:hetionet CHEBI:15854 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0002994 infores:hetionet CHEBI:135935 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0039070 infores:hetionet CAID:CA913180290 biolink:causes MONDO:0044970 infores:clingen CAID:CA913180290 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PM6_Supporting PP1, PP3, BP4, PS4, PS2, PS3 The m.5702A>G variant in MT-TN has been reported in one individual with primary mitochondrial disease to date (PMID: 32161153; this appears to be the same individual reported in an abstract, https://www.nmd-journal.com/article/S0960-8966(16)30622-8/abstract, and included in the ClinVar submission for this variant). Clinical features in this woman include ophthalmoplegia, ptosis, myopathy, and ragged red and COX-negative fibers on muscle biopsy. The variant is present in the proband at 60% heteroplasmy muscle, 10% in urine, and absent in blood and skin fibroblasts. The variant is absent in blood and urine from her mother and four asymptomatic siblings (PM6_supporting; https://www.nmd-journal.com/article/S0960-8966(16)30622-8/abstract). There are no additional individuals or families reported with de novo occurrences of this variant or with this variant segregating with clinical manifestations to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 73.9%; HmtVAR: 0.05). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913180290/MONDO:0044970/015 2024-09-24 2024-11-21 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:47781 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0151636 infores:hetionet CHEBI:3215 biolink:causes NCIT:C34887 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0030201 infores:hetionet CHEBI:6121 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0235063 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0032326 infores:hetionet CHEBI:50122 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0016658 infores:hetionet CHEBI:17823 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0000737 infores:hetionet CHEBI:10125 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0025345 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0235744 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0235744 infores:hetionet CAID:CA018361 biolink:causes MONDO:0005045 infores:clingen CAID:CA018361 MONDO:0005045 PMID: Likely Benign BS1, PP2 PS3, BS3, PM2 NM_001018005.2(TPM1):c.797A>G (p.Lys266Arg). This variant has been reported in individuals with HCM and other cardiomyopathies (Wash 2017 PMID: 27532257, Burstein 2021 PMID: 32746448, Rippert 2023 PMID: 40225148). This variant is not statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI <5] and thus the PS4 criterion is not invoked. This missense variant is in a gene that has been determined to have a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2; Walsh et al. 2019 PMID:30696458). Computational prediction tools do not provide evidence for or against an impact to the protein (REVEL score <0.70). Additionally, this variant has been identified in 20 out of 24958 (BS1; 0.04% GroupMax FAF 95% CI) of African chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel. Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while this missense variant is in a gene that has a low rate of benign variation (PP2), this evidence code was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for hypertrophic cardiomyopathy in an autosomal dominant manner based on BS1 and PP2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA018361/MONDO:0005045/100 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63617 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0231528 infores:hetionet CHEBI:28748 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0687713 infores:hetionet CHEBI:5118 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0019079 infores:hetionet CAID:CA120620 biolink:causes MONDO:0044970 infores:clingen CAID:CA120620 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS4, PS2, PS3, PM6 The m.15197T>C (p.S151P) variant in MT-CYTB has been reported in one individual with primary mitochondrial disease to date. This individual had exercise intolerance in early childhood and had the variant present at 80% heteroplasmy in muscle. The variant was undetectable in blood and skin fibroblasts. Complex III activity was reduced at 17% of controls in muscle, 28% in blood, and 50% in skin fibroblasts (PMID: 11454242). There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.72 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120620/MONDO:0044970/015 2024-01-08 2024-07-24 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA8459494 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459494 MONDO:0011132 PMID:31566583PMID:37419334 Benign BA1, BP4 PP4, BP2, BS3, BS4 The NM_001369369.1(FOXN1):c.1288C>T (p.Pro430Ser) missense variant has a gnomAD popmax filtering allele frequency of 0.04634 based on 6036/128650 alleles in the European (non-Finnish) population, which is greater than >0.00447 and thus meets BA1. The variant has a REVEL score of 0.168, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. Of note, this variant has been reported (PMID: 31566583) in the context of T cell immunodeficiency, however it was in trans with c.1465del which is considered to be the causal variant. Pro430Ser is not considered to contribute to the phenotype, which is consistent with functional studies of the variant which found the variant had no significant effect on expression or Luciferase activity compared to WT (PMID: 31566583) and a heterozygous mouse model was unaffected (PMID: 37419334). In summary this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria, as specified by the ClinGen SCID VCEP: BA1, BP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459494/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:50223 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0031542 infores:hetionet UNII:DJJ95FJP1H biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0877047 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0038367 infores:hetionet CHEBI:68584 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0085584 infores:hetionet CHEBI:4659 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0085605 infores:hetionet UMLS:C0657912 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1456784 infores:hetionet CHEBI:10023 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018926 infores:hetionet CHEBI:6801 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0013378 infores:hetionet CHEBI:3310 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0085616 infores:hetionet CHEBI:49960 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0010038 infores:hetionet CHEBI:27732 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0162119 infores:hetionet CHEBI:94807 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0021400 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0541879 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0541879 infores:hetionet CHEBI:2668 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0043094 infores:hetionet CHEBI:9907 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018834 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011570 infores:hetionet CHEBI:135961 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0085606 infores:hetionet CHEBI:70746 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0026858 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0037199 infores:hetionet CHEBI:66903 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0006826 infores:hetionet CHEBI:9588 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0018965 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0920108 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0920108 infores:hetionet CHEBI:8412 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0003862 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0031117 infores:hetionet CAID:CA117007 biolink:causes MONDO:0011225 infores:clingen CAID:CA117007 MONDO:0011225 PMID: Pathogenic PP1, PM2_Supporting, PS3_Moderate, PM3_Strong, PP4_Moderate PP3, BS2 The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp).The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID: 25917813).This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320).At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID: 24481607).In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA117007/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135876 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0042029 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0235520 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0235520 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0028960 infores:hetionet CHEBI:3181 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0043352 infores:hetionet UMLS:C0010592 biolink:causes HP:0032620 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151465 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0031117 infores:hetionet CHEBI:7565 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085932 infores:hetionet CHEBI:3723 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018524 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0855242 infores:hetionet CHEBI:18248 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0162285 infores:hetionet CHEBI:3387 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151662 infores:hetionet CHEBI:31705 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0031350 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039971 infores:hetionet CHEBI:2666 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0855333 infores:hetionet CHEBI:8772 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0404521 infores:hetionet CHEBI:8764 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0026826 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009241 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0276908 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0276908 infores:hetionet CHEBI:2611 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0026837 infores:hetionet CAID:CA135146 biolink:causes MONDO:0021060 infores:clingen CAID:CA135146 MONDO:0021060 PMID: Likely Benign BS2, BP4 The c.92C>G variant in the BRAF gene is a missense variant predicted to cause substitution of alanine by glycine at amino acid 31 (p.Ala31Gly). The minor allele frequency in gnomAD v4 of this variant is 0.01119% (128/1143560 alleles) for the European (non-Finnish) population (PM2_Supporting/BS1/BA1 are not met). The REVEL computational prediction analysis tool produced a score of 0.207, which meets the threshold for BP4 application. This variant has been identified in at least 1 individual with clinical features of a RASopathy (PS4 not met; Partners LMM internal data; GTR ID's 21766; SCV000061629.5). However, the p.Ala31Gly variant was observed in at least one healthy adult individual who did not have clinical features of a RASopathy (BS2; Partners LMM and GeneDx internal data; GTR ID's 21766, 26957; SCV000061629.5, SCV000207745.9). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BS2, BP4 (Specification Version 2.1, 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135146/MONDO:0021060/049 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5383 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C3665347 infores:hetionet CHEBI:43968 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0039231 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0549310 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0033975 infores:hetionet CHEBI:94609 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0030312 infores:hetionet CHEBI:45951 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0026837 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0019348 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0028738 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0008370 infores:hetionet CHEBI:171719 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0424295 infores:hetionet CAID:CA226732 biolink:causes MONDO:0010725 infores:clingen CAID:CA226732 MONDO:0010725 PMID: Likely Benign PM2_Supporting, BP7, BP4 The NM_000330.4(RS1):c.426T>C variant is a synonymous variant at amino acid 142. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The splicing impact predictor SpliceAI gives a delta score of 0.02 acceptor gain, which is below the ClinGen X- linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on RS1 splicing (BP4). This silent variant c.426T>C causing a synonymous variant at codon 142 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.02 for acceptor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and does not strongly predict an impact on RS1 splicing (BP7). In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, BP4, and BP7 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226732/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:31236 biolink:causes UMLS:C0863087 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0863087 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0034150 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004844 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023532 infores:hetionet CHEBI:28001 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0004604 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0392025 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0860811 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0860811 infores:hetionet CHEBI:6950 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0026826 infores:hetionet CHEBI:3506 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0151539 infores:hetionet CHEBI:116278 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0085593 infores:hetionet CHEBI:47519 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0018418 infores:hetionet CHEBI:66964 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C1142412 infores:hetionet CHEBI:36795 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0549622 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1112369 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1112369 infores:hetionet CHEBI:17698 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0038362 infores:hetionet NCBIGene:4054 biolink:causes MONDO:0054722 infores:monarchinitiative not_provided not_provided HGNC:6716 MONDO:0054722 uuid:9cb08099-dca2-4f27-be5a-ce97e7015c16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0009917 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0029134 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0038362 infores:hetionet CHEBI:3561 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020555 infores:hetionet CHEBI:3181 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0035455 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1610069 infores:hetionet CHEBI:70735 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0026837 infores:hetionet CHEBI:50729 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0011175 infores:hetionet CHEBI:4911 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0027540 infores:hetionet CHEBI:27899 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0030305 infores:hetionet CHEBI:28915 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0002792 infores:hetionet CHEBI:63631 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020620 infores:hetionet CHEBI:5893 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020453 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0233472 infores:hetionet CHEBI:71415 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0028738 infores:hetionet CHEBI:6887 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0015672 infores:hetionet CHEBI:39585 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0013604 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0007971 infores:hetionet CHEBI:5001 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0026858 infores:hetionet CHEBI:63637 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0038325 infores:hetionet CHEBI:63598 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151723 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0034063 infores:hetionet CHEBI:45979 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0013144 infores:hetionet CHEBI:4708 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0034886 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0026946 infores:hetionet CAID:CA314606 biolink:causes MONDO:0100040 infores:clingen CAID:CA314606 MONDO:0100040 PMID: Uncertain Significance BS2_Supporting BS1, PM2, PP3, BP4 The highest population minor allele frequency of the p.Gly168Val variant in FOXG1 in gnomAD v4.1 is 0.000018 in the European (Finnish) population (not sufficient to meet BS1 criteria). The p.Gly168Val variant is observed in at least 1 unaffected individual (Internal database - Ambry) (BS2_Supporting). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In summary, the p.Gly168Val variant in FOXG1 is classified as a variant of unknown significance based on the ACMG/AMP criteria (BS2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314606/MONDO:0100040/035 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:2000226 biolink:causes GO:0035270 infores:ubergraph knowledge_assertion manual_agent GO:2000226 GO:0035270 CHEBI:82960 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0242339 infores:hetionet CHEBI:31859 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0438142 infores:hetionet CHEBI:51137 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0178298 infores:hetionet CHEBI:3181 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0037763 infores:hetionet CHEBI:131512 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0004093 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0040822 infores:hetionet CHEBI:47780 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085593 infores:hetionet CHEBI:8871 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0149871 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020651 infores:hetionet CHEBI:37924 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042023 infores:hetionet CHEBI:6375 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0003862 infores:hetionet CHEBI:145499 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0040460 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0178298 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1142412 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0392025 infores:hetionet CHEBI:114785 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0004604 infores:hetionet CHEBI:45652 biolink:causes UMLS:C0039242 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0039242 infores:hetionet CHEBI:47519 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0014591 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0020517 infores:hetionet CHEBI:6367 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0022107 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0034065 infores:hetionet CHEBI:17630 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0235280 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0037199 infores:hetionet NCBIGene:55617 biolink:causes MONDO:0033532 infores:monarchinitiative not_provided not_provided HGNC:15859 MONDO:0033532 uuid:8bcd27a1-8b03-4e9a-b7f8-8620bd84b1c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA645372923 biolink:causes MONDO:0015967 infores:clingen CAID:CA645372923 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PVS1 The c.1137del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 380 (NM_000545.8), adding 4 novel amino acids before encountering a stop codon (p.Val380SerfsTer4). This variant, located in biologically-relevant exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 33538814, internal lab contributors). This variant also segregated with diabetes, with 5 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1137del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645372923/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83531 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0085635 infores:hetionet CHEBI:42355 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0008031 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0018799 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0521509 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037199 infores:hetionet CHEBI:2682 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0003578 infores:hetionet CHEBI:4887 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0018965 infores:hetionet CHEBI:8107 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0022107 infores:hetionet CHEBI:100241 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0575081 infores:hetionet CAID:CA16613385 biolink:causes MONDO:0700270 infores:clingen CAID:CA16613385 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.5681_5682del (p.Glu1894Alafs*9) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). The filtering allele frequency (the upper threshold of the 95% CI of 2/1179252) of the c.5681_5682del variant in ATM is 0.0000002800 for European (non-Finnish) chromosomes by gnomAD v4.1.0, which is lower than the HBOP VCEP threshold (<0.00001) for PM2_Supporting, and therefore meets this criterion. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613385/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16469 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0392025 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0017152 infores:hetionet CHEBI:91541 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0026961 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0948594 infores:hetionet CHEBI:6909 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1291077 infores:hetionet CHEBI:31638 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C2979982 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0006145 infores:hetionet CHEBI:35854 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0015672 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0009450 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020517 infores:hetionet CHEBI:567361 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C2047937 infores:hetionet CHEBI:3219 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0344232 infores:hetionet CHEBI:50648 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018790 infores:hetionet CHEBI:6888 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0026846 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0022904 infores:hetionet CHEBI:3176 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423153 infores:hetionet CHEBI:7956 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0011206 infores:hetionet CHEBI:4469 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0003467 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0268732 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0268732 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151815 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151815 infores:hetionet CAID:CA409105868 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105868 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PVS1_Strong PS4 The c.427-2A>G variant in the HNF4A gene, is predicted to remove a canonical splice acceptor site in intron 4 of NM_175914.4. This variant is predicted to cause an in-frame deletion of biologically-relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal laboratory collaborators, PMID 36504295). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with three informative meioses in 1 family with MODY (PP1; internal laboratory collaborators). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and history of macrosomia and neonatal hypoglycemia) (PP4_Moderate; internal laboratory collaborators). In summary, c.427-2A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PVS1_Strong, PM2_Supporting, PP1, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105868/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63608 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0001824 infores:hetionet NCBIGene:55294 biolink:causes MONDO:0859280 infores:monarchinitiative not_provided not_provided HGNC:16712 MONDO:0859280 uuid:9029e3e1-979d-40a9-90d1-b10d7f09e07d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3845 biolink:causes MONDO:0013767 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0013767 uuid:b4517ea5-dae6-4ca6-b893-97d9b52ae0db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0035542 biolink:causes GO:0006906 infores:ubergraph knowledge_assertion manual_agent GO:0035542 GO:0006906 CHEBI:8776 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0018790 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0037274 infores:hetionet CHEBI:4995 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0149745 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0235639 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0041912 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0028173 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009241 infores:hetionet CHEBI:453011 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0011616 infores:hetionet CHEBI:9352 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0041657 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020517 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042075 infores:hetionet CHEBI:74947 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0856054 infores:hetionet CHEBI:31401 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0035317 infores:hetionet CAID:CA355961228 biolink:causes MONDO:0001586 infores:clingen CAID:CA355961228 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PM2_Supporting, PS1_Supporting PP4 The NM_000203.5:c.385+1G>A variant in IDUA occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3 out of 14, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with a diagnosis of MPSI has been reported to be compound heterozygous, phase unconfirmed, for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 21394825) (0.5 points), and another patient has been reported to be homozygous for the variant (PMID: 38425718) (0.5 points). Total 1 point (PM3). While the details provided for these patients are consistent with a diagnosis of MPS I there is insufficient evidence to apply PP4. The variant is absent in gnomAD v4.1.0. Another variant at the same position, c.385+1G>C (ClinVar Variation ID: 551966), has been classified as pathogenic by the ClinGen LD VCEP (PS1_Supporting, PMID: 37352859). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel: PVS1, PM3, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355961228/MONDO:0001586/091 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports CAID:CA136168 biolink:causes MONDO:0021060 infores:clingen CAID:CA136168 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.553A>G (p.Ile185Val) variant in the SOS1 gene is 0.087% (16/11574) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136168/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3441 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0000737 infores:hetionet CHEBI:10023 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030794 infores:hetionet CHEBI:7476 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013447 infores:hetionet GO:1902738 biolink:causes GO:0048705 infores:ubergraph knowledge_assertion manual_agent GO:1902738 GO:0048705 CHEBI:4909 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0009421 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042267 infores:hetionet CHEBI:75275 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0030193 infores:hetionet CHEBI:8212 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0233565 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0233494 infores:hetionet CHEBI:100241 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042023 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019348 infores:hetionet CAID:CA3054201757 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201757 MONDO:0011071 PMID: Uncertain Significance PM4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.597_598insGCC (p.Gly199_Pro200insAla) is an in-frame insertion variant which has not been featured in functional or case studies. This variant has not been reported in any populations featured in any version of gnomAD, allowing for application of PM2_Supporting. This in-frame insertion affects the R201 and R204 hotspot residues within the Runt Homology Domain (RHD), allowing for application of PM4. In summary, this variant meets criteria to be classified as a variant of uncertain significance (VUS). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PM4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201757/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410206832 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206832 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.718C>T (p.Pro240Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206832/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6062 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0039240 infores:hetionet NCBIGene:84433 biolink:causes MONDO:0014645 infores:monarchinitiative not_provided not_provided HGNC:16393 MONDO:0014645 uuid:5edeb919-8ce4-42df-9e8b-3269ef64a12a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8412 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0233471 infores:hetionet CHEBI:9288 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0014457 infores:hetionet CHEBI:74947 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085641 infores:hetionet CHEBI:178699 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0151826 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0038454 infores:hetionet CHEBI:32221 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0013604 infores:hetionet CHEBI:4876 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C1443060 infores:hetionet CHEBI:6715 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011168 infores:hetionet CHEBI:63619 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0040264 infores:hetionet CHEBI:6950 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0039070 infores:hetionet CHEBI:8093 biolink:causes NCIT:C112176 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0948786 infores:hetionet CHEBI:31348 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0037383 infores:hetionet CHEBI:135005 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0042029 infores:hetionet CHEBI:63622 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0004245 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0151735 infores:hetionet UMLS:C0011701 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0016204 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0877047 infores:hetionet CHEBI:70735 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0001824 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0236048 infores:hetionet CHEBI:4024 biolink:causes MONDO:0001280 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0008526 infores:hetionet CHEBI:7496 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0392525 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0235874 infores:hetionet CHEBI:5120 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0002170 infores:hetionet CHEBI:45409 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0232462 infores:hetionet CHEBI:79699 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0750394 infores:hetionet CHEBI:6472 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0011991 infores:hetionet CHEBI:3485 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0008031 infores:hetionet CHEBI:7773 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0020523 infores:hetionet CHEBI:4798 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0151662 infores:hetionet CHEBI:4657 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0231218 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0013595 infores:hetionet CHEBI:15552 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0232292 infores:hetionet CHEBI:83804 biolink:causes HP:0030213 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0233469 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006849 infores:hetionet CHEBI:4046 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0030554 infores:hetionet CHEBI:9738 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0028084 infores:hetionet CHEBI:51380 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0231218 infores:hetionet CHEBI:34385 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C1384353 infores:hetionet CHEBI:27732 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1384353 infores:hetionet CHEBI:35778 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0241157 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1274594 infores:hetionet CHEBI:5296 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0014457 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0852810 infores:hetionet CHEBI:2687 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0011168 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1328337 infores:hetionet CHEBI:52717 biolink:causes UMLS:C2242576 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2242576 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0021053 infores:hetionet CHEBI:8890 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0085649 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0877517 infores:hetionet NCBIGene:6513 biolink:causes MONDO:0011724 infores:monarchinitiative not_provided not_provided HGNC:11005 MONDO:0011724 uuid:3d15d297-0715-42a4-8b21-53c6a5cb21a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151828 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0235490 infores:hetionet CHEBI:72564 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011168 infores:hetionet CHEBI:45863 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0023380 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0042373 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0027765 infores:hetionet CHEBI:63631 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232487 infores:hetionet CHEBI:63791 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0016204 infores:hetionet CHEBI:6741 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0004093 infores:hetionet CHEBI:44423 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0740394 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0010709 infores:hetionet CHEBI:9086 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0009763 infores:hetionet CHEBI:64198 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0030554 infores:hetionet CHEBI:59773 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0022107 infores:hetionet CHEBI:32139 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0006277 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0023890 infores:hetionet CAID:CA2830782976 biolink:causes MONDO:0010305 infores:clingen CAID:CA2830782976 MONDO:0010305 PMID: Likely Pathogenic PM2_Supporting, PP4_Strong, PVS1_Moderate The NM_005629.4(SLC6A8):c.1767+1_1767+2insA variant disrupts the donor splice site of the final intron (intron 12) of SLC6A8. If exon 12 is skipped, this results in an in frame deletion of 57 amino acids. However, SpliceAI predicts possible use of a cryptic splice site 98 nucleotides upstream in the exon (score for donor gain = 0.58) which, if used, would result in a frameshift and loss of about 80 amino acids of the normal SLC6A8 protein. Without RNA studies, the impact is not known (PVS1_Moderate). One male with clinical features consistent with creatine transporter deficiency, elevated urine creatine/creatinine ratio, and significantly reduced creatine peak on brain magnetic resonance spectroscopy has been reported (PMID: 37305710) (PP4_Strong). The variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PVS1_Moderate, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2830782976/MONDO:0010305/027 2025-01-07 2025-01-09 X-linked inheritance HP:0001417 Supports CHEBI:6541 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0038325 infores:hetionet CHEBI:45863 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030196 infores:hetionet CHEBI:4903 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0019080 infores:hetionet CAID:CA913184731 biolink:causes MONDO:0100326 infores:clingen CAID:CA913184731 MONDO:0100326 PMID:7529063 Pathogenic PM4, PP4_Moderate, PP1, PM2_Supporting, PS3, PM3_Supporting The c.2473_2478delinsTCACCAGGGCCTTCACCTCAGCATCCACCAG frameshift variant in ITGA2B occurs within exon 25. It is predicted to result in an out of frame deletion of 6 bp and an insertion of 31 bp at the beginning of exon 25 of the GPllb gene. This is predicted to result in a frameshift with a premature stop codon in exon 27 of 30, which would be expected to result in NMD. However, the predominant platelet GPIIb mRNA of the proband, reported in PMID: 7529063, was a product of the splicing of exon 24 to a cryptic AG acceptor site in the insertion and encodes for a substitution of 10 amino acids Leu817-Asn826 by an altered sequence of 8 amino acids, followed by normal translation of the rest of the protein. Overall the protein had a length reduction of 2 amino acids (PM4). At least one patient (Patient 1 in PMID: 7529063) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, immunoblotting showed small amounts of GPIIIa and minute amounts of pro-GPIlb confirming type 1 GT (PP4_moderate). The variant has been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus one affected family member (PMID: 7529063) , both with the homozygous genotype with the p.Val825SerfsTer? variant (PP1; PM3_supporting). Surface expression of αIIbβ3 measured by flow cytometry in COS-7 cells transiently co-transfected with the c.2473_2478delinsTCACCAGGGCCTTCACCTCAGCATCCACCAG variant αIIb and wild type β3 showed decreased expression at <5% WT levels, indicating that this variant impacts protein function (PMID:7529063 )(PS3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PP4_Moderate, PM4, PP1, PM2_Supporting and PM3_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184731/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5103 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0009676 infores:hetionet CHEBI:46195 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0040822 infores:hetionet CHEBI:261649 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0011603 infores:hetionet CHEBI:68478 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0041834 infores:hetionet CHEBI:4974 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0030554 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0687713 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005165 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0086692 infores:hetionet CHEBI:5864 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0237849 infores:hetionet CHEBI:72292 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0008031 infores:hetionet CHEBI:65349 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C2973529 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0948349 infores:hetionet CHEBI:2675 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0013144 infores:hetionet CHEBI:8093 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0085612 infores:hetionet CHEBI:63631 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0338908 infores:hetionet NCBIGene:5979 biolink:causes MONDO:0008082 infores:monarchinitiative not_provided not_provided HGNC:9967 MONDO:0008082 uuid:161fcbf7-6209-46a3-b85b-f2b0b0602ddf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0037763 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0687133 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042075 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0541900 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020538 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151763 infores:hetionet CHEBI:31236 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026821 infores:hetionet CHEBI:3223 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C1510410 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C1565489 infores:hetionet CHEBI:16347 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0518015 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0948482 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0948482 infores:hetionet CHEBI:63608 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0014518 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0235318 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0235318 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0426576 infores:hetionet CHEBI:3219 biolink:causes MONDO:0013189 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040953 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0162429 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029445 infores:hetionet CHEBI:28901 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085611 infores:hetionet CHEBI:3441 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C3263723 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0522051 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0522051 infores:hetionet CHEBI:8412 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0004134 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0008370 infores:hetionet CHEBI:9570 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0438717 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0021053 infores:hetionet NCBIGene:6609 biolink:causes MONDO:0011871 infores:monarchinitiative not_provided not_provided HGNC:11120 MONDO:0011871 uuid:153366a0-c60c-4dc0-b343-abfb20865a3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29013 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0853875 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020676 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0015397 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0149931 infores:hetionet CHEBI:66919 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0002871 infores:hetionet CHEBI:4657 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0020443 infores:hetionet CHEBI:231425 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0232462 infores:hetionet CHEBI:76607 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0268000 infores:hetionet CHEBI:8890 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0009676 infores:hetionet CHEBI:8713 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0002994 infores:hetionet CHEBI:9654 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0002170 infores:hetionet CHEBI:71255 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0011603 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0026826 infores:hetionet CHEBI:4653 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0013456 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0151505 infores:hetionet CHEBI:135736 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0006277 infores:hetionet CAID:CA314812 biolink:causes MONDO:0012999 infores:clingen CAID:CA314812 MONDO:0012999 PMID: Pathogenic PM2_Supporting, PP4_Strong, PM3, PVS1_Strong The NM_000156.6:c.522G>A (p.Trp174Ter) variant is a nonsense variant in the last 50bp of the penultimate exon of GAMT, predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). At least six probands and two siblings have been reported with clinical and biochemical features consistent with GAMT deficiency including 3 probands and one sibling with elevated plasma GAA (PMID 23660394, https://adc.bmj.com/content/103/2/e1.24), 1 proband with enzyme deficiency (PMID 17171576), 2 probands with reduced plasma creatine, elevated plasma GAA, and reduced creatine peak on MRS (PMID 23583224, 24071436), and a sibling of one of these patients with reduced plasma creatine and elevated plasma GAA (PMID 23583224) (PP4_Strong). Of these probands 4 are compound heterozygous for the variant and a variant that is classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown (PMIDs 17171576, 19027335, 23583224, 23660394, 24071436, 24268530, https://adc.bmj.com/content/103/2/e1.24 (PM3). Another two probands are compound heterozygous for the variant and a missense variant, either c.491G>A (p.Gly164Asp) or c.505T>C (p.Cys169Arg) (PMID 23660394, 24268530). The in trans data from these patients will be used in the assessment of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (7/113306 alleles) in the European non-Finnish population, which is less that the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205584). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314812/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36791 biolink:causes MONDO:0004833 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149756 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0085932 infores:hetionet CAID:CA119181 biolink:causes MONDO:0020367 infores:clingen CAID:CA119181 MONDO:0020367 PMID: Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4, PP1_Strong BS1, BS3, BP7, PM6, PM5, PM4, PS1, PS2, BA1, BP4 The c.1297T>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 433 (p.Cys433Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Cys433Arg protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands). In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119181/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Supports GO:0031991 biolink:causes GO:0044837 infores:ubergraph knowledge_assertion manual_agent GO:0031991 GO:0044837 CHEBI:6367 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018681 infores:hetionet CHEBI:63618 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0427055 infores:hetionet CHEBI:7954 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0234913 infores:hetionet CHEBI:8805 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0006277 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0162429 infores:hetionet CAID:CA10585614 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585614 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1793T>A (p.Ile598Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS4_supporting - Variant meets PM2 and is identified in 2 unrelated FH index cases with LDL cholesterol >95th percentile for age and sex and/or presence of tendon xantomas from PMID: 9157944 (Pimstone et al., 1997), Netherlands.PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585614/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7496 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0000737 infores:hetionet CHEBI:3314 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0009676 infores:hetionet NCBIGene:8496 biolink:causes MONDO:0859283 infores:monarchinitiative not_provided not_provided HGNC:9249 MONDO:0859283 uuid:01e5bffb-77b9-4f7d-a52a-db03044c9281 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135925 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0020517 infores:hetionet CHEBI:87681 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0042963 infores:hetionet CHEBI:71415 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0038325 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0151773 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0858635 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0240417 infores:hetionet CHEBI:2639 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0086565 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0042373 infores:hetionet CHEBI:40237 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0042963 infores:hetionet CHEBI:9445 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0013378 infores:hetionet GO:0141073 biolink:causes GO:0008228 infores:ubergraph knowledge_assertion manual_agent GO:0141073 GO:0008228 CAID:CA658824421 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824421 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.339del (p.Ile114fs) is a frameshift variant predicted to undergo NMD (PVS1 SNV tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824421/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8764 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0024299 infores:hetionet CHEBI:7494 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0014591 infores:hetionet CHEBI:6472 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0030312 infores:hetionet CHEBI:9654 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0686347 infores:hetionet CHEBI:7443 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0004096 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0009450 infores:hetionet CHEBI:63629 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0023518 infores:hetionet CHEBI:7444 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0917801 infores:hetionet CHEBI:10650 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013428 infores:hetionet CHEBI:6541 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0002994 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019158 infores:hetionet CHEBI:72297 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0014869 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0151773 infores:hetionet CHEBI:175901 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0024312 infores:hetionet CHEBI:35677 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C2047937 infores:hetionet CAID:CA294451 biolink:causes MONDO:0007648 infores:clingen CAID:CA294451 MONDO:0007648 PMID:26911350 Benign BS1, BS2, BP2 BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BA1, PS1, PS3, PS4, PS2 The c.304G>A variant has an allele frequency of 0.00188 (0.19%, 58/30,780 alleles) in the South Asian subpopulation of the gnomAD 2.1.1 cohort (BS1; http://gnomad.broadinstitute.org). The variant was observed in the homozygous state in gnomAD 2.1.1 (BP2). The variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000210895.12; SCV000186827.5). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2, BP2 . CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294451/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:50381 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0231218 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0033687 infores:hetionet CHEBI:51860 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0019080 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0151579 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0240972 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0240972 infores:hetionet CHEBI:47381 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0015672 infores:hetionet CHEBI:3216 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013456 infores:hetionet CHEBI:3732 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0037763 infores:hetionet CHEBI:45652 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0032708 infores:hetionet CHEBI:9137 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1368065 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004833 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0149756 infores:hetionet CAID:CA016588 biolink:causes MONDO:0005835 infores:clingen CAID:CA016588 MONDO:0005835 PMID: Uncertain Significance BS4_Supporting PP3, BA1, BP4, BP5, BS1, BS3, PM2 The MSH6 c.884A>G variant results in a missense change, p.(Lys295Arg). MCAF (95% CI) is 0.013% in GnomAD v2.1.1 and Grpmax is 0.01964% in GnomAD v4.1 (below BS1 threshold). In silico predictions are inconclusive. It has found in an individual affected by CRC showing MSH6 expression (LOVD). Lack of segregation with cancer (LR: 0.7, LOVD). Nuclear localization in DLD-1 cells (PMID 21437237). Therefore, the variant is classified as variant of unknown significance. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA016588/MONDO:0005835/138 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9763 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0035229 infores:hetionet CHEBI:3756 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0085623 infores:hetionet CHEBI:4659 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0022346 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0041969 infores:hetionet CHEBI:5118 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0016204 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0017675 infores:hetionet CHEBI:10102 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0025874 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0040034 infores:hetionet CHEBI:41423 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0340865 infores:hetionet CHEBI:3312 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0042401 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0149931 infores:hetionet CHEBI:78543 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0004604 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010232 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010232 uuid:9981630c-d136-4b39-98c6-e01e04b458b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16335 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C2747891 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0341012 infores:hetionet CHEBI:29688 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0026896 infores:hetionet UMLS:C0120107 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0232849 infores:hetionet CAID:CA358793 biolink:causes MONDO:0010315 infores:clingen CAID:CA358793 MONDO:0010315 PMID: Pathogenic PM1_Strong, PS3_Supporting, PM5, PP4_Moderate, PM2_Supporting, PS4 The NM_000206.3:c.677G>A variant in IL2RG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 226 (p.Arg226His). The variant has been observed in at least 9 probands with SCID/Ommen Syndrome (PMIDs 7668284, 9058718, 17598841, 21184155) (PS4). Among these probands, one presented with symptoms reminiscent of Omenn syndrome. The proband exhibited a T-B-NK+ lymphocyte profile. CD132 was absent in every lymphocyte subpopulation, and the NK cells isolated from the patient did not respond to IL-2 stimulation (PMID 17598841) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.677G, which is defined as a mutational hotspot by the ClinGen SCID VCEP (PMID 7668284) (PM1_Strong). Surface expression of the IL-2 receptor gamma chain in patient B cells showed that the variant causes decreased surface localization of the protein, indicating that this variant impacts protein function (PMID 9058718)(PS3_Supporting). In addition, another missense variant c.676C>T, p.Arg226Cys (ClinVar Variation ID 225195) in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM1_Strong, PS4_Strong, PM5, PP4_Moderate, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA358793/MONDO:0010315/129 2024-03-08 2024-03-08 X-linked inheritance HP:0001417 Supports CHEBI:7444 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0234192 infores:hetionet CHEBI:40303 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C2004489 infores:hetionet CHEBI:2682 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0014457 infores:hetionet CHEBI:2904 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0014591 infores:hetionet CHEBI:49375 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0311468 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0029191 infores:hetionet CAID:CA024850 biolink:causes MONDO:0018493 infores:clingen CAID:CA024850 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 2591 of the RYR1 protein, p.(Arg2591Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, this does not meet PS4 (PMID:16917943). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.697 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024850/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6375 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151824 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0033975 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0234373 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0234373 infores:hetionet CHEBI:9622 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C2830004 infores:hetionet CHEBI:63619 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004093 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0853334 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0853334 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0162287 infores:hetionet CHEBI:4466 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0268000 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021845 infores:hetionet UMLS:C0065374 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0392699 infores:hetionet CHEBI:9139 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C3665346 infores:hetionet CHEBI:50742 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151786 infores:hetionet NCBIGene:1009 biolink:causes MONDO:0008885 infores:monarchinitiative not_provided not_provided HGNC:1750 MONDO:0008885 uuid:effce402-7d64-431f-b32f-2456cf87ec29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0235660 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1384666 infores:hetionet CHEBI:7496 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0026821 infores:hetionet CHEBI:4814 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0042963 infores:hetionet CHEBI:6950 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C3495920 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011615 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0018099 infores:hetionet CHEBI:28901 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020621 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0027765 infores:hetionet CHEBI:44185 biolink:causes MONDO:0016463 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0086438 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0002871 infores:hetionet CHEBI:28939 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C2830004 infores:hetionet CHEBI:6402 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0025345 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151576 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027947 infores:hetionet CAID:CA10603972 biolink:causes MONDO:0010278 infores:clingen CAID:CA10603972 MONDO:0010278 PMID: Benign BS2, BP4, BA1, BP5_Strong The highest population minor allele frequency of the p.Thr674Met variant in SLC9A6 in gnomAD v4.1 is 0.001143 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Thr674Met variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Thr674Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Thr674Met variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). In summary, the p.Thr674Met variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5_Strong). (SLC9A6 Specifications v3.0.0, curation approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603972/MONDO:0010278/033 2024-08-30 2024-12-19 X-linked inheritance HP:0001417 Contradicts true CHEBI:472657 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0853149 infores:hetionet CHEBI:63611 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0016204 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0017178 infores:hetionet CHEBI:61058 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0013595 infores:hetionet GO:2000354 biolink:causes GO:0046545 infores:ubergraph knowledge_assertion manual_agent GO:2000354 GO:0046545 CHEBI:6950 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0036974 infores:hetionet CHEBI:4514 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0233407 infores:hetionet CHEBI:9943 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151529 infores:hetionet CAID:CA343720209 biolink:causes MONDO:0005338 infores:clingen CAID:CA343720209 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.14G>A variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 5 (p.Cys5Tyr). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.044, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 32476818), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343720209/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes MONDO:0005300 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0748318 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030305 infores:hetionet UMLS:C0004609 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0011168 infores:hetionet CHEBI:7915 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0423791 infores:hetionet NCBIGene:60482 biolink:causes MONDO:0014939 infores:monarchinitiative not_provided not_provided HGNC:14025 MONDO:0014939 uuid:f6c3d68e-73eb-42a5-ab25-795c08de50b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2048 biolink:causes MONDO:0032765 infores:monarchinitiative not_provided not_provided HGNC:3393 MONDO:0032765 uuid:8335599a-bd5f-4c59-9304-f6c9a4437edb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0023610 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0151735 infores:hetionet CHEBI:47781 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0031256 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0349506 infores:hetionet CHEBI:404903 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020580 infores:hetionet CHEBI:42797 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085649 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0010414 infores:hetionet CHEBI:6640 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0232493 infores:hetionet CHEBI:85078 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0015230 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042109 infores:hetionet CHEBI:9738 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2225524 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0038999 infores:hetionet CHEBI:5855 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0037763 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0234215 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0026113 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0234987 infores:hetionet CHEBI:5103 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0003811 infores:hetionet CHEBI:63580 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C2047937 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0002871 infores:hetionet GO:0072199 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0072199 GO:0007275 CHEBI:44032 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042109 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0233472 infores:hetionet CHEBI:63599 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0151766 infores:hetionet CHEBI:7983 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0011603 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0948594 infores:hetionet CHEBI:28001 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0042571 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C1971624 infores:hetionet CHEBI:116278 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0085631 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0549429 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0549429 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0004936 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0002871 infores:hetionet CHEBI:27690 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0036572 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0175167 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0852733 infores:hetionet GO:0060374 biolink:causes CL:0000097 infores:ubergraph knowledge_assertion manual_agent GO:0060374 CL:0000097 UMLS:C0005740 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0032285 infores:hetionet CHEBI:2675 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0027424 infores:hetionet CHEBI:64312 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020672 infores:hetionet CAID:CA410203423 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203423 MONDO:0011071 PMID: Likely Pathogenic PM5, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.329A>G (p.Lys110Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant affects a hotspot residue within the Runt Homology Domain (RHD) (Lys110) (PM1), and occurs at the same residue where a different missense change has been previously established as a pathogenic variant (PM5). It is also predicted to have a deleterious effect on protein function with a REVEL score of 0.95 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203423/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0025241 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0043250 infores:hetionet CHEBI:5613 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0013144 infores:hetionet CHEBI:2663 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0038325 infores:hetionet CHEBI:7444 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0013404 infores:hetionet CHEBI:4911 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0038325 infores:hetionet CHEBI:63620 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151970 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0392197 infores:hetionet CHEBI:5864 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0011206 infores:hetionet CHEBI:82981 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0012833 infores:hetionet CAID:CA367401929 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401929 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.454T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 152 (p.(Phe152Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.992, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in seven unrelated individuals with hyperglycemia (PS4; PMID: 16965331, internal lab contributors]). This variant segregated with diabetes/hyperglycemia, with at least four informative meioses in two families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibody) (PP4_Moderate; internal lab contributors]). In summary, c.454T>C meets the criteria to be classified as a variant of pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4, PM2_Supporting, PP3, PP2, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401929/MONDO:0015967/086 2024-04-18 2024-04-18 Semidominant inheritance HP:0032113 Supports CHEBI:41423 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042024 infores:hetionet HP:0031377 biolink:causes MONDO:0008170 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D010051 DB01005_MESH_D010051_1 CHEBI:51230 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0151907 infores:hetionet CHEBI:465284 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002792 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0021843 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151735 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0042109 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0948873 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0948594 infores:hetionet CAID:CA151479 biolink:causes MONDO:0017623 infores:clingen CAID:CA151479 MONDO:0017623 PMID:27884173 Likely Benign BS2_Supporting, BS1, BP2 PVS1, PM6, PM2, BP5, BP7, BS3, BS4, PP4, PP1, PP2, PP3, PM1, PM4, PM5, BA1, BP4, PS2, PS3, PS4, PS1 PTEN c.-1084C>T (NC_000010.10:g.89623142C>T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0025 (0.25%, 38/14,966 alleles) in the European subpopulation of the gnomAD cohort. (PMID 27535533)BP2: At least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. (internal laboratory contributor(s) SCV000149464.4)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (PMID 27884173, internal laboratory contributor(s) SCV000149464.4, SCV000185343.1) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA151479/MONDO:0017623/003 2018-11-28 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42797 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013595 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0005249 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D011014 DB00833_MESH_D011014_1DB01059_MESH_D011014_1DB00759_MESH_D011014_1DB01017_MESH_D011014_1DB00447_MESH_D011014_1DB02703_MESH_D011014_1 CHEBI:3423 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0242656 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0152198 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0413252 infores:hetionet CHEBI:28864 biolink:causes MONDO:0007426 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C2607947 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027651 infores:hetionet CHEBI:75045 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0423791 infores:hetionet CHEBI:367163 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0042023 infores:hetionet CHEBI:2950 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0231218 infores:hetionet CHEBI:4877 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C1443060 infores:hetionet CHEBI:42797 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1142412 infores:hetionet CHEBI:28901 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151907 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0029456 infores:hetionet GO:0097432 biolink:causes CL:1001571 infores:ubergraph knowledge_assertion manual_agent GO:0097432 CL:1001571 CHEBI:50885 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0009938 infores:hetionet CHEBI:4530 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0027497 infores:hetionet CAID:CA10014526 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014526 MONDO:0011071 PMID: Likely Benign BP4, BP7, BS1 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 The NM_001754.5(RUNX1):c.352-8G>A variant is an intronic variant, reported at a MAF of 0.0003508 (0.04%, 7/19954 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort, meeting BS1 criteria. The variant has a SpliceAI score of 0.01, meeting BP4 criteria (SpliceAI ≤ 0.20). It is not evolutionarily conserved, with a phyloP100 way score of -0.697. In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014526/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085612 infores:hetionet CHEBI:31236 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015403 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005029 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0040028 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0233632 infores:hetionet CHEBI:4887 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0014457 infores:hetionet CHEBI:6950 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0022568 infores:hetionet CHEBI:27504 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0003123 infores:hetionet CHEBI:7575 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0017178 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0541832 infores:hetionet CHEBI:3242 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0015230 infores:hetionet CHEBI:66964 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C1443060 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0034069 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034186 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0221714 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151560 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151560 infores:hetionet CHEBI:36704 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0162834 infores:hetionet CAID:CA1251467 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251467 MONDO:0013144 PMID: Uncertain Significance BP4 PS4, BS1, BS2, PM2 The c.100G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 6 (p.Gly34Arg). The computational predictor REVEL gives a score of 0.115, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: BP4. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251467/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA658795287 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795287 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The NM_000152.5(GAA):c.2380del (p.Arg794ValfsTer12) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant has been reported with infantile onset Pompe disease and <1% GAA normal GAA activity in skin fibroblasts (PMIDs 18458862) (PP4_Moderate). This patient is compound heterozygous for the c.2380del variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.1935C>A (p.Asp645Glu). The phase is unknown (PMIDs 10338092, 18458862) (PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795287/MONDO:0009290/010 2022-01-04 2022-05-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:17474 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0021053 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0233414 infores:hetionet CHEBI:3216 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0855333 infores:hetionet CHEBI:51041 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0233471 infores:hetionet CHEBI:46295 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151904 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0340726 infores:hetionet CAID:CA412372976 biolink:causes MONDO:0010725 infores:clingen CAID:CA412372976 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3_Strong PS4 The NM_000330.4(RS1):c.203C>G variant is a missense variant encoding the substitution of Proline with Arginine at amino acid 68. Amino acids 67-74 have been shown to interface with adjacent octamer subunits. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.942, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.0 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. This variant has been reported in at least 1 proband (PMID: 30551202). However, the number of individuals meeting the PS4 requirement of at least two males diagnosed with X-linked retinoschisis was not sufficient, so PS4_Supporting was not met. Sergeev et al. evaluated the atomic structures of 55 mutant proteins associated with X-linked retinoschisis, among them P68R, however the results are not shown (PMID: 20061330). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting and PP3_strong (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412372976/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:175901 biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0860433 infores:hetionet CHEBI:7824 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011206 infores:hetionet GO:1900117 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:1900117 GO:0006915 CHEBI:2948 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0025289 infores:hetionet CHEBI:144551 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0085932 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0036572 infores:hetionet CHEBI:16469 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151636 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0948594 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0027765 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0235146 infores:hetionet CHEBI:50729 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0038362 infores:hetionet GO:0060651 biolink:causes GO:0060649 infores:ubergraph knowledge_assertion manual_agent GO:0060651 GO:0060649 CHEBI:135736 biolink:causes UMLS:C0003044 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003044 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018418 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0267792 infores:hetionet CHEBI:6339 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151904 infores:hetionet CAID:CA012811 biolink:causes MONDO:0005021 infores:clingen CAID:CA012811 MONDO:0005021 PMID: Uncertain Significance PM2, PS4_Supporting, PP1_Moderate PM1, PM5, PP3, PS3, BS4, BS3, PS1, BP4 The NM_000257.4(MYH7):c.2678C>T (p.Ala893Val) variant in MYH7 has been reported in 4 individuals with DCM (PS4_Supporting; Lakdawala 2012 PMID:22464770; Miller 2013 PMID:23054336; LMM pers. comm.). This variant segregated with disease in 5 affected individuals with DCM in 2 families (PP1_Moderate; Lakdawala 2012 PMID:22464770; LMM pers. comm.); however, in one of these families the variant was absent from a set of identical twins with mild LV dysfunction prior to testing at 4 months of age and additional clinical data was not available. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. In addition, computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient and conflicting evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM5_Moderate, PM2. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012811/MONDO:0005021/002 2021-09-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63619 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0021400 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0917798 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C34791 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0853698 infores:hetionet CHEBI:61049 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0857305 infores:hetionet CHEBI:9738 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0278134 infores:hetionet CHEBI:32315 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011253 infores:hetionet CHEBI:8874 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0237849 infores:hetionet CHEBI:261649 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0023380 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0332575 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037195 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0522224 infores:hetionet CHEBI:94440 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0917801 infores:hetionet CHEBI:6904 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0085649 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0151479 infores:hetionet CHEBI:16796 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0039070 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0041969 infores:hetionet CHEBI:7824 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013378 infores:hetionet CHEBI:92511 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0018932 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0029445 infores:hetionet GO:1901834 biolink:causes GO:0031086 infores:ubergraph knowledge_assertion manual_agent GO:1901834 GO:0031086 NCBIGene:23299 biolink:causes MONDO:0014121 infores:monarchinitiative not_provided not_provided HGNC:17208 MONDO:0014121 uuid:af9dc6ca-66d3-4659-8250-74452646aa76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6640 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0032343 infores:hetionet CHEBI:17474 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0026826 infores:hetionet CHEBI:80630 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0009782 infores:hetionet CHEBI:75984 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0002170 infores:hetionet CHEBI:10119 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0039070 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0030312 infores:hetionet CHEBI:49375 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027121 infores:hetionet CHEBI:68478 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0013404 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0027769 infores:hetionet CHEBI:5847 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0011991 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020538 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0917798 infores:hetionet CHEBI:8874 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011206 infores:hetionet CHEBI:135005 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C2584688 infores:hetionet CHEBI:681850 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0011175 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0878544 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0023895 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0003123 infores:hetionet CHEBI:10127 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013378 infores:hetionet CHEBI:8356 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2607914 infores:hetionet CHEBI:5790 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151740 infores:hetionet CHEBI:3223 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0017672 infores:hetionet UMLS:C0065374 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0040264 infores:hetionet CAID:CA1907773 biolink:causes MONDO:0018958 infores:clingen CAID:CA1907773 MONDO:0018958 PMID: Pathogenic PS3, PP3, PP4, PM3_Very Strong BP4, BA1, BS1, PM2 The c.19097G>T (p.Ser6366Ile) variant in NEB is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 6366. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004723 (30/63518 alleles) in the European (Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1. However, this variant is excluded from the application of BA1/BS1 by the ClinGen Congenital Myopathies VCEP as it is a well established pathogenic variant. The computational predictor REVEL gives a score of 0.829, which is above the threshold of 0.7, evidence that correlates with impact to NEB function (PP3). This variant has been detected in 10 individuals with nemaline myopathy. Eight of those individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 2 of those were confirmed in trans by family testing. Two individuals were homozygous for the variant (PMIDs: 25205138, 15336686, 17525139) (PM3_VeryStrong). At least one patient with this variant displayed nemaline rods, which is highly specific for nemaline myopathy (PP4, PMID: 17525139). A typical NM mouse model with compound heterozygous variants (p.Ser6366Ile and NebΔExon55) mimics features found in NM patients such as growth-retardation, muscle weakness, and atrophic muscles that contain nemaline rods and structural features consistent with NM. The S6366I-Homozygous model has a phenotype that develops with age and appears to share similarities with Finnish distal myopathy patients (PMID: 32483185)(PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PS3, PP3, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1907773/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9139 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018099 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0948089 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0520588 infores:hetionet NCBIGene:131118 biolink:causes MONDO:0012435 infores:monarchinitiative not_provided not_provided HGNC:30528 MONDO:0012435 uuid:b4546a61-74be-4da1-8f43-b5bb59522818 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9445 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0026205 infores:hetionet NCBITaxon:632 biolink:causes MONDO:0019095 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:632 MESH:D010930 DB00218_MESH_D010930_1DB01017_MESH_D010930_1DB01082_MESH_D010930_1 CAID:CA8623518 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623518 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.2331G>A (p.Thr777=), no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.0002004 (5/24952 alleles) in the African/African American population, which does not meet threshold for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -2.347 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623518/MONDO:0100326/011 2023-08-15 2023-08-15 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:2676 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0002792 infores:hetionet CAID:CA360714779 biolink:causes MONDO:0021056 infores:clingen CAID:CA360714779 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting The c.8530T>G (p.Ter2844Glu) variant in APC is a stop-loss variant where the termination codon at position 2844 is replaced by amino acid glutamic acid. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, due to insufficient evidence, this is a variant of unknown significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA360714779/MONDO:0021056/089 2023-02-26 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45951 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0041834 infores:hetionet CHEBI:77260 biolink:causes HP:0025289 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235592 infores:hetionet CHEBI:474180 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0041969 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0518015 infores:hetionet CHEBI:34967 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0011991 infores:hetionet CHEBI:28593 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0017178 infores:hetionet CHEBI:567361 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0241136 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0042109 infores:hetionet CHEBI:45863 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0039070 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020649 infores:hetionet CHEBI:92923 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0015230 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0855242 infores:hetionet CAID:CA410147752 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147752 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS4, PS2, PS3, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1219T>C (p.Tyr407His) is a missense variant which has a REVEL score < 0.50 (0.404) and a SpliceAI score ≤ 0.20, indicating no predicted impact on splicing (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147752/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39867 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002453 infores:hetionet CHEBI:9738 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0042023 infores:hetionet CHEBI:4975 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0231528 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0522064 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0522064 infores:hetionet CHEBI:32588 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0015230 infores:hetionet NCBIGene:170302 biolink:causes MONDO:0010224 infores:monarchinitiative not_provided not_provided HGNC:18060 MONDO:0010224 uuid:81f27a6e-4132-4959-bc61-2b27f2d4e05b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10771 biolink:causes MONDO:0014486 infores:monarchinitiative not_provided not_provided HGNC:16966 MONDO:0014486 uuid:f7f12e94-3115-473e-9634-c033b4c65e22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA3232074 biolink:causes MONDO:0012163 infores:clingen CAID:CA3232074 MONDO:0012163 PMID: Uncertain Significance BS2_Supporting NM_002185.5(IL7R):c.707G>A is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at amino acid 236 (p.Gly236Glu). This variant was found in 4 homozygotes in gnomAD v4 (BS2_supporting).There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3232074/MONDO:0012163/119 2024-06-14 2024-06-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63611 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042510 infores:hetionet CHEBI:9635 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0017178 infores:hetionet CHEBI:31236 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0311468 infores:hetionet CHEBI:64321 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0032781 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C1956346 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0857112 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0857112 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0851341 infores:hetionet CHEBI:50692 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0012833 infores:hetionet CHEBI:101278 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0085614 infores:hetionet CHEBI:63791 biolink:causes HP:0002176 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0037926 infores:hetionet NCBIGene:54332 biolink:causes MONDO:0011916 infores:monarchinitiative not_provided not_provided HGNC:15968 MONDO:0011916 uuid:55d6678d-fd00-43a5-bef6-897c78406c9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6933 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0020453 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0020676 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0016385 infores:hetionet CHEBI:8764 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0000768 infores:hetionet CHEBI:4909 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013604 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0085649 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0917799 infores:hetionet CAID:CA913184761 biolink:causes MONDO:0009290 infores:clingen CAID:CA913184761 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000152.5:c.40_47del (p.Ala14ArgfsTer18) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with infantile onset Pompe disease has been reported in multiple publications. Features include increased left ventricular mass, GAA activity <1% normal in skin fibroblasts, and improvement on enzyme replacement therapy (PP4_Moderate) (PMIDs: 17151339, 22658377, 29422078, 31193175). This patient is compound heterozygous for c.40_47del8 and c.1465G>A (p.Asp489Asn). The in trans data will be used in the assessment of p.Asp489Asn and is not included here to avoid circular logic (PMID: 29422078). The variant in absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (specifications version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP, February 7, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913184761/MONDO:0009290/010 2023-02-07 2023-03-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UNII:G4PX8C4HKV biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0012833 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1262141 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027765 infores:hetionet CHEBI:68610 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0001339 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030305 infores:hetionet CHEBI:4953 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0033774 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0021359 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0234458 infores:hetionet CHEBI:7986 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0037763 infores:hetionet CAID:CA8815554 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815554 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3_Supporting "The NM_000152.5:c.1941C>G variant in GAA is a missense variant that is predicted to result in substitution of cysteine by tryptophan at amino acid 647 (p.Cys647Trp). At least 10 patients with this variant have been reported to have Pompe disease including two with documented laboratory values showing deficiency of GAA, one of whom also had reported symptoms consistent with infantile onset Pompe disease (PMID: 7981676, 9535769, 17723315) (meeting PP4_Moderate), three patients with reported symptoms consistent with infantile onset Pompe disease (PMID: 7981676, 19588081, 22658377, 31510962), one patient on enzyme replacement therapy (PMID: 31086307) (all meeting PP4). Four patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic for Pompe disease including c.-32-13T>G (PMID: 25681614, 31931849; 2 patients), c.2481+110_2646+39del (exon 18 deletion, PMID: 7981676), and c.1655T>C (p.Leu552Pro) (PMID: 19588081), all phase unconfirmed. In another patient, the variant is confirmed in trans with an allele containing two pathogenic variants, c.1456_1468del (p.Ala486fsTer30) (confirmed de novo) and c.2238G>C (p.Trp746Cys) (PMID: 7981676), and two patients are homozygous for the variant (PMID: 9535769, 31510962) (PM3_Very Strong). In addition, two patients are compound heterozygous for the variant and either c.1846G>A (p.Asp616Asn) (PMID: 31086307) or c.1781G>C (p.Arg594Pro) (PMID: 19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. In another patient, no second variant was found (PMID: 25681614). When expressed in GAA-deficient SV40 immortalized fibroblasts, the variant resulted in <1% GAA activity compared to the normal control ( PMID: 9535769) (PS3_Supporting).The computational predictor REVEL gives a score of 0.802 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00002 (3/124712 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Of note, the highest population minor allele frequency in gnomAD v2.1.1 is in the ""other"" population, 0.00014 (1/7006 alleles) which also meets the PM2_Supporting threshold. There is a ClinVar entry for this variant (Variation ID: 550327). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Very_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on Nov. 15, 2022." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815554/MONDO:0009290/010 2022-11-15 2022-11-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:50859 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0013404 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0029445 infores:hetionet CHEBI:7454 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0476273 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151849 infores:hetionet CHEBI:171719 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0005758 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020538 infores:hetionet CHEBI:16335 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C2830004 infores:hetionet CHEBI:36791 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0036974 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0235416 infores:hetionet NCBITaxon:6199 biolink:causes MONDO:0042488 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6199 MONDO:0042488 CHEBI:119573 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0242073 infores:hetionet CHEBI:7476 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085605 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0859032 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0859032 infores:hetionet CHEBI:38940 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0741494 infores:hetionet CHEBI:34967 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0009782 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0004239 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0235282 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0235282 infores:hetionet CHEBI:4445 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0018681 infores:hetionet CHEBI:15553 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0011991 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0740278 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0740278 infores:hetionet CHEBI:50648 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0237849 infores:hetionet CHEBI:45783 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0015672 infores:hetionet CHEBI:3077 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0043094 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0273115 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0273115 infores:hetionet CAID:CA496157186 biolink:causes MONDO:0007648 infores:clingen CAID:CA496157186 MONDO:0007648 PMID:21271559PMID:16061854 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS4, BS3, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS2, PS3 The c.2276delG (p.Gly759Glufs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 16061854). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA496157186/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:16664 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0018681 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0521839 infores:hetionet CHEBI:7492 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0235267 infores:hetionet CHEBI:5134 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0043037 infores:hetionet CHEBI:3398 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0162830 infores:hetionet CHEBI:9943 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151825 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0020538 infores:hetionet CHEBI:4356 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0002792 infores:hetionet CHEBI:9907 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0852911 infores:hetionet CAID:CA1139665157 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665157 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1684_1685del (p.Gln562fs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 18/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported once as a result of a positive newborn screening for VLCADD (PMID:26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665157/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:137814 biolink:causes MONDO:0016581 infores:monarchinitiative not_provided not_provided HGNC:32940 MONDO:0016581 uuid:57fb4c79-efe3-420c-9aef-ff869e932122 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9588 biolink:causes UMLS:C3267156 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C3267156 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0020538 infores:hetionet NCBIGene:105371045 biolink:causes MONDO:0032857 infores:monarchinitiative not_provided not_provided HGNC:52293 MONDO:0032857 uuid:3a7e469c-c4db-45d6-af1b-4c14bdcda207 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9YCX42I8IU biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0012813 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1443060 infores:hetionet NCBIGene:91057 biolink:causes MONDO:0031077 infores:monarchinitiative not_provided not_provided HGNC:25079 MONDO:0031077 uuid:25fc986c-4f54-4026-b6c4-6857bb238318 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0853875 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0021053 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036130 infores:hetionet UMLS:C1738934 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1456784 infores:hetionet NCBIGene:23600 biolink:causes MONDO:0008967 infores:monarchinitiative not_provided not_provided HGNC:451 MONDO:0008967 uuid:a6760b31-faf4-4239-8464-92bfaafffe71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085631 infores:hetionet CHEBI:9073 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0002994 infores:hetionet CHEBI:194135 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0036830 infores:hetionet CHEBI:40279 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020621 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0227791 infores:hetionet CHEBI:68478 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0242339 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0033117 infores:hetionet NCBITaxon:5970 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5970 MONDO:0001867 CHEBI:4672 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0235025 infores:hetionet NCBIGene:2782 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:4396 MONDO:0013108 uuid:266f7da4-19d4-4780-995d-89640f4d5111 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0003862 infores:hetionet CHEBI:6541 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0687713 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009806 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0234215 infores:hetionet CAID:CA023585 biolink:causes MONDO:0007750 infores:clingen CAID:CA023585 MONDO:0007750 PMID: Pathogenic PS4, PM5, PM3, PS3_Supporting, PM2, PP3, PP4 BA1, BP4, BP2, PS1, PS2, BS1, BS3, BS4, BP7, PM4, PM1, PM6, PVS1, BS2, PP1 The NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5, PS3_supporting, PS4, PP4, PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - PopMax MAF = 0.0002389 (0.02389%) in European (Finnish) exomes+genomes (gnomAD v2.1.1), since this is a founder effect variant in Finnish population (PMID: 11585102) we can consider PopMax MAF = 0.00005012 (0.005012%) in East Asian exomes+genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.956.It is above 0.75, so PP3 is Met.PM5 - 2 other missense variants in the same codon:- NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) (ClinVar ID: 252029) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.PS3_supporting - Level 3 assay: PMID 11585102:Heterozygous patient cells, 125I-LDL assays - result - 70% LDL-LDLR binding, 54-49% LDL-LDLR uptake and degradation.---- functional study is consistent with damaging effect, so PS3_Supporting is Met.PS4 - Variant meets PM2 and is identified in 11 unrelated index cases: 1 index case with Simon Broome definite criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 4 index cases with DLCN criteria for FH (LDL > 95th percentile and presence of tendon xanthomas) from Finland (PMID: 11585102), 1 index case with FH criteria suggested by the Japan Atherosclerosis Society (TC > 260 mg/dL with tendon xanthomas OR TC > 260 mg/dL and TC > 260 mg/dL with tendon xanthomas in first or second degree relatives) from Japan ( PMID: 18718593), 1 index case with DLCN criteria for FH (score=8) from Sweden (PMID: 29974534), 1 index case with DLCN criteria for FH (score>=6) from Argentina (PMID: 30270055), 2 index cases with DLCN criteria for FH (score>=6) from Russia (PMID: 33418990), 1 index case with homozygous FH phenotype (LDL = 16 mmol/L) from The Netherlands (PMID: 24585268), so PS4 is Met.PP4 - Variant meets PM2 and is identified in 11 unrelated index cases as described before, so PP4 is Met.PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 16 mmol/L) and LDLR variant c.(1705+1_1706-1)_(*2514_?)del (described as 16kb deletion exon 12-18) (PMID: 24585268), classified as Pathogenic by these guidelines, in trans, so PM3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023585/MONDO:0007750/013 2022-02-02 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA386966158 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966158 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM5_Strong, PM1, PS3_Supporting, PP3, PP1 PP4 The c.788G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to leucine at codon 263 (p. (Arg263Leu) of transcript, e.g. NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1(PM2_Supporting). Two other missense variants, c.787C>T (p.Arg263Cys) and c.788G>A (p.Arg263His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg263Leu has a greater Grantham distance than p.Arg263His (PM5_Strong). Functional studies demonstrated the p.Arg263Leu protein has no DNA binding activity, indicating that this variant impacts protein function (PS3_Supporting, PMID: 12712243). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID: 12712243). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (MODY probability calculator result >50%); however, HNF1A was not tested, and PP4 is not applied (PMID: 12712243). In summary, c.790G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PM5_Strong, PS3_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966158/MONDO:0015967/017 2022-04-14 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6129 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020649 infores:hetionet CHEBI:7445 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0011603 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0034150 infores:hetionet CHEBI:8382 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0042384 infores:hetionet CHEBI:100246 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C1443060 infores:hetionet CHEBI:3176 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0558489 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0518015 infores:hetionet CHEBI:8212 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0547030 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019348 infores:hetionet CAID:CA915949642 biolink:causes MONDO:0011132 infores:clingen CAID:CA915949642 MONDO:0011132 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PS4 The NM_001369369.1(FOXN1):c.1418del (p.Pro473HisfsTer?) variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). The variant is absent from gnomADv4.0 (PM2_Supporting). At least one heterozygous patient has been reported with a specific phenotype of nail dystrophy and T−B+NK+ SCID (Patient P19 of PMID: 31447097,also reported as P16 in PMID: 31566583; PP4). A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. This variant had 1.5% luciferase activity compared to WT. In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, and PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949642/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:68841 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0015967 infores:hetionet CHEBI:36795 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0233471 infores:hetionet NCBIGene:8050 biolink:causes MONDO:0009503 infores:monarchinitiative not_provided not_provided HGNC:21350 MONDO:0009503 uuid:a544e42d-b683-4485-8b4d-01206e27505e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:617099 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0027497 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0178298 infores:hetionet CHEBI:71219 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0852911 infores:hetionet NCBIGene:51780 biolink:causes MONDO:0030012 infores:monarchinitiative not_provided not_provided HGNC:1337 MONDO:0030012 uuid:04698122-99e1-4c93-aaa5-96c93a152e06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:76010 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0004936 infores:hetionet CHEBI:4511 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0013395 infores:hetionet CHEBI:9449 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0027769 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151505 infores:hetionet CHEBI:36795 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0038325 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039503 infores:hetionet CHEBI:32588 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0522055 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0242354 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0242354 infores:hetionet NCBIGene:5832 biolink:causes MONDO:0011006 infores:monarchinitiative not_provided not_provided HGNC:9722 MONDO:0011006 uuid:2d4765fd-7355-43bc-bc4a-8cee8dd8e948 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6916 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0011124 infores:hetionet CHEBI:8060 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0015672 infores:hetionet CHEBI:6030 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0497156 infores:hetionet CHEBI:3314 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0428977 infores:hetionet CHEBI:68558 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018944 infores:hetionet CHEBI:75045 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020461 infores:hetionet CHEBI:474053 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0002878 infores:hetionet CHEBI:2569 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0020440 infores:hetionet CHEBI:3219 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0231528 infores:hetionet CHEBI:94807 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C2830004 infores:hetionet CAID:CA1251401 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251401 MONDO:0013144 PMID: Likely Benign BS1, BP4 The c.553A>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 185 (p.Thr185Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001796 (55/30616 alleles) in the South Asian population, which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.168, which is below the threshold of 0.3, and the splice site predictors VarSEAK and Splice AI indicated that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BS4 Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251401/MONDO:0013144/084 2023-07-25 2023-09-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7915 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0267596 infores:hetionet CHEBI:72564 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0015371 infores:hetionet CHEBI:7936 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0012569 infores:hetionet CHEBI:74947 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0025289 infores:hetionet CHEBI:8207 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0024902 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0221490 infores:hetionet CHEBI:617099 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0011603 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0151734 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0015397 infores:hetionet CHEBI:2950 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0016867 infores:hetionet CHEBI:101278 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0010200 infores:hetionet CHEBI:9635 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0020437 infores:hetionet CHEBI:32139 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0038999 infores:hetionet CHEBI:49662 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0022346 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0087169 infores:hetionet CHEBI:46081 biolink:causes HP:0040213 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0235546 infores:hetionet GO:0033077 biolink:causes CL:0000893 infores:ubergraph knowledge_assertion manual_agent GO:0033077 CL:0000893 CHEBI:3647 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0085649 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0162287 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0041969 infores:hetionet CHEBI:10650 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017168 infores:hetionet CHEBI:7476 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0242429 infores:hetionet CHEBI:68534 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0023067 infores:hetionet CHEBI:5165 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0003862 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235639 infores:hetionet CHEBI:367163 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0220981 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235431 infores:hetionet GO:0060657 biolink:causes GO:0061180 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0061180 NCBITaxon:210 biolink:causes MONDO:0006781 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:210 MONDO:0006781 CHEBI:9328 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151205 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0233472 infores:hetionet CHEBI:2639 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0039971 infores:hetionet CHEBI:37941 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0035455 infores:hetionet CHEBI:27779 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0027720 infores:hetionet CHEBI:7454 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0038450 infores:hetionet CHEBI:3403 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0016382 infores:hetionet GO:0090199 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0090199 GO:0051716 CHEBI:408174 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0006840 infores:hetionet CHEBI:51173 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0004093 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0235431 infores:hetionet CHEBI:9448 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0018681 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0236075 infores:hetionet CHEBI:15854 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0012569 infores:hetionet CHEBI:101278 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042029 infores:hetionet CHEBI:9435 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0033774 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017152 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0234215 infores:hetionet CHEBI:48273 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0233794 infores:hetionet CHEBI:6775 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085624 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0553548 infores:hetionet CHEBI:39585 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0030196 infores:hetionet CHEBI:64312 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020461 infores:hetionet CHEBI:31625 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0920171 infores:hetionet CHEBI:66899 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0349790 infores:hetionet CHEBI:5613 biolink:causes MONDO:0015991 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0175683 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005291 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0007766 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0860745 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0860745 infores:hetionet CHEBI:47381 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0520966 infores:hetionet CHEBI:36791 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0024902 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0025061 infores:hetionet CHEBI:17698 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0151773 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0851341 infores:hetionet CHEBI:681569 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0017181 infores:hetionet NCBIGene:7490 biolink:causes MONDO:0006292 infores:monarchinitiative not_provided not_provided HGNC:12796 MONDO:0006292 uuid:ff0ccafc-dd39-4d83-971d-5a54d3c1ed10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0040264 infores:hetionet CHEBI:31236 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0231919 infores:hetionet CHEBI:36795 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0014742 infores:hetionet CHEBI:8772 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0017178 infores:hetionet CHEBI:101278 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0015672 infores:hetionet CHEBI:71417 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0014457 infores:hetionet CHEBI:31348 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011071 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151828 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0520588 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0152021 infores:hetionet CHEBI:92923 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0151907 infores:hetionet CHEBI:50223 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0006826 infores:hetionet CHEBI:209807 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0015967 infores:hetionet CHEBI:18258 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0002962 infores:hetionet CHEBI:64045 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0002453 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0235214 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235214 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0429059 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0429059 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0314719 infores:hetionet CHEBI:4315 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0020564 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0349506 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0005940 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0021167 infores:hetionet CHEBI:8069 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0041657 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0521500 infores:hetionet CAID:CA320603659 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603659 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.735C>T (p.Pro245=) is a synonymous variant which has a SpliceAI score < 0.20 (BP4). A REVEL score is not available. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603659/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16469 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0332575 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0022650 infores:hetionet CHEBI:2618 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0026826 infores:hetionet CHEBI:6437 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0015967 infores:hetionet CHEBI:2639 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0030193 infores:hetionet CHEBI:135351 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0022107 infores:hetionet CHEBI:74947 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0700225 infores:hetionet CHEBI:8890 biolink:causes HP:0030917 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0549400 infores:hetionet CHEBI:3181 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0003467 infores:hetionet CHEBI:3314 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C1142412 infores:hetionet CAID:CA226378 biolink:causes MONDO:0100437 infores:clingen CAID:CA226378 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1835dup (p.Asn612LysfsTer18) is a frameshift variant due to a one-nucleotide duplication introducing a premature stop codon in exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one male proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), first-decade onset (1 pt), decreased central visual acuity (0.5 pts), moderate myopia (0.5 pts), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (4 points, PMID: 10937588, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226378/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Supports CHEBI:63607 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0029132 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0277925 infores:hetionet CHEBI:10112 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0027497 infores:hetionet CHEBI:17334 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0031542 infores:hetionet CAID:CA010639 biolink:causes MONDO:0005045 infores:clingen CAID:CA010639 MONDO:0005045 PMID:20428263PMID:27532257PMID:22429680PMID:21835320PMID:15858117PMID:20800588PMID:20428263 Pathogenic PP3, PM6, PM5, PM1, PM2, PS4 The c.1358G>A (p.Arg453His) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:20428263; PMID:15858117; PMID:20800588; PMID:21835320; PMID:22429680; Partners LMM ClinVar SCV000059369.5; Invitae ClinVar SCV000253816.4; SHaRe consortium, PMID: 30297972). This variant was been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:20428263). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1357C>T p.Arg453Cys; ClinVar Variation ID 14089). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PM6; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010639/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5130 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C2242737 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151799 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0013395 infores:hetionet CHEBI:9316 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0018790 infores:hetionet CHEBI:2676 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0687713 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0008035 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0518015 infores:hetionet CHEBI:10100 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0242429 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0086543 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0006266 infores:hetionet CHEBI:63598 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0423791 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0007787 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0234952 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234952 infores:hetionet CHEBI:8874 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0522055 infores:hetionet CHEBI:15765 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0000737 infores:hetionet CHEBI:10119 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0547030 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0003123 infores:hetionet CHEBI:9763 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0004134 infores:hetionet CHEBI:53691 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0023052 infores:hetionet CHEBI:4710 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0558401 infores:hetionet CHEBI:3732 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0750394 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018799 infores:hetionet CHEBI:47381 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042963 infores:hetionet NCBIGene:5805 biolink:causes MONDO:0009863 infores:monarchinitiative not_provided not_provided HGNC:9689 MONDO:0009863 uuid:fd81993b-2f1c-4f29-9a8f-f943a0a49995 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6916 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C1443060 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0007959 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0007959 uuid:3733d258-06b0-4af9-b58b-890da79b24ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0740394 infores:hetionet CHEBI:9445 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0017152 infores:hetionet CHEBI:5001 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0423791 infores:hetionet CHEBI:8888 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018681 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0085096 infores:hetionet CHEBI:8356 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2937358 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0347390 infores:hetionet CHEBI:83804 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151878 infores:hetionet CAID:CA2580612101 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612101 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP1, PP4 The c.1132_1133del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 378 in NM_000162.5, adding 80 novel amino acids before encountering a stop codon (p.(Ala378CysfsTer80)). While this variant, located in exon 9 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1132_1133del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612101/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:51860 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0041657 infores:hetionet CHEBI:101853 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0015672 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0235874 infores:hetionet CHEBI:28748 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036974 infores:hetionet CAID:CA5416976 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416976 MONDO:0011225 PMID: Uncertain Significance BA1, PM2, BS1, PM5 The c.212C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 71 (p.Thr71Met).The filtering allele frequency (the upper threshold of the 95% CI of 303/1179486 alleles) of the c.212C>T variant in DCLRE1C is 0.0002288 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416976/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:846 biolink:causes MONDO:0009397 infores:monarchinitiative not_provided not_provided HGNC:1514 MONDO:0009397 uuid:6c1294b2-6491-475a-b715-5b6d65ec43e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4469 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0338614 infores:hetionet CHEBI:15640 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0085593 infores:hetionet CHEBI:3219 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042963 infores:hetionet CHEBI:7820 biolink:causes HP:0008665 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0156394 infores:hetionet CHEBI:28445 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0018790 infores:hetionet CHEBI:134991 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0917801 infores:hetionet CHEBI:66876 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0017168 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0038663 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002329 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0039584 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0042075 infores:hetionet CHEBI:31932 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C1291078 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0042109 infores:hetionet CAID:CA305300092 biolink:causes MONDO:0007750 infores:clingen CAID:CA305300092 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 PS3, PM3, PM5 The NM_000527.5 (LDLR):c.1367T>C (p.Leu456Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00006 in African population in gnomAD (gnomAD 2.1.1).PP3: REVEL=0.862.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill criteria for FH (1 case meeting Simon Broome criteria from UT Southwestern Medical Center, US, in PMID 23064986 (Ahmad et al., 2012); 1 case from University of Pennsylvania, US, in PMID 19026292 (Kolansky et al., 2008) with total cholesterol of 836 mg/dl at age of 8 yrs and pathogenic LDLR variant c.1846-1G>A. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305300092/MONDO:0007750/013 2024-06-23 2024-10-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UNII:3U02EL437C biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0023518 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0151736 infores:hetionet NCBIGene:5836 biolink:causes MONDO:0009294 infores:monarchinitiative not_provided not_provided HGNC:9725 MONDO:0009294 uuid:c3e7b08f-19ad-4ed4-9129-accfb118608c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0037384 infores:hetionet CHEBI:10119 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022660 infores:hetionet CHEBI:9445 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0002962 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013395 infores:hetionet CHEBI:7447 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0042963 infores:hetionet CHEBI:7865 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0004093 infores:hetionet CAID:CA16020734 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020734 MONDO:0009861 PMID: Pathogenic PM3, PVS1, PM2, PP4, PP1_Moderate The c.169-2A>G variant has been identified in at least 1 proband with classic PKU (PMID: 24368688; PP4). It has been detected in the homozygous form (PMID: 20188615) as well as in trans with the pathogenic variant Gly272Ter (PMID: 24368688) (PM3). Family one (PMID: 20188615), with the segregating c.169-2A>G variant (reported as c.168-2A>G) had three affected individuals (proband, sibling, and cousin) all homozygous. Not including the proband, the two additional affected family members meet PP1_Moderate. This variant is present at very low allele frequencies; 0.000007993 overall in gnomAD with a MAF of 0.00003267 (1/30612) in the South Asian population (PM2). Computational analysis predicts an alteration of the WT acceptor site, most probably affecting splicing, generating a frameshift, and leading to nonsense mediated decay (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP1_Moderate, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020734/MONDO:0009861/006 2019-08-25 2024-09-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3011 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0030252 infores:hetionet NCBIGene:7173 biolink:causes MONDO:0010133 infores:monarchinitiative not_provided not_provided HGNC:12015 MONDO:0010133 uuid:63f8c767-5a53-4436-909d-ecac6980e8e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA345144967 biolink:causes MONDO:0100084 infores:clingen CAID:CA345144967 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_Moderate, PM5_Supporting The c.1001C>T (NM_001100.4(ACTA1):c.1001C>T (p.Pro334Leu)) variant in ACTA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 334 (p.Pro334Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.814, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Another missense variant p.Pro334Arg (c.1001C>G) [ClinVar Variation ID: 1031829] in the same codon has been classified as likely pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5_supporting). This variant has been identified in 4 probands with autosomal dominant alpha-actinopathy. At least one patient with this variant displayed rods on a muscle biopsy, which is highly specific for alpha-actinopathy (PS4_moderate, PP4_moderate; Invitae, Paris-East Créteil University internal data, Alan Beggs personal communication, LOVD). Of note, all probands displayed later than typical onset of symptoms with onset ranging from late teens to the 5th or 6th decade of life. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_supporting, PP3, PP2, PM5_supporting, PS4_moderate, PP4_moderate (ClinGen Congenital Myopathies VCEP Specifications Version 2.0; 9/9/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345144967/MONDO:0100084/147 2024-09-09 2025-04-02 Autosomal dominant inheritance HP:0000006 Supports GO:0060217 biolink:causes CL:0002418 infores:ubergraph knowledge_assertion manual_agent GO:0060217 CL:0002418 CHEBI:42797 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0852733 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027765 infores:hetionet CHEBI:63635 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013378 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0014742 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0018939 infores:hetionet CHEBI:168396 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0017181 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0541879 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0541879 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0162429 infores:hetionet CHEBI:17688 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1443060 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0022408 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0239488 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014549 infores:hetionet NCBIGene:56916 biolink:causes MONDO:0008416 infores:monarchinitiative not_provided not_provided HGNC:18398 MONDO:0008416 uuid:d14a3c3d-90e6-4c93-bed6-ec88f5034175 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8232 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151872 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042514 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0009450 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0038525 infores:hetionet CHEBI:474180 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0580413 infores:hetionet CHEBI:4356 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0033774 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027651 infores:hetionet CHEBI:17698 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0015967 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0018799 infores:hetionet CAID:CA502178465 biolink:causes MONDO:0009290 infores:clingen CAID:CA502178465 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000152.5:c.1431del (p.Ile477MetfsTer43) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient from Saudi Arabia, homozygous for the variant, has been reported with infantile onset Pompe disease, on enzyme replacement therapy (PMID: 27629047, 30023291) (PM3_Supporting, PP4). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 694453). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0.0): PVS1, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 26, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA502178465/MONDO:0009290/010 2025-06-26 2025-07-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31348 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0542571 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0424000 infores:hetionet CHEBI:101278 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013390 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0042139 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042139 infores:hetionet CHEBI:6741 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151539 infores:hetionet CHEBI:3380 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0041582 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0155919 infores:hetionet CAID:CA343724521 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724521 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PM5_Supporting, PP3, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PS1, PS4, PS3, PS2, BA1, BP4 The c.1151A>G variant in MYOC is a missense variant predicted to cause substitution of Aspartate by Glycine at amino acid 384 (p.Asp384Gly). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.975, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 8 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 22876119), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 22876119), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1150G>A, p.Asp384Asn, Grantham score = 23, ClinVar ID: 1342205) in the same codon has been classified as likely pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1151A>G, p.Asp384Gly, PMID: 22876119 variant has a higher Grantham score (= 94) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PM2_Supporting, PM5_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724521/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4953 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0600142 infores:hetionet CHEBI:10101 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0019079 infores:hetionet CHEBI:75722 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011206 infores:hetionet CAID:CA410202790 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202790 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, PVS1, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.352G>T (p.Val118Leu) is a missense variant which has a REVEL score ≥ 0.88 (0.926) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202790/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0027796 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085614 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0262985 infores:hetionet CHEBI:68642 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0042029 infores:hetionet CHEBI:15765 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0497327 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0948525 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0025061 infores:hetionet CHEBI:5893 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0024141 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042514 infores:hetionet CHEBI:2663 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0003467 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0005940 infores:hetionet CAID:CA367403326 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403326 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1, BP4 The c.167A>C variant in the glucokinase gene, GCK, causes an amino acid change of lysine to threonine at codon 56 (p.(Lys56Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 33852230, ClinVar VCV001807279.3, Internal lab contributors). In summary, c.167A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PP2, PP3, PP1_Moderate, PM2_Supporting, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403326/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:63598 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0032617 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0037199 infores:hetionet CHEBI:52717 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013384 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0007787 infores:hetionet CHEBI:51860 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0424109 infores:hetionet CHEBI:9649 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0239134 infores:hetionet CHEBI:65173 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0392525 infores:hetionet CAID:CA132255 biolink:causes MONDO:0019497 infores:clingen CAID:CA132255 MONDO:0019497 PMID: Likely Pathogenic PP1_Strong, PP3, PM2_Supporting, PS4_Supporting PM5 The c.2558G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 853. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been reported in 3 probands/families with hearing loss (PS4_Supporting; PMIDs: 26969326, 32097363, ClinVar SCV: SCV000059742.6, LMM). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID: 32097363). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PS4_P, PM2_P, PP3 (Hearing Loss VCEP specifications version 2; 10/31/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132255/MONDO:0019497/005 2022-10-31 2023-01-25 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:11236 biolink:causes MONDO:0007763 infores:monarchinitiative not_provided not_provided HGNC:17023 MONDO:0007763 uuid:d962d989-0796-4a39-8fdd-a56db5d52276 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009763 infores:hetionet CHEBI:36704 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0033774 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0009806 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0836924 infores:hetionet CHEBI:50659 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0011615 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0242350 infores:hetionet CHEBI:9168 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151692 infores:hetionet NCBIGene:51305 biolink:causes MONDO:0012856 infores:monarchinitiative not_provided not_provided HGNC:6283 MONDO:0012856 uuid:3b964bfb-23d2-4262-98c7-15b50d62b38d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231594 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0018944 infores:hetionet CHEBI:39585 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0033774 infores:hetionet CHEBI:3756 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0344232 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0267596 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020517 infores:hetionet CHEBI:135925 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0011603 infores:hetionet CHEBI:9649 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0030554 infores:hetionet NCBIGene:5621 biolink:causes MONDO:0011299 infores:monarchinitiative not_provided not_provided HGNC:9449 MONDO:0011299 uuid:bdb5c8ef-fd43-479b-a9ab-2d96cc91574b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0018926 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0475858 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C2363731 infores:hetionet CHEBI:9738 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0003811 infores:hetionet CHEBI:6715 biolink:causes MONDO:0016056 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025958 infores:hetionet CHEBI:3347 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0948594 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0042769 infores:hetionet CHEBI:28148 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0268000 infores:hetionet CAID:CA400025209 biolink:causes MONDO:0100326 infores:clingen CAID:CA400025209 MONDO:0100326 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PM2_Supporting The ITGB3 nonsense variant NM_000212.3:c.921C>A (p.Tyr307Ter) introduces a premature termination codon in exon 6 of 15 total exons and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in three individuals with a phenotype specific for Glanzmann's thrombasthenia (GT) and haplotype analysis suggests a founder effect (GT21, GT25, GT55, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3, PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400025209/MONDO:0100326/011 2021-07-14 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9137 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0015469 infores:hetionet CHEBI:127342 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0085593 infores:hetionet CHEBI:2038 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0041834 infores:hetionet CHEBI:9168 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0031154 infores:hetionet NCBIGene:115650 biolink:causes MONDO:0013284 infores:monarchinitiative not_provided not_provided HGNC:17755 MONDO:0013284 uuid:ec43220c-87e2-4f62-b0a4-148af9593ad0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9398 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0162429 infores:hetionet CHEBI:35677 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0033774 infores:hetionet CHEBI:135351 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0040409 infores:hetionet CHEBI:9725 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0520887 infores:hetionet CHEBI:9727 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0017565 infores:hetionet CHEBI:8356 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233762 infores:hetionet CHEBI:63608 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0002962 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0031085 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019158 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0149745 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0010823 infores:hetionet NCBIGene:7045 biolink:causes MONDO:0011855 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0011855 uuid:bd3936f5-66b8-4291-abc3-80aad4962bc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:724125 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0015230 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0012833 infores:hetionet CHEBI:28901 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C2937358 infores:hetionet CHEBI:8884 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0042963 infores:hetionet CAID:CA913175296 biolink:causes MONDO:0044970 infores:clingen CAID:CA913175296 MONDO:0044970 PMID:32419253 Uncertain Significance PP3, PM2_Supporting, PM6_Supporting, PS3_Supporting PS4 The m.15958A>T variant in MT-TP has been reported in one individual from one family to date (PMID: 27816331), in a boy with myopathy and failure to thrive. Muscle biopsy showed ragged red fibers, COX-deficient fibers, mitochondrial proliferation, complex I deficiency, and complex IV deficiency. The variant was present at 94% heteroplasmy in muscle, 78% in urine, 48% in skin fibroblasts, 9% in blood, and was undetectable in buccal sample. The variant was undetectable in urine, blood, and buccal sample from his mother (PM6_supporting, PMID: 27816331). The computational predictor MitoTIP suggests this variant is pathogenic (93.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.4 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (96.10% ± 1.66) than in COX positive fibers (68.78% ± 18.11), p=0.0002 (PS3_supporting, PMID: 32419253). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913175296/MONDO:0044970/015 2024-04-23 2024-05-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5893 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0232333 infores:hetionet CAID:CA1562832 biolink:causes MONDO:0019497 infores:clingen CAID:CA1562832 MONDO:0019497 PMID: Uncertain Significance PM3_Supporting, PP3, BS1_Supporting PS4, PM2, BS2, PP4, BP4, BA1 The NM_194248.3:c.5405C>T variant in the OTOF gene is a missense variant predicted to cause the substitution of alanine by valine at amino acid 1802 (p.Ala1802Val). The filtering allele frequency in gnomAD v4.1.0 was 0.09139% (47/44874 alleles) in the East Asian population meeting BS1_Supporting. The REVEL computational prediction analysis tool produced a score of 0.729, which is above the threshold necessary to apply PP3, and the amino acid residue is well conserved in UCSC (PP3). This variant has been identified in compound heterozygous state with rare variants in 2 patients with hearing loss meeting PM3_Supporting (PMID: 31095577, 34536124). The variant was also observed in the heterozygous state along with heterozygous variants in other hearing loss related genes (Laboratory for Molecular Medicine at Mass General Brigham, ClinVar Accsession SCV001365886.1). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1_Supporting, PM3_Supporting, PP3 (ClinGen Hearing Loss VCEP specifications version 1; 3/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1562832/MONDO:0019497/023 2025-03-12 2025-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf true CHEBI:4903 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0021308 infores:hetionet CHEBI:40303 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0151480 infores:hetionet CHEBI:84883 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0011603 infores:hetionet CHEBI:51860 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0428977 infores:hetionet CHEBI:28925 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0002878 infores:hetionet CHEBI:29688 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C3665347 infores:hetionet CHEBI:5098 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0232459 infores:hetionet CAID:CA213721 biolink:causes MONDO:0015967 infores:clingen CAID:CA213721 MONDO:0015967 PMID: Likely Pathogenic PS4, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1153G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 385 (p.(Gly385Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in at least seven unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.1153G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_supporting, PS4, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213721/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Supports CHEBI:2704 biolink:causes UMLS:C0877035 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0877035 infores:hetionet NCBIGene:55107 biolink:causes MONDO:0859289 infores:monarchinitiative not_provided not_provided HGNC:21625 MONDO:0859289 uuid:47fe1dae-4007-498c-8acf-0aabce7af0d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412729425 biolink:causes MONDO:0100437 infores:clingen CAID:CA412729425 MONDO:0100437 PMID: Likely Benign PM2_Supporting, BP4 PS4 NM_001034853.2(RPGR):c.2930G>T (p.Gly977Val) is a missense variant that substitutes glycine with valine at amino acid 977. This variant has been reported in at least 1 proband without detailed clinical phenotype information (PMID: 34985506). The number of individuals meeting the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent cone and/or rod electroretinogram responses was fewer than the 2 unrelated probands required to meet PS4_Supporting. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.022, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting and BP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412729425/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:8665 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0004096 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0017178 infores:hetionet CHEBI:7476 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0220870 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0877336 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0877336 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0917801 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0018802 infores:hetionet CHEBI:16335 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0494475 infores:hetionet CHEBI:51173 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0687713 infores:hetionet CHEBI:49040 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0917801 infores:hetionet CHEBI:94848 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0013428 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0521839 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151849 infores:hetionet CHEBI:6067 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0029089 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0149904 infores:hetionet NCBITaxon:63417 biolink:causes MONDO:0000242 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:63417 MONDO:0000242 CHEBI:31176 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0027497 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0426576 infores:hetionet NCBIGene:3852 biolink:causes MONDO:0012258 infores:monarchinitiative not_provided not_provided HGNC:6442 MONDO:0012258 uuid:1e1d0356-1a20-403f-8dca-e35e9c1491d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA200490 biolink:causes MONDO:0100040 infores:clingen CAID:CA200490 MONDO:0100040 PMID: Benign BA1 The allele frequency of the c.*4 C>T variant in FOXG1 is 0.3% in Latino sub population in gnomAD v2.1.1, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions. In summary, the c.*4 C>T variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA200490/MONDO:0100040/035 2024-04-18 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42797 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042075 infores:hetionet CHEBI:41423 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0033774 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0497327 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0006145 infores:hetionet CHEBI:5790 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0040822 infores:hetionet CHEBI:3314 biolink:causes UMLS:C1328540 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C1328540 infores:hetionet CAID:CA410206725 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206725 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM5, PM1, PM3, PM4, PP2, PP3, PP1, PP4, BS2 NM_001754.5:c.770C>T (p.Thr257Ile) is a missense variant located in exon 7 of RUNX1. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206725/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6076 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0015230 infores:hetionet CHEBI:84050 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0022346 infores:hetionet CHEBI:135530 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0004238 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0151505 infores:hetionet CHEBI:10102 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0014848 infores:hetionet CHEBI:83804 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020672 infores:hetionet NCBIGene:11153 biolink:causes MONDO:0975746 infores:monarchinitiative not_provided not_provided HGNC:18416 MONDO:0975746 uuid:c4f1f9fa-acec-46f0-9a6b-478e6daee408 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0241934 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151735 infores:hetionet CHEBI:39585 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0235431 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0948807 infores:hetionet CHEBI:6909 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0232849 infores:hetionet CHEBI:17334 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0019080 infores:hetionet UNII:2N4O9L084N biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0028643 infores:hetionet CHEBI:63607 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0700345 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0221743 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0221743 infores:hetionet CHEBI:31236 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028768 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0235293 infores:hetionet CHEBI:474053 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0002792 infores:hetionet NCBIGene:5833 biolink:causes MONDO:0032906 infores:monarchinitiative not_provided not_provided HGNC:8756 MONDO:0032906 uuid:fc1979fa-04bf-4c70-b47c-874d13752157 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0948089 infores:hetionet NCBIGene:8643 biolink:causes MONDO:0007959 infores:monarchinitiative not_provided not_provided HGNC:9586 MONDO:0007959 uuid:3205fa82-3300-45e6-b776-2da49f1640c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7601 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0231528 infores:hetionet CHEBI:16796 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0017178 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0268732 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0268732 infores:hetionet CHEBI:16755 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018965 infores:hetionet NCBITaxon:727 biolink:causes MONDO:0005249 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:727 MESH:D011014 DB01208_MESH_D011014_1 CAID:CA2580618260 biolink:causes MONDO:0001586 infores:clingen CAID:CA2580618260 MONDO:0001586 PMID: Uncertain Significance PVS1_Moderate, PM2_Supporting PM3, PP4 The NM_000203.5(IDUA):c.1827_1828delinsT (p.Asp610fsTer?) variant in IDUA replaces the last two nucleotides of the penultimate exon of IDUA (exon 13) with a single nucleotide. SpliceAI predicts that this variant will disrupt the donor splice site from intron 13 (score for donor loss = 1.0). This is predicted to cause skipping of exon 13, resulting in splicing of exon 12 to the last exon of IDUA (exon 14), with a frameshift replacing the last 43 amino acids of the protein with 48 altered amino acids before a stop codon is reached. Less than 10% of the normal sequence is lost (PVS1_Moderate). To our knowledge, no patients with this variant have been reported in the literature. However, one patient has been identified by a clinical diagnostic testing laboratory. This patient has IDUA activity at the upper end of the affected range. No other clinical or laboratory details are available. The patient is compound heterozygous for c.1827_1828delinsT and a variant that has been classified as a VUS by the ClinGen LD VCEP (Insufficient evidence to apply PP4 or PM3). The variant is absent in gnomAD v4.1.0.. (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Mucopolysaccharidosis type I. IDUA-specific criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PVS1_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580618260/MONDO:0001586/091 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA16020722 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020722 MONDO:0009861 PMID:17502162PMID:17502162 Likely Pathogenic PM3, PM2, PP4, PP3 BP4, BP7 Likely pathogenic: The c. 60+4A>T was reported in two patients with PKU, who carried a second pathogenic variant (PMID: 17502162, parental studies not reported). Further, computational splice site algorithms predict a reduction at the donor site of intron 1. This variant is absent from population databases, including 1000 Genomes, ESP, and gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020722/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8776 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0030193 infores:hetionet CHEBI:43968 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C1384353 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0037317 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0007787 infores:hetionet CHEBI:3044 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0003123 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1287298 infores:hetionet CHEBI:6129 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151529 infores:hetionet CHEBI:39669 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0030920 infores:hetionet CHEBI:47499 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0015371 infores:hetionet CHEBI:3175 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0013395 infores:hetionet CHEBI:6759 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0003578 infores:hetionet CAID:CA009682 biolink:causes MONDO:0021056 infores:clingen CAID:CA009682 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.4669_4670del (p.Ile1557Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/250082 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 1 point (PS4_Supporting [PMID: 17135276]). The variant is reported in two additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 15108288 and LOVD individual ID 00014662). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA009682/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17303 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0152020 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0948525 infores:hetionet CHEBI:63619 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0234632 infores:hetionet CHEBI:4562 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0035357 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0853746 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0853746 infores:hetionet CHEBI:3013 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0026821 infores:hetionet CHEBI:51230 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0022568 infores:hetionet CHEBI:31624 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0010200 infores:hetionet CHEBI:6128 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0036104 infores:hetionet CHEBI:6541 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0003811 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0021843 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0002871 infores:hetionet CHEBI:4975 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0162830 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0024314 infores:hetionet GO:0044509 biolink:causes GO:0007165 infores:ubergraph knowledge_assertion manual_agent GO:0044509 GO:0007165 CHEBI:3723 biolink:causes UMLS:C0239725 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0239725 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036130 infores:hetionet CHEBI:474180 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0015967 infores:hetionet CHEBI:66964 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0852908 infores:hetionet CHEBI:2038 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0008031 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006840 infores:hetionet CHEBI:27999 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0015230 infores:hetionet CHEBI:6741 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0040822 infores:hetionet CHEBI:8764 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0015402 infores:hetionet CHEBI:7627 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0016204 infores:hetionet CHEBI:44032 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0392525 infores:hetionet CHEBI:45783 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0025323 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020676 infores:hetionet CHEBI:7465 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0025362 infores:hetionet CHEBI:4653 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0012833 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042029 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0031542 infores:hetionet CHEBI:7903 biolink:causes UMLS:C1262168 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C1262168 infores:hetionet CAID:CA1244332 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244332 MONDO:0005338 PMID:36267417 Uncertain Significance PM2_Supporting, PS3_Moderate, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS1, PS2, BA1 The c.73T>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 25 (p.Cys25Arg). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000002542 (3 alleles out of 1,180,020), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.225, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. The Cys25Arg protein had increased insolubility and reduced secretion levels to wild type myocilin protein in this study (PMID: 36267417). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. Only 1 proband with juvenile open angle glaucoma (JOAG) had been reported (PMID: 12860809), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Only 1 segregation had been reported for JOAG (PMID: 12860809), not meeting the ≥ 3 segregations required for PP1. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PS3_Moderate, BP4, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244332/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:57167 biolink:causes MONDO:0007836 infores:monarchinitiative not_provided not_provided HGNC:15924 MONDO:0007836 uuid:ca66c1c6-89e8-4372-ba53-3b6b08fa41de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA6265054 biolink:causes MONDO:0700270 infores:clingen CAID:CA6265054 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.2508dup (p.Ser837Ilefs*5) variant in ATM is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.2.1.1. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6265054/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0005740 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0162834 infores:hetionet CHEBI:64310 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085649 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0040034 infores:hetionet CHEBI:63619 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2747891 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0241863 infores:hetionet CHEBI:171719 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0038990 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0151736 infores:hetionet CHEBI:6129 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013144 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020517 infores:hetionet CHEBI:2663 biolink:causes HP:6000154 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0238796 infores:hetionet CHEBI:9316 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0085593 infores:hetionet CHEBI:49713 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0000737 infores:hetionet CHEBI:53766 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0025874 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0021400 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0031350 infores:hetionet CHEBI:7565 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0392699 infores:hetionet CHEBI:8499 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0038325 infores:hetionet CHEBI:41879 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0014868 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0234215 infores:hetionet CHEBI:16347 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0522063 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0857353 infores:hetionet CHEBI:8707 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0855329 infores:hetionet CHEBI:6413 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0013404 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0020517 infores:hetionet CAID:CA404082654 biolink:causes MONDO:0007750 infores:clingen CAID:CA404082654 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PM5 The NM_000527.5 (LDLR): c.970G>T (p.Gly324Cys) variant is classified as Uncertain significance -insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP3 Met: REVEL = 0.865, which is above the threshold of 0.75.There is one other variant in the same codon: LDLR: NM_000527:c.970G>T, (p.Gly324Ser) which is classified as Benign by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404082654/MONDO:0007750/013 2022-02-09 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63617 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0009450 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1258215 infores:hetionet CAID:CA16020821 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020821 MONDO:0009861 PMID:25550961 Pathogenic PVS1, PM2, PP4 The c.584dup PAH variant has been identified in at least one patient with PKU (PMID: 25550961) and is absent from 1000G, ESP, and gnomAD databases. This variant leads to the frameshift Ser196ValfsTer4, creating a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020821/MONDO:0009861/006 2020-10-30 2020-10-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53691 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0020458 infores:hetionet CAID:CA402995333 biolink:causes MONDO:0012999 infores:clingen CAID:CA402995333 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate PP4, PM3 The NM_000156.6:c.410A>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by serine at amino acid 137 (p.Tyr137Ser). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001336 (1/74840) alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.8 which is in the range of 0.773-0.932, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen CCDS VCEP (PMID: 36413997) (PP3_Moderate). To our knowledge, this variant has not been reported in an individual with GAMT deficiency in the published literature and the result of functional studies are not available. However, there is a ClinVar entry for this variant (Variation ID: 430374). This variant has been observed as heterozygous without a second variant in GAMT in at least 3 unrelated children referred for exome based testing with autism and developmental delay SCV000241197.11) (insufficient evidence for PP4 or PM3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PP3_Moderate, PM2_Supporting(Classification approved by the Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 22, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402995333/MONDO:0012999/026 2025-05-22 2025-05-22 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3696 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151798 infores:hetionet CAID:CA400032927 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032927 MONDO:0100326 PMID: Uncertain Significance PP1, PM2_Supporting, PM3_Supporting PP3, PP4 The NM_000212.3(ITGB3):c.1955A>T (p.His652Leu) missense variant has been reported homozygous in two affected siblings (Ssyl and Ssab in PMID: 11798398; PM3_supporting; PP1). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032927/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:70746 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0151905 infores:hetionet CHEBI:2955 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020580 infores:hetionet CHEBI:41879 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0026846 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011991 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0700031 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0700031 infores:hetionet CHEBI:3223 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0549249 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002884 infores:hetionet CHEBI:8871 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0917801 infores:hetionet CHEBI:10124 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0041657 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0235639 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002884 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006892 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0236018 infores:hetionet GO:1905044 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:1905044 GO:0048699 CHEBI:28445 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0085631 infores:hetionet CHEBI:145499 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0080274 infores:hetionet CHEBI:60761 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0015230 infores:hetionet CHEBI:42797 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013428 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0521491 infores:hetionet CHEBI:3219 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0035410 infores:hetionet CHEBI:17334 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0040034 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0574067 infores:hetionet CHEBI:3732 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014518 infores:hetionet CHEBI:9168 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151701 infores:hetionet CHEBI:5778 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C2830004 infores:hetionet CAID:CA291041 biolink:causes MONDO:0012996 infores:clingen CAID:CA291041 MONDO:0012996 PMID: Benign BA1, BP4, BP7 The NM_001482.3:c.1239G>A (p.Arg413=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00102 (36/35408 alleles) in the Latino population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 137451) with 2 submitters classifying the variant as benign/likely benign. In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291041/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:49575 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C3263723 infores:hetionet CAID:CA233294 biolink:causes MONDO:0018947 infores:clingen CAID:CA233294 MONDO:0018947 PMID: Likely Pathogenic PS4, PP2, PP3, PM2_Supporting BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, BP5, BP7, PM5, PM4, PM3, PM1, PVS1, PM6, PP1, PP4, BS2 The NM_001005361.3:c.1567A>G variant in DNM2 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 523 (p.Arg523Gly). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The Z-score in gnomAD v4.1.0 is 4.87 (PP2). The REVEL computational prediction analysis tool gives a score of 0.713, which is above the threshold necessary to apply PP3. This variant has been reported in at least three probands with centronuclear myopathy (PS4; PMIDs: 22396310, 25501959; Genetic Services Laboratory, University of Chicago, ClinVar: SCV000193041.1). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 6/9/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA233294/MONDO:0018947/148 2025-06-09 2025-06-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6375 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0015967 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0015230 infores:hetionet CHEBI:46557 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0028081 infores:hetionet CHEBI:6904 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0009763 infores:hetionet CHEBI:63611 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042963 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0020550 infores:hetionet UMLS:C0120107 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0039231 infores:hetionet CHEBI:17347 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151746 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011615 infores:hetionet CAID:CA512319101 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319101 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.558C>G (p.Val186=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.39)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319101/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9352 biolink:causes UMLS:C0268732 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0268732 infores:hetionet CHEBI:49575 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0023380 infores:hetionet CHEBI:724125 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0085624 infores:hetionet NCBIGene:64131 biolink:causes MONDO:0014343 infores:monarchinitiative not_provided not_provided HGNC:15516 MONDO:0014343 uuid:dd9c4b8a-d1a0-47af-a309-1207ba2851c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2158 biolink:causes MONDO:0010432 infores:monarchinitiative not_provided not_provided HGNC:3551 MONDO:0010432 uuid:da97d882-5223-45c6-b4fa-5972c7705a90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0006277 infores:hetionet CHEBI:31236 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0392156 infores:hetionet CHEBI:28918 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0030232 infores:hetionet CHEBI:75722 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C3665347 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1142135 infores:hetionet CHEBI:47657 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0009806 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0013395 infores:hetionet CAID:CA16020757 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020757 MONDO:0009861 PMID:19786003 Pathogenic PM3, PM2, PVS1, PP4 Variant c.253A>T (p.Lys85Ter) in PAH was found in 3 Moroccan patients with Phe levels >600 umol/L (PMID: 19786003) (PP4). This is a nonsense variant in exon 3 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). Three patients were homozygous for p.K85X (PMID: 19786003) (PM3). Parental and familial DNA were sequenced. The variant was absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied:PVS1, PM3, PP4, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020757/MONDO:0009861/006 2020-05-08 2020-05-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:188986 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042164 infores:hetionet CHEBI:10125 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0232461 infores:hetionet CHEBI:5138 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0522178 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0029408 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0920193 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0920193 infores:hetionet CHEBI:681569 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0038325 infores:hetionet CHEBI:134991 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0428977 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0234934 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0234934 infores:hetionet CHEBI:9586 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0522055 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0392525 infores:hetionet CAID:CA024433 biolink:causes MONDO:0018493 infores:clingen CAID:CA024433 MONDO:0018493 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024433/MONDO:0018493/012 2022-01-03 2022-01-03 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:32315 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0009763 infores:hetionet CHEBI:135342 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0011175 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0012833 infores:hetionet CHEBI:40279 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151579 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004431 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018924 infores:hetionet UNII:R43D2573WO biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0239340 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0314719 infores:hetionet NCBIGene:3480 biolink:causes MONDO:0010038 infores:monarchinitiative not_provided not_provided HGNC:5465 MONDO:0010038 uuid:c139c415-3248-4dd4-a224-b4f5cb8878a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:184555 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0029134 infores:hetionet CHEBI:175901 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0041582 infores:hetionet CHEBI:31413 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0006277 infores:hetionet CHEBI:32020 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0687713 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020517 infores:hetionet CHEBI:8232 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0014591 infores:hetionet CHEBI:39585 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0030662 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0011609 infores:hetionet CHEBI:27899 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0041969 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0162429 infores:hetionet CHEBI:40050 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0853034 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027765 infores:hetionet CHEBI:9763 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0034880 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002173 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0273482 infores:hetionet CHEBI:184555 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0025323 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0025061 infores:hetionet CAID:CA10529812 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529812 MONDO:0010604 PMID: Likely Benign BP7, BP4 BS1 The c.582T>G variant (NM_000133.4) is a synonymous (silent) variant(p.Thr194=) that is not predicted by SpliceAI to impact splicing (BP4). The nucleotide is/ is not conserved based on a phyloP 100 vertebrates score of 0.36152 (threshold <0.1) and PhastCons 100 vertebrates score of 0 (threshold <0.5), meeting/ not meeting criteria for BP7. In summary, the variant meets criteria to be classified as likely benign/uncertain significance for hemophilia B. ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F9: BP4, BP7 (version 1.0.0, released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529812/MONDO:0010604/080 2024-10-16 2025-07-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:5002 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0018681 infores:hetionet CHEBI:63621 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0005779 infores:hetionet CHEBI:47612 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0041834 infores:hetionet CHEBI:3380 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0022661 infores:hetionet CHEBI:63619 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0429097 infores:hetionet CHEBI:7445 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0241633 infores:hetionet CHEBI:63580 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0558401 infores:hetionet CHEBI:204928 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152027 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0677500 infores:hetionet CAID:CA16041859 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041859 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c.308_309del (p.Lys103Argfs*20) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity; a second distinct pathogenic or likely pathogenic variant in ACADVL was not reported in this individual (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#2; 05-00-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041859/MONDO:0008723/021 2022-05-10 2022-05-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6367 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0015371 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0948594 infores:hetionet CHEBI:7447 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0023052 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0152027 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042769 infores:hetionet CHEBI:168396 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C2129214 infores:hetionet CHEBI:91834 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0020580 infores:hetionet CAID:CA124481 biolink:causes MONDO:0015967 infores:clingen CAID:CA124481 MONDO:0015967 PMID: Pathogenic PM1_Supporting, PP1_Strong, PS3_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4, PM2 The c.827C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to aspartic acid at codon 276 (p.(Ala276Asp)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody-negative, and response to low-dose sulfonylurea (PP4_Moderate, internal lab contributors). Another missense variant, c.827C>G (p.Ala276Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Also, the variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated abnormal nuclear localization, DNA binding less than 40% of wildtype, and normal transactivation (PS3_Supporting; PMID:12574234). This variant is absent from the gnomAD European non-Finnish population, but two copies are present in the African population; therefore PM2_Supporting cannot be applied. This variant was identified in at least 12 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 12574234, internal lab contributors). In summary, c.827C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM5_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA124481/MONDO:0015967/017 2022-04-18 2022-04-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9352 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C2047937 infores:hetionet CHEBI:4909 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0027947 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1443060 infores:hetionet CHEBI:32588 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0030193 infores:hetionet CHEBI:5130 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0025289 infores:hetionet CHEBI:8774 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0039070 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0003864 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019917 infores:hetionet CHEBI:63580 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0085605 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0028738 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0040485 infores:hetionet CHEBI:2618 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0085649 infores:hetionet CHEBI:2038 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0041657 infores:hetionet CHEBI:6887 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0497156 infores:hetionet NCBIGene:1605 biolink:causes MONDO:0013440 infores:monarchinitiative not_provided not_provided HGNC:2666 MONDO:0013440 uuid:403a8fc1-c68c-4af1-ba7b-90011ab19945 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042164 infores:hetionet CHEBI:7931 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0028081 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0031350 infores:hetionet CHEBI:205919 biolink:causes UMLS:C1323189 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C1323189 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235818 infores:hetionet CHEBI:66964 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C1306341 infores:hetionet CHEBI:51230 biolink:causes UMLS:C1536145 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1536145 infores:hetionet CHEBI:84050 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0042963 infores:hetionet CHEBI:68841 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0438142 infores:hetionet CHEBI:9939 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C1145670 infores:hetionet CHEBI:134991 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C2047937 infores:hetionet CHEBI:31536 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0011603 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001617 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0338591 infores:hetionet CHEBI:63925 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0011615 infores:hetionet CAID:CA1706490 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706490 MONDO:0015152 PMID: Benign PM4, BA1 The NM_003494.4: c.3191_3196dup p.(Glu1065_Gly1066insAlaGlu) variant in DYSF, which is also known as NM_001130987.2: c.3245_3250dup p.(Glu1083_Gly1084insAlaGlu), is predicted to cause a change in the length of the protein due to an in-frame insertion of two amino acids in a non-repeat region (PM4). The filtering allele frequency for this variant is 0.05714 in the European (non-Finnish) population of gnomAD v4.1.0 (the lower threshold of the 95% CI of 3989/68004 genome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of ≥0.003 for BA1 (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/14/2025): BA1, PM4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706490/MONDO:0015152/180 2025-03-14 2025-04-04 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0497365 infores:hetionet CHEBI:2955 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042384 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0028738 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1096035 infores:hetionet CHEBI:31348 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011168 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0232492 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0041912 infores:hetionet CHEBI:2208 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0038362 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0233632 infores:hetionet CHEBI:71415 biolink:causes UMLS:C0341439 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0341439 infores:hetionet CHEBI:4672 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0231528 infores:hetionet CHEBI:3696 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151723 infores:hetionet CHEBI:9649 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0011603 infores:hetionet CHEBI:4710 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0026821 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0162296 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0162296 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0235573 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235573 infores:hetionet CHEBI:45863 biolink:causes HP:0000649 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0522214 infores:hetionet CHEBI:63598 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0424790 infores:hetionet CHEBI:63581 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0014724 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0009144 infores:hetionet CHEBI:16796 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C2697368 infores:hetionet CHEBI:63608 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0687713 infores:hetionet CHEBI:6532 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0340865 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0021845 infores:hetionet CHEBI:8428 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0002994 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0235431 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0853760 infores:hetionet CHEBI:6128 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0017181 infores:hetionet CHEBI:9445 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0027424 infores:hetionet CHEBI:71219 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0025874 infores:hetionet CHEBI:9352 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0014742 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0271650 infores:hetionet CHEBI:5893 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042384 infores:hetionet CHEBI:27504 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0035222 infores:hetionet CHEBI:84050 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0038362 infores:hetionet CHEBI:135888 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0010200 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0007286 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005723 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085436 infores:hetionet CAID:CA10585778 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585778 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BP1, BP4, BP3, BA1, PS3, PS4, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008802 (0.0008802%) in European (non-Finnish) (gnomAD v2.1.1). PopMax MAF < 0.02%, therefore PM2 is met. // PopMax MAF = 0.00006695 (0.0066950%) in European (non-Finnish) (gnomAD v4).PP3: REVEL = 0.771. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical DLCN criteria for FH (DLCN ≥ 6) from the Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585778/MONDO:0007750/013 2024-02-23 2025-09-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:2469 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0041969 infores:hetionet CHEBI:10119 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151564 infores:hetionet CHEBI:70735 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C1384353 infores:hetionet CHEBI:63624 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C2047937 infores:hetionet CHEBI:59773 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0917801 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234458 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0042109 infores:hetionet CHEBI:47780 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0004604 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0278016 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0278016 infores:hetionet CHEBI:6128 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0085593 infores:hetionet CHEBI:184555 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C1443060 infores:hetionet CHEBI:3508 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0011991 infores:hetionet CHEBI:63638 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0017178 infores:hetionet CHEBI:10102 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020443 infores:hetionet CHEBI:93363 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0018681 infores:hetionet CHEBI:50859 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0438215 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0851341 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0028738 infores:hetionet CHEBI:63791 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0206061 infores:hetionet CHEBI:31348 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040822 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0039971 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0022660 infores:hetionet CHEBI:28748 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0232461 infores:hetionet CHEBI:5383 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0438215 infores:hetionet NCBIGene:122481 biolink:causes MONDO:0054731 infores:monarchinitiative not_provided not_provided HGNC:20091 MONDO:0054731 uuid:bb9e42d3-e21d-4cf1-bd23-7b8a9a7d7607 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0017181 infores:hetionet CHEBI:50673 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0919715 infores:hetionet CHEBI:64064 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0699744 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0497247 infores:hetionet CHEBI:135939 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0014742 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0302295 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0948525 infores:hetionet CHEBI:31711 biolink:causes HP:0010547 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0026825 infores:hetionet CHEBI:49713 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0520966 infores:hetionet CHEBI:2659 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0728899 infores:hetionet CAID:CA16024864 biolink:causes MONDO:0021056 infores:clingen CAID:CA16024864 MONDO:0021056 PMID: Uncertain Significance BP1, PS3_Moderate, PM2_Supporting PP3, PS4 The c.1627G>T variant in APC is a missense variant predicted to cause a substitution of valine by phenylalanine at amino acid position 543 (p.Val543Phe). This variant is located at the first base of exon 14. RT-PCR of the exons flanking the target site in a patient with AFAP shows that the variant c.1627G>T impacts splicing by leading to exon 14 skipping, which is an in-frame event (PS3_Moderate; PMID22987206). This variant scored 0.5 phenotype points based on information available in 3 individuals (PS4_variable not met; PMID 22987206, Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In silico predictions by SpliceAI, MaxEntScan and VarSEAK showed conflicting results (PP3 not met). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_moderate, and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16024864/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9150 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0151786 infores:hetionet CHEBI:49662 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0043094 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0242350 infores:hetionet CHEBI:15551 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0008031 infores:hetionet CHEBI:2687 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0009782 infores:hetionet CHEBI:7577 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0023218 infores:hetionet CHEBI:3213 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0014518 infores:hetionet CHEBI:3723 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040264 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0010709 infores:hetionet CHEBI:4672 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0235266 infores:hetionet NCBIGene:10019 biolink:causes MONDO:0008554 infores:monarchinitiative not_provided not_provided HGNC:29605 MONDO:0008554 uuid:c848bc2d-a9cf-455c-bde4-921ea055747b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63618 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0022354 infores:hetionet CHEBI:50730 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0014518 infores:hetionet CHEBI:6456 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0151311 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0521839 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0031350 infores:hetionet CAID:CA10014501 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014501 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+4C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.98) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014501/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9637 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0020621 infores:hetionet CHEBI:3723 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020625 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0233571 infores:hetionet NCBIGene:7827 biolink:causes MONDO:0010974 infores:monarchinitiative not_provided not_provided HGNC:13394 MONDO:0010974 uuid:98af0e16-acbe-42a1-9609-3833da0a39af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0026946 infores:hetionet NCBIGene:11311 biolink:causes MONDO:0014118 infores:monarchinitiative not_provided not_provided HGNC:14579 MONDO:0014118 uuid:21a6d908-09c5-4b6b-b69a-918931714524 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512318843 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318843 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP2, BP1, BP3, PM6, PVS1, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP2, PP3, PP1 NM_001754.5(RUNX1):c.304C>T (p.Leu102=) is a synonymous variant. This synonymous variant has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318843/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2922 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0034902 infores:hetionet NCBIGene:122402 biolink:causes MONDO:0020851 infores:monarchinitiative not_provided not_provided HGNC:20122 MONDO:0020851 uuid:a81639c9-3bcd-49a0-859f-ef593b791c76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0017566 infores:hetionet CHEBI:50131 biolink:causes UMLS:C1328428 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1328428 infores:hetionet GO:0072304 biolink:causes GO:0003338 infores:ubergraph knowledge_assertion manual_agent GO:0072304 GO:0003338 CHEBI:8768 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0086565 infores:hetionet CHEBI:84883 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0151905 infores:hetionet CHEBI:49375 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0011124 infores:hetionet CHEBI:7640 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0231218 infores:hetionet CHEBI:7478 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0028643 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005030 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015934 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0018799 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0863079 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0863079 infores:hetionet NCBIGene:57609 biolink:causes MONDO:0007634 infores:monarchinitiative not_provided not_provided HGNC:29284 MONDO:0007634 uuid:458ed38d-d6cc-4cb5-a8fe-998473c232c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6030 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0024141 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0029882 infores:hetionet CAID:CA16602489 biolink:causes MONDO:0011071 infores:clingen CAID:CA16602489 MONDO:0011071 PMID: Likely Pathogenic PM5_Supporting, PS1_Moderate, PM1, PM2_Supporting, PP3 PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.486G>C (p.Arg162Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376022, 376021) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>C variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376019) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5_supporting, PS1_moderate, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602489/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA147595 biolink:causes MONDO:0021060 infores:clingen CAID:CA147595 MONDO:0021060 PMID: Benign BA1, BP5, BP7 PP3, PM2, BS1 The c.694-8_694-7dupTC variant is an intronic variant located in intron 6 of the MAP2K1 gene. The filtering allele frequency in gnomAD v4.1.0 is 4.669% (3488/74934 alleles) in the African/African American population, which meets the threshold to apply BA1. The computational predictor SpliceAI predicts no impact on splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL genetics internal data 26957, 21766, 500060; ClinVar SCV000111925.5; SCV000204171.4; SCV000207934.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5, BP7 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147595/MONDO:0021060/045 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042133 infores:hetionet CHEBI:4911 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0424790 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0002994 infores:hetionet CHEBI:49575 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0020672 infores:hetionet CAID:CA273110 biolink:causes MONDO:0009861 infores:clingen CAID:CA273110 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PM3_Strong, PP3_Moderate, PS3_Supporting The c.533A>G variant in PAH is a missense variant predicted to cause substitution of glutamine by glycine at amino acid 178 (p.Glu178Gly). At least 5 patients with this variant displayed serum Phe levels > 6.5–10 mg/dl which is highly specific for PAH deficiency; BH4 deficiency was excluded (PP4_moderate, PMID: 18299955, PMID:9634518). Of those individuals, 4 probands were compound heterozygous for the variant and a pathogenic variant and 1 proband was compound heterozygous with a likely pathogenic variant (phase unknown, 2.25 points). The population allele frequency in gnomAD v4.1 is 0.00003965 which is lower than the ClinGen PAH VCEP threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting). The results from in silico predictors [REVEL=0.841], predict a damaging effect on PAH function (PP3_moderate). Enzyme activity assay showed 39% residual phenylalanine hydroxylase activity indicating that this variant impacts protein function (PMID:17935162)(PS3_supporting). In summary, this variant meets criteria to be classified as pathogenic for PAH deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Expert Panel: PM2_supporting, PP3_moderate, PS3_supporting, PP4_Moderate, PM3_Strong (version 2.0, 11/16/2024). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273110/MONDO:0009861/006 2025-04-18 2025-04-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes MONDO:0002089 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0035326 infores:hetionet CAID:CA2580098630 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098630 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+8C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098630/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:72296 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0020517 infores:hetionet NCBITaxon:5820 biolink:causes MONDO:0005136 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5820 MESH:D008288 DB00908_MESH_D008288_1 CHEBI:7627 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0349506 infores:hetionet CHEBI:49960 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0428977 infores:hetionet CHEBI:51364 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0011124 infores:hetionet CHEBI:2950 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0002453 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0012739 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0015376 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019158 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0041349 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0042373 infores:hetionet CHEBI:75275 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0041582 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0011991 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0549475 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0234215 infores:hetionet CHEBI:10023 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151907 infores:hetionet CHEBI:8764 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0030252 infores:hetionet CAID:CA220577 biolink:causes MONDO:0009861 infores:clingen CAID:CA220577 MONDO:0009861 PMID:23430918 Pathogenic PM3, PVS1, PM2, PP4 This c.1200-1G>A variant in PAH was reported in 2 Caucasian patients with PAH deficiency (PMID: 23430918) detected with pathogenic variants p.Phe55Leu and c.1315+1G>A. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the -1 splice acceptor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220577/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes UMLS:C0427160 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0427160 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0038362 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0853813 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0022660 infores:hetionet CHEBI:92712 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0041657 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0277925 infores:hetionet CAID:CA10578326 biolink:causes MONDO:0021056 infores:clingen CAID:CA10578326 MONDO:0021056 PMID: Benign BS2, BP4, BP7, BS1 The c.1746A>G (p.Glu582=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in a heterozygous state in 12 unrelated healthy adult individuals worth 12 (≥ 10) healthy individual points in total (BS2; Ambry internal data). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 0.0001148 in African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis threshold (≥ 0.0001) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BS1, BS2, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578326/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9654 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0028084 infores:hetionet CHEBI:59445 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C1112525 infores:hetionet CHEBI:63589 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0040822 infores:hetionet CHEBI:4907 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0002994 infores:hetionet CHEBI:38562 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0027121 infores:hetionet CHEBI:5002 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0028961 infores:hetionet NCBIGene:54101 biolink:causes MONDO:0009901 infores:monarchinitiative not_provided not_provided HGNC:496 MONDO:0009901 uuid:422193a3-3189-4ec1-8c49-f5cadc6b9fa6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0000833 infores:hetionet CHEBI:5001 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013404 infores:hetionet CHEBI:9725 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0043352 infores:hetionet CHEBI:28918 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0031924 infores:hetionet CHEBI:3485 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0030312 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0032781 infores:hetionet CHEBI:4530 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0497247 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0030920 infores:hetionet CHEBI:77032 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0015230 infores:hetionet CHEBI:28241 biolink:causes UMLS:C0235194 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0235194 infores:hetionet CHEBI:94501 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0039070 infores:hetionet CHEBI:8228 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0018965 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0549475 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235901 infores:hetionet CHEBI:6067 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0237849 infores:hetionet NCBITaxon:487 biolink:causes MONDO:0006670 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:487 MESH:D016920 DB00760_MESH_D016920_2DB00415_MESH_D016920_1DB00438_MESH_D016920_1 CHEBI:6950 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0015967 infores:hetionet CHEBI:94392 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0231528 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0151955 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151955 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0021400 infores:hetionet CHEBI:42068 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0038362 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040034 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020538 infores:hetionet CHEBI:50730 biolink:causes UMLS:C1611157 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C1611157 infores:hetionet CHEBI:8768 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0009763 infores:hetionet GO:0061294 biolink:causes GO:0061228 infores:ubergraph knowledge_assertion manual_agent GO:0061294 GO:0061228 CHEBI:5864 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0162429 infores:hetionet CHEBI:6438 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0009676 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0241863 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011609 infores:hetionet CHEBI:41423 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0085649 infores:hetionet CAID:CA9871464 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871464 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting PM5 The c.935A>G (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 312 (p.Lys312Arg).The filtering allele frequency (the upper threshold of the 95% CI of (4/418132 alleles) of the c.935A>G variant in ADA is 0.000003240 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Another missense variant [c.934A>C, p.Lys312Gln] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871464/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6375 biolink:causes UMLS:C0948002 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948002 infores:hetionet CHEBI:7478 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0278134 infores:hetionet NCBIGene:199221 biolink:causes MONDO:0033281 infores:monarchinitiative not_provided not_provided HGNC:26551 MONDO:0033281 uuid:d858b233-521a-4e43-a171-fe0aaf744401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013428 infores:hetionet CHEBI:2955 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0000737 infores:hetionet CHEBI:2654 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0039231 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0027769 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0232431 infores:hetionet CHEBI:9943 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020625 infores:hetionet CHEBI:49375 biolink:causes MONDO:0006591 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0030326 infores:hetionet GO:0048378 biolink:causes GO:0048370 infores:ubergraph knowledge_assertion manual_agent GO:0048378 GO:0048370 NCBIGene:3778 biolink:causes MONDO:0060551 infores:monarchinitiative not_provided not_provided HGNC:6284 MONDO:0060551 uuid:cd3dd79f-402b-4de3-9ffb-c075b5d2ffe3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64045 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0009806 infores:hetionet CHEBI:9448 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0037763 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0235649 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235649 infores:hetionet GO:1901371 biolink:causes GO:0048366 infores:ubergraph knowledge_assertion manual_agent GO:1901371 GO:0048366 CHEBI:478164 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0085593 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0036572 infores:hetionet CHEBI:10124 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0039231 infores:hetionet CHEBI:45409 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0043352 infores:hetionet CHEBI:63617 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0003811 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0233472 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0037274 infores:hetionet CAID:CA891844334 biolink:causes MONDO:0100040 infores:clingen CAID:CA891844334 MONDO:0100040 PMID: Uncertain Significance PS4, BS1, PM2, BP3 The highest population minor allele frequency of the c.321_323dup (p.Pro112dup) variant in FOXG1 in gnomAD v4.1 is 0.000036 in the South Asian population (not sufficient to meet BS1). In summary, the p.Pro112dup variant in FOXG1 is classified as a variant of unknown significance based on the ACMG/AMP criteria (no criteria applied). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844334/MONDO:0100040/035 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4798 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235146 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0027947 infores:hetionet CHEBI:8764 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004093 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0919980 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0349506 infores:hetionet CHEBI:6916 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0344232 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020456 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0003864 infores:hetionet CHEBI:76010 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0700225 infores:hetionet CHEBI:2904 biolink:causes UMLS:C1610080 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C1610080 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0233414 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0042769 infores:hetionet CHEBI:36791 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233754 infores:hetionet CHEBI:6909 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0025874 infores:hetionet CHEBI:3387 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0032617 infores:hetionet CHEBI:2549 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0006277 infores:hetionet CHEBI:44185 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0162834 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0020651 infores:hetionet CHEBI:31397 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0004604 infores:hetionet CHEBI:45863 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151907 infores:hetionet CHEBI:2659 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0018965 infores:hetionet NCBIGene:3340 biolink:causes MONDO:0014499 infores:monarchinitiative not_provided not_provided HGNC:7680 MONDO:0014499 uuid:333ec5a8-52d3-49e3-9ed3-2738f7580610 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135530 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0178298 infores:hetionet CHEBI:6413 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0015230 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0007177 infores:hetionet CHEBI:8207 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0232462 infores:hetionet CHEBI:4657 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0026961 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0037274 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0034359 infores:hetionet CHEBI:3207 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0019080 infores:hetionet CHEBI:5778 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C2939147 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027441 infores:hetionet CHEBI:10110 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0002792 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013395 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0853149 infores:hetionet CAID:CA410204312 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204312 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.104G>A (p.Ser35Asn) is a missense variant which has a REVEL score ≤ 0.50 (0.398) and a SpliceAI score ≤ 0.30 (0.06, 6 bp acceptor gain) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204312/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135613 biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0016385 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0340464 infores:hetionet CHEBI:4885 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0017178 infores:hetionet CHEBI:499361 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0038362 infores:hetionet CHEBI:6538 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0028084 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0018799 infores:hetionet CHEBI:3181 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0030920 infores:hetionet CHEBI:47657 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0009782 infores:hetionet CHEBI:135876 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0028173 infores:hetionet UMLS:C0065374 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C3665346 infores:hetionet CHEBI:180905 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0600142 infores:hetionet CAID:CA314840 biolink:causes MONDO:0012999 infores:clingen CAID:CA314840 MONDO:0012999 PMID:24415674 Likely Benign BS2, BS3_Supporting PM2, PP3, PP4, PM3, BP4 The NM_000156.6:c.22C>A variant in GAMT is a missense variant that is predicted to result in the substitution of proline by threonine at amino acid 8 (p.Pro8Thr). One patient, who is heterozygous for the variant, has been reported. This individual, who presented with severe global developmental delay, hypotonia, and intractable seizures, died at 11 months of age. Urine and plasma guanidinoacetate were elevated 2.5 and 1.8 times, respectively. However, on 1H-MRS, creatine peak was about 90% of normal, marginally low, which was not suggestive of GAMT deficiency(PMID: 24415674) (PP4 not applied). GAA-deficient fibroblasts overexpressing the c.22C>A (p.Pro8Thr) variant showed similar GAMT enzyme activity as those transfected with wild-type cDNA (PMID: 24415674) (BS3_Supporting). The computational predictor REVEL gives a score of 0.479 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). The highest population minor allele frequency (MAF) in gnomAD v4.1.0 is 0.002564 (10/3900 alleles) in the Middle Eastern population; there is one homozygote in the European non-Finnish population, in gnomAD v4.1.0. While the MAF is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), PM2_Supporting is not met due to presence of a homozygote. Because GAMT deficiency is a severe, pediatric onset condition, the presence of a homozygote supports benignity (BS2). There is a ClinVar entry for this variant (Variation ID: 205598). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 2.0.0.): BS2, BS3_Supporting(Classification approved by the ClinGen Cerebral Creatine Deficiencies VCEP on October 8, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314840/MONDO:0012999/026 2025-10-08 2025-10-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:82960 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027765 infores:hetionet CHEBI:94848 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0030252 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0700594 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0015397 infores:hetionet CHEBI:9435 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0851578 infores:hetionet UMLS:C0004609 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0016382 infores:hetionet CAID:CA068623 biolink:causes MONDO:0018493 infores:clingen CAID:CA068623 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 2248 of the RYR1 protein, p.(Arg2248Cys). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000231, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:20681998, PMID:30236257). However, the high MAF in the AMR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.694 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA068623/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3219 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151517 infores:hetionet CHEBI:4551 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0221185 infores:hetionet CHEBI:9328 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C1368065 infores:hetionet CHEBI:44185 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085633 infores:hetionet CHEBI:5784 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0042384 infores:hetionet CHEBI:5441 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0162830 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0403723 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0403723 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0852925 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0852925 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0015397 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0027651 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0232492 infores:hetionet CHEBI:473990 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0003962 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0349506 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020538 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0029408 infores:hetionet CHEBI:6741 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0003873 infores:hetionet NCBIGene:64116 biolink:causes MONDO:0014746 infores:monarchinitiative not_provided not_provided HGNC:20862 MONDO:0014746 uuid:6c48a1b7-5a30-4adf-bb26-c67c4d2a4edc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63925 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0024440 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0013395 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0009806 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0027051 infores:hetionet CHEBI:3756 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0029877 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0003467 infores:hetionet CHEBI:52172 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0011603 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0233494 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0743295 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0743295 infores:hetionet CHEBI:4975 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0030554 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0521496 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0521496 infores:hetionet CHEBI:10101 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0085631 infores:hetionet CHEBI:6541 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020615 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0005779 infores:hetionet CHEBI:39585 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0017672 infores:hetionet CHEBI:39585 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0344232 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0851341 infores:hetionet CHEBI:24564 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0854467 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0001807 infores:hetionet CHEBI:4636 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0235146 infores:hetionet CHEBI:8212 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0917801 infores:hetionet CHEBI:27565 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0017181 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0039971 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019340 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0031212 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0973461 infores:hetionet CHEBI:3172 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0027424 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0007193 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0267596 infores:hetionet CHEBI:6437 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C3263723 infores:hetionet GO:0006954 biolink:causes MONDO:0011849 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D015535 DB00005_MESH_D015535_1DB00065_MESH_D015535_1DB08904_MESH_D015535_1DB06674_MESH_D015535_1DB05676_MESH_D015535_1DB00051_MESH_D015535_1 CL:0000236 biolink:causes GO:0019724 infores:ubergraph knowledge_assertion manual_agent CL:0000236 GO:0019724 CHEBI:3996 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0020458 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0020649 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0022116 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0178298 infores:hetionet CHEBI:40279 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042790 infores:hetionet CAID:CA410148204 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148204 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1078G>C (p.Val360Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Multiple lines of computational evidence suggest no impact on the gene/gene product (REVEL: 0.434, SpliceAI: Δ score 0.00) (BP4). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148204/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42944 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0013395 infores:hetionet CHEBI:2676 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0019080 infores:hetionet CHEBI:29688 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0011991 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0853700 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0423602 infores:hetionet CHEBI:135929 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0039070 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027051 infores:hetionet CHEBI:17347 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0151766 infores:hetionet CHEBI:134936 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0948595 infores:hetionet CHEBI:40303 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0029089 infores:hetionet CHEBI:5103 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0042571 infores:hetionet CAID:CA400034479 biolink:causes MONDO:0100326 infores:clingen CAID:CA400034479 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM2_Supporting, PVS1_Strong PM3 The NM_000212.3(ITGB3):c.2301+1G>C variant occurs within the canonical splice site of intron 14, predicted to cause skipping of exon 14 with a subsequent frameshift resulting in a premature stop codon in exon 15 (the final exon), which would escape NMD. However it disrupts a functionally important region (affecting the transmembrane and cytoplasmic domains of ITGB3) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient GT-2 in ASH Abstract (https://ashpublications.org/blood/article/140/Supplement%201/2695/488999) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10%, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_strong, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400034479/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8378 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0152459 infores:hetionet CAID:CA401325061 biolink:causes MONDO:0009290 infores:clingen CAID:CA401325061 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2383G>T (p.Glu795Ter) variant in GAA is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients have been identified with GAA activity in the deficient range; one of these patients has no detectectable GAA protein on Western blot of protein from skin fibroblasts i.e. CRIM-negative (clinical diagnostic laboratory) (PP4_Moderate). The CRIM-negative patient is compound heterozygous for the variant and a variant that has been classified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP) as pathogenic, c.2560C>T(p.Arg854Ter). The phase is unknown (clinical diagnostic laboratory). The other patient is compound heterozygous for the variant and c.1904A>C (p.Asp635Thr). The allelic data from this patient will be used in the classification of p.Asp635Thr and is not included here to avoid circular logic (PM3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting).There is a ClinVar entry for this variant (Variation ID: 649354). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specification Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401325061/MONDO:0009290/010 2023-06-27 2023-09-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5558 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C3665347 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0011991 infores:hetionet CHEBI:9123 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1527344 infores:hetionet CHEBI:2611 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0025345 infores:hetionet CHEBI:10101 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0016382 infores:hetionet CAID:CA222807 biolink:causes MONDO:0010726 infores:clingen CAID:CA222807 MONDO:0010726 PMID: Likely Benign BS2_Supporting, BP7, BP4, PM2_Supporting Computational analysis prediction tools suggest that the p.Val312= variant in MECP2 (NM_004992) does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The silent p.Val312= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). The p.Val312= variant is observed in at least 1 unaffected individual (GeneDx-internal database) (BS2_Supporting). The p.Val312= variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary, the p.Val312= variant meets the criteria to be classified as Likely Benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: (BP4, BP7, BS2_Supporting, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222807/MONDO:0010726/016 2022-05-24 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:4784 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0014591 infores:hetionet CHEBI:7496 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0520573 infores:hetionet CHEBI:2549 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1609512 infores:hetionet CHEBI:63627 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0015672 infores:hetionet CHEBI:6062 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0012569 infores:hetionet CHEBI:3398 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0042109 infores:hetionet CAID:CA399795582 biolink:causes MONDO:0100326 infores:clingen CAID:CA399795582 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS3, PVS1_Moderate, PM3_Supporting PP3 The NM_000419.5(ITGA2B):c.2449-1G>C variant disrupts of a splice acceptor site which is predicted to cause an in frame deletion of exon 25 (4.9% of the protein), however cDNA studies in the patient harboring this variant (PMID 15293575) found a 21-amino acid deletion (Leu817_Gln837) due to abnormal splicing in exon 25, indicating that this variant results in the use of a cryptic splice site in exon 25 which leads to a deletion of 21 amino acid residues (2% of the protein; PVS1_moderate). The patient this variant was discovered in had a history of bleeding. They had absent platelet aggregation in response to ADP, epinephrine, and collagen but a normal response to ristocetin. Flow cytometry confirmed the absence of platelet GPIIb-IIIa complexes on the cell surface (PP4_Moderate). This variant was identified in the homozygous state (PMID 15293575; PM3_Supporting). A cDNA construct of the mutant GPIIb in which the 63-bp nucleotide sequence (nucleotides 2449-2511) was deleted was cotransfected into 293 T cells with normal GPIIIa cDNA. Flow cytometric analysis demonstrated no detectable amounts of GPIIb-IIIa complexes (analyzed by T10) or GPIIb (SZ22) on the cell surface, whereas normal expression was observed in the simultaneous experiment with the wildtype cDNA of GPIIb. RT-PCR analysis of these transfected cells demonstrated that both the transcript of the mutant GPIIb and that of the wild-type GPIIb were present within the cells, indicating comparable transfection efficiency (PS3). This variant is not reported in the gnomAD database v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PS3, PP4_Moderate, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399795582/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:168396 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085649 infores:hetionet GO:1901246 biolink:causes GO:0060541 infores:ubergraph knowledge_assertion manual_agent GO:1901246 GO:0060541 CHEBI:16335 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0038454 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0013295 infores:hetionet CHEBI:74947 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0000737 infores:hetionet NCBIGene:866 biolink:causes MONDO:0012675 infores:monarchinitiative not_provided not_provided HGNC:1540 MONDO:0012675 uuid:e3bb2881-47aa-4e0e-8233-30c02ce0fb93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0281774 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0005779 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0349231 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0853760 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1306341 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0025061 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019372 infores:hetionet CHEBI:5118 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0023218 infores:hetionet CHEBI:231594 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0268000 infores:hetionet CHEBI:16796 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0042963 infores:hetionet CAID:CA658824776 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824776 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.448dup (p.Ala150GlyfsTer27) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 551530). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824776/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA8622859 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622859 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PP4, PS1 The NM_000212.3(ITGB3):c.155G>T (p.Cys52Phe) missense variant has been reported in one patient (Patient 5, PMID: 31029159) stated to have clinical diagnosis of Glanzmann thrombasthenia but insufficient information was available to determine if the phenotype is highly specific to GT. It has a REVEL score of 0.989, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00003266 (1/30616 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622859/MONDO:0100326/011 2023-04-06 2023-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA410202603 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202603 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS3, PS4, PS2, PS1, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.440C>T (p.Ala147Val) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting).. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Supporting, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202603/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9907 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0349506 infores:hetionet CHEBI:7936 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0428977 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034069 infores:hetionet CHEBI:32315 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085932 infores:hetionet CHEBI:27974 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0024902 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0542184 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0853785 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0853785 infores:hetionet CHEBI:101085 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0740394 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0521490 infores:hetionet CHEBI:499361 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0042029 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0027651 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151596 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0233632 infores:hetionet CHEBI:76010 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0011609 infores:hetionet CHEBI:15544 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0010200 infores:hetionet CHEBI:9667 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0011615 infores:hetionet CHEBI:51230 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0006277 infores:hetionet CHEBI:83804 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085649 infores:hetionet CHEBI:2379 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0541782 infores:hetionet CHEBI:74947 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020461 infores:hetionet CHEBI:4885 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0020676 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038454 infores:hetionet CHEBI:2379 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0015967 infores:hetionet CHEBI:3738 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0022893 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0233632 infores:hetionet CHEBI:63115 biolink:causes MONDO:0015540 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0024291 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0021400 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0267792 infores:hetionet CHEBI:31625 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0161479 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0339383 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0339383 infores:hetionet CHEBI:17347 biolink:causes HP:0034801 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1167709 infores:hetionet NCBIGene:6606 biolink:causes MONDO:0009669 infores:monarchinitiative not_provided not_provided HGNC:11117 MONDO:0009669 uuid:548bd2de-b529-4e42-be4b-8b875ba854c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2239 biolink:causes MONDO:0009720 infores:monarchinitiative not_provided not_provided HGNC:4452 MONDO:0009720 uuid:c72b99a7-6979-40d6-a1bb-c88b927af727 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042029 infores:hetionet CAID:CA229405 biolink:causes MONDO:0009861 infores:clingen CAID:CA229405 MONDO:0009861 PMID: Pathogenic PM3, PM5, PP3_Strong, PP4_Moderate, PM2_Supporting The NM_000277.3(PAH):c.1229T>C variant in PAH is a missense variant predicted to cause substitution of phenylalanine to serine at amino acid 410 (p.Phe410Ser). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) and sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism which is highly specific for Phenylketonuria (PP4_moderate; PMIDs:26542770, 10679941). This variant has been detected in 2 individuals with Phenylketonuria. Of those individuals, both were compound heterozygous for the variant and distinct likely pathogenic p.P281L (parental testing was not reported) and pathogenic p.I306V (in trans) variants (PM3; PMID: 26542770). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008476 in European (non-Finnnish) population, which is lower than the ClinGen PAH Variant Curation Expert Panel threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.992, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). Two different missense variants, c.1229T>G (p.Phe410Cys) and c.1229T>G (p.Phe410Cys) are in the same codon have been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3, PP3_strong, PP4_moderate, PM5. Version 2.0, 7/16/2024. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229405/MONDO:0009861/006 2025-08-15 2025-08-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes MONDO:0007972 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025281 infores:hetionet GO:0061924 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0007275 CHEBI:49375 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151609 infores:hetionet CHEBI:37941 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0000731 infores:hetionet NCBIGene:3708 biolink:causes MONDO:0011694 infores:monarchinitiative not_provided not_provided HGNC:6180 MONDO:0011694 uuid:fe155360-96f9-4cf4-9346-5d450c310f51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3347 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0040034 infores:hetionet CHEBI:17474 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0162529 infores:hetionet CHEBI:480999 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0085932 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235234 infores:hetionet CHEBI:28241 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0232462 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0852733 infores:hetionet CAID:CA10014471 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014471 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS3, BA1, BP2, BP1, BS1, BS3, PM2, PM3, PM5, BS2, PP4, PP2, PP3 NM_001754.5(RUNX1):c.613+20G>T is an intronic variant which is not predicted by SpliceAI to impact splicing (BP4). Additionally, an evolutionary conservation algorithm predicts the site as not being highly conserved (PhyloP score = 1.29065 in GRCh38) (BP7). The highest population minor allele frequency in gnomAD v2 and v4 is 0.00002891 (1/34,590 alleles) and 0.00002241 (1/44,630 alleles), respectively, in the admixed American population. This variant has not been reported in the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014471/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:71940 biolink:causes MONDO:0001828 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0155018 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0033860 infores:hetionet NCBIGene:54507 biolink:causes MONDO:0009152 infores:monarchinitiative not_provided not_provided HGNC:19706 MONDO:0009152 uuid:db4e54ad-ae04-4e12-a15f-a2eea2f1f8d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0233632 infores:hetionet NCBIGene:4784 biolink:causes MONDO:0011244 infores:monarchinitiative not_provided not_provided HGNC:7788 MONDO:0011244 uuid:56b344c3-d6e2-4b90-82d3-6fc3421f4ef8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8713 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0030554 infores:hetionet CHEBI:9086 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0005747 infores:hetionet CHEBI:6897 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0002962 infores:hetionet GO:0090256 biolink:causes GO:0035220 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0035220 CHEBI:42944 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C1457883 infores:hetionet CHEBI:5847 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0018802 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0004623 infores:hetionet CHEBI:53760 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013182 infores:hetionet CAID:CA913163377 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163377 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PS4, PS3, PM6 The m.10460T>C variant in MT-TR has been reported in one individual with primary mitochondrial disease to date (PMID: 31965079) however clinical details were not provided. No information was provided on family member affected status or testing. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly pathogenic (72 percentile) but HmtVAR predicts it to be likely benign with a score of 0.05. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163377/MONDO:0044970/015 2024-12-09 2025-05-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7824 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0023066 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0919823 infores:hetionet CHEBI:4909 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0015672 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0858765 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0858765 infores:hetionet GO:0060800 biolink:causes GO:0001892 infores:ubergraph knowledge_assertion manual_agent GO:0060800 GO:0001892 CHEBI:4470 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0085631 infores:hetionet CHEBI:3761 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0011603 infores:hetionet NCBIGene:1642 biolink:causes MONDO:0859169 infores:monarchinitiative not_provided not_provided HGNC:2717 MONDO:0859169 uuid:a5085bc6-dbaa-4f8d-927e-b3fe5c0b03ba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0038362 infores:hetionet CHEBI:3561 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013404 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C2225524 infores:hetionet NCBIGene:440138 biolink:causes MONDO:0013349 infores:monarchinitiative not_provided not_provided HGNC:32456 MONDO:0013349 uuid:61ae8015-4dc7-4b9d-9177-97ade26a1da8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16796 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0178298 infores:hetionet NCBIGene:1730 biolink:causes MONDO:0010350 infores:monarchinitiative not_provided not_provided HGNC:2877 MONDO:0010350 uuid:62a17c86-1592-4c14-8a74-b7b194b1fb1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0042109 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0015397 infores:hetionet CHEBI:6832 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0240327 infores:hetionet CHEBI:63623 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0027424 infores:hetionet CHEBI:7823 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0013144 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0033975 infores:hetionet CHEBI:9943 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0236075 infores:hetionet CHEBI:5383 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0001807 infores:hetionet CHEBI:15765 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0019521 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0006145 infores:hetionet NCBIGene:2815 biolink:causes MONDO:0009276 infores:monarchinitiative not_provided not_provided HGNC:4444 MONDO:0009276 uuid:1c09a58a-e42d-44ca-8fe8-32e70e951c51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA279164 biolink:causes MONDO:0007113 infores:clingen CAID:CA279164 MONDO:0007113 PMID: Pathogenic PP4, PS2_Very Strong, PS4, PM4_Supporting, PM2_Supporting The c.2503_2508del p.(Leu835_Lys836del) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.(Leu835_Lys836del) variant has been observed in at least 5 individuals with a diagnosis of Angelman syndrome or a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 24796722; ClinVar SCV000829845.4, SCV000491076.2, SCV000332262.4) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (ClinVar SCV000491076.2, SCV000829845.4, SCV000332262.4) (PS2_Very strong). The p.(Leu835_Lys836del) variant causes a change in the length of 2 amino acids in the protein due to an in-frame deletion or insertion in a non-repeat region of UBE3A (PM4_supporting). In summary, the c.2503_2508del p.(Leu835_Lys836del) variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4_strong, PP4, PM2_supporting, PM4_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA279164/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:142290 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0344232 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0041912 infores:hetionet CHEBI:94385 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0235490 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0272195 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0272195 infores:hetionet CHEBI:63605 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0020621 infores:hetionet CHEBI:4858 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085593 infores:hetionet NCBIGene:579 biolink:causes MONDO:0013228 infores:monarchinitiative not_provided not_provided HGNC:951 MONDO:0013228 uuid:ee4e7708-f452-44a1-83b6-d4dcab08a898 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0235002 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235002 infores:hetionet CHEBI:63618 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0020580 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0042109 infores:hetionet CHEBI:28748 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C2939420 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0021053 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0424000 infores:hetionet CHEBI:51041 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0013404 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0677500 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0041912 infores:hetionet CHEBI:6715 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023222 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0242461 infores:hetionet CAID:CA16616264 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616264 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.708G>C (p.Met236Ile) is a missense variant which has a REVEL score < 0.50 (0.444) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616264/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:40303 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0004093 infores:hetionet GO:0030710 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:0030710 GO:0060429 CHEBI:44032 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0162429 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0152029 infores:hetionet CHEBI:31413 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0015967 infores:hetionet CAID:CA222210 biolink:causes MONDO:0015152 infores:clingen CAID:CA222210 MONDO:0015152 PMID:35028538 Pathogenic PP4_Strong, PM3_Strong, PP3, PM2_Supporting, PS3_Moderate The NM_003494.4: c.755C>T variant in DYSF, which is also known as NM_001130987.2: c.851C>T p.(Thr284Met), is a missense variant predicted to cause substitution of threonine by methionine at amino acid 252, p.(Thr252Met). This variant has been observed in at least 12 individuals with features consistent with LGMD (PMID: 30564623; 36575883; 34559919; 33927379; 27647186; 21522182; LOVD DYSF_000768), including in a homozygous state in at least two patients without reported familial consanguinity (1.0 pt; PMID: 36575883; 21522182) and in unknown phase with a pathogenic variant in at least two patients (NM_003494.4: c.3790_3797_del p.(Ser1264ValfsTer9), 0.5 pts, PMID: 34559919, LOVD Individual #00375911; NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 30564623, LOVD Individual #00221967) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD/Miyoshi myopathy and significantly reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PP4_Strong; PMID: 21522182). The highest population frequency for this variant in gnomAD v4.1.0 is 0.00004458 (2/44866 East Asian chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting and therefore meets this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Thr252Met protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3). In addition, the computational predictor REVEL gives a score of 0.926, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/17/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222210/MONDO:0015152/180 2025-06-17 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042035 infores:hetionet CHEBI:83531 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0233471 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020538 infores:hetionet CHEBI:64064 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0231528 infores:hetionet CHEBI:3698 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0011603 infores:hetionet CHEBI:49575 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0010520 infores:hetionet CHEBI:404903 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0017181 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235750 infores:hetionet CAID:CA305299648 biolink:causes MONDO:0007750 infores:clingen CAID:CA305299648 MONDO:0007750 PMID: Uncertain Significance BP4, BS3, PM2, PP4 BA1, PS3, BS1, PP3 NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln) variant is classified as Uncertain significance - conflicting evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, BP4, BS3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: PopMax MAF = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1).. BP4: REVEL = 0.373. it is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) Variant not on limits.B) Variant does not create GT.Variant is predicted not to alter splicing.. BS3: Level 1 assays: PMID 31106925Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305299648/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:0048079 biolink:causes GO:0042335 infores:ubergraph knowledge_assertion manual_agent GO:0048079 GO:0042335 CHEBI:9907 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0011570 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0040034 infores:hetionet CHEBI:82960 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0017675 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1320835 infores:hetionet CHEBI:50859 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085605 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0027765 infores:hetionet CHEBI:63613 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0687713 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0178298 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023052 infores:hetionet CHEBI:50777 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0040460 infores:hetionet CHEBI:6640 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0018681 infores:hetionet CHEBI:5383 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0043352 infores:hetionet CHEBI:9288 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0234233 infores:hetionet CHEBI:60761 biolink:causes MONDO:0041959 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0520571 infores:hetionet NCBIGene:6794 biolink:causes MONDO:0010108 infores:monarchinitiative not_provided not_provided HGNC:11389 MONDO:0010108 uuid:b70ee162-424e-4bb1-b78b-9f8d02fdf9c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009421 infores:hetionet CHEBI:51860 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1268766 infores:hetionet CHEBI:135935 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0020580 infores:hetionet UMLS:C0145185 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0032961 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0154769 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0154769 infores:hetionet CHEBI:36791 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0302809 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0518015 infores:hetionet CHEBI:47780 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1443060 infores:hetionet CHEBI:31932 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0011603 infores:hetionet NCBITaxon:5476 biolink:causes MONDO:0002258 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5476 MESH:D010612 DB00681_MESH_D010612_1 CHEBI:64312 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0012813 infores:hetionet CHEBI:8774 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0006277 infores:hetionet CHEBI:9599 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0017178 infores:hetionet CHEBI:2904 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018790 infores:hetionet NCBITaxon:210 biolink:causes MONDO:0005318 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:210 MESH:D013281 DB00257_MESH_D013281_1 CHEBI:63631 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0038367 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0015469 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040409 infores:hetionet CHEBI:724125 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0022568 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011570 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0243026 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0234458 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0027430 infores:hetionet CHEBI:3757 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0025289 infores:hetionet NCBIGene:7021 biolink:causes MONDO:0014878 infores:monarchinitiative not_provided not_provided HGNC:11743 MONDO:0014878 uuid:aab3c8df-35d6-498f-be03-d429a992b752 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3347 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0017178 infores:hetionet CHEBI:553473 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0027497 infores:hetionet CHEBI:16480 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0020649 infores:hetionet CHEBI:119573 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0026826 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0314719 infores:hetionet CHEBI:49662 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0028961 infores:hetionet GO:2000980 biolink:causes GO:0043583 infores:ubergraph knowledge_assertion manual_agent GO:2000980 GO:0043583 CHEBI:23765 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0020580 infores:hetionet CHEBI:47898 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0549567 infores:hetionet CHEBI:9448 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0027497 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1258215 infores:hetionet CHEBI:9927 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0004093 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0013395 infores:hetionet CHEBI:51364 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0812387 infores:hetionet CHEBI:39112 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0042075 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0027769 infores:hetionet CHEBI:15365 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0041582 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151888 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0014591 infores:hetionet CHEBI:4814 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020458 infores:hetionet CHEBI:7822 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0030554 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0015397 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005181 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0162292 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0011168 infores:hetionet CHEBI:71940 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0155305 infores:hetionet CHEBI:6539 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0235063 infores:hetionet CHEBI:16914 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0041834 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027441 infores:hetionet CHEBI:7465 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0011175 infores:hetionet CHEBI:3640 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0001824 infores:hetionet CHEBI:3223 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0040034 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0851341 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0240292 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0240292 infores:hetionet CHEBI:94501 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0011551 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0042075 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0426732 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0851341 infores:hetionet CHEBI:175901 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0023530 infores:hetionet CHEBI:8214 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0004245 infores:hetionet CHEBI:16469 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0575081 infores:hetionet CHEBI:83804 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151818 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0031542 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020295 infores:hetionet CHEBI:4653 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0004238 infores:hetionet CHEBI:63580 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0700590 infores:hetionet CHEBI:7809 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0020517 infores:hetionet CHEBI:10650 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0010200 infores:hetionet CHEBI:408174 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0518988 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0011991 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017160 infores:hetionet CHEBI:10023 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0041834 infores:hetionet CHEBI:135613 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0004238 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0008325 infores:hetionet CHEBI:16899 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0242429 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2973529 infores:hetionet CHEBI:3387 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0233715 infores:hetionet CHEBI:63622 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0027497 infores:hetionet CHEBI:5106 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0278134 infores:hetionet CHEBI:3568 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020443 infores:hetionet GO:2000387 biolink:causes GO:0042698 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0042698 CHEBI:7445 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0423791 infores:hetionet CHEBI:7983 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0015230 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0037274 infores:hetionet CHEBI:3441 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020458 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0264909 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0264909 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0340726 infores:hetionet CAID:CA10568510 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568510 MONDO:0010602 PMID: Uncertain Significance PP3 BS1, PM2, BA1, PS4 The c.1030A>C variant in F8 is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 344 (p.Lys344Gln). The variant is present in hemizygotes and its Grpmax Filtering AF of 0.000003840 meets none of the population codes. The computational predictor REVEL gives a score of 0.642, which is above the threshold of >=0.6, evidence that correlates with impact to F8 function meeting PP3. This variant has been reported in probands with hemophilia A, but PS4 was not applied due to a likely pathogenic variant being in cis with this variant in at least 3 individuals and von Willebrand type 2N was not ruled out for a fourth proband (PMID: 18217193). In summary, due to insufficient evidence, this variant meets the criteria to be classified as a variant of uncertain significance for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency (CFD) VCEP (version 1.0.0, released 10/5/2023): PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568510/MONDO:0010602/071 2025-06-06 2025-06-06 X-linked inheritance HP:0001417 Inconclusive true CHEBI:47426 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0085631 infores:hetionet CHEBI:9073 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0151559 infores:hetionet CHEBI:68647 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0033687 infores:hetionet CHEBI:32315 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0040264 infores:hetionet CHEBI:2636 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0037383 infores:hetionet CHEBI:63605 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0013404 infores:hetionet CHEBI:5551 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0015230 infores:hetionet NCBIGene:64132 biolink:causes MONDO:0011604 infores:monarchinitiative not_provided not_provided HGNC:15517 MONDO:0011604 uuid:a3fc14db-37d2-4d6b-8b09-af3829c5a565 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0860239 infores:hetionet CAID:CA10632766 biolink:causes MONDO:0017623 infores:clingen CAID:CA10632766 MONDO:0017623 PMID: Likely Pathogenic PVS1, PM2 PM6, BS4, BS3, BS1, BP5, BP7, BS2, PP1, PP3, PP2, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS4, PS3, PS1 PTEN c.802-2del (IVS7-2del) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10632766/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72690 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0026858 infores:hetionet NCBIGene:11338 biolink:causes MONDO:0957810 infores:monarchinitiative not_provided not_provided HGNC:23156 MONDO:0957810 uuid:e7579876-0aeb-4f65-8abd-c3053f0abc1b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6633 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0019080 infores:hetionet CHEBI:135939 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0013362 infores:hetionet CHEBI:8028 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0151889 infores:hetionet CHEBI:7445 biolink:causes MONDO:0021439 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0496901 infores:hetionet CHEBI:46557 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0278134 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0030312 infores:hetionet CHEBI:724125 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0237849 infores:hetionet CHEBI:6888 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0006266 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0014591 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021053 infores:hetionet CHEBI:8346 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0009676 infores:hetionet NCBIGene:5230 biolink:causes MONDO:0010392 infores:monarchinitiative not_provided not_provided HGNC:8896 MONDO:0010392 uuid:78330fbb-0c60-45b1-8ab9-bf0324c3bb58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3504 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0003467 infores:hetionet CHEBI:8060 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0004134 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0021167 infores:hetionet CHEBI:4453 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0014743 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0221490 infores:hetionet CHEBI:18248 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0038999 infores:hetionet CHEBI:87715 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0011603 infores:hetionet CAID:CA913189168 biolink:causes MONDO:0100326 infores:clingen CAID:CA913189168 MONDO:0100326 PMID:19170775PMID:19691478PMID:19170775 Uncertain Significance PM2_Supporting, BP2 PP4 NG_008331.1:g.951G>A is an ITGA2B promoter variant and is reported in GT patients, in cis with the pathogenic variant, Leu343Pro (PMIDs: 19170775, 19691478; BP2). It is absent from population databases including gnomADv2.1.1 (PM2). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP2, PM2_supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189168/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63613 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0237849 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0033860 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017178 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0700184 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027051 infores:hetionet CHEBI:3219 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011603 infores:hetionet UMLS:C0010592 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0497156 infores:hetionet CHEBI:9566 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0085688 infores:hetionet CHEBI:91583 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C2830004 infores:hetionet CHEBI:10112 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0022346 infores:hetionet CHEBI:63620 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0404521 infores:hetionet CHEBI:94501 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0040034 infores:hetionet CHEBI:2922 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0027497 infores:hetionet CHEBI:6715 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0013362 infores:hetionet CHEBI:18248 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0011603 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0001122 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0003811 infores:hetionet CHEBI:135791 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0151514 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020651 infores:hetionet CAID:CA382534080 biolink:causes MONDO:0700270 infores:clingen CAID:CA382534080 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PM5_Supporting, PVS1 The ATM c.1442T>G (p.Leu481Ter) variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID 21665257: PM3_Strong). This variant is absent in GnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382534080/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6838 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0001824 infores:hetionet CHEBI:408174 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0017160 infores:hetionet CHEBI:45409 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0338831 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0518015 infores:hetionet CHEBI:35778 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0014518 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002127 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0041974 infores:hetionet CHEBI:64355 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0026821 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001296 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0152202 infores:hetionet CHEBI:63611 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151754 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0234913 infores:hetionet CHEBI:27834 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0151578 infores:hetionet NCBIGene:84100 biolink:causes MONDO:0010832 infores:monarchinitiative not_provided not_provided HGNC:13210 MONDO:0010832 uuid:d922a40c-8a62-470f-856c-f0eabc0a0182 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0038454 infores:hetionet CHEBI:3347 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0015230 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0178298 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019087 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0559546 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0009782 infores:hetionet CAID:CA367401928 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401928 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP2, PP3, PP4, PM2_Supporting The c.454T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to isoleucine at codon 153 (p.(Phe152Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Two other missense variants, c.454T>C p.(Phe152Leu) and c.455T>C p.(Phe152Ser)​ have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.454T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2, PM5_Strong, PP4, PM1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401928/MONDO:0015967/086 2024-04-18 2024-04-18 Semidominant inheritance HP:0032113 Supports NCBIGene:10216 biolink:causes MONDO:0008828 infores:monarchinitiative not_provided not_provided HGNC:9364 MONDO:0008828 uuid:c7f5eebe-3451-4c15-af78-09fb8cbd9c0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0087169 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0022904 infores:hetionet CHEBI:7915 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0518988 infores:hetionet NCBIGene:27130 biolink:causes MONDO:0011190 infores:monarchinitiative not_provided not_provided HGNC:17870 MONDO:0011190 uuid:6cde73f1-df1a-4d88-9a55-ab137bf9d1ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9571 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0013404 infores:hetionet CHEBI:61049 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0023518 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0018021 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0042373 infores:hetionet CHEBI:8871 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0239134 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006849 infores:hetionet CHEBI:61049 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151744 infores:hetionet CHEBI:40279 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085661 infores:hetionet CHEBI:8404 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0035229 infores:hetionet CHEBI:6375 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0917801 infores:hetionet CHEBI:71417 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0002453 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0162429 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0152029 infores:hetionet CHEBI:2469 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0015967 infores:hetionet CHEBI:36704 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0043352 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005159 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0600139 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0038661 infores:hetionet NCBIGene:28958 biolink:causes MONDO:0033649 infores:monarchinitiative not_provided not_provided HGNC:24990 MONDO:0033649 uuid:b87d0b85-6c5b-4a55-84c4-cd670078ee94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3504 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0151905 infores:hetionet CHEBI:8382 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0549567 infores:hetionet CHEBI:10101 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1443060 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0000737 infores:hetionet CHEBI:6950 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0086565 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0521592 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0028738 infores:hetionet GO:2001014 biolink:causes GO:0060538 infores:ubergraph knowledge_assertion manual_agent GO:2001014 GO:0060538 CHEBI:2038 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0001126 infores:hetionet CHEBI:45081 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0232292 infores:hetionet CHEBI:82960 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0233514 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001442 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013415 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042029 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233472 infores:hetionet UMLS:C0010592 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0018965 infores:hetionet CHEBI:50777 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0030554 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232459 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018799 infores:hetionet CHEBI:4753 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0332575 infores:hetionet CHEBI:66903 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0235996 infores:hetionet CHEBI:31348 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0917801 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0178298 infores:hetionet CHEBI:116278 biolink:causes HP:0004386 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1535950 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0521490 infores:hetionet CHEBI:16467 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0221201 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0746883 infores:hetionet NCBIGene:29957 biolink:causes MONDO:0012853 infores:monarchinitiative not_provided not_provided HGNC:20662 MONDO:0012853 uuid:2444cb08-723c-4cfd-8af1-e705c6d5b683 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0021845 infores:hetionet CAID:CA902465 biolink:causes MONDO:0100368 infores:clingen CAID:CA902465 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting BA1, BP4, PM3, BS1, PP3, PP4 NM_000329.3(RPE65):c.565G>A is a missense variant causing substitution of valine with isoleucine at position 189. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00009487, with 7 alleles / 35374 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa who harbored the variant in the heterozygous state (PMID: 18722466). However, PM3 was not met because no second variant was described. The computational predictor REVEL gives a score of 0.464, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02 for acceptor loss and donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902465/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:17303 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0237314 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042514 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0518015 infores:hetionet CHEBI:4708 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151766 infores:hetionet CHEBI:82716 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0016204 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0521616 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0521616 infores:hetionet CHEBI:453011 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0241057 infores:hetionet CHEBI:46195 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0018681 infores:hetionet CAID:CA410205735 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205735 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS4, PS1, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.74T>G (p.Met25Arg) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). It also has not been reported in patients with the RUNX1-defined phenotype. The computational predictor REVEL gives a score of 0.26, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205735/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17026 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020458 infores:hetionet CHEBI:53766 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0020517 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0853026 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0853026 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017675 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0022354 infores:hetionet CHEBI:7478 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085624 infores:hetionet NCBITaxon:12059 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12059 GO:0006954 DB00427_MESH_D003139_1DB00455_MESH_D003139_1 UMLS:C0011701 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0041657 infores:hetionet CHEBI:51380 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0162557 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0035258 infores:hetionet CHEBI:82960 biolink:causes MONDO:0003199 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0279637 infores:hetionet CHEBI:171719 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0876994 infores:hetionet CHEBI:6375 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0428977 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0009676 infores:hetionet CHEBI:63580 biolink:causes MONDO:0021783 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0036689 infores:hetionet CHEBI:15552 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0018681 infores:hetionet CHEBI:4514 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0013395 infores:hetionet CHEBI:32192 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0232462 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0854069 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0235818 infores:hetionet CHEBI:4907 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0151825 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0852679 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0852679 infores:hetionet CHEBI:31401 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0035455 infores:hetionet CHEBI:17334 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0002994 infores:hetionet CHEBI:50861 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0042029 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0948525 infores:hetionet CHEBI:4876 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0233485 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151717 infores:hetionet CAID:CA515708824 biolink:causes MONDO:0100437 infores:clingen CAID:CA515708824 MONDO:0100437 PMID: Likely Benign PM2_Supporting, BP4, BP7 NM_001034853.2(RPGR):c.2685A>G (p.Gly895=) is a synonymous variant in exon 15 of 15 at codon 895 with no predicted impact on splicing (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00 for all splicing types, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BP4, BP7, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA515708824/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:7822 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0231218 infores:hetionet CHEBI:3219 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0008033 infores:hetionet CHEBI:15551 biolink:causes MONDO:0004846 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0000832 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0151664 infores:hetionet CHEBI:50861 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0020621 infores:hetionet CHEBI:3638 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0010038 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0870082 infores:hetionet CHEBI:32184 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0162834 infores:hetionet CHEBI:9168 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0149871 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0031117 infores:hetionet UMLS:C0009315 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0013378 infores:hetionet CHEBI:567361 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0003862 infores:hetionet CHEBI:78543 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0015967 infores:hetionet CAID:CA287437667 biolink:causes MONDO:0008723 infores:clingen CAID:CA287437667 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 PP4 The c.1019G>T (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by valine at amino acid 340 (p.Gly340Val). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305, 27246109). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287437667/MONDO:0008723/021 2024-08-27 2024-08-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50729 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0740425 infores:hetionet CHEBI:8356 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030662 infores:hetionet CHEBI:6067 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0043094 infores:hetionet CHEBI:4653 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0016204 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0233414 infores:hetionet CHEBI:8059 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0039231 infores:hetionet CHEBI:5864 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030193 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004678 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011636 infores:hetionet CHEBI:5847 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0013378 infores:hetionet CHEBI:7640 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0004093 infores:hetionet NCBIGene:389549 biolink:causes MONDO:0014461 infores:monarchinitiative not_provided not_provided HGNC:22788 MONDO:0014461 uuid:3d793dc9-aaf3-4933-a350-d13fe0f06065 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0151636 infores:hetionet CHEBI:28177 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0036974 infores:hetionet CHEBI:4903 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0041969 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009938 infores:hetionet CHEBI:4562 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0004093 infores:hetionet CHEBI:28787 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0344232 infores:hetionet CHEBI:367163 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0021655 infores:hetionet CHEBI:6954 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0947912 infores:hetionet CL:0000336 biolink:causes MONDO:0004974 infores:ubergraph knowledge_assertion manual_agent CL:0000336 MONDO:0004974 CHEBI:28918 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0042963 infores:hetionet CAID:CA320251383 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251383 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, BP5, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1185G>C (p.Pro395=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-3.50)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251383/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5118 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0034065 infores:hetionet CHEBI:6897 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0003864 infores:hetionet CHEBI:135530 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0004093 infores:hetionet CHEBI:5165 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0232726 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005201 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0007196 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0031117 infores:hetionet NCBIGene:7516 biolink:causes MONDO:0030869 infores:monarchinitiative not_provided not_provided HGNC:12829 MONDO:0030869 uuid:48535b12-df48-47dd-8404-9f055f95f397 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70735 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0267792 infores:hetionet CHEBI:4784 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C1443060 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0037274 infores:hetionet CAID:CA287533033 biolink:causes MONDO:0100453 infores:clingen CAID:CA287533033 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.2516del (p.Thr839ArgfsTer27) is a frameshift variant that introduces a premature stop codon into exon 13 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00002604, with 42 alleles / 1613212 total alleles , which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), flat ERG responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), and reduced visual acuity (1 pt), which together are specific for GUCY2D-related recessive retinopathy (4 pts total, PMID: 29178642, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA287533033/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6954 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0595930 infores:hetionet CHEBI:50841 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0030554 infores:hetionet CHEBI:3752 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003962 infores:hetionet CHEBI:7444 biolink:causes MONDO:0008364 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0034734 infores:hetionet CHEBI:49662 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C2979982 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0242350 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0020598 infores:hetionet CHEBI:53691 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0085631 infores:hetionet CAID:CA229536 biolink:causes MONDO:0009861 infores:clingen CAID:CA229536 MONDO:0009861 PMID: Uncertain Significance PM2, BP7 The c.411C>T (p.Ser137Ser) variant is absent from population databases (PM2). Human splice finder does not predict impact on a consensus splice site or creation of a new one, and there was no result in MaxEntScan (BP7). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229536/MONDO:0009861/006 2020-03-26 2021-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28748 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151827 infores:hetionet GO:1903519 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:1903519 GO:0030879 CHEBI:37941 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0392171 infores:hetionet NCBIGene:846 biolink:causes MONDO:0007791 infores:monarchinitiative not_provided not_provided HGNC:1514 MONDO:0007791 uuid:543030b4-d787-4575-8445-3a68b1489b89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31638 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0042029 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0025517 infores:hetionet CHEBI:9288 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0595916 infores:hetionet CHEBI:9943 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235660 infores:hetionet CHEBI:63621 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038160 infores:hetionet CHEBI:71417 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0085684 infores:hetionet CHEBI:125354 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0234215 infores:hetionet CHEBI:6078 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0497156 infores:hetionet NCBIGene:6335 biolink:causes MONDO:0009459 infores:monarchinitiative not_provided not_provided HGNC:10597 MONDO:0009459 uuid:b2c39136-1db1-48a4-8493-dcfd04c03380 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0060542 biolink:causes GO:0006310 infores:ubergraph knowledge_assertion manual_agent GO:0060542 GO:0006310 NCBIGene:4982 biolink:causes MONDO:0009394 infores:monarchinitiative not_provided not_provided HGNC:11909 MONDO:0009394 uuid:9c3d1e84-4bf5-4861-8872-be9c3da06c95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28148 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0031542 infores:hetionet NCBIGene:5908 biolink:causes MONDO:0958000 infores:monarchinitiative not_provided not_provided HGNC:9857 MONDO:0958000 uuid:78607e27-6f82-4e02-9e84-eca2a1d74b96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0085616 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0009938 infores:hetionet CHEBI:9757 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0004093 infores:hetionet CHEBI:8802 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0042510 infores:hetionet CHEBI:2955 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0040264 infores:hetionet CHEBI:9123 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015672 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020039 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0149931 infores:hetionet CHEBI:3127 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2242996 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020678 infores:hetionet CHEBI:5383 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0917801 infores:hetionet CHEBI:8426 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0027726 infores:hetionet CHEBI:3216 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0036974 infores:hetionet CHEBI:135935 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0232487 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019158 infores:hetionet CHEBI:7443 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0027497 infores:hetionet CHEBI:9570 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0857305 infores:hetionet CHEBI:168396 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0235031 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0234987 infores:hetionet CHEBI:2636 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0039070 infores:hetionet CAID:CA228592 biolink:causes MONDO:0019565 infores:clingen CAID:CA228592 MONDO:0019565 PMID:37011710PMID:32573891PMID:19694940PMID:37011710PMID:32573891PMID:19694940 Uncertain Significance PM2_Supporting PP3, PP4, BS2, BP4, PS3, BS3 NM_000552.5(VWF):c.4399C>T is a missense variant in VWF predicted to encode substitution of proline by serine at amino acid 1467. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/74910 alleles in the African/African American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.503, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function, while the computational splicing predictor SpliceAI indicates that the variant has no impact on splicing. At least 1 patient with this variant displayed a laboratory phenotype of low VWF:RCo/VWF:Ag ratio (0.09), but lacked the excessive mucocutaneous bleeding required for a phenotype specific to VWD type 2M (PMID: 19694940). Two members of the proband's family similarly harbored the variant but lacked the bleeding phenotype, but BS2 is considered not applicable. Flow cytometry and ELISA-based assays show no binding of the recombinant variant to fixed platelets or wild-type GPIb when induced by ristocetin, but normal binding of the variant to both targets when triggered in a ristocetin-independent manner (PMID: 19694940, PMID: 32573891). However, BS3_Supporting is not considered applicable. This variant is classified as a variant of unknown significance for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228592/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Inconclusive true CHEBI:132233 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0338614 infores:hetionet NCBITaxon:5691 biolink:causes MONDO:0005459 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5691 MESH:D014353 DB00738_MESH_D014353_1DB12864_MESH_D014353_1DB04786_MESH_D014353_1DB06243_MESH_D014353_1 UMLS:C0009315 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0018681 infores:hetionet CHEBI:10119 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027066 infores:hetionet CHEBI:4708 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0000731 infores:hetionet CHEBI:4659 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0232487 infores:hetionet CHEBI:134991 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0011168 infores:hetionet CHEBI:3614 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0003862 infores:hetionet CAID:CA500436058 biolink:causes MONDO:0100326 infores:clingen CAID:CA500436058 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting BP7, BP2, BP4 The c.1815C>T variant in ITGB3 is a single nucleotide substitution that does not alter the protein sequence (p.Gly605=). RT-PCR and sequencing analysis revealed a 100-nucleotide deletion, corresponding to the 3’-end of exon 11 (c.1814_1913del), in the patient. The deletion results in a shift of the reading frame and the appearance of a premature stop codon (in exon 11 of 15) after 30 altered amino acids (p.Gly605Glufs*31), which is predicted to result in nonsense mediated decay (PVS1). Exon trapping analysis of genomic DNA encompassing either the normal or mutated exon 11, demonstrated that the identified mutation was forcing alternative splicing of β3-mRNA. One proband is reported, meeting the bleeding phenotype criteria. Platelet aggregation in response to ADP, thrombin, collagen and adrenaline was absent and Ristocetin was normal. Flow cytometry analysis revealed undetectable levels of platelet glycoproteins αIIb and β3. (PMID: 15886806) (PP4_Moderate). This variant has been detected homozygous (PMID: 15886806) (PM3_Supporting). This variant is absent from gnomADv4.0.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM3_Supporting, PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500436058/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:9620 biolink:causes MONDO:0007921 infores:monarchinitiative not_provided not_provided HGNC:1850 MONDO:0007921 uuid:ebfe9958-82ec-4b2b-a749-fc1579e30f2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31401 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042109 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0029445 infores:hetionet CHEBI:4792 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0027497 infores:hetionet CHEBI:9332 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0020461 infores:hetionet CHEBI:28748 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151766 infores:hetionet NCBIGene:6310 biolink:causes MONDO:0008119 infores:monarchinitiative not_provided not_provided HGNC:10548 MONDO:0008119 uuid:b7bda3d2-2acc-4899-a0b4-1b64c44f95ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47781 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0013144 infores:hetionet UMLS:C0065374 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0085649 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0233571 infores:hetionet CHEBI:50648 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015967 infores:hetionet CHEBI:47780 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0231530 infores:hetionet CHEBI:72564 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0003467 infores:hetionet CHEBI:2663 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0041834 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0040034 infores:hetionet CHEBI:6339 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0006142 infores:hetionet CHEBI:42944 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0037763 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0424000 infores:hetionet CHEBI:3077 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0232461 infores:hetionet NCBIGene:90678 biolink:causes MONDO:0013753 infores:monarchinitiative not_provided not_provided HGNC:25135 MONDO:0013753 uuid:18f44f06-107e-42d5-8db7-72b79a588ef6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C2979982 infores:hetionet CHEBI:3561 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0043349 infores:hetionet CHEBI:50729 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0009676 infores:hetionet CHEBI:101085 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0012833 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0038941 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0038941 infores:hetionet CHEBI:116278 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151827 infores:hetionet CHEBI:72564 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1306341 infores:hetionet CHEBI:6541 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0028734 infores:hetionet CHEBI:6128 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C1443060 infores:hetionet CHEBI:82866 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0237849 infores:hetionet CHEBI:3398 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0030554 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0002871 infores:hetionet CHEBI:119915 biolink:causes EFO:0801084 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0596240 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1510450 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1510450 infores:hetionet CAID:CA229839 biolink:causes MONDO:0009861 infores:clingen CAID:CA229839 MONDO:0009861 PMID:8533759PMID:8533759 Likely Pathogenic PM2, PM5, PM3, PP3, PP4 The c.899C>T (p.Ala300Val) variant in PAH has been reported in at least 1 individual with PKU, detected in trans with pathogenic variant p.R408W (PMID: 8533759). This variant is absent in population databases. Computational evidence support a deleterious effect. Another missense variant at the same amino acid (p.A300S) is pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PM5, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229839/MONDO:0009861/006 2020-09-24 2022-02-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49960 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0037199 infores:hetionet CHEBI:63605 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1258215 infores:hetionet CHEBI:8888 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027497 infores:hetionet CHEBI:119915 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006277 infores:hetionet CHEBI:184555 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0085606 infores:hetionet CHEBI:3423 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0542571 infores:hetionet CHEBI:45081 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0085633 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0018802 infores:hetionet CHEBI:3638 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0002170 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0009782 infores:hetionet CHEBI:71219 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C2979982 infores:hetionet CHEBI:10124 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0018926 infores:hetionet CHEBI:3757 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0015967 infores:hetionet CHEBI:94686 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1145628 infores:hetionet CHEBI:3423 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151692 infores:hetionet CHEBI:4657 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0042571 infores:hetionet CHEBI:3314 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0020437 infores:hetionet CHEBI:61033 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0151578 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0041969 infores:hetionet UMLS:C1738934 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0039070 infores:hetionet NCBIGene:89781 biolink:causes MONDO:0013556 infores:monarchinitiative not_provided not_provided HGNC:15844 MONDO:0013556 uuid:be7c6e27-d8f4-4269-90e6-b107289746bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52010 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0233414 infores:hetionet CHEBI:6931 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0547030 infores:hetionet CAID:CA2580100887 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100887 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2730_2731del (p.Glu911GlyfsTer?) is a frameshift variant due to 2-nucleotide deletion introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including onset at age 5 years (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), pigment deposits (0.5 pts), optic disc pallor (0.5 pts), and genotyping by next-generation sequencing identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 1 family (PP1_Moderate; PMID: 36276946). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP1_Moderate, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100887/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:8776 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0235660 infores:hetionet CHEBI:3568 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0007286 infores:hetionet CHEBI:5130 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0438142 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020649 infores:hetionet CHEBI:64045 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0393593 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0853149 infores:hetionet CHEBI:27779 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0006840 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0033975 infores:hetionet CHEBI:3749 biolink:causes MONDO:0006978 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0037998 infores:hetionet CHEBI:31705 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0037763 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0302813 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0302813 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0031212 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0948594 infores:hetionet NCBIGene:23545 biolink:causes MONDO:0018163 infores:monarchinitiative not_provided not_provided HGNC:18481 MONDO:0018163 uuid:fa7c4347-0a68-4867-8650-5d54a0666016 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32588 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0233471 infores:hetionet CHEBI:100241 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013604 infores:hetionet CHEBI:2611 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0085649 infores:hetionet CHEBI:17823 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0392525 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002878 infores:hetionet CHEBI:59582 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0020555 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0003123 infores:hetionet CHEBI:2676 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0043352 infores:hetionet CHEBI:6472 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0242528 infores:hetionet CHEBI:6775 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0000731 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0039240 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0574067 infores:hetionet CL:0000148 biolink:causes MONDO:0021143 infores:ubergraph knowledge_assertion manual_agent CL:0000148 MONDO:0021143 CAID:CA229264 biolink:causes MONDO:0009861 infores:clingen CAID:CA229264 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting The c.1006C>T (p.Gln336Ter) nonsense variant occurs in exon 10 of 13 and is predicted to result in NMD. It absent from population databases, including gnomAD. It has been reported in at least one patient with cPKU (PMID: 23764561), compound heterozygous with R408W (ClinVar 577 Pathogenic, reviewed by PAH VCEP). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229264/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4798 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0008325 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0017152 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0014130 infores:hetionet CAID:CA220220 biolink:causes MONDO:0008723 infores:clingen CAID:CA220220 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM3, PVS1_Moderate, PP4_Moderate The c.753-2A>C variant in ACADVL occurs within the canonical splice acceptor site (+/- 1,2) of intron 8. It is predicted to cause skipping of biologically-relevant-exon 9/20, resulting in an in frame deletion (removes amino acids 252-293) that is predicted to escape nonsense mediated decay (PVS1_moderate). This variant has been identified by positive newborn screen in several individuals and in individuals presenting with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27246109, 26385305, 21378393, 17999356, 16488171, 10738914, 10077518, 9973285). This variant is reported in two individuals with a beta-oxidation flux less than 20% of normal which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. (PP4_Moderate, PMID: 21378393, 17999356, 20060901). At least three individuals were compound heterozygous for the variant and a distinct pathogenic or likely pathogenic variant, not confirmed in trans (PM3; PMID: 27246109, 16488171, 20060901, 21378393, 17999356). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting, PM3, PP4_Moderate (VCEP specifications v2.0, approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220220/MONDO:0008723/021 2023-05-09 2023-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63791 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019372 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0281825 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0281825 infores:hetionet CHEBI:47898 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0236075 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0595878 infores:hetionet CHEBI:64312 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0086565 infores:hetionet CHEBI:2948 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0042164 infores:hetionet CHEBI:31236 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022107 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0948089 infores:hetionet CHEBI:6715 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019209 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0011616 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0010692 infores:hetionet CHEBI:51364 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0004093 infores:hetionet CHEBI:17549 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0037274 infores:hetionet CHEBI:34385 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003862 infores:hetionet CHEBI:4027 biolink:causes NCIT:C171138 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C2747813 infores:hetionet CHEBI:77733 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0522224 infores:hetionet CHEBI:5118 biolink:causes MONDO:0006903 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0270810 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0234215 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009938 infores:hetionet CHEBI:49375 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0000731 infores:hetionet CHEBI:68584 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0041657 infores:hetionet CHEBI:28918 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0027497 infores:hetionet CHEBI:8107 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151610 infores:hetionet CHEBI:2950 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0235086 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0235912 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235912 infores:hetionet CHEBI:50648 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C1527344 infores:hetionet CHEBI:28915 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0013395 infores:hetionet CHEBI:9599 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0027424 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0020649 infores:hetionet NCBIGene:3853 biolink:causes MONDO:0014324 infores:monarchinitiative not_provided not_provided HGNC:6443 MONDO:0014324 uuid:64506e7a-2f82-4984-90c3-2de58e4e4b3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0241934 infores:hetionet CHEBI:9907 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0151907 infores:hetionet CHEBI:367163 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0030554 infores:hetionet CAID:CA2573106197 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573106197 MONDO:0015967 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting The c.421del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 141 of NM_175914.5, adding 29 novel amino acids before encountering a stop codon (p.(Arg141AspfsTer29)). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hyperinsulinemic hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; PMID: 23796040). This variant segregated with diabetes, with three informative meioses in a single family with MODY (PP1; internal lab contributor). In summary, c.421del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PVS1, PP1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106197/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50859 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0149745 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151888 infores:hetionet CHEBI:27974 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0000737 infores:hetionet CHEBI:9332 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0002878 infores:hetionet CHEBI:50673 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0042963 infores:hetionet CHEBI:28787 biolink:causes HP:0046507 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0231837 infores:hetionet CHEBI:8707 biolink:causes HP:0007514 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0239819 infores:hetionet CHEBI:9150 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0009676 infores:hetionet NCBIGene:162 biolink:causes MONDO:0009440 infores:monarchinitiative not_provided not_provided HGNC:554 MONDO:0009440 uuid:2320f0d2-e450-4b71-8985-4e34eaa34ec6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47499 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0030312 infores:hetionet CHEBI:4911 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0003578 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0037199 infores:hetionet CHEBI:9674 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0231218 infores:hetionet CHEBI:32139 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0008031 infores:hetionet CAID:CA211326 biolink:causes MONDO:0010880 infores:clingen CAID:CA211326 MONDO:0010880 PMID: Likely Benign BP2, BP5 PM2, PP3 The NM_000020.3: c.88C>T variant in ACVRL1 is a missense variant predicted to cause substitution of proline by serine at amino acid 30 (p.Pro30Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004916 (17/34584 alleles) in the Admixed American population. This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ENG variant) (BP5; PMID: 32573726). This variant has been observed in trans with the variant c.191delA, p.Gln64Argfs*58 (PMID: 16752392), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in an individual with Hereditary Hemorrhagic Telangiectasia. The phase of the variants was confirmed by family testing (BP2). The computational predictor REVEL gives a score of 0.499, which is neither above nor below the thresholds predicting a damaging or benign impact on ACVRL1 function. In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BP2, BP5 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA211326/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9139 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085636 infores:hetionet CHEBI:68478 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042023 infores:hetionet CHEBI:3215 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0234518 infores:hetionet CHEBI:4907 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0015230 infores:hetionet CHEBI:27732 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0017152 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0687133 infores:hetionet CHEBI:6375 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0232461 infores:hetionet CHEBI:5001 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151904 infores:hetionet NCBIGene:182 biolink:causes MONDO:0016862 infores:monarchinitiative not_provided not_provided HGNC:6188 MONDO:0016862 uuid:9f4a5063-e744-4787-b1c6-57d3c420c6b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0030305 infores:hetionet CHEBI:41879 biolink:causes MONDO:0019801 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151467 infores:hetionet CAID:CA226356 biolink:causes MONDO:0100437 infores:clingen CAID:CA226356 MONDO:0100437 PMID:16935610 Likely Pathogenic PP1_Moderate, PP3, PP4, PS4_Supporting, PM2_Supporting PS3, BP4 NM_001034853.2(RPGR):c.1307G>A (p.Gly436Asp) is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 436. The computational predictor REVEL gives a score of 0.271, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives delta scores of 0.48 for acceptor loss and 0.41 for acceptor gain, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a deleterious impact on splicing (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 26164827, PMID: 36445968, PMID: 32209785, PMID: 32098976, and PMID: 28863407, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), showing a milder phenotype in affected females (1 pt), reduced visual acuity (0.5 pts), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (4 points, PMID: 10937588, PP4). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PMID: 10937588, PP1_Moderate). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PP3, PM2_Supporting, PS4_Supporting, PP4, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226356/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Supports CHEBI:5165 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0003123 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0042514 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0031350 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0851341 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0004238 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151596 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020649 infores:hetionet NCBIGene:54808 biolink:causes MONDO:0009130 infores:monarchinitiative not_provided not_provided HGNC:21317 MONDO:0009130 uuid:21841d20-36a3-42ad-8754-788803e240aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63115 biolink:causes MONDO:0020744 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0264907 infores:hetionet CHEBI:8888 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018944 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0240972 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0240972 infores:hetionet CAID:CA16020894 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020894 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4 The c.912+1G>C variant in PAH is a canonical splice donor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was reported in 2 patients with PKU (PMID 25550961, 31332730). Additionally, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020894/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3561 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0009450 infores:hetionet CHEBI:9139 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0234022 infores:hetionet CHEBI:9943 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018524 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020517 infores:hetionet CHEBI:45373 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00259 UMLS:C0085624 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0026946 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0235030 infores:hetionet CAID:CA228504 biolink:causes MONDO:0015630 infores:clingen CAID:CA228504 MONDO:0015630 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate PP1, BP2, PM5, BP5 The missense variant NM_000552.5(VWF):c.3944G>A (p.Arg1315His) is a rare variant which occurs at a Grpmax filtering allele frequency in gnomAD v4.1 is 0.00002255 (based on 4/60004 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_supporting). The computational predictor REVEL gives a score of 0.815, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Portuguese patient P30, with this variant, (PMID: 26988807) displayed excessive mucocutaneous bleeding (bleeding score 7) as well as a laboratory phenotype of normal multimers, low VWF:RCo/VWF:Ag ratio (VWF:RCo 11%, VWF:Ag 16%, ratio 0.69) and an abnormal collagen binding assay (VWF:CB 19%), which together are highly specific for VWD type 2M (PP4_moderate). At least 3 additional probands have been reported with this variant and VWD reported as type 1 (but with VWF:RCo/VWF:Ag ratio <0.7) or type 2M (PMID: 26986123, 25689060, 16985174; PS4_moderate). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM2_supporting, PP3, PP4_moderate, PS4_moderate. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228504/MONDO:0015630/081 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5779 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0036572 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0009806 infores:hetionet CHEBI:70735 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0033774 infores:hetionet CHEBI:17474 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0017178 infores:hetionet CHEBI:7447 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C1443060 infores:hetionet GO:2000764 biolink:causes GO:0003151 infores:ubergraph knowledge_assertion manual_agent GO:2000764 GO:0003151 UNII:D27V6190PM biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0010034 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0033975 infores:hetionet CHEBI:131512 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0004134 infores:hetionet CHEBI:6541 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0004093 infores:hetionet CHEBI:7931 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C2363731 infores:hetionet CAID:CA631301057 biolink:causes MONDO:0012999 infores:clingen CAID:CA631301057 MONDO:0012999 PMID: Pathogenic PVS1, PP4_Strong, PM3_Supporting PM2 The NM_000156.6(GAMT):c.11_36dup (p.Gly13ProfsTer38) variant in GAMT (also reported as c.36_c.37ins26) is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. However, the read depth is <20X at this position and therefore allele frequency data cannot be accurately assessed. Three individuals with biochemical and clinical features consistent with GAMT deficiency have been described including two with reduced creatine peak and guanidinoacetate (GAc) peak on MRS as well as elevated GAc in serum (PMID 19027335, 23660394, 24415674, 29506905) and one with deficient GAMT activity in fibroblasts (PMID 24415674) (PP4_Strong). These individuals are all compound heterozygous for the variant and a second variant in GAMT, phase unknown, including c.327G>A (PMID 19027335, 23660394; pathogenic based on assessment with the ClinGen CCDS VCEP; 0.5 points), c.133T>A (p.Trp45Arg), and c.439C>T (p.His147Tyr). The in trans data for the patients with c.133T>A (p.Trp45Arg) and c.439C>T (p.His147Tyr) will be used in the assessment of those variants and is not included here in order to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 858462). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP, September 12, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA631301057/MONDO:0012999/026 2023-09-12 2023-09-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes MONDO:0001515 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0155118 infores:hetionet CHEBI:9586 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0015732 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0152128 infores:hetionet GO:0035887 biolink:causes CL:0002539 infores:ubergraph knowledge_assertion manual_agent GO:0035887 CL:0002539 CHEBI:7824 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1368065 infores:hetionet CHEBI:404903 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0034642 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0746883 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0232431 infores:hetionet NCBIGene:2304 biolink:causes MONDO:0009437 infores:monarchinitiative not_provided not_provided HGNC:3806 MONDO:0009437 uuid:ffaca405-7fd1-4a8b-bd48-2608fd00b923 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0030312 infores:hetionet CHEBI:3441 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0014742 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0332575 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1258215 infores:hetionet CHEBI:15367 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0014743 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0009578 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0009578 uuid:9a669cf2-60f3-4e5d-8605-4fd2422d12a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23129 biolink:causes MONDO:0859532 infores:monarchinitiative not_provided not_provided HGNC:9107 MONDO:0859532 uuid:013521aa-4256-44ef-986f-a158ba32461f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA349680 biolink:causes MONDO:0007648 infores:clingen CAID:CA349680 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS3, BS1, BS4, PM1, PM4, PM5, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BP3, BP1, BP4, BP2, BA1, PS3, PS1, PS2, PS4 The c.2076_2077inv (p.Gly693Ser) variant has been observed in >10 (41) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000260738.9). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2 CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA349680/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63637 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0020517 infores:hetionet GO:2000477 biolink:causes GO:0072244 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0072244 CHEBI:4822 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0027497 infores:hetionet CHEBI:9123 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0004134 infores:hetionet CHEBI:51450 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0039231 infores:hetionet CHEBI:47499 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0015672 infores:hetionet CHEBI:119486 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0267797 infores:hetionet CHEBI:31401 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0016204 infores:hetionet CHEBI:3127 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0008031 infores:hetionet CHEBI:10101 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0016927 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002871 infores:hetionet GO:0060687 biolink:causes GO:0001655 infores:ubergraph knowledge_assertion manual_agent GO:0060687 GO:0001655 NCBITaxon:12059 biolink:causes MONDO:0005709 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12059 MESH:D003139 DB00427_MESH_D003139_1DB00455_MESH_D003139_1DB00366_MESH_D003139_1 CHEBI:40009 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0234535 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0267596 infores:hetionet CHEBI:2682 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0040822 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0003864 infores:hetionet CHEBI:82981 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0020517 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0020538 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040053 infores:hetionet UMLS:C0879264 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0085649 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0002871 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0521494 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0521494 infores:hetionet CHEBI:50378 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0023530 infores:hetionet CHEBI:50275 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151786 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0235146 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0423636 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0423636 infores:hetionet GO:0060639 biolink:causes GO:0035272 infores:ubergraph knowledge_assertion manual_agent GO:0060639 GO:0035272 CHEBI:499361 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0009676 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0549209 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0039520 infores:hetionet CHEBI:404903 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0231218 infores:hetionet CHEBI:51450 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0006277 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0009450 infores:hetionet NCBIGene:57094 biolink:causes MONDO:0013741 infores:monarchinitiative not_provided not_provided HGNC:17245 MONDO:0013741 uuid:9260a5a4-ddb0-48f9-8cc0-f715241a1a6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0600142 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0020517 infores:hetionet CAID:CA214096 biolink:causes MONDO:0010938 infores:clingen CAID:CA214096 MONDO:0010938 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting, PP4 The c.678_679del (p.Cys227ProfsTer?) (NM_000215.4) variant in JAK3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003577 (1/27956) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting, meeting this criterion (PM2_Supporting).One patient compound heterozygous with variant c.1767C>T (PMID: 23384681). It was not evaluated at this moment because the pathogenic level was already reached. One homozygous patient described on ClinVar (3billion, T-B+ severe combined immunodeficiency due to JAK3 deficiency) affected status: yes. Hepatosplenomegaly (present), Pneumonia (present) - (0.5pt). PM3_Supporting.Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), T-B+NK- lymphocyte subset profile (0.5pt), total=1pt, PP4. (PMID: 23384681).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PP4, PM2_supporting and PM3_supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214096/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8874 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0853714 infores:hetionet CHEBI:2659 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0020621 infores:hetionet NCBIGene:2035 biolink:causes MONDO:0012731 infores:monarchinitiative not_provided not_provided HGNC:3377 MONDO:0012731 uuid:8e0a4d15-b93f-40ca-8177-2463f4f7165d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042035 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030305 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0235146 infores:hetionet CHEBI:49960 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C3160858 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0021308 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0233472 infores:hetionet CHEBI:231594 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0029927 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0948594 infores:hetionet CHEBI:50122 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0267792 infores:hetionet CAID:CA410204209 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204209 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.133A>G (p.Thr45Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204209/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63624 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0030554 infores:hetionet GO:0072094 biolink:causes GO:0072283 infores:ubergraph knowledge_assertion manual_agent GO:0072094 GO:0072283 CHEBI:38940 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0853986 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002418 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0040034 infores:hetionet NCBIGene:6569 biolink:causes MONDO:0012850 infores:monarchinitiative not_provided not_provided HGNC:11019 MONDO:0012850 uuid:5ae6b90d-e3c4-4e92-b574-1a4d02c44561 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014742 infores:hetionet UMLS:C0657912 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030193 infores:hetionet NCBIGene:2130 biolink:causes MONDO:0012817 infores:monarchinitiative not_provided not_provided HGNC:3508 MONDO:0012817 uuid:48fae435-e381-4fa6-839b-a5bca5938588 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0574067 infores:hetionet CHEBI:68579 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0019079 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0029445 infores:hetionet CHEBI:127342 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1112442 infores:hetionet CHEBI:17141 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0035078 infores:hetionet CHEBI:3732 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0020458 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0020649 infores:hetionet CHEBI:3286 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0021122 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0041976 infores:hetionet CHEBI:49713 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0231530 infores:hetionet CHEBI:681569 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0033771 infores:hetionet CHEBI:61033 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0018965 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0264344 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0264344 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0003615 infores:hetionet CHEBI:51230 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0020555 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0037274 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0853714 infores:hetionet CHEBI:8412 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0003123 infores:hetionet CHEBI:51164 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0018681 infores:hetionet CHEBI:9435 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0011991 infores:hetionet CAID:CA10643872 biolink:causes MONDO:0015967 infores:clingen CAID:CA10643872 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 PP3 The c.50-4791_50-4788del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a 4-nucleotide-deletion within intron 1 of NM_175914.5. The computational splicing predictor SpliceAI gives a score of 0.00 for donor and acceptor loss, suggesting that the variant has no impact on splicing (BP4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.50-4791_50-4788del meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10643872/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7931 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0017152 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0005779 infores:hetionet CHEBI:63589 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C2711227 infores:hetionet CHEBI:87681 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0016204 infores:hetionet CHEBI:31236 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151662 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0743323 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0743323 infores:hetionet CHEBI:127780 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C1443060 infores:hetionet CHEBI:5165 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0009763 infores:hetionet CHEBI:135285 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0027497 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0242350 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0018801 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0242151 infores:hetionet GO:1904412 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1904412 GO:0007275 CHEBI:32139 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0042963 infores:hetionet CAID:CA226412 biolink:causes MONDO:0100437 infores:clingen CAID:CA226412 MONDO:0100437 PMID:36276946 Pathogenic PVS1, PP4, PM2_Supporting, PS4_Supporting PP3, PP1, PS3 NM_001034853.2(RPGR):c.310+3A>G is an intronic variant located in intron 4. The splicing impact predictor SpliceAI gives a score of 0.93 for donor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, while cells transected with the variant intron showed no mCherry signal relative to the wild-type intron control, indicating severely defective splicing.(PMID: 36276946, PVS1). The PP3 and PS3_Supporting codes were not met as PVS1 has been applied instead. This variant is absent from hemizygotes in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 16969763, PMID: 21857984, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), reduced visual acuity (0.5 pts), reduction in visual fields (0.5 pts), optic disc pallor (0.5 pts), night blindness (0.5 pts), pigmentary deposits (0.5 pts), nondetectable electroretinogram responses, and genotyping by next-generation sequencing with a panel of 483 genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5.5 pts, PP4). The variant has been reported to segregate through at least 2 meioses from 1 family, however, the PP1 code was not met as the female carriers were not described as affected (PMID: 36276946). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PP4, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226412/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:7443 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0041349 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0234458 infores:hetionet CAID:CA274304 biolink:causes MONDO:0009290 infores:clingen CAID:CA274304 MONDO:0009290 PMID:19862843PMID:14972326 Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting, PM3_Strong, PS3_Supporting The NM_000152.5:c.2104C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 702 (p.Arg702Cys). At least 1 patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PMID: 14972326). At least 1 patient with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID: 25687148). Other patients with this variant who were noted to have Pompe disease were found in the literature, but enzyme activity was not discussed (PMID: 20308911, 31086307) (PP4_Moderate). This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and -32-13T>G a pathogenic variant by the ClinGen Lysosomal Diseases VCEP (phase unknown)(PMID: 20308911, 24158270) and 1 individual was compound heterozygous for the variant and c.2481+110_2646+39del (confirmed in trans by parental/family testing)(PMID: 14972326). Two individuals were homozygous for the variant (PMID: 25687148, 31086307), meetings the criteria for PM3_Strong. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/254192 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS resulted in less than 2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID: 14972326, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants [c.2105G>T (p.Arg702Leu, ClinVar Variation ID: 92472) and c.2105G>A (p.Arg702His, ClinVar Variation ID: 426278)], in the same codon have been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 189040). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_Moderate, PM3_Strong, PM2_Supporting, PS3_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 11, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274304/MONDO:0009290/010 2025-01-11 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:56154 biolink:causes MONDO:0054729 infores:monarchinitiative not_provided not_provided HGNC:11738 MONDO:0054729 uuid:956e10d2-488f-445c-a0a9-77f5d789f97b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94411 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0012833 infores:hetionet CHEBI:94385 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C1443060 infores:hetionet CHEBI:6965 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0039231 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0235146 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0235416 infores:hetionet NCBIGene:10861 biolink:causes MONDO:0957268 infores:monarchinitiative not_provided not_provided HGNC:10993 MONDO:0957268 uuid:8bc3a223-a365-4a89-b81f-59c4af26fe9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0854082 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0240066 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0240066 infores:hetionet CHEBI:6437 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0424295 infores:hetionet CHEBI:134990 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0011991 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0860160 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0860160 infores:hetionet CHEBI:8364 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0027424 infores:hetionet CHEBI:8871 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013390 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0021400 infores:hetionet CHEBI:50859 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085595 infores:hetionet CHEBI:30659 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0151786 infores:hetionet NCBIGene:23209 biolink:causes MONDO:0024555 infores:monarchinitiative not_provided not_provided HGNC:17082 MONDO:0024555 uuid:82032b7d-93ca-4215-b043-5023dde801ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018524 infores:hetionet CHEBI:46081 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0151908 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0017675 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0497247 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0235146 infores:hetionet CHEBI:77260 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0038325 infores:hetionet CHEBI:585948 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0006277 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030920 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018099 infores:hetionet NCBIGene:6569 biolink:causes MONDO:0014851 infores:monarchinitiative not_provided not_provided HGNC:11019 MONDO:0014851 uuid:02851cfe-c4e3-45cf-a72e-625f8ec33855 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16028070 biolink:causes MONDO:0021056 infores:clingen CAID:CA16028070 MONDO:0021056 PMID: Uncertain Significance PM5_Supporting, PM2_Supporting, PS4_Supporting BP1, BP4 The c.3077A>C variant in APC is a missense variant predicted to cause the substitution of asparagine by threonine at amino acid position 1026 (p.Asn1026Thr). This variant has been reported in 3 probands with FAP worth 1.5 phenotype points (PS4_Supporting; Ambry Internal Data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.3077A>G (p.Asn1026Ser) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting; PMID 18166348). In summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PS4_Supporting, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16028070/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true PUBCHEM.COMPOUND:12162152 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0032343 infores:hetionet CHEBI:49713 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0039070 infores:hetionet CHEBI:9943 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0019079 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0240449 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0240449 infores:hetionet NCBIGene:1822 biolink:causes MONDO:0032781 infores:monarchinitiative not_provided not_provided HGNC:3033 MONDO:0032781 uuid:277a3bbb-caac-4763-bc3a-d27cff4dde90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28918 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0151744 infores:hetionet CHEBI:47612 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0030193 infores:hetionet CHEBI:135613 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0012833 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0178298 infores:hetionet NCBIGene:154 biolink:causes GO:0097366 infores:drugmechdb knowledge_assertion manual_agent UniProtKB:P07550 GO:0097366 DB01364_MESH_D001991_1 CHEBI:85078 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0549405 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0151736 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0746883 infores:hetionet CHEBI:2675 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0039070 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020649 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C1510497 infores:hetionet CHEBI:28001 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0040046 infores:hetionet CHEBI:63607 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0026821 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151763 infores:hetionet CHEBI:31236 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2939147 infores:hetionet CAID:CA410203862 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203862 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.223G>T (p.Asp75Tyr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203862/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9123 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0004245 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0042109 infores:hetionet CAID:CA512341151 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341151 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1272G>C (p.Ser424=) is a synonymous variant. Evolutionary conservation algorithms predict the site as not being conserved (PhyloP -2.00124 < 2.0), meeting BP7. Since it is synonymous, no REVEL score is applicable, and SpliceAI score is ≤ 0.20 (0.00), meeting BP4. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341151/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7822 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0700590 infores:hetionet CAID:CA390868420 biolink:causes MONDO:0100216 infores:clingen CAID:CA390868420 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, PM6, BP2, BA1, BS2, PP3, PP1, PP4, PM1, PM5, PS3, PS1, PS2, PS4, BS1, BS3, BS4 The NM_177438.2:c.4449G>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 1483 (p.Met1483Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005782 (2/34590 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.039; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.2.0; 01/09/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390868420/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50922 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0037274 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027707 infores:hetionet CHEBI:5775 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0234215 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0018801 infores:hetionet CHEBI:10650 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0017672 infores:hetionet CHEBI:51860 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C2363730 infores:hetionet CHEBI:8597 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0013144 infores:hetionet CHEBI:7936 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0028754 infores:hetionet CHEBI:553473 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0014457 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0027769 infores:hetionet CHEBI:5138 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0086439 infores:hetionet CHEBI:83804 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0003862 infores:hetionet CHEBI:50861 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0015672 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0854059 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0854059 infores:hetionet CHEBI:51164 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0003467 infores:hetionet CHEBI:27666 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0016436 infores:hetionet CAID:CA340748885 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748885 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PP1, PM2_Supporting NM_000329.3(RPE65):c.242G>T is a missense variant causing substitution of arginine by isoleucine at position 81. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.0001576, with 24 alleles / 59020 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 30870047). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) variant confirmed in trans (1 pt, PMID: 30870047), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), onset at 1 month of age (1 pt), undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nyctalopia (0.5 pts), reduced visual acuity (1 pt), light gazing (1 pt), RPE mottling (0.5 pts), optic nerve pallor (0.5 pt), nystagmus (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total points, PMID: 30870047, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PMID: 30870047, PP1). The computational predictor REVEL gives a score of 0.849, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting, PM3_Strong, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748885/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4657 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0232492 infores:hetionet NCBIGene:1349 biolink:causes MONDO:0010474 infores:monarchinitiative not_provided not_provided HGNC:2291 MONDO:0010474 uuid:84230ebb-8469-41ad-99db-9a7f442e84fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes UMLS:C0241266 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0241266 infores:hetionet CHEBI:3732 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0853225 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0022660 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0002170 infores:hetionet NCBIGene:6711 biolink:causes MONDO:0859178 infores:monarchinitiative not_provided not_provided HGNC:11275 MONDO:0859178 uuid:e4f1d1d4-7e97-4782-8741-3f08d2d3d709 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49668 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0004093 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0012833 infores:hetionet CHEBI:2788 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0011603 infores:hetionet CHEBI:34967 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0037763 infores:hetionet CHEBI:145499 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0917801 infores:hetionet NCBIGene:8468 biolink:causes MONDO:0031083 infores:monarchinitiative not_provided not_provided HGNC:3722 MONDO:0031083 uuid:d6887dcc-2d75-4cad-92b4-3c927c422038 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9939 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0026846 infores:hetionet CHEBI:74947 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085684 infores:hetionet CHEBI:142290 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0030554 infores:hetionet CHEBI:3219 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233477 infores:hetionet CHEBI:4888 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0015230 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0018621 infores:hetionet CHEBI:2038 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0027424 infores:hetionet CAID:CA512319138 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319138 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.510G>A (p.Gly170=) is a synonymous variant. REVEL score not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.450016 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319138/MONDO:0011071/008 2022-04-25 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16335 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0013404 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0032584 infores:hetionet CHEBI:42944 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0004238 infores:hetionet CHEBI:63637 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0027497 infores:hetionet CHEBI:3568 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015672 infores:hetionet CHEBI:8774 biolink:causes HP:0001920 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0035067 infores:hetionet CHEBI:194135 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0025323 infores:hetionet CHEBI:31236 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232461 infores:hetionet CHEBI:46557 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0232495 infores:hetionet CHEBI:9086 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151905 infores:hetionet CHEBI:63115 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0004245 infores:hetionet CHEBI:44915 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151723 infores:hetionet CHEBI:2704 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0030193 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C2240374 infores:hetionet CHEBI:3698 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0008031 infores:hetionet CAID:CA10385761 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385761 MONDO:0100437 PMID: Benign BA1 PM2, BP4, BS1, BP7 NM_001034853.2(RPGR):c.-52C>A is a variant in the 5' untranslated region of RPGR. This variant is present in gnomAD v4.1.0 at a frequency of 0.01509 among hemizygous individuals, with 5,110 variant alleles / 338,637 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing. However, BP4 is not considered applicable to 5' UTR variants in RPGR, so this code was not met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385761/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:63791 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0311468 infores:hetionet NCBIGene:1299 biolink:causes MONDO:0010964 infores:monarchinitiative not_provided not_provided HGNC:2219 MONDO:0010964 uuid:d0da4288-c201-4496-8830-cf8a8bd23ed2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020742 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020742 MONDO:0009861 PMID:28754886PMID:28754886 Pathogenic PM3, PP4_Moderate, PM2, PVS1 The c.190_194delCACAT variant in PAH has been previously reported as a single variant, found in trans with the Likely Pathogenic (per internal PAH ClinGen Working Group classification -see PAH0095) p.Ala156Pro variant in a female Chinese proband with classic PKU (PM3) (PMID: 28754886); the authors report that BH4 deficiency was excluded by “analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes” (PP4_Moderate) (PMID: 28754886). The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020742/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10591407 biolink:causes MONDO:0700268 infores:clingen CAID:CA10591407 MONDO:0700268 PMID:30209399 Likely Pathogenic PP3, PM2_Supporting, PS3 The variant c.5056C>T in BRCA1 is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 1686 (p.His1686Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and a SpliceAI score of 0.21 indicates a predicted impact on splicing. The computational predictor BayesDel (noAF) gives a score of 0.36, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change (PP3 met). Missense variant predicted to alter splicing, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit function similar to pathogenic control variants (PMID:30209399) (PS3 met). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PM2_Supporting, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10591407/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:74947 biolink:causes UMLS:C0000772 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0000772 infores:hetionet CHEBI:39867 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0149745 infores:hetionet CHEBI:3314 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0013604 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0520589 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0595879 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0595879 infores:hetionet NCBIGene:6558 biolink:causes MONDO:0033665 infores:monarchinitiative not_provided not_provided HGNC:10911 MONDO:0033665 uuid:11572236-db6f-4eb2-898e-62a345b65955 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3716 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0003123 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0852909 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0852909 infores:hetionet NCBIGene:56246 biolink:causes MONDO:0011826 infores:monarchinitiative not_provided not_provided HGNC:1304 MONDO:0011826 uuid:d2539580-7fa1-4f35-a07f-ed6af63d09de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes UMLS:C0016722 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016722 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0687707 infores:hetionet CHEBI:4784 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0023518 infores:hetionet CHEBI:4551 biolink:causes MONDO:0017863 infores:ubergraph knowledge_assertion manual_agent CHEBI:4551 MONDO:0017863 CHEBI:38940 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020488 infores:hetionet CAID:CA228265 biolink:causes MONDO:0015628 infores:clingen CAID:CA228265 MONDO:0015628 PMID:9569179 Likely Pathogenic PP4_Moderate, PM2_Supporting, PS3, PM4 PM3 The NM_000552.5:c.1213_1214insATCCCA variant is predicted to cause a change in the length of the protein due to an in-frame insertion of 2 amino acids in a non-repeat region (p.Phe404_Thr405insAsnPro) (PM4). This variant is absent from gnomAD v4.1 (PM2_Supporting). Multimerization assay performed with the NM_000552.5:c.1213_1214insATCCCA (p.Phe404_Thr405insAsnPro) recombinant mutant and WT control vWF expressed by COS-7 showed abnormal multimers indicating that this variant has a damaging effect on protein function (PMID 9569179)(PS3). The publication includes HMWM gels for the patient and the COS-7 model. At least 1 patient with this variant displayed excessive mucocutaneous bleeding (bleeding time >30 min.) as well as laboratory phenotypes of very low VWF activity (VWF:RCo 10 U/dL), low VWF:RCo/VWF:Ag ratio (0.2), and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID: 9569179, PMID: 6982283). The additional consistent phenotype of FVIII activity consistent with VWF antigen (ratio 1.34) was also reported. Family studies indicate a recessive mode of inheritance. In summary, this variant meets the criteria to be classified as likely pathogenic for von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PM4, PM2_Supporting, and PS3. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; date of approval) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228265/MONDO:0015628/081 2024-12-03 2024-12-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31176 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0020517 infores:hetionet CHEBI:145499 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003537 infores:hetionet CHEBI:63635 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0015402 infores:hetionet CHEBI:190729 biolink:causes MONDO:0700296 infores:ubergraph knowledge_assertion manual_agent CHEBI:22271 MONDO:0700296 CAID:CA338398676 biolink:causes MONDO:0100283 infores:clingen CAID:CA338398676 MONDO:0100283 PMID: Uncertain Significance PP2, PM2_Supporting, PM1_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM3, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.5432G>T(NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of arginine by leucine at amino acid 1811 (p.Arg1811Leu). In gnomAD v4.1.0, this variant has a minor allele frequency of 0.00006% in the Admixed American population and a filtering allele frequency is not provided (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BM VCEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_Supporting, PP2, PM1_Supporting; 3 points (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA338398676/MONDO:0100283/018 2025-07-01 2025-07-01 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CAID:CA320251021 biolink:causes MONDO:0011071 infores:clingen CAID:CA320251021 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP4, BP2, PM2, PM6, PVS1, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.*134C>T is a 3' UTR change located in exon 9. It has been identified in three individuals in gnomAD v2 and two individuals in gnomAD v3, with minor allele frequencies (MAF) of 0.00005783 and 0.00001328, respectively. So far, this variant has not been reported in any patients with RUNX1-related diseases. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251021/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50648 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042963 infores:hetionet CHEBI:51230 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0030252 infores:hetionet CHEBI:15365 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C1522133 infores:hetionet CHEBI:63791 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0152030 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0860713 infores:hetionet CHEBI:5613 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0085623 infores:hetionet CHEBI:36704 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0858635 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0031212 infores:hetionet CHEBI:28925 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0003123 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0241863 infores:hetionet CHEBI:15407 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0030252 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030305 infores:hetionet UMLS:C1738934 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030252 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0006840 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0021400 infores:hetionet CHEBI:45409 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0025222 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0035085 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0035085 infores:hetionet CHEBI:53760 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0042963 infores:hetionet CHEBI:30830 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0085631 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0029408 infores:hetionet CHEBI:135342 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0041969 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0033975 infores:hetionet GO:0060338 biolink:causes GO:0071357 infores:ubergraph knowledge_assertion manual_agent GO:0060338 GO:0071357 CHEBI:135961 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0041969 infores:hetionet CHEBI:3723 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0162285 infores:hetionet CHEBI:135961 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0917801 infores:hetionet CHEBI:182080 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0030554 infores:hetionet UMLS:C0004609 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151315 infores:hetionet CHEBI:31536 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151747 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024299 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0042075 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0027765 infores:hetionet CHEBI:63635 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0038002 infores:hetionet CHEBI:15854 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0029124 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0015397 infores:hetionet UMLS:C1738934 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0018681 infores:hetionet CHEBI:63791 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030193 infores:hetionet CHEBI:6950 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0007859 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0424000 infores:hetionet CHEBI:50173 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0037763 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037274 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0235431 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013395 infores:hetionet CAID:CA10585236 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585236 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - There are 2 other missense variants in the same codon:(1) NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) - 2 stars, Likely pathogenic in ClinVar; Pathogenic by these guidelines (FH VCEP training August 2020).(2) NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) - 1 star, VUS in ClinVar; VUS by these guidelines (PM2, PM5, PP3) with no case data.There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is metPP3 - REVEL = 0.937. It is above 0.75, so PP3 is met.PP4- variant meets PM2 and was identified in 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001), Spain; so PP4 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585236/MONDO:0007750/013 2022-01-28 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:9137 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0030252 infores:hetionet CHEBI:5118 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0002792 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002905 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0026884 infores:hetionet CHEBI:4681 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0042029 infores:hetionet CHEBI:47426 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0016204 infores:hetionet CHEBI:3127 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2981158 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0239150 infores:hetionet CHEBI:7936 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0917801 infores:hetionet CHEBI:2038 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0020621 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1384353 infores:hetionet CHEBI:4027 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0011633 infores:hetionet CHEBI:167309 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0011124 infores:hetionet CHEBI:168396 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151578 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0032285 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0018802 infores:hetionet CHEBI:50777 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0018944 infores:hetionet CHEBI:119915 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231919 infores:hetionet NCBIGene:57539 biolink:causes MONDO:0013569 infores:monarchinitiative not_provided not_provided HGNC:29250 MONDO:0013569 uuid:c4f2019d-3b42-4c59-830c-27ccebf5bd6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes MONDO:0007079 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0001973 infores:hetionet NCBIGene:91181 biolink:causes MONDO:0975958 infores:monarchinitiative not_provided not_provided HGNC:29915 MONDO:0975958 uuid:a1c26210-7359-4cd4-a951-311dd5e67c9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027497 infores:hetionet CAID:CA415087684 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087684 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong PP1, PS4 The NM_005629.4:c.1456C>T (p.Gln486Ter) variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 10/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in two monozygotic male twins with developmental delay, elevated urine creatine/creatinine, and absent creatine peak on brain MRS (PMID: 22196490) and was inherited from their mother, who had intellectual disability (PP4_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, August 7, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087684/MONDO:0010305/027 2023-08-07 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:94449 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0021843 infores:hetionet CHEBI:6076 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151904 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0027765 infores:hetionet UNII:T58MSI464G biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C2242588 infores:hetionet CHEBI:35778 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0027497 infores:hetionet CHEBI:63627 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0042029 infores:hetionet CHEBI:10650 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0236000 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0853813 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151713 infores:hetionet CHEBI:480999 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030193 infores:hetionet CHEBI:3723 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0149741 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0025061 infores:hetionet CHEBI:38562 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0033774 infores:hetionet CHEBI:10102 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0404521 infores:hetionet CHEBI:7443 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0040822 infores:hetionet CAID:CA410676856 biolink:causes MONDO:0009276 infores:clingen CAID:CA410676856 MONDO:0009276 PMID: Uncertain Significance PM3, PP4, PM2_Supporting PP3, BP4 The NM_000407.5(GP1BB):c.244C>T (p.Arg82Cys) missense variant is absent from gnomAD v4.1 (PM2_Supporting). One compound heterozygote has been reported with Tyr113Cys (classified Likely Pathogenic by PD VCEP) and Arg82Cys confirmed in trans from heterozygous parents (PMID: 24051937; PM3). The patient (PMID: 24051937) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry revealed severely decreased GPIbα (6.3% WT) and GPIX (4.8% WT) on the patient’s platelets, which is specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM3, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410676856/MONDO:0009276/082 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6375 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027121 infores:hetionet CHEBI:52717 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0028643 infores:hetionet CHEBI:4325 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0015967 infores:hetionet CHEBI:34829 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0677500 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0006849 infores:hetionet NCBIGene:3040 biolink:causes MONDO:0011399 infores:monarchinitiative not_provided not_provided HGNC:4824 MONDO:0011399 uuid:dcf79d7f-4283-4dba-895f-6014f9998845 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231594 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0344315 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0006145 infores:hetionet CHEBI:72296 biolink:causes UMLS:C1168175 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C1168175 infores:hetionet CHEBI:5801 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0006266 infores:hetionet CHEBI:8093 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0547030 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0948594 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0522172 infores:hetionet CHEBI:4027 biolink:causes HP:0001510 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151686 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0003123 infores:hetionet CHEBI:6741 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0423791 infores:hetionet CHEBI:119915 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235198 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0038454 infores:hetionet CHEBI:27834 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0085633 infores:hetionet CAID:CA410207965 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207965 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM5_Supporting, PM2_Supporting, PP3 PS4, PS1, PS2, BA1, BP1, BP4, BP2, BP3, BP5, BP7, BS1, BS4, PVS1, PM6, PM3, PM4, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.596G>C (p.Gly199Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_Supporting). This variant has been reported in several patients with AML (PMID: 17485549; PMID: 21294243; PMID: 27288520; Ned Tijdschr Klin Chem Labgeneesk 2016, 41: 244-252) and in a patient with a diagnosis of sitosterolemia who had related lifelong macrothrombocytopenia (PMID: 28983057), but germline origin could not be confirmed for any of these individuals. However, another missense variant, c.596G>A/p.Gly199Glu (ClinVar Variation ID: 869210), in the same codon has been classified as likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome by the ClinGen Myeloid Malignancy VCEP (PM5_Supporting). The computational predictor REVEL gives a score of 0.934, which is above the threshold of 0.88, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does predict a damaging effect on RUNX1 function (PP3). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207965/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0065374 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0002962 infores:hetionet CHEBI:135930 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0023518 infores:hetionet CHEBI:68606 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0018681 infores:hetionet CHEBI:31709 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0151744 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0003864 infores:hetionet CHEBI:31980 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0009421 infores:hetionet NCBIGene:81846 biolink:causes MONDO:0011475 infores:monarchinitiative not_provided not_provided HGNC:2135 MONDO:0011475 uuid:c23fbf31-bcf9-4406-8940-d2215f499316 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233494 infores:hetionet CHEBI:8245 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0040822 infores:hetionet CHEBI:3638 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0002994 infores:hetionet CHEBI:5847 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0004238 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0003123 infores:hetionet CHEBI:9123 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0086439 infores:hetionet CHEBI:6129 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030252 infores:hetionet CHEBI:37924 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0033687 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0854114 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0854114 infores:hetionet CHEBI:131512 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0428977 infores:hetionet CHEBI:8028 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020615 infores:hetionet CHEBI:31515 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0040479 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0154933 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0154933 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005236 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0302314 infores:hetionet CHEBI:474180 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0235378 infores:hetionet CHEBI:28748 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151799 infores:hetionet CHEBI:135342 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C2047937 infores:hetionet CHEBI:71417 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0004509 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0349506 infores:hetionet CHEBI:61033 biolink:causes UMLS:C1262281 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1262281 infores:hetionet GO:1900032 biolink:causes GO:0045165 infores:ubergraph knowledge_assertion manual_agent GO:1900032 GO:0045165 CHEBI:5893 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0037763 infores:hetionet UMLS:C1738934 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0022107 infores:hetionet CHEBI:28593 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0687713 infores:hetionet CHEBI:9570 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0344232 infores:hetionet CHEBI:109549 biolink:causes UMLS:C0852928 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0852928 infores:hetionet CHEBI:15365 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0017181 infores:hetionet CHEBI:3207 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0022107 infores:hetionet GO:0060656 biolink:causes GO:0060652 infores:ubergraph knowledge_assertion manual_agent GO:0060656 GO:0060652 GO:0007553 biolink:causes GO:0002165 infores:ubergraph knowledge_assertion manual_agent GO:0007553 GO:0002165 CHEBI:7936 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233494 infores:hetionet CHEBI:47657 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0042963 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002792 infores:hetionet CHEBI:7478 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0232849 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0178298 infores:hetionet CAID:CA203400 biolink:causes MONDO:0100368 infores:clingen CAID:CA203400 MONDO:0100368 PMID: Likely Benign BS1 BP4 NM_000329.3(RPE65):c.675C>G is a missense variant that causes substitution of isoleucine with methionine at codon 225. It is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.005741, with 157 alleles / 24964 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The computational predictor REVEL gives it a score of 0.238, which is below the ClinGen LCA / eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a delta score of 0.17 for acceptor loss, which is between the ClinGen LCA / eoRD VCEP recommended thresholds of >0.2 (PP3) and <0.1 (BP4) and does not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA203400/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:51173 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0233477 infores:hetionet CHEBI:4315 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0852795 infores:hetionet CHEBI:2668 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042384 infores:hetionet CHEBI:2469 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0017178 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0863084 infores:hetionet CHEBI:18357 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0018681 infores:hetionet CHEBI:6887 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018965 infores:hetionet CHEBI:28787 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0009676 infores:hetionet CHEBI:75722 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0034642 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0021400 infores:hetionet CHEBI:3380 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0032617 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0221722 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0221722 infores:hetionet NCBITaxon:43351 biolink:causes MONDO:0024608 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:43351 MONDO:0024608 CHEBI:63589 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0919823 infores:hetionet CAID:CA410149674 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149674 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BA1, BP7, BS1, BS3, PM6, PVS1, PM5, PM4, PM1, PP3 NM_001754.5(RUNX1):c.910C>T (p.Pro304Ser) is a missense variant which is completely absent from population databases which provide at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score of 0.167, which is less than 0.50 and a spliceAI score >0.2 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149674/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:499361 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0043144 infores:hetionet CHEBI:9738 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0016382 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0026946 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0004936 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0031117 infores:hetionet CHEBI:63598 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004134 infores:hetionet CHEBI:135736 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020453 infores:hetionet CHEBI:7494 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085593 infores:hetionet CHEBI:5001 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0011603 infores:hetionet CHEBI:85078 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0004604 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0236053 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0236053 infores:hetionet UMLS:C0025241 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0020625 infores:hetionet CHEBI:8382 biolink:causes MONDO:0019801 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151467 infores:hetionet CHEBI:5893 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1504494 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020649 infores:hetionet NCBIGene:7466 biolink:causes MONDO:0009101 infores:monarchinitiative not_provided not_provided HGNC:12762 MONDO:0009101 uuid:691e724f-a7dd-458a-b484-40719e5a9ea1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0019360 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0948089 infores:hetionet CHEBI:9571 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0022346 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0423628 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0423628 infores:hetionet CHEBI:50777 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0231218 infores:hetionet CAID:CA241475 biolink:causes MONDO:0044970 infores:clingen CAID:CA241475 MONDO:0044970 PMID: Uncertain Significance BS2 BA1, BP4, BS1 The c.578G>A (p.Arg193Gln) variant in POLG has been reported with an allele frequency in the population at 0.2 % in African Americans in gnomAD. It is also seen in the homozygous state in 1 individual in gnomAD (BS2). This variant is not reported in the literature and no computational data is available. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA241475/MONDO:0044970/014 2021-05-07 2021-05-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8207 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0000768 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0155365 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0022116 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0011175 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0878544 infores:hetionet GO:1901620 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:1901620 GO:0043009 CHEBI:2639 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C1167965 infores:hetionet CHEBI:92712 biolink:causes HP:0003487 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0034935 infores:hetionet CHEBI:3013 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0018939 infores:hetionet CHEBI:40279 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020625 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0004936 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0019825 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0518015 infores:hetionet CHEBI:4702 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0857305 infores:hetionet CAID:CA340928 biolink:causes MONDO:0044970 infores:clingen CAID:CA340928 MONDO:0044970 PMID: Pathogenic PP1_Moderate, PS3_Supporting, PM2_Supporting, PP3, PS4, PM6 PP4 The m.9185T>C (p.L220P) variant in MT-ATP6 has been reported in more than 16 individuals with features of primary mitochondrial disease with manifestations including Leigh syndrome, MELAS, NARP, neuropathy, ataxia, exercise intolerance, muscle weakness, developmental delay, and seizures (PS4; PMIDs: 28429146, 33717984, 27290639, 24153443, 27783406, 32042921, 31500933, 29116603, 31187502, 22577227, 25548692, 18461509, 17352390, 29228836, 16217706). There are at least two reports of de novo occurrences of this variant (PM6; PMIDs: 33717984, 29228836). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 16217706, 17352390,20546952). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (three occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). Studies in cybrids support the functional impact of this variant (PS3_supporting; PMID: 24153443). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.94 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PS3_supporting, PP1_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340928/MONDO:0044970/014 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA5416811 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416811 MONDO:0011225 PMID: Uncertain Significance BS2, BA1, PM2, BS1 The c.526A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Isoleucine by Valine at amino acid 176 (p.Ile176Val).The filtering allele frequency (the upper threshold of the 95% CI of 15/75028 alleles) of the c.526A>G variant in DCLRE1C is 0.0001227 for African/African American chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416811/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2549 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0024115 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0014130 infores:hetionet CHEBI:10101 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0152031 infores:hetionet CHEBI:47780 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0278106 infores:hetionet CHEBI:134991 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0026827 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0042075 infores:hetionet CHEBI:4702 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0023066 infores:hetionet NCBIGene:4137 biolink:causes MONDO:0008243 infores:monarchinitiative not_provided not_provided HGNC:6893 MONDO:0008243 uuid:6dbadffe-a829-416c-9705-552d62b3b24a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0038990 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0009806 infores:hetionet CAID:CA2802065 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802065 MONDO:0001586 PMID: Pathogenic PP3_Moderate, PP4_Moderate, PM2_Supporting, PM3_Very Strong PS3, PM5 The NM_000203.5: c.713T>A variant in IDUA is a missense variant predicted to cause substitution of Leu by Gln at amino acid 238 (p.Leu238Gln). This variant has been detected in at least 18 individuals with MPS I, the majority of whom had phenotypes consistent with a clinical diagnosis of Hurler-Scheie (PMID: 32188113, 31839529, 34984346, 26260077, 28125077, and others). All of those individuals were compound heterozygous for the variant and another variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases; it is unknown if these variants were confirmed in trans. For example, in compound heterozygous patients, the second variant is p.Gln70Ter (1 patient, 0.5 points, PMID: 31194252), p.Trp402Ter (2 patients, 2 x 0.5 points, PMID: 31194252), c.386-2A>G (1 patient 0.5 points, PMID: 31194252), p.Glu182Lys (1 patient, 0.5 points, PMID: 31194252), Int3-2a>g (1 patient, 0.5 points, PMID: 31839529) and 63del (one patient, 0.5 points, PMID: 31839529)Total 4 points (PM3_VeryStrong). One of these individuals was an adult male with clinical features consistent with MPS I including coarse facial features, joint stiffness, heart murmur, mitral and aortic stenosis, retinal degeneration and optic disc edema, and ventriculomegaly, elevated urine keratan sulfate and dermatan sulfate, undetectable serum IDUA activity (PMID: 34984346) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004 (3/74,858 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Another missense variant c.713T>C p.Leu238Pro in the same codon has been reported in the ClinVar database in association with MPS I (ClinVar Variation ID 1517837). However, this variant has not yet been evaluated by the ClinGen Lysosomal Diseases VCEP (PM5 not met). Expression of the variant in CHO cells showed 5.88% wild type IDUA activity (PMID: 15300847). However, this result does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP to apply PS3_Supporting criterion because the activity level was above the threshold of <2% established for this assay. The computational predictor REVEL gives a score of 0.904, which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 265418). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802065/MONDO:0001586/091 2024-12-06 2025-06-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:38940 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0152227 infores:hetionet NCBIGene:4668 biolink:causes MONDO:0012221 infores:monarchinitiative not_provided not_provided HGNC:7631 MONDO:0012221 uuid:39ba369c-043c-4a72-9f8a-7a7b48940d14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8337697 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337697 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PP4, PVS1 The c.428_467del; p.Gly143AlafsTer61 variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has also been reported once in a heterozygote patient with Very long chain acyl-coA dehydrogenase deficiency (VLCADD) (PP4, PMID:26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1+PM2_supporting, PP4). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337697/MONDO:0008723/021 2022-09-20 2022-09-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:92511 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0014591 infores:hetionet CHEBI:92607 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0085617 infores:hetionet NCBITaxon:1781 biolink:causes MONDO:0043314 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1781 MONDO:0043314 CHEBI:8768 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0005741 infores:hetionet CAID:CA13630270 biolink:causes MONDO:0009861 infores:clingen CAID:CA13630270 MONDO:0009861 PMID: Benign BA1, BP7 The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA13630270/MONDO:0009861/006 2019-11-08 2019-11-08 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA172224 biolink:causes MONDO:0019497 infores:clingen CAID:CA172224 MONDO:0019497 PMID:25288386PMID:15365987PMID:17041943PMID:17666888PMID:26969326 Likely Pathogenic BS1, PP3, PM3_Very Strong, PM5 BP7, BP5, BS4, BS3, PP2, PP4, PP1, BS2, PM4, PM1, PM2, PM6, PVS1, BA1, BP4, BP1, BP3, BP2, PS1, PS2, PS4, PS3 The c.34G>T (NM_004004.6) in GJB2 is a missense variant predicted to cause the substitution of glycine by cysteine at amino acid 12 (p.Gly12Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0036 (128/35104 alleles) in the Latino/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). This is a high enough frequency that, in absence of conflicting data, might warrant a likely benign classification based on the thresholds defined by the ClinGen Hearing Loss VCEP for autosomal recessive hearing loss variants. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. This variant has been detected in at least 10 patients with hearing loss. Of those individuals, at least 4 were compound heterozygous or the variant and a pathogenic or likely pathogenic variant was observed in trans and one proband was homozygous for the variant (c.35delG, p.V37I, p.Val198fs, p.Lys122Ile, PMID: 15365987, 17041943, 17666888, 25288386, 26969326, 31035178, SCV000061501.5) (PM3_Very Strong). A different pathogenic missense variant (p.Gly12Val) (ClinVar Variation ID 21387) in the same codon of GJB2 has been classified as likely pathogenic and pathogenic for hearing loss by 7 labs who are in concordance that this variant is LP/P (PM5). The computational predictor REVEL gives a score of 0.838, and the nucleotide is heavily conserved in UCSC, which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM3_Very Strong, PM5, PP3, BS1 (ClinGen Hearing Loss VCEP specifications version 2; 10/19/2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA172224/MONDO:0019497/005 2022-10-19 2023-02-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:8869 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0023218 infores:hetionet CHEBI:38545 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0231528 infores:hetionet CHEBI:6456 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0042510 infores:hetionet CHEBI:7565 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0043352 infores:hetionet CHEBI:50859 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0004604 infores:hetionet CHEBI:50742 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0086525 infores:hetionet CHEBI:7496 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0011603 infores:hetionet CHEBI:28241 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0011991 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0234215 infores:hetionet CHEBI:4975 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0026858 infores:hetionet CAID:CA16020800 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020800 MONDO:0009861 PMID:23225039PMID:26503515 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.494C>A (p.Ala165Asp) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26503515). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants p.R111X and p.R176X (PM3; PMID: 23225039). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020800/MONDO:0009861/006 2019-04-07 2019-04-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:74947 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0917798 infores:hetionet CHEBI:36791 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151786 infores:hetionet CHEBI:5441 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0013404 infores:hetionet UMLS:C0011701 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0030252 infores:hetionet CHEBI:45327 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0151740 infores:hetionet GO:0035157 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0035157 GO:0007275 CHEBI:6931 biolink:causes UMLS:C0221161 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0221161 infores:hetionet CAID:CA128033 biolink:causes MONDO:0100084 infores:clingen CAID:CA128033 MONDO:0100084 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PP4_Moderate, PP1_Moderate PS4 The c.1007A>C (NM_001100.4(ACTA1):c.1007A>C (p.Glu336Ala)) variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by alanine at amino acid 336 (p.Glu336Ala). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.874, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). At least one patient with this variant displayed cores and fiber type disproportion on muscle biopsy, which is highly specific for actin accumulation myopathy (PP4_Moderate, PMID: 15520409). This variant has been reported in 5 individuals from one family with muscle weakness (PP1_Moderate; PMID: 15520409). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP2, PP3, PP4_Moderate, PP1_Moderate (Congenital Myopathies VCEP Specifications Version 2.0; July 8, 2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA128033/MONDO:0100084/147 2024-07-08 2025-04-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36791 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149871 infores:hetionet CHEBI:50659 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0151723 infores:hetionet CHEBI:94411 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0013144 infores:hetionet CHEBI:9943 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013390 infores:hetionet CHEBI:9907 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0687713 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004260 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0030925 infores:hetionet CHEBI:7445 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0702166 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0162820 infores:hetionet CAID:CA10587778 biolink:causes MONDO:0005021 infores:clingen CAID:CA10587778 MONDO:0005021 PMID: Uncertain Significance PP1, PP3, PM2_Supporting, PS4_Moderate PS3, BA1, PM1, PM6, PM5, PM4, BP3, BS1, BS4, BS3, PS2, PS1, BP5, BP4, BP7, BP2, PVS1 The NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn) variant has been identified in cis with with another MYH7 variant (NM_000257.4:c.2863G>A (p.Asp955Asn)) in at least 5 individuals with DCM, two of whom also had LVNC and in isolation in 1 individual with DCM (PS4_Moderate: van den Berg 2010 PMID: 20952769, van Spaendonck-Zwarts 2013 PMID: 23349452, Invitae pers. comm., Ambry pers. comm.). The combination of MYH7 variants were also identified in 1 individual with LVNC (Hoedemaekers 2007 PMID: 17947214) and 1 individual with ARVC (Invitae pers. comm). Additionally, both MYH7 variants segregated with DCM in 3 affected relatives from 1 family (PP1: van den Berg 2010 PMID: 20952769) and with LVNC in 4 affected relatives from another family (Hoedemaekers 2007 PMID: 17947214). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. This variant was identified in 0.0003% (FAF 95% CI; 2/113730) of European chromosomes by gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes (Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Based on the majority of available evidence to date, this variant has been observed primarily in cis with MYH7 p.Asp955Asn and has rarely been reported in isolation; therefore, the clinical significance of the p.Asp545Asn variant alone is unclear. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM2_Supporting, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587778/MONDO:0005021/002 2022-07-31 2022-07-31 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10587803 biolink:causes MONDO:0007947 infores:clingen CAID:CA10587803 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1_Strong PP4, PM5 The NM_00138 c.6032G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2011 (p.Cys2011Tyr). This variant has been reported four times in ClinVar: once as pathogenic, twice as likely pathogenic, and once as uncertain significance (Variation ID: 263898). At least two probands with clinical features of Marfan syndrome carry the same variant (internal lab data, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other missense variants disrupting the Cysteine at this position, (i.e. p.Cys2011Arg and p.Cys2011Ser), have been reported in individuals with features of Marfan syndrome (PMID 29907982, 31163209). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.921, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PS4_Sup, PM2_Sup, PP2, PP3 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587803/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7476 biolink:causes MONDO:0024291 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0158570 infores:hetionet CHEBI:64355 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0043094 infores:hetionet CHEBI:4672 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0239571 infores:hetionet CHEBI:63622 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0232462 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002418 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0232431 infores:hetionet CHEBI:31348 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0235710 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006581 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0162423 infores:hetionet CAID:CA386959900 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959900 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1_Supporting, PP1_Strong, PS3_Supporting, PP3, PP4 The c.425C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 142 (p.(Ser142Phe)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This is supported by functional studies that demonstrated the p.Ser142Phe protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, PMID: 10585442). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 9 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 31968686, PMID 9097962, PMID: 23610083, PMID: 21224407, internal lab contributors). This variant segregated with diabetes, with 14 informative meioses in 5 families with MODY (PP1_Strong; PMID 31968686, PMID 9097962, internal lab contributors). This variant was identified in an individual with diabetes with a calculated MODY probability of <50%, however the presence of a moderate level of criteria (persistent C-peptide) allows the application of this criteria at a supporting level per the ClinGen MDEP's approval (PP4; PMID 31968686). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied (specification version 1.0, approved 8/24/21): PP1_Strong, PS4, PP3, PP4, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959900/MONDO:0015967/017 2021-08-24 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0879264 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0687713 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0262397 infores:hetionet CHEBI:127780 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0542571 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0242656 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0242656 infores:hetionet CHEBI:7954 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0004093 infores:hetionet CHEBI:31184 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0015230 infores:hetionet CHEBI:408174 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0015230 infores:hetionet CHEBI:94449 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0235309 infores:hetionet CHEBI:4562 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0151827 infores:hetionet CHEBI:205919 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0085641 infores:hetionet CHEBI:4858 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0015967 infores:hetionet CHEBI:135342 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042963 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0024115 infores:hetionet CHEBI:7465 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0018681 infores:hetionet CHEBI:75246 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0040822 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026848 infores:hetionet CHEBI:28864 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0018681 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0973461 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0021053 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014130 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0006142 infores:hetionet CAID:CA367401925 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401925 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM5, PP4_Moderate, PP2, PP3, PM2_Supporting The c.455T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 152 (p.(Phe152Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.981, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibody) (PP4_Moderate; PMID: 21978167). This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; PMID: 21978167, internal lab contributors]). Another missense variant, c.454T>C p.(Phe152Leu)​ has been interpreted as pathogenic by the ClinGen MDEP, and p.(Phe152Ser)​ has an equal or greater Grantham distance (PM5). In summary, c.455T>C meets the criteria to be classified as a variant of pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2, PM5, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401925/MONDO:0015967/086 2024-04-18 2024-04-18 Semidominant inheritance HP:0032113 Supports CHEBI:5138 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234458 infores:hetionet CHEBI:50131 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0232462 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0037199 infores:hetionet CHEBI:8871 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0920289 infores:hetionet CHEBI:7954 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C2363731 infores:hetionet CHEBI:6437 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085583 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0035455 infores:hetionet CHEBI:5118 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0025874 infores:hetionet CAID:CA410148798 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148798 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.983C>A (p.Thr328Lys) is a missense variant which has a REVEL score < 0.50 (0.099) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148798/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68554 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0018681 infores:hetionet CAID:CA340532 biolink:causes MONDO:0019497 infores:clingen CAID:CA340532 MONDO:0019497 PMID:10025409PMID:25116015PMID:10025409PMID:25116015PMID:18786918PMID:10025409PMID:10369879PMID:8035838PMID:10025409PMID:10369879PMID:8035838 Pathogenic PP1_Strong, PS3_Supporting, PM1, PM5, PS4_Supporting, PM2 BP5, BP7, BS4, BS1, BS2, PP4, PP3, PM3, PM4, PM6, PVS1, BP2, BP3, BP4, BA1, PS2, PS1 The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID: 10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6244, PMID: 10369879). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID: 23717403; https://www.uniprot.org/uniprot/P56696). A functional study demonstrates that this variant may impact protein function (PS3_P; PMID: 10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA340532/MONDO:0019497/005 2018-09-11 2019-07-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:15854 biolink:causes UMLS:C0155002 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0155002 infores:hetionet CHEBI:45863 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0003862 infores:hetionet CHEBI:5106 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0231218 infores:hetionet CHEBI:3723 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016927 infores:hetionet CHEBI:5383 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0002994 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0686377 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0686377 infores:hetionet CHEBI:8764 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011253 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0086543 infores:hetionet CHEBI:175901 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0019080 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0023067 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027726 infores:hetionet CHEBI:87681 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0232462 infores:hetionet NCBIGene:55851 biolink:causes MONDO:0013397 infores:monarchinitiative not_provided not_provided HGNC:30100 MONDO:0013397 uuid:b70b2dec-14d3-43a8-8290-864ca9b25d31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72690 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0018681 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1368065 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0033975 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0012797 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0041912 infores:hetionet CHEBI:45081 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0004093 infores:hetionet CHEBI:5784 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0026821 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002465 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006271 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0349506 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013395 infores:hetionet CAID:CA024799 biolink:causes MONDO:0007783 infores:clingen CAID:CA024799 MONDO:0007783 PMID:26115329PMID:27857962 Pathogenic PS3_Moderate, PS1, PS4_Moderate, PM1_Supporting, PP3_Moderate, PP1_Moderate BS1, BS3, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID: 21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024799/MONDO:0007783/012 2022-09-08 2022-09-08 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:31711 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0152227 infores:hetionet CHEBI:36791 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235660 infores:hetionet CHEBI:31184 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0011616 infores:hetionet GO:0002628 biolink:causes GO:0048002 infores:ubergraph knowledge_assertion manual_agent GO:0002628 GO:0048002 CHEBI:41423 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014742 infores:hetionet CHEBI:3219 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027497 infores:hetionet CHEBI:134991 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0231528 infores:hetionet CHEBI:4562 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0542571 infores:hetionet CHEBI:472657 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0023530 infores:hetionet CHEBI:80630 biolink:causes EFO:1001816 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0343387 infores:hetionet CHEBI:63621 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013456 infores:hetionet CHEBI:8888 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0009917 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0027813 infores:hetionet CAID:CA274104 biolink:causes MONDO:0009290 infores:clingen CAID:CA274104 MONDO:0009290 PMID:10377006PMID:20817528 Pathogenic PM2, PP4_Moderate, PVS1, PM3 This variant, c.172C>T (p.Gln58Ter), is a nonsense variant, predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The variant is not in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.525delT, confirmed in trans (PMID 10377006), and the other with c.841C>T (p.Arg281Trp), identified in a clinical diagnostic laboratory. This data meets PM3. Of note, pseudodeficiency variants are absent in the latter patient, allowing PP4_Moderate to be applied. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 20817528). There is a ClinVar entry for this variant (Variation ID: 188903, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274104/MONDO:0009290/010 2020-04-20 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8871 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0021775 infores:hetionet CHEBI:4495 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C1443060 infores:hetionet CAID:CA2695202184 biolink:causes MONDO:0100368 infores:clingen CAID:CA2695202184 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The NM_000329.3(RPE65):c.806_809delinsTGGAGCCATGAAG (p.Ser269MetfsTer4) variant is a frameshift variant that introduces a premature stop codon into exon 8 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including Severely decreased rod ERG (0.5 pt), previous exome, genome or 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pt), symptomatic onset between birth and age five years (1 pt), and evidence of cone involvement on ERG (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 33952291, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.1444G>A Asp482Asn variant confirmed in trans (PMID: 33952291). However, this case was not considered for this variant to avoid circularity in the use of the PM3 code. In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202184/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015403 infores:hetionet CHEBI:18332 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0003811 infores:hetionet NCBIGene:84274 biolink:causes MONDO:0033615 infores:monarchinitiative not_provided not_provided HGNC:28722 MONDO:0033615 uuid:f6bbbeb0-92f2-45df-a17a-e861dbe8ca14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4702 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0034063 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0948349 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0022658 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040435 infores:hetionet CHEBI:17650 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0040038 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0013295 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0009806 infores:hetionet CHEBI:7447 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0033774 infores:hetionet CHEBI:31625 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0235259 infores:hetionet CHEBI:8207 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0006277 infores:hetionet NCBIGene:9256 biolink:causes MONDO:0957542 infores:monarchinitiative not_provided not_provided HGNC:16831 MONDO:0957542 uuid:018ef96e-437e-455a-99b1-b79c37b382de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63581 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C2711227 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011053 infores:hetionet CHEBI:135276 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0018524 infores:hetionet CHEBI:17474 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0231528 infores:hetionet CHEBI:465284 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0043352 infores:hetionet CHEBI:31932 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0030252 infores:hetionet NCBIGene:64145 biolink:causes MONDO:0975795 infores:monarchinitiative not_provided not_provided HGNC:20759 MONDO:0975795 uuid:dbd264d0-9c33-4a84-9fa7-8aa1bdc90581 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085633 infores:hetionet CHEBI:31859 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0686347 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0281778 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0281778 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0948349 infores:hetionet CHEBI:48390 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0013404 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0018801 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0027339 infores:hetionet UMLS:C0657912 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0554976 infores:hetionet CHEBI:71940 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C2979982 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0240211 infores:hetionet CHEBI:82941 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0019080 infores:hetionet CHEBI:5109 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0151908 infores:hetionet CHEBI:6887 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0007820 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C1258215 infores:hetionet CHEBI:28241 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C1443060 infores:hetionet CHEBI:34967 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0232462 infores:hetionet CHEBI:681569 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0085649 infores:hetionet CHEBI:42944 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0085614 infores:hetionet CHEBI:49375 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0002962 infores:hetionet CHEBI:17698 biolink:causes UMLS:C1368107 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C1368107 infores:hetionet CHEBI:6541 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0015967 infores:hetionet CHEBI:8356 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042023 infores:hetionet CHEBI:3504 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0033687 infores:hetionet CHEBI:36795 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0014866 infores:hetionet CHEBI:2379 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0030196 infores:hetionet CHEBI:51141 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0022408 infores:hetionet CHEBI:4784 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0542571 infores:hetionet CHEBI:9123 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018520 infores:hetionet CHEBI:7476 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042023 infores:hetionet CHEBI:65173 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0011603 infores:hetionet CHEBI:75246 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0004604 infores:hetionet CHEBI:7824 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0030193 infores:hetionet NCBIGene:170692 biolink:causes MONDO:0014195 infores:monarchinitiative not_provided not_provided HGNC:17110 MONDO:0014195 uuid:e1bcf1b6-d79b-49cc-b3c8-c5865203ee2b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0237314 infores:hetionet CHEBI:6710 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0022081 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0040034 infores:hetionet CHEBI:50223 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0917801 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0948586 infores:hetionet CHEBI:50648 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020443 infores:hetionet CHEBI:9586 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0233471 infores:hetionet CHEBI:4784 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0033687 infores:hetionet CHEBI:6759 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0085593 infores:hetionet CHEBI:10101 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151578 infores:hetionet CHEBI:15640 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0022660 infores:hetionet GO:1902829 biolink:causes GO:0021510 infores:ubergraph knowledge_assertion manual_agent GO:1902829 GO:0021510 CHEBI:7577 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0002418 infores:hetionet CHEBI:72564 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C2242588 infores:hetionet CHEBI:5280 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1257843 infores:hetionet CHEBI:45081 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020461 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020517 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002622 infores:hetionet CHEBI:480999 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0002994 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0019158 infores:hetionet CHEBI:5864 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0035410 infores:hetionet CHEBI:42944 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0010692 infores:hetionet NCBIGene:1134 biolink:causes MONDO:0009668 infores:monarchinitiative not_provided not_provided HGNC:1955 MONDO:0009668 uuid:4b3addb5-1fb3-45c0-ad9f-9371127170cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0340865 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018991 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0004936 infores:hetionet CAID:CA000129 biolink:causes MONDO:0017623 infores:clingen CAID:CA000129 MONDO:0017623 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PVS1_Strong PM6, BS1, BS3, BS4, BP5, BP7, BS2, PP1, PP2, PP3, PP4, PM3, PM4, PM1, PM5, BA1, BP1, BP4, BP2, BP3, PS2, PS3, PS1 NM_000314.8(PTEN):c.165-1G>A meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1_Strong: in-frame but truncated/altered region is critical to protein function. PM2_P: Absent in large sequenced populations in the gnomAD cohort. (PMID 27535533).PS4_P: Probands with phenotype specificity score of 1-1.5. (PMID: 21659347). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000129/MONDO:0017623/003 2024-04-05 2024-04-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:408174 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0042029 infores:hetionet CHEBI:6935 biolink:causes MONDO:0004570 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0042961 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020651 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0021308 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0549433 infores:hetionet CHEBI:63629 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0025874 infores:hetionet CHEBI:8081 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0042963 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0006266 infores:hetionet CHEBI:4024 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0520966 infores:hetionet NCBIGene:85366 biolink:causes MONDO:0008647 infores:monarchinitiative not_provided not_provided HGNC:16243 MONDO:0008647 uuid:3bbd3ba6-d639-4da8-a450-7c335e5d7d10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017168 infores:hetionet CHEBI:3215 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0040264 infores:hetionet CHEBI:3561 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0002792 infores:hetionet CAID:CA16020941 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020941 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM3 PP3 The c.1105C>G (p.Leu369Val) variant in PAH has been reported in 2 individuals with mild HPA (BH4 deficiency excluded). (PP4_Moderate; PMID: 18299955). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants p.T380M and p.V230I (Parental analysis not reported, PM3). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020941/MONDO:0009861/006 2020-01-20 2021-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8890 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0025517 infores:hetionet CHEBI:7640 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0011603 infores:hetionet CHEBI:3814 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0015672 infores:hetionet CAID:CA6264537 biolink:causes MONDO:0700270 infores:clingen CAID:CA6264537 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PM5_Supporting, PVS1 The c.217_218del (p.Glu73Metfs*26) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMIDs 26677768; 26896183; 22649200; 10817650). This variant is absent from gnomAD v2.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA6264537/MONDO:0700270/020 2023-09-05 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7565 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0242429 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0919823 infores:hetionet CHEBI:42797 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0542571 infores:hetionet CHEBI:64321 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0017979 infores:hetionet CHEBI:9622 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0314719 infores:hetionet CAID:CA410202720 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202720 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS2, BP1, BP3, PM6, BS3, PP2, PP4 NM_001754.5(RUNX1):c.388G>C (p.Val130Leu) is a missense variant which has a REVEL score ≥ 0.88 (0.915) (PP3). This variant affects a residue within the Runt Homology Domain (AA 89-204) but does not affect an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202720/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:367163 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019158 infores:hetionet CHEBI:119915 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0038325 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0025061 infores:hetionet CHEBI:38562 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C3263723 infores:hetionet CHEBI:44185 biolink:causes MONDO:0018312 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0019655 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0409974 infores:hetionet CHEBI:6935 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0011991 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0018802 infores:hetionet CHEBI:52172 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0023380 infores:hetionet CHEBI:119915 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151786 infores:hetionet CHEBI:5613 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0011071 infores:hetionet CHEBI:73275 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0227791 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0022660 infores:hetionet CHEBI:45863 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0008031 infores:hetionet CHEBI:8888 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027540 infores:hetionet CHEBI:50777 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0006277 infores:hetionet CHEBI:51450 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042420 infores:hetionet CHEBI:45409 biolink:causes UMLS:C1167863 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C1167863 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0340464 infores:hetionet CHEBI:4672 biolink:causes MONDO:0043919 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0206063 infores:hetionet NCBIGene:374407 biolink:causes MONDO:0014909 infores:monarchinitiative not_provided not_provided HGNC:30718 MONDO:0014909 uuid:0b4f91e9-3c66-4cea-adcb-99a903233043 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0032584 infores:hetionet CHEBI:15551 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0085593 infores:hetionet CAID:CA001442 biolink:causes MONDO:0011450 infores:clingen CAID:CA001442 MONDO:0011450 PMID: Benign BP1_Strong, BS1, BP5_Strong The c.2155A>G variant in BRCA1 is a missense variant predicted to cause substitution of Lysine by Glutamic acid at amino acid 719 (p.Lys719Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0000515 (based on Family History LR= 0.0000515), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001442/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:2N4O9L084N biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0547030 infores:hetionet CHEBI:16586 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0231218 infores:hetionet CHEBI:79699 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0231528 infores:hetionet CHEBI:2618 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0231919 infores:hetionet CHEBI:36791 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151908 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004596 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0034072 infores:hetionet CHEBI:27834 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0042029 infores:hetionet CAID:CA035378 biolink:causes MONDO:0007750 infores:clingen CAID:CA035378 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PM2, PVS1, PP4 BA1, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP1, BS2 The NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is nonsense upstream of amino acid 830, so PVS1 is met.PM2 - PopMax MAF = 0.000008792 (0.0009%) in European Non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP4 - variant meets PM2.identified in: - 1 index case who fulfills SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge.- 1 index case who fulfills SB criteria from Marduel et al. 2010 (PMID: 20809525).so PP4 is met.PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases from different labs (please see PP4 for details), so PS4_Supporitng is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA035378/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:7986 biolink:causes UMLS:C0854062 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0854062 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1610069 infores:hetionet CHEBI:3216 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0035455 infores:hetionet CHEBI:4975 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0022107 infores:hetionet CHEBI:8382 biolink:causes HP:0100578 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C1280433 infores:hetionet CHEBI:5103 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0013144 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0020615 infores:hetionet CHEBI:188986 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042907 infores:hetionet UMLS:C0010592 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0000731 infores:hetionet CHEBI:6437 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0086769 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0553713 infores:hetionet CHEBI:136040 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0013378 infores:hetionet CHEBI:2663 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0575081 infores:hetionet CHEBI:63584 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0004093 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030312 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0542224 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0542224 infores:hetionet CAID:CA10014362 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014362 MONDO:0011071 PMID: Likely Benign BP4, BS3 PS4, PS3, PS2, PS1, BA1, BP1, BP2, BP3, BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 The c.749G>A variant in RUNX1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 250 (p.R250H). A luciferase reporter assaying in U937 cells showed that this variant has normal transcriptional activity, and an EMSA assay using COS7 cells showed that this variant has normal DNA-binding and β-subunit interaction with normal nuclear localization in NIH3T3 cells, indicating that this variant does not impact protein function (PMID: 23817177) (BS3). The computational predictor, REVEL, gives a score of 0.488, which is below the threshold of 0.50, evidence that suggests no impact on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS3 and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014362/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3756 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0016658 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0019348 infores:hetionet GO:1905651 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1905651 GO:0007275 CHEBI:144551 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0600260 infores:hetionet CHEBI:39112 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0002792 infores:hetionet CAID:CA410203832 biolink:causes MONDO:0100083 infores:clingen CAID:CA410203832 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.236T>A (p.Val79Glu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203832/MONDO:0100083/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9586 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0004604 infores:hetionet CHEBI:8081 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0027497 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0028738 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0011849 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0039971 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0014868 infores:hetionet CAID:CA496152715 biolink:causes MONDO:0007648 infores:clingen CAID:CA496152715 MONDO:0007648 PMID:19269290PMID:15235021 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP4, PP3, PP2, PP1, BS2, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2 The c.382delC (p.His128Ilefs*87) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 15235021). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA496152715/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:9445 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0037011 infores:hetionet CHEBI:63624 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0234233 infores:hetionet CHEBI:6809 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0242350 infores:hetionet CHEBI:17347 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0476273 infores:hetionet CHEBI:6067 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036973 infores:hetionet CAID:CA367401189 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401189 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PVS1, PP4, PM2_Supporting PM1 The c.660C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 220 (p.(Cys220Ter)) of NM_000162.5. This variant, located in exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 9790256). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in multiple families (PP1_Strong; internal lab contributors). This variant was identified in at least 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 21348868, 3347750, 31638168, 20337973, 12627330, 16602010, internal lab contributors. This variant was identified in at least 2 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.660C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401189/MONDO:0015967/086 2023-10-13 2023-10-13 Semidominant inheritance HP:0032113 Supports CHEBI:8327 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0009806 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0152025 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0162429 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013395 infores:hetionet CHEBI:41977 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0027540 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0948594 infores:hetionet CHEBI:6690 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0235660 infores:hetionet NCBIGene:29954 biolink:causes MONDO:0013162 infores:monarchinitiative not_provided not_provided HGNC:19743 MONDO:0013162 uuid:8213a550-01a3-4f98-98f7-f57b4fe66de9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0011570 infores:hetionet CHEBI:28971 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0014356 infores:hetionet CHEBI:84500 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0600142 infores:hetionet CHEBI:45863 biolink:causes HP:4000214 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0238844 infores:hetionet CHEBI:68610 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0241863 infores:hetionet CHEBI:135342 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0018681 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0341742 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0007137 infores:hetionet CHEBI:63617 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C2830004 infores:hetionet CHEBI:135888 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0017178 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0150450 infores:hetionet CHEBI:45863 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085661 infores:hetionet CHEBI:2687 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0019080 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0038454 infores:hetionet CHEBI:63616 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0013404 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0037274 infores:hetionet CHEBI:87681 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0018965 infores:hetionet CHEBI:10650 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235710 infores:hetionet CHEBI:63717 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0023787 infores:hetionet CHEBI:8707 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151878 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0039971 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0014742 infores:hetionet CHEBI:63619 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013298 infores:hetionet CHEBI:6904 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0007166 infores:hetionet CHEBI:180905 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0040822 infores:hetionet CAID:CA8815557 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815557 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting BS2 The NM_000152.5:c.1958C>A variant in GAA is a missense variant predicted to cause substitution of threonine by asparagine at amino acid 653 (p.Thr653Asn). At least three probands with Pompe disease have been reported with this variant (PMIDs 21232767, 24513544, clinical laboratory data), two with documented deficiency of GAA activity (PMID: 23884227, 25612604) (PP4_Moderate). One patient is compound heterozygous for (c.1958C>A p.Thr653Asn) and (c.752 C>T; 761 C>T, p.Ser251Leu; Ser254Leu, P/LP haplotype based on classification by the ClinGen Lysosomal Diseases VCEP); phase confirmed by parental testing (1 point, PMID: 21232767). Another patient was identified on newborn screen, currently asymptomatic, therefore data not included, compound heterozygous for the variant and c.424_440del17 (PMID: 24513544). Another patient is compound heterozygous for the variant and c.1551G>T. The allelic data from this patient may be used in the classification of c.1551 and is not include here to avoid circular logic (PMID: 29995633). Total 1 point (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002548 (5/19624 alleles) in the East Asian population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for meeting PM2_Supporting (PM2_Supporting). The computational predictor REVEL gives a score of 0.748 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 972798). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Expert panel on July 21, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815557/MONDO:0009290/010 2024-07-21 2024-12-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:35778 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0231218 infores:hetionet CHEBI:3207 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0152031 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0038367 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005301 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026769 infores:hetionet CHEBI:3640 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0740394 infores:hetionet CHEBI:63580 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151825 infores:hetionet CHEBI:50922 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013447 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0040034 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0151773 infores:hetionet CHEBI:6888 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0030554 infores:hetionet GO:2001212 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:2001212 GO:0001568 CHEBI:40237 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0006384 infores:hetionet CHEBI:8665 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0423153 infores:hetionet CHEBI:2611 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013362 infores:hetionet NCBIGene:5309 biolink:causes MONDO:0007138 infores:monarchinitiative not_provided not_provided HGNC:9006 MONDO:0007138 uuid:9bd0da92-ef03-4433-841e-6f9d291069ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:617099 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0020517 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0700184 infores:hetionet CHEBI:41977 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0039070 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233414 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0239385 infores:hetionet GO:0033599 biolink:causes GO:0061180 infores:ubergraph knowledge_assertion manual_agent GO:0033599 GO:0061180 CHEBI:2654 biolink:causes UMLS:C1258192 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C1258192 infores:hetionet CHEBI:70735 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0085614 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0541799 infores:hetionet CHEBI:116278 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0003811 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0853326 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0853326 infores:hetionet CHEBI:391960 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0344232 infores:hetionet CHEBI:7915 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0035455 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037199 infores:hetionet CHEBI:8874 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0014724 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0302295 infores:hetionet CAID:CA658683963 biolink:causes MONDO:0007648 infores:clingen CAID:CA658683963 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2144del (p.Gly715fs) variant is predicted to result in a premature stop codon at position 7 of the new reading frame that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683963/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:31236 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1510410 infores:hetionet CHEBI:8356 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0025874 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0020649 infores:hetionet CHEBI:48273 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0043352 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0948089 infores:hetionet CAID:CA412352481 biolink:causes MONDO:0100039 infores:clingen CAID:CA412352481 MONDO:0100039 PMID: Uncertain Significance PS3_Supporting, PP3 PM1, PM2, PS4 "The highest population minor allele frequency of the c.530A>G (p.Tyr177Cys) variant in CDKL5 in gnomAD v4.1 is 0.00002 in ""Remaining"" populations (does not meet PM2 criteria). The computational predictor REVEL gives a score of 0.872, which is above the threshold of 0.75, evidence that correlates with impact to CDKL5 function (PP3). In vitro kinase assays showed that this variant impacts protein function (PMID 27265524) (PS3_Supporting). The p.Tyr177Cys variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 27265524, 33436160). However, PS4 cannot be applied because PM2 does not apply (PS4_not met). In summary, the p.Tyr177Cys variant in CDKL5 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PP3, PS3_Supporting) (CDKL5 Specifications v.3.0; curation approved on 02/28/2025)." Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412352481/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3423 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151827 infores:hetionet CAID:CA10014635 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014635 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.61T>C (p.Cys21Arg) is a missense variant which has a REVEL score < 0.50 (0.31), and a SpliceAI score ≤ 0.20 (0.06) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014635/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7915 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014457 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011991 infores:hetionet CHEBI:253342 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1443060 infores:hetionet CHEBI:3061 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0015967 infores:hetionet CHEBI:7959 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0008372 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0595877 infores:hetionet CHEBI:8356 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151636 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0020538 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0860700 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0860700 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0259799 infores:hetionet CHEBI:63791 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002994 infores:hetionet CHEBI:45863 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1142520 infores:hetionet CHEBI:5001 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C3665347 infores:hetionet CHEBI:50742 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0015967 infores:hetionet CAID:CA1939819 biolink:causes MONDO:0100038 infores:clingen CAID:CA1939819 MONDO:0100038 PMID: Benign BA1, BP4 PS1, PS3, PS4, PS2, BS3, BS4, PM5, PM1, PM2, PM6, PP3, PP1, BP2 The NM_001040142.2(SCN2A):c.1399G>A variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 467 (p.Ala467Thr). The highest population minor allele frequency in gnomAD 4.1.0 is 0.01501% (9/59978 alleles) in the Admixed American population, which is higher than the ClinGen Epilepsy Sodium Channel VCEP threshold (>0.01%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.269, (which is below the threshold of 0.290), evidence that does not predict a damaging effect on SCN2A function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BP4, BA1. (Specification Version 2.0.0; 1/7/2025). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1939819/MONDO:0100038/068 2025-06-24 2025-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10119 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0424295 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0040046 infores:hetionet CHEBI:27974 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0011124 infores:hetionet CHEBI:8707 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0232462 infores:hetionet CHEBI:3738 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0030252 infores:hetionet CHEBI:31980 biolink:causes UMLS:C2939062 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C2939062 infores:hetionet CHEBI:8060 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0026837 infores:hetionet CHEBI:125354 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0030193 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009946 infores:hetionet CHEBI:4868 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0003467 infores:hetionet CHEBI:194135 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085682 infores:hetionet CHEBI:8081 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0232492 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0027813 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007222 infores:hetionet CHEBI:3638 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0018681 infores:hetionet CHEBI:4636 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0349506 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0013922 infores:hetionet CHEBI:4562 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0042514 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0020517 infores:hetionet CAID:CA10585504 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585504 MONDO:0007750 PMID: Likely Pathogenic PP1_Strong, PM5, PM2, PP3 BP1, BP4, BP2, BA1, PS1, PS4, PS3, PS2, BS4, BS1, BS3, BP5, PM1, PM3, PM6, BS2, PP2, PP4 The NM_000527.5(LDLR):c.1567G>T (p.Val523Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1).PP3: REVEL = 0.904.PM5: There is 1 missense variant in the same codon, NM_000527.5(LDLR):c.1567G>A (p.Val523Met), classified as Pathogenic by these guidelines.PP1_Strong: Variant segregates with FH phenotype in 7 informative meioses from 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585504/MONDO:0007750/013 2023-01-27 2024-10-07 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ GO:0060398 biolink:causes GO:0071378 infores:ubergraph knowledge_assertion manual_agent GO:0060398 GO:0071378 CHEBI:231594 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0041657 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0155713 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0155713 infores:hetionet CHEBI:63791 biolink:causes HP:0031846 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0015802 infores:hetionet CHEBI:175901 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0085605 infores:hetionet CHEBI:32184 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0162835 infores:hetionet CHEBI:18295 biolink:causes GO:0043117 infores:drugmechdb knowledge_assertion manual_agent MESH:D006632 GO:0043117 DB06691_MESH_D014581_1DB08799_MESH_D014581_1 CHEBI:6359 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0020625 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0235097 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235097 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0027651 infores:hetionet CHEBI:4887 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0011991 infores:hetionet CHEBI:4024 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0392676 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027051 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0024115 infores:hetionet CHEBI:7865 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C3665347 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0235431 infores:hetionet CHEBI:15407 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0011603 infores:hetionet CHEBI:64321 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0018965 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0032285 infores:hetionet CHEBI:9130 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0006266 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0919874 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0235431 infores:hetionet CHEBI:31236 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011206 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0037274 infores:hetionet CHEBI:63580 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0032617 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027339 infores:hetionet CHEBI:3723 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026858 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0521839 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0162287 infores:hetionet NCBIGene:5428 biolink:causes MONDO:0009783 infores:monarchinitiative not_provided not_provided HGNC:9179 MONDO:0009783 uuid:f17cf170-8f26-40c8-a5f4-b95556952959 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002871 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0151763 infores:hetionet CHEBI:2654 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0042963 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0742006 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0742006 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0029408 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0542224 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0542224 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0233414 infores:hetionet CHEBI:2950 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0231528 infores:hetionet CHEBI:75722 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0028084 infores:hetionet CHEBI:31397 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0019080 infores:hetionet CHEBI:8768 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0085593 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042571 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0001126 infores:hetionet CHEBI:42944 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042023 infores:hetionet NCBIGene:55612 biolink:causes MONDO:0008260 infores:monarchinitiative not_provided not_provided HGNC:15889 MONDO:0008260 uuid:59d20b2e-8777-4635-ad28-d1248f30c81e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0424605 infores:hetionet CAID:CA10549325 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549325 MONDO:0010305 PMID: Uncertain Significance BS1 PP3, BP4 The NM_005629.4:c.778-8C>G variant in SLC6A8 is an intronic variant affecting a nucleotide within the consensus splice site of intron 4. To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00047 (9/19012 alleles) in the South Asian population and 13 hemizygotes across all populations (BS1). SpliceAI predicts possible alteration of splicing (score 0.21), less than the cutoff for PP3 (≥0.5) but less than the cutoff for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 511341, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; two submitters: likely benign; one submitter: benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549325/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:32315 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085631 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0031350 infores:hetionet GO:1904653 biolink:causes GO:0060541 infores:ubergraph knowledge_assertion manual_agent GO:1904653 GO:0060541 CHEBI:3499 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0234215 infores:hetionet CHEBI:63638 biolink:causes HP:0000369 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0239234 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0151479 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0232492 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0178298 infores:hetionet CHEBI:8863 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0026827 infores:hetionet CAID:CA902307 biolink:causes MONDO:0100368 infores:clingen CAID:CA902307 MONDO:0100368 PMID: Pathogenic PVS1, PP1, PM2_Supporting PM3 The NM_000329.3(RPE65):c.1067dup (p.Asn356fs) variant is a frameshift in exon 10 of 14 that is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been observed in multiple probands in the compound heterozygous state with other variants (PMID: 26906952, PMID: 35129589), but has not been evaluated for the PM3 code. In one case, the variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 32032261, PP1). This variant is present in gnomAD v2.1.1 at a GrpMax Filtering allele frequency of 0.00007526 with 7 alleles / 35330 total alleles in the Latino / Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902307/MONDO:0100368/120 2024-01-31 2024-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8597 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0242350 infores:hetionet CHEBI:47898 biolink:causes MONDO:0018881 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0026985 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0021053 infores:hetionet CHEBI:6954 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0151786 infores:hetionet CHEBI:70735 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0042075 infores:hetionet CHEBI:75045 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0221201 infores:hetionet CHEBI:6761 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0023530 infores:hetionet CHEBI:39669 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0008031 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0750394 infores:hetionet CHEBI:5784 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0012833 infores:hetionet CHEBI:31859 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042963 infores:hetionet CHEBI:4710 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1320835 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0152025 infores:hetionet CHEBI:136040 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0013428 infores:hetionet CAID:CA2580650458 biolink:causes MONDO:0009276 infores:clingen CAID:CA2580650458 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PP4, PM3 The NM_000173.7(GP1BA):c.1601_1602delinsTGG frameshift variant in exon 2, of 2, results in an a premature stop codon that is not predicted to trigger NMD, instead truncating 6% of the protein (PVS1_moderate). This variant is absent from gnomADv4.1 (PM2_supporting). The patient is compound heterozygote with Gln196Ter, which is classified VUS by the PD EP (PM3_NotMet). One patient has been reported with this variant in a BSS cohort, however there was insufficient information on individual patients to meet PP4 (PMID: 24934643). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580650458/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:93635 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0012833 infores:hetionet CHEBI:7903 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0015672 infores:hetionet CHEBI:4885 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0019158 infores:hetionet CHEBI:70746 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0011991 infores:hetionet CHEBI:63607 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0027497 infores:hetionet CHEBI:31859 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0026826 infores:hetionet CHEBI:45409 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0917801 infores:hetionet CAID:CA023914 biolink:causes MONDO:0007783 infores:clingen CAID:CA023914 MONDO:0007783 PMID: Uncertain Significance PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with isoleucine at codon 3840 of the RYR1 protein, p.(Val3840Ile). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00040, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.648 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023914/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA400032606 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032606 MONDO:0100326 PMID:22116617 Uncertain Significance PM2_Supporting, BP4 PS3 The variant NM_000212.3(ITGB3):c.1818G>T is a missense variant causing a substitution of lysine for asparagine at amino acid position 606. The highest population minor allele frequency for this variant in gnomAD v 2.1.1 is 0.000008791 (1/113750 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (>0.00158) for PM2_Supporting. The computational predictor REVEL gives a score of REVEL gives a score of .202, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGB3 function. The variant was identified in relation to Neonatal alloimmune thrombocytopenia (PMID:22116617), and has not been associated with any individuals with Glanzmann thrombasthenia thus far in the scientific literature or in the GT database. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032606/MONDO:0100326/011 2023-02-02 2023-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:10125 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020456 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0035258 infores:hetionet CHEBI:83804 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0026827 infores:hetionet CHEBI:135736 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0034886 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0424605 infores:hetionet CHEBI:28939 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0012833 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0025061 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0011991 infores:hetionet CHEBI:478164 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0038220 infores:hetionet CHEBI:47898 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1321686 infores:hetionet CHEBI:63580 biolink:causes HP:0012231 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0154822 infores:hetionet CHEBI:64045 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0233494 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0039070 infores:hetionet CHEBI:171719 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0014742 infores:hetionet CHEBI:9667 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0017979 infores:hetionet CHEBI:6887 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013491 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042109 infores:hetionet CHEBI:8863 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0040136 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013922 infores:hetionet CHEBI:74947 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0338908 infores:hetionet CHEBI:3441 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0006384 infores:hetionet CHEBI:75998 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0028081 infores:hetionet GO:0008359 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0019953 CHEBI:63598 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235996 infores:hetionet CHEBI:53766 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0011603 infores:hetionet CHEBI:63619 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0005758 infores:hetionet CHEBI:7915 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009676 infores:hetionet CHEBI:2948 biolink:causes MONDO:0042487 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0851140 infores:hetionet CHEBI:63618 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0038325 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0426576 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0023895 infores:hetionet CHEBI:161680 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C1257843 infores:hetionet CHEBI:50841 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0011603 infores:hetionet CHEBI:41879 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0002994 infores:hetionet NCBIGene:26960 biolink:causes MONDO:0030930 infores:monarchinitiative not_provided not_provided HGNC:7648 MONDO:0030930 uuid:8f82e1c8-ac4e-43ad-ad37-3fa5b085686e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5779 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0917801 infores:hetionet CHEBI:49040 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0014742 infores:hetionet CHEBI:8774 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0232462 infores:hetionet CHEBI:2636 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0039240 infores:hetionet NCBIGene:3554 biolink:causes MONDO:0958177 infores:monarchinitiative not_provided not_provided HGNC:5993 MONDO:0958177 uuid:984048c6-fc76-44b0-85a1-315ecda04096 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085605 infores:hetionet CHEBI:7936 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011253 infores:hetionet CHEBI:161680 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0917801 infores:hetionet NCBIGene:10660 biolink:causes MONDO:0030539 infores:monarchinitiative not_provided not_provided HGNC:16960 MONDO:0030539 uuid:1b06856b-1f09-4f57-afc8-1275d83cc724 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0000729 infores:hetionet CHEBI:49662 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0034886 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0037199 infores:hetionet CHEBI:31705 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0236024 infores:hetionet CHEBI:6520 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0854467 infores:hetionet CAID:CA414445371 biolink:causes MONDO:0010604 infores:clingen CAID:CA414445371 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PP3, PP4_Moderate, PM6 PM1 The c.1010C>T (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by valine at amino acid 337 (p.Ala337Val). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant is reported in at least 4 unique probands with mild hemophilia B (PMID: 33760382; PMID: 29296726; PMID: 9450791), meeting phenotypic criteria for F9, including at least one patient with with assumed de novo occurrence (PMID: 9450791). The computational predictor REVEL gives a score of 0.727, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4 + PP4_Moderate + PM2_Supporting + PP3 + PM6. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414445371/MONDO:0010604/080 2024-04-26 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:63617 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0233632 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1096393 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1096393 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0041912 infores:hetionet CHEBI:171719 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0020598 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033687 infores:hetionet CAID:CA412370008 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370008 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PM1_Strong, PM5 PP3 NM_000330.4(RS1):c.669T>G (p.Cys223Trp) is a missense variant encoding the substitution of cysteine with tryptophan at amino acid 223. This missense variant affects a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). Another missense variant in the same codon, NM_000330.4(RS1):c.667T>C (p.Cys223Arg) (PMID: 30652005, PMID: 33460243, PMID: 10533068, PMID: 34645606, PMID: 16361673), has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (215) than the comparison variant (180), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function. However, the PM1_Strong code has been met, which is ineligible to be used in combination with the PP3 code at any strength, so the PP3_Moderate code was not met. The computational splicing predictor SpliceAI gives a delta score of 0.02 for splice gain, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, and PM5. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370008/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:3499 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0151872 infores:hetionet CHEBI:3478 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0007859 infores:hetionet CHEBI:3723 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041296 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0392162 infores:hetionet CHEBI:168396 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042024 infores:hetionet CAID:CA409107360 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107360 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4, PP1_Strong The c.692G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 231 (p.(Arg231Gln)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.896, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:12413008, PMID:12627330, internal lab contributors). This variant segregated with diabetes, with at least four informative meioses in two families (PP1_Strong; PMID:12413008, internal lab contributor). One individual has a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative autoantibodies, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). In summary, c.692G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107360/MONDO:0015967/085 2024-05-10 2024-05-10 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004690 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0011991 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0160390 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040034 infores:hetionet CAID:CA347984 biolink:causes MONDO:0100488 infores:clingen CAID:CA347984 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1585A>G (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Thr by Ala at amino acid 529 (p.Thr529Ala). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; PMID: 30287823, Ambry, Invitae). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA347984/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true UMLS:C0657912 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011053 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0948594 infores:hetionet NCBIGene:10060 biolink:causes MONDO:0013545 infores:monarchinitiative not_provided not_provided HGNC:60 MONDO:0013545 uuid:a06a6948-d6cc-4bc4-988f-93f399e60429 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0037036 infores:hetionet UNII:T58MSI464G biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0086565 infores:hetionet NCBIGene:254394 biolink:causes MONDO:0014520 infores:monarchinitiative not_provided not_provided HGNC:21484 MONDO:0014520 uuid:b4ebd8da-e004-4275-8b65-fe334397c5d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1904130 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:1904130 GO:0043009 NCBITaxon:168 biolink:causes MONDO:0006019 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:168 MONDO:0006019 CHEBI:567361 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0016204 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0549249 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0234192 infores:hetionet CHEBI:6339 biolink:causes HP:0030840 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0238656 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0231303 infores:hetionet CHEBI:9649 biolink:causes HP:0012101 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0428282 infores:hetionet CHEBI:2549 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0021368 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018991 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0236071 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004936 infores:hetionet CHEBI:31413 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0439857 infores:hetionet CHEBI:83531 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0547030 infores:hetionet CAID:CA1619838 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619838 MONDO:0800472 PMID: Likely Pathogenic PP3, PM2_Supporting, PM3, PP1_Moderate BP4, BA1, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4, PVS1 The c.1198C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Proline by Serine at amino acid 400 (p.Pro400Ser). The highest minor allele frequency of this variant was in the Remaining genetic ancestry group of gnomAD (v4.1.0) = 0.00004801 (3 alleles out of 62,486), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.674, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 19234632). 2 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 28384041, ANZRAG database [E. Souzeau pers. comm.]), which fulfilled PP1_Moderate. This variant has been identified in 3 individuals with a CYP1B1-related phenotype. 1 individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) and 2 individuals are homozygous for the variant (1 consanguineous and 1 non-consanguineous) (PMIDs: 28384041, 17718864, 19234632). Total proband points = 1.25, meeting PM3. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3, PP1_Moderate, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619838/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41879 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1510472 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0022658 infores:hetionet CHEBI:2549 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0022107 infores:hetionet CHEBI:6339 biolink:causes HP:0012532 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0150055 infores:hetionet CHEBI:135736 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042023 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0000833 infores:hetionet CHEBI:6801 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0027497 infores:hetionet CHEBI:6717 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0014518 infores:hetionet CHEBI:3219 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013182 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015256 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0005741 infores:hetionet CAID:CA9090854 biolink:causes MONDO:0021060 infores:clingen CAID:CA9090854 MONDO:0021060 PMID: Uncertain Significance PP3, PP2 PS1, PS2, PS3, PS4, PM5, PM4, PM1, BP7, BP5, BS4, BS3, BS1, PM6, PM2, PP1, BS2, BP3, BP2, BP4, BP1, BA1 The c.692G>A (p.Arg231His) variant in MAP2K2 has been identified in a patient with clinical features consistent with cardiomyopathy (PS4 not met; Invitae internal data, GTR Lab ID 500031; ClinVar SCV000776886.1). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg231His variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg231His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9090854/MONDO:0021060/004 2019-05-17 2019-06-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6375 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0006826 infores:hetionet CAID:CA026041 biolink:causes MONDO:0012933 infores:clingen CAID:CA026041 MONDO:0012933 PMID:33609447 Pathogenic PP3, PM2_Supporting, PS3, PP4_Strong The variant c.9227G>T in BRCA2 is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 3076 (p.Gly3076Val). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.398, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. SpliceAI predictor score of 0.01 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33609447) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3104.98 (based on Cosegregation LR=770.85; Pathology LR=1.89; Co-occurrence LR=1.08; Family History LR=1.98), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31853058, Internal lab contributors).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA026041/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:84500 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0014724 infores:hetionet CHEBI:5138 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C3263723 infores:hetionet CHEBI:48273 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0042510 infores:hetionet CHEBI:8346 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C1112525 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0017563 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1735601 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0426584 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0426584 infores:hetionet NCBIGene:4363 biolink:causes MONDO:0030058 infores:monarchinitiative not_provided not_provided HGNC:51 MONDO:0030058 uuid:6e766909-c43e-4299-85e5-85561123783b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1306341 infores:hetionet CHEBI:72690 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0015967 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0041912 infores:hetionet CHEBI:75722 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026826 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0037274 infores:hetionet NCBIGene:9907 biolink:causes MONDO:0013342 infores:monarchinitiative not_provided not_provided HGNC:22197 MONDO:0013342 uuid:e299ce4a-a3f1-462f-97db-78ab38939f57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000644 biolink:causes MONDO:0017623 infores:clingen CAID:CA000644 MONDO:0017623 PMID: Uncertain Significance PM2 PTEN c.-943C>T (NC_000010.10:g.89623283C>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000644/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51450 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0023890 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027765 infores:hetionet CHEBI:7476 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0004093 infores:hetionet CHEBI:43968 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0231218 infores:hetionet CHEBI:135920 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0043352 infores:hetionet CHEBI:6887 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011124 infores:hetionet CHEBI:44423 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0728899 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0041912 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042256 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0003862 infores:hetionet CHEBI:9150 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0033774 infores:hetionet UMLS:C0065374 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0546817 infores:hetionet CHEBI:9332 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0151579 infores:hetionet CHEBI:8665 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0020517 infores:hetionet CAID:CA167533 biolink:causes MONDO:0007648 infores:clingen CAID:CA167533 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM5, PM4, PM2, PM6, PVS1, PP4, PP1, PP2, PP3, BS2, BP1, BP4, BP3, PS2, PS4, PS3, PS1 The NM_004360.5(CDH1):c.2253C>T (p.Asn751=) variant has an allele frequency of 0.10006 (10%, 3546/35438 alleles, 185 homozygotes) in the Latino subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA167533/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6933 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0004936 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0037199 infores:hetionet GO:0150011 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:0150011 GO:0048666 CHEBI:8707 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0575090 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0497365 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0853018 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0853018 infores:hetionet CHEBI:3647 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0036974 infores:hetionet CHEBI:45783 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0038325 infores:hetionet CHEBI:2453 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0220870 infores:hetionet CHEBI:5106 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0003126 infores:hetionet CHEBI:63619 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0043144 infores:hetionet GO:0099044 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:0099044 GO:0016192 CHEBI:5001 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0018681 infores:hetionet CHEBI:6339 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0006277 infores:hetionet CHEBI:63632 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0333355 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0234215 infores:hetionet CHEBI:8356 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2173677 infores:hetionet CHEBI:5384 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0036974 infores:hetionet CHEBI:3723 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235710 infores:hetionet CHEBI:46557 biolink:causes HP:0011227 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0742906 infores:hetionet NCBIGene:5406 biolink:causes MONDO:0013700 infores:monarchinitiative not_provided not_provided HGNC:9155 MONDO:0013700 uuid:ca2ace12-33a9-4ba5-ba09-9be6b7bbc317 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:520 biolink:causes MONDO:0005077 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:520 MONDO:0005077 CAID:CA136152 biolink:causes MONDO:0021060 infores:clingen CAID:CA136152 MONDO:0021060 PMID: Uncertain Significance PP2 The c.3721A>G (p.Lys1241Glu) variant in SOS1 was present in 0.0017% (1/113488 CI 95%) of European alleles in gnomADv2.1.1 (BS1 not met; PMID: 29493581). It has been identified in healthy individuals without clinical features of a RASopathy, but this information does not meet the current criteria to apply BS2 (Ambry Genetics internal data). The variant is located in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Lys1241Glu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136152/MONDO:0021060/004 2020-07-23 2020-07-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:6137 biolink:causes MONDO:0032885 infores:monarchinitiative not_provided not_provided HGNC:10303 MONDO:0032885 uuid:ace018c7-7100-4528-9733-8857294ba653 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0015672 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0234215 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0023530 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027765 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027726 infores:hetionet CHEBI:134991 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0022408 infores:hetionet CHEBI:8435 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0013604 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0162429 infores:hetionet CHEBI:7798 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0006277 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0021053 infores:hetionet CAID:CA226372 biolink:causes MONDO:0100437 infores:clingen CAID:CA226372 MONDO:0100437 PMID: Likely Pathogenic PP1_Moderate, PS1_Moderate, PP3, PP4, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.1573-8A>G is a non-coding variant in intron 13 that is located outside the +/- 1,2 dinucleotide but is part of the same splice acceptor motif and has the same predicted impact on splice acceptor loss as another variant, NM_001034853.2(RPGR):c.1573-1G>A, that was previously classified as pathogenic by the X-linked IRD VCEP (PS1_Moderate). The splicing impact predictor SpliceAI gives delta scores of 0.81 for acceptor loss, 0.65 for acceptor gain, and 0.28 for donor loss, which are above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing (PP3). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 21857984, PMID: 9222238, PS4_Supporting). The proband phenotype included family history consistent with X-linked inheritance, including no male-to-male transmission (2 pts), first/second decade onset (1 pts), rod involvement relatively greater than cone involvement (1 pt), and myopia (0.5 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 9222238, PP4). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family. (PP1_Moderate; PMID: 9222238). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PS1_Moderate, PP3, PP4, PP1_Moderate, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226372/MONDO:0100437/106 2025-10-05 2025-10-05 X-linked inheritance HP:0001417 Supports CHEBI:4027 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0024141 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235922 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235922 infores:hetionet CHEBI:15367 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0043352 infores:hetionet CHEBI:2955 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0025323 infores:hetionet CHEBI:4710 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0236075 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020517 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0851302 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0851302 infores:hetionet CHEBI:63791 biolink:causes NCIT:C35306 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0262613 infores:hetionet CHEBI:3561 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0000731 infores:hetionet CHEBI:9674 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0156404 infores:hetionet CHEBI:4495 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020458 infores:hetionet NCBIGene:6392 biolink:causes MONDO:0030937 infores:monarchinitiative not_provided not_provided HGNC:10683 MONDO:0030937 uuid:dd9418a2-cbb1-4a6b-9904-52c53898753d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0025222 infores:hetionet CHEBI:3223 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0043352 infores:hetionet CHEBI:7915 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040822 infores:hetionet CHEBI:17688 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0028643 infores:hetionet NCBIGene:1674 biolink:causes MONDO:0008407 infores:monarchinitiative not_provided not_provided HGNC:2770 MONDO:0008407 uuid:39fd0836-6888-4969-8a30-2b2cae26be8e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0162429 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1096049 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1096049 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0005940 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0849835 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0849835 infores:hetionet CHEBI:6888 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0002994 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0002871 infores:hetionet CHEBI:42797 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0549249 infores:hetionet CHEBI:50131 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0004238 infores:hetionet CHEBI:27732 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0020437 infores:hetionet CAID:CA012685 biolink:causes MONDO:0005045 infores:clingen CAID:CA012685 MONDO:0005045 PMID:27247418 Likely Pathogenic PM2, PM1, PP1_Moderate, PS4_Supporting PM3, PM5, PM6, PP3, PS3, BA1, BS1, BS4, BS3, PS2, BP4, BP2, BP5 The c.2593A>G (p.Lys865Glu) variant in MYH7 has been identified in 4 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; GeneDx pers. comm., Invitae pers. comm.). This variant segregated with HCM in 5 affected relatives from 2 families (PP1_Moderate; GeneDx, pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1_Moderate; PM2; PM1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012685/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0017797 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0008031 infores:hetionet CHEBI:2704 biolink:causes MONDO:0008600 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0158328 infores:hetionet CHEBI:70746 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0019080 infores:hetionet CHEBI:10110 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C2830004 infores:hetionet CHEBI:8888 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235309 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0002871 infores:hetionet CHEBI:3011 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0025222 infores:hetionet CHEBI:27565 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0012833 infores:hetionet CAID:CA397316321 biolink:causes MONDO:0009276 infores:clingen CAID:CA397316321 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting, BP4 NM_000173.7(GP1BA):c.409C>T is a missense variant predicted to cause a substitution of arginine to cysteine at amino acid position 137 (p.Arg137Cys). After a comprehensive literature search, the variant has not reported in any individuals with Bernard-Soulier syndrome. The computational predictor REVEL gives a score of 0.108, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BA function and SpliceAI predicts no impact on splicing (delta scores 0.00) (BP4). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00001425 (based on 4/91088 alleles) in the South Asian population, which is below the <0.0001114 threshold for PM2_supporting. In summary, this variant meets the criteria to be classified as Variant of Uncertain significance, insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, PM2_supporting (PD VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397316321/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50777 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0023903 infores:hetionet CHEBI:135736 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0002390 infores:hetionet CHEBI:17688 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0232461 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0333516 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0333516 infores:hetionet CHEBI:135530 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0009676 infores:hetionet NCBIGene:23431 biolink:causes MONDO:0013401 infores:monarchinitiative not_provided not_provided HGNC:573 MONDO:0013401 uuid:2343941d-e7f5-49cd-893e-b4226c160f14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0392525 infores:hetionet CHEBI:8461 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0012569 infores:hetionet CHEBI:6062 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0007859 infores:hetionet CHEBI:119915 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013182 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0039971 infores:hetionet CHEBI:53691 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0030232 infores:hetionet CHEBI:17347 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0149745 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0239385 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0233632 infores:hetionet CHEBI:2950 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0015967 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0156308 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0156308 infores:hetionet CHEBI:119915 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0268000 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0039971 infores:hetionet CHEBI:47426 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0001339 infores:hetionet NCBIGene:29928 biolink:causes MONDO:0030017 infores:monarchinitiative not_provided not_provided HGNC:17317 MONDO:0030017 uuid:8a520669-6a1e-4187-8604-81607579a7ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020437 infores:hetionet CHEBI:8382 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0013491 infores:hetionet CHEBI:8764 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C3263723 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0345904 infores:hetionet CHEBI:7494 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0008031 infores:hetionet NCBIGene:6712 biolink:causes MONDO:0014159 infores:monarchinitiative not_provided not_provided HGNC:11276 MONDO:0014159 uuid:96cefb5f-fbfa-49d7-9a7d-fa17b391468f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681850 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0520887 infores:hetionet CHEBI:4710 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0011124 infores:hetionet CHEBI:135930 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027540 infores:hetionet CHEBI:47519 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0232461 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0021053 infores:hetionet NCBIGene:51082 biolink:causes MONDO:0013385 infores:monarchinitiative not_provided not_provided HGNC:20422 MONDO:0013385 uuid:b3ec9654-0a1e-404c-8896-4442e45adaba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009676 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0042510 infores:hetionet CHEBI:68584 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0267792 infores:hetionet CHEBI:3219 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0004604 infores:hetionet CHEBI:2038 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0497156 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0041912 infores:hetionet CHEBI:6129 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0423153 infores:hetionet CHEBI:45979 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0014394 infores:hetionet CHEBI:3286 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0232462 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0151763 infores:hetionet CHEBI:45081 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027796 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0424000 infores:hetionet NCBIGene:10046 biolink:causes MONDO:0010423 infores:monarchinitiative not_provided not_provided HGNC:2568 MONDO:0010423 uuid:047c2948-2ff9-44ba-9071-b5977e8202e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28148 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0001122 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042109 infores:hetionet CHEBI:4814 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0423791 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085584 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018799 infores:hetionet CHEBI:135925 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0013404 infores:hetionet CHEBI:6472 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0020517 infores:hetionet CHEBI:16755 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0036974 infores:hetionet CHEBI:6715 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0000768 infores:hetionet CHEBI:567361 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0220981 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0235032 infores:hetionet CHEBI:3387 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0234518 infores:hetionet CHEBI:3756 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235266 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0948089 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0034150 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0006266 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027441 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0006147 infores:hetionet CHEBI:127780 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085612 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0014549 infores:hetionet CHEBI:52172 biolink:causes HP:0032227 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0406484 infores:hetionet CHEBI:16586 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0040034 infores:hetionet CHEBI:31174 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0030353 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005073 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027960 infores:hetionet CHEBI:3716 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0014518 infores:hetionet CHEBI:10127 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C1320474 infores:hetionet CHEBI:77733 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0541782 infores:hetionet CHEBI:64318 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0013609 infores:hetionet CHEBI:63620 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151836 infores:hetionet CHEBI:127780 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0085614 infores:hetionet CHEBI:44915 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0033774 infores:hetionet CAID:CA404089744 biolink:causes MONDO:0007750 infores:clingen CAID:CA404089744 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PS4, PM5, PP3 The NM_000527.5(LDLR):c.1765G>T (p.Asp589Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.BP4 - REVEL = 0.447. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available.A) variant not on limits.B) does not create AG or GTVariant is not predicted to alter splicing Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404089744/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7476 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020443 infores:hetionet CHEBI:32293 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C1443060 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085593 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235025 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0014518 infores:hetionet CHEBI:64310 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0241057 infores:hetionet CHEBI:2704 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0024236 infores:hetionet CHEBI:6456 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0028643 infores:hetionet CHEBI:42797 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011168 infores:hetionet CHEBI:75722 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0162298 infores:hetionet CHEBI:9434 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0085593 infores:hetionet CHEBI:8890 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0002994 infores:hetionet CHEBI:3996 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0022346 infores:hetionet CHEBI:3647 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0022346 infores:hetionet CHEBI:6149 biolink:causes UMLS:C2939427 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C2939427 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0242350 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0241379 infores:hetionet CHEBI:6965 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0013384 infores:hetionet CHEBI:45285 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0041349 infores:hetionet CHEBI:3242 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0003578 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0031350 infores:hetionet CHEBI:47381 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018965 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0002871 infores:hetionet CHEBI:15544 biolink:causes MONDO:0006965 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0178703 infores:hetionet CHEBI:64312 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042790 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0021400 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151605 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0007137 infores:hetionet CHEBI:15551 biolink:causes HP:0100718 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0042143 infores:hetionet CHEBI:8768 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0206061 infores:hetionet CHEBI:75988 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0006266 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0162429 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0232492 infores:hetionet CHEBI:3219 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0018524 infores:hetionet CHEBI:8093 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0428977 infores:hetionet CHEBI:7820 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0030781 infores:hetionet CHEBI:32192 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0018926 infores:hetionet CHEBI:50378 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0033774 infores:hetionet CHEBI:2663 biolink:causes MONDO:0019056 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0027868 infores:hetionet CHEBI:5441 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020678 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0001517 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D004403 DB01165_MESH_D004403_1DB00415_MESH_D004403_1 CHEBI:66876 biolink:causes UMLS:C0269002 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0269002 infores:hetionet UMLS:C0010592 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C1761613 infores:hetionet CHEBI:8869 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0020438 infores:hetionet CHEBI:63632 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0030193 infores:hetionet CHEBI:4356 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0002994 infores:hetionet CHEBI:168396 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019270 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0030312 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0026848 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0004096 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0343863 infores:hetionet CHEBI:4784 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0002878 infores:hetionet CHEBI:408174 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020615 infores:hetionet CHEBI:17474 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0151671 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0853089 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0853089 infores:hetionet CHEBI:10650 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0033774 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0151539 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0036454 infores:hetionet CHEBI:68606 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0438717 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0008325 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0574067 infores:hetionet CHEBI:73275 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB04938 UMLS:C0236075 infores:hetionet NCBIGene:3931 biolink:causes MONDO:0009515 infores:monarchinitiative not_provided not_provided HGNC:6522 MONDO:0009515 uuid:14418cca-940c-495f-be22-1b37809d1deb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45599 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0010520 infores:hetionet CHEBI:474180 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C2939147 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0853908 infores:hetionet CHEBI:6775 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085605 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0858307 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0858307 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085584 infores:hetionet CHEBI:39585 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0018834 infores:hetionet CHEBI:75722 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0231218 infores:hetionet CHEBI:2687 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0344232 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0948586 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0150450 infores:hetionet CHEBI:9123 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0035455 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0521498 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0521498 infores:hetionet GO:0099041 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:0099041 GO:0010256 CAID:CA386954172 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954172 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.259A>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 87 (p.(Lys87Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors), and PP4 cannot be applied. In summary, c.259A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954172/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:367163 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0242350 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0027765 infores:hetionet CHEBI:6062 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C2129214 infores:hetionet CAID:CA16020854 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020854 MONDO:0009861 PMID:29316886PMID:21307867 Likely Pathogenic PM3, PM5, PP4_Moderate, PM2, PP3 The c.755G>C (p.Arg252Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded, PMID: 21307867). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. Other missense variants at the p.Arg252 amino acid are pathogenic (p.Arg252Gln/Trp/Gly). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020854/MONDO:0009861/006 2020-03-15 2020-03-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10125 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002886 infores:hetionet CHEBI:8346 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0036830 infores:hetionet CHEBI:18248 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0002962 infores:hetionet CHEBI:6437 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0917801 infores:hetionet CHEBI:4562 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0404521 infores:hetionet CHEBI:3568 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030232 infores:hetionet CHEBI:8107 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0039231 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0015230 infores:hetionet CAID:CA367400485 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400485 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4 The c.821A>G variant in the glucokinase gene, GCK, is a missense variant resulting in an amino acid change of aspartic acid to glycine at codon 274 (p.(Asp274Gly)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 36178555, internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with hyperglycemia with two informative meioses in two families (PP1; internal lab contributors. Another missense variant, c.821A>C p.(Asp274Ala), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Asp274Gly) (PM5_Supporting). In summary, c.821A>G variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PM5_Supporting, PP1, PP2, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400485/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:4702 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0233472 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0031350 infores:hetionet CHEBI:77733 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0004245 infores:hetionet NCBIGene:113179 biolink:causes MONDO:0014119 infores:monarchinitiative not_provided not_provided HGNC:25151 MONDO:0014119 uuid:cde0cbe5-fcfd-4902-ac43-a6cb9789265f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0030252 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0020649 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0549209 infores:hetionet CHEBI:3723 biolink:causes HP:0041220 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0159321 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0009450 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031085 infores:hetionet CHEBI:74947 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0015967 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0018802 infores:hetionet CHEBI:127342 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042420 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0002418 infores:hetionet CHEBI:2453 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0001807 infores:hetionet CHEBI:63589 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0003467 infores:hetionet CHEBI:28901 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0010828 infores:hetionet CAID:CA243279 biolink:causes MONDO:0021060 infores:clingen CAID:CA243279 MONDO:0021060 PMID: Uncertain Significance BP5, PM6, PP2 PM2, PP3 The c.244A>G (p.Met82Val) variant in PTPN11 was present in 0.006152% (1/16256) of African alleles in gnomAD (gnomad.broadinstitute.org). It was identified as a de novo occurrence in 1 proband (PM6; PMID: 30577886). It was also observed in a proband with features of Noonan syndrome with an alternate molecular mechanism of disease (BP5; GeneDx internal data, SCV000057386.12). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Met82Val variant in PTPN11 is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PP2, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA243279/MONDO:0021060/004 2020-05-28 2020-07-01 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true UMLS:C0879264 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0036572 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0003123 infores:hetionet NCBIGene:2218 biolink:causes MONDO:0009678 infores:monarchinitiative not_provided not_provided HGNC:3622 MONDO:0009678 uuid:590222e3-2949-44fb-a843-caf497a237b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027947 infores:hetionet CHEBI:27899 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020458 infores:hetionet CAID:CA024976 biolink:causes MONDO:0007783 infores:clingen CAID:CA024976 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PS4_Moderate, PP3_Moderate, PP1_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 3104 of the RYR1 protein, p.(Arg3104Lys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 30236257). This variant segregates with MHS in five individuals, PP1_Moderate (PMID: 28403410). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.869) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024976/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:41423 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0034065 infores:hetionet CHEBI:5134 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0344232 infores:hetionet CHEBI:10119 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085614 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042373 infores:hetionet CHEBI:474180 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0917801 infores:hetionet CHEBI:45081 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0917801 infores:hetionet CHEBI:7565 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0032343 infores:hetionet CHEBI:6541 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0232462 infores:hetionet CHEBI:3698 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0850149 infores:hetionet CAID:CA16621203 biolink:causes MONDO:0010278 infores:clingen CAID:CA16621203 MONDO:0010278 PMID: Benign BS2, BP4, BS1 The allele frequency of the c.-5del variant in SLC9A6 (NM_006359.2) is 0.02% in European (non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.-5del variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In sumarry, the c.-5del variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621203/MONDO:0010278/033 2024-02-23 2024-03-31 X-linked inheritance HP:0001417 Contradicts true CHEBI:63580 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0032584 infores:hetionet CHEBI:2663 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0233407 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1306341 infores:hetionet CAID:CA320642585 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642585 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.351+14G>A is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score of 0.00 (≤ 0.20), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 0.53 ≤ 2.0), supporting BP7. Multiple lines of computational evidence suggest no impact on the gene or gene product, with a SpliceAI score of 0.00, supporting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642585/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9137 biolink:causes MONDO:0006846 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020540 infores:hetionet CHEBI:93305 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0005758 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0018801 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0021899 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0021899 infores:hetionet CAID:CA248628 biolink:causes MONDO:0011071 infores:clingen CAID:CA248628 MONDO:0011071 PMID:27112265PMID:19357396PMID:27112265PMID:19357396PMID:27112265PMID:19357396 Likely Pathogenic PM1_Supporting, PP1_Strong, PS4_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP7, BP5, BS3, BS1, BS4, PVS1, PM5, PM4, PM3, PP2, PP4, BS2 The NM_001754.4:c.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 19357396, 27112265). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_Strong, PM2_supporting, PP3, PM1_Supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248628/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:29967 biolink:causes MONDO:0957538 infores:monarchinitiative not_provided not_provided HGNC:31708 MONDO:0957538 uuid:730c53e9-1eb8-4617-89d7-df2e15ff81c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015469 infores:hetionet CHEBI:17688 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0278134 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030578 infores:hetionet CAID:CA2580610965 biolink:causes MONDO:0010305 infores:clingen CAID:CA2580610965 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 The NM_005629.4:c.1556_1557insTTTC (p.Met519IfsTer41) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in exon 12/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in one male proband with elevated urine creatine/creatinine (PMID: 23660394) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP: August 10, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610965/MONDO:0010305/027 2023-08-10 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:8888 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232849 infores:hetionet CHEBI:6129 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151836 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0003123 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0042109 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0241705 infores:hetionet CHEBI:4672 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151825 infores:hetionet NCBIGene:10641 biolink:causes MONDO:0014924 infores:monarchinitiative not_provided not_provided HGNC:24969 MONDO:0014924 uuid:fd4da905-af47-4a9e-8cda-9aea9be72cc0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44032 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020517 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0877440 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0877440 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0878544 infores:hetionet CHEBI:47898 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042023 infores:hetionet CHEBI:49668 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0004238 infores:hetionet CHEBI:8378 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0040046 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0027651 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0037199 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0005940 infores:hetionet CHEBI:135961 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0013428 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0024115 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0040034 infores:hetionet CHEBI:7581 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0424295 infores:hetionet CHEBI:10119 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020458 infores:hetionet CAID:CA1705983 biolink:causes MONDO:0015152 infores:clingen CAID:CA1705983 MONDO:0015152 PMID: Likely Benign BS1 BP4 The NM_003494.4: c.1877T>C variant in DYSF, which is also known as NM_001130987.2: c.1931T>C p.(Met644Thr), is a missense variant predicted to cause substitution of methionine by threonine at amino acid 626 (p.Met626Thr). The filtering allele frequency of the variant is 0.002276 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 323/251362), which is higher than the VCEP threshold of 0.001 (BS1). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.12, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BS1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1705983/MONDO:0015152/180 2025-01-08 2025-02-07 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA168677 biolink:causes MONDO:0100488 infores:clingen CAID:CA168677 MONDO:0100488 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM1, PM3, PM4, PP2, PP3, PP4, PP1, BP2, BP1, BP4, BP3, BA1, PS1, PS3, PS2, PS4 The NM_004360.5(CDH1):c.394G>A (p.Val132Ile) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA168677/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63717 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0019163 infores:hetionet CHEBI:28915 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0025345 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0021053 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0087169 infores:hetionet CHEBI:3286 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0011253 infores:hetionet CHEBI:7494 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0010692 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0332575 infores:hetionet CHEBI:31413 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0033774 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0005940 infores:hetionet CHEBI:4877 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0151766 infores:hetionet CHEBI:7820 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0027540 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0149931 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0004936 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0494559 infores:hetionet CHEBI:6888 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0917801 infores:hetionet GO:0021522 biolink:causes CL:0011001 infores:ubergraph knowledge_assertion manual_agent GO:0021522 CL:0011001 CHEBI:49662 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0242528 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037199 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0740411 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0740411 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0003123 infores:hetionet CHEBI:49668 biolink:causes EFO:0801084 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0596240 infores:hetionet CHEBI:31859 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0043094 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027765 infores:hetionet CHEBI:46295 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0026837 infores:hetionet CHEBI:6076 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0002170 infores:hetionet CHEBI:9907 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042023 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0234458 infores:hetionet CHEBI:91541 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0428977 infores:hetionet CHEBI:3738 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C2830004 infores:hetionet CHEBI:50859 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0231218 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0008035 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0008035 infores:hetionet CAID:CA410202584 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202584 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.451A>T (p.Met151Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202584/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7915 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0039971 infores:hetionet CHEBI:7823 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0013362 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0162429 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0020649 infores:hetionet CHEBI:94449 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0020620 infores:hetionet CHEBI:6931 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0013384 infores:hetionet CHEBI:168396 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0030196 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0235431 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0034150 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027726 infores:hetionet CHEBI:6950 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0006277 infores:hetionet NCBIGene:90522 biolink:causes MONDO:0030878 infores:monarchinitiative not_provided not_provided HGNC:30511 MONDO:0030878 uuid:267b19e5-33fb-43f8-8559-1b581575762a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:33325 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0546817 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0040034 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0002170 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0000833 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0700594 infores:hetionet CHEBI:8871 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023218 infores:hetionet CHEBI:28364 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0011603 infores:hetionet CHEBI:132233 biolink:causes MONDO:0007661 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0040517 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0750016 infores:hetionet CHEBI:44423 biolink:causes HP:0040303 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0235988 infores:hetionet CAID:CA410203853 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203853 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP2, BP3, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM5, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.227G>C (p.Arg76Pro) is a missense variant. This variant is completely absent from all population databases with 30x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). The REVEL score is ≥ 0.88 (0.906) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203853/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135939 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0009782 infores:hetionet CHEBI:48669 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C1145670 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0037274 infores:hetionet CHEBI:135566 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0423153 infores:hetionet NCBIGene:79977 biolink:causes MONDO:0012083 infores:monarchinitiative not_provided not_provided HGNC:2799 MONDO:0012083 uuid:23efaedc-242f-4bdf-9bf5-d380bdda6cbc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000032 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000032 GO:0007275 CHEBI:36791 biolink:causes UMLS:C1611174 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1611174 infores:hetionet CHEBI:3219 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0085633 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0017152 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0424444 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0424444 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0340464 infores:hetionet CHEBI:3761 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0744727 infores:hetionet CHEBI:80630 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0042963 infores:hetionet CHEBI:66903 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0037274 infores:hetionet CHEBI:5109 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0151505 infores:hetionet CHEBI:8356 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006625 infores:hetionet GO:0030221 biolink:causes CL:0000767 infores:ubergraph knowledge_assertion manual_agent GO:0030221 CL:0000767 CHEBI:3181 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0233763 infores:hetionet CHEBI:52172 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0162834 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0035455 infores:hetionet CHEBI:17650 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0340865 infores:hetionet CHEBI:134745 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0018681 infores:hetionet CAID:CA200046 biolink:causes MONDO:0015152 infores:clingen CAID:CA200046 MONDO:0015152 PMID: Uncertain Significance PP3, PM2_Supporting BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PM6, PVS1, BS2, PP2, PP1, PP4 The NM_000337.6: c.91C>G variant in SGCD is a missense variant predicted to cause substitution of arginine by glycine at amino acid 31 (p.Arg31Gly). This variant is absent from gnomAD v2.1.1 and v4.1.0 genomes (note that the variant fails filter in exome data, suggesting it may be a sequencing artifact) (PM2_Supporting). The computational predictor REVEL gives a score of 0.85, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCD function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA200046/MONDO:0015152/186 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28748 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0037036 infores:hetionet CHEBI:18248 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0014724 infores:hetionet CHEBI:7915 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0162830 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0039231 infores:hetionet CHEBI:75246 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0015672 infores:hetionet CHEBI:7492 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0018681 infores:hetionet CHEBI:291342 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0015672 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0948586 infores:hetionet CHEBI:50922 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0006277 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162830 infores:hetionet CHEBI:6367 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C3495920 infores:hetionet NCBIGene:132001 biolink:causes MONDO:0859323 infores:monarchinitiative not_provided not_provided HGNC:25187 MONDO:0859323 uuid:d6e12182-e40f-4511-9fe2-2f9870dca297 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0858635 infores:hetionet CHEBI:7936 biolink:causes HP:0011273 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0221278 infores:hetionet CHEBI:100241 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018524 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031350 infores:hetionet CHEBI:59750 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0011616 infores:hetionet NCBIGene:208 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:392 MONDO:0005148 uuid:533ebf3d-fcdb-4f55-9424-706e2dd448a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:29978 biolink:causes MONDO:0010459 infores:monarchinitiative not_provided not_provided HGNC:12509 MONDO:0010459 uuid:b57a9992-daa0-445b-93e2-88745fac4c88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6240 biolink:causes MONDO:0957993 infores:monarchinitiative not_provided not_provided HGNC:10451 MONDO:0957993 uuid:5e92111d-06dd-4bdb-91d8-9dfc5450c415 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7627 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0021359 infores:hetionet CHEBI:127342 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0039591 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0232492 infores:hetionet CHEBI:7956 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0016204 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C1368065 infores:hetionet CHEBI:15553 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0018681 infores:hetionet CL:0008019 biolink:causes MONDO:0002616 infores:ubergraph knowledge_assertion manual_agent CL:0008019 MONDO:0002616 CHEBI:3568 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0522224 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0042109 infores:hetionet CHEBI:6520 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C0235896 infores:hetionet CHEBI:63598 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038325 infores:hetionet CHEBI:17347 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0424295 infores:hetionet GO:0044082 biolink:causes GO:0007264 infores:ubergraph knowledge_assertion manual_agent GO:0044082 GO:0007264 CHEBI:52172 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0004093 infores:hetionet CHEBI:3228 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0009806 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015230 infores:hetionet CHEBI:91834 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0030554 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0014130 infores:hetionet CAID:CA512318734 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318734 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.430C>T (p.Leu144=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318734/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7478 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0003862 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0234458 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013595 infores:hetionet CHEBI:15940 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0041657 infores:hetionet CHEBI:6129 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0424295 infores:hetionet CHEBI:101853 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0041657 infores:hetionet CHEBI:63607 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0404521 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0026946 infores:hetionet CHEBI:35778 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0042024 infores:hetionet CHEBI:2569 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0030193 infores:hetionet CHEBI:3175 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0012833 infores:hetionet GO:0140885 biolink:causes GO:0045087 infores:ubergraph knowledge_assertion manual_agent GO:0140885 GO:0045087 CHEBI:3647 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0035309 infores:hetionet CHEBI:84883 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0015230 infores:hetionet CHEBI:49040 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0033774 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0006849 infores:hetionet NCBIGene:6853 biolink:causes MONDO:0010251 infores:monarchinitiative not_provided not_provided HGNC:11494 MONDO:0010251 uuid:10bc40b5-5f01-477c-9918-7e03a0be5657 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0032290 infores:hetionet CHEBI:2666 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0015672 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0009144 infores:hetionet CHEBI:6797 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0022346 infores:hetionet CHEBI:5790 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0032617 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0853193 infores:hetionet CHEBI:28787 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0085624 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0549453 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0549453 infores:hetionet CHEBI:82716 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0020461 infores:hetionet CHEBI:6822 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0017979 infores:hetionet CHEBI:9130 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0043352 infores:hetionet CHEBI:205919 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0030193 infores:hetionet NCBIGene:3859 biolink:causes MONDO:0020791 infores:monarchinitiative not_provided not_provided HGNC:6414 MONDO:0020791 uuid:faf4b574-b51d-494d-83fc-919ce32956da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA024847 biolink:causes MONDO:0018493 infores:clingen CAID:CA024847 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glycine at codon 2591 of the RYR1 protein, p.(Arg2591Gly). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00004, a frequency consistent with pathogenicity for MHS. To our knowledge, this variant has not been reported in any individuals with a clear personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16835904, unclear MH history). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.642 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024847/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:5778 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C1318520 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0919980 infores:hetionet CHEBI:6538 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0020649 infores:hetionet CHEBI:51860 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011603 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0242350 infores:hetionet CHEBI:6888 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C2047937 infores:hetionet CHEBI:4995 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0702166 infores:hetionet GO:0061294 biolink:causes GO:0061243 infores:ubergraph knowledge_assertion manual_agent GO:0061294 GO:0061243 CHEBI:27436 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0005778 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0475858 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0151614 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0151614 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0042373 infores:hetionet CHEBI:3508 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0024282 infores:hetionet CHEBI:6078 biolink:causes HP:0032061 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0745091 infores:hetionet CHEBI:8356 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0002962 infores:hetionet CHEBI:2611 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0019158 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151849 infores:hetionet CHEBI:17650 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0003811 infores:hetionet CHEBI:18385 biolink:causes UMLS:C0344329 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0344329 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0042514 infores:hetionet CHEBI:3757 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0039231 infores:hetionet GO:0032954 biolink:causes GO:0000910 infores:ubergraph knowledge_assertion manual_agent GO:0032954 GO:0000910 CHEBI:4466 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085614 infores:hetionet CHEBI:68478 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0235896 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0948089 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0023533 infores:hetionet CHEBI:681569 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0011603 infores:hetionet CHEBI:91834 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0278134 infores:hetionet CHEBI:84500 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0001807 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0006145 infores:hetionet CHEBI:46557 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0011175 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0041912 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235146 infores:hetionet NCBIGene:5727 biolink:causes MONDO:0011556 infores:monarchinitiative not_provided not_provided HGNC:9585 MONDO:0011556 uuid:72fea269-9699-4d3c-b7a1-1b638f965a73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229626 biolink:causes MONDO:0009861 infores:clingen CAID:CA229626 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting, PS3_Supporting PM5 The c.561G>C (p.Trp187Cys) variant in PAH has been reported in a Japanese PKU patient (BH4 deficiency ruled out, genotype not reported; 21307867), and 2 Brazilian siblings with PKU (PMID: 30829006). It was detected with the pathogenic variant p.Val388Met in the siblings. PAH activity for this variant was 1% compared to wild type in a COS cell expression system (PMID: 9860305). This variant is absent in population databases, and predicted deleterious in multiple lines of computational evidence. In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PS3_supporting, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229626/MONDO:0009861/006 2021-10-31 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6367 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0947912 infores:hetionet UMLS:C0120107 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0043352 infores:hetionet CHEBI:2668 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0917801 infores:hetionet CHEBI:3082 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0022281 infores:hetionet CAID:CA269832799 biolink:causes MONDO:0015152 infores:clingen CAID:CA269832799 MONDO:0015152 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong PM5, PVS1 The NM_000070.3: c.363C>G variant in CAPN3 is a missense variant predicted to cause substitution of isoleucine by methionine at amino acid 121 (p.Ile121Met). This variant has been detected in at least five individuals with LGMD (PMID: 230564623; LOVD CAPN3_000401; ClinVar SCV003459936.1 internal data communication). In at least three of these patients, the variant was identified in unknown phase with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 1.0 pt; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts), and in one patient it was confirmed in trans with a pathogenic variant (c.146G>A (p.Arg49His), 1.0 pt) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 230564623; LOVD Individual #00213632) (PP4). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00002412 (1/41464 African/African American genome alleles), which is lower than the LGMD VECP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.89, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Strong, PP4, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA269832799/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0209366 biolink:causes UMLS:C0521305 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0521305 infores:hetionet CAID:CA2387254395 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387254395 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM5, PM4, PM1, PM3, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1230_1235dup (p.Ala411_Gly412dup) is an in-frame duplication of two amino acids, which does not involve any critical residues within the runt homology domain (PM4 not met). This variant is absent from gnomAD v2, v3, and v4 (PM2_supporting). It has not been reported in any patients. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387254395/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3723 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2830004 infores:hetionet CHEBI:9649 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C1443060 infores:hetionet CHEBI:135930 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0002390 infores:hetionet CHEBI:48273 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0002792 infores:hetionet CHEBI:6128 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0013144 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010279 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010279 uuid:74f508ed-105e-4af0-871e-5f3490b302b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0013182 infores:hetionet NCBIGene:2879 biolink:causes MONDO:0009593 infores:monarchinitiative not_provided not_provided HGNC:4556 MONDO:0009593 uuid:b9f86542-7c7d-4c14-8cb1-5bc48304f10c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0948089 infores:hetionet CHEBI:2675 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0040822 infores:hetionet CHEBI:32315 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085641 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0857980 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0857980 infores:hetionet NCBIGene:1482 biolink:causes MONDO:0013752 infores:monarchinitiative not_provided not_provided HGNC:2488 MONDO:0013752 uuid:06f58774-12d1-4310-a620-4bda759ac580 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA386954869 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954869 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM1_Supporting, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 PS4 The c.319C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to isoleucine at codon 107 (p.(Leu107Ile)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.7509, which is greater than the MDEP threshold of 0.70 (PP3). Functional studies have also demonstrated the p.Leu107Ile protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PMID:12488960). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 10447526, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibody) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes with eight informative meioses in one family (PP1_Strong; PMID:10447526). Taken together, this evidence supports the classification of c.319C>A as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954869/MONDO:0015967/017 2025-07-16 2025-07-25 Autosomal dominant inheritance HP:0000006 Supports UMLS:C1738934 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0234215 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0233494 infores:hetionet CHEBI:9086 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0152032 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002345 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0007860 infores:hetionet CHEBI:6128 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0017672 infores:hetionet CAID:CA1139532911 biolink:causes MONDO:0015152 infores:clingen CAID:CA1139532911 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.1948del p.(Leu650TyrfsTer6) variant in DYSF, which is also known as NM_001130987.2: c.2002del p.(Leu668TyrfsTer6), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 21/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three unrelated individuals with clinical signs of limb girdle muscular dystrophy, including in a homozygous state in two patients (0.5 pts, PMID: 18853459, 19309282) and in trans with a pathogenic variant in one patient (c.2643+1G>A, 1.0 pt, PMID: 36983702) (PM3). At least one of these patients displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702, 19309282). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532911/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:3857 biolink:causes MONDO:0007758 infores:monarchinitiative not_provided not_provided HGNC:6447 MONDO:0007758 uuid:3d5df405-0f72-434b-9e39-bbb0d734bfe5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9435 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0011570 infores:hetionet CHEBI:3647 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C2363730 infores:hetionet CHEBI:63620 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0027796 infores:hetionet CHEBI:6950 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013384 infores:hetionet CHEBI:9123 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C3665347 infores:hetionet CHEBI:9599 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C2363730 infores:hetionet CAID:CA232966 biolink:causes MONDO:0010726 infores:clingen CAID:CA232966 MONDO:0010726 PMID: Likely Benign BP5, BS2_Supporting, PM2_Supporting PP3 The c.438C>T (p.Gly146=) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.Gly146= variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). The p.Gly146= variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The Rett and Angelman-like Disorders Variant Curation Expert Panel classified this variant as Likely Benign based on BS2_supporting and BP5. Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA232966/MONDO:0010726/016 2021-11-24 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:9332 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0010200 infores:hetionet CHEBI:8499 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0042963 infores:hetionet CHEBI:31413 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0043094 infores:hetionet CAID:CA9870414 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870414 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP1_Moderate, PP3, PP4, PM2_Supporting, PM1_Supporting BA1, BP4, BS1 The c.926G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to histidine at codon 309 (p.(Arg309His)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.765, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the South Asian subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hyperinsulinemic hypoglycemia and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). This variant segregated with diabetes and/or diazoxide-responsive hyperinsulinemic hypoglycemia, with 4 informative meioses in 1 family (PP1_Moderate; internal lab contributors). Another missense variant, c.925C>T p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309His (PM5_Supporting). In summary, c.926G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870414/MONDO:0015967/085 2024-08-01 2024-08-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2675 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0015967 infores:hetionet CHEBI:8232 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0014518 infores:hetionet CHEBI:5855 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027424 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0027765 infores:hetionet CHEBI:8768 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042345 infores:hetionet CHEBI:7581 biolink:causes HP:0030187 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0701824 infores:hetionet CHEBI:7852 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0030554 infores:hetionet CHEBI:38562 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0038990 infores:hetionet CHEBI:8107 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0021368 infores:hetionet CHEBI:68554 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0016059 infores:hetionet CAID:CA409106015 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106015 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 The c.498T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 166 (p.(Cys166Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 5 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID: 520675). In summary, c.498T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106015/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3084 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0039231 infores:hetionet CHEBI:8665 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0085631 infores:hetionet CHEBI:46295 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0023052 infores:hetionet CHEBI:3077 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0547030 infores:hetionet CHEBI:2676 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0877055 infores:hetionet CHEBI:61390 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0009806 infores:hetionet CHEBI:7823 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0023380 infores:hetionet CHEBI:94807 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C2047937 infores:hetionet CHEBI:4495 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020456 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0022876 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0022876 infores:hetionet CHEBI:2682 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0028961 infores:hetionet CHEBI:63638 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0040460 infores:hetionet CAID:CA2573157367 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157367 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS4, PS2, PS3, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS4, BS3, PM4, PM5, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968-8C>A is an intronic variant which is not predicted by SpliceAI to impact splicing (BP4). Additionally, evolutionary conservation algorithms predict the site is not highly conserved (PhyloP score = 0.744953 in GRCh38) (BP7). This variant is absent from gnomAD v2, v3, and v4, and it has not been reported in cases or the literature. In summary, this variant meets criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157367/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3696 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0035078 infores:hetionet CHEBI:63717 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0041969 infores:hetionet CHEBI:8665 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0002418 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0032285 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017566 infores:hetionet CHEBI:119486 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011206 infores:hetionet CHEBI:168396 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0239340 infores:hetionet CHEBI:63619 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0236075 infores:hetionet NCBIGene:57165 biolink:causes MONDO:0013179 infores:monarchinitiative not_provided not_provided HGNC:17494 MONDO:0013179 uuid:5a4786be-a61c-4f06-b464-994d5d292fcb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9555 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0854467 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0034902 infores:hetionet GO:0001923 biolink:causes CL:0000819 infores:ubergraph knowledge_assertion manual_agent GO:0001923 CL:0000819 CHEBI:3219 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0033975 infores:hetionet CHEBI:9586 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013604 infores:hetionet NCBIGene:80210 biolink:causes MONDO:0033308 infores:monarchinitiative not_provided not_provided HGNC:20730 MONDO:0033308 uuid:f606d53a-6326-462f-8e15-f3e7f577611e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0017178 infores:hetionet NCBIGene:119559 biolink:causes MONDO:0014261 infores:monarchinitiative not_provided not_provided HGNC:16088 MONDO:0014261 uuid:00c13778-080d-4641-ba78-0793f9b9eaf1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37941 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0038325 infores:hetionet CHEBI:94449 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0030252 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0243026 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0948349 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0858318 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0858318 infores:hetionet CHEBI:68478 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042963 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0004238 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020517 infores:hetionet CHEBI:6367 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0242422 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0005575 uuid:75ec2956-b7df-4475-b666-18dd61a55a30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1586 biolink:causes MONDO:0008730 infores:monarchinitiative not_provided not_provided HGNC:2593 MONDO:0008730 uuid:de492dda-ee4c-4a4b-98fc-3d81dfd12c15 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135005 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0022107 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023418 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0036572 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042075 infores:hetionet CHEBI:7915 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017979 infores:hetionet CHEBI:75998 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020461 infores:hetionet CAID:CA414446705 biolink:causes MONDO:0010604 infores:clingen CAID:CA414446705 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3 The c.1234G>T (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of glycine by tryptophan at amino acid 412 (p.Gly412Trp). This variant has been reported in 3 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Moderate; PMID: 23093250, EAHAD F9 database, PMID: 30648777). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). Another missense variant c.1235G>A, p.Gly412Glu in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). The computational predictor REVEL gives a score of 0.983, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PM5, PS4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414446705/MONDO:0010604/080 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Supports CHEBI:240107 biolink:causes UMLS:C0748725 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0748725 infores:hetionet CAID:CA504731701 biolink:causes MONDO:0012999 infores:clingen CAID:CA504731701 MONDO:0012999 PMID: Pathogenic PVS1, PP4_Strong, PM3 PM2 The NM_000156.6:c.58dup (p.Trp20LeufsTer65) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in one individual with GAMT deficiency, who was compound heterozygous for the variant and a pathogenic variant, with the phase confirmed in trans by family testing (PMID: 24766785). This individual had elevated urine GAA, deficient GAMT activity in fibroblasts and reduced creatine peak on brain MRS (PMID: 24766785) (PP4_Strong). This variant is not present in gnomAD v2.1.1 but the coverage is <20X and therefore PM2_Supporting is not met. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM3, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA504731701/MONDO:0012999/026 2023-05-25 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0687133 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042267 infores:hetionet CHEBI:7773 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0030193 infores:hetionet CHEBI:3510 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0595916 infores:hetionet CAID:CA037376 biolink:causes MONDO:0007750 infores:clingen CAID:CA037376 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP2, BP4, PS4, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PM6, PVS1, PP4, PP1, BS2 The NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00009643 (0.009643%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.95.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037376/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:17347 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1142412 infores:hetionet CHEBI:134991 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0002792 infores:hetionet CHEBI:7773 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0003467 infores:hetionet CHEBI:45409 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027121 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0004239 infores:hetionet CHEBI:15367 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0152030 infores:hetionet CHEBI:7494 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0917801 infores:hetionet CHEBI:3223 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085628 infores:hetionet CAID:CA349039608 biolink:causes MONDO:0100038 infores:clingen CAID:CA349039608 MONDO:0100038 PMID: Likely Pathogenic PS3, PM6_Supporting, PP3_Moderate, PM2_Supporting, PS4_Supporting The c.5636T>C variant in SCN2A is a missense variant predicted to cause substitution of methionine by threonine at amino acid 1879 (p.Met1879Thr). This variant has been reported in one individual as de novo with unconfirmed parental relationships (PMID:32750235) (PM6_Supporting), and in one individual without parental segregation (PMID: 27779742) (PS4_Supporting), both with consistent phenotypes. Another missense variant at the same position in SCN2A (p.Met1879Ile) has been reported in the literature (PMID: 34055682), however, this variant does not reach Likely Pathogenic per these criteria so was not included for PM5. This variant is absent from the population database gnomAD v4.0 (PM2_Supporting). Functional evidence has demonstrated that this variant impacts normal protein function. Specifically, heterologous expression with voltage clamping has shown a shift of at least 4.1mV in voltage dependence of inactivation (PS3). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6_Supporting, PS4_Supporting, PM2_Supporting, PS3, PP3_Moderate. (version 1.0; March 26, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349039608/MONDO:0100038/068 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2639 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0013428 infores:hetionet CHEBI:70746 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0002792 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003123 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0032285 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0004936 infores:hetionet CHEBI:3077 biolink:causes UMLS:C1535948 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1535948 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0262985 infores:hetionet CHEBI:2549 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0002962 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0547030 infores:hetionet CHEBI:39867 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0011168 infores:hetionet CHEBI:2666 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0009806 infores:hetionet CHEBI:194135 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011168 infores:hetionet CAID:CA229678 biolink:causes MONDO:0009861 infores:clingen CAID:CA229678 MONDO:0009861 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The c.664_665del (p.Asp222Ter) variant in PAH is a nonsense variant in exon 6 of 13, with nonsense mediated decay predicted to occur (PVS1). This variant was detected in at least one patient with mild PKU where BH4 deficiency was excluded by analysis of neopterin and biopterin in urine and measurement of dihydropteridine reductase activity in dried blood spots (PMID:16290003, PP4_moderate). It was found to co-occur (phase unknown) with the pathogenic variant IVS10-3C>T (PM3_supporting). This deletion has a MAF of 0.00003874 in the European (non-Finnish) population in GnomAD v2.1.1 (PM2_supporting). Therefore this variant is classified as Pathogenic by the PAH VCEP; PAH-specific ACMG/AMP criteria applied: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229678/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020517 infores:hetionet CAID:CA024360 biolink:causes MONDO:0100150 infores:clingen CAID:CA024360 MONDO:0100150 PMID: Benign BA1 PS4, BS1, PM2 The variant NM_000540.3:c.2677G>A in RYR1 is a missense variant predicted to cause substitution of glycine by serine at amino acid 893 (p.Gly893Ser). The highest population minor allele frequency in gnomAD v4.1.1 is 0.005439 (483/75052 alleles) for the African population, which is higher than the ClinGen congenital myopathy RYR1 threshold ( ≥ 0.0000486) for BA1, and therefore meets this criterion (BA1). This variant has been reported in one proband in the literature, who lacked a second allele and presented with type I muscle fiber predominance, proximal, axial, and facial weakness, limited upward gaze, and achilles tendon contracture. However, the father had the variant but was unaffected (PMID: 22473935). In summary, the variant meets criteria to be classified as benign for AD RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024360/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2663 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0855242 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020569 infores:hetionet CHEBI:5147 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0085631 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013922 infores:hetionet NCBIGene:81034 biolink:causes MONDO:0014795 infores:monarchinitiative not_provided not_provided HGNC:29683 MONDO:0014795 uuid:33957b57-c6ac-4d2f-8ef4-f06832547a91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009946 infores:hetionet CHEBI:52717 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0740394 infores:hetionet CHEBI:44032 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0000731 infores:hetionet CHEBI:50567 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0018681 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0037274 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0233472 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0542101 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0009806 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0036572 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0018418 infores:hetionet CHEBI:404903 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011206 infores:hetionet CHEBI:70735 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0042029 infores:hetionet CHEBI:63607 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0030305 infores:hetionet CHEBI:63580 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0016204 infores:hetionet CHEBI:8502 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0011606 infores:hetionet CHEBI:4735 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0040046 infores:hetionet CHEBI:50742 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0423791 infores:hetionet CHEBI:3647 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0030312 infores:hetionet CAID:CA246541 biolink:causes MONDO:0015967 infores:clingen CAID:CA246541 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PP2, PM2_Supporting The c.601G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 201 (p.(Ala201Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in one family (PP1_Strong; internal lab contributors). In summary, c.605T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PS4_Moderate, PP1_Strong, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA246541/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Supports CHEBI:8874 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020621 infores:hetionet UNII:R43D2573WO biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0042023 infores:hetionet CHEBI:4710 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027497 infores:hetionet CAID:CA014235 biolink:causes MONDO:0004994 infores:clingen CAID:CA014235 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3918C>T (p.Leu1306=) variant in the MYH7 gene is 0.55% (60/8654) of East Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014235/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5790 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085631 infores:hetionet CHEBI:8430 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0020538 infores:hetionet CHEBI:3510 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0027424 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0392176 infores:hetionet CHEBI:75922 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0235266 infores:hetionet CAID:CA229493 biolink:causes MONDO:0009861 infores:clingen CAID:CA229493 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting The NM_000277.3(PAH):c.231T>G (p.Tyr77Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases including gnomAD, ExAC, and ESP, and is present at an extremely low allele frequency (MAF < 0.0002) in the 1000 Genomes (PM2_supporting). The variant has been previously reported in a patient with PKU (plasma Phe level not specified) and BH4 deficiency excluded (PMID: 9860305; PMID: 21307867) (PP4_Moderate); the patient’s genotype was not specified. It has also been noted (PMID: 28982351) in a patient with mild PKU (plasma Phe 720 uM) and BH4 deficiency excluded (PP4_Moderate), who harbored it in trans with the p.Asp101Asn (Likely Pathogenic in ClinVar, ID 553851) and p.Gly247Arg (Likely Pathogenic in ClinVar, ID 102816) alleles (PM3). In summary, this variant meets criteria to be classified as for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229493/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9168 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0014356 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027339 infores:hetionet CHEBI:74947 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0031154 infores:hetionet CAID:CA8328415 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328415 MONDO:0100438 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Strong, PM4_Supporting NM_014336.5(AIPL1):c.727_729del (p.Lys243del) is an in-frame deletion of three nucleotides predicted to cause a change in the length of the protein due to deletion of 1 amino acid in a non-repeat region, with at least one of the deleted base pairs highly conserved with a PhyloP conservation score of 2.5 (PM4_Supporting). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00001115, with 18 / 1,614,218 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, VCEP member-provided data). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) variant suspected in trans (0.5 points, PMID: 32865313), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP, or the NM_014336.5(AIPL1):c.190G>A (p.Gly64Arg) variant confirmed in trans (1 point, VCEP member-provided data, Blueprint Genetics), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). A fourth proband with retinal dystrophy has been reported harboring the variant in the compound heterozygous state with the NM_014336.5(AIPL1):c.364G>A (p.Gly122Arg) variant, however, additional information will be required for inclusion in PM3 (VCEP member-provided data). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with light-seeking behavior (1 pt) from birth (1 pt), nystagmus (1 pt), central visual acuity limited to light perception (1 pt), and relatively normal fundus appearance at age 1 year with very mild granular RPE pigmentation (0.5 pts), which together are specific for AIPL1-related retinopathy (total 4 points, PMID: 32865313, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM4_Supporting, PM2_Supporting, PM3_Strong, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328415/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2611 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0026827 infores:hetionet CHEBI:10124 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0015967 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0235396 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0235396 infores:hetionet CHEBI:31932 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0027441 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0002622 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0027051 infores:hetionet CHEBI:6413 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0232462 infores:hetionet CHEBI:31485 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0152459 infores:hetionet CHEBI:63580 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0086565 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0751476 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0751476 infores:hetionet CAID:CA10585679 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585679 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP4, BP2, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.939.It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 1 index cases with criteria for FH (TC and LDL >95th percentile and autosomal dominant transmission of hypercholesterolemia in the family) from France (PMID: 20809525), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585679/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7936 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0041582 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0151505 infores:hetionet CHEBI:72564 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C2830004 infores:hetionet CHEBI:35778 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0014742 infores:hetionet CHEBI:15428 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0037036 infores:hetionet CHEBI:92712 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0037822 infores:hetionet CHEBI:63598 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002962 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020651 infores:hetionet CHEBI:91541 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0549249 infores:hetionet CHEBI:63589 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0014742 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0920102 infores:hetionet CHEBI:63629 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151878 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0011991 infores:hetionet CHEBI:63791 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0015967 infores:hetionet CHEBI:135736 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0019521 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0019158 infores:hetionet NCBIGene:55863 biolink:causes MONDO:0032633 infores:monarchinitiative not_provided not_provided HGNC:30883 MONDO:0032633 uuid:776f81f1-8e15-4e62-bf50-54ffba3a602c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0005940 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017675 infores:hetionet CHEBI:17650 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151907 infores:hetionet CHEBI:5165 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0423791 infores:hetionet CHEBI:48390 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0037763 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0853149 infores:hetionet CHEBI:7454 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0004096 infores:hetionet CHEBI:3752 biolink:causes MONDO:0009876 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0013336 infores:hetionet CHEBI:6375 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151904 infores:hetionet CHEBI:3756 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0234047 infores:hetionet CHEBI:127342 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0235309 infores:hetionet NCBIGene:1829 biolink:causes MONDO:0013030 infores:monarchinitiative not_provided not_provided HGNC:3049 MONDO:0013030 uuid:32130721-f1f4-4607-ac35-6f7f44bcd561 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16796 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0853692 infores:hetionet CHEBI:6775 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0032227 infores:hetionet CHEBI:45409 biolink:causes HP:0005305 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151945 infores:hetionet CHEBI:50173 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0035317 infores:hetionet CHEBI:5384 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0023530 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018802 infores:hetionet CHEBI:47898 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020461 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0234987 infores:hetionet CAID:CA2697547499 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547499 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.228dup (p.Ser77GlnfsTer?) is a frameshift variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM5_supporting, PVS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547499/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50730 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0021053 infores:hetionet CHEBI:465284 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0001122 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232492 infores:hetionet CHEBI:8485 biolink:causes UMLS:C0860516 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0860516 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0033774 infores:hetionet CHEBI:83527 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0015672 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0025061 infores:hetionet CHEBI:499361 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0858635 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0017178 infores:hetionet CHEBI:15407 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0341742 infores:hetionet CHEBI:585948 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0013395 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0549293 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0549293 infores:hetionet CAID:CA1624855 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624855 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.141T>C (p.Tyr47=) variant in the SOS1 gene is 0.116% (16/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624855/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6792 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0015672 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0344315 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027051 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0038454 infores:hetionet CAID:CA10558498 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558498 MONDO:0010726 PMID: Benign BP5, BS1, BS2 BP4, PP3 The allele frequency of the p.Pro379Ser variant in MECP2 (NM_004992.3) is 0.017% in African sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro379Ser variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro379Ser variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5). In summary, the p.Pro379Ser variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558498/MONDO:0010726/036 2024-02-23 2024-06-27 X-linked inheritance HP:0001417 Contradicts true CHEBI:7820 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0151798 infores:hetionet CHEBI:31176 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0340865 infores:hetionet CAID:CA043240 biolink:causes MONDO:0007750 infores:clingen CAID:CA043240 MONDO:0007750 PMID: Uncertain Significance PS3 BA1, BP3, BP2, BP1, BP4, PS1, PS4, PS2, BP7, BP5, BS3, BS1, BS4, PM5, PM1, PM4, PM3, PVS1, PM2, PM6, PP1, PP2, PP3, PP4, BS2 The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA043240/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6067 biolink:causes MONDO:0002185 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020492 infores:hetionet GO:0060472 biolink:causes GO:0060468 infores:ubergraph knowledge_assertion manual_agent GO:0060472 GO:0060468 CAID:CA405687052 biolink:causes MONDO:0018493 infores:clingen CAID:CA405687052 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate PS3, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with leucine at codon 4808 of the RYR1 protein, p.(Phe4808Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 23460944). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (.923) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405687052/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:101278 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0038358 infores:hetionet NCBIGene:116150 biolink:causes MONDO:0014904 infores:monarchinitiative not_provided not_provided HGNC:21042 MONDO:0014904 uuid:0f37f132-fe7b-4805-bf66-d33aff321445 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0004936 infores:hetionet CHEBI:28001 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0030193 infores:hetionet CHEBI:119915 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0340865 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001741 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020502 infores:hetionet CHEBI:50922 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0231530 infores:hetionet CHEBI:50730 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0018681 infores:hetionet CHEBI:119915 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042029 infores:hetionet CHEBI:7627 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0009782 infores:hetionet CHEBI:4753 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0423153 infores:hetionet CHEBI:70707 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0013378 infores:hetionet CHEBI:50173 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0003862 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0017574 infores:hetionet CHEBI:52172 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003850 infores:hetionet CHEBI:40303 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0438717 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017178 infores:hetionet CHEBI:36795 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0025345 infores:hetionet CHEBI:63598 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0028643 infores:hetionet CHEBI:3504 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0040264 infores:hetionet CHEBI:18243 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0042963 infores:hetionet GO:1901739 biolink:causes GO:0061061 infores:ubergraph knowledge_assertion manual_agent GO:1901739 GO:0061061 CHEBI:8772 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0149931 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0349506 infores:hetionet CHEBI:45924 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0151773 infores:hetionet CHEBI:3175 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0022575 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001828 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0155018 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0042571 infores:hetionet CHEBI:63598 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042790 infores:hetionet CHEBI:47657 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0042029 infores:hetionet CHEBI:2567 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0013295 infores:hetionet NCBIGene:629 biolink:causes MONDO:0014255 infores:monarchinitiative not_provided not_provided HGNC:1037 MONDO:0014255 uuid:f3d0c042-a162-4508-af15-ca6f345a00a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes MONDO:0005265 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0021390 infores:hetionet CHEBI:9435 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0013362 infores:hetionet CHEBI:135929 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0011991 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0003123 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0948089 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151849 infores:hetionet CHEBI:50885 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0016655 infores:hetionet CAID:CA6904209 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904209 MONDO:0019497 PMID: Uncertain Significance PM2 BS1, BS3, BS4, BP7, BP5, BS2, PP3, PP2, PP4, PP1, PM5, PM4, PM1, PM3, PM6, PVS1, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2, PS4 The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID: 17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904209/MONDO:0019497/005 2023-09-26 2023-10-05 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:82981 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0042963 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0155003 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0849907 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0849907 infores:hetionet CHEBI:7454 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0034063 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017574 infores:hetionet CHEBI:6847 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0342579 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0002871 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0020649 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151734 infores:hetionet CHEBI:8430 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0036830 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0152517 infores:hetionet CHEBI:46195 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0242528 infores:hetionet CHEBI:3207 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0232493 infores:hetionet CHEBI:2675 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0009806 infores:hetionet CHEBI:3423 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0162834 infores:hetionet CHEBI:6888 biolink:causes MONDO:0018616 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0730328 infores:hetionet CHEBI:50173 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020458 infores:hetionet CHEBI:3478 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C1443060 infores:hetionet CHEBI:135736 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1519353 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0032285 infores:hetionet CHEBI:231594 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0036396 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0037274 infores:hetionet CHEBI:3752 biolink:causes MONDO:0000755 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0032987 infores:hetionet CHEBI:94392 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0542571 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0037274 infores:hetionet CHEBI:119573 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0033774 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0455204 infores:hetionet CHEBI:82960 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0003862 infores:hetionet CAID:CA902468 biolink:causes MONDO:0100368 infores:clingen CAID:CA902468 MONDO:0100368 PMID: Pathogenic PM3, PP3_Moderate, PP1_Strong, PP4, PM2_Supporting BA1, BS1 NM_000329.3(RPE65):c.560G>A is a missense variant that causes substitution of glycine with glutamic acid at position 187. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000009590, with 2 alleles / 34536 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinitis pigmentosa with onset at age 2 years (1 pt), night blindness (0.5 pts), visual field reduction (1 pt), bone spicule pigmentation (0.5 pts), loss of central vision (1 pt), and undetectable electroretinogram responses from rods (0.5 pts) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 pts, PMID: 34492281, PP4). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 31878136, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through three probands plus 4 similarly affected relatives, with the variant present in the homozygous state (PP1_Strong; PMID: 31878136). The computational predictor REVEL gives a score of 0.939, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.774 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3, PP1_Strong, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902468/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CAID:CA410203707 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203707 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.278A>G (p.Asp93Gly)is a missense variant which has a REVEL score ≥ 0.88 (0.894) (PP3). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203707/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6121 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0020649 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151736 infores:hetionet CHEBI:71272 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0034150 infores:hetionet CHEBI:7823 biolink:causes UMLS:C0233796 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0233796 infores:hetionet CHEBI:478164 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0014742 infores:hetionet CHEBI:5280 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151610 infores:hetionet CHEBI:6846 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0085702 infores:hetionet CHEBI:3561 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011175 infores:hetionet CHEBI:44185 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151799 infores:hetionet CHEBI:168396 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0426390 infores:hetionet NCBIGene:7134 biolink:causes MONDO:0012745 infores:monarchinitiative not_provided not_provided HGNC:11943 MONDO:0012745 uuid:c0d244de-03ee-4288-88e9-5c201c16b55a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0037763 infores:hetionet NCBIGene:3166 biolink:causes MONDO:0012802 infores:monarchinitiative not_provided not_provided HGNC:5017 MONDO:0012802 uuid:fb1245eb-c190-4f25-81b6-2724d5bf96c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474053 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0036974 infores:hetionet CAID:CA374977914 biolink:causes MONDO:0008535 infores:clingen CAID:CA374977914 MONDO:0008535 PMID: Likely Pathogenic PM2_Supporting, PP4_Moderate, PS4_Moderate, PP1_Strong The NM_001114753.3: c.1319T>G variant in ENG is a missense variant predicted to cause substitution of valine by glycine at amino acid 440 (p.Val440Gly). This variant has been reported in more than 2 probands with a phenotype consistent with HHT (PS4_Moderate; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with Hereditary Hemorrhagic Telangiectasia in 5 affected meioses from 1 family (PP1_Strong; Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.385, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting (specifications version 1.1.0; 11/12/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374977914/MONDO:0008535/136 2024-11-12 2025-03-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:66876 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0595877 infores:hetionet CHEBI:135351 biolink:causes HP:0012343 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0241012 infores:hetionet CHEBI:10101 biolink:causes HP:0031057 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0221245 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0521839 infores:hetionet CHEBI:681848 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0003467 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0037199 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151970 infores:hetionet CHEBI:4672 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085635 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0521591 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013395 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017152 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0023895 infores:hetionet NCBIGene:55621 biolink:causes MONDO:0032665 infores:monarchinitiative not_provided not_provided HGNC:25980 MONDO:0032665 uuid:61f071a8-dd6e-471d-aa72-69bf2ffe334d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3215 biolink:causes UMLS:C0013221 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013221 infores:hetionet CHEBI:8890 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0011603 infores:hetionet CHEBI:3696 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C3665347 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0857353 infores:hetionet CHEBI:3219 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0017565 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0152027 infores:hetionet CHEBI:72564 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013428 infores:hetionet CHEBI:6149 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0040822 infores:hetionet CHEBI:10119 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015967 infores:hetionet CHEBI:2682 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0043352 infores:hetionet CAID:CA2837582287 biolink:causes MONDO:0015152 infores:clingen CAID:CA2837582287 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NC_000002.12: g.71503055_71504556del variant (GRCh38) is an intragenic deletion with intronic breakends that encompasses exon 4 of the DYSF gene, NM_003494.4: c.237_342del. RNAseq analysis has demonstrated that this variant results in skipping of exon 4, which is expected to lead to a frameshift, premature truncation (p.Phe80ProfsTer36), and nonsense mediated decay in a gene for which loss of function is a known disease mechanism (PMID: 36983702; PVS1_RNA). This variant has been reported in unknown phase with a pathogenic variant in an individual with LGMD (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 36983702) (PM3_Supporting). This patient displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong). A similar deletion has also been reported in ClinVar (SCV003791359.2). No similar deletions are observed in gnomAD SVs or CNVs v4.1.0 or in the Database of Genomic Variants (PMID: 24174537; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/11/2025): PVS1_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2837582287/MONDO:0015152/180 2025-04-11 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6067 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235031 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0221203 infores:hetionet UMLS:C1738934 biolink:causes HP:0012764 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085619 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0233485 infores:hetionet NCBIGene:8288 biolink:causes MONDO:0043364 infores:monarchinitiative not_provided not_provided HGNC:3423 MONDO:0043364 uuid:ca5e9c1d-4ef9-4efe-a383-849f90d72da5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C3665347 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0151578 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0012833 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0427008 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0152198 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0852908 infores:hetionet CHEBI:465284 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020458 infores:hetionet CHEBI:5383 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0039231 infores:hetionet CHEBI:4858 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0014742 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0233414 infores:hetionet CHEBI:4868 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0152227 infores:hetionet CHEBI:3485 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0700345 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020542 infores:hetionet CHEBI:28177 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0018926 infores:hetionet CHEBI:9570 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0010828 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0851341 infores:hetionet CAID:CA10014631 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014631 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS1, PS3, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM1, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.91G>A (p.Val31Ile) is a missense variant which has a REVEL score < 0.50 (0.272) and a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 30103613). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014631/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7915 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014868 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0836924 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0853714 infores:hetionet CAID:CA229676 biolink:causes MONDO:0009861 infores:clingen CAID:CA229676 MONDO:0009861 PMID:9781015PMID:10479481PMID:8406445PMID:10479481PMID:12655546PMID:10479481 Pathogenic PM2, PP3, PP4, PP1, PM3_Very Strong PS3 The c.653G>T (p.Gly218Val) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 8406445, 9781015, 10479481). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: p.R158Q, p.I65T (PMID: 10479481); p.Y414C (PMID: 8632937); c.1066-11G>A, p.Arg270Lys, (PMID: 26666653); p.P281L (PMID: 24368688); p.R408W (PMID: 11032331); p.S349P (PMID: 22841515); c.1223G > A (p.R408Q) (PMID: 29102225). It co-segregated with disease (PKU) in 2 sisters (PMID: 8831077). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP1, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229676/MONDO:0009861/006 2020-07-09 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41423 biolink:causes UMLS:C0235906 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0235906 infores:hetionet CHEBI:64321 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0042963 infores:hetionet CHEBI:204928 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0086565 infores:hetionet CHEBI:8874 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003635 infores:hetionet CAID:CA410203869 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203869 MONDO:0011071 PMID: Uncertain Significance BP4, PS4_Supporting PS3, PS2, PS1, BA1, BP3, BP1, BP5, BS1, BS4, BS3, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.220G>C (p.Gly74Arg) is a missense variant which has been reported in one patient with myeloid malignancy (PMID: 31911633) (PS4_supporting). The computational predictor REVEL gives a score of 0.423, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203869/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63599 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0011175 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0852878 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0852878 infores:hetionet CHEBI:84883 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0232726 infores:hetionet CHEBI:31859 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151662 infores:hetionet CHEBI:10102 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0001807 infores:hetionet CHEBI:135193 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0033774 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1368065 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0020649 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0020517 infores:hetionet CHEBI:2788 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0155169 infores:hetionet CHEBI:3216 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0009763 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235169 infores:hetionet NCBIGene:6548 biolink:causes MONDO:0014572 infores:monarchinitiative not_provided not_provided HGNC:11071 MONDO:0014572 uuid:096615aa-a29b-4ce2-afad-fc202d315cc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0267792 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0038587 infores:hetionet NCBIGene:60529 biolink:causes MONDO:0013268 infores:monarchinitiative not_provided not_provided HGNC:450 MONDO:0013268 uuid:e9543233-2f10-407e-a203-5cff80c7a4ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0043352 infores:hetionet CHEBI:51173 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0220870 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0010692 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0549622 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0019087 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0234458 infores:hetionet CHEBI:44032 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0041657 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013447 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0025061 infores:hetionet CHEBI:31859 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0038362 infores:hetionet CHEBI:63613 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0015672 infores:hetionet CHEBI:36704 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0007222 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0038999 infores:hetionet CHEBI:63617 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085593 infores:hetionet NCBIGene:10804 biolink:causes MONDO:0009076 infores:monarchinitiative not_provided not_provided HGNC:4288 MONDO:0009076 uuid:6d12cf58-2bf8-4c7c-848d-855dc5dd4c88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2636 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0234192 infores:hetionet CAID:CA915946431 biolink:causes MONDO:0100216 infores:clingen CAID:CA915946431 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PS4 The NM_177438.3:c.145-4C>T variant in DICER1 is an intronic variant occurring in intron 2. Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA915946431/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50777 biolink:causes UMLS:C0241618 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0241618 infores:hetionet CHEBI:44915 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0002792 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0497365 infores:hetionet CHEBI:63612 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0151699 infores:hetionet CHEBI:9434 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C1443060 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0002994 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0344320 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235639 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0022650 infores:hetionet CAID:CA383498765 biolink:causes MONDO:0015628 infores:clingen CAID:CA383498765 MONDO:0015628 PMID: Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PS4_Supporting, PS3 PS1 The NM_000552.5(VWF):c.4885G>C (p.Gly1629Arg) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 30 IU/dl and almost no binding of plasma VWF to GPIb), low activity/VWF:Ag ratio (0.30), and loss of high and intermediate molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID: 30044032). Additional consistent phenotypes were also reported in the patient including FVIII activity consistent with VWF antigen and a reduced RIPA. At least one additional type 2A patient has been reported with VWF:RCo/ VWF:Ag ratio between 0.08-0.22 and absence of HMW multimers (PMID: 37215093; PS4_supporting). At least one family (PMID: 37215093) has at least 2 segregations and all affected family members have VWF:RCo/ VWF:Ag ratio between 0.08-0.22 and absence of HMW multimers (PP1). Multimerization assay performed with the Gly1629Arg recombinant mutant vWF expressed by Cos-7 cells had a slight decrease in the highest molecular weight multimers indicating that this variant has a damaging effect on protein function (PS3; PMID: 15377475). Additionally, mutated rVWF showed a moderately weakened capacity for binding to platelets, when compared to WT-rVWF. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PM2_Supporting, PP3, PP1, PS4_supporting, PS3. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383498765/MONDO:0015628/081 2025-05-06 2025-05-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64312 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085612 infores:hetionet NCBIGene:4053 biolink:causes MONDO:0009633 infores:monarchinitiative not_provided not_provided HGNC:6715 MONDO:0009633 uuid:69b9420b-7f29-458f-983f-70d823843dfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0024141 infores:hetionet CHEBI:49662 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0039070 infores:hetionet CHEBI:2549 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0004093 infores:hetionet CHEBI:4995 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0015672 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0002871 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0034882 infores:hetionet NCBIGene:6774 biolink:causes MONDO:0014414 infores:monarchinitiative not_provided not_provided HGNC:11364 MONDO:0014414 uuid:2849b2e1-ed03-44d7-a8cd-abf87ee8beeb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0404521 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0003123 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0267596 infores:hetionet CHEBI:32599 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0728899 infores:hetionet CAID:CA387460990 biolink:causes MONDO:0019497 infores:clingen CAID:CA387460990 MONDO:0019497 PMID:20201936PMID:15790391PMID:31195736 Pathogenic PP1_Strong, PM3_Supporting, PP3, PS4 PM2, BA1 The p.Trp172Cys variant in the GJB2 gene was absent from gnomAD (PM2). However, this variant has been identified at an allele frequency of 1.9% (6/314) in unaffected Tuvinian individuals (PMID: 20201936). This frequency would normally lead to application of BA1 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, the variant was found to have a statistically higher prevalence in affected Tuvinian individuals (66/440 alleles) over ethnically-matched controls (6/314 alleles) (15% vs 1.9%; p<0.0001, PS4; PMID: 20201936) suggesting that this is actually a high frequency founder variant in this population. This variant has been detected in trans with two pathogenic variants in probands with hearing loss (PM3_supporting PMID:20201936; 15790391). The p.Trp172Cys variant in GJB2 has been reported to segregate with hearing loss in at least 9 affected family members (PP1_Strong; PMID: 20201936). The REVEL computational prediction analysis tool produced a score of 0.7 (rounded up from 0.687), which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PS4, PP1_Strong, PP3, PM3_supporting). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387460990/MONDO:0019497/005 2019-07-28 2019-10-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:79809 biolink:causes MONDO:0013442 infores:monarchinitiative not_provided not_provided HGNC:25660 MONDO:0013442 uuid:5c780e2d-29d3-42dc-8368-2085c8361f16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024205 infores:hetionet CHEBI:9654 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0232461 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151785 infores:hetionet CHEBI:83531 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0013395 infores:hetionet CHEBI:31536 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0018965 infores:hetionet NCBIGene:760 biolink:causes MONDO:0009818 infores:monarchinitiative not_provided not_provided HGNC:1373 MONDO:0009818 uuid:57290f00-2f1d-4797-bb05-71481708f39d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027796 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0017152 infores:hetionet CHEBI:6775 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0000729 infores:hetionet CAID:CA396457842 biolink:causes MONDO:0007648 infores:clingen CAID:CA396457842 MONDO:0007648 PMID: Uncertain Significance PP1, PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM1, PM3, PM6, PVS1, PP3, PP2, PP4, BS2, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2 The c.535A>G (p.Lys179Glu) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 4 meioses observed (PP1; internal laboratory contributor). This variant has also been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; internal laboratory contributor). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP1, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396457842/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5779 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0003467 infores:hetionet CHEBI:8869 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0000737 infores:hetionet CHEBI:4975 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0232462 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0700184 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017178 infores:hetionet CAID:CA291039 biolink:causes MONDO:0012996 infores:clingen CAID:CA291039 MONDO:0012996 PMID: Benign BA1 BP7 The NM_001482.3:c.1041C>T variant in GATM is a synonymous (silent) variant (p.Asp347=). SpliceAI does not predict an impact on splicing, but BP7 was not applied because the nucleotide is conserved (GERP score > 5). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00101 (31/30616 alleles) in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 137450). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291039/MONDO:0012996/025 2024-08-20 2024-09-20 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0005740 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0033774 infores:hetionet CHEBI:15940 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0003962 infores:hetionet CHEBI:9086 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0542571 infores:hetionet CHEBI:61058 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0018418 infores:hetionet UMLS:C0903898 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0040822 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0014742 infores:hetionet CHEBI:15544 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0018681 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042267 infores:hetionet CHEBI:585948 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0031350 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1699201 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1699201 infores:hetionet CAID:CA2061283 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061283 MONDO:0015924 PMID:36675162 Likely Benign PS3_Supporting, BS1 PM2, PP2, PP3, BA1, BP1, BP4, PS4, PS1, PM5, PM1 The NM_001204.7(BMPR2) c.1042G>A variant is a missense variant predicted to cause a valine to isoleucine substitution at amino acid 348 (p.Val348Ile). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.88% (62/7044) alleles in the “Other” East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met. The computational predictor REVEL gives a score of 0.744 which is below the threshold of >0.75 for pathogenicity. Densitometry analysis indicated a modest reduction in p-SMAD levels but this was not consolidated by additional experimental analysis (PS3_supporting). In summary the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PS3_supporting (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061283/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3510 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0017178 infores:hetionet UMLS:C1738934 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151786 infores:hetionet CAID:CA2579830510 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830510 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PP4 The c.-136A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within the HNF6/OC2 binding site of the promoter (c.-132 to c.-141) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, therefore PP4 will not be applied (internal lab contributors). In summary, c.-136A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830510/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8310 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0151315 infores:hetionet NCBIGene:91147 biolink:causes MONDO:0011202 infores:monarchinitiative not_provided not_provided HGNC:28396 MONDO:0011202 uuid:2d2b2a41-9470-4994-9ac7-65615dc6e434 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C2225524 infores:hetionet CHEBI:5132 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0014518 infores:hetionet CHEBI:71417 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0012569 infores:hetionet CHEBI:10119 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0494475 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0497365 infores:hetionet CHEBI:61049 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020443 infores:hetionet CHEBI:7443 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0877359 infores:hetionet CHEBI:140621 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0039231 infores:hetionet CHEBI:50742 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0039070 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0027769 infores:hetionet CHEBI:465284 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1761613 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0017601 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018099 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0232693 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0232693 infores:hetionet CHEBI:175901 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0011603 infores:hetionet CHEBI:78543 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0028081 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0235818 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0340464 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0020649 infores:hetionet CHEBI:38940 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0037763 infores:hetionet CHEBI:63631 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0438142 infores:hetionet CHEBI:8888 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085633 infores:hetionet CHEBI:94609 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0162285 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0854382 infores:hetionet CHEBI:63638 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0004093 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0010346 infores:hetionet CHEBI:15367 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0332563 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0031350 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0032285 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0031212 infores:hetionet CHEBI:2673 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0085631 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0039971 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C1504494 infores:hetionet CHEBI:75998 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151578 infores:hetionet CHEBI:63611 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0232849 infores:hetionet CHEBI:6402 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0085682 infores:hetionet CHEBI:144093 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0027497 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0948594 infores:hetionet CHEBI:31524 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0151744 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020517 infores:hetionet CHEBI:6402 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0151825 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0042373 infores:hetionet CHEBI:4858 biolink:causes HP:0025388 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0040137 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0853692 infores:hetionet CHEBI:4710 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013404 infores:hetionet CHEBI:39112 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0151905 infores:hetionet CHEBI:64312 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C3665386 infores:hetionet CHEBI:6822 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0002874 infores:hetionet CHEBI:63617 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085628 infores:hetionet CHEBI:135939 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0029408 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0009241 infores:hetionet NCBIGene:6928 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:11630 MONDO:0005148 uuid:801098f0-3eed-492c-989a-be043c521778 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4974 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0017178 infores:hetionet CHEBI:50275 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0086565 infores:hetionet CHEBI:10101 biolink:causes NCIT:C37903 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1142163 infores:hetionet NCBIGene:6010 biolink:causes MONDO:0007639 infores:monarchinitiative not_provided not_provided HGNC:10012 MONDO:0007639 uuid:2376aac1-ff6f-4443-9d80-8fd5602f44c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39585 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0004604 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0026848 infores:hetionet CHEBI:50659 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C2242588 infores:hetionet CHEBI:2611 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0040822 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0040034 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0277925 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0016204 infores:hetionet CHEBI:3219 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0549622 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0008301 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0948594 infores:hetionet CHEBI:7931 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0030193 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0162429 infores:hetionet CAID:CA2918441 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918441 MONDO:0015152 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_000232.5: c.282A>G p.(Pro94=) variant in SGCB is a synonymous (silent) variant that is not predicted to influence splicing by SpliceAI (score 0) (BP4, BP7). The highest population minor allele frequency in gnomAD v3.1.2 is 0.0009626 (5/5194 genome alleles) in the East Asian population (PM2_Supporting, BS1, BA1 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918441/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:28148 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0002063 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0031350 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0851341 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0948089 infores:hetionet CHEBI:49960 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0003467 infores:hetionet CAID:CA10585425 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585425 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1361C>A (p.Thr454Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - Level 1 FS: Etxebarria et al. 2015 (PMID 25378237): Heterologous cells (CHO) with FACS - results: 65% LDL-LDLR binding, uptake and cell surface LDLR--- activity is below 70% of wild-type, so PS3 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - variant meets PM2 and was identified in 1 index case with MEDPED clinical criteria of FH (45 year old female with TC 398mg/dl) from PMID: 19007590 (Civeira et al. 2008), Spain; so PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585425/MONDO:0007750/013 2022-01-31 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:4562 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0016382 infores:hetionet CHEBI:7476 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0043352 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0267596 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0026857 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151883 infores:hetionet CHEBI:53760 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0040822 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0744235 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0744235 infores:hetionet CAID:CA16620602 biolink:causes MONDO:0008723 infores:clingen CAID:CA16620602 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate The c.1807dup (p.Cys603fs) variant in ACADVL, also known as p.Cys603LeufsTer2, is a frameshift variant that may cause loss of function of the protein; however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 27590926). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620602/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4735 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0018965 infores:hetionet CHEBI:9445 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0040034 infores:hetionet CHEBI:31184 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0175167 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0037274 infores:hetionet CHEBI:9123 biolink:causes HP:0003690 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0587246 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011849 infores:hetionet CHEBI:9570 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C2937358 infores:hetionet CHEBI:2948 biolink:causes MONDO:0006736 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0007868 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020557 infores:hetionet CHEBI:31624 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0030232 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040053 infores:hetionet CHEBI:9599 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0042963 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0008370 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0424605 infores:hetionet NCBIGene:7139 biolink:causes MONDO:0012900 infores:monarchinitiative not_provided not_provided HGNC:11949 MONDO:0012900 uuid:56ca8ec2-c9f9-4a88-a7d6-9faee2fada1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0344232 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042109 infores:hetionet CHEBI:31397 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0008031 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0029882 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0011991 infores:hetionet GO:1905079 biolink:causes GO:0030902 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0030902 UNII:15G12L5X8K biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018790 infores:hetionet CHEBI:9586 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019348 infores:hetionet CHEBI:7514 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0042075 infores:hetionet CHEBI:9654 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0039231 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0003123 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0235194 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235194 infores:hetionet CHEBI:8356 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233763 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027769 infores:hetionet CHEBI:50275 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0036454 infores:hetionet CHEBI:63612 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0085593 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017605 infores:hetionet CHEBI:3441 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151599 infores:hetionet CHEBI:50730 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0000737 infores:hetionet CHEBI:3698 biolink:causes UMLS:C1961112 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C1961112 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037195 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017168 infores:hetionet CHEBI:135351 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0002994 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0700217 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D000071074 DB02703_MESH_D000071074_1 CHEBI:5130 biolink:causes MONDO:0004597 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0034074 infores:hetionet CHEBI:7936 biolink:causes HP:0001622 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151526 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0015230 infores:hetionet CHEBI:617099 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C1443060 infores:hetionet CHEBI:6062 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0015672 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021315 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0153392 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0006145 infores:hetionet CAID:CA281459 biolink:causes MONDO:0007648 infores:clingen CAID:CA281459 MONDO:0007648 PMID:17545690PMID:17545690PMID:17545690PMID:17545690PMID:18427545 Pathogenic PP1, PM2_Supporting, PS4, PVS1_Strong BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM1, PM3, PM6, PP4, PP3, PP2, BS2, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2 The c.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID: 17545690). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4, PP1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA281459/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf UMLS:C1738934 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0033975 infores:hetionet CHEBI:15367 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0033687 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0236000 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0003123 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0025061 infores:hetionet CHEBI:4562 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0036974 infores:hetionet CHEBI:52717 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002064 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0019348 infores:hetionet CHEBI:6715 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0025323 infores:hetionet CHEBI:7959 biolink:causes MONDO:0016474 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0263591 infores:hetionet NCBIGene:23676 biolink:causes MONDO:0010238 infores:monarchinitiative not_provided not_provided HGNC:11122 MONDO:0010238 uuid:f77882bb-99db-4350-9627-36f4360a3638 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011168 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0007160 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0007160 uuid:85d62f2d-6bc9-4898-b208-6950b4bbf8a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028077 infores:hetionet NCBIGene:22858 biolink:causes MONDO:0012980 infores:monarchinitiative not_provided not_provided HGNC:21219 MONDO:0012980 uuid:2e9e0638-0567-4800-8233-2f3bbed07ca3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2659 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0234533 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003864 infores:hetionet CAID:CA9090706 biolink:causes MONDO:0021060 infores:clingen CAID:CA9090706 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1074G>A (p.Ala358=) variant in the MAP2K2 gene is 0.174% (10/3124) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9090706/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:80185 biolink:causes MONDO:0014238 infores:monarchinitiative not_provided not_provided HGNC:26262 MONDO:0014238 uuid:82948142-bfc5-4828-a933-a27283d49224 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0040479 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0236071 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0232492 infores:hetionet CHEBI:7494 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0032617 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0019054 infores:hetionet CHEBI:63611 biolink:causes HP:0010702 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151669 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0521500 infores:hetionet CAID:CA000677 biolink:causes MONDO:0018875 infores:clingen CAID:CA000677 MONDO:0018875 PMID: Benign BP4, BS3, BS2 BA1, PS3, PS1, PS4, PS2, PM5, PM1, BP7, BS1, BS4, PM2, PVS1, PP3, PP1, PP4 The NM_000546.6:c.1120G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 374 (p.Gly374Arg). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributors: SCV000273745.6). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (PMIDs: 12826609, 29979965, 30224644) (BS3). Computational predictor scores (BayesDel = -0.0546; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4_moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000677/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6887 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0012569 infores:hetionet CHEBI:184555 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0038525 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0036572 infores:hetionet CHEBI:5441 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C1443060 infores:hetionet CHEBI:8874 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0031154 infores:hetionet GO:0009994 biolink:causes CL:0000023 infores:ubergraph knowledge_assertion manual_agent GO:0009994 CL:0000023 CHEBI:45409 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0030794 infores:hetionet CHEBI:134990 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0085631 infores:hetionet CHEBI:31401 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0542571 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0549201 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0549201 infores:hetionet CHEBI:3504 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C1142412 infores:hetionet CHEBI:17823 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0917801 infores:hetionet CHEBI:51209 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0002962 infores:hetionet CAID:CA402991040 biolink:causes MONDO:0012999 infores:clingen CAID:CA402991040 MONDO:0012999 PMID: Uncertain Significance PP4_Strong, PM2_Supporting PM3, PP3, BP4 The NM_000156.6:c.578A>G variant in GAMT is predicted to result in the substitution of glutamine by arginine at amino acid 193 (p.Gln193Arg). This variant has been identified in one individual with absent creatine peak on brain magnetic resonance spectroscopy (3pts) and elevated urine GAA with low creatine (1pt) with full GAMT gene sequencing (PP4_Strong, 4pts total) (PMID: 23846910). This individual was compound heterozygous for the variant and another variant in GAMT that has been classified as likely pathogenic for GAMT deficiency by the ClinGen CCDS VCEP, c.391G>C (p.Gly131Arg (ClinVar Variation ID: 2446458); phase unknown) (PMID: 23846910) (0.25 points, PM3_Not met). The computational predictor REVEL gives a score of 0.626 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function. SpliceAI gives a score of 0.23 for acceptor gain 4 bp upstream (>0.2 suggests possible impact on splicing, but presence of this cryptic splice site is not confirmed by experimental studies). There is a ClinVar entry for this variant (Variation ID: 1328978). In summary, the clinical significance of the p.Gln193Arg variant is uncertain. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications Version 2.0.0): PP4_Strong, PM2_Supporting, (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402991040/MONDO:0012999/025 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9150 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0030305 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0235295 infores:hetionet CHEBI:194135 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0234632 infores:hetionet CHEBI:4784 biolink:causes HP:0003365 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0019559 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027813 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0553713 infores:hetionet CHEBI:135736 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0231530 infores:hetionet CHEBI:8768 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2047937 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0020039 infores:hetionet CHEBI:63617 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019270 infores:hetionet CHEBI:3176 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0428977 infores:hetionet CHEBI:3696 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0085631 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0240840 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0240840 infores:hetionet CHEBI:9674 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013146 infores:hetionet CHEBI:39867 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151904 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0001122 infores:hetionet CAID:CA410205685 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205685 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.86G>A (p.Arg29Lys) is a missense variant which is completely absent from all population databases (PM2_Supporting) and has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. This missense variant has a REVEL score < 0.50 (0.317) and a SpliceAI score ≤ 0.20 (0.06) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205685/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6950 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0149931 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0042109 infores:hetionet CHEBI:3757 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0028734 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0021564 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0021564 infores:hetionet CAID:CA10580924 biolink:causes MONDO:0018875 infores:clingen CAID:CA10580924 MONDO:0018875 PMID: Pathogenic PS3, PM5_Strong, PP3_Moderate, PM1, PS2_Supporting, PP4_Moderate, PP1, PS4_Supporting, PM2_Supporting BP4, BA1, PS1, BS1, BS3, BS4, BS2 The NM_000546.6: c.743G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 248 (p.Arg248Leu). This variant has been reported in 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of of 1-1.5 points. (PS4_Supporting; PMIDs 1359493, 25584008, ClinVar SCV SCV000273723.7, Internal lab contributor). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a moderately LFS-associated cancer totaling 1 phenotype point (PS2_Supporting; Internal lab contributors: SCV000273723.7). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 1359493). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000273723.7). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Two different missense variants, c.743G>A; p.Arg248Gln and c.742C>T; p.Arg248Trp, ClinVar IDs 12347 and 12356, in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5_Strong). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.570318; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, TP53 c.743G>T; p.Arg248Leu meets criteria to be classified as Pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PS2_Supporting, PP1, PP4_Moderate, PS3, PM5_Strong, PM1, PM2_Supporting, PP3_Moderate. (Bayesian Points: 18; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580924/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8060 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0033975 infores:hetionet CHEBI:135736 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0008031 infores:hetionet CAID:CA290777 biolink:causes MONDO:0011229 infores:clingen CAID:CA290777 MONDO:0011229 PMID: Benign BA1 PM3, PP4, PP1, BS2, PS2, PM2, PM6, PVS1 The c.227-9C>G (NM_014297.5) variant in ETHE1 is an intronic variant which is located in intron 2 (intron 2/6). The highest population minor allele frequency for the c.227-9C>G in gnomAD v2.1.1 is 0.00321 (905/282370 alleles, no homozygotes) in the general population, which is higher than the ClinGen ETHE1 threshold >0.001 for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign, and therefore not causative of Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): BA1. Approved 7/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA290777/MONDO:0011229/014 2021-07-27 2021-07-27 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0030554 infores:hetionet CHEBI:61049 biolink:causes EFO:0020909 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0877167 infores:hetionet CHEBI:6367 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0423791 infores:hetionet CHEBI:46345 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0233715 infores:hetionet NCBIGene:8452 biolink:causes MONDO:0013782 infores:monarchinitiative not_provided not_provided HGNC:2553 MONDO:0013782 uuid:bfccc4c0-6c92-4f0f-aab3-a9b0302c4dd8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151779 infores:hetionet CHEBI:7773 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0038999 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0233494 infores:hetionet CHEBI:5138 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1443060 infores:hetionet CHEBI:84500 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0004604 infores:hetionet NCBIGene:10395 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:2897 MONDO:0005575 uuid:f3051567-88d1-4cb3-b55e-56efe18befa6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039070 infores:hetionet CHEBI:8207 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0917801 infores:hetionet GO:0030516 biolink:causes GO:0007409 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0007409 CHEBI:3215 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151786 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0022650 infores:hetionet CHEBI:23765 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0040822 infores:hetionet CHEBI:3176 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0020452 infores:hetionet CHEBI:28748 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0042029 infores:hetionet CHEBI:32315 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0028084 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0038367 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0032285 infores:hetionet CHEBI:7809 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0238106 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027932 infores:hetionet CHEBI:53760 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0038999 infores:hetionet CHEBI:77260 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0231218 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027651 infores:hetionet CHEBI:63616 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C1145670 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0037199 infores:hetionet CHEBI:42797 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0241934 infores:hetionet CHEBI:7773 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0037317 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0278079 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0001824 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0030846 infores:hetionet CHEBI:6367 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0235660 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0747979 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0747979 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0014549 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020456 infores:hetionet CHEBI:50777 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0025218 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0028643 infores:hetionet CHEBI:38940 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0011603 infores:hetionet CHEBI:37924 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0022346 infores:hetionet CHEBI:6129 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235266 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0476327 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0006384 infores:hetionet CHEBI:3696 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0004604 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C1443060 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043349 infores:hetionet CHEBI:3752 biolink:causes MONDO:0017441 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0031575 infores:hetionet CHEBI:5296 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0004093 infores:hetionet CHEBI:51364 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042963 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020175 infores:hetionet CAID:CA658683577 biolink:causes MONDO:0017623 infores:clingen CAID:CA658683577 MONDO:0017623 PMID: Uncertain Significance PM2, BP4 PTEN c.493-7C>T (IVS5-7C>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA658683577/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135961 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0004238 infores:hetionet CHEBI:404903 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C2004489 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0009324 infores:hetionet CAID:CA409106265 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106265 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, BS3_Supporting, PM1_Supporting, PS4_Moderate, PP1_Strong The c,577G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine (p.(Asp193Tyr)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.951, which is greater than the MDEP VCEP threshold of 0.70 (PP3). However, functional studies demonstrated the p.Asp193Tyr protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 21323639). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least four unrelated individuals/families with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 17407387, 15830177, internal lab contributors). This variant segregated with diabetes, with at least 12 informative meioses in families with MODY (PP1_Strong; PMID: 17407387, internal lab contributors). At least one individual also had a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and history of LGA infant in the absence of maternal hyperglycemia) (PP4_Moderate; internal lab contributor). In summary, c.577G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Suppoting, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106265/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31536 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0041349 infores:hetionet CHEBI:17303 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026961 infores:hetionet CHEBI:6062 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0236075 infores:hetionet CHEBI:47499 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0162834 infores:hetionet CHEBI:83531 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0032617 infores:hetionet CHEBI:47781 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0004245 infores:hetionet CHEBI:27974 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0019572 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004096 infores:hetionet CHEBI:15551 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0026826 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042109 infores:hetionet CHEBI:4636 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0086525 infores:hetionet CHEBI:16755 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0009782 infores:hetionet CHEBI:5855 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0011124 infores:hetionet CHEBI:6128 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0003811 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034902 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0038454 infores:hetionet CAID:CA386303909 biolink:causes MONDO:0009861 infores:clingen CAID:CA386303909 MONDO:0009861 PMID: Likely Pathogenic PVS1, PM2 PM5, PP4, PS1 The c.3G>C (p.Met1Ile) variant in PAH is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant is absent in population databases (PM2). This variant has not been reported in an affected individual in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386303909/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes MONDO:0043209 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0001916 infores:hetionet GO:0002914 biolink:causes GO:0002340 infores:ubergraph knowledge_assertion manual_agent GO:0002914 GO:0002340 CHEBI:3568 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011168 infores:hetionet CHEBI:49960 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0232462 infores:hetionet UMLS:C0010592 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0037299 infores:hetionet UMLS:C0011701 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0015967 infores:hetionet CHEBI:28445 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0004134 infores:hetionet CHEBI:28748 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013362 infores:hetionet CAID:CA120558 biolink:causes MONDO:0044970 infores:clingen CAID:CA120558 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6_Supporting, PS3_Supporting PP1 The m.12315G>A variant in MT-TL2 has been reported in five affected and unrelated individuals from five families (PMIDs: one subject is reported in three different publications – 8923013, 9361028, 10332036; other subjects are reported in 12398839, 19718780, 18977334, 21819490; PS4_moderate). Age of onset ranged from childhood to adulthood (30s) and features included chronic progressive external ophthalmoplegia (CPEO), myopathy, pigmentary retinopathy, and sensorineural hearing loss. Muscle biopsies showed ragged red fibers, COX-deficiency, and reduced respiratory chain enzyme activities. Heteroplasmy levels ranged from 62-94% in muscle, from undetectable to 17% in blood, and were absent when assessed in other tissues. This variant occurred de novo in one individual (variant absent in blood, urine, and hair from healthy mother; PM6_supporting, PMID: 12398839).There were no similarly affected family members and no reports of transmission within a family to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in two separate instances. This was first reported in 1996 (PMID: 8923013) and showed higher levels of the variant in fibers with no detectable COX activity (95 ± 1%, range 93–98%) than in apparently normal fibers (54 ± 33%, range 11 to 90%). Single fiber studies were again performed on a different subject in 2002 (PMID: 12398839) and revealed higher levels of the variant in COX-negative fibers (N=7, 75.34 ± 5.19% heteroplasmy, range 67.01–81.86%) than in COX-positive fibers (N=6, 32.20 ± 9.05% heteroplasmy, range 16.29–34.93%; PS3_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (82.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120558/MONDO:0044970/015 2022-11-30 2023-01-05 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8665 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0042023 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0221490 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0004604 infores:hetionet CHEBI:5138 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0027796 infores:hetionet CHEBI:44915 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0004245 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0041349 infores:hetionet CHEBI:31711 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C1142412 infores:hetionet CHEBI:43968 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0042024 infores:hetionet CHEBI:8214 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0013404 infores:hetionet CHEBI:47381 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0019270 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038454 infores:hetionet CHEBI:4710 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0392676 infores:hetionet CAID:CA342802812 biolink:causes MONDO:0021060 infores:clingen CAID:CA342802812 MONDO:0021060 PMID:29734338 Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS2_Very Strong, PS3_Supporting PP2 The c.268A>G (p.Met90Val) variant in RIT1 was absent from both versions of gnomAD (PM2_Supporting; gnomad.broadinstitute.org). The p.Met90Val variant has been observed in at least 7 probands with a RASopathy or clinical features of a RASopathy (PS4_Moderate; PMID: 27109146, 30712878, 30293990, 32304219, Hopital Robert Debre internal data ClinVar SCV001438552.1, GeneDx internal data ClinVar SCV000808482.1). Of note, the majority of these were fetal cases. It has been reported as a de novo occurrence with parental confirmation in 3 probands and without confirmation in 3 probands (PS2_VeryStrong). Computational prediction tools and conservation analysis suggest that the p.Met90Val variant may impact the protein (PP3). ERK1/2 phosphorylation assays in HEK293T cells showed elevated and prolonged ERK1/2 phosphorylation indicating that this variant impacts protein function (PMID:29734338; PS3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PS2_VeryStrong, PS4_Moderate, PM2_Supporting, PP3, PS3_supporting (Version 2.1; 09/27/24). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA342802812/MONDO:0021060/047 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:87681 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C1384666 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0162429 infores:hetionet CAID:CA10585217 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585217 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Supporting, PM2, PP4, PP1 The NM_000527.5 (LDLR): c.941-12G>A variant is classified as Likely Pathogenic evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Supporting Met: Variant meets PM2, and is identified in 4 unrelated index cases who fulfil DLCN criteria for FH diagnosis from 2 different labs: Three cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); one case from Robarts Research Institute, Canada. PP1 Met: Variant segregates with FH phenotype in 3 informative meiosis in one family (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID: 20809525).PS3_Supporting: RNA assay using patient monocytes (level 3 functional assay) was reported from one research lab. Abnormal splicing of intron 6 was observed by gel electrophoresis only in patient cDNA but not in controls, using forward primer with 5' end located at c.864 (exon 6) and the reverse primer with 3' end at c.941-11. Sequencing confirmation on abnormal RT-PCR product was not performed and aberrant transcript was not quantified (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID: 20809525). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585217/MONDO:0007750/013 2022-03-30 2022-03-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA000612 biolink:causes MONDO:0017623 infores:clingen CAID:CA000612 MONDO:0017623 PMID:17847000PMID:17847000 Uncertain Significance PM2_Supporting PVS1, PM6, BP7, BP5, BS3, BS1, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.-861G>T (NC_000010.10:g.89623365G>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000612/MONDO:0017623/003 2025-06-06 2025-10-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7931 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0003864 infores:hetionet CHEBI:135939 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0018524 infores:hetionet CAID:CA367401656 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401656 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4 The c.530A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to aspartic acid at codon 177 (p.(Glu177Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.86, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 22941762, 30663027). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3 mmol/l)) (PP4_Moderate; PMID: 22941762). Furthermore, this variant segregated with diabetes with three informative meioses in a single family (PP1, PMID: 22941762). In summary, c.530A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401656/MONDO:0015967/086 2024-11-16 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:8871 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0005747 infores:hetionet CHEBI:4858 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0497156 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1510472 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018939 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0021400 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020517 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0003460 infores:hetionet CHEBI:39585 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0043352 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020651 infores:hetionet CHEBI:6062 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0023518 infores:hetionet CHEBI:10119 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0231528 infores:hetionet CHEBI:134966 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0012569 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0042373 infores:hetionet UMLS:C0657912 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0001925 infores:hetionet CAID:CA404041025 biolink:causes MONDO:0018947 infores:clingen CAID:CA404041025 MONDO:0018947 PMID: Likely Pathogenic PS4_Moderate, PP1_Moderate, PP2, PM2_Supporting BP4, PP3 The variant NM_001005361.3:c.1840G>A in DNM2 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 614 (p.Asp614Asn). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.549, which does not meet any codes. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in one proband who presented with distal weakness, radial distribution of sarcoplasmic strands in the majority of type I fibers, and characteristic muscle imaging (0.5pt, PS4_Moderate; PMID: 23374900). In addition, the family had four affected segregations reported (PP1_Moderate; PMID: 23374900). In summary, the variant meets criteria to be classified as likely pathogenic for centronuclear myopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP (Specification Version 1): PS4_Moderate, PP1_Moderate, PM2_Supporting, PP2 (ClinGen Congenital Myopathies VCEP specifications version 1; May 12th, 2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA404041025/MONDO:0018947/148 2025-05-12 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:35854 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0011175 infores:hetionet NCBIGene:23259 biolink:causes MONDO:0014018 infores:monarchinitiative not_provided not_provided HGNC:29106 MONDO:0014018 uuid:a907bd80-b5bf-41c4-b1ef-bc1a457cff2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0042571 infores:hetionet CHEBI:17650 biolink:causes HP:0002953 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0262431 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0003123 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0042401 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006829 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0023501 infores:hetionet CHEBI:29007 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C1443060 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020039 infores:hetionet CHEBI:15366 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB03166 UMLS:C0020488 infores:hetionet CHEBI:45863 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151825 infores:hetionet CHEBI:92923 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0002962 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0022660 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0948594 infores:hetionet CHEBI:4657 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0010520 infores:hetionet CHEBI:10112 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C2047937 infores:hetionet CHEBI:9130 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0023518 infores:hetionet CHEBI:8485 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0022568 infores:hetionet CHEBI:71417 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0027497 infores:hetionet CHEBI:7907 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0035229 infores:hetionet CHEBI:9599 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0085636 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0017160 infores:hetionet CHEBI:75722 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011168 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013595 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017675 infores:hetionet CHEBI:40237 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0476281 infores:hetionet CAID:CA145842 biolink:causes MONDO:0100453 infores:clingen CAID:CA145842 MONDO:0100453 PMID: Benign BA1, BP4, BS2 The NM_000180.4(GUCY2D):c.154G>T (p.Ala52Ser) variant is predicted to replace the alanine at position p.52 with serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.6857, with 26306 alleles / 37974 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 95,479 adult individuals in gnomAD v4.1.0 (BS2). The computational predictor REVEL gives a score of 0.126, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA145842/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true UNII:9430ZR8ZAN biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0232602 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0013395 infores:hetionet CHEBI:87681 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0547030 infores:hetionet CHEBI:9598 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0151825 infores:hetionet CHEBI:16469 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0392684 infores:hetionet CHEBI:6761 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0857305 infores:hetionet CHEBI:4858 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0018681 infores:hetionet CHEBI:49668 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0242184 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0005940 infores:hetionet CAID:CA229543 biolink:causes MONDO:0009861 infores:clingen CAID:CA229543 MONDO:0009861 PMID:26503515PMID:26322415PMID:28982351PMID:27121329PMID:26322415PMID:30050108 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The c.440C>T (p.Pro147Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 27121329, 26322415, 16527067, 30050108, 28982351). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variants p.R261Ter (PMID: 27121329); c.611A>G (PMID: 30050108); p.S70del (PMID: 28982351) (PM3_strong). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229543/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports UNII:3QJA87N40S biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0013404 infores:hetionet CHEBI:32293 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0005741 infores:hetionet CHEBI:51230 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0010037 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0178298 infores:hetionet CHEBI:31711 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0019080 infores:hetionet CHEBI:50131 biolink:causes UMLS:C1096243 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1096243 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011849 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0008370 infores:hetionet CHEBI:114785 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0020621 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0340464 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002878 infores:hetionet CHEBI:145499 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0008350 infores:hetionet NCBIGene:7428 biolink:causes MONDO:0007763 infores:monarchinitiative not_provided not_provided HGNC:12687 MONDO:0007763 uuid:24e71290-23f1-4f4f-870e-c1346763c7e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0231807 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0018801 infores:hetionet CHEBI:50730 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0151904 infores:hetionet CAID:CA9301512 biolink:causes MONDO:0010938 infores:clingen CAID:CA9301512 MONDO:0010938 PMID: Likely Benign BS1 The NM_000215.4(JAK3):c.2773C>A (p.Arg925Ser) missense variant has a popmax filtering allele frequency in gnomAD v2.1.1 is 0.002278 (based on 94/34558 alleles in the Latino/Admixed American population), which is above the ClinGen SCID VCEP threshold of >0.00100 (BS1). To our knowledge, the variant has not been reported in a SCID patient in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9301512/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9139 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004245 infores:hetionet CHEBI:42355 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0013378 infores:hetionet CHEBI:27504 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C2939420 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0021053 infores:hetionet CHEBI:8768 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0018965 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0037274 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0036572 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0033975 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003150 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017412 infores:hetionet CHEBI:61049 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0542571 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0852908 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0033975 infores:hetionet CHEBI:5103 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0027424 infores:hetionet CHEBI:63681 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0235025 infores:hetionet CHEBI:52717 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0700200 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0007787 infores:hetionet NCBITaxon:35788 biolink:causes MONDO:0000227 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:35788 MONDO:0000227 CHEBI:3423 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0917801 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085096 infores:hetionet CHEBI:49575 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0002622 infores:hetionet CHEBI:6437 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0004134 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0003469 infores:hetionet CHEBI:4657 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C1291077 infores:hetionet CHEBI:2549 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0030193 infores:hetionet NCBIGene:1258 biolink:causes MONDO:0013413 infores:monarchinitiative not_provided not_provided HGNC:2151 MONDO:0013413 uuid:5616fb2d-233a-4620-9c98-cc8994882be0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011551 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0162429 infores:hetionet CHEBI:3223 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C2047937 infores:hetionet CHEBI:47780 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0024902 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0162429 infores:hetionet CHEBI:4995 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0022346 infores:hetionet CHEBI:135351 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0041834 infores:hetionet CHEBI:75922 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0042907 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1956346 infores:hetionet GO:1902366 biolink:causes GO:0001756 infores:ubergraph knowledge_assertion manual_agent GO:1902366 GO:0001756 CHEBI:63616 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0030305 infores:hetionet CHEBI:3423 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0030554 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0022660 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0020649 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027796 infores:hetionet CHEBI:144551 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0043352 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0011616 infores:hetionet CHEBI:68575 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C1260880 infores:hetionet CHEBI:45863 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013362 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0027769 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0010823 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0233571 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0037199 infores:hetionet CHEBI:50131 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0085077 infores:hetionet CHEBI:6539 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0234518 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0006852 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0546947 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0546947 infores:hetionet CHEBI:63632 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0019080 infores:hetionet CHEBI:17334 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0231528 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0003864 infores:hetionet CHEBI:9130 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0011603 infores:hetionet NCBIGene:6948 biolink:causes MONDO:0010149 infores:monarchinitiative not_provided not_provided HGNC:11653 MONDO:0010149 uuid:b4d10bdb-7a0a-44ba-8532-b11012b3d528 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0231218 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0474381 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0474381 infores:hetionet CHEBI:4453 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0085633 infores:hetionet CHEBI:94385 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0018790 infores:hetionet CHEBI:10125 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0851578 infores:hetionet NCBIGene:4654 biolink:causes MONDO:0033548 infores:monarchinitiative not_provided not_provided HGNC:7611 MONDO:0033548 uuid:d7df1b1a-2f4b-415f-a151-304db3e9f13e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8461 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0022346 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1384353 infores:hetionet CHEBI:7936 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037763 infores:hetionet CHEBI:8888 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011124 infores:hetionet CHEBI:8869 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0027796 infores:hetionet CHEBI:31932 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0027707 infores:hetionet CAID:CA512341293 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341293 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1122C>G (p.Ala374=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341293/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:188986 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0033774 infores:hetionet CHEBI:7478 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0039070 infores:hetionet CHEBI:135342 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020625 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0684249 infores:hetionet CHEBI:46195 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0036973 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151828 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0032285 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019360 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0040034 infores:hetionet CHEBI:142290 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0009763 infores:hetionet NCBIGene:526 biolink:causes MONDO:0014646 infores:monarchinitiative not_provided not_provided HGNC:854 MONDO:0014646 uuid:495865e1-912e-4a3f-af89-6032e1e05a84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011615 infores:hetionet CHEBI:36704 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0231218 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027769 infores:hetionet CHEBI:3176 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0231919 infores:hetionet CHEBI:135961 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0030252 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0852925 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0852925 infores:hetionet CHEBI:253342 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C2607914 infores:hetionet CHEBI:28445 biolink:causes MONDO:0004004 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0235025 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006826 infores:hetionet CHEBI:4784 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0037383 infores:hetionet CHEBI:4995 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085628 infores:hetionet CHEBI:6339 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0149745 infores:hetionet CHEBI:52717 biolink:causes HP:0012415 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0476337 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0008325 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0017601 infores:hetionet CHEBI:59773 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0042384 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151609 infores:hetionet CAID:CA187442 biolink:causes MONDO:0007648 infores:clingen CAID:CA187442 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2 The CDH1 c.4G>A (p.Gly2Ser) missense variant has a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; unpublished). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA187442/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6532 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0037274 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0235960 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235960 infores:hetionet NCBITaxon:543 biolink:causes DOID:50360 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:543 MESH:D004756 DB01112_MESH_D004756_1DB01607_MESH_D004756_1DB00415_MESH_D004756_1DB00319_MESH_D004756_1DB01332_MESH_D004756_1DB01165_MESH_D004756_1DB00684_MESH_D004756_1DB00355_MESH_D004756_1DB01212_MESH_D004756_1DB00438_MESH_D004756_1DB00479_MESH_D004756_1DB02703_MESH_D004756_1DB09324_MESH_D004756_1DB00798_MESH_D004756_1DB01326_MESH_D004756_1 CHEBI:6847 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0085631 infores:hetionet CAID:CA1244277 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244277 MONDO:0005338 PMID: Likely Benign BS1, BP4 BS3, BP7, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.440G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 147 (p.Arg147Gln). The highest minor allele frequency of this variant was in the Ashkenazi Jewish genetic ancestry group of gnomAD (v4.1.0) = 0.008748, which met the ≥ 0.001 threshold set for BS1 (259 alleles out of 29,606, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.082, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1, BP4_Moderate Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244277/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63605 biolink:causes UMLS:C0854080 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0854080 infores:hetionet CHEBI:145499 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013428 infores:hetionet CHEBI:64019 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0011991 infores:hetionet CHEBI:51860 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085595 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0031350 infores:hetionet CHEBI:135929 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0033117 infores:hetionet CHEBI:6541 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0023222 infores:hetionet CHEBI:7903 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0023380 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037274 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C1720775 infores:hetionet CHEBI:7577 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0151786 infores:hetionet CHEBI:7824 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0547030 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0948089 infores:hetionet NCBIGene:8888 biolink:causes MONDO:0029131 infores:monarchinitiative not_provided not_provided HGNC:6946 MONDO:0029131 uuid:731f9ca0-ac35-46fc-8b04-6b820281eb26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:197322 biolink:causes MONDO:0013661 infores:monarchinitiative not_provided not_provided HGNC:27288 MONDO:0013661 uuid:bd06a9e3-b276-47af-8368-3e75103342c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042963 infores:hetionet CHEBI:63621 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020433 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0035258 infores:hetionet NCBIGene:196 biolink:causes MONDO:0032689 infores:monarchinitiative not_provided not_provided HGNC:348 MONDO:0032689 uuid:9bd6db1b-88ad-46d1-9d9a-910317ef0207 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes UMLS:C0238201 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0238201 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0036830 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0333641 infores:hetionet CHEBI:3723 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1457883 infores:hetionet CHEBI:63620 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0019080 infores:hetionet CHEBI:15552 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0003467 infores:hetionet CAID:CA16603033 biolink:causes MONDO:0018875 infores:clingen CAID:CA16603033 MONDO:0018875 PMID: Pathogenic PS3, PS2, PM1_Supporting, PP3_Moderate, PP4, PM2_Supporting BP4, BA1, PS4, PS1, PM5, BS1, BS3, BS4, BP7, PVS1, PP1, BS2 The NM_000546.6: c.578A>C variant in TP53 is a missense variant predicted to cause substitution of histidine by proline at amino acid 193 (p.His193Pro). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.5922; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). At least one individual with this variant was found to have a variant allele fraction of 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: SCV002651939.1). This variant has an allele frequency of 6.196e-7 (1/1614048 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has 8 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3_Moderate, PS2, PP4, PM2_Supporting, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603033/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7936 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0392525 infores:hetionet CHEBI:136040 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0027497 infores:hetionet CAID:CA8365468 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365468 MONDO:0100453 PMID: Benign BP4, BS1, BS2 BP2 The NM_000180.4(GUCY2D):c.74C>T (p.Ser25Phe) variant is expected to replace the serine at position p.25 with phenylalanine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.004327, with 5044 alleles / 1138600 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 8 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.146, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). This variant has been reported in a proband with early-onset severe retinal dystrophy in the heterozygous state, either in cis or in trans with the NM_000180.4(GUCY2D):c.2516C>G (p.Thr839Arg) variant, which has been previously reported in association with GUCY2D-related dominant retinopathy (PMID: 35205358). Since the carrier status of this variant in a patient with an alternative cause of disease does not support or refute the evidence that this variant may cause disease, the BP2 code is not met. In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2, BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365468/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4356 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0011253 infores:hetionet CAID:CA3232037 biolink:causes MONDO:0012163 infores:clingen CAID:CA3232037 MONDO:0012163 PMID: Pathogenic PM2_Supporting, PM3, PVS1 The c.616C>T (p.Arg206Ter) (NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The filtering allele frequency (the upper threshold of the 95% CI of 4/60022) of the c.616C>T variant in IL7R is 0.00001779 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Patients (PMIDs : 15615257,35464432, 28747913, 33628209, 32482412) were found to be homozygous for this mutation (1 pt.) (PM3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met,PM2_Supporting,PM3 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3232037/MONDO:0012163/119 2024-01-30 2024-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45716 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0009450 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0340726 infores:hetionet CHEBI:71940 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0013404 infores:hetionet CAID:CA397723170 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723170 MONDO:0008723 PMID:20060901 Uncertain Significance PM2_Supporting, PP3, PM3_Supporting, PP4_Moderate PM5, PM1, PM4, BP2, PS1, BP7, PVS1 The c.562G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by serine at amino acid 188 (p.Gly188Ser). Information provided to the ACADVL VCEP provided by an external clinical laboratory shows increased C14:1 level in a pattern consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in one patient (PP4_moderate) who was homozygous for the variant (PM3_supporting). One publication describes this variant in an affected individual, but this individual does not meet our PP4 guidelines and was not counted (Nikolayeva, E.A. et al., Symptomatic epilepsy as a manifestation of very long chain acyl-CoA dehydrogenase deficiency. 2008. Rossiiskii Vestnik Perinatologii i Pediatrii 53(3): 87-91 (in Russian)). This variant is absent from gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.882, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PM3_supporting, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated April 12, 2022 and the recurated classification was approved by the expert panel on April 11, 2023. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723170/MONDO:0008723/021 2023-04-11 2023-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3441 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0863113 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0948594 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0042075 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0160390 infores:hetionet CHEBI:135351 biolink:causes HP:0030218 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C1963933 infores:hetionet GO:0021936 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0021936 GO:0007399 CHEBI:10102 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0028738 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0022346 infores:hetionet CHEBI:35854 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0018681 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0038454 infores:hetionet CHEBI:32315 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0231218 infores:hetionet CHEBI:474180 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0085649 infores:hetionet CHEBI:27565 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0042384 infores:hetionet CHEBI:8874 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004093 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0917798 infores:hetionet CHEBI:7798 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0027424 infores:hetionet CHEBI:5165 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0017152 infores:hetionet CHEBI:28364 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0948594 infores:hetionet NCBIGene:5429 biolink:causes MONDO:0010214 infores:monarchinitiative not_provided not_provided HGNC:9181 MONDO:0010214 uuid:bc94cf47-e5ab-49ee-8f90-de1faf02b378 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0002878 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235876 infores:hetionet NCBIGene:51181 biolink:causes MONDO:0009846 infores:monarchinitiative not_provided not_provided HGNC:18985 MONDO:0009846 uuid:40967b1c-bdcf-4a44-b4d2-f15a238c033a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0033774 infores:hetionet CAID:CA229875 biolink:causes MONDO:0009861 infores:clingen CAID:CA229875 MONDO:0009861 PMID:26322415PMID:26322415PMID:18590700 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PS3_Supporting PM5, PM2, BA1, BS1 The NM_000277.1(PAH):c.964G>A (p.Ala322Thr) variant is a missense variant in exon 9/13 of PAH. The variant has been found to reduce PAH enzymatic activity to 11% of wild-type in an Intinc system and 20% of wild-type in a cDNA system in transfected cells (PMID: 18590700) (PS3_supporting). The variant has been previously noted in at least four PKU patients among whom BH4 deficiency was excluded, including in trans with Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4 points); PP4_Moderate). The variant has been previously reported in a Chinese patient with mild hyperphenylalanemia in trans with the p.R111* variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 30050108; PMID: 26322415). It has been noted in a Spanish patient with mild hyperphenylalanemia in trans with the p.S349P variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID: 27121329). It was found in a Slovak patient with mild hyperphenylalanemia in trans with the p.A403V variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded (PMID: 23764561). It has been noted in a Chinese patient with PKU (plasma Phe >120 umol/L; no further specification) and BH4 deficiency excluded in trans with p.R176* (Pathogenic in ClinVar and by the ClinGen PAH VCEP) (PMID: 26600521). Another missense variant at the same site, p.A322G, is classified Pathogenic in ClinVar (ID 616) and by the ClinGen PAH VCEP. 18 heterozygotes and zero homozygotes are present for the variant in gnomAD, corresponding to a global frequency of 0.0000716 and a maximum population frequency of 0.000261; these frequencies exceed the 0.0002 cutoff for use of PM2, but is lower than the 0.002 cutoff for use of BS1. The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.889) (PP3).Classification: PathogenicSupporting Criteria: PS3_supporting; PM3_VeryStrong; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229875/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51173 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0018790 infores:hetionet CAID:CA367400134 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400134 MONDO:0015967 PMID: Likely Pathogenic PM5, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.884G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to valine at codon 295 (p.(Gly295Val)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, another missense variant, c.883G>A p.Gly295Ser, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Lastly, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). In summary, c.884G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Suporting, PP2, PP3, PM1, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400134/MONDO:0015967/086 2023-08-11 2023-08-11 Semidominant inheritance HP:0032113 Supports CAID:CA412745725 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745725 MONDO:0100437 PMID: Pathogenic PP3, PP4, PM2_Supporting, PS4, PP1_Strong NM_001034853.2(RPGR):c.154G>A (p.Gly52Arg) is an apparent missense variant encoding the substitution of glycine with arginine at amino acid 52, and is located in the final nucleotide of exon 2. The splicing impact predictor SpliceAI gives a score of 0.66 for splice donor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinitis pigmentosa with electroretinogram responses characteristic of rod-cone dystrophy (1 pt), genotyping by exome sequencing identifying no alternative basis for inherited retinal disease (2 pts), visual field changes (0.5 pts), and fundus abnormalities (0.5 pts), which together are specific for RPGR-related retinopathy (4 points, PMID: 33372982, PP4). The variant has been reported to segregate with retinal dystrophy through at least 4 affected meioses from 2 families (PP1_Strong; PMID: 22888088, DOI 10.1055/s-0044-1779398). This variant has been reported in at least 6 apparently unrelated probands meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 16969763, PMID: 22888088, PMID: 35432464, PMID: 36445968, PMID: 28559085, DOI 10.1055/s-0044-1779398, PS4_Strong). Other publications have reported probands carrying this variant but did not meet the requirements for inclusion in the PS4 code (PMID: 34985506, PMID: 31213501, PMID: 37798099, PMID: 33372982). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP3, PP4, PP1_Strong, and PS4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745725/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:3286 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0004093 infores:hetionet NCBIGene:91624 biolink:causes MONDO:0013147 infores:monarchinitiative not_provided not_provided HGNC:29557 MONDO:0013147 uuid:67f955e8-79a7-43fe-aa89-80c891e40e78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0333641 infores:hetionet CHEBI:63589 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020580 infores:hetionet CHEBI:135342 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C3203358 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0948089 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0011609 infores:hetionet GO:0030516 biolink:causes GO:0061564 infores:ubergraph knowledge_assertion manual_agent GO:0030516 GO:0061564 NCBITaxon:10239 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10239 GO:0006954 DB00719_MESH_D003139_1DB00967_MESH_D003139_1DB01114_MESH_D003139_1DB01176_MESH_D003139_1DB09488_MESH_D003139_1DB04837_MESH_D003139_1DB00341_MESH_D003139_1DB06691_MESH_D003139_1 CHEBI:76010 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0018681 infores:hetionet CHEBI:36795 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0151905 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0042571 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0040034 infores:hetionet CHEBI:6129 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0004093 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151849 infores:hetionet CHEBI:31859 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0043352 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0948089 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030312 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0009450 infores:hetionet CHEBI:15765 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0344232 infores:hetionet CHEBI:3732 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0017178 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0007785 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0235318 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0235318 infores:hetionet CHEBI:40279 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0232462 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020615 infores:hetionet CHEBI:6888 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0240735 infores:hetionet CHEBI:6532 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0085932 infores:hetionet CHEBI:39669 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0040034 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0267792 infores:hetionet CHEBI:3756 biolink:causes HP:0000496 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0497202 infores:hetionet CHEBI:35553 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0020458 infores:hetionet NCBIGene:126206 biolink:causes MONDO:0957231 infores:monarchinitiative not_provided not_provided HGNC:21269 MONDO:0957231 uuid:d6d36c74-1621-4d6a-880f-4e64de38712a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0231218 infores:hetionet CHEBI:3723 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0497156 infores:hetionet CHEBI:36791 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0558401 infores:hetionet CHEBI:135342 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0036508 infores:hetionet CAID:CA16020975 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020975 MONDO:0009861 PMID:24350308 Uncertain Significance PM2, PP4, PP3, PM3_Supporting The c.1235T>G (p.Val412Gly) variant in PAH meets criteria to be classified as uncertain significance due to insufficient evidence. PAH-specific ACMG/AMP criteria applied: PM2: Absent from population databases (1000 Genomes, ExAC). PP3: Computational prediction tools suggest that the c.1235T>G variant is damaging to protein function. Evolutionarily conserved. PP4: Patient has classic PKU (PMID:24350308). PM3_Supporting: Found to co-occur with p.R408W in one patient with classic PKU, but no additional studies to demonstrate phase of variants. No other PAH variants identified in patient (PMID:24350308). Undefined BH4 responsiveness (PMID:24350308) Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020975/MONDO:0009861/006 2020-06-25 2020-06-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:188986 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0178298 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0036454 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1258215 infores:hetionet CHEBI:71415 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0231218 infores:hetionet CHEBI:8382 biolink:causes HP:0033688 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0701810 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0919823 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0919823 infores:hetionet CHEBI:61033 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0080274 infores:hetionet CHEBI:41879 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0338831 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011848 infores:hetionet CHEBI:5132 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0438215 infores:hetionet CHEBI:4027 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0036980 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0032285 infores:hetionet CHEBI:5790 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0009676 infores:hetionet CHEBI:75722 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033771 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0040034 infores:hetionet UMLS:C0145185 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0948089 infores:hetionet CHEBI:15765 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0026827 infores:hetionet CHEBI:31236 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0497156 infores:hetionet CHEBI:4562 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0003467 infores:hetionet CHEBI:9720 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0344232 infores:hetionet CHEBI:6539 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0004134 infores:hetionet CHEBI:474180 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0030193 infores:hetionet CHEBI:39112 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0013182 infores:hetionet CAID:CA410204071 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204071 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.160G>A (p.Glu54Lys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204071/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:66876 biolink:causes UMLS:C0949070 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0949070 infores:hetionet CAID:CA320250819 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250819 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*316G>T is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant remains uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250819/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6904 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0085633 infores:hetionet CHEBI:31348 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151908 infores:hetionet CHEBI:3213 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0012833 infores:hetionet CAID:CA254241 biolink:causes MONDO:0800472 infores:clingen CAID:CA254241 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PP1_Strong, PP3_Strong BP4, BA1, PM1, PM4, PM5, PS3, PS1, PS2, BP7, BS1, BS4, PVS1 The c.1159G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Glutamic acid by Lysine at amino acid 387 (p.Glu387Lys). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1) = 0.0004333 (26 alleles out of 59998), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.961, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assay reported did not meet the OddsPath threshold (> 2.1) (PMIDs: 23218183, 27243976) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). 3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 18414103), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in five individuals with a CYP1B1-related phenotype. Three of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) (PMIDs: 21815720, 23218701). Two individuals are homozygous (non-consanguineous) for the variant (PMIDs: 21081970, 16735994). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 17 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very strong, PP1_Strong, PP3_Strong, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA254241/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50742 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0011603 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0042514 infores:hetionet GO:0048374 biolink:causes GO:0048369 infores:ubergraph knowledge_assertion manual_agent GO:0048374 GO:0048369 CHEBI:5138 biolink:causes UMLS:C0233697 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0233697 infores:hetionet CHEBI:8245 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0043352 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0019158 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0013395 infores:hetionet CAID:CA343724529 biolink:causes MONDO:0005338 infores:clingen CAID:CA343724529 MONDO:0005338 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PP3_Moderate, PP1_Strong BS1, BS3, BP7, PM5, PM4, PS3, PS1, PS2, BA1, BP4 The c.1150G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 384 (p.Asp384Asn). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00001667 (1 allele out of 59,992), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.914, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The assay in this study (PMID: 19234343), measuring solubility of the Asp384Asn protein, did not meet the OddsPath threshold for PS3_Supporting (> 2.1). 20 segregations in 3 families, with JOAG or POAG, have been reported (PMIDs: 23826516, 19234343, 34273563), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 5 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23826516, 11853639, 19234343, 32476818, 34273563), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP1_Strong, PP3_Moderate, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724529/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CAID:CA320642967 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642967 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.145C>A (p.Pro49Thr) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642967/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51860 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0011551 infores:hetionet CHEBI:4887 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C1306341 infores:hetionet CHEBI:39867 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0344232 infores:hetionet CHEBI:2663 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040822 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0019151 infores:hetionet CHEBI:51041 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0019270 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1167965 infores:hetionet CAID:CA10578369 biolink:causes MONDO:0021056 infores:clingen CAID:CA10578369 MONDO:0021056 PMID: Uncertain Significance BP1, PS4_Moderate, PM2_Supporting The NM_000038.6(APC):c.4139C>T variant in APC is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid position 1380 (p.Thr1380Ile). This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 points (PS4_Moderate [Ambry Genetics, Invitae]). The variant has been reported in 2 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one unaffected individual with a positive family history for colorectal polyposis (Invitae). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria BP1, PS4_Moderate, PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578369/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA16611747 biolink:causes MONDO:0021056 infores:clingen CAID:CA16611747 MONDO:0021056 PMID: Pathogenic PP3, PS3, PS4_Moderate, PM2_Supporting The c.532-8G>A variant in APC is an intronic variant which is located 8 nucleotides upstream of the splice acceptor site for exon 6. This variant has been reported in 3 families meeting phenotypic criteria, resulting in a total phenotype score of 2.5 (PS4_Moderate; Ambry internal data; Invitae internal data; Leiden, Bonn, PMID 24599579; PMID19196998). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 5 of APC (PP3). RT-PCR and minigene assay demonstrate that this variant impacts splicing by creating a novel splice acceptor site six nucleotides upstream of the regular splice acceptor site of exon 6 which results in the inclusion of six nucleotides including a premature termination codon. A complete splice defect was confirmed using transcript-specific PCR and SNP analysis of c.1458T>C (PS3_VeryStrong; PMID 19196998). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_VeryStrong; PS4_moderate; PM2_supporting; PP3 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16611747/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5130 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0041582 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0017605 infores:hetionet CAID:CA2739267603 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267603 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1432_1433del (p.Arg478AlafsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267603/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CAID:CA253918 biolink:causes MONDO:0015152 infores:clingen CAID:CA253918 MONDO:0015152 PMID:35028538 Pathogenic PM5, PP4_Strong, PM3_Supporting, PP3, PP1, PS3_Moderate, PM2_Supporting The NM_003494.4: c.895G>T variant in DYSF, which is also known as NM_001130987.2: c.991G>T p.(Gly331Trp), is a missense variant predicted to cause substitution of glycine by tryptophan at amino acid 299, p.(Gly299Trp). This variant has been reported in a homozygous state in at least one individual with clinical features of LGMD (0.5 pts, PMID: 18306167, 28877744; PM3_Supporting). At least one patient had a clinical diagnosis or suspicion of LGMD and severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 28877744; PP4_Strong). This variant has also been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 18306167; PP1). The highest frequency for this variant in gnomAD v4.1.0 is 0.00001098 in the South Asian population (1/91082 alleles), which is lower than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly299Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). The computational predictor REVEL gives a score of 0.968, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In addition, another missense variant at the same codon, p.(Gly299Arg) resulting from either c.895G>A or c.895G>C, has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA253918/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31980 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0042373 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0947999 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0034065 infores:hetionet CHEBI:8888 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0232461 infores:hetionet UMLS:C0065374 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0220870 infores:hetionet CAID:CA2573054926 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573054926 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.999dup (p.Arg334fs) is a frameshift variant in exon 8 which is predicted to not undergo nonsense-mediated mRNA decay (PVS1_strong). It is downstream of c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573054926/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16469 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0392171 infores:hetionet CHEBI:17026 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0220870 infores:hetionet CHEBI:9720 biolink:causes MONDO:0005900 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0030583 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853312 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853312 infores:hetionet CHEBI:59773 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0002994 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0521839 infores:hetionet CAID:CA16616458 biolink:causes MONDO:0010305 infores:clingen CAID:CA16616458 MONDO:0010305 PMID: Uncertain Significance PM2, BP4 The NM_005629.4(SLC6A8):c.116G>A (p.Gly39Asp) variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Aspartic Acid at amino acid 39 (p.Gly39Asp). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.107 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing (BP4). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:410221). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616458/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CAID:CA229414 biolink:causes MONDO:0009861 infores:clingen CAID:CA229414 MONDO:0009861 PMID:21307867PMID:9860305 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS3 PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229414/MONDO:0009861/006 2018-08-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8207 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0027497 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0019061 infores:hetionet CHEBI:50378 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0037274 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0403632 infores:hetionet CHEBI:10023 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0221201 infores:hetionet NCBIGene:10312 biolink:causes MONDO:0009815 infores:monarchinitiative not_provided not_provided HGNC:11647 MONDO:0009815 uuid:8e0659f4-ed06-4866-ac49-2a4076dec707 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030196 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0037274 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0027765 infores:hetionet CHEBI:490877 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0340865 infores:hetionet CAID:CA412741113 biolink:causes MONDO:0100437 infores:clingen CAID:CA412741113 MONDO:0100437 PMID: Uncertain Significance PS1_Moderate, PP3, PM2_Supporting PS4 NM_001034853.2(RPGR):c.934G>T (p.Asp312Tyr) is a missense variant located in the final nucleotide of exon 8, and encodes the substitution of aspartic acid with tyrosine at amino acid 312. The splicing impact predictor SpliceAI gives a score of 0.97, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3). This variant is outside the +/- 1,2 dinucleotide and meets the PP3 code due to predicted splicing disruption and another predicted splicing variant in the same donor site, NM_001034853.2(RPGR):c.934+1G>T (PMID: 14564670), was previously classified as a pathogenic variant for RPGR-related retinopathy by ClinGen X-linked IRD VCEP (PS1_Moderate). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 affected proband (PMID: 14564670), however, the number of individuals meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, with decreased or absent cone and/or rod electroretinogram responses, was fewer than the requirement of 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0: PS1_Moderate, PP3, and PM2_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412741113/MONDO:0100437/106 2025-07-31 2025-07-31 X-linked inheritance HP:0001417 Inconclusive true CHEBI:4814 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0018099 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0001339 infores:hetionet CHEBI:31638 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0042963 infores:hetionet CHEBI:8597 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0001824 infores:hetionet CHEBI:50275 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020625 infores:hetionet NCBIGene:51816 biolink:causes MONDO:0014306 infores:monarchinitiative not_provided not_provided HGNC:1839 MONDO:0014306 uuid:704e6543-c691-4793-bc8c-f7cbbc4241c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92712 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0013404 infores:hetionet CHEBI:171719 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0026896 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1861172 infores:hetionet CAID:CA10360807 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360807 MONDO:0010725 PMID: Likely Benign BS1 BP4, PP3 The NM_000330.4(RS1):c.88G>A variant is a missense variant encoding the substitution of Glutamic acid with Lysine at amino acid 30. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001598 among hemizygous individuals, with 63 variant alleles / 394247 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >>0.00002 (BS1). The computational predictor REVEL gives a score of 0.479, which is between the ClinGen X-linked IRD VCEP threshold of >0.664 and <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes do not apply. In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BS1. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360807/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:48947 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0019080 infores:hetionet GO:2000028 biolink:causes GO:0048608 infores:ubergraph knowledge_assertion manual_agent GO:2000028 GO:0048608 NCBIGene:265 biolink:causes MONDO:0010521 infores:monarchinitiative not_provided not_provided HGNC:461 MONDO:0010521 uuid:8b9d9b42-67ba-44ed-a501-c1e0a90ba604 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410202793 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202793 MONDO:0011071 PMID:26175287PMID:26175287PMID:26175287 Pathogenic PVS1, PS4_Supporting, PM2_Supporting, PP1 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS3, BS1, BS4, BP7, BP5, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP4 The NM_001754.4:c.352-1G>A variant is a canonical splice site variant that is predicted to introduce a frameshift and premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 26175287). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202793/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50381 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0151786 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040261 infores:hetionet CHEBI:35677 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0234215 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0860871 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0162830 infores:hetionet CHEBI:63629 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0033774 infores:hetionet CAID:CA386960044 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960044 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1, PP4_Moderate, PP3 PS4 The c.439C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to aspartic acid at codon 147(p.(His147Asp)) of NM_000545.8. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonyurea sensitive) (PP4_Moderate; internal lab contributors). In summary, c.439C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PM1, PP4_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960044/MONDO:0015967/017 2025-10-27 2025-11-21 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7986 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0013378 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0160390 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0600041 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0600041 infores:hetionet CHEBI:50861 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0042963 infores:hetionet CHEBI:15553 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020458 infores:hetionet CHEBI:3215 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013144 infores:hetionet CHEBI:7959 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0002390 infores:hetionet CAID:CA340742486 biolink:causes MONDO:0100368 infores:clingen CAID:CA340742486 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP4, PP1, PP3, PM2_Supporting NM_000329.3(RPE65):c.1301C>A is a missense variant encoding a substitution of alanine by glutamic acid at codon 434. This variant is present in gnomAD v.4.0.0 at a frequency of 0.0000008994, with 1/1111886 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In the Middle Eastern genetic ancestry group, the frequency of 1/5768 alleles (0.0001734) is also lower than the PM2_Supporting threshold. This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variant confirmed in trans (1 pt, PMID: 31273949), the NM_000329.3(RPE65):c.95-2A>T variant suspected in trans (0.5 pts, LOVD), or the NM_000329.3(RPE65):c.74C>T (p.Pro25Leu) variant suspected in trans (0.5 pts, PMID: 29033008) all of which were previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31273949, PP1). The computational predictor REVEL gives a score of 0.769, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RPE65 function (PP3). At least one proband harboring this variant exhibits a phenotype including extinguished rod ERG responses (0.5 pts), fundus albipunctatus / white dots (2 pts), onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), and night blindness (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 pts, PMID: 31273949, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340742486/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49662 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0007097 infores:hetionet CAID:CA2580611076 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580611076 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 PS4, PP4 The c.675del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 225 (NM_000545.8), adding 8 novel amino acids before encountering a stop codon (p.(Ser225ArgfsTer8)). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:11806470, PMID:33245425, PMID:1883825). One of the individuals and her sister had a phenotype suggestive of HNF1A-monogenic diabetes; however, the MODY probability was slightly below 50% and HNF4A was not evaluated, and PP4 could not be applied (PMID:11806470). This variant segregated with diabetes, with at least seven informative meioses in two families with MODY (PP1; PMID:11806470, PMID:33245425). In summary, c.675del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580611076/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3561 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0006277 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0028738 infores:hetionet CHEBI:5864 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0035222 infores:hetionet CHEBI:45863 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0003962 infores:hetionet CHEBI:7956 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0341012 infores:hetionet CHEBI:100241 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011168 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0234215 infores:hetionet CHEBI:91583 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0948594 infores:hetionet CHEBI:6121 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0015230 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0037274 infores:hetionet CHEBI:8665 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0036572 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0595930 infores:hetionet CHEBI:6754 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0549249 infores:hetionet CHEBI:10023 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1720775 infores:hetionet CHEBI:39585 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0013404 infores:hetionet CHEBI:28241 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0003123 infores:hetionet CHEBI:32139 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0035078 infores:hetionet CHEBI:8378 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0031256 infores:hetionet CHEBI:39867 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0027540 infores:hetionet CHEBI:521033 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0021053 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0034063 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0857172 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0857172 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151735 infores:hetionet CHEBI:63577 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0006277 infores:hetionet CHEBI:68534 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0018944 infores:hetionet CHEBI:27779 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0002994 infores:hetionet CHEBI:585948 biolink:causes HP:0003365 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0019559 infores:hetionet CHEBI:8080 biolink:causes MONDO:0001999 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0152171 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0004238 infores:hetionet CHEBI:93305 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0001824 infores:hetionet CHEBI:63681 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0015672 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0085584 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0015376 infores:hetionet CHEBI:6912 biolink:causes HP:5200231 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0235013 infores:hetionet CHEBI:9571 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0040034 infores:hetionet CHEBI:3647 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0040822 infores:hetionet CHEBI:50729 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C1443060 infores:hetionet CHEBI:3499 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0518015 infores:hetionet CHEBI:31236 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085631 infores:hetionet CAID:CA320250714 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250714 MONDO:0011071 PMID: Benign BP4, BP7, BS1 PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*569T>G has a MAF of 0.00092 (0.092%, 8/8686, 31186 alleles) in the African subpopulation of the gnomAD cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). REVEL score not available because synonymous variant and SpliceAI predicts 0.00 splicing impact for donor/acceptor loss/gain which is ≤ 0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.420291 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250714/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50381 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0004604 infores:hetionet NCBIGene:3735 biolink:causes MONDO:0030967 infores:monarchinitiative not_provided not_provided HGNC:6215 MONDO:0030967 uuid:a9960fd3-1c79-41cc-931d-d7ca8961471b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C3665347 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017152 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0281981 infores:hetionet CAID:CA6401966 biolink:causes MONDO:0019565 infores:clingen CAID:CA6401966 MONDO:0019565 PMID: Uncertain Significance PP3 PM2, PP4, PM5, BP5, BS1 NM_000552.5:c.6553C>T is a missense variant in VWF predicted to cause substitution of arginine by tryptophan at amino acid 2185. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0001538 (based on 21/91066 alleles in the South Asian population). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold (>0.01) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. At least 1 patient with this variant has been diagnosed with VWD Type 1 based on reduced quantity of VWF, with limited detail available (PMID: 28916584). A second patient was part of a VWD 2M cohort but has lab phenotypes more consistent with VWD Type 1, particularly reduced quantity of VWF:Ag and proportional decreases in VWF activity, collagen binding, and Factor VIII activity, with normal multimers (PMID: 34758185, PMID: 35747851). Although this variant has been observed in 1 patient with the p.Pro1266Leu and p.Val1279Ile variants also present (either in cis or in trans, PMID: 34758185), BP5 was not considered as neither variant has yet been classified by the ClinGen VWD VCEP. The computational predictor REVEL gives a score of 0.73, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6401966/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Inconclusive true CHEBI:75722 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0006145 infores:hetionet CHEBI:7445 biolink:causes HP:0025694 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0346306 infores:hetionet CHEBI:2611 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233754 infores:hetionet CAID:CA281951 biolink:causes MONDO:0021060 infores:clingen CAID:CA281951 MONDO:0021060 PMID: Likely Pathogenic PM1, PM6, PM2, PP3, PP2, PS4_Supporting PS1, PS3, PS2, BS3, BS4, BS1, BP5, BP7, PM5, PM4, BS2, PP1, BP3, BP2, BP4, BP1, BA1 The c.740T>C (p.Phe247Ser) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6, PS4_Supporting; GeneDx internal data; GTR Lab ID: 26957; NOT SUBMITTED TO CLINVAR YET). A different pathogenic missense variant has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not applied due to PM1 application; ClinVar 55793, 180784). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe247Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PM1, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA281951/MONDO:0021060/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4995 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0040479 infores:hetionet CAID:CA915940723 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940723 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The ITGA2B frameshift variant NM_000419.5:c.245dup is expected to introduce a premature termination codon 20 amino acids downstream (p.Gly83ArgfsTer20) in exon 2/30 and the resulting mRNA product is predicted to be susceptible to nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT06, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PP4_moderate, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940723/MONDO:0100326/011 2021-08-17 2021-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA350338507 biolink:causes MONDO:0015924 infores:clingen CAID:CA350338507 MONDO:0015924 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP3, PM4 The NM_001204.7(BMPR2) c.529+2T>C variant is located in the canonical donor splice site of intron 4. It is predicted to cause skipping of biologically relevant exon 4 (111 bp), resulting in an in-frame deletion of amino acids Ser140-Thr176 within the transmembrane domain, that is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1, so PP3 was not applied to avoid double counting. Although the variant is predicted to cause a change in the length of the protein due to in-frame deletion, no functional data are available and thus PM4 was not applied. This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350338507/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:51422 biolink:causes MONDO:0008685 infores:monarchinitiative not_provided not_provided HGNC:9386 MONDO:0008685 uuid:af905c34-d8e1-4e7b-a1ec-653bd67d8120 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013362 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0036454 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0006145 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0021053 infores:hetionet CHEBI:681850 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0428974 infores:hetionet CHEBI:6375 biolink:causes HP:0030142 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0159060 infores:hetionet UMLS:C0657912 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235267 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0024305 infores:hetionet CHEBI:39867 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0018524 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0549373 infores:hetionet CHEBI:136040 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0018681 infores:hetionet CHEBI:5118 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2830004 infores:hetionet CHEBI:8499 biolink:causes MONDO:0008364 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0034734 infores:hetionet CHEBI:10127 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0015732 infores:hetionet UMLS:C0004609 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020580 infores:hetionet CHEBI:119486 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027540 infores:hetionet NCBIGene:5956 biolink:causes MONDO:0010563 infores:monarchinitiative not_provided not_provided HGNC:9936 MONDO:0010563 uuid:ec56f7fb-285e-4bd0-ab49-60a1e6bc0f13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0233472 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0029882 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020676 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020456 infores:hetionet CHEBI:63611 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0344232 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0027769 infores:hetionet CHEBI:82960 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085610 infores:hetionet CHEBI:7903 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0032227 infores:hetionet CHEBI:101278 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0014591 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1443060 infores:hetionet CAID:CA088845 biolink:causes MONDO:0005045 infores:clingen CAID:CA088845 MONDO:0005045 PMID: Uncertain Significance BP4, BA1, PS4, BS1, PM2, PP3, PP1 NM_001276345.2(TNNT2):c.886C>T (p.Arg296Cys) - This variant has been reported in individuals with HCM (PMIDs: 12707239, 15958377, 23785128, 25524337, 27532257, 28790153), but is not statistically increased in individuals with HCM compared to controls [OR lower 95% CI <5] with respect to autosomal dominant disease. Therefore, the PS4 criterion has not been applied. This variant is present in gnomAD (v2.1.1), but did not meet the threshold for PM2. This variant has been observed to segregate with disease (OMGL Data), but is insufficient to apply PP1. Computational prediction tools are inconclusive about the potential impact of this variant (REVEL score <0.7). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA088845/MONDO:0005045/099 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63613 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0231528 infores:hetionet CHEBI:94807 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0235431 infores:hetionet CHEBI:45409 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020458 infores:hetionet CHEBI:8356 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011206 infores:hetionet CHEBI:42797 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0231218 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0235234 infores:hetionet CHEBI:119915 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013456 infores:hetionet CHEBI:3696 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0004093 infores:hetionet CHEBI:100147 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0002994 infores:hetionet CHEBI:8207 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0018681 infores:hetionet CHEBI:28177 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0038220 infores:hetionet CHEBI:7478 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C1096250 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0023530 infores:hetionet CHEBI:135005 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0151908 infores:hetionet CHEBI:127780 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0016204 infores:hetionet NCBIGene:55773 biolink:causes MONDO:0054669 infores:monarchinitiative not_provided not_provided HGNC:25622 MONDO:0054669 uuid:58666e39-2687-43b0-bd34-4c7136811e45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014518 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0178298 infores:hetionet CHEBI:145499 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0025874 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235848 infores:hetionet CHEBI:53760 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0025222 infores:hetionet CHEBI:7565 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0015230 infores:hetionet CHEBI:72292 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0086565 infores:hetionet CAID:CA410202486 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202486 MONDO:0011071 PMID: Uncertain Significance PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.499A>G (p.Ser167Gly) is a missense variant which affects at least one of the following hotspot residues within the RHD: S167 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.908) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202486/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51230 biolink:causes MONDO:0005844 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0007933 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0877517 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0877517 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009763 infores:hetionet CHEBI:15553 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042963 infores:hetionet CHEBI:4024 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0000731 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0574067 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0011991 infores:hetionet CAID:CA343723635 biolink:causes MONDO:0005338 infores:clingen CAID:CA343723635 MONDO:0005338 PMID: Uncertain Significance BP7, BS1, BS3, PM2, PP3, PP1, PM5, PM4, PS1, PS3, PS2, PS4, BP4, BA1 The c.1349A>G variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 450 (p.Asn450Ser). The highest minor allele frequency of this variant was in the Ashkenazi Jewish genetic ancestry group of gnomAD (v4.1.0) = 0.0001013 (3 alleles out of 29,608), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.551, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): none. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723635/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA409110425 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110425 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PS4_Moderate PP3, PM1, BP4 The c.1283C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of proline to leucine at codon 428 (p.(Pro428Leu)) of NM_175914.5. This variant has a REVEL score of 0.169, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 10447526, internal lab contributors). One of these individuals had a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11) (PP4; internal lab contributors). In summary, c.1283C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4_Moderate, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110425/MONDO:0015967/085 2024-04-07 2024-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes UMLS:C1142017 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1142017 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0027769 infores:hetionet CHEBI:6909 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0011603 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005236 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0302314 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0022660 infores:hetionet CHEBI:32315 biolink:causes MONDO:0003040 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002624 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0003621 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0025061 infores:hetionet CHEBI:50859 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0014724 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018799 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1527311 infores:hetionet CHEBI:7627 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0015230 infores:hetionet CHEBI:63619 biolink:causes UMLS:C3160771 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C3160771 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0518015 infores:hetionet CHEBI:64321 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0015230 infores:hetionet CHEBI:31401 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0017178 infores:hetionet CHEBI:5128 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0020458 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022408 infores:hetionet CHEBI:63607 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0000729 infores:hetionet CHEBI:3437 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0003811 infores:hetionet CHEBI:28971 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0302295 infores:hetionet CHEBI:8768 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0005818 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0040479 infores:hetionet CHEBI:8871 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040822 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0011991 infores:hetionet NCBITaxon:4751 biolink:causes UMLS:C0033775 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D011538 DB09321_MESH_D011538_1 CHEBI:9555 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0003123 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0014130 infores:hetionet GO:2000870 biolink:causes GO:0001553 infores:ubergraph knowledge_assertion manual_agent GO:2000870 GO:0001553 CHEBI:66899 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0042164 infores:hetionet CHEBI:4445 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0264893 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042267 infores:hetionet CHEBI:4653 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0221512 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0948089 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0239062 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0239062 infores:hetionet CHEBI:50131 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0030193 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0854212 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0854212 infores:hetionet CHEBI:31622 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0037317 infores:hetionet CHEBI:9738 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0085631 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0042769 infores:hetionet CHEBI:6539 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0009421 infores:hetionet CAID:CA414913556 biolink:causes MONDO:0010602 infores:clingen CAID:CA414913556 MONDO:0010602 PMID: Likely Pathogenic PM2_Supporting, PP3, PP4, PP1, PS4 The c.5186G>A variant in F8 is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 1729 (p.Gly1729Glu). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The missense variant has a REVEL score of 0.861 (>0.6), meeting criteria for PP3. This variant has been reported in at least 5 patients with mild hemophilia A and type 2N VWD has been ruled out via sequencing of VWF exons 17–20 and 24–27 in at least 1 proband (PMID: 21883705, PMID: 19719828, PMID: 21592259, internal laboratory data). This variant was found to co-segregate with disease in affected family members, with 2 meioses observed in a family (PMID:21592259). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4, PP4_moderate, PP3, PP1, PM2_Supporting. Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414913556/MONDO:0010602/071 2024-10-11 2025-01-07 X-linked inheritance HP:0001417 Supports CHEBI:61390 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0009450 infores:hetionet CAID:CA347216867 biolink:causes MONDO:0015152 infores:clingen CAID:CA347216867 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1_Strong, PM3_Supporting, PM2_Supporting PS1 The NM_003494.4: c.3031G>C variant in DYSF, which is also known as NM_001130987.2: c.3085G>C p.(Gly1029Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1011, p.(Gly1011Arg). This variant affects the last nucleotide of exon 28, and RNAseq analysis has demonstrated two different splice effects: inclusion of intron 28 and skipping of exon 28. Both of these events result in a frameshift and premature truncation for which nonsense mediated decay is expected; however, the possibility of retention of some degree of constitutive splicing was not ruled out (PVS1_Strong_RNA). This variant has been observed in unknown phase with a pathogenic variant in one patient with features consistent with LGMD (NM_003494.4: c.855+1del, 0.5 pts, PMID: 36983702; PM3_Supporting). This patient had a clinical diagnosis of LGMD and absent dysferlin protein expression by immunohistochemistry and western blot of skeletal muscle (PMID: 36983702, 33610434; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/26/2025): PVS1_Strong_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347216867/MONDO:0015152/180 2025-08-26 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2663 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0002878 infores:hetionet CHEBI:70746 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0016204 infores:hetionet GO:0007317 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0048477 CHEBI:2675 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234632 infores:hetionet CHEBI:31439 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00265 UMLS:C0015230 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0267792 infores:hetionet NCBIGene:24148 biolink:causes MONDO:0013516 infores:monarchinitiative not_provided not_provided HGNC:15860 MONDO:0013516 uuid:e3474c3e-96f6-4af9-a353-68006dc08d56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59560 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0037274 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011570 infores:hetionet CHEBI:63608 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0011606 infores:hetionet CHEBI:50648 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0005778 infores:hetionet CHEBI:49375 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0035410 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0162429 infores:hetionet CHEBI:3647 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0002878 infores:hetionet NCBIGene:79058 biolink:causes MONDO:0011655 infores:monarchinitiative not_provided not_provided HGNC:13825 MONDO:0011655 uuid:fbac85ba-5449-4cad-b1a3-335af6256afe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA913171920 biolink:causes MONDO:0044970 infores:clingen CAID:CA913171920 MONDO:0044970 PMID:17266923 Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM6_Supporting, PS3_Supporting The m.14724G>A variant in MT-TE has been reported in two individual with primary mitochondrial disease (PS4_supporting; PMIDs: 17266923, 23847141). The first reported case was a four-year-old boy with encephalopathy, unsteady gait, hypotonia, and cerebellar ataxia (PMID: 17266923). Brain imaging showed periventricular white matter hyperlucencies and basal ganglia calcifications and he had elevated blood lactate. Muscle biopsy showed ragged red and COX-negative fibers, and activities of complexes I and IV were reduced in muscle. The variant was present at 94% heteroplasmy in muscle and 62% in peripheral leukocytes. The variant was undetectable in blood from his mother, sister, and two maternal relatives (PM6_supporting; PMID: 17266923). The second reported case was a 16-year-old boy with psychomotor delay, cerebellar ataxia, exercise intolerance, renal involvement, pigmentary retinopathy, deafness, gastrointestinal involvement, and diabetes mellitus (PMID: 23847141). Brain MRI showed leukodystrophy and cerebellar atrophy and blood lactate was elevated. Muscle biopsy showed ragged red fibers. Heteroplasmy levels and information on family member testing were not provided. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (88.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). Single fiber testing showed higher levels of the variant in COX negative fibers (95.8±1.2%, n=20) than in COX positive fibers (85.8±2.7%, n=17), p<0.01 (PS3_supporting, PMID: 17266923). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913171920/MONDO:0044970/015 2024-03-26 2025-06-13 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:134966 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0032617 infores:hetionet CHEBI:231425 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020456 infores:hetionet CHEBI:50131 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0042023 infores:hetionet CHEBI:6339 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0009676 infores:hetionet CHEBI:3996 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0011124 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C2939465 infores:hetionet CHEBI:6954 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0232462 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0020649 infores:hetionet CHEBI:31413 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0012569 infores:hetionet CHEBI:44032 biolink:causes UMLS:C1387528 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C1387528 infores:hetionet NCBIGene:9780 biolink:causes MONDO:0014797 infores:monarchinitiative not_provided not_provided HGNC:28993 MONDO:0014797 uuid:b1433837-5a71-4913-8a56-55f1a0c3aa98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0221490 infores:hetionet CHEBI:92607 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0004245 infores:hetionet CAID:CA357242 biolink:causes MONDO:0009861 infores:clingen CAID:CA357242 MONDO:0009861 PMID:24350308PMID:24350308PMID:24078561 Likely Pathogenic PM3, PM2, PP4, PP3 The c.110T>C (p.Leu37Pro) variant in PAH is reported in 1 patient with mild PKU. Assessment of BH4 deficiencies not reported. It was detected with a known pathogenic variant, p.R408W. (PMID: 24350308) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, and MutationTaster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA357242/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232498 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0392176 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0006145 infores:hetionet CHEBI:10650 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C3665347 infores:hetionet CHEBI:93635 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0021167 infores:hetionet CHEBI:7494 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151905 infores:hetionet CHEBI:79699 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0027497 infores:hetionet CHEBI:63627 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0011603 infores:hetionet CHEBI:4710 biolink:causes HP:0025233 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0456511 infores:hetionet CHEBI:3698 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0024141 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0011849 infores:hetionet CHEBI:37924 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151579 infores:hetionet CHEBI:132233 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0878544 infores:hetionet CHEBI:6931 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0018790 infores:hetionet REACT:R-HSA-2454202 biolink:causes GO:0002561 infores:drugmechdb knowledge_assertion manual_agent REACT:R-HSA-2454202 GO:0002561 DB00043_MESH_D001249_1DB00043_MESH_D000080223_1 CHEBI:9943 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151904 infores:hetionet CHEBI:63611 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030554 infores:hetionet CHEBI:46081 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0004134 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0853692 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020542 infores:hetionet CHEBI:65173 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0001807 infores:hetionet CHEBI:6804 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C1322281 infores:hetionet CHEBI:5801 biolink:causes UMLS:C1168188 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C1168188 infores:hetionet CAID:CA2499226689 biolink:causes MONDO:0100437 infores:clingen CAID:CA2499226689 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2455_2468dup (p.Gly824Ter) is an insertion variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including childhood onset (1 pt), optic nerve pallor (0.5 pts), pigmentary retinopathy (0.5 pts), poor pupillary light response (0.5 pts), and decreased central vision acuity (0.5 pts), with genotyping by a 365-gene next-generation sequencing panel that excluded alternative causes of disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 34828430, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499226689/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:5050 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0917801 infores:hetionet CHEBI:135342 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0022107 infores:hetionet CHEBI:5280 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151603 infores:hetionet CAID:CA229539 biolink:causes MONDO:0009861 infores:clingen CAID:CA229539 MONDO:0009861 PMID:11385716PMID:17096675PMID:12655553PMID:8659548PMID:23514811PMID:24368688PMID:8659548PMID:26666653 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229539/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16347 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0013395 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0027769 infores:hetionet CHEBI:68642 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0020488 infores:hetionet CHEBI:6149 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0002792 infores:hetionet CHEBI:63611 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151610 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002622 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0001339 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0332534 infores:hetionet NCBIGene:2475 biolink:causes MONDO:0011818 infores:monarchinitiative not_provided not_provided HGNC:3942 MONDO:0011818 uuid:52ff4106-aae8-4f06-9698-3c261b6b854c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0235431 infores:hetionet CHEBI:9137 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0851578 infores:hetionet NCBIGene:9990 biolink:causes MONDO:0000902 infores:monarchinitiative not_provided not_provided HGNC:10914 MONDO:0000902 uuid:2f2de729-1833-4301-beee-a5ee09e3517f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0023530 infores:hetionet CHEBI:8028 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0014457 infores:hetionet CHEBI:3077 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C2047937 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0038454 infores:hetionet NCBIGene:7157 biolink:causes MONDO:0018875 infores:monarchinitiative not_provided not_provided HGNC:11998 MONDO:0018875 uuid:64a8d25d-7fb7-4a13-9324-0d858457b484 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0558489 infores:hetionet CHEBI:15640 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0424790 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0037274 infores:hetionet CHEBI:75246 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0040264 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1519353 infores:hetionet CHEBI:63617 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0242184 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0009806 infores:hetionet CAID:CA251534 biolink:causes MONDO:0009861 infores:clingen CAID:CA251534 MONDO:0009861 PMID:23500595PMID:23500595PMID:8268925 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS3 PM5 The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925; PMID: 23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID: 23500595). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251534/MONDO:0009861/006 2018-08-05 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CAID:CA415086699 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086699 MONDO:0010305 PMID:22281021PMID:22281021 Likely Pathogenic PP1_Moderate, PP3, PM2_Supporting, PP4_Strong BS3, BS4, BS2, PS3 The NM_005629.4: c.1271G>A variant in the SLC6A8 is a missense variant in exon 9 predicted to result in substitution of glycine by aspartic acid at position 424 (p.Gly424Asp). This variant has been reported in three male siblings with mild intellectual disability, elevated urine creatine/creatinine, and reduced creatine peak on brain MRS (PP4_strong). Their mother was heterozygous for the same variant, had a mild reduction of creatine on MRS and indicate the mother had attention deficit, impulsiveness and intelligence below average (PMID: 24137762) (PP1_moderate). This variant was not found in gnomAD v2.1.1. (PM2_supporting). In silico predictions suggest this variant will be damaging to the function of the canonical protein (REVEL = 0.90) (PP3). There is no ClinVar entry for this variant. Functional studies of this variant demonstrated residual creatine uptake of 29% of the wildtype transfection level, indicating that this variant may affect the function of the protein but not meeting the threshold required by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (<10%) (PMID: 22281021) (PS3_Supporting not met). In summary, this variant meets criteria to be classified as a likely pathogenic variant for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0) (PP4_strong, PP1_moderate, PM2_supporting, PP3).(Classification approved by the ClinGen Cerebral Cretine Deficiency Syndromes Variant Curation Expert Panel on March 29, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086699/MONDO:0010305/027 2024-03-29 2024-03-29 X-linked inheritance HP:0001417 Supports CHEBI:4903 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0013595 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0549445 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0549445 infores:hetionet CHEBI:84050 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0853034 infores:hetionet CHEBI:63791 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0026827 infores:hetionet CAID:CA180669 biolink:causes MONDO:0019501 infores:clingen CAID:CA180669 MONDO:0019501 PMID:9382091PMID:23770805PMID:9382091PMID:23770805PMID:29490346PMID:18181211PMID:27460420PMID:22135276 Uncertain Significance PP1, PP4, PM3, BA1 BS2, PP3, PM5, BP4, PS1, PS4 The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA180669/MONDO:0019501/005 2023-01-18 2023-02-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:63608 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0023787 infores:hetionet CHEBI:119915 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011603 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0236071 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0000833 infores:hetionet CAID:CA10587278 biolink:causes MONDO:0008723 infores:clingen CAID:CA10587278 MONDO:0008723 PMID: Likely Benign BP4, BP7 The c.1533G>A (p.Arg511=) variant is a synonymous (silent) variant that is not predicted by (SpliceAI, MaxEntScn, NNSplice) to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). This variant is absent from gnomAD v2.1.1; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587278/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:38940 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0025222 infores:hetionet CHEBI:6062 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0008031 infores:hetionet CAID:CA10606240 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606240 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_213599.3: c.108_109del p.(Glu36AspfsTer7) variant in ANO5 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 3/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two patients with features consistent with ANO5-related muscle disease (PMID: 32367299, 39666917, 30564623; LOVD Individuals #00460288, #00221640), including in unknown phase with a pathogenic ANO5 variant in one patient with hyperCKemia, signs of myopathy on EMG, mitochondrial signs on muscle biopsy, and typical changes on muscle MRI (c.191dup p.(Asn64LysfsTer15), 0.5 pts, PMID: 32367299, 39666917; LOVD Individual #00460288) (PM3_Supporting). At least one patient reported with this variant and a second presumed diagnostic ANO5 variant had a clinical suspicion of LGMD (PMID: 30564623; LOVD Individual #00221640) (PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606240/MONDO:0015152/188 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50861 biolink:causes UMLS:C1096714 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C1096714 infores:hetionet CAID:CA10558501 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558501 MONDO:0010726 PMID: Likely Benign BP4, BS2 BP7, BS1 The c.1125C>T (p.Ser375=) variant in MECP2 (NM_004992.3) is present in 2 XY individuals in gnomAD (0.001%) (not sufficient to meet BS1 criteria). The p.Ser375= variant is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the p.Ser375= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558501/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:3082 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0013604 infores:hetionet CHEBI:3723 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022107 infores:hetionet CHEBI:9168 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0085593 infores:hetionet CAID:CA386304006 biolink:causes MONDO:0009861 infores:clingen CAID:CA386304006 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM5 PP3 The c.311C>T (p.Ala104Val) missense variant in PAH has been reported in 1 Chinese patient with classic PKU (Phe >1200umol/L; BH4 deficiency excluded) (PMID: 29499199; PP4_Moderate). This variant is absent from population databases (PM2), and is located at same location a c.311C>A (p.Ala104Asp), reported as Pathogenic in ClinVar (VarID:102650). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386304006/MONDO:0009861/006 2022-07-30 2022-07-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75722 biolink:causes UMLS:C0549277 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549277 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0852810 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0852810 infores:hetionet CHEBI:7903 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0042029 infores:hetionet CHEBI:3181 biolink:causes MONDO:0016028 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0014804 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007222 infores:hetionet CAID:CA229455 biolink:causes MONDO:0009861 infores:clingen CAID:CA229455 MONDO:0009861 PMID:30747360 Uncertain Significance PM2, PP4_Moderate, PP3 PM3 The c.168+5G>T variant has been identified in at least 2 probands, with at least 1 classic PKU proband excluding BH4 deficiency (PMIDs: 30747360). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229455/MONDO:0009861/006 2019-08-25 2019-08-25 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0657912 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006145 infores:hetionet CHEBI:2038 biolink:causes MONDO:0018824 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0085652 infores:hetionet CHEBI:85161 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0030196 infores:hetionet CHEBI:78543 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0231528 infores:hetionet CHEBI:8665 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0040586 infores:hetionet CHEBI:50122 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0004093 infores:hetionet CHEBI:7936 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018378 infores:hetionet CHEBI:4445 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0015672 infores:hetionet CHEBI:9130 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151766 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025362 infores:hetionet NCBIGene:658 biolink:causes MONDO:0007216 infores:monarchinitiative not_provided not_provided HGNC:1077 MONDO:0007216 uuid:f5626b96-05ad-4266-989e-9c851ec7477c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50730 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0017178 infores:hetionet CHEBI:231594 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0020458 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0041912 infores:hetionet CHEBI:28864 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0015230 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0017601 infores:hetionet CHEBI:144551 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0035455 infores:hetionet CHEBI:16755 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0043352 infores:hetionet CAID:CA412745374 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745374 MONDO:0100437 PMID: Likely Pathogenic PP1_Moderate, PM5_Supporting, PP4, PM2_Supporting, PS4_Supporting, PP3_Moderate NM_001034853.2(RPGR):c.296C>T (p.Thr99Ile) is a missense variant predicted to substitute threonine with isoleucine at amino acid 99. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), a family history consistent with X-linked inheritance (2 pt), visual field constriction (0.5 pts), and rod involvement greater than cone (1 pt), which together are specific for RPGR-related retinopathy (4.5pts, PMID: 21857984, PP4). This variant has been reported in at least 2 additional apparently unrelated probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years or decreased or absent cone and/or rod electroretinogram responses (PMID: 32702353, 31213501, 21857984, PS4_supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_moderate; PMID: 21857984). Another missense variant in the same codon, NM_001034853.2(RPGR):c.296C>A (p.Thr99Asn), (PMIDs: 32531858, 32702353, 10482958, and 28863407) has previously been classified as likely pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (89) than the comparison variant (65), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). The computational predictor REVEL gives a score of 0.813, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.03 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PM5_supporting, PP1_moderate, PP3_moderate, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745374/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:35778 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0476273 infores:hetionet CAID:CA412489564 biolink:causes MONDO:0100039 infores:clingen CAID:CA412489564 MONDO:0100039 PMID: Likely Pathogenic PP4, PS2, PM2_Supporting BS1, PM1, PM5, PP3, PM6, BA1, BP4, PS1 The p.Phe13Ser variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database) and as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 31313283) (PS2). The p.Phe13Ser variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database) (PP4). The p.Phe13Ser variant in CDKL5 is absent from gnomAD (PM2_Supporting). In summary, the p.Phe13Ser variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PP4, PM2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412489564/MONDO:0100039/016 2022-09-01 2022-09-06 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA265917282 biolink:causes MONDO:0100216 infores:clingen CAID:CA265917282 MONDO:0100216 PMID: Uncertain Significance PM2, BP4, BA1, PP3, BS2, PM5, PM1, BS1 The NM_177438.3:c.1453G>A variant in DICER1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 485 (p.Gly485Arg). To our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition. The total allele frequency in gnomAD v4.1.0 is 0.000007435 (12/1613916 alleles) with a highest population minor allele frequency of 0.00001017 (12/1179952 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.681, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). A different missense variant, c.1454G>A (p.Gly485Glu), in the same codon has been reported (ClinVar Variation ID: 2738880). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: no criteria met. (Bayesian Points: 0; VCEP specifications version 1.3.0; 10/22/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA265917282/MONDO:0100216/024 2024-10-22 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:72564 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0029118 infores:hetionet NCBIGene:57863 biolink:causes MONDO:0030433 infores:monarchinitiative not_provided not_provided HGNC:17601 MONDO:0030433 uuid:9cd8751a-7865-4434-8cd4-727d3baef7a3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C2129214 infores:hetionet NCBIGene:56623 biolink:causes MONDO:0012423 infores:monarchinitiative not_provided not_provided HGNC:21474 MONDO:0012423 uuid:f3454b09-2bbb-4660-a00b-f990c4215f7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38545 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0033687 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0009806 infores:hetionet CHEBI:3219 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0016242 infores:hetionet CHEBI:28001 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0042029 infores:hetionet CHEBI:2704 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0231528 infores:hetionet CHEBI:74947 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0239571 infores:hetionet CHEBI:101853 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0017675 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0009241 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0039103 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0033975 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0027947 infores:hetionet CAID:CA341741642 biolink:causes MONDO:0018997 infores:clingen CAID:CA341741642 MONDO:0018997 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PS3_Moderate, PS1, PM1, PP3 BP4 The NM_002524.5:c.173C>T variant in NRAS is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 58 (p.Thr58Ile). This variant is absent from gnomAD v2.1.1 (PM2_P). The computational predictor REVEL gives a score of 0.959, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant resides within the Switch 2 region (amino acids 57 – 64), of NRAS that is defined as a critical functional domain (PM1). 2 different missense variants, (KRAS):c.173C>T (p.Thr58Ile) (PMID: 16474405; ClinVar ID: 12588) and (HRAS):c.173C>T (p.Thr58Ile) (PMID: 18247425; ClinVar ID: 12610), in the same codon have been classified as pathogenic for RASopathy by the ClinGen RASopathy VCEP (PS1). This variant has been reported in 1 proband with RASopathy (PS4_Supporting; PMID:28594414). ERK (and AKT) activation assays in HEK293T cells promoted enhanced activation of ERK and AKT, even in the absence of stimulation. Additionally, a higher level of NRASThr58Ile in its GTP-bound, active form was observed, indicating that this variant causes gain of function (PMID: 28594414) (PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS1, PS3_Moderate, PM1, PS4_Supporting, PM2_Supporting, PP3. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA341741642/MONDO:0018997/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5778 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0039971 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0162429 infores:hetionet CAID:CA410203612 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203612 MONDO:0011071 PMID: Uncertain Significance PS4_Moderate, PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.296G>A (p.Cys99Tyr) is a missense variant that impacts one of the residues within the runt homology domain, but not a known hotspot residue (PM1_supporting). This variant has a REVEL score >0.88 (0.963) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 30291338, PMID: 36436542). Additionally, this variant was reported in ClinVar in 2021 by GeneDx, but the affected status of the proband is unknown (Variation ID 1321699). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_Moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203612/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44185 biolink:causes MONDO:0007243 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0006413 infores:hetionet CHEBI:8888 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0028961 infores:hetionet UMLS:C1738934 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0013404 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0233523 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233523 infores:hetionet CHEBI:49960 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0853193 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0020517 infores:hetionet CHEBI:4670 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0237849 infores:hetionet NCBIGene:5156 biolink:causes MONDO:0008285 infores:monarchinitiative not_provided not_provided HGNC:8803 MONDO:0008285 uuid:48c30591-3c4d-48a0-9c4a-02104d5867f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0031350 infores:hetionet CHEBI:8382 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0009782 infores:hetionet CHEBI:52717 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0702166 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0236065 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860866 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030312 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005451 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013473 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0235893 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0235893 infores:hetionet CHEBI:15854 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0003537 infores:hetionet CHEBI:27300 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0009806 infores:hetionet CHEBI:47898 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0037287 infores:hetionet CHEBI:2611 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0220870 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0033777 infores:hetionet CHEBI:4702 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0015230 infores:hetionet UMLS:C0657912 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018524 infores:hetionet CAID:CA1139666829 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666829 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*3281G>T is a UTR variant which has not been featured in functional or case studies. Computational data has been used to evaluate this variant. It has a SpliceAI score of 0 and a PhyloP score of 0.68, however as a UTR variant neither BP4 and BP7 may be applied. In summary, this variant meets criteria to be classified as VUS. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: none Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666829/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:2000093 biolink:causes GO:0061215 infores:ubergraph knowledge_assertion manual_agent GO:2000093 GO:0061215 CHEBI:8802 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0005779 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0009938 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027765 infores:hetionet CHEBI:27777 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0234215 infores:hetionet CHEBI:134990 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0028084 infores:hetionet CHEBI:8597 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0080274 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0851341 infores:hetionet CHEBI:4315 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0549567 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0858259 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020615 infores:hetionet CAID:CA412370013 biolink:causes MONDO:0010725 infores:clingen CAID:CA412370013 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PM5_Supporting, PP3_Strong PM1 NM_000330.4(RS1):c.667T>G (p.Cys223Gly) is a missense variant encoding the substitution of cysteine with glycine at amino acid 223. Another missense variant in the same codon, NM_000330.4(RS1):c.668G>C (p.Cys223Ser), (PMID: 12746437) has been classified as likely pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (159) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5_Supporting). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.951, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). However, the PP3_Strong code has been met, which is ineligible to be used in combination with the PM1 code at any strength, so the PM1 code was not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_ Strong, and PM5_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412370013/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:6950 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0001824 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0004936 infores:hetionet CHEBI:5280 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0017181 infores:hetionet CHEBI:4653 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0011168 infores:hetionet CHEBI:35778 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085593 infores:hetionet NCBIGene:7276 biolink:causes MONDO:0971004 infores:monarchinitiative not_provided not_provided HGNC:12405 MONDO:0971004 uuid:a2a99dd8-2bc2-477b-8ac5-540814b3f21b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0152029 infores:hetionet CHEBI:8405 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0013395 infores:hetionet CHEBI:31643 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0040822 infores:hetionet CHEBI:45367 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0151905 infores:hetionet CHEBI:63580 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018681 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004690 infores:hetionet CHEBI:408174 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0003850 infores:hetionet CHEBI:63631 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0236075 infores:hetionet CAID:CA10644616 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644616 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PM6, PM2, PVS1, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*2886T>C variant in the 3' UTR has an MAF of 0.006523 (0.6%, 421/64542 alleles) in the non-Finnish European subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 2 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644616/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true GO:2000018 biolink:causes GO:0046546 infores:ubergraph knowledge_assertion manual_agent GO:2000018 GO:0046546 CHEBI:17347 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0005778 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1384666 infores:hetionet CHEBI:3312 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0016204 infores:hetionet CHEBI:36791 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020625 infores:hetionet CHEBI:15367 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018524 infores:hetionet NCBIGene:6887 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:11557 MONDO:0013108 uuid:f36235ca-eb88-4606-a0ee-8b307feeb74e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:6000655 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015806 infores:hetionet CHEBI:6715 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0030252 infores:hetionet CHEBI:168396 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013491 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0425945 infores:hetionet CHEBI:44915 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0013456 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0005940 infores:hetionet CHEBI:4909 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0017675 infores:hetionet CHEBI:15553 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0014591 infores:hetionet CHEBI:27882 biolink:causes NCIT:C78210 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0426390 infores:hetionet CHEBI:45409 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0206062 infores:hetionet CHEBI:142290 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0003811 infores:hetionet CHEBI:3485 biolink:causes UMLS:C3203466 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C3203466 infores:hetionet CHEBI:27882 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0028960 infores:hetionet CHEBI:5296 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0035078 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0149931 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549250 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549250 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0948089 infores:hetionet CHEBI:2914 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C3263723 infores:hetionet CHEBI:135342 biolink:causes HP:0001712 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0149721 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0034150 infores:hetionet CHEBI:68558 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0010200 infores:hetionet GO:0141023 biolink:causes GO:0098609 infores:ubergraph knowledge_assertion manual_agent GO:0141023 GO:0098609 CHEBI:4672 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0014591 infores:hetionet CAID:CA132685 biolink:causes MONDO:0010134 infores:clingen CAID:CA132685 MONDO:0010134 PMID: Uncertain Significance BS1, PP3 PP4, PM3 The c.1924T>C variant in SLC26A4 is a missense variant predicted to cause substitution of serine by proline at amino acid 642. The highest population minor allele frequency in gnomAD v4.1 is 0.004332 (260/60022 alleles) in the Admixed-American population, which is higher than the ClinGen HL VCEP threshold (>0.003]) for BS1, and therefore meets this criterion (BS1 met). The computational predictor REVEL gives a score of 0.724, which is above the threshold of 0.7, evidence that correlates with impact on SLC26A4 function. (PP3 met). This variant has been observed in the homozygous state in at least nine apparently healthy adults (GeneDx internal data, SCV001816539.1, Invitae internal data, SCV001113490.7). This variant has also been observed with two co-occurring pathogenic variants in SLC26A4 phase unknown, in one patient reported to have hearing loss and enlarged vestibular aqueduct (Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060117.6). However, given its high allele frequency in the population and unknown phase with the co-occurring variant, PM3 was not applied. In summary, this variant meets the criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 8/20/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132685/MONDO:0010134/005 2025-08-20 2025-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true UMLS:C0879264 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151905 infores:hetionet CHEBI:50729 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0030312 infores:hetionet CHEBI:94686 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0004093 infores:hetionet CHEBI:3752 biolink:causes MONDO:0017419 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0002447 infores:hetionet CHEBI:6715 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0014743 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151828 infores:hetionet CHEBI:6438 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0428977 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0003123 infores:hetionet CHEBI:4798 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042075 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0423729 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0423729 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0009806 infores:hetionet CHEBI:39867 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014394 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0520962 infores:hetionet CHEBI:72564 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151908 infores:hetionet CHEBI:2904 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0004134 infores:hetionet CAID:CA1706701 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706701 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.3708delA p.(Asp1237ThrfsTer24) variant in DYSF, which is also known as NM_001130987.2: c.3762del p.(Asp1255ThrfsTer24), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 34/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three unrelated individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pts, PMID: 25046369, 30919934) and in trans with a pathogenic variant in at least one patient (c.1662C>T p.(Arg555Trp), 1.0 pt, PMID: 19015158) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 19015158). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706701/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0011701 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0232461 infores:hetionet NCBIGene:6138 biolink:causes MONDO:0014245 infores:monarchinitiative not_provided not_provided HGNC:10306 MONDO:0014245 uuid:da0ef062-bad6-45b8-bb12-46dcd971730c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0005779 infores:hetionet CHEBI:6067 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019214 infores:hetionet CHEBI:4903 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0011991 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0032961 infores:hetionet NCBIGene:84720 biolink:causes MONDO:0013882 infores:monarchinitiative not_provided not_provided HGNC:23215 MONDO:0013882 uuid:e5192362-dbd0-4566-8128-251cac31ef20 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes UMLS:C0595882 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0595882 infores:hetionet CHEBI:4046 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0040034 infores:hetionet CHEBI:34829 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0001622 infores:hetionet CHEBI:474180 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0002994 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0409974 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0010692 infores:hetionet CHEBI:4710 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0006277 infores:hetionet CAID:CA10577579 biolink:causes MONDO:0018875 infores:clingen CAID:CA10577579 MONDO:0018875 PMID: Pathogenic PS3, PM1, PP4_Moderate, PS4_Supporting, PM2_Supporting BP4, BA1, PS2, PS1, PM5, BS3, BS1, BS4, PVS1, PP3, PP1, BS2 The NM_000546.6: c.517G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 173 (p.Val173Met). This variant has been reported in a proband meeting Classic criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID16494995). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000278424.6). This variant has an allele frequency of 0.000001695 (2/1180054 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has 27 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (PM1, ≥ 10 somatic occurrences, PMID: 30311369). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP4_Moderate, PM2_Supporting, PM1, PS3. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577579/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:84634 biolink:causes MONDO:0008302 infores:monarchinitiative not_provided not_provided HGNC:4510 MONDO:0008302 uuid:159511f7-a9d8-4044-9336-8d8bd1cf5c0d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3506 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0015967 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0042401 infores:hetionet CHEBI:7565 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0030252 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0032285 infores:hetionet GO:1901894 biolink:causes GO:0070588 infores:ubergraph knowledge_assertion manual_agent GO:1901894 GO:0070588 CHEBI:17334 biolink:causes MONDO:0019633 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0035021 infores:hetionet CHEBI:63589 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0014457 infores:hetionet CHEBI:31236 biolink:causes HP:0002808 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022821 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040046 infores:hetionet CHEBI:127780 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151662 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011570 infores:hetionet CHEBI:101853 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151754 infores:hetionet NCBIGene:1303 biolink:causes MONDO:0014654 infores:monarchinitiative not_provided not_provided HGNC:2188 MONDO:0014654 uuid:8bcef21b-c44d-4df1-be84-37efe058f7c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63599 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0031350 infores:hetionet CHEBI:7915 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0311468 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0031350 infores:hetionet CHEBI:3387 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011603 infores:hetionet CHEBI:23765 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0039231 infores:hetionet CHEBI:42944 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0235437 infores:hetionet CHEBI:40279 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0237849 infores:hetionet CHEBI:32315 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0028643 infores:hetionet CHEBI:8107 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2242737 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017178 infores:hetionet CHEBI:27779 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0009676 infores:hetionet CHEBI:51450 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0344232 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0009450 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0595877 infores:hetionet CAID:CA214257 biolink:causes MONDO:0015967 infores:clingen CAID:CA214257 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 The c.1129delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 377 (NM_000545.8), adding 7 novel amino acids before encountering a stop codon (p.(Leu377SerfsTer7)). This variant, located in biologically-relevant exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Also, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.1129delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 6/4/2021): PVS1, PP4, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214257/MONDO:0015967/017 2021-12-31 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36500 biolink:causes MONDO:0018150 infores:drugmechdb knowledge_assertion manual_agent MESH:D005963 MESH:D005776 DB08876_MESH_D005776_1DB06720_MESH_D005776_1DB04878_MESH_D005776_1 CHEBI:8890 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0030552 infores:hetionet CHEBI:87715 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0002792 infores:hetionet CHEBI:17263 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0269189 infores:hetionet CHEBI:16755 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002878 infores:hetionet CHEBI:10124 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0423153 infores:hetionet CHEBI:63599 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0017181 infores:hetionet CHEBI:3011 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0026858 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0004096 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0340726 infores:hetionet CHEBI:5790 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085628 infores:hetionet CAID:CA346328674 biolink:causes MONDO:0800472 infores:clingen CAID:CA346328674 MONDO:0800472 PMID: Likely Pathogenic PP3, PM2_Supporting, PM3_Strong PP1, BP4, BA1, PM1, PM4, PM5, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.710C>A variant in CYP1B1 is a missense variant predicted to cause substitution of Alanine by Glutamic acid at amino acid 237 (p.Ala237Glu). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008475 (1 allele out of 1,179,982), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.717, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699). This variant has been identified in four individuals with a CYP1B1-related phenotype. Two of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 phase unknown and 1 confirmed in trans) and two individuals are homozygous (non-consanguineous) (PMIDs: 21815720, 23218183, 25950505, ClinVar). Total proband points = 2.5, meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346328674/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135939 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0233414 infores:hetionet CHEBI:188986 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0152227 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0948070 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0948070 infores:hetionet CHEBI:45081 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0030305 infores:hetionet CHEBI:15407 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0027497 infores:hetionet CHEBI:94392 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0042963 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0019112 infores:hetionet NCBIGene:7840 biolink:causes MONDO:0008763 infores:monarchinitiative not_provided not_provided HGNC:428 MONDO:0008763 uuid:6e5f9179-5a91-4721-a80a-a5c88c8f5617 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0013922 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0025061 infores:hetionet CHEBI:5141 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0004604 infores:hetionet CAID:CA410207975 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207975 MONDO:0011071 PMID:23848403PMID:17290219 Likely Pathogenic PS3_Supporting, PM1, PS4_Supporting, PM2_Supporting, PP3, PP1 PS1, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS1, BS4, BS3, PM5, PM4, PM3, PP2, PP4, BS2 NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.964) (PP3). Yeast assays showed significant decreased DNA binding, CBFbeta binding and promoter activation indicating that this variant impacts protein function (PMIDs 17290219, 23848403)(PS3_Supporting). This variant has been reported in 3 probands of a family meeting RUNX-1 phenotypic criteria (FPD and/or AML) (PMID 11675361) (PS4_supporting, PP1_supporting).In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP1_supporting, PP3, PM2_supporting, PS3_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207975/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71219 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1608945 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1291078 infores:hetionet CHEBI:17823 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0041834 infores:hetionet CAID:CA012807 biolink:causes MONDO:0005045 infores:clingen CAID:CA012807 MONDO:0005045 PMID: Uncertain Significance PM1, PM2, PS4_Supporting PP2, PP4, BS2, PM3, PM6, PM4, PM5, PP3, PP1, BA1, PS3, BP1, BP3, BS1, BS3, BS4, PS2, PS1, BP4, BP2, BP5, BP7, PVS1 The NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu) variant has been reported in 3 individuals with HCM (PS4_Supporting; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with HCM in 2 relatives from 2 families (GeneDx pers. comm.; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012807/MONDO:0005045/002 2021-03-10 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1706771 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706771 MONDO:0015152 PMID: Likely Benign BP4, BS1 PM3, BP7 The NM_003494.4: c.38844-4C>G variant in DYSF, which is also known as NM_001130987.2: c.3898-4C>G, is an intronic variant located in intron 34 of 54. The filtering allele frequency for this variant is 0.001881 for the South Asian population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 184/86258 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). While this variant is located in a splice region (+7/-21) (BP7 not met), the SpliceAI score is 0.03, which is less than the LGMD VCEP threshold of 0.05 (BP4). This variant appears to have been reported in an individual undergoing genetic testing for muscular dystrophy, but only as a single hit (LOVD DYSF_001370). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706771/MONDO:0015152/180 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:58 biolink:causes MONDO:0859517 infores:monarchinitiative not_provided not_provided HGNC:129 MONDO:0859517 uuid:f376d1f1-c4f6-4ce4-85d2-62d23a961d8e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0549567 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0262397 infores:hetionet CHEBI:4887 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0015230 infores:hetionet CHEBI:27777 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0232487 infores:hetionet CHEBI:85078 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C1112214 infores:hetionet CHEBI:8228 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0002994 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0042373 infores:hetionet UMLS:C0065374 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0428977 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0564622 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0564622 infores:hetionet NCBIGene:3242 biolink:causes MONDO:0010162 infores:monarchinitiative not_provided not_provided HGNC:5147 MONDO:0010162 uuid:b80221fc-2757-4899-b51e-0af255be341c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3515 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0853813 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0027769 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0549376 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0549376 infores:hetionet CHEBI:8707 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017565 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0162429 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0004936 infores:hetionet CHEBI:9139 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027796 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085584 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0024137 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042571 infores:hetionet CHEBI:17630 biolink:causes MONDO:0007972 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0025281 infores:hetionet CHEBI:63616 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0003811 infores:hetionet CAID:CA340747191 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747191 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting PM4 The NM_000329.3(RPE65):c.515T>A (p.Val172Asp) variant is a missense variant in RPE65 causing a substitution of valine with aspartic acid at position 172. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.811, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the Arg91Trp variant confirmed in trans (1 point, PMIDs: 27874104), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of retinitis pigmentosa with detailed phenotype demonstrating early-onset severe retinal dystrophy including macular atrophy (0.5 pt), nystagmus (1 pt), symptomatic onset between birth and age five years (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pt), optic atrophy (0.5 pt), decreased central visual acuity (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 27874104, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PP3_Moderate, PM3, PP4 (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747191/MONDO:0100368/120 2025-03-31 2025-03-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0086769 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151505 infores:hetionet CHEBI:6128 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0022346 infores:hetionet CHEBI:63611 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C2047937 infores:hetionet CHEBI:18243 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0085612 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0029456 infores:hetionet CHEBI:100241 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027066 infores:hetionet CHEBI:9139 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1260880 infores:hetionet CHEBI:66876 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0155305 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0024894 infores:hetionet CHEBI:49375 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0017565 infores:hetionet CHEBI:9555 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0020433 infores:hetionet CHEBI:8481 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0039231 infores:hetionet CHEBI:6062 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013604 infores:hetionet CHEBI:63629 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0002792 infores:hetionet GO:0045694 biolink:causes GO:0007292 infores:ubergraph knowledge_assertion manual_agent GO:0045694 GO:0007292 CHEBI:6965 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0011603 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235351 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011570 infores:hetionet NCBITaxon:55194 biolink:causes MONDO:0006608 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:55194 MESH:D012628 DB00825_MESH_D012628_1DB00971_MESH_D012628_1 CHEBI:5118 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C3665347 infores:hetionet CHEBI:3723 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0038325 infores:hetionet CHEBI:3347 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0687713 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0042769 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0233494 infores:hetionet CHEBI:42797 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0032617 infores:hetionet CHEBI:17303 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013604 infores:hetionet CHEBI:6909 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0011124 infores:hetionet CHEBI:63608 biolink:causes MONDO:0020325 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0206180 infores:hetionet CHEBI:10102 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151904 infores:hetionet CHEBI:94392 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0000731 infores:hetionet CHEBI:7454 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0036572 infores:hetionet CAID:CA10605540 biolink:causes MONDO:0100039 infores:clingen CAID:CA10605540 MONDO:0100039 PMID: Likely Pathogenic PS4_Supporting, PM2_Supporting, PS2 PM6 The p.Arg717= variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in an individual (Invitae internal database )(PS2). The p.Arg717= variant in CDKL5 occurs in the de novo state (biological parentage unconfirmed) in an individual (GeneDx internal database). The p.Arg717= variant has been observed in at least 2 individuals with neurological disease (Invitae and GeneDx internal database). The p.Arg717= variant in CDKL5 is absent from gnomAD (PM2_supporting). In summary, the p.Arg717= variant in CDKL5 is classified as likely pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PS4_supporting, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605540/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Supports CHEBI:4672 biolink:causes UMLS:C0151738 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151738 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0235416 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038454 infores:hetionet CHEBI:17303 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085649 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151717 infores:hetionet CHEBI:47499 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0018524 infores:hetionet CHEBI:4470 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0022107 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0853336 infores:hetionet CHEBI:7798 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0151827 infores:hetionet CHEBI:36791 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151827 infores:hetionet CHEBI:9086 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085623 infores:hetionet CAID:CA355964729 biolink:causes MONDO:0001586 infores:clingen CAID:CA355964729 MONDO:0001586 PMID: Likely Pathogenic PM3_Strong, PP4_Moderate, PM2_Supporting BP4, PP3 The NM_000203.5:c.1499A>G variant in IDUA is predicted to result in a missense substitution, p.Gln500Arg. This variant has been identified in at least 3 individuals, including an adult with clinical features consistent with MPS1, and documented laboratory values showing elevated urine GAGs, and deficient IDUA activity in leukocytes (PMID: 35848209) (PP4_Moderate). Each of these patients is compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including c.876delC (ClinVar Variation ID: 456720), phase not confirmed (PMID: 35848209), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909), phase not confirmed (clinical diagnostic laboratory); and c.536C>T (p.Thr179Met) (ClinVar Variation ID: 1455223), confirmed in trans (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002389 (1/41866 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.603 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. No impact on splicing was predicted by SpliceAI. There is a ClinVar entry for this variant (Variation ID: 1309246). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disease Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355964729/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5004 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0034063 infores:hetionet CHEBI:83804 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0041105 infores:hetionet CAID:CA215447 biolink:causes MONDO:0021060 infores:clingen CAID:CA215447 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.854-32A>C variant in the PTPN11 gene is 15.2% for Latino chromosomes by the Exome Aggregation Consortium (1824/11514 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA215447/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:77260 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020458 infores:hetionet CHEBI:31236 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151772 infores:hetionet NCBITaxon:517 biolink:causes MONDO:0037872 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:517 MONDO:0037872 CHEBI:30830 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0037672 infores:hetionet CHEBI:6129 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0011606 infores:hetionet CHEBI:8207 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0016382 infores:hetionet CHEBI:194135 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0039240 infores:hetionet CHEBI:101278 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018524 infores:hetionet CHEBI:131512 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0020458 infores:hetionet CAID:CA005196 biolink:causes MONDO:0005045 infores:clingen CAID:CA005196 MONDO:0005045 PMID: Likely Pathogenic PP1_Strong, PS3_Moderate, PM2_Supporting BA1, BP2, PS4, PS2, BS1, PVS1, PM6 NM_001276345.2(TNNT2):c.851+1G>A. This variant has been reported in individuals with HCM and other cardiomyopathies (LMM data, Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523, Varnava 2001 PMID: 11560853) and is absent from large population studies (PM2_supporting; gnomAdD v2.1). It is not statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied. The variant segregated with HCM in at least 13 affected relatives from one family (PP1_Strong; Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. This alteration is shown to affect the second to last exon, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro and in vivo functional studies provide some evidence that this variant affected protein function (PS3_Moderate; Thierfelder 1994 PMID: 8205619, Watkins 1996 PMID: 8958207, Tardiff 1998 PMID: 9637714, Mukherjea 1999 PMID: 10529204, Szczesna 2000 PMID: 10617660, Gafurov 2004 PMID: 15568820, Becker 2011 PMID: 21245263). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PM2_Supporting, PP1_Strong and PS3_Moderate. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA005196/MONDO:0005045/099 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31397 biolink:causes HP:0000419 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0151790 infores:hetionet CHEBI:48131 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0030554 infores:hetionet CHEBI:204734 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0011603 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0020517 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017178 infores:hetionet CHEBI:4702 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0002170 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0037274 infores:hetionet CHEBI:7478 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0522055 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0302295 infores:hetionet NCBIGene:10483 biolink:causes MONDO:0009134 infores:monarchinitiative not_provided not_provided HGNC:10702 MONDO:0009134 uuid:331a9adf-ed77-44bd-b7b5-233c692a42d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31199 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0175167 infores:hetionet CHEBI:31401 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0036974 infores:hetionet CHEBI:63115 biolink:causes HP:0012156 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0876991 infores:hetionet CAID:CA291996 biolink:causes MONDO:0021060 infores:clingen CAID:CA291996 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.690G>A (p.Thr230=) variant in the MAP2K2 gene is 0.1273% for Latino chromosomes by the Exome Aggregation Consortium (3/642 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA291996/MONDO:0021060/004 2018-11-15 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3696 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0018681 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020538 infores:hetionet CHEBI:40050 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0009782 infores:hetionet CHEBI:45951 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0013595 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021843 infores:hetionet CHEBI:9654 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0003862 infores:hetionet CHEBI:3723 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037287 infores:hetionet CHEBI:41423 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014591 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0015469 infores:hetionet CHEBI:3757 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0003862 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0002871 infores:hetionet CHEBI:3013 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0018099 infores:hetionet CHEBI:82960 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0004604 infores:hetionet UNII:V7I58RC5EJ biolink:causes GO:0008219 infores:drugmechdb knowledge_assertion manual_agent MESH:C495575 GO:0008219 DB08870_MESH_D006689_1 NCBIGene:6558 biolink:causes MONDO:0033667 infores:monarchinitiative not_provided not_provided HGNC:10911 MONDO:0033667 uuid:b3c73433-dbe0-4469-83cf-cfa348964a76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64317 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0080203 infores:hetionet CHEBI:9943 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013428 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0267792 infores:hetionet CAID:CA10014386 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014386 MONDO:0011071 PMID: Benign BP4, BP7, BS1 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 The c.648C>T (p.Pro216=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -2.75191 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The highest population minor allele frequency for this variant in gnomAD v3 is 0.05079% (21/41346 alleles) in the African/African American population, which is higher than the ClinGen Myeloid Malignancy VCEP threshold of 0.015% (BS1). The variant also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS1, BP4, and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014386/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45783 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1274594 infores:hetionet UMLS:C0657912 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234022 infores:hetionet CHEBI:18332 biolink:causes MONDO:0018382 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0149887 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0021308 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0042373 infores:hetionet CHEBI:45409 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151786 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0012359 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C2973529 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0012359 infores:hetionet CHEBI:50223 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0004093 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0040034 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234215 infores:hetionet CHEBI:9150 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0015672 infores:hetionet CHEBI:5778 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002792 infores:hetionet CHEBI:3723 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0000731 infores:hetionet CHEBI:135939 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0151766 infores:hetionet UMLS:C0009315 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0040460 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0152964 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0152964 infores:hetionet CHEBI:49575 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0019521 infores:hetionet CHEBI:31397 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0038999 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0853893 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0853893 infores:hetionet GO:0021707 biolink:causes CL:0001031 infores:ubergraph knowledge_assertion manual_agent GO:0021707 CL:0001031 CHEBI:4453 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0002170 infores:hetionet CHEBI:94449 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0231919 infores:hetionet CAID:CA253893 biolink:causes MONDO:0019497 infores:clingen CAID:CA253893 MONDO:0019497 PMID:25230692PMID:14512963 Uncertain Significance BS3_Supporting BP7, BP5, BS1, BS4, PP3, PP2, PP1, PP4, BS2, PM4, PM5, PM1, PM3, PVS1, PM2, PM6, BP4, BP1, BP3, BP2, BA1, PS1, PS4, PS2, PS3 The c.355G>A (NM_004086.3) variant in COCH gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 119 p.(Ala119Thr). The highest population minor allele frequency in gnomAD v.4 is 0.08199% (7/44876 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational Revel gives a score of 0.394, which is neither above nor below the thresholds predicting a damaging or benign impact on COCH function. Functional studies show no differences between wild-type and p.A119T variant cochlin localization and secretion (PMID: 25230692) (BS3_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMPcriteria applied, as specified by the ClinGen ClinGen Hearing Loss VCEP: (BS3_Supporting) (Hearing Loss VCEP specifications version 2; 8/26/2025) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA253893/MONDO:0019497/005 2025-08-26 2025-09-23 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3286 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0857353 infores:hetionet CHEBI:100147 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0030554 infores:hetionet CHEBI:77260 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C2047937 infores:hetionet NCBIGene:7048 biolink:causes MONDO:0013695 infores:monarchinitiative not_provided not_provided HGNC:11773 MONDO:0013695 uuid:66aa508e-8766-488b-a9a4-a71ebe76e893 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0242350 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0020538 infores:hetionet CHEBI:68575 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0236072 infores:hetionet CHEBI:9139 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011603 infores:hetionet CHEBI:36704 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0030252 infores:hetionet CAID:CA1912012 biolink:causes MONDO:0018958 infores:clingen CAID:CA1912012 MONDO:0018958 PMID: Pathogenic PVS1, PM3_Very Strong BA1, BS1, PM2 The c.78+1G>A variant in NEB occurs within the canonical splice donor site +1 of intron 4. It is expected to disrupt RNA splicing of in-frame exon 4 leading to loss of protein function and loss-of-function of NEB is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007461 (88/1179410) in non-Finnish European which does not meet the threshold for PM2_Supporting (≤ 0.0000559). This variant has been detected in more than four unrelated affected individuals with a second pathogenic variant (PM3_Very Strong, Internal lab contributor: Invitae, SCV001578888.4; PMID: 25205138, 30859559). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Very Strong (Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1912012/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:101853 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0017168 infores:hetionet CHEBI:31644 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0037763 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0042963 infores:hetionet CHEBI:65346 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08897 UMLS:C0039231 infores:hetionet CHEBI:3568 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0042023 infores:hetionet CHEBI:36791 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232849 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0011609 infores:hetionet CHEBI:3223 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C1320474 infores:hetionet CHEBI:5778 biolink:causes NCIT:C50599 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0700363 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0007018 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0042996 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0149931 infores:hetionet CHEBI:9139 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0040822 infores:hetionet CHEBI:6541 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020461 infores:hetionet CHEBI:8060 biolink:causes UMLS:C0234983 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0234983 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0041969 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0022890 infores:hetionet CAID:CA346329774 biolink:causes MONDO:0800472 infores:clingen CAID:CA346329774 MONDO:0800472 PMID:27243976 Uncertain Significance PP3, PM2_Supporting, PM1 PP1, BA1, BP4, PM5, PM3, PM4, PS1, PS3, PS2, BP7, BS1, BS4, PVS1 The c.171G>T variant in CYP1B1 is a missense variant predicted to cause substitution of Tryptophan by Cysteine at amino acid 57 (p.Trp57Cys). This missense variant is located in the hinge region, meeting PM1. This variant was not found in any genetic ancestry group of gnomAD (v4.1), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.721, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). This variant has not been identified as homozygous or compound heterozygous with another variant in CYP1B1, therefore PM3 was not applied. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM1, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346329774/MONDO:0800472/104 2025-11-19 2025-11-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31859 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0042023 infores:hetionet CHEBI:48273 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0151744 infores:hetionet CAID:CA326989717 biolink:causes MONDO:0100039 infores:clingen CAID:CA326989717 MONDO:0100039 PMID: Uncertain Significance BP4 BS1 "The highest population minor allele frequency of the p.Val732Met variant in CDKL5 in gnomAD v4.1 is 0.00002163 in the ""remaining"" population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a 0.276 of p.Val732Met, which is below the threshold of 0.29. The splice site predictor, SpliceAI, indicated that the variant has no impact on splicing. Based on this evidence, p.Val732Met does not predict a damaging effect on CDKL5 function (BP4). The p.Val732Met variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Val732Met variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025])" Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA326989717/MONDO:0100039/034 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:144093 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151908 infores:hetionet CHEBI:10112 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0009806 infores:hetionet CHEBI:10101 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0023218 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0232459 infores:hetionet CHEBI:63681 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0033774 infores:hetionet CHEBI:75984 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0030252 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0856049 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0856049 infores:hetionet CHEBI:8024 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042029 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0032961 infores:hetionet CHEBI:3228 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0039070 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005770 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019342 infores:hetionet CHEBI:61049 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0242301 infores:hetionet CAID:CA052256 biolink:causes MONDO:0100150 infores:clingen CAID:CA052256 MONDO:0100150 PMID: Likely Benign BP7, BS1, BP4 BS3, PVS1, PM2, BS2, BP3, BA1, PM4, PM5, PS3, PS1 The NM_000540.3:c.10048C>A variant in the RYR1 gene is a synonymous variant (p.Arg3350=). The filtering allele frequency (the lower threshold of the 95% CI of 195/1180010) of the c.10048C>A variant in RYR1 is 0.0001406 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (0.0001406) for BS1, and therefore meets this criterion (BS1). This silent variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets the criteria to be classified as likely benign for RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA052256/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CAID:CA367401322 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401322 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PM3_Supporting, PP1_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate The c.622G>A variant in the glucokinase gene, GCK causes an amino acid change of Ala to Thr at codon 208 (p.(Ala208Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.905, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an uncomputable Grpmax filtering allele frequency in the gnomAD v2.1.1 due to only one copy in the European non-Finnish population and no copies in another subpopulation (PM2_Supporting). This variant was identified in the heterozygous state in 5 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant has been detected in the homozygous state in an individual with permanent neonatal diabetes (PM3_Supporting, PMID: 25015100). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with 3 informative meioses in 2 families (PP1_Moderate; PMID 25015100; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ala208Thr has RAI<0.50 (PS3_Moderate; PMID: 25015100). Another missense variant, c.623C>T p.Ala208Val, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala208Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3, approved 8/11/2023): PP3, PP2, PM2_Supporting, PP4_Moderate, PM5_Supporting, PS4_Moderate, PM3_Supporting, PP1_Moderate, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401322/MONDO:0015967/086 2025-02-11 2025-02-11 Semidominant inheritance HP:0032113 Supports CHEBI:6970 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0949059 infores:hetionet NCBITaxon:5475 biolink:causes UMLS:C0011974 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D003963 DB00681_MESH_D003963_1 CHEBI:5134 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0234238 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1384353 infores:hetionet CHEBI:135005 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0039591 infores:hetionet CHEBI:6129 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042963 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0836924 infores:hetionet CHEBI:15553 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085612 infores:hetionet CHEBI:408174 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0004245 infores:hetionet CHEBI:2682 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0039240 infores:hetionet CHEBI:8212 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0392676 infores:hetionet GO:0140137 biolink:causes GO:0003012 infores:ubergraph knowledge_assertion manual_agent GO:0140137 GO:0003012 CHEBI:3084 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0004096 infores:hetionet GO:1900260 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:1900260 GO:0010467 CHEBI:6541 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042510 infores:hetionet CHEBI:70735 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C2225524 infores:hetionet CAID:CA6831859 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831859 MONDO:0015967 PMID: Uncertain Significance BS1 BP4, PP3 The c.872C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 291 (p.(Pro291Leu)) of NM_000545.8. This variant has a Grpmax Filtering allele frequency in gnomAD v.4.1.0 of 0.000052, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant has a REVEL score of 0.353, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.872C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831859/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3515 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0227791 infores:hetionet CHEBI:75246 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011991 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0152517 infores:hetionet CHEBI:8430 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0033774 infores:hetionet CAID:CA9870022 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870022 MONDO:0015967 PMID: Uncertain Significance BP5 BP4, BA1, PS4, BS1, PM2, PP3 The c.7A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to arginine at codon 3 (p.(Ser3Arg)) of NM_175914.5. This variant has a REVEL score of 0.256, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. While c.7A>C has a GrpMax filtering allele frequency of less than 0.000003 in the European non-Finnish population in gnomAD v2.1.1, but it has 11 copies in the Ashkenazi Jewish subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.7A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870022/MONDO:0015967/017 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135686 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0017178 infores:hetionet CAID:CA000350 biolink:causes MONDO:0017623 infores:clingen CAID:CA000350 MONDO:0017623 PMID: Likely Pathogenic PM2, PP2, PS4_Supporting, PS3 BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PP3, PP4, PP1, BS2, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS2 PTEN c.209T>C (p.Leu70Pro) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor(s) ClinVar Organization ID: 26957) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000350/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31643 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0340865 infores:hetionet CHEBI:43968 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0003123 infores:hetionet CHEBI:4995 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0033774 infores:hetionet CHEBI:8774 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0034068 infores:hetionet CHEBI:8863 biolink:causes NCIT:C50547 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1704212 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005386 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C1306889 infores:hetionet NCBIGene:5788 biolink:causes MONDO:0800104 infores:monarchinitiative not_provided not_provided HGNC:9666 MONDO:0800104 uuid:e61e0a60-0ca0-4678-8f5e-ede41e93473f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes MONDO:0001244 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042880 infores:hetionet CHEBI:8871 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013378 infores:hetionet CHEBI:17688 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0025345 infores:hetionet CHEBI:4551 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0018524 infores:hetionet CHEBI:480999 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151799 infores:hetionet CHEBI:2704 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0015230 infores:hetionet CHEBI:63580 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0344232 infores:hetionet CHEBI:16914 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0011991 infores:hetionet CHEBI:7903 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0038999 infores:hetionet CHEBI:31413 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0028084 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0004623 infores:hetionet CHEBI:8871 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151744 infores:hetionet CHEBI:68478 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018790 infores:hetionet CHEBI:63584 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0311468 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020538 infores:hetionet CHEBI:8776 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0015230 infores:hetionet CAID:CA350341903 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341903 MONDO:0015924 PMID: Likely Pathogenic PS1_Moderate, PP3, PM2_Supporting, PM1_Strong BA1, BP4, PS4, PM5, BS1 The BMPR2 c.1228G>A variant is a missense variant predicted to cause a glycine to arginine substitution at amino acid position 410. The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Gly410Arg is located in the catalytic kinase domain and Gly410 is a known critical residue (PM1_strong). The variant was reported in two manuscripts (PMID: 26387786 and PMID: 21737554) describing the same individual; no other probands with the variant were identified (PS4 not met). A different variant affecting the same amino acid, c.1228 G>C (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate). Other pathogenic missense variants causing a different amino acid change at the same residue have not been reported (PM5 is not met). The REVEL score is 0.984, which meets the ClinGen Pulmonary Hypertension VCEP pathogenicity threshold of >=0.75 (PP3 met, BP4 not met). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. Functional data was not available (BS3 and PS3 not evaluated). In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1_moderate, PM1_strong, PM2_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341903/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:7414 biolink:causes MONDO:0013200 infores:monarchinitiative not_provided not_provided HGNC:12665 MONDO:0013200 uuid:2c5ba7ba-a63f-4b5c-ab1a-a656d42ca6cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6690 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0013384 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042790 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0859062 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0859062 infores:hetionet CHEBI:6832 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0020649 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0235431 infores:hetionet CAID:CA134659 biolink:causes MONDO:0021060 infores:clingen CAID:CA134659 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.255C>T (p.His85=) variant in the PTPN11 gene is 7.417% (818/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134659/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:61033 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0392197 infores:hetionet CHEBI:10125 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0015672 infores:hetionet NCBIGene:8635 biolink:causes MONDO:0013058 infores:monarchinitiative not_provided not_provided HGNC:21686 MONDO:0013058 uuid:a93217ed-a86a-45cd-b896-763a35d58bd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020882 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020882 MONDO:0009861 PMID:29413232PMID:24705691PMID:26503515PMID:31178897PMID:26322415 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong The c.875C>T (p.Pro292Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PMID: 26503515, 24705691, 29413232). This variant has extremely low frequency in gnomAD (MAF=0.00006). This variant was detected in trans with pathogenic variants c.913-7A>G (PMID: 26322415) and p.Arg243Gln (PMID: 31178897). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020882/MONDO:0009861/006 2020-06-26 2020-06-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:194135 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0853748 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0042267 infores:hetionet CHEBI:31348 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0522153 infores:hetionet NCBIGene:83893 biolink:causes MONDO:0007060 infores:monarchinitiative not_provided not_provided HGNC:29935 MONDO:0007060 uuid:d12eb525-2256-48c1-8f00-46820818a946 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011124 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025061 infores:hetionet CHEBI:71219 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0428977 infores:hetionet CHEBI:5613 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0003467 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0546817 infores:hetionet CHEBI:6121 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0003811 infores:hetionet CHEBI:5778 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151905 infores:hetionet CHEBI:27779 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0023530 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0031212 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0007787 infores:hetionet UMLS:C0005740 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0008033 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151736 infores:hetionet CHEBI:8364 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C1443060 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0027441 infores:hetionet NCBIGene:255738 biolink:causes MONDO:0011369 infores:monarchinitiative not_provided not_provided HGNC:20001 MONDO:0011369 uuid:b6e60a3c-a197-46db-97a3-e579f0c0bb25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0027849 infores:hetionet CHEBI:3175 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0241136 infores:hetionet CHEBI:3757 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0026821 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C2047937 infores:hetionet CHEBI:3127 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0476273 infores:hetionet CAID:CA000895 biolink:causes MONDO:0011450 infores:clingen CAID:CA000895 MONDO:0011450 PMID: Pathogenic PVS1, PP4_Strong, PS3 PM2, BA1, BS1 The c.135-1G>T variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 3 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RNAseq demonstrated that the variant impacts splicing by resulting in skipping of exon 4 from the transcript (PMID: 30101128). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 234999878.51 (based on Cosegregation LR=9528; Pathology LR=2.009; Family History LR=12277.7), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PS3, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000895/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38562 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0013404 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0948089 infores:hetionet CHEBI:7986 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0038990 infores:hetionet CHEBI:50922 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0007820 infores:hetionet CHEBI:2948 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0014742 infores:hetionet CHEBI:5280 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0013604 infores:hetionet CHEBI:53691 biolink:causes UMLS:C1328540 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C1328540 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0007971 infores:hetionet CHEBI:44185 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C2981158 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0015397 infores:hetionet CHEBI:3515 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C1384353 infores:hetionet CHEBI:40237 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0001339 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011570 infores:hetionet CHEBI:92712 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0237849 infores:hetionet GO:0075045 biolink:causes GO:0044002 infores:ubergraph knowledge_assertion manual_agent GO:0075045 GO:0044002 CHEBI:7823 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0040822 infores:hetionet CHEBI:5818 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0043352 infores:hetionet CHEBI:93305 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0012833 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0003123 infores:hetionet CHEBI:31981 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0001824 infores:hetionet CHEBI:7573 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0028734 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0006849 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0034150 infores:hetionet GO:0045113 biolink:causes GO:0007009 infores:ubergraph knowledge_assertion manual_agent GO:0045113 GO:0007009 CHEBI:168396 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0149745 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042109 infores:hetionet CHEBI:39867 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0232461 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0020456 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C3665347 infores:hetionet CHEBI:9649 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018681 infores:hetionet CHEBI:38940 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0002994 infores:hetionet CHEBI:8435 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0013144 infores:hetionet CHEBI:6970 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0008031 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0006444 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0242350 infores:hetionet NCBIGene:9401 biolink:causes MONDO:0009955 infores:monarchinitiative not_provided not_provided HGNC:9949 MONDO:0009955 uuid:1d44f6bf-96de-4e1e-9af4-70de2ffac010 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1244303 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244303 MONDO:0020367 PMID: Uncertain Significance BP7, BS1, BS3, PM2, PM6, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.271C>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Arginine at amino acid 91. Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0001087 (2 alleles out of 18,394), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for juvenile open angle glaucoma (PMID: 24825108), not meeting the ≥ 3 segregations required for PP1. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): none Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244303/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:567361 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0162429 infores:hetionet GO:0060998 biolink:causes GO:0030182 infores:ubergraph knowledge_assertion manual_agent GO:0060998 GO:0030182 CHEBI:64028 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0020649 infores:hetionet CHEBI:50648 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013404 infores:hetionet CHEBI:51380 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0041969 infores:hetionet CHEBI:63598 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004604 infores:hetionet CHEBI:72564 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0235198 infores:hetionet CHEBI:70746 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018965 infores:hetionet CHEBI:64312 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0010038 infores:hetionet CAID:CA414896830 biolink:causes MONDO:0010602 infores:clingen CAID:CA414896830 MONDO:0010602 PMID: Likely Pathogenic PM2_Supporting, PP3, PS4 The c.7015A>T (Arg2339Trp) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been reported in at least four probands with severe hemophilia A (>4 probands & 0 gnomAD alleles) meeting phenotypic criteria for F8 (PMID: 30913330, 20331761, 18691168, 18217193). This missense variant has a REVEL score of 0.878 (>0.6). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414896830/MONDO:0010602/071 2024-06-19 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:4710 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0018681 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0019917 infores:hetionet CHEBI:8212 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0027497 infores:hetionet CAID:CA367401683 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401683 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PP1, PP4 The c.524G>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to valine at codon 175 (p.(Gly175Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.523G>A p.Gly175Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly175Val (PM5_Supporting). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 11315851​). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID:28012402, 11315851, internal lab contributors). In summary, c.524G>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401683/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:49603 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0013395 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0027765 infores:hetionet CHEBI:9586 biolink:causes MONDO:0041526 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0156543 infores:hetionet CHEBI:3738 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0013144 infores:hetionet CHEBI:65173 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0017152 infores:hetionet CHEBI:45863 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0236075 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0035258 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0031212 infores:hetionet CHEBI:52717 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0239571 infores:hetionet CHEBI:79699 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0041969 infores:hetionet CHEBI:4909 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0011603 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027441 infores:hetionet CHEBI:64321 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0043352 infores:hetionet CHEBI:5118 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151594 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0021400 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0178298 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0008915 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0008915 uuid:1cff1c9d-6976-4d88-ac43-349489b7ebf6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9555 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0027497 infores:hetionet CHEBI:9086 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0008489 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0917799 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0011304 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0011304 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004998 infores:hetionet CHEBI:6888 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151692 infores:hetionet CHEBI:119915 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0404521 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011570 infores:hetionet CHEBI:7565 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0428977 infores:hetionet CHEBI:4470 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0017178 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022650 infores:hetionet CHEBI:7915 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0558489 infores:hetionet CHEBI:3347 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0004093 infores:hetionet CAID:CA280144 biolink:causes MONDO:0044970 infores:clingen CAID:CA280144 MONDO:0044970 PMID:19460299PMID:20550934PMID:33380464 Likely Pathogenic PM2_Supporting, PS3_Moderate, PS4_Moderate, PM6_Supporting PP3 The m.3242G>A variant in MT-TL1 has been reported in at least six unrelated individuals with primary mitochondrial disease (PMIDs: 15870203, 19460299, 10214753, 21364701, 14576046, 22781753, 24667782, 31965079, 37038312; PS4_moderate). Clinical features in affected individuals include Leigh syndrome spectrum disorder, encephalomyopathy, myopathy, hypertrophic and dilated cardiomyopathy, and renal insufficiency. The variant occurred de novo in two of these individuals (PMID: 22781753; PM6_supporting). There are no families reported where the variant segregated with clinical manifestations. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is likely benign (18.5 percentile) but HmtVAR predicts it to be possibly pathogenic with a score of 0.6. A cybrid study (PMID: 19460299) from cells derived from the index case (PMID: 15870203) demonstrated reduced activity of complex IV. Additional studies showed this variant eliminated transcriptional termination activity with a modest decrease (30%–50%) of mtRNase P activity (PMID: 20550934), and that this variant was associated with decreased single-turnover methyltransferase and cleavage activity of human mitochondrial mtRNase P (PS3_moderate). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate, PM2_supporting, PM6_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA280144/MONDO:0044970/015 2024-11-11 2025-05-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:83970 biolink:causes MONDO:0800388 infores:ubergraph knowledge_assertion manual_agent CHEBI:83970 MONDO:0800388 CAID:CA000252 biolink:causes MONDO:0018875 infores:clingen CAID:CA000252 MONDO:0018875 PMID: Likely Pathogenic BS3_Supporting, PS4_Moderate, PP3_Moderate, PM1, PM5, PP4, PM2_Supporting BA1, BP4, PS3, PS2, PS1, BS1, PP1, BS2 The NM_000546.6: c.524G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 175 (p.Arg175Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 16707427; Internal lab contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).Computational predictor scores (BayesDel = 0.57303; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PM2_Supporting, BS3_Supporting, PP3_Moderate, PP4, PM1, PM5 (Bayesian Points: 9; VCEP specifications version 2.0; 9/6/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000252/MONDO:0018875/009 2024-09-06 2024-09-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8768 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0023890 infores:hetionet CHEBI:34380 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00600 UMLS:C0085624 infores:hetionet CAID:CA10558434 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558434 MONDO:0010726 PMID: Likely Benign BP4, BP7, BS1 The allele frequency of the c.1374C>T p.Arg458= variant in MECP2 (NM_004992.3) is 0.016% in the South Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Arg458= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1374C>T p.Arg458= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558434/MONDO:0010726/032 2023-06-15 2023-06-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:8481 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0018843 infores:hetionet CHEBI:3314 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0039070 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C1306341 infores:hetionet CHEBI:63580 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0206061 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0151736 infores:hetionet CHEBI:42820 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0020649 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0456909 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0032326 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0027765 infores:hetionet CAID:CA294623 biolink:causes MONDO:0010726 infores:clingen CAID:CA294623 MONDO:0010726 PMID: Uncertain Significance BP5 PM4, BS1, PM2 The highest population minor allele frequency of the p.Leu382_Pro390del variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.000006732 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Leu382_Pro390del variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5). This in-frame deletion occurs in the Proline-rich region of the gene (p.381-p.405) where other in-frame deletions have been known to occur and their significance uncertain (PM4 not met). In summary, the p.Leu382_Pro390del variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294623/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Inconclusive true CHEBI:9168 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0595930 infores:hetionet CHEBI:37941 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042384 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0038362 infores:hetionet CHEBI:3219 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030193 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017563 infores:hetionet CHEBI:75998 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0232462 infores:hetionet CHEBI:75998 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0042909 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0004096 infores:hetionet CHEBI:5147 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0232849 infores:hetionet CHEBI:6888 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0000731 infores:hetionet CHEBI:3387 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0877055 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1527411 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006277 infores:hetionet CHEBI:8461 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0040485 infores:hetionet CHEBI:9654 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1306577 infores:hetionet CAID:CA134746 biolink:causes MONDO:0021060 infores:clingen CAID:CA134746 MONDO:0021060 PMID: Likely Benign BP5, BS4 The c.66T>G (p.Phe22Leu) variant has been identified in patients with clinical features of a RASopathy, however the variant did not segregate with disease in affected family members (BS4; GeneDx, Partners LMM, Invitae internal data GTR ID's: 26957, 21766, 500031; ClinVar SCV000218672.4; SCV000061358.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; LMM internal data; SCV000061358.5). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134746/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true NCBIGene:51218 biolink:causes MONDO:0014803 infores:monarchinitiative not_provided not_provided HGNC:20134 MONDO:0014803 uuid:55e1b02d-e8e6-446e-9557-119ef92a77a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0027059 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017675 infores:hetionet CHEBI:50777 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0149741 infores:hetionet CHEBI:6375 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011603 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0948692 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0014130 infores:hetionet CHEBI:79699 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0015230 infores:hetionet CHEBI:55346 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0026766 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002418 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003460 infores:hetionet CHEBI:68642 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0600228 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0003864 infores:hetionet CHEBI:9599 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0235266 infores:hetionet CHEBI:10124 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0041834 infores:hetionet CHEBI:36795 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009676 infores:hetionet CHEBI:3176 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0233471 infores:hetionet CHEBI:16714 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0009806 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0032285 infores:hetionet NCBITaxon:39054 biolink:causes MONDO:0005779 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:39054 MONDO:0005779 CHEBI:46557 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0086543 infores:hetionet CHEBI:9674 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0026821 infores:hetionet CHEBI:87715 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0476281 infores:hetionet CHEBI:63630 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042024 infores:hetionet CHEBI:28748 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018681 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0403632 infores:hetionet CHEBI:41774 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0600142 infores:hetionet CHEBI:2567 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0349790 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022660 infores:hetionet CHEBI:7447 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0542184 infores:hetionet CHEBI:10112 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0019158 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0277889 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0277889 infores:hetionet CHEBI:84500 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0162298 infores:hetionet CHEBI:41774 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151578 infores:hetionet CHEBI:4702 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0011570 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020621 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0039971 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0221155 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0221155 infores:hetionet CHEBI:31623 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0151514 infores:hetionet CHEBI:3082 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0030252 infores:hetionet CHEBI:8597 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0234708 infores:hetionet CHEBI:3215 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151907 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151605 infores:hetionet CHEBI:119486 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0022346 infores:hetionet CHEBI:68534 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0020580 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0009806 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0861020 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0861020 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0332534 infores:hetionet CHEBI:45863 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2363731 infores:hetionet CHEBI:63618 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0338908 infores:hetionet CHEBI:480999 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C2047937 infores:hetionet CHEBI:7809 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0023066 infores:hetionet NCBIGene:8270 biolink:causes MONDO:0033006 infores:monarchinitiative not_provided not_provided HGNC:26058 MONDO:0033006 uuid:b85f1080-3925-4544-ae16-3118992d7088 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes MONDO:0006875 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0028840 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0521839 infores:hetionet CHEBI:28748 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1510410 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020651 infores:hetionet NCBITaxon:34105 biolink:causes MONDO:0006941 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:34105 MESH:D011906 DB09320_MESH_D011906_1 CHEBI:8356 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029882 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0242350 infores:hetionet CHEBI:5141 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0015967 infores:hetionet CAID:CA014078 biolink:causes MONDO:0004994 infores:clingen CAID:CA014078 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3777C>T (p.His1259=) variant in the MYH7 gene is 0.14% (22/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014078/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:18332 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0013404 infores:hetionet CHEBI:520985 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0041657 infores:hetionet CHEBI:2379 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0311468 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004623 infores:hetionet NCBIGene:28985 biolink:causes MONDO:0958030 infores:monarchinitiative not_provided not_provided HGNC:23357 MONDO:0958030 uuid:bbe93a2e-e78d-4976-a7ec-b99bc0e03b2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135530 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0232849 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0541919 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002265 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0038273 infores:hetionet CAID:CA005411 biolink:causes MONDO:0021056 infores:clingen CAID:CA005411 MONDO:0021056 PMID: Benign BA1, BP4, BP7 The c.1635G>A (p.Ala545=) variant is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.82 (15756 in 19198 alleles) in the East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.001) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP4, and BP7. (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA005411/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8874 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0243026 infores:hetionet CHEBI:45979 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0221490 infores:hetionet CHEBI:4909 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0040264 infores:hetionet CAID:CA14870737 biolink:causes MONDO:0011071 infores:clingen CAID:CA14870737 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS4, PS3, PS2, BP1, BP3, PM2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 The c.58+103A>G variant is a deep intronic variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being weakly conserved (PhyloP score = 0.00181102 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The variant's highest population minor allele frequency in gnomAD v2 is 0.8144 (7069/8680 alleles) in the African/African American population, which is higher than the ClinGen Myeloid Malignancy threshold (>0.0015) for BA1; in addition, this allele count includes 2892 homozygotes, and there are no reports of probands with homozygous pathogenic variants plus RUNX1-deficient mice are embryonic lethal (BP2). The variant also has not been reported in germline cases (PMID: 24211365, PMID: 25056374, PMID: 32277576, COSMIC ID: COSV55892632) or functionally evaluated in the literature. In summary, this variant meets the criteria to be classified as benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BA1, BP2, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14870737/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7773 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0520887 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0549433 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0021400 infores:hetionet CAID:CA229481 biolink:causes MONDO:0009861 infores:clingen CAID:CA229481 MONDO:0009861 PMID:8533759PMID:8592329PMID:26351554 Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong The c.199T>C (p.Ser67Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; 8533759; 26351554). This variant has an extremely low allele frequency in ExAC (MAF=0.00002, PM2). This variant was detected in trans with L48S (PMID: 8592329), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) PMID: 26351554 (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229481/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47499 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0020580 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151713 infores:hetionet CHEBI:5864 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0023524 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0009806 infores:hetionet CHEBI:167309 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0041657 infores:hetionet CAID:CA8337802 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337802 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.652_682dup (p.Ile228ArgfsTer35) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PVS1 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337802/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:3835 biolink:causes MONDO:0011335 infores:monarchinitiative not_provided not_provided HGNC:6391 MONDO:0011335 uuid:d7bbea91-0ee0-4b73-bea6-7bd1022af849 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014234 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014234 MONDO:0011071 PMID: Likely Benign BP4, BP7, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968-16C>T is an intronic variant with a MAF of 0.0007794 (0.07794%, 53/68004, 53 alleles) in the European (non-finnish) subpopulation of the gnomAD 3.1.2 cohort which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.12) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014234/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31401 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0019079 infores:hetionet CHEBI:63577 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0003467 infores:hetionet CHEBI:39867 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085631 infores:hetionet CHEBI:6402 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0004364 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020649 infores:hetionet CHEBI:9571 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0700590 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002252 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0235369 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020621 infores:hetionet CHEBI:93635 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0030554 infores:hetionet CHEBI:7824 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0003537 infores:hetionet CHEBI:9943 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0262662 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0948349 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0549209 infores:hetionet CHEBI:205919 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0010481 infores:hetionet CAID:CA16605219 biolink:causes MONDO:0015967 infores:clingen CAID:CA16605219 MONDO:0015967 PMID: Pathogenic PS4, PS2, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate PM1 The c.703A>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to valine at codon 235 (p.(Met235Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.852, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.45, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 17186219). This variant was identified in 15 unrelated individuals with hyperglycemia (PS4; PMID: 17186219, 24323243, 26552609, 31595705, 32086287; internal lab contributors). Furthermore, this variant segregated with hyperglycemia with 12 informative meioses in five families (PP1_Strong; PMID: 17186219, 31595705, 32086287; internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3mmol/L)) (PP4_Moderate; PMID: 17186219). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6) (PS2; PMID: 24323243). In summary, c.703A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS2, PS4, PP1_Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16605219/MONDO:0015967/086 2025-09-17 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:3216 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0000737 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0021053 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0011849 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020039 infores:hetionet CHEBI:66901 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0012833 infores:hetionet CHEBI:7573 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0004604 infores:hetionet CHEBI:65349 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C1368065 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0836924 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0001126 infores:hetionet CHEBI:31980 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0085702 infores:hetionet CHEBI:8768 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0917801 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0948089 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0021053 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0024299 infores:hetionet NCBIGene:5078 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:8618 MONDO:0005148 uuid:5bfb1aa1-369a-43a4-b80f-b4eda81ea8fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3419 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0013395 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0012797 infores:hetionet CHEBI:6073 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0027497 infores:hetionet CHEBI:50859 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0001925 infores:hetionet CHEBI:4657 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0030193 infores:hetionet CHEBI:75246 biolink:causes MONDO:0001517 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0013369 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0265547 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0265547 infores:hetionet CHEBI:31236 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1527344 infores:hetionet CHEBI:9674 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0235266 infores:hetionet CHEBI:64198 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0027497 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0020676 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0002871 infores:hetionet CHEBI:3485 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0427086 infores:hetionet CHEBI:3561 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0438717 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0017160 infores:hetionet CHEBI:2038 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0085605 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0007137 infores:hetionet CHEBI:135342 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0424295 infores:hetionet CHEBI:51380 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0020458 infores:hetionet CHEBI:9943 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085932 infores:hetionet NCBIGene:284217 biolink:causes MONDO:0014419 infores:monarchinitiative not_provided not_provided HGNC:6481 MONDO:0014419 uuid:8913c12f-60c9-4ae3-8470-c333adecaaec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72292 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0018799 infores:hetionet CHEBI:9927 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0022661 infores:hetionet CAID:CA8328674 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328674 MONDO:0100438 PMID:28973376 Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PP3_Moderate, PM3, PS3_Supporting NM_014336.5(AIPL1):c.50T>C (p.Leu17Pro) is a missense variant predicted to replace leucine with proline at amino acid 17. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 6.195e-7, with 1 / 1614234 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Lys214Asn variant (currently unclassified) confirmed in trans (0.25 points, PMID:21900377). This variant has also been reported in 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 24265693). A second homozygous patient was reported (PMID:32531858) but was not counted towards PM3 because the phenotype was listed as arRP with no age of onset. A third homozygous patient with LCA was reported by a VCEP member (0.5 pts) (1.25 total points, PM3). At least one proband harboring this variant exhibits a phenotype including severely reduced electroretinogram responses from both rods (0.5 pts) and cones (1 pt) and was diagnosed with LCA (0.5 pts) within the first year of life (1 pt). Additional phenotypes include nystagmus (1 pt), sluggish pupils (0.5 pts), photophobia (1 pt), vascular attenuation, RPE mottling (0.5 pts) severe visual field loss (1 pt), and central macular atrophy. LCA gene panel screening revealed no other likely variants (2 pts). Together these are highly specific for AIPL1-related retinopathy (total 9 points, PMID: 21900377, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 21900377). The computational predictor REVEL gives a score of 0.83, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). Cells exogenously expressing the variant protein exhibit more than 60% reduction of cGMP levels relative to the wild-type control, which was equivalent to the control lacking AIPL1, while the variant protein exhibits loss of interaction with HSP90α and HSP90β in yeast-2-hybrid and ELISA experiments (PMID: 28973376). In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP4_moderate, PP1, PM2_supporting, PM3, PP3_moderate, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328674/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8356 biolink:causes MONDO:0015074 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040136 infores:hetionet CHEBI:71941 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C3665347 infores:hetionet CHEBI:691037 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0085624 infores:hetionet CHEBI:9555 biolink:causes MONDO:0001221 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0014867 infores:hetionet CHEBI:50838 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0085633 infores:hetionet UMLS:C0010592 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0268000 infores:hetionet CHEBI:8356 biolink:causes MONDO:0044339 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0158252 infores:hetionet CHEBI:465284 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085682 infores:hetionet CAID:CA916083878 biolink:causes MONDO:0100437 infores:clingen CAID:CA916083878 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Moderate NM_001034853.2(RPGR):c.3039_3040del (p.Glu1014GlyfsTer?) is a frameshift variant due to a 2-nucleotide deletion introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 4 apparently unrelated probands meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 23681342, PMID: 29528978, PMID: 35806195, PMID: 36445968, PS4_Moderate). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA916083878/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:31413 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0278079 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0021400 infores:hetionet CHEBI:10119 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2363730 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0030922 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0030922 infores:hetionet CHEBI:47898 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151786 infores:hetionet CAID:CA10576296 biolink:causes MONDO:0007750 infores:clingen CAID:CA10576296 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4_Supporting, PP1_Moderate, PM2, PP4 BA1, BP4, BS1, BS3, BS4, PM1, PVS1, PP3 NM_000527.4(LDLR): c.1049G>C (p.Arg350Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting, PP1_Moderate, PP4, and PS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: This variant is absent from gnomAD (gnomAD v2.1.1).. PS4_Supporting: Variant meets PM2 and is identified in 5 index cases: 4 cases with DLCN criteria>=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case with DLCN criteria>=6 in Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. PP1_Moderate: Variant segregates with FH phenotype in 5 informative meioses in 3 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). 3 relatives without the phenotype and the variant, 2 relatives with the phenotype and the variant. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6 after alternative causes of high cholesterol were excluded. Data is from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.. PS3_moderate: Level 2 assays: PMID 15100232Heterologous cells (CHO) ACS, WB and NMR Spectroscopy<10% cell surface LDLR, 65% binding, (WB), ~10% expression Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576296/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UNII:R43D2573WO biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0027707 infores:hetionet CAID:CA398326165 biolink:causes MONDO:0011132 infores:clingen CAID:CA398326165 MONDO:0011132 PMID: Pathogenic PM2_Supporting, PM5, PVS1 PP4, PS4 NM_001369369.1(FOXN1):c.1367T>A (p.Leu456Ter) is a nonsense variant in exon 8, of 9, which is predicted to undergo NMD (PVS1). This variant is absent from gnomADv2.1.1 (PM2_supporting). There are two entries for this variant in ClinVar (SCV003327540.1 and SCV003807599.1) but it has not been reported in the literature in individuals with FOXN1-related disease. Two pathogenic variants p.Gln474Ter and p.Ser459Ter curated by the SCID VCEP causes premature termination codons in the same exon and downstream to the variant under assessment. In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM5, and PM2_Supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398326165/MONDO:0011132/113 2024-07-24 2025-07-23 Semidominant inheritance HP:0032113 Supports CHEBI:5855 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0239571 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0178298 infores:hetionet CAID:CA8622896 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622896 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1, PM2 After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.201G>A (p.Lys67=), no individuals with Glanzmann thrombasthenia were reported with the variant and has only been observed in a ostensibly healthy population. The variant has a minor allele frequency of 0.00110 (38/34590 alleles) in the Latino population in gnomAD, which does not meet our threshold criteria for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -0.08 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622896/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:28148 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020649 infores:hetionet CHEBI:27690 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0011991 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0013395 infores:hetionet CHEBI:35854 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0004604 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020649 infores:hetionet CHEBI:4798 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042024 infores:hetionet CHEBI:39669 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0014724 infores:hetionet NCBIGene:8864 biolink:causes MONDO:0011442 infores:monarchinitiative not_provided not_provided HGNC:8846 MONDO:0011442 uuid:7457419d-adf3-447e-960f-8e683e65d47d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0037763 infores:hetionet CHEBI:63621 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013404 infores:hetionet CHEBI:5050 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0013456 infores:hetionet CHEBI:48538 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0917801 infores:hetionet CHEBI:32588 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0020649 infores:hetionet CHEBI:3393 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0027947 infores:hetionet CHEBI:4672 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0042963 infores:hetionet CHEBI:6339 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0015672 infores:hetionet CHEBI:3732 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0022346 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0022650 infores:hetionet CHEBI:6792 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0039070 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0699893 infores:hetionet NCBITaxon:7387 biolink:causes MONDO:0005805 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:7387 MONDO:0005805 CHEBI:6888 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0016655 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0024902 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0162429 infores:hetionet CHEBI:3485 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0015230 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0041969 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020538 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0012833 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001014 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1279296 infores:hetionet CHEBI:5778 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0017979 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002309 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0854165 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042109 infores:hetionet UNII:R15UI3245N biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0034063 infores:hetionet CHEBI:4910 biolink:causes UMLS:C0235524 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0235524 infores:hetionet UNII:7662KG2R6K biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0038999 infores:hetionet CHEBI:66919 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0518015 infores:hetionet CHEBI:9139 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1262144 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0235431 infores:hetionet CHEBI:63623 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0012833 infores:hetionet CHEBI:100241 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0270996 infores:hetionet CHEBI:3127 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0039231 infores:hetionet GO:0110107 biolink:causes GO:0048737 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0048737 CHEBI:3650 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0002874 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0036572 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0003460 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0003123 infores:hetionet CHEBI:2611 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0015230 infores:hetionet CHEBI:9586 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0080274 infores:hetionet CAID:CA016723 biolink:causes MONDO:0004994 infores:clingen CAID:CA016723 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.732C>T (p.Phe244=) variant in the MYH7 gene is 53.63% (5704/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016723/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49713 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0023380 infores:hetionet UMLS:C0065374 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0013378 infores:hetionet CHEBI:24564 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0151313 infores:hetionet CHEBI:16347 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0003811 infores:hetionet CHEBI:63619 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0270611 infores:hetionet CHEBI:5893 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002994 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235960 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235960 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0038525 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0020649 infores:hetionet CHEBI:63589 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020443 infores:hetionet CHEBI:32315 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0232461 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0854717 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0854717 infores:hetionet CHEBI:681850 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0011991 infores:hetionet NCBIGene:170302 biolink:causes MONDO:0010268 infores:monarchinitiative not_provided not_provided HGNC:18060 MONDO:0010268 uuid:2d87f60f-20b0-4974-87c3-924082b58584 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0024902 infores:hetionet CHEBI:2948 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0030305 infores:hetionet CHEBI:7931 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0009806 infores:hetionet GO:1901546 biolink:causes GO:0016188 infores:ubergraph knowledge_assertion manual_agent GO:1901546 GO:0016188 UNII:3U02EL437C biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0036508 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0278080 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042075 infores:hetionet CHEBI:92712 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0231835 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0005959 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0005959 infores:hetionet CHEBI:49713 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0011603 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011849 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018099 infores:hetionet CHEBI:135930 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C1167965 infores:hetionet CHEBI:4469 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0015967 infores:hetionet CHEBI:63624 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0026858 infores:hetionet CHEBI:3723 biolink:causes UMLS:C3251821 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C3251821 infores:hetionet CHEBI:75045 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0085682 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002871 infores:hetionet CHEBI:119915 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234133 infores:hetionet CHEBI:6149 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0035229 infores:hetionet CHEBI:68642 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0600142 infores:hetionet CHEBI:18248 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0027497 infores:hetionet CHEBI:49375 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020458 infores:hetionet CHEBI:7476 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011603 infores:hetionet CHEBI:4887 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0042075 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0151908 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0518015 infores:hetionet CHEBI:15940 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0040409 infores:hetionet CHEBI:50729 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0042963 infores:hetionet CHEBI:6367 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0023218 infores:hetionet NCBIGene:4784 biolink:causes MONDO:0013885 infores:monarchinitiative not_provided not_provided HGNC:7788 MONDO:0013885 uuid:cebde8e5-b639-4138-8d10-bb43ba051e79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3172 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0700590 infores:hetionet NCBIGene:11012 biolink:causes MONDO:0957783 infores:monarchinitiative not_provided not_provided HGNC:6359 MONDO:0957783 uuid:1126c935-ae78-40b7-9aa0-2a460d370cc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0020621 infores:hetionet CAID:CA314582 biolink:causes MONDO:0100040 infores:clingen CAID:CA314582 MONDO:0100040 PMID: Benign BS1, BP5_Strong, BS2 PM2, BA1 The highest population minor allele frequency of the p.Gly126Ser variant in FOXG1 in gnomAD v4.1 is 0.0001782 in European (non-Finnish) population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Gly126Ser variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Gly126Ser variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5_Strong). In summary, the p.Gly126Ser variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5_Strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA314582/MONDO:0100040/035 2024-08-30 2024-10-25 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:8692 biolink:causes MONDO:0976127 infores:monarchinitiative not_provided not_provided HGNC:5321 MONDO:0976127 uuid:31abebc8-394d-4e17-956d-f072b6fdf503 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4046 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0015672 infores:hetionet CHEBI:9555 biolink:causes MONDO:0005080 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0020541 infores:hetionet CHEBI:5118 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014457 infores:hetionet CHEBI:75984 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0852911 infores:hetionet CAID:CA120636 biolink:causes MONDO:0044970 infores:clingen CAID:CA120636 MONDO:0044970 PMID: Likely Pathogenic PP3, PP1, PM2_Supporting, PS4_Moderate, PS3_Supporting, PM5 PS2, PM6 The m.11777C>A (p.R340S) variant in MT-ND4 has been reported in at least eight unrelated individuals with primary mitochondrial disease and features including Leigh syndrome, stroke-like episodes, and cardiomyopathy (PS4_moderate; PMIDs: 12707444, 16120329, 15576045, 20502985, 24642831, 29428506). Ages of onset varied from the first few days of life to the 60s and heteroplasmy levels in affected individuals ranged from 50-93%. There is one report of the variant being absent in mother’s blood (PMID: 16120329) however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. This variant segregated with disease in one family, as two healthy family members had lower to undetectable levels of the variant (PP1; PMID: 20502985). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is a known pathogenic variant – m.11778G>A (p.R340H, PM5). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 16120329). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.83 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PS3_supporting, PM2_supporting, PM5, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120636/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria NCBIGene:65975 biolink:causes MONDO:0971000 infores:monarchinitiative not_provided not_provided HGNC:14568 MONDO:0971000 uuid:8f6872ee-20e3-4a35-b268-c74fcc62858f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151907 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0521491 infores:hetionet CHEBI:7445 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0151786 infores:hetionet CHEBI:8428 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0031046 infores:hetionet GO:0072307 biolink:causes GO:0072234 infores:ubergraph knowledge_assertion manual_agent GO:0072307 GO:0072234 CHEBI:75922 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0234632 infores:hetionet NCBIGene:11113 biolink:causes MONDO:0014908 infores:monarchinitiative not_provided not_provided HGNC:1985 MONDO:0014908 uuid:4c6c14c4-de5c-426b-8776-4af655fed65a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0034155 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0030920 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0021053 infores:hetionet CHEBI:23765 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C3263723 infores:hetionet CHEBI:7852 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011124 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0032285 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0242461 infores:hetionet CHEBI:64354 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0033774 infores:hetionet CAID:CA16041867 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041867 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1077+1G>T variant in ACADVL is a splice site variant affecting the canonical donor splice site in intron 10. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present at low frequency (1 allele, <0.1%) in large population database (PM2_supporting, gnomad). This variant has been reported in abnormal newborn screen with 36% residual enzyme activity (PP4 not met) without clinical confirmation or a second variant identified (PMID 21932095). In summary, this variant meets criteria to be classified as likely pathogenic for VLCAD in an AR manner. ACADVL-specific ACMG/AMP criteria applied: PVS1, PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041867/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8024 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0028734 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0037274 infores:hetionet CAID:CA512319058 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319058 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.612A>G (p.Arg204=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319058/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6413 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C2937358 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0027497 infores:hetionet CAID:CA134569 biolink:causes MONDO:0021060 infores:clingen CAID:CA134569 MONDO:0021060 PMID: Likely Benign BP5, BP7, BS1, BP4 PM2, BA1, PP3 The NM_002524.5:c.360G>A (p.Leu120=) variant is a synonymous (silent) variant in NRAS that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 77/129188) of the c.360G>A variant in NRAS is 0.0004832 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). Observed in 1 individual with a co-occurring likely pathogenic/pathogenic variant in a gene that explains their condition, Noonan syndrome (Invitae internal data, ClinVar SCV000253394.6). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4, BP5, BP7. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134569/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:63931 biolink:causes MONDO:0032712 infores:monarchinitiative not_provided not_provided HGNC:14049 MONDO:0032712 uuid:c91343d2-8c6b-4e13-924c-39846b451bd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0013428 infores:hetionet CHEBI:4027 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0009676 infores:hetionet CHEBI:9086 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0235063 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0234215 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0241863 infores:hetionet CHEBI:64321 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0042029 infores:hetionet CAID:CA024676 biolink:causes MONDO:0007783 infores:clingen CAID:CA024676 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, BS1, BA1, BP4 TThis pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with methionine at codon 2346 of the RYR1 protein, p.(Val2346Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, these individuals were not counted for PS4 as they have a second RYR1 variant phase unknown (PMID:16163667, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.944) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024676/MONDO:0007783/012 2024-02-28 2024-02-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7809 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0151766 infores:hetionet CHEBI:17026 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0149741 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0178298 infores:hetionet CHEBI:6741 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042029 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0549373 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1274594 infores:hetionet CHEBI:5383 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0001824 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0038661 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0011849 infores:hetionet CAID:CA406175434 biolink:causes MONDO:0011229 infores:clingen CAID:CA406175434 MONDO:0011229 PMID: Pathogenic PM3_Supporting, PVS1, PM2, PP4_Moderate PP1, BS2, BA1, BP2, BP5, BS1, BS4 The c.505+1G>T variant (NM_014297.5) in ETHE1 occurs within the canonical splice donor/acceptor site (+1) of exon/intron 4 boundary (exon 4/7). It is predicted to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 14732903). This prediction is supported by the absence of protein on Western blot of fibroblasts from patient J who was homozygous for this variant (PMID: 14732903). This variant is absent from gnomAD v2.1.1 (PM2). This variant was originally reported in a homozygote with developmental delay, petechiae, orthostatic acrocyanosis, chronic diarrhea, and ethylmalonic aciduria which is a phenotype highly specific to ethylmalonic encephalopathy (PP4_moderate; PMID: 14732903 patient J). While there are at least four homozygotes with ethylmalonic encephalopathy reported to date, parental linkage analyses have only been performed in one of these patients to confirm the variants were in trans (PM3_supporting; Total Score- 0.5; PMID: 14732903, PMID: 22584649, PMID: 18593870). In summary, this variant meets the criteria to be classified as pathogenic for Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): PVS1, PM2, PM3_supporting, PP4_Moderate. Approved 7/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA406175434/MONDO:0011229/014 2021-07-27 2021-07-27 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:18248 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0013404 infores:hetionet CHEBI:45951 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0020615 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C2939465 infores:hetionet GO:0060129 biolink:causes CL:0000476 infores:ubergraph knowledge_assertion manual_agent GO:0060129 CL:0000476 MONDO:0100299 biolink:causes NCBIGene:5079 infores:ubergraph knowledge_assertion manual_agent MONDO:0100299 HGNC:8619 CHEBI:75246 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0020580 infores:hetionet CHEBI:367163 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0002994 infores:hetionet CHEBI:31980 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0002792 infores:hetionet CHEBI:7478 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0036974 infores:hetionet CHEBI:3640 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0262988 infores:hetionet CHEBI:7494 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0038325 infores:hetionet CHEBI:4877 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0027813 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0017152 infores:hetionet CHEBI:63791 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0575081 infores:hetionet CHEBI:66899 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C1761613 infores:hetionet CHEBI:8874 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0025874 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0240066 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0240066 infores:hetionet CHEBI:6710 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0003123 infores:hetionet CHEBI:2618 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0009676 infores:hetionet CAID:CA410203415 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203415 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS3, BS1, BS4, PM4, PM5, PM3, BS2, PP2, PP1, PP4 NM_001754.4(RUNX1):c.331A>G (p.Thr111Ala) is a missense variant that affects one of the residues (AA 105-204) within the Runt Homology Domain (RHD), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score of 0.939 (> 0.75), supporting PP3. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203415/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C2937350 infores:hetionet CHEBI:9586 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0231218 infores:hetionet CHEBI:27363 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01593 UMLS:C0030305 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0002622 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0027121 infores:hetionet CHEBI:4974 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0020458 infores:hetionet CHEBI:3011 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0030305 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0233414 infores:hetionet CHEBI:7907 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0015230 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0020649 infores:hetionet CHEBI:119486 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085631 infores:hetionet CHEBI:15640 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0023380 infores:hetionet CHEBI:5280 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0014591 infores:hetionet CHEBI:10110 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0011168 infores:hetionet NCBIGene:55023 biolink:causes MONDO:0035133 infores:monarchinitiative not_provided not_provided HGNC:15673 MONDO:0035133 uuid:1bd58753-421b-42f1-8e6d-f4d50c95a0a0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013378 infores:hetionet CHEBI:59773 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0019825 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0442886 infores:hetionet CHEBI:78543 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0002170 infores:hetionet CHEBI:8597 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0011253 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0031117 infores:hetionet CAID:CA16020914 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020914 MONDO:0009861 PMID:26503515 Uncertain Significance PM2, PP4_Moderate, PP3 PM5 The c.983C>A (p.Thr328Asn) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded, PMID: 26503515). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020914/MONDO:0009861/006 2020-08-10 2021-09-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50777 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0151735 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0239211 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0239211 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0029882 infores:hetionet CAID:CA261262 biolink:causes MONDO:0044970 infores:clingen CAID:CA261262 MONDO:0044970 PMID:20153673 Uncertain Significance PP3, PS3_Moderate, PM2_Supporting PP1, PS4, PM6 The m.7505T>C variant in MT-TS1 has been reported in two families with primary mitochondrial disease. Affected individuals had nonsyndromic hearing loss (PMIDs: 20153673, 33638616). The variant was present at homoplasmy in affected and unaffected family members. There are no reported de novo occurrences of this variant. There is one homoplasmic occurrence of this variant in the Helix dataset and this variant is absent in the MITOMAP GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (58.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Cybrid studies support the functional impact of this variant as they showed the variant was associated with decreased levels of tRNASer(UCN), altered conformation of the tRNA, altered stability of tRNASer(UCN), variable reductions of mitochondrial proteins, decreased enzymatic activities of mitochondrial respiratory chain complexes, decreased respiration, and increased reactive oxygen species (PS3_moderate; PMID: 20153673). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA261262/MONDO:0044970/015 2024-08-27 2025-04-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true GO:0039602 biolink:causes GO:0006366 infores:ubergraph knowledge_assertion manual_agent GO:0039602 GO:0006366 CHEBI:94385 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0040046 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0030332 infores:hetionet CHEBI:15640 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0015376 infores:hetionet CAID:CA8603350 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603350 MONDO:0100326 PMID: Likely Benign BP7, BS1 The c.799+15C>T variant in ITGA2B is an intronic variant which occurs in intron 7/29. The highest population minor allele frequency in gnomAD v4 is 0.002027 (21/10358 alleles) in the Ashkenazi Jewish population, which is higher than the ClinGen PD VCEP threshold (>0.00158), and therefore meets this criterion (BS1).This variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.8264 (BP7).In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS1, BP7. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603350/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7983 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0151735 infores:hetionet CAID:CA172185 biolink:causes MONDO:0100040 infores:clingen CAID:CA172185 MONDO:0100040 PMID: Benign BP5, BA1 The allele frequency of the p.Gly163= variant in FOXG1 is 0.09% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Gly163= variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly163= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172185/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true UNII:9430ZR8ZAN biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0030252 infores:hetionet CHEBI:8890 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0037763 infores:hetionet CHEBI:135276 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0080274 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0423602 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0518015 infores:hetionet CHEBI:31236 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235710 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002940 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0948594 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0027441 infores:hetionet NCBIGene:64682 biolink:causes MONDO:0016368 infores:monarchinitiative not_provided not_provided HGNC:19988 MONDO:0016368 uuid:a3724b73-976d-4e3c-80b8-a4d3ae81c7fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5050 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0004238 infores:hetionet CHEBI:27504 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0041657 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0242350 infores:hetionet CHEBI:2208 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0015230 infores:hetionet CHEBI:65349 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0000737 infores:hetionet CHEBI:16714 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0231218 infores:hetionet CHEBI:3568 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0232726 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0004245 infores:hetionet CHEBI:71272 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0017152 infores:hetionet GO:0061050 biolink:causes GO:0003301 infores:ubergraph knowledge_assertion manual_agent GO:0061050 GO:0003301 CHEBI:5790 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0002622 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0232492 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0013922 infores:hetionet CHEBI:37924 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0019209 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0005940 infores:hetionet CHEBI:17347 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0039070 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0006840 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0040034 infores:hetionet CHEBI:49713 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0028961 infores:hetionet CHEBI:4653 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0030920 infores:hetionet CHEBI:10125 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0010692 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1096035 infores:hetionet CHEBI:52717 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023052 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0149931 infores:hetionet GO:0072043 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072006 CHEBI:45652 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0026837 infores:hetionet GO:0048905 biolink:causes CL:2000035 infores:ubergraph knowledge_assertion manual_agent GO:0048905 CL:2000035 CHEBI:72564 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0011053 infores:hetionet CHEBI:32020 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0009676 infores:hetionet CAID:CA134721 biolink:causes MONDO:0021060 infores:clingen CAID:CA134721 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.212A>G (p.Asn71Ser) variant in the RAF1 gene is 0.14% for Latino chromosomes by the Exome Aggregation Consortium (24/11578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134721/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:135451 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0020461 infores:hetionet CHEBI:9570 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0015371 infores:hetionet CHEBI:47780 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C1527344 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013395 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0034069 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151661 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151661 infores:hetionet CHEBI:50648 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0016199 infores:hetionet CHEBI:49575 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0231528 infores:hetionet CHEBI:2673 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0018681 infores:hetionet CHEBI:7492 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0035455 infores:hetionet CHEBI:184555 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0009763 infores:hetionet CHEBI:367163 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0017168 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0027051 infores:hetionet NCBIGene:582 biolink:causes MONDO:0008854 infores:monarchinitiative not_provided not_provided HGNC:966 MONDO:0008854 uuid:a3232e3d-b5e6-4ca9-b4d9-b17a0e02869f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0242350 infores:hetionet CHEBI:4514 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0522224 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0152029 infores:hetionet CHEBI:9073 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0018524 infores:hetionet CAID:CA355945567 biolink:causes MONDO:0001586 infores:clingen CAID:CA355945567 MONDO:0001586 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The NM_000203.5:c. c.123G>A (p.Trp41Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with Hurler syndrome, presenting with IDUA deficiency within the affected range, increased excretion of urinary dermatan sulfate and heparan sulfate, and clinical features specific to MPS I including Macrocephaly, joint stiffness, Mongolian macula, hepatosplenomegaly, hernia, cardiac disease, and airway obstruction (PMID 21480867) (PP4_moderate). This individual is compound heterozygous for the variant and c.300-1G>C, p.(?). The allelic data for this patient will be used to support the classification of c.300-1G>C and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0 is 8.889e-7 (1/1,124,963 alleles) in the Non-Finnish European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (>0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2734632). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): (PVS1, PP4 moderate, PM2 supporting). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355945567/MONDO:0001586/091 2025-04-07 2025-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:171719 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0020615 infores:hetionet CAID:CA024397 biolink:causes MONDO:0007783 infores:clingen CAID:CA024397 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 1140 of the RYR1 protein, p.Arg1140Cys. The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.00012, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257). However, the high MAF in the AMR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.807 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024397/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:27504 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0027540 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0232910 infores:hetionet GO:0042665 biolink:causes GO:0010668 infores:ubergraph knowledge_assertion manual_agent GO:0042665 GO:0010668 CHEBI:6437 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085641 infores:hetionet CHEBI:135736 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018932 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0002871 infores:hetionet CHEBI:74947 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0026826 infores:hetionet CHEBI:43968 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0000731 infores:hetionet CHEBI:63607 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0002994 infores:hetionet CAID:CA343726262 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726262 MONDO:0020367 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS2_Moderate, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS3, PS1, BP4, BA1 The c.752T>C variant in MYOC is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 251 (p.Val251Ala). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.839, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 17 segregations in 3 families with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 32937162, 23517641 and Pasutto pers. comm.), which fulfilled PP1_Strong (≥ 7 meioses in >1 family). 3 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 32937162, 23517641 and Pasutto pers. comm.), which met PS4_Supporting (≥ 2 probands). One of these was a confirmed de novo proband with JOAG (PMID: 23517641) (PS2_Moderate). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS2_Moderate, PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726262/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49575 biolink:causes UMLS:C0235113 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0235113 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020039 infores:hetionet NCBIGene:57560 biolink:causes MONDO:0012644 infores:monarchinitiative not_provided not_provided HGNC:29262 MONDO:0012644 uuid:5c649b70-d77e-4926-a082-73de21df47fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63613 biolink:causes UMLS:C0235046 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0235046 infores:hetionet CHEBI:2663 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0009676 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0015695 infores:hetionet CHEBI:64355 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020580 infores:hetionet CHEBI:16469 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013456 infores:hetionet CHEBI:5296 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0020580 infores:hetionet CHEBI:47612 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0162830 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0017168 infores:hetionet CAID:CA273745 biolink:causes MONDO:0021060 infores:clingen CAID:CA273745 MONDO:0021060 PMID:29493581 Pathogenic PS4, PM1, PM2, PP2, PP3, PM6_Strong PM5 The c.788T>G (p.Val263Gly) variant in RAF1 has been reported as a de novo occurrence in at least two patients with clinical features of a RASopathy (PM6_Strong; PMID: 30732632; GeneDx internal data, ClinVar SCV000209021.10). The p.Val263Gly variant has been identified in at least 5 other independent occurrences in patients with a RASopathy (PS4; PMID: 30732632, 31560489, 31145547; Partners Laboratory for Molecular Medicine, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; ClinVar SCV000061370.6). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Different pathogenic missense variants have been previously identified at this codon of RAF1, which may indicate that this residue is critical to the function of the protein (PM5 not applied; ClinVar ID: 496189, 40608). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Val263Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6_Strong, PM1, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA273745/MONDO:0021060/004 2020-06-25 2020-07-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CAID:CA226491 biolink:causes MONDO:0100368 infores:clingen CAID:CA226491 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PP1, PM2_Supporting NM_000329.3(RPE65):c.118G>A is a missense variant predicted to replace glycine with serine at position 40. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00006, with 2 alleles/24966 total alleles in the African/African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.984, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited <2 % enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16150724 ). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 25257057, PMID: 33608557). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant confirmed in trans (1 pt, PMID: 9501220, PMID: 11462243), the c.11+5G>A variant suspected in trans (0.5 pts, PMID: 18441371), or the p.Arg91Gln variant suspected in trans (0.5 pts, PMID: 19117922), all of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (total 3 pts, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 9501220, PP1). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), absent or severely reduced rod ERG (0.5 pts), decreased central visual acuity (1 pt), and significant improvement of visual function by FST after gene-specific gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (total 10 pts, PMID: 21911650, PP4_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226491/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2549 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0042075 infores:hetionet UMLS:C1709429 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0020625 infores:hetionet CHEBI:2922 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0023530 infores:hetionet CHEBI:63621 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0030554 infores:hetionet CHEBI:63608 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0497156 infores:hetionet CHEBI:3286 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0018681 infores:hetionet CHEBI:3215 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0023518 infores:hetionet CHEBI:3387 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0013378 infores:hetionet CHEBI:35553 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0039070 infores:hetionet CHEBI:135876 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0151539 infores:hetionet CHEBI:5893 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0232849 infores:hetionet CHEBI:75246 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0004093 infores:hetionet CHEBI:49713 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0029124 infores:hetionet CHEBI:32221 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0038362 infores:hetionet NCBIGene:845 biolink:causes MONDO:0012762 infores:monarchinitiative not_provided not_provided HGNC:1513 MONDO:0012762 uuid:134f1310-3e30-4ece-bff2-434f32921502 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0677500 infores:hetionet CHEBI:50131 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0027947 infores:hetionet CHEBI:9073 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0039070 infores:hetionet CHEBI:61049 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0023218 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0025202 infores:hetionet CHEBI:6715 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006625 infores:hetionet UMLS:C0004609 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C2937350 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0878544 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004522 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1264610 infores:hetionet CHEBI:71417 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0042023 infores:hetionet CHEBI:84050 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0020433 infores:hetionet CHEBI:119915 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0232849 infores:hetionet CAID:CA10385150 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385150 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.3371T>A (p.Val1124Asp) is a missense variant causing substitution of valine by aspartic acid at amino acid 1124. This variant is present in gnomAD v4.1.0 at a frequency of 0.0005116 among hemizygous individuals, with 203 variant alleles / 396,827 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385150/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:63607 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0017675 infores:hetionet CHEBI:6717 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0028961 infores:hetionet CHEBI:44032 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0004604 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549280 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549280 infores:hetionet CHEBI:6539 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0013144 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018799 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0019158 infores:hetionet NCBIGene:84140 biolink:causes MONDO:0011630 infores:monarchinitiative not_provided not_provided HGNC:25808 MONDO:0011630 uuid:644b92dd-a1c1-43e2-9d1a-672d915c555c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0012813 infores:hetionet CAID:CA645373277 biolink:causes MONDO:0015967 infores:clingen CAID:CA645373277 MONDO:0015967 PMID: Pathogenic PP4, PM2_Supporting, PS4, PM1_Supporting, PP1_Strong PM4, BA1, BS1 The c.956_958dup variant in the hepatocyte-nuclear factor 4-alpha gene, HNF4A, is a 3 base pair insertion resulting in the in-frame addition of 1 amino acid at codon 319 (p.(Leu_319_Pro320insLeu)) within exon 8 of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 15830177, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, family member with diazoxide-responsive neonatal hyperinsulinism) (PP4; internal lab contributors). This variant segregated with diabetes, with 6 informative meioses in 4 families (PP1_Strong; PMID: 15830177, internal lab contributors). While the c.956_958dup variant is predicted to change the length of the protein due to an in-frame insertion of a single amino acid, it is in a repeat region where the reference sequence contains a tract of 5 leucines and there is a relatively common 4 leucine variant (c.956_958del p.Leu319del, Popmax filtering allele frequency = 0.00011), and PM4 was not applied. In summary, c.956_958dup meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645373277/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:168396 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0014130 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0236071 infores:hetionet CHEBI:167309 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0037383 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1168134 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1168134 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005479 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0546959 infores:hetionet CHEBI:84500 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0018681 infores:hetionet UMLS:C0120107 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0019080 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0038454 infores:hetionet CHEBI:61058 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0027497 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0042109 infores:hetionet CHEBI:83527 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0013378 infores:hetionet CHEBI:3723 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023222 infores:hetionet CHEBI:7443 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0231218 infores:hetionet UMLS:C0120107 biolink:causes HP:0002176 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0037926 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0009782 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027441 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0151474 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0029456 infores:hetionet CHEBI:2950 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0004093 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0549209 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0022660 infores:hetionet UMLS:C0120107 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085649 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0009450 infores:hetionet CAID:CA401369044 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369044 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PS3_Moderate PP3, BP4 "The NM_000152.5:c.1710C>G (p.Asn570Lys) variant in GAA has a minor allele frequency in gnomAD of 0.0001149 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. At least three individuals have been reported with this variant and documented GAA activity in the affected range and/or were reported to be on enzyme replacement therapy for Pompe disease (PMID: 17151339, 22538254, 29122469, 32248831) (PP4_Moderate). This variant was found in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1), phase unconfirmed, in at least one patient with Pompe disease (PMID: 22538254, 22658377, 29122469, 31193175)(0.5 points), and confirmed in trans in a patient with c.953T>C (p.Met318Thr) (ClinVar Variation ID: 4021; SCV002583364.1) (PMID: 36636589) (1 point). Another patient with the variant, along with with c.-32-13T>G and a rare synonymous variant c.1923G>A (p.Leu641=) has been reported (PMID: 32248831). While the allelic data from the latter patient is likely supportive of pathogenicity for c.1710C>G (p.Asn570Lys), it is not included here because the impact of p.Leu641= is unknown (Total 1.5 points) (PM3). Functional assays support a deleterious effect of this variant. When expressed in COS cells, this variant was classified as Class B (""potentially less severe"") by Kroos et al, 2012 (PMID:22644586). This includes 0.9% GAA activity in cells and 0.5% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate). Computational evidence is inconclusive, REVEL score = 0.662 which is lower than the LD VCEP threshold for PP3 (>0.7) but higher than the LD VCEP threshold for BP4 (<0.5), and therefore does not meet either criterion. There is a ClinVar entry for this variant (Variation ID: 555153). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel. GAA-specific GAA-specific ACMG/AMP criteria met (Specifications Version 2.0): PS3_Moderate, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369044/MONDO:0009290/010 2024-11-22 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63589 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0344232 infores:hetionet GO:0035477 biolink:causes GO:0035474 infores:ubergraph knowledge_assertion manual_agent GO:0035477 GO:0035474 CHEBI:3696 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020621 infores:hetionet CHEBI:92712 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0428974 infores:hetionet CHEBI:94501 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151636 infores:hetionet CHEBI:4784 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011606 infores:hetionet CHEBI:5062 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0085649 infores:hetionet CHEBI:6715 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019080 infores:hetionet CHEBI:47381 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0037763 infores:hetionet CHEBI:47381 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0041657 infores:hetionet UNII:0RK7M7IABE biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0151664 infores:hetionet NCBIGene:270 biolink:causes MONDO:0014220 infores:monarchinitiative not_provided not_provided HGNC:468 MONDO:0014220 uuid:20e9700a-438c-42e2-b397-738e80f5f6cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0035455 infores:hetionet CHEBI:73274 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0032617 infores:hetionet CHEBI:10100 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0027497 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0267596 infores:hetionet CAID:CA000127 biolink:causes MONDO:0017623 infores:clingen CAID:CA000127 MONDO:0017623 PMID: Likely Benign BP4, BS1_Supporting PVS1, PM2, PM6, BS3, BS4, BP7, BP5, BS2, PP2, PP3, PP1, PP4, PM3, PM4, PM1, PM5, BP1, BP2, BP3, BA1, PS3, PS1, PS2, PS4 NM_000314.8(PTEN):c.159A>G (p.Val53=) meets criteria to be classified as Likely Benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00004593 (9 alleles v4 gnomAD).BP4: Synonymous variant where SpliceAI model predict no splicing impact (acceptor gain 0.08, donor gain 0.13). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000127/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45327 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0151744 infores:hetionet CHEBI:100147 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0162830 infores:hetionet CHEBI:4657 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0020580 infores:hetionet CHEBI:5118 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017181 infores:hetionet CAID:CA229855 biolink:causes MONDO:0009861 infores:clingen CAID:CA229855 MONDO:0009861 PMID:15503242PMID:25894915PMID:15503242PMID:25894915PMID:18590700 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting BS3 The NM_000277.1(PAH):c.929C>T (p.Ser310Phe) variant is a missense variant in exon 9/13 of PAH. The variant has been found to result in <1% of wild-type PAH enzyme activity in a standard cDNA and an Intinc system (PMID: 18590700) (PS3_supporting). It has been found in at least 8 PKU patients, including among those whom BH4 deficiency was excluding and in trans with other Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4.75 points); PP4_Moderate). It has been found in 2 alleles in a survey of German PKU patients (PMID: 12655553); in trans with the c.442-1G>A (Pathogenic in ClinVar and by ClinGen PAH VCEP) variant in a Korean patient with moderate PKU (plasma Phe 600-1200 umol/L) with BH4 deficiency excluded by urinary pterin analysis and dihydropteridine reductase (DHPR) assay (PMID: 15503242). It has been found in as a homozygous variant in a Syrian patient with classic PKU (plasma Phe 1262 umol/L) (PMID: 23856132). It has been found in two Chinese patients with classic PKU and BH4 deficiency excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes: one harbored it in trans with the p.R111* variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) and one in trans with the p.Y356* variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) (PMID: 30050108). It has been found in a Chinese patient with mild hyperphenylalanemia (plasma Phe 120-360 umol/L) in trans with p.R241C (Pathogenic in ClinVar and by ClinGen PAH VCEP); BH4 deficiency was excluded (PMID: 25894915). It has been found in trans with p.F302V (unclassified) in a Chinese patient with mild PKU (plasma Phe 360–1200 μmol/L) and BH4 deficiency excluded (PMID: 30459323). It has been reported in trans with c.1066-3C>T (Pathogenic/Likely Pathogenic in ClinVar and by ClinGen PAH VCEP)in a PKU patient (PMID: 23430918). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.993) (PP3).Classification: PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229855/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:167309 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0687133 infores:hetionet CAID:CA8337766 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337766 MONDO:0008723 PMID:20060901 Likely Pathogenic PM2_Supporting, PVS1 PM1 The c.603C>G (p.Tyr201Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant has been observed in only one publication with no information provided about the proband (PMID: 25087612). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_Supporting (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337766/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9907 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0004238 infores:hetionet CHEBI:32315 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0023218 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0013604 infores:hetionet CHEBI:2379 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0013144 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0241863 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0019209 infores:hetionet CHEBI:2453 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151578 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235467 infores:hetionet CAID:CA512340983 biolink:causes MONDO:0011071 infores:clingen CAID:CA512340983 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, PVS1, BS1, BS3, BS4, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1359G>A (p.Val453=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.12)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512340983/MONDO:0011071/008 2024-09-11 2024-09-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94392 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0011603 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0025061 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022650 infores:hetionet CAID:CA229353 biolink:causes MONDO:0009861 infores:clingen CAID:CA229353 MONDO:0009861 PMID:8069318 Pathogenic PM2, PVS1, PP4 The c.1117_1118del (p.Ala373fs) variant in PAH has been reported in 1 French patient with typical PKU, serum Phe > 1.2mM, BH4 deficiency not excluded (PP4). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 11 out of 13 coding exons (11 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229353/MONDO:0009861/006 2020-10-29 2020-10-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0231218 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011630 infores:hetionet CHEBI:3756 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0270611 infores:hetionet CHEBI:3380 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0034642 infores:hetionet NCBIGene:65250 biolink:causes MONDO:0013824 infores:monarchinitiative not_provided not_provided HGNC:25801 MONDO:0013824 uuid:48cf7df9-92c7-41bd-bb6a-f73435e5f2da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0021368 infores:hetionet CHEBI:63598 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0015371 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0002453 infores:hetionet CHEBI:6809 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0009806 infores:hetionet CHEBI:46557 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0013604 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0042571 infores:hetionet CHEBI:107736 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0085637 infores:hetionet CAID:CA512232261 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232261 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.861C>T (p.Tyr287=) is a synonymous variant which has a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232261/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31711 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0013404 infores:hetionet CHEBI:8207 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C1306341 infores:hetionet NCBIGene:22796 biolink:causes MONDO:0054559 infores:monarchinitiative not_provided not_provided HGNC:6546 MONDO:0054559 uuid:435e9fd1-6cec-4149-9213-a0088b2a9867 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011206 infores:hetionet CHEBI:50648 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013428 infores:hetionet CHEBI:5855 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0027796 infores:hetionet CHEBI:45327 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0162297 infores:hetionet CAID:CA409108558 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108558 MONDO:0015967 PMID: Pathogenic PVS1, PM2_Supporting, PP1_Strong PS4 The c.1000C>T variant in the HNF4 homeobox A gene, HNF4A, results in a premature termination at codon 334 (p.(Gln334Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 5 informative meioses in a single family (PP1_Strong; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 23348805, 36257325). In summary, c.1000C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108558/MONDO:0015967/085 2024-11-27 2024-11-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63580 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0015967 infores:hetionet CHEBI:6909 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0278134 infores:hetionet CHEBI:64355 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151603 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0006266 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0033774 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0854985 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0854985 infores:hetionet CHEBI:36795 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020458 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0851341 infores:hetionet CHEBI:8426 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0027497 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0277925 infores:hetionet CHEBI:51041 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0149745 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0160390 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151883 infores:hetionet CHEBI:50131 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0340865 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026848 infores:hetionet CAID:CA512232233 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232233 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.891C>T (p.His297=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232233/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3387 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0151766 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0235315 infores:hetionet CHEBI:567361 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0014457 infores:hetionet CHEBI:9943 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0424295 infores:hetionet CHEBI:72297 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0038354 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0243026 infores:hetionet NCBIGene:5076 biolink:causes MONDO:0007352 infores:monarchinitiative not_provided not_provided HGNC:8616 MONDO:0007352 uuid:1da75960-d1eb-439b-bb44-e8de3becc3f9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410203843 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203843 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.232A>C (p.Met78Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203843/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2950 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0027769 infores:hetionet CHEBI:92511 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0403632 infores:hetionet CHEBI:101278 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0740394 infores:hetionet CHEBI:85083 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0162429 infores:hetionet CHEBI:2955 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C2129214 infores:hetionet CHEBI:8888 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085583 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0027769 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041747 infores:hetionet CHEBI:135613 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0085612 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0019158 infores:hetionet CHEBI:31859 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0007859 infores:hetionet CHEBI:8060 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0042963 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0162429 infores:hetionet CHEBI:63624 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0042963 infores:hetionet CHEBI:63589 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0023787 infores:hetionet CHEBI:6076 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0030193 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0012833 infores:hetionet CHEBI:9086 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027849 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0041912 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0836924 infores:hetionet CHEBI:3757 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0151878 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0009806 infores:hetionet CHEBI:3752 biolink:causes MONDO:0008213 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0016842 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042075 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0009241 infores:hetionet CHEBI:31644 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151905 infores:hetionet CHEBI:6413 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0007286 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0030517 infores:hetionet CHEBI:4653 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0034886 infores:hetionet NCBIGene:55768 biolink:causes MONDO:0800044 infores:monarchinitiative not_provided not_provided HGNC:17646 MONDO:0800044 uuid:c439cc09-60cd-4ff9-863e-dadab21dae38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0948089 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0948594 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0042571 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0017160 infores:hetionet CHEBI:6375 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151905 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1291078 infores:hetionet CHEBI:2038 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0023530 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0155305 infores:hetionet CAID:CA10584830 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584830 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP4, BP2, BP3, PS1, PS3, PS4, BP7, BS1, BS3, BS4, PM5, PM3, PM4, PM1, PVS1, PP3, PP1, BS2 The NM_000527.5(LDLR):c.292G>C (p.Gly98Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584830/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7915 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0039231 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0684249 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0040046 infores:hetionet CHEBI:2453 biolink:causes UMLS:C3665444 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C3665444 infores:hetionet CHEBI:18358 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0011570 infores:hetionet CHEBI:10110 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0032617 infores:hetionet CHEBI:64321 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0011603 infores:hetionet CHEBI:4530 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0233477 infores:hetionet CHEBI:37333 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0011603 infores:hetionet CHEBI:6935 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0267596 infores:hetionet NCBIGene:203068 biolink:causes MONDO:0014341 infores:monarchinitiative not_provided not_provided HGNC:20778 MONDO:0014341 uuid:5b95e43f-2eb8-4e78-8eb6-ffa0bddd3b56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5384 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0023895 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0033860 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0087169 infores:hetionet CHEBI:5856 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0006384 infores:hetionet CHEBI:6539 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0023518 infores:hetionet CHEBI:82941 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0162429 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0027769 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0235966 infores:hetionet CHEBI:45863 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0000737 infores:hetionet CHEBI:6909 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013604 infores:hetionet CHEBI:51230 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C1761613 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0007971 infores:hetionet CAID:CA10360227 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360227 MONDO:0100039 PMID: Uncertain Significance BS2_Supporting BP5, BS1, BS3, BS4, PM5, PM1, PM3, PP3, PP1, PP4, PM2, PM6, BP4, BP2, BA1, PS1, PS3, PS4, PS2 The c.239G>A (p.Arg80His) variant was observed in at least 1 unaffected heterozygous individual (internal database - Invitae) (BS2_supporting). This variant is also present in one XY individual in gnomAD v4 (0.00008%) (not sufficient to meet BS1 criteria). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Arg80His variant in CDKL5 is classified as a Variant of Unknown Significance for CDKL5-associated disorder based on the ACMG/AMP criteria (BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360227/MONDO:0100039/034 2023-12-06 2023-12-08 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Inconclusive true CHEBI:63632 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0854467 infores:hetionet GO:2000028 biolink:causes GO:0009791 infores:ubergraph knowledge_assertion manual_agent GO:2000028 GO:0009791 CHEBI:3228 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0020649 infores:hetionet CHEBI:3242 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0030232 infores:hetionet CHEBI:114785 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0149871 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020676 infores:hetionet CHEBI:135888 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C2363730 infores:hetionet NCBIGene:79751 biolink:causes MONDO:0012245 infores:monarchinitiative not_provided not_provided HGNC:19954 MONDO:0012245 uuid:9fe0fb27-6076-487c-b6dc-54f63d29c9cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020877 infores:hetionet CHEBI:27666 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0007971 infores:hetionet CHEBI:8245 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0039231 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0013395 infores:hetionet CHEBI:87681 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0575081 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0392025 infores:hetionet CHEBI:94449 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0021122 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0019158 infores:hetionet CHEBI:3568 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C2242737 infores:hetionet CHEBI:9398 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0231218 infores:hetionet CHEBI:167638 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0004093 infores:hetionet NCBIGene:8929 biolink:causes MONDO:0800026 infores:monarchinitiative not_provided not_provided HGNC:9143 MONDO:0800026 uuid:ce21eafd-237a-4bbb-ae5d-fb22fdfd4683 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3506 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0018681 infores:hetionet CHEBI:71941 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0016204 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0948594 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0860967 infores:hetionet CHEBI:3723 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030554 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0740411 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0740411 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0032584 infores:hetionet CHEBI:3561 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235886 infores:hetionet CAID:CA000166 biolink:causes MONDO:0018875 infores:clingen CAID:CA000166 MONDO:0018875 PMID: Likely Pathogenic PS3, PP4_Moderate, PP3, PM2_Supporting, PS4_Supporting BP1, BP4, BP3, BP2, BA1, PS2, PM4, PM1, PM3, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PP2, PP1 The NM_000546.6: c.412G>C variant in TP53 is a missense variant predicted to cause substitution of alanine by proline at amino acid 138 (p.Ala138Pro). This variant has been reported in 1 proband/family meeting Classic LFS criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 9569035). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5846; Align GVGD = Class 25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PM2_supporting, PS4_supporting, PP4_moderate. (Bayesian Points: 9; VCEP specifications version 2.3). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000166/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:59773 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0015672 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030312 infores:hetionet CHEBI:3814 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0027497 infores:hetionet CHEBI:7445 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0013378 infores:hetionet CHEBI:9566 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0085637 infores:hetionet CHEBI:421707 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0002874 infores:hetionet NCBIGene:8547 biolink:causes MONDO:0013467 infores:monarchinitiative not_provided not_provided HGNC:3625 MONDO:0013467 uuid:f0b78a05-9a37-44e1-b862-23ac2b11b579 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020517 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0015230 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0153690 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0153690 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0877107 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0877107 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0877089 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0877089 infores:hetionet CHEBI:2453 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0008031 infores:hetionet CHEBI:4858 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0025222 infores:hetionet CHEBI:7773 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151818 infores:hetionet CHEBI:194135 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0340865 infores:hetionet CAID:CA410147373 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147373 MONDO:0011071 PMID: Uncertain Significance PS4_Supporting PS1, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1322T>G (p.Leu441Arg) is a missense variant which has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147373/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9139 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004936 infores:hetionet CHEBI:28593 biolink:causes UMLS:C1879328 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C1879328 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0853784 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0853784 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0003123 infores:hetionet CHEBI:32139 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0948089 infores:hetionet CAID:CA405682843 biolink:causes MONDO:0007783 infores:clingen CAID:CA405682843 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate PS3, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 324 of the RYR1 protein, p.(Glu324Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:24433488). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.927) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405682843/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6456 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0023066 infores:hetionet CHEBI:31709 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0025287 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1443060 infores:hetionet CHEBI:15940 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0947912 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235750 infores:hetionet CHEBI:9586 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011606 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0018799 infores:hetionet CHEBI:16796 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0002962 infores:hetionet CAID:CA120885 biolink:causes MONDO:0010315 infores:clingen CAID:CA120885 MONDO:0010315 PMID: Pathogenic PP1_Strong, PP4_Moderate, PM2_Supporting, PS4 PP3, PS3 The NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys) missense variant has been reported in several (atypical) SCID cases, including male (0.5pt) patient P1 (PMID: 29948574) in whom the variant was detected by WES (1pt) and there was a family history of SCID (first-degree male relatives from the maternal side with suspected primary immune deficiency, who were not available for this study; 0.5pt), additionally STAT5 phosphorylation after exposure to IL-2 was virtually absent in CD4 and CD8 T cells (1pt); together these are highly specific for SCID due to gamma chain deficiency (3pt; PP4_moderate). There are 5 genotype/phenotype positive individuals in the pedigree through 11 segregations of this variant (PMID: 29948574); P1 plus four second cousins are all hemizygous for this variant and affected with atypical SCID and an additional great uncle was also affected but not available for genotyping (5+ segregations; PP1_Strong). At least 15 additional male X-SCID patients have been reported (PMIDs: 25042067, 16227049, 10794431, 7557965) with this hemizygous variant (total 11pt; PS4) and this variant is absent from gnomADv2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PS4, Pp1_Strong, PP4_Moderate and PM2_supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA120885/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:44423 biolink:causes MONDO:0006544 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0085273 infores:hetionet CHEBI:71219 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151904 infores:hetionet CAID:CA10587354 biolink:causes MONDO:0015967 infores:clingen CAID:CA10587354 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 The c.670+18C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a single nucleotide variant within intron 6 of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). However, the computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that this variant has no impact on splicing (BP4). In summary, c.670+18C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10587354/MONDO:0015967/085 2024-08-01 2024-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50378 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0086543 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151849 infores:hetionet UBERON:0009847 biolink:causes UBERON:0009845 infores:ubergraph knowledge_assertion manual_agent UBERON:0009847 UBERON:0009845 CHEBI:5893 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042029 infores:hetionet CHEBI:8093 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0085636 infores:hetionet NCBIGene:1605 biolink:causes MONDO:0014683 infores:monarchinitiative not_provided not_provided HGNC:2666 MONDO:0014683 uuid:5badf4b5-b895-4d58-94e0-4314bbacc9e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0231530 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0012833 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020651 infores:hetionet CHEBI:15367 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0234632 infores:hetionet CHEBI:7865 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0023066 infores:hetionet CHEBI:408174 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C3665386 infores:hetionet CHEBI:8081 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0030193 infores:hetionet CHEBI:50648 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018808 infores:hetionet CHEBI:39867 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0086439 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C1306341 infores:hetionet CHEBI:231594 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0003467 infores:hetionet CHEBI:5106 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0027424 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0233571 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0018799 infores:hetionet GO:1903722 biolink:causes GO:0007099 infores:ubergraph knowledge_assertion manual_agent GO:1903722 GO:0007099 CHEBI:8871 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0262385 infores:hetionet CHEBI:6062 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085633 infores:hetionet CHEBI:8060 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0017601 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0541832 infores:hetionet CHEBI:46557 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0010200 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0004936 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0014742 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0347390 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0039971 infores:hetionet CHEBI:9434 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013604 infores:hetionet CHEBI:53691 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0037822 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0853314 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0853314 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0043094 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0235431 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0100310 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0238154 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0019372 infores:hetionet CHEBI:50275 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0015672 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0004619 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0025007 infores:hetionet CHEBI:7822 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0015230 infores:hetionet NCBIGene:2622 biolink:causes MONDO:0014750 infores:monarchinitiative not_provided not_provided HGNC:4166 MONDO:0014750 uuid:48f905d7-6076-44c1-9667-d5c44ef0360a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0854467 infores:hetionet CHEBI:135929 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C1260880 infores:hetionet CHEBI:41774 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0019080 infores:hetionet CHEBI:72564 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0019080 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0039971 infores:hetionet CHEBI:9445 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0009676 infores:hetionet CHEBI:7465 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0030252 infores:hetionet CHEBI:6709 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0344232 infores:hetionet CHEBI:4909 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0232462 infores:hetionet CHEBI:7934 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01421 UMLS:C0027497 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0025517 infores:hetionet CHEBI:10119 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0014591 infores:hetionet NCBIGene:6950 biolink:causes MONDO:0976124 infores:monarchinitiative not_provided not_provided HGNC:11655 MONDO:0976124 uuid:e5008f1d-2f5d-4e90-9bb9-210cea66ae8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0687133 infores:hetionet CHEBI:31638 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0085649 infores:hetionet CHEBI:47780 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0080274 infores:hetionet CHEBI:10100 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0160390 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042075 infores:hetionet CHEBI:9907 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0018965 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020649 infores:hetionet CHEBI:50922 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0039070 infores:hetionet CHEBI:2687 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0042963 infores:hetionet CAID:CA000139 biolink:causes MONDO:0017623 infores:clingen CAID:CA000139 MONDO:0017623 PMID:29706350 Uncertain Significance PM2, PP2, BS3_Supporting PVS1, PM6, BP7, BP5, BS1, BS4, PP3, PP1, PP4, BS2, PM4, PM5, PM1, PM3, BA1, BP3, BP4, BP1, BP2, PS1, PS3, PS4, PS2 PTEN c.304A>C (p.Lys102Gln) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000139/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6539 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151763 infores:hetionet CAID:CA2061113 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061113 MONDO:0015924 PMID: Benign BS2, BA1, BP4 The BMPR2 c.419-38del is an intronic variant at Intron 3. The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.1814 (2514/13856 alleles) in European (Finnish) population, which is higher than the ClinGen Pulmonary Hypertension Expert Panel threshold (>0.01) for BA1, and therefore meets this stand-alone criterion (BA1). This variant has been observed in 1160 times in homozygous state in healthy individuals (BS2). The computational splicing predictor SpliceAI gives a score of (0.00) for acceptor splice site loss suggesting that the variant has no impact on splicing (BP4). In summary, the variant is classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1, BS2, BP4 (VCEP specification version v 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061113/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15367 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0853034 infores:hetionet CHEBI:144551 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151603 infores:hetionet CHEBI:63611 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151744 infores:hetionet NCBIGene:93589 biolink:causes MONDO:0012507 infores:monarchinitiative not_provided not_provided HGNC:20202 MONDO:0012507 uuid:7a103770-417b-4f75-bc4b-74125474543e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0687707 infores:hetionet CHEBI:6367 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017181 infores:hetionet CHEBI:9727 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0231218 infores:hetionet CHEBI:27690 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0020580 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0006145 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018801 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151613 infores:hetionet CHEBI:3756 biolink:causes MONDO:0001584 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0028850 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0456909 infores:hetionet CAID:CA916080172 biolink:causes MONDO:0700268 infores:clingen CAID:CA916080172 MONDO:0700268 PMID:30209399 Likely Pathogenic PM2, PP3, PS3 PS1 The c.4987-7A>G variant is an intronic variant occurring in intron 15 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.65, predicting an impact on splicing (score threshold ≥0.2) (PP3 met). This intronic variant has functional data from an assay that measures the effect via mRNA and protein. It was reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_supporting, PP3, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA916080172/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5134 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0205204 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0232462 infores:hetionet CHEBI:64045 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0018790 infores:hetionet CHEBI:6715 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C2979982 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0021053 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0393593 infores:hetionet CHEBI:64312 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013182 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0028738 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0339807 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0339807 infores:hetionet CHEBI:63612 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0278134 infores:hetionet CHEBI:127780 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0025222 infores:hetionet CHEBI:36704 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0040435 infores:hetionet CAID:CA399805805 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805805 MONDO:0100326 PMID:12506038 Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3 PM3 The NM_000419.5:c.520T>C variant in ITGA2B is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 174 (p.Tyr174His). At least one patient (Patient Osaka-12 in PMID: 12506038) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, patient platelets expressed 36%-41% αIIbβ3 but failed to bind soluble ligands, including a high-affinity αIIbβ3-specific peptidomimetic antagonist (OP-G2 and PAC-1). The computational predictor REVEL gives a score of 0.815, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). An expression vector that contained the wild-type or mutant His174 form of αIIb was cotransfected with a wild-type β3 vector into 293 cells. Flow cytometric analysis using FITC-AP3 or FITC-TP80 mAb showed that the expression levels of Tyr174HisαIIbβ3 were essentially the same as wild-type αIIbβ3. In sharp contrast, Tyr174HisαIIbβ3 failed to bind OP-G2 mAb, FITC-PAC-1 mAb, or FITC-fibrinogen in the presence of PT25-2 mAb, indicating that this variant impacts protein function (PMID: 12506038; PS3). The highest population minor allele frequency in gnomAD v4.1 is 0.00004459 (2/44856 alleles) in the East Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PP3 and PM2_Supporting, PS3 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805805/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:28748 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0041969 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040259 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018418 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0042769 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0403632 infores:hetionet CHEBI:28925 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0011570 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151849 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0019158 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0010709 infores:hetionet CHEBI:6931 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0037383 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0239150 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0021843 infores:hetionet CHEBI:47780 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017181 infores:hetionet CHEBI:38940 biolink:causes MONDO:0010138 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0040156 infores:hetionet CHEBI:17650 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0156404 infores:hetionet CHEBI:4445 biolink:causes UMLS:C1536055 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C1536055 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0012833 infores:hetionet NCBITaxon:951 biolink:causes MONDO:0000332 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:951 MONDO:0000332 CHEBI:75045 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0239981 infores:hetionet CHEBI:3764 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0085624 infores:hetionet CHEBI:119486 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151907 infores:hetionet CHEBI:9667 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C3263723 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004623 infores:hetionet CHEBI:127780 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0001925 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0702166 infores:hetionet CHEBI:51041 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042024 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0553704 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0553704 infores:hetionet CHEBI:16755 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0041657 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0030305 infores:hetionet CHEBI:64355 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0231530 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0018794 infores:hetionet CHEBI:10127 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0003467 infores:hetionet CHEBI:3696 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013378 infores:hetionet CHEBI:3441 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151744 infores:hetionet CHEBI:15552 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0004093 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027769 infores:hetionet CHEBI:16335 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0004238 infores:hetionet CHEBI:47780 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013390 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0038454 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0029882 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0036572 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0034065 infores:hetionet CHEBI:9667 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0037383 infores:hetionet CAID:CA386971548 biolink:causes MONDO:0015967 infores:clingen CAID:CA386971548 MONDO:0015967 PMID: Likely Benign PM2_Supporting, BS4, PP3 PS4, PM5, PP4 The c.1505T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to histidine at codon 502 (p.(Leu502His)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8429, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). The MODY probability for both individuals is unable to be calculated, and so PP4 cannot be applied (internal lab contributors). In one of these families, the variant did not segregate with diabetes (genotype negative, phenotype positive) (BS4, internal lab contributors). Another missense variant, c.1504C>G (p.Leu502Val), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1505T>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BS4, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386971548/MONDO:0015967/017 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2611 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0027769 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0019158 infores:hetionet NCBIGene:4437 biolink:causes MONDO:0044300 infores:monarchinitiative not_provided not_provided HGNC:7326 MONDO:0044300 uuid:f545a7a0-dacf-4b3c-8874-dbc5e09768e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020461 infores:hetionet NCBIGene:2628 biolink:causes MONDO:0024525 infores:monarchinitiative not_provided not_provided HGNC:4175 MONDO:0024525 uuid:fc54e283-6fda-4c39-b9a7-e069fa7c6732 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0021053 infores:hetionet CHEBI:6076 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0333355 infores:hetionet CAID:CA143497 biolink:causes MONDO:0019501 infores:clingen CAID:CA143497 MONDO:0019501 PMID:18273898PMID:26969326PMID:25097241PMID:20507924PMID:17405132PMID:28944237PMID:26969326PMID:25097241PMID:20507924PMID:17405132PMID:28944237 Likely Benign BS1_Supporting, BP2 BS2, PM3 The p.Leu1572Phe variant in USH2A gene has a filtering allele frequency= 0.12% in Latino in gnomAD (54/35388 with 95% CI) which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1 supporting). It was reported in multiple publications as a polymorphism or as non-pathogenic based on detection among normal control chromosomes or other evidence (PMID: 18273898, 19881469 and 17085681). Although the variant was reported in trans with c.2299delG in one patient diagnosed with Usher syndrome type II and in another with unclassified Usher syndrome (PMID: 25097241 and 28944237), it was also identified in cis with c.2299delG; p.Glu767Serfs and in unknown configuration with c.2299delG and a stop codon (PMID: 25472526), both in patients with Usher syndrome type II (BP2; PMID: 20507924, 25097241, 17405132 and 26969326). Computational prediction using REVEL was 0.65 which did not meet the Hearing Loss Expert Panel (HL EP) specified threshold of >0.7 for PP3. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive Usher syndrome, type 2A based on the HL EP-specified ACMG/AMP criteria applied (BS1, BP2). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA143497/MONDO:0019501/005 2019-07-28 2019-08-16 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6754 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0016059 infores:hetionet CAID:CA6748923 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748923 MONDO:0009861 PMID: Uncertain Significance BP7 PM2 The c.442-18G>A variant in PAH has not been reported in the literature to our knowledge. This variant has a MAF of 0.00067 in the gnomAD Latino population. This is too high for PM2, but too low for BS1 per PAH EP guidelines. No splicing impact is predicted in HSF or MaxEnt (BP7). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748923/MONDO:0009861/006 2019-09-27 2019-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:100246 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0008370 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0031117 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0002170 infores:hetionet CHEBI:2687 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0015230 infores:hetionet CHEBI:8888 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085680 infores:hetionet NCBIGene:2984 biolink:causes MONDO:0013825 infores:monarchinitiative not_provided not_provided HGNC:4688 MONDO:0013825 uuid:9560c3d4-a792-41a0-aa28-96e53d7f2811 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0030232 infores:hetionet CHEBI:7986 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0030312 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018801 infores:hetionet CHEBI:46295 biolink:causes UMLS:C1148477 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C1148477 infores:hetionet CHEBI:44423 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0002888 infores:hetionet CHEBI:7476 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0237849 infores:hetionet CHEBI:63791 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1527344 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0232492 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0034069 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151589 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151589 infores:hetionet CHEBI:28593 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0151786 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0007222 infores:hetionet CHEBI:30659 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0033774 infores:hetionet CHEBI:59445 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0015376 infores:hetionet CHEBI:114785 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0037274 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0041969 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0039231 infores:hetionet GO:2001222 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2001222 GO:0007275 CHEBI:4653 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0002871 infores:hetionet CHEBI:209807 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0022346 infores:hetionet NCBIGene:23324 biolink:causes MONDO:0976261 infores:monarchinitiative not_provided not_provided HGNC:29623 MONDO:0976261 uuid:2c919187-0a71-4a79-9904-ddf4594757dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0029408 infores:hetionet CHEBI:10125 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013378 infores:hetionet CHEBI:499361 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0162830 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0232492 infores:hetionet CHEBI:114785 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0009763 infores:hetionet CHEBI:8871 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151576 infores:hetionet CHEBI:9907 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0015967 infores:hetionet CHEBI:49960 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0038362 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020039 infores:hetionet CHEBI:5130 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0033774 infores:hetionet CAID:CA222121 biolink:causes MONDO:0015152 infores:clingen CAID:CA222121 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PP1_Moderate, PVS1, PP4_Moderate, PM2_Supporting The NM_003494.4: c.107_108del p.(Lys36SerfsTer12) variant in DYSF, which is also known as NM_001130987.2: c.110_111del p.(Lys37SerfsTer12), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least four individuals with features consistent with LGMD (PMID: 19528035, 18853459; ClinVar SCV004229601.1 internal data communication), including in unknown phase with a pathogenic variant (NM_003494.4: c.2643+1G>A, 0.5 pts, ClinVar SCV004229601.1 internal data communication) (PM3_Supporting). This variant has been reported to co-segregate with autosomal recessive LGMD in two affected family members from two families (PMID: 18853459, 19528035; PP1_Moderate). In addition, at least one patient with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 18853459, 17698709; PP4_Moderate, capped with PP1_Moderate). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.000016374 (the lower threshold of the 95% CI of 11/1111948 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3_Supporting, PP1_Moderate, PP4_Moderate, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222121/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75722 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018926 infores:hetionet GO:2001212 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:2001212 GO:0035295 CHEBI:6402 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0025222 infores:hetionet CHEBI:50648 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0043144 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0020517 infores:hetionet CHEBI:76607 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0006277 infores:hetionet CAID:CA376065885 biolink:causes MONDO:0011225 infores:clingen CAID:CA376065885 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2 The c.57C>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 19 (p.Phe19Leu).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1c-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376065885/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36791 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C3665386 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020437 infores:hetionet CHEBI:16467 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0020580 infores:hetionet CHEBI:4822 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0014863 infores:hetionet CHEBI:15544 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0039240 infores:hetionet CHEBI:31236 biolink:causes HP:0030213 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233469 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0521839 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017605 infores:hetionet CHEBI:134991 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0013456 infores:hetionet CHEBI:31932 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020433 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1095967 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1095967 infores:hetionet CHEBI:32221 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0155169 infores:hetionet CHEBI:9086 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0037299 infores:hetionet CHEBI:7459 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0042963 infores:hetionet CHEBI:5893 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0016204 infores:hetionet CHEBI:5693 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00756 UMLS:C0332575 infores:hetionet CHEBI:2668 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0004604 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0017160 infores:hetionet CHEBI:32315 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002792 infores:hetionet NCBIGene:4694 biolink:causes MONDO:0026720 infores:monarchinitiative not_provided not_provided HGNC:7683 MONDO:0026720 uuid:e78d0232-5f98-439c-b05e-8435b85c90b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4659 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C2242996 infores:hetionet CHEBI:116278 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1456784 infores:hetionet CHEBI:9241 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0024902 infores:hetionet CHEBI:6822 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0030312 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0948089 infores:hetionet CAID:CA023717 biolink:causes MONDO:0007750 infores:clingen CAID:CA023717 MONDO:0007750 PMID: Likely Pathogenic PS3_Moderate, PS4_Moderate, PM1, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS2, BS1, BS3, BS4, PM5, PM4, PM3, PM6, PVS1, PP3, PP1, BS2 The NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v4.0.0). PM1: Variant meets PM2 and is a missense in exon 4. PS3_Moderate: Level 2 assay: PMID 21868016 (Garcia-Garcia A et al., 2011): COS-7 cells. Mature/precursor LDLR forms ratio ~60% ---- Overall LDLR biosynthesis is below 70% of wild-type activity. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case from PMID 16250003 (Fouchier SW et al., 2005); 2 cases with MedPed and Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793 (Tichý L et al., 2012); 2 cases meeting Simon Broome and DLCN criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023717/MONDO:0007750/013 2024-02-23 2024-09-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA171640 biolink:causes MONDO:0100039 infores:clingen CAID:CA171640 MONDO:0100039 PMID: Likely Benign BS1, BP4, BP2 The allele frequency of the p.Pro976Leu variant in CDKL5 is 0.01% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro976Leu variant is observed in the CDKL5 gene where a second pathogenic variant in the same gene is present in the patient (internal database) (BP2). Computational analysis prediction tools suggest that the p.Pro976Leu variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro976Leu variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171640/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7444 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0041657 infores:hetionet CHEBI:39669 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0020517 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0027441 infores:hetionet CHEBI:44915 biolink:causes HP:0001708 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C2939447 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0243065 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0233472 infores:hetionet CHEBI:70735 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0151905 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0015395 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0015395 infores:hetionet CHEBI:7565 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018418 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549453 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549453 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0040822 infores:hetionet CHEBI:28001 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0221201 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0009450 infores:hetionet CHEBI:4514 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C1443060 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005855 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0026393 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005302 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1263846 infores:hetionet CHEBI:61033 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0021845 infores:hetionet CHEBI:10124 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0038990 infores:hetionet CAID:CA350341667 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341667 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PM1 BA1, BP4, PM5, PS4, PS1, BS1 The c.1133G>T (p.Gly378Val) variant is a missense variant harboured in exon 9 of the BMPR2 gene, predicted to cause substitution of glycine to valine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating critical or non-critical (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.828, AlphaMissense is 0.994 indicating pathogenicity (PP3_met). The variant has been reported only once in a PAH subject (PMID: 29650961) (PS4 not met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341667/MONDO:0015924/125 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:3U02EL437C biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0021368 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0242172 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0243026 infores:hetionet CHEBI:47519 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0038999 infores:hetionet CHEBI:39867 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0575081 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0151698 infores:hetionet CHEBI:135736 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C2979982 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0004096 infores:hetionet CHEBI:32315 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0240327 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0015397 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0235744 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0235744 infores:hetionet NCBIGene:2645 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:4195 MONDO:0005148 uuid:a3ea9d8b-9cff-4641-8aae-4b1a57b7e09b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63622 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0013395 infores:hetionet CHEBI:45599 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0002792 infores:hetionet CAID:CA1139665143 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665143 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4: c.797_798del (p.Pro266ArgfsTer31) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665143/MONDO:0008723/021 2023-01-10 2023-01-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:70735 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0023530 infores:hetionet UMLS:C0010592 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0600142 infores:hetionet CHEBI:47381 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0025290 infores:hetionet CHEBI:8024 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C2939186 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877497 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877497 infores:hetionet GO:0030154 biolink:causes CL:0000000 infores:ubergraph knowledge_assertion manual_agent GO:0030154 CL:0000000 CHEBI:28864 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0549373 infores:hetionet CHEBI:34967 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0011570 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020615 infores:hetionet CHEBI:28830 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C2939419 infores:hetionet CHEBI:474180 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0750394 infores:hetionet CHEBI:8673 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0030312 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0011053 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0234215 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0235360 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235360 infores:hetionet CHEBI:28177 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0031542 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0031350 infores:hetionet CHEBI:49375 biolink:causes MONDO:0044037 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085642 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0017601 infores:hetionet NCBIGene:4647 biolink:causes MONDO:0010807 infores:monarchinitiative not_provided not_provided HGNC:7606 MONDO:0010807 uuid:c45f5255-db9d-4dd8-a642-5c85ceb3e71e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0010896 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1271398 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0018799 infores:hetionet CAID:CA384897562 biolink:causes MONDO:0010880 infores:clingen CAID:CA384897562 MONDO:0010880 PMID: Uncertain Significance PM2_Supporting PP3 The NM_000020.3: c.113G>A variant in ACVRL1 is a missense variant predicted to cause substitution of serine by asparagine at amino acid 38 (p.Ser38Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002814 (3/106620 alleles) in European (non-Finnish) population, which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<0.00004, or <6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.321, which is neither above nor below the thresholds predicting a damaging or benign impact on ACVRL1 function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting (specification version 1.0.0; 1/04/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA384897562/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47898 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020649 infores:hetionet CHEBI:63632 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0017178 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0023895 infores:hetionet CHEBI:7915 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0259749 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0027697 infores:hetionet CHEBI:119486 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0041582 infores:hetionet CHEBI:17303 biolink:causes NCIT:C102529 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0344375 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0435002 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0542149 infores:hetionet CHEBI:9168 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004509 infores:hetionet CHEBI:84500 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0018932 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0040034 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040435 infores:hetionet CHEBI:44032 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151579 infores:hetionet CHEBI:64355 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030193 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0016034 infores:hetionet CHEBI:135930 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0028961 infores:hetionet GO:0060836 biolink:causes CL:0002138 infores:ubergraph knowledge_assertion manual_agent GO:0060836 CL:0002138 UMLS:C0657912 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029124 infores:hetionet GO:0060563 biolink:causes CL:0000710 infores:ubergraph knowledge_assertion manual_agent GO:0060563 CL:0000710 CHEBI:8871 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006444 infores:hetionet GO:1901163 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1901163 GO:0007275 CHEBI:83531 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0028949 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1167965 infores:hetionet UMLS:C1738934 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0015967 infores:hetionet CHEBI:520985 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C1443060 infores:hetionet CHEBI:3223 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0026837 infores:hetionet CHEBI:3215 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0025289 infores:hetionet NCBIGene:57505 biolink:causes MONDO:0013570 infores:monarchinitiative not_provided not_provided HGNC:21022 MONDO:0013570 uuid:9da24a68-aaa0-45df-b23f-30f6712f0a47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0242184 infores:hetionet CHEBI:7476 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0019214 infores:hetionet NCBIGene:29899 biolink:causes MONDO:0011411 infores:monarchinitiative not_provided not_provided HGNC:29501 MONDO:0011411 uuid:ca3c4e46-1ab5-4e02-980a-07417134bd77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042023 infores:hetionet CHEBI:32293 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0012569 infores:hetionet NCBIGene:113246 biolink:causes MONDO:0009033 infores:monarchinitiative not_provided not_provided HGNC:29521 MONDO:0009033 uuid:d285b161-779e-4a91-ba58-d630d28fffa4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA254931 biolink:causes MONDO:0100437 infores:clingen CAID:CA254931 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Supporting PM6, BS2, PP1, PP3, PM4, PM5, PS2, PS1, PS3, BA1, BP3, BP4, BS1, BS4, BP7 NM_001034853.2(RPGR):c.2650G>T (p.Glu884Ter) is a nonsense variant that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 17325176, PMID: 30567410, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including onset of visual defects before the age of 30 years, fundus autofluorescence imaging showing radial pattern reflex, a family history consistent with X-linked inheritance with no male-to-male transmission (2 pts) and delayed/milder phenotype in females (1 pt), night blindness (0.5 pts), and pigmentary retinopathy (0.5 pts) which together are specific for RPGR-related retinopathy (4 points, PMID: 30567410, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS4_Supporting, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA254931/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:6062 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0231528 infores:hetionet CHEBI:28748 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0014457 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0227791 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0003469 infores:hetionet CHEBI:5864 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042384 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1141938 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1141938 infores:hetionet CHEBI:5132 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0232462 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020557 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0235146 infores:hetionet CAID:CA376059471 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059471 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting PM1 The c.623C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Alanine by Valine at amino acid 208 (p.Ala208Val).The filtering allele frequency (the upper threshold of the 95% CI of 11/1180008 alleles) of the c.623C>T variant in DCLRE1C is 0.000005310 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059471/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:61033 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0149514 infores:hetionet CAID:CA10524772 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524772 MONDO:0010278 PMID: Benign BS2, BP4, BP7, BP5_Strong, BS1 The allele frequency of the p.Leu381= variant in SLC9A6 (NM_006359.2) is 0.024% in European (Non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Leu381= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Leu381= variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2_strong). The p.Leu381= variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5_strong). In summary, the p.Leu381= variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BP7, BS2_strong, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524772/MONDO:0010278/033 2024-02-23 2024-03-31 X-linked inheritance HP:0001417 Contradicts true CHEBI:194135 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C2242996 infores:hetionet CHEBI:63618 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0877359 infores:hetionet CHEBI:9757 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0030193 infores:hetionet CHEBI:10124 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0022346 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0035455 infores:hetionet CHEBI:15367 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0016204 infores:hetionet NCBIGene:5651 biolink:causes MONDO:0009173 infores:monarchinitiative not_provided not_provided HGNC:9490 MONDO:0009173 uuid:5f61cbfe-34d2-4f6c-bb28-5a124ce36ab5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0027121 infores:hetionet CHEBI:3077 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0011991 infores:hetionet CHEBI:3175 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0344232 infores:hetionet CHEBI:50648 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0241729 infores:hetionet CHEBI:3077 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0039231 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0022408 infores:hetionet CHEBI:3082 biolink:causes MONDO:0000749 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151463 infores:hetionet CHEBI:3752 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0231528 infores:hetionet CHEBI:31705 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0005778 infores:hetionet CHEBI:4511 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151970 infores:hetionet CHEBI:4702 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0030252 infores:hetionet CHEBI:9434 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0036396 infores:hetionet UMLS:C0010592 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0010200 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0853761 infores:hetionet CHEBI:6375 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020433 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0016382 infores:hetionet CHEBI:8412 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0011570 infores:hetionet CHEBI:29688 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0014724 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0919568 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0919568 infores:hetionet CAID:CA916081958 biolink:causes MONDO:0011071 infores:clingen CAID:CA916081958 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP2, BP1, BP4, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.45dup (p.Cys16fs) is a frameshift variant in an exon which is absent from RUNX1 isoform a and b (c.1-c.97 as per VCEP specifications) (PVS1_NA). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081958/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:60761 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C1167791 infores:hetionet CHEBI:39585 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0001824 infores:hetionet CHEBI:7640 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0855333 infores:hetionet CHEBI:70746 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0027497 infores:hetionet CHEBI:44241 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0037274 infores:hetionet CAID:CA10604804 biolink:causes MONDO:0015152 infores:clingen CAID:CA10604804 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PP3, PM2_Supporting, PS3_Moderate The NM_003494.4: c.206T>G variant in DYSF, which is also known as NM_001130987.2: c.209T>G p.(Val70Gly), is a missense variant predicted to cause substitution of valine to glycine at amino acid 69, p.(Val69Gly). This variant has been reported in at least four patients with suspected LGMD (PMID: 33250842, 35723113, 39925440), including in a homozygous state in two individuals without known familial consanguinity (1 pt; PMID: 33250842, 35723113) and in unknown phase with a pathogenic variant in one individual (NM_003494.4: c.5668-824C>T, 0.5 pts, PMID: 39925440) (PM3). At least one of the patients with a second presumed diagnostic DYSF variant displayed progressive muscle weakness and absent dysferlin expression in muscle biopsy, which is highly specific for DYSF-related LGMD (PMID: 33250842) (PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Val69Gly protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.83, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604804/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94686 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0023218 infores:hetionet CHEBI:6339 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0700225 infores:hetionet CHEBI:37941 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0013604 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235234 infores:hetionet CHEBI:8764 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085649 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027441 infores:hetionet NCBIGene:219972 biolink:causes MONDO:0030973 infores:monarchinitiative not_provided not_provided HGNC:29619 MONDO:0030973 uuid:64e9bbc9-1990-4d6d-8cbe-9b9811393dd1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4953 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0004093 infores:hetionet CHEBI:7809 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0030312 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0231218 infores:hetionet GO:0051282 biolink:causes GO:0006874 infores:ubergraph knowledge_assertion manual_agent GO:0051282 GO:0006874 CHEBI:8024 biolink:causes UMLS:C0241950 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0241950 infores:hetionet CHEBI:63638 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1384353 infores:hetionet CAID:CA119185 biolink:causes MONDO:0020367 infores:clingen CAID:CA119185 MONDO:0020367 PMID:11004290 Likely Pathogenic PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting, PP1_Strong BP7, BS1, BS3, PM6, PM4, PM5, PS1, PS2, BP4, BA1 The c.754G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 252 (p.Gly252Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.798, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Gly252Arg protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 17 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17210859, 10873982, 15326130), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 17210859, 10873982, 9772276, 15326130), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PP3, PM2_Supporting, PS4_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119185/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16619147 biolink:causes MONDO:0700270 infores:clingen CAID:CA16619147 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM5_Supporting, PVS1 The c.2730_2731insAG (p.Ala911Argfs*19) variant in ATM is a frameshift variant in biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619147/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51860 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0522224 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0235818 infores:hetionet CHEBI:5959 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0010200 infores:hetionet NCBIGene:1828 biolink:causes MONDO:0014218 infores:monarchinitiative not_provided not_provided HGNC:3048 MONDO:0014218 uuid:517fe0c4-229f-46b0-9a2f-9fd74d966a16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3499 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0836924 infores:hetionet CHEBI:15367 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085633 infores:hetionet CHEBI:63607 biolink:causes UMLS:C1306792 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C1306792 infores:hetionet CHEBI:52010 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0080274 infores:hetionet CHEBI:61049 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019521 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0010043 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0004936 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0032961 infores:hetionet CHEBI:27999 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0040034 infores:hetionet CAID:CA011747 biolink:causes MONDO:0005045 infores:clingen CAID:CA011747 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PP3, PS4_Moderate BA1, PM5, PS3, PM6, PP1, BS1, BS3, BS4, PS1, PS2, BP4, BP2, BP5 The NM_000257.4(MYH7):c.2129C>A (p.Pro710His) variant has been identified in in at least 7 individuals with HCM (PM4_Moderate; Kindel 2012 PMID:22555271; Miller 2013 PMID:23054336; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant was also observed to segregated with HCM in 1 affected relative (LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PM1, PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011747/MONDO:0005045/002 2021-09-28 2021-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:46081 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0030554 infores:hetionet CHEBI:53691 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0027497 infores:hetionet CAID:CA320250606 biolink:causes MONDO:0011071 infores:clingen CAID:CA320250606 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*821G>A is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320250606/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5001 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027765 infores:hetionet CHEBI:7581 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0086168 infores:hetionet CHEBI:404903 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013604 infores:hetionet CHEBI:50924 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0004093 infores:hetionet CHEBI:3515 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0002874 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0036572 infores:hetionet CHEBI:9637 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0003862 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0852733 infores:hetionet CHEBI:10023 biolink:causes UMLS:C1262064 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1262064 infores:hetionet CHEBI:8888 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0008031 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0022660 infores:hetionet CHEBI:6775 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002792 infores:hetionet CHEBI:421707 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0026858 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0019158 infores:hetionet CHEBI:8214 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0917801 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027441 infores:hetionet CHEBI:4710 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0009782 infores:hetionet GO:2000702 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0072001 CHEBI:9332 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0011570 infores:hetionet CHEBI:50131 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020625 infores:hetionet CHEBI:4728 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0018681 infores:hetionet CAID:CA386959782 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959782 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS3_Supporting, PP4_Moderate, PP3, PP1 The c.416T>C variant in the HNF1 homeobox A] gene, HNF1A, causes an amino acid change of leucine to proline at codon 139 (p.(Leu139Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Leu139Pro protein has transactivation activity and DNA binding <40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32017842). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 individuals with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; PMIDs: 32017842, 37396173). This variant segregated with diabetes with 2 informative meioses in these 2 families (PP1; PMIDs: 37396173, 32017842). In summary, c.416T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP1, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959782/MONDO:0015967/017 2024-09-24 2024-09-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA167509 biolink:causes MONDO:0700270 infores:clingen CAID:CA167509 MONDO:0700270 PMID: Benign BP4, BA1, BP7, BP2_Strong The ATM c.1176C>G (p.Gly392=) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.878% (AFR) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). This is a synonymous variant (BP7) and in silico predictors find that this variant is unlikely to affect splicing (Splice AI/MaxENTScan 0%) (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA167509/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10023 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014038 infores:hetionet CHEBI:3479 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C2830004 infores:hetionet CHEBI:27666 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0151766 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0086543 infores:hetionet CHEBI:4511 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C1443060 infores:hetionet CHEBI:135930 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0863113 infores:hetionet CHEBI:68610 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0271710 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0036341 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0151560 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0151560 infores:hetionet CHEBI:4653 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0015230 infores:hetionet CHEBI:71255 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0037763 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151609 infores:hetionet CHEBI:3696 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013404 infores:hetionet CAID:CA294716 biolink:causes MONDO:0010726 infores:clingen CAID:CA294716 MONDO:0010726 PMID: Likely Benign BP5, BS2 BS1, PP3, PM2, BP4, PS4 The p.Gly231Arg variant in MECP2 (NM_004992.3) is observed in 3 unaffected individuals (PMID: 28250423, internal database) (BS2). The p.Gly243Arg variant is reported in one male with autism, and one female with intellectual and developmental disabilities and seizures (PMID: 28250423, 24321989) (PS4 not met). The p.Gly231Arg variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly231Arg variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294716/MONDO:0010726/016 2022-12-08 2022-12-23 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CAID:CA220591 biolink:causes MONDO:0009861 infores:clingen CAID:CA220591 MONDO:0009861 PMID:8659548 Pathogenic PVS1, PM2, PP4 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00006.; PVS1: Canonical +1 splice site; PP4: Detected in 5 patients with classical PKU. (PMID:8659548). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220591/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44185 biolink:causes MONDO:0017776 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0028242 infores:hetionet CHEBI:47898 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1519353 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0026848 infores:hetionet CHEBI:7798 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0002994 infores:hetionet CHEBI:16469 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0028643 infores:hetionet CHEBI:100246 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0015967 infores:hetionet CHEBI:17141 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0009676 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0424000 infores:hetionet CHEBI:2549 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0220870 infores:hetionet CHEBI:3032 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0033774 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001220 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020626 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0012739 infores:hetionet NCBIGene:81570 biolink:causes MONDO:0030726 infores:monarchinitiative not_provided not_provided HGNC:30664 MONDO:0030726 uuid:0f5cadef-8e0d-47a8-932d-1325f245552d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1709429 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0004093 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0023895 infores:hetionet CHEBI:50924 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0030193 infores:hetionet CHEBI:408174 biolink:causes MONDO:0850283 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0349790 infores:hetionet CHEBI:8869 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0026858 infores:hetionet CHEBI:51141 biolink:causes HP:0500104 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0277890 infores:hetionet CAID:CA16026241 biolink:causes MONDO:0021056 infores:clingen CAID:CA16026241 MONDO:0021056 PMID: Pathogenic PVS1, PS4_Moderate, PM2_Supporting, PM6_Supporting The NM_000038.6:c.2240C>G p.(Ser747Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 7 probands meeting phenotypic criteria, resulting in a total phenotype score 3.5 (PS4_Moderate, [PMID: 20223039, PMID: 20685668, PMID: 22135120, internal data Institute of Human Genetics, Bonn]). The variant has been reported in 4 additional probands with a polyposis associated phenotype not meeting phenotypic criteria (PMID: 35189564). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with FAP, resulting in a total de novo score of 0.5 (PM6_Supporting, [PMID: 22135120]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4_Moderate, PM2_Supporting and PM6_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16026241/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41423 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0002965 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0018799 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0235467 infores:hetionet CHEBI:64354 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0040264 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0009241 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013595 infores:hetionet CHEBI:182080 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0014457 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0948525 infores:hetionet CHEBI:28148 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0085681 infores:hetionet GO:1905261 biolink:causes GO:0007131 infores:ubergraph knowledge_assertion manual_agent GO:1905261 GO:0007131 CHEBI:63613 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0151905 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0040034 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0518015 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013182 infores:hetionet CAID:CA10014269 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014269 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.925G>A (p.Gly309Ser) is a missense variant which has a REVEL score < 0.50 (0.325) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014269/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0917798 infores:hetionet NCBIGene:255101 biolink:causes MONDO:0032859 infores:monarchinitiative not_provided not_provided HGNC:25325 MONDO:0032859 uuid:a4afa02a-2066-4cf9-baf8-3ebc1d9ef4cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410148360 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148360 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1045T>C (p.Tyr349His) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148360/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8707 biolink:causes UMLS:C1096340 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1096340 infores:hetionet CHEBI:5778 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0038999 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005810 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0021345 infores:hetionet CHEBI:71219 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0085593 infores:hetionet NCBIGene:755 biolink:causes MONDO:0060507 infores:monarchinitiative not_provided not_provided HGNC:1260 MONDO:0060507 uuid:0a5d8168-8fa1-410b-bab4-7d2ccd6137d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042514 infores:hetionet CHEBI:5138 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0035305 infores:hetionet CHEBI:49713 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0240211 infores:hetionet CHEBI:28830 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0029944 infores:hetionet CHEBI:7852 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0004093 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0149931 infores:hetionet CAID:CA229880 biolink:causes MONDO:0009861 infores:clingen CAID:CA229880 MONDO:0009861 PMID:24941924PMID:11385716PMID:24941924PMID:8659548 Uncertain Significance PM3, PP4_Moderate, PP3 PM2 The c.969+6T>A variant in PAH has been reported in 2 patients with benign HPA (BH4 deficiency excluded) (PP4_Moderate; PMID: 8659548, 24941924). It was detected with known pathogenic variant c.1162G>A, (p.Val388Met) (PMID: 24941924). This variant has a frequency of 0.00033 in Latino population, which is higher than our PM2 cut-off (0.0002). A deleterious effect is predicted in HSF and TraP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229880/MONDO:0009861/006 2020-01-26 2020-01-31 Autosomal recessive inheritance HP:0000007 Inconclusive true PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0009763 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0948299 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948299 infores:hetionet CHEBI:6887 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0600142 infores:hetionet GO:0072039 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072039 GO:0072006 NCBIGene:4905 biolink:causes MONDO:0023659 infores:monarchinitiative not_provided not_provided HGNC:8016 MONDO:0023659 uuid:e285f395-b4f3-441f-b88f-10bf07add285 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0035981 biolink:causes CL:0002673 infores:ubergraph knowledge_assertion manual_agent GO:0035981 CL:0002673 CHEBI:31236 biolink:causes UMLS:C0857979 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0857979 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0031350 infores:hetionet CHEBI:3219 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151830 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0595877 infores:hetionet CHEBI:7773 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0877303 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0243026 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0017160 infores:hetionet UMLS:C0025241 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0019080 infores:hetionet CHEBI:30659 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0011175 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0160390 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0009763 infores:hetionet CHEBI:42944 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011175 infores:hetionet CHEBI:408174 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C1262144 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0234215 infores:hetionet CHEBI:4046 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0917801 infores:hetionet CHEBI:72564 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0575081 infores:hetionet CHEBI:4672 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C2363731 infores:hetionet CHEBI:4995 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C3665386 infores:hetionet CHEBI:72292 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0151878 infores:hetionet CHEBI:9139 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018790 infores:hetionet CHEBI:17026 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013404 infores:hetionet CHEBI:31705 biolink:causes MONDO:0000663 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0234507 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0032584 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004623 infores:hetionet CHEBI:6904 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0231807 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0267792 infores:hetionet CAID:CA2573052014 biolink:causes MONDO:0015152 infores:clingen CAID:CA2573052014 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 The NM_003494.4: c.4609del p.(Glu1537LysfsTer5) variant in DYSF, which is also known as NM_001130987.2: c.4726del p.(Glu1576LysfsTer5), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 42/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported with a second presumed diagnostic DYSF variant in at least two individuals with progressive limb girdle muscle weakness (PMID: 34559919; LOVD Individuals #00375983, #00376095) (PP4). It is also absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/19/2025): PVS1, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573052014/MONDO:0015152/180 2025-08-19 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:421707 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0162429 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0029134 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002453 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0015469 infores:hetionet CHEBI:180905 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0231528 infores:hetionet CHEBI:39585 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0020625 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0029456 infores:hetionet CHEBI:77260 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0038367 infores:hetionet CHEBI:4856 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0085631 infores:hetionet CHEBI:72564 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085632 infores:hetionet CHEBI:135736 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0522251 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0042373 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0015300 infores:hetionet CHEBI:41977 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0740394 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0233494 infores:hetionet CHEBI:3756 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0015967 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0037274 infores:hetionet GO:0031285 biolink:causes GO:0031154 infores:ubergraph knowledge_assertion manual_agent GO:0031285 GO:0031154 NCBIGene:4173 biolink:causes MONDO:0012383 infores:monarchinitiative not_provided not_provided HGNC:6947 MONDO:0012383 uuid:e0501f95-4132-44c7-898a-7e6a78debc5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033575 infores:hetionet CHEBI:6923 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C2047937 infores:hetionet CHEBI:6367 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013447 infores:hetionet CHEBI:3011 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0340865 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0007785 infores:hetionet NCBIGene:23435 biolink:causes MONDO:0012790 infores:monarchinitiative not_provided not_provided HGNC:11571 MONDO:0012790 uuid:64985b4e-8c6f-4db6-874a-1175ddf3830a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28915 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0018681 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151559 infores:hetionet CHEBI:31705 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0011991 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0234913 infores:hetionet CAID:CA8603041 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603041 MONDO:0100326 PMID: Benign BP7, BA1, BP4 After a comprehensive literature search of the intronic variant NM_000419.5(ITGA2B):c.1545-8C>A, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.04631 (1156/24960 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets benign criterion (BA1). In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of 0.57 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603041/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:28901 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0035222 infores:hetionet CHEBI:10127 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042963 infores:hetionet NCBIGene:103 biolink:causes MONDO:0007483 infores:monarchinitiative not_provided not_provided HGNC:225 MONDO:0007483 uuid:6e2c6289-0c2d-4a30-9b7f-7989f7623b7c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75998 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0015967 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0234215 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0221165 infores:hetionet CHEBI:3437 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0013378 infores:hetionet CHEBI:4708 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0015732 infores:hetionet CHEBI:7640 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0235347 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0236071 infores:hetionet CHEBI:6775 biolink:causes MONDO:0018824 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085652 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0018939 infores:hetionet CAID:CA392000775 biolink:causes MONDO:0015152 infores:clingen CAID:CA392000775 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4, PM2_Supporting, PVS1_Strong The NM_000070.3: c.1855C>T variant in CAPN3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 16/24, p.(Gln619Ter), leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. However, this variant may also disrupt splicing, with a SpliceAI score of 0.64 for donor loss and 0.58 for acceptor loss, suggesting that in-frame skipping of exon 16 may occur. (PVS1_Strong) This variant has been reported in at least 6 patients with features of LGMD (PMID: 25135358, 37974208, 32994280; ClinVar SCV001385372.6 internal data communication), including in a homozygous state in two unrelated individuals with a clinical diagnosis of LGMD and no reported familial consanguinity (0.5 pts x2, ClinVar SCV001385372.6 internal data communication) (PM3). At least one individual with this variant and a second presumed diagnostic CAPN3 allele displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PMID: 37974208; PP4). This variant is absent from gnomAD v.4.1.0, meeting the criteria for PM2_Supporting. In summary, this variant meets the criteria to be classified as Likely pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/28/2025): PVS1_Strong, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA392000775/MONDO:0015152/187 2025-10-28 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042029 infores:hetionet CHEBI:4657 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0013604 infores:hetionet CAID:CA410204329 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204329 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP4, BP2, BA1, PM6, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PP3, PP1 The c.98-2A>G is a canonical splice site variant that is predicted to disrupt exon 4 acceptor splice site recognition (SpliceAI prediction: acceptor loss 0.75, at -2 bp), introduce exon 4 skipping, and produce a frameshift with a premature stop codon, resulting in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2.1 and v3.1) with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in three probands (PMID: 27288520, 29932212, and 36436542). They were diagnosed with myelodysplastic syndromes (one case) or acute myeloid leukemia (two cases). However, the germinal origin of the variant cannot be confirmed in any of them. In addition, another variant, the c.98-1G>A change, was discovered in a family with a patient who was diagnosed with an inherited platelet disorder. This latter has an impact on the same acceptor splice site and is likely to have the same effects on splicing (PMID: 32935436). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204329/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7476 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0232487 infores:hetionet CHEBI:7514 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0162297 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0743323 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0743323 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0234215 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0520589 infores:hetionet CHEBI:4046 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0018524 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0242172 infores:hetionet CHEBI:724125 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0004093 infores:hetionet CHEBI:2659 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0231835 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0032787 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0032787 infores:hetionet CHEBI:3568 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020461 infores:hetionet CHEBI:63584 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0151908 infores:hetionet CHEBI:84500 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020580 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042023 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0013447 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001277 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0007773 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020615 infores:hetionet CHEBI:2038 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0004238 infores:hetionet CHEBI:74947 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004134 infores:hetionet CHEBI:6067 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0033687 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162533 infores:hetionet CHEBI:7581 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0220870 infores:hetionet CHEBI:47519 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0028960 infores:hetionet CAID:CA915940324 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940324 MONDO:0100326 PMID: Likely Pathogenic PM4, PP4_Strong, PM2_Supporting, PM3_Supporting NM_000419.5(ITGA2B):c.2326_2331dup (p.Glu776_Ala777dup) variant is predicted to cause a change in the length of the protein due to an in-frame insertion of 2 amino acids in a non-repeat region (PM4). At least one patient (Patient GT12 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry (PP4_strong). The patient is compound heterozygous for the maternal c.2326_2331dup variant and Tyr319Ter (classified Pathogenic by the PD-EP). Confirmation of trans phase was not reported (PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180034 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM4, PP4_strong, PM3_supporting, PM2_supporting. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940324/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA410147587 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147587 MONDO:0011071 PMID: Benign BP4, BA1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1265A>G (p.Glu422Gly) is a missense variant with a MAF of 0.003913 (0.3913%, 114/29136, 114 alleles) in the East Asian subpopulation of the gnomAD v4.0.0 cohort is ≥ 0.0015 (0.15%) (BA1). This missense variant has a REVEL score < 0.50 (0.086) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147587/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3219 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0019080 infores:hetionet CHEBI:75722 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2363730 infores:hetionet CHEBI:3515 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0041105 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0263443 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0263443 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042267 infores:hetionet CHEBI:39585 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0040034 infores:hetionet CHEBI:28971 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0014742 infores:hetionet CAID:CA320638000 biolink:causes MONDO:0011071 infores:clingen CAID:CA320638000 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.414A>T (p.Glu138Asp) is a missense variant which is found within the Runt Homology Domain, but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320638000/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10584809 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584809 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, PM5, PP3 The NM_000527.5(LDLR):c.250C>T (p.Pro84Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from PMID 11810272 Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584809/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:46195 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0011603 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0002418 infores:hetionet CHEBI:3479 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0036572 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0013395 infores:hetionet CHEBI:9927 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0013378 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0014130 infores:hetionet CHEBI:9943 biolink:causes MONDO:0009693 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026764 infores:hetionet CHEBI:4702 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0002962 infores:hetionet CHEBI:8768 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013390 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151479 infores:hetionet GO:1900217 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:1900217 GO:0072001 CHEBI:2469 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151766 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0031350 infores:hetionet GO:0072304 biolink:causes GO:0072273 infores:ubergraph knowledge_assertion manual_agent GO:0072304 GO:0072273 PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0003467 infores:hetionet CHEBI:2639 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0151517 infores:hetionet CHEBI:32139 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0033774 infores:hetionet CAID:CA013406 biolink:causes MONDO:0004994 infores:clingen CAID:CA013406 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3156G>A (p.Lys1052=) variant in the MYH7 gene is 0.14% (21/10404) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013406/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:178699 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0027540 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0079102 infores:hetionet NCBIGene:84631 biolink:causes MONDO:0957203 infores:monarchinitiative not_provided not_provided HGNC:13449 MONDO:0957203 uuid:1bcee9a0-ce03-4f10-ac9a-6a8b608bfc7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0023524 infores:hetionet CHEBI:3699 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0014518 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1619712 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018939 infores:hetionet UMLS:C0011701 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0085593 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0031046 infores:hetionet CHEBI:17823 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0011991 infores:hetionet CHEBI:3752 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0018681 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0235567 infores:hetionet CHEBI:92998 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0000731 infores:hetionet CAID:CA10578350 biolink:causes MONDO:0021056 infores:clingen CAID:CA10578350 MONDO:0021056 PMID: Likely Pathogenic PP1_Moderate, PS3_Supporting, PM5_Supporting, PS4_Moderate, PM2_Supporting PS1 The c.3084T>A variant in APC is a missense variant predicted to cause the substitution of serine by arginine at amino acid position 1028 p.(Ser1028Arg). This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 (PS4_Moderate; Ambry Genetics internal data). This variant has been reported to segregate with FAP in 3 meioses in 2 families (6 meiosis in total) (PP1_Moderate; Ambry Genetics internal data). This variant is demonstrated to increased β-catenin regulated transcription activity and decreased binding to β-catenin by surface plasmon resonance (PS3_Supporting, Barcelona internal data). Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_Moderate, PP1_Moderate, PS3_Supporting, PM2_Supporting, PM5_Supporting (VCEP Specification version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578350/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5779 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0017168 infores:hetionet CHEBI:42797 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1527344 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1258215 infores:hetionet CHEBI:6456 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C2830004 infores:hetionet CAID:CA1244214 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244214 MONDO:0005338 PMID: Uncertain Significance BP4 BP7, BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.611C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 204 (p.Thr204Met). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.0006908 (31 alleles out of 44,878), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.242, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in participants of the control cohorts. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244214/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7454 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0042109 infores:hetionet CHEBI:408174 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020456 infores:hetionet CHEBI:10102 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0037384 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0015397 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0022660 infores:hetionet CHEBI:9086 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020453 infores:hetionet CHEBI:3614 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0039503 infores:hetionet CHEBI:45863 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013404 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0008325 infores:hetionet CHEBI:7852 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0015230 infores:hetionet CHEBI:7936 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085649 infores:hetionet CAID:CA014400 biolink:causes MONDO:0005045 infores:clingen CAID:CA014400 MONDO:0005045 PMID: Pathogenic PM2, PP3, PP1_Strong, PS4 PS3, PM5, PM1, PM6, BS3, PS1, PS2 The NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys) variant has been identified in at least 40 individuals with HCM, including 1 with features of RCM (PS4; Brito 2005 PMID: 16335287; Van Driest 2004 PMID: 15358028; Perrot 2005 PMID: 15856146; Theis 2009 PMID: 19808356; Brito 2012 PMID: 22857948; Zou 2013 PMID: 23283745; Lopes 2013 PMID: 23396983; Núñez 2013 PMID: 23782526; Captur 2014 PMID: 24704860; Homburger 2016 PMID: 27247418; Walsh 2017 PMID: 27532257; Mademont-Soler 2017 PMID: 28771489; Lu 2018 PMID: 30165862; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregates with HCM in at least 10 relatives from 5 families (PP1_Strong; LMM pers. comm.; OMGL pers. comm.; Stanford Inherited Heart Center pers. comm.). This variant was also reported to segregate with disease in a family with HCM, although details were not provided (Brito 2012 PMID: 22857948). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant alters protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Armel 2010 PMID: 19913502; Wolny 2013 PMID: 24047955). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1_Strong, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014400/MONDO:0005045/002 2021-11-30 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports UNII:2N4O9L084N biolink:causes MONDO:0003699 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0349231 infores:hetionet CHEBI:3696 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0038990 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0085584 infores:hetionet CHEBI:134990 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0022346 infores:hetionet CHEBI:31622 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0700361 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0006266 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009450 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0392386 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2711227 infores:hetionet CHEBI:63617 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0025323 infores:hetionet CHEBI:101278 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0030554 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0700345 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0004936 infores:hetionet CHEBI:31705 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0017178 infores:hetionet CHEBI:9332 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0022354 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0221490 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0005741 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0030252 infores:hetionet CHEBI:8776 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C2981158 infores:hetionet CHEBI:2682 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085631 infores:hetionet CHEBI:7445 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0013604 infores:hetionet CAID:CA267654 biolink:causes MONDO:0009861 infores:clingen CAID:CA267654 MONDO:0009861 PMID:22526846PMID:22526846 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The c.441+6T>A variant in PAH has been reported in at least 2 patients with PKU (BH4 deficiency ruled out), who carried pathogenic variants (ClinVar IDs: 589 & 576) (PMID: 22526846). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF= 0.000004). This intronic variant changes a moderately conserved nucleotide, and computational analyses (Alamut) predict that this variant may weaken (~60%) the splice donor site of intron 4. Based on the available information, this variant is considered to be likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PP4_M, PM2, PM3_S. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267654/MONDO:0009861/006 2019-08-06 2019-08-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16899 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0034063 infores:hetionet CHEBI:3215 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0037763 infores:hetionet CHEBI:31485 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0151601 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0948266 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0948266 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0267596 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0012569 infores:hetionet CHEBI:83804 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151603 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0152128 infores:hetionet CHEBI:38562 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0040435 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0235639 infores:hetionet CHEBI:8874 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0035229 infores:hetionet CHEBI:30830 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0040264 infores:hetionet CAID:CA008297 biolink:causes MONDO:0005835 infores:clingen CAID:CA008297 MONDO:0005835 PMID: Likely Benign BP4, BP7, PM2_Supporting BP5 The MLH1 c.2040C>T variant is predicted as a synonymous variant, p.(Cys680=). It is extremely rare in gnomAD v2.1.1 using the non-cancer dataset and in gnomAD v4.1 (<1 in 50,000 alleles: <0,002%). It is not predicted to affect splicing (predictions from http://priors.hci.utah.edu/PRIORS and SpliceAI). Therefore, this variant is classified as likely benign. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA008297/MONDO:0005835/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3485 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0232459 infores:hetionet CHEBI:9445 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0013395 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0086543 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151998 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0234913 infores:hetionet CHEBI:41879 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0162835 infores:hetionet NCBITaxon:727 biolink:causes MONDO:0004652 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:727 MESH:D018410 DB00303_MESH_D018410_1 CHEBI:45863 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085602 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0341012 infores:hetionet CHEBI:36791 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026837 infores:hetionet CHEBI:44185 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0032231 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0233472 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0007222 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0178298 infores:hetionet CHEBI:4814 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C3665386 infores:hetionet NCBIGene:494551 biolink:causes MONDO:0020837 infores:monarchinitiative not_provided not_provided HGNC:19684 MONDO:0020837 uuid:a64e93d5-4ac8-4906-a0e7-e74991841169 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0149931 infores:hetionet CHEBI:2904 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0030193 infores:hetionet GO:1900123 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:1900123 GO:0023052 CHEBI:35778 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0023066 infores:hetionet CHEBI:473990 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0017178 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0233494 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018418 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0013395 infores:hetionet CHEBI:50381 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0004134 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0748055 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0748055 infores:hetionet CHEBI:70735 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0020458 infores:hetionet CHEBI:4784 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0018681 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0877153 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0014868 infores:hetionet CHEBI:51364 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0236075 infores:hetionet CHEBI:8502 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0013144 infores:hetionet CHEBI:50922 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1443060 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0042514 infores:hetionet CHEBI:7565 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1287298 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0040034 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020701 infores:hetionet CHEBI:3423 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0235896 infores:hetionet CAID:CA261663 biolink:causes MONDO:0021060 infores:clingen CAID:CA261663 MONDO:0021060 PMID: Pathogenic PM1, PM2, PP3, PP2, PS4_Supporting, PM6_Strong The c.722C>A (p.Thr241Lys) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been identified in 1 individual with Noonan syndrome and 1 individual with cardiofaciocutaneous syndrome (PS4_Supporting; Otto von Guericke University Magdeburg internal data, Laboratory for Molecular Medicine internal data; ClinVar SCV000061619.5). It has been reported at least twice as a de novo occurrence without confirmation of maternity or paternity (PM6_Strong; Fulgent Genetics, Laboratory for Molecular Medicine internal data, SCV000061619.5). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; 29493581). In addition, 3 other pathogenic or likely pathogenic variants have been identified at this codon (PM5 not applied; ClinVar ID: 29805, 29806, 29807). Computational prediction tools and conservation analysis suggest that the p.Thr241Lys variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS4_Supporting, PM6_Strong, PM1, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261663/MONDO:0021060/004 2020-06-25 2020-07-01 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6067 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0026858 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0521839 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013182 infores:hetionet CHEBI:147675 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00249 UMLS:C1761613 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020517 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0024117 infores:hetionet CHEBI:9123 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085633 infores:hetionet CHEBI:49713 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0037299 infores:hetionet UMLS:C0010592 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013428 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0392025 infores:hetionet UMLS:C0145185 biolink:causes UMLS:C0239513 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0239513 infores:hetionet CHEBI:8874 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0015732 infores:hetionet CHEBI:34967 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0030318 infores:hetionet CHEBI:41423 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011168 infores:hetionet CHEBI:72296 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0012833 infores:hetionet CHEBI:5001 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0016204 infores:hetionet CHEBI:7507 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0042963 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0032285 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0426576 infores:hetionet CHEBI:6912 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0151579 infores:hetionet CHEBI:27882 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0017178 infores:hetionet CHEBI:8069 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0041834 infores:hetionet CHEBI:8707 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0851578 infores:hetionet CHEBI:5864 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0333355 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0267596 infores:hetionet CHEBI:6887 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0232461 infores:hetionet CHEBI:6078 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0015672 infores:hetionet CHEBI:47780 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0037299 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0038362 infores:hetionet CHEBI:9150 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0011991 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0022658 infores:hetionet CHEBI:50663 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0004096 infores:hetionet CAID:CA120626 biolink:causes MONDO:0044970 infores:clingen CAID:CA120626 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PP1, PS4, PS3, PS2, PM6 The m.14596A>T (p.I26M) variant in MT-ND6 has been reported in one family with primary mitochondrial disease to date (PMID: 8644732). Affected individuals had clinical features consistent with Leber Hereditary Optic Neuropathy (LHON) and/or spastic dystonia. Of note, another variant was seen in this family (m. 11696G>A), however this is present in healthy population databases and likely haplogroup-associated. The m.14596A>T variant was present at homoplasmy in affected individuals. As all tested individuals were homoplasmic for the variant, segregation evidence could not be considered. There are no additional families reported with de novo occurrences to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computation predictor APOGEE predicts this variant to be deleterious (score 0.95 in APOGEE1 and 0.86 in APOGEE2; PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 14, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120626/MONDO:0044970/015 2023-08-14 2024-08-12 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:267 biolink:causes MONDO:0957274 infores:monarchinitiative not_provided not_provided HGNC:463 MONDO:0957274 uuid:5c2440fa-ea02-4d6c-b485-c8474c837795 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63616 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0038454 infores:hetionet CHEBI:135285 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0016204 infores:hetionet CAID:CA16020960 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020960 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4, PM3_Supporting The c.1199+1G>T variant in exon 11 of PAH disrupts a canonical splice donor site. It is predicted to cause skipping of biologically-relevant-exon 11/13, resulting in a frameshift leading to nonsense mediated decay (PVS1). At least one patient (PMID: 31623983) with this variant had classic PKU with a serum phenylalanine level >1200uM (PP4). This patient is compound heterozygous for c.1199+1G>T and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP) without confirmation of phase (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PP4, PM3, PM2. (PAH VCEP specifications version 1; date of approval xx/xx/xxxx). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020960/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71219 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0024312 infores:hetionet NCBIGene:7018 biolink:causes MONDO:0008846 infores:monarchinitiative not_provided not_provided HGNC:11740 MONDO:0008846 uuid:f1ee019d-342b-46f6-a873-b9973acaef44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA214212 biolink:causes MONDO:0000573 infores:clingen CAID:CA214212 MONDO:0000573 PMID: Likely Pathogenic PP4, PS3_Moderate, PM1, PM3 BS2, BA1, BS1, PM2 The c.1247G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Tryptophan by Leucine at amino acid 416 (p.Trp416Leu).The Popmax Filtering AF (95% confidence) in gnomAD v.4 is 0.0002998, based on 36/91078 alleles in the South Asian population. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygotes have been observed in gnomAD (BS2 is not met).This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1.The variant was found in at least four individuals in the literature, with diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met. All of them are homozygous, reaching 1 point for homozygous occurrence. PM3_Moderate (PMID: 17572155). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, PP4 is met (PMID: 29772310).The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 1.4% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM3, PP4, and PS3_Moderate (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214212/MONDO:0000573/124 2024-04-01 2024-04-01 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15765 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0010200 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0019061 infores:hetionet CAID:CA322708 biolink:causes MONDO:0010880 infores:clingen CAID:CA322708 MONDO:0010880 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3, PM1, PM2_Supporting The NM_000020.3: c.998G>T variant in ACVRL1 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 333 (p.Ser333Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent of HHT (PS4; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with disease in a large HHT family (PP1_Strong; Internal lab contributors). This variant resides within a region, Arg329-Asn335 (catalytic loop), of ACVRL1 that is defined as a critical functional domain/residue by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1). The computational predictor REVEL gives a score of 0.975, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, western blot in HEK293T, COS7 and Hep3B mutant cells showed reduced surface expression of the variant protein and dominant-negative effect. Moreover, the variant induces embryonic dorsalization indicating that this variant impacts protein function (PS3_Supporting; PMID: 16282348). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM1, PM2_Supporting, PS4, PS3_Supporting, PP1_Strong, PP3, PP4_Moderate (specification version 1.0.0; 1/04/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA322708/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:100241 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0740394 infores:hetionet CHEBI:94392 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0042023 infores:hetionet CHEBI:15553 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C2830004 infores:hetionet CHEBI:8069 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0042963 infores:hetionet CHEBI:42797 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0424295 infores:hetionet CHEBI:5280 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0085631 infores:hetionet CHEBI:8890 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0034359 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0031350 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0233818 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233818 infores:hetionet CHEBI:134990 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C1384353 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1142257 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1142257 infores:hetionet CHEBI:134991 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0699828 infores:hetionet CHEBI:6897 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0152227 infores:hetionet CHEBI:5441 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0030305 infores:hetionet CL:0000182 biolink:causes MONDO:0007256 infores:ubergraph knowledge_assertion manual_agent CL:0000182 MONDO:0007256 CHEBI:46345 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0429029 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0700345 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0855242 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0031315 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0031315 infores:hetionet CHEBI:7640 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0015672 infores:hetionet CHEBI:31949 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0020517 infores:hetionet CHEBI:45409 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C2047937 infores:hetionet CHEBI:167638 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C2242996 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0021053 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004139 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085577 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0423736 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0423736 infores:hetionet CHEBI:8764 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085605 infores:hetionet CHEBI:31413 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0004930 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0013395 infores:hetionet CHEBI:6801 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0232807 infores:hetionet GO:0048349 biolink:causes GO:0048342 infores:ubergraph knowledge_assertion manual_agent GO:0048349 GO:0048342 CHEBI:2682 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0013428 infores:hetionet CHEBI:465284 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151772 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0243026 infores:hetionet CAID:CA229532 biolink:causes MONDO:0009861 infores:clingen CAID:CA229532 MONDO:0009861 PMID:1301947PMID:1301947PMID:23514811PMID:23514811PMID:27121329PMID:1301947PMID:23514811 Pathogenic PS2_Moderate, PP4_Moderate, PVS1, PM2, PP1, PM3_Strong PM5 The c.3G>A (p.Met1Ile) variant is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has been detected in multiple patients with PKU, BH4 deficiency excluded. PMID: 1301947, 23514811 (PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variants IVS12+1G>A (PMID: 1301947) and p.F55L (27121329) (PM3_Strong). This variant has been detected de novo (PS2_moderate; PMID: 1301947), and in affected siblings (PP1; 23514811) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PVS1, PM2, PP4_Moderate, PS2_moderate, PP1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229532/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9570 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0042963 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0031046 infores:hetionet NCBIGene:3784 biolink:causes MONDO:0024540 infores:monarchinitiative not_provided not_provided HGNC:6294 MONDO:0024540 uuid:35ec22dd-cc00-46a9-9733-0b862b7e10bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61390 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0037763 infores:hetionet UMLS:C0065374 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0019079 infores:hetionet CHEBI:5100 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0020621 infores:hetionet CHEBI:64354 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0151723 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0032285 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0162429 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0160390 infores:hetionet CHEBI:5123 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0018418 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0948594 infores:hetionet NCBIGene:55526 biolink:causes MONDO:0014012 infores:monarchinitiative not_provided not_provided HGNC:23537 MONDO:0014012 uuid:038308b9-e9c6-49c5-b239-5590e2f4ed9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0015230 infores:hetionet CHEBI:7640 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0016382 infores:hetionet CHEBI:32221 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0003123 infores:hetionet CHEBI:5138 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0558489 infores:hetionet CHEBI:4974 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0011603 infores:hetionet CHEBI:4995 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1456784 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002622 infores:hetionet CHEBI:46557 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0004093 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0026636 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020514 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0038661 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0235416 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006649 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0155305 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0008476 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0008476 uuid:7f6e5760-2602-4f25-939e-bc0256b7d777 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0003123 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0948089 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0948594 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0002871 infores:hetionet CHEBI:87715 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0019079 infores:hetionet CHEBI:6950 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0025874 infores:hetionet CHEBI:5864 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0013428 infores:hetionet CHEBI:42944 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0039070 infores:hetionet CHEBI:8888 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1142135 infores:hetionet NCBITaxon:781 biolink:causes MONDO:0005677 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:781 MONDO:0005677 CHEBI:5001 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151849 infores:hetionet CHEBI:9763 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0038450 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0242891 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0242891 infores:hetionet CHEBI:3654 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0030305 infores:hetionet CAID:CA915940255 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940255 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1784_1802delinsGTCACA variant results in a frameshift (p.Ser595CysfsTer70) with a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT41 of PMID: 29675921 who meets the criteria for PP4_strong. GT41 is comopund heterozygous for this variant and Trp579Ter (classified Pathogenic by the PD-VCEP (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940255/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA10585046 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585046 MONDO:0007750 PMID: Pathogenic PS4_Moderate, PS3, PP1_Strong, PM1, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, BS2, PP2 NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS3, PM1, PM2, PS4_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PP1_Strong - Variant segregates with phenotype in 7 informative meiosis in at least 4 families from different labs (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)): 6 affected family members have the variant and 1 non-affected family members do not have the variant.PS3 - PMID: 34167030 - Level 1 assay - Heterologous cells (CHO), FACS: Normal cell surface LDLR, 5% LDL-LDLR binding and 8% uptake.PM1 - Missense at codon 221. PM2 is Met and it is exon 4.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS4_moderate - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).PP3 - REVEL = 0.978.PP4 - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585046/MONDO:0007750/013 2022-06-01 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:127780 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151828 infores:hetionet CHEBI:39585 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0012569 infores:hetionet NCBIGene:50814 biolink:causes MONDO:0010621 infores:monarchinitiative not_provided not_provided HGNC:13398 MONDO:0010621 uuid:60127e59-1b4a-422a-bd7a-97a033370405 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0233472 infores:hetionet CHEBI:73274 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0020461 infores:hetionet GO:0001742 biolink:causes CL:0000487 infores:ubergraph knowledge_assertion manual_agent GO:0001742 CL:0000487 NCBITaxon:237561 biolink:causes MONDO:0005915 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:237561 MESH:D014010 DB00257_MESH_D014010_1DB00239_MESH_D014010_1DB06820_MESH_D014010_1 CHEBI:9352 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0022346 infores:hetionet CHEBI:74947 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020453 infores:hetionet CHEBI:5106 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0085649 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0687707 infores:hetionet CHEBI:50742 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0021177 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0037274 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0314719 infores:hetionet CHEBI:7445 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0028961 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0855242 infores:hetionet CAID:CA392326316 biolink:causes MONDO:0007947 infores:clingen CAID:CA392326316 MONDO:0007947 PMID: Uncertain Significance PP2, PP3, PM2_Supporting, PS4_Supporting PM1 The NM_00138 c.1147G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by aspartic acid at amino acid 1143 (p.Gly1143Asp), in a cbEGF-like domain of the protein. This variant has been reported three times in ClinVar: once as likely pathogenic, and twice as uncertain significance (Variation ID: 617874). This variant has been reported in the literature in two individuals with aortic root aneurysm and/or annuloaortic ectasia (PMID 26621581, 34363016, PS4_Sup). This variant has been identified in 3/1180042 (0.0003%) individuals of European non-Finnish origin (PM2_sup; https://gnomad.broadinstitute.org/ v4.1.0). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.843, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Sup, PM2_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392326316/MONDO:0007947/022 2024-05-23 2024-10-31 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:367163 biolink:causes MONDO:0024388 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0009062 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014868 infores:hetionet CHEBI:4710 biolink:causes NCIT:C78403 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0877027 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0595930 infores:hetionet NCBIGene:10533 biolink:causes MONDO:0030323 infores:monarchinitiative not_provided not_provided HGNC:16935 MONDO:0030323 uuid:31d70a0d-aaa2-4f29-b10c-ebeeb2ed1ead biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030232 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0242350 infores:hetionet CHEBI:5134 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C2363730 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0015397 infores:hetionet CHEBI:132233 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0017178 infores:hetionet CHEBI:72564 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0015732 infores:hetionet CHEBI:3515 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0013428 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0007642 infores:hetionet CHEBI:15367 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0011168 infores:hetionet CHEBI:8774 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0009782 infores:hetionet CHEBI:63584 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0042029 infores:hetionet CHEBI:10102 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0032227 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0035309 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0025061 infores:hetionet CAID:CA367400479 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400479 MONDO:0015967 PMID: Pathogenic PP1_Strong, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.823C>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 275 (p.(Arg275Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.792, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.823C>T p.Arg275Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275Gly. In addition, the missense variant c.824G>T p.Arg275 Leu has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with hyperglycemia with 8 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.823C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400479/MONDO:0015967/086 2025-01-10 2025-01-10 Semidominant inheritance HP:0032113 Supports CHEBI:32315 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0004604 infores:hetionet CHEBI:3082 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0030848 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0042769 infores:hetionet CAID:CA229721 biolink:causes MONDO:0009861 infores:clingen CAID:CA229721 MONDO:0009861 PMID:16165389PMID:23430859PMID:1363838PMID:15464430PMID:8981952PMID:1363838PMID:10234516PMID:12655546PMID:7749420 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 PM5, PS3 The c.731C>T (p.Pro244Leu) variant in PAH has been reported in 2 individuals with mild PKU or benign HPA (BH4 deficiency excluded). It was detected in trans with pathogenic variants I65T, PMID: 1363838 and p.R261Q )parental analysis not reported PMID: 23430859). This variant has extremely low frequency in gnomAD (MAF= 0.00002979) and ExAC (MAF=0.00009). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229721/MONDO:0009861/006 2020-05-22 2020-05-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:46557 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0030193 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0036572 infores:hetionet CHEBI:9445 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0011570 infores:hetionet CHEBI:5790 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1456784 infores:hetionet CHEBI:6062 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0030193 infores:hetionet CHEBI:8874 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013384 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0030332 infores:hetionet CHEBI:5138 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0018926 infores:hetionet CAID:CA392331935 biolink:causes MONDO:0007947 infores:clingen CAID:CA392331935 MONDO:0007947 PMID: Likely Pathogenic PM6, PP2, PP3, PP4, PM2_Supporting, PM1, PM5 PVS1, BS2, PP1, BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS2, PS4, PM3, PM4, BP5, BP7, BS1, BS3, BS4 The NM_000138 c.2669G>A variant is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid position 890. This variant has not been reported in the literature but was identified at one institution as de novo in proband with ectopia lentis and a systemic score of 2 (PP4, PM6; UZG). This variant has also been reported four times in ClinVar, with two classifications of likely pathogenic and two classifications of pathogenic (Variation ID: 431935). It is not present in gnomAD v2.1.1 or 3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in the hybrid 2 domain; cysteine residues in the hybrid domains are believed to be important for proper protein folding (PM1). Computational prediction tools and conservation analysis support that this variant may impact the protein (PP3; REVEL = 0.926). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Three other missense variants at the same amino acid position (p.Cys890Arg, p.Cys890Gly, p.Cys890Trp) have been identified and are classified as likely pathogenic (PM5; PMIDs: 12938084, 16222657, 20564469). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PM6, PM2_supporting, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392331935/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:28901 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0549567 infores:hetionet CHEBI:2038 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0010200 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0006145 infores:hetionet NCBIGene:3190 biolink:causes MONDO:0014700 infores:monarchinitiative not_provided not_provided HGNC:5044 MONDO:0014700 uuid:9b601065-2728-4377-a73b-25efcef8c1a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:375611 biolink:causes MONDO:0013471 infores:monarchinitiative not_provided not_provided HGNC:9359 MONDO:0013471 uuid:eb9bc521-38ab-4f87-ad1c-71d84a0d1252 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3996 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0085631 infores:hetionet CHEBI:9654 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0014848 infores:hetionet CHEBI:205919 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0009450 infores:hetionet CHEBI:51230 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0017178 infores:hetionet CHEBI:7494 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020443 infores:hetionet CHEBI:3636 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0020649 infores:hetionet CHEBI:4027 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0004509 infores:hetionet CHEBI:9139 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014236 infores:hetionet GO:0006954 biolink:causes MONDO:0005301 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D009103 DB00108_MESH_D009103_1 CAID:CA400027662 biolink:causes MONDO:0100326 infores:clingen CAID:CA400027662 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 The variant NM_000212.3(ITGB3):c.1157G>A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 386. This variant has not been found in any individuals with Glanzmann thrombasthenia after a thorough literature search. This variant is found in the European (non-Finnish) population at a rate of 0.00000508 (6/1179952) in gnomADv4.1, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.25, which predicts no damaging effect on ITGB3 function. This variant was identified by Illumina and found in a screen of an ostensibly healthy population. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting and BP4 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400027662/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7825 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00239 UMLS:C0332563 infores:hetionet CHEBI:3756 biolink:causes HP:0002317 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0231686 infores:hetionet CHEBI:8597 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0278134 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029124 infores:hetionet CHEBI:101853 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0546884 infores:hetionet CHEBI:37924 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0036508 infores:hetionet CHEBI:85161 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0023066 infores:hetionet NCBIGene:286676 biolink:causes MONDO:0012326 infores:monarchinitiative not_provided not_provided HGNC:28741 MONDO:0012326 uuid:7140abe7-481f-4645-9f17-3e9c95d2a9b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63115 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0235996 infores:hetionet CHEBI:4466 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0151723 infores:hetionet CHEBI:8863 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C3263723 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0027813 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0521591 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0234913 infores:hetionet CHEBI:50924 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0018418 infores:hetionet NCBIGene:51761 biolink:causes MONDO:0014104 infores:monarchinitiative not_provided not_provided HGNC:13533 MONDO:0014104 uuid:15a25a7d-b1ee-48ba-bf3a-b780848976d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA645509248 biolink:causes MONDO:0007750 infores:clingen CAID:CA645509248 MONDO:0007750 PMID: Uncertain Significance PS3_Supporting, PM2 BP2, PP4 The NM_000527.5 (LDLR):c.-187_185del variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 April 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PS3_Supporting: Level 3 experiment, heterologous cells (HepG2) were used for luciferase assays, 8% reporter gene expression observed, PMID 9610768 (Peeters et al., 1998). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509248/MONDO:0007750/013 2023-04-28 2024-10-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UNII:3QJA87N40S biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C2747793 infores:hetionet CHEBI:16335 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0002792 infores:hetionet CHEBI:9449 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0027497 infores:hetionet CHEBI:4702 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0008031 infores:hetionet CHEBI:142290 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C1443060 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0233494 infores:hetionet CHEBI:9086 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0043094 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018021 infores:hetionet CAID:CA000240 biolink:causes MONDO:0018875 infores:clingen CAID:CA000240 MONDO:0018875 PMID: Pathogenic PS3, PS2, PP3_Moderate, PM1, PP4_Moderate, PS4_Supporting, PM2_Supporting BP4, BA1, PS1, BS1, BS3, BS4, PP1, BS2 The NM_000546.6: c.488A>G variant in TP53 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 163 (p.Tyr163Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). This variant has been reported in 2 additional unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs 21601526, 8164043). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000581096.5). This variant has an allele frequency of 6.196e-7 (1/1613972 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 54 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences) (PM1, PMID: 30311369). Computational predictor scores (BayesDel = 0.54; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 16; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000240/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2469 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0013395 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0042109 infores:hetionet CHEBI:50648 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0041582 infores:hetionet CHEBI:5855 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0003811 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0233472 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0234215 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0041969 infores:hetionet CHEBI:37941 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0162557 infores:hetionet CHEBI:15544 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0026946 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0041747 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0001126 infores:hetionet CHEBI:51450 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0043349 infores:hetionet GO:0075054 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0075054 GO:0009653 CHEBI:63599 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0015672 infores:hetionet CHEBI:9328 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0025637 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232910 infores:hetionet UMLS:C0879264 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0039231 infores:hetionet CAID:CA320741276 biolink:causes MONDO:0011071 infores:clingen CAID:CA320741276 MONDO:0011071 PMID: Likely Benign BS1, PP3 PS3, PS1, PS2, PS4, BP3, BP1, BP4, BP2, BA1, BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM4, PM1, PM3, PM5, BS2, PP4, PP2, PP1 The c.-60+5G>C variant (NM_001754.5) is a canonical splice site substitution in the 5' UTR of RUNX1. Because the variant is located in the 5' UTR, it is not expected to alter the amino acid sequence. However, the computational splicing predictor SpliceAI gives a Δ score of 0.62 for donor loss at c.-60 and 0.32 for acceptor loss at c.-59, predicting that the variant disrupts both the acceptor and donor splice sites of intron 1 of RUNX1 (SSF-like and MES do not predict an effect on the canonical acceptor splice site). As this variant represents c.-162051G>C in NM_001001890.3 (isoform B) and NM_001122607.2 (isoform A), meaning the effect is not the same across isoforms and is less detrimental in isoforms A and B, PVS1 would not apply per the MM-VCEP. Finally, the highest population minor allele frequency in gnomAD v3 is 0.001046 (9/8602 alleles) in the African/African American population, which is higher than the ClinGen MM-VCEP threshold of >0.00015 (BS1). The variant also has not been reported in patients who meet the RUNX1 phenotype criteria. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen MM-VCEP: BS1, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320741276/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10101 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027769 infores:hetionet CHEBI:3441 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0009676 infores:hetionet CHEBI:70707 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0036572 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042571 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0162429 infores:hetionet CHEBI:27779 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0012833 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0241705 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0149931 infores:hetionet CAID:CA157918200 biolink:causes MONDO:0015967 infores:clingen CAID:CA157918200 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PM1, PP1 The c.389T>CT variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to threonine at codon 130 (p.(Ile130Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.932, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.17, which is below the MDEP cutoff (<0.5) (PMID: 22291974). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in at least 6 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 36257325, 19790256, 14517956, 22291974, 34362814, internal lab contributor). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID: 22291974). In summary, c.389T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PS3_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA157918200/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:31644 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0009763 infores:hetionet CHEBI:71940 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0030193 infores:hetionet CHEBI:6539 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0547030 infores:hetionet CHEBI:63631 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1510410 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003864 infores:hetionet CHEBI:31643 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0231218 infores:hetionet GO:0098689 biolink:causes GO:0019045 infores:ubergraph knowledge_assertion manual_agent GO:0098689 GO:0019045 CHEBI:16480 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0007785 infores:hetionet NCBIGene:54766 biolink:causes MONDO:0033564 infores:monarchinitiative not_provided not_provided HGNC:13862 MONDO:0033564 uuid:8ad8b86f-a969-4d00-bee3-46b2cdba5bd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0178298 infores:hetionet CHEBI:145499 biolink:causes EFO:0002460 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0020564 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0006147 infores:hetionet CHEBI:47780 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0549249 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0012833 infores:hetionet CHEBI:127780 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0038450 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0234458 infores:hetionet CHEBI:4710 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0858635 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013595 infores:hetionet CHEBI:5165 biolink:causes HP:0003487 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0034935 infores:hetionet CHEBI:63791 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2004489 infores:hetionet CHEBI:135930 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0033687 infores:hetionet NCBIGene:11117 biolink:causes MONDO:0971179 infores:monarchinitiative not_provided not_provided HGNC:19880 MONDO:0971179 uuid:c2bde90b-4e84-46b3-b3b8-0317d831c557 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5132 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0040034 infores:hetionet CHEBI:73274 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0546884 infores:hetionet CHEBI:3207 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0017160 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0178298 infores:hetionet CHEBI:42944 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0014591 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0040046 infores:hetionet CHEBI:31413 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0040822 infores:hetionet NCBIGene:2566 biolink:causes MONDO:0032725 infores:monarchinitiative not_provided not_provided HGNC:4087 MONDO:0032725 uuid:da405309-d374-49b0-930c-d63a55ad2d47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0017574 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0152165 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0152165 infores:hetionet CHEBI:5100 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0002871 infores:hetionet CHEBI:8888 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014591 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009319 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0043251 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0948594 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0006840 infores:hetionet CHEBI:10102 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0019521 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151735 infores:hetionet CHEBI:32184 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0007971 infores:hetionet GO:0090318 biolink:causes GO:0097006 infores:ubergraph knowledge_assertion manual_agent GO:0090318 GO:0097006 CHEBI:4027 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0041364 infores:hetionet CHEBI:45409 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0004093 infores:hetionet CHEBI:9635 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C3665347 infores:hetionet CHEBI:5004 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0039240 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039503 infores:hetionet CHEBI:50378 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0086565 infores:hetionet CHEBI:9635 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0004604 infores:hetionet CHEBI:41977 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0042963 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0003469 infores:hetionet CHEBI:9460 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0232462 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0009450 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1956346 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017160 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0235295 infores:hetionet CHEBI:84500 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0018926 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0005959 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0005959 infores:hetionet CHEBI:5134 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0162820 infores:hetionet UMLS:C0005740 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0004093 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0947999 infores:hetionet CHEBI:5098 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0003862 infores:hetionet CHEBI:8207 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0038450 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0004239 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0020517 infores:hetionet GO:0014807 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:0014807 GO:0043009 CHEBI:6128 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0042401 infores:hetionet CHEBI:63589 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0002962 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0518015 infores:hetionet CHEBI:8461 biolink:causes HP:0012195 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0425492 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0005741 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0178298 infores:hetionet CHEBI:31859 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0231218 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0566948 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0566948 infores:hetionet GO:2000595 biolink:causes GO:0021554 infores:ubergraph knowledge_assertion manual_agent GO:2000595 GO:0021554 CHEBI:28830 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0002878 infores:hetionet CHEBI:27899 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020621 infores:hetionet CHEBI:8874 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C3263723 infores:hetionet CHEBI:6933 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0151908 infores:hetionet CHEBI:5109 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0162820 infores:hetionet CHEBI:5138 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151878 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0151664 infores:hetionet CHEBI:2636 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C2047937 infores:hetionet CHEBI:28177 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0036572 infores:hetionet CHEBI:3561 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0039070 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0037822 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0017178 infores:hetionet NCBIGene:3373 biolink:causes MONDO:0011093 infores:monarchinitiative not_provided not_provided HGNC:5320 MONDO:0011093 uuid:7f69d0d5-7a6a-47d5-94c4-742562b0ec61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042571 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0035309 infores:hetionet CHEBI:2668 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0041969 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151735 infores:hetionet CHEBI:6965 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0018418 infores:hetionet CHEBI:465284 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0038002 infores:hetionet NCBIGene:84879 biolink:causes MONDO:0014660 infores:monarchinitiative not_provided not_provided HGNC:25897 MONDO:0014660 uuid:27762b51-bd20-43af-9a84-904a62cca66b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0079043 infores:hetionet NCBIGene:79718 biolink:causes MONDO:0011213 infores:monarchinitiative not_provided not_provided HGNC:29529 MONDO:0011213 uuid:5a51917f-a02b-4fce-936d-033e90183df9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0027497 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0013395 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0948525 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0151892 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151892 infores:hetionet CHEBI:8707 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C3263723 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0234936 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0234936 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0858598 infores:hetionet CHEBI:135285 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0009782 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0851341 infores:hetionet CHEBI:17303 biolink:causes UMLS:C2363912 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C2363912 infores:hetionet CHEBI:72690 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0035243 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042131 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0009806 infores:hetionet NCBIGene:28234 biolink:causes MONDO:0009379 infores:monarchinitiative not_provided not_provided HGNC:10961 MONDO:0009379 uuid:e310aade-186c-404e-a8f9-6da2439d46de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes MONDO:0005752 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0270629 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234987 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0518015 infores:hetionet CHEBI:63791 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151723 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0547030 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0018939 infores:hetionet CHEBI:63630 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0013456 infores:hetionet CHEBI:10650 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020580 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0595930 infores:hetionet CHEBI:9674 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0917801 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0948594 infores:hetionet CHEBI:50659 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0919924 infores:hetionet CHEBI:4027 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C2363731 infores:hetionet CHEBI:9288 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0033687 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0020437 infores:hetionet NCBIGene:4087 biolink:causes MONDO:0859213 infores:monarchinitiative not_provided not_provided HGNC:6768 MONDO:0859213 uuid:1c91d2ed-7f88-47f8-bbd3-076edc25e778 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10023 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0022346 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0037199 infores:hetionet CHEBI:50742 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042023 infores:hetionet CHEBI:39867 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0039231 infores:hetionet CHEBI:28915 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0014457 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0878544 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151828 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0233558 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0233558 infores:hetionet CHEBI:63577 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0020453 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0424605 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0008370 infores:hetionet UMLS:C0657912 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030794 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0948594 infores:hetionet CHEBI:4856 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0009676 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0002622 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0013595 infores:hetionet CHEBI:31623 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0234708 infores:hetionet CHEBI:145499 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1142412 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0021053 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0340464 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0314719 infores:hetionet CAID:CA915950963 biolink:causes MONDO:0100437 infores:clingen CAID:CA915950963 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2964_2965del (p.Glu989GlyfsTer?) is a frameshift variant due to a 2-nucleotide deletion introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 4 apparently unrelated probands (PMIDs: 34985506, 37217489, 29528978, and 32679846). However, the number of individuals meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 32679846). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915950963/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:32315 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0242301 infores:hetionet CHEBI:41774 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0003862 infores:hetionet CHEBI:7956 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0020580 infores:hetionet CHEBI:30659 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0013404 infores:hetionet CHEBI:45783 biolink:causes HP:0012886 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0473311 infores:hetionet CHEBI:61390 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0011603 infores:hetionet CHEBI:50742 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151766 infores:hetionet NCBIGene:201595 biolink:causes MONDO:0014271 infores:monarchinitiative not_provided not_provided HGNC:30611 MONDO:0014271 uuid:e8d05520-13a9-49ec-b288-390e878473a9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1112525 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0521490 infores:hetionet CHEBI:3614 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0013395 infores:hetionet CHEBI:9587 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0085692 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0034065 infores:hetionet GO:0060921 biolink:causes CL:1000409 infores:ubergraph knowledge_assertion manual_agent GO:0060921 CL:1000409 CHEBI:3478 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0836924 infores:hetionet CHEBI:9566 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0085623 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0242350 infores:hetionet CHEBI:8356 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015967 infores:hetionet CHEBI:2379 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0231528 infores:hetionet CHEBI:5441 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0000731 infores:hetionet CHEBI:6444 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0043352 infores:hetionet CHEBI:63598 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0338831 infores:hetionet CHEBI:48131 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0013604 infores:hetionet CAID:CA397836247 biolink:causes MONDO:0018875 infores:clingen CAID:CA397836247 MONDO:0018875 PMID: Pathogenic PS4_Moderate, PP4_Moderate, PVS1, PM2_Supporting BP4, BP3, BA1, PS2, PS3, PM4, PM1, BP7, BP5, BS1, BS3, BS4, PP3, PP1, BS2 The NM_000546.6: c.919+1G>A is a TP53 variant within the canonical donor site of exon 8. This change is observed to produce aberrant transcripts encoding premature truncations predicted to induce nonsense-mediated decay. (PVS1 (RNA); PMID: 17066464, 31092812). This variant has been reported in 1 proband meeting Classic criteria and 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points (PS4_Moderate; PMIDs: 29324801, 31081129, 20805372, ClinVar SCV001382474). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, ClinVar SCV001382474). This variant is absent from gnomAD v3.1.2 (non-cancer) and gnomAD v2.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PP4_Moderate, PS4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397836247/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51860 biolink:causes HP:0100034 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0751900 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0851341 infores:hetionet CHEBI:6339 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0027497 infores:hetionet CHEBI:6970 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0013395 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0853692 infores:hetionet CHEBI:7466 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0022107 infores:hetionet CHEBI:64028 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0020458 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0036572 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0036983 infores:hetionet CHEBI:6067 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0026766 infores:hetionet CHEBI:4681 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0006384 infores:hetionet CHEBI:17347 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0036830 infores:hetionet NCBIGene:2132 biolink:causes MONDO:0014731 infores:monarchinitiative not_provided not_provided HGNC:3513 MONDO:0014731 uuid:ad176b77-bf33-4dea-bfb4-a45cbbafe219 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2379 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0428977 infores:hetionet CHEBI:5790 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0151836 infores:hetionet CHEBI:28148 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020598 infores:hetionet CHEBI:3216 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0002994 infores:hetionet CHEBI:16480 biolink:causes GO:0099163 infores:ubergraph knowledge_assertion manual_agent CHEBI:16480 GO:0099163 CHEBI:75275 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0018681 infores:hetionet CAID:CA2695202181 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695202181 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting, PS4_Moderate NM_001034853.2(RPGR):c.2311del (p.Glu771ArgfsTer?) is a frameshift variant due to a 1-nucleotide deletion that introduces a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1, PMID: 33446141). This variant has been reported in at least 3 apparently unrelated probands meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent cone and/or rod electroretinogram responses (PMID: 33446141, PMID: 33576794, PS4_Moderate). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PP1, PS4_Moderate, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202181/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CAID:CA390864677 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864677 MONDO:0100216 PMID: Pathogenic PP3, PM2_Supporting, PS4_Supporting, PM1, PS2, PS3_Supporting BP4, BP2, BA1, PP1, PP4, BS2, PM5, PM3, PS1, BS1, BS3, BS4 The NM_177438.2:c.5428G>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by tyrosine at amino acid 1810 (p.Asp1810Tyr). This variant received a total of 1 phenotype point across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting, PMID: 26925222). This variant was identified as a de novo occurrence with constitutional mosaicism (PS2; PMID: 26925222). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assays showed that this variant fails to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting, PMID:26545620). The computational predictor REVEL gives a score of 0.923, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides in the p.D1810 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1, PMID: 31342592). In summary, this variant meets the criteria to be classified as PATHOGENIC for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, PS3_Supporting, PP3, PM1 (Bayesian Points: 10; VCEP specifications version 1.3.0; 01/07/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864677/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28901 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0043094 infores:hetionet CHEBI:49668 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0702166 infores:hetionet CHEBI:40279 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0015230 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0235467 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0235467 infores:hetionet CHEBI:63612 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020615 infores:hetionet CHEBI:92712 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0152198 infores:hetionet CAID:CA321073 biolink:causes MONDO:0008535 infores:clingen CAID:CA321073 MONDO:0008535 PMID: Pathogenic PM2_Supporting, PP4_Moderate, PS4, PP1_Strong The NM_001114753.3: c.1586G>A variant in ENG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 529 (p.Arg529His). This variant has been reported in more than 10 probands with a phenotype consistent with HHT (PS4; PMID: 22991266, 16752392, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in more than 20 affected family members from multiple families (PP1_Strong; Internal lab contributors). The overall minor allele frequency in gnomAD v2.1.1 is 0.000004 (1/251282 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.579, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4, PP4_Moderate, PP1_Strong (specifications version 1.1.0; 09/11/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA321073/MONDO:0008535/136 2024-09-11 2024-09-19 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:1280 biolink:causes MONDO:0006668 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D003234 DB00537_MESH_D003234_1DB01059_MESH_D003234_1 CAID:CA316756 biolink:causes MONDO:0044970 infores:clingen CAID:CA316756 MONDO:0044970 PMID: Likely Pathogenic PP3, PM3_Strong, PM2 PP4 The c.3286 C>T (p.Arg1096Cys) variant in POLG is seen at an allele frequency of 0.00001 in gnomAd and 0.00002 in ExAC with no homozygotes (PM2). This variant has a Revel score of 0.837 (PP3). There are 7 cases in the literature reported with an Alpers phenotype in individuals who are homozygous for the c.3286 C>T (p.Arg1096Cys) (PM3_strong; PMID:21305355; PMID:21880868; PMID:18546365). There are also 6 cases reported with other pathogenic variants with phasing unknown 2 siblings reported compound heterozygous with Thr914Pro, another reported with Trp748Ser, another cases with Leu591Phe, another case with Ala467Thr, and another case with Gly848Ser. Each case was reported with POLG related disease with Alpers, liver related disease, and other neurological phenotypes (PM3_strong; PMID:18487244; PMID:30021052; PMID:24265579; PMID:27111573; PMID:21880868). In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PM2, PP3, PM3_strong Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA316756/MONDO:0044970/014 2021-05-23 2021-05-23 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:10125 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0028734 infores:hetionet CHEBI:9123 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0278106 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014549 infores:hetionet CHEBI:65173 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0028768 infores:hetionet CHEBI:83804 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0575081 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0549373 infores:hetionet GO:0140099 biolink:causes GO:0042730 infores:ubergraph knowledge_assertion manual_agent GO:0140099 GO:0042730 CHEBI:9727 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0518015 infores:hetionet CHEBI:75922 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0014236 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0038990 infores:hetionet CHEBI:94449 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0011175 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0021053 infores:hetionet CHEBI:4466 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020598 infores:hetionet CAID:CA10605410 biolink:causes MONDO:0001586 infores:clingen CAID:CA10605410 MONDO:0001586 PMID: Likely Pathogenic PP3_Moderate, PM3, PP4, PM2_Supporting PM5 The NM_000203.5:c.1898C>G variant in IDUA is a missense variant predicted to cause substitution of serine by tryptophan at amino acid 633 (p.Ser633Trp). This variant has been detected in at least 4 individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (phase not confirmed, 0.5 points, PMID: 24798265). Three individuals were homozygous for the variant (max 1 point, PMIDs: 24798265, 33389473). Total: 1.5 points (PM3). One of these patients had documented IDUA deficiency within the affected range in dried blood spot and clinical features specific to MPS I including dysostosis multiplex, arthropathy, and corneal involvement (PMID: PMID: 33389473) (PP4). The computational predictor REVEL gives a score of 0.871 which is above the threshold of 0.773 (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60010 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Another variant at the same amino acid position, p.Ser633Leu, has been reported in individuals with MPS I (PMID: 11735025, 21480867. This variant has not yet been classified by the ClinGen LD VCEP, therefore, PM5 was not applied. There is a ClinVar entry for this variant (Variation ID: 286242). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PM3, PP3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605410/MONDO:0001586/091 2024-12-06 2025-06-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:65349 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0037199 infores:hetionet CAID:CA512318903 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318903 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, BP5, BP7, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.231C>T (p.Ser77=) is a synonymous variant which has a MAF of 0.00001 (0.001%, 108718/243164, 1 allele) in the European (Non-Finnish) subpopulations of the gnomAD cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). No splicing impact or creation of cryptic splice sites is predicted by SSF and MES. SpliceAI predicts no impact to splicing (score: 0.00) (BP4). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 861921). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318903/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:37941 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042109 infores:hetionet CHEBI:9123 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0023218 infores:hetionet CHEBI:9137 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C2047937 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0032285 infores:hetionet CHEBI:45409 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0231218 infores:hetionet CHEBI:135276 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0178298 infores:hetionet CHEBI:47781 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0220870 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0017574 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0344315 infores:hetionet CHEBI:135888 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0027497 infores:hetionet CHEBI:52717 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085636 infores:hetionet CHEBI:4445 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0003578 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042373 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C3263723 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0037199 infores:hetionet CAID:CA386966233 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966233 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4 The c.798C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to lysine at codon 266 (p.(Asn266Lys)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.837, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributor). Another missense variant at the same residue, c.797A>G p.(Asn266Ser) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, this evidence supports the classification of c.798C>G as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966233/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0006285 infores:hetionet CHEBI:39585 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0011991 infores:hetionet NCBIGene:23498 biolink:causes MONDO:0060554 infores:monarchinitiative not_provided not_provided HGNC:4796 MONDO:0060554 uuid:125b5603-1dd0-4e4e-a8cd-e9a4a4609406 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0497156 infores:hetionet CHEBI:9362 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0033774 infores:hetionet NCBIGene:3035 biolink:causes MONDO:0013788 infores:monarchinitiative not_provided not_provided HGNC:4816 MONDO:0013788 uuid:f6a7704c-e136-44dd-860c-4272d0a3eea5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151798 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0042109 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0541832 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0005741 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0007194 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151601 infores:hetionet CAID:CA358045 biolink:causes MONDO:0009290 infores:clingen CAID:CA358045 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Supporting, PM5_Supporting PS1 The NM_000152.5:c.854C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 285 (p.Pro285Arg). The highest population minor allele frequency in gnomAD v4.0.1 is 0.000001784 (1/ 1120816 alleles) in the European non-finish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).At least two probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant, both with documented deficiency of GAA activity (PMID: 28196920, 19862843). One proband had juvenile-onset (after 1 year of age) (PMID: 14695532) (PP4_Moderate). One patient was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811); phase unconfirmed (PMID: 12213618, 14695532). Another individual is compound heterozygous for the variant and c.2303C>T (Pro768Leu) (PMID: 28196920). The allelic data from this patient will be used toward the classification of p.Pro768Leu and is not included here to avoid circular logic. Additional reports of this variant identified in newborn screening (PMID: 28196920, 12213618, 14695532, 19862843). Total 0.5 points (PM3_Supporting).Expression of the variant in COS cell type resulted in 2-10% (~ 5%) of wild-type GAA activity and evidence of abnormal GAA synthesis and processing (PMID: 19862843, 14695532, 19862843). The variant was described as Class C (“less severe”), indicating that this variant may impact protein function (PMID: 14695532) (PS3_Moderate).The computational predictor REVEL gives a score of 0.883, which is above the threshold of 0.7, evidence that correlates with impact on GAA function (PP3).Another missense variant (c.853C>T, p.Pro285Ser) (PMID: 18425781, 21484825, 21550241; ClinVar Variation ID 281052) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting).There is a ClinVar entry for this variant (Variation ID: 526532; 2-star review status) with four submitters classifying the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_Moderate, PM3_Supporting, PS3_Moderate, PM5_Supporting, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 18, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA358045/MONDO:0009290/010 2025-07-18 2025-08-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:71940 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0027765 infores:hetionet UMLS:C0657912 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151746 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006266 infores:hetionet CHEBI:499361 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0017168 infores:hetionet CHEBI:50749 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C2242996 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0003123 infores:hetionet CHEBI:8871 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014724 infores:hetionet CHEBI:7915 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0043094 infores:hetionet CHEBI:45863 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0700590 infores:hetionet CHEBI:4708 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085633 infores:hetionet CHEBI:7465 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0017168 infores:hetionet CHEBI:8024 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1443060 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1565489 infores:hetionet CHEBI:9943 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0000768 infores:hetionet NCBIGene:8737 biolink:causes MONDO:0030018 infores:monarchinitiative not_provided not_provided HGNC:10019 MONDO:0030018 uuid:e92a6d8f-047e-447e-b419-01a69566437b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0005758 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0042075 infores:hetionet CHEBI:10650 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0013604 infores:hetionet CAID:CA8970418 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970418 MONDO:0012589 PMID: Likely Benign BP7, BS1 The allele frequency of the p.Ser229= variant in TCF4 is 0.027% in East Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Ser229= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ser229= variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970418/MONDO:0012589/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:10102 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0034880 infores:hetionet CHEBI:48844 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0012833 infores:hetionet CHEBI:66876 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0030196 infores:hetionet CAID:CA10585287 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585287 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP1, PP4 PS4 The variant NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP1, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP1 - variant segregates with FH phenotype in 2 informative meiosis in 1 family from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obeste et des Dyslipidemies (APHP Sorbonne Univeristie Hopitalde la Pitie-Salpetriere): 2 affected family members have the variant. PP3 - REVEL=0.947PP4 - Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded.PM5: 4 other missense variants in the same codon:1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines.2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines.3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines.4) NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) (ClinVar ID 440623) - Likely Pathogenic by these guidelines.There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585287/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UNII:8NZ41MIK1O biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0029456 infores:hetionet CHEBI:47898 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0022346 infores:hetionet UMLS:C0065374 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0018965 infores:hetionet NCBIGene:5593 biolink:causes MONDO:0030553 infores:monarchinitiative not_provided not_provided HGNC:9416 MONDO:0030553 uuid:50e3e2d8-0478-4c67-ae72-8ae147458659 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585190 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585190 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP1, PP4 BA1, BP4, BP3, BP2, PS3, PS2, PS1, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP3, BS2 The NM_000527.5(LDLR):c.914G>C (p.Trp305Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PP1, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4_Supporting: Variant meets PM2 and is identified in 2 index cases with DLCN criteria of probable FH from Lille University & CHRU Lille. So, PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So, PP1 is met. PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded (see PS4 for details). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585190/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:2636 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0002792 infores:hetionet CHEBI:2950 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0152227 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0856136 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0856136 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0160390 infores:hetionet CHEBI:116278 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0020458 infores:hetionet CHEBI:480999 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0008031 infores:hetionet NCBIGene:1289 biolink:causes MONDO:0019567 infores:monarchinitiative not_provided not_provided HGNC:2209 MONDO:0019567 uuid:e625500a-2770-44e4-b292-6075b5ed3bc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019214 infores:hetionet CHEBI:37333 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0025222 infores:hetionet CAID:CA8338094 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338094 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PM3_Supporting, PP4_Moderate The c.1411T>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 471 (p.Phe471Leu). At least one patient with this variant in the homozygous state displayed reduced very long chain acyl CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PM3_Supporting, PP4_moderate; PMID: 24305961, 25834949). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.838, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338094/MONDO:0008723/021 2023-11-28 2023-11-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:92712 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0029408 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0037284 infores:hetionet GO:0061295 biolink:causes GO:0061215 infores:ubergraph knowledge_assertion manual_agent GO:0061295 GO:0061215 CHEBI:63620 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0231218 infores:hetionet UNII:F64QU97QCR biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0855775 infores:hetionet CHEBI:8232 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0085932 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0020517 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0009806 infores:hetionet CHEBI:51209 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0011603 infores:hetionet CHEBI:53760 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0011124 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0948089 infores:hetionet CHEBI:4995 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085682 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0015376 infores:hetionet CHEBI:3510 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0042963 infores:hetionet CHEBI:9123 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C2979982 infores:hetionet NCBIGene:4204 biolink:causes MONDO:0010726 infores:monarchinitiative not_provided not_provided HGNC:6990 MONDO:0010726 uuid:94612929-58cb-4c49-aa8a-5f344177c03d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0042384 infores:hetionet CHEBI:3723 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0042963 infores:hetionet CHEBI:5959 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0278134 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151763 infores:hetionet CHEBI:5004 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C2830004 infores:hetionet CAID:CA10644634 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644634 MONDO:0011071 PMID: Benign BA1, BP2 PS3, PS1, PS2, BP1, BP4, BP3, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*683G>T is a 3' UTR variant. MAF of 0.004105 (0.4105%, 19/4628 alleles) in the South Asian subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%). One homozygote is present in gnomADv3.1.2. In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644634/MONDO:0011071/008 2022-02-11 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2788 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0042401 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018991 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C1268766 infores:hetionet NCBITaxon:6181 biolink:causes MONDO:0015254 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6181 MESH:D012552 DB01058_MESH_D012552_1 CHEBI:3650 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0021141 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0235416 infores:hetionet CHEBI:4024 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0016382 infores:hetionet CHEBI:4858 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0004093 infores:hetionet CHEBI:85083 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0344232 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0020538 infores:hetionet CHEBI:8776 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0025289 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0851341 infores:hetionet CHEBI:7773 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0085637 infores:hetionet CHEBI:4868 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0423798 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0038362 infores:hetionet CHEBI:16469 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042790 infores:hetionet CHEBI:4995 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0015371 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0235487 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235487 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0020557 infores:hetionet CHEBI:31859 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0687713 infores:hetionet CHEBI:59773 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0011603 infores:hetionet CHEBI:63616 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0002792 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0162429 infores:hetionet CHEBI:7822 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0002874 infores:hetionet CHEBI:7565 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018965 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027339 infores:hetionet CHEBI:4315 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0018681 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0392162 infores:hetionet CHEBI:9137 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042029 infores:hetionet CHEBI:3219 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0033893 infores:hetionet CHEBI:142290 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0038990 infores:hetionet CHEBI:101853 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0236075 infores:hetionet CHEBI:39585 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0026821 infores:hetionet CHEBI:47781 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0030252 infores:hetionet CHEBI:9150 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0086565 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0343495 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0343495 infores:hetionet CHEBI:45863 biolink:causes HP:0034192 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0524702 infores:hetionet CAID:CA190548 biolink:causes MONDO:0700270 infores:clingen CAID:CA190548 MONDO:0700270 PMID: Likely Benign BP4, BP7 BA1, BS1, PM2 The ATM c.5544T>C (p.Asp1848=) variant is not predicted to impact splicing in multiple RNA in silico tools (BP4). This variant creates a synonymous change (BP7). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA190548/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10101 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0242073 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0262397 infores:hetionet CHEBI:64028 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0042075 infores:hetionet CHEBI:4315 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0520589 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0003864 infores:hetionet CHEBI:50663 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0011603 infores:hetionet CHEBI:6717 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0018834 infores:hetionet CHEBI:40237 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0016204 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0429774 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0429774 infores:hetionet CHEBI:4953 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0006277 infores:hetionet CHEBI:6775 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022346 infores:hetionet CHEBI:3387 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0152198 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0012359 infores:hetionet CHEBI:8871 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0240211 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221714 infores:hetionet CHEBI:83804 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0018790 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0023510 infores:hetionet CHEBI:3647 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0039070 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0042963 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1720775 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0027769 infores:hetionet NCBIGene:5993 biolink:causes MONDO:0971016 infores:monarchinitiative not_provided not_provided HGNC:9986 MONDO:0971016 uuid:0185e918-87fc-4560-a299-6c553bcc5596 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes UMLS:C0344304 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0344304 infores:hetionet CHEBI:6062 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013378 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042075 infores:hetionet CHEBI:51141 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0004093 infores:hetionet CHEBI:50885 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0002792 infores:hetionet CHEBI:7823 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0233407 infores:hetionet NCBIGene:7873 biolink:causes MONDO:0957997 infores:monarchinitiative not_provided not_provided HGNC:15461 MONDO:0957997 uuid:5c71258a-ecb9-4ccc-9ba7-70c72d9c9649 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0151786 infores:hetionet CHEBI:4911 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0014742 infores:hetionet CHEBI:9927 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0020461 infores:hetionet CHEBI:8764 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151746 infores:hetionet NCBIGene:56945 biolink:causes MONDO:0012718 infores:monarchinitiative not_provided not_provided HGNC:14508 MONDO:0012718 uuid:e5e4b255-237b-4fc4-9eef-262e42997873 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70746 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0947999 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0011053 infores:hetionet CHEBI:8428 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C2047937 infores:hetionet CHEBI:5778 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0038325 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020538 infores:hetionet CHEBI:25367 biolink:causes MONDO:0024650 infores:ubergraph knowledge_assertion manual_agent CHEBI:25367 MONDO:0024650 CHEBI:135736 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0026821 infores:hetionet CHEBI:34385 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0042029 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0009450 infores:hetionet CHEBI:49662 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0042963 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0025061 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0012833 infores:hetionet CHEBI:47898 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004134 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0021400 infores:hetionet CAID:CA380135709 biolink:causes MONDO:0000572 infores:clingen CAID:CA380135709 MONDO:0000572 PMID:29772310 Pathogenic PM2_Supporting, PS3_Moderate, PVS1 The c.2877G>A (p.Trp959Ter) (NM_000448.3) variant in RAG1 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. However, it is predicted to truncate part of the core region (between aa 387-1011) critical to the function of the protein (PVS1 Met). The filtering allele frequency (the upper threshold of the 95% CI of 6/86258) of the c.2877G>A variant in RAG1 is 0.00002995 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The recombination activity assay (described in PMID 29772310) showed activity of this variant compared to wildtype RAG1 is 0 %, which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate) (Dr. Notarangelo's lab, internal communication).In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1 Met, PM2_Supporting,PS3_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380135709/MONDO:0000572/123 2024-03-04 2024-03-04 Autosomal recessive inheritance HP:0000007 Supports CAID:CA2573157346 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157346 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP2, BP3, BP1, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM3, PM4, PM1, PM5, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.613+6T>C is a variant in intron 6 which affects a nucleotide within the consensus splice site. However, splice prediction algorithms do not predict an effect on splicing (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The nucleotide is highly conserved (phyloP100 way = 9.19). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157346/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45863 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030554 infores:hetionet CHEBI:8863 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0852911 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0518015 infores:hetionet NCBIGene:2317 biolink:causes MONDO:0010094 infores:monarchinitiative not_provided not_provided HGNC:3755 MONDO:0010094 uuid:0bfe30b2-f94d-44a2-b833-2bd6b13d3577 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0031542 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0011551 infores:hetionet CHEBI:94686 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1443060 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042594 infores:hetionet CHEBI:104011 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0026821 infores:hetionet CHEBI:3216 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0025362 infores:hetionet CHEBI:63611 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0231528 infores:hetionet CHEBI:41774 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151905 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1535879 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1535879 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0029134 infores:hetionet CHEBI:71255 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0003862 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0233494 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0018801 infores:hetionet CHEBI:50922 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0028643 infores:hetionet CAID:CA386965177 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965177 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PM1, PM5, PP1_Moderate, PP4_Moderate, PP3 The c.686G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to proline at codon 229 (p.Arg229Pro) of NM_000545.8. This variant segregated with diabetes, with 14 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). Also, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in 6 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, positive C-peptide, and 2 were antibody negative) (PP4_Moderate; internal lab contributors). Another missense variant, c.686G>A p.Arg229Gln has been interpreted as pathogenic by the ClinGen MDEP and p.Arg229Pro has an equal or greater Grantham distance (PM5). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 15928245, internal lab contributors). In summary, c.686G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM1_Supporting, PM2_Supporting, PP4_Moderate, PM5, PP3, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965177/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4717 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0020514 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0022346 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0020649 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0728725 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0728725 infores:hetionet CHEBI:52172 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085932 infores:hetionet NCBIGene:84823 biolink:causes MONDO:0030929 infores:monarchinitiative not_provided not_provided HGNC:6638 MONDO:0030929 uuid:cb63a608-f794-44ce-b749-d15d7dc84da0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4702 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0234238 infores:hetionet CHEBI:8356 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039239 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0020517 infores:hetionet CHEBI:7507 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0011991 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0221040 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0221040 infores:hetionet CHEBI:2379 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0242429 infores:hetionet CHEBI:17698 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0036974 infores:hetionet CHEBI:31401 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0017181 infores:hetionet CHEBI:7959 biolink:causes MONDO:0015265 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0006272 infores:hetionet CHEBI:6950 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0149745 infores:hetionet CHEBI:63635 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0026826 infores:hetionet CHEBI:63589 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0030305 infores:hetionet CAID:CA10585407 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585407 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM5, PM2, PP3, PP4 PM3 The NM_000527.5(LDLR):c.1328G>C (p.Trp443Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0000006841 (0.00006841 %) in European (non-Finnish) exomes (gnomAD version 4.1.0).PP3: REVEL = 0.934.PM5: 1 other missense variant in the same codon: NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) (ClinVar ID 251792)- Pathogenic by these guidelines.PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 9 unrelated index cases who fulfill criteria for FH: 1 case meeting Simon Broome criteria from PMID 17142622 (Humphries et al., 2006), UK; 1 case meeting Simon Broome possible FH criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 3 cases with DLCN >=6 from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France; 4 cases with DLCN >=6 from PMID 34871818 (Tada et al., 2022), Japan. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585407/MONDO:0007750/013 2025-01-31 2025-02-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:2208 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0149745 infores:hetionet CAID:CA404080674 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080674 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.854A>G (p.His285Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1).BP4: REVEL = 0.419, splicing evaluation required.A.) Not on limits.B.) Does not create AG.C.) There is an AG nearby.Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080674/MONDO:0007750/013 2023-03-24 2024-12-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6775 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0019112 infores:hetionet NCBIGene:3937 biolink:causes MONDO:0030302 infores:monarchinitiative not_provided not_provided HGNC:6529 MONDO:0030302 uuid:51049664-ae31-41a5-af44-17c90300ea9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135005 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0009760 infores:hetionet CHEBI:3654 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C1291078 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0746883 infores:hetionet CHEBI:5147 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0042029 infores:hetionet CHEBI:2675 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0428974 infores:hetionet CHEBI:3696 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151786 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005810 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0021345 infores:hetionet CHEBI:7443 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0022346 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0232459 infores:hetionet CHEBI:28001 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0037763 infores:hetionet CHEBI:71417 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0002962 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0086543 infores:hetionet CHEBI:85078 biolink:causes MONDO:0006672 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0004690 infores:hetionet CHEBI:46195 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0917801 infores:hetionet CHEBI:45783 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020621 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0002871 infores:hetionet CHEBI:47898 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0438142 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0234913 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0033975 infores:hetionet CHEBI:28445 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151904 infores:hetionet CHEBI:17347 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0019572 infores:hetionet CHEBI:3403 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0013390 infores:hetionet NCBIGene:54345 biolink:causes MONDO:0019073 infores:monarchinitiative not_provided not_provided HGNC:11194 MONDO:0019073 uuid:ee5e0aac-62e8-4aeb-843d-763a2d598e6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0030920 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151477 infores:hetionet CHEBI:63611 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020578 infores:hetionet CHEBI:28593 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0041948 infores:hetionet CHEBI:49375 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0030252 infores:hetionet CHEBI:4027 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0015672 infores:hetionet CHEBI:16335 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0039070 infores:hetionet CHEBI:6076 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235896 infores:hetionet CHEBI:3387 biolink:causes HP:0002926 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0857576 infores:hetionet CHEBI:8774 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027497 infores:hetionet CHEBI:52717 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0028961 infores:hetionet CHEBI:465284 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0017178 infores:hetionet CHEBI:6375 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151908 infores:hetionet CHEBI:7601 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C2830004 infores:hetionet CHEBI:3699 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0033975 infores:hetionet CHEBI:63616 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C2939186 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011630 infores:hetionet CHEBI:47519 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0025345 infores:hetionet CHEBI:4909 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0018965 infores:hetionet NCBIGene:2683 biolink:causes MONDO:0011772 infores:monarchinitiative not_provided not_provided HGNC:924 MONDO:0011772 uuid:53ca857b-951a-4c03-8bf6-30b38b593963 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18248 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0017178 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0020456 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0013922 infores:hetionet NCBIGene:4750 biolink:causes MONDO:0009642 infores:monarchinitiative not_provided not_provided HGNC:7744 MONDO:0009642 uuid:729cddc7-cd84-48dc-ac52-4211d86c6cb5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10229 biolink:causes MONDO:0014754 infores:monarchinitiative not_provided not_provided HGNC:2244 MONDO:0014754 uuid:ba429b05-fefa-45a7-99f4-bea28a36f824 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042401 infores:hetionet NCBIGene:175 biolink:causes MONDO:0008830 infores:monarchinitiative not_provided not_provided HGNC:318 MONDO:0008830 uuid:19845b5f-759c-40a7-9548-1e00c6438f50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3515 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C1257843 infores:hetionet CHEBI:63631 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013604 infores:hetionet CAID:CA916084428 biolink:causes MONDO:0009861 infores:clingen CAID:CA916084428 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate PVS1, PM3 The p.Intron3del899 (g.103272488_103273387del) variant is an 899bp deletion in Intron 3 of PAH. It has been previously reported as a variant of “uncertain clinical significance” in patient with PKU (plasma Phe levels not provided in paper; BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate), who also harbored a deletion in exon 5 (g.103272488_103273386del, leading to a frameshift at His170) and the c.994G>A (p.G322R) missense variant (unclassified/VUS) (PMID: 23942198). It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2).Classification: VUS Supporting criteria: PM2; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084428/MONDO:0009861/006 2020-12-25 2022-03-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA059509 biolink:causes MONDO:0017623 infores:clingen CAID:CA059509 MONDO:0017623 PMID:28677221PMID:9425889PMID:30306255PMID:16773562PMID:28677221 Benign BS3, BA1 PM6, PM2, PVS1, BS4, BS1, BP7, BP5, PP1, PP3, PP2, BS2, PM1, PM4, PM5, BP2, BP4, PS3, PS2, PS4, PS1 PTEN c.210-39A>G (IVS3-39A>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.01015 (1.01%, 252/24,818 alleles) in the European (Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA059509/MONDO:0017623/003 2020-06-18 2020-06-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7476 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151908 infores:hetionet CHEBI:17334 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0242184 infores:hetionet CHEBI:6950 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0040822 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0016664 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0016664 infores:hetionet CAID:CA902460 biolink:causes MONDO:0100368 infores:clingen CAID:CA902460 MONDO:0100368 PMID: Likely Benign BP4, BP7, BS1 NM_000329.3(RPE65):c.585C>T is a synonymous variant in codon 195, near the center of exon 6. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.001447, with 56 alleles / 30602 total alleles in the South Asian population (with 1 homozygote), which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902460/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:45285 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0027497 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0021053 infores:hetionet NCBIGene:100507217 biolink:causes MONDO:0975874 infores:monarchinitiative not_provided not_provided HGNC:48626 MONDO:0975874 uuid:2fab6de3-7a22-4436-8450-72568c28a140 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034359 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0018099 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027765 infores:hetionet CAID:CA226122 biolink:causes MONDO:0100453 infores:clingen CAID:CA226122 MONDO:0100453 PMID: Likely Pathogenic PM3_Strong, PP4, PP1, PM2_Supporting PM5, PP3 NM_000180.4(GUCY2D):c.307G>A (p.Glu103Lys) is a missense variant that is predicted to replace glutamic acid with lysine at position p.103. Another missense variant in the same codon, NM_000180.4(GUCY2D):c.308A>T (p.Glu103Val), has been reported in association with GUCY2D-related recessive retinopathy (PMID: 21602930), and splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. However, this second variant has not yet been classified by the ClinGen LCA / eoRD VCEP, so PM5 is not met. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0001749, with 257 alleles / 1,469,548 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000180.4(GUCY2D):c.2595del (p.Lys866fs) variant or the NM_000180.4(GUCY2D):c.91dup (p.Arg31fs) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 points, PMID: 29178642, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31704230, PP1). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), nystagmus (1 pt), visual acuity limited to light perception (1 pt) since birth (1 pt), flat ERG responses from both rods (0.5 pts) and cones (1 pt), high hypermetropia, being drawn to bright light, sluggish pupillary responses (0.5 pts), eye poking, and normal appearing fundus with some abnormality in the reflection from the inner limiting membrane at high magnification, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 29178642, PP4). The computational predictor REVEL gives a score of 0.547, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP1 and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226122/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3749 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0042963 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0497365 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0017601 infores:hetionet CHEBI:28593 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0036974 infores:hetionet CHEBI:5106 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0010481 infores:hetionet CHEBI:7565 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0012569 infores:hetionet CHEBI:94686 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0043352 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023533 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0518015 infores:hetionet CHEBI:71940 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0038325 infores:hetionet CHEBI:51364 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0025345 infores:hetionet NCBIGene:7453 biolink:causes MONDO:0060585 infores:monarchinitiative not_provided not_provided HGNC:12729 MONDO:0060585 uuid:2358af25-8753-48d6-8d4d-0764f778014d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10014511 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014511 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.453G>T (p.Met151Ile) is a missense variant which is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014511/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51041 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0033774 infores:hetionet CHEBI:15365 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0040264 infores:hetionet CHEBI:63638 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0002994 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0476089 infores:hetionet CHEBI:681848 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0233407 infores:hetionet CHEBI:2668 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0043352 infores:hetionet CAID:CA320255629 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255629 MONDO:0011071 PMID: Uncertain Significance PS4_Supporting PS3, PS1, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.849G>C (p.Gln283His) is a missense variant which has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 36819173). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255629/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3371 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0042109 infores:hetionet GO:0052040 biolink:causes GO:0012501 infores:ubergraph knowledge_assertion manual_agent GO:0052040 GO:0012501 CAID:CA16041878 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041878 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PS1_Supporting, PM3, PVS1_Strong PP3 The NM_000152.5:c.-32-3C>A variant is located in the splice acceptor region of intron 1 and has been shown to impact splicing. In fibroblasts from an individual with Pompe disease who was compound heterozygous for the variant and a missense variant in GAA, RT-PCR revealed loss of exon 2 (p.M1_T182del, which includes the 27 residues of signal sequence, the 42 residues of the propeptide and the first 113 amino acids of the mature protein (from 70 to 182) (PMID: 18429042). A later study, in which the variant was expressed in a minigene, showed that the variant results in about 20% of transcripts with normal splicing of exon 2 (of note, this is a slightly lower level of normal splicing than observed for a well known pathogenic variant in the same splice region, c.-32-13T>G). Abnormal splicing events included complete loss of exon 2 (r.-32_546del) and activation of a cryptic splice site (r.‐32_486del) (PMID: 31301153). Due to loss of a critical region (the signal sequence) in aberrantly spliced transcripts, but with presence of some normal transcript (albeit at a lower level than a known pathogenic variant in the same splice region), PVS1 was applied at the strong level (PMID: 37352859) (PVS1_Strong, PS1_Supporting applied based on recommendations in PMID: 37352859). This variant has been reported in at least 6 probands with late onset Pompe disease including two individuals with documented GAA activity <30% normal in fibroblasts (PMID: 19046416, 21550241) (PP4_Moderate). Two of these probands have been reported to have this variant in compound heterozygosity, phase unknown, with another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.1655T>C (p.Leu552Pro) (PMID: 18429042) and c.482_483del (PMID: 21550241). In addition, three affected siblings have been reported to be homozygous for the variant (PMID: 19588081, 20464284, 25681614) (PM3). Another three patients are compound heterozygous for the variant and a missense variant (either c.1905C>A (p.Asn635Lys), c.1447G>A (p.Gly483Arg), or c.2173C>T (p.Arg725Trp)) (PMID: 19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.0. is 0.000007314 (8/1093866 alleles) in the European non-Finnish populationn, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371662). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1_Strong, PM3, PS1_Supporting, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041878/MONDO:0009290/010 2023-11-21 2023-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8863 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0027697 infores:hetionet CAID:CA274334 biolink:causes MONDO:0009290 infores:clingen CAID:CA274334 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong The NM_000152.5:c.655G>A variant i GAA is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 219 (p.Gly219Arg). Over 20 individuals have been reported with this variant, at least 8 with GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay (PMIDs 11738358, 20033296, 23266370, 23601496, 24844452, 25037089, 25139343, 29124014) (PP4_Moderate). At least 12 individuals are compound heterozygous for the variant and another variant in GAA that has been classified by the ClinGen LD VCEP as as pathogenic for Pompe disease, phase unknown, including c.-32-13T>G (PMID: 21550241, 21753173, 24844452, 27711114, 30155607, 30564623; multiple individuals, max 2 x 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points). At least 3 individuals are homozygous for the variant (PMID: 23787031, 25139343, 29289479, 30023291; max 2 x 0.5 points point). Total 3 points (PM3_Strong). Further individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), c.784G>A (p.Glu262Lys) (PMID 11738358), c.923A>C (p.His308Pro) (PMID: 14695532), c.1796C>A (p.Ser599Tyr) (PMID: 18429042) or p.Trp376CysfsTer15 (PMID: 20033296). The allelic data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00004006 (3/74892 alleles) in the African/African American population, which is lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in <2% wild type GAA activity and it is abnormally processed (PMIDs 14695532; 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.872 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID 189065). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PM3_Strong, PS3_Moderate, PP4, Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Sept. 9, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274334/MONDO:0009290/010 2025-09-09 2025-09-09 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8707 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0687133 infores:hetionet NCBIGene:10319 biolink:causes MONDO:0013583 infores:monarchinitiative not_provided not_provided HGNC:6494 MONDO:0013583 uuid:c700f423-6a2f-474b-9823-dfa141709e69 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0042109 infores:hetionet CHEBI:82716 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0000833 infores:hetionet CAID:CA229266 biolink:causes MONDO:0009861 infores:clingen CAID:CA229266 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3_Supporting PM5 The c.1007A>G (p.Gln336Arg) variant in PAH has been reported in a Chinese patient with classical PKU, BH4 deficiency not assessed. It was detected with pathogenic variant p.R243Q, parental analysis not reported (PMID: 16256386). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.958. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PP4, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229266/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0012569 infores:hetionet CHEBI:5120 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0027497 infores:hetionet CHEBI:8707 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085623 infores:hetionet CHEBI:32293 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0271051 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0029408 infores:hetionet CHEBI:6413 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0009782 infores:hetionet CHEBI:28748 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0149745 infores:hetionet CHEBI:45863 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0023218 infores:hetionet CHEBI:53760 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0220870 infores:hetionet NCBIGene:2643 biolink:causes MONDO:0100186 infores:monarchinitiative not_provided not_provided HGNC:4193 MONDO:0100186 uuid:1cca3c7f-e6b3-439f-92b3-224159dbd524 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5103 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0235146 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C74591 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0234925 infores:hetionet CHEBI:52717 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0876994 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0041912 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0151626 infores:hetionet CHEBI:5864 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0151636 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0242350 infores:hetionet CHEBI:76010 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0027121 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0021053 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0149931 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0020598 infores:hetionet CHEBI:4653 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0424790 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0027651 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020538 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0032285 infores:hetionet CHEBI:50922 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0004604 infores:hetionet CHEBI:6129 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C2363731 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0549297 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0549297 infores:hetionet CAID:CA399787956 biolink:causes MONDO:0100326 infores:clingen CAID:CA399787956 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting, BP4, PM3_Supporting The NM_000419.5(ITGA2B):c.3062T>C (p.Val1021Ala) missense variant has been reported in at least two Glanzmann thrombasthenia patients (PMID: 21113249). Patient SB displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 23%, as measured by flow cytometry, and there was 12-13% binding to PAC-1. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong; PMID: 21113249). Patient LN is homozygous for c.3062T>C (PM3_supporting; PMID: 21113249). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.084, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, and BP4. (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399787956/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9445 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C1735601 infores:hetionet CHEBI:51860 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0086565 infores:hetionet CHEBI:6931 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0033774 infores:hetionet CAID:CA392350265 biolink:causes MONDO:0007947 infores:clingen CAID:CA392350265 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP3, PM2_Supporting, PM1_Strong NM_000138.5(FBN1):c. 911G>A is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid 304 (p.Cys304Tyr). This variant was found in a proband with classical MFS with clinical Thoracic Aortic Dissection, Ectopia Lentis and a SS=7pt (Internal data Tokyo; PP4). This variant has been reported 1 time in ClinVar as Likely pathogenic and 1 time as uncertain significance (Variation ID: 632813). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.1.0). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). The constraint z-score for missense variants affecting FBN1 is 8.2 (gnomAD v.4.1.0, PP2). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.986, PP3). In summary, this variant meets criteria to be classified as Likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_Strong, PM2_Sup, PP4, PP3, PP2. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392350265/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:480999 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0004093 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020649 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0029408 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233632 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0235082 infores:hetionet CHEBI:6062 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0040435 infores:hetionet CHEBI:75045 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0242528 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0018799 infores:hetionet CHEBI:2567 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0042164 infores:hetionet CHEBI:32315 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0008031 infores:hetionet CHEBI:6015 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0027540 infores:hetionet CHEBI:6633 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0014457 infores:hetionet CHEBI:50156 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C1112525 infores:hetionet UMLS:C0065374 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0015967 infores:hetionet CHEBI:34385 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0002792 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042267 infores:hetionet CHEBI:50173 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0022346 infores:hetionet CHEBI:40279 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042029 infores:hetionet CHEBI:7443 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0232461 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0015397 infores:hetionet CHEBI:7773 biolink:causes MONDO:0002263 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0017411 infores:hetionet CHEBI:8356 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0740394 infores:hetionet CHEBI:2379 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0917801 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0549373 infores:hetionet NCBIGene:2066 biolink:causes MONDO:0014223 infores:monarchinitiative not_provided not_provided HGNC:3432 MONDO:0014223 uuid:1c95b0db-c0aa-4542-84cc-9052402ca2ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0423791 infores:hetionet CHEBI:31348 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0019080 infores:hetionet CHEBI:134991 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0004134 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040435 infores:hetionet CHEBI:9449 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0030252 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0267465 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0267465 infores:hetionet CHEBI:9738 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0004245 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0152008 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0152008 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1863751 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1863751 infores:hetionet CHEBI:2922 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0013395 infores:hetionet GO:1903581 biolink:causes GO:0002276 infores:ubergraph knowledge_assertion manual_agent GO:1903581 GO:0002276 UNII:2N4O9L084N biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0151610 infores:hetionet CHEBI:135961 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0004604 infores:hetionet CHEBI:136040 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0030554 infores:hetionet CHEBI:2639 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0018681 infores:hetionet CHEBI:4975 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C1443060 infores:hetionet CHEBI:9927 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0232492 infores:hetionet CHEBI:5147 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0020473 infores:hetionet CHEBI:135193 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0018681 infores:hetionet CHEBI:74947 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0542571 infores:hetionet CHEBI:8404 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0004093 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0549288 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0549288 infores:hetionet CHEBI:9137 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0085702 infores:hetionet CHEBI:5959 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0085631 infores:hetionet CHEBI:63632 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0854069 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042267 infores:hetionet CHEBI:51860 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233471 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0428974 infores:hetionet CHEBI:2682 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232487 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0520459 infores:hetionet CAID:CA229821 biolink:causes MONDO:0009861 infores:clingen CAID:CA229821 MONDO:0009861 PMID:9521426PMID:26413448 Pathogenic PM5, PP4_Moderate, PM2, PP3, PM3_Strong The c.848T>A (p.Ile283Asn) variant in PAH is absent from population databases and predicted damaging with in silico predictors. It is a novel missense change in a residue where a different pathogenic variant has been identified (c.847A>T (p.Ile283Phe). It has been identified in multiple affected individuals in trans with known pathogenic variants (PMID: 9521426, 26413448), and was identified in a patient in which a defect in BH4 metabolism had been excluded. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229821/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:480999 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0853813 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1443060 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0018799 infores:hetionet CHEBI:94501 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C2830004 infores:hetionet CHEBI:3219 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0687713 infores:hetionet CHEBI:45716 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0015672 infores:hetionet CHEBI:4822 biolink:causes UMLS:C0241950 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0241950 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0021053 infores:hetionet CHEBI:7865 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C1443060 infores:hetionet CHEBI:135005 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0027849 infores:hetionet CAID:CA412743099 biolink:causes MONDO:0100437 infores:clingen CAID:CA412743099 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.628G>T (p.Glu210Ter) is a nonsense variant introducing a premature stop in codon 210 within exon 7 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband (PMID: 31645972, PMID: 36284460), however, the individual did not meet one of the PS4 requirements of some functional vision impairment in affected males by age 30 years and/or decreased or absent electroretinogram responses, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412743099/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:36795 biolink:causes UMLS:C0221155 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0221155 infores:hetionet CAID:CA291013 biolink:causes MONDO:0012999 infores:clingen CAID:CA291013 MONDO:0012999 PMID: Likely Benign BP4, BS1 BP7 The NM_000156.6(GAMT):c.225G>A (p.Ala75=) variant is a synonymous variant for which splicing prediction algorithms (SpliceAI, varSEAK) predict no impact to the splice consensus sequence nor the creation of a new splice site (BP4); however, the residue altered (Ala75) is conserved through zebrafish. Thus, BP7 is not met. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00117 (21/17954 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). There is a ClinVar entry for this variant (Variation ID: 137433). In summary, this variant meets the crietria to be classified as likely benign for GAMT deficiency. GAMT-specific criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP): BS1, BP4.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA291013/MONDO:0012999/026 2023-03-09 2023-03-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:72564 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0424790 infores:hetionet CAID:CA023926 biolink:causes MONDO:0007783 infores:clingen CAID:CA023926 MONDO:0007783 PMID: Likely Pathogenic PS4, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 3903 of the RYR1 protein, p.(Arg3903Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000026, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:20681998, PMID:24433488, PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.97) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023926/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3650 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0022354 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0541799 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151763 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003873 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002265 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0038273 infores:hetionet CHEBI:94848 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0036572 infores:hetionet CAID:CA404086103 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086103 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP2, PS4, PS3, PS2, PS1, BS1, BS3, BS4, BP7, PM5, PM4, PM3, PM1, PM6, PVS1, BS2, PP4, PP1 The NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.951.It is above 0.75, so PP3 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086103/MONDO:0007750/013 2023-04-29 2023-04-29 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63619 biolink:causes UMLS:C0861148 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0861148 infores:hetionet NCBITaxon:6183 biolink:causes MONDO:0044345 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6183 MONDO:0044345 CHEBI:4315 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0235082 infores:hetionet CHEBI:3312 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0549249 infores:hetionet CHEBI:31949 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0003862 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0267792 infores:hetionet NCBIGene:8565 biolink:causes MONDO:0030375 infores:monarchinitiative not_provided not_provided HGNC:12840 MONDO:0030375 uuid:7fc8b3dc-f3e4-4fcc-bf39-89e051ffdf3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015672 infores:hetionet NCBIGene:54903 biolink:causes MONDO:0009571 infores:monarchinitiative not_provided not_provided HGNC:7121 MONDO:0009571 uuid:6677d4ad-fa96-4412-9e6b-f7ee09f848b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50378 biolink:causes UMLS:C0745761 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0745761 infores:hetionet CHEBI:44185 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C3160947 infores:hetionet UMLS:C0657912 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024902 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0004766 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0038218 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0234930 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027947 infores:hetionet CAID:CA16041904 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041904 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The NM_000152.5:c.2242del (p.Glu748ArgfsTer16) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One Chinese patient with late-onset Pompe disease has been described who is compound heterozygous for the variant and c.1634C>T (p.Pro545Leu). This individual has documented values showing deficiency GAA activity in dried blood spots (PMID: 35071497) (PP4_Moderate). The allelic data from this individual will be used in the classification of p.Pro545Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 370639). This variant was initially classified by the ClinGen Lysosomal Diseases VCEP on Sept 07, 2021 as likely pathogenic. Recuration, on Jan 15, 2023, led to reclassification as pathogenic due to the availability of new case-level data (PMID: 35071497). GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Jan 15, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041904/MONDO:0009290/010 2024-01-15 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:367163 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0877192 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034359 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027765 infores:hetionet CAID:CA410203432 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203432 MONDO:0011071 PMID: Uncertain Significance BP2, PM1, PS4_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, BP3, BP4, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.328A>C (p.Lys110Gln) is a missense variant which is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, both of which provide coverage of at least 20x for the RUNX1 gene at this genomic position (PM2_supporting). This variant has a REVEL score higher than 0.88 (0.957) (PP3) and affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant represents a missense change at residue p.Lys110, where multiple other missense changes (three or more) have been previously classified as likely pathogenic or pathogenic according to ClinVar and ClinGen data. Specifically, ClinVar IDs 1518631 and 561234 (ClinGen IDs CA410203418 and CA410203419) are listed as likely pathogenic, and ClinVar ID 14465 (ClinGen ID CA248613) is classified as pathogenic based on MM-VCEP rules for RUNX1 and RNA data. Although SpliceAI predicts no splicing effects, the application of PM5_strong is not applicable when PM1 is already applied. This variant has been reported in two studies by the same authors, both describing the Leucegene RUNX1 AML patient group. In one study, the variant is reported as somatic (patient #17 in PMID: 32315381), as buccal DNA did not reveal the variant's presence, although it was homozygous at RNA-seq calling. In the second study, the variant is reported as germline in samples 03H030 and 09H092, being germline and homozygous according to the information in Figure 5B and Supplementary Table S2 (BP2). The patient carrying this variant was younger than 60 years and diagnosed with acute myeloid leukemia, providing evidence for PS4_supporting. In summary, the clinical significance of this variant is uncertain, meeting the ACMG/AMP criteria as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PS4_supporting, and BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203432/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9566 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0002453 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0020649 infores:hetionet CHEBI:9332 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0012833 infores:hetionet CHEBI:3181 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0012739 infores:hetionet CHEBI:3561 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0010200 infores:hetionet GO:1901673 biolink:causes GO:0000070 infores:ubergraph knowledge_assertion manual_agent GO:1901673 GO:0000070 CHEBI:63681 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0036572 infores:hetionet CHEBI:5138 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0232462 infores:hetionet GO:0061930 biolink:causes GO:0043353 infores:ubergraph knowledge_assertion manual_agent GO:0061930 GO:0043353 CHEBI:10023 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018133 infores:hetionet CHEBI:4911 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0037763 infores:hetionet CAID:CA412373781 biolink:causes MONDO:0100039 infores:clingen CAID:CA412373781 MONDO:0100039 PMID: Likely Benign BS2 BS1, PVS1, PM2, PS4 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2941C>T (p.Arg981Ter) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3221G>A) is present in 14 XX and 7 XY individuals in gnomAD v4 (0.0043%) (not sufficient to meet BS1 criteria). The p.Arg981Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (not sufficient to meet PVS1 criteria). Additionally, the p.Arg981Ter variant is observed in at least 6 unaffected individuals (internal database - Invitae, internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Arg981Ter variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412373781/MONDO:0100039/034 2023-12-06 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:5138 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011334 infores:hetionet CHEBI:91541 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C2830004 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0262385 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0018799 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009806 infores:hetionet CHEBI:28787 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0041657 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0009450 infores:hetionet NCBIGene:4215 biolink:causes MONDO:0975952 infores:monarchinitiative not_provided not_provided HGNC:6855 MONDO:0975952 uuid:f6b0523f-0948-45b2-b5a6-09491cf000c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4659 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0027813 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0858600 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0858600 infores:hetionet CHEBI:42797 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0038220 infores:hetionet CHEBI:6128 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C1565489 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0403632 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0426576 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0003123 infores:hetionet CHEBI:10101 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0000731 infores:hetionet CHEBI:6067 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0241057 infores:hetionet CHEBI:49603 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0232462 infores:hetionet GO:0010453 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:0010453 GO:0030154 CHEBI:41774 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0023530 infores:hetionet NCBIGene:2322 biolink:causes MONDO:0013108 infores:monarchinitiative not_provided not_provided HGNC:3765 MONDO:0013108 uuid:9b131d37-cb77-4eea-b732-5c06bb47f26e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0019080 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0595877 infores:hetionet CHEBI:27882 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0023530 infores:hetionet CHEBI:8356 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0004604 infores:hetionet CHEBI:15940 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0014724 infores:hetionet CHEBI:48669 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0017178 infores:hetionet CHEBI:7824 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027497 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005280 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0033581 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030305 infores:hetionet CHEBI:4784 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0004134 infores:hetionet CHEBI:31711 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0007222 infores:hetionet GO:0060297 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0009653 CHEBI:474180 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0085605 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0267792 infores:hetionet NCBIGene:11080 biolink:causes MONDO:0957224 infores:monarchinitiative not_provided not_provided HGNC:14886 MONDO:0957224 uuid:398aceb4-4f13-4945-8bf8-23729cff45fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31644 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0518015 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0014457 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0267792 infores:hetionet NCBITaxon:5207 biolink:causes MONDO:0005724 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5207 MONDO:0005724 CHEBI:3423 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0034065 infores:hetionet CHEBI:9635 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0015672 infores:hetionet CHEBI:49375 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0021368 infores:hetionet CHEBI:3647 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0857305 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0017601 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0233494 infores:hetionet CHEBI:84050 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0016382 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0036572 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042109 infores:hetionet CHEBI:10119 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2939147 infores:hetionet CHEBI:3732 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0002792 infores:hetionet CHEBI:50173 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0438215 infores:hetionet CAID:CA386952326 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952326 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS2, PM1_Supporting, PP4_Moderate PS4, PP3 The c.28A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to proline at codon 10 (p.(Thr10Pro)) of NM_000545.8. This variant is located within a conserved region of the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate; internal lab contributor). Lastly, this variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A (PS2; PMID:28701371). This variant has a REVEL score of 0.656, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:28701371, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP4_Moderate, PS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952326/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:37924 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042373 infores:hetionet CHEBI:6847 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0002874 infores:hetionet CHEBI:17026 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0041657 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151795 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0027765 infores:hetionet CHEBI:46295 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0014236 infores:hetionet CHEBI:31638 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0151825 infores:hetionet CHEBI:8772 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0021400 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0042109 infores:hetionet CHEBI:36704 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0870082 infores:hetionet CHEBI:73274 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0221201 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0039971 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0008370 infores:hetionet CHEBI:5383 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0221395 infores:hetionet CHEBI:64064 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C1142412 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0178298 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017574 infores:hetionet CHEBI:4672 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0043094 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007593 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0278151 infores:hetionet CAID:CA8603540 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603540 MONDO:0100326 PMID: Uncertain Significance BP4 PM2 The c.118A>G (p.Thr40Ala variant in ITGA2B is a missense variant predicted to cause substitution of threonine by alanine at amino acid 40 .It has been reported in ClinVar in association with possible Glanzmann Thrombastheina (affected status: unknown). After a thorough literature search, this variant was not found to be published in any patients with Glanzmann Thrombasthenia. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0002830 (334/1180028 alleles) in the European (non-Finnish) population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.232, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). In summary, this variant meets the criteria to be classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603540/MONDO:0100326/011 2024-10-15 2024-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true NCBIGene:60482 biolink:causes MONDO:0008024 infores:monarchinitiative not_provided not_provided HGNC:14025 MONDO:0008024 uuid:f33e7840-1720-4a9c-9bef-d26dd0868232 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes MONDO:0018874 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0023467 infores:hetionet CHEBI:41977 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0018799 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0001125 infores:hetionet CHEBI:28748 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019214 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0857807 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0857807 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151883 infores:hetionet CHEBI:9571 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0017979 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C2711227 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0027769 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0015397 infores:hetionet CHEBI:7466 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0042109 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020437 infores:hetionet CHEBI:2639 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0002170 infores:hetionet NCBIGene:4677 biolink:causes MONDO:0100348 infores:monarchinitiative not_provided not_provided HGNC:7643 MONDO:0100348 uuid:87b7629e-259f-49b9-8720-be169bf24dba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0700225 infores:hetionet CHEBI:3380 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C2047937 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0004936 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034065 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0574067 infores:hetionet CHEBI:4653 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0033774 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151883 infores:hetionet CHEBI:9241 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0156404 infores:hetionet CAID:CA271902 biolink:causes MONDO:0018947 infores:clingen CAID:CA271902 MONDO:0018947 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4, PP1_Moderate, PS3_Supporting BA1, BP4, BS1 The NM_000252.3:c.575A>G variant in MTM1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 192. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in 5 probands with centronuclear myopathy (PS4_Strong; PMID: 20434914, http://dx.doi:10.1016/j.nmd.2014.06.056, ClinVar SCV: SCV000634492.8, Invitae). The variant has been reported to segregate with X-linked centronuclear myopathy in at least 3 affected family members from 2 families (PP1_Moderate; http://dx.doi:10.1016/j.nmd.2014.06.056, ClinVar SCV: SCV000634492.8, Invitae). Myotubularin level was lower in cells from one patient compared to control. Semi-quantitative analysis compared to GAPDH level suggested a decrease of about 7 times compared to control (PS3_Supporting; PMID: 20434914). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA271902/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Supports CHEBI:15553 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0040046 infores:hetionet CHEBI:8435 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0018681 infores:hetionet CHEBI:5558 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0030232 infores:hetionet CHEBI:8356 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0023218 infores:hetionet CHEBI:10119 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015230 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0162429 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0858635 infores:hetionet CHEBI:71940 biolink:causes UMLS:C2242621 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C2242621 infores:hetionet CHEBI:28748 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020473 infores:hetionet GO:0008359 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0009790 CHEBI:9086 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0038663 infores:hetionet NCBIGene:4626 biolink:causes MONDO:0012137 infores:monarchinitiative not_provided not_provided HGNC:7578 MONDO:0012137 uuid:b7846f05-6d80-49c9-a055-13fc381b40c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0522224 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0232492 infores:hetionet CHEBI:6633 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0151773 infores:hetionet CHEBI:40279 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0043049 infores:hetionet UNII:7F465U79Q1 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0015376 infores:hetionet CHEBI:39112 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0542571 infores:hetionet CHEBI:8707 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085649 infores:hetionet CHEBI:71229 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0546817 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0314719 infores:hetionet CHEBI:3561 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020580 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042075 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0878544 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0031350 infores:hetionet CHEBI:63577 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0013604 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0025637 infores:hetionet CHEBI:63619 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C3665386 infores:hetionet NCBIGene:125150 biolink:causes MONDO:0030787 infores:monarchinitiative not_provided not_provided HGNC:26993 MONDO:0030787 uuid:bae0a4b2-1b8e-43d6-bbec-ad19796b6e58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7447 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C1565489 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0037274 infores:hetionet CHEBI:10023 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0234133 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0041582 infores:hetionet CHEBI:31711 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0423153 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0006325 infores:hetionet CHEBI:15544 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0023222 infores:hetionet CHEBI:3286 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0035357 infores:hetionet CHEBI:91834 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0040435 infores:hetionet CHEBI:4672 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0039070 infores:hetionet CHEBI:6690 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0429097 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0041912 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0343886 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042487 infores:hetionet GO:2001049 biolink:causes GO:0035989 infores:ubergraph knowledge_assertion manual_agent GO:2001049 GO:0035989 GO:0044468 biolink:causes GO:0007596 infores:ubergraph knowledge_assertion manual_agent GO:0044468 GO:0007596 CHEBI:119486 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0035078 infores:hetionet CHEBI:94440 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0040264 infores:hetionet CHEBI:52717 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034933 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0022116 infores:hetionet CHEBI:75246 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0236075 infores:hetionet CHEBI:8863 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0025222 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0424000 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0022904 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0267792 infores:hetionet CHEBI:2668 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C2129214 infores:hetionet CHEBI:64028 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0004134 infores:hetionet CHEBI:64310 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0023530 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0006444 infores:hetionet CHEBI:91541 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0231274 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0233472 infores:hetionet CHEBI:5864 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0302809 infores:hetionet CHEBI:8080 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0018790 infores:hetionet CHEBI:7565 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0025222 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0392386 infores:hetionet CHEBI:5134 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0006277 infores:hetionet CHEBI:16714 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0026837 infores:hetionet CHEBI:15367 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027424 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0235416 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0677500 infores:hetionet CHEBI:2379 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0030193 infores:hetionet CHEBI:64355 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042029 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085681 infores:hetionet CHEBI:3242 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013144 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0349506 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0221776 infores:hetionet CHEBI:15552 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0033774 infores:hetionet CHEBI:465284 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0030196 infores:hetionet CHEBI:4702 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0547030 infores:hetionet CHEBI:194135 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C3665347 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003864 infores:hetionet CHEBI:52717 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0236124 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0085606 infores:hetionet CHEBI:63791 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030554 infores:hetionet CHEBI:10023 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020443 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0153676 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0153676 infores:hetionet CHEBI:44915 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0003811 infores:hetionet NCBIGene:10565 biolink:causes MONDO:0859263 infores:monarchinitiative not_provided not_provided HGNC:15772 MONDO:0859263 uuid:b3bd4e52-d5ae-4429-9c88-47790675d18c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7465 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0236075 infores:hetionet CHEBI:77733 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0031256 infores:hetionet CHEBI:42797 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085583 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0011551 infores:hetionet CAID:CA288025 biolink:causes MONDO:0100488 infores:clingen CAID:CA288025 MONDO:0100488 PMID: Likely Benign BS2 BP5, BS1, BS4, BS3, PM6, PP3, PP1, BP2, BA1, PS4, PS2, PS3 The c.1273G>A (p.Val425Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 6 in 152,140 alleles in the gnomAD v3.1.2 population database. This variant was observed in a proband with oral clefting (PMID:27227907). However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288025/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:5383 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020625 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0178298 infores:hetionet CAID:CA10014632 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014632 MONDO:0011071 PMID: Likely Benign BP2, BS1 PS3, PS2, PS4, PS1, BP3, BP1, BP4, BA1, BP7, BP5, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1): c.82_84del (p.Ser28del) encodes an in-frame deletion of one amino acid in a non-repeat region, which does not affect a hotspot or critical residue (89-204) of the runt homology domain (PM4 not met). The highest population minor allele frequency in gnomAD v2 is 0.0004041 (10/24746 alleles) in the AFR population, which is higher than the allele frequency calculated based on the disease incidence (>0.00015) per the ClinGen Myeloid Malignancy VCEP (BS1). This variant has also been observed in one homozygous individual with no RUNX1-phenotypic features from the gnomAD v3 non-cancer/control/biobank cohort (BP2). Due to the high MAF, PS4 cannot be applied to probands meeting the phenotypic criteria (PS4_supporting not met). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BS1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014632/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6931 biolink:causes UMLS:C1096717 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C1096717 infores:hetionet CHEBI:4798 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0236075 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0008311 infores:hetionet CHEBI:50275 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0031345 infores:hetionet CHEBI:49375 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0003862 infores:hetionet CHEBI:50223 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0019080 infores:hetionet UNII:T58MSI464G biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0013604 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0917798 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015393 infores:hetionet CHEBI:7903 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0001824 infores:hetionet CHEBI:31174 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0085641 infores:hetionet CHEBI:83527 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0549622 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0232409 infores:hetionet NCBIGene:2259 biolink:causes MONDO:0008654 infores:monarchinitiative not_provided not_provided HGNC:3671 MONDO:0008654 uuid:8e1ba56c-c619-41ac-aced-21a76973e68d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0032708 infores:hetionet CHEBI:10102 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151315 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027726 infores:hetionet CHEBI:28830 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0042963 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0575090 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0277925 infores:hetionet CHEBI:31644 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013378 infores:hetionet CHEBI:53691 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0003460 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0023530 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0042109 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0476280 infores:hetionet CHEBI:135888 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0013404 infores:hetionet CAID:CA261726 biolink:causes MONDO:0018997 infores:clingen CAID:CA261726 MONDO:0018997 PMID:28378436PMID:26214590PMID:27236105PMID:21784453PMID:21387466PMID:29037749PMID:25337068PMID:21274610PMID:30266093PMID:26918529PMID:30266093PMID:26686981PMID:30266093PMID:26686981 Pathogenic PS3, PS4, PM1_Strong, PS2_Very Strong, PM2, PP3, PP2 PS1, BS4, BS3, BS1, BP7, BP5, PM5, PM4, PM6, BS2, PP1, BA1, BP3, BP2, BP4, BP1 The c.1655G>A (p.Arg552Lys) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837, 17143282, 30266093, 26686981). This variant has been detected in at least 7 independent occurrences with clinical features of a RASopathy (PS4; PMIDs: 17586837, 22420426, 28378436, 29037749, 25337068, 21387466, 21784453, 26918529, 21274610). In vitro functional studies provide some evidence that the p.Arg552Lys variant may impact protein function (PS3; PMID: 21784453). This residue has been defined as a PM1 hotspot by the RAS VCEP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg552Lys variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1_Strong, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261726/MONDO:0018997/004 2019-05-10 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63791 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0277925 infores:hetionet CHEBI:64312 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027066 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027765 infores:hetionet CHEBI:3568 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0043349 infores:hetionet CHEBI:94501 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0030193 infores:hetionet CHEBI:4315 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0152031 infores:hetionet CHEBI:46195 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C2242588 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0018965 infores:hetionet CHEBI:50922 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0016204 infores:hetionet CHEBI:30830 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0023218 infores:hetionet CHEBI:32139 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020621 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877096 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877096 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040046 infores:hetionet CHEBI:10101 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2584688 infores:hetionet CHEBI:3723 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013428 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0549418 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0392386 infores:hetionet CHEBI:50663 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0039070 infores:hetionet CHEBI:3636 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0037383 infores:hetionet CHEBI:8707 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002792 infores:hetionet GO:0035645 biolink:causes CL:0002504 infores:ubergraph knowledge_assertion manual_agent GO:0035645 CL:0002504 CHEBI:6741 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0019080 infores:hetionet CAID:CA000057 biolink:causes MONDO:0018875 infores:clingen CAID:CA000057 MONDO:0018875 PMID:15489903PMID:15489903 Benign BP4, BS2_Supporting, BS1 BA1, BP1, BP2, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BS3, BS4, PM2, PP2, PP3, PP1, PP4 The NM_000546.6: c.145G>C variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 49 (p.Asp49His). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). The filtering allele frequency is 0.0007696 in the East Asian population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644, 15489903, 12901974, 18199664). Computational predictor scores (BayesDel = -0.0307; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). This variant has been reported as a putative founder variant in the Japanese population (PMID: 27545002). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS1, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.1.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000057/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45863 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234913 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0020649 infores:hetionet CHEBI:75998 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0030305 infores:hetionet CAID:CA342004 biolink:causes MONDO:0019497 infores:clingen CAID:CA342004 MONDO:0019497 PMID: Uncertain Significance PS3_Moderate, PM3 BS1, PP3, PM2, BA1, BP4 The c.339T>G variant in GJB2 is a missense variant predicted to cause substitution of serine by arginine at amino acid 113. The highest population minor allele frequency in gnomAD v4.0.0 is 0.02% (7/26136 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL provides a score of 0.553 which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function (PP3 and BP4 are not met). An in vitro functional study performed in Xenopus oocytes showed that variant junctional conductance for p.Ser113Arg was similar to water (negative control), indicating a loss of function impact on protein function (PS3_Moderate; PMID:12505163). The p.Ser113Arg variant has been reported in several probands with hearing loss, including 3 individuals with a second pathogenic variant without phase confirmation (1.5 points, PM3, PMID: 15365987, 11439000, 9529365, 16380907, 24078562). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PS3_Moderate, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA342004/MONDO:0019497/005 2024-01-17 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:83804 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042023 infores:hetionet CAID:CA410147560 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147560 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM3, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.1270T>G (p.Ser424Ala) is a missense variant predicted to cause the substitution of serine by alanine at amino acid 424 (p.S424A). This variant is absent from gnomAD v2, but in gnomAD v3, the highest population minor allele frequency is 0.1702% (7/4114 alleles) in the South Asian population, and in gnomAD v4, it is 1.053% (255/24222 alleles) in the East Asian population. These frequencies are higher than the overall allele frequency of all disease-causing alleles derived by the ClinGen Myeloid Malignancy-VCEP. However, allele balance in gnomAD v3 and v4 is heavily skewed, and site quality appears lower compared to some common, known pathogenic variants (BA1 not met).Given the frequency in gnomAD, it is not surprising that this variant has been reported in several individuals with relevant phenotypes: a 32-year-old female with thrombocytopenia and a delayed secretion defect (PMID: 32935436), a Chinese patient with newly diagnosed AML (PMID: 34234861), and a Chinese infant with AML (PMID: 35814831). However, the confirmation status of the alteration and/or germline origin was not available for these cases, and the variant's presence in gnomAD precludes the use of PS4.Functional data exist for this variant, but it does not meet the criteria for established assays assessing RUNX1 function (PS3/BS3 not met). In vitro studies have demonstrated that Ser424 is a phosphorylation target of CDK/Cyclin complexes (PMID: 18003885). However, the S424A variant does not appear to impair transactivation, affect interaction with HDAC1, or alter levels of marrow progenitor proliferation compared to the wild type, although collective alterations at S48, S303, and S424 may impact this pathway (PMID: 18003885; PMID: 21059642). The computational predictor REVEL gives a score of 0.284, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, suggesting it does not predict a damaging effect on RUNX1 function (BP4).In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147560/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31174 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C1302752 infores:hetionet CHEBI:34385 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0027497 infores:hetionet CHEBI:9943 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0001925 infores:hetionet NCBIGene:79628 biolink:causes MONDO:0011113 infores:monarchinitiative not_provided not_provided HGNC:29427 MONDO:0011113 uuid:8d8259ec-6bb1-48be-9190-6b41f571640f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018939 infores:hetionet CHEBI:2654 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0013144 infores:hetionet CHEBI:8356 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0700361 infores:hetionet CHEBI:5118 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1456784 infores:hetionet CAID:CA405655316 biolink:causes MONDO:0018493 infores:clingen CAID:CA405655316 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, BP4 PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with valine at codon 1814 of the RYR1 protein, p.(Met1814Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.486) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405655316/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9907 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0268000 infores:hetionet CHEBI:31401 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0033774 infores:hetionet CHEBI:7903 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0037763 infores:hetionet CHEBI:75998 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C2979982 infores:hetionet CHEBI:66899 biolink:causes UMLS:C1142111 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C1142111 infores:hetionet CHEBI:3749 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0027796 infores:hetionet CAID:CA7623922 biolink:causes MONDO:0021060 infores:clingen CAID:CA7623922 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.438+8A>T variant in the MAP2K1 gene is 0.075% (19/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7623922/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA349036836 biolink:causes MONDO:0100038 infores:clingen CAID:CA349036836 MONDO:0100038 PMID: Likely Pathogenic PP3_Moderate, PM5_Supporting, PM6, PM2_Supporting The c.4782G>T variant in SCN2A is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 1594 (p.Trp1594Cys). The variant has been identified in multiple individuals meeting criteria for complex neurodevelopmental disorder (PM6)(PMID: 35365919, 23603762). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.924, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. The same amino acid change (p.Trp1594Cys), resulting from a different nucleotide change [c.4782G>C] (PMID: 34004075, internal lab contributors) is classified as likely pathogenic for complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP. Additionally, another missense variant in the same codon c.4780T>A, p.Trp1594Arg reaches likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; November 26, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA349036836/MONDO:0100038/068 2024-11-26 2025-02-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50861 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0040046 infores:hetionet CHEBI:7915 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017168 infores:hetionet CHEBI:144093 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0016658 infores:hetionet CL:0000766 biolink:causes GO:0002444 infores:ubergraph knowledge_assertion manual_agent CL:0000766 GO:0002444 CHEBI:9757 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0085636 infores:hetionet CHEBI:64355 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151878 infores:hetionet CHEBI:64354 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0022354 infores:hetionet CHEBI:63630 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003578 infores:hetionet CHEBI:6931 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0013144 infores:hetionet CHEBI:44915 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0018790 infores:hetionet CHEBI:31705 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C2047937 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0085740 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085740 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0853813 infores:hetionet CHEBI:44185 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0003862 infores:hetionet CHEBI:83531 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0344232 infores:hetionet CHEBI:8884 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0015230 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0027059 infores:hetionet CAID:CA205378 biolink:causes MONDO:0010726 infores:clingen CAID:CA205378 MONDO:0010726 PMID: Likely Benign BP4, BP7, BS1 The allele frequency of the c.714G>A p.Gly238= variant in MECP2 is 0.008% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Gly238= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.714G>A p.Gly238= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA205378/MONDO:0010726/032 2023-06-15 2023-06-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:140621 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0270611 infores:hetionet NCBIGene:80025 biolink:causes MONDO:0009319 infores:monarchinitiative not_provided not_provided HGNC:15894 MONDO:0009319 uuid:2c64ace0-5009-492c-b58d-d1f28a0157e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0036508 infores:hetionet CHEBI:41774 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0029927 infores:hetionet CHEBI:8364 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0013404 infores:hetionet CHEBI:10102 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0003862 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0037274 infores:hetionet CAID:CA16020750 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020750 MONDO:0009861 PMID:26503515PMID:25456745 Likely Pathogenic PM5, PM2, PP4_Moderate PP3 The c.224A>G (p.Asp75Gly) variant in PAH is reported in 1 Chinese PKU patient. BH4 deficiency was assessed. (PMID: 26503515) It is absent from ExAC, gnomAD, 1000G, and ESP. Computational evidence is conflicting. Another missense change at this amino acid is interpreted as likely pathogenic by our PAH VCEP, c.224A>T (p.Asp75Val). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020750/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports UNII:Y2V2R4W9TQ biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0002064 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042571 infores:hetionet CHEBI:3219 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011606 infores:hetionet CL:0002328 biolink:causes MONDO:0002806 infores:ubergraph knowledge_assertion manual_agent CL:0002328 MONDO:0002806 CHEBI:6931 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0025061 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0015397 infores:hetionet CHEBI:2453 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0259799 infores:hetionet CHEBI:8207 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0003467 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0006849 infores:hetionet CHEBI:60761 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0040034 infores:hetionet CHEBI:6950 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151904 infores:hetionet CAID:CA16041881 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041881 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.281_282del (p.Pro94ArgfsTer51) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 370458). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041881/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ UNII:Z5N076G8YQ biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0043352 infores:hetionet CHEBI:52010 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0003467 infores:hetionet CHEBI:204928 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0015967 infores:hetionet CAID:CA367401902 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401902 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.464G>C variant in the glucokinase gene, GCK, causes an amino acid change of arginine to threonine at codon 155 (p.(Arg155Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.814, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.465G>T p.(Arg155Ser), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative ) (PP4_Moderate; PMID: 19410318). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:19410318​, ClinVar). In summary, c.464G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PM5_Supporting, PP3, PP2, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401902/MONDO:0015967/086 2024-04-19 2024-04-19 Semidominant inheritance HP:0032113 Supports CHEBI:9654 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0156404 infores:hetionet CAID:CA367398995 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398995 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting PP4 The c.1099G>T variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 367 (p.(Val367Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.813, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1099G>A p.(Val367Met), has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Val367Leu has a greater Grantham distance (PM5). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0 approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398995/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:3077 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0009763 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0002871 infores:hetionet CHEBI:2904 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C1443060 infores:hetionet CHEBI:135876 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0232726 infores:hetionet CHEBI:6062 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0037317 infores:hetionet CHEBI:3172 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0023380 infores:hetionet CHEBI:6375 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018681 infores:hetionet CHEBI:135920 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0151662 infores:hetionet CHEBI:3504 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0013378 infores:hetionet CHEBI:7492 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0012833 infores:hetionet CHEBI:8874 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0028734 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0009450 infores:hetionet CHEBI:23765 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0005741 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0022660 infores:hetionet CHEBI:9671 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0242528 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0009806 infores:hetionet CHEBI:6710 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0009806 infores:hetionet CAID:CA019962 biolink:causes MONDO:0005045 infores:clingen CAID:CA019962 MONDO:0005045 PMID: Likely Pathogenic PM2_Supporting, PP3, PS4_Moderate, PP1_Moderate PM1, PP2, BP1, BP4, BA1, BS1, BS4 NM_005159.5(ACTC1):c.850A>T (p.Ile284Phe) - This variant has been identified in individuals with HCM as well as other cardiomyopathies (deciphergenomics.org, OMGL data, PMID 27532257) and is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criteria has been applied. This variant segregated with disease in 3 affected relatives with HCM in 3 families and 3 affected relatives with DCM/LVNC in one family (UK Laboratories; PP1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). Therefore, this variant is classified as Likely Pathogenic for HCM in an autosomal dominant manner based on PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA019962/MONDO:0005045/101 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63631 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018965 infores:hetionet CHEBI:3011 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0020458 infores:hetionet GO:0141069 biolink:causes GO:0007165 infores:ubergraph knowledge_assertion manual_agent GO:0141069 GO:0007165 CAID:CA229826 biolink:causes MONDO:0009861 infores:clingen CAID:CA229826 MONDO:0009861 PMID:14722928PMID:14722928PMID:24401910 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS3 The c.856G>A (p.Glu286Lys) variant in PAH is present with low frequency in population databases (1.2e-4), and is predicted to be deleterious using in silico algorithms. It has been identified in trans with pathogenic variants in two independent patients (R243Q, R241C), and has been identified in a patients with Phenylketonuria in which a defect in BH4 metabolism has been excluded (PMID: 14722928, 24401910). Enzyme activity has been measured as 1% of wild type controls (BioPKU). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PS3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229826/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:553473 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0836924 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020517 infores:hetionet CHEBI:38562 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0042029 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0011551 infores:hetionet CHEBI:23765 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0231530 infores:hetionet CHEBI:51230 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0271051 infores:hetionet CHEBI:47780 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0558489 infores:hetionet CHEBI:134745 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0015672 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0553548 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0019360 infores:hetionet CHEBI:9763 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0018524 infores:hetionet CHEBI:8707 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0086439 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0008031 infores:hetionet CHEBI:31980 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0007859 infores:hetionet CHEBI:6413 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0042487 infores:hetionet CHEBI:4798 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0011168 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0009450 infores:hetionet CHEBI:681569 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0039231 infores:hetionet CAID:CA410202774 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202774 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM5, PM4, PM3, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.361C>A (p.Leu121Ile) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases (gnomAD v3) with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202774/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135888 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C1527358 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0040034 infores:hetionet NCBIGene:133396 biolink:causes MONDO:0013502 infores:monarchinitiative not_provided not_provided HGNC:18969 MONDO:0013502 uuid:107c8348-2aa0-4592-a861-2b0f949e252b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68584 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0013395 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011615 infores:hetionet CHEBI:194135 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013456 infores:hetionet CHEBI:68579 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151754 infores:hetionet CHEBI:80630 biolink:causes NCIT:C180702 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0312422 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0020538 infores:hetionet CHEBI:47381 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0027497 infores:hetionet CHEBI:36704 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0004604 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020621 infores:hetionet CHEBI:3568 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0019080 infores:hetionet CAID:CA6832194 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832194 MONDO:0015967 PMID: Uncertain Significance BP4, BS1, PM2, PP4, PP3 The c.1778G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 593 (p.(Ser593Thr)) of NM_000545.8. The Grpmax filtering allele frequency of the c.1778G>C variant in gnomAD v4.1.0 is 0.00003549, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. Additionally, this variant has a REVEL score of 0.3129, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to the age of diagnosis over 35 yo (internal lab contributors). In summary, c.1778G>A meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): None. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832194/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17303 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0006145 infores:hetionet CHEBI:15367 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C3665347 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0151838 infores:hetionet CHEBI:465284 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0025222 infores:hetionet CHEBI:70746 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0019079 infores:hetionet CAID:CA377482091 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482091 MONDO:0017623 PMID:29706350 Likely Pathogenic PP2, PP3, PM2_Supporting, PS3_Moderate, PM5, PM1 NM_000314.8(PTEN):c.278A>C (p.His93Pro) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_Moderate: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.95 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7848, SCV000886857.1). PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant =0.974). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482091/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5855 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1287298 infores:hetionet CHEBI:34385 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0015230 infores:hetionet CHEBI:10127 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C2047937 infores:hetionet CHEBI:45409 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0032617 infores:hetionet CHEBI:175901 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0004509 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0014868 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0267596 infores:hetionet CHEBI:3216 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0000731 infores:hetionet CHEBI:75722 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085631 infores:hetionet CHEBI:7478 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0424295 infores:hetionet CHEBI:9241 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0041582 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0851341 infores:hetionet CHEBI:5138 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042384 infores:hetionet CHEBI:50173 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0149745 infores:hetionet CHEBI:3061 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0232462 infores:hetionet NCBITaxon:5037 biolink:causes MONDO:0005249 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5037 MESH:D011014 DB00681_MESH_D011014_1 CHEBI:31980 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0231528 infores:hetionet CHEBI:85161 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0013378 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0029134 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0036572 infores:hetionet CAID:CA392255072 biolink:causes MONDO:0012996 infores:clingen CAID:CA392255072 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4 PM5 The NM_001482.3:c.1162A>G variant in GATM is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 388 (p.Ile388Val). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. The highest population minor allele frequency in gnomAD v4.1.0 is 8.700e-7 (1/1149438 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.131 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 654184). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA392255072/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45367 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0852911 infores:hetionet CHEBI:3996 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0151596 infores:hetionet CAID:CA14885658 biolink:causes MONDO:0011071 infores:clingen CAID:CA14885658 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP5, PVS1, BS1, BS3, BS4, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.508+259C>T is an intronic variant with a MAF of 0.2807 (28.07%, 2440/8694,) in the African/African American subpopulation of gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). This variant is observed in 942 homozygotes in a population database (gnomAD) (BP2). This intronic variant has a SpliceAI score ≤ 0.20 (Acceptor Loss 0.0) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.65 < 2.0) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA14885658/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:34967 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0236075 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0948594 infores:hetionet CHEBI:51041 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0013491 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0032326 infores:hetionet CHEBI:31397 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C1260880 infores:hetionet CHEBI:45924 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0085932 infores:hetionet CHEBI:204928 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C2047937 infores:hetionet CHEBI:17688 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0037383 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0948586 infores:hetionet CHEBI:27446 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0151596 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020433 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0039971 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0548823 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0687133 infores:hetionet CHEBI:78543 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0023380 infores:hetionet CHEBI:6887 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0040460 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042109 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002021 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0017563 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0175167 infores:hetionet CHEBI:44032 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027121 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0855775 infores:hetionet CHEBI:31980 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0003811 infores:hetionet CHEBI:7496 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0085631 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0151773 infores:hetionet CHEBI:64355 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0424790 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0020538 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005311 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0004153 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0234215 infores:hetionet CHEBI:6715 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0004604 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0017152 infores:hetionet CHEBI:3077 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0221166 infores:hetionet CHEBI:31397 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0013395 infores:hetionet CHEBI:4466 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0004144 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0948089 infores:hetionet CHEBI:4551 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0015230 infores:hetionet CAID:CA367398751 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398751 MONDO:0015967 PMID: Pathogenic PS4, PM5, PP1, PP2, PP3, PP4, PM2_Supporting The c.1145G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 382 (p.(Cys382Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.922 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in the homozygous state in three individuals with neonatal diabetes and negative testing for ABCC8, KCNJ11, and INS (internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 1 family with MODY (PP1; internal lab contributors). Another missense variant, c.1144T>C p.Cys382Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Cys382Tyr has a greater Grantham distance (PM5). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Zubkova N.A et al, World J PM. 2017;1(1):40-48, https://doi.org/10.14341/WJPM9298, internal lab contributors). In summary, c.1145G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PP1, PP2, PP3, PM2_Supporting, PM5, PP4, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398751/MONDO:0015967/086 2023-07-16 2023-07-16 Semidominant inheritance HP:0032113 Supports CHEBI:45716 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0700225 infores:hetionet CAID:CA10581258 biolink:causes MONDO:0044970 infores:clingen CAID:CA10581258 MONDO:0044970 PMID: Uncertain Significance BP4 PS4, PS3, PM2 The m.8704A>G (p.M60V) variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on September 26, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.039%, 24/61,883; gnomAD v3.1.2: 0.023%, 13/56,434 homoplasmic occurrences; Helix: 0.009%, 18/195,893 homoplasmic occurrences in addition to three heteroplasmic occurrences). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.37 (Min=0, Max=1), which predicts no effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581258/MONDO:0044970/015 2023-09-26 2025-06-04 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8107 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0023518 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0032961 infores:hetionet NCBIGene:55149 biolink:causes MONDO:0013354 infores:monarchinitiative not_provided not_provided HGNC:25532 MONDO:0013354 uuid:59f2b8ba-0405-4b47-a6d0-7bc5f0703ea9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0863112 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0863112 infores:hetionet CHEBI:32184 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C1325847 infores:hetionet CHEBI:68478 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027796 infores:hetionet CHEBI:28787 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0340865 infores:hetionet CHEBI:15854 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0151766 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0027651 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001833 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0022906 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151883 infores:hetionet CHEBI:31536 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0041969 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0314719 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0267792 infores:hetionet CHEBI:6633 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0030312 infores:hetionet CHEBI:114785 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0038325 infores:hetionet CHEBI:6121 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0344232 infores:hetionet CHEBI:63631 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0424109 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0156384 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0156384 infores:hetionet CHEBI:31644 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0004604 infores:hetionet CHEBI:8461 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0007398 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040586 infores:hetionet NCBIGene:7466 biolink:causes MONDO:0010963 infores:monarchinitiative not_provided not_provided HGNC:12762 MONDO:0010963 uuid:83fb76e7-2d52-48e1-9675-4c27a053b79d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50841 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0686347 infores:hetionet CHEBI:4708 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0035243 infores:hetionet CHEBI:4562 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0033774 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C2242737 infores:hetionet CHEBI:17549 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0007114 infores:hetionet CAID:CA229325 biolink:causes MONDO:0009861 infores:clingen CAID:CA229325 MONDO:0009861 PMID: Uncertain Significance PM2 PP3 The c.1066T>C (p.Tyr356His variant in PAH has been not reported in a patient with PAH deficiency (to our knowledge). It was reported to the BioPKU database by Tyfield in 1996. This variant has an extremely low frequency in gnomAD (MAF=0.00016). There are conflicting interpretations of pathogenicity: SIFT (T); PolyPhen2 (P); MutationTaster (D); REVEL=0.794. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229325/MONDO:0009861/006 2019-12-22 2021-05-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8207 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0007859 infores:hetionet CHEBI:94848 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0085631 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0162429 infores:hetionet CHEBI:68478 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018965 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015397 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0520806 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0037274 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0039446 infores:hetionet CHEBI:125354 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0917801 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0858738 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0858738 infores:hetionet CAID:CA023475 biolink:causes MONDO:0007750 infores:clingen CAID:CA023475 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Strong, PM2, PP4 BA1, BP4, BP2, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP3, BS2 The NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: MAF= 0.00002331 (0.002331%) in European (Non-Finnish) exomes (gnomAD v4.0.0).PS4_Supporting, PP4: Three unrelated index cases fulfill FH criteria, reported in PMID 23815734 (Mollaki et al., 2013 - Greece) and 16465405 (Cefalù et al., 2006 - Italy).PP1_Strong: Variant segregates with phenotype in 8 informative meiosis from 3 families, affected relatives tested positive for the variant, reported in PMID 23815734 and 16465405. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023475/MONDO:0007750/013 2024-02-23 2025-02-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:4027 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0152227 infores:hetionet CHEBI:51450 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0017168 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020649 infores:hetionet NCBIGene:5745 biolink:causes MONDO:0007434 infores:monarchinitiative not_provided not_provided HGNC:9608 MONDO:0007434 uuid:3774fc98-9ec6-4aba-8f58-64dc3db2593d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0002450 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0520477 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0002170 infores:hetionet CHEBI:92923 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0030554 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0031039 infores:hetionet CHEBI:2567 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0000731 infores:hetionet CAID:CA2573132570 biolink:causes MONDO:0100368 infores:clingen CAID:CA2573132570 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1501_1505del (p.Tyr501ProfsTer10) is a frameshift variant in RPE65 that creates a premature translational stop codon in exon 14 of 14 and is predicted not to trigger nonsense-mediated decay but rather to C-terminally truncate the protein product before position 528, disrupting functionally critical residues required for the active site (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinal dystrophy with onset before age 2 years (1 pt), genotyping by targeted exome sequencing of 126 retinal genes without identifying an alternative cause of disease (2 pts), visual impairment (1 pt), night blindness (0.5 pts), tapetoretinal degeneration of the fundus with attenuated retinal vessels (0.5 pts), and extinguished ERG responses from rods (0.5 pts) and cones (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 31273949, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PSV1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573132570/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6062 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0003811 infores:hetionet CHEBI:5893 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0344232 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0010692 infores:hetionet CHEBI:9168 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0003962 infores:hetionet CHEBI:15940 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0162834 infores:hetionet CHEBI:63620 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0392525 infores:hetionet CHEBI:79699 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0029163 infores:hetionet CHEBI:46195 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C2830004 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0037199 infores:hetionet CHEBI:8665 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C1504494 infores:hetionet CHEBI:6532 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0043352 infores:hetionet CAID:CA8602787 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602787 MONDO:0100326 PMID: Benign BP7, BP4, BA1 After a comprehensive literature search of the intronic variant NM_000419.5(ITGA2B):c.2188-7C>G, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.4311 (6420/14892 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets benign criterion (BA1). In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of 0.287 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602787/MONDO:0100326/011 2023-09-07 2023-09-21 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:41423 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0039231 infores:hetionet CHEBI:15553 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0031542 infores:hetionet CHEBI:2788 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0009763 infores:hetionet NCBIGene:6770 biolink:causes MONDO:0008725 infores:monarchinitiative not_provided not_provided HGNC:11359 MONDO:0008725 uuid:254ecb8b-46ab-4812-a633-f283ad9589c3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0456909 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0235146 infores:hetionet CHEBI:45863 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0428977 infores:hetionet CHEBI:175901 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1262013 infores:hetionet NCBIGene:23308 biolink:causes MONDO:0970993 infores:monarchinitiative not_provided not_provided HGNC:17087 MONDO:0970993 uuid:ae799882-68ed-444c-9941-0d0b741d5af5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042109 infores:hetionet CHEBI:3504 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0013428 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0853760 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0267596 infores:hetionet CHEBI:10102 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0231218 infores:hetionet CHEBI:8764 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C2979982 infores:hetionet CHEBI:3207 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0016658 infores:hetionet CHEBI:27834 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0004096 infores:hetionet CHEBI:231425 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020461 infores:hetionet CHEBI:47780 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0009763 infores:hetionet CAID:CA902351 biolink:causes MONDO:0100368 infores:clingen CAID:CA902351 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting BA1, BS1 NM_000329.3(RPE65):c.886dup (p.Arg296fs) is a frameshift variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). At least 3 affected patients have been reported harboring this variant (PMID: 20683928, PMID: 28838317, PMID: 26906952). 1 affected patient harbors p.Arg296fs confirmed in trans with c.11+5G>A, which has been classified Pathogenic by this VCEP (PMID: 20683928, ClinVar ID: 98825, PM3), while a second affected patient harbors this variant in the homozygous state (PMID: 28838317). At least 1 of these patients harboring the variant exhibits an undetectable electroretinogram responses from rods (0.5 pts) and cones (1 pt) with infantile onset (1 pt), nystagmus (1 pt), and reduced visual acuity (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 pts total, PMID: 20683928, PP4). The GrpMax Filtering AF for this variant in gnomAD v2.1.1 is 0.00001082 in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, PP4, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902351/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31932 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0549373 infores:hetionet GO:2000266 biolink:causes GO:0072378 infores:ubergraph knowledge_assertion manual_agent GO:2000266 GO:0072378 CHEBI:17347 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0549433 infores:hetionet CHEBI:2668 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0022408 infores:hetionet CHEBI:5109 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0271738 infores:hetionet CHEBI:101278 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151825 infores:hetionet CHEBI:2208 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0017178 infores:hetionet CHEBI:63598 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0238106 infores:hetionet CHEBI:253342 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0038990 infores:hetionet CHEBI:3441 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C1306341 infores:hetionet CHEBI:2948 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0267792 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0000833 infores:hetionet CHEBI:5296 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0853034 infores:hetionet CHEBI:17630 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0028961 infores:hetionet CHEBI:63611 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023380 infores:hetionet CAID:CA359426752 biolink:causes MONDO:0012163 infores:clingen CAID:CA359426752 MONDO:0012163 PMID: Uncertain Significance PM2_Supporting NM_002185.5(IL7R):c.135G>C is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 45 (p.Gln45His). The variant is only reported in bottleneck population i.e. Middle Eastern in gnomAD v4 in which the minor allele frequency is 0.0001650 (1/6060) (PM2_Supporting). Another missense variant NM_002185.5(IL7R):c.134A>C (p.Gln45Pro) in the same codon has been reported (PM5 not evaluated).To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359426752/MONDO:0012163/119 2024-06-17 2024-06-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:71940 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0231528 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0030312 infores:hetionet CHEBI:6539 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0040822 infores:hetionet CHEBI:63613 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0232462 infores:hetionet CHEBI:9139 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0600142 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151970 infores:hetionet CHEBI:44915 biolink:causes MONDO:0100086 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0270075 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0860871 infores:hetionet CHEBI:15544 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0030193 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0003123 infores:hetionet NCBIGene:2720 biolink:causes MONDO:0009260 infores:monarchinitiative not_provided not_provided HGNC:4298 MONDO:0009260 uuid:58f6f84f-5bbd-4218-8f07-bca3d0108c5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412744915 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744915 MONDO:0100437 PMID:19815619PMID:19815619 Likely Pathogenic PP3_Strong, PM2_Supporting, PS4_Supporting, PM5 PP4, PS3, BS3 NM_001034853.2(RPGR):c.494G>T (p.Gly165Val) is a missense variant causing substitution of glycine by valine at amino acid 165. Another missense variant in the same codon, NM_001034853.2(RPGR):c.494G>A (p.Gly165Asp), has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (109) than the comparison variant (94), and SpliceAI has been used to confirm that neither variant has a predicted impact on RPGR splicing (PM5_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 34745198, PMID: 31630094, PS4_Supporting). The computational predictor REVEL gives a score of 0.982, which is above the ClinGen X-linked IRD VCEP threshold of ≥ 0.932 and predicts a damaging effect on RPGR function (PP3_Strong). The splicing predictor SpliceAI gives a delta score of 0.06 for splice donor loss, which is lower than the threshold of >0.2 and does not strongly predict a disruption of splicing. Injection of human RPGR mRNA harboring the variant into zebrafish embryos rescued ciliary defects associated with rpgr silencing comparably to wild-type RPGR (PMID: 19815619). However, the BS3_Supporting code is not considered applicable for RPGR. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP3_Strong, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744915/MONDO:0100437/106 2025-09-07 2025-09-08 X-linked inheritance HP:0001417 Supports CHEBI:9123 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011124 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0030305 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0009760 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0178298 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018799 infores:hetionet CHEBI:3082 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0039231 infores:hetionet CHEBI:28445 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0025323 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0425481 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0425481 infores:hetionet CHEBI:44032 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0015644 infores:hetionet NCBIGene:10472 biolink:causes MONDO:0012869 infores:monarchinitiative not_provided not_provided HGNC:13030 MONDO:0012869 uuid:f0e95889-626d-4054-b1fd-1b384effe36f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0392171 infores:hetionet CHEBI:7824 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0024141 infores:hetionet CHEBI:6838 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0039231 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0221752 infores:hetionet CHEBI:8212 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0151564 infores:hetionet CAID:CA10014366 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014366 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP3, BP2, BP1, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.728C>T (p.Pro243Leu) is a missense variant which has a REVEL score of 0.439, which is less than 0.50, and a SpliceAI score of ≤ 0.20 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014366/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31705 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0033774 infores:hetionet CHEBI:94411 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0002792 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004766 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0038218 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0026857 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C2973529 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0235431 infores:hetionet CHEBI:3181 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0009806 infores:hetionet CAID:CA023592 biolink:causes MONDO:0007750 infores:clingen CAID:CA023592 MONDO:0007750 PMID: Uncertain Significance PP1 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP2, PP3, PP4 The NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - 2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023592/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6367 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0497156 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0948595 infores:hetionet CHEBI:38562 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0003811 infores:hetionet CHEBI:7936 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039239 infores:hetionet CAID:CA913169952 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169952 MONDO:0044970 PMID:15591266PMID:20022607 Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6_Supporting, PS3_Supporting The m.12276G>A variant in MT-TL2 has been reported in four unrelated individuals with primary mitochondrial disease. Chronic progressive external ophthalmoplegia and myopathy were seen in three cases (PMIDs: 15649400, 15591266, 23847141), and two of these cases had pigmentary retinopathy (PMIDs: 15649400, 23847141). The fourth case had a progressive encephalopathy (PMID: 20022607). Muscle biopsies in affected individuals showed ragged red fibers, COX-negative fibers, and normal to reduced respiratory chain enzyme activities. Heteroplasmy levels were consistently highest in muscle, ranging from 18-81%, and were low (6-8%) to undetectable in other tissues (PS4_moderate, PMIDs: 15649400, 15591266, 23847141, 20022607). The variant was confirmed to have occurred de novo in one of the reported individuals (variant absent in blood and urine of healthy mother and sister, PMID: 20022607; PM6_supporting). There are no large families reported in the medical literature with testing performed to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic (74.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). This variant is absent in the Helix dataset and gnomAD v3.1.2, and the single occurrence in the GenBank dataset is from an affected individual (PM2_supporting). Single fiber testing was performed in two of the four reported cases (PS3_supporting). In one case, fibers with <75% of the variant exhibited normal COX/SDH ratios and fibers with 80% or higher had severe deficiency of COX activity (PMID: 15591266). In another individual (PMID: 20022607), COX-deficient fibers had ~80% heteroplasmy and COX-positive fibers had ~25% heteroplasmy, a statistically significant difference (p<0.001). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169952/MONDO:0044970/015 2022-11-30 2023-01-10 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:75722 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233494 infores:hetionet GO:1902490 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1902490 GO:0019953 CHEBI:72564 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0026848 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2711227 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0152008 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0152008 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0151826 infores:hetionet CHEBI:64064 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0003811 infores:hetionet CAID:CA10585743 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585743 MONDO:0007750 PMID: Pathogenic PP1_Strong, PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP2, BS2 NM_000527.5(LDLR):c.2043C>G (p.Cys681Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM1, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_strong - Variant segregates with FH phenotype in 7 informative meioses in 1 family from PMID: 16092059.PM1 - Variant meets PM2 and is one of listed Cysteine. PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1).PP3 - REVEL: 0,83. PP4 - Variant meet PM2. PMID: 16092059 - 1 case who fulfills Simon-Broome criteria for FH. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585743/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:39112 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0015672 infores:hetionet CHEBI:4708 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0600142 infores:hetionet CHEBI:135939 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0027947 infores:hetionet CHEBI:5118 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151825 infores:hetionet CHEBI:63629 biolink:causes MONDO:0044872 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013363 infores:hetionet CHEBI:63608 biolink:causes HP:0000255 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0149512 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0022650 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0025061 infores:hetionet CHEBI:31236 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085593 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0277925 infores:hetionet CHEBI:63580 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0022346 infores:hetionet CHEBI:8869 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0021368 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C1971624 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0037274 infores:hetionet CHEBI:6717 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0041582 infores:hetionet CHEBI:36795 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1322281 infores:hetionet CHEBI:42820 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0027497 infores:hetionet CHEBI:7865 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0039070 infores:hetionet CHEBI:8802 biolink:causes HP:0003111 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1704431 infores:hetionet CAID:CA8337734 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337734 MONDO:0008723 PMID: Benign BA1 BP4 The c.478-22_478-21del variant in ACADVL is an intronic variant which occurs in intron 6. The highest population minor allele frequency in gnomAD v2.1.1 is 0.2253 in the African population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from in silico splicing predictors (SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337734/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Contradicts true NCBITaxon:3110 biolink:causes MONDO:0700045 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:3110 MONDO:0700045 CHEBI:44032 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0856151 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0040409 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0015397 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0521591 infores:hetionet CHEBI:3698 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0013378 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0340464 infores:hetionet CHEBI:31401 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C1142412 infores:hetionet CAID:CA016087 biolink:causes MONDO:0005021 infores:clingen CAID:CA016087 MONDO:0005021 PMID:19477645 Likely Pathogenic PM6, PM2, PP3, PS4_Supporting The c.5401G>A (p.Glu1801Lys) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy, one of whom had additional myopathy features (PS4_Supporting; PMID:19477645; Partners LMM ClinVar SCV000059616.5). Additionally, in two of the probands with dilated cardiomyopathy, the variant occurred de novo (PM6; Partners LMM ClinVar SCV000059616.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM6; PP3; PS4_ Supporting Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016087/MONDO:0005021/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports GO:0033132 biolink:causes GO:0051156 infores:ubergraph knowledge_assertion manual_agent GO:0033132 GO:0051156 CHEBI:5141 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0042963 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0003123 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0003123 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0007971 infores:hetionet CHEBI:6067 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0043144 infores:hetionet CHEBI:31236 biolink:causes NCIT:C121574 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1504561 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0005940 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0041912 infores:hetionet CHEBI:6690 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0392156 infores:hetionet CAID:CA397724272 biolink:causes MONDO:0008723 infores:clingen CAID:CA397724272 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting The NM_000018.4: c.1064T>C (p.Ile355Thr) in ACADVL is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 355 (p.Ile355Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000013 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been reported in the literature in three patients with an abnormal newborn screen who are apparently heterozygous carriers for the variant (PMID: 26385305), but this information is insufficient to use toward classification. The computational predictor REVEL gives a score of 0.65, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724272/MONDO:0008723/021 2024-09-24 2024-10-02 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6715 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0424605 infores:hetionet CHEBI:584020 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0039231 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0010823 infores:hetionet CHEBI:52172 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0086565 infores:hetionet CAID:CA10641190 biolink:causes MONDO:0015967 infores:clingen CAID:CA10641190 MONDO:0015967 PMID: Likely Benign BP4, BS1 BP7, PM2 The c.30G>A variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 10 (p.Thr10=) of NM_000545.8. This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00006311, which is greater than the ClinGen MDEP threshold for BS1 (0.000033) (BS1). This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) (BP4). This synonymous variant is not predicted by SpliceAI to impact splicing, but it is conserved with phyloP100way = 2.835 > 2; therefore, BP7 does not apply. In summary, c.30G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10641190/MONDO:0015967/017 2025-08-29 2025-08-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6710 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0009319 infores:hetionet CHEBI:6933 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0018681 infores:hetionet CHEBI:63632 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0013390 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0027441 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0027947 infores:hetionet NCBIGene:4131 biolink:causes MONDO:0030723 infores:monarchinitiative not_provided not_provided HGNC:6836 MONDO:0030723 uuid:96b81ed7-18bc-4103-a46b-26688b9fc54d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0038358 infores:hetionet CHEBI:42068 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0236075 infores:hetionet CHEBI:15765 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0030554 infores:hetionet CHEBI:204734 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0162820 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0854382 infores:hetionet NCBIGene:2629 biolink:causes MONDO:0009265 infores:monarchinitiative not_provided not_provided HGNC:4177 MONDO:0009265 uuid:6864196e-5fb2-49a9-b37f-0ce688bf2d86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48669 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0004604 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0948294 infores:hetionet CHEBI:48273 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0151786 infores:hetionet CAID:CA229622 biolink:causes MONDO:0009861 infores:clingen CAID:CA229622 MONDO:0009861 PMID:28982351PMID:18956252PMID:23074961PMID:28982351PMID:18956252 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong BP4, BA1, BS1 The PAH: c.559T>C (p.Trp187Arg) variant was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg allele, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (BH4 deficiency excluded. PP4_moderate. PMID: 28982351). The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is predicted damaging by multiple lines of computational evidence: SIFT, Polyphen2, Mutation Taster, REVEL = 0.918 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229622/MONDO:0009861/006 2018-12-11 2019-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8060 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0234215 infores:hetionet CHEBI:4562 biolink:causes HP:0001686 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0003564 infores:hetionet CHEBI:9139 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035078 infores:hetionet CHEBI:6538 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0037274 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0003123 infores:hetionet CHEBI:53691 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0013378 infores:hetionet CHEBI:4708 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0086439 infores:hetionet CHEBI:2904 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0030554 infores:hetionet CHEBI:52717 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1527344 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0235567 infores:hetionet CHEBI:8707 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C2979982 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0100338 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D014552 DB06799_MESH_D014552_1DB00595_MESH_D014552_1DB01139_MESH_D014552_1DB01326_MESH_D014552_1DB01602_MESH_D014552_1DB00618_MESH_D014552_1DB01328_MESH_D014552_1DB00456_MESH_D014552_1DB13092_MESH_D014552_1DB01060_MESH_D014552_1DB01333_MESH_D014552_1DB01000_MESH_D014552_1DB00199_MESH_D014552_1 CHEBI:50861 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0015230 infores:hetionet CHEBI:101278 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0001824 infores:hetionet CHEBI:3756 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0004134 infores:hetionet NCBITaxon:485 biolink:causes MONDO:0003619 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:485 MESH:D012488 DB01607_MESH_D012488_1 CHEBI:6076 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0232462 infores:hetionet GO:2000260 biolink:causes GO:0072378 infores:ubergraph knowledge_assertion manual_agent GO:2000260 GO:0072378 CHEBI:100246 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0033777 infores:hetionet CHEBI:231594 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0016436 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020517 infores:hetionet CAID:CA410204309 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204309 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.105C>A (p.Ser35Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204309/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:87715 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0012833 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0023895 infores:hetionet CHEBI:27899 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0040034 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0234458 infores:hetionet CHEBI:6539 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0005779 infores:hetionet CHEBI:63791 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0231528 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002450 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0520477 infores:hetionet CHEBI:6897 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0423153 infores:hetionet NCBIGene:60558 biolink:causes MONDO:0014895 infores:monarchinitiative not_provided not_provided HGNC:25799 MONDO:0014895 uuid:e2dfb8d7-5683-4767-ad46-0427de7b66c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0040303 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235988 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0034882 infores:hetionet CHEBI:5001 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C1443060 infores:hetionet CHEBI:8863 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0012569 infores:hetionet CHEBI:127780 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0027121 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0017152 infores:hetionet CAID:CA512319027 biolink:causes MONDO:0100083 infores:clingen CAID:CA512319027 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP1, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM5, PM1, PM3, PP2, PP3, PP1, PP4, BS2 This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant has a Splice AI Δ scores < 0.2 (BP4, BP7). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.662) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319027/MONDO:0100083/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6916 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0036572 infores:hetionet CHEBI:520985 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0003862 infores:hetionet NCBIGene:10125 biolink:causes MONDO:0032803 infores:monarchinitiative not_provided not_provided HGNC:9878 MONDO:0032803 uuid:61b9c1f4-e1c7-4864-ab64-bd531f4605c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6887 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1325847 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0006444 infores:hetionet CHEBI:175901 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0268000 infores:hetionet CHEBI:681569 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0232462 infores:hetionet CHEBI:18067 biolink:causes MONDO:0019340 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0011644 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0919659 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0919659 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151889 infores:hetionet CHEBI:5959 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027497 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0005970 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D011023 DB01330_MESH_D011023_1DB01603_MESH_D011023_1 CHEBI:10023 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0595930 infores:hetionet UBERON:0000924 biolink:causes MONDO:0042983 infores:ubergraph knowledge_assertion manual_agent UBERON:0000924 MONDO:0042983 CHEBI:35778 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0025061 infores:hetionet CHEBI:59560 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0027424 infores:hetionet CHEBI:37941 biolink:causes HP:0012151 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0019123 infores:hetionet CHEBI:72296 biolink:causes UMLS:C3665900 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C3665900 infores:hetionet CHEBI:2950 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0558401 infores:hetionet CHEBI:63608 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0022354 infores:hetionet CHEBI:9362 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0234215 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005148 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011860 infores:hetionet CHEBI:5118 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0702166 infores:hetionet CHEBI:3011 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0015230 infores:hetionet UMLS:C0065374 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0242429 infores:hetionet CHEBI:2379 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0002170 infores:hetionet NCBIGene:5897 biolink:causes MONDO:0011086 infores:monarchinitiative not_provided not_provided HGNC:9832 MONDO:0011086 uuid:cce09e3f-c095-40eb-a68f-381aab62ec27 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9725 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0162830 infores:hetionet CHEBI:3738 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0027424 infores:hetionet CHEBI:50275 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0039591 infores:hetionet CHEBI:188986 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0039231 infores:hetionet CHEBI:9434 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0039070 infores:hetionet CHEBI:7822 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0497156 infores:hetionet CHEBI:10650 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0039070 infores:hetionet CHEBI:5100 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0000737 infores:hetionet CHEBI:94501 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0004238 infores:hetionet NCBITaxon:5475 biolink:causes MONDO:0002026 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5475 MESH:D002177 DB00681_MESH_D002177_1 CHEBI:68558 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018681 infores:hetionet CHEBI:50648 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0010520 infores:hetionet CHEBI:28864 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0011175 infores:hetionet CAID:CA288054 biolink:causes MONDO:0007648 infores:clingen CAID:CA288054 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.2104G>A (p.GLu702Lys) variant has an allele frequency of 0.001714 (0.2%, 71/41,414 alleles) in the African subpopulation of the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288054/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:41423 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0085610 infores:hetionet CHEBI:63617 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011124 infores:hetionet CHEBI:27732 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0270611 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0162429 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0549209 infores:hetionet CHEBI:75998 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0917801 infores:hetionet CHEBI:5558 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0013604 infores:hetionet CHEBI:7798 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0015672 infores:hetionet CHEBI:5775 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0040034 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0235315 infores:hetionet CHEBI:16714 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0027497 infores:hetionet CHEBI:6073 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0428977 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0026946 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0020649 infores:hetionet CHEBI:7959 biolink:causes MONDO:0015194 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0002896 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0009676 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0034150 infores:hetionet CHEBI:9570 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0001824 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0340726 infores:hetionet NCBIGene:1137 biolink:causes MONDO:0010899 infores:monarchinitiative not_provided not_provided HGNC:1958 MONDO:0010899 uuid:0cdbd788-ef74-40ed-bf93-06036867b044 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3534 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0178298 infores:hetionet GO:0044478 biolink:causes GO:0030168 infores:ubergraph knowledge_assertion manual_agent GO:0044478 GO:0030168 CHEBI:78543 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0006145 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0152027 infores:hetionet UMLS:C0145867 biolink:causes HP:0002046 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0231274 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020569 infores:hetionet CHEBI:8871 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043049 infores:hetionet CHEBI:63619 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0750426 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011551 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0877098 infores:hetionet CAID:CA037904 biolink:causes MONDO:0007750 infores:clingen CAID:CA037904 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, PS4, PP3, PP4 The NM_000527.5(LDLR):c.1988-13T>G variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2).The supporting evidence is as follows: PM2: PopMax MAF = 0.000076 (0.0076%) in European (Non-Finnish) exomes/genomes (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037904/MONDO:0007750/013 2025-02-20 2025-06-17 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31644 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0011603 infores:hetionet CHEBI:17688 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0009676 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020456 infores:hetionet CHEBI:4877 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0231218 infores:hetionet CHEBI:6437 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013384 infores:hetionet CHEBI:521033 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C2981158 infores:hetionet CHEBI:45716 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0854467 infores:hetionet CHEBI:41774 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0235439 infores:hetionet NCBITaxon:777 biolink:causes MONDO:0019186 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:777 MESH:D011778 DB00618_MESH_D011778_1DB02703_MESH_D011778_1DB13092_MESH_D011778_1DB00254_MESH_D011778_1DB01017_MESH_D011778_1DB00759_MESH_D011778_1DB00595_MESH_D011778_1 CHEBI:15765 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0015371 infores:hetionet CHEBI:9622 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0043349 infores:hetionet CHEBI:31348 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0013404 infores:hetionet CHEBI:4995 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0020672 infores:hetionet CHEBI:7465 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0027441 infores:hetionet CHEBI:7575 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0020625 infores:hetionet UMLS:C0065374 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0043352 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0017152 infores:hetionet CHEBI:66899 biolink:causes UMLS:C1142112 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C1142112 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0948594 infores:hetionet CHEBI:44915 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0018794 infores:hetionet CHEBI:5558 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0018681 infores:hetionet CHEBI:465284 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0016204 infores:hetionet CHEBI:91834 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013604 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0013395 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0036508 infores:hetionet CHEBI:119915 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0023218 infores:hetionet UMLS:C0879264 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0004604 infores:hetionet CAID:CA412746906 biolink:causes MONDO:0100437 infores:clingen CAID:CA412746906 MONDO:0100437 PMID: Likely Benign BP4 PM2, BS1 NM_001034853.2(RPGR):c.16G>C variant is a missense variant predicted to result in the substitution of glutamic acid with glutamine at amino acid 6. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002592 among hemizygous individuals, with 1 variant allele / 385,738 total alleles, which is lower than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 but higher than the PM2_Supporting threshold of <0.0000005, so neither population code was met. The computational predictor REVEL gives a score of 0.051, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BP4_Moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412746906/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:7824 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038358 infores:hetionet NCBIGene:8763 biolink:causes MONDO:0014854 infores:monarchinitiative not_provided not_provided HGNC:1632 MONDO:0014854 uuid:84f6acb6-0969-4a2e-a114-1122e3cf5334 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6923 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C2364111 infores:hetionet CAID:CA114121 biolink:causes MONDO:0015629 infores:clingen CAID:CA114121 MONDO:0015629 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PS4_Supporting, PS3 PP3 "The p.Trp1313Cys variant has a REVEL score of 0.629, which is below the VWD VCEP threshold of > 0.644 and therefore, the variant does not predict a damaging effect on VWF function. The variant is absent from gnomADv4, thus, meeting PM2_Supporting criteria. There is at least one proband with the variant exhibiting a risk of excessive bleeding, RIPA assay showing GOF, and a loss of HMWM which is consistent with VWD type 2B (PP4_Moderate). This patient is also a carrier for the p.Val1565Leu variant (PMID: 35772170) which has been classified as Benign by the VWD VCEP. ""Genotyping previously confirmed the diagnosis in each patient with type 2B VWD"" (PMID: 35772170). Functional data demonstrated that mammalian CHO-K1 cells transfected with mutant plasmid (p.W1313C) exhibited a 10-fold affinity to GPIb in the presence of ristocetin compared to wildtype cells (PMID: 2011604) (PS3). This variant has been reported in at least 1 additional proband meeting PP4 laboratory phenotype criteria (PS4_supporting); PMIDs: 31939074. Taken together, the variant has been classified as likely pathogenic for VWD type 2B by the Von Willebrand Disease variant curation expert panel. PP4_Moderate, PM2_Supporting, PS3, PS4_Supporting." von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114121/MONDO:0015629/081 2025-04-01 2025-04-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3219 biolink:causes MONDO:0001875 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0014488 infores:hetionet CHEBI:9137 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0162830 infores:hetionet NCBIGene:54916 biolink:causes MONDO:0044321 infores:monarchinitiative not_provided not_provided HGNC:20185 MONDO:0044321 uuid:09d8c7b3-e303-4da4-b08a-700996ff3596 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0013428 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0011609 infores:hetionet CHEBI:63598 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0340865 infores:hetionet CAID:CA003238 biolink:causes MONDO:0700268 infores:clingen CAID:CA003238 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.5098A>G variant in BRCA1 is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 1700 (p.(Thr1700Ala)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.41, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.14 indicates an unclear predicted impact on splicing (score threshold 0.10-0.20) (PP3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003238/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3504 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C1257843 infores:hetionet CHEBI:100147 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0011603 infores:hetionet CHEBI:4511 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0042963 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0031350 infores:hetionet CHEBI:6704 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0027947 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020538 infores:hetionet CHEBI:119915 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018926 infores:hetionet CHEBI:17347 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085649 infores:hetionet GO:0010965 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0010965 GO:0140014 CHEBI:2948 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1384353 infores:hetionet CHEBI:84883 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0039231 infores:hetionet CHEBI:4953 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0162298 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0002170 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0040046 infores:hetionet CHEBI:63791 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0043144 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0027051 infores:hetionet CHEBI:39867 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0024141 infores:hetionet CHEBI:31859 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C3665386 infores:hetionet CHEBI:39585 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0040822 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0027765 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0037822 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0018799 infores:hetionet CHEBI:8871 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030196 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0744403 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0744403 infores:hetionet CHEBI:9168 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0040822 infores:hetionet CAID:CA184505 biolink:causes MONDO:0019501 infores:clingen CAID:CA184505 MONDO:0019501 PMID:28944237PMID:25404053PMID:27460420 Pathogenic PP3, PP4, PM5, PM2, PM3_Strong The c.3503G>A (p.Arg1168Gln) variant in MYO7A has been detected in at least 4 probands with Usher syndrome. For two of those probands, a pathogenic or suspected-pathogenic variants was observed in trans, and in one individual, the variant was observed with a pathogenic or suspected-pathogenic variant, but it was unclear if phasing was performed (PM3_Strong, PP4; PMID:25404053, 27460420, 28944237). The allele frequency of this variant is 0.004%% (1/26850) of South Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The c.3503G>A (p.Arg1168Gln) variant is located in the last base of the exon, which is part of the 5’ consensus sequence, and computational tools suggest an impact to splicing. Furthermore, tThe REVEL computational prediction analysis tool produced a score of 0.9, which is above the threshold necessary to apply PP3. A different likely pathogenic or suspected-pathogenic variant at the same nucleotide (c.3503G>C, Arg1168Pro) has been previously identified in an individual with Usher syndrome who was compound heterozygous for a second pathogenic truncating variant (PMID: 16470552). In addition, a minigene assay demonstrated that the 3503G>C variant led to skipping of exon 27 (PMID: 20052763) suggesting that variants that alter the c.3503G nucleotide may cause abnormal splicing (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Strong, PP4, PM2, PP3, PM5_Supporting. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA184505/MONDO:0019501/005 2019-09-16 2019-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CAID:CA6832059 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832059 MONDO:0015967 PMID: Pathogenic PS3, PP1_Strong, PP4 PS4, PM1, BS1, PM2 The c.1501G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 501 (p.(Ala501Thr)) of NM_000545.8. Minigene-splicing assay demonstrates that this variant results in abnormal splicing and the in-frame deletion of exon 7, resulting in resulting in p.Gly437_His500del (PS3; Bouvet et al., 2023). The Grpmax filtering allele frequency of this variant in gnomAD v2.1.1 is 0.00001271, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs: 12832318, 23348805, 23517481, internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors). Additionally, this variant segregated with diabetes with 4 informative meioses in 3 families (PP1_Strong; PMID: 12832318, internal lab contributors). In summary, c.1501G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): PS3, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832059/MONDO:0015967/017 2025-04-07 2025-04-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4027 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0011849 infores:hetionet CHEBI:4885 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0011570 infores:hetionet CHEBI:8874 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0344232 infores:hetionet CHEBI:68841 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0020651 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0011616 infores:hetionet CHEBI:8245 biolink:causes UMLS:C0232124 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0232124 infores:hetionet GO:1904717 biolink:causes GO:0099173 infores:ubergraph knowledge_assertion manual_agent GO:1904717 GO:0099173 NCBITaxon:4751 biolink:causes MONDO:0015908 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D002862 DB01263_MESH_D002862_1 CHEBI:17650 biolink:causes MONDO:0002325 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0040436 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0031350 infores:hetionet CHEBI:231594 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0234233 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0575090 infores:hetionet CAID:CA405668522 biolink:causes MONDO:0007783 infores:clingen CAID:CA405668522 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with valine at codon 4128 of the RYR1 protein, p.(Ala4128Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.248) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405668522/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:135920 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0004604 infores:hetionet UMLS:C0011701 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0009421 infores:hetionet CHEBI:9434 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020461 infores:hetionet CHEBI:94807 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0011991 infores:hetionet CHEBI:6367 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0043352 infores:hetionet CHEBI:3478 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C2047937 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0234215 infores:hetionet GO:1903587 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0035295 CHEBI:68575 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0700184 infores:hetionet CHEBI:8024 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0231528 infores:hetionet CHEBI:6809 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0042109 infores:hetionet CHEBI:50305 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0012833 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0235234 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0023067 infores:hetionet CHEBI:5165 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151604 infores:hetionet CAID:CA037694 biolink:causes MONDO:0007750 infores:clingen CAID:CA037694 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, BP4, PM2, PP4 BA1, BP1, BP3, PS3, BP7, BS1, BS3, BS4, PM4, PVS1, PP2, PP3, PP1, BS2 The NM_000527.5(LDLR):c.1987+10G>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, PS4_Supporting and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows:PM2: PopMax MAF = 0.00008220 (0.00822%) in Non-Finnish European (gnomAD v4.1.0).PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated cases who fulfill Simon Broome criteria for possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France.BP4: No REVEL, splicing evaluation required. SpliceAI: acceptor loss = 0.01, donor loss = 0.04. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037694/MONDO:0007750/013 2025-03-24 2025-03-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:94609 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0000737 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0003811 infores:hetionet CHEBI:50742 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0700590 infores:hetionet CHEBI:8871 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0008350 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0233632 infores:hetionet NCBIGene:5428 biolink:causes MONDO:0013350 infores:monarchinitiative not_provided not_provided HGNC:9179 MONDO:0013350 uuid:9fb09a28-7e6b-4a13-afbb-10de4a590e28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4315 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0344232 infores:hetionet CHEBI:68478 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0333355 infores:hetionet CHEBI:40303 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C2047937 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0497247 infores:hetionet CHEBI:31547 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0917801 infores:hetionet CHEBI:3732 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0000731 infores:hetionet CHEBI:8346 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0040034 infores:hetionet CHEBI:23765 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0006277 infores:hetionet CHEBI:7789 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0018681 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0233494 infores:hetionet CHEBI:3441 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0043094 infores:hetionet CAID:CA6748708 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748708 MONDO:0009861 PMID:23357515PMID:23357515 Likely Pathogenic PM3, PM5, PM2, PP4 PP3 The c.1218A>G (p.Ile406Met) variant in PAH is reported in 2 individuals with non-PKU HPA. BH4 assessment was not stated. It was detected with a known pathogenic variant, p.Arg408Trp. (PMID: 23357515) This variant has a low allele frequency in gnomAD and ExAC (MAF=0.00003) and is absent in 1000G. Computational evidence is discordant. Another missense change at this amino acid is interpreted as likely pathogenic by the PAH VCEP (p.I406T). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PM5, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748708/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:83804 biolink:causes MONDO:0007593 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0278151 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0014549 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0007642 infores:hetionet CHEBI:4885 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0232459 infores:hetionet CHEBI:4995 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0012569 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948594 infores:hetionet CHEBI:15940 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0016059 infores:hetionet CHEBI:28177 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0235082 infores:hetionet CHEBI:6887 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1760428 infores:hetionet CAID:CA5950313 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950313 MONDO:0000572 PMID: Likely Benign BP7, BS1 BS2 The c.2751G>A (p.Gln917=) variant (NM_000448.3) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The highest population minor allele frequency in gnomAD v2.1.1 is 0.007464 (220/24818 alleles) in African/African American population, which is higher than the ClinGen SCID VCEP threshold (>0.00195) for BS1, and therefore meets this criterion (BS1). No homozygous has been reported. (BS2 not met).In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BS1 and BP7. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950313/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8404 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0020580 infores:hetionet CHEBI:2955 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0017178 infores:hetionet NCBIGene:5328 biolink:causes MONDO:0011136 infores:monarchinitiative not_provided not_provided HGNC:9052 MONDO:0011136 uuid:e8a39e5b-ff7c-4323-be0d-ed8d81d24bbf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:585948 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0037383 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151717 infores:hetionet CHEBI:3403 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0232602 infores:hetionet GO:0051146 biolink:causes CL:0000737 infores:ubergraph knowledge_assertion manual_agent GO:0051146 CL:0000737 CHEBI:63605 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027796 infores:hetionet CAID:CA254836 biolink:causes MONDO:0044970 infores:clingen CAID:CA254836 MONDO:0044970 PMID: Pathogenic PS3_Supporting, PP1_Moderate, PP3, PS4 PS2, PM6 The m.8344A>G variant in MT-TK was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features. While this variant is classically associated with the mitochondrial disease clinical syndrome MERRF (myoclonic epilepsy with ragged red fibers), affected individuals can have any number of features including but not limited to ataxia, myoclonus, seizures, Leigh syndrome, muscle weakness, exercise intolerance, sensorineural hearing loss, neuropathy, and lipomas, with onset ranging from childhood to adulthood (PS4; PMIDs: 2112427, 1910259, 23635963). This variant heteroplasmy level segregated with severity in >10 family members from >10 families (PP1_moderate; PMIDs: 2112427, 23635963). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 0.90 (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMIDs: 1848674, 7739567). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PP1_moderate, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254836/MONDO:0044970/014 2021-11-03 2021-11-03 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:61058 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0012833 infores:hetionet CAID:CA415087873 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087873 MONDO:0010305 PMID: Likely Benign BS2 PM2, PP3, BP4 The NM_005629.4:c.1483G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of an alanine by a threonine at amino acid position 495 (p.Ala495Thr). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0, the highest population allele frequency is 0.000006729 (6/891685 alleles; 3 hemizygotes); in the European (non-Finnish) population. While this MAF meets the threshold for PM2_Supporting (<0.0002), the criterion is not met due to the presence of hemizygotes. There is a total of 3 hemizygotes in gnomAD v4.1.0., all of them in the European non-Finnish population (BS2). The computational predictor REVEL gives a score of 0.57, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 942968). Due to the presence of 3 hemizygotes in gnomAD v4.1.0. in the absence of any evidence for pathogenicity, the consensus of the ClinGen CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087873/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:480999 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0854069 infores:hetionet CHEBI:6717 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0030554 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0521491 infores:hetionet CHEBI:71415 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0085593 infores:hetionet CHEBI:31536 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C2711227 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042571 infores:hetionet CHEBI:92712 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0423791 infores:hetionet CHEBI:68554 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C2937358 infores:hetionet CHEBI:3215 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C3160947 infores:hetionet CHEBI:101085 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0015230 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0034065 infores:hetionet CHEBI:46295 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0026821 infores:hetionet CAID:CA400032429 biolink:causes MONDO:0100326 infores:clingen CAID:CA400032429 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.1736G>A (p.Trp579Ter) nonsense variant creates a premature stop codon in exon 11/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT41 of PMID: 29675921 who meets the criteria for PP4_strong. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP4_strong. (VCEP specifications version 2; date of approval 11/04/2021) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400032429/MONDO:0100326/011 2021-11-04 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA000366 biolink:causes MONDO:0017623 infores:clingen CAID:CA000366 MONDO:0017623 PMID: Uncertain Significance PP3, PS3_Moderate, PM2_Supporting PTEN c.254-2A>G (IVS4-2A>G) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_Moderate: RNA, mini-gene, or other assay shows impact on splicing (internal laboratory contributor: SCV002742473.1). PM2_Supporting: Absent in large sequenced populations. PP3: In silico models predict a splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000366/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64312 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042487 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0007820 infores:hetionet CHEBI:4315 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0043094 infores:hetionet CHEBI:167309 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0030252 infores:hetionet CHEBI:17650 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0019080 infores:hetionet CHEBI:31643 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0018790 infores:hetionet CHEBI:135613 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0042963 infores:hetionet CHEBI:6761 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0234518 infores:hetionet CHEBI:5050 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0030196 infores:hetionet NCBIGene:338917 biolink:causes MONDO:0012408 infores:monarchinitiative not_provided not_provided HGNC:1975 MONDO:0012408 uuid:9e9a5ffa-bf93-4a1a-9688-459cea3aa636 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0033247 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0948089 infores:hetionet CHEBI:7822 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0036974 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0009806 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0521839 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0003123 infores:hetionet CHEBI:63791 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2981158 infores:hetionet CHEBI:50742 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0003537 infores:hetionet CHEBI:17347 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0024141 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0855235 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0855235 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0039971 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0032708 infores:hetionet CHEBI:5790 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0004093 infores:hetionet CAID:CA404081019 biolink:causes MONDO:0007750 infores:clingen CAID:CA404081019 MONDO:0007750 PMID: Uncertain Significance PM1, PM2, PP3 BP4, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP1, PP4, BS2 The NM_000527.5(LDLR):c.904T>C (p.Cys302Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).PP3: REVEL = 0.972.PM1: Variant meets PM2 and alters Cys302, one of the cysteine residues listed. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404081019/MONDO:0007750/013 2023-06-23 2025-10-29 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:23347 biolink:causes MONDO:0008031 infores:monarchinitiative not_provided not_provided HGNC:29090 MONDO:0008031 uuid:859945af-6f60-4722-8b51-f4a7f01f458d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151854 infores:hetionet NCBITaxon:620 biolink:causes MONDO:0019345 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:620 MESH:D004405 DB00576_MESH_D004405_1 CHEBI:144551 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0028734 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002418 infores:hetionet CHEBI:6375 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1527344 infores:hetionet CHEBI:84500 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0014356 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020550 infores:hetionet CAID:CA10585235 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585235 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PS3, PP1_Strong, PM2, PP3, PP4 BP4, BA1, BS3, BS1, BS4 PP1_strong: Variant segregates with FH phenotype in at least 28 informative meiosis (minimum 2) from 9 families from different labs (Laboratory of Genetics and Molecular Cardiology). PS3: PMID: 32015373. Level 1 assay. Heterologous cells (CHO), FACS assays. Normal cell surface LDLR (90%), 50% binding and 48% uptake.PS4_supporting: variant meets PM2 and is identified in 1 index case who fulfills SB criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and 1 index case with DLCN >6 from PMID 30270055, Corral et al., 2018 (Argentina) so PS4_Supporting is met PM2: No population data was found for this variant in gnomAD (gnomAD version 2.1.1). PP3: REVEL = 0.927. PP4: Variant meets PM2 and is identified in 1 index case who fulfils SB for FH from different labs (Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and Laboratory of Genetics and Molecular Cardiology). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585235/MONDO:0007750/013 2022-04-05 2022-04-05 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:2914 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0020517 infores:hetionet CHEBI:63611 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0149745 infores:hetionet CHEBI:10124 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0006277 infores:hetionet CHEBI:9939 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0009782 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0035854 infores:hetionet CAID:CA8602664 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602664 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PP4 The c.2504C>T variant in ITGA2B is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 835 (p.Pro835Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002900 (1/34480 alleles) in the Latino/Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.763, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating with Glanzmann thrombasthenia were found in the literature. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting and PP3 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602664/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true UMLS:C0657912 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1328337 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0585186 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0948089 infores:hetionet CHEBI:63619 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020546 infores:hetionet CHEBI:125354 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0270996 infores:hetionet CHEBI:50305 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0011603 infores:hetionet CHEBI:5384 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C3665347 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0042109 infores:hetionet NCBITaxon:7147 biolink:causes MONDO:0019147 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:7147 MONDO:0019147 CHEBI:30830 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0005940 infores:hetionet CHEBI:10110 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0014591 infores:hetionet NCBIGene:113457 biolink:causes MONDO:0054771 infores:monarchinitiative not_provided not_provided HGNC:24071 MONDO:0054771 uuid:2ffbe82f-9d00-47f0-8f79-e9ad68b4866c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151826 infores:hetionet CHEBI:135939 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0002170 infores:hetionet CHEBI:17549 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0085641 infores:hetionet CHEBI:3441 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0015967 infores:hetionet CHEBI:31236 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0005747 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0027051 infores:hetionet CHEBI:42068 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0004238 infores:hetionet CAID:CA081610 biolink:causes MONDO:0018493 infores:clingen CAID:CA081610 MONDO:0018493 PMID: Uncertain Significance PP1, PP3, PM1, PS4, PS3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 1583 of the RYR1 protein, p.(Arg1583Cys). The maximum allele frequency (MAF) for this variant among the six major gnomAD populations is NFE: 0.000122, a frequency consistent with pathogenicity for MHS. However, the MAF in the Finnish population is 0.0014 which is higher than expected for a single pathogenic variant. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted); both of these individuals had a other RYR1 variants identified in cis (p.Gly248Arg and p.Glu5034Val, likely pathogenic and VUS, PMID:19346234; p.Val2102Leu, VUS, PMID:23035052). A third individual was identified with this variant and masseter muscle rigidity (PMID:30864471), a precursor to MH. The available case data combined with the high MAF in the NFE and FIN populations in gnomAD does not allow for the use of PS4. This variant segregates with MHS in two families, however, PP1 was not implemented due to the presence of other RYR1 variants in cis (PMID:19346234, PMID:23035052). Functional studies were carried out in B-lymphoblastoid cells from three family members with both the p.Arg1583Cys and p.Val2102Leu RYR1 variants (PMID:23035052). These cells were hypersensitive to agonist compared to wild type cells, however PS3 was not implemented as all cells were from the same family (two or more independent studies are required) and other variants in cis complicated the interpretation. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.586 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA081610/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6367 biolink:causes MONDO:0000665 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0003635 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0242073 infores:hetionet CHEBI:63619 biolink:causes HP:0002919 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0162275 infores:hetionet CHEBI:6367 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013362 infores:hetionet CHEBI:8232 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0019080 infores:hetionet CHEBI:50131 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013404 infores:hetionet CHEBI:63620 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0014591 infores:hetionet CHEBI:8764 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0206062 infores:hetionet CAID:CA254239 biolink:causes MONDO:0800472 infores:clingen CAID:CA254239 MONDO:0800472 PMID:12807732PMID:11740343PMID:27243976PMID:19234632 Pathogenic PP3, PM3_Very Strong, PM1, PP1_Strong, PS3_Supporting BA1, BP4, PM5, PM4, PS1, PS2, BS1, BS4, BP7, PM2, PVS1 The c.1405C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 469 (p.Arg469Trp). This missense variant is located in the L-helix including the haem-binding domain, meeting PM1. The highest minor allele frequency of this variant was in the Middle Eastern genetic ancestry group of gnomAD (v4.1.0) = 0.0009901 (6 alleles out of 6,060), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The REVEL score = 0.723, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 12807732) demonstrated that the Arg469Trp protein had reduced Benzo[a]pyrene Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. This variant was also assessed in PMIDs: 27243976, 19234632, 11740343, however, the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined. 3 affected segregations with a CYP1B1-related phenotype have been reported (PMIDs: 9497261), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in 5 individuals with a CYP1B1-related phenotype. 3 individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) and 2 are homozygous (non-consanguineous) for the variant (PMIDs: 9497261, 19234632, 23922489). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 16 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very-Strong, PP1_Strong, PM1, PP3, PS3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA254239/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16899 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0858635 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0021400 infores:hetionet CHEBI:50742 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0002884 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1565489 infores:hetionet CHEBI:6754 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0162297 infores:hetionet CAID:CA386953852 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953852 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP4 The c.225C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to glutamate at codon 75 (p.(Asp75Glu)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%; therefore, PP4 could not be applied (internal lab contributors). In summary, c.225C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953852/MONDO:0015967/017 2022-04-08 2022-07-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8888 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027769 infores:hetionet CAID:CA226354 biolink:causes MONDO:0100437 infores:clingen CAID:CA226354 MONDO:0100437 PMID: Benign BP4_Strong, BA1 NM_001034853.2(RPGR):c.1291A>G (p.Ile431Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 431. This variant is present in gnomAD v4.1.0 at a frequency of 0.04121 among hemizygous individuals, with 16,241 variant alleles / 394,110 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of hemizygous >0.00005 (BA1). The computational predictor REVEL gives a score of 0.005, which is below the ClinGen X-linked IRD VCEP threshold of <0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226354/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:4995 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235063 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006044 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0027719 infores:hetionet CHEBI:3638 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0232462 infores:hetionet GO:0014059 biolink:causes GO:0007267 infores:ubergraph knowledge_assertion manual_agent GO:0014059 GO:0007267 CHEBI:75998 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020437 infores:hetionet CHEBI:6950 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013362 infores:hetionet CHEBI:63580 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027796 infores:hetionet CHEBI:51364 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0030193 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0006277 infores:hetionet CHEBI:7915 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011168 infores:hetionet CHEBI:135686 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06274 UMLS:C0042075 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0342579 infores:hetionet NCBIGene:203 biolink:causes MONDO:0012967 infores:monarchinitiative not_provided not_provided HGNC:361 MONDO:0012967 uuid:67a6614b-5f7b-4bd8-a22e-c58ac5ed5b1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA040267 biolink:causes MONDO:0007750 infores:clingen CAID:CA040267 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP1, BS2 NM_000527.5(LDLR):c.2389+4A>G variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000008798 (0.0009%) in European non-Finnish (gnomAD v2.1.1). PP3 - No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located at -3 to +6 from canonical donor splice site Ratio variant/wt canonical acceptor/donor = 0,786004057 ---- It is below 0.8PP4 - Variant meets PM2. Identified in 1 FH case from Ambry Genetics who fulfills Simon-Broome criteria. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040267/MONDO:0007750/013 2021-06-22 2021-06-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true GO:1905270 biolink:causes CL:2000056 infores:ubergraph knowledge_assertion manual_agent GO:1905270 CL:2000056 CHEBI:2663 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0040046 infores:hetionet CHEBI:32192 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0002792 infores:hetionet NCBIGene:4914 biolink:causes MONDO:0009746 infores:monarchinitiative not_provided not_provided HGNC:8031 MONDO:0009746 uuid:aaca366c-3b1d-4436-bba4-afc53eb6bdba biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63618 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0206062 infores:hetionet CHEBI:40009 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0013362 infores:hetionet CHEBI:63616 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0151904 infores:hetionet CHEBI:6715 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042023 infores:hetionet CHEBI:9943 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085633 infores:hetionet CHEBI:7476 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151827 infores:hetionet CHEBI:68534 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0033774 infores:hetionet CHEBI:18248 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0006266 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0233414 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0006668 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D003234 DB00218_MESH_D003234_1 CHEBI:9150 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0018418 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020676 infores:hetionet NCBIGene:1121 biolink:causes MONDO:0010557 infores:monarchinitiative not_provided not_provided HGNC:1940 MONDO:0010557 uuid:9cf04cad-74f8-41f7-b1a2-8067e09117d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0017152 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0149931 infores:hetionet CHEBI:6741 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0023530 infores:hetionet GO:1904790 biolink:causes GO:0032200 infores:ubergraph knowledge_assertion manual_agent GO:1904790 GO:0032200 CHEBI:44423 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0037274 infores:hetionet NCBIGene:4598 biolink:causes MONDO:0008293 infores:monarchinitiative not_provided not_provided HGNC:7530 MONDO:0008293 uuid:482784ad-b830-4584-90cb-c4341b51f6b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0575081 infores:hetionet CHEBI:44032 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0002878 infores:hetionet CAID:CA8337710 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337710 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, BP4 The c.477+17G>A variant in ACADVL is an intronic variant which occurs in intron 6. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0 for donor loss suggesting that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021). This variant was originally curated March 8, 2022 and the recurated classification was approved by the expert panel on April 11, 2023. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337710/MONDO:0008723/021 2023-04-11 2023-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA023621 biolink:causes MONDO:0007750 infores:clingen CAID:CA023621 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3_Moderate, PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PS3_Moderate, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Variant meets PM2 and is one of listed Cysteine.PM2 - PopMax MAF = 0.000008794 (0.0009%) in European non-Finnish exomes (gnomAD v2.1.1).PS3_moderate - PMID:2318961 - Level 2 assay - study on hmz patient's fibroblasts, after 2 hours pulse-chase, only 20% of receptors were processed to the mature form. Also here PMID: 14993243 and here PMID: 10906332 is shown that this mutant is retained on ER. In last two papers not whole LDLR cycle was studied.PP3 - REVEL: 0,986. PP4 - Variant meets PM2. Variant found in 5 unrelated index cases fulfilling validated clinical criteria for FH.PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from Ambry Genetics with Simon-Broome criteria; 1 case from GeneDx Inc. with Simon-Broome criteria; 2 cases from University of British Columbia with DLCN score 16 and 10, respectively). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023621/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:9586 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C2979982 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0541919 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0011053 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0948089 infores:hetionet CHEBI:100241 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0520966 infores:hetionet NCBIGene:5476 biolink:causes MONDO:0009737 infores:monarchinitiative not_provided not_provided HGNC:9251 MONDO:0009737 uuid:ef22b331-014b-44e2-812a-7b1a82b30f4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011616 infores:hetionet CHEBI:8768 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1443060 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0085631 infores:hetionet NCBIGene:2902 biolink:causes MONDO:0013655 infores:monarchinitiative not_provided not_provided HGNC:4584 MONDO:0013655 uuid:91f029a1-8a07-45cc-861d-d5126330c282 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32139 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0392176 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0006852 infores:hetionet CHEBI:4708 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0030232 infores:hetionet CHEBI:87681 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0018524 infores:hetionet CHEBI:31623 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0013604 infores:hetionet UMLS:C0004609 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0004134 infores:hetionet CHEBI:490877 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0085593 infores:hetionet CHEBI:5893 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011603 infores:hetionet CHEBI:45863 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151799 infores:hetionet CAID:CA16620349 biolink:causes MONDO:0011132 infores:clingen CAID:CA16620349 MONDO:0011132 PMID:37419334 Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong PP1, PS3, PS4 The NM_001369369.1(FOXN1):c.907del (p.Glu303SerfsTer?) frameshift variant in exon 6 results in a premature stop codon in the final exon (exon 9) at codon 549. It is not predicted to cause NMD but would truncate 15% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). This variant is absent from gnomADv2.1.1 (PM2_supporting). It was detected heterozygous in P2 (PMID: 31447097) with nail dystrophy and T lymphopenia, CD3 992 cells/ul [nv:2500-5500], CD4 595 cells/ul [nv:1660-4000], CD8 368 cells/ul [nv:560-1700] (PP4). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620349/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:68595 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0267596 infores:hetionet CHEBI:50275 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0542571 infores:hetionet CHEBI:135925 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0017178 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151705 infores:hetionet GO:0046780 biolink:causes GO:0000398 infores:ubergraph knowledge_assertion manual_agent GO:0046780 GO:0000398 CHEBI:2704 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0595930 infores:hetionet CAID:CA000010 biolink:causes MONDO:0018875 infores:clingen CAID:CA000010 MONDO:0018875 PMID: Pathogenic PS3, PS2, PS4, PM1, PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting BP4, BS1, BS3, PP1 The NM_000546.6(TP53):c.1009C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 337 (p.Arg337Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a moderately LFS-associated cancer totaling 5 phenotype points (PS2; PMID: 18511570, Internal lab contributors). This variant has been reported in 10 unrelated families meeting Revised Chompret; 1 family meeting classic; and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 1353190, 9452042; Internal lab contributors). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 36 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.316468; Align GVGD = Class C45) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Three missense variants (p.Arg337Ser, p.Arg337Pro, p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, PS4, PP3, PP4_Moderate, PM2_Supporting, PM5_Supporting, PS2. (Bayesian Points: 19; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000010/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:4774 biolink:causes MONDO:0100478 infores:monarchinitiative not_provided not_provided HGNC:7784 MONDO:0100478 uuid:9f7c0188-6540-4c7c-a38e-94b1f2e233e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:125354 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0039070 infores:hetionet CHEBI:8772 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0030193 infores:hetionet CHEBI:100241 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0026838 infores:hetionet NCBIGene:11253 biolink:causes MONDO:0013624 infores:monarchinitiative not_provided not_provided HGNC:6823 MONDO:0013624 uuid:3fb571a2-adb3-439d-91c3-a71e006ef6b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0014742 infores:hetionet CHEBI:9738 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0011124 infores:hetionet CHEBI:4657 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0151786 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0406317 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0406317 infores:hetionet CHEBI:4911 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0206062 infores:hetionet CHEBI:4551 biolink:causes UMLS:C0274727 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0274727 infores:hetionet CHEBI:7443 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0030554 infores:hetionet CHEBI:2038 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0700590 infores:hetionet CHEBI:100246 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0085605 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0234192 infores:hetionet CHEBI:5138 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0032708 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0009450 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0221490 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0034359 infores:hetionet CHEBI:6472 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0038325 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042075 infores:hetionet CHEBI:51860 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0031256 infores:hetionet CHEBI:5050 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C1260880 infores:hetionet CAID:CA915952642 biolink:causes MONDO:0011071 infores:clingen CAID:CA915952642 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This intronic variant has a SpliceAI score ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.88 < 2.0) (BP7). Variant is not present in population databases (gnomAD v2.1 or v3.1.2) (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952642/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2038 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0424790 infores:hetionet CHEBI:10110 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0917801 infores:hetionet CHEBI:3207 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0268000 infores:hetionet CHEBI:8428 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0239150 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0836924 infores:hetionet CHEBI:17263 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0042267 infores:hetionet CHEBI:27882 biolink:causes MONDO:0100345 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0022951 infores:hetionet UMLS:C0004609 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0007166 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0948586 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0011609 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0233494 infores:hetionet CHEBI:3441 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0013404 infores:hetionet CAID:CA891834518 biolink:causes MONDO:0009290 infores:clingen CAID:CA891834518 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PS1_Supporting, PM3_Supporting PP4 The NM_000152.5:c.2799+5G>A variant alters the splice donor region of intron 19, the last intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.63 for donor loss, predicting that the variant disrupts the donor splice site of this intron (PP3). One patient, who is homozygous for the variant, has been described with clinical features consistent with Pompe disease and deficient activity of acid-glucosidase, specific values not provided (PM3_Supporting). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). Additional variants in this splice region have been identified including c.2799+2C>A (classified by the ClinGen LD VCEP as a VUS), c.2799+2C>T (classified by the ClinGen LD VCEP as a VUS), and c.2799+4A>G (PMID: 26873529, 30564623; SpliceAI score = 0.62) (classified by the ClinGen LD VCEP as likely pathogenic) (PS1_Supporting based on a likely pathogenic variant in the same splice region; Walker et al, 2023; https://www.medrxiv.org/content/10.1101/2023.02.24.23286431v1) (PS1_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PP3, PS1_Supporting, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 18, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA891834518/MONDO:0009290/010 2023-04-19 2023-07-11 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CAID:CA8365473 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365473 MONDO:0100453 PMID: Benign BS1, BS2 PM3 The NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del) variant is the deletion of 2 amino acids from a repetitive region of the protein's leader sequence. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.005906, with 514 alleles / 80814 total alleles in the South Asian population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 21 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365473/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0002994 infores:hetionet CAID:CA915952644 biolink:causes MONDO:0011071 infores:clingen CAID:CA915952644 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.289_299delinsCTCCTTCCGCTG (p.Phe97fs) is a frameshift variant. The transcript product is predicted to undergo NMD (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant was reported in ClinVar in 2018 by Invitae but the affected status of the proband is unknown (Variation ID 647118). This variant is a frameshift change or agreement in splicing predictors (SSF and MES) showing no splicing effects (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952644/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6897 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0004238 infores:hetionet CHEBI:9637 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C2363731 infores:hetionet CHEBI:135342 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0740394 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019193 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0031350 infores:hetionet CHEBI:6950 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0262662 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0340726 infores:hetionet CHEBI:63581 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0151763 infores:hetionet CAID:CA512318873 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318873 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.264G>A (p.Glu88=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.06) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318873/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16714 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0011570 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042035 infores:hetionet CAID:CA10360603 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360603 MONDO:0010725 PMID: Benign BP7, BA1, BP4 The NM_000330.4(RS1):c.576C>T variant is a synonymous variant at codon 192. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0003976 among hemizygous individuals, with 158 variant alleles / 397377 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00 for all delta-type changes, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This silent variant causing a synonymous variant at codon 192 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for all delta-type changes which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP7). In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1, BP4, and BP7 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360603/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:4814 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C1443060 infores:hetionet CHEBI:6438 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0012833 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0009231 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0009231 uuid:fb396abf-3011-4567-9918-f1ab987dd9c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0018965 infores:hetionet CHEBI:70718 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0020456 infores:hetionet CAID:CA308097442 biolink:causes MONDO:0018493 infores:clingen CAID:CA308097442 MONDO:0018493 PMID: Uncertain Significance BP4 PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 1964 of the RYR1 protein, p.(Arg1964Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a positive in vitro contracture test (IVCT), however, it was unclear as to whether an MH event had occurred in this individual or a relative. As well, the individual had a second variant in RYR1 of unknown significance (p.Gln1219Pro), PS4 was not implemented (PMID:21965348). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score 0.5 (0.232) supports a benign status for this variant, BP4. This variant has been classified as Likely Benign. Criteria implemented: BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308097442/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:5194 biolink:causes MONDO:0013949 infores:monarchinitiative not_provided not_provided HGNC:8855 MONDO:0013949 uuid:2f954abb-ae3c-47b9-b7a2-a048fa9771bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63925 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0009782 infores:hetionet CHEBI:29013 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0267792 infores:hetionet NCBIGene:83987 biolink:causes MONDO:0013627 infores:monarchinitiative not_provided not_provided HGNC:25367 MONDO:0013627 uuid:ff3b6de8-2a81-4b58-bd8f-a1bdaed497d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75988 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0015376 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0018801 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0027765 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0948586 infores:hetionet CHEBI:64198 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0042963 infores:hetionet CHEBI:50692 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0030196 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005193 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0282612 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0162429 infores:hetionet NCBIGene:26137 biolink:causes MONDO:0009798 infores:monarchinitiative not_provided not_provided HGNC:13503 MONDO:0009798 uuid:8f9d2d5a-a16c-42e2-9d60-66bae58880be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50173 biolink:causes MONDO:0001557 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0263962 infores:hetionet CHEBI:4551 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0008489 infores:hetionet CHEBI:134991 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0085631 infores:hetionet GO:0039656 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0039656 GO:0010467 CHEBI:7514 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0039070 infores:hetionet CHEBI:31236 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039231 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0178298 infores:hetionet CHEBI:231425 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0311468 infores:hetionet CHEBI:72292 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0018681 infores:hetionet CHEBI:8874 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030554 infores:hetionet CHEBI:231425 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0004093 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0267792 infores:hetionet CAID:CA10549610 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549610 MONDO:0010305 PMID: Likely Benign BS2, BP4 The NM_005629.4(SLC6A8):c.1646A>C (p.Asn549Thr)variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Asparagine at amino acid 549 (p.Asn549Thr). There is a ClinVar entry for this variant (Variation ID:1012671, conflicting interpretations) with classifications as Variant of Uncertain Significance (n=1), Likely Benign (n=2), and Benign (n=1). This variant is found with an allele frequency of 0.00006027 in gnomADv2.1.1 with 3 hemizygotes present in that population database. Given the presence of >2 hemizygotes in gnomADv2.1.1, BS2 is applicable for this variant. The computational predictor REVEL gives a score of 0.182 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable. At the time of this curation, this variant has not been reported in individuals with suspected Creatine Transporter Deficiency in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS2, BP4(Classification approved by the ClinGen CCDS VCEP on February 23, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549610/MONDO:0010305/027 2023-02-23 2023-03-09 X-linked inheritance HP:0001417 Contradicts true CHEBI:5050 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0041912 infores:hetionet CHEBI:3286 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0032285 infores:hetionet CHEBI:51230 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0259799 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0015230 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027441 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018799 infores:hetionet CHEBI:4975 biolink:causes MONDO:0004866 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0271468 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0263445 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0263445 infores:hetionet CHEBI:31236 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0520966 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0233523 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0233523 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005495 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0001621 infores:hetionet CHEBI:6710 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0234632 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0151479 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013595 infores:hetionet CHEBI:6402 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0003862 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020456 infores:hetionet CHEBI:35778 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0311468 infores:hetionet CHEBI:44915 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0026837 infores:hetionet CHEBI:8107 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0037287 infores:hetionet GO:2000592 biolink:causes GO:0072221 infores:ubergraph knowledge_assertion manual_agent GO:2000592 GO:0072221 CHEBI:83527 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0009782 infores:hetionet CHEBI:68478 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0016436 infores:hetionet CHEBI:9448 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0687713 infores:hetionet CHEBI:3508 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0595916 infores:hetionet CHEBI:63608 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0032617 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018500 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0037290 infores:hetionet CHEBI:474180 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0231528 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0029882 infores:hetionet CHEBI:63638 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1457883 infores:hetionet CHEBI:135736 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853034 infores:hetionet CHEBI:4888 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0004093 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0011991 infores:hetionet CHEBI:7444 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0043352 infores:hetionet CHEBI:5441 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0687713 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549249 infores:hetionet CHEBI:64312 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1145670 infores:hetionet CHEBI:37941 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C2242588 infores:hetionet CHEBI:28748 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0005758 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0024236 infores:hetionet CHEBI:17688 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0015230 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0024115 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151736 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0239150 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042769 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0858259 infores:hetionet CHEBI:48390 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0008031 infores:hetionet CHEBI:209807 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0027497 infores:hetionet CHEBI:68610 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0020615 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0034065 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0262397 infores:hetionet CHEBI:9674 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233407 infores:hetionet CAID:CA000475 biolink:causes MONDO:0017623 infores:clingen CAID:CA000475 MONDO:0017623 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting, PS2 PM6, BS1, BS4, BS3, BP7, BP5, BS2, PP3, PP2, PP1, PP4, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3 NM_000314.8(PTEN):c.492+2T>G variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (SCV002821528.2). PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (SCV001499809.1) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000475/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports GO:0048913 biolink:causes CL:1000239 infores:ubergraph knowledge_assertion manual_agent GO:0048913 CL:1000239 CHEBI:8888 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0041657 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0262385 infores:hetionet CHEBI:7444 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0344232 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0024117 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0080203 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C168489 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0232285 infores:hetionet CHEBI:7823 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0018681 infores:hetionet CHEBI:9622 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0011991 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013395 infores:hetionet CHEBI:63581 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0085593 infores:hetionet CHEBI:17303 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013428 infores:hetionet CHEBI:10125 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0011551 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014742 infores:hetionet CHEBI:44423 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0027947 infores:hetionet CHEBI:9599 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0858635 infores:hetionet CHEBI:6970 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0004096 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234916 infores:hetionet CHEBI:91541 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0002418 infores:hetionet CHEBI:63624 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0917801 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0004238 infores:hetionet CHEBI:3380 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030305 infores:hetionet CHEBI:82960 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0010200 infores:hetionet CHEBI:5134 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0231218 infores:hetionet CAID:CA2825000789 biolink:causes MONDO:0100326 infores:clingen CAID:CA2825000789 MONDO:0100326 PMID: Uncertain Significance BP7, PP4_Moderate, PM2_Supporting The NM_000419.5(ITGA2B):c.1947-9T>C variant is an intronic variant that is not predicted by SpliceAI to impact splicing (delta scores <0.05). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.425 (BP7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband (https://doi.org/10.1182/blood-2023-182694) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent or reduced, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. In summary, this variant is of uncertain significance. GT-specific criteria applied: BP7, PP4_Moderate, PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2825000789/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA8603110 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603110 MONDO:0100326 PMID: Likely Benign BP7, BP4 BS1 The c.1394-14C>T variant in ITGA2B is an intronic variant located within intron 13 of ITGA2B. It has been reported in ClinVar as part of a predisposition screen in an ostensibly healthy population. Thec.1394-14C>T variant is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 0.023 (BP4, BP7). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0004941 (45/91078 alleles) in the South Asian population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. After a thorough literature search, this variant was not found to be reported in any published papers containing individuals with Glanzmann thrombasthenia. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603110/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:8107 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0015967 infores:hetionet CAID:CA280060 biolink:causes MONDO:0021060 infores:clingen CAID:CA280060 MONDO:0021060 PMID:18039235PMID:18413255PMID:28524057 Pathogenic PS4, PS3, PM2, PP3, PP2, PM6_Strong PM5 The c.1455G>T (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 5 patients with clinical features of a RASopathy, 2 of which were reported as unconfirmed de novo cases (PS4; PM6_Strong; PMIDs: 18039235, 28524057, SCV000832735.1, SCV000204150.4, SCV000965953.1, Otto-von-Guericke-Universität Magdeburg internal communication). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID: 18413255). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Additionally, computational prediction tools and conservation analysis suggest that this variant may affect the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6_Strong, PS3, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA280060/MONDO:0021060/004 2020-02-27 2020-02-27 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63580 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013404 infores:hetionet CHEBI:6456 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0013362 infores:hetionet CHEBI:3732 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0017675 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0863093 infores:hetionet CHEBI:2208 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0027497 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0034011 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0034011 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0860803 infores:hetionet NCBIGene:4747 biolink:causes MONDO:0036484 infores:monarchinitiative not_provided not_provided HGNC:7739 MONDO:0036484 uuid:4461bb3b-7d66-46d6-8e97-7e2987245722 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0043352 infores:hetionet CHEBI:7954 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0023066 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0267792 infores:hetionet CHEBI:8890 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151904 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0002792 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0020039 infores:hetionet CHEBI:63611 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022346 infores:hetionet CHEBI:136040 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0086769 infores:hetionet CHEBI:50693 biolink:causes MONDO:0011827 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0013274 infores:hetionet CHEBI:63621 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011603 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0920102 infores:hetionet CHEBI:2549 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0232462 infores:hetionet CHEBI:71415 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0040034 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0234215 infores:hetionet CHEBI:79699 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0009763 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0012797 infores:hetionet CHEBI:3011 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0014457 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030332 infores:hetionet CHEBI:7936 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0032708 infores:hetionet CHEBI:34764 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00663 UMLS:C0011603 infores:hetionet CHEBI:132233 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0012833 infores:hetionet CHEBI:31638 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C1384353 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0521854 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0521854 infores:hetionet CHEBI:63580 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151908 infores:hetionet CHEBI:6897 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0009763 infores:hetionet CAID:CA10604473 biolink:causes MONDO:0015967 infores:clingen CAID:CA10604473 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PM3 The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.873, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 39 unrelated individuals with hyperglycemia (PS4; PMID: 30259503, 29927023, 29510678, 29207974, 29056535, 27256595, 25953829, 25555642, 24918535, 20337973, 19309449, 11508276, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 13 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Another missense variant, c.571C>T p.(Arg191Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg191Gln) (PM5_Supporting). In summary, c.572G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10604473/MONDO:0015967/086 2024-04-19 2024-04-19 Semidominant inheritance HP:0032113 Supports CHEBI:53691 biolink:causes MONDO:0005136 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0024530 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0022658 infores:hetionet CHEBI:76010 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0015672 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0850001 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0850001 infores:hetionet CHEBI:142290 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0037299 infores:hetionet CHEBI:44185 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013144 infores:hetionet CHEBI:87715 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0011991 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042029 infores:hetionet CHEBI:421707 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0011603 infores:hetionet GO:0072095 biolink:causes GO:0072028 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0072028 CHEBI:50156 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0011603 infores:hetionet CHEBI:9352 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0030305 infores:hetionet GO:0002643 biolink:causes GO:0002520 infores:ubergraph knowledge_assertion manual_agent GO:0002643 GO:0002520 UMLS:C0010592 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042963 infores:hetionet NCBIGene:3848 biolink:causes MONDO:0700249 infores:monarchinitiative not_provided not_provided HGNC:6412 MONDO:0700249 uuid:f2865339-9901-4e84-abe9-b97d21c3e879 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0002614 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0029400 infores:hetionet NCBIGene:54539 biolink:causes MONDO:0010494 infores:monarchinitiative not_provided not_provided HGNC:20372 MONDO:0010494 uuid:a1abb19d-f890-47b3-8524-3807499be44a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020621 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0013395 infores:hetionet CHEBI:4911 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0010520 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1257843 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0016436 infores:hetionet CHEBI:10102 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151908 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0267792 infores:hetionet CHEBI:131512 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0002170 infores:hetionet CHEBI:8772 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C1140680 infores:hetionet CHEBI:28830 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0002871 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0006145 infores:hetionet NCBIGene:57704 biolink:causes MONDO:0013737 infores:monarchinitiative not_provided not_provided HGNC:18986 MONDO:0013737 uuid:104f0e30-0737-4bae-b813-bf10a19af7fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020615 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0027707 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0700345 infores:hetionet CHEBI:7954 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0858678 infores:hetionet GO:0090049 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0007275 CHEBI:85078 biolink:causes EFO:0011046 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0858970 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0011615 infores:hetionet CHEBI:83527 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0017605 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040425 infores:hetionet CHEBI:8107 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011168 infores:hetionet CHEBI:3723 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014457 infores:hetionet CAID:CA305300102 biolink:causes MONDO:0007750 infores:clingen CAID:CA305300102 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, PS1, BS1, PM5, PP3 The NM_000527.5(LDLR):c.1431C>G (p.Asp477Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0000008475 (0.00008475%) in European (non-Finnish) exomes (gnomAD v4.1.0).BP4: REVEL = 0.477, it is below 0.50, so splicing evaluation required.Functional data on splicing not available.A) not on limits.B) it creates an AG.MES scores: de novo donor = -14.48, authentic donor = 6.76.De novo score is negative. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305300102/MONDO:0007750/013 2025-02-28 2025-04-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0041912 infores:hetionet CHEBI:61058 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0006145 infores:hetionet CHEBI:31644 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085616 infores:hetionet GO:1900618 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900618 GO:0007275 CAID:CA8366346 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366346 MONDO:0100453 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.3224+1G>C disrupts a canonical splice site in intron 18 and is predicted to lead to skipping of an out-of-frame exon and disruption of a critical C-terminal region of GUCY2D (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000005125, with 8 alleles /1561036 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), decreased central visual acuity (1 pt) with onset in the first year of life (1 pt), nystagmus (1 pt), decreased peripheral vision (1 pt), retinal vessel attenuation with granularity of peripheral fundus (0.5 pts), outer nuclear layer thickness on OCT within normal limits (1 pt), poor pupillary light response (0.5 pts), and undetectable electroretinogram responses from rods (0.5 pts). and cones (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy but cannot reach the PP4_Moderate level without genetic testing details (total 8 points, PMID: 23035049, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366346/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3650 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0018681 infores:hetionet CHEBI:49662 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020625 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0007194 infores:hetionet CHEBI:3181 biolink:causes UMLS:C0239513 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0239513 infores:hetionet CHEBI:3752 biolink:causes UMLS:C1142117 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1142117 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948594 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0029882 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0233494 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0854524 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0854524 infores:hetionet CHEBI:76607 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0018681 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0221165 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0413252 infores:hetionet CAID:CA350341740 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341740 MONDO:0015924 PMID:34400635 Likely Pathogenic PM5_Supporting, PP3, PM2_Supporting, PM1_Strong BP4, PS1 The NM_001204.7(BMPR2):c.1157A>G (p.Glu386Gly) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). The variant has been reported once in an IPAH subject (PMID: 21801371). The variant is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The REVEL prediction algorithm score is 0.993, AlphaMissense is 0.9902 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Ala, p.Glu386Gln, p.Glu386Lys, p.Glu386Val) have been reported at the same position (PMID: 26387786) (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PP3, PM5_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341740/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:87681 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0014457 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009946 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0027497 infores:hetionet CHEBI:7852 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020580 infores:hetionet NCBIGene:9531 biolink:causes MONDO:0013061 infores:monarchinitiative not_provided not_provided HGNC:939 MONDO:0013061 uuid:9930b486-02dc-4dca-92ad-335665220933 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0004604 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0949070 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0949070 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0442874 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0235093 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0235093 infores:hetionet CHEBI:27504 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0040034 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0012833 infores:hetionet CHEBI:16469 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0017178 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0151602 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151623 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0018799 infores:hetionet CHEBI:6541 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042963 infores:hetionet CHEBI:168396 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0038990 infores:hetionet CHEBI:135738 biolink:causes UMLS:C1328539 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C1328539 infores:hetionet CAID:CA5252800 biolink:causes MONDO:0008535 infores:clingen CAID:CA5252800 MONDO:0008535 PMID: Likely Benign BS1_Supporting, BP4, BS3_Supporting The NM_001114753.3: c.1316A>C variant in ENG is a missense variant predicted to cause substitution of lysine by threonine at amino acid 439 (p.Lys439Thr). The filtering allele frequency (the lower threshold of the 95% CI of 15/10368) of the c.1316A>C variant in ENG is 0.0008918 for Ashkenazi Jewish chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.041, which is below the threshold of ≤0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Additionally, functional assays showed the variant protein localized to the cell surface and had normal BMP9 response indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1_Supporting, BP4, BS3_Supporting (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5252800/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48273 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0314719 infores:hetionet CHEBI:6847 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0034063 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0034067 infores:hetionet CHEBI:47780 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0025345 infores:hetionet NCBIGene:2009 biolink:causes MONDO:0010873 infores:monarchinitiative not_provided not_provided HGNC:3330 MONDO:0010873 uuid:e72d156d-ac45-4d4e-8f69-c18568383e35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0836924 infores:hetionet CHEBI:31397 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0235259 infores:hetionet CHEBI:7822 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0162830 infores:hetionet CAID:CA238570 biolink:causes MONDO:0020367 infores:clingen CAID:CA238570 MONDO:0020367 PMID: Likely Benign BS1, BP7, BP4 BS3, PM2, PM6, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.366C>T variant in MYOC is a synonymous variant (p.Gly122=). The highest allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.005694 , which met the ≥ 0.001 threshold set for BS1 (59 alleles out of 10,362, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.347 which met the ≤ 10 threshold for BP4, and the GERP score = -3.49 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA238570/MONDO:0020367/019 2022-02-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50924 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0311468 infores:hetionet CAID:CA512341257 biolink:causes MONDO:0100083 infores:clingen CAID:CA512341257 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 This synonymous variant has a SpliceAI Δ score of 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.008 (< 2)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341257/MONDO:0100083/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4903 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0004604 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0013595 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0027765 infores:hetionet CHEBI:135613 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0006266 infores:hetionet CHEBI:7025 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0037274 infores:hetionet CHEBI:9586 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151315 infores:hetionet CHEBI:59773 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C1527344 infores:hetionet CHEBI:136040 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0040822 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0041969 infores:hetionet CHEBI:63717 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C1384353 infores:hetionet CHEBI:231594 biolink:causes HP:0003249 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0151281 infores:hetionet CHEBI:50730 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0038325 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0521490 infores:hetionet CHEBI:45409 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0039231 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235834 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235834 infores:hetionet CHEBI:9434 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0014457 infores:hetionet CHEBI:3478 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0002874 infores:hetionet NCBIGene:1947 biolink:causes MONDO:0010570 infores:monarchinitiative not_provided not_provided HGNC:3226 MONDO:0010570 uuid:b4b88dd5-072f-4849-bcb3-bb867f97833e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0476273 infores:hetionet CHEBI:94501 biolink:causes HP:0005542 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151563 infores:hetionet CHEBI:3756 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0424296 infores:hetionet CHEBI:194135 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0014743 infores:hetionet CHEBI:474180 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0027497 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017160 infores:hetionet CHEBI:6078 biolink:causes UMLS:C0240273 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0240273 infores:hetionet CAID:CA410205727 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205727 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.76A>C (p.Asn26His) is a missense variant which has a REVEL score < 0.50 (0.319) and a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205727/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31644 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0008031 infores:hetionet CHEBI:44185 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0015672 infores:hetionet NCBIGene:1280 biolink:causes MONDO:0007895 infores:monarchinitiative not_provided not_provided HGNC:2200 MONDO:0007895 uuid:c6c1b9da-94eb-43ba-b05d-d76d6e087548 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003811 infores:hetionet CHEBI:84500 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0041834 infores:hetionet NCBIGene:7372 biolink:causes MONDO:0009797 infores:monarchinitiative not_provided not_provided HGNC:12563 MONDO:0009797 uuid:fb9131e1-32d2-4a15-ac86-dace429d389f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085633 infores:hetionet CHEBI:63581 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0278134 infores:hetionet CAID:CA014994 biolink:causes MONDO:0004994 infores:clingen CAID:CA014994 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4452C>T (p.Leu1484=) variant in the MYH7 gene is 0.74% (92/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014994/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3647 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0857353 infores:hetionet CHEBI:23765 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0018524 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0040409 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0034882 infores:hetionet CHEBI:4530 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013395 infores:hetionet CHEBI:10101 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1510410 infores:hetionet CHEBI:91834 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013390 infores:hetionet CHEBI:51041 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0017181 infores:hetionet CAID:CA410203840 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203840 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS3, PS4, PS2, PS1, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM1, PM3, PM5, PP2, PP1, PP4 NM_001754.5(RUNX1):c.233T>C (p.Met78Thr) is a missense variant and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score ≥ 0.88 (0.915) (PP3). The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203840/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9123 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002871 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0162429 infores:hetionet CAID:CA160252 biolink:causes MONDO:0010938 infores:clingen CAID:CA160252 MONDO:0010938 PMID: Benign BA1, BS2_Supporting BS1 The NM_000215.4(JAK3):c.452C>G (p.Pro151Arg) variant in JAK3 is a missense variant predicted to cause the substitution of Proline by Arginine at amino acid 151 (p.Pro151Arg). The Popmax Filtering allele frequency (95% CI) of the variant is 0.008679 in gnomAD v.4 for European (non-Finnish) population 10486/1179548 alleles, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, therefore, meets this criterion (BA1). Also, 59 homozygous adults are reported on GnomAD v2.1.1 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160252/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6128 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0030920 infores:hetionet CHEBI:10101 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0014724 infores:hetionet CHEBI:39669 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0006266 infores:hetionet CHEBI:8774 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151798 infores:hetionet CHEBI:4551 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0027540 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0005940 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0518015 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0020649 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0038367 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0474378 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0015376 infores:hetionet CHEBI:8774 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0002878 infores:hetionet CHEBI:8874 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042024 infores:hetionet CHEBI:3441 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0015230 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0031542 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0948349 infores:hetionet CHEBI:42944 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0030196 infores:hetionet CHEBI:10124 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C2363730 infores:hetionet CAID:CA386970411 biolink:causes MONDO:0015967 infores:clingen CAID:CA386970411 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS1, PP4 The c.1501+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 7 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 7 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to insufficient clinical information (PMID: 19169489). Therefore, PP4 cannot be applied. The nucleotide change c.1501G>A is predicted to disrupt the intron 7 splice donor site to a similar extent as c.1501+1G>T, however, the c.1501+1G>A variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. Therefore, PS1_Supporting cannot be applied. In summary, c.1501+1G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386970411/MONDO:0015967/017 2022-05-03 2022-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44915 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0151578 infores:hetionet NCBIGene:285600 biolink:causes MONDO:0032785 infores:monarchinitiative not_provided not_provided HGNC:28532 MONDO:0032785 uuid:15ebb5fd-9ff6-4a12-8fa5-a98decbf53d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020625 infores:hetionet CHEBI:16714 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0011603 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0852913 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004001 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0009492 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151574 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151574 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0030517 infores:hetionet NCBIGene:23169 biolink:causes MONDO:0010013 infores:monarchinitiative not_provided not_provided HGNC:20800 MONDO:0010013 uuid:8821f64f-a0ea-4c29-8ebf-4e6263099698 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018099 infores:hetionet CHEBI:7494 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0014868 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0521839 infores:hetionet CAID:CA10014361 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014361 MONDO:0011071 PMID: Likely Benign BP4, BS1, PS4_Supporting PS1, PS3, PS2, BP1, BP2, BP3, BA1, BP5, BP7, BS3, BS4, PVS1, PM2, PM6, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.764A>G (p.His255Arg) is a missense variant with a MAF of 0.0003937 (0.03937%, 2/5080, 2 alleles) in the East Asian subpopulation of the gnomAD v3.1.2 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score < 0.50 (0.483) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 31034769). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014361/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31236 biolink:causes UMLS:C0005826 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0005826 infores:hetionet CHEBI:92712 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0020452 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011053 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0239779 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0239779 infores:hetionet CHEBI:92511 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0020538 infores:hetionet UMLS:C0657912 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004134 infores:hetionet CAID:CA203395661 biolink:causes MONDO:0011225 infores:clingen CAID:CA203395661 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting BS2, PS1, PM5 The c.614A>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Asparagine by Isoleucine at amino acid 205 (p.Asn205Ile).The filtering allele frequency (the upper threshold of the 95% CI of 13/1180046 alleles) of the c.614A>T variant in DCLRE1C is 0.000005750 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA203395661/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7903 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0023530 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0242973 infores:hetionet NCBIGene:54796 biolink:causes MONDO:0032833 infores:monarchinitiative not_provided not_provided HGNC:30988 MONDO:0032833 uuid:925eecb8-eec6-4035-b88f-0e1fcf2c2acf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA024718 biolink:causes MONDO:0007783 infores:clingen CAID:CA024718 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PM1, PS4_Moderate, PP3_Moderate, PP1_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with alanine at codon 2375 of the RYR1 protein, p.(Gly2375Ala). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, four of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 12434264, 24433488, 25268394). This variant segregates with MHS in six individuals, PP1_Moderate (PMID:12434264, 14641996). Functional studies in HEK293 cells and patient myotubes showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648, 15210166). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.905) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024718/MONDO:0007783/012 2022-07-11 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:7478 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0268000 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151602 infores:hetionet CAID:CA2573153938 biolink:causes MONDO:0100326 infores:clingen CAID:CA2573153938 MONDO:0100326 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 The NM_000419.5(ITGA2B):c.2169del (p.Met724Ter) frameshift variant results in an immediate premature stop codon in exon 21 of 30 and is predicted to cause nonsense mediated decay (PVS1). This variant is absent from gnomAD v4.0.0 (PM2_Supporting). This variant is reported in one Glanzmann thrombasthenia patient in ClinVar (ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology). However, the phenotypic detail of this patient is not enough to apply PP4 by the PD VCEP. The patient is compound heterozygous with the Likely pathogenic variant NM_000419.5(ITGA2B):c.2174del (p.Lys725ArgfsTer6). No other cases of the variant segregating in GT patients were found in the literature. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_Supporting (VCEP specifications version 2; date of approval 04/16/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573153938/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:17650 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0151786 infores:hetionet CHEBI:28830 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0040034 infores:hetionet CHEBI:75722 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013362 infores:hetionet CHEBI:50777 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0085606 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0242350 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0521839 infores:hetionet CHEBI:70735 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C1760428 infores:hetionet CHEBI:27834 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0877359 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0700345 infores:hetionet CHEBI:63617 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085583 infores:hetionet CHEBI:31932 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0032285 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0041912 infores:hetionet CHEBI:116278 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0010520 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0242422 infores:hetionet CHEBI:6413 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0019080 infores:hetionet CAID:CA294722 biolink:causes MONDO:0010726 infores:clingen CAID:CA294722 MONDO:0010726 PMID: Benign BP5, BS1, BS2 The p.Ile293Met variant (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ile305Met variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). The allele frequency of the p.Ile293Met variant in MECP2 is 0.00027% in the East Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). In summary, the p.Ile293Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5, BS1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294722/MONDO:0010726/016 2021-12-13 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3216 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0020651 infores:hetionet CHEBI:184555 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0151872 infores:hetionet NCBIGene:23405 biolink:causes MONDO:0011014 infores:monarchinitiative not_provided not_provided HGNC:17098 MONDO:0011014 uuid:535470f0-6684-4e55-a848-1323e8ffde08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C1443060 infores:hetionet CHEBI:4953 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0003467 infores:hetionet CHEBI:31236 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0029453 infores:hetionet CHEBI:46557 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0700590 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151849 infores:hetionet CHEBI:9725 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0018418 infores:hetionet CHEBI:61049 biolink:causes HP:0011902 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0349705 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0011053 infores:hetionet NCBIGene:7066 biolink:causes MONDO:0008554 infores:monarchinitiative not_provided not_provided HGNC:11795 MONDO:0008554 uuid:b9a5a6bb-7d63-458c-888d-762c20e210b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0004093 infores:hetionet CHEBI:6076 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0038325 infores:hetionet CHEBI:51450 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0085636 infores:hetionet CHEBI:9635 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0042790 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0005940 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0009319 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0162429 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018799 infores:hetionet CAID:CA350341382 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341382 MONDO:0015924 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM1 PVS1, PM5, PS1 The BMPR2 c.1019T>C (p.Leu340Pro) variant is an exonic variant which is located in exon 8. This variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting met). The variant is located in a well-established protein kinase domain (PM1_met) and has been identified in 3 apparently unrelated individuals with PAH to date (PMIDs 18356561, 19555857, 32581362; PS4_supporting met). In silico prediction is consistent with a pathogenic effect ((REVEL score 0.980 (>0.75; PP3 met)). PP1 was not assessed due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for pulmonary arterial hypertension (PS1, PM5 not assessed). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting, PP3, PS4_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341382/MONDO:0015924/125 2024-09-20 2024-09-20 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:3664 biolink:causes MONDO:0007334 infores:monarchinitiative not_provided not_provided HGNC:6121 MONDO:0007334 uuid:f2ad62ec-659f-4ebc-b611-395867fc29e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027540 infores:hetionet CHEBI:50156 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0011991 infores:hetionet CHEBI:3213 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C1384666 infores:hetionet CHEBI:131512 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0030232 infores:hetionet CHEBI:4551 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0003123 infores:hetionet CHEBI:8245 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0011603 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0553713 infores:hetionet CHEBI:31932 biolink:causes MONDO:0000812 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0037933 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0011609 infores:hetionet CHEBI:42355 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0040264 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0948594 infores:hetionet CHEBI:49662 biolink:causes UMLS:C1504411 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1504411 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0008325 infores:hetionet CHEBI:119915 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0010520 infores:hetionet CHEBI:63623 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0031117 infores:hetionet CHEBI:3207 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0235439 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0162429 infores:hetionet CHEBI:8871 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007398 infores:hetionet CHEBI:145499 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2363730 infores:hetionet CHEBI:3175 biolink:causes UMLS:C3544060 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C3544060 infores:hetionet CAID:CA913163341 biolink:causes MONDO:0044970 infores:clingen CAID:CA913163341 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS3, PM2 The m.10455A>G variant in MT-TR was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported only once in the literature (PMID: 23463613; Supp Table S1B) in the homoplasmic state in an individual from H haplogroup and mother was not available for testing. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. There are no large families reported in the medical literature to consider for evidence of segregation. There are several occurrences of this variant in GenBank sequences queried through MITOMAP on 6/29/2020 (seen in 1-4 individuals from several haplogroups including J1c, H1b, H1j, U5a, N1a for a total of 12/51,192 frequency). The computational predictor MitoTIP suggests this variant is likely benign (10th percentile) and HmtVAR predicts it to be likely polymorphic (BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913163341/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:10110 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0010200 infores:hetionet UMLS:C0879264 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0086565 infores:hetionet CHEBI:119915 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0232461 infores:hetionet CHEBI:3223 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C1306341 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0242350 infores:hetionet CHEBI:8430 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0340865 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0041349 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013395 infores:hetionet CHEBI:8869 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0015672 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151773 infores:hetionet CHEBI:28925 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0002453 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0442886 infores:hetionet CHEBI:41977 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0032617 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0042401 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0042514 infores:hetionet UMLS:C0070099 biolink:causes MONDO:0001566 infores:drugmechdb knowledge_assertion manual_agent MESH:D044162 HP:0003072 DB00959_MESH_C562390_1DB00620_MESH_C562390_1DB00860_MESH_C562390_1DB00443_MESH_C562390_1DB01380_MESH_C562390_1DB00741_MESH_C562390_1DB00635_MESH_C562390_1 CHEBI:3419 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0041657 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0039971 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0003123 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0001824 infores:hetionet CAID:CA127025 biolink:causes MONDO:0019497 infores:clingen CAID:CA127025 MONDO:0019497 PMID:10633133PMID:10983956PMID:12352684 Pathogenic BS1, PM3_Very Strong, PS3_Moderate, PVS1 PP3, PM2, BA1 The filtering allele frequency of the p.Leu79CysfsX3 variant in the GJB2 gene is 0.55% (121/ 18870) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1 code will not contribute to the overall classification. The p.Leu79CysfsX3 variant in GJB2 is predicted to cause a premature stop codon in the only exon of the gene, leading to absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 10983956, 10633133). A dye transfer assay, a functional study, has shown that the variant impacts protein function (PS3_M; PMID: 12352684). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS3_M, BS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA127025/MONDO:0019497/005 2018-09-14 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:2453 biolink:causes UMLS:C0235573 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0235573 infores:hetionet CHEBI:9586 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0040822 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0024528 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0024528 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0009450 infores:hetionet CHEBI:3215 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0034063 infores:hetionet GO:2000477 biolink:causes GO:0072248 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0072248 CHEBI:28901 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0021368 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151765 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151765 infores:hetionet GO:1905770 biolink:causes GO:0007498 infores:ubergraph knowledge_assertion manual_agent GO:1905770 GO:0007498 CHEBI:17347 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011616 infores:hetionet CHEBI:8764 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151836 infores:hetionet CHEBI:9288 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0020598 infores:hetionet CHEBI:31643 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0020649 infores:hetionet CHEBI:5441 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0014457 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0151698 infores:hetionet CAID:CA8623360 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623360 MONDO:0100326 PMID: Uncertain Significance BS1 BP7, BS2 The NM_000212.3(ITGB3):c.1800G>A (p.Leu600=) synonymous variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population but has not been reported in a GT patient. The variant occurs at an allele frequency greater than expected for the disorder with a MAF of 0.01233 (365/29608 alleles, with 5 homozygotes) in the gnomADv4.0.0 Ashkenazi Jewish population (BS1). It is not predicted to have an impact on splicing consensus sites but the nucleotide is highly conserved. In summary there is insufficient evidence resulting in a classification of Uncertain Significance. GT-specific criteria applied: BS1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623360/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:63577 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0025061 infores:hetionet CHEBI:408174 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0040822 infores:hetionet NCBIGene:7516 biolink:causes MONDO:0030870 infores:monarchinitiative not_provided not_provided HGNC:12829 MONDO:0030870 uuid:ba10ebcf-9955-4847-8b4f-37dfa9b9de6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0019360 infores:hetionet NCBIGene:6663 biolink:causes MONDO:0012198 infores:monarchinitiative not_provided not_provided HGNC:11190 MONDO:0012198 uuid:889b5a00-6eea-4d28-b990-578e8df423ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0014591 infores:hetionet CHEBI:32315 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011175 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018418 infores:hetionet CHEBI:6437 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0542571 infores:hetionet NCBIGene:6578 biolink:causes MONDO:0013756 infores:monarchinitiative not_provided not_provided HGNC:10955 MONDO:0013756 uuid:52cb9cf4-7757-4599-989d-2b20f5a7fa8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4027 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0542203 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0860239 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020517 infores:hetionet CHEBI:38562 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C1384353 infores:hetionet CHEBI:40279 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002994 infores:hetionet CAID:CA10603706 biolink:causes MONDO:0010305 infores:clingen CAID:CA10603706 MONDO:0010305 PMID: Uncertain Significance PP4, PM2_Supporting, PM4 PP3, BP4 "The NM_005629.4:c.1072_1095del variant in SLC6A8 is a deletion of 24 nucleotides within exon 7 of the SLC6A8 gene and is predicted to lead to the deletion of 8 amino acids (p.Val358_Phe365del) (PM4). This variant has been previously reported in one hemizygous individual with elevated urinary creatine/creatinine (PMID: 34050321) (PP4). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). The in silico predictor MutPred-Indel gives a score of 0.85553 (>0.70 suggests that the variant is deleterious with a false positive rate of 5%), but MutationTaster predicts that the variant is a ""polymorphism"". Due to conflicting results, neither PP3 nor BP4 is met).There is a ClinVar entry for this variant (Variation ID: 280226). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM4, PP4, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 7, 2025)" Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603706/MONDO:0010305/027 2025-01-07 2025-01-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:3504 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0004096 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0235818 infores:hetionet CHEBI:51173 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0013144 infores:hetionet CHEBI:63619 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0086565 infores:hetionet CAID:CA355265058 biolink:causes MONDO:0100283 infores:clingen CAID:CA355265058 MONDO:0100283 PMID: Uncertain Significance PP2, PM2_Supporting, BP2, PS4_Moderate BP5 The NM_006218.4:c.1631C>A variant in the PIK3CA gene is a missense variant predicted to cause substitution of threonine by asparagine at amino acid 544. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Variant Curation Expert Panel (BM VCEP) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The variant was identified in a patient with colorectal cancer and a high-grade 3 cm tumor (PMID:22357840). The variant was also reported in association with 6 additional tumor samples in COSMIC (PS4_Moderate). Of note, in PIK3CA the variant has been observed in cis with the pathogenic variant c.1624G>A (p.Glu542Lys) (PMID:25722288) in an individual with features consistent with this disorder (BP2). This proband had a phenotype consistent with the condition, where neuroimaging demonstrated at least one large cerebral hemisphere with cortical malformations (PMID:25722288). In summary, due to conflicting information, this variant meets the criteria to be classified as uncertain significance for overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen BM VCEP: PM2_Supporting, PP2, PS4_Moderate, BP2 (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA355265058/MONDO:0100283/018 2025-06-06 2025-06-30 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true NCBIGene:135935 biolink:causes MONDO:0012689 infores:monarchinitiative not_provided not_provided HGNC:22448 MONDO:0012689 uuid:664399de-f914-4122-aa55-6ed2edb2932a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0013604 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0021400 infores:hetionet CHEBI:10125 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027497 infores:hetionet CHEBI:38562 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0039070 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042571 infores:hetionet CHEBI:47426 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0011175 infores:hetionet CHEBI:4681 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0027497 infores:hetionet CHEBI:6950 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2363731 infores:hetionet CHEBI:10125 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0036396 infores:hetionet CHEBI:92712 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0151878 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0267509 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0267509 infores:hetionet CHEBI:63631 biolink:causes HP:0003750 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0242979 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015300 infores:hetionet CHEBI:7476 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0085649 infores:hetionet CHEBI:63598 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0275524 infores:hetionet NCBIGene:50628 biolink:causes MONDO:0060664 infores:monarchinitiative not_provided not_provided HGNC:15717 MONDO:0060664 uuid:04c4113d-75aa-46f3-8e91-86d72d3f8b88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0038002 infores:hetionet CHEBI:3215 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0020580 infores:hetionet NCBIGene:91851 biolink:causes MONDO:0010649 infores:monarchinitiative not_provided not_provided HGNC:29861 MONDO:0010649 uuid:7dcdc906-816c-494b-ab5e-3843ad73270a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0021368 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0042373 infores:hetionet CHEBI:6456 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0038362 infores:hetionet CHEBI:41774 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0854467 infores:hetionet CHEBI:63622 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0042510 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015397 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0029134 infores:hetionet CHEBI:5959 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0947912 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0340464 infores:hetionet CHEBI:63619 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0030252 infores:hetionet GO:2000014 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:2000014 GO:0061458 CHEBI:9445 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0030252 infores:hetionet CHEBI:51209 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0231919 infores:hetionet CHEBI:5613 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C2981158 infores:hetionet CHEBI:10101 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0080274 infores:hetionet CHEBI:51141 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0085612 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006507 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018995 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151505 infores:hetionet CHEBI:17334 biolink:causes EFO:0005632 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C2243080 infores:hetionet CAID:CA10014523 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014523 MONDO:0011071 PMID: Likely Benign PM1_Supporting, BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, BS2, PP2, PP3, PP4, PP1 In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM1_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014523/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014742 infores:hetionet CHEBI:104011 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0030554 infores:hetionet CHEBI:40050 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0232462 infores:hetionet CHEBI:27504 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0234215 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235431 infores:hetionet CHEBI:9649 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0043352 infores:hetionet CHEBI:50693 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0020649 infores:hetionet CHEBI:8869 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0037011 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0007642 infores:hetionet CHEBI:28748 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C3665347 infores:hetionet CAID:CA415083182 biolink:causes MONDO:0010305 infores:clingen CAID:CA415083182 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_005629.4:c.786C>G variant in SLC6A8 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/13 (p.Tyr262Ter) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been previously reported in at least one male individual with elevated urinary creatine/creatinine, severely decreased creatine peak on brain MRS (PP4_Strong) (PMID: 12536364, PMID: 12889669). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415083182/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:7852 biolink:causes UMLS:C0741453 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0741453 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0520587 infores:hetionet CHEBI:8382 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0003708 infores:hetionet CHEBI:8863 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0039231 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0577730 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0577730 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0587094 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0587094 infores:hetionet NCBIGene:57592 biolink:causes MONDO:0014792 infores:monarchinitiative not_provided not_provided HGNC:29277 MONDO:0014792 uuid:af70c15a-8cea-4832-9229-c4adab2e029a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0343863 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0033860 infores:hetionet CHEBI:8080 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0027769 infores:hetionet GO:1905715 biolink:causes GO:0043588 infores:ubergraph knowledge_assertion manual_agent GO:1905715 GO:0043588 CHEBI:49603 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0022660 infores:hetionet CHEBI:10110 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0002874 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0595930 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006609 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0221244 infores:hetionet CAID:CA1139663116 biolink:causes MONDO:0700268 infores:clingen CAID:CA1139663116 MONDO:0700268 PMID: Uncertain Significance PM2, PVS1, PM5 The c.615_622dup variant in BRCA1 is a deletion of 8 nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 29 of the frameshift, or amino acid 236 (p.(Thr208AsnfsTer29)). This insertion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant in Exon 9(10) which is absent from biologically relevant transcript (PVS1_N/A, PM5_N/A). In summary, this variant did not meet any criteria and is classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (v1.2). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139663116/MONDO:0700268/092 2025-08-27 2025-08-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5138 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0039520 infores:hetionet CHEBI:6741 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0232462 infores:hetionet CAID:CA350341606 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341606 MONDO:0015924 PMID: Uncertain Significance PM2, PM1 PM6, PP3, BP4, PS4 The BMPR2 c.1126G>A (p.Glu376Lys) variant is an exonic variant located 3 base pairs before the end of exon 8. The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_Supporting). The variant has not been reported in pulmonary arterial hypertension patients to date. The variant has been identified in a patient with progressive myositis ossificans and a patient with unknown phenotype (ClinVar ID 977222) (PS4_not met). The variant is located in the well-established kinase domain (PM1_met). However, protein and splice-site prediction algorithms do not predict pathogenicity ((REVEL score 0.47 (>0,25-<0.75); Splice AI score 0 (benign)) (PP3_not met, BP4_not met). PP1 was not evaluated due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for PAH (PS1, PM5 not assessed). In summary, this variant meets the criteria to be classified as VUS for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341606/MONDO:0015924/125 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:36791 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019080 infores:hetionet CHEBI:4717 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0015967 infores:hetionet CHEBI:101278 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0232849 infores:hetionet CHEBI:31348 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0024236 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0014676 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0014676 uuid:065d501a-16ba-44fa-affc-09fb4c1174ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0851341 infores:hetionet CAID:CA16041893 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041893 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PM5_Supporting, PS3_Supporting The NM_000152.5:c.1564C>G variant in GAA is a missense variant predicted to cause substitution of proline by alanine at amino acid 522 (p.Pro522Ala). This variant has been detected in at least 7 unrelated patients reported to have Pompe disease including four individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 26800218, 33301762, 34072668, Duke University), and three for whom GAA activity was not reported (PMID: 18429042, 37087815) (PP4_Moderate). Of those individuals, 6 were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP: c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 18429042), c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728, SCV001371736.1) (PMID: 18429042), c.1465G>A (p.Asp489Asn) (ClinVar Variation ID: 92465, SCV003852732.1) (PMID: 34072668), and c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 26800218, 37087815, Clinical Diagnostic Laboratory; at least 3 unrelated patients). The phase is not confirmed for any of these individuals. One individual was homozygous for this variant (PMID: 33301762) (PM3_Strong). Another missense variant, c.1564C>T, p.Pro522Ser (ClinVar Variation ID: 972746) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cell line resulted in 0% wild type GAA activity when measured using fluorogenic substrate 4-methylumbelliferyl-α-D glucopyranoside. This was further supported via Western blot analysis demonstrating deficient GAA protein expression (PMID: 18429042) (PS3_Supporting). The computational predictor REVEL gives a score of 0.883 which is above the threshold predicting a damaging (>0.7) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 371277). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PM5_Supporting PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041893/MONDO:0009290/010 2024-03-19 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:59773 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0013604 infores:hetionet CHEBI:31711 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085593 infores:hetionet UMLS:C0657912 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0520888 infores:hetionet CHEBI:8673 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0018965 infores:hetionet CHEBI:9130 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151602 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0221255 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0221255 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0423271 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0423271 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0026636 infores:hetionet CHEBI:30659 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0000729 infores:hetionet CHEBI:42944 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003537 infores:hetionet CHEBI:45716 biolink:causes UMLS:C0016169 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0016169 infores:hetionet CHEBI:41879 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0018681 infores:hetionet CHEBI:75722 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0438142 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151971 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0009450 infores:hetionet CHEBI:51141 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0027497 infores:hetionet CHEBI:75998 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151904 infores:hetionet GO:1905902 biolink:causes GO:0007498 infores:ubergraph knowledge_assertion manual_agent GO:1905902 GO:0007498 CAID:CA229653 biolink:causes MONDO:0009861 infores:clingen CAID:CA229653 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong The c.611A>G (p.Tyr204Cys) variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 15503242). This variant has a MAF (0.00016) in gnomAD. This variant creates a fully active, novel 5 ́ donor splice site which results in an aberrantly spliced mRNA with a 96-nt deletion at the 3 ́-end of exon 6 PMID: 8990021 (aka Ex6-96A>G). Multiple lines of computational evidence support a deleterious effect. This variant was detected in trans with multiple pathogenic variants including: p.R111* (2); c.442-1G>A; p.R158W; p.L255S; p.P281L; p.K363Nfs*37; p.V399V; p.R408W; p.R241C (2); p.R243Q; p.R261Q (2); p.S349A; p.R413P; p.A434D (2) (PMID: 26322415). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3_very-strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229653/MONDO:0009861/006 2021-03-26 2021-03-26 Autosomal recessive inheritance HP:0000007 Supports CAID:CA397723077 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723077 MONDO:0008723 PMID: Likely Pathogenic PP3, PM3_Supporting, PP4_Moderate, PM2 The c.515T>C variant in ACADVL is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 172 (p.Leu172Pro). At least one patient with this variant displayed enzyme data which is highly specific for VLCAD. A proband with this variant had residual enzyme activity of 1% of controls (PP4_moderate) PMID 30194637. The computational predictor REVEL gives a score of 0.835, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been detected in at least 2 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 1 was compound heterozygous for the variant and a distinct pathogenic variant. The case was not confirmed in trans by parental or other testing methods. The other variant in this case was c.1332+2T>A, 0.5 points were applied to arrive at PM3_supporting. (PMID 30194637). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM2, PP3, PM3 (VCEP specifications version 1; 11/8/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723077/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1384666 infores:hetionet CHEBI:39112 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0035243 infores:hetionet CHEBI:75984 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018790 infores:hetionet CHEBI:6931 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0001807 infores:hetionet CHEBI:521033 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0018418 infores:hetionet CHEBI:4657 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0027769 infores:hetionet CHEBI:6888 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0009676 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0349506 infores:hetionet CHEBI:8874 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017181 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0022408 infores:hetionet CAID:CA10642025 biolink:causes MONDO:0012996 infores:clingen CAID:CA10642025 MONDO:0012996 PMID: Benign BA1 The NM_001482.3:c.*699A>C variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00149 (23/15424 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316205). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10642025/MONDO:0012996/025 2022-06-06 2022-10-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:465284 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0017181 infores:hetionet CHEBI:15544 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0031154 infores:hetionet CHEBI:5109 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0020517 infores:hetionet NCBIGene:2697 biolink:causes MONDO:0009035 infores:monarchinitiative not_provided not_provided HGNC:4274 MONDO:0009035 uuid:23f10f55-dad7-414b-9fbf-3711b164a8ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0030554 infores:hetionet GO:1901739 biolink:causes GO:0014902 infores:ubergraph knowledge_assertion manual_agent GO:1901739 GO:0014902 CHEBI:70718 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0428977 infores:hetionet CHEBI:4672 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C2939419 infores:hetionet CHEBI:31932 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0151904 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0037822 infores:hetionet CHEBI:168396 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020433 infores:hetionet CHEBI:50777 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0231528 infores:hetionet CHEBI:3764 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0042963 infores:hetionet CAID:CA8366018 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366018 MONDO:0100453 PMID: Likely Pathogenic PM3_Supporting, PP3_Moderate, PP4_Moderate, PM2_Supporting The NM_000180.4(GUCY2D):c.2132C>T (p.Pro711Leu) variant is predicted to replace the proline at position p.711 with leucine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000006199, with 10 alleles / 1,613,180 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.857, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5), present at birth (1 pt.), visual acuity of LP (light perception) (1 pt), visual field loss (1 pt), nystagmus (1 pt), photophobia (1 pt), non-recordable ERGs (1.5 pts), and without alternative variants after large gene panel testing (2 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 9 points, PMID: 23847139, PP4_Moderate). This variant has been reported in at least one proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 23847139). This variant has also been reported in one proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Glu196Val variant suspected in trans (0 points, PMID:20683928), which has not been classified by the ClinGen LCA/eoRD VCEP (0.5 total points, PM3_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3_Moderate, PP4_Moderate, PM3_Supporting, and PM2_Supporting.(VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366018/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CAID:CA157913750 biolink:causes MONDO:0015967 infores:clingen CAID:CA157913750 MONDO:0015967 PMID: Benign BS4, PP2, BS2 PS4, PM5, BS1, BS3, PM2, PP3 The c.1024A>C variant in the glucokinase gene, GCK, causes an amino acid change of threonine to proline at codon 342 (p.(Thr342Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a Popmax filtering allele frequency of 0.000004789, which is between the MDEP thresholds for PM2_Supporting and BS1. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21604084, PMID: 33046911). However, this variant was identified in multiple individuals with a normal fasting glucose (BS2; PMID: 23799006, PMID 21604084). Additionally, this variant does not segregate with diabetes in one family in the literature (BS4; PMID: 21604084). This variant has a REVEL score of 0.296, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. Additionally, functional studies are inconclusive on whether the p.Thr342Pro variant impacts glucokinase function (normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA interaction) (PMID 25015100). Two other missense variants, c.1024A>T (p.Thr342Ser) and c.1025C>T p.Thr342Met have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Taken together, the c.1024A>C variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS2, BS4, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA157913750/MONDO:0015967/086 2024-02-02 2024-02-02 Semidominant inheritance HP:0032113 Contradicts true CAID:CA410203506 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203506 MONDO:0011071 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 The NM_001754.5(RUNX1):c.317G>A (p.Trp106Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 24100448). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_Supporting and PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203506/MONDO:0011071/008 2022-01-20 2022-06-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5383 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0011603 infores:hetionet CHEBI:17303 biolink:causes MONDO:0041052 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0032768 infores:hetionet UMLS:C1144403 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0043144 infores:hetionet CHEBI:29007 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0023530 infores:hetionet CHEBI:553473 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0011991 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009938 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017601 infores:hetionet CHEBI:94411 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0039231 infores:hetionet CHEBI:144093 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151578 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0262385 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0848309 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0848309 infores:hetionet CHEBI:29007 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0014457 infores:hetionet CHEBI:48273 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C2004489 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0851341 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0521839 infores:hetionet CHEBI:68642 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0002871 infores:hetionet CHEBI:28748 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085641 infores:hetionet UMLS:C0004609 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0027424 infores:hetionet CHEBI:100246 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0018378 infores:hetionet CHEBI:7936 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0855333 infores:hetionet CHEBI:9570 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0162835 infores:hetionet CHEBI:3723 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C3263723 infores:hetionet NCBIGene:6011 biolink:causes MONDO:0013259 infores:monarchinitiative not_provided not_provided HGNC:10013 MONDO:0013259 uuid:dcd06d64-ddbf-4e8b-9b2a-e42b0643b544 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0010592 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C3665386 infores:hetionet CHEBI:68606 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0151578 infores:hetionet CHEBI:5778 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013404 infores:hetionet CHEBI:50841 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0036508 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235290 infores:hetionet CAID:CA10014271 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014271 MONDO:0011071 PMID: Uncertain Significance PS4, PS3, PS1, PS2, BA1, BP1, BP4, BS1, BS3, BS4, PM2, PM6, PVS1, PM3, PM1, PM5, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.916C>T (p.Arg306Cys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014271/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6954 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0085692 infores:hetionet CHEBI:17549 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151908 infores:hetionet CHEBI:9086 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0025874 infores:hetionet CHEBI:31236 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028084 infores:hetionet CHEBI:31932 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0039231 infores:hetionet CAID:CA10585617 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585617 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, PP3 The NM_000527.5(LDLR):c.1796T>G (p.Leu599Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1)PP4 - Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible/definite FH criteria for FH from PMID 22881376., after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585617/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA367401894 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401894 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP4, PP2, PP3, PM2_Supporting The c.466C>G variant in the glucokinase gene, GCK, causes an amino acid change of histidine to aspartate at codon 156 (p.(His156Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.836, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Another missense variant, c.466C>T p.His156Tyr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.466C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2, PM5_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401894/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Inconclusive true NCBIGene:8625 biolink:causes MONDO:0971013 infores:monarchinitiative not_provided not_provided HGNC:9987 MONDO:0971013 uuid:332a3205-9aea-4317-b01d-d138c1e96e45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3636 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0015967 infores:hetionet CHEBI:8107 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0221269 infores:hetionet NCBIGene:199857 biolink:causes MONDO:0014542 infores:monarchinitiative not_provided not_provided HGNC:28287 MONDO:0014542 uuid:e8684184-4744-4fd0-a6d3-739570729589 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0152031 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0853748 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0027651 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0232910 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0027726 infores:hetionet CHEBI:32293 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0015230 infores:hetionet CHEBI:7496 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0151904 infores:hetionet CHEBI:45081 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0041834 infores:hetionet CHEBI:4858 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0085631 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006849 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0027769 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0233494 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0948594 infores:hetionet CHEBI:63638 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0038450 infores:hetionet CHEBI:63611 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0852911 infores:hetionet CHEBI:6367 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0702166 infores:hetionet CHEBI:3614 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0041912 infores:hetionet CHEBI:63612 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0037822 infores:hetionet CHEBI:8378 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0015403 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0162119 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020538 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0520589 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0162820 infores:hetionet CHEBI:408174 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0019348 infores:hetionet CHEBI:51860 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C2047937 infores:hetionet CAID:CA8337965 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337965 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 PP4 The c.1103A>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glutamine by proline at amino acid 368 (p.Gln368Pro). Several individuals with this variant were identified by newborn screen or were identified in individuals without additional laboratory data to support affected status, so this information is insufficient to use toward classification (PMID: 26385305, 31031081). This variant is only detected on one allele in gnomAD v2.1.1, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337965/MONDO:0008723/021 2024-09-10 2024-12-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:119915 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235567 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0033975 infores:hetionet NCBITaxon:39824 biolink:causes MONDO:0005777 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:39824 MESH:D006100 DB00618_MESH_D006100_1DB13092_MESH_D006100_1DB01017_MESH_D006100_1DB00759_MESH_D006100_1DB00254_MESH_D006100_1DB01082_MESH_D006100_1DB02703_MESH_D006100_1DB00595_MESH_D006100_1 CHEBI:134745 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0042963 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019917 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085762 infores:hetionet CHEBI:63627 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0278134 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026848 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0746883 infores:hetionet CHEBI:6931 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0009806 infores:hetionet CHEBI:92511 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0038325 infores:hetionet CHEBI:7025 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0011616 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0009450 infores:hetionet CHEBI:8874 biolink:causes UMLS:C1262022 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1262022 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0243026 infores:hetionet CAID:CA010203 biolink:causes MONDO:0005021 infores:clingen CAID:CA010203 MONDO:0005021 PMID: Uncertain Significance PP3, PM2, PM5 BS4, PP2, PP1, PM6, PVS1, PM4, PM1, BP4, PS1, PS3, PS4, PS2 NM_000257.4(MYH7):c.1106G>C (p.Arg369Pro). This variant has been described in individuals with DCM and other cardiomyopathies (Variation ID 164379), including in an individual with LVNC in which the variant was presumed to be a de novo occurrence. However, because the reported phenotype is not specific enough, the PM6 criterion was not invoked. This variant was absent from large population studies (gnomAD v2.1). This variant is not statistically increased in individuals with DCM compared to controls; [OR lower 95% CI <5]. Therefore, the PS4 criteria has not been applied and the PM2_Supporting criterion has been applied (PM2_Supporting). This variant lies in the head region of the protein (aa 167-931) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2019 PMID: 30696458), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. A different missense variant for DCM/LVNC that has been classified as likely pathogenic by this expert panel has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5_supporting; ClinVar Variation ID 42822). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner based on PM2_Supporting, PM5_Supporting, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010203/MONDO:0005021/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:18385 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0549386 infores:hetionet CHEBI:3655 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0031256 infores:hetionet CHEBI:39867 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0030252 infores:hetionet CAID:CA16020936 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020936 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting The c.1081A>C (p.Lys361Gln) variant in PAH has been reported in 1 individual with benign (untreated) HPA (Phe 120-360 uM), BH4 deficiency excluded. It was detected with pathogenic variant p.R243X (PMID: 23500595, 27121329) This variant is absent in population databases (PM2). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020936/MONDO:0009861/006 2019-12-16 2021-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:205919 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0162820 infores:hetionet CHEBI:100147 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C2939465 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0031117 infores:hetionet CHEBI:3698 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0032617 infores:hetionet CHEBI:92712 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0026636 infores:hetionet CHEBI:63617 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085636 infores:hetionet CHEBI:50729 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0030193 infores:hetionet CHEBI:27690 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0030554 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151664 infores:hetionet CAID:CA288013 biolink:causes MONDO:0100488 infores:clingen CAID:CA288013 MONDO:0100488 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1004G>A (p.Arg335Gln) missense variant has a maximum subpopulation frequency of 0.0085% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 140 probands not meeting HDGC phenotype criteria (BS2; SCV000149741.15, SCV000185512.7, SCV003926714.1, SCV000288411.10). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288013/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true NCBIGene:1286 biolink:causes MONDO:0008762 infores:monarchinitiative not_provided not_provided HGNC:2206 MONDO:0008762 uuid:3eaefd97-4fab-47fe-8f14-05cd981dfdfd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82960 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0006145 infores:hetionet CHEBI:3176 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0151766 infores:hetionet CHEBI:9757 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0234913 infores:hetionet CHEBI:5147 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0015672 infores:hetionet NCBITaxon:5061 biolink:causes MONDO:0021935 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5061 MONDO:0021935 CAID:CA016701 biolink:causes MONDO:0004994 infores:clingen CAID:CA016701 MONDO:0004994 PMID: Uncertain Significance PP3, PM2, PS4_Supporting PP1, BA1, PM5, PM1, PS3, PM6, BS1, BS3, BS4, PS1, PS2, BP4, BP2, BP5 The c.728G>A (p.Arg243His) variant in MYH7 has been identified in 3 individuals with HCM (Arad 2005 PMID:16267253; van Velzen 2016 PMID:27476098; GeneDx pers. comm.), 2 individuals with DCM (one of whom carried a VUS in another DCM gene; Walsh 2017 PMID:27532257; GeneDx pers. comm.), 1 individual with LVNC, dilation, and congestive heart failure prior to transplant at 26 yo - Klaassen 2008 PMID:18506004) and 6 individuals with LVNC or non-compaction cardiomyopathy (van Waning 2018 29447731; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant segregated in 7 individuals with LVNC, 1 with LV dysfunction, and 1 with DCM from 5 families (Klaassen et al 2008, PMID 18506004; GeneDx, pers. comm.; Invitae, pers. comm.; OMGL, pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the PS4_Supporting criterion is being applied for the DCM phenotypes. Additionally, current evidence is insufficient to establish segregation with DCM or HCM and therefore the PP1 criterion has not been applied. This variant was identified in 0.003% (1/34592) of Latino chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes that are predominant for this variant; therefore PM1 is not applicable. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to variable and conflicting evidence, this variant is classified as uncertain significance for inherited cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016701/MONDO:0004994/002 2021-06-16 2021-06-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15367 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0232462 infores:hetionet GO:2000027 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:2000027 GO:0048513 CHEBI:31705 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0700225 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C1971624 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0032961 infores:hetionet CHEBI:5790 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C1167965 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0851341 infores:hetionet CHEBI:7983 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0151559 infores:hetionet CHEBI:6888 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0423798 infores:hetionet CHEBI:490877 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0020580 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0023067 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0019158 infores:hetionet CHEBI:38562 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0013395 infores:hetionet CHEBI:5280 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0038362 infores:hetionet CHEBI:2668 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0016382 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0022568 infores:hetionet NCBIGene:57282 biolink:causes MONDO:0958278 infores:monarchinitiative not_provided not_provided HGNC:13811 MONDO:0958278 uuid:1b40b74d-29ea-41d3-99a4-6ba1a5ed711e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0152031 infores:hetionet CHEBI:9086 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0020625 infores:hetionet CHEBI:3219 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020578 infores:hetionet CHEBI:63621 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0027121 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0948594 infores:hetionet CHEBI:63577 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0041657 infores:hetionet CHEBI:94449 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0042963 infores:hetionet CHEBI:4814 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0232462 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0001824 infores:hetionet CHEBI:8707 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040460 infores:hetionet CAID:CA10650417 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650417 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*2366G>A is a 3' UTR variant which has a MAF of 0.0001176 (0.01176%, 8/68044, 8 alleles) in the European (non-finnish) subpopulation of the gnomAD v3.1.2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650417/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10101 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0016204 infores:hetionet CHEBI:47898 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085612 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0392197 infores:hetionet CHEBI:168396 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151904 infores:hetionet CHEBI:3614 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0017675 infores:hetionet CHEBI:10023 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0231528 infores:hetionet CAID:CA201503 biolink:causes MONDO:0015967 infores:clingen CAID:CA201503 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting, PS3_Moderate PM1 The c.118G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 40 (p.(Glu40Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.069, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 25015100). This variant was identified in at least 33 unrelated individuals with hyperglycemia (PS4; PMID: 22332836, 29207974, 25015100, Internal lab contributors). This variant segregated with hyperglycemia, with four informative meioses in three families (PP1_Strong; PMID: 24804978, Internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative) (PP4_Moderate; Internal lab contributor). This variant has been detected in the homozygous state in one individual with neonatal diabetes (PM3_Supporting; PMID: 25015100). In summary, c.118G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PS3_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting, PM3_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA201503/MONDO:0015967/086 2025-01-29 2025-01-29 Semidominant inheritance HP:0032113 Supports CHEBI:51041 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0015230 infores:hetionet CHEBI:71219 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C2830004 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0010692 infores:hetionet CAID:CA000283 biolink:causes MONDO:0017623 infores:clingen CAID:CA000283 MONDO:0017623 PMID: Likely Pathogenic PS1_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting NM_000314.8(PTEN):c.106G>C (p.Gly36Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS1_M: Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change (ClinVar Variation ID: 1334551)PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.69 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM2_P: Absent in gnomAD.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.995) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000283/MONDO:0017623/003 2023-10-11 2023-10-18 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:57505 biolink:causes MONDO:0014387 infores:monarchinitiative not_provided not_provided HGNC:21022 MONDO:0014387 uuid:42dbf60c-7933-4b4f-b991-509ce1771de7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0025323 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0232492 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017152 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0038367 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020517 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030312 infores:hetionet CHEBI:2611 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0151766 infores:hetionet CHEBI:5138 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0025222 infores:hetionet NCBIGene:8560 biolink:causes MONDO:0032730 infores:monarchinitiative not_provided not_provided HGNC:13709 MONDO:0032730 uuid:2cbe50e3-31b6-4f2c-b17c-93012231da67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4911 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C2242996 infores:hetionet CHEBI:9123 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003537 infores:hetionet CHEBI:94449 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0020456 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0027051 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0023895 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0178298 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0851341 infores:hetionet CHEBI:31236 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004044 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0151735 infores:hetionet CHEBI:45081 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151908 infores:hetionet CHEBI:31711 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0039231 infores:hetionet CHEBI:9738 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0009806 infores:hetionet CHEBI:8214 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0038990 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020437 infores:hetionet CHEBI:7915 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0023218 infores:hetionet CAID:CA10014737 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014737 MONDO:0011071 PMID: Likely Benign BP2, BS1 PS1, PS3, PS2, PS4, BP3, BP1, BP4, BA1, PVS1, PM2, PM6, BP5, BP7, BS4, BS3, PM3, PM4, PM5, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.-2C>T is a 5' UTR substitution variant which has a MAF of 0.0005758 for East Asian chromosomes by gnomAD v4, exceeding the ClinGen Myeloid Malignancy VCEP threshold (>0.00015) (BS1). Additionally, it has been observed in one homozygote in gnomAD v4 (BP2). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014737/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7447 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0027540 infores:hetionet CHEBI:36795 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0344232 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0038362 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0039971 infores:hetionet CHEBI:45409 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151970 infores:hetionet CHEBI:75998 biolink:causes EFO:0009879 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0235325 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0021053 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0340726 infores:hetionet CHEBI:8890 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0231218 infores:hetionet NCBIGene:535 biolink:causes MONDO:0031021 infores:monarchinitiative not_provided not_provided HGNC:865 MONDO:0031021 uuid:ae380895-0151-45fd-bdf8-e33c2b26a02f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7575 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0027765 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1142135 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0020538 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027441 infores:hetionet CHEBI:51450 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0037299 infores:hetionet CHEBI:9139 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035317 infores:hetionet CHEBI:6804 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0018790 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0009782 infores:hetionet CHEBI:3506 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0151872 infores:hetionet CHEBI:45716 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0012833 infores:hetionet CHEBI:6129 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0232849 infores:hetionet CHEBI:9571 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0018790 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0542101 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0740447 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0740447 infores:hetionet CAID:CA6831955 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831955 MONDO:0015967 PMID: Benign BA1, PM5_Supporting, PP3 PS4, PM1, BP5, PM2 The c.1135C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 379 (p.(Pro379Ala)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While this variant has been identified in >20 unrelated individuals with diabetes in the literature (ClinVar ID 431970, PMID:18003757, 23348805, 29207974, 21761282, 23607861), the Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.0005027, which is greater than the MDEP threshold for BA1 (>0.0001) (BA1). Therefore, PS4 cannot be applied. Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but this variant has a greater Grantham distance than p.Pro379Ala (PM5_Supporting). In summary, the c.1135C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BA1, PP3, PM5_Supporting. It may, however, confer an increased risk of type 2 diabetes (OR = 11.8, p = 0.0007324 at https://t2d.hugeamp.org/). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831955/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:32315 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002418 infores:hetionet CHEBI:82866 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01153 UMLS:C0041834 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0267792 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0151736 infores:hetionet GO:1903341 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1903341 GO:0019953 CHEBI:3499 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0008370 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948715 infores:hetionet CAID:CA16022351 biolink:causes MONDO:0021056 infores:clingen CAID:CA16022351 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.471G>A (p.Trp157Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 5 in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/233100 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 1.0 (PS4_Supporting, PMID: 20399906). Moreover, the variant has been reported in at least 4 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 22941256, 8381580, 20685668; ClinVar ID: VCV000411479.17). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications version 2.0.3; date of approval: 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16022351/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:39112 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0852913 infores:hetionet CHEBI:6888 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0003811 infores:hetionet CHEBI:10127 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009421 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0011609 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0007564 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0007564 uuid:04cbe1eb-9b06-4193-8ec7-52971b8a60e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0015397 infores:hetionet CHEBI:135613 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C2830004 infores:hetionet CAID:CA159995 biolink:causes MONDO:0015967 infores:clingen CAID:CA159995 MONDO:0015967 PMID:25555642PMID:10690959 Benign BA1 PS4, PM2, PP3, PP1 The c.155_156delinsCT variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Glycine to Alanine at codon 52 (p.(Gly52Ala)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0024, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). In summary, c.155_156delinsCT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA159995/MONDO:0015967/017 2022-05-03 2022-05-03 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:84320 biolink:causes MONDO:0968976 infores:monarchinitiative not_provided not_provided HGNC:23339 MONDO:0968976 uuid:895bb860-3e25-441d-b6b9-0a9a558cbed1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA267623 biolink:causes MONDO:0009861 infores:clingen CAID:CA267623 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 The c.1004A>C (p.Lys335Thr) variant in PAH has not been reported in a patient to our knowledge. It was reported to BioPKU in 2013 by Namour B. This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267623/MONDO:0009861/006 2020-04-10 2020-04-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4798 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0034152 infores:hetionet CHEBI:6339 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0008031 infores:hetionet CHEBI:16469 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0009676 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0877153 infores:hetionet CHEBI:8228 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0016204 infores:hetionet NCBIGene:8974 biolink:causes MONDO:0014982 infores:monarchinitiative not_provided not_provided HGNC:8547 MONDO:0014982 uuid:92f483dc-a8c4-4784-b947-d590cda9b49b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6149 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0522055 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026946 infores:hetionet CHEBI:144093 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020458 infores:hetionet CHEBI:480999 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0242379 infores:hetionet GO:0019182 biolink:causes GO:0051381 infores:ubergraph knowledge_assertion manual_agent GO:0019182 GO:0051381 CHEBI:5147 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0019270 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0151541 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151541 infores:hetionet CAID:CA16609138 biolink:causes MONDO:0010305 infores:clingen CAID:CA16609138 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_005629.4:c.48C>A variant in SLC6A8 is a missense variant predicted to result in substitution of aspartate by glutamate at amino acid 16 (p.Asp16Glu). The variant is absent in gnomAD v2.1.1, although low coverage is noted (PM2_Supporting). The computational predictor REVEL gives a score of 0.123, evidence that does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been reported in any patients with creatine transporter deficiency in the literature. There is a ClinVar entry for this variant (Variation ID: 392671). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609138/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true CHEBI:85161 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0011603 infores:hetionet CHEBI:50156 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0027497 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0038661 infores:hetionet CHEBI:101278 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0006277 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042267 infores:hetionet CAID:CA2580098818 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098818 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1110del (p.Met371TrpfsTer?) is a frameshift variant which terminates 223 residues later. It is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098818/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0231835 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0270994 infores:hetionet NCBIGene:3265 biolink:causes MONDO:0008566 infores:monarchinitiative not_provided not_provided HGNC:5173 MONDO:0008566 uuid:12867828-bc6c-4288-a2f5-35d659392be9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0015376 infores:hetionet CHEBI:59445 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0041582 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0009806 infores:hetionet CHEBI:75246 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0002994 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002170 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0235723 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0235723 infores:hetionet CHEBI:6375 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1510410 infores:hetionet CHEBI:5558 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0023222 infores:hetionet CHEBI:63611 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0041834 infores:hetionet CHEBI:64354 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C1368065 infores:hetionet CHEBI:51164 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0030662 infores:hetionet CHEBI:5134 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0020456 infores:hetionet CHEBI:7465 biolink:causes HP:0005224 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0267566 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0020649 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151773 infores:hetionet CHEBI:17026 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151904 infores:hetionet CHEBI:46295 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0231528 infores:hetionet CHEBI:5784 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0011991 infores:hetionet CHEBI:6541 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042384 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0542184 infores:hetionet CHEBI:50777 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0002453 infores:hetionet CHEBI:47381 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013378 infores:hetionet CHEBI:3127 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0162830 infores:hetionet CHEBI:64312 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0151662 infores:hetionet CHEBI:15551 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0004096 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233479 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233479 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0038587 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0030353 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0022650 infores:hetionet CHEBI:127780 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0040053 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0039503 infores:hetionet CHEBI:168396 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0438142 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0004936 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0001824 infores:hetionet CHEBI:231594 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0231530 infores:hetionet CHEBI:71272 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0853692 infores:hetionet UMLS:C0145185 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0018681 infores:hetionet CHEBI:180905 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0009763 infores:hetionet CHEBI:17549 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0699893 infores:hetionet CHEBI:5778 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0039070 infores:hetionet CHEBI:42820 biolink:causes HP:0004743 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0238304 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0027497 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0019360 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0027765 infores:hetionet NCBIGene:5894 biolink:causes MONDO:0014396 infores:monarchinitiative not_provided not_provided HGNC:9829 MONDO:0014396 uuid:a6874b6e-0484-466e-bdcb-2308afce90f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6970 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0175167 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0034150 infores:hetionet CHEBI:37941 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042790 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027947 infores:hetionet CAID:CA410147564 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147564 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1270T>C (p.Ser424Pro) is a missense variant predicted to cause the substitution of serine by proline at amino acid 424 (p.S424P). This variant is absent from gnomAD v2, but in gnomAD v3, the highest population minor allele frequency is 0.07016% (4/4276 alleles) in the East Asian population, and in gnomAD v4, it is 2.641% (624/23626 alleles) in the East Asian population. Both frequencies are higher than the overall allele frequency of all disease-causing alleles derived by the ClinGen Myeloid Malignancy-VCEP. However, genomes failed a quality filter (AS_VQSR) in gnomAD v3 and v4, allele balance is heavily skewed, and site quality seems lower compared to some common, known pathogenic variants (BA1 not met).This variant has been reported in a 59-year-old female with thrombocytopenia and a secondary defect, who also carried RUNX1 c.1256T>G (p.Val419Gly) (phasing unclear) and a 2.5 Mb deletion including FLI1, although the germline origin was presumed rather than confirmed by tissue or familial testing (PMID: 32935436). Additionally, one individual in a Japanese family with B-ALL, likely due to PAX5 G183R, was found to carry this variant, while two siblings were negative (PMID: 35902733). Another patient reportedly with hereditary thrombocytopenia and hematological cancer predisposition associated with RUNX1 carried this variant in the germline, but an unspecified number of affected relatives in the family were negative (ClinVar Accession: SCV002515682.3). The variant has also been reported in patients with AML (PMID: 36900179), MDS (PMID: 36932114), and other tumors (PMID: 30239046; PMID: 30246500; PMID: 32943879; PMID: 35626111; PMID: 37160887; PMID: 37994105), though the variant allele fraction mostly suggests somatic origin or artifact (unconfirmed).No relevant functional data are available for this specific missense variant, but in vitro studies have demonstrated that Ser424 is a phosphorylation target of CDK/Cyclin complexes (PMID: 18003885). The computational predictor REVEL gives a score of 0.465, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, suggesting it does not predict a damaging effect on RUNX1 function (BP4).In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147564/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4653 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0541782 infores:hetionet CHEBI:63621 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0013604 infores:hetionet CAID:CA6748812 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748812 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting BP7 The NM_000277.3:c.870T>C variant in PAH is a synonymous (silent) variant (p.His290=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001694 (6/35412 alleles) in the Latino/Admixed American population, which is lower than the ClinGen PAH VCEP’s threshold for PM2_Supporting (<0.0002), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 991620, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748812/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8869 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0019360 infores:hetionet CAID:CA386964424 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964424 MONDO:0015967 PMID:1985954PMID:12453420PMID:21683639PMID:16917892PMID:23674172 Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP1_Strong, PP4_Moderate, PP3 BA1, BP4, BS1 The c.620G>A variant in the HNF1 Homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 207 (p.(Gly207Asp)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate). Furthermore, this variant segregated with diabetes, with 10 informative meioses, in one family with MODY (PP1_Strong). The glycine at the 207 codon position is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.620G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM1_Supporting, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964424/MONDO:0015967/017 2022-06-10 2022-06-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4798 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042029 infores:hetionet CAID:CA390881994 biolink:causes MONDO:0100216 infores:clingen CAID:CA390881994 MONDO:0100216 PMID:28012864PMID:28012864 Uncertain Significance PP3, BS2_Supporting PM2, PM6, BA1, BP4, BP2, PP1, PP4, PM5, PM1, PS1, PS2, PS3, PS4, BS1, BS4, BS3 The NM_177438.3:c.2455T>C variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 819 (p.Tyr819His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMIDs: 28012864, Internal lab contributors). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000006198 (10/1613442 alleles) with a highest population minor allele frequency of 0.000007631 (9/1179402 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.876) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_supporting, PP3. (Bayesian Points: 0; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390881994/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2663 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0085610 infores:hetionet NCBIGene:55366 biolink:causes MONDO:0859205 infores:monarchinitiative not_provided not_provided HGNC:13299 MONDO:0859205 uuid:d29ad95e-bf3c-4c01-94b3-3af4a3d251a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA233657 biolink:causes MONDO:0100039 infores:clingen CAID:CA233657 MONDO:0100039 PMID: Likely Benign BS2, BP5 The p.Ser796= variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ser796= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database)(BP5). In summary, the p.Ser796= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA233657/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Contradicts true CHEBI:44032 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0948525 infores:hetionet CHEBI:9137 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0015967 infores:hetionet CHEBI:44241 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0030312 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0001824 infores:hetionet CHEBI:8212 biolink:causes UMLS:C0542224 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0542224 infores:hetionet CHEBI:92712 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0151539 infores:hetionet CHEBI:6775 biolink:causes MONDO:0000494 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0151650 infores:hetionet CAID:CA2497028747 biolink:causes MONDO:0015967 infores:clingen CAID:CA2497028747 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP1, PP4 The c.1379_*2del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), causing a deletion of amino acids 26-265 and adding 146 novel amino acids before encountering a stop codon (p.(p.Ala460_Gln465delins146)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes. However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). Insufficient clinical information was available to evaluate for PP4. This variant segregated with diabetes with one informative meiosis in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.1379_*2del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2, approved 6/7/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2497028747/MONDO:0015967/086 2023-06-18 2023-06-18 Semidominant inheritance HP:0032113 Supports GO:0048345 biolink:causes GO:0048343 infores:ubergraph knowledge_assertion manual_agent GO:0048345 GO:0048343 CHEBI:7507 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0042769 infores:hetionet CHEBI:9086 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0043387 infores:hetionet CHEBI:6062 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0022408 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0151888 infores:hetionet CHEBI:31932 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020458 infores:hetionet CHEBI:134743 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0018681 infores:hetionet CHEBI:39112 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0040264 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0086543 infores:hetionet CHEBI:135935 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0004134 infores:hetionet CHEBI:3568 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003862 infores:hetionet CHEBI:9130 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0008031 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004936 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0574067 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0024894 infores:hetionet CHEBI:17823 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0852911 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233459 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235398 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235398 infores:hetionet CAID:CA16042049 biolink:causes MONDO:0010725 infores:clingen CAID:CA16042049 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1 The NM_000330.4(RS1):c.498C>A variant is a nonsense variant in amino acid 166, which results in a premature stop codon and causes a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 30025115, 32860923, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PVS1, and PS4_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042049/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CAID:CA2695224148 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224148 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong The c.932_933del (p.Val311GlyfsTer39) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient 1 in PMID: 9241731) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by Western blot, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224148/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15552 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0036974 infores:hetionet CAID:CA638053819 biolink:causes MONDO:0011071 infores:clingen CAID:CA638053819 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.968-10C>T is an intronic variant which is not predicted to impact splicing. This variant has a SpliceAI score ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.22 < 2.0) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638053819/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135935 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0041657 infores:hetionet CHEBI:10127 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0012569 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0013922 infores:hetionet CHEBI:50729 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0876994 infores:hetionet CHEBI:3219 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0022346 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0853761 infores:hetionet CHEBI:71255 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0040034 infores:hetionet CHEBI:68610 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0042029 infores:hetionet CHEBI:72690 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020458 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0520893 infores:hetionet CAID:CA10014499 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014499 MONDO:0011071 PMID: Uncertain Significance PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.508+5G>A is an intronic variant located within intron 5. This variant has a SpliceAI score of 0.44 (>0.38), suggesting a risk that this variant disrupts splicing (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014499/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:553473 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0332534 infores:hetionet CHEBI:79699 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0031039 infores:hetionet CHEBI:16796 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0151908 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0028738 infores:hetionet CHEBI:94392 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0232462 infores:hetionet GO:0060651 biolink:causes GO:0060603 infores:ubergraph knowledge_assertion manual_agent GO:0060651 GO:0060603 CHEBI:40237 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0030305 infores:hetionet CHEBI:41879 biolink:causes UMLS:C1608950 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1608950 infores:hetionet CHEBI:5778 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0687713 infores:hetionet CHEBI:72297 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0311468 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0277585 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C1761613 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C2225524 infores:hetionet CHEBI:2636 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0521465 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0836924 infores:hetionet CHEBI:100241 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0041657 infores:hetionet CHEBI:63599 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0919924 infores:hetionet NCBIGene:3192 biolink:causes MONDO:0033363 infores:monarchinitiative not_provided not_provided HGNC:5048 MONDO:0033363 uuid:43d6ae63-4332-4f13-9636-a4e00a32c9ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7867 biolink:causes MONDO:0014920 infores:monarchinitiative not_provided not_provided HGNC:6888 MONDO:0014920 uuid:82d9685a-f187-4e18-b4e0-c8f8a2e16567 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018799 infores:hetionet CHEBI:28748 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0032227 infores:hetionet CHEBI:31413 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0042790 infores:hetionet NCBIGene:80347 biolink:causes MONDO:0014290 infores:monarchinitiative not_provided not_provided HGNC:29932 MONDO:0014290 uuid:ec21bd7d-2a3e-4630-bb50-5a422e1aab6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2659 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0011616 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0340515 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0340515 infores:hetionet GO:0001949 biolink:causes CL:2000021 infores:ubergraph knowledge_assertion manual_agent GO:0001949 CL:2000021 CHEBI:16796 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0037763 infores:hetionet CHEBI:7465 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0004604 infores:hetionet CAID:CA170438 biolink:causes MONDO:0100039 infores:clingen CAID:CA170438 MONDO:0100039 PMID:19253388 Benign BS1, BS2, BP4 PM2, PS4 The highest population minor allele frequency of the p.Asn399Thr variant in CDKL5 in gnomAD v4.1 is 0.0000156 in Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0000083) for BS1, and therefore meets this criterion (BS1). The p.Asn399Thr variant in CDKL5 is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Asn399Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn399Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170438/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0017178 infores:hetionet CHEBI:59773 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027947 infores:hetionet CHEBI:3732 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0340865 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0007642 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006147 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151826 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0151705 infores:hetionet CHEBI:9654 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0085593 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0037199 infores:hetionet CHEBI:36791 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007398 infores:hetionet CHEBI:135530 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0039231 infores:hetionet CHEBI:10101 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0494475 infores:hetionet CAID:CA404085034 biolink:causes MONDO:0007750 infores:clingen CAID:CA404085034 MONDO:0007750 PMID: Uncertain Significance PM5, PM2 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM5: 3 other missense variants in the same codon:- NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines- NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404085034/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3398 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0013144 infores:hetionet CHEBI:3215 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1145670 infores:hetionet CHEBI:46345 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0151908 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235168 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235168 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0413252 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0392386 infores:hetionet CHEBI:3215 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C2939147 infores:hetionet CHEBI:7565 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0042024 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0232462 infores:hetionet CHEBI:17630 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0522224 infores:hetionet NCBIGene:5271 biolink:causes MONDO:0014923 infores:monarchinitiative not_provided not_provided HGNC:8952 MONDO:0014923 uuid:75e77f40-09c4-462d-bf0d-ca8ebebf31aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50692 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0025061 infores:hetionet CHEBI:80630 biolink:causes MONDO:0021063 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0007102 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0027769 infores:hetionet CHEBI:61033 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020598 infores:hetionet CHEBI:101853 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0016204 infores:hetionet CAID:CA012953 biolink:causes MONDO:0005045 infores:clingen CAID:CA012953 MONDO:0005045 PMID:27532257PMID:8483915PMID:1638703PMID:27532257PMID:12473556PMID:8483915PMID:1638703PMID:12975413 Pathogenic PP3, PM1, PM2, PP1_Strong, PS4 The c.2722C>G (p.Leu908Val) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1638703; PMID:8483915 PMID:12473556; PMID:12975413; PMID:27532257; Partners LMM ClinVar SCV000059471.5; AGCMC Sydney ClinVar SCV000692499.1; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:1638703; PMID:8483915; Partners LMM ClinVar SCV000059471.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012953/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7852 biolink:causes UMLS:C0235318 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235318 infores:hetionet CHEBI:52172 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0023518 infores:hetionet CHEBI:3176 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0042023 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0031350 infores:hetionet CHEBI:63791 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151636 infores:hetionet CHEBI:7494 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0232849 infores:hetionet CHEBI:63620 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013362 infores:hetionet CHEBI:63608 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0024305 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0038525 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0497365 infores:hetionet CHEBI:84883 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0232462 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0012833 infores:hetionet CHEBI:9599 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0020452 infores:hetionet CAID:CA415300768 biolink:causes MONDO:0010726 infores:clingen CAID:CA415300768 MONDO:0010726 PMID: Pathogenic PVS1, PS2, PM2_Supporting The c.-99+2T>G variant in MECP2 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.-99+2T>G variant in MECP2 occurs in the de novo state (biological parentage confirmed) in an individual with Rett syndrome (PS2). The c.-99+2T>G variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the c.-99+2T>G variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415300768/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:6541 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020649 infores:hetionet CHEBI:100246 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0013604 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0041912 infores:hetionet NCBIGene:1285 biolink:causes MONDO:0007086 infores:monarchinitiative not_provided not_provided HGNC:2204 MONDO:0007086 uuid:4dd5fc57-8071-4c5b-9a81-1f5b3ad4933b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes HP:0011458 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0740651 infores:hetionet CHEBI:209807 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0002874 infores:hetionet CHEBI:3568 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0012569 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233414 infores:hetionet CHEBI:31981 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0917801 infores:hetionet CHEBI:472657 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0038325 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0036572 infores:hetionet CHEBI:3638 biolink:causes UMLS:C1168188 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C1168188 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0574067 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018824 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C0581883 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0581883 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0231528 infores:hetionet NCBIGene:3257 biolink:causes MONDO:0008748 infores:monarchinitiative not_provided not_provided HGNC:5163 MONDO:0008748 uuid:60d68b6d-e81f-46f6-9ae5-9180a9ddecf8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68575 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0030252 infores:hetionet CHEBI:63617 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0006142 infores:hetionet CHEBI:101853 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0014742 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0027769 infores:hetionet CHEBI:51041 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0014236 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0235409 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0235409 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027932 infores:hetionet CHEBI:135285 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0043094 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0021400 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013395 infores:hetionet CAID:CA367398826 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398826 MONDO:0015967 PMID: Pathogenic PS4, PP4, PP2, PP3, PM2_Supporting, PS3_Moderate PP1 The c.1129C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 377 (p.(Arg377Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.992, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 7 unrelated individuals with hyperglycemia (PS4; PMID 16731834, 20337973, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 20337973). This variant segregated with hyperglycemia with two informative meioses in a single family with diabetes, however, this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg377Cys has RAI=0.01, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate, PMID: 16731834). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PS4, PS3_Moderate, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398826/MONDO:0015967/086 2023-08-08 2023-08-08 Semidominant inheritance HP:0032113 Supports CAID:CA396459533 biolink:causes MONDO:0007648 infores:clingen CAID:CA396459533 MONDO:0007648 PMID:20624523PMID:20624523PMID:22118538PMID:20624523PMID:20373070PMID:22118538PMID:20824432PMID:21424370PMID:22225527PMID:20624523PMID:18391748 Pathogenic PP1_Moderate, PM5_Supporting, PS3_Supporting, PM2_Supporting, PS4_Moderate, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS2 The c.833-2A>G variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). There is multiple RNA assays demonstrating abnormal out-of-frame transcript for this variant (PS3_Supporting; PMID: 22118538, 20624523). The variant is absent in the gnomAD cohort. (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 3 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 22118538, 18391748, 21424370, 20624523, internal laboratory contributor). This variant was found to co-segregate with disease in multiple affected family members, with 5 meioses observed over two families (PP1_Moderate; PMID: 20624523, internal laboratory contributor). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS3_Supporting, PM2_Supporting, PS4_Moderate, PP1_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396459533/MONDO:0007648/007 2023-08-28 2023-08-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf UMLS:C0010592 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235086 infores:hetionet CHEBI:39867 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0008031 infores:hetionet CHEBI:42944 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0037036 infores:hetionet CHEBI:3504 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0424295 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0040034 infores:hetionet CHEBI:50742 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020488 infores:hetionet CHEBI:10125 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0080274 infores:hetionet CHEBI:4453 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0178298 infores:hetionet CHEBI:2567 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0438717 infores:hetionet CHEBI:44915 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0041657 infores:hetionet CHEBI:63619 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0428974 infores:hetionet CHEBI:9449 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0039231 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027339 infores:hetionet CHEBI:8707 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0497156 infores:hetionet CAID:CA410779953 biolink:causes MONDO:0021060 infores:clingen CAID:CA410779953 MONDO:0021060 PMID: Pathogenic PVS1, PM2_Supporting, PM3 BA1, PS3, BS1 The c.2178C>A (p.Tyr726Ter) variant in LZTR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 18/21 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 1/34568) of the c.2178C>A variant in LZTR1 is 0 for Admixed American chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in 1 individual with autosomal recessive RASopathy. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was confirmed in trans by family testing (c.1943-256C>T, 1 PM3 point, PMID:29469822) (PM3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM3, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410779953/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2038 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0042029 infores:hetionet CHEBI:72564 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0006277 infores:hetionet CHEBI:2663 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0006266 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0012594 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0730345 infores:hetionet CHEBI:49575 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0030554 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0233472 infores:hetionet CHEBI:50275 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0003862 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0029408 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014868 infores:hetionet CHEBI:7798 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0030196 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015376 infores:hetionet CHEBI:30830 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0023518 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0020598 infores:hetionet CAID:CA229740 biolink:causes MONDO:0009861 infores:clingen CAID:CA229740 MONDO:0009861 PMID:16256386PMID:11360625PMID:16256386 Likely Pathogenic PM2, PM5, PP3, PP4, PM3_Supporting The c.746T>A (p.Leu249His) variant in PAH has been reported in 1 individual with mild PKU (PMID: 11360625). This variant is absent in population databases. This variant was detected with pathogenic variant p.R243Q (PMID: 16256386). Computational evidence supports a deleterious effect. Another missense change at the same amino acid (p.L249F) is interpreted as pathogenic by multiple submitters. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PM3_supporting, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229740/MONDO:0009861/006 2020-11-13 2022-03-11 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10642702 biolink:causes MONDO:0100150 infores:clingen CAID:CA10642702 MONDO:0100150 PMID: Uncertain Significance PP3 BP4, BA1, BS1, PM2 The c.577T>A variant in RYR1 is a missense variant predicted to cause substitution of serine by threonine at amino acid 193 (p.Ser193Thr). The highest population minor allele frequency in gnomAD v4.1 is 0.00002712 (32/1179992) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL score is 0.78, which is greater than the threshold of ≥ 0.7 set by the CM VCEP (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for AD/AR RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by theClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10642702/MONDO:0100150/150 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52172 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0010200 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0006826 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0015393 infores:hetionet CHEBI:119573 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0039231 infores:hetionet GO:0060069 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0060069 GO:0000278 CHEBI:59773 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0423153 infores:hetionet GO:1903859 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:1903859 GO:0048699 CHEBI:8356 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0001430 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027726 infores:hetionet CHEBI:6339 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0026821 infores:hetionet CHEBI:3650 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0017178 infores:hetionet CHEBI:64310 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085624 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0027765 infores:hetionet CAID:CA516771304 biolink:causes MONDO:0010315 infores:clingen CAID:CA516771304 MONDO:0010315 PMID: Likely Pathogenic PP4_Moderate, PM4, PP3, PP1, PM2_Supporting BP7 The NM_000206.3(IL2RG):c.924G>A (p.Ser308=) synonymous variant occurs at the final nucleotide of exon 7 and is predicted to impact the splice consensus sequence (SpliceAI score 0.95; varSEAK -64.86 %, class 5; MaxEntScan 8.51-->2.69, -68% change) with loss of the donor splice site (PP3). The variant has been reported to segregate with X-SCID through 3 affected segregations. The mutation was confirmed by Sanger sequencing in patients 1 and 2 (maternal first cousins), as well as their mothers (PMID: 30850927; PP1). Patient 1 is a male (0.5pt) with atypical X-SCID, presenting with persistent cutaneous viral infection. There is a family history of SCID (0.5pt) and the patient was sequenced on a panel of 29 SCID causing genes (0.5pt). Phosphorylation of STAT5 after IL-2 stimulation in T cells exhibited a weaker response (1pt). Together these phenotypes and family history are highly specific for SCID due to gamma chain deficiency (2.5pt; PP4_moderate). Validation of a splicing defect was found in IL2RG mRNA analysis in patients 1 and 2 (PMID: 30850927). Skipping of exon 7 was detected which would cause a frameshift in exon 8 (the final exon) with a stop loss and elongation of the protein by 31 amino acids. Of note, products of non-spliced intron 7, other abnormal splicings, and even normal splicing were also detected (PM4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM4, PP1, PP3, PP4_moderate. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA516771304/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:83804 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011071 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152227 infores:hetionet CAID:CA024240 biolink:causes MONDO:0012933 infores:clingen CAID:CA024240 MONDO:0012933 PMID: Likely Benign BP1_Strong PM2, BP5, BS1, PP4, BA1 The c.663T>G variant in BRCA2 is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 221 (p.Phe221Leu). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.396 (based on Co-occurrence LR=1.08; Family History LR=1.3), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA024240/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7565 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002962 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0018799 infores:hetionet CHEBI:63638 biolink:causes UMLS:C1737329 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1737329 infores:hetionet CHEBI:4907 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0022408 infores:hetionet CAID:CA6831658 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831658 MONDO:0015967 PMID:37798422 Uncertain Significance PM1_Supporting, PS3_Supporting, PP4_Moderate, PP3 BS1, PM2 The c.66C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to arginine at codon 22 (p.(Ser22Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.758, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Functional studies demonstrated the p.Ser22Arg protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 37798422). The Popmax filtering allele frequency of the c.66C>G variant in gnomAD v2.1.1 is 0.00001134, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.000033); thus, neither criterion will be applied. This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.66C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831658/MONDO:0015967/017 2025-01-22 2025-01-22 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64019 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0033860 infores:hetionet CHEBI:46345 biolink:causes MONDO:0041959 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0520571 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0014549 infores:hetionet CHEBI:50730 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0027497 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027651 infores:hetionet CHEBI:50122 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0271051 infores:hetionet CHEBI:38562 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0030196 infores:hetionet CHEBI:2611 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0037763 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1291078 infores:hetionet CHEBI:42355 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C1384666 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002418 infores:hetionet CHEBI:63612 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0476281 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0006840 infores:hetionet CHEBI:16755 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C2047937 infores:hetionet CAID:CA658796665 biolink:causes MONDO:0015152 infores:clingen CAID:CA658796665 MONDO:0015152 PMID: Likely Benign BP4, BP7, PM2_Supporting BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000337.6: c.-44+11_-44+13del variant is located in the 5’UTR of SGCD. Because the variant is located in the 5’UTR, it is not expected to alter the amino acid sequence. This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This variant is not located in a splice region, and the computational splicing predictor SpliceAI gives a score of 0.05 for donor loss and 0.00 for acceptor loss, suggesting that the variant has no impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658796665/MONDO:0015152/186 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2038 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0221706 infores:hetionet CHEBI:7852 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0019521 infores:hetionet CHEBI:63681 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0085605 infores:hetionet GO:0070167 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:0070167 GO:0048513 CHEBI:63610 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0009806 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0021308 infores:hetionet NCBITaxon:1279 biolink:causes MONDO:0024313 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1279 MESH:D013203 DB01140_MESH_D013203_1DB01150_MESH_D013203_1DB01112_MESH_D013203_1DB01053_MESH_D013203_1DB01332_MESH_D013203_1DB00199_MESH_D013203_1DB00713_MESH_D013203_1DB06149_MESH_D013203_1DB00618_MESH_D013203_1DB00684_MESH_D013203_1DB00607_MESH_D013203_2DB00607_MESH_D013203_1 CHEBI:404903 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027497 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0011570 infores:hetionet CHEBI:31236 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162297 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0022658 infores:hetionet CHEBI:68610 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0011991 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0019360 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0019917 infores:hetionet CHEBI:9939 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0035229 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0021400 infores:hetionet CAID:CA295639 biolink:causes MONDO:0100135 infores:clingen CAID:CA295639 MONDO:0100135 PMID: Benign BA1 This is a missense variant in SCN1A, c.4393A>G, (p.Ile1465Val). This variant is present in gnomAD at 0.04% within the total population, with the highest sub-population frequency of 0.4% within the African/African population American population (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 (version 1.0; approved 6/13/23). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA295639/MONDO:0100135/067 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:194135 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0392171 infores:hetionet CHEBI:6375 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0000737 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013220 infores:hetionet CHEBI:76607 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C1384353 infores:hetionet CHEBI:48131 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0041834 infores:hetionet CHEBI:8888 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018965 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0853959 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0853959 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034359 infores:hetionet CHEBI:421707 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0004364 infores:hetionet CAID:CA016126 biolink:causes MONDO:0008409 infores:clingen CAID:CA016126 MONDO:0008409 PMID: Uncertain Significance PP3, PM2 PM3, BA1, PP1, PM1, PM5, PS3, PM6, PM4, PP2, PP4, BS2, BS1, BS3, BS4, BP1, BP3, PS1, PS4, PS2, BP4, BP2, BP5, BP7 The c.5458C>T (p.Arg1820Trp) variant in MYH7 has been identified in the homozygous state in 2 brothers with myosin storage myopathy exhibiting scapuloperoneal and respiratory weakness as well as dilated cardiomyopathy (Yüceyar 2015 PMID:25666907); however, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.00027% (FAF 95% CI; 2/129152) of Non-Finnish European chromosomes, 0.00142% (FAF 95% CI; 2/24966) of African chromosomes, and 1/19954 of East Asian chromosomes by gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for myosin storage myopathy and cardiomyopathy. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016126/MONDO:0008409/002 2021-06-16 2021-06-16 Inconclusive true GO:0009934 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0009934 GO:0009653 CAID:CA2499226544 biolink:causes MONDO:0010725 infores:clingen CAID:CA2499226544 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP1 The NM_000330.4(RS1):c.53-713_78+266del variant is a frameshift variant due to 1005 nucleotide deletion resulting in exon 2 deletion and leading to nonsense mediated decay. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 33546218). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family (PMID: 33546218), however, it is not clear whether the proband's family member was affected, so the PP1 code is not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting and PVS1 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499226544/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:7565 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0036980 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0242350 infores:hetionet CHEBI:5790 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0011603 infores:hetionet CHEBI:175901 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0006266 infores:hetionet CHEBI:91834 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013456 infores:hetionet CHEBI:10125 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0036974 infores:hetionet CHEBI:4995 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0917801 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0267792 infores:hetionet CAID:CA10014573 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014573 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.182C>T (p.Pro61Leu) is a missense variant which has a REVEL score < 0.50 (0.385) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014573/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2704 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0023380 infores:hetionet CHEBI:6402 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0206061 infores:hetionet CHEBI:24564 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0030312 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0021053 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0087169 infores:hetionet CAID:CA120437 biolink:causes MONDO:0018997 infores:clingen CAID:CA120437 MONDO:0018997 PMID: Pathogenic PP3, PS3_Moderate, PS4_Supporting, PM2_Supporting, PM1, PS2_Very Strong BP4, BA1, BS1 The c.215A>T (p.Gln72Leu) variant in RRAS2 is a missense variant predicted to cause substitution of glutamine by leucine at amino acid 72. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.918, which is above the threshold of 0.7, evidence that correlates with impact to RRAS2 function (PP3). This variant resides within the Switch II domain (amino acids 68 – 75) of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 2 probands with features of RASopathy (PS4_Supporting; PMID:31130285, 33686258). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMID:31130285, 33686258). Pull-down assays with the Raf-Ras-binding domain (RBD, residues 1–149) of RAF1 in HEK293 cells showed increased binding of activated RAS indicating that this variant impacts protein function. Similar results were seen in an immunoblotting assay of the cell lysates expressing WT/variant RRAS2 using anti-phospho-MEK1/2 and phospho-ERK1/2 antibodies. Additionally, Zebrafish embryos injected with variant mRNA showed significantly increased ceratohyal angles compared to the uninjected controls (PMID:31130285)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS3_Moderate, PM1, PS4_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA120437/MONDO:0018997/127 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17303 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0010200 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0687133 infores:hetionet CAID:CA14972954 biolink:causes MONDO:0009276 infores:clingen CAID:CA14972954 MONDO:0009276 PMID: Benign BP7, BA1, BP4 BS2 The variant NM_000407.5(GP1BB):c.*107C>T is a variant found in the 3' UTR. This variant has a Grpmax filtering allele frequency in gnomADv4.1 is 0.5859 based on the African/African American population, which is greater than 0.001 and thus meets BA1. Additionally, the variant is predicted by splice AI not to impact splicing and occurs at a nucleotide position that is not highly conserved (BP4, BP7). In summary, this variant meets criteria for benign for Bernard-Soulier syndrome based upon the ACMG criteria applied: BA1, BP4, and BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA14972954/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6775 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0015230 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0033575 infores:hetionet CHEBI:63629 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151786 infores:hetionet CHEBI:4868 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0013404 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027651 infores:hetionet CHEBI:18332 biolink:causes UMLS:C0235395 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0235395 infores:hetionet CHEBI:6935 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C0021843 infores:hetionet CAID:CA8337740 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337740 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The c.481G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 161 (p.Ala161Thr) and is also known as Ala121Thr by traditional nomenclature. The variant has been described in at least three individuals who displayed increased C14:1 acylcarnitines, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 28755359, 26385305, 16488171). In at least one of these individuals, the variant was confirmed as occurring in trans to a variant the ACADVL VCEP has classified as likely pathogenic and not confirmed in trans to a variant the ACADVL VCEP has classified as pathogenic (PM3, 1.5 points, PMID: 16488171, 16950999). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001975 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337740/MONDO:0008723/021 2024-08-13 2024-08-13 Autosomal recessive inheritance HP:0000007 Supports CAID:CA000135 biolink:causes MONDO:0017623 infores:clingen CAID:CA000135 MONDO:0017623 PMID: Uncertain Significance PP3 PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PP2, PP1, BS2, PM4, PM1, PM5, BA1, BP4, BP2, PS3, PS1, PS2, PS4 PTEN c.209+3A>T (IVS3+3A>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populationsPP3: At least 2 out of 3 in silico models predict a splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000135/MONDO:0017623/003 2020-03-23 2020-03-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7822 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0018926 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0011616 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0853800 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0853800 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0035455 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0595930 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020456 infores:hetionet CHEBI:135285 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0017178 infores:hetionet CHEBI:71028 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C2830004 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0235922 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0235922 infores:hetionet CAID:CA024740 biolink:causes MONDO:0012933 infores:clingen CAID:CA024740 MONDO:0012933 PMID: Likely Benign BP7_Strong, PM2_Supporting PP3, BP4 The c.7008-5T>C variant is an intronic variant occurring in intron 13 of the BRCA2 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score of 0.12 indicates that impact on splicing is unclear (score range 0.10-0.20) (PP3 and BP4 not met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 31191615), considered strong evidence against pathogenicity (BP7_Strong (RNA)).In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, BP7_Strong (RNA)). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA024740/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0657912 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0016034 infores:hetionet CHEBI:15551 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0700200 infores:hetionet CHEBI:3387 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0015967 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0040034 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0037199 infores:hetionet CHEBI:7025 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0014591 infores:hetionet CHEBI:49575 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0030232 infores:hetionet CHEBI:8245 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0004093 infores:hetionet CHEBI:7514 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0004245 infores:hetionet CHEBI:36791 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020578 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0037199 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0017566 infores:hetionet CAID:CA16620600 biolink:causes MONDO:0008723 infores:clingen CAID:CA16620600 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 The c.1022G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of arginine by threonine at amino acid 341 (p.Arg341Thr). To our knowledge, this variant is not reported in the medical literature. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620600/MONDO:0008723/021 2024-08-27 2024-08-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9943 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0016867 infores:hetionet CAID:CA123244 biolink:causes MONDO:0100326 infores:clingen CAID:CA123244 MONDO:0100326 PMID: Pathogenic PP4_Strong, PP3, PP1, PM2_Supporting, PM3_Strong PS3 The NM_000212.2(ITGB3):c.1199G>A (p.Cys400Tyr) missense has been identified in at least 4 probands, including GT11 and GT15a of PMID: 29675921 meeting the criteria for PP4_strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. Siblings GT15a and GT15b are both compound heterozygous for Cys400Tyr and pathogenic variant c.1525del (PP1; PMID: 29675921) with confirmation of trans phase was reported in PMID: 18788610. Additionally, two homozygous patients have been reported (PMIDs: 8781422, 35198519) (PM3_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_strong, PP1, PP3, PP4_strong. (VCEP specifications version 2; date of approval 06/06/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123244/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA16616941 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616941 MONDO:0011071 PMID:23848403PMID:25840971PMID:11830488PMID:28960434PMID:26175287PMID:28960434PMID:10508512PMID:26175287PMID:28960434PMID:26175287PMID:10508512PMID:10508512 Pathogenic PS3, PS4_Moderate, PM6_Supporting, PM1, PM2_Supporting, PP3, PP1 PS1, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, BP7, BP5, BS3, BS4, BS1, PM5, PM4, PM3, PP2, PP4, BS2 Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.497G>A (p.Arg166Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 10508512, 28960434, 26175287). This variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.962) (PP3). There are two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 8960434, 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM1, PS4_Moderate, PM2_supporting, PP3, PM6_Supporting, PP1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616941/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49960 biolink:causes UMLS:C1275515 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1275515 infores:hetionet CHEBI:7824 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C1142135 infores:hetionet CHEBI:4909 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C1167965 infores:hetionet CHEBI:3387 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0014518 infores:hetionet CHEBI:9649 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0085631 infores:hetionet CHEBI:6076 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0002792 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0162429 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0857483 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0857483 infores:hetionet CHEBI:92712 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0007760 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0235763 infores:hetionet UMLS:C0657912 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019521 infores:hetionet CHEBI:28918 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0151799 infores:hetionet CHEBI:145499 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0028643 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020615 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0035309 infores:hetionet CHEBI:27999 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0151474 infores:hetionet CHEBI:4027 biolink:causes HP:0001700 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1442837 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0948595 infores:hetionet CHEBI:3437 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0152227 infores:hetionet NCBIGene:9401 biolink:causes MONDO:0016369 infores:monarchinitiative not_provided not_provided HGNC:9949 MONDO:0016369 uuid:81bf5a1f-b550-4509-9e06-7180aa126f40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15552 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0858797 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0233632 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005324 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0018621 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0015397 infores:hetionet CHEBI:4911 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0149745 infores:hetionet CHEBI:63580 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0013390 infores:hetionet CHEBI:3568 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020903 infores:hetionet CHEBI:9398 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0009806 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0022408 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0013295 infores:hetionet CHEBI:5778 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0014591 infores:hetionet NCBIGene:113235 biolink:causes MONDO:0009238 infores:monarchinitiative not_provided not_provided HGNC:30521 MONDO:0009238 uuid:7b5de800-03ed-467e-872d-8149ce2bf06a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0595877 infores:hetionet CHEBI:50841 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0233494 infores:hetionet CHEBI:7852 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232461 infores:hetionet CHEBI:4710 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0022354 infores:hetionet CAID:CA390890030 biolink:causes MONDO:0100216 infores:clingen CAID:CA390890030 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, BA1, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.3:c.192A>T variant in DICER1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 64 (p.Leu64Phe). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMID: 28562508, Internal lab contributors). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors: Ambry, LabCorp Genetics). The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1613934 alleles) with a highest population minor allele frequency of 0.00001335 (1/74926 alleles) in the African/African American population and with multiple alleles present in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.432; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390890030/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8871 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0028754 infores:hetionet CHEBI:131512 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0019158 infores:hetionet CHEBI:116278 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C3665347 infores:hetionet CHEBI:2904 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0008372 infores:hetionet CHEBI:68478 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042847 infores:hetionet CHEBI:68584 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0233794 infores:hetionet CHEBI:63622 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0851578 infores:hetionet CHEBI:8499 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0085633 infores:hetionet CHEBI:31485 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0018681 infores:hetionet CHEBI:8874 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C3665347 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014868 infores:hetionet CHEBI:4466 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0003578 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0004623 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002089 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035326 infores:hetionet CAID:CA10558582 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558582 MONDO:0010726 PMID: Benign BP4, BP5, BS1, BS2 BP7 The allele frequency of the c.597C>G (p.Pro199=) variant in MECP2 (NM_004992.3) is 0.013% in East Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro199= variant is observed in at least 6 unaffected individuals (internal database - Invitae) (BS2). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The p.Pro199= variant is found in at least 2 individuals with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the p.Pro199= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558582/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Contradicts true NCBIGene:91147 biolink:causes MONDO:0011821 infores:monarchinitiative not_provided not_provided HGNC:28396 MONDO:0011821 uuid:3ee62e0b-cf6d-44bb-9df1-8afbec522b52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0086565 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0021416 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0262493 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0040034 infores:hetionet CHEBI:68845 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0037274 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235030 infores:hetionet CHEBI:473990 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0232492 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0392025 infores:hetionet CHEBI:47381 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002962 infores:hetionet CHEBI:9738 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0012833 infores:hetionet GO:0090095 biolink:causes GO:0072185 infores:ubergraph knowledge_assertion manual_agent GO:0090095 GO:0072185 CHEBI:6541 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0016382 infores:hetionet CHEBI:39112 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0015967 infores:hetionet CHEBI:5120 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0002792 infores:hetionet CHEBI:9445 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0004093 infores:hetionet CHEBI:134990 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0009782 infores:hetionet CHEBI:40237 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0030193 infores:hetionet CHEBI:63580 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0001807 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0020517 infores:hetionet CHEBI:8874 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018989 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0032285 infores:hetionet CHEBI:47519 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0235378 infores:hetionet CHEBI:6062 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0026858 infores:hetionet GO:2000794 biolink:causes GO:0060425 infores:ubergraph knowledge_assertion manual_agent GO:2000794 GO:0060425 CHEBI:71219 biolink:causes UMLS:C0240291 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0240291 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0018802 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0033860 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0023787 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151810 infores:hetionet CHEBI:8059 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0003123 infores:hetionet CHEBI:135005 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0855242 infores:hetionet CHEBI:49662 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0232493 infores:hetionet CHEBI:2704 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0013404 infores:hetionet CHEBI:74947 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151827 infores:hetionet CHEBI:92712 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0015967 infores:hetionet CHEBI:4466 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0028961 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0015376 infores:hetionet CHEBI:7640 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0028734 infores:hetionet CHEBI:45783 biolink:causes MONDO:0015687 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0346421 infores:hetionet CHEBI:7822 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C2830004 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027051 infores:hetionet CHEBI:3640 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0042963 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0009319 infores:hetionet CHEBI:50156 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0031542 infores:hetionet NCBIGene:857 biolink:causes MONDO:0014135 infores:monarchinitiative not_provided not_provided HGNC:1527 MONDO:0014135 uuid:e44bb738-87d5-496a-8d55-ddd2dd2cfd3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007117 infores:hetionet CHEBI:5134 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0700345 infores:hetionet CHEBI:8869 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0042164 infores:hetionet CHEBI:8890 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0028084 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1720775 infores:hetionet NCBIGene:6892 biolink:causes MONDO:0971012 infores:monarchinitiative not_provided not_provided HGNC:11566 MONDO:0971012 uuid:9f957ea3-d66b-40dc-80cf-6116b4639293 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6572 biolink:causes MONDO:0014983 infores:monarchinitiative not_provided not_provided HGNC:10936 MONDO:0014983 uuid:51504b50-ae0a-4706-bfe6-5dde1b81c99c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0040046 infores:hetionet CHEBI:64355 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151539 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0520854 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0520854 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0029445 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0035078 infores:hetionet CHEBI:4024 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0344232 infores:hetionet CHEBI:134966 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0021400 infores:hetionet CHEBI:134966 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0001807 infores:hetionet CHEBI:9434 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0231218 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1262113 infores:hetionet CHEBI:101278 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0002170 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0392386 infores:hetionet CHEBI:37333 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0007222 infores:hetionet CHEBI:50663 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0231218 infores:hetionet CHEBI:8890 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0232726 infores:hetionet CHEBI:5138 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1306341 infores:hetionet CAID:CA16020761 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020761 MONDO:0009861 PMID:26322415PMID:26503515PMID:26322415 Likely Pathogenic PM3, PM2, PP4_Moderate PP3 The c.292T>G (p.Leu98Val) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26322415, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with p.R408W (P, 16 submitters) (PM3). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020761/MONDO:0009861/006 2019-04-08 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9570 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018681 infores:hetionet CHEBI:71255 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0043352 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037199 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0002170 infores:hetionet CHEBI:3723 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026821 infores:hetionet CHEBI:28901 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0003862 infores:hetionet CAID:CA410202614 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202614 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.436A>T (p.Asn146Tyr) is a missense variant which has a REVEL score ≥ 0.88 (0.978) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202614/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68595 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C2242737 infores:hetionet CHEBI:9635 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0013604 infores:hetionet CHEBI:36791 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085605 infores:hetionet CHEBI:5959 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0011168 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042571 infores:hetionet CHEBI:3510 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0404521 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0017675 infores:hetionet CAID:CA386952415 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952415 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.35T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 12 (p.(Leu12Arg)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9409, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history suggestive of HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributors). While this variant segregated with diabetes with two informative meioses in a single family, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributors). Lastly, other missense variants at this same codon, c.34C>G, (p.Leu12Val) and c.34C>T (p.Leu12Phe), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952415/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:335 biolink:causes MONDO:0859238 infores:monarchinitiative not_provided not_provided HGNC:600 MONDO:0859238 uuid:6effd347-b53e-4615-8d40-e49faf5a0e2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2704 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0267797 infores:hetionet CHEBI:5790 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235710 infores:hetionet CHEBI:9586 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085631 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0948089 infores:hetionet CHEBI:473990 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0019151 infores:hetionet CAID:CA10539219 biolink:causes MONDO:0018947 infores:clingen CAID:CA10539219 MONDO:0018947 PMID: Pathogenic PP3, PP1, PP4, PM2_Supporting, PS4_Very Strong, PS3_Supporting The NM_000252.3(MTM1):c.1210G>A variant in MTM1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 404 (p.Glu404Lys). This variant has been reported in 10 probands meeting X-linked centronuclear myopathy (PS4_VeryStrong; PMIDs: 19084976, 33164942, 25957634, 9285787, 38544359, 38259611, 12467749, 30902907, 17005396). At least one patient with this variant displayed muscle biopsy with rounded muscle fibers with a single centrally located nucleus surrounded by a halo devoid of contractile elements, but containing mitochondria, which is highly specific for X-linked centronuclear myopathy (PP4; PMID: 17005396). The variant has been reported to segregate with disease in 4 affected individuals from 2 families (PP1; PMIDs: 17005396, 33164942). The variant is absent from gnomAD v.4.1.0 (PM2_Supporting). Immunofluorescence and western blot assays in COS cells (fibroblast-like cells derived from monkey kidney) showed unstable protein with aggregates in the cytoplasm and near the nucleus, probably in the Golgi, and very low myotubularin levels on western blot, indicating that this variant impacts protein function (PS3_Supporting; PMID: 12118066). The computational predictor REVEL gives a score of 0.759, which is above the threshold of 0.7 evidence that correlates with impact to MTM1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 2/20/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10539219/MONDO:0018947/149 2025-02-20 2025-03-27 X-linked inheritance HP:0001417 Supports CAID:CA915940799 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940799 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM2_Supporting, PVS1_Strong, PM3_Supporting The NM_000419.5(ITGA2B):c.2883del variant that results in the p.Phe961LeufsTer? frameshift has been reported homozygous in at least one GT patient (PMID: 22190468) with a highly specific phenotype. The variant causes stop loss and the addition of 90 amino acids to the ITGA2B protein, which alters the transmembrane domain. The variant is absent from population databases. In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PM3_supporting, PP4_Strong. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940799/MONDO:0100326/011 2021-07-08 2021-08-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5165 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0023518 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0005940 infores:hetionet CHEBI:6775 biolink:causes MONDO:0015265 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006272 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0152025 infores:hetionet CHEBI:9139 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0231218 infores:hetionet CAID:CA341572 biolink:causes MONDO:0012999 infores:clingen CAID:CA341572 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP2, BP4, BP7 PP4 The NM_000156.6:c.438A>G (p.Thr146=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -4.7) (BP4, BP7). This variant has been previously reported in an individual with GAMT deficiency who had significantly decreased creatine peak on MRS (PMID: 7808840) and GAMT activity <0.1% versus normal in fibroblasts (PMID: 11978605). Familial analysis showed that this individual harbored the variant in cis with NM_000156.6:c.299_311dup, (ClinVar Variation ID: 8302; pathogenic based on classification by the ClinGen CCDS VCEP) and had co-inherited these variants from his unaffected mother (BP2); he harbored these variants in trans with the pathogenic variant c.327G>A (ClinVar ID: 21065), inherited from his father. Of note, his unaffected brother was heterozygous for the two maternally co-inherited (c.438A>G and c.299_311dup) variants. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60006 alleles) in the Admixed American, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 21066). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. Although the evidence is tending likely benign, the lack of data regarding the impact of this variant on it's own, in the ansence of the other two variants, led to a VUS classification based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP2, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA341572/MONDO:0012999/026 2025-03-13 2025-03-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31932 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0027947 infores:hetionet CHEBI:43968 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0744727 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0234458 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0231694 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0231694 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0027769 infores:hetionet GO:0090199 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0090199 GO:0023052 CHEBI:42355 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0332575 infores:hetionet NCBITaxon:66225 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:66225 MONDO:0001867 CHEBI:175901 biolink:causes UMLS:C0854144 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0854144 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0012833 infores:hetionet CHEBI:63629 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0003862 infores:hetionet CAID:CA8459606 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459606 MONDO:0011132 PMID: Likely Benign BS1 PP3, BP4, PS3, BS3 The missense variant NM_001369369.1(FOXN1):c.1706C>A (p.Ser569Tyr) has a gnomADv2.1.1 minor allele frequency in the Ashkenazi Jewish population of 0.002526 (26/10294 alleles) which meets the BS1 threshold of >0.00141. This variant has a REVEL score of 0.41, below the PP3 threshold of ≥0.644 but above the the BP4 threshold of <0.290. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant does meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria, as specified by the ClinGen SCID VCEP: BS1. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459606/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:6801 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C1260880 infores:hetionet CHEBI:18332 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0004093 infores:hetionet CHEBI:47381 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0700590 infores:hetionet CHEBI:27779 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0019158 infores:hetionet CHEBI:6067 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0023518 infores:hetionet CHEBI:38940 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0231807 infores:hetionet CHEBI:5864 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0004509 infores:hetionet CAID:CA023643 biolink:causes MONDO:0007750 infores:clingen CAID:CA023643 MONDO:0007750 PMID: Pathogenic PS4_Moderate, PP1_Strong, PS3_Supporting, PM2, PVS1, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, BS2 NM_000527.5(LDLR):c.2140+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Strong, PM2, PS4_Moderate, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is in canonical splice site and predicts a frameshift in exon 15.PP1_strong - Variant segregates with FH phenotype in 9 members of 4 families (9 informative meioses).PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1).PS4_moderate - Variant meets PM2. Variant identified in 7 unrelated index cases fulfilling validated clinical criteria for FH from different labs.PP4 - Variant meets PM2. Variant found in 7 unrelated index cases fulfilling validated clinical criteria for FH.PS3_supporting - PMID:12522687 - Level 3 assay - study on htz patient's lymphocytes. An additional mRNA transcript of ~730 bp was detected; 214 bp retention of intron 14 causing a premature stop codon 99 amino acids later was the identified using cDNA sequencing. 46% LDLR particle clearance. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023643/MONDO:0007750/013 2021-06-18 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:51450 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0017160 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0162429 infores:hetionet CHEBI:39867 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014724 infores:hetionet CHEBI:8869 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0392525 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0240204 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0240204 infores:hetionet CHEBI:6367 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0024902 infores:hetionet CHEBI:44185 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0234909 infores:hetionet CHEBI:16469 biolink:causes MONDO:0000647 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0154002 infores:hetionet CHEBI:28148 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0036974 infores:hetionet CAID:CA5252756 biolink:causes MONDO:0008535 infores:clingen CAID:CA5252756 MONDO:0008535 PMID: Likely Benign BS1_Supporting, BP4 The NM_001114753.3: c.1447G>A variant in ENG is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 483 (p.Val483Ile). The filtering allele frequency (the lower threshold of the 95% CI of 28/19926) of the c.1447G>A variant in ENG is 0.0009914 for East Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.094, which is below the threshold of ≤0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1_Supporting, BP4 (specifications version 1.1.0; 02/04/2025). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA5252756/MONDO:0008535/136 2025-02-04 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63638 biolink:causes EFO:0700083 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1739111 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0235818 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151547 infores:hetionet CHEBI:135920 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0013378 infores:hetionet CHEBI:3286 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0034069 infores:hetionet CHEBI:16899 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0018681 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004936 infores:hetionet UNII:0RK7M7IABE biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0012833 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0853760 infores:hetionet CHEBI:9241 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C2047937 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0038454 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0027765 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020517 infores:hetionet GO:0072106 biolink:causes GO:0060675 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0060675 CHEBI:6792 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0027769 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0022658 infores:hetionet CHEBI:75988 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0086565 infores:hetionet CAID:CA132664 biolink:causes MONDO:0010134 infores:clingen CAID:CA132664 MONDO:0010134 PMID: Benign PP3, BA1 PM1, PM5, PS1 The filtering allele frequency of the p.Ile455Phe variant in the SLC26A4 gene is 3% (981/30778) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high frequency that is consistent with benign classification based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132664/MONDO:0010134/005 2018-09-28 2019-07-17 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6847 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0022346 infores:hetionet CHEBI:45924 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0034150 infores:hetionet CHEBI:28177 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0029944 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0853714 infores:hetionet CHEBI:45783 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020453 infores:hetionet CHEBI:15765 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0575081 infores:hetionet CHEBI:9123 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0043387 infores:hetionet CHEBI:52717 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0239340 infores:hetionet CHEBI:4888 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0042963 infores:hetionet CHEBI:5855 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0019521 infores:hetionet CHEBI:63620 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151942 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0234215 infores:hetionet CHEBI:44185 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0267797 infores:hetionet NCBIGene:9894 biolink:causes MONDO:0014848 infores:monarchinitiative not_provided not_provided HGNC:29099 MONDO:0014848 uuid:185cb459-f16f-4e6c-bceb-4aee128981fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0234930 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0340464 infores:hetionet CHEBI:39867 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0001339 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0020538 infores:hetionet CHEBI:3084 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0234215 infores:hetionet CHEBI:16347 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032131 infores:hetionet CHEBI:32139 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C2939147 infores:hetionet NCBIGene:1147 biolink:causes MONDO:0013334 infores:monarchinitiative not_provided not_provided HGNC:1974 MONDO:0013334 uuid:83ae0739-317a-475c-a8e9-74b6858a77ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0080274 infores:hetionet CAID:CA1139666838 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666838 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PS4_Supporting, PM2_Supporting PS3, PS1, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1216del (p.Tyr406fs) is a frameshift variant predicted to not undergo NMD (PVS1_strong SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 29722345, Table 1). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666838/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:85078 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0009806 infores:hetionet CHEBI:50777 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0151825 infores:hetionet CHEBI:3242 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0004093 infores:hetionet CAID:CA410202477 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202477 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 This variant NM_001754.5(RUNX1):c.502G>T (p.Gly168Ter) is a nonsense variant predicted to undergo NMD (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202477/MONDO:0011071/008 2022-01-20 2022-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:66876 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0600142 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020456 infores:hetionet CHEBI:10125 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0236075 infores:hetionet CHEBI:6897 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0948089 infores:hetionet CHEBI:47381 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014852 infores:hetionet CAID:CA10606170 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606170 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.5529G>A p.(Trp1843Ter) variant in DYSF, which is also known as NM_001130987.2: c.5646G>A p.(Trp1882Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 50/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least two unrelated individuals with dysferlinopathy. One patient was homozygous (0.5 pts, PMID: 17994539) while in the second patient, the variant was identified in unknown phase with a confirmed pathogenic variant (c.2811-2A>C, 1.0 pt, PMID: 30564623) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 17994539). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606170/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports GO:0045444 biolink:causes CL:0000136 infores:ubergraph knowledge_assertion manual_agent GO:0045444 CL:0000136 CHEBI:10100 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0037199 infores:hetionet CHEBI:75722 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027497 infores:hetionet CAID:CA5950510 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950510 MONDO:0000573 PMID: Benign BA1, BS2_Supporting The c.878A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Glycine at amino acid 293 (p.Glu293Gly).The filtering allele frequency (the lower threshold of the 95% CI of 7999/75012 alleles) of the c.878A>G variant in RAG2 is 0.1047 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1).Additionally, 437 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting)In summary, this variant meets the criteria to be classified as Benign for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950510/MONDO:0000573/124 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8707 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085602 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0877077 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0877077 infores:hetionet CAID:CA6748987 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748987 MONDO:0009861 PMID:17627389 Uncertain Significance PP4, BP4 PM2 PAH-specific ACMG/AMP criteria applied: BP4: Tolerated in SIFT, benign in Polyphen-2, Polymorphism in MutationTaster. REVEL=0.511; PP4: Seen in patient with mild HPA (PMID:17627389). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748987/MONDO:0009861/006 2018-08-07 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5893 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0012833 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0541832 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233494 infores:hetionet CHEBI:61049 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0518988 infores:hetionet CHEBI:4710 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0855329 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0024117 infores:hetionet CHEBI:474180 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C2240374 infores:hetionet CHEBI:3077 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0011253 infores:hetionet CHEBI:5103 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C1456784 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015230 infores:hetionet CAID:CA220143 biolink:causes MONDO:0021060 infores:clingen CAID:CA220143 MONDO:0021060 PMID: Pathogenic PM5_Strong, PM2, PP2, PP3, PM6_Strong The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3). At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM5_Strong, PM2, PP3, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220143/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:63616 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0014742 infores:hetionet CHEBI:31000 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0151505 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013922 infores:hetionet CHEBI:7447 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0231218 infores:hetionet CAID:CA347213670 biolink:causes MONDO:0015152 infores:clingen CAID:CA347213670 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.1177C>T p.(Glu393Ter) variant in DYSF, which is also known as NM_001130987.2: c.1273C>T p.(Gln425Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 12/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified with a second DYSF variant in at least three unrelated individuals with features consistent with LGMD (PMID: 18853459, 33610434; LOVD DYSF_000044), including in unconfirmed phase with a pathogenic variant (NM_003494.4: c.1180+5G>A, 0.5 pts, LOVD Individual #00215246; PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant had both a clinical diagnosis of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 33610434). The highest population allele frequency of this variant in gnomAD v.1.0 is 0.00001352 (1/73984 African/African American chromosomes), which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347213670/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37333 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0042075 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0029408 infores:hetionet CHEBI:3752 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0039231 infores:hetionet NCBIGene:9391 biolink:causes MONDO:0975806 infores:monarchinitiative not_provided not_provided HGNC:14280 MONDO:0975806 uuid:782fc830-7efb-4b21-a5a4-7d7a234e2130 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017152 infores:hetionet CHEBI:3568 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C2979982 infores:hetionet CHEBI:64312 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015371 infores:hetionet CHEBI:3614 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0006277 infores:hetionet CHEBI:17026 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013390 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0497365 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013395 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020649 infores:hetionet CHEBI:6539 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0003578 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0034063 infores:hetionet CHEBI:47381 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0237849 infores:hetionet CHEBI:6717 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C1443060 infores:hetionet CHEBI:8214 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0013604 infores:hetionet CHEBI:2611 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0392156 infores:hetionet CHEBI:75988 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0518015 infores:hetionet UMLS:C0023610 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0000786 infores:hetionet CHEBI:6931 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0027441 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0015734 infores:hetionet CHEBI:39585 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0011253 infores:hetionet CHEBI:92998 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0015230 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0042373 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0948594 infores:hetionet CAID:CA410204124 biolink:causes MONDO:0011071 infores:clingen CAID:CA410204124 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP4, BP2, BA1, PVS1, PM6, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.149G>A (p.Gly50Asp) is a missense variant which is absent from all population databases which provide coverage of at least 20x for the RUNX1 gene at this genomic position (PM2_supporting). In summary, the clinical significance of this variant is uncertain, and it meets ACMG/AMP criteria as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410204124/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15365 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0042571 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0243026 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0001122 infores:hetionet CHEBI:59773 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0013395 infores:hetionet CHEBI:94807 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C1443060 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004245 infores:hetionet CAID:CA421939232 biolink:causes MONDO:0020367 infores:clingen CAID:CA421939232 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, BP4 BS1, BS3, BP7, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.468G>A variant in MYOC is a synonymous variant (p.Lys156=). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The CADD score (v1.6) = 7.948, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 3.22 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022, Pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421939232/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0022650 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0009782 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0032326 infores:hetionet CHEBI:4887 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0002874 infores:hetionet CHEBI:7494 biolink:causes HP:0003552 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0221170 infores:hetionet CHEBI:83527 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0232462 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0024115 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0037290 infores:hetionet CHEBI:7936 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1510410 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020538 infores:hetionet NCBIGene:3814 biolink:causes MONDO:0013915 infores:monarchinitiative not_provided not_provided HGNC:6341 MONDO:0013915 uuid:d7b9a8bf-354a-4051-9063-50d7b1539c60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0018799 infores:hetionet CHEBI:63584 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0019112 infores:hetionet CHEBI:7465 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0037763 infores:hetionet CAID:CA10558575 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558575 MONDO:0010726 PMID: Benign BS1, BS2 BP4, PM2, PP3 The highest population minor allele frequency of the p.Leu213Val variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00008908 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Leu213Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In summary, the p.Leu213Val variant in MECP2 (NM_004992.4) is classified as benign based on the ACMG/AMP criteria (BS1, BS2). (MECP2 Specifications v.4.1; curation approved on 06/25/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558575/MONDO:0010726/036 2025-06-25 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:6715 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0542571 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0349506 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0037274 infores:hetionet CAID:CA415084391 biolink:causes MONDO:0010305 infores:clingen CAID:CA415084391 MONDO:0010305 PMID: Pathogenic PVS1, PM6, PP4, PM2_Supporting The NM_005629.4:c.913-1G>A variant occurs within the canonical acceptor splice site of intron 5. . It is predicted to cause skipping of biologically-relevant-exon 6/13 (104 bp), resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in a patient with elevated creatine/creatinine ratio on two occassions (there is a discrepancy in the biological sex of the patient between the main text and supplemental file) (PMID: 23660394). The variant is reported to be de novo in the patient (PM6). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM6, PP4, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, August 22, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415084391/MONDO:0010305/027 2023-08-22 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:3223 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0085932 infores:hetionet CHEBI:15640 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0015967 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0856054 infores:hetionet UNII:3U02EL437C biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0013428 infores:hetionet CHEBI:77260 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0085593 infores:hetionet CHEBI:36791 biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016167 infores:hetionet CAID:CA8815288 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815288 MONDO:0009290 PMID: Likely Benign BP4, BP7, BS1 The NM_000152.5:c.1332T>C (p.Pro444=) variant in GAA is a synonymous (silent) variant that is not predicted to impact splicing; the nucleotide is not highly conserved (PhyloP 100 way score is -2.4 (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 286018). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 13, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815288/MONDO:0009290/010 2023-03-13 2023-03-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:10650 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1527411 infores:hetionet CHEBI:68558 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0018801 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0234913 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0853149 infores:hetionet CHEBI:8774 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C1510410 infores:hetionet CHEBI:77733 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0018790 infores:hetionet CAID:CA152946 biolink:causes MONDO:0012996 infores:clingen CAID:CA152946 MONDO:0012996 PMID: Benign BA1, BP4, BP7 PM2 The NM_001482.3:c.1252T>C (p.Leu418=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9186 (18317/19940 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing, and the nucleotide is not highly conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 129137). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA152946/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5779 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0233477 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0150450 infores:hetionet CHEBI:3437 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0012833 infores:hetionet CAID:CA7435573 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435573 MONDO:0007113 PMID: Uncertain Significance BS1 BP4, PP3 The allele frequency of the c.926A>G p.Asn309Ser variant in UBE3A (NM_130838.2) is 0.016% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In summary, the c.926A>G p.Asn309Ser variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435573/MONDO:0007113/032 2023-06-15 2023-06-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63599 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0456909 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0853028 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0853028 infores:hetionet CHEBI:478164 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0041834 infores:hetionet CHEBI:32888 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0033774 infores:hetionet CHEBI:46557 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0002792 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0040034 infores:hetionet CHEBI:231594 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0011991 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0016034 infores:hetionet CHEBI:8768 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013428 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0236023 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0236023 infores:hetionet CHEBI:8499 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0011570 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0521491 infores:hetionet CHEBI:101853 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151878 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0022408 infores:hetionet CAID:CA8815317 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815317 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Strong The NM_000152.5:c.1432G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 478 (p.Gly478Arg). At least seven probands with symptoms consistent with infantile-onset-Pompe disease or late-onset Pompe disease with documented deficiency of GAA activity have been reported with this variant (PMIDs 25998610, 25213570, 17616415, 28394184) (PP4_Moderate). Six of these probands are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; the variants were confirmed in trans by parental testing for one of the patients (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1,1 is 0.00002895 (Latino) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_supporting, meeting this criterion. Expression of the variant in COS7 cells resulted in <2% GAA activity in cells, indicating that this variant may impact protein function (PMID 22253258, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551295, 2 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 2 submitters classfying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM3_Strong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815317/MONDO:0009290/010 2024-11-05 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:15854 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0002878 infores:hetionet CHEBI:9435 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0002170 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0162429 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0020651 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0027651 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042373 infores:hetionet CHEBI:37941 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0015967 infores:hetionet CHEBI:7627 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0151691 infores:hetionet CHEBI:47781 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0024205 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027765 infores:hetionet CHEBI:6715 biolink:causes HP:0200097 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0853945 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0007785 infores:hetionet CHEBI:63619 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0034359 infores:hetionet CHEBI:45716 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0027497 infores:hetionet CHEBI:135005 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0010692 infores:hetionet CHEBI:4911 biolink:causes UMLS:C1328537 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1328537 infores:hetionet CHEBI:5118 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151636 infores:hetionet CHEBI:3504 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0151594 infores:hetionet CAID:CA2802049 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802049 MONDO:0001586 PMID: Likely Benign BP7, BP4 BS1, PM2 The NM_000203.5(IDUA):c.666C>T (p.Gly222=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (all scores are <0.1). In addition, the variant is not in the first nucleotide or last three nucleotides of an exon (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0009485 (71/74858; 0 homozygotes) in the African/African American population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), and lower than the threshold for BS1 (>0.0025). Therefore, none of the population data codes are met. There is a ClinVar entry for this variant (Variation ID: 721826). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802049/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:75722 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002994 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0267596 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235431 infores:hetionet CHEBI:6073 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0020458 infores:hetionet NCBIGene:4072 biolink:causes MONDO:0013184 infores:monarchinitiative not_provided not_provided HGNC:11529 MONDO:0013184 uuid:c318b6d6-b5f0-425b-8bb8-e4f5f489501f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA337096487 biolink:causes MONDO:0044970 infores:clingen CAID:CA337096487 MONDO:0044970 PMID:23273904 Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PS3_Supporting, PM6 The m.3291T>C variant in MT-TL1 has been reported in at least eight unrelated individuals with primary mitochondrial disease. Ages of onset varied from 6- to 40-years old. Affected individuals had variable features including those consistent with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) as well as myopathy, sensorineural hearing loss, and cognitive decline. Muscle biopsies in affected individuals showed ragged red fibers (RRF), whereas respiratory chain enzyme deficiencies were variable. Heteroplasmy levels ranged from 20-95% (PS4_moderate; PMIDs: 7520241, 10899447, 18977334, 20943236, 21996807, 21863273, 23273904). There are at least two de novo occurrences of this variant reported (PM6_moderate; PMIDs: 20943236, 7520241). Heteroplasmy levels tracked with disease manifestations in at least three families (PP1_moderate; PMIDs: 23273904, 21863273, 10899447). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18) than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM6_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA337096487/MONDO:0044970/015 2022-10-03 2022-10-13 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8713 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0002792 infores:hetionet CAID:CA229379 biolink:causes MONDO:0009861 infores:clingen CAID:CA229379 MONDO:0009861 PMID:11214902PMID:11214902PMID:23271928PMID:11214902 Pathogenic PM3, PP4_Moderate, PM2, PS3 PM5 The c.1197A>T (p.Val399=) variant in PAH has been reported on 7 alleles of PKU patients (BH4 deficiency excluded). (PP4_Moderate; PMID: 23271928; PMID: 11214902). This variant has an extremely low allele frequency (0.000004064) in gnomAD (PM2; http://gnomAD.broadinstitute.org). This variant induces post-transcriptional skipping of exon 11 (PS3; PMID: 11214902). This variant was detected in trans with R408W (Pathogenic in ClinVar) (PM3; PMID: 11214902). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229379/MONDO:0009861/006 2018-07-28 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:78543 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0553702 infores:hetionet CHEBI:15367 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0039231 infores:hetionet CHEBI:28939 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0235710 infores:hetionet GO:1904838 biolink:causes GO:0007283 infores:ubergraph knowledge_assertion manual_agent GO:1904838 GO:0007283 CHEBI:51041 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0027051 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0020557 infores:hetionet CHEBI:92998 biolink:causes MONDO:0001223 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0030517 infores:hetionet CAID:CA10585179 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585179 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PS3_Supporting, PM2, PP4 PM5, PP3 The NM_000527.5 (LDLR): c.895G>A (p.Ala299Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: PopMAX MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in > 1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH (1 case from Unidad de Biof´ısica , Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025).PS3_Supporting Met: Heterozygous patient lymphocytes FACS assays (level 3 functional assay) showed normal cell surface localization, but 50% LDL-LDLR uptake and binding (Etxebarria et al, Unidad de Biof´ısica, Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180).PP3 not met: REVEL score = 0.543, which is below the threshold of 0.75. This variant does not creating de novo acceptor or donor site and is not predicted to alter splicing.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>T (p.Ala299Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585179/MONDO:0007750/013 2022-02-10 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:520985 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0162529 infores:hetionet CHEBI:5147 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0231528 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1258215 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C3263723 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0022660 infores:hetionet CHEBI:92923 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0239375 infores:hetionet CHEBI:28918 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0026961 infores:hetionet CHEBI:63681 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0237314 infores:hetionet CAID:CA409106055 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106055 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PP1, PM1 The c.514C>A variant in the hepatocyte nuclear factor 4-alpha, HNF4A, causes an amino acid of glutamine to lysine at codon 172 (p.(Gln172Lys)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, family history of persistent neonatal hypoglycemia) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with two informative meioses in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106055/MONDO:0015967/085 2024-05-01 2024-05-01 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:2778 biolink:causes MONDO:0007078 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0007078 uuid:7371f598-c7c0-4861-82c5-9666d597b5c9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019521 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0014130 infores:hetionet CHEBI:7822 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0015967 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0241705 infores:hetionet CAID:CA222856 biolink:causes MONDO:0100040 infores:clingen CAID:CA222856 MONDO:0100040 PMID: Likely Benign BP5, BS2, BP4 PM2 The p.Pro109Leu variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Pro109Leu variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). Computational analysis prediction tools suggest that the p.Pro109Leu variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). This position in gnomAD does not have at least 2,000 observed alleles in any continental population dataset (not sufficient to meet any population frequency criteria). In summary, the p.Pro109Leu variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA222856/MONDO:0100040/016 2022-09-01 2022-09-06 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:135925 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0030252 infores:hetionet CHEBI:3380 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0002792 infores:hetionet CHEBI:65349 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0221201 infores:hetionet CHEBI:3515 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0852911 infores:hetionet CHEBI:5864 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0162834 infores:hetionet CHEBI:51380 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C2981158 infores:hetionet CHEBI:8024 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0025345 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0033860 infores:hetionet CAID:CA220140 biolink:causes MONDO:0018997 infores:clingen CAID:CA220140 MONDO:0018997 PMID:15834506PMID:17661820PMID:17020470PMID:15834506 Pathogenic PS4_Moderate, PS3, PP3, PP2, PM6_Strong PM2 The c.1510A>G (p.Met504Val) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients and 3 independent occurrences in patients with clinical features of a RASopathy (PM6_Strong, PS4; GeneDx internal data; GTR Lab ID: 26957; SCV000057454.12; PMID: 15834506, 17661820, 17020470). In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function (PS3; PMID: 15834506). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Met504Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM6_Strong, PS4_Moderate, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220140/MONDO:0018997/004 2017-04-03 2019-06-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:64355 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085605 infores:hetionet CHEBI:31536 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0032617 infores:hetionet CAID:CA512341399 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341399 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.975C>T (p.Pro325=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-3.37)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341399/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:Y2V2R4W9TQ biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0456909 infores:hetionet CHEBI:36791 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1260922 infores:hetionet CHEBI:10127 biolink:causes MONDO:0006527 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0003028 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0020649 infores:hetionet CHEBI:63598 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0575081 infores:hetionet CAID:CA000484 biolink:causes MONDO:0018875 infores:clingen CAID:CA000484 MONDO:0018875 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Supporting BP4, BA1, PS2, PS3, PS1, PM1, PM5, BP7, BS1, BS3, BS4, PP1, PP3, BS2 The NM_000546.6 c.892G>T (p.Glu298Ter) is a TP53 nonsense variant inducing a premature termination codon upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1). This variant has been observed in 1 family meeting Revised Chompret criteria. This proband was under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: SCV000278127.7). At least one individual with this variant was found to have a variant allele fraction 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, SCV000278127.7). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000484/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52717 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0002878 infores:hetionet CAID:CA401367167 biolink:causes MONDO:0009290 infores:clingen CAID:CA401367167 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting PS1 The NM_000152.5:c.1551+1G>C variant alters the canonical donor splice site of intron 10 of GAA. Sequence analysis of cDNA from an individual who is compound heterozygous for this variant revealed that the variant results in skipping of exon 10 (GAA has 20 exons). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID: 29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 7 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 2 patients and was deficient (<10% residual activity) (PMID: 7881425, 25673129) (PP4_Moderate). At least 5 patients are compound heterozygous for the variant and c.-32-13T>G (known pathogenic variant) (ClinVar Variation ID: 4027) (phase unknown, max 2 x 0.5 points) (PMID: 7881425, 16917947, 25673129). Two patients are compound heterozygous for the variant and another variant in GAA, either c.1437+2T>C (PMID: 11343339) or c.1755-1G>A (PMID: 17056254); both confirmed in trans. The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1. In gnomAD v4.1.0., the highest population minor allele frequency is 0.000001695 (2/1179958 alleles; 0 homozygotes) which is lower that the ClinGen LD VCEP's threshold for PM2_Supporting (<0.001), in the European non-Finnish population, meeting this criterion (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>A, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). These variants have not yet been classified by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 554983). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 4, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401367167/MONDO:0009290/010 2024-10-04 2024-10-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31413 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0000731 infores:hetionet CHEBI:31236 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0022346 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0042109 infores:hetionet CHEBI:38940 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0040053 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0020672 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0020517 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0521591 infores:hetionet CHEBI:47780 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027497 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042514 infores:hetionet CAID:CA913177679 biolink:causes MONDO:0044970 infores:clingen CAID:CA913177679 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM6_Supporting PP1, PS3 The m.4308G>A variant in MT-TI has been reported in two unrelated individuals with primary mitochondrial disease with onset ranging from the first decade to third decade of life and features include bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), exercise intolerance, decreased BMI, and hyperCKemia. Muscle biopsy showed paracrystalline inclusions, ragged red fibers, COX negative fibers, and respiratory chain deficiencies across complexes I, III, and IV. In both cases, the variant was undetectable in blood when the individuals were tested in their 30s and 50s. The variant was heteroplasmic in muscle, however the exact heteroplasmy level was only reported in one of these cases at 47%. Neither case had any positive family history (PS4_supporting; PMIDs: 20884012; 21292040). This variant occurred de novo in one individual (absent in blood and muscle from mother via RFLP; PM6_supporting, PMID: 21292040). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (82.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3, PM6_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913177679/MONDO:0044970/015 2022-10-10 2022-10-12 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3077 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0042909 infores:hetionet CHEBI:135736 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0036396 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0015397 infores:hetionet GO:0060723 biolink:causes GO:0001892 infores:ubergraph knowledge_assertion manual_agent GO:0060723 GO:0001892 CHEBI:3387 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0424295 infores:hetionet CHEBI:52717 biolink:causes NCIT:C107587 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015544 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0740471 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0740471 infores:hetionet CHEBI:3485 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0038325 infores:hetionet CHEBI:50173 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151905 infores:hetionet CHEBI:8768 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0032617 infores:hetionet CHEBI:45285 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0018099 infores:hetionet CHEBI:63925 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0027765 infores:hetionet CHEBI:31705 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0023052 infores:hetionet CHEBI:44915 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0085593 infores:hetionet CHEBI:49603 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0038362 infores:hetionet CHEBI:3441 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0728899 infores:hetionet CHEBI:66964 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0012833 infores:hetionet CHEBI:9599 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0005741 infores:hetionet CHEBI:231594 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0017178 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0022658 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0236053 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0236053 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040485 infores:hetionet CAID:CA398643026 biolink:causes MONDO:0019497 infores:clingen CAID:CA398643026 MONDO:0019497 PMID: Pathogenic PM3_Supporting, PM2_Supporting, PVS1 The allele frequency of the c.10045C>T (p.Gln3349Ter) variant in the MYO15A gene is 0.002% (2/112392) of European non-Finnish alleles by gnomAD v2.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a pathogenic variant (PM3_Supporting, Partners LMM internal data SCV001365783.1). The p.Gln3349Ter variant in MYO15A is predicted to cause a premature stop codon in biologically-relevant-exon 62/66 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Supporting, PVS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA398643026/MONDO:0019497/005 2021-09-28 2022-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:32888 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0030554 infores:hetionet CHEBI:7494 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0018965 infores:hetionet CHEBI:17347 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0040460 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0040046 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005045 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0007194 infores:hetionet CHEBI:36795 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085615 infores:hetionet CHEBI:8871 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020458 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0042075 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151826 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0003621 infores:hetionet CHEBI:47781 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0019158 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0242350 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0027651 infores:hetionet CHEBI:18332 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0232602 infores:hetionet CHEBI:63638 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0520966 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0036572 infores:hetionet CHEBI:10119 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0004604 infores:hetionet CHEBI:50663 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0014742 infores:hetionet CHEBI:3423 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151740 infores:hetionet CHEBI:7956 biolink:causes NCIT:C50526 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0235827 infores:hetionet GO:0072106 biolink:causes GO:0016331 infores:ubergraph knowledge_assertion manual_agent GO:0072106 GO:0016331 CHEBI:2704 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151905 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0032961 infores:hetionet CHEBI:7809 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0001824 infores:hetionet CHEBI:31236 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015402 infores:hetionet CHEBI:3723 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0558489 infores:hetionet CAID:CA343724571 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724571 MONDO:0020367 PMID:16297911PMID:16466712PMID:15069026PMID:10545602 Pathogenic PM5_Supporting, PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate, PP1_Strong BP7, BS1, BS3, PM6, PM4, PS1, PS2, BP4, BA1 The c.1139A>C variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Alanine at amino acid 380 (p.Asp380Ala). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.97, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Asp380Ala protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 31 segregations in 6 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17893668, 9863594, 9832047), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 7 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 17893668, 9863594, 9832047), which met PS4_Moderate (≥ 6 probands). Another missense variant (c.1138G>C, p.Asp380His, Grantham score = 81, ClinVar ID: 7961) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1139A>C, p.Asp380Ala variant has a higher Grantham score (= 126) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 11 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724571/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32315 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018418 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0039971 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0019158 infores:hetionet UMLS:C0657912 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0039239 infores:hetionet NCBIGene:7156 biolink:causes MONDO:0020628 infores:monarchinitiative not_provided not_provided HGNC:11992 MONDO:0020628 uuid:8f44664b-90e0-461c-9991-7834e25a19f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0853875 infores:hetionet CAID:CA319091 biolink:causes MONDO:0012589 infores:clingen CAID:CA319091 MONDO:0012589 PMID: Benign BA1, BP4, BP5, BS2 The highest population minor allele frequency of the p.Ala664Thr variant in TCF4 in gnomAD v4.1 is 0.007675 in the Amish population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Ala664Thr variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ala664Thr variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala664Thr variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Ala664Thr variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). (TCF4 specification v.3; approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA319091/MONDO:0012589/032 2024-08-30 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8776 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0001339 infores:hetionet CHEBI:127780 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0149745 infores:hetionet CAID:CA410677579 biolink:causes MONDO:0009276 infores:clingen CAID:CA410677579 MONDO:0009276 PMID: Uncertain Significance PP3, PM2_Supporting PP4 “The c.470T>C (p.Leu157Pro) variant in GP1BB is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 157 (p.Leu157Pro). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.680, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on GP1BB function (PP3). At least one BSS patient (BS-9 from PMID: 21699652) is reported in the literature. This patient was not scored because they are reported to be homozygous for the c.462G>C (p.Gln154His) variant in GP1BB, homozygous c.470T>C (p.Leu157Pro) in GP1BB and heterozygous for c.1522T>C (p.Tyr508His) in GP1BA. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410677579/MONDO:0009276/082 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8435 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0855775 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009319 infores:hetionet NCBITaxon:5039 biolink:causes MONDO:0005672 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5039 MESH:D001759 DB01167_MESH_D001759_1DB01026_MESH_D001759_1 CHEBI:41977 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0017565 infores:hetionet CHEBI:31236 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0242422 infores:hetionet NCBIGene:26353 biolink:causes MONDO:0008025 infores:monarchinitiative not_provided not_provided HGNC:30171 MONDO:0008025 uuid:971defb3-9e4b-41c8-ae1a-308f9a3d40fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0023518 infores:hetionet CAID:CA16620235 biolink:causes MONDO:0100488 infores:clingen CAID:CA16620235 MONDO:0100488 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.315delC p.(Thr106Profs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620235/MONDO:0100488/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:64064 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C3263723 infores:hetionet CHEBI:28918 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0039231 infores:hetionet CHEBI:100246 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0162298 infores:hetionet GO:0140884 biolink:causes GO:0060333 infores:ubergraph knowledge_assertion manual_agent GO:0140884 GO:0060333 CHEBI:72297 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C2047937 infores:hetionet CHEBI:72296 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0041657 infores:hetionet CHEBI:8888 biolink:causes MONDO:0043494 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0003860 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085593 infores:hetionet GO:0046597 biolink:causes GO:0044409 infores:ubergraph knowledge_assertion manual_agent GO:0046597 GO:0044409 CHEBI:8888 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0948594 infores:hetionet CHEBI:421707 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0851578 infores:hetionet CAID:CA2580098648 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098648 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.385_395del (p.Leu129AspfsTer5) is a frameshift variant that occurs which terminates 5 amino acids downstream and is predicted to undergo NMD (As per modified RUNX1 PVS1 decision tree ) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098648/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10119 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040034 infores:hetionet CAID:CA343723062 biolink:causes MONDO:0020367 infores:clingen CAID:CA343723062 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting BP7, BS1, BS3, PM6, PM4, PM5, PS3, PS1, PS2, BP4, BA1 The c.1456C>T variant in MYOC is a missense variant predicted to cause substitution of Leucine by Phenylalanine at amino acid 486 (p.Leu486Phe). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.891, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 5 segregations in 1 family, with juvenile open angle glaucoma, have been reported (PMID: 27900994), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 24825108, 27900994), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343723062/MONDO:0020367/019 2022-12-14 2022-12-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA410147084 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147084 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1370G>T (p.Gly457Val) is a missense variant which has a REVEL score < 0.50 (0.412), and a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147084/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63681 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0003467 infores:hetionet NCBIGene:3913 biolink:causes MONDO:0013621 infores:monarchinitiative not_provided not_provided HGNC:6487 MONDO:0013621 uuid:f1b40f51-9cdc-4a8f-b6b5-d5195ac19348 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA171642 biolink:causes MONDO:0100039 infores:clingen CAID:CA171642 MONDO:0100039 PMID: Benign BS1, BS2, BP4 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.3008T>C (p.Met1003Thr) variant in CDKL5 transcript (NM_003159.2) is c.184+3194A>G in RS1 transcript (NM_000330.4). The highest population minor allele frequency of the p.Met1003Thr variant in CDKL5 in gnomAD v4.1 is 0.0000134 in Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0000083) for BS1, and therefore meets this criterion (BS1). The p.Met1003Thr variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The computational predictor REVEL gives a score of 0.115, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). In summary, the p.Met1003Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171642/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Contradicts true CHEBI:45951 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0015967 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0042109 infores:hetionet CHEBI:205919 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0011603 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0021400 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002418 infores:hetionet CAID:CA320255506 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255506 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS2, PS4, BA1, BP2, BP1, BP7, BS1, PM6, PVS1, PM3, PM5, PM1, PP2, PP3 NM_001754.5(RUNX1):c.895G>A (p.Ala299Thr) is a missense variant which is absent from gnomAD v2 and v3 (PM2_supporting). This variant has not been reported in the literature. The computational predictor REVEL gives a score of 0.112, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255506/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8214 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0028084 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042109 infores:hetionet CAID:CA410146990 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146990 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1381A>G (p.Asn461Asp) is a missense variant whiuch has a REVEL score < 0.50 (0.22) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146990/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4315 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0008033 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0015397 infores:hetionet CHEBI:7577 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0026826 infores:hetionet CHEBI:72564 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0237849 infores:hetionet CHEBI:17688 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1260880 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020517 infores:hetionet CHEBI:6438 biolink:causes MONDO:0004773 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0022073 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0016436 infores:hetionet CAID:CA386965901 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965901 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 PS4 The c.745T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to proline at codon 249 (p.(Ser249Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.924, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability estimated between 45.5-75.5% based on available clinical information, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 16249556, 23771925, internal lab contributor). In summary, c.745C>T meets the criteria to be classified as a variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965901/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31413 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0043352 infores:hetionet CHEBI:6067 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018790 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0423773 infores:hetionet CHEBI:63629 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0025323 infores:hetionet CHEBI:75998 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0010200 infores:hetionet CHEBI:44915 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0030554 infores:hetionet CHEBI:9434 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0043352 infores:hetionet CHEBI:145499 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042023 infores:hetionet CHEBI:44241 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0232487 infores:hetionet NCBIGene:89953 biolink:causes MONDO:0700288 infores:monarchinitiative not_provided not_provided HGNC:21624 MONDO:0700288 uuid:be615dcd-e775-48d4-abe5-dc809e0d4de0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0231807 infores:hetionet CHEBI:83804 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151564 infores:hetionet CHEBI:10110 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0028081 infores:hetionet CHEBI:7577 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0034642 infores:hetionet CHEBI:70735 biolink:causes MONDO:0007488 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0752347 infores:hetionet CHEBI:78543 biolink:causes MONDO:0006978 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0037998 infores:hetionet CHEBI:39867 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0018681 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0039971 infores:hetionet CHEBI:16755 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0006145 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017178 infores:hetionet CHEBI:47519 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0012833 infores:hetionet NCBIGene:5321 biolink:causes MONDO:0018794 infores:monarchinitiative not_provided not_provided HGNC:9035 MONDO:0018794 uuid:ff4cb208-a6bc-464f-9e81-451164a2fa89 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28864 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0438717 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0178298 infores:hetionet CHEBI:2682 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027709 infores:hetionet CHEBI:92923 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0020580 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0031350 infores:hetionet CHEBI:27666 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0023380 infores:hetionet UMLS:C1738934 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0221150 infores:hetionet CHEBI:6367 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151904 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017178 infores:hetionet CHEBI:3479 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0221512 infores:hetionet CHEBI:31236 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0267792 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0020580 infores:hetionet CHEBI:6954 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C2830004 infores:hetionet CHEBI:3380 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030554 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0019360 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085606 infores:hetionet CHEBI:8888 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085624 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0278678 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0278678 infores:hetionet CAID:CA399794330 biolink:causes MONDO:0100326 infores:clingen CAID:CA399794330 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000419.5(ITGA2B):c.2578C>T (p.Gln860Ter) nonsense variant in exon 25/30 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Glanzmann thrombasthenia Patient 6 of PMID: 34267460 is homozygous for this variant (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399794330/MONDO:0100326/011 2022-04-15 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:63621 biolink:causes MONDO:0012897 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0015523 infores:hetionet CHEBI:28001 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0014518 infores:hetionet CHEBI:87681 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0233407 infores:hetionet CHEBI:63681 biolink:causes GO:0006955 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0020964 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0037195 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0948824 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0948824 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0022408 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0027497 infores:hetionet CHEBI:2654 biolink:causes UMLS:C0042380 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0042380 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151763 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0002418 infores:hetionet CHEBI:9352 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0085605 infores:hetionet CHEBI:6413 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C2830004 infores:hetionet CHEBI:3175 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0039070 infores:hetionet CHEBI:50749 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0016436 infores:hetionet CHEBI:6541 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0262988 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0235351 infores:hetionet CHEBI:681848 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0424295 infores:hetionet CHEBI:77733 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0038990 infores:hetionet CHEBI:6888 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0011603 infores:hetionet NCBIGene:51776 biolink:causes MONDO:0014816 infores:monarchinitiative not_provided not_provided HGNC:17797 MONDO:0014816 uuid:de9e8885-a120-470d-b794-50995923ecac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6078 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0040822 infores:hetionet CHEBI:23765 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151905 infores:hetionet UNII:3U02EL437C biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C1291077 infores:hetionet CHEBI:5147 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0917801 infores:hetionet CHEBI:391960 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0231919 infores:hetionet CAID:CA913172991 biolink:causes MONDO:0044970 infores:clingen CAID:CA913172991 MONDO:0044970 PMID: Uncertain Significance PP3 PP1, PS4, PS3, PM2 The m.15117T>C (p.M124T) variant in MT-CYB was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There is one occurrence in the GenBank sequences queried through MITOMAP on 6/29/2020 (1 individual from haplogroup T1a). In silico tools (APOGEE) predict this variant to be pathogenic with a score of 0.7 (PP3). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913172991/MONDO:0044970/014 2021-12-10 2021-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:48669 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0018989 infores:hetionet CHEBI:51141 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0033117 infores:hetionet CAID:CA10644623 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644623 MONDO:0011071 PMID: Benign BA1, BP2 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 The c.*2770C>G variant in the 3' UTR has an MAF of 0.03955 (3.9%, 2554/64570 alleles) in the non-Finnish European subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 70 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644623/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:36704 biolink:causes UMLS:C0948300 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0948300 infores:hetionet CHEBI:567361 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0233407 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006266 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0022660 infores:hetionet CAID:CA10585102 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585102 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 PS1, PM5, PP3 NM_000527.5(LDLR):c.709C>T (p.Arg237Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.00009799 (0.01%) in South Asian exomes (gnomAD v2.1.1).PS4_Supporting - Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936).PP4 - Variant meets PM2 and is reported in 3 unrelated index cases, two with possible SB criteria (PMID 20236128 and Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)), one with DLCN >= 6 criteria (PMID 30293936). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585102/MONDO:0007750/013 2022-04-30 2022-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA244513452 biolink:causes MONDO:0015967 infores:clingen CAID:CA244513452 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM5_Supporting BP4, PP3 The c.1780A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to arginine at codon 594 (p.(Ser594Arg)) of NM_000545.8. This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.8e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). Another missense variant at the same residue, c. 1781G>T p.Ser594Ile, has been classified as pathogenic by the ClinGen MDEP, but this variant has a larger Grantham distance than p.Ser594Arg (PM5_Supporting). In summary, c.1780A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved (6/30/2025): PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244513452/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7575 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0031542 infores:hetionet NCBIGene:79577 biolink:causes MONDO:0007768 infores:monarchinitiative not_provided not_provided HGNC:16783 MONDO:0007768 uuid:82ef2d22-5781-4d3f-a7a5-c2af80483a49 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0518015 infores:hetionet CHEBI:8871 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0036508 infores:hetionet CHEBI:63581 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0030305 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0002871 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0347390 infores:hetionet CHEBI:28901 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0221436 infores:hetionet CAID:CA193735 biolink:causes MONDO:0007648 infores:clingen CAID:CA193735 MONDO:0007648 PMID: Likely Benign BP7, BS2_Supporting, PM2_Supporting BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.69G>A (p.Glu23=) variant is absent from the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org). In silico splice site predictors do not suggest that this variant impacts splicing, and the G allele is not highly conserved across species (BP7).The variant has also been observed in >3 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2_Supporting; SCV000216307.4, SCV000545385.4, internal laboratory). Use of the Bayesian point system for this variant with conflicting evidence and classify this variant as likely benign. In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BP7, BS2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA193735/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6437 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0004936 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005982 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0040247 infores:hetionet CHEBI:8871 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085605 infores:hetionet CHEBI:7936 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0036974 infores:hetionet CHEBI:10127 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013604 infores:hetionet CHEBI:77260 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0030554 infores:hetionet CAID:CA10603019 biolink:causes MONDO:0021060 infores:clingen CAID:CA10603019 MONDO:0021060 PMID:19206169PMID:28650561PMID:19206169 Pathogenic PS4_Moderate, PS3, PM1, PS2_Very Strong, PM2, PP2 PM5, PP3 The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; PMIDs: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication). In two of these patients, as well as one proband with phenotypic features suggestive of a RASopathy but no clinical diagnosis, the variant occurred de novo; parentage was confirmed in 2 of these cases (PS2_VS; PMIDs: 19206169, 28650561; GeneDx internal data, SCV000329761.7). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). In vitro functional studies provide some evidence that the p.Thr599Arg variant may impact protein function (PS3; PMID: 19206169). Additionally, the variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4_Moderate, PM1, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603019/MONDO:0021060/004 2020-03-24 2020-03-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:41879 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020649 infores:hetionet CHEBI:6759 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0012833 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0162429 infores:hetionet CHEBI:45367 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0541832 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0033975 infores:hetionet CHEBI:100241 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0009676 infores:hetionet CHEBI:94440 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0015672 infores:hetionet CHEBI:7936 biolink:causes MONDO:0010052 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0232981 infores:hetionet CHEBI:50275 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0023052 infores:hetionet CHEBI:74947 biolink:causes UMLS:C1096448 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1096448 infores:hetionet CHEBI:82960 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1527344 infores:hetionet CHEBI:9328 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0002874 infores:hetionet CHEBI:46195 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0014724 infores:hetionet CHEBI:53760 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C1320474 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0554309 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0554309 infores:hetionet CHEBI:63791 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020621 infores:hetionet CHEBI:9123 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151786 infores:hetionet CHEBI:6888 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0151740 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0027765 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0541799 infores:hetionet CHEBI:84500 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0011168 infores:hetionet CHEBI:101278 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151904 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013395 infores:hetionet CHEBI:72564 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C1535939 infores:hetionet CAID:CA404082666 biolink:causes MONDO:0007750 infores:clingen CAID:CA404082666 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 BA1, BP4, BP2, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, PP4, PP1, BS2 The NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.918.It is above 0.75, so PP3 is Met.PM5 - 2 missense variants in the same codon: - NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) (ClinVar ID: 251582) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) (ClinVar ID: 251581) - Pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404082666/MONDO:0007750/013 2022-02-14 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA044568 biolink:causes MONDO:0007750 infores:clingen CAID:CA044568 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PS1, PS4, PS3, BS3, PM5, PP4 NM_000527.5(LDLR):c.710G>A (p.Arg237His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 29 April 2022.The supporting evidence is as follows:PM2: PopMax MAF = 0.00008673 (0.009%) in Latino/Admixed American exomes (gnomAD v2.1.1).PP3: REVEL = 0.751. It is above 0.75. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA044568/MONDO:0007750/013 2022-04-29 2025-02-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:10124 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0021053 infores:hetionet CAID:CA410146662 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146662 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP2, BP1, BP4, BP3, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM3, PM4, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1417G>T (p.Glu473Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146662/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:35778 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0013456 infores:hetionet CHEBI:40237 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0232462 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0032285 infores:hetionet CHEBI:49375 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013491 infores:hetionet CHEBI:8207 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0037299 infores:hetionet CHEBI:7865 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0003578 infores:hetionet CHEBI:145499 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0522055 infores:hetionet NCBIGene:26119 biolink:causes MONDO:0011374 infores:monarchinitiative not_provided not_provided HGNC:18640 MONDO:0011374 uuid:cf09f3dc-cf4d-4c3b-bf9a-970836611bd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0948594 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0423232 infores:hetionet CHEBI:3756 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0037383 infores:hetionet CHEBI:47612 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0026821 infores:hetionet CHEBI:8245 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0027497 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027651 infores:hetionet CAID:CA396452065 biolink:causes MONDO:0100488 infores:clingen CAID:CA396452065 MONDO:0100488 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS4, BS3, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2, PS3 The c.112A>C (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution in exon 2 (p.Thr38Pro). This variant was observed in seven individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae). Note that this includes two individuals with a family history of stomach cancer NOS. This variant is absent from gnomAD 2.1.1 (PM2_Spporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396452065/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:8871 biolink:causes UMLS:C0270729 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0270729 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011630 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0021053 infores:hetionet CHEBI:367163 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085649 infores:hetionet CHEBI:5002 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0037763 infores:hetionet CHEBI:83804 biolink:causes MONDO:0043209 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0001916 infores:hetionet CHEBI:6904 biolink:causes MONDO:0008364 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0034735 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0151730 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151730 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027765 infores:hetionet CHEBI:45951 biolink:causes UMLS:C1112182 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C1112182 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0373705 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0373705 infores:hetionet CAID:CA130100 biolink:causes MONDO:0015152 infores:clingen CAID:CA130100 MONDO:0015152 PMID: Pathogenic PM3, PP1_Strong, PVS1, PM2_Supporting, PP4 The NM_000023.4: c.574C>T p.(Arg192Ter) variant in SGCA is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/10, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in four individuals with autosomal recessive limb girdle muscular dystrophy, all of whom were homozygous for the variant. Consanguinity was reported in one of the four families (1.0 pt, PMID: 26934379, 22303798; PM3). The variant has also been reported to co-segregate with autosomal recessive limb girdle muscular dystrophy in eight affected meioses from four families (PP1_Strong; PMID: 26934379, 22303798). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced expression of alpha-sarcoglycan protein in skeletal muscle, which is specific for SGCA-related LGMD (PP4; PMID: 26934379) (capped with PP1_Strong). The highest population minor allele frequency of this variant in gnomAD v2.1.1 is 0.00001 (1/71080 alleles) in the European (non-Finnish) population, which is lower than the VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PP1_Strong, PP4, PM3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA130100/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4672 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027651 infores:hetionet CAID:CA347217058 biolink:causes MONDO:0015152 infores:clingen CAID:CA347217058 MONDO:0015152 PMID: Pathogenic PM5, PM3, PP4_Strong, PP3, PS3_Moderate, PM2_Supporting The NM_003494.4: c.3113G>C variant in DYSF, which is also known as NM_001130987.2: c.3167G>C p.(Arg1056Pro), is a missense variant predicted to cause substitution of arginine by proline at amino acid 1038, p.(Arg1038Pro). This variant has been reported in at least one individual with features consistent with LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pt, PMID: 36983702, 33610434) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 33610434; 36983702). The filtering allele frequency of this variant is 0.000014124 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 9/1111952 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.89, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Another missense variant at the same codon, c.3113G>A p.(Arg1038Gln), has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/16/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347217058/MONDO:0015152/180 2025-04-16 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002994 infores:hetionet CHEBI:32315 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0231530 infores:hetionet CAID:CA16020924 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020924 MONDO:0009861 PMID:26503515 Uncertain Significance PP4_Moderate, PM2, BP4 This c.1066-12delT (IVS10-12delT) variant in PAH was reported in one Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. This non-coding variant is not located in a splice region and is not predicted to have splice-altering consequences. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4, BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020924/MONDO:0009861/006 2019-11-06 2019-11-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31174 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0549386 infores:hetionet CHEBI:6904 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0041657 infores:hetionet CHEBI:17141 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0015230 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0016204 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0020649 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0018801 infores:hetionet CHEBI:94392 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0036572 infores:hetionet GO:1903072 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:1903072 GO:0006915 CHEBI:63598 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038587 infores:hetionet CHEBI:3515 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0011603 infores:hetionet CHEBI:45924 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0041834 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0026113 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040213 infores:hetionet CHEBI:2668 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0010200 infores:hetionet CHEBI:3499 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0019080 infores:hetionet CHEBI:91834 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0522251 infores:hetionet CHEBI:3732 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0233514 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0029132 infores:hetionet CHEBI:44915 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0031350 infores:hetionet CHEBI:8207 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085595 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0031117 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0854717 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0854717 infores:hetionet CAID:CA024309 biolink:causes MONDO:0007783 infores:clingen CAID:CA024309 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Aspartic Acid with Asparagine at codon 60 of the RYR1 protein, p.(Asp60Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000016, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257 ). A functional study was published for this variant analyzing the effect of the variant on the stability of the protein, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:23422674). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.736 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024309/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:9605 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0018965 infores:hetionet CHEBI:5001 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151539 infores:hetionet CHEBI:10650 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0162830 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C1368065 infores:hetionet NCBIGene:50619 biolink:causes MONDO:0030457 infores:monarchinitiative not_provided not_provided HGNC:2760 MONDO:0030457 uuid:f89ce990-2f7f-40fc-ad89-39d20cece0c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3176 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0233494 infores:hetionet CHEBI:100241 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003862 infores:hetionet CHEBI:45951 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0039621 infores:hetionet CHEBI:31623 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0162285 infores:hetionet CHEBI:50648 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0043349 infores:hetionet CHEBI:50648 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0149745 infores:hetionet CHEBI:63631 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025323 infores:hetionet CHEBI:100241 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0428977 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0080276 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0332575 infores:hetionet CHEBI:9139 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C1443060 infores:hetionet CAID:CA412725857 biolink:causes MONDO:0100437 infores:clingen CAID:CA412725857 MONDO:0100437 PMID: Likely Pathogenic PP4_Moderate, PP1, PM2_Supporting, PM4_Strong PM5, PS4 NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) is a stop-loss variant that disrupts the stop codon at the end of exon 15 and is predicted to result in extension of the RPGR C-terminus by 38 additional amino acids before the occurrence of the next stop codon (PM4_strong). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including early onset (1 pt) family history consistent with X-linked inheritance (2 pts), exome sequencing-based genotyping excluding other causes of retinal disease (2 pts), myopia (0.5 pts), loss of central visual acuity (0.5 pts), difficulties in color discrimination (0.5 pts), night blindness (0.5 pts), retinal pigment epithelium mottling (0.5 pts), and optic disc pallor (0.5 pts), which together are highly specific for RPGR-related retinopathy (8 points, PMID: 33805381, PP4_moderate). This variant has been reported in at least 2 apparently probands meeting the PS4 requirement of some functional vision impairment in affected males by age 30, or decreased/absent cone and/or rod electrogram responses. However, PS4_supporting was not met because the probands appear to have a shared ancestor (PMIDs: 33805381). The variant has been reported to segregate with retinal dystrophy through more than 2 affected meioses from 1 family (PP1; PMID: 33805381). Another variant in the same codon, NM_001034853.2:c.3457T>A (p.Ter1153Lysext*38), has been reported in association with RPGR-related retinopathy (PMID: 36835250). Both variants are predicted to extend the C-terminus of RPGR by 38 residues in the same frame, however, they replace the start codon with serine and lysine, respectively. PM5_Supporting has not been considered for this variant in order to avoid circularity. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PM4_strong, PP1_moderate, PP4_moderate. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412725857/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:3387 biolink:causes MONDO:0043475 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0001396 infores:hetionet GO:0044480 biolink:causes GO:0043303 infores:ubergraph knowledge_assertion manual_agent GO:0044480 GO:0043303 CHEBI:116278 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0035455 infores:hetionet CHEBI:724125 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0011603 infores:hetionet CHEBI:9635 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0236075 infores:hetionet GO:1904978 biolink:causes GO:0010256 infores:ubergraph knowledge_assertion manual_agent GO:1904978 GO:0010256 CHEBI:4868 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0151827 infores:hetionet CHEBI:4822 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0018965 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002170 infores:hetionet CHEBI:204928 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0038325 infores:hetionet CHEBI:3084 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0231218 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233472 infores:hetionet CAID:CA226411 biolink:causes MONDO:0100437 infores:clingen CAID:CA226411 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PS1_Supporting, PM2_Supporting PS4 NM_001034853.2(RPGR):c.310+1G>C is a canonical splice site variant in intron 4 and is predicted to induce skipping of exon 4, which is expected to disrupt a critical functional domain in RPGR (PVS1). Another variant at the same position in the donor +1/+2 dinucleotide, NM_001034853.2(RPGR):c.310+1G>A, has previously been classified pathogenic by the X-linked IRD VCEP (PS1_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands (PMID: 10937588, PMID: 11992260, https://www.proquest.com/dissertations-theses/defining-genetic-molecular-basis-inherited-eye/docview/2440334553/se-2). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. The variant has been reported to segregate through at least 3 meioses in one family (PP1_Moderate; https://www.proquest.com/dissertations-theses/defining-genetic-molecular-basis-inherited-eye/docview/2440334553/se-2). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PS1_Supporting, PM2_Supporting, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226411/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CAID:CA073266 biolink:causes MONDO:0018493 infores:clingen CAID:CA073266 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 3051 of the RYR1 protein, p.(Arg3051His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000929, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted)( PMID:30236257 ). However, the high MAF in the Ashkenazi Jewish population in gnomAD (0.0046) precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.581 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA073266/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3219 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026826 infores:hetionet CHEBI:135925 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0232462 infores:hetionet NCBIGene:10861 biolink:causes MONDO:0020722 infores:monarchinitiative not_provided not_provided HGNC:10993 MONDO:0020722 uuid:7034fbff-f60c-4eb1-a1b0-bd568ae662de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0013378 infores:hetionet CHEBI:5130 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0085605 infores:hetionet CHEBI:64355 biolink:causes MONDO:0019338 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036202 infores:hetionet CHEBI:83804 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085623 infores:hetionet CHEBI:8863 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0019080 infores:hetionet CHEBI:5280 biolink:causes HP:0100583 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0339293 infores:hetionet CHEBI:8207 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042023 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151313 infores:hetionet CHEBI:472657 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0687713 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0020649 infores:hetionet CHEBI:18358 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0020649 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020538 infores:hetionet CHEBI:31711 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0231528 infores:hetionet CHEBI:9588 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0232462 infores:hetionet CHEBI:27974 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0234233 infores:hetionet CAID:CA170269 biolink:causes MONDO:0010726 infores:clingen CAID:CA170269 MONDO:0010726 PMID: Likely Benign BS1, BS2_Supporting BP4 The allele frequency of the p.Pro72Leu variant in MECP2 (NM_004992.3) is 0.01338% in the Ashkenazi Jewish sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro72Leu variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro72Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170269/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:4909 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0232849 infores:hetionet CAID:CA340924 biolink:causes MONDO:0044970 infores:clingen CAID:CA340924 MONDO:0044970 PMID:17878308PMID:15184630 Uncertain Significance PP3, PS3_Moderate, PM2_Supporting PM6 The m.611G>A variant in MT-TF has been reported in one individual with primary mitochondrial disease (PMID: 15184630). This individual had a clinical diagnosis of myoclonic epilepsy with ragged red fibers (MERRF) characterized by progressive myoclonus, migraines, exercise intolerance, imbalance, memory impairment, progressive sensorineural hearing loss, restricted upgaze, and short stature. Muscle biopsy showed ragged red and COX-deficient fibers. The variant was present at 91% in skeletal muscle and was undetectable in blood, buccal cells, and urinary sediment. The variant was not detected in blood, buccal cells, or urinary sediment from the mother, brother, and daughter. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). MitoTIP predicts the variant is possibly pathogenic (51.2 percentile) and HmtVAR predicts the variant is pathogenic (score of 0.85, PP3). Single fiber testing showed higher levels of the variant in COX-negative ragged red fibers (93.3 ± 4%, n=10) than in COX-positive non-ragged red fibers (17.4 ± 7.3%, n=10, PMID: 15184630). Furthermore, additional functional studies showed a decrease in aminoacylation activity compared to wild type (PMID: 17878308; PS3_moderate). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340924/MONDO:0044970/015 2024-06-10 2025-10-31 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:9568 biolink:causes MONDO:0060659 infores:monarchinitiative not_provided not_provided HGNC:4507 MONDO:0060659 uuid:f1443cba-f82c-4814-9116-cb3aa04f43f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020557 infores:hetionet CHEBI:34911 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0011603 infores:hetionet NCBIGene:2516 biolink:causes MONDO:0013065 infores:monarchinitiative not_provided not_provided HGNC:7983 MONDO:0013065 uuid:3fcbe3e4-13d4-4871-be10-fa5f4e3fb868 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151826 infores:hetionet CHEBI:8461 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0042487 infores:hetionet CHEBI:64310 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0003811 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0022660 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0027051 infores:hetionet CHEBI:31949 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0020458 infores:hetionet NCBIGene:51741 biolink:causes MONDO:0014533 infores:monarchinitiative not_provided not_provided HGNC:12799 MONDO:0014533 uuid:bdaab994-cd0e-4d60-ae25-758192036643 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0035243 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0410256 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0410256 infores:hetionet CHEBI:2637 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0040822 infores:hetionet CHEBI:4717 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0546884 infores:hetionet CHEBI:119486 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0015672 infores:hetionet CHEBI:9566 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0009676 infores:hetionet CHEBI:194135 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0392699 infores:hetionet CHEBI:3242 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C1306341 infores:hetionet CHEBI:15367 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0003862 infores:hetionet CHEBI:5558 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0232495 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019112 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1861172 infores:hetionet CHEBI:9654 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1443060 infores:hetionet CHEBI:91541 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0013144 infores:hetionet CHEBI:4911 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0012833 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0086543 infores:hetionet CHEBI:7496 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0151878 infores:hetionet NCBIGene:54919 biolink:causes MONDO:0013940 infores:monarchinitiative not_provided not_provided HGNC:26013 MONDO:0013940 uuid:ed007e1f-a63d-4559-92c5-026a7f6b5c93 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2676 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0178298 infores:hetionet CHEBI:64354 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0018681 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0160390 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001874 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0235280 infores:hetionet CHEBI:2682 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0013404 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0027051 infores:hetionet CHEBI:50648 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003537 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017178 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0314719 infores:hetionet CHEBI:5847 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0033774 infores:hetionet CHEBI:63620 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013384 infores:hetionet NCBITaxon:1773 biolink:causes MONDO:0005861 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1773 MESH:D018088 DB08903_MESH_D018088_1 CHEBI:7820 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0018418 infores:hetionet CHEBI:63925 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0012569 infores:hetionet CHEBI:135342 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0009763 infores:hetionet CHEBI:4858 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0008031 infores:hetionet CHEBI:8435 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0575081 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0034065 infores:hetionet CHEBI:75722 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0522055 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0031099 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0240291 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0240291 infores:hetionet CHEBI:92923 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0013378 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0025061 infores:hetionet CHEBI:5138 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C2242996 infores:hetionet CHEBI:63608 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0021368 infores:hetionet CAID:CA170313 biolink:causes MONDO:0010726 infores:clingen CAID:CA170313 MONDO:0010726 PMID: Benign BA1, BS2 BP4, PS4, PM1, PP3 The highest population minor allele frequency of the NM_004992.4:c.515C>T (p.Pro172Leu) variant in MECP2 in gnomAD v4.1 is 0.0004 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The Pro172Leu variant is observed in at least 2 unaffected individuals (internal data, Labcorp Genetics Inc.) (BS2). The Pro172Leu variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the Pro172Leu variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170313/MONDO:0010726/036 2025-02-28 2025-03-26 X-linked inheritance HP:0001417 Contradicts true CHEBI:63580 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0014130 infores:hetionet CHEBI:8412 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0162429 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0039971 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020517 infores:hetionet CHEBI:6904 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0004093 infores:hetionet CAID:CA8622981 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622981 MONDO:0100326 PMID:11806996 Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3, PM3_Supporting The 563C>T variant in ITGB3 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 188 (p.Ser188Leu). Surface expression of αIIbβ3 measured by Western blot in COS-7 cells transiently co-transfected with Ser188 β3 (wild type) and Leu188 β3 (mutant) showed absent immunoprecipitation, indicating that this variant impacts protein function (PMID: 9684783)(PS3). At least one patient (Patient BL in PMID: 9684783) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). The GT patient from PMID: 9684783 was homozygous for this variant (0.5 PM3 points, PM3_Supporting). The computational predictor REVEL gives a score of 0.771, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1180026 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PP3, PP4_Moderate, PM2_Supporting and PM3_Supporting (VCEP specifications version 2; date of approval 06/06/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622981/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8207 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0034063 infores:hetionet CHEBI:50841 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0393593 infores:hetionet CHEBI:3752 biolink:causes MONDO:0009774 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0345217 infores:hetionet CHEBI:63613 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0030305 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001584 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0028850 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0016508 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0016508 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0233414 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0853149 infores:hetionet CHEBI:28925 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0024312 infores:hetionet CHEBI:7466 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0022346 infores:hetionet CHEBI:9352 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0038325 infores:hetionet GO:0043405 biolink:causes GO:0023052 infores:ubergraph knowledge_assertion manual_agent GO:0043405 GO:0023052 CHEBI:15552 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0042963 infores:hetionet CHEBI:46081 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0022346 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0003864 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1565489 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0856808 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0856808 infores:hetionet CHEBI:3534 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151578 infores:hetionet CHEBI:72292 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0852913 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0014236 infores:hetionet CHEBI:6958 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0151735 infores:hetionet CHEBI:5123 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0023052 infores:hetionet CHEBI:15854 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0428977 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0034186 infores:hetionet CHEBI:42944 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0017152 infores:hetionet CHEBI:60761 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0017152 infores:hetionet CHEBI:9667 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0031256 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040034 infores:hetionet CHEBI:6741 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0030196 infores:hetionet CHEBI:3515 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0022107 infores:hetionet CHEBI:47780 biolink:causes EFO:0009845 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0007370 infores:hetionet CHEBI:4887 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0015672 infores:hetionet CHEBI:3219 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042023 infores:hetionet CHEBI:2675 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0085631 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0019372 infores:hetionet CHEBI:17347 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0851578 infores:hetionet CHEBI:6909 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013428 infores:hetionet CHEBI:63632 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0032227 infores:hetionet CL:0000236 biolink:causes MONDO:0004095 infores:ubergraph knowledge_assertion manual_agent CL:0000236 MONDO:0004095 CHEBI:7565 biolink:causes MONDO:0019072 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0008372 infores:hetionet CHEBI:2676 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0027497 infores:hetionet CHEBI:68534 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0040034 infores:hetionet CHEBI:9332 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0003862 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0018939 infores:hetionet CHEBI:16469 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0022107 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0020651 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0020433 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0018799 infores:hetionet CHEBI:681850 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0009806 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0233414 infores:hetionet UMLS:C0005740 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0013404 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0012833 infores:hetionet CHEBI:2038 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0002170 infores:hetionet CHEBI:15407 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0018681 infores:hetionet CHEBI:61033 biolink:causes UMLS:C1868809 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C1868809 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0017178 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0853700 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0025290 infores:hetionet CHEBI:3479 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0014518 infores:hetionet CHEBI:127342 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042023 infores:hetionet CHEBI:567361 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0009676 infores:hetionet GO:0048395 biolink:causes GO:0048389 infores:ubergraph knowledge_assertion manual_agent GO:0048395 GO:0048389 CHEBI:4027 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0311468 infores:hetionet NCBIGene:55835 biolink:causes MONDO:0013358 infores:monarchinitiative not_provided not_provided HGNC:17272 MONDO:0013358 uuid:678d1d4d-759f-43f0-80be-09997aa36ff5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CL:0000233 biolink:causes GO:0002554 infores:ubergraph knowledge_assertion manual_agent CL:0000233 GO:0002554 CHEBI:28748 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085661 infores:hetionet CAID:CA007948 biolink:causes MONDO:0021056 infores:clingen CAID:CA007948 MONDO:0021056 PMID: Benign BS2, BP1, BP2, BP5, BS1 PP1, PP4, PVS1, PM6, PM5, PM1, PS4, PS1, PS3, PS2, BP7, BS3, BS4 The c.295C>T variant in APC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid position 99 (p.Arg99Trp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency of the variant c.295C>T in gnomAD v2.1.1 (non-cancer) is 0.0007355 (95/129170 alleles) in the European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1 (BS1). This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae and Ambry Genetics internal data). It has also been observed once in a homozygous state (Ambry Genetics internal data). This variant has been observed 4 times with other APC variants deemed (likely) pathogenic by the HCCP VCEP in individuals with FAP (BP2; PMIDs 23159591, 25604157, Bonn internal data). Finally, this variant has been observed in 6 patients with an alternate molecular basis for disease (BP5; Leiden University Medical Center internal data). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA007948/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:480999 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0947912 infores:hetionet CHEBI:94392 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0003123 infores:hetionet CHEBI:31397 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0151905 infores:hetionet CHEBI:9654 biolink:causes HP:0001820 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0240182 infores:hetionet CHEBI:9150 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0021368 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0178298 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0034065 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0020517 infores:hetionet CHEBI:94609 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0278134 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027441 infores:hetionet CHEBI:9352 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0231528 infores:hetionet CHEBI:28748 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0423791 infores:hetionet CHEBI:6933 biolink:causes MONDO:0002303 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0154841 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038362 infores:hetionet CHEBI:4356 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0042963 infores:hetionet CAID:CA10014183 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014183 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1349G>A (p.Ser450Asn) is a missense variant which has a REVEL score < 0.50 (0.168), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014183/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA1251357 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251357 MONDO:0013144 PMID: Likely Benign BS1, PP3, BS3_Supporting PS4, PM2 The NM_000488.4(SERPINC1):c.719A>G variant predicts a missense change at position 240, from Asparagine to Serine. This variant is present gnomAD (v2.1.1 and v3.1.1) with a MAF of 0.0208% and no homozygotes. Functional testing of HEK293 cells transfected with c.719A>G (p.Asn240Ser) revealed AT antigen levels of 88.8± 4.5%, AT specific activity of 105.4± 2.0%, and Anti-FXa total activity of 95.7± 2.7%. This missense variant has a REVEL score of 0.732, meeting criteria for PP3. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BS3_Supporting, PP3. While the variant meets conflicting pathogenic (PP3) and benign (BS1, BS3_Supproting) codes, the overall score based on the Bayesian framework is -4 (PMID: 32720330), resulting in a likely benign classification. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251357/MONDO:0013144/084 2023-07-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7931 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0155169 infores:hetionet CHEBI:33325 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0020625 infores:hetionet CHEBI:9332 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0011603 infores:hetionet NCBIGene:348180 biolink:causes MONDO:0020647 infores:monarchinitiative not_provided not_provided HGNC:28005 MONDO:0020647 uuid:adeeabce-e593-4c2a-9c55-f7968f5b327f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042571 infores:hetionet CHEBI:8869 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0011615 infores:hetionet CAID:CA1484103 biolink:causes MONDO:0100283 infores:clingen CAID:CA1484103 MONDO:0100283 PMID: Likely Benign BP7, BP4 BS1, PM2, BA1 The NM_005465.7(AKT3):c.504G>A (p.Lys168=) variant is a synonymous (silent) variant that occurs at a nucleotide that is not conserved according to a PhyloP <0.1 (BP7). The results from in silico splicing predictors MaxEntScan, spliceAI and varSEAK support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as Likely benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: BP4, BP7; -2 points (VCEP specifications version 1; Approved: 1/31/2021) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA1484103/MONDO:0100283/018 2022-02-11 2022-02-11 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Contradicts https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:10101 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0030193 infores:hetionet CAID:CA320215 biolink:causes MONDO:0011229 infores:clingen CAID:CA320215 MONDO:0011229 PMID: Pathogenic PS3_Supporting, PM5, PP3, PM3_Strong, PP4_Moderate BS2, BA1, BP4, BP2, PS1, PS2, PVS1, PM6, PM2, BP5, BS1 The c.488G>A (NM_014297.5) variant in ETHE1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 163 (p.R163Q). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 (13/251,458 alleles) in the general population, which is higher than the ClinGen ETHE1 threshold < 0.00002 for PM2, thus it does not meet this criterion. This variant was originally reported in two compound heterozygous (c.131_132delAG; p. E44fsX105) relatives who both had developmental delay, petechiae, orthostatic acrocyanosis, chronic diarrhea, and ethylmalonic aciduria which is a phenotype highly specific to ethylmalonic encephalopathy (PP4_moderate; PMID: 14732903). This variant has been detected in at least 9 patients reported in the literature with ethylmalonic encephalopathy, however, many of the cases are not scoreable according to the SVI recommendation for in trans criterion for PM3, as parental phasing was not performed or the second variant was a VUS (PMID: 18593870; PMID: 16183799, PMID: 30298498). After review of scoreable cases, it was determined by the ETHE1 VCEP that four reported cases were scorable. A single relative from family L from PMID: 14732903 was awarded 1.0 as this patient was a compound heterozygote for an upstream truncating variant (c.131_132delAG; p. E44fsX105), which was confirmed in trans by segregation analysis. Additionally, while the p.E44fsX105 has not been formally curated at this time, given that the p.E44fsX105 is a truncating variant that is predicted to undergo nonsense mediated decay, it is also a strong candidate for a pathogenic classification; the VCEP agreed that this was justification to score this case as 1.0. Patients reported in PMID: 22020834 and PMID: 27771676 were each awarded 0.25 for their respective VUS’s, which were also confirmed in trans. A homozygous patient reported in PMID: 27391121 in whom homozygosity was confirmed via trio WES including parental samples was scored 0.5. This was confirmed by Baylor Genetics who performed the testing for this study (PM3_Strong; Total score- 2.0). ETHE1 encodes persulfide dioxygenase. Persulfide dioxygenase activity measured in recombinant human ETHE1 proteins (both wild-type and p.R163Q) expressed in E.Coli (purified to homogeneity) showed that the p.R163Q recombinant E.Coli only exhibited ~10% of wild-type catalytic activity, indicating that this variant impacts protein function (PS3_supporting; PMID: 25198162). One other missense variant [c.487C>T, p.R163W; PMID 14732903, PMID 16828325, PMID 16183799, PMID 28698729; ClinVar Variation ID: 2317], in the same codon has been classified as pathogenic for ethylmalonic encephalopathy by the ClinGen ETHE1 VCEP (PM5). The computational predictor [REVEL] gives a score of 0.928, which is above the threshold of 0.75, evidence that correlates with impact on ETHE1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): PM3_strong, PP4_Moderate, PS3_supporting, PM5, PP3. Approved 7/12/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA320215/MONDO:0011229/014 2021-07-27 2021-07-27 Autosomal recessive inheritance HP:0000007 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:94392 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0687713 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0037274 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0851341 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0036454 infores:hetionet CHEBI:10112 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0042029 infores:hetionet CHEBI:2549 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0030232 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0042373 infores:hetionet CHEBI:2469 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0151905 infores:hetionet CHEBI:3219 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0241060 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0030920 infores:hetionet CHEBI:4953 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C1527344 infores:hetionet CHEBI:3561 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0035455 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0699885 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0001824 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0236065 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0234215 infores:hetionet GO:1901207 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0007507 CHEBI:92923 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0863084 infores:hetionet CHEBI:15553 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0026826 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0034882 infores:hetionet CHEBI:4530 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0012833 infores:hetionet NCBIGene:4089 biolink:causes MONDO:0015278 infores:monarchinitiative not_provided not_provided HGNC:6770 MONDO:0015278 uuid:ae75f9d8-6663-48ef-ac8a-9c651a435687 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3044 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0017178 infores:hetionet CHEBI:2675 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085649 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0019158 infores:hetionet CHEBI:231594 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C3665347 infores:hetionet CHEBI:6375 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0037036 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0007222 infores:hetionet CHEBI:10124 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013604 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0234913 infores:hetionet CHEBI:41423 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0004604 infores:hetionet CAID:CA000521 biolink:causes MONDO:0017623 infores:clingen CAID:CA000521 MONDO:0017623 PMID: Likely Pathogenic PVS1, PM2_Supporting PM6, BP7, BP5, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM4, PM1, PM3, PM5, BA1, BP4, BP1, BP3, BP2, PS3, PS4, PS2, PS1 PTEN c.564T>A (p.Y188X) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria v3 (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4). PM2_P: Absent in gnomad v4. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000521/MONDO:0017623/003 2025-10-03 2025-10-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5103 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0012569 infores:hetionet NCBIGene:129685 biolink:causes MONDO:0859266 infores:monarchinitiative not_provided not_provided HGNC:17300 MONDO:0859266 uuid:06e936da-5b93-4334-92e4-8d726d94049c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:107736 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C1565489 infores:hetionet CHEBI:6801 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0009782 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0522224 infores:hetionet UMLS:C0657912 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151937 infores:hetionet CHEBI:5790 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013362 infores:hetionet CHEBI:140621 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0015230 infores:hetionet CHEBI:9086 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0015672 infores:hetionet CHEBI:3723 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019270 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0018799 infores:hetionet CHEBI:61049 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1145670 infores:hetionet CHEBI:79699 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151603 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151810 infores:hetionet CHEBI:3506 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0155862 infores:hetionet CHEBI:2549 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0085593 infores:hetionet CHEBI:15553 biolink:causes HP:0031274 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0020683 infores:hetionet CHEBI:28918 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0013144 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151826 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0021400 infores:hetionet CHEBI:42355 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0015230 infores:hetionet CHEBI:75045 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151723 infores:hetionet CHEBI:85078 biolink:causes MONDO:0007018 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042996 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0027765 infores:hetionet CHEBI:50692 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0042963 infores:hetionet CAID:CA10585393 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585393 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM3, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM1, PM4, PVS1, PM6, BS2, PP3 The NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM3, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 10 unrelated cases, as follows: 6 patients with DLCN >=6 and 2 patients with Simon-Broome criteria of possible FH from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 1 case with MedPed criteria from PMID 21868016 (Garcia-Garcia et al., 2011); 1 case with DLCN>6 from PMID 10634824 (Deiana et al., 2000). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM3: Variant meets PM2 and is identified in 2 siblings from PMID 29306853 with childhood total cholesterol levels >700 mg/dL and homozygous for this variant. So PM3 is met. PP1_Strong: Variant segregates with FH phenotype in >1 families, as follows: 6 affected family members from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 10 affected members tested positive and 7 unaffected members tested negative in one family in 17 informative meiosis from PMID 21868016, so PP1_Strong is met.PP4: Variant meets PM2 and is identified in 10 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585393/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:9137 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0149745 infores:hetionet CHEBI:9445 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0042023 infores:hetionet CHEBI:42797 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151889 infores:hetionet CHEBI:31932 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0003862 infores:hetionet CHEBI:8382 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0013604 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151736 infores:hetionet CHEBI:72297 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0152031 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0005940 infores:hetionet CHEBI:16755 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0392171 infores:hetionet CHEBI:27565 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0040034 infores:hetionet CHEBI:520985 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0039070 infores:hetionet CHEBI:72296 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0036974 infores:hetionet CHEBI:4653 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0340865 infores:hetionet CHEBI:45716 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0018681 infores:hetionet CHEBI:45924 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0002792 infores:hetionet CHEBI:34967 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0039503 infores:hetionet CHEBI:3084 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0038990 infores:hetionet CHEBI:83804 biolink:causes HP:0004796 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0236124 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0162429 infores:hetionet CHEBI:31638 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0030554 infores:hetionet NCBIGene:2811 biolink:causes MONDO:0009276 infores:monarchinitiative not_provided not_provided HGNC:4439 MONDO:0009276 uuid:69e010da-0823-43fe-a0e9-85132dec9c4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0008370 infores:hetionet CHEBI:17630 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0003578 infores:hetionet CHEBI:4653 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0700590 infores:hetionet CHEBI:7852 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151603 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0022408 infores:hetionet CHEBI:50729 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0002792 infores:hetionet CHEBI:15552 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0030193 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020615 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0475858 infores:hetionet CHEBI:119915 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018965 infores:hetionet CHEBI:7915 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0231528 infores:hetionet CHEBI:45863 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011603 infores:hetionet CHEBI:7931 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0022408 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0027765 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0267792 infores:hetionet CHEBI:8107 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0014591 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007117 infores:hetionet CHEBI:6954 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0011603 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0178298 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0003123 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0031542 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0024137 infores:hetionet CHEBI:31859 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0022107 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0027051 infores:hetionet CHEBI:28939 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0018799 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0018802 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0234458 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0948089 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0948807 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0020649 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C2047937 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0151623 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151623 infores:hetionet CHEBI:6950 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0522178 infores:hetionet CHEBI:2453 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0542571 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0236071 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017160 infores:hetionet CHEBI:6888 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0332601 infores:hetionet CHEBI:101278 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151529 infores:hetionet CHEBI:3723 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020433 infores:hetionet CHEBI:61049 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009676 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0018799 infores:hetionet CHEBI:3044 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0018681 infores:hetionet CHEBI:41774 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1458155 infores:hetionet CHEBI:3403 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0020578 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011849 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0019054 infores:hetionet CHEBI:18248 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020615 infores:hetionet CHEBI:63617 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085641 infores:hetionet CHEBI:9737 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0036572 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0009324 infores:hetionet CHEBI:17630 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0027497 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0029882 infores:hetionet CAID:CA2573051033 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051033 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP1 PP4 The c.129_130delinsA variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids before encountering a stop codon (p.(Leu44TrpfsTer111). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant segregated with diabetes, with 3 informative meioses in one family with MODY (PP1; PMID: 11692182) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four individuals in one family with diabetes; however, the MODY probability is unable to be calculated due to insufficient clinical information (PMID: 11692182). In summary, c.129_130delinsA meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30.21): PVS1, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051033/MONDO:0015967/017 2022-05-04 2022-05-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:125354 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C1443060 infores:hetionet CHEBI:585948 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0428977 infores:hetionet CHEBI:142290 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0040264 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0031542 infores:hetionet CHEBI:63613 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0018213 infores:hetionet NCBIGene:7846 biolink:causes MONDO:0012703 infores:monarchinitiative not_provided not_provided HGNC:20766 MONDO:0012703 uuid:8c3c3718-1d04-4253-b52e-39286625ea26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3732 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0011991 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013395 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0042109 infores:hetionet CHEBI:16796 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0006145 infores:hetionet NCBITaxon:1279 biolink:causes MONDO:0005970 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1279 MESH:D011023 DB00607_MESH_D011023_1DB00607_MESH_D011023_2DB01212_MESH_D011023_1DB00485_MESH_D011023_1DB01331_MESH_D011023_1DB01139_MESH_D011023_1DB01327_MESH_D011023_1DB00493_MESH_D011023_1DB00713_MESH_D011023_1DB01333_MESH_D011023_1DB01112_MESH_D011023_1DB01326_MESH_D011023_1 CHEBI:15367 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0241164 infores:hetionet UNII:D27V6190PM biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0043352 infores:hetionet CHEBI:6897 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0344232 infores:hetionet CHEBI:7865 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0009806 infores:hetionet CHEBI:76010 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0020456 infores:hetionet CHEBI:3441 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042029 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0036572 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0011570 infores:hetionet CHEBI:68579 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151539 infores:hetionet CHEBI:37333 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C3665386 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0025061 infores:hetionet CHEBI:50663 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0542571 infores:hetionet CHEBI:65349 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0004238 infores:hetionet CHEBI:171719 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0034155 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0264268 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0264268 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0020517 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001956 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0343084 infores:hetionet CHEBI:51364 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0040128 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0267792 infores:hetionet CHEBI:63620 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0021177 infores:hetionet CHEBI:8888 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0162298 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0009450 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0026650 infores:hetionet CHEBI:63608 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1291077 infores:hetionet CHEBI:6970 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0152459 infores:hetionet CHEBI:168396 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020578 infores:hetionet NCBIGene:3861 biolink:causes MONDO:0007445 infores:monarchinitiative not_provided not_provided HGNC:6416 MONDO:0007445 uuid:c246e736-d095-4b65-a953-bc7f94208b19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1168034 infores:hetionet CHEBI:4995 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0162830 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0012241 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0012241 infores:hetionet CHEBI:3403 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0039231 infores:hetionet CHEBI:119915 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0267028 infores:hetionet CHEBI:3215 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0033117 infores:hetionet CHEBI:4877 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0018524 infores:hetionet NCBITaxon:785 biolink:causes MONDO:0000330 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:785 MESH:D014437 DB00254_MESH_D014437_1DB02703_MESH_D014437_1 CHEBI:31638 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0009782 infores:hetionet NCBIGene:259232 biolink:causes MONDO:0014556 infores:monarchinitiative not_provided not_provided HGNC:19082 MONDO:0014556 uuid:2bca0059-1e0c-4457-a31e-d42699c529de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2038 biolink:causes UMLS:C0235632 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0235632 infores:hetionet CHEBI:3181 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0038220 infores:hetionet NCBIGene:9241 biolink:causes MONDO:0020733 infores:monarchinitiative not_provided not_provided HGNC:7866 MONDO:0020733 uuid:45c06fbb-170e-4a3b-9ea6-e1691ef40c52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28830 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0002170 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0276141 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0276141 infores:hetionet CHEBI:4027 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0004093 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0740425 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011334 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038358 infores:hetionet CHEBI:63610 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0042029 infores:hetionet CHEBI:2704 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C2830004 infores:hetionet CHEBI:6715 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0234233 infores:hetionet CHEBI:15551 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0023218 infores:hetionet CAID:CA8338148 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338148 MONDO:0008723 PMID: Uncertain Significance BP4, PM2 The c.1533-4T>A variant in ACADVL is an intronic variant which occurs in intron 15. The result from in silico splicing predictor (SpliceAI) support that this variant does not affect splicing (BP4). The highest population minor allele frequency in gnomAD v4.1 is 0.0006 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).To our knowledge, this variant has not been reported in the literature in any individuals with autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, PM2_Supporting (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338148/MONDO:0008723/021 2025-05-27 2025-05-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3387 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009763 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0026975 infores:hetionet CHEBI:9288 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0002871 infores:hetionet CHEBI:7640 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0026961 infores:hetionet CHEBI:8232 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0041834 infores:hetionet CAID:CA024605 biolink:causes MONDO:0007783 infores:clingen CAID:CA024605 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PM1 PP3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Valine with Isoluecine at codon 218 of the RYR1 protein, p.(Val218Ile). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000023, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, one of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257; PMID:16732084). One individual (without contracture testing) had a second variant of unknown significance in RYR1 (p.Glu4283Val) and was not counted toward PS4, PS4_Supporting was implemented. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1, (PMID: 21118704). A REVEL score 0f 0.801 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024605/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6541 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0043352 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0151825 infores:hetionet CHEBI:6541 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0231218 infores:hetionet CHEBI:70718 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0030193 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0178298 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1258215 infores:hetionet CHEBI:5801 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0029124 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0021053 infores:hetionet CAID:CA16020796 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020796 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting The frameshift variant c.456_463dup generates a stop codon in exon 6 of 13 and is predicted to undergo NMD. The variant is absent from population databases, including gnomAD. It has been reported in at least one compound heterozygous patient with classical PKU (PMID: 24401910), in trans with pathogenic variant c.611A>G (ClinVar 590). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020796/MONDO:0009861/006 2022-01-22 2022-06-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135736 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042487 infores:hetionet CHEBI:3723 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2981158 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0235431 infores:hetionet CHEBI:42797 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085641 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0442874 infores:hetionet CHEBI:41977 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0003811 infores:hetionet CAID:CA286501 biolink:causes MONDO:0009861 infores:clingen CAID:CA286501 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5 The c.368G>T (p.Arg123Ile) variant in PAH has not been reported in the literature to our knowledge. A reference listed in BioPKU/PAHdb cannot be located (Carducci, C 2009). This variant is absent from ExAC, gnomAD, 1000G, and ESP. Deleterious effect is predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.864. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286501/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8356 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0235146 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235416 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0015230 infores:hetionet NCBIGene:4723 biolink:causes MONDO:0032609 infores:monarchinitiative not_provided not_provided HGNC:7716 MONDO:0032609 uuid:e5fe5007-abe7-4ae4-855f-42b73473454b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5050 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0232292 infores:hetionet UMLS:C0209366 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0595939 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0027765 infores:hetionet CHEBI:5864 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0033774 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0521490 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0002170 infores:hetionet CHEBI:36791 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020453 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0855625 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0855625 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011616 infores:hetionet GO:0021914 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0021914 GO:0007417 CHEBI:7822 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0340865 infores:hetionet CHEBI:474180 biolink:causes HP:0012282 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0234918 infores:hetionet CHEBI:5775 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0086565 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0231303 infores:hetionet CAID:CA1906606 biolink:causes MONDO:0018958 infores:clingen CAID:CA1906606 MONDO:0018958 PMID: Uncertain Significance PVS1_Strong, BS1 PM3 The NM_001164508.2:c.22590+2T>C variant in NEB occurs within the canonical splice donor site (+2) of intron 154. It is predicted to cause skipping of biologically-relevant-exon 154/182, resulting in an in-frame deletion (removes amino acids V7494-E7530). As per ClinGen Congenital Myopathies VCEP specifications, in-frame exon skipping of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy (PVS1_Strong). The highest population minor allele frequency in gnomAD v4.1 is 0.0004030 (469/1163744 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold ≥0.000237 for BS1 and therefore meets this criterion (BS1). Although this variant has been seen in the general population in a heterozygous state, with no homozygous observations, its frequency is not high enough to rule out a pathogenic role. This variant has been observed in individuals with congenital myopathies in a heterozygous state without a second variant. Therefore, no codes were applied (Internal data: GeneDx SCV000619698.7, CeGaT Center for Human Genetics Tuebingen SCV001152434.31, Fulgent Genetics SCV005650398.1). In summary, due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies: PVS1_Strong, BS1. (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 06/16/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1906606/MONDO:0018958/146 2025-06-16 2025-06-24 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:36791 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549405 infores:hetionet CAID:CA512319000 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319000 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.102C>A (p.Ala34=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319000/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:DJJ95FJP1H biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C1443060 infores:hetionet CHEBI:63608 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0009763 infores:hetionet CAID:CA16020817 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020817 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The c.560G>A (p.Trp187Ter) variant in PAH is a nonsense variant in exon 6 of 13 predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a patient from Korea with mild hyperphenylalaninemia, detected with pathogenic variant c.1068C>A p.Tyr356X, phase unknown (PMID: 18985011; PP4_M); however, the VCEP is concerned that these variants are in cis due to genotype (2 LoF variants) discrepant with clinical phenotype (MHP). So we are not applying PM3 evidence. This variant is absent from gnomAD. In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020817/MONDO:0009861/006 2024-02-23 2024-07-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030554 infores:hetionet CHEBI:6437 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0009782 infores:hetionet CAID:CA167953 biolink:causes MONDO:0007648 infores:clingen CAID:CA167953 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1118C>T (p.Pro373Leu) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA167953/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true UNII:15G12L5X8K biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0853149 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0034150 infores:hetionet CHEBI:63631 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0011615 infores:hetionet CHEBI:63619 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0232462 infores:hetionet CHEBI:8356 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0027066 infores:hetionet CHEBI:8093 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0020546 infores:hetionet CHEBI:3387 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0011168 infores:hetionet CHEBI:3011 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0002170 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0032326 infores:hetionet CHEBI:9586 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0003862 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0007642 infores:hetionet CHEBI:209807 biolink:causes UMLS:C1167654 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C1167654 infores:hetionet CHEBI:9168 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0015230 infores:hetionet CAID:CA414443538 biolink:causes MONDO:0010604 infores:clingen CAID:CA414443538 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PS2_Moderate, PM5, PP3 PM1 The c.802T>G (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 268 (p.Cys268Gly). There is at least 1 proband with isolated reduction in FIX activity levels meeting phenotypic criteria for F9, with assumed de novo occurrence (PS4_Supporting & PS2_Moderate: PMID: 10647899). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3.1/ gnomAD v4.1.0), meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). A different missense variant causing a change at the same residue (p.Cys268Tyr) has been established as pathogenic for F9 and SpliceAI predicts no impact on splicing (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Supporting + PM2_Supporting + PP3 + PM5 + PS2_Moderate. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414443538/MONDO:0010604/080 2025-10-03 2025-10-07 X-linked inheritance HP:0001417 Supports CHEBI:63631 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0086439 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0033777 infores:hetionet CHEBI:9566 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0030446 infores:hetionet CHEBI:28901 biolink:causes MONDO:0011996 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0023473 infores:hetionet CHEBI:63791 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151766 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0029408 infores:hetionet UMLS:C0065374 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0232462 infores:hetionet CHEBI:40237 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0017168 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0234215 infores:hetionet CAID:CA039774 biolink:causes MONDO:0007750 infores:clingen CAID:CA039774 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.2323G>A (p.Val775Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001114 (0.011%) in East Asian exomes+genomes (gnomAD v4.1.0). BP4: REVEL=0.123. It is below 0.5, so splicing evaluation is required.A) not on limitsB) does not create AGC) there is an AG nearby.MES scores: variant cryptic = 2.05, wt cryptic = 2.52, canonical acceptor = 11.36.Ratio variant cryptic/wt cryptic: 0.81 --- it is below 1.1.Ratio variant cryptic/canonical acceptor: 0.18--- it is below 0.9.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA039774/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6128 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0037036 infores:hetionet CHEBI:6456 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0004093 infores:hetionet CAID:CA658655932 biolink:causes MONDO:0021056 infores:clingen CAID:CA658655932 MONDO:0021056 PMID:20685668 Likely Pathogenic PP3, PS4_Moderate, PS3_Moderate, PM2_Supporting The NM_000038.6(APC):c.1409-3T>G variant in APC is an intronic variant which is located at the 3rd nucleotide upstream of exon 12. This variant has been reported in 4 probands meeting phenotypic criteria resulting in a total phenotype score of 2.0 points (PS4_Moderate, internal data Ambry Genetics and Labcorp Genetics [formerly Invitae], PMID: 20685668). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from ≥ 2 in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the acceptor site of intron 11 of APC and/or by creating a strong alternate acceptor (PP3). Mini-gene assay demonstrated that the variant impacts splicing by skipping of exon 12 resulting in a frameshift and premature termination (PS3_Moderate, PMID: 20685668). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: criteria PS3_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications version 2.0.3; date of approval: 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658655932/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6375 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020649 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0017160 infores:hetionet GO:0048891 biolink:causes CL:2000031 infores:ubergraph knowledge_assertion manual_agent GO:0048891 CL:2000031 NCBIGene:4747 biolink:causes MONDO:0011902 infores:monarchinitiative not_provided not_provided HGNC:7739 MONDO:0011902 uuid:bde9ec04-98dd-4649-92b0-cb75a514e0d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3638 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0011991 infores:hetionet CHEBI:63598 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0476273 infores:hetionet CHEBI:64354 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0014591 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0441713 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0441713 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0033975 infores:hetionet CHEBI:8707 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0043352 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0031117 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0020517 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0036572 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0085393 infores:hetionet CHEBI:3077 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0027540 infores:hetionet CHEBI:63631 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C2981158 infores:hetionet CHEBI:8435 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0023052 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0027051 infores:hetionet CHEBI:35677 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0232493 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020877 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0853149 infores:hetionet CHEBI:135613 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C1443060 infores:hetionet CHEBI:75045 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0011175 infores:hetionet NCBIGene:3181 biolink:causes MONDO:0958195 infores:monarchinitiative not_provided not_provided HGNC:5033 MONDO:0958195 uuid:45a59d44-da6d-46df-bfcf-d7a6b939318a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020946 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020946 MONDO:0009861 PMID:21890392 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 PM5 The c.1129T>G (p.Tyr377Asp) variant in PAH has been reported in 1 Armenian individual with classic PKU (BH4 deficiency ruled out) (PP4_Moderate; PMID: 21890392). This variant is absent in population databases (PM2). This variant was detected in trans with c.1066-11G>A (Pathogenic in ClinVar) (PM3, PMID: 21890392). This variant is prediction to be deleterious by SIFT, PolyPhen, and MutationTaster, and REVEL = 0.932 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020946/MONDO:0009861/006 2020-05-09 2020-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28971 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0235347 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0009443 infores:hetionet CAID:CA392317923 biolink:causes MONDO:0007947 infores:clingen CAID:CA392317923 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PS4_Supporting, PM2_Supporting NM_00138 c.4255C>T is a nonsense variant in FBN1 predicted to cause a substitution of a Glutamine by a termination codon at amino acid 1419 (p.Gln1419*), which likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with thoracic aortic aneurysm or dissection (TAAD) and a systemic score ≥7 (PMID: 29357934) (PS4_supporting). This variant was also found in an internal proband who meets the revised Ghent criteria for a diagnosis of Marfan syndrome (TAAD, systemic score ≥7) (PP4). This variant is not present in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4_supporting, PM2_supporting, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392317923/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:6775 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1510410 infores:hetionet GO:1904259 biolink:causes GO:0010172 infores:ubergraph knowledge_assertion manual_agent GO:1904259 GO:0010172 CHEBI:50730 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0917801 infores:hetionet CHEBI:724125 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0005758 infores:hetionet CHEBI:3223 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0233477 infores:hetionet CAID:CA8328680 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328680 MONDO:0100438 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PM3 NM_014336.5(AIPL1):c.34dup (p.Val12GlyfsTer?) is a 1 bp duplication that changes amino acid p.12 from valine to glycine and alters the reading frame, with a new stop codon encountered after 32 amino acids. This premature stop codon in exon 1 of 6 is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000001859, with 3 /1614036 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 32531858). However, the proband was not counted for PM3_Supporting because the other variant p.Arg80Trp is currently classified as a VUS and was not confirmed to be in trans. In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1 and PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328680/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41977 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0687713 infores:hetionet CHEBI:9635 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0004134 infores:hetionet CHEBI:9139 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0019080 infores:hetionet CAID:CA2573143980 biolink:causes MONDO:0008535 infores:clingen CAID:CA2573143980 MONDO:0008535 PMID: Uncertain Significance PP3, PM2_Supporting The NM_001114753.3: c.1312-3C>G variant in ENG is an intronic variant located in intron 10. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.21 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 10 of ENG (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PP3 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573143980/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0235639 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0025061 infores:hetionet CHEBI:82960 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0028081 infores:hetionet CHEBI:617099 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0242429 infores:hetionet CHEBI:45783 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042384 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0020517 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0011849 infores:hetionet CHEBI:36791 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151934 infores:hetionet CAID:CA061023 biolink:causes MONDO:0018493 infores:clingen CAID:CA061023 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, BP4 PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 4757 of the RYR1 protein, p.(Arg4757His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000159, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score <0.50 (0.452) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA061023/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:74947 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0242350 infores:hetionet CHEBI:168396 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0023530 infores:hetionet CHEBI:32192 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0004096 infores:hetionet CHEBI:41423 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0013428 infores:hetionet CHEBI:38562 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0392699 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235966 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235966 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020437 infores:hetionet CHEBI:31348 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C3665624 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0006849 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1257843 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0475858 infores:hetionet CHEBI:5123 biolink:causes UMLS:C0542165 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0542165 infores:hetionet CHEBI:135929 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0041657 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0034063 infores:hetionet CHEBI:29688 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0003123 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549374 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549374 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0541820 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0541820 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0281981 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0022354 infores:hetionet CHEBI:63623 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0009443 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0029445 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0012797 infores:hetionet CHEBI:134966 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0033774 infores:hetionet CHEBI:4702 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0036454 infores:hetionet CHEBI:31524 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0012833 infores:hetionet CHEBI:9588 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0151766 infores:hetionet CHEBI:231594 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0346156 infores:hetionet CHEBI:8597 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C1320835 infores:hetionet CHEBI:4495 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0012569 infores:hetionet CHEBI:135342 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0030554 infores:hetionet CHEBI:8107 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0010200 infores:hetionet CHEBI:85161 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0267792 infores:hetionet CHEBI:7986 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0027424 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014534 infores:hetionet CHEBI:63630 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0017181 infores:hetionet CHEBI:63638 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0030193 infores:hetionet CHEBI:75722 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0547030 infores:hetionet CAID:CA220403 biolink:causes MONDO:0009290 infores:clingen CAID:CA220403 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting "The NM_000152.5: c.2544del (p.Lys849ArgfsTer38) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 19/20. Although the premature stop codon is thought to occur in the penultimate exon of the gene, it is not within the last 50 base pairs of the exon and, therefore, it is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. A patient with this variant has been reported to have no GAA cross-reactive material (CRIM-negative)(PMID 23763753), supporting that this variant is a loss of function variant (PVS1). This patient, who has symptoms consistent with infantile onset Pompe disease, and another individual with late-onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID 30363678), both meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. The first patient (CRIM-negative) is compound heterozygous for the variant and a ""complex deletion"". Because details of the complex deletion are unavailable, this data was not included for PM3. The second patient is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 30363678)(0.5 points, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92480, one star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220403/MONDO:0009290/010 2021-12-02 2021-12-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:68478 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018801 infores:hetionet CAID:CA8603436 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603436 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 The intronic variant NM_000419.5(ITGA2B):c.574+10A>G has not been reported in the literature. It has previously been submitted to ClinVar (SCV000403390.2 and SCV001006746.1) however the affected status of the individuals is not reported. The highest population minor allele frequency in gnomAD v4.0.0 is 0.00003843 (2/52046alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). It is not predicted to have an impact on splicing and is not highly conserved (BP4, BP7). In summary, the c.574+10A>G variant is classified as likely benign based on GT-specific criteria applied: PM2_supporting, BP4, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603436/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:68554 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0522153 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0020649 infores:hetionet CHEBI:7983 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C3203358 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0000833 infores:hetionet CHEBI:76010 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0018213 infores:hetionet CHEBI:16714 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0031924 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0424230 infores:hetionet CHEBI:71272 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0037199 infores:hetionet CHEBI:10110 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1167965 infores:hetionet CHEBI:15551 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0232292 infores:hetionet CHEBI:64355 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0033771 infores:hetionet CHEBI:7573 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0041657 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009760 infores:hetionet CHEBI:4681 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0687713 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020538 infores:hetionet CHEBI:9398 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0011603 infores:hetionet CHEBI:63581 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0038362 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1384353 infores:hetionet NCBIGene:6809 biolink:causes MONDO:0859170 infores:monarchinitiative not_provided not_provided HGNC:11438 MONDO:0859170 uuid:83e2f7f7-16b7-4666-8226-ec496d1008a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:691037 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0041834 infores:hetionet CAID:CA410202643 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202643 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, BP1, BP4, BP3, BA1, BS1, BP5, BP7, PM4, PM3, PM1, PP2, PP3, PP4, BS2 NM_001754.5(RUNX1):c.422C>A (p.Ser141Ter) is a nonsense variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1, PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202643/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8232 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0013604 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0919980 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0080203 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C1258215 infores:hetionet NCBIGene:203286 biolink:causes MONDO:0014158 infores:monarchinitiative not_provided not_provided HGNC:26724 MONDO:0014158 uuid:4dc81f6f-0308-4240-9812-63ed211549f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3485 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0034150 infores:hetionet CHEBI:7494 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0034880 infores:hetionet CAID:CA386959975 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959975 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PM5_Supporting, PP3 PS4, PP4 The c.433T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to proline at codon 145 (p.(Ser145Pro)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant at the same codon, c.434C>T p.(Ser145Phe), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser145Pro (PM5_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, therefore PP4 was not applied (internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 34362814, internal lab contributors). In summary, c.433T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PP3, PM2_Supporting, PM1, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959975/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:UMD7G2653W biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0038999 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0151849 infores:hetionet CHEBI:119486 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0011603 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0151763 infores:hetionet CHEBI:6888 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0033774 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0948521 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0948521 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0860713 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0860713 infores:hetionet CHEBI:145499 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0014394 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0025202 infores:hetionet CHEBI:36791 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0041105 infores:hetionet CHEBI:119573 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0019521 infores:hetionet CHEBI:68554 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0027121 infores:hetionet UBERON:0004064 biolink:causes UBERON:0002328 infores:ubergraph knowledge_assertion manual_agent UBERON:0004064 UBERON:0002328 CHEBI:78543 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0037274 infores:hetionet CHEBI:18358 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0013604 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002622 infores:hetionet CHEBI:8435 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0003811 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026946 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021063 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007102 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0234215 infores:hetionet UNII:3QJA87N40S biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0038999 infores:hetionet CHEBI:6741 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0149745 infores:hetionet CHEBI:5778 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042384 infores:hetionet CAID:CA10584708 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584708 MONDO:0007750 PMID:31395865 Uncertain Significance PS3_Moderate, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP2, PP3, PP1, BS2 The NM_000527.4(LDLR):c.-136C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PS3_moderate - 2 Level 3 FS: (1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression(2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression--- in both studies, transcription levels are below 50% of wild-type, so PS3_Moderate is met.PP4 - Variant meets PM2 and is identified in 1 index case who fulfills DLCN >6 criteria for FH from PMID: 21538688, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584708/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8764 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151826 infores:hetionet CHEBI:6539 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0017181 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0025061 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0234215 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0033975 infores:hetionet NCBIGene:8328 biolink:causes MONDO:0008553 infores:monarchinitiative not_provided not_provided HGNC:4238 MONDO:0008553 uuid:e6b83fbe-c201-4688-b4bb-5c3d6815b83a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4887 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0040409 infores:hetionet CHEBI:8863 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0232461 infores:hetionet CAID:CA410207009 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207009 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.657G>C (p.Leu219Phe) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207009/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52172 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151479 infores:hetionet NCBIGene:1462 biolink:causes MONDO:0007740 infores:monarchinitiative not_provided not_provided HGNC:2464 MONDO:0007740 uuid:65e7e775-d171-4ffa-8957-9c7880bf4e1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes UMLS:C0263445 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0263445 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0009450 infores:hetionet CHEBI:6078 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0235267 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020649 infores:hetionet CAID:CA10014584 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014584 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.145C>G (p.Pro49Ala) is a missense variant which has a REVEL score < 0.50 (0.496), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014584/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8356 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0428974 infores:hetionet CHEBI:31949 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0700361 infores:hetionet CHEBI:6538 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0424295 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0028734 infores:hetionet CHEBI:3242 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0013384 infores:hetionet CHEBI:8356 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0851578 infores:hetionet CHEBI:50861 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0040034 infores:hetionet CHEBI:36791 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014518 infores:hetionet CHEBI:3077 biolink:causes UMLS:C1096278 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1096278 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0015397 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0015732 infores:hetionet CHEBI:8024 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030807 infores:hetionet NCBITaxon:1980476 biolink:causes MONDO:0017879 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1980476 MONDO:0017879 CHEBI:80630 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C3665347 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151664 infores:hetionet CHEBI:82960 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C2830004 infores:hetionet CHEBI:5855 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0344232 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0034065 infores:hetionet NCBIGene:9131 biolink:causes MONDO:0010437 infores:monarchinitiative not_provided not_provided HGNC:8768 MONDO:0010437 uuid:9ccdd937-f261-4223-9575-92ccf1a3ddb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7575 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0018681 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0008370 infores:hetionet NCBIGene:220136 biolink:causes MONDO:0013887 infores:monarchinitiative not_provided not_provided HGNC:26530 MONDO:0013887 uuid:dee57331-eaf3-4e44-9412-4d78bdf57c95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085682 infores:hetionet CHEBI:5128 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0004093 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0855217 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0855217 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0013144 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0004096 infores:hetionet GO:2000772 biolink:causes GO:0033554 infores:ubergraph knowledge_assertion manual_agent GO:2000772 GO:0033554 GO:1900032 biolink:causes GO:0010026 infores:ubergraph knowledge_assertion manual_agent GO:1900032 GO:0010026 NCBIGene:8787 biolink:causes MONDO:0958180 infores:monarchinitiative not_provided not_provided HGNC:10004 MONDO:0958180 uuid:45d096af-7a61-4c89-8a37-2182f02d74cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018133 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0027765 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0042963 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004096 infores:hetionet CAID:CA392330332 biolink:causes MONDO:0007947 infores:clingen CAID:CA392330332 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PS4_Supporting, PM2_Supporting, PM1, PM5 NM_00138 c. 7016G>A is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid 2339 (p.Cys2339Tyr). This variant has been identified in one individual with clinical features of Marfan syndrome (PS4_Sup). This variant has been reported 1 time in ClinVar as Likely pathogenic and 1 time as uncertain significance (VariationID:495644).This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.0.0). This variant affects a cysteine residue in a TB domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.992, PP3). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_Sup, PM2_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392330332/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:135285 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C1384353 infores:hetionet CHEBI:6339 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0020461 infores:hetionet CHEBI:8764 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0080274 infores:hetionet CHEBI:15407 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0232286 infores:hetionet CHEBI:5558 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0003813 infores:hetionet CAID:CA367396714 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396714 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PP1 The c.1398A>T variant in the glucokinase gene, GCK, causes a change from the stop codon to cysteine in the final exon (10/10), resulting in the addition of 144 amino acids at the end of the protein (p.(Ter466CysextTer144)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L and negative antibodies) (PP4_Moderate; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with hyperglycemia with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1398A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396714/MONDO:0015967/086 2024-01-02 2024-01-02 Semidominant inheritance HP:0032113 Supports CHEBI:15367 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0037199 infores:hetionet CHEBI:36795 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0231218 infores:hetionet CHEBI:41423 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1458155 infores:hetionet CHEBI:135888 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0242301 infores:hetionet CHEBI:16714 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0020517 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0007222 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0424296 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C2242996 infores:hetionet CHEBI:85083 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0015672 infores:hetionet NCBIGene:23241 biolink:causes MONDO:0054845 infores:monarchinitiative not_provided not_provided HGNC:23794 MONDO:0054845 uuid:acb188f5-c6a7-4487-80ae-57b692eb6c5f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA405670927 biolink:causes MONDO:0018493 infores:clingen CAID:CA405670927 MONDO:0018493 PMID: Uncertain Significance PS4_Moderate, PP3_Moderate PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with arginine at codon 4230 of the RYR1 protein, p.(Met4230Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 23558838, 30236257, 25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405670927/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA2801110 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801110 MONDO:0001586 PMID: Uncertain Significance BP4 PM3, PM2, PP4 The NM_000203.4:c.76G>A variant in IDUA is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 26 (p.Ala26Thr). PP4 is not met as there is only one entry of this variant. The infant had IDUA activity in the reference range and negative GAG tests. There is no phenotypic or family history data provided. The infant was compound heterozygous, phase unconfirmed, for the variant and another variant in IDUA that is classified as pathogenic by the ClinGen LD VCEP, c.911delT (p.V304fs) (ClinVarID: 1184991) (PMID: 29801497). Since disease status is unknown in this infant, PM3 is not met. The computational predictor REVEL gives a score of 0.264 which is below the threshold of 0.29, evidence that does not predict a damaging effect on IDUA function (PMID: 36413997)(BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0004 (31/69978 alleles) in the South Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), and lower than the threshold for BS1 (>0.0025). Therefore, none of the population data codes are met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.1.0): BP4(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 6, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801110/MONDO:0001586/091 2025-10-06 2025-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:367163 biolink:causes MONDO:0006687 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0006430 infores:hetionet CHEBI:8060 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0392676 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013922 infores:hetionet CHEBI:15765 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0028084 infores:hetionet CHEBI:17474 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0013390 infores:hetionet CAID:CA1624224 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624224 MONDO:0021060 PMID: Likely Benign BS1, BP5 The c.3322G>A (p.Asp1108Asn) variant in SOS1 was present in 0.039% (10/13658 with 95% CI) of Latino alleles in gnomAD v3 (BS1). This variant has been identified in a patient with Noonan syndrome who had an alternate molecular basis for disease (BP5; SCV000966758.1; ClinVar ID: 44603). It was also identified in a homozygous state in an individual who also carried a variant in TRMT1 (BP5 not met; Baylor College of Medicine internal data). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624224/MONDO:0021060/004 2020-06-25 2020-06-25 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:31536 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0004093 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0267596 infores:hetionet CHEBI:40279 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0221512 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001382 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0019212 infores:hetionet NCBIGene:1588 biolink:causes MONDO:0013301 infores:monarchinitiative not_provided not_provided HGNC:2594 MONDO:0013301 uuid:a3a0b488-1a30-4619-9d72-2ff381f055b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64354 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0221490 infores:hetionet CHEBI:27899 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C1287298 infores:hetionet CHEBI:3127 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0162834 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0023418 infores:hetionet CHEBI:5134 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0005758 infores:hetionet CHEBI:8024 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0080274 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0542203 infores:hetionet CHEBI:3286 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0016059 infores:hetionet CHEBI:8214 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0043094 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0392386 infores:hetionet CHEBI:3723 biolink:causes EFO:0010817 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0522178 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0009450 infores:hetionet CHEBI:31174 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0009763 infores:hetionet CHEBI:4657 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0024141 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151735 infores:hetionet CHEBI:10023 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011168 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0345904 infores:hetionet CHEBI:17263 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0018681 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0007117 infores:hetionet CHEBI:2904 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0013604 infores:hetionet CHEBI:16899 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0011603 infores:hetionet CHEBI:5558 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0004245 infores:hetionet CHEBI:3312 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0036974 infores:hetionet CHEBI:48273 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0011168 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0542203 infores:hetionet CHEBI:9445 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0013604 infores:hetionet CHEBI:7903 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0030554 infores:hetionet CHEBI:10101 biolink:causes UMLS:C1456786 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1456786 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0553702 infores:hetionet CHEBI:50693 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0018681 infores:hetionet NCBIGene:28976 biolink:causes MONDO:0012624 infores:monarchinitiative not_provided not_provided HGNC:21497 MONDO:0012624 uuid:eb238ad1-3983-4de6-b5bf-a180c4fdfea2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15553 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0687713 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0032285 infores:hetionet CHEBI:51364 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0242422 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0037274 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0948586 infores:hetionet CAID:CA367399062 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399062 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1088A>G variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to glycine at codon 363 (p.(Asp363Gly)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0(PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes (in a family not used for PP1)) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 37045781, internal lab contributors). In summary, c.1088A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS4_Moderate, PP4_Moderate, PP1_Strong, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399062/MONDO:0015967/086 2025-09-19 2025-09-19 Semidominant inheritance HP:0032113 Supports CHEBI:31932 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0392171 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0233794 infores:hetionet CHEBI:3561 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011124 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0040034 infores:hetionet CHEBI:3996 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0012569 infores:hetionet CHEBI:64045 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0085612 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0019163 infores:hetionet CHEBI:9241 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0011609 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0005684 infores:hetionet CHEBI:94848 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0040822 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0235074 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0235074 infores:hetionet CHEBI:617099 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0030312 infores:hetionet CHEBI:194135 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018520 infores:hetionet CHEBI:8404 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0233407 infores:hetionet CHEBI:7852 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0037822 infores:hetionet CHEBI:8774 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0022346 infores:hetionet CHEBI:64045 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0235660 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0424000 infores:hetionet CHEBI:404903 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0085631 infores:hetionet CHEBI:49668 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0030193 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0040046 infores:hetionet CHEBI:3568 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085632 infores:hetionet NCBITaxon:1496 biolink:causes MONDO:0000705 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1496 MESH:D004761 DB08874_MESH_D004761_1DB00512_MESH_D004761_1 CHEBI:17650 biolink:causes UMLS:C0410198 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0410198 infores:hetionet CHEBI:7903 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C1260880 infores:hetionet CHEBI:49375 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009676 infores:hetionet CHEBI:29013 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0027497 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0235431 infores:hetionet CHEBI:32315 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0520966 infores:hetionet CHEBI:2659 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0035410 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009938 infores:hetionet CHEBI:44915 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0004093 infores:hetionet CHEBI:4653 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0039240 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027051 infores:hetionet CHEBI:9720 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0085631 infores:hetionet CHEBI:63598 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0231218 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011615 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0027765 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0267792 infores:hetionet CHEBI:8874 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013404 infores:hetionet NCBITaxon:10298 biolink:causes MONDO:0043653 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10298 MESH:D006560 DB00632_MESH_D006560_1DB00787_MESH_D006560_1DB00299_MESH_D006560_1DB00577_MESH_D006560_2 CAID:CA278663 biolink:causes MONDO:0019501 infores:clingen CAID:CA278663 MONDO:0019501 PMID: Pathogenic PP3, PP1, PP4, PM2_Supporting, PM3_Very Strong The c.401T>A (p.Ile134Asn) is a missense variant in MYO7A predicted to cause a substitution of isoleucine to asparagine at amino acid 134. The filtering allele frequency (the lower threshold of the 95% CI of 60/1179894) of this variant is 0.004019% in the European (non-Finnish) population which meets the threshold (≤0.00007, 0.007%) defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction tool produced a score of 0.938, which is above the threshold necessary to apply PP3 (PP3). This variant has been detected in 7 probands with Usher syndrome. For 2 of those probands, pathogenic variants (c.19-1G>A and p.Gly214Arg) were observed in trans, and in the other 5 probands, a pathogenic variant was observed with unknown phase (4.5 points, PM3_Very Strong, PMIDs: 25468891, 26969326, 33089500, 37510321, Partners LMM Internal Data ClinVar SCV000059786.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM Internal Data ClinVar SCV000059786.6). At least one patient with this variant displayed features of sensorineural hearing loss and retinitis pigmentosa, which are consistent for Usher syndrome, a condition highly specific for MYO7A (PP4, Partners LMM Internal Data ClinVar SCV000059786.6). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel (PM3_Very Strong, PM2_Supporting, PP1, PP3, PP4). (ClinGen Hearing Loss VCEP specifications version 2; 9/18/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278663/MONDO:0019501/005 2024-09-18 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBIGene:4763 biolink:causes MONDO:0011035 infores:monarchinitiative not_provided not_provided HGNC:7765 MONDO:0011035 uuid:2dd82c2c-db5b-4a85-bad9-b8c7b90fa35b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013384 infores:hetionet UMLS:C1738934 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0004604 infores:hetionet CHEBI:10127 biolink:causes HP:0000750 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0233715 infores:hetionet CHEBI:9137 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0011124 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0278080 infores:hetionet CHEBI:5383 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0021141 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013395 infores:hetionet CHEBI:2914 biolink:causes UMLS:C1140716 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C1140716 infores:hetionet CHEBI:9586 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0018681 infores:hetionet CHEBI:8404 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0020517 infores:hetionet CAID:CA10014186 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014186 MONDO:0011071 PMID: Uncertain Significance PS3, PS4, PS2, PS1, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1322T>C (p.Leu441Pro) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014186/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44915 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0700184 infores:hetionet UMLS:C0145867 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0234233 infores:hetionet CHEBI:6759 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0036974 infores:hetionet GO:0043012 biolink:causes GO:0007338 infores:ubergraph knowledge_assertion manual_agent GO:0043012 GO:0007338 CHEBI:63607 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C2129214 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018799 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0521491 infores:hetionet CHEBI:17303 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232807 infores:hetionet CHEBI:82716 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0020625 infores:hetionet CHEBI:135791 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0442886 infores:hetionet CHEBI:9150 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0006277 infores:hetionet CHEBI:71940 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0235309 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0520888 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0026848 infores:hetionet NCBIGene:27077 biolink:causes MONDO:0013630 infores:monarchinitiative not_provided not_provided HGNC:24123 MONDO:0013630 uuid:e5f17e13-59a7-4ad3-9c12-01b2d2c57605 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47781 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0012833 infores:hetionet CHEBI:9654 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0037822 infores:hetionet CHEBI:6887 biolink:causes NCIT:C50526 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0235827 infores:hetionet NCBIGene:7443 biolink:causes MONDO:0957876 infores:monarchinitiative not_provided not_provided HGNC:12718 MONDO:0957876 uuid:f76abb41-eafd-4e35-a331-81f7215d6bb9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134990 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0151849 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0023066 infores:hetionet CHEBI:8435 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0392156 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0020625 infores:hetionet CHEBI:144093 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0392171 infores:hetionet CAID:CA000103 biolink:causes MONDO:0017623 infores:clingen CAID:CA000103 MONDO:0017623 PMID: Pathogenic PM2, PVS1, PS4_Moderate PTEN c.1026+1G>A (IVS8+1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4) (PMID 28677221).PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28677221, internal laboratory contributor(s) SCV000212764.4) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000103/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3371 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0239571 infores:hetionet CHEBI:6062 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013456 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0235431 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0035455 infores:hetionet CAID:CA418279967 biolink:causes MONDO:0100368 infores:clingen CAID:CA418279967 MONDO:0100368 PMID: Likely Benign BP4, BP7, PM2_Supporting NM_000329.3(RPE65):c.903T>C (p.Asn301=) is a synonymous variant in codon 301 that is located near the center of exon 9. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The splicing impact predictor SpliceAI gives a delta score of 0.01 for donor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA418279967/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3011 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0017152 infores:hetionet CHEBI:65349 biolink:causes MONDO:0013577 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0398370 infores:hetionet UMLS:C0010592 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0008031 infores:hetionet CHEBI:9168 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0001122 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0002871 infores:hetionet CHEBI:3240 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C1963790 infores:hetionet CHEBI:175901 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0032227 infores:hetionet CHEBI:8245 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0027424 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0021359 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0851341 infores:hetionet CHEBI:135736 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853225 infores:hetionet CHEBI:8874 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0030252 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0037763 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1320835 infores:hetionet CHEBI:37924 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0000737 infores:hetionet CHEBI:85078 biolink:causes HP:0033587 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0262666 infores:hetionet CHEBI:74947 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002962 infores:hetionet NCBIGene:1294 biolink:causes MONDO:0011852 infores:monarchinitiative not_provided not_provided HGNC:2214 MONDO:0011852 uuid:ee3a9cea-c995-4d74-99f7-7c199602ee7f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0178298 infores:hetionet CHEBI:8805 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0030252 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0687133 infores:hetionet CHEBI:6690 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0151766 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0020517 infores:hetionet CHEBI:6402 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0235378 infores:hetionet CHEBI:6912 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0002871 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0403632 infores:hetionet CHEBI:6076 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0010200 infores:hetionet CHEBI:65349 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0151905 infores:hetionet CAID:CA2580612111 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612111 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS1, PM1 PS4, PP4, PP1 The c.474_475delinsCT variant in the HNF1 homeobox A gene, HNF1A, is an inframe indel that results in two amino acid substitutions: lysine to asparagine at codon 158 and arginine to tryptophan at codon 159 (p.Lys158_Arg159delinsAsnTrp)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The p.Lys158_Arg159delinsAsnTrp variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor), so PP4 does not apply and this number of cases does not meet the threshold for PS4_Moderate. However, these individual missense variants that result in the same amino acid changes, c.474G>T (p.Lys158Asn) and c.475C>T (p.Arg159Trp), have been classified as likely pathogenic and pathogenic, respectively, by the ClinGen MDEP (PS1). In summary, c.474_475delinsCT meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PS1, PM1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612111/MONDO:0015967/017 2025-06-27 2025-06-27 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0879264 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0020649 infores:hetionet CHEBI:6950 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0014457 infores:hetionet CHEBI:7454 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0039231 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0029882 infores:hetionet CHEBI:3215 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0027497 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0456909 infores:hetionet CHEBI:18385 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0019080 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0235453 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0235453 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0020456 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011053 infores:hetionet CHEBI:3077 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0033774 infores:hetionet CHEBI:3478 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0030554 infores:hetionet CHEBI:40303 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0162830 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0013395 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0018939 infores:hetionet CHEBI:63620 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013378 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0023890 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0009450 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020456 infores:hetionet CAID:CA397319104 biolink:causes MONDO:0009276 infores:clingen CAID:CA397319104 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.882C>G (p.Tyr294Ter) variant in GP1BA is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient V in PMID:22672365) with this variant had less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 0.00000553 (based on 2/60024 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397319104/MONDO:0009276/079 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10112 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0003862 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0948594 infores:hetionet CHEBI:16664 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0042109 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0853761 infores:hetionet CHEBI:27899 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0234233 infores:hetionet CHEBI:17688 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0005758 infores:hetionet CHEBI:36704 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0035455 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0003123 infores:hetionet CHEBI:8481 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0011603 infores:hetionet CHEBI:3001 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0004604 infores:hetionet CHEBI:6888 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0009782 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0042109 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0948525 infores:hetionet CHEBI:499361 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0033687 infores:hetionet CHEBI:68558 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0231807 infores:hetionet NCBIGene:6736 biolink:causes MONDO:0020712 infores:monarchinitiative not_provided not_provided HGNC:11311 MONDO:0020712 uuid:f8432c52-cfb0-44f6-8186-718ca9c80288 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92511 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0014742 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0018099 infores:hetionet CHEBI:6030 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0013395 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235969 infores:hetionet CHEBI:37924 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0016204 infores:hetionet CHEBI:3723 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026961 infores:hetionet CHEBI:46081 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0014742 infores:hetionet NCBIGene:23558 biolink:causes MONDO:0033199 infores:monarchinitiative not_provided not_provided HGNC:12738 MONDO:0033199 uuid:b69ac3b0-501c-4e9f-a352-d413664c03cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9YCX42I8IU biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0011991 infores:hetionet CHEBI:8232 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0036572 infores:hetionet CHEBI:63717 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0017178 infores:hetionet CHEBI:10102 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0025209 infores:hetionet CHEBI:4672 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0002965 infores:hetionet CHEBI:184555 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0231528 infores:hetionet CHEBI:51041 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018681 infores:hetionet NCBIGene:51339 biolink:causes MONDO:0054582 infores:monarchinitiative not_provided not_provided HGNC:17748 MONDO:0054582 uuid:36a12ade-9f10-4047-9adc-102e918e55bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151825 infores:hetionet CHEBI:2038 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0015230 infores:hetionet CHEBI:3207 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0015230 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0178298 infores:hetionet CHEBI:64312 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0004604 infores:hetionet CHEBI:49575 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0015672 infores:hetionet CHEBI:2611 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0014742 infores:hetionet CAID:CA227890 biolink:causes MONDO:0100438 infores:clingen CAID:CA227890 MONDO:0100438 PMID: Benign BP7, BS2, BA1, BP4 The variant NM_014336.5(AIPL1):c.651A>G (p.Pro217=), is a synonymous variant in exon 5 of 6 in which the A nucleotide is replaced with a G at position c.651 and the amino acid at p.217 remains as proline. This variant is present in gnomAD v.4.1.0 at a Grpmax filtering allele frequency of 0.8496, with 5,269 alleles / 6,062 total alleles in the Middle Eastern population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of greater than or equal to 0.0057 (BA1). The variant has been found in the homozygous state in 439,818 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The splicing impact predictor SpliceAI gives a delta score of 0.08 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing. Additionally, the PhyloP score is -0.327, which suggests that the nucleotide is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/240/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227890/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:38940 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0854467 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0497365 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0028259 infores:hetionet CHEBI:9943 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151772 infores:hetionet CHEBI:16842 biolink:causes MONDO:0023176 infores:ubergraph knowledge_assertion manual_agent CHEBI:16842 MONDO:0023176 GO:0110116 biolink:causes GO:0001745 infores:ubergraph knowledge_assertion manual_agent GO:0110116 GO:0001745 CHEBI:6761 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0012833 infores:hetionet CHEBI:64355 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020433 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0852922 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0852922 infores:hetionet CHEBI:45863 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0043094 infores:hetionet CHEBI:4636 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C2830004 infores:hetionet CHEBI:135566 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0235259 infores:hetionet CHEBI:31236 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0030196 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0234233 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235969 infores:hetionet CHEBI:7496 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0015230 infores:hetionet CHEBI:45863 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0041657 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0424605 infores:hetionet CHEBI:3478 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0036830 infores:hetionet CHEBI:80630 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0027497 infores:hetionet CHEBI:3757 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0232462 infores:hetionet CHEBI:31401 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0236075 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020569 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0031117 infores:hetionet GO:1902872 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0007275 CHEBI:77260 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0016655 infores:hetionet CHEBI:6437 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0035455 infores:hetionet NCBIGene:1749 biolink:causes MONDO:0008464 infores:monarchinitiative not_provided not_provided HGNC:2918 MONDO:0008464 uuid:b514e678-fee0-469e-b44b-b8754f1ab7e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100246 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0232462 infores:hetionet CHEBI:29007 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0004134 infores:hetionet CHEBI:31348 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0428977 infores:hetionet NCBIGene:286204 biolink:causes MONDO:0009063 infores:monarchinitiative not_provided not_provided HGNC:18688 MONDO:0009063 uuid:7319d7ef-0e23-4d1a-8b33-c4b078c546ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4822 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0030252 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0021053 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013447 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004610 infores:hetionet CHEBI:49668 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0855333 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0032226 infores:hetionet CHEBI:64321 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0917801 infores:hetionet CHEBI:3757 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0003811 infores:hetionet CAID:CA011635 biolink:causes MONDO:0005045 infores:clingen CAID:CA011635 MONDO:0005045 PMID: Uncertain Significance PM2, PM1, PP3, PS4_Supporting PM3, BA1, PM5, PM4, PS3, PM6, PP1, BS1, BS3, BS4, BP3, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 The c.2069T>C (p.Met690Thr) variant in MYH7 has been reported in at least 3 individuals with HCM (PS4_Supporting; Coppini 2014 PMID:25524337; Homberger 2016 PMID:27247418; Weissler-Snir 2017 PMID:28193612; Walsh 2017 PMID:27532257; CHEO pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Based on criteria selected, this variant would be classified as likely pathogenic; however the expert panel deemed the bulk of available evidence as being derived from predictive models. Therefore, in the absence of additional case or segregation data, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PM2; PM1; PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011635/MONDO:0005045/002 2021-09-22 2021-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0036396 infores:hetionet CHEBI:10100 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C1527407 infores:hetionet CAID:CA10584213 biolink:causes MONDO:0007356 infores:clingen CAID:CA10584213 MONDO:0007356 PMID: Pathogenic PVS1, PP4, PM2_Supporting BA1, BP1, BP4, BP2, BP3, PS4, PS2, PS3, PS1, PM3, PM4, PM1, PM5, BP5, BP7, BS1, BS4, BS3, PM6, PP2, PP3, PP1, BS2 NM_000251.3(MSH2):c.1276G>A variant results in a splicing aberration according to mRNA assay using RNA derived from patient constitutional biological samples which indicate that the variant allele (with evidence that the variant allele produces no full-length/reference transcript) leads to an in-frame deletion disrupting the lever domain and MSH6/MSH3 interaction domain (PMID: 28577310). Confirmed by minigene assay (LOVD Variant #0000846861). In addition, there is 1 endometrial tumour with loss of MSH2/MSH6 expression (PMID: 28577310). The variant is absent from gnomAD v4.1. Therefore, this variant is classified as pathogenic. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584213/MONDO:0007356/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CAID:CA367401125 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401125 MONDO:0015967 PMID: Uncertain Significance PM1, PM5_Supporting, PP2, PM2_Supporting PP3, PP4 The c.676G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 226 (p.(Val226leu)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting). This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868). In summary, c.676G>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401125/MONDO:0015967/086 2024-02-02 2024-02-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:37941 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0021053 infores:hetionet CHEBI:6950 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0027497 infores:hetionet CHEBI:5613 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0013604 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0032326 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011053 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0031212 infores:hetionet CHEBI:6904 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0428977 infores:hetionet UMLS:C0145867 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0151786 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0162119 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0221100 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0002957 infores:hetionet CHEBI:31401 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0030252 infores:hetionet GO:0006954 biolink:causes MONDO:0016168 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D056587 DB00026_MESH_D056587_1DB06372_MESH_D056587_1 CHEBI:50275 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0018681 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0006849 infores:hetionet CHEBI:188986 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0042373 infores:hetionet CHEBI:6887 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002994 infores:hetionet NCBIGene:1363 biolink:causes MONDO:0859150 infores:monarchinitiative not_provided not_provided HGNC:2303 MONDO:0859150 uuid:1250a997-5a4c-488b-9430-f445c1ede771 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6717 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0013395 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0242350 infores:hetionet CHEBI:28241 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0009806 infores:hetionet CHEBI:31705 biolink:causes EFO:0009445 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0003130 infores:hetionet CHEBI:5165 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0013491 infores:hetionet CHEBI:6804 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0033774 infores:hetionet CHEBI:16796 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0009782 infores:hetionet CHEBI:7573 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0600142 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0152128 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042514 infores:hetionet CHEBI:63619 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0041657 infores:hetionet NCBIGene:6662 biolink:causes MONDO:0007251 infores:monarchinitiative not_provided not_provided HGNC:11204 MONDO:0007251 uuid:7909c861-81d2-4998-8f6e-836f547bc121 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0145867 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0232602 infores:hetionet NCBIGene:6663 biolink:causes MONDO:0013202 infores:monarchinitiative not_provided not_provided HGNC:11190 MONDO:0013202 uuid:dadc5797-eb9c-4e71-9e0b-6c21b6a8691a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151826 infores:hetionet CHEBI:31236 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0427086 infores:hetionet NCBIGene:79840 biolink:causes MONDO:0975809 infores:monarchinitiative not_provided not_provided HGNC:25737 MONDO:0975809 uuid:2bd37dbf-0f4f-4952-9cd0-7accbd8135eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7824 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020538 infores:hetionet CHEBI:75722 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1510431 infores:hetionet CHEBI:45863 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042487 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005316 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0085166 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0009319 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0948525 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0860433 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0860433 infores:hetionet NCBITaxon:12090 biolink:causes MONDO:0005634 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12090 MONDO:0005634 CHEBI:63630 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0023067 infores:hetionet CAID:CA405689274 biolink:causes MONDO:0018493 infores:clingen CAID:CA405689274 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with alanine at codon 518 of the RYR1 protein, p.(Val518Ala). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000649, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:23558838). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.738 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405689274/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA10580117 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580117 MONDO:0007648 PMID:10477433 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.1488_1494delCGAGGAC p.(Glu497Leufs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is present in <1/50,000 alleles in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 10477433). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580117/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:474180 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0016382 infores:hetionet CHEBI:47780 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0004134 infores:hetionet CHEBI:135530 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C2830004 infores:hetionet CHEBI:4024 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0152227 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0033775 infores:hetionet CHEBI:63635 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0017178 infores:hetionet CHEBI:6931 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0019521 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0020517 infores:hetionet NCBIGene:5744 biolink:causes MONDO:0013244 infores:monarchinitiative not_provided not_provided HGNC:9607 MONDO:0013244 uuid:02a592f7-06f1-4f1e-b20e-d2d41d7e5740 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes UMLS:C0242453 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0242453 infores:hetionet CHEBI:47519 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0042963 infores:hetionet CHEBI:71219 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0006826 infores:hetionet CHEBI:8888 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2939147 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0009806 infores:hetionet NCBITaxon:5754 biolink:causes MONDO:0021747 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5754 MONDO:0021747 CHEBI:9586 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0024902 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0020651 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0042109 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0259972 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0259972 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0001430 infores:hetionet CHEBI:60761 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0687713 infores:hetionet CHEBI:31711 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0151889 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0011570 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948579 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948579 infores:hetionet CHEBI:31623 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0042963 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0041969 infores:hetionet CHEBI:74947 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C3495920 infores:hetionet CHEBI:10125 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1384353 infores:hetionet NCBIGene:3981 biolink:causes MONDO:0011686 infores:monarchinitiative not_provided not_provided HGNC:6601 MONDO:0011686 uuid:865bbdae-d7ba-401b-bee1-4f88bf9fc75f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0038454 infores:hetionet CAID:CA118524 biolink:causes MONDO:0054637 infores:clingen CAID:CA118524 MONDO:0054637 PMID:25563136PMID:24458587PMID:19684605PMID:22528146PMID:23918763PMID:19684605PMID:21548061 Pathogenic PS4, PS3, PM2, PS2_Very Strong, PP2 The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA118524/MONDO:0054637/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:3077 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0342579 infores:hetionet NCBIGene:1147 biolink:causes MONDO:0859154 infores:monarchinitiative not_provided not_provided HGNC:1974 MONDO:0859154 uuid:b8789d87-d19b-489e-9cdc-b0448a83e7d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:253342 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0003811 infores:hetionet NCBIGene:55869 biolink:causes MONDO:0010471 infores:monarchinitiative not_provided not_provided HGNC:13315 MONDO:0010471 uuid:a893b339-66bb-4176-88ff-eb570c0145e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63717 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0027765 infores:hetionet CHEBI:63610 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C3665347 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0027769 infores:hetionet CHEBI:2038 biolink:causes EFO:1001478 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0242966 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0948089 infores:hetionet CHEBI:59773 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0220870 infores:hetionet NCBIGene:2273 biolink:causes MONDO:0010400 infores:monarchinitiative not_provided not_provided HGNC:3702 MONDO:0010400 uuid:68402a61-5b6b-4178-93bf-2aa3e78a397e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6923 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0027497 infores:hetionet CAID:CA288064 biolink:causes MONDO:0007648 infores:clingen CAID:CA288064 MONDO:0007648 PMID: Likely Benign BS2 BP5, BP7, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PM2, PM6, PVS1, PP3, PP2, PP1, PP4, BP4, BP1, BP2, BP3, BA1, PS1, PS3, PS4, PS2 The c.2635G>A (p.Gly879Ser) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288064/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA120431 biolink:causes MONDO:0015152 infores:clingen CAID:CA120431 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PP1 PM5, PM2 The NM_000023.4: c.850C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 284 (p.Arg284Cys). This variant has been detected in at least five individuals with autosomal recessive limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.241C>T p.(Arg81Cys), 1 pt, PMID: 17994539), and two were homozygous for the variant (1 pt, PMID: 26404900, 26453141) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in SGCA displayed progressive limb girdle muscle weakness and significantly reduced or absent alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; UCSD internal clinic data communication, PMID: 17994539). In addition, the variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 17994539). The minor allele frequency for this variant is 0.0002205 in the European (non-Finnish) population of gnomAD v3.1.2 (15/68028 genome chromosomes), which exceeds the LGMD VCEP threshold of 0.00009 for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.754, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4_Strong, PP1, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA120431/MONDO:0015152/189 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2955 biolink:causes UMLS:C1262006 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C1262006 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0027765 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0042373 infores:hetionet CHEBI:7488 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0151827 infores:hetionet CHEBI:9649 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0700200 infores:hetionet NCBIGene:7042 biolink:causes MONDO:0013897 infores:monarchinitiative not_provided not_provided HGNC:11768 MONDO:0013897 uuid:9345251f-3c3a-4256-949a-6ec9c5973f79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8093 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0233494 infores:hetionet CHEBI:52717 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014236 infores:hetionet CAID:CA386964769 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964769 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PP4 The c.650C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glycine at codon 217 (p.(Ala217Gly)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.753, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, this variant is located within the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 18003757, internal lab contributor). In summary, c.650C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964769/MONDO:0015967/017 2022-08-05 2022-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9649 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0236075 infores:hetionet CHEBI:114785 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0011168 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0587094 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0587094 infores:hetionet NCBIGene:55213 biolink:causes MONDO:0014955 infores:monarchinitiative not_provided not_provided HGNC:18243 MONDO:0014955 uuid:ad46623e-3cd1-45fb-84fa-23cbabecad6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018944 infores:hetionet CAID:CA214295 biolink:causes MONDO:0015967 infores:clingen CAID:CA214295 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PP1_Strong, PP4_Moderate, PP3 PS4 The c.281C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 94 (p.(Pro94Leu)) of NM_000545.8. This variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP threshold of 0.70 (PP3). Furthermore, this variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, response to sulfonylurea, antibody negative and persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 1 family (PP1_Strong; PMID: 27236918, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM2_Supporting, PP3, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214295/MONDO:0015967/017 2025-06-27 2025-06-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:175901 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0001824 infores:hetionet UMLS:C0065374 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0340865 infores:hetionet CHEBI:9241 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0002453 infores:hetionet CHEBI:17698 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0042963 infores:hetionet CHEBI:51364 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0085632 infores:hetionet CHEBI:42944 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0009676 infores:hetionet CHEBI:161680 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0042963 infores:hetionet CHEBI:63577 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0022346 infores:hetionet CHEBI:6706 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0234987 infores:hetionet CHEBI:6775 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0852911 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0013595 infores:hetionet CHEBI:8871 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023518 infores:hetionet CHEBI:5138 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0015672 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0014868 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0580493 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0580493 infores:hetionet CHEBI:31199 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0151514 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0007787 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0033860 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0021053 infores:hetionet CHEBI:31949 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0428977 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0161479 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011570 infores:hetionet CHEBI:59582 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0162835 infores:hetionet CHEBI:161680 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0017181 infores:hetionet CHEBI:209807 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0030193 infores:hetionet CHEBI:2379 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0018681 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0020676 infores:hetionet CHEBI:63630 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0851578 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042109 infores:hetionet CAID:CA10585437 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585437 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BA1, BP1, BP4, BP3, PS1, PS4, BS1, BP7, PM5, PM4, PVS1, PP2, PP1 The NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2022.The supporting evidence is as follows: PM2: Variant is absent from gnomAD v2.1.1.PP3: REVEL = 0.77.PP4: Variant meets PM2 and is identified in 1 case with definite FH by Simon Broome criteria from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585437/MONDO:0007750/013 2022-10-28 2025-02-07 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:94411 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0027497 infores:hetionet CHEBI:63631 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0004134 infores:hetionet CHEBI:49375 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0013404 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0948594 infores:hetionet CHEBI:46081 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0038325 infores:hetionet CHEBI:9448 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0003467 infores:hetionet CHEBI:10112 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0042963 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0314719 infores:hetionet UNII:R43D2573WO biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0019209 infores:hetionet CHEBI:5893 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0028734 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020649 infores:hetionet CHEBI:9635 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0232462 infores:hetionet CHEBI:10101 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0030252 infores:hetionet CAID:CA066427 biolink:causes MONDO:0018493 infores:clingen CAID:CA066427 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with leucine at codon 1588 of the RYR1 protein, p.(Pro1588Leu).The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000163, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.735 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA066427/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:204734 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0085641 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0948089 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0042373 infores:hetionet CHEBI:6792 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C2830004 infores:hetionet CHEBI:184555 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0013404 infores:hetionet CHEBI:28939 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0027497 infores:hetionet GO:2000764 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:2000764 GO:0072359 CHEBI:39585 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0020538 infores:hetionet CHEBI:253342 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0033247 infores:hetionet CHEBI:8888 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0404521 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0009806 infores:hetionet CHEBI:59773 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0423791 infores:hetionet CHEBI:144093 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0037763 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0003123 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0699893 infores:hetionet CAID:CA039172 biolink:causes MONDO:0007750 infores:clingen CAID:CA039172 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 PM5, PP3 The NM_000527.5(LDLR):c.2225C>T (p.Thr742Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.000003390 (0.0003390%) in European (non-Finnish) exomes + genomes (gnomAD v4.1.0).PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill Simon Broome criteria for possible FH after alternative causes of high cholesterol were excluded (1 case from PMID 11462246 (Nauck et al., 2001), Germany; 1 case from PMID 17142622 (Humphries et al., 2006), UK). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA039172/MONDO:0007750/013 2025-02-28 2025-04-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:594 biolink:causes MONDO:0023692 infores:monarchinitiative not_provided not_provided HGNC:987 MONDO:0023692 uuid:5069c329-d7be-47bf-8620-4ea1b1cc287c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011253 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0235146 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0017675 infores:hetionet CHEBI:47426 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0085932 infores:hetionet CAID:CA402528894 biolink:causes MONDO:0012589 infores:clingen CAID:CA402528894 MONDO:0012589 PMID: Likely Pathogenic PM1, PM5, PM2_Supporting, PS4_Supporting, PP3 PM6 The p.Arg582Cys variant in TCF4 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg582Cys variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of the TCF4 (PM1). A pathogenic missense variant (p.R582P) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 22460224, PMID 26621827, PMID 20184619, internal database) (PM5). The p.Arg582Cys variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with an unspecified neurodevelopmental disorder (PMID 33994118). The p.Arg582Cys variant has been observed in at least 2 individuals with clinical features of Pitt-Hopkins syndrome (PMID 33994118, internal database) (PS4_Supporting). In summary, the p.Arg582Cys variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_Supporting, PP3, PM1, PM5, PS4_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA402528894/MONDO:0012589/032 2023-08-23 2023-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45863 biolink:causes MONDO:0006715 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0242231 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C2225524 infores:hetionet CHEBI:63577 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0700292 infores:hetionet GO:0060687 biolink:causes GO:0060512 infores:ubergraph knowledge_assertion manual_agent GO:0060687 GO:0060512 CHEBI:7514 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0042109 infores:hetionet CHEBI:28487 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0003467 infores:hetionet CHEBI:9352 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0038990 infores:hetionet CHEBI:3181 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C3665347 infores:hetionet CHEBI:100241 biolink:causes UMLS:C3665818 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C3665818 infores:hetionet CHEBI:50275 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0008031 infores:hetionet CAID:CA390887361 biolink:causes MONDO:0100216 infores:clingen CAID:CA390887361 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PVS1, PM2, PM6, BP1, BP3, BP2, BA1, PP2, PP3, PP4, PP1, PM4, PM1, PM3, PM5, PS3, PS2, PS4, PS1, BP7, BP5, BS1, BS3, BS4 The NM_177438.2:c.925G>A variant in DICER1 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 309 (p.Val309Ile). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributor). This variant was seen in a child with pleuropulmonary blastoma; however, the child harbored a second germline variant (c.2256+2T>C, phase unknown) in DICER1 (PS4 and BP2 not met). The total allele frequency in gnomAD v4.1.0 is 0.00001550 (25/1613198 alleles) with a highest population minor allele frequency of 0.00006669 (4/59980 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.189; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 04/23/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390887361/MONDO:0100216/024 2024-04-23 2024-05-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4784 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0017566 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0041912 infores:hetionet CHEBI:9570 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0033774 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0036572 infores:hetionet CHEBI:35778 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1443060 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0017675 infores:hetionet CHEBI:9168 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0042075 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0021359 infores:hetionet CHEBI:9649 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0000731 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0042769 infores:hetionet CHEBI:2950 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0012833 infores:hetionet CHEBI:61049 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0236075 infores:hetionet CHEBI:5130 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014457 infores:hetionet CHEBI:50742 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013595 infores:hetionet NCBIGene:5376 biolink:causes MONDO:0007311 infores:monarchinitiative not_provided not_provided HGNC:9118 MONDO:0007311 uuid:f6722f2a-3211-4b23-a77a-89a1deef2855 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0012569 infores:hetionet CHEBI:16586 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0035410 infores:hetionet CHEBI:8024 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0151825 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0151970 infores:hetionet CHEBI:46195 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0009421 infores:hetionet CHEBI:7773 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0851578 infores:hetionet NCBIGene:4208 biolink:causes MONDO:0013266 infores:monarchinitiative not_provided not_provided HGNC:6996 MONDO:0013266 uuid:4306a958-5d1c-40d1-92a4-659252bc9c1f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9445 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0022408 infores:hetionet CHEBI:6970 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0006840 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235901 infores:hetionet CAID:CA7510919 biolink:causes MONDO:0015152 infores:clingen CAID:CA7510919 MONDO:0015152 PMID: Likely Benign BS1 BP4, BP2, PP3 The NM_000070.3: c.329G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 110 (p.Arg110Gln). The filtering allele frequency for this variant is 0.001227 for the East Asian population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 61/39696 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). This variant has been reported in an individual with LGMD, but it was observed in unknown phase with a benign variant (PMID: 32994280; LOVD Individual #00311334). The REVEL score for this variant is 0.384 and the SpliceAI score is 0.01 (BP4, PP3 not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 10/28/2025): BS1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7510919/MONDO:0015152/187 2025-10-28 2025-11-17 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA180914 biolink:causes MONDO:0021060 infores:clingen CAID:CA180914 MONDO:0021060 PMID: Uncertain Significance BP5, PM2, PP3 BS2 The c.806C>G (p.Pro269Arg) variant in MAP2K2 is absent from gnomAD (PM2). This variant has been observed in an individual with an alternate mechanism of disease (VCV000013329.8; Laboratory for Molecular Medicine internal data; BP5). Four apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time. Computational prediction tools and conservation analysis suggest that the p.Pro269Arg variant may impact the protein (PP3). In summary, the clinical significance of the p.Pro269Arg variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP3, PM2, BP5. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180914/MONDO:0021060/004 2020-03-09 2020-03-09 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63622 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0004096 infores:hetionet CHEBI:2955 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0003811 infores:hetionet CHEBI:116278 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0025874 infores:hetionet CHEBI:68841 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0340865 infores:hetionet CHEBI:63608 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1260922 infores:hetionet CHEBI:9332 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0040264 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0151981 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0151981 infores:hetionet GO:1905790 biolink:causes GO:0009612 infores:ubergraph knowledge_assertion manual_agent GO:1905790 GO:0009612 CHEBI:127780 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0031117 infores:hetionet CHEBI:17347 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020453 infores:hetionet CHEBI:135342 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0043352 infores:hetionet CHEBI:3082 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0021400 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002801 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0009377 infores:hetionet NCBIGene:9842 biolink:causes MONDO:0012679 infores:monarchinitiative not_provided not_provided HGNC:29017 MONDO:0012679 uuid:256db576-72aa-4493-aa62-371668b9399e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83531 biolink:causes UMLS:C0700613 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0700613 infores:hetionet CHEBI:9649 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0005818 infores:hetionet CHEBI:91541 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0033975 infores:hetionet NCBIGene:83844 biolink:causes MONDO:0859478 infores:monarchinitiative not_provided not_provided HGNC:13485 MONDO:0859478 uuid:67db386e-ea0c-4bdb-aef4-865991cb2a0e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75998 biolink:causes UMLS:C0860493 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0860493 infores:hetionet CHEBI:45783 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0542571 infores:hetionet CHEBI:68584 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0037763 infores:hetionet CAID:CA2697547494 biolink:causes MONDO:0011071 infores:clingen CAID:CA2697547494 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.528del (p.Ile177SerfsTer34) is a frameshift variant. The single-base deletion c.528del creates a (-1) frameshift downstream of c.98 (PM5_supporting), leading to a premature stop codon and resulting in a predicted null variant, p.Ile177Serfs*34 (PVS1). This variant is absent from the population database gnomAD v3 (PM2_supporting). There are no confirmed germline cases or functional evidence reported in the literature. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2697547494/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes MONDO:0004892 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034951 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0518988 infores:hetionet CHEBI:7577 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0404521 infores:hetionet CHEBI:9073 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C1145670 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0013395 infores:hetionet CHEBI:2611 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0009782 infores:hetionet CHEBI:4710 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0151636 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085136 infores:hetionet CHEBI:3084 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C1443060 infores:hetionet CHEBI:15552 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0009782 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011849 infores:hetionet CHEBI:9150 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C2047937 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0007256 uuid:3acddcc9-103c-4389-a929-e52cdd28b495 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0917801 infores:hetionet CHEBI:5778 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0013604 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0004592 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D007169 DB01256_MESH_D007169_1 CHEBI:100241 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0152031 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0340608 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0340608 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0012833 infores:hetionet CHEBI:35854 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0002994 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0032285 infores:hetionet CAID:CA512341119 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341119 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1285C>T (p.Leu429=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.00) (BP4) and is predicted by evolutionary conservation algorithms to occur at a site that is not conserved (PhyloP score ≤ 2.0 (1.99)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341119/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51364 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0030554 infores:hetionet CHEBI:18248 biolink:causes MONDO:0007150 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0003742 infores:hetionet CHEBI:50648 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0030252 infores:hetionet CHEBI:9907 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013390 infores:hetionet CHEBI:45327 biolink:causes UMLS:C2747891 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C2747891 infores:hetionet CHEBI:9586 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0036974 infores:hetionet CHEBI:40237 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0231218 infores:hetionet CHEBI:64064 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0040822 infores:hetionet CHEBI:47499 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0022346 infores:hetionet NCBIGene:778 biolink:causes MONDO:0010371 infores:monarchinitiative not_provided not_provided HGNC:1393 MONDO:0010371 uuid:f4c97a8d-a18c-4f3d-9944-65bb4283dd59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018944 infores:hetionet CHEBI:15553 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0030554 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0033775 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0023530 infores:hetionet NCBIGene:4751 biolink:causes MONDO:0014256 infores:monarchinitiative not_provided not_provided HGNC:7745 MONDO:0014256 uuid:2d175e80-5bb8-4795-95e9-cfa0b2f74bc9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1443060 infores:hetionet CHEBI:5138 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151786 infores:hetionet CAID:CA355270988 biolink:causes MONDO:0100283 infores:clingen CAID:CA355270988 MONDO:0100283 PMID: Uncertain Significance PP2, PM2_Supporting, PS4_Supporting, BS3_Supporting, PM1_Supporting The NM_006218.4:c.93A>G variant in the PIK3CA gene is a missense variant predicted to cause substitution of isoleucine by methionine at amino acid 31. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Variant Curation Expert Panel (BM VCEP) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the adaptor binding domain of PIK3CA that is defined as a critical functional domain by the ClinGen BM VCEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). This variant has been identified in two tumor samples in COSMIC (COSV55898376, COSV55887259) and in a patient with aggressive breast adenoid cystic carcinoma who also has a variant in PTEN (PS4_Supporting, PMID: 17669465). This variant has been shown to exhibit near wild type levels of cell growth and did not promote colony formation, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 26627007). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen BM VCEP: PM2_Supporting, PP2, PM1_Supporting, BS3_Supporting, PS4_Supporting (ClinGen Brain Malformations VCEP Specifications Version 1.1). Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA355270988/MONDO:0100283/018 2025-06-06 2025-06-30 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true GO:0021822 biolink:causes GO:0021801 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0021801 CHEBI:9674 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0233795 infores:hetionet CHEBI:4856 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0041969 infores:hetionet CHEBI:16586 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0011991 infores:hetionet NCBIGene:10 biolink:causes MONDO:0009472 infores:monarchinitiative not_provided not_provided HGNC:7646 MONDO:0009472 uuid:a4c447d9-f132-44e7-b443-ed324f7ce7f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948594 infores:hetionet CHEBI:6067 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0025345 infores:hetionet CHEBI:7577 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0003467 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0162830 infores:hetionet CHEBI:2955 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0004364 infores:hetionet CHEBI:9738 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0015672 infores:hetionet CHEBI:9674 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0011253 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0241379 infores:hetionet CHEBI:51364 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1260880 infores:hetionet CHEBI:44185 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0023380 infores:hetionet CHEBI:5784 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0015230 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011570 infores:hetionet CHEBI:84883 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0015469 infores:hetionet UMLS:C0065374 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C1260880 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0030305 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0027947 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0232492 infores:hetionet UNII:T58MSI464G biolink:causes UMLS:C0919671 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0919671 infores:hetionet CHEBI:45951 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0009806 infores:hetionet CAID:CA235373 biolink:causes MONDO:0021060 infores:clingen CAID:CA235373 MONDO:0021060 PMID:22465605PMID:29493581 Pathogenic PS4_Moderate, PM1, PM2, PP2, PM6_Strong The c.781C>T (p.Leu261Phe) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 22465605; GeneDx, Cave lab internal data ClinVar SCV000057404.12). The p.Leu261Phe variant has also been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; SCV000061319.5, SCV000207687.1 PMID: 22465605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PM1, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235373/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:472657 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0014457 infores:hetionet CAID:CA2573106208 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573106208 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PP1, PS4 The c.1061del variant in the hepatocyte nuclear factor 4-alpha, HNF4A, causes a frameshift in the protein at codon 354 (NM_175914.5), adding 18 novel amino acids before encountering a stop codon (p.(Gly354Glufs*18)). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 1 individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 23348805). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 23348805). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 23348805). In summary, c.1061del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2024): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573106208/MONDO:0015967/085 2024-12-02 2024-12-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8080 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0043352 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009806 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0015230 infores:hetionet NCBIGene:259236 biolink:causes MONDO:0010965 infores:monarchinitiative not_provided not_provided HGNC:30800 MONDO:0010965 uuid:d3886b50-4607-450a-93f0-1c8b0a413f5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:92998 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0038358 infores:hetionet CHEBI:499361 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0037036 infores:hetionet CHEBI:7936 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025289 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0020517 infores:hetionet CHEBI:101278 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0017178 infores:hetionet CHEBI:6775 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0016204 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0009450 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853700 infores:hetionet GO:1902872 biolink:causes GO:0010842 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0010842 CHEBI:23765 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013922 infores:hetionet CHEBI:31348 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0039239 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027707 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0917799 infores:hetionet NCBIGene:4629 biolink:causes MONDO:0859157 infores:monarchinitiative not_provided not_provided HGNC:7569 MONDO:0859157 uuid:3a31c7df-cae4-4cb0-98b2-06bd22a1b4c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2303 biolink:causes MONDO:0007922 infores:monarchinitiative not_provided not_provided HGNC:3801 MONDO:0007922 uuid:c5069b22-8671-4982-aa0a-ad58759b5ad1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0558489 infores:hetionet CHEBI:5778 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0009806 infores:hetionet NCBIGene:3845 biolink:causes MONDO:0008097 infores:monarchinitiative not_provided not_provided HGNC:6407 MONDO:0008097 uuid:57a1d80e-bdc9-4795-ac7c-1f54c5db5e83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0231528 infores:hetionet NCBIGene:391356 biolink:causes MONDO:0958323 infores:monarchinitiative not_provided not_provided HGNC:33782 MONDO:0958323 uuid:e7d6bec1-7c50-46ba-be5f-190a53676724 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0039070 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0009450 infores:hetionet CHEBI:63598 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1368065 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0026946 infores:hetionet CHEBI:5847 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0015230 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0005940 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0008325 infores:hetionet CAID:CA6904336 biolink:causes MONDO:0019497 infores:clingen CAID:CA6904336 MONDO:0019497 PMID: Pathogenic PM3_Supporting, PM5, PM2_Supporting, PVS1 PP3 The c.2T>C (p.Met1Thr) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 550716, 551915). This variant has been observed in 0.0074% (8/107882) of the African population in the All of Us database (PM2_Supporting). It was identified in 1 patient with bilateral sensorineural hearing loss who also harbored an assumed trans pathogenic variant (0.5 PM3_Supporting points; Athena Diagnostics internal data, SCV001143666.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting (VCEP specifications version 2; 10.18.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6904336/MONDO:0019497/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:4356 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0004096 infores:hetionet CHEBI:74947 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004364 infores:hetionet CHEBI:6804 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0151517 infores:hetionet CHEBI:45783 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0002962 infores:hetionet CHEBI:47381 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0231528 infores:hetionet CHEBI:3568 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0009421 infores:hetionet CHEBI:5002 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0019080 infores:hetionet NCBIGene:1135 biolink:causes MONDO:0012474 infores:monarchinitiative not_provided not_provided HGNC:1956 MONDO:0012474 uuid:9271213d-a057-40e9-a1d8-6a5c4006fa22 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15940 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0855242 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0442886 infores:hetionet CHEBI:4784 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0013395 infores:hetionet CHEBI:9757 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0241705 infores:hetionet CHEBI:6538 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C1443060 infores:hetionet CHEBI:9137 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017181 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0034150 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0023530 infores:hetionet NCBIGene:1277 biolink:causes MONDO:0008148 infores:monarchinitiative not_provided not_provided HGNC:2197 MONDO:0008148 uuid:3417b15b-f028-402f-b17a-e05a08a29d2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3698 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0037199 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020542 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0032285 infores:hetionet CHEBI:15551 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0030554 infores:hetionet CAID:CA405687698 biolink:causes MONDO:0018493 infores:clingen CAID:CA405687698 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with isoleucine at codon 4853 of the RYR1 protein, p.(Thr4853Ile). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result without a clear MH event (PMID: 16244682), PS4 not met. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.982) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405687698/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6950 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0018524 infores:hetionet CHEBI:3510 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0008370 infores:hetionet CHEBI:27834 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0003862 infores:hetionet CHEBI:72292 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0151904 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0039971 infores:hetionet CHEBI:35553 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0917801 infores:hetionet CHEBI:64355 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003811 infores:hetionet CHEBI:7476 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0041834 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0234215 infores:hetionet CHEBI:4910 biolink:causes HP:0025267 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0037384 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0027947 infores:hetionet CHEBI:46557 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0003811 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0017160 infores:hetionet CHEBI:161680 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0000731 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0013395 infores:hetionet CHEBI:145499 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017178 infores:hetionet CHEBI:72690 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0027497 infores:hetionet CAID:CA16020714 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020714 MONDO:0009861 PMID:26503515 Pathogenic PVS1, PM2, PP4 The PAH: c.13delG variant is a frameshift variant occurring in exon 1 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). The variant has been previously reported the heterozygous state in 1 Chinese PKU case (PMID: 26503515); no further information regarding the patient’s phenotype or the other accompanying allele was given (PP4). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020714/MONDO:0009861/006 2019-02-26 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CAID:CA1139665140 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665140 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.3(ACADVL):c.625del (p.Glu209ArgfsTer8) variant in ACADVL is a frameshift variant predicted cause a premature stop codon in biologically-relevant-exon 8/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665140/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3175 biolink:causes UMLS:C1736167 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1736167 infores:hetionet CHEBI:9137 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042345 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0948594 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042109 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0233494 infores:hetionet CAID:CA1620036 biolink:causes MONDO:0800472 infores:clingen CAID:CA1620036 MONDO:0800472 PMID:27243976 Uncertain Significance PM2_Supporting PP3, PP1, BP4, BA1, PS1, PS3, PS2, PM5, PM1, PM3, PM4, BP7, BS1, BS4, PVS1 The c.431A>G variant in CYP1B1 is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 144 (p.Gln144Arg). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1) = 0.0003193 (28 alleles out of 87702), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This missense variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), and the REVEL score = 0.445, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on CYP1B1 function. PS3_Supporting was not applied as the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined (PMID: 27243976). This variant has not been identified as homozygous or compound heterozygous with one other variant. One affected individual carries the Gln144Arg variant but they also carry two other CYP1B1 variants (Phe156Cys and His413_I414delinsGlnLys, both VUS), phase unknown. This person is excluded from assessing PM3 as the causative variant cannot be determined. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1620036/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:39112 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0031039 infores:hetionet CHEBI:5147 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0030193 infores:hetionet CHEBI:91834 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0013395 infores:hetionet CHEBI:9570 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C1384353 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0554309 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0554309 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0549418 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0017979 infores:hetionet CHEBI:3515 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0041969 infores:hetionet CHEBI:10119 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2129214 infores:hetionet CHEBI:27565 biolink:causes UMLS:C0577115 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0577115 infores:hetionet NCBIGene:23394 biolink:causes MONDO:0014379 infores:monarchinitiative not_provided not_provided HGNC:15766 MONDO:0014379 uuid:a0a2a60a-854b-4836-b855-f69d9fc1d3a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1328337 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019372 infores:hetionet CHEBI:7581 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0009806 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0018799 infores:hetionet CHEBI:63622 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0002170 infores:hetionet CHEBI:10650 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0015371 infores:hetionet CHEBI:8069 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0085633 infores:hetionet CHEBI:7443 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0041657 infores:hetionet NCBIGene:51053 biolink:causes MONDO:0014794 infores:monarchinitiative not_provided not_provided HGNC:17493 MONDO:0014794 uuid:6fffd320-7df0-4b5d-a7b4-ca59c79aa95a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0233494 infores:hetionet CAID:CA913191009 biolink:causes MONDO:0009290 infores:clingen CAID:CA913191009 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The NM_000152.5:c.1952del (p.Gly651AlafsTer45) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two adult siblings who are compound heterozygous for the variant (labeled as c.1951del in the publication) and a pathogenic variant in GAA, c.-32-13T>G, phase unknown, were identified with deficient GAA activity on a screening study in dried blood spots. Both have limb girdle muscular weakness and elevated CK. One of the siblings also has dyspnea, rigid spine, cachexia, reduced pulmonary function, and is on enzyme replacement therapy (PMID: 31125121) (PP4, PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 632822). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913191009/MONDO:0009290/010 2023-04-19 2023-04-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:28148 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0028961 infores:hetionet CHEBI:7581 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0015230 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0239182 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0239182 infores:hetionet CHEBI:8059 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0338614 infores:hetionet NCBITaxon:523103 biolink:causes MONDO:0000242 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:523103 MONDO:0000242 CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0086565 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0086543 infores:hetionet CHEBI:4909 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0020538 infores:hetionet CAID:CA274615 biolink:causes MONDO:0010726 infores:clingen CAID:CA274615 MONDO:0010726 PMID: Likely Pathogenic PM1, PM4_Strong, PS4_Supporting PP4, PM2 The p.Ile293_Ser350del variant in MECP2 (NM_004992.3) causes an in-frame deletion of 58 amino acids in a non-repeat region of MECP2, which results in a deletion of greater than 10% of the total protein length (PM4_strong). The p.Ile293_Ser350del variant occurs in the well-characterized transcription repression functional domain of the MECP2 gene (PM1). The p.Ile293_Ser350del variant has been observed in at least 2 individuals with Rett syndrome or atypical Rett syndrome (PMID 22277191, internal database - Invitae) (PS4_supporting). In summary, the p.Ile293_Ser350del variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM4_strong, PM1, PS4_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274615/MONDO:0010726/016 2022-10-13 2022-12-02 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CAID:CA014718 biolink:causes MONDO:0005045 infores:clingen CAID:CA014718 MONDO:0005045 PMID: Likely Pathogenic PM2, PP3, PS4 PM5, PM1, PM6, PP1, PS3, BA1, BS1, BS3, BS4, PS1, PS2, BP4, BP5 The NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp) variant has been reported in >15 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease (PS4_Strong; Van Driest 2004 PMID: 15358028; Millat 2010 PMID: 20624503; Millat 2010 PMID: 20800588; Teirlinck 2012 PMID:23140321; Zou 2013 PMID:23283745; Berge 2014 PMID: 24111713; Ntusi 2016 PMID: 27841901; Homburger 2016 PMID: 27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID: 30297972; Gene Dx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.0003% (FAF 95% CI; 2/113756) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014718/MONDO:0005045/002 2021-12-09 2021-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49603 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0162119 infores:hetionet CAID:CA132671 biolink:causes MONDO:0010134 infores:clingen CAID:CA132671 MONDO:0010134 PMID:20621367PMID:20621367 Likely Benign BP7, BS1_Supporting, BP4 PP4, PM3, PM1 The SLC26A4 p.Asn538Asn variant has been reported in the heterozygous state in one individual with unilateral hearing loss (PMID: 20621367). However, this variant is synonymous and is not predicted by computational prediction analysis, using MaxEntScan, to impact splicing (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 60/24964) of the p.Asn538Asn variant in SLC26A4 is 0.19168% for African chromosomes in gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting; http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43517). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4, BP7. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132671/MONDO:0010134/005 2019-07-29 2019-10-02 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6339 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0020651 infores:hetionet CHEBI:7494 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085610 infores:hetionet CHEBI:33325 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0232487 infores:hetionet CHEBI:63635 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0015732 infores:hetionet CHEBI:51860 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013447 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0012813 infores:hetionet CHEBI:6149 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C1368065 infores:hetionet CHEBI:5855 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020639 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002622 infores:hetionet CHEBI:44423 biolink:causes MONDO:0024880 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C2939419 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0022568 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0002957 infores:hetionet CHEBI:161680 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0016382 infores:hetionet CHEBI:36795 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0392156 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0009806 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013922 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0475858 infores:hetionet CHEBI:8356 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151827 infores:hetionet NCBIGene:819 biolink:causes MONDO:0859357 infores:monarchinitiative not_provided not_provided HGNC:1471 MONDO:0859357 uuid:f0d930ff-3e7b-4fca-b575-f82fa73b6d5d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0851341 infores:hetionet CHEBI:46195 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0080274 infores:hetionet CHEBI:70735 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0221423 infores:hetionet CHEBI:47381 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0855775 infores:hetionet CAID:CA030068 biolink:causes MONDO:0007750 infores:clingen CAID:CA030068 MONDO:0007750 PMID: Likely Pathogenic PS3, PM2 BP4, PS4, PM1, PM5, PP3, PP4 The NM_000527.5(LDLR):c.898A>G (p.Arg300Gly) variant is classified as likely Pathogenic variant for Familial Hypercholesterolemia by applying evidence code PM2, PS3 and PS4 supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2_Met : PopMax MAF = 0.00003 in European (Non-Finnish) exomes (gnomAD v2.1.1)PS3_Met : Level 1 assay: Study of the whole LDLR cycle in Heterologous cells (CHO-ldlA7 cells), WB+FACS+CLSM. LDLR expression was not statistically different as compared to control. Conversely, LDL binding (<60%) and uptake (<60%) were significantly decreased (P<0.001). Interestingly, although the variant affects LDL binding and uptake, do not affect VLDL uptake. This reveals that the conformational change occurring in the module does not propagate to the whole ligand binding domain. (from PMID:25545329) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA030068/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:52717 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0699744 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151773 infores:hetionet GO:0010058 biolink:causes GO:0010055 infores:ubergraph knowledge_assertion manual_agent GO:0010058 GO:0010055 CHEBI:4858 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0000737 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0009450 infores:hetionet CHEBI:6444 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0036572 infores:hetionet CHEBI:144551 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0025222 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0349506 infores:hetionet CHEBI:9014 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0002792 infores:hetionet CHEBI:31638 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0026858 infores:hetionet CHEBI:100241 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022107 infores:hetionet CHEBI:4672 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151766 infores:hetionet CHEBI:51380 biolink:causes UMLS:C2609176 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C2609176 infores:hetionet CAID:CA340926 biolink:causes MONDO:0044970 infores:clingen CAID:CA340926 MONDO:0044970 PMID: Benign BA1 PP3, PS4 The m.4336T>C variant in MT-TQ was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on February 12, 2024. This variant has not been reported in the medical literature as causative in individuals or families with primary mitochondrial disease to our knowledge. However, this variant has been reported to be associated with Parkinson and Alzheimer diseases. There are many occurrences of this variant in healthy population databases, including in gnomAD v3.1.2 (737/56,424 or 1.306%), in the Helix dataset (3,949/195,983 or 2.015%), and in the GenBank dataset (535/61,134 or 0.875%), and this variant is seen across haplogroups including haplogroups H, U, A, B, J, HV, K, L3, M, Z, T, C, and V (BA1). Computational predictors are discordant as MitoTIP suggests this variant is benign (37.7 percentile) and HmtVAR predicts it to be pathogenic (0.4). In summary, as association studies linking this variant with Parkinson and Alzheimer diseases are outside the scope of this curation, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340926/MONDO:0044970/015 2024-02-12 2024-07-31 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3419 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0027497 infores:hetionet CHEBI:5784 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C1368065 infores:hetionet CHEBI:16586 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0018681 infores:hetionet CHEBI:16469 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2981158 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C1971624 infores:hetionet CAID:CA5950130 biolink:causes MONDO:0000572 infores:clingen CAID:CA5950130 MONDO:0000572 PMID: Benign BA1, BS2_Supporting The NM_000448.3:c.1346G>A variant in RAG1 is a missense variant predicted to cause the substitution of Arginine by Lysine at amino acid 449 (p.Arg449Lys). The filtering allele frequency (the lower threshold of the 95% CI of 21803/1180030) of the c.1346G>A variant in RAG1 is 0.01837 for European (non-Finnish) chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and, therefore, meets this criterion (BA1). Additionally, 207 homozygous adults are reported on gnomAD v.4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950130/MONDO:0000572/123 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31980 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0003862 infores:hetionet CHEBI:4046 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0015230 infores:hetionet CHEBI:3048 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0233794 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0574067 infores:hetionet CAID:CA8366374 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366374 MONDO:0100453 PMID:27881908PMID:27881908 Pathogenic PM3_Strong, PVS1_Strong, PP4, PP1, PM2_Supporting PS3, BS3 NM_000180.4(GUCY2D):c.3271C>T (p.Arg1091Ter) is a nonsense variant that introduces a premature stop codon into exon 19 of 20, and is predicted to lead to C-terminal truncation of a gene product in which loss-of-function is an established mechanism of disease (PVS1_Strong). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000005058, with 8 alleles / 1,581,610 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant (suspected in trans, 0.5 points, PMID: 23847139) or the NM_000180.4(GUCY2D):c.937C>T (p.Arg313Cys) variant (confirmed in trans, 1 pt, VCEP member-provided data), both of which were previously classified either pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP. The variant has also been reported in 1 proband diagnosed with retinitis pigmentosa with onset between ages 5-10 years with the NM_000180.4(GUCY2D):c.2516del (p.Thr839ArgfsTer27) variant suspected in trans, which was previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, VCEP member-provided data, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (VCEP member-provided data, PP1). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with congenital onset (1 pt), genotyping by a large gene panel that did not provide an alternative explanation for retinal disease (2 pts), nystagmus (1 pt), nyctalopia (0.5 pts), and undetectable electroretinogram responses from rods (0.5 pts) and cones (1.0 pt), which together are specific for GUCY2D-related recessive retinopathy (6.5 points, PMID: 23847139, PP4). The variant showed successsful rescue of rod and cone function when delivered by subretinal injection into Gucy2e−/−Gucy2f−/− knockout mouse retinas, but this model was not considered sufficient evidence of non-pathogenicity in humans so was not considered applicable for BS3 (PMID: 27881908). In vitro, guanylate cyclase activity is reduced to 25% but is not less than LCA/eoRD cutoff of <10% activity (PMID: 23035049) In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1_Strong, PM2_Supporting, PM3_Strong, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366374/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135005 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0595930 infores:hetionet NCBIGene:282996 biolink:causes MONDO:0013168 infores:monarchinitiative not_provided not_provided HGNC:27424 MONDO:0013168 uuid:630f018b-1745-4cd2-b8eb-136ff26dbb40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94385 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0235818 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151763 infores:hetionet CHEBI:16755 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0016204 infores:hetionet CHEBI:9757 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0677500 infores:hetionet CHEBI:8888 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017979 infores:hetionet CHEBI:53691 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0085610 infores:hetionet CHEBI:41774 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0085605 infores:hetionet CHEBI:3380 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0023052 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0015397 infores:hetionet CHEBI:63577 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0017160 infores:hetionet CHEBI:474180 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0042029 infores:hetionet NCBIGene:5830 biolink:causes MONDO:0008954 infores:monarchinitiative not_provided not_provided HGNC:9719 MONDO:0008954 uuid:c2a946b8-1741-4df5-a0f1-3a33d6c3fcce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085633 infores:hetionet CHEBI:10650 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0520966 infores:hetionet UMLS:C0657912 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032227 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0856069 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0856069 infores:hetionet NCBIGene:80184 biolink:causes MONDO:0014442 infores:monarchinitiative not_provided not_provided HGNC:29021 MONDO:0014442 uuid:a28fb42e-276e-41f9-bd74-ccc27a42d580 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0012833 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0853942 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853942 infores:hetionet UMLS:C1872203 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0000731 infores:hetionet CHEBI:10124 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0037036 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0017574 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005376 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0017665 infores:hetionet CAID:CA412744364 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744364 MONDO:0100437 PMID:36276946 Pathogenic PVS1, PP4, PM2_Supporting PP3, PP1, PS3 NM_001034853.2(RPGR):c.619+2T>A is a canonical splice site variant in intron 6 and is predicted to induce skipping of exon 6, which is expected to disrupt a critical functional domain in RPGR (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Cells transected with the variant intron showed no mCherry signal relative to the wild-type intron control, indicating severely defective splicing.(PMID: 36276946), however, PS3_Supporting was not met as PVS1 has already been applied. At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), mid-periphery pigment deposits (0.5 pts), and genotyping by next-generation sequencing with a panel of genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PP4). The variant has been reported to segregate through at least 2 meioses from 1 family, however, the PP1 code is not met as the female is not affected (PMID: 36276946). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744364/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:17549 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0011991 infores:hetionet CHEBI:63620 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011168 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0020517 infores:hetionet CHEBI:8346 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0546817 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0920166 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0920166 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0221722 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0221722 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0011616 infores:hetionet CHEBI:51364 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1368065 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0003123 infores:hetionet CHEBI:3216 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013362 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151578 infores:hetionet CHEBI:15367 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0241729 infores:hetionet CHEBI:231594 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0040435 infores:hetionet CHEBI:7025 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0002994 infores:hetionet CHEBI:47898 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013384 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0020701 infores:hetionet CHEBI:31932 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0151825 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0235431 infores:hetionet CHEBI:61390 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0042075 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0009450 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0235146 infores:hetionet CHEBI:7476 biolink:causes MONDO:0008698 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014848 infores:hetionet CAID:CA340745829 biolink:causes MONDO:0100368 infores:clingen CAID:CA340745829 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP1, PP4, PM2_Supporting NM_000329.3(RPE65):c.755T>C (p.Phe252Ser) is a missense variant in exon 8 of 14, changing the phenylalanine at position 252 to serine. The variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.986, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who is compound heterozygous with the NM_000329.3(RPE65):c.1360del (p.Thr454LeufsTer?) variant confirmed in trans (1 point, PMIDs:28130426), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). NM_000329.3(RPE65):c.755T>C (p.Phe252Ser) has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 28130426). At least one proband (RF.T.111, patient II-I) harboring this variant exhibits a phenotype including severely decreased ERG responses (0.5 pt), optic disc pallor (0.5pt), pigmentary retinopathy with attenuated vessels (0.5 pt), symptomatic onset between birth an age five years (1 pt), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 28130426, PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3, PP1, PP3_moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340745829/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17347 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0851536 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0948089 infores:hetionet CHEBI:9566 biolink:causes UMLS:C1096355 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C1096355 infores:hetionet CHEBI:15365 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0039070 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0017152 infores:hetionet CHEBI:8081 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0948089 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0020649 infores:hetionet CHEBI:68478 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020461 infores:hetionet CAID:CA16020783 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020783 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3_Moderate, PM3_Supporting PM5 The c.395C>T (p.Ala132Val) in PAH is reported in a Japanese patient with mild hyperphenylalaninemia (BH4 deficiency ruled out), detected with pathogenic variant p.Arg413Pro (PMID: 21307867). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect (REVEL=0.878). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3_supporting, PP3_moderate, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020783/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7936 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0687707 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235969 infores:hetionet CAID:CA10583408 biolink:causes MONDO:0007648 infores:clingen CAID:CA10583408 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.360dupG (p.His121Alafs*47) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting, SCV000288479.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583408/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:10102 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C2979982 infores:hetionet CHEBI:8461 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0022354 infores:hetionet CHEBI:9943 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0152459 infores:hetionet CHEBI:76607 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0020649 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0027051 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0025202 infores:hetionet CAID:CA8314729 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314729 MONDO:0009276 PMID: Benign BP4, BA1 The missense variant NM_000173.7(GP1BA):c.256C>T (p.Leu86Phe) occurs at a Grpmax Filtering allele frequency in gnomAD v4.1 of 0.01894 (based on 899/44894 alleles) in the East Asian population, (>0.001; BA1). And the computational predictor REVEL gives a score of 0.182, which predicts no damaging effect (<0.290; BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 (ClinGen Platelet Disorders VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314729/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4858 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0033774 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0475858 infores:hetionet CHEBI:4530 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0042963 infores:hetionet CHEBI:71415 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C2830004 infores:hetionet CHEBI:6775 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1291077 infores:hetionet CHEBI:10119 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0917801 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0003123 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0860210 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0004096 infores:hetionet CHEBI:91541 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0015397 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151626 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C1269683 infores:hetionet CHEBI:36704 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0241157 infores:hetionet CHEBI:10127 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038990 infores:hetionet CAID:CA5416353 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416353 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting PP3, PS1, PM5 NM_001033855.3(DCLRE1C):c.1991G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 664 (p.Arg664Gln).The filtering allele frequency (the upper threshold of the 95% CI of 4/59972) of the c.1991G>A variant in DCLRE1C is 0.00002985 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416353/MONDO:0011225/116 2024-03-08 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:40303 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0030193 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0302295 infores:hetionet CHEBI:7789 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0233494 infores:hetionet CAID:CA10385528 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385528 MONDO:0100437 PMID: Benign BA1 BP4 NM_001034853.2(RPGR):c.1163C>T (p.Ala388Val) is a missense variant that replaces alanine with valine at amino acid 388. This variant is present in gnomAD v4.1.0 at a frequency of 0.0001435 among hemizygous individuals, with 57 variant alleles / 397,112 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.049, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives a delta score of 0.11 for donor loss, which falls in the intermediate range above the ClinGen X-linked IRD VCEP recommended BP4 threshold of <0.1 but below the PP3 threshold of >0.2, so neither in silico code was met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385528/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CAID:CA409108099 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108099 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting The c.881A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to proline at codon 294 (p.(Gln294Pro)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v.4.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, it was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and SU sensitive) (PP4_Moderate; internal lab contributors). In summary, c.881A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108099/MONDO:0015967/085 2025-04-07 2025-06-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47381 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0267792 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0000833 infores:hetionet NCBIGene:5524 biolink:causes MONDO:0957576 infores:monarchinitiative not_provided not_provided HGNC:9308 MONDO:0957576 uuid:5f0acecb-5860-4813-a419-4bb14de2c052 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7581 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0520966 infores:hetionet CHEBI:52717 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004604 infores:hetionet CHEBI:28918 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0020456 infores:hetionet CAID:CA399805725 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805725 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting PM5, PP3, BP4, PS1 The NM_000419.5(ITGA2B):c.560T>C variant in ITGA2B is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 187. This variant was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805725/MONDO:0100326/011 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true NCBITaxon:1496 biolink:causes MONDO:0000705 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1496 MONDO:0000705 CAID:CA10014265 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014265 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.938T>G (p.Leu313Arg) is a missense variant.This missense variant has a REVEL score <0.50 (0.202) (BP4) and SpliceAI ≤0.20 (0.01 -29bp Donor Gain). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014265/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39867 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151735 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0021053 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0038587 infores:hetionet CHEBI:135566 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0858617 infores:hetionet CHEBI:144093 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0428977 infores:hetionet NCBIGene:478 biolink:causes MONDO:0013900 infores:monarchinitiative not_provided not_provided HGNC:801 MONDO:0013900 uuid:aec3237c-a951-40a6-bc2d-5259e1c65260 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038454 infores:hetionet GO:0050684 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:0050684 GO:0032774 CHEBI:7575 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0151905 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0022116 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0178298 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0038454 infores:hetionet CHEBI:74947 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0392699 infores:hetionet CAID:CA367400661 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400661 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.737G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to alanine at codon 246 (p.(Gly246Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.839, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID:27256595, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate, PMID:27256595). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). Another missense variant, c.736G>A p.Gly246Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly246Ala (PM5_Supporting). In summary, c.737G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP4_Moderate, PS4_Moderate, PP1_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400661/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:9137 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0701811 infores:hetionet CAID:CA160025 biolink:causes MONDO:0015967 infores:clingen CAID:CA160025 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 BP2, BA1, PS3, PS4, PS2, PM1, BP5, BS1, BS3, BS4, PM6, PP1, BS2 The c.1720_1733del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 578 (NM_000545.8), adding 82 novel amino acids before encountering a stop codon (p.(Leu578ArgfsTer82)). While this variant, located in exon 9 of 10, is predicted to cause a premature stop codon in a position that escapes nonsense mediated decay, it results in the loss of a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1733del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA160025/MONDO:0015967/017 2022-04-17 2022-04-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63791 biolink:causes UMLS:C0555971 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0555971 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0038661 infores:hetionet CHEBI:135193 biolink:causes UMLS:C0750194 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0750194 infores:hetionet CHEBI:2788 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0033774 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004936 infores:hetionet CHEBI:68478 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0000731 infores:hetionet CHEBI:42820 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0000729 infores:hetionet CAID:CA405668010 biolink:causes MONDO:0007783 infores:clingen CAID:CA405668010 MONDO:0007783 PMID: Uncertain Significance PM1, PS4_Moderate PP3, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of cysteine with tryptophan at codon 2363 of the RYR1 protein, p.(Cys2363Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.78 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405668010/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:5681 biolink:causes MONDO:0975807 infores:monarchinitiative not_provided not_provided HGNC:9529 MONDO:0975807 uuid:175bec2f-1604-40fb-90a4-540666e1d108 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9588 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0014591 infores:hetionet CHEBI:6887 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0015230 infores:hetionet CHEBI:63612 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0027497 infores:hetionet NCBIGene:2652 biolink:causes MONDO:0010563 infores:monarchinitiative not_provided not_provided HGNC:4206 MONDO:0010563 uuid:125c9dca-0a09-4019-bfb8-e6336ff479f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:110423 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0085669 infores:hetionet CHEBI:45599 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0021845 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0851341 infores:hetionet CHEBI:6375 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151766 infores:hetionet CHEBI:16714 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0220870 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0040584 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0031085 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0042373 infores:hetionet CHEBI:75246 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0011606 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042514 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0750197 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0750197 infores:hetionet CAID:CA8815662 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815662 MONDO:0009290 PMID:21484825PMID:9535769PMID:29122469PMID:16917947 Pathogenic PM2, PVS1, PP4 PM3 This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815662/MONDO:0009290/010 2020-05-04 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA229497 biolink:causes MONDO:0009861 infores:clingen CAID:CA229497 MONDO:0009861 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM3_Strong, PM5_Supporting The c.241A>C (p.Thr81Pro) variant in PAH has been reported in at least two individuals with classic PKU, where it was observed without confirmed phase with c.117C>G (p.Phe39Leu) (classified as pathogenic by PAH VCEP Variation ID 605) and c.842+1G>A (classified as pathogenic by PAH VCEP Variation ID 599) (PMID: 8659548, PMID: 9169088, PMID: 11328945). It has also been described without a specified subtype or phase with two additional pathogenic variants: p.R408W (Variation ID: 577, PMID: 23430918); c.822_832del (p.Lys274fs) (Variation ID: 102852, PMID: 23430918). Exclusion of BH4 deficiency was not specified. In-vitro functional studies are unavailable. This variant has extremely low frequency in gnomAD v4.1.0 (MAF=0.000007629). In-silico predictions support pathogenicity of this variant (REVEL=0.74). Another missense variant [c.242C>A (p.Thr81Asn)] in the same codon has been classified as likely pathogenic by the ClinGen Phenylketonuria Variant Curation Expert Panel. In summary, this variant is likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4, PM2_supporting, PM5_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229497/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Supports CAID:CA020379 biolink:causes MONDO:0008667 infores:clingen CAID:CA020379 MONDO:0008667 PMID:9398721 Benign BA1 The variant NM_000551.4(VHL):c.463+8C>T is an intronic variant. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001101 (1359/1179388 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). Therefore this variant meets the criterion for (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020379/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:30659 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0033845 infores:hetionet CHEBI:127780 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C1167965 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0021400 infores:hetionet CHEBI:55346 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0000737 infores:hetionet NCBIGene:121214 biolink:causes MONDO:0033092 infores:monarchinitiative not_provided not_provided HGNC:29958 MONDO:0033092 uuid:c4edd9c9-b9d2-4719-af65-9afe74cbc206 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8093 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0042109 infores:hetionet NCBIGene:84317 biolink:causes MONDO:0014789 infores:monarchinitiative not_provided not_provided HGNC:28178 MONDO:0014789 uuid:f6d8e644-58d4-4e5a-a2f1-7bcd94f0a2ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75246 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0948594 infores:hetionet CHEBI:4551 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0232462 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0858797 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019158 infores:hetionet UNII:3QJA87N40S biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0234233 infores:hetionet CHEBI:6149 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0025289 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0022081 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0243026 infores:hetionet CHEBI:38545 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0687713 infores:hetionet CHEBI:7931 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0085649 infores:hetionet CHEBI:17347 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1325847 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0027947 infores:hetionet CHEBI:92712 biolink:causes HP:0002169 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0009024 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0151665 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151665 infores:hetionet CHEBI:4562 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0026837 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0426576 infores:hetionet CHEBI:8207 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0005747 infores:hetionet CHEBI:465284 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0014742 infores:hetionet CHEBI:36791 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233471 infores:hetionet CHEBI:2469 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0015230 infores:hetionet CHEBI:9667 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0041657 infores:hetionet CHEBI:45863 biolink:causes EFO:0011048 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1167791 infores:hetionet CHEBI:261649 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0009806 infores:hetionet CHEBI:63619 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0003578 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0017601 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0027765 infores:hetionet CHEBI:29013 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0001824 infores:hetionet CHEBI:101278 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013491 infores:hetionet CHEBI:17474 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0232849 infores:hetionet CHEBI:8028 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0004044 infores:hetionet CHEBI:51041 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0032617 infores:hetionet CHEBI:4710 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0020458 infores:hetionet CHEBI:8764 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004144 infores:hetionet CHEBI:31205 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0151766 infores:hetionet CHEBI:6076 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0024902 infores:hetionet NCBIGene:3482 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:5467 MONDO:0007256 uuid:9a816d9d-5503-44ed-9c8a-46885d5f9789 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10119 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020621 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0007097 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0025061 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0242461 infores:hetionet CHEBI:63627 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0027497 infores:hetionet CHEBI:9328 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0011606 infores:hetionet CHEBI:3387 biolink:causes NCIT:C61050 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853711 infores:hetionet CHEBI:31174 biolink:causes HP:0031244 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0240211 infores:hetionet CHEBI:10124 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0034880 infores:hetionet CHEBI:8107 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0026961 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014742 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0011570 infores:hetionet CHEBI:63611 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030193 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035078 infores:hetionet NCBIGene:6329 biolink:causes MONDO:0957247 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0957247 uuid:71c2c609-b5b1-4d36-8390-1a4ec548aba8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2469 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0003123 infores:hetionet CHEBI:9571 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0023530 infores:hetionet CHEBI:63580 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0004134 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0233472 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0948525 infores:hetionet CHEBI:8764 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020461 infores:hetionet CHEBI:36704 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0041582 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549475 infores:hetionet CHEBI:63611 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085682 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0033860 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0518015 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004238 infores:hetionet CHEBI:31980 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0030193 infores:hetionet CHEBI:465284 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0033774 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0262397 infores:hetionet CHEBI:7445 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0018418 infores:hetionet CHEBI:6741 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0344232 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020542 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853619 infores:hetionet CHEBI:8430 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0344232 infores:hetionet NCBIGene:1908 biolink:causes MONDO:0013201 infores:monarchinitiative not_provided not_provided HGNC:3178 MONDO:0013201 uuid:f53514a1-da1d-41c6-878d-c878c4f769c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6792 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0012833 infores:hetionet CHEBI:7936 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0852911 infores:hetionet CHEBI:31622 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0012833 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C71033 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0877038 infores:hetionet CHEBI:45783 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0344232 infores:hetionet CHEBI:9571 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0156404 infores:hetionet CHEBI:72564 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0549567 infores:hetionet CHEBI:17076 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0242528 infores:hetionet CHEBI:49375 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C2047937 infores:hetionet CHEBI:49713 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0015371 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020517 infores:hetionet CHEBI:8356 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039240 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0521592 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0694536 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0004623 infores:hetionet CHEBI:5001 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0042023 infores:hetionet GO:0052031 biolink:causes GO:0006952 infores:ubergraph knowledge_assertion manual_agent GO:0052031 GO:0006952 CHEBI:63629 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0233632 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0854135 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0854135 infores:hetionet CHEBI:7983 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0003578 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0234913 infores:hetionet CHEBI:4792 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0855775 infores:hetionet CHEBI:135935 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0015672 infores:hetionet CHEBI:7936 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1112442 infores:hetionet CHEBI:4708 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151744 infores:hetionet CHEBI:63577 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0011168 infores:hetionet CHEBI:135888 biolink:causes UMLS:C1262170 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C1262170 infores:hetionet CHEBI:3614 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0043352 infores:hetionet CHEBI:68855 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0006826 infores:hetionet NCBIGene:3145 biolink:causes MONDO:0008294 infores:monarchinitiative not_provided not_provided HGNC:4982 MONDO:0008294 uuid:89b3f181-5668-44cd-a17f-f5ff9e96de0f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0003811 infores:hetionet CAID:CA1624230 biolink:causes MONDO:0021060 infores:clingen CAID:CA1624230 MONDO:0021060 PMID: Uncertain Significance PM1, BS1, PM2, PP2, BS2, BA1, BP4 The c.3286T>A (p.Ser1096Thr) variant in SOS1 has been observed in 0.01864% (24/128738) of non-Finnish European chromosomes in gnomAD v2.1.1. This variant was seen in several individuals whose clinical presentations lacked clear associations with a RASopathy (PMIDs: 22589294, 26580448, 27153395; Invitae internal data, SCV000659145.1; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=14) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1624230/MONDO:0021060/004 2020-03-19 2020-03-23 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5138 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019372 infores:hetionet CHEBI:50693 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0040822 infores:hetionet CHEBI:63580 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003873 infores:hetionet CHEBI:3723 biolink:causes EFO:0009618 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0272774 infores:hetionet CHEBI:52717 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0042023 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0860901 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0860901 infores:hetionet CHEBI:3568 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0026961 infores:hetionet CHEBI:64321 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0041834 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0855931 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0855931 infores:hetionet GO:0042682 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0042682 GO:0007275 CHEBI:61049 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0004238 infores:hetionet CHEBI:8378 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0040038 infores:hetionet UMLS:C0004609 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0232462 infores:hetionet CHEBI:7798 biolink:causes MONDO:0020686 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0001361 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011551 infores:hetionet CHEBI:37924 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0268000 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042109 infores:hetionet NCBIGene:54806 biolink:causes MONDO:0012078 infores:monarchinitiative not_provided not_provided HGNC:21575 MONDO:0012078 uuid:ea34666c-8126-41ad-a0e7-8622c932f0be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6062 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0232462 infores:hetionet CHEBI:2639 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0007859 infores:hetionet CHEBI:8888 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151205 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0178298 infores:hetionet CHEBI:40279 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0022346 infores:hetionet UMLS:C0010592 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0035410 infores:hetionet CAID:CA1139771067 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139771067 MONDO:0011071 PMID:34166225 Pathogenic PM5_Supporting, PVS1, PS3_Moderate, PM2_Supporting PS1, PS4, PS2, BP1, BP2, BP3, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.696del (p.Arg233AlafsTer4) is a variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) (17.93%) (PS3_moderate). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS3_moderate, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771067/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9137 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0392025 infores:hetionet CHEBI:31643 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0015967 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0149931 infores:hetionet NCBIGene:124997 biolink:causes MONDO:0012430 infores:monarchinitiative not_provided not_provided HGNC:26600 MONDO:0012430 uuid:86ed012a-4954-4231-8a76-791302e97f68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10360782 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360782 MONDO:0100039 PMID: Benign BP5_Strong, BS2, BP4, BA1 PM1 RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The allele frequency of the c.3083C>T (p.Thr1028Met) variant in CDKL5 transcript (NM_003159.2) (RS1 c.184+3119G>A) is 0.046% in the Middle Eastern sub population in gnomAD v4, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Computational analysis prediction tools suggest that the p.Thr1028Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). Additionally, the p.Thr1028Met variant is observed in at least 20 unaffected individuals (internal database - Invitae, internal database - GeneDx) (BS2) and at least 7 patients with an alternate molecular basis of disease (internal database – Ambry Genetics, internal database - Invitae, internal database - GeneDx) (BP5_Strong). In summary, the p.Thr1028Met variant in CDKL5 (NM_003159.2) is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BS2, BP5_Strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360782/MONDO:0100039/034 2023-12-06 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:3723 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0031212 infores:hetionet CHEBI:2675 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C1306341 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0851341 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0277525 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0277525 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0011991 infores:hetionet CHEBI:4466 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0040034 infores:hetionet CHEBI:204734 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0041834 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0919980 infores:hetionet CAID:CA10014719 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014719 MONDO:0011071 PMID: Benign BP4, BP2, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This intronic variant has a MAF of 0.008015 (0.8015%, 545/67996 alleles) in the European (non-Finnish) subpopulation of gnomAD v3.1.2 cohort is ≥0.0015 (0.15%) (BA1). It is detected in a homozygous state in 9 individuals within the European (non-Finnish) population in gnomAD v2.1.1 (NB: MAF for this allele within the European (non-Finnish) population of gnomAD v2.1.1 is 0.008492 (0.8492%, 1097/129174 alleles) (BP2). It has a SpliceAI Δ score of ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.666583 is <2.0). The variant is the reference nucleotide in at least 3 mammalian species. It is not the reference nucleotide in any primate (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014719/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8863 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0043387 infores:hetionet NCBIGene:56997 biolink:causes MONDO:0012784 infores:monarchinitiative not_provided not_provided HGNC:16812 MONDO:0012784 uuid:c647968c-418d-481f-ad16-0d25e83d987d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0020296 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0003855 infores:hetionet CHEBI:205919 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0162835 infores:hetionet CHEBI:8874 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027066 infores:hetionet CHEBI:17026 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013456 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1167965 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011053 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0032617 infores:hetionet CHEBI:119915 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0241136 infores:hetionet CHEBI:251408 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0015644 infores:hetionet CHEBI:31859 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0235996 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020649 infores:hetionet CHEBI:5127 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0033774 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0020517 infores:hetionet CHEBI:8871 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151786 infores:hetionet CHEBI:63629 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0020621 infores:hetionet CHEBI:100246 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0027066 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006678 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0005683 infores:hetionet CHEBI:6149 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0037763 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0004096 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0009806 infores:hetionet CHEBI:6339 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0033687 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1262038 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1262038 infores:hetionet NCBIGene:317662 biolink:causes MONDO:0032902 infores:monarchinitiative not_provided not_provided HGNC:29162 MONDO:0032902 uuid:4f7ad1e2-a4d1-48a0-9773-6a4622f46c7a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0017168 infores:hetionet CAID:CA387462311 biolink:causes MONDO:0019497 infores:clingen CAID:CA387462311 MONDO:0019497 PMID: Likely Pathogenic PM2_Supporting, PVS1 The 1A>T (p.Met1Leu) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 551915, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting (VCEP specifications version 2; 10.18.2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA387462311/MONDO:0019497/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf NCBITaxon:6248 biolink:causes MONDO:0005974 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6248 MONDO:0005974 CHEBI:64312 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0015732 infores:hetionet CHEBI:65173 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0039231 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0017178 infores:hetionet CHEBI:31981 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0549567 infores:hetionet CAID:CA10014227 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014227 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.4(RUNX1):c.984A>G (p.Thr328=) is a synonymous variant. There is NO predicted effect on the gene product; REVEL is not calculable. SpliceAI predicts: Acceptor loss 0.00, Donor loss 0.00, Acceptor gain 0.00, Donor gain 0.00. As such, there appears to be NO effect on splicing (BP4. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.2495 which is < 2.0)(BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014227/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9605 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0030193 infores:hetionet CHEBI:92712 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0221201 infores:hetionet CAID:CA10577531 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577531 MONDO:0007648 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.61C>A (p.Leu21Ile) variant results in a non-synonymous amino acid change in exon 2. The A allele has not been observed in the gnomAD population database (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in at least three individuals without DGC, SRC tumours and whose families do not suggest HDGC (BS2_supporting; SCV000760847.1, SCV000279855.9) In summary, the clinical significance of this variant is uncertain based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577531/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:135961 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0026858 infores:hetionet CHEBI:5118 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015967 infores:hetionet CHEBI:5613 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020458 infores:hetionet CHEBI:7798 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0003862 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0234215 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0178298 infores:hetionet CHEBI:231594 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0041834 infores:hetionet CHEBI:3752 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0917801 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0233632 infores:hetionet CHEBI:7465 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0231528 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0262397 infores:hetionet CHEBI:28925 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0030312 infores:hetionet CHEBI:92998 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0036974 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0033931 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0033931 infores:hetionet NCBIGene:1140 biolink:causes MONDO:0014581 infores:monarchinitiative not_provided not_provided HGNC:1961 MONDO:0014581 uuid:32880dcc-8364-4627-9986-f0f22db87baf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C2047937 infores:hetionet GO:1900101 biolink:causes GO:0034620 infores:ubergraph knowledge_assertion manual_agent GO:1900101 GO:0034620 CHEBI:16899 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0232492 infores:hetionet CHEBI:119486 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085932 infores:hetionet CHEBI:10101 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0028734 infores:hetionet CHEBI:68610 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0043094 infores:hetionet CHEBI:3647 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0427086 infores:hetionet NCBIGene:124404 biolink:causes MONDO:0013901 infores:monarchinitiative not_provided not_provided HGNC:26348 MONDO:0013901 uuid:473c0896-2e0f-417f-89de-fc5fc276b924 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0232462 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0574067 infores:hetionet CHEBI:6062 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0231218 infores:hetionet CAID:CA177518 biolink:causes MONDO:0021060 infores:clingen CAID:CA177518 MONDO:0021060 PMID: Uncertain Significance PM2_Supporting, PP3 BS1, BP4, BA1 The NM_002524.5:c.368G>A variant in NRAS is a missense variant predicted to cause substitution of arginine by lysine at amino acid 123 (p.Arg123Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.759, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_Supporting, PP3. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA177518/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:194135 biolink:causes MONDO:0005077 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0043167 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1168034 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0010692 infores:hetionet CAID:CA16041884 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041884 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3, PM3_Strong BP7 The NM_000152.5:c.546C>T (p.Thr182=) variant in GAA is a synonymous (silent) variant that alters the last nucleotide of exon 2 and has been found to impact splicing of intron 2 (PMID 19609281, 21757382, 33168984). At least 20 patients with Pompe disease and this variant have been reported including 17 patients with documented laboratory values for GAA activity <10% of normal mean control level of GAA activity in leukocytes, <30% of normal mean control level of GAA activity in cultured fibroblasts or activity in the affected range in cultured skin fibroblasts, leukocytes, lymphocytes, or dried blood spot (PMID 19609281, 21982629, 25388776, 28433475, 29124014, 30093193); pseudodeficiency variants are confirmed absent in one of these patients (PMID 28433475)(PP4_Moderate). The patients typically have late onset Pompe disease and are of East Asian descent. Of these patients, two are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, including c.118C>T (p.Arg40Ter) (PMID 29124014, ClinVar SCV SCV001371737.1), and c.1935C>A (p.Asp645Glu)(PMID 21757382), and seven patients are homozygous for the variant (PMID 20202878, 21982629, 29124014, 30093193). Additional patients are compound heterozygous for the variant and a missense variant - c.796C>T (p.Pro266Ser) (PMID 29124014), c.1099T>G (p.Trp367Gly) (PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 28433475), p.Arg600Cys (PMID 19609281, 20202878, 21982629), c.2171C>A (p.Ala724Asp)(PMID 25388776), c.2481G>A (p.Gln827His) (PMID 29124014); the in trans data from these patients will be used in assessment of these variants and is not included here in order to avoid circular logic (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Results of RT-PCR and subsequent sequencing of cDNA from patient skin fibroblasts from multiple studies are consistent with c.546G>T being a leaky splice variant, with production of some normal transcript in addition to skipping of exon 2 and use of a cryptic splice site in intron 2 (PMID 19609281, 21757382, 33168984)(PS3). Consistent with this finding, the computational splicing predictor SpliceAI gives a score of 0.69 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). Of note, additional variants at this position, c.546G>A (ClinVar Variation ID: 280955) and c.546G>C (ClinVar Variation ID: 281056), have also been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 370637, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PS3, PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041884/MONDO:0009290/010 2021-12-02 2021-12-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4710 biolink:causes MONDO:0004821 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0027438 infores:hetionet CHEBI:116278 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0011551 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0041349 infores:hetionet CHEBI:32599 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0020598 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0235063 infores:hetionet CHEBI:5801 biolink:causes UMLS:C1963822 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C1963822 infores:hetionet CHEBI:8764 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020625 infores:hetionet CHEBI:44241 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0151773 infores:hetionet NCBIGene:29969 biolink:causes MONDO:0031043 infores:monarchinitiative not_provided not_provided HGNC:28870 MONDO:0031043 uuid:54c6a1e2-1d50-4a54-b33d-450188173a67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3423 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085669 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0009450 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017574 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0744403 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0744403 infores:hetionet CAID:CA016328 biolink:causes MONDO:0005045 infores:clingen CAID:CA016328 MONDO:0005045 PMID: Uncertain Significance PP3, PM2, PS4_Supporting PM3, PP1, BA1, PS3, PM5, PM4, PM1, PM6, BP3, BS1, BS4, BS3, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys)The c.5647G>A (p.Glu1883Lys) variant in MYH7 has been reported in the homozygous state in 1 individual from a consanguineous family with myosin storage myopathy, HCM and a family history consistent with recessive inheritance (Tajharghi 2007 PMID 17372140) and in 4 individuals with HCM from testing laboratories (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has been identified in 0.01% (1/18716) of African/African American chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but absent from all other populations (PM2). In vitro functional studies provide conflicting evidence on the impact of this on protein function, with some suggesting a potential impact (Viswanathan 2017 PMID: 28973424; Armel 2009 PMID: 19336582), while another suggests that it has a similar function as its wild time counterpart (Dahl-Halvarsson PMID 28125727). Therefore, this data is currently insufficient to establish functional impact and apply PS3. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016328/MONDO:0005045/002 2021-07-26 2021-07-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8093 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0020538 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0018802 infores:hetionet CHEBI:10102 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0014457 infores:hetionet CAID:CA024821 biolink:causes MONDO:0007783 infores:clingen CAID:CA024821 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PS4, PP3_Moderate, PM6_Supporting PM1, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 2508 of the RYR1 protein, p.(Arg2508His). This variant is not present in the six major gnomAD populations at the time this variant was interpreted. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, six of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:23460944, PMID:25960145). This variant was determined to be de novo without confirmed parentage in one individual, PS2/PM6_Supporting (PMID:17483490). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26381711, PMID:27586648). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS.A REVEL score >0.85 (0.898) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS2/PM6_Supporting, PS3_Moderate, PS4, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024821/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3423 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085649 infores:hetionet CAID:CA915940530 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940530 MONDO:0100326 PMID: Uncertain Significance PP4_Strong, PM2_Supporting, PM3_Supporting BP7 The NM_000419.5(ITGA2B):c.*165T>C 3'UTR variant was identified homozygous (PM3_supporting) in at least one patient (GT75 in PMID: 25728920) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1). These criteria reach Likely Pathogenic however, to our knowledge, there is no known disease mechanism for 3'UTR variants in Glanzmann thrombasthenia. In the absence of additional cases or functional data the ClinGen PD VCEP classifies this variant as uncertain significance for autosomal recessive Glanzmann Thrombasthenia. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940530/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:2788 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C2047937 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0149931 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0852733 infores:hetionet CHEBI:3699 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0235378 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0162429 infores:hetionet CHEBI:61049 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C2830004 infores:hetionet CHEBI:6367 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0038325 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0162119 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0424296 infores:hetionet CHEBI:53760 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0028643 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0234987 infores:hetionet CHEBI:4717 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0011071 infores:hetionet CHEBI:8871 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0855333 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0021053 infores:hetionet CAID:CA7331148 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331148 MONDO:0100216 PMID: Likely Benign BP4, BS2 PM2, BA1, PM1, PM5, PS4, BS1 The NM_177438.3:c.2951A>G variant in DICER1 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 984 (p.Asn984Ser). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00002603 (42/1613822 alleles) with a highest population minor allele frequency of 0.0001068 (8/74908 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). Two different missense variants, c.2950A>C (p.Asn984His) and c.2952C>A (p.Asn984Lys), in the same codon have been reported (ClinVar Variation ID: 2716149, 1015034). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.136; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as likely benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BP4. (Bayesian Points: -5; VCEP specifications version 1.3.0; 01/07/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331148/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7445 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0520966 infores:hetionet CHEBI:71940 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0019080 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0037274 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0014173 infores:hetionet CHEBI:82960 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0030252 infores:hetionet CHEBI:5775 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0018965 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0392025 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0012833 infores:hetionet CAID:CA367397309 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397309 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP2, PP3, PS3_Moderate, PM2_Supporting PP1 The c. 1256T>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 419 (p.(Phe419Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 22493702). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Phe419Ser has RAI<0.01, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 22493702). This variant segregated with disease with two informative meioses in a single family with diabetes, however this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918) (PMID 22493702). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS3_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397309/MONDO:0015967/086 2023-10-10 2023-10-10 Semidominant inheritance HP:0032113 Supports NCBIGene:8233 biolink:causes MONDO:0975827 infores:monarchinitiative not_provided not_provided HGNC:23019 MONDO:0975827 uuid:b2d384f4-dcba-4282-a31e-be5981600653 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0040479 infores:hetionet CHEBI:45951 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0037290 infores:hetionet GO:2000733 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0072001 CHEBI:10650 biolink:causes MONDO:0008538 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1956391 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0860210 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0003123 infores:hetionet CHEBI:41774 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0311394 infores:hetionet UMLS:C1872203 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0042963 infores:hetionet CHEBI:9150 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0030193 infores:hetionet CHEBI:4858 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0043352 infores:hetionet CHEBI:3219 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0023218 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0151763 infores:hetionet CAID:CA8623258 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623258 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3 PM3, BS1, PM2, BP2 The NM_000212.3(ITGB3):c.1412G>T (p.Ser471Ile) missense variant has a REVEL gives a score of 0.756, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001865 14/75048 alleles in the African/African American population, which is below than the ClinGen PD VCEP threshold (>0.00158) for BS1 but above the <0.0001 threshold for PM2_supporting. At least one patient (Proband 1 in PMID:18788610) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_moderate, PP3 (VCEP specifications version 2; date of approval 06/06/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623258/MONDO:0100326/011 2024-06-06 2024-06-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6887 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0041834 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0855242 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0021400 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0003467 infores:hetionet CHEBI:50859 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0014457 infores:hetionet NCBIGene:5332 biolink:causes MONDO:0013845 infores:monarchinitiative not_provided not_provided HGNC:9059 MONDO:0013845 uuid:eb587dbe-91a9-4fe6-be6f-e0337673a3ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040409 infores:hetionet CHEBI:94440 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0040822 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1565489 infores:hetionet CHEBI:16586 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0027424 infores:hetionet NCBIGene:286204 biolink:causes MONDO:0014539 infores:monarchinitiative not_provided not_provided HGNC:18688 MONDO:0014539 uuid:ae0464f3-f6f5-473e-9bf3-dc6b3d8bd401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027765 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0003123 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0027726 infores:hetionet CHEBI:37333 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0027497 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0236080 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0236080 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0267596 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0023067 infores:hetionet GO:0006954 biolink:causes MONDO:0004773 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D015863 DB00253_MESH_D015863_1 CHEBI:15552 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C1285577 infores:hetionet CHEBI:17630 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01172 UMLS:C0015230 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002242 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0272315 infores:hetionet CHEBI:119486 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0000731 infores:hetionet CHEBI:6367 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C2830004 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0042109 infores:hetionet CHEBI:31709 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0151786 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0240925 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0240925 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0041912 infores:hetionet CHEBI:65349 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0004604 infores:hetionet CHEBI:8245 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0030252 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0853847 infores:hetionet CHEBI:9139 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085631 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0037274 infores:hetionet CHEBI:9570 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0018524 infores:hetionet CHEBI:9727 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0024141 infores:hetionet CHEBI:8428 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0231218 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0853946 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0853946 infores:hetionet NCBIGene:1836 biolink:causes MONDO:0009189 infores:monarchinitiative not_provided not_provided HGNC:10994 MONDO:0009189 uuid:993f98bf-3446-4e96-b220-afb72cf92e9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4975 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0235234 infores:hetionet CHEBI:39867 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014743 infores:hetionet CHEBI:28901 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0019080 infores:hetionet CHEBI:64355 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020461 infores:hetionet GO:0061520 biolink:causes CL:0000453 infores:ubergraph knowledge_assertion manual_agent GO:0061520 CL:0000453 CHEBI:36791 biolink:causes HP:0004411 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549397 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0003864 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0242350 infores:hetionet GO:0060297 biolink:causes GO:0061061 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0061061 PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0038999 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0795692 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085096 infores:hetionet CHEBI:4511 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C1565489 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C1527407 infores:hetionet CHEBI:7444 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0023380 infores:hetionet CHEBI:6933 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C1142412 infores:hetionet CHEBI:6909 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0033774 infores:hetionet CHEBI:2663 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0264906 infores:hetionet CHEBI:8707 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0014591 infores:hetionet CHEBI:3181 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027849 infores:hetionet NCBIGene:6710 biolink:causes MONDO:0054780 infores:monarchinitiative not_provided not_provided HGNC:11274 MONDO:0054780 uuid:e33d0978-85d4-45e7-8aa0-a5b1616abbd3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0040053 infores:hetionet CHEBI:31174 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0022573 infores:hetionet CHEBI:8863 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0206062 infores:hetionet CHEBI:52172 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0231528 infores:hetionet NCBIGene:7450 biolink:causes MONDO:0010191 infores:monarchinitiative not_provided not_provided HGNC:12726 MONDO:0010191 uuid:7d8708f0-fdb4-4220-b66d-057390918ffd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0010200 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0240322 infores:hetionet CHEBI:10100 biolink:causes MONDO:0015943 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0008728 infores:hetionet CHEBI:3757 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030232 infores:hetionet CHEBI:48947 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0518015 infores:hetionet CHEBI:6129 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0085593 infores:hetionet CAID:CA320251541 biolink:causes MONDO:0100083 infores:clingen CAID:CA320251541 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PVS1, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1073C>T (p.Thr358Met) is a missense variant that is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251541/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7824 biolink:causes MONDO:0006892 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0236018 infores:hetionet CHEBI:31859 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0004134 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0011175 infores:hetionet CHEBI:167309 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0039231 infores:hetionet CHEBI:31859 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C2830004 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0232492 infores:hetionet CHEBI:72296 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0013491 infores:hetionet CAID:CA402994533 biolink:causes MONDO:0012999 infores:clingen CAID:CA402994533 MONDO:0012999 PMID: Pathogenic PP3, PP4_Strong, PM2_Supporting, PM3_Strong, PM5_Supporting The NM_000156.6:c.505T>C variant in GAMT is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 169 (p.Cys169Arg). This variant has been identified in 3 individuals with a diagnosis of GAMT deficiency. One of these individuals had pretreatment marked elevation of guanidinoacetate and low/low normal creatine in plasma, urine, and CSF, and diminished creatine peak on brain MRS (ACD registry). Another proband was reported with elevated guanidinoacetate in plasma (PMID: 23660394, PMID: 24268530) (PP4_Strong). These individuals are all compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP including c.522G>A (p.Trp174Ter) (ClinVar Variation ID: 205584, SCV002600143.1), confirmed in trans by parental testing (PMID: 23660394, PMID: 24268530) (1 point), c.299_311dup (ClinVar Variation ID: 8302, SCV002600154.1) confirmed in trans by parental testing (Association for Creatine Deficiencies registry) (1 point), and c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303, SCV004009593.1), phase unconfirmed (Association for Creatine Deficiencies registry) (0.5 points) (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.828, evidence that correlates with impact to GAMT function (PP3). A different missense variant at the same codon, c.506G>A (p.Cys169Tyr) (ClinVar ID: 8304, SCV004009598.1),has been classified as likely pathogenic by the ClinGen CCDS VCEP (PM5_Supporting) There is a ClinVar entry for this variant (Variation ID: 818179). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM3_Strong, PP4_Strong, PP3, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 13, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402994533/MONDO:0012999/026 2024-06-13 2024-06-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0232462 infores:hetionet CHEBI:6532 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0041969 infores:hetionet CHEBI:31644 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C3263723 infores:hetionet NCBIGene:65217 biolink:causes MONDO:0012293 infores:monarchinitiative not_provided not_provided HGNC:14674 MONDO:0012293 uuid:f0f54b3c-4d7d-41a9-80f0-43074dc53eef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55262 biolink:causes MONDO:0032694 infores:monarchinitiative not_provided not_provided HGNC:25604 MONDO:0032694 uuid:b61b8249-b302-4756-bf65-287d1e3b9383 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50841 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0041657 infores:hetionet GO:0039593 biolink:causes GO:0010458 infores:ubergraph knowledge_assertion manual_agent GO:0039593 GO:0010458 CHEBI:135276 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0855775 infores:hetionet NCBIGene:8493 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:9277 MONDO:0016419 uuid:fa88d443-1036-4cb1-855b-0039db981d55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0023610 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0027765 infores:hetionet CAID:CA367398712 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398712 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PS4, PP4 The c.1154G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to glutamate at codon 385 (p.(Gly385Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and not enough clinical information is provided to apply PP4 (PMID: 39859454, ClinVar). Other missense variants at the same codon, c.1153G>T (p.Gly385Trp) and c.1153G>A (p.Gly385Arg), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1154G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP2, PP3, PM2_supporting, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398712/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:171719 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042109 infores:hetionet CHEBI:9586 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0030794 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0003123 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0156308 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0156308 infores:hetionet CAID:CA345912 biolink:causes MONDO:0044970 infores:clingen CAID:CA345912 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PP1, PS4, PS3, PS2, PM6 The m.5523T>G variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 19349200). This was a boy with Leigh syndrome spectrum, hearing loss, and pigmentary retinopathy. The variant was present at 66% heteroplasmy in blood. There was no information provided on family member testing. There are no other individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (80.9 percentile) but HmtVAR predicts it to be neutral with a score of 0.25. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345912/MONDO:0044970/015 2024-05-13 2024-12-04 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA10014497 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014497 MONDO:0011071 PMID: Likely Benign BP4, BP7, BS1 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 MAF of 0.00018 (0.018%, 23/129128 alleles) in the European (Non-Finnish) subpopulation of the gnomAD cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This intronic variant has a SpliceAI score ≤ 0.20 (0.02) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved, as it is the reference nucleotide in chimps in UCSC GRCh38 (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014497/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27974 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1861172 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1258215 infores:hetionet CHEBI:2639 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0033774 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235315 infores:hetionet CHEBI:52172 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0542571 infores:hetionet CAID:CA10014389 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014389 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS4, PS2, PS3, BP1, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.630A>G (p.Leu210=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014389/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15544 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151698 infores:hetionet CHEBI:50275 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0043352 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0155003 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0018801 infores:hetionet CAID:CA367397333 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397333 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4, PP1 The c.1254-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000162.5. While this variant is predicted to cause skipping of biologically-relevant exon 10 of 10 and to escape nonsense-mediated decay, it results in the loss of a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, persistent FBG and HbA1c in this range, and a strong family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). In summary, c.1254-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397333/MONDO:0015967/086 2023-11-03 2023-11-03 Semidominant inheritance HP:0032113 Supports CHEBI:3723 biolink:causes MONDO:0008093 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0334082 infores:hetionet NCBIGene:6898 biolink:causes MONDO:0010160 infores:monarchinitiative not_provided not_provided HGNC:11573 MONDO:0010160 uuid:bac60b8e-99e9-470e-a6ba-c3afb669a2a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0029882 infores:hetionet CHEBI:61390 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C1761613 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0023067 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0011849 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C3665386 infores:hetionet CHEBI:8802 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0003578 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0006266 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0746883 infores:hetionet CHEBI:47381 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0028084 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042134 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0004239 infores:hetionet CHEBI:4868 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0020488 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0037822 infores:hetionet CHEBI:8707 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085583 infores:hetionet CHEBI:8863 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0024902 infores:hetionet CHEBI:9654 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0917801 infores:hetionet CHEBI:5118 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0006277 infores:hetionet CHEBI:194135 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151936 infores:hetionet CHEBI:3441 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0027424 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042109 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011570 infores:hetionet CHEBI:39867 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C2697368 infores:hetionet CHEBI:8430 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0015672 infores:hetionet CHEBI:4356 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0547030 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0595877 infores:hetionet CAID:CA235608 biolink:causes MONDO:0100039 infores:clingen CAID:CA235608 MONDO:0100039 PMID: Pathogenic PVS1, PS4, PM6_Strong, PM2_Supporting The p.Glu416Valfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu416Valfs variant has been observed in at least 5 individuals with CDKL5 disease (PMID: 27779742, 27864847, 23064044, ClinVar Variation ID 189554) (PS4). The p.XX variant in GENE has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (PMID XX) (PMID 27779742, 27864847) (PM6_strong). This variant is absent from gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria applied (PVS1, PS4, PM6_strong, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA235608/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf NCBIGene:9342 biolink:causes MONDO:0012290 infores:monarchinitiative not_provided not_provided HGNC:11133 MONDO:0012290 uuid:35638b7e-b948-4a20-a487-0667ff546783 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0019233 biolink:causes HP:0012532 infores:drugmechdb knowledge_assertion manual_agent GO:0019233 MESH:D059350 DB00193_MESH_D059350_1 CHEBI:63619 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0025222 infores:hetionet CHEBI:4708 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0014534 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011991 infores:hetionet CAID:CA410208238 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208238 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.35C>T (p.Ser12Leu) is a missense variant which has a MAF of 0.001644 (0.01644%, 1/6084 alleles) in the Middle Eastern subpopulation of the gnomAD v4.1.0 cohort, meeting the threshold for BS1. This variant has a REVEL score < 0.50 (0.305) and a SpliceAI score ≤ 0.20 (0.06) (BP4). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208238/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49662 biolink:causes UMLS:C1737224 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1737224 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C1306341 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042267 infores:hetionet CHEBI:16469 biolink:causes MONDO:0019623 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0019243 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0236068 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0025061 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0038362 infores:hetionet CHEBI:64355 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1384353 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0233931 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0233931 infores:hetionet CHEBI:28787 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0030554 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0009443 infores:hetionet CHEBI:9448 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0010200 infores:hetionet CHEBI:9586 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0018524 infores:hetionet CHEBI:7443 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0013298 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006964 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020503 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0233472 infores:hetionet CAID:CA023909 biolink:causes MONDO:0007783 infores:clingen CAID:CA023909 MONDO:0007783 PMID: Likely Pathogenic PS4_Moderate, PP3_Moderate, PP1_Strong, BS2_Supporting PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 3772 of the RYR1 protein, p.(Arg3772Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, seven of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, three of these individuals were homozygous for this variant and were not considered for PS4, PS4_Moderate was applied (PMID: 30236257, 17483490). This variant segregates with MHS in at least seven individuals, PP1_Strong (PMID:19645060, 22473935). This variant has been identified in an individual with a negative IVCT/CHCT result. BS2_Moderate (PMID: 30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023909/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:465284 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151746 infores:hetionet CHEBI:3181 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0338831 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0027339 infores:hetionet CHEBI:8874 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011253 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0022568 infores:hetionet CHEBI:6375 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0085633 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0015397 infores:hetionet CHEBI:28864 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0151632 infores:hetionet CHEBI:3640 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0035078 infores:hetionet CHEBI:6076 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042024 infores:hetionet CAID:CA10360819 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360819 MONDO:0010725 PMID: Benign BA1 BP4, PP3 The NM_000330.4(RS1):c.76G>A variant is a missense variant encoding the substitution of Glutamic acid with Lysine at amino acid 26. This variant is present in gnomAD v.4.1.0. at a frequency of 0.0004493 among hemizygous individuals, with 174 variant alleles / 387285 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The computational predictor REVEL gives a score of 0.491, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 and <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.03 (Acceptor Gain), which is below the ClinGen X-linked IRD VCEP recommended threshold of >0.2 and does not strongly predict an impact on splicing. As a result, the BP4 and PP3 codes were not met. In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360819/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CAID:CA404098878 biolink:causes MONDO:0007750 infores:clingen CAID:CA404098878 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BS1, PVS1, PP3, PP4 NM_000527.4(LDLR): c.2448G>C (p.Lys816Asn) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: PopMax MAF = 0.00006482 (0.007%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).. BP4: REVEL = 0.5. It is not below 0.5, splicing evaluation is needed. Functional data on splicing not available. A) variant is not on limitsB) Variant does not create GT or AGVariant is not predicted to affect splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404098878/MONDO:0007750/013 2023-04-28 2023-04-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:2663 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0162281 infores:hetionet CHEBI:10102 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0018524 infores:hetionet CHEBI:3441 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0026827 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011849 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0038454 infores:hetionet CHEBI:40050 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0004093 infores:hetionet CHEBI:50223 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0020625 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0162429 infores:hetionet CHEBI:15854 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0857305 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0009450 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0031542 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0020649 infores:hetionet NCBIGene:6606 biolink:causes MONDO:0009672 infores:monarchinitiative not_provided not_provided HGNC:11117 MONDO:0009672 uuid:689f9f42-3492-4e98-9c97-540a7a76f4fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA1908771 biolink:causes MONDO:0018958 infores:clingen CAID:CA1908771 MONDO:0018958 PMID: Likely Benign BS1 BP4 The c.11341C>T (NM_001164508.2(NEB):c.11341C>T (p.Arg3781Trp)) variant in NEB is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 3781 (p.Arg3781Trp). The groupmax filtering allele frequency (95 % confidence interval) in gnomAD v4.1.0 is 0.0005221 in the East Asian population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.258, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function (no codes met). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1 (ClinGen Congenital Myopathies VCEP Specifications Version 1.0; 11/19/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1908771/MONDO:0018958/146 2024-11-19 2025-03-27 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:51380 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0017178 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0854706 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0854706 infores:hetionet CHEBI:2453 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0235031 infores:hetionet CHEBI:8805 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0002792 infores:hetionet CAID:CA414773304 biolink:causes MONDO:0044970 infores:clingen CAID:CA414773304 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PM6_Supporting PS4, PS2, PS3 The m.3685T>C (p.Y127H) variant in MT-ND1 has been reported in one individual with primary mitochondrial disease to date, in a girl with Leigh syndrome (PMID: 35217561). She had developmental delay and regression, generalized tonic clonic seizures, and constipation. Brain MRI showed bilateral asymmetric basal ganglia signal hyperintensities and MRS showed elevated lactate and glucose in the basal ganglia. Labs showed elevated lactate, alanine, and GDF15. Complex I activity was slightly reduced in skin fibroblasts. The variant was present at 62.5% heteroplasmy in blood and was absent in her healthy mother’s blood (PM6_supporting; PMID: 35217561). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.750 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414773304/MONDO:0044970/015 2024-10-28 2025-08-07 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4551 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0547030 infores:hetionet CHEBI:41423 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0016658 infores:hetionet CHEBI:42944 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0033036 infores:hetionet CHEBI:5001 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C1384353 infores:hetionet CAID:CA16020890 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020890 MONDO:0009861 PMID: Likely Pathogenic PM5, PM2, PP4_Moderate, PP3 PM3 The c.903G>T (p.Gln301His) variant in PAH has been reported in at least 1 individual with PKU however without indication of the genotype (BH4 deficiency ruled out) (PMID: 21307867) . The p.Gln301His variant is absent in gnomAD and the ESP population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.831. This variant is located in the C-terminal aromatic amino acid hydroxylase domain and a different amino acid change at the same codon has been reported (PMID: 19292873 ). Overall, the c.903G>T variant is classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4_M, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020890/MONDO:0009861/006 2019-08-02 2019-08-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:75998 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0042963 infores:hetionet NCBITaxon:29908 biolink:causes MONDO:0005968 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:29908 MONDO:0005968 CHEBI:51041 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0016204 infores:hetionet CAID:CA10581287 biolink:causes MONDO:0044970 infores:clingen CAID:CA10581287 MONDO:0044970 PMID: Benign BP4, BA1 The m.12239C>T variant in MT-TS2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in 3.631% of individuals in the GenBank dataset (BA1), including in haplogroup B4a (90.9% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 0.2% including in haplogroup B at 7%. If an affected individual is not a member this haplogroup, further evaluation of the variant in that particular individual should be considered. The computational predictor MitoTIP suggests this variant does not impact the function of this tRNA with a score in the 5th percentile, as does HmtVar with a score of <0.35 (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581287/MONDO:0044970/014 2022-01-10 2022-01-10 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3752 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0029927 infores:hetionet CAID:CA401364487 biolink:causes MONDO:0009290 infores:clingen CAID:CA401364487 MONDO:0009290 PMID:12923862PMID:29880332PMID:12923862 Pathogenic PM2, PVS1, PP4 PM3 This variant, c.989G>A (p.Trp330Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Two individuals with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been reported in the literature. These individuals are non-identical twins and are compound heterozyous for the variant and c.1655T>C (p.Leu552Pro); this in trans data was used in the assessment of p.Leu552Pro and therefore was not included here in order to avoid a circular argument. Another individual was reported to be compound heterozygous for the variant and c.-32-13T>G (PMID 29880332). While this patient was described as having reduced GAA activity in dried blood spots, the normal range for the assay was not provided and therefore this data was not included. The variant is absent in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID 550355; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG-AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401364487/MONDO:0009290/010 2020-04-21 2020-05-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8207 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0009763 infores:hetionet CHEBI:6759 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0042024 infores:hetionet CHEBI:92923 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0010200 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0029456 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0022658 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151882 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151882 infores:hetionet CHEBI:51164 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0043352 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1096668 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1096668 infores:hetionet CHEBI:92712 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0002994 infores:hetionet CHEBI:9139 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0007820 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020538 infores:hetionet CHEBI:8776 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0011603 infores:hetionet NCBIGene:801 biolink:causes MONDO:0014548 infores:monarchinitiative not_provided not_provided HGNC:1442 MONDO:0014548 uuid:54da9ae3-b73d-45f9-b354-1905ffe08990 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0234215 infores:hetionet CHEBI:9588 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0030920 infores:hetionet GO:0072298 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:0072298 GO:0072210 CHEBI:231594 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0036508 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233472 infores:hetionet CHEBI:5893 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0085631 infores:hetionet CHEBI:6541 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0013378 infores:hetionet CHEBI:10124 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0438215 infores:hetionet CHEBI:15640 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0700225 infores:hetionet CHEBI:5959 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0038435 infores:hetionet CHEBI:31236 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0239783 infores:hetionet CHEBI:182080 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0233571 infores:hetionet CAID:CA10014498 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014498 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+12G>A is an intronic variant. Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.304181 < 2.0) (BP7). No splicing impact or creation of cryptic splice sites predicted by SSF and MES. Splice AI predicts no impact to splicing (score: 0.03) (BP4). This variant was reported in ClinVar in 2023 by Invitae, but the affected status of the proband is unknown (Variation ID 1219872). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP7, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014498/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49713 biolink:causes UMLS:C0263465 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0263465 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0235969 infores:hetionet CHEBI:8874 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042345 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0027430 infores:hetionet CHEBI:36791 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026826 infores:hetionet CHEBI:16796 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0027441 infores:hetionet CHEBI:135566 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0015403 infores:hetionet CHEBI:16755 biolink:causes HP:0033608 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0034079 infores:hetionet CHEBI:3061 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0011570 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0235324 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235324 infores:hetionet CAID:CA7330596 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330596 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PVS1, PM6, BP3, BP2, BA1, BS2, PP3, PP1, PP4, PM5, PM4, PM1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4 The NM_177438.3(DICER1):c.5761A>C variant in DICER1 is a missense variant predicted to cause substitution of asparagine by histidine at amino acid 1921 (p.Asn1921His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.0000006196 (1/1613836 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.152; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 02/25/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330596/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA000235 biolink:causes MONDO:0017623 infores:clingen CAID:CA000235 MONDO:0017623 PMID: Likely Pathogenic PVS1, PM2 PM6, BS4, BS3, BS1, BP7, BP5, BS2, PP3, PP2, PP1, PM5, PM1, PM4, BP2, BP4, BA1, PS4, PS2, PS1, PS3 PTEN c.964A>T (p.Lys322Ter) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000235/MONDO:0017623/003 2020-03-23 2020-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7936 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017160 infores:hetionet CHEBI:5893 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013604 infores:hetionet CHEBI:2663 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0086565 infores:hetionet CHEBI:9637 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0546884 infores:hetionet CHEBI:43968 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0013378 infores:hetionet CHEBI:18243 biolink:causes HP:0034033 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0235532 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0015397 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0002453 infores:hetionet NCBIGene:84984 biolink:causes MONDO:0014309 infores:monarchinitiative not_provided not_provided HGNC:28209 MONDO:0014309 uuid:9f2f3d33-dbca-4137-879c-648a42f098da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4995 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0029882 infores:hetionet CHEBI:28445 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0038990 infores:hetionet UNII:54Z8M50D6Q biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0677500 infores:hetionet CHEBI:63610 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0024902 infores:hetionet CHEBI:4027 biolink:causes MONDO:0021960 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0041959 infores:hetionet CHEBI:4858 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0041582 infores:hetionet CHEBI:31622 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0221100 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0019112 infores:hetionet CHEBI:6888 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C2586050 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0852911 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0151490 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0151490 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0015230 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0009450 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0346156 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0278079 infores:hetionet CHEBI:9434 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0086565 infores:hetionet CHEBI:27300 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0027709 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0342579 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0740435 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0740435 infores:hetionet CHEBI:8888 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0344232 infores:hetionet CHEBI:6402 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0242429 infores:hetionet CHEBI:6909 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0000731 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0853149 infores:hetionet CHEBI:63638 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0023380 infores:hetionet CHEBI:94411 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0152032 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0151588 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151588 infores:hetionet CHEBI:474180 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0231835 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0162316 infores:hetionet CAID:CA410203381 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203381 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting PS1, PS2, BP1, PM6, PM5, PP2, PP4 NM_001754.5(RUNX1):c.341T>C (p.Ile114Thr) is a missense variant which is found within the runt homology domain but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203381/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:23765 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0041349 infores:hetionet CHEBI:3216 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0011175 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0155169 infores:hetionet CHEBI:44185 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0232849 infores:hetionet CHEBI:50223 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151905 infores:hetionet CHEBI:3638 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0027497 infores:hetionet CHEBI:64321 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0236075 infores:hetionet CHEBI:41237 biolink:causes EFO:0020984 infores:sider not_provided not_provided DRUGBANK:DB00676 UMLS:C2939094 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019087 infores:hetionet CHEBI:4315 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0026821 infores:hetionet CHEBI:63115 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0853697 infores:hetionet NCBIGene:285489 biolink:causes MONDO:0009690 infores:monarchinitiative not_provided not_provided HGNC:26594 MONDO:0009690 uuid:1ac80d2b-2951-453a-be61-95d624801f90 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31547 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0032285 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0012833 infores:hetionet CAID:CA401366487 biolink:causes MONDO:0009290 infores:clingen CAID:CA401366487 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PP3, PM5, PM3 The NM_000152.5:c.1390A>T variant in GAA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 464 (p.Arg464Trp). To our knowledge, this variant has not been reported in the literature in any individuals with Pompe disease and functional studies have not been performed. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.694 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 843677). In summary, this variant meets the criteria to be classified as Uncertain Significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 30, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401366487/MONDO:0009290/010 2025-10-30 2025-10-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CAID:CA2739267618 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267618 MONDO:0011071 PMID: Uncertain Significance PM4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.330_331delinsTT (p.Lys110_Thr111delinsAsnSer) is an in-frame deletion and insertion affects the following hotspot residue within the runt homology domain: K110 (PM4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267618/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144093 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0162429 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0699885 infores:hetionet CHEBI:17549 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0870082 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0015397 infores:hetionet NCBIGene:7156 biolink:causes MONDO:0020845 infores:monarchinitiative not_provided not_provided HGNC:11992 MONDO:0020845 uuid:fde7b245-9733-4ec6-91a5-5914c0a72f2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0427055 infores:hetionet CHEBI:16480 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0518015 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0020557 infores:hetionet CHEBI:9398 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0041657 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0015376 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006892 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0236018 infores:hetionet CHEBI:7852 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011168 infores:hetionet CHEBI:55346 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0344232 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0036572 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0024280 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0162323 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038362 infores:hetionet CHEBI:9570 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0015672 infores:hetionet CHEBI:8805 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0042029 infores:hetionet CHEBI:9943 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0019521 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0017178 infores:hetionet CAID:CA016427 biolink:causes MONDO:0004994 infores:clingen CAID:CA016427 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.5736C>T (p.Ile1912=) variant in the MYH7 gene is 0.36% (72/16512) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016427/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8888 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020550 infores:hetionet CHEBI:63611 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0235710 infores:hetionet NCBIGene:4158 biolink:causes MONDO:0024536 infores:monarchinitiative not_provided not_provided HGNC:6930 MONDO:0024536 uuid:0ac65dce-09bc-4661-aa98-a8c111ccd31c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151838 infores:hetionet CHEBI:7494 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0494475 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0003123 infores:hetionet CHEBI:5864 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0206062 infores:hetionet CHEBI:64310 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0015672 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C2830004 infores:hetionet CHEBI:15553 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0030446 infores:hetionet CHEBI:28901 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0236075 infores:hetionet CHEBI:47781 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0028084 infores:hetionet CAID:CA389475372 biolink:causes MONDO:0100040 infores:clingen CAID:CA389475372 MONDO:0100040 PMID: Likely Pathogenic PP3, PM1, PM5, PM2_Supporting The p.Leu189Val variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). The p.Leu189Val variant in FOXG1 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). A pathogenic missense variant (p.Leu189Phe) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 28661489, GeneDx internal database)(PM5). In summary, the p.Leu189Val variant in FOXG1 is classified as likely pathogenic for a FOXG1-related disorder based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, PM5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389475372/MONDO:0100040/033 2023-04-14 2023-06-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2618 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0085637 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0037274 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0025061 infores:hetionet CHEBI:79699 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151905 infores:hetionet CHEBI:499361 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0233407 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0010692 infores:hetionet CHEBI:63612 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0013404 infores:hetionet CHEBI:79699 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0021845 infores:hetionet CHEBI:28915 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0015230 infores:hetionet CHEBI:6444 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0234458 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0851341 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0235146 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0020649 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0009938 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013298 infores:hetionet GO:1905518 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:1905518 GO:0044085 CHEBI:2904 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0033860 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0349506 infores:hetionet CHEBI:29013 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0151786 infores:hetionet CHEBI:63630 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0232462 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0239302 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0239302 infores:hetionet CHEBI:17650 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0152459 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0025517 infores:hetionet CHEBI:5138 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151474 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0150450 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151736 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0021845 infores:hetionet CHEBI:8888 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085593 infores:hetionet CHEBI:50305 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0037274 infores:hetionet CHEBI:64355 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0542571 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0013604 infores:hetionet CHEBI:8107 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0004604 infores:hetionet CHEBI:50922 biolink:causes MONDO:0019060 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0005967 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0022876 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0022876 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0020517 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0413252 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019112 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009319 infores:hetionet CL:0002576 biolink:causes MONDO:0002547 infores:ubergraph knowledge_assertion manual_agent CL:0002576 MONDO:0002547 CHEBI:68478 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0040259 infores:hetionet CHEBI:2682 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0231835 infores:hetionet CHEBI:63621 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0014591 infores:hetionet CHEBI:9332 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0004134 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0549634 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0549634 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009806 infores:hetionet CHEBI:119915 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003467 infores:hetionet CHEBI:16899 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0242184 infores:hetionet CHEBI:2567 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0026858 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0030567 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020651 infores:hetionet CHEBI:6067 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235710 infores:hetionet UNII:R15UI3245N biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08941 UMLS:C0042963 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0012833 infores:hetionet CHEBI:91541 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0033774 infores:hetionet CAID:CA2695202259 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695202259 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 NM_001034853.2(RPGR):c.2764del (p.Glu922ArgfsTer?) is a frameshift variant due to a 1-nucleotide deletion introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), childhood-onset (1 pt), electroretinogram responses consistent with rod-cone dystrophy (1 pt), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 23681342, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202259/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:63638 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0000731 infores:hetionet CHEBI:5864 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0036980 infores:hetionet CHEBI:47381 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0232462 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0687707 infores:hetionet CHEBI:50859 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030193 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0009450 infores:hetionet CHEBI:7496 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C2830004 infores:hetionet CHEBI:8435 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0085649 infores:hetionet CHEBI:18248 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0020580 infores:hetionet CHEBI:36795 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011168 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0860871 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0860871 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151490 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151490 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0008325 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0948089 infores:hetionet CHEBI:15940 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0033575 infores:hetionet CHEBI:8888 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0015672 infores:hetionet CHEBI:9586 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0025222 infores:hetionet CHEBI:63607 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020615 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0853960 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0853960 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0017178 infores:hetionet CHEBI:78543 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151662 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235832 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235832 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0948089 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0015732 infores:hetionet CHEBI:23765 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0024902 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0042109 infores:hetionet CAID:CA410202459 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202459 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.4:c.508+2T>C variant is a donor splice site variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is downstream of c.98 (PM5_supporting). Two patients reported with this variant in the literature do not meet criteria for PS4 (PMID: 30520015; 29296763). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202459/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9123 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234458 infores:hetionet CHEBI:4562 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0917801 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0021053 infores:hetionet CHEBI:49603 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0851341 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0549374 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0549374 infores:hetionet CHEBI:44915 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0428974 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0020175 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020175 infores:hetionet CHEBI:7936 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018524 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0007785 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0037274 infores:hetionet CAID:CA199433 biolink:causes MONDO:0100040 infores:clingen CAID:CA199433 MONDO:0100040 PMID:22739344PMID:26344814 Pathogenic PP4, PVS1, PS4_Moderate, PM6_Strong, PM2_Supporting The p.Gln86Argfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln86Argfs variant in FOXG1 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with FOXG1 disorder (PMID 22739344, 2634418) (PM6_strong, PP4). This variant has been observed in at least 3 other individuals with FOXG1 disorder (PMID 22739344, 26344814) (PS4_moderate). The c.256delC variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Gln86Argfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199433/MONDO:0100040/016 2021-03-25 2021-05-10 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:46295 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0020649 infores:hetionet CHEBI:3723 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0012691 infores:hetionet CHEBI:3215 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0085610 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0014742 infores:hetionet NCBITaxon:34105 biolink:causes MONDO:0020533 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:34105 MONDO:0020533 CHEBI:15367 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0836924 infores:hetionet CHEBI:15367 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020443 infores:hetionet CHEBI:2682 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0035455 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042769 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0221203 infores:hetionet CHEBI:10023 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0232807 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042109 infores:hetionet CHEBI:9586 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151836 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0349506 infores:hetionet CHEBI:101278 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0035078 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0042373 infores:hetionet CHEBI:3699 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0085393 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0002170 infores:hetionet NCBIGene:2323 biolink:causes MONDO:0975749 infores:monarchinitiative not_provided not_provided HGNC:3766 MONDO:0975749 uuid:4e482b63-a7f7-43a5-a89d-e401cfb13ccc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4779 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0011603 infores:hetionet CHEBI:72323 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0030305 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0948594 infores:hetionet CHEBI:51209 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C2937358 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0235295 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0235295 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0152227 infores:hetionet CHEBI:32315 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0085649 infores:hetionet CHEBI:63791 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085605 infores:hetionet CHEBI:87681 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0020649 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0003864 infores:hetionet CHEBI:9586 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013390 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0227791 infores:hetionet CHEBI:30659 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0042109 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020877 infores:hetionet CAID:CA410207974 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207974 MONDO:0011071 PMID: Likely Pathogenic PM5_Supporting, PM1, PM2_Supporting, PS4_Supporting, PP3 PS3, PS2, PS1, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM3, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.593A>C (p.Asp198Ala) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant affects an amino acid residue within the RHD domain that is defined as a mutational hotspot by the ClinGen MM-VCEP (PM1). The REVEL score is ≥ 0.88 (0.962) (PP3). Two other missense variants (c.593A>T, p.Asp198Val, ClinVar Variation ID 627342 and c.592G>T (p.Asp198Tyr), CA410207975) in the same codon has been classified as likely pathogenic for Hereditary thrombocytopenia and hematologic cancer predisposition syndrome by the ClinGen MMVCEP (PM5_Supporting). This variant has been reported in a proband with AML, meeting RUNX1-phenotypic criteria (PS4_supporting, internal data from PreventionGenetics). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PP3, PM5_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207974/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2636 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0033774 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005561 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003493 infores:hetionet CHEBI:63681 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0030554 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019360 infores:hetionet PUBCHEM.COMPOUND:2350 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04890 UMLS:C0011603 infores:hetionet CHEBI:72564 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0019348 infores:hetionet CAID:CA401369920 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369920 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM5, PM3_Supporting PP4 The NM_000152.5:c.1940G>T variant in GAA is a missense variant predicted to cause substitution of cysteine by phenylalanine at amino acid 647 (p.Cys647Phe). One case identified by newborn screening with documented deficiency of GAA activity has been reported with this variant, but the symptoms are not highly specific for Pompe disease (PMID: 37087815, clinical laboratory data) (PP4 not met). This patient is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G (ClinVar Variation ID: 4027), with unknown phase (PM3_supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.908 which is above the thresholds predicting a damaging (>0.7) evidence that correlates with impact to GAA function (PP3). Another missense variant c.1941C>G (p.Cys647Trp) (ClinVar Variation ID: 550327) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 1219617). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease, based on the specifications of the ClinGen Lysosomal Disease VCEP. GAA-specific ACMG/AMP specifications met, (Specifications Version 2.0): PM5, PM3_supporting, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Feb 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369920/MONDO:0009290/010 2024-02-06 2024-03-26 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:17698 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0027813 infores:hetionet CHEBI:135342 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0040264 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0006988 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0038732 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0003864 infores:hetionet CHEBI:3504 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0033247 infores:hetionet CHEBI:84500 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013604 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028768 infores:hetionet CHEBI:7936 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025323 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020676 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0239511 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0239511 infores:hetionet CHEBI:6149 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0018681 infores:hetionet GO:0021773 biolink:causes CL:1001474 infores:ubergraph knowledge_assertion manual_agent GO:0021773 CL:1001474 CHEBI:4469 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0948089 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0858598 infores:hetionet CAID:CA170245 biolink:causes MONDO:0010726 infores:clingen CAID:CA170245 MONDO:0010726 PMID: Likely Benign BS2 BA1, BP2, BS1, PM2 The p.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID: 12655490) (BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID 12655490); however, it is unknown if the variants are in cis or trans (BP5 - not met). The highest population minor allele frequency of the p.Ser477Thr variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008933 in European (non-Finnish) population (not sufficient to meet BA1, BS1, or PM2 criteria). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Ser477Thr variant in MECP2 (NM_004992.3) is classified as likely benign for Rett syndrome based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170245/MONDO:0010726/036 2024-08-30 2024-11-15 X-linked inheritance HP:0001417 Contradicts true CHEBI:17698 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0011991 infores:hetionet CHEBI:119573 biolink:causes MONDO:0013577 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0398370 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0521495 infores:hetionet CHEBI:63599 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0014742 infores:hetionet NCBITaxon:774 biolink:causes MONDO:0018984 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:774 MONDO:0018984 CHEBI:474180 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020649 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001730 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0156279 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0520893 infores:hetionet CHEBI:75045 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0027441 infores:hetionet CHEBI:8863 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011206 infores:hetionet CHEBI:15854 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0687713 infores:hetionet CHEBI:367163 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020443 infores:hetionet CHEBI:47898 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020672 infores:hetionet CHEBI:7865 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0018681 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0080194 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0004238 infores:hetionet CHEBI:45716 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0006826 infores:hetionet CHEBI:4710 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0034642 infores:hetionet CHEBI:585948 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0023222 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0836924 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0155919 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0456909 infores:hetionet CHEBI:32221 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0014356 infores:hetionet NCBIGene:342618 biolink:causes MONDO:0014830 infores:monarchinitiative not_provided not_provided HGNC:32689 MONDO:0014830 uuid:863f2867-317f-4c41-9848-8d7f41283c80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94440 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0011991 infores:hetionet CHEBI:5790 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0001807 infores:hetionet NCBIGene:84520 biolink:causes MONDO:0030471 infores:monarchinitiative not_provided not_provided HGNC:20356 MONDO:0030471 uuid:bcfa5bdc-ffb1-4569-92b8-010706118842 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0008031 infores:hetionet CHEBI:51380 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0003467 infores:hetionet CAID:CA16024566 biolink:causes MONDO:0021056 infores:clingen CAID:CA16024566 MONDO:0021056 PMID: Likely Benign BS2, BP1, PM2_Supporting PP1, PP4, PM5, PM1, PM3, PM6, BP4, BP2, PS1, PS3, PS4, PS2, BP5, BS3, BS4 The c.1487C>T variant in APC is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 496 (p.Thr496Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in a heterozygous state in 18 unrelated healthy adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, and GeneDX internal data). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2 and BP1 (VCEP specifications version 1.0, date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16024566/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5779 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0948594 infores:hetionet CHEBI:6741 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0035243 infores:hetionet CHEBI:63638 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0003862 infores:hetionet CHEBI:168396 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0013404 infores:hetionet CHEBI:9137 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0036974 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0856882 infores:hetionet CAID:CA10580156 biolink:causes MONDO:0007648 infores:clingen CAID:CA10580156 MONDO:0007648 PMID:29156750 Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.2293C>T (p.Gln765*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000839094.1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580156/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:6456 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0009676 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0239385 infores:hetionet CHEBI:7986 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0423153 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853986 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0151560 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151560 infores:hetionet CHEBI:45599 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0011991 infores:hetionet CHEBI:94501 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0085612 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0400877 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0400877 infores:hetionet CHEBI:6067 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018681 infores:hetionet CHEBI:6067 biolink:causes HP:0012164 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0232766 infores:hetionet GO:0098694 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0098694 GO:0051641 CHEBI:7454 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0392703 infores:hetionet CHEBI:8863 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085631 infores:hetionet CHEBI:8356 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151836 infores:hetionet CHEBI:8888 biolink:causes NCIT:C50611 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235821 infores:hetionet NCBITaxon:91493 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:91493 MONDO:0001867 CHEBI:63631 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0027769 infores:hetionet CAID:CA8603205 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603205 MONDO:0100326 PMID: Likely Benign BP7, BP4 PM2, PP3 The c.1210+8A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of -0.54 (BP4 and BP7). This variant was submitted to ClinVar in one patient with Glanzmann Thrombasthenia. After a thorough literature search, this variant was not found to be reported in any patients with Glanzmann Thrombasthenia. The highest population minor allele frequency in gnomAD v4.0.0 is 0.0006283 (47/74808 alleles) in the African/African American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4, BP7. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603205/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:3752 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0085635 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018799 infores:hetionet CHEBI:3756 biolink:causes HP:0030840 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0238656 infores:hetionet CHEBI:4910 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0242184 infores:hetionet CHEBI:2788 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0043352 infores:hetionet CHEBI:6846 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0012833 infores:hetionet CAID:CA064406 biolink:causes MONDO:0018493 infores:clingen CAID:CA064406 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 1032 of the RYR1 protein, p.(Arg1032His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000206, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.547 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA064406/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6715 biolink:causes MONDO:0004604 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1266194 infores:hetionet CAID:CA386952489 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952489 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3, PP4 PS4, PP1 The c.44C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 15 (p.(A15V)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.879, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the South Asian population and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). Also, this variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). Taken together, this evidence supports the classification of c.44C>T as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PP3, PP4, PM1_Supporting, PM2_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952489/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:171719 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0004936 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020456 infores:hetionet CAID:CA135992 biolink:causes MONDO:0021060 infores:clingen CAID:CA135992 MONDO:0021060 PMID: Likely Benign BP5, BP7, BS1, BP4 PM2, PP3, BA1 The c.510G>A variant in the HRAS gene is a synonymous (silent) variant (p.Lys170=) at a nucleotide that is not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v4.1.0 is 0.02525% (17/44900 alleles) in the East Asian population meeting BS1. This variant has been identified in patients with an alternate molecular basis for disease (BP5; LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000062144.5; SCV000168832.9). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BS1, BP4, BP5, BP7 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135992/MONDO:0021060/046 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:55346 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0236075 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0033975 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0025061 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0687133 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017152 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013395 infores:hetionet NCBIGene:2677 biolink:causes MONDO:0012570 infores:monarchinitiative not_provided not_provided HGNC:4247 MONDO:0012570 uuid:4497827d-9449-4372-a0c6-690b3af3e9e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55689 biolink:causes MONDO:0014055 infores:monarchinitiative not_provided not_provided HGNC:25489 MONDO:0014055 uuid:752dfbc1-1085-47ba-8426-4f1583550efc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:178699 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0002792 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0233569 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0233569 infores:hetionet CHEBI:63631 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0006277 infores:hetionet CHEBI:15551 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0037763 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0038454 infores:hetionet CHEBI:50692 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0017178 infores:hetionet CHEBI:17688 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0027424 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0497247 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0243026 infores:hetionet CHEBI:175901 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0006826 infores:hetionet CHEBI:47898 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151827 infores:hetionet CHEBI:4735 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0278134 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0314719 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0231530 infores:hetionet CHEBI:3347 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0700225 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0342548 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0342548 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0475765 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0475765 infores:hetionet CHEBI:3175 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C3665347 infores:hetionet CHEBI:28787 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0232488 infores:hetionet CHEBI:68478 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0237849 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0012813 infores:hetionet CHEBI:64321 biolink:causes MONDO:0007817 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020523 infores:hetionet CHEBI:45599 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0011603 infores:hetionet CHEBI:15553 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0855775 infores:hetionet CHEBI:9943 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018681 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0178298 infores:hetionet CHEBI:50777 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0025874 infores:hetionet CHEBI:6847 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0015967 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0018799 infores:hetionet CHEBI:63621 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043349 infores:hetionet CHEBI:31705 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0035455 infores:hetionet CHEBI:3011 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0027769 infores:hetionet CHEBI:32315 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0016867 infores:hetionet CHEBI:63630 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0004093 infores:hetionet CHEBI:6532 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0232492 infores:hetionet CHEBI:6078 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0004093 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0029408 infores:hetionet CHEBI:3207 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0016655 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0004238 infores:hetionet UMLS:C1738934 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0231218 infores:hetionet CHEBI:47381 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0423153 infores:hetionet CHEBI:3752 biolink:causes MONDO:0016064 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0008925 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0812387 infores:hetionet CAID:CA343726243 biolink:causes MONDO:0005338 infores:clingen CAID:CA343726243 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, PM5, PP3_Moderate BP7, BS1, BS3, PP1, PM4, PS1, PS4, PS3, PS2, BP4, BA1 The c.761C>G variant in MYOC is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 254 (p.Pro254Arg). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.924, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for juvenile open angle glaucoma (JOAG) (PMID: 26095806), not meeting the ≥ 3 segregations required for PP1. Only 1 proband with JOAG had been reported (PMID: 26095806), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Two other missense variants (c.760C>A, p.Pro254Thr, Grantham score = 38, ClinVar ID: 2429764 and c.761C>T, p.Pro254Leu, Grantham score = 98, ClinVar ID: 1342967) at the same codon have been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.761C>G, p.Pro254Arg variant has a higher Grantham score (= 103) than the previously classified amino acid changes, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5 to apply. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM5, PP3_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726243/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4672 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0033774 infores:hetionet CHEBI:17026 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0232461 infores:hetionet CHEBI:6339 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0036396 infores:hetionet CAID:CA414915806 biolink:causes MONDO:0010602 infores:clingen CAID:CA414915806 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PP3, PS4_Very Strong PM5 The c.1244C>T, p.Ala415Val variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3 - PM2_Supporting). The missense variant has a REVEL score of 0.829 (>0.6 - PP3). At least 27 patients of French origin are reported with moderate-severe hemophilia A in (PMID: 29656491 - PS4_Very strong). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very Strong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414915806/MONDO:0010602/071 2024-12-06 2024-12-06 X-linked inheritance HP:0001417 Supports CHEBI:6402 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0013428 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011609 infores:hetionet CHEBI:5118 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030252 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0009806 infores:hetionet CHEBI:3485 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0085605 infores:hetionet CHEBI:47612 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0038325 infores:hetionet CAID:CA229329 biolink:causes MONDO:0009861 infores:clingen CAID:CA229329 MONDO:0009861 PMID:11139255PMID:11139255 Likely Pathogenic PM3, PM2, PP4, PP3 The c.1069T>G (p.Cys357Gly) variant in PAH has been reported in 1 individual with classic PKU in trans with pathogenic variant p.R176X (PMID: 11139255). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229329/MONDO:0009861/006 2020-06-05 2020-06-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5855 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0033687 infores:hetionet CHEBI:119486 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018965 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0559546 infores:hetionet CHEBI:142290 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0043094 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0042373 infores:hetionet CHEBI:17688 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0233471 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0151773 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0009806 infores:hetionet CAID:CA645373260 biolink:causes MONDO:0007750 infores:clingen CAID:CA645373260 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1 The NM_000527.4(LDLR):c.-142C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met.PP4: Variant meets PM2 and is identified in 1 case with definite FH based on DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille . So PP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA645373260/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:2618 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0012833 infores:hetionet CHEBI:8461 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0002792 infores:hetionet CHEBI:6076 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0852911 infores:hetionet CHEBI:144093 biolink:causes NCIT:C113751 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C2242708 infores:hetionet CHEBI:63630 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0011603 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0034063 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0042571 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0549373 infores:hetionet CHEBI:2639 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0042023 infores:hetionet CHEBI:3478 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0917801 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020517 infores:hetionet CHEBI:10127 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011175 infores:hetionet CHEBI:9907 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0010692 infores:hetionet CHEBI:78543 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151744 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151828 infores:hetionet CHEBI:7577 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013456 infores:hetionet CHEBI:3215 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235032 infores:hetionet CAID:CA000585 biolink:causes MONDO:0017623 infores:clingen CAID:CA000585 MONDO:0017623 PMID: Likely Benign BS1, BP4 PTEN c.801+23G>A (IVS7+23G>A) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0024 (0.24%, 58/24,016 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533)BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000585/MONDO:0017623/003 2018-09-26 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9763 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C3665347 infores:hetionet NCBIGene:3861 biolink:causes MONDO:0010976 infores:monarchinitiative not_provided not_provided HGNC:6416 MONDO:0010976 uuid:d690e20f-4ac7-4242-82ff-b4c4f9cc06f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32588 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0027540 infores:hetionet UNII:R43D2573WO biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020546 infores:hetionet CAID:CA415076058 biolink:causes MONDO:0010305 infores:clingen CAID:CA415076058 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_005629.4(SLC6A8):c.56A>C (p.Lys19Thr) variant in SLC6A8 is a missense variant predicted to cause substitution of Lysine for Threonine at amino acid 19 (p.Lys19Thr). In gnomAD v2.1.1, the highest population minor allele frequency is 0.00012 (1/8552) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), and there are no hemizygotes, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.142 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function. To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:432463). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415076058/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Inconclusive true PUBCHEM.COMPOUND:657309 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0018681 infores:hetionet CHEBI:3403 biolink:causes UMLS:C1963921 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C1963921 infores:hetionet CAID:CA120637 biolink:causes MONDO:0044970 infores:clingen CAID:CA120637 MONDO:0044970 PMID: Pathogenic PP3, PM6_Strong, PM2_Supporting, PS4, PS3_Supporting PP1 The m.10191T>C (p.S45P) variant in MT-ND3 has been reported in at least 30 unrelated individuals with primary mitochondrial disease. Of note, to our knowledge, all reported individuals have been the only affected person in the family. Affected individuals had variable ages of onset (birth to 20s) and outcomes (death in first month of life to alive in 20s at the time of report). Features included Leigh syndrome, MELAS-like syndrome, and Leigh/MELAS overlap, as well as epilepsia partialis continua (EPC) and optic atrophy. Heteroplasmy levels ranged from 13%-100% in affected individuals (PS4; PMIDs: 11456298, 14684687, 15576045, 14705112, 16044424, 16023078, 17535832, 18078792, 19135620, 19617458, 19520270, 20691940, 20226758, 20972245, 22364517, 28429146, 27450679, 30128709, 31261379). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 3% in blood (PMID: 11456298), however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant was seen in the mother’s blood in two other families (36% heteroplasmy in PMID: 16044424; 5% in mother’s blood and undetectable in maternal grandmother’s blood in PMID: 16023078), however no clinical details were provided on these family members to know if they were healthy or affected. There are at least six reports of de novo occurrences of this variant (PM6_strong; PMIDs: 14705112, 18078792, 19520270, 22364517, 27450679). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 14705112). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting, PM6_strong, PS4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120637/MONDO:0044970/015 2022-08-23 2022-09-02 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:63584 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0021843 infores:hetionet CHEBI:3478 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C2830004 infores:hetionet CHEBI:52172 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0000731 infores:hetionet CHEBI:9434 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042023 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0595878 infores:hetionet CHEBI:135005 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0043352 infores:hetionet CHEBI:63621 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0702166 infores:hetionet CHEBI:83531 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C1291077 infores:hetionet NCBITaxon:194924 biolink:causes MONDO:0006708 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:194924 MONDO:0006708 CHEBI:63622 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0010200 infores:hetionet CHEBI:8435 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0009806 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0024115 infores:hetionet CHEBI:2611 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0086565 infores:hetionet CHEBI:44185 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0027497 infores:hetionet NCBITaxon:5661 biolink:causes MONDO:0005445 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5661 MESH:D007898 DB09031_MESH_D007898_1DB00681_MESH_D007898_1 CAID:CA410147789 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147789 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, BA1, BP2, BP7, BS1, BS3, BS4, PVS1, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.1202C>T (p.Pro401Leu) is a missense variant which is completely absent from all population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). In addition, it has a REVEL score <0.50 (0.116) (BP4). To the best of our knowledge, this variant has not been reported in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147789/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0006266 infores:hetionet CHEBI:8412 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0002871 infores:hetionet CAID:CA2580085936 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580085936 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.981del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 328 in (NM_000545.8), adding 14 novel amino acids before encountering a stop codon (p.(Ser328ValfsTer14)). This variant, located in biologically-relevant exon 5 of 10 , is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). In summary, c.981del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580085936/MONDO:0015967/017 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0028738 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0948594 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151500 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151500 infores:hetionet CHEBI:64355 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151594 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151717 infores:hetionet CHEBI:92712 biolink:causes MONDO:0003432 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0038379 infores:hetionet CHEBI:61058 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C1384353 infores:hetionet CHEBI:35778 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0009676 infores:hetionet CHEBI:3127 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0007820 infores:hetionet CHEBI:8364 biolink:causes MONDO:0021107 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0027404 infores:hetionet CHEBI:5855 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0003862 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0033777 infores:hetionet CHEBI:109549 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0013378 infores:hetionet GO:0060617 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:0060617 GO:0030879 CHEBI:31236 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017979 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0042109 infores:hetionet CHEBI:63631 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0004093 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151505 infores:hetionet CHEBI:8502 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0518015 infores:hetionet CHEBI:50777 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0030193 infores:hetionet CAID:CA367401193 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401193 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PP4 The c.659G>T variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to phenylalanine at codon 220 (p.(Cys220Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.658T>C p.Cys220Arg, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.659G>T meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401193/MONDO:0015967/086 2024-01-18 2024-01-18 Semidominant inheritance HP:0032113 Inconclusive true GO:0110159 biolink:causes GO:0000022 infores:ubergraph knowledge_assertion manual_agent GO:0110159 GO:0000022 GO:1903975 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1903975 GO:0007275 CHEBI:16586 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0020649 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0221100 infores:hetionet NCBIGene:89874 biolink:causes MONDO:0032932 infores:monarchinitiative not_provided not_provided HGNC:14411 MONDO:0032932 uuid:3eb7b629-9387-407a-9d11-53b4ae267716 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0497156 infores:hetionet CHEBI:27834 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0042384 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0034186 infores:hetionet CHEBI:45783 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085077 infores:hetionet CHEBI:53760 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151908 infores:hetionet CHEBI:32221 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0042109 infores:hetionet NCBIGene:701 biolink:causes MONDO:0009759 infores:monarchinitiative not_provided not_provided HGNC:1149 MONDO:0009759 uuid:e1d83395-2024-4088-bca0-9aa0cbdea56f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75045 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0024236 infores:hetionet CHEBI:94440 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0018524 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0021053 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0026857 infores:hetionet CHEBI:6741 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C2830004 infores:hetionet CHEBI:6950 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011124 infores:hetionet UMLS:C0657912 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151908 infores:hetionet CHEBI:28864 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0013404 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0042376 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0162429 infores:hetionet CHEBI:4445 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0151905 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0006325 infores:hetionet CHEBI:9605 biolink:causes UMLS:C0860155 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0860155 infores:hetionet CAID:CA255218 biolink:causes MONDO:0010602 infores:clingen CAID:CA255218 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PP3, PS4 The NM_000132.3(F8):c.6744G>T (p.Trp2248Cys) is reported in at least 19 patients with mild, moderate or severe hemophilia A in the literature reviewed (PMID: 17222201, 18691168, 15921397, 1301932, 17610560). There are several additional probands with the variant reported in the EAHAD database, recorded from the literature and unpublished sources. There are also individuals reported with a history of inhibitor development to factor VIII replacement therapy (EAHAD/CDC Champs Databases). The variant is absent from gnomAD v2.1.1 and v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.925 (>0.6), meeting criteria for PP3. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very Strong, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255218/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports NCBIGene:4067 biolink:causes MONDO:0957271 infores:monarchinitiative not_provided not_provided HGNC:6735 MONDO:0957271 uuid:d7dc346e-9fdc-4296-9417-84bc3fdfec48 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0022281 infores:hetionet CHEBI:9241 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0012833 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0162429 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0233414 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0041912 infores:hetionet CHEBI:17141 biolink:causes MONDO:0020324 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0334660 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0151828 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0024117 infores:hetionet CHEBI:135276 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0235063 infores:hetionet CHEBI:36795 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0028734 infores:hetionet CHEBI:9123 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0542571 infores:hetionet CHEBI:6640 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0085628 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0020649 infores:hetionet GO:0060591 biolink:causes CL:0000058 infores:ubergraph knowledge_assertion manual_agent GO:0060591 CL:0000058 CHEBI:16899 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0011175 infores:hetionet CHEBI:63619 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042487 infores:hetionet CHEBI:84500 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1443060 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0019348 infores:hetionet CAID:CA410676172 biolink:causes MONDO:0009276 infores:clingen CAID:CA410676172 MONDO:0009276 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PM5 The NM_000407.5:c.1A>T (p.Met1Leu) variant in GP1BB may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There is no alternative in-frame methionine in GP1BB (PVS1). The Grpmax filtering allele frequency in gnomaDv4.1is 6.800e-7 (based on 3/1176548 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. One heterozygous macrothrombocytopenia patient has been reported with this variant (PMID: 28983057; PS4_NotMet). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1 and PM2_Supporting (VCEP specifications 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA410676172/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44241 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0030193 infores:hetionet CHEBI:8426 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0042109 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0025061 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0033975 infores:hetionet CHEBI:3219 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1260922 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0033860 infores:hetionet CHEBI:8764 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0235996 infores:hetionet CHEBI:17334 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0039070 infores:hetionet CAID:CA306136434 biolink:causes MONDO:0010938 infores:clingen CAID:CA306136434 MONDO:0010938 PMID: Pathogenic PVS1, PM2_Supporting, PM3, PP4 BS3, PS3, PM1 The c.1351C>T (p.Arg451Ter)(NM_000215.4) variant in JAK3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 10/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001150 (1/8692 alleles) in the African/African American population, which is the same as the ClinGen SCID VCEP threshold (<0.0001150 ) for PM2_supporting because this was the variant used to set our PM2 threshold (The most frequently pathogenic variant following SCID VCEP specifications). As the variant is pretty rare in genomes (1/8692) and is not found in exomes PM2 was applied at the supporting level of evidence.Two patients were reported in the literature:* Patient 8: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), SCID gene panel or exome/genome sequencing conducted (0.5pt), T-B+NK- lymphocyte subset profile (0.5pt), total 1.5pt, PP4_Supporting. PMID: 33040328. * Patient 54: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt), SCID gene panel or exome/genome sequencing conducted (0.5pt), T-B+NK- lymphocyte subset profile (0.5pt), total 1.5pt, PP4_Supporting. PMID: 30778343. Both of them were homozygous for the variant: 0.5 pts each, 1 pt total, PM3_moderate. (Patient 8, PMID: 33040328 and Patient 54, PMID: 30778343). Two additional patients were reported on ClinVar with no genetic information available; Confirmed affected status just for one of them.In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM3, PP4, and PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA306136434/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63599 biolink:causes UMLS:C0236151 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0236151 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0014742 infores:hetionet CHEBI:2549 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013447 infores:hetionet CHEBI:6904 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0476273 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0002170 infores:hetionet CHEBI:36791 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0241633 infores:hetionet CHEBI:231425 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0235416 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042131 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0687133 infores:hetionet CHEBI:40303 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0015967 infores:hetionet NCBIGene:79734 biolink:causes MONDO:0014620 infores:monarchinitiative not_provided not_provided HGNC:25705 MONDO:0014620 uuid:93da5a2e-83df-4b08-a825-4b04c6f23a8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0013428 infores:hetionet CHEBI:75045 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0006826 infores:hetionet CHEBI:9599 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0004095 infores:hetionet CHEBI:127780 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0014742 infores:hetionet CHEBI:2682 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0034063 infores:hetionet CHEBI:41774 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151744 infores:hetionet CHEBI:144093 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018965 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0233494 infores:hetionet CHEBI:52717 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0149871 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0022354 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0010037 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0240173 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0240173 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0948089 infores:hetionet CHEBI:8707 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002962 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0002170 infores:hetionet NCBIGene:64840 biolink:causes MONDO:0010592 infores:monarchinitiative not_provided not_provided HGNC:17652 MONDO:0010592 uuid:71ff391f-7ba3-415d-8f81-c6d745886457 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0027813 infores:hetionet CHEBI:3403 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0231528 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0007222 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0011991 infores:hetionet CHEBI:8212 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0026821 infores:hetionet CHEBI:85161 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0042963 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0042401 infores:hetionet CHEBI:48669 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0003862 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0042373 infores:hetionet CHEBI:5893 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0162830 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0020517 infores:hetionet CHEBI:46295 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0002965 infores:hetionet CHEBI:51364 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0043352 infores:hetionet CHEBI:3127 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0151827 infores:hetionet CHEBI:8869 biolink:causes HP:0033331 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0001349 infores:hetionet CHEBI:47898 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0030252 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0262397 infores:hetionet CHEBI:29688 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0231528 infores:hetionet CHEBI:6062 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0851578 infores:hetionet CHEBI:5147 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0035243 infores:hetionet CHEBI:31348 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0242429 infores:hetionet CHEBI:5001 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0014868 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0687133 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0005741 infores:hetionet NCBIGene:64858 biolink:causes MONDO:0859319 infores:monarchinitiative not_provided not_provided HGNC:17641 MONDO:0859319 uuid:a3e102f6-5edd-4eac-ac0e-79a938a08961 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31397 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0031350 infores:hetionet CHEBI:553473 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0011603 infores:hetionet CHEBI:94807 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0522153 infores:hetionet CHEBI:7956 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0009676 infores:hetionet CHEBI:63611 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0851578 infores:hetionet CHEBI:4995 biolink:causes HP:0005518 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0855791 infores:hetionet CHEBI:28593 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0039070 infores:hetionet CHEBI:7936 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0086565 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0854303 infores:hetionet CHEBI:9434 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0206062 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0549475 infores:hetionet CHEBI:63630 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0242301 infores:hetionet NCBIGene:6999 biolink:causes MONDO:0010907 infores:monarchinitiative not_provided not_provided HGNC:11708 MONDO:0010907 uuid:98d301fe-7435-429d-bb17-c1dbe7b5f1bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018772 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0011616 infores:hetionet CHEBI:31515 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0030252 infores:hetionet CAID:CA9301626 biolink:causes MONDO:0010938 infores:clingen CAID:CA9301626 MONDO:0010938 PMID: Uncertain Significance PM2_Supporting BA1, BS1, PS1, PM5, PM1, BS2 NM_000215.4(JAK3):c.2317G>A variant in JAK3 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 773 (p.Val773Ile). The total Grpmax Filtering allele frequency (the upper threshold of the 95% confidence) is 0.00004416 for East Asian chromosomes by gnomeAD v 4.0.0, which is lower than the ClinGen SCID JAK3 VCEP threshold [(<0,000115)] for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been found in ClinVar; however, the affected status of the patient is unknown (VCV000933853.6)This variant does not meet the criteria to be classified as pathogenic, likely pathogenic, benign or likely benign for T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID JAK3 VCEP (PM2_Supporting); therefore is classified as a variant of unknown significance (VUS) for this disease. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9301626/MONDO:0010938/121 2024-02-21 2024-02-21 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:77260 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0851578 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0009450 infores:hetionet CHEBI:44032 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0020443 infores:hetionet CHEBI:68855 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0027765 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0042109 infores:hetionet CHEBI:8207 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0003862 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020624 infores:hetionet CHEBI:68478 biolink:causes UMLS:C3160756 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C3160756 infores:hetionet CAID:CA14089290 biolink:causes MONDO:0044970 infores:clingen CAID:CA14089290 MONDO:0044970 PMID: Benign BA1 The c.1250+188A>G variant in POLG has been reported with an allele frequency in the population of 58% in gnomAD (BA1). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA14089290/MONDO:0044970/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:6413 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0151908 infores:hetionet CAID:CA1020748 biolink:causes MONDO:0021060 infores:clingen CAID:CA1020748 MONDO:0021060 PMID: Uncertain Significance BP4 BS1, PM2, BA1 The NM_002524.5:c.250A>G variant in NRAS is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 84 (p.Ile84Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003870 (5/129184 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.247, which is below the threshold of 0.3, evidence that does not predict a damaging effect on NRAS function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1020748/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50131 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0015672 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0521591 infores:hetionet CHEBI:3696 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0239739 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020621 infores:hetionet CHEBI:31638 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0011991 infores:hetionet CHEBI:36795 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C2981158 infores:hetionet CHEBI:9649 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0022354 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042075 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0010709 infores:hetionet CHEBI:7822 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C1167965 infores:hetionet CHEBI:46195 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C1704272 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0009806 infores:hetionet CAID:CA396457656 biolink:causes MONDO:0007648 infores:clingen CAID:CA396457656 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.457A>T (p.Lys153Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396457656/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0243026 infores:hetionet CHEBI:107736 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0751494 infores:hetionet NCBIGene:79728 biolink:causes MONDO:0012565 infores:monarchinitiative not_provided not_provided HGNC:26144 MONDO:0012565 uuid:9010c5a7-5d3f-4ff2-be20-894547f8f981 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0140433 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0140433 GO:0051321 CHEBI:73274 biolink:causes HP:0012213 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0853068 infores:hetionet GO:0045697 biolink:causes GO:0009561 infores:ubergraph knowledge_assertion manual_agent GO:0045697 GO:0009561 CHEBI:4702 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0009763 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015734 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0026946 infores:hetionet UNII:3U02EL437C biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0600228 infores:hetionet CHEBI:37924 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151517 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004849 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034067 infores:hetionet CAID:CA10585694 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585694 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP1, PP4, BS2 The NM_000527.5(LDLR):c.1952A>T (p.Asp651Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3: REVEL = 0.793. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585694/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true NCBIGene:1427 biolink:causes MONDO:0007284 infores:monarchinitiative not_provided not_provided HGNC:2417 MONDO:0007284 uuid:f288db67-8744-4c6a-a166-1f50e0432e47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70718 biolink:causes UMLS:C0151569 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0151569 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002032 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0699790 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0031117 infores:hetionet CHEBI:77733 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0522055 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0086543 infores:hetionet CHEBI:41423 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C1704272 infores:hetionet CHEBI:7627 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C1291077 infores:hetionet CHEBI:94449 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0016204 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0037274 infores:hetionet CAID:CA024914 biolink:causes MONDO:0018493 infores:clingen CAID:CA024914 MONDO:0018493 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with serine at codon 2787 of the RYR1 protein, p.(Thr2787Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.029867, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024914/MONDO:0018493/012 2021-12-22 2021-12-22 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3419 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0036974 infores:hetionet NCBIGene:51422 biolink:causes MONDO:0009867 infores:monarchinitiative not_provided not_provided HGNC:9386 MONDO:0009867 uuid:9bc4b9ad-2568-4425-b93b-f31330c84971 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16664 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0038325 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003123 infores:hetionet UMLS:C0025241 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0919924 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151883 infores:hetionet CHEBI:63631 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003537 infores:hetionet CHEBI:8107 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0019572 infores:hetionet CHEBI:48273 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0542571 infores:hetionet CHEBI:9435 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0022346 infores:hetionet CHEBI:6741 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0700225 infores:hetionet CHEBI:4653 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0231528 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0232492 infores:hetionet NCBITaxon:5721 biolink:causes MONDO:0002154 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5721 MESH:D014245 DB00916_MESH_D014245_1 CHEBI:63608 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0009782 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004277 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018081 infores:hetionet CAID:CA350015 biolink:causes MONDO:0007648 infores:clingen CAID:CA350015 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM4, PM5, BS2, PP1, PP4, PP2, PP3, BP3, BP1, BP4, PS2, PS4, PS3, PS1 The NM_004360.5(CDH1):c.-71C>G variant has an allele frequency of 0.01628 (1.628%, 251/15418 alleles, 2 homozygotes) in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA350015/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:70746 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0030252 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0009806 infores:hetionet CHEBI:72297 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0030252 infores:hetionet CHEBI:77733 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C1456822 infores:hetionet CHEBI:8378 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0030554 infores:hetionet CHEBI:7494 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0004604 infores:hetionet CHEBI:5864 biolink:causes HP:0002352 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0270612 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0162830 infores:hetionet CHEBI:8863 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030312 infores:hetionet CAID:CA8366036 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366036 MONDO:0100453 PMID: Uncertain Significance PP3 PM5, BS1, PM2 The NM_000180.4(GUCY2D):c.2179G>A (p.Gly727Ser) variant is predicted to replace the glycine at position p.727 with serine. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.0004901, with 791 alleles / 1613966 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. This variant has a Grpmax allele frequency of 0.0005812, with 730 alleles / 1179954 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion as well. The computational predictor REVEL gives a score of 0.695, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function (PP3). The variant has also been identified as a heterozygous occurrence in at least one proband with an alternative basis for retinal disease in the NMNAT1 gene, however, the BP5 code is not applicable due to the absence of a second GUCY2D variant in the proband and the high genetic heterogeneity and limited phenotypic specificities of retinal dystrophies. A different amino acid substitution at this position, NM_000180.4(GUCY2D):c.2180G>A (p.Gly727Asp), has an entry in ClinVar with a classification of likely pathogenic for recessive optic atrophy but would not meet the LCA/eoRD VCEP requirements for GUCY2D-related recessive retinopathy so does not satisfy the requirements for PM5. In summary, this variant meets the criteria to be classified as a VUS for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP3. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366036/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8890 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0014549 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0015376 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027697 infores:hetionet CHEBI:36791 biolink:causes MONDO:0000922 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0242172 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0948089 infores:hetionet CHEBI:6367 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020429 infores:hetionet CHEBI:68579 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0086565 infores:hetionet CHEBI:167309 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0004093 infores:hetionet CHEBI:3061 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0013144 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0017601 infores:hetionet CHEBI:4466 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0004238 infores:hetionet CHEBI:16335 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0039231 infores:hetionet CHEBI:15365 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0020538 infores:hetionet NCBIGene:4438 biolink:causes MONDO:0030975 infores:monarchinitiative not_provided not_provided HGNC:7327 MONDO:0030975 uuid:da7ea890-995e-4d56-9702-ab29d40c6cda biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0002884 infores:hetionet CHEBI:71255 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0027497 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017675 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0041912 infores:hetionet CHEBI:6128 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0011991 infores:hetionet NCBIGene:55857 biolink:causes MONDO:0014345 infores:monarchinitiative not_provided not_provided HGNC:15865 MONDO:0014345 uuid:53afd9b2-8b89-4d0d-ba2d-a22bfe281562 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1302752 infores:hetionet CHEBI:3387 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0002792 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0004936 infores:hetionet CHEBI:8356 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0042029 infores:hetionet CHEBI:41879 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0023380 infores:hetionet CHEBI:46345 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0162834 infores:hetionet CHEBI:5118 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0235660 infores:hetionet UMLS:C1738934 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0149871 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0235567 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0034186 infores:hetionet CHEBI:36791 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022107 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018802 infores:hetionet CHEBI:7773 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C1868752 infores:hetionet CHEBI:17076 biolink:causes HP:0012651 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0877217 infores:hetionet CHEBI:5002 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0027424 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0424000 infores:hetionet CAID:CA286887 biolink:causes MONDO:0700270 infores:clingen CAID:CA286887 MONDO:0700270 PMID: Pathogenic PM3_Strong, PM5_Supporting, PVS1 PS4, BS1, PM2 The c.5290del (p.Leu1764TyrfsTer12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least four individuals with Ataxia-Telangiectasia (PMIDs: 22649200, 10425038, 12552559, 18634022, 15928302, 10330348, 18634022, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001763 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_Strong, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA286887/MONDO:0700270/020 2023-09-15 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63608 biolink:causes MONDO:0015288 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0019357 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0413252 infores:hetionet CHEBI:39669 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0013604 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0019372 infores:hetionet CHEBI:50305 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0234233 infores:hetionet CAID:CA229430 biolink:causes MONDO:0009861 infores:clingen CAID:CA229430 MONDO:0009861 PMID:26503515PMID:28982351PMID:16256386PMID:25456745PMID:23932990 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong This c.1315+4A>G variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in four patients diagnosed with PAH deficiency (PMID: 16256386, 28982351, 25456745, 23932990). This variant is present in the population database gnomAD at a frequency below 0.0002. According to in silico splicing predictions, this alteration is probably damaging (TraP score 0.992). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229430/MONDO:0009861/006 2019-11-05 2019-11-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47780 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040034 infores:hetionet CHEBI:27958 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0020517 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1142412 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0011849 infores:hetionet CHEBI:71417 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0011603 infores:hetionet CHEBI:50305 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0237849 infores:hetionet CHEBI:261649 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0038358 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0014130 infores:hetionet CHEBI:42944 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0233762 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0009450 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0086543 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235750 infores:hetionet CHEBI:49040 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0002994 infores:hetionet CHEBI:42797 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0026827 infores:hetionet CHEBI:63631 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0424295 infores:hetionet CHEBI:27974 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0036974 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0009806 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0262576 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0262576 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027769 infores:hetionet CHEBI:6541 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0850149 infores:hetionet CHEBI:43968 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0023530 infores:hetionet CHEBI:53760 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0151904 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0018799 infores:hetionet CHEBI:64317 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0018790 infores:hetionet CHEBI:3515 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0595916 infores:hetionet NCBIGene:5728 biolink:causes MONDO:0011537 infores:monarchinitiative not_provided not_provided HGNC:9588 MONDO:0011537 uuid:89dc68a5-b39f-4b08-88b6-136c4df924fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17698 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0178298 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004623 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011849 infores:hetionet CHEBI:17026 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0022346 infores:hetionet CHEBI:6717 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0011603 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0037199 infores:hetionet CHEBI:38940 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C1145670 infores:hetionet CHEBI:4798 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020580 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027765 infores:hetionet CHEBI:63577 biolink:causes UMLS:C1142520 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1142520 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0152128 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0948525 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0012833 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0022116 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0037274 infores:hetionet CHEBI:3479 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0030312 infores:hetionet CHEBI:28148 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C1720775 infores:hetionet CHEBI:10119 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0041657 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0025061 infores:hetionet CAID:CA163740 biolink:causes MONDO:0007648 infores:clingen CAID:CA163740 MONDO:0007648 PMID: Benign BS1, BS2 BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, PP1, PP2, PP3, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, PS4 The c.546A>C (p.Lys182Asn) variant has an allele frequency of 0.00104 (>0.1%, 9 out of 8628 alleles) in the East Asian subpopulation of the ExAC cohort (BS1). The variant has also been observed in >10 (56) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000637839.5; SCV000566004.5). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA163740/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:8888 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007642 infores:hetionet CHEBI:15367 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0002792 infores:hetionet CHEBI:7577 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0022281 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C74591 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0234925 infores:hetionet CHEBI:9622 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0002994 infores:hetionet CHEBI:5165 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1262144 infores:hetionet CAID:CA645580182 biolink:causes MONDO:0007648 infores:clingen CAID:CA645580182 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BP5, BP7, BS4, BS1, BS3, PM3, PM1, PM4, PM6, PP4, PP1, PP2, PP3, BS2, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.1733dup p.(Gly579fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000779005.2). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645580182/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:55346 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0750394 infores:hetionet CHEBI:8499 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C1368065 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0002888 infores:hetionet CHEBI:6359 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0037763 infores:hetionet CHEBI:7478 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0030318 infores:hetionet CHEBI:4792 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0160390 infores:hetionet CAID:CA267634 biolink:causes MONDO:0009861 infores:clingen CAID:CA267634 MONDO:0009861 PMID:31332730PMID:21147011PMID:21147011PMID:26666653PMID:23062575 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The c.1196T>C (p.Val399Ala) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded) detected with pathogenic variants P281L, E178G PMID: 21147011, p.R408W PMID: 23062575, c.1066-11G>A PMID: 26666653, parental analysis not performed. This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267634/MONDO:0009861/006 2020-07-10 2020-07-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6062 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0948525 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0037274 infores:hetionet CHEBI:70735 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0234133 infores:hetionet CHEBI:27786 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0013404 infores:hetionet NCBIGene:23299 biolink:causes MONDO:0032660 infores:monarchinitiative not_provided not_provided HGNC:17208 MONDO:0032660 uuid:1d944cbe-5744-425b-a95e-87692cabcbde biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226447 biolink:causes MONDO:0100437 infores:clingen CAID:CA226447 MONDO:0100437 PMID: Pathogenic PS3_Supporting, PP1_Moderate, PP3_Strong, PP4, PM2_Supporting, PS4_Supporting PM5 NM_001034853.2(RPGR):c.823G>A (p.Gly275Ser) is a missense variant predicted to cause substitution of glycine by serine at amino acid 275. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 4 families, with 1 proband exhibiting a family history consistent with X-linked inheritance, functional vision impairment by age 30 years, decreased cone and rod electroretinogram responses, optic disc pallor, attenuation of vessels, pigmentary retinopathy, abnormal autofluorescence, reduced visual acuity, and abnormal color vision, which together are specific for RPGR-related retinopathy (4 points, PMID: 17480003, PP4). This finding has been combined with reports of the variant in at least 2 additional apparently unrelated probands meeting the requirement of some functional vision impairment in affected males by age 30, with decreased or absent cone and/or rod electroretinogram responses (PMID: 17480003, PMID: 16969763, PS4_Supporting). The variant has been reported to segregate with the phenotype through 12 affected meioses in 2 families, meeting the ClinGen X-linked IRD VCEP PP1_Strong requirement of ≥4 meioses in >1 family (PP1_Strong; PMID: 17480003). At least 4 other missense variants at the same codon (p.Gly275Arg, p.Gly275Cys, p.Gly275Val, and p.Gly275Asp) have been reported in association with retinal disease, however, all of them have a higher Grantham score than this variant, so PM5 is not met. The computational predictor REVEL gives a score of 0.968, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_strong). Fluorescence microscopy-based localization assay performed with the p.Gly275Ser mutant and wild-type RPGR exogenously expressed as GFP-fusion proteins by RPE1 cells showed complete loss of localization to the primary cilia (PMID: 30622176). Tag-based RPGR pull-down from HEK293T cells using anti-Flag beads followed by western blotting-based detection of endogenous PDE6D, RPGRIP1L, or INPP5 showed that the mutant had complete loss of interaction with INPP5E and RPGRIP1L, further indicating a damaging effect on protein function (PMID: 30622176; PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PS3_Supporting, PS4_Supporting, PM2_Supporting, PP1_Strong, PP3_Strong, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226447/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Supports UMLS:C0120107 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0151735 infores:hetionet CAID:CA024578 biolink:causes MONDO:0007783 infores:clingen CAID:CA024578 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with arginine at codon 2130 of the RYR1 protein, p.Gly2130Arg. The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000055, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual described as having a malignant hyperthermia (MH) reaction without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4 was not implemented (PMID:18063506). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.894) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024578/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA2579830370 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830370 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1 PP1, PP4 The c.-179T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the promoter region of NM_175914.5. This variant is located within the HNF1A/HNF1B binding region (c.-170 to c.-173 and c.-178 to c.-181) of the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 27552834; internal lab contributors). This variant segregated with diabetes with a single informative meiosis in one family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.-179T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PM1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830370/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0023518 infores:hetionet CHEBI:3125 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0011175 infores:hetionet CAID:CA7511243 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511243 MONDO:0015152 PMID: Likely Pathogenic PP3, PP4, PM3_Strong PM5, PM2 The NM_000070.3: c.1099G>A variant in CAPN3 is a missense variant expected to result in the substitution of glycine with serine at amino acid 367, p.(Gly367Ser). This variant has been identified in at least 7 patients with features consistent with LGMD (PMID: 15689361, 17236769, 25079074, 32403337, 33250842, 34201303; ClinVar SCV000645461.5 internal data communication), including confirmed in trans with a whole gene deletion in one individual (1.0 pt, ClinVar SCV000645461.5 internal data communication) and in unconfirmed phase with a pathogenic variant in two cases (c.759_761del p.(Lys254del), 0.5 pts, PMID: 15689361; c.1322del p.(Gly441ValfsTer22), 0.5 pts, PMID: 34201303) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 allele displayed progressive limb girdle muscle weakness (PP4). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003851 (the upper threshold of the 95% CI of 23/84620 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.955, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/28/2025): PP3, PM3_Strong, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511243/MONDO:0015152/187 2025-10-28 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8481 biolink:causes MONDO:0006527 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0003028 infores:hetionet CHEBI:3698 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0002878 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0008311 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0520821 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0520821 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005077 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0043167 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0877365 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0877365 infores:hetionet CHEBI:27974 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0003467 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020651 infores:hetionet CHEBI:3127 biolink:causes MONDO:0008364 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0034735 infores:hetionet CHEBI:83804 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0023380 infores:hetionet CHEBI:472657 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0155862 infores:hetionet CHEBI:7465 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0015672 infores:hetionet CHEBI:38940 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0030554 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0155169 infores:hetionet CHEBI:2659 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0032617 infores:hetionet CHEBI:8871 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0424295 infores:hetionet CHEBI:63622 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0012359 infores:hetionet PUBCHEM.COMPOUND:3000391 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB05389 UMLS:C0013604 infores:hetionet CHEBI:45783 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0152031 infores:hetionet CHEBI:3077 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0022568 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0021053 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0020538 infores:hetionet CHEBI:4974 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0018681 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0162386 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0162386 infores:hetionet CAID:CA2580616965 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580616965 MONDO:0100437 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.838_842del (p.Phe279_Leu280insTer) is a frameshift variant due to 7-nucleotide deletion which results in a premature stop codon within exon 8 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 17325176, PMID: 21857984; PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616965/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:5893 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0017178 infores:hetionet CAID:CA410147430 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147430 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.947A>G (p.Glu316Gly) is a missense variant which has not been reported in any populations featured in any version of gnomAD, allowing for application of PM2_Supporting. This variant has a SpliceAI score of 0 and a REVEL score of 0.325, allowing for application of BP4. In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147430/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0853619 infores:hetionet CAID:CA410203907 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203907 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.206G>A (p.Gly69Asp) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203907/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0021822 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:0021822 GO:0007417 CHEBI:39585 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0241426 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0151734 infores:hetionet UMLS:C0145867 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0009676 infores:hetionet CHEBI:91583 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0015230 infores:hetionet CHEBI:2639 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0017181 infores:hetionet CHEBI:209807 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0853813 infores:hetionet CAID:CA120633 biolink:causes MONDO:0044970 infores:clingen CAID:CA120633 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate PP4, PS2, PS3, PM6 The m.13042G>A (p.A236T) variant in MT-ND5 has been reported in six unrelated individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and features variably consistent CPEO, LHON, MERRF/MELAS, Leigh-like syndrome (PS4_moderate; PMIDs: 15767514; 17400793; 31996177; 16816025). This variant segregated with disease in a family with LHON as the proband's heteroplasmy was 41% in urine and his affected sister had the variant present at 39% in urine and 91% in muscle. There were unaffected sisters (heteroplasmy levels of 4% and 20% in urine) as well as an unaffected brother with the variant present at 43% urine. In another family, this variant segregated with Leigh syndrome in the proband (heteroplasmy level in in blood was 77%, in muscle was 84%, in fibroblasts was 86%); the healthy mother harbored the variant in hair (25%) and blood (11%); and the proband’s maternal grandmother was found to have the variant at < 2% in blood and between 4-6% in muscle (PP1_moderate, PMIDs: 16816025 17400793). There are no reports of confirmed de novo occurrences to our knowledge. This variant is absent in the Helix dataset and gnomAD v3.1.2, and there is only one occurrence in the GenBank dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.85 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120633/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA1938411 biolink:causes MONDO:0100062 infores:clingen CAID:CA1938411 MONDO:0100062 PMID:31871067PMID:32183904 Benign BP4, BA1, PM1 PS1, PS3, PS2, BS3, PM2, PM6, PM5, PP3 The c.5407G>A variant in SCN3A is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 1803 (p.Asp1803Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01653 (143/8652 alleles) in East Asian population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.0001) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.114, which is below the threshold of 0.183, evidence that does not predict a damaging effect on SCN3A function (BP4_moderate). This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP (PM1). Although there are both pathogenic and benign types of evidence for this variant, the high frequency of this variant in gnomAD strongly supports a benign classification, and the only evidence in support of pathogenicity is based on a prediction that this variant may lie in a mutational hotspot. In summary, this variant meets the criteria to be classified as Benign for autosomal dominant developmental and epileptic encephalopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4, and PM1. (VCEP specifications version 1; 6/27/2023). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1938411/MONDO:0100062/069 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9943 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0019112 infores:hetionet CHEBI:4975 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0026821 infores:hetionet CHEBI:63611 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020473 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027765 infores:hetionet CAID:CA8366285 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366285 MONDO:0100453 PMID: Benign BP4, BA1, BP7, BS2 The intronic variant NM_000180.4(GUCY2D):c.3043+11C>T is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.02165, with 2985 alleles / 124736 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 458 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025) Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366285/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63620 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0233471 infores:hetionet CHEBI:40050 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0231528 infores:hetionet CHEBI:4784 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0013378 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0521839 infores:hetionet CHEBI:70707 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0012833 infores:hetionet NCBIGene:57211 biolink:causes MONDO:0014670 infores:monarchinitiative not_provided not_provided HGNC:13841 MONDO:0014670 uuid:31cc3a45-08e6-4423-9830-539ff764c27f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0013604 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0242350 infores:hetionet CHEBI:16899 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C2047937 infores:hetionet CHEBI:8382 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0151908 infores:hetionet CHEBI:4646 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00449 UMLS:C0039231 infores:hetionet CHEBI:31643 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0042024 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0232462 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0314719 infores:hetionet CHEBI:8378 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0018790 infores:hetionet CHEBI:119573 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C3665596 infores:hetionet CHEBI:9598 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0004093 infores:hetionet CAID:CA229296 biolink:causes MONDO:0009861 infores:clingen CAID:CA229296 MONDO:0009861 PMID:21147011PMID:8659548PMID:21147011 Likely Pathogenic PP3_Strong, PP4_Moderate, PM2_Supporting, PM3_Supporting PM5, BP4 The c.1039C>T (p.Leu347Phe) variant in PAH has been reported twice in patients with PAH deficiency with BH4 deficiency excluded (PMID: 8659548, 21147011) (PP4_Moderate). One of these individuals was homozygous for the variant (PMID: 21147011) (PM3_Supporting). This variant is absent in population databases (PM2_Supporting). Multiple lines of computational evidence support a deleterious effect, including REVEL score 0.951 (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PP4_Moderate, PM3_Supporting, PP3_Strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229296/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10112 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0023895 infores:hetionet CHEBI:6076 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0162830 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0455899 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0455899 infores:hetionet NCBIGene:87 biolink:causes MONDO:0014078 infores:monarchinitiative not_provided not_provided HGNC:163 MONDO:0014078 uuid:15b957c8-6fc4-4e67-be93-3c0c2141e830 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0332575 infores:hetionet CHEBI:9086 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0231528 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0235416 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0235818 infores:hetionet CHEBI:68534 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0031350 infores:hetionet CHEBI:36704 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1384606 infores:hetionet CAID:CA038175 biolink:causes MONDO:0007750 infores:clingen CAID:CA038175 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PP1_Strong, PM2, PP3, PP4 PM3 The NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.853. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill criteria for FH (2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793; 1 case from PMID 27824480). PP1_Strong: Variant segregates with FH phenotype in at least 8 informative meioses from 4 families (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic): 5 affected family members have the variant and 3 unaffected family members do not have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038175/MONDO:0007750/013 2024-07-02 2024-09-19 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ UNII:F64QU97QCR biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0040034 infores:hetionet CHEBI:63622 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0085614 infores:hetionet CHEBI:5855 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0232849 infores:hetionet CHEBI:9571 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0020514 infores:hetionet CHEBI:71417 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0022346 infores:hetionet CHEBI:3127 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013378 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0011609 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0010520 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0007642 infores:hetionet CHEBI:9586 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151827 infores:hetionet CHEBI:5893 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042963 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0242350 infores:hetionet CHEBI:63925 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0013595 infores:hetionet CHEBI:3568 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0009676 infores:hetionet CAID:CA410208133 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208133 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PS4_Supporting, PM2_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP2, BP3, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM3, PM4, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.520A>C (p.Thr174Pro) is a missense variant. This variant is absent from the population database gnomAD v3 (PM2_supporting). Multiple other predictors (Provean, SIFT) predict a deleterious impact (PP3). This variant affects one of the residues (AA 89-204) within the RHD (PM1_Supporting). The variant has been reported in two siblings with thrombocytopenia in childhood with family history of AML in multiple affected family members (PS4_supporting). In summary, this variant meets criteria to be classified as variant of uncertain significant. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting, PP3 and PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208133/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9435 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0009421 infores:hetionet CHEBI:9654 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0019087 infores:hetionet NCBIGene:60528 biolink:causes MONDO:0014190 infores:monarchinitiative not_provided not_provided HGNC:14198 MONDO:0014190 uuid:b06da110-fe28-45f1-b7b0-b7b86b5c1ee3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234913 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0003123 infores:hetionet CAID:CA386296575 biolink:causes MONDO:0009861 infores:clingen CAID:CA386296575 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM3, PP3, PM2_Supporting PM5 The c.684A>C (p.Glu228Asp) variant in PAH is a missense variant in exon 6/13 that is predicted damaging by REVEL (REVEL score 0.688) (PP3_Supporting). It has been previously reported in one individual with PAH deficiency (960μmol/L Phe) with BH4 cofactor deficiency excluded (PMID: 28982351) (PP4_Moderate), who harbored it in trans with the known pathogenic/likely pathogenic variant p.Arg243Gln (ClinVar ID 591) (1pt; PM3_Moderate). A different missense variant at the same site, p.Glu228Lys, is classified as a VUS in ClinVar by the PAH VCEP (ID 120284); thus PM5 is not met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Moderate, PP4_Moderate, PP3_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386296575/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16469 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0343863 infores:hetionet CHEBI:10102 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013390 infores:hetionet CHEBI:48669 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0002962 infores:hetionet CHEBI:167638 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0001824 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0008370 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030305 infores:hetionet NCBIGene:4808 biolink:causes MONDO:0030684 infores:monarchinitiative not_provided not_provided HGNC:7818 MONDO:0030684 uuid:eaa8753b-e9b5-4d44-80e1-ea79c37be09a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020456 infores:hetionet CHEBI:3638 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0014742 infores:hetionet CL:0000071 biolink:causes MONDO:0006500 infores:ubergraph knowledge_assertion manual_agent CL:0000071 MONDO:0006500 CHEBI:4657 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0151578 infores:hetionet CHEBI:4027 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0024305 infores:hetionet CHEBI:119915 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020458 infores:hetionet CHEBI:50567 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0042373 infores:hetionet CHEBI:50777 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0239571 infores:hetionet CHEBI:5864 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0007398 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0042571 infores:hetionet NCBIGene:4700 biolink:causes MONDO:0032636 infores:monarchinitiative not_provided not_provided HGNC:7690 MONDO:0032636 uuid:09421ccc-5877-4a88-abac-6883fce11d52 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042963 infores:hetionet CHEBI:68647 biolink:causes UMLS:C1096303 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C1096303 infores:hetionet CHEBI:2676 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C1384353 infores:hetionet CHEBI:80630 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0917801 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0027562 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027562 infores:hetionet CHEBI:585948 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0018681 infores:hetionet CHEBI:9943 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011606 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0151955 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151955 infores:hetionet CHEBI:17688 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0233794 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0006145 infores:hetionet CHEBI:35778 biolink:causes MONDO:0015294 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1619692 infores:hetionet CHEBI:15765 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0035455 infores:hetionet CHEBI:71255 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0235660 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042109 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0032285 infores:hetionet CHEBI:205919 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0020555 infores:hetionet CHEBI:2659 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0015376 infores:hetionet CAID:CA410203954 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203954 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.193G>C (p.Ala65Pro) is a missense variant in exon 4. This variant has not been observed in any population according to gnomAD (PM2_Supporting). The nucleotide substitution is not predicted to disrupt splicing (SpliceAI score = 0.01). The effect of the amino acid change is uncertain, as the REVEL score of 0.545 falls between 0.5 and 0.88, and functional evidence is not available in the literature for this variant. There are no reported cases. Overall, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203954/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA291224490 biolink:causes MONDO:0100326 infores:clingen CAID:CA291224490 MONDO:0100326 PMID:20020534 Uncertain Significance PS3_Supporting, PP3, PM2_Supporting PM3, PP4 The ITGB3 missense variant NM_000212.3:c.191G>A replaces the cysteine residue with a tyrosine residue (p.Cys64Tyr). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-21 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-15% compared to wild type; PMID: 20020534; PS3_supporting). The variant is also absent from control population databases including gnomADv4.1.0 (PM2_supporting) and predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.981; PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291224490/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true UNII:3QJA87N40S biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0948089 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235876 infores:hetionet GO:0055024 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0055024 GO:0007275 PUBCHEM.COMPOUND:5284632 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0011603 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1384353 infores:hetionet CHEBI:119573 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0029118 infores:hetionet CHEBI:50924 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0085682 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C2225524 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009319 infores:hetionet CHEBI:10125 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0014591 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0235901 infores:hetionet CHEBI:50378 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0011606 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0687133 infores:hetionet NCBIGene:4638 biolink:causes MONDO:0013418 infores:monarchinitiative not_provided not_provided HGNC:7590 MONDO:0013418 uuid:e5c5807d-0629-41f7-acb0-0d6e43025a3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45979 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C1761613 infores:hetionet CHEBI:3216 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0043352 infores:hetionet NCBIGene:84699 biolink:causes MONDO:0859149 infores:monarchinitiative not_provided not_provided HGNC:18855 MONDO:0859149 uuid:cec53158-6e8b-4101-a7b8-d40adeba3101 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66903 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0004093 infores:hetionet CAID:CA10014547 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014547 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP3, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM3, PM1, PM5, PM4, BS2, PP2, PP3, PP1, PP4 The c.351+6G>T variant in RUNX1 is an intronic variant located at a non-conserved nucleotide in intron 4 of NM_001754.5 (BP7); the variant is also known as c.270+6G>T in intron 1 of NM_001001890.3. The results from the in silico splicing predictor SpliceAI supports that this variant does not affect splicing (BP4). The highest population minor allele frequency in gnomAD v2 is 0.01241% (2/16122 alleles) and in gnomAD v3 is 0.009646% (4/41466 alleles) in the African/African American population, and the germline variant has not been reported in patients with the RUNX1-defined phenotype. In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014547/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7494 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0232461 infores:hetionet NCBIGene:207063 biolink:causes MONDO:0975846 infores:monarchinitiative not_provided not_provided HGNC:18399 MONDO:0975846 uuid:9d2059d3-2f63-4751-b3fe-473fccc57ba6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3696 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0006849 infores:hetionet CHEBI:31515 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0011071 infores:hetionet CHEBI:31622 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C2830004 infores:hetionet CHEBI:45327 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0151699 infores:hetionet GO:0140502 biolink:causes GO:0009863 infores:ubergraph knowledge_assertion manual_agent GO:0140502 GO:0009863 NCBITaxon:1213463 biolink:causes MONDO:0003781 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1213463 MESH:D001991 DB00671_MESH_D001991_1 CHEBI:119486 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085649 infores:hetionet CAID:CA10014727 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014727 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS4, BP2, BA1, PVS1, PM6, PM2, BS3, BS4, BS1, PM5, PM1, PM4, PP1, PP3 This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created. In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score: -1.41 < 0.1 [-14.1;6.4]) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014727/MONDO:0011071/008 2020-04-10 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:G4PX8C4HKV biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0392703 infores:hetionet CHEBI:51041 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0039231 infores:hetionet CHEBI:61033 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0028961 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043251 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0236071 infores:hetionet CHEBI:15553 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085624 infores:hetionet CHEBI:45783 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162835 infores:hetionet CAID:CA160111 biolink:causes MONDO:0012163 infores:clingen CAID:CA160111 MONDO:0012163 PMID: Benign BS2_Supporting, BA1 The c.1043A>C (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Asparagine by Threonine at amino acid 348 (p.Asn348Thr).The filtering allele frequency (the lower threshold of the 95% CI of 20801/1179968 alleles) of the c.1043A>C variant in IL7R is 0.01743 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 215 adult homozygous occurrences are described in gnomAD (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160111/MONDO:0012163/119 2024-04-03 2024-04-03 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:32315 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020443 infores:hetionet CHEBI:3215 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0003811 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0031350 infores:hetionet CHEBI:32293 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0005758 infores:hetionet CAID:CA038161 biolink:causes MONDO:0007750 infores:clingen CAID:CA038161 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, PS3, PS4, BS3, PM5, PM1, PP3 The NM_000527.5(LDLR):c.2017A>C (p.Ser673Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows:PM2: PopMax MAF= 0.0000008474 (0.00008474%) in European non-Finnish exomes + genomes (gnomAD v.4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA038161/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:119573 biolink:causes NCIT:C121623 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0221470 infores:hetionet CHEBI:16796 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0038354 infores:hetionet CHEBI:31623 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0271298 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0035204 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030469 infores:hetionet CHEBI:194135 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004093 infores:hetionet CHEBI:2666 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C1443060 infores:hetionet CHEBI:75722 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0221776 infores:hetionet CHEBI:6076 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0004093 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0086543 infores:hetionet CHEBI:4657 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0409974 infores:hetionet CHEBI:171719 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0262988 infores:hetionet CHEBI:50275 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0018524 infores:hetionet CHEBI:35854 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0162830 infores:hetionet CAID:CA367401329 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401329 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PP2, PP3, PP4, PM2_Supporting PM1 The c.619G>T variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 207 (p.(Val207Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.94, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 31063852). This variant segregated with hyperglycemia, with 4 informative meioses in 1 family (PP1_Moderate; PMID: 31063842). In summary, c.619G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Moderate, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401329/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:135736 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0497247 infores:hetionet CHEBI:41774 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C2939186 infores:hetionet CHEBI:5103 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0039621 infores:hetionet CHEBI:27777 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0030252 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0032285 infores:hetionet CHEBI:3698 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0002962 infores:hetionet CHEBI:9241 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0001824 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037822 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0009319 infores:hetionet UMLS:C0004609 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0232292 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0152025 infores:hetionet CHEBI:2567 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0019080 infores:hetionet CHEBI:46295 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0236075 infores:hetionet CHEBI:474180 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1145670 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0007971 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0027769 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0948525 infores:hetionet CL:0002293 biolink:causes MONDO:0006451 infores:ubergraph knowledge_assertion manual_agent CL:0002293 MONDO:0006451 CHEBI:64310 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C3665347 infores:hetionet CHEBI:50275 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0009676 infores:hetionet NCBIGene:2109 biolink:causes MONDO:0009282 infores:monarchinitiative not_provided not_provided HGNC:3482 MONDO:0009282 uuid:5d82fd14-1933-46c6-8143-c79839370bc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0178298 infores:hetionet CHEBI:10125 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233795 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0027051 infores:hetionet CHEBI:32293 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0234632 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042075 infores:hetionet CHEBI:6887 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0003467 infores:hetionet NCBIGene:3008 biolink:causes MONDO:0044323 infores:monarchinitiative not_provided not_provided HGNC:4718 MONDO:0044323 uuid:58c36eda-04ae-4a55-82ab-30bd814d6f9c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017565 infores:hetionet CHEBI:3479 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0004093 infores:hetionet CHEBI:50275 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0220870 infores:hetionet CHEBI:5138 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0549622 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0227791 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0392171 infores:hetionet CHEBI:7789 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C1291078 infores:hetionet CHEBI:7025 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0178298 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0347390 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021359 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013298 infores:hetionet NCBIGene:84188 biolink:causes MONDO:0036212 infores:monarchinitiative not_provided not_provided HGNC:26222 MONDO:0036212 uuid:9a01ed6b-e477-426e-be3b-80aee4749a96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77733 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0151517 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042075 infores:hetionet NCBITaxon:39831 biolink:causes MONDO:0005945 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:39831 MESH:D012226 DB00355_MESH_D012226_1DB01607_MESH_D012226_1DB00479_MESH_D012226_1DB00766_MESH_D012226_1DB00537_MESH_D012226_1DB09324_MESH_D012226_1DB01139_MESH_D012226_1DB02703_MESH_D012226_1DB01060_MESH_D012226_1DB00438_MESH_D012226_1DB01331_MESH_D012226_1DB00415_MESH_D012226_1DB01212_MESH_D012226_1DB01059_MESH_D012226_1DB01112_MESH_D012226_1DB00218_MESH_D012226_1DB01165_MESH_D012226_1DB00684_MESH_D012226_1DB06590_MESH_D012226_1DB00798_MESH_D012226_1DB00319_MESH_D012226_1DB01332_MESH_D012226_1 CHEBI:4909 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0040822 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027339 infores:hetionet CHEBI:5384 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0162830 infores:hetionet CHEBI:7903 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0340865 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018801 infores:hetionet CHEBI:6444 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0012833 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020676 infores:hetionet CHEBI:135736 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1761613 infores:hetionet CHEBI:42944 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0020621 infores:hetionet CHEBI:2611 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0026821 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0521591 infores:hetionet CAID:CA229500 biolink:causes MONDO:0009861 infores:clingen CAID:CA229500 MONDO:0009861 PMID:9634518PMID:8659548PMID:15503242PMID:11328945PMID:19609714PMID:23430918 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting The c.250G>T (p.Asp84Tyr) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant has an extremely low allele frequency (MAF=0.00002) in gnomAD. This variant was detected with multiple pathgenic variants: F39L (PMID:11328945), Y356X (PMID: 15503242), P281L (PMID: 23430918), R158Q (PMID: 19609714) (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.819) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2_supporting, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229500/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2788 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0234632 infores:hetionet CHEBI:29013 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0041834 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0019360 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0032285 infores:hetionet CHEBI:8768 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002962 infores:hetionet CHEBI:8863 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013404 infores:hetionet CHEBI:3127 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0026821 infores:hetionet CHEBI:114785 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0151825 infores:hetionet CHEBI:5001 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027497 infores:hetionet CHEBI:16664 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0002170 infores:hetionet CHEBI:4702 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0030193 infores:hetionet CHEBI:6904 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0857305 infores:hetionet CHEBI:28445 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0080274 infores:hetionet CHEBI:3654 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0001824 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0232431 infores:hetionet CHEBI:82960 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C3665347 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0042109 infores:hetionet CHEBI:134966 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0040822 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0162429 infores:hetionet CHEBI:9445 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C3665347 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0086543 infores:hetionet CHEBI:71417 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0003962 infores:hetionet CHEBI:63629 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0085631 infores:hetionet CHEBI:63631 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151474 infores:hetionet CHEBI:127780 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0041969 infores:hetionet CHEBI:135679 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0015672 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0021400 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0851536 infores:hetionet CAID:CA410146616 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146616 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1426G>A (p.Val476Met) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146616/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135876 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0011991 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0006849 infores:hetionet CHEBI:7852 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151740 infores:hetionet CAID:CA409106723 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106723 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4, PS4 The c.583G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to methionine at codon 195 (p.(Val195Met)) of NM_175914.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.819, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 and so PP4 cannot be applied (internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (Internal lab contributors). In summary, c.583G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 4.0.0, approved 10/10/2025): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106723/MONDO:0015967/085 2025-10-28 2025-10-28 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:231594 biolink:causes MONDO:0021050 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042258 infores:hetionet CHEBI:6073 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C2047937 infores:hetionet CHEBI:2948 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0002888 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0037274 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0162429 infores:hetionet CHEBI:119915 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085628 infores:hetionet CHEBI:4903 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0015967 infores:hetionet CHEBI:8356 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0497156 infores:hetionet CHEBI:50729 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0017181 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0948349 infores:hetionet CHEBI:478164 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0034186 infores:hetionet UMLS:C0657912 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0242528 infores:hetionet CHEBI:5134 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0006266 infores:hetionet CHEBI:4708 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0017181 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0162429 infores:hetionet CHEBI:63630 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0015230 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151734 infores:hetionet CHEBI:8874 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0018932 infores:hetionet CHEBI:7496 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0012833 infores:hetionet CHEBI:31236 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0558401 infores:hetionet CHEBI:47780 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020555 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0007114 infores:hetionet CHEBI:9570 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0004604 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235329 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235329 infores:hetionet CHEBI:9139 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0030252 infores:hetionet CHEBI:10119 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0152030 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0042571 infores:hetionet CHEBI:204928 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0019158 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0011991 infores:hetionet CHEBI:15553 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0004604 infores:hetionet CAID:CA226109 biolink:causes MONDO:0100453 infores:clingen CAID:CA226109 MONDO:0100453 PMID: Pathogenic PM3_Strong, PVS1, PP1, PM2_Supporting The NC_000017.11:g.8015503del variant has been published as NM_000180.4(GUCY2D):c.2944+1del and NM_000180.4(GUCY2D):c.2943del, and is the result of the deletion of a base at the exon15/intron 15 junction. This variant disrupts the canonical splice site and is predicted to lead to skipping of a critical exon, resulting in a frameshift. This frameshift is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.0002241, with 361 alleles / 1,610,570 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). It has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 12325031, 39244273). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg768Trp variant confirmed in trans (1 point, PMID: 39244273), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP. This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Val989Leu variant confirmed in trans (not counted), which has not been classified by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PP1; PMID: 12325031). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3_Strong, PM2_Supporting, PP1. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226109/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16469 biolink:causes UMLS:C0542243 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0542243 infores:hetionet GO:2000387 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0007275 CHEBI:408174 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0035243 infores:hetionet CHEBI:2682 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151539 infores:hetionet CHEBI:38940 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0333355 infores:hetionet CHEBI:5123 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0011606 infores:hetionet CHEBI:3082 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0007398 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0242891 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0242891 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0027813 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0855242 infores:hetionet CHEBI:567361 biolink:causes MONDO:0002321 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0151313 infores:hetionet CHEBI:45863 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0333355 infores:hetionet CHEBI:41879 biolink:causes MONDO:0018373 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0027543 infores:hetionet CAID:CA10642026 biolink:causes MONDO:0012996 infores:clingen CAID:CA10642026 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting The NM_001482.3:c.*104A>G variant is a single nucleotide substitution in the 3'UTR of GATM. To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence, and SpliceAI predicts no impact on splicing. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000004811 (2/415744 alleles) in the European non-Finnish population. This is below the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 316208). In summary, this variant meets the criteria to be classified as uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on October 7, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10642026/MONDO:0012996/025 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8888 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0278106 infores:hetionet GO:0044494 biolink:causes GO:0005248 infores:ubergraph knowledge_assertion manual_agent GO:0044494 GO:0005248 CHEBI:75045 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0003862 infores:hetionet CHEBI:127780 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151905 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0042109 infores:hetionet NCBIGene:56978 biolink:causes MONDO:0014717 infores:monarchinitiative not_provided not_provided HGNC:13993 MONDO:0014717 uuid:17635933-e898-49c9-9e8e-2761250ee5ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68647 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0018681 infores:hetionet NCBIGene:9573 biolink:causes MONDO:0013376 infores:monarchinitiative not_provided not_provided HGNC:4218 MONDO:0013376 uuid:7064d415-63f7-4293-ae86-deaa5ffe0f2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA044382 biolink:causes MONDO:0007750 infores:clingen CAID:CA044382 MONDO:0007750 PMID: Uncertain Significance BP4 BA1, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.694+25C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA044382/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:64355 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0009806 infores:hetionet NCBIGene:94137 biolink:causes MONDO:0013316 infores:monarchinitiative not_provided not_provided HGNC:15946 MONDO:0013316 uuid:be527f93-7be8-4923-b26c-476107d9353c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7478 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0015230 infores:hetionet NCBIGene:865 biolink:causes MONDO:0859307 infores:monarchinitiative not_provided not_provided HGNC:1539 MONDO:0859307 uuid:f8289387-efa9-4998-b7b1-85e20322ac24 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6073 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0018681 infores:hetionet CHEBI:8435 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0686347 infores:hetionet CHEBI:43968 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0032227 infores:hetionet CAID:CA913179793 biolink:causes MONDO:0044970 infores:clingen CAID:CA913179793 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PP3 PM5, PP1, PP4, PS2, PS4, PVS1 The m.5538G>A variant in MT-TW was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in three affected individuals in two families (PMID: 20708751, PMID: 29043143), however haplogroups were not provided as necessary to apply PS4_supporting. No instances of de novo inheritance have been reported. There has been only one report of multiple family members with this variant and only mother and proband were reported although variant heteroplasmy load did correlate with symptoms in proband and mother (PMID: 20708751). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 76.70%, as does HmtVar with a score of 0.75 (PP3). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. While this variant is reported in three affected individuals, absent from population databases, and predicted to effect tRNA function, additional evidence of pathogenicity is not yet present. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913179793/MONDO:0044970/014 2021-10-26 2021-10-26 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63577 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0231218 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0235032 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0525045 infores:hetionet CHEBI:6149 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0018794 infores:hetionet CHEBI:36791 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549249 infores:hetionet CHEBI:53760 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0497156 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0221203 infores:hetionet CHEBI:16335 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0541782 infores:hetionet CAID:CA228340 biolink:causes MONDO:0015631 infores:clingen CAID:CA228340 MONDO:0015631 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3 The NM_000552.4(VWF):c.2435C>T (p.Pro812Leu) variant in VWF is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 812. 1 case has been reported with proposed type 1/2N VWD however insufficient information was provided to meet PP4 (PMID: 17681836). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0004081 (based on 48/91064 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.005 (PM2_Supporting). The computational predictor REVEL gives a score of 0.668, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive type 2N VWD. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_Supporting, PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228340/MONDO:0015631/090 2024-07-09 2024-08-12 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:27148 biolink:causes MONDO:0030332 infores:monarchinitiative not_provided not_provided HGNC:17209 MONDO:0030332 uuid:7f0cedc2-029d-413c-8bdf-fddc979ba4e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004093 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027813 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0014549 infores:hetionet CHEBI:15552 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0235710 infores:hetionet CHEBI:63621 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0027497 infores:hetionet CHEBI:15367 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0029089 infores:hetionet UMLS:C0879264 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0003578 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0006145 infores:hetionet GO:0060617 biolink:causes GO:0071696 infores:ubergraph knowledge_assertion manual_agent GO:0060617 GO:0071696 NCBIGene:10020 biolink:causes MONDO:0011603 infores:monarchinitiative not_provided not_provided HGNC:23657 MONDO:0011603 uuid:20703bc3-7c83-4336-b2b5-bd71437e8ff5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0428977 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0036572 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0424000 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014742 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0349506 infores:hetionet CHEBI:8874 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0033774 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018799 infores:hetionet CHEBI:7865 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0042075 infores:hetionet CHEBI:52172 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0041364 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042109 infores:hetionet CHEBI:4027 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0151934 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0677500 infores:hetionet CHEBI:27834 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0002962 infores:hetionet CHEBI:2379 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0030554 infores:hetionet CHEBI:10023 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0019079 infores:hetionet CHEBI:4887 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0013144 infores:hetionet CAID:CA214288 biolink:causes MONDO:0015967 infores:clingen CAID:CA214288 MONDO:0015967 PMID: Likely Benign BS3_Supporting, BS1, PP4 PS4, PM2, PP3 The c.1745A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to arginine at codon 582 (p.(His582Arg)) of NM_000545.8. This variant has a REVEL score of 0.6869, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function, and functional studies demonstrated the p.His582Arg protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003916, which is greater than or equal to the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in at least 3 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar ID 36811, PMID: 27913849, PMID: 23624530, PMID: 23348805, internal lab contributor). One individual has a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgment applied given that the individual was diagnosed before age 30 with a non-obese BMI, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4). In summary, the c.1745A>G variant meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2, approved 8/4/2022): PP4, BS1, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214288/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17026 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0231528 infores:hetionet CHEBI:66876 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0006145 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0013612 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0013612 uuid:aba8ccb3-a452-4441-9a91-7bd052e27ff0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0575081 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022568 infores:hetionet CHEBI:3125 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C0018681 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151605 infores:hetionet UMLS:C0657912 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151579 infores:hetionet CHEBI:474053 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C1320835 infores:hetionet CHEBI:9586 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0220870 infores:hetionet CHEBI:3640 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0014518 infores:hetionet GO:0005813 biolink:causes GO:0090222 infores:ubergraph knowledge_assertion manual_agent GO:0005813 GO:0090222 CHEBI:7494 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0017675 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0392197 infores:hetionet GO:1902869 biolink:causes GO:0060041 infores:ubergraph knowledge_assertion manual_agent GO:1902869 GO:0060041 CHEBI:49040 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0919715 infores:hetionet CHEBI:63621 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0004604 infores:hetionet CHEBI:92769 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0018681 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0013928 infores:hetionet CHEBI:64028 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0234133 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0948594 infores:hetionet CHEBI:63611 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085631 infores:hetionet CHEBI:52717 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0919924 infores:hetionet CHEBI:132233 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0027769 infores:hetionet CHEBI:15544 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0240717 infores:hetionet CHEBI:55346 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0009782 infores:hetionet CHEBI:45327 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0085614 infores:hetionet CHEBI:6129 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151603 infores:hetionet CHEBI:9757 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0259799 infores:hetionet CHEBI:8863 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0086565 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0038454 infores:hetionet CHEBI:63637 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0151662 infores:hetionet CHEBI:567361 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0010200 infores:hetionet CHEBI:5165 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0006277 infores:hetionet CHEBI:8713 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0035078 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0041912 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151849 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0948349 infores:hetionet CHEBI:94686 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0404521 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234215 infores:hetionet CHEBI:9907 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0702166 infores:hetionet CHEBI:18332 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0042963 infores:hetionet CHEBI:9613 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0022354 infores:hetionet CHEBI:4653 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0004245 infores:hetionet CHEBI:3756 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0038999 infores:hetionet CHEBI:135961 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0043352 infores:hetionet CHEBI:135736 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0239783 infores:hetionet NCBIGene:5324 biolink:causes MONDO:0030118 infores:monarchinitiative not_provided not_provided HGNC:9045 MONDO:0030118 uuid:486c5e52-9906-40fe-a309-15eea4379b48 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135566 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0161479 infores:hetionet CHEBI:15854 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0023530 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038454 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0855242 infores:hetionet CAID:CA16020952 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020952 MONDO:0009861 PMID:17557229PMID:26503515 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1159T>G (p.Tyr387Asp) variant in PAH has been reported in 3 individuals with mild and classic PKU (BH4 deficiency excluded, PMID: 17557229, 26503515), detected in trans with pathogenic variants: p.Y356*; p.R413P; p.R261Q (PMID: 30050108). This variant is absent in population databases. Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020952/MONDO:0009861/006 2020-08-10 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CAID:CA397394869 biolink:causes MONDO:0100438 infores:clingen CAID:CA397394869 MONDO:0100438 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3 NM_014336.5(AIPL1):c.815G>C (p.Arg272Pro) is a missense variant predicted to replace arginine with proline at amino acid p.272. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.4:c.(?_-1)_(276+1_277-1)del variant suspected in trans (0.25 points, PMID: 30718709), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP. The variant has also been reported in a second proband with early-onset severe retinal dystrophy who was heterozygous with no second AIPL1 variant identified in trans (PMID: 26626312). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by next-generation sequencing panel targeting more than 150 inherited retinal disease-associated genes (2 pts), which together are not sufficiently specific for AIPL1-related retinopathy to meet PP4 (total 2.5 points, PMID: 30718709). The computational predictor REVEL gives a score of 0.692, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function (PP3). The splicing impact predictor SpliceAI gives a score of 0.02 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397394869/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA414891065 biolink:causes MONDO:0010602 infores:clingen CAID:CA414891065 MONDO:0010602 PMID: Uncertain Significance PM2_Supporting, BP4 BP7 The c.6429_10901G>A variant is absent from males in gnomAD v2.1.1/v3.1 meeting PM2_Supporting. This intronic variant is predicted by Splice AI to have no impact on splicing meeting BP4; however, the nucleotide is conserved based on agreement between PhyloP (1.6) and PhastCons (0.0561) scores greater than the thresholds 0.1 and 0.5 respectively. In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM2_Supporting, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414891065/MONDO:0010602/071 2025-10-03 2025-10-07 X-linked inheritance HP:0001417 Inconclusive true CHEBI:45863 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0152227 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0687707 infores:hetionet CHEBI:4856 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0006266 infores:hetionet CHEBI:9587 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0015230 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005258 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1510586 infores:hetionet CHEBI:6741 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0018926 infores:hetionet CHEBI:8232 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151786 infores:hetionet CHEBI:6950 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0004134 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018799 infores:hetionet CHEBI:8481 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C1443060 infores:hetionet GO:0034243 biolink:causes GO:0006366 infores:ubergraph knowledge_assertion manual_agent GO:0034243 GO:0006366 CAID:CA2499224898 biolink:causes MONDO:0008723 infores:clingen CAID:CA2499224898 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4(ACADVL): c.388del (p.Glu130Argfs*87) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated November 16, 2021 and the recurated classification was approved by the expert panel on February 27, 2024. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499224898/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63617 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0232849 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1142034 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1142034 infores:hetionet CAID:CA5950404 biolink:causes MONDO:0000573 infores:clingen CAID:CA5950404 MONDO:0000573 PMID: Likely Benign BS1, BS2_Supporting PP4, PM3, BS3 The NM_000536.4(RAG2):c.1504A>G (p.Met502Val) variant has been reported in one individual with SCID, and two individuals with Omenn Syndrome. In two of those cases, the variant has been reported in cis with the likely pathogenic RAG1 variant p.Met435Val in one patient with SCID and one patient with Omenn syndrome (PMIDs:19178939 and 26457731). In the remaining patient with Omenn Syndrome, the variant was reported with another VUS RAG2 variant p.Ser160Leu, phasing unspecified (PMID:16960852, PM3 not met). This patient met diagnostic criteria for Omenn syndrome but genome sequencing was limited only to RAG1 and RAG2 genes (PP4 not met). Additionally, the variant has recombination activity equivalent to WT (99.6%) from PMID:29772310 (functional activity not considered by this VCEP, BS3 not met). The variant has a popmax filtering allele frequency of 0.007669 in the European (Finnish) population, which is greater than 0.00195 and thus meets BS1. The variant is observed in the homozygous state 6 times in gnomAD v4.1.0 (BS2). In summary, this variant meets the criteria to be classified as likely benign for recombinase activating gene 2 deficiency based upon the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BS1 and BS2 (VCEP specifications version 2). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5950404/MONDO:0000573/124 2025-09-26 2025-09-26 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:11431811 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0023222 infores:hetionet CHEBI:63581 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020458 infores:hetionet CHEBI:74947 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020598 infores:hetionet CAID:CA320249943 biolink:causes MONDO:0011071 infores:clingen CAID:CA320249943 MONDO:0011071 PMID: Likely Benign BP4, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS3, BS4, BP5, BP7, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*1788A>G is an intronic variant which has a MAF of 0.001389 (0.1389%, 23/16564, 23 alleles) in the East Asian subpopulation of the v4.0.0 gnomAD cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This synonymous variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320249943/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28593 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0042790 infores:hetionet CAID:CA024673 biolink:causes MONDO:0018493 infores:clingen CAID:CA024673 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with aspartic acid at codon 2344 of the RYR1 protein, p.(Glu2344Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode but without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4 was not implemented (PMID:16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.657 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024673/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:50924 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0014518 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0026946 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0038450 infores:hetionet CHEBI:39867 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0023218 infores:hetionet NCBIGene:3590 biolink:causes MONDO:0013615 infores:monarchinitiative not_provided not_provided HGNC:5967 MONDO:0013615 uuid:4dfb01f6-7cbb-4ab6-a3f5-4d7d6259e9d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0231528 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0003864 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0026848 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029443 infores:hetionet CHEBI:46345 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0423791 infores:hetionet CHEBI:17141 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0011603 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0235969 infores:hetionet CHEBI:15551 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0042267 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0948089 infores:hetionet CHEBI:51380 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0043387 infores:hetionet CHEBI:5558 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0040822 infores:hetionet CAID:CA229269 biolink:causes MONDO:0009861 infores:clingen CAID:CA229269 MONDO:0009861 PMID:21147011PMID:7913581PMID:16601866PMID:7913581 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PM5, PP3 The c.1012G>T (p.Asp338Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 27121329, PMID: 21147011). This variant has an extremely low allele frequency in gnomAD (MAF=0.00002). This variant was detected with multiple pathogenic variants: p.P281L (PMID: 16601866); p.F299C (PMID: 7913581); p.I65T (PMID: 17502162); c.1066-11G>A (PMID: 31623983); p.Arg261*, p.Phe55Leu (PMID: 26655635). Multiple lines of computational evidence do not agree on predicted pathogenicity (Deleterious in SIFT, PolyPhen, Polymorphism in MutationTaster). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229269/MONDO:0009861/006 2020-11-09 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31949 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0020651 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0948586 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020580 infores:hetionet CAID:CA000442 biolink:causes MONDO:0017623 infores:clingen CAID:CA000442 MONDO:0017623 PMID:23335809PMID:23160955PMID:23335809PMID:28250423PMID:29785012PMID:21828076PMID:29706350PMID:23160955PMID:23335809PMID:28250423PMID:23160955PMID:23335809 Pathogenic PM2, PP2, PM6_Strong, PS3, PS4_Moderate PVS1, BP5, BP7, BS4, BS3, BS1, PP1, PP4, PP3, BS2, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS1 PTEN c.392C>T (p.Thr131Ile) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID 23160955, 23335809 author communication)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 23160955, 23335809)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000442/MONDO:0017623/003 2018-11-28 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:152137 biolink:causes MONDO:0011832 infores:monarchinitiative not_provided not_provided HGNC:18111 MONDO:0011832 uuid:3fdc873f-02ee-45be-8de9-2bb3cae2f526 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42355 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0086565 infores:hetionet NCBIGene:84816 biolink:causes MONDO:0020737 infores:monarchinitiative not_provided not_provided HGNC:18647 MONDO:0020737 uuid:1d25ed0e-fb05-4a14-9e81-43752cb186b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63681 biolink:causes NCIT:C121623 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0221470 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0038358 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0014130 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0007642 infores:hetionet CHEBI:37941 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0002962 infores:hetionet CHEBI:9086 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085632 infores:hetionet CHEBI:2038 biolink:causes MONDO:0015692 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0280028 infores:hetionet CHEBI:3013 biolink:causes HP:0003127 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0020599 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0017152 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0021400 infores:hetionet CHEBI:75246 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C1321898 infores:hetionet CAID:CA233935 biolink:causes MONDO:0015152 infores:clingen CAID:CA233935 MONDO:0015152 PMID: Likely Benign BP4, BP7_Strong PM3, BP2, PM2 The NM_003494.4: c.3702T>C p.(Tyr1234=) variant in DYSF, which is also known as NM_001130987.2: c.3756T>C (p.Tyr1252=), is a synonymous (silent) variant that affects the last nucleotide of exon 33. The SpliceAI prediction score for this variant is 0.00 (BP4), and RNASeq data showed this variant does not affect splicing (PMID: 36983702; BP7_Strong_RNA). This variant has been identified in three individuals with suspected LGMD, all with at least two additional DYSF variants including those classified as pathogenic. However, phase was not known in any of these individuals (PMID: 18853459, 36983702; PM3 and BP2 not met). The Grpmax variant allele frequency for this variant in gnomAD v4.1.0 is 0.0005834 (35/59994 Admixed American chromosomes), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). This population also includes one homozygous individual. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/29/2025): BP4, BP7_Strong_RNA. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA233935/MONDO:0015152/180 2025-10-29 2025-11-11 Autosomal recessive inheritance HP:0000007 Contradicts true NCBIGene:23114 biolink:causes MONDO:0032698 infores:monarchinitiative not_provided not_provided HGNC:29866 MONDO:0032698 uuid:874e9e55-e6b8-45b6-9f9f-d733b9b52052 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0040435 infores:hetionet GO:1905079 biolink:causes GO:0021549 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0021549 CHEBI:68647 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0030193 infores:hetionet CHEBI:9137 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0043352 infores:hetionet CHEBI:61049 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0522224 infores:hetionet CHEBI:49375 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0017181 infores:hetionet CHEBI:6904 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0043352 infores:hetionet CHEBI:51032 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0018681 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0020649 infores:hetionet CHEBI:231594 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0002453 infores:hetionet CAID:CA8129842 biolink:causes MONDO:0007648 infores:clingen CAID:CA8129842 MONDO:0007648 PMID: Likely Benign BS2, BP4 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS1, PS3, PS2, PS4 c.387+6T>C is an intronic variant in the splice donor region of intron 3. This variant has an allele frequency of 0.0001 (5/34548 alleles) in the gnomAD v2.1 Latino/admixed American sub-population (http://gnomad.broadinstitute.org). This variant has been reported in at least 13 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000637825.4). This variant is predicted to have no impact on splicing by multiple in silico splice site predictors (BP4; SpliceAI, varSEAK, MaxEntScan). In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA8129842/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7852 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0026826 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0151505 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0030312 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0027769 infores:hetionet CHEBI:8888 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1141861 infores:hetionet CHEBI:4877 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0232462 infores:hetionet CHEBI:7640 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0242350 infores:hetionet CHEBI:31644 biolink:causes MONDO:0004822 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0006267 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0178298 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0851341 infores:hetionet CHEBI:39585 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0151539 infores:hetionet CHEBI:63611 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003578 infores:hetionet CHEBI:116735 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0013404 infores:hetionet CHEBI:51450 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0018989 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042075 infores:hetionet CHEBI:421707 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0023530 infores:hetionet CHEBI:31302 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0162429 infores:hetionet CHEBI:3561 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0152198 infores:hetionet CAID:CA386972011 biolink:causes MONDO:0015967 infores:clingen CAID:CA386972011 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3, PP1 PS4, PM5 The c.1576G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to tyrosine at codon 526 (p.(Asp526Tyr)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9729, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18003757, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in two families (PP1; PMID: 18003757; internal lab contributors). Another missense variant, c.1576G>A (p.(Asp526Asn)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1576G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PP1, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386972011/MONDO:0015967/017 2025-08-25 2025-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:85078 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042029 infores:hetionet CHEBI:63620 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0022568 infores:hetionet CHEBI:63611 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020443 infores:hetionet CAID:CA383499032 biolink:causes MONDO:0019565 infores:clingen CAID:CA383499032 MONDO:0019565 PMID: Uncertain Significance PM2_Supporting, PM5 PP3 The NM_000552.5(VWF):c.4826G>A variant in VWF is a missense variant predicted to cause substitution of glycine by glutamate at amino acid 1609. This variant is absent from gnomAD v4.1 (PM2_Supporting). Another missense variant NM_000552.5:c.4825G>A (p.Gly1609Arg) in the same codon has been classified as pathogenic for VWD by the ClinGen VWD VCEP (PM5). Splicing prediction using SpliceAI revealed no expected effects on splicing due to either of these variants. There is a single case reported to ClinVar with this variant and to be affected however no clinical details were provided. This variant was also not found in any publication or the LOVD database. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM2_Supporting, PM5_Supporting. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383499032/MONDO:0019565/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28748 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0023380 infores:hetionet CHEBI:15553 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0019521 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0857353 infores:hetionet CHEBI:9588 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0013395 infores:hetionet CHEBI:8346 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0035455 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1263960 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1263960 infores:hetionet CHEBI:63577 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0037278 infores:hetionet CHEBI:39867 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C2830004 infores:hetionet CHEBI:2663 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042487 infores:hetionet CHEBI:3403 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0042420 infores:hetionet CHEBI:4910 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0042963 infores:hetionet CHEBI:3082 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0040053 infores:hetionet UMLS:C0010592 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0151827 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030305 infores:hetionet CAID:CA320648446 biolink:causes MONDO:0100083 infores:clingen CAID:CA320648446 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BA1, PVS1, PM6, BS1, BS3, BS4, PM5, PM4, PM1, PP1, PP4, BS2 NM_001754.5(RUNX1):c.97+12T>C is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This intronic variant has a SpliceAI ∆ score ≤ 0.20 and PhyloP score <2.0 (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320648446/MONDO:0100083/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2659 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0000737 infores:hetionet CHEBI:4636 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0040034 infores:hetionet CHEBI:71417 biolink:causes MONDO:0008364 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0034734 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0004604 infores:hetionet CHEBI:27974 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0013395 infores:hetionet CAID:CA658658531 biolink:causes MONDO:0008723 infores:clingen CAID:CA658658531 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 The c.138+2dup (NM_000018.4) variant in ACADVL is an intronic variant which is located in intron 2 close to a donor splice site. This variant is absent from GnomAD v2.1.1 (PM2_Supporting). The results from three in silico splicing predictors (SpliceSiteFinder, MaxEntScn, and SpliceAI [donor loss = 0.59]) indicate that this variant may affect splicing by disrupting the donor splice site of intron 2 of ACADVL (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658531/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:16586 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0853813 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0025061 infores:hetionet CHEBI:23765 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0030252 infores:hetionet CHEBI:6149 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C2830004 infores:hetionet CHEBI:47426 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1167965 infores:hetionet CHEBI:31236 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0041657 infores:hetionet CHEBI:64354 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C1291077 infores:hetionet CHEBI:50859 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151603 infores:hetionet CAID:CA410147948 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147948 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1150C>T (p.Pro384Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147948/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA000393 biolink:causes MONDO:0017623 infores:clingen CAID:CA000393 MONDO:0017623 PMID:15987703PMID:29706350PMID:10400993PMID:15987703PMID:29706350 Likely Pathogenic PM2, PM6, PP2, PS4_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PP3, PP4, PP1, BS2, PM5, PM4, PM1, PM3, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS2 PTEN c.314G>A (p.Cys105Tyr) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000393/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45716 biolink:causes EFO:0011050 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C1142499 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020676 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233494 infores:hetionet CHEBI:5106 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0007859 infores:hetionet CHEBI:8874 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0231218 infores:hetionet CHEBI:408174 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C1302752 infores:hetionet CHEBI:63618 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0035243 infores:hetionet CHEBI:44423 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0085932 infores:hetionet CHEBI:60761 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0003123 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0022408 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0012817 infores:hetionet CHEBI:472657 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0008370 infores:hetionet CHEBI:10102 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0011603 infores:hetionet CHEBI:9674 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0036974 infores:hetionet NCBIGene:999 biolink:causes MONDO:0100488 infores:monarchinitiative not_provided not_provided HGNC:1748 MONDO:0100488 uuid:d1251965-01bb-47eb-8608-5ff62745b818 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0235266 infores:hetionet CHEBI:6775 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0025874 infores:hetionet CHEBI:44915 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0231530 infores:hetionet CHEBI:9566 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0393593 infores:hetionet CHEBI:75722 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2047937 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0023646 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011551 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0178298 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0019348 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0042075 infores:hetionet CHEBI:5959 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0009782 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0853813 infores:hetionet CHEBI:3176 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C3665347 infores:hetionet CHEBI:32293 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0750394 infores:hetionet CHEBI:9073 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0003467 infores:hetionet CHEBI:85161 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0917801 infores:hetionet CHEBI:5118 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0041657 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002536 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0347390 infores:hetionet CHEBI:3561 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0000737 infores:hetionet CHEBI:66899 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0015397 infores:hetionet CAID:CA274228 biolink:causes MONDO:0009290 infores:clingen CAID:CA274228 MONDO:0009290 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000152.5(GAA):c.343C>T (p.Gln115Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least three individuals have been reported to have Pompe disease and this variant (PMIDs 17041744, 17616415, 32528171). GAA activity is reduced in the patients for whom it was reported (13-35% normal) but PP4 was not applied because the activity does not meet the strict thresholds specified by the ClinGen LD VCEP. ONe of these individuals is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1076-1G>C, phase unknown (PMID: 17616415). Two additional reports describe a child who is compound heterozygous for the variant and p.Pro482Leu (PMID: 17041744, 17616415). The allelic data will be used in the classification of p.Pro482Leu and is not included here to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 188996). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274228/MONDO:0009290/010 2023-03-07 2023-03-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:135736 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0027497 infores:hetionet CHEBI:6690 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0600142 infores:hetionet CHEBI:51032 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0035455 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0035078 infores:hetionet CHEBI:41774 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0015672 infores:hetionet CHEBI:17026 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0006142 infores:hetionet UNII:D27V6190PM biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0858635 infores:hetionet CAID:CA386973441 biolink:causes MONDO:0015967 infores:clingen CAID:CA386973441 MONDO:0015967 PMID: Uncertain Significance BP4, BS1, PM2, PP4, PP3 The c.1768C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 590 (p.(Val590Met)) of NM_000545.8. This variant has a Grpmax filtering allele frequency of 0.00000553 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.442, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, therefore PP4 does not apply (PMID: 33477506). In summary, c.1768C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): none. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386973441/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:4163 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:6935 MONDO:0005575 uuid:11888483-b5a7-44c0-a543-5391fddd224f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0001339 infores:hetionet CHEBI:50922 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013604 infores:hetionet CHEBI:17026 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0392171 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0031350 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0020649 infores:hetionet CHEBI:10110 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0015672 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0021359 infores:hetionet CAID:CA518744234 biolink:causes MONDO:0010278 infores:clingen CAID:CA518744234 MONDO:0010278 PMID: Likely Benign BS2, PM2_Supporting, BP4, BP7 The p.Phe192= variant in SLC9A6 (NM_006359.2) is observed in the hemizygous state in at least 3 unaffected individuals (internal database - GeneDx) (BS2). The p.Phe172= variant in SLC9A6 is absent from gnomAD (PM2_Supporting). The silent p.Phe172= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 3 unaffected hemizygous individuals, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified the p.Phe192= variant in SLC9A6 as Likely Benign (BS2, BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA518744234/MONDO:0010278/033 2023-10-13 2023-12-11 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:4868 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0017181 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1306341 infores:hetionet CHEBI:135351 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0028084 infores:hetionet CAID:CA1908826 biolink:causes MONDO:0018958 infores:clingen CAID:CA1908826 MONDO:0018958 PMID: Benign BA1, BP4 BS1, PM2, PP3 The c.11181T>A (p.Asp3727Glu) variant in NEB is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 3727. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.007676 (684/84234 alleles, 4 homozygotes) in the South Asian population, which is higher than the ClinGen Congenital Myopathies threshold (≥0.00559) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.119, which is below the threshold of 0.15 and the variant is not predicted by SpliceAI to impact splicing, and does not predict a damaging effect on NEB function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA1908826/MONDO:0018958/146 2024-08-07 2024-10-01 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:45367 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0019158 infores:hetionet CHEBI:480999 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151578 infores:hetionet CHEBI:2639 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0023895 infores:hetionet CHEBI:9943 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030794 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0267596 infores:hetionet CHEBI:46295 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0011168 infores:hetionet CHEBI:71417 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0233485 infores:hetionet NCBIGene:3702 biolink:causes MONDO:0013081 infores:monarchinitiative not_provided not_provided HGNC:6171 MONDO:0013081 uuid:b31fe67b-8e87-48dc-a50d-b2f42d162877 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004134 infores:hetionet CHEBI:63618 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0549622 infores:hetionet CHEBI:4858 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0030252 infores:hetionet CAID:CA10585457 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585457 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP4, BP2, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM4, PM5, PM3, PM1, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.914.It is above 0.75, so PP3 is Met.PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases (1 index case with Simon-Broome/DLCN criteria of definite FH (LDL=12,4 mmol/L and tendinous xanthomas) from Ireland (PMID 8535447); 3 index case with Simon-Broome criteria of possible FH from UK (PMID 17539906); 1 index case with FH criteria (LDL-C >95th percentile and AD inheritance pattern of hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease) from The Netherlands (PMID 21382890), so PS4_Supporting is met.PP4 - Variant meets PM2 and is identified in at least one index case who fulills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585457/MONDO:0007750/013 2023-04-29 2023-04-29 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:171719 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0242184 infores:hetionet CHEBI:5118 biolink:causes UMLS:C2732728 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2732728 infores:hetionet CHEBI:47519 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C1325847 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0015376 infores:hetionet CHEBI:10127 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0497156 infores:hetionet CHEBI:17263 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0948594 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0038363 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235315 infores:hetionet CHEBI:585948 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0030196 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0040034 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0013687 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0013687 infores:hetionet NCBIGene:324 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:583 MONDO:0001056 uuid:b1971eaf-0498-401c-a726-b34eb3c66cb5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6539 biolink:causes UMLS:C0085617 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0085617 infores:hetionet CHEBI:50922 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0009676 infores:hetionet CHEBI:63619 biolink:causes HP:0031657 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0577822 infores:hetionet CHEBI:28787 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0009421 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0009806 infores:hetionet CAID:CA6831769 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831769 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PVS1, PP4_Moderate The c.526C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 176 (p.(Gln176Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant also was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 18003757, internal lab contributors). This variant has a minor allele frequency of 0.000008856 in the gnomAD v2.1.1 European non-Finnish population and zero copies in other subpopulations, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). Additionally, this variant segregated with diabetes, with 5 informative meioses in 4 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.526C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PS4, PM2_Supporting, PP1_Strong, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831769/MONDO:0015967/017 2022-04-10 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15367 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009450 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0034150 infores:hetionet CHEBI:8404 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0002792 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1610069 infores:hetionet CHEBI:64355 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0037287 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0917798 infores:hetionet CHEBI:5123 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0151889 infores:hetionet CHEBI:53760 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002453 infores:hetionet CAID:CA10585683 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585683 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 PM5, PP3 The NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).BP4: REVEL = 0.481; score is below 0.50, splicing evaluation required. A). Not on limits.B). it creates a GT. Variant is exonic and at least 50bp upstream/downstream from canonical donor/acceptor site and creates a de novo GT. MES scores: variant cryptic site = -9.79, WT cryptic site = -17.54, canonical donor site= 10.28. De novo score is negative, so it is not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon-Broome criteria for FH (PMID 20809525) after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585683/MONDO:0007750/013 2024-07-02 2024-09-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8764 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0010692 infores:hetionet CHEBI:4887 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0027092 infores:hetionet CHEBI:9139 biolink:causes MONDO:0011382 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0002895 infores:hetionet CHEBI:65349 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0038325 infores:hetionet CHEBI:68642 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0004093 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0041912 infores:hetionet CHEBI:50742 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C2047937 infores:hetionet CHEBI:44032 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0917801 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0235620 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235620 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0948594 infores:hetionet NCBIGene:4715 biolink:causes MONDO:0032628 infores:monarchinitiative not_provided not_provided HGNC:7704 MONDO:0032628 uuid:e2b974eb-5e71-4e63-bad3-00aa293b1136 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49575 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0009676 infores:hetionet CHEBI:28748 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0039239 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0042373 infores:hetionet CHEBI:3723 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0043387 infores:hetionet CHEBI:63613 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0030193 infores:hetionet CHEBI:408174 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0042075 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0267596 infores:hetionet CHEBI:8356 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233514 infores:hetionet UNII:7662KG2R6K biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0858635 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0409974 infores:hetionet CHEBI:63581 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0232462 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0687707 infores:hetionet CHEBI:7936 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0497156 infores:hetionet CHEBI:31547 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0522055 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0043049 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017574 infores:hetionet CHEBI:5128 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0012833 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0041657 infores:hetionet CHEBI:15428 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0085584 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029927 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860803 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0014130 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0558368 infores:hetionet CAID:CA410203802 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203802 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1): c.251A>G (p.Asp84Gly) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203802/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51860 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0039971 infores:hetionet CHEBI:9130 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0438142 infores:hetionet CAID:CA410148831 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148831 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP2, PM2, PM6, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.968C>T (p.Thr323Met) is a missense variant located in exon 9. Although absent in gnomAD v3.1.2, the variant has been found in one individual in gnomAD v2.1.1 (MAF: 0.000005414). This missense variant has a REVEL score <0.50 (0.074) and SpliceAI ∆ scores ≤ 0.20 (0.00) (BP4). Furthermore, this variant affects amino acid 323, which is outside the RHD or residues 89-204. To our knowledge, there is no previous record of this variant, and no other pathogenic or likely pathogenic missense variants affecting the same amino acid residue or resulting in the same residue have been reported. However, the RUNX1 p.Thr323Ala variant has been validated as germline in a pediatric patient with B-ALL, despite being classified as likely benign (PMID: 34166225). In summary, the clinical significance of this variant is uncertain, and it meets ACMG/AMP criteria as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148831/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7466 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C1704272 infores:hetionet CHEBI:28915 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0151905 infores:hetionet NCBIGene:1339 biolink:causes MONDO:0033653 infores:monarchinitiative not_provided not_provided HGNC:2279 MONDO:0033653 uuid:6fcdefba-d799-4779-867d-ef89d80f0730 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0016199 infores:hetionet CHEBI:5384 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0085593 infores:hetionet CHEBI:15940 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0042963 infores:hetionet CAID:CA10014207 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014207 MONDO:0011071 PMID:19808697 Benign BP4, BA1, BP7 PS1, PS4, PS3, BP2, PVS1, PM6, PM2, BS4, BS3, BS1, PM5, PM4, PM1, PP1, PP3 This synonymous variant has a MAF of 0.002828 (0.2828%, 61/21570, 43140 alleles) in the African (gnomAD) cohort is ≥ 0.0015 (0.15%) (BA1). It is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -0.12 < 0.1 [-14.1;6.4]) (BP4+BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014207/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10650 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0027497 infores:hetionet CHEBI:3314 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C1443060 infores:hetionet CHEBI:52172 biolink:causes UMLS:C1557335 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1557335 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0948089 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0027769 infores:hetionet CAID:CA392324665 biolink:causes MONDO:0007947 infores:clingen CAID:CA392324665 MONDO:0007947 PMID: Uncertain Significance PP2, PP3, PM2_Supporting, PM1 PP4, PS2 The NM_00138 c.7763A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 2588 (p.Tyr2588Cys). This cysteine-creating variant impacts a tyrosine within a calcium-binding (cb) (D)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain, important for protein stability (PM1, PMID 10766875, 26281765). This variant has been reported twice in ClinVar: once as likely pathogenic, and once as uncertain significance (Variation ID: 571222). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.915, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM2_Sup, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392324665/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3568 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014868 infores:hetionet CHEBI:16469 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0002622 infores:hetionet CAID:CA410150203 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150203 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.842A>G (p.Tyr281Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150203/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3696 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0041976 infores:hetionet CAID:CA343772066 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772066 MONDO:0013144 PMID: Uncertain Significance PS3_Supporting, PP3, PM2_Supporting, PS4_Supporting The c.1376C>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 459 (p.Ala459Asp). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. One proband had a family history of disease with reported antithrombin activity level and one proband had a family history of disease but no antithrombin activity level was reported (PS4_Supporting; PMIDs: 8401542, 23809926). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). AT activity levels are shown to be reduced (27%) of WT when Ala459Asp was expressed in COS (PMID: 23809926), meeting criteria for PS3_Supporting.In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772066/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:100241 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0438717 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013595 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0559031 infores:hetionet CL:0000049 biolink:causes MONDO:0019454 infores:ubergraph knowledge_assertion manual_agent CL:0000049 MONDO:0019454 CHEBI:46195 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0162830 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0877046 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0948594 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0392702 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C1956346 infores:hetionet CHEBI:6741 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0233407 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001741 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0020502 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011609 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020517 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042109 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0162830 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0035078 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0001339 infores:hetionet CHEBI:41879 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0018790 infores:hetionet CHEBI:52717 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0392699 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0518015 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0233414 infores:hetionet CHEBI:50922 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020433 infores:hetionet CHEBI:45367 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0036572 infores:hetionet CHEBI:5128 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0340865 infores:hetionet CHEBI:4530 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0231528 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0014457 infores:hetionet NCBIGene:10398 biolink:causes MONDO:0030296 infores:monarchinitiative not_provided not_provided HGNC:15754 MONDO:0030296 uuid:0abc0b2e-b106-48b1-b5f3-eb9d783016c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31536 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151578 infores:hetionet CHEBI:101278 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013378 infores:hetionet CHEBI:51450 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0002792 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0314719 infores:hetionet CHEBI:16335 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0033036 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002529 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0553723 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0948349 infores:hetionet CAID:CA202695 biolink:causes MONDO:0008535 infores:clingen CAID:CA202695 MONDO:0008535 PMID: Benign BA1 PP3 The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BA1 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA202695/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5864 biolink:causes UMLS:C0743072 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0743072 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0010709 infores:hetionet CHEBI:37941 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0006277 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040409 infores:hetionet CHEBI:3127 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0040264 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0005575 uuid:c589e3f0-18c7-468b-a1d5-1185babdc823 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:132233 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0151736 infores:hetionet CAID:CA913189044 biolink:causes MONDO:0100040 infores:clingen CAID:CA913189044 MONDO:0100040 PMID: Uncertain Significance PM6, BP3, PM2_Supporting The p.His55_His57dup variant in FOXG1 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with clinical features of FOXG1 disorder (internal database, GeneDx) (PM6). The p.His55_His57dup variant in FOXG1 is absent in gnomAD (PM2_supporting). The p.His55_His57dup variant is an in-frame deletion/duplication present in a repetitive region of FOXG1 (BP3). In summary, the p.His55_His57dup variant in FOXG1 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM6, PM2_supporting, BP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA913189044/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7983 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0039070 infores:hetionet CHEBI:68575 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0027441 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0021439 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0496901 infores:hetionet CHEBI:68575 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0042571 infores:hetionet CHEBI:77733 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0014742 infores:hetionet CHEBI:51209 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0917801 infores:hetionet CHEBI:127780 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0038367 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030332 infores:hetionet CHEBI:6472 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0042109 infores:hetionet CHEBI:7454 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0020517 infores:hetionet CHEBI:7581 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0039070 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0037822 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009763 infores:hetionet CHEBI:47781 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0234133 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0036508 infores:hetionet CHEBI:8888 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0547030 infores:hetionet CHEBI:83804 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0232849 infores:hetionet CHEBI:50922 biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085702 infores:hetionet CAID:CA10577535 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577535 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.337A>T (p.Lys113Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577535/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7931 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0026946 infores:hetionet CHEBI:8214 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C1456822 infores:hetionet CHEBI:50173 biolink:causes NCIT:C35105 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0041981 infores:hetionet CHEBI:48844 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0038325 infores:hetionet CHEBI:6822 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0151798 infores:hetionet CHEBI:5864 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0014742 infores:hetionet GO:0030851 biolink:causes CL:0000094 infores:ubergraph knowledge_assertion manual_agent GO:0030851 CL:0000094 CHEBI:15940 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0003123 infores:hetionet CHEBI:5134 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0030252 infores:hetionet CHEBI:6375 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0232602 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0021364 infores:hetionet CHEBI:42944 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0027497 infores:hetionet CHEBI:101278 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013604 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038362 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0038325 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0010692 infores:hetionet CHEBI:35778 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0030232 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0025061 infores:hetionet CHEBI:50838 biolink:causes UMLS:C1096458 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C1096458 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0002418 infores:hetionet NCBIGene:90459 biolink:causes MONDO:0958005 infores:monarchinitiative not_provided not_provided HGNC:23994 MONDO:0958005 uuid:d1b68f1a-c9a9-48cf-a0cb-8b7055ac9405 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0037317 infores:hetionet CHEBI:6904 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0009806 infores:hetionet CAID:CA327914520 biolink:causes MONDO:0100437 infores:clingen CAID:CA327914520 MONDO:0100437 PMID: Likely Benign BP4, BS1 NM_001034853.2(RPGR):c.3317A>C (p.Lys1106Thr) is a missense variant causing substitution of lysine by threonine at amino acid 1106. This variant is present in gnomAD v4.1.0 at a frequency of 0.000005039 among hemizygous individuals, with 2 variant alleles / 396,888 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.064, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1 and BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327914520/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:135736 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0011053 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0424000 infores:hetionet CHEBI:4710 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0026961 infores:hetionet CHEBI:8768 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042029 infores:hetionet CHEBI:3568 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0404521 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0043251 infores:hetionet CHEBI:18332 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0038990 infores:hetionet CHEBI:9654 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0018790 infores:hetionet CHEBI:3398 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0040034 infores:hetionet CHEBI:72297 biolink:causes HP:0012701 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0426636 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0149931 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020538 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0413252 infores:hetionet UMLS:C1144403 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0027497 infores:hetionet CHEBI:17026 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0000786 infores:hetionet CHEBI:100241 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151632 infores:hetionet CHEBI:50173 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0019080 infores:hetionet CHEBI:84500 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0549622 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0015397 infores:hetionet CHEBI:17347 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0013404 infores:hetionet CHEBI:100246 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0000737 infores:hetionet CHEBI:17303 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0746961 infores:hetionet CHEBI:12777 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00162 UMLS:C0002792 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0017178 infores:hetionet CAID:CA238566 biolink:causes MONDO:0001586 infores:clingen CAID:CA238566 MONDO:0001586 PMID: Likely Pathogenic PM3_Strong, PP4_Moderate, PM2_Supporting BP4, PP1, PP3 The NM_000203.5:c.53T>C variant in IDUA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 18 (p.Leu18Pro). This variant has been detected in at least 10 individuals with MPS I. This variant has been detected in at least 10 individuals with MPS I. Of those individuals, three were homozygous for the variant (PMID 25256405, max 2 x 0.5 = 1 point). Four of the remaining individuals are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP including c.1205G>A p.(Trp402Ter) (ClinVar Variation ID: 11908) (PMID 31194252, at least one patient, phase not confirmed, 0.5 point), c.208C>T p.(Gln70Ter) (ClinVar Variation ID: 11909) (PMID 31194252, 255574391 2 patients, phase not confirmed, 2 x 0.5 point), and c.1487C>G p.(Pro496Arg) (PMID 31194252, 1 patient, phase not confirmed, 0.25 point). Two patients are compound heterozygous for the variant and c.1163C>A, p.(Thr388Lys), however the allelic data for these patients will be used to support the classification of Thr388Lys and is not included here in order to avoid circular logic (2.75 points, PM3_strong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of attenuated MPS1, presenting with reduced IDUA enzyme activity (0.73 nmol/h/mg, reference range 32-56) and increased GAG excretion in urine (188ug GAGs/g creatinine, age-related reference 67-124). His brother, also homozygous for the variant is reported to have attenuated MPS1, with similar clinical features (PMID 25256405) (PP4_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002779 (1/35,980 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.319 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. There is a ClinVar entry for this variant (Variation ID: 193062). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 1.0.0): PM3_strong, PP4_moderate, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 19, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA238566/MONDO:0001586/091 2025-05-19 2025-05-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:61049 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0041657 infores:hetionet CHEBI:31515 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0018681 infores:hetionet UMLS:C0004609 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0040264 infores:hetionet CHEBI:48844 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0030305 infores:hetionet CHEBI:63621 biolink:causes MONDO:0017373 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0032371 infores:hetionet CAID:CA399795012 biolink:causes MONDO:0100326 infores:clingen CAID:CA399795012 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4, PM3_Supporting PP4 The c.2507G>C variant in ITGA2B is a missense variant predicted to cause substitution of Glycine by Alanine at amino acid 836 (p.Gly836Ala). This variant is absent from gnomAD v4.0.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.152, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). A male patient is reported homozygous this variant (TGP0413 in PMID: 31064749; PM3_Supporting) however, his phenotype is not detailed enough to apply PP4 as specified by the PD VCEP. Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM3_Supporting and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399795012/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true NCBITaxon:1313 biolink:causes MONDO:0005114 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1313 MONDO:0005114 CHEBI:9727 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C2047937 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0018129 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0018129 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0034065 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0019360 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0878544 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0026858 infores:hetionet CHEBI:4653 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0151827 infores:hetionet CHEBI:167638 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0018794 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1384353 infores:hetionet CHEBI:68606 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0151905 infores:hetionet CHEBI:39585 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0018681 infores:hetionet CHEBI:167638 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0019158 infores:hetionet CHEBI:36704 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0038999 infores:hetionet CHEBI:8874 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0338908 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0003123 infores:hetionet GO:0072034 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072034 GO:0072006 CHEBI:49375 biolink:causes UMLS:C0849925 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0849925 infores:hetionet CHEBI:182080 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0039231 infores:hetionet CHEBI:72564 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0005779 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0040034 infores:hetionet CHEBI:8713 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0027497 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0003834 infores:hetionet CHEBI:39585 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0002170 infores:hetionet CHEBI:135876 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0013428 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0086543 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0021400 infores:hetionet CHEBI:135930 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0542571 infores:hetionet CHEBI:3561 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0016655 infores:hetionet CHEBI:32221 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0003467 infores:hetionet CHEBI:28901 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0025320 infores:hetionet CHEBI:47499 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0012833 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0948594 infores:hetionet CHEBI:3732 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0010038 infores:hetionet CAID:CA2695202151 biolink:causes MONDO:0700270 infores:clingen CAID:CA2695202151 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PM5_Supporting, PVS1 The c.4389del p. Phe1463Leufs*10 variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v2.1.1. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1, PM2_Supporting, PM3_Strong, PM5_supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202151/MONDO:0700270/020 2024-02-26 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45327 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0004238 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0003123 infores:hetionet CHEBI:47898 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019345 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0017160 infores:hetionet CHEBI:2549 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0010200 infores:hetionet CHEBI:75722 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233754 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005371 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0525045 infores:hetionet CHEBI:63631 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0344232 infores:hetionet CHEBI:5109 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0263449 infores:hetionet CHEBI:44185 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0003708 infores:hetionet CHEBI:10102 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0002792 infores:hetionet CHEBI:3347 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0023530 infores:hetionet CHEBI:45951 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0014553 infores:hetionet CHEBI:10102 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0086439 infores:hetionet CHEBI:3213 biolink:causes HP:0020226 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0240521 infores:hetionet CHEBI:3761 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027769 infores:hetionet CHEBI:45081 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0015230 infores:hetionet CHEBI:5141 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0018681 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020517 infores:hetionet CHEBI:9123 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0549249 infores:hetionet CHEBI:51141 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0004238 infores:hetionet CHEBI:5864 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0042024 infores:hetionet UMLS:C0025241 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0010200 infores:hetionet CHEBI:82716 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0011991 infores:hetionet CAID:CA10584833 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584833 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.299A>G (p.Asp100Gly) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PP4, PS4_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: - PM2: This variant is absent from gnomAD (gnomAD v2.1.1).- PP1: variant segregates with FH phenotype in 3 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology: 2 relatives with the phenotype and the variant and 1 relative without the phenotype and without the variant.- PP3: REVEL = 0.9.- PP4: Variant meets PM2 and is identified in at least 1 index case (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH), after alternative causes of high cholesterol were excluded.- PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH) Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584833/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:101278 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0085641 infores:hetionet CHEBI:134990 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0027765 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0087169 infores:hetionet CHEBI:49960 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0032584 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0007785 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0004238 infores:hetionet CHEBI:32293 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0947912 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0541799 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020615 infores:hetionet CHEBI:3479 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0015967 infores:hetionet CHEBI:44423 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0333355 infores:hetionet CHEBI:15367 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0085932 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0034882 infores:hetionet GO:0061046 biolink:causes GO:0060425 infores:ubergraph knowledge_assertion manual_agent GO:0061046 GO:0060425 CHEBI:61033 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0542203 infores:hetionet CHEBI:34829 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0547030 infores:hetionet CHEBI:4975 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C1761613 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C1527344 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002170 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151580 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151580 infores:hetionet NCBIGene:207 biolink:causes MONDO:0014048 infores:monarchinitiative not_provided not_provided HGNC:391 MONDO:0014048 uuid:6de6f8f7-7f44-4b62-9ef5-8d4ec5cc6b77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135351 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0858635 infores:hetionet CHEBI:47499 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0037317 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0031350 infores:hetionet CHEBI:8597 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0232462 infores:hetionet CHEBI:8481 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0233494 infores:hetionet CAID:CA000569 biolink:causes MONDO:0017623 infores:clingen CAID:CA000569 MONDO:0017623 PMID:9832032 Pathogenic PM6, PVS1, PM2, PS4_Supporting BP5, BP7, BS4, BS3, BS1, PP4, PP1, PP2, PP3, BS2, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS3, PS1 PTEN c.766G>T (p.E256X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 9832032)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 9832032) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000569/MONDO:0017623/003 2018-04-06 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45979 biolink:causes UMLS:C0221185 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0221185 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011616 infores:hetionet NCBIGene:6341 biolink:causes MONDO:0033636 infores:monarchinitiative not_provided not_provided HGNC:10603 MONDO:0033636 uuid:98e244ed-e5b5-4738-abf9-6e2962a38615 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17823 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0020517 infores:hetionet CHEBI:4027 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1260880 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0011991 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0028077 infores:hetionet CHEBI:31236 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0016658 infores:hetionet CHEBI:17688 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C3665347 infores:hetionet CHEBI:10023 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011124 infores:hetionet CAID:CA333390 biolink:causes MONDO:0007113 infores:clingen CAID:CA333390 MONDO:0007113 PMID:26255772PMID:25212744PMID:25212744 Pathogenic PS3_Supporting, PM5, PP1_Strong, PP3, PM2_Supporting, PS4_Supporting The variant has been reported to segregate in at least five informative meioses (PMID 25212744, internal database) (PP1_Strong). A pathogenic missense variant (p.Thr106Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 15054837) (PM5). Protein expression analysis in transfected cell lines has shown that this variant reduces protein function (PMID 26255772) PS3_Supporting). The p.Thr106Lys variant has been observed in at least 1 other individual with Angelman syndrome (PMID 25212744) (PS4_Supporting). The p.Thr106Lys variant in UBE3A is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr106Lys variant in UBE3A is classified as pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PP1_strong, PM5, PS3_supporting, PS4_supporting, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333390/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:5106 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0677500 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0041912 infores:hetionet CHEBI:41423 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014724 infores:hetionet NCBIGene:2064 biolink:causes MONDO:0030399 infores:monarchinitiative not_provided not_provided HGNC:3430 MONDO:0030399 uuid:965db265-8058-4885-87f8-3000579baf4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0855775 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0948525 infores:hetionet CHEBI:404903 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0003862 infores:hetionet CHEBI:553473 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0234233 infores:hetionet CHEBI:45863 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2363730 infores:hetionet UNII:D27V6190PM biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0004604 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0014868 infores:hetionet CHEBI:77733 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0022346 infores:hetionet CHEBI:8768 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0025345 infores:hetionet CHEBI:4046 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0031117 infores:hetionet NCBIGene:23184 biolink:causes MONDO:0032846 infores:monarchinitiative not_provided not_provided HGNC:13520 MONDO:0032846 uuid:b0eb6a63-d919-4d87-b2cb-7e7d1b446a87 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0231218 infores:hetionet CHEBI:8404 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0235063 infores:hetionet CHEBI:421707 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0917801 infores:hetionet CHEBI:135530 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0011570 infores:hetionet CHEBI:17076 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0011053 infores:hetionet CHEBI:30830 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C1443060 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0270458 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0231365 infores:hetionet CHEBI:41774 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0085649 infores:hetionet CHEBI:8212 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0151818 infores:hetionet CHEBI:18248 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0027441 infores:hetionet CHEBI:32020 biolink:causes UMLS:C0853875 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0853875 infores:hetionet CHEBI:27974 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0023218 infores:hetionet CHEBI:681569 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0476280 infores:hetionet CAID:CA10576816 biolink:causes MONDO:0019497 infores:clingen CAID:CA10576816 MONDO:0019497 PMID: Uncertain Significance PP3, PM2 PM3 The NM_022124.6:c.6866A>G variant in the CDH23 gene is a missense variant predicted to cause substitution of asparagine to serine at amino acid 2289 (p.Asn2289Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.534, which is neither above nor below the thresholds predicting a damaging or benign impact. This variant was reported in two individuals with sensorineural hearing loss and one individual with postlingual deafness and bilateral vestibular areflexia (LMM unpublished data SCV000271567.2, ARUP Labs unpublished data SCV000602954.2, University Hospital of Geneva unpublished data SCV000494445.1). One individual had a second variant of uncertain significance in trans, and one had a second variant of uncertain significance phase unknown (SCV000602954.2, SCV000494445.1) (Does not meet PM3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting. (VCEP specifications version 2.0.0; Dec 21, 2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA10576816/MONDO:0019497/005 2022-12-21 2023-02-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:6931 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0037317 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0022116 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0086543 infores:hetionet CHEBI:27732 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1167965 infores:hetionet CHEBI:59560 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0948089 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0178298 infores:hetionet CHEBI:84500 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042345 infores:hetionet CHEBI:3219 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027066 infores:hetionet CHEBI:6375 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C3665347 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0235698 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0235698 infores:hetionet NCBIGene:80326 biolink:causes MONDO:0009773 infores:monarchinitiative not_provided not_provided HGNC:13829 MONDO:0009773 uuid:cf29d2e3-4220-4382-88e6-34739fb932f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042769 infores:hetionet CHEBI:7476 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018524 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003397 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0017567 infores:hetionet NCBIGene:5885 biolink:causes MONDO:0012657 infores:monarchinitiative not_provided not_provided HGNC:9811 MONDO:0012657 uuid:94bb973e-11ae-4d8a-9cd8-67b6c638bd64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6888 biolink:causes UMLS:C0740409 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0740409 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0042373 infores:hetionet CHEBI:6367 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014457 infores:hetionet CHEBI:84500 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0033774 infores:hetionet CHEBI:8707 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0010200 infores:hetionet CHEBI:3654 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C1368065 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0006145 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0521991 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0521991 infores:hetionet NCBIGene:1962 biolink:causes MONDO:0014275 infores:monarchinitiative not_provided not_provided HGNC:3247 MONDO:0014275 uuid:573b38e1-9e8e-45dd-9bc3-dda3694c63fb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0001824 infores:hetionet CHEBI:45081 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0575081 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030312 infores:hetionet CAID:CA340745797 biolink:causes MONDO:0100368 infores:clingen CAID:CA340745797 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting NM_000329.3(RPE65):c.770T>G (p.Val257Gly) is a missense variant predicted to replace valine with glycine at amino acid p.257. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PMID: 40087508, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset between birth and age 5 years (1 pt), nystagmus (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), reduced best-corrected visual acuity (1 pt), and pigmentary retinopathy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 40087508, PP4). The computational predictor REVEL gives a score of 0.979, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340745797/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:70746 biolink:causes UMLS:C0852361 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0852361 infores:hetionet UMLS:C0065374 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0004134 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020615 infores:hetionet CHEBI:2618 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C2830004 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151698 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0151511 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0151511 infores:hetionet CAID:CA512341385 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341385 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.999G>C (p.Pro333=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.13) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341385/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA258396558 biolink:causes MONDO:0100040 infores:clingen CAID:CA258396558 MONDO:0100040 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting PM4, BP3 The p.Leu104_Pro105insGlnPro variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). The p.Leu104_Pro105insGlnPro variant is observed in at least 1 unaffected individual (internal database - Labcorp (formerly Invitae)) (BS2_Supporting). In summary, the p.Leu104_Pro105insGlnPro variant in FOXG1 is classified as uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, BS2_Supporting). (FOXG1 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA258396558/MONDO:0100040/035 2025-08-27 2025-10-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71415 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0033845 infores:hetionet CHEBI:83804 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013428 infores:hetionet UMLS:C0120107 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0009676 infores:hetionet NCBIGene:26278 biolink:causes MONDO:0010041 infores:monarchinitiative not_provided not_provided HGNC:10519 MONDO:0010041 uuid:6c4b37ae-70a7-4731-8507-15ec6b115e96 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0025241 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0518015 infores:hetionet CHEBI:3994 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0018681 infores:hetionet CHEBI:6062 biolink:causes EFO:0009472 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0206504 infores:hetionet CHEBI:5855 biolink:causes HP:0012051 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0271710 infores:hetionet CHEBI:2950 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0231919 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0152027 infores:hetionet CHEBI:49960 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0206062 infores:hetionet CHEBI:31515 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0042109 infores:hetionet CAID:CA229760 biolink:causes MONDO:0009861 infores:clingen CAID:CA229760 MONDO:0009861 PMID:26600521PMID:26600521PMID:8222245 Uncertain Significance PP4_Moderate, PM2, PP3 PM3, PM5 The c.789C>G (p.Phe263Leu) variant in PAH is reported in 1 patient with classical PKU, and 1 Chinese PKU patient. (BH4 deficiency excluded. PMID: 8222245, 26600521) This variant is absent from 1000G and ESP with extremely low frequency in ExAC/gnomAD (MAF=0.00003). It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.929. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229760/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6888 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0854100 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0521839 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0009760 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0853692 infores:hetionet CHEBI:63791 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151699 infores:hetionet CHEBI:9727 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0231303 infores:hetionet CHEBI:39112 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0853034 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0231365 infores:hetionet CHEBI:9654 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0039070 infores:hetionet CAID:CA345921 biolink:causes MONDO:0044970 infores:clingen CAID:CA345921 MONDO:0044970 PMID:24118886 Uncertain Significance PP1, PP3, PM2_Supporting, PS3_Supporting The m.8839G>C (p.A105P) variant in MT-ATP6 has been reported in one individual with primary mitochondrial disease to date (PMID: 24118886), in a woman with pigmentary retinopathy, partial motor epilepsy, ataxia, dysmetria, and axonal polyneuropathy. The variant was present at 87% heteroplasmy in muscle, 88% in buccal mucosa, 78% in urine, and 21% in blood. The variant was also present in asymptomatic family members - 40% in blood from her mother; and 22% in buccal mucosa, 9.5% in urine, and 1.3% in blood from her sister (PP1; PMID: 24118886). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.934 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrids with the variant showed reduced cell proliferation in galactose, elevated mitochondrial DNA copy number, increased oxidative phosphorylation protein levels, and decreased mitochondrial membrane potential. Mitochondrial respiratory chain enzyme activities and ATP synthesis were similar between mutant and wild type cybrids (PS3_supporting, PMID: 24118886). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345921/MONDO:0044970/015 2024-10-28 2025-08-07 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true GO:1904933 biolink:causes GO:0030901 infores:ubergraph knowledge_assertion manual_agent GO:1904933 GO:0030901 CHEBI:63791 biolink:causes MONDO:0005272 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002893 infores:hetionet GO:1901722 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:1901722 GO:0072001 CHEBI:50648 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011615 infores:hetionet CAID:CA8815476 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815476 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PS3_Moderate, PM2_Supporting, PM5_Supporting The NM_000152.5:c.1781G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 594 (p.Arg594Pro). This variant has been detected in at least 3 probands with Pompe disease (PMID: 34952985, 19588081, 18425781, clinical diagnostic laboratory). Two of these individuals are reported to have clinical features consistent with the condition, and one is reported to be on enzyme replacement therapy, but residual GAA activity was not provided (PMID: 19588081, 34952985). Another patient, identified by a clinical diagnostic laboratory, has deficiency GAA activity in dried blood spot and a brother reported to have Pompe disease (PP4_Moderate). Each of the 3 probands is compound heterozygous, phase unknown, for the variant and another pathogenic variant in GAA, either c.525delT (clinical diagnostic laboratory), c.32‐13T>G (PMID: 34952985) or c.1941C>G (p.Cys647Trp) (PMID: 19588081) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111938 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 1.2% wild type GAA activity leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.941 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change (c.1781G>T, p.Arg594His) at the same amino acid residue has been classified as likely pathogenic by the ClinGen LSD VCEP (PM5_Suppporting).There is a ClinVar entry for this variant (Variation ID: 289361, 1 star review status) with one submitter classifying the variant as pathogenic, 3 as likely pathogenic, and one as uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815476/MONDO:0009290/010 2022-11-15 2022-11-29 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8874 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0392525 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0234913 infores:hetionet CAID:CA271787 biolink:causes MONDO:0018947 infores:clingen CAID:CA271787 MONDO:0018947 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6 PP2, BP1, BP4, BA1, BS1 The NM_000252.3:c.1353G>A variant in MTM1 is a synonymous variant (p.Gln451=) located near the canonical donor site of intron 12. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The silent variant is predicted to impact splicing by SpliceAI (PP3). This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia. One of the three was a de novo occurrence with unconfirmed parental relationships (PS4_Moderate, PM6; PMID: 10790201; LabCorp, ClinVar: SCV001391223.5). In summary, the variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM6, PM2_Supporting, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA271787/MONDO:0018947/149 2025-01-13 2025-03-27 X-linked inheritance HP:0001417 Supports PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0027765 infores:hetionet CHEBI:45951 biolink:causes EFO:0009446 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0004044 infores:hetionet CHEBI:5775 biolink:causes UMLS:C0221733 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0221733 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0022104 infores:hetionet CHEBI:47426 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0023218 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0027947 infores:hetionet CHEBI:8107 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0018790 infores:hetionet CHEBI:107736 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0038661 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0025362 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027339 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0036572 infores:hetionet UMLS:C0879264 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0010200 infores:hetionet CHEBI:17474 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0002453 infores:hetionet CAID:CA294762 biolink:causes MONDO:0100039 infores:clingen CAID:CA294762 MONDO:0100039 PMID: Uncertain Significance BS1, BP4, PS2 PP3, PP4, PM1, PM6, PS4 The highest population minor allele frequency of the c.2684C>T (p.Pro895Leu) variant in CDKL5 in gnomAD v4.1 is 0.0001 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). This variant has been identified as a de novo occurrence in 1 individual mosaic for this variant (mosaicism confirmed, PMID: 37088138) (PS2). The p.Pro895Leu variant has been reported in 1 proband with a neurodevelopmental phenotype consistent with CDKL5 disorder. However, PS4 cannot be applied because PM2 does not apply (PS4_not met) and the described phenotype does not meet PP4 criteria (PMID: 27770071) (PP4_Not met). The computational predictor REVEL gives a score of 0.241, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). In summary, the p.Pro895Leu variant in CDKL5 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS1, PS2, BP4) (CDKL5 Specifications v4.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294762/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:37333 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C1145628 infores:hetionet CHEBI:3077 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0003708 infores:hetionet NCBIGene:6910 biolink:causes MONDO:0007732 infores:monarchinitiative not_provided not_provided HGNC:11604 MONDO:0007732 uuid:1da1d3cb-ae04-4ac0-96ba-8a93a0db179f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0014591 infores:hetionet CHEBI:7809 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0015230 infores:hetionet CHEBI:478164 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0042029 infores:hetionet CHEBI:9168 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0917801 infores:hetionet CHEBI:175901 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0015967 infores:hetionet NCBIGene:59345 biolink:causes MONDO:0014074 infores:monarchinitiative not_provided not_provided HGNC:20731 MONDO:0014074 uuid:8f61d549-6ff1-43e0-a374-f4373800669a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8890 biolink:causes MONDO:0002782 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0151311 infores:hetionet CAID:CA1139666830 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666830 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*3028T>C is a 3’UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666830/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA006800 biolink:causes MONDO:0100316 infores:clingen CAID:CA006800 MONDO:0100316 PMID:21164565PMID:29021305PMID:29532034PMID:32797034PMID:21164565PMID:29021305PMID:29532034PMID:32797034 Uncertain Significance BP4, PS3, BS1, BS3, BS4, PM2, PM1, PP3, PP1 NM_000218.3(KCNQ1):c.328G>A is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 110 (p.Val110Ile). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008307, with 98 alleles / 1,179,710 total alleles in the European (non-Finnish) population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. Functional studies have been performed on this variant (PMID: 21164565, 29532034, and 29021305) but do not meet VCEP criteria for PS3/BS3. The computational predictor REVEL gives a score of 0.562, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of greater than or equal to 0.2 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: None. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA006800/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10023 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0012569 infores:hetionet CHEBI:6775 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0235378 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0040409 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0036572 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0947999 infores:hetionet CAID:CA116590 biolink:causes MONDO:0009290 infores:clingen CAID:CA116590 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PM2_Supporting, PS3_Supporting The NM_000152.5:c.953T>C variant in GAA is a missense variant predicted to cause substitution of methionine by threonine at amino acid 318 (p.Met318Thr). Twelve probands with a diagnosis of Pompe disease were identified with this variant. At least 9 of them have GAA activity in the affected range in dried blood spots or <30% normal GAA activity in fibroblasts (PMIDs: 1652892, 19862843, 25139343, 30214072, 34357340, clinical laboratory data) with pseudodeficiency variants confirmed absent in three of these patients (clinical laboratory data) (PP4_Moderate). Of these patients, 10 are compound heterozygous for c.953T>C (p.Met318Thr) and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP; either c.2560C>T (p.Arg854Ter), confirmed in trans (PMID: 1652892, 19862843), c.1979G>A (p.Arg660His), confirmed in trans by parental testing (clinical diagnostic laboratory); c.-32-13T>G, phase unknown (PMIDs: 29122469, 31904026, 32317649, clinical diagnostic laboratory) (at least 5 patients, 1 confirmed in trans) c.2481+102_2646+31del (p.Gly828_Asn882del), phase unknown (clinical diagnostic laboratory), c.1292_1295dupTGCA, phase unknown (PMID: 30214072), or c.1082C>T (p.Pro361Leu), phase unknown (PMID: 25139343). One patient is homozygous for the variant (PMID: 34357340) (0.5 points) (PM3_Very Strong). Another patient is compound heterozygous for the variant and c.692+5G>T (PMID: 29181627) but the allelic data from this patient will be used in the classification of c.692+5G>T and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Suporting, and therefore meets this criterion (PM2_Supporting). Functional studies involving expression of the variant in cultured cells indicate that the variant impacts function, resulting in <2% GAA activity (PMID: 1652892, 19862843). The computational predictor REVEL gives a score of 0.89, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 4021; 1 star review status) with 3 submitters classifying the variant as pathogenic, two as likley pathogenic and one as a variant of uncertain significance. With data from the published literature and a clinical laboratory, we find that the variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3.Classification approved by the ClinGen LSD VCEP on Sept. 6, 2022. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116590/MONDO:0009290/010 2022-09-06 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:64355 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020557 infores:hetionet CAID:CA343725312 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725312 MONDO:0005338 PMID:23129764PMID:21612213PMID:25524706 Likely Pathogenic PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting, PS3_Moderate BS1, BS3, BP7, PM4, PM5, PS1, PS2, BA1, BP4 The c.967G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 323 (p.Glu323Lys). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.759, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Glu323Lys protein had increased insolubility, instability and reduced secretion levels compared to wild type myocilin protein in this these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3). This protein has also been assessed in these other studies (PMIDs: 11004290, 10545602, 15069026, 16297911), however, the same level of evidence was not met. 10 segregations in 1 family, with juvenile open angle glaucoma, have been reported (PMID: 9772276), which fulfilled PP1_Moderate (≥ 5 meioses in ≥ 1 family, but not the ≥ 7 meioses in > 1 family for the strong criterion). 5 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 9772276, 12616399, 37485465), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 7 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PS3_Moderate, PP1_Moderate, PP3, PS4_Supporting, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725312/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63622 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0013378 infores:hetionet CHEBI:18358 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0038814 infores:hetionet GO:0045704 biolink:causes GO:0048645 infores:ubergraph knowledge_assertion manual_agent GO:0045704 GO:0048645 CHEBI:72297 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0018926 infores:hetionet NCBITaxon:5855 biolink:causes MONDO:0005921 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5855 MONDO:0005921 CHEBI:50131 biolink:causes UMLS:C0860901 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0860901 infores:hetionet CAID:CA070164 biolink:causes MONDO:0018493 infores:clingen CAID:CA070164 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with cysteine at codon 2587 of the RYR1 protein, p.(Tyr2587Cys). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000116, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:25960145). However, the high MAF in the AMR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.911) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA070164/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3441 biolink:causes UMLS:C0028173 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0028173 infores:hetionet CHEBI:9137 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0025874 infores:hetionet CHEBI:101085 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0235416 infores:hetionet CHEBI:3207 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0700590 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0028961 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0235340 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0235340 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0020557 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0026857 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0013595 infores:hetionet CHEBI:134991 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0013395 infores:hetionet GO:0035026 biolink:causes CL:0000730 infores:ubergraph knowledge_assertion manual_agent GO:0035026 CL:0000730 CHEBI:31348 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040034 infores:hetionet CHEBI:6887 biolink:causes HP:5200231 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0235013 infores:hetionet CHEBI:8428 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0036974 infores:hetionet CHEBI:5147 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0003862 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0040034 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0003123 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0038362 infores:hetionet CHEBI:50173 biolink:causes MONDO:0007127 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020498 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0011551 infores:hetionet CHEBI:9570 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0232462 infores:hetionet CHEBI:16755 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0019080 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151479 infores:hetionet CHEBI:64312 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018808 infores:hetionet CHEBI:87715 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0004238 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014869 infores:hetionet CHEBI:72292 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0019158 infores:hetionet CHEBI:63619 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151529 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009782 infores:hetionet CHEBI:10125 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0030232 infores:hetionet CHEBI:52010 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0030252 infores:hetionet CHEBI:49375 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C1112320 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0235146 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0413252 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0043246 infores:hetionet NCBIGene:2182 biolink:causes MONDO:0010313 infores:monarchinitiative not_provided not_provided HGNC:3571 MONDO:0010313 uuid:dcea5e76-8dcc-4c9a-9975-ecd599a0c16b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA409104032 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104032 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM1 PS4 The c.224G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to lysine at codon 75 (p.Arg75Lys)) of NM_175914.5. This variant resides in an amino acid within the HNF4α DNA binding domain that are necessary for homodimer formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.777, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar: 430844, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.224G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 4.0.0, approved 10/10/2025): PM1, PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104032/MONDO:0015967/085 2025-10-28 2025-10-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7824 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0232462 infores:hetionet NCBITaxon:48796 biolink:causes MONDO:0005957 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:48796 MONDO:0005957 CHEBI:75722 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151908 infores:hetionet CHEBI:6456 biolink:causes NCIT:C118302 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235195 infores:hetionet CHEBI:135342 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0542571 infores:hetionet CHEBI:6129 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1306341 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0151736 infores:hetionet CHEBI:7822 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0041349 infores:hetionet CHEBI:6741 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0036974 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0034150 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0403632 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0542184 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235848 infores:hetionet CHEBI:63599 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0243065 infores:hetionet CHEBI:66876 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0026858 infores:hetionet CHEBI:4672 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0015672 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0043145 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043145 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0042109 infores:hetionet CHEBI:2682 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0037299 infores:hetionet GO:0060222 biolink:causes GO:0042670 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0042670 CHEBI:114785 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0003467 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0158350 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0006826 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0040425 infores:hetionet CHEBI:231594 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C2225524 infores:hetionet CHEBI:4784 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0392699 infores:hetionet CAID:CA658795282 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795282 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2300del (p.Phe767SerfsTer14) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Western blot of protein from the cultured skin fibroblasts of a patient with this variant showed no GAA cross-reactive material i.e. CRIM-negative (PMID: 22252923), supporting that c.2300del is a loss of function variant (PVS1). This patient has <1% normal GAA activity in skin fibroblasts (PP4_Moderate) and is homozygous for the variant (PMID: 22252923, personal communication) (PM3_Supporting). A patient with Pompe disease who is heterozygous for the variant has been reported but further details are unavailable and the second variant was not reported (PMID: 18425781). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555341; 1 star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795282/MONDO:0009290/010 2021-08-27 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2038 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0007642 infores:hetionet CHEBI:47780 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014173 infores:hetionet CHEBI:472657 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0340865 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0340464 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0034150 infores:hetionet CHEBI:6456 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0018790 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0021843 infores:hetionet CHEBI:50131 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0017565 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0235818 infores:hetionet CHEBI:63623 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C2363730 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0020649 infores:hetionet CHEBI:63589 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0231218 infores:hetionet NCBIGene:50945 biolink:causes MONDO:0010560 infores:monarchinitiative not_provided not_provided HGNC:11600 MONDO:0010560 uuid:3de8c3e9-52bc-4dca-9a76-92428a327389 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0032285 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0042769 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0241712 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0241712 infores:hetionet CHEBI:231594 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0004096 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0542184 infores:hetionet CHEBI:40237 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0015230 infores:hetionet CHEBI:520985 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0235266 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0233414 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0242461 infores:hetionet CHEBI:64355 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0027424 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0033777 infores:hetionet CHEBI:83527 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0004093 infores:hetionet CHEBI:28830 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0020517 infores:hetionet CHEBI:51041 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0006277 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0521839 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0497365 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0162429 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C1443060 infores:hetionet CHEBI:61390 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0027497 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151547 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0234458 infores:hetionet CHEBI:31625 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0014236 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085649 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0013395 infores:hetionet CHEBI:5118 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030232 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0162429 infores:hetionet CHEBI:6129 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0017181 infores:hetionet CHEBI:3207 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0018965 infores:hetionet CHEBI:8713 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0948594 infores:hetionet CHEBI:41774 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0037763 infores:hetionet CHEBI:63598 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023218 infores:hetionet CAID:CA891842376 biolink:causes MONDO:0011071 infores:clingen CAID:CA891842376 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.351+1_351+2dup is a splicing variant which alters a canonical splice site (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA891842376/MONDO:0011071/008 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6437 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0233471 infores:hetionet CHEBI:110423 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0015230 infores:hetionet CHEBI:63612 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0030193 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0392176 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0027813 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0032326 infores:hetionet CHEBI:31949 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0013395 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0267792 infores:hetionet CHEBI:94411 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0152198 infores:hetionet CHEBI:84500 biolink:causes EFO:0020909 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0877167 infores:hetionet CHEBI:68579 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0022346 infores:hetionet NCBIGene:123264 biolink:causes MONDO:0859180 infores:monarchinitiative not_provided not_provided HGNC:29956 MONDO:0859180 uuid:98a0cea7-b975-4cd8-ab94-9daacd5fdff2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135930 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0039070 infores:hetionet CHEBI:2569 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0009676 infores:hetionet UMLS:C0657912 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013456 infores:hetionet CHEBI:10101 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020488 infores:hetionet CHEBI:4466 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C3665386 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027051 infores:hetionet CHEBI:7465 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0600142 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006266 infores:hetionet CHEBI:28864 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C1384353 infores:hetionet CHEBI:6073 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0004093 infores:hetionet CHEBI:31932 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020473 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0025202 infores:hetionet CAID:CA8314693 biolink:causes MONDO:0009276 infores:clingen CAID:CA8314693 MONDO:0009276 PMID: Uncertain Significance BS1 PP3, PP4, BS2, BP4, PM5 The missense variant NM_000173.7(GP1BA):c.92T>C (p.Val31Ala) has been reported in one macrothrombocytopenia patient heterozygous for this variant (PMID: 34400424) however the same variant was detected in the mother with normal laboratory parameters. No BSS patients have been reported to our knowledge. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0006253 (based on 784/1179792 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0005; BS1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS1 (ClinGen Platelet Disorders VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8314693/MONDO:0009276/079 2025-02-11 2025-02-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:46081 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0236075 infores:hetionet CHEBI:47499 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0030252 infores:hetionet CHEBI:45599 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0220870 infores:hetionet CHEBI:8461 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0040264 infores:hetionet CHEBI:182080 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0040822 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0032584 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0948594 infores:hetionet CHEBI:31176 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C2939147 infores:hetionet NCBIGene:6904 biolink:causes MONDO:0044646 infores:monarchinitiative not_provided not_provided HGNC:11581 MONDO:0044646 uuid:cbac184c-998f-415d-b923-7711ece6847c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0039070 infores:hetionet CHEBI:47426 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0004093 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0435630 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0435630 infores:hetionet NCBIGene:375307 biolink:causes MONDO:0023664 infores:monarchinitiative not_provided not_provided HGNC:25062 MONDO:0023664 uuid:3fb81092-0079-4090-85dd-f5eb0c251f56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:100820829 biolink:causes MONDO:0971175 infores:monarchinitiative not_provided not_provided HGNC:43444 MONDO:0971175 uuid:61c7f726-2a4b-4a39-bae8-0cc6c385cf4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3127 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0041657 infores:hetionet CHEBI:9168 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151798 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0847631 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0847631 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0746883 infores:hetionet CHEBI:63589 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0027769 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0040034 infores:hetionet CHEBI:5118 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0017565 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0037274 infores:hetionet GO:0099148 biolink:causes GO:0016079 infores:ubergraph knowledge_assertion manual_agent GO:0099148 GO:0016079 CHEBI:8707 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013456 infores:hetionet CHEBI:9566 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0237314 infores:hetionet NCBIGene:55904 biolink:causes MONDO:0032793 infores:monarchinitiative not_provided not_provided HGNC:18541 MONDO:0032793 uuid:8066fa32-cca2-4ae3-8971-f9660929f331 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0009450 infores:hetionet CHEBI:55346 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151636 infores:hetionet CHEBI:63620 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0026826 infores:hetionet CAID:CA320638113 biolink:causes MONDO:0011071 infores:clingen CAID:CA320638113 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.352-141_352-137del variant is an intronic variant which is absent from all population databases, including gnomAD v2.1.1 and v3.1.2, with at least 20x coverage for RUNX1 (PM2_supporting). In addition, splicing algorithms predicted no effect on splicing (SpliceAI score < 0.20) (BP4), and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP100way (GRCh38/hg38) scores 0.0926535 to -0.560732 < 2.0 for all deleted nucleotides) (BP7). To our knowledge, this variant has not been found in patients with FPD/AML phenotype, and no functional studies are available. In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320638113/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9586 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0039231 infores:hetionet CHEBI:6741 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0025222 infores:hetionet CHEBI:490877 biolink:causes HP:0007894 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0151891 infores:hetionet GO:0007317 biolink:causes GO:0007350 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0007350 CHEBI:3127 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0003537 infores:hetionet CHEBI:116278 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0003862 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0878544 infores:hetionet CHEBI:47898 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0007859 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0027765 infores:hetionet CHEBI:4710 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0001824 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0004936 infores:hetionet CHEBI:49575 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013491 infores:hetionet CHEBI:63611 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0028081 infores:hetionet CHEBI:5778 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0000731 infores:hetionet CHEBI:145499 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0278134 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0006277 infores:hetionet CHEBI:38940 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0162285 infores:hetionet CHEBI:724125 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0241157 infores:hetionet CHEBI:5778 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0018681 infores:hetionet CHEBI:4562 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0700590 infores:hetionet CHEBI:6931 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0231835 infores:hetionet CHEBI:135005 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0085631 infores:hetionet CAID:CA2387257554 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387257554 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP2, BP3, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.806-7T>G is an intronic variant predicted by SpliceAI not to impact splicing (BP4). However, it is located at a conserved nucleotide (PhyloP score = 2.8582 in GRCh38), and the variant is not the reference nucleotide in one primate and/or three mammal species. It is absent from gnomAD v2 and v3 (PM2_Supporting) and has not been reported in cases or the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387257554/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6775 biolink:causes HP:0045082 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0231255 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0917798 infores:hetionet CHEBI:10023 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014518 infores:hetionet CHEBI:3077 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0023380 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0042024 infores:hetionet CHEBI:63580 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0024141 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0021843 infores:hetionet CHEBI:2675 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0080274 infores:hetionet CHEBI:68575 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0040822 infores:hetionet CHEBI:18248 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0034882 infores:hetionet CAID:CA10584693 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584693 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP2, BP1, BP4, BP3, PS3, PS4, PS2, PS1, BP5, BP7, BS3, BS1, BS4, PM3, PM4, PM1, PM5, PM6, PVS1, PP1, PP2, PP3, BS2 The NC_000019.10:g.11089341A>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP4: Variant meets PM2 and is identified in 1 index case with DLCN score >=6 from De Castro-Orós et al., 2011 (PMID 21538688).PS3_Supporting (PMID 31395865) and BS3_Supporting (PMID 21538688) both met, but not applied as functional studies are conflicting. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584693/MONDO:0007750/013 2024-10-28 2025-01-13 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9086 biolink:causes UMLS:C0562057 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0562057 infores:hetionet CHEBI:46195 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0151798 infores:hetionet CHEBI:134745 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0012833 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0017178 infores:hetionet CHEBI:16899 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0015230 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0023470 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017152 infores:hetionet CHEBI:5280 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0423006 infores:hetionet CHEBI:408174 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0027441 infores:hetionet CHEBI:16755 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0235896 infores:hetionet CHEBI:51860 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027497 infores:hetionet CHEBI:5001 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0014724 infores:hetionet NCBIGene:3930 biolink:causes MONDO:0008214 infores:monarchinitiative not_provided not_provided HGNC:6518 MONDO:0008214 uuid:b17cde01-c404-420e-8e9e-0a4f4298b80f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15553 biolink:causes UMLS:C1963921 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C1963921 infores:hetionet NCBITaxon:1717 biolink:causes MONDO:0005504 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1717 MESH:D004165 DB09320_MESH_D004165_1DB00199_MESH_D004165_1DB01053_MESH_D004165_1 CHEBI:2668 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0011991 infores:hetionet CAID:CA135988 biolink:causes MONDO:0021060 infores:clingen CAID:CA135988 MONDO:0021060 PMID: Uncertain Significance PP2 PS4, PM2 The c.412G>A (p.Gly138Ser) variant in the HRAS gene has been identified in 1 Asian woman with Noonan Syndrome and 1 Asian man with Costello Syndrome (Laboratory for Molecular Medicine internal data). It has been also identified in 1 patient who had a combined cardiac panel (GeneDx internal data) and was observed in 3 unrelated women with breast cancer and 1 woman with uterine cancer (Invitae internal data). PS4_Supporting not met due to conflicting phenotypes between the identified patients. HRAS has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Gly138Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135988/MONDO:0021060/004 2019-07-25 2019-12-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3568 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151908 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0020651 infores:hetionet CHEBI:2453 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0151766 infores:hetionet CHEBI:8024 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0700225 infores:hetionet CHEBI:5098 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0018834 infores:hetionet CHEBI:7627 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C2937358 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151736 infores:hetionet CHEBI:43968 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0002994 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020456 infores:hetionet CHEBI:114785 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0002878 infores:hetionet CHEBI:3757 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0027497 infores:hetionet CHEBI:135613 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0264906 infores:hetionet CHEBI:8356 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0032781 infores:hetionet NCBITaxon:666 biolink:causes MONDO:0015766 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:666 MESH:D002771 DB01017_MESH_D002771_1DB00254_MESH_D002771_1DB02703_MESH_D002771_1 CHEBI:6965 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0700075 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002622 infores:hetionet CHEBI:47519 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151740 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0855242 infores:hetionet CHEBI:27974 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0043094 infores:hetionet CHEBI:15367 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1527344 infores:hetionet CHEBI:94807 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0041657 infores:hetionet CHEBI:65173 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0015371 infores:hetionet CHEBI:9123 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015402 infores:hetionet CHEBI:31236 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011168 infores:hetionet CHEBI:31859 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C2937350 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0021843 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0152029 infores:hetionet CHEBI:50730 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0002994 infores:hetionet CHEBI:6970 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0235761 infores:hetionet CHEBI:5138 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0497156 infores:hetionet CHEBI:63610 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0004093 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0034150 infores:hetionet CHEBI:3175 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0423006 infores:hetionet NCBIGene:114798 biolink:causes MONDO:0007661 infores:monarchinitiative not_provided not_provided HGNC:20297 MONDO:0007661 uuid:8feb67c0-4fa8-4ec3-961d-e340946029e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA519184963 biolink:causes MONDO:0010305 infores:clingen CAID:CA519184963 MONDO:0010305 PMID: Likely Benign BP7, PM2_Supporting, BP4 The NM_005629.4:c.354C>T (p.Ala118=) variant in SLC6A8 is a synonymous (silent) variant that is not predicted by SpliceAI or varSEAK to impact splicing, and it occurs at a nucleotide that is not conserved (BP4, BP7). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in any patients with creatine transporter deficiency in the literature. There is a ClinVar entry for this variant (Variation ID: 511340). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA519184963/MONDO:0010305/027 2022-06-06 2022-10-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:9130 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0039070 infores:hetionet CHEBI:45081 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0242528 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0043241 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0043241 infores:hetionet CHEBI:42797 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0231528 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005012 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151779 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0005940 infores:hetionet CHEBI:8346 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0036104 infores:hetionet NCBIGene:11200 biolink:causes MONDO:0700275 infores:monarchinitiative not_provided not_provided HGNC:16627 MONDO:0700275 uuid:57cbce7e-7523-4327-a594-43b39b42ef07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4907 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0031117 infores:hetionet CHEBI:135736 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0018808 infores:hetionet CHEBI:75045 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0011603 infores:hetionet CHEBI:53691 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0009421 infores:hetionet CHEBI:50223 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0278134 infores:hetionet CHEBI:31643 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0020517 infores:hetionet CHEBI:9130 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0022346 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0021843 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001266 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014733 infores:hetionet CHEBI:31644 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0036974 infores:hetionet CHEBI:47381 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0003873 infores:hetionet CHEBI:63599 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0033687 infores:hetionet CHEBI:6456 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0004245 infores:hetionet GO:0006110 biolink:causes GO:0009060 infores:ubergraph knowledge_assertion manual_agent GO:0006110 GO:0009060 CHEBI:6538 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0013144 infores:hetionet CAID:CA318202 biolink:causes MONDO:0100038 infores:clingen CAID:CA318202 MONDO:0100038 PMID: Likely Benign BS1, BP4 PS1, PM2, PM5, PM1, PP3, PP4 The filtering allele frequency (the lower threshold of the 95% CI of 21/1,613,966) of thec.1526A>G variant in SCN2A is 0.00001144 for Non-Finnish European chromosomes by gnomAD v4.1.0, which is higher than the ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel threshold (>0.0002%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.243 (REVEL threshold for BP4 supporting 0.183-0.290, PMID: 36413997), evidence that does not predict a damaging effect on SCN2A function (BP4). This missense change has been observed in one individual with seizures (PMID: 25131622). However, the inheritance and a detailed information of the phenotype is not described. In summary, this variant has been classified as likely benign for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the Epilepsy Sodium Channel Expert Panel: BS1, BP4 (version 2.0; approved 8/26/25). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA318202/MONDO:0100038/068 2025-08-26 2025-10-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7852 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0015967 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151826 infores:hetionet CAID:CA410148333 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148333 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1051G>A (p.Gly351Ser) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score < 0.50 (0.16) and SpliceAI score is ≤ 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148333/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64310 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085636 infores:hetionet CHEBI:8871 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085610 infores:hetionet CHEBI:47780 biolink:causes MONDO:0019170 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0031036 infores:hetionet CHEBI:9943 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0392156 infores:hetionet CHEBI:4995 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085932 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0151580 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151580 infores:hetionet CHEBI:94686 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0028754 infores:hetionet CHEBI:2663 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151744 infores:hetionet CHEBI:4717 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0002994 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0857353 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004238 infores:hetionet CHEBI:17474 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0043094 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0541900 infores:hetionet CAID:CA399805518 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805518 MONDO:0100326 PMID: Likely Pathogenic PM5, PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The ITGA2B missense variant NM_000419.5:c.641T>G replaces the leucine residue with an arginine residue (p.Leu214Arg). This variant has been observed in homozygosity in a proband (Patient B, PMID: 26096001; PM3_supporting) with a phenotype specific for Glanzmann's thrombasthenia (GT), including a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin (PP4_Moderate). This variant has not been reported in population databases, including gnomADv4.1.0 (PM2_supporting) and is predicted to be damaging by in silico tools (REVEL score 0.797; PP3). Furthermore, a different missense change at this amino acid residue (ITGA2B c.641T>C (p.Leu214Pro)) is classified as pathogenic by the Platelet Disorders VCEP (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporting, PM5, PP4_moderate, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805518/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:55243 biolink:causes MONDO:0030962 infores:monarchinitiative not_provided not_provided HGNC:15734 MONDO:0030962 uuid:5b95b096-a992-4e16-8de5-b775c5121a1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0019158 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0521491 infores:hetionet CAID:CA10568501 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568501 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM1, PP3, PS4 BS1, PM2, PP1 The NM_000132.3(F8):c.1094A>G variant predicts a missense change, Tyr365Cys, in the a1 interdomain of FVIII protein, reported to impair activation and deactivation of the protein meeting PM1 criteria (PMID: 12139751). This variant does not meet the rarity population criteria. It is reported in multiple individuals (>32) in the literature (PMID: 29296726, PMID: 12139751, PMID: 21645180, PMID: 17445092, PMID: 21751985, PMID: 18691168, PMID: 18034822, PMID: 19456877, PMID: 15810915, PMID: 11857744). Of note, this variant is associated with discrepant factor VIII activity levels between the one-stage and two-stage, or chromogenic, assay, and individuals with factor VIII levels measured on a two-stage assay may be within the normal range (EAHAD/CDC Champs databases). Additionally, individuals with this variant may have a mild to no bleeding history. The variant has a REVEL score of 0.756 (threshold >0.6) meeting PP3 criteria. In summary, the variant meets criteria to be classified as pathogenic causing decreased factor VIII activity levels, but may have a lower penetrant bleeding phenotype. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Expert Panel for F8: PS4_Very Strong, PM1, PP4_Moderate, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568501/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:465284 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0948594 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011127 infores:hetionet CAID:CA533262859 biolink:causes MONDO:0015152 infores:clingen CAID:CA533262859 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.4872delG p.(Glu1624AspfsTer10) variant in DYSF, which is also known as NM_001130987.2: c.4989del (p.Glu1663AspfsTer10), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 45/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 13 unrelated patients with phenotypes consistent with LGMD in a homozygous state in all individuals, with reported consanguinity in at least one family (1.0 pt, PMID: 10825360, 35723113, 17698709) (PM3). Many of these families were Jewish and from Libya. At least one of these individuals displayed muscle weakness and reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 17698709; PP4_Strong). The highest population frequency of this variant in gnomAD v4.1.0 is 0.00001335 in the African/African American population (1/74922 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/14/2025): PVS1, PP4_Strong, PM3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA533262859/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8212 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0039231 infores:hetionet CHEBI:64312 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011253 infores:hetionet CHEBI:44185 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151907 infores:hetionet CHEBI:49603 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0023530 infores:hetionet NCBIGene:5566 biolink:causes MONDO:0014359 infores:monarchinitiative not_provided not_provided HGNC:9380 MONDO:0014359 uuid:0732b102-0eef-4265-94d7-1d8133438276 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23230 biolink:causes MONDO:0008695 infores:monarchinitiative not_provided not_provided HGNC:1908 MONDO:0008695 uuid:725f2fff-5531-43f4-aff2-27bc520d0ea6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0231919 infores:hetionet CHEBI:499361 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0151786 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0004238 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020538 infores:hetionet CHEBI:6888 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0035455 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0549356 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0019348 infores:hetionet CAID:CA000514 biolink:causes MONDO:0018875 infores:clingen CAID:CA000514 MONDO:0018875 PMID: Benign BP7_Strong, BS2, PM2_Supporting BA1, BP4, PS3, PS4, PS2, PM1, BS1, BS3, BS4, PM6, PP3, PP1, PP4 The NM_000546.6:c.97-3C>T variant in TP53 is an intronic variant located in intron 3. This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor). This variant has an allele frequency of 0.000004337 (7/1614174 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). The c.97-3C>T variant is an intronic variant for which RNA splicing assay data demonstrates no splicing aberration (Internal lab contributors). To our knowledge, functional assays have not been reported for this variant (PS3/BS3 not met). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BP7_Strong (RNA). (Bayesian Points: -7; VCEP specifications version 2.3). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000514/MONDO:0018875/009 2025-04-11 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4974 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0011206 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0206062 infores:hetionet CHEBI:31348 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040264 infores:hetionet CHEBI:474180 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C3665624 infores:hetionet GO:0042802 biolink:causes GO:0051262 infores:drugmechdb knowledge_assertion manual_agent GO:0042802 GO:0051262 DB05352_MESH_D000686_1 CAID:CA658799414 biolink:causes MONDO:0011071 infores:clingen CAID:CA658799414 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.98-20_98-18del is an intronic variant which has a SpliceAI Δ score ≤ 0.20 (0.00 except for 0.05 at acceptor gain) (BP4). It is completely absent from all population databases (gnomAD v2.1.1, gnomAD v3.1.2, and ExAC v1.0) with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799414/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135888 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0040586 infores:hetionet CHEBI:5118 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151474 infores:hetionet CHEBI:3696 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0023218 infores:hetionet CHEBI:31932 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020625 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1384353 infores:hetionet CHEBI:3561 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0025345 infores:hetionet CHEBI:6367 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027424 infores:hetionet CHEBI:6970 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0042963 infores:hetionet CHEBI:9757 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0016382 infores:hetionet CHEBI:5790 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085593 infores:hetionet CHEBI:72564 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0235378 infores:hetionet CHEBI:4814 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0040264 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0339916 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0015672 infores:hetionet CHEBI:8871 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0278134 infores:hetionet CHEBI:23765 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0030193 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0030312 infores:hetionet NCBIGene:4891 biolink:causes MONDO:0008787 infores:monarchinitiative not_provided not_provided HGNC:10908 MONDO:0008787 uuid:cf68494b-a0b5-476d-937f-01c2d673a269 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6811 biolink:causes MONDO:0957540 infores:monarchinitiative not_provided not_provided HGNC:11440 MONDO:0957540 uuid:e0a89497-2bef-4aa7-beb4-682e2fb2bbff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA915950961 biolink:causes MONDO:0100437 infores:clingen CAID:CA915950961 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PS4_Supporting PP1 NM_001034853.2(RPGR):c.3104_3105del (p.Glu1035GlyfsTer?) is a frameshift variant due to a 2-nucleotide deletion introducing a premature stop codon within exon 15 of 15, which is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 35806195, 28863407, PS4_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), childhood-onset (1 pt), myopia (0.5 pts), visual field constriction (0.5 pts), and genotyping by whole exome sequencing with a panel of 238 genes that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (6 points, 31645972, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PS4_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915950961/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Supports CAID:CA169363 biolink:causes MONDO:0007648 infores:clingen CAID:CA169363 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM3, PM5, PM1, PM4, PM2, PM6, PVS1, PP4, PP1, PP2, PP3, BS2, BP1, BP4, BP3, PS4, PS2, PS1, PS3 The NM_004360.5(CDH1):c.2076T>C (p.Ala692=) variant has an allele frequency of 0.88894 (88.89%, 22156/24924 alleles, 9856 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2_Supporting). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA169363/MONDO:0007648/007 2023-08-09 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:18248 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0004093 infores:hetionet CHEBI:6954 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0333355 infores:hetionet CAID:CA16619910 biolink:causes MONDO:0007113 infores:clingen CAID:CA16619910 MONDO:0007113 PMID: Uncertain Significance BP4 PM2, PS4 The p.Val267Ile variant in UBE3A is present in one individual in gnomAD (does not meet PM2_supporting or BS1). Computational analysis prediction tools suggests that the p.Val267Ile variant in UBE3A does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Val267Ile variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619910/MONDO:0007113/016 2021-04-02 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:36704 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0041657 infores:hetionet CHEBI:4469 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C3263723 infores:hetionet CHEBI:8764 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0043352 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0340464 infores:hetionet CHEBI:45409 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085649 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0037274 infores:hetionet CHEBI:31980 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0018944 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0234215 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030920 infores:hetionet CAID:CA7435667 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435667 MONDO:0007113 PMID: Likely Benign BP4, BP7 BS1 The c.282C>T p.Gly94= variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0069% in the European (non-Finnish) sub population (no criteria met). The silent p.Gly94= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.282C>T p.Gly94= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435667/MONDO:0007113/032 2023-06-15 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64355 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0700590 infores:hetionet GO:0052150 biolink:causes GO:0006915 infores:ubergraph knowledge_assertion manual_agent GO:0052150 GO:0006915 CHEBI:2948 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0038238 infores:hetionet CHEBI:53760 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0392525 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151883 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0027765 infores:hetionet CHEBI:3347 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020461 infores:hetionet NCBIGene:85465 biolink:causes MONDO:0032905 infores:monarchinitiative not_provided not_provided HGNC:29361 MONDO:0032905 uuid:3496373b-bbc1-4816-8a1a-5c56db3ec1d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1901620 biolink:causes GO:0021915 infores:ubergraph knowledge_assertion manual_agent GO:1901620 GO:0021915 CHEBI:28748 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0031046 infores:hetionet CHEBI:4702 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0027424 infores:hetionet NCBIGene:22953 biolink:causes MONDO:0011994 infores:monarchinitiative not_provided not_provided HGNC:15459 MONDO:0011994 uuid:f5b967d6-45d6-49e3-b82d-3982452de162 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0233472 infores:hetionet CHEBI:5106 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0042571 infores:hetionet CHEBI:2904 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0277925 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0151735 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0004936 infores:hetionet CHEBI:63577 biolink:causes UMLS:C1963822 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1963822 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0152227 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0239549 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0239549 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0006277 infores:hetionet NCBITaxon:287 biolink:causes MONDO:0004795 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:287 MESH:D010032 DB03166_MESH_D010032_1 CHEBI:9927 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0006277 infores:hetionet CHEBI:3441 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020453 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0149931 infores:hetionet CHEBI:5118 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027849 infores:hetionet CHEBI:49668 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0014518 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0038358 infores:hetionet CHEBI:71255 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0039231 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0021843 infores:hetionet CHEBI:8874 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0043094 infores:hetionet CHEBI:161680 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0006266 infores:hetionet CHEBI:3172 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0041657 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027765 infores:hetionet CHEBI:3814 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0018834 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005665 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0376175 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001433 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042251 infores:hetionet CAID:CA2573157362 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157362 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP2, BP3, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, BS2, PP1, PP2, PP3, PP4 The NM_001754.5(RUNX1):c.259_260dup (p.Glu88AlafsTer?) is a null variant that affects all biologically relevant transcripts (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). The variant Impacts the 88th amino acid just outside the RHD domain (PM4_supporting applied to amino acid residues 89-204 within the RHD). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157362/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:32315 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0278134 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0747979 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0747979 infores:hetionet CHEBI:31624 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0030193 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0031350 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0853777 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0001824 infores:hetionet CHEBI:116278 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0235063 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0038999 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1368065 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0041747 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151626 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151626 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030305 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0040147 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003864 infores:hetionet CHEBI:10650 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011175 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0877322 infores:hetionet CHEBI:2659 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0022107 infores:hetionet CHEBI:63598 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0012569 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0267792 infores:hetionet CAID:CA226156 biolink:causes MONDO:0100453 infores:clingen CAID:CA226156 MONDO:0100453 PMID:11328726PMID:11328726 Likely Pathogenic PM3, PP4_Moderate, PP1, PM2_Supporting PS3, BS3, PP3 NM_000180.4(GUCY2D):c.937C>T (p.Arg313Cys) is a missense variant predicted to replace arginine with cysteine at position p.313. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000009334, with 15 alleles / 1,607,084 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who also harbored either the NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter) variant (suspected but not confirmed in trans, PMID:10951519) or the NM_000180.4(GUCY2D):c.3078_3083dup (p.Ile1027_Leu1028dup) variant (confirmed in trans, PMID: 34048777), each which have been previously classified as either pathogenic or likely pathogenic by the LCA/eoRD VCEP (1.5 total pts, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (VCEP member-provided data, PP1). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with onset at age 0.3 years (1 pt), genotyping by exome sequencing with no alternative cause of retinal disease identified (4 pts), poor vision with no light perception (1 pt), roving nystagmus (1 pt), attenuated vessels (0.5 pts), and extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (9.5 total points, PMID: 34048777, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP1, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226156/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15854 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0178298 infores:hetionet CHEBI:127780 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0003467 infores:hetionet CHEBI:6754 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C1443060 infores:hetionet NCBITaxon:27973 biolink:causes MONDO:0005743 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:27973 MONDO:0005743 CHEBI:4315 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0011603 infores:hetionet CHEBI:7824 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0344232 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0017574 infores:hetionet CHEBI:4681 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0011071 infores:hetionet CHEBI:28787 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0039231 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0085584 infores:hetionet CHEBI:4530 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C2047937 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0041969 infores:hetionet CAID:CA891843836 biolink:causes MONDO:0012996 infores:clingen CAID:CA891843836 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong BA1, BS1 The NM_001482.3:c.1209del (p.Gly404AlafsTer24) variant in GATM is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed; however, the truncated/altered region includes the active site residue Cys407 that is critical to protein function (PVS1_Strong; PMIDs 9148748, 9218780, 9266688). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 570204). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA891843836/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2663 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0018524 infores:hetionet CHEBI:75984 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0085605 infores:hetionet CHEBI:5855 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014457 infores:hetionet CHEBI:127780 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0011175 infores:hetionet CHEBI:94411 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0027769 infores:hetionet CHEBI:3723 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0012569 infores:hetionet CHEBI:4717 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0015230 infores:hetionet CHEBI:9398 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0231528 infores:hetionet CHEBI:27690 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0040264 infores:hetionet CHEBI:7466 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0014534 infores:hetionet GO:2000313 biolink:causes GO:0021999 infores:ubergraph knowledge_assertion manual_agent GO:2000313 GO:0021999 NCBIGene:10486 biolink:causes MONDO:0957545 infores:monarchinitiative not_provided not_provided HGNC:20039 MONDO:0957545 uuid:b371e24a-c080-4a04-8b24-ede51a68345e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4657 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0003123 infores:hetionet CHEBI:32293 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0033575 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0281914 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0281914 infores:hetionet CHEBI:3387 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0700361 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0015397 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0948296 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948296 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0878544 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0340464 infores:hetionet CHEBI:9737 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0011603 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0854100 infores:hetionet CHEBI:2682 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0231218 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0037274 infores:hetionet CHEBI:70746 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0011168 infores:hetionet CHEBI:63619 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0009676 infores:hetionet CHEBI:175901 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0162529 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0037199 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0040261 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036983 infores:hetionet CHEBI:7454 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C2939147 infores:hetionet CHEBI:9123 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013428 infores:hetionet CHEBI:6073 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C1167965 infores:hetionet CHEBI:9014 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0011603 infores:hetionet CHEBI:45951 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0232461 infores:hetionet CHEBI:114785 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0085605 infores:hetionet CHEBI:17026 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0010692 infores:hetionet CHEBI:134991 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0022904 infores:hetionet CHEBI:16899 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0235710 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0233494 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0863093 infores:hetionet CAID:CA10443955 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443955 MONDO:0010315 PMID: Likely Benign BS2 BS1, PM5, PM2, BA1, PS4 NM_000206.3(IL2RG):c.74C>T is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 25 (p.Thr25Met).The variant is observed in 23 hemizygotes in gnomAD v4 (BS2 met).In summary, this variant meets the criteria to be classified as a Likely Benign variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2 (VCEP specifications version 2). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443955/MONDO:0010315/129 2025-11-19 2025-11-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:3423 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0035317 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020651 infores:hetionet CHEBI:77260 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0344232 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017566 infores:hetionet CHEBI:465284 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0086565 infores:hetionet CHEBI:2038 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009421 infores:hetionet NCBIGene:63982 biolink:causes MONDO:0014019 infores:monarchinitiative not_provided not_provided HGNC:14004 MONDO:0014019 uuid:0a8e7da0-678b-4ac7-8006-61c407b52e66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0340865 infores:hetionet CHEBI:91834 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0041657 infores:hetionet CHEBI:116278 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0009806 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0548823 infores:hetionet CHEBI:63612 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0000737 infores:hetionet CAID:CA020488 biolink:causes MONDO:0008667 infores:clingen CAID:CA020488 MONDO:0008667 PMID:15574766PMID:17700531PMID:16452184PMID:12097293PMID:19030229PMID:10878807PMID:30890701PMID:31980715PMID:19228690PMID:19602254PMID:11331613PMID:11331612PMID:12944410PMID:27517496PMID:23772956PMID:18567581PMID:17898043PMID:16585181PMID:26846855PMID:28235946 Uncertain Significance BS1, PM1, PP3, BS2, PS3_Supporting The variant NM_000551.4(VHL):c.562C>G (p.Leu188Val) is a missense variant predicted to cause substitution of Valine for Leucine at position 188. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00002474 (39/1180038 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). From pooled laboratory data: 105 probands carried this variant, and none met Danish criteria for VHL. 18/105 had a single VHL feature. 27 known carriers were 60+ years old and did not have VHL phenotypes. At least 11 of those 60+ without VHL features had no VHL features reported in the family history (BS2), while 8 had VHL features reported in family history (including a carrier relative who met diagnostic VHL criteria). In most functional studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability. (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). The L188V variant is located within the alpha domain (156-192), a key functional domain of VHL (PM1). The computational predictor REVEL gives a score of 0.796, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). Note: This variant has been reported as a putative low penetrance VHL type 2C variant; however at this time, the VHL VCEP does not have low-penetrance specific classification recommendations (see ClinGen Low Penetrance / Risk Allele Working Group). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020488/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41774 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0220870 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0234215 infores:hetionet UMLS:C0009315 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0015967 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151814 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151814 infores:hetionet CHEBI:42797 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0518988 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0424000 infores:hetionet CHEBI:63581 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0877192 infores:hetionet CHEBI:3756 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0026603 infores:hetionet CHEBI:16664 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0023530 infores:hetionet CHEBI:48669 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C1443060 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0007222 infores:hetionet CHEBI:9086 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0855775 infores:hetionet CHEBI:3011 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0010200 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0155002 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0155002 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0026857 infores:hetionet NCBIGene:84992 biolink:causes MONDO:0014780 infores:monarchinitiative not_provided not_provided HGNC:28213 MONDO:0014780 uuid:e601db70-745b-4637-8f8d-25aeb60ed4ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027796 infores:hetionet NCBIGene:7403 biolink:causes MONDO:0010465 infores:monarchinitiative not_provided not_provided HGNC:12637 MONDO:0010465 uuid:4696c3e8-ea39-4127-8f2f-e01253a0708c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA376064378 biolink:causes MONDO:0011225 infores:clingen CAID:CA376064378 MONDO:0011225 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PP4_Moderate, PVS1 The c.161+2T>G (NM_001033855.3) variant in DCLRE1C occurs within the canonical splice donor site (+2) of intron 2. It is predicted to cause skipping of a biologically relevant exon, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Although patients carrying this variant have not been published in the literature, there is one ClinVar entry from Cowan and Puck Lab, Allergy Immunology and BMT Division, UCSF Benioff Children's Hospital Accession: SCV002598533.1. By internal communication, 0.5 pts for the information that the patient is homozygous. PM3_Suppoting.The patient presented: * Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination: 2 points, PP4_Moderate.In summary, this variant meets the criteria to be classified as a Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376064378/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042035 infores:hetionet CHEBI:50859 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020488 infores:hetionet CHEBI:3223 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0423798 infores:hetionet CHEBI:48273 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0699828 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020651 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1302752 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0006266 infores:hetionet CAID:CA227899 biolink:causes MONDO:0100438 infores:clingen CAID:CA227899 MONDO:0100438 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PP1_Strong NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) is a nonsense variant that introduces a premature stop codon into exon 6 of 6, and is predicted to lead to C-terminal truncation of a region that is critical to AIPL1 function (PVS1). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 3 probands plus 11 similarly affected relatives, with the variant present in the homozygous state (PP1_Strong; PMID: 10615133). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with blindness (1 pt) from birth (1 pt), absence of electroretinogram responses from both rods (0.5 pts) and cones (1 pt), and a fundus exam indicating pigmentary retinopathy with attenuated blood vessels (0.5 pts) and macular degeneration, which together are specific for AIPL1-related retinopathy (4.5 pts, PMID: 10615133). This variant is present in gnomAD v.4.1.0 at an allele frequency of 0.0003542, with 569/1606522 alleles which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP1_Strong, PP4, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 9/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227899/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10558620 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558620 MONDO:0010726 PMID: Benign BP5, BA1 BP7 The allele frequency of the c.378-6C>G variant in MECP2 is 0.032% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The c.378-6C>G variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the c.378-6C>G variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558620/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true NCBIGene:284184 biolink:causes MONDO:0032910 infores:monarchinitiative not_provided not_provided HGNC:33551 MONDO:0032910 uuid:69545150-b375-46d5-bfe1-e917bb3a72d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042373 infores:hetionet CAID:CA220578 biolink:causes MONDO:0009861 infores:clingen CAID:CA220578 MONDO:0009861 PMID:21147011PMID:21147011 Uncertain Significance PM2, PP4_Moderate, PM3_Supporting PP3 PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ESP MAF=0.00012.; PP4_Moderate: Detected in a patient with mild HPA. Assessment of the PAH, PTS, and QDPR genes was performed. (PMID:21147011); PM3-supporting: Detected with V388M, pathogenic in ClinVar, but parental testing not performed. (PMID:21147011). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_supporting). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220578/MONDO:0009861/006 2019-04-26 2019-04-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3756 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0344320 infores:hetionet CHEBI:28445 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0856054 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0553732 infores:hetionet CHEBI:135939 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0036974 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0012833 infores:hetionet CHEBI:5106 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0015967 infores:hetionet CAID:CA011642 biolink:causes MONDO:0005045 infores:clingen CAID:CA011642 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PP3, PP1, PS4_Moderate PS3, PM5, PM6, BS3, PS1, PS2, BP5 The NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys) has been identified in at least 15 individuals with HCM, including 3 who also carried other potentially disease-causing variants (PS4_Moderate; Andersen 1999 PMID:10563488; Havndrup 2003 PMID:12566107; Andersen 2004 PMID:15114369; Van Driest 2004 PMID:15358028; Van Driest 2004 PMID:15519027; Olivotto 2008 PMID:18533079; Ho 2009 PMID:20031602; Jensen 2013 PMID:23197161; Witjas-Paalberends 2013 PMID:23674513; Coppini 2014 PMID:25524337; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry pers. comm; GeneDx pers. comm; Invitae pers. comm; LMM pers. comm). This variant segregated with disease in 4 affected relatives with HCM from 2 families (PP1; Andersen 2004 PMID:15114369; GeneDx pers. comm.). This variant was identified in 0.001% (FAF 95% CI; 4/113682) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM2, PM1, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011642/MONDO:0005045/002 2022-07-30 2022-07-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15365 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C1443060 infores:hetionet CAID:CA294887086 biolink:causes MONDO:0009290 infores:clingen CAID:CA294887086 MONDO:0009290 PMID: Uncertain Significance PM3, PM2_Supporting, PS3_Supporting PP3, PP4, PM5, BP4 The NM_000152.5:c.316C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 106 (p.Arg106Cys). The variant has been detected in at least two individuals with suspected late-onset Pompe disease identified by newborn screening. One of those individuals was compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G (ClinVar Variation ID: 4027), confirmed in trans by parental testing (PMID: 36246652, 37670900); this patient reportedly had abnormalities on muscle ultrasound and mild gross motor delays (PM3). The genotype of another newborn screening case is unknown (PMID: 33073007). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001668 (1/59968 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in HEK293 cells resulted in 10.7% GAA activity and the evidence of reduced protein relative to activity and normal processing on western blot, indicating that variant may impact protein function (PMID-36246652). The computational predictor REVEL gives a score of 0.567 which is is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants c.316C>G (p.Arg106Gly) (ClinVar variation ID: 840775 ) and c.317G>A (p.Arg106His) (PMID-31076647), in the same codon have been reported in patients identified by newborn screen. However, these variants have been classified as variants of uncertain significance by the ClinGen Lysosomal Diseases VCEP and, therefore this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 971945). In summary this variant meets the criteria to be classified as a variant of uncertain significance for Pome disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PM2_Supporting, PS3_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Nov 4, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294887086/MONDO:0009290/010 2025-11-04 2025-11-04 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:68554 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0018799 infores:hetionet CHEBI:41879 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0268000 infores:hetionet NCBIGene:6253 biolink:causes MONDO:0971150 infores:monarchinitiative not_provided not_provided HGNC:10468 MONDO:0971150 uuid:8334bb02-581b-43f4-8c1a-7dc89e503b07 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1443060 infores:hetionet GO:0044472 biolink:causes GO:0005262 infores:ubergraph knowledge_assertion manual_agent GO:0044472 GO:0005262 CHEBI:66876 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0033038 infores:hetionet CHEBI:145499 biolink:causes NCIT:C78566 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0032781 infores:hetionet CAID:CA229692 biolink:causes MONDO:0009861 infores:clingen CAID:CA229692 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5 The c.689T>G (p.Val230Gly) variant in PAH was reported to the McGill PAHdb by Carducci in 1999, but has not been found in the literature. This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229692/MONDO:0009861/006 2020-08-20 2021-12-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4657 biolink:causes UMLS:C0264909 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0264909 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0001824 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0948595 infores:hetionet CHEBI:135929 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0236068 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0235818 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0235339 infores:hetionet CHEBI:42068 biolink:causes EFO:1001816 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0343387 infores:hetionet CHEBI:7573 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C3665386 infores:hetionet CHEBI:6437 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0013491 infores:hetionet CHEBI:8232 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0020458 infores:hetionet CHEBI:7573 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0020580 infores:hetionet CAID:CA414444915 biolink:causes MONDO:0010604 infores:clingen CAID:CA414444915 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PS2, PP3 PM1, PM5 The c.952C>T; p.Leu318Phe variant is completely absent from gnomAD v2.1.1 and v3.1.1. This missense variant has a REVEL score of 0.943 and meets PP3 criteria (threshold >0.6). At least 4 patients are reported in the literature with moderate-severe hemophilia B and this variant, meeting F9 phenotype criteria for PS4. There is at least 1 proband with isolated reduction in FIX activity levels meeting phenotypic criteria for F9, with confirmed de novo (maternity confirmed in an affected male) occurrence (PMID: 30648777). In summary, this variant meets criteria to be classified as pathogenic. The ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel, for F9: PS4, PS2, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414444915/MONDO:0010604/080 2024-10-11 2024-11-01 X-linked inheritance HP:0001417 Supports CHEBI:134966 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0021167 infores:hetionet CHEBI:7465 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0040264 infores:hetionet CAID:CA015944 biolink:causes MONDO:0005045 infores:clingen CAID:CA015944 MONDO:0005045 PMID:11861413PMID:27532257PMID:21239446 Uncertain Significance PP3 PM2, PS4 The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID: 30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015944/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50305 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0015230 infores:hetionet CHEBI:3001 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0030193 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0085606 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0016385 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0016385 infores:hetionet GO:0075071 biolink:causes GO:0006914 infores:ubergraph knowledge_assertion manual_agent GO:0075071 GO:0006914 CHEBI:3181 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0031046 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0178298 infores:hetionet CAID:CA211932 biolink:causes MONDO:0010726 infores:clingen CAID:CA211932 MONDO:0010726 PMID: Benign BA1 The allele frequency of the p.Ala201Val (NM_004992) variant in MECP2 is 1.045% in East Asian sub population in gnomAD, which is high enough to be classified as Benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Ala201Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA211932/MONDO:0010726/016 2022-05-10 2022-06-28 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7575 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0702166 infores:hetionet CHEBI:49662 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151701 infores:hetionet CHEBI:553473 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0014742 infores:hetionet CHEBI:63925 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0004096 infores:hetionet NCBIGene:197 biolink:causes MONDO:0021035 infores:monarchinitiative not_provided not_provided HGNC:349 MONDO:0021035 uuid:5875ccf9-2eaa-43e7-9ff2-6fc557f8520a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68642 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0018799 infores:hetionet CHEBI:50922 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1368065 infores:hetionet CAID:CA410202641 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202641 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PS4_Moderate, PM2_Supporting, PP3 PS1, PS2, PS3, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS4, BS3, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.4(RUNX1):c.422C>T (p.Ser141Leu) is a missense variant which is completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3). REVEL score = 0.906, which is higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20). Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204), but within residues 89-204. The germline variant has been reported in a male patient with CMML diagnosed at 67 years and antecedent thrombocytopenia (PMID: 34028844), and in a patient with myeloid disease that may have also had a history of thrombocytopenia (Nielsen et al., 2016, ASH Abstract 602/DOI: 10.1182/blood.V128.22.3926.3926).The variant has also been reported in several patients with MDS or CMML (PMID: 19282830; PMID: 20880116; PMID: 24030381; PMID: 25840971; PMID: 29515765), AML (PMID: 16627249; PMID: 17485549; PMID: 24923295; PMID: 27288520; PMID: 32855275), AML-MRC (PMID: 31728617), chronic neutrophilic leukemia (PMID: 31844143), and myeloid sarcoma (PMID: 31866570), but germline origin is unclear. Germline origin was also unclear in 3 patients tested at Invitae - 2 of whom were possibly mosaic and 1 of whom was heterozygous (although blood was limited) - without RUNX1-related phenotype. Finally, the somatic variant has been reported in a TCGA AML (PMID: 23634996/COSMIC ID: COSV55867675/cBioPortal), 2 MDS (PMID: 24047651), a urothelial carcinoma (PMID: 25096233/cBioPortal), and cecal carcinoma (PMID: 28481359/cBioPortal). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM1_supporting, PP3, and PS4_moderate Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202641/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135342 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0438215 infores:hetionet CHEBI:101278 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0011603 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009450 infores:hetionet CHEBI:490877 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0028643 infores:hetionet CHEBI:4953 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0020555 infores:hetionet CHEBI:51041 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0042963 infores:hetionet CHEBI:32315 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0033774 infores:hetionet CHEBI:116278 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0018965 infores:hetionet CHEBI:10112 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0026837 infores:hetionet CHEBI:8874 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0014591 infores:hetionet CAID:CA064203 biolink:causes MONDO:0007783 infores:clingen CAID:CA064203 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 975 of the RYR1 protein, (p.Arg975Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00002, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.329) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA064203/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:79699 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151849 infores:hetionet CHEBI:7809 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0231528 infores:hetionet CHEBI:3216 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0085633 infores:hetionet CHEBI:2208 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0267792 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002121 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235880 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0232492 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018801 infores:hetionet CHEBI:48669 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0018794 infores:hetionet CHEBI:9168 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0340865 infores:hetionet CHEBI:61390 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C1565489 infores:hetionet CAID:CA024455 biolink:causes MONDO:0007783 infores:clingen CAID:CA024455 MONDO:0007783 PMID: Likely Benign BS1 PP3, PM1, PS4, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Isoleucine with Valine at codon 1571 of the RYR1 protein, p.(Ile1571Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0014, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:25958340, PMID:20681998, PMID:25658027, PMID:25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.56 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1.  Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024455/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:71219 biolink:causes UMLS:C1704381 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C1704381 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0233472 infores:hetionet CHEBI:119486 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0035455 infores:hetionet CHEBI:4814 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0004093 infores:hetionet NCBIGene:3459 biolink:causes MONDO:0014429 infores:monarchinitiative not_provided not_provided HGNC:5439 MONDO:0014429 uuid:99546c48-1790-428c-bdda-892237090449 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71941 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0948586 infores:hetionet CHEBI:27999 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0027497 infores:hetionet CHEBI:3723 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028754 infores:hetionet CHEBI:9649 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0023052 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0028738 infores:hetionet CHEBI:4514 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0344232 infores:hetionet CHEBI:30830 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0085632 infores:hetionet CHEBI:8597 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0030554 infores:hetionet CHEBI:3403 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0546817 infores:hetionet CHEBI:16335 biolink:causes MONDO:0020806 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0037188 infores:hetionet CHEBI:8874 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151746 infores:hetionet CHEBI:36795 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085605 infores:hetionet CHEBI:18248 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0026826 infores:hetionet CHEBI:64064 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0017601 infores:hetionet CHEBI:31236 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004604 infores:hetionet NCBIGene:57545 biolink:causes MONDO:0012848 infores:monarchinitiative not_provided not_provided HGNC:29253 MONDO:0012848 uuid:e5a0fdc5-c458-458a-af3c-1cec5fd83caa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:474180 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0235309 infores:hetionet CHEBI:44032 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0036974 infores:hetionet CHEBI:9086 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085614 infores:hetionet CHEBI:8232 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0018524 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0877134 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0877134 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0162429 infores:hetionet CHEBI:32315 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0008350 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0020517 infores:hetionet CAID:CA400030168 biolink:causes MONDO:0100326 infores:clingen CAID:CA400030168 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1641C>A (p.Cys547Ter) variant in exon 10/15 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It has been reported homozygous (PM3_supporting) in at least one GT proband (P18 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3_supporting, PP4_strong. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400030168/MONDO:0100326/011 2022-09-20 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:5130 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0231528 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0039503 infores:hetionet CHEBI:7445 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0227791 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0162429 infores:hetionet NCBIGene:23322 biolink:causes MONDO:0012695 infores:monarchinitiative not_provided not_provided HGNC:29168 MONDO:0012695 uuid:40621030-9da7-491b-8d57-6a4346cc0efd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023470 infores:hetionet CHEBI:251408 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C1761613 infores:hetionet CHEBI:63627 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0016382 infores:hetionet CHEBI:53760 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0014742 infores:hetionet CHEBI:4814 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0035410 infores:hetionet GO:0035818 biolink:causes GO:0035810 infores:ubergraph knowledge_assertion manual_agent GO:0035818 GO:0035810 CHEBI:5134 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0858617 infores:hetionet CHEBI:6775 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085593 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0002871 infores:hetionet CHEBI:2379 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0178298 infores:hetionet CHEBI:42355 biolink:causes MONDO:0021680 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0038395 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151736 infores:hetionet CHEBI:68478 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0031154 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0178298 infores:hetionet NCBIGene:201134 biolink:causes MONDO:0033622 infores:monarchinitiative not_provided not_provided HGNC:28514 MONDO:0033622 uuid:8c2fd5c1-c9bf-4061-9e72-454af1fca794 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085583 infores:hetionet CHEBI:52010 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0004093 infores:hetionet CHEBI:50173 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0034886 infores:hetionet CHEBI:49668 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0085692 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0007642 infores:hetionet CHEBI:16469 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0032617 infores:hetionet CHEBI:5103 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0086769 infores:hetionet CAID:CA400029341 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029341 MONDO:0100326 PMID: Uncertain Significance PP3, PP1, PM2_Supporting PM3, PP4 The NM_000212.3(ITGB3):c.1451G>T (p.Gly484Val) missense variant has been reported in two affected siblings (PP1; PMID: 34066320). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.905, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM2_supporting, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029341/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:135888 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0004096 infores:hetionet CHEBI:6640 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0012833 infores:hetionet CHEBI:36791 biolink:causes HP:0030213 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233469 infores:hetionet CHEBI:31980 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0151908 infores:hetionet CHEBI:134991 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235086 infores:hetionet CHEBI:23765 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0028734 infores:hetionet CHEBI:3647 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0007398 infores:hetionet CHEBI:7798 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0086565 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014534 infores:hetionet CHEBI:31302 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0085631 infores:hetionet CAID:CA410147676 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147676 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1245G>T (p.Gln415His) is a missense variant which has a REVEL score < 0.50 (0.324) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147676/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0005740 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0231528 infores:hetionet CHEBI:10112 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0231218 infores:hetionet CHEBI:15428 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0020649 infores:hetionet CHEBI:50223 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0151578 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0006444 infores:hetionet CHEBI:9448 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0036830 infores:hetionet CHEBI:63580 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0036974 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042401 infores:hetionet CHEBI:3207 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0019112 infores:hetionet CHEBI:100246 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0026896 infores:hetionet CHEBI:6754 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0428977 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0178298 infores:hetionet UMLS:C0023610 biolink:causes HP:0011854 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0019065 infores:hetionet CHEBI:64321 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0235710 infores:hetionet CHEBI:5383 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0002792 infores:hetionet CHEBI:7852 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042075 infores:hetionet CHEBI:28864 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0231528 infores:hetionet CHEBI:93305 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0085932 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0002170 infores:hetionet CHEBI:119573 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0750857 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0858635 infores:hetionet CHEBI:2611 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0520966 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0234215 infores:hetionet CHEBI:50730 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0037278 infores:hetionet NCBIGene:1776 biolink:causes MONDO:0013743 infores:monarchinitiative not_provided not_provided HGNC:2959 MONDO:0013743 uuid:4fc7f68b-7368-4b68-890d-65bce93e9eb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0033975 infores:hetionet CAID:CA892691290 biolink:causes MONDO:0015152 infores:clingen CAID:CA892691290 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PVS1, PM2_Supporting The NM_003494.4: c.2077del p.(His693ThrfsTer4) variant in DYSF, which is also known as NM_001130987.2: c.2131del p.(His711ThrfsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 22/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least seven patients with LGMD (PMID: 21522182, 17994539, 36983702), including in a homozygous state in two individuals (1.0 pt, PMID: 21522182) (PM3). At least one patient with this variant had a clinical suspicion of LGMD and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 21522182, 17994539; PP4_Strong). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA892691290/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28939 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C1325847 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1368065 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0006840 infores:hetionet CHEBI:3650 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0011606 infores:hetionet CHEBI:66876 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0009782 infores:hetionet CHEBI:71023 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06766 UMLS:C0018681 infores:hetionet CHEBI:8430 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0700590 infores:hetionet UMLS:C0011701 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0232462 infores:hetionet CHEBI:8499 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0030848 infores:hetionet CAID:CA16020997 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020997 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong, PM3_Supporting The c.1318G>T (p.E440*) is a nonsense variant in exon 13 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to lead to premature truncation of the protein at amino acid 440/453 (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in premature truncation of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).It has been previously reported in one proband with abnormal blood Phe (BH4 deficiency does not appear to have been formally excluded) (PP4) (PMID: 23842451), in presumed trans with the p.R243* mutation (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3_Supporting; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020997/MONDO:0009861/006 2020-05-15 2020-05-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:465284 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C3665347 infores:hetionet CHEBI:32315 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0002453 infores:hetionet NCBIGene:5337 biolink:causes MONDO:0008913 infores:monarchinitiative not_provided not_provided HGNC:9067 MONDO:0008913 uuid:66918abe-f41f-44a4-ab89-737bf1931395 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0018799 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0231218 infores:hetionet CHEBI:63612 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0344232 infores:hetionet NCBIGene:6891 biolink:causes MONDO:0971011 infores:monarchinitiative not_provided not_provided HGNC:44 MONDO:0971011 uuid:50a4fce5-e432-42e3-ab57-ad5e4b6b3c41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4877 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0948594 infores:hetionet CHEBI:4708 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0085636 infores:hetionet CHEBI:9727 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0497156 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0267792 infores:hetionet CHEBI:31623 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0344232 infores:hetionet CHEBI:8768 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0018681 infores:hetionet CHEBI:15365 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0008031 infores:hetionet CHEBI:31980 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0027497 infores:hetionet CHEBI:8214 biolink:causes UMLS:C0542052 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0542052 infores:hetionet GO:0035779 biolink:causes CL:0000566 infores:ubergraph knowledge_assertion manual_agent GO:0035779 CL:0000566 CAID:CA347213551 biolink:causes MONDO:0015152 infores:clingen CAID:CA347213551 MONDO:0015152 PMID: Uncertain Significance PM3, PP3, PP4, PM2_Supporting PM5, PS3 The NM_003494.4: c.1160G>C variant in DYSF, which is also known as NM_001130987.2: c.1256G>C p.(Arg419Pro), is a missense variant predicted to cause substitution of arginine to proline at amino acid 387, p.(Arg387Pro). This variant has been reported in three patients with LGMD (PMID: 30564623, 39548682), including in an unknown phase with a pathogenic variant (c.2163-2A>G, 0.5 pts, PMID: 30564623, LOVD Individual #00222090) and in a homozygous state in two individuals, both with known consanguinity (0.25 pts for each patient; PMID: 39548682, LOVD Individuals #00392018, #00391975) (PM3; PP4). The highest minor allele frequency for this variant is 0.00002519 (1/39700 exome chromosomes) in the East Asian population in gnomAD v4.1.0, which is less than the VCEP threshold of 0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PM2_Supporting, PM3, PP4, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347213551/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:8NZ41MIK1O biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0023895 infores:hetionet CHEBI:31236 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027424 infores:hetionet CHEBI:3125 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB09020 UMLS:C2242737 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0948349 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017178 infores:hetionet CHEBI:63717 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0017979 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151888 infores:hetionet CHEBI:73274 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0232849 infores:hetionet CHEBI:50648 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0040053 infores:hetionet CHEBI:51209 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0235146 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235876 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0009806 infores:hetionet CHEBI:724125 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0162285 infores:hetionet CHEBI:23765 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0558489 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0851341 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0015376 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0424000 infores:hetionet CHEBI:553473 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0030193 infores:hetionet CHEBI:9654 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0017168 infores:hetionet CAID:CA399805999 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805999 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.432G>A (p.Trp144Ter) nonsense variant creates a premature stop codon in exon 4/30 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). . At least two probands has been reported with this variant, including GT34 of PMID: 29675921 who meets the criteria for PP4_strong. A second patient in PMID: 30138987 is homozygous for Trp144Ter (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805999/MONDO:0100326/011 2021-06-30 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:2663 biolink:causes UMLS:C0861171 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0861171 infores:hetionet CHEBI:45327 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0018681 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021141 infores:hetionet CHEBI:16899 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0043144 infores:hetionet CHEBI:49668 biolink:causes MONDO:0000469 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0428908 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0028960 infores:hetionet CHEBI:7809 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0033774 infores:hetionet CHEBI:3077 biolink:causes MONDO:0018373 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0027543 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0025061 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0242151 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0242151 infores:hetionet CHEBI:119573 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0004364 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0012833 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001539 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0035321 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011334 infores:hetionet CHEBI:10023 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042029 infores:hetionet CHEBI:5280 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0022573 infores:hetionet CHEBI:6375 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0206062 infores:hetionet NCBIGene:79625 biolink:causes MONDO:0030010 infores:monarchinitiative not_provided not_provided HGNC:26256 MONDO:0030010 uuid:1175d151-4014-405c-b97a-8d5e52eb9745 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3749 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0014457 infores:hetionet CHEBI:465284 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0009782 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0392025 infores:hetionet CHEBI:2668 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0151908 infores:hetionet CHEBI:7959 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0026896 infores:hetionet CHEBI:9150 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0028084 infores:hetionet CHEBI:5118 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0035317 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151538 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151538 infores:hetionet CHEBI:4995 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0580413 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042401 infores:hetionet CHEBI:4702 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C3665347 infores:hetionet CHEBI:6954 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020517 infores:hetionet CHEBI:127342 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0018681 infores:hetionet CHEBI:45863 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0241136 infores:hetionet CHEBI:3077 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0858617 infores:hetionet CHEBI:27882 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0002874 infores:hetionet CHEBI:9667 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0036974 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0162429 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0034359 infores:hetionet CHEBI:9654 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0085628 infores:hetionet CHEBI:691037 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0011616 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0011991 infores:hetionet NCBIGene:2819 biolink:causes MONDO:0013771 infores:monarchinitiative not_provided not_provided HGNC:4455 MONDO:0013771 uuid:7f11c012-e8a6-4785-afb3-318e313c21c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0162429 infores:hetionet CHEBI:7824 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0162830 infores:hetionet CHEBI:44423 biolink:causes HP:0100644 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1142305 infores:hetionet CHEBI:47780 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014457 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0017658 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0948525 infores:hetionet CHEBI:7798 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0013456 infores:hetionet GO:0043012 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0043012 GO:0019953 CHEBI:66876 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0042023 infores:hetionet NCBITaxon:1301 biolink:causes MONDO:0024355 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1301 MESH:D012141 DB00833_MESH_D012141_1 CHEBI:50859 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0016867 infores:hetionet CHEBI:8024 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0001339 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015230 infores:hetionet CAID:CA120565 biolink:causes MONDO:0044970 infores:clingen CAID:CA120565 MONDO:0044970 PMID: Likely Pathogenic PP1, PM2_Supporting, PS4_Moderate, PS3_Supporting PP3, PS2, PM6 The m.3251A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease to date. Age of onset ranged from the first decade of life to adulthood and clinical features in affected individuals were variably consistent with chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and early death. Heteroplasmy ranged from 13-95% in affected individuals (PS4_moderate; PMIDs: 8265770, 38465286, 8786060, 30837005). This variant segregated with clinical manifestations in one family with CPEO, progressive muscle weakness, and early death. The variant was present in the proband at 81% in muscle and 13% in blood and was present in maternal cousins at heteroplasmy levels of 25-16% (PP1; PMID: 8265770). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 43.5%; HmtVAR: 0.75). Single fiber testing showed higher levels of the variant in COX-negative fibers (61%, range 15-88%) than in COX-positive fibers (28%, range 3%-86%; p<0.001; PS3_supporting, PMID: 8786060). There is additional evidence showing deleterious effects of this variant on the tRNA (PMID: 33380464). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the compelling functional validation and consistent phenotype observed in reported cases. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120565/MONDO:0044970/015 2024-04-22 2024-11-20 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CAID:CA3054201759 biolink:causes MONDO:0011071 infores:clingen CAID:CA3054201759 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.588_594del (p.Val197fs) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98–c.779 as per VCEP specifications) (PVS1). This variant is downstream of c.98 (PM5_Supporting) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_Supporting, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3054201759/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17303 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020651 infores:hetionet CHEBI:8028 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0012833 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0022658 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0235431 infores:hetionet CHEBI:53760 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0022107 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0948168 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0948168 infores:hetionet CHEBI:2639 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0011124 infores:hetionet CHEBI:42797 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151908 infores:hetionet CAID:CA8970611 biolink:causes MONDO:0012589 infores:clingen CAID:CA8970611 MONDO:0012589 PMID: Likely Benign BP4, BS2 BA1, PM2, BS1 The highest population minor allele frequency of the p.Ser82Asn variant in TCF4 in gnomAD v2.1.1 is 0.00006 in African/African American population (not sufficient to meet BS1 criteria). The p.Ser82Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx and Invitae) (BS2). Computational analysis prediction tools suggest that the p.Ser82Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ser82Asn variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). (TCF4 specifications v.3; approved on 8/30/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8970611/MONDO:0012589/032 2024-08-30 2024-12-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3310 biolink:causes UMLS:C0085618 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0085618 infores:hetionet CHEBI:66919 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0012833 infores:hetionet CHEBI:75045 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0018965 infores:hetionet CHEBI:9398 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0042063 infores:hetionet CHEBI:4024 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0040822 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0011615 infores:hetionet CHEBI:10023 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C3665386 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0011053 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0041969 infores:hetionet CHEBI:16755 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0003811 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0042109 infores:hetionet CHEBI:7798 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C2363731 infores:hetionet CAID:CA512319211 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319211 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.27A>C (p.Ser9=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319211/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:675 biolink:causes MONDO:0011584 infores:monarchinitiative not_provided not_provided HGNC:1101 MONDO:0011584 uuid:c2c1665e-c34d-48aa-a922-e23907a2ce2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0039070 infores:hetionet CHEBI:7478 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0018808 infores:hetionet CHEBI:63610 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0018965 infores:hetionet CHEBI:119486 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0000737 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002622 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1611167 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1611167 infores:hetionet NCBIGene:149465 biolink:causes MONDO:0975747 infores:monarchinitiative not_provided not_provided HGNC:26485 MONDO:0975747 uuid:a74b9ada-0e7b-4b70-9f60-1afaa2950c5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0043144 infores:hetionet CHEBI:31348 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0236075 infores:hetionet CHEBI:10119 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151818 infores:hetionet CHEBI:78543 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0011603 infores:hetionet CHEBI:42797 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0702166 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002444 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0025193 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0855242 infores:hetionet CHEBI:63621 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151578 infores:hetionet CHEBI:63631 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085610 infores:hetionet CHEBI:63623 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0003811 infores:hetionet CHEBI:4784 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0011168 infores:hetionet CAID:CA10580080 biolink:causes MONDO:0100488 infores:clingen CAID:CA10580080 MONDO:0100488 PMID: Likely Benign BP7, BS2_Supporting, PM2_Supporting, BP4 BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS3, PS2, PS1, PS4 The c.297G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Leu99=) that is not predicted by SpliceAI, SSF, MaxEnt to impact splicing (BP4, BP7). In addition, it occurs at a nucleotide that is not conserved as shown by phastCons and (BP7). This variant has been observed in more than 3 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2_Supporting, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580080/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:77733 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0006266 infores:hetionet CHEBI:204928 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0234233 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0025362 infores:hetionet CHEBI:28487 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0013404 infores:hetionet CHEBI:71229 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0020625 infores:hetionet CHEBI:28445 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0235416 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020456 infores:hetionet CHEBI:50223 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0006145 infores:hetionet CHEBI:9943 biolink:causes UMLS:C2242621 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C2242621 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0000833 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0037199 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003123 infores:hetionet CHEBI:45951 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0001824 infores:hetionet CHEBI:44032 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027497 infores:hetionet CHEBI:6950 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085649 infores:hetionet CHEBI:9168 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0011603 infores:hetionet NCBITaxon:5059 biolink:causes HP:0020103 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5059 MESH:D055744 DB01167_MESH_D055744_1 CHEBI:31236 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151610 infores:hetionet CAID:CA226352 biolink:causes MONDO:0100437 infores:clingen CAID:CA226352 MONDO:0100437 PMID:23213406 Uncertain Significance PS3_Supporting, PM2_Supporting, PP3_Moderate PP1, PP4, PS4 NM_001034853.2(RPGR):c.128G>A (p.Gly43Glu) is a missense variant encoding the substitution of glycine with glutamic acid at amino acid 43. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband meeting the PS4 requirement of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 10937588). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The proband phenotype included diagnosis of retinitis pigmentosa, a family history consistent with X-linked inheritance (2 pts), reduced visual acuity (0.5 pts), visual field constriction (0.5 pts), moderate myopia (0.5 pts), and non-recordable electroretinogram responses, which together are not sufficiently specific for RPGR-related retinopathy to meet PP4 (3.5 points, PMID: 10937588, PMID: 17325176). The variant has been reported within a family with multiple family members genotyped, however, no individuals were affected other than the proband, so PP1 was not met (PMID: 10937588). The computational predictor REVEL gives a score of 0.925, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. Exogenously expressed RPGR harboring the variant exhibits reduced interaction with RPGRIP1 in a yeast-2-hybrid experiment (PMID: 23213406, PS3_Supporting). In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PP3_Moderate, and PS3_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226352/MONDO:0100437/106 2025-10-05 2025-10-06 X-linked inheritance HP:0001417 Inconclusive true CHEBI:7565 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0014457 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085606 infores:hetionet CHEBI:204928 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0002878 infores:hetionet NCBIGene:4703 biolink:causes MONDO:0009725 infores:monarchinitiative not_provided not_provided HGNC:7720 MONDO:0009725 uuid:962910b6-2fb1-4ef7-8f7d-903ba20064fd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15553 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0006266 infores:hetionet CHEBI:5062 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0031350 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020651 infores:hetionet CHEBI:39585 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0017178 infores:hetionet CHEBI:7466 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C1527344 infores:hetionet CHEBI:41879 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0020452 infores:hetionet CHEBI:5138 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0032617 infores:hetionet CHEBI:50777 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0006145 infores:hetionet CHEBI:209807 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0042109 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0018799 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0427008 infores:hetionet CHEBI:6931 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0023066 infores:hetionet CAID:CA409110472 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110472 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 PM1, PS4 The c.1309C>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of proline to threonine at codon 437 (p.(Pro437Thr)) of NM_175914.5. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.143, which is less than the MDEP threshold of 0.15 (BP4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29758564, internal lab contributors). In summary, c.1309C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110472/MONDO:0015967/085 2024-08-01 2024-08-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA015251 biolink:causes MONDO:0004994 infores:clingen CAID:CA015251 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4716C>T (p.Ile1572=) variant in the MYH7 gene is 4.59% (514/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015251/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5118 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0028960 infores:hetionet CHEBI:8499 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0006277 infores:hetionet CHEBI:8382 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0039070 infores:hetionet CHEBI:8665 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0016204 infores:hetionet CHEBI:45924 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0042164 infores:hetionet CHEBI:6067 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0220870 infores:hetionet CHEBI:8888 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0023518 infores:hetionet CHEBI:2659 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0220870 infores:hetionet CHEBI:7443 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0017152 infores:hetionet CHEBI:3380 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0020461 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0281774 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0270458 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0235146 infores:hetionet CHEBI:40303 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0011603 infores:hetionet NCBITaxon:6210 biolink:causes MONDO:0005738 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6210 MESH:D004443 DB00518_MESH_D004443_1 CHEBI:3077 biolink:causes UMLS:C1608950 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C1608950 infores:hetionet CHEBI:617099 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0033774 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0853700 infores:hetionet CHEBI:51380 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0011991 infores:hetionet GO:0003418 biolink:causes CL:1000217 infores:ubergraph knowledge_assertion manual_agent GO:0003418 CL:1000217 CHEBI:2636 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0085593 infores:hetionet CHEBI:35553 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0011603 infores:hetionet NCBIGene:165918 biolink:causes MONDO:0012764 infores:monarchinitiative not_provided not_provided HGNC:26661 MONDO:0012764 uuid:a0a9b970-80a6-4ebf-b7b2-99f66e4f2c72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:80184 biolink:causes MONDO:0012432 infores:monarchinitiative not_provided not_provided HGNC:29021 MONDO:0012432 uuid:c0314f8b-f403-45d8-99e8-8483e8031b42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135276 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0000737 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0178298 infores:hetionet CHEBI:10102 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0232849 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0002871 infores:hetionet GO:2000074 biolink:causes GO:0035270 infores:ubergraph knowledge_assertion manual_agent GO:2000074 GO:0035270 CHEBI:32293 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0151578 infores:hetionet CHEBI:145499 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0028081 infores:hetionet CHEBI:79699 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0917801 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0032584 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0018799 infores:hetionet CHEBI:6933 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes HP:0002527 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085639 infores:hetionet CHEBI:5118 biolink:causes MONDO:0020779 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0008449 infores:hetionet CHEBI:46345 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0854467 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0004238 infores:hetionet CHEBI:50648 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038325 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017160 infores:hetionet CAID:CA229750 biolink:causes MONDO:0009861 infores:clingen CAID:CA229750 MONDO:0009861 PMID:9323556PMID:9323556 Likely Pathogenic PP3_Strong, PM5, PP4, PM2_Supporting, PM3_Supporting PM1 The c.769G>T variant in PAH is a missense variant predicted to cause substitution of Glycine by Cysteine at amino acid 257 (p.Gly257Cys). One patient with this variant displayed elevated plasma Phenylalanine and reduced Phe tolerance of < 12mg of Phe/kg of body weight per day, which is highly specific for PAH deficiency; BH4 deficiency was not reported to be ruled out (PP4, PMID: 9323556). This individual was compound heterozygous for the variant and a pathogenic variant [phase not reported] (c.1066-11G>A, aka IVS10nt546) (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.958, which is above the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_strong). Another missense variant c.770G>T, (p.Gly257Val) [ClinVar Variation ID102830] in the same codon has been classified as pathogenic for PAH deficiency by the ClinGen PAH VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4, PM3_supporting, PM2_supporting, PP3_strong, PM5. (PAH VCEP specifications version 2.0.0; 01/05/2025). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229750/MONDO:0009861/006 2025-04-18 2025-04-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6715 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0041657 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0025061 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0002871 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0037199 infores:hetionet CHEBI:28177 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0340865 infores:hetionet CHEBI:6923 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0231218 infores:hetionet NCBITaxon:6211 biolink:causes MONDO:0017282 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6211 MONDO:0017282 CHEBI:4858 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0020517 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0544618 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0544618 infores:hetionet CHEBI:64064 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0003862 infores:hetionet GO:0039502 biolink:causes GO:0060337 infores:ubergraph knowledge_assertion manual_agent GO:0039502 GO:0060337 CHEBI:50859 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020580 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0035410 infores:hetionet CHEBI:18332 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0016382 infores:hetionet CHEBI:40279 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085684 infores:hetionet CHEBI:27300 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0085602 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0854082 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0854082 infores:hetionet CHEBI:145499 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C1291077 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020639 infores:hetionet CHEBI:2549 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0026826 infores:hetionet CHEBI:38562 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0026821 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0595930 infores:hetionet CHEBI:39867 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009676 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0038454 infores:hetionet CHEBI:51450 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0013428 infores:hetionet CHEBI:17987 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0020580 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0852733 infores:hetionet CAID:CA229268 biolink:causes MONDO:0009861 infores:clingen CAID:CA229268 MONDO:0009861 PMID: Uncertain Significance PM2, PP4 PM5, PP3 The c.1010G>T (p.Gly337Val) variant in PAH has been reported in a patient with PKU, BH4 deficiency not assessed. (PMID: 9012412) This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. Computational evidence is conflicting (Deleterious effect predicted in SIFT, MutationTaster, REVEL=0.816. PolyPhen2 HVAR predicts benign). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229268/MONDO:0009861/006 2019-12-15 2021-05-14 Inconclusive true CHEBI:4717 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0012833 infores:hetionet CHEBI:8207 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0008031 infores:hetionet CHEBI:119915 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0231528 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1956346 infores:hetionet CHEBI:2666 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0338831 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0349506 infores:hetionet CAID:CA386953008 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953008 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1 The c.121G>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 41 (p.(Glu41Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant segregated with diabetes, with 9 informative meioses in one family with MODY (PP1_Strong; PMID: 20690076) and is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.121G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953008/MONDO:0015967/017 2022-04-02 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3387 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0231530 infores:hetionet CHEBI:83527 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0236075 infores:hetionet CHEBI:77733 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0042384 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042109 infores:hetionet CHEBI:47781 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0042109 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0700201 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0700201 infores:hetionet CHEBI:63619 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151908 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0003123 infores:hetionet CHEBI:36791 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013428 infores:hetionet CHEBI:64321 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0687713 infores:hetionet CHEBI:30830 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0030252 infores:hetionet CHEBI:94848 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0003123 infores:hetionet CHEBI:8774 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0085605 infores:hetionet NCBIGene:5071 biolink:causes MONDO:0008170 infores:monarchinitiative not_provided not_provided HGNC:8607 MONDO:0008170 uuid:6d5f01d4-816e-4d02-9586-b6bfbf649193 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000014 biolink:causes MONDO:0018875 infores:clingen CAID:CA000014 MONDO:0018875 PMID: Likely Pathogenic PM1_Supporting, PS3, PM5_Supporting, PS2_Supporting, PP3, PM2_Supporting BP4, PS4, BS3, BS4, BS2, PP1, PP4 The NM_000546.6(TP53):c.1010G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 337 (p.Arg337Pro). This variant received a total of 0.5 points across 1 proband and therefore PS4 cannot be applied (PS4 not met; PMID: 25584008). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a moderately LFS-associated cancer totaling 1 phenotype point (PS2_Supporting; Internal contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 3 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Computational predictor scores (BayesDel = 0.407328, Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PS2_Supporting, PM1_Supporting, PM2_Supporting, PM5_Supporting. (Bayesian Points: 9; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000014/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5130 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0038525 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0009450 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1535849 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1535849 infores:hetionet CHEBI:5002 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0518015 infores:hetionet CHEBI:119486 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0877192 infores:hetionet CHEBI:27732 biolink:causes MONDO:0006952 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0035344 infores:hetionet CHEBI:585948 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0017566 infores:hetionet CHEBI:135961 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0037287 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0332534 infores:hetionet UMLS:C0010592 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0013404 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0038358 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0012739 infores:hetionet CHEBI:7514 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0232208 infores:hetionet CHEBI:64321 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0600142 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0016034 infores:hetionet CAID:CA16620646 biolink:causes MONDO:0009290 infores:clingen CAID:CA16620646 MONDO:0009290 PMID:29122469PMID:25741864 Pathogenic PM2, PVS1, PP4, PM3_Supporting This variant, c.1075G>T (p.Gly359Ter), is predicted to result in a premature stop codon and nonsense-mediated decay, resulting in lack of gene product. Of note, the variant alters the last nucleotide of exon 6 and splicing predictors indicate that splicing may be impacted. The impact of a splicing defect, if it occurs, is not known. However, a patient with infantile onset Pompe disease who is homozygous for the variant has no GAA cross reactive immunological material in cultured skin fibroblasts i.e. CRIM-negative, indicating that the variant results in lack of GAA protein. Based on this data, PVS1 was applied. This patient, who has infantile onset Pompe disease, also has low residual GAA activity, meeting PP4, and is homozygous for the variant, meeting PM3_Supporting. The variant is absent in gnomAD v2.1.1 meeting PM2. There is a ClinVar entry for this variant (Variation ID: 420101, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620646/MONDO:0009290/010 2020-10-05 2020-11-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:71415 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0151905 infores:hetionet NCBIGene:6204 biolink:causes MONDO:0013216 infores:monarchinitiative not_provided not_provided HGNC:10383 MONDO:0013216 uuid:d997ae3b-1e8b-4b01-a6a6-ff56d42d98f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3478 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0424295 infores:hetionet CHEBI:2668 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0687713 infores:hetionet CHEBI:253342 biolink:causes MONDO:0004628 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0267166 infores:hetionet CHEBI:35778 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0030794 infores:hetionet CHEBI:7577 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0039240 infores:hetionet CHEBI:6904 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0011124 infores:hetionet NCBIGene:283635 biolink:causes MONDO:0976264 infores:monarchinitiative not_provided not_provided HGNC:19829 MONDO:0976264 uuid:7165be86-7baf-4a8b-ba28-b197149e64d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0023380 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0009450 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0235416 infores:hetionet CHEBI:119486 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0311468 infores:hetionet CHEBI:63580 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0037383 infores:hetionet CHEBI:3723 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0024902 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0043251 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038661 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0014591 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151904 infores:hetionet CHEBI:61033 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0233407 infores:hetionet CHEBI:3479 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0038999 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151596 infores:hetionet CHEBI:63577 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0877359 infores:hetionet CHEBI:18248 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0003873 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0004936 infores:hetionet CHEBI:7496 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0035455 infores:hetionet CHEBI:28748 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151723 infores:hetionet CHEBI:50648 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085649 infores:hetionet CHEBI:585948 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0027441 infores:hetionet CHEBI:9570 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151662 infores:hetionet NCBIGene:26873 biolink:causes MONDO:0009825 infores:monarchinitiative not_provided not_provided HGNC:8149 MONDO:0009825 uuid:645f2974-3794-4e1b-9e29-f2e9b30c2e43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0009450 infores:hetionet CHEBI:15367 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0476273 infores:hetionet CHEBI:31624 biolink:causes MONDO:0001613 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0042568 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0234215 infores:hetionet CHEBI:171719 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0947912 infores:hetionet CHEBI:53691 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0340865 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0948594 infores:hetionet CHEBI:240107 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0948595 infores:hetionet CHEBI:15640 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0042109 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0400007 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0032519 infores:hetionet CHEBI:5558 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0020517 infores:hetionet UMLS:C0004609 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0028961 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021400 infores:hetionet CHEBI:167309 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0812387 infores:hetionet CHEBI:47781 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C2830004 infores:hetionet CHEBI:2618 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0424000 infores:hetionet CHEBI:168396 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042963 infores:hetionet CHEBI:6129 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C3665386 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0340515 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0340515 infores:hetionet CAID:CA278713 biolink:causes MONDO:0019501 infores:clingen CAID:CA278713 MONDO:0019501 PMID:28439001PMID:10930322PMID:10930322PMID:10930322PMID:28439001 Likely Pathogenic PP3, PP4, PM2_Supporting, PM3 BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP1, PM5, PM4, PM1, PVS1, PM6, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.6560G>A variant in MYO7A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 2187. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001190 (1/84018 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.915, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A (PP3). At least one patient with this variant displayed profound congenital deafness and retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10930322). This variant has been detected in at least two individuals with Usher syndrome. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant published by multiple submitters in ClinVar (c.2904G>T (p.Glu968Asp) and c.3719G>A (p.R1240Q)) and both of those were presumed in trans (1 PM3 point, PMID:10930322, LMM) (PM3). In summary, this variant was reviewed by the ClinGen Hearing Loss VCEP and classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278713/MONDO:0019501/005 2022-08-03 2022-08-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:3561 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020538 infores:hetionet CHEBI:9123 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0017178 infores:hetionet CHEBI:53691 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0038999 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038663 infores:hetionet CHEBI:31236 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042420 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0340464 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0235431 infores:hetionet CHEBI:82960 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0018681 infores:hetionet CHEBI:5778 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0037317 infores:hetionet CHEBI:6775 biolink:causes MONDO:0021398 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0034887 infores:hetionet CAID:CA378924686 biolink:causes MONDO:0021060 infores:clingen CAID:CA378924686 MONDO:0021060 PMID:29493581 Uncertain Significance PM1, PM2, PP2 PS4, PM5, PP3, BS2 The c.175G>T (p.Ala59Ser) variant in HRAS was absent from large population studies (PM2; gnomad.broadinstitute.org). It was identified in 1 fetus with clinical features of a RASopathy; however, it was also observed in the proband’s unaffected mother (PS4 not met; Hospital for Sick Children internal data). The variant is located in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID: 29493581). Of note, 3 different likely pathogenic missense variants have been previously reported at this codon of HRAS (p.Ala59Thr, ClinVar ID: 40435; p.Ala59Leu, and p.Ala59Phe), which may indicate that this residue is critical to the function of the protein; however, these variants have not yet met criteria to be classified as pathogenic (PM5 not met). In summary, the clinical significance of the p.Ala59Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA378924686/MONDO:0021060/004 2021-01-25 2021-01-25 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:657309 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0015672 infores:hetionet CHEBI:4717 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0262385 infores:hetionet CHEBI:7494 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085641 infores:hetionet CHEBI:17263 biolink:causes UMLS:C0919714 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0919714 infores:hetionet CHEBI:5100 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0086565 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0856677 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0856677 infores:hetionet CHEBI:7478 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0011615 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0036572 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0028738 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0853700 infores:hetionet CHEBI:3216 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233477 infores:hetionet CHEBI:17987 biolink:causes UMLS:C1142498 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C1142498 infores:hetionet UNII:7662KG2R6K biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0239978 infores:hetionet CHEBI:79699 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0702166 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235315 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235315 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0005822 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:D013592 DB01053_MESH_D013592_1DB09320_MESH_D013592_1 CHEBI:3568 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0002453 infores:hetionet CHEBI:84883 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C1443060 infores:hetionet CHEBI:499361 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0039231 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0349506 infores:hetionet CHEBI:24564 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0040034 infores:hetionet CHEBI:6912 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0041105 infores:hetionet CHEBI:15854 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0085593 infores:hetionet CHEBI:3441 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C3665386 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011570 infores:hetionet CHEBI:2682 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0700225 infores:hetionet CHEBI:4653 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0600142 infores:hetionet CHEBI:5383 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0085605 infores:hetionet CHEBI:6078 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0010200 infores:hetionet CHEBI:5441 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0040822 infores:hetionet CHEBI:5790 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0020453 infores:hetionet CHEBI:16914 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0014591 infores:hetionet CHEBI:40050 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0520573 infores:hetionet NCBIGene:8456 biolink:causes MONDO:0011132 infores:monarchinitiative not_provided not_provided HGNC:12765 MONDO:0011132 uuid:dcc41161-7503-478d-adf9-e7173509098b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0233472 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0019158 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0749389 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0749389 infores:hetionet CHEBI:49040 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0600142 infores:hetionet CAID:CA155058 biolink:causes MONDO:0100038 infores:clingen CAID:CA155058 MONDO:0100038 PMID: Benign BS2, BA1 The c.2723A>G variant in SCN2A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 908 (p.Lys908Arg). This variant is present in gnomAD v2.1 at an allele frequency of 0.4% (1190/282874 alleles), with the highest sub-population minor allele frequency of 0.6% in the European (non-Finnish) population, which exceeds the ClinGen Epilepsy Sodium Channel threshold (0.01%) for BA1. Additionally, gnomAD v2.1.1 reports 7 individuals with this variant in a homozygous state (BS1). In summary, this variant meets the criteria to be classified as Benign for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BS1 (VCEP specifications version 1.0; 6/13/2023) Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA155058/MONDO:0100038/068 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42797 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0575081 infores:hetionet CHEBI:61033 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0038999 infores:hetionet CHEBI:6129 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0023052 infores:hetionet GO:0033281 biolink:causes GO:0043953 infores:ubergraph knowledge_assertion manual_agent GO:0033281 GO:0043953 CHEBI:7824 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0016382 infores:hetionet CHEBI:8874 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0042963 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027339 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0016436 infores:hetionet CHEBI:63598 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0079102 infores:hetionet CHEBI:6367 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0033774 infores:hetionet CHEBI:2663 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0021141 infores:hetionet CHEBI:2666 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0041657 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003811 infores:hetionet CHEBI:474053 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0151578 infores:hetionet CHEBI:63624 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0040034 infores:hetionet NCBIGene:673 biolink:causes MONDO:0007963 infores:monarchinitiative not_provided not_provided HGNC:1097 MONDO:0007963 uuid:3fd346ff-64e4-4737-a06c-bdbba1dff025 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1903072 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:1903072 GO:0007154 CHEBI:5818 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0042109 infores:hetionet CHEBI:51860 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0037763 infores:hetionet CHEBI:63610 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0025874 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0162429 infores:hetionet CHEBI:6761 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0003460 infores:hetionet CHEBI:9168 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0001925 infores:hetionet CHEBI:63577 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0221773 infores:hetionet CHEBI:100147 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0043251 infores:hetionet CHEBI:41774 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0234909 infores:hetionet CHEBI:5004 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0027497 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0235329 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0235329 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0011570 infores:hetionet CAID:CA340750344 biolink:causes MONDO:0100368 infores:clingen CAID:CA340750344 MONDO:0100368 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 NM_000329.3(RPE65):c.16G>T (p.Glu6Ter) is a frameshift variant that introduces a premature stop codon into exon 2 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis with Leber congenital amaurosis (0.5 pts, PMID: 25257057) and significant, documented improvement of retinal sensitivity by dark-adapted perimetry and microperimetry after treatment with RPE65 gene therapy (8 pts, PMID: 25938638), which together are highly specific for RPE65-related recessive retinopathy (total 8.5 pts, PP4_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) variant suspected but not confirmed in trans (PMID: 25257057). However, the proband was not counted for PM3 in order to avoid circularity. In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340750344/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15407 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0027769 infores:hetionet CHEBI:7565 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0023052 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149904 infores:hetionet CHEBI:70707 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0027497 infores:hetionet CAID:CA229801 biolink:causes MONDO:0009861 infores:clingen CAID:CA229801 MONDO:0009861 PMID:26503515 Likely Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Supporting The c.832A>G (p.Thr278Ala) variant in PAH has been reported in multiple individuals with PKU and MHP (BH4 deficiency excluded). (PMID: 26503515, 30050108). This variant is absent in population databases. This variant was detected in the homozygous state in 1 patient (confirmed by parental testing). Computational evidence supports a deleterious effect. Another variant at this same amino acid is interpreted as pathogenic (p.Thr278Ile). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PM3_supporting PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229801/MONDO:0009861/006 2020-06-11 2021-09-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0016382 infores:hetionet UMLS:C0657912 biolink:causes HP:0012251 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0520886 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0235146 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0014130 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0860207 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020651 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0015230 infores:hetionet CHEBI:45409 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042164 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0033687 infores:hetionet CHEBI:92607 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0015230 infores:hetionet CHEBI:45979 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0004093 infores:hetionet CHEBI:66901 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C1384353 infores:hetionet CHEBI:18248 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0033774 infores:hetionet NCBIGene:404672 biolink:causes MONDO:0014619 infores:monarchinitiative not_provided not_provided HGNC:21157 MONDO:0014619 uuid:8ad29262-7121-4c51-8c20-63eb388c84bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0278079 infores:hetionet CHEBI:3479 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0042963 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0856049 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0856049 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0151888 infores:hetionet NCBIGene:2193 biolink:causes MONDO:0100220 infores:monarchinitiative not_provided not_provided HGNC:3592 MONDO:0100220 uuid:3124022e-2a34-43d4-adad-e9c81f7a3d5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes MONDO:0001627 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0497327 infores:hetionet CHEBI:17347 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0002792 infores:hetionet CHEBI:7514 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0017178 infores:hetionet CHEBI:2567 biolink:causes UMLS:C0743575 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0743575 infores:hetionet CHEBI:63632 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0015967 infores:hetionet NCBIGene:2627 biolink:causes MONDO:0008542 infores:monarchinitiative not_provided not_provided HGNC:4174 MONDO:0008542 uuid:0b6ce43c-2263-412c-8a6a-52fe08a52913 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:205919 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0020517 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1861172 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0041912 infores:hetionet CHEBI:27834 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0242301 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0235004 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0235004 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0034525 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0034530 infores:hetionet CHEBI:84050 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0009806 infores:hetionet CHEBI:70746 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0039070 infores:hetionet CHEBI:4672 biolink:causes EFO:0801084 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0596240 infores:hetionet CHEBI:42944 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0028084 infores:hetionet CHEBI:10100 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0231218 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0033975 infores:hetionet CHEBI:77260 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0392699 infores:hetionet CHEBI:17263 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0015230 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0006277 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0007117 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0877398 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0877398 infores:hetionet CHEBI:3175 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0026205 infores:hetionet CHEBI:6456 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0019080 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0021843 infores:hetionet CHEBI:39112 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0013378 infores:hetionet CHEBI:8404 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0746961 infores:hetionet CHEBI:474180 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0019158 infores:hetionet CAID:CA10585780 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585780 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP1, BP4, BP3, BA1, PS3, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM5, PVS1, PP2, PP1 NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.964. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN score >=6 from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score >=6 from Robarts Research Institute, Canada). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585780/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:4466 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0002871 infores:hetionet CHEBI:4885 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0085631 infores:hetionet CHEBI:9907 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0232849 infores:hetionet CHEBI:16347 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0008031 infores:hetionet CHEBI:8310 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0041969 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0343886 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0343886 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0027765 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0232492 infores:hetionet CHEBI:9086 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0855329 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0267792 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034063 infores:hetionet CHEBI:8764 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0016867 infores:hetionet CHEBI:4717 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0234133 infores:hetionet CHEBI:18332 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0018681 infores:hetionet CHEBI:61049 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235896 infores:hetionet CHEBI:9139 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0546817 infores:hetionet CHEBI:134743 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0027497 infores:hetionet CHEBI:55346 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0149871 infores:hetionet CHEBI:77733 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0017566 infores:hetionet CHEBI:45716 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0232462 infores:hetionet CHEBI:3732 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1320474 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0151480 infores:hetionet CHEBI:47780 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014591 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002656 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0699893 infores:hetionet CHEBI:3749 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0011570 infores:hetionet CHEBI:9435 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0023380 infores:hetionet CHEBI:194135 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042963 infores:hetionet CHEBI:31397 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0600260 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0009450 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020649 infores:hetionet CHEBI:5118 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0031256 infores:hetionet CHEBI:70746 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0267792 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0041912 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877639 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877639 infores:hetionet CHEBI:28925 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0011991 infores:hetionet CHEBI:3223 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0028643 infores:hetionet CHEBI:49575 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0013404 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0011570 infores:hetionet CHEBI:17688 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0004093 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0005940 infores:hetionet CHEBI:41879 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0003467 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0541832 infores:hetionet NCBIGene:153201 biolink:causes MONDO:0007677 infores:monarchinitiative not_provided not_provided HGNC:18762 MONDO:0007677 uuid:5db980c8-d02c-470f-a390-57b479ebc589 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31174 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0015256 infores:hetionet NCBIGene:5993 biolink:causes MONDO:0971014 infores:monarchinitiative not_provided not_provided HGNC:9986 MONDO:0971014 uuid:0342b39e-276b-47ce-b774-b77fe09cb086 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50924 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0002871 infores:hetionet CHEBI:9448 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0001824 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0042373 infores:hetionet CHEBI:101278 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0042963 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0011570 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0021053 infores:hetionet UMLS:C0005740 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0237849 infores:hetionet CHEBI:9137 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C3263723 infores:hetionet CHEBI:472657 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0042109 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0851341 infores:hetionet CHEBI:17263 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0085633 infores:hetionet CHEBI:50173 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0025222 infores:hetionet NCBIGene:1804 biolink:causes MONDO:0014580 infores:monarchinitiative not_provided not_provided HGNC:3010 MONDO:0014580 uuid:cae6e12b-6249-4891-a1e8-94724fa3262a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA397725788 biolink:causes MONDO:0008723 infores:clingen CAID:CA397725788 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP4, PM3 The NM_000018.4(ACADVL): c.1748C>T (p.Ser583Leu) variant in ACADVL is a missense variant predicted to cause substitution of serine by leucine at amino acid 583 (p.Ser583Leu). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, both were homozygous for the variant; Moreover, this variant was co-detected with c.848T>C (p.Val283Ala) variant with unknown phase (PM3 point 1.5, PMIDs 32518924, 23774949) (PM3). At least two patients with this variant in homozygous state displayed clinical phonotypes, NBS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305).The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.674, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PM2_Supporting, PP4_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397725788/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3223 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0233632 infores:hetionet CHEBI:63608 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0023067 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0521839 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1321686 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0006444 infores:hetionet CAID:CA10385154 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385154 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.3348A>G (p.Lys1116=) is a synonymous variant in exon 15 of 15 that does not have predicted splicing impact (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v4.1.0 at a frequency of 0.00008308 among hemizygous individuals, with 33 variant alleles / 397,193 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385154/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:116278 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0002871 infores:hetionet CHEBI:45783 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0162285 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009763 infores:hetionet CHEBI:17347 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0030554 infores:hetionet CHEBI:6067 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020443 infores:hetionet CHEBI:3207 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0037383 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0234215 infores:hetionet GO:1902214 biolink:causes GO:0071353 infores:ubergraph knowledge_assertion manual_agent GO:1902214 GO:0071353 CHEBI:82941 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0022650 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0852908 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0020651 infores:hetionet CAID:CA229482 biolink:causes MONDO:0009861 infores:clingen CAID:CA229482 MONDO:0009861 PMID:24941924PMID:24941924 Pathogenic PM3, PVS1, PM2, PP4 PM5 The PAH:p.M1L variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106); There are no other PAH RefSeq transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant was reported in trans with the pathogenic variant p.Arg241His (PM3) in 1 Mexican proband with mild PKU (PMID: 24941924; PP4). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229482/MONDO:0009861/006 2019-07-07 2019-07-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10023 biolink:causes MONDO:0005894 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030409 infores:hetionet CHEBI:4046 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0039070 infores:hetionet CHEBI:3732 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0010200 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0410959 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0410959 infores:hetionet CHEBI:63598 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151798 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017675 infores:hetionet CHEBI:4911 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0004093 infores:hetionet CHEBI:9150 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0011603 infores:hetionet CHEBI:28593 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0003460 infores:hetionet NCBIGene:23322 biolink:causes MONDO:0012694 infores:monarchinitiative not_provided not_provided HGNC:29168 MONDO:0012694 uuid:858d1264-fbcd-4967-870a-0925f1f61faf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C2225524 infores:hetionet CHEBI:51164 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0012833 infores:hetionet CHEBI:2704 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0085649 infores:hetionet CHEBI:7454 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0004093 infores:hetionet CHEBI:3127 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C3263723 infores:hetionet GO:1905063 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1905063 GO:0072359 CHEBI:168396 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042514 infores:hetionet CHEBI:45783 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0239340 infores:hetionet CHEBI:2654 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0015967 infores:hetionet CHEBI:135736 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042133 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0595930 infores:hetionet CAID:CA243572 biolink:causes MONDO:0007113 infores:clingen CAID:CA243572 MONDO:0007113 PMID: Benign BP7, BS1 BS2 The allele frequency of the p.Phe426= variant in UBE3A (NM_130838.2) is 0.014% in European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Phe426= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Phe426= variant in UBE3A (NM_130838.2) is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA243572/MONDO:0007113/016 2022-12-08 2022-12-23 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0020651 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0009450 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0009319 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0521839 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0002878 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0009241 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0162429 infores:hetionet CHEBI:3814 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0085649 infores:hetionet NCBIGene:79947 biolink:causes MONDO:0044326 infores:monarchinitiative not_provided not_provided HGNC:20603 MONDO:0044326 uuid:248eb504-c73a-4cfd-8f67-eed0db87a5cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3223 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0855242 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0948089 infores:hetionet CHEBI:63577 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0026821 infores:hetionet CHEBI:63611 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C3263723 infores:hetionet CAID:CA658795239 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795239 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The NM_000152.5:c.828_850del (p.Thr277AlafsTer45) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon in biologically-relevant-exon 6 (GAA has 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with clinical symptoms consistent with infantile onset Pompe disease and documented laboratory values showing deficient (<10% normal) activity in lymphocytes has been reported (PMID: 12923862)(PP4_Moderate). This patient is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic, c.2188G>T (p.Glu730Ter) (ClinVar Variation ID: 495665, SCV001371759.1). The variants were confirmed to be in trans by parental testing (PMID: 12923862). The c.2188G>T (p.Glu730Ter) variant would be classified as pathogenic even without the in trans data from this patient; confirmed in trans by parental testing, thus avoiding circular logic. This variant is not in gnomAD v2.1.1. or v4.1.0. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as classified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 4, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795239/MONDO:0009290/010 2024-09-04 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5864 biolink:causes EFO:0011051 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0920103 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0007642 infores:hetionet GO:1905207 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1905207 GO:0007507 GO:0003293 biolink:causes CL:1000147 infores:ubergraph knowledge_assertion manual_agent GO:0003293 CL:1000147 CAID:CA235301 biolink:causes MONDO:0018997 infores:clingen CAID:CA235301 MONDO:0018997 PMID: Pathogenic PS4_Moderate, PM5, PS3_Supporting, PS2_Very Strong, PP3, PP2, PM2_Supporting BS1, BP4, BA1 The c.101C>T variant in the KRAS gene is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). A different pathogenic missense variant has been previously identified at this codon of KRAS (c.101C>G (p.Pro34Arg)) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). This variant has been reported in 3 individuals as two confirmed de novo occurrences and one unconfirmed de novo occurrence with clinical features of a RASopathy (PS4_Moderate, PS2_VeryStrong; PMIDs: 17056636, 30732632, ClinVar SCV: SCV000207884.10, Internal lab contributors: GeneDx). A RAS activation assay showed that this variant led to increased RAS activation (PS3_Supporting; PMID: 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PM5, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235301/MONDO:0018997/004 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:8863 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011551 infores:hetionet CAID:CA399805912 biolink:causes MONDO:0100326 infores:clingen CAID:CA399805912 MONDO:0100326 PMID:18976939 Pathogenic PP4_Strong, PP3, PM2_Supporting, PS3, PM3_Supporting PP1 The NM_000419.5:c.470C>A variant in ITGA2B is a missense variant predicted to cause substitution of Proline by Histidine at amino acid 157 (p.Pro157His). At least one patient (Patient 1 in PMID: 18976939) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0%, as measured by flow cytometry and Western blot. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). Surface expression of αIIbβ3 measured by flow cytometry in CHO cells transiently co-transfected with the NM_000419.5:c.470C>A (p.Pro157His) variant αIIb and wild type αIIb showed decreased expression at 0% of WT levels, indicating that this variant impacts protein function (PMID: 18976939)(PS3). The computational predictor REVEL gives a score of 0.782, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant has been detected in at least 1 probands with Glanzmann thrombasthenia. This individual was homozygous for the variant (PMID: 18976939, 0.5 PM3 points) Total points: 0.5 (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PDVCEP: PP4_Strong, PS3, PP3, PM2_Supporting and PM3_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399805912/MONDO:0100326/011 2023-02-02 2023-02-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7476 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0009421 infores:hetionet CHEBI:42944 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0080274 infores:hetionet CHEBI:135925 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0014518 infores:hetionet CHEBI:5138 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0023218 infores:hetionet CHEBI:68575 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0009782 infores:hetionet CHEBI:8356 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013144 infores:hetionet CHEBI:6832 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C1443060 infores:hetionet CHEBI:194135 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003862 infores:hetionet CAID:CA6571849 biolink:causes MONDO:0100038 infores:clingen CAID:CA6571849 MONDO:0100038 PMID: Benign BS2, BS1 PM6, PP3, BP4, PS4, PS2 The c.4687A>G variant in SCN8A is a missense variant predicted to cause the substitution of isoleucine by valine at amino acid 1563 (p.Ile1563Val). The variant is present at a frequency of 0.000008674 (14 alleles) of the total population in gnomAD v4.0, which exceeds the threshold for BS1. Additionally, the variant was identified in 7 unaffected adults who were referred for clinical testing as part as trio exome analysis (internal data, GeneDx, July 2023). It was identified as homozygous in an individual undergoing trio exome sequencing for an unrelated condition, without a neurodevelopmental disorder, in which both parents were heterozygous and unaffected (BS2, GeneDx internal data, July 2023). In summary, this variant meets the criteria for BENIGN for Autosomal Dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 7/25/23): BS1, BS2 Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA6571849/MONDO:0100038/070 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2038 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0232498 infores:hetionet CHEBI:32888 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0011616 infores:hetionet CHEBI:28925 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0042963 infores:hetionet CHEBI:8069 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0004096 infores:hetionet CHEBI:101853 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0151539 infores:hetionet CAID:CA512341305 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341305 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, BA1, BP2, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PP3, PP1 The variant NM_001754.5(RUNX1):c.1101C>T (p.Gly367=) is a synonymous change. It is not present in any population databases (gnomAD v2.1.1 and v3.1.2) with at least 20x coverage for RUNX1 (PM2_supporting). Furthermore, the variant has a SpliceAI score of ≤ 0.20 (SpliceAI DG:0.11), indicating a low likelihood of affecting splicing. Evolutionary conservation prediction algorithms suggest that the site is not conserved (PhyloP score 1.12 < 2.0) or that the variant is the reference nucleotide in only one primate and/or three mammal species (BP7). Additionally, there is no previous report of this variant. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341305/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:41423 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0017168 infores:hetionet CHEBI:8382 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0030554 infores:hetionet CHEBI:72690 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0002871 infores:hetionet CHEBI:5120 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0005779 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0017152 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0017178 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0021053 infores:hetionet CAID:CA392347946 biolink:causes MONDO:0007947 infores:clingen CAID:CA392347946 MONDO:0007947 PMID: Pathogenic PP4, PM2_Supporting, PVS1_Strong, PP1_Strong PM6, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PM3, PM4, PM5, PM1, PS4, PS2, PS3, PS1, BP7, BS1, BS3 NM_00138 c.989-1G>C in FBN1 is a splice site variant predicted to affect an acceptor splice site in intron 8 of the gene. Experimental cDNA sequencing studies have demonstrated that this variant disrupts mRNA splicing, causing the in-frame deletion of exon 9 and resulting in abnormal protein product (PVS1_strong; PMID: 15241795). This variant was found in one proband (reported twice in the literature) meeting the revised Ghent criteria for clinical diagnoses of Marfan syndrome (PP4; PMIDs: 15241795, 24161884); in one family, the variant was found to segregate with features of Marfan syndrome in at least 10 family members (PP1_strong; PMID: 15241795This variant has been reported 1 time in ClinVar as pathogenic (Variation ID: 549476). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_strong, PP1_strong, PM2_supporting, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392347946/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:27732 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0019080 infores:hetionet CHEBI:8874 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0043352 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0037274 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0948594 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0239488 infores:hetionet CHEBI:17334 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0027080 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151773 infores:hetionet CHEBI:72297 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0043352 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038814 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005089 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1261473 infores:hetionet CHEBI:4657 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0041657 infores:hetionet CHEBI:17650 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0015967 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042373 infores:hetionet CHEBI:94686 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0016658 infores:hetionet CHEBI:3207 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C2973529 infores:hetionet CHEBI:6809 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0233477 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0009806 infores:hetionet CHEBI:59773 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0015230 infores:hetionet CHEBI:94385 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0018681 infores:hetionet CHEBI:31643 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C2047937 infores:hetionet CHEBI:116278 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0023218 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0221714 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0221714 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0009676 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0521491 infores:hetionet CHEBI:9943 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0037317 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0042109 infores:hetionet UMLS:C0017797 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0015672 infores:hetionet CHEBI:28918 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0016382 infores:hetionet NCBIGene:1380 biolink:causes MONDO:0013862 infores:monarchinitiative not_provided not_provided HGNC:2336 MONDO:0013862 uuid:7bd2a3d9-7a58-4a93-83e7-ea05991d8226 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0854467 infores:hetionet CAID:CA400025098 biolink:causes MONDO:0100326 infores:clingen CAID:CA400025098 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.892C>T (p.Gln298Ter) nonsense variant creates a premature stop codon in exon 6/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least two probands has been reported with this variant, including GT28 of PMID: 29675921 who meets the criteria for PP4_strong. A second patient in PMID: 21136216 is homozygous for Gln298Ter (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400025098/MONDO:0100326/011 2021-06-30 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:47781 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0013604 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0017160 infores:hetionet CAID:CA214336 biolink:causes MONDO:0015967 infores:clingen CAID:CA214336 MONDO:0015967 PMID: Benign BA1 PS4, PM5, PM2, PP3, BS2 The c.872C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 291 (p.(Pro291Arg)) of NM_000545.8. This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00022, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and the MAF is above the PM2_Supporting cutoff (internal lab contributors). Lastly, this variant has a REVEL score of 0.4189, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.872C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BA1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214336/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49960 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0026857 infores:hetionet CHEBI:4974 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0003862 infores:hetionet GO:0010081 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0010081 GO:0061458 CHEBI:52717 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0878773 infores:hetionet CHEBI:3127 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0034063 infores:hetionet CHEBI:27470 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0013378 infores:hetionet CHEBI:7773 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0039240 infores:hetionet UMLS:C0010592 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0014724 infores:hetionet CHEBI:5118 biolink:causes HP:0008665 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0156394 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0948817 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0948817 infores:hetionet CHEBI:585948 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C2973529 infores:hetionet CHEBI:31705 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0041834 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042514 infores:hetionet CHEBI:9763 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0037299 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0152029 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0162429 infores:hetionet CHEBI:4356 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0151825 infores:hetionet CHEBI:5847 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0040034 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0031046 infores:hetionet CHEBI:8499 biolink:causes HP:0002173 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0877056 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0475858 infores:hetionet CHEBI:7494 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0028734 infores:hetionet CHEBI:4551 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0233471 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0521591 infores:hetionet CHEBI:63791 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020580 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011551 infores:hetionet NCBIGene:10058 biolink:causes MONDO:0014169 infores:monarchinitiative not_provided not_provided HGNC:47 MONDO:0014169 uuid:a686ba22-2f06-4d3f-bd10-a043f9394d13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1902627 biolink:causes GO:0042255 infores:ubergraph knowledge_assertion manual_agent GO:1902627 GO:0042255 CHEBI:6887 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0035455 infores:hetionet CHEBI:32139 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0020458 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0948586 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0851341 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030312 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0549452 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0549452 infores:hetionet CHEBI:46081 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0015967 infores:hetionet CHEBI:140621 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C3263723 infores:hetionet CHEBI:8713 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0008031 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1262141 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1262141 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0011616 infores:hetionet CAID:CA915940726 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940726 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong PM3 The NM_000419.5:c.2929_2930del (p.Glu979SerfsTer56) variant in ITGA2B is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it leads to alteration of a functionally important region (alters amino acids 979-1034, which includes the transmembrane domain) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Proband GT 26 in PMID: 16463284) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_moderate, and PM2_supporting. (VCEP specifications version 2; date of approval 12/21/2021). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940726/MONDO:0100326/011 2021-12-21 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:4469 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0038454 infores:hetionet CHEBI:63598 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0019521 infores:hetionet GO:2000232 biolink:causes GO:0042254 infores:ubergraph knowledge_assertion manual_agent GO:2000232 GO:0042254 CHEBI:134966 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0004093 infores:hetionet NCBIGene:57176 biolink:causes MONDO:0014397 infores:monarchinitiative not_provided not_provided HGNC:21642 MONDO:0014397 uuid:13378756-4f2f-44ba-bc4e-060840ee10cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA414447210 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447210 MONDO:0010604 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PM5, PP3 The NM_000133.4:c.1303T>A variant in F9 is a missense variant predicted to cause substitution of Cys by Ser at amino acid 435 (p.Cys435Ser). This variant has been reported in 1 proband meeting F9 phenotype criteria (PS4_Supporting; PMID: 21118338). This variant is absent from gnomAD v2, v3 and v4 (PM2_Supporting). Another missense variant c.1304G>A (p.Cys435Tyr) in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). The computational predictor REVEL gives a score of 0.962, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_Supporting, PM2_Supporting, PP3, PM5. (Version 1.0.0, 10/05/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447210/MONDO:0010604/080 2024-05-09 2024-07-11 X-linked inheritance HP:0001417 Inconclusive true UMLS:C0010592 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0340865 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0031046 infores:hetionet CHEBI:4995 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0080274 infores:hetionet CHEBI:31859 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0232849 infores:hetionet CHEBI:9725 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0262385 infores:hetionet CHEBI:9649 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0003862 infores:hetionet CHEBI:15940 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0013395 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0236993 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0236993 infores:hetionet CHEBI:5801 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0011603 infores:hetionet CHEBI:51860 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0003467 infores:hetionet CHEBI:7936 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0003811 infores:hetionet CHEBI:8802 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0028084 infores:hetionet CHEBI:71255 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0012833 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151828 infores:hetionet CAID:CA415088445 biolink:causes MONDO:0010305 infores:clingen CAID:CA415088445 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting PS4 The NM_005629.4:c.1554G>A (p.Trp518Ter) variant in SLC6A8 is is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 11/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in one male proband with elevated urine creatine/creatinine (PMID: 23660394) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP, August 10, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415088445/MONDO:0010305/027 2023-08-10 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:6456 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0011603 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0031350 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0851341 infores:hetionet CHEBI:72297 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0017178 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0011616 infores:hetionet CHEBI:4995 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0235490 infores:hetionet CHEBI:10119 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0235660 infores:hetionet CHEBI:50131 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0011168 infores:hetionet UMLS:C0005740 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0043144 infores:hetionet CHEBI:119573 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0149745 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0010692 infores:hetionet CAID:CA10385632 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385632 MONDO:0100437 PMID: Benign BA1, BP4 NM_001034853.2(RPGR):c.552G>T (p.Gln184His) is a missense variant causing substitution of glutamine by histidine at amino acid 184. This variant is present in gnomAD v4.1.0 at a frequency of 0.003034 among hemizygous individuals, with 1,194 variant alleles / 393,499 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.000005 (BA1). The computational predictor REVEL gives a score of 0.17, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Moderate.. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385632/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:72296 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0027765 infores:hetionet CHEBI:116278 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0028084 infores:hetionet CHEBI:3756 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0019348 infores:hetionet GO:0006954 biolink:causes MONDO:0004980 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003876 DB00547_MESH_D003876_1DB01130_MESH_D003876_1DB00337_MESH_D003876_1DB00557_MESH_D003876_1 CAID:CA658798631 biolink:causes MONDO:0007648 infores:clingen CAID:CA658798631 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM6, PM3, PM1, PM4, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1917_1918del p.(Ile640fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798631/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7577 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0010200 infores:hetionet CHEBI:8890 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0013404 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151601 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0021053 infores:hetionet CAID:CA410208264 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208264 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.23A>G (p.Glu8Gly) is a missense variant which has a REVEL score < 0.50 (0.372) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208264/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:18358 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0012833 infores:hetionet CHEBI:145499 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C3665386 infores:hetionet CHEBI:6067 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0016436 infores:hetionet NCBIGene:10117 biolink:causes MONDO:0007092 infores:monarchinitiative not_provided not_provided HGNC:3344 MONDO:0007092 uuid:3c76a4be-eae3-40c8-8d8b-52f56d7f723e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0004096 infores:hetionet CHEBI:47381 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0002792 infores:hetionet CHEBI:9613 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0542184 infores:hetionet CHEBI:2676 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0232462 infores:hetionet CHEBI:3723 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020555 infores:hetionet NCBIGene:51741 biolink:causes MONDO:0013687 infores:monarchinitiative not_provided not_provided HGNC:12799 MONDO:0013687 uuid:8d094e99-7699-487b-9f13-14a1fd0a4448 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013456 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0700345 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0034186 infores:hetionet CHEBI:44032 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0851578 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0003864 infores:hetionet NCBIGene:5244 biolink:causes MONDO:0010939 infores:monarchinitiative not_provided not_provided HGNC:45 MONDO:0010939 uuid:e0a480db-e6f9-4fef-93fb-533e5c1feb57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3515 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C2830004 infores:hetionet CHEBI:119486 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0497365 infores:hetionet CHEBI:45327 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0020578 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011849 infores:hetionet CHEBI:8774 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0013378 infores:hetionet CAID:CA251993 biolink:causes MONDO:0007064 infores:clingen CAID:CA251993 MONDO:0007064 PMID: Benign BA1, BS2_Supporting The NM_000022.4:c.239A>G variant in ADA is a missense variant predicted to cause substitution of lysine by arginine at amino acid 80 (p.Lys80Arg). The Popmax filtering allele frequency of this variant in the gnomAD v2.1.1 database is 0.06430, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 (BA1). This variant has been observed in 551 homozygous individuals with no feature of SCID, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA251993/MONDO:0007064/114 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8364 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0002962 infores:hetionet NCBIGene:2058 biolink:causes MONDO:0054782 infores:monarchinitiative not_provided not_provided HGNC:3418 MONDO:0054782 uuid:3a994d08-be4e-4b77-a2c9-ff4295ca3c83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0917801 infores:hetionet CHEBI:171719 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0038325 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0033860 infores:hetionet CAID:CA402994365 biolink:causes MONDO:0012999 infores:clingen CAID:CA402994365 MONDO:0012999 PMID: Uncertain Significance PM2, PP3 PM5 The NM_000156.6:c.522G>C variant in GAMT is a missense variant predicted to cause substitution of a tryptophan by cysteine at amino acid 174 (p.Trp174Cys). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.0. is 0.00002227 (1/44900 alleles) in the East Asian population, which lower is than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.813 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 2421360. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP3, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 12, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402994365/MONDO:0012999/026 2023-12-12 2023-12-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9720 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0009241 infores:hetionet CHEBI:75722 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020453 infores:hetionet NCBIGene:4141 biolink:causes MONDO:0030518 infores:monarchinitiative not_provided not_provided HGNC:6898 MONDO:0030518 uuid:e3b65000-2f14-41c2-bc46-126e74a2ac40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50730 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0948594 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020039 infores:hetionet CHEBI:63577 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0015967 infores:hetionet CHEBI:4868 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0232462 infores:hetionet CHEBI:5138 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0234047 infores:hetionet NCBITaxon:6314 biolink:causes MONDO:0005994 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6314 MONDO:0005994 CHEBI:9352 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C1443060 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005619 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0041466 infores:hetionet CHEBI:50742 biolink:causes HP:0032964 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151582 infores:hetionet CHEBI:63598 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0029944 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0917799 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0041909 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0041909 infores:hetionet CHEBI:8107 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085628 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0031039 infores:hetionet CHEBI:9667 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0015672 infores:hetionet CHEBI:75722 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0007286 infores:hetionet CHEBI:7025 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0013595 infores:hetionet NCBIGene:5155 biolink:causes MONDO:0014204 infores:monarchinitiative not_provided not_provided HGNC:8800 MONDO:0014204 uuid:9cba772e-232f-47f0-ae1c-b22b197277fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0034065 infores:hetionet NCBIGene:3207 biolink:causes MONDO:0024558 infores:monarchinitiative not_provided not_provided HGNC:5101 MONDO:0024558 uuid:f77e4211-9666-4fc1-b602-bc95fc75cce2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0039971 infores:hetionet CHEBI:50885 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0041834 infores:hetionet CHEBI:36791 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0547030 infores:hetionet CAID:CA338385973 biolink:causes MONDO:0100283 infores:clingen CAID:CA338385973 MONDO:0100283 PMID: Uncertain Significance PP2, PS4_Supporting BS1, PM5, PM1, PM2, BA1 The c.6752G>A (NM_004958.4) is a missense variant in MTOR predicted to cause substitution of arginine by glutamine at amino acid 2251 (p.Arg2251Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.001600% (1/62482 alleles) in the Remaining population. There are 4 total allele counts (PM2_Supporting, BS1, and BA1 not met). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has also been reported in two tumor samples in COSMIC (0.5 pts, PS4_Supporting; COSV63872621). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PP2, PS4_Supporting; 2 points (VCEP specifications version 1.1) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA338385973/MONDO:0100283/018 2025-07-01 2025-07-01 Autosomal dominant inheritance (mosaic) HP:0000006HP:0001442 Inconclusive https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:6367 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0036974 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0948692 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0009782 infores:hetionet CHEBI:10102 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0149745 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151726 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151726 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0948089 infores:hetionet CHEBI:42355 biolink:causes MONDO:0100239 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0700639 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0520588 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0520588 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085584 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0007787 infores:hetionet CHEBI:4888 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0027497 infores:hetionet CHEBI:8802 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0043352 infores:hetionet CHEBI:80630 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0019209 infores:hetionet CAID:CA145717 biolink:causes MONDO:0015152 infores:clingen CAID:CA145717 MONDO:0015152 PMID: Benign BP4, BA1, BP7 The NM_000070.3: c.1537-48T>C variant in CAPN3 is an intronic variant. The filtering allele frequency for this variant is 0.9344 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 31266/33150 African/African American exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold ≥0.003 for BA1 (BA1). The SpliceAI prediction of 0.00 indicates no splicing impact and does not exceed the LGMD VCEP threshold of ≤0.05 (BP4). This variant is also not in a splice region (BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/14/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA145717/MONDO:0015152/187 2025-03-14 2025-04-04 Autosomal recessive inheritance HP:0000007 Contradicts true GO:1904133 biolink:causes GO:0021593 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0021593 CHEBI:7824 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0025323 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0022408 infores:hetionet CAID:CA10650430 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650430 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS2, PS3, PS1, BP1, BP4, BP3, BP5, BP7, BS1, BS4, BS3, PM2, PM6, PVS1, PM3, PM5, PM4, PM1, BS2, PP1, PP4, PP2, PP3 NM_001754.5(RUNX1):c.*667del is a 3' UTR variant. This variant has a MAF of 0.01 (1.37%, 569/41428 alleles) in the African/African American subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 8 homozygotes in gnomAD v3.1.2 (BP2). In summary, this variant meets the criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650430/MONDO:0011071/008 2022-01-28 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8863 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0085628 infores:hetionet CHEBI:5127 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0020517 infores:hetionet CHEBI:5120 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0019080 infores:hetionet CHEBI:66899 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0022281 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0029882 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0234215 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042133 infores:hetionet CHEBI:44185 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C3665347 infores:hetionet GO:1905063 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:1905063 GO:0001944 CHEBI:9637 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0014742 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0162830 infores:hetionet CHEBI:7478 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0009676 infores:hetionet CAID:CA367400788 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400788 MONDO:0015967 PMID: Pathogenic PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting PS4 The c.683C>A variant in the glucokinase gene, GCK, causes an amino acid change of threonine to lysine at codon 228 (p.(Thr228Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19790256, internal lab contributor). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (persistent FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(PP4_Moderate; internal lab contributor). Two other missense variants, c.683C>T p.Thr228Met and c.682A>G p.Thr228Ala, have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.683C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Strong, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400788/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:5855 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0009676 infores:hetionet CHEBI:8713 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0041657 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0033975 infores:hetionet CHEBI:94440 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0004134 infores:hetionet CHEBI:50275 biolink:causes MONDO:0001221 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0014867 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151849 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0221742 infores:hetionet CHEBI:4708 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011603 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0948594 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002453 infores:hetionet CHEBI:15854 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0027497 infores:hetionet CHEBI:72564 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0030193 infores:hetionet CHEBI:45863 biolink:causes HP:0500105 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0277885 infores:hetionet CAID:CA314874 biolink:causes MONDO:0012996 infores:clingen CAID:CA314874 MONDO:0012996 PMID:27233232 Likely Benign BS3_Supporting, BP4, BS1 PM5 The NM_001482.3:c.692C>G variant in GATM is a missense variant predicted to cause the substitution of a serine by a cysteine at amino acid position 231 (p.Ser231Cys). To our knowledge, this variant has not be reported in the literature in an individual with AGAT deficiency. The Grpmax Filtering Allele Frequency (95% confidence) in gnomAD v4.1.0. is 0.0002459 (347/1613966 alleles) in the European non-Finnish population. This is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). Expression of the variant in HeLa cells resulted in 100% wild type AGAT activity indicating that this variant does not impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function. In addition, SpliceAI predicts that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 205616). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BS1, BS3_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 10, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314874/MONDO:0012996/025 2025-04-10 2025-04-10 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:27953 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00981 UMLS:C0037036 infores:hetionet CHEBI:31236 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027066 infores:hetionet CHEBI:3207 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0014591 infores:hetionet CHEBI:3228 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0020517 infores:hetionet CHEBI:3242 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0030196 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0234953 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0234953 infores:hetionet CHEBI:52172 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0231218 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0020569 infores:hetionet CAID:CA1706625 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706625 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PM2_Supporting The NM_003494.4: c.3517dup p.(Ser1173PhefsTer2) variant in DYSF, which is also known as NM_001130987.2: c.3571dup p.(Ser1191PhefsTer2), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 32/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least six patients with dysferlinopathy (PMID: 19528035, 18853459, 27447704, 36983702), including in a homozygous state in two individuals without reported familial consanguinity (1.0 pts, PMID: 19528035, 27447704), confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 1.0 pt, PMID: 36983702), and in unknown phase with a pathogenic variant (NM_003494.4: c.5836_5839del p.(Gln1946TrpfsTer19), 0.5 pts, PMID: 36983702) (PM3_Strong). At least one of the patients with this variant and a second presumed diagnostic DYSF variant displayed progressive proximal muscle weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 18853459, 36983702). The filtering allele frequency of this variant is 0.000053899 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 47/1111990 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 05/14/2025): PVS1, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706625/MONDO:0015152/180 2025-05-14 2025-06-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0700590 infores:hetionet CHEBI:3647 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0549567 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0027051 infores:hetionet CHEBI:6832 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0002792 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0002871 infores:hetionet NCBIGene:121391 biolink:causes MONDO:0013975 infores:monarchinitiative not_provided not_provided HGNC:28929 MONDO:0013975 uuid:17c1f59e-8fa3-4de4-b2f2-3a39d87b0d63 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0013378 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0497247 infores:hetionet CHEBI:3387 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027066 infores:hetionet CHEBI:10101 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0014236 infores:hetionet CHEBI:64064 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0011603 infores:hetionet CHEBI:3696 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0017979 infores:hetionet CHEBI:63608 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0014457 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0035204 infores:hetionet CAID:CA8603165 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603165 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The c.1355T>G variant in ITGA2B is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 452 (p.Leu452Arg). At least one patient (Patient 7 in PMID:36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIb and β3 surface expression were both absent, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). The computational predictor REVEL gives a score of 0.849, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002196 (2/91088 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Strong, PP3, PM2_supporting and PM3_supporting (VCEP specifications version 2; date of approval 12/17/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603165/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6375 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0235431 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0497365 infores:hetionet CHEBI:7798 biolink:causes MONDO:0005906 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0031157 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0027932 infores:hetionet CHEBI:8768 biolink:causes UMLS:C1142446 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C1142446 infores:hetionet CHEBI:8346 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0023530 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030305 infores:hetionet CHEBI:3011 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0020651 infores:hetionet CHEBI:7903 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0151766 infores:hetionet CHEBI:404903 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0022346 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0014868 infores:hetionet CHEBI:6541 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030193 infores:hetionet CHEBI:8024 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0542571 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0015376 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0853760 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0004096 infores:hetionet NCBITaxon:480418 biolink:causes MONDO:0005124 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:480418 MONDO:0005124 NCBIGene:5322 biolink:causes MONDO:0009235 infores:monarchinitiative not_provided not_provided HGNC:9038 MONDO:0009235 uuid:a7dae6a5-3eb9-4216-895b-c0ab2738a54b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144093 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0948525 infores:hetionet CHEBI:63791 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085633 infores:hetionet CHEBI:63611 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026896 infores:hetionet CHEBI:92607 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0011991 infores:hetionet CHEBI:171719 biolink:causes HP:0100507 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0016412 infores:hetionet CHEBI:391960 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0004936 infores:hetionet CHEBI:8768 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0025874 infores:hetionet CHEBI:119915 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0000731 infores:hetionet CHEBI:9927 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0015672 infores:hetionet UMLS:C0120107 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0008031 infores:hetionet GO:1905000 biolink:causes GO:0086014 infores:ubergraph knowledge_assertion manual_agent GO:1905000 GO:0086014 CHEBI:63632 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0267792 infores:hetionet CHEBI:15551 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0558368 infores:hetionet CHEBI:31547 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0853034 infores:hetionet CHEBI:6413 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0233794 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0242350 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0020456 infores:hetionet CHEBI:5098 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0038325 infores:hetionet GO:0044556 biolink:causes GO:0010459 infores:ubergraph knowledge_assertion manual_agent GO:0044556 GO:0010459 CHEBI:66876 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0018681 infores:hetionet CHEBI:46081 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0424295 infores:hetionet CHEBI:101853 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0020625 infores:hetionet CHEBI:168396 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0043352 infores:hetionet CAID:CA398324705 biolink:causes MONDO:0011132 infores:clingen CAID:CA398324705 MONDO:0011132 PMID: Uncertain Significance PP4, PM2_Supporting, PP3_Moderate The variant NM_001369369.1(FOXN1):c.1036T>C is predicted to cause a tryptophan to arginine substitution at amino acid position 346. The variant is absent from gnomAD 4.0 (PM2_supporting). The meta predictor REVEL predicts a potential disrupting effect on protein function with a score of .952, above the ≥0.932 threshold for PP3_moderate. The variant was found in the heterozygous state in patient NS-03 from PMID:35729475 who had abnormally low TREC values of 0.43 copies/uL and CD3 T cell lymphopenia 860 uL (0.5). The patient received exome sequencing for SCID related genes (0.5) (PP4 met). The patient also displayed recurrent infection, BPD, patent ductus arteriosus, and a patent foramen ovale with ongoing ventilator and G tube dependency. In summary this variant meets criteria to be classified as Variant of Uncertain significance- insufficient evidence for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PP3_moderate, PP4, and PM2_supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA398324705/MONDO:0011132/113 2024-10-25 2024-10-25 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA415084325 biolink:causes MONDO:0010305 infores:clingen CAID:CA415084325 MONDO:0010305 PMID:29478817PMID:17101918 Likely Pathogenic PP3, PM2_Supporting, PP4_Strong PS3 "The NM_005629.4:c.912G>A variant in SLC6A8 is a synonymous variant (p.Gln304=) that alters the last nucleotide of exon 5. The variant has been reported in a male with ""no creatine peak"" on brain H-magnetic resonance spectroscopy, urine creatine/creatinine ratio of 2.7 (normal range for age-matched controls 0.02 – 0.7) and normal urine guanidinoacetate level. A subsequent publication, presumably on the same patient (PMID: 29478817), indicates deficient creatine uptake in fibroblasts (PP4_Strong). One publication states that a patient with this variant has a ""splicing error"" resulting in p.Ile260_Gln304del ( PMID: 29478817). No details are provided regarding how this was determined and, therefore, this evidence was not applied. The computational splicing predictor SpliceAI gives a score of 0.54 for donor loss, and varSEAK predicts a ""likely splicing effect"" (Class 4) with ""Likely loss of function for authentic Splice Site"" predicting that the variant may disrupt the donor splice site of intron 5 of SLC6A8 (PP3). The variant is not in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PP3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on January 12, 2023)." Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415084325/MONDO:0010305/027 2023-01-12 2023-03-09 X-linked inheritance HP:0001417 Supports CHEBI:47499 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0020458 infores:hetionet CHEBI:61033 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0042029 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0005940 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0271308 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0271308 infores:hetionet CHEBI:7478 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0020453 infores:hetionet NCBIGene:51103 biolink:causes MONDO:0032617 infores:monarchinitiative not_provided not_provided HGNC:18828 MONDO:0032617 uuid:3aeeec47-0e58-468f-b8a7-28c413ad9a7e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0007114 infores:hetionet CHEBI:3423 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151836 infores:hetionet CHEBI:44423 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0151539 infores:hetionet CAID:CA2499225885 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225885 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.140_150del (p.Leu47fs) is a frameshift variant that is predicted to undergo nonsense mediated decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Frameshift variant downstream of c.98 (in transcript NM_001754.5) (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225885/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8028 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0236071 infores:hetionet CHEBI:5132 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0019151 infores:hetionet CHEBI:15367 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0014591 infores:hetionet CHEBI:42820 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C2363730 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0027947 infores:hetionet CHEBI:6129 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0000731 infores:hetionet CHEBI:31711 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0541782 infores:hetionet CHEBI:9288 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0001126 infores:hetionet CHEBI:132233 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0008031 infores:hetionet NCBIGene:775 biolink:causes MONDO:0859286 infores:monarchinitiative not_provided not_provided HGNC:1390 MONDO:0859286 uuid:34b67d7d-8196-4727-8b40-6735696de7b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0151773 infores:hetionet CHEBI:31932 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0014518 infores:hetionet CHEBI:2673 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C2830004 infores:hetionet CHEBI:421707 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0004093 infores:hetionet CHEBI:9434 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0013378 infores:hetionet UMLS:C1144403 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0741494 infores:hetionet CHEBI:10119 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0023530 infores:hetionet CHEBI:9086 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0023380 infores:hetionet CHEBI:47898 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151714 infores:hetionet CHEBI:119573 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0009676 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0037274 infores:hetionet CHEBI:3510 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C1320835 infores:hetionet CHEBI:85078 biolink:causes MONDO:0021259 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0033578 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0042963 infores:hetionet CHEBI:15365 biolink:causes HP:0001950 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0002064 infores:hetionet NCBIGene:55681 biolink:causes MONDO:0032903 infores:monarchinitiative not_provided not_provided HGNC:19286 MONDO:0032903 uuid:1c21e8d5-f0fe-41f3-9198-d6b8c9e81130 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0020676 infores:hetionet CHEBI:37941 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0022408 infores:hetionet UMLS:C0657912 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033774 infores:hetionet CHEBI:63616 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0041657 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0151500 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151500 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013298 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0014549 infores:hetionet NCBIGene:285203 biolink:causes MONDO:0014124 infores:monarchinitiative not_provided not_provided HGNC:28526 MONDO:0014124 uuid:82951f75-8dc3-450a-93ce-1f1230d05669 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0877046 infores:hetionet CHEBI:3647 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0002874 infores:hetionet NCBIGene:2702 biolink:causes MONDO:0007171 infores:monarchinitiative not_provided not_provided HGNC:4279 MONDO:0007171 uuid:aa91fd7b-139c-47cb-acac-cccfff66bd41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6809 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0085631 infores:hetionet CHEBI:9137 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042023 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0002792 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0497365 infores:hetionet CHEBI:6832 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0018681 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0403632 infores:hetionet CHEBI:7931 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151825 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0002871 infores:hetionet CHEBI:4798 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0026821 infores:hetionet CAID:CA6401585 biolink:causes MONDO:0019565 infores:clingen CAID:CA6401585 MONDO:0019565 PMID: Likely Benign BP4, BP7, BS1 The NM_000552.5:c.7698G>A (p.Lys2566=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4, BP7). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02812 based on 2187/75070 alleles in the African/African American population, including 36 homozygotes, which is higher than the ClinGen VWD VCEP threshold of >0.01 for BS1. In summary, this variant meets the criteria to be classified as likely benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP4, BP7 BS1. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; July 1, 2025) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6401585/MONDO:0019565/081 2025-07-01 2025-07-01 Undetermined mode of inheritance Contradicts true CHEBI:3387 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0522063 infores:hetionet NCBIGene:8313 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:904 MONDO:0005575 uuid:3fa2eead-ef08-4f75-b7fe-35936909e7fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:145499 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0043144 infores:hetionet CHEBI:4708 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0016382 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0030312 infores:hetionet CAID:CA9871466 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871466 MONDO:0007064 PMID: Uncertain Significance PM2, BA1, PM5, BS1, PS1 The c.932C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 311 (p.Thr311Ile).The filtering allele frequency (the upper threshold of the 95% CI of 19/60010 alleles) of the c.932C>T variant in ADA is 0.0002067 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold for BS1 (>0.00161) and BA1 (>0.00721) but higher than the threshold (<0.0001742) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871466/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63608 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0012359 infores:hetionet CAID:CA024772 biolink:causes MONDO:0007783 infores:clingen CAID:CA024772 MONDO:0007783 PMID: Uncertain Significance PM1, PP3_Moderate PS4, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with glutamine at codon 2452 of the RYR1 protein, p.(Arg2452Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID: PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024772/MONDO:0007783/012 2021-12-21 2021-12-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:31711 biolink:causes MONDO:0006670 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0085437 infores:hetionet CHEBI:9725 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0001824 infores:hetionet CAID:CA1139771059 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139771059 MONDO:0011071 PMID:34166225 Pathogenic PVS1, PS3_Moderate, PM2_Supporting PS1, PS4, PS2, BP3, BP1, BP4, BP2, BA1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.697del (p.Arg233AlafsTer4) is a variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) (17.93%) (PS3_moderate). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS3_moderate, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771059/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CAID:CA229552 biolink:causes MONDO:0009861 infores:clingen CAID:CA229552 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PVS1 The c.443_509+1del (p.Ex5del) variant in PAH is a deletion of exon 5 and is predicted to lead to a frameshift at His170, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2).It has been previously reported in one patient with PKU (BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate) (PMID: 23942198) in presumed trans with the p.G332R variant (unclassified/VUS). It is also noted in ClinVar (ID 102681) without a classification. Classification: Pathogenic Supporting Criteria: PVS1; PM2; PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229552/MONDO:0009861/006 2020-05-22 2021-03-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6129 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151827 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0018801 infores:hetionet CHEBI:4702 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0022281 infores:hetionet CHEBI:16335 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0012833 infores:hetionet CHEBI:6375 biolink:causes HP:0500167 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0853890 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0234987 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0242350 infores:hetionet CAID:CA8622904 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622904 MONDO:0100326 PMID:9116286 Uncertain Significance PM2_Supporting, BP4 BS3, PM3, PP4 The NM_000212.3(ITGB3):c.263G>A variant in ITGB3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 88 (Arg88Gln). One patient with the heterozygous Arg88Gln variant and a platelet function defect in PMID: 31064749; however other information such as bleeding history, platelet aggregometry or glycoprotein expression is not available. PP4 criteria not met. The variant is described as a platelet antigen in the literature, determining the HPA-10 genotype. The computational predictor REVEL gives a score of 0.167, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGB3 function and no splicing impact is expected (SpliceAI predicts a donor gain at at -14bp with a delta score of 0.04) (BP4). The highest population minor allele frequency in gnomAD v4.1 is 0.00006682 (3/44894 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Due to insufficient and conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: BP4, PM2. ( VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622904/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:42944 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0015672 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0017574 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0155919 infores:hetionet CHEBI:8863 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0086439 infores:hetionet CHEBI:47612 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0151576 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0699885 infores:hetionet CHEBI:119486 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0003467 infores:hetionet CHEBI:50648 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0016382 infores:hetionet CHEBI:3176 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0039231 infores:hetionet CAID:CA120537 biolink:causes MONDO:0044970 infores:clingen CAID:CA120537 MONDO:0044970 PMID:18400783 Likely Pathogenic PP3, PS3_Moderate, PM2_Supporting, PS4_Moderate PS2, PM6 The m.1624C>T variant in MT-TV has been reported in two families with primary mitochondrial disease (PMIDs: 11799391, 23063709). The proband in the first family reported was a woman with migraines, muscle weakness, reduced COX activity on histochemistry in skeletal muscle, and reduced activities of complexes I and IV in skeletal muscle. The variant was present at homoplasmy in her blood and muscle sample. She had a son with Leigh syndrome with the variant present at homoplasmy in buccal sample. She had six other children who died in the first days of life due to lactic acidosis, including one child who also had severe cardiac failure and hypertrophic cardiomyopathy who was found to have the variant present at homoplasmy in blood, muscle, and cardiac tissue. She also had three siblings who died in early infancy (PMID: 11799391). The proband in the second family reported was a man with adult-onset Leigh syndrome. He presented at age 25 years with transient mild consciousness disturbance and agitation. By 29 years he had left ventricular hypertrophy, constricted visual fields, ataxic gait, slurred speech, and poor coordination. By his mid-30s, he has personality changes and cognitive decline. He had elevated blood and cerebrospinal fluid lactate levels. Brain imaging at ages 25 years and 35 years revealed mild frontal lobe atrophy and low and high signal intensity spots on T1- and T2-weighted images, respectively, in the right caudate head and bilateral putamen. The variant was present in muscle (89% at age 29 years, 60% at age 36 years) and blood (48% at 29 years, 34% at age 36 years). His mother had onset of stroke-like episodes in her mid-30s in addition to psychiatric involvement. She was noted to have left-sided paresis in her 40s. The variant was present in her blood at 17% (PMID: 23063709). Additionally, an Expert Panel member knew of an additional two cases (one baby, one adult) who were very ill and had the variant present at homoplasmy (PS4_moderate). There are no de novo occurrences of this variant reported to our knowledge. This variant is absent in MITOMAP. There are no homoplasmic occurrences in gnomAD v3.1.2 or the Helix dataset, however there is one heteroplasmic occurrence in gnomAD and two heteroplasmic occurrences in Helix. Although there are several heteroplasmic occurrences, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (68.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.45 (PP3). Strong cybrid studies and analysis in patient myoblasts and fibroblasts support the functional impact of this variant (PS3_moderate; PMID: 18400783). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120537/MONDO:0044970/015 2024-09-24 2025-05-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria UMLS:C0657912 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0948594 infores:hetionet CHEBI:6472 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0085641 infores:hetionet CAID:CA658799362 biolink:causes MONDO:0015967 infores:clingen CAID:CA658799362 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PS4 The c.100delG variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 34 of NM_175914.5, adding 70 novel amino acids before encountering a stop codon (p.(Val34SerfsTer70)). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information and PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor; ClinVar ID: 524154). In summary, c.100delG meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799362/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2666 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0013144 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0151698 infores:hetionet CHEBI:3994 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0086565 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0018801 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0041349 infores:hetionet CHEBI:42355 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0041349 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0011991 infores:hetionet CHEBI:37941 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0030193 infores:hetionet CAID:CA013721 biolink:causes MONDO:0007947 infores:clingen CAID:CA013721 MONDO:0007947 PMID: Likely Benign BP2, BP5, BS1 PM2, PM6, BS2, PP1, PP4, PP2, PP3, BP1, BP4, BA1, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BS3, BS4 The NM_000138 c.3058A>G, is a missense variant in FBN1 predicted to cause a substitution of a Threonine by Alanine at amino acid 1020 (p.Thr1020Ala). This variant was found in 12 probands with variable phenotypes, mostly thoracic aortic aneurysm or a marfanoid habitus. One proband additionally presented ectopia lentis. Two of these probands carried two other pathogenic variants: a variant in FBN1 (BP2) and a variant in TGFBR1 (BP5). The variant in FBN1 has been reported ten times in ClinVar: 8 times as likely benign and two times as a variant of uncertain significance (Variation ID: 42325). The variant has been reported in the literature in multiple affected individuals including one individual with classical Marfan syndrome (PMID: 11175294), one individual with incomplete Marfan syndrome (PMID: 18435798), one patient with MASS syndrome (PMID: 25944730), and an individual with bicuspid aortic valve and aortic root aneurysm (PMID: 28387797). This variant has also been reported in 3 patients with Lujan-Fryns syndrome (PMID: 19293843, PMID: 28027854), including two brothers with marfanoid habitus, learning disabilities without cardiac defects (PMID: 28027854). These brothers also share a variant in MECP2. Segregation analysis in one family showed that the variant was also present in four additional family members, none of which had aortic aneurysm, two had a marfanoid habitus This variant has been identified in 80 individuals of European-non-Finnish origin (MAF: 0.062%) in gnomad v2.1.1 (https://gnomad.broadinstitute.org/) (BS1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2, BP5. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA013721/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:4792 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0085593 infores:hetionet NCBIGene:37 biolink:causes MONDO:0008723 infores:monarchinitiative not_provided not_provided HGNC:92 MONDO:0008723 uuid:cd0fc04e-d2b5-4b9d-9c61-f79e14ba2cfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0687133 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0032326 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0027697 infores:hetionet NCBIGene:8842 biolink:causes MONDO:0012983 infores:monarchinitiative not_provided not_provided HGNC:9454 MONDO:0012983 uuid:afd8403c-9258-4365-8784-1c94c9d7229a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9288 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0020621 infores:hetionet CHEBI:6541 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030196 infores:hetionet CHEBI:75998 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0743400 infores:hetionet CHEBI:3223 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0003862 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0178298 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0235032 infores:hetionet NCBIGene:10159 biolink:causes MONDO:0026765 infores:monarchinitiative not_provided not_provided HGNC:18305 MONDO:0026765 uuid:d516c0e8-37de-4026-bda8-5d48a612bdae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0497156 infores:hetionet CAID:CA2580616386 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580616386 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP2, BP3, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM3, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1233_1236dup (p.Ser413fs) is a frameshift variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580616386/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:7058 biolink:causes MONDO:0971044 infores:monarchinitiative not_provided not_provided HGNC:11786 MONDO:0971044 uuid:0d43b9a4-c9db-4222-b17c-2908542a9c78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6923 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0018939 infores:hetionet CHEBI:15553 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0015967 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0037274 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0549433 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0855242 infores:hetionet CHEBI:72297 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0085593 infores:hetionet CHEBI:92712 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0010520 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020649 infores:hetionet CHEBI:10101 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0522224 infores:hetionet CHEBI:46081 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0002792 infores:hetionet CHEBI:64028 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0003467 infores:hetionet CHEBI:5138 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0232726 infores:hetionet CHEBI:63621 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0235266 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0236068 infores:hetionet CHEBI:46557 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0151714 infores:hetionet NCBIGene:169522 biolink:causes MONDO:0012475 infores:monarchinitiative not_provided not_provided HGNC:19698 MONDO:0012475 uuid:ea00b89b-42ff-44dd-b41e-25197ca45e28 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5280 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0042267 infores:hetionet NCBIGene:7053 biolink:causes MONDO:0014989 infores:monarchinitiative not_provided not_provided HGNC:11779 MONDO:0014989 uuid:f5bdb804-46e7-4d3d-ab81-74330a5d6164 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0013390 infores:hetionet CHEBI:3216 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151786 infores:hetionet CHEBI:10101 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0221150 infores:hetionet CHEBI:4907 biolink:causes MONDO:0043455 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0149911 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0034882 infores:hetionet CHEBI:3638 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0042963 infores:hetionet CHEBI:6801 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0236024 infores:hetionet CHEBI:18248 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0016382 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0027051 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0030554 infores:hetionet CHEBI:135920 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0027765 infores:hetionet CHEBI:7956 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0853619 infores:hetionet CHEBI:8024 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0038325 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0020651 infores:hetionet CHEBI:30830 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0393761 infores:hetionet CHEBI:9725 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0855775 infores:hetionet CHEBI:38940 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0019079 infores:hetionet CHEBI:4975 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0036974 infores:hetionet CHEBI:63115 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0013404 infores:hetionet CHEBI:4995 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0038325 infores:hetionet CHEBI:7824 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085637 infores:hetionet CHEBI:2663 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0085623 infores:hetionet CAID:CA6748733 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748733 MONDO:0009861 PMID: Uncertain Significance BP7 BS1 The c.1161C>T (p.Tyr387=) variant in PAH has not been reported in the literature to our knowledge. It is a silent variant with no splice impact predicted. It is present at low frequencies in population databases (MAF 0.00024 in gnomAd and ExAc, 0 homozygotes) which is above our threshold for PM2 (<0.0002) but below our threshold for BS1 (>0.002). Therefore, it meets criteria to be classified as uncertain significance. PAH-specific ACMG/AMP criteria applied: BP7. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748733/MONDO:0009861/006 2021-09-26 2021-11-21 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50122 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0043094 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0235351 infores:hetionet CHEBI:31625 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0948595 infores:hetionet CHEBI:9649 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0016204 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0012833 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026946 infores:hetionet CHEBI:144093 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018418 infores:hetionet CHEBI:5613 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042963 infores:hetionet CAID:CA291858 biolink:causes MONDO:0021060 infores:clingen CAID:CA291858 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.90C>T (p.Asp30=) variant in the KRAS gene is 0.0292% (5/6746) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA291858/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:45357473 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013378 infores:hetionet CHEBI:47898 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020639 infores:hetionet CHEBI:36795 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018524 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0020538 infores:hetionet NCBIGene:673 biolink:causes MONDO:0008903 infores:monarchinitiative not_provided not_provided HGNC:1097 MONDO:0008903 uuid:05301ff9-dcf8-4771-a694-93a37992931d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0031085 infores:hetionet CHEBI:6375 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0026858 infores:hetionet CHEBI:7773 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C2830004 infores:hetionet CHEBI:8435 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0151818 infores:hetionet CHEBI:46081 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C2830004 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0024299 infores:hetionet NCBIGene:1890 biolink:causes MONDO:0011283 infores:monarchinitiative not_provided not_provided HGNC:3148 MONDO:0011283 uuid:be6e8d69-53f9-4314-927b-c6a03d2cc03d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1904444 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0061458 CHEBI:18248 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0026821 infores:hetionet CHEBI:49960 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0013428 infores:hetionet CHEBI:46195 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0027947 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0855242 infores:hetionet CHEBI:3242 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0009676 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042267 infores:hetionet CHEBI:15551 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0018681 infores:hetionet CHEBI:64028 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0013404 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0162429 infores:hetionet NCBIGene:54757 biolink:causes MONDO:0008771 infores:monarchinitiative not_provided not_provided HGNC:23015 MONDO:0008771 uuid:520cc860-9cf5-438a-88b1-8e902a846f2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0015967 infores:hetionet CHEBI:5134 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0264267 infores:hetionet NCBIGene:27286 biolink:causes MONDO:0010388 infores:monarchinitiative not_provided not_provided HGNC:30668 MONDO:0010388 uuid:c4ac61f9-cadc-4cf0-8bee-918d318d8dbb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7575 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0020649 infores:hetionet CHEBI:8802 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020461 infores:hetionet CHEBI:50223 biolink:causes UMLS:C1167779 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C1167779 infores:hetionet CHEBI:3082 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020473 infores:hetionet CHEBI:49575 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0151907 infores:hetionet CHEBI:75998 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0002871 infores:hetionet CHEBI:47519 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C2047937 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0013395 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0040034 infores:hetionet CHEBI:3207 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0006266 infores:hetionet CHEBI:135351 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0549373 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0238425 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0238425 infores:hetionet CAID:CA10650447 biolink:causes MONDO:0011071 infores:clingen CAID:CA10650447 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.-132G>C is a UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10650447/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3534 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0022354 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0005940 infores:hetionet CHEBI:94449 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0917801 infores:hetionet CAID:CA2017997773 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997773 MONDO:0015967 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PM2_Supporting PS4 The c.1335_1345del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 8 novel amino acids before encountering a stop codon (p.(Arg447ProfsTer8)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate. However, this individual has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 14517956, internal lab contributor). This variant segregates with disease with 4 informative meiosis in this individual's family (PP1_moderate; internal lab contributor). In summary, the c.1335_1345del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP1_moderate, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997773/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:8107 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0040264 infores:hetionet CHEBI:43968 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0700345 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1291078 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0018799 infores:hetionet GO:2000790 biolink:causes GO:0030323 infores:ubergraph knowledge_assertion manual_agent GO:2000790 GO:0030323 CHEBI:367163 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0009676 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0232459 infores:hetionet CHEBI:48390 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0020598 infores:hetionet CHEBI:5855 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0855775 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0424000 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0086132 infores:hetionet CHEBI:61049 biolink:causes HP:0040303 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235988 infores:hetionet CHEBI:32293 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0011603 infores:hetionet CHEBI:5280 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1096274 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0009938 infores:hetionet CAID:CA171648 biolink:causes MONDO:0100039 infores:clingen CAID:CA171648 MONDO:0100039 PMID:23583054 Likely Pathogenic PP3, PP4, PP1, PM6_Strong, PM2_Supporting PM5 The p.Asp193Gly variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in affected individuals (PMID 23583054) (PM6_Strong). The p.Asp193Gly variant in CDKL5 is absent from gnomAD (PM2_Supporting). The variant has been reported to segregate in two informative meioses (PMID: 23583054) (PP1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asp193Gly variant in CDKL5 has been reported in an individual with a clinical phenotype suggestive of a CDKL5-associated disorder (PP4). In summary, the p.Asp193Gly variant in CDKL5 is classified as likely pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PM6_strong, PM2_supporting, PP1, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA171648/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:37924 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0043094 infores:hetionet CHEBI:6367 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0023518 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0042109 infores:hetionet CHEBI:8428 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0151480 infores:hetionet CHEBI:68554 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0022408 infores:hetionet CHEBI:31515 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0013604 infores:hetionet CHEBI:9435 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C1443060 infores:hetionet CHEBI:64355 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0037763 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0042029 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0267596 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0043251 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0853692 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000942 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0010034 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0004623 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0339916 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0339916 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0162119 infores:hetionet CAID:CA2573055152 biolink:causes MONDO:0010726 infores:clingen CAID:CA2573055152 MONDO:0010726 PMID: Likely Benign BP5, BS2 PM2 The p.His372_Ser373delinsProGln variant in MECP2 (NM_004992.4) is present in at least 6 alleles in gnomAD v4.1; however this variant is reported as 3 separate entries in the gnomAD database. The p.His372_Ser373delinsProGln variant is observed in at least 4 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.His372_Ser373delinsProGln variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.His372_Ser373delinsProGln variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573055152/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:45081 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0039231 infores:hetionet CHEBI:8327 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0027497 infores:hetionet CHEBI:6887 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013144 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C3665347 infores:hetionet CHEBI:100246 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0700225 infores:hetionet CHEBI:8863 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C2364111 infores:hetionet GO:0050932 biolink:causes GO:0048066 infores:ubergraph knowledge_assertion manual_agent GO:0050932 GO:0048066 CHEBI:92998 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0085681 infores:hetionet CAID:CA902309 biolink:causes MONDO:0100368 infores:clingen CAID:CA902309 MONDO:0100368 PMID: Likely Pathogenic PM3, PM5_Supporting, PP4_Moderate, PM2_Supporting PP3 NM_000329.3(RPE65):c.1040G>A (p.Arg347His) is a missense variant predicted to replace arginine at position 347 with histidine. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.00000365, with 2 / 91062 alleles in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Tyr368His variant, confirmed in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 point, PMID: 35129589). Three other probands with early-onset severe retinal dystrophy were compound heterozygous with three different variants - one with the confirmed pathogenic variant c.95-2A>T, suspected in trans (0.5 pts, PMID:35129589), one with the p.Ala357_Ala360del variant, not yet curated, confirmed in trans (0.25 pts, PMID:3483051), and one with the p.Leu38Arg variant, not yet curated, suspected in trans (0 pts, VCEP member data) (1.75 total points, PM3). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts), diagnosis of fundus albipuncatus with white-yellow dots scattered in mid periphery of retina (2 pts), onset in early childhood (1 pt), OCT examination normal (1 pt), focal areas of hypoautofluorescence (2 pts) at the middle retinal periphery, mild reduction of visual field (1 pt), full field ERG showed scotopic responses below the noise level (0.5 pts), and clinical exome sequencing did not reveal alternative cause of disease (2 pts). Together these are highly specific for RPE65-related recessive retinopathy (total 10 points, PMID: 35129589, PP4_Moderate). Another missense variant in the same codon (c.1039C>T, p.Arg347His) has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5_Supporting, PMID: 36017377). In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP:PP4_moderate, PM3, PM2_supporting, PM5_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902309/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151827 infores:hetionet CHEBI:9123 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0043094 infores:hetionet CHEBI:45599 biolink:causes UMLS:C2747793 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C2747793 infores:hetionet CHEBI:167309 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0151740 infores:hetionet CHEBI:6339 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0029927 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0858217 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0858217 infores:hetionet NCBIGene:6091 biolink:causes MONDO:0957210 infores:monarchinitiative not_provided not_provided HGNC:10249 MONDO:0957210 uuid:60771514-7265-42f4-9e2d-637d4e3e3317 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4659 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0033975 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0027051 infores:hetionet CHEBI:240107 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0022081 infores:hetionet CAID:CA120625 biolink:causes MONDO:0044970 infores:clingen CAID:CA120625 MONDO:0044970 PMID: Pathogenic PP1_Moderate, PS3_Supporting, PP3, PS4, PM6 PM5 The m.14459G>A (p.A72V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features ranging from Leber Hereditary Optic Neuropathy (LHON) with or without dystonia, Leigh syndrome, bilateral basal ganglia lesions, ataxia, and migraines (PS4; PMIDs: 8016139, 7654063, 16380132, 10894222, 14735584, 21749722, 14735585, 28503604, 32045392, 29408632, 22426787). This variant has been identified as a de novo occurrence in at least 2 probands with primary mitochondrial disease (PM6; PMIDs: 14735584, 10894222). This variant heteroplasmy level segregated with severity in six family members from four families (PP1_moderate; PMIDs: 22426787, 21749722, 7654063, 8016139). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.93 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMID: 8622678). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PP1_moderate, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120625/MONDO:0044970/014 2021-11-01 2021-11-01 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria GO:1902691 biolink:causes CL:0002633 infores:ubergraph knowledge_assertion manual_agent GO:1902691 CL:0002633 CHEBI:8024 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0040264 infores:hetionet CHEBI:6067 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0042075 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018177 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C1621958 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0036572 infores:hetionet CHEBI:15552 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020580 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0162429 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0233472 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151436 infores:hetionet CHEBI:3286 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0016204 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0235416 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0854375 infores:hetionet CHEBI:472657 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0518015 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151763 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0948594 infores:hetionet CHEBI:51450 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0022346 infores:hetionet CHEBI:3640 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0235416 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0019348 infores:hetionet CHEBI:80630 biolink:causes MONDO:0700048 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0549410 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1167965 infores:hetionet CHEBI:7601 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0011991 infores:hetionet CHEBI:3504 biolink:causes DOID:722 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0000786 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0003123 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027051 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235818 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027769 infores:hetionet CHEBI:6909 biolink:causes NCIT:C74591 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0234925 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0392525 infores:hetionet NCBITaxon:4751 biolink:causes UMLS:C0011974 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4751 MESH:D003963 DB00825_MESH_D003963_1 CAID:CA000576 biolink:causes MONDO:0017623 infores:clingen CAID:CA000576 MONDO:0017623 PMID: Benign BS3, BS1 PTEN c.79+35C>T (IVS1+35C>T) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00178 (1.78%, 492/277,200 alleles) in the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 17636424) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000576/MONDO:0017623/003 2016-09-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6076 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011124 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0521839 infores:hetionet CHEBI:2666 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0152198 infores:hetionet GO:0048924 biolink:causes CL:2000038 infores:ubergraph knowledge_assertion manual_agent GO:0048924 CL:2000038 CHEBI:16664 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0858678 infores:hetionet CHEBI:114785 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0003811 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0270994 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0270994 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020456 infores:hetionet CAID:CA645509535 biolink:causes MONDO:0007648 infores:clingen CAID:CA645509535 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM6, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.1341del (p.Lys447fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509535/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:50223 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0853149 infores:hetionet CHEBI:3510 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0038325 infores:hetionet CHEBI:7986 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0392171 infores:hetionet CHEBI:3732 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0014724 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0243026 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151736 infores:hetionet CHEBI:68647 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020625 infores:hetionet CHEBI:31709 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0700200 infores:hetionet CHEBI:9168 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0542571 infores:hetionet CHEBI:5855 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018834 infores:hetionet CAID:CA16602336 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602336 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1738T>C (p.Ser580Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.911. PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602336/MONDO:0007750/013 2023-11-07 2024-09-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9448 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0014724 infores:hetionet CHEBI:8764 biolink:causes MONDO:0043959 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0221269 infores:hetionet CAID:CA512318739 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318739 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.423G>C (p.Ser141=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-2.29)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318739/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:100241 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011053 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0340726 infores:hetionet CHEBI:7903 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0020517 infores:hetionet CHEBI:7936 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027796 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0235032 infores:hetionet CHEBI:66876 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0017178 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0687707 infores:hetionet CAID:CA367401755 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401755 MONDO:0015967 PMID: Pathogenic PM5_Strong, PS4_Moderate, PP1_Strong, PM1, PS3_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.502A>C variant in the glucokinase gene, GCK causes an amino acid change of The to Pro at codon 168 (p.(Thr168Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with diabetes (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 3 families with diabetes (PP1_Strong; PMID:9049484, internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Gly175Arg has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657). The c.502A>G, p.Thr168Ala and c.503C>A, p.Thr168Asn variants have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PM1, PP3, PS3_Supporting, PP1_Strong, PM5_Strong, PS4_Moderate, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401755/MONDO:0015967/086 2023-07-29 2023-07-29 Semidominant inheritance HP:0032113 Supports NCBIGene:9054 biolink:causes MONDO:0030311 infores:monarchinitiative not_provided not_provided HGNC:15910 MONDO:0030311 uuid:20f5503b-1b69-4e30-afe1-e30f1c469c39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020649 infores:hetionet CHEBI:8356 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085932 infores:hetionet CHEBI:135961 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0438717 infores:hetionet CHEBI:44423 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0013395 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0019193 infores:hetionet CHEBI:4784 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151905 infores:hetionet CHEBI:520985 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0013404 infores:hetionet CHEBI:45081 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0010200 infores:hetionet CHEBI:6690 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0009806 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030567 infores:hetionet CHEBI:47426 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0011991 infores:hetionet NCBIGene:10073 biolink:causes MONDO:0971171 infores:monarchinitiative not_provided not_provided HGNC:14245 MONDO:0971171 uuid:ed3f66d8-3a91-43c1-b891-abb68f9cf775 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C3665386 infores:hetionet CHEBI:83527 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0007820 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0042769 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0021400 infores:hetionet CHEBI:9943 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0553721 infores:hetionet CHEBI:15940 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0344232 infores:hetionet CHEBI:135351 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0033771 infores:hetionet CHEBI:2567 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0085649 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033860 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0031350 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0392168 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0392168 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004096 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0149931 infores:hetionet CHEBI:4356 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0018524 infores:hetionet CAID:CA10014211 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014211 MONDO:0100083 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1070C>T (p.Pro357Leu) is a missense variant which has a REVEL score < 0.50 (0.471), and a SpliceAI score ≤0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014211/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83531 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0040822 infores:hetionet CHEBI:70735 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0027441 infores:hetionet CHEBI:490877 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0027497 infores:hetionet CHEBI:9398 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0002994 infores:hetionet CHEBI:4710 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0241934 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0948089 infores:hetionet CHEBI:10127 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151766 infores:hetionet CHEBI:50648 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0043094 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0006444 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0039971 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0497365 infores:hetionet CHEBI:31644 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0017178 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1384597 infores:hetionet CHEBI:9123 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151205 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0234913 infores:hetionet NCBIGene:123041 biolink:causes MONDO:0014385 infores:monarchinitiative not_provided not_provided HGNC:10978 MONDO:0014385 uuid:070cb2df-5a73-4f1b-adcd-f2a51b57e499 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0003123 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0020517 infores:hetionet CHEBI:367163 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0033687 infores:hetionet CHEBI:3181 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0917801 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549433 infores:hetionet CHEBI:32192 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0009319 infores:hetionet CHEBI:6532 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0038325 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0427008 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151998 infores:hetionet CAID:CA410206731 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206731 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.767C>T (p.Ser256Phe) is a missense variant which has a REVEL score < 0.50 (0.317), and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206731/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020473 infores:hetionet CHEBI:6715 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151905 infores:hetionet NCBIGene:6927 biolink:causes MONDO:0010894 infores:monarchinitiative not_provided not_provided HGNC:11621 MONDO:0010894 uuid:4a3fc2d0-b431-4a2b-9a44-9d315091df1d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011606 infores:hetionet CHEBI:2676 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0040034 infores:hetionet CAID:CA16608444 biolink:causes MONDO:0007064 infores:clingen CAID:CA16608444 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4(ADA):c.575G>A is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 192 (p.Ser192Asn). The variant is absent in gnomAD v4 (PM2_supporting).There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as Variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608444/MONDO:0007064/114 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:1903010 biolink:causes GO:0001501 infores:ubergraph knowledge_assertion manual_agent GO:1903010 GO:0001501 CHEBI:9086 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0026946 infores:hetionet CAID:CA410207977 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207977 MONDO:0011071 PMID: Likely Pathogenic PM5_Supporting, PM1, PM2_Supporting, PS4_Supporting, PP3 PS1, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS4, PM6, PVS1, PM4, PM3, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.592G>A (p.Asp198Asn) is a missense mutation affecting a hotspot residue within the RHD (PM1). This variant is a missense change at the same residue (p.D198) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 627342) based on MM-VCEP rules for RUNX1 (PM5_Supporting). This missense variant has a REVEL score ≥ 0.88 (0.93) (PP3). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 26175287). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PM5_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207977/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CAID:CA120586 biolink:causes MONDO:0044970 infores:clingen CAID:CA120586 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PS4, PS3 The m.10438A>G variant in MT-TR has been reported in one individual with primary mitochondrial disease (PMID: 15286228). This individual had decreased vision, nystagmus, developmental delay, intellectual disability, clumsiness, and hypotonia. He had elevated blood lactate and pyruvate, and brain imaging showed cerebral atrophy. Complex IV was mildly reduced in muscle. The variant was present in muscle at 88% heteroplasmy and in blood at 73% heteroplasmy. The variant was present in his asymptomatic mother’s blood, buccal epithelium, skin fibroblasts and muscle at approximately 19%, and in his maternal grandmother’s blood at 17% and buccal epithelium at 8%. Of note, nuclear genetic etiologies were not evaluated in this family. A second individual with Leber Hereditary Optic Neuropathy (LHON) caused by m.11778G>A was also found to have this variant at homoplasmy, and this variant was considered an LHON modifier (PMID: 35623556). Multiple family members were also found to have the variant present at homoplasmy. There is one heteroplasmic occurrence in gnomAD v3.1.2, one heteroplasmic and one homoplasmic occurrence in the Helix dataset, and the variant is absent in the MITOMAP GenBank dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is possibly benign (12.4 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.35. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120586/MONDO:0044970/015 2024-02-26 2025-10-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5123 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0013404 infores:hetionet NCBITaxon:10372 biolink:causes MONDO:0000337 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10372 MONDO:0000337 CHEBI:94807 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0234215 infores:hetionet CHEBI:44185 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0011991 infores:hetionet CHEBI:167309 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0016655 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020456 infores:hetionet CHEBI:6954 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C3665347 infores:hetionet CHEBI:4728 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0018965 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0022660 infores:hetionet CHEBI:7494 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0011551 infores:hetionet CHEBI:45924 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0014591 infores:hetionet CHEBI:6367 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030252 infores:hetionet CHEBI:8863 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018790 infores:hetionet CHEBI:31624 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0040046 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1696946 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1696946 infores:hetionet CHEBI:17347 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0030252 infores:hetionet CHEBI:7936 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0025345 infores:hetionet CHEBI:3757 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0030554 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0029191 infores:hetionet CHEBI:71255 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0036974 infores:hetionet NCBIGene:8450 biolink:causes MONDO:0010306 infores:monarchinitiative not_provided not_provided HGNC:2555 MONDO:0010306 uuid:d4b4abb2-8a9f-4bda-9435-a32dd4f4b250 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA605238909 biolink:causes MONDO:0010880 infores:clingen CAID:CA605238909 MONDO:0010880 PMID: Uncertain Significance PM4, PM2_Supporting The NM_000020.3: c.442_444del variant in ACVRL1 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu148del) (PM4). The overall minor allele frequency in gnomAD v2.1.1 is 0.00003184 (1/31404 alleles, Note: variant failed random forest filters), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM4, PM2_Supporting (specification version 1.0.0; 1/04/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA605238909/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6541 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C2047937 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0849796 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0849796 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0003123 infores:hetionet CHEBI:15367 biolink:causes MONDO:0012105 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C3495801 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0038454 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0014175 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0042373 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0027707 infores:hetionet NCBIGene:324 biolink:causes MONDO:0017790 infores:monarchinitiative not_provided not_provided HGNC:583 MONDO:0017790 uuid:22d27b52-afde-469e-890e-9181c8e34d16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0041956 infores:hetionet NCBIGene:93426 biolink:causes MONDO:0014847 infores:monarchinitiative not_provided not_provided HGNC:28852 MONDO:0014847 uuid:24377f53-ae5f-456a-8fe0-4e3c8855819f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0237849 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0006826 infores:hetionet CAID:CA410207013 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207013 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, BA1, BP1, BP4, BP3, BP2, PVS1, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PP2, PP3, PP1 NM_001754.5(RUNX1):c.656T>C (p.Leu219Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207013/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31348 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020546 infores:hetionet CHEBI:3499 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C1609512 infores:hetionet CHEBI:64019 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0151691 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011609 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011615 infores:hetionet CHEBI:490877 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C2242996 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0042373 infores:hetionet CHEBI:63621 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019080 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0008301 infores:hetionet CHEBI:4885 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0018681 infores:hetionet CHEBI:4814 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0018681 infores:hetionet CHEBI:51041 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0025323 infores:hetionet CAID:CA343726232 biolink:causes MONDO:0005338 infores:clingen CAID:CA343726232 MONDO:0005338 PMID: Uncertain Significance PP1_Moderate, PM2_Supporting BP7, BS1, BS3, PP3, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.764T>C variant in MYOC is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 255 (p.Leu255Pro). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.421, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 5 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 27485216), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 27485216), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP1_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726232/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0120107 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0041912 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0033775 infores:hetionet CHEBI:116278 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0542571 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0009760 infores:hetionet CHEBI:8871 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0018926 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0233494 infores:hetionet CHEBI:49668 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0041969 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0158350 infores:hetionet NCBIGene:55229 biolink:causes MONDO:0030465 infores:monarchinitiative not_provided not_provided HGNC:19366 MONDO:0030465 uuid:5c969696-8eee-40a0-b0b3-88443bc62ae0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39112 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0149725 infores:hetionet NCBIGene:712 biolink:causes MONDO:0958182 infores:monarchinitiative not_provided not_provided HGNC:1241 MONDO:0958182 uuid:54208231-3028-4d69-a276-24257a03bbed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0085096 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0853595 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853595 infores:hetionet GO:0031982 biolink:causes GO:0016192 infores:ubergraph knowledge_assertion manual_agent GO:0031982 GO:0016192 CHEBI:41977 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0497156 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0035078 infores:hetionet UMLS:C1738934 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0233763 infores:hetionet UMLS:C0120107 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0002962 infores:hetionet CHEBI:135876 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0032285 infores:hetionet CHEBI:28487 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0003123 infores:hetionet CHEBI:61033 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0008031 infores:hetionet CHEBI:8888 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0149745 infores:hetionet CHEBI:3699 biolink:causes MONDO:0005974 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0038463 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0021400 infores:hetionet CHEBI:41977 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C2242737 infores:hetionet CHEBI:8212 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0018418 infores:hetionet CHEBI:8502 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C2830004 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0037822 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0017160 infores:hetionet CHEBI:724125 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0037299 infores:hetionet CHEBI:6067 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0740394 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0042267 infores:hetionet CHEBI:61049 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0152030 infores:hetionet CHEBI:47499 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0028643 infores:hetionet CHEBI:63617 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013428 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0011570 infores:hetionet CHEBI:2453 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0232462 infores:hetionet CHEBI:52717 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0041657 infores:hetionet CHEBI:35677 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0042401 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0007222 infores:hetionet CHEBI:9654 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C1504494 infores:hetionet CHEBI:465284 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0020456 infores:hetionet CHEBI:3380 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0018681 infores:hetionet CHEBI:16899 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0013456 infores:hetionet CHEBI:6933 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0038363 infores:hetionet CHEBI:3127 biolink:causes MONDO:0037829 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0268104 infores:hetionet CHEBI:9566 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0341047 infores:hetionet NCBIGene:11280 biolink:causes MONDO:0014247 infores:monarchinitiative not_provided not_provided HGNC:10583 MONDO:0014247 uuid:84dda21d-6e24-4d8b-878b-30dd46c52cfa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030252 infores:hetionet CHEBI:2453 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0042384 infores:hetionet NCBIGene:5189 biolink:causes MONDO:0011101 infores:monarchinitiative not_provided not_provided HGNC:8850 MONDO:0011101 uuid:d0ca06a1-9a41-4c3a-9b9b-91776a3d87a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0061999 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:0061999 GO:0048513 CHEBI:4659 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0302295 infores:hetionet CHEBI:9241 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0042963 infores:hetionet NCBITaxon:6213 biolink:causes MONDO:0000288 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6213 MONDO:0000288 CHEBI:5280 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009760 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018021 infores:hetionet CHEBI:18357 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0042963 infores:hetionet CHEBI:8327 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0020651 infores:hetionet CHEBI:2682 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020625 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0423729 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0423729 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0948089 infores:hetionet CHEBI:52717 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018965 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151996 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027651 infores:hetionet CHEBI:9738 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C2363731 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0314719 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0029134 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040046 infores:hetionet CHEBI:2955 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0008031 infores:hetionet CHEBI:8232 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151539 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0156312 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0521839 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0151883 infores:hetionet CHEBI:142290 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0030193 infores:hetionet CAID:CA10014507 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014507 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.464T>C (p.Val155Ala) is a missense variant which has a REVEL score ≥ 0.88 (0.942) (PP3). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014507/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA9870336 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870336 MONDO:0015967 PMID: Uncertain Significance PP4, BP4 PM2, BS1 The c.670+7C>T variant in the HNF4 homeobox A gene, HNF4A, is a single nucleotide variant within intron 6 of NM_175914.5. The computational splicing predictor SpliceAI gives a score of 0.00 for donor loss, suggesting that the variant has no impact on splicing (BP4). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00002141 which is lower than the MDEP threshold for BS1 (0.000033) and greater than the MDEP threshold for PM2 (0.000003). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributor).In summary, c.670+7C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870336/MONDO:0015967/085 2025-01-29 2025-01-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:474180 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0035222 infores:hetionet CHEBI:8874 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0236075 infores:hetionet CHEBI:9073 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0004134 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0232492 infores:hetionet CHEBI:6775 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0032231 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0016034 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0855775 infores:hetionet CHEBI:41774 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0156404 infores:hetionet CHEBI:94807 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0039070 infores:hetionet CAID:CA180987 biolink:causes MONDO:0019501 infores:clingen CAID:CA180987 MONDO:0019501 PMID:28041643PMID:28041643 Likely Benign BS1 BP7, BP5, BS4, BS3, BS2, PP1, PP4, PP2, PP3, PM3, PM1, PM5, PM4, PVS1, PM2, PM6, BP2, BP1, BP3, BA1, PS4, PS2, PS3, PS1 The c.14276G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 4759 (p.Gly4759Glu). The filtering allele frequency (the lower threshold of the 95% CI of (295/75006) of this variant is 0.35% for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen Hearing Loss VCEP threshold >0.3% for BS1, and therefore meets this criterion (BS1). It has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa; however, given the allele frequency and lack of a second pathogenic variant in trans, no evidence is met (PS4/PM3 not met; SCV000204243.5, PMID 28041643). In summary, this variant has been classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA180987/MONDO:0019501/005 2025-05-21 2025-06-30 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3286 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0043352 infores:hetionet CHEBI:9123 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0151905 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0009806 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0243026 infores:hetionet CHEBI:142290 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0042029 infores:hetionet CHEBI:4814 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020443 infores:hetionet UMLS:C0010592 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0344232 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0948594 infores:hetionet CHEBI:31859 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0236000 infores:hetionet CHEBI:9139 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085635 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005453 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0018798 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0016436 infores:hetionet CHEBI:2948 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0006826 infores:hetionet CHEBI:6847 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0001824 infores:hetionet CHEBI:29688 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0020621 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0007193 infores:hetionet CHEBI:3752 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0239571 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0858678 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0858678 infores:hetionet CAID:CA8603504 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603504 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting, PM3_Supporting PP4 The NM_000419.5(ITGA2B):c.286T>A (p.Cys96Ser) missense variant has been reported in one patient (Patient 11, PMID: 31029159) with a clinical diagnosis of GT as well as abnormal platelet aggregation. No other lab studies were provided to point to a highly specific GT phenotype. This variant was homozygous in the reported individual (Patient 11, PMID: 31029159) with a clinical diagnosis of GT (PM3_Supporting). The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00003269 (1/30594 alleles) in the South Asian population (PM2_Supporting). This variant has a REVEL score of 0.8 which is above the threshold of >0.7 established by the PD EP (PP3_Met). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_Supporting, PP3 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603504/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:42355 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0003811 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0542184 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0015397 infores:hetionet CHEBI:50173 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0022281 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0424296 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014549 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0031117 infores:hetionet CHEBI:681848 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0013404 infores:hetionet CAID:CA297648 biolink:causes MONDO:0021060 infores:clingen CAID:CA297648 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1028G>A (p.Arg343Gln) variant in the PTPN11 gene is 0.116% (27/16494) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA297648/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8874 biolink:causes UMLS:C0852913 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0852913 infores:hetionet CHEBI:50275 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0000731 infores:hetionet CHEBI:28830 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0014742 infores:hetionet CHEBI:474180 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151723 infores:hetionet CHEBI:37924 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0264906 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0542149 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0542149 infores:hetionet CAID:CA658795802 biolink:causes MONDO:0015152 infores:clingen CAID:CA658795802 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3_Supporting, PVS1_Moderate, PM2_Supporting The NM_003494.4: c.5526-7T>G variant in DYSF, which is also known as NM_001130987.2: c.5643-7T>G, occurs within the splice acceptor region of intron 49. The SpliceAI score for this variant is 0.97 for loss of the essential splice acceptor and 0.99 for acceptor gain. RNAseq analysis has demonstrated that this variant results in activation of the predicted cryptic splice acceptor site, resulting in an inframe insertion of two amino acids to exon 50, p.Gly1842_Trp1843insSerSer (PMID: 36983702; PVS1_Moderate_RNA). This variant has been identified in a homozygous state in one patient with a clinical suspicion of LGMD (0.5 pts, PMID: 36983702, 30564623; PM3_Supporting). The homozygous patient with this variant was shown to have disease range dysferlin expression in blood monocytes, which is highly specific for DYSF-associated LGMD (PMID: 30564623, 36983702; PP4_Strong). While this individual was also homozygous for a synonymous variant in DYSF, NM_003494.4: c.2079C>T, a potential contribution of that variant was ruled out through RNAseq analysis. This variant is not present in gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 02/25/2025): PVS1_Moderate_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795802/MONDO:0015152/180 2025-02-25 2025-03-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:391960 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0344315 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034150 infores:hetionet CHEBI:9588 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0019158 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0392025 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0042373 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0231303 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002622 infores:hetionet CHEBI:188986 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C2047937 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0160390 infores:hetionet CHEBI:3716 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0002792 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0162830 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0027765 infores:hetionet CAID:CA2580617739 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580617739 MONDO:0015967 PMID: Likely Pathogenic PM4, PP4_Moderate, PP1, PM2_Supporting PS4, PM1 The c.1298_1309del variant in the glucokinase gene, GCK, is a 12 base pair deletion resulting in the in-frame deletion of 4 amino acid(s) at codon 433 (p.(Ser433_Ile436del)) within exon 10 of NM_000162.5. The c.1298_1309del variant is predicted to change the length of the protein due an in-frame deletion of 4 amino acids in a nonrepeat region (PM4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 12955723, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributors). In summary, c.1298_1309del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PM4, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580617739/MONDO:0015967/086 2023-11-24 2023-11-24 Semidominant inheritance HP:0032113 Supports CHEBI:3219 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027769 infores:hetionet UMLS:C0065374 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0013404 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0035078 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0019529 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0270769 infores:hetionet CHEBI:34967 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0026821 infores:hetionet CHEBI:9150 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0027497 infores:hetionet CHEBI:3176 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C2363731 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0235339 infores:hetionet CHEBI:27882 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0002994 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0033975 infores:hetionet CHEBI:3504 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0018802 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0030920 infores:hetionet CHEBI:231594 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0039503 infores:hetionet CHEBI:10119 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C1096250 infores:hetionet CHEBI:6076 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0042029 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0542476 infores:hetionet CHEBI:4495 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0030305 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0022650 infores:hetionet CAID:CA182517 biolink:causes MONDO:0019497 infores:clingen CAID:CA182517 MONDO:0019497 PMID:26969326PMID:26969326 Likely Benign BS1 BP7, PP3, PM3, PM4, PM5, PM2, PVS1, BA1, BP2, BP3, BP4, PS1 The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA182517/MONDO:0019497/005 2019-04-29 2019-07-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true GO:0048349 biolink:causes GO:0048343 infores:ubergraph knowledge_assertion manual_agent GO:0048349 GO:0048343 NCBIGene:2744 biolink:causes MONDO:0032685 infores:monarchinitiative not_provided not_provided HGNC:4331 MONDO:0032685 uuid:62aed80e-e92a-424d-9c58-94610b704a1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:291342 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0002792 infores:hetionet CHEBI:5103 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0013404 infores:hetionet CHEBI:231425 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C1443060 infores:hetionet CHEBI:7601 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0392525 infores:hetionet CHEBI:28901 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0015672 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040261 infores:hetionet CHEBI:9586 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011071 infores:hetionet NCBIGene:22995 biolink:causes MONDO:0013443 infores:monarchinitiative not_provided not_provided HGNC:29298 MONDO:0013443 uuid:0334f66e-2257-4a41-adf9-a451361df0e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0243026 infores:hetionet CHEBI:474053 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0221742 infores:hetionet CHEBI:131512 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0039070 infores:hetionet CHEBI:63629 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0015967 infores:hetionet CHEBI:10119 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0028961 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0040034 infores:hetionet CHEBI:48844 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0002792 infores:hetionet CHEBI:31236 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027849 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020538 infores:hetionet CHEBI:10102 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0575081 infores:hetionet CHEBI:8802 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0016382 infores:hetionet CHEBI:6954 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0344232 infores:hetionet CHEBI:8869 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0013491 infores:hetionet CHEBI:94440 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0085593 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235567 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017601 infores:hetionet CAID:CA6402474 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402474 MONDO:0019565 PMID: Benign BA1, BP4 PP4, BP2, BP5 The NM_000552.4(VWF):c.4693G>T (p.Val1565Leu) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 is 0.3882 (based on 17604/44790 alleles in the east Asian population, including 3463 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor REVEL gives a score of 0.183, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402474/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true CHEBI:63613 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0948594 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0856105 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0856105 infores:hetionet CHEBI:3219 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037383 infores:hetionet CHEBI:2611 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0009676 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0340464 infores:hetionet GO:1901207 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0009790 CHEBI:2955 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0013428 infores:hetionet CHEBI:135613 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0520887 infores:hetionet CHEBI:7443 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C3665386 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005386 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C1306889 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151763 infores:hetionet CHEBI:8707 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0018946 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0027947 infores:hetionet CHEBI:681848 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0151889 infores:hetionet CAID:CA214209 biolink:causes MONDO:0000573 infores:clingen CAID:CA214209 MONDO:0000573 PMID: Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM1_Supporting, PM3_Strong, PM5_Supporting BS2, PS1 The c.104G>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glycine by Alanine at amino acid 35 (p.Gly35Ala).The filtering allele frequency (the upper threshold of the 95% CI of 23/1179974 alleles) of the c.104G>C variant in RAG2 is 0.00001295 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 22.1% (SEM 3.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).This variant has been detected in at least 5 individuals with SCID/Leaky SCID/Omenn syndrome in the literature. Of those individuals, one (Proband 35, PMID: 30778343) is compound heterozygous for p.K58STer73, which is at least LP according to our specifications. Mother and Father are carriers; the trans phase is confirmed. 1 point. Another proband (Proband 9, PMID: 29772310) is a compound heterozygous with E437K, classified as Likely Pathogenic according to SCID VCEP. This patient is being evaluated in the p.Glu437Lys variant curation, so it will not be counted here to avoid circularity. Additionally, 3 individuals were homozygous for the variant (probands 6, 7, and 8, PMID: 29772310), reaching the maximum of 1 point for homozygous occurrence; The total is 2 points, PM3_Strong. At least one patient present: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + * Decreased presence of TCRVα7.2 in CD3+ T lymphocytes 0.5 points. The total is 1 point, and then PP4 is met (PMID: 29772310). Another missense variant [NM_000536.4(RAG2):c.104G>T (p.Gly35Val)] in the same codon has been reported. The variant was classified as Likely Pathogenic by the ClinGen SCID VCEP (PM5_Supporting).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PM1_Supporting, PS3_Moderate, PM3_Strong, PP4, PM5_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214209/MONDO:0000573/124 2024-05-13 2024-05-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45599 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0854375 infores:hetionet CAID:CA10585162 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585162 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PM2, PP3, PP4 PS3, PM5, PM3 The NM_000527.5 (LDLR):c.859G>T (p.Gly287Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4, PP1_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.928.PP4: Variant meets PM2 and is identified in ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded.PS4: Variant meets PM2 and is identified in at least 11 unrelated index cases fulfil DLCN ≥ 6 reported in ClinGen VCI, PubMed and ClinVar: 7 cases reported in VCI, 6 of them from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France, and 1 from Research Lab of Molecular Genetics of Lipid Metabolism-Prof. M.Arca; 3 cases reported from PubMed and at least 1 additional case reported in ClinVar from U4M-Lille University, France. From PubMed, 1 case reported In PMID 12730724 by El Messal et al, 2003, from Laboratoire de Biochimie, Faculte des Sciences Ain Chock, Casablanca, Morocco; 1 case reported in PMID 17196209 by Campagna et al, 2008, from University of Rome, Italy; 1 case reported in PMID 22669020 by El Aziz et al, 2012, from Ibn Rochd University Hospital, Casablanca, Morocco.PP1_Strong: Variant segregates with FH phenotype in 6 informative meiosis from 6 families reported from different laboratories: 4 affected relatives from 4 families tested positive for the variant, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 affected relative is positive for the variant, reported in PMID 17196209 by Campagna et al, 2008, from University of Rome, Italy, and in PMID 22669020 by El Aziz et al, 2012, from Ibn Rochd University Hospital, Casablanca, Morocco.PS3 not met: Functional data is not available.PM5 not met: One other variant at same codon: NM_000527.5(LDLR):c.859G>A (p.Gly287Ser), ClinVar ID 161280, is classified as Uncertain significance by these guidelines, therefore PM5 is not met.PM3 not met: One case reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. The subject is homozygous for the variant, however patient’s LDL-C is 5.32 mmol/l and no indication of lipid lowering medication. In PMID 22669020, two brothers of 21 and 18 years old are homozygous for the variant with untreated LDL-C at 12.8 mmol/l and 10.1 mmol/l respectively, which are just below 13 mmol/l threshold for HoFH phenotype. Additionally, one of 2 brothers (21 yrs with LDL-C 12.8 mmol/l) also had Type 1 diabetes. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585162/MONDO:0007750/013 2023-03-24 2023-04-01 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:135342 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0152032 infores:hetionet CHEBI:50648 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0424323 infores:hetionet CHEBI:4876 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0020456 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014549 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0014356 infores:hetionet CHEBI:51141 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C2047937 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0518015 infores:hetionet CHEBI:31980 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0234913 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0267792 infores:hetionet CHEBI:7496 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0003864 infores:hetionet CHEBI:2950 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0011616 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0030312 infores:hetionet CHEBI:28901 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0041834 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002089 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0035326 infores:hetionet CAID:CA226362 biolink:causes MONDO:0100437 infores:clingen CAID:CA226362 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1477del (p.Gly494GlufsTer7) is a 1-nucleotide deletion variant in exon 12 of 15, which results in a frameshift and premature stop codon after 7 amino acids and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts), non-recordable electroretinogram responses, high myopia (1 pt), reduced visual acuity (0.5 pts), and genotyping by next-generation sequencing panel that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (PMID: 32702353, 5.5 points, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226362/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Supports CHEBI:72296 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0002871 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0042514 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0031542 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0948594 infores:hetionet CHEBI:46295 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151578 infores:hetionet CHEBI:31515 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0022107 infores:hetionet CHEBI:47499 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0016382 infores:hetionet CHEBI:9139 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020580 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0018681 infores:hetionet CHEBI:71941 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0018681 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0016204 infores:hetionet CHEBI:31236 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013428 infores:hetionet CHEBI:8059 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0033975 infores:hetionet CHEBI:6909 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0025323 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042267 infores:hetionet CHEBI:9571 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0036974 infores:hetionet CHEBI:6887 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002962 infores:hetionet CHEBI:3371 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0042571 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0149904 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0024528 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0024528 infores:hetionet CHEBI:5790 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0575081 infores:hetionet CHEBI:31622 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0038990 infores:hetionet CHEBI:6640 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0235063 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0435002 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0011849 infores:hetionet NCBIGene:27031 biolink:causes MONDO:0008833 infores:monarchinitiative not_provided not_provided HGNC:7907 MONDO:0008833 uuid:b865c836-9eea-4da5-8aaf-291b3854d6cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0042267 infores:hetionet CHEBI:17549 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0015230 infores:hetionet CHEBI:8069 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0020517 infores:hetionet CHEBI:63925 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0151205 infores:hetionet CAID:CA390876705 biolink:causes MONDO:0100216 infores:clingen CAID:CA390876705 MONDO:0100216 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PS4_Supporting PM6, BA1, BP4, BP2, BS2, PP1, PM5, PM1, PS1, PS3, PS2, BS1, BS3, BS4 The NM_177438.2:c.3161T>C variant in DICER1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 1054 (p.Leu1054Pro). This variant received a total of 1 phenotype point across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal Contributors). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 related tumor predisposition (PP4; Internal Contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PP3. (Bayesian Points: 4; VCEP specifications version 1.3.0; 02/25/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390876705/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4911 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0021368 infores:hetionet CAID:CA320642680 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642680 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP2, BP1, BA1, BS1, BS3, BS4, BP5, PVS1, PM6, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 Synonymous variant (no REVEL score applicable), and SpliceAI score is ≤ 0.20 (0.01) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -3.228 (< 2.0)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642680/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5130 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0149931 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0029878 infores:hetionet CHEBI:63577 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0041834 infores:hetionet NCBIGene:3313 biolink:causes MONDO:0014801 infores:monarchinitiative not_provided not_provided HGNC:5244 MONDO:0014801 uuid:96b24a95-95f7-42ec-8ad6-23823f356a55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0014518 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0234193 infores:hetionet CHEBI:63617 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0424295 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085096 infores:hetionet CHEBI:3534 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0018524 infores:hetionet CHEBI:3393 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0404521 infores:hetionet CAID:CA293658 biolink:causes MONDO:0021060 infores:clingen CAID:CA293658 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.1647A>G (p.Thr549=) variant in the SOS1 gene is 0.0251% (6/10398) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA293658/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8871 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006266 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020538 infores:hetionet CAID:CA410206799 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206799 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.733C>T (p.Pro245Ser) is a missense variant which has a REVEL score < 0.50 (0.444) and a SpliceAI score ≤ 0.20 (0.02) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206799/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94440 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0027769 infores:hetionet CHEBI:681569 biolink:causes UMLS:C1096262 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1096262 infores:hetionet CAID:CA410147609 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147609 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, BA1, BP3, BP2, PVS1, PM2, BS1, BS3, PM5, PM4, PM3, PP4 NM_001754.5(RUNX1):c.1261G>A (p.Gly421Ser) is a missense variant which has a REVEL score < 0.50 (0.45) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147609/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68595 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0232461 infores:hetionet CHEBI:17549 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C1384353 infores:hetionet CAID:CA1139666831 biolink:causes MONDO:0100083 infores:clingen CAID:CA1139666831 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.*2912A>G is a 3' UTR variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666831/MONDO:0100083/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75988 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0011603 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042571 infores:hetionet CHEBI:7903 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0206061 infores:hetionet CAID:CA16020791 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020791 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.443G>T (p.Gly148Val) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 27121329, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variant p.Ser349Pro. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020791/MONDO:0009861/006 2020-01-26 2021-02-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:23765 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0032285 infores:hetionet CHEBI:78543 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1527411 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0015230 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0349506 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0018799 infores:hetionet CHEBI:119486 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0151786 infores:hetionet NCBIGene:114928 biolink:causes MONDO:0044702 infores:monarchinitiative not_provided not_provided HGNC:25169 MONDO:0044702 uuid:65fd9324-c66a-41ff-976c-a05a9012117a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0162285 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027932 infores:hetionet CHEBI:3242 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0010200 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085631 infores:hetionet CHEBI:2453 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0021368 infores:hetionet UMLS:C0145867 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0028961 infores:hetionet CHEBI:40303 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0338656 infores:hetionet CHEBI:2611 biolink:causes NCIT:C117171 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0455769 infores:hetionet CHEBI:3419 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C2830004 infores:hetionet UNII:54Z8M50D6Q biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0027540 infores:hetionet CHEBI:9073 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0003578 infores:hetionet CHEBI:46345 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0014457 infores:hetionet CHEBI:3506 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0011603 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0018801 infores:hetionet CHEBI:17474 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C3495440 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0242350 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0235431 infores:hetionet CAID:CA10585456 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585456 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP1 The NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.987. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines;- NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines; - NM_000527.5(LDLR):c.1444G>C (p.Asp482His) (ClinVar ID 251844) - Likely Pathogenic by these guidelines;There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 index case who fulfills WHO criteria for FH from PMID 20145306 (Chmara M et al., 2010), after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585456/MONDO:0007750/013 2023-06-23 2024-09-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA8815545 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815545 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3_Supporting PM5 The NM_000152.5:c.1912G>T variant in GAA is predicted to result in the substitution of glycine by tryptophan at amino acid 638, (p.Gly638Trp). At least 14 individuals diagnosed with Pompe disease have been reported with this variant. Of those individuals, two have symptoms reported to be consistent with infantile onset Pompe disease (including cardiac symptoms and hypotonia) and are on enzyme replacement therapy (PMIDs:19588081, 28763149, 31086307), and two patients with late onset Pompe disease are reported with laboratory values showing reduced GAA activity (PMIDs: 36299500) and two of them are also treated with ERT (PMIDs: 24923245, 17573812, 17643989, 21484825, 25455803, 27189384) (PP4_Moderate). Ten individuals are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. The second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (7 individuals, all phase unknown; max 1 point counted) (PMIDs: 10737124, 24923245, 28763149, 29181627, 30564623, 36299500); c.2481+102_2646+31del, phase unknown, 0.5 points (PMID: 29122469), and c.2608C>T (p.Arg870Ter) (ClinVar Variation ID: 189009, SCV001371741.1) (confirmed in trans, 1 point) (PMID: 28763149, 31086307) (ClinVar Variation ID: 189009, SCV001371741.1), and c.1913G>T (p.Gly638Val) (confirmed in trans, 1 point) (PMID: 19588081). At least one individual is homozygous for the variant (PMIDs: 18429042, 31086307). Total 4 points (PM3_VeryStrong). In addition, three individuals are compound heterozygous for the variant and either c.1829C>T (p.Ala610Val) (PMID: 17573812, 17643989, 21484825, 25455803, 27189384), c.2294G>A (p.Gly765Asp) (PMID: 24627108), c.2294G>A (p.Gly765Asp) (PMID: 31086307). The allelic data for these individuals will be used in the assessment of the second variant and was not included here to avoid circular logic. The highest population minor allele frequency (MAF) in gnomAD v2.1.1. is 0.00006752 (1/14810 alleles) in the African/African-American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In gnomAD v4.1. the highest MAF is 0.00001335 (1/74902 alleles) in the African/African-American population, also meeting PM2_Supporting. When expressed in COS-7 cells, the variant resulted in <2% control activity (PMID: 19862843). The computational predictor REVEL gives a score of 0.988 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another amino acid change at the same position, c.1913G>T (p.Gly638Val), has been reported in patients with Pompe disease. This data was used in the assessment of p.Gly638Val and is not included here to avoid circular logic.. There is a ClinVar entry for this variant (ClinVar Variation ID: 280954) In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815545/MONDO:0009290/010 2024-06-06 2024-06-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:9758 biolink:causes MONDO:0010509 infores:monarchinitiative not_provided not_provided HGNC:29007 MONDO:0010509 uuid:55a43e50-4518-4300-9b75-592dcd76665c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681569 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0020649 infores:hetionet UMLS:C0145867 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0039231 infores:hetionet CHEBI:6541 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0237849 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0020517 infores:hetionet CHEBI:32315 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013144 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0232431 infores:hetionet CHEBI:119915 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0028961 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0029878 infores:hetionet CHEBI:5441 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0541900 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005030 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0015934 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0024115 infores:hetionet CHEBI:6375 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0004093 infores:hetionet CHEBI:7824 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0002792 infores:hetionet CHEBI:61033 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020433 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0027947 infores:hetionet CHEBI:3510 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0011991 infores:hetionet CHEBI:70718 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0020461 infores:hetionet NCBIGene:55746 biolink:causes MONDO:0032693 infores:monarchinitiative not_provided not_provided HGNC:18016 MONDO:0032693 uuid:6b5f48c1-ce00-4e00-85d3-585346e245cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0687707 infores:hetionet CHEBI:5384 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0011991 infores:hetionet CHEBI:465284 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0438215 infores:hetionet CL:0000771 biolink:causes GO:0002447 infores:ubergraph knowledge_assertion manual_agent CL:0000771 GO:0002447 CHEBI:44915 biolink:causes UMLS:C0428982 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0428982 infores:hetionet CHEBI:50648 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0000737 infores:hetionet CHEBI:9435 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0043352 infores:hetionet CHEBI:9137 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0018790 infores:hetionet CHEBI:6538 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0917801 infores:hetionet CHEBI:31709 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0428977 infores:hetionet CHEBI:8228 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0917801 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0020517 infores:hetionet CHEBI:6437 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C1306341 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0038362 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020437 infores:hetionet CHEBI:50692 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0033774 infores:hetionet CHEBI:367163 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0027947 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151763 infores:hetionet CHEBI:37924 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151905 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0549452 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0549452 infores:hetionet CAID:CA132282 biolink:causes MONDO:0019497 infores:clingen CAID:CA132282 MONDO:0019497 PMID: Benign BA1 BS1, BS4, BP5, PP3, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The filtering allele frequency of the p.Tyr108= variant in the MYO7A gene is 1.45% (300/18658) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132282/MONDO:0019497/005 2018-09-28 2019-07-17 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:8768 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0018099 infores:hetionet CHEBI:4753 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0042164 infores:hetionet CHEBI:6633 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0030193 infores:hetionet CHEBI:3757 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C1145670 infores:hetionet CHEBI:10102 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0040264 infores:hetionet CHEBI:8356 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037011 infores:hetionet CAID:CA367400662 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400662 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PM1, PP1 The c.737G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to glutamic acid at codon 246 (p.(Gly246Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.882, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PMIDs: 30663027, 18248649, internal lab contributors). This variant was identified in 2 unrelated individuals and one related individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, and negative antibodies) (PP4_Moderate, internal lab contributors). Another missense variant, c.736G>A p.Gly246Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance. In addition c.737C>G p.Gly246Ala has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.737G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400662/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Supports CHEBI:404903 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0021053 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0853813 infores:hetionet CAID:CA915949552 biolink:causes MONDO:0100453 infores:clingen CAID:CA915949552 MONDO:0100453 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.1245del (p.Phe415Leufs*73) is a loss of function variant in which the deletion of a T at c.1245 in exon 4 of 20 causes a frameshift and early termination 73 codons after p.Phe415. This premature stop codon is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v. 4.1.0 (PM2_Supporting). The variant has been reported to segregate with LCA through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 32865313). The patient's phenotype or family history is highly specific for the gene, with at least one proband harboring this variant exhibiting a phenotype including a diagnosis of LCA / eoRD (0.5pts), previous genetic testing that did not provide an alternative explanation for visual impairment (2 pts), symptomatic onset between birth and 5 years (1 pt), nystagmus (1 pt), decreased peripheral vision (1 pt), and decreased central vision (1 pt) which together are specific for GUCY2D-related recessive retinopathy (6.5 total points, PMID: 32865313, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949552/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10124 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0025874 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0860210 infores:hetionet CHEBI:3499 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0014742 infores:hetionet CHEBI:4551 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0018418 infores:hetionet CHEBI:4672 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0221345 infores:hetionet CHEBI:87715 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0040034 infores:hetionet CHEBI:101278 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C3665386 infores:hetionet CHEBI:48390 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0007097 infores:hetionet CHEBI:7496 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0232493 infores:hetionet CHEBI:45599 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0002063 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027339 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0235146 infores:hetionet CHEBI:50305 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0085932 infores:hetionet CHEBI:3314 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0009806 infores:hetionet CAID:CA6909546 biolink:causes MONDO:0015152 infores:clingen CAID:CA6909546 MONDO:0015152 PMID: Likely Benign BP4 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM4, PM5, BS2, PP2, PP3, PP1, PP4, BP1, BP2, BP3, BA1, PS4, PS2, PS3, PS1 The NM_000231.3: c.1-3C>T variant is an intronic SGCG variant that is located in a splice region. The computational splicing predictor SpliceAI gives a score of 0.02 for acceptor loss, suggesting that the variant has no impact on splicing since it does not exceed the designated LGMD VCEP threshold (≤0.05) (BP4). The highest minor allele frequency of this variant is 0.0003793 (6/15820 exome chromosomes) in the African/African American population in gnomAD v2.1.1, which is greater than the ClinGen LGMD threshold (≤0.00009) for PM2_Supporting, and therefore does not meet this criterion (PM2_Supporting, BA1, BS1 criteria not met). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Limb-Girdle Muscular Dystrophy VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6909546/MONDO:0015152/185 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:465284 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0234215 infores:hetionet CHEBI:5855 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0002994 infores:hetionet CHEBI:18385 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0027497 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0037822 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0038362 infores:hetionet NCBIGene:242 biolink:causes MONDO:0009439 infores:monarchinitiative not_provided not_provided HGNC:430 MONDO:0009439 uuid:9b45deee-3c5f-48cd-93c2-5b168633c5e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0020473 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0020517 infores:hetionet CHEBI:116278 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0042963 infores:hetionet CHEBI:7865 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0233794 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0948089 infores:hetionet CHEBI:16469 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0013384 infores:hetionet CHEBI:9649 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0600142 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019193 infores:hetionet CHEBI:567361 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0027947 infores:hetionet CHEBI:567361 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0043144 infores:hetionet CHEBI:2950 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0006277 infores:hetionet CHEBI:145499 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235086 infores:hetionet CHEBI:63791 biolink:causes HP:0000023 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019294 infores:hetionet CHEBI:6761 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0857353 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022408 infores:hetionet CHEBI:6909 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0162830 infores:hetionet CHEBI:63791 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0013404 infores:hetionet CHEBI:8874 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0242422 infores:hetionet CHEBI:8428 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0013378 infores:hetionet CHEBI:3723 biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016167 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017152 infores:hetionet CHEBI:5123 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0013595 infores:hetionet CHEBI:94609 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0010709 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007760 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0041969 infores:hetionet CHEBI:16755 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0026821 infores:hetionet CHEBI:38545 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0948586 infores:hetionet CHEBI:9123 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085649 infores:hetionet CHEBI:17347 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0033575 infores:hetionet CHEBI:94385 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0017086 infores:hetionet CHEBI:3756 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0156404 infores:hetionet CHEBI:3640 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0037023 infores:hetionet CHEBI:28787 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0036974 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0035078 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0006840 infores:hetionet CHEBI:8888 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0035229 infores:hetionet CHEBI:63791 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0018965 infores:hetionet CHEBI:51041 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0852911 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0026848 infores:hetionet CHEBI:5893 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013428 infores:hetionet CHEBI:209807 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0027947 infores:hetionet CHEBI:7443 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0013404 infores:hetionet CHEBI:135930 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C2363730 infores:hetionet CHEBI:6741 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0011175 infores:hetionet CHEBI:50156 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0015967 infores:hetionet UMLS:C0011701 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0011603 infores:hetionet CHEBI:75045 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0085593 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033860 infores:hetionet CHEBI:5132 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0003123 infores:hetionet CHEBI:182080 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0085593 infores:hetionet CAID:CA16020861 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020861 MONDO:0009861 PMID:26322415PMID:18798839 Pathogenic PM2, PVS1, PP4_Moderate, PM3_Strong The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD.The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10‐11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID: 18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020861/MONDO:0009861/006 2020-05-09 2020-05-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3568 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0162830 infores:hetionet CHEBI:16838 biolink:causes GO:0110094 infores:ubergraph knowledge_assertion manual_agent CHEBI:16838 GO:0110094 CHEBI:4856 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0027051 infores:hetionet CHEBI:47780 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027849 infores:hetionet CHEBI:27899 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0031542 infores:hetionet CHEBI:6067 biolink:causes MONDO:0022096 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085653 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042373 infores:hetionet CHEBI:7986 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0340865 infores:hetionet CAID:CA409120739 biolink:causes MONDO:0007064 infores:clingen CAID:CA409120739 MONDO:0007064 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.603C>A (p.Tyr201Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The highest population minor allele frequency in gnomAD v4 is 0.00001166 (1/85734 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification. In summary, this variant meets the criteria to be classified as Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409120739/MONDO:0007064/114 2024-04-04 2024-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8888 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022104 infores:hetionet CHEBI:8426 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0003123 infores:hetionet CHEBI:2922 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0002170 infores:hetionet CHEBI:6129 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015672 infores:hetionet CHEBI:85083 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0149931 infores:hetionet CHEBI:9130 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0151636 infores:hetionet CHEBI:119573 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0232461 infores:hetionet CHEBI:15552 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0424295 infores:hetionet CHEBI:9599 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0344232 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0020649 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0011849 infores:hetionet CHEBI:9763 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151827 infores:hetionet CHEBI:7915 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0004604 infores:hetionet CHEBI:82941 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0009782 infores:hetionet CAID:CA287437583 biolink:causes MONDO:0008723 infores:clingen CAID:CA287437583 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate The c.953C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 318 (p.Pro318Leu). This variant has been described in an individual with increased C14:1 acylcarnitine and fibroblasts derived from this individual showed a significantly reduced VLCAD enzyme activity, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMID: 10529389). This individual also carried a pathogenic nonsense variant on the opposite chromosome (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_moderate, PM3, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287437583/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9137 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0242301 infores:hetionet CHEBI:6456 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0042963 infores:hetionet CHEBI:6339 biolink:causes HP:0030837 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0239589 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0027441 infores:hetionet CHEBI:135939 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0494559 infores:hetionet CHEBI:66903 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0037763 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0852733 infores:hetionet CAID:CA10652918 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652918 MONDO:0011071 PMID: Benign BA1, BP2 PS1, PS3, PS4, BP4, PVS1, PM6, PM2, BS3, BS4, BS1, BP7, PM5, PM1, PM4, PP1, PP3 The NM_001754.4:c.*2285A>C variant in the 3' UTR has an MAF of 0.1077 (10.8%; 937/8698 alleles) in the African subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 212 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652918/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true NCBITaxon:6181 biolink:causes MONDO:0015254 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6181 MONDO:0015254 CHEBI:10125 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0547030 infores:hetionet CHEBI:36795 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0040264 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0041912 infores:hetionet CAID:CA10603780 biolink:causes MONDO:0015152 infores:clingen CAID:CA10603780 MONDO:0015152 PMID: Likely Pathogenic PVS1_Strong, PM3_Supporting, PS1_Moderate, PP4, PM2_Supporting The NM_003494.4: c.5057+5G>T variant in DYSF, which is also known as NM_001130987.2: c.5174+5G>T, occurs within the splice donor motif of intron 45. RNAseq analysis has demonstrated that this variant disrupts splicing, resulting in a frameshift and premature truncation with nonsense mediated decay expected; however, the possibility for retention of some degree of constitutive splicing was not ruled out (PMID: 36983702; PVS1_Strong_RNA). This variant has been reported in unknown phase with a second presumed diagnostic DYSF variant in at least one individual with a clinical suspicion of LGMD (PMID: 6983702; PP4). The highest population minor allele frequency is 0.00001600 (1/62486 alleles) in the Remaining population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another nucleotide change affecting the same position of the splice motif and with the same experimentally demonstrated splice effect, NM_003494.4: c.5057+5G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/26/2025): PVS1_Strong_RNA, PP4, PM2_Supporting, PS1_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603780/MONDO:0015152/180 2025-08-26 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7514 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0041969 infores:hetionet CAID:CA274356 biolink:causes MONDO:0009290 infores:clingen CAID:CA274356 MONDO:0009290 PMID:19862843 Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Very Strong, PS3_Supporting PM5 The NM_000152.5:c.1309C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 437 (p.Arg437Cys). This variant has been reported in at least 16 East Asian individuals with late onset Pompe disease (PMID: 34356580) including 11 individuals with documented laboratory values reporting GAA activity <10% normal in muscle or skin fibroblasts or in the affected range in a clinically validated dried blood spot assay and/or histological features consistent with Pompe disease in muscle, and/or on enzyme replacement therapy for Pompe disease (PMID 22521436, 29786057, 27692865, 30360039)(PP4_Moderate). Ten individuals are reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including one confirmed in trans, c.1082C>T (p.Pro361Leu) (PMID: 12601120), and 9 phase unknown, c.796C>T (p.Pro266Ser) (PMID: 25526786), c.1082C>T (p.Pro361Leu) (PMID: 27692865), c.1316T>A (p.Met439Lys) (PMID: 25388776), c.1822C>T (p.Arg608Ter) (PMID: 30360039), c.1978C>T (p.Arg600Cys) (PMID: 29124014, 3 probands), c.2238G>C (p.Trp746Cys) (PMID: 27692865), c.2297A>G (p.Tyr766Cys) (PMID: 29124014) (PM3_VeryStrong). The variant has also been reported in compound heterozygosity with c.1544T>A (p.Met515Lys) (PMID: 24190153), c.1562A>T (p.Glu521Val) (PMID: 29786057), c.1857C>G (p.Ser619Arg) (PMID: 291240140, c.2051C>A (p.Pro684Gln) (PMID: 29451150), c.2177C>G (p.Pro726Arg) (PMID: 29124014), and c.2297A>C (p.Tyr766Ser) (PMID: 22521436). The allelic data from these patients will be used in the classification of the second variant and is not included here in order to avoid circular logic. Additional patients have also been reported but the data was not included because the cDNA sequences of the variants was not included (PMID: 18495398, 21471980, 21704464). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (2/21914 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cells showed no detectable GAA enzyme activity, and another study showed abnormal synthesis and processing of GAA when the variant was expressed in COS cells, indicating that this variant may impact protein function (PMID: 12601120, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.782, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A novel variant at the same amino acid position, c.1310G>A (p.Arg437His) has been reported in a patient with Pompe disease (PMID: 25681614) but has not yet been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP and, therefore, PM5 is not applied. There is a ClinVar entry for this variant (Variation ID: 189082, 2 star review status) with 6 submitters classifying the variant as pathogenic and two as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274356/MONDO:0009290/010 2022-06-30 2022-06-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:45979 biolink:causes MONDO:0010030 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C1527336 infores:hetionet CHEBI:16480 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0235710 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003265 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0001546 infores:hetionet NCBIGene:6335 biolink:causes MONDO:0008179 infores:monarchinitiative not_provided not_provided HGNC:10597 MONDO:0008179 uuid:b7a69353-60a3-402c-b9e8-6410e9222a6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10124 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0036572 infores:hetionet CHEBI:6846 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0917801 infores:hetionet CHEBI:31623 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0005741 infores:hetionet CHEBI:8764 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0041657 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005923 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0851886 infores:hetionet CHEBI:10650 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085631 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0029456 infores:hetionet CHEBI:8888 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0086439 infores:hetionet CHEBI:251408 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0428977 infores:hetionet CHEBI:45327 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0497247 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020649 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020538 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027051 infores:hetionet NCBITaxon:5551 biolink:causes MONDO:0005984 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5551 MESH:D014008 DB00857_MESH_D014008_1DB01110_MESH_D014008_1DB01127_MESH_D014008_1DB01153_MESH_D014008_1DB08933_MESH_D014008_1DB01026_MESH_D014008_1 CAID:CA345915 biolink:causes MONDO:0044970 infores:clingen CAID:CA345915 MONDO:0044970 PMID: Uncertain Significance PP1 PP3, PS4, PS3, PM2 The m.9478T>C (p.Val91Ala) variant in MT-CO3 has been reported in one family with primary mitochondrial disease (PMID: 20525945). There were two affected siblings in this family and clinical features included Leigh syndrome, childhood onset vision loss, ophthalmoplegia, dystonia, tremor, and spastic paraplegia. The variant was present at 88-89% in blood, 91-95% in buccal mucosa, and 0-4% in hair follicles in the affected individuals. The unaffected mother also had high heteroplasmy levels of this variant although lower than the affected children (85% in blood, 87% in buccal mucosa) and an unaffected brother had the variant present at 62% in blood (PP1). Of note, nuclear genetic etiologies, with the exception of SURF1-related disorders, were not evaluated in this family. This variant is present in population databases (GenBank dataset, Helix dataset, and gnomAD v3.1.2) at frequencies ranging from 0.027%-0.36%. The computational predictor APOGEE1 gives a consensus rating of pathogenic with a score of 0.59 (Min=0, Max=1), which predicts a damaging effect on gene function, however we note APOGEE2 predicts this variant is likely benign with a score of 0.149. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345915/MONDO:0044970/015 2024-01-22 2025-10-28 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63791 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0021368 infores:hetionet NCBIGene:64841 biolink:causes MONDO:0859203 infores:monarchinitiative not_provided not_provided HGNC:19980 MONDO:0859203 uuid:25d30023-43da-49c6-b25f-c2c67dbfea91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63580 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1443060 infores:hetionet CAID:CA915940544 biolink:causes MONDO:0100084 infores:clingen CAID:CA915940544 MONDO:0100084 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3 The c.1092delC (p.Tyr364*) variant in ACTA1 is a deletion variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 363-377) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMIDs:16945536, 17187373). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in one homozygous individual with features consistent with nemaline myopathy, including a muscle biopsy with multiple small nemaline rods in most fibers (PM3, PP4 PMID:17187373). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3, PM2_Supporting, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940544/MONDO:0100084/169 2024-08-07 2024-12-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4702 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C2363730 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235169 infores:hetionet CHEBI:175901 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151603 infores:hetionet NCBIGene:10743 biolink:causes MONDO:0008434 infores:monarchinitiative not_provided not_provided HGNC:9834 MONDO:0008434 uuid:cbed7247-bc9c-4bcd-bc46-ce8f020e72a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0009763 infores:hetionet NCBIGene:140801 biolink:causes MONDO:0030515 infores:monarchinitiative not_provided not_provided HGNC:17976 MONDO:0030515 uuid:abba9011-9449-418d-a157-1e09131165a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31397 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0750426 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0948288 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0948288 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0038663 infores:hetionet CHEBI:127780 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C2047937 infores:hetionet CHEBI:92712 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0011603 infores:hetionet NCBIGene:868 biolink:causes MONDO:0957388 infores:monarchinitiative not_provided not_provided HGNC:1542 MONDO:0957388 uuid:f3e5b710-8e57-4e06-b521-5a83565eafac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0009450 infores:hetionet CHEBI:4024 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C2830004 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0239150 infores:hetionet CHEBI:6931 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0344232 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0025345 infores:hetionet CHEBI:42797 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022346 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0033036 infores:hetionet CHEBI:4909 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0151539 infores:hetionet CHEBI:3752 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0236075 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0235431 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0162429 infores:hetionet NCBIGene:84197 biolink:causes MONDO:0014489 infores:monarchinitiative not_provided not_provided HGNC:26267 MONDO:0014489 uuid:4c67a0b0-31ea-414b-9401-c6bf576d5732 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1609512 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0020517 infores:hetionet CHEBI:15407 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0008031 infores:hetionet CHEBI:8214 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0018681 infores:hetionet CHEBI:3181 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0920289 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C3495920 infores:hetionet CHEBI:94686 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0426576 infores:hetionet CHEBI:3723 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0242422 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0035309 infores:hetionet CHEBI:35854 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0002792 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0233494 infores:hetionet CHEBI:28487 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0027424 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0687133 infores:hetionet CHEBI:31981 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0025323 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0595878 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0595878 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013595 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042487 infores:hetionet CHEBI:8874 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151907 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020538 infores:hetionet CHEBI:4903 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0025874 infores:hetionet CHEBI:10119 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022281 infores:hetionet CHEBI:48131 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0011603 infores:hetionet CHEBI:5106 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0011991 infores:hetionet CHEBI:71417 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0085593 infores:hetionet CHEBI:499361 biolink:causes UMLS:C1096091 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1096091 infores:hetionet CHEBI:8428 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0042510 infores:hetionet CHEBI:7476 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0917801 infores:hetionet CHEBI:37333 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0006266 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013447 infores:hetionet CHEBI:3423 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085631 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0009806 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0024312 infores:hetionet CHEBI:5147 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0017152 infores:hetionet CHEBI:6950 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0003467 infores:hetionet CHEBI:63598 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0001925 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0027092 infores:hetionet CHEBI:104011 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0042963 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0034065 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0232459 infores:hetionet CHEBI:10119 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0003811 infores:hetionet CAID:CA6831746 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831746 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PS2, PP1_Strong, PM1, PS3_Supporting, PP4_Moderate, PP3 The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3), which is supported by functional studies that demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype (PMID: 32910913 and PMID: 10585442) (PS3_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors). This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243). Additionally, at least 2 individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP1_Strong, PS2, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831746/MONDO:0015967/017 2021-08-11 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:182080 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0232462 infores:hetionet CHEBI:2663 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0423798 infores:hetionet CHEBI:9907 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002170 infores:hetionet CHEBI:8772 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0027497 infores:hetionet CHEBI:61049 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013362 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0002871 infores:hetionet CHEBI:8028 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0015371 infores:hetionet CHEBI:567361 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0011991 infores:hetionet CHEBI:31236 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549249 infores:hetionet CHEBI:37924 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0039070 infores:hetionet NCBIGene:9197 biolink:causes MONDO:0012928 infores:monarchinitiative not_provided not_provided HGNC:95 MONDO:0012928 uuid:0a9dd411-aad4-4814-86da-61285c7cddea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8404 biolink:causes UMLS:C0474529 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0474529 infores:hetionet CHEBI:107736 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0700075 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0262397 infores:hetionet CHEBI:7466 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0019572 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0948089 infores:hetionet NCBIGene:8557 biolink:causes MONDO:0011843 infores:monarchinitiative not_provided not_provided HGNC:11610 MONDO:0011843 uuid:63fae4f1-475f-4fde-94d1-547e33ec2e25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA300814398 biolink:causes MONDO:0012589 infores:clingen CAID:CA300814398 MONDO:0012589 PMID: Benign BS1, BS2 PS4, BP4, PM2, PP3 The highest population minor allele frequency of the p.Gly428Val variant in TCF4 in gnomAD v4.1 is 0.0001001 in the Admixed American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Gly428Val variant is observed in at least 2 unaffected individuals (internal database - Ambry Genetics) (BS2). In summary, the p.Gly428Val variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). (TCF4 Specifications v.4.0; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA300814398/MONDO:0012589/032 2025-06-25 2025-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31859 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0016204 infores:hetionet CHEBI:9587 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0027497 infores:hetionet CHEBI:8707 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0022107 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0221047 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0221047 infores:hetionet CHEBI:44915 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1145670 infores:hetionet CHEBI:8461 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0015672 infores:hetionet CHEBI:521033 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C2225524 infores:hetionet CHEBI:49603 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0009806 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0221100 infores:hetionet CHEBI:2788 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0030252 infores:hetionet CHEBI:2038 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0858635 infores:hetionet CHEBI:171719 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0027497 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0234930 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0031350 infores:hetionet CHEBI:171719 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0040822 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0021117 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0024121 infores:hetionet CAID:CA512319117 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319117 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, BA1, BP1, BP3, BP2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.534T>G (p.Thr178=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-4.60) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319117/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:17474 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0027765 infores:hetionet CHEBI:9586 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0010692 infores:hetionet CHEBI:6717 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0030252 infores:hetionet CAID:CA120546 biolink:causes MONDO:0044970 infores:clingen CAID:CA120546 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting, PP1_Moderate The m.7512T>C variant in MT-TS1 has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 7669057, 17894844, 9778262). Clinical features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as seizures, cognitive decline, dementia, muscle atrophy, muscle weakness, ataxia, developmental regression, and sensorineural hearing loss. Muscle biopsy in some cases showed ragged red fibers. Heteroplasmy levels in affected individuals ranged from 24% to homoplasmy. There are no reported de novo occurrences of this variant reported to our knowledge. The variant segregated with clinical features in all reported families (PP1_moderate; PMIDs: 7669057, 17894844, 9778262). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (64.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). Single fiber analysis showed significantly higher levels of the variant in COX-negative fibers (n=10, median 97%, range: 94–99%) compared with COX-positive fibers (n=10, median 36%, range: 12–91%) (PS3_supporting, PMID: 17894844). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120546/MONDO:0044970/015 2024-07-08 2025-04-28 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:70735 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0231218 infores:hetionet CHEBI:71415 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0231528 infores:hetionet CAID:CA10014400 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014400 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, PM2, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-20C>T is an intronic variant which meets criteria for likely benign classification. It has a SpliceAI score ≤ 0.20 (0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.44)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014400/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:61049 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151766 infores:hetionet CHEBI:51450 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0009763 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0028738 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0032326 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0003864 infores:hetionet GO:0031383 biolink:causes GO:0032989 infores:ubergraph knowledge_assertion manual_agent GO:0031383 GO:0032989 CAID:CA000220 biolink:causes MONDO:0018875 infores:clingen CAID:CA000220 MONDO:0018875 PMID: Likely Benign BP4, BS3_Supporting, BS2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, PP3, PP4, PP1 The NM_000546.6:c.469G>A variant in TP53 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 157 (p.Val157Ile). This variant has been observed in at least 2 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal Contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.057; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3_supporting, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.0, 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000220/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5130 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020517 infores:hetionet CHEBI:27436 biolink:causes HP:0008665 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0156394 infores:hetionet CHEBI:5790 biolink:causes HP:0010547 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0026825 infores:hetionet NCBIGene:4286 biolink:causes MONDO:0015014 infores:monarchinitiative not_provided not_provided HGNC:7105 MONDO:0015014 uuid:0fcfebf3-1a05-44bc-aa92-10ada642380d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0027796 infores:hetionet CHEBI:6916 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0152032 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0863084 infores:hetionet CAID:CA401327501 biolink:causes MONDO:0009290 infores:clingen CAID:CA401327501 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PVS1, PP3 The NM_000152.5:c.2799+2C>T variant alters the donor splice site of intron 19, the final intron of GAA. Of note, the first two nucleotides of intron 19 are GC, rather than the typical GT. Therefore, the variant alters GC to GT, the first two nucleotides of a canonical splice site. In fact. the computational splicing predictor SpliceAI gives a score of 0.37 for donor gain at the normal donor splice site of intron 19, suggesting that the variant may generate a stronger intron 19 donor splice site. To our knowledge, the results of studies to analyze the impact of this variant on splicing are unavailable. Because this variant may strengthen the normal splice site, PVS1 has not been applied. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, There is a ClinVar entry for the variant (Variant ID: 574052). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401327501/MONDO:0009290/010 2023-04-04 2023-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3082 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0006266 infores:hetionet CHEBI:23765 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0037036 infores:hetionet CHEBI:78543 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151904 infores:hetionet NCBITaxon:11309 biolink:causes MONDO:0005812 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:11309 MESH:D007251 DB12466_MESH_D007251_1 CHEBI:38940 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0038362 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0015397 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001200 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0155616 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0521509 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0521509 infores:hetionet CHEBI:9123 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0231528 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0085136 infores:hetionet CHEBI:83804 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0038999 infores:hetionet CHEBI:61049 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030554 infores:hetionet CHEBI:2453 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0042571 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0005940 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C1861172 infores:hetionet CHEBI:31932 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020456 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042267 infores:hetionet CHEBI:2663 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0085631 infores:hetionet CHEBI:3723 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0520966 infores:hetionet CHEBI:31397 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0438215 infores:hetionet CHEBI:29007 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0012833 infores:hetionet CHEBI:16714 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0026821 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C1565489 infores:hetionet CHEBI:7852 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0151908 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003873 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151737 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151737 infores:hetionet CHEBI:41977 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0034886 infores:hetionet CHEBI:5130 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0235996 infores:hetionet CHEBI:78543 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0002963 infores:hetionet CHEBI:5100 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C1443060 infores:hetionet CHEBI:17303 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011175 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0042029 infores:hetionet CHEBI:7514 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0041657 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0025061 infores:hetionet CHEBI:584020 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0018834 infores:hetionet NCBIGene:51473 biolink:causes MONDO:0018816 infores:monarchinitiative not_provided not_provided HGNC:18141 MONDO:0018816 uuid:be339dfb-393b-400b-af4b-e2ab7c86427b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151559 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0003123 infores:hetionet CHEBI:3403 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0242184 infores:hetionet CHEBI:64019 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0033774 infores:hetionet CHEBI:6067 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020453 infores:hetionet CHEBI:6715 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0039240 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0011991 infores:hetionet CHEBI:6541 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0151908 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0234458 infores:hetionet CHEBI:6909 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0038325 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151763 infores:hetionet CHEBI:68478 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0085631 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0041969 infores:hetionet CHEBI:7476 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0026826 infores:hetionet CAID:CA9043556 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043556 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4, PM5_Supporting The NM_000156.6:c.622C>T variant in GAMT is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 208 (p.Arg208Cys). The highest continental population minor allele frequency in gnomAD v4.1.0. is 0.00003294 (3/91086 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.131 which is below the threshold of 0.29, evidence that correlates with no impact to GAMT function (BP4). SpliceAI predicts that the variant has no impact on splicing. Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208His has been classified as a VUS (PM5_Supporting). To our knowledge, c.622C>T (p.Arg208Pro) has not been previously reported in the published literature, but has been noted in ClinVar (Variation ID: 544261). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0: PM2_Supporting, PM5_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043556/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:47612 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0235431 infores:hetionet CHEBI:10100 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0442874 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0267596 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011849 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0919591 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0919591 infores:hetionet CHEBI:77260 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0026821 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0241618 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0241618 infores:hetionet CHEBI:61049 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0024314 infores:hetionet CHEBI:5141 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0014457 infores:hetionet GO:0075030 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0075030 GO:0048856 NCBIGene:317761 biolink:causes MONDO:0030939 infores:monarchinitiative not_provided not_provided HGNC:19849 MONDO:0030939 uuid:7c7349b5-f12a-4c75-a566-a231ab31d7e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA278072 biolink:causes MONDO:0015924 infores:clingen CAID:CA278072 MONDO:0015924 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting BA1, PM1, BS1 The c.218C>G, (p.Ser73Ter) (NM_001204.7) variant in BMPR2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 16429395). This variant has been reported in 2 pulmonary arterial hypertension probands (PS4_Supporting) (PMID: 26387786 ; PMID: 32581362). This variant is absent from gnomAD v2.1.1 controls (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 11, 1/18/2024): PVS1, PS4_Supporting, PM2_Supporting. Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA278072/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CAID:CA549264677 biolink:causes MONDO:0001586 infores:clingen CAID:CA549264677 MONDO:0001586 PMID: Uncertain Significance PM4_Supporting, PP4, PP3, PM2_Supporting PS1, PM5, PM1, PM3, BP4 The NM_000203.5:c.1195_1197del variant in IDUA is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid in a non-repeat region (p.Glu399del) (PM4_Supporting). One individuals with this variant had clinical features specific to MPS I including hepatosplenomegaly and corneal involvement, and reduced IDUA activity (2.5%) in dried blood spots (range observed in cohort was 0-4.8%; mean 2.5%) (PP4). This individual is compound heterozygous for the variant and c.1249_1275del (p.Thr417_His425del) (ClinVar Variation ID: 556156), phase unconfirmed (variant not yet classified by the ClinGen LD VCEP, currently VUS in ClinVar (PMID: 33301762); another individual, with hepatosplenomegaly, is homozygous for the variant with insufficient clinical data to support the diagnosis of MPS I (ClinVar SCV003915947.2). PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002607 (2/76708 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor MutPred-Indel gives a score of 0.77931 which above the threshold of 0.5 and the computational predictor PROVEAN gives a score of -7.064 which below the threshold of -2.5, evidence that correlates with impact to IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 2498386. In summary, this variant meets the criteria to be classified as a VUS due to insufficient evidence for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM4_supporting, PM2_supporting. PP3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, May 23, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA549264677/MONDO:0001586/091 2025-05-23 2025-05-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6129 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C3665347 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002453 infores:hetionet CHEBI:2208 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0235378 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018991 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013395 infores:hetionet CHEBI:2549 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0000731 infores:hetionet CHEBI:8776 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0595916 infores:hetionet NCBIGene:84628 biolink:causes MONDO:0032878 infores:monarchinitiative not_provided not_provided HGNC:14288 MONDO:0032878 uuid:19935b79-52fb-4136-9fac-4284465468e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0017160 infores:hetionet CHEBI:7640 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2830004 infores:hetionet CHEBI:681569 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1384353 infores:hetionet CHEBI:9927 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0026821 infores:hetionet CHEBI:8802 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0036973 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020701 infores:hetionet CHEBI:32315 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020453 infores:hetionet CHEBI:2637 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0003862 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006566 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0022593 infores:hetionet CHEBI:520985 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0392703 infores:hetionet CHEBI:68534 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C3263723 infores:hetionet CHEBI:3757 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0043352 infores:hetionet CHEBI:29688 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C2240374 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0040034 infores:hetionet CHEBI:71417 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0040822 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0002792 infores:hetionet CHEBI:31413 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0013132 infores:hetionet CHEBI:7494 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0014742 infores:hetionet NCBITaxon:287 biolink:causes MONDO:0040732 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:287 MONDO:0040732 CHEBI:50777 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0151828 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0020517 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0004096 infores:hetionet CHEBI:6690 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0235347 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1368065 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0032584 infores:hetionet CAID:CA254845 biolink:causes MONDO:0044970 infores:clingen CAID:CA254845 MONDO:0044970 PMID:16476954 Uncertain Significance PP3, PM2_Supporting, PP1_Moderate, PS3_Supporting PS2, PS4, PM6 The m.5591G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease (PMIDs: 16476954, 29139113). This was a male who presented in his 40s with progressive muscle weakness, myalgia, elevated creatine kinase (CK), and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, and electron transport chain complexes I, III, and IV deficiency. Heteroplasmy ranged from 79% (blood) to >99% (hair shaft). This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID: 16476954). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (99.5%) than in COX-positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID: 16476954). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PS3_supporting, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254845/MONDO:0044970/015 2024-03-11 2025-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:72297 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0017168 infores:hetionet CHEBI:3176 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0237314 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0234983 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0234983 infores:hetionet CAID:CA2387321999 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387321999 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP4, BS2 NM_001754.5(RUNX1):c.59-48942A>G is an intronic variant which has a SpliceAI score ≥ 0.38 (Donor Gain: 0.42; Acceptor Gain: 0.29) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387321999/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8869 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0009938 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020877 infores:hetionet NCBIGene:10352 biolink:causes MONDO:0060578 infores:monarchinitiative not_provided not_provided HGNC:12730 MONDO:0060578 uuid:1829e8aa-e2c9-41ad-a283-dda5ca2464b2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0009938 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0948594 infores:hetionet CHEBI:499361 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0032617 infores:hetionet CHEBI:75045 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0151578 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0007642 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0858357 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0858357 infores:hetionet CHEBI:50859 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0004093 infores:hetionet CAID:CA120623 biolink:causes MONDO:0044970 infores:clingen CAID:CA120623 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1, PS4, PS2, PS3, PM6 The m.14849T>C (p.S35P) variant in MT-CYB has been reported in two unrelated men. The first reported individual had developmental delay, microcephaly, lactic acidosis and rhabdomyolysis with illness, short stature, dysdiadokinesia, ataxia, exercise intolerance, fatigue, Wolff-Parkinson-White, left ventricular hypertrophy, retinitis pigmentosa, septo-optic dysplasia, and cerebellar hypoplasia (PMID: 11891837) and the second reported individual had exercise intolerance, depressive episodes, and myopathy with ragged red fibers seen on muscle biopsy (PMID: 20544923). Both individuals had onset of features in childhood and heteroplasmy levels in various tissues ranged from 6-85%. Haplogroup information was not reported for all cases precluding consideration for PS4. The variant was reported de novo in the first case report as it was absent in mother’s blood (PMID: 11891837), however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.74 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120623/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7824 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085632 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0151602 infores:hetionet CHEBI:3011 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0004093 infores:hetionet CHEBI:75722 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235996 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C1306577 infores:hetionet CHEBI:15940 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020433 infores:hetionet CAID:CA10585833 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585833 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 PS3, PM5 The NM_000527.5 (LDLR):c.2374A>T (p. Ile792Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.764.PS3_Moderate not met: Level 2 experiment, heterologous cells (HepG2) were used for western blot and immunoprecipitation assays showed normal cell surface LDLR, reported by Strøm et al, 2015, (PMID 26220972), Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics and Department of Microbiology and Bioinformatics Core Facility, University of Oslo and Oslo University Hospital, Oslo, Norway.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2375T>C (p.Ile792Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585833/MONDO:0007750/013 2022-08-26 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7443 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0043352 infores:hetionet CHEBI:8069 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C1145670 infores:hetionet CHEBI:10124 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0558489 infores:hetionet CHEBI:8428 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0855329 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0034065 infores:hetionet CHEBI:7798 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0028084 infores:hetionet CHEBI:134966 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0028738 infores:hetionet CHEBI:6129 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235063 infores:hetionet CHEBI:36704 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0034886 infores:hetionet CHEBI:180905 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0149871 infores:hetionet CHEBI:7915 biolink:causes MONDO:0008277 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0236048 infores:hetionet CAID:CA16603036 biolink:causes MONDO:0018875 infores:clingen CAID:CA16603036 MONDO:0018875 PMID:12826609PMID:30224644PMID:29979965 Likely Pathogenic PM1_Supporting, PS3, PM5, PP3, PM2_Supporting BP4, BA1, PS1, PS4, PS2, BS1, BS3, BS4, BS2, PP1, PP4 The NM_000546.6: c.641A>T variant in TP53 is a missense variant predicted to cause substitution of histidine by leucine at amino acid 214 (p.His214Leu). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Computational predictor scores (BayesDel = 0.323206; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant(c.641A>G, p.His214Arg) (ClinVar Variation ID: 376615), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. In addition, missense variant (c.640C>T, p.His214Tyr) (ClinVar Variation ID 1053808) in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP's specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PM1_Supporting, PM2_Supporting, PM5. (Bayesian Points: 9; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603036/MONDO:0018875/009 2025-05-07 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49375 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0032285 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0041969 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0424605 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0027651 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0013395 infores:hetionet CHEBI:9674 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0027497 infores:hetionet CHEBI:73274 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0687713 infores:hetionet CHEBI:31485 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0043094 infores:hetionet NCBIGene:7291 biolink:causes MONDO:0008391 infores:monarchinitiative not_provided not_provided HGNC:12428 MONDO:0008391 uuid:f6e094be-1eae-45f6-87a2-e0f6b321aba6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1519353 infores:hetionet CHEBI:31859 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0231528 infores:hetionet CHEBI:47898 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031256 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042401 infores:hetionet CHEBI:17076 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0015230 infores:hetionet CHEBI:47499 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0085616 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011991 infores:hetionet CHEBI:3561 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0016867 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0009324 infores:hetionet CHEBI:8245 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0013604 infores:hetionet CHEBI:135925 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0344232 infores:hetionet CHEBI:28925 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0019360 infores:hetionet CHEBI:6067 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020580 infores:hetionet CHEBI:31547 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020458 infores:hetionet NCBIGene:115908 biolink:causes MONDO:0013662 infores:monarchinitiative not_provided not_provided HGNC:18831 MONDO:0013662 uuid:5bdd1f71-de77-4f67-8dfc-8b63513caef1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:1279 biolink:causes MONDO:0024313 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1279 MONDO:0024313 CHEBI:17303 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020625 infores:hetionet CHEBI:27882 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0162429 infores:hetionet CHEBI:91541 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0015967 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0233794 infores:hetionet CAID:CA16613442 biolink:causes MONDO:0700270 infores:clingen CAID:CA16613442 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5_Supporting, PVS1 PP3 The c.5236G>A (p.Gly1746Arg) variant in ATM is a missense variant observed to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (Ambry internal data). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in at least one individual with Ataxia-Telangiectasia (PMID: 26896183). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 in European (non-Finnish) population, which is lower than the HBOP threshold (<0.00001) for PM2_Supporting, meeting this criterion. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PM5_Supporting, PM3_Supporting, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA16613442/MONDO:0700270/020 2025-09-03 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8499 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0851578 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0857353 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0027947 infores:hetionet CHEBI:16914 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0018834 infores:hetionet CAID:CA228547 biolink:causes MONDO:0019565 infores:clingen CAID:CA228547 MONDO:0019565 PMID:27785872 Uncertain Significance PP3, PM2_Supporting, BP5 PP4, PP1, PS4, PS3 The NM_000552.5:c.4135C>T variant in VWF is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1379 (p.Arg1379Cys). Some patients harbor this variant as part of a gene conversion event, being found alongside: p.Ile1343Val, Val1360Ala, Phe1369Ile, Ser1378Phe, Arg1379Cys (PMID: 37732159). This variant has been observed in at least 6 patients with an alternate molecular basis for disease. The patients also harbor the p.Phe1369Ile variant which has been classified pathogenic for VWD type 2M by the VWD VCEP (BP5; PMID 35452508). The gnomAD v4.1 Grpmax filtering allele frequency in gnomAD v4.1 is 0.00002154 (based on 35/1179840 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.731, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). There are assertions of this variant being associated with VWD types 1, 2M, and 2B. The majority of evidence indicates that when ristocetin induced aggregation is measured, this variant has a type 2B phenotype. It should be noted however that all of the scored cases in this curation had normal multimers, which is not typically associated with VWD type 2B. Further complicating interpretation, many cases were compound heterozygotes for additional variants in VWF or carried gene conversion related variants. Lastly, there are reports that patients carrying this variant do not experience thrombocytopenia after DDAVP treatment which would be typical of a VWD type 2B variant (PMID 27353798). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM2_Supporting, PP3, BP5. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228547/MONDO:0019565/081 2025-10-07 2025-10-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:101278 biolink:causes HP:0032940 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0086168 infores:hetionet NCBIGene:26504 biolink:causes MONDO:0009007 infores:monarchinitiative not_provided not_provided HGNC:105 MONDO:0009007 uuid:25040857-3324-4b4b-877c-3888f23ff798 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3393 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0043352 infores:hetionet CHEBI:8707 biolink:causes HP:0006677 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0235475 infores:hetionet CHEBI:3515 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0037763 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0020649 infores:hetionet CHEBI:47612 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0016204 infores:hetionet CHEBI:2618 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0001824 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151717 infores:hetionet CHEBI:119486 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C1167965 infores:hetionet CAID:CA343725268 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725268 MONDO:0005338 PMID: Likely Pathogenic PP1_Moderate, PP3_Strong, PM2_Supporting, PS3_Moderate BS1, BS3, BP7, PM4, PM5, PS4, PS1, PS2, BA1, BP4 The c.976G>C variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 326 (p.Gly326Arg). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.948, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on MYOC function. The Gly326Arg protein had reduced secretion levels compared to wild type myocilin protein in this study (PMID: 16466712). The assay met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 14 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (Sarfarazi et al, Invest Ophthalmol Vis Sci 2000; 41:S822), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (from the family), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3_Strong, PS3_Moderate, PP1_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725268/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151539 infores:hetionet CAID:CA10549662 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549662 MONDO:0010305 PMID: Benign BS1, BS2, BP4 The NM_005629.4:c.1778A>G variant in SLC6A8 is a missense variant predicted to cause the substitution of a histidine by an arginine at amino acid position 593 (p.His593Arg). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency is 0.0004421 (20/45238 alleles; 2 homozygotes, 0 hemizygotes) in the Admixed American population. This MAF is higher than the ClinGen CCDS VCEP's threshold for BS1 (>0.0002), meeting this criterion (BS1). Overall, across all populations, there are 3 homozygotes and 7 hemizygotes in gnomAD v4.1.0. (BS2). The computational predictor REVEL gives a score of 0.133 suggesting that the variant has no impact on protein function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465144). In summary, this variant meets criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549662/MONDO:0010305/027 2025-03-18 2025-03-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:6062 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0521839 infores:hetionet NCBIGene:5293 biolink:causes MONDO:0023655 infores:monarchinitiative not_provided not_provided HGNC:8977 MONDO:0023655 uuid:e0c985c2-d222-4313-92af-a1f6f71e204b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:2 biolink:causes MONDO:0004773 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D015863 DB00634_MESH_D015863_1 CHEBI:63629 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0032285 infores:hetionet CHEBI:17303 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0018681 infores:hetionet CHEBI:45327 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0027497 infores:hetionet CAID:CA658820730 biolink:causes MONDO:0009276 infores:clingen CAID:CA658820730 MONDO:0009276 PMID:11054083 Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting, PS3_Supporting The c.165_168del (p.Ser55ArgfsTer12) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes the final 598 amino acids) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient 1 in PMID: 11054083) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). They also had a history of recurrent epistaxis and spontaneous skin bruises and a low platelet count (84x10^9/l). This variant has been detected in at least 2 probands with Bernard-Soulier syndrome. One of those individuals was compound heterozygous for this variant and the c.1601_1602del (p.Tyr534CysfsTer?) variant in GP1BA, confirmed in trans by parental testing (PMID: 11054083). This second variant was classified as Pathogenic by the VCEP. (not included here to avoid circularity). The other proband was homozygous for the c.165_168del (p.Ser55ArgfsTer12) variant (PMID: 18791947; PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). From PMID: 11054083, flow cytometric analysis was performed for GP Iba on CHO cells transiently transfected with the WT + c.165_168del (p.Ser55ArgfsTer12), which had around 60% WT expression levels above sham. They also tested c.165_168del + c.1601_1602del, which had around 5% WT expression levels above sham. Due to the methods used in this assay (where c.165_168del was not tested independently), the usual threshold of <25% WT levels to apply PS3_supporting is not the appropriate measure. The 60% expression of WT + c.165_168del is considered sufficient, particularly in light of the c.165_168del + c.1601_1602del, which had around 5% WT expression levels (PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting and PM3_Supporting, PS3_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658820730/MONDO:0009276/079 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:66901 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0851341 infores:hetionet CHEBI:75722 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018520 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0856882 infores:hetionet CHEBI:5130 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0027947 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0033975 infores:hetionet CHEBI:10119 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0010200 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0008031 infores:hetionet UNII:3U02EL437C biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0025345 infores:hetionet CHEBI:31536 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0001125 infores:hetionet CHEBI:5062 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0038999 infores:hetionet CHEBI:92923 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0031350 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0521839 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020649 infores:hetionet CHEBI:2668 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0030554 infores:hetionet GO:2001281 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:2001281 GO:0070887 NCBIGene:518 biolink:causes MONDO:0859215 infores:monarchinitiative not_provided not_provided HGNC:843 MONDO:0859215 uuid:ead058af-9e30-48f1-957a-521a4ac2179c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0039070 infores:hetionet CHEBI:45081 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0003862 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0009450 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0151479 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1142412 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0009806 infores:hetionet CHEBI:3242 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0030252 infores:hetionet CAID:CA376060000 biolink:causes MONDO:0011225 infores:clingen CAID:CA376060000 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.470A>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Lysine by Threonine at amino acid 157 (p.Lys157Thr).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376060000/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3485 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0231170 infores:hetionet CHEBI:50730 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0013456 infores:hetionet CHEBI:10119 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0023066 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0003123 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0036508 infores:hetionet CAID:CA152950 biolink:causes MONDO:0015967 infores:clingen CAID:CA152950 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1112G>T variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to phenylalanine at codon 371 (p.(Cys371Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.931, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was hyperglycemia (PS4; PMID 24735133, internal lab contributors). This variant segregated with hyperglycemia with 12 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% as well as either OGTT increment < 3 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PP1_Strong, PS4, PP4_Moderate . Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA152950/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports UNII:9430ZR8ZAN biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0028961 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0948594 infores:hetionet CAID:CA120554 biolink:causes MONDO:0044970 infores:clingen CAID:CA120554 MONDO:0044970 PMID: Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PP1_Moderate, PS3_Supporting PS2, PM6 The m.8356T>C variant in MT-TK has been reported in at least 11 individuals from two kindreds with primary mitochondrial disease. Age of onset ranged from the first decade of life to adulthood. Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF), ataxia, generalized seizures, hearing loss, and lactic acidosis. Heteroplasmy levels were consistently lower in blood and higher in muscle, ranging from 43.4% to homoplasmy (PMIDs: 8069654, 1361099; PS4_supporting). Of note, there is an additional family reported in the literature that was not considered for this variant curation given the presence of another pathogenic variant, m.3243A>G. These individuals had features similar to those seen in individuals with m.8356T>C, as well as features classic for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; PMID: 20610441). This variant segregated with disease manifestations in multiple members of one family reported (PMID: 8069654; PP1_moderate). There are no reported cases of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (88.8 percentile) as does HmtVar with a score of 0.75 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In cybrid cell lines homoplasmic for this variant, reduced oxygen consumption was reported, supporting the functional impact of this variant (PMID: 7739567; PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4_supporting, PP1_moderate, PP3, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120554/MONDO:0044970/015 2023-03-13 2023-03-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8435 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0043094 infores:hetionet CHEBI:5120 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0030781 infores:hetionet CHEBI:8346 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0042487 infores:hetionet CAID:CA512341102 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341102 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PVS1, PM6, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1293C>T (p.Pro431=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (0.75) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341102/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0011701 biolink:causes UMLS:C0232826 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0232826 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0012797 infores:hetionet CHEBI:7915 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0016382 infores:hetionet CHEBI:9738 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0151596 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853124 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853124 infores:hetionet NCBIGene:6231 biolink:causes MONDO:0013217 infores:monarchinitiative not_provided not_provided HGNC:10414 MONDO:0013217 uuid:54cfdb4a-6fb2-4801-abbb-e34e8098a6ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9449 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C2973529 infores:hetionet CHEBI:10101 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0423791 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0009806 infores:hetionet CHEBI:3515 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0700345 infores:hetionet CHEBI:82960 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0877192 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1302752 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0023895 infores:hetionet CHEBI:18358 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0011603 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0033575 infores:hetionet CHEBI:51173 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0009806 infores:hetionet UMLS:C0011701 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0036974 infores:hetionet CHEBI:15553 biolink:causes UMLS:C0152159 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0152159 infores:hetionet CHEBI:7773 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0019080 infores:hetionet CHEBI:127342 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0393761 infores:hetionet CHEBI:44032 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0010200 infores:hetionet CHEBI:6456 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0017178 infores:hetionet CHEBI:102216 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0235063 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014130 infores:hetionet CHEBI:7773 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0042029 infores:hetionet CHEBI:50663 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0018524 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042029 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0232492 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036529 infores:hetionet CHEBI:7447 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0022658 infores:hetionet CHEBI:119573 biolink:causes HP:0032310 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C1282609 infores:hetionet CHEBI:9727 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0042963 infores:hetionet CHEBI:9123 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0014394 infores:hetionet CHEBI:9288 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0027497 infores:hetionet CAID:CA8337899 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337899 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000152.5: c.881_884dup (p.Pro296AlafsTer3) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting. (ACADVL VCEP specifications version 1; approved February 28, 2023) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337899/MONDO:0008723/021 2023-02-28 2023-02-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1456784 infores:hetionet CHEBI:63791 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0700200 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0020538 infores:hetionet CHEBI:7823 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0015230 infores:hetionet CHEBI:2618 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0220870 infores:hetionet CHEBI:31348 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0002878 infores:hetionet CHEBI:100241 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151701 infores:hetionet CHEBI:23765 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C1167965 infores:hetionet CHEBI:63631 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1456784 infores:hetionet NCBIGene:23162 biolink:causes MONDO:0032755 infores:monarchinitiative not_provided not_provided HGNC:6884 MONDO:0032755 uuid:46503e7a-3eb9-4d9f-9ace-fb2defa817cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes EFO:1001816 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0343387 infores:hetionet CHEBI:204734 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0234894 infores:hetionet CAID:CA1139663873 biolink:causes MONDO:0012996 infores:clingen CAID:CA1139663873 MONDO:0012996 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_001482.3:c.959del (p.Pro320LeufsTer41) variant in GATM is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 6 out of a total of 9 exons leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). To our knowledge, this variant has not been reported in the literature in any individuals with AGAT deficiency. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 955458). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139663873/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3219 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0028734 infores:hetionet CHEBI:3723 biolink:causes HP:0030213 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233469 infores:hetionet CHEBI:8412 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0012833 infores:hetionet CHEBI:6715 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235660 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0003834 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0033860 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0017574 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0235146 infores:hetionet CHEBI:28915 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0004093 infores:hetionet CHEBI:41774 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151766 infores:hetionet CHEBI:27999 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0162533 infores:hetionet CHEBI:7915 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0008350 infores:hetionet CHEBI:51450 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0010692 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0002871 infores:hetionet CHEBI:3082 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0026821 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151436 infores:hetionet CHEBI:132233 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0011991 infores:hetionet CAID:CA1244138 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244138 MONDO:0005338 PMID: Uncertain Significance BS1, BS3, BP7, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.854C>T variant in MYOC is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 285 (p.Thr285Met). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.0001170 (7 alleles out of 59,840), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.612, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): none Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244138/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:119915 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0242350 infores:hetionet CHEBI:93635 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0018681 infores:hetionet CHEBI:49603 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0600142 infores:hetionet CHEBI:75722 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0558489 infores:hetionet CHEBI:5384 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0022354 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0231365 infores:hetionet CHEBI:135276 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0233472 infores:hetionet CHEBI:52717 biolink:causes HP:0007141 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1112256 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0031212 infores:hetionet CHEBI:72564 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151662 infores:hetionet CHEBI:50223 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0852911 infores:hetionet CHEBI:31348 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0003862 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0234930 infores:hetionet CHEBI:6541 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C1318520 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027651 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020550 infores:hetionet CHEBI:41977 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0039239 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0233494 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0413252 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034186 infores:hetionet CHEBI:4814 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0002994 infores:hetionet CHEBI:9927 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042384 infores:hetionet CHEBI:6887 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011603 infores:hetionet CAID:CA658799063 biolink:causes MONDO:0012589 infores:clingen CAID:CA658799063 MONDO:0012589 PMID: Likely Pathogenic PVS1, PM2_Supporting The p.R639KfsX71 variant in TCF4 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a TCF4 where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the TCF4 is pathogenic (PVS1). The p.R639KfsX71 variant in TCF4 is absent from gnomAD (PM2_Supporting). In summary, the p.R639KfsX71 variant in TCF4 is classified as likely pathogenic based on the ACMG/AMP criteria (PVS1, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799063/MONDO:0012589/016 2021-04-02 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:9674 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0017672 infores:hetionet CHEBI:28864 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0028961 infores:hetionet CHEBI:10650 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0005758 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151736 infores:hetionet CHEBI:31515 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0027497 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0011609 infores:hetionet CHEBI:39867 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0007398 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0029456 infores:hetionet CHEBI:6801 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C3263723 infores:hetionet CHEBI:6076 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0085605 infores:hetionet CHEBI:7931 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0027441 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020649 infores:hetionet CHEBI:9445 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0030196 infores:hetionet NCBIGene:25981 biolink:causes MONDO:0054615 infores:monarchinitiative not_provided not_provided HGNC:2940 MONDO:0054615 uuid:7741020c-5865-48c3-b13e-74bc0e2ef3b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0020538 infores:hetionet CHEBI:144551 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0030193 infores:hetionet CHEBI:31536 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0275524 infores:hetionet GO:0039693 biolink:causes MONDO:0005109 infores:drugmechdb knowledge_assertion manual_agent GO:0039693 MESH:D015658 DB01048_MESH_D015658_1 CHEBI:63635 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0030305 infores:hetionet CHEBI:3437 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0018794 infores:hetionet GO:1904157 biolink:causes CL:0000808 infores:ubergraph knowledge_assertion manual_agent GO:1904157 CL:0000808 CHEBI:5100 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0019080 infores:hetionet CHEBI:31413 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011991 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0032285 infores:hetionet CAID:CA396457824 biolink:causes MONDO:0007648 infores:clingen CAID:CA396457824 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PM2_Supporting, PVS1_Strong, PS4_Moderate BS1, BS4, BS3, BP5, BP7, PM6, PM3, PM1, PM4, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.531+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two family meeting HDGC clinical criteria (PS4_moderate; SCV000580690.3; SCV000637838.2). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS4_moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396457824/MONDO:0007648/007 2024-03-28 2024-03-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:144551 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151810 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029191 infores:hetionet CAID:CA1022028185 biolink:causes MONDO:0011071 infores:clingen CAID:CA1022028185 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP2, BP3, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-3T>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.10) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1022028185/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52010 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0085593 infores:hetionet NCBIGene:79971 biolink:causes MONDO:0859209 infores:monarchinitiative not_provided not_provided HGNC:30238 MONDO:0859209 uuid:e4aa8f9f-74cc-4a25-825c-a5d15d2fc321 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0041657 infores:hetionet CHEBI:63630 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0043352 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0002170 infores:hetionet CHEBI:8107 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0031350 infores:hetionet CHEBI:9086 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0678222 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0027651 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0009450 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0015397 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0392378 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0392378 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0036572 infores:hetionet CHEBI:84500 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0018524 infores:hetionet CHEBI:41977 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0442886 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0008370 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0029456 infores:hetionet CHEBI:7986 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0006266 infores:hetionet CHEBI:50841 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0700184 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0555120 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0424605 infores:hetionet CAID:CA10443891 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443891 MONDO:0010315 PMID: Uncertain Significance PP4_Moderate PM2 NM_000206.3(IL2RG):c.292A>G is a missense variant predicted to cause substitution of Lysine by Glutamic Acid at amino acid 98 (p.Lys98Glu). The filtering allele frequency (the upper threshold of the 95% CI of 55/893392) of the 292A>G variant in IL2RG is 0.00004918 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000124 ) for PM2_Supporting. However, 14 hemizygotes have been observed in gnomAD. (PM2_not met). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.),T-B+NK- lymphocyte subset profile (0.5 pt.); total :2.5 pts (PP4_Moderate) (PMID: 10794430).In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443891/MONDO:0010315/129 2024-01-10 2024-01-10 X-linked inheritance HP:0001417 Inconclusive true CHEBI:2704 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0029408 infores:hetionet CHEBI:9123 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232462 infores:hetionet CHEBI:119573 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085631 infores:hetionet CAID:CA226686 biolink:causes MONDO:0010725 infores:clingen CAID:CA226686 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4, PM1_Strong, PS3_Supporting, PP1 PP3 NM_000330.4(RS1):c.329G>A (p.Cys110Tyr) is a missense encoding the substitution of cysteine with tyrosine at amino acid 110, which is a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 9618178, PMID: 28348004, PMID: 34822951, PMID: 38219857, PMID: 30551202, PMID: 31456290, PMID: 35456422, PMID: 34645606, PS4). The variant has been reported to segregate with X-linked retinoschisis through two affected brothers from a single family (PP1; PMID: 32856788, PMID: 35456422). The computational predictor REVEL gives a score of 0.882, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function. PP3_Moderate is not met as the code is ineligible to be used in combination with PM1_Strong. The computational splicing predictor SpliceAI gives a delta score of <0.02 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control due to intracellular retention and failure of the variant protein to properly assemble into multimers (PMID: 19849666, PS3_Supporting). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PM1_Strong, PS3_Supporting, PS4, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226686/MONDO:0010725/126 2025-10-04 2025-10-05 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports UMLS:C0011701 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0011175 infores:hetionet CHEBI:15367 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0030252 infores:hetionet CAID:CA025321 biolink:causes MONDO:0012933 infores:clingen CAID:CA025321 MONDO:0012933 PMID: Pathogenic PM2_Supporting, PS3, PP4_Strong PP3, BP1, BP4 The c.7879A>T variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 2627 (p.Ile2627Phe). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.25 indicating that impact on BRCA2 function via protein change is unclear (score range 0.18-0.30). SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (no bioinformatic code is applied). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 29988080, 33609447, 32444794) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 406 (based on Cosegregation LR=1.88; Co-occurrence LR=1.28; Family History LR=168.6), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 17924331, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP4_Very strong, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025321/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63791 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017178 infores:hetionet CAID:CA135073 biolink:causes MONDO:0021060 infores:clingen CAID:CA135073 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1383A>G (p.Gln461=) variant in the BRAF gene is 0.986% (120/10404) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135073/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true UNII:15G12L5X8K biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0427457 infores:hetionet CHEBI:71272 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0016658 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235889 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0424000 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0037274 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020538 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0234215 infores:hetionet CHEBI:6067 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0152030 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0017574 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0031085 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0037199 infores:hetionet CHEBI:8428 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C1565489 infores:hetionet CHEBI:6904 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0267792 infores:hetionet GO:0046668 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0046668 GO:0007275 CHEBI:42797 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0152198 infores:hetionet NCBIGene:549 biolink:causes MONDO:0009610 infores:monarchinitiative not_provided not_provided HGNC:890 MONDO:0009610 uuid:584013e0-4157-4280-a665-4f259fe4f4a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5103 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0020580 infores:hetionet NCBIGene:1513 biolink:causes MONDO:0009940 infores:monarchinitiative not_provided not_provided HGNC:2536 MONDO:0009940 uuid:219af9e4-dbd1-48ea-99cf-54927d1af32b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3994 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0020649 infores:hetionet CHEBI:134966 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0011603 infores:hetionet CHEBI:5165 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151636 infores:hetionet CHEBI:4887 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0026821 infores:hetionet CHEBI:9150 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0234238 infores:hetionet CHEBI:8028 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0700075 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0232492 infores:hetionet CHEBI:3504 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0034886 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0585186 infores:hetionet CHEBI:6970 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0013390 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0033931 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033931 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0948089 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151911 infores:hetionet NCBIGene:9051 biolink:causes MONDO:0011174 infores:monarchinitiative not_provided not_provided HGNC:9580 MONDO:0011174 uuid:e9fc3957-f820-4a49-97b6-afd9aff46e88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0232461 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0541919 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0541919 infores:hetionet CAID:CA1139664609 biolink:causes MONDO:0700272 infores:clingen CAID:CA1139664609 MONDO:0700272 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PM5 The c.3543del (p.Phe1181fs) variant in PALB2 is a frameshift variant predicted to alter a region that is critical to protein function. The C-terminal end of the WD40 domain is substituted by an alternative extended sequence. This variant is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Strong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139664609/MONDO:0700272/077 2023-06-01 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9649 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0151744 infores:hetionet CHEBI:77260 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042963 infores:hetionet CHEBI:59560 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C1384353 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0574067 infores:hetionet CHEBI:40279 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0600228 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0948594 infores:hetionet CHEBI:63611 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085819 infores:hetionet CHEBI:63621 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0085682 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0518015 infores:hetionet CHEBI:31859 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0020458 infores:hetionet CHEBI:45863 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1260880 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0021053 infores:hetionet CHEBI:48538 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0013404 infores:hetionet CHEBI:43968 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0008370 infores:hetionet CHEBI:4027 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0242184 infores:hetionet CHEBI:31711 biolink:causes MONDO:0002904 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0013528 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0687133 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151599 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0042373 infores:hetionet CAID:CA000272 biolink:causes MONDO:0018875 infores:clingen CAID:CA000272 MONDO:0018875 PMID: Likely Benign BP4, BS3 BA1, PS3, PS4, PS2, PS1, PM1, PM5, BP7, BS1, BS4, PVS1, PM2, BS2, PP1, PP4, PP3 The NM_000546.6: c.572C>G variant in TP53 is a missense variant predicted to cause substitution of proline by arginine at amino acid 191 (p.Pro191Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00005 (3/59996 alleles) in the Admixed American population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0942; Align GVGD Class 35) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BP4. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000272/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:71223 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0015967 infores:hetionet CHEBI:34911 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0011991 infores:hetionet CHEBI:135930 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0019825 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0233494 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011570 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0043251 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0014549 infores:hetionet CHEBI:5818 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00557 UMLS:C0011603 infores:hetionet CAID:CA386966270 biolink:causes MONDO:0015967 infores:clingen CAID:CA386966270 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 PS4, PP1 The c.802T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to leucine at codon 268 (p.(Phe268Leu)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.952 (PP3). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in two individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 20132997, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID: 20132997). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 20132997). Another missense variant at the same codon, c.803T>C (p.Phe268Ser), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.802T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386966270/MONDO:0015967/017 2025-08-05 2025-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28748 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0026858 infores:hetionet CHEBI:114785 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0917801 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0036508 infores:hetionet CAID:CA279171 biolink:causes MONDO:0100039 infores:clingen CAID:CA279171 MONDO:0100039 PMID: Likely Pathogenic PP3, PM5, PS4_Supporting, PM2_Supporting, PS2 PP4 The p.Ala157Val variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with infantile epilepsy (GeneDx Internal Database) (PS2). The p.Ala157Val variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Ala157Val variant has been observed in individuals reported to have Rett syndrome or CDKL5 Deficiency disorder, however, additional clinical and segregation information was not provided (PMID: 32472944; 31313283) (PS4_supporting_met, PP4_not met). A pathogenic missense variant (p.Ala157Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (Invitae internal database). In summary, the p.Ala157Val variant in CDKL5 is classified as likely pathogenic for CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PP3, PM2_supporting, PS4_supporting,PM5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA279171/MONDO:0100039/033 2023-04-14 2023-06-16 X-linked inheritance HP:0001417 Supports CHEBI:9168 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0518015 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0013595 infores:hetionet CHEBI:9943 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026205 infores:hetionet CHEBI:71255 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0085649 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0020538 infores:hetionet CHEBI:3175 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0022281 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0855625 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0855625 infores:hetionet CHEBI:45367 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0151849 infores:hetionet CHEBI:231594 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0030196 infores:hetionet CHEBI:567361 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0917801 infores:hetionet CAID:CA16020875 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020875 MONDO:0009861 PMID: Pathogenic PP4_Moderate, PM2, PM3_Very Strong BP7 The c.843-5T>C variant in PAH is absent from population databases (PM2). It has been observed in several classic PKU patients with BH4 deficiency excluded (PMID: 24048906 and PMID: 22526846; PP4). has been reported in at least 6 homozygous patients and 12 compound heterozygous patients harboring 7 additional Pathogenic/Likely Pathogenic variants (PMIDs: 31924462, 29892150, 30159852, 24048906, 22526846, PM3. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_VeryStrong, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020875/MONDO:0009861/006 2020-09-12 2020-09-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3082 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0700361 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0314719 infores:hetionet CHEBI:28748 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0231218 infores:hetionet CHEBI:2682 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0011603 infores:hetionet CHEBI:7496 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0853034 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0231530 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0424000 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0948089 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0553698 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0553698 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0240515 infores:hetionet CHEBI:31932 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0015967 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0853785 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0853785 infores:hetionet CHEBI:64355 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1306341 infores:hetionet CHEBI:64028 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0015967 infores:hetionet CHEBI:27666 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0234215 infores:hetionet CHEBI:63618 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0002792 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0549475 infores:hetionet CHEBI:68478 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019080 infores:hetionet CHEBI:2038 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C2047937 infores:hetionet CHEBI:7936 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085932 infores:hetionet CHEBI:63791 biolink:causes HP:0000832 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0700502 infores:hetionet CHEBI:28939 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0042963 infores:hetionet CAID:CA275338 biolink:causes MONDO:0009861 infores:clingen CAID:CA275338 MONDO:0009861 PMID:10394930PMID:26600521PMID:26600521 Pathogenic PVS1, PM2, PP4_Moderate, PM3_Strong PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF: 0.00010; PP4_Moderate: BH4 defect excluded in all patients in Liu 2015. Identified in 6 patients in this study (PMID:10394930; PMID:26600521); PM3_Strong: Identified in 6 patients, in trans with R243Q and R241C (both pathogenic) (PMID:26600521). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA275338/MONDO:0009861/006 2018-08-13 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA49752733 biolink:causes MONDO:0015152 infores:clingen CAID:CA49752733 MONDO:0015152 PMID: Benign BA1, BP4, BP7 PM3 The NM_003494.4: c.4509+1586dup variant in DYSF, which is also known as NM_001130987.2: c.4626+1586dup, is located in intron 41 and is not expected to alter the amino acid sequence. This duplication was identified in a heterozygous state with a second DYSF variant in one patient with slowly progressive muscle weakness and disease range dysferlin expression in blood monocytes, in whom it was considered a VUS due to an unknown population frequency (PMID: 36983702). However, genome data now available indicate this duplication is present in the majority of individuals and should be considered the major allele at this position, with a filtering allele frequency in gnomAD v4.1.0 genomes of 0.9937 (the lower bound of the 95% CI of 68009/68012 European (non-Finnish) chromosomes) (BA1). In addition, this duplication is not located in a splice region and is not predicted to impact splicing (SpliceAI score 0) (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/04/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA49752733/MONDO:0015152/180 2025-06-04 2025-07-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:465284 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0030554 infores:hetionet CHEBI:27899 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0085682 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C1565489 infores:hetionet CHEBI:17141 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0041969 infores:hetionet CHEBI:16714 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0085633 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0012833 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0015397 infores:hetionet CAID:CA10624373 biolink:causes MONDO:0012163 infores:clingen CAID:CA10624373 MONDO:0012163 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 PP4 The NM_002185.5(IL7R):c.83-2A>T variant occurs within the canonical splice acceptor site of intron 1. It is predicted to cause skipping of biologically relevant exon 2, resulting in a frameshift with a premature stop codon in exon 3/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Patient P4, of PMID: 15661025, is homozygous for this variant (PM3_supporting). At least four probands have been reported in the literature with this variant; however, insufficient information was available to apply PP4 (PMIDs: 32888943, 24578017, 21664875, 15661025). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005649 (2/35406 alleles) in the Latino/Admixed American population, which is lower than the ClinGen SCID VCEP threshold (<0.00004129; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PM3_supporting. (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10624373/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:404903 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042998 infores:hetionet CHEBI:9635 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0151907 infores:hetionet CHEBI:27565 biolink:causes HP:0032510 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0231529 infores:hetionet CHEBI:8207 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013604 infores:hetionet CHEBI:5864 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0033687 infores:hetionet CHEBI:36791 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0851578 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0007642 infores:hetionet NCBIGene:57716 biolink:causes MONDO:0007790 infores:monarchinitiative not_provided not_provided HGNC:13797 MONDO:0007790 uuid:67f5e6ae-f121-49a8-b75a-ec1ea4d52623 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0043094 infores:hetionet CHEBI:3638 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0004093 infores:hetionet CHEBI:59582 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0026113 infores:hetionet CHEBI:4995 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0003862 infores:hetionet GO:0090334 biolink:causes GO:0042546 infores:ubergraph knowledge_assertion manual_agent GO:0090334 GO:0042546 CHEBI:404903 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0241863 infores:hetionet CHEBI:31981 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0392676 infores:hetionet CHEBI:194135 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151937 infores:hetionet CHEBI:5801 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0018681 infores:hetionet CAID:CA397318711 biolink:causes MONDO:0009276 infores:clingen CAID:CA397318711 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting, PP1_Moderate The c.800C>G (p.Ser267Ter) variant in GP1BA is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient 3 in PMID: 26044173) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). The variant has been reported to segregate in the proband plus 2 additional homozygous BSS affected siblings (2 PP1 points, PP1_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP1_Moderate, PP4, PM2_Supporting and PM3_Supporting (VCEP specifications version 1.0.0). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA397318711/MONDO:0009276/079 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8764 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0021845 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0086543 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0687133 infores:hetionet GO:0060693 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0060693 GO:0007275 CHEBI:36791 biolink:causes HP:0033842 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0239233 infores:hetionet GO:0060622 biolink:causes GO:0030437 infores:ubergraph knowledge_assertion manual_agent GO:0060622 GO:0030437 CHEBI:9667 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0026113 infores:hetionet CHEBI:17263 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0019572 infores:hetionet CHEBI:7465 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0043094 infores:hetionet NCBIGene:81031 biolink:causes MONDO:0008818 infores:monarchinitiative not_provided not_provided HGNC:13444 MONDO:0008818 uuid:e508f87b-757f-49b5-8b59-3f7946bbc624 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50663 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0518015 infores:hetionet CHEBI:10119 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020672 infores:hetionet CHEBI:39585 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0030193 infores:hetionet CHEBI:9398 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0033774 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0022650 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0521839 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0015376 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0031117 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0152517 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018500 infores:hetionet CHEBI:6923 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0024312 infores:hetionet CHEBI:72297 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0015397 infores:hetionet CHEBI:52172 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018965 infores:hetionet CHEBI:6375 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0039070 infores:hetionet CHEBI:3219 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233471 infores:hetionet CHEBI:46345 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0392699 infores:hetionet CHEBI:8874 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151878 infores:hetionet NCBIGene:2218 biolink:causes MONDO:0012699 infores:monarchinitiative not_provided not_provided HGNC:3622 MONDO:0012699 uuid:4b1acc5d-f34c-4713-9425-99fcda43e496 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0003862 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0240322 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0543698 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0234215 infores:hetionet NCBIGene:1303 biolink:causes MONDO:0034022 infores:monarchinitiative not_provided not_provided HGNC:2188 MONDO:0034022 uuid:4b5549c3-e3af-4130-a3bf-50b57d1e7a6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes UMLS:C0521662 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0521662 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0027947 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036454 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0013985 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0003123 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0022430 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0031190 infores:hetionet CHEBI:37941 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0005778 infores:hetionet CHEBI:100246 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0151937 infores:hetionet CHEBI:9939 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0235063 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0948586 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015469 infores:hetionet CHEBI:9671 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0020461 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0494165 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0494165 infores:hetionet CHEBI:48131 biolink:causes MONDO:0021036 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0263383 infores:hetionet CAID:CA1943263 biolink:causes MONDO:0018214 infores:clingen CAID:CA1943263 MONDO:0018214 PMID: Likely Benign PP3_Moderate, BS1 PP1, BS2, PM2, PM6, BP2, BP4, BA1, PS2, PS4, PS3, PS1, PM1, PM5, BP5, BS4, BS3 The c.1678C>T (NM_001165963) variant in SCN1A is a missense variant predicted to cause substitution of arginine by cystine at amino acid 560. To our knowledge, this variant has not been reported in the literature in any individuals with SCN1A-related conditions. The highest population minor allele frequency in gnomAD v2.1 is 0.00015 in the European Finnish population, which is higher than the ClinGen Epilepsy Sodium Channel VCEP threshold (>0.0004%) for BS1, and therefore meets this criterion (BS1). The REVEL computational prediction analysis tool gives a score of 0.877, which is above the threshold of 0.773, evidence that correlates with impact to SCN1A function (PP3_mod). Another missense variant, c.1679G>A, (p.R560H), in the same codon has been reported in a patient with unspecified epilepsy (PMID: 30182498). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by ClinGen Epilepsy Sodium Channel VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as likely benign for SCN1A-related conditions (Dravet syndrome, Genetic Epilepsy with Febrile Seizures Plus and Developmental and Epileptic Encephalopathy) based on the ACMG/AMP criteria applied, as specified by the Epilepsy Sodium Channel VCEP: (BS1, PP3_mod). v1.0.0; 08/27/24 Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA1943263/MONDO:0018214/067 2024-09-03 2024-11-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6775 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0019572 infores:hetionet CHEBI:135005 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0027497 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0015376 infores:hetionet CHEBI:7465 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0011124 infores:hetionet CHEBI:125354 biolink:causes MONDO:0006831 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0282548 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0151736 infores:hetionet CAID:CA234739 biolink:causes MONDO:0021060 infores:clingen CAID:CA234739 MONDO:0021060 PMID: Pathogenic PS3_Moderate, PP1, PP3, PP2, PM1, PS4, PS2_Very Strong PM2 The c.794G>A (NM_002834.5(PTPN11):c.794G>A (p.Arg265Gln)) variant in PTPN11 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 265 (p.Arg265Gln). The highest MAF for this variant in gnomAD v2.1.1 is 0.00006349 (7/110252 alleles) in the European (non-Finnish) population (no homozygotes) (no population codes met). The computational predictor REVEL gives a score of 0.814, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common. The Z-score for missense variants in PTPN11 in gnomAD v4.1.0 is 4.95 (PP2; PMID: 29493581). This variant resides at a residue (amino acid 265) of PTPN11 that is defined as a mutational hotspot and/or critical functional domain by the ClinGen RASopathy VCEP (PM1; PMID 29493581). The p.Arg265Gln variant has been identified in 7 probands with clinical features of Noonan Syndrome included in this curation (PS4, 6.5 points.; PMIDs: 28074573, 32233106, Ann and Robert H. Lurie Children's Hospital of Chicago (Center for Genomics; SCV003920365) and GeneDx (SCV000057406) internal data). The c.794G>A p.Arg265Gln variant in PTPN11 has been reported as an unconfirmed de novo occurrence in 1 patient with clinical features of a RASopathy, and as a confirmed de novo case in 2 patients included in this curation (5.0 PS2 points; PMID: 28074573, Ann and Robert H. Lurie Children's Hospital of Chicago (Center for Genomics; SCV003920365) and GeneDx (SCV000057406) internal data). Additional case level-data is available, but enough evidence to apply PS4 and PS2_VeryStrong, the maximum strengths of these codes, have already been met. Two studies, an analysis in HEK293 cells and an in-vitro phosphatase assay, both showed significantly increased phosphatase activity for the p.Arg265Gln mutant compared to the wild-type (PS3_moderate; PMID 28074573). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PP3, PP2, PM1, PS4, PS2_VeryStrong, PS3_moderate (VCEP specifications version 2.3.0; 9/9/2025). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA234739/MONDO:0021060/043 2025-09-09 2025-09-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63577 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0019209 infores:hetionet CHEBI:2666 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C2830004 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0017178 infores:hetionet CAID:CA658658250 biolink:causes MONDO:0100040 infores:clingen CAID:CA658658250 MONDO:0100040 PMID: Pathogenic PVS1, PS2, PM2_Supporting The p.Pro63Alafs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Pro63Alafs variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with FOXG1-associated disorder (Internal database - GeneDx) (PS2). The p.Pro63Alafs variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Pro63Alafs variant in FOXG1 is classified as Pathogenic for FOXG1-associated disorder based on the ACMG/AMP criteria (PVS1, PS2, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658250/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf UNII:D27V6190PM biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0259799 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007476 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013312 infores:hetionet GO:1902256 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1902256 GO:0007507 CHEBI:5893 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0029877 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0009450 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020538 infores:hetionet CHEBI:8888 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030232 infores:hetionet CHEBI:35778 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0030193 infores:hetionet CHEBI:8772 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0178298 infores:hetionet CHEBI:7959 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0852911 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020615 infores:hetionet CHEBI:74947 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0037299 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0020517 infores:hetionet CHEBI:110423 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0033774 infores:hetionet CHEBI:8461 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0520966 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0477371 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0477371 infores:hetionet CHEBI:8713 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0002418 infores:hetionet CHEBI:3207 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0026826 infores:hetionet CHEBI:38562 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0009676 infores:hetionet CHEBI:100241 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0016512 infores:hetionet CHEBI:5106 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0043094 infores:hetionet CHEBI:16469 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151766 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0036572 infores:hetionet CHEBI:119573 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020461 infores:hetionet CHEBI:31623 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0423153 infores:hetionet CHEBI:6923 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0017178 infores:hetionet CHEBI:44032 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0039070 infores:hetionet CAID:CA2499225402 biolink:causes MONDO:0012999 infores:clingen CAID:CA2499225402 MONDO:0012999 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PVS1_Strong PM3 The NM_000156.6:c.526del (p.Glu176SerfsTer2) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon/the last exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). This variant has been reported in one individual with GAMT deficiency who had elevated GAA and low creatine in plasma and in urine (PMID: 19288536) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002229 (1/44860 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1067935). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Strong, PM2_Supporting, PP4_Moderate.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225402/MONDO:0012999/026 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports UMLS:C1738934 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C1527344 infores:hetionet CHEBI:4562 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0085628 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0034065 infores:hetionet CHEBI:46557 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042373 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0948089 infores:hetionet CHEBI:50275 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0020580 infores:hetionet NCBIGene:6197 biolink:causes MONDO:0010561 infores:monarchinitiative not_provided not_provided HGNC:10432 MONDO:0010561 uuid:1cc3b050-ebab-404a-9892-9dc1418ecfaa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32293 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0013595 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0948594 infores:hetionet CHEBI:7915 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0004093 infores:hetionet CHEBI:134991 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0034880 infores:hetionet NCBIGene:30008 biolink:causes MONDO:0013754 infores:monarchinitiative not_provided not_provided HGNC:3219 MONDO:0013754 uuid:45727ef4-ce53-43fa-9ab9-618be58baa57 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0151827 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0007222 infores:hetionet CAID:CA226550 biolink:causes MONDO:0100368 infores:clingen CAID:CA226550 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting NM_000329.3(RPE65):c.430T>G is a missense variant predicted to replace tyrosine with aspartic acid at position 144. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 19117922, PMID: 11462243, PMID: 28127548, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), reduced visual acuity (1 pt), macular atrophic changes (0.5 pts), abnormal electroretinogram responses, visual field constriction (1 pt), retinal vessel attenuation (0.5 pts), and retinal pigment epithelium depigmentation and granularity in the fundus (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 4 pts, PMID: 19117922, PP4). The computational predictor REVEL gives a score of 0.977, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited no detectable enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 16828753, PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226550/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports GO:0008228 biolink:causes GO:0006909 infores:ubergraph knowledge_assertion manual_agent GO:0008228 GO:0006909 CHEBI:5132 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0541832 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0033774 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002172 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0155428 infores:hetionet CHEBI:68642 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0028734 infores:hetionet CHEBI:45783 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0002874 infores:hetionet CHEBI:74947 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0740394 infores:hetionet CHEBI:7445 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0855242 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0026946 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003864 infores:hetionet CHEBI:231594 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0232462 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020433 infores:hetionet CHEBI:7445 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0030554 infores:hetionet CHEBI:32315 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0231528 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0031046 infores:hetionet CHEBI:4887 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0017178 infores:hetionet CHEBI:9738 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0018418 infores:hetionet CHEBI:50305 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0018965 infores:hetionet NCBIGene:169792 biolink:causes MONDO:0012436 infores:monarchinitiative not_provided not_provided HGNC:28510 MONDO:0012436 uuid:2d24d49a-8392-4b85-a369-13767e69a7d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0877046 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0877046 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0007760 infores:hetionet CHEBI:63635 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0043352 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0278107 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0278107 infores:hetionet CHEBI:135276 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0017178 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0008301 infores:hetionet CHEBI:47519 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0006145 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0035204 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006500 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0018916 infores:hetionet GO:1905261 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:1905261 GO:0007127 CHEBI:93635 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0023380 infores:hetionet CHEBI:15553 biolink:causes HP:0003811 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0410916 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0023895 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0035455 infores:hetionet CHEBI:4672 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0206061 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0038362 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0518015 infores:hetionet CHEBI:92712 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0085636 infores:hetionet CAID:CA409103994 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103994 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1 The c.209A>G variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes an amino acid change of Histidine to Arginine at codon 70 (p.(His70Arg)) of NM_175914.5. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8529, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.209A>G meets the criteria to be classified as a Variant of Uncertain Significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PM1, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103994/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA157083 biolink:causes MONDO:0700270 infores:clingen CAID:CA157083 MONDO:0700270 PMID: Benign BP4, BA1, BP2_Strong The ATM c.2614C>T (p.Pro872Ser) variant has a GnomAD FAF 4.6% (AFR) exceeding ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous or compound heterozygous state (presumed and/or confirmed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, Clinical Diagnostic Laboratories). This variant is predicted tolerated by multiple protein in silico tools (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA157083/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8435 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0013404 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0423273 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0423273 infores:hetionet CHEBI:168396 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151754 infores:hetionet CHEBI:49960 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0333355 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151717 infores:hetionet NCBIGene:55505 biolink:causes MONDO:0958193 infores:monarchinitiative not_provided not_provided HGNC:14378 MONDO:0958193 uuid:f5c42da4-0f1c-441b-8654-dacf0ee3463a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29007 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0023518 infores:hetionet CHEBI:6887 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018808 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0746883 infores:hetionet CHEBI:75722 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0234632 infores:hetionet CHEBI:5147 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0518988 infores:hetionet UMLS:C0657912 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151878 infores:hetionet CAID:CA512318895 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318895 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.243G>C (p.Val81=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.32)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318895/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3996 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0013378 infores:hetionet CHEBI:75998 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C1519353 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0012813 infores:hetionet CHEBI:82981 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0002792 infores:hetionet CHEBI:209807 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0595916 infores:hetionet CAID:CA410208246 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208246 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.31C>G (p.Pro11Ala) is a missense variant which has a REVEL score < 0.50 (0.452) and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208246/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:91583 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0033774 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0860210 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0860210 infores:hetionet NCBIGene:3561 biolink:causes MONDO:0010315 infores:monarchinitiative not_provided not_provided HGNC:6010 MONDO:0010315 uuid:35d059b1-0cc2-49b1-8064-266be5f74898 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53766 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0018965 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0235567 infores:hetionet NCBIGene:6208 biolink:causes MONDO:0007925 infores:monarchinitiative not_provided not_provided HGNC:10387 MONDO:0007925 uuid:0b0cffdd-5dcc-4893-9706-521beb2ae119 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0004037 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0242420 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0271650 infores:hetionet CHEBI:4710 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0040822 infores:hetionet NCBIGene:567 biolink:causes MONDO:0971010 infores:monarchinitiative not_provided not_provided HGNC:914 MONDO:0971010 uuid:0e6be79c-2e57-4ea6-9ce0-0437e207b577 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0032285 infores:hetionet CAID:CA340923 biolink:causes MONDO:0044970 infores:clingen CAID:CA340923 MONDO:0044970 PMID: Uncertain Significance PS4_Moderate, PS3_Supporting, PM5_Supporting PP1, PP3, BP4, PS2, PM2, PM6 The m.7445A>C (p.*514S) variant in MT-CO1 has been reported in five unrelated individuals with primary mitochondrial disease to date (PS4_moderate; PMIDs: 10577941, 17659260, 18639500, 19705751). These individuals were of Asian background and had childhood onset hearing loss. Some had hearing loss after illness and in others no precipitating event could be identified. The variant was present at homoplasmy in these individuals. Detailed family history information was not provided in several cases. One family had three affected siblings however all were homoplasmic, precluding consideration for PP1 (PMID: 19705751). This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.028%; Helix's 196,554 sequences: AF=0.001%; gnomAD v3.1.2: absent). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Functional studies showed inefficient processing by tRNAseZ in the presence of this variant (PS3_supporting; PMID: 16361254). Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_supporting, PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340923/MONDO:0044970/015 2024-07-08 2024-12-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63608 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0029882 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011334 infores:hetionet CHEBI:5855 biolink:causes UMLS:C2609264 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C2609264 infores:hetionet CAID:CA383495656 biolink:causes MONDO:0015630 infores:clingen CAID:CA383495656 MONDO:0015630 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PS4_Supporting PP1 The NM_000552.5(VWF):c.5336G>T (p.Arg1779Leu) missense variant has been reported in at least 2 unrelated probands with excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio and low collagen binding, which together are specific for VWD Type 2M (PS4_Supporting, PMID: 28971901). At least 1 reported proband displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio, low collagen binding, and normal VWF high-MW multimers, which together are highly specific for VWD Type 2M (PP4_Moderate, PMID: 29924855). Low FVIII activity, an inconsistent phenotype, was also reported in these patients, as well as low VWF antigen, leading in two cases to a diagnosis of VWD Type 1 (PMID: 28971901). The computational predictor REVEL gives a score of 0.659, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/60024 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). In summary, the variant meets the criteria to be classified as a Variant of Uncertain Significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3, and PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383495656/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:94449 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0013144 infores:hetionet CHEBI:63613 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0015967 infores:hetionet NCBIGene:8295 biolink:causes MONDO:0032911 infores:monarchinitiative not_provided not_provided HGNC:12347 MONDO:0032911 uuid:03ddeb13-9b00-48da-bc73-1fe1dfdd4ec9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007859 infores:hetionet CHEBI:45409 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0423791 infores:hetionet CHEBI:51230 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0151827 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0855242 infores:hetionet CHEBI:63631 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0152169 infores:hetionet CHEBI:94501 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151662 infores:hetionet CHEBI:51860 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151907 infores:hetionet CHEBI:2379 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0011606 infores:hetionet CHEBI:7478 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085636 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0039446 infores:hetionet CHEBI:6923 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0015230 infores:hetionet CHEBI:119915 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1145670 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0021400 infores:hetionet CHEBI:136040 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0023530 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0027051 infores:hetionet CHEBI:127342 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C1291078 infores:hetionet CHEBI:71941 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0029132 infores:hetionet CHEBI:28001 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0011606 infores:hetionet CHEBI:8802 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0020538 infores:hetionet CHEBI:7444 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0233407 infores:hetionet CHEBI:27999 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0017178 infores:hetionet CHEBI:6950 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151772 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0032285 infores:hetionet GO:1905132 biolink:causes GO:0140013 infores:ubergraph knowledge_assertion manual_agent GO:1905132 GO:0140013 CHEBI:16899 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0017672 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033777 infores:hetionet CHEBI:6717 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0001824 infores:hetionet CHEBI:63581 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0013378 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0235082 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0235082 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0019193 infores:hetionet CHEBI:27666 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0854467 infores:hetionet CHEBI:8772 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042345 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0019340 infores:hetionet CHEBI:2659 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0013395 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0042109 infores:hetionet CHEBI:32293 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0085932 infores:hetionet CHEBI:17026 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0917801 infores:hetionet CHEBI:7915 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0043352 infores:hetionet NCBIGene:7012 biolink:causes MONDO:0013879 infores:monarchinitiative not_provided not_provided HGNC:11727 MONDO:0013879 uuid:1404fa7f-89ca-4e3e-84a6-3994588c1667 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0031117 infores:hetionet NCBIGene:56203 biolink:causes MONDO:0014513 infores:monarchinitiative not_provided not_provided HGNC:6649 MONDO:0014513 uuid:4332b7d3-d8bf-4f82-9dfc-a1523540cdd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5106 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0036974 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0020517 infores:hetionet CHEBI:5864 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0085628 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0233472 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0037199 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0750016 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0750016 infores:hetionet CHEBI:4315 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0015967 infores:hetionet CHEBI:142290 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0025061 infores:hetionet CAID:CA039237 biolink:causes MONDO:0007750 infores:clingen CAID:CA039237 MONDO:0007750 PMID: Likely Benign BP4, PM2, BS2 BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PVS1, PM6, PP2, PP3, PP1, PP4 NM_000527.5(LDLR): c.2251C>T (p.Arg751Trp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes PM2, BS2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001202 (0.01202%) in African/African American exomes+genomes (gnomAD v2.1.1).BP4 - REVEL = 0.428, it is below 0.50, splicing evaluation required. Variant is exonic and at least 50bp downstream from canonical donor site, but it does not create AG/GT.BS2 - Variant identified in 717 heterozygotes and 72 homozygotes (PMID: 25414273). These subjects had the same level of LDLc as non-carriers (N=2408). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA039237/MONDO:0007750/013 2022-05-26 2022-06-30 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8888 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0016204 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032285 infores:hetionet CHEBI:35854 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0020538 infores:hetionet CAID:CA383505783 biolink:causes MONDO:0019565 infores:clingen CAID:CA383505783 MONDO:0019565 PMID: Uncertain Significance PM5_Supporting, PM2_Supporting PP3, PP4 The NM_000552.5:c.4010C>A variant in VWF is a missense variant predicted to cause substitution of proline by glutamine at amino acid 1337. The Popmax filtering allele frequency in gnomAD v4.1 is 0.000000619 (based on 1/44872 alleles in the East Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for type 2 (PM2_Supporting). Another missense variant, c.4010C>T (p.Pro1337Leu) in the same codon has been classified as likely pathogenic for VWD 2B by the ClinGen VWD VCEP (PM5_Supporting). Only a single case has been submitted to ClinVar but affected status and asserted condition are not reported. Additionally, there are no reports of cases with the variant in the literature or LOVD. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PM2_Supporting, PM5_Supporting (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383505783/MONDO:0019565/081 2025-11-04 2025-11-04 Undetermined mode of inheritance Inconclusive true CHEBI:47780 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151744 infores:hetionet CHEBI:3242 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0042109 infores:hetionet CHEBI:134990 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0917801 infores:hetionet CHEBI:9907 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0027497 infores:hetionet CHEBI:70707 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0043352 infores:hetionet CHEBI:2038 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0009806 infores:hetionet CHEBI:2676 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0036830 infores:hetionet CHEBI:4798 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0549622 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027441 infores:hetionet CHEBI:17026 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0004604 infores:hetionet CHEBI:36791 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085593 infores:hetionet CHEBI:65349 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C1112214 infores:hetionet CHEBI:8772 biolink:causes MONDO:0000931 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0151622 infores:hetionet CAID:CA2573157369 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157369 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.965del (p.Ser322Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157369/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50692 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0027497 infores:hetionet CHEBI:92712 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0231919 infores:hetionet CHEBI:17347 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151908 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0541976 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0541976 infores:hetionet CHEBI:7903 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0009763 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0521503 infores:hetionet CHEBI:4325 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0151602 infores:hetionet CHEBI:17026 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0020598 infores:hetionet GO:0141069 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0141069 GO:0007154 CHEBI:3764 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0041834 infores:hetionet CAID:CA8459509 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459509 MONDO:0011132 PMID: Pathogenic PM2_Supporting, PM5_Supporting, PVS1 The NM_001369369.1:c.1376C>A variant in FOXN1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 8/9 leading to nonsense mediated decay (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1180000 alleles) in European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.00002412) for PM2_Supporting. No homozygous individual has been observed (PM2_Supporting). A pathogenic variant p.Gln474Ter curated by the SCID VCEP causes premature termination codon in the same exon and downstream to the variant under assessment (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PM5_Supporting. (VCEP specifications version 2.0.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459509/MONDO:0011132/113 2025-04-25 2025-07-14 Semidominant inheritance HP:0032113 Supports UMLS:C0879264 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151662 infores:hetionet CAID:CA327940150 biolink:causes MONDO:0100437 infores:clingen CAID:CA327940150 MONDO:0100437 PMID: Benign BP4, BA1, BP7 NM_001034853.2(RPGR):c.310+167G>A is an intron 4 variant that is located outside of the splice donor region (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v4.1.0 at a frequency of 0.02328 among hemizygous individuals, with 814 variant alleles / 34,973 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327940150/MONDO:0100437/106 2025-09-06 2025-09-07 X-linked inheritance HP:0001417 Contradicts true NCBIGene:1107 biolink:causes MONDO:0032600 infores:monarchinitiative not_provided not_provided HGNC:1918 MONDO:0032600 uuid:3cfa2603-e40a-4d96-a52b-99e28885b71f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7601 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0002871 infores:hetionet CHEBI:63624 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0020580 infores:hetionet CHEBI:4027 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0392699 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0017574 infores:hetionet CHEBI:63612 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0041657 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0005940 infores:hetionet CHEBI:5106 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0022107 infores:hetionet CHEBI:63598 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085612 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019112 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0549322 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0549322 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011053 infores:hetionet CAID:CA137959 biolink:causes MONDO:0021060 infores:clingen CAID:CA137959 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.660C>A (p.Ile220=) variant in the MAP2K2 gene is 65.271% (3631/5412) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137959/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:2549 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020580 infores:hetionet CHEBI:3061 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0428977 infores:hetionet CHEBI:3996 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C1368065 infores:hetionet CAID:CA222125 biolink:causes MONDO:0015152 infores:clingen CAID:CA222125 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.1368C>A p.(Cys456Ter) variant in DYSF, which is also known as NM_001130987.2: c.1464C>A p.(Cys488Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 15/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least five individuals with features consistent with dysferlinopathy (PMID: 33927379, 33610434, 36983702), including in a homozygous state without reported familial consanguinity in two individuals (1.0 pt, PMID: 33610434; LOVD Individual #00327594, #00326989) (PM3). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive muscle wasting and absent dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 33610434, 36983702; PP4_Strong). In gnomAD v4.1.0, the upper bound of the 95% confidence interval of the Grpmax variant allele frequency is 0.000046991 (based on 43/1179974 European (non-Finnish) alleles), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/06/2025): PVS1, PM3, PM2_Supporting, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222125/MONDO:0015152/180 2025-10-06 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7798 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0036572 infores:hetionet CHEBI:39867 biolink:causes MONDO:0001083 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015624 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0149931 infores:hetionet CHEBI:61390 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0010692 infores:hetionet CHEBI:47780 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151827 infores:hetionet CAID:CA016472 biolink:causes MONDO:0007947 infores:clingen CAID:CA016472 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM1, PS4, PP1_Strong PM2, PM6, PVS1, BS2, BP1, BP4, BP3, BP2, BA1, PM4, PM3, PM5, PS3, PS1, PS2, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.6448C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 2150 (p.Arg2150Cys). This variant has been identified in more than 15 patients with features suggestive of, or consistent with, Marfan syndrome (MFS), including at least three who meet clinical diagnostic criteria for MFS and more than 10 individuals who do not meet MFS diagnostic criteria but have thoracic aortic aneurysm and dissection (TAAD), with or without additional clinical features of MFS (PS4, PP4; Bichat, University of Tokyo, UZA, Invitae, & GeneDx internal data; PMIDs: 37042257, 19161152, 37558401, 33059708, 31730815). The variant was found to segregate with a clinical diagnosis of MFS in one patient’s parent, and with mild features suggestive of MFS or another connective tissue disorder in approximately 11 affected family members between two additional families (PP1_strong; UZA & Invitae internal data); notably, this variant is associated with particularly variable expressivity and incomplete penetrance of the MFS phenotype. It is present in gnomAD with a maximum frequency of 0.0008% (1/113462 alleles European, non-Finnish; https://gnomad.broadinstitute.org/, v2.1.1). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.923). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; gnomAD v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_strong, PM1, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA016472/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:39585 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0019825 infores:hetionet CHEBI:16347 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0042029 infores:hetionet CAID:CA10585655 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585655 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PM2, PP3, PP4 PM5 The NM_000527.5 (LDLR): c.1856T>C (p.Phe619Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1)PP3 Met: REVEL = 0.832, which is above the threshold for 0.75.PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Moderate Met: Variant meets PM2, and is identified in 6 unrelated index cases who fulfil DLCN criteria for FH from different labs. Two index cases reported from U4M – Lille University &CHRU Lille, University de Lille – CHRU de Lille (SCV000583896.1). Four French index cases reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, (SCV000503427.1, PMID20809525).There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>G (p.Phe619Cys), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585655/MONDO:0007750/013 2022-04-21 2022-04-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:41423 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0031350 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0022904 infores:hetionet CHEBI:28148 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0027540 infores:hetionet CHEBI:41977 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0013404 infores:hetionet CHEBI:4708 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C1510410 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0020517 infores:hetionet CHEBI:45783 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0040053 infores:hetionet CHEBI:74947 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0237849 infores:hetionet CHEBI:391960 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0011991 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0036572 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020651 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0575090 infores:hetionet CHEBI:2611 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0424790 infores:hetionet CHEBI:5130 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0151889 infores:hetionet GO:0010807 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0010807 GO:0051641 CHEBI:68647 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0015230 infores:hetionet CHEBI:48273 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0152227 infores:hetionet CHEBI:61390 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0038362 infores:hetionet CHEBI:8024 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0023518 infores:hetionet CAID:CA345259 biolink:causes MONDO:0044970 infores:clingen CAID:CA345259 MONDO:0044970 PMID: Uncertain Significance PS2_Supporting, PM2_Supporting, BP4 PP3, PP4, PP1, PS3, PS4 The m.3376G>A (p.E24K) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features in the MELAS/LHON spectrums and harbored the variant at 98% heteroplasmy in muscle, 18% in blood, and 67% in urine. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant was de novo in the single reported case, as the proband's mother and siblings did not have the variant in blood or urine via PCR-RFLP (PS2_supporting; PMID: 15657614). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a borderline pathogenicity predictor score, 0.5 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on February 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria (PMID: 32906214): PS2_supporting, PM2_supporting, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345259/MONDO:0044970/014 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:4562 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0232849 infores:hetionet CHEBI:76010 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0011603 infores:hetionet CHEBI:5778 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0700225 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0235431 infores:hetionet CHEBI:3441 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151517 infores:hetionet CAID:CA199489 biolink:causes MONDO:0010726 infores:clingen CAID:CA199489 MONDO:0010726 PMID: Benign BS1, BS2 PS4 The allele frequency of the p.Ala443Thr variant in MECP2 (NM_004992.3) is 0.015% in Latino population and 0.014% in East Asian population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala443Thr variant is observed in at least 2 unaffected individuals (RettBASE, PMID 22277191, GeneDx internal database, Invitae internal database) (BS2). In summary, the p.Ala443Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199489/MONDO:0010726/016 2022-02-18 2022-12-02 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:2379 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0162529 infores:hetionet CHEBI:8874 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0010692 infores:hetionet CHEBI:16899 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0235063 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0234215 infores:hetionet CAID:CA410207216 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207216 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, BP1, BP4, BP2, BP3, BA1, BS1, BS4, BP5, BP7, PVS1, PM6, PM3, PM5, PM4, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.617A>G (p.His206Arg) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1. In summary, the clinical significance of this variant is uncertain (PM2_supporting). ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207216/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:391960 biolink:causes UMLS:C0341742 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0341742 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0039971 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0948089 infores:hetionet NCBIGene:476 biolink:causes MONDO:0020788 infores:monarchinitiative not_provided not_provided HGNC:799 MONDO:0020788 uuid:b1de696d-9de4-4680-8774-d2cb012c798b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:76010 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0019158 infores:hetionet NCBIGene:8626 biolink:causes MONDO:0011535 infores:monarchinitiative not_provided not_provided HGNC:15979 MONDO:0011535 uuid:a53caf8d-f7d6-46ca-a627-ff04987673cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63610 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0002170 infores:hetionet CHEBI:27899 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151799 infores:hetionet CHEBI:68478 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0038363 infores:hetionet GO:2000248 biolink:causes GO:0055059 infores:ubergraph knowledge_assertion manual_agent GO:2000248 GO:0055059 CHEBI:6775 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0917801 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020039 infores:hetionet CHEBI:48273 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0011175 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0233494 infores:hetionet CHEBI:9588 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0040034 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0023052 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020517 infores:hetionet CHEBI:7936 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0016867 infores:hetionet NCBIGene:4838 biolink:causes MONDO:0700112 infores:monarchinitiative not_provided not_provided HGNC:7865 MONDO:0700112 uuid:dcff8acd-592b-449d-90c2-d5e11b2c3102 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4439 biolink:causes MONDO:0030972 infores:monarchinitiative not_provided not_provided HGNC:7328 MONDO:0030972 uuid:9fafb027-f708-48d6-868d-b9fe7a113a71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8364 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0428977 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0349506 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1565662 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1565662 infores:hetionet CHEBI:64064 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0242429 infores:hetionet CHEBI:9763 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0600142 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0037199 infores:hetionet CAID:CA024659 biolink:causes MONDO:0007783 infores:clingen CAID:CA024659 MONDO:0007783 PMID: Benign BS2, PM1, BS1, BS3_Supporting PP3, PS4, PS3, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with valine at codon 2321 of the RYR1 protein p.(Ile2321Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00081, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257; PMID:23558838). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in families with genotype positive/ phenotype negative individuals (IVCT) supporting a benign status, BS2 (PMID:30236257, personal communications). Variant did not show increased sensitivity to RYR1 agonists in HEK293 assay (personal communication), BS3_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.712 does not support pathogenic or a benign status. This variant has been classified as Benign. Criteria implemented: BS1, BS2, BS3_Supporting, PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024659/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63629 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0031350 infores:hetionet NCBIGene:5116 biolink:causes MONDO:0008872 infores:monarchinitiative not_provided not_provided HGNC:16068 MONDO:0008872 uuid:fbbb7f63-66dd-4e9b-b9ee-9f3884e25cef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0090049 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0035295 CHEBI:71417 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0002878 infores:hetionet CHEBI:7903 biolink:causes UMLS:C0027627 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0027627 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0041912 infores:hetionet NCBIGene:83706 biolink:causes MONDO:0013016 infores:monarchinitiative not_provided not_provided HGNC:23151 MONDO:0013016 uuid:8f3f59bf-4d17-4c8a-930b-6e92a4c8530d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28787 biolink:causes UMLS:C0344329 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0344329 infores:hetionet CHEBI:4754 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01127 UMLS:C0041834 infores:hetionet NCBIGene:6843 biolink:causes MONDO:0007164 infores:monarchinitiative not_provided not_provided HGNC:12642 MONDO:0007164 uuid:40183a01-d2bf-4359-b8d2-9e3ee0d9847b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0035078 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026650 infores:hetionet CHEBI:63638 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0011603 infores:hetionet CHEBI:8713 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0030807 infores:hetionet CHEBI:84883 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0025222 infores:hetionet CHEBI:9398 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0015967 infores:hetionet CHEBI:82960 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0221201 infores:hetionet CHEBI:9445 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C1443060 infores:hetionet CHEBI:9123 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0034886 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0003123 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0015256 infores:hetionet CHEBI:5118 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0031212 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0014130 infores:hetionet CHEBI:91541 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0042075 infores:hetionet CHEBI:10102 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0041105 infores:hetionet CHEBI:64019 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0235490 infores:hetionet CHEBI:47780 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0003862 infores:hetionet CHEBI:391960 biolink:causes HP:0012450 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0401149 infores:hetionet CHEBI:29007 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0014742 infores:hetionet CHEBI:39669 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0233494 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0016479 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0042401 infores:hetionet CAID:CA410203402 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203402 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.335T>A (p.Leu112Gln) is a missense variant which has a REVEL score ≥ 0.88 (0.978) (PP3). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203402/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5864 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0005779 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0302295 infores:hetionet CHEBI:119915 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0031154 infores:hetionet NCBIGene:1600 biolink:causes MONDO:0014410 infores:monarchinitiative not_provided not_provided HGNC:2661 MONDO:0014410 uuid:5d625921-a0e8-4ed6-b4e1-d2410f8204d3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38562 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C2981158 infores:hetionet CHEBI:3216 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0015672 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0029408 infores:hetionet CAID:CA367398721 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398721 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PP1 The c.1151C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 384 (p.(Ala384Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.902, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 24735133, 30663027, 31576961, 36504295, internal lab contributors). Additionally, at least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 24735133). Another missense variant at the same codon, c.1151C>A (p.Ala384Glu), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala384Val (PM5_Supporting). In summary, c.1151C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398721/MONDO:0015967/086 2025-06-06 2025-06-06 Semidominant inheritance HP:0032113 Supports CHEBI:6715 biolink:causes MONDO:0006248 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0549315 infores:hetionet CHEBI:3423 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C3665386 infores:hetionet CHEBI:51450 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0239340 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0020649 infores:hetionet CHEBI:45327 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0003578 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0040046 infores:hetionet CHEBI:6078 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0042165 infores:hetionet CHEBI:17650 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0239488 infores:hetionet NCBIGene:6331 biolink:causes MONDO:0024562 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0024562 uuid:0c25147b-5399-4af0-a409-771c069e5fec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0270996 infores:hetionet CHEBI:8665 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0042109 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0021068 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0919267 infores:hetionet CHEBI:63619 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0018794 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0012833 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014742 infores:hetionet CHEBI:91834 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0042963 infores:hetionet CHEBI:7773 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0013428 infores:hetionet CHEBI:3380 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0042023 infores:hetionet CHEBI:7465 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0039231 infores:hetionet CHEBI:31705 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0085649 infores:hetionet CHEBI:3011 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0004604 infores:hetionet CHEBI:3441 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235886 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0030446 infores:hetionet CHEBI:209807 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0042963 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0004239 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0085649 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0011849 infores:hetionet CHEBI:4909 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0003811 infores:hetionet UNII:VL0L558GCB biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0009676 infores:hetionet CHEBI:10102 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0010520 infores:hetionet CHEBI:18248 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0031542 infores:hetionet GO:0060379 biolink:causes CL:0000513 infores:ubergraph knowledge_assertion manual_agent GO:0060379 CL:0000513 CHEBI:2682 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0033975 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0037274 infores:hetionet CAID:CA16043045 biolink:causes MONDO:0008723 infores:clingen CAID:CA16043045 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL): c.1730_1740del (p.Ala577Glyfs*11) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 18 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16043045/MONDO:0008723/021 2023-03-27 2023-03-27 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:221264 biolink:causes MONDO:0958206 infores:monarchinitiative not_provided not_provided HGNC:33814 MONDO:0958206 uuid:f07b7c5b-3494-47ed-bb5b-51b9054ac0aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9570 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0025320 infores:hetionet CAID:CA512318876 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318876 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.261C>G (p.Gly87=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.30) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318876/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA23569514 biolink:causes MONDO:0100368 infores:clingen CAID:CA23569514 MONDO:0100368 PMID: Likely Pathogenic PM3_Supporting, PP3_Moderate, PP1_Moderate, PP4, PM2_Supporting NM_000329.3(RPE65):c.1039C>T (p.Arg347Cys) is a missense substitution, replacing arginine with cysteine at position 347. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.00000124, with 5 alleles / 1179740 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.789, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with onset of symptoms at age 4 months (1 pt), nystagmus (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), decreased central visual acuity (1 pt), diminished rod (0.5 pts) and cone (1 pt) electroretinogram responses, poor pupillary light response (0.5 pts), and decreased peripheral vision (1 pt), which together are specific for RPE65-related recessive retinopathy (total 7 points, PMID: 36017377, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 36017377). This variant has been reported in 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points. PMID: 36017377, PM3_Supporting). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the variant p.Ala360Pro confirmed in trans (PMID: 33952291), which was not counted to avoid circularity. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PP1_moderate, PP3_moderate, PM2_supporting, PM3_supporting, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA23569514/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63681 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0032961 infores:hetionet CAID:CA367403035 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403035 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.234C>G variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to glutamic acid at codon 78 (p.(Asp78Glu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.90, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in seven unrelated individuals with hyperglycemia (PS4; PMID: 17573900, 30663027, 36504295, 14517956, internal lab contributors). Furthermore, one of these reported individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative autoantibodies) (PP4_Moderate; PMID: 22060211). Additonally, this variant segregated with hyperglycemia, with 4 informative meioses in three families with hyperglycemia (PP1_Strong; internal lab contributors). In summary, c.234C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PS4, PP4_Moderate, PP1_Strong). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403035/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:77260 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0032533 infores:hetionet CHEBI:32293 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0036454 infores:hetionet CHEBI:7823 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0022346 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009938 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0009938 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0003467 infores:hetionet CHEBI:64312 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003862 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0340464 infores:hetionet CHEBI:15854 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0041948 infores:hetionet CHEBI:15544 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0039591 infores:hetionet CHEBI:3752 biolink:causes HP:0030049 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0006105 infores:hetionet CHEBI:6970 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0151692 infores:hetionet CHEBI:6539 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C1443060 infores:hetionet CHEBI:3506 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0042267 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0851341 infores:hetionet CHEBI:45081 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0206062 infores:hetionet CHEBI:94686 biolink:causes UMLS:C1735348 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1735348 infores:hetionet CHEBI:72690 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0020461 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0036572 infores:hetionet CAID:CA220593 biolink:causes MONDO:0009861 infores:clingen CAID:CA220593 MONDO:0009861 PMID:24350308PMID:22526846PMID:23430918PMID:10679941 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 The c.974A>G (p.Tyr325Cys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). It was detected with pathogenic/LP variants p.L194P (LP) PMID: 23430918 L348V (P) PMID: 10679941 p.P281L (LP) PMID: 22526846 p.R408W (P) with parental analysis not reported for 1.5 points. This variant has extremely low frequency in gnomAD (MAF=0.00001). Computational evidence supports a a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220593/MONDO:0009861/006 2020-02-23 2020-02-23 Autosomal recessive inheritance HP:0000007 Supports CAID:CA367402020 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402020 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PS4 The c.424A>T variant in the glucokinase gene, GCK, results in a premature termination at codon 142 (p.(Lys142Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 33477506, MDEP internal lab contributor). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persistently) (PP4_Moderate; internal lab contributor). In summary, c.424A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402020/MONDO:0015967/086 2024-12-02 2024-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:45863 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0014742 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0002453 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0151713 infores:hetionet CHEBI:65173 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0233565 infores:hetionet CHEBI:204928 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0019080 infores:hetionet CHEBI:8502 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0002874 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0241705 infores:hetionet CHEBI:51230 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0021368 infores:hetionet MONDO:0005804 biolink:causes MONDO:0001836 infores:drugmechdb knowledge_assertion manual_agent MESH:D006966 MESH:D000568 DB00589_MESH_D000568_1 CHEBI:45863 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0795692 infores:hetionet CHEBI:9448 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0014457 infores:hetionet CHEBI:47657 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0040822 infores:hetionet CHEBI:94807 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0013395 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005433 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0236663 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0042109 infores:hetionet CHEBI:36795 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0036974 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0151828 infores:hetionet CHEBI:32293 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0013404 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0020538 infores:hetionet CHEBI:94848 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0031117 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0026848 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020649 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0005959 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0005959 infores:hetionet CHEBI:18248 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0231218 infores:hetionet CHEBI:61390 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0178298 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0856880 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0856880 infores:hetionet CHEBI:83527 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0162830 infores:hetionet CHEBI:32293 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C3495920 infores:hetionet CHEBI:10102 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0042024 infores:hetionet CHEBI:3568 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151905 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0948089 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0042963 infores:hetionet CHEBI:63630 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0015371 infores:hetionet CHEBI:63605 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0600142 infores:hetionet CHEBI:32020 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0020517 infores:hetionet CHEBI:41977 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0085633 infores:hetionet NCBIGene:387787 biolink:causes MONDO:0060562 infores:monarchinitiative not_provided not_provided HGNC:37216 MONDO:0060562 uuid:e255d621-7dfd-4acc-97ed-c59953418009 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0162557 infores:hetionet CAID:CA119169 biolink:causes MONDO:0020367 infores:clingen CAID:CA119169 MONDO:0020367 PMID:19234343PMID:35196929PMID:15069026 Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4_Moderate, PP1_Strong BS1, BS3, BP7, PM6, PM4, PM5, PS1, PS2, BA1, BP4 The c.1309T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 437 (p.Tyr437His). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.966, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Tyr437His protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 39 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9535666, 30612094), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 6 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 10196380, 9792882, 30612094), which met PS4_Moderate (≥ 6 probands). In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119169/MONDO:0020367/019 2022-03-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28939 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0476273 infores:hetionet CHEBI:17303 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0003467 infores:hetionet CAID:CA638053822 biolink:causes MONDO:0011071 infores:clingen CAID:CA638053822 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS4, PS2, PS1, PS3, BA1, BP1, BP2, BP3, BS1, BS4, BP5, PM6, PVS1, PM1, PM3, PM4, PM5, BS2, PP2, PP3, PP1, PP4 This intronic variant has a SpliceAI score 0.04 <0.50 (BP4). It has a SpliceAI score ≤ 0.20 (0.04) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.042)) (BP7). And this variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638053822/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8764 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0029445 infores:hetionet CHEBI:3219 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232462 infores:hetionet UMLS:C1872203 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151905 infores:hetionet CAID:CA2830665544 biolink:causes MONDO:0011071 infores:clingen CAID:CA2830665544 MONDO:0011071 PMID: Uncertain Significance PM4_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP1, BP4, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.331_336del (p.Thr111_Leu112del) is an in-frame deletion which affects residues within the Runt Homology Domain, but not an established hotspot residue (PM4_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2830665544/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7476 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020461 infores:hetionet CHEBI:135736 biolink:causes HP:0034807 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1956415 infores:hetionet CHEBI:47519 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0151878 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0042373 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0518015 infores:hetionet CHEBI:5132 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C1443060 infores:hetionet CHEBI:75984 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0020458 infores:hetionet CHEBI:70746 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0017181 infores:hetionet CHEBI:29688 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0002994 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020649 infores:hetionet CHEBI:104011 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0042109 infores:hetionet CAID:CA2499225876 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225876 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This synonymous/intronic/UTR/frameshift variant has a SpliceAI score ≤ 0.20 (0) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.3 < 2.0) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225876/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:167309 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0040034 infores:hetionet CHEBI:64064 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0010200 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0948594 infores:hetionet CHEBI:3757 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0011124 infores:hetionet CHEBI:8871 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013362 infores:hetionet CHEBI:391960 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0085649 infores:hetionet CHEBI:15552 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0236000 infores:hetionet CHEBI:8772 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0008031 infores:hetionet CHEBI:85161 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0026603 infores:hetionet CAID:CA380143726 biolink:causes MONDO:0000573 infores:clingen CAID:CA380143726 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PM5 The c.302A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Asparagine by Serine at amino acid 101 (p.Asn101Ser).The filtering allele frequency (the upper threshold of the 95% CI of 2/1112008 alleles) of the c.302A>G variant in RAG2 is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting.To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PM1_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380143726/MONDO:0000573/124 2024-05-13 2024-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:50648 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003123 infores:hetionet CHEBI:4653 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0086565 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085614 infores:hetionet CHEBI:63612 biolink:causes UMLS:C0853750 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0853750 infores:hetionet CHEBI:3216 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0040264 infores:hetionet NCBIGene:6041 biolink:causes MONDO:0011098 infores:monarchinitiative not_provided not_provided HGNC:10050 MONDO:0011098 uuid:a4227a31-a56a-480b-a333-882c90f2058f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:681850 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0030193 infores:hetionet CHEBI:2208 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0006849 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0008031 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0151888 infores:hetionet CHEBI:31644 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0013428 infores:hetionet CHEBI:3216 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0231528 infores:hetionet CHEBI:47381 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0086439 infores:hetionet CAID:CA320617998 biolink:causes MONDO:0011071 infores:clingen CAID:CA320617998 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS4, PS2, PS3, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM1, PM5, PM4, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.579C>T (p.Ile193=) is a synonymous variant which is not predicted to have any splicing impact per SpliceAI and has a REVEL score and conservation data that do not support a damaging effect (BP4). This variant is present once in gnomAD v3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320617998/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51860 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027765 infores:hetionet CHEBI:131512 biolink:causes UMLS:C0231613 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0231613 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0009782 infores:hetionet CHEBI:63630 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020443 infores:hetionet CHEBI:70735 biolink:causes MONDO:0019771 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C2242577 infores:hetionet CHEBI:4856 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0030232 infores:hetionet CHEBI:41774 biolink:causes HP:0032004 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0033778 infores:hetionet CHEBI:5050 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0233494 infores:hetionet CAID:CA410147412 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147412 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1312G>A (p.Gly438Ser) is a missense variant which has a REVEL score < 0.50 (0.23), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147412/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31623 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0010037 infores:hetionet CHEBI:3732 biolink:causes UMLS:C1262535 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1262535 infores:hetionet CHEBI:64028 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0027497 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0013395 infores:hetionet CHEBI:65349 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0404521 infores:hetionet CAID:CA400024802 biolink:causes MONDO:0100326 infores:clingen CAID:CA400024802 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.842A>C (p.His281Pro) missense variant has been identified in at least 1 probands, GT11 of PMID: 29675921 meeting the criteria for PP4_strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. GT11 of PMID: 29675921 is compound heterozygous for His281Pro and Cys400Tyr (classified Pathogenic by the PD-VCEP; PM3_Supporting) without confirmation of phasing . This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.988, which predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3, PP4_strong, PM3_supporting. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400024802/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:367163 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0038362 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0003123 infores:hetionet CHEBI:9667 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0456909 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0243026 infores:hetionet CHEBI:5893 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0004604 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0521839 infores:hetionet CAID:CA023953 biolink:causes MONDO:0007783 infores:clingen CAID:CA023953 MONDO:0007783 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glycine with valine at codon 3990 of the RYR1 protein, p.(Gly3990Val). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 11 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 11 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in 10 individuals, PP1_Strong (PMID:28403410). A REVEL score of 0.75 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PP1_Strong. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023953/MONDO:0007783/012 2022-09-08 2022-09-08 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:27899 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0042487 infores:hetionet CHEBI:18248 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0039231 infores:hetionet CHEBI:48273 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0037383 infores:hetionet CHEBI:29688 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0006384 infores:hetionet CHEBI:5855 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0231218 infores:hetionet CHEBI:9757 biolink:causes UMLS:C1112489 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C1112489 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0042109 infores:hetionet CAID:CA10385635 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385635 MONDO:0100437 PMID: Uncertain Significance PP3, PM2_Supporting BP4 NM_001034853.2(RPGR):c.529G>A (p.Val177Ile) is a missense variant causing substitution of valine by Isoleucine at amino acid 177. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.245, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives a delta score of 0.73 for donor loss, which is above the ClinGen X-linked IRD VCEP recommended threshold of >0.2 and predicts an impact on RPGR splicing (PP3). In summary, this variant is classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting and PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385635/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Inconclusive true CHEBI:567361 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0031256 infores:hetionet CHEBI:27690 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C1306571 infores:hetionet CHEBI:85083 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0019196 infores:hetionet NCBIGene:5195 biolink:causes MONDO:0013952 infores:monarchinitiative not_provided not_provided HGNC:8856 MONDO:0013952 uuid:399c2087-9ec0-4d36-9bbf-851c94053c63 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100147 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0003862 infores:hetionet CHEBI:4814 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0004096 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1142272 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1142272 infores:hetionet CHEBI:41879 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0019572 infores:hetionet CHEBI:27565 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0020615 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0020456 infores:hetionet CHEBI:63624 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0687713 infores:hetionet CHEBI:63617 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C3203358 infores:hetionet CHEBI:3393 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0017675 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0006840 infores:hetionet CHEBI:63791 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0854467 infores:hetionet CHEBI:16469 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042963 infores:hetionet CHEBI:84500 biolink:causes UMLS:C1141893 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1141893 infores:hetionet CHEBI:48947 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0030193 infores:hetionet UMLS:C0009315 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0019079 infores:hetionet NCBIGene:3796 biolink:causes MONDO:0014170 infores:monarchinitiative not_provided not_provided HGNC:6318 MONDO:0014170 uuid:f17ffa47-4311-4409-b51f-b4ca5a16e34a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0003339 biolink:causes GO:0072009 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0072009 CHEBI:49960 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0392699 infores:hetionet CHEBI:41977 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0041582 infores:hetionet CHEBI:2704 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0007222 infores:hetionet CHEBI:6775 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0024523 infores:hetionet CHEBI:10650 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0547030 infores:hetionet CHEBI:64355 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0011603 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017178 infores:hetionet CHEBI:5893 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0018681 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151763 infores:hetionet CHEBI:135876 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0232849 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0265050 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0265050 infores:hetionet CHEBI:49713 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0016436 infores:hetionet CHEBI:50922 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0025323 infores:hetionet CHEBI:23765 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002792 infores:hetionet CHEBI:3387 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C1510497 infores:hetionet CHEBI:7573 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0000737 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0009450 infores:hetionet CHEBI:64355 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0008350 infores:hetionet CHEBI:7936 biolink:causes HP:0040088 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0580550 infores:hetionet UMLS:C0145867 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0013404 infores:hetionet CHEBI:82960 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0001339 infores:hetionet CHEBI:3044 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0012833 infores:hetionet NCBIGene:90665 biolink:causes MONDO:0027048 infores:monarchinitiative not_provided not_provided HGNC:18502 MONDO:0027048 uuid:f23f75d8-f08e-4abf-a765-a52b8a0ab57e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0008359 biolink:causes GO:0009952 infores:ubergraph knowledge_assertion manual_agent GO:0008359 GO:0009952 CHEBI:6402 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C2363730 infores:hetionet CHEBI:7465 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0042029 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0877322 infores:hetionet CHEBI:3723 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085605 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0006852 infores:hetionet CHEBI:2639 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0032617 infores:hetionet CHEBI:7573 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151905 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0009806 infores:hetionet CAID:CA401364531 biolink:causes MONDO:0009290 infores:clingen CAID:CA401364531 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting, PM5_Supporting The NM_000152.5:c.1000G>A variant in GAA is a missense variant predicted to cause substitution of glycine by serine at amino acid 334 (p.Gly334Ser). Two individuals with LOPD and this variant have been reported in the literature (PMID: 21687968, 33741225) with one individual having deficient GAA enzyme activity in leukocytes (PMID: 33741225) (PP4_moderate). Both individuals were compound heterozygous for the variant and a second pathogenic or likely pathogenic GAA variant, phase not reported (PM3_Supporting). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.855 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1000G>T, p.Gly334Ser] [ClinVar Variation ID: 843318] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID:843318). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PP4_moderate, PM3_supporting, PM2_supporting, PP3, PM5_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, Sept. 16, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401364531/MONDO:0009290/010 2025-09-16 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ NCBIGene:2627 biolink:causes MONDO:0016581 infores:monarchinitiative not_provided not_provided HGNC:4174 MONDO:0016581 uuid:67c875fa-d965-45b9-b52b-bd5fbf1e1f98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0542571 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0037822 infores:hetionet CHEBI:91541 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0027497 infores:hetionet CHEBI:3044 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0013395 infores:hetionet CHEBI:75722 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026827 infores:hetionet CAID:CA10549212 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549212 MONDO:0010305 PMID: Uncertain Significance BP4 BS1, PM2 The NM_005629.4:c.617G>A variant in SLC6A8 is a missense variant predicted to cause a substitution of an arginine by a histidine at amino acid position 206 (p.Arg206His). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00010 (2/19079 alleles, 2 hemizygotes) in the South Asian population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.098 for the amino acid substitution (BP4). There is a ClinVar entry for this variant (Variation ID: 2181706, one-star review status), with conflicting interpretations of pathogenicity (two submitters: uncertain significance; one submitter: benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549212/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:64310 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0004093 infores:hetionet CAID:CA380144219 biolink:causes MONDO:0000573 infores:clingen CAID:CA380144219 MONDO:0000573 PMID: Likely Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM1_Supporting, PM3_Supporting BS2 The NM_000536.4:c.193G>T variant in RAG2 is a missense variant predicted to cause substitution of aspartic acid by tyrosine at amino acid 65 (p.Asp74Tyr). The variant has been reported in one individual with SCID. The individual was homozygous of this variant (PM3_Supporting, PMID 21624848). The individual had a T-B-NK+ lymphocyte profile and showed reduced T-cell proliferation under PHA stimulation, which supports a diagnosis of leaky/atypical SCID (PP4, PMID 21624848). The highest population minor allele frequency of this variant in gnomAD v2.1.1 is 0.000008791 (1/113758 alleles) in the European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.0000588) for PM2_Supporting. No homozygous individual has been observed in the gnomAD v2.1.1 (PM2_Supporting). This variant resides within the core domain (amino acids 1-383) of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP. (PM1_Supporting). An in vitro recombination activity assay shows that the relevant activity of the p.D65Y variant compared to wildtype RAG2 is 6.8%, which is below the threshold (<25%) established by the SCID VCEP for PS3_Moderate (PS3_Moderate, PMID 29772310). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PP4, PM3_Supporting, PM2_Supporting, PM1_Supporting, and PS3_Moderate (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144219/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3515 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0236068 infores:hetionet CAID:CA2586966740 biolink:causes MONDO:0100368 infores:clingen CAID:CA2586966740 MONDO:0100368 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3 NM_000329.3(RPE65):c.651del (p.Asp218IlefsTer3) is a frameshift variant that introduces a premature stop codon into exon 7 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of inherited retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 30268864) with the NM_000329.3(RPE65):c.1580A>C (p.His527Pro) variant suspected but not confirmed in trans. However, the proband was not counted for PM3_Supporting to avoid circularity. In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1 and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586966740/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3696 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0035455 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151970 infores:hetionet CHEBI:5855 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0011168 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0746883 infores:hetionet CHEBI:17549 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0013604 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0024103 infores:hetionet CHEBI:194135 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0012569 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0518015 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0151698 infores:hetionet CHEBI:5118 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042384 infores:hetionet CHEBI:15940 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0237849 infores:hetionet CHEBI:5004 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0018772 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0917799 infores:hetionet CHEBI:17650 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0017979 infores:hetionet CHEBI:39867 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151872 infores:hetionet CHEBI:31644 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0014591 infores:hetionet CHEBI:63621 biolink:causes MONDO:0000328 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0085681 infores:hetionet CHEBI:8888 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040460 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0262578 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0262578 infores:hetionet CHEBI:168396 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0029118 infores:hetionet CHEBI:31236 biolink:causes EFO:0020909 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877167 infores:hetionet CHEBI:77733 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0700361 infores:hetionet CHEBI:23765 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0600228 infores:hetionet CAID:CA040070 biolink:causes MONDO:0007750 infores:clingen CAID:CA040070 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, PS3, BP7, BS3, PP3 The NM_000527.5(LDLR): c.2388C>T (p.Ile796=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows:PM2: PopMax MAF= 0.00004238 (0.004238%) in European non-Finnish exomes + genomes (gnomAD v.4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA040070/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6413 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0011991 infores:hetionet CHEBI:135351 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0020651 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0033975 infores:hetionet CHEBI:63637 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0009782 infores:hetionet UMLS:C0011701 biolink:causes NCIT:C101172 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0234230 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0022660 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0860866 infores:hetionet CHEBI:8107 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0014518 infores:hetionet CHEBI:8107 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2047937 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0042510 infores:hetionet CHEBI:6931 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0035508 infores:hetionet CAID:CA410208258 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208258 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.25T>A (p.Ser9Thr) is a missense variant which has a REVEL score < 0.50 (0.414), and a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208258/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8059 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0013146 infores:hetionet CHEBI:30830 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0149745 infores:hetionet CHEBI:75246 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0002871 infores:hetionet CHEBI:127780 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0009676 infores:hetionet CHEBI:3508 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0011615 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C1112320 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1112320 infores:hetionet CAID:CA349520 biolink:causes MONDO:0007648 infores:clingen CAID:CA349520 MONDO:0007648 PMID:26182300 Benign BS1, BS2 BP5, BP7, BS3, BS4, PM2, PM6, PVS1, PM5, PM3, PM1, PM4, PP3, PP2, PP1, PP4, BP4, BP1, BP2, BP3, BA1, PS1, PS3, PS4, PS2 The c.286A>G (p.Ile96Val) variant has an allele frequency of 0.00122 (0.12%, 41/33,578 alleles) in the Latino subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA349520/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:17263 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0235955 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0853761 infores:hetionet NCBIGene:1938 biolink:causes MONDO:0012246 infores:monarchinitiative not_provided not_provided HGNC:3214 MONDO:0012246 uuid:7d36f971-3737-44d2-87a8-9a6bec515c5b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020453 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019360 infores:hetionet CAID:CA16041875 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041875 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1532+2T>C variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 15. It is predicted to cause skipping of biologically-relevant-exon 15/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1 is 0.00005440 in the East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting. (ACADVL VCEP specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041875/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50648 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0018801 infores:hetionet CHEBI:47780 biolink:causes HP:5200205 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020903 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0152029 infores:hetionet CHEBI:4514 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0002792 infores:hetionet CHEBI:44185 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0011071 infores:hetionet CHEBI:75922 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0027765 infores:hetionet CHEBI:134936 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0314719 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0006840 infores:hetionet CHEBI:7478 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2047937 infores:hetionet CHEBI:47381 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030193 infores:hetionet NCBITaxon:5754 biolink:causes MONDO:0005629 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5754 MESH:D015823 DB03808_MESH_D015823_1 CHEBI:63629 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0040479 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0015397 infores:hetionet CHEBI:50648 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0000731 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0521839 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C1443060 infores:hetionet CHEBI:3698 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0027540 infores:hetionet CHEBI:6775 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C2939147 infores:hetionet CHEBI:6078 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0003862 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0027769 infores:hetionet CHEBI:2567 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0014518 infores:hetionet CHEBI:3061 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0151766 infores:hetionet UMLS:C0005740 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0085593 infores:hetionet CHEBI:2567 biolink:causes UMLS:C3495947 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C3495947 infores:hetionet CHEBI:10102 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085932 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0235032 infores:hetionet CHEBI:68575 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0037763 infores:hetionet CHEBI:44185 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0032617 infores:hetionet CHEBI:68478 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027424 infores:hetionet CHEBI:42820 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0041349 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0004239 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0017601 infores:hetionet CAID:CA7724149 biolink:causes MONDO:0044970 infores:clingen CAID:CA7724149 MONDO:0044970 PMID: Uncertain Significance PM2, BP7 The c.3405 C>T (p.Asp1135=) variant in POLG is present in population databases at the following frequencies: ESP Allele Frequency: 0.00023 with 0 homozygotes (PM2). This is a silent variant and no change in amino acid (BP7). In summary, there is insufficient evidence to characterize this variant and therefore it remains a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, BP7 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA7724149/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA414447533 biolink:causes MONDO:0010604 infores:clingen CAID:CA414447533 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PVS1_Moderate, PP4_Moderate, PM6 The variant c.1359G>A (p.Trp453Ter) introduces a premature stop codon in the last exon and is predicted to result in a truncated protein with more than 90% of the protein intact. This variant has been reported in at least 5 probands with severe hemophilia B, including as a de novo occurrence with assumed maternity and paternity, meeting phenotypic criteria for F9 (PMID: 36347023; PMID: 10698280; PMID: 8091381; PMID: 29296726). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria are applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PVS1_moderate + PM2 supporting + PS4 + PP4_Moderate. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0, Released 10/5/2023). Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414447533/MONDO:0010604/080 2024-04-26 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:9434 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0267792 infores:hetionet NCBIGene:4595 biolink:causes MONDO:0012041 infores:monarchinitiative not_provided not_provided HGNC:7527 MONDO:0012041 uuid:44b7729c-8ab9-46cc-96f3-5caef2287b3d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA414793459 biolink:causes MONDO:0044970 infores:clingen CAID:CA414793459 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS2, PS3, PM6, PM2 The m.7724A>T variant in MT-CO2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 24, 2023. There are no individuals or families with this variant reported in the medical literature to our knowledge. There are several occurrences in population databases. This variant is present in 0.031% of individuals in GenBank MITOMAP sequences, in 0.039% of individuals in gnomAD v3.1.2 (homoplasmic in all individuals), and in 0.088% of individuals in the Helix dataset (homoplasmic in all individuals). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.3 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414793459/MONDO:0044970/015 2023-07-24 2023-08-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:36795 biolink:causes UMLS:C0549418 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0549418 infores:hetionet CHEBI:3508 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0086565 infores:hetionet CHEBI:8869 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0037763 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0236141 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0236141 infores:hetionet CHEBI:31199 biolink:causes UMLS:C1323189 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C1323189 infores:hetionet CAID:CA10607042 biolink:causes MONDO:0008723 infores:clingen CAID:CA10607042 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.869dup (p.Ile291HisfsTer7) variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has also been in a patient with Very long chain acyl-coA dehydrogenase deficiency (VLCADD) (PMID:26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1+PM2_supporting). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA10607042/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7465 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0012833 infores:hetionet CHEBI:71941 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C1368065 infores:hetionet GO:0072043 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072001 CHEBI:68558 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0085649 infores:hetionet CHEBI:47499 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0162830 infores:hetionet CHEBI:145499 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0027796 infores:hetionet NCBIGene:6606 biolink:causes MONDO:0009673 infores:monarchinitiative not_provided not_provided HGNC:11117 MONDO:0009673 uuid:9d91243b-4dbd-48d1-9acc-3a00d00f45bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48273 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0000737 infores:hetionet CAID:CA267647 biolink:causes MONDO:0009861 infores:clingen CAID:CA267647 MONDO:0009861 PMID: Uncertain Significance PM4, PM2 PAH-specific ACMG/AMP criteria applied: PM2: chr12-103288654--GAGAAG; Absent from population databases; PM4: in-frame insertion. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267647/MONDO:0009861/006 2018-08-10 2019-08-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15367 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020877 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0314719 infores:hetionet NCBIGene:7473 biolink:causes MONDO:0060764 infores:monarchinitiative not_provided not_provided HGNC:12782 MONDO:0060764 uuid:eda24b03-3239-4413-9b2e-68ad7c165b77 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0000751 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007873 infores:hetionet CHEBI:31236 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0023518 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0035078 infores:hetionet CAID:CA10585551 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585551 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 BA1, BP2, PS3, PS1, PS4, PS2, BS1, BS3, BS4, BP7, PM4, PM1, PM5, PM3, PM6, PVS1, BS2, PP3, PP1 The NM_000527.5(LDLR):c.1661C>T (p.Ser554Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 May 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0).PP4: Variant meets PM2 and is identified in at least 1 index case with Possible FH by Simon-Broome criteria from Taiwan (PMID 22353362 (Chiou et al., 2012); PMID 33994402 (Huang et al., 2022)), after alternative causes of high cholesterol were excluded.BP4: REVEL = 0.456, it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limitsB) variant is exonic and at least 50bp downstream from the canonical donor and acceptor site, but it does not create AG/GT. The variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585551/MONDO:0007750/013 2025-05-09 2025-10-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA10558429 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558429 MONDO:0010726 PMID: Benign BP5, BS1, BS2 The allele frequency of the p.Glu473Asp variant in MECP2 (NM_004992.3) is 0.019% in Other sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Glu473Asp variant is observed in at least 4 unaffected individuals (internal database - Invitae) (BS2). The p.Glu473Asp variant is found in an individual with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the p.Glu473Asp variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558429/MONDO:0010726/036 2023-10-13 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:8863 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0023067 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C1384353 infores:hetionet CHEBI:16755 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C3665347 infores:hetionet CHEBI:4511 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0040034 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002170 infores:hetionet CHEBI:6532 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0012833 infores:hetionet CHEBI:2453 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0085631 infores:hetionet NCBIGene:9757 biolink:causes MONDO:0030969 infores:monarchinitiative not_provided not_provided HGNC:15840 MONDO:0030969 uuid:4dd3b477-605e-4d06-bbab-38984451489d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6717 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0151746 infores:hetionet CHEBI:63580 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0235198 infores:hetionet CHEBI:6367 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085649 infores:hetionet CHEBI:8874 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0007097 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0235889 infores:hetionet CHEBI:31625 biolink:causes UMLS:C1735373 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C1735373 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0009806 infores:hetionet CHEBI:52717 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151907 infores:hetionet CHEBI:5165 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0040822 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042134 infores:hetionet CHEBI:31711 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C2242996 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0040046 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0039971 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0149904 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0423602 infores:hetionet CHEBI:114785 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0333355 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0007222 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0948089 infores:hetionet CHEBI:135920 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0017178 infores:hetionet CHEBI:4708 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0032617 infores:hetionet NCBIGene:23529 biolink:causes MONDO:0012467 infores:monarchinitiative not_provided not_provided HGNC:17412 MONDO:0012467 uuid:49ed4f87-8668-4f60-8122-dd08547ec1de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2576142335 biolink:causes MONDO:0100438 infores:clingen CAID:CA2576142335 MONDO:0100438 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3 NM_014336.5(AIPL1):c.618_619dup (p.Cys207SerfsTer3) is a duplication of two nucleotides at position c.618_619. This is a frameshift variant that introduces a premature stop codon into exon 4 of 6 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg) variant confirmed in trans (PMID: 39986747), however, the proband was not counted for PM3_Supporting to avoid circularity. At least one proband harboring this variant exhibits a phenotype including a diagnosis of AIPL1-related retinal dystrophy, severe visual disturbances in infancy or early childhood (1 pt), severely reduced visual acuity (1 pt), and participation in a gene therapy trial with strict inclusion criteria and subsequent positive results (2 pts), which together are specific for AIPL1-related retinopathy (total 4 points, PMID: 39986747, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2576142335/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31711 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0028961 infores:hetionet CHEBI:63598 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0021368 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235146 infores:hetionet CHEBI:4953 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0042029 infores:hetionet CHEBI:4822 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0010073 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0029408 infores:hetionet CHEBI:30659 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0015672 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017160 infores:hetionet CHEBI:74947 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020639 infores:hetionet CHEBI:8228 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0241863 infores:hetionet CHEBI:3752 biolink:causes MONDO:0001046 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003466 infores:hetionet CHEBI:16899 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0031542 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020649 infores:hetionet CHEBI:2549 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0020458 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023533 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0856110 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0856110 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0233472 infores:hetionet CHEBI:37941 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0037763 infores:hetionet CHEBI:80630 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0007785 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0442874 infores:hetionet CHEBI:3207 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0151610 infores:hetionet CHEBI:40237 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0010200 infores:hetionet CHEBI:31236 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017675 infores:hetionet CHEBI:61390 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0917801 infores:hetionet CHEBI:63619 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0242429 infores:hetionet CHEBI:15940 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0016867 infores:hetionet CHEBI:63611 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020639 infores:hetionet CHEBI:27779 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0027726 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0038826 infores:hetionet CAID:CA1139662707 biolink:causes MONDO:0010880 infores:clingen CAID:CA1139662707 MONDO:0010880 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting The NM_000020.3: c.1377+4A>T variant in ACVRL1 is an intronic variant located in intron 9. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; Internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.39 for donor loss, predicting that the variant disrupts the donor splice site of intron 9 of ACVRL1 (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, PP3 (specification version 1.0.0; 1/04/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139662707/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8107 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0542571 infores:hetionet CHEBI:75984 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0080274 infores:hetionet NCBIGene:26123 biolink:causes MONDO:0013896 infores:monarchinitiative not_provided not_provided HGNC:24519 MONDO:0013896 uuid:7a9682e9-4717-49bd-ba66-266a231b67ea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8597 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0520966 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0030446 infores:hetionet CHEBI:9674 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0004134 infores:hetionet CHEBI:6339 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0085649 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0037822 infores:hetionet CHEBI:5001 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0005758 infores:hetionet CHEBI:3723 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233407 infores:hetionet CHEBI:521033 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0027651 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0079043 infores:hetionet CHEBI:2611 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C2047937 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0392525 infores:hetionet CHEBI:83804 biolink:causes MONDO:0001584 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0028850 infores:hetionet CHEBI:53691 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0020580 infores:hetionet CHEBI:63599 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0023530 infores:hetionet CHEBI:8888 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0233407 infores:hetionet CHEBI:37941 biolink:causes MONDO:0018373 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0027543 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0042373 infores:hetionet CAID:CA16619071 biolink:causes MONDO:0017623 infores:clingen CAID:CA16619071 MONDO:0017623 PMID: Uncertain Significance PM4, PM2_Supporting PVS1, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP3, PP1, PP4, PM5, PM1, PM3, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 NM_000314.8(PTEN):c.1133_1136del (p.Arg378IlefsTer37) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_P: Absent in large sequenced populations (PMID 27535533).PM4: Variant causes protein extension (NM_000314.4) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619071/MONDO:0017623/003 2024-02-09 2024-03-04 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948525 infores:hetionet CHEBI:3207 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0037763 infores:hetionet CHEBI:77733 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0037763 infores:hetionet CHEBI:125354 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0042109 infores:hetionet CHEBI:9445 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0003467 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001648 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0239295 infores:hetionet CHEBI:6067 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0033774 infores:hetionet CHEBI:8802 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018524 infores:hetionet CHEBI:5864 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0086769 infores:hetionet CHEBI:7459 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0000729 infores:hetionet CHEBI:3082 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151904 infores:hetionet CHEBI:7488 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00826 UMLS:C0423153 infores:hetionet CHEBI:64310 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0016242 infores:hetionet CHEBI:3638 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0019158 infores:hetionet CAID:CA9487821 biolink:causes MONDO:0011229 infores:clingen CAID:CA9487821 MONDO:0011229 PMID: Benign BA1, BP7 PM5, BS2, PP3, BP4, PS1, PM2 The filtering allele frequency of the c.573C>T variant in the ETHE1 gene is 0.373% by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Mito Variant Curation Expert Panel (BA1) Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA9487821/MONDO:0011229/014 2020-08-18 2021-10-22 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:2955 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0020538 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0521546 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0521546 infores:hetionet CHEBI:5134 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0851578 infores:hetionet NCBIGene:79840 biolink:causes MONDO:0012650 infores:monarchinitiative not_provided not_provided HGNC:25737 MONDO:0012650 uuid:869c1685-88fc-430c-9c96-8d52f44fe080 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013447 infores:hetionet CHEBI:7915 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0011603 infores:hetionet CHEBI:63681 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0392684 infores:hetionet CHEBI:9674 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C2830004 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549433 infores:hetionet CHEBI:4822 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0023218 infores:hetionet CHEBI:31302 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0013985 infores:hetionet NCBIGene:10908 biolink:causes MONDO:0012787 infores:monarchinitiative not_provided not_provided HGNC:16268 MONDO:0012787 uuid:b1767fd9-bad5-4b7a-87fb-43d51642160b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0547030 infores:hetionet CHEBI:31859 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0040822 infores:hetionet CHEBI:5856 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0085612 infores:hetionet CAID:CA386965775 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965775 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PM5_Supporting, PP4_Moderate, PP3, PP1 The c.721T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to arginine at codon 241 (p.(Cys241Arg)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant at the same codon, c.721T>G p.(Cys241Gly)​, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant segregated with disease with 2 informative meioses in 2 families (PP1; internal lab contributor). In summary, c.721T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM2_Supporting, PP3, PM1_Supporting, PS4_Moderate, PP1, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965775/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CAID:CA294003 biolink:causes MONDO:0007648 infores:clingen CAID:CA294003 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM2, PM6, PVS1, PM5, PM3, PM1, PM4, PP1, PP4, PP2, PP3, BS2, BP1, BP4, BP3, PS4, PS2, PS1, PS3 The NM_004360.5(CDH1):c.833-16C>G variant has an allele frequency of 0.01066 (1%, 266/24958 alleles, 2 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294003/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:100246 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0009676 infores:hetionet CHEBI:3181 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0027441 infores:hetionet CHEBI:5138 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0428977 infores:hetionet CHEBI:2639 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C1443060 infores:hetionet CHEBI:29007 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0014518 infores:hetionet NCBIGene:9320 biolink:causes MONDO:0030914 infores:monarchinitiative not_provided not_provided HGNC:12306 MONDO:0030914 uuid:1ede5da1-3adc-4dc4-8012-48d0b24c7d6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0428974 infores:hetionet CAID:CA396458612 biolink:causes MONDO:0007648 infores:clingen CAID:CA396458612 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PM6, PVS1, PP3, PP2, PP1, PP4, BS2, BP4, BP1, BP2, BP3, BA1, PS3, PS1, PS2 The c.760G>C (p.Asp254His) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; internal laboratory contributor). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396458612/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:9073 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0011606 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0235431 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0042109 infores:hetionet CHEBI:51364 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0033774 infores:hetionet CHEBI:27899 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0020461 infores:hetionet CAID:CA6748709 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748709 MONDO:0009861 PMID:26503515 Likely Pathogenic PM5, PM2, PP4_Moderate, PP3 The c.1216A>G (p.Ile406Val) variant in PAH is reported in an individual with PKU. Dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were collected. (PMID: 26503515) This variant has a low frequency in ExAC/gnomAD (MAF=0.00016) and is absent from 1000G. A deleterious effect is predicted by SIFT, Polyphen, and MutationTaster. Another missense variant at this amino acid is interpreted as likely pathogenic by our PAH VCEP (p.I406T). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748709/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45951 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0002994 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0014868 infores:hetionet CHEBI:2666 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0233571 infores:hetionet CAID:CA2825002847 biolink:causes MONDO:0011071 infores:clingen CAID:CA2825002847 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.801del (p.Met267IlefsTer?) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2825002847/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CAID:CA956853 biolink:causes MONDO:0800406 infores:clingen CAID:CA956853 MONDO:0800406 PMID: Likely Benign BP7 BS1, PM5, PM2, PP3, BA1, BP4 The NM_000350.3:c.6498C>T is a synonymous variant (p.Ile2166=). The total minor allele frequency in gnomAD v4.1.0 is 0.001166 (1882/1614158 alleles), and the GroupMax filtering allele frequency is 0.002456. This is higher than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), and lower than the threshold for BS1_Supporting (>0.00163). Therefore, no population codes are applied. SpliceAI gives this synonymous variant a delta score of 0.01 for acceptor gain which is below the ClinGen ABCA4 VCEP threshold of <0.1 and does not strongly predict a splicing defect. To our knowledge, there is no known conflicting minigene or other functional data available (BP7_Moderate). In summary, this variant meets the criteria to be classified as likely benign for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): BP7_Moderate. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA956853/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:63791 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027497 infores:hetionet CHEBI:17474 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0006142 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0037274 infores:hetionet CHEBI:8356 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0036974 infores:hetionet CHEBI:50922 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0017178 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0000833 infores:hetionet CHEBI:63630 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0014868 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009450 infores:hetionet CHEBI:29688 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0700590 infores:hetionet CHEBI:9671 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0020517 infores:hetionet CHEBI:5855 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0233407 infores:hetionet CAID:CA410147913 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147913 MONDO:0011071 PMID: Uncertain Significance BP4, PS1_Moderate, PM2_Supporting PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1162T>A (p.Ser388Thr) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD (PM2_supporting). This missense variant has a REVEL score <0.50 (0.154) and a spliceAI score <0.2 (0.0) (BP4). The c.1162T>A variant is the same amino acid change (p.Ser388Thr) as a previously established likely pathogenic variant (ClinVar ID 561222) curated using MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PS1_Moderate). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, PS1_moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147913/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0001824 infores:hetionet CHEBI:50922 biolink:causes UMLS:C1096250 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1096250 infores:hetionet NCBITaxon:2702 biolink:causes MONDO:0005316 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:2702 MONDO:0005316 CHEBI:77260 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0162429 infores:hetionet CHEBI:3286 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0009806 infores:hetionet CHEBI:75179 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0162285 infores:hetionet CHEBI:7903 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0392171 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0403632 infores:hetionet CHEBI:31348 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0032617 infores:hetionet CHEBI:9434 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0018965 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005724 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0010414 infores:hetionet GO:1904444 biolink:causes GO:0046546 infores:ubergraph knowledge_assertion manual_agent GO:1904444 GO:0046546 CHEBI:15365 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0239571 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0031117 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0020517 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151849 infores:hetionet CHEBI:5613 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0018418 infores:hetionet CHEBI:68478 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0025323 infores:hetionet GO:2000477 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000477 GO:0072001 CHEBI:6149 biolink:causes HP:6000500 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235248 infores:hetionet CHEBI:39585 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0027849 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0423172 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0423172 infores:hetionet CHEBI:3423 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0494475 infores:hetionet CAID:CA913177431 biolink:causes MONDO:0044970 infores:clingen CAID:CA913177431 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP3, PS4, PS3 The m.7566G>A variant in MT-TD has been reported in one individual with primary mitochondrial disease in the medical literature however this report was part of a large cohort and clinical details were not provided precluding consideration of this case for this curation (PMID: 31965079). This variant is absent in MITOMAP, there is one homoplasmic occurrence and two heteroplasmic occurrences in gnomAD V3.1.2, and there is one heteroplasmic occurrence in the Helix dataset. Although there are several occurrences, the frequency is still low (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (65.6 percentile) but HmtVAR predicts it to be neutral with a score of 0.05. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913177431/MONDO:0044970/015 2024-10-28 2025-05-14 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true UMLS:C0004609 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020672 infores:hetionet CAID:CA401368835 biolink:causes MONDO:0009290 infores:clingen CAID:CA401368835 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Strong PP3, BA1 The NM_000152.5:c.1657C>T (p.Gln553Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 12 out of 20 exons leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism, meeting PVS1. At least 10 patients with this variant have been reported with Pompe disease (6 with IOPD, and 4 with LOPD); 8 were reported to be on enzyme replacement therapy for Pompe disease, and 6 individuals who are homozygous for the variants were reported to be CRIM negative (PMID: 30023291, 31378569, 34530085, 35605642) (PP4_Moderate). Three of these individuals are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP, c.-32-13T>G (ClinVar Variation ID: 4027 (PMID: 35605642, 31378569); the phase is unconfirmed in all cases (max 0.5 x 2 points). In addition, six individuals from Saudi Arabia are homozygous for the variant (PMID: 30023291) (max 2 x 0.5 points). Another patients with the variant has been reported but the second variant was not provided (PMID: 34530085). Total 2 points (PM3_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 982109). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PVS1, PM3_Strong, PP4_Moderate, and PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401368835/MONDO:0009290/010 2025-04-15 2025-05-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8232 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0340865 infores:hetionet CHEBI:16335 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0240327 infores:hetionet CHEBI:4784 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C2363731 infores:hetionet CHEBI:8890 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0438142 infores:hetionet CHEBI:10102 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C2047937 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0232197 infores:hetionet CHEBI:681569 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C1306577 infores:hetionet CHEBI:681569 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0003467 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0585186 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0012797 infores:hetionet CAID:CA377781947 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781947 MONDO:0017623 PMID: Uncertain Significance PM6, PS3_Supporting, PP2, PM2_Supporting, BP4 PS4 NM_000314.8(PTEN):c.49C>G (p.Gln17Glu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor)PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. (PMIDs: 24292679, 29706633).PM2_P: Absent in gnomADPP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BP4: REVEL score < 0.5 (score=0.498)Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic moderate, 3 pathogenic supporting codes get -1 + 2 + (1*3) points; total is 4 (Uncertain significance). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781947/MONDO:0017623/003 2023-10-11 2024-03-01 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:7157 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:11998 MONDO:0007256 uuid:9b110a74-b59f-4ac0-bb2e-6aea86f2415c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3647 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0026961 infores:hetionet NCBIGene:56910 biolink:causes MONDO:0011930 infores:monarchinitiative not_provided not_provided HGNC:18063 MONDO:0011930 uuid:4cfc3ffc-f608-4e50-96fe-bcfc6bbb51b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0011603 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020039 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0743680 infores:hetionet CHEBI:63584 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0013604 infores:hetionet CHEBI:2639 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0026821 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0032290 infores:hetionet CHEBI:31644 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151767 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0162429 infores:hetionet CHEBI:4024 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0080274 infores:hetionet NCBIGene:8891 biolink:causes MONDO:0957871 infores:monarchinitiative not_provided not_provided HGNC:3259 MONDO:0957871 uuid:cced9e13-0afd-4e09-b8d3-98422013a3b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:40279 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018099 infores:hetionet CHEBI:9150 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0003467 infores:hetionet CHEBI:8764 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002063 infores:hetionet CHEBI:9907 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0026821 infores:hetionet CHEBI:27565 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0042963 infores:hetionet CHEBI:3696 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013456 infores:hetionet CHEBI:5130 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0035317 infores:hetionet CAID:CA409103960 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103960 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PP1, PM5 The c.194G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to asparagine at codon 65 (p.(Ser65Asn)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.913, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also located within the DNA binding domain (codons 37-113 of HNF4A), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.195C>A (p.(Ser65Arg)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.194G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0 approved 10/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103960/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:UMD7G2653W biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C2173677 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0041912 infores:hetionet CHEBI:2904 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0234238 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0267596 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0035078 infores:hetionet CHEBI:31199 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0011603 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0232498 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0232498 infores:hetionet CHEBI:9086 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0035305 infores:hetionet CHEBI:9943 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0037763 infores:hetionet CHEBI:8768 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0497156 infores:hetionet CHEBI:3764 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0518015 infores:hetionet CHEBI:82941 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0520573 infores:hetionet CHEBI:107736 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0013384 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151603 infores:hetionet CHEBI:63581 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0018378 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0521839 infores:hetionet NCBIGene:81693 biolink:causes MONDO:0100157 infores:monarchinitiative not_provided not_provided HGNC:14604 MONDO:0100157 uuid:02b0bfc6-c773-4469-afa0-fbf13779751e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7986 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0020649 infores:hetionet CHEBI:2687 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C1368065 infores:hetionet NCBIGene:10459 biolink:causes MONDO:0014985 infores:monarchinitiative not_provided not_provided HGNC:6764 MONDO:0014985 uuid:4af4fbf5-bb0f-4c97-8e7b-8e2f70be8b98 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0013609 infores:hetionet CAID:CA10385189 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385189 MONDO:0100437 PMID: Benign BP3, BA1 BP5 NM_001034853.2(RPGR):c.3108_3122del (p.Glu1037_Glu1041del) is an in-frame deletion of 15 base pairs encoding amino acids 1037 through 1041. This deletion occurs within a low-complexity region that extends approximately from amino acids 728 through 1084 in RPGR (BP3). This variant is present in gnomAD v.4.1.0 at a frequency of 0.0007471 among hemizygous individuals, with 288 variant alleles / 385,485 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in one female proband harboring other disease-causing variants found (PMIDs: 27620828). However, the BP5 code is considered not applicable for RPGR-related retinopathy. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385189/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true NCBIGene:4591 biolink:causes MONDO:0009664 infores:monarchinitiative not_provided not_provided HGNC:7523 MONDO:0009664 uuid:4aae1332-aaf0-4a14-865b-6486e8042c5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:2N4O9L084N biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0042023 infores:hetionet CAID:CA132675 biolink:causes MONDO:0010134 infores:clingen CAID:CA132675 MONDO:0010134 PMID: Likely Pathogenic PP3, PP4, PM3_Strong BP5, BP7, BS1, BS4, BS2, PP2, PP1, PM5, PM1, PM4, PVS1, PM2, PM6, BP1, BP4, BP2, BP3, BA1, PS1, PS4, PS2 The c.1708G>A variant in SLC26A4 is a missense variant predicted to cause the substitution of valine by isoleucine at amino acid 570 (p.Val570Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computations predictor REVEL gives a score of 0.547, which is neither above nor below the thresholds predicting a damaging or benign impact on SLC26A4 function. This variant is located at the first nucleotide of the exon and is heavily conserved in UCSC. Splice prediction analysis using MaxEntScan suggests an impact on splicing from the loss of the 3' consensus splice sequence (PP3). The c.1708G>A (p.Val570Ile) variant in SLC26A4 has also been detected in 3 different patients with hearing loss and the variant was found in trans with the pathogenic variant p.Leu117Phe.This variant has been detected in at least 3 individuals with Pendred syndrome. All of these individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (3 PM3 points, PMID: 34170635, SCV000060111.6) (PM3_Strong). At least two probands with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PMID: 34170635, SCV000060111.6) (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132675/MONDO:0010134/005 2022-10-31 2023-01-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:681569 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C2830004 infores:hetionet CHEBI:78543 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0020456 infores:hetionet NCBIGene:81570 biolink:causes MONDO:0014561 infores:monarchinitiative not_provided not_provided HGNC:30664 MONDO:0014561 uuid:3fa81949-8972-4c36-9f96-e73e4648cd80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399803370 biolink:causes MONDO:0100326 infores:clingen CAID:CA399803370 MONDO:0100326 PMID:19734576 Likely Pathogenic PP4_Moderate, PS3_Moderate, PM2_Supporting, PM3_Supporting PP3 The NM_000419.5(ITGA2B):c.1429G>C (p.Ala477Pro) missense variant was detected in a patient with GT (PMID 15946231) with epistaxis, gingival bleeding, and purpura. This variant is absent from the gnomAD database v2.1.1 (PM2_Supporting). This variant was detected in the homozygous state in a patient with GT (PMID 15946231; PM3_supporting). Transfected CHO cells were used to measure the surface expression of normal and mutant αIIbβ3 receptors was performed using MoAb SZ22; only 14% expression was noted (PS3_Moderate). This variant was identified in a patient (PMID 15946231) with recurrent epistaxis, gingival hemorrhage, and purpura. They demonstrated a normal platelet count, prolonged bleeding time, and absence of platelet aggregation in response to adenosine diphosphate (ADP), epinephrine, and collagen; he had a normal response to ristocetin and decreased αIIbβ3 expression (PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Moderate, PS3_Moderate, PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399803370/MONDO:0100326/011 2023-05-16 2023-05-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:50173 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0234632 infores:hetionet CHEBI:421707 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0024312 infores:hetionet CHEBI:63635 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0026858 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0034063 infores:hetionet CHEBI:7823 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0021167 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0037822 infores:hetionet CHEBI:51230 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0423153 infores:hetionet CHEBI:16469 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0027424 infores:hetionet CHEBI:92712 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0687713 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0016397 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0016397 infores:hetionet CHEBI:63624 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0267792 infores:hetionet CHEBI:101278 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0497156 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018824 infores:hetionet CHEBI:7476 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151315 infores:hetionet CAID:CA273109 biolink:causes MONDO:0009861 infores:clingen CAID:CA273109 MONDO:0009861 PMID:21147011PMID:19292873PMID:8659548PMID:8632937PMID:21147011PMID:19292873 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA273109/MONDO:0009861/006 2018-10-01 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63791 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0008031 infores:hetionet CHEBI:5088 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01148 UMLS:C0030252 infores:hetionet GO:0010081 biolink:causes GO:0010229 infores:ubergraph knowledge_assertion manual_agent GO:0010081 GO:0010229 CHEBI:3441 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011606 infores:hetionet CHEBI:31623 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0234894 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011206 infores:hetionet CHEBI:37941 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0030554 infores:hetionet CHEBI:63629 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042963 infores:hetionet CHEBI:5855 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1527344 infores:hetionet CHEBI:8024 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0232461 infores:hetionet CHEBI:18358 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C2047937 infores:hetionet CHEBI:47381 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0007859 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0004096 infores:hetionet CHEBI:3011 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0011603 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0006325 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020542 infores:hetionet CHEBI:7865 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0855775 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020615 infores:hetionet CHEBI:50924 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0476273 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0232492 infores:hetionet CHEBI:7773 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0239571 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0021400 infores:hetionet CHEBI:119915 biolink:causes EFO:0020923 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151821 infores:hetionet CHEBI:87681 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0151539 infores:hetionet UMLS:C0145867 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0151529 infores:hetionet CHEBI:681848 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C3203358 infores:hetionet CHEBI:109549 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0003862 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0041912 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0426732 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0242350 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021040 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0030297 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0151849 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0011053 infores:hetionet NCBIGene:7253 biolink:causes MONDO:0011309 infores:monarchinitiative not_provided not_provided HGNC:12373 MONDO:0011309 uuid:5f23c39b-ded7-48bc-9797-813353c95d4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17688 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0040128 infores:hetionet CHEBI:7640 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0429097 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0009450 infores:hetionet CHEBI:63616 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0428974 infores:hetionet CHEBI:63620 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085631 infores:hetionet CHEBI:171719 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042790 infores:hetionet CHEBI:7573 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0011991 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0227791 infores:hetionet CHEBI:51450 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0008031 infores:hetionet CHEBI:3510 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0015967 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0917801 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0234215 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018021 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0018802 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0007117 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0042109 infores:hetionet CHEBI:10124 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0042510 infores:hetionet CHEBI:27899 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0042075 infores:hetionet CHEBI:46557 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0023530 infores:hetionet CHEBI:3228 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0028084 infores:hetionet CHEBI:51450 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0014742 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0151763 infores:hetionet CHEBI:127780 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C2830004 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0006840 infores:hetionet CHEBI:9434 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0000731 infores:hetionet NCBIGene:57096 biolink:causes MONDO:0013446 infores:monarchinitiative not_provided not_provided HGNC:13436 MONDO:0013446 uuid:9c075abf-034e-4dd5-9b50-6cf42f0e0165 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412379067 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379067 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3, PP4 PS4 NM_000330.4(RS1):c.35T>C (p.Leu12Pro) is a missense variant encoding the substitution of leucine with proline at amino acid 12. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.701, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 30652005, PMID: 36165991, PP4). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP4, and PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379067/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:6532 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0000729 infores:hetionet CHEBI:3312 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0009806 infores:hetionet CHEBI:8764 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031256 infores:hetionet CHEBI:27899 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0235031 infores:hetionet CHEBI:37941 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0002994 infores:hetionet CHEBI:6950 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2937350 infores:hetionet CHEBI:3219 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0037317 infores:hetionet CHEBI:168396 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1145670 infores:hetionet CAID:CA913187307 biolink:causes MONDO:0008723 infores:clingen CAID:CA913187307 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS1 The c.335dup (p.Phe113LeufsTer11) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs  9973285, 11590124). The variant, to our knowledge, is not reported in the medical literature. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA913187307/MONDO:0008723/021 2023-02-13 2023-02-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63638 biolink:causes MONDO:0003608 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0029124 infores:hetionet CHEBI:41879 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0026946 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0013595 infores:hetionet CHEBI:8869 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0017152 infores:hetionet CHEBI:421707 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0030193 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0917801 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0022660 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0948594 infores:hetionet CHEBI:6128 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0232943 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0854113 infores:hetionet CHEBI:63681 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0004093 infores:hetionet CHEBI:490877 biolink:causes MONDO:0005080 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0020541 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002170 infores:hetionet CHEBI:5106 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0232461 infores:hetionet CAID:CA658824418 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824418 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1 The NM_001754.4:c.501del (p.Ser167fs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported in patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge; however one unpublished proband meeting at least one of the RUNX1 phenotype criteria is noted (PS4_Supporting; SCV000807785.1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting, PS4_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824418/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7444 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0020557 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0002957 infores:hetionet CHEBI:76010 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0267792 infores:hetionet NCBIGene:78987 biolink:causes MONDO:0011650 infores:monarchinitiative not_provided not_provided HGNC:14630 MONDO:0011650 uuid:a10aacb0-d6dd-4a26-9c79-c5357f16d2b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C2047937 infores:hetionet CHEBI:63610 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0015230 infores:hetionet CHEBI:64198 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06782 UMLS:C0000737 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0549493 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0234458 infores:hetionet CHEBI:3723 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085932 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0002453 infores:hetionet CHEBI:7494 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0233794 infores:hetionet CHEBI:135925 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C3665347 infores:hetionet CHEBI:3084 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0036104 infores:hetionet CHEBI:39867 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1443060 infores:hetionet CHEBI:6809 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01577 UMLS:C0232459 infores:hetionet CAID:CA10585410 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585410 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS1, PM2, PP3, PP4 The NM_000527.5(LDLR):c.1329G>T (p.Trp443Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0000006841 (0.00006841%) in European (non-Finnish) exomes (gnomAD v4.1.0).PP3: REVEL = 0.961.PS1: 1 missense variant that leads to the same amino acid change- NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant (ClinVar ID 251792), classified as Pathogenic by these guidelines.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (2 cases from Robarts Research Institute, Canada; 1 case from PMID 11810272- Fouchier et al., 2001, The Netherlands). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585410/MONDO:0007750/013 2025-01-31 2025-02-03 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:18258 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00279 UMLS:C0231530 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0012833 infores:hetionet CHEBI:7903 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0595916 infores:hetionet CAID:CA286508 biolink:causes MONDO:0009861 infores:clingen CAID:CA286508 MONDO:0009861 PMID:26666653PMID:21462123PMID:26503515PMID:26666653 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PM5 The c.812A>G (p.His271Arg) variant in the PAH gene has been reported in PKU patients in Henan, and France. Dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were collected for the Chinese patient. (PMID: 21462123, 26666653, 26503515). This variant was detected with R408W (PMID: 26666653). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.969. It has an extremely low frequency in ExAC and gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286508/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50692 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0043352 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0037199 infores:hetionet CAID:CA037362 biolink:causes MONDO:0007750 infores:clingen CAID:CA037362 MONDO:0007750 PMID: Pathogenic PS4, PM3, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1898G>A (p.Arg633His) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PP3, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows: PM2: PopMax MAF = 0.0001 (0.01%) in Ashkenazi Jewish exomes/genomes (gnomAD version 2.1.1).PP3: REVEL= 0.901.PS4, PP4: Variant meets PM2 and is identified in at least 10 unrelated index cases who fulfill criteria for FH (Simon-Broome criteria or with DLCN score >=6) from different labs (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; PMID 16250003 (Fouchier et al., 2005), The Netherlands; PMID 33668494 (Sabatel-Pérez et al., 2021), Spain; PMID 33418990 (Meshkov et al., 2021), Russia), after alternative causes of high cholesterol were excluded.PM3: Compound heterozygote reported in PMID 27784735 (Sánchez-Hernández et al., 2016), diagnosed using HoFH clinical criteria, with ex17/18 deletion confirmed in trans. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037362/MONDO:0007750/013 2023-11-07 2025-08-26 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:53760 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085632 infores:hetionet CHEBI:9448 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C2047937 infores:hetionet CHEBI:520985 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0002792 infores:hetionet CAID:CA405662842 biolink:causes MONDO:0007783 infores:clingen CAID:CA405662842 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PS2_Moderate, PP3_Moderate, BS3_Supporting PM1, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 3983 of the RYR1 protein, p.(Arg3983Cys). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:21918424). In one individual the variant was determined to be de novo with confirmed parentage, PS2_Moderate (PMID:21918424). Functional studies in HEK293 cells have not shown a significant increase in sensitivity to RYR1 agonists BS3_Supporting (PMID:21918424). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.931) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS2_Moderate, PS4_Supporting, PP3_Moderate, BS3_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405662842/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63631 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0554976 infores:hetionet UNII:7662KG2R6K biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0012833 infores:hetionet CHEBI:51450 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0581912 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0003811 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001221 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0014867 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0233494 infores:hetionet CHEBI:5132 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0013491 infores:hetionet CHEBI:17688 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0858635 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0549493 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0549493 infores:hetionet CHEBI:18248 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0560024 infores:hetionet CAID:CA343722912 biolink:causes MONDO:0005338 infores:clingen CAID:CA343722912 MONDO:0005338 PMID:10545602 Uncertain Significance PM2_Supporting, BS3_Supporting BS1, BP7, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1, BP4 The c.1483G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 495 (p.Val495Ile). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.424, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Val495Ile protein had similar solubility levels compared to wild type myocilin protein in this study (PMID: 10545602). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS3_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343722912/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7789 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0002792 infores:hetionet CHEBI:31199 biolink:causes MONDO:0002922 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0034212 infores:hetionet CHEBI:135361 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C2364111 infores:hetionet CHEBI:2453 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0241057 infores:hetionet CHEBI:5165 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0038990 infores:hetionet CHEBI:6847 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0004093 infores:hetionet CHEBI:101085 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0152169 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0877661 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0877661 infores:hetionet CHEBI:4469 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0002792 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0009938 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1321686 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1321686 infores:hetionet CHEBI:6129 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1368065 infores:hetionet CHEBI:8776 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0041834 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042514 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0241742 infores:hetionet NCBIGene:8449 biolink:causes MONDO:0032890 infores:monarchinitiative not_provided not_provided HGNC:2739 MONDO:0032890 uuid:d7865ab0-9401-49d3-9436-c46077f55838 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0004609 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0030232 infores:hetionet CHEBI:63605 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0042029 infores:hetionet CAID:CA9870403 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870403 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PM5 The c.882G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to histidine at codon 294 (p.(Gln294His)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.851, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Other missense variants at this same codon, c.881A>C p.(Gln294Pro) and c.881A>G p.(Gln294Arg), have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.882G>C meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870403/MONDO:0015967/085 2025-04-08 2025-06-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15765 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0042075 infores:hetionet CHEBI:7496 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0014742 infores:hetionet CHEBI:8707 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151908 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151785 infores:hetionet CHEBI:63581 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C2242996 infores:hetionet CHEBI:28915 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0011603 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0016204 infores:hetionet CHEBI:2704 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0595929 infores:hetionet CHEBI:585948 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0042401 infores:hetionet CAID:CA915940891 biolink:causes MONDO:0010602 infores:clingen CAID:CA915940891 MONDO:0010602 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The c.1701del (p.Ile567MetfsTer12) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 11/26 and expected to result in nonsense-mediated mRNA decay, which meets PVS1 criteria. This variant is completely absent from males in gnomAD v2.1.1 and gnomAD v3 meeting PM2_Supporting criteria. There is one patient from a research cohort with hemophilia A who carries the Ile567MetfsTer12 variant (internal VCEP contributor). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Supporting, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940891/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:9137 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151539 infores:hetionet CHEBI:3441 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0019080 infores:hetionet CHEBI:681569 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0008350 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0037290 infores:hetionet CHEBI:7640 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0028643 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004681 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0023186 infores:hetionet CHEBI:50673 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0040034 infores:hetionet CAID:CA128831 biolink:causes MONDO:0044970 infores:clingen CAID:CA128831 MONDO:0044970 PMID:21060018 Uncertain Significance PP3, PM2_Supporting, PS4_Supporting, PM6_Supporting, PS3_Supporting The m.586G>A variant in MT-TF has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 21060018, 31463198). One individual was a 57-year-old woman with hearing loss onset in her mid 40s that progressed to profound hearing loss in her 50s, myopathy and progressive exercise intolerance with reduced mobility and falls onset in her late 40s, and spasticity, facial grimacing, dementia, and psychiatric manifestations in her mid 50s (PMID: 21060018). Brain imaging showed generalized cerebral, cerebellar, and brainstem atrophy. Cerebrospinal fluid lactate was elevated. Muscle biopsy showed ragged red fibers and COX-deficient fibers. The variant was present in muscle at 85% heteroplasmy, urinary epithelia at 29%, and blood at 3%. Her mother had died however DNA from paraffin-embedded breast tissue was obtained and revealed the variant at 13% heteroplasmy. The other individual was a 14-year-old boy with exercise intolerance and muscle weakness that followed a stable course (PMID: 31463198). Brain imaging was normal. Lactate was elevated in blood. Muscle biopsy showed ragged red fibers, COX-negative fibers, and mitochondrial respiratory chain complexes I, III, and IV deficiency. The variant was present at >90% in muscle, 40% in urinary epithelia, and was present at trace levels in blood. The variant was undetectable in his mother’s blood and urinary epithelia (PM6_supporting; PMID: 31463198). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (89.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (99.4±0.2%, n=11) than in COX-positive fibers (72.1±8.5%, n=9; p<0.001; PS3_supporting, PMID: 21060018). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PP3, PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA128831/MONDO:0044970/015 2024-06-10 2024-12-06 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:100241 biolink:causes NCIT:C185671 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151577 infores:hetionet CHEBI:10023 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013428 infores:hetionet CHEBI:499361 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0575081 infores:hetionet CHEBI:5130 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0232487 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030305 infores:hetionet GO:1904451 biolink:causes GO:0071805 infores:ubergraph knowledge_assertion manual_agent GO:1904451 GO:0071805 CHEBI:64321 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C2047937 infores:hetionet CHEBI:5098 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0042963 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0019348 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0012797 infores:hetionet CHEBI:3655 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C2047937 infores:hetionet CHEBI:8430 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0003862 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0034882 infores:hetionet CHEBI:4995 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0016204 infores:hetionet CHEBI:17263 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0037763 infores:hetionet CHEBI:2639 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0030196 infores:hetionet CHEBI:50729 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0011603 infores:hetionet CHEBI:50924 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0017178 infores:hetionet CHEBI:4784 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0040822 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003397 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0017567 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C1384666 infores:hetionet CHEBI:6709 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00737 UMLS:C0043352 infores:hetionet CHEBI:8207 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0344232 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0042109 infores:hetionet CHEBI:7443 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0017675 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042514 infores:hetionet CHEBI:5613 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0392676 infores:hetionet CAID:CA10014288 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014288 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.822A>T (p.Gln274His) is a missense variant which has a REVEL score < 0.50 (0.401) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014288/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:32315 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0037672 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0029456 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0042401 infores:hetionet CHEBI:17141 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0042963 infores:hetionet CHEBI:6367 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0010200 infores:hetionet CHEBI:42797 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0039231 infores:hetionet CHEBI:8802 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C1258215 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0019360 infores:hetionet CAID:CA638053818 biolink:causes MONDO:0011071 infores:clingen CAID:CA638053818 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.968-9G>T is an intronic variant. SpliceAI predicts no impact on splicing (score: 0.01), supporting BP4. Additionally, evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score of -4.717 (≤ 2.0), supporting BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638053818/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8069 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0151735 infores:hetionet CHEBI:51860 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085631 infores:hetionet CHEBI:6933 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0041969 infores:hetionet CAID:CA118655 biolink:causes MONDO:0018947 infores:clingen CAID:CA118655 MONDO:0018947 PMID: Pathogenic PS4, PP1_Strong, PM6, PP2, PP3, PM2_Supporting The c.1106 G>A (NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)) variant in DNM2 is a missense variant predicted to cause substitution of Arg by Gln at amino acid 369. The variant was found in at least 16 individuals from 2 families, all with centronuclear myopathy (PS4; PMIDs: 16227997, 26908122). The mutation segregated in 14 affected family members from 2 families (PP1_strong; PMIDs: 16227997, 26908122). This variant has been identified as a de novo occurrence with an unconfirmed parental relationship in 1 individual with centronuclear myopathy (PM6; PMID: 16227997). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.7, (rounded from 0.698), which meets the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: (PS4, PP1_strong, PM6, PM2_supporting, PP3, PP2; Version 1, 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA118655/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3127 biolink:causes MONDO:0004634 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235522 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0424000 infores:hetionet CHEBI:135276 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0009676 infores:hetionet CHEBI:79699 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0085593 infores:hetionet CHEBI:10119 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C2979982 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0037199 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0235360 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0235360 infores:hetionet CHEBI:71940 biolink:causes MONDO:0020677 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0011057 infores:hetionet CHEBI:9571 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0344232 infores:hetionet CHEBI:6888 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0040038 infores:hetionet CHEBI:7903 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0015967 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0025061 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0020649 infores:hetionet CHEBI:3699 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0242350 infores:hetionet CHEBI:63580 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002792 infores:hetionet CHEBI:64317 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0006266 infores:hetionet CHEBI:63611 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030252 infores:hetionet CHEBI:4710 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0917801 infores:hetionet CHEBI:116278 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0002792 infores:hetionet NCBIGene:51422 biolink:causes MONDO:0010946 infores:monarchinitiative not_provided not_provided HGNC:9386 MONDO:0010946 uuid:2b333936-349c-4ffe-8c1e-01a391413c4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0014868 infores:hetionet CHEBI:6965 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0043352 infores:hetionet CHEBI:47898 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0340865 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0858775 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0858775 infores:hetionet CHEBI:205919 biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0234222 infores:hetionet CHEBI:10023 biolink:causes UMLS:C2609264 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2609264 infores:hetionet CHEBI:50924 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151908 infores:hetionet CHEBI:17026 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0017178 infores:hetionet CHEBI:9150 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0004093 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031542 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0236071 infores:hetionet CHEBI:46557 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0030332 infores:hetionet CHEBI:3568 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085932 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0853813 infores:hetionet NCBIGene:23116 biolink:causes MONDO:0030933 infores:monarchinitiative not_provided not_provided HGNC:19959 MONDO:0030933 uuid:221c37b6-f5c2-4f90-a44f-4e0426eba21d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229356 biolink:causes MONDO:0009861 infores:clingen CAID:CA229356 MONDO:0009861 PMID:9450182 Pathogenic PVS1, PM2, PP4 The c.1129delT (p.Tyr377Thrfs) variant in PAH has been reported in an Icelandic PKU cohort. (PP4; PMID: 9450182). This variant is absent from gnomAD (PM2). It is a frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229356/MONDO:0009861/006 2020-06-26 2020-06-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5790 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0085632 infores:hetionet CHEBI:50885 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0033845 infores:hetionet CHEBI:8382 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0010481 infores:hetionet CHEBI:29007 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0024282 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0151773 infores:hetionet CHEBI:85078 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0020625 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0015663 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0003123 infores:hetionet CHEBI:142290 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0004093 infores:hetionet NCBIGene:64327 biolink:causes MONDO:0017454 infores:monarchinitiative not_provided not_provided HGNC:13243 MONDO:0017454 uuid:7aa6b267-8ee0-4fbc-943d-0127816615b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0151514 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085606 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027051 infores:hetionet CHEBI:7822 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0917801 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0014549 infores:hetionet CHEBI:7496 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0002871 infores:hetionet CHEBI:171719 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0036974 infores:hetionet CHEBI:68610 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0009450 infores:hetionet CHEBI:74947 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C2047937 infores:hetionet CHEBI:681569 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0741494 infores:hetionet CAID:CA060921 biolink:causes MONDO:0018493 infores:clingen CAID:CA060921 MONDO:0018493 PMID: Likely Benign PM1_Supporting, BS2_Supporting PP3, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 4723 of the RYR1 protein, p.(Arg4723His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000325, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant was also identified in a relative with negative IVCT/CHCT results, BS2_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.79 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PM1_Supporting, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA060921/MONDO:0018493/012 2021-05-31 2021-05-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7824 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0021177 infores:hetionet CHEBI:167309 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C1260880 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005159 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0600139 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020649 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0027051 infores:hetionet CHEBI:7789 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0042109 infores:hetionet NCBIGene:79133 biolink:causes MONDO:0032621 infores:monarchinitiative not_provided not_provided HGNC:15899 MONDO:0032621 uuid:3d2649ca-8a7f-409f-9b61-a451cc9690f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4897 biolink:causes MONDO:0859236 infores:monarchinitiative not_provided not_provided HGNC:7994 MONDO:0859236 uuid:d73c92ea-2084-4107-971f-2dcd5162eb3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0013456 infores:hetionet CHEBI:83804 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0017979 infores:hetionet CHEBI:9763 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0340865 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0032285 infores:hetionet NCBIGene:63895 biolink:causes MONDO:0009564 infores:monarchinitiative not_provided not_provided HGNC:26270 MONDO:0009564 uuid:e07d9345-c5ae-4225-adb0-da18ea0b66e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:2719 biolink:causes MONDO:0020602 infores:monarchinitiative not_provided not_provided HGNC:4451 MONDO:0020602 uuid:05836740-f257-4218-8e50-ffd0c0e447fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61033 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0006277 infores:hetionet CHEBI:9123 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0025874 infores:hetionet CHEBI:5127 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0151514 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0521839 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0010692 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0009443 infores:hetionet GO:1905079 biolink:causes GO:0060322 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0060322 CHEBI:3510 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0518015 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0000833 infores:hetionet CAID:CA000559 biolink:causes MONDO:0017623 infores:clingen CAID:CA000559 MONDO:0017623 PMID: Pathogenic PM2, PS2_Very Strong, PP2, PS4 PTEN c.737C>T (p.P246L) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 23934111, internal laboratory contributor(s) SCV000222227.10)PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10)PM2: Absent in large sequenced populations. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000559/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:72296 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0042075 infores:hetionet CHEBI:4702 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0009676 infores:hetionet CHEBI:75998 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0018799 infores:hetionet CHEBI:6775 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0004509 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0948715 infores:hetionet CHEBI:3485 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0009763 infores:hetionet CHEBI:6456 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0013404 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0034150 infores:hetionet CHEBI:2654 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0023530 infores:hetionet CHEBI:135342 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151786 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0021053 infores:hetionet CHEBI:2453 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0030193 infores:hetionet CHEBI:3723 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011124 infores:hetionet CHEBI:10023 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0000731 infores:hetionet NCBITaxon:1496 biolink:causes MONDO:0024388 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1496 MESH:D003015 DB08874_MESH_D003015_1DB13140_MESH_D003015_1 CHEBI:61390 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0017178 infores:hetionet CHEBI:10110 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0038002 infores:hetionet CHEBI:51860 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0036830 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0001824 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0018799 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0041969 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0042401 infores:hetionet NCBIGene:767 biolink:causes MONDO:0013188 infores:monarchinitiative not_provided not_provided HGNC:1382 MONDO:0013188 uuid:a6434f5d-74f5-4c33-8e16-12c4849cc761 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16914 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0023380 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0031350 infores:hetionet CHEBI:49575 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0033774 infores:hetionet CHEBI:3814 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C1291077 infores:hetionet CHEBI:9073 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0009676 infores:hetionet CHEBI:6062 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0028084 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0030193 infores:hetionet CAID:CA10585439 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585439 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 The NM_000527.5(LDLR):c.1403T>A (p.Val468Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.823PP4 - Variant meet PM2. PMID: 20828696 (Medeiros et al., 2010), 1 case who fulfills Simon-Broome criteria for FH, after alternative causes of high cholesterol have been excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585439/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:92712 biolink:causes MONDO:0006527 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0003028 infores:hetionet CAID:CA645369474 biolink:causes MONDO:0017623 infores:clingen CAID:CA645369474 MONDO:0017623 PMID: Likely Pathogenic PVS1, PM2_Supporting PM6, BP7, BP5, BS1, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM4, PM1, PM3, PM5, BP4, BP1, BP3, BP2, BA1, PS3, PS4, PS2, PS1 NM_000314.8(PTEN):c.270dup (p.Glu91Ter) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.8). PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort (PMID:27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369474/MONDO:0017623/003 2023-06-14 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:3425 biolink:causes MONDO:0011759 infores:monarchinitiative not_provided not_provided HGNC:5391 MONDO:0011759 uuid:ed7df2da-3f0e-49f9-9709-eb08cc837729 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:22978 biolink:causes MONDO:0013165 infores:monarchinitiative not_provided not_provided HGNC:8022 MONDO:0013165 uuid:d6a3507b-d380-4f8c-935a-4e651e36dd0c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0025234 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0030508 infores:hetionet CHEBI:3723 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0004134 infores:hetionet CHEBI:50673 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0042109 infores:hetionet CHEBI:10125 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151827 infores:hetionet CHEBI:28748 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011168 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0340464 infores:hetionet NCBIGene:1041 biolink:causes MONDO:0007805 infores:monarchinitiative not_provided not_provided HGNC:1802 MONDO:0007805 uuid:a09565f6-8338-44c2-8d7f-ab861f061b43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2654 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0002871 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0009450 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0086543 infores:hetionet CHEBI:47781 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0042023 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0265031 infores:hetionet CHEBI:75722 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085632 infores:hetionet CHEBI:63621 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0236000 infores:hetionet CHEBI:9763 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0086565 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0235416 infores:hetionet CHEBI:8499 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0030193 infores:hetionet CHEBI:63681 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0014742 infores:hetionet CHEBI:63637 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0030196 infores:hetionet CHEBI:50173 biolink:causes HP:0000963 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0423757 infores:hetionet CHEBI:473990 biolink:causes UMLS:C2609199 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C2609199 infores:hetionet CHEBI:5134 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0011615 infores:hetionet CHEBI:3696 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0575081 infores:hetionet CHEBI:50922 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0014591 infores:hetionet CHEBI:15551 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0036973 infores:hetionet CHEBI:55346 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0041834 infores:hetionet CHEBI:465284 biolink:causes UMLS:C2747852 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C2747852 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0836924 infores:hetionet CHEBI:6078 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0232492 infores:hetionet CHEBI:46345 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0030193 infores:hetionet CHEBI:8346 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0038999 infores:hetionet CHEBI:8428 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0085605 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0015663 infores:hetionet CHEBI:61049 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151662 infores:hetionet CHEBI:2788 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0003811 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235818 infores:hetionet CHEBI:135791 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0033774 infores:hetionet CHEBI:6149 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0025287 infores:hetionet CHEBI:8871 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085649 infores:hetionet NCBITaxon:263 biolink:causes MONDO:0018077 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:263 MESH:D014406 DB01082_MESH_D014406_1DB02703_MESH_D014406_1DB01017_MESH_D014406_1DB00254_MESH_D014406_1 CHEBI:8768 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0011603 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0016382 infores:hetionet CHEBI:2663 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0013595 infores:hetionet NCBIGene:51126 biolink:causes MONDO:0030533 infores:monarchinitiative not_provided not_provided HGNC:15908 MONDO:0030533 uuid:5890770a-f7fe-497d-8aab-8b4090d9a3e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:472657 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0011991 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0001824 infores:hetionet UNII:2N4O9L084N biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0028084 infores:hetionet CHEBI:142290 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0878544 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0349506 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0034150 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0015408 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015408 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019348 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0040261 infores:hetionet CAID:CA412379051 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379051 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000330.4(RS1):c.37C>G (p.Leu13Val) is a missense variant encoding the substitution of leucine with valine at amino acid 13. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.475, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of <0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379051/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance HP:0001417 Inconclusive true CHEBI:100246 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0235146 infores:hetionet CAID:CA410148335 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148335 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP4, BP3, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM3, PM1, PM5, PM4, BS2, PP2, PP3, PP1, PP4 The 1049C>T (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 350 (p.P350L). This variant is absent from gnomAD v2 and v3 (PM2_Supporting). It also has not been reported in patients with the RUNX1-defined phenotype. The computational predictor REVEL gives a score of 0.577, which is neither below the BP4 threshold of 0.50 or above the PP3 threshold of 0.88, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148335/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7565 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0003123 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0518015 infores:hetionet CAID:CA658760344 biolink:causes MONDO:0007113 infores:clingen CAID:CA658760344 MONDO:0007113 PMID: Uncertain Significance PP3, PP1, PS4_Supporting, PM2_Supporting The c.1549-8A>G variant in UBE3A (NM_130838.2) is absent from gnomAD v4.1 (PM2_Supporting). The c.1549-8A>G variant has been observed in at least 2 individuals with Angelman syndrome (PMID 8988171, Internal database – Ambry) (PS4_Supporting). The variant has been reported to segregate in two informative meioses (PMID 8988171) (PP1). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). In summary, the c.1549-8A>G variant in UBE3A is classified as a variant of unknown significance based on the ACMG/AMP criteria (PS4_Supporting, PM2_Supporting, PP1, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760344/MONDO:0007113/037 2024-06-25 2024-10-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5141 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0003460 infores:hetionet CHEBI:28787 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0235710 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0948226 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0162429 infores:hetionet CHEBI:47781 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0018794 infores:hetionet CHEBI:8245 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0012833 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0021053 infores:hetionet CHEBI:63617 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1443060 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0267792 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020649 infores:hetionet CHEBI:9123 biolink:causes MONDO:0018902 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0206669 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0023895 infores:hetionet CAID:CA410149625 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149625 MONDO:0011071 PMID: Uncertain Significance BP4, PM2 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.935C>A (p.Thr312Asn) is a missense variant which is not present in population databases (gnomAD v2.1 or v3.1.2) (PM2_supporting). This missense variant has a REVEL score ≤0.50 (0.064) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149625/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0547030 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0234215 infores:hetionet CHEBI:63611 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011175 infores:hetionet CHEBI:75722 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0003862 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0027765 infores:hetionet CHEBI:44423 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0018524 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0518988 infores:hetionet GO:0070587 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:0070587 GO:0007369 CHEBI:6741 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C3665347 infores:hetionet NCBIGene:4882 biolink:causes MONDO:0014551 infores:monarchinitiative not_provided not_provided HGNC:7944 MONDO:0014551 uuid:c684559d-af63-49f7-b828-79ee1d92a212 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135679 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0004093 infores:hetionet GO:0060575 biolink:causes CL:0002563 infores:ubergraph knowledge_assertion manual_agent GO:0060575 CL:0002563 CHEBI:3647 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0010200 infores:hetionet CHEBI:7476 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0037286 infores:hetionet CHEBI:53760 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0037036 infores:hetionet CHEBI:3441 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042024 infores:hetionet NCBITaxon:519 biolink:causes MONDO:0001353 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:519 MONDO:0001353 CHEBI:4027 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0041834 infores:hetionet CHEBI:8207 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020433 infores:hetionet CHEBI:51041 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0030332 infores:hetionet NCBIGene:6786 biolink:causes MONDO:0024531 infores:monarchinitiative not_provided not_provided HGNC:11386 MONDO:0024531 uuid:360c2aec-cc39-4627-a7f9-e5ae54ad8de4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:110423 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0028961 infores:hetionet CAID:CA025372 biolink:causes MONDO:0012933 infores:clingen CAID:CA025372 MONDO:0012933 PMID: Pathogenic PVS1, PP4_Strong PM2, BS1, BA1 The c.7977-1G>C variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 17 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1921581780 (based on Cosegregation LR=1984740; Pathology LR=10.2; Family History LR=94.9), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025372/MONDO:0012933/097 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3510 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0030312 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0023067 infores:hetionet CHEBI:9123 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235198 infores:hetionet CHEBI:31547 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0016382 infores:hetionet CHEBI:7986 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0018681 infores:hetionet CAID:CA020507 biolink:causes MONDO:0008667 infores:clingen CAID:CA020507 MONDO:0008667 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PVS1 The NM_000551.3(VHL):c.586A>T (p.Lys196Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 196, which resides in the second Beta domain (PVS1). One proband has been identified with this variant, and has a family history of VHL and clinical features of VHL (CNS hemangioblastoma, renal cell carcinoma in a female of reported age 17 (Hwang et al (PMID:25078357)). One case meeting Danish VHL criteria equates to supporting evidence (PS4_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020507/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4511 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C1257843 infores:hetionet CHEBI:135342 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0438142 infores:hetionet CHEBI:70746 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C1291078 infores:hetionet CHEBI:9332 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0085593 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0233472 infores:hetionet CAID:CA1705618 biolink:causes MONDO:0015152 infores:clingen CAID:CA1705618 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PS1_Moderate, PP3, PP1 PVS1, PM2 The NM_003494.4: c.1053+4A>G variant in DYSF, which is also known as NM_001130987.2: c.1149+4A>G, occurs within the splice donor motif of intron 11. SpliceAI gives a delta score of 0.66 for loss of the donor site (alt score 0.00), which is greater than the threshold of 0.50 (PP3). Skipping of exon 11 is predicted. This variant has been reported in a homozygous state in at least four unrelated patients with clinical features consistent with LGMD, with known consanguinity in one case (1.0 pt; PMID: 30564623, 37564451; LOVD Individuals #00219592, #00219464; ClinVar SCV006074893.1 internal data communication; Jain Foundation Dysferlin Registry internal data communication). It was also reported in unknown phase with a pathogenic variant in a fifth patient (NM_003494.4: c.755C>T p.(Thr252Met), 0.5 pts, Jain Foundation Dysferlin Registry internal data communication) (PM3). At least one patient homozygous for this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle or blood monocytes (ClinVar SCV002168581.4 internal data communication, Jain Foundation Dysferlin Registry internal data communication; PP4_Strong). This variant also co-segregated with autosomal recessive LGMD in one homozygous affected family member (ClinVar SCV002168581.4 internal data communication; PP1). The filtering allele frequency of this variant is 0.0001154 in gnomAD v4.1.0 (the upper bound of the 95% CI of 5/86252 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). At least one other variant affecting the same splice region, NM_003494.4: c.1053+5G>A, is predicted to have the same splice effect as the c.1053+4A>G variant (skipping of exon 11) and is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Moderate). A mini-gene assay also confirmed skipping of exon 11 due to the presence of the c.1053+5G>A variant (PMID: 25312915). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/26/2025): PP3, PM3, PP4_Strong, PP1, PS1_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1705618/MONDO:0015152/180 2025-08-26 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71219 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0267792 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0234215 infores:hetionet CHEBI:4995 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0232462 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0302295 infores:hetionet CHEBI:2948 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0085593 infores:hetionet CHEBI:45081 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0232602 infores:hetionet CHEBI:3215 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0015967 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002603 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0206633 infores:hetionet CHEBI:6904 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0007222 infores:hetionet CHEBI:15765 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0043352 infores:hetionet CHEBI:3127 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C3665347 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0475858 infores:hetionet NCBIGene:6916 biolink:causes MONDO:0009274 infores:monarchinitiative not_provided not_provided HGNC:11609 MONDO:0009274 uuid:2c09f501-1d36-42c9-b504-b893392ddfd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0009450 infores:hetionet CHEBI:40050 biolink:causes UMLS:C2939103 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C2939103 infores:hetionet CHEBI:18357 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0030232 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0013395 infores:hetionet GO:0110073 biolink:causes GO:0010004 infores:ubergraph knowledge_assertion manual_agent GO:0110073 GO:0010004 CHEBI:521033 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0039591 infores:hetionet GO:0062041 biolink:causes GO:0051757 infores:ubergraph knowledge_assertion manual_agent GO:0062041 GO:0051757 CHEBI:31413 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0948525 infores:hetionet CHEBI:49575 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0520966 infores:hetionet CHEBI:63611 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023222 infores:hetionet CHEBI:4798 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020443 infores:hetionet UMLS:C0025241 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0011603 infores:hetionet GO:0060222 biolink:causes GO:0003407 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0003407 NCBIGene:7043 biolink:causes MONDO:0007152 infores:monarchinitiative not_provided not_provided HGNC:11769 MONDO:0007152 uuid:2b57ef74-8629-45bd-89c6-978588d4e3b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0018524 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0021400 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0038454 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0017178 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020538 infores:hetionet CHEBI:5165 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0041657 infores:hetionet CHEBI:63618 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0002962 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0038663 infores:hetionet CHEBI:44185 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0242184 infores:hetionet CHEBI:127342 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0439857 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042571 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020649 infores:hetionet CHEBI:4562 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0085616 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1384666 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0031542 infores:hetionet CHEBI:253342 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1168034 infores:hetionet CHEBI:50777 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0235939 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0011603 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0277925 infores:hetionet CHEBI:8707 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020456 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0014130 infores:hetionet CHEBI:83531 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0020458 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0006145 infores:hetionet CHEBI:3013 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0392176 infores:hetionet CHEBI:6909 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0043352 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1368065 infores:hetionet CHEBI:8356 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0024305 infores:hetionet CHEBI:135005 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0039070 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0012739 infores:hetionet CHEBI:51860 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013491 infores:hetionet CHEBI:6916 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0687713 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0020039 infores:hetionet CHEBI:3127 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C2363731 infores:hetionet CHEBI:6690 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0011253 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002172 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0155428 infores:hetionet CAID:CA10360394 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360394 MONDO:0100039 PMID: Benign BP5, BS1, BS2 PM1, PP3, PM2, BP4, PS4 The allele frequency of the p.Leu522Val variant in CDKL5 is 0.011% in European Non-Finnish sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Additionally, the p.Leu522Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Ambry Genetics) (BS2) and is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Leu522Val variant in CDKL5 is classified as Benign for CDKL5-associated disorder according to ACMG/AMP criteria (BS1, BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360394/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:40009 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00260 UMLS:C0030552 infores:hetionet CHEBI:52010 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0221490 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0424230 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005282 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0024137 infores:hetionet CHEBI:8707 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151825 infores:hetionet CHEBI:31644 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0040822 infores:hetionet NCBIGene:7297 biolink:causes MONDO:0012682 infores:monarchinitiative not_provided not_provided HGNC:12440 MONDO:0012682 uuid:dbef341e-64d3-4c56-94eb-66eeb8180615 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0032326 infores:hetionet CAID:CA229651 biolink:causes MONDO:0009861 infores:clingen CAID:CA229651 MONDO:0009861 PMID:23430918PMID:18321666PMID:18321666 Uncertain Significance PM2, PP4, PP3 PM3 The c.60G>C (p.Q20H) variant has been reported in 1 patient with PKU (not excluding BH4 deficiency), who carried 2 pathogenic variants (p.R158Q, p.R408W) in PAH (PMID: 18321666, PMID: 23430918). This variant is absent from population databases, including 1000 Genomes, ESP, and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.571. In summary, this variant meets our criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229651/MONDO:0009861/006 2019-03-23 2019-08-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA512319081 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319081 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS2, PS3, BP1, BP2, BP3, BA1, PM2, PM6, PVS1, BP5, BS1, BS4, BS3, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 The c.588A>G (p.Thr196=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -3.26187 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The variant also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319081/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27834 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0008031 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0042165 infores:hetionet CAID:CA16020716 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020716 MONDO:0009861 PMID:22513348PMID:22513348 Pathogenic PVS1, PM2, PP4 PM3 The PAH: c.43_44insAG variant is a frameshift variant occurring in exon 1 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). The variant has been reported with the IVS8-2A>G (c.913-2A>G) splice-site variant (PMID: 22513348), a recurrent splice-site variant among Central European PKU cases (see PMID: 23160875) in one Slovenian proband with classic PKU as assessed by plasma Phe levels; BH4 deficiency does not appear to have been formally excluded by biochemical or genetic testing (PP4). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020716/MONDO:0009861/006 2019-08-12 2019-08-12 Autosomal recessive inheritance HP:0000007 Supports UNII:VL0L558GCB biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0522224 infores:hetionet CAID:CA10443771 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443771 MONDO:0010315 PMID: Likely Benign BP7, BS2 BS1, PM2, PP3, BA1 The c.963G>A (p.Leu321=) variant (NM_000206.3) is a synonymous (silent) variant that is not predicted by SpliceAI, varSEAK, and NNSplice. BP7 is met. It occurs at an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0001435 (based on 7/14709 alleles in the East Asian population) which is below the SCID VCEP established threshold of >0.00249. for BS1 and above the PM2 threshold of <0.000124. (BS1 not met, BA1 not met, PM2_Supporting not met). Additionally, three adult hemizygous males with this variant are present in the East Asian population in gnomAD v2.1.1 and one additional in the Other population (BS2).In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443771/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance HP:0001417 Contradicts true CHEBI:63620 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0021053 infores:hetionet CHEBI:9943 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0740394 infores:hetionet CHEBI:9649 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0030252 infores:hetionet CHEBI:36795 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0600142 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0813230 infores:hetionet CHEBI:83527 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0025061 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042401 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0002884 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0234215 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0010399 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0017574 infores:hetionet CHEBI:8764 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0003811 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1868752 infores:hetionet CAID:CA8459205 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459205 MONDO:0011132 PMID: Uncertain Significance BP4 PM5, BS1, PM2 The missense variant NM_001369369.1(FOXN1):c.361G>A (p.Ala121Thr) has a gnomADv2.1.1 popmax filtering allele frequency of 0.00009547 based on the Latino/Admixed American population (7/34284 alleles), which is below the BS1 threshold of >0.00141 but above the PM2 threshold of <0.00002412. The variant has a REVEL score of 0.132, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP4. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459205/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:9150 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0235309 infores:hetionet CHEBI:474053 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0030193 infores:hetionet CHEBI:41977 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0004604 infores:hetionet CHEBI:50730 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0011991 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0024115 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0853761 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005554 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0009326 infores:hetionet CAID:CA8366302 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366302 MONDO:0100453 PMID: Benign BA1, BP4, BS2 The variant NM_000180.4(GUCY2D):c.3044-7G>T is located in intron 16. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.04452, with 52,788 alleles / 1,177,142 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in >6 adult individuals in gnomAD (1363 individuals, gnomAD version 4.1.0; BS2). In addition, the splicing impact predictor SpliceAI gives a delta score of 0.04, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366302/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135929 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0022346 infores:hetionet CHEBI:8364 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0026205 infores:hetionet CHEBI:63620 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0151827 infores:hetionet CHEBI:7959 biolink:causes MONDO:0007529 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0221271 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0018802 infores:hetionet CHEBI:4911 biolink:causes UMLS:C0853777 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0853777 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003038 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234144 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002884 infores:hetionet UMLS:C0879264 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0232462 infores:hetionet CAID:CA512232128 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232128 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1395C>T (p.Asn465=) is a synonymous variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP 1.74357 is <2.0) meeting BP7. The variant is synonymous therefore no REVEL score and SpliceAI is ≤0.20 (0.00)(BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232128/MONDO:0011071/008 2022-04-08 2022-07-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:188986 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0018681 infores:hetionet CHEBI:5441 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0085932 infores:hetionet CHEBI:37941 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0014518 infores:hetionet CHEBI:8412 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0001824 infores:hetionet CHEBI:6950 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085593 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001410 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0221392 infores:hetionet CHEBI:7494 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0002962 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0234215 infores:hetionet UNII:T58MSI464G biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00284 UMLS:C0160390 infores:hetionet CHEBI:61390 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0206062 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0002170 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0149931 infores:hetionet CHEBI:10101 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027796 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0038367 infores:hetionet NCBIGene:55610 biolink:causes MONDO:0859216 infores:monarchinitiative not_provided not_provided HGNC:25956 MONDO:0859216 uuid:e381d529-e797-4d0e-82c3-1c4872f838bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3738 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0162830 infores:hetionet NCBITaxon:565995 biolink:causes MONDO:0005737 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:565995 MONDO:0005737 CHEBI:46295 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151766 infores:hetionet CHEBI:8863 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0039070 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0020517 infores:hetionet CHEBI:63791 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2607914 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0018799 infores:hetionet GO:1904596 biolink:causes GO:0002246 infores:ubergraph knowledge_assertion manual_agent GO:1904596 GO:0002246 CHEBI:75722 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0036572 infores:hetionet CHEBI:251408 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0021167 infores:hetionet CHEBI:2955 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0032227 infores:hetionet CHEBI:7915 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0014518 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0233494 infores:hetionet CAID:CA377482278 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482278 MONDO:0017623 PMID:29706350PMID:21828076 Pathogenic PM2, PP2, PS4_Supporting, PM1, PS3 PTEN c.367C>G (p.His123Asp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 29706350, 21828076)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000580072.3) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482278/MONDO:0017623/003 2019-11-22 2019-12-04 Autosomal dominant inheritance HP:0000006 Supports CHEBI:15552 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0015672 infores:hetionet CHEBI:3175 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0003811 infores:hetionet CHEBI:6801 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0030554 infores:hetionet CAID:CA229638 biolink:causes MONDO:0009861 infores:clingen CAID:CA229638 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4_Moderate, PM3_Strong The c.592_613del (p.Tyr198fs) variant in PAH is a frameshift variant predicted to cause termination at amino acid 334 in exon 10, resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in multiple patients with PAH deficiency with pathogenic variants: c.782G>A (p.Arg261Gln) (PMID: 21890392); c.1222C>T (p.Arg408Trp) (PMID:26481238); c.969+1G>A (IVS9 + 1G>A) (PMID:18321666); c.311C>A (p.A104D), c.755G>A (p.R252Q) (PMID:23942198). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PM3_strong, PP4_moderate, PVS1 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229638/MONDO:0009861/006 2023-03-16 2023-03-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:28593 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C1443060 infores:hetionet CHEBI:5801 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0004134 infores:hetionet CHEBI:4445 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0030252 infores:hetionet CHEBI:8245 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0041657 infores:hetionet CHEBI:28748 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085680 infores:hetionet CHEBI:17026 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C3495440 infores:hetionet CHEBI:50567 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0011991 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0033975 infores:hetionet CHEBI:8764 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0438215 infores:hetionet CHEBI:83804 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0009676 infores:hetionet CHEBI:7936 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0037299 infores:hetionet CHEBI:102216 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0151828 infores:hetionet CHEBI:17334 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0016382 infores:hetionet CHEBI:51041 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0011168 infores:hetionet CHEBI:71223 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0014591 infores:hetionet CHEBI:16480 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0013404 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0948050 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0948050 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0236072 infores:hetionet CAID:CA409108291 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108291 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting, PM1_Supporting PP4 The c.937G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of glycine to arginine at codon 313 (p.(Gly313Arg)) of NM_175914.5. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991 (PP3). This variant is located within the ligand binding of HNF4A, which is critical for the protein’s function (PM1_Supporting). This variant was identified in one individual with diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate. Another missense variant, c.938G>T p.Gly313Val, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.937G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PM1_Supporting, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108291/MONDO:0015967/085 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4657 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0234215 infores:hetionet CHEBI:63791 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0009676 infores:hetionet CHEBI:33325 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0011603 infores:hetionet CHEBI:63581 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0030193 infores:hetionet NCBIGene:2157 biolink:causes MONDO:0859082 infores:monarchinitiative not_provided not_provided HGNC:3546 MONDO:0859082 uuid:bf2e426e-2839-4079-ba99-8030b20fee53 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:73274 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0595883 infores:hetionet CHEBI:77733 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0002994 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0027051 infores:hetionet CHEBI:5280 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1456784 infores:hetionet CHEBI:71028 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0004093 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0028738 infores:hetionet CHEBI:48273 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0020580 infores:hetionet CHEBI:63631 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232495 infores:hetionet CHEBI:64355 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085628 infores:hetionet CHEBI:10650 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0002962 infores:hetionet CAID:CA161490 biolink:causes MONDO:0100283 infores:clingen CAID:CA161490 MONDO:0100283 PMID: Benign BS2, PP2, BA1, PM1_Supporting The c.1173A>G (NM_006218.4) variant in PIK3CA is a missense variant predicted to cause substitution of (p.Ile391Met). This variant resides within the kinase domain of PIK3CA that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 26637981, 24459181, 27631024) (PM1_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.2113 in African/African American population, which is higher than the ClinGen BMEP threshold ([>=0.00185]) for BA1, and therefore meets this criterion (BA1). This variant was identified the homozygous state in >3 individuals within control databases (BS2). PIK3CA, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In summary, this variant meets the criteria to be classified as Benign for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM1_P, BA1, BS2, PP2; -10 points (VCEP specifications version 1; Approved: 1/31/2021) Brain Malformations VCEP https://erepo.genome.network/evrepo/ui/classification/CA161490/MONDO:0100283/018 2022-02-17 2022-02-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/ true CHEBI:9398 biolink:causes NCIT:C26921 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0085594 infores:hetionet CHEBI:15551 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0011991 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0746883 infores:hetionet CHEBI:116278 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151539 infores:hetionet CHEBI:28001 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0039231 infores:hetionet CHEBI:74947 biolink:causes MONDO:0024298 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0376286 infores:hetionet CHEBI:8346 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0037023 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0027051 infores:hetionet CHEBI:261649 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0042109 infores:hetionet CHEBI:136040 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0039240 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0410198 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0410198 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0018939 infores:hetionet CHEBI:17688 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0022107 infores:hetionet CHEBI:4027 biolink:causes MONDO:0012105 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C3495801 infores:hetionet GO:2000015 biolink:causes GO:0048262 infores:ubergraph knowledge_assertion manual_agent GO:2000015 GO:0048262 CHEBI:567361 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0032584 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0004936 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0595930 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0019360 infores:hetionet CHEBI:15940 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0549386 infores:hetionet CHEBI:10101 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0013404 infores:hetionet NCBIGene:3891 biolink:causes MONDO:0011177 infores:monarchinitiative not_provided not_provided HGNC:6462 MONDO:0011177 uuid:a1dd9bc3-3660-43ed-a69e-148769c93953 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:7662KG2R6K biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0023380 infores:hetionet NCBIGene:9095 biolink:causes MONDO:0008720 infores:monarchinitiative not_provided not_provided HGNC:11596 MONDO:0008720 uuid:6e087236-6863-4ba3-81d4-711f074c2919 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes MONDO:0007886 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042133 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0008049 infores:hetionet CHEBI:27882 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0232462 infores:hetionet CAID:CA410203825 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203825 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM1, PM5, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.239A>C (p.Glu80Ala) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203825/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:92998 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0423791 infores:hetionet CHEBI:100246 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0009763 infores:hetionet CHEBI:136040 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0152032 infores:hetionet CHEBI:9086 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030196 infores:hetionet CHEBI:34967 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0015230 infores:hetionet CHEBI:52717 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0026827 infores:hetionet CHEBI:10101 biolink:causes NCIT:C78701 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0236082 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0029882 infores:hetionet CHEBI:8232 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0151662 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0037315 infores:hetionet CAID:CA229794 biolink:causes MONDO:0009861 infores:clingen CAID:CA229794 MONDO:0009861 PMID:9634518PMID:16198137 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PP3 The c.826A>G (p.Met276Val) variant in PAH is absent from population databases. It has been identified in trans with pathogenic variants in two patients (A300S and R261Q; PMID: 16198137), and identified in an additional patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 9634518). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229794/MONDO:0009861/006 2018-12-09 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10127 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0231528 infores:hetionet CHEBI:6715 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0085669 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0878544 infores:hetionet CHEBI:8665 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C1262144 infores:hetionet CHEBI:8707 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0575081 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013182 infores:hetionet CHEBI:3568 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0025874 infores:hetionet NCBIGene:8930 biolink:causes MONDO:0859267 infores:monarchinitiative not_provided not_provided HGNC:6919 MONDO:0859267 uuid:1ed77de0-ccd7-4905-9756-ea8241ab8e26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:4786 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0917801 infores:hetionet CHEBI:50648 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036973 infores:hetionet CAID:CA10385514 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385514 MONDO:0100437 PMID: Benign BP4, BA1 NM_001034853.2(RPGR):c.1240G>C is a missense variant predicted to cause the substitution of glutamate by glutamine at amino acid 414. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00008303 among hemizygous individuals, with 33 variant alleles / 397,426 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.119, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on the RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1, and BP4_moderate. (VCEP specifications version 1.0.0; date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385514/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CAID:CA397725473 biolink:causes MONDO:0008723 infores:clingen CAID:CA397725473 MONDO:0008723 PMID: Likely Pathogenic PVS1, PM2 The c.1605+2T>C (p.?) variant in ACADVL occurs within the canonical splice donor site (+2) of intron 16. It is predicted to cause skipping of biologically-relevant-exon 16/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 09-05-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397725473/MONDO:0008723/021 2022-09-05 2023-06-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3387 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0852911 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0000731 infores:hetionet CHEBI:135351 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0332563 infores:hetionet NCBIGene:4867 biolink:causes MONDO:0009962 infores:monarchinitiative not_provided not_provided HGNC:7905 MONDO:0009962 uuid:9ebbed4e-54c5-485a-a177-97c8b3a854fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0149904 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0314719 infores:hetionet CHEBI:135736 biolink:causes MONDO:0003282 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0029927 infores:hetionet CAID:CA2573157352 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157352 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, PM4, PM5, PM1, PM3, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+8A>T is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This intronic variant has a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.04) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.4) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157352/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:15854 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0036974 infores:hetionet CAID:CA151524 biolink:causes MONDO:0007648 infores:clingen CAID:CA151524 MONDO:0007648 PMID: Benign BS2, BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PM2, PM6, PVS1, PP3, PP2, PP1, PP4, BP4, BP1, BP2, BP3, PS3, PS1, PS4, PS2 The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA151524/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:167638 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0151539 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0033774 infores:hetionet NCBIGene:23204 biolink:causes MONDO:0014304 infores:monarchinitiative not_provided not_provided HGNC:697 MONDO:0014304 uuid:7566dd3d-81a2-45d8-ab19-985fc725dc0c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17650 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0003467 infores:hetionet CHEBI:9943 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042164 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0006809 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0007780 infores:hetionet CHEBI:31949 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0232488 infores:hetionet CHEBI:3508 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0015230 infores:hetionet CHEBI:17688 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0037317 infores:hetionet CHEBI:478164 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0086565 infores:hetionet CHEBI:94449 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0018794 infores:hetionet NCBITaxon:5501 biolink:causes MONDO:0005706 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5501 MESH:D003047 DB01263_MESH_D003047_1 UMLS:C0145867 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0015672 infores:hetionet CHEBI:6402 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0033774 infores:hetionet CHEBI:31932 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0002170 infores:hetionet CHEBI:28445 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0740394 infores:hetionet CHEBI:5118 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1963951 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0004936 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033038 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0004936 infores:hetionet CHEBI:36795 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0012813 infores:hetionet CHEBI:100241 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030554 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0178298 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017152 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0034063 infores:hetionet NCBIGene:23118 biolink:causes MONDO:0014000 infores:monarchinitiative not_provided not_provided HGNC:17075 MONDO:0014000 uuid:182b1c64-e03b-47a9-b439-1f60087f2202 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8346 biolink:causes UMLS:C0238201 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0238201 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002367 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0740457 infores:hetionet CHEBI:8107 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085633 infores:hetionet CHEBI:4822 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0026896 infores:hetionet CHEBI:253342 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0041582 infores:hetionet CHEBI:3568 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151746 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020649 infores:hetionet CHEBI:4445 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0231835 infores:hetionet CHEBI:15765 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0007222 infores:hetionet CHEBI:75722 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014724 infores:hetionet CHEBI:10102 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0038999 infores:hetionet NCBIGene:8405 biolink:causes MONDO:0032942 infores:monarchinitiative not_provided not_provided HGNC:11254 MONDO:0032942 uuid:974e1fd7-a7a3-4197-b368-d07c63d52dab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5383 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0085631 infores:hetionet CHEBI:134991 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C2830004 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0855242 infores:hetionet CHEBI:31205 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C0030193 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0021053 infores:hetionet CHEBI:16714 biolink:causes UMLS:C0235360 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0235360 infores:hetionet CHEBI:8356 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0344232 infores:hetionet CAID:CA16041870 biolink:causes MONDO:0008723 infores:clingen CAID:CA16041870 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM4, PM1, PM3_Strong, PP4_Moderate The c.1141_1143delGAG variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu381del) (PM4). The variant is reported in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (PMID: 25834949, 24305961, 21814341, 8845838). Six individuals were reported to have both elevated C14:1 levels and reduced VLCAD enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8845838, 21814341, 24305961, 25834949, 31031081). Of these individuals, one individual was homozygous for this variant, at least two of the individuals also carried an additional pathogenic variant not confirmed in trans, and at least four confirmed in trans to variants not yet curated by the VCEP (PM3; PMID: 24305961, 25834949, 32276429). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within a region of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_supporting, PM3, PM4, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041870/MONDO:0008723/021 2022-08-09 2022-08-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31711 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0023218 infores:hetionet NCBIGene:9382 biolink:causes MONDO:0012637 infores:monarchinitiative not_provided not_provided HGNC:6545 MONDO:0012637 uuid:843493a9-3b65-40aa-bf23-14fc21da8c50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2676 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0017675 infores:hetionet CHEBI:100241 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0010200 infores:hetionet CHEBI:63611 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0522055 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0851341 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0035078 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038363 infores:hetionet CHEBI:100246 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0043352 infores:hetionet CHEBI:9667 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013404 infores:hetionet CHEBI:3061 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0035243 infores:hetionet NCBIGene:1777 biolink:causes MONDO:0800132 infores:monarchinitiative not_provided not_provided HGNC:2960 MONDO:0800132 uuid:1f66024d-25f0-44a0-9c06-1facaa46c851 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA357805 biolink:causes MONDO:0017623 infores:clingen CAID:CA357805 MONDO:0017623 PMID: Uncertain Significance PM2, PP2 BS3, PS3 PTEN c.344A>G (p.Asp115Gly) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA357805/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63611 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C2973529 infores:hetionet CHEBI:7824 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0232602 infores:hetionet CHEBI:3654 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0027497 infores:hetionet CHEBI:51860 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0003811 infores:hetionet CHEBI:188986 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0030332 infores:hetionet CHEBI:42944 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0023380 infores:hetionet CHEBI:93635 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0011991 infores:hetionet CHEBI:8382 biolink:causes HP:0002385 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0221166 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011615 infores:hetionet CHEBI:79699 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0741494 infores:hetionet CHEBI:50648 biolink:causes HP:0001013 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0221252 infores:hetionet CHEBI:9588 biolink:causes UMLS:C3203457 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C3203457 infores:hetionet CHEBI:4672 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C3257803 infores:hetionet CHEBI:7915 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0021368 infores:hetionet GO:2000061 biolink:causes GO:0072001 infores:ubergraph knowledge_assertion manual_agent GO:2000061 GO:0072001 CHEBI:6904 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0008031 infores:hetionet CHEBI:7640 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0022346 infores:hetionet CHEBI:6030 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0027813 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0178298 infores:hetionet CHEBI:7447 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0006266 infores:hetionet CHEBI:6715 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0080274 infores:hetionet CHEBI:50730 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0009763 infores:hetionet CHEBI:42797 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0086565 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002418 infores:hetionet NCBITaxon:942 biolink:causes MONDO:0006922 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:942 MONDO:0006922 CHEBI:6067 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0037274 infores:hetionet GO:0060657 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0035295 CHEBI:63681 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0151786 infores:hetionet CHEBI:9667 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013395 infores:hetionet CHEBI:6375 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0039231 infores:hetionet CAID:CA8602772 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602772 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting, PM3_Supporting PM5, PP3 The NM_000419.5:c.2264G>C variant in ITGA2B is a missense variant predicted to cause substitution of arginine by proline at amino acid 755 (p.Arg755Pro). At least one patient (Patient PV in PMID: 12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% as measured by flow cytometry (PP4_Moderate). This variant has been detected in at least 3 probands with Glanzmann thrombasthenia. For two of those individuals (GM and PV in PMID: 12083483), this variant was observed in homozygosity along with additional ITGA2B variants (c.1139G>A (p.Gly380Asp) in heterozygosity in GM; c.2264G>C (p.Arg755Pro) in homozygosity in both GM and PV) (not considered here due to complex genotypes). One additional proband (reported in PMID: 19172520) was homozygous for only this variant (PM3_supporting). This variant is absent from gnomADv4.0 (PM2_Supporting). In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM3_Supporting, PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602772/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:2668 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0035455 infores:hetionet CHEBI:10102 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085649 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0032285 infores:hetionet NCBIGene:6331 biolink:causes MONDO:0013530 infores:monarchinitiative not_provided not_provided HGNC:10593 MONDO:0013530 uuid:76b88eb5-56c9-495e-a629-59d70f49241a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0021053 infores:hetionet CHEBI:101278 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0014236 infores:hetionet CHEBI:45599 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0042109 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005055 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036220 infores:hetionet CHEBI:6375 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0030554 infores:hetionet CHEBI:2955 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0010200 infores:hetionet NCBIGene:9690 biolink:causes MONDO:0859519 infores:monarchinitiative not_provided not_provided HGNC:16803 MONDO:0859519 uuid:389c4b8b-75f9-45c1-aeda-87db2f8939f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8869 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0151936 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151763 infores:hetionet CAID:CA915940323 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940323 MONDO:0100326 PMID: Likely Pathogenic PM4, PP4_Strong, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.3092del (p.Leu1031ArgfsTer?) variant causes a frameshift and subsequent stop loss. This results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain (PM4). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient (Patient GT11 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced between 5% and 20% and function was pathological, as measured by flow cytometry (PP4_strong). This patient is compound heterozygous for the maternal c.3092del variant and Leu214Pro (classified Pathogenic by the PD-EP), without confirmation of trans phase (PM3_supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PM4. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940323/MONDO:0100326/011 2021-12-02 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:44185 biolink:causes MONDO:0024354 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0276253 infores:hetionet CHEBI:47898 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0004604 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0009806 infores:hetionet CHEBI:32315 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0024894 infores:hetionet CHEBI:32139 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0011168 infores:hetionet CHEBI:5138 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0036974 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0948525 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0032285 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0027769 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027059 infores:hetionet CHEBI:83804 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011124 infores:hetionet CHEBI:119915 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235710 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0700590 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0031117 infores:hetionet CHEBI:10101 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0043352 infores:hetionet CAID:CA412745399 biolink:causes MONDO:0100437 infores:clingen CAID:CA412745399 MONDO:0100437 PMID: Likely Pathogenic PP3_Strong, PP4, PP1, PM2_Supporting, PS4_Moderate PM5 NM_001034853.2(RPGR):c.284G>A (p.Gly95Glu) is a missense variant that replaces glycine with glutamic acid at amino acid 95. Another missense variant in the same codon, NM_001034853.2(RPGR):c.283G>A (p.Gly95Arg; PMID: 28488341) has been classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. Glycine-to-glutamate has a lower Grantham’s distance (98) than the glycine-to-arginine (125), so PM5_Supporting cannot be met. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 apparently unrelated probands meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent electroretinogram responses (PMID: 33598457, PMID: 34287692, PMID: 36445968, PS4_Moderate). At least one proband harboring this variant exhibits a phenotype including childhood onset (1 pt), rod-specific b-wave that was reduced or undetectable (1 pt), accumulation of bone spicules (0.5 pts), and reduced visual acuity (0.5 pts), with genotyping by exome sequencing using a 77-gene panel followed by a 161-gene panel that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID 28512305, PP4). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: [33598457]). The computational predictor REVEL gives a score of 0.983, which is above the ClinGen X-linked IRD VCEP threshold of ≥0.932 and predicts a damaging effect on RPGR function (PP3_Strong). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_Supporting, PS4_Moderate, PP3_Strong, PP4, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412745399/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:135935 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0948594 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0151609 infores:hetionet CHEBI:8863 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0005741 infores:hetionet CAID:CA345150112 biolink:causes MONDO:0100084 infores:clingen CAID:CA345150112 MONDO:0100084 PMID: Pathogenic PP2, PP3, PM2_Supporting, PS4_Moderate, PP4_Strong, PS2_Supporting BA1, BP1, BP4, BS1 The c.283G>A variant in ACTA1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 95 (legacy nomenclature: p.Glu93Lys). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 4 probands with severe hypotonia and/or congenital myopathy (PS4_Moderate; PMID: 35810298, Invitae, ClinVar SCV:SCV000950636.2). In one of those four individuals, the variant has been identified as a de novo occurrence with confirmed parental relationships (PS2; Invitae, ClinVar SCV:SCV000950636.2). At least one patient with this variant displayed intranuclear rods and type 1 muscle fiber predominance, which is highly specific for alpha-actinopathy and has had exome testing that is negative for all other causes of myopathy (PP4_Strong, PMID: 35810298). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP4_Strong, PS4_Moderate, PS2_Supporting, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA345150112/MONDO:0100084/147 2024-08-27 2025-01-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64028 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0026837 infores:hetionet CHEBI:6904 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0013604 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0034902 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0267596 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027651 infores:hetionet CAID:CA222201 biolink:causes MONDO:0015152 infores:clingen CAID:CA222201 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PVS1, PM2_Supporting The NM_003494.4: c.610C>T p.(Arg204Ter) variant in DYSF, which is also known as NM_001130987.2: c.706C>T p.(Arg236Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two patients with clinical features consistent with LGMD, including in a homozygous state in an individual from a consanguineous family (0.25 pts, PMID: 35422632) and in trans with a pathogenic variant (NM_003494.4: c.855+1del, 1.0 pt, PMID: 18853459) (PM3). At least one of these patients had a clinical diagnosis of LGMD (Miyoshi myopathy) and severely reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 18853459). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.00006973 (the upper threshold of the 95% CI of 3/1111878 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222201/MONDO:0015152/180 2025-07-08 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63599 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0030554 infores:hetionet CHEBI:9137 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003811 infores:hetionet CHEBI:5134 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0151934 infores:hetionet NCBIGene:64321 biolink:causes MONDO:0013356 infores:monarchinitiative not_provided not_provided HGNC:18122 MONDO:0013356 uuid:37582743-8d71-49cf-b2a9-2a9669fa9328 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7798 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0239571 infores:hetionet CHEBI:35778 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085606 infores:hetionet CHEBI:51141 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0040034 infores:hetionet CHEBI:5778 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C1167965 infores:hetionet GO:1903023 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0019953 UMLS:C0657912 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017658 infores:hetionet CHEBI:17549 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0018989 infores:hetionet CHEBI:51860 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085633 infores:hetionet CHEBI:16467 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0027497 infores:hetionet CHEBI:101853 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0235639 infores:hetionet CHEBI:3534 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0014457 infores:hetionet CHEBI:404903 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0750426 infores:hetionet CHEBI:6690 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0042510 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0040409 infores:hetionet CHEBI:3647 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0020456 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0017601 infores:hetionet CHEBI:3441 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0036974 infores:hetionet CHEBI:51041 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020458 infores:hetionet CHEBI:15367 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0017181 infores:hetionet CHEBI:28148 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0022107 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0038663 infores:hetionet CAID:CA10549676 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549676 MONDO:0010305 PMID: Likely Benign BS2 BS1, PM2, PP3, BP4 The NM_005629.4:c.1879A>C variant in SLC6A8 is a missense variant predicted to cause the substitution of a lysine by a glutamine at amino acid position 627 (p.Lys627Gln). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) in a continental population is 0.00003167 (28/883996 alleles; 7 hemizygotes) in the European non-Finnish population. This MAF is higher that the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.00002) but lower than the threshold for BS1 (>0.0002). Therefore, no population codes are met. Of note, the highest MAF in any population is 0.0009383 (42/44763 alleles, 13 hemizygotes) in the Finnish population. Overall, there are 22 hemizygotes in gnomAD v4.1.0. (13 in the European Finnish, 7 in the European non-Finnish, and 2 in the remaining population) (BS2). The computational predictor REVEL gives a score of 0.333, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 432943). Due to the presence of 22 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549676/MONDO:0010305/027 2025-03-13 2025-03-14 X-linked inheritance HP:0001417 Contradicts true CHEBI:46345 biolink:causes HP:0001310 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0234162 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0011570 infores:hetionet CHEBI:16480 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0019080 infores:hetionet CHEBI:567361 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0206062 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005133 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0014175 infores:hetionet CHEBI:50663 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0003467 infores:hetionet CHEBI:474180 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0003811 infores:hetionet CHEBI:8382 biolink:causes UMLS:C2586050 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C2586050 infores:hetionet CHEBI:8093 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0344232 infores:hetionet NCBIGene:2645 biolink:causes MONDO:0007453 infores:monarchinitiative not_provided not_provided HGNC:4195 MONDO:0007453 uuid:73320a3e-5a48-48e5-bd78-cce86f61f3ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6438 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0854097 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1443060 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151609 infores:hetionet CHEBI:9654 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0020458 infores:hetionet CHEBI:6832 biolink:causes GO:0090075 infores:drugmechdb knowledge_assertion manual_agent MESH:D008721 GO:0090075 DB00423_MESH_D009128_1 CHEBI:3423 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0040046 infores:hetionet CHEBI:5801 biolink:causes MONDO:0007128 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0234906 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034359 infores:hetionet CHEBI:63631 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1527344 infores:hetionet CHEBI:63630 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0085633 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0518015 infores:hetionet CHEBI:9570 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0043094 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0027609 infores:hetionet CHEBI:2208 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0010709 infores:hetionet CAID:CA396463469 biolink:causes MONDO:0007648 infores:clingen CAID:CA396463469 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.1531C>T p.(Gln511*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_supporting). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least two families meeting HDGC clinical criteria (PS4_moderate; PMID: 31600923 and SCV000580698.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_supporting, PS4_moderate, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396463469/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf UMLS:C1738934 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0027424 infores:hetionet CHEBI:2668 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0009763 infores:hetionet NCBIGene:51227 biolink:causes MONDO:0033364 infores:monarchinitiative not_provided not_provided HGNC:3046 MONDO:0033364 uuid:910b8d07-6ab0-4a6c-947f-976dbe5a427a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63622 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0014457 infores:hetionet CAID:CA220599791 biolink:causes MONDO:0000572 infores:clingen CAID:CA220599791 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting PS3 The NM_000448.3:c.29G>T variant in RAG1 is a missense variant predicted to cause a substitution of glycine by Valine at amino acid 10 (p.Gly10Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV002304851.2). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA220599791/MONDO:0000572/123 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3242 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0016204 infores:hetionet CHEBI:17303 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026205 infores:hetionet CHEBI:421707 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0149745 infores:hetionet CHEBI:31949 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01580 UMLS:C0020615 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0031542 infores:hetionet CHEBI:63631 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151905 infores:hetionet CHEBI:27999 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0002878 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0011991 infores:hetionet NCBIGene:23545 biolink:causes MONDO:0010208 infores:monarchinitiative not_provided not_provided HGNC:18481 MONDO:0010208 uuid:e5e15365-98ff-4d95-9625-22c8263b187b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0030332 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0011334 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0151479 infores:hetionet CAID:CA1619862 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619862 MONDO:0800472 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate PP1, BP4, BA1, PM5, PM4, PM1, PS1, PS3, PS2, BP7, BS1, PVS1, PM2 The c.1102C>T variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 368 (p.Arg368Cys). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.0007331 (44 alleles out of 60,018), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0005) or the BS1 allele frequency threshold (≥ 0.01). The REVEL score = 0.833, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on CYP1B1 function. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in five individuals with a CYP1B1-related phenotype. Three of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 phase unknown, 2 confirmed in trans) (PMID: 36343799, ClinVar) and two individuals are homozygous (1 assumed non-consanguineous) for the variant (PMID: 36343799, ClinVar). Total proband points = 3.5, meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 6 and to be classified as a Likely pathogenic variant (likely pathogenic classification range 6 to 9-7, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PP3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619862/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7865 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0015967 infores:hetionet CHEBI:2788 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C1142412 infores:hetionet CHEBI:499361 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0039070 infores:hetionet CHEBI:63925 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0271051 infores:hetionet CHEBI:3723 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151905 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0018681 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0030305 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0178298 infores:hetionet CHEBI:6076 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0231218 infores:hetionet CHEBI:4657 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0013144 infores:hetionet CHEBI:63637 biolink:causes MONDO:0020311 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0023480 infores:hetionet CHEBI:136040 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0017178 infores:hetionet CHEBI:5893 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151539 infores:hetionet CHEBI:63610 biolink:causes EFO:0009578 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0242669 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0520966 infores:hetionet CAID:CA386963548 biolink:causes MONDO:0015967 infores:clingen CAID:CA386963548 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate BP4, PM5, PP3 The c.539C>G variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of alanine to glycine at codon 180 (p.(Ala180Gly)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylurea treatment) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.539C>T (p.Ala180Val) has been classified as a likely benign by the ClinGen MDEP; therefore, PM5 will not be applied. This variant has a REVEL score of 0.492, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.539C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/111/2023): PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386963548/MONDO:0015967/017 2024-07-29 2024-07-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9599 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1956346 infores:hetionet CHEBI:50663 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0085631 infores:hetionet CHEBI:3371 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00314 UMLS:C0151723 infores:hetionet CHEBI:63618 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0013378 infores:hetionet CHEBI:32139 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0021843 infores:hetionet CHEBI:110423 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0023470 infores:hetionet CHEBI:32315 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0019521 infores:hetionet CHEBI:47519 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0023530 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0150450 infores:hetionet CAID:CA401370051 biolink:causes MONDO:0009290 infores:clingen CAID:CA401370051 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting The NM_000152.5:c.2003A>G variant in GAA is a missense variant predicted to cause substitution of Tyr by Cys at amino acid 668 (p.Tyr668Cys). This variant was identified in one patient with Pompe disease and documented deficiency of GAA activity whose sibling was identified on newborn screen. The proband was compound heterozygous for the variant and c.-32-13T>G, with the variants confirmed to be in trans (clinical laboratory data) (1 point, PM3; PP4_Moderate). The variant has also been reported in 3 individuals identified by newborn screen, including one individual with low GAA activity in DBS and fibroblast (PMID 31076647, 33073027, 34922579) and 2 individuals (clinical laboratories data) with deficiency of GAA activity. One of these individuals was compound heterozygous for the variant and c.752C>T+c.761C>T and pseudodeficiency variants c.1726G>A and c.2065G>A (PMID 31076647, 33073027, 34922579), another was compound heterozygous for the variant and c.-32-13T>G, and another had no second variant identified. As none of these individuals had symptoms of Pompe disease at the time of report, the data was not included. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.929 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3).There is a ClinVar entry for this variant (Variation ID: 546808). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, PP4_Moderate, PM3, PP3.(Classification approved by the ClinGen Lysosomal Diseases VCEP on August 8, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401370051/MONDO:0009290/010 2025-08-08 2025-10-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:74947 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151596 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0011570 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0233494 infores:hetionet CHEBI:49375 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0015967 infores:hetionet CHEBI:45783 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006840 infores:hetionet CHEBI:31485 biolink:causes MONDO:0006884 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0030332 infores:hetionet CHEBI:38940 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0011071 infores:hetionet CHEBI:72296 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0018946 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0281981 infores:hetionet CHEBI:8764 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0242301 infores:hetionet CHEBI:3387 biolink:causes MONDO:0800486 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0005944 infores:hetionet CHEBI:49960 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C1384353 infores:hetionet CHEBI:3996 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0235347 infores:hetionet CHEBI:474180 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0240671 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1306341 infores:hetionet CHEBI:465284 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013428 infores:hetionet CHEBI:6950 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0267792 infores:hetionet CAID:CA6748985 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748985 MONDO:0009861 PMID:11244681PMID:11244681 Uncertain Significance PM3, PP4, BP4 PM2 PAH-specific ACMG/AMP criteria applied: BP4: In silico overwhelmingly predict benign. REVEL = 0.553; PP4: Detected in a patient with non PKU hyperphe (PMID:11244681); PM3: H100R detected with IVS10 (PMID:11244681). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748985/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9586 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0162830 infores:hetionet CHEBI:42355 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C3263723 infores:hetionet CHEBI:65173 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0015967 infores:hetionet CHEBI:4511 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0018965 infores:hetionet CHEBI:135351 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0030554 infores:hetionet CHEBI:5118 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020625 infores:hetionet CHEBI:116278 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0027051 infores:hetionet CAID:CA000494 biolink:causes MONDO:0017623 infores:clingen CAID:CA000494 MONDO:0017623 PMID: Pathogenic PM6, PM2, PVS1, PS4_Moderate PTEN c.511C>T (p.Q171X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 22595938)PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 17043057, PMID 22595938) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000494/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63622 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0003467 infores:hetionet CHEBI:72296 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0039070 infores:hetionet CHEBI:135005 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0151830 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0003123 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0029882 infores:hetionet CHEBI:41423 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0024902 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0003621 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0003621 infores:hetionet CHEBI:10110 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1443060 infores:hetionet CHEBI:3515 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0027947 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0004604 infores:hetionet CHEBI:5893 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0476273 infores:hetionet CHEBI:50861 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0003862 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0021053 infores:hetionet CHEBI:4466 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085631 infores:hetionet CHEBI:15854 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0151786 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001208 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0264490 infores:hetionet CHEBI:9674 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0020458 infores:hetionet CAID:CA10585196 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585196 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 PM5 The NM_000527.5(LDLR):c.919G>C (p.Asp307His) variant is classified as VUS for Familial Hypercholesterolemia by applying evidence codesPM2, PP3, and PP4 as defined by the ClinGen FamilialHypercholesterolemia Expert Panel LDLR-specific variant curation guidelines(https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.988.PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB definiteFH after alternative causes of high cholesterol were excluded (PMID: 17094996). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585196/MONDO:0007750/013 2023-06-23 2023-07-28 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6715 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0040053 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0024117 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0858581 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0858581 infores:hetionet CHEBI:63616 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0014518 infores:hetionet CHEBI:29688 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C1609512 infores:hetionet CHEBI:17688 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1268766 infores:hetionet CHEBI:7809 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0009319 infores:hetionet UMLS:C0657912 biolink:causes HP:0012223 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038000 infores:hetionet CHEBI:135005 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020580 infores:hetionet NCBIGene:2776 biolink:causes MONDO:0008501 infores:monarchinitiative not_provided not_provided HGNC:4390 MONDO:0008501 uuid:fc78427d-e7ec-4177-89c6-09d3748d55a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0231528 infores:hetionet CHEBI:3996 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0013362 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151849 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0034186 infores:hetionet GO:1904948 biolink:causes CL:2000097 infores:ubergraph knowledge_assertion manual_agent GO:1904948 CL:2000097 PUBCHEM.COMPOUND:45357473 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0023222 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0413252 infores:hetionet NCBIGene:57122 biolink:causes MONDO:0054850 infores:monarchinitiative not_provided not_provided HGNC:29914 MONDO:0054850 uuid:c9cef953-218c-43f3-bf52-9193c0e5b09e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15407 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0278080 infores:hetionet CHEBI:9332 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0032617 infores:hetionet CHEBI:5100 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0013404 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0027765 infores:hetionet CHEBI:34385 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0011603 infores:hetionet NCBIGene:3418 biolink:causes MONDO:0013345 infores:monarchinitiative not_provided not_provided HGNC:5383 MONDO:0013345 uuid:e479f64b-50d4-464e-ba19-844c3db360dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:180905 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0027051 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0009806 infores:hetionet CHEBI:28364 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0042963 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0027765 infores:hetionet CHEBI:15552 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0003862 infores:hetionet CHEBI:4909 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0340865 infores:hetionet CHEBI:5118 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0024282 infores:hetionet CHEBI:119573 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0018965 infores:hetionet CAID:CA409106085 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106085 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, BP2 PP1, PP4 The c.530T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to aspartic acid at codon 177 (p.(Val177Asp)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.978​, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has been observed in two families with diabetes in cis with c.553G>A p.Ala185Thr, which is classified as likely pathogenic by the ClinGen MDEP (BP2). The c.530T>A variant has not been observed independently of the c.553G>A variant. While this variant was observed in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MPC>50% and negative HNF4A testing), this individual also harbored the likely pathogenic variant c.553G>A p.Ala185Thr; therefore PP4 will not be applied. This variant segregated with diabetes with 5 informative meioses in 2 families; however the variant and diabetes cosegregated with c.553G>A p.Ala185Thr, which has been classifed as likely pathogenic by the MDEP, in all instances; therefore PP1 will not be applied (internal lab contributors). In summary, c.530T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106085/MONDO:0015967/085 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49662 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0014743 infores:hetionet CHEBI:94392 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0019054 infores:hetionet CHEBI:85161 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0041969 infores:hetionet CHEBI:63580 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0037672 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0001824 infores:hetionet CHEBI:59750 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0026113 infores:hetionet CHEBI:68558 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0015672 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0033575 infores:hetionet CAID:CA16020948 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020948 MONDO:0009861 PMID:18346471PMID:18346471 Likely Pathogenic PM2, PP3, PP4, PS1, PM3_Supporting PS3 The c.1146C>G (p.Phe382Leu) variant in PAH has been reported in at least 1 individual with mild HPA (PP4; PMID: 18346471). The compound heterozygous individual also harbored the known pathogenic variant Arg252Trp (ClinVar 584) (PM3_suppporting). The c.1146C>G variant is absent in population databases (PM2). Computational prediction tools suggest that the variant may impact the protein (PP3). This variant generates the same amino acid change as c.1144T>C (p.Phe382Leu) which has been interpreted as Pathogenic by the ClinGen PAH Expert Panel (PS1). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS1, PM2, PP4, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020948/MONDO:0009861/006 2019-12-22 2019-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31397 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0029453 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0155003 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0155003 infores:hetionet CHEBI:15407 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0038990 infores:hetionet CHEBI:127780 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0035229 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017574 infores:hetionet CAID:CA386964246 biolink:causes MONDO:0015967 infores:clingen CAID:CA386964246 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS2, PS4, PP1_Strong, PM1, PM5, PP4_Moderate, PP3 PS3 The c.607C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 203 (p.(Arg203Cys)) of NM_000545.8. This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly consistent with HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (internal lab contributors). (PS2; internal lab contributors). Additionally, this variant was identified in eight unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs:15928245, 10078571, 18811724,20393147,23517481, internal lab contributors). The c.607C>T variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive or antibody negative (PP4_Moderate; internal lab contributors). Another missense variant, c.608G>A (p.Arg203His) has been interpreted as pathogenic by the ClinGen MDEP, and p. Arg203Cys has a greater Grantham distance (PM5). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant segregated with diabetes, with at least five informative meioses in three families with MODY (PP1_Strong; PMID:18811724; internal lab contributors). Functional studies demonstrated the p.Arg203Cys protein has transactivation 53% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3_Supporting and BS3_Supporting (PMID: 15522234). In summary, c.607C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS2, PS4, PM1, PM2_Supporting, PP4_Moderate, PM5, PP3, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386964246/MONDO:0015967/017 2022-04-11 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27882 biolink:causes MONDO:0004183 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0270921 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0041912 infores:hetionet NCBIGene:80739 biolink:causes MONDO:0044316 infores:monarchinitiative not_provided not_provided HGNC:13937 MONDO:0044316 uuid:fb542f7b-6cbe-430c-ad61-26dc9c51bb75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0036572 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1619702 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1619702 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0025061 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0036974 infores:hetionet CHEBI:44423 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0542571 infores:hetionet CHEBI:7936 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0029261 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042373 infores:hetionet CHEBI:38940 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0428977 infores:hetionet CHEBI:82941 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0017168 infores:hetionet CHEBI:39669 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C2830004 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151717 infores:hetionet CHEBI:51450 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0042571 infores:hetionet CHEBI:49375 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085077 infores:hetionet NCBIGene:6566 biolink:causes MONDO:0012396 infores:monarchinitiative not_provided not_provided HGNC:10922 MONDO:0012396 uuid:d067ccd9-f56b-48a9-866e-12a13aa65ca1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9613 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0162830 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0232459 infores:hetionet CHEBI:7577 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0020621 infores:hetionet CHEBI:63620 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0004604 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0152029 infores:hetionet CHEBI:2549 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0038362 infores:hetionet CHEBI:50275 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0851578 infores:hetionet CAID:CA915940332 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940332 MONDO:0100326 PMID: Pathogenic PP4_Strong, PM2_Supporting, PVS1_Strong PM3 The NM_000419.5(ITGA2B):c.2902del (p.Tyr968MetfsTer?) frameshift variant in exon 28 of 30 is predicted to alter the remaining 72 amino acids followed by a stop loss and the addition of 90 amino acids to the ITGA2B protein. This alters the transmembrane domain of the protein which is considered a critical region for protein function by the Platelet Disorders VCEP (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It has been reported in at least one patient (GT14 in PMID: 25728920), whom displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to<5%, as measured by flow cytometry (PP4_strong). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PP4_strong, PM2_supporting. (VCEP specifications version 2.1) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940332/MONDO:0100326/011 2022-04-15 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:63619 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0438142 infores:hetionet CAID:CA399803822 biolink:causes MONDO:0100326 infores:clingen CAID:CA399803822 MONDO:0100326 PMID: Likely Pathogenic PM2_Supporting, PM3_Supporting, PVS1_Strong PP4 The NM_000419.5(ITGA2B):c.1211-1G>C splice variant is predicted to result in the loss of exon 13, causing an in-frame deletion of 60 amino acids. This exon loss occurs within the critical ligand binding extracellular domain (PVS1_strong). The variant is absent from gnomADv4.0.0 (PM2_supporting). The variant has has been reported in one homozygous patient stated to Glanzmann thrombasthenia (PM3_supporting, PMID: 31064749). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3_supporting, PVS1_strong (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399803822/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3387 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0034063 infores:hetionet CHEBI:45783 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0026821 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0014544 infores:hetionet CHEBI:17688 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0037036 infores:hetionet CHEBI:8768 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151636 infores:hetionet CHEBI:3647 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0017979 infores:hetionet NCBITaxon:562 biolink:causes MONDO:0006753 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:562 MESH:D020814 DB00415_MESH_D020814_1DB01212_MESH_D020814_1DB00493_MESH_D020814_1DB00479_MESH_D020814_1 CHEBI:28915 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0687713 infores:hetionet CHEBI:7773 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0004238 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0004096 infores:hetionet CHEBI:5441 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0003123 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0021400 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0948715 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0948715 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0233494 infores:hetionet CHEBI:9123 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030193 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0265935 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0265935 infores:hetionet CHEBI:6775 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0034886 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0149931 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0521491 infores:hetionet CHEBI:4822 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0042963 infores:hetionet CHEBI:4708 biolink:causes UMLS:C2712122 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C2712122 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1268766 infores:hetionet CHEBI:53691 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0013404 infores:hetionet CHEBI:7773 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0004096 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0026821 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0235234 infores:hetionet CHEBI:17347 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0234233 infores:hetionet CHEBI:100241 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0034886 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0001430 infores:hetionet CHEBI:4995 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0015967 infores:hetionet CHEBI:144551 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0019521 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0027769 infores:hetionet CHEBI:101278 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0030252 infores:hetionet CHEBI:18332 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0022107 infores:hetionet CHEBI:63598 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0404521 infores:hetionet CHEBI:408174 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0003862 infores:hetionet CAID:CA222141 biolink:causes MONDO:0015152 infores:clingen CAID:CA222141 MONDO:0015152 PMID: Pathogenic PP4_Strong, PS1, PM3_Strong, PVS1_Moderate BS1 The NM_003494.4: c.2643+1G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>A, occurs within the canonical splice donor site of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids. Skipping of exon 25 was confirmed by minigene assay and RNAseq (PMID 25312915, 36983702; PVS1_Moderate_RNA). This variant has been detected in at least eight unrelated individuals with LGMD (PMID: 30564623, 36983702, 33927379, 23243261, 22246893, 18853459). Of these individuals, four were homozygous (1.0 pt), and four were compound heterozygous; in at least two cases, the variant was confirmed in trans with a pathogenic or likely pathogenic variant (c.1948delC p.(Leu650TyrfsTer6), 1.0 pt; c.4497delT p.(Phe1499LeufsTer4), 1.0 pt) (PM3_Strong). At least one of these patients displayed a progressive limb girdle pattern of muscle weakness and absent dysferlin expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702, 33927379). The filtering allele frequency for this variant is 0.001335 in gnomAD v2.1.1 African/African American genomes (the lower threshold of the 95% CI of 18/8708), which is higher than the LGMD VCEP threshold of 0.001 for BS1; however, this variant is a frequently observed variant among patients, and the VCEP opted not to apply this code (BS1 exception). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the threshold for the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. Although the population frequency of this variant provides benign evidence, the VCEP considers this not inconsistent with the final classification given the frequency at which it is observed in the patient population. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate_RNA, PS1, PM3_Strong, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222141/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119573 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0085605 infores:hetionet NCBITaxon:5741 biolink:causes MONDO:0001103 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5741 MESH:D005873 DB00911_MESH_D005873_1DB12834_MESH_D005873_1DB00916_MESH_D005873_1DB00507_MESH_D005873_1DB01103_MESH_D005873_1 CHEBI:3478 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0030252 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1291078 infores:hetionet GO:0048773 biolink:causes CL:0000574 infores:ubergraph knowledge_assertion manual_agent GO:0048773 CL:0000574 CHEBI:36791 biolink:causes UMLS:C0856081 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0856081 infores:hetionet CAID:CA8814826 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814826 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM3, PM2_Supporting The NM_000152.5:c.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 10 patients with this variant and reported to have Pompe disease have been reported. This includes two patients with documented laboratory values showing GAA deficiency meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate; one of them on enzyme replacement therapy (PMID 21484825, 31467850), a further 7, at least, patients on enzyme replacement therapy, without documented values for GAA activity, meeting specifications for PP4 (PMID 26873529, 31086307, 31392188, 31676142, 32248831), and additional patients with insufficient details to meet the requirements for PP4 (PMID 10206684, 16917947, 29961517, 30564623). At least 7 patients are compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G, in GAA (PM3). Another two patients are compound heterozygous for the variant and either c.1195-8G>A (PMID 21484825) or c.1115A>T (p.His372Leu) (PMID 31467850). The in trans data from both of these patients will be used in the assessment of the other variant and is, therefore, not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 282842, 2 star review status) with five submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific GAA criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814826/MONDO:0009290/010 2021-09-28 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:9137 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1443060 infores:hetionet CHEBI:135929 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0036974 infores:hetionet CHEBI:100241 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0040434 infores:hetionet CAID:CA016843 biolink:causes MONDO:0005835 infores:clingen CAID:CA016843 MONDO:0005835 PMID:32849802 Pathogenic PS3, PP3_Moderate, PP4_Moderate, PP1, PM2_Supporting The NM_000251.3:c.1012G>A variant in MSH2 is a missense variant predicted to cause substitution of Glycine to Arginine at amino acid 338 (p.Gly338Arg). The prior probability for pathogenicity of this missense variant is 0.96 according to http://priors.hci.utah.edu/PRIORS (PP3_moderate). This variant has been identified in at least two independent patients with CRC: one tumor with loss of MSH2 and MSH6 protein expression and one tumour with loss of MSH2 protein expression (PP4_moderate). Results of functional and segregation odds support the evidence of pathogenicity of the variant (PS3 and PP1). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).In summary, this variant meets the criteria to be classified as pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PP3_Mod, PP4_Mod, PS3, PP1 and PM2_Sup (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA016843/MONDO:0005835/137 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:8200 biolink:causes MONDO:0014125 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0014125 uuid:04dd23e8-5a2d-442e-ba10-24d5033650c7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3764 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0232849 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018021 infores:hetionet CHEBI:15765 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0037011 infores:hetionet CHEBI:50275 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C3665347 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0003811 infores:hetionet CHEBI:2675 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0341047 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0016658 infores:hetionet CAID:CA120553 biolink:causes MONDO:0044970 infores:clingen CAID:CA120553 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PM5_Supporting PP1, PP3, PS4 The m.616T>G variant in MT-TF has been reported in one individual with primary mitochondrial disease (PMID: 20142618). This individual had generalized tonic clonic seizures, continuous partial seizures, and myoclonus. Muscle biopsy showed many COX-deficient fibers and combined deficiency of mitochondrial respiratory chain complexes I, III, and IV. The exact heteroplasmy level was not provided but was described as “very high” in muscle and homoplasmic in blood. Maternal family members were not tested for the variant. This variant is absent in the Helix dataset and gnomAD v3.1.2, and there is one occurrence in the MITOMAP GenBank sequences (PM2_supporting). MitoTIP predicts the variant is likely pathogenic (95.6 percentile) and HmtVAR predicts the variant is neutral (score of 0.25). A variant at the same position, m.616T>C, was classified as likely pathogenic by this Expert Panel (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120553/MONDO:0044970/015 2024-06-10 2025-10-31 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3403 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0344232 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C3665347 infores:hetionet CAID:CA1139532470 biolink:causes MONDO:0009861 infores:clingen CAID:CA1139532470 MONDO:0009861 PMID:28982351 Pathogenic PVS1, PM2, PP4 This variant c.463del (p.Arg155ValfsTer?) in PAH was reported in at least 1 Han Chinese patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 28982351), although a defect in BH4 metabolism was excluded by urinary pterin analysis only. This is a frameshift variant in exon 5 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3'-most exon or the 3'-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139532470/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7640 biolink:causes UMLS:C0558148 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0558148 infores:hetionet CHEBI:9943 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020453 infores:hetionet CHEBI:8774 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151766 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0948525 infores:hetionet CHEBI:3698 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0857305 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0003123 infores:hetionet CHEBI:27690 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0012833 infores:hetionet CHEBI:6775 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011124 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0863083 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0863083 infores:hetionet CHEBI:17026 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013428 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0852919 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0852919 infores:hetionet CHEBI:567361 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0085605 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0151602 infores:hetionet CHEBI:50122 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0003862 infores:hetionet CHEBI:4562 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0006266 infores:hetionet CHEBI:5134 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0026113 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0009806 infores:hetionet CHEBI:2682 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0037287 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0011570 infores:hetionet CHEBI:75998 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C2363731 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235969 infores:hetionet CHEBI:59773 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0030554 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0004610 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0028259 infores:hetionet CHEBI:15552 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0013604 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0042075 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0040479 infores:hetionet CHEBI:2904 biolink:causes UMLS:C1610056 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C1610056 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0016382 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0038587 infores:hetionet CHEBI:8871 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0085633 infores:hetionet CHEBI:4974 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0151625 infores:hetionet CHEBI:5790 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0231218 infores:hetionet NCBIGene:5506 biolink:causes MONDO:0005148 infores:monarchinitiative not_provided not_provided HGNC:9291 MONDO:0005148 uuid:2aac9f68-c507-4df4-b377-5d6fe925b09f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0022116 infores:hetionet NCBIGene:10651 biolink:causes MONDO:0030880 infores:monarchinitiative not_provided not_provided HGNC:7506 MONDO:0030880 uuid:726e3ca4-a7ad-4adb-b9e4-d5d8b8338d91 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6916 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0012833 infores:hetionet CHEBI:4653 biolink:causes NCIT:C50495 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C1456822 infores:hetionet CHEBI:135961 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0035078 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0026650 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0019360 infores:hetionet CHEBI:6539 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0011603 infores:hetionet NCBIGene:6499 biolink:causes MONDO:0013818 infores:monarchinitiative not_provided not_provided HGNC:10898 MONDO:0013818 uuid:311b86e9-15eb-4070-95ff-a129106e15eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0236075 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0687707 infores:hetionet CHEBI:48669 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0042373 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0851341 infores:hetionet CHEBI:50663 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0006277 infores:hetionet CHEBI:50922 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0043094 infores:hetionet CHEBI:8768 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0024902 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0919777 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0919777 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0006277 infores:hetionet CAID:CA16020803 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020803 MONDO:0009861 PMID:26503515PMID:30747360PMID:30050108PMID:28982351 Pathogenic PP4_Moderate, PM2, PP3, PM3_Very Strong The c.505C>A (p.Arg169Ser) variant in PAH is detected in 4 Chinese patients with Phe levels >120 umol/l (PMID 26503515, 30747360, 30050108, 28982351 ) (PP4-Moderate). The variant was detected in trans with pathogenic variants p.R241C, p.R413P, R408Q, p.R243Q (PMID: 30050108, 28982351). The validation tests on parents were performed using Sanger sequencing (PM3-Very Strong). This variant is absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). This variant is predicted to be damaging in SIFT, PolyPhen2, and MutationTaster. REVEL score = 0.805 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Very Strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020803/MONDO:0009861/006 2020-05-14 2020-05-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63584 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0013428 infores:hetionet CHEBI:9763 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0011168 infores:hetionet CHEBI:44915 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C3665386 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0242073 infores:hetionet CAID:CA128830 biolink:causes MONDO:0044970 infores:clingen CAID:CA128830 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PM5_Supporting PP3, BP4, PS2, PS3, PM6 The m.14674T>G variant in MT-TE has been reported in two affected individuals with reversible infantile respiratory chain deficiency from a Japanese cohort (PMID: 21194154). One girl presented with congenital myopathy and muscle weakness, and muscle biopsy at age 8 months showed ragged red fibers. Blood and cerebrospinal fluid (CSF) lactate levels were normal. By age 15 years, she had no persistent medical concerns. The variant was present at homoplasmy in muscle. The other reported individual, also a girl, presented with mitochondrial myopathy and failure to thrive. Muscle biopsy at age 5 months showed ragged red fibers and reduced respiratory chain enzyme activities. She had elevated blood creatine kinase and lactate, and elevated CSF lactate. By age 11 years, she had mild exercise intolerance only. The variant was present at homoplasmy in muscle. There was no mention of testing in family members of either proband. There are no reported de novo occurrences to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are inconsistent for this variant as MitoTIP suggests this variant is benign (29.4 percentile) and HmtVAR predicts it to be deleterious (0.4). Another variant at this position was classified as likely pathogenic by this Expert Panel (m.14674T>C, PM5_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PM5_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA128830/MONDO:0044970/015 2024-03-26 2024-07-26 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63599 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0034069 infores:hetionet CHEBI:34967 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0017178 infores:hetionet CHEBI:91541 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0085631 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0034186 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0856882 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0856882 infores:hetionet CHEBI:28925 biolink:causes HP:0000876 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0028949 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0039971 infores:hetionet CHEBI:84500 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0015967 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0024225 infores:hetionet CAID:CA8328578 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328578 MONDO:0100438 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting NM_014336.5(AIPL1):c.276+1G>A disrupts a canonical splice site in intron 2 and is predicted to lead to skipping of a critical exon known to be required for protein function. (PVS1).This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000004339, with 7 /1613424 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has also been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Trp278X variant suspected in trans (0.5 points, PMID: 25596619), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (0.5 total points, PM3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, PM3_supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328578/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16755 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0151825 infores:hetionet CAID:CA228405673 biolink:causes MONDO:0700270 infores:clingen CAID:CA228405673 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 The c.6372C>G (p.Tyr2124Ter) variant in ATM is a nonsense variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant was observed in an individual with Ataxia-Telangiectasia (PMID:26896183), and is absent from gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM3, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA228405673/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:36795 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0038358 infores:hetionet CHEBI:8888 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042963 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0860239 infores:hetionet CHEBI:3242 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0011603 infores:hetionet CHEBI:47426 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0018681 infores:hetionet CHEBI:7824 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0004245 infores:hetionet CHEBI:31348 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0033771 infores:hetionet GO:0072043 biolink:causes GO:0072009 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0072009 CHEBI:38545 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0012833 infores:hetionet CHEBI:50663 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0011175 infores:hetionet GO:0010975 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:0010975 GO:0007399 CHEBI:114785 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0033774 infores:hetionet CHEBI:3561 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151786 infores:hetionet CHEBI:8461 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0003811 infores:hetionet CHEBI:9725 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0242422 infores:hetionet CHEBI:4495 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0151904 infores:hetionet CHEBI:64312 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0006384 infores:hetionet UMLS:C0009315 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0232462 infores:hetionet CAID:CA16020855 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020855 MONDO:0009861 PMID:19786003PMID:23514811 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Supporting PM5 The c.773T>C (p.Leu258Pro) variant in PAH has been reported in 3 individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 19786003, 23514811). This variant is absent in population databases (PM2). This variant was present in two homozygous patients. Genetic analysis in parents confirmed homozygosity. PMID: 23514811 (PM3-supporting). Computational evidence supports a deleterious effect . In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020855/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64354 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0349506 infores:hetionet CHEBI:50381 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0027497 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1167965 infores:hetionet CHEBI:71223 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0033774 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0033777 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0033777 infores:hetionet CHEBI:91541 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0013595 infores:hetionet CHEBI:9727 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C1443060 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0022408 infores:hetionet CHEBI:83531 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0043352 infores:hetionet CHEBI:6970 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0234894 infores:hetionet NCBIGene:8567 biolink:causes MONDO:0033561 infores:monarchinitiative not_provided not_provided HGNC:6766 MONDO:0033561 uuid:e3375837-d1f8-42d6-930b-dbd0f127536d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101853 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0235431 infores:hetionet CHEBI:8871 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C2830004 infores:hetionet CHEBI:42068 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0002792 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001909 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0001126 infores:hetionet CHEBI:6367 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0085932 infores:hetionet CHEBI:51041 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0008325 infores:hetionet CHEBI:31236 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0392525 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0040479 infores:hetionet CHEBI:3510 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0424295 infores:hetionet CHEBI:70746 biolink:causes UMLS:C3665900 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C3665900 infores:hetionet CHEBI:6792 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0036974 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0014549 infores:hetionet CHEBI:135930 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0035078 infores:hetionet CAID:CA024011 biolink:causes MONDO:0018493 infores:clingen CAID:CA024011 MONDO:0018493 PMID: Uncertain Significance PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with valine at codon 4283 of the RYR1 protein, p.(Glu4283Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction, a second variant of uncertain significance, p.(Val218Ile), was also identified. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID: 16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.561 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024011/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:53760 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002418 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013395 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0004093 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0859978 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0859978 infores:hetionet CHEBI:209807 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0687713 infores:hetionet CHEBI:7820 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0518015 infores:hetionet CAID:CA645369492 biolink:causes MONDO:0017623 infores:clingen CAID:CA645369492 MONDO:0017623 PMID:29706350 Uncertain Significance PM2, PS4_Supporting PS3 PTEN c.39_41del (p.Arg15del) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 30528446) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369492/MONDO:0017623/003 2021-06-04 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:101278 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018681 infores:hetionet CAID:CA294895008 biolink:causes MONDO:0009290 infores:clingen CAID:CA294895008 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting PM3 "The NM_000152.5:c.1564C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 522 (p.Pro522Ser). Two probands with a confirmed diagnosis of IOPD have been reported with this variant (PMID: 32518148, 38250073), both CRIM-positive, one with documented symptoms of IOPD and the other on ERT (PP4_Moderate). Both probands are compound heterozygotes for the variant and other variants that have yet to be classified by the ClinGen Lysosomal Diseases VCEP (PM3_Not Met). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001761 in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2, meeting this criterion. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B (""potentially less severe""). This includes 0.8% GAA activity in cells and 0.8% in medium, and evidence of abnormal synthesis and processing on Western blot (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.932 which is higher than the ClinGen LD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 972746). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PS3_Moderate, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA294895008/MONDO:0009290/010 2024-03-19 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:37924 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0017152 infores:hetionet CHEBI:15854 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0022346 infores:hetionet CHEBI:63619 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0085932 infores:hetionet CHEBI:478164 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0030312 infores:hetionet CHEBI:6887 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0392676 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151559 infores:hetionet CAID:CA387792666 biolink:causes MONDO:0700269 infores:clingen CAID:CA387792666 MONDO:0700269 PMID: Pathogenic PVS1, PS3 PM2, PM5 The c.6859A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual arginine at amino acid 2287 (p.(Arg2287Ter)). This variant is present in gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Nonsense of exon 12 variant predicted to cause a premature stop codon in biologically-relevant-exon 12/27 leading to nonsense mediated decay (PVS1 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:32046981) (PS3 met).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA387792666/MONDO:0700269/097 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6062 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0232459 infores:hetionet CHEBI:51141 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C1384353 infores:hetionet UNII:R43D2573WO biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011124 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0687707 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0518015 infores:hetionet CHEBI:41879 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0011603 infores:hetionet CHEBI:63630 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0020578 infores:hetionet NCBIGene:7555 biolink:causes MONDO:0011266 infores:monarchinitiative not_provided not_provided HGNC:13164 MONDO:0011266 uuid:6c6901fe-b44a-42df-abc5-54c4a0c56a2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5296 biolink:causes UMLS:C0857323 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0857323 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0028961 infores:hetionet CHEBI:41423 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0232726 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0040034 infores:hetionet CHEBI:28915 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0002994 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0236171 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0236171 infores:hetionet CHEBI:63631 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232849 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002905 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0026884 infores:hetionet CAID:CA10014513 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014513 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.445G>A (p.Ala149Thr) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014513/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8597 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0948089 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0034068 infores:hetionet CHEBI:2549 biolink:causes UMLS:C1258192 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C1258192 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006266 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1384666 infores:hetionet GO:0002067 biolink:causes CL:0000150 infores:ubergraph knowledge_assertion manual_agent GO:0002067 CL:0000150 CHEBI:3515 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0012833 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020676 infores:hetionet CHEBI:94609 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0234233 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0032961 infores:hetionet NCBIGene:8021 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:8064 MONDO:0018874 uuid:0297ef20-858f-4eba-add5-8d288fa6aa6b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6916 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C2830004 infores:hetionet CHEBI:50730 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0034359 infores:hetionet CHEBI:127342 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0039070 infores:hetionet CHEBI:31401 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0023218 infores:hetionet CHEBI:6775 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0595916 infores:hetionet CHEBI:51450 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0023530 infores:hetionet CHEBI:4975 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0010200 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0018099 infores:hetionet CHEBI:10023 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0558489 infores:hetionet CHEBI:8430 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0002994 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1142412 infores:hetionet CHEBI:16796 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0233794 infores:hetionet CAID:CA10443887 biolink:causes MONDO:0010315 infores:clingen CAID:CA10443887 MONDO:0010315 PMID: Likely Benign BS2 BS1, PM5, PM2 The NM_000206.3(IL2RG):c.332T>C (p.Ile111Thr) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. It occurs at an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0001413 (based on 6/14830 alleles in the East Asian population) which is below the SCID VCEP established threshold of >0.00249 for BS1 and above the PM2 threshold of <0.000124. Three adult hemizygous males with this variant are present in the East Asian population in gnomADv2.1.1 (BS2). In summary, this variant is classified as Likely Benign. Criteria applied: BS2 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10443887/MONDO:0010315/129 2024-01-17 2024-01-17 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Contradicts true UMLS:C0004609 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0007097 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020550 infores:hetionet CHEBI:31625 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0017601 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011334 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0006444 infores:hetionet CHEBI:114785 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0085641 infores:hetionet CHEBI:63611 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0086565 infores:hetionet CHEBI:116735 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0011603 infores:hetionet CHEBI:66964 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0040264 infores:hetionet NCBIGene:50485 biolink:causes MONDO:0009458 infores:monarchinitiative not_provided not_provided HGNC:11102 MONDO:0009458 uuid:a6d645d4-4e5e-4701-bb07-ada76d387c71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10585816 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585816 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PVS1, PM6, PP3, PP1, BS2 The NM_000527.5(LDLR):c.2297C>T (p.Thr766Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0). PP4: Variant meets PM2 and is identified in one index case who fulfils DLCN criteria for probable FH after alternative causes of high cholesterol excluded, reported in PMID 16250003 (Fouchier et al., 2005), The Netherlands. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585816/MONDO:0007750/013 2024-10-28 2025-01-20 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50693 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0002962 infores:hetionet CHEBI:3393 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00578 UMLS:C0020517 infores:hetionet CHEBI:9460 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0497247 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0011991 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0036572 infores:hetionet CHEBI:3387 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0041657 infores:hetionet CHEBI:47781 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0043094 infores:hetionet NCBIGene:25861 biolink:causes MONDO:0011767 infores:monarchinitiative not_provided not_provided HGNC:16361 MONDO:0011767 uuid:631de32b-3a5c-4d7f-84e8-2357370cefe4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038362 infores:hetionet CHEBI:28445 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0575081 infores:hetionet CHEBI:8028 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0239375 infores:hetionet CHEBI:4876 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0011603 infores:hetionet CHEBI:7931 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0038990 infores:hetionet CHEBI:77260 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1443060 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0919980 infores:hetionet CHEBI:231425 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0013378 infores:hetionet CHEBI:7575 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0042373 infores:hetionet CHEBI:82960 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0030554 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0948692 infores:hetionet CHEBI:4903 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0013428 infores:hetionet CHEBI:5847 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0042963 infores:hetionet GO:0090107 biolink:causes GO:0097006 infores:ubergraph knowledge_assertion manual_agent GO:0090107 GO:0097006 CHEBI:28864 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0700184 infores:hetionet CHEBI:3207 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0013456 infores:hetionet CHEBI:7447 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0948586 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0014544 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002453 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0013220 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0003864 infores:hetionet NCBIGene:10299 biolink:causes MONDO:0013322 infores:monarchinitiative not_provided not_provided HGNC:30550 MONDO:0013322 uuid:ed8dc452-1f92-4a7d-b106-f15b8a1581c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085682 infores:hetionet CHEBI:94501 biolink:causes UMLS:C1697642 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C1697642 infores:hetionet CHEBI:8869 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C2697368 infores:hetionet CHEBI:94392 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0020546 infores:hetionet CAID:CA7724119 biolink:causes MONDO:0044970 infores:clingen CAID:CA7724119 MONDO:0044970 PMID: Benign BS2, BA1 The c.3483-41 A>C variant in POLG is present in population databases at the following frequencies: 1000 genomes at 1.7%; gnomad at 1.4% with 246 homozygotes; ExAC 1.3% with 104 homozygotes (BA1; observed > 1% frequency and BS2). In summary, there is sufficient evidence to characterize this variant as benign for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1, BS2 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA7724119/MONDO:0044970/014 2021-05-06 2021-05-06 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:132233 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0015672 infores:hetionet CAID:CA10529735 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529735 MONDO:0010604 PMID: Benign BP7, BP4, BA1 The c.108C>T (p.Asn36=) variant is reported at an MAF of 0.0002820 (5/17730 alleles) in the South Asian population in gnomAD v2.1.1 with 1 hemizygote, meeting BA1 criteria of MAF > 0.0000556. SpliceAI predicts no splicing impact, with delta scores of 0, meeting BP4. The nucleotide is not conserved, with PhyloP score of -0.14 and PhastCons score of 0.031, meeting BP7. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4, BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529735/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Contradicts true GO:0048079 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0048079 GO:0007275 CHEBI:16469 biolink:causes UMLS:C0853074 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853074 infores:hetionet CHEBI:38940 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020453 infores:hetionet CHEBI:83804 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0001807 infores:hetionet CHEBI:6958 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0003811 infores:hetionet CAID:CA16028086 biolink:causes MONDO:0021056 infores:clingen CAID:CA16028086 MONDO:0021056 PMID: Likely Pathogenic PM5_Supporting, PS4, PM2_Supporting PP2, PP3, PP1, BP1 The c.3083G>T variant in APC is a missense variant predicted to cause the substitution of serine by isoleucine at amino acid position 1028 (p.Ser1028Ile). This variant has been reported in 6 individuals resulting in a total phenotype score of 4.5 (PS4, Ambry, Invitae, Melbourne internal data). Another missense variant c.3084T>A (p.Ser1028Arg) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Splicing prediction using SpliceAI and varSEAK revealed no expected effects on splicing due to any of these variants. Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16028086/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3723 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235639 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0700345 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0007137 infores:hetionet CHEBI:50730 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0233794 infores:hetionet CHEBI:79699 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0014591 infores:hetionet CHEBI:8107 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C2242996 infores:hetionet CHEBI:4495 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0042963 infores:hetionet CHEBI:44032 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0023222 infores:hetionet UMLS:C0145185 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0151636 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0032285 infores:hetionet CHEBI:145499 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0162316 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0027051 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0044792 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0044792 uuid:bba2c952-3c80-44e4-986e-490a64592b05 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0015663 infores:hetionet CHEBI:125354 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0231218 infores:hetionet CHEBI:27786 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0041834 infores:hetionet CHEBI:44423 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0034063 infores:hetionet CHEBI:5138 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1760428 infores:hetionet UMLS:C0009315 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0476273 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C1443060 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0018801 infores:hetionet CHEBI:7865 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0015672 infores:hetionet CHEBI:167638 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0013428 infores:hetionet CHEBI:68606 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0311468 infores:hetionet CAID:CA320617945 biolink:causes MONDO:0011071 infores:clingen CAID:CA320617945 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.613+20G>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.29) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320617945/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2704 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0002962 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0040479 infores:hetionet CHEBI:83527 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0039231 infores:hetionet CHEBI:101085 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0004134 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0031542 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0022660 infores:hetionet CAID:CA226036 biolink:causes MONDO:0100453 infores:clingen CAID:CA226036 MONDO:0100453 PMID:25477517 Likely Pathogenic PM3_Strong, PS3_Supporting, PP4_Moderate, PP3, PM2_Supporting PM6 The NM_000180.4(GUCY2D):c.1052A>G (p.Tyr351Cys)variant is predicted to replace the tyrosine at position p.351 with cysteine. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000005622, with 9 alleles / 1,600,764 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.733, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function. This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 32865313, 15024725). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg1059Ter variant confirmed in trans (did not count, PMID: 27208204), which has not yet been classified by the ClinGen LCA/eoRD VCEP. It has also been reported in another proband with with early-onset severe retinal dystrophy who was compound heterozygous with the c.2943del variant, classified as pathogenic by the VCEP, confirmed in trans (1 point, PMID: 17525851). (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with an age of onset before age 4 (1 pt). Reported to have nystagmus (1 pt), sluggish pupils (0.5 pts), decreased peripheral vision (1 pt), and decreased central visual acuity (1 pt). ERG and multifocal ERG below normal thresholds (1 pt). Fundoscopy and blue autofluorescence unremarkable. Genetic testing using the ASPER Biotech LCA-Microarray (2006) did not reveal any additional likely variants. (2 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 17525851, PP4_Moderate). The protein exhibits a dramatically reduced RD3 signal compared to wild-type control in a GUCY2D pull-down assay. (PS3_Supporting, PMID: 25477517). This variant has been identified as a de novo occurrence in 1 individual with a phenotype specific for GUCY2D-related recessive retinopathy at the PP4_Moderate level (PMID: 17525851). However, the PM6 code was not met since the variant was hypothesized to be on the paternal allele and the genotyping methods were not sufficient to confirm the paternal relationship. In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226036/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:71255 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0852733 infores:hetionet CAID:CA16020900 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020900 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4_Moderate PM3 The frameshift variant c.933del occurs in exon 9 of 13 and is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One patient has been reported (PMID: 21307867) with this variant. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020900/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports GO:0006954 biolink:causes MONDO:0005178 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D010003 DB01397_MESH_D010003_1DB01600_MESH_D010003_1 CHEBI:119915 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151836 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151736 infores:hetionet CHEBI:9241 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0013144 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0025061 infores:hetionet GO:1903538 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:1903538 GO:0051321 CHEBI:36791 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022568 infores:hetionet CHEBI:5775 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0003467 infores:hetionet CHEBI:7986 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0033774 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0919894 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0919894 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0042373 infores:hetionet GO:0060046 biolink:causes GO:0007338 infores:ubergraph knowledge_assertion manual_agent GO:0060046 GO:0007338 CHEBI:16469 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0178298 infores:hetionet CAID:CA1244290 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244290 MONDO:0005338 PMID: Likely Benign BS1, BP7, BP4 BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.369C>T variant in MYOC is a synonymous variant (p.Thr123=). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.002718, which met the ≥ 0.001 threshold set for BS1 (122 alleles out of 44,884), meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met.Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1, BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244290/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6923 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0003123 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0006277 infores:hetionet CHEBI:4798 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0037011 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0549478 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0549478 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0677500 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0009319 infores:hetionet CHEBI:17334 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0041657 infores:hetionet CAID:CA016824 biolink:causes MONDO:0005045 infores:clingen CAID:CA016824 MONDO:0005045 PMID:15008060PMID:9829907 Pathogenic PP3, PM1, PM2, PP1_Strong, PS4 The c.788T>C (p.Ile263Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:15008060; PMID:9829907; PMID:12707239; PMID:22429680; PMID:20624503; Partners LMM ClinVar SCV000059656.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 10 affected individuals (PP1_Strong: PMID:15008060; PMID:9829907). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PP1_Strong, PM1, PM2, PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016824/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:37333 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0035455 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0002871 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0038362 infores:hetionet CAID:CA013640 biolink:causes MONDO:0004994 infores:clingen CAID:CA013640 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3351G>A (p.Glu1117=) variant in the MYH7 gene is 0.34% (212/55890) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013640/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9943 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0032231 infores:hetionet NCBIGene:23500 biolink:causes MONDO:0031008 infores:monarchinitiative not_provided not_provided HGNC:18143 MONDO:0031008 uuid:c1312fef-d31e-42f1-89b0-3da00babeca0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0010692 infores:hetionet CHEBI:63607 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0009806 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151849 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0042075 infores:hetionet CAID:CA6831850 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831850 MONDO:0015967 PMID: Uncertain Significance BP4, PS4, PM2, PP3 The c.866C>T variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 289 (p.(Pro289Leu)) of NM_000545.8. The Grpmax filtering allele frequency of the this variant in gnomAD v2.1.1 is 0.000003090, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff and the case count is below the MDEP threshold (PMID: 31291970, internal lab contributors). This variant has a REVEL score of 0.663, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. Other missense variants at this amino acid position, c.866C>A (p.Pro289His), p.866C>G (p.Pro289Arg) and c.865C>T (p.Pro289Ser), have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.866C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): none. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831850/MONDO:0015967/017 2024-11-16 2024-11-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17474 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C1384606 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0011053 infores:hetionet CHEBI:4995 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085611 infores:hetionet CHEBI:72297 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0151908 infores:hetionet CHEBI:63630 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027497 infores:hetionet CHEBI:102216 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0037036 infores:hetionet CAID:CA5949886 biolink:causes MONDO:0000572 infores:clingen CAID:CA5949886 MONDO:0000572 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PP4, PM1, PM3, BA1, PS3, BS1, BS3 The NM_000448.3:c.1A>G (p.Met1Val) variant in RAG1 is an initiation codon variant that is not expected to result in nonsense-mediated mRNA decay but may cause a truncated protein by using an alternative start codon (Met183). There is one frameshift variant (p.K86VfsX33) that occurs upstream of codon 183, which causes the production of an N-terminally truncated RAG1 with low recombination activity and altered cellular localization (PMIDs 24290284, 11121059, 27301863) (PVS1_Moderate). The gnomAD 2.1.1 Popmax filtering allele frequency of this variant is 0.0001017, which is lower than the SCID VCEP threshold for PM2 (0.000102), and no homozygous individual has been observed in the gnomAD. Therefore it meets this criterion (PM2_Supporting).The variant has been detected in at least four individuals diagnosed with primary immunodeficiency. Patient A, reported by PMID 26186701, was heterozygous for this variant and a p.R737H variant (not curated by the SCID-VCEP), 0 pt. The other three individuals were reported in ClinVar entries without the information of the second allele, and in all three entries, the variant was classified as Uncertain Significance (Illumina Laboratory Services, SCV000371654.2; Illumina Laboratory Services, SCV000371655.2; Invitae, SCV001230493.3). The reported patient information is not sufficient to meet PM3 or PP4 criteria. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Moderate, PM2_Supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5949886/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:135613 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0003862 infores:hetionet CHEBI:7494 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013491 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0438173 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0438173 infores:hetionet CHEBI:75984 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0011606 infores:hetionet CHEBI:28918 biolink:causes UMLS:C1735322 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C1735322 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085584 infores:hetionet CHEBI:15765 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0015230 infores:hetionet CHEBI:8024 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0020461 infores:hetionet CHEBI:6067 biolink:causes HP:0010588 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151628 infores:hetionet CHEBI:10101 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2363730 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0003123 infores:hetionet CHEBI:16755 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0231528 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0435002 infores:hetionet CHEBI:100241 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0404521 infores:hetionet CHEBI:51860 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0003862 infores:hetionet CHEBI:9570 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0151828 infores:hetionet CHEBI:7496 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0038362 infores:hetionet CHEBI:50859 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011603 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020517 infores:hetionet NCBIGene:1200 biolink:causes MONDO:0008769 infores:monarchinitiative not_provided not_provided HGNC:2073 MONDO:0008769 uuid:d50969e6-e855-4838-88b1-79d12736f7f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6437 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0031350 infores:hetionet CAID:CA16020955 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020955 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5, PP4 The c.1166C>G (p.Ala389Gly) variant in PAH has been reported in 1 non-English article that is not accessible. This variant is absent from population databases (PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.954 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020955/MONDO:0009861/006 2020-08-24 2020-08-24 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:2687 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0428977 infores:hetionet CHEBI:34967 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0085633 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0235750 infores:hetionet CHEBI:6367 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1609512 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0037274 infores:hetionet CHEBI:49662 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0031256 infores:hetionet CAID:CA359427654 biolink:causes MONDO:0012163 infores:clingen CAID:CA359427654 MONDO:0012163 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.235G>T (p.Glu79Ter) (NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met). The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules,1 very strong and 1 supporting criteria results in a Likely Pathogenic classification.In summary, this variant meets the criteria to be classified as Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met,PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359427654/MONDO:0012163/119 2024-01-30 2024-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7466 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0542203 infores:hetionet NCBIGene:284086 biolink:causes MONDO:0014174 infores:monarchinitiative not_provided not_provided HGNC:13387 MONDO:0014174 uuid:aa2d54ac-dd1c-4e58-bcfd-44e5432bf765 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3084 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0020649 infores:hetionet CHEBI:63611 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0020621 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0518015 infores:hetionet CHEBI:3756 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0231530 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0233472 infores:hetionet CHEBI:9667 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0004604 infores:hetionet CHEBI:5864 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0011603 infores:hetionet CHEBI:7444 biolink:causes UMLS:C0242461 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0242461 infores:hetionet CHEBI:7496 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0232462 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0178298 infores:hetionet CHEBI:6909 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0041657 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0855247 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0855247 infores:hetionet CHEBI:8346 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0027497 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0852733 infores:hetionet CHEBI:209807 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0036572 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0428196 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0428196 infores:hetionet CHEBI:68554 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0015397 infores:hetionet CHEBI:161680 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0014742 infores:hetionet CHEBI:253342 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0013595 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0022116 infores:hetionet NCBIGene:9570 biolink:causes MONDO:0859336 infores:monarchinitiative not_provided not_provided HGNC:4431 MONDO:0859336 uuid:9a777975-97b9-4a0b-9800-608ca2736588 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47519 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0236075 infores:hetionet CHEBI:7494 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0042267 infores:hetionet CHEBI:2704 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0038325 infores:hetionet CHEBI:63635 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C3665347 infores:hetionet CHEBI:408174 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0030193 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0234458 infores:hetionet CHEBI:17688 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0030554 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0030920 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009806 infores:hetionet CHEBI:52010 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0232292 infores:hetionet CHEBI:40279 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0542571 infores:hetionet CHEBI:68841 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0151828 infores:hetionet CHEBI:691037 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0162835 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0013395 infores:hetionet CHEBI:94501 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0027497 infores:hetionet CHEBI:7822 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0041582 infores:hetionet HP:0031377 biolink:causes MONDO:0005086 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D002292 DB00877_MESH_D002292_1DB01590_MESH_D002292_1 CHEBI:74947 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0009806 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0030554 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085606 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0032326 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0016542 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0016542 infores:hetionet CHEBI:2676 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0023530 infores:hetionet CHEBI:167638 biolink:causes MONDO:0018056 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0023648 infores:hetionet CAID:CA10581716 biolink:causes MONDO:0100437 infores:clingen CAID:CA10581716 MONDO:0100437 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting PP4 NM_001034853.2(RPGR):c.808C>T (p.Gln270Ter) is a nonsense variant that introduces a premature stop in codon 270 within exon 8 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses (PMID: 32094925, PMID: 27208204, https://hdl.handle.net/10371/177779], PS4_Supporting). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PS4_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581716/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:47780 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0008031 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0029408 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0014130 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0027765 infores:hetionet CHEBI:4551 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0264906 infores:hetionet CHEBI:9649 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0011124 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0221706 infores:hetionet CHEBI:29013 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0021368 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0027651 infores:hetionet NCBIGene:5091 biolink:causes MONDO:0009949 infores:monarchinitiative not_provided not_provided HGNC:8636 MONDO:0009949 uuid:c9475180-240d-487f-b515-6a6b1528884b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3242 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0085628 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0342579 infores:hetionet CHEBI:2788 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C2830004 infores:hetionet CHEBI:38940 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0542571 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027769 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0239062 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0239062 infores:hetionet NCBIGene:3741 biolink:causes MONDO:0012828 infores:monarchinitiative not_provided not_provided HGNC:6224 MONDO:0012828 uuid:6d5d54ce-a338-40ee-9051-69b720b0f413 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15544 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0042023 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0031350 infores:hetionet CAID:CA320255546 biolink:causes MONDO:0011071 infores:clingen CAID:CA320255546 MONDO:0011071 PMID: Uncertain Significance PS3, PS1, PS2, PS4, BP1, BP4, BP3, BP2, BA1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.884C>T (p.Ser295Phe) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320255546/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63620 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0038990 infores:hetionet CHEBI:47381 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0032617 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0232495 infores:hetionet CHEBI:31624 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C2047937 infores:hetionet CHEBI:51041 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0687713 infores:hetionet CHEBI:8707 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151905 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0034069 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0349506 infores:hetionet CHEBI:4466 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0042790 infores:hetionet CHEBI:77260 biolink:causes MONDO:0000702 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0400821 infores:hetionet CHEBI:49662 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0015672 infores:hetionet NCBIGene:1340 biolink:causes MONDO:0033637 infores:monarchinitiative not_provided not_provided HGNC:2280 MONDO:0033637 uuid:3c266600-ad26-4ba8-a8b6-5b21dd2d7e64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:182080 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0037763 infores:hetionet CHEBI:161680 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0037383 infores:hetionet CHEBI:61390 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C1260880 infores:hetionet CHEBI:127342 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0004093 infores:hetionet NCBITaxon:11909 biolink:causes MONDO:0021183 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11909 MONDO:0021183 CHEBI:27786 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0018790 infores:hetionet CHEBI:68647 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0024312 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0021400 infores:hetionet CHEBI:135276 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0043352 infores:hetionet CHEBI:7936 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011603 infores:hetionet CHEBI:17026 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1609512 infores:hetionet CHEBI:6444 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0428977 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151885 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151885 infores:hetionet GO:0060629 biolink:causes GO:0007127 infores:ubergraph knowledge_assertion manual_agent GO:0060629 GO:0007127 UMLS:C0120107 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0016658 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0020538 infores:hetionet CHEBI:10023 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0740394 infores:hetionet CHEBI:167638 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0028084 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0549452 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0549452 infores:hetionet NCBIGene:6323 biolink:causes MONDO:0100079 infores:monarchinitiative not_provided not_provided HGNC:10585 MONDO:0100079 uuid:28e4e3e6-5fd8-4cdc-a407-c2cf2fc1b687 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0021400 infores:hetionet CHEBI:9943 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0030232 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0041948 infores:hetionet CHEBI:36795 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0267792 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017178 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1609512 infores:hetionet CHEBI:7601 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0027497 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0008370 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002871 infores:hetionet CHEBI:55346 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151827 infores:hetionet CHEBI:681569 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0038362 infores:hetionet CAID:CA386296891 biolink:causes MONDO:0009861 infores:clingen CAID:CA386296891 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, PP3_Moderate, PM3_Supporting PM5 The c.552G>T (p.Lys184Asn) variant in PAH is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 184. It has been detected in a patient with phenylketonuria with pathogenic variant c.442-1G>A, phase unconfirmed (PMID: 25456745). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect (REVEL= 0.827). In summary, this variant is classified as likely pathogenic due to insufficient evidence based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_supporting, PP3_moderate, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386296891/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53691 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0010200 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0740425 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C1510497 infores:hetionet CHEBI:3380 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0004093 infores:hetionet CHEBI:8772 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0149871 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0001824 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0032326 infores:hetionet CHEBI:47781 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0241934 infores:hetionet CHEBI:5778 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0004134 infores:hetionet GO:0042670 biolink:causes CL:0000573 infores:ubergraph knowledge_assertion manual_agent GO:0042670 CL:0000573 CHEBI:15367 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0151907 infores:hetionet NCBIGene:79628 biolink:causes MONDO:0013237 infores:monarchinitiative not_provided not_provided HGNC:29427 MONDO:0013237 uuid:8e3b306e-78e7-4665-8ab1-7b517cededd0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0855242 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0577115 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0577115 infores:hetionet CHEBI:63577 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0018681 infores:hetionet CHEBI:171719 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0030193 infores:hetionet CHEBI:3082 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0036104 infores:hetionet CHEBI:7494 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151904 infores:hetionet NCBIGene:6391 biolink:causes MONDO:0011719 infores:monarchinitiative not_provided not_provided HGNC:10682 MONDO:0011719 uuid:71a6b582-98e8-4117-982c-def2d65d02c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5001 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0043094 infores:hetionet GO:1905449 biolink:causes GO:0006909 infores:ubergraph knowledge_assertion manual_agent GO:1905449 GO:0006909 GO:2000354 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000354 GO:0007275 CHEBI:28748 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011615 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0233632 infores:hetionet NCBIGene:4099 biolink:causes MONDO:0014729 infores:monarchinitiative not_provided not_provided HGNC:6783 MONDO:0014729 uuid:1b3ff45f-4400-4bbc-a117-c9af0b47c640 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0234913 infores:hetionet CHEBI:8764 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0024314 infores:hetionet CHEBI:6067 biolink:causes HP:0012587 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0473237 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0521839 infores:hetionet CHEBI:520985 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0037383 infores:hetionet CHEBI:7476 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0233407 infores:hetionet UNII:7F465U79Q1 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00516 UMLS:C0020625 infores:hetionet CHEBI:8093 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0030232 infores:hetionet CAID:CA199357 biolink:causes MONDO:0100039 infores:clingen CAID:CA199357 MONDO:0100039 PMID: Benign BS2_Supporting, BA1 The allele frequency of the p.Ala486_Lys487del variant in CDKL5 is 0.03% in Latino/Admixed American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala486_Lys487del variant is observed in 1 unaffected individual (RettBASE, PMID 22867051) (BS2_supporting). In summary, the p.Ala486_Lys487del variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199357/MONDO:0100039/016 2022-02-18 2022-06-30 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:47780 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0018932 infores:hetionet CHEBI:64321 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0009806 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0005741 infores:hetionet CHEBI:45409 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0016204 infores:hetionet CHEBI:9086 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0007859 infores:hetionet CHEBI:8024 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0522055 infores:hetionet CHEBI:5893 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002874 infores:hetionet CHEBI:240107 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0030193 infores:hetionet CHEBI:231594 biolink:causes HP:0100878 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0151994 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0424823 infores:hetionet CHEBI:6640 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0014742 infores:hetionet CHEBI:100241 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018808 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0233494 infores:hetionet CHEBI:9737 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0235431 infores:hetionet CHEBI:8356 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151692 infores:hetionet CHEBI:64355 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0333355 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0151602 infores:hetionet CAID:CA2695201659 biolink:causes MONDO:0021056 infores:clingen CAID:CA2695201659 MONDO:0021056 PMID:33740971 Likely Pathogenic PP3, PP1_Moderate, PS3_Moderate, PS4_Supporting, PM2_Supporting The NM_000038.6(APC):c.1312+4_1312+19del variant in APC is an intronic variant which is located in intron 10. This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, [PMID: 33740971]). This variant has been reported to segregate with FAP in 7 meioses in 1 family (PP1_Moderate, [PMID: 33740971]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). RT-PCR and sequencing of cDNA demonstrated that the variant impacts splicing by causing exon 10 skipping and results in a frameshift in a gene in which loss-of-function is an established disease mechanism (PS3_Moderate, [PMID: 33740971]). The results from 2 in silico splicing predictors (MaxEntScan and VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 10 of APC (PP3_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS4_Supporting, PP1_Moderate, PM2_Supporting, PS3_Moderate, PP3_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/23). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695201659/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31981 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0002453 infores:hetionet CAID:CA8623244 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623244 MONDO:0100326 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting BS2, PP4 The c.1309G>T (p.Glu437Ter) variant in exon 10 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 10 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00002319 (2/86254 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant is reported in ClinVar (SCV002546491.1) in a homozygous Glanzmann thrombasthenia patient (PM3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM3_Supporting, and PM2_Supporting (VCEP specifications version 2; date of approval 04/16/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623244/MONDO:0100326/011 2024-04-16 2024-04-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9654 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0080274 infores:hetionet CHEBI:7824 biolink:causes HP:0001310 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0234162 infores:hetionet CHEBI:10650 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0011168 infores:hetionet CHEBI:15640 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C1443060 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0015397 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0013395 infores:hetionet CHEBI:5280 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C1565489 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0027765 infores:hetionet CHEBI:39867 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C2242588 infores:hetionet CHEBI:91541 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0042963 infores:hetionet CHEBI:31236 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0149745 infores:hetionet CHEBI:3380 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0232462 infores:hetionet CHEBI:38940 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151692 infores:hetionet CHEBI:2659 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0032343 infores:hetionet CHEBI:64312 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0010692 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0235266 infores:hetionet CHEBI:65349 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0039231 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0003123 infores:hetionet CHEBI:135736 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015230 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1306341 infores:hetionet CHEBI:135939 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0015230 infores:hetionet NCBITaxon:36827 biolink:causes MONDO:0015803 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:36827 MONDO:0015803 UNII:D27V6190PM biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0151908 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0004096 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0240130 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0240130 infores:hetionet CHEBI:209807 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0027707 infores:hetionet CHEBI:16335 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0085633 infores:hetionet CHEBI:32293 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0002871 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0518988 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234215 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0242350 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030552 infores:hetionet CHEBI:3757 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0014591 infores:hetionet CHEBI:17347 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0085932 infores:hetionet CHEBI:9599 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0002962 infores:hetionet CHEBI:6413 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0151942 infores:hetionet CHEBI:47381 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0008031 infores:hetionet NCBIGene:124997 biolink:causes MONDO:0054794 infores:monarchinitiative not_provided not_provided HGNC:26600 MONDO:0054794 uuid:ce39ea9d-8e9a-4178-b9b5-a8a78e888e6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:2000702 biolink:causes GO:0060675 infores:ubergraph knowledge_assertion manual_agent GO:2000702 GO:0060675 CHEBI:8707 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151315 infores:hetionet CHEBI:53760 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0033774 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0085605 infores:hetionet CHEBI:31397 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0542571 infores:hetionet CHEBI:135342 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020578 infores:hetionet CHEBI:7936 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040264 infores:hetionet CHEBI:29688 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0302809 infores:hetionet CHEBI:51041 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C1167965 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0009806 infores:hetionet CHEBI:28915 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0311468 infores:hetionet CHEBI:46195 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0085631 infores:hetionet CHEBI:59773 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0013144 infores:hetionet CHEBI:17474 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0025874 infores:hetionet CHEBI:2719 biolink:causes GO:0070294 infores:drugmechdb knowledge_assertion manual_agent MESH:D000804 GO:0070294 DB00584_MESH_D006333_1DB00519_MESH_D006973_1DB00542_MESH_D006973_1DB09477_MESH_D006973_1DB01197_MESH_D003928_1DB09477_MESH_D006333_1DB00584_MESH_D006973_1DB01197_MESH_D006973_1DB01348_MESH_D006973_1 CHEBI:63580 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0232461 infores:hetionet CHEBI:16469 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0028081 infores:hetionet CHEBI:38940 biolink:causes HP:0000832 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0700502 infores:hetionet CHEBI:101853 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0549448 infores:hetionet CHEBI:8774 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0032617 infores:hetionet CHEBI:80630 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0033247 infores:hetionet CHEBI:4514 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0027424 infores:hetionet CHEBI:50730 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0014743 infores:hetionet CHEBI:63624 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0030196 infores:hetionet NCBIGene:5979 biolink:causes MONDO:0008234 infores:monarchinitiative not_provided not_provided HGNC:9967 MONDO:0008234 uuid:fc1513f8-e661-4ac4-a022-fa44db58e60e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8772 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0042029 infores:hetionet CHEBI:4657 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0152198 infores:hetionet CAID:CA353655 biolink:causes MONDO:0007947 infores:clingen CAID:CA353655 MONDO:0007947 PMID: Pathogenic PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PM1_Strong PVS1, PM6, PP1, BS2, BP1, BP4, BP3, BP2, BA1, PM4, PM3, PM5, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4330T>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by serine at amino acid 1444 (p.Cys1444Ser). This variant has been identified in an adult patient with Marfan syndrome with bilateral ectopia lentis (EL), borderline thoracic aortic aneurysm and dissection (TAAD), and systemic features (PP4; Invitae internal data). A different nucleotide substitution (c.4331G>C) resulting in the same amino acid change has been identified in three individuals with clinical diagnoses of Marfan syndrome, all of whom were noted to have have EL in addition to other features of Marfan syndrome (PS4_moderate; University of Tokyo, Bichat, & Invitae internal data); in one family, c.4331G>C was found to segregate with annuloaortic ectasia and arachnodactyly in an infant child (University of Tokyo internal data). Of note, there is no predicted difference in splicing patterns between the two nucleotide substitutions. The c.4330T>A variant is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org, v2.1.1 & v3.1.2). It affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis further support that this variant is likely to impact the protein (PP3; REVEL = 0.949). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, c.4330T>A (p.Cys1444Ser) meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA353655/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CAID:CA8815387 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815387 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 The NM_000152.5:c.1593C>T (p.Asp531=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (-2.52) (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0003 (18/60014 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). It has not been reported in any individuals with Pompe disease to our knowledge. There is a ClinVar entry for this variant (Variation ID: 498567). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815387/MONDO:0009290/010 2025-01-21 2025-02-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:17334 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0442874 infores:hetionet CHEBI:41977 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0011991 infores:hetionet CHEBI:15553 biolink:causes HP:0100718 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0042143 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0003123 infores:hetionet CHEBI:35778 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0003811 infores:hetionet CHEBI:116278 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0030554 infores:hetionet CHEBI:17688 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0231528 infores:hetionet CHEBI:47381 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0851578 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0575090 infores:hetionet CHEBI:71417 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0002871 infores:hetionet CHEBI:40303 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0013378 infores:hetionet CHEBI:6539 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0027849 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020651 infores:hetionet CHEBI:10119 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0024282 infores:hetionet CHEBI:80630 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0004604 infores:hetionet CHEBI:144551 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0027424 infores:hetionet CAID:CA658824779 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824779 MONDO:0009290 PMID:29124014 Pathogenic PVS1, PM2, PP4 PM3 This variant, c.755dup (p.Pro253AlafsTer77), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP’s specifications for PP4 and who is compound heterozygous for the variant and c.569G>A (p.Arg190His) (PMID 29124014). The phase is unknown. This is intrans data will be used in the assessment of p.Arg190His and is therefore not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 553981, one star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824779/MONDO:0009290/010 2020-07-20 2020-11-11 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:77733 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0812387 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0025061 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031542 infores:hetionet CHEBI:5002 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0042963 infores:hetionet CHEBI:240107 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0014591 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0032584 infores:hetionet CHEBI:18385 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0518015 infores:hetionet CHEBI:9738 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0341047 infores:hetionet CHEBI:9352 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0013428 infores:hetionet CHEBI:70718 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0015230 infores:hetionet CHEBI:194135 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0028643 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0162429 infores:hetionet CHEBI:182080 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0014518 infores:hetionet CHEBI:3723 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0023218 infores:hetionet CHEBI:473990 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0017979 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0544618 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0544618 infores:hetionet CHEBI:6754 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0027066 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0234215 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0032226 infores:hetionet GO:0110107 biolink:causes GO:0007472 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0007472 CHEBI:28864 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0041834 infores:hetionet CHEBI:4876 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0040264 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0442874 infores:hetionet CAID:CA9870244 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870244 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, PP4, PM1 The c.422G>A variant in the hepatocyte nuclear factor 4-alpha, HNF4A, causes an amino acid change of arginine to glutamine at codon 141 (p.(Arg141Gln)) of NM_175914.4. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to zero copies in the European non-Finnish subpopulation and one copy in another subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (PMID:11232004). This variant has a REVEL score of 0.539, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870244/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2682 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0021053 infores:hetionet CHEBI:8214 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C2830004 infores:hetionet NCBIGene:1832 biolink:causes MONDO:0011831 infores:monarchinitiative not_provided not_provided HGNC:3052 MONDO:0011831 uuid:2ee42119-200a-4df0-a82d-65986408c2fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0013362 infores:hetionet CHEBI:125354 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0016204 infores:hetionet CHEBI:6950 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0004604 infores:hetionet CAID:CA2018007653 biolink:causes MONDO:0015967 infores:clingen CAID:CA2018007653 MONDO:0015967 PMID: Likely Pathogenic PM5_Strong, PP4, PP2, PM2_Supporting The c.627_628delinsAG variant in the glucokinase gene, GCK, is a deletion of GA followed by an insertion of AG, resulting in an amino acid change of methionine to valine at codon 210 (p.(Met210Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). Additionally, two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.627_628delinsAG meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 3/23/2023): PM5_Strong, PP2, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2018007653/MONDO:0015967/086 2023-05-26 2023-05-26 Semidominant inheritance HP:0032113 Supports CHEBI:10125 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0851341 infores:hetionet CHEBI:5138 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0043352 infores:hetionet CHEBI:31485 biolink:causes EFO:0003822 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0020452 infores:hetionet CHEBI:51860 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0009782 infores:hetionet CHEBI:4858 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0042024 infores:hetionet CHEBI:8673 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00205 UMLS:C0002888 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0030305 infores:hetionet CHEBI:9086 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0428977 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0542101 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0542101 infores:hetionet NCBIGene:7291 biolink:causes MONDO:0007042 infores:monarchinitiative not_provided not_provided HGNC:12428 MONDO:0007042 uuid:4adcf669-8fc9-45be-86f1-2ca092c207cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31932 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0162830 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0003123 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005810 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0021345 infores:hetionet CHEBI:6954 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0033687 infores:hetionet CHEBI:16347 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0546817 infores:hetionet CHEBI:9588 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0595929 infores:hetionet CHEBI:2639 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0428977 infores:hetionet CHEBI:10125 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0009806 infores:hetionet CAID:CA10014236 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014236 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BA1, BP1, BP3, BP2, PM2, PVS1, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.968-18C>T is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.0) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014236/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:9430ZR8ZAN biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0039070 infores:hetionet CHEBI:4514 biolink:causes UMLS:C0857257 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0857257 infores:hetionet GO:1903125 biolink:causes GO:0097237 infores:ubergraph knowledge_assertion manual_agent GO:1903125 GO:0097237 NCBIGene:4683 biolink:causes MONDO:0015909 infores:monarchinitiative not_provided not_provided HGNC:7652 MONDO:0015909 uuid:2ee647a3-ea5c-4fd5-889a-15c07563d09b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53760 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0038367 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1971624 infores:hetionet CHEBI:28864 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0162835 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018099 infores:hetionet CHEBI:7577 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0020580 infores:hetionet CHEBI:45951 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0162830 infores:hetionet CAID:CA367401572 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401572 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.559G>C variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to histidine at codon 187 (p.(Asp187His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (persistent FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate; internal lab contributor). Another missense variant, c.559G>T p.Asp187Tyr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.559G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Suppporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401572/MONDO:0015967/086 2024-06-09 2024-06-09 Semidominant inheritance HP:0032113 Supports CHEBI:8356 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0017086 infores:hetionet CHEBI:27565 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0178298 infores:hetionet CHEBI:8764 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1720775 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0549225 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0549225 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0031117 infores:hetionet NCBIGene:79083 biolink:causes MONDO:0012220 infores:monarchinitiative not_provided not_provided HGNC:29643 MONDO:0012220 uuid:5c345985-8bbf-4075-831c-7c4aa1987b59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3655 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0017178 infores:hetionet CAID:CA000191 biolink:causes MONDO:0017623 infores:clingen CAID:CA000191 MONDO:0017623 PMID: Likely Benign BP7, BP4, BS1_Supporting PM6, PM2, PVS1, BP5, BS4, BS3, BS2, PP1, PP3, PP2, PM1, PM4, PM5, BP2, BA1, PS2, PS4, PS3, PS1 PTEN c.720C>T (p.Tyr240=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted.BS1_P: Allele frequency of 0.00010 (0.010%, 13/129,168 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000191/MONDO:0017623/003 2019-11-22 2019-12-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63611 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042594 infores:hetionet CHEBI:3077 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0002994 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0948089 infores:hetionet CHEBI:17334 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0151596 infores:hetionet CAID:CA10014568 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014568 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.206G>T (p.Gly69Val) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014568/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7824 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0162429 infores:hetionet CAID:CA414802276 biolink:causes MONDO:0044970 infores:clingen CAID:CA414802276 MONDO:0044970 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting PS3 The m.9134A>G (p.Glu203Gly) variant in MT-ATP6 has been reported in two individuals with primary mitochondrial disease to date (PMIDs: 22231385, 30763462, 32652755; PS4_supporting). The first reported case was newborn with hypotonia, intrauterine growth restriction, hypsarrhythmia, hypertrophic cardiomyopathy, and lactic acidosis (PMID: 22231385, included in cohort summary in PMID: 30763462). A defect in ATP synthesis was noted in muscle. The variant was present but heteroplasmy was not reported. The second case was an individual with hypotonia, lactic acidosis, and hypertrophic cardiomyopathy (PMID: 32652755). The variant was present at 81.4% in blood. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.824 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 3, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414802276/MONDO:0044970/015 2024-12-03 2025-10-02 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true UNII:3QJA87N40S biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0020649 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0004096 infores:hetionet CHEBI:7476 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0338656 infores:hetionet CHEBI:41237 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00676 UMLS:C0677500 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0023533 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0042373 infores:hetionet GO:0048378 biolink:causes GO:0048368 infores:ubergraph knowledge_assertion manual_agent GO:0048378 GO:0048368 CHEBI:3223 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0392162 infores:hetionet CHEBI:84050 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0035410 infores:hetionet NCBIGene:859 biolink:causes MONDO:0013686 infores:monarchinitiative not_provided not_provided HGNC:1529 MONDO:0013686 uuid:be356fc7-697c-43df-82de-6f360ada2a4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes HP:0032043 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0221150 infores:hetionet CHEBI:28148 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0016204 infores:hetionet CHEBI:35854 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0740399 infores:hetionet NCBITaxon:5658 biolink:causes MONDO:0005446 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5658 MESH:D016773 DB09031_MESH_D016773_1 CHEBI:17650 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0020649 infores:hetionet GO:0060685 biolink:causes GO:0061138 infores:ubergraph knowledge_assertion manual_agent GO:0060685 GO:0061138 CAID:CA10585234 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585234 MONDO:0007750 PMID: Likely Pathogenic PS4_Moderate, PS3_Supporting, PM1, PM2, PP3, PP4 PM5 The NM_000527.5 (LDLR): c. 974G>A (p.Cys325Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM1, PS4_Moderate, PP3, PP4, PS3_Supporting,) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP3 Met: REVEL = 0.977, which is above the threshold of 0.75.PM1 Met: The variant meets PM2, and alters Cys325, which is located in EGF-like 1 domain and is one of 60 highly conserved cysteine residues.PS3_Supporting Met: FACS assay using heterozygous patients’ lymphocytes (level 3 functional assay) showed 50-60% LDLR activity compared to wild type, from one research lab (CEINGE-Biotecnologie Avanzate, Napoli, Italy, PMID21865347). PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.PS4_Moderate Met: Variant meets PM2 and is identified in 8 unrelated index cases. Five of the index cases fulfil DLCN criteria for FH from 5 different laboratories (1 case from Mayo Clinic Atherosclerosis and Lipid genomics Laboratory, LabID500068; 1 case from University of Genova-University of Modena and Reggio Emilia, Italy, PMID32977124; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Spain, PMID19318025; 1 case from Centre for Heart Lung Innovation, University of British Columbia, Canada, PMID31345425; and 1case from Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, China, PMID30526649). One index case fulfil FH diagnosis criteria established by the Societa Italiana per lo Studio della Arteriosclerosi, CEINGE-Biotecnologie Avanzate, Napoli, Italy, PMID21865347. Two index cases fulfil Japanese FH guidelines, from Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan, PMID31491741.There are three other variants in the same codon: LDLR: NM_000527: c.973T>C (p.Cys325Arg), LDLR: NM_000527: c.974G>C (p.Cys325Ser), LDLR: NM_000527: c.974G>T (p.Cys325Phe), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585234/MONDO:0007750/013 2022-02-09 2022-04-25 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:28918 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0857121 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0948089 infores:hetionet CHEBI:31644 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0004936 infores:hetionet CHEBI:50275 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002962 infores:hetionet CHEBI:5856 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0042514 infores:hetionet CHEBI:53760 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0037672 infores:hetionet CHEBI:5613 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0013390 infores:hetionet CHEBI:71417 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0040053 infores:hetionet CHEBI:72564 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0030252 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0002622 infores:hetionet CAID:CA287216296 biolink:causes MONDO:0009276 infores:clingen CAID:CA287216296 MONDO:0009276 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP4, PM3 The NM_000173.7(GP1BA):c.586C>T (p.Gln196Ter) nonsense variant in exon 2, of 2, is not predicted to trigger NMD, instead truncating 70% of the protein, including the critical transmembrane domain (PVS1_strong). The Grpmax filtering allele frequency in gnomADv4.1 is 0.00003775 (based on 57/1179906 alleles) in the European (non-Finnish) population which is below the <0.0001114 threshold for PM2_supporting. Two patients have been reported with this variant however information was insufficient to confirm that the phenotype was specific to BSS (PMID: 24934643 and internal data). Both patients are compound heterozygotes with second variants (c.1601_1602delinsTGG and c.1436del respectively) classified VUS by the PD VCEP (PM3_NotMet). In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong and PM2_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA287216296/MONDO:0009276/079 2025-02-11 2025-02-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5893 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0002622 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0234894 infores:hetionet CHEBI:68841 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0032961 infores:hetionet CHEBI:3011 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0700225 infores:hetionet CAID:CA410147172 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147172 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1353C>A (p.Asp451Glu) is a missense variant which has a REVEL score < 0.50 (0.106), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147172/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8597 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0231218 infores:hetionet CHEBI:145499 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0039070 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0332575 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0233472 infores:hetionet CHEBI:2948 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0030781 infores:hetionet CHEBI:15551 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0036974 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011991 infores:hetionet CAID:CA10385495 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385495 MONDO:0100437 PMID: Benign BP4_Strong, BA1 NM_001034853.2(RPGR):c.1296A>T (p.Glu432Asp) is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 432. This variant is present in gnomAD v4.1.0 at a frequency of 0.0009778 among hemizygous individuals, with 385 variant alleles / 393,794 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.009, which is below the ClinGen X-linked IRD VCEP threshold of <0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385495/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true CL:0000066 biolink:causes MONDO:0004328 infores:ubergraph knowledge_assertion manual_agent CL:0000066 MONDO:0004328 GO:0090256 biolink:causes GO:0002165 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0002165 CHEBI:31302 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0043352 infores:hetionet CAID:CA549265042 biolink:causes MONDO:0001586 infores:clingen CAID:CA549265042 MONDO:0001586 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting The NM_000203.5:c.300-3C>G variant in IDUA occurs within the splice acceptor region of intron 2. RT-PCR of fibroblast RNA from an individual who is compound heterozygous for the variant (labeled as 388-3C>G in the publication) revealed that the variant results in insertion of 58 intronic nucleotides, which would result in a frameshift). Analysis of heterozygous polymorphic markers showed that the variant caused a significant decrease in the level of IDUA mRNA derived from the allele with the c.300-3C>G variant. Furthermore, expression of the variant in COS-7 cells resulted in 1.6% wild type IDUA activity with no IDUA protein detected on western blot (PMID: 10735634) (PVS1). Two patients with this variant had documented IDUA deficiency within the affected range in leukocytes, urinary GAGs above the normal range, or clinical features specific to MPS I including hepatosplenomegaly, corneal involvement, skeletal and cardiac abnormalities (PMID: 10735634, 29801497). (PP4_Moderate). These individuals are compound heterozygous for the variant and another variant in IDUA, c.1037T>G or c.1874A>C) (PMID: 10735634, 29801497). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PM3 not applied). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004557 (2/44876 alleles) in the EAS population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 23, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA549265042/MONDO:0001586/091 2025-05-23 2025-05-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2676 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0011606 infores:hetionet CHEBI:32293 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0033774 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151517 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0021053 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0014868 infores:hetionet CHEBI:4657 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C2242996 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0018802 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0042075 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0040409 infores:hetionet CHEBI:63613 biolink:causes NCIT:C113751 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C2242708 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0021053 infores:hetionet CHEBI:31644 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0024902 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0027339 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0026961 infores:hetionet CHEBI:9907 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0233494 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0011991 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0679048 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0679048 infores:hetionet CHEBI:17263 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C1510431 infores:hetionet CHEBI:145499 biolink:causes MONDO:0043494 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0003860 infores:hetionet CHEBI:6456 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C2363731 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002917 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0018500 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0030161 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0042256 infores:hetionet CHEBI:45783 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0740394 infores:hetionet CHEBI:71219 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0037299 infores:hetionet CHEBI:2654 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0018681 infores:hetionet CHEBI:52717 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0030232 infores:hetionet CHEBI:3640 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0004093 infores:hetionet NCBIGene:4487 biolink:causes MONDO:0008582 infores:monarchinitiative not_provided not_provided HGNC:7391 MONDO:0008582 uuid:0bab735d-a214-4cd0-97f6-ba81df24d18c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0027813 infores:hetionet CHEBI:64355 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C1142135 infores:hetionet CHEBI:4046 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0349506 infores:hetionet CHEBI:7025 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0031350 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0020456 infores:hetionet CHEBI:3127 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0020453 infores:hetionet CHEBI:48947 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0038999 infores:hetionet CHEBI:50742 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151798 infores:hetionet CHEBI:8764 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0039240 infores:hetionet CHEBI:2788 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C1510410 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0158350 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0158350 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0019163 infores:hetionet CHEBI:6067 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0162834 infores:hetionet UMLS:C0145867 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0700590 infores:hetionet CHEBI:9328 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0020517 infores:hetionet CHEBI:68554 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0341047 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0413252 infores:hetionet CAID:CA210779 biolink:causes MONDO:0013144 infores:clingen CAID:CA210779 MONDO:0013144 PMID: Pathogenic PS4_Very Strong, PP3, PM2_Supporting PP1 The c.482G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 161 (p.Arg161Gln also known as ATIII Geneva). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European population, which is lower than the ClinGen SERPINC1 threshold ([<0.00002]) for PM2_supporting, and therefore meets this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.691, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. The variant has been reported in at least 9 probands with AT deficiency in the literature meeting PS4_very strong (9 points applied PMID 28300866, 2229057, 3603409). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PM2_supporting, PP3, PS4_very strong. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210779/MONDO:0013144/084 2024-07-03 2024-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6715 biolink:causes UMLS:C0035085 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0035085 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027947 infores:hetionet CHEBI:16467 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0042963 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0009806 infores:hetionet CHEBI:9649 biolink:causes MONDO:0100431 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0338480 infores:hetionet CHEBI:28748 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009676 infores:hetionet CHEBI:7465 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0151905 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0039503 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0024299 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0332575 infores:hetionet CHEBI:5959 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0013378 infores:hetionet CHEBI:2611 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0917801 infores:hetionet CHEBI:3387 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0004134 infores:hetionet CHEBI:5855 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0497156 infores:hetionet CHEBI:31711 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0003537 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151505 infores:hetionet CHEBI:94385 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0018926 infores:hetionet CAID:CA7542755 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542755 MONDO:0012996 PMID: Uncertain Significance PP3, BP4, BS1, PM2 The NM_001482.3: c.1231G>A variant in GATM is a missense variant predicted to cause substitution of aspartate by asparagine at amino acid 411 (p.Asp411Asn). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007289 (86/1179782 alleles) in the European non-Finnish population. This is higher than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), and lower than the threshold for BS1 (Grpmax >0.0001). Therefore, none of the population data codes are met. The computational predictor REVEL gives a score of 0.477 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 625953). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): No criteria met(Classification approved by the ClinGen CCDS VCEP on April 11, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542755/MONDO:0012996/025 2025-04-11 2025-04-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8356 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018418 infores:hetionet CHEBI:63618 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0011633 infores:hetionet CHEBI:63598 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0013144 infores:hetionet CHEBI:63717 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0917801 infores:hetionet CHEBI:7476 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0039231 infores:hetionet CHEBI:64312 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019270 infores:hetionet CHEBI:6804 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0012833 infores:hetionet CHEBI:6912 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0687713 infores:hetionet CHEBI:68478 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0240671 infores:hetionet CHEBI:52717 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0162830 infores:hetionet NCBIGene:8892 biolink:causes MONDO:0957870 infores:monarchinitiative not_provided not_provided HGNC:3258 MONDO:0957870 uuid:0f557f5f-0b5e-40fc-935a-4783c81a33e4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46195 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0221242 infores:hetionet CHEBI:6375 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019825 infores:hetionet CHEBI:131512 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0001824 infores:hetionet CHEBI:175901 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0018965 infores:hetionet CHEBI:7809 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0027947 infores:hetionet CHEBI:9587 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01607 UMLS:C0011991 infores:hetionet CHEBI:10102 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0232461 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0002957 infores:hetionet CHEBI:7824 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0558489 infores:hetionet CAID:CA10549484 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549484 MONDO:0010305 PMID: Likely Benign BS1, BP4 The NM_005629.4(SLC6A8):c.1285C>G (p.Leu429Val) variant in SLC6A8 is a missense variant predicted to cause substitution of Valine for Leucine at amino acid 429 (p.Leu429Val). There is a ClinVar entry for this variant (Variation ID:715196, conflicting interpretations) with classifications as Variant of Uncertain Significance (n=1), Likely Benign (n=1), and Benign (n=1). This variant is found with an allele frequency of 0.00004401 in gnomADv2.1.1 with 5 hemizygotes present in that population database. Given the presence of 5 hemizygotes in gnomADv2.1.1, BS1 is applicable for this variant. The computational predictor REVEL gives a score of 0.101 which is below the threshold of 0.20, suggesting a benign effect of this variant on protein function, therefore BP4 criteria is applicable. At the time of this curation, this variant has not been reported in affected individuals in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BP4(Classification approved by the ClinGen CCDS VCEP on February 23, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549484/MONDO:0010305/027 2023-02-23 2024-04-10 X-linked inheritance HP:0001417 Contradicts true CHEBI:63617 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0019360 infores:hetionet CHEBI:50648 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0042023 infores:hetionet CHEBI:84500 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0004093 infores:hetionet CHEBI:3175 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0009421 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0036572 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0235431 infores:hetionet CHEBI:44185 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0042384 infores:hetionet CHEBI:5118 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020580 infores:hetionet CHEBI:40237 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0040460 infores:hetionet CHEBI:63611 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1142135 infores:hetionet UNII:2N4O9L084N biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0151559 infores:hetionet CAID:CA10014728 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014728 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.36G>T (p.Ser12=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.06) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.06) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.11)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014728/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5098 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0027697 infores:hetionet CHEBI:3310 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0006663 infores:hetionet CHEBI:66901 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0027424 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0021843 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0033575 infores:hetionet UMLS:C0017797 biolink:causes UMLS:C0553713 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0553713 infores:hetionet CHEBI:8888 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004134 infores:hetionet CAID:CA314807 biolink:causes MONDO:0012999 infores:clingen CAID:CA314807 MONDO:0012999 PMID: Likely Pathogenic PP4, PM3, PM2_Supporting, PP3_Moderate PM5 The NM_000156.6:c.491G>A variant in GAMT is a missense variant predicted to cause the substitution of a glycine by an aspartate at amino acid position 164 (p.Gly164Asp). This variant has been previously reported in one patient who had elevated plasma guanidinoacetate levels on two occasions (PP4) and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.522G>A (p.Trp174Ter, ClinVar ID: 205584), confirmed in trans by parental testing (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001667 (1/59992 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.919, evidence that correlates with impact to GAMT function (PP3_Moderate applied for REVEL score range 0.773-0.932). There is a ClinVar entry for this variant (Variation ID: 203539). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM3, PP4, PP3_Moderate, PM2_Supporting.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314807/MONDO:0012999/026 2024-09-11 2024-09-12 Autosomal recessive inheritance HP:0000007 Supports CAID:CA134687 biolink:causes MONDO:0021060 infores:clingen CAID:CA134687 MONDO:0021060 PMID: Pathogenic PS4_Moderate, PM2, PP2, PP3, PM6_Strong The c.1082G>C (p.Gly361Ala) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381 ClinVar SCV000209024.9). The p.Gly361Ala variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000209024.9, SCV000061333.5). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly361Ala variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134687/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CAID:CA414778366 biolink:causes MONDO:0044970 infores:clingen CAID:CA414778366 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong PP3, PP1, PS4, PS2, PS3, PM6 The m.4983C>T (p.Q172Term) variant in MT-ND2 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on October 14, 2024. There are no individuals with this variant reported in the medical literature to our knowledge. There is one prior report in ClinVar for this variant, however details are not provided precluding consideration of this case for this curation. As such, there are no reported de novo occurrences or large families to consider for evidence of variant segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation of the MT-ND2 protein (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 14, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414778366/MONDO:0044970/015 2024-10-14 2024-12-10 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5138 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0016658 infores:hetionet CHEBI:50648 biolink:causes HP:6000956 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0263634 infores:hetionet CHEBI:140621 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0021053 infores:hetionet CHEBI:6916 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0018681 infores:hetionet CHEBI:10101 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0231919 infores:hetionet CHEBI:4784 biolink:causes MONDO:0043786 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0036749 infores:hetionet UMLS:C0004609 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0039231 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0026946 infores:hetionet CHEBI:144093 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0004238 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0027013 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0027013 infores:hetionet CAID:CA2580098850 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098850 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting BP1, BP3, BP5, PM3, PP2, PP4 NM_001754.5(RUNX1):c.806-19C>T is an intronic variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score ≤ 0.20 (0.13) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.13) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.57) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098850/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:7161 biolink:causes MONDO:0030346 infores:monarchinitiative not_provided not_provided HGNC:12003 MONDO:0030346 uuid:98f69c5f-0eac-4334-aeb7-a429d699bf06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151872 infores:hetionet CHEBI:71272 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0011603 infores:hetionet CHEBI:3347 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0003862 infores:hetionet CHEBI:10119 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027497 infores:hetionet CHEBI:9939 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0855775 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0035258 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003123 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0029408 infores:hetionet CHEBI:8356 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0012569 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004059 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011432 infores:hetionet CHEBI:4798 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C2830004 infores:hetionet CHEBI:46195 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0085682 infores:hetionet CHEBI:8764 biolink:causes MONDO:0850421 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0267940 infores:hetionet CHEBI:84500 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0080274 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0039240 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0031117 infores:hetionet CHEBI:79699 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0038363 infores:hetionet CHEBI:32588 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0020625 infores:hetionet CHEBI:34385 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0178298 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0232492 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042769 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038454 infores:hetionet CHEBI:2549 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0027497 infores:hetionet CHEBI:46081 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0231528 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015300 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020615 infores:hetionet NCBITaxon:629 biolink:causes MONDO:0007023 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:629 MONDO:0007023 CHEBI:41423 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0015402 infores:hetionet CHEBI:55346 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0017178 infores:hetionet CHEBI:3504 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0038362 infores:hetionet CHEBI:3387 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0080274 infores:hetionet CHEBI:7465 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1260880 infores:hetionet NCBIGene:9652 biolink:causes MONDO:0024541 infores:monarchinitiative not_provided not_provided HGNC:23639 MONDO:0024541 uuid:41798b89-4467-43be-a17c-ae53b4d28d06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0042075 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0018801 infores:hetionet CHEBI:9398 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0017178 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0178298 infores:hetionet CHEBI:61049 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151827 infores:hetionet CHEBI:180905 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C2363731 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0011053 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0234215 infores:hetionet CHEBI:15367 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0043349 infores:hetionet CHEBI:194135 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0542571 infores:hetionet CHEBI:63581 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0020580 infores:hetionet CHEBI:8060 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0017178 infores:hetionet CHEBI:4911 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0041969 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0022408 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0004238 infores:hetionet CHEBI:74947 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0030193 infores:hetionet CHEBI:3756 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233794 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0031350 infores:hetionet CHEBI:520985 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0015672 infores:hetionet CHEBI:31709 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0040053 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005300 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C1561643 infores:hetionet CHEBI:50841 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0314719 infores:hetionet CHEBI:94440 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0018681 infores:hetionet CHEBI:68845 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0740394 infores:hetionet CHEBI:48669 biolink:causes UMLS:C0457436 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0457436 infores:hetionet CHEBI:2704 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C1527411 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0019348 infores:hetionet CHEBI:7459 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0011991 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0919582 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0919582 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002884 infores:hetionet CHEBI:10102 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0039231 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0031117 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0854100 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0854100 infores:hetionet CHEBI:34967 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0011603 infores:hetionet CHEBI:47381 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0086565 infores:hetionet CHEBI:8069 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0160390 infores:hetionet CHEBI:9654 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0043352 infores:hetionet CHEBI:2682 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0162557 infores:hetionet CHEBI:127342 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0021400 infores:hetionet CHEBI:135342 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0151766 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020550 infores:hetionet CHEBI:167638 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0013404 infores:hetionet CHEBI:17650 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0041834 infores:hetionet CHEBI:50922 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151772 infores:hetionet CHEBI:66919 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0019360 infores:hetionet CHEBI:5864 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0008031 infores:hetionet CAID:CA916081733 biolink:causes MONDO:0100216 infores:clingen CAID:CA916081733 MONDO:0100216 PMID: Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PS3 PVS1, PM6, BA1, BP1, BP4, BP3, BP2, PP2, PP1, PP4, BS2, PM4, PM1, PM3, PM5, PS2, PS1, BP5, BP7, BS1, BS3, BS4 The NM_177438.3:c.1908-3C>G variant in DICER1 is an intronic variant resulting in an C to G substitution 3 nucleotides upstream from coding exon 12. This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributors). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PM2_Supporting, PS3, PP3. (Bayesian Points: 7; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081733/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:421707 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0015230 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0009938 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C1971624 infores:hetionet CAID:CA410147747 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147747 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS4, PS2, PS3, BP3, BP2, BP1, BP4, BA1, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1221C>G (p.Tyr407Ter) is a nonsense variant which is predicted to escape nonsense-mediated decay and instead result in truncation of the functionally important C-terminal region, including the transactivation domain, inhibitory domain, and the VWRPY motif (PVS1_Strong). This variant is absent from gnomAD v2/v3/v4 (PM2_supporting), but it has not been reported in patients with RUNX1-related disease. This variant is downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147747/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Supports CHEBI:44423 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0015230 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235792 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235792 infores:hetionet CHEBI:3655 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0220870 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0549386 infores:hetionet CAID:CA10585468 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585468 MONDO:0007750 PMID: Uncertain Significance PM2, PP4, PP3 BA1, BP2, BP4, PS3, PS4, PS2, PS1, BS1, BS3, BS4, BP7, PM5, PM1, PM3, PM4, PVS1, PM6, PP1, BS2 The NM_000527.5(LDLR):c.1463T>G (p.Ile488Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.905. PP4: Variant meets PM2 and is identified in at least 1 FH index case with definite FH by Simon Broome criteria from PMID 20236128 (Taylor et al., 2010), UK, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585468/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA293902 biolink:causes MONDO:0007648 infores:clingen CAID:CA293902 MONDO:0007648 PMID: Benign BP2, BA1 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, PS1, PS3, PS4, PS2 The c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD cohort (BA1, BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA293902/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:75246 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C1619712 infores:hetionet CHEBI:6775 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0149745 infores:hetionet CHEBI:10124 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0235710 infores:hetionet CHEBI:94501 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0015230 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1112182 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1112182 infores:hetionet NCBIGene:6117 biolink:causes MONDO:0030690 infores:monarchinitiative not_provided not_provided HGNC:10289 MONDO:0030690 uuid:1535654f-c020-4069-aeb3-4e37a493d7ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2569 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0021053 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0017178 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0853813 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0858598 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0858598 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151602 infores:hetionet CHEBI:72564 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0233514 infores:hetionet CHEBI:3223 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0235660 infores:hetionet CAID:CA410202773 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202773 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.361C>G (p.Leu121Val) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score ≥ 0.88 (0.883) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant was also reported in ClinVar in 2022 by Invitae but the affected status of the proband is unknown (Variation ID 2088789). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202773/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10585386 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585386 MONDO:0007750 PMID: Pathogenic PS1, PM5, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS4, PS2, PS3, BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1285G>T (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS1, PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.764. PM5: There is 1 missense variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285GC (p.Val429Leu), ClinVar ID 226353.PP4: Variant meets PM2 and is identified in at least 1 index case meeting Simon Broome criteria for FH from PMID 9727746 (Nissen et al., 1998). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585386/MONDO:0007750/013 2023-03-27 2024-10-04 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:45599 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0039070 infores:hetionet CHEBI:2549 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0043144 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0162429 infores:hetionet CHEBI:61033 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C2939147 infores:hetionet CHEBI:391960 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0948873 infores:hetionet CHEBI:51164 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0013404 infores:hetionet CHEBI:46195 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0231530 infores:hetionet CHEBI:15940 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0085593 infores:hetionet NCBIGene:26276 biolink:causes MONDO:0008822 infores:monarchinitiative not_provided not_provided HGNC:12712 MONDO:0008822 uuid:b4c277ac-545f-4a83-b9b4-f0ee94b50e06 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0232849 infores:hetionet CHEBI:31348 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151744 infores:hetionet CHEBI:134745 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0017178 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0278079 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0278079 infores:hetionet CHEBI:5790 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0547030 infores:hetionet CHEBI:70735 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0242339 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0549567 infores:hetionet CHEBI:71219 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0917801 infores:hetionet CAID:CA267655 biolink:causes MONDO:0009861 infores:clingen CAID:CA267655 MONDO:0009861 PMID: Pathogenic PM3, PVS1, PM2, PP4 The c.442-2A>C variant in PAH is a canonical splice acceptor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was documented in 3 patients with classic PKU (PMID 26666653, 18937047, 9048935). It was detected with pathogenic variants c.1042C>G and p.Tyr204Cys (PMID 18937047, 9048935). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267655/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0085631 infores:hetionet CHEBI:3504 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0002170 infores:hetionet CHEBI:6933 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0014742 infores:hetionet CHEBI:63631 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085595 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0043251 infores:hetionet CHEBI:37941 biolink:causes MONDO:0019139 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1096116 infores:hetionet CHEBI:41774 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0013604 infores:hetionet CHEBI:2704 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0086543 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0020538 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0948595 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0427008 infores:hetionet GO:0045704 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0045704 GO:0007275 CHEBI:17303 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020619 infores:hetionet CHEBI:109549 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0002792 infores:hetionet CAID:CA367401117 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401117 MONDO:0015967 PMID: Pathogenic PS3, PS4, PP1_Strong, PP3, PM2_Supporting The c.679G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 227 (p.(Gly227Ser)) of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in nine individuals with hyperglycemia (PS4; PMID: 37838154; internal lab contributors). This variant segregated with hyperglycemia with at least five meioses in five families (PP1_Strong; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.63 for donor loss, predicting that the variant disrupts the donor site of intron 6 (PP3). Furthermore, there is evidence from RNA studies that this variant results in aberrant splicing with minigene assay showing a complex alteration of residual full-length transcripts and 2 alternative transcripts (deletion of the last 4 bp of exon 6 (r.676_679del, p.Val226Alafs*67) and deletion of the last 16 bp of exon 6 (r.663_679del, p.Val222Alafs*67) (PS3; PMID 40225161). In summary, c.679G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS3, PS4, PP1_Strong, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401117/MONDO:0015967/086 2025-09-26 2025-09-26 Semidominant inheritance HP:0032113 Supports GO:0060768 biolink:causes GO:0030850 infores:ubergraph knowledge_assertion manual_agent GO:0060768 GO:0030850 CHEBI:31236 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0340726 infores:hetionet CHEBI:50859 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0542571 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0574067 infores:hetionet CHEBI:6539 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0009806 infores:hetionet CHEBI:4466 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085682 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0235551 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235551 infores:hetionet CHEBI:4784 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0006277 infores:hetionet CHEBI:5147 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0017160 infores:hetionet CHEBI:2618 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0002170 infores:hetionet CHEBI:75922 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0259799 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0035078 infores:hetionet CHEBI:131512 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0018681 infores:hetionet CAID:CA342005 biolink:causes MONDO:0019497 infores:clingen CAID:CA342005 MONDO:0019497 PMID: Pathogenic PP1, PM2_Supporting, PM3_Very Strong, PS3_Moderate The variant NM_004004.6:c.56G>C in GJB2 is a missense variant predicted to cause substitution of serine by threonine at amino acid 19 (p.Ser19Thr). The highest filtering allele frequency in gnomAD v4 is 0.00111% (19/1111946 CI 95%) in the non-Finnish European population (PM2_Supporting). This variant has been detected in 5 probands with hearing loss. For 4 of those probands, a pathogenic or suspected-pathogenic variants was observed in trans (PM3_VeryStrong; PMIDs: 16077952, 26553399, 10982180, 15146474, Partners Laboratory for Molecular Medicine internal data). Of note, 1 proband was compound-heterozygous for Ser19Thr with c.35delG and also carried Arg32Ser in cis; another proband had Ser19Thr, Arg32Ser and E47* in unspecified zygosity though it is assumed that Ser19Thr and Arg32Ser were in cis based on prior observation. These cases were not counted towards PM3 because contribution of the Arg32Ser variant can not be ruled out. The p.Ser19Thr variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 16077952). A functional study has shown that p.Ser19Thr impacts protein function (PS3_Moderate; PMID: 12176036). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP1 (ClinGen Hearing Loss VCEP specifications version 2; 1/3/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA342005/MONDO:0019497/005 2024-01-03 2024-01-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:9907 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0009763 infores:hetionet CHEBI:37333 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0022660 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0006840 infores:hetionet CHEBI:75722 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042029 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0037284 infores:hetionet GO:1903775 biolink:causes GO:0006302 infores:ubergraph knowledge_assertion manual_agent GO:1903775 GO:0006302 CHEBI:5130 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042267 infores:hetionet CHEBI:7820 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0085129 infores:hetionet CHEBI:3485 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0041657 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0234215 infores:hetionet CHEBI:15552 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0003962 infores:hetionet CHEBI:31547 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0020621 infores:hetionet NCBIGene:1769 biolink:causes MONDO:0033673 infores:monarchinitiative not_provided not_provided HGNC:2952 MONDO:0033673 uuid:b112bcf3-bfec-454b-b11f-3c20e8c5a4a1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82941 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0038325 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0426747 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0426747 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0277961 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0277961 infores:hetionet CHEBI:140621 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0007222 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C2830004 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0162429 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0948594 infores:hetionet CHEBI:51209 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0030232 infores:hetionet CHEBI:84500 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0015469 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0948586 infores:hetionet CHEBI:144551 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0016382 infores:hetionet CHEBI:10023 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011603 infores:hetionet CHEBI:66964 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0009763 infores:hetionet CHEBI:8327 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0022354 infores:hetionet CHEBI:63598 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0520966 infores:hetionet NCBIGene:940 biolink:causes MONDO:0971177 infores:monarchinitiative not_provided not_provided HGNC:1653 MONDO:0971177 uuid:d19fe36f-a0db-4be1-94e0-b0388a885de7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0098906 biolink:causes GO:0061337 infores:ubergraph knowledge_assertion manual_agent GO:0098906 GO:0061337 CHEBI:68584 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0029408 infores:hetionet CHEBI:8863 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0014742 infores:hetionet CHEBI:3996 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0233407 infores:hetionet CHEBI:45716 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0034065 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0342579 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0027813 infores:hetionet CHEBI:5893 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0042023 infores:hetionet CHEBI:49603 biolink:causes MONDO:0024883 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C2939420 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0027769 infores:hetionet CHEBI:31236 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018843 infores:hetionet CHEBI:16899 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0039231 infores:hetionet CHEBI:73274 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0016658 infores:hetionet CHEBI:180905 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C2047937 infores:hetionet CHEBI:7459 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0011570 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001889 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0747102 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0086543 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0022107 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0040034 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020514 infores:hetionet CHEBI:3082 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0344232 infores:hetionet CHEBI:6444 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0013395 infores:hetionet CAID:CA16615353 biolink:causes MONDO:0007648 infores:clingen CAID:CA16615353 MONDO:0007648 PMID:15780560PMID:17221870PMID:15780560PMID:17221870PMID:17221870PMID:15780560PMID:10072428PMID:17221870 Pathogenic PM5_Supporting, PP1, PM2_Supporting, PS3_Moderate, PS4_Moderate, PVS1_Strong BS1, BS4, BS3, BP7, BP5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS2 The c.49-2A>G variant is a canonical splice variant predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed across at least two families (PP1; PMID: 17221870, 15780560). This variant has also been reported in at least three families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17221870, 15780560, 10072428). The c.49-2A>C allele was demonstrated to alter splicing through RT-PCR analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 17221870). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PP1, PS4_Moderate, PS3_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16615353/MONDO:0007648/007 2023-08-30 2023-08-30 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:63580 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030554 infores:hetionet CHEBI:6437 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0038362 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002170 infores:hetionet CHEBI:63577 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0021368 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0020514 infores:hetionet CHEBI:5864 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0231528 infores:hetionet CHEBI:15407 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0022107 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0042373 infores:hetionet CHEBI:8028 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0037036 infores:hetionet CHEBI:15407 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0085631 infores:hetionet GO:0060224 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:0060224 GO:0043010 CHEBI:6375 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0031350 infores:hetionet CHEBI:41977 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0028734 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0021167 infores:hetionet GO:2000090 biolink:causes GO:0061215 infores:ubergraph knowledge_assertion manual_agent GO:2000090 GO:0061215 CHEBI:91541 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0039971 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0852733 infores:hetionet CAID:CA8337772 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337772 MONDO:0008723 PMID: Uncertain Significance BP4 The NM_000018.4(ACADVL):c.622+12C>A variant in ACADVL is an intronic variant which is located in intron 7. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0027 in South Asian population. The results from two in silico splicing predictors (SpliceSiteFinder-like and NNSPLICE) support that this variant does not affect splicing (BP4). Due to limited evidence, this variant is classified as a variant of unknown significance for autosomal recessive very long chain acyl CoA dehydrogenase (VLCAD) deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337772/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:61049 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013404 infores:hetionet NCBIGene:3747 biolink:causes MONDO:0030957 infores:monarchinitiative not_provided not_provided HGNC:6234 MONDO:0030957 uuid:e4a4363e-ac58-4f8a-9bb2-5093889fb375 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68642 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0231528 infores:hetionet CHEBI:61049 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0028084 infores:hetionet CHEBI:51137 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0040822 infores:hetionet CAID:CA202443 biolink:causes MONDO:0007113 infores:clingen CAID:CA202443 MONDO:0007113 PMID: Benign BP7, BA1 The allele frequency of the p.Thr448= variant in UBE3A is 1.9% in the East Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Thr448= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Thr448= variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA202443/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:16796 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0020538 infores:hetionet CHEBI:3738 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0004093 infores:hetionet GO:1904235 biolink:causes GO:0006929 infores:ubergraph knowledge_assertion manual_agent GO:1904235 GO:0006929 UMLS:C0657912 biolink:causes MONDO:0002108 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007115 infores:hetionet CHEBI:8888 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0700200 infores:hetionet CHEBI:64312 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0006266 infores:hetionet CHEBI:6847 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0344232 infores:hetionet CHEBI:50648 biolink:causes MONDO:0000709 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020877 infores:hetionet CHEBI:3638 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0040264 infores:hetionet CHEBI:39867 biolink:causes MONDO:0022687 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0740279 infores:hetionet CHEBI:82960 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0085631 infores:hetionet CHEBI:27882 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0037763 infores:hetionet CHEBI:499361 biolink:causes NCIT:C74591 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0234925 infores:hetionet CHEBI:8764 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151539 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0002170 infores:hetionet CHEBI:63577 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1260880 infores:hetionet CHEBI:84500 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0006145 infores:hetionet CHEBI:51860 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233763 infores:hetionet CHEBI:8207 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0036130 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0036572 infores:hetionet CAID:CA332354 biolink:causes MONDO:0700270 infores:clingen CAID:CA332354 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PM5_Supporting, PVS1 PP3 The c.6807G>A variant in ATM has been demonstrated to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (Ambry internal data). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. The highest population minor allele frequency in gnomAD v3.1.2 is [0.009614%] (1/10402 alleles) in European (Finnish) population, which is lower than the ClinGen HBOP threshold for PM2_Supporting, meeting this criterion. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID:  30549301). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1(RNA), PM3_supporting, PM2_supporting, PM5_supporting). Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA332354/MONDO:0700270/020 2024-01-25 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2682 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085692 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0403632 infores:hetionet CHEBI:75722 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018965 infores:hetionet CHEBI:63791 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040460 infores:hetionet CHEBI:38940 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C3665624 infores:hetionet CAID:CA6401404 biolink:causes MONDO:0019565 infores:clingen CAID:CA6401404 MONDO:0019565 PMID: Benign BA1 PP3, PP4, BP4 The NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg) variant in VWF is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 2705. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1227 (based on 11352/91062 alleles in the South Asian population, including 829 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. As reported in PMID: 26105150 the variant is significantly associated with lower plasma levels of FVIII but not vWF. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1 von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6401404/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true CHEBI:9649 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0041969 infores:hetionet CHEBI:84883 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0009806 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0007971 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0235431 infores:hetionet CHEBI:64354 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0442874 infores:hetionet CAID:CA024053 biolink:causes MONDO:0007783 infores:clingen CAID:CA024053 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with glycine at codon 4502 of the RYR1 protein, p.(Glu4502Gly). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000146, a frequency consistent with pathogenicity for MHS. This variant has to our knowledge not been reported in any individuals with a personal or family history of an MH episode or a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.532 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024053/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:31401 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042023 infores:hetionet CHEBI:49662 biolink:causes HP:6000383 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0235884 infores:hetionet CHEBI:9599 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0030848 infores:hetionet CHEBI:7865 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0011991 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0027497 infores:hetionet CHEBI:50648 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0023052 infores:hetionet CHEBI:8028 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0002878 infores:hetionet NCBIGene:6528 biolink:causes MONDO:0020716 infores:monarchinitiative not_provided not_provided HGNC:11040 MONDO:0020716 uuid:4c373261-110f-4212-b685-9bed317eaeed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:38940 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151907 infores:hetionet CHEBI:41977 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0392676 infores:hetionet CHEBI:50922 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C3495920 infores:hetionet CHEBI:7577 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0013404 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151763 infores:hetionet CHEBI:7936 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039621 infores:hetionet CHEBI:16586 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0012833 infores:hetionet CHEBI:39669 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0037763 infores:hetionet GO:0061187 biolink:causes GO:1990700 infores:ubergraph knowledge_assertion manual_agent GO:0061187 GO:1990700 CHEBI:50924 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0041657 infores:hetionet CHEBI:66913 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0027441 infores:hetionet NCBIGene:5145 biolink:causes MONDO:0013437 infores:monarchinitiative not_provided not_provided HGNC:8785 MONDO:0013437 uuid:e7704983-4533-46eb-8551-b9a5d0afccf2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63577 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0008031 infores:hetionet CHEBI:75045 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0040034 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0027765 infores:hetionet CHEBI:4708 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0031350 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042373 infores:hetionet CHEBI:17334 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0002792 infores:hetionet CAID:CA399804316 biolink:causes MONDO:0100326 infores:clingen CAID:CA399804316 MONDO:0100326 PMID: Uncertain Significance PP3, PM2_Supporting PM3, PP4 The NM_000212.3(ITGB3):c.1451G>T (p.Gly484Val) missense variant has been reported in GT patient (PMID: 34066320). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.905, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399804316/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:7773 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0026650 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004729 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0014863 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0012813 infores:hetionet CHEBI:63581 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0015230 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0242073 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013395 infores:hetionet CHEBI:520985 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0037036 infores:hetionet CHEBI:8888 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006142 infores:hetionet CHEBI:3996 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0026961 infores:hetionet CHEBI:63630 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0231218 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0011849 infores:hetionet CHEBI:4995 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1306341 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0235431 infores:hetionet CHEBI:31624 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0018681 infores:hetionet CHEBI:74947 biolink:causes MONDO:0019121 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1535939 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0018939 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0037199 infores:hetionet CHEBI:40303 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0026821 infores:hetionet CHEBI:50381 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0392171 infores:hetionet CHEBI:184555 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0231218 infores:hetionet CHEBI:6775 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0013390 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020488 infores:hetionet CHEBI:6704 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0000737 infores:hetionet NCBIGene:920 biolink:causes MONDO:0030981 infores:monarchinitiative not_provided not_provided HGNC:1678 MONDO:0030981 uuid:9c6c7b62-fa37-436d-9784-2dc1432c1dcb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17141 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0003123 infores:hetionet CAID:CA233425 biolink:causes MONDO:0008723 infores:clingen CAID:CA233425 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PM3, PP4_Moderate, PVS1, PS3_Supporting PM1, PM4, PM5, BP2, BP1, PS1, BP7 The NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). Immunoblot shows no VLCAD enzyme on patients' fibroblasts (PMID 10790204)(PS3_Supporting). Metabolic activity as measured by MTT assay showed reduced proliferation rate in primary patient fibroblasts and CRISPR knock-in Hs27 cells when compared to normal (PMID:32010688) (PS3_Supporting). This variant has been detected in at least 35 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, 34 of whom were homozygous for the variant (PMID: 28980192, 32010688, 10790204), and one compound heterozygous for a likely pathogenic without phase confirmation (PMID: 24801231)(PM3, Total points assigned = 1.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Multiple cases are observed with elevated C14:1 from NBS and reduced ACADVL activity, which is highly specific for VLCADD (PMID: 28980192,10790204)(PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified this variant as pathogenic based on PVS1,PS3_Supporting, PM3, PM2_Supporting, PP4_Moderate. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA233425/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45863 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0947912 infores:hetionet CHEBI:36791 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0086769 infores:hetionet CHEBI:4995 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0004134 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020538 infores:hetionet NCBIGene:6228 biolink:causes MONDO:0044311 infores:monarchinitiative not_provided not_provided HGNC:10410 MONDO:0044311 uuid:94030e15-0f16-4730-ad81-818d269a326d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45367 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0023510 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0231919 infores:hetionet CHEBI:9586 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020443 infores:hetionet CHEBI:8207 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0025323 infores:hetionet CAID:CA367402231 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402231 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PM5_Supporting, PP2, PP3, PP4, PM2_Supporting PS4 The c.364C>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to valine at codon 122 (p.(Leu122Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 11508276, 32468610, internal lab contributors). Two of these individuals and one relative had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 32468610, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1; PMIDs: 32468610). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>G as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Moderate, PM5_Supporting, PM2_Supporting, PP2, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402231/MONDO:0015967/086 2024-03-11 2024-03-11 Semidominant inheritance HP:0032113 Supports UMLS:C0657912 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019270 infores:hetionet CHEBI:31547 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0151746 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0235819 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0235819 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0004239 infores:hetionet CHEBI:63622 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0039070 infores:hetionet CHEBI:2955 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0699744 infores:hetionet CHEBI:42797 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018794 infores:hetionet CAID:CA229531 biolink:causes MONDO:0009861 infores:clingen CAID:CA229531 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PVS1, PM3_Strong This c.398_401del (p.Asn133fs) variant in PAH was detected with pathogenic and likely pathogenic variants in multiple patients with classic PKU and one with mild hyperphenylalaninemia (PMID: 22513348, 22526846, 8659548, 22917871, 26666653). This variant was absent in population databases. This is a frameshift variant in exon 4 of 13 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Strong, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229531/MONDO:0009861/006 2022-10-14 2022-10-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7915 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0027769 infores:hetionet CHEBI:63620 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0085649 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0948089 infores:hetionet CHEBI:7798 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0014518 infores:hetionet CHEBI:7025 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0021053 infores:hetionet NCBIGene:221481 biolink:causes MONDO:0958242 infores:monarchinitiative not_provided not_provided HGNC:21099 MONDO:0958242 uuid:75bc139d-2be0-4b2a-be5b-868839fc95d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9123 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C2047937 infores:hetionet CAID:CA6831856 biolink:causes MONDO:0007453 infores:clingen CAID:CA6831856 MONDO:0007453 PMID: Likely Benign BP2, BS3_Supporting, BS1 PS4, PM1, PM5, BP5, BS2, PP3, PP1 The c.871C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 291 (p.(Pro291Ser)) of NM_000545.8. •This variant has been observed in unknown phase with the variant c.494G>A, p.Trp165Ter (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). Functional studies demonstrated the p.Pro291Ser protein has abnormal nuclear localization above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). Lastly, this variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00001163, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.871C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): BP2, BS3_Supporting, BS1 Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831856/MONDO:0007453/017 2022-04-21 2022-04-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3479 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0013144 infores:hetionet CHEBI:49575 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0039231 infores:hetionet CHEBI:6375 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0019112 infores:hetionet CHEBI:7627 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0027051 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0031350 infores:hetionet CHEBI:61058 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0018681 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1868790 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1868790 infores:hetionet NCBIGene:3952 biolink:causes MONDO:0013991 infores:monarchinitiative not_provided not_provided HGNC:6553 MONDO:0013991 uuid:ffffea6a-8a16-4c61-82b4-2fbf036dbdb8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0021655 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0013395 infores:hetionet CAID:CA519704534 biolink:causes MONDO:0010726 infores:clingen CAID:CA519704534 MONDO:0010726 PMID: Likely Benign BP4, BP5, BS2_Supporting BS1, PM2 The highest population minor allele frequency of the p.Pro474= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008935 in European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro474= variant is observed in at least 1 unaffected individual (GeneDx internal database) (BS2_supporting). The p.Pro474= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Splice prediction analysis does not suggest an impact to splicing (BP4). In summary, the p.Pro474= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2_supporting, BP5, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA519704534/MONDO:0010726/036 2024-04-18 2025-03-13 X-linked inheritance HP:0001417 Contradicts true CHEBI:49662 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013362 infores:hetionet CHEBI:23765 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0231528 infores:hetionet CHEBI:61033 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C2242996 infores:hetionet NCBIGene:10730 biolink:causes MONDO:0015011 infores:monarchinitiative not_provided not_provided HGNC:12843 MONDO:0015011 uuid:ed2db759-4066-4480-93cf-206acf6ee684 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0518015 infores:hetionet CHEBI:9586 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0575081 infores:hetionet CHEBI:63598 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038999 infores:hetionet CAID:CA120575 biolink:causes MONDO:0044970 infores:clingen CAID:CA120575 MONDO:0044970 PMID:12682337 Uncertain Significance PP3, PM2_Supporting, PP1_Moderate, PS3_Supporting PS4, PS2, PM6 The m.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, hypogonadism, retinopathy, cataracts, and sensorineural hearing loss (PMID: 12682337, also included in analysis in PMID: 19718780). The variant was present at 87.2% heteroplasmy in muscle and 38.3% in blood. This man’s sister had sensorineural hearing and pigmentary retinopathy, with the variant present at 21.2% in blood. Their mother with myopathy, cataracts, and hearing loss had the variant present at 12.4% in blood. The variant was undetectable in three healthy maternal aunts and one healthy maternal uncle (PP1_moderate; PMID: 12682337). There are no reported de novo occurrences to our knowledge. There is one occurrence in population databases (GenBank dataset, 1/61,134, an individual in haplogroup L3f; absent in gnomAD v3.1.2 and Helix dataset), however the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative and ragged red fibers (91.4% ± 4.9, n=7) than in COX-positive fibers (58.4% ± 12.8, n=7), p<0.005 (PS3_supporting, PMID: 12682337). The computational predictor MitoTIP suggests this variant is pathogenic (70.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PM2_supporting, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120575/MONDO:0044970/015 2024-03-26 2024-07-31 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:63629 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0948089 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0036508 infores:hetionet CHEBI:7640 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0043094 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0424000 infores:hetionet CHEBI:63630 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0018965 infores:hetionet CHEBI:75246 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0035243 infores:hetionet CHEBI:75722 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0014518 infores:hetionet CAID:CA383510975 biolink:causes MONDO:0015628 infores:clingen CAID:CA383510975 MONDO:0015628 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4, PM5 The NM_000552.5:c.3569G>A variant in VWF is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 1190 (p.Cys1190Tyr). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 34532631). Additional consistent phenotypes were also reported in the patient, specifically, FVIII activity consistent with VWF antigen. This variant has been reported in 5 additional probands meeting PP4 laboratory phenotype criteria (PS4; PMID 20351307, 32864553, 32803740, 34355501). Another missense variant NM_000552.5:c.3568T>C (p.Cys1190Arg) in the same codon has been classified as pathogenic for VWD type 2A by the ClinGen VWD VCEP (PM5). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0000006195 (1/1180046 European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for type 2A (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWF type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP4_Moderate, PS4, PM5, PM2_Supporting, PP3. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383510975/MONDO:0015628/081 2025-05-06 2025-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:37941 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C1145628 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0019087 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151717 infores:hetionet CHEBI:8890 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0004238 infores:hetionet CHEBI:8378 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0009763 infores:hetionet CHEBI:2567 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0041582 infores:hetionet CHEBI:17303 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026821 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0017675 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0012833 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0221706 infores:hetionet CHEBI:4445 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0149931 infores:hetionet CAID:CA314830 biolink:causes MONDO:0012999 infores:clingen CAID:CA314830 MONDO:0012999 PMID: Likely Benign PM2_Supporting, BS3_Supporting, BP4 The NM_000156.6:c.670G>A variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by threonine at amino acid 224 (p.Ala224Thr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00034 (12/35338 alleles) in the Latino population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.147 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). Expression of the variant in GAMT-deficient fibroblasts showed that it resulted in similar GAMT enzymatic activity to wild-type (BS3_Supporting). There is a ClinVar entry for this variant (Variant ID: 205593). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BS3_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on February 23, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314830/MONDO:0012999/026 2023-02-09 2023-03-09 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0145867 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0003467 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0948281 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0948281 infores:hetionet CHEBI:16755 biolink:causes MONDO:0019065 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0002726 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0267792 infores:hetionet CHEBI:2636 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0012833 infores:hetionet CHEBI:32221 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0026821 infores:hetionet NCBIGene:8398 biolink:causes MONDO:0013060 infores:monarchinitiative not_provided not_provided HGNC:9039 MONDO:0013060 uuid:5cbda699-4c98-46d0-9586-00f130916a1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0234215 infores:hetionet CHEBI:5138 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013404 infores:hetionet CHEBI:71940 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0232495 infores:hetionet CAID:CA399794538 biolink:causes MONDO:0100326 infores:clingen CAID:CA399794538 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 PP4 The c.2556G>C variant in ITGA2B is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid (p.Gln852His). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.051, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating with Glanzmann thrombasthenia were found in the literature. Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting and BP4 (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399794538/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5134 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0151514 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0011849 infores:hetionet CHEBI:48538 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0027497 infores:hetionet CHEBI:3723 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022281 infores:hetionet CHEBI:5280 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0002994 infores:hetionet CAID:CA10014557 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014557 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM2, PM6, PVS1, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.276C>T (p.Thr92=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.64) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014557/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:84883 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0007859 infores:hetionet CHEBI:51141 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0231218 infores:hetionet CHEBI:10023 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0020433 infores:hetionet NCBIGene:11077 biolink:causes MONDO:0030985 infores:monarchinitiative not_provided not_provided HGNC:5226 MONDO:0030985 uuid:e2521fc3-a377-4904-bfb8-49a242200a72 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68579 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0004604 infores:hetionet GO:1904933 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:1904933 GO:0007399 CHEBI:68478 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0023895 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020598 infores:hetionet CHEBI:6970 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0026858 infores:hetionet CHEBI:42797 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151636 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0041912 infores:hetionet CHEBI:31348 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0232462 infores:hetionet CHEBI:63598 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0017086 infores:hetionet UMLS:C0209366 biolink:causes MONDO:0700032 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0152096 infores:hetionet CHEBI:3441 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151905 infores:hetionet CHEBI:45783 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151701 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0021061 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0021061 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0005940 infores:hetionet CHEBI:16335 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0020580 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0002170 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003864 infores:hetionet CHEBI:3996 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0231530 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0022573 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0403632 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0227791 infores:hetionet CHEBI:63577 biolink:causes HP:0030829 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0231856 infores:hetionet CHEBI:42820 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C1443060 infores:hetionet CHEBI:2549 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0018681 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0521592 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0549334 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0549334 infores:hetionet CHEBI:4636 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0012569 infores:hetionet CHEBI:41423 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0237849 infores:hetionet CHEBI:119915 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0039103 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020649 infores:hetionet CHEBI:6078 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0085584 infores:hetionet CHEBI:4735 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0003862 infores:hetionet CHEBI:2549 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C2047937 infores:hetionet CHEBI:75722 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0232602 infores:hetionet CHEBI:6775 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0032290 infores:hetionet CHEBI:45081 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0030312 infores:hetionet NCBIGene:54982 biolink:causes MONDO:0008768 infores:monarchinitiative not_provided not_provided HGNC:2077 MONDO:0008768 uuid:a3a89066-fd5a-46c5-a88f-ea9dd7b97549 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:144551 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1328337 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0858249 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0858249 infores:hetionet CHEBI:184555 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0149745 infores:hetionet CHEBI:64321 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C2938875 infores:hetionet CHEBI:51164 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0004093 infores:hetionet CHEBI:194135 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0004604 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0007785 infores:hetionet CHEBI:63580 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0010043 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020517 infores:hetionet CHEBI:64064 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0027497 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0521492 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521492 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005011 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0010346 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0014868 infores:hetionet CAID:CA658658500 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658500 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.2505_2506dupTG (p.Glu836ValfsTer11) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and downstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Moderate, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658500/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:40303 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C3267047 infores:hetionet CHEBI:36795 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085633 infores:hetionet UMLS:C0145185 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0039231 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0541947 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0541947 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020456 infores:hetionet CHEBI:63623 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0027497 infores:hetionet CHEBI:7573 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0030193 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0543467 infores:hetionet GO:0062003 biolink:causes GO:0042572 infores:ubergraph knowledge_assertion manual_agent GO:0062003 GO:0042572 CHEBI:47780 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0231528 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0233494 infores:hetionet CAID:CA16614674 biolink:causes MONDO:0007947 infores:clingen CAID:CA16614674 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PS4_Supporting, PM1_Strong PVS1, PM6, PP4, PP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PM5, PM4, PM3, BP7, BS1, BS3, BS4 NM_00138 c.1538G>T is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 513 (p.Cys513Phe). This variant has not been reported in the literature but has been found in at least two probands; this includes one individual with bilateral ectopia lentis and thoracic aortic aneurysm and dissection, and one with unspecified features of a connective tissue disorder (PS4_supporting; Invitae & LabCorp internal data, ClinVar Variation ID: 406288). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium binding EGF domain; cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Several other variants affecting this codon have been reported in association with Marfan syndrome (p.Cys513Gly, p.Cys513Ser, p.Cys513Tyr, p.Cys513Arg). Computational prediction tools and conservation analysis strongly support that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PM2_supporting, PS4_supporting, PP2, PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614674/MONDO:0007947/022 2023-11-16 2023-11-16 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:83527 biolink:causes MONDO:0040674 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0029261 infores:hetionet NCBITaxon:4827 biolink:causes MONDO:0019136 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:4827 MESH:D009091 DB06636_MESH_D009091_1DB00681_MESH_D009091_1 CHEBI:4907 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0027497 infores:hetionet CHEBI:4858 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0034150 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0009782 infores:hetionet CHEBI:24564 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0852911 infores:hetionet UMLS:C0657912 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151671 infores:hetionet CHEBI:6690 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0151773 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0858775 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0858775 infores:hetionet CHEBI:6067 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0005778 infores:hetionet CHEBI:4858 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0270996 infores:hetionet CHEBI:30830 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0028084 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0152517 infores:hetionet CHEBI:2379 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0009806 infores:hetionet CHEBI:28487 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0855242 infores:hetionet CHEBI:5106 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0013456 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0039971 infores:hetionet CHEBI:3752 biolink:causes MONDO:0009348 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0019829 infores:hetionet CAID:CA16042048 biolink:causes MONDO:0010725 infores:clingen CAID:CA16042048 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PM4_Strong The NM_000330.4(RS1):c.673T>C variant is a stop-loss variant encoding the substitution of a termination codon with Arginine. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant is a stop-loss that disrupts the stop codon at the end of exon 6 and is predicted to result in extension of the RS1 C-terminus by 42 additional amino acids before the occurrence of the next stop codon (PM4_Strong). In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting and PM4_strong (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042048/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:127780 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020639 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0021843 infores:hetionet CHEBI:94440 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0013404 infores:hetionet CHEBI:47381 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011603 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0549373 infores:hetionet NCBIGene:85365 biolink:causes MONDO:0011933 infores:monarchinitiative not_provided not_provided HGNC:23159 MONDO:0011933 uuid:63fa3b3c-b44e-47ea-ad4b-7ac75dcbeac3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45924 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0025637 infores:hetionet CHEBI:134990 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0043352 infores:hetionet CHEBI:2038 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C1443060 infores:hetionet CHEBI:3228 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0549249 infores:hetionet CAID:CA16020993 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020993 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4, PVS1_Strong The c.1315+1G>T variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 13 (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in ClinVar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon.It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).The variant has been previously reported in one Catalonian PKU case (as determined by abnormal blood Phe levels), without additional information (PMID: 10598814) (PP4). It is also noted in ClinVar (ID 370074), where it is classified as Likely Pathogenic by one lab, with this published reported cited. Classification: Likely PathogenicSupporting Criteria: PVS1_Strong; PM2; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020993/MONDO:0009861/006 2020-05-18 2020-05-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63580 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019209 infores:hetionet CHEBI:8863 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0039240 infores:hetionet NCBIGene:23078 biolink:causes MONDO:0957314 infores:monarchinitiative not_provided not_provided HGNC:29071 MONDO:0957314 uuid:554f36df-ba00-4646-8d49-a3997f89ae38 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0006145 infores:hetionet CHEBI:28148 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020488 infores:hetionet CHEBI:50673 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0948594 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0041349 infores:hetionet CHEBI:9586 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C3665386 infores:hetionet CHEBI:6375 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0021368 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0042109 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0036572 infores:hetionet CHEBI:7507 biolink:causes MONDO:0020598 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0024523 infores:hetionet CHEBI:50924 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0016382 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0859023 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0859023 infores:hetionet CHEBI:71272 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0015230 infores:hetionet CHEBI:8028 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0151786 infores:hetionet CHEBI:119573 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0003864 infores:hetionet CAID:CA355962322 biolink:causes MONDO:0001586 infores:clingen CAID:CA355962322 MONDO:0001586 PMID: Likely Pathogenic PP3_Moderate, PM3, PP4, PM2_Supporting "The NM_000203.5(IDUA):c.809T>G variant in IDUA is a missense variant predicted to cause substitution of isoleucine by serine at amino acid 270 (p.Ile270Ser). One patient with this variant and a ""severe, Hurler"" phenotype has been reported with documented IDUA deficiency within the affected range in leukocytes (PMID: 16435195) (PP4). This individual was compound heterozygous for the variant and another variant in IDUA that has been classified as likely pathogenic for MPS I by the ClinGen LD VCEP, c.1882C>T (p.Arg628Ter); the variants were confirmed to be in trans by parental testing (PMID: 16435195; PM3). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.776 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997; PP3_Moderate). In addition, SpliceAI suggests that the variant may impact splicing (acceptor loss = 0.2; note that the acceptor splice site for exon 7 is 17 bp upstream). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0: PM3, PP3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on 12/6/2024)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355962322/MONDO:0001586/091 2024-12-06 2025-06-07 Autosomal recessive inheritance HP:0000007 Supports CAID:CA333425 biolink:causes MONDO:0007113 infores:clingen CAID:CA333425 MONDO:0007113 PMID: Benign BA1, BP4 The allele frequency of the c.1064G>C p.(Ser355Thr) variant in UBE3A (NM_130839.5) is 0.078% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1064G>C p.(Ser355Thr) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333425/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:83531 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0340464 infores:hetionet CHEBI:31638 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0015967 infores:hetionet CHEBI:32293 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0851578 infores:hetionet CAID:CA235376 biolink:causes MONDO:0021060 infores:clingen CAID:CA235376 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1629G>C (p.Thr543=) variant in the RAF1 gene is 0.054% (9/8654) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235376/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:4814 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0231218 infores:hetionet CHEBI:83804 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0151786 infores:hetionet CHEBI:8310 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0003578 infores:hetionet CHEBI:107736 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0547030 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0022650 infores:hetionet NCBIGene:170691 biolink:causes MONDO:0013176 infores:monarchinitiative not_provided not_provided HGNC:17109 MONDO:0013176 uuid:3fd167d6-2c2b-495e-9663-bdc17cb939e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6078 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0549249 infores:hetionet CHEBI:5165 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0231528 infores:hetionet CHEBI:2453 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C2973529 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011991 infores:hetionet CHEBI:78543 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0016436 infores:hetionet CHEBI:63617 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0026826 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0392171 infores:hetionet CHEBI:3756 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0851578 infores:hetionet CHEBI:4974 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0162285 infores:hetionet CAID:CA120628 biolink:causes MONDO:0044970 infores:clingen CAID:CA120628 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS2_Moderate PS3 The m.12706T>C (p.F124L) variant in MT-ND5 has been reported in at least seven unrelated individuals with primary mitochondrial disease and features including Leigh syndrome, MELAS and MELAS-like, and ophthalmoplegia (PS4_moderate; PMIDs: 34200828, 17317336, 21364701, 23847141, 14684687, 11938446). There is one report of a de novo occurrence of this variant (PS2_moderate, PMID: 17317336). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS2_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120628/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:8890 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0036974 infores:hetionet CHEBI:92712 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C2981158 infores:hetionet CHEBI:6715 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0034152 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0178298 infores:hetionet CHEBI:9168 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020458 infores:hetionet CHEBI:94807 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0030794 infores:hetionet CHEBI:31981 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0428974 infores:hetionet CHEBI:71940 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0027497 infores:hetionet CHEBI:6541 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0027121 infores:hetionet NCBIGene:340665 biolink:causes MONDO:0013997 infores:monarchinitiative not_provided not_provided HGNC:20577 MONDO:0013997 uuid:476587a6-fdcd-47c4-8930-e6aa3443155a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50859 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0151746 infores:hetionet CAID:CA16609268 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609268 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting The c.748C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 250 (p.(Arg250Cys)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK: This variant was identified in 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 30245511, 17204055, 19069349, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L and 3 generation family history of diabetes/hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; PMID: 30245511, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944 which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.748C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PS4, PP4_Moderate, PP1_Strong, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609268/MONDO:0015967/086 2023-10-25 2023-10-25 Semidominant inheritance HP:0032113 Supports NCBIGene:121512 biolink:causes MONDO:0012250 infores:monarchinitiative not_provided not_provided HGNC:19125 MONDO:0012250 uuid:016fbd16-387b-47b5-b2ad-e8d65226d218 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3207 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0010481 infores:hetionet CHEBI:71255 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0043094 infores:hetionet CAID:CA10585809 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585809 MONDO:0007750 PMID: Pathogenic PM2, PVS1, PP4 PS3, PS4 The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PVS1 - Stop in codon 739. It is upstream of amino acid 830.PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585809/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:30830 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0004093 infores:hetionet CAID:CA5416943 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416943 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.247A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Isoleucine by Valine at amino acid 83 (p.Ile83Val).The filtering allele frequency (the upper threshold of the 95% CI of 3/84132 alleles) of the c.247A>G variant in DCLRE1C is 0.000009470 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Another missense variant NM_001033855.3(DCLRE1C):c.247A>C (p.Ile83Leu) in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416943/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9943 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027813 infores:hetionet CHEBI:8764 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0013491 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0024115 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0020456 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0270458 infores:hetionet CAID:CA2802457 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802457 MONDO:0001586 PMID: Likely Benign BS1 BP4, PP3 The NM_000203.5:c.1856G>A variant in IDUA is predicted to result in the missense substitution of arginine by glutamine at amino acid 619 (p.Arg619Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004206 (383/91066 alleles; 2 homozygotes; GrpMax Filtering Allele Frequency (95% confidence) = 0.003859) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.0025), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.641 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. The computational predictor SpliceAI indicates that the variant has no impact on splicing. To our knowledge, this variant has not been reported in the literature. There is a ClinVar entry for this variant (Variation ID: 558900). In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1 based on assessment by the ClinGen LD VCEP. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Gene Curation Expert Panel (Specifications Version 1.0.0): BS1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802457/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:135736 biolink:causes UMLS:C0521634 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0521634 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005207 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0008497 infores:hetionet CHEBI:4636 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0042023 infores:hetionet CHEBI:28748 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0020578 infores:hetionet CAID:CA10590980 biolink:causes MONDO:0700268 infores:clingen CAID:CA10590980 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.5282T>G variant in BRCA1 is a missense variant predicted to cause substitution of Phenylalanine by Cysteine at amino acid 1761 (p.(Phe1761Cys)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.47, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting; PP3; PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10590980/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8028 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0424823 infores:hetionet CHEBI:64312 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C2937358 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0080276 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0242350 infores:hetionet CHEBI:131512 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0019080 infores:hetionet CHEBI:28148 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0015967 infores:hetionet CHEBI:2208 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0162834 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0677500 infores:hetionet CHEBI:29013 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0009763 infores:hetionet CHEBI:10023 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0014457 infores:hetionet CHEBI:45783 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085641 infores:hetionet CHEBI:9241 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C2830004 infores:hetionet NCBIGene:8076 biolink:causes MONDO:0014514 infores:monarchinitiative not_provided not_provided HGNC:29673 MONDO:0014514 uuid:31852661-f390-4581-9c9a-35bc31bd12e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135342 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0012569 infores:hetionet CHEBI:48273 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C1167965 infores:hetionet CHEBI:31205 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01025 UMLS:C2363730 infores:hetionet CHEBI:42068 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0740394 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0332575 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020651 infores:hetionet CHEBI:63717 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0020517 infores:hetionet CHEBI:3478 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0018681 infores:hetionet CHEBI:2639 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0020625 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043251 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0003123 infores:hetionet CHEBI:8888 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037383 infores:hetionet CHEBI:17987 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0030554 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0877098 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0018418 infores:hetionet CHEBI:135888 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0013604 infores:hetionet CHEBI:47519 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0687713 infores:hetionet CAID:CA024702 biolink:causes MONDO:0007783 infores:clingen CAID:CA024702 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with valine at codon 2364 of the RYR1 protein, p.(Phe2364Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score ≥0.85 (0.85) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024702/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:28864 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0027424 infores:hetionet CHEBI:6846 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0232462 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0000737 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0020039 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0009806 infores:hetionet CHEBI:9445 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0233494 infores:hetionet CHEBI:47898 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0013404 infores:hetionet CHEBI:27974 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1510431 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018799 infores:hetionet GO:0031630 biolink:causes GO:0007268 infores:ubergraph knowledge_assertion manual_agent GO:0031630 GO:0007268 CHEBI:71417 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0162830 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027932 infores:hetionet CHEBI:5001 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0018418 infores:hetionet NCBIGene:6884 biolink:causes MONDO:0044313 infores:monarchinitiative not_provided not_provided HGNC:11546 MONDO:0044313 uuid:eccc78d9-798a-4f90-994c-e73120fd5489 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:465284 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151734 infores:hetionet CHEBI:15765 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0019825 infores:hetionet CHEBI:28241 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0018681 infores:hetionet CHEBI:17026 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1384606 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0037274 infores:hetionet NCBIGene:6608 biolink:causes MONDO:0011134 infores:monarchinitiative not_provided not_provided HGNC:11119 MONDO:0011134 uuid:2fb9badb-7b8a-48ec-967a-575f10c70f92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3064 biolink:causes MONDO:0054573 infores:monarchinitiative not_provided not_provided HGNC:4851 MONDO:0054573 uuid:36730287-1194-4260-9ee4-855897158c6a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0018799 infores:hetionet UMLS:C0065374 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0687713 infores:hetionet UNII:D27V6190PM biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0011603 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0027765 infores:hetionet CHEBI:9927 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0020625 infores:hetionet CHEBI:63611 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023218 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0687133 infores:hetionet NCBIGene:286262 biolink:causes MONDO:0013215 infores:monarchinitiative not_provided not_provided HGNC:26894 MONDO:0013215 uuid:a582fdb9-1e13-4dd2-8f17-d21a1225e804 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3814 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0039231 infores:hetionet CHEBI:17141 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0041349 infores:hetionet CHEBI:8212 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0011570 infores:hetionet CHEBI:4903 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0014743 infores:hetionet CAID:CA220582 biolink:causes MONDO:0009861 infores:clingen CAID:CA220582 MONDO:0009861 PMID:21147011PMID:12655554PMID:21147011 Likely Pathogenic PP4_Moderate, PP3, PM3_Strong PM2 PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM3_Strong, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220582/MONDO:0009861/006 2018-07-29 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports GO:0048324 biolink:causes GO:0048318 infores:ubergraph knowledge_assertion manual_agent GO:0048324 GO:0048318 CHEBI:8707 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0026650 infores:hetionet CHEBI:3756 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0040822 infores:hetionet CHEBI:8356 biolink:causes UMLS:C2242575 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2242575 infores:hetionet CHEBI:47898 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020433 infores:hetionet CHEBI:72564 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0014742 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0030920 infores:hetionet CHEBI:52717 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0043094 infores:hetionet CHEBI:3515 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151830 infores:hetionet CHEBI:8871 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0522055 infores:hetionet CHEBI:404903 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0002792 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0233472 infores:hetionet CHEBI:16796 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0028084 infores:hetionet CHEBI:31515 biolink:causes UMLS:C0857980 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0857980 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0009806 infores:hetionet CHEBI:6456 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0002792 infores:hetionet CHEBI:4995 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0032285 infores:hetionet CHEBI:63607 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020625 infores:hetionet NCBIGene:9915 biolink:causes MONDO:0014404 infores:monarchinitiative not_provided not_provided HGNC:16876 MONDO:0014404 uuid:edab04de-5432-497e-b961-08d2750bc7bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0282074 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0282074 infores:hetionet CAID:CA10014367 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014367 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.720A>C (p.Pro240=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (-0.04) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014367/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:72296 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0241742 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0221490 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0021400 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0575090 infores:hetionet CHEBI:100241 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232726 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0020514 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0149931 infores:hetionet CHEBI:71255 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0027849 infores:hetionet CHEBI:45327 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0085624 infores:hetionet CHEBI:3380 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0008031 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0233632 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0740425 infores:hetionet UMLS:C0145185 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0000729 infores:hetionet CAID:CA123224 biolink:causes MONDO:0100326 infores:clingen CAID:CA123224 MONDO:0100326 PMID: Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting, PS3 PM5 The NM_000212.2(ITGB3):c.719G>A (p.Arg240Gln) missense variant has been reported in at least four patients (PMIDs: 1371279, 29084015, 29675921, 30138987) with a phenotype highly specific to GT. This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP and is predicted to have a deleterious effect (REVEL score 0.819). The functional impact has been assessed by transfection in CHO cells, showing normal αIIbβ3 surface expression with a deficiency in binding of fibrinogen and PAC-1 in response to mAb 62 stimulation (PMID: 1371279). In summary this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS3, PM2_Supporting, PM3, PP3, and PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA123224/MONDO:0100326/011 2021-07-08 2021-08-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:15367 biolink:causes UMLS:C0702266 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0702266 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085584 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0234215 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0010073 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0234215 infores:hetionet CHEBI:6129 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0041657 infores:hetionet CAID:CA10014220 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014220 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS2, PS4, PS3, BA1, BP2, BP1, BP3, PM6, PM2, BP5, BS4, BS3, BS1, PVS1, PM3, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1029C>T (p.Ser343=) is a synonymous variant. This variant is not predicted to impact splicing and not conserved (PhyloP = 1.99) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014220/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2666 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0015371 infores:hetionet CHEBI:31705 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0036454 infores:hetionet CHEBI:44241 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0042373 infores:hetionet CAID:CA261555 biolink:causes MONDO:0021060 infores:clingen CAID:CA261555 MONDO:0021060 PMID: Pathogenic PM2_Supporting, PP3, PP2, PS4, PS2 The c.155C>T (NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile)) variant in PTPN11 is a missense variant predicted to cause substitution of threonine byisoleucine at amino acid 52 (p.Thr52Ile). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are a common mechanism of disease (PP2; PMID: 29493581). This variant has been reported in 11 probands from 9 families with features of Noonan Syndrome (PS4, 8.0 pts.; PMIDs: 22465605, 25804457, 32059087; GeneDx, Partners Laboratory for Molecular Medicine, & Service de Génétique Moléculaire (Hélène Cave) internal data: ClinVar SCV000057357, SCV000061283, & SCV001438499). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with Noonan Syndrome (PS2, 2.0 pts.; Service de Génétique Moléculaire (Hélène Cave) internal data: SCV001438499). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: (PM2_supporting, PP3, PP2, PS4, PS2. (Specification Version 2.3.0, 07/08/25). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261555/MONDO:0021060/043 2025-07-08 2025-09-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17347 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002170 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0232492 infores:hetionet CHEBI:84050 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0009782 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022660 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0015230 infores:hetionet CAID:CA386959454 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959454 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM5_Strong, PM1, PP3 PS4 The c.392G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to leucine at codon 131 (p.(R131L)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.392G>A (p.Arg131Gln) and c.391C>T (p.Arg131Trp), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID: 447488). Taken together, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PM5_Strong, PM1, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959454/MONDO:0015967/017 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020550 infores:hetionet CAID:CA008494 biolink:causes MONDO:0100316 infores:clingen CAID:CA008494 MONDO:0100316 PMID:28491751PMID:29021305 Uncertain Significance BS3_Supporting, PP3 PS4, BS1, PM2, PM5, PP4 NM_000218.3(KCNQ1):c.860C>A is a missense variant that replaces alanine with glutamic acid at codon 287. Three missense variants in the same codon, NM_000218.3(KCNQ1):c.859G>T (p.Ala287Ser), NM_000218.3(KCNQ1):c.859G>A (p.Ala287Thr), and NM_000218.3(KCNQ1):c.860C>T (p.Ala287Val), have been reported in association with long QT syndrome (PMID: 23631430, SCV004024206.1, SCV003288475.1) but have not yet been classified for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 is not yet met. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00008334, with 5 alleles / 59,998 total alleles in the Admixed American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, with confirmation of a prolonged QTc interval (PMID: 16414944), however, the requirement for 2 unrelated probands has not been reached so the PS4_Supporting code is not yet met. Available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMID: 16414944). The computational predictor REVEL gives a score of 0.847, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). This variant has been shown to have a non-deleterious impact on KCNQ1 function in a manual patch-clamp assay (PMID:28491751; BS3_Supporting). Also, the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29) gave this variant an IKs_classification of normal (confidence score 19.5), V1/2_classification of normal (confidence score 19.5), act_classification of normal (confidence score 51.0), and deact_classification of normal (confidence score 51.0). These confidence scores are all below the thresholds for high confidence scores (>57 for IKs, > 55 for V1/2, >59 for tau_act, and >59 for tau_deact) (PMID: 29021305). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BS3_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA008494/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:12083 biolink:causes MONDO:0017373 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12083 MONDO:0017373 CHEBI:8060 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0234022 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0041969 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0019158 infores:hetionet CHEBI:9622 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0687713 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0009782 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0010692 infores:hetionet UBERON:0003244 biolink:causes MONDO:0002483 infores:ubergraph knowledge_assertion manual_agent UBERON:0003244 MONDO:0002483 CHEBI:6472 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0033775 infores:hetionet CAID:CA8814958 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814958 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM5, PS3_Moderate, PM2_Supporting "The NM_000152.5:c.671G>A variant in GAA is a missense variant predicted tocause substitution of arginine by glutamine at amino acid 224 (p.Arg224Gln). This variant has been reported in one individual with documented GAA deficiency (PMID: 23000108), meeting criteria for PP4_moderate. This individual is compound heterozygous for the variant and a pathogenic variant based on the ClinGen LSD VCEP's specifications. It has also been reported in two individuals described as having late-onset Pompe disease diagnosed after positive newborn screening in Taiwan, though no phenotype is reported. One individual is compound heterozygous for the variant and a pathogenic variant based on the ClinGen LSD VCEP's specifications (PM3) and the other is compound heterozygous for the variant and a pathogenic or likely pathogenic variant that has not been assessed according to the ClinGen LSD VCEP's specifications. The highest population minor allele frequency in gnomAD is 0.00004 (3/74944 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion. When expressed in COS cells, this variant was classified as Class B (""potentially less severe"") by Kroos et al, 2012 (PMID:22644586). This includes 0.7% GAA activity in cells and 0.1% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3. The computational predictor REVEL gives a score of 0.757 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.670C>T, p.Arg224Trp] [ClinVar Variation ID:186994] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 646875, 2-star review status) with 5submitters classifying the variant as likely pathogenic (3) or pathogenic (2). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PS3_moderate, PP3, PM5(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023)." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814958/MONDO:0009290/010 2023-12-19 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3175 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0413252 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0031046 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0020456 infores:hetionet CHEBI:50924 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0231528 infores:hetionet CHEBI:50859 biolink:causes UMLS:C1274594 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C1274594 infores:hetionet CHEBI:4466 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0000737 infores:hetionet UMLS:C0004609 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0009421 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0151828 infores:hetionet CHEBI:119915 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0004093 infores:hetionet CAID:CA10568476 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568476 MONDO:0010602 PMID: Uncertain Significance BS1 BP7, BA1, PS4 The c.1272-5T>C variant is reported at an MAF of 0.0002955 (27/91365 alleles) in the European non-Finnish population in gnomAD v2.1.1, with 5 hemizygotes, meeting BS1 criteria of MAF > 0.000167. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: BS1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568476/MONDO:0010602/071 2024-05-09 2024-05-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:8212 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0040485 infores:hetionet NCBIGene:3651 biolink:causes MONDO:0024547 infores:monarchinitiative not_provided not_provided HGNC:6107 MONDO:0024547 uuid:9dc91c17-8492-4842-90b4-3fdae7c046d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0522153 infores:hetionet CHEBI:50223 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0043352 infores:hetionet CHEBI:28445 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0009421 infores:hetionet CAID:CA333552 biolink:causes MONDO:0007113 infores:clingen CAID:CA333552 MONDO:0007113 PMID: Pathogenic PM6, PVS1, PS4, PM2_Supporting The p.Lys836Argfs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). This variant has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Angelman syndrome (PMID 9887341) (PM6). This variant has been observed in at least 4 other individuals with Angelman syndrome (PMID 9887341, 25212744, ClinVar) (PS4). The p.Lys836Argfs variant in UBE3A is absent from gnomAD (PM2_supporting). In summary, the p.Lys836Argfs variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4, PM6, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333552/MONDO:0007113/016 2021-03-26 2021-05-17 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:68558 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0009806 infores:hetionet CHEBI:94501 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0013604 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0233494 infores:hetionet CHEBI:10127 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0032290 infores:hetionet CAID:CA16020895 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020895 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 The c.912+1G>T variant is a canonical splice donor in PAH in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was identified in 1 patient with PAH deficiency in a Catalonian cohort (PMID 10598814). This variant is absent from population databases. In summary, c.912+1G>T in PAH meets criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020895/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:134991 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0030193 infores:hetionet CHEBI:7575 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0019158 infores:hetionet CHEBI:127780 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0424790 infores:hetionet NCBIGene:2073 biolink:causes MONDO:0014696 infores:monarchinitiative not_provided not_provided HGNC:3437 MONDO:0014696 uuid:2fba5868-cb23-4bfb-8251-da82a9bf47a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0020542 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0018772 infores:hetionet CHEBI:3504 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0043144 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0034065 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0009319 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0151763 infores:hetionet CHEBI:367163 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0008031 infores:hetionet CHEBI:63624 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0026848 infores:hetionet CHEBI:8776 biolink:causes MONDO:0037821 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0032708 infores:hetionet CHEBI:4953 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0011603 infores:hetionet UMLS:C1872203 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151662 infores:hetionet CHEBI:31536 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C1167965 infores:hetionet CHEBI:8776 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0014742 infores:hetionet CHEBI:6076 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151754 infores:hetionet CHEBI:31644 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0231528 infores:hetionet CAID:CA343725112 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725112 MONDO:0005338 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BS1, BS3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1, BP4 The c.1011G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 337 (p.Gln337His). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00002712 (32 alleles out of 1,180,040), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.65, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open-angle glaucoma had been reported (PMID: 32476818), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725112/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:G4PX8C4HKV biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0037822 infores:hetionet CHEBI:6909 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0006826 infores:hetionet CHEBI:8093 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0030193 infores:hetionet CHEBI:50729 biolink:causes HP:0011873 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0580317 infores:hetionet CHEBI:10112 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0037199 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0012797 infores:hetionet CHEBI:8890 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C2047937 infores:hetionet CHEBI:35677 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C1142412 infores:hetionet CHEBI:144551 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0026961 infores:hetionet CHEBI:5165 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0028961 infores:hetionet GO:0030856 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:0030856 GO:0060429 CHEBI:64310 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0178298 infores:hetionet CHEBI:44185 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004134 infores:hetionet NCBIGene:10413 biolink:causes MONDO:0007355 infores:monarchinitiative not_provided not_provided HGNC:16262 MONDO:0007355 uuid:f51437fd-c5f4-494a-8996-9695ab1ddeb6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6970 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0162835 infores:hetionet CHEBI:6923 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0239739 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0575090 infores:hetionet CHEBI:100241 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0031542 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0434437 infores:hetionet CHEBI:68855 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0018681 infores:hetionet CHEBI:82960 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0014724 infores:hetionet CHEBI:10102 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0017675 infores:hetionet CHEBI:5165 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0151766 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018099 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034186 infores:hetionet CHEBI:63631 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233514 infores:hetionet CHEBI:4814 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0687713 infores:hetionet GO:1901490 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:1901490 GO:0001944 CHEBI:8412 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0033975 infores:hetionet CHEBI:3723 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040822 infores:hetionet CHEBI:44915 biolink:causes UMLS:C1096717 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1096717 infores:hetionet CHEBI:31236 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0026858 infores:hetionet CAID:CA412352546 biolink:causes MONDO:0100039 infores:clingen CAID:CA412352546 MONDO:0100039 PMID: Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PM6, PS2 PM5, PM1, PS3, PS1 The p.Leu182Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with epileptic encephalopathy (PMID 23708187) (PS2). The p.Leu182Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with epileptic encephalopathy (internal database - GeneDx) (PM6). The p.Leu182Pro variant has been observed in at least 2 individuals with epileptic encephalopathy (PMID 23708187, internal database - GeneDx) (PS4_supporting). The p.Leu182Pro variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu182Pro variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PS4_supporting, PM6, PM2_Supporting, PP3). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412352546/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Supports CHEBI:3738 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0235146 infores:hetionet CHEBI:8890 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0009421 infores:hetionet CHEBI:6437 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085632 infores:hetionet CHEBI:4024 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C1142412 infores:hetionet NCBIGene:1315 biolink:causes MONDO:0031002 infores:monarchinitiative not_provided not_provided HGNC:2231 MONDO:0031002 uuid:7e86f651-1388-470d-9903-18612463bf81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:717 biolink:causes MONDO:0009006 infores:monarchinitiative not_provided not_provided HGNC:1248 MONDO:0009006 uuid:b5016824-cbed-414e-8459-5ab9b721c160 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39867 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C1142412 infores:hetionet CHEBI:116735 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0038999 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0947999 infores:hetionet CHEBI:135961 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0021368 infores:hetionet CHEBI:71223 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0009806 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0037763 infores:hetionet CAID:CA312255 biolink:causes MONDO:0008723 infores:clingen CAID:CA312255 MONDO:0008723 PMID: Uncertain Significance PP3, PP4, PM3_Supporting, BS1 PM1, BA1, PM2 The NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala) in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 273 (p. Gly273Ala). The highest population minor allele frequency in gnomAD v3.1.2 is 0.003621 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). At least one patient with this variant displayed an increased C14:1 level, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Supporting, PMID: 24503138), from whom a pathogenic variant was also identified with unknown phase (PM3 point 0.5, PM3_Supporting, PMID: 24503138). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 32778825). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, PP4_Supporting, PM3_Supporting, PP3) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312255/MONDO:0008723/021 2023-09-26 2023-09-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3207 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0001622 infores:hetionet CAID:CA386958691 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958691 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 PS4, PS1 The c.327-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 2 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 2/10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1. (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgment applied given that the individual was diagnosed before age 30 with a non-obese BMI, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4). The nucleotide change c.327-1G>T has been reported in a patient with MODY; however, the c.327-1G>T variant has not met the criteria to be classified as pathogenic provided by the ClinGen MDEP without the supporting evidence from this variant, and PS1 cannot be applied. Taken together, this evidence supports the classification of this variant as pathogenic for HNF1A-MODY by the ClinGen MDEP. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958691/MONDO:0015967/017 2022-08-05 2022-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3127 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0018681 infores:hetionet CAID:CA386952577 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952577 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PM1_Supporting, PS4_Moderate, PP1_Strong, PS3_Supporting, PP4_Moderate, PP3 PS1 The c.58G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 20 (p.(G20R)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP threshold of 0.70 (PP3), and functional studies demonstrated the p.Gly20Arg protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:12107757). This variant is absent in the gnomAD v2.1.1 European non-Finnish population and has one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor), with at least one of these individuals having a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with at least 5 informative meioses in two families with MODY (PP1_Strong; PMID:15657605, internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_Strong, PP4_Moderate, PS4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting). Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952577/MONDO:0015967/017 2021-08-18 2021-10-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7931 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0027651 infores:hetionet CHEBI:6958 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0021053 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0021400 infores:hetionet CHEBI:61049 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085649 infores:hetionet CHEBI:5383 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C2973529 infores:hetionet CHEBI:65349 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0003862 infores:hetionet CHEBI:8884 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0035508 infores:hetionet CHEBI:17303 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0015230 infores:hetionet CHEBI:7956 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0151907 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0262397 infores:hetionet CHEBI:9943 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0014457 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011570 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0021400 infores:hetionet NCBIGene:5813 biolink:causes MONDO:0014512 infores:monarchinitiative not_provided not_provided HGNC:9701 MONDO:0014512 uuid:34cc67c0-66be-4cf5-9dcc-6b2af358adad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:408174 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0151908 infores:hetionet CHEBI:161680 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0013404 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017168 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0025061 infores:hetionet NCBIGene:23135 biolink:causes MONDO:0032790 infores:monarchinitiative not_provided not_provided HGNC:29012 MONDO:0032790 uuid:20685e49-5781-4445-98bb-15a3ec0da97a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63613 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C1519353 infores:hetionet CHEBI:567361 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0040053 infores:hetionet CHEBI:119486 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0392171 infores:hetionet GO:0044865 biolink:causes GO:0051301 infores:ubergraph knowledge_assertion manual_agent GO:0044865 GO:0051301 CHEBI:70707 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0020458 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013395 infores:hetionet NCBIGene:583 biolink:causes MONDO:0014432 infores:monarchinitiative not_provided not_provided HGNC:967 MONDO:0014432 uuid:c32b8f30-6738-4e38-aeff-1e63e626ede1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C3665386 infores:hetionet CHEBI:6073 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0242429 infores:hetionet CAID:CA024104 biolink:causes MONDO:0007783 infores:clingen CAID:CA024104 MONDO:0007783 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate, BS3_Supporting PS4, PS3, BS1, BP4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of threonine with methionine at codon 4709 of the RYR1 protein, p.(Thr4709Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with recessive myopathies (PMID:17033962, PMID:21062345, PMID:22473935). A knock-in mouse model does not demonstrate a response to isoflurane in the heterozygous state, this is considered evidence against pathogenicity for autosomal dominantly inherited MH, BS_Supporting (PMID:31107960). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate, BS3_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024104/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:2687 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0232462 infores:hetionet CHEBI:59582 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0016436 infores:hetionet CHEBI:47381 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0702166 infores:hetionet CAID:CA512319108 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319108 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.546C>T (p.Asn182=) is a synonymous variant. No REVEL score because synonymous variant and SpliceAI is ≤0.20 (0.00) meeting BP4. Evolutionary conservation prediction algorithms predict the site as not being conserved (phyloP 1.42 < 2.0) meeting BP7. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319108/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:49375 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0085682 infores:hetionet CHEBI:9927 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0917801 infores:hetionet CHEBI:51164 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0034069 infores:hetionet CHEBI:4798 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0750394 infores:hetionet CAID:CA024934 biolink:causes MONDO:0018493 infores:clingen CAID:CA024934 MONDO:0018493 PMID: Uncertain Significance PP3_Moderate PM1, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with glutamine at codon 2867 of the RYR1 protein, p.(Leu2867Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in any individuals with a clear personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.923) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024934/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3485 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0014742 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0020517 infores:hetionet CHEBI:41977 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C2830004 infores:hetionet CHEBI:5441 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C2973529 infores:hetionet CHEBI:8665 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0004093 infores:hetionet CHEBI:75722 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020598 infores:hetionet CHEBI:50275 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0009763 infores:hetionet CHEBI:7444 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0033774 infores:hetionet CHEBI:93635 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0581912 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0349398 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0349398 infores:hetionet CHEBI:4798 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0028084 infores:hetionet NCBIGene:7048 biolink:causes MONDO:0012427 infores:monarchinitiative not_provided not_provided HGNC:11773 MONDO:0012427 uuid:e54c9468-0afb-469b-8305-3e7e0db90cf0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0086439 infores:hetionet CHEBI:63632 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0037763 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004802 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0034068 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0259749 infores:hetionet CHEBI:31980 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0016382 infores:hetionet CHEBI:30830 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0085649 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0700184 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0040034 infores:hetionet CAID:CA069115 biolink:causes MONDO:0007783 infores:clingen CAID:CA069115 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of glutamic acid with lysine at codon 2362 of the RYR1 protein, p.(Glu2362Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.885)supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA069115/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:15365 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0011991 infores:hetionet CHEBI:473990 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0035078 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0040046 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0221203 infores:hetionet CAID:CA274626 biolink:causes MONDO:0010726 infores:clingen CAID:CA274626 MONDO:0010726 PMID: Pathogenic PP3, PM5_Strong, PS4, PM2_Supporting The p.Pro101Arg variant in MECP2 (NM_004992.4) has been observed in 4 other individuals with Rett Syndrome (PMID 10991689, RettBASE proband ID: 4426, 6597, 6598) and another individual with Angelman syndrome-like phenotype (PMID 11283202) (PS4). Multiple pathogenic missense variants (p.Pro101His, p.Pro101Leu, p.Pro101Thr, p.Pro101Ser) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11269512, RettBASE)(PM5_Strong). The p.Pro101Arg variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary the p.Pro101Arg variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS4, PM5_Strong, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA274626/MONDO:0010726/016 2022-04-28 2023-01-04 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:52717 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0031256 infores:hetionet CAID:CA386969829 biolink:causes MONDO:0015967 infores:clingen CAID:CA386969829 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP3 PS4, PM5, PP4 The c.1295C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to cysteine at codon 432 (p.(Ser432Cys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable Popmax filtering allele frequency due to 0 copies in the European non-Finnish and 1 copy in another subpopulation (East Asian), which is less than the ClinGen MDEP threshold for PM2_Supporting (ENF Popmax FAF < 0.000003 and <=2 copies in ENF and <= 1 copy in any other subpopulation) (PM2_Supporting). Two other missense variants, c.1295C>T p.Ser432Phe and c.1295C>A p.Ser432Tyr, have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in an individual with a diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 10588527). In summary, c.1295C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 1/11/2023): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386969829/MONDO:0015967/017 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:499361 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0011175 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0039971 infores:hetionet CHEBI:50841 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0917801 infores:hetionet GO:0052027 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0052027 GO:0051716 CHEBI:188986 biolink:causes UMLS:C1112366 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C1112366 infores:hetionet CHEBI:45081 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0023530 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0019158 infores:hetionet CHEBI:50663 biolink:causes UMLS:C3495832 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C3495832 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0151477 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151477 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0002871 infores:hetionet CHEBI:8713 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0340865 infores:hetionet CHEBI:27974 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0017178 infores:hetionet CHEBI:9352 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0027813 infores:hetionet CHEBI:17026 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151662 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0007787 infores:hetionet CHEBI:3640 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C1318520 infores:hetionet CHEBI:3398 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0036572 infores:hetionet CHEBI:50381 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0027813 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0853800 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0853800 infores:hetionet CHEBI:5118 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0023380 infores:hetionet CHEBI:63612 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0023530 infores:hetionet CHEBI:31711 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0018524 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0020615 infores:hetionet CHEBI:9649 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0001824 infores:hetionet CHEBI:31236 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020443 infores:hetionet NCBIGene:2539 biolink:causes MONDO:0010480 infores:monarchinitiative not_provided not_provided HGNC:4057 MONDO:0010480 uuid:8d8884b1-d558-4dce-8cf0-3291a52447a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7865 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0011603 infores:hetionet CHEBI:31401 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0151636 infores:hetionet CHEBI:45924 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0231528 infores:hetionet NCBIGene:22900 biolink:causes MONDO:0033643 infores:monarchinitiative not_provided not_provided HGNC:17057 MONDO:0033643 uuid:18dfe948-1d3e-4af2-ae94-b2af5905e8f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0344232 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0403632 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0233472 infores:hetionet CHEBI:31401 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0040409 infores:hetionet CHEBI:4856 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0003467 infores:hetionet NCBIGene:63925 biolink:causes MONDO:0014043 infores:monarchinitiative not_provided not_provided HGNC:15807 MONDO:0014043 uuid:19a7323f-fab8-4d71-8907-c3b9a060f1b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235996 infores:hetionet CHEBI:45409 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019521 infores:hetionet CHEBI:31236 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018926 infores:hetionet CHEBI:63925 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0010037 infores:hetionet CHEBI:63584 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C1443060 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0037274 infores:hetionet CHEBI:18067 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0027540 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0267596 infores:hetionet CHEBI:4672 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085932 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0042109 infores:hetionet CHEBI:3310 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C1443060 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0013395 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020538 infores:hetionet CHEBI:131512 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0497247 infores:hetionet CHEBI:28748 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036690 infores:hetionet CHEBI:31859 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0152115 infores:hetionet CHEBI:8871 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151908 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0009763 infores:hetionet CHEBI:64064 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0018681 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0011570 infores:hetionet CHEBI:6775 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0020453 infores:hetionet CHEBI:32588 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C2129214 infores:hetionet CHEBI:77260 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C2242737 infores:hetionet CHEBI:36791 biolink:causes HP:0041159 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0035522 infores:hetionet CHEBI:3423 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0031542 infores:hetionet CHEBI:10127 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0036454 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0027726 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0267596 infores:hetionet CHEBI:7640 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0041657 infores:hetionet CHEBI:5778 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C3665347 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001595 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0008489 infores:hetionet CHEBI:27834 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0233632 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0851341 infores:hetionet CHEBI:50378 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0006826 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0036572 infores:hetionet CHEBI:41977 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0236075 infores:hetionet CHEBI:44185 biolink:causes MONDO:0003987 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0519063 infores:hetionet CHEBI:3568 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003873 infores:hetionet NCBIGene:3570 biolink:causes MONDO:0030069 infores:monarchinitiative not_provided not_provided HGNC:6019 MONDO:0030069 uuid:92b00193-ebbe-47c2-b34d-6523e8a82d4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:F64QU97QCR biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C1096035 infores:hetionet CAID:CA10118325 biolink:causes MONDO:0021060 infores:clingen CAID:CA10118325 MONDO:0021060 PMID: Likely Pathogenic PVS1, PM2_Supporting BA1, BS1 The c.263+1G>A variant in LZTR1 occurs within the canonical splice donor site (+1) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2/21 (out of frame), resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 3/35430) of the c.263+1G>A variant in LZTR1 is 0.00002299 for Admixed American chromosomes by gnomAD v2.1.1, which is lower than the ClinGen RASopathy VCEP threshold (≤0.000025) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PVS1, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10118325/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:231594 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0240717 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0027765 infores:hetionet NCBIGene:5442 biolink:causes MONDO:0859228 infores:monarchinitiative not_provided not_provided HGNC:9200 MONDO:0859228 uuid:e89518b4-62d9-43a1-90d1-ff6bff6adce6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042024 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0015927 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0015927 infores:hetionet CHEBI:28864 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0011603 infores:hetionet NCBITaxon:1314 biolink:causes MONDO:0001266 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1314 MESH:D004886 DB01053_MESH_D004886_1DB00417_MESH_D004886_1DB09320_MESH_D004886_1DB01053_MESH_D004886_2 CHEBI:7822 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0237938 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0344315 infores:hetionet NCBIGene:56006 biolink:causes MONDO:0014833 infores:monarchinitiative not_provided not_provided HGNC:25763 MONDO:0014833 uuid:5ade9a61-e1ca-4434-a438-57e88187df3a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015672 infores:hetionet CHEBI:3638 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0040485 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005376 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0017665 infores:hetionet CHEBI:3723 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233471 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0227791 infores:hetionet NCBIGene:2626 biolink:causes MONDO:0011938 infores:monarchinitiative not_provided not_provided HGNC:4173 MONDO:0011938 uuid:395dca93-5cd6-4e1f-9fe0-d2094b43f6cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0032285 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0917798 infores:hetionet CHEBI:6775 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042571 infores:hetionet CHEBI:17823 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0022661 infores:hetionet CHEBI:5001 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0035455 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0011849 infores:hetionet CHEBI:5123 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0085637 infores:hetionet CHEBI:30659 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0011168 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0877197 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0877197 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235030 infores:hetionet CHEBI:10101 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017979 infores:hetionet CAID:CA391629706 biolink:causes MONDO:0005045 infores:clingen CAID:CA391629706 MONDO:0005045 PMID: Uncertain Significance PM2_Supporting, PP3 PM5, PP1, PS1, PS3, PS4, BP4, BP2, BA1, BP5, BS1, BS3, BS4 NM_005159.5(ACTC1):c.797C>T (p.Pro266Leu). This variant has been identified in 1 individual in a cohort of 5126 HCM cases (https://www.deciphergenomics.org/sequence-variant/15-34792101-G-A/annotation/disease-cohorts/cardiac/hcm) and was absent from large population studies (PM2_Supporting; gnomAD, v.2.1). This variant is not statistically increased compared to controls (lower 95% CI<5), therefore, the PS4 criterion has not been applied. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PM2_Supporting and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA391629706/MONDO:0005045/101 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31622 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0575090 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0403632 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0877322 infores:hetionet CHEBI:2549 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0232602 infores:hetionet CHEBI:44032 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0004364 infores:hetionet CAID:CA2582131592 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582131592 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, PM4 PP3, PP4 The NM_005629.4:c.250_255del variant in SLC6A8 is predicted to result in the inframe deletion of two amino acids (p.Lys84_Asn85del) (PM4). The variant was reported in a patient with creatine transporter deficiency but no individual phenotype or biochemical data is available (PMID: 23644449) (PP4 not met). The in silico predictors MutPredIndel and MutationTaster give conflicting results regarding the impact of this variant on protein function (neither PP3 nor BP4 is met); SpliceAI predicts no impact on splicing. This variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM1, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel, Jan 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582131592/MONDO:0010305/027 2025-01-07 2025-01-09 X-linked inheritance HP:0001417 Inconclusive true CHEBI:47780 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0016658 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0022650 infores:hetionet CHEBI:135736 biolink:causes HP:0033073 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0221248 infores:hetionet CHEBI:9727 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0030554 infores:hetionet CHEBI:5613 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0015230 infores:hetionet CHEBI:51860 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013384 infores:hetionet CHEBI:8364 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0151480 infores:hetionet NCBIGene:708 biolink:causes MONDO:0054677 infores:monarchinitiative not_provided not_provided HGNC:1243 MONDO:0054677 uuid:7b8d097c-2653-487c-a8c9-20bcf164e68e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:10804 biolink:causes MONDO:0012975 infores:monarchinitiative not_provided not_provided HGNC:4288 MONDO:0012975 uuid:3495d0c8-e7e2-48ef-bcfa-435be511de30 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0870082 infores:hetionet CHEBI:3738 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0011991 infores:hetionet CHEBI:9130 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0019521 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005313 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0520459 infores:hetionet CHEBI:5130 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0043352 infores:hetionet CHEBI:4445 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0004096 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0018802 infores:hetionet CHEBI:7478 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0011175 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0002453 infores:hetionet CAID:CA346327979 biolink:causes MONDO:0800472 infores:clingen CAID:CA346327979 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 PP1, PP3, BP4, BA1, PS3, PS1, PS2, PM1, PM4, PM5, BP7, BS1, BS4, BS3 The c.1044-2A>G variant in CYP1B1 is a single nucleotide splice site variant (p.?). The highest minor allele frequency of this variant was in the Ashkenazi Jewish genetic ancestry group of gnomAD (v4.1.0) = 0.00003379 (1 allele out of 29,594), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This splice site variant was predicted to lead to exon skipping, intron inclusion or use of a cryptic splice site, disrupting the reading frame. It was not predicted to undergo NMD but removes the haem-binding domain (PVS1 met).There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is homozygous (non-consanguineous) for the variant (ClinVar Accession: SCV002073149.1). Total proband points = 0.5, meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM2_Supporting, PM3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346327979/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2567 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C2004489 infores:hetionet CHEBI:4728 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0231530 infores:hetionet CHEBI:6413 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0227791 infores:hetionet CHEBI:27436 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0002170 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0006145 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0423602 infores:hetionet CAID:CA256124 biolink:causes MONDO:0001586 infores:clingen CAID:CA256124 MONDO:0001586 PMID:8213840PMID:14559116 Pathogenic PM3_Strong, PP3_Moderate, PM1, PP4, PM2_Supporting PS3, PM5, PP1 The NM_000203.5:c.266G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 89 (p.Arg89Gln). This variant accounts for up to 24% of alleles in Japanese individuals with MPS I (PMID: 8664897). At least 8 probands have been reported with the variant, typically with milder clinical features of MPS I and reduced IDUA activity (PMID: 8213840, 8664897, 2148086) (PP4). Of those individuals, 4 probands and one sibling, were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. None of those were confirmed in trans. The second variants is c.1205G>A (p.Trp402Ter) (PMID: 8213840, 2 patients, 2 x 0.5) and c.613_617dup (p.Glu207AlafsTer29) (PMID: 8664897, 2 probands, 0.5 x 2). Four individuals are homozygous for the variant (PMIDs: 8664897, 21480867, max 2 x 0.5 points). Total 3 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001662 (1/6016 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). This variant alters amino acid Arg89, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 14559116;15862278) (PM1). The computational predictor REVEL gives a score of 0.941 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). When expressed in CHO cells, the variant results in <5% WT activity (PMID: 14559116), and reduced amount of protein, and reduced specific activity (PMID: 14559116). Two other variants at the same amino acid position, c.265C>G (p.Arg89Gly) (ClinVar Variation ID: 2843836) and c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), have been reported. The evidence for pathogenicity for p.Arg89Gln will be used in the classification of the other two variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 11922). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 1.0.0): PM3_strong, PM1, PP4, PP3_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA256124/MONDO:0001586/091 2025-04-07 2025-06-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5134 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0521839 infores:hetionet CHEBI:63624 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0036396 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0012833 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0853326 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0853326 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0340464 infores:hetionet NCBIGene:3508 biolink:causes MONDO:0014511 infores:monarchinitiative not_provided not_provided HGNC:5542 MONDO:0014511 uuid:3c748c2a-47b4-4983-bd5f-1a3a8b1f1416 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50275 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0003467 infores:hetionet CHEBI:7903 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0085631 infores:hetionet CHEBI:28001 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0000737 infores:hetionet CHEBI:5147 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0687713 infores:hetionet CHEBI:49960 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0392525 infores:hetionet CHEBI:585948 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C2242996 infores:hetionet CHEBI:63619 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151662 infores:hetionet CHEBI:145499 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0006625 infores:hetionet CHEBI:171719 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0428977 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0025061 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0851341 infores:hetionet NCBIGene:859 biolink:causes MONDO:0007402 infores:monarchinitiative not_provided not_provided HGNC:1529 MONDO:0007402 uuid:0c24c88c-a585-41b8-835f-9a6a8f0db022 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:35778 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0392197 infores:hetionet CHEBI:2682 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0001925 infores:hetionet GO:2000592 biolink:causes GO:0072235 infores:ubergraph knowledge_assertion manual_agent GO:2000592 GO:0072235 CHEBI:45783 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0034063 infores:hetionet GO:1900055 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1900055 GO:0007275 CHEBI:9434 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0002962 infores:hetionet CHEBI:8764 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018926 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0455899 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0455899 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0027051 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0948525 infores:hetionet CHEBI:84500 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0013404 infores:hetionet CHEBI:46195 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0085593 infores:hetionet CHEBI:66919 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0018681 infores:hetionet CHEBI:3084 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0085606 infores:hetionet CHEBI:45979 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0003123 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0243026 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0038362 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0020649 infores:hetionet CHEBI:7565 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1443060 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0549475 infores:hetionet NCBIGene:10588 biolink:causes MONDO:0032705 infores:monarchinitiative not_provided not_provided HGNC:7437 MONDO:0032705 uuid:4e8c10bd-8f70-4930-b109-bed93a3f4fef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0015300 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0040034 infores:hetionet CHEBI:5134 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0010200 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0031350 infores:hetionet CHEBI:51041 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0023218 infores:hetionet CHEBI:135930 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0231218 infores:hetionet CHEBI:5779 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0042963 infores:hetionet CHEBI:9448 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0877055 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0038454 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0036974 infores:hetionet CHEBI:4511 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0033687 infores:hetionet CAID:CA2573051043 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051043 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4_Moderate PS4 The c.1802del variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 601 (p.(Ser601Ter)) of NM_000545.8. While this variant, located 5' of c.1803 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein, which is defined as critical for protein function by the ClinGen MDEP (PVS1_Strong). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.800e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant was identified in a total of two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1802del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1_Strong, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051043/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5775 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0019158 infores:hetionet CHEBI:39867 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0037274 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0007117 infores:hetionet CHEBI:4027 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0149745 infores:hetionet CHEBI:135961 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0020458 infores:hetionet CHEBI:38562 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0011991 infores:hetionet CHEBI:3515 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0015230 infores:hetionet CHEBI:50305 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0332575 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002965 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152128 infores:hetionet CHEBI:15367 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0086543 infores:hetionet CHEBI:94440 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0042023 infores:hetionet CHEBI:75722 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0015967 infores:hetionet CHEBI:59560 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0017178 infores:hetionet CHEBI:46557 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0041657 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0948294 infores:hetionet CHEBI:6741 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0015967 infores:hetionet CHEBI:474053 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0008370 infores:hetionet CAID:CA1707541 biolink:causes MONDO:0015152 infores:clingen CAID:CA1707541 MONDO:0015152 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PS1, PP4 The NM_003494.4: c.5768-1G>C variant in DYSF, which is also known as NM_001130987.2: c.5885-1G>C, occurs within the canonical splice acceptor site (+/- 1,2) of intron 51. SpliceAI gives a delta score of 1.0 for loss of the canonical acceptor and of 0.96 for gain of a cryptic acceptor 11 bp into the exon. RNAseq showed that this variant results in an 11 bp deletion at the start of exon 52, which is expected to lead to a frameshift, p.(Gly1923AlafsTer23), with nonsense mediated decay expected (PVS1_RNA). This variant has been observed confirmed in trans with a likely pathogenic or pathogenic variant in one individual with 51% of normal dysferlin levels by blood monocyte assay but no clinical details available (NM_003494.4: c.6124C>T p.(Arg2042Cys), PMID: 36983702). The filtering allele frequency of this variant is 0.000018589 in gnomAD v4.1.0 (the upper threshold of the 95% CI of 13/1111846 European (non-Finnish) exome chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1_RNA, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1707541/MONDO:0015152/180 2025-07-29 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31643 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0012833 infores:hetionet CAID:CA199482 biolink:causes MONDO:0010726 infores:clingen CAID:CA199482 MONDO:0010726 PMID: Benign PM6, BP5, BS1, BS2 PS4 The p.Pro384Leu variant in MECP2 (NM_004992.4) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with a neurological condition (PMID 22277191) (PM6). The p.Pro384Leu variant has been observed in 1 additional individual with intellectual disability (PMID 22277191) (not sufficient to meet PS4_supporting criteria). The p.Pro384Leu variant is observed in at least 8 unaffected individuals, most of whom are male (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro384Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The highest population minor allele frequency of the p.Pro384Leu variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.0000662 in Non-Finnish European population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0000083) for BS1, and therefore meets this criterion (BS1). In summary, the p.Pro384Leu variant in MECP2 (NM_004992.4) is classified as benign based on the ACMG/AMP criteria (BS1, PM6, BS2, BP5). Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. (MECP2 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199482/MONDO:0010726/036 2025-08-27 2025-10-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:27999 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0023530 infores:hetionet CHEBI:7852 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0232488 infores:hetionet CHEBI:135736 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0015967 infores:hetionet CHEBI:9586 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0404521 infores:hetionet CHEBI:119915 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1527344 infores:hetionet CHEBI:2682 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C2242737 infores:hetionet CHEBI:63623 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0948586 infores:hetionet CHEBI:4784 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0016204 infores:hetionet CHEBI:51209 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0003467 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0019158 infores:hetionet CAID:CA645287926 biolink:causes MONDO:0010305 infores:clingen CAID:CA645287926 MONDO:0010305 PMID:18350323 Likely Pathogenic PS3_Supporting, PM2_Supporting, PM4, PP4_Strong The NM_005629.4: c.1059_1061del variant in SLC6A8 is predicted to cause a change in the length of the protein (p.(Phe354del)) due to an in-frame deletion of 1 amino acid in a non-repeat region (PM4). This variant is absent from gnomAD v2.1.1, meeting the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002). The c.1059_1061del, p.(Phe354del) variant has been identified in a proband and his brother with intellectual disability, autistic behavior, and clumsy gait. The proband had elevated urine creatinine/creatine ratio and MRS showing markedly reduced creatine peak (PMID:18350323), meeting criteria for PP4_Strong. Site directed mutagenesis and transfection with this variant (pEGFP-SLC6A8-Phe354del) demonstrated significantly reduce creatine uptake with physiological creatine concentration of 25 µM (PS3_Supp). In summary, this variant meets the criteria to be classified as Likely Pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM4, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645287926/MONDO:0010305/027 2023-09-14 2024-02-11 X-linked inheritance HP:0001417 Supports CHEBI:6935 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00491 UMLS:C1258215 infores:hetionet CHEBI:4702 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1145670 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0520589 infores:hetionet CHEBI:63791 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0019087 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0227791 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0423602 infores:hetionet CHEBI:61033 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C2830004 infores:hetionet CHEBI:6062 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0740394 infores:hetionet GO:1903772 biolink:causes GO:0019058 infores:ubergraph knowledge_assertion manual_agent GO:1903772 GO:0019058 CHEBI:7476 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022658 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020649 infores:hetionet CHEBI:4858 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0042963 infores:hetionet GO:0060492 biolink:causes GO:0060431 infores:ubergraph knowledge_assertion manual_agent GO:0060492 GO:0060431 CHEBI:61049 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002884 infores:hetionet CHEBI:50173 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0035455 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0021053 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0233472 infores:hetionet CHEBI:131512 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0040034 infores:hetionet CHEBI:51364 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C3665386 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0004936 infores:hetionet CHEBI:31348 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0001824 infores:hetionet CAID:CA386953772 biolink:causes MONDO:0015967 infores:clingen CAID:CA386953772 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.217G>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 73 (p.(Glu73Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 cannot be applied (internal lab contributor). In summary, c.217G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386953772/MONDO:0015967/017 2025-04-11 2025-06-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17334 biolink:causes UMLS:C0235874 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0235874 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0034063 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0405580 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0005586 infores:hetionet CHEBI:119573 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151610 infores:hetionet CHEBI:75246 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0027765 infores:hetionet CHEBI:4530 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0008031 infores:hetionet CAID:CA10580957 biolink:causes MONDO:0018875 infores:clingen CAID:CA10580957 MONDO:0018875 PMID:35043155 Likely Benign BP4, BS3, BS2_Supporting, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM6, PP3, PP1, PP4 The NM_000546.6: c.188C>G variant in TP53 is a missense variant predicted to cause substitution of Alanine by Glycine at amino acid 63 (p.Ala63Gly). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). This variant has an allele frequency of 0.00001525 (18/1180022 alleles) in the European non-Finnish population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.156; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -6; VCEP specifications version 2.1; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10580957/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4657 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0152032 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011127 infores:hetionet CHEBI:9086 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0013491 infores:hetionet CHEBI:135613 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0030554 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0020517 infores:hetionet CHEBI:31709 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0039070 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002957 infores:hetionet CHEBI:63624 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0027947 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0004604 infores:hetionet CHEBI:7640 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0020580 infores:hetionet CHEBI:64064 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0010481 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0009676 infores:hetionet CHEBI:63599 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002871 infores:hetionet CHEBI:34967 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0687713 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0034150 infores:hetionet CHEBI:9139 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0022107 infores:hetionet CHEBI:63717 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0020621 infores:hetionet GO:0055011 biolink:causes CL:0002129 infores:ubergraph knowledge_assertion manual_agent GO:0055011 CL:0002129 CHEBI:367163 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0015230 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0149931 infores:hetionet NCBITaxon:10298 biolink:causes MONDO:0012521 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10298 MESH:D020803 DB00787_MESH_D020803_1 CHEBI:6339 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0020517 infores:hetionet CAID:CA193897 biolink:causes MONDO:0700270 infores:clingen CAID:CA193897 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PVS1_Strong PM2 The c. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID: 9887333, 21965147; Ambry internal data). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 21965147, 26896183, 30819809). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000035 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1_Strong (RNA), PM3_Very Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA193897/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71219 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0018932 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151849 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0006145 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1443060 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1739418 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1739418 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0162830 infores:hetionet NCBIGene:2796 biolink:causes MONDO:0013914 infores:monarchinitiative not_provided not_provided HGNC:4419 MONDO:0013914 uuid:fa1f8099-c14e-47d5-ac05-52de9d1489b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0020456 infores:hetionet CAID:CA6748958 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748958 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting BP7 The NM_000277.3:c.420G>A variant in PAH is a synonymous (silent) variant (p.Ala140=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001384 (1/7226 alleles) in the Other population, which is lower than the ClinGen PAH VCEP’s threshold for PM2_Supporting (<0.0002), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 991623, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748958/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:84883 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0033774 infores:hetionet NCBIGene:2200 biolink:causes MONDO:0012013 infores:monarchinitiative not_provided not_provided HGNC:3603 MONDO:0012013 uuid:f15e8093-d0e4-4f36-acc1-4f1156e05b56 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0002878 infores:hetionet UMLS:C0657912 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013378 infores:hetionet NCBIGene:3455 biolink:causes MONDO:0014727 infores:monarchinitiative not_provided not_provided HGNC:5433 MONDO:0014727 uuid:2c6e880f-fe8e-4f9f-bc06-c2988194c2a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0085633 infores:hetionet CHEBI:31401 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0013298 infores:hetionet CHEBI:135888 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0042963 infores:hetionet CHEBI:16714 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0013404 infores:hetionet CHEBI:3761 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0233494 infores:hetionet CHEBI:61033 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0002792 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0017675 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0015397 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0948525 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020456 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0033331 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0001349 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0948089 infores:hetionet CHEBI:9014 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C0015230 infores:hetionet CHEBI:3176 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0011124 infores:hetionet CHEBI:175901 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0033687 infores:hetionet CHEBI:78543 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0740394 infores:hetionet CHEBI:3568 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013456 infores:hetionet CHEBI:41879 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1096274 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151736 infores:hetionet CHEBI:36795 biolink:causes UMLS:C1696943 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1696943 infores:hetionet CHEBI:135961 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0267792 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0267596 infores:hetionet CHEBI:50742 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0002170 infores:hetionet CHEBI:72564 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0232462 infores:hetionet CAID:CA290954030 biolink:causes MONDO:0100326 infores:clingen CAID:CA290954030 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The nonsense variant, NM_000419.5(ITGA2B):c.1051C>T (p.Arg351Ter), has been reported in one compound heterozygous proband (PMID: 29675921) and is absent from population databases. This nonsense variant occurs in exon 12 and is predicted to result in NMD. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PP4_strong, and PM2_Supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA290954030/MONDO:0100326/011 2021-08-17 2021-08-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:9332 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0027720 infores:hetionet CHEBI:5103 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0019521 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0858797 infores:hetionet CHEBI:8713 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0041969 infores:hetionet CHEBI:46345 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0085932 infores:hetionet CAID:CA308126441 biolink:causes MONDO:0007783 infores:clingen CAID:CA308126441 MONDO:0007783 PMID: Uncertain Significance PS3_Moderate, PS4_Supporting, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with threonine at codon 4938 of the RYR1 protein, p.(Ile4938Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:19191329). This variant has been identified in one individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19191329). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (Noda et al. 2023), however, ex vivo studies on patient myotubes show decreased sensitivity to 4-CMC, BS3_Sup (Noda et al. 2023). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.956) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as a Variant of Unknown Significance, (PMID: 29300386). Criteria implemented: PS3_Mod, PS4_Sup, PM1_Sup, PP3_Moderate, BS2_Moderate, BS3_Sup. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA308126441/MONDO:0007783/012 2023-12-15 2023-12-15 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6367 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040409 infores:hetionet CHEBI:61049 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020433 infores:hetionet UNII:D27V6190PM biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0241057 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0162429 infores:hetionet CHEBI:7459 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0424295 infores:hetionet CHEBI:68595 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0042963 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013922 infores:hetionet CHEBI:16469 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0018681 infores:hetionet CAID:CA382523477 biolink:causes MONDO:0700270 infores:clingen CAID:CA382523477 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PM3, PP3 The c.8678C>A variant in ATM is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 2893 (p.Ala2893Asp). This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v.2.1.1. The computational predictor REVEL gives a score of 0.901, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_Supporting, PP3) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382523477/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:59773 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0038362 infores:hetionet CHEBI:44032 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0017672 infores:hetionet CHEBI:44185 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0522224 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0021775 infores:hetionet NCBIGene:1436 biolink:causes MONDO:0032772 infores:monarchinitiative not_provided not_provided HGNC:2433 MONDO:0032772 uuid:a2e38ac3-d33a-446c-aa72-14ececabc534 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64321 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0013378 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0022660 infores:hetionet CHEBI:63638 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C1443060 infores:hetionet CHEBI:3752 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0040264 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0015256 infores:hetionet CHEBI:3814 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0013144 infores:hetionet CHEBI:45979 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C3665347 infores:hetionet CHEBI:27786 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0017178 infores:hetionet CHEBI:391960 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0232849 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0012701 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0426636 infores:hetionet CHEBI:4653 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0011603 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0152227 infores:hetionet CHEBI:50381 biolink:causes HP:0030177 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0853150 infores:hetionet CHEBI:31176 biolink:causes UMLS:C0549386 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0549386 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235146 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0014549 infores:hetionet CAID:CA172580 biolink:causes MONDO:0010726 infores:clingen CAID:CA172580 MONDO:0010726 PMID: Likely Benign BP4, BP7, BS2_Supporting BS1 The p.Pro272= variant in MECP2 (NM_004992.3) is present in 3 XX and 2 XY individual(s) in gnomAD v2 (0.002%) (not sufficient to meet BS1 criteria). The silent p.Pro272= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Pro272= variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro272= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BP4, BP7, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA172580/MONDO:0010726/036 2024-02-23 2024-06-27 X-linked inheritance HP:0001417 Contradicts true CHEBI:5062 biolink:causes HP:0033839 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0039591 infores:hetionet CHEBI:7915 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232461 infores:hetionet CHEBI:35778 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0039231 infores:hetionet GO:0160068 biolink:causes GO:0048868 infores:ubergraph knowledge_assertion manual_agent GO:0160068 GO:0048868 CHEBI:15765 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0009806 infores:hetionet CHEBI:16755 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0025323 infores:hetionet CHEBI:478164 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0042267 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0020538 infores:hetionet CHEBI:135876 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0011603 infores:hetionet CHEBI:127342 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0152032 infores:hetionet GO:0060657 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0030879 NCBITaxon:1648 biolink:causes MONDO:0006752 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1648 MONDO:0006752 CHEBI:3213 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0012797 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0392197 infores:hetionet CHEBI:4995 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0014457 infores:hetionet CHEBI:31515 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0233407 infores:hetionet CHEBI:6456 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0013144 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0340464 infores:hetionet CHEBI:18248 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0030232 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0795692 infores:hetionet CHEBI:6931 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0004134 infores:hetionet CHEBI:9168 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0013428 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002135 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0029132 infores:hetionet CHEBI:253342 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0010692 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0011849 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0002170 infores:hetionet CHEBI:9738 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0013378 infores:hetionet CHEBI:63618 biolink:causes UMLS:C0520962 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0520962 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0152128 infores:hetionet CHEBI:8455 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0232462 infores:hetionet CAID:CA10578936 biolink:causes MONDO:0017623 infores:clingen CAID:CA10578936 MONDO:0017623 PMID: Pathogenic PM2, PM4, PS2, PS4_Moderate PM6, BS4, BS3, BS1, BP7, BP5, BS2, PP3, PP2, PP1, PM5, PM1, BP2, BP4, BA1, PS1, PS3 PTEN c.1212A>T (p.Ter404CysextTer8) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957)PM2: Absent in large sequenced populations (PMID 27535533).PM4: Variant causes protein extension.PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributors ClinVar Organization ID: 26957, SCV000278659.5) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578936/MONDO:0017623/003 2019-11-22 2019-12-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:38545 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0026857 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0852733 infores:hetionet CHEBI:6965 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0036104 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0333494 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0333494 infores:hetionet CHEBI:9599 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0423153 infores:hetionet CHEBI:68478 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C2364111 infores:hetionet CHEBI:61033 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0009806 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005080 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020541 infores:hetionet CHEBI:66876 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0011603 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0006826 infores:hetionet CHEBI:28901 biolink:causes MONDO:0001927 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0034088 infores:hetionet CHEBI:53760 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0085641 infores:hetionet CHEBI:45783 biolink:causes HP:0007902 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042909 infores:hetionet CHEBI:9086 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042029 infores:hetionet CHEBI:180905 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0004245 infores:hetionet CHEBI:27666 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0149745 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0031212 infores:hetionet CHEBI:8707 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0080274 infores:hetionet GO:0052042 biolink:causes GO:0012501 infores:ubergraph knowledge_assertion manual_agent GO:0052042 GO:0012501 CHEBI:4953 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0149871 infores:hetionet CHEBI:5141 biolink:causes HP:0032061 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0745091 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0232841 infores:hetionet CHEBI:135736 biolink:causes MONDO:0024280 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0162323 infores:hetionet NCBIGene:51284 biolink:causes MONDO:0859083 infores:monarchinitiative not_provided not_provided HGNC:15631 MONDO:0859083 uuid:2659a245-91da-4176-8d98-bc66bf4eb551 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7903 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0022281 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1291078 infores:hetionet CHEBI:28901 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018524 infores:hetionet CHEBI:9907 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0231528 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020651 infores:hetionet CAID:CA228408 biolink:causes MONDO:0015628 infores:clingen CAID:CA228408 MONDO:0015628 PMID: Pathogenic PP3, PP4, PM2_Supporting, PS3, PS4_Very Strong PP1 The NM_000552.4(VWF):c.3437A>G (p.Tyr1146Cys) missense variant has been reported in at least 22 VWD type 2A patients. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/37812 alleles in the African/African-American population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.872, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of low VWF activity (VWF:RCo 16, VWF:CB 7) and VWF:Ag of 20 for a low VWF:CB activity/VWF:Ag ratio of 0.35, which is specific for VWD type 2A. (PP4; PMID: 24598842). Eight additional VWD 2A patients, with confirmatory lab values including very low VWF:RCo, low VWF:GPIb, and or low VWF activity/ VWF:Ag ratio, have been reported (PMIDs: 22871923, 16985174, 35452508, 20351307; PS4_VeryStrong). Multimer analysis in 293 cells expressing recombinant variant VWF showed reduced high molecular weight multimers indicating that this variant has a damaging effect on protein function (PMID: 20351307 Figure 3, PMID: 27533707 Figure 2; PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_VeryStrong, PS3, PM2_supporting, PP3, PP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228408/MONDO:0015628/081 2024-08-13 2024-08-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63630 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0029408 infores:hetionet CAID:CA213715 biolink:causes MONDO:0015967 infores:clingen CAID:CA213715 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1130G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 377 (p.(Arg377His)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.981, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID 30155490, 17573900, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of hyperglycemia) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.Arg377Cys, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377His. Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213715/MONDO:0015967/086 2023-08-08 2023-08-08 Semidominant inheritance HP:0032113 Supports CHEBI:71415 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0011606 infores:hetionet CHEBI:8888 biolink:causes NCIT:C78529 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0240717 infores:hetionet CHEBI:7443 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C2047937 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0034065 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0006840 infores:hetionet CHEBI:4315 biolink:causes MONDO:0024477 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0023903 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002123 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0006663 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0040409 infores:hetionet CHEBI:4868 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0016204 infores:hetionet CHEBI:9943 biolink:causes HP:0003146 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151718 infores:hetionet CHEBI:6715 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1140680 infores:hetionet CHEBI:61033 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0039621 infores:hetionet CHEBI:3437 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C1761613 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009806 infores:hetionet CHEBI:2682 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0012569 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0518015 infores:hetionet CHEBI:8768 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030794 infores:hetionet CHEBI:36791 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149745 infores:hetionet CHEBI:10650 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0019080 infores:hetionet CHEBI:40050 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0037274 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151736 infores:hetionet CHEBI:46345 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C2242996 infores:hetionet CHEBI:9613 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0302295 infores:hetionet NCBIGene:176 biolink:causes MONDO:0012019 infores:monarchinitiative not_provided not_provided HGNC:319 MONDO:0012019 uuid:62c694c9-6f7e-4a6e-b7ab-58e2a40aa0a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0263386 infores:hetionet CHEBI:5103 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0027769 infores:hetionet CHEBI:27470 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0234215 infores:hetionet CHEBI:490877 biolink:causes MONDO:0004790 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C2711227 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011615 infores:hetionet CHEBI:3696 biolink:causes MONDO:0004390 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0028841 infores:hetionet CHEBI:100147 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0029134 infores:hetionet CAID:CA2654379899 biolink:causes MONDO:0011071 infores:clingen CAID:CA2654379899 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, BP1, BP3, BA1, PVS1, BP5, BS1, BS3, PM3, PM5, PM1, BS2, PP2, PP3, PP4 NM_001754.5(RUNX1):c.614-8C>A is an intronic variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.97) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2654379899/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6775 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0004096 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0043251 infores:hetionet CHEBI:50275 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0013390 infores:hetionet CHEBI:5134 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0009763 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1096403 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1096403 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0341012 infores:hetionet NCBIGene:1778 biolink:causes MONDO:0013805 infores:monarchinitiative not_provided not_provided HGNC:2961 MONDO:0013805 uuid:b3d5d668-c291-4da3-a486-2dc5dd593205 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4903 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0014742 infores:hetionet CHEBI:9566 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0085612 infores:hetionet CHEBI:3216 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0162285 infores:hetionet GO:0075184 biolink:causes GO:0048856 infores:ubergraph knowledge_assertion manual_agent GO:0075184 GO:0048856 CHEBI:10125 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0014335 infores:hetionet CAID:CA7511816 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511816 MONDO:0015152 PMID: Pathogenic PM2, PVS1, PP4, PM3_Supporting The NM_000070.3: c.2279dup p.(Asn760LysfsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 22/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least four individuals with LGMD (PMID: 18055493, 30564623; LOVD CAPN3_000399), including in trans with a variant not yet curated by the VCEP and considered VUS in two cases (0.5 pts) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.000008797 (1/113680 exome alleles) in the European (non-Finnish) population in gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511816/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:23765 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0857305 infores:hetionet CHEBI:64321 biolink:causes UMLS:C0520904 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0520904 infores:hetionet CHEBI:28593 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0004093 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011849 infores:hetionet CHEBI:68841 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0020580 infores:hetionet CHEBI:8405 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0000737 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011849 infores:hetionet CHEBI:39669 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0017181 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002032 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0699790 infores:hetionet CHEBI:45863 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0015967 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0403632 infores:hetionet NCBITaxon:51022 biolink:causes MONDO:0005645 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:51022 MESH:D000724 DB00848_MESH_D000724_1 CHEBI:46295 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0522251 infores:hetionet CHEBI:3207 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0002170 infores:hetionet CHEBI:41774 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0234215 infores:hetionet CHEBI:8405 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0023530 infores:hetionet CHEBI:15640 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0232495 infores:hetionet UMLS:C0023610 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0013922 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0017152 infores:hetionet CHEBI:404903 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0856054 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0860564 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0860564 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0013395 infores:hetionet CHEBI:64019 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0011603 infores:hetionet CHEBI:42797 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0024282 infores:hetionet UNII:9430ZR8ZAN biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0340865 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0020569 infores:hetionet CAID:CA415079462 biolink:causes MONDO:0010305 infores:clingen CAID:CA415079462 MONDO:0010305 PMID: Uncertain Significance PS3_Supporting, PP3, PP4, PM2_Supporting The NM_005629.4:c.634G>A variant in SLC6A8 is a missense variant that is predicted to result in the substitution of an aspartate for lysine at amino acid 212 (p.Glu212Lys). This variant has been previously reported in one male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in undetectable creatine transport activity when expressed in SLC6A8 deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.885 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.2.0): PS3_Supporting, PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on July 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415079462/MONDO:0010305/027 2024-07-11 2025-08-13 X-linked inheritance HP:0001417 Inconclusive true NCBIGene:3791 biolink:causes MONDO:0011191 infores:monarchinitiative not_provided not_provided HGNC:6307 MONDO:0011191 uuid:52bd9329-5b61-45f3-b55a-5c7d8708d6ed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes MONDO:0007500 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0266589 infores:hetionet CHEBI:5778 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0028734 infores:hetionet NCBIGene:4233 biolink:causes MONDO:0007256 infores:monarchinitiative not_provided not_provided HGNC:7029 MONDO:0007256 uuid:c9304e16-a739-430a-9981-39bc1cd5ac8e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2582120572 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582120572 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.1417_1420del variant in SLC6A8 is frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/13 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (p.Phe473ThrfsTer37) (PVS1). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 17101918) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582120572/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:10125 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151849 infores:hetionet CHEBI:135736 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0231835 infores:hetionet CHEBI:2453 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0030252 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0022904 infores:hetionet CHEBI:46345 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0263386 infores:hetionet CHEBI:8764 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0015732 infores:hetionet CHEBI:136040 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C2830004 infores:hetionet CHEBI:9654 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0016204 infores:hetionet CHEBI:2567 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C1443060 infores:hetionet CHEBI:116278 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0026896 infores:hetionet CHEBI:64312 biolink:causes UMLS:C2173677 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C2173677 infores:hetionet CHEBI:6538 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0036974 infores:hetionet CHEBI:63631 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0017168 infores:hetionet CHEBI:7496 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0085633 infores:hetionet CHEBI:10119 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0040147 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020538 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0687133 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0027769 infores:hetionet CHEBI:47381 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151908 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0027769 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0015734 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0314719 infores:hetionet NCBIGene:1180 biolink:causes MONDO:0008055 infores:monarchinitiative not_provided not_provided HGNC:2019 MONDO:0008055 uuid:d9f7b356-6128-4ccd-a1c0-4733eb57982e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63612 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0746883 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0038454 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0043144 infores:hetionet CHEBI:5893 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0019270 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0027051 infores:hetionet CHEBI:135351 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0744727 infores:hetionet CHEBI:16467 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0039231 infores:hetionet CHEBI:2704 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0007859 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0002170 infores:hetionet CHEBI:175901 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0035222 infores:hetionet CHEBI:63681 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0017178 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0342579 infores:hetionet CAID:CA227866 biolink:causes MONDO:0100438 infores:clingen CAID:CA227866 MONDO:0100438 PMID: Uncertain Significance PP3, PM2_Supporting PS3, PM3 NM_014336.5(AIPL1):c.157C>T (p.Arg53Trp) is a missense variant resulting in replacement of arginine by tryptophan at amino acid p.53. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00006320, with 102 / 1,613,924 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 probands diagnosed with either macular degeneration (VCEP member-provided data, GeneDx) or Leber congenital amaurosis (PMID: 33067476) who harbored the variant in the heterozygous state . However, the probands were not counted for PM3 because no second AIPL1 variant was detected. The computational predictor REVEL gives a score of 0.669, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function (PP3). Additionally, the splicing impact predictor SpliceAI gives a score of 0.03 for acceptor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. The exogenously expressed variant exhibited localization to intracellular inclusions in some studies (PMID: 33067476) but not others (PMID: 27268253). However, these assays are too ambiguous to interpret so PS3_Supporting has not been applied. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227866/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0657912 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0002871 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0023530 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0426649 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0426649 infores:hetionet CHEBI:6149 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0085631 infores:hetionet CHEBI:7915 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0030252 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0015397 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0877211 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0877211 infores:hetionet CHEBI:42068 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0232462 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0019054 infores:hetionet CHEBI:49375 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0019080 infores:hetionet CHEBI:7822 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0003123 infores:hetionet CHEBI:63613 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0035078 infores:hetionet CHEBI:404903 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0018524 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0006145 infores:hetionet CHEBI:17347 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0003862 infores:hetionet CHEBI:18385 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0004093 infores:hetionet CHEBI:135961 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0020580 infores:hetionet CHEBI:50223 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0002170 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0002170 infores:hetionet CHEBI:47780 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0424295 infores:hetionet CHEBI:17263 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0000737 infores:hetionet CHEBI:28593 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C1142412 infores:hetionet CHEBI:5893 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0232462 infores:hetionet CHEBI:135930 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0042963 infores:hetionet CHEBI:28487 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0017601 infores:hetionet CHEBI:2663 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0264893 infores:hetionet CHEBI:5558 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0013404 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0030552 infores:hetionet CAID:CA481333203 biolink:causes MONDO:0009861 infores:clingen CAID:CA481333203 MONDO:0009861 PMID:30459323 Uncertain Significance PM2, PP4, PM3_Supporting, BP7 This c.285C>T (p.Ile95Ile) variant in PAH was reported in one patient with classic PKU, detected with pathogenic variant p.Y204C (phase unknown). BH4 cofactor deficiency was ruled out through unknown methods (PMID: 30459323). This variant is absent from controls in population databases. Computational prediction algorithms predict that this synonymous variant does not impact the splice consensus sequence nor does it create a new splice site. In summary, this variant meets criteria to be classified as Uncertain Significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4, and BP7. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA481333203/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:51164 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0029221 infores:hetionet CHEBI:6541 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0008031 infores:hetionet CHEBI:9907 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0009782 infores:hetionet CHEBI:75722 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151905 infores:hetionet CHEBI:5118 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0028734 infores:hetionet CHEBI:4710 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0428977 infores:hetionet CAID:CA229396 biolink:causes MONDO:0009861 infores:clingen CAID:CA229396 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4, PM2_Supporting, PP3_Moderate PM5 The c.1204T>C (p.Phe402Leu) variant in PAH has been detected in 1 Croatian patient with mild PKU, serum Phe = 600-1200 umol/L, BH4 deficiency not excluded (PMID: 12655552;PP4). This variant was detected with c.1169A>G (p.Glu390Gly) in this patient, reported as Pathogenic in ClinVar, VarID: 625, phase unknown (PMID: 12655552), and has also been reported in unknown phase with the pathogenic p.Arg408Gln variant (ClinVar ID: 577) in another individual with PAH deficiency (PMID: 32668217) (1pt total, PM3). This variant is absent from population databases (PM2_Supporting), and is predicted damaging by REVEL (REVEL score 0.918, PP3_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3, PP3_Moderate, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229396/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:37333 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C1565489 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0033771 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0006145 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020517 infores:hetionet NCBIGene:57479 biolink:causes MONDO:0971007 infores:monarchinitiative not_provided not_provided HGNC:29217 MONDO:0971007 uuid:c8e44377-d1cd-4367-a4a8-19ebc5bb6059 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0030193 infores:hetionet CHEBI:78543 biolink:causes HP:0100539 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0151205 infores:hetionet CHEBI:6904 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0549622 infores:hetionet CHEBI:8080 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0232286 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0863084 infores:hetionet CHEBI:15854 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0162830 infores:hetionet CHEBI:4911 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0001824 infores:hetionet CAID:CA6748897 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748897 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PM3_Strong PM2, PP3 The c.516G>T (p.Gln172His) variant in PAH has been reported in multiple affected individuals (1-MHP, 1-classic PKU). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 26322415. This variant has a highest MAF (East Asian) of 0.00055 in gnomAD, which is above the PAH VCEP AF cutoff (0.0002). This variant was detected in trans with known pathogenic variants: p.R243Q (PMID: 26322415), R408Q (PMID: 26600521) and p.Arg111* (PMID: 28982351; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748897/MONDO:0009861/006 2019-11-17 2021-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:84050 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0036983 infores:hetionet CHEBI:9139 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0009763 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0023067 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0233459 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0233459 infores:hetionet CHEBI:100241 biolink:causes MONDO:0016595 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0155866 infores:hetionet CAID:CA915940780 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940780 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PM3 The c.539del (p.Asn180ThrfsTer3) variant in exon 4 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient # 1 in PMID:18326913 ) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_strong). Additionally, αIIbβ3 surface expression was absent, as measured by Western blot. . Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, and PM2_supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940780/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CAID:CA170263 biolink:causes MONDO:0010726 infores:clingen CAID:CA170263 MONDO:0010726 PMID: Benign BA1 PM1, BP4 The allele frequency of the p.His52Arg variant in MECP2 (NM_004992.3) is 0.121% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.His52Arg variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170263/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:6339 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0010709 infores:hetionet CHEBI:144551 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1384353 infores:hetionet CHEBI:10110 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0030554 infores:hetionet CHEBI:63621 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011124 infores:hetionet CHEBI:9649 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0039070 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011615 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1384353 infores:hetionet CHEBI:53691 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0522224 infores:hetionet CHEBI:63608 biolink:causes MONDO:0018905 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0079744 infores:hetionet CHEBI:6904 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0028084 infores:hetionet NCBIGene:140679 biolink:causes MONDO:0958324 infores:monarchinitiative not_provided not_provided HGNC:11018 MONDO:0958324 uuid:74970704-0acf-46b2-9936-f9442c3f144d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8707 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0340726 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0021141 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0742224 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0742224 infores:hetionet CAID:CA145844 biolink:causes MONDO:0100453 infores:clingen CAID:CA145844 MONDO:0100453 PMID: Benign BP4, BA1, BS2 BS3 The NM_000180.4(GUCY2D):c.61T>C (p.Trp21Arg) variant is a missense variant predicted to replace the tryptophan at position p.21 with arginine. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.2550, with 18,276 alleles / 70,794 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 3,593 adult individuals in gnomAD v4.1.0, which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.141, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). The variant exhibited ~100% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA/eoRD VCEP BS3_Supporting threshold of >50% activity, indicating that it does not trigger a severe defect in protein function, however, it lies in the signal peptide and may be considered ineligible for PS3 or BS3 due to incompatibility with in vitro activity assays (PMID: 11328726, Figure 1). In summary, this variant meets the criteria to be classified as benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1, BS2, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA145844/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8107 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0037763 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0003123 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0853692 infores:hetionet CHEBI:9586 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0012569 infores:hetionet CHEBI:3441 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0042510 infores:hetionet CHEBI:135613 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0036974 infores:hetionet CHEBI:63621 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0220870 infores:hetionet CHEBI:3699 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0027947 infores:hetionet CHEBI:2666 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0003467 infores:hetionet CHEBI:6916 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0085612 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0010709 infores:hetionet CHEBI:7773 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0030252 infores:hetionet CHEBI:61049 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003962 infores:hetionet CHEBI:29013 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0020517 infores:hetionet CHEBI:3636 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0023052 infores:hetionet CHEBI:7514 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0020517 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0948525 infores:hetionet CHEBI:39112 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0268000 infores:hetionet CHEBI:82960 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0234894 infores:hetionet CHEBI:32221 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0014742 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0033575 infores:hetionet CHEBI:35553 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0015672 infores:hetionet CHEBI:31413 biolink:causes MONDO:0003398 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0233795 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0151763 infores:hetionet CHEBI:3176 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0014236 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0014130 infores:hetionet CHEBI:3077 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0019521 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C1167965 infores:hetionet CHEBI:5280 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0015967 infores:hetionet CHEBI:3698 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0085593 infores:hetionet CHEBI:4995 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0019080 infores:hetionet CHEBI:8707 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0039239 infores:hetionet CHEBI:490877 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0035410 infores:hetionet CHEBI:7959 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0042963 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0233494 infores:hetionet CHEBI:32588 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0042487 infores:hetionet CHEBI:4027 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0040822 infores:hetionet CHEBI:8069 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0027540 infores:hetionet CHEBI:8060 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0037317 infores:hetionet CHEBI:134966 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0042024 infores:hetionet CHEBI:47657 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0011570 infores:hetionet CHEBI:8461 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0028084 infores:hetionet CHEBI:32139 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0031542 infores:hetionet CHEBI:68584 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0004093 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0205204 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020651 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0031046 infores:hetionet NCBIGene:7476 biolink:causes MONDO:0010164 infores:monarchinitiative not_provided not_provided HGNC:12786 MONDO:0010164 uuid:468e4dfe-5018-4a5f-9e72-8cacdb705191 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C2242996 infores:hetionet CHEBI:61033 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0178298 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027769 infores:hetionet CHEBI:100246 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0851578 infores:hetionet CAID:CA915940724 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940724 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The ITGA2B frameshift variant NM_000419.5:c.2015del is expected to introduce a premature termination codon 23 amino acids downstream (p.Gly672AlafsTer23) in exon 20/30 and the resulting mRNA product is predicted to be susceptible to nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT12, PMID: 16463284). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PP4_moderate, PM2_supporting, and PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940724/MONDO:0100326/011 2021-07-08 2021-08-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3216 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0234518 infores:hetionet CHEBI:2904 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0027497 infores:hetionet CHEBI:48131 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0702166 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0013922 infores:hetionet CHEBI:3506 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0041834 infores:hetionet CHEBI:32588 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0015967 infores:hetionet CHEBI:3181 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0040264 infores:hetionet CAID:CA261743 biolink:causes MONDO:0021060 infores:clingen CAID:CA261743 MONDO:0021060 PMID:29402968 Likely Pathogenic PM5, PM2, PM6, PP2, PS4_Supporting PS1, PS3, PS2, PM1, PM4, BP7, BP5, BS4, BS3, BS1, BS2, PP1, PP3, BP3, BP2, BP1, BP4, BA1 The c.512T>C (p.Val171Ala) variant in SOS1 has been reported as an unconfirmed de novo occurrence in a patient with clinical features of a Noonan spectrum disorder (PM6; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062240.5). The p.Val171Ala variant has also been identified in another independent occurrences in patients with clinical features of a familial RASopathy (PS4_Supporting; PMID: 29402968). This variant was absent from large population studies (PM2; gnomAD, http://gnomAD.broadinstitute.org). A different pathogenic missense variant (p.Val171Gly) has been previously identified at this codon of SOS1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40654). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PS4_Supporting, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA261743/MONDO:0021060/004 2019-02-28 2019-07-15 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:104011 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00345 UMLS:C0037763 infores:hetionet CHEBI:8869 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0178298 infores:hetionet CHEBI:4953 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0006826 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0541799 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0541799 infores:hetionet CHEBI:50648 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085641 infores:hetionet GO:0075260 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0075260 GO:0061458 CHEBI:8890 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0018524 infores:hetionet CHEBI:70735 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0042963 infores:hetionet CHEBI:3216 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0549249 infores:hetionet CHEBI:3504 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0030252 infores:hetionet CHEBI:44423 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0030305 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0015397 infores:hetionet CHEBI:44423 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0042373 infores:hetionet CHEBI:8768 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0206062 infores:hetionet CHEBI:17347 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0438215 infores:hetionet CHEBI:47381 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0018681 infores:hetionet CHEBI:478164 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0404521 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0005779 infores:hetionet CHEBI:16899 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0004093 infores:hetionet CHEBI:9907 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0040053 infores:hetionet CHEBI:45716 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0036974 infores:hetionet CHEBI:135005 biolink:causes NCIT:C118205 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0455204 infores:hetionet CHEBI:4909 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0003467 infores:hetionet CHEBI:31705 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0014868 infores:hetionet CHEBI:6375 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0038325 infores:hetionet CHEBI:63791 biolink:causes HP:0041167 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0262414 infores:hetionet CAID:CA10014574 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014574 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.181C>T (p.Pro61Ser) is a missense variant which has a REVEL score < 0.50 (0.379) and a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014574/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31397 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0027497 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0423602 infores:hetionet CHEBI:15854 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0231528 infores:hetionet CHEBI:144093 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0013428 infores:hetionet CHEBI:5855 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0041582 infores:hetionet CHEBI:4530 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0344232 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0018799 infores:hetionet CHEBI:27882 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C1368065 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0034065 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0003123 infores:hetionet CHEBI:15854 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0026896 infores:hetionet CAID:CA010455 biolink:causes MONDO:0005045 infores:clingen CAID:CA010455 MONDO:0005045 PMID: Likely Pathogenic PP3, PM1, PS4_Moderate, PM2_Supporting BS3, BP4, BA1, PS1, PS3 NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp). This variant has been identified in individuals with HCM and other cardiomyopathies (ClinVar Variation ID 164114) and was absent from large population studies (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR lower 95% CI>10), therefore, the PS4 criterion has been applied at moderate strength (PS4_Moderate) and the PM2_Supporting criterion has been applied (PM2_Supporting). This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1_Strength; Walsh 2019 PMID: 30696458). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3; REVEL score ≥0.70). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PM1, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010455/MONDO:0005045/095 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:42797 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0013395 infores:hetionet CHEBI:50885 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0036572 infores:hetionet CHEBI:9168 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0003467 infores:hetionet CHEBI:5775 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0016382 infores:hetionet NCBIGene:10558 biolink:causes MONDO:0008086 infores:monarchinitiative not_provided not_provided HGNC:11277 MONDO:0008086 uuid:966860a0-1fe7-410e-8594-8380762e504b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9738 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0087169 infores:hetionet CHEBI:9123 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042023 infores:hetionet CAID:CA16620352 biolink:causes MONDO:0011132 infores:clingen CAID:CA16620352 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PS4, PVS1_Strong PP1, PS3 The NM_001369369.1(FOXN1):c.1201_1216del (p.Pro401AlafsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 544. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). This variant is absent from gnomADv2.1.1 (PM2_supporting). This variant has been reported heterozygous in at least 10 patients (PS4) with T lymphopenia, particularly low CD8+ cell counts, at least one of whom also had nail dystrophy (P13 of PMID: 31447097; PP4). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, PS4 and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620352/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CAID:CA145741 biolink:causes MONDO:0800472 infores:clingen CAID:CA145741 MONDO:0800472 PMID:10910054 Benign BA1, BP4 PP3, PP1, PM3, PM1, PM4, PM5, PS3, PS1, PS2, BS1, BS4, BP7, PM2, PVS1 The c.355G>T variant in CYP1B1 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 119 (p.Ala119Ser). The highest minor allele frequency of this variant, in a genetic ancestry group of at least 2,000 alleles, was in the African/African American genetic ancestry group of gnomAD (v4.1) = 0.4805, which met the ≥ 0.05 threshold set for BA1 (35944 alleles out of 74804, meeting the threshold of ≥ 5 observed alleles). The REVEL score = 0.095, which was within the 0.017-0.183 range for BP4_Moderate and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1), suggesting that the variant does not impact CYP1B1 function. PS3_Supporting was not applied as the assay reported in PMID: 10910054 did not meet the OddsPath threshold (> 2.1). In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1, BP4_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145741/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15367 biolink:causes UMLS:C0281856 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0281856 infores:hetionet CHEBI:6339 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0030196 infores:hetionet CHEBI:28445 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0311394 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0017178 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0000833 infores:hetionet CHEBI:32221 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0032617 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0002871 infores:hetionet NCBIGene:49855 biolink:causes MONDO:0032594 infores:monarchinitiative not_provided not_provided HGNC:13081 MONDO:0032594 uuid:14ef8463-eadd-4813-85ab-5238621e5fc3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA409106859 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106859 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4, PS4 The c.617T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 206 (p,Leu206Pro) of NM_175914.5. This variant is located within the ligand binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.981, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Additionally, the MODY probability is unable to be calculated due to age of diagnosis over 35 and lack of clinical information (internal lab contributors). In summary, c.617T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106859/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52717 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0746883 infores:hetionet GO:0061888 biolink:causes GO:0150076 infores:ubergraph knowledge_assertion manual_agent GO:0061888 GO:0150076 CHEBI:4027 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0003862 infores:hetionet CAID:CA410206807 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206807 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, BP2, BA1, PVS1, BS1, BS3, BS4, PM5, PM3, PP4, PP1 NM_001754.5(RUNX1):c.730G>A (p.Ala244Thr) is a missense variant which has a REVEL score < 0.50 (0.277) and a SpliceAI score ≤ 0.20 (0.08) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206807/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2948 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0011991 infores:hetionet CHEBI:135930 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0085649 infores:hetionet CHEBI:8874 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0700200 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0855242 infores:hetionet CAID:CA340748547 biolink:causes MONDO:0100368 infores:clingen CAID:CA340748547 MONDO:0100368 PMID: Uncertain Significance PM2_Supporting BP4, PM3, PM5, PP3, PP4 NM_000329.3(RPE65):c.257C>A is a missense variant causing substitution of threonine with asparagine at position 86. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 1 affected proband who harbored the variant in the homozygous state due to consanguinity (parents first cousins, VCEP member-provided data). However, the proband was not counted for PM3 because sufficient phenotype details were unavailable. The computational predictor REVEL gives a score of 0.637, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.06 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Another missense variant in the same codon, NM_000329.3(RPE65):c.257C>T (p.Thr86Ile), has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so PM5 is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340748547/MONDO:0100368/120 2024-02-19 2024-02-19 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:32139 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C1720775 infores:hetionet NCBIGene:3039 biolink:causes MONDO:0007705 infores:monarchinitiative not_provided not_provided HGNC:4823 MONDO:0007705 uuid:8e0e0b43-7dcb-4946-b1fd-bcfa37bb189b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0036454 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085636 infores:hetionet CHEBI:9288 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0015376 infores:hetionet CHEBI:7565 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0026826 infores:hetionet CHEBI:47381 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0917801 infores:hetionet CHEBI:36704 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0020443 infores:hetionet CHEBI:5801 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0023530 infores:hetionet CHEBI:585948 biolink:causes UMLS:C1096286 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C1096286 infores:hetionet CHEBI:75246 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0018681 infores:hetionet CHEBI:209807 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0011606 infores:hetionet CHEBI:47381 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0232849 infores:hetionet NCBIGene:5567 biolink:causes MONDO:0030877 infores:monarchinitiative not_provided not_provided HGNC:9381 MONDO:0030877 uuid:806e249f-f945-4eff-887e-e8e8c8ffd57e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C1443060 infores:hetionet CHEBI:6801 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0424790 infores:hetionet CL:0002573 biolink:causes MONDO:0002546 infores:ubergraph knowledge_assertion manual_agent CL:0002573 MONDO:0002546 CHEBI:2038 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0017181 infores:hetionet CAID:CA345036 biolink:causes MONDO:0010305 infores:clingen CAID:CA345036 MONDO:0010305 PMID:17465020 Pathogenic PP1_Moderate, PP3, PM2_Supporting, PP4_Strong, PS4_Moderate PS3 The NM_005629.4:c.1661C>T variant in SLC6A8 is predicted to result in the substitution of proline by leucine at amino acid 554 (p.Pro554Leu). This variant has been reported in a hemizygous male with clinical features consistent with creatine transporter deficiency, elevated urine creatine/creatinine ratio, and deficient creatine uptake in fibroblasts (PMID: 15690373, 21556832, 24789340) (PP4_Strong). This variant has also been reported in another 4 unrelated probands, all with clinical features consistent with creatine transporter deficiency. Two of these individuals (one male, one female) have biochemical and/or brain magnetic resonance spectroscopy (MRS) data to support the diagnosis (PMID: 15154114, 17465020, 21836662; 33164824) (PS4_Moderate). Supportive biochemical, MRS, or creatine uptake results are not available for the other two patients (PMID: 23660394, 30293248). One proband has an affected brother, with elevated creatine/creatinine ratio in urine and deficient creatine transport in fibroblasts; their mother is heterozygous for the variant and has mild learning difficulties (PMID: 15690373) (2 segregations, PP1_Moderate). Segregation of the clinical symptoms with the variant has been reported in other families, but no biochemical, MRS, or creatine uptake studies were performed in the affected individuals and, therefore, this data will not be counted towards PP1 (PMID: 15154114 - 5 segregations; PMID: 33164824). The variant is not in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). Overexpression of the variant in SLC6A8-deficient fibroblasts did not result in a significant increase in creatine transport. Studies were carried out with 500uM creatine (PMID: 17465020). The CCDS VCEP requires that studies are carried out with <125uM creatine. Therefore, PS3 is not met. The computational predictor REVEL gives a score of 0.937 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variant ID: 65693). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PS4_Moderate, PP1_Moderate, PP3, PM2_Supporting.)Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on Jan 7, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA345036/MONDO:0010305/027 2025-01-07 2025-01-09 X-linked inheritance HP:0001417 Supports CHEBI:7565 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0149931 infores:hetionet CHEBI:64312 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0019079 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0235735 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0235735 infores:hetionet CHEBI:9137 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042024 infores:hetionet CL:0002138 biolink:causes MONDO:0002013 infores:ubergraph knowledge_assertion manual_agent CL:0002138 MONDO:0002013 CHEBI:465284 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0038454 infores:hetionet CHEBI:135736 biolink:causes HP:0041159 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0035522 infores:hetionet CHEBI:31623 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0234632 infores:hetionet CHEBI:7824 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151662 infores:hetionet CHEBI:52172 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151514 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020538 infores:hetionet CHEBI:41977 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0041657 infores:hetionet CHEBI:4702 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0030196 infores:hetionet CHEBI:5856 biolink:causes HP:0031676 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0344431 infores:hetionet CAID:CA415077486 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077486 MONDO:0010305 PMID: Uncertain Significance PM2 PP3, PP4, PP1, BP4 The NM_005629.4:c.301G>A variant in SLC6A8 is predicted to results in the substitution of glycine by arginine at amino acid 101 (p.Gly101Arg). The variant has been reported in two brothers from China and their mother. The proband has developmental delays and seizures, normal guanidinoacetate and mildly reduced creatine in blood. Urine creatine level, brain creaine level on MRS, and creatine uptake studies are not available. Insufficient evidence to apply PP4 or PP1) (PMID: 35588794). The variant is absent in gnomAD v2.1.1. and v4.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.685 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. SpliceAI gave a score for acceptor gain of 0.34, 25 bp upstream, but the impact on splicing is unclear. In summary, the variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0.): PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 18, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077486/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Inconclusive true CHEBI:46557 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0026821 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030305 infores:hetionet CHEBI:52717 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020621 infores:hetionet CHEBI:2704 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0877359 infores:hetionet CHEBI:6062 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0232726 infores:hetionet CHEBI:63607 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0014742 infores:hetionet CHEBI:28915 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0029134 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0022660 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009450 infores:hetionet CHEBI:7492 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0043352 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0392162 infores:hetionet GO:0044560 biolink:causes GO:0034220 infores:ubergraph knowledge_assertion manual_agent GO:0044560 GO:0034220 CHEBI:5383 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0162533 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042769 infores:hetionet CHEBI:3504 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0917801 infores:hetionet CHEBI:50777 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0236075 infores:hetionet CHEBI:5138 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0016867 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020517 infores:hetionet CL:0000138 biolink:causes MONDO:0024469 infores:ubergraph knowledge_assertion manual_agent CL:0000138 MONDO:0024469 CHEBI:5103 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0085593 infores:hetionet CAID:CA399801285 biolink:causes MONDO:0100326 infores:clingen CAID:CA399801285 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP4 PP4 The c.1888 variant in ITGA2B is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 630 (p.Val630Ile). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00003891 (2/51402 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.076, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting and BP4 (VCEP specifications version 2; date of approval 03/07/2024). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399801285/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:50922 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042109 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0041912 infores:hetionet CHEBI:10023 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0025222 infores:hetionet CHEBI:3011 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0002994 infores:hetionet GO:0014725 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0014725 GO:0150063 CHEBI:8356 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015732 infores:hetionet CHEBI:5613 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0085688 infores:hetionet CHEBI:3478 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0023530 infores:hetionet CHEBI:6067 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2047937 infores:hetionet CHEBI:28177 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0039240 infores:hetionet CHEBI:17026 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0241633 infores:hetionet CHEBI:17650 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0026946 infores:hetionet GO:2000733 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0001823 GO:0002301 biolink:causes CL:0000793 infores:ubergraph knowledge_assertion manual_agent GO:0002301 CL:0000793 CHEBI:9130 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0231365 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1262144 infores:hetionet CHEBI:92923 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C2242996 infores:hetionet CHEBI:6888 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0022107 infores:hetionet CHEBI:83527 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C2830004 infores:hetionet CHEBI:84500 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C2047937 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009241 infores:hetionet CHEBI:404903 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042023 infores:hetionet CHEBI:94848 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0013395 infores:hetionet CHEBI:3534 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0015967 infores:hetionet CHEBI:2618 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0085628 infores:hetionet UMLS:C0145867 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0022107 infores:hetionet CHEBI:8207 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0014591 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0009450 infores:hetionet CHEBI:70735 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0085637 infores:hetionet CHEBI:135925 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0025061 infores:hetionet CAID:CA340741708 biolink:causes MONDO:0100368 infores:clingen CAID:CA340741708 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4, PP1, PM2_Supporting NM_000329.3(RPE65):c.1444G>A (p.Asp482Asn) is a missense variant predicted to replace aspartic acid with asparagine at codon 482. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.1543C>T (p.Arg515Trp) or NM_000329.3(RPE65):c.806_809delinsTGGAGCCATGAAG (p.Ser269MetfsTer4) variants confirmed in trans, which were both previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PMID: 34830511, PMID: 33952291, PM3_Strong). One genotype was published twice by two independent groups, but it has only been counted once as it is not clear whether the two probands might be the same or related individuals (PMID: 34830511, PMID: 33952291). At least one proband harboring this variant exhibits a phenotype including severely decreased rod ERG (0.5 pt), genotyping by next-generation sequencing gene panel of 586 IRD-related genes that did not provide an alternative explanation for visual impairment (2 pt), symptomatic onset between birth and age five years (1 pt), evidence of cone involvement on ERG (1 pt), and white/yellow dots on color photography of the type seen in fundus albipunctatus in the context of severe retinal dysfunction (2 pt), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 33952291, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 33952291, PP1). The computational predictor REVEL gives a score of 0.946, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340741708/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8888 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030920 infores:hetionet CHEBI:7773 biolink:causes MONDO:0004901 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0152115 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0233472 infores:hetionet GO:2000244 biolink:causes GO:0019954 infores:ubergraph knowledge_assertion manual_agent GO:2000244 GO:0019954 CHEBI:17347 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0017181 infores:hetionet CHEBI:63638 biolink:causes HP:0000153 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026633 infores:hetionet CHEBI:38562 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0015672 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0042769 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005132 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0010823 infores:hetionet CHEBI:6076 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151905 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005765 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0016514 infores:hetionet CAID:CA5045836 biolink:causes MONDO:0009595 infores:clingen CAID:CA5045836 MONDO:0009595 PMID: Uncertain Significance PM2 This variant is present in a frequency of 0.001105 in the Middle Eastern population. Overall, 89 variants have been observed in a total of 694012 alleles (0.0001282). The Grpmax Filtering AF is 0.0003011, which is above the PM2 threshold the SCID VCEP has established (0.0000447). To date, there are no patients reported with this variant, and therefore none of the phenotypic codes are applicable. In summary, this variant is classified as uncertain significance with none of the codes being applicable. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5045836/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0004609 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0270458 infores:hetionet CHEBI:3216 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0007222 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0267596 infores:hetionet CHEBI:8228 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0034063 infores:hetionet NCBIGene:3861 biolink:causes MONDO:0007554 infores:monarchinitiative not_provided not_provided HGNC:6416 MONDO:0007554 uuid:70151fa9-6b62-4872-bc10-d372245ef961 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75045 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0019080 infores:hetionet CHEBI:2955 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0021051 infores:hetionet CHEBI:9123 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0040264 infores:hetionet CHEBI:135613 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0151878 infores:hetionet CHEBI:45979 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0085605 infores:hetionet CHEBI:144551 biolink:causes UMLS:C1261562 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C1261562 infores:hetionet CHEBI:15428 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0011175 infores:hetionet CHEBI:45863 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0022575 infores:hetionet CHEBI:64355 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0522055 infores:hetionet CHEBI:48947 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0020621 infores:hetionet NCBIGene:646 biolink:causes MONDO:0032881 infores:monarchinitiative not_provided not_provided HGNC:1081 MONDO:0032881 uuid:18cfab62-b340-42db-9669-94b53bb605f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0020538 infores:hetionet CHEBI:5123 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0023530 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0240515 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006145 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0242073 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0027726 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0948089 infores:hetionet CHEBI:52717 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C3160858 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0011991 infores:hetionet CHEBI:135736 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0162834 infores:hetionet CHEBI:9123 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0026827 infores:hetionet CHEBI:31705 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C1510410 infores:hetionet CHEBI:8212 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C3665347 infores:hetionet CHEBI:63618 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151908 infores:hetionet GO:0060297 biolink:causes GO:0051146 infores:ubergraph knowledge_assertion manual_agent GO:0060297 GO:0051146 UNII:0RK7M7IABE biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0027497 infores:hetionet CHEBI:9130 biolink:causes EFO:1001328 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0016325 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0852733 infores:hetionet CHEBI:45409 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020672 infores:hetionet CHEBI:3216 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0027497 infores:hetionet CHEBI:50742 biolink:causes HP:0001065 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0152459 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151664 infores:hetionet CAID:CA2579584446 biolink:causes MONDO:0100437 infores:clingen CAID:CA2579584446 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2506del (p.Glu836LysfsTer?) is a frameshift variant due to 1-nucleotide deletion in codon 836 introducing a premature stop codon in exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 10 years (1 pt), reduced visual acuity (0.5 pts), reduced rod electroretinogram responses, pigment deposits in the periphery (0.5 pts), severe macular degeneration, and genotyping by next-generation sequencing with a panel of 483 genes identifying no alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (4.5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579584446/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports NCBIGene:1991 biolink:causes MONDO:0042490 infores:monarchinitiative not_provided not_provided HGNC:3309 MONDO:0042490 uuid:0a7c4024-072a-47e9-b170-63af56a28b4a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412739890 biolink:causes MONDO:0100437 infores:clingen CAID:CA412739890 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS3, PS4 NM_001034853.2(RPGR):c.1154T>A (p.Leu385Ter) is a nonsense variant that substitutes a premature stop codon for amino acid 385 in exon 10 of 15 and is predicted to trigger nonsense-mediated decay (PVS1). Fibroblast cells expressing the variant exhibit loss of RPGR localization to the ciliary axoneme (PMID: 33182541). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 37541846). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412739890/MONDO:0100437/106 2025-08-01 2025-08-01 X-linked inheritance HP:0001417 Supports CHEBI:52172 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0162830 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0795692 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0795692 infores:hetionet CHEBI:10102 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0151636 infores:hetionet NCBIGene:51311 biolink:causes MONDO:0024777 infores:monarchinitiative not_provided not_provided HGNC:15632 MONDO:0024777 uuid:897725c9-48d1-4b48-ab55-568d35ba6f92 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5280 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151905 infores:hetionet CAID:CA294755 biolink:causes MONDO:0100039 infores:clingen CAID:CA294755 MONDO:0100039 PMID: Benign BS1, BP5_Strong, BS2 PP3, BP4 The allele frequency of the p.Pro574Leu variant in CDKL5 is 0.021% in European (Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro574Leu variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Pro574Leu variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5_strong). In summary, the p.Pro574Leu variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294755/MONDO:0100039/034 2024-02-23 2024-07-31 X-linked inheritance HP:0001417 Contradicts true CHEBI:5775 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0030554 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0006849 infores:hetionet CHEBI:73274 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0012797 infores:hetionet CHEBI:68575 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C2363731 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0743680 infores:hetionet CHEBI:480999 biolink:causes MONDO:0008433 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0149925 infores:hetionet CHEBI:9757 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0020517 infores:hetionet CHEBI:3638 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0015230 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0039971 infores:hetionet CAID:CA1589147 biolink:causes MONDO:0021060 infores:clingen CAID:CA1589147 MONDO:0021060 PMID: Benign BP7, BA1, BP4 The c.27C>T (p.Asp9=) variant in PPP1CB is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population minor allele frequency in gnomAD v4 is 0.002280 (2698/1145756 alleles) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/24) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1589147/MONDO:0021060/128 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4708 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0242379 infores:hetionet CHEBI:3207 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0232462 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0234987 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011991 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0010692 infores:hetionet UBERON:0000176 biolink:causes HP:0000989 infores:drugmechdb knowledge_assertion manual_agent UBERON:0000176 HP:0000989 DB00972_MESH_D065631_1DB00972_MESH_D006255_1 CHEBI:161680 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0011606 infores:hetionet CAID:CA390887165 biolink:causes MONDO:0100216 infores:clingen CAID:CA390887165 MONDO:0100216 PMID: Uncertain Significance BP4 PVS1, PM6, PM2, BP1, BP3, BP2, BA1, PP2, PP3, PP1, PP4, BS2, PM4, PM3, PM1, PM5, PS2, PS4, PS3, PS1, BP5, BP7, BS1, BS4, BS3 The NM_177438.3:c.1011A>C variant in DICER1 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 337 (p.Gln337His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1613908 alleles) with a highest population minor allele frequency of 00004391 (4/91086 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.18; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.4.0; 10/28/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390887165/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4469 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0220870 infores:hetionet CHEBI:9674 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0232462 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0003123 infores:hetionet CHEBI:63638 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0000768 infores:hetionet CHEBI:32020 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0012833 infores:hetionet CHEBI:144551 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0542571 infores:hetionet CHEBI:44032 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0033046 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1096091 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1096091 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0426576 infores:hetionet CHEBI:8107 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0004144 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C1720775 infores:hetionet CHEBI:63618 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0349506 infores:hetionet CHEBI:8356 biolink:causes MONDO:0003038 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234144 infores:hetionet CHEBI:584020 biolink:causes MONDO:0043683 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0023370 infores:hetionet CAID:CA658658815 biolink:causes MONDO:0018493 infores:clingen CAID:CA658658815 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting PP3, PS4, PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of phenylalanine with asparagine at codon 4808 of the RYR1 protein, p.(Phe4808Asn), c.14422_14423delinsAA. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 21455645), PS4 was not met. This variant has also been identified in individuals with myopathy (PMID:27447704, PMID:28357410, PMID:30155738 and others). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). No REVEL score was available. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658815/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:8382 biolink:causes MONDO:0031054 infores:monarchinitiative not_provided not_provided HGNC:7853 MONDO:0031054 uuid:c31c3982-00a2-4867-abce-61edddcb67ec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91834 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0031350 infores:hetionet CHEBI:135005 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0023530 infores:hetionet CHEBI:6633 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0011991 infores:hetionet CHEBI:7476 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0151970 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0034150 infores:hetionet CHEBI:5864 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0033036 infores:hetionet CHEBI:499361 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C2047937 infores:hetionet CHEBI:51860 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0023530 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0007097 infores:hetionet CHEBI:2663 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0233565 infores:hetionet UMLS:C0657912 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151699 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0151602 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0003123 infores:hetionet CHEBI:6775 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0025323 infores:hetionet CHEBI:63611 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042023 infores:hetionet CHEBI:9943 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0155365 infores:hetionet CHEBI:4735 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0027720 infores:hetionet CHEBI:5004 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0242528 infores:hetionet CHEBI:4887 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0009782 infores:hetionet CHEBI:6062 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0030554 infores:hetionet CAID:CA405692068 biolink:causes MONDO:0018493 infores:clingen CAID:CA405692068 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with threonine at codon 3266 of the RYR1 protein, p.(Met3266Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.742 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405692068/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true NCBIGene:3710 biolink:causes MONDO:0859311 infores:monarchinitiative not_provided not_provided HGNC:6182 MONDO:0859311 uuid:ee0cc52a-dc62-4a7d-8d05-ed8471b13798 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0032227 infores:hetionet CHEBI:2955 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0231218 infores:hetionet CHEBI:87681 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0012833 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1384606 infores:hetionet CHEBI:119915 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003578 infores:hetionet NCBIGene:9719 biolink:causes MONDO:0009269 infores:monarchinitiative not_provided not_provided HGNC:14631 MONDO:0009269 uuid:01f0d676-4bba-4723-a738-0903a0a0bcf5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31485 biolink:causes UMLS:C3665888 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C3665888 infores:hetionet CAID:CA10588624 biolink:causes MONDO:0007648 infores:clingen CAID:CA10588624 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BS1, BS4, BS3, BP5, BP7, PM3, PM1, PM4, PM6, BS2, PP4, PP1, PP2, PP3, BA1, BP2, BP3, BP1, BP4, PS4, PS2, PS3, PS1 The c.1578G>A p.(Trp526Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588624/MONDO:0007648/007 2023-08-30 2023-08-30 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:27899 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0002871 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0878544 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0541900 infores:hetionet CHEBI:3561 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042029 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0009450 infores:hetionet CHEBI:8093 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0013404 infores:hetionet CHEBI:4027 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0595916 infores:hetionet CHEBI:32315 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0001807 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0392386 infores:hetionet CAID:CA355965038 biolink:causes MONDO:0001586 infores:clingen CAID:CA355965038 MONDO:0001586 PMID: Uncertain Significance PM3, PP4_Moderate, PM2_Supporting BP4, PP3 The NM_000203.5(IDUA):c.1603C>T variant in IDUA is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 535 (p.Leu535Phe). This variant has been reported in a proband and sibling with MPS I (PMID: 20026495, 30809705, 21394825). Both of them are compound heterozygous for c.1603C>T (p.Leu535Phe) and another variant in IDUA that has been classified by the ClinGen LD VCEP as pathogenic for MPS I c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908); (1 point due to phase known, PM3_Moderate). The female proband had been diagnosed with the Hurler-Scheie form of MPSI based on clinical findings (including joint stiffness, corneal clouding, hepatosplenomegaly, valvular disease, and dysostosis multiplex), an elevated urinary glycosaminoglycan level, and low-L-iduronidase activity in leukocytes. started laronidase at 5 years of age. Her younger brother was diagnosed with MPS1 at 3 days by enzyme assay. At that time, he had no clinical features of MPS I other than elevated urinary GAGs, with a predominance of heparan sulfate and dermatan sulfate. Urinary glycosaminoglycan excretion decreased to normal levels for age within 4 months of therapy, with a complete disappearance of dermatan and heparan sulfate bands on electrophoresis. (PP4_Moderate). The variant is absent from gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.584, which is neither above nor below the thresholds of predicted damaging >0.644 or benign <0.29 impact on IDUA Function. There is a ClinVar entry for this variant (Variation ID: 638076). In summary, this variant meets the criteria to be classified as VUS for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3, PP4_Moderate, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, July 21, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355965038/MONDO:0001586/091 2025-07-21 2025-09-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63638 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0549373 infores:hetionet CHEBI:2950 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0001925 infores:hetionet CHEBI:44032 biolink:causes MONDO:0018660 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0684275 infores:hetionet CHEBI:31236 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151836 infores:hetionet CHEBI:4735 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0028643 infores:hetionet CHEBI:40279 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0024282 infores:hetionet CHEBI:4325 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0042963 infores:hetionet CHEBI:6916 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C3665347 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0004936 infores:hetionet CHEBI:4911 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0206061 infores:hetionet CHEBI:8356 biolink:causes MONDO:0006882 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0029191 infores:hetionet CHEBI:27882 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0001824 infores:hetionet CAID:CA345918 biolink:causes MONDO:0044970 infores:clingen CAID:CA345918 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6_Supporting, PM5, PS3_Supporting PP1, PS1, PM4, PVS1 The m.13514A>G (p.D393G) variant in MT-ND5 has been reported in at least 12 unrelated individuals with primary mitochondrial disease with onset ranging from childhood to adulthood and features variably consistent with Leigh syndrome and MELAS, as well as hypertrophic cardiomyopathy, optic atrophy, and neuropathy (PS4_moderate; PMIDs: 26341968, 25974876, 32504279, 20972245, 23847141, 21712854, 15576045, 14684687, 11198278). Heteroplasmy levels in affected individuals ranged from 55-70% in muscle, 12-55% in fibroblasts, 4-50% in blood, and 90% heart. This variant has been identified as a de novo occurrence in at least two probands with primary mitochondrial disease (PM6_supporting; PMIDs: 14684687, 11198278). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by this Expert Panel – m.13513G>A (p. D393N, PM5). Cybrid studies showed a tight correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 11198278). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PM5, PS3_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345918/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:50275 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0002878 infores:hetionet CHEBI:63791 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C3665347 infores:hetionet CAID:CA069103 biolink:causes MONDO:0007783 infores:clingen CAID:CA069103 MONDO:0007783 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate, PM5_Supporting PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 2359 of the RYR1 protein, p.(Arg2359Trp). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in a mutation report without clinical details and this does not satisfy PS4 (PMID:16521288). No functional studies were identified for this variant. Another variant assessed as likely pathogenic occurs at this codon, p.(Arg2359Gln), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.93) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PM5_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA069103/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6887 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0162429 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0040822 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0494165 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0494165 infores:hetionet CHEBI:7822 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0039231 infores:hetionet CHEBI:5893 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C1291078 infores:hetionet CHEBI:6367 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0018524 infores:hetionet CHEBI:8597 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0235347 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0242350 infores:hetionet CHEBI:3994 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0231530 infores:hetionet CHEBI:6339 biolink:causes MONDO:0017395 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0221242 infores:hetionet CHEBI:9328 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0034150 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006111 infores:hetionet CHEBI:39112 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0151479 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0011974 infores:hetionet CHEBI:27974 biolink:causes UMLS:C1328561 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1328561 infores:hetionet NCBITaxon:1502 biolink:causes MONDO:0023149 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1502 MONDO:0023149 CHEBI:7640 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0008370 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0019158 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0036572 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0042401 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0242350 infores:hetionet CHEBI:28148 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0020621 infores:hetionet CHEBI:6030 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0302295 infores:hetionet CHEBI:7789 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0344232 infores:hetionet CHEBI:63608 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0039070 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0239739 infores:hetionet CHEBI:15367 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0700361 infores:hetionet CHEBI:31485 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0019348 infores:hetionet CHEBI:2950 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0003873 infores:hetionet CHEBI:64354 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0023380 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233472 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0340726 infores:hetionet NCBIGene:51119 biolink:causes MONDO:0044204 infores:monarchinitiative not_provided not_provided HGNC:19440 MONDO:0044204 uuid:40a43a5a-0fe1-4717-8ecc-be3a4915bdcb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8863 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0234458 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0302295 infores:hetionet CHEBI:4911 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0020580 infores:hetionet CHEBI:119486 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0001125 infores:hetionet CHEBI:93635 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0009421 infores:hetionet CHEBI:28487 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0012833 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0004936 infores:hetionet CHEBI:4551 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0011991 infores:hetionet CHEBI:4814 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0392171 infores:hetionet GO:0060707 biolink:causes CL:0002488 infores:ubergraph knowledge_assertion manual_agent GO:0060707 CL:0002488 CHEBI:567361 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0041834 infores:hetionet CHEBI:5138 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0025345 infores:hetionet CHEBI:7915 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0740394 infores:hetionet CHEBI:6888 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C2242996 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0235431 infores:hetionet CHEBI:135736 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0002170 infores:hetionet CHEBI:50648 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0235857 infores:hetionet CHEBI:100246 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0015230 infores:hetionet CHEBI:135342 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0085593 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020456 infores:hetionet CHEBI:194135 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0043352 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0853692 infores:hetionet NCBIGene:64834 biolink:causes MONDO:0032798 infores:monarchinitiative not_provided not_provided HGNC:14418 MONDO:0032798 uuid:2e1b84cd-f602-4d0f-ad6f-84785ac9e340 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0086565 infores:hetionet CAID:CA020186 biolink:causes MONDO:0008667 infores:clingen CAID:CA020186 MONDO:0008667 PMID: Pathogenic PS4, PM2_Supporting, PP1_Strong The variant NM_000551.4(VHL):c.257C>T (p.Pro86Leu) is a missense variant predicted to cause substitution of Proline by Leucine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 10 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 7.5, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:7728151; 27527340; 29437867; 21463266). The variant has been reported to segregate with von Hippel Lindau syndrome in at least 7 affected family members from 2 families (PP1_Strong; PMID: 7728151). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024 Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020186/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:691037 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0017979 infores:hetionet CHEBI:6706 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0009806 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0233494 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0026961 infores:hetionet CHEBI:3698 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0013428 infores:hetionet CAID:CA412729749 biolink:causes MONDO:0100437 infores:clingen CAID:CA412729749 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2800G>T (p.Glu934Ter) is a nonsense variant introducing a premature stop in codon 934 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) with onset at age 3 years (1 pt), reduced visual acuity (0.5 pts), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with pigment deposits (0.5 pts), optic disc pallor (0.5 pts), cataract, severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412729749/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:63611 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0392025 infores:hetionet CHEBI:8028 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0036974 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0003864 infores:hetionet CHEBI:135276 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0025061 infores:hetionet CHEBI:2668 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C2047937 infores:hetionet CHEBI:63622 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0701811 infores:hetionet CHEBI:2704 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C3263723 infores:hetionet NCBIGene:54894 biolink:causes MONDO:0014919 infores:monarchinitiative not_provided not_provided HGNC:18505 MONDO:0014919 uuid:3f7fc0e9-767d-4998-a42e-d3efa4504cc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0232459 infores:hetionet CHEBI:6456 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0700590 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0340464 infores:hetionet NCBIGene:51473 biolink:causes MONDO:0012442 infores:monarchinitiative not_provided not_provided HGNC:18141 MONDO:0012442 uuid:a620af66-6c64-47d9-95a2-9a501bdaca29 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0021053 infores:hetionet GO:0006954 biolink:causes MONDO:0005709 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003139 DB08936_MESH_D003139_1 CHEBI:27899 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0030353 infores:hetionet CHEBI:134966 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0040034 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006840 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1868911 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1868911 infores:hetionet CAID:CA367397075 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397075 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1310C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to isoleucine at codon 437 (p.(Thr437Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.7269, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in 4 unrelated individuals with hyperglycemia; (PS4_Moderate; ClinVar ID 585914, PMID 28323911, internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and documented persistent impaired fasting glucose or negative antibodies) (PP4_Moderate; PMID: 28323911, internal lab contributors). In summary, c.1310C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397075/MONDO:0015967/086 2024-01-28 2024-01-28 Semidominant inheritance HP:0032113 Supports CHEBI:8869 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0042373 infores:hetionet CHEBI:75045 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0041834 infores:hetionet CHEBI:100246 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0003467 infores:hetionet CHEBI:6923 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0015672 infores:hetionet CHEBI:480999 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0595916 infores:hetionet CHEBI:3441 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002170 infores:hetionet CHEBI:63791 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020615 infores:hetionet CAID:CA658760377 biolink:causes MONDO:0009276 infores:clingen CAID:CA658760377 MONDO:0009276 PMID: Likely Pathogenic PVS1_Strong, PM3_Supporting, PP4, PM2_Supporting The c.437_474dup (p.Ala159ArgfsTer?) variant in GP9 is a frameshift variant that does not cause a premature stop codon , however the elongation includes the functionally important transmembrane domain of amino acids 148-169 in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BS-12 in PMID: 21699652) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome Additionally, the patient had excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 2; date of approval xx/xx/xxxx). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760377/MONDO:0009276/083 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:7273 biolink:causes MONDO:0011362 infores:monarchinitiative not_provided not_provided HGNC:12403 MONDO:0011362 uuid:903ecdfb-9692-4b9b-8de2-f9a37c39ead2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151907 infores:hetionet CHEBI:3732 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0700345 infores:hetionet CHEBI:4784 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0013428 infores:hetionet CAID:CA367400482 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400482 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PM1 The c.822C>A variant in the glucokinase gene, GCK, is a missense variant resulting in an amino acid change of aspartic acid to glutamic acid at codon 274 (p.(Asp274Glu)) of NM_000162.5. This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to the presence of only 1 copy in any subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF less than or equal to 0.000003) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 19790256, 34440516, 36178555; internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 36178555, internal lab contributors). Another missense variant, c.821A>C p.(Asp274Ala), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Asp274Glu) (PM5_Supporting). In summary, c.822C>A variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 7/23/2025): PM2_Supporting, PM5_Supporting, PP2, PP3, PP4_Moderate, PS4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400482/MONDO:0015967/086 2025-09-08 2025-09-08 Semidominant inheritance HP:0032113 Supports CHEBI:50131 biolink:causes UMLS:C0152965 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0152965 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0020649 infores:hetionet CHEBI:4514 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0013404 infores:hetionet CHEBI:10119 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0019521 infores:hetionet CHEBI:3568 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030193 infores:hetionet CHEBI:71941 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0015967 infores:hetionet CHEBI:27777 biolink:causes HP:0001923 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0206160 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0027765 infores:hetionet GO:2000172 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:2000172 GO:0007399 CAID:CA10524605 biolink:causes MONDO:0010278 infores:clingen CAID:CA10524605 MONDO:0010278 PMID: Likely Benign BS1, BP4 The allele frequency of the p.Ile5Met variant in SLC9A6 is 0.013% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Ile5Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ile5Met variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10524605/MONDO:0010278/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:46345 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0002170 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0038587 infores:hetionet CHEBI:116278 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0004604 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0852733 infores:hetionet CHEBI:8430 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0018524 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0034150 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1442903 infores:hetionet CHEBI:135930 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0497156 infores:hetionet CAID:CA16041897 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041897 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting PM5, PS3 The NM_000152.5:c.1832G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 611 (p.Gly611Asp). Four patients with a diagnosis of Pompe disease and this variant have been reported including two with documented features of infantile onset Pompe disease and laboratory values showing deficient GAA activity <1% in skin fibroblasts (PMID: 22252923) or in the affected range in dried blood spot assay (PMID: 25681614), and another reported with features consistent with infantile onset Pompe disease and deficient GAA activity but the laboratory value was not provided (PMID: 24269976). Finally, a patient with deficient GAA activity (level not known) was identified in clinical laboratory data (PP4_Moderate). Of the reported patients, three are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.2501_2502delCA, (pathogenic, presumed in trans, clinical laboratory data), c.1848dupC (clinical laboratory data) (pathogenic, phase unknown), and c.1843G>A (p.Gly615Arg) (PMID: 24269976) (likely pathogenic, phase unknown), and one patient is homozygous (PMID: 25681614). Another patient is compound heterozygous for the variant and c.1570A>T (p.Asn524Tyr). However, the allelic data from this patient with be used in the assessment of p.Asn524Tyr and is not included here to avoid circular logic. (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.821 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1831G>A, p.Gly611Ser) (ClinVar variation ID: 935199) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP. However, the data from c.1832 (p.Gly611Asp) was used in the classification of p.Gly611Ser, and therefore the data is not ncluded here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 371226, 1 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041897/MONDO:0009290/010 2022-09-06 2022-09-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:75984 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0040822 infores:hetionet CAID:CA658795296 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795296 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PVS1_Moderate The NM_000152.5:c.2647-20T>G variant in GAA is an intronic variant predicted to result in a cryptic acceptor splice site 20 nucleotides upstream of exon 19. There has been one documented individual with this variant described as having late-onset Pompe disease with deficient GAA enzyme activity in dried blood spot and mild clinical symptoms (PMID: 23062590) (PP4_moderate). This individual is compound heterozygous for the variant and another variant in GAA that has been classified as pahtogenic by the Clingen LD VCEP, c.-32-13T>G (ClinVar Variation ID: 4027), phase unknown (PM3_supporting). RT-PCR by electrophoresis and direct sequencing of patient RNA extracted from muscle confirmed the creation of a cryptic splice acceptor site in intron 18, 20 bases upstream of exon 19. This leads to an insertion of 20 bases in the spliced mRNA and creates a frameshift resulting in a premature stop codon after 14 bases in exon 19. Gel electrophoresis showed misplaced produced in the patient samples that is slightly larger than the controls. (PVS1_Moderate). The computational splicing predictor SpliceAI gives a score of 1.0 for acceptor gain at this position, suggesting that the variant results in a cryptic splice acceptor site of intron 18 of GAA; however, PP3 was not applied to avoid double counting the experimental evidence. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000016 (2/1179754 alleles) in the Non-Finnish European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555277, 2 star review status) with 3 submitters classifying the variant as likely pathogenic (2 submitters) or uncertain significance (1 submitter). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PP4_moderate, PVS1_moderate, PM3_supporting, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, August 5, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795296/MONDO:0009290/010 2025-08-05 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:42944 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0043352 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020649 infores:hetionet CHEBI:4672 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0032227 infores:hetionet NCBIGene:29925 biolink:causes MONDO:0014142 infores:monarchinitiative not_provided not_provided HGNC:22932 MONDO:0014142 uuid:5c5151e8-a606-40c2-8eb3-fa16c488c16b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0036104 infores:hetionet CHEBI:31536 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151907 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0853813 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0852970 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0852970 infores:hetionet CHEBI:63619 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0236000 infores:hetionet CHEBI:38562 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0003467 infores:hetionet CHEBI:15552 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0020461 infores:hetionet CHEBI:50730 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0008049 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0521616 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0521616 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0400823 infores:hetionet CHEBI:49662 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0031117 infores:hetionet UMLS:C0010592 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0016658 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0856133 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0856133 infores:hetionet UMLS:C0120107 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013604 infores:hetionet CHEBI:5141 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0522172 infores:hetionet NCBIGene:83538 biolink:causes MONDO:0014910 infores:monarchinitiative not_provided not_provided HGNC:25280 MONDO:0014910 uuid:0f501f48-401c-42f8-bef2-d0d3a4075b35 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9599 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0018799 infores:hetionet NCBIGene:6121 biolink:causes MONDO:0013425 infores:monarchinitiative not_provided not_provided HGNC:10294 MONDO:0013425 uuid:5c896839-322c-426b-b5d1-296c2a0a6ce3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6128 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0013378 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0002957 infores:hetionet CHEBI:47426 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0151723 infores:hetionet CHEBI:46345 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0232462 infores:hetionet CAID:CA220161 biolink:causes MONDO:0021060 infores:clingen CAID:CA220161 MONDO:0021060 PMID:18413255PMID:16439621PMID:25463315 Pathogenic PS3, PM1, PM2, PP2, PP3, PM6_Strong The c.1787G>T (p.Gly596Val) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16439621, 25463315, Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000197137, SCV000057237). In vitro functional studies provide some evidence that the p.Gly596Val variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly596Val variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PP2, PP3, PM1. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA220161/MONDO:0021060/004 2017-04-03 2020-01-23 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CL:0000084 biolink:causes MONDO:0020283 infores:drugmechdb knowledge_assertion manual_agent CL:0000084 MESH:D014605 DB11693_MESH_D014605_1 CHEBI:7565 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0009806 infores:hetionet CHEBI:9434 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0017178 infores:hetionet CHEBI:63607 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0232462 infores:hetionet NCBIGene:3778 biolink:causes MONDO:0012276 infores:monarchinitiative not_provided not_provided HGNC:6284 MONDO:0012276 uuid:38e3ed62-f77c-4af8-b06a-a6ddc8bc10b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31536 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0033774 infores:hetionet CHEBI:85161 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0039231 infores:hetionet CHEBI:28148 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0232462 infores:hetionet CAID:CA120306 biolink:causes MONDO:0010938 infores:clingen CAID:CA120306 MONDO:0010938 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PP3 The c.1333C>T (p.Arg445Ter) (NM_000215.4) variant in JAK3 is a nonsense variant observed to cause a premature stop codon in a gene in which loss-of-function is an established disease mechanism (PVS1).The filtering allele frequency in gnomAD v4.1.0 is 0.0000002800 (2/1179170 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed in gnomAD. (PM2_Supporting). At least one patient in the literature, LP1, presents JAk3 expression and phosphorylation absent; STAT5a phosphorylation is absent, and STAT6 phosphorylation is reduced. Thus: *Reduced or constitutive cytokine-induced tyrosine phosphorylation in patient cells (1pt) + *Reduced cytokine-induced phosphorylation of STAT5 in patient-derived T or B cells (1pt). Total 2 points, PP4_Moderate (PMID 9618765).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA120306/MONDO:0010938/121 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45409 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013395 infores:hetionet CHEBI:6640 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0013395 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0267596 infores:hetionet CHEBI:64310 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0851341 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0038362 infores:hetionet NCBIGene:3000 biolink:causes MONDO:0032811 infores:monarchinitiative not_provided not_provided HGNC:4689 MONDO:0032811 uuid:2dc4f61f-fa23-4a10-9047-4f6890bf1cce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0061074 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:0061074 GO:0043010 CHEBI:7954 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0007398 infores:hetionet CHEBI:6838 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0349506 infores:hetionet CHEBI:31859 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0004093 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0948089 infores:hetionet CHEBI:29007 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0580413 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0851341 infores:hetionet CAID:CA065638 biolink:causes MONDO:0007783 infores:clingen CAID:CA065638 MONDO:0007783 PMID: Likely Benign PM1, BS2_Supporting, BP4 PP3, PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with threonine at codon 140 of the RYR1 protein, p.(Ala140Thr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0002, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), this does not meet the requirement for PS4 (PMID:21455645). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (PMID:21455645). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.261) supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is classified as Likely Benign (PMID: 29300386).Criteria implemented: BS2_Moderate, PM1, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA065638/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:4858 biolink:causes UMLS:C0232861 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0232861 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0234458 infores:hetionet CHEBI:681569 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0023380 infores:hetionet CAID:CA229834 biolink:causes MONDO:0009861 infores:clingen CAID:CA229834 MONDO:0009861 PMID:10394930PMID:10394930 Pathogenic PM2, PVS1, PP4 PM3 The c.884C>G (p.S295*) variant in PAH has been reported in 1 individual with PKU, however without indication of complete genotype (PMID:10394930). This variant is absent in population databases, including 1000 Genomes, Exome Sequencing Project (ESP) and the Genome Aggregation database (gnomAD). This is a nonsense variant in exon 8 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. Overall this variant meets criteria to be classified as pathogenic for PAH. ACMG/AMP criteria applied: PM2, PVS1, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229834/MONDO:0009861/006 2019-07-14 2019-07-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63681 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0015397 infores:hetionet CHEBI:9674 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0029408 infores:hetionet CHEBI:10102 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0917801 infores:hetionet CAID:CA16038900 biolink:causes MONDO:0021057 infores:clingen CAID:CA16038900 MONDO:0021057 PMID: Uncertain Significance PM2_Supporting BS2, PVS1 The NM_000038.6(APC):c.8090C>G (p.Ser2697Ter) variant in APC is a nonsense variant located downstream of codon 2645, therefore PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in one individual without a colorectal cancer/polyposis associated phenotype not meeting criteria for BS2 (BS2 not met, internal data Labcorp Genetics (formerly Invitae)). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16038900/MONDO:0021057/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6715 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0243026 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0021053 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0948594 infores:hetionet CHEBI:8768 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0085610 infores:hetionet CHEBI:5138 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011606 infores:hetionet CHEBI:92712 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C1519353 infores:hetionet CHEBI:77733 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0085649 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0851341 infores:hetionet CHEBI:31236 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020625 infores:hetionet CHEBI:102216 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0040046 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0027651 infores:hetionet CAID:CA191461 biolink:causes MONDO:0007648 infores:clingen CAID:CA191461 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2 The c.1999del (p.Leu667fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least three families meeting HDGC clinical criteria (PS4_Moderate; SCV000329231.6, SCV000950815.1, SCV000215304.5). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA191461/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:3749 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0162830 infores:hetionet CHEBI:28177 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0234533 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0038587 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0580493 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0580493 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0541832 infores:hetionet CHEBI:9566 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0041834 infores:hetionet CHEBI:35553 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0029134 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0948594 infores:hetionet CHEBI:9137 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151610 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0566951 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0566951 infores:hetionet CHEBI:8327 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0017979 infores:hetionet CHEBI:5801 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0000729 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151911 infores:hetionet CHEBI:10650 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0456909 infores:hetionet CHEBI:3738 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0043144 infores:hetionet CAID:CA273683 biolink:causes MONDO:0009290 infores:clingen CAID:CA273683 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Supporting, PM5_Supporting The NM_000152.5:c.1004G>A variant in GAA is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid #335 (p.Gly335Glu). At least two (2) patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, or muscle samples and were described as having infantile-onset Pompe disease (PMIDs: 30214072, 32711049). It has been reported in two patients described as having LOPD but without documented GAA deficiency (PMID: 36105079, 27649523). It has been reported in one patient with a positive newborn screen for Pompe disease with documented GAA enzyme deficiency in dried blood spot, but no clinical information is available (internal data, Duke Molecular Genetics Laboratory) (PP4_moderate). This variant has been reported in compound heterozygosity (phase unconfirmed) with a second variant in GAA classified as likely pathogenic by the ClinGen LD VCEP (c.1841C>A; PMID: 30214072). It has also been reported in compound heterozygosity in two patients with a variant in GAA classified as pathogenic by the LD VCEP (c.-32-13T>G; PMID: 27649523). Additionally, it has been reported in compound heterozygosity in two separate patients with two variants classified as likely pathogenic or pathogenic in ClinVar, but have not been reviewed by the ClinGen LD VCEP (c.797C>T and c.1634C>T; PMIDs: 32711049 and 36105079 respectively) (PM3_supporting). The highest population minor allele frequency in gnomAD v4.0. is 0.000001695 (2/118,0038 alleles) in the European population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.897 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1003G>A, p.Gly335Arg (ClinVar Variation ID: 972790, PMIDs: 31510962, 26497565, 31193175, 24685124) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP. Data from p.Gly335Arg was not used in the classification of p.Gly335Glu to avoid a circular logic (PM5_Supporting). This variant results in 0.2% GAA activity (and is abnormally synthesized and/or processed) when expressed in COS cells, (and was classified as Class B (potentially less severe) by Kroos et al, 2012 (PMID 22644586), meeting the ClinGen LD VCEP specifications for PS3_moderate. There is a ClinVar entry for this variant (Variation ID: 180142, 1-star review status) with 4 submitters classifying the variant as pathogenic (3) or likely pathogenic (1). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PS3_moderate, PM3_supporting, PM5_supporting, PM2_supporting, PP3(Classification approved by the ClinGen Variant Curation Expert Panel on September 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA273683/MONDO:0009290/010 2024-09-17 2024-09-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:3996 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0030446 infores:hetionet CHEBI:23765 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0002994 infores:hetionet CHEBI:17303 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0003862 infores:hetionet CHEBI:6149 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0013144 infores:hetionet CHEBI:6804 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0232292 infores:hetionet CHEBI:3216 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C2939147 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151763 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0235097 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0235097 infores:hetionet CAID:CA296052 biolink:causes MONDO:0009026 infores:clingen CAID:CA296052 MONDO:0009026 PMID: Uncertain Significance BS4 PS3, PS4, PS2, PS1, BP5, BP7, BS3, BS1, PM1, PM4, PM5, PM6, PM2, BS2, PP1, PP3, PP2, BP2, BP3, BP4, BP1, BA1 The c.508A>T (p.Lys170Ter) variant in the HRAS gene has been identified in patients with cancer and individuals who underwent testing for RASopathies, however it was also identified in an unaffected parent (BS4; Invitae, GeneDx internal data, GTR Lab ID: 26957, 500031; SCV000207840.14, SCV000635092.3). The filtering allele frequency of the p.Lys170Ter variant is 0.0034% for European (non-Finnish) chromosomes by the gnomAD aggregation database (8/249358 with 95% CI), which is not a high enough frequency to meet thresholds defined by the ClinGen RASopahty Expert panel for autosomal dominant RASopathy variants (BA1/BS1 not met). Furthermore, LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore the PVS1 rule is not applicable. In summary, the clinical significance of the p.Lys170Ter variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296052/MONDO:0009026/004 2019-06-27 2019-06-28 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:3441 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0085614 infores:hetionet CHEBI:3752 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0600142 infores:hetionet CHEBI:6754 biolink:causes MONDO:0006710 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0149958 infores:hetionet CHEBI:5790 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0019209 infores:hetionet CAID:CA490236561 biolink:causes MONDO:0012996 infores:clingen CAID:CA490236561 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 The NM_001482.3:c.297A>G variant in GATM is a synonymous (silent) variant (p.Thr99=) that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.323) (BP4, BP7). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30566 alleles) in the East Asian population, which is which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 853965). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA490236561/MONDO:0012996/025 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:28748 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151883 infores:hetionet CHEBI:9907 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0002962 infores:hetionet NCBIGene:84892 biolink:causes MONDO:0013904 infores:monarchinitiative not_provided not_provided HGNC:25902 MONDO:0013904 uuid:3bc73570-bb84-4ba7-b65c-eeb0bf022973 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31623 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0022281 infores:hetionet CHEBI:119573 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0018524 infores:hetionet CHEBI:10023 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0010038 infores:hetionet CHEBI:231594 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0002994 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0150450 infores:hetionet CHEBI:4909 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0009676 infores:hetionet CHEBI:6078 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0234233 infores:hetionet CHEBI:50648 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0007859 infores:hetionet CHEBI:28148 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0035078 infores:hetionet CAID:CA512341107 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341107 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP3, BP2, BP1, BA1, BS1, BS3, BS4, BP5, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, PP4, PP2, PP3, PP1, BS2 Synonymous variant (no REVEL score applicable), and SpliceAI score is ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.254 (< 2.0)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341107/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:R43D2573WO biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0476280 infores:hetionet CAID:CA120612 biolink:causes MONDO:0044970 infores:clingen CAID:CA120612 MONDO:0044970 PMID: Likely Pathogenic PM2_Supporting, PM6_Supporting, PVS1_Strong, PS3_Supporting PP3, BP4, PS2 The m.6930G>A (p.G343Ter) variant in MT-CO1 has been reported in one individual to date, in a woman with a multisystem disorder (PMID: 10441567). Clinical features included cataracts, profound sensorineural hearing loss, myoclonic epilepsy, cerebellar ataxia, progressive muscle weakness and atrophy, progressive vision loss due to optic atrophy, and a severe sensorimotor neuropathy. Brain imaging showed diffuse cerebellar atrophy and bilateral small symmetrical nodular hyperintensities in the basal ganglia (head of the caudatus and putamen). She had elevated blood lactate (5.8 mM, normal 0.1-2.2) and CK (1000 UI/L; normal <150). Muscle biopsy showed that only 10% of fibers showed normal COX staining and her complex IV activity was 10% of controls. The variant was present at 27% heteroplasmy in blood, 75% in muscle, and 33% in myoblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from her mother, sister, and four maternal aunts (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in loss of the last 170 amino acids (33% of the protein, PVS1_strong). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10441567, 11595737). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120612/MONDO:0044970/015 2024-01-22 2024-03-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:367163 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151479 infores:hetionet CAID:CA413496512 biolink:causes MONDO:0010315 infores:clingen CAID:CA413496512 MONDO:0010315 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_000206.3:c.455-2A>T variant in IL2RG occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4 (SpliceAI score 0.59), resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been identified in one male individual who was diagnosed with SCID (PMID 28747913). The individual had a T-B+NK- lymphocyte profile (CD3+, 504/uL; CD19+, 2867/uL; CD16/56+, 58.3/uL) (PP4). The variant is absent from gnomAD v2.1.1 and gnomAD v4.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PP4, PM2_Supporting. (VCEP specifications version 1) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413496512/MONDO:0010315/129 2024-03-08 2024-03-08 X-linked inheritance HP:0001417 Supports CHEBI:31711 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0022658 infores:hetionet CAID:CA10585682 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585682 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 PM5, PP3 The NM_000527.5(LDLR):c.1927G>C (p.Ala643Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for FH (PMID 17539906) after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585682/MONDO:0007750/013 2024-07-02 2024-09-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UMLS:C0657912 biolink:causes MONDO:0003425 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029089 infores:hetionet GO:0110073 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:0110073 GO:0060429 CHEBI:8207 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C2364111 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0043250 infores:hetionet CHEBI:8597 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0000729 infores:hetionet CHEBI:63638 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0151827 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001076 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0271650 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0851341 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0242350 infores:hetionet CAID:CA384152083 biolink:causes MONDO:0021060 infores:clingen CAID:CA384152083 MONDO:0021060 PMID: Likely Pathogenic PS2, PM2, PP2, PS4_Supporting The c.194G>T (p.Ser65Ile) variant in KRAS was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 2 probands with clinical features of a RASopathy (PS4_Supporting; SCV000599968.1, PMID: 26822237, 25326635, Invitae internal data). The variant arose de novo in one of the probands with confirmed parentage (PS2; SCV000599968.1, PMID:26822237, 25326635). The variant is located in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581):, PS2, PS4_Supporting, PM2, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA384152083/MONDO:0021060/004 2020-05-18 2020-05-21 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ NCBIGene:1634 biolink:causes MONDO:0012401 infores:monarchinitiative not_provided not_provided HGNC:2705 MONDO:0012401 uuid:a61c04cd-f140-4a5a-bb2d-7616e7c04ec4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6933 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0036454 infores:hetionet CAID:CA2580612102 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580612102 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting The c.1030_1039del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 344 (NM_000162.5), adding six novel amino acids before encountering a stop codon (p.(Asp344Argfs*6)). While this variant, located in exon 9 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6% and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1030_1039del meets criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612102/MONDO:0015967/086 2024-01-27 2024-01-27 Semidominant inheritance HP:0032113 Supports CHEBI:4903 biolink:causes UMLS:C0236080 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0236080 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0853761 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0746883 infores:hetionet CHEBI:47898 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151578 infores:hetionet CAID:CA8337611 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337611 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c.266del variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 4/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The variant has been identified in at least one individual identified by abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency without an additional ACADVL variant identified or follow-up plasma acylcarnitines (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005437 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 12/14/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337611/MONDO:0008723/021 2022-04-06 2022-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52172 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0233477 infores:hetionet CHEBI:5118 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1443060 infores:hetionet CAID:CA400029525 biolink:causes MONDO:0100326 infores:clingen CAID:CA400029525 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PM3, PP3, PM2_Supporting The NM_000212.3(ITGB3):c.1495T>C (p.Cys499Arg) missense variant has been reported in at least two Glanzmann thrombasthenia patients (PMIDs: 29675921, 30138987). Patient GT25 of PMID: 29675921 displayed mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry (PP4_strong). GT25 of PMID: 29675921 is homozygous for this variant and Case 7 of PMID: 30138987 is compound heterozygous for Cys499Arg and pathogenic variant c.1728del (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.914 (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM3, PM2_supporitng, PP3. (VCEP specifications version 2; date of approval 12/21/2021). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400029525/MONDO:0100326/011 2021-12-21 2021-12-23 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8764 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042514 infores:hetionet CAID:CA409110424 biolink:causes MONDO:0015967 infores:clingen CAID:CA409110424 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP4, PP3, BP4 The c.1283C>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to arginine at codon 428 (p.(Pro428Arg)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant has a REVEL score of 0.167, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, c.1283C>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409110424/MONDO:0015967/085 2024-12-13 2024-12-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0853019 infores:hetionet CHEBI:68478 biolink:causes MONDO:0001437 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034050 infores:hetionet NCBIGene:3709 biolink:causes MONDO:0007118 infores:monarchinitiative not_provided not_provided HGNC:6181 MONDO:0007118 uuid:c4c861e0-d4d0-4329-b81d-0e2be10f1769 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0014866 infores:hetionet CHEBI:68584 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0002170 infores:hetionet CHEBI:45367 biolink:causes MONDO:0007243 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0006413 infores:hetionet CHEBI:45863 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0221201 infores:hetionet CHEBI:3504 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0404521 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C1384353 infores:hetionet CHEBI:5123 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0004096 infores:hetionet CHEBI:49375 biolink:causes HP:0001056 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0345996 infores:hetionet CAID:CA367400790 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400790 MONDO:0015967 PMID: Pathogenic PS4, PM1, PM5_Supporting, PP2, PP3, PM2_Supporting PS3 The c.682A>G variant in the glucokinase gene, GCK, causes an amino acid change of threonine to alanine at codon 228 (p.(Thr228Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.931 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the East Asian subpopulation and no copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4, PMIDs: 31638168, 12955723, internal lab contributors). Another missense variant, c.683C>T p.Thr228Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr228Ala (PM5_Supporting). In summary, c.682A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400790/MONDO:0015967/086 2024-02-28 2024-02-28 Semidominant inheritance HP:0032113 Supports CHEBI:82716 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0232487 infores:hetionet CHEBI:2682 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0546817 infores:hetionet CAID:CA404093517 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093517 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PS3, PS4, BS3, PM1, PM5, PP3, PP4 The NM_000527.5(LDLR): c.2018G>A (p.Ser673Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows:PM2: PopMax MAF= 0.00005329 (0.005329%) in African /African American exomes + genomes (gnomAD v.4.1.0).BP4: REVEL= 0.352, it is below 0.50, splicing required. Functional data on splicing not available. A) not on limits B) does not create AG C) there is an AG nearby but splicing scores are negative. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093517/MONDO:0007750/013 2025-03-28 2025-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5004 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0034150 infores:hetionet CHEBI:63599 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0016199 infores:hetionet CAID:CA343776228 biolink:causes MONDO:0013144 infores:clingen CAID:CA343776228 MONDO:0013144 PMID: Uncertain Significance PP3, PM2_Supporting PS4 The c.592T>C variant in SERPINC1 is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 198 (p.Tyr198His). This variant is absent from gnomAD v2.1.1 and 3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343776228/MONDO:0013144/084 2024-07-03 2024-07-03 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:10848 biolink:causes MONDO:0957795 infores:monarchinitiative not_provided not_provided HGNC:18838 MONDO:0957795 uuid:6ac7b56a-bff7-47b3-a43d-01e3086137c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:131512 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C1443060 infores:hetionet CHEBI:161680 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0008031 infores:hetionet CHEBI:4469 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0022107 infores:hetionet CHEBI:6149 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0030554 infores:hetionet CAID:CA10360246 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360246 MONDO:0100039 PMID: Benign BP7, BS1, BS2 PP4, PM2, BA1 The allele frequency of the p.Leu97= variant in CDKL5 is 0.011% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Leu97= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Leu97= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). The p.Leu97= variant in CDKL5 has been reported apparently homozygous in an individual with infantile epileptic encephalopathy (PMID 28454995); no criteria were applied for this case. In summary, the p.Leu97= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360246/MONDO:0100039/016 2022-09-01 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:4445 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C2047937 infores:hetionet CHEBI:3181 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0080274 infores:hetionet CHEBI:68478 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0018989 infores:hetionet CAID:CA10014398 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014398 MONDO:0011071 PMID: Likely Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.614-19_614-15del is an intronic variant with a MAF of 0.00049 (12/26,640 alleles) in the African subpopulation of the gnomAD 2.1 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Splice AI predicts no impact to splicing (score: 0.03). (BP4) This variant has a SpliceAI score ≤ 0.20 (0.03) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.921) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014398/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119915 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0033687 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0476414 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0476414 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085932 infores:hetionet CHEBI:51364 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042571 infores:hetionet CHEBI:10119 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015402 infores:hetionet CHEBI:63627 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0017178 infores:hetionet CAID:CA343724604 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724604 MONDO:0020367 PMID: Uncertain Significance PP1_Moderate, PP3, PM2_Supporting BP7, BS1, BS3, PM6, PM5, PM4, PS4, PS1, PS3, PS2, BP4, BA1 The c.1130C>G variant in MYOC is a missense variant predicted to cause substitution of Threonine by Arginine at amino acid 377 (p.Thr377Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.897, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 7 segregations in 1 family, with juvenile open angle glaucoma (JOAG), have been reported (PMID: 23886590), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 23886590), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724604/MONDO:0020367/019 2023-02-15 2023-02-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA396451877 biolink:causes MONDO:0100488 infores:clingen CAID:CA396451877 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.92G>T (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Gly by Val at amino acid 31 (p.Gly31Val) in exon 2. This variant was observed in more than ten individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; Invitae, Ambry). This variant is absent from gnomAD 2.1.1 (PM2_Spporting). In summary, this variant meets the criteria to be classified as likely benign for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2. (CDH1 VCEP specifications version 3.1; 05/06/2022) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396451877/MONDO:0100488/007 2023-08-02 2023-08-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:15367 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0423791 infores:hetionet UMLS:C0010592 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0232461 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0043345 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0029456 infores:hetionet CAID:CA640873789 biolink:causes MONDO:0100437 infores:clingen CAID:CA640873789 MONDO:0100437 PMID: Benign BA1, BP4, BP7 PM2 NM_001034853.2(RPGR):c.28+280dup is a 1-base pair insertion within intron 1 that is located outside of the splice donor region (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This variant is present in gnomAD v4.1.0 at a frequency of 0.004925 among hemizygous individuals, with 301 variant alleles / 61122 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BP4, and BP7. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA640873789/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:48844 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0042963 infores:hetionet CHEBI:8028 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0162830 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0020517 infores:hetionet CHEBI:44423 biolink:causes HP:0100507 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0016412 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042373 infores:hetionet CHEBI:84883 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0002792 infores:hetionet CHEBI:7936 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0000737 infores:hetionet CHEBI:82960 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0014591 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0037274 infores:hetionet CAID:CA229321 biolink:causes MONDO:0009861 infores:clingen CAID:CA229321 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting The c.1066-14C>G PAH variant has been reported in 1 Chinese patient with PAH deficiency (Phe =512μmol/L) detected with the pathogenic PAH variant c.1222C>T (PMID: 29499199). A defect in BH4 metabolism was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant is absent from population databases gnomAD, 1000 Genomes and ESP. Splicing prediction algorithms predict this variant to be probably damaging. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PP3, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229321/MONDO:0009861/006 2020-12-11 2021-03-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49662 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0014742 infores:hetionet CHEBI:100246 biolink:causes HP:0002197 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0234533 infores:hetionet CHEBI:45863 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0004134 infores:hetionet CHEBI:15365 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0013395 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0399459 infores:hetionet CHEBI:3127 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0022904 infores:hetionet CHEBI:8024 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1527344 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0015397 infores:hetionet CHEBI:4046 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0340464 infores:hetionet CHEBI:116278 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0020615 infores:hetionet CHEBI:6538 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0039070 infores:hetionet CHEBI:51450 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0232462 infores:hetionet CHEBI:8802 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0011168 infores:hetionet GO:2000722 biolink:causes GO:0060976 infores:ubergraph knowledge_assertion manual_agent GO:2000722 GO:0060976 CHEBI:9738 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0039231 infores:hetionet CHEBI:61049 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0002063 infores:hetionet CHEBI:50924 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0003962 infores:hetionet CHEBI:5384 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0012833 infores:hetionet CHEBI:51860 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013595 infores:hetionet CHEBI:32588 biolink:causes UMLS:C0429098 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0429098 infores:hetionet CHEBI:7824 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0268000 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0242973 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0242973 infores:hetionet CHEBI:6541 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042023 infores:hetionet CAID:CA481332664 biolink:causes MONDO:0009861 infores:clingen CAID:CA481332664 MONDO:0009861 PMID:30459323 Uncertain Significance PM2, PP4 PM3, PP3, BP7 The c.441T>C (p.Pro147=) PAH variant has been reported in 1 Chinese patient with mild hyperphenylalaninemia (PMID: 30459323) detected with the PAH variant of uncertain significance p.Arg53His. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. It is a synonymous variant with conflicting predictions by splicing prediction algorithms. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA481332664/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31236 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0008325 infores:hetionet CHEBI:38940 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020625 infores:hetionet CHEBI:3732 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004238 infores:hetionet CAID:CA397723957 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723957 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PP4 The NM_000018.4(ACADVL):c.911C>T variant in ACADVL is a missense variant predicted to cause substitution of alanine by valine at amino acid 304 (p.Ala304Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with this variant displayed reduced enzyme levels (21% of wildtype), which is highly specific for VLCAD deficiency (PP4, PMID: 21932095). The variant is detected in at least one consanguineous patient in homozygous fashion, but clinical phenotype is not specific enough to establish supporting evidence (PMID: 32558070). The computational predictor REVEL gives a score of 0.88, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3, PP4. (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723957/MONDO:0008723/021 2023-11-27 2023-11-27 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:6970 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0014591 infores:hetionet CHEBI:8871 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0011570 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0018799 infores:hetionet NCBIGene:5972 biolink:causes MONDO:0013128 infores:monarchinitiative not_provided not_provided HGNC:9958 MONDO:0013128 uuid:5d054f97-6c69-440b-9839-c8322ecd8be1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020649 infores:hetionet CHEBI:46557 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0004604 infores:hetionet UMLS:C0004609 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0015732 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0021053 infores:hetionet CHEBI:15854 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0008031 infores:hetionet CAID:CA913175543 biolink:causes MONDO:0044970 infores:clingen CAID:CA913175543 MONDO:0044970 PMID:32419253 Uncertain Significance PM2_Supporting, PS3_Supporting PP1, PS4 The m.590A>G variant in MT-TF has been reported in one individual to date, in a woman with childhood onset mitochondrial myopathy. She had exercise intolerance, cerebellar ataxia, and retinitis pigmentosa. Muscle biopsy showed many ragged red fibers, 60% COX-negative fibers, and lipid overload. Respiratory chain enzyme activities were normal. The variant was present at 92% in muscle and was undetectable in blood, urine, and buccal sample. Haplogroup was H80 (PMID: 32419253). The variant was present at <5% in blood from her healthy mother and was undetectable in mother’s urine and buccal sample, and was undetectable in blood, buccal sample, and urine from her healthy sister. This cannot be considered evidence of de novo status as the variant was also undetectable in the proband’s blood. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (89.10±9.3%; N = at least 10) than in COX-positive fibers (44.74±24.79%; N = at least 10), p<0.0001 (PS3_supporting, PMID: 32419253). The computational predictor MitoTIP suggests this variant is neutral (16.3 percentile) and HmtVAR predicts it to be polymorphic with a score of 0.05. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913175543/MONDO:0044970/015 2024-06-24 2024-08-08 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:84500 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1527344 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0029408 infores:hetionet CHEBI:51860 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0221201 infores:hetionet UMLS:C0209366 biolink:causes GO:0009566 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0015914 infores:hetionet CHEBI:63629 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0232849 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0233571 infores:hetionet CHEBI:36704 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0542571 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0035309 infores:hetionet CHEBI:3403 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0030554 infores:hetionet CHEBI:6916 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0231218 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0041657 infores:hetionet CHEBI:2788 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0011616 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018802 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C1269683 infores:hetionet CHEBI:4856 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0030193 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0274435 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0274435 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0006840 infores:hetionet CHEBI:46345 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0000768 infores:hetionet CHEBI:38562 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0013378 infores:hetionet CHEBI:74947 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1142412 infores:hetionet CHEBI:134991 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020615 infores:hetionet CHEBI:473990 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0012833 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0854456 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0854456 infores:hetionet CHEBI:7025 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0151908 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0027765 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0919882 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0919882 infores:hetionet NCBIGene:9841 biolink:causes MONDO:0013553 infores:monarchinitiative not_provided not_provided HGNC:21143 MONDO:0013553 uuid:47a03fd2-5b49-4678-a92f-6efe81880a4e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63629 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0003864 infores:hetionet CAID:CA123975 biolink:causes MONDO:0011071 infores:clingen CAID:CA123975 MONDO:0011071 PMID:10068652PMID:12200707PMID:10068652PMID:23817177 Likely Benign BS1, BS3, PP3 PS4, PS3, PS1, BP2, BP4, BA1, PVS1, PM2, PM6, BS4, BP7, PM1, PM4, PM5, PP1 The NM_001754.4:c.253C>A (p.His85Asn) variant has a MAF of 0.00043 (0.043%, 8/18,768 alleles) in the East Asian subpopulation of the gnomAD cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.852) (PP3). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID: 23817177, PMID: 10068652). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA123975/MONDO:0011071/008 2019-07-26 2019-08-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50378 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0029877 infores:hetionet CAID:CA208646 biolink:causes MONDO:0011071 infores:clingen CAID:CA208646 MONDO:0011071 PMID: Benign BP2, BP4, BA1 PS4, PS3, PS1, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM1, PM4, PM5, PP1, PP3 This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least >5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although evolutionary conservation prediction algorithms predict the site as being moderately conserved (PhyloP score: 3.03 > 0.1 [-14.1;6.4]) and the variant is not the reference nucleotide in one primate and/or three mammal species, it is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, and BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA208646/MONDO:0011071/008 2020-08-08 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:83804 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0234047 infores:hetionet CHEBI:15854 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C1443060 infores:hetionet CHEBI:5779 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0235063 infores:hetionet GO:0001177 biolink:causes GO:0006367 infores:ubergraph knowledge_assertion manual_agent GO:0001177 GO:0006367 CHEBI:8764 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151636 infores:hetionet CAID:CA10585878 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585878 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PVS1_Moderate, PM2, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP1 NM_000527.5(LDLR):c.2546C>A (p.Ser849Ter) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1_Moderate, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1).PVS1_moderate - Variant is nonsense after amino acid 830 (NM_000527.5:p.Lys830).PP4 - Variant meets PM2. Variant identified in 2 index FH cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515).PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585878/MONDO:0007750/013 2021-06-22 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:36795 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0851341 infores:hetionet CHEBI:15544 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0518988 infores:hetionet CHEBI:167638 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0030848 infores:hetionet CHEBI:8059 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0000737 infores:hetionet CAID:CA402990219 biolink:causes MONDO:0012999 infores:clingen CAID:CA402990219 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000156.6:c.701C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 234 (p.Thr234Ile). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74914 alleles) in the African / African American population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.268 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). SpliceAI predicts that the variant will have no impact on splicing. To our knowledge, this variant has not been reported in the published literature. It has been previously noted in ClinVar (ID 544252). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402990219/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4466 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0001122 infores:hetionet CHEBI:15552 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0037763 infores:hetionet CHEBI:68595 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0740394 infores:hetionet CHEBI:119915 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0022408 infores:hetionet CHEBI:83804 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1527344 infores:hetionet CHEBI:4735 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C2242996 infores:hetionet CAID:CA645293968 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293968 MONDO:0015924 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS1 The BMPR2 c.968-3C>G is an intronic variant in intron 7. This variant is absent from both gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The variant has been reported in 2 unrelated PAH patients (PMID: 26387786 and GeneDx submission to ClinVar) (PS4_Supporting). PVS1 is not applied because it is a non-canonical splice site variant without mRNA processing data. The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 (PP3). The variant affects the same nucleotide as c.968-5A>G, classified as pathogenic by the PH VCEP (PS1). In summary, the variant is classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PS4_supporting, PP3 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293968/MONDO:0015924/125 2025-09-10 2025-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9667 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0235761 infores:hetionet NCBITaxon:1280 biolink:causes UMLS:C1443237 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1280 MESH:D000077299 DB00319_MESH_D000077299_1DB02703_MESH_D000077299_1DB00537_MESH_D000077299_1DB01059_MESH_D000077299_1DB00479_MESH_D000077299_1DB00684_MESH_D000077299_1 CAID:CA404095155 biolink:causes MONDO:0007750 infores:clingen CAID:CA404095155 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PM5, PP4 The NM_000527.5(LDLR):c.2224A>G (p.Thr742Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0000008475 (0.00008475%) in European (non-Finnish) exomes + genomes (gnomAD v4.1.0).BP4: REVEL = 0.23, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic, at least 50bp upstream from the canonical donor site and it creates AG. MES scores: de novo variant = -15.06; canonical acceptor = 8.76 --- de novo score is negative, so it is not used. Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404095155/MONDO:0007750/013 2025-02-28 2025-04-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:3756 biolink:causes UMLS:C0856864 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0856864 infores:hetionet CHEBI:68478 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0003862 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0020542 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001437 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034050 infores:hetionet CHEBI:8207 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0233632 infores:hetionet CAID:CA016540 biolink:causes MONDO:0005045 infores:clingen CAID:CA016540 MONDO:0005045 PMID: Uncertain Significance PM2, PM1, PS4_Supporting PS3, BA1, PM6, PP3, PP1, BS1, BS3, BS4, BP4, BP2, BP5, PS2, PS1 The NM_000257.4(MYH7):c.610C>T (p.Arg204Cys) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.) and in 1 infant with LVH/RVH and other complex heart disease (GeneDx pers. comm.). This variant was identified in 0.0026% (FAF 95% CI; 3/30616) South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016540/MONDO:0005045/002 2021-04-21 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4798 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0020615 infores:hetionet CHEBI:28939 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0027441 infores:hetionet CHEBI:63629 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0027796 infores:hetionet CHEBI:9588 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0023418 infores:hetionet CHEBI:6923 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0151662 infores:hetionet CHEBI:68584 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0392525 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027059 infores:hetionet CHEBI:7986 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0700361 infores:hetionet CHEBI:2950 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0232461 infores:hetionet CHEBI:584020 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0027947 infores:hetionet CHEBI:15428 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0012797 infores:hetionet CHEBI:3506 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C1257843 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0746883 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0011609 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0442874 infores:hetionet CHEBI:82981 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0027497 infores:hetionet CHEBI:6741 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0220870 infores:hetionet CHEBI:50922 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0010073 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0151565 infores:hetionet CHEBI:127780 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0032617 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0015376 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0243026 infores:hetionet NCBIGene:91147 biolink:causes MONDO:0012539 infores:monarchinitiative not_provided not_provided HGNC:28396 MONDO:0012539 uuid:f644c1fb-6f63-44ee-8fe1-757735105b64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46557 biolink:causes MONDO:0041086 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0338908 infores:hetionet CHEBI:38940 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0221776 infores:hetionet CHEBI:135351 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0036974 infores:hetionet CHEBI:478164 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0085631 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0233414 infores:hetionet CHEBI:9649 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0023518 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0151565 infores:hetionet CHEBI:68855 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0013378 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0314719 infores:hetionet CHEBI:51450 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0039070 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0027765 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0518015 infores:hetionet CHEBI:42944 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0041912 infores:hetionet CAID:CA380140584 biolink:causes MONDO:0000573 infores:clingen CAID:CA380140584 MONDO:0000573 PMID: Likely Pathogenic PP4, PS3_Moderate, PM2_Supporting, PM1, PM3_Supporting PM5 The c.1338C>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Cysteine by Tryptophan at amino acid 446 (p.Cys446Trp).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate.The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 2.9% (SEM 0.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, PP4 is met (PMID: 20234091). A second report describes one homozygous patient, 0.5 pts, PM3_Supporting (PMID: 31973905). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PS3_Moderate, PM3_Supporting, and PP4 (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380140584/MONDO:0000573/124 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5138 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0424295 infores:hetionet CHEBI:7852 biolink:causes MONDO:0015129 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0001403 infores:hetionet CHEBI:63611 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085636 infores:hetionet NCBIGene:5424 biolink:causes MONDO:0970994 infores:monarchinitiative not_provided not_provided HGNC:9175 MONDO:0970994 uuid:cbcbc343-fdcd-4d90-a1b2-4d31b361fb4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9667 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0011849 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0011616 infores:hetionet CHEBI:63598 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0031256 infores:hetionet CHEBI:5775 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C2047937 infores:hetionet CHEBI:36791 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0393760 infores:hetionet CHEBI:127342 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0041969 infores:hetionet CHEBI:9150 biolink:causes MONDO:0016367 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0011633 infores:hetionet CAID:CA16020804 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020804 MONDO:0009861 PMID: Pathogenic PM5, PP4_Moderate, PM2, PP3, PM3_Strong The variant c.505C>G (p.R169G) in PAH has been detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462) (PP4-Moderate). This variant was detected in trans with pathogenic variants p.R243Q, p.R241Pfs*100; the validation tests on parents were performed using Sanger sequencing. Also found with pathogenic variant p.Y414C; parental testing not confirmed (PMID: 30050108, 31924462) (PM3-Strong). This variant is absent from controls in gnomAD, 1000 Genomes or ESP (PM2). Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848 (PP4). Missesense variant p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP, located at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Strong, PP3, PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020804/MONDO:0009861/006 2021-02-12 2021-02-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17474 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0014743 infores:hetionet CHEBI:6640 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0220870 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011334 infores:hetionet NCBIGene:23426 biolink:causes MONDO:0054739 infores:monarchinitiative not_provided not_provided HGNC:18708 MONDO:0054739 uuid:e0ee2661-e08c-440b-acf3-34ffad9f2649 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA170154 biolink:causes MONDO:0010726 infores:clingen CAID:CA170154 MONDO:0010726 PMID: Uncertain Significance BA1, BP4, BP2, PS1, PS3, PS4, PS2, PM5, PM1, PM3, BP5, BS1, BS3, BS4, PM2, PM6, PP3, PP1, PP4 The highest population minor allele frequency of the p.Arg354His variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.000001117 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Arg354His variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (no criteria met). (MECP2 specification v3.0.0; approved on 12/18/2024) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA170154/MONDO:0010726/036 2024-12-18 2025-03-26 X-linked inheritance HP:0001417 Inconclusive true CAID:CA013815 biolink:causes MONDO:0005021 infores:clingen CAID:CA013815 MONDO:0005021 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate PP2, PP4, BS2, PM6, PM5, PM4, PM1, PS3, BA1, BS1, BS4, BS3, BP1, BP3, PS2, PS1, BP4, BP2, BP5, BP7, PVS1 NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) - This variant has been reported in individuals with DCM (LMM data, OMGL data, PMIDs: 22464770, 24503780, 27532257, 29300372) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criterion has been applied. This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM data; OMGL data). This variant is present in gnomAD (v2.1.1), but did meet the threshold for PM2_Supporting. Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Likely Pathogenic for DCM in an autosomal dominant manner based on PS4_Moderate, PP1_Moderate, PM2_Supporting, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013815/MONDO:0005021/002 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:167309 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0018681 infores:hetionet CHEBI:8212 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0042510 infores:hetionet CHEBI:87681 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0020458 infores:hetionet CHEBI:3176 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0006277 infores:hetionet GO:0060219 biolink:causes CL:0010009 infores:ubergraph knowledge_assertion manual_agent GO:0060219 CL:0010009 CAID:CA214285 biolink:causes MONDO:0015967 infores:clingen CAID:CA214285 MONDO:0015967 PMID: Benign BA1, BP5 The c.1720A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to glycine at codon 574 (p.(Ser574Gly)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.996; however, given that the G (Gly) alternate allele has frequencies ≥95% in all subpopulations, we have recalculated the Popmax Filtering allele frequency based on the highest prevalence of the A (Ser) reference allele being found in the African/African-American subpopulation (1144/24164 = 0.0473). The newly calculated Popmax Filtering allele frequency is 0.0447, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1720A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214285/MONDO:0015967/017 2022-04-18 2022-04-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7936 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011616 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0241863 infores:hetionet CHEBI:45373 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00259 UMLS:C0234215 infores:hetionet CHEBI:134743 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0009450 infores:hetionet NCBIGene:117581 biolink:causes MONDO:0008693 infores:monarchinitiative not_provided not_provided HGNC:20670 MONDO:0008693 uuid:e4b6720e-b844-4f0b-868c-6330e2487137 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27899 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0476327 infores:hetionet CHEBI:31980 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C3665386 infores:hetionet NCBIGene:7157 biolink:causes MONDO:0015278 infores:monarchinitiative not_provided not_provided HGNC:11998 MONDO:0015278 uuid:06d31733-92fa-41e4-9323-ca5e9ea0a225 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116278 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0015672 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007114 infores:hetionet NCBIGene:7025 biolink:causes MONDO:0014320 infores:monarchinitiative not_provided not_provided HGNC:7975 MONDO:0014320 uuid:4a874553-d994-4eb3-8591-791677b5623c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0043094 infores:hetionet CHEBI:15854 biolink:causes UMLS:C1879328 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C1879328 infores:hetionet UNII:U6XF9NP8HM biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0037036 infores:hetionet CHEBI:15553 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0034065 infores:hetionet CHEBI:4910 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0020538 infores:hetionet CHEBI:101278 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0020458 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0011168 infores:hetionet CHEBI:47381 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151798 infores:hetionet CHEBI:7478 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0003467 infores:hetionet CHEBI:51164 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0021177 infores:hetionet CHEBI:168396 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085680 infores:hetionet CHEBI:17347 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0026636 infores:hetionet UMLS:C0010592 biolink:causes HP:6000364 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0085648 infores:hetionet CHEBI:8382 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0002792 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0027697 infores:hetionet NCBIGene:6505 biolink:causes MONDO:0009110 infores:monarchinitiative not_provided not_provided HGNC:10939 MONDO:0009110 uuid:fddb85d5-5826-456e-a9ec-626c3c0178c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:55858 biolink:causes MONDO:0013870 infores:monarchinitiative not_provided not_provided HGNC:30760 MONDO:0013870 uuid:1801b492-ec6c-4dcc-a8d7-07a30d84d171 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0034069 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C1971624 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0281981 infores:hetionet CHEBI:2611 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0231218 infores:hetionet CHEBI:31302 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0017178 infores:hetionet CHEBI:63620 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0013428 infores:hetionet CHEBI:3216 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0013182 infores:hetionet CHEBI:9332 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0015967 infores:hetionet CHEBI:50777 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0004604 infores:hetionet CHEBI:8802 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0010200 infores:hetionet CHEBI:47381 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C3665386 infores:hetionet CAID:CA389474457 biolink:causes MONDO:0100040 infores:clingen CAID:CA389474457 MONDO:0100040 PMID: Likely Benign BS2_Supporting, BP4 PS4, BS1, PM2 The highest population minor allele frequency of the p.His44Pro variant in FOXG1 in gnomAD v4.1 is 0.00002649 in the Non-Finnish European population (not sufficient to meet BS1 criteria). The p.His44Pro variant is observed in at least 1 unaffected individual (Internal database - Ambry Genetics) (BS2_Supporting). The computational predictor REVEL gives a score of 0.041, which is below the threshold of 0.290, evidence that does not predict a damaging effect on FOXG1 function (BP4). In summary, the p.His44Pro variant in FOXG1 is classified as likely benign based on the ACMG/AMP criteria (BS2_Supporting, BP4). (FOXG1 Specifications v.4.1; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389474457/MONDO:0100040/035 2025-06-25 2025-06-30 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63612 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0009676 infores:hetionet NCBIGene:112858 biolink:causes MONDO:0033008 infores:monarchinitiative not_provided not_provided HGNC:16197 MONDO:0033008 uuid:be621b0f-b9e5-4ae3-b11b-05794ff32080 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000533 biolink:causes MONDO:0018875 infores:clingen CAID:CA000533 MONDO:0018875 PMID: Benign BP4, BS3, BS2 BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, PP3, PP1 The NM_000546.6: c.998G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 333 (p.Arg333His). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; ClinVar SCVs: SCV000285219.10). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0924; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.3; 3/4/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000533/MONDO:0018875/009 2025-03-04 2025-06-23 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA220400 biolink:causes MONDO:0009290 infores:clingen CAID:CA220400 MONDO:0009290 PMID: Pathogenic PVS1, PM2, PP4 This variant, c.2512C>T (p.Gln838Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African population, meeting PM2. It has been reported in two siblings with infantile onset Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4, and who are compound heterozygous for the variant and c.2105G>T (p.Arg702Leu) (PMID 26167453). However, this in trans data will be used in the assessment of p.Arg702Leu and is not included here in order to avoid a circular argument. Another patient, with limb girdle muscular dystrophy, has been reported to be compound heterozygous for the variant and c.-32-13T>G. However, residual GAA activity was not provided, and therefore this data was not included (PMID 30564623). There is a ClinVar entry for this variant (Variation ID: 92479, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA220400/MONDO:0009290/010 2020-05-04 2020-05-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:15544 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C3263723 infores:hetionet CHEBI:63621 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0231528 infores:hetionet NCBIGene:5192 biolink:causes MONDO:0013936 infores:monarchinitiative not_provided not_provided HGNC:8851 MONDO:0013936 uuid:d8cb08a0-bdc5-47a5-a755-92a3d617e6b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135930 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0011849 infores:hetionet CAID:CA000581 biolink:causes MONDO:0017623 infores:clingen CAID:CA000581 MONDO:0017623 PMID: Uncertain Significance BS1, BS3, PM2 PTEN c.-798G>C (NC_000010.10:g.89623428G>C) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000581/MONDO:0017623/003 2025-03-07 2025-10-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA229775 biolink:causes MONDO:0009861 infores:clingen CAID:CA229775 MONDO:0009861 PMID:10767174PMID:9521426PMID:21871829PMID:10767174PMID:14726806PMID:9521426 Pathogenic PM2, PP4_Moderate, PP3, PM3_Very Strong The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Very-strong, PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229775/MONDO:0009861/006 2018-12-10 2019-05-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0010520 infores:hetionet CAID:CA227878 biolink:causes MONDO:0100438 infores:clingen CAID:CA227878 MONDO:0100438 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting NM_014336.5(AIPL1):c.277-2A>G disrupts a canonical splice site in intron 2 and is predicted to lead to skipping of a critical exon (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00008366, with 135 alleles / 1,613,758 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.784G>A (p.Gly262Ser) variant suspected in trans (0.5 points, PMID: 22412862), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (0.5 total points, PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset before the age of 5 years (1 pt), poor vision (1 pt), nystagmus (1 pt), photoattraction (1 pt), moderate pigmentary retinopathy (1 pt), macular atrophy (0.5 pts), optic disc drusen (0.5 pts), white retinal dots, posterior subcapsular cataract (0.5 pts), moderate myopia, and poor pupillary light response (0.5 pts), which together are specific for AIPL1-related retinopathy (total 7.5 points, PMID: 22412862, PP4). In summary, this variant meets the criteria to be classified as pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227878/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:391960 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0003862 infores:hetionet CHEBI:3215 biolink:causes MONDO:0001294 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0019937 infores:hetionet CHEBI:8356 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0151937 infores:hetionet CHEBI:10650 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0039621 infores:hetionet CHEBI:33325 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0009450 infores:hetionet CHEBI:27666 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C1443060 infores:hetionet CHEBI:27899 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0016204 infores:hetionet CHEBI:2955 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C2047937 infores:hetionet CHEBI:8060 biolink:causes HP:0031814 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0392185 infores:hetionet NCBIGene:3858 biolink:causes MONDO:0012208 infores:monarchinitiative not_provided not_provided HGNC:6413 MONDO:0012208 uuid:c68d3a1c-29aa-459e-8181-37568003e9e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:11588 biolink:causes MONDO:0017880 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11588 MONDO:0017880 CHEBI:144093 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0036974 infores:hetionet CAID:CA018598 biolink:causes MONDO:0007783 infores:clingen CAID:CA018598 MONDO:0007783 PMID: Pathogenic PS3, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Supporting, PM5_Supporting BS1, BS3, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 163 of the RYR1 protein p.(Arg163Cys). This variant is not present in a large population databases (gnomAD). This variant has been reported in over 40 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 (PMID:30236257, PMID:12151923, PMID:16163667, PMID:8220423, PMID:11575529, PMID:12059893, PMID:23558838 and others). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists. A knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, as well ex vivo studies show increased response to agonist with increased calcium release, PS3 (PMID:20461000, PMID:9334205, PMID:17122579). Another variant assessed as likely pathogenic occurs at this codon, p.(Arg163Leu), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS over seven individuals, PP1_Strong (PMID:30236257, PMID:12059893, PMID:7889656). A REVEL score > 0.85 (0.959) supports pathogenicity, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3, PM1_Supporting, PM5_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA018598/MONDO:0007783/012 2022-03-29 2022-03-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:408174 biolink:causes UMLS:C0031085 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0031085 infores:hetionet CHEBI:6710 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0344232 infores:hetionet CHEBI:47499 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0039070 infores:hetionet GO:0072182 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072182 GO:0072006 CHEBI:3568 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235750 infores:hetionet CHEBI:43968 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0011206 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1257843 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0025061 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020538 infores:hetionet CAID:CA340747756 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747756 MONDO:0100368 PMID: Likely Pathogenic PM3_Strong, PP3_Moderate, PP4, PP1, PM2_Supporting PM5 NM_000329.3(RPE65):c.434C>A is a missense variant that causes substitution of alanine with aspartic acid at position 145. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of fundus albipunctatus (2 pts) with genotyping by exome sequencing without finding an alternative explanation for disease (2 pts), nyctalopia (0.5 pts), onset at age 3.3 years (1 pt), undetectable dark-adapted electroretinogram (0.5 pts), and severely reduced light-adapted electroretinogram (1 pt), which together are specific for RPE65-related recessive retinopathy (7 total pts, PMID: 31273949, PP4). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.200T>G (p.Leu67Arg) or the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variants confirmed in trans, which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 points, PMID: 23661369, PMID: 31273949, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31273949, PP1). Two other missense variants in the same codon, NM_000329.3(RPE65):c.433G>A (p.Ala145Thr) (PMID: 26906952) and NM_000329.3(RPE65):c.433G>C (p.Ala145Pro) (PMID: 28224992) have been classified for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, however, the PM5 code has not been considered in order to avoid circularity. The computational predictor REVEL gives a score of 0.929, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747756/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3561 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0042075 infores:hetionet CHEBI:5132 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0206062 infores:hetionet CHEBI:3996 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0021141 infores:hetionet CHEBI:32192 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0030252 infores:hetionet CHEBI:71255 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0002453 infores:hetionet CHEBI:8802 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0042963 infores:hetionet NCBIGene:22983 biolink:causes MONDO:0032648 infores:monarchinitiative not_provided not_provided HGNC:19034 MONDO:0032648 uuid:11e09464-2e7b-4b77-ac12-3ded59399a5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA389476217 biolink:causes MONDO:0100040 infores:clingen CAID:CA389476217 MONDO:0100040 PMID: Uncertain Significance BS2_Supporting, PM2_Supporting BP4 The p.His318Leu variant in FOXG1 is absent from gnomAD (PM2_supporting). The p.His318Leu variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.His318Leu variant in FOXG1 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389476217/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42355 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0237849 infores:hetionet CHEBI:47898 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1527344 infores:hetionet CHEBI:9123 biolink:causes HP:0012878 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0234047 infores:hetionet CHEBI:50838 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0011570 infores:hetionet NCBIGene:11277 biolink:causes MONDO:0009165 infores:monarchinitiative not_provided not_provided HGNC:12269 MONDO:0009165 uuid:697bf8cb-318c-4755-b9d0-6ff1e0da1f55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA410208164 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208164 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.509-1G>A is an intronic variant that is predicted to cause skipping of exon 6, resulting in an in-frame deletion affecting amino acids 171-205, including G170 (GGG->GGA), within the Runt Homology Domain (RHD) (PVS1_strong). SpliceAI predicts a high likelihood of impact on splicing, with an Acceptor Gain score of 0.98 and an Acceptor Loss score of 1. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208164/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:404903 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0041912 infores:hetionet CHEBI:499361 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0014724 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0948525 infores:hetionet CHEBI:3568 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0016382 infores:hetionet CHEBI:9943 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042024 infores:hetionet CAID:CA9043628 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043628 MONDO:0012999 PMID: Pathogenic PM2_Supporting, PP4_Strong, PVS1_Strong, PM3_Supporting "The NM_000156.6:c.491dup (p.Val165ArgfsTer26) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong; PMID: 11136556). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in the East Asian population, which is less than the ClinGen CCDS VCEP's threshold (<0.0004) (PM2_Supporting). The variant was found in homozygosity in one patient who meets the ClinGen CCDS VCEP's PP4 specifications (PMID 12557293). This variant was also found in compound heterozygosity in two patients who meet ClinGen CCDS VCEP’s PP4 specifications; one with the variant c.564G>T (p. Met188Ile) (PMID 28438604) or ""IVS5-3C>G"" (PMID 11136556). However, the in trans data from these two patients will be used in the assessment of the second variant and is not included here to avoid circular logic. (PM3_Supporting). Three patients have been reported with this variant and clinical and biochemical features consistent with GAMT deficiency including an adult patient with low creatine and elevated GAA in urine, plasma, and CSF, <10% normal GAMT activity in fibroblasts, and absent creatine peak with GAA detected on MRS (PMID 12557293), low creatine and elevated GAA in plasma and urine and absent creatine peak on MRS (PMID 28438604), and elevated GAA in plasma, urine, and CSF, and lacking creatine peak on brain MRS (PMID 1136556)(PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 495685) In summary, this variant meets the criteria to be classified as Pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022)." Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043628/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3127 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C1167965 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0023533 infores:hetionet CHEBI:63589 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0026636 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853760 infores:hetionet NCBIGene:2155 biolink:causes MONDO:0009211 infores:monarchinitiative not_provided not_provided HGNC:3544 MONDO:0009211 uuid:f7cd31ba-73b1-4e04-b370-f0328a94ac0b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5123 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0236071 infores:hetionet CHEBI:194135 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0033774 infores:hetionet CHEBI:4710 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0043144 infores:hetionet NCBIGene:51114 biolink:causes MONDO:0010427 infores:monarchinitiative not_provided not_provided HGNC:18475 MONDO:0010427 uuid:1138c313-1895-4042-869a-24d2fbdc5b82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0086439 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0542571 infores:hetionet CHEBI:49040 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0041912 infores:hetionet CHEBI:8874 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0013362 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0853193 infores:hetionet CHEBI:6067 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235857 infores:hetionet CHEBI:3048 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0033975 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034186 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0750194 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0750194 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0151664 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0020651 infores:hetionet CAID:CA10584820 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584820 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP2, BP3, PS2, PS3, PS1, PS4, BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PM5_Strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PM5 - Four more missense variants described in same codon, 3 variants classified as Pathogenic, so PM5 is Met.PP3 - REVEL = 0.958. It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria from Center of molecular biology and gene therapy. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584820/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3127 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0015967 infores:hetionet CHEBI:63608 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018524 infores:hetionet NCBIGene:6330 biolink:causes MONDO:0012737 infores:monarchinitiative not_provided not_provided HGNC:10592 MONDO:0012737 uuid:c562b3fb-5b82-4c62-b116-4dff27950291 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0016382 infores:hetionet CHEBI:5001 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0031350 infores:hetionet CHEBI:2549 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0017675 infores:hetionet CHEBI:7931 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151529 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1328395 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1328395 infores:hetionet CHEBI:4702 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0476273 infores:hetionet CHEBI:63598 biolink:causes UMLS:C1963951 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1963951 infores:hetionet CHEBI:94440 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0700590 infores:hetionet CHEBI:135736 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C2939147 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0442874 infores:hetionet GO:0048631 biolink:causes GO:0007519 infores:ubergraph knowledge_assertion manual_agent GO:0048631 GO:0007519 CHEBI:119486 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0005758 infores:hetionet CAID:CA288019 biolink:causes MONDO:0007648 infores:clingen CAID:CA288019 MONDO:0007648 PMID: Likely Benign BS2, BP2 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BA1, PS1, PS3, PS4, PS2 The c.1174G>A variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in trans with a known pathogenic CDH1 variant (phase unknown) and observed in the homozygous state in gnomAD v2.0.2 (BP2; internal laboratory contributor and gnomAD). Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288019/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:92923 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0235818 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0858797 infores:hetionet CHEBI:15407 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0231919 infores:hetionet CHEBI:8214 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0037317 infores:hetionet NCBIGene:70 biolink:causes MONDO:0013261 infores:monarchinitiative not_provided not_provided HGNC:143 MONDO:0013261 uuid:0381df4a-c7b7-459c-ae61-8d8b2a6dd4af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0232493 infores:hetionet CHEBI:4858 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0035455 infores:hetionet NCBIGene:8481 biolink:causes MONDO:0010431 infores:monarchinitiative not_provided not_provided HGNC:2567 MONDO:0010431 uuid:c3ad24b2-1796-4a5b-a2e3-4de009afb19c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA179708 biolink:causes MONDO:0008723 infores:clingen CAID:CA179708 MONDO:0008723 PMID: Benign BA1, BP4 The c.623-8C>T variant in ACADVL is an intronic variant which occurs in the polypyrimidine tract of intron 7. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0289 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from 2 in silico splicing predictors (SpliceAI, NNSplice) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA179708/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:5147 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027051 infores:hetionet CHEBI:28971 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0221776 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0030252 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006626 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011882 infores:hetionet CHEBI:5790 biolink:causes MONDO:0006896 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0014869 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0013922 infores:hetionet CAID:CA199435 biolink:causes MONDO:0100040 infores:clingen CAID:CA199435 MONDO:0100040 PMID:19806373PMID:28661489 Pathogenic PS2_Very Strong, PVS1, PS4, PM2_Supporting The p.Glu154Glyfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu154Glyfs variant in FOXG1 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with FOXG1 disorder (PMID 19806373, 28661489, Internal database-GeneDx) (PS2_VS). The p.Glu154Glyfs variant has also has been observed in at least 10 other individuals with FOXG1 disorder (PMID 19806373, 24836831, 26344814, 28851325, 29595814, 29655203, 29322350, 28661489) (PS4). The p.Glu154Glyfs variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Glu154Glyfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PS2_VS, PS4, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199435/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:92712 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0003467 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0011616 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020456 infores:hetionet CAID:CA270398 biolink:causes MONDO:0010726 infores:clingen CAID:CA270398 MONDO:0010726 PMID: Pathogenic PM5, PM1, PP3, PP4, PS4_Moderate, PS2, PM2_Supporting The p.Ser134Phe variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 2 individuals with Rett syndrome (PMID 15737703, internal database - GeneDx) (PS2, PP4). The p.Ser134Phe variant has been observed in at least 1 other individual with Rett syndrome (PMID 21160487) (PS4_moderate). A pathogenic missense variant (p.Ser134Cys) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10814718, 11738864, 17089071, 12655490, 21160487, 11738883, 18337588, 10767337, 23696494, 22182064) (PM5). The p.Ser134Phe variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). The p.Ser134Phe variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ser134Phe variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PS4_moderate, PM1, PM5, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270398/MONDO:0010726/016 2021-10-26 2021-12-27 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:100241 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085635 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0857153 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0857153 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0920166 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0920166 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0020437 infores:hetionet CHEBI:7936 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151908 infores:hetionet GO:0021861 biolink:causes CL:0013000 infores:ubergraph knowledge_assertion manual_agent GO:0021861 CL:0013000 CHEBI:7459 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C1510472 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0240322 infores:hetionet CHEBI:31236 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151904 infores:hetionet CHEBI:8093 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0008031 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0521491 infores:hetionet CHEBI:2676 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0234913 infores:hetionet CHEBI:50742 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0019080 infores:hetionet CHEBI:28939 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0033774 infores:hetionet CHEBI:15367 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2937358 infores:hetionet CHEBI:2038 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0000737 infores:hetionet CHEBI:17347 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0011124 infores:hetionet CHEBI:84050 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0004093 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151735 infores:hetionet CHEBI:63605 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0005779 infores:hetionet CHEBI:48273 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0034880 infores:hetionet CHEBI:52717 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0151610 infores:hetionet CAID:CA523302413 biolink:causes MONDO:0100368 infores:clingen CAID:CA523302413 MONDO:0100368 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PP1, PM2_Supporting The NM_000329.3(RPE65):c.106del (p.Leu36SerfsTer?) variant introduces a premature stop codon into exon 3 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at an allele frequency of 8.474e-7 , with 1 allele / 1180032 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (confirmed in trans) with a Pathogenic variant previously classified by the LCA/eoRD VCEP (1 pt, PM3)(PMID: 33308271). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with nystagmus (1 pt), myopia, retinal degeneration at 2-years-old (1 pt), sluggish pupillary responses (0.5 pts), extensive atrophic retinal changes, salt and pepper fundus appearance (2 pts), optic disc pallor, and extinguished rod and cone ERG (1.5 pts). Screening by NGS did not reveal any additional variants of interest (2 pts). Together these phenotypes are highly specific for RPE65-related recessive retinopathy (total 8.5 points, PMID: 33308271, PP4_Moderate).The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 33308271).In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, PP4_moderate, PP1, PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA523302413/MONDO:0100368/120 2025-03-27 2025-03-27 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0657912 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025202 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0160390 infores:hetionet CHEBI:161680 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C1443060 infores:hetionet NCBIGene:24 biolink:causes MONDO:0009549 infores:monarchinitiative not_provided not_provided HGNC:34 MONDO:0009549 uuid:b5400960-1abe-4bec-a893-a0bc92d2f3b4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0231218 infores:hetionet NCBIGene:5528 biolink:causes MONDO:0014602 infores:monarchinitiative not_provided not_provided HGNC:9312 MONDO:0014602 uuid:158de445-0cd5-4925-93fe-b97a6f2c795b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:25 biolink:causes MONDO:0011996 infores:drugmechdb knowledge_assertion manual_agent UniProtKB:P00519 MESH:D015464 DB00619_MESH_D015464_1 CHEBI:9571 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C2830004 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0235996 infores:hetionet NCBIGene:2688 biolink:causes MONDO:0009879 infores:monarchinitiative not_provided not_provided HGNC:4261 MONDO:0009879 uuid:08d0857e-f7b3-4a58-930b-07bc94fe5ce3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8069 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0013144 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0314719 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0037822 infores:hetionet CHEBI:27974 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0042267 infores:hetionet CHEBI:5130 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0855775 infores:hetionet CHEBI:38940 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0518988 infores:hetionet CHEBI:171719 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0002878 infores:hetionet CAID:CA410147824 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147824 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS4, PS2, PS1, BP1, BP3, BP2, BA1, PM2, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1188C>G (p.Phe396Leu) is a missense variant which has a REVEL score < 0.50 (0.203) and a SpliceAI score ≤ 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147824/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA16020880 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020880 MONDO:0009861 PMID:29499199PMID:26503515 Uncertain Significance PM2, PP4_Moderate, PP3 The c.871G>T (p.Val291Leu) variant in PAH has been reported in a Chinese patient with mild hyperphenylalaninemia (BH4 deficiency excluded) (PMID: 26503515, 29499199) This variant is absent from population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020880/MONDO:0009861/006 2020-06-18 2020-06-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:144551 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0013378 infores:hetionet CHEBI:63925 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0344232 infores:hetionet CHEBI:47780 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0085633 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0853761 infores:hetionet CHEBI:10112 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0235378 infores:hetionet CHEBI:31709 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0687713 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0022650 infores:hetionet CHEBI:135736 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0149514 infores:hetionet CHEBI:51860 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0242429 infores:hetionet CHEBI:180905 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0231218 infores:hetionet CHEBI:27882 biolink:causes UMLS:C0302813 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0302813 infores:hetionet CHEBI:490877 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0023530 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0011991 infores:hetionet CHEBI:42797 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003578 infores:hetionet NCBIGene:3988 biolink:causes MONDO:0019149 infores:monarchinitiative not_provided not_provided HGNC:6617 MONDO:0019149 uuid:c490fd82-fcd1-4ef7-b1ac-ca9da676c254 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:3QJA87N40S biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0085593 infores:hetionet CHEBI:78543 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0476281 infores:hetionet CHEBI:9720 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0039231 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0948594 infores:hetionet CHEBI:9435 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0022107 infores:hetionet CHEBI:2914 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0037274 infores:hetionet CHEBI:63616 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0232462 infores:hetionet CHEBI:15544 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0033117 infores:hetionet CHEBI:473990 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0004936 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013395 infores:hetionet CHEBI:3347 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0151746 infores:hetionet CHEBI:63791 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0015672 infores:hetionet CHEBI:36791 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0085631 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C1142492 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C1142492 infores:hetionet CHEBI:2788 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0013404 infores:hetionet CHEBI:3640 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0002874 infores:hetionet NCBIGene:11145 biolink:causes MONDO:0958034 infores:monarchinitiative not_provided not_provided HGNC:17825 MONDO:0958034 uuid:5cae08d5-33e5-4a26-808f-d8f7241c8469 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019080 infores:hetionet CHEBI:28593 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0233407 infores:hetionet CHEBI:92998 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0027497 infores:hetionet NCBIGene:1636 biolink:causes MONDO:0009970 infores:monarchinitiative not_provided not_provided HGNC:2707 MONDO:0009970 uuid:f0ffa05a-88bb-46ec-8c3a-0c3bba9c2667 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:251408 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0000729 infores:hetionet CHEBI:2618 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C1306341 infores:hetionet CHEBI:32020 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0033774 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0392025 infores:hetionet CHEBI:8028 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0007398 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019348 infores:hetionet CHEBI:28787 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0015230 infores:hetionet CHEBI:5280 biolink:causes MONDO:0100073 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0343401 infores:hetionet CHEBI:7627 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0025874 infores:hetionet CHEBI:127342 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0030794 infores:hetionet GO:1905787 biolink:causes GO:0050975 infores:ubergraph knowledge_assertion manual_agent GO:1905787 GO:0050975 CAID:CA404075813 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075813 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP4 PP3 The NM_000527.5(LDLR):c.300C>G (p.Asp100Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PS4_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill SB possible for FH from PMID 26361156.PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from PMID 26361156, after alternative causes for high cholesterol were excluded Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075813/MONDO:0007750/013 2023-04-28 2023-05-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9139 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0030196 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0151735 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0013395 infores:hetionet CHEBI:367163 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0424790 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151596 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0031542 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0948594 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0020538 infores:hetionet CHEBI:4657 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0009806 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0002962 infores:hetionet CHEBI:408174 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0232849 infores:hetionet CHEBI:6062 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018965 infores:hetionet CHEBI:5959 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0016204 infores:hetionet CHEBI:119915 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037299 infores:hetionet CHEBI:9738 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0233407 infores:hetionet CHEBI:8665 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0015732 infores:hetionet CHEBI:194135 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018794 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0031117 infores:hetionet CHEBI:8028 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0041105 infores:hetionet CHEBI:2549 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0700361 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0032961 infores:hetionet CHEBI:5893 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0220870 infores:hetionet CHEBI:31413 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0235996 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042373 infores:hetionet CHEBI:7454 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0039070 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009319 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0018802 infores:hetionet CHEBI:8805 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0014742 infores:hetionet CAID:CA902595 biolink:causes MONDO:0100368 infores:clingen CAID:CA902595 MONDO:0100368 PMID: Likely Benign BP4, BP7 BS1, PM2 NM_000329.3(RPE65):c.102C>A is a synonymous variant encoding isoleucine at position p.34, and is located at the 8th nucleotide from the start of exon 3, outside of the first 3 nucleotides considered to be important for splicing. The splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). This variant is present in gnomAD v.4.1.0 with a GrpMax allele frequency of 0.0005837, with 733 alleles / 1,180,046 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 but lower than the BS1 threshold of >0.0008 and fails to meet either criterion. This variant has been reported in at least 1 proband with adult-onset retinal dystrophy who harbored the variant in the compound heterozygous state (PMID 35569774). However, the proband was not counted for PM3 because of the age of onset and because the NM_000329.3(RPE65):c.1237C>T (p.Arg413Cys) variant in trans has not yet been classified by the LCA / eoRD VCEP. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902595/MONDO:0100368/120 2025-06-30 2025-06-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:66876 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0235996 infores:hetionet CHEBI:50922 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0003811 infores:hetionet CHEBI:116278 biolink:causes UMLS:C1142011 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1142011 infores:hetionet CAID:CA229679 biolink:causes MONDO:0009861 infores:clingen CAID:CA229679 MONDO:0009861 PMID:9429153PMID:12409276PMID:15589814PMID:23842451PMID:24510552PMID:9429153PMID:15589814PMID:23842451PMID:25757997 Likely Pathogenic PM2, PP4_Moderate, PM3_Strong PM5, PP3 The c.665A>G (p.Asp222Gly) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 24510552, 9429153); One had BH4 cofactor deficiency excluded (PMID: 15589814). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.A104D (PMID: 9429153); p.R408W (PMID: 15589814); c.1066-11G>A (PMID: 23842451); p.L48S (PMID: 25757997); p.I65T (PMID: 16165389). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229679/MONDO:0009861/006 2020-07-09 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0264893 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0235344 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0235344 infores:hetionet CHEBI:63621 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0221512 infores:hetionet CHEBI:4710 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0235267 infores:hetionet CHEBI:79699 biolink:causes MONDO:0019369 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0458219 infores:hetionet CHEBI:71940 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0423153 infores:hetionet CHEBI:27300 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C1306341 infores:hetionet CHEBI:36791 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0852911 infores:hetionet CHEBI:94501 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0013404 infores:hetionet CHEBI:18248 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0027424 infores:hetionet CHEBI:48669 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0015672 infores:hetionet CHEBI:7445 biolink:causes MONDO:0006908 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0032001 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0011616 infores:hetionet CHEBI:16899 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0002962 infores:hetionet CHEBI:63637 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0017178 infores:hetionet CHEBI:6539 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0030193 infores:hetionet CHEBI:8665 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0040046 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0027947 infores:hetionet UMLS:C0657912 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085611 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0442874 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0042109 infores:hetionet CHEBI:6715 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042029 infores:hetionet CHEBI:4046 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0231919 infores:hetionet GO:0140134 biolink:causes GO:0008015 infores:ubergraph knowledge_assertion manual_agent GO:0140134 GO:0008015 CHEBI:31348 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0149725 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0917799 infores:hetionet CHEBI:36791 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0699828 infores:hetionet CHEBI:16899 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0039971 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0021053 infores:hetionet CHEBI:182080 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0018524 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0340464 infores:hetionet CHEBI:194135 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0016204 infores:hetionet CHEBI:9763 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0021368 infores:hetionet CHEBI:6539 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0017178 infores:hetionet CHEBI:3723 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028734 infores:hetionet CHEBI:68478 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0423791 infores:hetionet CHEBI:94449 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0085633 infores:hetionet CHEBI:15854 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0042790 infores:hetionet CHEBI:7581 biolink:causes MONDO:0006642 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0001957 infores:hetionet CHEBI:184555 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0033774 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0851341 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0009763 infores:hetionet CHEBI:38940 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C3160858 infores:hetionet CHEBI:3698 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0037763 infores:hetionet CHEBI:72292 biolink:causes UMLS:C0161679 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0392620 infores:hetionet CHEBI:3048 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0027497 infores:hetionet CAID:CA2580612187 biolink:causes MONDO:0100368 infores:clingen CAID:CA2580612187 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting BP1, BP4, BP3, BA1, PM5, PM4, PS3, PS4, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM6, PP2, PP3, PP1, PP4 NM_000329.3(RPE65):c.1336dup (p.Arg446LysfsTer4) is a frameshift variant that introduces a premature stop codon into exon 12 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 30268864, PM3). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_supporting, PM3. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580612187/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0020625 infores:hetionet CAID:CA10644121 biolink:causes MONDO:0007648 infores:clingen CAID:CA10644121 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM5, PM4, PVS1, PM2, PM6, BS2, PP1, PP4, PP2, PP3, BP1, BP4, BP3, PS2, PS4, PS3, PS1 The NM_004360.5(CDH1):c.*1662G>C variant has an allele frequency of 0.02032 (2%, 177/8712 alleles, 3 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644121/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:49662 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0853760 infores:hetionet CHEBI:6801 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0026821 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011849 infores:hetionet CHEBI:47898 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027497 infores:hetionet CHEBI:49713 biolink:causes HP:0002378 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0239842 infores:hetionet CHEBI:63632 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0023380 infores:hetionet CHEBI:7798 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0038999 infores:hetionet CHEBI:47780 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0040822 infores:hetionet NCBIGene:2782 biolink:causes MONDO:0018881 infores:monarchinitiative not_provided not_provided HGNC:4396 MONDO:0018881 uuid:5529d371-69e4-40b9-a463-59b6b114fd00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0151610 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0232462 infores:hetionet CHEBI:50885 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0016658 infores:hetionet CHEBI:94449 biolink:causes UMLS:C1096275 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C1096275 infores:hetionet CHEBI:3242 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0151827 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0015397 infores:hetionet CHEBI:3441 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0002965 infores:hetionet CHEBI:2663 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0232462 infores:hetionet CHEBI:63605 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0019080 infores:hetionet NCBIGene:54658 biolink:causes MONDO:0011725 infores:monarchinitiative not_provided not_provided HGNC:12530 MONDO:0011725 uuid:5db6c08b-8c0a-412c-8a37-53416b0298c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes HP:0012668 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0042420 infores:hetionet CHEBI:9654 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0549249 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0233472 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0009806 infores:hetionet CHEBI:6741 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0014724 infores:hetionet CHEBI:5441 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0547030 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0236065 infores:hetionet CHEBI:64312 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0043352 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0030554 infores:hetionet CHEBI:4710 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0002170 infores:hetionet NCBIGene:5422 biolink:causes MONDO:0010523 infores:monarchinitiative not_provided not_provided HGNC:9173 MONDO:0010523 uuid:7404b97c-f6aa-4ad3-8764-5ea57f7e027e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0152227 infores:hetionet CHEBI:9448 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0008370 infores:hetionet CHEBI:4672 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0152227 infores:hetionet CHEBI:145499 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0014724 infores:hetionet CHEBI:51173 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0012833 infores:hetionet CHEBI:5001 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0009782 infores:hetionet CHEBI:83804 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0034642 infores:hetionet CHEBI:50861 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0006277 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0877047 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0877047 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0342406 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0342406 infores:hetionet CHEBI:6367 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0027947 infores:hetionet CHEBI:8802 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0038450 infores:hetionet CHEBI:3082 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0149745 infores:hetionet CHEBI:9332 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0009782 infores:hetionet CAID:CA16020942 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020942 MONDO:0009861 PMID:26503515 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1115C>G (p.Thr372Arg) variant in PAH has been reported in 3 individuals with classic PKU (BH4 deficiency excluded, PMID: 26503515) detected in trans with pathogenic variants: p.R176* (2 patients) and p.R408W (PMID: 30050108). This variant is absent in population databases. Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020942/MONDO:0009861/006 2020-08-10 2021-09-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15365 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C2830004 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0948089 infores:hetionet CHEBI:167638 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0015967 infores:hetionet CHEBI:93363 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB06711 UMLS:C0259799 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0541832 infores:hetionet CHEBI:28748 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1527344 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0700345 infores:hetionet CAID:CA512318917 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318917 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS4, PS2, PS1, BP3, BP1, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.210G>A (p.Lys70=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). No splicing impact or creation of cryptic splice sites is predicted by SSF and MES, and SpliceAI predicts no impact to splicing (score: 0.00) (BP4). Evolutionary conservation prediction algorithms show the variant as the reference nucleotide in one primate and/or three mammal species (BP7). This variant was reported in ClinVar in 2021 by Invitae, but the affected status of the proband is unknown (Variation ID 1665576). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318917/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4814 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0014868 infores:hetionet CHEBI:27690 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0857305 infores:hetionet CAID:CA287433650 biolink:causes MONDO:0008723 infores:clingen CAID:CA287433650 MONDO:0008723 PMID: Pathogenic PM2_Supporting, PVS1, PP4_Moderate PP2, PM5, PM1, BP1, BA1, PS1, BS1 The c.37C>T (p.Gln13Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed VLCAD enzyme levels of <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 20060901, 17999356). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287433650/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CAID:CA502402648 biolink:causes MONDO:0009290 infores:clingen CAID:CA502402648 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3 The NM_000152.5:c.768dup (p.Ile257TyrfsTer73) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). The variant has been reported in a patient with Pompe disease but further details regarding the second variant and residual GAA activity are unavailable (PMID: 18425781). There is a ClinVar entry for this variant (Variation ID: 556534). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA502402648/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:36791 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235750 infores:hetionet CAID:CA000405 biolink:causes MONDO:0017623 infores:clingen CAID:CA000405 MONDO:0017623 PMID:29706350PMID:25248401 Uncertain Significance PP2, PP3, PM2_Supporting, BS3_Supporting PM6, PVS1, BS1, BS4, BP7, BP5, BS2, PP1, PM5, PM4, PM1, PM3, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 PTEN c.338G>T (p.S113I) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (this variant: score=0.797)BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000405/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64312 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027947 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0021845 infores:hetionet CAID:CA16020833 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020833 MONDO:0009861 PMID:23842451PMID:23842451 Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The c.510-19_667del variant in PAH involves part of exon 6, predicted to result in frameshift and NMD (PVS1). It has been reported in 1 individual with PKU. (PP4; PMID: 23842451). This variant is absent from gnomAD (PM2_supporting). This variant was detected with p.G272* (Pathogenic in ClinVar; PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020833/MONDO:0009861/006 2023-12-30 2023-12-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:51364 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0002878 infores:hetionet CHEBI:49575 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0086439 infores:hetionet CAID:CA163603 biolink:causes MONDO:0007648 infores:clingen CAID:CA163603 MONDO:0007648 PMID:17660459PMID:24763289PMID:25186627PMID:26270727 Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Moderate BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS2, PS3, PS1 The c.521dupA p.(Asn174Lysfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17660459 and doi:10.1200/PO.16.00021). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Moderate, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA163603/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:2950 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0042023 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0520589 infores:hetionet NCBIGene:80169 biolink:causes MONDO:0024564 infores:monarchinitiative not_provided not_provided HGNC:26169 MONDO:0024564 uuid:501acb36-fdf0-4029-8c43-dab4c61f11d7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63627 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0027765 infores:hetionet CHEBI:6129 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0042384 infores:hetionet CHEBI:3403 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0019521 infores:hetionet CHEBI:16469 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0010200 infores:hetionet CHEBI:35677 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0232492 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0032285 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0039971 infores:hetionet NCBIGene:23247 biolink:causes MONDO:0014771 infores:monarchinitiative not_provided not_provided HGNC:29068 MONDO:0014771 uuid:346f36c3-f9a7-4b69-947a-6bd0ddd72670 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68534 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0017178 infores:hetionet CHEBI:83527 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0278106 infores:hetionet CHEBI:8764 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0001925 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0687133 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0010709 infores:hetionet CHEBI:63717 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C1720775 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0852990 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0852990 infores:hetionet CHEBI:6804 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB06709 UMLS:C0151826 infores:hetionet CHEBI:6710 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0011991 infores:hetionet CHEBI:7476 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0220981 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0009450 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0392025 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0521845 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0521845 infores:hetionet CHEBI:6775 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0030193 infores:hetionet CHEBI:5779 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0948226 infores:hetionet CHEBI:2379 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0476273 infores:hetionet CHEBI:5441 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0022346 infores:hetionet CHEBI:4466 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C1443060 infores:hetionet CHEBI:28864 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0423153 infores:hetionet CHEBI:2950 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0031350 infores:hetionet CHEBI:3478 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0040822 infores:hetionet CHEBI:8378 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0010043 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0039971 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0853761 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0853761 infores:hetionet CHEBI:45327 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0520887 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235431 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0010200 infores:hetionet CHEBI:17303 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085633 infores:hetionet CHEBI:68554 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0014591 infores:hetionet CHEBI:5779 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0015967 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0022408 infores:hetionet NCBIGene:55624 biolink:causes MONDO:0013161 infores:monarchinitiative not_provided not_provided HGNC:19139 MONDO:0013161 uuid:fb225461-0dbd-4f74-98cf-d4b8db2733d5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229816 biolink:causes MONDO:0009861 infores:clingen CAID:CA229816 MONDO:0009861 PMID: Pathogenic PVS1, PM2, PP4 PM3 The c.843-2A>T variant in PAH has been reported in 1 homozygote individual with classic PKU (PMID: 9452062). This variant disrupts the canonical splice acceptor site of intron 8 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 8 is present in biologically-relevant transcript. This variant is absent from population databases, including: 1000 Genomes, ESP, and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229816/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:57231 biolink:causes MONDO:0014601 infores:monarchinitiative not_provided not_provided HGNC:14977 MONDO:0014601 uuid:184fbebf-4059-4b5c-8662-c864d1011669 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0018681 infores:hetionet CHEBI:4792 biolink:causes HP:0012417 infores:sider not_provided not_provided DRUGBANK:DB00228 UMLS:C0085383 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0035309 infores:hetionet CHEBI:3077 biolink:causes MONDO:0007017 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0042907 infores:hetionet CHEBI:8378 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0030193 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0034642 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0522757 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0522757 infores:hetionet CHEBI:45716 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0020456 infores:hetionet CHEBI:9939 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0042109 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0018939 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0948349 infores:hetionet CHEBI:6741 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0038358 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0042109 infores:hetionet CHEBI:48538 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0012833 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0027051 infores:hetionet CHEBI:71223 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0015230 infores:hetionet CHEBI:2611 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0041969 infores:hetionet CHEBI:6367 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0232849 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0007787 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0178298 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0233472 infores:hetionet CHEBI:2955 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0000768 infores:hetionet CAID:CA16020766 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020766 MONDO:0009861 PMID:23357515 Pathogenic PVS1, PM2, PP4 This variant c.324_328del (p.Glu108AspfsTer4) in PAH was reported in at least 1 Czech patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This is a frameshift variant in exon 3 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3'-most exon or the 3'-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020766/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:119486 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0018802 infores:hetionet CHEBI:8707 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0035410 infores:hetionet CHEBI:119573 biolink:causes MONDO:0007547 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014511 infores:hetionet NCBIGene:6304 biolink:causes MONDO:0030990 infores:monarchinitiative not_provided not_provided HGNC:10541 MONDO:0030990 uuid:399335f6-1269-46d3-9926-c87f7bb9085a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0344232 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235146 infores:hetionet CHEBI:16347 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0000729 infores:hetionet CAID:CA658824783 biolink:causes MONDO:0009290 infores:clingen CAID:CA658824783 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, PM4 PP3, BP4 The NM_000152.5:c.1819_1836dup variant in GAA is predicted to cause a change in the length of the protein (p.Gly607_His612dup) due to an in-frame duplication of 6 amino acids in a non-repeat region (PM4). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). Computational evidence is conflicting; PROVEAN predicts a deleterious impact on the protein, while Mutation Taster predicts no impact. To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 556265). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PM4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 17, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824783/MONDO:0009290/010 2024-06-17 2024-06-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:8435 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0027849 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011570 infores:hetionet CAID:CA2580610925 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580610925 MONDO:0015967 PMID: Pathogenic PVS1, PP4, PM2_Supporting The c.1254-12_1257del variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 10 of 10, not expected to lead to nonsense mediated decay but to result of the loss of a functionally important region of in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 9790256). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1254-12_1257del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610925/MONDO:0015967/086 2023-09-20 2023-09-20 Semidominant inheritance HP:0032113 Supports CHEBI:116735 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0033774 infores:hetionet CHEBI:3723 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0007286 infores:hetionet CHEBI:175901 biolink:causes HP:0001265 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0700078 infores:hetionet CHEBI:2687 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0243026 infores:hetionet CHEBI:79699 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0017178 infores:hetionet CHEBI:49713 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0011334 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0947999 infores:hetionet CHEBI:6888 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0019080 infores:hetionet CHEBI:61049 biolink:causes NCIT:C50810 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0241729 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0018802 infores:hetionet CHEBI:5128 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0151904 infores:hetionet CHEBI:3515 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0040586 infores:hetionet CHEBI:45081 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0018524 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0007642 infores:hetionet CHEBI:92712 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0022107 infores:hetionet CHEBI:32315 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013390 infores:hetionet CHEBI:7852 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0026205 infores:hetionet CHEBI:32221 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0025222 infores:hetionet CHEBI:47381 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0085593 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0022081 infores:hetionet CHEBI:47381 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0231218 infores:hetionet CHEBI:7824 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014591 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0314719 infores:hetionet CHEBI:4822 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0040264 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0042373 infores:hetionet CHEBI:16480 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0025637 infores:hetionet GO:0060860 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0060860 GO:0061458 CHEBI:7931 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0404521 infores:hetionet CHEBI:4710 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1368065 infores:hetionet CHEBI:7565 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151827 infores:hetionet CHEBI:6472 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0000737 infores:hetionet CHEBI:3441 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0086439 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0021400 infores:hetionet UMLS:C0657912 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037299 infores:hetionet CHEBI:6444 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0016382 infores:hetionet CAID:CA023715 biolink:causes MONDO:0007750 infores:clingen CAID:CA023715 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, BS4, PM1, PM3, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, PM5, PM4, PVS1, PM6, BS2, PP2 NM_000527.5(LDLR): c.530C>T (p.Ser177Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PM1, PM2, PM3, PP1_Strong, PP3, PP4 and BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PS3 - PMID: 31578082 - Level 1 assay - Heterologous cells (CHO), FACS assays and CLSM: 65% cell surface LDLR, 10% binding and <2% uptake. PMID: 2760205 - Level 2 assay - Homozygous patient fibroblast, 125I-LDL assays: <2% LDLR activity. PMID: 25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assays: LDLR activity decreased compared to WT - considered as disruptive.PS4 - Variant meets PM2. Variant identified in 30 unrelated index cases (5 cases (2 with DLCN≥6; 3 with Simon-Broome possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Simon-Broome possible from GeneDx Inc.; 11 cases with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 13 cases with Simon-Broome possible/definite from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PM1 - Variant meets PM2 and is missense in exon 4.PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes+genomes (gnomAD v2.1.1).PM3 - Patient 3 from PMID: 18263977 has LDL = 19.7 mmol/l and also LDLR p.Arg350* in trans - Pathogenic by these guidelines. Two true homozygotes (FHF23 and FHF57) published in PMID: 27816806 had LDL = 16.2 mmol/l and 22.6 mmol/l, respectively.PP1_Strong - Variant segregates with FH phenotype in 52 informative meiosis in 26 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 43 relatives tested positive had LDL-C >75th percentile + 9 relatives tested negative had LDL-C <50th percentile.PP3 - REVEL = 0.886.PP4 - Variant meets PM2. Variant identified in 30 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details).BS4 - Variant does not segregate with phenotype in 14 informative meiosis from at least 6 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 13 relatives tested negative but had LDL-C >75th percentile + 1 relative tested positive but LDL-C <50th percentile.Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023715/MONDO:0007750/013 2022-06-03 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:404903 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0039231 infores:hetionet CHEBI:8871 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0042510 infores:hetionet CHEBI:8764 biolink:causes HP:0001605 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0042928 infores:hetionet CHEBI:15367 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0220870 infores:hetionet CHEBI:6078 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0241057 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0595883 infores:hetionet CHEBI:9168 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0019080 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0004096 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0011849 infores:hetionet CHEBI:50648 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0015672 infores:hetionet CHEBI:36795 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0151904 infores:hetionet CHEBI:4974 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0232462 infores:hetionet CHEBI:8232 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C2129214 infores:hetionet CHEBI:68610 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0030305 infores:hetionet CHEBI:31236 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085633 infores:hetionet CHEBI:8874 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0019270 infores:hetionet CHEBI:4708 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0022346 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0243026 infores:hetionet CHEBI:6715 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0003467 infores:hetionet CHEBI:27446 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0221490 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0002170 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0700184 infores:hetionet CHEBI:63605 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0010200 infores:hetionet GO:2000028 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:2000028 GO:0061458 CHEBI:28925 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0085932 infores:hetionet GO:1904073 biolink:causes GO:0001832 infores:ubergraph knowledge_assertion manual_agent GO:1904073 GO:0001832 NCBIGene:196527 biolink:causes MONDO:0009885 infores:monarchinitiative not_provided not_provided HGNC:25240 MONDO:0009885 uuid:8ec773a5-35e5-4b84-890d-9a20c689d29b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0025241 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0442874 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0233485 infores:hetionet NCBIGene:3954 biolink:causes MONDO:0859304 infores:monarchinitiative not_provided not_provided HGNC:6556 MONDO:0859304 uuid:9bc52fb5-664f-4818-b6b0-4034a6af325c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:84061 biolink:causes MONDO:0026729 infores:monarchinitiative not_provided not_provided HGNC:28880 MONDO:0026729 uuid:4f4c78d0-951f-43ac-a3d0-137ef32d3515 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C3665386 infores:hetionet CHEBI:135613 biolink:causes UMLS:C0399459 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0399459 infores:hetionet CHEBI:107736 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0039231 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0022876 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0022876 infores:hetionet UMLS:C0145867 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0151578 infores:hetionet CHEBI:29013 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0030193 infores:hetionet NCBIGene:2074 biolink:causes MONDO:0008955 infores:monarchinitiative not_provided not_provided HGNC:3438 MONDO:0008955 uuid:8b0299f0-bb31-412e-8213-6d231fee7289 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0262985 infores:hetionet CHEBI:66964 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0037199 infores:hetionet CHEBI:27732 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0020615 infores:hetionet CHEBI:50692 biolink:causes UMLS:C0919567 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0919567 infores:hetionet CHEBI:68558 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0009676 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020517 infores:hetionet CAID:CA1139771046 biolink:causes MONDO:0013144 infores:clingen CAID:CA1139771046 MONDO:0013144 PMID: Pathogenic PS4_Moderate, PP1_Strong, PP4, PM2_Supporting, PVS1 The variant SERPINC1 p.Glu277ValfsTer20 is predicted to lead to a loss of function by nonsense mediated mRNA decay (NMD) with the being exon present in biologically relevant transcripts. The variant has been reported in 5 individuals in the literature (PMID: 33220012, 30721820, 1868237, 33725558) meeting the SERPINC1 phenotype criteria; however only 1 of them was reported with repeat AT testing meeting PP4 and PS4_Moderate criteria. To date, the variant has not been reported in the general population (gnomAD v2.1.1 and v3.1) found in neither the genomes nor exomes meeting PM2_Supporting. The variant has been reported in 18 segregations across 3 families in the literature meeting PP1_Strong (PMIDs: 33220012, 1868237, 33725558). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PVS1, PP1_strong, PS4_Moderate, PP4, PM2_supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771046/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CAID:CA120538 biolink:causes MONDO:0044970 infores:clingen CAID:CA120538 MONDO:0044970 PMID:6095966PMID:11071502 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, BP4, PS4, PS2, PM6 The m.5874T>C variant in MT-TY has been reported in one individual with primary mitochondrial disease to date (PMIDs: 6095966, 11071502). This woman had exercise intolerance onset in childhood, muscle weakness, ptosis, and ragged red fibers on muscle biopsy. The variant was present at 89% heteroplasmy in muscle and was absent in blood. It was also absent in blood from her healthy mother and siblings, however technology at the time would not have reliably detected presence of the variant at low heteroplasmy levels. There are no other individuals with this variant reported to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is benign (38.9 percentile) but HmtVAR predicts it to be deleterious with a score of 0.65. Single fiber testing showed higher levels of the variant in COX-negative fibers (92.3±6.7%; n=12) than in COX-positive fibers (29.9±11.8%; n=12; p<0.000001; PS3_supporting, PMID: 11071502). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 10, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120538/MONDO:0044970/015 2024-06-10 2024-12-09 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA645614129 biolink:causes MONDO:0011071 infores:clingen CAID:CA645614129 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.952dup (p.Ser318PhefsTer?) is a frameshift variant. This variant is not predicted to undergo nonsense-mediated decay (NMD), and the truncated/altered region is critical for protein function (frameshift (+) c.780-c.1440 as per VCEP specifications) (PVS1_Strong). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645614129/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63598 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085628 infores:hetionet CHEBI:31199 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0235259 infores:hetionet CHEBI:9168 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0232462 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0042134 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0004239 infores:hetionet CHEBI:3696 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0023052 infores:hetionet CHEBI:9566 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0221152 infores:hetionet CHEBI:4562 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0549249 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0022660 infores:hetionet CAID:CA293878 biolink:causes MONDO:0012589 infores:clingen CAID:CA293878 MONDO:0012589 PMID: Benign BS2_Supporting, BA1 The allele frequency of the p.Val168= variant in TCF4 is 0.057% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val168= variant is observed in 1 unaffected individual (Baylor Genetics internal database) (BS2_supporting). In summary, p.Val168= variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA293878/MONDO:0012589/016 2022-02-18 2022-06-30 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:7824 biolink:causes MONDO:0008661 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0042900 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0522172 infores:hetionet CHEBI:63622 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0220870 infores:hetionet CHEBI:3504 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0086565 infores:hetionet CHEBI:6715 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C3495440 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0855622 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0855622 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C2939186 infores:hetionet CHEBI:63608 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C1145670 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151765 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151765 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0006145 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0027765 infores:hetionet CHEBI:93635 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0004134 infores:hetionet CHEBI:135930 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0030554 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0037199 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0015397 infores:hetionet GO:0061190 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:0061190 GO:0048513 CHEBI:119573 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0040460 infores:hetionet CHEBI:47499 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0037822 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0678222 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0002871 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0948089 infores:hetionet GO:1903023 biolink:causes GO:0031321 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0031321 CHEBI:61049 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018989 infores:hetionet NCBIGene:10913 biolink:causes MONDO:0009147 infores:monarchinitiative not_provided not_provided HGNC:2895 MONDO:0009147 uuid:21d29bcc-f567-4f5b-834e-20c6a61571eb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4708 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0011175 infores:hetionet CHEBI:75722 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2697368 infores:hetionet CAID:CA229884 biolink:causes MONDO:0009861 infores:clingen CAID:CA229884 MONDO:0009861 PMID: Uncertain Significance PM2, PM3, PP3 PP4 The c.970-6T>G variant in PAH is absent from population databases (PM2). It has been observed in at least one PKU patient (PMID: 7766957) compound heterozygous with pathogenic variant R413P (ClinVar592; PM3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229884/MONDO:0009861/006 2020-07-09 2022-06-28 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:1902890 biolink:causes GO:0090558 infores:ubergraph knowledge_assertion manual_agent GO:1902890 GO:0090558 CHEBI:8597 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0043094 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C3665347 infores:hetionet CHEBI:75722 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151691 infores:hetionet CAID:CA1139771319 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139771319 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 PS4, PP3, PP4 The c.1254-13C>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 9 of NM_000162.5. The computational splicing predictor SpliceAI gives a score of 0.03 for acceptor loss, suggesting that the variant has no impact on splicing (BP4). This variant was identified in an individual referred for genetic testing with a family history of diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1254-13C>A meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): BP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139771319/MONDO:0015967/086 2024-02-16 2024-02-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011124 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0233494 infores:hetionet CAID:CA404085864 biolink:causes MONDO:0007750 infores:clingen CAID:CA404085864 MONDO:0007750 PMID: Uncertain Significance BP4, PM5, PM2, PP4 PS1, PS4, PS3, BS3, PP3 The NM_000527.5(LDLR):c.1414G>A (p.Asp472Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001120 (0.0112%) in Remaining exomes+genomes (gnomAD v4.1.0); PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (ClinVar ID 183116) -Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines; BP4 - REVEL = 0.318, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create AG. Variant is not predicted to alter splicing; PP4 - Variant meets PM2. Identified in at least 1 index case fulfilling Japanese Atherosclerosis Society criteria for FH from PMID 36229376, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404085864/MONDO:0007750/013 2025-01-31 2025-02-27 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31709 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0020649 infores:hetionet CHEBI:10127 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151754 infores:hetionet CHEBI:27565 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0003123 infores:hetionet CHEBI:63598 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0041296 infores:hetionet NCBITaxon:10258 biolink:causes MONDO:0005717 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10258 MONDO:0005717 CHEBI:6413 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0039231 infores:hetionet CHEBI:8461 biolink:causes HP:0020219 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0751494 infores:hetionet CAID:CA10014264 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014264 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.946G>C (p.Glu316Gln) is a missense variant which has a REVEL score < 0.50 (0.079) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014264/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8863 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018524 infores:hetionet CHEBI:92998 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0438215 infores:hetionet NCBIGene:79867 biolink:causes MONDO:0014724 infores:monarchinitiative not_provided not_provided HGNC:25774 MONDO:0014724 uuid:184e202a-0487-4b45-833d-280c4a83a732 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0037299 infores:hetionet CHEBI:6339 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0012833 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002525 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0154251 infores:hetionet CHEBI:68595 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0014457 infores:hetionet CHEBI:421707 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0035410 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004623 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0042109 infores:hetionet NCBIGene:55627 biolink:causes MONDO:0032838 infores:monarchinitiative not_provided not_provided HGNC:32949 MONDO:0032838 uuid:ac4fff5e-5b38-4093-b727-54ee68264be5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5147 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0006266 infores:hetionet CHEBI:114785 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0235378 infores:hetionet NCBIGene:4143 biolink:causes MONDO:0009607 infores:monarchinitiative not_provided not_provided HGNC:6903 MONDO:0009607 uuid:a2393d9a-0a8e-4ccb-96b1-663965c71ea9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5127 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0162835 infores:hetionet CHEBI:68554 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0232461 infores:hetionet CHEBI:3723 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020598 infores:hetionet CHEBI:2948 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0002170 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0853700 infores:hetionet CHEBI:135930 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0021053 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0392176 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0004936 infores:hetionet CHEBI:8228 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0020458 infores:hetionet CHEBI:10127 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0041657 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0521839 infores:hetionet CHEBI:3478 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0036974 infores:hetionet GO:0036479 biolink:causes GO:0097237 infores:ubergraph knowledge_assertion manual_agent GO:0036479 GO:0097237 CHEBI:47780 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0028866 infores:hetionet CHEBI:6067 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027441 infores:hetionet CHEBI:7915 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020473 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0021400 infores:hetionet CHEBI:8060 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0080274 infores:hetionet CHEBI:134991 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0032617 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151730 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151730 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0162429 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0240204 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0240204 infores:hetionet CHEBI:63598 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0042164 infores:hetionet CHEBI:39867 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0003811 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0549209 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235818 infores:hetionet NCBIGene:1410 biolink:causes MONDO:0014073 infores:monarchinitiative not_provided not_provided HGNC:2389 MONDO:0014073 uuid:6557afd6-63f9-4956-82a7-ac7f4bf071e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0162830 infores:hetionet CHEBI:4779 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0151827 infores:hetionet CHEBI:6367 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C2364111 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0332691 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0332691 infores:hetionet CHEBI:3219 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0004096 infores:hetionet CHEBI:119486 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0520966 infores:hetionet CHEBI:9328 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0085624 infores:hetionet CHEBI:84883 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0036974 infores:hetionet CHEBI:7443 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0015672 infores:hetionet CHEBI:5165 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0232462 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0011991 infores:hetionet CHEBI:6950 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151786 infores:hetionet CHEBI:3176 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0234708 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0852908 infores:hetionet CHEBI:71417 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0010200 infores:hetionet CHEBI:28748 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0019521 infores:hetionet NCBIGene:2018 biolink:causes MONDO:0010011 infores:monarchinitiative not_provided not_provided HGNC:3341 MONDO:0010011 uuid:1e003e32-e980-4680-b974-7ae3a8ed34f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0237849 infores:hetionet CHEBI:8888 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0152031 infores:hetionet CHEBI:3723 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0851578 infores:hetionet CHEBI:6888 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0030486 infores:hetionet CHEBI:102216 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0042963 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0042109 infores:hetionet CHEBI:7824 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0022107 infores:hetionet CHEBI:71417 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0014591 infores:hetionet CHEBI:119486 biolink:causes HP:0000855 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0021655 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0018799 infores:hetionet CHEBI:10101 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C1260880 infores:hetionet CHEBI:119486 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0017178 infores:hetionet CAID:CA120607 biolink:causes MONDO:0044970 infores:clingen CAID:CA120607 MONDO:0044970 PMID:11558799PMID:22342700 Pathogenic PM2_Supporting, PM6_Supporting, PVS1_Strong, PS3_Supporting PP3, BP4, PS4, PS2 The m.7896G>A (p.W104Ter) variant in MT-CO2 has been reported in one individual to date (PMID: 11558799), in a three-year-old child with psychomotor delay, failure to thrive, and cardiac hypertrophy from infancy who later developed cerebral atrophy and pigmentary retinopathy. Complex IV deficiency was noted in muscle. The variant was present at 76% heteroplasmy in muscle, 67% in blood, and 60% in fibroblasts. The variant was undetectable in blood from her mother and sister (PM6_supporting). There are no additional individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (52%) of the MT-CO2 protein (PVS1_strong). There were several compelling studies performed detailing functional validation (PS3_supporting). Activities and assembly of complexes I and IV (and of any COX-containing supercomplexes) were impaired in cybrid cell lines with the variant present at homoplasmy (PMID: 22342700). Single fiber testing showed higher levels of the variant in COX-deficient fibers (n = 9; 70.8 ± 8.1%) than in COX-positive fibers (n = 10; 17.6 ± 17.8%; p < 0.0001; PMID: 11558799). Immunoblot analysis in muscle from the proband revealed a 53% reduction of the COX II polypeptide and a 48% reduction of COX I polypeptide compared to controls (PMID: 11558799). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given the compelling functional validation and variant type. We note that some experts on this panel felt likely pathogenic was the more appropriate classification. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120607/MONDO:0044970/015 2024-02-12 2024-11-15 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:38545 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0033774 infores:hetionet CAID:CA226591 biolink:causes MONDO:0100368 infores:clingen CAID:CA226591 MONDO:0100368 PMID: Pathogenic PM3, PP4_Moderate, PVS1, PP1, PM2_Supporting BS1 The NM_000329.3(RPE65):c.95-2A>T variant disrupts a canonical splice site in intron 2 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). At least 6 probands have been reported with this variant, one of whom displayed markedly impaired night vision (0.5 pts), reduced visual acuity 20/60 from an early age (1 pt), nystagmus (1 pt), RPE demelanization (0.5 pts), poor pupillary light response (0.5 pts), significant outer nuclear layer preservation for the severity of visual loss (1 pt), nondetectable ERG responses from rods (0.5 pts) and cones (1 pt), and minimal autofluorescence (2 pts), which together are highly specific for RPE65 retinopathy (8 pts total, PP4_Moderate, PMID: 20604683). The proband's affected sibling II:2 is also homozygous for this variant (PP1). At least 3 probands with the required phenotype of extinguished ERG harbor the variant in the homozygous state (1 point, PMID: 20604683, PMID: 17724218, PMID: 15024725, PM3). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002298, with 3 alleles / 34592 total alleles in the Admixed American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, PM2_Supporting, PM3, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226591/MONDO:0100368/120 2023-12-22 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50859 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0242301 infores:hetionet CHEBI:168396 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0027441 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0002170 infores:hetionet CHEBI:5004 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0030920 infores:hetionet CHEBI:47781 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0003467 infores:hetionet CHEBI:3814 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0003862 infores:hetionet CHEBI:47780 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011206 infores:hetionet CAID:CA253916 biolink:causes MONDO:0015152 infores:clingen CAID:CA253916 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3, PP3, PP1, PM2_Supporting, PS3_Moderate The NM_003494.4: c.895G>A variant in DYSF, which is also known as NM_001130987.2: c.991G>A (p.Gly331Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 299, p.(Gly299Arg). This variant has been reported in at least two individuals with clinical features consistent with LGMD, including confirmed in trans with a pathogenic variant in one patient (NM_003494.4: c.855+1del, 1.0 pt, PMID: 16705711, 28877744; PM3). At least one of these patients had a clinical diagnosis of LGMD and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 16705711; PP4_Strong). This variant has also been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 16705711; PP1). The frequency of this variant in the East Asian population in gnomAD v4.1.0 is 0.00002228 (1/44890 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly299Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). The computational predictor REVEL gives a score of 0.968, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PM3, PP4_Strong, PP1, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA253916/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0011701 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0027424 infores:hetionet NCBITaxon:747 biolink:causes MONDO:0040998 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:747 MONDO:0040998 CHEBI:75722 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0022893 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0442874 infores:hetionet CHEBI:2663 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0036974 infores:hetionet CHEBI:31705 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0006266 infores:hetionet NCBIGene:56916 biolink:causes MONDO:0007507 infores:monarchinitiative not_provided not_provided HGNC:18398 MONDO:0007507 uuid:5a5b0d3e-c961-466b-bce9-76e4a194256e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31397 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0700184 infores:hetionet CHEBI:6887 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0151889 infores:hetionet CHEBI:6741 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0232487 infores:hetionet NCBIGene:20 biolink:causes MONDO:0032930 infores:monarchinitiative not_provided not_provided HGNC:32 MONDO:0032930 uuid:1ca17dd1-96e6-4829-87f5-75751c667564 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6761 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0423791 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0021400 infores:hetionet CHEBI:52717 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2979982 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0011053 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0750857 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0235416 infores:hetionet CHEBI:73274 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0010692 infores:hetionet CHEBI:2618 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0547030 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0004604 infores:hetionet NCBIGene:8676 biolink:causes MONDO:0011336 infores:monarchinitiative not_provided not_provided HGNC:11429 MONDO:0011336 uuid:9f648ad4-2a8a-49c6-a7a5-03bb73882789 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA397722016 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722016 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PM3 The c.63-2A>C variant in ACADVL occurs within the canonical splice acceptor site (+/- 1,2) of intron 1. It is predicted to cause skipping of biologically-relevant-exon 2/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in an abnormal newborn screen without clinical confirmation or a second pathogenic ACADVL variant identified (PMID 26385305, 27209629). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722016/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10585677 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585677 MONDO:0007750 PMID: Likely Pathogenic PM5, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM4, PM1, PM3, PM6, PVS1, PP1, BS2 The NM_000527.5(LDLR):c.1898G>T (p.Arg633Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP4 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows:PM2: Absent from gnomAD version v2.1.1.PP3: REVEL= 0.899. PM5: There is a variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1898G>A (p.Arg633His) (ClinVar ID: 226380).PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills criteria for FH from PMID 16250003 (Fouchier et al., 2005), The Netherlands, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585677/MONDO:0007750/013 2023-11-07 2025-08-26 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6067 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0149745 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0011616 infores:hetionet CHEBI:4657 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0235996 infores:hetionet CHEBI:7852 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1306341 infores:hetionet UNII:R43D2573WO biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0033774 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0152128 infores:hetionet CHEBI:4530 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0013384 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0152128 infores:hetionet CHEBI:36791 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0344232 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0027339 infores:hetionet CHEBI:7986 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0003123 infores:hetionet CHEBI:367163 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0035222 infores:hetionet CHEBI:8107 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0235378 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0035204 infores:hetionet CHEBI:31623 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0012569 infores:hetionet UMLS:C0879264 biolink:causes HP:0033126 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151799 infores:hetionet CHEBI:49662 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0149745 infores:hetionet CHEBI:83804 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0853034 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0041969 infores:hetionet CHEBI:9667 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0151740 infores:hetionet CHEBI:10023 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151908 infores:hetionet CHEBI:3286 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0003467 infores:hetionet CHEBI:31302 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0027497 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0948594 infores:hetionet NCBIGene:4761 biolink:causes MONDO:0032710 infores:monarchinitiative not_provided not_provided HGNC:7763 MONDO:0032710 uuid:eb2c5aa6-0f91-4dc0-b360-80e993e361ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6741 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013447 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0235416 infores:hetionet NCBIGene:5073 biolink:causes MONDO:0014600 infores:monarchinitiative not_provided not_provided HGNC:8609 MONDO:0014600 uuid:4a177f69-f8a5-463e-8409-c14274ecb26b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes HP:0010588 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0151628 infores:hetionet CHEBI:50922 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0012569 infores:hetionet CHEBI:63598 biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003126 infores:hetionet GO:1903587 biolink:causes GO:0002040 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0002040 CHEBI:7824 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0236075 infores:hetionet CHEBI:2666 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0011124 infores:hetionet CHEBI:7494 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0002994 infores:hetionet CHEBI:9398 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0014591 infores:hetionet CHEBI:7565 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0004093 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0003615 infores:hetionet CHEBI:142290 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0031350 infores:hetionet CHEBI:135530 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0030252 infores:hetionet CHEBI:47780 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0497156 infores:hetionet GO:1903251 biolink:causes CL:0005012 infores:ubergraph knowledge_assertion manual_agent GO:1903251 CL:0005012 CHEBI:6402 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C1318520 infores:hetionet CHEBI:135925 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0338831 infores:hetionet CHEBI:6822 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0023530 infores:hetionet CHEBI:36795 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0085593 infores:hetionet CHEBI:6931 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0020440 infores:hetionet GO:0090049 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:0090049 GO:0001568 CHEBI:167309 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0027441 infores:hetionet CHEBI:31236 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0015967 infores:hetionet CHEBI:3478 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0016204 infores:hetionet CHEBI:5098 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0231218 infores:hetionet CHEBI:28787 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0151594 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151883 infores:hetionet NCBIGene:55210 biolink:causes MONDO:0014958 infores:monarchinitiative not_provided not_provided HGNC:25567 MONDO:0014958 uuid:22b66acb-c887-4063-bf07-5d6d506f46df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020453 infores:hetionet CHEBI:6715 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0022107 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0152128 infores:hetionet CHEBI:63622 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0522055 infores:hetionet CHEBI:41423 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0039103 infores:hetionet CAID:CA412729953 biolink:causes MONDO:0100437 infores:clingen CAID:CA412729953 MONDO:0100437 PMID: Pathogenic PP1_Moderate, PVS1, PP4, PS4_Supporting, PM2_Supporting NM_001034853.2(RPGR):c.2716G>T (p.Glu906Ter) is a nonsense variant that introduces a premature stop in codon 906 within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including family history consistent with X-linked inheritance (2 pts), first/second decade onset (1 pt), decreased visual acuity (0.5 pts), cone involvement greater than rod involvement consistent with the variant location after position c.2128 (1 pt), photophobia (1 pt), central scotoma / macular atrophy (1 pt), abnormal color vision (0.5 pts), and pigmentary retinopathy (0.5 pts), which together are specific for RPGR-related retinopathy (7.5 points, PMID: 29769798, PP4). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, in addition to the apparently unrelated proband previously used for the PP4 code (PMID: 17325176, PMID: 29769798, PMID: 22807293; PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 22807293). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, PS4_Supporting, PP4, and PP1_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412729953/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:8802 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0231530 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0240322 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0240322 infores:hetionet CHEBI:4953 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0009806 infores:hetionet CHEBI:8485 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00807 UMLS:C0027540 infores:hetionet CHEBI:7565 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0006145 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0015397 infores:hetionet CAID:CA023780 biolink:causes MONDO:0007750 infores:clingen CAID:CA023780 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.853C>T (p.His285Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003 (0.003%) in European (Non-Finnish) exomes (gnomAD v2.1.1).BP4: REVEL= 0.489, splicing evaluation required.A.) Not on limits.B.) Does not create AG.C.) There is an AG nearby.MES scores: variant cryptic = -2.89, wt cryptic = -4.15Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023780/MONDO:0007750/013 2023-03-24 2024-12-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:68558 biolink:causes UMLS:C1696110 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C1696110 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0022568 infores:hetionet CHEBI:51860 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1384353 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1442826 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0574067 infores:hetionet CHEBI:75246 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0268000 infores:hetionet CHEBI:50648 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0278134 infores:hetionet CAID:CA010365 biolink:causes MONDO:0005045 infores:clingen CAID:CA010365 MONDO:0005045 PMID:8614836PMID:27532257PMID:1975517PMID:1638703PMID:12975413PMID:27532257PMID:1975517PMID:12707239PMID:20800588PMID:7789380PMID:10725281PMID:24268868PMID:1638703PMID:12975413 Pathogenic PP3, PS3, PM1, PM5, PM2, PP1_Strong, PS4 The c.1208G>A (p.Arg403Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy and segregated with disease in >30 affected family members (PS4 and PP1_Strong; PMID:1638703; PMID:1975517; PMID:7789380; PMID:12975413; PMID:24268868; PMID:10725281; PMID:20800588; PMID:12707239; PMID:27532257; AGCMC Sydney ClinVar SCV000692503.1; Invitae ClinVar SCV000253815.4; Partners LMM ClinVar SCV000059359.5; SHaRe consortium, PMID: 30297972). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:8614836). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1207C>T (p.Arg403Trp) - Variation ID 14102). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS3; PS4; PP1_ Strong; PM1; PM2; PM5; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010365/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports UNII:R43D2573WO biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0002888 infores:hetionet CAID:CA397842125 biolink:causes MONDO:0018875 infores:clingen CAID:CA397842125 MONDO:0018875 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting BA1, BP4, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS3, BS4, PP1, PP4, BS2 The NM_000546.6: c.460G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 154 (p.Gly154Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). Computational predictor scores (BayesDel = 0.3308; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP3_Moderate, PM2_Supporting. (Bayesian Points: 3; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397842125/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2379 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0039070 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0017160 infores:hetionet CHEBI:80630 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0009676 infores:hetionet CHEBI:5004 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0002792 infores:hetionet GO:0075329 biolink:causes GO:0044002 infores:ubergraph knowledge_assertion manual_agent GO:0075329 GO:0044002 CHEBI:367163 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0013378 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0011616 infores:hetionet CHEBI:421707 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0033774 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0021053 infores:hetionet CHEBI:6015 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C1258215 infores:hetionet CHEBI:50275 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0852911 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0852995 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0852995 infores:hetionet CHEBI:7809 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0014457 infores:hetionet CHEBI:50692 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C2830004 infores:hetionet CHEBI:367163 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0267797 infores:hetionet CHEBI:46557 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0003862 infores:hetionet CAID:CA2573051041 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051041 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PP4 PP1 The c.1772_1773del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 591 NM_000545.8, adding 57 novel amino acids before encountering a stop codon (p.(Ser591PhefsTer57)). While this variant, located in exon 10 of 10, is not predicted to result in nonsense-mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong; PMID: 23348805). Additionally, this variant was identified in at least one individual with a clinical history specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; [internal lab contributors]). In summary, c.1772_1733del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/25): PVS1_Strong, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051041/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:77260 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0015967 infores:hetionet CAID:CA4239714 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239714 MONDO:0015967 PMID: Likely Benign BS2, PP2, BP2 PM1, BS1, PM2, PP3, PP4, PP1, BP4 The c.142G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 48 (p.(Glu48Lys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The Popmax filtering allele frequency of the c.142G>A variant in gnomAD v2.1.1 is 0.00001685, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. This variant was observed in unknown phase with the variant c.461T>G p.Val154Gly (internal lab contributors), which is classified as likely pathogenic by the ClinGen MDEP, in an individual with a phenotype highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(BP2). This variant segregated with hyperglycemia with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in an individual with normal fasting glucose (BS2; PMID: 23799006, internal lab contributor). This variant has a REVEL score of 0.6959, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. In summary, c.142G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS2, BP2, PP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239714/MONDO:0015967/086 2024-12-26 2024-12-26 Semidominant inheritance HP:0032113 Contradicts true UMLS:C0005740 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0038454 infores:hetionet CHEBI:7565 biolink:causes MONDO:0006846 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0020540 infores:hetionet NCBIGene:7439 biolink:causes MONDO:0007931 infores:monarchinitiative not_provided not_provided HGNC:12703 MONDO:0007931 uuid:8ee30940-093d-4eda-841c-81d66b7b1b50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:780 biolink:causes MONDO:0006956 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:780 MESH:D012282 DB02703_MESH_D012282_1DB00446_MESH_D012282_1DB00254_MESH_D012282_1 UNII:UMD7G2653W biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0242528 infores:hetionet CHEBI:5959 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0851578 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005397 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018021 infores:hetionet CHEBI:3216 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0856054 infores:hetionet CHEBI:2668 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0043349 infores:hetionet CHEBI:28787 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0085631 infores:hetionet CAID:CA658795238 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795238 MONDO:0009290 PMID: Pathogenic PVS1, PM2_Supporting, PM3 PP4 The NM_000152.5:c.827_845del (p.Ile276ThrfsTer32) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with clinical features consistent with late onset Pompe disease, elevated creatine kinase, and histological features of Pompe disease was reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.2238G>C (p.Trp746Cys) (ClinVar variation ID: 265160, SCV002032122.1). The variants were confirmed to be in trans by parental DNA analysis (PMID 27099502) (PM3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specification Version 2.0): PVS1, PM3, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 21, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795238/MONDO:0009290/010 2024-05-21 2024-06-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:161680 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C1368065 infores:hetionet CHEBI:39112 biolink:causes MONDO:0005682 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0006285 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0031117 infores:hetionet CHEBI:15854 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0085631 infores:hetionet CHEBI:4466 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020649 infores:hetionet CHEBI:42944 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0009241 infores:hetionet CAID:CA390864480 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864480 MONDO:0100216 PMID: Uncertain Significance BP4, PM1_Supporting, BS2_Supporting PM2, PVS1, BP2, BA1, PP3, PP1, PP4, PM5, PM4, PS1, PS4, PS2, PS3, BP7, BS1, BS4, BS3 The NM_177438.3:c.5515C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 1839 (p.Arg1839Trp). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001363 (22/1613858 alleles) with a highest population minor allele frequency of 0.00006402 (4/62482 alleles) in a population of unknown ancestry (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.398; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4, PM1_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864480/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5109 biolink:causes UMLS:C0858708 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0858708 infores:hetionet CHEBI:17698 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0010520 infores:hetionet CHEBI:6950 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0003537 infores:hetionet CHEBI:49375 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0542571 infores:hetionet CHEBI:63621 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0041834 infores:hetionet CHEBI:7444 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0011570 infores:hetionet CHEBI:31644 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0010200 infores:hetionet CHEBI:45327 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0028643 infores:hetionet CAID:CA320251220 biolink:causes MONDO:0100083 infores:clingen CAID:CA320251220 MONDO:0100083 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PM2, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1403C>T (p.Pro468Leu) is a missense variant which has a REVEL score < 0.50 (0.05999) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320251220/MONDO:0100083/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:34825 biolink:causes MONDO:0005984 infores:sider not_provided not_provided DRUGBANK:DB08933 UMLS:C0040259 infores:hetionet NCBIGene:200205 biolink:causes MONDO:0014132 infores:monarchinitiative not_provided not_provided HGNC:27302 MONDO:0014132 uuid:3ec7ae98-791e-4888-b344-c09c078717cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6931 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0858797 infores:hetionet CHEBI:44032 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030252 infores:hetionet CHEBI:4702 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0031350 infores:hetionet CAID:CA10568446 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568446 MONDO:0010602 PMID: Benign BA1 BP7, BP4 The c.1508G>A (p.Arg503His) variant is reported at an MAF of 0.01797(342/19037 alleles) in the African/African-American population in gnomAD v2.1.1 with 94 hemizygotes and 3 homozygotes, meeting BA1 criteria of MAF >0.000333. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568446/MONDO:0010602/071 2024-02-01 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:31236 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233763 infores:hetionet CHEBI:45716 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0039070 infores:hetionet NCBIGene:111 biolink:causes MONDO:0030625 infores:monarchinitiative not_provided not_provided HGNC:236 MONDO:0030625 uuid:224b9db7-ac29-478a-8c2c-dc0defa2717d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0013298 infores:hetionet GO:0035477 biolink:causes GO:0048514 infores:ubergraph knowledge_assertion manual_agent GO:0035477 GO:0048514 CHEBI:17303 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0017168 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0030920 infores:hetionet CHEBI:9352 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0011991 infores:hetionet CHEBI:18332 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0033774 infores:hetionet CHEBI:231594 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0232495 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0852952 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0852952 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0038454 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042769 infores:hetionet CHEBI:7494 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0013362 infores:hetionet CHEBI:50663 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0948594 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0242785 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0242785 infores:hetionet NCBIGene:5896 biolink:causes MONDO:0011338 infores:monarchinitiative not_provided not_provided HGNC:9831 MONDO:0011338 uuid:e30949a0-579e-4325-a10f-e432971089a2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0278080 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0278080 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C3263723 infores:hetionet CHEBI:40303 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0852911 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0027765 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006170 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0009759 infores:hetionet CHEBI:2955 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0014868 infores:hetionet CHEBI:28864 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0023067 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0031117 infores:hetionet NCBIGene:23384 biolink:causes MONDO:0010850 infores:monarchinitiative not_provided not_provided HGNC:29022 MONDO:0010850 uuid:a0d683e7-6bbd-411c-a980-208c0706404a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44185 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0151436 infores:hetionet CHEBI:6076 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011603 infores:hetionet CHEBI:4681 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0003862 infores:hetionet CHEBI:144093 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0003467 infores:hetionet CHEBI:3077 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0027497 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151971 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151971 infores:hetionet CHEBI:63791 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0162830 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0003460 infores:hetionet CHEBI:8768 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042024 infores:hetionet CHEBI:8356 biolink:causes HP:0025679 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0012624 infores:hetionet CHEBI:5296 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0151480 infores:hetionet CHEBI:50173 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0020443 infores:hetionet CHEBI:3077 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0085633 infores:hetionet CAID:CA252231 biolink:causes MONDO:0019501 infores:clingen CAID:CA252231 MONDO:0019501 PMID:10729113PMID:26969326 Pathogenic PP1, PP4, PM3_Very Strong BS1, PP3, PM2, BP4, BA1 The c.956G>A variant in USH2A is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 319. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002679 (15/34508 alleles) in the Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.524, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. At least one patient was homozygous for this variant and displayed moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10729113). This variant has been detected in 5 individuals with Usher syndrome. For 5 of those individuals, 4 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by family testing (c.3408T>A (p.Ser1136Arg), c.12067-2A>G, c.5329C>T (p.Arg1777Trp), c.15089C>A (p.S5030X)), (4 PM3 points, PMID: 26969326, 33089500, LMM internal data, EGL internal data). One individual was homozygous for the variant (0.5 PM3 points, PMID:10729113) (PM3_VeryStrong). One of the individuals who was compound heterozygous for the variant and another pathogenic variant in USH2A (RCV000599950.1), had an affected sibling in whom both variants segregated (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP4, PM3_VS, PP1 (Hearing Loss VCEP specifications version 2; 6/15/2022). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA252231/MONDO:0019501/005 2022-08-03 2022-08-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:91541 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C3665347 infores:hetionet CHEBI:64028 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0027849 infores:hetionet CHEBI:75722 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0233477 infores:hetionet CHEBI:2549 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0002792 infores:hetionet GO:2000826 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:2000826 GO:0072359 CHEBI:8874 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0085606 infores:hetionet UMLS:C0657912 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151603 infores:hetionet CAID:CA016495 biolink:causes MONDO:0007947 infores:clingen CAID:CA016495 MONDO:0007947 PMID: Pathogenic PP3, PP4, PM2_Supporting, PS3, PS4, PP1_Strong The NM_000138.5 c.6453C>T variant in FBN1does not result in an amino acid substitution. This variant was found in a proband with thoracic aortic aneurysm and/or dissection, and a systemic score of 8, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent university Hospital) (PP4). This variant has been reported 6 times in ClinVar: 4 times as pathogenic, 2 times as likely pathogenic, and once as variant of uncertain significance (Variation ID: 200193). The variant has been reported in the literature in at least two unrelated individuals with a clinical diagnosis of Marfan syndrome, and in at least four unrelated individuals with clinical features of Marfan syndrome (PMID 26787436, 36517271, 21907952, 32679894, 36517271, InvitaeClinVarentry) (PS4). This variant was also found to segregate with disease in at least 5 affected relatives from multiple families (PMID 21907952, internal data) (PP1_Strong). In silico prediction programs predict that this variant may impact splicing (PP3). RNA functional studies confirmed that this variant results in the creation of a cryptic donor splice site resulting in an abnormal truncated protein (PMID 21907952, 26787436, 32123317) (PS3). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS3, PS4, PP1_Strong, PM2_Sup, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA016495/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:52172 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0004238 infores:hetionet CHEBI:45327 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0041657 infores:hetionet CHEBI:9139 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C2937358 infores:hetionet CHEBI:9654 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0013362 infores:hetionet GO:1901074 biolink:causes GO:0043277 infores:ubergraph knowledge_assertion manual_agent GO:1901074 GO:0043277 CHEBI:3749 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0009806 infores:hetionet CHEBI:82941 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0013182 infores:hetionet CHEBI:10124 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0039520 infores:hetionet CAID:CA401363495 biolink:causes MONDO:0009290 infores:clingen CAID:CA401363495 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM2_Supporting, BP4, PM3_Strong, PS3_Supporting PP3, PM5, PS1 The NM_000152.5:c.796C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 266 (p.Pro266Ser). At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented laboratory values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014) (PP4_Moderate). These patients are all compound heterozygous for the variant and another variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175,), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001333 (1/70356 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843). Additional variants at this amino acid positions have been reported (c.797C>T (p.Pro266Leu); c.796C>A (p.Pro266Thr) (PMID: 29451150); these variants have not been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. The score from the in silico metapredictor REVEL is 0.476 (BP4), which is a single piece of conflicting evidence in comparison with the evidence for pathogenicity. There is a ClinVar entry for this variant (Variation ID:556117, 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, based on the overall evidence, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 3, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401363495/MONDO:0009290/010 2025-06-03 2025-07-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63619 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0011570 infores:hetionet CHEBI:5001 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151746 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0036572 infores:hetionet CHEBI:7824 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0009676 infores:hetionet CHEBI:8346 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0008031 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0005940 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0341164 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0341164 infores:hetionet NCBIGene:51095 biolink:causes MONDO:0014850 infores:monarchinitiative not_provided not_provided HGNC:17341 MONDO:0014850 uuid:4741cf06-4fc5-4846-b7f5-cba84f510bfc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51173 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0039070 infores:hetionet CHEBI:46345 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0008031 infores:hetionet CHEBI:32184 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0520893 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0009319 infores:hetionet CHEBI:4672 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0392699 infores:hetionet CAID:CA3232088 biolink:causes MONDO:0012163 infores:clingen CAID:CA3232088 MONDO:0012163 PMID: Likely Benign BS1 BS2 The c.778G>A (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 260 (p.Ala260Thr). The filtering allele frequency (the lower threshold of the 95% CI of 115/24962) of the c.778G>A variant in IL7R is 0.003885 in exomes and 0.003267 in genomes (no homozygous reported) for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1).The variant has not been identified in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3232088/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:180905 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0917801 infores:hetionet CHEBI:3504 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0011991 infores:hetionet CHEBI:2569 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0235146 infores:hetionet GO:0014037 biolink:causes CL:0000218 infores:ubergraph knowledge_assertion manual_agent GO:0014037 CL:0000218 CHEBI:27504 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0232807 infores:hetionet CAID:CA000434 biolink:causes MONDO:0018875 infores:clingen CAID:CA000434 MONDO:0018875 PMID: Pathogenic PS3, PS2, PS4, PM1, PP4_Moderate, PP3, PM2_Supporting BP4, BA1, PS1, PM5, BS3, BS1, BS2 The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000434/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:727 biolink:causes MONDO:0024355 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:727 MESH:D012141 DB00447_MESH_D012141_1DB01333_MESH_D012141_1DB00671_MESH_D012141_1 CHEBI:465284 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151766 infores:hetionet CHEBI:32293 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0019080 infores:hetionet CHEBI:474180 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020598 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0037199 infores:hetionet CHEBI:9613 biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0162533 infores:hetionet CAID:CA023951 biolink:causes MONDO:0007783 infores:clingen CAID:CA023951 MONDO:0007783 PMID: Uncertain Significance PP1, PS4, BS3_Supporting PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with glutamic acid at codon 3986 of the RYR1 protein, p.(Asp3986Glu). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257; PMID:23558838). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID: 28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in four individuals/families, PP1_Supporting (PMID:28403410). A REVEL score of 0.763 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Variant of Unknown Significance (PMID: 29300386). Criteria implemented: PS4, BS3_Supporting, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023951/MONDO:0007783/012 2022-09-08 2022-09-08 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true UNII:K2J09EMJ52 biolink:causes MONDO:0005775 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C2939465 infores:hetionet CHEBI:84050 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0085605 infores:hetionet CHEBI:18248 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0029442 infores:hetionet CHEBI:4710 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0438717 infores:hetionet CHEBI:46557 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0018681 infores:hetionet CHEBI:64355 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0000737 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0232459 infores:hetionet CAID:CA023637 biolink:causes MONDO:0007750 infores:clingen CAID:CA023637 MONDO:0007750 PMID: Uncertain Significance PM2, PP4, PP3 PS3, PM5 The NM_000527.5 (LDLR): c.2113G>C (p.Ala705Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: PopMAX MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, PMID 11810272).PP3 Met: REVEL score = 0.78, which is above the threshold of 0.75.PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>T (p.Ala705Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023637/MONDO:0007750/013 2022-02-11 2022-04-25 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:6710 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0041582 infores:hetionet CHEBI:42355 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0302295 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0497247 infores:hetionet NCBIGene:134701 biolink:causes MONDO:0014694 infores:monarchinitiative not_provided not_provided HGNC:21390 MONDO:0014694 uuid:1d1e1a77-3181-4a87-933b-05ed13818363 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8069 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0151763 infores:hetionet CHEBI:391960 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0012833 infores:hetionet CHEBI:171719 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0015230 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151717 infores:hetionet CHEBI:17303 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026827 infores:hetionet CAID:CA262105 biolink:causes MONDO:0019501 infores:clingen CAID:CA262105 MONDO:0019501 PMID:26310143PMID:26310143PMID:26338283PMID:26310143PMID:23737954PMID:25356976PMID:26338283PMID:26310143PMID:23737954PMID:25356976 Pathogenic PP4, PP1, PP3, PM2_Supporting, PS4, PM3_Strong BP5, BP7, BS4, BS1, BS2, PM1, PM4, PM5, PVS1, PM6, BP3, BP2, BP4, BA1, PS2, PS3, PS1 The allele frequency of the p.Gly1861Ser variant in USH2A is 0.017% (3/17184) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). This variant has been detected in 4 patients with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3_S; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 26310143). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). Computational prediction tools and conservation analysis suggest that the p.Gly1861Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PM2_P, PP3, PM3_S, PP1, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA262105/MONDO:0019501/005 2018-09-14 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:6887 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0162834 infores:hetionet GO:2001207 biolink:causes GO:0042790 infores:ubergraph knowledge_assertion manual_agent GO:2001207 GO:0042790 NCBIGene:29119 biolink:causes MONDO:0000908 infores:monarchinitiative not_provided not_provided HGNC:2511 MONDO:0000908 uuid:a2e3d314-e6ac-4ba2-85db-bd01647316f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0917801 infores:hetionet GO:0034182 biolink:causes GO:0007064 infores:ubergraph knowledge_assertion manual_agent GO:0034182 GO:0007064 CAID:CA137421 biolink:causes MONDO:0019497 infores:clingen CAID:CA137421 MONDO:0019497 PMID: Benign BP7, BA1, BP4 The filtering allele frequency of the c.429+4G>A variant in CDH23 is 1.13% for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). This silent variant in CDH23 is not predicted by the computational prediction analysis using MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel (BA1, BP7, BP4). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA137421/MONDO:0019497/005 2020-01-15 2020-05-29 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3756 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0231218 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001650 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0149523 infores:hetionet CHEBI:6832 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0344232 infores:hetionet CHEBI:65173 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0040264 infores:hetionet UMLS:C0879264 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0424790 infores:hetionet CHEBI:421707 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0015672 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0037274 infores:hetionet CHEBI:135736 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0404521 infores:hetionet CAID:CA000177 biolink:causes MONDO:0017623 infores:clingen CAID:CA000177 MONDO:0017623 PMID:29706350PMID:26443266PMID:26443266PMID:28097321PMID:21194675 Uncertain Significance PP2, PP3, PM2_Supporting PVS1, PM6, BP7, BP5, BS1, BS3, BS4, BS2, PP1, PP4, PM5, PM4, PM1, PM3, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2 PTEN c.545T>C (p.Leu182Ser) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). Of note, this variant may be disease-causing when present in the homozygous state (PMID: 26443266), but this expert panel curation is based on presence in the heterozygous state. PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.972) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000177/MONDO:0017623/003 2023-12-01 2023-12-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5801 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0151766 infores:hetionet CHEBI:10127 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0042024 infores:hetionet CHEBI:31547 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0851341 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0008301 infores:hetionet CAID:CA226557 biolink:causes MONDO:0100368 infores:clingen CAID:CA226557 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PP4_Moderate, PP1, PM2_Supporting NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) is a missense variant predicted to replace aspartic acid with tyrosine at position 167. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000007020 with 3 alleles / 113490 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 36547097). This variant has also been reported in at least 5 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.16G>T (p.Glu6Ter), NM_000329.3(RPE65):c.292_311del (p.Ile98HisfsTer26), NM_000329.3(RPE65):c.938A>G (p.His313Arg), or NM_000329.3(RPE65):c.778_785del (p.Asn260GlnfsTer18) variants suspected in trans (2 pts, PMID: 11095629, PMID: 35129589, PMID: 25257057), as well as the NM_000329.3(RPE65):c.11+5G>A variant confirmed in trans (1 pt, PMID: 35904185, PMID: 28224992), all of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (3.5 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts, PMID: 25257057), undetectable ERG response from rods (0.5 pts) and reduced ERG responses from cones (1 pt, PMID: 18441371) and significant, documented improvement of retinal sensitivity by dark-adapted perimetry and microperimetry after treatment with RPE65 gene therapy (8 pts, PMID: 25938638), which together are highly specific for RPE65-related recessive retinopathy (total 10 pts, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through a proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 28224992, PP1). The computational predictor REVEL gives a score of 0.93, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226557/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17549 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151717 infores:hetionet CHEBI:3640 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0018965 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0032961 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C2981158 infores:hetionet CHEBI:135566 biolink:causes HP:0100689 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C1096274 infores:hetionet CHEBI:49960 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0085612 infores:hetionet CHEBI:3561 biolink:causes MONDO:0850230 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0263338 infores:hetionet CHEBI:63617 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0013456 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0858277 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0858277 infores:hetionet GO:2000794 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000794 GO:0007275 CHEBI:35553 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0086525 infores:hetionet CAID:CA9870057 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870057 MONDO:0015967 PMID: Likely Benign BP4, BS1 The c.50-4700G>A variant in the HNF4 homeobox A gene, HNF4A, is a single nucleotide variant within intron 1 of NM_175914.5. The computational splicing predictor SpliceAI gives a score of 0.01 for donor loss and 0.00 for acceptor loss, suggesting that the variant has no impact on splicing (BP4). This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00003422, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). In summary, c.50-4700G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1, BP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870057/MONDO:0015967/085 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31644 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0018681 infores:hetionet CHEBI:6801 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0020615 infores:hetionet CHEBI:66903 biolink:causes UMLS:C0232409 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0232409 infores:hetionet CHEBI:10127 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0030554 infores:hetionet CHEBI:2904 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0004093 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0162281 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017675 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027769 infores:hetionet CHEBI:82941 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0027947 infores:hetionet CHEBI:28918 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C1565489 infores:hetionet CAID:CA10605515 biolink:causes MONDO:0015152 infores:clingen CAID:CA10605515 MONDO:0015152 PMID: Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Strong PM5, PM4, PM1, PVS1, PM6, BP1, BP4, BP2, BP3, BA1, BS2, PP2, PP1, BP7, BP5, BS1, BS3, BS4, PS1, PS3, PS2, PS4 The NM_000070.3: c.1524G>A variant in CAPN3 is a synonymous (silent) variant (p.Glu508=) that affects the last nucleotide of exon 11. This variant has been detected in at least seven individuals with LGMD (PMID: 26404900, 17236769, 17994539, 16141003, 32528171; ClinVar SCV001423802.2 internal data communication). Of those individuals, at least three were compound heterozygous, and in at least two, the variant was confirmed in trans with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 2.0 pts, PMID: 17236769, 17994539). In addition, at least one individual was homozygous for the variant (0.5 pts, PMID: 17994539) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3 protein, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17236769). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The SpliceAI prediction score for this variant is 0.66 (donor loss), which is greater than the VCEP threshold of ≥ 0.50 and suggestive of an impact on splicing (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10605515/MONDO:0015152/187 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5132 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0522153 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1258215 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0242350 infores:hetionet NCBIGene:9516 biolink:causes MONDO:0010995 infores:monarchinitiative not_provided not_provided HGNC:16841 MONDO:0010995 uuid:5ecd38b1-709f-45e0-8193-cebbbe6f9a11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA000297 biolink:causes MONDO:0017623 infores:clingen CAID:CA000297 MONDO:0017623 PMID:29785012PMID:29706350 Uncertain Significance PP2, PP3, PM2_Supporting, PS3_Moderate PVS1, PM6, BP5, BP7, BS1, BS3, BS4, BS2, PP1, PP4, PM5, PM4, PM1, PM3, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2 NM_000314.8(PTEN):c.112C>T (p.Pro38Ser) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.515 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM2_P: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant =0.957) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000297/MONDO:0017623/003 2024-02-09 2024-03-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:52717 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034886 infores:hetionet CHEBI:6339 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0018790 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C3263723 infores:hetionet CAID:CA16608795 biolink:causes MONDO:0100039 infores:clingen CAID:CA16608795 MONDO:0100039 PMID: Uncertain Significance PM2_Supporting BS1, PP3, BP4, BA1 The p.Leu644Phe variant in CDKL5 is absent from gnomAD (PM2_Supporting). In summary, the p.Leu644Phe variant in CDKL5 is classified as Uncertain significance based on the ACMG/AMP criteria (VUS). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608795/MONDO:0100039/016 2023-02-20 2023-03-31 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:119915 biolink:causes UMLS:C0151694 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151694 infores:hetionet CHEBI:474053 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0018681 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0006840 infores:hetionet CHEBI:10101 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0002170 infores:hetionet CAID:CA2580100850 biolink:causes MONDO:0100437 infores:clingen CAID:CA2580100850 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.1302dup (p.Leu435SerfsTer18) is a frameshift variant due to 1-nucleotide duplication in exon 11 of 15 introducing a premature stop codon after 18 amino acids, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a family history consistent with X-linked inheritance (2 pts) with female relatives presenting with a milder phenotype (1 pt), early onset (1 pt), electroretinogram responses consistent with diagnosis of retinitis pigmentosa (0.5 pts), night blindness (0.5 pts), progressive visual loss (0.5 pts), hearing loss, and genotyping by whole exome sequencing that did not identify an alternative basis for retinal disease (2 pts), which together are specific for RPGR-related retinopathy (7.5 points, PMID: 38404254, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580100850/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Supports NCBIGene:5296 biolink:causes MONDO:0011313 infores:monarchinitiative not_provided not_provided HGNC:8980 MONDO:0011313 uuid:a11aafad-cbe0-438a-b303-d327743fdce4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8378 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0042109 infores:hetionet CHEBI:4453 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0018681 infores:hetionet CHEBI:9654 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0033860 infores:hetionet CHEBI:63115 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0151517 infores:hetionet CHEBI:63599 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0015230 infores:hetionet CHEBI:9939 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0011603 infores:hetionet CHEBI:41423 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0020580 infores:hetionet CHEBI:5138 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0030554 infores:hetionet CHEBI:6129 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0030920 infores:hetionet CHEBI:5613 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0086439 infores:hetionet CHEBI:63621 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0600142 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0012833 infores:hetionet CHEBI:4657 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0000731 infores:hetionet CAID:CA410149567 biolink:causes MONDO:0011071 infores:clingen CAID:CA410149567 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP2, BP3, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM3, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.965C>G (p.Ser322Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). It is not expected to undergo nonsense-mediated decay, and the resulting frameshift affects positions c.759-c.1440 as per VCEP specifications, which are critical for protein function (PVS1_Strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410149567/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042510 infores:hetionet CHEBI:3437 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0428977 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034150 infores:hetionet CHEBI:71417 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0013362 infores:hetionet CHEBI:3219 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0025874 infores:hetionet CHEBI:66899 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0155169 infores:hetionet CHEBI:4530 biolink:causes MONDO:0005149 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C2973725 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034882 infores:hetionet CHEBI:2666 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0036572 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0349506 infores:hetionet CAID:CA267691 biolink:causes MONDO:0009861 infores:clingen CAID:CA267691 MONDO:0009861 PMID:26666653 Pathogenic PVS1, PM2, PP4 The c.155delT (p.Leu52Cysfs) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 1 individual with PKU (BH4 deficiency not excluded), who carried a second nonsense variant in PAH (PP4; PMID: 26666653 ). This variant is absent from population databases (PM2). In summary, this variant meets our criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267691/MONDO:0009861/006 2019-04-03 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4708 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0700590 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0038362 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0424230 infores:hetionet GO:0043379 biolink:causes CL:0000813 infores:ubergraph knowledge_assertion manual_agent GO:0043379 CL:0000813 CHEBI:64355 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0948594 infores:hetionet CAID:CA295247 biolink:causes MONDO:0018997 infores:clingen CAID:CA295247 MONDO:0018997 PMID:29493581PMID:16329078PMID:21438134 Pathogenic PS4_Moderate, PM1, PM2, PS2_Very Strong, PP2, PP3 The c.37G>T (p.Gly13Cys) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly13Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA295247/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:44423 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1291078 infores:hetionet NCBIGene:4000 biolink:causes MONDO:0011569 infores:monarchinitiative not_provided not_provided HGNC:6636 MONDO:0011569 uuid:8198441a-3ce9-4918-aa22-ea599efa7bc8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4910 biolink:causes UMLS:C0858765 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0858765 infores:hetionet CHEBI:45599 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0018681 infores:hetionet CHEBI:5118 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0028961 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0948586 infores:hetionet CHEBI:6717 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0018802 infores:hetionet CHEBI:41977 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0004093 infores:hetionet CAID:CA658658491 biolink:causes MONDO:0007648 infores:clingen CAID:CA658658491 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting BP7, BP5, BS1, BS4, BS3, PM4, PM1, PM3, PM6, PP1, PP2, PP3, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.1590dup (p.Asn531fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). This variant has been reported in a family meeting HDGC clinical criteria (PS4_Supporting, PMID: 10477433). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658491/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CAID:CA658656804 biolink:causes MONDO:0100083 infores:clingen CAID:CA658656804 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, PM6, PVS1, BS1, BS3, BS4, PM5, PM4, PM1, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.351+5T>C is an intronic variant has spliceAI ∆ scores ≤ 0.20 (BP4)Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score (0.3) < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7).This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658656804/MONDO:0100083/008 2022-08-23 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63635 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0030312 infores:hetionet CHEBI:92712 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0042510 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004245 infores:hetionet CHEBI:724125 biolink:causes UMLS:C0919599 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0919599 infores:hetionet CHEBI:17823 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0004093 infores:hetionet CHEBI:71255 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0026837 infores:hetionet NCBITaxon:5807 biolink:causes MONDO:0015474 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5807 MONDO:0015474 CHEBI:75722 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013404 infores:hetionet CHEBI:6339 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0032584 infores:hetionet NCBIGene:10324 biolink:causes MONDO:0014326 infores:monarchinitiative not_provided not_provided HGNC:16905 MONDO:0014326 uuid:df8bd9a7-0bb7-4a83-a7f7-6b57253c83b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4887 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0021053 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0011616 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0011570 infores:hetionet CAID:CA16606643 biolink:causes MONDO:0007113 infores:clingen CAID:CA16606643 MONDO:0007113 PMID: Likely Benign BP4, BP7 BS1 The c.1212C>T p.Pro404= variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0062% in the European (non-Finnish) sub population (no criteria met). The silent p.Pro404= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1212C>T p.Pro404= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606643/MONDO:0007113/032 2023-06-16 2023-06-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8665 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0009676 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0948089 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013395 infores:hetionet CHEBI:61049 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0042029 infores:hetionet CHEBI:125354 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0004093 infores:hetionet CHEBI:3312 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0015230 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0012311 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0085702 infores:hetionet CHEBI:63598 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0267797 infores:hetionet CHEBI:50841 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0020517 infores:hetionet CHEBI:6456 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0006266 infores:hetionet CHEBI:8764 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0020621 infores:hetionet CHEBI:39867 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0262988 infores:hetionet CHEBI:9674 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0037672 infores:hetionet CHEBI:43968 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C2830004 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0006145 infores:hetionet CHEBI:31709 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0151828 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0235004 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0235004 infores:hetionet CHEBI:16914 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00936 UMLS:C0009806 infores:hetionet CHEBI:31709 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0017178 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002331 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027720 infores:hetionet CHEBI:9674 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0013144 infores:hetionet CHEBI:64321 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0004093 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0242350 infores:hetionet CHEBI:71219 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C2363731 infores:hetionet CHEBI:32293 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0162830 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0438173 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0438173 infores:hetionet CHEBI:50777 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0022107 infores:hetionet CHEBI:681850 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C1384353 infores:hetionet CHEBI:5106 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0152227 infores:hetionet CHEBI:31981 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0085611 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1384353 infores:hetionet CHEBI:617099 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0231218 infores:hetionet CAID:CA8815303 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815303 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PP3, PM3, PM5 The NM_000152.5c.1392G>C variant in GAA is a missense variant predicted to cause substitution of Arginine by Serine at amino acid 464 (p.Arg464Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (13/128364 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.634 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Another missense variant c.1390A>T, p.Arg464Trp in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 843677). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP. There is a ClinVar entry for this variant (Variation ID: 432217, 1 star review status) with 4 submitters classifying the variant as Uncertain Significance and 1 submitter classifying the variant as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815303/MONDO:0009290/010 2022-09-19 2022-09-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true UMLS:C1709429 biolink:causes NCIT:C185320 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0349410 infores:hetionet CHEBI:48538 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0009806 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0024115 infores:hetionet CHEBI:70735 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0012833 infores:hetionet CHEBI:4511 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0011603 infores:hetionet CHEBI:41977 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0013604 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0017160 infores:hetionet CHEBI:31236 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1291077 infores:hetionet CAID:CA415080522 biolink:causes MONDO:0010305 infores:clingen CAID:CA415080522 MONDO:0010305 PMID:30885608 Likely Pathogenic PP3, PM2_Supporting, PP4_Strong PS4, PS3 The NM_005629.4:c.757G>C variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a glycine for an arginine at amino acid 253 (p.Gly253Arg). This variant has been previously reported in one male individuals(PMID: 23644449, PMID: 22713831) (PS4_Supporting) who had elevated urinary creatine/creatinine, undetectable creatine uptake in fibroblasts, and reduced creatine peak on brain MRS (PMID: 22713831) (PP4_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.90 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415080522/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:71272 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0020517 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0549209 infores:hetionet CHEBI:28925 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0014742 infores:hetionet CHEBI:28748 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0038367 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0033860 infores:hetionet CHEBI:6339 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0037763 infores:hetionet CHEBI:584020 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0020651 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0040034 infores:hetionet CHEBI:520985 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0014591 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0269002 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0269002 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0027765 infores:hetionet CHEBI:63638 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0006277 infores:hetionet CHEBI:101278 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0036974 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0521501 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0521501 infores:hetionet CHEBI:134966 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0392525 infores:hetionet CHEBI:132233 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0027497 infores:hetionet CHEBI:6375 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014742 infores:hetionet CHEBI:7573 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0002871 infores:hetionet CHEBI:63608 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0033774 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0151773 infores:hetionet CHEBI:8874 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C2242737 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549369 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549369 infores:hetionet CHEBI:8214 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0018802 infores:hetionet CHEBI:37924 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0011603 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0948594 infores:hetionet CHEBI:6923 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C1963790 infores:hetionet CAID:CA512341319 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341319 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1083C>T (p.Thr361=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.87)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341319/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9435 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0344232 infores:hetionet CHEBI:5100 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0349506 infores:hetionet CHEBI:7903 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0004604 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0042769 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020615 infores:hetionet CHEBI:5778 biolink:causes HP:0003365 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0019559 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0267792 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0033117 infores:hetionet CHEBI:8805 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0948089 infores:hetionet CHEBI:63599 biolink:causes NCIT:C2979 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0010828 infores:hetionet CHEBI:45409 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151825 infores:hetionet CHEBI:47898 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0600142 infores:hetionet CHEBI:3723 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233763 infores:hetionet NCBIGene:56776 biolink:causes MONDO:0014524 infores:monarchinitiative not_provided not_provided HGNC:14074 MONDO:0014524 uuid:5a783b8e-cad6-4102-a99e-141b86c33a4b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017574 infores:hetionet CHEBI:79699 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0232849 infores:hetionet CHEBI:45599 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0220983 infores:hetionet CHEBI:63577 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0011175 infores:hetionet CHEBI:3561 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0009806 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0221752 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0221752 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0010399 infores:hetionet CHEBI:6015 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0026837 infores:hetionet CAID:CA222174 biolink:causes MONDO:0015152 infores:clingen CAID:CA222174 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1 PM2 The NM_003494.4: c.4756C>T p.(Arg1586Ter) variant in DYSF, which is also known as NM_001130987.2: c.4873C>T p.(Arg1625Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 43/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least five patients with features consistent with LGMD (PMID: 36983702; 23641709; 23530687; 11468312), including in a homozygous state in one individual without reported familial consanguinity (0.5 pts, PMID: 11468312) and in trans with a likely pathogenic or pathogenic variant in two individuals (NM_003494.4: c.265C>T p.(Arg89Ter), 1.0 pt, PMID: 23641709; NM_003494.4: c.3113G>C p.(Arg1038Pro), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 36983702; 33610434). The filtering allele frequency of this variant is 0.0001061 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 4/86258 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/16/2025): PVS1, PM3_Strong, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222174/MONDO:0015152/180 2025-04-16 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4858 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0040264 infores:hetionet CHEBI:28748 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0027540 infores:hetionet CHEBI:2038 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0018681 infores:hetionet GO:1903023 biolink:causes GO:0032989 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0032989 CHEBI:9727 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0013144 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0035078 infores:hetionet CHEBI:9137 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0022904 infores:hetionet CHEBI:42068 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0333355 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0007971 infores:hetionet CHEBI:116278 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0027769 infores:hetionet CHEBI:4710 biolink:causes HP:0002918 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0151714 infores:hetionet CHEBI:480999 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0027540 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0037822 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0332534 infores:hetionet CHEBI:31401 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0020473 infores:hetionet CHEBI:28593 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0011603 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0851341 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0553702 infores:hetionet CHEBI:3228 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0027497 infores:hetionet CHEBI:63115 biolink:causes UMLS:C0856120 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0856120 infores:hetionet CHEBI:7824 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0036572 infores:hetionet CHEBI:6710 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0030446 infores:hetionet CAID:CA271909 biolink:causes MONDO:0018947 infores:clingen CAID:CA271909 MONDO:0018947 PMID: Pathogenic PP3, PM2_Supporting, PS3_Moderate, PS4, PM6 BA1, BP4, BS1, PM1 The c.614C>T variant in MTM1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 205. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which is above the Congenital Myopathies VCEP threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in at least ten individuals with centronuclear myopathy (PS4; PMIDs: 28685322, 11793470, 8640223, 15725586, 10063835). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with X-linked centronuclear myopathy. (PM6; PMID: 10063835). A phosphatase assay using recombinant human myotubularin as a fusion protein in E. coli, showed that the mutation dramatically reduced phosphatase activity, indicating that this variant may impact protein function (PS3_Moderate; PMID: 10900271). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PM6, PS3_Moderate, PP3, PM2_Supporting. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA271909/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:45367 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0000737 infores:hetionet CHEBI:66901 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0017178 infores:hetionet CHEBI:59750 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00223 UMLS:C0162820 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0403632 infores:hetionet CHEBI:2788 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0013604 infores:hetionet CHEBI:15367 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020473 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0039971 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002043 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013592 infores:hetionet CAID:CA402990982 biolink:causes MONDO:0012999 infores:clingen CAID:CA402990982 MONDO:0012999 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong, PS3_Supporting The NM_000156.6:c.590T>C variant in GAMT is a missense variant predicted to cause substitution of leucine by proline at amino acid 197 (p.Leu197Pro). This variant has been detected in two unrelated individuals with GAMT deficiency. Of those individuals, one was compound heterozygous for the variant and a likely pathogenic variant, c.526delG, in unknown phase (PMID: 19288536) and one individual was homozygous for the variant (PMID: 16293431) (0.75 points total) (PM3_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). One patient with this variant had elevated GAA with low creatine in plasma and elevated GAA with low creatine in urine (PMID: 19288536) and another patient with this variant had elevated GAA with low creatine in plasma, elevated GAA with low creatine in urine, absent creatine peak on brain MRS (PMID: 16293431) (PP4_Strong). Expression of the variant in GAMT-deficient human fibroblast cell line resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.925 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1,0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP4_Strong, PP3.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA402990982/MONDO:0012999/026 2023-05-25 2023-05-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49575 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0574067 infores:hetionet CAID:CA262122 biolink:causes MONDO:0019501 infores:clingen CAID:CA262122 MONDO:0019501 PMID:19023448PMID:19023448PMID:24853665PMID:19023448PMID:25133613PMID:26338283PMID:19737284PMID:25356976PMID:24853665PMID:19023448PMID:25133613PMID:26338283PMID:19737284PMID:25356976PMID:20596040 Pathogenic PP1_Strong, PP4, PM2_Supporting, PM3_Very Strong, PM4 BS1, BS4, BP7, BP5, BS2, PP3, PM1, PM5, PM6, PVS1, BA1, BP2, BP4, BP3, PS3, PS2, PS4, PS1 The c.8559-2A>G has been detected in >4 patients with Usher syndrome who were compound heterozygous for the this variant in trans with a truncating variant (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). Segregation data was also available for two reported families with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (PM4, PMID: 20596040) The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss and Usher syndrome (PM2_Supporting). Several patients reported to harbor this variant displayed clinical features of Usher syndrome (PP4; PMID: 25356976, 19737284, 26338283, 19023448). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM4, PM3_VS, PP1_S, PP4, PM2_P. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA262122/MONDO:0019501/005 2018-10-09 2019-07-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:6129 biolink:causes UMLS:C0423285 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0423285 infores:hetionet CHEBI:2453 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0002874 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0151826 infores:hetionet CHEBI:63580 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0010520 infores:hetionet NCBIGene:54938 biolink:causes MONDO:0013458 infores:monarchinitiative not_provided not_provided HGNC:17697 MONDO:0013458 uuid:c2b95607-7ae3-472e-90a5-51619022c5de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0018784 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018799 infores:hetionet CHEBI:53766 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0011991 infores:hetionet CHEBI:9654 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0235267 infores:hetionet CHEBI:31623 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0035305 infores:hetionet CHEBI:49575 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0000737 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0549444 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0549444 infores:hetionet CAID:CA934459766 biolink:causes MONDO:0100316 infores:clingen CAID:CA934459766 MONDO:0100316 PMID: Uncertain Significance PM2_Supporting, BP4 BP7 NM_000218.3(KCNQ1):c.604+3_604+6dup is a variant in intron 3 that duplicates four base pairs adjacent to exon 3. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.000002542, with 3 alleles / 1,179,978 total alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.07 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing (BP4). This intronic variant is located within one of the regions immediately flanking the exon (between +1 and +7 or between -1 and -21), and so is not eligible for the BP7 code. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PM2_Supporting and BP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA934459766/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7789 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0002874 infores:hetionet CHEBI:84500 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0021177 infores:hetionet CHEBI:7514 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0948594 infores:hetionet CHEBI:7915 biolink:causes HP:0005542 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151563 infores:hetionet CHEBI:15365 biolink:causes GO:0007596 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0005778 infores:hetionet CHEBI:7640 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C1443060 infores:hetionet CHEBI:4659 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0086525 infores:hetionet CHEBI:63621 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0019209 infores:hetionet CHEBI:28787 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0085649 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0037274 infores:hetionet CHEBI:3698 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0035455 infores:hetionet CHEBI:8212 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0015230 infores:hetionet CAID:CA208666 biolink:causes MONDO:0010726 infores:clingen CAID:CA208666 MONDO:0010726 PMID: Uncertain Significance BP5, PM2_Supporting BP4, BS4, PP3 The p.Cys413Arg variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_Supporting). The p.Cys413Arg variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary the p.Cys413Arg variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208666/MONDO:0010726/032 2023-05-05 2023-06-21 X-linked inheritance HP:0001417 Inconclusive true CHEBI:4798 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0036104 infores:hetionet NCBIGene:8632 biolink:causes MONDO:0032845 infores:monarchinitiative not_provided not_provided HGNC:2946 MONDO:0032845 uuid:42f93f5f-84e0-4153-869b-bff032a6694d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8228 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C3665347 infores:hetionet CHEBI:4995 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0013428 infores:hetionet CHEBI:2682 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0085649 infores:hetionet CHEBI:27786 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0039231 infores:hetionet CHEBI:16796 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0033774 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0162287 infores:hetionet CHEBI:35553 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0004134 infores:hetionet CHEBI:7852 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0006277 infores:hetionet GO:0039635 biolink:causes GO:0009252 infores:ubergraph knowledge_assertion manual_agent GO:0039635 GO:0009252 CAID:CA343718468 biolink:causes MONDO:0020367 infores:clingen CAID:CA343718468 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.407G>T variant in MYOC is a missense variant predicted to cause substitution of Arginine by Isoleucine at amino acid 136 (p.Arg136Ile). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.062, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (https://doi.org/10.21203/rs.3.rs-270413/v1), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343718468/MONDO:0020367/019 2022-12-14 2022-12-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31644 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0006266 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003864 infores:hetionet CHEBI:8228 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0011991 infores:hetionet CHEBI:135351 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0018524 infores:hetionet CHEBI:7959 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0020507 infores:hetionet CHEBI:2637 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0595916 infores:hetionet CHEBI:9168 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0002792 infores:hetionet CHEBI:64355 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0424295 infores:hetionet CHEBI:77260 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0014518 infores:hetionet NCBIGene:9851 biolink:causes MONDO:0014932 infores:monarchinitiative not_provided not_provided HGNC:29110 MONDO:0014932 uuid:c6e2282e-bdda-4f2d-bbc2-4c9ff5eea42e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9448 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0011606 infores:hetionet NCBIGene:58484 biolink:causes MONDO:0014498 infores:monarchinitiative not_provided not_provided HGNC:16412 MONDO:0014498 uuid:e2bd4984-e109-49dd-b913-d6e1c8ca7d59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5959 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0011849 infores:hetionet CHEBI:8884 biolink:causes HP:0005317 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C1867423 infores:hetionet CAID:CA134601 biolink:causes MONDO:0015280 infores:clingen CAID:CA134601 MONDO:0015280 PMID: Pathogenic PP3, PP2, PM6_Very Strong, PM2_Supporting, PS4_Moderate BA1, BP4, BS1 The c.275T>G variant in the MAP2K1 gene is a missense variant predicted to cause substitution of leucine by arginine at amino acid 92 (p.Leu92Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.793 (PP3). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in 4 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 2 as unconfirmed de novo occurrences (PS4_Moderate, PM6_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5, PMID: 35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM6_VeryStrong, PS4_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134601/MONDO:0015280/045 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:199857 biolink:causes MONDO:0033572 infores:monarchinitiative not_provided not_provided HGNC:28287 MONDO:0033572 uuid:75b90c54-f286-4e0a-8c10-9da14fd5e8ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:261649 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0027497 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0006266 infores:hetionet CHEBI:8077 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00925 UMLS:C0013144 infores:hetionet CHEBI:6402 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0029944 infores:hetionet CHEBI:61033 biolink:causes MONDO:0018048 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0272285 infores:hetionet CAID:CA2573135709 biolink:causes MONDO:0015152 infores:clingen CAID:CA2573135709 MONDO:0015152 PMID: Pathogenic PM3, PP4_Strong, PS1, PVS1_Moderate, PM2_Supporting The NM_003494.4: c.2643+5G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+5G>A, occurs in a splice donor motif in intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids. Skipping of exon 25 was confirmed by RNAseq (PMID 36983702; PVS1_Moderate_RNA). This variant has been identified in at least one individual with features consistent with LGMD, where it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 0.5 pts, PMID: 33610434, 36983702; PM3_Supporting). This patient displayed progressive weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702). The highest population minor allele frequency is 0.000001695 (2/11800362 alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another nucleotide change affecting the same splice site and with the same experimentally demonstrated splice effect, NM_003494.4: c.2643+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP(LGMD VCEP specifications version 1.0.0; 03/18/2025): PVS1_Moderate_RNA, PM3_Supporting, PP4_Strong, PS1, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573135709/MONDO:0015152/180 2025-03-18 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7494 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020649 infores:hetionet GO:0061101 biolink:causes CL:0000165 infores:ubergraph knowledge_assertion manual_agent GO:0061101 CL:0000165 CHEBI:8764 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0041948 infores:hetionet CHEBI:33325 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0027540 infores:hetionet CHEBI:7824 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0017178 infores:hetionet CHEBI:49375 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0333243 infores:hetionet CHEBI:46195 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0231218 infores:hetionet CAID:CA409118697 biolink:causes MONDO:0007064 infores:clingen CAID:CA409118697 MONDO:0007064 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting The c.975+1G>A (NM_000022.4) variant in ADA occurs within the canonical splice site donor of intron 10. It is expected to disrupt RNA splicing, disrupting the reading frame, and is predicted to undergo NMD. (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 2/1111992 alleles) of the c.975+1G>A variant in ADA is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.At least one patient with this variant displayed * Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), which is highly specific for ADA SCID (PP4_Moderate, PMID: 8227344).In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PVS1, PM2_Supporting, and PP4_Moderate. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409118697/MONDO:0007064/114 2024-02-21 2024-02-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7565 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0037763 infores:hetionet CHEBI:51230 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0392163 infores:hetionet CHEBI:64321 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C1384353 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0700184 infores:hetionet CHEBI:7465 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1443060 infores:hetionet CHEBI:45783 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0041969 infores:hetionet CHEBI:17334 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0040264 infores:hetionet NCBIGene:3572 biolink:causes MONDO:0030756 infores:monarchinitiative not_provided not_provided HGNC:6021 MONDO:0030756 uuid:dba6545d-03d0-46e5-a581-642cd27d67f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0553732 infores:hetionet CHEBI:63589 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0232462 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1609512 infores:hetionet CHEBI:5130 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0085636 infores:hetionet CHEBI:8802 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0002792 infores:hetionet CHEBI:37941 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0039070 infores:hetionet CHEBI:9435 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0232487 infores:hetionet CHEBI:15553 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0085593 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0011849 infores:hetionet CHEBI:499361 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0040034 infores:hetionet CHEBI:6129 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0423791 infores:hetionet CAID:CA410147792 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147792 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1201C>T (p.Pro401Ser) is a missense variant which has a REVEL score under 0.5 (0.15) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147792/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:214035 biolink:causes MONDO:0019498 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:214035 MONDO:0019498 CHEBI:4514 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0085633 infores:hetionet CAID:CA16020885 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020885 MONDO:0009861 PMID: Uncertain Significance PP4_Moderate, PM2, PP3 PM5, PM3 The c.886G>C (p.Asp296His) variant in PAH has been reported in a PKU patient from mainland China, BH4 deficiency assessed (PMID: 26503515). A change to glycine at the same codon has been observed associated with phenylketonuria. This variant is absent from 1000G, ESP, and gnomAD databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.949. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020885/MONDO:0009861/006 2019-07-14 2019-07-14 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9168 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151838 infores:hetionet CHEBI:16586 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0002792 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0004134 infores:hetionet CHEBI:3752 biolink:causes MONDO:0018271 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0206093 infores:hetionet CHEBI:9649 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0002878 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0027051 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0340464 infores:hetionet CAID:CA410206667 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206667 MONDO:0011071 PMID: Pathogenic PVS1, PS4_Supporting, PM2_Supporting PS1, PS2, PS3, BA1, BP2, BP3, BP1, BP4, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM3, PM4, PM1, PP1, PP2, PP3, BS2 The c.796C>T (p.Gln266Ter) variant in RUNX1 (NM_001754.5) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2, v3, and v4 (PM2_Supporting). The variant has been reported in many individuals with AML (PMID: 27881874; PMID: 29988082; PMID: 36819173; PMID: 37680325; PMID: 38418452; PMID: 39725148), MDS (PMID: 27210295), or CMML (PMID: 20421268), as well as in various solid tumors (PMID: 36969747; cBioPortal; COSMIC). The only confirmed germline instance was in a 16yo male with AML whose father with mild thrombocytopenia and asymptomatic brother were also carriers (PMID: 36819173) (PS4_Supporting). In addition, other nonsense/frameshift variants have been reported as pathogenic/likely pathogenic in exon 8 (PMID: 35764482). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PS4_Supporting, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval) Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206667/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:63419 biolink:causes MONDO:0000245 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:63419 MONDO:0000245 CHEBI:3561 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0013428 infores:hetionet UMLS:C0657912 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026827 infores:hetionet CHEBI:6754 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0012833 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004096 infores:hetionet CHEBI:50777 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0232849 infores:hetionet CHEBI:16469 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0025345 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0231528 infores:hetionet CHEBI:27666 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0014868 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0004936 infores:hetionet CHEBI:5147 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0004093 infores:hetionet CHEBI:3082 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0155169 infores:hetionet CHEBI:4453 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0221717 infores:hetionet CHEBI:5103 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0036973 infores:hetionet CHEBI:6832 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0040046 infores:hetionet CHEBI:48390 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0085649 infores:hetionet CHEBI:135613 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0236000 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0037274 infores:hetionet CHEBI:27666 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0020517 infores:hetionet CAID:CA354449503 biolink:causes MONDO:0009276 infores:clingen CAID:CA354449503 MONDO:0009276 PMID: Likely Pathogenic PVS1_Strong, PM3_Supporting, PP4, PP1, PM2_Supporting The c.450G>A (p.Trp150Ter) variant in GP9 is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove 15% of the protein (PVS1_Strong). This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patient (Case in PMID: 20497174) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Surface expression of GP1BA and GP9 were absent. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. This individual was homozygous for the variant (PM3_supporting, PMID:20497174). In PMID: 20497174, all 12 older siblings of the proband (III:1) died of bleeding but were not genotyped, there are several known heterozygous family members: the mother (II:3) and older cousin (III:2) had decreased expression of GP9 and GPP1BA (PP1). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_strong, PM2_supporting, PP4, PP1, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA354449503/MONDO:0009276/083 2025-05-01 2025-05-02 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44032 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030554 infores:hetionet CHEBI:23765 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151937 infores:hetionet CHEBI:51860 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0028768 infores:hetionet UMLS:C0010592 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0016382 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0013781 infores:hetionet CHEBI:8435 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0340865 infores:hetionet CHEBI:5613 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0162830 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1167965 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0595883 infores:hetionet CHEBI:6912 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0027497 infores:hetionet NCBIGene:4632 biolink:causes MONDO:0034109 infores:monarchinitiative not_provided not_provided HGNC:7582 MONDO:0034109 uuid:2b54c5df-b8a1-4869-a9e7-2798aafa6140 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28177 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0015376 infores:hetionet CAID:CA7435334 biolink:causes MONDO:0007113 infores:clingen CAID:CA7435334 MONDO:0007113 PMID: Uncertain Significance BS1 The c.*4A>G variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0068% in the European (non-Finnish) sub population (no criteria met). In summary, the c.*4A>G variant in UBE3A is classified as Variant of Uncertain Significance based on the ACMG/AMP criteria (no criteria met). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA7435334/MONDO:0007113/032 2023-06-15 2023-06-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2668 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0032617 infores:hetionet CHEBI:6062 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0085593 infores:hetionet NCBIGene:5318 biolink:causes MONDO:0012180 infores:monarchinitiative not_provided not_provided HGNC:9024 MONDO:0012180 uuid:12ce6c2c-6a5a-45fc-85b7-5c78df9e23d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0032285 infores:hetionet CHEBI:72297 biolink:causes HP:6000060 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0001707 infores:hetionet CHEBI:72690 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0041364 infores:hetionet CHEBI:87681 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0003467 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0948594 infores:hetionet CHEBI:9130 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0038450 infores:hetionet CHEBI:83531 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0233407 infores:hetionet CHEBI:4315 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0039070 infores:hetionet CHEBI:100241 biolink:causes HP:0012088 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0278045 infores:hetionet CHEBI:32139 biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C2748540 infores:hetionet CHEBI:119573 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0032617 infores:hetionet CHEBI:5103 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0033975 infores:hetionet NCBIGene:3674 biolink:causes MONDO:0031332 infores:monarchinitiative not_provided not_provided HGNC:6138 MONDO:0031332 uuid:7a2d752f-24e2-426f-9a38-035d7ef18536 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50693 biolink:causes UMLS:C0750194 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0750194 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0026848 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0012797 infores:hetionet CHEBI:63618 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0032533 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0232492 infores:hetionet CHEBI:107736 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0549622 infores:hetionet CAID:CA347220794 biolink:causes MONDO:0015152 infores:clingen CAID:CA347220794 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Supporting, PVS1, PM2_Supporting The NM_003494.4: c.3477C>A p.(Tyr1159Ter) variant in DYSF, which is also known as NM_001130987.2: c.3531C>A p.(Tyr1177Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 32/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two individuals with features consistent with LGMD (PMID: 18853459), including in unknown phase with a pathogenic variant (NM_003494.4: c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 18853459) (PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 18853459). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 07/29/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347220794/MONDO:0015152/180 2025-07-29 2025-08-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0234215 infores:hetionet CHEBI:4445 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0476273 infores:hetionet CHEBI:134966 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0344232 infores:hetionet GO:2000495 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:2000495 GO:0150063 UMLS:C1738934 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0011053 infores:hetionet CHEBI:49668 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0018965 infores:hetionet GO:0072124 biolink:causes GO:0072109 infores:ubergraph knowledge_assertion manual_agent GO:0072124 GO:0072109 UMLS:C0657912 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085684 infores:hetionet CHEBI:135342 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0264886 infores:hetionet CHEBI:10127 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151905 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0521839 infores:hetionet CHEBI:101853 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0006840 infores:hetionet CAID:CA400031593 biolink:causes MONDO:0100326 infores:clingen CAID:CA400031593 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3:c.92G>A variant in ITGB3 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 31 (p.Cys31Tyr). This variant has been observed in homozygosity in one individual (GT39 in PMID: 19691478) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.848, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400031593/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6759 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0003467 infores:hetionet CHEBI:8382 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0022107 infores:hetionet CHEBI:44185 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0149745 infores:hetionet CHEBI:9674 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0687713 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0853117 infores:hetionet CHEBI:9168 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0040053 infores:hetionet CHEBI:75984 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0151907 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0020456 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0178298 infores:hetionet CHEBI:101085 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0023530 infores:hetionet CHEBI:17303 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0020429 infores:hetionet GO:1902733 biolink:causes GO:0003417 infores:ubergraph knowledge_assertion manual_agent GO:1902733 GO:0003417 CHEBI:31624 biolink:causes MONDO:0005266 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0011884 infores:hetionet CHEBI:41774 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0025345 infores:hetionet CHEBI:92712 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0024205 infores:hetionet CHEBI:50173 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151691 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018099 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019348 infores:hetionet CAID:CA10644611 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644611 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5:c.*4003C>T is a 3' UTR variant located in exon 9. Although absent in gnomAD v2.1.1, this variant has been found in four individuals in gnomAD v3.1.2 (MAF: 0.00002629). Additionally, this variant has not been reported in any patients with RUNX1-related diseases. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644611/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:F64QU97QCR biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0040046 infores:hetionet CHEBI:31348 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0017181 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042267 infores:hetionet CHEBI:63635 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0151723 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0235492 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0235492 infores:hetionet CHEBI:119915 biolink:causes HP:0030804 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0546956 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0015397 infores:hetionet CHEBI:6076 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0014742 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0271051 infores:hetionet CHEBI:31644 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151786 infores:hetionet CHEBI:7936 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0233565 infores:hetionet NCBIGene:25953 biolink:causes MONDO:0700089 infores:monarchinitiative not_provided not_provided HGNC:9153 MONDO:0700089 uuid:aac254e4-0606-4ab4-9b6d-f9db1533e056 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5613 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0023066 infores:hetionet CHEBI:37333 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0521491 infores:hetionet CHEBI:17334 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0020649 infores:hetionet CHEBI:4858 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0030554 infores:hetionet CHEBI:51209 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0015230 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0241742 infores:hetionet GO:0021701 biolink:causes CL:0000119 infores:ubergraph knowledge_assertion manual_agent GO:0021701 CL:0000119 CHEBI:5864 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0009676 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0002871 infores:hetionet CHEBI:44185 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0237938 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0863084 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0863084 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0033860 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0234913 infores:hetionet NCBIGene:197135 biolink:causes MONDO:0021575 infores:monarchinitiative not_provided not_provided HGNC:33630 MONDO:0021575 uuid:6c65c817-1538-4022-bc59-6fa77d72914f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018932 infores:hetionet UMLS:C0010592 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0015672 infores:hetionet CHEBI:64064 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0030252 infores:hetionet CHEBI:70746 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0010200 infores:hetionet CHEBI:5959 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0037763 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0030793 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030793 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030446 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0032961 infores:hetionet CAID:CA8623057 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623057 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PVS1_Moderate PM3, PP4 The variant NM_000212.3(ITGB3):c.778-2A>G occurs within a canonical splice site and is predicted to cause skipping of biologically-relevant-exon 6, resulting in an in-frame deletion, removing amino acids Glu260 to Met313, and removing <10% of the protein (PVS1_Moderate). The variant has a rate of 0.00004846 (2/41268 alleles) in the East Asian population in gnomADv4.0.0, which is less than the threshold (<0.0001) for PM2_Supporting. The variant has been found in at least one individual with GT, ClinVar entry (SCV000891201.1) by the Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota. The patient is compound heterozygous with Likely Pathogenic variant NM_000212.3(ITGB3):c.325del (p.Val109SerfsTer?), phasing not confirmed. The patient had bleeding since childhood, abnormal aggregation, and flow cytometry low levels of GPIIb/IIIa. Patient information is consistent with GT but insufficient for PP4. In summary, this variant meets the criteria to be classified as variant of uncertain significance- insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PM2_supporting (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623057/MONDO:0100326/011 2024-05-02 2024-05-03 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6887 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0026603 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0040479 infores:hetionet GO:0072301 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:0072301 GO:0072210 CHEBI:63621 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0423791 infores:hetionet CHEBI:44185 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0025287 infores:hetionet CHEBI:16899 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0036572 infores:hetionet CHEBI:49668 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0235267 infores:hetionet CAID:CA226533 biolink:causes MONDO:0100368 infores:clingen CAID:CA226533 MONDO:0100368 PMID: Pathogenic PM3_Strong, PS3_Supporting, PP4_Moderate, PP1, PP3, PM2_Supporting PM5 NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) is a missense variant that replaces arginine with glutamine at position 91 in RPE65. At least one proband harboring this variant has been genotyped by next-generation sequencing analysis of 586 candidate genes without an alternative explanation for visual impairment (2 pts), with phenotypes including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), extinguished scotopic (0.5 pts) and photopic (1 pt) electroretinogram responses, bone spicule pigmentation (0.5 pts), white or yellow dots in the fundus (2 pts), and nystagmus (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 points, PP4_Moderate). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.1022T>C (p.Leu341Ser) variant or the c.370C>T (p.Arg124Ter) variant suspected in trans (1 point, PMID: 32865313, PMID: 27102010), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP. This variant has also been reported in the homozygous state in at least 2 probands with early-onset severe retinal dystrophy (1 point, PMID: 32865313, PMID: 34492281; 2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through a proband plus 1 similarly affected relative, both of whom harbor the variant present in the compound heterozygous state with the c.725+4A>G variant confirmed in trans (PP1; PMID: 11462243). This variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.0001609, with 8 alleles / 24940 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.659, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.644 and predicts a damaging effect on RPE65 function (PP3). The variant also exhibited 1.33% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, Table 2, PMID: 19431183). Two other missense variants encoding different amino acid substitutions at the same codon have been reported in association with RPE65-related recessive retinopathy (PMID: 17724218, PMID: 9501220). However, c.271C>T (p.Arg91Trp) and c.272G>C (p.Arg91Pro) have not yet been classified by the ClinGen LCA / eoRD VCEP, and PM5 was not considered to avoid circularity. In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3, PP4_Moderate (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226533/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:79699 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0036572 infores:hetionet CHEBI:4975 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0023530 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0004096 infores:hetionet CHEBI:3479 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0003862 infores:hetionet CAID:CA6748745 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748745 MONDO:0009861 PMID: Likely Pathogenic PM3, PM2, PP3, PP4 PM5 This c.1084C>T (p.Pro362Ser) variant in PAH was reported in a patient with classic PKU in trans with the pathogenic variant p.Arg413Pro (PMID: 28982351). This variant was present at an extremely low frequency in ExAC and absent in the gnomAD population database. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748745/MONDO:0009861/006 2022-12-09 2022-12-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9086 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0027051 infores:hetionet CHEBI:39867 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0025345 infores:hetionet CHEBI:52717 biolink:causes UMLS:C2745924 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C2745924 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005020 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0021831 infores:hetionet CHEBI:49668 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0231218 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0577730 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0577730 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002614 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0029400 infores:hetionet CHEBI:472657 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0042267 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0234215 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0234215 infores:hetionet CHEBI:64028 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0020651 infores:hetionet CAID:CA121997 biolink:causes MONDO:0007648 infores:clingen CAID:CA121997 MONDO:0007648 PMID:8557030 Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS4, BS3, PM6, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS2, PS3 The c.781G>T (p.Glu261Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA121997/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:63612 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0150450 infores:hetionet CHEBI:61049 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0232462 infores:hetionet GO:0090256 biolink:causes GO:0007552 infores:ubergraph knowledge_assertion manual_agent GO:0090256 GO:0007552 CHEBI:2618 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0023380 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0235901 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0233488 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0233488 infores:hetionet CHEBI:6710 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0014743 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0917798 infores:hetionet CHEBI:17688 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0002994 infores:hetionet CHEBI:68575 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0020456 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0851341 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0025061 infores:hetionet CHEBI:135935 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0009782 infores:hetionet CHEBI:553473 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0853149 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0021053 infores:hetionet CHEBI:75988 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0031117 infores:hetionet CHEBI:37941 biolink:causes MONDO:0004431 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0018924 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0038454 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0009443 infores:hetionet CAID:CA512318858 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318858 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.285C>T (p.Pro95=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.27) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318858/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0009315 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0003578 infores:hetionet CHEBI:47612 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0008370 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0013395 infores:hetionet CAID:CA1139666833 biolink:causes MONDO:0011071 infores:clingen CAID:CA1139666833 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.*467T>C is a 3' UTR variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139666833/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6950 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0702166 infores:hetionet CHEBI:6062 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0025637 infores:hetionet CAID:CA396469209 biolink:causes MONDO:0007648 infores:clingen CAID:CA396469209 MONDO:0007648 PMID: Likely Pathogenic PM5_Supporting, PS4_Supporting, PM2_Supporting, PVS1_Strong BS1, BS4, BS3, BP5, BP7, PM3, PM4, PM1, PM6, BS2, PP1, PP4, PP2, PP3, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.2165-1G>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). The variant has been reported in one proband meeting clinical criteria for HDGC (PS4_supporting; Ambry). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PS4_supporting, PM2_supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396469209/MONDO:0007648/007 2023-08-24 2023-08-24 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:10023 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0009421 infores:hetionet CHEBI:17026 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0086565 infores:hetionet CHEBI:499361 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0855775 infores:hetionet CAID:CA226621 biolink:causes MONDO:0010725 infores:clingen CAID:CA226621 MONDO:0010725 PMID:12746437 Pathogenic PS4, PP3_Moderate, PP1_Strong, PS3_Supporting, PM1, PP4 BS1, PM2 The NM_000330.4(RS1):c.214G>A variant is a missense variant encoding the substitution of Glutamic acid with Lysine at amino acid 72. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002508 among hemizygous individuals, with 1 variant alleles / 398646 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.921, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 12746437, PS3_Supporting). This variant p.Glu72Lys, of the RS1 gene, is an established residue involved in cross-linking the adjacent RS1 subunit by the ClinGen X-linked IRD VCEP (PMID: 27114531, PM1). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family (PP1_Strong; PMID: 11246454, 38317323, 19324861). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 23288992, PP4). This variant has been reported in at least 6 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 30025115, 28348004, 19324861, 22245991, 32531858, 29851975, PS4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PP3_moderate, PP1_strong, PP4, PS4, PS3_supporting, and PM1 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226621/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:31236 biolink:causes UMLS:C0438167 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0438167 infores:hetionet CAID:CA410148832 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148832 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.968C>A (p.Thr323Lys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score <0.50 (0.04) (BP4). This variant was reported in ClinVar in 2019 by Invitae, but the affected status of the proband is unknown (Variation ID 864259). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148832/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA121991 biolink:causes MONDO:0007648 infores:clingen CAID:CA121991 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PVS1, PM2, PM6, PM5, PM4, PM1, PM3, BS2, PP3, PP2, PP1, PP4, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA121991/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63613 biolink:causes UMLS:C1262113 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C1262113 infores:hetionet CAID:CA007963 biolink:causes MONDO:0005835 infores:clingen CAID:CA007963 MONDO:0005835 PMID: Likely Benign BS2, BP4 BS1 The MSH6 (NM_000179.3):c.107C>T is a missense variant predicted to cause substitution of Alanine to Valine at amino acid 36 (p.Ala36Val). The prior probability for pathogenicity of this missense variant is 0.04 according to http://priors.hci.utah.edu/PRIORS (BP4). The gnomAD v4.1 Grpmax AF is 0.0001535, not meeting BS1 criteria according to the Maximum Credible Allele Frequency (MCAF) cutoffs for MSH6. Co-occurrence with truncating variant MSH6 c.3202C>T (p.Arg1068*) in a patient with CRC and no signs of CMMR-D (BS2).In summary, this variant meets the criteria to be classified as LIKELY BENIGN for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: BS2 and BP4 (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA007963/MONDO:0005835/138 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:51594 biolink:causes MONDO:0013889 infores:monarchinitiative not_provided not_provided HGNC:15625 MONDO:0013889 uuid:037c6460-9497-4d8c-9ad0-a9ee16971ee0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:175901 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0004093 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0037274 infores:hetionet CHEBI:6402 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0423791 infores:hetionet CHEBI:92607 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0027497 infores:hetionet CAID:CA413496806 biolink:causes MONDO:0010315 infores:clingen CAID:CA413496806 MONDO:0010315 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting The c.328G>T (p.Glu110Ter) NM_000206.3 variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 3/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met). The variant is absent in gnomAD v4 (PM2_supporting). The variant was found in a *Male patient (0.5 pts) with SCID (0.5 pts) and exome sequencing (1 pt). Total is 2 pts, PP4_Moderate. (PMID: 10794430).In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA413496806/MONDO:0010315/129 2024-04-23 2024-04-23 X-linked inheritance HP:0001417 Supports CHEBI:9599 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0012569 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0853813 infores:hetionet CHEBI:4779 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0013378 infores:hetionet NCBIGene:1756 biolink:causes MONDO:0010679 infores:monarchinitiative not_provided not_provided HGNC:2928 MONDO:0010679 uuid:d412f6ca-fee5-4e85-be4f-6ce2d897bf6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0042487 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0018799 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0948089 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0236065 infores:hetionet CHEBI:9139 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0014591 infores:hetionet CHEBI:32315 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0025874 infores:hetionet CAID:CA116622 biolink:causes MONDO:0009290 infores:clingen CAID:CA116622 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PS3_Moderate, PM2_Supporting, PM3_Strong The NM_000152.5:c.877G>A variant in GAA is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 293 (p.Gly293Arg). Patients with a diagnosis of Pompe disease reported with this variant include five individuals with documented laboratory values showing deficient GAA activity meeting the specifications of the ClinGen LSD VCEP (PMIDs: 23566438, 24590251, 26497565), one of whom also has features reported that are consistent with infantile onset Pompe disease (PMID: 31510962) and additional patients reported to be on enzyme replacement therapy but without documentation of residual GAA activity (PMID: 18607768, 21605996) (PP4_Moderate). At least 6 patients are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 18607768, 21605996, 23566438, 24590251, 25455803, 29181627, 31710733), c.2481+102_2646+31del (PMID: 18429042) and c.716del (p.Leu239fsTer28) (PMID: 14695532), and at least two individuals are homozygous for the variant (PMIDs: 31510962, 26497565) (2 x 0.5 points) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and either c.719C>T (p.Phe240Ser; note that reference sequence has a T at position 719) (PMID: 25455803) or c.710C>T (p.Ala237Val) (PMIDs: 15668445, 17573812, 17643989. The allelic data from these patients will be used in the classification of p.Phe240Ser and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00006 (2/35062 alleles) in the Latino / Admixed American population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in <2% residual GAA activity in medium and cells (PMIDs 14695532, 19862843). No GAA protein was observed on Western blot of COS cells expressing the variant (PMID 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.931 which is above the threshold of 0.7, evidence that correlates with impact to GAA function, and SpliceAI predicts the creation of a cryptic splice site 2 nucleotides downstream from the variant (PP3). There is a ClinVar entry for this variant (Variation ID: 4036; 2 star review status) with 6 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. )Classification approved by the ClinGen LSD VCEP on Nov. 2, 2022) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116622/MONDO:0009290/010 2022-11-02 2022-11-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4315 biolink:causes UMLS:C0037290 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0037290 infores:hetionet CAID:CA000382 biolink:causes MONDO:0018875 infores:clingen CAID:CA000382 MONDO:0018875 PMID: Pathogenic PS3, PS2, PS4, PP1_Strong, PP3_Moderate, PM1, PM5, PP4_Moderate, PM2_Supporting BA1, BP4, PS1, BP5, BS3, BS4, BS1, PVS1, BS2 The NM_000546.6: c.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000382/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0013395 infores:hetionet NCBIGene:1828 biolink:causes MONDO:0007859 infores:monarchinitiative not_provided not_provided HGNC:3048 MONDO:0007859 uuid:deab1af8-72c2-48ef-a651-0b4254191016 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9927 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0002792 infores:hetionet CHEBI:8665 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C2830004 infores:hetionet CHEBI:8346 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0030312 infores:hetionet CHEBI:50381 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0017178 infores:hetionet CHEBI:474180 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0033771 infores:hetionet CHEBI:4995 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0034152 infores:hetionet CHEBI:3223 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0020517 infores:hetionet CHEBI:161680 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0030312 infores:hetionet CHEBI:7936 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0033036 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0009782 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0042075 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030846 infores:hetionet CHEBI:27899 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0017178 infores:hetionet CHEBI:71415 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0235896 infores:hetionet CHEBI:3013 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0242350 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0333641 infores:hetionet UMLS:C0657912 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011253 infores:hetionet CHEBI:5062 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0011603 infores:hetionet CHEBI:74947 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151744 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0037822 infores:hetionet CHEBI:71219 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0162285 infores:hetionet CAID:CA404086609 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086609 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP2, PP1, PP4 NM_000527.5(LDLR):c.1577C>A (p.Pro526His) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.946. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086609/MONDO:0007750/013 2022-01-18 2022-06-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:15552 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0042373 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0007193 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0574067 infores:hetionet CHEBI:5004 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0015230 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032584 infores:hetionet CHEBI:453011 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0011603 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0036572 infores:hetionet GO:0043317 biolink:causes GO:0002286 infores:ubergraph knowledge_assertion manual_agent GO:0043317 GO:0002286 CHEBI:3752 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003811 infores:hetionet CHEBI:49040 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0032533 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0021400 infores:hetionet CHEBI:7936 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0041657 infores:hetionet NCBIGene:80055 biolink:causes MONDO:0014348 infores:monarchinitiative not_provided not_provided HGNC:25712 MONDO:0014348 uuid:f03e4b3a-1178-4816-b2c7-9215a3af7329 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5790 biolink:causes UMLS:C0853117 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0853117 infores:hetionet CAID:CA367401550 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401550 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP2, PP3, PP4, PM2_Supporting PM1 The c.566T>C variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to threonine at codon 189 (p.Ile189Thr) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant was identified in at least one individual with a clinical history highly specific for GCK-MODY (fasting glucose = 125 mg/dl and HbA1c = 6.5%) (PP4, internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). In summary, c.566T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 3/23/2023): PM2_Supporting, PP3, PP2, PP4, PP1_Strong, PS4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401550/MONDO:0015967/086 2023-05-08 2023-05-08 Semidominant inheritance HP:0032113 Supports CHEBI:5118 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085932 infores:hetionet CHEBI:3380 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0038362 infores:hetionet CHEBI:7809 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0040414 infores:hetionet CHEBI:567361 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0019080 infores:hetionet GO:0021514 biolink:causes CL:0000099 infores:ubergraph knowledge_assertion manual_agent GO:0021514 CL:0000099 CHEBI:64321 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0002871 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0012833 infores:hetionet CAID:CA015216 biolink:causes MONDO:0004994 infores:clingen CAID:CA015216 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4671G>A (p.Lys1557=) variant in the MYH7 gene is 0.16% (34/15896) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015216/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6149 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0427008 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0236071 infores:hetionet CHEBI:45783 biolink:causes MONDO:0018373 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027543 infores:hetionet CHEBI:37333 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0151744 infores:hetionet CAID:CA10014185 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014185 MONDO:0011071 PMID: Benign BP2, BP4, BP7, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BA1, BP5, BS3, BS4, PVS1, PM2, PM6, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP1, PP4 This c.1338C>T (p.Leu446=) synonymous variant, located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = -0.004008 in GRCh38), is not predicted to have any splicing impact per SpliceAI (BP4+BP7). In addition, the variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (South Asian subpopulation: 0.03506% in v2 and 0.1449% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and was found in homozygosity in the population database (BP2). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP2, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014185/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63621 biolink:causes MONDO:0005906 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0031157 infores:hetionet CHEBI:205919 biolink:causes MONDO:0001576 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0039446 infores:hetionet CAID:CA000035 biolink:causes MONDO:0018875 infores:clingen CAID:CA000035 MONDO:0018875 PMID: Likely Benign BP4, BS3, BS2, PM2_Supporting BA1, PS3, PS1, PS4, PS2, PM1, PM5, BS4, BS1, PVS1, PP1, PP3, PP4 The NM_000546.6: c.1093C>T variant in TP53 is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 365 (p.His365Tyr). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors: SCV000184430.7). This variant has an allele frequency of 0.000006785 (8/1179138 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.1352; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_moderate, PM2_Supporting BS3, BP4. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000035/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6775 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0038325 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0004691 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0085096 infores:hetionet CHEBI:4046 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0004093 infores:hetionet CHEBI:194135 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018681 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0009450 infores:hetionet CHEBI:6710 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00939 UMLS:C0234215 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0042790 infores:hetionet CAID:CA379131380 biolink:causes MONDO:0100316 infores:clingen CAID:CA379131380 MONDO:0100316 PMID:29021305 Uncertain Significance PS3_Moderate, PM2_Supporting, PM5_Supporting, PP3 BP1, BP4, BP2, BP3, BA1, PS1, PS2, PS4, BP5, BP7, BS1, BS4, PVS1, PM6, PM3, PM4, PM1, PP1, PP2, PP4, BS2 NM_000218.3(KCNQ1):c.817C>G (p.Leu273Val) is a missense variant in KCNQ1 that replaces leucine with valine at codon 273. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.000001695, with 2 alleles / 1180024 total alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). Another missense variant NM_000218.3(KCNQ1):c.817C>T (p.Leu273Phe) in the same codon has been classified as likely pathogenic for long QT syndrome by the ClinGen Potassium Channel Arrhythmia VCEP, while no benign missense variants have been identified in this codon (PM5_Supporting). This residue has been confirmed to be highly conserved across all 5 human KCNQ paralogues, and SpliceAI has been used to confirm that neither variant has a predicted impact on KCNQ1 splicing. The computational predictor REVEL gives a score of 0.822, (which is above the threshold of 0.75, evidence that correlates with impact to KCNQ1 function (PP3). This variant has been shown to disrupt KCNQ1 function in at least three experimental assays, including Manual patch-clamp and Experimental/Structural/Functional Simulation (PS3_Moderate; PMID: 15649981, PMID: 29021305, PMID: 36674868). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS3_Moderate, PM2_Supporting, PM5_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA379131380/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50648 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0948594 infores:hetionet CHEBI:135361 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0026961 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0002622 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0027769 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0041349 infores:hetionet CHEBI:135929 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0151766 infores:hetionet CHEBI:63599 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0014518 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0948594 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0030305 infores:hetionet CHEBI:8869 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0027497 infores:hetionet CHEBI:71417 biolink:causes HP:0001892 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C1458140 infores:hetionet CAID:CA304350 biolink:causes MONDO:0007947 infores:clingen CAID:CA304350 MONDO:0007947 PMID: Uncertain Significance PP3 PM2, PP2, BA1, BP1, BP4, PM5, PS1, BS1 The NM_00138 c.6163+2dup variant in FBN1 occurs in the intron near the invariant region (+1/2) of the consensus donor splice site; the c.6163+2T nucleotide is moderately conserved. In silico prediction programs (GeneSplicer, MaxEntScan, NNSplice) predict this variant to weaken/ destroy the canonical donor site of this intron, which is expected to disrupt mRNA splicing and result in absent or truncated protein product (PP3). However, this prediction has not been confirmed by RNA functional studies. This variant has been reported five times in ClinVar: once as pathogenic, four times as uncertain significance (Variation ID: 200167). This variant has been reported in individuals with thoracic aortic aneurysm and/or dissection who carried other cardiogenetic variants (GeneDx, Murdoch Childrens Research Institute ClinVar entry). It has also been reported in an individual without structural heart disease (PMID 28659821). This variant is present in 2/113448 (0.0018%) of alleles tested from the European non-Finnish population in gnomAD (https://gnomad.broadinstitute.org/ v2.1.1). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP3. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA304350/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:7478 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C1368065 infores:hetionet CHEBI:182080 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0855775 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0003123 infores:hetionet CAID:CA1022028196 biolink:causes MONDO:0011071 infores:clingen CAID:CA1022028196 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.614-11C>G is an intronic variant which has a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.02) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.27) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1022028196/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3403 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0036983 infores:hetionet GO:0001177 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:0001177 GO:0010467 UMLS:C0004609 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020538 infores:hetionet CHEBI:7466 biolink:causes UMLS:C1696685 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C1696685 infores:hetionet CHEBI:29007 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0026826 infores:hetionet CHEBI:45081 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0085649 infores:hetionet CHEBI:6129 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0344232 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0343863 infores:hetionet CHEBI:135530 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0232462 infores:hetionet NCBIGene:5238 biolink:causes MONDO:0014353 infores:monarchinitiative not_provided not_provided HGNC:8907 MONDO:0014353 uuid:ef7d5e51-d01e-4801-a06b-826c7259f5ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0877055 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0149836 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0016056 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0025958 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0007642 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0012817 infores:hetionet CHEBI:68841 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0600142 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0403632 infores:hetionet CHEBI:3347 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0002962 infores:hetionet CHEBI:47426 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0030554 infores:hetionet CAID:CA512341220 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341220 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1215G>C (p.Leu405=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.00)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341220/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8024 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C1167965 infores:hetionet CHEBI:36795 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011175 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027609 infores:hetionet CHEBI:474180 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0018802 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0042373 infores:hetionet CHEBI:83804 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0549249 infores:hetionet CHEBI:4672 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027051 infores:hetionet CHEBI:65349 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0017152 infores:hetionet CHEBI:3723 biolink:causes EFO:0011023 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006107 infores:hetionet CAID:CA10585855 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585855 MONDO:0007750 PMID: Uncertain Significance PM4, PM2, PP4 BS3, PM1 The NM_000527.5(LDLR):c.2407_2424dup (p.Cys803_Leu808dup) is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PM4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow:PM2_Met : Absent from controls in GnomAD (gnomAD v2.1.1).PM4_Met : The variant is an in-frame insertion which consists of a duplication of 18 nucleotides in exon 17, resulting in the in-frame insertion of six amino acids at the end of the transmembrane domain of the receptor protein smaller than whole exon. The variant met PM2 code as absent from controls in Gnomad database PP4_Met: variant met PM2 and was found in PMID: 11810272 in one patient with definite FH by SB criteria Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585855/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:404903 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0035508 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0392025 infores:hetionet CHEBI:499361 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020621 infores:hetionet CHEBI:4511 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151747 infores:hetionet CHEBI:63580 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0237849 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0019163 infores:hetionet CHEBI:5002 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0027051 infores:hetionet CHEBI:49713 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0018681 infores:hetionet CHEBI:15553 biolink:causes UMLS:C1868769 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C1868769 infores:hetionet CHEBI:94385 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0022660 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0948586 infores:hetionet CHEBI:10125 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0004604 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0340464 infores:hetionet CHEBI:8499 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0595883 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0008301 infores:hetionet CHEBI:70746 biolink:causes UMLS:C2010560 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C2010560 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0553732 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0553732 infores:hetionet CHEBI:23765 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013428 infores:hetionet CAID:CA399802364 biolink:causes MONDO:0100326 infores:clingen CAID:CA399802364 MONDO:0100326 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting PM3 The c.1642C>T (p.Gln548Ter) variant in exon 17 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 1 in PMID: 23624894) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% (<25%), as measured by flow cytometry. Molecular genetic analysis was performed for the ITGA2B, but no genotyping was performed for ITGB3 (PP4_moderate). This variant has been detected in at least 1 proband with Glanzmann thrombasthenia (PMID:23624894). This individual was compound heterozygous for this variant and the NM_000419.3:c.1750C>T (Arg584Ter) variant, which was classified as Pathogenic by the PD VCEP (but occurs at too high a frequency to consider for PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_Moderate, PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399802364/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51230 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0344232 infores:hetionet CHEBI:64028 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0013428 infores:hetionet CHEBI:43968 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0023518 infores:hetionet CHEBI:94385 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0020517 infores:hetionet CHEBI:71417 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C1443060 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0014868 infores:hetionet CHEBI:31644 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0027497 infores:hetionet CHEBI:4858 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0038325 infores:hetionet CHEBI:39867 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0014457 infores:hetionet CHEBI:4903 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0022107 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020517 infores:hetionet CHEBI:8356 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0019521 infores:hetionet CHEBI:63631 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C3665347 infores:hetionet CHEBI:28864 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0023067 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0155169 infores:hetionet CHEBI:28939 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0013144 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0025061 infores:hetionet CHEBI:31236 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003537 infores:hetionet CHEBI:31348 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0221201 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0403632 infores:hetionet NCBIGene:23404 biolink:causes MONDO:0044634 infores:monarchinitiative not_provided not_provided HGNC:17097 MONDO:0044634 uuid:40fabdde-6575-4a0e-88de-0e98d3fb990a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes UMLS:C0919907 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0919907 infores:hetionet CHEBI:16469 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0000731 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020651 infores:hetionet CHEBI:3534 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C1257843 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0518015 infores:hetionet CHEBI:8871 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235939 infores:hetionet CAID:CA000412 biolink:causes MONDO:0017623 infores:clingen CAID:CA000412 MONDO:0017623 PMID: Likely Benign BP7, BP4 PTEN c.360A>C (p.A120=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP4: Synonymous variant where at least 2 out of 3 in silico models predict no splicing impact.BP7: Variant is synonymous (silent), nucleotide is not conserved, and no splicing impact is predicted. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000412/MONDO:0017623/003 2016-12-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA645369681 biolink:causes MONDO:0100488 infores:clingen CAID:CA645369681 MONDO:0100488 PMID: Uncertain Significance PS3_Supporting, PM2_Supporting, PS4_Moderate BP7, BS1, PM4, PM1, PM3, BS2, PP2, PP3, PP4, BP1, BP4, BP3, BA1, PS1 The c.1711+5G>A variant in CDH1 is an intronic variant which switches a G to an A in the +5 position of intron 11. This variant is known in five families, three of which meet HDGC criteria (PS4_moderate; PMID: 15235021, AmbryGenetics, Invitae, Color and CeTaG internal data). This variant is completely absent from population databases such as gnomAD (PM2_supporting). There is evidence of abnormal RNA expression of this variant allele as a functional consequence of incorrect slicing, but further studies are required to confirm this evidence (PS3_supporting; PMID: 15235021). In summary, this variant is classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen CDH1 Variant Curation Expert Panel: PS3_supporting, PS4_moderate, PM2_supporting. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369681/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:50729 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0009763 infores:hetionet GO:2000367 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:2000367 GO:0019953 CHEBI:45409 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0426576 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0919666 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0919666 infores:hetionet CHEBI:2639 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0004093 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0009443 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0221512 infores:hetionet CHEBI:80630 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0040053 infores:hetionet CHEBI:36791 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0522055 infores:hetionet CHEBI:100241 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0542571 infores:hetionet UNII:Z5N076G8YQ biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0042963 infores:hetionet CHEBI:32020 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0948594 infores:hetionet CHEBI:3423 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1456784 infores:hetionet CHEBI:65173 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0156404 infores:hetionet CHEBI:17347 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0014534 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0855223 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0855223 infores:hetionet CAID:CA454606568 biolink:causes MONDO:0015967 infores:clingen CAID:CA454606568 MONDO:0015967 PMID: Likely Benign BP7, PM2_Supporting, BP2, BP4 PS4, PP4 The c.1317C>T variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 439 (p.(Ile439=)) of NM_000162.5. This synonymous variant is not predicted to impact splicing (SpliceAI score of 0.00 for donor gain, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of 0.274, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID 515200). The MODY probability is unable to be calculated for this individual due to lack of clinical information (ClinVar ID 515200). This variant has been observed in in unknown phase with the variant c.128G>A p.Arg43His (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). In summary, c.1317C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3,0, approved 8/11/2023): PM2_Supporting, BP2, BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA454606568/MONDO:0015967/086 2024-01-22 2024-01-22 Semidominant inheritance HP:0032113 Contradicts true CHEBI:45409 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011603 infores:hetionet CAID:CA340740566 biolink:causes MONDO:0100368 infores:clingen CAID:CA340740566 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting BA1, PP2 NM_000329.3(RPE65):c.1583G>T (p.Gly528Val) is a missense variant that replaces glycine with valine at amino acid 528. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.0000008477, with 1 allele / 1,179,706 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.669delCA (now known as NM_000329.3(RPE65):c.615_616del (p.Ile206fs)) variant suspected in trans (0.5 points, PMID: 11095629), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP. This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant suspected in trans (0.5 points, PMID: 32865313), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), night blindness (0.5 pts), nystagmus, (1 pt), poor central visual acuity (1 pt), visual field constriction (1 pt), and nonrecordable electroretinogram responses (0.5 pts for rods and 1 for cones), which together are specific for RPE65-related recessive retinopathytotal 5.5 points, PMID: 11095629, PP4). The computational predictor REVEL gives a score of 0.982, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited <2 % enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16150724). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP4, PP3_Moderate, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340740566/MONDO:0100368/120 2025-06-11 2025-06-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:52717 biolink:causes MONDO:0005404 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0015674 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002565 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0026975 infores:hetionet CHEBI:50275 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151610 infores:hetionet CHEBI:3176 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0042075 infores:hetionet CHEBI:50567 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0027497 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0853692 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0004936 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0233414 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0027765 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0005961 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D012852 DB13092_MESH_D012852_1DB00618_MESH_D012852_1DB01147_MESH_D012852_1DB01602_MESH_D012852_1DB00595_MESH_D012852_1DB00254_MESH_D012852_1DB00713_MESH_D012852_1 CHEBI:61049 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0030196 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014534 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0037274 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0151744 infores:hetionet CHEBI:6472 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0002874 infores:hetionet CAID:CA377781914 biolink:causes MONDO:0017623 infores:clingen CAID:CA377781914 MONDO:0017623 PMID: Uncertain Significance PS3_Supporting, PP2, PP3, PM2_Supporting, PS4_Supporting NM_000314.8(PTEN):c.40A>G (p.Arg14Gly) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:28526761)PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. Mingo et al. 2018 (PMID: 29706633).PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: in silico REVEL score of 0.811 (>0.7) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377781914/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44032 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042023 infores:hetionet CAID:CA367398280 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398280 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PM5_Strong, PM1, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1235T>G variant in the glucokinase gene, GCK, causes an amino acid change of valine to glycine at codon 412 (p.(Val412Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.99, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 34362814, 36939643, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Two other missense variants, c.1235T>C p.Val412Ala and p.1235T>A p.Val412Glu, have been interpreted as pathogenic by the ClinGen MDEP, and p.Val412Gly has a greater Grantham distance than p.Val412Ala (PM5_Strong). In summary, c.1235T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PM5_Strong, PM1, PP2, PP3, PP4_Moderate, PS4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398280/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:8461 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0009806 infores:hetionet CHEBI:9907 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0015672 infores:hetionet UMLS:C1144403 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0151904 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085622 infores:hetionet NCBIGene:5096 biolink:causes MONDO:0011628 infores:monarchinitiative not_provided not_provided HGNC:8654 MONDO:0011628 uuid:612f38b3-bda1-4d5c-ba32-7462f4055394 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3699 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0011606 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0948594 infores:hetionet CHEBI:50922 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0015967 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0010692 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0860645 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0860645 infores:hetionet CHEBI:7478 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0001807 infores:hetionet CHEBI:7514 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0855775 infores:hetionet CHEBI:16796 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0033687 infores:hetionet CAID:CA10585450 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585450 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP1 The NM_000527.5(LDLR):c.1436T>C (p.Leu479Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD v4.0.0.PP3: REVEL= 0.949.PS4_Supporting, PP4: At least four unrelated index cases fulfil FH criteria: one reported in VCI with DLCN ≥6 from Robarts Research Institute, Canada; one case in ClinVar with probable FH by DLCNC reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, France; at least one index case fulfils Simon Broome criteria, reported from UK in PMID 11313767 (Table 1), 16389549 (Table 2) and 20736250 (Table 1, Figure 1); at least one case reported in PMID 19318025 with DLCN ≥6 (Supplementary table B). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585450/MONDO:0007750/013 2024-02-23 2025-02-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:5847 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0009763 infores:hetionet CHEBI:68478 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0002962 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0002871 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0221780 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0221780 infores:hetionet CHEBI:51041 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020039 infores:hetionet CAID:CA70052558 biolink:causes MONDO:0008667 infores:clingen CAID:CA70052558 MONDO:0008667 PMID: Pathogenic PS4_Moderate, PM2_Supporting, PVS1 BS1, BA1 The NM_000551.3(VHL):c.583C>T (p.Gln195Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 195, which resides in the second Beta domain (PVS1). A total of 13 probands or families have been identified with this variant, and they have clinical features of VHL (some Type 1, some Type 2A). 11 probands or families were identified in the following PMIDs: 20660572, 8707293, 23298237, 21463266, 9408111, 17661816, 25867206, 17024664. CIViC EIDs (https://civicdb.org) are: 5472, 5360, 5691, 8693, 9255, 5097, 6623, 5134. Two additional affected cases were contributed by a commercial laboratory, with VHL phenotypes and one case has segregation data. The case total of 13 equates to moderate evidence (PS4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA70052558/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6741 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0002871 infores:hetionet CHEBI:31623 biolink:causes UMLS:C0162279 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0162279 infores:hetionet CHEBI:478164 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0036974 infores:hetionet CHEBI:9086 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C2830004 infores:hetionet CHEBI:9599 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C1145670 infores:hetionet CHEBI:127342 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0022107 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0854121 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0854121 infores:hetionet CHEBI:4710 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0080274 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0413252 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0004936 infores:hetionet CAID:CA16020829 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020829 MONDO:0009861 PMID:23357515 Pathogenic PVS1, PM2, PP4 This variant c.607dup (p.Cys203LeufsTer3) in PAH was reported in at least 1 Czech patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This is a frameshift variant in exon 6 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3'-most exon or the 3'-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020829/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10549215 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549215 MONDO:0010305 PMID: Likely Benign BP7, BP4 BS1, PM2, PP4 The NM_005629.4:c.644+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 3. This variant was reported in a female patient with intellectual disability (LOVD, https://databases.lovd.nl/shared/genes/SLC6A8; individual #00185850) but details of biochemical testing or brain MRS are not available (PMID: 20717164). The computational splicing predictors SpliceAI and varSEAK suggest that the variant has no impact on splicing (BP4). This is also supported by the reported results of 5 different predictors (Netgene2, Fruitfly (i.e. NNSplice), Splice predictor, Genscan W, FSplice) (PMID 20717164). PhyloP100 way score for this intronic variant is 0.35, which is below the threshols of 2.0, indicating that this nucleotide is not highly conserved (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001061 in the African population. This allele frequency is between the ClinGen CCDS VCEP’s allele frequency thresholds for PM2 (<0.00002) and BS1 (>0.0002). Therefore, neither code is met. There is a ClinVar entry for this variant (Variation ID: 416004) In summary, this variant meets the criteria to be classified as likely benign for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications verion 1.1.0): BP4. BP7.This classification was approved by the ClinGen CCDS VCEP on Jan 12, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549215/MONDO:0010305/027 2023-01-12 2023-01-24 X-linked inheritance HP:0001417 Contradicts true CHEBI:63611 biolink:causes UMLS:C0877048 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0877048 infores:hetionet GO:0060617 biolink:causes GO:0071697 infores:ubergraph knowledge_assertion manual_agent GO:0060617 GO:0071697 CHEBI:5147 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0948594 infores:hetionet CHEBI:41879 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0338656 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0521839 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020649 infores:hetionet CAID:CA658658177 biolink:causes MONDO:0015967 infores:clingen CAID:CA658658177 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.722_725dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 242 of NM_000545.8, adding 76 novel amino acids before encountering a stop codon (p.Ile242MetfsTer76). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability calculator cannot be used due to insufficient clinical data, so PP4 cannot be applied (internal lab contributors). In summary, c.722_725dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658177/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:51364 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0344232 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0036572 infores:hetionet CHEBI:68554 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0015967 infores:hetionet CAID:CA229881 biolink:causes MONDO:0009861 infores:clingen CAID:CA229881 MONDO:0009861 PMID:18590700 Uncertain Significance PM2, BS3_Supporting BP2, BP7 The c.969A>G (p.Thr323=) variant in PAH has been found in a patient with PAH deficiency in cis with pathogenic variant IVS2–13T→G (PMID: 10394930). This variant has an extremely low frequency in gnomAD (MAF=0.00001). Splicing predictions are conflicting (HSF/MaxENT: probably no impact; TRAP 0.831: probably damaging). A functional study shows no significant effect on protein activity as compared to wild type (Relative PAH activity 114 +/-18, PMID: 18590700). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, BS3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229881/MONDO:0009861/006 2021-02-13 2021-04-09 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:27470 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0232459 infores:hetionet CHEBI:7986 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0009676 infores:hetionet CHEBI:36791 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020620 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0852733 infores:hetionet CHEBI:63619 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0852911 infores:hetionet CHEBI:100246 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0028738 infores:hetionet CHEBI:142290 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0002418 infores:hetionet CHEBI:68579 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0036974 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0233632 infores:hetionet CHEBI:100241 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0043352 infores:hetionet CHEBI:3696 biolink:causes MONDO:0060779 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0341702 infores:hetionet CHEBI:27882 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0034150 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0027441 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0151490 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0151490 infores:hetionet GO:1902872 biolink:causes GO:0048593 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0048593 CHEBI:63580 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042790 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0549310 infores:hetionet CHEBI:135888 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0542571 infores:hetionet CHEBI:72564 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0236075 infores:hetionet CHEBI:135935 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C1443060 infores:hetionet CHEBI:184555 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0011570 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0948525 infores:hetionet CHEBI:47780 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0231218 infores:hetionet CHEBI:9943 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0686347 infores:hetionet CHEBI:64355 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235437 infores:hetionet CHEBI:8888 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0542571 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1610622 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1610622 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0233494 infores:hetionet CAID:CA5416845 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416845 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.436A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Glycine at amino acid 146 (p.Arg146Gly).The filtering allele frequency (the upper threshold of the 95% CI of 23/1179976 alleles) of the c.436A>G variant in DCLRE1C is 0.00001298 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416845/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:15544 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0013604 infores:hetionet CHEBI:10102 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0262662 infores:hetionet CAID:CA16619450 biolink:causes MONDO:0015967 infores:clingen CAID:CA16619450 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1, PP3 PM5 The c.55T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to alanine at codon 19 (p.(Ser19Ala)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.835, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.56C>T (p.Ser19Leu), has been classified by the ClinGen MDEP as a VUS; therefore, PM5 will not be applied. In summary, c.55T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619450/MONDO:0015967/017 2022-04-01 2022-04-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64064 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0000737 infores:hetionet CHEBI:2922 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C2129214 infores:hetionet CHEBI:50305 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0004691 infores:hetionet CHEBI:39669 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C1443060 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0549373 infores:hetionet CHEBI:52717 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011603 infores:hetionet CHEBI:94449 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0035455 infores:hetionet CHEBI:6541 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0043251 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0017178 infores:hetionet CHEBI:408174 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0019270 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0015726 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0015726 infores:hetionet CHEBI:8412 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0011603 infores:hetionet CHEBI:4779 biolink:causes UMLS:C0423232 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0423232 infores:hetionet CHEBI:194135 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0497156 infores:hetionet CHEBI:32315 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0025222 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0013609 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0234215 infores:hetionet CHEBI:44915 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C3665347 infores:hetionet CHEBI:28593 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0015967 infores:hetionet NCBIGene:8048 biolink:causes MONDO:0012804 infores:monarchinitiative not_provided not_provided HGNC:2472 MONDO:0012804 uuid:d9961ee7-1837-40fe-9042-837194d79462 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10127 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0039231 infores:hetionet CHEBI:50131 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0018808 infores:hetionet CHEBI:2038 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C2937358 infores:hetionet CAID:CA2602720 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602720 MONDO:0009276 PMID: Likely Benign BP4, BP7 BS1, PM2, PP4 The c.459G>A variant is a synonymous (silent) variant (p.Ala153=) that is not predicted by splice AI to impact splicing (BP4) and occurs at a nucleotide that is not highly conserved as shown by phyloP score of -3.75 (BP7). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00003753 (based on 7/86580 alleles) in the South Asian population, which is above the ClinGen PD VCEP PM2_supporting threshold (<0.0000329) but below the BS1 threshold (>0.0007).In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Bernard-Soulier syndrome based on PD specifications of ACMG/AMP guidelines: BP4, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602720/MONDO:0009276/083 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:36791 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0025061 infores:hetionet CHEBI:3084 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0006266 infores:hetionet CAID:CA10014630 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014630 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PM2, PVS1, BP5, BS3, BS4, BS1, PM4, PM5, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.96C>T (p.His32=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.09) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 [-0.498]) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014630/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA10014191 biolink:causes MONDO:0100083 infores:clingen CAID:CA10014191 MONDO:0100083 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 This synonymous variant has SpliceAI ∆ scores ≤ 0.20 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -2.375) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014191/MONDO:0100083/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5134 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0003467 infores:hetionet CHEBI:7577 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0030252 infores:hetionet CHEBI:17303 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0013384 infores:hetionet CHEBI:9943 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0027497 infores:hetionet CHEBI:140621 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0178298 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0948525 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0015397 infores:hetionet CHEBI:4975 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0009806 infores:hetionet GO:0052038 biolink:causes GO:0046907 infores:ubergraph knowledge_assertion manual_agent GO:0052038 GO:0046907 CHEBI:63630 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0040409 infores:hetionet CAID:CA248610 biolink:causes MONDO:0011071 infores:clingen CAID:CA248610 MONDO:0011071 PMID:10508512PMID:28748566PMID:27112265PMID:23817177PMID:11830488PMID:22318203PMID:23848403PMID:17290219PMID:25840971PMID:28748566PMID:10508512PMID:27112265PMID:28748566PMID:10508512PMID:27112265 Pathogenic PS4, PS3, PM2, PM1, PP1, PP3 PS1, BP2, BP4, BA1, PVS1, PM6, BP7, BS1, BS4, BS3, PM5, PM4 Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID: 27112265, 28748566, 10508512). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID: 27112265, 28748566, 10508512). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PS4, PM1, PM2, PP1, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA248610/MONDO:0011071/008 2019-07-30 2019-08-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:24564 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0027651 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0033975 infores:hetionet CAID:CA208363 biolink:causes MONDO:0100040 infores:clingen CAID:CA208363 MONDO:0100040 PMID: Benign BP5, BA1 PP3, BP4 The allele frequency of the p.Ser462Gly variant in FOXG1 is 0.147% in South Asian sub population in gnomAD v2, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The Ser462Gly variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the p.Ser462Gly variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA208363/MONDO:0100040/035 2024-02-23 2024-07-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2955 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0015672 infores:hetionet CHEBI:3699 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0039231 infores:hetionet CHEBI:78543 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0015672 infores:hetionet CHEBI:7575 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00393 UMLS:C0231528 infores:hetionet CHEBI:23765 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0014742 infores:hetionet CHEBI:5098 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0027947 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0232492 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0017672 infores:hetionet CHEBI:7478 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C1443060 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0036572 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0002957 infores:hetionet CHEBI:135736 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014236 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0541922 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0541922 infores:hetionet CHEBI:9434 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0853034 infores:hetionet NCBIGene:3081 biolink:causes MONDO:0008753 infores:monarchinitiative not_provided not_provided HGNC:4892 MONDO:0008753 uuid:ad14a312-c589-408b-9632-d8f7910bb9be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0065374 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0232197 infores:hetionet CHEBI:2549 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0016204 infores:hetionet CHEBI:168396 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0039240 infores:hetionet CHEBI:85161 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0003862 infores:hetionet CHEBI:94440 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0027497 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0041657 infores:hetionet CHEBI:50885 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C3263723 infores:hetionet UMLS:C0025241 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0015672 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0026857 infores:hetionet CHEBI:52717 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0149745 infores:hetionet CAID:CA1706331 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706331 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PP3, PP1, PM2_Supporting, PS3_Moderate PVS1 The NM_003494.4: c.2875C>T variant in DYSF, which is also known as NM_001130987.2: c.2929C>T p.(Arg977Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 959, p.(Arg959Trp). This variant has been reported in at least ten patients with dysferlinopathy (PMID: 14678801, 19528035, 21522182, 27602406, 33715265, 36983702), including in a homozygous state in four unrelated individuals without reported familial consanguinity (1 pt; PMID: 21522182, 27602406, 33715265), confirmed in trans with a pathogenic variant in two affected siblings (NM_003494.4: c.4003G>A p.(Glu1335Lys), 1.0 pt, PMID: 14678801), and in unconfirmed phase with a pathogenic variant in one case (NM_003494.4: c.3517dup p.(Ser1173PhefsTer2), 0.5 pts, PMID: 19528035) (PM3_Strong). At least one of the patients with this variant displayed progressive muscle weakness and absent or reduced dysferlin expression in muscle biopsy or monocytes, which is highly specific for DYSF-related LGMD (PMID: 14678801, 21522182, 27602406, 36983702) (PP4_Strong). This variant was also shown to co-segregate with autosomal recessive LGMD in one affected family member (PMID: 14678801; PP1). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000052686 (49/1180020 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg959Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.77, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/06/2025): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706331/MONDO:0015152/180 2025-10-06 2025-11-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:182080 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0004093 infores:hetionet NCBIGene:2175 biolink:causes MONDO:0009215 infores:monarchinitiative not_provided not_provided HGNC:3582 MONDO:0009215 uuid:e3928497-97b2-4ff8-8124-b0bbd1b1198f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:567361 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0004623 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes UMLS:C0749249 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0749249 infores:hetionet CHEBI:7773 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0344232 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0042109 infores:hetionet CHEBI:48844 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0002994 infores:hetionet CHEBI:6073 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0085612 infores:hetionet CHEBI:41977 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0002792 infores:hetionet CHEBI:3499 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0687713 infores:hetionet CHEBI:5784 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0002874 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0687133 infores:hetionet CHEBI:3723 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0025209 infores:hetionet CHEBI:7931 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0041969 infores:hetionet NCBIGene:10939 biolink:causes MONDO:0013776 infores:monarchinitiative not_provided not_provided HGNC:315 MONDO:0013776 uuid:75b2cf01-5954-4262-aac8-87a2e7319e80 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0002327 biolink:causes CL:0000816 infores:ubergraph knowledge_assertion manual_agent GO:0002327 CL:0000816 CHEBI:44915 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1443060 infores:hetionet CAID:CA166005 biolink:causes MONDO:0100488 infores:clingen CAID:CA166005 MONDO:0100488 PMID: Likely Benign BS2 BP7, BS1, PVS1, PM2, PM1, PM3, PP2, PP3, PP4, BP1, BP4, BP3, BA1, PS1 The NM_004360.5(CDH1):c.184G>A (p.Gly62Ser) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166005/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:66919 biolink:causes MONDO:0008315 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0376358 infores:hetionet CHEBI:7627 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0014743 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0948349 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234930 infores:hetionet CHEBI:9555 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0085762 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004425 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0020550 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004986 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0699885 infores:hetionet CHEBI:7773 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0264906 infores:hetionet CHEBI:52172 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0019080 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0032961 infores:hetionet CHEBI:10124 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0017574 infores:hetionet CHEBI:7852 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042963 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0855242 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0855242 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0042109 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0161479 infores:hetionet CHEBI:4657 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0030554 infores:hetionet CHEBI:7915 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0233407 infores:hetionet CHEBI:5118 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009676 infores:hetionet CHEBI:8764 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0038990 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0011603 infores:hetionet CHEBI:31515 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0023218 infores:hetionet CHEBI:32020 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0022346 infores:hetionet CHEBI:5775 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0011991 infores:hetionet CHEBI:63630 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0030662 infores:hetionet CHEBI:8863 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0001127 infores:hetionet CHEBI:3286 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0030252 infores:hetionet CHEBI:6846 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0038325 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0231441 infores:hetionet CAID:CA145878 biolink:causes MONDO:0001586 infores:clingen CAID:CA145878 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.24C>A variant in IDUA is a synonymous (silent) variant (p.Ala8=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.5236 in the Admixed American population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92638). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145878/MONDO:0001586/091 2025-01-02 2025-01-02 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:2668 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0013604 infores:hetionet NCBIGene:3659 biolink:causes MONDO:0958011 infores:monarchinitiative not_provided not_provided HGNC:6116 MONDO:0958011 uuid:6291f7ca-3ff5-4a7b-a392-28099dd009f3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135920 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0917801 infores:hetionet CHEBI:53691 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0037763 infores:hetionet CHEBI:71272 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0027497 infores:hetionet CHEBI:135276 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0013404 infores:hetionet CHEBI:53760 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0020453 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0235969 infores:hetionet CHEBI:2569 biolink:causes UMLS:C0854693 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0854693 infores:hetionet CHEBI:9927 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0235996 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0740411 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0740411 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0009938 infores:hetionet NCBIGene:5604 biolink:causes MONDO:0014113 infores:monarchinitiative not_provided not_provided HGNC:6840 MONDO:0014113 uuid:b5583d9e-3d7a-4226-896c-2ab0da527399 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4562 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0085593 infores:hetionet CAID:CA7542974 biolink:causes MONDO:0012996 infores:clingen CAID:CA7542974 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 The NM_001482.3:c.222C>T variant in GATM is a synonymous (silent) variant (p.Pro74=) that is not predicted by SpliceAI to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -3.04) (BP4, BP7). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 316212). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA7542974/MONDO:0012996/025 2024-11-08 2024-11-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10125 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0024902 infores:hetionet CHEBI:63607 biolink:causes MONDO:0001593 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0034882 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085096 infores:hetionet CHEBI:50922 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0020453 infores:hetionet CHEBI:9763 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0015230 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0178298 infores:hetionet CAID:CA003392 biolink:causes MONDO:0700268 infores:clingen CAID:CA003392 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP4, BP5 The c.5252G>C variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Proline at amino acid 1751 (p.(Arg1751Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234, 35196514) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.619 (based on Co-occurrence LR=1.1; Family History LR=0.56), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMIDs: 31853058, 31131967). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003392/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135925 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0037274 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0002871 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0948594 infores:hetionet CHEBI:68642 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0037274 infores:hetionet NCBIGene:27245 biolink:causes MONDO:0014358 infores:monarchinitiative not_provided not_provided HGNC:25230 MONDO:0014358 uuid:b38c74e0-9686-462c-93b0-61c6e4a8e1ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0022107 infores:hetionet CHEBI:6062 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020443 infores:hetionet CHEBI:261649 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0015967 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233632 infores:hetionet CHEBI:40237 biolink:causes MONDO:0850420 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0267941 infores:hetionet CHEBI:3698 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C1443060 infores:hetionet CHEBI:77032 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0033774 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0542224 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0542224 infores:hetionet CHEBI:4798 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0014742 infores:hetionet CHEBI:7907 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0003578 infores:hetionet CHEBI:45409 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0016867 infores:hetionet CHEBI:5165 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0233632 infores:hetionet CHEBI:50275 biolink:causes MONDO:0019735 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0032533 infores:hetionet CAID:CA9871625 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871625 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting NM_000022.4:c.578T>A is a missense variant predicted to cause substitution of Leucine by Histidine at amino acid 193 (p.Leu193His). The filtering allele frequency (the upper threshold of the 95% CI of 133/1179808) of the c.578T>A variant in ADA is 0.0001002 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as Variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0):PM2_supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871625/MONDO:0007064/114 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:51173 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0039231 infores:hetionet NCBIGene:6440 biolink:causes MONDO:0024465 infores:monarchinitiative not_provided not_provided HGNC:10802 MONDO:0024465 uuid:b30005ff-3b09-461e-959d-87d101c6b531 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0018932 infores:hetionet CHEBI:110423 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0086565 infores:hetionet NCBIGene:80232 biolink:causes MONDO:0054636 infores:monarchinitiative not_provided not_provided HGNC:21208 MONDO:0054636 uuid:51bcbb95-15b7-44a9-b867-d296863c14a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27882 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0038238 infores:hetionet CHEBI:4814 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0003467 infores:hetionet CAID:CA274404 biolink:causes MONDO:0008723 infores:clingen CAID:CA274404 MONDO:0008723 PMID: Benign BP4, BA1 The c.1605+6T>C variant in ACADVL is an intronic variant which occurs in intron 16. The highest population minor allele frequency in gnomAD v2.1.1 is 0.66 in European Finnish population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from in silico splicing predictors (SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation ExpertPanel: BA1, BP4. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA274404/MONDO:0008723/021 2023-06-27 2023-06-27 Autosomal recessive inheritance (with genetic anticipation) HP:0000007 Contradicts true CHEBI:63621 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018944 infores:hetionet CHEBI:3441 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0030252 infores:hetionet CHEBI:2666 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0003811 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004323 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026846 infores:hetionet CHEBI:167638 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0851578 infores:hetionet CHEBI:4356 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0034186 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0559546 infores:hetionet CHEBI:10110 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0000737 infores:hetionet CAID:CA8815566 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815566 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3_Strong, PS3_Supporting, PM5_Supporting The NM_000152.5:c.2015G>A variant in GAA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 672 (p.Arg672Gln). At least 8 probands with Pompe disease have been reported with this variant, including 4 probands and one sibling with published data showing GAA activity below the normal range in muscle or cultured fibroblasts (PMID: 9535769, 17092519, 33578445), three of whom also showed clinical improvement on enzyme replacement therapy (PMID 33578445)(PP4_Moderate). Five probands are homozygous for the variant (PMIDs 9535769, 25712382, 28937052, 33578445). Two probands are compound heterozygous for the variant and a pathogenic variant in GAA; the second variant is either c.118C>T (p.Arg40Ter)(ClinVar SCV001371737.1)(phase unknown), or c.1857C>G (p.Ser619Arg)(phase unknown)(PM3_Strong). Another proband is heterozygous for the variant with the second variant unidentified (PMID 11053688). When generated by site-directed mutagenesis and expressed in SV40-immortalized GAA deficient fibroblasts or COS cells, the variant resulted in very low (<2%) residual GAA activity (PMID 9535769, 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.955 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest population minor allele frequency in gnomAD is 0.0001107 (East Asian) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting (PM2_Supporting). Two other missense variants at the same amino acid position, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported in patients with Pompe disease, suggesting that this residue may be important in GAA function. Two other missense variants, c.2014C>T (p.Arg672Trp) and c.2015G>T (p.Arg672Leu)(PMID 29122469), have been reported at the same amino acid position; c.2014C>T (p.Arg672Trp) has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. PM5_Supporting is applied here because c.2014C>T (p.Arg672Trp) is only likely pathogenic without PM5 data from c.2015G>A (p.Arg672Gln), thus avoiding circular logic (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 371126, 2 star review status) with 3 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815566/MONDO:0009290/010 2022-01-04 2022-01-04 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8502 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0919715 infores:hetionet CHEBI:80630 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0311468 infores:hetionet CHEBI:3219 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235198 infores:hetionet CHEBI:7936 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011175 infores:hetionet NCBIGene:375 biolink:causes MONDO:0032588 infores:monarchinitiative not_provided not_provided HGNC:652 MONDO:0032588 uuid:62d0f86c-7452-4ae0-9da2-69aa5a55a7e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0232462 infores:hetionet CHEBI:39867 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009763 infores:hetionet CAID:CA410206881 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206881 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.692T>C (p.Leu231Pro) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206881/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:61033 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0041582 infores:hetionet CHEBI:32139 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0151529 infores:hetionet CHEBI:231425 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0151904 infores:hetionet CHEBI:9588 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0002994 infores:hetionet CHEBI:4672 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151905 infores:hetionet CHEBI:49040 biolink:causes MONDO:0005281 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0016977 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0542051 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0542051 infores:hetionet CHEBI:5864 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0009782 infores:hetionet CHEBI:38940 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151934 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0233485 infores:hetionet CHEBI:8888 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0040264 infores:hetionet CHEBI:3614 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0040409 infores:hetionet CAID:CA902590 biolink:causes MONDO:0100368 infores:clingen CAID:CA902590 MONDO:0100368 PMID: Likely Pathogenic PM3, PP3_Moderate, PP4, PM2_Supporting PS3 NM_000329.3(RPE65):c.124C>T is a missense variant that replaces leucine with phenylalanine at position 42. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.00003588, with 7 alleles / 91068 total alleles in the South Asian population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) variant (PMID: 30996589) or the NM_000329.3(RPE65):c.495+1dup variant (VCEP member-provided data) suspected in trans, both of which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset in the first few months of life (1 pt), genotyping by targeted exome sequencing focused on 194 IRD genes without identifying an alternative basis for disease (2 points), poor vision limited to hand movement (1 pt), nystagmus (1 pt), maculopathy (0.5 pts), peripheral hyperpigmentation, and retinal vascular attenuation (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 6.5 points, PMID: 30996589, PP4). The computational predictor REVEL gives a score of 0.879, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. A molecular dynamics and simulation-based model of the variant predicts that the variant would destabilize the structure of RPE65 (PMID: 32072079). However, this is not currently an approved form of functional evidence, so the PS3_Supporting code is not met. In summary, this variant meets the criteria to be classified as Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_supporting, PM3, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902590/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45327 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0042514 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0852733 infores:hetionet CHEBI:2663 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0011206 infores:hetionet CAID:CA340993 biolink:causes MONDO:0010604 infores:clingen CAID:CA340993 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PS4, PVS1, PP4_Moderate The F9 c.223C>T; p.Arg75Ter causes a protein truncation that is expected to undergo NMD, meeting PVS1. The variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting. Over 75 patients are reported in the literature with moderate-severe hemophilia B, some with a history of inhibitors to factor replacement products, meeting F9 phenotype criteria for PS4_Very strong and PP4_Moderate (EAHAD database; PMID: 29296726). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PVS1, PS4_Very strong, PP4_Moderate, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA340993/MONDO:0010604/080 2024-02-09 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:5165 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1609512 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027765 infores:hetionet NCBIGene:3911 biolink:causes MONDO:0031061 infores:monarchinitiative not_provided not_provided HGNC:6485 MONDO:0031061 uuid:c0c4dfc7-97b2-4235-8eed-c76341fa368b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:79029 biolink:causes MONDO:0030480 infores:monarchinitiative not_provided not_provided HGNC:28762 MONDO:0030480 uuid:1a5817a3-417a-4214-9a01-f5d932242d9e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:175901 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0151888 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002871 infores:hetionet CHEBI:101278 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0033774 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0020701 infores:hetionet CHEBI:94501 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0030554 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0855242 infores:hetionet CHEBI:27834 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0428977 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020649 infores:hetionet CHEBI:5134 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0003811 infores:hetionet CHEBI:63622 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C2830004 infores:hetionet CHEBI:47519 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0014742 infores:hetionet CHEBI:63611 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0234632 infores:hetionet CHEBI:46081 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0032617 infores:hetionet CHEBI:4903 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C2981158 infores:hetionet CHEBI:8805 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0017178 infores:hetionet CHEBI:17688 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0021053 infores:hetionet CHEBI:6754 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0013384 infores:hetionet CHEBI:15940 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0030920 infores:hetionet CHEBI:17303 biolink:causes HP:0009027 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0085684 infores:hetionet CHEBI:6759 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0039070 infores:hetionet CHEBI:8802 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0041657 infores:hetionet CHEBI:6541 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0013491 infores:hetionet CHEBI:180905 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0151828 infores:hetionet CHEBI:134991 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0030554 infores:hetionet CHEBI:10650 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0575081 infores:hetionet CHEBI:4708 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0231530 infores:hetionet CHEBI:2687 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0004093 infores:hetionet CHEBI:31236 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0080274 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0948594 infores:hetionet CHEBI:41977 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0151908 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0011991 infores:hetionet CHEBI:10023 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0085636 infores:hetionet CHEBI:50131 biolink:causes HP:0001954 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0277799 infores:hetionet CHEBI:63627 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0232462 infores:hetionet CHEBI:41879 biolink:causes MONDO:0009468 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0033845 infores:hetionet CHEBI:6078 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0014236 infores:hetionet CHEBI:9720 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0018681 infores:hetionet CHEBI:5280 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151937 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0027651 infores:hetionet CHEBI:9674 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0039231 infores:hetionet GO:2000310 biolink:causes GO:0035235 infores:ubergraph knowledge_assertion manual_agent GO:2000310 GO:0035235 CHEBI:49575 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0439857 infores:hetionet CHEBI:4551 biolink:causes EFO:1001482 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0876994 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0021400 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0235146 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011616 infores:hetionet CHEBI:3696 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0016382 infores:hetionet CHEBI:7454 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0013404 infores:hetionet CHEBI:9649 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0037763 infores:hetionet CHEBI:48844 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0042109 infores:hetionet CHEBI:36791 biolink:causes EFO:0009618 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0272774 infores:hetionet CHEBI:8028 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0010200 infores:hetionet CAID:CA512341010 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341010 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1341G>A (p.Pro447=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.38)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341010/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48390 biolink:causes MONDO:0024879 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C1384494 infores:hetionet CHEBI:7465 biolink:causes MONDO:0043653 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0019345 infores:hetionet CHEBI:75722 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0699828 infores:hetionet CHEBI:7444 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0013362 infores:hetionet CHEBI:41879 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0231528 infores:hetionet GO:1900133 biolink:causes GO:0008015 infores:ubergraph knowledge_assertion manual_agent GO:1900133 GO:0008015 CHEBI:94686 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C2242737 infores:hetionet CHEBI:681848 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0018524 infores:hetionet CHEBI:3756 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0043349 infores:hetionet CHEBI:64312 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1258215 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0595930 infores:hetionet CHEBI:5123 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0032285 infores:hetionet CAID:CA410205687 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205687 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.86G>C (p.Arg29Thr) is a missense variant which has a REVEL score < 0.50 (0.285), and a SpliceAI score ≤ 0.20 (0.11) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205687/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50648 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011991 infores:hetionet CHEBI:16469 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0041582 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0242350 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1384353 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004970 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0001418 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0026857 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0160390 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001818 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0015467 infores:hetionet CHEBI:51041 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0017178 infores:hetionet CHEBI:119915 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0043144 infores:hetionet CHEBI:72296 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0011849 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0006145 infores:hetionet CHEBI:6715 biolink:causes HP:0025328 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0269608 infores:hetionet CHEBI:9586 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0008350 infores:hetionet CAID:CA347212126 biolink:causes MONDO:0015152 infores:clingen CAID:CA347212126 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3_Supporting, PP3, PM2_Supporting PM5, PS3 The NM_003494.4: c.1004G>C variant in DYSF, which is also known as NM_001130987.2: c.1100G>C p.(Gly367Ala), is a missense variant predicted to cause substitution of glycine to alanine at amino acid 335, p.(Gly335Ala). This variant has been reported in one patient with suspected LGMD in unknown phase with a pathogenic variant (c.1663C>T p.(Arg555Trp), 0.5 pts) and a benign variant (c.509C>A p.(Ala170Glu)) (PMID: 36983702). The c.1004G>C p.(Gly335Ala) variant was previously described as homozygous in this individual, but a heterozygous state has been confirmed (personal communication with the authors of PMIDs 18853459 and 36983702) (PM3_Supporting). This patient displayed progressive axial and proximal muscle weakness as well as absent dysferlin protein expression on muscle biopsy, which is highly specific for DYSF-related LGMD (PMID: 18853459, personal data communication; PP4_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In addition, another missense variant at the same codon, p.(Gly335Asp) resulting from c.1004G>A, has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP; however, the SpliceAI score=0.12, which is greater than the ClinGen LGMD VCEP threshold of ≤0.10 (PM5_Supporting not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/25/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347212126/MONDO:0015152/180 2025-03-25 2025-04-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:35854 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0013595 infores:hetionet NCBIGene:6690 biolink:causes MONDO:0011986 infores:monarchinitiative not_provided not_provided HGNC:11244 MONDO:0011986 uuid:cae5708b-0281-4789-8aa5-e36f7bf0cf94 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:22872 biolink:causes MONDO:0032849 infores:monarchinitiative not_provided not_provided HGNC:17052 MONDO:0032849 uuid:56411a34-edfc-4011-97a4-c4949e4b80bf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512318871 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318871 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.267G>A (p.Leu89=) is a synonymous variant which has a spliceAI score of 0, indicating a low likelihood of affecting splicing (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318871/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA258396556 biolink:causes MONDO:0100040 infores:clingen CAID:CA258396556 MONDO:0100040 PMID: Likely Benign BP5, BS2, PM2_Supporting, BP4 BS1, BA1 The p.Arg88Gln variant in FOXG1 is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Arg88Gln variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). Computational analysis prediction tools suggest that the p.Arg88Gln variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Arg88Gln variant in FOXG1 is absent from gnomAD (PM2_Supporting). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 2 unaffected individuals and 1 individual with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified the p.Arg88Gln variant in FOXG1 as likely benign (BS2, BP5, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA258396556/MONDO:0100040/035 2023-08-23 2023-10-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:45783 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0008033 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0041834 infores:hetionet CAID:CA024264 biolink:causes MONDO:0018493 infores:clingen CAID:CA024264 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.TThis sequence variant predicts a substitution of aspartic acid with glutamic acid at codon 4939 of the RYR1 protein, p.Asp4939Glu. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, two of these individuals had a likely pathogenic variant in RYR1 (p.Val2346Met) and were not considered for PS4, PS4_Supporting (PMID:23558838, PMID:30236257, PMID:16163667). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.808 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Sup. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024264/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3752 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0344232 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0001824 infores:hetionet CHEBI:3219 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0234708 infores:hetionet CHEBI:114785 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0013395 infores:hetionet CHEBI:6801 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0009806 infores:hetionet CHEBI:61049 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0428977 infores:hetionet CHEBI:49375 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0020598 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0494559 infores:hetionet CHEBI:7601 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0004604 infores:hetionet CHEBI:71941 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0038362 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0002622 infores:hetionet CAID:CA500273575 biolink:causes MONDO:0100326 infores:clingen CAID:CA500273575 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting PP3, PP4 The NM_000419.5(ITGA2B):c.1392A>G (p.Pro464=) has been reported in a patient (Patient 10, PMID: 31029159) with a clinical diagnosis of GT but insufficient information for a highly specific diagnosis. This variant is reported in gnomAD v2.1.1 in the non-Finnish European population with a MAF of 0.000008792 (1/113738 alleles). This MAF is less than the 0.0001 MAF established by the PD VCEP to assign this code (PM2_Supporting). This variant was homozygous in the reported individual (Patient 10, PMID: 31029159) with a clinical diagnosis of GT. Since this was a homozygous occurrence and this variant was not seen in the literature elsewhere; per SVI recommendations this receives 0.5pt since this variant has a MAF of <0.0001 (PM3_Supporting). This variant was identified as heterozygous in parents and not homozygous in healthy individuals in the family. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_Supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA500273575/MONDO:0100326/011 2023-10-17 2023-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31485 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0423602 infores:hetionet CAID:CA319094 biolink:causes MONDO:0012589 infores:clingen CAID:CA319094 MONDO:0012589 PMID: Likely Benign BP4, BS2 PM5, BS1 The p.Ser102Asn variant in TCF4 is present in 1 XX individual in gnomAD v4.0 (0.00016%) (not sufficient to meet BS1 criteria). The p.Ser102Asn variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ser102Asn variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ser102Asn variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA319094/MONDO:0012589/032 2024-06-25 2024-08-23 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:37941 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0042075 infores:hetionet CHEBI:94807 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0002871 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0000729 infores:hetionet CHEBI:5106 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0037383 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0009450 infores:hetionet CHEBI:63581 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0231528 infores:hetionet CAID:CA014652 biolink:causes MONDO:0005045 infores:clingen CAID:CA014652 MONDO:0005045 PMID: Uncertain Significance PM2, PM5, PM1, PM6, BA1, PP1, PP3, BS1, BS4, PS4, PS1, PS2, BP4 The c.4210G>A (p.Val1404Met) variant in MYH7 has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae pers. comm.) and also segregated in 1 affected relative with HCM (Invitae pers. comm.); however this data is currently insufficient to apply PP1. Of note, 1 of the 2 affected individuals from Invitae also carried a splice variant in MYBPC3 and was in their mid 20s at the time of testing. This variant was identified in 0.004% (FAF 95% CI; 9/129152) of European chromosomes by gnomAD v2.1.1 (http://gnomad.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): none. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014652/MONDO:0005045/002 2021-06-16 2021-06-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9674 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0241705 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0036454 infores:hetionet CHEBI:15854 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0034063 infores:hetionet CHEBI:145499 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0428977 infores:hetionet CHEBI:9674 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0040264 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0265031 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0242350 infores:hetionet CHEBI:9123 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003811 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0041912 infores:hetionet CAID:CA229424 biolink:causes MONDO:0009861 infores:clingen CAID:CA229424 MONDO:0009861 PMID: Uncertain Significance PM2, PP3 PM5, BS2, BA1, PS3, PS1, BS1 The NM_000277.2:c.1271T>C (p.Leu424Ser) variant in PAH has not been reported in the medical literature. This variant is absent from 1000G, ESP, ExAC, and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, and REVEL=0.966. Overall, there is not enough evidence to classify the p.Leu424Ser variant with certainty. PAH-specific ACMG/AMP criteria applied: PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229424/MONDO:0009861/006 2019-03-31 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA367398705 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398705 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP2, PP3, PM2_Supporting The c.1156C>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to valine at codon 386 (p.(Leu386Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.745, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 13 unrelated individuals with hyperglycemia (PS4; PMID: 19790256, internal lab contributors). This variant segregated with hyperglycemia, with at least 5 informative meioses in multiple families (PP1_Strong; internal lab contributors). In summary, c.1156C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398705/MONDO:0015967/086 2024-04-28 2024-04-28 Semidominant inheritance HP:0032113 Supports CHEBI:79699 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0033771 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0018802 infores:hetionet CHEBI:2922 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0016204 infores:hetionet CAID:CA386960572 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960572 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP1 The c.498C>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 166 (p.(Tyr166Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.498C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023: PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960572/MONDO:0015967/017 2024-09-19 2024-09-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9332 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0033774 infores:hetionet CAID:CA409121257 biolink:causes MONDO:0007064 infores:clingen CAID:CA409121257 MONDO:0007064 PMID: Likely Pathogenic PVS1_Strong, PP4, PM2_Supporting PM3 The NM_000022.4(ADA):c.363-2A>G variant is a splice site variant predicted to cause skipping of exon four causing an in frame deletion of p.Cys75_Gly122 and removing 13% of the protein (PVS1_strong). At least one pathogenic variant has been reported in this region, NM_000022.4(ADA):c.311C>T (p.Pro104Leu) (ClinVar ID 565486, Pathogenic; provisionally classified Likely Pathogenic by the SCID VCEP). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient has been reported with this variant, P14 (PMID: 30778343) has T-B-NK- SCID (0.5pt) meeting diagnostic criteria (absent T cells and low TRECs (0-11); 0.5pt)(PP4_moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for adenosine deaminase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1_strong, PP4 and PM2_Supporting. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA409121257/MONDO:0007064/114 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0281981 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0013395 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0035258 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1956346 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151559 infores:hetionet CHEBI:8707 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0085614 infores:hetionet CHEBI:48273 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0085616 infores:hetionet UMLS:C0005740 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0010200 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0231919 infores:hetionet CHEBI:17688 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0013604 infores:hetionet CAID:CA340743482 biolink:causes MONDO:0100368 infores:clingen CAID:CA340743482 MONDO:0100368 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_000329.3(RPE65):c.1129-2A>G variant disrupts a canonical splice site in intron 10 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). At least one proband harboring this variant exhibits a phenotype including diagnosis of eoRD which was present from birth (1.0 pt), poor visual acuity (1 pt), diffuse retinal atrophy with pigmented clumps (0.5 pts) and no other likely cause of disease found after whole exome sequencing (2 pts), which together are specific for RPE65-related recessive retinopathy (total 4.5 points, PMID: 27874104, PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) and has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 27874104). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3_Supporting, PP4, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340743482/MONDO:0100368/120 2024-12-12 2024-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2704 biolink:causes MONDO:0007275 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0007286 infores:hetionet CHEBI:63717 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0022672 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085096 infores:hetionet CHEBI:6538 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0002792 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0020458 infores:hetionet CHEBI:4798 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0030252 infores:hetionet CHEBI:9123 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0152198 infores:hetionet CHEBI:3223 biolink:causes UMLS:C0424091 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0424091 infores:hetionet GO:0098910 biolink:causes GO:0086026 infores:ubergraph knowledge_assertion manual_agent GO:0098910 GO:0086026 CHEBI:8871 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151907 infores:hetionet CHEBI:7640 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0235660 infores:hetionet UNII:9YCX42I8IU biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0015672 infores:hetionet CHEBI:16714 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0009676 infores:hetionet CHEBI:4877 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0003862 infores:hetionet CHEBI:5855 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0042571 infores:hetionet CHEBI:47780 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0235660 infores:hetionet CAID:CA210754 biolink:causes MONDO:0013144 infores:clingen CAID:CA210754 MONDO:0013144 PMID: Pathogenic PS4, PS3_Supporting, PP1_Strong, PP3, PP4, PM2_Supporting The NM_000488.4(SERPINC1):c.1277C>T variant predicts a missense change from Serine to Leucine at position 426. Several probands and related individuals are reported in the literature with antithrombin deficiency and the Ser426Leu variant, meeting criteria for PS4 and PP4 (PMID: 34800304, 36093136, 3563966, 28300866, 30721820). The variant was seen across a total of 8 meioses amongst 3 families meeting PP1_Strong (PMID: 30721820, 3512602, 3563966). The variant was shown to impair complex formation with thrombin when the variant was expressed in rabbit reticulocytes (PMID: 2207328). The variant is absent in gnomAD (v2.1.1 and v3.1.1) meeting PM2_Supporting. It has a REVEL score of 0.88, which meets the PP3 set threshold (>0.6). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel: PS4, PP1_Strong, PP3, PP4, PS3_Supporting, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210754/MONDO:0013144/084 2024-09-21 2024-09-30 Autosomal dominant inheritance HP:0000006 Supports PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0039971 infores:hetionet CHEBI:7640 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0917801 infores:hetionet CHEBI:70718 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0031542 infores:hetionet CHEBI:135736 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0428977 infores:hetionet CHEBI:3219 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027796 infores:hetionet CHEBI:85161 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0019521 infores:hetionet CHEBI:6916 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0030305 infores:hetionet CHEBI:135961 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0151786 infores:hetionet CHEBI:47898 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C3665386 infores:hetionet CHEBI:27974 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1368065 infores:hetionet CHEBI:3756 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0009676 infores:hetionet CHEBI:46081 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0015230 infores:hetionet CHEBI:63620 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0023530 infores:hetionet CHEBI:39867 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0004604 infores:hetionet CHEBI:194135 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0023510 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0012833 infores:hetionet CHEBI:63612 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0003537 infores:hetionet CHEBI:50648 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009763 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0042075 infores:hetionet UMLS:C0065374 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0003862 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0392025 infores:hetionet UMLS:C0657912 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003962 infores:hetionet CHEBI:91834 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0039231 infores:hetionet CHEBI:204928 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0014518 infores:hetionet CAID:CA404071092 biolink:causes MONDO:0007750 infores:clingen CAID:CA404071092 MONDO:0007750 PMID: Likely Pathogenic PVS1_Moderate, PM5, PM2 BP4, BA1, PS3, PS1, BP7, BS1, BS3, PM4, PP3, PP4 The NM_000527.5(LDLR):c.2T>C (p.Met1Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012)The supporting evidence is as follows:PM2 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404071092/MONDO:0007750/013 2022-04-22 2022-04-22 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3207 biolink:causes MONDO:0018373 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0027543 infores:hetionet CHEBI:63581 biolink:causes UMLS:C1142358 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C1142358 infores:hetionet CAID:CA1244341 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244341 MONDO:0020367 PMID: Uncertain Significance BP7, PM2_Supporting, PS4_Supporting, BP4 BS1, BS3, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BA1 The c.42G>A variant in MYOC is a synonymous variant (p.Glu14=). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002892 (1 allele out of 34,578), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 4.764 which met the ≤ 10 threshold for BP4, and the GERP score = -3.28 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 probands with juvenile open angle glaucoma have been reported carrying this variant (PMID: Yadav et al, 2022 pre-print), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, BP7, PS4_Supporting. PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244341/MONDO:0020367/019 2023-05-03 2023-05-03 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:1904130 biolink:causes GO:0014022 infores:ubergraph knowledge_assertion manual_agent GO:1904130 GO:0014022 CHEBI:4798 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0030193 infores:hetionet GO:1905933 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:1905933 GO:0030154 CHEBI:45599 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0000737 infores:hetionet CAID:CA409106207 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106207 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PM1_Supporting The c.561C>G variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of cysteine to tryptophan at codon 187 (p.(Cys187Trp)) of NM_175914.4. This variant is located within the ligand binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). In summary, the c.561C>G variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106207/MONDO:0015967/085 2023-08-13 2023-08-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:30659 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0015967 infores:hetionet CAID:CA024163 biolink:causes MONDO:0007783 infores:clingen CAID:CA024163 MONDO:0007783 PMID: Likely Pathogenic PS4_Moderate, PM1_Supporting, PP3_Moderate, PS3_Supporting BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with valine at codon 4838 of the RYR1 protein, p.(Leu4838Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in seven unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID: 19191329, 30236257, 11928716, 16732084, 21157159). A functional study in CHO cells shows an increased sensitivity to RYR1 agonists, PS3_Supporting (PMID: 28687594). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.882) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Supporting, PS4_Moderate, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024163/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:50381 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0917801 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0948594 infores:hetionet CAID:CA178113 biolink:causes MONDO:0019497 infores:clingen CAID:CA178113 MONDO:0019497 PMID: Likely Benign BS1, PP3 The filtering allele frequency of the c.5836T>C (p.Tyr1946His) variant in the TECTA gene is 0.495% for Ashkenazi Jewish chromosomes by gnomAD (64/10370 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3. The HL EP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case since computational scores are error prone, especially when predicting pathogenicity. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PP3. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA178113/MONDO:0019497/005 2019-01-28 2019-07-17 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:8597 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0241934 infores:hetionet CAID:CA397722206 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722206 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4(ACADVL):c.155C>G (p.Ser52Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 3/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant nor has the variant been reported in the literature in any individuals with VLCADD. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated November 9, 2021 and the recurated classification was approved by the expert panel on February 27, 2024. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722206/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4653 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0037011 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0020649 infores:hetionet CHEBI:47612 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0027051 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0853149 infores:hetionet CHEBI:16796 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0040034 infores:hetionet CHEBI:6444 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C1443060 infores:hetionet CHEBI:45367 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0426576 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0243026 infores:hetionet CHEBI:91834 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0018681 infores:hetionet CHEBI:5441 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0004093 infores:hetionet CHEBI:46295 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0687713 infores:hetionet CAID:CA005255 biolink:causes MONDO:0100316 infores:clingen CAID:CA005255 MONDO:0100316 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3 PS3, BS3, PP4, PP1, PM5 NM_000218.3(KCNQ1):c.1096C>T is a missense variant that causes substitution of arginine with tryptophan at position 366. This variant is present in gnomAD v.4.0.0 at a maximum allele frequency of 0.0000008993, with 1 allele / 1111974 total alleles in the European non-Finnish population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is rare and has been reported in 7 apparently unrelated probands affected with long QT syndrome 1 (PS4; PMID: 29497013, PMID: 24606995, PMID: 9693036, PMID: 26063740, PMID: 24363352, PMID: 19841300). The computational predictor REVEL gives a score of 0.921, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant has been reported to segregate with long QT syndrome 1 through the proband and 3 affected family members from one family, however, each affected family member lacks the confirmation of the Schwartz score >3.5 or QTc >480ms or syncope necessary to be included / counted for the PP1 code (PMID: 21499742). This variant has been reported in at least one affected proband exhibiting QTc prolongation above 480 milliseconds, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 code is not met (PMID: 29497013). This variant has been shown to disrupt KCNQ1 function in one experimental assay, manual patch clamp (PMID: 16556865), and shown not to disrupt KCNQ1 function in another experimental assay, the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), which has generated a prediction of normal effects of the mutant on IKs_classification, V1/2_classification, act_classification, and deact_classification (PMID: 29021305), so neither PS3_Supporting nor BS3_Supporting were met. In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4, PM2_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA005255/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7903 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C1096343 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0015734 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0015734 infores:hetionet CHEBI:4911 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0004604 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0002871 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0030305 infores:hetionet CHEBI:75275 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0015376 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0015397 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0855242 infores:hetionet NCBIGene:6023 biolink:causes MONDO:0054560 infores:monarchinitiative not_provided not_provided HGNC:10031 MONDO:0054560 uuid:f402cb81-2dca-403d-a7f1-9a87de809822 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0048631 biolink:causes GO:0060538 infores:ubergraph knowledge_assertion manual_agent GO:0048631 GO:0060538 CHEBI:31515 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0023380 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0549385 infores:hetionet CHEBI:367163 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C2047937 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0235763 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0235763 infores:hetionet CHEBI:5165 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0033975 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0746883 infores:hetionet NCBIGene:6141 biolink:causes MONDO:0032668 infores:monarchinitiative not_provided not_provided HGNC:10310 MONDO:0032668 uuid:8f0b570e-c1b4-43ac-8975-ca9bea34bf37 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:84343 biolink:causes MONDO:0013555 infores:monarchinitiative not_provided not_provided HGNC:15597 MONDO:0013555 uuid:e03687d9-5cf4-4a82-bef2-c5ada85cacd9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6715 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1112214 infores:hetionet CHEBI:92923 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0026826 infores:hetionet CHEBI:3638 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0000729 infores:hetionet CHEBI:47381 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0022281 infores:hetionet CHEBI:2704 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0241633 infores:hetionet NCBIGene:83990 biolink:causes MONDO:0012187 infores:monarchinitiative not_provided not_provided HGNC:20473 MONDO:0012187 uuid:568b22cd-995e-4560-9d6c-280e5c58c3d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48947 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0085692 infores:hetionet CHEBI:51450 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0151517 infores:hetionet CHEBI:5801 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0002874 infores:hetionet CHEBI:10119 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0027849 infores:hetionet GO:1902829 biolink:causes GO:0021516 infores:ubergraph knowledge_assertion manual_agent GO:1902829 GO:0021516 CHEBI:9168 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0005940 infores:hetionet CHEBI:15544 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0039231 infores:hetionet CHEBI:73274 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0028734 infores:hetionet CHEBI:74947 biolink:causes MONDO:0043875 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0041364 infores:hetionet NCBITaxon:10359 biolink:causes MONDO:0850289 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10359 MONDO:0850289 CHEBI:5801 biolink:causes HP:0033832 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0332579 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0027765 infores:hetionet CHEBI:4798 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0010200 infores:hetionet CHEBI:91541 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C1868752 infores:hetionet CHEBI:8356 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0476273 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0475746 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0475746 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151888 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0009241 infores:hetionet CHEBI:77733 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0234133 infores:hetionet CHEBI:5132 biolink:causes MONDO:0006988 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0038732 infores:hetionet CHEBI:8327 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0030554 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0017574 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0086565 infores:hetionet CHEBI:28487 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0242422 infores:hetionet CHEBI:5864 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0034069 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0429029 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0429029 infores:hetionet NCBIGene:10801 biolink:causes MONDO:0008076 infores:monarchinitiative not_provided not_provided HGNC:7323 MONDO:0008076 uuid:9e3d0275-db37-4b35-b73c-4246d6f58a00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94686 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C1971624 infores:hetionet CHEBI:6129 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013428 infores:hetionet CAID:CA226446 biolink:causes MONDO:0100437 infores:clingen CAID:CA226446 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting PP3, PS4 NM_001034853.2(RPGR):c.779-1G>A is a variant disrupting a canonical splice site in intron 7 that is predicted to trigger in-frame skipping of exon 8, encoding a critical domain in the RPGR gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 1 affected meiosis from 1 family, with mother and son both affected (PP1; PMID: 21857984). This variant has been reported in at least 2 probands (PMID: 14564670, PMID: 21857984), only one of whom has been described in detail, so that PS4_Supporting is not met. One proband harboring this variant exhibits a phenotype including rod involvement relatively greater than cone involvement (1 pt), a delayed or milder phenotype in females (1 pt), and a family history showing no male-to-male transmission ( 2 pts), which together are specific for RPGR-related retinopathy (4 points, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, PP1, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226446/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:63791 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0011603 infores:hetionet CAID:CA120548 biolink:causes MONDO:0044970 infores:clingen CAID:CA120548 MONDO:0044970 PMID:16199753 Likely Pathogenic PP3, PS4_Supporting, PS3_Supporting, PP1_Moderate, PM2 PS2, PM6 The m.7497G>A variant in MT-TS1 has been reported in three unrelated individuals with primary mitochondrial disease with shared features of exercise intolerance, proximal myopathy, lactic acidosis, and myalgia. Age at presentation ranged from three years old to the 30s. Muscle biopsies showed ragged red fibers, COX-negative fibers, and reduced activities of complexes I and IV. All probands were homoplasmic for the variant in muscle and it was present in various other tissues at levels >90%. (PS4_supporting; PMIDs: 14605505, 9778262). This variant segregated with disease in each of the three families reported (PP1_moderate). The probands were homoplasmic for the variant muscle and/or blood. In one family, the unaffected mother harbored the variant at 10% in blood (PMID: 14605505). In the second family, the unaffected mother harbored the variant at 62% and the unaffected brother had the variant at 62% in blood (PMID: 9778262). In the third family, an affected daughter with myalgia had the variant at 90% in blood and an unaffected brother has the variant at 70% (PMID: 9778262). There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (92.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activities (PS3_supporting, PMID: 16199753). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120548/MONDO:0044970/015 2023-04-17 2023-05-19 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:75722 biolink:causes UMLS:C0027531 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0027531 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0700184 infores:hetionet CHEBI:49668 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0019158 infores:hetionet CHEBI:6367 biolink:causes HP:0002345 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234376 infores:hetionet CHEBI:6933 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0017178 infores:hetionet NCBIGene:123606 biolink:causes MONDO:0010878 infores:monarchinitiative not_provided not_provided HGNC:17043 MONDO:0010878 uuid:d443c130-cdfb-47a9-9af7-3e8947ce0159 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15552 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0003123 infores:hetionet CHEBI:499361 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0687133 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0020649 infores:hetionet CHEBI:8404 biolink:causes UMLS:C0235030 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0235030 infores:hetionet CHEBI:261649 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0520893 infores:hetionet CAID:CA412376878 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376878 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting BP4, PP3 NM_000330.4(RS1):c.61G>A (p.Gly21Arg) is a missense variant encoding the substitution of glycine with arginine at amino acid 21. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.601, which is below the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and above the BP4 threshold of >0.290 and does not predict a damaging effect on RS1 function. The splicing impact predictor SpliceAI gives scores of 0.13 for acceptor loss and 0.12 for donor loss, which are below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and do not strongly predict an impact on splicing, so neither PP3 nor BP4 is met. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376878/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:188986 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0021053 infores:hetionet CHEBI:7478 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0549249 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020456 infores:hetionet CHEBI:63618 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0239571 infores:hetionet CHEBI:63616 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0027497 infores:hetionet CHEBI:31236 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151907 infores:hetionet CHEBI:8707 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011880 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0038454 infores:hetionet CHEBI:31981 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0034065 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0018802 infores:hetionet CHEBI:28748 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006840 infores:hetionet CHEBI:681848 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0027497 infores:hetionet CHEBI:8024 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0699744 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0004623 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0028738 infores:hetionet CHEBI:9168 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0151603 infores:hetionet CHEBI:63791 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0030794 infores:hetionet CHEBI:47519 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0917801 infores:hetionet CHEBI:6931 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0029408 infores:hetionet CHEBI:77260 biolink:causes MONDO:0006733 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0013238 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0857121 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0857121 infores:hetionet CHEBI:66964 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0015732 infores:hetionet GO:0045694 biolink:causes GO:0009561 infores:ubergraph knowledge_assertion manual_agent GO:0045694 GO:0009561 CHEBI:6933 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0235169 infores:hetionet CHEBI:15367 biolink:causes HP:0500011 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0332601 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0233494 infores:hetionet CHEBI:63631 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1457883 infores:hetionet CHEBI:100241 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0234632 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0027765 infores:hetionet CHEBI:6690 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0018681 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0332575 infores:hetionet CHEBI:64312 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1302752 infores:hetionet CHEBI:9763 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C1257843 infores:hetionet NCBIGene:8363 biolink:causes MONDO:0030730 infores:monarchinitiative not_provided not_provided HGNC:4785 MONDO:0030730 uuid:091f2eca-334a-48bd-b413-7490fcca0fec biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15407 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0033975 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0007114 infores:hetionet CHEBI:3077 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0019080 infores:hetionet CHEBI:3380 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0015230 infores:hetionet CHEBI:9907 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0011603 infores:hetionet CHEBI:3699 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0015672 infores:hetionet CHEBI:44185 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0018926 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0235969 infores:hetionet CHEBI:135613 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0151517 infores:hetionet CHEBI:63589 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0030193 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0036454 infores:hetionet GO:1901620 biolink:causes GO:0021904 infores:ubergraph knowledge_assertion manual_agent GO:1901620 GO:0021904 CHEBI:8776 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0011616 infores:hetionet CHEBI:15940 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0232462 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0006840 infores:hetionet CAID:CA3232180 biolink:causes MONDO:0012163 infores:clingen CAID:CA3232180 MONDO:0012163 PMID: Likely Benign BS1, BS2_Supporting, BP7 The c.1020T>G (p.Leu340=) variant (NM_002185.5) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 84/24966) of the c.1020T>G variant in IL7R is 0.002614 for African/African American chromosomes by gnomAD v 2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). No homozygous individuals have been reported (BS2_Supporting).In summary, this variant is classified as Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BS1, BS2_Supporting, and BP7. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3232180/MONDO:0012163/119 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31236 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021400 infores:hetionet CAID:CA213965 biolink:causes MONDO:0015967 infores:clingen CAID:CA213965 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PS4 The c.575_582+10del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of NM_175914.5. This variant, located in biologically relevant exon 5, is predicted to disrupt the canonical splice site and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (ClinVar ID: 36355). In summary, the c.575_582+10del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213965/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA10568504 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568504 MONDO:0010602 PMID: Benign BP7, BP4, BA1 PS4 The c.1086G>A (p.Ala362=) variant is reported at an MAF of 0.03761 (713/18957 alleles) in the African/African-American population in gnomAD v2.1.1 with 201 hemizygotes, meeting BA1 criteria of MAF > 0.000333. SpliceAI predicts no impact on splicing with scores of 0, and the nucleotide is not conserved based on agreement between PhyloP (-2.25) and PhastCons (0) scores meeting BP4 and BP7. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: BA1, BP4, BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568504/MONDO:0010602/071 2024-02-01 2024-07-11 X-linked inheritance HP:0001417 Contradicts true CHEBI:10125 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0020651 infores:hetionet CHEBI:50777 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0020580 infores:hetionet CHEBI:194135 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0085593 infores:hetionet CHEBI:4469 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0014518 infores:hetionet CHEBI:31515 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0042023 infores:hetionet CHEBI:4710 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0026946 infores:hetionet CHEBI:68558 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0004093 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0004238 infores:hetionet CAID:CA323959 biolink:causes MONDO:0019169 infores:clingen CAID:CA323959 MONDO:0019169 PMID: Pathogenic PM1, PP3, PP4, PS2, PM2 PM5, BS2, BA1, PS1, BS1 The c.506C>T variant in the PDHA1 gene is a missense mutation occurring in a hotspot domain (aa position A169, located in α β heterodimer interface (PM1). This variant is absent from population databases (PM2). This variant has been reported in three individuals in the literature with presentations consistent with PDHA1-related disease. These three cases include two assumed de novo cases (PMID: 20002461 and PMID: 21914562), and one maternity confirmed de novo case via exome sequencing in PMID: 31683770 (PS2). PMID: 20002461 Western Blot studies showed reduced E1a, and Imbard et al 2011 PDC studies indicate activity <3rd percentile in fibroblasts (PP4). In silico predictors suggest a deleterious effect (REVEL score – 0.946; PP3). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM1, PM2, PS2, PP3, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA323959/MONDO:0019169/014 2021-05-06 2021-05-06 X-linked inheritance HP:0001417 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:119915 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151602 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0009450 infores:hetionet CHEBI:15640 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0340865 infores:hetionet CHEBI:8874 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0006142 infores:hetionet CHEBI:17650 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0020488 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0239150 infores:hetionet GO:0070170 biolink:causes GO:0042476 infores:ubergraph knowledge_assertion manual_agent GO:0070170 GO:0042476 CHEBI:72690 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0010200 infores:hetionet CHEBI:63115 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0264906 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0162429 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0854121 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0854121 infores:hetionet CHEBI:34385 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0851341 infores:hetionet CHEBI:6741 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0014518 infores:hetionet CHEBI:3314 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00326 UMLS:C0042963 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0029882 infores:hetionet CHEBI:6076 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0547030 infores:hetionet NCBIGene:5699 biolink:causes MONDO:0971001 infores:monarchinitiative not_provided not_provided HGNC:9538 MONDO:0971001 uuid:33bb18ab-1d15-4d7f-bd74-0e48607daf36 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0235905 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0235905 infores:hetionet CHEBI:3219 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013362 infores:hetionet CHEBI:52172 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0039070 infores:hetionet CHEBI:9943 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0026827 infores:hetionet CHEBI:31711 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C3665346 infores:hetionet CHEBI:2955 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0023530 infores:hetionet CHEBI:474053 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0085631 infores:hetionet CAID:CA1589199 biolink:causes MONDO:0021060 infores:clingen CAID:CA1589199 MONDO:0021060 PMID: Benign BP7, BA1, BP4 The c.201A>G (p.Gln67=) variant in PPP1CB is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, the computational predictor REVEL does not predict a damaging effect on PPP1CB function (BP4, BP7). The filtering allele frequency in gnomAD v2 is 60.64% in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1589199/MONDO:0021060/128 2024-12-03 2025-03-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9123 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0035243 infores:hetionet CAID:CA024932 biolink:causes MONDO:0100150 infores:clingen CAID:CA024932 MONDO:0100150 PMID: Benign BP7, BA1, BP4 BS1, PM2, PP3 The c.8589T>C (p.Ser2863=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 40732/91032, 9442 homozygotes) of the c.8589T>C variant in RYR1 is 0.4430 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA024932/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CHEBI:15367 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0853700 infores:hetionet CAID:CA147717 biolink:causes MONDO:0015152 infores:clingen CAID:CA147717 MONDO:0015152 PMID: Benign BA1, BP2 BP4 The NM_003494.4: c.1120G>C variant in DYSF, which is also known as NM_001130987.2: c.1216G>C p.(Val406Leu), is a missense variant predicted to cause substitution of valine by leucine at amino acid 374 (p.Val374Leu). The filtering allele frequency of the variant is 0.009514 for European (non-Finnish) genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 926/152226), which is higher than the VCEP threshold of 0.003 (BA1). This variant has also been observed in cis with the variant c.610C>T p.(Arg204Ter), which is classified as pathogenic by the ClinGen LGMD VCEP (PMID: 25135358) (BP2). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.21, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1, BP2. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA147717/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA2579830398 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830398 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1 PP1, PP4 The c.-170A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is located within the HNF1A/HNF1B binding region (c.-170 to c.-173 and c.-178 to c.-181) of the P2 promoter of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF4A-monogenic diabetes, however, PP4 is unable to be applied due to lack of sufficient clinical data. This variant segregated with diabetes with a single meiosis in one family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.-170A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 4.0.0, approved 10/10/2025): PM1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830398/MONDO:0015967/085 2025-10-13 2025-10-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5109 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01047 UMLS:C0027424 infores:hetionet CHEBI:7465 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0030446 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0162429 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0029408 infores:hetionet CHEBI:15544 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2937358 infores:hetionet GO:0090175 biolink:causes GO:0060429 infores:ubergraph knowledge_assertion manual_agent GO:0090175 GO:0060429 CHEBI:3761 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0004134 infores:hetionet CHEBI:50663 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0027497 infores:hetionet CHEBI:3752 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0015230 infores:hetionet CHEBI:46557 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0004096 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0033975 infores:hetionet CAID:CA9043668 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043668 MONDO:0012999 PMID: Likely Benign PM2_Supporting, BP4, BP7 The NM_000156.6:c.408G>A (p.Thr136=) variant in GAMT is a synonymous variant in exon 4. It is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 (1/ 18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). This variant does not appear to have been previously reported in the published literature. It is noted in ClinVar (Variation ID: 699986). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational predicttion suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GAMT-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043668/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:28177 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0030920 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002453 infores:hetionet CHEBI:63584 biolink:causes EFO:1001412 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0152169 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0149931 infores:hetionet NCBIGene:5062 biolink:causes MONDO:0100119 infores:monarchinitiative not_provided not_provided HGNC:8591 MONDO:0100119 uuid:7bf1fb18-0e21-47be-8392-e39cc6174a67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0034065 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0948594 infores:hetionet CHEMBL.COMPOUND:CHEMBL2367706 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00364 UMLS:C0020625 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0574067 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0041912 infores:hetionet CAID:CA2580098642 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098642 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.509-10G>C is an intronic variant that has a SpliceAI score ≤ 0.20 (0.00) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.88) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098642/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9566 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0018418 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0234215 infores:hetionet CHEBI:50663 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0521839 infores:hetionet CHEBI:50173 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0014591 infores:hetionet CHEBI:64064 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0039231 infores:hetionet GO:1905292 biolink:causes GO:0048513 infores:ubergraph knowledge_assertion manual_agent GO:1905292 GO:0048513 CHEBI:4466 biolink:causes HP:0012416 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020440 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0235234 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0178298 infores:hetionet CHEBI:2904 biolink:causes MONDO:1030008 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0026266 infores:hetionet NCBIGene:6929 biolink:causes MONDO:0859234 infores:monarchinitiative not_provided not_provided HGNC:11633 MONDO:0859234 uuid:a8853562-9a6f-4da8-8845-1b755d8602d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27565 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0024299 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0006277 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0270458 infores:hetionet CHEBI:9654 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0003467 infores:hetionet CHEBI:4975 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0151773 infores:hetionet CAID:CA6909604 biolink:causes MONDO:0015152 infores:clingen CAID:CA6909604 MONDO:0015152 PMID: Likely Benign BS1, BP4 BP7 The NM_000231.3: c.196-7_196-6del variant in SGCG is an intronic deletion. The filtering allele frequency for this variant is 0.001107 for the African/African American population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 38/25708 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.0009 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0, which is less than the LGMD threshold of 0.05 for this criterion (BP4). Because this variant occurs in a splice region (+7/-21), BP7 is not applicable. In summary, this variant meets the criteria to be classified as Likely benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA6909604/MONDO:0015152/185 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8093 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0042373 infores:hetionet CHEBI:72564 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0085631 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1096035 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1096035 infores:hetionet CHEBI:18243 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0020538 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0314719 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0233494 infores:hetionet CHEBI:17347 biolink:causes HP:0011902 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0349705 infores:hetionet CHEBI:3508 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0042963 infores:hetionet CHEBI:63791 biolink:causes MONDO:0020108 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0002880 infores:hetionet CHEBI:32293 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0022281 infores:hetionet CHEBI:92769 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0020517 infores:hetionet CHEBI:4551 biolink:causes MONDO:0020744 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0264907 infores:hetionet NCBIGene:57165 biolink:causes MONDO:0012125 infores:monarchinitiative not_provided not_provided HGNC:17494 MONDO:0012125 uuid:5b563cdc-e777-4492-bba9-b7cdc360f202 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10650 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0036973 infores:hetionet GO:0070235 biolink:causes GO:0043029 infores:ubergraph knowledge_assertion manual_agent GO:0070235 GO:0043029 CHEBI:127342 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0600142 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0162429 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0027051 infores:hetionet CHEBI:188986 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0011570 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0178298 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0041969 infores:hetionet GO:2000311 biolink:causes GO:0034220 infores:ubergraph knowledge_assertion manual_agent GO:2000311 GO:0034220 CHEBI:5790 biolink:causes GO:0097195 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0031924 infores:hetionet GO:0048324 biolink:causes GO:0048319 infores:ubergraph knowledge_assertion manual_agent GO:0048324 GO:0048319 UMLS:C0010592 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0333641 infores:hetionet CHEBI:144093 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0013395 infores:hetionet CAID:CA024161 biolink:causes MONDO:0018493 infores:clingen CAID:CA024161 MONDO:0018493 PMID: Likely Benign PS4_Supporting, BS2_Supporting, BS3_Supporting PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This frameshift variant, p.Gln4837Argfs*3, predicts the substitution of glutamine with arginine at codon 4837 and a premature stop codon at position 3 of the new reading frame. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:17293538). Two relatives of this individual were shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented. This variant predicts a loss of function due to nonsense mediated decay, loss of function variants are not expected to cause MH. Experiments expressing this variant in HEK293 cells did not demonstrate NMD as determined by protein expression on a Western blot. Expression of this variant alone showed no calcium release upon stimulation with caffeine, when the variant was transfected with wild-type RYR1 the EC50 was comparable to that observed in cells expressing wild-type RYR1 alone, BS3_Supporting was applied (PMID:17293538). Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386), (relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024161/MONDO:0018493/012 2022-03-14 2022-03-14 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:3752 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0004093 infores:hetionet CHEBI:2038 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0017565 infores:hetionet CAID:CA404093185 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093185 MONDO:0007750 PMID: Uncertain Significance BP4, PM2, PP4 PS3, PM5 The NM_000527.5 (LDLR):c.1957G>A (p.Val653Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows:PM2: This variant is absent in all specified genetic ancestry groups (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who meets Simon Broome criteria for FH after alternative causes of high cholesterol were excluded, reported in VCI by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP. Sorbonne Université, Hospital de la Pitié-Salpêtrière, France.BP4: REVEL=0.372, it is below 0.5, splicing evaluation required. MES: A) variant not on limits. B) Variant not on limit creating de novo acceptor; variant is on limit however does not create GT. C) there is not a GT nearby. Variant is not predicted to alter splicing, and result is confirmed by SpliceAI, therefore BP4 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093185/MONDO:0007750/013 2024-02-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:134991 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C3665347 infores:hetionet CHEBI:2788 biolink:causes NCIT:C112176 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0948786 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0038941 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0038941 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0349506 infores:hetionet CHEBI:35778 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0858635 infores:hetionet CHEBI:8364 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0015230 infores:hetionet CHEBI:47780 biolink:causes MONDO:0011728 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0005747 infores:hetionet CHEBI:45716 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0008031 infores:hetionet CHEBI:3181 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042023 infores:hetionet CHEBI:3814 biolink:causes UMLS:C0265031 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0265031 infores:hetionet CHEBI:2453 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0687713 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0024115 infores:hetionet CHEBI:63577 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0001122 infores:hetionet CHEBI:85161 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0015672 infores:hetionet CHEBI:63610 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0151632 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1443060 infores:hetionet CHEBI:84500 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0043352 infores:hetionet CHEBI:50122 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0004604 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0018099 infores:hetionet CHEBI:7852 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0014591 infores:hetionet CHEBI:9123 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011253 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018991 infores:hetionet UMLS:C0065374 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0033774 infores:hetionet CHEBI:3994 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0022354 infores:hetionet UMLS:C0004609 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0026205 infores:hetionet CHEBI:92712 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0009676 infores:hetionet UMLS:C0657912 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0542571 infores:hetionet CHEBI:63605 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C2937358 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004169 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0376356 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0235431 infores:hetionet CHEBI:6912 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0018524 infores:hetionet CAID:CA270424 biolink:causes MONDO:0010726 infores:clingen CAID:CA270424 MONDO:0010726 PMID: Pathogenic PM2_Supporting, PS4, PM1, PM5, PM6_Very Strong, PS3_Supporting, PP4, PP3 The p.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270424/MONDO:0010726/036 2021-10-26 2024-09-09 X-linked inheritance HP:0001417 Supports CHEBI:64312 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017178 infores:hetionet CHEBI:63617 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085632 infores:hetionet CHEBI:6970 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0002994 infores:hetionet CHEBI:6128 biolink:causes HP:0033838 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0233477 infores:hetionet CHEBI:49603 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0236075 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0242350 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0267792 infores:hetionet CHEBI:8768 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0017675 infores:hetionet CHEBI:64028 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0085636 infores:hetionet CHEBI:31624 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0231218 infores:hetionet CHEBI:4974 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0022354 infores:hetionet CHEBI:3814 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0020517 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233485 infores:hetionet UMLS:C0120107 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0013144 infores:hetionet CHEBI:7445 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0013404 infores:hetionet CHEBI:3716 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0012833 infores:hetionet CHEBI:3223 biolink:causes HP:0007994 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C2937228 infores:hetionet CHEBI:7492 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0030193 infores:hetionet CHEBI:3696 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013447 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0155169 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151517 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0001122 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549445 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549445 infores:hetionet CHEBI:63925 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0013404 infores:hetionet NCBITaxon:59263 biolink:causes MONDO:0005987 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:59263 MONDO:0005987 CHEBI:8435 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0262385 infores:hetionet CHEBI:7936 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151610 infores:hetionet CHEBI:3654 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0011603 infores:hetionet CHEBI:63620 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0009763 infores:hetionet GO:1904412 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:1904412 GO:0007507 CL:0000775 biolink:causes GO:0070942 infores:drugmechdb knowledge_assertion manual_agent CL:0000775 GO:0070942 DB01394_MESH_D006073_1DB01394_MESH_D010505_1 CAID:CA1244136 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244136 MONDO:0020367 PMID: Likely Benign BP7, BS1, BP4 BS3, PM2, PM6, PP1, PP3, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.864C>T variant in MYOC is a synonymous variant (p.Ile288=). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.003060, which met the ≥ 0.001 threshold set for BS1 (61 alleles out of 19 934, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.181 which met the ≤ 10 threshold for BP4, and the GERP score = -6.07 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244136/MONDO:0020367/019 2022-02-21 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA415075833 biolink:causes MONDO:0010305 infores:clingen CAID:CA415075833 MONDO:0010305 PMID: Uncertain Significance PP4, PM2_Supporting, PVS1_Moderate The NM_005629.4:c.1A>G p.(Met1Val) variant in SLC6A8 variant in SLC6A8 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Moderate). The variant was identified in a family with increased urinary creatine to creatinine ratio; additional details not provided (PMID: 23644449) (PP4). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. At the time of this curation, this variant has not been reported in individuals with suspected Creatine Transporter Deficiency in the literature. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 23, 2023). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415075833/MONDO:0010305/027 2023-03-23 2024-03-29 X-linked inheritance HP:0001417 Inconclusive true CHEBI:5790 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C2939147 infores:hetionet CHEBI:135566 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0234708 infores:hetionet CHEBI:3479 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0404521 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0020651 infores:hetionet CHEBI:135736 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0039231 infores:hetionet CHEBI:171719 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0034063 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0014130 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0006852 infores:hetionet CAID:CA7330611 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330611 MONDO:0100216 PMID: Likely Benign BP4, BS2_Supporting PM2, PM6, BA1, BP2, PP3, PP1, PP4, PM5, PM1, PS1, PS3, PS4, PS2, BS1, BS3, BS4 The NM_177438.2:c.5623G>A variant in DICER1 is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 1875 (p.Asp1875Asn). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007811 (5/64012 alleles) in European (Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.321, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). Another missense variant c.5623G>T, p.Asp1875Tyr in the same codon has been reported (ClinVar Variation ID: 412042). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER1 VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as likely benign for DICER1 related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4 (Bayesian Points: -2; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330611/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6456 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0855775 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0205204 infores:hetionet CHEBI:2675 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C1368065 infores:hetionet NCBIGene:7042 biolink:causes MONDO:0011690 infores:monarchinitiative not_provided not_provided HGNC:11768 MONDO:0011690 uuid:43595ba3-1cf1-4d27-b62a-2dba6eae2afa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94440 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0036572 infores:hetionet CHEBI:51041 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C2830004 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005883 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019364 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005510 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0020295 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0548823 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0020517 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0314719 infores:hetionet NCBIGene:8943 biolink:causes MONDO:0014885 infores:monarchinitiative not_provided not_provided HGNC:568 MONDO:0014885 uuid:0b612062-51f1-4fcc-90e4-3b5e49a8a835 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135939 biolink:causes MONDO:0002427 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0007760 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0036572 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0004093 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042075 infores:hetionet CHEBI:7514 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C2830004 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0006145 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0151613 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151613 infores:hetionet CHEBI:194135 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041834 infores:hetionet CHEBI:15551 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0012739 infores:hetionet CHEBI:37333 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C3665347 infores:hetionet CAID:CA2582115911 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582115911 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting, PM4_Supporting The NM_005629.4(SLC6A8):c.1607_1612del variant in SLC6A8 is a deletion of 6 nucleotides within exon 12/13 of the SLC6A8 gene and is predicted to lead to an in-frame deletion of 2 amino acids (p.Ile536_Phe537del) (PM4). This variant has been previously reported (PMID: 22281021); however, no data, including zygosity and/or phenotypic features, regarding the individual/s with this variant is provided. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM4, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582115911/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Inconclusive true CHEBI:7445 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0002170 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005082 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007112 infores:hetionet CHEBI:64310 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0030554 infores:hetionet CHEBI:135888 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0151514 infores:hetionet CHEBI:40303 biolink:causes UMLS:C1142028 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C1142028 infores:hetionet CHEBI:31644 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C2242737 infores:hetionet CHEBI:3732 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C3263723 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0042963 infores:hetionet CHEBI:5002 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0030252 infores:hetionet CHEBI:135613 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0042373 infores:hetionet CHEBI:64028 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0575081 infores:hetionet CHEBI:61049 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013447 infores:hetionet CHEBI:3752 biolink:causes MONDO:0019015 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0795690 infores:hetionet CHEBI:8871 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0013384 infores:hetionet CAID:CA410202714 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202714 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS3, BS1, BS4, PM4, PM5, PM3, PP2, PP1, PP4, BS2 NM_001754.4:c.391A>G (p.Thr131Ala) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score >0.75 (0.942) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202714/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6149 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0002871 infores:hetionet CHEBI:49575 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0026827 infores:hetionet CHEBI:31643 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0007222 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0558368 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0558368 infores:hetionet CAID:CA8338048 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338048 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3, PM3_Supporting, PP4_Moderate The c.1269G>A (NM_000018.4) variant in ACADVL is a synonymous variant which occurs in the final nucleotide of exon 12, a position that is generally considered highly conserved. At least one patient with this variant displayed reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels in lymphocytes, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 30194637). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000046 (0.0046%) in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.79 for donor loss, predicting that the variant disrupts the donor splice site of intron 12 of ACADVL (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338048/MONDO:0008723/021 2024-09-10 2024-12-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:44915 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0340464 infores:hetionet CAID:CA377482104 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482104 MONDO:0017623 PMID:29706350PMID:29706350 Uncertain Significance PP3, PP2_Moderate, PM2_Supporting, PS4_Supporting BS3, PS3 NM_000314.8(PTEN):c.283C>A (p.Pro95Thr) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.854).PM2_P: Absent in gnomAD. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482104/MONDO:0017623/003 2025-10-03 2025-10-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:47381 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0242528 infores:hetionet CHEBI:6367 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0948594 infores:hetionet CHEBI:5134 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0031350 infores:hetionet CHEBI:94411 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C2364111 infores:hetionet CAID:CA10584696 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584696 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PS3_Supporting, PM2, PP4 BA1, BP4, BP2, PS1, PS2, BS1, BS3, BS4, BP7, PM4, PM1, PM3, PM5, PM6, PVS1, BS2, PP3, PP1 The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS3_supporting - Level 3 assay: PMID 31395865:Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant).---- functional study is consistent with damaging effect.PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532).PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584696/MONDO:0007750/013 2023-03-20 2023-03-31 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:31199 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB00288 UMLS:C0241157 infores:hetionet CHEBI:77260 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0235266 infores:hetionet CHEBI:7931 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0034063 infores:hetionet CHEBI:3654 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0002874 infores:hetionet CHEBI:520985 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C1306341 infores:hetionet CHEBI:473990 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0015230 infores:hetionet NCBIGene:84679 biolink:causes MONDO:0026723 infores:monarchinitiative not_provided not_provided HGNC:17123 MONDO:0026723 uuid:ef33cf54-4dc7-4831-8a45-a84e1a5cd401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0520887 infores:hetionet CHEBI:9763 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0027497 infores:hetionet NCBIGene:5339 biolink:causes MONDO:0009181 infores:monarchinitiative not_provided not_provided HGNC:9069 MONDO:0009181 uuid:1344dd53-392a-47ad-95ae-a29874d9df14 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17026 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0008370 infores:hetionet CHEBI:63635 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0015967 infores:hetionet CAID:CA512318755 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318755 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.396G>A (p.Val132=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 [-0.65]) (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Bayesian analysis calculates this variant as likely benign. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318755/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50131 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0011570 infores:hetionet CHEBI:9586 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011175 infores:hetionet CHEBI:49668 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0234233 infores:hetionet NCBITaxon:1351 biolink:causes MONDO:0005121 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1351 MONDO:0005121 CHEBI:9448 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0024141 infores:hetionet CAID:CA286506 biolink:causes MONDO:0009861 infores:clingen CAID:CA286506 MONDO:0009861 PMID:8268925PMID:21147011PMID:15943553PMID:11161839PMID:17924342 Likely Pathogenic PP4_Moderate, PM3_Very Strong PM5, PM2, PP3, PS3 PAH-specific ACMG/AMP criteria applied: PP4_Moderate: V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_VeryStrong: Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup. (PMID:15943553; PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA286506/MONDO:0009861/006 2018-08-12 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5855 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C1443060 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0022107 infores:hetionet CAID:CA400021881 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021881 MONDO:0100326 PMID: Pathogenic PM3, PP4_Strong, PP1_Moderate, PP3, PM2_Supporting The NM_000212.3:c.422A>G variant in ITGB3 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 141 (p.Tyr141Cys). At least one patient (Patient 12 in PMID: 36672149) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, there was absence of GPIIbIIIa platelet surface expression by flow cytometry and ITGA2B and ITGB3 were reported to be sequenced across all exons and intron/exon boundaries (PP4_Strong).Patient GT53 reported in PMID: 19691478 is compound heterozygous for this variant and the ITGB3 variant c.415G>C (p.Asp139His, classified by the Platelet Disorders VCEP as Likely Pathogenic, trans phase confirmed - not considered here to avoid circularity). GT1-III2, of PMID: 32558238, patient No.1 of PMID: 15748237, and patients 11/12 of PMID: 36672149 are all homozygous for Tyr141Cys 1pt. Total 1pt (PM3). The variant has been reported to segregate with Glanzmann thrombasthenia (confirmed by bleeding phenotype and platelet aggregometry) in the GT1-III2 proband plus two affected family members, all homozygous for Tyr141Cys genotype. (PP1_moderate; PMID: 32558238). The highest population minor allele frequency in gnomAD v4.1 is 0.00005489 (5/91090 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.939, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PP3, PP4_Strong, PM3, PP1_moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021881/MONDO:0100326/011 2025-06-17 2025-06-27 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:41423 biolink:causes UMLS:C0014860 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0014860 infores:hetionet CHEBI:5123 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0032617 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0162429 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0011606 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0019158 infores:hetionet CAID:CA10585360 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585360 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM3, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, BS2, PP2, PP1 The NM_000527.5(LDLR):c.1211C>T (p.Thr404Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2022. The supporting evidence is as follows: PM2: This variant is absent from gnomAD v2.1.1.PP3: REVEL = 0.928.PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill criteria for FH after alternative causes of high cholesterol were excluded (1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, Italy; 1 case from PMID 19446849).PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype and LDLR variant (c.428G>A (p.Cys143Tyr)) classified as Pathogenic by these guidelines, in trans (PMID 14570618, 19073363). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585360/MONDO:0007750/013 2022-10-28 2024-12-09 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:66919 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0028081 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0001277 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0007773 infores:hetionet CHEBI:75998 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0035078 infores:hetionet CHEBI:31859 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0032617 infores:hetionet CHEBI:31859 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0002418 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0856151 infores:hetionet CHEBI:3478 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0026826 infores:hetionet CHEBI:61058 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0015967 infores:hetionet CHEBI:47519 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0042373 infores:hetionet CHEBI:4710 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0004134 infores:hetionet CHEBI:16899 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0015967 infores:hetionet CHEBI:6456 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0008031 infores:hetionet CHEBI:63599 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0013404 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0497247 infores:hetionet CHEBI:27974 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0016204 infores:hetionet CAID:CA244536012 biolink:causes MONDO:0015967 infores:clingen CAID:CA244536012 MONDO:0015967 PMID: Uncertain Significance BS1 PS4, PM2, PP3, PP4 The c.1504C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 502 (p.(Leu502Val)) of NM_000545.8. This variant has a Grpmax Filtering allele frequency in gnomAD v4.1.0 of 0.00007227, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant has a REVEL score of 0.557, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. Additionally, the c.1504C>G variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and PP4 cannot be applied due to lack of clinical information (PMID: 23771925, internal lab contributors). In summary, c.1504C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA244536012/MONDO:0015967/017 2025-09-26 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3478 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0008370 infores:hetionet CHEBI:31348 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0852911 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1443060 infores:hetionet UMLS:C1144403 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0012833 infores:hetionet CHEBI:17549 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0031256 infores:hetionet NCBIGene:57492 biolink:causes MONDO:0007617 infores:monarchinitiative not_provided not_provided HGNC:18040 MONDO:0007617 uuid:f585baff-2b58-49ac-a506-5aab787605b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3242 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0041657 infores:hetionet CAID:CA409103971 biolink:causes MONDO:0015967 infores:clingen CAID:CA409103971 MONDO:0015967 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5, PM1, PS4, PP1_Strong The c.199C>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 67 (p.(Arg67Trp)) of NM_175914.5. This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 25555642, 20164212, internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and history of large for gestational age in the absence of sufficient maternal hyperglycemia) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 3 families (PP1_Strong; PMID:20164212, internal lab contributors). Another missense variant, c.200G>A (p.(Arg67Gln)) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Arg67Trp)​ has a greater Grantham distance (PM5). In summary, c.199C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PM1, PM5, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409103971/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9123 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0037199 infores:hetionet CHEBI:27974 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0855242 infores:hetionet CAID:CA915952341 biolink:causes MONDO:0010604 infores:clingen CAID:CA915952341 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3 The F9: c.88+5G>T variant is completely absent in population databases (gnomAD v2.1.1/gnomAD v3.1.2) meeting PM2_Supporting. This intronic variant is predicted to alter splicing based on SpliceAI prediction that the canonical donor site is lost, with a score of 0.91 (>0.5) meeting PP3 criteria. It has been reported in at least 4 probands in the literature with moderate to severe hemophilia B meeting phenotypic criteria for F9 (PMIDs: 31064749, 9452115, 10094553). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA915952341/MONDO:0010604/080 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Supports NCBIGene:54205 biolink:causes MONDO:0012775 infores:monarchinitiative not_provided not_provided HGNC:19986 MONDO:0012775 uuid:63bb1be7-b05c-4d6f-b02c-563e718b7514 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68584 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0973461 infores:hetionet CHEBI:10100 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0019080 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0035258 infores:hetionet CHEBI:499361 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C1565489 infores:hetionet CHEBI:17549 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0018979 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0025061 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027765 infores:hetionet CHEBI:49375 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151904 infores:hetionet CHEBI:404903 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0035455 infores:hetionet CHEBI:6909 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013395 infores:hetionet CHEBI:47426 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0017979 infores:hetionet CAID:CA386952150 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952150 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PP4 The c.14T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 5 (p.(Leu5Arg) of NM_000545.8. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting).  Additionally, this variant is located within dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 23348805, internal lab contributor). Lastly, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.934, which is greater than the MDEP threshold of 0.70 (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952150/MONDO:0015967/017 2025-04-11 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7640 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0017605 infores:hetionet CHEBI:6775 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0040409 infores:hetionet CHEBI:63598 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0011606 infores:hetionet GO:0060222 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0043010 CHEBI:3756 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0917801 infores:hetionet CHEBI:116278 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0033774 infores:hetionet NCBIGene:10943 biolink:causes MONDO:0026730 infores:monarchinitiative not_provided not_provided HGNC:7370 MONDO:0026730 uuid:8fdf4cd9-0526-44c1-b9ad-8de720f472e7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5092 biolink:causes MONDO:0009908 infores:monarchinitiative not_provided not_provided HGNC:8646 MONDO:0009908 uuid:628c4dc4-c0f6-4be4-ad24-2eeebcf4d90e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1738934 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0037199 infores:hetionet UMLS:C0903898 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0022346 infores:hetionet CHEBI:47381 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1761613 infores:hetionet CHEBI:2682 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0029163 infores:hetionet CHEBI:3219 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0003811 infores:hetionet CHEBI:465284 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0231528 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0020619 infores:hetionet CHEBI:8713 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0011603 infores:hetionet CHEBI:2673 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C3203358 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0851341 infores:hetionet CHEBI:64064 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0013404 infores:hetionet CHEBI:167638 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0033774 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0043251 infores:hetionet CHEBI:6801 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0162287 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008093 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0334082 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0021843 infores:hetionet CHEBI:4856 biolink:causes MONDO:0005356 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0010073 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0038454 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006849 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0024894 infores:hetionet CHEBI:49662 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C1291077 infores:hetionet CHEBI:4653 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0030193 infores:hetionet CHEBI:119573 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151786 infores:hetionet NCBIGene:5860 biolink:causes MONDO:0009862 infores:monarchinitiative not_provided not_provided HGNC:9752 MONDO:0009862 uuid:974441fd-d00a-4395-b0dd-6b7cc5477645 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3061 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0040479 infores:hetionet CHEBI:28748 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0344232 infores:hetionet CHEBI:4466 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020615 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0575090 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020517 infores:hetionet CAID:CA6403049 biolink:causes MONDO:0019565 infores:clingen CAID:CA6403049 MONDO:0019565 PMID: Likely Benign BP4, BS1 BS2, PP3, PP4 The NM_000552.5(VWF):c.2510C>A variant in VWF is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 837. TheGrpmax filtering allele frequency in gnomAD v4.1 is 0.02238 (based on 1748/75040 alleles, with 22 homozygotes in the African/African-American population), which is above the ClinGen VWD VCEP threshold of >0.01 for BS1. The computational predictor REVEL gives a score of 0.059, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. This variant is classified as likely benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6403049/MONDO:0019565/090 2024-07-09 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:4856 biolink:causes MONDO:0006805 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0002965 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002043 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013592 infores:hetionet CHEBI:473990 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0021053 infores:hetionet CHEBI:4858 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0162429 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006384 infores:hetionet CHEBI:64312 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0041657 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0948586 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0240925 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0240925 infores:hetionet CAID:CA412376879 biolink:causes MONDO:0010725 infores:clingen CAID:CA412376879 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PVS1, PP4 NM_000330.4(RS1):c.61G>T (p.Gly21Ter) is a nonsense variant that introduces a premature stop codon within exon 2 of 6, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including the appearance of schisis, reduced visual acuity before age 13 years, and electroretinogram showing a reduction in the b-wave amplitude, which together are specific for X-linked retinoschisis (PMID: 15932525, PP4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PVS1, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412376879/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance HP:0001417 Supports CHEBI:72690 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0040034 infores:hetionet CHEBI:50742 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0027497 infores:hetionet GO:0046602 biolink:causes GO:0000278 infores:ubergraph knowledge_assertion manual_agent GO:0046602 GO:0000278 CHEBI:39669 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C1384666 infores:hetionet CHEBI:27690 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0014518 infores:hetionet CHEBI:9671 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0392525 infores:hetionet CHEBI:4903 biolink:causes UMLS:C1112353 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1112353 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0595930 infores:hetionet CAID:CA916079880 biolink:causes MONDO:0010602 infores:clingen CAID:CA916079880 MONDO:0010602 PMID: Likely Benign BP7, PM2_Supporting, BP4 PS4 The c.5586+27A>C variant is absent from males in gnomAD v2.1.1 and v3, meeting PM2_Supporting. SpliceAI predicts no impact on splicing due to this variant: 0.00 scores for acceptor loss/gain and donor loss. A donor gain 27bp downstream is predicted with a low score of 0.01. The nucleotide appears to be not conserved based on agreement between PhyloP and PhastCons. PhyloP score: -595433 and PhastCons score: 0.0. BP4 and BP7 are applied based on SpliceAI predictions and conservation. This variant is not reported in the literature; however, 1 proband with severe hemophilia A is reported from internal laboratory data with an alternate pathogenic variant. In summary, based on the evidence available at this time, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PM2_Supporting, BP4, BP7. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA916079880/MONDO:0010602/071 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Contradicts true CAID:CA158267 biolink:causes MONDO:0100216 infores:clingen CAID:CA158267 MONDO:0100216 PMID: Likely Benign BP4, BS2 PM2, BP2, BA1, PP1, PP4, PM1, PS4, PS2, BS1, BS4 The NM_177438.3:c.179C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 60 (p.Thr60Ile). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMIDs: 29399970, 37019617, 24728327, Internal lab contributors). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.0001599 (258/1613772 alleles) with a highest population minor allele frequency of 0.0002144 (253/1179916 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.32; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BP4. (Bayesian Points: -5; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA158267/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9168 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0002871 infores:hetionet CHEBI:10119 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0019080 infores:hetionet CHEBI:49713 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0043094 infores:hetionet CHEBI:18243 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0340464 infores:hetionet CHEBI:63611 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0424295 infores:hetionet CAID:CA390869397 biolink:causes MONDO:0100216 infores:clingen CAID:CA390869397 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting PVS1, BP2, BA1, PP3, PP1, PP4, BS2, PM4, PM5, PM1, PS1, PS3, PS2, PS4, BP7, BS1, BS3, BS4 The NM_177438.2:c.4313A>G variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 1438 (p.Tyr1438Cys). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.2; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390869397/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2704 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0404521 infores:hetionet CHEBI:3219 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C1619712 infores:hetionet CHEBI:7822 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0016204 infores:hetionet CAID:CA274902 biolink:causes MONDO:0001586 infores:clingen CAID:CA274902 MONDO:0001586 PMID: Pathogenic PP3_Moderate, PP4, PM3_Very Strong, PM2_Supporting The NM_000203.5(IDUA):c.152G>A variant in IDUA is predicted to result in a missense substitution, p.Gly51Asp. This variant has been reported in 9-13% of Italian MPS1 alleles (PMID: 9427149, 12203999, 21394825), and has been identified in patients from other European countries as well as Iran, Egypt, and India (PMID: 19839758, 31298590, 33301762). When reported, the diagnosis confirmed by deficiency of iduronidase activity (PMID: 7951228, 9427149, 12203999, 21394825) including one patient with detailed clinical features and residual enzyme activity values provided (PMID: 33301762) (PP4). At least 7 patients are homozygous for the variant (PMIDs: 9427149, 12203999, 19839758, 21394825, 31298590, 33301762). In addition, at least 6 patients are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, all phase unknown, including c.208C>T (p.Gln70Ter) (2 patients, PMID: 12203999), c.1205G>A (p.Trp402Ter) (PMID: 7951228), and c.1598C>G (p.Pro533Arg) (at least 2 patients, PMID: 9427149, 12203999, 21394825), and c.1163delC (PMID: 12203999) (PM3_Very Strong). Further patients have been reported who are compound heterozygous for the variant but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PMID: 9427149, 12203999, 21394825). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002447 (2/81730 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.914 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PP3_Moderate). SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 193061). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274902/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3732 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0162429 infores:hetionet CHEBI:31236 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017672 infores:hetionet CHEBI:6062 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0009676 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549373 infores:hetionet CHEBI:253342 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0037278 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0860207 infores:hetionet CAID:CA410148056 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148056 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1118C>T (p.Ser373Leu) is a missense variant which has a REVEL score of 0.382 and a SpliceAI score of 0.00, both of which are below their respective thresholds (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148056/MONDO:0011071/008 2024-09-12 2024-09-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:49575 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011168 infores:hetionet CHEBI:8713 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C1368065 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0001339 infores:hetionet CHEBI:194135 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151611 infores:hetionet CHEBI:16899 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0855775 infores:hetionet CHEBI:42944 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0233763 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1096343 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0947999 infores:hetionet CHEBI:10125 biolink:causes MONDO:0021100 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C1458155 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0231365 infores:hetionet CAID:CA9870242 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870242 MONDO:0015967 PMID: Uncertain Significance PP3, PP4, BS2 PM2, PP1, PM1, PS4, BS1 The c.407C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to valine at codon 136 (p.(Ala136Val)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.823, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a Grpmax filtering allele frequency of 0.00000954 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 24097065, 38054414; ClinVar SCV002600226.1; internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (BS2; internal lab contributors). In summary, c.407C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): BS2, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870242/MONDO:0015967/085 2025-09-17 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4710 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0162429 infores:hetionet CHEBI:107736 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018790 infores:hetionet CHEBI:127780 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0235086 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0003864 infores:hetionet CHEBI:31348 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2697368 infores:hetionet CHEBI:3387 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0042029 infores:hetionet CHEBI:47381 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0004093 infores:hetionet CHEBI:9727 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0014742 infores:hetionet CHEBI:42797 biolink:causes MONDO:0012819 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011880 infores:hetionet CHEBI:6076 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0035455 infores:hetionet CHEBI:3061 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0426576 infores:hetionet CHEBI:15765 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0393593 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014868 infores:hetionet CHEBI:144551 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0014591 infores:hetionet CHEBI:18357 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0001125 infores:hetionet NCBIGene:443 biolink:causes MONDO:0010079 infores:monarchinitiative not_provided not_provided HGNC:756 MONDO:0010079 uuid:912cf6bf-6635-4051-876a-90da65092a84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8404 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0012833 infores:hetionet CAID:CA305287212 biolink:causes MONDO:0007750 infores:clingen CAID:CA305287212 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BP2, BA1, PS3, PS4, PS1, PS2, BP7, BS1, BS3, BS4, PM4, PM5, PM3, PM1, PVS1, PM6, BS2, PP4, PP3, PP1 The NC_000019.10:g.11089263C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA305287212/MONDO:0007750/013 2023-04-29 2023-04-29 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:8228 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0518988 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1861172 infores:hetionet CHEBI:9316 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0006266 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0178298 infores:hetionet CHEBI:6129 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C1443060 infores:hetionet CAID:CA026202 biolink:causes MONDO:0700269 infores:clingen CAID:CA026202 MONDO:0700269 PMID: Benign BS1, BS3, BP4 BP5, PP4 The c.9538C>T variant in BRCA2 is a missense variant predicted to cause substitution of Leucine by Phenylalanine at amino acid 3180 (p.(Leu3180Phe)). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0002240 in the East Asian population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). Reported by three calibrated studies to exhibit protein function similar to benign control variants (PMIDs:33314489, 39779857, 39779848) (BS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.13, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (BP4 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.875 (based on Family History LR=0.875), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BS3, BP4). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA026202/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28748 biolink:causes UMLS:C1720798 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1720798 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0009319 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0018799 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0011616 infores:hetionet CHEBI:51164 biolink:causes MONDO:0002869 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0018824 infores:hetionet CHEBI:70735 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0344232 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0039070 infores:hetionet CHEBI:5127 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0302295 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0042109 infores:hetionet CHEBI:6965 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C2830004 infores:hetionet CHEBI:3127 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0035455 infores:hetionet CHEBI:7852 biolink:causes MONDO:0005087 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0035204 infores:hetionet CHEBI:7565 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0023218 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0036454 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0595877 infores:hetionet CHEBI:6904 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0155626 infores:hetionet NCBIGene:9060 biolink:causes MONDO:0019666 infores:monarchinitiative not_provided not_provided HGNC:8604 MONDO:0019666 uuid:cc539f30-30e7-44f1-bf94-7253ff439df6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes NCIT:C80112 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0040434 infores:hetionet CHEBI:28901 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0022354 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0860711 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0860711 infores:hetionet CHEBI:63610 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0231528 infores:hetionet NCBIGene:2531 biolink:causes MONDO:0033014 infores:monarchinitiative not_provided not_provided HGNC:4021 MONDO:0033014 uuid:4b5547b4-766d-4e11-bef0-8a6745097b9b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0231919 infores:hetionet CHEBI:7478 biolink:causes HP:0002183 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0751466 infores:hetionet CHEBI:6149 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0042514 infores:hetionet CHEBI:204734 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0022107 infores:hetionet CAID:CA252008 biolink:causes MONDO:0007064 infores:clingen CAID:CA252008 MONDO:0007064 PMID: Pathogenic PP1_Strong, PP4_Moderate, PM2_Supporting, PS3_Moderate, PM3_Strong PP2, PP3, BP1, BP4, PM1, PS4 NM_000022.4 :c.646G>A is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 216 (p.Gly216Arg). The filtering allele frequency (the upper threshold of the 95% CI of 46/1180026) of the c.646G>A variant in ADA is 0.00002743 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The variant has been reported to segregate with SCID in 4 affected family members from 2 families (PP1_strong; PMID : 26255240). This variant has been detected in 15 individuals with ADA deficient SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant (Glu319Glyfs*320 ,confirmed in trans ,1pt.). 12 individuals were homozygous for the variant (1 pt.) (total: 2 pts; PM3_Strong ,PMID : 26255240). Male patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.), reduced ADA enzyme activity in patient cells (1 pt),SCID phenotype corrected by exogenous ADA supplementation (1 pt.),Increased dATP in pretreatment erythrocytes (2 pts.). (PP4_Moderate (5 pts.), PMID: 1680289). ADA activity in SØ3834 was 30.4 nmol/h/mg protein which is .012 % of wild type ADA activity indicating that this variant impacts protein function (PMID : 9758612, PS3_Moderate). Based on the above evidence, the variant may be classified as pathogenic for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_strong,PM2_supporting,PM3_strong,PP4_moderate,PS3_moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA252008/MONDO:0007064/114 2024-01-24 2024-01-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10101 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0392171 infores:hetionet UMLS:C0065374 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0039231 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0235955 infores:hetionet NCBIGene:2146 biolink:causes MONDO:0010193 infores:monarchinitiative not_provided not_provided HGNC:3527 MONDO:0010193 uuid:58f12fc7-bc2a-4aa0-a31e-d316f1a72530 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0011603 infores:hetionet CHEBI:9139 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0085637 infores:hetionet CHEBI:50378 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0424295 infores:hetionet CAID:CA10585382 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585382 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1274A>T (p.Asn425Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in at least 1 case with DLCN score ≥6 in PMID 11810272 (Fouchier et al., 2001), The Netherlands, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585382/MONDO:0007750/013 2023-06-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63605 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0038362 infores:hetionet CHEBI:8597 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0152198 infores:hetionet CHEBI:17334 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0003467 infores:hetionet CHEBI:6887 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0242429 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0029882 infores:hetionet CHEBI:5784 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0022354 infores:hetionet CHEBI:41879 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0041582 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0004096 infores:hetionet CHEBI:6413 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0023530 infores:hetionet CHEBI:4784 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0152031 infores:hetionet CHEBI:4909 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0013395 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001618 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0004691 infores:hetionet CHEBI:27834 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0085669 infores:hetionet CHEBI:66919 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0009450 infores:hetionet CHEBI:75722 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0239340 infores:hetionet CHEBI:6775 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0002390 infores:hetionet CHEBI:31859 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0013378 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1167965 infores:hetionet CHEBI:3699 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0080274 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0017574 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0021359 infores:hetionet NCBIGene:8506 biolink:causes MONDO:0020766 infores:monarchinitiative not_provided not_provided HGNC:8011 MONDO:0020766 uuid:4150125c-5b52-48a9-bffc-22251d73ab4d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA512232110 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232110 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM6, BP5, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1419G>A (p.Glu473=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.38) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232110/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:48273 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0085623 infores:hetionet CAID:CA1139662321 biolink:causes MONDO:0700270 infores:clingen CAID:CA1139662321 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PP3 BP4 The ATM c.5556_5557delinsGA (p.Asp1853Asn) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico predictors (NNSplice/ESE Finder) are in agreement this variant affects splicing (PP3). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139662321/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0234215 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0349506 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0541832 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0015397 infores:hetionet CHEBI:65173 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0013428 infores:hetionet CHEBI:31859 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0015230 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0149866 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0149866 infores:hetionet CHEBI:18332 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0917801 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0014544 infores:hetionet CHEBI:5959 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0428977 infores:hetionet CHEBI:45979 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0040264 infores:hetionet NCBIGene:23019 biolink:causes MONDO:0032787 infores:monarchinitiative not_provided not_provided HGNC:7877 MONDO:0032787 uuid:455c2129-80d0-4172-b0fe-f4a9eb90022f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6121 biolink:causes MONDO:0017394 infores:ubergraph knowledge_assertion manual_agent CHEBI:6121 MONDO:0017394 CHEBI:28748 biolink:causes MONDO:0006040 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0001125 infores:hetionet CHEBI:32020 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C3267047 infores:hetionet CHEBI:7565 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0392703 infores:hetionet NCBIGene:493856 biolink:causes MONDO:0011502 infores:monarchinitiative not_provided not_provided HGNC:24212 MONDO:0011502 uuid:6652cd76-1531-4394-9aa8-d60eae6a4e25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:66876 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0002962 infores:hetionet CHEBI:5693 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00756 UMLS:C0162830 infores:hetionet CHEBI:3723 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232849 infores:hetionet CHEBI:3696 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0000737 infores:hetionet NCBIGene:8884 biolink:causes MONDO:0033546 infores:monarchinitiative not_provided not_provided HGNC:11041 MONDO:0033546 uuid:f75d44e3-11f3-44f8-b425-8653aa9d6153 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes MONDO:0021003 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0152427 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0002170 infores:hetionet UMLS:C0010592 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0232807 infores:hetionet CHEBI:6965 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0013404 infores:hetionet CAID:CA358778 biolink:causes MONDO:0010315 infores:clingen CAID:CA358778 MONDO:0010315 PMID: Pathogenic PM1_Strong, PS3_Supporting, PP4, PM2_Supporting, PS4 The NM_000206.3:c.670C>T variant in IL2RG is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 224 (p.Arg226Trp). The variant has been observed in at least 10 male probands with SCID (PMIDs 28747913, 21184155, 10792291, 9633906, 9058718, 9049783) (PS4). Among these probands, one proband hemizygous for this variant was diagnosed with SCID and presented a T-B+NK- lymphocyte profile (PMID 9049783) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.670C, which is defined as a mutational hotspot by the ClinGen SCID VCEP (PMID 7668284) (PM1_Strong). Surface expression of the IL-2 receptor gamma chain in patient B cells showed that the variant causes decreased surface localization of the protein, indicating that this variant impacts protein function (PMID 9058718)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM1_Strong, PS4, PP4_Supporting, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA358778/MONDO:0010315/129 2024-03-08 2024-03-08 X-linked inheritance HP:0001417 Supports CHEBI:31547 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0014457 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0239725 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0239725 infores:hetionet CHEBI:47898 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019521 infores:hetionet CHEBI:6754 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0003123 infores:hetionet CHEBI:7496 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0020456 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0029134 infores:hetionet CHEBI:5441 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0027497 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0860749 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0860749 infores:hetionet CHEBI:4657 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0036974 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0034063 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0037274 infores:hetionet CHEBI:63605 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0002962 infores:hetionet CHEBI:8024 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0040034 infores:hetionet CAID:CA410202522 biolink:causes MONDO:0100083 infores:clingen CAID:CA410202522 MONDO:0100083 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS3, PS4, PS2, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM4, PM3, PM5, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.479A>G (p.Asp160Gly) is a missense variant which has a REVEL score >0.88 (0.983) (PP3). This variant affects one of the residues within the RHD (AA 89-204) (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202522/MONDO:0100083/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5864 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0001824 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0009806 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0853908 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C1269683 infores:hetionet CHEBI:119915 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0085593 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0006840 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0234939 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0234939 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0017574 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0031117 infores:hetionet CHEBI:10119 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0014394 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0152227 infores:hetionet CHEBI:8430 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0003467 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0235431 infores:hetionet CHEBI:38940 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0012813 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020651 infores:hetionet CHEBI:85161 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0003813 infores:hetionet CAID:CA512341265 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341265 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1155C>T (p.Tyr385=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341265/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:42797 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0023530 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0853149 infores:hetionet CHEBI:15367 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0231835 infores:hetionet CHEBI:63611 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023518 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0038045 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0038045 infores:hetionet CHEBI:404903 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0236075 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0029882 infores:hetionet CHEBI:9434 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0006145 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0019360 infores:hetionet CHEBI:404903 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1260880 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0234913 infores:hetionet CHEBI:9613 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C2047937 infores:hetionet CHEBI:8888 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0017181 infores:hetionet CHEBI:465284 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0030312 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1384353 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0341439 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0341439 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0233632 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020437 infores:hetionet CHEBI:64312 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0085602 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0152128 infores:hetionet CAID:CA1139663662 biolink:causes MONDO:0100216 infores:clingen CAID:CA1139663662 MONDO:0100216 PMID: Likely Pathogenic PP4, PP3, PM2_Supporting, PS4_Supporting, PS3 BA1, PM5, PS1, BS1, BS3 The NM_177438.3:c.2257-7A>G variant in DICER1 is an intronic variant which in intron 14/26. This variant received a total of 1.5 phenotype points across 2 unrelated probands, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs, Internal lab contributors). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; PMIDs, Internal lab contributors). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PS3, PP3. (Bayesian Points: 8; VCEP specifications version 1.3.0; 02/25/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139663662/MONDO:0100216/024 2025-02-25 2025-06-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8356 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040053 infores:hetionet CHEBI:63598 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014743 infores:hetionet CHEBI:8772 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0917801 infores:hetionet CHEBI:2668 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0235490 infores:hetionet CHEBI:4909 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0027707 infores:hetionet UNII:54Z8M50D6Q biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0234233 infores:hetionet CHEBI:63598 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0014591 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0948089 infores:hetionet CAID:CA012013 biolink:causes MONDO:0005045 infores:clingen CAID:CA012013 MONDO:0005045 PMID:8483915PMID:15563892PMID:27532257PMID:15358028PMID:20031618PMID:8483915PMID:15563892 Pathogenic PP1, PP3, PM6, PM5, PM1, PM2, PS4 The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>T p.Gly741Trp - Variation ID 177665). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PM6; PP1; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012013/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:465284 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013395 infores:hetionet CHEBI:5132 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0085932 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0034150 infores:hetionet NCBITaxon:10239 biolink:causes MONDO:0005709 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10239 MESH:D003139 DB00719_MESH_D003139_1DB00967_MESH_D003139_1DB01114_MESH_D003139_1DB01176_MESH_D003139_1DB09488_MESH_D003139_1DB04837_MESH_D003139_1DB00341_MESH_D003139_1DB06691_MESH_D003139_1 CHEBI:5132 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0403632 infores:hetionet CAID:CA129336 biolink:causes MONDO:0100216 infores:clingen CAID:CA129336 MONDO:0100216 PMID: Likely Pathogenic PP4, PM2_Supporting, PS4_Supporting, PS3_Supporting, PP1_Moderate BP4, BP2, BA1, PP3, BS2, PM5, PM1, PS1, PS2, BS1, BS3, BS4 The NM_177438.2:c.2516C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 839 (p.Ser839Phe). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). All reported phenotypes to date have been thyroid phenotypes (multi-nodular goiter and thyroid cancer, including pediatric). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMIDs: 27459524, 26033159). The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Ser839Phe showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID: 37333613). The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1_Moderate, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.2.0; 01/09/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA129336/MONDO:0100216/024 2024-01-09 2024-01-17 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0022650 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0233401 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233401 infores:hetionet CHEBI:167309 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0232462 infores:hetionet CHEBI:72564 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0344232 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0860661 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0860661 infores:hetionet CHEBI:64312 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013428 infores:hetionet CHEBI:31413 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0014742 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0015397 infores:hetionet CHEBI:4995 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0011168 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042514 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0006849 infores:hetionet CHEBI:5551 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00874 UMLS:C0027497 infores:hetionet CHEBI:3423 biolink:causes MONDO:0006670 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0085437 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0007193 infores:hetionet CHEBI:75922 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0010043 infores:hetionet NCBIGene:2099 biolink:causes MONDO:0016419 infores:monarchinitiative not_provided not_provided HGNC:3467 MONDO:0016419 uuid:2e80d699-4247-4013-94dd-78e350854ecf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5778 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0027947 infores:hetionet CAID:CA16619319 biolink:causes MONDO:0000572 infores:clingen CAID:CA16619319 MONDO:0000572 PMID:32655540 Uncertain Significance PP4, PS3_Moderate, PM2_Supporting, PM1_Supporting NM_000448.3(RAG1):c.2690G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 897 (p.Arg897Gln). This missense variant is located in the core domain (amino acids 387-1011) (PM1_Supporting). The filtering allele frequency (the upper threshold of the 95% CI of 2/1112010) of the c.2690G>A variant in RAG1 is 3.000e-7 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Patient with SCID (0.5 pt.) and T-B-NK- lymphocyte subset profile (0.5 pt.) : total :1 pt. (PP4) PMID: 32655540. RAG activity was found to be 3.7 ± 0.2 by flow cytometry. (PS3_Moderate) PMID: 32655540. The patient was found to be heterozygous for c.2690G>A, p.R897Q & с.1229G>A, p.R410Q (not classified by SCID VCEP) : PM3 not evaluated.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_Supporting, PM2_Supporting,PP4,PS3_Moderate (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA16619319/MONDO:0000572/123 2024-05-28 2024-05-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:29688 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0700345 infores:hetionet CHEBI:6690 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0018524 infores:hetionet CHEBI:50567 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00922 UMLS:C0009806 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0008350 infores:hetionet CHEBI:63622 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0034063 infores:hetionet CHEBI:6916 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0040822 infores:hetionet CHEBI:3242 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0000737 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0162429 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001628 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0040261 infores:hetionet CHEBI:61049 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011606 infores:hetionet CHEBI:63617 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020458 infores:hetionet CHEBI:4315 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0085633 infores:hetionet CHEBI:51141 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0033774 infores:hetionet CHEBI:2955 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0042023 infores:hetionet CHEBI:61049 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0855775 infores:hetionet CAID:CA128833 biolink:causes MONDO:0044970 infores:clingen CAID:CA128833 MONDO:0044970 PMID:19809478 Likely Pathogenic PM2_Supporting, PS3_Supporting PP3, PS4 The m.5556G>A variant in MT-TW has been reported in one individual with mitochondrial disease to date (PMID: 19809478). This was a girl with feeding difficulty and reflux onset shortly after birth and developmental regression beginning at age seven months. She also had constipation, failure to thrive, and died at 13 months due to respiratory insufficiency. She had metabolic acidosis and elevated blood and cerebrospinal fluid lactate. There was reduced activities of complexes I, III, and IV in skeletal muscle and fibroblasts, and reduced levels of fully assembled complexes I, III, IV, and V in fibroblast cell line. Mitochondrial protein synthesis and tRNA tryptophan levels were reduced in patient fibroblasts. The variant was present at 92% heteroplasmy in fibroblasts and 93% in skeletal muscle. The variant was not detectable in mother’s blood, hair, urine, or skeletal muscle (PM6_supporting; PMID: 27450679). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). In silico prediction tools are conflicting as the computational predictor MitoTIP suggests this variant is tolerated (44.5 percentile) but HmtVAR predicts it to be deleterious (score of 0.85). Cybrids with high heteroplasmy levels (90%, 93%, 96%) were generated and showed a pattern consistent with patient fibroblasts, and tRNA tryptophan levels were reduced in cybrids to 33% (PS3_supporting; PMID: 19809478). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the high heteroplasmy levels correlating with a severe phenotype with confirmed de novo status of the variant and compelling functional validation. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA128833/MONDO:0044970/015 2024-05-28 2025-07-16 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:231425 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0235431 infores:hetionet CAID:CA16020731 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020731 MONDO:0009861 PMID:25920592PMID:25920592 Likely Pathogenic PM5, PM2, PP4, PP3 PM3 The c.136G>C (p.Gly46Arg) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency not totally excluded). (PP4; PMID: 25920592). This variant is absent in population databases (PM2). This variant was detected with a novel large deletion of exons 12 and 13: c.1200-?_1359+?del (EX12_13del). Computational evidence support a deleterious effect. A different pathogenic missense change has been seen at p.G46 (p.G46S) In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020731/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31932 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0020651 infores:hetionet CHEBI:9649 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0014742 infores:hetionet CHEBI:51450 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0011991 infores:hetionet CHEBI:42820 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0039231 infores:hetionet CHEBI:49375 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0151610 infores:hetionet CAID:CA410146905 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146905 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1391C>T (p.Thr464Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146905/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA421938891 biolink:causes MONDO:0005338 infores:clingen CAID:CA421938891 MONDO:0005338 PMID: Uncertain Significance BP7, PM2_Supporting, PS4_Supporting, BP4 BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, BA1 The c.141C>T variant in MYOC is a synonymous variant (p.Cys47=). The highest minor allele frequency of this variant was in the Admixed American genetic ancestry group of gnomAD (v4.1.0) = 0.00003333 (2 alleles out of 59,998), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 2 probands with primary open angle glaucoma have been reported carrying this variant (PMID: 33725475), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, BP7, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA421938891/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63598 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0018099 infores:hetionet CHEBI:31401 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0267792 infores:hetionet CHEBI:10124 biolink:causes MONDO:0006021 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0002963 infores:hetionet CHEBI:36791 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027849 infores:hetionet CHEBI:3011 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0040264 infores:hetionet CHEBI:9137 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0338614 infores:hetionet CHEBI:66913 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB05013 UMLS:C0853700 infores:hetionet CHEBI:28593 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0040264 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0221780 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0221780 infores:hetionet CHEBI:114785 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0085932 infores:hetionet GO:1904653 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:1904653 GO:0007275 CHEBI:50173 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0040038 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011570 infores:hetionet CHEBI:28925 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0033774 infores:hetionet CHEBI:9720 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0004093 infores:hetionet CHEBI:5138 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0600228 infores:hetionet CHEBI:7445 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0042024 infores:hetionet CHEBI:7476 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0235063 infores:hetionet CHEBI:6128 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0038990 infores:hetionet CHEBI:48844 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C1368065 infores:hetionet UNII:3U02EL437C biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0026821 infores:hetionet CHEBI:8212 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0026837 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1956346 infores:hetionet CHEBI:5134 biolink:causes MONDO:0022205 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0152081 infores:hetionet CHEBI:34825 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB08933 UMLS:C0011616 infores:hetionet CHEBI:75722 biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2607914 infores:hetionet CHEBI:4672 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0600142 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0007642 infores:hetionet CHEBI:68841 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C3665347 infores:hetionet UMLS:C1738934 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0039231 infores:hetionet CHEBI:5118 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233471 infores:hetionet CHEBI:63619 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151786 infores:hetionet CHEBI:36791 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043387 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0023524 infores:hetionet CHEBI:4708 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0018965 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0015397 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0438215 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0162429 infores:hetionet CHEBI:94848 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0027813 infores:hetionet CHEBI:27786 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C1443060 infores:hetionet CHEBI:51141 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0027796 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004830 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015645 infores:hetionet CHEBI:9763 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0018520 infores:hetionet CHEBI:45863 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151798 infores:hetionet CHEBI:7494 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0041657 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0948349 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042373 infores:hetionet NCBITaxon:160 biolink:causes MONDO:0007000 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:160 MESH:D014211 DB09320_MESH_D014211_1 PUBCHEM.COMPOUND:3467 biolink:causes UMLS:C0595882 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0595882 infores:hetionet CHEBI:15640 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0036974 infores:hetionet CHEBI:2668 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0036974 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0151824 infores:hetionet UMLS:C0120107 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0033774 infores:hetionet CHEBI:9586 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0013404 infores:hetionet CHEBI:6775 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011168 infores:hetionet CHEBI:7865 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0030193 infores:hetionet CHEBI:64355 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0221201 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0403632 infores:hetionet CHEBI:6970 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C1322281 infores:hetionet NCBIGene:79001 biolink:causes MONDO:0007390 infores:monarchinitiative not_provided not_provided HGNC:23663 MONDO:0007390 uuid:9da63875-150e-4226-bbe8-062650f04bbb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367396980 biolink:causes MONDO:0015967 infores:clingen CAID:CA367396980 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1 The c.1331G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 444 (p.(Gly444Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 34826540, internal lab contributors). In summary, c.1331G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367396980/MONDO:0015967/086 2023-11-23 2023-11-23 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:16755 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0037317 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0233632 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0031099 infores:hetionet GO:0061924 biolink:causes GO:0007420 infores:ubergraph knowledge_assertion manual_agent GO:0061924 GO:0007420 CAID:CA16020935 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020935 MONDO:0009861 PMID: Pathogenic PM2, PVS1, PP4 PM3 The c.1078G>T (p.Glu360Ter) nonsense variant occurs in exon 11 of 13 and is predicted to result in NMD. It absent from population databases, including gnomAD. It has been reported in at least one HPA patient (PMID: 10693064 ). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020935/MONDO:0009861/006 2022-06-12 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10127 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011603 infores:hetionet CHEBI:50122 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0002871 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005647 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0009663 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0027051 infores:hetionet CAID:CA1244272 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244272 MONDO:0005338 PMID:16466712PMID:14688426PMID:36267417 Likely Benign BS1, BS3_Supporting BP7, PM2, PP3, PP1, PM4, PM5, PS3, PS4, PS1, PS2, BA1, BP4 The c.473G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 158 (p.Arg158Gln). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.001760, which met the ≥ 0.001 threshold set for BS1 (79 alleles out of 44,878), meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.52, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function. The Arg158Gln protein had similar secretion levels to wild type myocilin protein in these studies (PMIDs: 36267417, 16466712). The assays met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. This protein has also been assessed in this other study (PMID: 14688426), however, the same level of evidence was not met. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1, BS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244272/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA16621909 biolink:causes MONDO:0008667 infores:clingen CAID:CA16621909 MONDO:0008667 PMID: Pathogenic PS4, PM2_Supporting, PVS1_Strong The variant NM_000551.3(VHL):c.463+1G>A is a canonical splice site within the 2nd intron of the VHL gene. If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1_Strong . Exon 2 is an in-frame exon (AA 114-156). Disruption of the splice donor site by this variant may cause skipping of exon 2. There is a known non-functional naturally occurring isoform missing exon 2 (PMID: 29891534, 31350093). (PVS1_Strong). There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (PM2_Supporting). Multiple cases are reported in the literature as follows: Case 1) a Japanese VHL family (table 1): retinal angioma, CNS hemangioblastoma, pancreatic cyst/tumor, RCC, Described as c.676+1G>A (PMID: 10761708) Case 2) South American VHL cohort, and variant described as IVS2+1G>A in a family with 5 affected members (table 1, PMID: 8956040 cited): CNS hemangioblastoma; retinal angioma; renal carcinoma; pancreatic cystadenoma (PMID: 12624160) Case 3) French VHL Study Group. The patient (no 23 from family 582) presented with pancreatic endocrine tumour and renal carcinoma (PMID: 18580449) Case 4) Brazilian patients. The patient, age 45, presented with renal cyst, pancreatic cyst and CNS hemangioblastoma (PMID: 31528828) Case 5) Italian patients. Found in one patient. Clinical manifestations include CNS hemangioblastoma, retinal hemangioblastoma, pancreatic cysts, and ovarian cysts (PMID: 19464396) Case 6) Male, clinical dx of VHL; multiple hemangioblastomas and spinal tumors in 20’s. Father and paternal half-siblings dx with VHL. (6 points, PS4). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621909/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:119915 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0026603 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0005779 infores:hetionet CHEBI:2659 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0018681 infores:hetionet CHEBI:5098 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0035078 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0205204 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0033860 infores:hetionet CHEBI:50692 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C2047937 infores:hetionet CHEBI:5147 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0010692 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0235318 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0235318 infores:hetionet CHEBI:7865 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0028961 infores:hetionet CHEBI:9599 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0085633 infores:hetionet CAID:CA392339987 biolink:causes MONDO:0007947 infores:clingen CAID:CA392339987 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP3, PS4_Supporting, PM2_Supporting, PM1 The NM_00138 c.5885A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 1962 (p.Tyr1962Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband diagnosed who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 27112580, PP4). This variant has been reported four times in ClinVar: once as likely pathogenic and three times as uncertain significance (Variation ID: 570737). At least two other probands with clinical features of MFS carry the same variant (PMID 33483583, Invitae ClinVar, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.972, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Sup, PM2_Sup, PP2, PP3, PP4 FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392339987/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7936 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0024312 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0037274 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0948089 infores:hetionet CHEBI:4356 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0205204 infores:hetionet CHEBI:63577 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0023530 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027932 infores:hetionet CHEBI:521033 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0234233 infores:hetionet CHEBI:5134 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0025323 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0042109 infores:hetionet CAID:CA386295265 biolink:causes MONDO:0009861 infores:clingen CAID:CA386295265 MONDO:0009861 PMID:28982351 Pathogenic PM3, PM2, PVS1, PP4 This c.804C>A (p.Tyr268Ter) variant in PAH was observed in a patient with classical PKU detected with pathogenic variant p.Arg243Gln (PMID: 28982351). This variant is absent from controls in population databases. This is a nonsense variant in exon 7 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, and PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA386295265/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Supports CAID:CA337726 biolink:causes MONDO:0021056 infores:clingen CAID:CA337726 MONDO:0021056 PMID: Likely Benign BP4, PM2_Supporting, BP7, BS2_Supporting PP3, BP1, BA1, BS1 The c.645+9C>A (p.?) variant in APC is an intronic variant at or beyond +7/–21 and is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth 6.5 (≥ 3) healthy individual points in total (BS2_Supporting; Ambry, Invitae internal data). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BS2_Supporting, BP4, and BP7 (VCEP specifications version 1.0; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA337726/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51364 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042373 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0042109 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0151911 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0151911 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C2720436 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C2720436 infores:hetionet CHEBI:6706 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0034063 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0521465 infores:hetionet CHEBI:31711 biolink:causes MONDO:0020594 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0271355 infores:hetionet CHEBI:44185 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0028259 infores:hetionet CHEBI:6444 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0242184 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020538 infores:hetionet CHEBI:47898 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151604 infores:hetionet CHEBI:9586 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0085136 infores:hetionet UNII:R43D2573WO biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0030193 infores:hetionet CHEBI:3698 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0011991 infores:hetionet CHEBI:585948 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0264906 infores:hetionet CHEBI:51164 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0025061 infores:hetionet CHEBI:31348 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0038999 infores:hetionet NCBIGene:5213 biolink:causes MONDO:0009295 infores:monarchinitiative not_provided not_provided HGNC:8877 MONDO:0009295 uuid:68c7d51e-ee50-40d5-9a0d-eee90ed7c04d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2453 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C1325847 infores:hetionet CHEBI:10110 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0006145 infores:hetionet CHEBI:4636 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0027769 infores:hetionet CHEBI:63619 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0019079 infores:hetionet CHEBI:78320 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0011603 infores:hetionet CHEBI:44915 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0037763 infores:hetionet CAID:CA10014276 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014276 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS4, PS2, PS3, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM1, PM5, PM3, BS2, PP2, PP3, PP4, PP1 This c.882T>C (p.Pro294=) synonymous variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = -0.178882 in GRCh38); it is not predicted to have any splicing impact per SpliceAI (BP7+BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014276/MONDO:0011071/008 2022-07-07 2022-07-07 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:39112 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0231218 infores:hetionet CAID:CA024741 biolink:causes MONDO:0007783 infores:clingen CAID:CA024741 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of aspartic acid with asparagine at codon 2431 of the RYR1 protein, p.(Asp2431Asn). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:11575529, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024741/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:6950 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0030252 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0400823 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0400823 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0032285 infores:hetionet CHEBI:9449 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0011603 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0021843 infores:hetionet CHEBI:204734 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0016436 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0009319 infores:hetionet CHEBI:70746 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0009938 infores:hetionet CAID:CA10529866 biolink:causes MONDO:0010604 infores:clingen CAID:CA10529866 MONDO:0010604 PMID: Benign BA1, BP4 PS4 The c.1048T>G variant in F9 is a missense variant predicted to cause substitution of Serine by Alanine at amino acid 350 (p.Ser350Ala). This variant has been reported in 1 proband meeting phenotypic criteria for mild Hemophilia B. However, PS4_Supporting cannot be applied because more than 3 males in gnomAD v2.1.1 are reported with this variant, as per CFD VCEP specifications (PMID: 23492913). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0006494 (9/13858 alleles) in the East Asian population, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.0000556) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.291, which is below the threshold (<= 0.3) and the splice site predictor Splice AI indicated that the variant has no impact on splicing (score = 0,0,0,0), evidence that does not predict a damaging effect on F9 function (BP4). In summary, this variant meets the criteria to be classified as Benign for Hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP (version 1.0.0, released 10/5/2023): BA1, BP4. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10529866/MONDO:0010604/080 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:45081 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0237849 infores:hetionet CHEBI:83527 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0041657 infores:hetionet CHEBI:16796 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0030196 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085584 infores:hetionet CHEBI:50223 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0085649 infores:hetionet CHEBI:50924 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0033687 infores:hetionet CHEBI:681850 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020456 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0235338 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0235338 infores:hetionet CHEBI:36791 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014335 infores:hetionet CAID:CA16040644 biolink:causes MONDO:0044970 infores:clingen CAID:CA16040644 MONDO:0044970 PMID: Uncertain Significance PS4_Supporting, BP4 PP1, PS2, PS3, PM6, PM2 The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 in Bacalhau et al., 2017, PMID: 28027978) however a subsequent publication reported the proband in this family had seizures, hypotonia, developmental delay, elevated blood lactate, and combined deficiency of electron transport chain enzyme activities (PMID: 32715519). The heteroplasmy level and information on family members and/or testing in family members were not reported in this first kindred. The second family reported was a large kindred from the Venezuelan Andes with axonal Charcot-Marie-Tooth (CMT) disease (motor and sensory neuropathy). Muscle weakness, muscle atrophy, and ataxia were also seen in the affected individuals in this family (Fay et al., 2020, PMID: 32715519). Muscle biopsies performed in several individuals showed denervation and reinnervation, in addition to mitochondrial hyperplasia, mildly increased glycogen, and the presence of mitochondrial crystalline arrays. Combined respiratory chain enzyme deficiencies were also seen in affected individuals from this kindred. The variant was present at homoplasmy in blood and/or muscle in both affected and unaffected individuals from this kindred. There are no reported de novo occurrences on this variant to our knowledge. The computational predictor MitoTIP suggests this variant is benign (27.6 percentile; BP4).This variant is present in population databases (MITOMAP: 1/61,168 sequences, AF=0.002%, haplogroup (Hg) H1c; Helix: 2/195,983 (0.001%), also 19 heteroplasmic occurrences, homoplasmic occurrences in Hg I and V, heteroplasmic in multiple haplogroups; and gnomAD v3.1.2: 2/56,398 (0.004%), also three heteroplasmic occurrences (heteroplasmy levels: 10-20%; 20-30%; 90-100%), one in Hg T, one in H, one in B, one in K, one in L3). Given the frequency of this variant, it does not meet PM2 criterion. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, BP4 Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16040644/MONDO:0044970/015 2023-10-23 2023-11-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:3223 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0241426 infores:hetionet CHEBI:63632 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0008031 infores:hetionet CHEBI:49713 biolink:causes MONDO:0003441 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0393593 infores:hetionet NCBIGene:79867 biolink:causes MONDO:0013482 infores:monarchinitiative not_provided not_provided HGNC:25774 MONDO:0013482 uuid:2b91b823-0c1b-4a11-90ff-fd13e7a295f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:4786 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0013144 infores:hetionet CAID:CA322080037 biolink:causes MONDO:0009276 infores:clingen CAID:CA322080037 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1_Strong PS4 The c.406G>T (p.Glu136Ter) variant in GP1BB is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove 34% (>10%) of the protein (PVS1_Strong). At least one patient (Patient 2 in PMID: 33217855) with this variant had impaired aggregation for ristocetin (aggregation in response to other agonists is not specifically mentioned). Additionally, this patient showed less than 10% expression of GPIba (0%) measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Full gene sequencing of all BSS genes was also performed for this patient by WES. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. The patient is homozygous for the variant (PM3_Supporting). The Grpmax filtering allele frequency in gnomaDv4.1 is 0.000002920 (based on 7/997364 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA322080037/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44915 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0917801 infores:hetionet CHEBI:6741 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0041969 infores:hetionet CHEBI:31236 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0236000 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0027769 infores:hetionet CHEBI:42797 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0234146 infores:hetionet CHEBI:41423 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0404521 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0423773 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0004936 infores:hetionet CHEBI:135736 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0025323 infores:hetionet CHEBI:83804 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0162298 infores:hetionet CHEBI:28593 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0013604 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1579838 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1579838 infores:hetionet CAID:CA2582121175 biolink:causes MONDO:0010305 infores:clingen CAID:CA2582121175 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.1372_1375del variant in SLC6A8 is frameshift variant predicted to cause a premature stop codon in biologically relevant exon 9/13 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (p.Asp458SerfsTer4) (PVS1). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2582121175/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CHEBI:51041 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C2239176 infores:hetionet CHEBI:3696 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042164 infores:hetionet GO:0030316 biolink:causes CL:0000092 infores:ubergraph knowledge_assertion manual_agent GO:0030316 CL:0000092 CHEBI:46557 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0020619 infores:hetionet CHEBI:367163 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0022346 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0037274 infores:hetionet CHEBI:51450 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0917801 infores:hetionet CHEBI:35778 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0085649 infores:hetionet NCBIGene:51244 biolink:causes MONDO:0014784 infores:monarchinitiative not_provided not_provided HGNC:28033 MONDO:0014784 uuid:7d0857b6-54af-4430-8d36-c44d8c3404ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16714 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0235063 infores:hetionet CHEBI:135530 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0040479 infores:hetionet CHEBI:2549 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0030554 infores:hetionet CHEBI:2676 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0014742 infores:hetionet CHEBI:71415 biolink:causes MONDO:0042976 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0042850 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0042109 infores:hetionet CHEBI:8863 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0018808 infores:hetionet NCBIGene:1297 biolink:causes MONDO:0013591 infores:monarchinitiative not_provided not_provided HGNC:2217 MONDO:0013591 uuid:0ffdcdd8-f5d5-450a-bbd3-8d42d571dbae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0015230 infores:hetionet CHEBI:8707 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0042790 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0860866 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0162429 infores:hetionet CHEBI:3207 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0004604 infores:hetionet CAID:CA1392668 biolink:causes MONDO:0019501 infores:clingen CAID:CA1392668 MONDO:0019501 PMID: Likely Benign BS1, BP4 BP7, BP5, BS3, BS4, PP3, PP2, PP1, PP4, BS2, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The variant NM_206933.4: c.15494C>G in USH2A is a missense variant predicted to cause substitution of alanine by glycine at amino acid 5165 (p.Ala5165Gly). The highest MAF in gnomAD v4.1 is 0.3091% (256/75052) in the African/African American population which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1). The computational predictor REVEL gives a score of 0.03 which is below the threshold of 0.15, evidence that does not predict a damaging effect on USH2A function (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied:BS1, BP4 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1392668/MONDO:0019501/005 2025-03-12 2025-03-28 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:585948 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0037199 infores:hetionet CHEBI:83527 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0338831 infores:hetionet CHEBI:8212 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0018681 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0042373 infores:hetionet CHEBI:134990 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0085605 infores:hetionet CHEBI:64028 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0232493 infores:hetionet CHEBI:2682 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020488 infores:hetionet CHEBI:47898 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0038454 infores:hetionet CHEBI:168396 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0015230 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0858794 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0858794 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0178298 infores:hetionet CHEBI:63618 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0028866 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0020517 infores:hetionet CHEBI:70746 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0744727 infores:hetionet CAID:CA376063361 biolink:causes MONDO:0011225 infores:clingen CAID:CA376063361 MONDO:0011225 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_001033855.3:c.206T>A (p.Leu69Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).This variant is absent from gnomAD v4 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PVS1 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376063361/MONDO:0011225/116 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63610 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C3665386 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0234930 infores:hetionet CHEBI:7445 biolink:causes UMLS:C3544094 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C3544094 infores:hetionet CHEBI:8772 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0009763 infores:hetionet CHEBI:4551 biolink:causes MONDO:0008848 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0004331 infores:hetionet UMLS:C1872203 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0948594 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0178298 infores:hetionet CHEBI:134745 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08909 UMLS:C0162429 infores:hetionet CHEBI:17334 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0011603 infores:hetionet CAID:CA404079680 biolink:causes MONDO:0007750 infores:clingen CAID:CA404079680 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP1, PP4 The NM_000527.5(LDLR):c.737G>T (p.Gly246Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2:This variant is absent from gnomAD (gnomAD version 2.1.1).PP3: REVEL score is 0.87, this is greater than 0.75. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404079680/MONDO:0007750/013 2023-04-01 2023-04-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:65173 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0011175 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0036508 infores:hetionet CAID:CA003509 biolink:causes MONDO:0700268 infores:clingen CAID:CA003509 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP4, BP5 The c.5339T>G variant in BRCA1 is a missense variant predicted to cause substitution of Leucine by Arginine at amino acid 1780 (p.(Leu1780Arg)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.41, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.99 (based on Family History LR=0.99), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003509/MONDO:0700268/092 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:17303 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0700200 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0037274 infores:hetionet CHEBI:29007 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0008370 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0232492 infores:hetionet CHEBI:63580 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042755 infores:hetionet NCBIGene:7862 biolink:causes MONDO:0015022 infores:monarchinitiative not_provided not_provided HGNC:14255 MONDO:0015022 uuid:6d0fd272-4ab5-476c-befa-e80c306cb8d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA226536 biolink:causes MONDO:0100368 infores:clingen CAID:CA226536 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PM2_Supporting NM_000329.2(RPE65):c.292_311del (p.Ile98Hisfs) is a deletion variant in exon 4 of 14 that causes a frameshift and introduces a premature stop after 26 codons. This frameshift is predicted to trigger nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). A number of affected patients have been reported harboring this variant, including at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 30870047, PM3). This variant has a Grpmax filtering allele frequency of 0.0001565 (10/34580) in the Latino / Admixed American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226536/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41977 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1565489 infores:hetionet CHEBI:3223 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0009676 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0009450 infores:hetionet CHEBI:15544 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0018944 infores:hetionet CHEBI:9137 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0575081 infores:hetionet CHEBI:28864 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0232807 infores:hetionet CHEBI:44185 biolink:causes MONDO:0034212 infores:ubergraph knowledge_assertion manual_agent CHEBI:44185 MONDO:0034212 CHEBI:132233 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0043352 infores:hetionet CAID:CA645372298 biolink:causes MONDO:0001586 infores:clingen CAID:CA645372298 MONDO:0001586 PMID: Likely Pathogenic PVS1, PM2_Supporting PM3, PP4 "The NM_000203.5:c.1240del (p.Ser414AlafsTer26) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 14 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). One individual with MPS I of ""unknown phenotypic severity"" and confirmed IDUA deficiency has been reported (insufficient detail to apply PP4). This individual is compound heterozygous for the variant and another variant in IDUA, c.614G>A (p.Cys205Tyr). The allelic data from this patient will be used in the classification of p.Cys205Tyr and is not be included here to avoid circular logic. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). IDUA-specification ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 16, 2025)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA645372298/MONDO:0001586/091 2025-06-16 2025-07-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3207 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0021843 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0149931 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0232492 infores:hetionet CHEBI:66901 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0006145 infores:hetionet CHEBI:3398 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00748 UMLS:C0340464 infores:hetionet CHEBI:3738 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0009676 infores:hetionet CAID:CA6748999 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748999 MONDO:0009861 PMID: Uncertain Significance PM2_Supporting BP7 The NM_000277.3:c.198A>G variant in PAH is a synonymous (silent) variant (p.Glu66=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002641 (3/113600 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PAH VCEP’s threshold for PM2_Supporting (<0.0002), meeting this criterion (PM2_Supporting).There is a ClinVar entry for this variant (Variation ID: 760907, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748999/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:100241 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0036974 infores:hetionet CHEBI:5864 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0017178 infores:hetionet CHEBI:5441 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0042963 infores:hetionet UMLS:C1872203 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0151878 infores:hetionet UMLS:C0004609 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0003578 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0549336 infores:hetionet NCBIGene:2263 biolink:causes MONDO:0013815 infores:monarchinitiative not_provided not_provided HGNC:3689 MONDO:0013815 uuid:186833f8-3f3d-40f3-91c8-9fffa05487f2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:5515 biolink:causes MONDO:0032697 infores:monarchinitiative not_provided not_provided HGNC:9299 MONDO:0032697 uuid:431de5fb-8166-4019-8d08-05839f720205 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0231218 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0024115 infores:hetionet CHEBI:3347 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0085649 infores:hetionet NCBIGene:284111 biolink:causes MONDO:0014392 infores:monarchinitiative not_provided not_provided HGNC:23089 MONDO:0014392 uuid:a62c7032-5ffb-41c8-9ac5-e537db42dab1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135935 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0042373 infores:hetionet CHEBI:50173 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235259 infores:hetionet CHEBI:63629 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0013395 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0003469 infores:hetionet CHEBI:17823 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0018681 infores:hetionet CHEBI:64355 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0015672 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0267596 infores:hetionet CHEBI:3814 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0267792 infores:hetionet CHEBI:76010 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0004093 infores:hetionet CHEBI:17688 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C2047937 infores:hetionet CHEBI:107736 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018418 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0595916 infores:hetionet CHEBI:42820 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C1368065 infores:hetionet CAID:CA132294 biolink:causes MONDO:0019497 infores:clingen CAID:CA132294 MONDO:0019497 PMID: Benign BA1 BS4, BP5, BP7, PP4, PP1, PP3, BS2, PM4, PM5, PM3, PM1, PVS1, PM6, BP3, BP2, BP4, PS1, PS2, PS4, PS3 The filtering allele frequency of the c.3503+12_3503+33del (p.Gly1172GlufsX34) variant in the MYO7A gene is 50.8% (11084/21494) of European (Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132294/MONDO:0019497/005 2018-09-28 2019-07-17 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:61049 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0518015 infores:hetionet NCBIGene:7003 biolink:causes MONDO:0007176 infores:monarchinitiative not_provided not_provided HGNC:11714 MONDO:0007176 uuid:15c22f57-34cd-45d6-b904-72dd0bedc0d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0028259 infores:hetionet CHEBI:7494 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0314719 infores:hetionet CHEBI:7852 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0018790 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0150450 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0013395 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0011849 infores:hetionet CHEBI:4657 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0344232 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0231365 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0231365 infores:hetionet CHEBI:4469 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0013390 infores:hetionet CHEBI:4907 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0241426 infores:hetionet NCBIGene:462 biolink:causes MONDO:0013144 infores:monarchinitiative not_provided not_provided HGNC:775 MONDO:0013144 uuid:d9427ee2-a494-40e6-a2ad-27b5246c6a86 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBITaxon:34390 biolink:causes MONDO:0005984 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:34390 MONDO:0005984 CHEBI:51164 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C2830004 infores:hetionet CHEBI:3568 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0038358 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0857448 infores:hetionet CHEBI:6129 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151904 infores:hetionet CAID:CA401325125 biolink:causes MONDO:0009290 infores:clingen CAID:CA401325125 MONDO:0009290 PMID: Pathogenic PVS1, PM2_Supporting, PM3_Supporting PP4 The NM_000152.5:c.2411G>A (p.Trp804Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 )out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient reported to have infantile-onset Pompe disease is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1802C>T (p.Ser601Leu) (ClinVar Variation ID: 194154, SCV002032130.1); the phase is unconfirmed (PMID: 28394184) (PM3_Supporting). There is insufficient data to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. Initially, the variant was classified a likely pathogenic by the ClinGen Lysosomal Diseases VCEP on August 17, 2021, but it was reclassified as pathogenic on Jan 15, 2024, due to the application of PM3_Supporting. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Panel on Feb 6, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401325125/MONDO:0009290/010 2024-03-06 2024-03-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:100241 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151904 infores:hetionet CHEBI:9943 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151827 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0574067 infores:hetionet CHEBI:6950 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0039231 infores:hetionet CHEBI:204928 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0042267 infores:hetionet CHEBI:61049 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0011991 infores:hetionet CHEBI:28971 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C1257843 infores:hetionet CHEBI:10125 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0012569 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0277925 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1443060 infores:hetionet CHEBI:8764 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151872 infores:hetionet CHEBI:50749 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0041834 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042109 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0003864 infores:hetionet CHEBI:5138 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0231218 infores:hetionet CHEBI:83804 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0520888 infores:hetionet CHEBI:4702 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0233407 infores:hetionet CAID:CA410147652 biolink:causes MONDO:0100083 infores:clingen CAID:CA410147652 MONDO:0100083 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1250C>G (p.Ser417Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score of 0.391, which is below the 0.50 threshold and a spliceAI score below the threshold of 0.2 (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147652/MONDO:0100083/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44423 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0043094 infores:hetionet CHEBI:100241 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1384353 infores:hetionet CHEBI:7577 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0037299 infores:hetionet UNII:54Z8M50D6Q biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0015376 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235807 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235807 infores:hetionet CHEBI:64354 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0010200 infores:hetionet GO:0072095 biolink:causes GO:0001658 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0001658 GO:0055024 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:0055024 GO:0072359 CAID:CA410147502 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147502 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1286T>G (p.Leu429Arg) is a missense variant which is absent from both gnomAD v2.1 and gnomAD v3.1.2 (PM2_supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. It has a REVEL score of 0.399, which is less than 0.50 (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147502/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4445 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0746961 infores:hetionet CAID:CA9870161 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870161 MONDO:0015967 PMID: Uncertain Significance BS2 PM2, PP3, PP4 The c.83C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to valine at codon 28 (p.(Ala28Val)) of NM_175914.5. This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (internal lab contributor) (BS2). The Grpmax filtering allele frequency of the c.83C>T variant in gnomAD v2.1.1 is 0.0007020%, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.186, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor). In summary, c.83C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 8/11/2023): BS2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870161/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6375 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014866 infores:hetionet CHEBI:85078 biolink:causes UMLS:C0581395 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0581395 infores:hetionet CHEBI:5613 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020651 infores:hetionet CHEBI:16755 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0010200 infores:hetionet CHEBI:9086 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C2364111 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0549391 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549391 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0041969 infores:hetionet CHEBI:6367 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151766 infores:hetionet CAID:CA410206829 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206829 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.719C>T (p.Pro240Leu) is a missense variant. It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206829/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:39112 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0023530 infores:hetionet CAID:CA2573102980 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573102980 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4 The c.1363dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 455 of NM_000162.5, adding 4 novel amino acids before encountering a stop codon (p.(Val455GlyfsTer4)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1363dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573102980/MONDO:0015967/086 2023-09-01 2023-09-01 Semidominant inheritance HP:0032113 Supports CHEBI:31174 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0542571 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002461 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0017662 infores:hetionet CHEBI:2663 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0085636 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0429774 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0429774 infores:hetionet CHEBI:47499 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011071 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027441 infores:hetionet CHEBI:65173 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0011124 infores:hetionet CHEBI:71940 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0917801 infores:hetionet CHEBI:63637 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0231528 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0003123 infores:hetionet CAID:CA226650 biolink:causes MONDO:0010725 infores:clingen CAID:CA226650 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4, PP3_Strong, PP4, PP1 The NM_000330.4(RS1):c.276G>C variant is a missense variant encoding the substitution of Tryptophan with Cysteine at amino acid 92. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.982, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes], which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through at least 1 meiosis in a family, which consists of 2 brothers and an unaffected mother (PP1; PMID: 9760195). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 10636421, PP4). This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: PMID: 9760195, 28348004, 31106028, 28272453, 33608557, 34624300, 39462066, and 20809529, PS4). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_strong, PP1, PS4, and PP4 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226650/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:6715 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235146 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0014130 infores:hetionet CHEBI:16469 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0037763 infores:hetionet CHEBI:63599 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0040034 infores:hetionet CAID:CA410147963 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147963 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS4, PS3, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BS1, BS3, BS4, BP7, PM4, PM1, PM5, PM3, PP2, PP4, PP1 NM_001754.5(RUNX1):c.1145C>T (p.Pro382Leu) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting) and has not been reported as a confirmed germline variant (PMID: 28069802; PMID: 28481359/COSMIC ID: COSV55870444/cBioPortal; PMID: 30761385). The computational predictor, REVEL, gives a score of 0.891, which is above the threshold of 0.88, and is evidence that correlates with impact to RUNX1 function (PP3); to our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting and PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147963/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:74947 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0034359 infores:hetionet CHEBI:63610 biolink:causes UMLS:C1868769 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C1868769 infores:hetionet CHEBI:10119 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0013132 infores:hetionet CHEBI:50648 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003811 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0233746 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233746 infores:hetionet CHEBI:474180 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0033774 infores:hetionet CHEBI:61049 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0026826 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0267792 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0011570 infores:hetionet NCBIGene:1376 biolink:causes MONDO:0012136 infores:monarchinitiative not_provided not_provided HGNC:2330 MONDO:0012136 uuid:9277a39c-22d8-499c-8e4e-f99ae83804b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6413 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0004093 infores:hetionet CHEBI:77733 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0033774 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020557 infores:hetionet CHEBI:3479 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0151539 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0037274 infores:hetionet UMLS:C0657912 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013491 infores:hetionet CHEBI:4710 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030554 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0009450 infores:hetionet NCBIGene:57670 biolink:causes MONDO:0032834 infores:monarchinitiative not_provided not_provided HGNC:22219 MONDO:0032834 uuid:dfe97243-1e84-4d5a-b861-67a3c76e5e08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1903587 biolink:causes GO:0001944 infores:ubergraph knowledge_assertion manual_agent GO:1903587 GO:0001944 CHEBI:9086 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0001807 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0085606 infores:hetionet CHEBI:64355 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0600228 infores:hetionet CAID:CA410206676 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206676 MONDO:0011071 PMID: Uncertain Significance BP4, PM2 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.793A>G (p.Ser265Gly) is a missense variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score < 0.50 (0.439) and a SpliceAI score ≤ 0.20 (0.04) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206676/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:37924 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151889 infores:hetionet CHEBI:51141 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0036974 infores:hetionet CHEBI:9130 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0002418 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0021053 infores:hetionet CHEBI:10124 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0020651 infores:hetionet CHEBI:8382 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0041296 infores:hetionet CHEBI:28918 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0085612 infores:hetionet CHEBI:472657 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0033774 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0948525 infores:hetionet CHEBI:3044 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0030252 infores:hetionet CHEBI:23765 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0018965 infores:hetionet NCBIGene:5083 biolink:causes MONDO:0011477 infores:monarchinitiative not_provided not_provided HGNC:8623 MONDO:0011477 uuid:7fbdbb27-8ede-453c-b464-e105430c5b67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5801 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0349506 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0428977 infores:hetionet CHEBI:63581 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0392525 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C3665347 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0849925 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0849925 infores:hetionet CHEBI:66899 biolink:causes UMLS:C1536145 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C1536145 infores:hetionet CHEBI:119486 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0017979 infores:hetionet CHEBI:9566 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0235660 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0863090 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0863090 infores:hetionet CHEBI:3756 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0232462 infores:hetionet CAID:CA227863 biolink:causes MONDO:0100438 infores:clingen CAID:CA227863 MONDO:0100438 PMID: Pathogenic PVS1, PP1, PP4, PM2_Supporting, PM3 NM_014336.5(AIPL1):c.1010_1011del (p.Glu337AlafsTer?) is a frameshift variant in exon 6 of 6 that is predicted not to trigger nonsense-mediated decay but rather to disrupt the protein product between amino acids 337 and 384, and to extend the C-terminus by 70 additional amino acids (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 37734845). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) variant confirmed in trans (1 point, PMID: 10615133), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), poor central vision (1 pt) from birth (1 pt), severe night blindness (0.5 pts), pendular nystagmus (1 pt), widespread retinal pigment epithelium changes in the fundus with severely attenuated retinal vessels (1 pt) and pigment clumping in the far periphery (0.5 pts), pronounced macular atrophy (0.5 pts), optic disc pallor (0.5 pts), and non-detectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 8 points, PMID: 10615133, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 10615133, PP1). In summary, this variant meets the criteria to be classified as Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA227863/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63611 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0025222 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0015393 infores:hetionet CHEBI:92712 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0042514 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0232492 infores:hetionet CHEBI:6954 biolink:causes MONDO:0016264 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0241910 infores:hetionet CAID:CA8603217 biolink:causes MONDO:0100326 infores:clingen CAID:CA8603217 MONDO:0100326 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PM3, PM5, BP2 The NM_000419.5:c.1139G>A variant in ITGA2B is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 380 (p.Gly380Asp). At least one patient (Patient GM in PMID: 12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% as measured by flow cytometry (PP4_Moderate). Although this variant was reported in heterozygosity in this individual (Patient GM in PMID: 12083483), PM3 was not applied at any level of strength because additional ITGA2B variants were also observed in the individual (c.2254C>G (p.Leu752Val) in homozygosity and c.2264G>C (p.Arg755Pro) in homozygosity). The highest gnomADv4.0 MAF is 0.000002858 (1/349874 alleles) in the European non-Finnish population (PM2_supporting). Furthermore, the computational predictor REVEL gives a score of 0.865, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PP4_Moderate, PM2_Supporting, PP3. (VCEP specifications version 2.1; date of approval 4/16/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8603217/MONDO:0100326/011 2024-04-16 2024-04-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5138 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0036572 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0162628 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0162628 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0037274 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C1565489 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005771 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0017677 infores:hetionet CHEBI:6931 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0030193 infores:hetionet CHEBI:66964 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0037822 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0235431 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0021400 infores:hetionet CAID:CA410205780 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205780 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP3, BP2, BP1, BP4, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.63C>A (p.Cys21Ter) is a nonsense variant which occurs in an exon which is not present in isoforms b or c (PVS1 not applicable). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205780/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0032961 infores:hetionet NCBIGene:54187 biolink:causes MONDO:0012495 infores:monarchinitiative not_provided not_provided HGNC:19237 MONDO:0012495 uuid:d0a45a86-e83b-4c78-8860-844135be2958 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0022660 infores:hetionet UMLS:C1709429 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0027497 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0012833 infores:hetionet CHEBI:8888 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033687 infores:hetionet CHEBI:47898 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0023530 infores:hetionet CHEBI:6741 biolink:causes UMLS:C0341163 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0341163 infores:hetionet CHEBI:37941 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0151970 infores:hetionet CHEBI:5775 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0030252 infores:hetionet CHEBI:32020 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0013395 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0853149 infores:hetionet CHEBI:7454 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0011570 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0948594 infores:hetionet NCBIGene:1420 biolink:causes MONDO:0100436 infores:monarchinitiative not_provided not_provided HGNC:2410 MONDO:0100436 uuid:f956398c-2b66-44a1-beea-ee865d853efe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0025061 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0009450 infores:hetionet CHEBI:49960 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0018965 infores:hetionet CHEBI:4975 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0018418 infores:hetionet CHEBI:84500 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0022107 infores:hetionet CHEBI:59445 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0011991 infores:hetionet CAID:CA367402684 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402684 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting PP4 The c.323A>G variant in the glucokinase gene, GCK, causes an amino acid change of tyrosine to cysteine at codon 108 (p.(Tyr108Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.968, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 2 individuals with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 12050210, internal lab contributors). Another missense variant, c.322T>C p.Tyr108His, has been interpreted as pathogenic by the ClinGen MDEP, and p.Tyr108Cys has a greater Grantham distance (PM5). In summary, c.323A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402684/MONDO:0015967/086 2023-11-22 2023-11-22 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA000343 biolink:causes MONDO:0018875 infores:clingen CAID:CA000343 MONDO:0018875 PMID: Benign BP4, BS3, BS4, BS2 BA1, PS3, PS4, PS2, PS1, PM1, PM5, BS1, PM2, PM6, PP3, PP1, PP4 The NM_000546.6: c.704A>G variant in TP53 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 235 (p.Asn235Ser). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor: SCV000185528.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported not to segregate with Li-Fraumeni syndrome in four affected family members from one family (BS4; PMID 17318340). Computational predictor scores (BayesDel = -0.0342; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BS4, BP4_Moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000343/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6715 biolink:causes UMLS:C0853908 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0853908 infores:hetionet GO:1904133 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0007417 CHEBI:29013 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0085624 infores:hetionet CHEBI:49375 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0037299 infores:hetionet NCBIGene:3815 biolink:causes MONDO:0010108 infores:monarchinitiative not_provided not_provided HGNC:6342 MONDO:0010108 uuid:65c765d8-17c7-48da-9f47-f9ec926f569d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA367401750 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401750 MONDO:0015967 PMID: Pathogenic PM5_Strong, PS4_Moderate, PM1, PP2, PP3, PP4, PM2_Supporting The c.503C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to isoleucine at codon 168 (p.(Thr168Ile)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.997 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). Two other missense variants, c.502A>G p.Thr168Ala and c.503C>A p.Thr168Asn, have been interpreted as pathogenic by the ClinGen MDEP, and p.Thr168Ile has a greater Grantham distance than p.Thr168Ala and p.Thr168Asn (PM5_Strong). In summary, c.503C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PP4, PS4_Moderate, PM5_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401750/MONDO:0015967/086 2023-12-01 2023-12-01 Semidominant inheritance HP:0032113 Supports CHEBI:8888 biolink:causes UMLS:C0235398 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235398 infores:hetionet CHEBI:63581 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0520573 infores:hetionet CHEBI:6128 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C2830004 infores:hetionet CHEBI:8107 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085593 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0042109 infores:hetionet CHEBI:4903 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0006145 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0149904 infores:hetionet CHEBI:6775 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0040264 infores:hetionet CHEBI:37333 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0043352 infores:hetionet CHEBI:6413 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0002792 infores:hetionet CHEBI:8207 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0039231 infores:hetionet CHEBI:465284 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0018524 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0151479 infores:hetionet CHEBI:9130 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0231530 infores:hetionet CHEBI:48273 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C1527344 infores:hetionet CHEBI:478164 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C1142412 infores:hetionet CHEBI:171719 biolink:causes EFO:0005054 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0429097 infores:hetionet NCBIGene:9131 biolink:causes MONDO:0010378 infores:monarchinitiative not_provided not_provided HGNC:8768 MONDO:0010378 uuid:46cce88e-aa05-404f-aaeb-bf10fd14b9aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA021738 biolink:causes MONDO:0005045 infores:clingen CAID:CA021738 MONDO:0005045 PMID:10806205 Uncertain Significance PM1, PS4_Supporting PM5, PP2, PP3, PP1, BP4, PS1, PS3 NM_000363.5(TNNI3):c.484C>T (p.Arg162Trp). This variant has been reported in individuals with HCM and other cardiomyopathies (Laboratory for Molecular Medicine (LMM) data, Oxford Medical Genomics Laboratory (OMGL) data, Kimura 1997 PMID: 9241277, Elliott 2000 PMID: 10806205, Takahashi-Yanaga 2001 PMID: 11735257, Garcia-Pavia 2011 PMID: 21896538, Kubo 2011 PMID: 21799269, Andreasen 2013 PMID: 23299917, Santos 2012 PMID: 22429680, Maron 2012 PMID: 21839045, Gray 2013 PMID: 23270746, Redwood 1999 PMID: 10615387, Walsh 2017 PMID: 27532257, Das 2014 PMID: 24113344, Wang 2014 PMID: 25132132, Hirota 2010 PMID: 20350521) and has also been identified in 3 out of 17978 (0.04% FAF 95% CI) of East Asian chromosomes in gnomAD (https://gnomad.broadinstitute.org/; v.2.1). The variant is statistically increased in individuals with HCM compared to controls (OR, lower 95% CI>5), therefore, the PS4 criterion has been applied at supporting weight (PS4_Supporting) and the PM2_Supporting criterion has not been applied. It was also identified in the homozygous state in 1 Indian and 1 Jordanian individuals with HCM and segregated with disease in the homozygous state in 3 affected relatives from 2 families, but none of the heterozygous relatives (<50 years old) were affected (Gray 2013 PMID: 23270746; Das 2014 PMID: 24113344; LMM data). Therefore, the PP1 criterion was not applied. This variant lies in a region of the protein where variants are statistically more likely to be disease-associated (PM1; Walsh 2019 PMID:30696458). In vitro functional studies provide some evidence that this variant could impact protein function (Elliott 2000 PMID: 10806205); however, this data is currently insufficient to establish functional impact and apply PS3. Additionally, computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (REVEL score <0.7). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Supporting, and PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA021738/MONDO:0005045/098 2025-11-14 2025-11-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:79699 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0014742 infores:hetionet CHEBI:94848 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0043352 infores:hetionet GO:2000387 biolink:causes GO:0046660 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0046660 CHEBI:47426 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0042963 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0039231 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0033975 infores:hetionet CAID:CA320642610 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642610 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS2, PS1, PS3, PS4, BA1, BP3, BP1, BP2, PM6, PM2, PVS1, BS1, BS3, BS4, BP5, PM5, PM4, PM1, PM3, BS2, PP1, PP2, PP3, PP4 NM_001754.5(RUNX1):c.336G>T (p.Leu112=) is a synonymous variant. This variant does not have a REVEL score and SpliceAI is ≤0.20 (0.01) which meets the criteria for BP4. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.05 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642610/MONDO:0011071/008 2022-08-23 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2704 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0042267 infores:hetionet CHEBI:17303 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0744727 infores:hetionet NCBIGene:6154 biolink:causes MONDO:0013964 infores:monarchinitiative not_provided not_provided HGNC:10327 MONDO:0013964 uuid:25ce85cf-6377-4603-b074-d02c365ba420 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63611 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0518015 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0004936 infores:hetionet CHEBI:45367 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0013395 infores:hetionet CHEBI:6715 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042963 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018799 infores:hetionet NCBIGene:7040 biolink:causes MONDO:0007542 infores:monarchinitiative not_provided not_provided HGNC:11766 MONDO:0007542 uuid:c7930e7b-c798-463b-b480-94cbcc3672c6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:91583 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0027497 infores:hetionet CHEBI:74947 biolink:causes MONDO:0021440 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0004998 infores:hetionet CHEBI:75722 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0021141 infores:hetionet CHEBI:50692 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0009806 infores:hetionet CAID:CA012740 biolink:causes MONDO:0005045 infores:clingen CAID:CA012740 MONDO:0005045 PMID:27532257PMID:7796500PMID:17703256PMID:12974739PMID:27532257PMID:7796500PMID:17703256PMID:12974739 Pathogenic PM1, PM2, PP1_Strong, PS4 The c.2609G>A (p.Arg870His) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:7796500; PMID:12974739; PMID:17703256; PMID:27532257; Partners LMM ClinVar SCV000059458.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >10 affected individuals (PP1_Strong; PMID:7796500; PMID:12974739; PMID:17703256). This variant was identified in 1/66732 European chromosomes (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012740/MONDO:0005045/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27834 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0392525 infores:hetionet CHEBI:15367 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0740394 infores:hetionet CAID:CA235344 biolink:causes MONDO:0018997 infores:clingen CAID:CA235344 MONDO:0018997 PMID:17586837PMID:19953625PMID:20683980 Pathogenic PM1, PM2, PS2_Very Strong, PP2, PP3 The c.806T>C (p.Met269Thr) variant in SOS1 has been reported in the literature in at least 2 unconfirmed and 1 confirmed de novo occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837; 19953625, 20683980). It has also been reported as a confirmed de novo occurrence in a patient with clinical features of a RASoapthy (PMID: 20683980). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS2_VeryStrong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA235344/MONDO:0018997/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4814 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0004238 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0234458 infores:hetionet CHEBI:38940 biolink:causes UMLS:C2747905 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C2747905 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005800 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0019917 infores:hetionet CHEBI:8228 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0235996 infores:hetionet CHEBI:94385 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0002962 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020557 infores:hetionet CHEBI:8069 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0015967 infores:hetionet CHEBI:3696 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042373 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0018802 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0232197 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0232197 infores:hetionet CAID:CA2018007656 biolink:causes MONDO:0015967 infores:clingen CAID:CA2018007656 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 BA1, PS4, BS1, PP4 The c.342dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 115 (NM_000545.8), adding 73 novel amino acids before encountering a stop codon (p.(Val115CysfsTer73)). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PS4_Moderate also cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). In summary, c.342dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2018007656/MONDO:0015967/017 2022-02-08 2022-07-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31705 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0086439 infores:hetionet CHEBI:92923 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0033774 infores:hetionet CHEBI:520985 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0155626 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0233794 infores:hetionet CHEBI:116278 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0231528 infores:hetionet CHEBI:499361 biolink:causes HP:0001959 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0085602 infores:hetionet CHEBI:2904 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0034063 infores:hetionet CHEBI:28915 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0744727 infores:hetionet GO:0021896 biolink:causes CL:0012000 infores:ubergraph knowledge_assertion manual_agent GO:0021896 CL:0012000 CHEBI:6367 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030567 infores:hetionet CAID:CA163889 biolink:causes MONDO:0700270 infores:clingen CAID:CA163889 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PM5_Supporting, PVS1 The c.8473C>T (p.Gln2825T*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 35260754, 16941484). The highest minor allele frequency in gnomAD v4.1.0 is 0.00001098 (1/91054 alleles) in the South Asian population; while this is higher than the HBOP VCEP threshold (≤0.00001) for PM2_Supporting, it is present in only one allele, meeting this criterion. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong, PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA163889/MONDO:0700270/020 2025-09-21 2025-10-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:3478 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151754 infores:hetionet CHEBI:68534 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0009782 infores:hetionet CHEBI:64354 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C2830004 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0855242 infores:hetionet CHEBI:5134 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0231919 infores:hetionet CHEBI:2666 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0026961 infores:hetionet CHEBI:10023 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151517 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0019158 infores:hetionet CHEBI:47780 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0019079 infores:hetionet CHEBI:5779 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0004093 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0549209 infores:hetionet CHEBI:15544 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C2004489 infores:hetionet NCBIGene:8915 biolink:causes MONDO:0007650 infores:monarchinitiative not_provided not_provided HGNC:989 MONDO:0007650 uuid:11d70d9e-224b-4989-bd28-e1574a18eee6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C2129214 infores:hetionet CHEBI:74947 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0152267 infores:hetionet CHEBI:31236 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151744 infores:hetionet CHEBI:2636 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0039231 infores:hetionet CHEBI:681569 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0333355 infores:hetionet CHEBI:53691 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C1720775 infores:hetionet CAID:CA254929 biolink:causes MONDO:0010725 infores:clingen CAID:CA254929 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PS3_Supporting, PP3_Strong, PS2_Moderate, PP4, PP1 PM1 NM_000330.4(RS1):c.667T>C (p.Cys223Arg) is a missense variant encoding the substitution of cysteine with arginine at amino acid 223. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMID: 34645606, PMID: 10533068, PMID: 30652005, PS4_Moderate). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 33460243, PP4). This variant has been identified as a de novo occurrence with confirmed parental relationships in an individual meeting the PS2 requirement of some functional vision impairment in affected males by age 13 (1 point, PS2_Moderate, PMID: 33460243). The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family with two affected brothers (PP1; PMID: 30652005). The computational predictor REVEL gives a score of 0.974, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. COS‐7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 16361673, PS3_Supporting). This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). However, the PP3_Strong code has been met, which is ineligible to be used in combination with the PM1 code at any strength, so the PM1 code was not met. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PS3_Supporting, PP1, PP4, PS2_Moderate, and PS4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA254929/MONDO:0010725/126 2025-09-19 2025-09-19 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:63791 biolink:causes MONDO:0005141 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0033817 infores:hetionet CHEBI:63608 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0438717 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0700594 infores:hetionet CHEBI:40237 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0004093 infores:hetionet CHEBI:9737 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0151905 infores:hetionet CHEBI:4672 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0009782 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0020649 infores:hetionet CHEBI:251408 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C1527344 infores:hetionet CHEBI:4876 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0030193 infores:hetionet CAID:CA288488 biolink:causes MONDO:0700272 infores:clingen CAID:CA288488 MONDO:0700272 PMID: Pathogenic PM3_Strong, PP1_Strong, PVS1 PS3, PM2 The c.3549C>A (p.Tyr1183Ter) variant in PALB2 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1183-1186) in a gene where loss-of-function is an established disease mechanism. This variant, or another variant leading to the same protein truncation, has been detected in three individuals with autosomal recessive FANCN. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and three of those were confirmed in trans by parental testing (co-occurring variants: c.2257C>T (p.Arg753Ter); c.2962C>T (p.Gln988Ter); c.3116delA (p.Asn1039Ilefs*2): PMID 17200671). The variant has been reported to segregate with breast and/or pancreatic cancer in 15 affected members from 6 families (Invitae; Ambry Genetics). This variant is non-functional in multiple different protein assays (PMID 31757951, PMID 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PP1_Strong, PM3_Strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA288488/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64045 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0017178 infores:hetionet CHEBI:31000 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0151908 infores:hetionet CHEBI:10110 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0008031 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0151838 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0259799 infores:hetionet CHEBI:68478 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0003962 infores:hetionet CHEBI:8356 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0016204 infores:hetionet CHEBI:168396 biolink:causes UMLS:C1096691 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C1096691 infores:hetionet CHEBI:6015 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0085631 infores:hetionet CHEBI:7915 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0036974 infores:hetionet CHEBI:3077 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0340865 infores:hetionet CHEBI:3011 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0013395 infores:hetionet CHEBI:31981 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0009676 infores:hetionet CHEBI:5165 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0040264 infores:hetionet CHEBI:3504 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0085631 infores:hetionet CHEBI:8435 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0015967 infores:hetionet CHEBI:68595 biolink:causes HP:0012390 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0016167 infores:hetionet CHEBI:3764 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C1291077 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0032285 infores:hetionet GO:1905000 biolink:causes GO:0061337 infores:ubergraph knowledge_assertion manual_agent GO:1905000 GO:0061337 CHEBI:36791 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0011616 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0855242 infores:hetionet CHEBI:91541 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0030193 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0022660 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0149836 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1262144 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0041976 infores:hetionet CHEBI:17688 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0235266 infores:hetionet CAID:CA340921 biolink:causes MONDO:0044970 infores:clingen CAID:CA340921 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate PS2, PS3, PM6 The m.7510T>C variant in MT-TS1 has been reported in at least nine individuals across six different families with primary mitochondrial disease (PS4_moderate; PMIDs: 29299381, 18028453, 23430555, 15292920, 10978361, 12471220). The most common feature in affected individuals was sensorineural hearing loss. Age of onset ranged from 2-70 years old, and heteroplasmy levels in affected individuals ranged from 90% to >99%. Of note, some unaffected family members had the variant present at homoplasmy, as well (PMID: 12471220). Additional clinical features were seen in at least two families. One family reported in the medical literature also had migraines, ataxia, short stature, epilepsy, cognitive impairment, tremor, and restless leg syndrome (PMID: 29299381). The second family was known to some members of this expert panel, and the expert panel agreed to include this case. This variant segregated with disease manifestations in two families with hearing loss as all affected individuals had the variant present at heteroplasmy levels ranging from 90% to >99% (PP1_moderate; PMIDs: 29299381, 10978361). There are no de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340921/MONDO:0044970/015 2023-03-13 2023-03-17 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria UMLS:C0065374 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0006145 infores:hetionet CHEBI:8024 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0030193 infores:hetionet CHEBI:17474 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0547030 infores:hetionet CHEBI:63622 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0020456 infores:hetionet NCBIGene:1287 biolink:causes MONDO:0010520 infores:monarchinitiative not_provided not_provided HGNC:2207 MONDO:0010520 uuid:98b7ccfa-55db-4d11-9d9d-5aac523a4c13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151763 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235567 infores:hetionet CHEBI:6897 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0013604 infores:hetionet CHEBI:7809 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0235378 infores:hetionet CHEBI:44032 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0014742 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0009938 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0235146 infores:hetionet CHEBI:7773 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0002994 infores:hetionet CHEBI:135935 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0151905 infores:hetionet GO:2000733 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0072006 CHEBI:7465 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0750426 infores:hetionet CHEBI:180905 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0015967 infores:hetionet CHEBI:38562 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0236075 infores:hetionet CHEBI:31515 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0149931 infores:hetionet CHEBI:50648 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0019825 infores:hetionet GO:0033599 biolink:causes GO:0030879 infores:ubergraph knowledge_assertion manual_agent GO:0033599 GO:0030879 CHEBI:65349 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0152031 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0009763 infores:hetionet CHEBI:6759 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0040264 infores:hetionet CHEBI:2453 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0021053 infores:hetionet CHEBI:7959 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C2364111 infores:hetionet CHEBI:63620 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0018681 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0178298 infores:hetionet CAID:CA8602779 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602779 MONDO:0100326 PMID: Uncertain Significance BP4 BS1, PM2, PP3 NM_000419.5(ITGA2B):c.2206G>T (p.Val736Leu) is a missense variant for which the computational predictor REVEL gives a score of 0.019, below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4), and no splicing effect is predicted by SpliceAI. The highest population minor allele frequency in gnomAD v4.1 is 0.000108 (6/55442 alleles) in the Admixed American genetic ancestry group, which is above than the ClinGen PD VCEP threshold of <0.0001 for PM2_Supporting but below the >0.00158 threshold for BS1. After a thorough literature search, this variant has not been reported in a Glanzmann thrombasthenia patient to our knowledge. ClinVar contains an entry for this variant (Variation ID: 2328709) with multiple VUS submissions (SCV003663171.2, SCV004296045.2, SCV005412749.1), none reporting an affected individual. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602779/MONDO:0100326/011 2025-11-06 2025-11-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5118 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085096 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085606 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0162429 infores:hetionet CAID:CA136149 biolink:causes MONDO:0021060 infores:clingen CAID:CA136149 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.3709C>A (p.Pro1237Thr) variant in the SOS1 gene is 0.0373% (11/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136149/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:0010981 biolink:causes GO:0071554 infores:ubergraph knowledge_assertion manual_agent GO:0010981 GO:0071554 CHEBI:100241 biolink:causes UMLS:C0853748 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853748 infores:hetionet GO:2000274 biolink:causes GO:0007424 infores:ubergraph knowledge_assertion manual_agent GO:2000274 GO:0007424 GO:1901342 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1901342 GO:0072359 CHEBI:6076 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0015397 infores:hetionet CHEBI:53766 biolink:causes HP:0011458 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0740651 infores:hetionet CHEBI:3696 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0006625 infores:hetionet CHEBI:8428 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0085593 infores:hetionet GO:1904133 biolink:causes GO:0021546 infores:ubergraph knowledge_assertion manual_agent GO:1904133 GO:0021546 CHEBI:63598 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0023222 infores:hetionet CHEBI:3181 biolink:causes MONDO:0001266 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0014714 infores:hetionet GO:0010742 biolink:causes CL:0000517 infores:ubergraph knowledge_assertion manual_agent GO:0010742 CL:0000517 CHEBI:63589 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0178298 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0086543 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001718 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0036416 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003123 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0595877 infores:hetionet CHEBI:3638 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0855329 infores:hetionet CHEBI:83804 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0026837 infores:hetionet CHEBI:9139 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0040264 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0858093 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0858093 infores:hetionet CHEBI:194135 biolink:causes MONDO:0100128 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0275524 infores:hetionet CHEBI:50381 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0042790 infores:hetionet CHEBI:75275 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0853813 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0034150 infores:hetionet CHEBI:3082 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0085593 infores:hetionet CHEBI:681850 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0032285 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0042075 infores:hetionet CHEBI:3698 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0151766 infores:hetionet CHEBI:8024 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042769 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0009443 infores:hetionet CHEBI:3219 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0020522 infores:hetionet CHEBI:63620 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0032617 infores:hetionet CHEBI:3215 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0039070 infores:hetionet CHEBI:9586 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011551 infores:hetionet CHEBI:63605 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0085624 infores:hetionet CHEBI:4495 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0700361 infores:hetionet CHEBI:6121 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0042963 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0314719 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0009782 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037199 infores:hetionet CHEBI:7476 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038999 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0027769 infores:hetionet UMLS:C0004609 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151786 infores:hetionet CHEBI:9566 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0392676 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0079043 infores:hetionet UNII:R43D2573WO biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0043251 infores:hetionet CHEBI:8382 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011615 infores:hetionet CAID:CA367358349 biolink:causes MONDO:0015967 infores:clingen CAID:CA367358349 MONDO:0015967 PMID: Uncertain Significance PVS1_Supporting, PM2_Supporting PP4 The c.3G>A variant in the glucokinase gene, GCK, results in the loss of the initiation codon (p.Met1?) of NM_000162.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Supporting; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.3G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367358349/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:681569 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0243026 infores:hetionet CHEBI:5864 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0041834 infores:hetionet CHEBI:4717 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0235660 infores:hetionet CHEBI:5855 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013362 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0948692 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0003123 infores:hetionet CHEBI:5613 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0344232 infores:hetionet CHEBI:75722 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0028734 infores:hetionet CHEBI:2654 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0231528 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005376 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0017665 infores:hetionet CHEBI:168396 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0001175 infores:hetionet CHEBI:9168 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0041948 infores:hetionet CHEBI:8764 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0947912 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0233632 infores:hetionet CHEBI:48273 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0032617 infores:hetionet CHEBI:44032 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151786 infores:hetionet CHEBI:29688 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0235309 infores:hetionet CHEBI:7773 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0392156 infores:hetionet CHEBI:50922 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0699828 infores:hetionet CHEBI:135613 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0002962 infores:hetionet CAID:CA379924765 biolink:causes MONDO:0015152 infores:clingen CAID:CA379924765 MONDO:0015152 PMID: Pathogenic PVS1, PM3, PP4, PM2_Supporting PS1, PS3, BP7, BS1, BS3, PM5, PM4, PM1, PP2, PP3, BA1, BP1, BP4, BP3 The NM_213599.3: c.148C>T p.(Arg50Ter) variant in ANO5 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/22 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least two individuals with LGMD, including confirmed in trans with a pathogenic or likely pathogenic variant (c.191dup, 1.0 pt, PMID: 23041008) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PMID: 28403181; PP4). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA379924765/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8774 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0232459 infores:hetionet CAID:CA16614968 biolink:causes MONDO:0007648 infores:clingen CAID:CA16614968 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PM2_Supporting, PS4, PP1_Strong, PVS1_Strong BP7, BP5, BS1, BS4, BS3, PM4, PM3, PM1, PM6, PP2, PP3, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS2, PS3, PS1 The c.1565+1G>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least four families meeting HDGC clinical criteria (PS4; PMID: 26182300, SCV000545383.5 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with at least nine meioses observed across four families (PP1_Strong; SCV000545383.5, SCV000665081.3 and internal laboratory contributor). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS4, PP1_Strong, PM2_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16614968/MONDO:0007648/007 2023-08-28 2023-08-28 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:83804 biolink:causes HP:0002486 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027125 infores:hetionet CHEBI:61049 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0017979 infores:hetionet UMLS:C0010592 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0032617 infores:hetionet CHEBI:51860 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0497156 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0012833 infores:hetionet CHEBI:6149 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0235031 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0236073 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0236073 infores:hetionet CHEBI:2379 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0036973 infores:hetionet CHEBI:50859 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0008031 infores:hetionet CHEBI:28593 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0041969 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0027051 infores:hetionet CHEBI:474180 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0151798 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0948525 infores:hetionet CHEBI:7465 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0234238 infores:hetionet CHEBI:4856 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0018794 infores:hetionet CAID:CA255144 biolink:causes MONDO:0010602 infores:clingen CAID:CA255144 MONDO:0010602 PMID:24108539 Benign BS2, PP3, BA1 PS4, PS3 The c.3169G>A variant in F8 is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 1057 (p.Glu1057Lys), affecting the B domain. The highest population minor allele frequency in gnomAD v2.1.1 is 0.006666 (99/14852 alleles) in the East Asian population with 28 hemizygotes, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.000333) for BA1. The computational predictor REVEL gives a score of 0.651, which is above the CFD VCEP threshold of >=0.6, evidence that correlates with impact to F8 function (PP3). This variant was also identified in a proband with a diagnosis of hemophilia B and not hemophilia A, so the BS2 code was applied. In summary, this variant is classified as a benign for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel (version 1.0.0, released 10/5/2023): BA1, BS2, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255144/MONDO:0010602/071 2025-05-02 2025-05-02 X-linked inheritance HP:0001417 Contradicts true CHEBI:6067 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0017658 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002039 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0009241 infores:hetionet CHEBI:3219 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0000731 infores:hetionet CAID:CA294622 biolink:causes MONDO:0010726 infores:clingen CAID:CA294622 MONDO:0010726 PMID: Uncertain Significance BS2_Supporting, BP5, PVS1, PM2_Supporting PP4, PS4 The c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Lys377ProfsTer9) variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.(Lys377ProfsTer9) variant has been reported in 1 individual with an epilepsy and neurodevelopmental disorder (PMID 29655203), and 1 individual with developmental delay and autism where it was inherited from a mother with a history of learning difficulties (ClinVar SCV000190972.2) (PS4_Supporting has not been applied as it is unclear whether these citations reflect two independent occurrences). The p.(Lys377ProfsTer9) variant has also been found in a patient with an alternate molecular basis of disease (PMID 29961512). This patient had early infantile epileptic encephalopathy, however did not meet the diagnostic criteria for either typical or atypical Rett. The p.(Lys377ProfsTer9) variant was found to be inherited from this patient's father, who was reported as having a history of seizures as a child and learning disability but was otherwise described as unaffected (BS2_Supporting). Furthermore, this patient was also found to be heterozygous for a de novo (biological parentage confirmed) GNAO1 missense variant that was deemed to be causative of this patient's clinical presentation (BP5). In summary, the c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PVS1, PM2_supporting, BP5, BS2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294622/MONDO:0010726/016 2022-07-21 2022-09-06 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3219 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0021845 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0009450 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004627 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0013298 infores:hetionet CHEBI:6078 biolink:causes HP:0034752 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0578735 infores:hetionet CHEBI:74947 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0040053 infores:hetionet CHEBI:49040 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0085605 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018418 infores:hetionet CHEBI:291342 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0030252 infores:hetionet CAID:CA9090817 biolink:causes MONDO:0021060 infores:clingen CAID:CA9090817 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.847G>T (p.Val283Leu) variant in the MAP2K2 gene is 0.0448% (6/5824) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA9090817/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50861 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0007859 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0037274 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0015408 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015408 infores:hetionet CHEBI:3561 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0015371 infores:hetionet CHEBI:31711 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027947 infores:hetionet CHEBI:7577 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0151907 infores:hetionet CAID:CA367397036 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397036 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PVS1, PP4_Moderate, PM2_Supporting The c.1318G>T variant in the glucokinase gene, GCK, results in a premature termination at codon 440 (p.(Glu440Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD (PM2_Supporting). This variant was identified in at least two individuals with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 23890519, 25041077, DOI: 10.1530/endoabs.35.P371, and internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 4 families with MODY (PP1_Strong; PMID: 25041077, DOI: 10.1530/endoabs.35.P371, internal lab contributors). In summary, the c.1318G>T variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4_Moderate, PS4, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397036/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:8707 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151849 infores:hetionet CHEBI:5134 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0242429 infores:hetionet CAID:CA1393090 biolink:causes MONDO:0019501 infores:clingen CAID:CA1393090 MONDO:0019501 PMID: Pathogenic PP4, PM3_Very Strong, PM2_Supporting PP3, PM5, BP4 The c.14219C>A (p.Ala4740Asp) variant in USH2A is a missense variant predicted to cause a substitution of alanine by aspartic acid at amino acid 4740. The highest population minor allele frequency in gnomAD v4.0.0 is 0.006102% (72/1180006) in the European (Non-Finish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.309, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least 2 individuals with Usher syndrome, and in at least 5 individuals with Retinitis Pigmentosa (RP) (4 PM3 pts). The two individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Arg737*, p.Ser1849fs; PMIDs: 33576794, 38465142). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4, PMID: 33576794). Of the individuals with RP, four individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Ser1849fs, p.Arg737*, c.7595-2144A>G, p.Arg4192Cys; PMIDs: 30718709, 34781295, 32531858). One individual was compound heterozygous and confirmed in trans by parental testing for the variant and a pathogenic or likely pathogenic variant (p.Arg1653*; PMIDs: 34781295) (PM3_VeryStrong). Patients with this variant may present with either autosomal recessive (AR) Usher syndrome or with AR isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3_VeryStrong, PP4; Version 2; 4/17/24). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1393090/MONDO:0019501/005 2024-06-28 2024-06-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:8107 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0034065 infores:hetionet CHEBI:5778 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030196 infores:hetionet CAID:CA16020986 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020986 MONDO:0009861 PMID: Likely Pathogenic PP4_Moderate, PP3_Strong, PM3, PM2_Supporting The NM_000277.3:c.1262T>G (p.Ile421Ser) variant is a missense variant in exon 12/13 of PAH. The variant has been previously reported in an Austrian patient with PKU (plasma Phe 780 umol/L) in confirmed trans with the p.F39L variant (ClinVar Pathogenic (ID 605) and Pathogenic by ClinGen PAH VCEP); BH4 deficiency was excluded by urinary pterins and dihydropterine reductase assays (PMID: 22526846) (PM3; PP4_Moderate). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.969) (PP3_strong).Classification: Likely PathogenicSupporting Criteria: PM2_supporting; PM3; PP4_Moderate; PP3_strong Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020986/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8871 biolink:causes MONDO:0009861 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0031485 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0011849 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0151586 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151586 infores:hetionet CHEBI:9720 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0042963 infores:hetionet CHEBI:28748 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0011206 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0178298 infores:hetionet CHEBI:64321 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0033774 infores:hetionet CHEBI:4887 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0021177 infores:hetionet CHEBI:63619 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0037763 infores:hetionet CHEBI:31624 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0021053 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0041969 infores:hetionet CAID:CA10014576 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014576 MONDO:0011071 PMID:23817177 Benign BS1, BS3 PS4, PS1, PS3, BP2, BP4, BA1, PVS1, PM6, PM2, BS4, BP7, PM1, PM4, PM5, PP1, PP3 The NM_001754.4:c.179C>T variant that results in the Ala60Val missense change has an MAF of 0.0002950 (0.02%, 10/33902 alleles) in the Latino subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Transactivation assays demonstrate normal transactivation (80-115% of wt) and data from a secondary EMSA demonstrate normal DNA binding (BS3; PMID: 23817177). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014576/MONDO:0011071/008 2021-01-11 2021-01-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2704 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0019193 infores:hetionet CHEBI:72297 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0041969 infores:hetionet CHEBI:9086 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0030252 infores:hetionet CHEBI:10119 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0015371 infores:hetionet NCBIGene:79797 biolink:causes MONDO:0014653 infores:monarchinitiative not_provided not_provided HGNC:20041 MONDO:0014653 uuid:dcb77651-7e84-44cd-9695-1b54b697f1ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151773 infores:hetionet CHEBI:167309 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0018524 infores:hetionet CHEBI:2639 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0242350 infores:hetionet CHEBI:8871 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0333243 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0242350 infores:hetionet CAID:CA412737308 biolink:causes MONDO:0100437 infores:clingen CAID:CA412737308 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1636G>T (p.Glu546Ter) is a nonsense variant introducing a premature stop in codon 546 within exon 4 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with a diagnosis of retinitis pigmentosa (PMID: 23372056), however, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in an affected male by age 30 years, and/or decreased or absent electroretinogram responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412737308/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:8871 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0003123 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0877117 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877117 infores:hetionet CHEBI:5138 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042024 infores:hetionet CHEBI:50924 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0016436 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0227791 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0836924 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0026848 infores:hetionet CHEBI:209807 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0002871 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0162429 infores:hetionet CAID:CA512341174 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341174 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1260C>T (p.Gly420=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.00)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341174/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10650 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0231528 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0234215 infores:hetionet UMLS:C0017797 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0030193 infores:hetionet CHEBI:3636 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0040822 infores:hetionet CHEBI:49375 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0039231 infores:hetionet CAID:CA8815778 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815778 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3 The NM_000152.5:c.2510G>A variant in GAA is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 837 (p.Arg837His). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00019 (3/16178 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.845 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). This variant has been detected in at least 3 individuals, but not with a pathogenic or likely pathogenic variant. Also, no symptoms of Pompe disease were described for any of the individuals (PMID: 27711114, internal laboratory data). Therefore, this does not meet PM3 or PP4. There is a ClinVar entry for this variant (Variation ID: 284232, 2 star review status) with 6 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 8, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815778/MONDO:0009290/010 2023-10-08 2024-02-11 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3698 biolink:causes UMLS:C0853746 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0853746 infores:hetionet CHEBI:194135 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003578 infores:hetionet CHEBI:4636 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0340464 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0262985 infores:hetionet CHEBI:9086 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0085593 infores:hetionet CAID:CA122000 biolink:causes MONDO:0100488 infores:clingen CAID:CA122000 MONDO:0100488 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM5, PM4, PVS1, PM2, PM6, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS4, PS2, PS3, PS1 The NM_004360.4(CDH1):c.-124-161C>A variant has an allele frequency of 0.27733 (27.73%, 4262/15368 alleles, 578 homozygotes) in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA122000/MONDO:0100488/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7573 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0018418 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0332575 infores:hetionet CHEBI:724125 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0162834 infores:hetionet CHEBI:52172 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0015672 infores:hetionet CHEBI:35854 biolink:causes HP:0001937 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0221021 infores:hetionet CHEBI:8871 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0040460 infores:hetionet CHEBI:17303 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0018418 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0043494 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0003860 infores:hetionet CAID:CA386958847 biolink:causes MONDO:0015967 infores:clingen CAID:CA386958847 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PP1_Strong, PVS1, PP4_Moderate PS4 The c.339G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 113 (p.(Trp113Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10 , is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 21437455, 11692182, 29439679). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies) (PP4_Moderate; PMID: 29439679). This variant segregated with diabetes with five informative meioses in two families (PP1_Strong, PMIDs: 27236918, 21437455; internal lab contributor). In summary, c.339G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP1_Strong, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386958847/MONDO:0015967/017 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports UNII:7662KG2R6K biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0232462 infores:hetionet CHEBI:5118 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151772 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0858259 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0858259 infores:hetionet CAID:CA340747763 biolink:causes MONDO:0100368 infores:clingen CAID:CA340747763 MONDO:0100368 PMID: Likely Pathogenic PP3_Moderate, PM3_Supporting, PS3_Supporting, PM5_Supporting, PP4, PM2_Supporting The NM_000329.3(RPE65):c.433G>C (p.Ala145Pro) is a predicted missense variant that changes the alanine at position 145 to proline. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited approximately 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, unpublished data from VCEP member). At least one proband harboring this variant exhibits a phenotype including diagnosis of severe early onset retinal dystrophy or retinitis pigmentosa with onset during the first decade of life, genotyping by hereditary retinal dystrophy panel showing no alternative explanation for disease (2 pts), reduced visual acuity (1 pt), peripheral visual field constriction (1 pt), and macular atrophy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 36017377, PP4). The reported proband was homozygous for the variant (PMID: 36017377, PM3_Supporting). Two other missense variants at the same codon have been reported in similarly affected individuals (NM_000329.3(RPE65):c.434C>A (p.Ala145Asp) in PMIDs: 31273949 and 23661369, and NM_000329.3(RPE65):c.433G>A (p.Ala145Thr) in PMID: 26906952). The p.Ala145Asp variant has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340747763/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2567 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0231528 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0235416 infores:hetionet CHEBI:2675 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0013604 infores:hetionet CHEBI:6367 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040822 infores:hetionet CHEBI:23765 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0206062 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0032285 infores:hetionet NCBIGene:673 biolink:causes MONDO:0013379 infores:monarchinitiative not_provided not_provided HGNC:1097 MONDO:0013379 uuid:c79fba3b-3091-4624-a156-1c1adcf141ff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2636 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0042109 infores:hetionet CHEBI:8356 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026827 infores:hetionet CHEBI:135738 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0027051 infores:hetionet CAID:CA16020912 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020912 MONDO:0009861 PMID:20188615 Pathogenic PVS1, PM2, PP4 The c.976del (p.Trp326GlyfsTer15) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has previously been reported in an Indian PKU case (blood Phe 439umol/L) (PMID: 24130151; PMID: 20188615) who was homozygous for the variant (PP4). Classification: PathogenicSupporting criteria: PVS1, PM2; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020912/MONDO:0009861/006 2020-04-13 2020-04-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47381 biolink:causes UMLS:C0560024 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0560024 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0854113 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0854113 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0549336 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549336 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0004610 infores:hetionet CHEBI:6822 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0004093 infores:hetionet CHEBI:5147 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0026821 infores:hetionet CHEBI:6076 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C2830004 infores:hetionet CAID:CA10606385 biolink:causes MONDO:0015152 infores:clingen CAID:CA10606385 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PS1_Moderate, PP3, PM2_Supporting The NM_003494.4: c.2810+5G>A variant in DYSF, which is also known as NM_001130987.2: c.2864+5G>A, occurs within the splice donor region of intron 26. SpliceAI gives a delta score of 0.92 for loss of the canonical donor and 0.53 for strengthening of a cryptic donor 21 nucleotides into exon 26 (PP3). Skipping of exon 26, which is out of frame, would be expected to introduce a frameshift and premature truncation resulting in nonsense mediated decay whereas use of the cryptic donor would cause an inframe deletion. This variant has been reported in at least nine individuals with features of LGMD or absent dysferlin protein expression (PMID: 34559919, 30564623, 33927379, 27647186; DYSF_000869; ClinVar SCV000769808.7 internal data communication), including in a homozygous state without reported familial consanguinity in 4 patients (1.0 pt; PMID: 34559919, LOVD individual #00305661; ClinVar SCV000769808.7 internal data communication) and confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.2875C>T p.(Arg959Trp), 1.0 pt, PMID: 33927379, LOVD individual #00327604) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF allele displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 33927379, 27647186; PP4_Strong). The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.00002196 (2/91070 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Another nucleotide change in this splice region, NM_003494.4: c.2810+1G>A, has been reported in association with LGMD and classified by the VCEP as Pathogenic. The c.2810+1G>A variant is predicted to result in the same missplicing events predicted for the c.2810+5G>A variant, and these altered splicing events were confirmed to occur by RNAseq (PS1_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/19/2025): PP3, PM3_Strong, PP4_Strong, PM2_Supporting, PS1_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10606385/MONDO:0015152/180 2025-08-19 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8888 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0948089 infores:hetionet CHEBI:7823 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C2830004 infores:hetionet CHEBI:52172 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C1443060 infores:hetionet UMLS:C0009315 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0549373 infores:hetionet CHEBI:16755 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0014591 infores:hetionet CHEBI:5864 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0221201 infores:hetionet CHEBI:63637 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0014742 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151464 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151464 infores:hetionet CHEBI:71415 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0008031 infores:hetionet CHEBI:7852 biolink:causes HP:0010547 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0026825 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0027765 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0021400 infores:hetionet CHEBI:63619 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0278134 infores:hetionet CHEBI:71940 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0042029 infores:hetionet CHEBI:584020 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C1167965 infores:hetionet CHEBI:92998 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020639 infores:hetionet CHEBI:7492 biolink:causes MONDO:0019122 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0242459 infores:hetionet CHEBI:135939 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C1443060 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549399 infores:hetionet CAID:CA343772824 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772824 MONDO:0013144 PMID: Pathogenic PS4_Moderate, PVS1_Strong, PP1_Strong, PP4, PM2_Supporting The c.1171C>T (p.Arg391Ter) variant in SERPINC1 is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent studies, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:29153735). This variant has been reported in at least four more probands meeting an antithrombin activity level of < 0.8 IU/mL; due to the absence of specified repeat testing, crossed electrophoresis showing abnormal results and family members with reported antithrombin activity levels below the threshold three of these probands were scored at only half a point. (2.5 points) (PS4_Moderate; PMIDs:34207366, 8217824, 31030036, 23932013). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 15 affected family members from two families (PP1_Strong; PMIDs:34207366, 23932013).The highest population minor allele frequency in gnomAD v4.1 is 0.000001 (2/1179816 alleles) in European non-Finnish population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PVS1_Strong, PP4, PS4_Moderate, PP1_Strong, PM2_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772824/MONDO:0013144/084 2024-12-20 2024-12-20 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40279 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0042075 infores:hetionet CHEBI:37924 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0027059 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0033038 infores:hetionet CHEBI:92511 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C2830004 infores:hetionet UMLS:C0657912 biolink:causes HP:0000419 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151790 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0435001 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0435001 infores:hetionet CHEBI:3485 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0232462 infores:hetionet CHEBI:3534 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0595916 infores:hetionet CHEBI:47781 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0151766 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0241832 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0241832 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0019112 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0085096 infores:hetionet NCBIGene:3043 biolink:causes MONDO:0007705 infores:monarchinitiative not_provided not_provided HGNC:4827 MONDO:0007705 uuid:44761c9f-f2c1-4594-b964-18c9c24e1e00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68647 biolink:causes MONDO:0002527 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0022572 infores:hetionet CHEBI:31000 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00632 UMLS:C0702166 infores:hetionet CAID:CA013125 biolink:causes MONDO:0005045 infores:clingen CAID:CA013125 MONDO:0005045 PMID: Uncertain Significance PP3, PM2, PM1 PP1, BA1, PM5, PM4, PS3, PM6, BS1, BS3, BS4, PS1, PS4, PS2, BP4, BP7, BP2, BP5, PVS1 The c.2804A>T (p.Glu935Val) variant in MYH7 has been identified in at least 1 individual with early-onset HCM (<25 yo) who also carried a second MYH7 variant (Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940). Due to the potential overlap in these cohorts and the presence of a second variant, the PS4_Supporting criterion is not met. This variant was also identified in 0.0003% (FAF 95% CI; 2/113768) of non-Finnish European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org/). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM1; PP3 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013125/MONDO:0005045/002 2021-06-16 2021-06-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2636 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C1443060 infores:hetionet CHEBI:36791 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016867 infores:hetionet CAID:CA274150 biolink:causes MONDO:0700270 infores:clingen CAID:CA274150 MONDO:0700270 PMID: Pathogenic PM3_Strong, PVS1 PM2 The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a premature stop codon and nonsense mediated decay. The highest minor allele frequency in gnomAD v2.1.1 is 0.00003517 (4/113738) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 26896183, 10817650, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA274150/MONDO:0700270/020 2024-01-24 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:39585 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042023 infores:hetionet CHEBI:16347 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0011603 infores:hetionet CHEBI:6078 biolink:causes UMLS:C0239182 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0239182 infores:hetionet CHEBI:3403 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0015967 infores:hetionet CHEBI:4659 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0234233 infores:hetionet CHEBI:6402 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0149745 infores:hetionet CHEBI:41774 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0085932 infores:hetionet CHEBI:474180 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0750426 infores:hetionet CHEBI:8455 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0003123 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002959 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0700594 infores:hetionet CHEBI:7465 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0037383 infores:hetionet CHEBI:31236 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0542571 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020651 infores:hetionet CHEBI:2682 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1306341 infores:hetionet CHEBI:94686 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0231218 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0038663 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0018802 infores:hetionet CHEBI:31705 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0022116 infores:hetionet CHEBI:7936 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0520966 infores:hetionet CHEBI:3082 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0549249 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0027813 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0233494 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0011630 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027813 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0860967 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0860967 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151736 infores:hetionet CHEBI:42068 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0009450 infores:hetionet CAID:CA003343 biolink:causes MONDO:0011450 infores:clingen CAID:CA003343 MONDO:0011450 PMID: Pathogenic PP3, PM2_Supporting, PP4_Strong PVS1 The c.5194-12G>A variant is an intronic variant occurring in intron 19 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.96, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant was reported to result in aberrant mRNA splicing by partial retention of intron 19 (PMIDs: 21673748, 21394826). Another study reported the same aberration as well as exon 20 skipping, however it also reported a higher proportion of full length transcript (PMID: 31843900) (PVS1 (RNA) not applied due to conflicting evidence). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1126348153 (based on Cosegregation LR=6.5; Pathology LR=12.7; Co-occurrence LR=1.3; Family History LR=10799731), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003343/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64355 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0034065 infores:hetionet CHEBI:63577 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0030312 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0007642 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0340861 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0340861 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0233494 infores:hetionet CHEBI:8107 biolink:causes HP:0032792 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0270844 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0018674 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018674 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0026848 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0151735 infores:hetionet CHEBI:2955 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0021368 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009319 infores:hetionet UMLS:C0145867 biolink:causes HP:0008441 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0014571 infores:hetionet CHEBI:141474 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00772 UMLS:C1325847 infores:hetionet NCBIGene:1950 biolink:causes MONDO:0012717 infores:monarchinitiative not_provided not_provided HGNC:3229 MONDO:0012717 uuid:344add8d-53cc-4bdb-97e2-721eff9d505e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59773 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0017675 infores:hetionet GO:0010695 biolink:causes GO:0061804 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0061804 CHEBI:7478 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0018939 infores:hetionet CHEBI:94609 biolink:causes MONDO:0009718 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0027145 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0235032 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005982 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0040247 infores:hetionet CHEBI:63598 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0600142 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0028259 infores:hetionet CHEBI:61049 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0032227 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0020538 infores:hetionet CHEBI:7852 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011175 infores:hetionet CHEBI:15367 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0549249 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0221165 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0221165 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0235496 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0235496 infores:hetionet CAID:CA340950 biolink:causes MONDO:0044970 infores:clingen CAID:CA340950 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting, PP3, PS4_Moderate PM5, PP1, BP4, PS1, PS2, PS3, PM6 The m.3733G>A (p.E143K) variant in MT-ND1 has been reported in 10 individuals with features of primary mitochondrial disease from 4 families. Affected individuals had features consistent with LHON and LHON-plus (PS4_moderate; PMIDs: 15505787, 27177320, 29387390). There are no reports of de novo occurrences of this variant. Segregation was only seen in one family, with healthy mother having lower heteroplasmy levels than affected child (PMID: 15505787), however this does not meet criteria for PP1_supporting (minimum 2 segregations). There are 2 occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease, and this variant is absent in gnomAD v3.1.2 and in Helix dataset (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340950/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9586 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0031212 infores:hetionet CHEBI:9241 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0023218 infores:hetionet CHEBI:31401 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0010200 infores:hetionet CHEBI:5893 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0151766 infores:hetionet CHEBI:63717 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0041912 infores:hetionet CHEBI:6904 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0035357 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0018801 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0022081 infores:hetionet CHEBI:3223 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0234518 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0040034 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0018799 infores:hetionet CAID:CA397722455 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722455 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate, PS3_Supporting PM1 The c.265C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by serine at amino acid 89 (p.Pro89Ser). This variant has been reported in two individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or variably increased C14:1 acylcarnitine levels (PP4_moderate; PMIDs: 11914034, Russian Paper). In these same probands, the variant was detected once confirmed in-trans with a pathogenic variant (PM3; PMIDs: 11914034). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Site-directed mutagenesis expression showed impaired VLCAD enzyme activity (PS3_supporting; PMIDs: 11914034). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722455/MONDO:0008723/021 2022-08-09 2022-08-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:44423 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0013404 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0020615 infores:hetionet NCBIGene:55755 biolink:causes MONDO:0011488 infores:monarchinitiative not_provided not_provided HGNC:18672 MONDO:0011488 uuid:d8a8164f-ec0b-4806-b306-57408e13384a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA409105438 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105438 MONDO:0015967 PMID: Uncertain Significance PS3_Supporting, PP3, PM2_Supporting, PM1 PP4 The c.337G>C variant in the hepatocyte nuclear factor -4 alpha gene, HNF4A, causes an amino acid change of asparagine to a histidine at codon 113 (p.(Asp113His)) of NM_175914.5. Functional studies have demonstrated the p. Asp113His protein has DNA binding below 40% of wild type indicating that this variant impacts protein function (PS3_Supporting; PMID: 15233628). Additionally, this variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA, which is necessary for homodimer formation and defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). Based on its REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70, this variant is predicted to be deleterious by computational evidence (PP3). The variant was found in an individual with diabetes who was a compound heterozygote for this variant and p.Asp113Tyr; however, the MODY probability calculator score was <50% and there was evidence of an autoimmune etiology, and PP4 could not be applied (PMID: 11232004). The p.Asp113Tyr variant is a VUS; therefore, PM5 could not be applied. In summary, c.337G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1,0, approved 11/16/2022): PS3_Supporting, PM1_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105438/MONDO:0015967/085 2023-03-26 2023-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4903 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042267 infores:hetionet CHEBI:7476 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018681 infores:hetionet CHEBI:135930 biolink:causes MONDO:0003397 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0017567 infores:hetionet CHEBI:9907 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042029 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0034150 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0853019 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004993 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0007097 infores:hetionet CHEBI:31236 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151889 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0857983 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0857983 infores:hetionet CHEBI:68558 biolink:causes UMLS:C1096225 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C1096225 infores:hetionet CHEBI:63612 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0009782 infores:hetionet NCBIGene:6497 biolink:causes MONDO:0008426 infores:monarchinitiative not_provided not_provided HGNC:10896 MONDO:0008426 uuid:3331f367-9b98-4a82-b6e7-4418afc482b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0233494 infores:hetionet CHEBI:63630 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1456784 infores:hetionet CHEBI:119573 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0015732 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0037284 infores:hetionet CHEBI:63617 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0522224 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0474378 infores:hetionet GO:0150011 biolink:causes GO:0048699 infores:ubergraph knowledge_assertion manual_agent GO:0150011 GO:0048699 CHEBI:9654 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0013378 infores:hetionet CHEBI:7640 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0011124 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0037199 infores:hetionet CHEBI:4466 biolink:causes HP:0030786 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0085635 infores:hetionet CHEBI:6909 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0013362 infores:hetionet CHEBI:10102 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0038367 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0302295 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0392525 infores:hetionet CHEBI:40279 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0086565 infores:hetionet CHEBI:3636 biolink:causes MONDO:0015270 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0268379 infores:hetionet CAID:CA380145362 biolink:causes MONDO:0000573 infores:clingen CAID:CA380145362 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Supporting, PM3, PM1_Supporting NM_000536.4(RAG2):c.3G>A is a missense variant predicted to cause substitution of Methionine by Isoleucine at amino acid 1 (p.Met1Ile).This sequence change affects the initiator methionine of the RAG2 mRNA. The next possible initiation codon is at codon 5. This region does not contain known pathogenic/likely pathogenic variants. (PVS1_Supporting).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). This variant was found in trans with p.Arg229Gln (classified as pathogenic by SCID VCEP) (1 pt.) (PM3) (Invitae proband; internal lab communication).Patient with SCID (0.5 pt.), SCID gene panel conducted (0.5 pt.),T- B- NK+ by flow cytometry (0.5 pt.); total :1.5 pts (PP4) (Invitae proband; internal lab communication). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Supporting,PM1_supporting,PM2_supporting,PM3,PP4 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380145362/MONDO:0000573/124 2024-03-04 2024-03-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8093 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C1325847 infores:hetionet CHEBI:6923 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0002994 infores:hetionet CHEBI:3441 biolink:causes MONDO:0800175 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0036980 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0332575 infores:hetionet CAID:CA379862795 biolink:causes MONDO:0021060 infores:clingen CAID:CA379862795 MONDO:0021060 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PM5_Strong, PS2, PS3_Supporting PP3, BA1, BP4, PM1, BS1 The NM_012250.6:c.68G>T variant in RRAS2 is a missense variant predicted to cause substitution of glycine by valine at amino acid 23 (p.Gly23Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.594, which is neither above nor below the thresholds predicting a damaging or benign impact on RRAS2 function. This amino acid residue is defined by the ClinGen RASopathy VCEP as an amino acid residue at which ≥2 different [likely] pathogenic residue changes at the same codon have been observed in ≥5 probands (PM5_Strong). This variant resides within the P Loop (amino acids 21 – 28), of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). PM1 is not applied due to PM5_Strong being met. This variant has been reported in 1 proband meeting polyhydramnios, poor feeding reported to require tube feeding, short stature (-3.3 SD), underweight (-1.4 SD), occipitofrontal head circumference (+2.5 SD), ventricular septal defect, facial anomalies typical of NS, mild motor delay, mild learning difficulties, Chiari malformation, lymphopenia, strabismus, and growth hormone deficiency (PS4_Supporting; PMID:31130282). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with NS presenting with polyhydramnios, poor feeding reported to require tube feeding, short stature (-3.3 SD), underweight (-1.4 SD), occipitofrontal head circumference (+2.5 SD), ventricular septal defect, facial anomalies typical of NS, mild motor delay, mild learning difficulties, Chiari malformation, lymphopenia, strabismus, and growth hormone deficiency (PS2; PMID:31130282). ERK Activation in HEK293T cells showed a slight increase in ERK phosphorylation indicating that this variant impacts protein function (PMID:31130282)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM5_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.1; 5/9/2022) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA379862795/MONDO:0021060/127 2022-05-09 2024-10-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6704 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0011603 infores:hetionet CHEBI:585948 biolink:causes HP:0025238 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0016512 infores:hetionet CHEBI:37333 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0020625 infores:hetionet CHEBI:3561 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0080274 infores:hetionet NCBIGene:4702 biolink:causes MONDO:0030997 infores:monarchinitiative not_provided not_provided HGNC:7692 MONDO:0030997 uuid:5d70efb9-3c5d-4719-b871-09929c393896 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68855 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0021053 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0085584 infores:hetionet CAID:CA16618466 biolink:causes MONDO:0015967 infores:clingen CAID:CA16618466 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PM1, PP1 The c.1087G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 363 (p.(Asp363Asn)) of NM_000162.5. This variant was identified in at least 1 individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:19790256, 36257325, internal lab contributor). The individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and three-generation, dominant family history of diabetes (in a family not used for PP1)) (PP4_Moderate; internal lab contributor).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.869, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1088A>G (p.Asp363Gly), has been classified as pathogenic by the ClinGen MDEP but has a larger Grantham distance than p.(Asp363Asn) (PM5_Supporting). In summary, c.1087G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16618466/MONDO:0015967/086 2025-03-05 2025-03-05 Semidominant inheritance HP:0032113 Supports CHEBI:84500 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0017181 infores:hetionet CAID:CA320638162 biolink:causes MONDO:0011071 infores:clingen CAID:CA320638162 MONDO:0011071 PMID: Benign BA1, BP4, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 MAF of 0.30140 (30.1%, 2621/8696, 11,317 alleles) in the African subpopulation of the gnomAD v2 cohort is ≥ 0.0015 (0.15%) (BA1). REVEL score not applicable. SpliceAI predicts: Acceptor loss 0,00, acceptor gain 0.00, donor loss 0.00, donor gain 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.550024 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA2, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320638162/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4909 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0016204 infores:hetionet CHEBI:45327 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0018790 infores:hetionet CHEBI:41879 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0027497 infores:hetionet CAID:CA10591040 biolink:causes MONDO:0700268 infores:clingen CAID:CA10591040 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 The c.5257A>G variant in BRCA1 is a missense variant predicted to cause substitution of Arg by Gly at amino acid 1753 (p.(Arg1753Gly)). Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMIDs:30209399, 38709234) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.36, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.0 predicts no impact on splicing (score threshold ≤0.1) (PP3 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3, PM2_supporting). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10591040/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5778 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0233794 infores:hetionet CHEBI:16469 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014591 infores:hetionet CHEBI:5118 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027497 infores:hetionet CHEBI:75984 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0036974 infores:hetionet CHEBI:4784 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0028961 infores:hetionet CHEBI:2950 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0392699 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0032961 infores:hetionet CHEBI:83527 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0011603 infores:hetionet CHEBI:3207 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0019348 infores:hetionet CHEBI:135935 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0002792 infores:hetionet CHEBI:32221 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0600142 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0549356 infores:hetionet CHEBI:4356 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0231528 infores:hetionet CHEBI:6129 biolink:causes MONDO:0021124 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0021361 infores:hetionet CHEBI:9671 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0015672 infores:hetionet CHEBI:52717 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0025289 infores:hetionet NCBITaxon:1980491 biolink:causes MONDO:0017879 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1980491 MONDO:0017879 PUBCHEM.COMPOUND:5284632 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0011206 infores:hetionet NCBIGene:4547 biolink:causes MONDO:0008692 infores:monarchinitiative not_provided not_provided HGNC:7467 MONDO:0008692 uuid:2235f909-0be0-4d4c-9da4-27a198e2988c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013395 infores:hetionet CHEBI:61058 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0151763 infores:hetionet NCBITaxon:1769 biolink:causes MONDO:0041751 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1769 MESH:D056006 DB00845_MESH_D056006_1 CHEBI:6950 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0006147 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0239026 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0239026 infores:hetionet CHEBI:63612 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0162297 infores:hetionet CHEBI:135930 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0020615 infores:hetionet CHEBI:136040 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0027947 infores:hetionet CHEBI:5383 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0162830 infores:hetionet CHEBI:7936 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017168 infores:hetionet NCBIGene:6392 biolink:causes MONDO:0011740 infores:monarchinitiative not_provided not_provided HGNC:10683 MONDO:0011740 uuid:ac90754d-70fa-45a0-8d08-80807b35e9e0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0085932 infores:hetionet CHEBI:64312 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0034155 infores:hetionet CHEBI:6375 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002962 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C1258215 infores:hetionet CHEBI:28001 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0004093 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002462 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017658 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C1720775 infores:hetionet CHEBI:47381 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0039231 infores:hetionet CHEBI:3061 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0003467 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0151838 infores:hetionet CHEBI:101278 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0264906 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0860805 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0860805 infores:hetionet CHEBI:2788 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0026961 infores:hetionet CHEBI:10650 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0033036 infores:hetionet CHEBI:2788 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0030193 infores:hetionet CHEBI:18332 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0039231 infores:hetionet GO:0039525 biolink:causes GO:0006325 infores:ubergraph knowledge_assertion manual_agent GO:0039525 GO:0006325 PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0392171 infores:hetionet CHEBI:23765 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151636 infores:hetionet CHEBI:135613 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0013404 infores:hetionet CHEBI:42820 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0033975 infores:hetionet CHEBI:4974 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0009806 infores:hetionet CHEBI:9086 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0037317 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0948089 infores:hetionet CHEBI:15367 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0016199 infores:hetionet CHEBI:91583 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0231528 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0243026 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0027765 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0011991 infores:hetionet CHEBI:29688 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0160390 infores:hetionet CHEBI:45863 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0016204 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002267 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0600260 infores:hetionet CHEBI:144093 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0011168 infores:hetionet CAID:CA220589 biolink:causes MONDO:0009861 infores:clingen CAID:CA220589 MONDO:0009861 PMID:15503242PMID:12655553PMID:15503242PMID:17935162PMID:25596310 Likely Pathogenic PM3, PP4_Moderate, PP3, PS3 PM2 PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: 2% activity in bioPKU (PAH0309) (PMID:25596310; PMID:17935162); PP4_Moderate: 2 patients with moderate or classical PKU; patients with severe PKU. BH4 deficiency ruled out. (PMID:15503242; PMID:12655553); PM3: IVS4-1G>A (P/LP) (PMID:15503242). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PP4_Moderate, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220589/MONDO:0009861/006 2018-08-27 2019-08-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94501 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0030252 infores:hetionet CHEBI:110423 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0002871 infores:hetionet CHEBI:68584 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0018524 infores:hetionet CHEBI:6375 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0852911 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0020538 infores:hetionet CHEBI:135361 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00462 UMLS:C0344232 infores:hetionet CAID:CA410203718 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203718 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, BP2, BP1, BP4, BA1, BS1, PM3, PM5, PP2 NM_001754.5(RUNX1):c.275C>T (p.Thr92Ile) is a missense variant which has a REVEL score ≥ 0.88 (0.973) (PP3). This variant is found within the runt homology domain but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203718/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3568 biolink:causes UMLS:C0242073 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0242073 infores:hetionet CHEBI:7640 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0242429 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0037274 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0038362 infores:hetionet CAID:CA891844265 biolink:causes MONDO:0008723 infores:clingen CAID:CA891844265 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1007_1026del (Ile336Argfs*16) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1.0; approved 07-03-2022). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA891844265/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:53760 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0016867 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0677500 infores:hetionet CHEBI:7640 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0011206 infores:hetionet CHEBI:2682 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151904 infores:hetionet CHEBI:77260 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151436 infores:hetionet NCBIGene:10735 biolink:causes MONDO:0026722 infores:monarchinitiative not_provided not_provided HGNC:11355 MONDO:0026722 uuid:02f8f706-8b2d-40c0-bedd-cd450b3574de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0008031 infores:hetionet CAID:CA10360710 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360710 MONDO:0010725 PMID: Benign BP7, BP4, BA1 The NM_000330.4(RS1):c.258G>A variant is a synonymous variant at amino acid 86. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0007234 among hemizygous individuals, with 286 variant alleles / 395365 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The splicing impact predictor SpliceAI gives delta scores of 0.02 acceptor gain and 0.01 donor gain, which are below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and do not predict a potential impact on RS1 splicing. This silent variant c.258G>A causing a synonymous variant at codon 86 does not have an impact at splicing sites according to Splice AI, which predicts delta scores of 0.02 for acceptor gain and 0.01 donor gain, which are below the ClinGen X-linked IRD VCEP recommended threshold of <0.2 and do not strongly predict an impact on splicing (BP7). In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1, BP4, and BP7 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360710/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:6539 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0010692 infores:hetionet CHEBI:9649 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0018099 infores:hetionet CAID:CA913169746 biolink:causes MONDO:0044970 infores:clingen CAID:CA913169746 MONDO:0044970 PMID: Uncertain Significance BP4 BA1, PS4, PS3, BS1, PM2 The m.12217A>G variant in MT-TS2 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 12/61,168 (0.020%). The frequency in the Helix dataset is 186/195,983 (0.095%) homoplasmic occurrences in addition to six heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 35/56,434 (0.062%). In all three population databases, this variant is seen in individuals from different haplogroups. MitoTIP suggests this variant is benign (5.8th percentile; BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that three experts on this panel felt likely benign was a more appropriate classification given the frequency in the general population and poor conservation at this site however the majority (four) agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913169746/MONDO:0044970/015 2023-08-22 2024-03-20 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:9130 biolink:causes UMLS:C0424332 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0424332 infores:hetionet NCBIGene:2033 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:3373 MONDO:0005575 uuid:b1492334-e1d4-44e6-b3fe-cfbab5ed1aa3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37333 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0340865 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0039971 infores:hetionet CHEBI:7936 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0424295 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0013038 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0013038 uuid:4ea99c54-99ce-41be-b854-e3863a9681da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0006384 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020514 infores:hetionet CHEBI:10124 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0013378 infores:hetionet UMLS:C0004609 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0018946 infores:hetionet CHEBI:63632 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0042109 infores:hetionet CHEBI:51141 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0041912 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0042487 infores:hetionet CHEBI:10023 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0034150 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0006444 infores:hetionet CHEBI:27306 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00165 UMLS:C0027497 infores:hetionet CHEBI:63620 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0003537 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0042514 infores:hetionet CHEBI:7494 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0344232 infores:hetionet CAID:CA404093163 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093163 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 PS1, PS3, PM5, PM1, PP1 The NM_000527.5(LDLR):c.1954A>T (p.Met652Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow:PM2_Met : the variant was absent from controls in Gnomad database (gnomAD v2.1.1).BP4_Met : REVEL score is 0.252, splicing evaluation required.Functional data on splicing not available.A) Variant not on limitsB) variant is exonic and at least 50bp upstream from canonical donor site, but does not create GTC) variant is exonic and there is no GT nearbyVariant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093163/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:142290 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0013362 infores:hetionet CAID:CA414445918 biolink:causes MONDO:0010604 infores:clingen CAID:CA414445918 MONDO:0010604 PMID: Uncertain Significance PM2_Supporting, PS4_Moderate, PP3, PM5_Supporting The F9 c.1105C>T, p.Leu369Phe variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). This variant has been reported in 2 probands meeting phenotypic criteria for hemophilia B (PS4_Moderate; PMID: 15921378, PMID: 25929987). There is another variant at this position (p.Leu369Pro) that has been curated by the Coagulation Factor Deficiency VCEP to be likely pathogenic, meeting PM5_Supporting. In summary, this variant meets the criteria to be classified as variant of uncertain significance for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP (version 1.0.0, released 10/5/2023): PS4_Moderate, PM2_Supporting, PP3, PM5_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414445918/MONDO:0010604/080 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Inconclusive true CHEBI:59773 biolink:causes MONDO:0005749 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C1527407 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0020517 infores:hetionet CHEBI:2453 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0239739 infores:hetionet CHEBI:4974 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0004936 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0031350 infores:hetionet CHEBI:6950 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013144 infores:hetionet CHEBI:50131 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0031256 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0042109 infores:hetionet CHEBI:4911 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0852911 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002177 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020459 infores:hetionet NCBIGene:23268 biolink:causes MONDO:0032735 infores:monarchinitiative not_provided not_provided HGNC:30373 MONDO:0032735 uuid:106b4416-18f9-45bb-baa5-9903d87d9f2f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0035243 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0030305 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0152517 infores:hetionet CHEBI:8107 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085610 infores:hetionet CHEBI:50131 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0039240 infores:hetionet CHEBI:46345 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0020517 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0427008 infores:hetionet UMLS:C0009315 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0003467 infores:hetionet CHEBI:135930 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0040034 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0858765 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0858765 infores:hetionet CHEBI:77260 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0023052 infores:hetionet CHEBI:7789 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01173 UMLS:C0040822 infores:hetionet CHEBI:31644 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0016204 infores:hetionet CAID:CA10585392 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585392 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM5, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS2, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met.PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon:- NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines- NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585392/MONDO:0007750/013 2022-10-28 2022-12-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5801 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0011606 infores:hetionet CHEBI:50841 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0004093 infores:hetionet CHEBI:3238 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01091 UMLS:C0033774 infores:hetionet CHEBI:9460 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0234238 infores:hetionet NCBIGene:10913 biolink:causes MONDO:0007509 infores:monarchinitiative not_provided not_provided HGNC:2895 MONDO:0007509 uuid:23fc52c5-387a-4cc6-8d6c-9df086dd3f95 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51450 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C2939147 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003868 infores:hetionet CAID:CA913190423 biolink:causes MONDO:0100437 infores:clingen CAID:CA913190423 MONDO:0100437 PMID: Pathogenic PVS1, PP4, PM2_Supporting NM_001034853.2(RPGR):c.2899dup (p.Glu967GlyfsTer?) is a frameshift variant due to a 1-nucleotide insertion introducing a premature stop codon within exon 15 of 15 that is predicted to disrupt a critical C-terminal region required for proper glutamylation of RPGR (PVS1, PMID: 36445968). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including presentation with night blindness (0.5 pts) and reduced visual acuity (0.5 pts) with onset at age 3 years (1 pt), diminished electroretinogram responses from rods, fundus appearance showing widespread retinal pigment epithelium degeneration with pigment deposits (0.5 pts), optic disc pallor (0.5 pts), cataract, severe macular degeneration, artery attenuation, and genotyping by next-generation sequencing with a 483-gene panel showing no alternative basis for inherited retinal disease (2 pts), which together are specific for RPGR-related retinopathy (5 points, PMID: 36276946, PP4). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, and PP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA913190423/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Supports CHEBI:8228 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0948089 infores:hetionet CHEBI:77733 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0235439 infores:hetionet CHEBI:8059 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0018681 infores:hetionet CHEBI:3061 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0155626 infores:hetionet NCBIGene:1969 biolink:causes MONDO:0007288 infores:monarchinitiative not_provided not_provided HGNC:3386 MONDO:0007288 uuid:154e0666-b561-48e1-ad8f-2a9cb17a4bc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28901 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0034642 infores:hetionet CHEBI:8354 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00733 UMLS:C0085631 infores:hetionet CHEBI:8713 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C1384353 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0027651 infores:hetionet CHEBI:28864 biolink:causes UMLS:C0239150 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0239150 infores:hetionet CHEBI:114785 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C2937358 infores:hetionet CHEBI:7573 biolink:causes NCIT:C78167 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151474 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0014534 infores:hetionet CHEBI:94686 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0002453 infores:hetionet CHEBI:64310 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0232462 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029456 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0019163 infores:hetionet CAID:CA267649 biolink:causes MONDO:0009861 infores:clingen CAID:CA267649 MONDO:0009861 PMID: Uncertain Significance PM2 The c.284_285delTCinsCA (p.Ile95Thr) indel variant in PAH has not been reported in the literature to our knowledge. It has been included in BioPKU/PAHdb (PAH0793) by online submission (Namour et al.,2013). It is absent from ExAC, gnomAD, 1000G, and ESP. There is not consensus among predictions of pathogenicity. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267649/MONDO:0009861/006 2020-01-25 2020-01-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:40050 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0877192 infores:hetionet CHEBI:135935 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0855775 infores:hetionet CHEBI:567361 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0030193 infores:hetionet CHEBI:6472 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0031542 infores:hetionet CHEBI:478164 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0002878 infores:hetionet CHEBI:68595 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0267792 infores:hetionet UNII:0RK7M7IABE biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB06800 UMLS:C0020458 infores:hetionet CHEBI:2636 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0023052 infores:hetionet CHEBI:2611 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0018524 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232431 infores:hetionet CHEBI:63635 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0041912 infores:hetionet CHEBI:5001 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0151905 infores:hetionet CHEBI:15367 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0018790 infores:hetionet NCBIGene:6938 biolink:causes MONDO:0030534 infores:monarchinitiative not_provided not_provided HGNC:11623 MONDO:0030534 uuid:b85d65e0-428d-46ec-be7b-7c6be7d0b7d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:283989 biolink:causes MONDO:0012438 infores:monarchinitiative not_provided not_provided HGNC:27561 MONDO:0012438 uuid:1c37442c-48fd-4c52-8e35-267dd7703fe5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0029408 infores:hetionet CHEBI:71417 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C1368065 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0017160 infores:hetionet CHEBI:31413 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0011124 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0007971 infores:hetionet CHEBI:45409 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0028734 infores:hetionet CHEBI:77733 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0231528 infores:hetionet NCBIGene:26353 biolink:causes MONDO:0976133 infores:monarchinitiative not_provided not_provided HGNC:30171 MONDO:0976133 uuid:309bdeab-682c-4221-a1e9-8991947f93e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:UMD7G2653W biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0542571 infores:hetionet CHEBI:45652 biolink:causes HP:0002380 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0015644 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0413252 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0149904 infores:hetionet CHEBI:10023 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0030252 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0004936 infores:hetionet CHEBI:135736 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0152227 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0263105 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0263105 infores:hetionet CHEBI:194135 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0035243 infores:hetionet CHEBI:5132 biolink:causes UMLS:C0235398 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0235398 infores:hetionet CHEBI:28939 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0006266 infores:hetionet CHEBI:8713 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0027051 infores:hetionet CHEBI:8884 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C1145670 infores:hetionet CHEBI:51860 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0001925 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0234215 infores:hetionet CHEBI:17549 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0042963 infores:hetionet CHEBI:64312 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1167965 infores:hetionet CHEBI:9288 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0744727 infores:hetionet CHEBI:48131 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00548 UMLS:C0011616 infores:hetionet CHEBI:63577 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0004604 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151735 infores:hetionet CHEBI:3506 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0036572 infores:hetionet CHEBI:6909 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0221423 infores:hetionet CHEBI:3423 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0018681 infores:hetionet CHEBI:63617 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0018926 infores:hetionet CHEBI:4975 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0014518 infores:hetionet CHEBI:3181 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0086525 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235146 infores:hetionet CAID:CA404075595 biolink:causes MONDO:0007750 infores:clingen CAID:CA404075595 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 The NM_000527.5(LDLR):c.239A>G (p.Asn80Ser)variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1) BP4 - REVEL = 0.176. It is below 0.50. splicing evaluation required. Functional data not availableA) not on limitsB) variant is exonic and at least 50bp upstream from canonical donor site and creates AGMES scores: de novo variant = -2.32; canonical acceptor = 7.07.Ratio de novo variant/canonical donor = -2.32/7.07 --- de novo score is negative, so it is not used.Variant is not predicted to alter splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404075595/MONDO:0007750/013 2022-08-29 2022-12-23 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9448 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0232492 infores:hetionet CAID:CA386954977 biolink:causes MONDO:0015967 infores:clingen CAID:CA386954977 MONDO:0015967 PMID: Pathogenic PS1_Supporting, PM2_Supporting, PP4_Moderate, PVS1 The c.326+1G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 1 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate; internal lab contributors). The c.326+1G>A and c.326+1G>T variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>C has a similar predicted impact on donor loss by Splice AI (0.98) (PS1_Supporting). Lastly, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.326+1G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1 approved 9/30/21): PVS1, PS1_Supporting, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386954977/MONDO:0015967/017 2022-06-10 2022-06-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9445 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0020649 infores:hetionet CAID:CA645293838 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293838 MONDO:0015924 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Moderate BA1, BS1 The BMPR2 c.1277-9A>G variant is a non-canonical splice site (-9) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in four cases (PMID: 18356561, 20534176, 27613157) (PS4_moderate). In silico prediction (SpliceAI) indicates likely loss of the acceptor splice site (score = 0.97). cDNA analysis demonstrated an aberrant splice product leading to premature truncation (p.Gly426Aspfs*47) and, thus, likely nonsense mediated decay (PMID: 18356561) (PVS1 (RNA)). No familial segregation data were available. In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1(RNA), PS4_moderate, PM2_supporting (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293838/MONDO:0015924/125 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:83531 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0038362 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0234215 infores:hetionet CHEBI:5062 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0033774 infores:hetionet CHEBI:5138 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0010520 infores:hetionet CHEBI:3219 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235710 infores:hetionet CHEBI:37924 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0019158 infores:hetionet CHEBI:7573 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0151904 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0438243 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0438243 infores:hetionet CAID:CA023782 biolink:causes MONDO:0007750 infores:clingen CAID:CA023782 MONDO:0007750 PMID: Uncertain Significance PM5, PM2, PP3 PS3 The NM_000527.5 (LDLR):c.859G>A (p.Gly287Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMaxMAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1).PP3: REVEL=0.902.PM5: One other variant at same codon: NM_000527.5 (LDLR):c.859G>T (p.Gly287Cys), ClinVarID 251489, is classified as Pathogenic by these guidelines, therefore PM5 is met.PS3 not met: Functional data is not available. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023782/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:50173 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0750394 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005582 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0596170 infores:hetionet CHEBI:36791 biolink:causes MONDO:0007156 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0574960 infores:hetionet CHEBI:2549 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0863093 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0575090 infores:hetionet CHEBI:8430 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0036974 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0035455 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0748726 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0748726 infores:hetionet CHEBI:28748 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0025222 infores:hetionet CHEBI:31348 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0014518 infores:hetionet CHEBI:63791 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0039231 infores:hetionet CHEBI:27786 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0234215 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005303 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1510472 infores:hetionet CHEBI:3568 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013390 infores:hetionet CHEBI:135005 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0015672 infores:hetionet CHEBI:8093 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0038525 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0006145 infores:hetionet CHEBI:64312 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018681 infores:hetionet CHEBI:4708 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0232461 infores:hetionet CHEBI:5893 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0005758 infores:hetionet CHEBI:5775 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C1368065 infores:hetionet NCBIGene:55997 biolink:causes MONDO:0011546 infores:monarchinitiative not_provided not_provided HGNC:18292 MONDO:0011546 uuid:731c187a-cfef-4f25-9ba7-06c8748fe7ce biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0021525 biolink:causes CL:0011002 infores:ubergraph knowledge_assertion manual_agent GO:0021525 CL:0011002 CHEBI:9328 biolink:causes NCIT:C171138 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C2747813 infores:hetionet CHEBI:6897 biolink:causes MONDO:0020283 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0042164 infores:hetionet CHEBI:50156 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0018794 infores:hetionet CHEBI:82981 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0231528 infores:hetionet CHEBI:32139 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0015376 infores:hetionet CHEBI:74947 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0702166 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0009938 infores:hetionet CHEBI:15940 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0020578 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0233472 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0035078 infores:hetionet UMLS:C1738934 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030232 infores:hetionet CHEBI:72296 biolink:causes HP:0000573 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0035317 infores:hetionet CHEBI:5103 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0011603 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0027726 infores:hetionet CHEBI:59773 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C1761613 infores:hetionet CHEBI:3215 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0018790 infores:hetionet CAID:CA4239709 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239709 MONDO:0015967 PMID:33273586 Pathogenic PS4, PP1_Strong, PS3_Supporting, PP2, PP3, PP4, PM2_Supporting PM1 The c.179C>T variant in the glucokinase gene, GCK causes an amino acid change of threonine to isoleucine at codon 60 (p.(Thr60Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to a single copy present in the South Asian population and 0 copies in any other subpopulation thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (gnomAD v4.1 Grpmax FAF ≤ 0.000003) (PM2_Supporting). This variant was identified in at least 11 unrelated individuals with hyperglycemia (PS4; PMID: 18248649, 34746319, internal lab contributors). At least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, this variant segregated with hyperglycemia with eight meioses in six families (PP1_Strong; PMID: 34746319, internal lab contributors). Functional studies of this variant demonstrate that it disrupts normal GK-GKRP binding (PS3_Supporting; PMID: 33273586). In summary, c.179C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PP1_Strong, PP2, PP3, PP4 PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239709/MONDO:0015967/086 2025-07-29 2025-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:4027 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0002390 infores:hetionet CHEBI:52172 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0241136 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0314719 infores:hetionet CHEBI:72564 biolink:causes MONDO:0000009 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0005818 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0038362 infores:hetionet CHEBI:6887 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0235309 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0855242 infores:hetionet CHEBI:8378 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0547030 infores:hetionet CHEBI:4027 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0034642 infores:hetionet CHEBI:194135 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0031256 infores:hetionet CHEBI:37941 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0006266 infores:hetionet CHEBI:45979 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0042963 infores:hetionet NCBIGene:3782 biolink:causes MONDO:0032854 infores:monarchinitiative not_provided not_provided HGNC:6292 MONDO:0032854 uuid:dd25f24d-c5e8-4a27-80e4-93242f3934c0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64310 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C1145670 infores:hetionet CAID:CA253314 biolink:causes MONDO:0010134 infores:clingen CAID:CA253314 MONDO:0010134 PMID: Uncertain Significance BS1, PS3_Supporting, PP4, PM3 BS3, BS4, BP5, BP7, PP3, PP2, PP1, BS2, PM4, PM5, PM1, PVS1, PM2, PM6, BA1, BP4, BP1, BP3, BP2, PS1, PS2, PS4 The c.-103T>C (NM_000441.2) variant is a substitution in the 5’ UTR of SLC26A4. Because the variant is located in the 5’ UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v4.0.0 is 0.3% (262/68066 alleles) in the European (non-Finnish) population, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). This variant has been detected in 2 individuals with hearing loss and additional features of Pendred syndrome (enlarged vestibular aqueducts (EVA) and Mondini dysplasia) who were compound heterozygous for the variant and a pathogenic variant with phase confirmed in trans in one individual (PMID: 19204907, 25991456). It has also been identified in two additional compound heterozygous individuals with hearing loss, one with a likely pathogenic and one with a variant of uncertain significance, though phase was not confirmed in either individual (SCV000491274.5). However, due to the allele frequency meeting BS1 criteria, PP4 and PM3 were not applied. There have been many reported heterozygous observations in individuals with EVA/Pendred syndrome (PMID:17503324, 23208854, 23965030, 25991456). Functional studies imply that the variant occurs in a binding site that is a major transcriptional regulatory element of SLC26A4 and is necessary for FOXI1-induced transcriptional activation of SLC26A4 (PMID:25910213, 17503324; PS3_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1, PS3_P (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA253314/MONDO:0010134/005 2024-01-17 2024-04-01 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:194135 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0034063 infores:hetionet CHEBI:16469 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C2242737 infores:hetionet CAID:CA414916092 biolink:causes MONDO:0010602 infores:clingen CAID:CA414916092 MONDO:0010602 PMID: Pathogenic PM2_Supporting, PP3, PS4_Very Strong PM1, PM5, PP4 The missense variant, NM_000132.3:c.1214T>C (p.Ile405Thr), is not reported in gnomAD v2.1.1 or v3 (PM2_Supporting). This variant has been reported in at least six male patients with moderate and severe Hemophilia A in the literature and meet phenotype criteria for F8 (PS4, PP4_Moderate, PMID: 29296726, 22103590, 24845853). The variant has a REVEL score of 0.981 (PP3, threshold >0.6). This variant reaches a classification of Pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414916092/MONDO:0010602/071 2024-12-06 2024-12-06 X-linked inheritance HP:0001417 Supports CHEBI:8028 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0011606 infores:hetionet CHEBI:135736 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0020443 infores:hetionet CAID:CA214091 biolink:causes MONDO:0010938 infores:clingen CAID:CA214091 MONDO:0010938 PMID: Benign BA1, BP7, BS2_Supporting PP4, PP1 The NM_000215.4(JAK3):c.2625C>T (p.Leu875=) synonymous variant occurs at a high allele frequency with a filtering allele frequency based on the European non-Finnish population (upper bound of 95% CI of 1934/129188 observed alleles) is 0.01456 in gnomAD v2.1.1 which is above the SCID-VCEP threshold (>0.00447; BA1). 17 adult homozygous individuals were reported in gnomAD, BS2_Supporting (European non-Finnish n=10, South Asian n=3, European Finnish n=2, and Other n=2).The variant has been reported in one patient in the literature (Patient 17 in PMID: 19203666). Patient 17 has T-B+NK- (0 CD3 T cells, 0.14x10^9 B cells/L, 0.01x10^9 NK cells/L) SCID (0.5pt) and absent IL-2–induced STAT5 phosphorylation (1pt). This combination is specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 1.5pt; PP4 not considered due to high allele frequency). A confirmed deleterious γc or JAK3 variant was not identified in Patient 17, although a number of sequence variants were identified in his JAK3 gene (IVS13-30c>t/wt, c.2625C>T (L875L)/wt, IVS 20+32T>C/wt). An affected sibling of Patient 17 also carried these same variants, whereas an unaffected sibling did not (PP1 not considered due to high allele frequency). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1, BS2_Supporting, and BP7. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA214091/MONDO:0010938/121 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CAID:CA347219737 biolink:causes MONDO:0015152 infores:clingen CAID:CA347219737 MONDO:0015152 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_003494.4: c.4705C>T p.(Gln1569Ter) variant in DYSF, which is also known as NM_001130987.2: c.4822C>T (p.Gln1608Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 43/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in two individuals with clinically suspected limb-girdle muscular dystrophy (LGMD), both of whom had the same second variant, NM_003494.4: c.5804C>T p.(Pro1935Leu), which is classified as Pathogenic by the LGMD VCEP. In one case, the variants were confirmed in trans (1.0 pt, ClinVar SCV001164498.1 internal data communication), whereas in the other the variants were in unknown phase (0.5 pts, GRASP-LGMD Consortium internal data communication) (PM3, PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 08/14/2025): PVS1, PM2_Supporting, PM3, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347219737/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8869 biolink:causes UMLS:C0205707 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0205707 infores:hetionet UMLS:C0017797 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0011175 infores:hetionet CHEBI:681569 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0025323 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0010709 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002884 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0342490 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0342490 infores:hetionet CHEBI:28918 biolink:causes UMLS:C1737214 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C1737214 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0011991 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0042373 infores:hetionet CHEBI:51230 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0151766 infores:hetionet CHEBI:3756 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011603 infores:hetionet GO:0160217 biolink:causes GO:0006367 infores:ubergraph knowledge_assertion manual_agent GO:0160217 GO:0006367 CHEBI:84500 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020458 infores:hetionet CHEBI:2611 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0011124 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0027769 infores:hetionet CHEBI:28901 biolink:causes NCIT:C26921 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085594 infores:hetionet CAID:CA401363493 biolink:causes MONDO:0009290 infores:clingen CAID:CA401363493 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, PS3_Moderate, BP4, PM3_Supporting, PM5_Supporting PP4, PS1 The NM_000152.5:c.796C>A variant in GAA is a missense variant predicted to cause substitution of proline by threonine at amino acid 266 (p.Pro266Thr). One patient with a diagnosis of Pompe disease has been reported who is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.2237G>A (p.Trp746Ter) (PMID: 29451150) (PM3_Supporting). Two other missense changes, c.796C>T (p.Pro266Ser) and c.797C>T (p.Pro266Leu) at the same amino acid residue have been reported. The first, c.796C>T (p.Pro266Ser), has been classified as likely pathogenic by the ClinGen LD VCEP. The second variant, c.797C>T (p.Pro266Leu), has not yet been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). Expression of the variant in HEK293 cells demonstrates loss of GAA activity, and western blot shows only the 110kDa precursor band suggesting abnormal GAA processing (using the assay reported in PMID: 36246652). The computational predictor REVEL gives a score of 0.262 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is a ClinVar entry for this variant (Variation ID: 1693549). In summary, this variant meet the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP codes met, based on the specifications of the ClinGen LD VCEP (Specifications Version 2.0.0): PS3_Moderate, PM2_Supporting, PM3_Supporting, PM5_Supporting, BP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401363493/MONDO:0009290/010 2025-06-03 2025-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:5893 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0947912 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0027769 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0151824 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0042401 infores:hetionet CHEBI:31932 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C2047937 infores:hetionet CHEBI:50841 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0039070 infores:hetionet CHEBI:71028 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0032285 infores:hetionet CHEBI:92998 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0015967 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C3263723 infores:hetionet CHEBI:5123 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0340865 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0029134 infores:hetionet CHEBI:7581 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0037036 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0036572 infores:hetionet CHEBI:63605 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0011175 infores:hetionet CHEBI:31623 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C3665347 infores:hetionet CHEBI:16347 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0151736 infores:hetionet CHEBI:5383 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0002871 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0233494 infores:hetionet CHEBI:6897 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C3665386 infores:hetionet CHEBI:18248 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0000833 infores:hetionet CHEBI:5801 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0086439 infores:hetionet NCBIGene:51163 biolink:causes MONDO:0957786 infores:monarchinitiative not_provided not_provided HGNC:15594 MONDO:0957786 uuid:77e48be5-6b11-4aeb-8711-9a3e18d081dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119915 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0236071 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0040479 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023530 infores:hetionet CHEBI:6375 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020458 infores:hetionet CL:0000173 biolink:causes MONDO:0002994 infores:ubergraph knowledge_assertion manual_agent CL:0000173 MONDO:0002994 CHEBI:6067 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0702166 infores:hetionet CHEBI:71940 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0039070 infores:hetionet CHEBI:41879 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0030486 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020456 infores:hetionet CHEBI:3698 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0030807 infores:hetionet CHEBI:44915 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1258215 infores:hetionet CHEBI:7915 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0015672 infores:hetionet CHEBI:63617 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0232462 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0030312 infores:hetionet CHEBI:3176 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0030196 infores:hetionet CHEBI:421707 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C1325847 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0236151 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0236151 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014130 infores:hetionet CHEBI:404903 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0003467 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001276 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0236826 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0039971 infores:hetionet CHEBI:92712 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0013428 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0017574 infores:hetionet CHEBI:47898 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0019080 infores:hetionet CHEBI:64321 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0010200 infores:hetionet CHEBI:8888 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018979 infores:hetionet CHEBI:65173 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0403673 infores:hetionet CHEBI:46345 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0917801 infores:hetionet CHEBI:404903 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0010200 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0015397 infores:hetionet CHEBI:68595 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0151602 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0000833 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0040034 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0018801 infores:hetionet CHEBI:8871 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0268000 infores:hetionet CAID:CA015008 biolink:causes MONDO:0004994 infores:clingen CAID:CA015008 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.4472C>G (p.Ser1491Cys) variant in the MYH7 gene is 0.98% (698/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA015008/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:23765 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0020453 infores:hetionet GO:0039636 biolink:causes GO:0042546 infores:ubergraph knowledge_assertion manual_agent GO:0039636 GO:0042546 CAID:CA10653549 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653549 MONDO:0011071 PMID: Likely Benign BS1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*3417A>G is a 3' UTR variant which has a MAF of 0.0001764 (0.01764%, 12/68008, 12 alleles) in the European (non-Finnish) subpopulation of the gnomAD v4 cohort which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653549/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7514 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0016382 infores:hetionet NCBIGene:4860 biolink:causes MONDO:0013171 infores:monarchinitiative not_provided not_provided HGNC:7892 MONDO:0013171 uuid:5d03f9e3-1d57-4642-86f1-d1cd47250944 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16755 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0030252 infores:hetionet CHEBI:92712 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0036974 infores:hetionet CHEBI:3647 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0001824 infores:hetionet NCBIGene:720 biolink:causes MONDO:0013721 infores:monarchinitiative not_provided not_provided HGNC:1323 MONDO:0013721 uuid:eb57979a-f460-45d8-98e7-6b4a6fab2322 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0151872 infores:hetionet CAID:CA10102315 biolink:causes MONDO:0009276 infores:clingen CAID:CA10102315 MONDO:0009276 PMID: Benign BA1 PP3, BP4 The NM_000407.5(GP1BB):c.119G>A variant in GP1BB is a missense variant predicted to cause substitution of glycine by glutamate at amino acid 40 (p.Gly40Glu). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.002267 (based on 133/50540 alleles) in the Admixed American population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). This variant has not been reported in relation to Bernard-Soulier Syndrome but is a known platelet antigen (HPA-12b, originally reported as Iy(a) in PMID: 10688847). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10102315/MONDO:0009276/082 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31302 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0021167 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0474378 infores:hetionet CHEBI:5050 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0018802 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0233494 infores:hetionet CHEBI:3310 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0003123 infores:hetionet CHEBI:34967 biolink:causes UMLS:C2939186 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C2939186 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0011551 infores:hetionet CHEBI:9445 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0023066 infores:hetionet CAID:CA199499 biolink:causes MONDO:0010726 infores:clingen CAID:CA199499 MONDO:0010726 PMID: Likely Benign BP3, BS1 PS4 The highest population minor allele frequency of the c.-143_-138del variant in MECP2 (NM_004992.4) in gnomAD v4.0 is 0.0001412 in the African/African American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). Larger deletions encompassing this region (c.-143_-138del) have been observed in an unaffected mother and father (Invitae internal database) (BP3). This variant has been observed in an individual with neurodevelopment disorder (PMID 1717659) (not sufficient for PS4_supporting). In summary, the c.-143_-138del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199499/MONDO:0010726/036 2024-04-18 2025-03-13 X-linked inheritance HP:0001417 Contradicts true CHEBI:10023 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0037284 infores:hetionet CHEBI:72292 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0023890 infores:hetionet CHEBI:478164 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0023895 infores:hetionet CHEBI:94385 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0243026 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0027947 infores:hetionet CHEBI:188986 biolink:causes MONDO:0000950 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0004095 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0520547 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0520547 infores:hetionet CHEBI:3996 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C2830004 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0017675 infores:hetionet CHEBI:6062 biolink:causes MONDO:0006898 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0031037 infores:hetionet CAID:CA409106116 biolink:causes MONDO:0015967 infores:clingen CAID:CA409106116 MONDO:0015967 PMID: Uncertain Significance PP3, PP4, PM2_Supporting, PM1_Supporting The c.539C>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of alanine to aspartic acid at codon 180 (p.(Ala180Asp)) of NM_175914.4. This variant is located within the ligand binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11) (PP4; internal lab contributor). In summary, the c.539C>A variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PP3, PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409106116/MONDO:0015967/085 2023-08-13 2023-08-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64355 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0020456 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0040034 infores:hetionet CHEBI:17263 biolink:causes MONDO:0850231 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0014743 infores:hetionet CHEBI:5118 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0040264 infores:hetionet CHEBI:15367 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0086769 infores:hetionet CHEBI:2682 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0043144 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0151596 infores:hetionet CHEBI:29688 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0016204 infores:hetionet CHEBI:4466 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020488 infores:hetionet CHEBI:8327 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0022346 infores:hetionet CHEBI:9332 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0857305 infores:hetionet CHEBI:9571 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0236071 infores:hetionet CHEBI:31536 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0029118 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0234458 infores:hetionet CHEBI:61049 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013390 infores:hetionet CHEBI:3699 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0231528 infores:hetionet CHEBI:253342 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0162529 infores:hetionet CHEBI:63629 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0344232 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0151555 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0151555 infores:hetionet CHEBI:9352 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0151786 infores:hetionet CHEBI:3181 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0042963 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0522172 infores:hetionet NCBIGene:815 biolink:causes MONDO:0054861 infores:monarchinitiative not_provided not_provided HGNC:1460 MONDO:0054861 uuid:90a6a8a7-063f-4133-a782-b0c32fbfd0c5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29688 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0542571 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027765 infores:hetionet CHEBI:6067 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0497156 infores:hetionet GO:0090249 biolink:causes GO:0043009 infores:ubergraph knowledge_assertion manual_agent GO:0090249 GO:0043009 CHEBI:168396 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0025202 infores:hetionet CHEBI:8707 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151610 infores:hetionet CHEBI:71415 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0013144 infores:hetionet CAID:CA180895 biolink:causes MONDO:0021060 infores:clingen CAID:CA180895 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1162C>T (p.Arg388Trp) variant in the MAP2K2 gene is 0.125% for African chromosomes by the Exome Aggregation Consortium (25/2788 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case-level data available: SCV000204180.4; SCV000252871.4. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA180895/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:52717 biolink:causes MONDO:0016318 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0023524 infores:hetionet CHEBI:63618 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0086565 infores:hetionet CHEBI:9943 biolink:causes NCIT:C92746 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085688 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0242350 infores:hetionet CHEBI:15544 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0041657 infores:hetionet CHEBI:5147 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0042963 infores:hetionet CHEBI:100241 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0038450 infores:hetionet CHEBI:63631 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0023218 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0034150 infores:hetionet CHEBI:16469 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0004093 infores:hetionet NCBIGene:738 biolink:causes MONDO:0032831 infores:monarchinitiative not_provided not_provided HGNC:1172 MONDO:0032831 uuid:de126dc4-452e-47dd-a15f-5580885a227a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4702 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0332575 infores:hetionet CHEBI:47898 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0917801 infores:hetionet CHEBI:3814 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0234238 infores:hetionet CHEBI:4657 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0004093 infores:hetionet CHEBI:36791 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0037763 infores:hetionet CHEBI:92998 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0542571 infores:hetionet CHEBI:8863 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0030193 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0011609 infores:hetionet CHEBI:63580 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0033774 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042769 infores:hetionet CHEBI:8874 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0036974 infores:hetionet GO:0072095 biolink:causes GO:0060675 infores:ubergraph knowledge_assertion manual_agent GO:0072095 GO:0060675 CHEBI:100246 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0018681 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027697 infores:hetionet CHEBI:4911 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C1262013 infores:hetionet CHEBI:50730 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0424295 infores:hetionet CHEBI:8228 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0009450 infores:hetionet NCBIGene:486 biolink:causes MONDO:0007937 infores:monarchinitiative not_provided not_provided HGNC:4026 MONDO:0007937 uuid:03e6b293-98ce-411f-a33c-a9052043356f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:480999 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0002170 infores:hetionet NCBIGene:78987 biolink:causes MONDO:0958329 infores:monarchinitiative not_provided not_provided HGNC:14630 MONDO:0958329 uuid:7a22ebbc-5c97-445c-a13d-1457836e31ca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:22931 biolink:causes MONDO:0013638 infores:monarchinitiative not_provided not_provided HGNC:14244 MONDO:0013638 uuid:0450a172-38ae-40a8-a8c7-01da2c7e27bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020893 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020893 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PP4, PM2_Supporting, PM3_Supporting, PS3_Supporting The NM_000277.3(PAH):c.911A>C variant is PAH is a missense variant predicted to cause substitution of glutamine by proline at amino acid 304 (p.Gln304Pro). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) (PP4, PMID: 19292873). This individual was compound heterozygous for the variant and a pathogenic variant (p.Leu48Ser) in unknown phase (PM3_supporting, PMID: 19292873). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The residual enzyme activity measured on total protein extracts in transfected cells showed <50% enzyme activity in vitro with < 10 benign/pathogenic variant controls indicating that this variant impacts protein function (PS3_supporting, PMID: 19292873). The computational predictor REVEL gives a score of 0.984, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM3_suppoting, PM2_supporting, PS3_supporting, PP3_strong. Version 2.0, 7/16/2024. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020893/MONDO:0009861/006 2025-10-12 2025-10-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:85161 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0020433 infores:hetionet CHEBI:15407 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0221490 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009450 infores:hetionet CHEBI:35778 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0700225 infores:hetionet CHEBI:63631 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030318 infores:hetionet CHEBI:31644 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0007859 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002070 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0018818 infores:hetionet CHEBI:7852 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0007859 infores:hetionet CHEBI:3696 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042165 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0151578 infores:hetionet CHEBI:8764 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0014335 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0019054 infores:hetionet CHEBI:28971 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0036830 infores:hetionet CHEBI:28939 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0038362 infores:hetionet CAID:CA146043 biolink:causes MONDO:0100368 infores:clingen CAID:CA146043 MONDO:0100368 PMID:19431183PMID:19431183 Likely Benign BA1, PP3_Moderate BP4, BP2, PM3, PM5, PS3, BS4, BS3, PP4 NM_000329.3(RPE65):c.881A>C is a missense variant that causes substitution of lysine with threonine at position 294. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.03554, with 1312 alleles / 35390 total alleles in the Admixed American population (with 33 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 19431183) with the NM_000329.3(RPE65):c.1078G>C (p.Ala360Pro) variant in trans and a 22-bp deletion within exon 12 in cis (PMID: 19431183). However, the proband was not counted for the PM3 or BP2 codes because the other two variants have not yet been classified by the ClinGen LCA / eoRD VCEP. The meta-predictor REVEL gives a score of 0.974, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited 16%-68% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is between the ClinGen LCA / eoRD VCEP thresholds of <10% activity (PS3_Supporting) and >50% activity (BS3_Supporting), so neither functional study code is met (PMID: 16150724, PMID: 19431183). Another missense variant in the same codon, NM_000329.2; c.880A>G, (p.Lys294Glu), has been observed in a proband with early-onset severe retinal dystrophy (VCEP member-provided data), but has been classified as a variant of uncertain significance for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP, so the PM5_Supporting code is not met. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1 and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA146043/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:32139 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0220870 infores:hetionet CHEBI:7492 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C0009763 infores:hetionet CHEBI:3176 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0004093 infores:hetionet CAID:CA16020909 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020909 MONDO:0009861 PMID: Likely Pathogenic PM2, PVS1_Strong The c.970-2A>G variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 10 (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).It has been previously reported in one case seen at an inborn errors of metabolism clinic; no further information appears to be given (PMID: 22106832). Classification: Likely PathogenicSupporting Criteria: PVS1_Strong; PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020909/MONDO:0009861/006 2020-05-15 2020-05-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100246 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0030252 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0011053 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0878544 infores:hetionet CHEBI:92607 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00353 UMLS:C0038454 infores:hetionet CHEBI:8412 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0018939 infores:hetionet CHEBI:47898 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041582 infores:hetionet CAID:CA267690 biolink:causes MONDO:0009861 infores:clingen CAID:CA267690 MONDO:0009861 PMID: Likely Pathogenic PM2, PVS1_Strong PP4 The c.970-1G>A variant in PAH is a splice-site variant predicted to result in skipping of exon 10, which is a key region of the encoded enzyme (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).It is reported Likely Pathogenic for PKU in Clinvar by a single lab (ID 120298), without further information. It has also been reported in the BioPKU database as an online submission in 2013, without further information. Classification: Likely PathogenicSupporting ACMG criteria: PVS1_Strong, PM2 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267690/MONDO:0009861/006 2020-04-30 2020-04-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63621 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020557 infores:hetionet CHEBI:9943 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0085682 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0027769 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151664 infores:hetionet CHEBI:63580 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0039070 infores:hetionet CHEBI:17026 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0013144 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0029456 infores:hetionet CHEBI:4975 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0040264 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0851341 infores:hetionet CHEBI:83804 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0027424 infores:hetionet CHEBI:65173 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0085614 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0948586 infores:hetionet CHEBI:9168 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0231218 infores:hetionet CHEBI:101278 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0027497 infores:hetionet NCBIGene:5375 biolink:causes MONDO:0033135 infores:monarchinitiative not_provided not_provided HGNC:9117 MONDO:0033135 uuid:1a1ca2a9-1902-4dd2-a4d0-5c3f76f77a00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:9430ZR8ZAN biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0040586 infores:hetionet CHEBI:45951 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0085631 infores:hetionet CHEBI:144093 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0008031 infores:hetionet CHEBI:9123 biolink:causes HP:0032141 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0232286 infores:hetionet CHEBI:9635 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0424790 infores:hetionet NCBIGene:27229 biolink:causes MONDO:0014592 infores:monarchinitiative not_provided not_provided HGNC:16691 MONDO:0014592 uuid:847fa43e-d9ff-45a4-8ba3-c0c47fe9f7df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes MONDO:0004795 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0029878 infores:hetionet CHEBI:15367 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0014518 infores:hetionet CAID:CA034365 biolink:causes MONDO:0007750 infores:clingen CAID:CA034365 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PS3_Supporting, PM2, PP4 BP4, BA1, PS1, BS1, PM5, PP3, PP1 The NM_000527.5(LDLR):c.1429G>A (p.Asp477Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.00003294 (0.003294%) in South Asian exomes + genomes (gnomAD v4.1.0).PS3_Supporting: Level 3 assays: PMID 39114568 (Jawabri et al., 2024); heterologous cells (CHO-ldlA7 and HeLa), immunocytochemistry, confocal microscopy. Result --> Normal cell surface LDLR, LDL internalization (~35%). Results of LDL internalization are below 85% of wild-type, so functional study is consistent with damaging effect.PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases with DLCN score >=6 (1 case from Brunham Lab, Centre for Heart and Lung Innovation (University of British Columbia), Canada; 1 case from PMID 16250003 (Fouchier SW. et. al., 2005), Netherlands). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA034365/MONDO:0007750/013 2025-02-28 2025-04-11 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA134712 biolink:causes MONDO:0021060 infores:clingen CAID:CA134712 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1830A>G (p.Gln610=) variant in the RAF1 gene is 0.11% (88/66740) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134712/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:27974 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0268000 infores:hetionet CAID:CA8338045 biolink:causes MONDO:0008723 infores:clingen CAID:CA8338045 MONDO:0008723 PMID: Uncertain Significance PM2 PP3, PM1, PM3 The NM_000018.4(ACADVL):c.1239A>G (p.Ile413Met) in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 613. The highest population minor allele frequency in gnomAD v4.1 is 0.00006 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.675 which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. This variant does not reside within a region of ACADVL that is defined as a mutational hotspot or critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel.To our knowledge, this variant has not been reported in the literature in any individuals with autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8338045/MONDO:0008723/021 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:4814 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0542571 infores:hetionet UMLS:C0010592 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0700225 infores:hetionet CHEBI:3757 biolink:causes HP:0033705 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0424109 infores:hetionet NCBIGene:3248 biolink:causes MONDO:0007343 infores:monarchinitiative not_provided not_provided HGNC:5154 MONDO:0007343 uuid:c5b4ee94-da4a-4775-8b28-ee1e71a25a7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15367 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0750394 infores:hetionet CHEBI:135613 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0004245 infores:hetionet CHEBI:3181 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0032231 infores:hetionet CHEBI:161680 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0013378 infores:hetionet CHEBI:7852 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0008370 infores:hetionet CHEBI:194135 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0026821 infores:hetionet CHEBI:31644 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0019080 infores:hetionet CHEBI:3752 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0271051 infores:hetionet CHEBI:3568 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0013404 infores:hetionet CHEBI:3219 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0009782 infores:hetionet CHEBI:8871 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0086525 infores:hetionet CHEBI:9599 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0014236 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0855242 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0024299 infores:hetionet CHEBI:9943 biolink:causes HP:0100750 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004144 infores:hetionet CHEBI:4909 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0002874 infores:hetionet CHEBI:17303 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0041657 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0003123 infores:hetionet CHEBI:5118 biolink:causes UMLS:C1328337 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C1328337 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0239987 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0239987 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0027707 infores:hetionet CHEBI:50777 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0156404 infores:hetionet CHEBI:45783 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0002994 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0025061 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0041969 infores:hetionet CHEBI:7465 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0001339 infores:hetionet CHEBI:3048 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0233471 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0855242 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0442874 infores:hetionet CHEBI:68534 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0042373 infores:hetionet CHEBI:16714 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0547030 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0948807 infores:hetionet CHEBI:3723 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C3665347 infores:hetionet CHEBI:94848 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0012569 infores:hetionet CHEBI:27432 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0014724 infores:hetionet CHEBI:6073 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0042075 infores:hetionet CHEBI:73274 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0011849 infores:hetionet CHEBI:7565 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1306341 infores:hetionet CHEBI:6832 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0036974 infores:hetionet CHEBI:7496 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0231218 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0013428 infores:hetionet CHEBI:9599 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0015672 infores:hetionet CHEBI:34911 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0018681 infores:hetionet CHEBI:6759 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0007166 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0151763 infores:hetionet NCBIGene:6576 biolink:causes MONDO:0032596 infores:monarchinitiative not_provided not_provided HGNC:10979 MONDO:0032596 uuid:8c6b58e3-787a-4c3f-882f-829cd30fcc43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8499 biolink:causes HP:0033850 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0812387 infores:hetionet CHEBI:32184 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0021368 infores:hetionet CHEBI:27899 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0021141 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0854375 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0854375 infores:hetionet CHEBI:3387 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0242528 infores:hetionet CAID:CA410202504 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202504 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS4, PS2, PS3, BP1, BP4, BP2, BP3, BA1, PVS1, PM6, BP5, BP7, BS1, BS4, BS3, PM5, PM3, PM4, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.488T>G (p.Phe163Cys) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a REVEL score ≥ 0.88 (0.986) (PP3). This missense variant is located within the Runt Homology Domain (AA 89–204), but does not occur in an established hotspot residue (PM1_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, PP3, PM1_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202504/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75998 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0851341 infores:hetionet CHEBI:9927 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0038999 infores:hetionet CHEBI:10127 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0015672 infores:hetionet CHEBI:47898 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0017181 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0235329 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0235329 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0541832 infores:hetionet CHEBI:28364 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0013395 infores:hetionet CHEBI:8093 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0010037 infores:hetionet CHEBI:92998 biolink:causes UMLS:C0549202 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0549202 infores:hetionet CHEBI:367163 biolink:causes MONDO:0010826 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0014553 infores:hetionet CHEBI:7798 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0020672 infores:hetionet CHEBI:47898 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1325847 infores:hetionet CHEBI:8346 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0035232 infores:hetionet CHEBI:32020 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0019158 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001039 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040425 infores:hetionet CHEBI:63580 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0014742 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0442874 infores:hetionet CHEBI:408174 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020438 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0233472 infores:hetionet CHEBI:68647 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0020621 infores:hetionet CAID:CA346328519 biolink:causes MONDO:0800472 infores:clingen CAID:CA346328519 MONDO:0800472 PMID: Pathogenic PM2_Supporting, PM3_Supporting, PVS1 PP1, PP3, BA1, BP4, PS1, PS2, PS3, PM1, PM4, PM5, BP7, BS1, BS4 The c.784G>T variant in CYP1B1 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic Acid at amino acid 262 (p.Glu262Ter). This variant was not found in any genetic ancestry group of gnomAD (v4.1), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This nonsense variant was predicted to undergo NMD (PVS1 met). PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 19234632). This variant has been identified in an individual with a CYP1B1-related phenotype (PMID:19234632). This individual is compound heterozygous for the variant and a likely pathogenic variant (phase unknown). Total proband points = 0.5, meeting PM3_Supporting. In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PVS1, PM2_Supporting, PM3_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA346328519/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2948 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0152267 infores:hetionet CHEBI:2611 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0855242 infores:hetionet CHEBI:9720 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0017605 infores:hetionet CHEBI:4856 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0151744 infores:hetionet CHEBI:3647 biolink:causes UMLS:C0151865 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0151865 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0027051 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0040046 infores:hetionet CHEBI:100241 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0344232 infores:hetionet CHEBI:63629 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C2242588 infores:hetionet CHEBI:3478 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0008031 infores:hetionet CHEBI:83804 biolink:causes HP:0011703 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0039239 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0851341 infores:hetionet CHEBI:75179 biolink:causes MONDO:0006712 infores:sider not_provided not_provided DRUGBANK:DB00432 UMLS:C0010037 infores:hetionet CHEBI:42797 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0333355 infores:hetionet GO:1902738 biolink:causes GO:0060350 infores:ubergraph knowledge_assertion manual_agent GO:1902738 GO:0060350 CHEBI:521033 biolink:causes UMLS:C0240515 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0240515 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0152227 infores:hetionet CHEBI:31932 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0858635 infores:hetionet CHEBI:31397 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0021053 infores:hetionet GO:0070799 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0070799 GO:0007275 CHEBI:40237 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0027441 infores:hetionet CHEBI:3347 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0004604 infores:hetionet CHEBI:5959 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0162830 infores:hetionet CHEBI:167638 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0037284 infores:hetionet GO:1903881 biolink:causes GO:0097398 infores:ubergraph knowledge_assertion manual_agent GO:1903881 GO:0097398 CHEBI:168396 biolink:causes MONDO:0005341 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007117 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0314719 infores:hetionet CHEBI:63635 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0344232 infores:hetionet UMLS:C0657912 biolink:causes HP:0003113 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085680 infores:hetionet CHEBI:63635 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0030193 infores:hetionet CHEBI:45285 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0015230 infores:hetionet CHEBI:15640 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0039070 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0853619 infores:hetionet CHEBI:44032 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0016199 infores:hetionet CHEBI:45863 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0024902 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0541832 infores:hetionet CHEBI:2666 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0009676 infores:hetionet CHEBI:6950 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013390 infores:hetionet CHEBI:7573 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0017181 infores:hetionet CHEBI:478164 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0031542 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0853011 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0853011 infores:hetionet CHEBI:46557 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0026636 infores:hetionet CHEBI:6715 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0149871 infores:hetionet CHEBI:9737 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0027497 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027051 infores:hetionet CHEBI:110423 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0023895 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0033975 infores:hetionet CHEBI:6888 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0039231 infores:hetionet CHEBI:45924 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0002878 infores:hetionet CHEBI:17026 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0015397 infores:hetionet CHEBI:8245 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0011991 infores:hetionet CHEBI:17347 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0006277 infores:hetionet CHEBI:39585 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0002994 infores:hetionet CHEBI:4868 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0011991 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0027707 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0004936 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0151559 infores:hetionet CHEBI:16899 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0019079 infores:hetionet CHEBI:39669 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C3665347 infores:hetionet CHEBI:4903 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0040053 infores:hetionet CHEBI:64312 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0036396 infores:hetionet CHEBI:79699 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0018681 infores:hetionet CHEBI:8228 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0020580 infores:hetionet CHEBI:100246 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0026821 infores:hetionet CHEBI:291342 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0006277 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0004936 infores:hetionet CHEBI:8024 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0011603 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005339 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0162311 infores:hetionet CHEBI:68642 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0151744 infores:hetionet CHEBI:75988 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0038362 infores:hetionet CHEBI:63620 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0015469 infores:hetionet NCBIGene:57158 biolink:causes MONDO:0013474 infores:monarchinitiative not_provided not_provided HGNC:14202 MONDO:0013474 uuid:10de62ad-efc6-429b-b09b-8d2262864eee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0016382 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0037199 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0034069 infores:hetionet CHEBI:3756 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0085633 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0233632 infores:hetionet CHEBI:3510 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0018681 infores:hetionet CHEBI:8028 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0234518 infores:hetionet CHEBI:5128 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0041657 infores:hetionet CHEBI:68575 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0027765 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0020615 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0549567 infores:hetionet CHEBI:2549 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0232493 infores:hetionet CAID:CA1139660055 biolink:causes MONDO:0007453 infores:clingen CAID:CA1139660055 MONDO:0007453 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4, PP4 The c.1280_1283dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 429 (NM_000162.5), adding 31 novel amino acids before encountering a stop codon (p.(Arg429AlafsTer31)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1280_1283dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139660055/MONDO:0007453/086 2023-11-03 2023-11-03 Semidominant inheritance HP:0032113 Supports NCBIGene:10379 biolink:causes MONDO:0032848 infores:monarchinitiative not_provided not_provided HGNC:6131 MONDO:0032848 uuid:111f5458-050e-448a-b047-a63c171a100f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022638 infores:hetionet CAID:CA397722281 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722281 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The NM_000018.4(ACADVL):c.190A>T (p.Lys64Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 3/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature in any individuals with VLCAD deficiency. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting, VCEP specifications v2.0; Approved 10-15-21. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722281/MONDO:0008723/021 2022-02-22 2022-02-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8499 biolink:causes HP:0033687 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0701811 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151736 infores:hetionet CHEBI:478164 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0002871 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0006852 infores:hetionet CHEBI:27300 biolink:causes MONDO:0001071 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0025362 infores:hetionet CHEBI:36795 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0522063 infores:hetionet CAID:CA023651 biolink:causes MONDO:0007750 infores:clingen CAID:CA023651 MONDO:0007750 PMID: Likely Benign BP4, BP2, PS3_Supporting BA1, BP1, BP3, PS1, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2 "The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 and PS3_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:BP4 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing.BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = ""high chol"".PS3_supporting - level 3 assay (PMID: 9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%.Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign." Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023651/MONDO:0007750/013 2022-05-27 2022-12-23 Semidominant inheritance HP:0032113 Contradicts https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9571 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0033774 infores:hetionet CHEBI:92712 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0018834 infores:hetionet CHEBI:9123 biolink:causes MONDO:0017291 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C3544214 infores:hetionet CHEBI:9571 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0027497 infores:hetionet CHEBI:75722 biolink:causes HP:0004277 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0435632 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0853149 infores:hetionet CHEBI:2636 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0232292 infores:hetionet CAID:CA004103 biolink:causes MONDO:0021056 infores:clingen CAID:CA004103 MONDO:0021056 PMID: Benign BS2, BA1, BP1, BP2 PP3, BP4, PS3, PS4, BP5, BS3 The c.1240C>T variant in APC is a missense variant predicted to cause the substitution of arginine by cysteine at amino acid 414 (p.Arg414Cys). This variant has been observed in heterozygous state in ≥ 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae, Ambry, and GeneDX internal data). It has been observed in trans with a variant classified as Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) in an individual with FAP (BP2). The highest allele frequency of this variant is 0.001835 in European (Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001) for BA1. Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BS2, BP1 and BP2 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA004103/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7986 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0043352 infores:hetionet CHEBI:5165 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0231530 infores:hetionet CHEBI:63629 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0014742 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0009450 infores:hetionet CAID:CA10360405 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360405 MONDO:0100039 PMID: Likely Benign BS2, BP4 BS1, PM1, PM2, PS4 The highest population minor allele frequency of the c.1684A>G (p.Thr562Ala) variant in CDKL5 in gnomAD v4.1 is 0.000004 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a score of 0.133, evidence that does not predict a damaging effect on CDKL5 function (BP4). The p.Thr562Ala variant is observed in at least 2 unaffected individuals (Ambry Genetics: internal database, Labcorp Genetics Inc. (formerly Invitae): internal database) (BS2). In summary, the p.Thr562Ala variant in CDKL5 is classified as Likely Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BP4, BS2) (CDKL5 Specifications v.3.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360405/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Contradicts true CHEBI:5123 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0162830 infores:hetionet NCBIGene:27145 biolink:causes MONDO:0958332 infores:monarchinitiative not_provided not_provided HGNC:21015 MONDO:0958332 uuid:a1261155-742c-477e-9f0a-fad9d1d78dfe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2663 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0016059 infores:hetionet CHEBI:63631 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0030196 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0034150 infores:hetionet CHEBI:47426 biolink:causes UMLS:C0853277 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0853277 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0497247 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0005940 infores:hetionet CHEBI:135920 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0011603 infores:hetionet CHEBI:8871 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0423791 infores:hetionet CHEBI:3423 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0003811 infores:hetionet CHEBI:68579 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0038999 infores:hetionet CHEBI:39867 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C3263723 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0005940 infores:hetionet CHEBI:2038 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0033774 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0677500 infores:hetionet CHEBI:49040 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0021368 infores:hetionet CHEBI:4562 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0035455 infores:hetionet CHEBI:134966 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0232492 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0149866 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0149866 infores:hetionet CHEBI:68610 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0002994 infores:hetionet CHEBI:101278 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0009450 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042514 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0037822 infores:hetionet CHEBI:31705 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0151744 infores:hetionet CHEBI:2567 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C2711248 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0036572 infores:hetionet CHEBI:68554 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0017979 infores:hetionet CHEBI:404903 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0017152 infores:hetionet CHEBI:6437 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0002170 infores:hetionet CHEBI:4027 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0019151 infores:hetionet CHEBI:681848 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0080274 infores:hetionet CHEBI:17688 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0020580 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0234916 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0013404 infores:hetionet CHEBI:42797 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C3203358 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0018418 infores:hetionet CHEBI:52172 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0004245 infores:hetionet CHEBI:36791 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027796 infores:hetionet CHEBI:32315 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020458 infores:hetionet NCBIGene:1829 biolink:causes MONDO:0012434 infores:monarchinitiative not_provided not_provided HGNC:3049 MONDO:0012434 uuid:c2791640-568d-493d-a40a-7aea2ee4c829 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8768 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0007222 infores:hetionet CHEBI:194135 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020453 infores:hetionet CHEBI:6076 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0031350 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002491 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0013146 infores:hetionet CHEBI:75722 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0040822 infores:hetionet CHEBI:7514 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0026821 infores:hetionet CHEBI:49575 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0004096 infores:hetionet CHEBI:3696 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0011606 infores:hetionet CHEBI:3387 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0041349 infores:hetionet CHEBI:50838 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0006145 infores:hetionet CAID:CA16041883 biolink:causes MONDO:0009290 infores:clingen CAID:CA16041883 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000152.5:c.471del (p.Thr158ProfsTer8) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in patients with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 371501). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16041883/MONDO:0009290/010 2023-03-10 2023-03-10 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:63631 biolink:causes MONDO:0024361 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0877792 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0034186 infores:hetionet CHEBI:168396 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0042029 infores:hetionet CHEBI:2914 biolink:causes UMLS:C0520758 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0520758 infores:hetionet CHEBI:3240 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00639 UMLS:C0234233 infores:hetionet CAID:CA16611276 biolink:causes MONDO:0008667 infores:clingen CAID:CA16611276 MONDO:0008667 PMID: Pathogenic PS4_Supporting, PM2_Supporting, PVS1 The NM_000551.4(VHL):c.422dup (p.Asn141fs) is a frameshift variant affecting position 141. This variant is not expected to undergo nonsense mediated decay, but is in a functional domain critical to the protein function (nuclear export domain) (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Two commercial laboratories report cases. Case 1 (0.5 points): displayed bilateral renal masses and likely pheochromocytoma, with a small Paraganglioma panel run. Case 2 (0.5): Multiple renal tumors in 40s, no other family history known, and a 13-gene panel was run for renal cancers (PS4_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA16611276/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Supports CHEBI:48669 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0018681 infores:hetionet CHEBI:2904 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C2047937 infores:hetionet CHEBI:6541 biolink:causes MONDO:0001735 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0030469 infores:hetionet CHEBI:2659 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0029944 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0012833 infores:hetionet NCBIGene:7456 biolink:causes MONDO:0013779 infores:monarchinitiative not_provided not_provided HGNC:12736 MONDO:0013779 uuid:0e6bf48a-bd49-445a-878c-b17937a8d1a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50381 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0023218 infores:hetionet CHEBI:33325 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB08913 UMLS:C0015376 infores:hetionet CHEBI:7476 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0392525 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0027051 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0004623 infores:hetionet CHEBI:92712 biolink:causes UMLS:C0549363 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0549363 infores:hetionet NCBIGene:643641 biolink:causes MONDO:0975841 infores:monarchinitiative not_provided not_provided HGNC:34519 MONDO:0975841 uuid:69deb52b-c55e-42b2-83d5-8a64f7fd13da biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0854268 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0854268 infores:hetionet CHEBI:30830 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0085606 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0038454 infores:hetionet CHEBI:63115 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C1306577 infores:hetionet CHEBI:9137 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0009763 infores:hetionet CHEBI:36795 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0027441 infores:hetionet CHEBI:15854 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0040822 infores:hetionet CHEBI:9622 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0020517 infores:hetionet NCBIGene:3000 biolink:causes MONDO:0011143 infores:monarchinitiative not_provided not_provided HGNC:4689 MONDO:0011143 uuid:db68ca87-14be-4e0f-801c-6a45078d4587 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4702 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0917798 infores:hetionet CHEBI:10119 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0022638 infores:hetionet CHEBI:8888 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0558489 infores:hetionet CHEBI:17026 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0027424 infores:hetionet CAID:CA389474374 biolink:causes MONDO:0100040 infores:clingen CAID:CA389474374 MONDO:0100040 PMID: Uncertain Significance BP5, BS2_Supporting, PM2_Supporting, BP4 The p.Asn32Ser variant in FOXG1 is absent from gnomAD v4.1 (PM2_Supporting). The p.Asn32Ser variant is observed in at least 1 unaffected individual (internal database - Labcorp Genetics) (BS2_Supporting). The p.Asn32Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Labcorp Genetics) (BP5). The computational predictor REVEL gives a score of 0.083, which is below the threshold of 0.290, evidence that does not predict a damaging effect on FOXG1 function (BP4). In summary, the p.Asn32Ser variant in FOXG1 is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BS2_Supporting, BP5, BP4). (FOXG1 Specifications v.4.1; curation approved on [06/25/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA389474374/MONDO:0100040/035 2025-06-25 2025-06-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:145499 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0151786 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0232492 infores:hetionet CHEBI:64312 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0028643 infores:hetionet CHEBI:3508 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0858797 infores:hetionet NCBIGene:165 biolink:causes MONDO:0054813 infores:monarchinitiative not_provided not_provided HGNC:303 MONDO:0054813 uuid:df16eb3a-316d-44f4-be86-45d105060976 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15765 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0033117 infores:hetionet CHEBI:127342 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0015672 infores:hetionet CHEBI:41423 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0004134 infores:hetionet CAID:CA1394316 biolink:causes MONDO:0019501 infores:clingen CAID:CA1394316 MONDO:0019501 PMID:26806561PMID:26927203PMID:26667666 Uncertain Significance PM3_Supporting, PM2 PP4, PP3, BP4 The c.9433C>T (p.Leu3145Phe) variant in USH2A is present in 0.0033% (1/30612) of South Asian allele in gnomAd v2.1.1 and in 0.0074% (1/13568) of Latino alleles in gnomAD v3 (PM2). This variant has been detected in 1 proband with bilateral sensorineural hearing loss in a homozygous state (PM3_Supporting, PMID: 26806561). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3_Supporting. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA1394316/MONDO:0019501/005 2020-07-28 2020-07-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:63638 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C2830004 infores:hetionet CHEBI:7494 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0231218 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0036983 infores:hetionet CHEBI:6950 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0085633 infores:hetionet CHEBI:4909 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0085932 infores:hetionet CHEBI:64312 biolink:causes EFO:0009959 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C1510475 infores:hetionet CHEBI:64355 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0236075 infores:hetionet CHEBI:6923 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0043352 infores:hetionet CHEBI:7931 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0917801 infores:hetionet CHEBI:7936 biolink:causes MONDO:0019297 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0024236 infores:hetionet CHEBI:2038 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0030196 infores:hetionet CHEBI:68558 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0015402 infores:hetionet CHEBI:7445 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0086565 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0917801 infores:hetionet CHEBI:3176 biolink:causes UMLS:C1096282 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C1096282 infores:hetionet CHEBI:231594 biolink:causes MONDO:0019623 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0019243 infores:hetionet GO:1905684 biolink:causes GO:0042060 infores:ubergraph knowledge_assertion manual_agent GO:1905684 GO:0042060 CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0240557 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0235969 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0009938 infores:hetionet CHEBI:171719 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0015967 infores:hetionet CHEBI:6456 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0013378 infores:hetionet CHEBI:17347 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0041834 infores:hetionet CHEBI:52172 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018944 infores:hetionet CHEBI:7865 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0178298 infores:hetionet CHEBI:2611 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0687713 infores:hetionet CHEBI:9763 biolink:causes UMLS:C0748023 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0748023 infores:hetionet CHEBI:3216 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0855775 infores:hetionet CHEBI:135005 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020458 infores:hetionet CHEBI:35778 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C2939147 infores:hetionet CHEBI:7514 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0027765 infores:hetionet CHEBI:9445 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0004096 infores:hetionet CHEBI:31624 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0018790 infores:hetionet CHEBI:53760 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013395 infores:hetionet CHEBI:9123 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013404 infores:hetionet CHEBI:7823 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0004134 infores:hetionet CHEBI:66919 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB08877 UMLS:C0043094 infores:hetionet NCBIGene:10021 biolink:causes MONDO:0013148 infores:monarchinitiative not_provided not_provided HGNC:16882 MONDO:0013148 uuid:ab795d06-e829-4412-9b53-f30b8c834f2c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA6831657 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831657 MONDO:0015967 PMID: Benign BP4, BA1, BP7 BS1, PM2 The c.42G>A variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 14 (p.Ala14=) of NM_000545.8. This variant has a Grpmax filtering allele frequency of 0.00010377 in gnomAD v4.1.0, which is above the ClinGen MDEP cutoff for BA1 (0.0001) (BA1). This synonymous variant is not predicted to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -1.735, which is below the MDEP cutoff of 2.0) (BP4, BP7). In summary, c.42G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): BA1, BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831657/MONDO:0015967/017 2025-08-29 2025-08-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63598 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0037822 infores:hetionet CHEBI:3403 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0232492 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0086543 infores:hetionet CAID:CA199370 biolink:causes MONDO:0100039 infores:clingen CAID:CA199370 MONDO:0100039 PMID: Likely Pathogenic PS3_Supporting, PP4, PP3, PM2_Supporting, PS4_Supporting, PS2 PM5, PM1, PS1 The p.Gln219Pro variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 23151060, internal database - Ambry) (PS4_Supporting). The p.Gln219Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database - Ambry) (PS2). The p.Gln219Pro variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database - Ambry) (PP4). The p.Gln219Pro variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In vitro kinase assay has shown that this variant impacts protein function (PMID: 32034940) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gln219Pro variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS4_Supporting, PS2, PP4, PM2_Supporting, PS3_Supporting, PP3). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA199370/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Supports CHEBI:9435 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0033687 infores:hetionet CHEBI:499361 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0015967 infores:hetionet NCBIGene:2253 biolink:causes MONDO:0012988 infores:monarchinitiative not_provided not_provided HGNC:3686 MONDO:0012988 uuid:322a94d3-a33e-4676-b132-c7706cd45544 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45783 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011570 infores:hetionet CHEBI:28915 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0002874 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0162429 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1610622 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1610622 infores:hetionet CHEBI:71940 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0151827 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0267596 infores:hetionet CHEBI:10102 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0013428 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0040046 infores:hetionet CHEBI:64355 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0014457 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0037274 infores:hetionet CHEBI:135613 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0855333 infores:hetionet CAID:CA2580098649 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098649 MONDO:0011071 PMID: Pathogenic PM1_Supporting, PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PP2, PP3, PP1, PP4, BS2 The NM_001754.5(RUNX1):c.391_392insATCG (p.Thr131AsnfsTer8) is a frameshift variant in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant affects one of the amino acid residues between 89-204 within the RHD (PM1_supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM1_supporting, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098649/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45081 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0006277 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0849913 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0849913 infores:hetionet NCBIGene:1859 biolink:causes MONDO:0013578 infores:monarchinitiative not_provided not_provided HGNC:3091 MONDO:0013578 uuid:c8694c65-b50b-472c-9706-e974413bd861 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50777 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0000731 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0021400 infores:hetionet CHEBI:9674 biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0235339 infores:hetionet CHEBI:63611 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0006266 infores:hetionet CHEBI:45783 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0004604 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0019112 infores:hetionet CHEBI:63577 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0042963 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0162830 infores:hetionet CAID:CA226452 biolink:causes MONDO:0100437 infores:clingen CAID:CA226452 MONDO:0100437 PMID: Benign PS3_Supporting, BA1 PP3, PP1, PP4, PS4, BP4 NM_001034853.2(RPGR):c.865A>G (p.Ile289Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 289. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001308 among hemizygous individuals, with 51 variant alleles / 389,832 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The variant co-segregates with X-linked retinitis pigmentosa or milder phenotypes in female carriers across 5 meioses in a single family, however, the description of phenotypes is insufficiently detailed to meet PP4 or PP1 (PMID: 10482958). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 32531858, 28863407). However, because the variant meets BA1, PS4_Supporting cannot be met. The variant protein exhibits decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID: 23213406, PS3_Supporting). The computational predictor REVEL gives the variant a score of 0.553, which is above the ClinGen X-linked IRD VCEP BP4 threshold of <0.290 and below the PP3 threshold of >0.644, so BP4 and PP3 are not met. The computational splicing predictor SpliceAI gives the variant a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP BP4 threshold of <0.2 and indicates that the variant has no predicted impact on splicing. In summary, this variant meets the criteria to be classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and PS3_Supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226452/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CAID:CA008122 biolink:causes MONDO:0100316 infores:clingen CAID:CA008122 MONDO:0100316 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP1_Strong, PS3_Supporting, PP3, PP4 PM5 NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)‌ is a missense variant in KCNQ1 predicted to replace valine with methionine at amino acid 254. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in affected probands exhibiting QTc prolongation above 480 milliseconds and an exercise-associated event, which together are highly specific for long QT syndrome 1 (PP4, PMID: 29439887). This variant has been reported in at least 4 additional probands affected with long QT syndrome 1 (PS4_Moderate; PMID: 29439887). The variant segregates with long QT syndrome through 10 affected family members of the 5 probands confirmed to be similarly affected by exhibiting QTc prolongation above 480 milliseconds and/or syncope and/or Schwartz score above 3.5 (PP1_Strong, PMID: 29439887). An additional family has been reported but has not been described in sufficient detail to be considered for family segregation (PMID: 8528244). The computational predictor REVEL gives a score of 0.918, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant has been shown to disrupt KCNQ1 function in two required experimental assays, both of them manual patch-clamp studies reporting a dominant negative electrophysiological defect (PS3_Supporting; PMID: 10376919, PMID: 14756674). In summary, this variant meets the criterion to be classified as pathogenic for long QT syndrome 1, as specified by the ClinGen Potassium Channel Arrhythmia VCEP; PS3_Supporting, PS4_Moderate PM2_Supporting, PP1_Strong, PP3, PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA008122/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Supports UMLS:C1738934 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0085649 infores:hetionet CAID:CA16607078 biolink:causes MONDO:0012996 infores:clingen CAID:CA16607078 MONDO:0012996 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_001482.3:c.675+3G>C variant in GATM is an intronic variant affecting a nucleotide within the consensus splice site of intron 4. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 387822). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607078/MONDO:0012996/025 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8707 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040034 infores:hetionet CHEBI:7865 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0004936 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0235416 infores:hetionet CHEBI:135613 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0015230 infores:hetionet CHEBI:50275 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235886 infores:hetionet CHEBI:6128 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0151539 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151544 infores:hetionet NCBIGene:4893 biolink:causes MONDO:0013767 infores:monarchinitiative not_provided not_provided HGNC:7989 MONDO:0013767 uuid:2b997a30-d4ae-40b4-9d58-f63f2cd11290 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63635 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0232462 infores:hetionet CHEBI:34967 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0017160 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0234215 infores:hetionet CHEBI:28148 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0038454 infores:hetionet CHEBI:31348 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151827 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004096 infores:hetionet CHEBI:47381 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0424295 infores:hetionet CHEBI:3387 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0009782 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0232492 infores:hetionet CAID:CA251529 biolink:causes MONDO:0009861 infores:clingen CAID:CA251529 MONDO:0009861 PMID:18299955PMID:11524738PMID:2574153PMID:25596310PMID:17935162 Pathogenic PM3, PM2, PP4, PP3, PS3 PM5 PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251529/MONDO:0009861/006 2018-08-13 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31236 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0853149 infores:hetionet CHEBI:28918 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0234192 infores:hetionet CHEBI:40279 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085631 infores:hetionet CHEBI:404903 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0406834 infores:hetionet CHEBI:7478 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0013144 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0234975 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0234975 infores:hetionet CHEBI:3485 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0023052 infores:hetionet CHEBI:3181 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C2830004 infores:hetionet CAID:CA158282 biolink:causes MONDO:0100216 infores:clingen CAID:CA158282 MONDO:0100216 PMID: Benign BP4, BS2, PM1_Supporting, BS1 PM2, PM6, BP2, BA1, PP3, PP4, PP1, PM5, PS1, PS3, PS4, PS2, BS3, BS4 The NM_177438.2:c.5276A>G variant in DICER1 is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 1759 (p.Lys1759Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00082 (5/6084 alleles) in the Middle Eastern population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors: 61756, 500031). The computational predictor REVEL gives a score of 0.444, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592)(PM1_Supporting). In summary, this variant meets the criteria to be classified as Benign for DICER1-related tumor predisposition. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: (BS1, BS2, BP4, PM1_Supporting). (Bayesian Points: -8; VCEP specifications version 1.4.0; 10/28/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA158282/MONDO:0100216/024 2025-10-28 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3403 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0030252 infores:hetionet CHEBI:31348 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0267792 infores:hetionet CHEBI:45652 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0020538 infores:hetionet CHEBI:8871 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0033893 infores:hetionet CHEBI:47519 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0033774 infores:hetionet CHEBI:41977 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0003862 infores:hetionet CHEBI:6775 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0038990 infores:hetionet CHEBI:16335 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0036974 infores:hetionet CHEBI:15367 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0015672 infores:hetionet CHEBI:63624 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0016199 infores:hetionet CHEBI:9362 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00870 UMLS:C0022081 infores:hetionet CHEBI:2569 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0855775 infores:hetionet CAID:CA401325305 biolink:causes MONDO:0009290 infores:clingen CAID:CA401325305 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PS3_Moderate, PM2_Supporting, PM5_Supporting "The NM_000152.5(GAA):c.2456G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 819 (p.Arg819Pro). This variant has been detected in at least 6 individuals with Pompe disease (PMID: 22644586, 22252923, 30214072) with deficient GAA activity. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and one was homozygous for the variant (PMID: 30214072, internal lab data), meeting PP4_Moderate and PM3. It is absent in gnomAD, meeting PM2. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B (""potentially less severe"") by Kroos et al, 2012 (PMID:22644586). This includes 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PP4_Moderate, PM3, PS3_Moderate, PP3, PM2_Supporting, and PM5_Supporting." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401325305/MONDO:0009290/010 2022-06-30 2022-06-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CAID:CA512319131 biolink:causes MONDO:0011071 infores:clingen CAID:CA512319131 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.519C>T (p.Phe173=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512319131/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63605 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0031117 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0348801 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0348801 infores:hetionet UNII:3QJA87N40S biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0151602 infores:hetionet CHEBI:63618 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0917801 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0403632 infores:hetionet CHEBI:4814 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0014591 infores:hetionet CHEBI:7852 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0162830 infores:hetionet CHEBI:61033 biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0002063 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0037822 infores:hetionet GO:0043304 biolink:causes GO:0002448 infores:ubergraph knowledge_assertion manual_agent GO:0043304 GO:0002448 CHEBI:45924 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0039070 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0015397 infores:hetionet CHEBI:40279 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0553548 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0025222 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0000833 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0085584 infores:hetionet CAID:CA386972013 biolink:causes MONDO:0015967 infores:clingen CAID:CA386972013 MONDO:0015967 PMID: Uncertain Significance PP3, PP4, BS2 PS4, PM5, BS3, BS1, PM2, PP1 The c.1576G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to asparagine at codon 526 (p.(Asp526Asn)) of NM_000545.8. This variant was identified in an individual who was normoglycemic at 70 years old, and the expected penetrance for HNF1A-monogenic diabetes is 95% by age 70 (BS2; internal lab contributors). Additionally it was identified in the homozygous state in an individual not diagnosed with diabetes until the age of 62. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.805, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). The Grpmax filtering allele frequency of the c.1576G>A variant in gnomAD v2.1.1 is 0.00001123, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. While studies exploring the effect of this variant on protein function have been performed, these studies were conflicting, with cell line showing >75% activity and one cell one showing activity between 40% and 75%, and BS3 cannot be applied (PMID: 32910913). This variant was identified in at least 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar: 562466, internal lab contributors). Another missense variant, c.1576G>T p.Asp526Tyr, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1576G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS2, PP3, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386972013/MONDO:0015967/017 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8874 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0027339 infores:hetionet CAID:CA1139665644 biolink:causes MONDO:0100326 infores:clingen CAID:CA1139665644 MONDO:0100326 PMID: Pathogenic PP4_Strong, PP1, PM2_Supporting, PVS1_Strong, PM3_Supporting The NM_000419.5(ITGA2B):c.2975_2979del variant (current HGVS nomenclature of c.2971_2975del) that results in the p.Glu992Glyfs*42 frameshift has been reported homozygous (PM3_supporting) in at least one GT proband (P16 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). An additional affected family member (P17) is also homozygous (PP1). The variant alters the critical transmembrane domain (PVS1). The variant is absent from population databases (PM2_supporting). In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PM3_supporting, PP1, PP4_strong. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665644/MONDO:0100326/011 2022-08-05 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8214 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0003862 infores:hetionet CHEBI:46557 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0006840 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0013395 infores:hetionet CHEBI:50648 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0003962 infores:hetionet CHEBI:4710 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0152198 infores:hetionet CHEBI:7459 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0042514 infores:hetionet NCBITaxon:122277 biolink:causes MONDO:0005122 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:122277 MONDO:0005122 CAID:CA916081960 biolink:causes MONDO:0011071 infores:clingen CAID:CA916081960 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, BP4, BP2, BA1, PVS1, BP7, BS1, BS3, BS4, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.-5_4del (p.Met1_Ala2del) is an in-frame deletion variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant affects the initiator methionine but is located outside of the Runt Homology Domain (AA 89-204), and does not alter the predicted protein structure or function; therefore, PM4 does not apply. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081960/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6912 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0235660 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0001364 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0234215 infores:hetionet CHEBI:4877 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0027697 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0178298 infores:hetionet CHEBI:8863 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0019521 infores:hetionet CHEBI:3996 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0008370 infores:hetionet CHEBI:85161 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0234215 infores:hetionet CHEBI:5855 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0026826 infores:hetionet CHEBI:50173 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0000737 infores:hetionet GO:0060708 biolink:causes CL:0002499 infores:ubergraph knowledge_assertion manual_agent GO:0060708 CL:0002499 CAID:CA146033 biolink:causes MONDO:0100437 infores:clingen CAID:CA146033 MONDO:0100437 PMID: Benign BP4_Strong, BA1 BP5 The NM_001034853.2(RPGR):c.1367A>G (p.Gln456Arg) variant is a missense variant encoding the substitution of Glutamine with Arginine at amino acid 456. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01145 among hemizygous individuals, with 4533 variant alleles / 395737 hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in three probands with an alternate molecular basis for the disease (PMIDs: 18552978, 22334370, 11992260). However, the BP5 code is considered not applicable for RPGR-related retinopathy. The computational predictor REVEL gives a score of 0.016, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.08, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1 and BP4_strong. (VCEP specifications version 1.0.0; date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA146033/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts true CHEBI:3510 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0004093 infores:hetionet CHEBI:52717 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1619712 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0008325 infores:hetionet CHEBI:42797 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0016655 infores:hetionet NCBIGene:2582 biolink:causes MONDO:0009257 infores:monarchinitiative not_provided not_provided HGNC:4116 MONDO:0009257 uuid:e8e55ebf-339d-423f-8cd0-265531fb21af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003467 infores:hetionet CHEBI:2663 biolink:causes MONDO:0022205 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0152081 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0013922 infores:hetionet CAID:CA228847 biolink:causes MONDO:0015628 infores:clingen CAID:CA228847 MONDO:0015628 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate, PS3, PS2_Moderate PP1, BA1, BP4, PM5, BS1 The NM_000552.5(VWF):c.8318G>C variant in VWF is a missense variant predicted to cause substitution of cysteine by serine at amino acid 2773. This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patients with this variant displayed laboratory phenotypes of excessive mucocutaneous bleeding, very low VWF activity (measured by VWF:RCo assay), low VWF:RCo/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD Type 2A (PP4_moderate, PMID: 17139364). This variant has been reported in 3 additional probands meeting type 2A laboratory criteria for PP4 (PS4_moderate; PMID: 21979291, 32664776, 28971901), and one was a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID: 32664776). Multimerization assay performed with the p.Cys2773Ser recombinant mutant and wild-type vWF co-expressed by HEK293 cells showed abnormal multimers (PMID: 17139364 Fig. 2) that were counteracted by an allele-specific siRNA targeting the mutant transgene, indicating that this variant has a damaging effect on protein function (PMID: 29734512)(PS3_supporting). The computational predictor REVEL gives a score of 0.876, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP4_Moderate, PS2_Moderate, PS4_Moderate, PS3, PP3, PM2_Supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228847/MONDO:0015628/081 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Supports UNII:R43D2573WO biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0014742 infores:hetionet CHEBI:50838 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0027497 infores:hetionet CAID:CA000219 biolink:causes MONDO:0017623 infores:clingen CAID:CA000219 MONDO:0017623 PMID: Pathogenic PM2, PVS1, PS4_Supporting PTEN c.892C>T (p.Q298X) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23470840) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000219/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:2675 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0235660 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0005940 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0014544 infores:hetionet CHEBI:100241 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0019079 infores:hetionet CAID:CA384901425 biolink:causes MONDO:0010880 infores:clingen CAID:CA384901425 MONDO:0010880 PMID: Likely Pathogenic PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting The NM_000020.3: c.982C>T variant in ACVRL1 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 328 (p.His328Tyr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 3 probands with a phenotype consistent of HHT (PS4_Moderate; PMID: 27077548, 32300199, 17384219, 34872578, 24196379, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The computational predictor REVEL gives a score of 0.991, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PP3, PP4_Moderate, PS4_Moderate (specification version 1.0.0; 1/04/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA384901425/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:82941 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0232462 infores:hetionet CHEBI:63612 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0018378 infores:hetionet CAID:CA177515 biolink:causes MONDO:0021060 infores:clingen CAID:CA177515 MONDO:0021060 PMID: Benign BA1 BP7, PM1 The NM_002524.5:c.159G>A variant is a synonymous (silent) variant (p.Leu53=) that is not predicted by SpliceAI to impact splicing, however, this nucleotide is highly conserved. The filtering allele frequency (the lower threshold of the 95% CI of 25/19928) of the c.159G>A variant in NRAS is 0.0009003 for East Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA177515/MONDO:0021060/039 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47780 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151717 infores:hetionet CHEBI:5558 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0027769 infores:hetionet CHEBI:31184 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00240 UMLS:C0162820 infores:hetionet CHEBI:64354 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0948594 infores:hetionet CHEBI:3423 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0042024 infores:hetionet CHEBI:5050 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0028084 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0877338 infores:hetionet CHEBI:480999 biolink:causes NCIT:C101172 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0234230 infores:hetionet CAID:CA146038 biolink:causes MONDO:0100437 infores:clingen CAID:CA146038 MONDO:0100437 PMID: Benign BP4_Strong, BA1 BS2 NM_001034853.2(RPGR):c.1598C>T (p.Thr533Met) is a missense variant predicted to cause substitution of threonine by methionine at amino acid 533. This variant is present in gnomAD v.4.1.0 at a frequency of 0.02249 among hemizygous individuals, with 8,907 variant alleles / 396,119 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been observed in more than 6 individuals with no features or family history of RPGR-related RP, a condition with full penetrance at an early age (PMIDs: 10482958, 11992260, 10980543, 19377476). However, it is not clear whether these individuals underwent a complete visual examination, so BS2 was not met. The computational predictor REVEL gives a score of 0.015, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA146038/MONDO:0100437/106 2025-08-03 2025-08-04 X-linked inheritance HP:0001417 Contradicts true CHEBI:3176 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0004936 infores:hetionet CHEBI:8356 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0233407 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085096 infores:hetionet CHEBI:135342 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0015967 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0349506 infores:hetionet CHEBI:51041 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0085632 infores:hetionet CHEBI:7494 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020615 infores:hetionet CHEBI:72296 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0018965 infores:hetionet CHEBI:63632 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0085932 infores:hetionet CHEBI:31981 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0855775 infores:hetionet CHEBI:9130 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020649 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0342579 infores:hetionet CHEBI:135920 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C1384353 infores:hetionet CHEBI:50223 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0011168 infores:hetionet CHEBI:681569 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0019348 infores:hetionet NCBIGene:8482 biolink:causes MONDO:0030815 infores:monarchinitiative not_provided not_provided HGNC:10741 MONDO:0030815 uuid:7d02d959-d438-4d6d-b761-fcd0766629e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8764 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0085632 infores:hetionet CAID:CA645373343 biolink:causes MONDO:0044970 infores:clingen CAID:CA645373343 MONDO:0044970 PMID: Uncertain Significance PM2_Supporting PP1, PP3, BP4, PS2, PS3, PM6 The m.12271T>C variant in MT-TL2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on March 11, 2024. There have been no affected individuals reported in the medical literature to our knowledge and there are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 67.9%; HmtVAR: 0.1). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA645373343/MONDO:0044970/015 2024-03-11 2024-11-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:135888 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0015967 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0012833 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151602 infores:hetionet CHEBI:4315 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0038990 infores:hetionet CHEBI:134936 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0015967 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0013595 infores:hetionet CHEBI:9727 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0015672 infores:hetionet CHEBI:38545 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0235996 infores:hetionet CHEBI:15854 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0013595 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0340726 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0027339 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0007137 infores:hetionet CHEBI:3213 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0857177 infores:hetionet GO:1903421 biolink:causes GO:0099504 infores:ubergraph knowledge_assertion manual_agent GO:1903421 GO:0099504 CHEBI:134991 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0040264 infores:hetionet CHEBI:17026 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1368065 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0233632 infores:hetionet UMLS:C0657912 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019209 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0032285 infores:hetionet CHEBI:167638 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0040822 infores:hetionet NCBIGene:1729 biolink:causes MONDO:0007424 infores:monarchinitiative not_provided not_provided HGNC:2876 MONDO:0007424 uuid:e39f867e-1f21-4656-8d61-38888d6f0948 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0013395 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020517 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027765 infores:hetionet CHEBI:47898 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C1262036 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0919980 infores:hetionet CHEBI:8028 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0002792 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0235639 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1565662 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1565662 infores:hetionet CHEBI:9448 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0011991 infores:hetionet GO:1905044 biolink:causes GO:0048666 infores:ubergraph knowledge_assertion manual_agent GO:1905044 GO:0048666 CHEBI:10650 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0234193 infores:hetionet UMLS:C1709429 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0151904 infores:hetionet GO:2000032 biolink:causes GO:0010016 infores:ubergraph knowledge_assertion manual_agent GO:2000032 GO:0010016 CHEBI:94686 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0012817 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0231528 infores:hetionet CHEBI:2666 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0015230 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0037822 infores:hetionet CHEBI:8028 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0392676 infores:hetionet CHEBI:6887 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013595 infores:hetionet CHEBI:35778 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1260880 infores:hetionet CHEBI:135961 biolink:causes UMLS:C1868893 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C1868893 infores:hetionet CHEBI:39867 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0015371 infores:hetionet CHEBI:8863 biolink:causes HP:0000225 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0017565 infores:hetionet CHEBI:63610 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0017181 infores:hetionet CHEBI:3127 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0002170 infores:hetionet CHEBI:50131 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0242184 infores:hetionet CHEBI:6375 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151830 infores:hetionet CHEBI:7496 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0019080 infores:hetionet CAID:CA256012 biolink:causes MONDO:0010305 infores:clingen CAID:CA256012 MONDO:0010305 PMID: Uncertain Significance PS3_Supporting, PP3, PM2_Supporting PP4, PS1 The NM_005629.4:c.259G>A variant in SLC6A8 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 87 (p.Gly87Arg). This variant is absent in population databases (PM2_Supporting) and has been described in the literature in an individual for whom biochemical testing could not be performed (PMID: 15154114). The computational predictor REVEL gives a score of 0.961 which is above the thresholds predicting a damaging (>0.75) impact on SLC6A8 function (PP3). When fibroblasts deficient for this SLC6A8 variant were grown in the presence of a physiological Cr concentration (25uM), the average creatine uptake was just above the detection limit, whereas in the control fibroblasts it was significantly higher (PMID: 17465020) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID:11700). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, July 13, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA256012/MONDO:0010305/027 2023-08-24 2023-08-24 X-linked inheritance HP:0001417 Inconclusive true CAID:CA182785 biolink:causes MONDO:0019501 infores:clingen CAID:CA182785 MONDO:0019501 PMID: Uncertain Significance BS1, PP4, PP3, PM3, PM2, BP2, BP4, BA1 The c.4000C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 1334. The filtering allele frequency of this variant in gnomAD v4.1 is 0.03882%, and the minor allele frequency is 0.05343% in the Admixed American population (PM2_Supporting, BA1, and BS1 not met). The computational predictor REVEL gives a score of 0.316, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function (BP4 and PP3 not met). This variant has been reported in 2 probands with nonsyndromic hearing loss, however, the evidence did not support a causative role for the variant. The variant was also identified in a proband presenting with a range of cardiac and developmental clinical features; however the variant was absent in an affected parent, and these clinical features are not associated with CDH23. Additionally, the variant has been seen as a single heterozygous variant in 6 individuals undergoing testing for hearing loss in whom a second CDH23 variant was not identified. All of these individuals also had additional variants reported that were classified as either VUS, likely pathogenic, or pathogenic (PM3 not met; SCV000297305.2, SCV000205132.4, SCV001822517.3). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: No criteria met (ClinGen Hearing Loss VCEP specifications version 2; 7/16/2025). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA182785/MONDO:0019501/005 2025-07-16 2025-09-23 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:64321 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0025061 infores:hetionet CHEBI:5790 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0242528 infores:hetionet CHEBI:38940 biolink:causes HP:0012086 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0522153 infores:hetionet CHEBI:6759 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0004604 infores:hetionet CHEBI:3048 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0233407 infores:hetionet CHEBI:9123 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0020555 infores:hetionet CAID:CA1139655402 biolink:causes MONDO:0015967 infores:clingen CAID:CA1139655402 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PP1_Strong PS4 The c.152dup variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, , causes a frameshift in the protein at codon 52 in transcript NM_175914.5, adding 5 novel amino acids before encountering a stop codon (p.(Ala52CysfsTer5)). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805 ). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and neonatal hypoglycemia that is responsive to diazoxide) (PP4_Moderate; PMID: 19566570). This variant segregated with diabetes with 6 meioses in one family (PP1_Strong; PMID: 19566570, internal lab contributors). In summary, c.152dup meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP4_Moderate, PP1_Strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139655402/MONDO:0015967/085 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31236 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0392025 infores:hetionet CHEBI:17347 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0007787 infores:hetionet CHEBI:28901 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0003123 infores:hetionet CHEBI:3286 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0017152 infores:hetionet CHEBI:167309 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0085631 infores:hetionet CHEBI:28445 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0009806 infores:hetionet CHEBI:68584 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0040822 infores:hetionet CHEBI:8776 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0020649 infores:hetionet CHEBI:3534 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0518015 infores:hetionet CHEBI:5132 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0232461 infores:hetionet CHEBI:4814 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0016204 infores:hetionet CHEBI:135005 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0232849 infores:hetionet CHEBI:9649 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0851578 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0029442 infores:hetionet CAID:CA628018362 biolink:causes MONDO:0009290 infores:clingen CAID:CA628018362 MONDO:0009290 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PM3 The NM_000152.5:c.1847dup (p.Asp616GlufsTer20) variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Asp616GlufsTer20), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009142 (1/109384 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. The variant was identified in a French patient with late onset Pompe disease (PMID 30155607). There is a ClinVar entry for this variant (Variation ID: 693996). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ) GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA628018362/MONDO:0009290/010 2023-05-26 2023-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:5118 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014534 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0332575 infores:hetionet NCBITaxon:28450 biolink:causes MONDO:0017775 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:28450 MONDO:0017775 CHEBI:63598 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0006277 infores:hetionet CHEBI:135925 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0018799 infores:hetionet NCBIGene:6016 biolink:causes MONDO:0014143 infores:monarchinitiative not_provided not_provided HGNC:10023 MONDO:0014143 uuid:c135cb72-b51f-48ef-95b5-f712174a6029 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47499 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0031256 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C2225524 infores:hetionet CHEBI:10101 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0151908 infores:hetionet CHEBI:94807 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0948594 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0162429 infores:hetionet CHEBI:6062 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0014591 infores:hetionet CHEBI:8382 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0085633 infores:hetionet CHEBI:75722 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018808 infores:hetionet CHEBI:4495 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0542203 infores:hetionet CHEBI:114785 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0232462 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0028077 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0020538 infores:hetionet CHEBI:7640 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0233407 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005052 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0022104 infores:hetionet CHEBI:63631 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0013428 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0079102 infores:hetionet CHEBI:63681 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0001807 infores:hetionet CHEBI:65173 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0004936 infores:hetionet CHEBI:31932 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0018681 infores:hetionet CHEBI:3478 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0232462 infores:hetionet CAID:CA367398947 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398947 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PP1 The c.1111T>C variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to arginine at codon 371 (p.(Cys371Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.98, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe)​, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Arg) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398947/MONDO:0015967/086 2023-08-09 2023-08-10 Semidominant inheritance HP:0032113 Supports CHEBI:135935 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0036974 infores:hetionet CHEBI:8412 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0547030 infores:hetionet CHEBI:2379 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0020651 infores:hetionet GO:0002574 biolink:causes CL:0000762 infores:ubergraph knowledge_assertion manual_agent GO:0002574 CL:0000762 CHEBI:15365 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0023530 infores:hetionet CHEBI:4779 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01084 UMLS:C0037199 infores:hetionet CHEBI:8028 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0002994 infores:hetionet CHEBI:2673 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0011606 infores:hetionet CHEBI:135920 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0549373 infores:hetionet CHEBI:31709 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0004936 infores:hetionet CHEBI:63631 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0428977 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0001339 infores:hetionet CHEBI:194135 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0015230 infores:hetionet CHEBI:50648 biolink:causes MONDO:0011959 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0085077 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0849918 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0849918 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0002871 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0522064 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0522064 infores:hetionet CHEBI:6456 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0012569 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2225524 infores:hetionet CHEBI:42797 biolink:causes MONDO:0012672 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0008350 infores:hetionet CHEBI:35553 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0012833 infores:hetionet CAID:CA042749 biolink:causes MONDO:0007750 infores:clingen CAID:CA042749 MONDO:0007750 PMID: Uncertain Significance BS3 BP4, BA1, PS3, PS1, BS1, PM5, PM2, PP3 The NM_000527.5(LDLR):c.292G>A (p.Gly98Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:BS3: Level 1 assays (PMID 28645073 - Jiang et al., 2017) performed using heterologous cells (CHO-ldlA7) with Western blot, flow cytometry and confocal microscopy, showed normal expression (95%), binding (98%) and uptake (110%), consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA042749/MONDO:0007750/013 2024-02-23 2024-12-02 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:82960 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0233414 infores:hetionet CHEBI:31980 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0023218 infores:hetionet CHEBI:47381 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0030554 infores:hetionet CAID:CA340937 biolink:causes MONDO:0044970 infores:clingen CAID:CA340937 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting PP1 The m.12848C>T (p.A171V) variant in MT-ND5 has been reported in one individual with primary mitochondrial disease to date, in a man with Leber Hereditary Optic Neuropathy (LHON). The variant was present at 54% heteroplasmy in blood (PMID: 16240359). The variant was present in his asymptomatic mother at 37% heteroplasmy in blood. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE suggests this variant is pathogenic (0.95, range 0-1; PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA340937/MONDO:0044970/015 2023-11-28 2025-06-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5855 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0151754 infores:hetionet CAID:CA169101 biolink:causes MONDO:0017623 infores:clingen CAID:CA169101 MONDO:0017623 PMID: Uncertain Significance PM2 PTEN c.304_306dupAAA (p.K102_P103insK) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA169101/MONDO:0017623/003 2017-11-08 2018-12-10 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50648 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0020458 infores:hetionet CHEBI:8245 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0016382 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0009806 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005003 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0149521 infores:hetionet CHEBI:5383 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0013144 infores:hetionet CHEBI:4708 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0232726 infores:hetionet CHEBI:39867 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0042024 infores:hetionet CHEBI:42797 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0028734 infores:hetionet CHEBI:8080 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0242350 infores:hetionet CAID:CA10584608 biolink:causes MONDO:0018947 infores:clingen CAID:CA10584608 MONDO:0018947 PMID:26199319 Likely Pathogenic PS4, PS3_Supporting, PM6, PP2, PM2_Supporting BP4, PP3 The NM_001005361.3:c.1678G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 560 (p.Glu560Lys). This variant is absent from gnomAD v4.1.0 (PM2_supporting). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.686, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function (no codes met). This variant has been reported in 2 probands with centronuclear myopathy (PS4; 1.0 pt.; PMIDs: 19122038, 22396310). This variant has been identified as a suspected de novo occurrence in one individual with centronuclear myopathy (PM6; PMID: 22396310). Membrane fission/dissociation assay using incubated DNM2 protein showed notably increased fission activity but reduced dissociation efficiency for the mutant indicating that this variant impacts protein function (PS3_supporting; PMID: 26199319). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PM6, PS3_Supporting, PM2_Supporting, PP2 (ClinGen Congenital Myopathies VCEP Specifications Version 1.0.0; 5/12/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584608/MONDO:0018947/148 2025-05-12 2025-06-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8863 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151766 infores:hetionet CHEBI:7601 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0022346 infores:hetionet CHEBI:6339 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0750394 infores:hetionet CHEBI:6923 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0025061 infores:hetionet CHEBI:3764 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0332575 infores:hetionet CHEBI:4702 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0917801 infores:hetionet CHEBI:47519 biolink:causes NCIT:C78492 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0221345 infores:hetionet CHEBI:182080 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0027497 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0234215 infores:hetionet CHEBI:28177 biolink:causes HP:0006543 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0600228 infores:hetionet CHEBI:2569 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0013144 infores:hetionet CAID:CA2573102976 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573102976 MONDO:0015967 PMID: Likely Pathogenic PVS1, PM2_Supporting The c.1391del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 464 (NM_000162.5), adding 150 novel amino acids before encountering a stop codon (p.(Gly464AlafsTer150)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1391del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573102976/MONDO:0015967/086 2023-06-18 2023-06-18 Semidominant inheritance HP:0032113 Supports CHEBI:119915 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0041582 infores:hetionet CHEBI:3175 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0035854 infores:hetionet CHEBI:9727 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0024299 infores:hetionet CHEBI:3312 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0039070 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0035243 infores:hetionet GO:0032888 biolink:causes GO:0007052 infores:ubergraph knowledge_assertion manual_agent GO:0032888 GO:0007052 CHEBI:8764 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0019079 infores:hetionet NCBIGene:1292 biolink:causes MONDO:0009714 infores:monarchinitiative not_provided not_provided HGNC:2212 MONDO:0009714 uuid:dba5d4ae-8f34-4ca8-a5f1-99ece29b2536 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3504 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0020639 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005466 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0917799 infores:hetionet CHEBI:617099 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0019080 infores:hetionet CAID:CA645293834 biolink:causes MONDO:0015924 infores:clingen CAID:CA645293834 MONDO:0015924 PMID: Likely Pathogenic PP3, PS1_Supporting, PM2_Supporting, PM1_Strong BP4, BA1, BS1 The BMPR2 c.1276+3A>T variant is a non-canonical splice site (+3) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with heritable PAH (PMID: 20534176). In silico prediction (SpliceAI = 0.97) indicates the variant will probably impact splicing with loss of the canonical donor site in intron 9 (PP3). This predicted splicing event matches a known likely pathogenic variant (c.1276+4A>G) within the same donor site (PS1_supporting) (PMID: 37352859). Exon skipping or use of a cryptic splice site would disrupt the region encoding the conserved intracellular kinase domain (PM1_strong). No familial segregation data were available, and no functional analysis has been reported for this variant. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PS1_supporting, PM2_supporting, PP3 (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645293834/MONDO:0015924/125 2025-04-29 2025-04-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4856 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0027497 infores:hetionet CHEBI:8382 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0031256 infores:hetionet CAID:CA290953790 biolink:causes MONDO:0100326 infores:clingen CAID:CA290953790 MONDO:0100326 PMID: Likely Pathogenic PM4, PP4_Strong, PM2_Supporting, PM3_Supporting BP7, PP1 The NM_000419.5(ITGA2B):c.1210+105A>G intronic variant is predicted, by SpliceAI (score 0.89), to cause gain of a donor splice site in intron 12. Electrophoresis gel results of PCR amplicons of platelet cDNA from patient TGP0060 confirmed that aberrant splicing occurred, and Sanger sequencing of the aberrant splice products found two mRNAs, one with a deletion of all of exon 13 coding sequence (p.Ile405_Asp465del) and the second with a 123 bp deletion (41 amino acids) in the exon 13 coding sequence (PM4; PMID: 31064749). The highest population minor allele frequency in gnomAD v4.1 is 0.00002539 (18/708848 alleles) in the European population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant has been reported in two Glanzmann thrombasthenia patients, homozygote TGP0060 of PMID: 31064749 (PM3_supporting) and compound heterozygote GT10 in PMID:25373348 (in trans with Likely Pathogenic variant c.3091del). At least one patient (Patient GT10 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PM4. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA290953790/MONDO:0100326/011 2024-12-17 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ NCBIGene:643418 biolink:causes MONDO:0013495 infores:monarchinitiative not_provided not_provided HGNC:23452 MONDO:0013495 uuid:822bbbcf-f0f1-4fe7-9602-4abe18f23f88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0042663 biolink:causes GO:0001711 infores:ubergraph knowledge_assertion manual_agent GO:0042663 GO:0001711 CHEBI:7936 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0016655 infores:hetionet CHEBI:46345 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0022107 infores:hetionet CAID:CA251528 biolink:causes MONDO:0009861 infores:clingen CAID:CA251528 MONDO:0009861 PMID:25596310PMID:25596310PMID:17935162PMID:25596310PMID:2014036 Pathogenic PP4_Moderate, PP3, PM3_Very Strong, PS3 PM2 PAH-specific ACMG/AMP criteria applied: PP3: tools predict damaging; PS3: 15.5-30% activity (PMID:2014036; PMID:25596310); PM3_VeryStrong: L48S, R408W, S349P, R243X (PMID:25596310; PMID:17935162); PP4_Moderate: (PMID:25596310). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PM3_VeryStrong, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251528/MONDO:0009861/006 2018-08-13 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27834 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0031542 infores:hetionet CHEBI:84883 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0013378 infores:hetionet CAID:CA8602667 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602667 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, PM3_Supporting PP3, PP4 The NM_000419.5(ITGA2B):c.2489T>G (p.Leu830Arg) missense variant has been reported in at least one homozygous patient (UPN 9 in PMID: 16879215; PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91048 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602667/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31859 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0151636 infores:hetionet CHEBI:45409 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085669 infores:hetionet CHEBI:7936 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0006142 infores:hetionet CAID:CA146028 biolink:causes MONDO:0017623 infores:clingen CAID:CA146028 MONDO:0017623 PMID:28677221 Benign BA1 PVS1, PM6, PM2, BP5, BP7, BS4, BS1, PP1, PP3, PP2, BS2, PM1, PM4, PM5, BP2, PS2, PS4, PS3, PS1 PTEN c.254-30dup (IVS4-30dup) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.01437 (1.437%, 3748/260,738 alleles) in the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA146028/MONDO:0017623/003 2019-11-22 2019-12-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3286 biolink:causes UMLS:C0919582 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0919582 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0221490 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0023895 infores:hetionet CHEBI:41423 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0008031 infores:hetionet CHEBI:100241 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0580413 infores:hetionet CHEBI:45924 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0014518 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0033117 infores:hetionet GO:0048374 biolink:causes GO:0048371 infores:ubergraph knowledge_assertion manual_agent GO:0048374 GO:0048371 CHEBI:3696 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151827 infores:hetionet CHEBI:100246 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0340865 infores:hetionet CHEBI:8382 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0003862 infores:hetionet NCBIGene:10309 biolink:causes MONDO:0014378 infores:monarchinitiative not_provided not_provided HGNC:18576 MONDO:0014378 uuid:279bef50-1bbe-455a-9a4a-3ee5b9dbae44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0010520 infores:hetionet CHEBI:7478 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0231218 infores:hetionet NCBITaxon:5721 biolink:causes MONDO:0002154 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5721 MONDO:0002154 CAID:CA658824399 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824399 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS4, PS2, PS3, PS1, BP2, BP1, BP4, BP3, BA1, PM6, BS1, BS4, BS3, BP5, BP7, PM3, PM1, PM4, PP1, PP4, PP2, PP3, BS2 The c.820del (p.Gln274AsnfsTer37) variant is a frameshift variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 310-480) is critical to protein function (PVS1_Strong). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). The variant is absent from gnomAD v2.1.1 and v3 with at least 20x coverage for RUNX1. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824399/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6909 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0151604 infores:hetionet CHEBI:8890 biolink:causes MONDO:0043775 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0035232 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0851341 infores:hetionet NCBIGene:22901 biolink:causes MONDO:0029141 infores:monarchinitiative not_provided not_provided HGNC:24102 MONDO:0029141 uuid:8a4b220b-e51c-4070-8dc2-d05014dd98d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7514 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0039231 infores:hetionet CHEBI:5165 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0002884 infores:hetionet NCBIGene:1736 biolink:causes MONDO:0958178 infores:monarchinitiative not_provided not_provided HGNC:2890 MONDO:0958178 uuid:a7fe1569-8bc8-4a09-9bbe-24ef9cc6a2cf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16467 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0151735 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042401 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151888 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0314719 infores:hetionet CHEBI:5165 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C1167965 infores:hetionet CHEBI:7986 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0002962 infores:hetionet CHEBI:8461 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0031542 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020649 infores:hetionet CHEBI:2611 biolink:causes HP:0002067 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0920289 infores:hetionet CHEBI:38562 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0009782 infores:hetionet CHEBI:144551 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0015397 infores:hetionet CHEBI:4911 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0020649 infores:hetionet CHEBI:5296 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0004238 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005089 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C1261473 infores:hetionet CHEBI:145499 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0341012 infores:hetionet CHEBI:9434 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0011603 infores:hetionet CHEBI:61049 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0037278 infores:hetionet CHEBI:9073 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C0020649 infores:hetionet GO:0072039 biolink:causes GO:0060993 infores:ubergraph knowledge_assertion manual_agent GO:0072039 GO:0060993 CHEBI:63608 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0039621 infores:hetionet UMLS:C0065374 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020461 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0340464 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0234913 infores:hetionet CHEBI:135530 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0232492 infores:hetionet CAID:CA410781238 biolink:causes MONDO:0021060 infores:clingen CAID:CA410781238 MONDO:0021060 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PS2 PP3, BA1, BP4, BS1 The NM_006767.4:c.848G>A variant in LZTR1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 283 (p.Arg283Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 5 probands with RASopathy (PS4_Moderate; PMID: 30368668, SCV000808536.4, GeneDx). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with RASopathy (PS2; PMID: 30368668, SCV000808536.4, GeneDx). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410781238/MONDO:0021060/094 2024-12-03 2025-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:84500 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0028734 infores:hetionet CHEBI:31413 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0178298 infores:hetionet CHEBI:194135 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0032227 infores:hetionet CHEBI:5165 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0011175 infores:hetionet CHEBI:8107 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0042963 infores:hetionet CAID:CA341517 biolink:causes MONDO:0008723 infores:clingen CAID:CA341517 MONDO:0008723 PMID: Benign BA1, BP4, BP2 The c.128G>A variant in ACADVL is well characterized as a benign polymorphism, being present in several VLCAD cases with alternate pathogenic variants (BP2; PMIDs: 11914034, 15210884, more in literature). The highest population minor allele frequency in gnomAD v2.1.1 is 0.17 in the East Asian population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.259, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP2; BP4 ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA341517/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4672 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0009806 infores:hetionet CHEBI:5864 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C3160947 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013595 infores:hetionet CHEBI:63599 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0042029 infores:hetionet CHEBI:50859 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0006826 infores:hetionet UNII:UMD7G2653W biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0013491 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0221717 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0221717 infores:hetionet CAID:CA410147897 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147897 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1166C>G (p.Ser389Trp) is a missense variant which has a REVEL score < 0.50 (0.286) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147897/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63581 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0012833 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0086543 infores:hetionet CHEBI:135930 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C2830004 infores:hetionet CHEBI:135736 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0024902 infores:hetionet CHEBI:144093 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0518988 infores:hetionet CHEBI:8707 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0162830 infores:hetionet CHEBI:134991 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0019080 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0403632 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0392025 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0235299 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0235299 infores:hetionet CAID:CA279960 biolink:causes MONDO:0015280 infores:clingen CAID:CA279960 MONDO:0015280 PMID:18042262 Pathogenic PM1, PS2_Very Strong, PM2, PP3, PP2 The c.169T>G (p.Phe57Val) variant in MAP2K2 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 18042262). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe57Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PM1, PM2, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA279960/MONDO:0015280/004 2017-05-09 2019-07-15 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:49960 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0027765 infores:hetionet CHEBI:9599 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0000737 infores:hetionet CHEBI:135925 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0009806 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0231303 infores:hetionet CHEBI:7824 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038002 infores:hetionet NCBIGene:6844 biolink:causes MONDO:0032900 infores:monarchinitiative not_provided not_provided HGNC:12643 MONDO:0032900 uuid:147ff3fe-fd12-4a6e-97bf-85f93a8ac95d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes MONDO:0003366 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1253936 infores:hetionet CHEBI:50729 biolink:causes MONDO:0012883 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0023487 infores:hetionet NCBIGene:11200 biolink:causes MONDO:0002629 infores:monarchinitiative not_provided not_provided HGNC:16627 MONDO:0002629 uuid:fad48cd7-d24e-422e-a3c6-10eae29f6dab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5280 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020615 infores:hetionet CHEBI:567361 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0015230 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0032285 infores:hetionet GO:0060405 biolink:causes GO:0007620 infores:ubergraph knowledge_assertion manual_agent GO:0060405 GO:0007620 CHEBI:17347 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0009450 infores:hetionet CAID:CA294667 biolink:causes MONDO:0010726 infores:clingen CAID:CA294667 MONDO:0010726 PMID: Likely Benign BS2 PM1, BP4, BS1 The p.Ala378Ser variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions. The p.Ala378Ser variant in MECP2 is present in 1 female and 1 male individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). In summary, the p.Ala378Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294667/MONDO:0010726/032 2023-05-22 2023-06-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:2955 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0003467 infores:hetionet CHEBI:5847 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0237849 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0037274 infores:hetionet CHEBI:3696 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0221423 infores:hetionet CHEBI:2469 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0037199 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0233472 infores:hetionet CAID:CA010307 biolink:causes MONDO:0005045 infores:clingen CAID:CA010307 MONDO:0005045 PMID: Uncertain Significance PP3 PP2, BA1, PM2, PM5, BP1, BS1, PS1, BP4 NM_000257.4(MYH7):c.115G>A (p.Val39Met) - This variant has been reported in individuals with HCM and other cardiomyopathies (PMIDs: 30052928, 27532257, 28798025, 27247418, 25637381, 25569433, 23299917, 18761664, 12707239), but is not statistically increased in individuals with HCM compared to controls [OR lower 95% CI <5]. Therefore, the PS4 criterion has not been applied. This variant is present in gnomAD (v2.1.1), but did not meet the threshold for PM2. Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). Therefore, this variant meets criteria for VUS based on PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010307/MONDO:0005045/002 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0010592 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0041969 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0021053 infores:hetionet CHEBI:45367 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0231528 infores:hetionet CHEBI:35778 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0043144 infores:hetionet CHEBI:49575 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0948089 infores:hetionet CHEBI:8404 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0038990 infores:hetionet CHEBI:6715 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0000737 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1861172 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042109 infores:hetionet CHEBI:4466 biolink:causes UMLS:C0235222 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0235222 infores:hetionet NCBIGene:24137 biolink:causes MONDO:0010740 infores:monarchinitiative not_provided not_provided HGNC:13339 MONDO:0010740 uuid:817f8f5b-f32d-4c77-ae24-51b56958dfa1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0041976 infores:hetionet CAID:CA410148122 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148122 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1102A>T (p.Met368Leu) is a missense variant which has a REVEL score < 0.50 (0.451) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148122/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45863 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0232492 infores:hetionet NCBIGene:5257 biolink:causes MONDO:0009868 infores:monarchinitiative not_provided not_provided HGNC:8927 MONDO:0009868 uuid:be6ccea0-aee1-4337-95b5-7f6d8a885836 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63630 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C2830004 infores:hetionet CHEBI:64355 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0001623 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0018418 infores:hetionet CHEBI:36791 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013390 infores:hetionet CHEBI:63605 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0030193 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0002170 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0003123 infores:hetionet NCBIGene:6885 biolink:causes MONDO:0008005 infores:monarchinitiative not_provided not_provided HGNC:6859 MONDO:0008005 uuid:fab41826-3d3f-4d33-96ea-2593b76ee294 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0428977 infores:hetionet CHEBI:3216 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0012569 infores:hetionet CHEBI:100241 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0438215 infores:hetionet CAID:CA024520 biolink:causes MONDO:0007783 infores:clingen CAID:CA024520 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, PS4, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with lysine at codon 1814 of the RYR1 protein, p.Met1814Lys. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, this individual had a second variant of uncertain significance in RYR1, p.Tyr2510His, PS4 was not implemented (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.81 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: None. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024520/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:7476 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C1956346 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0007971 infores:hetionet CHEBI:7907 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C0020649 infores:hetionet CHEBI:4798 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0231528 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002037 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0032226 infores:hetionet CHEBI:38940 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0020621 infores:hetionet CHEBI:499361 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0948594 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0413252 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0040046 infores:hetionet CHEBI:135530 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0018524 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0040034 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1112789 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1112789 infores:hetionet CHEBI:4657 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0037274 infores:hetionet CHEBI:2549 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0040822 infores:hetionet CHEBI:28148 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0220870 infores:hetionet NCBIGene:3757 biolink:causes MONDO:0013367 infores:monarchinitiative not_provided not_provided HGNC:6251 MONDO:0013367 uuid:a223c8e5-91a7-4265-989f-69da7d3d0a5e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3534 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0000737 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0341012 infores:hetionet CHEBI:3423 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0030312 infores:hetionet CHEBI:3723 biolink:causes HP:0004097 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0410740 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0009319 infores:hetionet CHEBI:15940 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0040264 infores:hetionet NCBITaxon:1313 biolink:causes MONDO:0005961 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1313 MESH:D012852 DB00415_MESH_D012852_1DB01603_MESH_D012852_1DB00759_MESH_D012852_1DB02703_MESH_D012852_1DB01017_MESH_D012852_1 CHEBI:520985 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0013456 infores:hetionet NCBIGene:9321 biolink:causes MONDO:0100325 infores:monarchinitiative not_provided not_provided HGNC:12305 MONDO:0100325 uuid:b84d6ced-63aa-4c2a-9821-91c066f04286 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0042509 biolink:causes GO:0007154 infores:ubergraph knowledge_assertion manual_agent GO:0042509 GO:0007154 CHEBI:3996 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0004093 infores:hetionet CHEBI:7601 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0008031 infores:hetionet CAID:CA10014379 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014379 MONDO:0011071 PMID: Uncertain Significance PS1, BP1, BP4, BP2, BP7, PVS1, PM5, PM3, PP2, PP3 NM_001754.5(RUNX1):c.683T>C (p.Leu228Pro) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014379/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4027 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0027424 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0029456 infores:hetionet CHEBI:63629 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0086565 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001828 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0155018 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0917798 infores:hetionet CHEBI:5130 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0026961 infores:hetionet GO:0060622 biolink:causes GO:0030154 infores:ubergraph knowledge_assertion manual_agent GO:0060622 GO:0030154 CAID:CA343726928 biolink:causes MONDO:0020367 infores:clingen CAID:CA343726928 MONDO:0020367 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PM6, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.713G>A variant in MYOC is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 238 (p.Ser238Asn). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.141, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (https://doi.org/10.21203/rs.3.rs-270413/v1), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343726928/MONDO:0020367/019 2022-08-28 2022-08-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA226531 biolink:causes MONDO:0100368 infores:clingen CAID:CA226531 MONDO:0100368 PMID: Pathogenic PM5, PM3_Strong, PP3_Moderate, PP1_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) is a missense variant predicted to replace arginine with tryptophan at position 91. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.0001329, with 16 alleles / 74990 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 4 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 35129589, 18722466). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.11+5G>A or NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) variants suspected in trans (1 point, PMIDs: 35129589, 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant was genotyped by next-generation sequencing analysis of 586 candidate genes which did not provide an alternative explanation for visual impairment (2 pts) and exhibits a phenotype including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), mild myopia, extinguished scotopic (0.5 pts) and photopic (1 pt) ERG responses, bone spicule pigmentation of the fundus (0.5 pts), white or yellow dots in fundus (2 pts), and nystagmus (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 total points, PMID: 31925606, PP4_Moderate). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PMID: 31925606, PP1_Moderate). The computational predictor REVEL gives a score of 0.852, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.22, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and predicts a damaging impact on splicing. Another missense variant in the same codon, NM_000329.3(RPE65):c.272G>A (p.Arg91Gln), has been classified as pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5). Splicing predictions using SpliceAI are equivalent for both of these variants. The variant exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 16754667, PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_strong, PP4_moderate, PP1_moderate, PP3_moderate, PM5, and PS3_supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226531/MONDO:0100368/120 2024-07-23 2024-07-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63598 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0149931 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0037199 infores:hetionet CHEBI:7565 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0340865 infores:hetionet CHEBI:10101 biolink:causes HP:0030831 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0035508 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0013220 infores:hetionet CHEBI:46195 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0030312 infores:hetionet CHEBI:71219 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0750394 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0015929 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0015929 infores:hetionet CHEBI:63612 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0013362 infores:hetionet GO:0003339 biolink:causes GO:0072283 infores:ubergraph knowledge_assertion manual_agent GO:0003339 GO:0072283 CHEBI:6541 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0239377 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0019112 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0037822 infores:hetionet CHEBI:8428 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0014457 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0013922 infores:hetionet CHEBI:31348 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C2047937 infores:hetionet CHEBI:63638 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013144 infores:hetionet NCBIGene:22995 biolink:causes MONDO:0013923 infores:monarchinitiative not_provided not_provided HGNC:29298 MONDO:0013923 uuid:8b217cef-8848-4698-b0ca-656cbe7453c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50838 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0042373 infores:hetionet CHEBI:15854 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0233407 infores:hetionet CHEBI:64312 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0011124 infores:hetionet CHEBI:4027 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0038362 infores:hetionet CHEBI:49662 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0018418 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0340726 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0973461 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0024115 infores:hetionet CHEBI:71415 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0027932 infores:hetionet CHEBI:4907 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0004096 infores:hetionet CHEBI:28748 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0438142 infores:hetionet CAID:CA229639 biolink:causes MONDO:0009861 infores:clingen CAID:CA229639 MONDO:0009861 PMID:27121329 Pathogenic PVS1, PP4_Moderate, PM2, PM3_Very Strong The c.593_614del (p.Tyr198fs) frameshift variant in PAH is predicted to undergo nonsense mediated-decay. This variant was reported in 9 patients with PAH deficiency (PMID 27121329, 26210745, 21871829, 26666653). A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329, 21871829). This variant was detected in trans with 3 pathogenic/LP variants (PMID 27121329) and in 6 patients with pathogenic/LP variants with unknown phasing (PMID 26210745, 21871829, 26666653). This variant is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 very strong, PM2, and PP4 moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229639/MONDO:0009861/006 2020-07-24 2020-07-24 Autosomal recessive inheritance HP:0000007 Supports CHEBI:116278 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0014742 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011616 infores:hetionet NCBIGene:23040 biolink:causes MONDO:0014678 infores:monarchinitiative not_provided not_provided HGNC:7623 MONDO:0014678 uuid:b739ed2d-e6b3-4adc-9cb6-388bdc8ee8df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4856 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0004936 infores:hetionet NCBIGene:7273 biolink:causes MONDO:0010870 infores:monarchinitiative not_provided not_provided HGNC:12403 MONDO:0010870 uuid:264f291e-23ae-4d53-9207-f0ac6806f932 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7931 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0030554 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0030312 infores:hetionet CHEBI:520985 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C2830004 infores:hetionet CHEBI:7465 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0233407 infores:hetionet CHEBI:5383 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0042109 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0008325 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0235431 infores:hetionet CHEBI:8356 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018800 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0221203 infores:hetionet CHEBI:8888 biolink:causes HP:0001269 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0018989 infores:hetionet CHEBI:84500 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0010200 infores:hetionet CHEBI:6128 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0023052 infores:hetionet CHEBI:50692 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0016199 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020649 infores:hetionet CHEBI:5062 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0030193 infores:hetionet CHEBI:10102 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0036974 infores:hetionet CHEBI:38940 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0013595 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0085632 infores:hetionet CHEBI:4814 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0037199 infores:hetionet CAID:CA410147305 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147305 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1334G>A (p.Ser445Asn) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a REVEL score < 0.50 (0.089) and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147305/MONDO:0011071/008 2025-03-26 2025-03-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA267687 biolink:causes MONDO:0009861 infores:clingen CAID:CA267687 MONDO:0009861 PMID:26666653PMID:26666653 Uncertain Significance PM3, PM2, PP4 The c.913-8A>G PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). It was detected in trans with the pathogenic variant c.1315+1G>A (ClinVar 576). This variant is absent from 1000G, ESP, and gnomAD databases. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267687/MONDO:0009861/006 2019-11-08 2019-11-08 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0075306 biolink:causes GO:0061794 infores:ubergraph knowledge_assertion manual_agent GO:0075306 GO:0061794 CHEBI:8378 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0042384 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0853019 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0853019 infores:hetionet UMLS:C0004609 biolink:causes EFO:0009852 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0392674 infores:hetionet CHEBI:5613 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0020615 infores:hetionet CHEBI:50673 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0001824 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0948594 infores:hetionet CAID:CA395129867 biolink:causes MONDO:0700272 infores:clingen CAID:CA395129867 MONDO:0700272 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PM5, PP1 The c.1684+1G>A variant in PALB2 occurs within the canonical splice donor (+1,2) of intron 4. Minigene analysis demonstrated that the variant impacts splicing by causing multicassette skipping of exons 4 and 5 which is predicted to result in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 30890586). This variant is absent from gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Strong(RNA), PM2_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA395129867/MONDO:0700272/077 2024-01-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:194135 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0235290 infores:hetionet CHEBI:50729 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0857093 infores:hetionet CHEBI:5103 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0034880 infores:hetionet CHEBI:44423 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C1443060 infores:hetionet CHEBI:209807 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0311468 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0032285 infores:hetionet CHEBI:63620 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020546 infores:hetionet CAID:CA414817725 biolink:causes MONDO:0044970 infores:clingen CAID:CA414817725 MONDO:0044970 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting PP1, PS1, PS3, PS2, PM5, PVS1, PM6 The m.13379A>G (p.H348R) variant in MT-ND5 has been reported in three individuals with LHON from two families (PMIDs: 31669237, 34177762; PS4_supporting). The two related individuals with LHON had this variant present at homoplasmy in blood and were haplogroup J (PMID: 34177762). No other details were provided on the family history of these two individuals. The third individual with LHON had the variant present at 47% in blood, 72% in urine, and homoplasmic in fibroblasts, and was haplogroup H5b. His healthy mother had the variant present at 45% blood, 78% urine, and not performed in fibroblasts, This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.56 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no functional studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414817725/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:50742 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0040053 infores:hetionet CHEBI:63629 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0151636 infores:hetionet CHEBI:71417 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0019080 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0020437 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0042109 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0033575 infores:hetionet CHEBI:53760 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013390 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0152128 infores:hetionet NCBIGene:57498 biolink:causes MONDO:0859184 infores:monarchinitiative not_provided not_provided HGNC:29508 MONDO:0859184 uuid:dbef31c2-e4ac-4e0d-b883-b3608ad22c60 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64355 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235896 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0021400 infores:hetionet CHEBI:8871 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C1384353 infores:hetionet CHEBI:45327 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0085633 infores:hetionet CHEBI:9763 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0151786 infores:hetionet CHEBI:28864 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0023380 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0041912 infores:hetionet CAID:CA3231911 biolink:causes MONDO:0012163 infores:clingen CAID:CA3231911 MONDO:0012163 PMID: Likely Benign PP4, BS1 PM5 NM_002185.5(IL7R):c.314G>A is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 105 (p.Ser105Asn). The filtering allele frequency (the lower threshold of the 95% CI of 143/44848) of the c.314G>A variant in IL7R is 0.003189 for East Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). Female with SCID (0.5 pt.), exome sequencing (0.5 pt.),T-B+ SCID (0.25 pt.); total : 1.25 pts. (PP4_met) (PMID: 30290665). Another missense variant c.315C>A, (p.Ser105Arg) in the same codon has been reported (classified as VUS by SCID VCEP) (PM5 not met)(PMID: 35482138).To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1_met,PP4_met (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA3231911/MONDO:0012163/119 2024-01-10 2024-01-10 Autosomal recessive inheritance HP:0000007 Contradicts true PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0151763 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0012797 infores:hetionet CHEBI:2038 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C1260880 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0341012 infores:hetionet CHEBI:40279 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0017152 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0235270 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0011849 infores:hetionet CHEBI:4551 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C3665347 infores:hetionet NCBIGene:6326 biolink:causes MONDO:0011904 infores:monarchinitiative not_provided not_provided HGNC:10588 MONDO:0011904 uuid:bb796798-32db-475b-9c57-0ca013cdc6c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9434 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0542571 infores:hetionet CAID:CA188783 biolink:causes MONDO:0007648 infores:clingen CAID:CA188783 MONDO:0007648 PMID: Likely Benign BS2_Supporting, BP7, PM2_Supporting, BP4 BP5, BS1, BS4, BS3, PM6, PVS1, PM1, PM3, PM4, PM5, PP2, PP3, PP1, PP4, BP1, BP2, BP3, BA1, PS4, PS2, PS1, PS3 The c.120G>A (p.Thr40=) variant results in a synonymous amino acid change in exon 2. Although this variant is absent from gnomAD (PM2_Supporting), it has been observed internally in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting, SCV000214188.4, SCV001041247.2). In addition, this variant is not predicted to result in aberrant splicing and is not highly conserved (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting, BP4, BP7, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA188783/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63791 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151744 infores:hetionet CHEBI:50729 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0030554 infores:hetionet CHEBI:6541 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020625 infores:hetionet CHEBI:55346 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151735 infores:hetionet CHEBI:10650 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C2047937 infores:hetionet NCBIGene:7421 biolink:causes MONDO:0010186 infores:monarchinitiative not_provided not_provided HGNC:12679 MONDO:0010186 uuid:aca56b43-4372-4f4e-95d6-be56a75eda09 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8327 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0002874 infores:hetionet CHEBI:60761 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0026821 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0035078 infores:hetionet CHEBI:9927 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0013404 infores:hetionet CAID:CA10652915 biolink:causes MONDO:0011071 infores:clingen CAID:CA10652915 MONDO:0011071 PMID: Benign BP2, BA1 PS1, PS4, PS3, BP4, PM6, PVS1, PM2, BP7, BS4, BS3, BS1, PM5, PM1, PM4, PP1, PP3 The RUNX1 c.*2467dup variant in the 3' UTR has an MAF of 0.006793 (0.68%, 285/41952 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 5 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10652915/MONDO:0011071/008 2020-05-13 2020-06-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4681 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0015469 infores:hetionet CHEBI:50859 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C2830004 infores:hetionet CHEBI:6888 biolink:causes MONDO:0015304 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0003708 infores:hetionet CAID:CA2695202182 biolink:causes MONDO:0100437 infores:clingen CAID:CA2695202182 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.35del (p.Gly12ValfsTer?) is a frameshift variant due to a 1-nucleotide deletion that introduces a premature stop codon after 56 amino acids within exon 2 of 15, which is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband, however, the available phenotypic details were not sufficient to meet one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent cone and/or rod electroretinogram responses (PMID: 12657579). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695202182/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance (primarily recessive with milder female expression) Supports CHEBI:8776 biolink:causes MONDO:0005240 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0022658 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008015 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0026603 infores:hetionet CHEBI:70746 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0015672 infores:hetionet CAID:CA512318950 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318950 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.171G>A (p.Pro57=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.95)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318950/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:3723 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0232492 infores:hetionet CHEBI:6149 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0392025 infores:hetionet CHEBI:391960 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0080274 infores:hetionet CHEBI:5134 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0687713 infores:hetionet CHEBI:82716 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0011603 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0027051 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020456 infores:hetionet CHEBI:40303 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0030554 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0497365 infores:hetionet CHEBI:3752 biolink:causes NCIT:C50638 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C3665346 infores:hetionet CHEBI:41879 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0917801 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0041969 infores:hetionet CHEBI:70735 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0024902 infores:hetionet CHEBI:4027 biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0042487 infores:hetionet CHEBI:7601 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0043352 infores:hetionet CAID:CA226477 biolink:causes MONDO:0100368 infores:clingen CAID:CA226477 MONDO:0100368 PMID: Pathogenic PM3_Strong, PVS1, PP4, PM2_Supporting NM_000329.3(RPE65):c.1067del (p.Asn356MetfsTer17) is a frameshift variant that introduces a premature stop codon into exon 10 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) or NM_000329.3(RPE65):c.11+5G>A variants confirmed in trans (2 points, PMID: 9326927, PMID: 37704110), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), decreased peripheral vision (1 pt), absent or severely decreased rod electroretinogram (ERG) responses (0.5 pts) and abnormal color vision or evidence of cone involvement on ERG (1 pt), which together are specific for RPE65-related recessive retinopathy (4 pts, PMID: 31273949, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_supporting, PM3_Strong and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226477/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6402 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0002962 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020517 infores:hetionet CHEBI:31859 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0023518 infores:hetionet NCBIGene:2956 biolink:causes MONDO:0013710 infores:monarchinitiative not_provided not_provided HGNC:7329 MONDO:0013710 uuid:a2742915-faff-4a20-b03f-277f42de6713 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9241 biolink:causes MONDO:0000620 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0346156 infores:hetionet NCBIGene:3236 biolink:causes MONDO:0008652 infores:monarchinitiative not_provided not_provided HGNC:5133 MONDO:0008652 uuid:2a6618a9-c443-4337-91e8-7ce164702c31 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63638 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0035304 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0855335 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0855335 infores:hetionet CHEBI:7936 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0086439 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0235416 infores:hetionet CHEBI:5959 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0026858 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0020517 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0027765 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0029408 infores:hetionet CHEBI:167309 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0020672 infores:hetionet CHEBI:3761 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0344232 infores:hetionet CHEBI:31981 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0011991 infores:hetionet CHEBI:135935 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0013362 infores:hetionet NCBIGene:340719 biolink:causes MONDO:0014172 infores:monarchinitiative not_provided not_provided HGNC:23044 MONDO:0014172 uuid:8175ebe4-f0b0-45ec-bb91-2ff91af503b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0010058 biolink:causes GO:0048364 infores:ubergraph knowledge_assertion manual_agent GO:0010058 GO:0048364 CHEBI:63607 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0020456 infores:hetionet NCBIGene:6664 biolink:causes MONDO:0014376 infores:monarchinitiative not_provided not_provided HGNC:11191 MONDO:0014376 uuid:9f0fca8d-1982-48e5-bfc6-2e798fe6a2de biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61049 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0149871 infores:hetionet CHEBI:10124 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0043352 infores:hetionet CHEBI:44915 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0026826 infores:hetionet CHEBI:40050 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0521591 infores:hetionet CHEBI:5165 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0042267 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0014130 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0027769 infores:hetionet CAID:CA194099 biolink:causes MONDO:0007648 infores:clingen CAID:CA194099 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS4, BS3, PVS1, PM2, PM6, PM5, PM4, PM3, PM1, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS2, PS3 The CDH1 c.163+4_163+6dupAGG variant occurs in the splice donor region of intron 2. This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in the gnomAD database (GRCh37) (http://gnomad.broadinstitute.org). This variant has been observed in more than ten individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000969083.1, SCV000216473.4, SCV000637738.2). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA194099/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:2704 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0262988 infores:hetionet UMLS:C0065374 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151539 infores:hetionet CHEBI:45863 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0020625 infores:hetionet CHEBI:6437 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0010200 infores:hetionet CHEBI:4672 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C3665347 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0000768 infores:hetionet CHEBI:5165 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0031256 infores:hetionet CHEBI:7903 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0235031 infores:hetionet CHEBI:7507 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00452 UMLS:C0442886 infores:hetionet CHEBI:28487 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00206 UMLS:C0027497 infores:hetionet CHEBI:2922 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0002874 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0038663 infores:hetionet CAID:CA645509328 biolink:causes MONDO:0015967 infores:clingen CAID:CA645509328 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong The c.1819dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 607, adding 42 novel amino acids before encountering a stop codon (p.(Gln607ProfsTer42) of NM_000545.8. While this variant, located in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein and add 16 additional amino acids to the end of the protein (PVS1_Strong). Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, c.1819dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1_Strong, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509328/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0392525 infores:hetionet CHEBI:63632 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0013404 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042373 infores:hetionet CHEBI:3515 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0235996 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0032961 infores:hetionet UMLS:C1738934 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0162285 infores:hetionet CAID:CA013546 biolink:causes MONDO:0004994 infores:clingen CAID:CA013546 MONDO:0004994 PMID:27532257PMID:25031304 Likely Benign PP3, BS1 PM2, PS4 The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3, BS1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013546/MONDO:0004994/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:16469 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C3665347 infores:hetionet CHEBI:2682 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0017178 infores:hetionet CHEBI:51041 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0151905 infores:hetionet CHEBI:9727 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C2979982 infores:hetionet CHEBI:32221 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0000737 infores:hetionet CHEBI:47499 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042109 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0152029 infores:hetionet CHEBI:5123 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0013384 infores:hetionet CHEBI:15640 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0033774 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0392025 infores:hetionet CHEBI:8890 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0235031 infores:hetionet CAID:CA915949635 biolink:causes MONDO:0011132 infores:clingen CAID:CA915949635 MONDO:0011132 PMID: Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1 NM_001369369.1(FOXN1):c.562del is a frameshift variant predicted to cause a premature stop codon and lead to nonsense mediated decay in a disease that is loss of function (PVS1). The variant has been found in at least one homozygous patient with SCID due to FOXN1 deficiency (PM3_supporting). This patient was whole exome sequenced and displayed phenotypes including alopecia, absent lymphocyte proliferation to PHA, and undetectable CD4+CD31+CD45RA+ recent thymic emigrants (PP4). The variant is absent from gnomADv4.0.0 (PM2_supporting). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup (specifications v1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA915949635/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Supports CHEBI:77260 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0232461 infores:hetionet CHEBI:6367 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0002878 infores:hetionet CHEBI:100241 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0018418 infores:hetionet CAID:CA2579830518 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830518 MONDO:0015967 PMID: Uncertain Significance PP4, PM2_Supporting, PM1_Supporting PP1 The c.-134T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within the HNF6/OC2 binding site of the promoter (c.-132 to c.-141) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.-134T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PP4, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830518/MONDO:0015967/085 2025-09-02 2025-09-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4681 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0030193 infores:hetionet GO:0002335 biolink:causes CL:0000785 infores:ubergraph knowledge_assertion manual_agent GO:0002335 CL:0000785 UMLS:C0010592 biolink:causes MONDO:0006637 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0022672 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0340726 infores:hetionet CHEBI:63599 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0549463 infores:hetionet CHEBI:9727 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0002874 infores:hetionet NCBIGene:23562 biolink:causes MONDO:0013537 infores:monarchinitiative not_provided not_provided HGNC:2035 MONDO:0013537 uuid:bca28df6-c69a-487c-a698-3809a4f9e9d6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50673 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0002874 infores:hetionet CHEBI:9435 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0009806 infores:hetionet CHEBI:404903 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042514 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0232492 infores:hetionet NCBITaxon:12086 biolink:causes MONDO:0017373 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:12086 MONDO:0017373 CHEBI:3181 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011603 infores:hetionet CHEBI:7865 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0026205 infores:hetionet CHEBI:16469 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0006142 infores:hetionet CHEBI:17026 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0001807 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011616 infores:hetionet CAID:CA160123 biolink:causes MONDO:0012163 infores:clingen CAID:CA160123 MONDO:0012163 PMID: Benign BS2_Supporting, BA1 The NM_002185.5(IL7R):c.1241C>T (p.Thr414Met) missense variant occurs at a frequency too high for the disease. The filtering allele frequency based on the South Asian population (upper bound of 95% CI of 1076/30502 observed alleles) is 0.03353 in gnomAD v2.1.1, which is above the SCID-VCEP BA1 threshold (>0.00566). Also, 46 adult homozygous individuals with this variant are present in gnomAD v2.1.1 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA160123/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:44032 biolink:causes MONDO:0002332 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0037997 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0239978 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0855242 infores:hetionet CAID:CA2579985999 biolink:causes MONDO:0010305 infores:clingen CAID:CA2579985999 MONDO:0010305 PMID: Pathogenic PVS1, PM2_Supporting, PP4_Strong The NM_005629.4:c.1235_1248del (p.Leu412GlnfsTer48) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay, in a gene in which loss-of-function is an established disease mechanism (PVS1). One male patient, with clinical features consistent with creatine transporter deficiency, elevated urine creatine/creatinine on one occassion, and reduced creatine peak on brain 1H-magnetic resonance spectroscopy, has been reported (PMID: 29435807) (PP4_Strong). The variant is absent in gnomad v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP, June 21, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579985999/MONDO:0010305/027 2023-06-21 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:5130 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0003864 infores:hetionet CHEBI:51137 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0030312 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0521491 infores:hetionet CHEBI:10023 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C2242588 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0039520 infores:hetionet CHEBI:45409 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0162830 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0037274 infores:hetionet NCBIGene:4625 biolink:causes MONDO:0013262 infores:monarchinitiative not_provided not_provided HGNC:7577 MONDO:0013262 uuid:aaa98337-f992-4d37-80a7-847707b5ecb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6954 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0016382 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0340464 infores:hetionet CHEBI:127342 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0085606 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0851341 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0702163 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0702163 infores:hetionet CHEBI:194135 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0687713 infores:hetionet CHEBI:31981 biolink:causes HP:0001000 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C1260926 infores:hetionet CHEBI:465284 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0947912 infores:hetionet CHEBI:8776 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0013404 infores:hetionet CHEBI:9150 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0026848 infores:hetionet NCBIGene:4647 biolink:causes MONDO:0700087 infores:monarchinitiative not_provided not_provided HGNC:7606 MONDO:0700087 uuid:34556c68-ad03-4429-a192-50ce43bbe7a6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4888 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0008031 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0314719 infores:hetionet CHEBI:520985 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0277925 infores:hetionet GO:0048345 biolink:causes GO:0048341 infores:ubergraph knowledge_assertion manual_agent GO:0048345 GO:0048341 CHEBI:44185 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0349506 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0003864 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0011991 infores:hetionet CHEBI:45863 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0019080 infores:hetionet CHEBI:5147 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0010709 infores:hetionet CHEBI:478164 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0013404 infores:hetionet CHEBI:31644 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0011168 infores:hetionet CHEBI:63580 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0007971 infores:hetionet CHEBI:78543 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C3665347 infores:hetionet CHEBI:5132 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0011849 infores:hetionet CHEBI:63580 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0025345 infores:hetionet CHEBI:84883 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0032584 infores:hetionet CHEBI:9168 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0006826 infores:hetionet CHEBI:36704 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C2830004 infores:hetionet CHEBI:50885 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0151740 infores:hetionet CHEBI:9328 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0030305 infores:hetionet CAID:CA229461 biolink:causes MONDO:0009861 infores:clingen CAID:CA229461 MONDO:0009861 PMID:18299955PMID:22106832PMID:18299955PMID:22106832 Likely Pathogenic PM4, PM2, PP4, PM3_Strong The c.169_171del in-frame deletion variant has been identified in at least 2 probands with phenotypes of mild to classic PKU (PMIDs: 18299955, 22106832). It has been detected in trans with pathogenic variants Ala403Val (PMID: 18299955) and c.1066-11G>A (PMID: 22106832). This variant is absent from 1000G, ESP, and gnomAD databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PM4, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229461/MONDO:0009861/006 2019-08-26 2019-08-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9123 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0024902 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0036983 infores:hetionet CHEBI:100241 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020443 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0475765 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0475765 infores:hetionet CHEBI:724125 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0027497 infores:hetionet CHEBI:6775 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0022354 infores:hetionet CHEBI:17334 biolink:causes NCIT:C34808 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0577559 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0029408 infores:hetionet CHEBI:6965 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0023530 infores:hetionet GO:0062042 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:0062042 GO:0007507 CHEBI:46345 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0027441 infores:hetionet CHEBI:31536 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0040034 infores:hetionet CHEBI:31859 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0014518 infores:hetionet CHEBI:6717 biolink:causes MONDO:0020108 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0002880 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0151773 infores:hetionet CHEBI:6067 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0241136 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027932 infores:hetionet CHEBI:3061 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0038990 infores:hetionet UMLS:C0145867 biolink:causes HP:0200114 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0220983 infores:hetionet CHEBI:74947 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020433 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009782 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0152027 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0152027 infores:hetionet GO:2000290 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:2000290 GO:0009790 CHEBI:47612 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0349506 infores:hetionet CHEBI:3723 biolink:causes MONDO:0015486 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0022578 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0851341 infores:hetionet CHEBI:51860 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0027424 infores:hetionet CAID:CA390887105 biolink:causes MONDO:0100216 infores:clingen CAID:CA390887105 MONDO:0100216 PMID: Uncertain Significance BP4 PM2, BA1, PP1, PP4, PP3, BS2, PM1, PM5, PS4, PS2, PS3, PS1, BS1, BS4, BS3 The NM_177438.3:c.1036T>G variant in DICER1 is a missense variant predicted to cause substitution of leucine by valine at amino acid 346 (p.Leu346Val). The total allele frequency in gnomAD v4.1.0 is 0.000006570 (1/152196 alleles) with a highest population minor allele frequency of 0.00002413 (1/41444 alleles) in African/African American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.261; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 04/23/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390887105/MONDO:0100216/024 2024-04-23 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63608 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0012833 infores:hetionet NCBIGene:402381 biolink:causes MONDO:0020855 infores:monarchinitiative not_provided not_provided HGNC:27845 MONDO:0020855 uuid:22932927-9fb3-4578-9888-c8d6b04369f5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0233414 infores:hetionet NCBIGene:55764 biolink:causes MONDO:0021093 infores:monarchinitiative not_provided not_provided HGNC:13556 MONDO:0021093 uuid:123a9f79-cc9b-422d-a37f-0b2a3c8029be biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9738 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0031117 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006879 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0030353 infores:hetionet CHEBI:50131 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0231528 infores:hetionet CHEBI:16469 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0600142 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0038814 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0262397 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0178298 infores:hetionet CHEBI:31709 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01362 UMLS:C0013404 infores:hetionet CHEBI:9613 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0033774 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0025061 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0011053 infores:hetionet CHEBI:8768 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0013395 infores:hetionet CHEBI:9571 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0001824 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0027813 infores:hetionet CHEBI:3723 biolink:causes HP:0041153 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0159877 infores:hetionet CHEBI:6950 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151603 infores:hetionet NCBITaxon:31704 biolink:causes MONDO:0005779 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:31704 MONDO:0005779 CAID:CA229841 biolink:causes MONDO:0009861 infores:clingen CAID:CA229841 MONDO:0009861 PMID:16256386PMID:9634518 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.907T>C (p.Ser303Pro) variant in PAH has been reported in 1 affected individual (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant is absent in population databases (PM2). This variant was detected with p.D282G (LP via PAH workgroup) (PM3; PMID: 16256386). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229841/MONDO:0009861/006 2019-04-03 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2611 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0234518 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0497247 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0235002 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235002 infores:hetionet CHEBI:6367 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0012569 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0013395 infores:hetionet CHEBI:8232 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0015967 infores:hetionet CHEBI:5118 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0043352 infores:hetionet CHEBI:9086 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C3665386 infores:hetionet CHEBI:63627 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0917801 infores:hetionet CHEBI:5138 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013456 infores:hetionet CHEBI:135888 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0019348 infores:hetionet CHEBI:6456 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C3665347 infores:hetionet NCBIGene:6890 biolink:causes MONDO:0971006 infores:monarchinitiative not_provided not_provided HGNC:43 MONDO:0971006 uuid:c5691340-4aa6-461a-b472-c48c957a1dc1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0032227 infores:hetionet CHEBI:63630 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0344232 infores:hetionet CHEBI:24564 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00488 UMLS:C0006826 infores:hetionet CHEBI:9943 biolink:causes MONDO:0041526 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0156543 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0005684 infores:hetionet CHEBI:6916 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0028738 infores:hetionet CHEBI:94609 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0015967 infores:hetionet CHEBI:64355 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151315 infores:hetionet CHEBI:45081 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0027424 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0853714 infores:hetionet UMLS:C0004609 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0031212 infores:hetionet CHEBI:68579 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0011603 infores:hetionet CHEBI:35677 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0016204 infores:hetionet CHEBI:39669 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0002792 infores:hetionet NCBIGene:7490 biolink:causes MONDO:0008682 infores:monarchinitiative not_provided not_provided HGNC:12796 MONDO:0008682 uuid:8e9cd4a9-1e4f-4d09-9088-1a738844ba4c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0005586 infores:hetionet CAID:CA10603769 biolink:causes MONDO:0009861 infores:clingen CAID:CA10603769 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate PM5, PM3, PP3 This c.1003A>G (p.Lys335Glu) variant in PAH was reported 1 time in a patient with PAH deficiency (>120 μmol/L Phe, BH4 deficiency ruled out (PMID: 26503515). Computational evidence for this missense variant is conflicting: damaging (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is absent from population databases gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA10603769/MONDO:0009861/006 2021-02-11 2022-06-05 Autosomal recessive inheritance HP:0000007 Inconclusive true GO:0044762 biolink:causes GO:0007269 infores:ubergraph knowledge_assertion manual_agent GO:0044762 GO:0007269 CHEBI:4466 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0020672 infores:hetionet NCBIGene:5950 biolink:causes MONDO:0014060 infores:monarchinitiative not_provided not_provided HGNC:9922 MONDO:0014060 uuid:8287a02d-c796-4e36-8381-8bb2b900d736 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7045 biolink:causes MONDO:0007377 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0007377 uuid:bd9cf1b6-e680-4fb6-b3e9-f7519ec9c46a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0039646 biolink:causes GO:0007049 infores:ubergraph knowledge_assertion manual_agent GO:0039646 GO:0007049 CHEBI:4511 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0040414 infores:hetionet CHEBI:27786 biolink:causes MONDO:0009891 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0032463 infores:hetionet CHEBI:6931 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0439857 infores:hetionet CHEBI:4511 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0015230 infores:hetionet CHEBI:72297 biolink:causes UMLS:C0580417 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0580417 infores:hetionet CHEBI:3757 biolink:causes HP:0000371 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0271429 infores:hetionet CHEBI:8356 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0600104 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013395 infores:hetionet CHEBI:48538 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0008031 infores:hetionet CHEBI:50730 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C2242588 infores:hetionet CHEBI:5123 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0037763 infores:hetionet GO:1905031 biolink:causes GO:0086001 infores:ubergraph knowledge_assertion manual_agent GO:1905031 GO:0086001 CHEBI:10100 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00549 UMLS:C0027947 infores:hetionet CHEBI:3478 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0151736 infores:hetionet GO:1903593 biolink:causes GO:0006955 infores:ubergraph knowledge_assertion manual_agent GO:1903593 GO:0006955 CHEBI:6775 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0542571 infores:hetionet CHEBI:135930 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0039231 infores:hetionet CHEBI:261649 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0019158 infores:hetionet CHEBI:6413 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0003862 infores:hetionet CHEBI:3752 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0232461 infores:hetionet GO:0110116 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0110116 GO:0150063 CHEBI:3640 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0027707 infores:hetionet CHEBI:44915 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0036974 infores:hetionet CHEBI:6792 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0033774 infores:hetionet CHEBI:6754 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C1610069 infores:hetionet CHEBI:31644 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0015967 infores:hetionet CHEBI:10127 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002874 infores:hetionet CHEBI:50777 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0036572 infores:hetionet CAID:CA410208072 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208072 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.548C>T (p.Pro183Leu) is a missense variant which is located within the Runt Homology Domain (AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It has a REVEL score ≥ 0.88 (0.966) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208072/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6076 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0013378 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0038663 infores:hetionet CHEBI:31401 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0008031 infores:hetionet CAID:CA410208001 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208001 MONDO:0011071 PMID: Uncertain Significance PM5_Supporting, PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.581A>C (p.Lys194Thr) is a missense variant which affects at least one of the following hotspot residues within the RHD: Lys194 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.949) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a missense change at the same residue (p.Lys194) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 561250) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208001/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:44915 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0220981 infores:hetionet CHEBI:5893 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C3160741 infores:hetionet NCBIGene:6389 biolink:causes MONDO:0013602 infores:monarchinitiative not_provided not_provided HGNC:10680 MONDO:0013602 uuid:b1303d58-f450-46a1-a6f9-14927c06672e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0009806 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0267792 infores:hetionet CHEBI:2666 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0235660 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0038661 infores:hetionet CHEBI:4798 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0002878 infores:hetionet CHEBI:6715 biolink:causes HP:0032408 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0024103 infores:hetionet CHEBI:617099 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0019158 infores:hetionet CAID:CA294161 biolink:causes MONDO:0007648 infores:clingen CAID:CA294161 MONDO:0007648 PMID: Likely Benign BS2 BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM1, PM3, PM4, PM5, PP1, PP4, PP2, PP3, BP2, BP1, BP4, BP3, BA1, PS4, PS3, PS2, PS1 The c.371G>A (p.Arg124His) missense variant has a frequency of 0.02010% in Africans (5/24870 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in ≥10 (31) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000637819.6, SCV000184938.6). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA294161/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:68534 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0948525 infores:hetionet CHEBI:474053 biolink:causes MONDO:0005972 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0155862 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0002622 infores:hetionet CHEBI:3764 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00257 UMLS:C0151904 infores:hetionet CHEBI:41423 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0030305 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0035078 infores:hetionet CHEBI:2639 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0011603 infores:hetionet CHEBI:3568 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0033247 infores:hetionet CHEBI:8871 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009917 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005711 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235833 infores:hetionet CHEBI:9649 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0027947 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0162429 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0024115 infores:hetionet CHEBI:45863 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C3263723 infores:hetionet CHEBI:127342 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0011603 infores:hetionet CHEBI:51450 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0038325 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0151705 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151705 infores:hetionet CHEBI:53760 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0027932 infores:hetionet NCBIGene:11160 biolink:causes MONDO:0957788 infores:monarchinitiative not_provided not_provided HGNC:1356 MONDO:0957788 uuid:99c922a7-3671-4b19-8396-8a07c441c83c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7577 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0232462 infores:hetionet CHEBI:31236 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0035455 infores:hetionet CHEBI:453011 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0041834 infores:hetionet CHEBI:64354 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0026821 infores:hetionet CHEBI:8768 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0027497 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0018939 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0020456 infores:hetionet CHEBI:145499 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0687713 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0277925 infores:hetionet CHEBI:110423 biolink:causes MONDO:0018378 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C2711248 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037274 infores:hetionet CHEBI:367163 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0021368 infores:hetionet CHEBI:499361 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0011991 infores:hetionet CHEBI:3387 biolink:causes MONDO:0018908 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0024305 infores:hetionet CAID:CA415079038 biolink:causes MONDO:0010305 infores:clingen CAID:CA415079038 MONDO:0010305 PMID: Likely Pathogenic PS3_Supporting, PP3, PM2_Supporting, PP4_Strong PS4 The NM_005629.4:c.541T>C variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a cysteine for an arginine at amino acid 181 (p.Cys181Arg). This variant has been previously reported in one male individual (PMID: 23644449, PMID: 21660517) who had elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 21660517) (PP4_Strong). This variant was reported to result in undetectable creatine transport activity when expressed in SLC6A8 deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.884 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415079038/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:4798 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0080274 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0042109 infores:hetionet CHEBI:68855 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0030554 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0041349 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235431 infores:hetionet CHEBI:144551 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0036974 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0009760 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0877127 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0877127 infores:hetionet GO:1903561 biolink:causes GO:0110077 infores:ubergraph knowledge_assertion manual_agent GO:1903561 GO:0110077 NCBIGene:10522 biolink:causes MONDO:0014357 infores:monarchinitiative not_provided not_provided HGNC:14677 MONDO:0014357 uuid:cf3af579-1607-4365-bb05-1d94ed42e78d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28241 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01113 UMLS:C0019158 infores:hetionet CHEBI:4562 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0031256 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0520532 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0520532 infores:hetionet CHEBI:27565 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0041969 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0234215 infores:hetionet CHEBI:91541 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0152198 infores:hetionet CHEBI:9654 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0004093 infores:hetionet CHEBI:3242 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0728899 infores:hetionet CHEBI:10124 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0041582 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853149 infores:hetionet CAID:CA8815488 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815488 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PVS1, PM2_Supporting, PM3_Strong The NM_000152.5:c.1822C>T (p.Arg608Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been identified in a patient with no GAA cross reactive immunological material in skin fibroblasts supporting that it is a loss of function variant (PMIDs 22252923, 32849613)(PVS1). This variant has been detected in at least 13 individuals reported to have Pompe disease. At least 10 patients, mostly East Asian, have been reported with features with high specificity for Pompe disease including documentation of laboratory values showing deficient GAA activity and/or clinical features consistent with infantile onset Pompe disease and/or treated with enzyme replacement therapy, all meeting the specifications for PP4_Moderate (PMID 21484825, 21940687, 23884227, 24269976, 26693141, 29124014, 29422078, 30360039, 31439017, 31875618, 32849613). Of the individuals with this variant who are reported to have Pompe disease, two individuals were compound heterozygous for the variant and a pathogenic variant; in one case, the variant was confirmed in trans with c.2662G>T (p.Glu888Ter)(PMID 31743840, ClinVar SCV SCV001371767.1), and in another case the variant was found in compound heterozygosity, phase unknown, with c.-32-13T>G (PMID 31545528)(phase unknown). Another individual was homozygous for the variant (PMID 29124014)(PM3_Strong). In addition, the variant was found in compound heterozygosity with the following variants, phase unknown - c.1935C>A (p.Asp645Glu) (PMID 24269976, 31439017), c.875A>G (p.Tyr292Cys)(PMID 21940687, 23884227, 30360039), c.1309C>T (p.Arg437Cys)(PMID 21940687, 23884227, 30360039), c.784G>A (p.Glu262Lys)(PMID 29422078), c.2238G>C (p.Trp746Cys)(PMID 28433475), c.953T>A (p.Met318Lys)(PMID 21484825), and c.1754+2T>A (PMID 26693141, 32849613), and it was confirmed in trans with c.2297A>C (p.Tyr766Ser)(PMID 31875618). The allelic data from these additional patients will be used in the assessment of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variant ID: 972803, 1 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting.Classification approved by the ClinGen LSD VCEP: Oct. 19th, 2021. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815488/MONDO:0009290/010 2021-10-26 2021-10-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7465 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0011206 infores:hetionet CAID:CA410147949 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147949 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP2, BP3, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1150C>A (p.Pro384Thr) is a missense variant which has a REVEL score ≥ 0.88 (0.88) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147949/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:465284 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0015230 infores:hetionet CHEBI:9927 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0850149 infores:hetionet CHEBI:78543 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0162285 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0409974 infores:hetionet NCBIGene:2137 biolink:causes MONDO:0044312 infores:monarchinitiative not_provided not_provided HGNC:3518 MONDO:0044312 uuid:bcd2e88c-8392-4f67-b926-66e9510c1545 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71417 biolink:causes EFO:0011060 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0919924 infores:hetionet CHEBI:421707 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0003467 infores:hetionet CHEBI:92712 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0234632 infores:hetionet GO:1903912 biolink:causes GO:0034976 infores:ubergraph knowledge_assertion manual_agent GO:1903912 GO:0034976 NCBIGene:59341 biolink:causes MONDO:0054551 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0054551 uuid:2d1d30dc-313a-4558-aef2-624c6e925408 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50122 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0086565 infores:hetionet CHEBI:48273 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0042109 infores:hetionet CHEBI:63623 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C1260880 infores:hetionet CHEBI:4027 biolink:causes MONDO:0009937 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0034091 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0087169 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0030312 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029456 infores:hetionet CHEBI:231425 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0042510 infores:hetionet CHEBI:135925 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0004093 infores:hetionet CHEBI:68595 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0041969 infores:hetionet CHEBI:63581 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0011849 infores:hetionet NCBIGene:84905 biolink:causes MONDO:0032654 infores:monarchinitiative not_provided not_provided HGNC:15992 MONDO:0032654 uuid:fdfa0173-fb64-44db-99d8-9613aaffbc64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0700225 infores:hetionet CAID:CA2573051036 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051036 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS1, PP1 The c.2186delT variant in the HNF1 homeobox A gene , HNF1A, causes a frameshift in the protein at codon 62 (NM_000545.8), adding 93 novel amino acids before encountering a stop codon (p.(Asn62LysfsTer93)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 26431509, 27236918). The nucleotide change c.185delA, which causes the same frameshift, has been classified as pathogenic by the ClinGen MDEP; however, PS1 is not applied to frameshift variants by the ClinGen MDEP. In summary, c.186delT meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051036/MONDO:0015967/017 2022-04-03 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports UNII:3QJA87N40S biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0015967 infores:hetionet CHEBI:499361 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0549249 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0340464 infores:hetionet CHEBI:64045 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0024902 infores:hetionet CHEBI:3485 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0013395 infores:hetionet CAID:CA229346 biolink:causes MONDO:0009861 infores:clingen CAID:CA229346 MONDO:0009861 PMID: Uncertain Significance PM3, PP3, PP4, PM2_Supporting The c.1101G>A (p.Leu367=) variant in PAH is reported in an individual with Classic PKU, in trans with p.R243Q. (PMID: 16256386) This variant is absent in population databases. Two splicing algorthms predict a deleterious effect (Human splicing finder: potential alteration of splicing; MaxEnt scan: +571.94% Variation). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229346/MONDO:0009861/006 2023-07-23 2023-07-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:119573 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151908 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0006840 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0235431 infores:hetionet CHEBI:92712 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0030193 infores:hetionet CHEBI:4887 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0042109 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0281981 infores:hetionet CAID:CA10585773 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585773 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PS3, PM2, PP3, PP4 BP4, BP2, BA1, PS1, PS2, BP7, BS1, BS4, BS3, PM4, PM5, PM1, PM3, PVS1, PM6, BS2, PP1 The NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4_Supporting, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PS3 - Level 1 assays: PMID 32015373:Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake.---- activity is below 70% of wild-type, so PS3 is Met.PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with FH criteria (CT>95th percentile, plus tendon xanthomata or pCHD in proband or 1st degree and hypercholesterolemia in family) from Spain (PMID: 11668640) and at least 1 index case with SB criteria for FH from China (PMID: 22353362), so PS4_Supporting is Met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.875.It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585773/MONDO:0007750/013 2022-03-25 2022-04-19 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:50173 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0085649 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0018418 infores:hetionet CHEBI:499361 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0021141 infores:hetionet CHEBI:135736 biolink:causes MONDO:0005642 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009766 infores:hetionet CHEBI:3640 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0018681 infores:hetionet CAID:CA024057 biolink:causes MONDO:0007783 infores:clingen CAID:CA024057 MONDO:0007783 PMID: Benign BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024057/MONDO:0007783/012 2021-03-17 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:50922 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0520966 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0033575 infores:hetionet CHEBI:8665 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0948525 infores:hetionet CHEBI:80630 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0546884 infores:hetionet CHEBI:9586 biolink:causes MONDO:0003619 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0036130 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0522058 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0522058 infores:hetionet CAID:CA1251444 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251444 MONDO:0013144 PMID: Likely Benign BS1, BP4 PM2 The c.299A>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 100 (p.Asp100Gly). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0002103, which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.141, which is below the threshold of 0.3, and the splice site predictor Splice AI indicate that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BP4 Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251444/MONDO:0013144/084 2024-08-16 2024-08-21 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:28001 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0162429 infores:hetionet CHEBI:6067 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151908 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0032529 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0032529 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020538 infores:hetionet CHEBI:77260 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0917801 infores:hetionet CHEBI:45367 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0000768 infores:hetionet CHEBI:71940 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0151766 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0852879 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0852879 infores:hetionet CHEBI:3478 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0741494 infores:hetionet CHEBI:5118 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0010200 infores:hetionet CHEBI:617099 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0151766 infores:hetionet CHEBI:5383 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C3263723 infores:hetionet CAID:CA386960397 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960397 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PM1, PP3, PP1, PP4 PS3 The c.474G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to asparagine at codon 158 (p.(Lys158Asn)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is critical for the protein’s function as defined by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Lys158Asn protein has a transactivation that is 50% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 10078571). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; Internal lab contributors, PMID: 10078571). Furthemore, one of these indivdiuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). This variant segregated with diabetes, with at least 2 informative meioses in 2 families (PP1; internal lab contributors). In summary, c.474G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.0, approved 8/11/2023): PM1, PM2_Supporting, PP3, PS4_Moderate, PP4, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960397/MONDO:0015967/017 2025-04-18 2025-04-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40303 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0002792 infores:hetionet CHEBI:3752 biolink:causes MONDO:0010911 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0033375 infores:hetionet CHEBI:4887 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0012833 infores:hetionet CHEBI:127342 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0009421 infores:hetionet CHEBI:6775 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0023530 infores:hetionet CHEBI:127342 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0025345 infores:hetionet NCBIGene:389207 biolink:causes MONDO:0013210 infores:monarchinitiative not_provided not_provided HGNC:31673 MONDO:0013210 uuid:3c8694c7-1acf-47e2-b544-fdde5d7d97d8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16467 biolink:causes UMLS:C0549433 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0549433 infores:hetionet CHEBI:63610 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0009676 infores:hetionet CAID:CA016210 biolink:causes MONDO:0004994 infores:clingen CAID:CA016210 MONDO:0004994 PMID: Uncertain Significance PM2, PP3 PM5, PM1, PM6, PM4, PP1, PS3, BA1, BS2, BS1, BS3, BS4, BP3, PS1, PS4, PS2, BP4, BP2, BP5, BP7, PVS1 The NM_000257.4(MYH7):c.5534G>A (p.Arg1845Gln) variant has been identified in 2 individuals with unspecified cardiomyopathy (van Lint FHM 2019 PMID: 30847666; GeneDx pers. comm.), in 1 individual with LVNC (van Waning 2020 PhD Thesis: https://repub.eur.nl/pub/124773/dissertation-van-Waning.pdf) and 1 individual with anthracycline-associated cardiomyopathy (Wasielewski 2014 PMID: 25332820); however, due to the nature of the associated phenotypes, this data is insufficient to apply the PS4 criterion. This variant has also been identified in 0.003% (1/34584) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon; however, it has been reported to cause myosin storage myopathy and the additional evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively (c.5533C>T p.Arg1845Trp- Variation ID 14114). Therefore, the PM5 criterion has not been applied. In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016210/MONDO:0004994/002 2021-11-19 2021-12-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:80630 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0019080 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0006840 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0424000 infores:hetionet CHEBI:101853 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0025160 infores:hetionet CHEBI:16469 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0030554 infores:hetionet CHEBI:15544 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020461 infores:hetionet CHEBI:27899 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0428977 infores:hetionet CHEBI:47780 biolink:causes MONDO:0001744 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0017605 infores:hetionet CHEBI:3127 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0003467 infores:hetionet CHEBI:3223 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0011991 infores:hetionet CHEBI:4495 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0013604 infores:hetionet CHEBI:3994 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0001824 infores:hetionet CHEBI:681569 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0948441 infores:hetionet CHEBI:36791 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0043037 infores:hetionet CAID:CA197209 biolink:causes MONDO:0700270 infores:clingen CAID:CA197209 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Very Strong, PVS1 The ATM c.2T>C (p.M1?) variant impacts the initiation codon and is not expected to produce a fully functional protein (PVS1). This variant has been observed in a compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 22146522, 3054930, 12552559, PM3_VeryStrong). This alteration has an allele frequency below 0.001% in the European (non-Finnish) subpopulation in GnomAD (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA197209/MONDO:0700270/020 2022-03-16 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:473990 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C2830004 infores:hetionet CHEBI:47780 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0030193 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0012833 infores:hetionet CHEBI:6754 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0013604 infores:hetionet CHEBI:15552 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C2830004 infores:hetionet CHEBI:7444 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0002170 infores:hetionet CHEBI:9635 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0017601 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0040034 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0700184 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0234192 infores:hetionet CHEBI:63580 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0022904 infores:hetionet CHEBI:50223 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0027497 infores:hetionet CHEBI:34385 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0020649 infores:hetionet CHEBI:42068 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0878544 infores:hetionet CHEBI:8207 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0020458 infores:hetionet CHEBI:5790 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0012569 infores:hetionet NCBIGene:6794 biolink:causes MONDO:0008280 infores:monarchinitiative not_provided not_provided HGNC:11389 MONDO:0008280 uuid:0fe73ebd-6a0b-49c6-b9fd-674d698d70c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6620 biolink:causes MONDO:0007488 infores:monarchinitiative not_provided not_provided HGNC:11140 MONDO:0007488 uuid:7622cab1-4fba-4906-be08-d60da087b553 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0042998 infores:hetionet CHEBI:8093 biolink:causes HP:0100832 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0016242 infores:hetionet CHEBI:63610 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0040034 infores:hetionet CHEBI:3048 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0009806 infores:hetionet CHEBI:82960 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0011991 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006147 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0020538 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0020649 infores:hetionet CAID:CA902628 biolink:causes MONDO:0100368 infores:clingen CAID:CA902628 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.74C>T is a missense variant predicted to replace proline with leucine at position 25 in exon 2 of RPE65. This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 18599565). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were either compound heterozygous with the c.893del p.Lys298fs variant confirmed in trans (1 pt), with the Arg515Trp variant suspected in trans (0.5 pts), or with the c.11+5G>A variant suspected in trans (0.5 pts), PMIDs: 35001204, 36672611, 30025081), which were all previously classified as pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). This variant has also been reported in additional probands in the compound heterozygous state with the Ala434Glu or Tyr79His variants, but these cases were not considered to avoid circularity in the application of the PM3 code or due to insufficient phenotype data (PMIDs 29033008, 32581362, 22807296). At least one proband harboring this variant exhibits a phenotype including significant, documented improvement of dark-adapted vision after treatment with RPE65 gene therapy (8 pt), congenital night blindness (0.5 pt), nystagmus (1 pt), decreased central visual acuity (1 pt), and onset between birth and age five years (1 pt), which together are highly specific for RPE65-related recessive retinopathy (11.5 points, PMID: 36672611, PP4_Moderate). The variant exhibited 7.75% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 18599565). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001, with 1/30582 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Strong, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM3_Supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA902628/MONDO:0100368/120 2024-04-22 2024-04-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:64317 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01064 UMLS:C0034063 infores:hetionet CHEBI:5558 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0030554 infores:hetionet CAID:CA410208153 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208153 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS4, PS3, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, PM6, PVS1, BP7, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.512A>T (p.Lys171Ile) is a missense variant which has a REVEL score ≥ 0.88 (0.942) (PP3). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208153/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15765 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0004134 infores:hetionet UMLS:C0017797 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0038358 infores:hetionet CHEBI:3219 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0042029 infores:hetionet CHEBI:50275 biolink:causes HP:0500167 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0853890 infores:hetionet GO:1903221 biolink:causes GO:1902969 infores:ubergraph knowledge_assertion manual_agent GO:1903221 GO:1902969 CHEBI:134991 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C1306341 infores:hetionet CHEBI:50730 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0001807 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0920193 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0920193 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0019360 infores:hetionet CHEBI:71941 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0008031 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0042109 infores:hetionet CAID:CA228567 biolink:causes MONDO:0015630 infores:clingen CAID:CA228567 MONDO:0015630 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS4_Moderate PP1 The NM_000552.5(VWF):c.4244G>A (p.Gly1415Asp) missense variant has been reported in at least 4 unrelated probands with a phenotype consistent with VWD Type 2M (PS4_Moderate, PMID: 28971901, PMID: 16985174). At least 2 of these probands displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio, low collagen binding, and normal VWF high-MW multimers, which together are highly specific for VWD Type 2M (PP4_Moderate, PMID: 29924855). Low FVIII activity, an inconsistent phenotype, was also reported in these patients, as well as low VWF antigen. The computational predictor REVEL gives a score of 0.823, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Moderate, PP4_moderate, PP3, and PM2_supporting. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA228567/MONDO:0015630/081 2024-08-13 2024-08-13 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:55624 biolink:causes MONDO:0014929 infores:monarchinitiative not_provided not_provided HGNC:19139 MONDO:0014929 uuid:543986d8-7ead-4f7a-9d61-8ed252e4bd9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA278077 biolink:causes MONDO:0015924 infores:clingen CAID:CA278077 MONDO:0015924 PMID: Likely Pathogenic PS3_Supporting, PM5_Supporting, PP3, PM2_Supporting, PS4 PP2, BP1, BP4, BA1, PS1, BS1 The NM_001204.7(BMPR2) c.1040A>C variant is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 347 (p.Cys347Tyr). This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The computational predictor REVEL gives a score of 0.939, which is above the thresholds predicting a damaging impact on BMPR2 function (PP3). A different change affecting the same amino acid (c.1039T>C p.(Cys347Arg); PMID: 26387786) has been reported as likely pathogenic (PM5_supporting). Cytoplasmatic retention assay demonstrates impaired signaling with subcellular localization in HeLa cells showing retainment in endoplasmatic reticulum, not significantly different to empty plasmid. However, this analysis lacks validation controls (PMID: 12045205; PS3_supporting). This variant has been reported in 5 probands meeting pulmonary arterial hypertension criteria (PS4 ; PMIDs 10973254; 26645265; 29631995; 31727138). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PS4, PP3, PM5_supporting, PS3_supporting (VCEP specifications version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA278077/MONDO:0015924/125 2024-05-01 2024-05-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64355 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0341012 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0030486 infores:hetionet NCBIGene:55240 biolink:causes MONDO:0014094 infores:monarchinitiative not_provided not_provided HGNC:24592 MONDO:0014094 uuid:c51912b2-1562-49b1-b750-4eec808f95e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0178298 infores:hetionet NCBIGene:4853 biolink:causes MONDO:0007057 infores:monarchinitiative not_provided not_provided HGNC:7882 MONDO:0007057 uuid:3a3b9f84-3688-4ff1-af26-d9ef85602bed biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0235032 infores:hetionet NCBIGene:54800 biolink:causes MONDO:0859372 infores:monarchinitiative not_provided not_provided HGNC:25947 MONDO:0859372 uuid:30245cc9-34c4-4ac3-a88a-391ceb03ade2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0020443 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020517 infores:hetionet CHEBI:2469 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0086565 infores:hetionet CHEBI:16755 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0028734 infores:hetionet CAID:CA10014374 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014374 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.697C>T (p.Arg233Cys) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014374/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45409 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0019214 infores:hetionet CHEBI:84500 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C3263723 infores:hetionet CAID:CA115937 biolink:causes MONDO:0700270 infores:clingen CAID:CA115937 MONDO:0700270 PMID:19431188 Pathogenic PM3_Very Strong, PS3_Supporting, PVS1 BA1, BS1, PM2, PP4 The ATM c.9139C>T (p.Arg3047Ter) variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is above the PM2 threshold of 0.001% but below the BS1 threshold of 0.05%. This variant is expected to produce an NMD-escaping transcript that adversely affects the critical FATKIN domain (PVS1). This variant has been observed in a compound heterozygous state (confirmed) in multiple individuals with ataxia-telangiectasia (PMIDs: 10980530, 26628246, 19691550, 22649200, PM3_verystrong). This variant is non-functional in a single ATM-specific protein assay (PMID: 19431188, PS3_supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA115937/MONDO:0700270/020 2022-03-18 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:39669 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0002994 infores:hetionet GO:2001074 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:2001074 GO:0001823 CHEBI:9570 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0035078 infores:hetionet CAID:CA134759 biolink:causes MONDO:0021060 infores:clingen CAID:CA134759 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.909A>C (p.Thr303=) variant in the RAF1 gene is 0.0285% (27/66658) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134759/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CAID:CA229334 biolink:causes MONDO:0009861 infores:clingen CAID:CA229334 MONDO:0009861 PMID: Uncertain Significance PM2, PP4_Moderate, BP4, PM3_Strong PP3 The c.1089G>T (p.Lys363Asn) variant in PAH has been reported in 3 patients with mild HPA and mild PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out. It was detected in trans with pathogenic variants Phe55Leufs*6 (PMID: 27121329) and c.442-1G>A (PMID: 29316886). This variant is absent in population databases. However, multiple lines of computation evidence suggest no impact on the PAH protein. In summary, computational evidence conflicts with case level evidence and is therefore classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229334/MONDO:0009861/006 2021-02-26 2021-02-26 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:70735 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0013395 infores:hetionet NCBIGene:6134 biolink:causes MONDO:0030908 infores:monarchinitiative not_provided not_provided HGNC:10298 MONDO:0030908 uuid:99ea0749-c8db-43bf-b0d1-9dc8c0567445 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28830 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0021141 infores:hetionet CHEBI:5138 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0019112 infores:hetionet CHEBI:52172 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0151578 infores:hetionet CHEBI:119915 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0151529 infores:hetionet CHEBI:27666 biolink:causes HP:0025322 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0948441 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0281839 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0281839 infores:hetionet CHEBI:9907 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0023530 infores:hetionet CHEBI:135876 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0042963 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0344315 infores:hetionet CHEBI:38940 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0235378 infores:hetionet NCBIGene:6010 biolink:causes MONDO:0012498 infores:monarchinitiative not_provided not_provided HGNC:10012 MONDO:0012498 uuid:e1455d20-a63b-40e4-b15b-4f49506e834c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151883 infores:hetionet NCBIGene:6674 biolink:causes MONDO:0014216 infores:monarchinitiative not_provided not_provided HGNC:11212 MONDO:0014216 uuid:69bfbb45-ccc7-44f4-bef9-3a7cf3a2311b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68478 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151603 infores:hetionet CHEBI:47780 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0043094 infores:hetionet NCBIGene:54101 biolink:causes MONDO:0008959 infores:monarchinitiative not_provided not_provided HGNC:496 MONDO:0008959 uuid:8c941cb5-12e9-4ac8-99c9-e1e3cc715d73 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:72323 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0011849 infores:hetionet NCBIGene:1646 biolink:causes MONDO:0013664 infores:monarchinitiative not_provided not_provided HGNC:385 MONDO:0013664 uuid:6b12d718-6c13-46e5-844a-93140d28bcef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0879264 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151602 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0740425 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0740425 infores:hetionet CHEBI:17549 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151662 infores:hetionet CHEBI:16714 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0016382 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0851341 infores:hetionet NCBIGene:4688 biolink:causes MONDO:0009310 infores:monarchinitiative not_provided not_provided HGNC:7661 MONDO:0009310 uuid:5f65a9df-cfa0-444f-9094-323858b1f8fc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:55346 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020621 infores:hetionet CHEBI:68579 biolink:causes HP:0100310 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0238154 infores:hetionet CAID:CA10360634 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360634 MONDO:0010725 PMID: Likely Benign BS1 BP4, PP3 The NM_000330.4(RS1):c.478C>T variant is a missense variant encoding the substitution of Arginine with Cysteine at amino acid 160. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00002772 among hemizygous individuals, with 11 variant alleles / 396847 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.00002 (BS1). The computational predictor REVEL gives a score of 0.391, which is between the ClinGen X-linked IRD VCEP thresholds of >0.664 to <0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Collectively, the BP4 and PP3 codes are not met. In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BS1 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360634/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:4710 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0013144 infores:hetionet CHEBI:7959 biolink:causes MONDO:0001705 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0034902 infores:hetionet CHEBI:2668 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0015230 infores:hetionet CHEBI:3757 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0015672 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0235351 infores:hetionet CHEBI:45863 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0038362 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0858751 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0858751 infores:hetionet NCBIGene:9343 biolink:causes MONDO:0012516 infores:monarchinitiative not_provided not_provided HGNC:30858 MONDO:0012516 uuid:17b6f67a-3345-4211-b966-437aae3d3cdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:15G12L5X8K biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0039231 infores:hetionet CHEBI:63598 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0030312 infores:hetionet CHEBI:36704 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0234233 infores:hetionet CHEBI:44185 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0041969 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0948349 infores:hetionet CHEBI:42944 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0003811 infores:hetionet CHEBI:567361 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0151825 infores:hetionet GO:0060629 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0060629 GO:0019953 CHEBI:175901 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0267792 infores:hetionet CHEBI:3638 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0542184 infores:hetionet CHEBI:5098 biolink:causes UMLS:C1112214 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C1112214 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003850 infores:hetionet CHEBI:68584 biolink:causes UMLS:C0541832 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0541832 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0267596 infores:hetionet CHEBI:4702 biolink:causes HP:0034808 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1142349 infores:hetionet CHEBI:9215 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0020517 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011991 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0020651 infores:hetionet CHEBI:82960 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0016436 infores:hetionet CHEBI:8207 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0038362 infores:hetionet CHEBI:83531 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0027769 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0013395 infores:hetionet CHEBI:2611 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0013404 infores:hetionet CHEBI:50122 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0948089 infores:hetionet NCBITaxon:816 biolink:causes MONDO:0006671 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:816 MONDO:0006671 UMLS:C0120107 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0003123 infores:hetionet CHEBI:37333 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0520966 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0017601 infores:hetionet CHEBI:52172 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0740394 infores:hetionet CHEBI:3310 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00258 UMLS:C0009676 infores:hetionet CHEBI:47612 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0009450 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0003123 infores:hetionet CHEBI:63607 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0018802 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0562057 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0562057 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0021053 infores:hetionet CHEBI:3216 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0006266 infores:hetionet CHEBI:145499 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0235266 infores:hetionet UNII:D27V6190PM biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0020580 infores:hetionet CHEBI:63612 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0011570 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0036572 infores:hetionet CHEBI:2379 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0259817 infores:hetionet CHEBI:7445 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0085595 infores:hetionet CAID:CA018416 biolink:causes MONDO:0005045 infores:clingen CAID:CA018416 MONDO:0005045 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PP2, PP3 BA1, BP4, PS1, PS2, PS3, BS1, BS4, BS3, BP5, PM5, PM1, PM4, PVS1, PM6, PP1 NM_001018005.2(TPM1):c.842T>C (p.Met281Thr) - This variant has been reported in individuals with HCM (PMIDs: 12860912, 18533079, 21835320, 25524337, 27532257) and is statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >5]. Therefore, the PS4_Supporting criterion has been applied. This variant is present in gnomAD (v2.1.1), but did meet the threshold for PM2_Supporting. This variant lies in a gene where variants are statistically more likely to be disease-associated (PP2; PMID: 30696458). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). In summary, this variant is classified as Uncertain Significance for HCM in an autosomal dominant manner based on PS4_Supporting, PM2_Supporting, PP2, and PP3. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA018416/MONDO:0005045/100 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9586 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C2047937 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0005779 infores:hetionet CHEBI:31413 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0013362 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0011849 infores:hetionet CHEBI:8805 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0038325 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0178421 infores:hetionet CHEBI:9352 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0016382 infores:hetionet CHEBI:8327 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01324 UMLS:C0232462 infores:hetionet CHEBI:4995 biolink:causes MONDO:0001549 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0019061 infores:hetionet CHEBI:63627 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0017675 infores:hetionet CHEBI:4975 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0013604 infores:hetionet CHEBI:27974 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C1291077 infores:hetionet CAID:CA1244164 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244164 MONDO:0005338 PMID:27092720PMID:27092720 Uncertain Significance PP3, PM2_Supporting, PS4_Supporting BP7, BS1, BS3, PP1, PM5, PM4, PS3, PS1, PS2, BP4, BA1 The c.731G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 244 (p.Gly244Val). The highest minor allele frequency of this variant was in the Remaining genetic ancestry group of gnomAD (v4.1.0) = 0.00004807 (3 alleles out of 62,404), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.748, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Gly244Val protein had similar secretion levels to wild type myocilin protein in this study (PMID: 27092720). The assay did not meet the OddsPath threshold for BS3_Supporting (< 4.8). No segregations have been reported in individuals carrying this variant and no other likely pathogenic or pathogenic variant. 2 probands with primary open angle glaucoma have been reported carrying this variant (PMID:17210859, E. Souzeau (pers. comm.)), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3, PS4_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244164/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71219 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0011603 infores:hetionet CHEBI:8863 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0019079 infores:hetionet CAID:CA10608383 biolink:causes MONDO:0005338 infores:clingen CAID:CA10608383 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.239C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Asparagine at amino acid 80 (p.Thr80Asn). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.000001696 (2 alleles out of 1,178,954), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.083, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma, thus PS4 did not apply. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA10608383/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135939 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0004245 infores:hetionet CHEBI:2666 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0011603 infores:hetionet CHEBI:36791 biolink:causes HP:0004097 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0410740 infores:hetionet CHEBI:6690 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0206061 infores:hetionet CHEBI:3614 biolink:causes UMLS:C0009144 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0009144 infores:hetionet CHEBI:17334 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0023066 infores:hetionet CHEBI:6887 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0013384 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0243026 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0027765 infores:hetionet CHEBI:51209 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0015967 infores:hetionet CHEBI:7936 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1609512 infores:hetionet CHEBI:4466 biolink:causes MONDO:0004646 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0011127 infores:hetionet NCBIGene:2317 biolink:causes MONDO:0007168 infores:monarchinitiative not_provided not_provided HGNC:3755 MONDO:0007168 uuid:7b283826-9b31-4433-aace-71f7fd3c04d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:39112 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0042109 infores:hetionet CHEBI:17688 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0085649 infores:hetionet CHEBI:3216 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0037763 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0160390 infores:hetionet CHEBI:50173 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0042963 infores:hetionet CHEBI:180905 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0032617 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0017566 infores:hetionet CHEBI:2469 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0030305 infores:hetionet CHEBI:135613 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0232487 infores:hetionet CAID:CA410207205 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207205 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1): c.619C>G (p.Arg207Gly) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207205/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA6831670 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831670 MONDO:0015967 PMID: Likely Benign BS3_Supporting, BS1 PS4, PM2, PP3, PP4 The c.142G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to lysine at codon 48 (p.(Glu48Lys)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). Functional studies demonstrated the p.Glu48Lys protein has normal nuclear localization, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 27899486). This variant was identified in at least 5 unrelated individuals with diabetes, but members of at least two families had evidence of autoimmunity; also, the variant does not meet the PM2_Supporting cutoff (PMID: 15928245, internal lab contributor). Therefore, PS4 could not be applied. This variant was not identified in any individuals with calculated MODY probability >=50%; therefore, PP4 could not be applied. In summary, c.142G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BS1, BS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831670/MONDO:0015967/017 2022-04-08 2022-07-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:4453 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0027651 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0149931 infores:hetionet NCBIGene:57122 biolink:causes MONDO:0032692 infores:monarchinitiative not_provided not_provided HGNC:29914 MONDO:0032692 uuid:0fa5e0a6-3f33-4bc2-9ba5-94a69d202e8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2379 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C3665386 infores:hetionet CHEBI:75246 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0009938 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151826 infores:hetionet CHEBI:63598 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0009319 infores:hetionet CHEBI:41879 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0026848 infores:hetionet CHEBI:31401 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0040479 infores:hetionet CHEBI:45409 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0000731 infores:hetionet CAID:CA242118 biolink:causes MONDO:0015152 infores:clingen CAID:CA242118 MONDO:0015152 PMID: Likely Pathogenic PM3_Strong, PM4, PP4, PM2_Supporting PS1, PS3, PS2, PS4, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM1, BS2, PP2, PP3, PP1, BP3, BP1, BP4, BP2, BA1 The NM_213599.3: c.2503_2505del variant in ANO5 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Phe835del) (PM4). This variant has been detected with a pathogenic ANO5 variant in at least four individuals with LGMD, including confirmed in trans in one patient (c.191dup, 1 pt, ClinVar SCV000767093.6 internal data communication) and in unknown phase in two patients (c.2018A>G p.(Tyr673Cys), 0.5 pts, ClinVar SCV000767093.6 internal data communication; c.191dup, 0.5 pts, ClinVar SCV000574876.19 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The filtering allele frequency of this variant is 0.000017531 (the upper threshold of the 95% CI of 12/1109046 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM4, PM3_Strong, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA242118/MONDO:0015152/188 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3213 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0023530 infores:hetionet CHEBI:64312 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C3665347 infores:hetionet CHEBI:32293 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0003862 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0035455 infores:hetionet CHEBI:3504 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0040435 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0037274 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010571 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010571 uuid:41b91ad3-ef14-4159-91e7-15497862d149 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:7067 biolink:causes MONDO:0013757 infores:monarchinitiative not_provided not_provided HGNC:11796 MONDO:0013757 uuid:9a3b8a3f-b3b7-4f3e-b17f-9eb403f68e7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:68558 biolink:causes UMLS:C0341164 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0341164 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0948089 infores:hetionet CAID:CA238814 biolink:causes MONDO:0100040 infores:clingen CAID:CA238814 MONDO:0100040 PMID: Benign BP5_Strong, BS2, BA1, BP3 PM2 The allele frequency of the p.Q70_P77del variant in FOXG1 is 0.03% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Q70_P77del variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Q70_P77del variant is an in-frame deletion present in a repetitive region of FOXG1 (BP3). The p.Q70_P77del variant is found in at least 3 patients with an alternate molecular basis of disease (internal database) (BP5_strong). In summary, the p.Q70_P77del variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP3, BP5_strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA238814/MONDO:0100040/016 2021-03-26 2021-05-17 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true NCBIGene:8313 biolink:causes MONDO:0012075 infores:monarchinitiative not_provided not_provided HGNC:904 MONDO:0012075 uuid:8900a866-9107-42ab-8a7e-5546800b1208 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0025241 biolink:causes MONDO:0002771 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0034069 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0031542 infores:hetionet CHEBI:2666 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0026837 infores:hetionet CHEBI:6437 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0085631 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0010709 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0439857 infores:hetionet CHEBI:119486 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0019209 infores:hetionet CHEBI:45863 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0042790 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0009450 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0032285 infores:hetionet GO:1903224 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:1903224 GO:0007369 CHEBI:63630 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0151827 infores:hetionet CHEBI:9763 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0023530 infores:hetionet NCBIGene:54585 biolink:causes MONDO:0014445 infores:monarchinitiative not_provided not_provided HGNC:6741 MONDO:0014445 uuid:2502145b-6dbe-44d0-b78a-bd489e80a9b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0039070 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042267 infores:hetionet CHEBI:46295 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0033038 infores:hetionet CHEBI:6801 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0030252 infores:hetionet CAID:CA404093609 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093609 MONDO:0007750 PMID: Uncertain Significance PM2, PP4, PP3 PS4, PM1, PP1 The NM_000527.5(LDLR):c.2039T>C (p.Leu680Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 11 July 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PM3: REVEL score = 0.918.PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills MEDPED criteria for FH from PMID 27824480 (Gabčová et al., 2017), Slovakia, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093609/MONDO:0007750/013 2025-07-11 2025-10-08 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CAID:CA10585632 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585632 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BA1, BP4, PS3, PS4, BS1, BS3, BS4, PP3, PP1 The NM_000527.5(LDLR):c.1825T>C (p.Phe609Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying AMCG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling FH criteria, after alternative causes of high cholesterol were excluded, from PMID 16250003 (Fouchier et al., 2005). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585632/MONDO:0007750/013 2025-03-28 2025-06-04 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:94501 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0020538 infores:hetionet CHEBI:5001 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0232462 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0162279 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0162279 infores:hetionet CHEBI:63599 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0042963 infores:hetionet CHEBI:4315 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0948089 infores:hetionet CHEBI:2379 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0009782 infores:hetionet CHEBI:119915 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0162297 infores:hetionet GO:0044735 biolink:causes GO:0160128 infores:ubergraph knowledge_assertion manual_agent GO:0044735 GO:0160128 CHEBI:50275 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0027497 infores:hetionet CHEBI:9434 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0022408 infores:hetionet CHEBI:8028 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0424295 infores:hetionet CHEBI:50131 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0013491 infores:hetionet CHEBI:50663 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0009450 infores:hetionet CHEBI:8024 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0424295 infores:hetionet CAID:CA410203897 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203897 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.209A>C (p.Lys70Thr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Clinical and functional information for this variant has not been reported in the literature. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203897/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3380 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0038363 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0026946 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0019196 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0546817 infores:hetionet CHEBI:15365 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0030920 infores:hetionet CHEBI:127342 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0016382 infores:hetionet CAID:CA2424848227 biolink:causes MONDO:0100437 infores:clingen CAID:CA2424848227 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.1375_1376del (p.Val459fs) is a 2-bp deletion variant in exon 11 of 15, which results in a frameshift and premature stop codon and is predicted to trigger nonsense-mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family (PP1; PMID: 28559085). This variant has been reported in at least 5 apparently unrelated probands (PMIDs: 28559085, 10480356, 34985506, 24154662, 14564670). However, the number of individuals meeting one of the PS4 requirements of some functional vision impairment in affected males by age 30 years, and/or decreased or absent ERG responses was fewer than the requirement of at least 2 unrelated probands, so PS4_Supporting was not met. In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_Supporting, and PP1. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2424848227/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Supports NCBIGene:9132 biolink:causes MONDO:0010817 infores:monarchinitiative not_provided not_provided HGNC:6298 MONDO:0010817 uuid:e7cc28b9-9da3-4e6b-9fe6-8dea8991e0d4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0014457 infores:hetionet CHEBI:3696 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0017574 infores:hetionet GO:0072071 biolink:causes CL:1000692 infores:ubergraph knowledge_assertion manual_agent GO:0072071 CL:1000692 CHEBI:7494 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0020039 infores:hetionet CHEBI:5778 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0151904 infores:hetionet CHEBI:47426 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1368065 infores:hetionet CAID:CA000490 biolink:causes MONDO:0017623 infores:clingen CAID:CA000490 MONDO:0017623 PMID:12471211PMID:12938083PMID:12471211PMID:12938083PMID:12471211 Pathogenic PVS1, PM6, PM2, PS4 BS4, BS3, BS1, BP5, BP7, BS2, PP1, PP2, PP3, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS3, PS1 PTEN c.507delC (p.Ser170Valfs) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 12471211)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 12471211) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000490/MONDO:0017623/003 2018-07-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports GO:1900136 biolink:causes GO:0060326 infores:ubergraph knowledge_assertion manual_agent GO:1900136 GO:0060326 CHEBI:8107 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0030312 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0037199 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0948594 infores:hetionet CAID:CA2580611121 biolink:causes MONDO:0015967 infores:clingen CAID:CA2580611121 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4_Moderate, PP4_Moderate, PVS1, PP1 The c.690_691del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 230 NM_000545.8), adding 8 novel amino acids before encountering a stop codon (p.(p.Glu230AspfsTer8)). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:18003757, internal lab contributors). At least two individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with 3 informative meioses in a family with MODY (PP1; internal lab contributor). In summary, c.690_691del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1, approved 8/11/2023): PVS1, PP4_Moderate, PS4_Moderate, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580611121/MONDO:0015967/017 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports GO:0044083 biolink:causes GO:0007266 infores:ubergraph knowledge_assertion manual_agent GO:0044083 GO:0007266 CHEBI:7601 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0242350 infores:hetionet CHEBI:64355 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0012569 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0015397 infores:hetionet CHEBI:72690 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0004604 infores:hetionet CHEBI:6128 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0018802 infores:hetionet CHEBI:408174 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C2047937 infores:hetionet CHEBI:63791 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0234632 infores:hetionet CAID:CA392327764 biolink:causes MONDO:0007947 infores:clingen CAID:CA392327764 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PP4, PM2_Supporting, PM1_Strong PVS1, PM6, PP1, BS2, BP1, BP4, BP2, BP3, BA1, PS3, PS4, PS1, PS2, PM3, PM4, PM5, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.7409G>T is a missense variant in FBN1 predicted to cause a substitution of a cysteine by phenylalanine at amino acid 2470 (p.Cys2470Phe). This variant was found in a proband with thoracic aortic aneurysm (TAA) and a systemic score ≥7 which is a specific phenotype that satisfies the revised Ghent criteria for a clinical diagnosis of Marfan syndrome (MFS) (PP4; PMID: 38374194). This variant has been reported 3 times in ClinVar as pathogenic (1) likely pathogenic (1), and of uncertain significance (1) (Variation ID: 1098776 ). It has been identified in a proband who does not meet diagnostic criteria for MFS but has TAA and several systemic features of MFS (Invitae internal data). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL = 0.989). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PP2, PP3, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392327764/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:17823 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0008031 infores:hetionet CHEBI:5778 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0028643 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001828 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0155018 infores:hetionet CHEBI:8093 biolink:causes UMLS:C0232191 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0232191 infores:hetionet CHEBI:135736 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0025874 infores:hetionet CHEBI:16899 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0016927 infores:hetionet CHEBI:9570 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0014591 infores:hetionet CHEBI:9622 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0018681 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0017152 infores:hetionet CHEBI:2673 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0028084 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0232459 infores:hetionet CAID:CA222583 biolink:causes MONDO:0015280 infores:clingen CAID:CA222583 MONDO:0015280 PMID:19376813PMID:18413255PMID:18042262PMID:16474404PMID:17551924 Pathogenic PS3, PM1, PM2, PS2_Very Strong, PP2, PP3 The c.770A>G (p.Gln257Arg) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID:18042262, PMID:17551924, PMID:16474404). In vitro functional studies provide some evidence that the p.Q257R variant may impact protein function (PS3; PMID:18413255; PMID:19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Furthermore, this variant is located in exon 6, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Q257R variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for cardio-facio-cutaneous syndrome in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222583/MONDO:0015280/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:43968 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C3263723 infores:hetionet CHEBI:8768 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0014724 infores:hetionet CHEBI:8455 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0178298 infores:hetionet CHEBI:15367 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0028643 infores:hetionet CHEBI:2569 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0006266 infores:hetionet CHEBI:6061 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0002962 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0235431 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0036572 infores:hetionet CAID:CA404084853 biolink:causes MONDO:0007750 infores:clingen CAID:CA404084853 MONDO:0007750 PMID: Uncertain Significance BP4, PM2 BA1, BP1, BP3, BP2, PS1, PS3, PS4, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1273A>G (p.Asn425Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2: PopMax MAF = 0.00002891 (0.003%) in Latino/Admixed American exomes+genomes (gnomAD v2.1.1).BP4: REVEL = 0.271, it is below 0.50, splicing evaluation required.Functional data on splicing not available.Scenario A, Acceptor site: The variant is NOT located at -20 to +3 bases of canonical acceptor splicing site of any exons.Scenario A, Donor site: The variant is NOT located at -3 to +6 bases of canonical splicing site of any exons.Scenario B, Acceptor site: The variant is located within the range and DOES NOT create de novo AG site.Scenario B, Donor site: The variant is located within range and DOES NOT create de novo GT site.Scenario C, Acceptor site: The variant is NOT located at -20 to +3 bases of intraexonic AG.Scenario C, Donor site: The variant is NOT located at -3 to +6 bases of intraexonic GT.Interpretation: The variant DOES NOT affect splicing. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404084853/MONDO:0007750/013 2023-06-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UNII:R43D2573WO biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0030252 infores:hetionet CHEBI:42797 biolink:causes HP:0001386 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0152031 infores:hetionet CHEBI:421707 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0018681 infores:hetionet CHEBI:63598 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003862 infores:hetionet CHEBI:28593 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0456909 infores:hetionet CHEBI:3219 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0151692 infores:hetionet CHEBI:6904 biolink:causes HP:0030830 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0034642 infores:hetionet CHEBI:64318 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0020538 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549209 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0015786 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015786 infores:hetionet CHEBI:45652 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0020517 infores:hetionet CHEBI:83531 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0018681 infores:hetionet UMLS:C0209366 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0424605 infores:hetionet CHEBI:36704 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0040147 infores:hetionet UMLS:C0065374 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0043094 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0677500 infores:hetionet CAID:CA392325203 biolink:causes MONDO:0007947 infores:clingen CAID:CA392325203 MONDO:0007947 PMID: Uncertain Significance PP4, PM2_Supporting, PM1, BP5 PVS1, PM6, BS2, PP2, PP3, PP1, BA1, BP1, BP4, BP2, BP3, PS1, PS2, PS3, PS4, PM3, PM4, PM5, BS1, BS4, BS3, BP7 NM_000138.5 c.3508C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1170 (p.Arg1170Cys). This variant has been identified in an individual with a clinical diagnosis of Marfan syndrome including thoracic aortic aneurysm and dissection (TAAD) and systemic features (PP4; Johns Hopkins internal data). It has also been identified in at least four individuals with non-specific features of a connective tissue disorder, only one of whom had TAAD (UZA, UZG, Invitae, & CeGaT internal data; ClinVar Variation ID: 549169); one of these individuals also harbored a disease-causing variant in the SKI gene (p.Thr180Arg) that provided an alternate molecular basis for their phenotype (BP5; UZA internal data). It was also reported in the literature as de novo in an individual with neurodevelopmental delay and congenital heart defects, without features of Marfan syndrome (PMID: 26785492). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis are unclear about this variant’s predicted impact to the protein (REVEL = 0.722). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM2_supporting, PP4, BP5. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392325203/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8869 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0021053 infores:hetionet CHEBI:27690 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0231218 infores:hetionet CAID:CA16020931 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020931 MONDO:0009861 PMID:26503515 Uncertain Significance PM2, PP4_Moderate, PP3 This c.1066T>G (p.Y356D) variant in PAH was reported in 1 Southern Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is present in African American populations at a frequency of 0.00003 and Native Hawaiian populations at a frequency of 0.00022 (PAGE). In silico modeling predicts that this missense variant is damaging (SIFT), probably damaging (PolyPhen2), and disease causing (mutation taster). In summary, this variant meets criteria to be classified as Uncertain Significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020931/MONDO:0009861/006 2019-11-05 2019-11-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3216 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0521495 infores:hetionet CHEBI:3568 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0003537 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0004623 infores:hetionet CHEBI:119573 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C2830004 infores:hetionet CHEBI:68584 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0036974 infores:hetionet CHEBI:9435 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0575090 infores:hetionet UNII:U6XF9NP8HM biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0040046 infores:hetionet CHEBI:5864 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1456784 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0086565 infores:hetionet CHEBI:45924 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0003862 infores:hetionet CHEBI:7565 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0007222 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0687707 infores:hetionet CHEBI:4672 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085624 infores:hetionet CHEBI:116278 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0039231 infores:hetionet CHEBI:79699 biolink:causes HP:0031188 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151604 infores:hetionet CHEBI:5001 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0034065 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0235416 infores:hetionet CHEBI:4027 biolink:causes HP:0005115 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0428974 infores:hetionet CHEBI:6078 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0015732 infores:hetionet CHEBI:39867 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0392171 infores:hetionet CHEBI:10119 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0702166 infores:hetionet UMLS:C0657912 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019079 infores:hetionet CHEBI:6413 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0032227 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0025061 infores:hetionet CAID:CA200462 biolink:causes MONDO:0007648 infores:clingen CAID:CA200462 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, BS2, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.48+6C>T variant has an allele frequency of 0.81161 (81%, 129,383/159,416 alleles) in the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA200462/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA020164 biolink:causes MONDO:0008667 infores:clingen CAID:CA020164 MONDO:0008667 PMID: Benign BP4, BA1 The variant NM_000551.4(VHL):c.246C>T (p.Arg82=) is a synonymous (silent) variant that does not display splicing impact according to SpliceAI and VarSeak (BP4). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0002832 (365/1179692 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020164/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:367163 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0016436 infores:hetionet CHEBI:6822 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0151773 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0019372 infores:hetionet CHEBI:17076 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0002418 infores:hetionet CHEBI:2637 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0003578 infores:hetionet CHEBI:171719 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0013604 infores:hetionet CHEBI:4856 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0178298 infores:hetionet CHEBI:7496 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0877192 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0042981 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003507 infores:hetionet CHEBI:9086 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0392684 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0162429 infores:hetionet CHEBI:51141 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0006277 infores:hetionet CHEBI:28925 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00888 UMLS:C0232462 infores:hetionet GO:0052160 biolink:causes GO:0009627 infores:ubergraph knowledge_assertion manual_agent GO:0052160 GO:0009627 CHEBI:63611 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151479 infores:hetionet CHEBI:94449 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0020580 infores:hetionet CHEBI:6073 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0232459 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0020517 infores:hetionet CHEBI:408174 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0020473 infores:hetionet CHEBI:10102 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0009763 infores:hetionet CHEBI:478164 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0014518 infores:hetionet CHEBI:50729 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0022660 infores:hetionet CHEBI:45979 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C0002792 infores:hetionet CHEBI:6129 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0011991 infores:hetionet CHEBI:9130 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0004093 infores:hetionet CAID:CA355963313 biolink:causes MONDO:0001586 infores:clingen CAID:CA355963313 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM5, PM2_Supporting The NM_000203.5:c.1090A>G variant in IDUA is a missense variant predicted to cause substitution of threonine by alanine at amino acid 364 (p.Thr364Ala). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I and no results of functional assays are available. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001104 (1/90550 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.875 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997; PP3_Moderate). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM2_Supporting, PP3_Moderate, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355963313/MONDO:0001586/091 2024-12-05 2025-03-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA410205747 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205747 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.71G>C (p.Gly24Ala) is a variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205747/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50742 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042373 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0041912 infores:hetionet CHEBI:8863 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0240735 infores:hetionet NCBIGene:56155 biolink:causes MONDO:0054727 infores:monarchinitiative not_provided not_provided HGNC:11737 MONDO:0054727 uuid:c53b6a76-5556-4cd0-ae51-da05544b964c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0030554 infores:hetionet CHEBI:4024 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0155169 infores:hetionet NCBIGene:2521 biolink:causes MONDO:0011951 infores:monarchinitiative not_provided not_provided HGNC:4010 MONDO:0011951 uuid:855ea168-43c8-417a-bdcd-268cf911a717 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7915 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151824 infores:hetionet CHEBI:68478 biolink:causes NCIT:C78325 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0239739 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085606 infores:hetionet CHEBI:63580 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0043144 infores:hetionet CHEBI:7773 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151878 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151544 infores:hetionet GO:0032888 biolink:causes GO:0000070 infores:ubergraph knowledge_assertion manual_agent GO:0032888 GO:0000070 CHEBI:5959 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0030305 infores:hetionet CHEBI:8093 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0237849 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0009760 infores:hetionet CHEBI:5855 biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0021845 infores:hetionet CHEBI:6030 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0220981 infores:hetionet CHEBI:8428 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0015967 infores:hetionet CHEBI:8874 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0034886 infores:hetionet UMLS:C0657912 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0019080 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0233407 infores:hetionet CHEBI:240107 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0235267 infores:hetionet CHEBI:44185 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0014457 infores:hetionet CHEBI:68642 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0948594 infores:hetionet CHEBI:7931 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0018790 infores:hetionet CHEBI:5856 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00308 UMLS:C0039070 infores:hetionet CHEBI:3181 biolink:causes HP:0031944 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0264545 infores:hetionet CHEBI:3996 biolink:causes MONDO:0005665 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0376175 infores:hetionet CHEBI:521033 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0549622 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0013985 infores:hetionet CHEBI:7915 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0151905 infores:hetionet CHEBI:64064 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0037383 infores:hetionet CHEBI:4708 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0033774 infores:hetionet CHEBI:7936 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0018681 infores:hetionet CAID:CA399791662 biolink:causes MONDO:0100326 infores:clingen CAID:CA399791662 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PP1 The c.2822G>A (p.Trp941Ter) variant in exon 27 is a nonsense variant predicted cause a premature stop codon in biologically-relevant-exon 27/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patient (Proband in PMID: 40126091) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. (PP4_moderate).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: (PVS1, PP4_Moderate, PM2_supporting). (VCEP specifications version 2; date of approval 05/14/2025) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399791662/MONDO:0100326/011 2025-06-19 2025-06-19 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7852 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0042029 infores:hetionet CHEBI:28593 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0085636 infores:hetionet CHEBI:4636 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0235710 infores:hetionet CHEBI:47381 biolink:causes UMLS:C3495920 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C3495920 infores:hetionet CHEBI:47519 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0392197 infores:hetionet CHEBI:188986 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0231528 infores:hetionet CHEBI:4995 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C1443060 infores:hetionet CAID:CA10644625 biolink:causes MONDO:0011071 infores:clingen CAID:CA10644625 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2678A>G is a 3'UTR variant. This 3'UTR variant has a SpliceAI score ≤ 0.20 (0.00) (BP4) and the variant is not highly conserved (PhyloP score ≤ 2.0 (1.316)) (BP7). In summary, the clinical significance of this variant Likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10644625/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:520985 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0015397 infores:hetionet CHEBI:94501 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0015967 infores:hetionet CHEBI:4325 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0018681 infores:hetionet CHEBI:6888 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0016658 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0003123 infores:hetionet CHEBI:3380 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0016382 infores:hetionet CHEBI:5790 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0015672 infores:hetionet CHEBI:3077 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0009760 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0392025 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0042109 infores:hetionet CHEBI:27666 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0040034 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1444565 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1444565 infores:hetionet NCBIGene:84811 biolink:causes MONDO:0700300 infores:monarchinitiative not_provided not_provided HGNC:28199 MONDO:0700300 uuid:062d9ab3-5a9b-4ccb-aab6-34d7a5b780cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:80206 biolink:causes MONDO:0030317 infores:monarchinitiative not_provided not_provided HGNC:26178 MONDO:0030317 uuid:8047d42b-063d-4ce4-b91d-acd64518defc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0699744 infores:hetionet CHEBI:2038 biolink:causes UMLS:C0521508 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0521508 infores:hetionet CHEBI:3403 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0476273 infores:hetionet CHEBI:7565 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0340464 infores:hetionet CHEBI:68642 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0020456 infores:hetionet CHEBI:83804 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0522055 infores:hetionet CHEBI:34967 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0019521 infores:hetionet CHEBI:15553 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0033774 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0002957 infores:hetionet CHEBI:66903 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0162429 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018099 infores:hetionet CHEBI:34385 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0003467 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0267158 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0267158 infores:hetionet CHEBI:3181 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0700200 infores:hetionet CHEBI:39112 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0232495 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0011991 infores:hetionet CHEBI:8665 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0018790 infores:hetionet CHEBI:6456 biolink:causes MONDO:0005693 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0392548 infores:hetionet CHEBI:4858 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0004134 infores:hetionet CHEBI:7936 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0011991 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0041912 infores:hetionet CHEBI:68610 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0004604 infores:hetionet CHEBI:9435 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0547030 infores:hetionet CAID:CA386959154 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959154 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PM5_Supporting, PP3 PS4, PP4 The c.368T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 123 (p.(Leu123Arg)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.963, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v4.1.0 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). This individual has a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor). Another missense variant at the same amino acid position, c.367C>G (p.Leu123Val), ​has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, the c.368T>G variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959154/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3568 biolink:causes UMLS:C1619712 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C1619712 infores:hetionet CHEBI:17688 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0016204 infores:hetionet CHEBI:367163 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0028081 infores:hetionet CHEBI:15428 biolink:causes UMLS:C3160741 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C3160741 infores:hetionet CHEBI:474053 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0019158 infores:hetionet CHEBI:134991 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0033774 infores:hetionet GO:0045664 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0045664 GO:0007275 CHEBI:47780 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0011615 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0549373 infores:hetionet CHEBI:2682 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151662 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0002884 infores:hetionet CHEBI:3216 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1145670 infores:hetionet CHEBI:8356 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0040264 infores:hetionet CHEBI:63631 biolink:causes MONDO:0020678 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0018784 infores:hetionet CHEBI:9667 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0240557 infores:hetionet CHEBI:7640 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0018418 infores:hetionet CHEBI:39867 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0242301 infores:hetionet CHEBI:6640 biolink:causes UMLS:C0085620 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0085620 infores:hetionet CHEBI:2687 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0311468 infores:hetionet CHEBI:9137 biolink:causes HP:0100827 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0024282 infores:hetionet CHEBI:63607 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0687707 infores:hetionet CHEBI:45285 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0231528 infores:hetionet CHEBI:3181 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0017181 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0037199 infores:hetionet CHEBI:127780 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0235431 infores:hetionet CHEBI:63581 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0013395 infores:hetionet CHEBI:2469 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0033774 infores:hetionet CHEBI:3738 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0917801 infores:hetionet GO:0072193 biolink:causes CL:1000979 infores:ubergraph knowledge_assertion manual_agent GO:0072193 CL:1000979 CHEBI:6539 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0027066 infores:hetionet CHEBI:31711 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0600142 infores:hetionet NCBIGene:3481 biolink:causes MONDO:0014663 infores:monarchinitiative not_provided not_provided HGNC:5466 MONDO:0014663 uuid:31c7d493-2511-4260-80fa-23ca9dfdb62c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63584 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0003862 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0232459 infores:hetionet CHEBI:8874 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0038325 infores:hetionet CHEBI:5138 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0039231 infores:hetionet CHEBI:2618 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0080274 infores:hetionet GO:0060721 biolink:causes GO:0090214 infores:ubergraph knowledge_assertion manual_agent GO:0060721 GO:0090214 NCBIGene:4286 biolink:causes MONDO:0008671 infores:monarchinitiative not_provided not_provided HGNC:7105 MONDO:0008671 uuid:da362268-d224-4bc9-bfbe-ce82d6a9f803 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:584020 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0043094 infores:hetionet CHEBI:4672 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0002792 infores:hetionet CHEBI:31623 biolink:causes UMLS:C1112489 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C1112489 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0855652 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0855652 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005101 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0009324 infores:hetionet NCBIGene:1509 biolink:causes MONDO:0012414 infores:monarchinitiative not_provided not_provided HGNC:2529 MONDO:0012414 uuid:890c23e5-500d-429b-837a-deb0f592b033 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0011206 infores:hetionet CHEBI:4636 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0011991 infores:hetionet CHEBI:3568 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0558489 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0029408 infores:hetionet NCBIGene:1806 biolink:causes MONDO:0010130 infores:monarchinitiative not_provided not_provided HGNC:3012 MONDO:0010130 uuid:cf369e80-6c99-44a1-bbc9-d5e7bf151935 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7565 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0150450 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0009806 infores:hetionet CHEBI:64312 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0020473 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0023067 infores:hetionet CHEBI:50275 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0917801 infores:hetionet CHEBI:101853 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0030252 infores:hetionet CHEBI:171719 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0014518 infores:hetionet CHEBI:52010 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0009946 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0015230 infores:hetionet CHEBI:9635 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0040034 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0518015 infores:hetionet CHEBI:480999 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0687713 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0151888 infores:hetionet CHEBI:42797 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0004238 infores:hetionet CHEBI:27446 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0235347 infores:hetionet CHEBI:64019 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0030554 infores:hetionet CHEBI:31859 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0232462 infores:hetionet CHEBI:50777 biolink:causes UMLS:C1535975 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C1535975 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0020517 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0242350 infores:hetionet CHEBI:66903 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0151934 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0233472 infores:hetionet CHEBI:6754 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0011206 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0001623 infores:hetionet GO:0080050 biolink:causes GO:0010154 infores:ubergraph knowledge_assertion manual_agent GO:0080050 GO:0010154 CHEBI:3504 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0239981 infores:hetionet CAID:CA392325153 biolink:causes MONDO:0007947 infores:clingen CAID:CA392325153 MONDO:0007947 PMID: Uncertain Significance PM2_Supporting, BP4, PM1, BS4 PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP3, PS1, PS3, PS4, PS2, PM5, PM3, PM4, BP7, BP5, BS1, BS3 NM_00138 c.7643T>A is a missense variant predicted to cause a substitution of a phenylalanine by a tyrosine at amino acid position 2548. This variant is present in 1 proband with TAAD, segregating with TAAD in 1 affected family member but not segregating in another affected family member (BS4; Universitair Ziekenhuis Antwerpen). This variant occurs at a conserved position in the consensus calcium-binding sequence in a cbEGF-like domain (PM1). It is not present in gnomAD v2.1.1 (PM2_supporting). Computational prediction and evolutionary conservation analysis tools suggest no impact to the gene (BP4; REVEL = 0.298). Due to conflicting and insufficient evidence, this variant is classified as of uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM2_supporting, BS4, BP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392325153/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:5847 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0015967 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0020649 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0027769 infores:hetionet CHEBI:46557 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0037763 infores:hetionet CHEBI:31174 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0020517 infores:hetionet CHEBI:68478 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C1720775 infores:hetionet CHEBI:48273 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C1510410 infores:hetionet CHEBI:3561 biolink:causes MONDO:0006314 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0027430 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0234458 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151436 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0003123 infores:hetionet CHEBI:17303 biolink:causes UMLS:C2981158 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C2981158 infores:hetionet CAID:CA1244091 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244091 MONDO:0005338 PMID: Benign BP7, BP4, BA1 BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2 The c.1041T>C variant in MYOC is a synonymous variant (p.Tyr347=). The highest minor allele frequency of this variant was in the Ashkenazi Jewish genetic ancestry group of gnomAD (v4.1.0) = 0.08019, which met the ≥ 0.01 threshold set for BA1 (2,374alleles out of 29,606, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0.01, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2, new_date_2024): BA1, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244091/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135876 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0231218 infores:hetionet CHEBI:474180 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0039231 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0521591 infores:hetionet CHEBI:4876 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0234215 infores:hetionet CHEBI:9352 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0002170 infores:hetionet CHEBI:72296 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0041969 infores:hetionet CHEBI:3082 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0040264 infores:hetionet CHEBI:51173 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0162429 infores:hetionet CHEBI:4636 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0042571 infores:hetionet CAID:CA2580098838 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098838 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS2, PS1, PS4, BP2, BP1, BA1, BS1, PM6, PM3, PM5, BS2, PP4, PP2, PP3 The c.967+6C>G intronic variant is not predicted by SpliceAI (Δ scores ≤ 0.20) to significantly impact canonical splice sites or create putative cryptic splice sites (BP4); in addition, an evolutionary conservation algorithm predicts the site as being weakly conserved (PhyloP score = 0.288362 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). While this variant is absent from gnomAD v2 and v3 (PM2_Supporting), it has not been reported in cases or in the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098838/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10119 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0020639 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0041912 infores:hetionet GO:0120313 biolink:causes GO:0048477 infores:ubergraph knowledge_assertion manual_agent GO:0120313 GO:0048477 CHEBI:63638 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0575081 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0025289 infores:hetionet CHEBI:9150 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0687133 infores:hetionet CHEBI:3082 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0042373 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0032584 infores:hetionet CHEBI:2922 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0030312 infores:hetionet CHEBI:15367 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0023052 infores:hetionet CHEBI:51041 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0231218 infores:hetionet CHEBI:48273 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0151888 infores:hetionet CAID:CA136085 biolink:causes MONDO:0021060 infores:clingen CAID:CA136085 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.195A>C (p.Arg65=) variant in the SOS1 gene is 10.978% (1192/10346) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136085/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63620 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0032227 infores:hetionet CHEBI:6640 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0004096 infores:hetionet UNII:9430ZR8ZAN biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0234233 infores:hetionet CHEBI:3215 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0428977 infores:hetionet CHEBI:8069 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0549249 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0038454 infores:hetionet CHEBI:9086 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0010200 infores:hetionet CAID:CA4239718 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239718 MONDO:0015967 PMID: Pathogenic PS4, PP1_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS3 The c.128G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 43 (p.(Arg43His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8159, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated that the p.Arg43His variant has normal relative activity index (RAI>0.5) and normal GKA/GKRP interaction; however the relative stability index (RSI) was not calculated and therefore neither PS3 or BS3 can be applied (PMID: 22611063). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 11942313, 22611063, 27106716, 25015100, 22493702, 30245511, 31638168, 33046911). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID: 30245511). This variant segregated with diabetes/hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 22611063, 22493702). Another missense variant, c.127C>T (p.Arg43Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg43His (PM5_Supporting). In summary, the c.128G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified for by the GlinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239718/MONDO:0015967/086 2023-08-25 2023-08-25 Semidominant inheritance HP:0032113 Supports CHEBI:68647 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0037274 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0435002 infores:hetionet CHEBI:8435 biolink:causes MONDO:0043510 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0270611 infores:hetionet CHEBI:2611 biolink:causes MONDO:0008268 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0033046 infores:hetionet CHEBI:135530 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0010200 infores:hetionet CHEBI:52717 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0007820 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0018802 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0013395 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0018799 infores:hetionet CHEBI:3176 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0155169 infores:hetionet CHEBI:5147 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0438142 infores:hetionet CHEBI:3485 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0006852 infores:hetionet CAID:CA367401530 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401530 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PS2_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PS3 The c.571C>T variant in the glucokinase gene, GCK causes an amino acid change of Arg to Trp at codon 191 (p.(Arg191Trp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable Popmax filtering allele frequency in gnomAD v2.1 due to only one copy in European non-Finnish population and one copy in another subpopulation, which is less than the MDEP threshold for PM2_Supporting (Popmax filtering FAF <= 0.000003 and <= 2 copies in ENF and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 100 unrelated individuals with diabetes/hyperglycemia (PS4; PMIDs: 10753050, 22060211, 23295292, 28170077, internal lab contributors). This variant segregated with diabetes with at least 72 informative meioses from 51 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 23295292). This variant was found de novo in an individual with a phenotype highly specific for GCK-MODY with unconfirmed parental relationships (PS2_Moderate; internal lab contributor). Functional studies demonstrated the p.Arg191Trp protein has RAI<0.5; however, the wild-type kinetic parameters didn’t pass the quality control, and the PS3 cannot be applied (PMID: 30592380). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): PS4, PP1_Strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401530/MONDO:0015967/086 2023-07-23 2023-07-23 Semidominant inheritance HP:0032113 Supports CHEBI:6792 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0010200 infores:hetionet CHEBI:5118 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0003873 infores:hetionet CHEBI:63624 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0232495 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0333641 infores:hetionet CHEBI:41879 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0700590 infores:hetionet NCBIGene:3579 biolink:causes MONDO:0030374 infores:monarchinitiative not_provided not_provided HGNC:6027 MONDO:0030374 uuid:f3875eea-2577-49ac-9a44-e401c27d212f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4903 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0234215 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0039971 infores:hetionet CHEBI:42944 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011206 infores:hetionet GO:0010520 biolink:causes GO:0051321 infores:ubergraph knowledge_assertion manual_agent GO:0010520 GO:0051321 CHEBI:68575 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB05039 UMLS:C0039231 infores:hetionet CHEBI:7824 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0020598 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0549405 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0917798 infores:hetionet CHEBI:4876 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0018099 infores:hetionet CHEBI:404903 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0040409 infores:hetionet CHEBI:27690 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0022354 infores:hetionet GO:1903719 biolink:causes GO:0007249 infores:ubergraph knowledge_assertion manual_agent GO:1903719 GO:0007249 CHEBI:45783 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0019360 infores:hetionet CHEBI:6887 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C3665347 infores:hetionet CHEBI:681569 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0235378 infores:hetionet CHEBI:27470 biolink:causes UMLS:C0233818 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0233818 infores:hetionet CHEBI:3242 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0042963 infores:hetionet CHEBI:28787 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0003811 infores:hetionet CHEBI:567361 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0035243 infores:hetionet CHEBI:72297 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0017152 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0877179 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0877179 infores:hetionet CAID:CA390885360 biolink:causes MONDO:0100216 infores:clingen CAID:CA390885360 MONDO:0100216 PMID: Likely Pathogenic PP3, PP1, PS4_Supporting, PM2_Supporting, PS3 PM6, PVS1, BA1, BP4, BP2, PP4, BS2, PM1, PM5, PM4, PS2, PS1, BP7, BS1, BS4, BS3 NM_177438.2(DICER1):c.1509G>C variant in DICER1 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). This variant received a total of 1 phenotype point across 1 unrelated proband/family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal lab data: Invitae). The variant has been reported to segregate with DICER1 phenotypes in 2 family members separated by 4 meioses from 1 family (PP1_Supporting; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor: Invitae). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP1, PM2_Supporting, PS3, PP3 (Bayesian Points: 8; VCEP specifications version 1.3.0; 02/25/2025). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390885360/MONDO:0100216/024 2025-02-25 2025-06-04 Autosomal dominant inheritance HP:0000006 Supports GO:1903684 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:1903684 GO:0019953 CHEBI:28748 biolink:causes UMLS:C0403639 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0403639 infores:hetionet CHEBI:50885 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0019572 infores:hetionet CHEBI:4453 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0149741 infores:hetionet CHEBI:231594 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0025218 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0235231 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235231 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0178298 infores:hetionet CHEBI:404903 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0037763 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0030578 infores:hetionet UMLS:C0657912 biolink:causes HP:0002150 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020438 infores:hetionet CHEBI:5141 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0027497 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0019340 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019340 infores:hetionet CHEBI:83804 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0149741 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005021 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0007193 infores:hetionet CAID:CA126216 biolink:causes MONDO:0015967 infores:clingen CAID:CA126216 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting The c.1132G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 378 (p.(Ala378Thr) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, it is absent in multiple large population cohorts (UKBiobank, BioMe, Geisinger, internal lab contributors) and therefore the ClinGen MDEP has approved the application of PM2_Supporting for this variant (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1133C>T (p.(Ala378Val)), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala378Thr (PM5_Supporting). Additionally, GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been identified in over 30 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID 18248649, PMID 16965331, internal lab contributors). This variant segregates with diabetes in 15 informative meioses in a large extended family with diabetes (PP1_Strong; internal lab contributor). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1132G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP3, PM5_Supporting, PP2, PS4, PP1_Strong, PP4_moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA126216/MONDO:0015967/086 2023-08-07 2023-08-07 Semidominant inheritance HP:0032113 Supports CHEBI:8869 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0042109 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0236068 infores:hetionet CHEBI:3723 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0037036 infores:hetionet CAID:CA229828 biolink:causes MONDO:0009861 infores:clingen CAID:CA229828 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, PP3 The c.864G>C (p.Leu288Phe) variant in PAH is absent from population databases, and in silico predictors suggest a damaging effect on protein function. It is listed in hPAHdb 2009 McGill, but there is no clinical information on any patient. To our current knowledge (December, 2018), this variant has not been previously reported in the literature. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229828/MONDO:0009861/006 2018-12-09 2019-04-06 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:7936 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0022568 infores:hetionet CHEBI:110423 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0151905 infores:hetionet CHEBI:472657 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0042029 infores:hetionet CHEBI:127342 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0009806 infores:hetionet CAID:CA320642689 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642689 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP4, BP2, BP3, BA1, BP5, BP7, BS3, BS1, BS4, PM6, PVS1, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.256C>G (p.Pro86Ala) is a missense variant which is located outside of the Runt Homology Domain. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The variant has a REVEL score of 0.561, which does not meet the threshold for PP3 (≥0.88) or BP4 (<0.50). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642689/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA2737529304 biolink:causes MONDO:0011071 infores:clingen CAID:CA2737529304 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.351+15A>C is an intronic variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.35)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2737529304/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:54Z8M50D6Q biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0036974 infores:hetionet CAID:CA915947736 biolink:causes MONDO:0700270 infores:clingen CAID:CA915947736 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3, PM5_Supporting, PVS1 BA1, BS1 The ATM c.1122_1123del (p.Glu376IlefsTer2) variant has a GnomAD (v2.1.1) allele frequency of 0.0000% which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a compound heterozygous state (presumed) in one individual with Ataxia-Telangiectasia (PMID: 24954719 PM3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA915947736/MONDO:0700270/020 2022-04-14 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5103 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0236075 infores:hetionet CAID:CA046422 biolink:causes MONDO:0021056 infores:clingen CAID:CA046422 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 The NM_000038.6(APC):c.6905C>G (p.Ser2302Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in 1 proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PS4 not met; Ambry Genetics). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004228 (1/236522 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1 and PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA046422/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:66964 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0010200 infores:hetionet CHEBI:45599 biolink:causes UMLS:C0542203 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0542203 infores:hetionet UMLS:C1738934 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0030193 infores:hetionet CHEBI:31236 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0494475 infores:hetionet CHEBI:4858 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0152032 infores:hetionet CHEBI:7565 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0085649 infores:hetionet CHEBI:135276 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0018681 infores:hetionet CHEBI:3387 biolink:causes MONDO:0008297 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0162532 infores:hetionet CHEBI:5801 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0085631 infores:hetionet CHEBI:10119 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0035410 infores:hetionet CHEBI:63616 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0015230 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0010200 infores:hetionet CHEBI:135791 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0333641 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0033975 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0042373 infores:hetionet CHEBI:68647 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0009782 infores:hetionet CHEBI:3568 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0740394 infores:hetionet CAID:CA346886 biolink:causes MONDO:0015152 infores:clingen CAID:CA346886 MONDO:0015152 PMID: Pathogenic PM4, PP4, PM3_Very Strong PM2 The NM_000070.3: c.759_761del variant in CAPN3, which is also known as c.756_758del, is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Lys254del) (PM4). This variant has been detected in at least 11 unrelated individuals with limb girdle muscular dystrophy (PMID: 26886200, 10330340, 16141003, 18055493, 30564623, 12461690, 35731190), including in a homozygous state in one case (0.5 pts; PMID: 18055493), confirmed in trans with a pathogenic variant in three cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 12461690; c.1746-20C>G, 2.0 pts, PMID: 35731190), and in unknown phase with a pathogenic variant in one case (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 18055493) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The filtering allele frequency of the variant is 0.0001933 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 7/68016), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM4, PM3_Very Strong, PP4. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346886/MONDO:0015152/187 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9150 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0919715 infores:hetionet CHEBI:63612 biolink:causes MONDO:0024333 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0036396 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0151849 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0042109 infores:hetionet CHEBI:3561 biolink:causes MONDO:0000483 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0085637 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0002871 infores:hetionet CHEBI:64312 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0235437 infores:hetionet CHEBI:73274 biolink:causes MONDO:0041182 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0031736 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011334 infores:hetionet CHEBI:3077 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0004093 infores:hetionet CHEBI:2687 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0018681 infores:hetionet CHEBI:2668 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0232461 infores:hetionet CHEBI:49040 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0232462 infores:hetionet CHEBI:32315 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0037763 infores:hetionet NCBITaxon:780 biolink:causes MONDO:0001195 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:780 MESH:D000073605 DB00759_MESH_D000073605_1DB01017_MESH_D000073605_1DB00618_MESH_D000073605_2DB00595_MESH_D000073605_1DB02703_MESH_D000073605_1DB00254_MESH_D000073605_1 CHEBI:8764 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C1258215 infores:hetionet CHEBI:3219 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0520966 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0522063 infores:hetionet CHEBI:51860 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0017178 infores:hetionet CHEBI:9637 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0015230 infores:hetionet CHEBI:31859 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0039070 infores:hetionet CHEBI:63632 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0035455 infores:hetionet CHEBI:75722 biolink:causes MONDO:0001882 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0004659 infores:hetionet NCBIGene:4233 biolink:causes MONDO:0003789 infores:monarchinitiative not_provided not_provided HGNC:7029 MONDO:0003789 uuid:3a80bd0c-e07c-44dc-8b57-9562f7878991 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0242184 infores:hetionet CHEBI:63632 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0027947 infores:hetionet CHEBI:391960 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0010200 infores:hetionet CAID:CA16020759 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020759 MONDO:0009861 PMID:17846916 Pathogenic PM3, PP4_Moderate, PM2, PVS1 The c.266_267insG variant in PAH has been previously reported as a homozygous variant in an Australian proband with PKU (not otherwise specified) from a consanguineous family; the paper does not state whether BH4 deficiency was excluded (PMID: 24368688). The variant was also found in a French proband with classic PKU in trans with the p.Pro281Leu variant, which has been classified as a VUS per internal PAH ClinGen Working Group classification (see PAH0660); the paper does not state whether BH4 deficiency was excluded (PMID: 26666653). The variant was also found in 1 Caucasian proband with classic PKU, in trans with the known pathogenic c.1066-11G>A variant (PMID: 23430918); BH4 deficiency was excluded via biochemical testing per the recruiting study protocol (PMID: 17846916). Finally, it was found in three Southern German probands with classic PKU; no further details regarding genotype and/or exclusion of BH4 deficiency were given (PMID: 12655553). Thus, PP4_Moderate and PM3 apply per the report in PMID: 17846916. The sequence change results in a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020759/MONDO:0009861/006 2019-04-04 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:7773 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0019521 infores:hetionet CHEBI:5134 biolink:causes HP:0007380 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0858684 infores:hetionet CHEBI:44032 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042075 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0030305 infores:hetionet CHEBI:5959 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0344232 infores:hetionet CHEBI:27834 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C2830004 infores:hetionet CAID:CA320642989 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642989 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 The NM_001754.5(RUNX1):c.98-4G>A is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has not been reported in any individuals meeting at least one of the RUNX1-phenotypic criteria. This intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642989/MONDO:0011071/008 2024-07-17 2024-07-17 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBITaxon:2 biolink:causes MONDO:0000265 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D011015 DB01053_MESH_D011015_1DB01190_MESH_D011015_1DB01061_MESH_D011015_1 CHEBI:63622 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0085633 infores:hetionet CHEBI:567361 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0152025 infores:hetionet CHEBI:63610 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0003467 infores:hetionet CHEBI:30659 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0018213 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0013922 infores:hetionet CHEBI:3757 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0004093 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151763 infores:hetionet CHEBI:41774 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030193 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0014518 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0522063 infores:hetionet CHEBI:40303 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C1443060 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0017160 infores:hetionet CHEBI:45081 biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0000729 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0014534 infores:hetionet CHEBI:6078 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0009676 infores:hetionet CHEBI:15551 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0042373 infores:hetionet CHEBI:31174 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0041834 infores:hetionet CHEBI:100246 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C1384666 infores:hetionet CAID:CA16621248 biolink:causes MONDO:0010726 infores:clingen CAID:CA16621248 MONDO:0010726 PMID: Uncertain Significance BP5, BS2_Supporting, PM6 PP3, PM2, BP4 The p.Arg85Cys variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in one individual (3billion) (PM6). The p.Arg85Cys variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). The p.Arg85Cys variant in MECP2 (NM_004992.3) is observed in 1 unaffected individuals (internal database) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Arg85Cys variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM6, BP5, BS2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621248/MONDO:0010726/016 2022-12-08 2022-12-23 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:3732 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0853149 infores:hetionet CHEBI:70746 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0013182 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0009763 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0020621 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020522 infores:hetionet CHEBI:5778 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0520966 infores:hetionet CHEBI:16335 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0027424 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0740319 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0740319 infores:hetionet CHEBI:27565 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00233 UMLS:C0018681 infores:hetionet CHEBI:2663 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0014518 infores:hetionet CAID:CA562217619 biolink:causes MONDO:0021056 infores:clingen CAID:CA562217619 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.7489dup (p.Ser2497PhefsTer14) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236770 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in 1 family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, Invitae internal data). Moreover, the variant has been reported in one additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and in three unaffected individuals with a family history of gastrointestinal cancer and/or colorectal polyps (Ambry Genetics and Invitae internal data). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen HCCP VCEP: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications version v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA562217619/MONDO:0021056/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63623 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0426576 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0235564 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0235564 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0080194 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0080194 infores:hetionet CHEBI:134991 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0016204 infores:hetionet CAID:CA9870170 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870170 MONDO:0015967 PMID: Likely Benign BP4, BP7 PM2, BS1 The c.123C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 41 (p.(Cys41=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.297, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.123C>T variant in gnomAD v2.1.1 is 0.00002295, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.123C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870170/MONDO:0015967/085 2023-01-12 2023-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8772 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0232849 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0235957 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0235957 infores:hetionet CHEBI:5893 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0017152 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0015230 infores:hetionet CHEBI:64355 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013404 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0409974 infores:hetionet CAID:CA015264 biolink:causes MONDO:0007947 infores:clingen CAID:CA015264 MONDO:0007947 PMID: Benign BA1 PM2, PM6, PP2, PP3, PP4, PP1, BP4, BP2, PS4, PS2, PS3, PM1, BP5, BS1, BS4, BS3 The NM_00138 c.4640C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by isoleucine at amino acid 1547 (p.Thr1547Ile). This variant was found one proband with Marfan syndrome (PMID 24793577) and in three apparently unrelated probands with features of Marfan syndrome (PMID 24793577, internal data). In one of these individuals with features of Marfan syndrome, this variant was also detected in the proband’s mother and sister, both of whom had a systemic score of 9, however relatedness of these individuals was not confirmed (internal data). This variant was also identified in an individual with features of Marfan syndrome but no diagnosis who also carried a pathogenic variant in FBN1, c.3193delG p.Glu1065Lysfs*23 (PMID 29543232). The variant in FBN1 has been reported 17 times in ClinVar: 6 times as uncertain significance and 11 times as likely benign (Variation ID: 42367). This variant has been identified in 37 individuals of Latino/Admixed American origin in gnomAD v3.1.2 (MAF: 0.24%) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.375). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA015264/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:2666 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C2364111 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0920102 infores:hetionet CHEBI:48273 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0040822 infores:hetionet CAID:CA312265 biolink:causes MONDO:0008723 infores:clingen CAID:CA312265 MONDO:0008723 PMID:20060901PMID:9973285 Likely Pathogenic PM2_Supporting, PP4, PP3, PM3, PM1 PM5 The c.1097G>A (p.Arg366His) variant in ACADVL has been reported in the literature in patients with VLCADD or increased C14:1 acylcarnitine levels (PP4; PMID: 9973285, 20060901, 27246109, 24263034, 32558070). The variant has been detected as homozygote (PMID:24263034), or compound heterozygote with truncating/pathogenic variants, however without phase confirmation (PMID: 32558070, 27246109, 20060901, PM3). The highest population minor allele frequency in gnomAD is 0.0001 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant resides within a region defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, 20060901, PM1). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PP4, PM1, PM3, PM2_Supporting, PP3). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312265/MONDO:0008723/021 2022-09-22 2022-09-22 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2704 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151547 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0234913 infores:hetionet CHEBI:136040 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0080274 infores:hetionet NCBIGene:835 biolink:causes MONDO:0957999 infores:monarchinitiative not_provided not_provided HGNC:1503 MONDO:0957999 uuid:b358916f-5f09-4c08-a37d-9fb40f330434 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167309 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0012833 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0027765 infores:hetionet CHEBI:2675 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0423153 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0023646 infores:hetionet CHEBI:8428 biolink:causes MONDO:0017989 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C0039235 infores:hetionet CHEBI:31236 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0036974 infores:hetionet CHEBI:47898 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0043094 infores:hetionet CHEBI:4798 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0015371 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0027765 infores:hetionet CHEBI:10119 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085615 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0013395 infores:hetionet CHEBI:724125 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0011616 infores:hetionet CHEBI:119915 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0043352 infores:hetionet CHEBI:94411 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0020620 infores:hetionet CHEBI:65173 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0003862 infores:hetionet CHEBI:36791 biolink:causes HP:0001373 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0012691 infores:hetionet CHEBI:46295 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C3665386 infores:hetionet CHEBI:15544 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C3665386 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0031350 infores:hetionet CHEBI:8245 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0009676 infores:hetionet CHEBI:119573 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0028734 infores:hetionet CHEBI:408174 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0030794 infores:hetionet CAID:CA367397019 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397019 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PVS1, PM2_Supporting PP4 The c.1322C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 441 (p.(Ser441Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD (PM2_Supporting). This variant was identified in multiple individuals with diabetes/hyperglycemia consistent with GCK-MODY; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 32710514, internal lab contributors). This variant segregated with diabetes, with 5 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). In summary, the c.1322C>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PS4_Moderate, PP1_strong. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397019/MONDO:0015967/086 2023-09-08 2023-09-08 Semidominant inheritance HP:0032113 Supports CHEBI:6129 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0035455 infores:hetionet UMLS:C0065374 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0231528 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0020456 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0020538 infores:hetionet CHEBI:3387 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0032343 infores:hetionet CHEBI:7959 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0002874 infores:hetionet CHEBI:6950 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0231218 infores:hetionet NCBIGene:21 biolink:causes MONDO:0012582 infores:monarchinitiative not_provided not_provided HGNC:33 MONDO:0012582 uuid:8600199f-daa2-4fec-b8cf-1b325cbe3ea5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2047937 infores:hetionet CAID:CA16020876 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020876 MONDO:0009861 PMID:27121329PMID:27121329 Likely Pathogenic PM3, PM5, PP4_Moderate, PM2 PP3 The c.847A>G (p.Ile283Val) variant in PAH is absent from all population databases, and is at the same amino acid as a previously established pathogenic variant (c.847A>T (p.Ile283Phe)). It has been identified in a patient with classic PKU (BH4 defect excluded), and in trans with a known pathogenic variant (c.1045T>C, p.Ser349Pro) PMID: 27121329. Summary evidence using PAH specific ACMG/AMP guidelines :PM2, PM5, PM3, PP4_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020876/MONDO:0009861/006 2018-12-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50173 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0086543 infores:hetionet CHEBI:8776 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0040034 infores:hetionet CHEBI:8207 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C3665347 infores:hetionet CHEBI:28864 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0232462 infores:hetionet CAID:CA212751 biolink:causes MONDO:0009861 infores:clingen CAID:CA212751 MONDO:0009861 PMID:8088845PMID:8088845PMID:8088845 Likely Pathogenic PM3, PM2, PP1, PP4, PP3 The c.1065+3A>G variant in PAH was detected in 2 siblings with an increased serum Phenylalanine level of 365 uM. BH4 deficiency was not assessed/reported. (PMID: 8088845) They were compound heterozygous for Y414C. The c.1065+3A>G variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted for this variant in HSF and MaxEnt (Alteration of the WT donor site; activation of an intronic cryptic donor site). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA212751/MONDO:0009861/006 2018-12-10 2019-05-04 Autosomal recessive inheritance HP:0000007 Supports CAID:CA8815251 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815251 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting PP3, BP4 The NM_000152.5:c.1288G>A (p.Glu430Lys) variant in GAA has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00043 (10/23086 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.577 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. SpliceAI predicts no impact on splicing. To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of functional studies are not available. However, there is a ClinVar entry for this variant (Variation ID: 501777). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 6, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815251/MONDO:0009290/010 2023-04-06 2024-04-12 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true PUBCHEM.COMPOUND:45357473 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013390 infores:hetionet CHEBI:68478 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0034155 infores:hetionet NCBIGene:6521 biolink:causes MONDO:0008368 infores:monarchinitiative not_provided not_provided HGNC:11027 MONDO:0008368 uuid:3b7e05a8-0fe7-41ac-9371-3af8c132573e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:453011 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0085624 infores:hetionet NCBIGene:55325 biolink:causes MONDO:0007726 infores:monarchinitiative not_provided not_provided HGNC:25640 MONDO:0007726 uuid:7460e8bd-bbeb-49f9-afa6-e705fe854ff6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3387 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0018802 infores:hetionet CHEBI:8060 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0344232 infores:hetionet GO:0009794 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:0009794 GO:0009790 UNII:3QJA87N40S biolink:causes MONDO:0006807 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0021845 infores:hetionet CHEBI:3568 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0392699 infores:hetionet CAID:CA2573131753 biolink:causes MONDO:0100326 infores:clingen CAID:CA2573131753 MONDO:0100326 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000419.5(ITGA2B):c.1999dup (p.Asp667GlyfsTer11) frameshift variant in exon 20 is predicted to cause a premature stop codon in biologically-relevant-exon 21/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It has been reported homozygous (PM3_supporting) in at least one GT proband (case 12 in PMID: 32089034) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was 0.2-4%, as measured by flow cytometry (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4_moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573131753/MONDO:0100326/011 2022-09-20 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:8802 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0007785 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0042373 infores:hetionet CHEBI:31236 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0151827 infores:hetionet CHEBI:119486 biolink:causes MONDO:0024280 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0162323 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0232097 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0232097 infores:hetionet CHEBI:3636 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0162297 infores:hetionet CHEBI:2549 biolink:causes NCIT:C111815 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0392703 infores:hetionet NCBIGene:2652 biolink:causes MONDO:0010564 infores:monarchinitiative not_provided not_provided HGNC:4206 MONDO:0010564 uuid:41e32af5-e560-45f9-8078-a63f94ff1fb7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28830 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0687713 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0162429 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0948089 infores:hetionet CHEBI:4027 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0005758 infores:hetionet CHEBI:16469 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0237849 infores:hetionet CAID:CA165011 biolink:causes MONDO:0700270 infores:clingen CAID:CA165011 MONDO:0700270 PMID: Uncertain Significance PM2_Supporting, PP3 BA1, BS1 The ATM c.1905_1910del (p.His365_His636del) variant is absent in the GnomAD v2.1.1 cohort (PM2_Supporting). In silico structural impact predictors (Provean, -3.857) predict that this alteration is deleterious (PP3). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA165011/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68478 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0041976 infores:hetionet CHEBI:391960 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0011603 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0234458 infores:hetionet CHEBI:51137 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0267792 infores:hetionet CAID:CA025007 biolink:causes MONDO:0007783 infores:clingen CAID:CA025007 MONDO:0007783 PMID:12883402 Likely Pathogenic PP1, PS3_Moderate, PS4_Supporting, PM1 PP3, BS1, BS3, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with tryptophan at codon 328 of the RYR1 protein p.(Arg328Trp). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00006 maf, a frequency consistent with pathogenicity for MHS. This variant has been reported in one proband with a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Supporting (PMID:12883402). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:12883402). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, ( PM1, PM1_Sup) (PMID: 21118704). This variant segregates with MHS in four individuals, PP1 (PMID:12883402). For these reasons, this variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Supporting, PS3_Moderate, PM1, PP1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA025007/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:3001 biolink:causes MONDO:0006640 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0001622 infores:hetionet CHEBI:145499 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0010692 infores:hetionet CHEBI:15365 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0034150 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017160 infores:hetionet CHEBI:45863 biolink:causes MONDO:0021040 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0346647 infores:hetionet CHEBI:36791 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0580413 infores:hetionet CHEBI:7581 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0011168 infores:hetionet CHEBI:2704 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0267792 infores:hetionet CHEBI:9086 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0040435 infores:hetionet CHEBI:83804 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0268000 infores:hetionet CHEBI:17347 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0858635 infores:hetionet CHEBI:46345 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0233407 infores:hetionet CHEBI:119915 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0917801 infores:hetionet CHEBI:10650 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0014724 infores:hetionet NCBIGene:4853 biolink:causes MONDO:0012439 infores:monarchinitiative not_provided not_provided HGNC:7882 MONDO:0012439 uuid:11694b6b-ded0-4980-968e-dbe6be9d8598 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0917801 infores:hetionet CAID:CA023868 biolink:causes MONDO:0100150 infores:clingen CAID:CA023868 MONDO:0100150 PMID: Benign BP7, BA1, BP4 BS1, BS3, PM2, PVS1, BP3, PM5, PM4, PS3, PS1 The NM_000540.3:c.-108T>C variant is located in exon 1 (5’ UTR) of the RYR1 gene. The filtering allele frequency (the lower threshold of the 95% CI of 8126/59394, 618 homozygotes) of the c.-108T>C variant in RYR1 is 0.1297 for African/African American chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). This variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets the criteria to be classified as benign for RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA023868/MONDO:0100150/179 2024-08-07 2024-10-02 Undetermined mode of inheritance Contradicts true CHEBI:18358 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0015230 infores:hetionet UMLS:C1709429 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0030196 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0027796 infores:hetionet CHEBI:194135 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020625 infores:hetionet CHEBI:3219 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013491 infores:hetionet CHEBI:2666 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0085605 infores:hetionet CHEBI:50730 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0233407 infores:hetionet NCBIGene:389434 biolink:causes MONDO:0010136 infores:monarchinitiative not_provided not_provided HGNC:21071 MONDO:0010136 uuid:33225fb0-4a40-4c05-978e-655ed0e4fc76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4511 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0015967 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0919883 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0919883 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0020649 infores:hetionet CHEBI:5138 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011124 infores:hetionet CHEBI:3176 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0022281 infores:hetionet CHEBI:65173 biolink:causes MONDO:0040871 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0395005 infores:hetionet CHEBI:404903 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0700345 infores:hetionet CHEBI:9599 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0023646 infores:hetionet CHEBI:8024 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042024 infores:hetionet CAID:CA023671 biolink:causes MONDO:0007750 infores:clingen CAID:CA023671 MONDO:0007750 PMID: Uncertain Significance PS3, BS1, PP3 BA1, BP1, BP4, BP3, BP2, PS1, PS4, PS2, BP7, BP5, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP4, PP1, BS2 The NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, PS3 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.003604 (0.3604%) in African/African American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.768.PS3: Level 1 assay, PMID 37739193 (Mori et al., 2024): Heterologous cells (HepG2 transfected cells with CRISPR/Cas9), FACS, WB, and CLSM assays. FACS: ~40% cell surface LDLR, 6% binding, and 7% uptake; WB: altered expression of LDLR in HepG2 cells transfected ---- results are below 70% of wild-type, consistent with damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023671/MONDO:0007750/013 2024-08-30 2024-10-09 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true UNII:D27V6190PM biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0010200 infores:hetionet CHEBI:28001 biolink:causes UMLS:C0151585 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0151585 infores:hetionet NCBIGene:5934 biolink:causes MONDO:0859217 infores:monarchinitiative not_provided not_provided HGNC:9894 MONDO:0859217 uuid:e4bc0294-5208-4d7d-be36-c9b308d1fb8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0018799 infores:hetionet CHEBI:74947 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0021141 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0233571 infores:hetionet CHEBI:94501 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C1262144 infores:hetionet CHEBI:9720 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C0235238 infores:hetionet CHEBI:6062 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0234215 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0034063 infores:hetionet CHEBI:7478 biolink:causes UMLS:C0240925 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0240925 infores:hetionet CAID:CA401369854 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369854 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PM3, PM2_Supporting, PM5_Supporting PP3, BP4 The NM_000152.5:c.1903A>G variant in GAA is predicted to result in a missense substitution from asparagine to aspartate at amino acid 635 (p.Asn635Asp). The variant has been identified in at least 3 probands, all identified by positive newborn screen, with confirmatory GAA activity in dried blood spot of 1.0, 1.3, and 1.34 pmol/punch/hour (affected range <3.88); pseudodeficiency variants are confirmed to be absent (Clinical Diagnostic Laboratory, PMID: 37087815) (PP4_Moderate). Each of these individuals is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, either c.2238G>C (p.Trp746Cys), c.2560C>T (p.Arg854Ter), and c.-32-13T>G; phase not confirmed (Clinical diagnostic laboratory) (PM3). The highest population minor allele frequency in gnomAD v4.0. is 0.000003602 (4/1110350 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.518 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Another missense variant at the same amino acid position, c.1905C>A (p.Asn635Lys), has been reported in four Brazilian probands with Pompe disease (PMID: 19588081) and has been classified as likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 1348299). In summary, this variant meets the criteria to e classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting, PM5_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369854/MONDO:0009290/010 2023-12-20 2023-12-22 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:45367 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0178298 infores:hetionet CHEBI:9570 biolink:causes MONDO:0002146 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020619 infores:hetionet CHEBI:4909 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0235996 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0235656 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0235656 infores:hetionet UNII:3U02EL437C biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0030794 infores:hetionet CHEBI:4903 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0269189 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0018382 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0149887 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0917798 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0240417 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0240417 infores:hetionet CHEBI:3082 biolink:causes MONDO:0044137 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0155365 infores:hetionet CHEBI:145499 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0033036 infores:hetionet CHEBI:50730 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0010200 infores:hetionet CHEBI:66876 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0011603 infores:hetionet CHEBI:5775 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0015300 infores:hetionet CHEBI:8404 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0522224 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020538 infores:hetionet CAID:CA9871463 biolink:causes MONDO:0007064 infores:clingen CAID:CA9871463 MONDO:0007064 PMID: Uncertain Significance PM2_Supporting BS2, PM5 The c.937C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 313 (p.Arg313Trp).The filtering allele frequency (the upper threshold of the 95% CI of 25/1180022 alleles) of the c.937C>T variant in ADA is 0.00001454 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Another missense variant [c.938G>A, p.Arg313Gln] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met).To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies.Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9871463/MONDO:0007064/114 2024-04-23 2024-04-23 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5779 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0011053 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0267596 infores:hetionet CHEBI:45327 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0264906 infores:hetionet CHEBI:71219 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0040053 infores:hetionet CHEBI:5132 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0151539 infores:hetionet CHEBI:17650 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0085633 infores:hetionet CHEBI:6801 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0428977 infores:hetionet CHEBI:2453 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0023222 infores:hetionet CHEBI:9139 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0438142 infores:hetionet CHEBI:367163 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020615 infores:hetionet CHEBI:7565 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0008031 infores:hetionet CHEBI:5118 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0699828 infores:hetionet CHEBI:8107 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0011616 infores:hetionet CHEBI:5613 biolink:causes MONDO:0021095 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0242422 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0851341 infores:hetionet CHEBI:2567 biolink:causes MONDO:0006858 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0026636 infores:hetionet CAID:CA16609060 biolink:causes MONDO:0011071 infores:clingen CAID:CA16609060 MONDO:0011071 PMID: Uncertain Significance BP4 PS4, PS3, PS2, PS1, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM5, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.1184C>G (p.Pro395Arg) is a missense variant which has a REVEL score of 0.334 and a SpliceAI score ≤ 0.20, meeting the threshold for BP4. It is reported at a MAF of 0.00002943 in the admixed American population (gnomAD v3), which does not meet any population criteria. Although it has been reported in a patient (PMID: 32554555), the proband does not meet criteria for PS4 due to lack of germline confirmation. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609060/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9168 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0034065 infores:hetionet CAID:CA512318894 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318894 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.243G>A (p.Val81=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.07) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.07) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.32) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318894/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:47519 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0241057 infores:hetionet CHEBI:8597 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0015371 infores:hetionet CHEBI:72690 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0750394 infores:hetionet CAID:CA9043553 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043553 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4, PM5_Supporting The NM_000156.6:c.623G>A variant in GAMT is a missense variant predicted to cause substitution of arginine by histidine at amino acid 208 (p.Arg208His). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001114 (5/44894 alleles) in the East Asian population. This is lower that the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), therefore meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.279 which is below the threshold of 0.29, evidence that correlates with no impact to GAMT function (BP4). In addition, SpliceAI predicts that the variant will have no impact on splicing. Two additional missense variants at this amino acid position have been reported - c.622C>T (p.Arg208Cys) (ClinVarID: 5442618) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208Cys has been classified as a VUS (PM5_Supporting). To our knowledge, c.623G>A (p.Arg208His) has not been previously reported in the published literature, but has been noted in ClinVar (ClinVar ID 577478). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0.: PM2_Supporting, PM5_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on April 28, 2025). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043553/MONDO:0012999/026 2025-04-28 2025-04-28 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8346 biolink:causes MONDO:0001220 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0020626 infores:hetionet CAID:CA386952758 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952758 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP2, PS4_Moderate, PM1_Supporting, PP3 PP4 The c.85G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 29 (p.(Ala29Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.908, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant has been observed in unknown phase in one individual with the c.143del variant, which is classified as likely pathogenic (PVS1, PM2_Supporting) by ClinGen MDEP HNF1A specifications (BP2; internal lab contributors). In summary, c.85G>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3, PS4_Moderate, BP2. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952758/MONDO:0015967/017 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3647 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0162830 infores:hetionet CHEBI:3215 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0001122 infores:hetionet CHEBI:6950 biolink:causes UMLS:C0694536 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0694536 infores:hetionet CHEBI:10650 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0003537 infores:hetionet CHEBI:83804 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0009763 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0011991 infores:hetionet CAID:CA000063 biolink:causes MONDO:0018875 infores:clingen CAID:CA000063 MONDO:0018875 PMID:12826609PMID:30224644 Benign BP4, BS3, BS2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BS1, BS4, PM2, PP3, PP1, PP4 The NM_000546.6: c.188C>T variant in TP53 is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 63 (p.Ala63Val). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor: Invitae). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.099; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.1; 1/16/2025). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000063/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA410147848 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147848 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1180G>A (p.Gly394Ser) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147848/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:27690 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0032617 infores:hetionet CHEBI:15854 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0040264 infores:hetionet CHEBI:4995 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0392171 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0426576 infores:hetionet CHEBI:10119 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0162298 infores:hetionet CHEBI:3127 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0011603 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005173 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0022602 infores:hetionet CHEBI:31401 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0011609 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0854303 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0854303 infores:hetionet CHEBI:27899 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151603 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0002520 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0162533 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0242350 infores:hetionet CHEBI:50648 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0152030 infores:hetionet CHEBI:31174 biolink:causes UMLS:C0281982 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0281982 infores:hetionet CHEBI:50861 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0004093 infores:hetionet CHEBI:31236 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0011175 infores:hetionet CHEBI:28864 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0033687 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0242350 infores:hetionet CHEBI:92511 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0019158 infores:hetionet NCBIGene:1278 biolink:causes MONDO:0008147 infores:monarchinitiative not_provided not_provided HGNC:2198 MONDO:0008147 uuid:57a91173-56a6-4da0-a785-94cd1761f525 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16899 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0239377 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0042514 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151734 infores:hetionet NCBIGene:58508 biolink:causes MONDO:0054701 infores:monarchinitiative not_provided not_provided HGNC:13726 MONDO:0054701 uuid:76741d29-190f-4176-bfd9-be06fd4679ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0236075 infores:hetionet CHEBI:37924 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0235031 infores:hetionet CHEBI:8871 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038999 infores:hetionet GO:2000733 biolink:causes GO:0060676 infores:ubergraph knowledge_assertion manual_agent GO:2000733 GO:0060676 CHEBI:4708 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0344232 infores:hetionet CHEBI:144551 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0042075 infores:hetionet CHEBI:46345 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0017178 infores:hetionet CHEBI:47898 biolink:causes HP:0001907 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0040038 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0015397 infores:hetionet CHEBI:31980 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0042109 infores:hetionet CHEBI:17141 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0178298 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023895 infores:hetionet CHEBI:7915 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0041657 infores:hetionet CAID:CA404093324 biolink:causes MONDO:0007750 infores:clingen CAID:CA404093324 MONDO:0007750 PMID: Uncertain Significance PM2, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP3, PP1 The NM_000527.5(LDLR):c.1981C>A (p.Pro661Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2 and is identified in 1 case in PMID 34456049 (Marco-Benedí et al., 2022), Spain, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404093324/MONDO:0007750/013 2023-06-23 2025-09-15 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:47781 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0018681 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018799 infores:hetionet CHEBI:45081 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0149745 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0013295 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042769 infores:hetionet CHEBI:145499 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0001807 infores:hetionet CHEBI:5855 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0234215 infores:hetionet CHEBI:3213 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0235431 infores:hetionet CHEBI:5801 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0013144 infores:hetionet CHEBI:66876 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0015967 infores:hetionet CHEBI:51209 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0013428 infores:hetionet CHEBI:9613 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0000731 infores:hetionet CHEBI:184555 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0038362 infores:hetionet CHEBI:75722 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085649 infores:hetionet CHEBI:45285 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0011603 infores:hetionet CHEBI:2948 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0234215 infores:hetionet CHEBI:44241 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0178298 infores:hetionet CHEBI:61049 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0036974 infores:hetionet NCBIGene:27032 biolink:causes MONDO:0008218 infores:monarchinitiative not_provided not_provided HGNC:13211 MONDO:0008218 uuid:a8299843-ec98-4607-833a-5722fd5f6bb3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:127780 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0020625 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0205204 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0205204 infores:hetionet CHEBI:5280 biolink:causes HP:0001325 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020617 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0033860 infores:hetionet CHEBI:45783 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0031350 infores:hetionet CHEBI:36795 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0028084 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0030196 infores:hetionet CHEBI:5118 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0028643 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0162830 infores:hetionet CHEBI:28593 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0003537 infores:hetionet CHEBI:3654 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0004093 infores:hetionet CHEBI:71940 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0033117 infores:hetionet CHEBI:75984 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0232462 infores:hetionet CHEBI:474180 biolink:causes HP:0034807 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1956415 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0031117 infores:hetionet CHEBI:7494 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151798 infores:hetionet CHEBI:3506 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0042109 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0178298 infores:hetionet CHEBI:3423 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0438717 infores:hetionet CHEBI:17334 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0010520 infores:hetionet CHEBI:61390 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0030578 infores:hetionet NCBIGene:5395 biolink:causes MONDO:0030843 infores:monarchinitiative not_provided not_provided HGNC:9122 MONDO:0030843 uuid:b8ca6160-b2c7-411f-8c25-f6e313a1433d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7494 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0542571 infores:hetionet CHEBI:47657 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0037763 infores:hetionet CHEBI:367163 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0019209 infores:hetionet CHEBI:80630 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0015376 infores:hetionet CHEBI:3219 biolink:causes HP:0000633 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0235857 infores:hetionet CHEBI:178699 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0000833 infores:hetionet CHEBI:6887 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0018524 infores:hetionet UNII:VL0L558GCB biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0853813 infores:hetionet CHEBI:64355 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0036508 infores:hetionet CHEBI:10127 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0013395 infores:hetionet CHEBI:31625 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0235266 infores:hetionet CHEBI:45863 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0035078 infores:hetionet CHEBI:8597 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0004134 infores:hetionet CHEBI:4027 biolink:causes MONDO:0019737 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C2717961 infores:hetionet CHEBI:4995 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0542571 infores:hetionet CHEBI:47898 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0520887 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0152025 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0006145 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0853149 infores:hetionet CHEBI:84500 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0020473 infores:hetionet NCBIGene:6709 biolink:causes MONDO:0957815 infores:monarchinitiative not_provided not_provided HGNC:11273 MONDO:0957815 uuid:b32687e6-77d8-47cb-9636-11bc07ef20e2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1457883 infores:hetionet CHEBI:51860 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0036974 infores:hetionet GO:0140166 biolink:causes GO:0002003 infores:ubergraph knowledge_assertion manual_agent GO:0140166 GO:0002003 CHEBI:49575 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0087169 infores:hetionet CHEBI:63620 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0392676 infores:hetionet CAID:CA386940977 biolink:causes MONDO:0015967 infores:clingen CAID:CA386940977 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PP3, PP4 The c.1781G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to isoleucine at codon 594 (p.(Ser594Ile)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9392505, internal lab contributors). This variant segregated with diabetes, with at least 5 informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% but antibody-negative and sulfonylurea-sensitive, negative genetic testing for HNF4A) (PP4; PMID: internal lab contributors). In summary, c.1781G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PP3, PM2_Supporting, PS4, PP1_Strong, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386940977/MONDO:0015967/017 2022-07-01 2022-07-01 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6367 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0241934 infores:hetionet CHEBI:7565 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0003467 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0948089 infores:hetionet CHEBI:100147 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C2830004 infores:hetionet CHEBI:50648 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0151825 infores:hetionet CHEBI:8713 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0011570 infores:hetionet CHEBI:37941 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0023646 infores:hetionet CHEBI:63622 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0015967 infores:hetionet CHEBI:135876 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0018681 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0233494 infores:hetionet CHEBI:41423 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0025222 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0178298 infores:hetionet CHEBI:55346 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0008370 infores:hetionet CAID:CA8337581 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337581 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4, PP3, PM1, PM3, PM5, PM4, BP2, PS1, BP7 The c.192del (p.Lys64fs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 3/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.0001603 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency has been reported with this variant (PMID: 26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337581/MONDO:0008723/021 2022-09-23 2022-09-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:83531 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0025874 infores:hetionet CHEBI:63630 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0312420 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020615 infores:hetionet CHEBI:9150 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0042963 infores:hetionet CAID:CA624860771 biolink:causes MONDO:0008723 infores:clingen CAID:CA624860771 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.1630_1645del (p.Ala544Profs*3) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 17/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624860771/MONDO:0008723/021 2022-12-15 2022-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5779 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0030196 infores:hetionet CHEBI:47612 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0011603 infores:hetionet CAID:CA255368 biolink:causes MONDO:0010604 infores:clingen CAID:CA255368 MONDO:0010604 PMID: Pathogenic PM2_Supporting, PM1, PS4_Very Strong, PP1, PS3_Supporting, PP4_Moderate PM5, PP3 The c.881G>A, p.Arg294Gln variant affects one of the functional domains (aa 227-459; Peptidase S1 domain) in the F9 protein meeting PM1. The variant is absent from male population databases (gnomAD v4.1) meeting PM2_Supporting. At least 30 patients with mild, moderate or severe hemophilia B have been reported in the literature reviewed meeting PS4_Very Strong and PP4_Moderate (PMID: 29296726, 15921378, 8091381). In-vitro functional studies show that the variant causes ER retention of the F9 protein, leading to reduced antigen levels meeting PS3_Supporting. REVEL score for this variant does not fall within the thresholds for pathogenic or benign predictions, and no splicing impact is noted by SpliceAI. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very Strong, PM1, PP4_Moderate, PS3_Supporting, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255368/MONDO:0010604/080 2024-11-01 2024-11-01 X-linked inheritance HP:0001417 Supports CHEBI:49960 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0013604 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0042267 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0021400 infores:hetionet CHEBI:27666 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0023530 infores:hetionet CHEBI:367163 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1260880 infores:hetionet CHEBI:4708 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0558489 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005043 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020507 infores:hetionet CHEBI:63608 biolink:causes NCIT:C113751 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C2242708 infores:hetionet CHEBI:9763 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0404521 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2225524 infores:hetionet CHEBI:100246 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0006444 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005246 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0029443 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0038363 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0149931 infores:hetionet CHEBI:5098 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0027497 infores:hetionet GO:1902869 biolink:causes GO:0007417 infores:ubergraph knowledge_assertion manual_agent GO:1902869 GO:0007417 CHEBI:35677 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0178298 infores:hetionet GO:1902869 biolink:causes GO:0043010 infores:ubergraph knowledge_assertion manual_agent GO:1902869 GO:0043010 CHEBI:27899 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0037763 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0026821 infores:hetionet CAID:CA254240 biolink:causes MONDO:0800472 infores:clingen CAID:CA254240 MONDO:0800472 PMID: Likely Pathogenic PP3, PM2_Supporting, PM3, PP1_Strong, PS3_Supporting BA1, BP4, PS1, PS2, PM1, PM4, PM5, BS1, BS4, BP7, PVS1 The c.1120G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 374 (p.Asp374Asn). The highest minor allele frequency of this variant was in the Middle Eastern genetic ancestry group of gnomAD (v4.1.0) = 0.0001651 (1 allele out of 6,058), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.701, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. A previous study (PMID: 12807732) demonstrated that the Asp374Asn protein had reduced Benzo[a]pyrene Activity levels compared to wild type CYP1B1 protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. ≥3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 19597567), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in five individuals with a CYP1B1-related phenotype. Two of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) and three of these individuals are homozygous (consanguineous) for this variant (PMIDs: 9463332, 19597567). Total proband points = 1.75, meeting PM3. In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PP1_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA254240/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100147 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0948594 infores:hetionet CHEBI:3061 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0017152 infores:hetionet CHEBI:63613 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0033774 infores:hetionet NCBIGene:2495 biolink:causes MONDO:0958012 infores:monarchinitiative not_provided not_provided HGNC:3976 MONDO:0958012 uuid:3afdc761-82fc-40b2-9e46-b6c691d2155e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0428977 infores:hetionet CHEBI:5127 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00846 UMLS:C0020555 infores:hetionet NCBIGene:6794 biolink:causes MONDO:0007963 infores:monarchinitiative not_provided not_provided HGNC:11389 MONDO:0007963 uuid:90f9ddbe-2b95-44a7-b505-784375d2b0fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:175901 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0700292 infores:hetionet CHEBI:8890 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0040822 infores:hetionet CAID:CA512341368 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341368 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.1017G>T (p.Leu339=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.37)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341368/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6887 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0340464 infores:hetionet CHEBI:32221 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0034150 infores:hetionet CHEBI:63611 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022660 infores:hetionet CHEBI:9168 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0009782 infores:hetionet CHEBI:75984 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0013395 infores:hetionet CHEBI:9123 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0025222 infores:hetionet CHEBI:18358 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0162835 infores:hetionet CAID:CA350337 biolink:causes MONDO:0007648 infores:clingen CAID:CA350337 MONDO:0007648 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM1, PM4, PM5, PM3, PVS1, PM2, PM6, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS3, PS1, PS2, PS4 The c.499G>A (p.Glu167Lys) variant has also been observed in >10 (28) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329225.7; SCV000259296.7). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA350337/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:140621 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0027765 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0042109 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0042401 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0009450 infores:hetionet CHEBI:2673 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0428977 infores:hetionet CHEBI:47612 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0006277 infores:hetionet CHEBI:101278 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0234215 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0020517 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0878544 infores:hetionet CHEBI:3219 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0156404 infores:hetionet CHEBI:3647 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0018939 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0435002 infores:hetionet CHEBI:6062 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0037287 infores:hetionet CHEBI:4495 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0027497 infores:hetionet CHEBI:8356 biolink:causes HP:0002304 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085623 infores:hetionet CHEBI:52717 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0021843 infores:hetionet CHEBI:9086 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0947912 infores:hetionet CHEBI:9215 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0015967 infores:hetionet CHEBI:38562 biolink:causes HP:0003493 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0151480 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0006840 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0039971 infores:hetionet CHEBI:31711 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0235086 infores:hetionet CHEBI:64354 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0151539 infores:hetionet CHEBI:59773 biolink:causes UMLS:C0850060 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0850060 infores:hetionet CHEBI:5280 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0018681 infores:hetionet CHEBI:135876 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0853813 infores:hetionet UNII:D27V6190PM biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0235266 infores:hetionet CHEBI:47499 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C2584688 infores:hetionet CHEBI:23765 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0232462 infores:hetionet CAID:CA376059956 biolink:causes MONDO:0011225 infores:clingen CAID:CA376059956 MONDO:0011225 PMID: Uncertain Significance PM2_Supporting The c.490T>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Leucine by Valine at amino acid 164 (p.Leu164Val).The highest population minor allele frequency in gnomAD v4 is 0.00002519 (1/39698 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA376059956/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:68478 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0232462 infores:hetionet CHEBI:7454 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0033774 infores:hetionet CHEBI:63621 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0151662 infores:hetionet CHEBI:47499 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0040822 infores:hetionet CHEBI:465284 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0149725 infores:hetionet CAID:CA410146985 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146985 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM1, PM4, PM3, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.1382A>T (p.Asn461Ile) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting) - (gnomAD v2.1.1, v3, v4). This missense variant has a REVEL score < 0.50 (0.305) and a SpliceAI score ≤ 0.20 (Δ score 0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146985/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:55346 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0085593 infores:hetionet CHEBI:63681 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0026821 infores:hetionet CHEBI:5130 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0014852 infores:hetionet CHEBI:49603 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0004093 infores:hetionet CHEBI:42797 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020625 infores:hetionet CHEBI:4717 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0018524 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0037274 infores:hetionet CHEBI:119915 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0017168 infores:hetionet GO:0048863 biolink:causes CL:0000034 infores:ubergraph knowledge_assertion manual_agent GO:0048863 CL:0000034 CHEBI:2788 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0235266 infores:hetionet CHEBI:83804 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013378 infores:hetionet CHEBI:101085 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01144 UMLS:C0017178 infores:hetionet CHEBI:41879 biolink:causes UMLS:C1096278 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C1096278 infores:hetionet CHEBI:3001 biolink:causes MONDO:0018912 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0010481 infores:hetionet CHEBI:73274 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0404521 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C1269683 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0518015 infores:hetionet CHEBI:9123 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085605 infores:hetionet NCBIGene:1499 biolink:causes MONDO:0014035 infores:monarchinitiative not_provided not_provided HGNC:2514 MONDO:0014035 uuid:d8a96f71-9aa4-4540-8ba4-2cd393bc3302 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4903 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0035455 infores:hetionet CHEBI:5128 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0011603 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0026848 infores:hetionet CHEBI:5062 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0006826 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0232849 infores:hetionet NCBIGene:9364 biolink:causes MONDO:0014153 infores:monarchinitiative not_provided not_provided HGNC:9768 MONDO:0014153 uuid:c507d9e1-9d0a-4567-a8c5-ab6a954492e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151664 infores:hetionet CHEBI:3223 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0040264 infores:hetionet CHEBI:16755 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0040053 infores:hetionet NCBIGene:1801 biolink:causes MONDO:0800438 infores:monarchinitiative not_provided not_provided HGNC:3003 MONDO:0800438 uuid:7b44fd75-9328-49e3-9945-520877fb0e39 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0233471 infores:hetionet CHEBI:171719 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C2830004 infores:hetionet CHEBI:63616 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0018834 infores:hetionet CHEBI:4702 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0001824 infores:hetionet CHEBI:5864 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0022661 infores:hetionet CHEBI:3347 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0015672 infores:hetionet CHEBI:63605 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0014742 infores:hetionet CAID:CA367399678 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399678 MONDO:0015967 PMID: Pathogenic PVS1, PM2_Supporting, PS1_Supporting PS4, PP4 The c.1019+1G>T variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with hyperglycemia; however, PP4 is not met because they do not meet MDEP requirements for PP4 (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PMID: 34440516). The c.1019+1G>A variant at the same canonical nucleotide has a similar predicted donor loss score by Splice AI (.96 and .96), and has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1_Supporting). In summary, c.1019+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS1_Supporting, PM2_Supporting, Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399678/MONDO:0015967/086 2023-11-24 2023-11-24 Semidominant inheritance HP:0032113 Supports CHEBI:473990 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0042963 infores:hetionet CHEBI:3242 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0020453 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0033687 infores:hetionet CHEBI:3044 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00865 UMLS:C0917801 infores:hetionet CHEBI:7903 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0010200 infores:hetionet CHEBI:39585 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0003467 infores:hetionet CHEBI:8707 biolink:causes UMLS:C1263960 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C1263960 infores:hetionet CHEBI:9757 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00809 UMLS:C0033774 infores:hetionet CHEBI:47898 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0151825 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013922 infores:hetionet CHEBI:7443 biolink:causes UMLS:C0521616 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0521616 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0855242 infores:hetionet CHEBI:6067 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0001807 infores:hetionet CAID:CA202234 biolink:causes MONDO:0005338 infores:clingen CAID:CA202234 MONDO:0005338 PMID: Benign BP7, BP4, BA1 BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2 The c.855G>T variant in MYOC is a synonymous variant (p.Thr285=). The highest minor allele frequency of this variant was in the European (Finnish) population of gnomAD (v4.1.0) = 0.01723, which met the ≥ 0.01 threshold set for BA1 (1,101 alleles out of 63,896, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with Juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BA1, BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA202234/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31348 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0015230 infores:hetionet CHEBI:5893 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0013456 infores:hetionet CHEBI:63617 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0428977 infores:hetionet CHEBI:6532 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0015672 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0006277 infores:hetionet CHEBI:107736 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0027849 infores:hetionet CHEBI:102216 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00474 UMLS:C0023066 infores:hetionet CHEBI:6887 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0030305 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0022354 infores:hetionet NCBIGene:7275 biolink:causes MONDO:0014522 infores:monarchinitiative not_provided not_provided HGNC:12406 MONDO:0014522 uuid:5731e693-45f1-4af4-9d7a-868db2871195 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0031542 infores:hetionet CHEBI:63618 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0151798 infores:hetionet CHEBI:3441 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0013604 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0006277 infores:hetionet NCBIGene:51008 biolink:causes MONDO:0013662 infores:monarchinitiative not_provided not_provided HGNC:24268 MONDO:0013662 uuid:4676bf83-a6ca-4dc1-9e9d-ce7a192e5e42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0039231 infores:hetionet CHEBI:9654 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0023518 infores:hetionet CHEBI:291342 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0235169 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0852922 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0852922 infores:hetionet CHEBI:47898 biolink:causes NCIT:C112180 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0239343 infores:hetionet CHEBI:110423 biolink:causes MONDO:0001567 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0027709 infores:hetionet CHEBI:3568 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0027796 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0033975 infores:hetionet CHEBI:61033 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0002994 infores:hetionet CHEBI:7476 biolink:causes MONDO:0004989 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0678222 infores:hetionet CHEBI:5134 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0015967 infores:hetionet CHEBI:3207 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C1443060 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0948594 infores:hetionet CHEBI:63630 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C2047937 infores:hetionet CAID:CA166866 biolink:causes MONDO:0007648 infores:clingen CAID:CA166866 MONDO:0007648 PMID:22723466PMID:17522512PMID:16061854PMID:22723466PMID:17522512PMID:16061854 Pathogenic PM5_Supporting, PVS1, PP1_Strong BS1, BS4, BS3, BP7, BP5, PM4, PM1, PM3, PM2, PM6, BS2, PP3, PP2, PP4, BA1, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.1003C>T (p.Arg335*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 16061854, 22723466, 17522512). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PP1_Strong, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA166866/MONDO:0007648/007 2023-08-29 2023-08-29 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:6909 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0232492 infores:hetionet CHEBI:3638 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0001824 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0018799 infores:hetionet CHEBI:51209 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00852 UMLS:C0013395 infores:hetionet CHEBI:8874 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C2979982 infores:hetionet CAID:CA229891 biolink:causes MONDO:0009861 infores:clingen CAID:CA229891 MONDO:0009861 PMID:21147011PMID:21147011 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting PM5 The c.982A>G (p.Thr328Ala) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded), detected with pathogenic variant p.L48S (PMID: 21147011). This variant has extremely low frequency in ExAC and gnomAD (MAF=0.00003). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229891/MONDO:0009861/006 2020-09-25 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:36704 biolink:causes UMLS:C0149836 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0149836 infores:hetionet CHEBI:31981 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0042963 infores:hetionet CHEBI:31536 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0026848 infores:hetionet CHEBI:9086 biolink:causes HP:0001785 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0235439 infores:hetionet CHEBI:27999 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0042109 infores:hetionet CHEBI:140621 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0009782 infores:hetionet GO:0046668 biolink:causes GO:0150063 infores:ubergraph knowledge_assertion manual_agent GO:0046668 GO:0150063 CHEBI:7865 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0025061 infores:hetionet CHEBI:7478 biolink:causes UMLS:C1142015 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C1142015 infores:hetionet CHEBI:3215 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0004604 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0033117 infores:hetionet CHEBI:3506 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0009676 infores:hetionet CHEBI:5004 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0013378 infores:hetionet CHEBI:27779 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0442874 infores:hetionet CHEBI:9566 biolink:causes HP:0002179 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0151818 infores:hetionet CAID:CA645509163 biolink:causes MONDO:0021056 infores:clingen CAID:CA645509163 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The NM_000038.6(APC):c.6510del (p.Glu2172ArgfsTer10) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting; internal data GeneDx and Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4_Supporting, and PM2_Supporting applied (VCEP specifications v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA645509163/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:64312 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0042029 infores:hetionet CHEBI:63611 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0017168 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151605 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0233571 infores:hetionet CHEBI:7903 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0038362 infores:hetionet CHEBI:48390 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0036572 infores:hetionet CHEBI:7809 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00713 UMLS:C0542184 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0030312 infores:hetionet CAID:CA915940325 biolink:causes MONDO:0100326 infores:clingen CAID:CA915940325 MONDO:0100326 PMID: Likely Pathogenic PP4_Strong, PP3, PM2_Supporting, PM3_Supporting The NM_000419.5 (ITGA2B):c.310+3_310+6del intronic variant is predicted to disrupt the donor splice site of intron 2; the computational splicing predictor SpliceAI gives a score of 0.97 for donor loss (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patient (Patient GT3 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was <5%, as measured by flow cytometry while αIIb was absent on Western blot and β3 was decreased. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). GT3 of PMID: 25373348 is homozygous for this variant (PM3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA915940325/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51173 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0009421 infores:hetionet CHEBI:44915 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0013604 infores:hetionet GO:0045765 biolink:causes GO:0035295 infores:ubergraph knowledge_assertion manual_agent GO:0045765 GO:0035295 CHEBI:23765 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0042267 infores:hetionet CHEBI:42797 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0853034 infores:hetionet CHEBI:63637 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0011991 infores:hetionet CHEBI:7903 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0004093 infores:hetionet CHEBI:35778 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0036454 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005783 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0019064 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0233472 infores:hetionet CHEBI:31547 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0012833 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0036572 infores:hetionet CHEBI:63638 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0232461 infores:hetionet CHEBI:68478 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0232849 infores:hetionet CAID:CA16020943 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020943 MONDO:0009861 PMID:23942198 Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting PM5 The c.1118C>A (p.Ala373Asp) variant in PAH is absent from population databases (PM2). A deleterious effect is predicted in SIFT, PolyPhen-2, MutationTaster, and REVEL = 0.958 (PP3). The variant was detected with R158Q, pathogenic in ClinVar, phase unknown (PM3_Supporting). Variant was detected in patient with HPA defined as excessive blood levels (>120 μmol/l) of phenylalanine (BH4 deficiency ruled out; PP4_Moderate; PMID: 23942198). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3, PM3_Supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020943/MONDO:0009861/006 2020-03-26 2020-03-26 Autosomal recessive inheritance HP:0000007 Supports CHEBI:31536 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0011581 infores:hetionet CHEBI:83531 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0011603 infores:hetionet NCBITaxon:5833 biolink:causes MONDO:0005920 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5833 MONDO:0005920 CHEBI:77260 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0232492 infores:hetionet CHEBI:5959 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0033774 infores:hetionet CHEBI:15940 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0042373 infores:hetionet CAID:CA229677 biolink:causes MONDO:0009861 infores:clingen CAID:CA229677 MONDO:0009861 PMID:10947211PMID:1679030PMID:8860005PMID:1679030 Likely Pathogenic PM3, PM2, PP4_Moderate, PP3 The c.662A>G (p.Glu221Gly) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded) and MHP. (PMID: 1679030 8860005 10947211). It was detected in trans with pathogenic variant L48S and in the homozygous state. This variant has extremely low frequency in ExAC (0.00001) and gnomAD (0.000004064). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229677/MONDO:0009861/006 2020-05-22 2020-05-22 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0010592 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0037199 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0043246 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0003123 infores:hetionet CHEBI:6076 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0015967 infores:hetionet CHEBI:10124 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151827 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0948349 infores:hetionet CHEBI:63791 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0085624 infores:hetionet UMLS:C0010592 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0019521 infores:hetionet CHEBI:16469 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0008031 infores:hetionet CHEBI:472657 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C2129214 infores:hetionet CAID:CA6748887 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748887 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Strong The c.618C>A (p.Tyr206Ter) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in 4 patients with classic PKU with known pathogenic variants: c.611A>G (PMID: 16256386); p.Arg241Cys (PMID:25456745); and c.1197A>T p.Val399Val (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.00005). In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_strong, PP4, PVS1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748887/MONDO:0009861/006 2023-10-13 2023-10-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:168396 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0023218 infores:hetionet CAID:CA10577550 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577550 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong BP7, BP5, BS1, BS3, BS4, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The c.2164+2T>C variant is a canonical splice variant predicted to result in a premature stop codon but not predicted to undergo NMD (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1_Strong, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577550/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:7494 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0220870 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0026848 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0413252 infores:hetionet UNII:D27V6190PM biolink:causes HP:0004409 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C2364082 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0233494 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0042373 infores:hetionet CHEBI:83531 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0037317 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002260 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0085160 infores:hetionet CHEBI:40279 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0011991 infores:hetionet CHEBI:71415 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0027497 infores:hetionet CHEBI:16469 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0039070 infores:hetionet CHEBI:5128 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0036974 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0917798 infores:hetionet CHEBI:50742 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0003123 infores:hetionet CHEBI:3082 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0476273 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0002622 infores:hetionet CHEBI:45409 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0206061 infores:hetionet CHEBI:135736 biolink:causes HP:0030788 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0021092 infores:hetionet CHEBI:101278 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0000731 infores:hetionet CHEBI:10125 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0039503 infores:hetionet CHEBI:8232 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0149871 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0851341 infores:hetionet CHEBI:9123 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0600142 infores:hetionet UNII:3U02EL437C biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0015967 infores:hetionet CHEBI:50223 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0004936 infores:hetionet CAID:CA367399428 biolink:causes MONDO:0015967 infores:clingen CAID:CA367399428 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4, PP1 The c.1020-1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in deletion of >10% of a protein encoded by a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 apparently unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT increment < 3 mmol/L)(PP4_Moderate, internal lab contributors). This variant segregated with hyperglycemia with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1020-1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367399428/MONDO:0015967/086 2024-03-31 2024-03-31 Semidominant inheritance HP:0032113 Supports CHEBI:3215 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0039231 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0025061 infores:hetionet CAID:CA122861 biolink:causes MONDO:0000573 infores:clingen CAID:CA122861 MONDO:0000573 PMID: Likely Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM3, PM1_Supporting The NM_000536.4:c.283G>A variant in RAG2 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 95 (p.Gly94Arg). This variant has a population max filtering allele frequency of 0.000007010, which is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant is located in the core domain (amino acids 1-383) of RAG2, which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). In experimental studies, this variant demonstrates a mean recombination activity that is 0.3% of wildtype, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% of wildtype activity) for PS3_Moderate. This variant has been reported in several individuals with severe combined immunodeficiency or Omenn syndrome. Two unrelated individuals are homozygous for this variant (PMID: 33599911, 30307608) (0.5p + 0.5p). Three individuals carry this variant along with a second co-occurring RAG2 variant (p.Trp453Arg (phase unknown, 0.25p), p.Glu480* (phase unknown, 0p), p.Arg229Trp (confirmed in trans, 0p)) (PMID: 10891502, 31838659, 15025726). (0.5p + 0.5p +0.25p = 1.25p, PS3). The p.Trp453Arg variant has been classified as Likely Pathogenic, whereas the p.Glu480* and p.Arg229Trp variants have not yet been classified by the ClinGen SCID VCEP. At least one of these reported patients meets PP4 criteria established by the ClinGen SCID VCEP: T-B-NK+ lymphocyte subset profile (0.5p), meets clinical diagnostic criteria for SCID (0.5p), testing via large SCID panel or exome sequencing (0.5p): 1.5p (PMID: 33599911). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM1_Supporting, PM2_Supporting, PS3_Moderate, PP4, and PM3 as specified by the ClinGen SCID VCEP (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA122861/MONDO:0000573/124 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:83804 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0003813 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0038362 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0027651 infores:hetionet CHEBI:63637 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0014518 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0235146 infores:hetionet CHEBI:145499 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0029408 infores:hetionet CHEBI:2704 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151691 infores:hetionet CHEBI:4708 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0015672 infores:hetionet CHEBI:85078 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0151539 infores:hetionet NCBIGene:23171 biolink:causes MONDO:0012728 infores:monarchinitiative not_provided not_provided HGNC:28956 MONDO:0012728 uuid:5df8c8a0-39b3-4b93-936b-8562d5a2076c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013456 infores:hetionet CHEBI:16755 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0033774 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0740380 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0740380 infores:hetionet GO:0050873 biolink:causes CL:0000449 infores:ubergraph knowledge_assertion manual_agent GO:0050873 CL:0000449 UMLS:C0145867 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0917801 infores:hetionet CHEBI:28918 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0030554 infores:hetionet CHEBI:42797 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0034063 infores:hetionet CHEBI:100241 biolink:causes HP:0020074 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151579 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005344 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0019163 infores:hetionet CHEBI:168396 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0033036 infores:hetionet CHEBI:63631 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0221776 infores:hetionet CHEBI:32139 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0344232 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0746883 infores:hetionet CAID:CA229788 biolink:causes MONDO:0009861 infores:clingen CAID:CA229788 MONDO:0009861 PMID: Pathogenic PM2, PP4_Moderate, PVS1, PM3_Very Strong The c.822_832delGCCCATGTATA (p.Lys274Asnfs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It has been previously reported in Clinvar (variation ID 102852) without any classification. It has been previously reported in at least 7 cases with PKU (confirmed by abnormal blood Phe levels) in whom BH4 deficiency was excluded (PP4_Moderate); it has also been noted in one case with hyperphenyalanemia. As detailed below, it has been found in confirmed trans with multiple known pathogenic variants (e.g., p.R408W, p.R261Q, p.F39del, p.A104D) in six probands total and in trans with a VUS (p.T81P variant) in one case (PM3_VeryStrong). These reports are as follows. It has been previously found in two unrelated German probands with classic PKU (determined by blood Phe levels); BH4 deficiency does not appear to have been formally excluded (PMID: 1363786). The two unrelated patients in this report (PMID: 1363786) were each confirmed compound heterozygotes: one carried it in trans with the known pathogenic p.R408W allele and the other carried it in trans with the known pathogenic p.R261Q allele (these two variants have been classified pathogenic per PAH VCEP). It has also been identified in two unrelated European PKU cases in whom BH4 deficiency was said to be excluded, each of whom were confirmed compound heterozygous for the variant with the known pathogenic p.R408Q allele (PMID: 24190797). In another report, it was found in confirmed trans in three white European cases in whom BH4 deficiency was said to be excluded and who presented with classic PKU by blood Phe levels: one case with the c.115_117delTTC (p.F39del) variant (Pathogenic per PAH VCEP), one case with the p.T81P variant (VUS per PAH VCEP), and one case with the p.A104D variant (Pathogenic per PAH VCEP) (PMID: 23430918). It has also been noted in a cohort of Czech patients with hyperphenylalanemia, but further detail does not appear to be provided (PMID: 23357515). Classification: PathogenicSupporting criteria: PVS1, PM2, PM3_VeryStrong, PP4_Moderate Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229788/MONDO:0009861/006 2020-04-05 2020-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:100241 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020578 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040435 infores:hetionet CHEBI:47781 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0040264 infores:hetionet CHEBI:7852 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0020672 infores:hetionet GO:0002784 biolink:causes GO:0061844 infores:ubergraph knowledge_assertion manual_agent GO:0002784 GO:0061844 CHEBI:4445 biolink:causes UMLS:C0919620 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0919620 infores:hetionet CHEBI:2469 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0042075 infores:hetionet CAID:CA278687 biolink:causes MONDO:0019501 infores:clingen CAID:CA278687 MONDO:0019501 PMID:29196752PMID:28000701PMID:16963483 Pathogenic PP1, PP4, PP3, PM2_Supporting, PM5, PM3_Strong The allele frequency of the p.Arg1873Gln variant in the MYO7A gene is 0.008% (2/24854) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and 2 probands with Usher syndrome. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, for 1 proband a pathogenic or suspected-pathogenic was suspected in trans, and for 1 of the probands, a rare variant of uncertain significance was observed in trans (PM3_Strong; PMID:23208854, 28000701, 29196752, Partners LMM internal data SCV000059849.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM internal data SCV000059849.6). A different pathogenic missense variant (p.Arg1873Trp) has been previously identified at this codon of MYO7A which may indicate that this residue is critical to the function of the protein (PM5; p.Arg1873Trp ClinVar Variation ID 43291). The REVEL computational prediction analysis tool produced a score of 0.936, which is above the threshold necessary to apply PP3. At least one of the above patients with the variant in this gene displayed features of Usher syndrome (PP4; Partners LMM internal data SCV000059849.6). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PM5, PP1, PP3, PP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA278687/MONDO:0019501/005 2019-11-26 2019-11-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:10023 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0013604 infores:hetionet CHEBI:4702 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C1510497 infores:hetionet CHEBI:6413 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0017178 infores:hetionet NCBIGene:8911 biolink:causes MONDO:0859313 infores:monarchinitiative not_provided not_provided HGNC:1396 MONDO:0859313 uuid:4115559e-04f2-47af-a4a9-cac07a26ea08 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2618 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0234518 infores:hetionet CHEBI:63622 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0035357 infores:hetionet CHEBI:8024 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0041969 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0028738 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0151596 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0005940 infores:hetionet CHEBI:27690 biolink:causes MONDO:0001068 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0029442 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0027769 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0043246 infores:hetionet CHEBI:4453 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0149931 infores:hetionet CHEBI:9907 biolink:causes NCIT:C26683 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0438215 infores:hetionet NCBIGene:55152 biolink:causes MONDO:0030054 infores:monarchinitiative not_provided not_provided HGNC:25536 MONDO:0030054 uuid:ae703a3d-be4a-40bd-81d3-7ed46b19c6ab biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:53691 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0030554 infores:hetionet CHEBI:46195 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C1720775 infores:hetionet CHEBI:50841 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0013378 infores:hetionet NCBIGene:8573 biolink:causes MONDO:0010417 infores:monarchinitiative not_provided not_provided HGNC:1497 MONDO:0010417 uuid:6b2937cf-3189-4b0f-987d-c74596e10dd5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0018799 infores:hetionet CHEBI:8356 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152198 infores:hetionet CHEBI:27446 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0040034 infores:hetionet CHEBI:84050 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0026766 infores:hetionet CHEBI:47657 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0037199 infores:hetionet NCBIGene:5161 biolink:causes MONDO:0030733 infores:monarchinitiative not_provided not_provided HGNC:8807 MONDO:0030733 uuid:900eab4b-66fa-4891-b7ac-366fa2333188 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3636 biolink:causes UMLS:C0002928 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0002928 infores:hetionet CHEBI:127780 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151746 infores:hetionet CHEBI:2611 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0554976 infores:hetionet CHEBI:4702 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0041657 infores:hetionet CHEBI:41423 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0340279 infores:hetionet CHEBI:16335 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0042109 infores:hetionet CHEBI:135342 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0030252 infores:hetionet CHEBI:5790 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0028961 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0853847 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853847 infores:hetionet CHEBI:16469 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0003537 infores:hetionet CHEBI:7565 biolink:causes UMLS:C1959797 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C1959797 infores:hetionet CHEBI:10023 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0232462 infores:hetionet CHEBI:5613 biolink:causes MONDO:0010096 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0686347 infores:hetionet CHEBI:7494 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0518988 infores:hetionet NCBIGene:26580 biolink:causes MONDO:0010020 infores:monarchinitiative not_provided not_provided HGNC:15832 MONDO:0010020 uuid:29a4b52e-b696-46ad-b7b1-182fc3cead42 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA10583686 biolink:causes MONDO:0018875 infores:clingen CAID:CA10583686 MONDO:0018875 PMID:12826609PMID:30224644PMID:29979965 Likely Benign BP4, BS3, PM2_Supporting BA1, PS1, PS3, PS4, PS2, PM5, PM1, BP7, BS1, BS4, PVS1, BS2, PP3, PP1, PP4 The NM_000546.6: c.11C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 4 (p.Pro4Leu). This variant has an allele frequency of 6.196e-7 (1/1613946 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.062909; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.0; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583686/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0017797 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0162429 infores:hetionet CHEBI:8890 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0424790 infores:hetionet CHEBI:6402 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0014868 infores:hetionet CHEBI:77733 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C1368065 infores:hetionet CAID:CA405686675 biolink:causes MONDO:0018493 infores:clingen CAID:CA405686675 MONDO:0018493 PMID: Uncertain Significance PM1 PP3, PS4, BS1, PM2, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with cysteine at codon 471 of the RYR1 protein, p.(Arg471Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID: 1354642). However, the proband was reported to have additional RYR1 variants including a variant classified as pathogenic, p.(Gly248Arg), and while p.(Arg471Cys) did not segregate with MHS in the family, p.(Gly248Arg) did. For these reasons PS4 was not implemented. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.578 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405686675/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6375 biolink:causes UMLS:C0740464 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0740464 infores:hetionet CHEBI:7507 biolink:causes UMLS:C0161479 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0161479 infores:hetionet CAID:CA8366252 biolink:causes MONDO:0100453 infores:clingen CAID:CA8366252 MONDO:0100453 PMID: Likely Benign BS1, BS2_Supporting BP4, PP3 The NM_000180.4(GUCY2D):c.2917G>T (p.Val973Leu) variant is predicted to replace the valine at position p.973 with leucine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0006200, with 1000 alleles / 1612860 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. The LCA/eoRD VCEP chose to use the population frequency in the Finnish population over the Grpmax frequency to meet the BS1 criteria - with a frequency of 0.01376 with 877 alleles / 63722 total alleles in the Finnish population, the BS1 cutoff >0.0016 is significantly exceeded (BS1). This variant has been found in the homozygous state in 3 adult individuals in gnomAD (gnomAD version 4.1.1; BS2_supporting). The computational predictor REVEL gives a score of 0.51, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 for PP3 and above the threshold of <0.290 for BP4. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which predicts a low or indeterminate impact on splicing. Neither PP3 nor BP4 is met. In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8366252/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:3723 biolink:causes HP:0001371 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009917 infores:hetionet CHEBI:408174 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0023218 infores:hetionet CHEBI:161680 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0011991 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0403632 infores:hetionet CHEBI:140621 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0006266 infores:hetionet CAID:CA000104 biolink:causes MONDO:0018875 infores:clingen CAID:CA000104 MONDO:0018875 PMID: Benign BP4, BS3_Supporting, BS1, BS2 BA1, PS3, PS4, PS2, PS1, PM1, PM5, BS4, PM2, PP3, PP1, PP4 The NM_000546.6: c.319T>C variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 107 (p.Tyr107His). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor: ClinVar SCV: SCV000172807.10). The filtering allele frequency is 0.0007936 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0202 Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS1, BS2, BS3_supporting, BP4 (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024). TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000104/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:44185 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0003460 infores:hetionet UMLS:C0657912 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0033036 infores:hetionet NCBIGene:91461 biolink:causes MONDO:0032935 infores:monarchinitiative not_provided not_provided HGNC:25123 MONDO:0032935 uuid:4d92f8f1-ab45-4672-a5c1-025fd10eb1aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0028734 infores:hetionet CHEBI:4995 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0018926 infores:hetionet CHEBI:681850 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0015967 infores:hetionet CHEBI:40279 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0023530 infores:hetionet CHEBI:5801 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C1760428 infores:hetionet CHEBI:4027 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1510410 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0235416 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027051 infores:hetionet CHEBI:50777 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0010692 infores:hetionet NCBIGene:79966 biolink:causes MONDO:0033668 infores:monarchinitiative not_provided not_provided HGNC:21088 MONDO:0033668 uuid:893cbce7-2222-43ac-a4da-18527fa35c71 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0016382 infores:hetionet CHEBI:15367 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0042384 infores:hetionet CHEBI:5441 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0002874 infores:hetionet GO:0035886 biolink:causes CL:0000359 infores:ubergraph knowledge_assertion manual_agent GO:0035886 CL:0000359 CAID:CA145887 biolink:causes MONDO:0001586 infores:clingen CAID:CA145887 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.590-8C>T variant is a nucleotide substitution in the acceptor splice site region of intron 5 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.2984 (27112/90864 alleles; 4285 homozygotes; Grpmax Filtering AF 95% confidence = 0.2954) in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92646). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145887/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:4798 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0031542 infores:hetionet CHEBI:9654 biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C2973529 infores:hetionet CAID:CA410202662 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202662 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1): c.415A>G (p.Asn139Asp) is a missense variant within the Runt Homology Domain (AA 89-204) (PM1_supporting). This variant has a REVEL score of 0.928 (PP3). Additionally, this variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202662/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135888 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0151907 infores:hetionet NCBIGene:81857 biolink:causes MONDO:0014643 infores:monarchinitiative not_provided not_provided HGNC:28845 MONDO:0014643 uuid:d163fdf4-bb29-4dd6-a43b-556ba7ad34fa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5134 biolink:causes MONDO:0019280 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0020555 infores:hetionet CHEBI:7573 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0086543 infores:hetionet CHEBI:10125 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0233471 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005041 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0017601 infores:hetionet CHEBI:6359 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00581 UMLS:C0000731 infores:hetionet CHEBI:28864 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0001824 infores:hetionet CAID:CA2580098631 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098631 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, PP4, PP2, PP3, PP1 The NM_001754.5(RUNX1):c.799_800dup p.(Met267IlefsTer45) is a frameshift variant not expected to undergo nonsense-mediated mRNA decay. Nevertheless, the altered region is crucial for protein function, as it involves a duplication that impacts the established positions for frameshift (+1) variants (i.e., c.780-c.1440) (PVS1_Strong) and is positioned downstream of c.98 (in transcript NM_001754.4) (PM5_Supporting). This variant is entirely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). To the best of our knowledge, this variant has not been reported in any study. In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, and PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098631/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27899 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0039621 infores:hetionet CHEBI:55346 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0151878 infores:hetionet CHEBI:465284 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0027497 infores:hetionet CHEBI:18248 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0013456 infores:hetionet CHEBI:5801 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0004093 infores:hetionet CHEBI:5613 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0013384 infores:hetionet CHEBI:127342 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0027497 infores:hetionet CHEBI:474180 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0555120 infores:hetionet NCBIGene:147872 biolink:causes MONDO:0957822 infores:monarchinitiative not_provided not_provided HGNC:26520 MONDO:0957822 uuid:ef640983-88ce-4b19-b2a4-ac7899012965 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4356 biolink:causes MONDO:0019136 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0026718 infores:hetionet UMLS:C0005740 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0016382 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0574067 infores:hetionet CHEBI:63627 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0009421 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0020649 infores:hetionet CHEBI:31348 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151872 infores:hetionet CHEBI:9907 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0040034 infores:hetionet CHEBI:6887 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019270 infores:hetionet CHEBI:28748 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004134 infores:hetionet CAID:CA658658713 biolink:causes MONDO:0009290 infores:clingen CAID:CA658658713 MONDO:0009290 PMID: Uncertain Significance PP3 PM2, PS1 The NM_000152.5:c.2132_2133delinsGG variant in GAA is a multinucleotide variant predicted to cause substitution of threonine by arginine at amino acid 711 (p.Thr711Arg). The same amino acid change, resulting from one of the two nucleotide changes observed in this multinucleotide variant, c.2132C>G, has been reported in a patient with Pompe disease (PMID: 20080426, 31342611). However, this other variant has conflicting evidence for pathogenicity based on guidelines by the ClinGen LSD VCEP (PMID: 18425781). The minor allele frequency of the c.2132C>G variant in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population, but was only seen in phase with c.2133A>G in 23 of the 24 heterozygotes reported in gnomAD v2.1.1. Therefore, the highest possible population minor allele frequency in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population (none of the population data codes are met). The computational predictors PROVEAN, Mutation Taster, and MutPredIndel suggest that this variant has a deleterious effect on the GAA gene, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 456391, 1 star review status) with 2 submitters, 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658658713/MONDO:0009290/010 2022-09-19 2022-09-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:3082 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0028084 infores:hetionet CHEBI:45783 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2937358 infores:hetionet CHEBI:3723 biolink:causes HP:0041159 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0035522 infores:hetionet CHEBI:5801 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0086525 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0027497 infores:hetionet CHEBI:7577 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011630 infores:hetionet CHEBI:45951 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0549567 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0521516 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0521516 infores:hetionet CHEBI:9570 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0025287 infores:hetionet NCBIGene:221711 biolink:causes MONDO:0970995 infores:monarchinitiative not_provided not_provided HGNC:21537 MONDO:0970995 uuid:427f493a-ce82-4aa8-b623-e05783cb6532 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7852 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1142412 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0231218 infores:hetionet CHEBI:36795 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C3665347 infores:hetionet CHEBI:6073 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0009782 infores:hetionet CHEBI:65349 biolink:causes NCIT:C39690 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C1519353 infores:hetionet CHEBI:6909 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0039070 infores:hetionet CHEBI:94501 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C1258215 infores:hetionet CHEBI:29007 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0015230 infores:hetionet CHEBI:63638 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0014130 infores:hetionet CHEBI:3077 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0015300 infores:hetionet CHEBI:8869 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0004936 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0877322 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0877322 infores:hetionet CAID:CA1706888 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706888 MONDO:0015152 PMID:23185377PMID:30292141PMID:35028538 Pathogenic PP4_Strong, PM3, PS3, PP3, PP1 PM2 The NM_003494.4: c.4022T>C variant in DYSF, which is also known as NM_001130987.2: c.4076T>C p.(Leu1359Pro), is a missense variant predicted to cause substitution of leucine by proline at amino acid 1341 (p.Leu1341Pro). This variant has been detected in a homozygous state in at least seven individuals with clinical signs of limb girdle muscular dystrophy (1.0 pt, PMID: 16705711, 19528035, 22057634, 26436962, 27647186, 28403181, 34559919, 34624274) (PM3). It has also been observed in trans with a nonsense variant, c.4228C>T p.(Gln1410Ter), in one affected individual (PMID: 34624274). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16705711, 21522182). The variant was also reported to co-segregate with the disease in six affected family members from three families (PMID: 16705711, 21522182, 34624274) (PP1, capped with PP4_Strong). The filtering allele frequency of the variants is 0.0003434 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 5/30616), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141) (PS3). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). The computational predictor REVEL gives a score of 0.89, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3, PP4_Strong, PP1, PS3, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706888/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50924 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0011168 infores:hetionet NCBIGene:7148 biolink:causes MONDO:0011670 infores:monarchinitiative not_provided not_provided HGNC:11976 MONDO:0011670 uuid:a7715a8c-fab9-4875-b58c-48f6f76a5243 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135738 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04920 UMLS:C0020649 infores:hetionet CHEBI:45652 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0037036 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0004936 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0037822 infores:hetionet CHEBI:51450 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0852911 infores:hetionet CHEBI:40303 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0014457 infores:hetionet CHEBI:2904 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0015672 infores:hetionet CHEBI:9448 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0042384 infores:hetionet CHEBI:27690 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0023530 infores:hetionet CHEBI:91834 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0009450 infores:hetionet NCBIGene:7167 biolink:causes MONDO:0014221 infores:monarchinitiative not_provided not_provided HGNC:12009 MONDO:0014221 uuid:01748772-165e-46d5-acba-a7ab549559b1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119573 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037199 infores:hetionet NCBITaxon:573 biolink:causes MONDO:0005945 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:573 MONDO:0005945 CHEBI:50381 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0000731 infores:hetionet CHEBI:59560 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0042029 infores:hetionet CHEBI:9130 biolink:causes HP:0010872 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0520888 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0013221 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0013221 infores:hetionet CHEBI:50924 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0004936 infores:hetionet NCBIGene:55036 biolink:causes MONDO:0013435 infores:monarchinitiative not_provided not_provided HGNC:26090 MONDO:0013435 uuid:811b016a-ae89-4f53-aae0-a3efc539a456 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA397722699 biolink:causes MONDO:0008723 infores:clingen CAID:CA397722699 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The NM_000018.4(ACADVL): c.343G>T (p.Glu115Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated November 16, 2021 and the recurated classification was approved by the expert panel on February 27, 2024. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397722699/MONDO:0008723/021 2024-02-27 2024-02-27 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0009315 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0149725 infores:hetionet CHEBI:478164 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0018681 infores:hetionet CHEBI:5280 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0017152 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0031117 infores:hetionet CHEBI:16755 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0206062 infores:hetionet CHEBI:41423 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0019360 infores:hetionet CHEBI:44032 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0042384 infores:hetionet CHEBI:3215 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C1868752 infores:hetionet CHEBI:48669 biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0032343 infores:hetionet GO:0090178 biolink:causes GO:0001843 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0001843 CHEBI:4975 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0015230 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0919714 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0919714 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0027651 infores:hetionet CAID:CA658798847 biolink:causes MONDO:0700268 infores:clingen CAID:CA658798847 MONDO:0700268 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PVS1, BP7 The c.134+3A>T variant is an intronic variant occurring in intron 3 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.83, predicting an impact on splicing (score threshold >0.20) (PP3 met). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and agarose gel electrophoresis demonstrated that the variant impacts splicing by exon 3 skipping (PMID: 32123317). The percent full-length and aberrant transcripts produced from the variant allele was not stated (PVS1 (RNA) and BP7_Strong (RNA) not met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798847/MONDO:0700268/092 2025-05-23 2025-05-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:68478 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0497365 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0002792 infores:hetionet CHEBI:45863 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0034155 infores:hetionet CHEBI:45951 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0235270 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0006277 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006736 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0007868 infores:hetionet CHEBI:6887 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0233763 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0221203 infores:hetionet CAID:CA397723393 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723393 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM1, PM3, PP4_Moderate PS3 The c.652G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 218 (p.Glu218Lys, also known as Glu178Lys in traditional nomenclature). At least two patients with this variant displayed elevated C14:1 by newborn screen and/or reduced very long chain acyl CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 34184355, 30194637). Of those individuals, one was homozygous for the variant, confirmed by parental testing, and one was presumed in trans to a pathogenic variant (PM3 1 point; PMIDs: 34184355, 30194637). Additionally, one patient carrying this variant displayed a reduced VLCAD protein level (PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000032 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 15, 2022 and the recurated classification was approved by the expert panel on November 13, 2023. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723393/MONDO:0008723/021 2023-11-28 2023-11-28 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4562 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0020580 infores:hetionet CHEBI:15544 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0027051 infores:hetionet CHEBI:2611 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0231530 infores:hetionet CHEBI:50841 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0156404 infores:hetionet CHEBI:51380 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0015397 infores:hetionet CHEBI:32315 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0947912 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151828 infores:hetionet NCBIGene:2984 biolink:causes MONDO:0013843 infores:monarchinitiative not_provided not_provided HGNC:4688 MONDO:0013843 uuid:5795ebd5-e2cf-49de-a42e-1da54e98cc47 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:774 biolink:causes MONDO:0032784 infores:monarchinitiative not_provided not_provided HGNC:1389 MONDO:0032784 uuid:a598c93e-f87e-45f4-aa8b-0b00af1ae1d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45863 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0011570 infores:hetionet CHEBI:63631 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0025218 infores:hetionet CHEBI:68534 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0042023 infores:hetionet CAID:CA2573051045 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051045 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PS4, PP1_Strong, PVS1_Strong, PP4_Moderate The c.1822_1823delAG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 608 (NM_000545.8), adding 40 novel amino acids before encountering a stop codon (p.(Ser608ProfsTer40)). While this variant, located 5' of c.1854 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). This variant was identified in eight unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with 8 informative meioses in two families with MODY (PP1_Strong; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in at least three individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.1822_1823delAG meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1 approved 9/30/21): PVS1_Strong, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051045/MONDO:0015967/017 2022-05-09 2022-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:41774 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0020437 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0857448 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0857448 infores:hetionet CHEBI:71417 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0029134 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0002418 infores:hetionet CHEBI:2611 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0233407 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1262144 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0235146 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020433 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0013922 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011849 infores:hetionet CHEBI:70746 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0151699 infores:hetionet CHEBI:31485 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0271051 infores:hetionet CHEBI:6472 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0023530 infores:hetionet CHEBI:63681 biolink:causes UMLS:C0417744 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0417744 infores:hetionet CHEBI:9727 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0494475 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014868 infores:hetionet CHEBI:4708 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C2697368 infores:hetionet CHEBI:4027 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0040053 infores:hetionet CHEBI:51230 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0027769 infores:hetionet CHEBI:3219 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C2979982 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0877338 infores:hetionet CHEBI:194135 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0231218 infores:hetionet CHEBI:8214 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0001807 infores:hetionet CHEBI:100246 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0008031 infores:hetionet CHEBI:49375 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0027497 infores:hetionet CHEBI:2611 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C2830004 infores:hetionet CHEBI:45924 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0042109 infores:hetionet CHEBI:45924 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0151436 infores:hetionet CHEBI:29688 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C2830004 infores:hetionet NCBIGene:85007 biolink:causes MONDO:0014008 infores:monarchinitiative not_provided not_provided HGNC:28249 MONDO:0014008 uuid:6fcc73ce-44a7-4c06-9a7f-9a7c180b242b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45716 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0002994 infores:hetionet NCBIGene:8550 biolink:causes MONDO:0859247 infores:monarchinitiative not_provided not_provided HGNC:6889 MONDO:0859247 uuid:7ace052d-3ff7-49b8-a0fa-b051fb7ebc58 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4495 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0234215 infores:hetionet CHEBI:27779 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0948586 infores:hetionet CHEBI:5134 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0011991 infores:hetionet CHEBI:4798 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0004238 infores:hetionet CHEBI:68534 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0014591 infores:hetionet CHEBI:51364 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0600142 infores:hetionet CHEBI:6367 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0234022 infores:hetionet CHEBI:7936 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151746 infores:hetionet NCBIGene:939 biolink:causes MONDO:0014054 infores:monarchinitiative not_provided not_provided HGNC:11922 MONDO:0014054 uuid:5f0a640a-18a7-4f63-8291-32ce05f6580c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6794 biolink:causes MONDO:0015278 infores:monarchinitiative not_provided not_provided HGNC:11389 MONDO:0015278 uuid:d30df0b6-1d29-4aaa-b385-3967b713d0a4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28445 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0041969 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0006325 infores:hetionet CHEBI:77733 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C1145670 infores:hetionet CHEBI:9613 biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0162566 infores:hetionet CHEBI:9139 biolink:causes MONDO:0006951 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0035328 infores:hetionet CHEBI:7565 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0002878 infores:hetionet CHEBI:46345 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C1112525 infores:hetionet CHEBI:68478 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0085682 infores:hetionet CHEBI:17026 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0015672 infores:hetionet CHEBI:64312 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0017574 infores:hetionet CHEBI:38545 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0027080 infores:hetionet CAID:CA377482291 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482291 MONDO:0017623 PMID: Pathogenic PP2, PP3, PM1, PM2_Supporting, PS3_Moderate, PS2 PTEN c.373A>G (p.Lys125Glu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history (internal laboratory contributor(s) SCV003642767.2).PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PS3_M: Multiple functional studies supportive of a damaging effect on the gene or gene product (PMIDs 29706350, 19457929, 21828076, 20926450, 23475934).PP3: REVEL score > 0.7 (score of this variant = 0.951.PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PM2_P: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482291/MONDO:0017623/003 2025-04-04 2025-06-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8707 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0267596 infores:hetionet CHEBI:9445 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0027441 infores:hetionet CHEBI:68606 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0042963 infores:hetionet CHEBI:40237 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0020651 infores:hetionet CHEBI:6888 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0263449 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0006826 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0002170 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0007222 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0032285 infores:hetionet CHEBI:9435 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C3665347 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0574067 infores:hetionet CHEBI:27436 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C1861172 infores:hetionet CHEBI:4027 biolink:causes UMLS:C1720775 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C1720775 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0021053 infores:hetionet CAID:CA412744378 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744378 MONDO:0100437 PMID: Likely Pathogenic PS1_Moderate, PP1_Moderate, PP4, PM2_Supporting, PP3_Moderate PS4 NM_001034853.2(RPGR):c.617C>T (p.Thr206Ile) is a missense variant in the last codon of RPGR exon 6 encoding substitution of threonine with isoleucine at amino acid 206 and potentially affecting RPGR splicing. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.883, which is between the ClinGen X-linked IRD VCEP threshold of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The splicing impact predictor SpliceAI gives a score of 0.41 for splice donor loss, which is below the ClinGen X-linked IRD VCEP recommended PP3 threshold of ≥0.2 and but indicates the possibility of a damaging impact on splicing. At least one proband harboring this variant exhibits a phenotype including early onset (1 pt), family pedigree consistent with X-linked inheritance (2 pts), with delayed or milder phenotype in females (1 pt), night blindness (0.5 pts), decreased central visual acuity (0.5 pts), and visual field constriction (0.5 pts), which together are specific for RPGR-related retinopathy (5.5 points, PP4, PMID: 21857984, with author communication of clinical details). The variant has been reported to segregate with retinal dystrophy through at least 3 affected meioses from 1 family (PP1_Moderate; PMID: 21857984, with author confirmation of unpublished clinical details). This variant is outside the +/- 1,2 dinucleotide and meets the PP3 code and another variant in the same donor/acceptor motif, NM_001034853.2(RPGR):c.619+2T>A, was previously classified as pathogenic for RPGR-related retinopathy by the ClinGen X-linked IRD VCEP (PS1_moderate). In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PP1_moderate, PP3, PS1_moderate, and PP4. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744378/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:8430 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0522224 infores:hetionet CHEBI:8863 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011175 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0006444 infores:hetionet CHEBI:8888 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0424790 infores:hetionet CHEBI:75045 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0015230 infores:hetionet CHEBI:4911 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0038362 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0340464 infores:hetionet CHEBI:84050 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0002170 infores:hetionet CHEBI:2914 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0002792 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0241863 infores:hetionet CHEBI:4784 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0037011 infores:hetionet CHEBI:4868 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0011603 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0860801 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0860801 infores:hetionet CHEBI:16469 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C1609512 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0236072 infores:hetionet CHEBI:9943 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017675 infores:hetionet CHEBI:4027 biolink:causes MONDO:0008627 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0153619 infores:hetionet CHEBI:474180 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0162285 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0021400 infores:hetionet CHEBI:7983 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C1443060 infores:hetionet CHEBI:3048 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C1971624 infores:hetionet CHEBI:74947 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0022904 infores:hetionet CHEBI:75722 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0039231 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0004610 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011334 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0027765 infores:hetionet CHEBI:42797 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0011175 infores:hetionet CHEBI:42797 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0018932 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0270795 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0270795 infores:hetionet CHEBI:39867 biolink:causes HP:0100507 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0016412 infores:hetionet CHEBI:6129 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151610 infores:hetionet CHEBI:47499 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0003811 infores:hetionet NCBIGene:5894 biolink:causes MONDO:0012690 infores:monarchinitiative not_provided not_provided HGNC:9829 MONDO:0012690 uuid:8aab1bf3-e9ad-4fc4-b577-ccbd89883529 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4653 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0014549 infores:hetionet CHEBI:101278 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0013395 infores:hetionet CHEBI:34764 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00663 UMLS:C0085624 infores:hetionet CAID:CA16020720 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020720 MONDO:0009861 PMID:18299955PMID:18299955 Pathogenic PVS1, PM2, PP4, PM3_Supporting Pathogenic: The c.48dup (p.D17*) variant has been reported in one individual with classic PKU, who carried a second pathogenic variant in PAH (p.L48S) (PM3, PP4; PMID: 18299955). This variant is absent from gnomAD, 1000 Genomes, and ESP databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3-supporting, PM2, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020720/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3568 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0006384 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0403632 infores:hetionet CHEBI:64064 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0917801 infores:hetionet CHEBI:72564 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0020538 infores:hetionet NCBIGene:2891 biolink:causes MONDO:0030060 infores:monarchinitiative not_provided not_provided HGNC:4572 MONDO:0030060 uuid:004f1c51-ebf1-4962-ac04-b81379327992 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8024 biolink:causes UMLS:C0277585 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0277585 infores:hetionet CHEBI:28748 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C1384353 infores:hetionet CHEBI:8888 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0085649 infores:hetionet NCBIGene:23261 biolink:causes MONDO:0013886 infores:monarchinitiative not_provided not_provided HGNC:18806 MONDO:0013886 uuid:01cccc16-9656-4a7d-9ad0-5a7f8f1a7ce0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0340464 infores:hetionet CHEBI:4953 biolink:causes MONDO:0008600 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0158328 infores:hetionet CHEBI:50729 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0035455 infores:hetionet CHEBI:114785 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0039070 infores:hetionet CHEBI:17347 biolink:causes MONDO:0001268 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0017572 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0268733 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0268733 infores:hetionet CHEBI:92511 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0010692 infores:hetionet CHEBI:7573 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0025222 infores:hetionet CHEBI:6073 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0032617 infores:hetionet CHEBI:4315 biolink:causes NCIT:C35161 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0149741 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0031350 infores:hetionet CAID:CA007244 biolink:causes MONDO:0021055 infores:clingen CAID:CA007244 MONDO:0021055 PMID: Pathogenic PVS1, PS4, PM2_Supporting The NM_000038.6(APC):c.220+2T>A variant in APC occurs within the canonical splice donor site (+2) of intron 3. RT-PCR and CaptureSeq of patient cDNA demonstrated that the variant impacts splicing by creating a substantial but incomplete aberrant splice defect that is predicted to cause a premature stop codon (r.220+1_220+15ins15 (p.K73_E74insGRF*)) (PVS1, [internal data from Ambry Genetics, Invitae, Copenhagen University Hospital]). This variant has been reported in 25 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 13.5 points (PS4, [Ambry Genetics, Invitae]). Moreover, the variant has been observed in heterozygous state in 20 additional individuals with a “Colorectal cancer/polyposis associated phenotype,” however, the available phenotype information is not sufficient to assign phenotype points (Invitae). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PVS1, PS4, PM2_Supporting (VCEP specifications v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA007244/MONDO:0021055/089 2025-05-16 2025-05-16 Autosomal dominant inheritance HP:0000006 Supports CAID:CA16621277 biolink:causes MONDO:0100039 infores:clingen CAID:CA16621277 MONDO:0100039 PMID: Pathogenic PVS1, PM2_Supporting, PS4_Supporting The p.Leu405Thrfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). This variant has been detected in at least one individual with CDKL5 disorder (ClinVar) (PS4_supporting). This variant is absent from the gnomAD (PM2_supporting). In summary, the p.Leu405Thrfs variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_supporting, PS4_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16621277/MONDO:0100039/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:36704 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0021400 infores:hetionet CHEBI:6015 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0233571 infores:hetionet CHEBI:391960 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0036974 infores:hetionet CAID:CA8814793 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814793 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BP4 The NM_000152.5:c.131G>T variant in GAA is predicted to result in the substitution of glycine by valine at amino acid 44 (p.Gly44Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (32/126504 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.245 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 325774). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM2_Supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 20, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814793/MONDO:0009290/010 2023-06-20 2023-06-26 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:77733 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0008370 infores:hetionet CHEBI:63584 biolink:causes MONDO:0009172 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0014356 infores:hetionet CHEBI:4822 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0027424 infores:hetionet CHEBI:85083 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0233794 infores:hetionet CHEBI:7581 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0023380 infores:hetionet CHEBI:8764 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0024902 infores:hetionet CHEBI:2663 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151878 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0243026 infores:hetionet CHEBI:4445 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0000737 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0595930 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0687707 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0687707 infores:hetionet CHEBI:72690 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0011603 infores:hetionet CHEBI:31711 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0232462 infores:hetionet CAID:CA320618045 biolink:causes MONDO:0011071 infores:clingen CAID:CA320618045 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM5, PM1, PM4, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.509-19C>T is an intronic variant in intron 5. It is reported at very low levels in gnomAD (0.00003), thus it is not absent but does not meet thresholds for BA1 or BS1. The nucleotide and surrounding sequence are not evolutionarily conserved, and the variant is not predicted to affect splicing, with a SpliceAI score ≤ 0.20 and a phyloP100 way score ≤ 2.0 (1.319) (BP4, BP7). The variant has not been described in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320618045/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8245 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0018681 infores:hetionet CAID:CA272714 biolink:causes MONDO:0012589 infores:clingen CAID:CA272714 MONDO:0012589 PMID: Pathogenic PS2_Very Strong, PM6, PS4_Supporting, PM2_Supporting, PP3 The p.Ser330= variant in TCF4 is absent from gnomAD v4 (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). The p.Ser330= variant has been observed in at least 2 individuals with intellectual disability/autism (PMIDs: 29695756, 25693842) (PS4_supporting). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with intellectual disability (PMID: 25693842, internal database -Invitae) (PM6). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 3 individuals with intellectual disability/autism (PMIDs: 29695756, 29158550, 31785789, 1981491, 33767182, internal database - Invitae) (PS2_very strong). In summary, the p.Ser330= variant in TCF4 is classified as pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_supporting, PP3, PS4_supporting, PM6, PS2_very strong). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA272714/MONDO:0012589/032 2024-02-23 2024-03-31 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:23530 biolink:causes MONDO:0013874 infores:monarchinitiative not_provided not_provided HGNC:7863 MONDO:0013874 uuid:d52405b2-f015-4125-9a79-defb53de1876 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:408174 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0043251 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0233414 infores:hetionet CHEBI:6715 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0023218 infores:hetionet CHEBI:3723 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C2225524 infores:hetionet CHEBI:36704 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1443060 infores:hetionet CHEBI:28901 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0011603 infores:hetionet CHEBI:50922 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0558489 infores:hetionet CHEBI:8890 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0003862 infores:hetionet CHEBI:28901 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0009806 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0018991 infores:hetionet CHEBI:47426 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1318520 infores:hetionet CHEBI:3216 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0233471 infores:hetionet CHEBI:41774 biolink:causes MONDO:0005461 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C1153706 infores:hetionet CHEBI:3181 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0020615 infores:hetionet CHEBI:7444 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0008031 infores:hetionet CHEBI:9737 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0033774 infores:hetionet CHEBI:3216 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0232462 infores:hetionet CHEBI:9586 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011253 infores:hetionet CHEBI:136040 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0041657 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0020624 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020624 infores:hetionet CHEBI:8707 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0149871 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0233632 infores:hetionet CHEBI:28445 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0231528 infores:hetionet CHEBI:2704 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C1142412 infores:hetionet CHEBI:2611 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0858635 infores:hetionet CHEBI:31236 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0019209 infores:hetionet UMLS:C0145867 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0042963 infores:hetionet CHEBI:2668 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0151786 infores:hetionet CHEBI:64321 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0020538 infores:hetionet CHEBI:45783 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0014591 infores:hetionet CHEBI:46557 biolink:causes UMLS:C1306580 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C1306580 infores:hetionet CHEBI:135930 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0035455 infores:hetionet CAID:CA226839 biolink:causes MONDO:0010725 infores:clingen CAID:CA226839 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PP3_Strong, PP4 The NM_000330.4(RS1):c.647T>C variant is a missense variant encoding the substitution of Leucine with Proline at amino acid 216. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 33460243, PP4). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 19324861, 19390641, 34822951, PS4_Moderate). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_strong, PP4, and PS4_moderate (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226839/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:63619 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C2363731 infores:hetionet CHEBI:39867 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0085633 infores:hetionet CHEBI:5103 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0424790 infores:hetionet CAID:CA410203418 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203418 MONDO:0011071 PMID: Likely Pathogenic PS3, PM1, PM2_Supporting, PP3 PS1, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS4, BS3, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEL score is greater than 0.88 (0.884) and SpliceAI is not greater than 0.38 (0.00) (PP3). This variant affects one of the hotspot (K110) residues established by the MM-VCEP for RUNX1 (PM1). The c.328A>G variant is the same amino acid change (p.K110E) as a previously established pathogenic variant (ClinVar ID 14465) curated using MM-VCEP rules for RUNX1 (PS1). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1, PS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203418/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:100241 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151825 infores:hetionet CHEBI:724125 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0012833 infores:hetionet CHEBI:9434 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0392171 infores:hetionet CAID:CA068024 biolink:causes MONDO:0018493 infores:clingen CAID:CA068024 MONDO:0018493 PMID: Uncertain Significance PM1, BP4 PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of methionine with lysine at codon 2101 of the RYR1 protein, p.(Met2101Lys). The maximum minor allele frequency (MAF) for this variant among the six major gnomAD populations is NFE: 0.000087, a frequency consistent with pathogenicity for MHS. However, the MAF in the Ashkenazi Jewish population is 0.0047 which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted). One of these individuals had a second variant of uncertain significance in RYR1 (p.Arg1469Trp, VUS) (PMID:20681998, PMID:25735680, PMID:30236257). The high MAF in the Ashkenazi Jewish population precludes implementing PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score <0.5 (0.392) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA068024/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8364 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C0042571 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0853020 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0853020 infores:hetionet CHEBI:49960 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0702166 infores:hetionet CHEBI:40303 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0026848 infores:hetionet CHEBI:10101 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0041657 infores:hetionet CHEBI:94411 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0917801 infores:hetionet CHEBI:50777 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0232462 infores:hetionet CHEBI:63611 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151746 infores:hetionet NCBITaxon:6333 biolink:causes MONDO:0019444 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:6333 MONDO:0019444 CHEBI:182080 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0080274 infores:hetionet CHEBI:5296 biolink:causes UMLS:C0085693 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0085693 infores:hetionet CHEBI:5790 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0041969 infores:hetionet CHEBI:8356 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2830004 infores:hetionet CHEBI:71272 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0030305 infores:hetionet CAID:CA386959402 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959402 MONDO:0015967 PMID:32017842 Likely Pathogenic PM2_Supporting, PM1, PS3_Supporting, PP4_Moderate, PP3 PS4 The c.388C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to glutamic acid at codon 130 (p.(Gln130Glu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Functional studies demonstrated the p.Gln130Gly protein has transactivation and DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32017842). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32017842, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.388C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959402/MONDO:0015967/017 2024-06-09 2024-06-09 Autosomal dominant inheritance HP:0000006 Supports NCBIGene:9371 biolink:causes MONDO:0030071 infores:monarchinitiative not_provided not_provided HGNC:6320 MONDO:0030071 uuid:f326072e-e979-496e-a292-c9bbee488e8d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9943 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0426732 infores:hetionet CAID:CA10014519 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014519 MONDO:0011071 PMID: Benign BP4, BS1, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BS3, BS4, BP5, PM4, PM5, PM1, PM3, BS2, PP2, PP3, PP1, PP4 The MAF of the NM_001754.4(RUNX1):c.423G>A (p.Ser141=) variant is 0.0001633 (0.016%, 5/30614 alleles, 251394 alleles) in the South Asian cohort (gnomAD), which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score: -1.49 < 0.1 [-14.1;6.4]) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014519/MONDO:0011071/008 2022-07-05 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63623 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0240327 infores:hetionet CHEBI:2904 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C3665347 infores:hetionet CAID:CA915942984 biolink:causes MONDO:0001586 infores:clingen CAID:CA915942984 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_000203.5(IDUA):c.1163delC (p.Thr388ArgfsTer52) variant in IDUA is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two Italian patients with this variant and severe MPS1 have been reported. The diagnosis was based on clinical features, elevated urine GAGs, and reduced IDUA activity in fibroblasts and/or leukocyte. However, individual data were not provided. One patient was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter); the phase is unknown (PMID: 12203999). The other patient was compound heterozygous for the variant and c.152G>A (p.Gly51Asp) (PMID: 12203999); the data from the patient will be used in the assessment of p.G;y51Asp and was not included here to avoid circular logic. (PM3_Supporting). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 828094). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA915942984/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3082 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0001824 infores:hetionet CHEBI:38562 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0030193 infores:hetionet CHEBI:15640 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00650 UMLS:C0009806 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0039971 infores:hetionet CHEBI:45863 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0036572 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0151601 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0151601 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001780 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0033038 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0032285 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0235431 infores:hetionet CHEBI:7465 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C1322281 infores:hetionet CHEBI:6413 biolink:causes HP:0031088 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0241633 infores:hetionet CHEBI:3757 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C2363731 infores:hetionet CAID:CA229363 biolink:causes MONDO:0009861 infores:clingen CAID:CA229363 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Strong PM5 The c.1159T>C (p.Tyr387His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 21890392). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.L48S, p.Y204X (PMID: 21147011); p.T323del (PMID: 9169088); c.754C>T, p.Arg252Trp (PMID: 21890392); p.Ala395Pro (PMID: 23357515); p.R261Q, c.782G>A (PMID: 23690520). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229363/MONDO:0009861/006 2020-08-17 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports UNII:2N4O9L084N biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0233472 infores:hetionet CAID:CA2602737 biolink:causes MONDO:0009276 infores:clingen CAID:CA2602737 MONDO:0009276 PMID: Benign BP4, BA1 The c.*38C>T variant in GP9 is a 3'UTR variant in exon 3/3. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.001390 (based on 1541/1062810 alleles) in European non-Finnish population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI indicated that the variant has no impact on splicing (score = 0) (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2602737/MONDO:0009276/083 2025-02-11 2025-02-14 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0657912 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0010520 infores:hetionet CHEBI:9737 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01157 UMLS:C0235378 infores:hetionet CHEBI:7465 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0028084 infores:hetionet CHEBI:3568 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0438142 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0042514 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151740 infores:hetionet NCBIGene:5498 biolink:causes MONDO:0957577 infores:monarchinitiative not_provided not_provided HGNC:9280 MONDO:0957577 uuid:2f49da32-c7b9-4477-bf65-09cf181f135a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0034065 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0151838 infores:hetionet CHEBI:4903 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0000731 infores:hetionet CHEBI:10110 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0016204 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0031350 infores:hetionet CHEBI:82960 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0600142 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0016053 infores:hetionet CAID:CA658798355 biolink:causes MONDO:0007947 infores:clingen CAID:CA658798355 MONDO:0007947 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM6, PP2, PP3, PP1, BS2, BA1, BP1, BP4, BP2, BP3, PS3, PS1, PS2, PS4, PM1, PM3, PM4, PM5, BP7, BP5, BS3, BS1, BS4 The NM_000138 c.5065+2dup in FBN1 is a splice site variant predicted to affect a donor splice site in intron 40 of the gene. By an RT-PCR assay in patient-derived aortic fibroblasts, this variant was determined to disrupt RNA splicing resulting in a frameshift deletion (r.5037_5065del); this is expected to result in an absent or disrupted protein product (PVS1 [RNA]; University of Tokyo internal data). This variant was found in an adult proband with thoracic aortic aneurysm and dissection (TAAD) and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (MFS) (PP4; University of Tokyo internal data). It has also been identified in a child with TAA and a positive family history of MFS (Invitae internal data). This variant has been reported 2 times in ClinVar as pathogenic (1) and of uncertain significance (1) (Variation ID: 519760). This variant is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PP4, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658798355/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:7954 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0151942 infores:hetionet CHEBI:63631 biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0220994 infores:hetionet CHEBI:94686 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0013378 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002714 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085136 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0700590 infores:hetionet CAID:CA023847 biolink:causes MONDO:0018493 infores:clingen CAID:CA023847 MONDO:0018493 PMID: Likely Benign BS2, PP3_Moderate, BS1 PP1, PM1, PS4, PS3, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 3539 of the RYR1 protein, p.(Arg3539His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00305, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257; PMID:23460944; PMID:23558838; PMID:24433488; PMID:25960145), however, the high MAF in the NFE population precludes the use of PS4. This variant has been identified in multiple individuals with negative IVCT/CHCT results, BS2 (PMID:18253926, PMID:22473935). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.877) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PP3_Moderate, BS1, BS2. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023847/MONDO:0018493/012 2021-11-10 2021-11-10 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:91541 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0016382 infores:hetionet CHEBI:23765 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0017160 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0007114 infores:hetionet CAID:CA414444922 biolink:causes MONDO:0010604 infores:clingen CAID:CA414444922 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PM5, PS4_Moderate, PP3, PM6, PP4_Moderate PM1 The c.953T>G; p.Leu318Arg variant is completely absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). This missense variant has a REVEL score of 0.979 and meets PP3 criteria (PP3, threshold >0.6). At least 3 patients are reported in the literature with severe hemophilia B and this variant, meeting F9 phenotype criteria (PS4_Moderate, PP4_Moderate; PMID: 29296726, PMID: 1897528, PMID: 12588353). There is at least 1 proband with hemophilia B meeting phenotypic criteria for F9, with assumed de novo (maternity not confirmed in an affected male) occurrence (PM6, PMID: 30648777). Leu318Phe is another pathogenic variant at the same residue (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. The ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel, for F9: PM5, PM6, PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414444922/MONDO:0010604/080 2024-10-11 2024-11-01 X-linked inheritance HP:0001417 Supports CHEBI:63791 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0151786 infores:hetionet CHEBI:480999 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0259749 infores:hetionet CHEBI:31643 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0151735 infores:hetionet CHEBI:31711 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0043144 infores:hetionet CHEBI:3756 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0023218 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0042373 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0011972 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0085083 infores:hetionet NCBIGene:1369 biolink:causes MONDO:0008910 infores:monarchinitiative not_provided not_provided HGNC:2312 MONDO:0008910 uuid:6d13d5e6-dd94-4acc-a2de-05f8f8945272 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0232462 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0034150 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004972 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0001430 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0520589 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0520589 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0018790 infores:hetionet CAID:CA145183 biolink:causes MONDO:0800472 infores:clingen CAID:CA145183 MONDO:0800472 PMID:18470941PMID:23028769PMID:19793111PMID:17363580PMID:27243976PMID:18622259PMID:19234632 Benign BA1 PP3, PP1, BP4, PM3, PM1, PM4, PM5, PS1, PS2, PS3, BP7, BS1, BS4, PVS1, PM2 The c.685G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 229 (p.Glu229Lys). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1) = 0.05176, which met the ≥ 0.05 threshold set for BA1 (4,701 alleles out of 90,816, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This missense variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.1) and the REVEL score = 0.395, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on CYP1B1 function. A previous study (PMID: 18470941) demonstrated that the 17B estradiol activity levels of the Glu229Lys protein were not below the established threshold for that assay (<20% relative activity compared to background haplotype). This variant was also assessed in PMIDs: 27243976, 19234632, 19793111, 18622259, 17363580 & 3028769, however, the assays reported did not meet the OddsPath threshold (> 2.1) or the threshold for abnormal impact on protein function in the assay could not be determined. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): BA1 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA145183/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6128 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0917801 infores:hetionet CHEBI:101278 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0043094 infores:hetionet CHEBI:43968 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0221423 infores:hetionet CHEBI:41879 biolink:causes MONDO:0000728 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0005745 infores:hetionet CHEBI:36795 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C1384353 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0038358 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0232910 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0016479 infores:hetionet CHEBI:44915 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0031117 infores:hetionet CHEBI:31348 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020580 infores:hetionet CHEBI:5118 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0025320 infores:hetionet CHEBI:16664 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0015230 infores:hetionet CHEBI:46557 biolink:causes UMLS:C0027627 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0027627 infores:hetionet CHEBI:63629 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0038325 infores:hetionet CHEBI:23765 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0151798 infores:hetionet CHEBI:6717 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0027497 infores:hetionet CHEBI:135929 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0917801 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0041969 infores:hetionet CHEBI:7956 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0022354 infores:hetionet CAID:CA024479 biolink:causes MONDO:0007783 infores:clingen CAID:CA024479 MONDO:0007783 PMID: Likely Benign PP3_Moderate, BS2_Supporting, BS1 PM1, PS4, PS3, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4.This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024479/MONDO:0007783/012 2021-03-18 2021-03-31 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:490877 biolink:causes MONDO:0012268 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0001175 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0038587 infores:hetionet CAID:CA173802 biolink:causes MONDO:0007113 infores:clingen CAID:CA173802 MONDO:0007113 PMID: Uncertain Significance PP4, BP5, BS1 The highest population minor allele frequency of the p.Arg39His variant in UBE3A (NM_130838.2) in gnomAD v4.1 is 0.00001667 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Arg39His variant in UBE3A (NM_130838.2) is classified as a variant of uncertain significance based on the ACMG/AMP criteria (no criteria met). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA173802/MONDO:0007113/037 2024-02-23 2024-12-23 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3638 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0009676 infores:hetionet CAID:CA10585085 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585085 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS3, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PVS1, PM6, PP2, PP1, BS2 The NM_000527.5(LDLR):c.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met.PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs.PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585085/MONDO:0007750/013 2021-06-07 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:161680 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0015967 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0015376 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0013922 infores:hetionet CHEBI:7824 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0014868 infores:hetionet CHEBI:15553 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0012739 infores:hetionet CHEBI:51860 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0026821 infores:hetionet CHEBI:116278 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0700345 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0878544 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0023530 infores:hetionet CHEBI:10023 biolink:causes MONDO:0019558 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0024138 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0007642 infores:hetionet CAID:CA645369679 biolink:causes MONDO:0007648 infores:clingen CAID:CA645369679 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS4, BS3, BP5, BP7, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.720del p.(Asn240fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000580709.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369679/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:64354 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0020437 infores:hetionet CHEBI:135930 biolink:causes MONDO:0021167 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0027121 infores:hetionet CHEBI:50275 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0004604 infores:hetionet CHEBI:135935 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0234458 infores:hetionet CHEBI:7852 biolink:causes HP:0002795 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C1260922 infores:hetionet CHEBI:73274 biolink:causes MONDO:0017773 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0151691 infores:hetionet CHEBI:7954 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0002622 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0011849 infores:hetionet CAID:CA2918446 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918446 MONDO:0015152 PMID: Likely Pathogenic PP3, PP4, PP1, PM2_Supporting, PM3_Strong The NM_000232.5: c.265G>A variant in SGCB is a missense variant predicted to cause substitution of valine by methionine at amino acid 89 (p.Val89Met). This variant has been detected in at least four individuals with symptoms of limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant (c.391C>T p.(Arg131Ter), 1 pt, ClinVar SCV000748307.5 internal data communication), and three patients were homozygous for the variant (1 pt, PMID: 28889091, 30838351, 29797799) (PM3_Strong). At least one of these patients displayed progressive limb girdle muscle weakness (PP4). This variant was also shown to co-segregate with autosomal recessive LGMD in one affected family member (PMID: 28889091; PP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Admixed American population (1/34588 exome alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.932, which is above the threshold of 0.7, evidence that correlates with impact to SGCB function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3_Strong, PP4, PM2_Supporting, PP3, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918446/MONDO:0015152/184 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10023 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C1384353 infores:hetionet CHEBI:63632 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0231218 infores:hetionet CHEBI:3437 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C1145670 infores:hetionet CHEBI:5778 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0040822 infores:hetionet CHEBI:63621 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0236075 infores:hetionet CHEBI:2618 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C1456784 infores:hetionet CHEBI:3510 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0012833 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0020517 infores:hetionet CAID:CA396464772 biolink:causes MONDO:0007648 infores:clingen CAID:CA396464772 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BS2, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2 The c.1566-2A>G variant is a canonical splice variant predicted to result in the use of a cryptic splice site which preserves the reading frame (PVS1_moderate). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in one individual meeting criteria for HDGC (PS4_supporting; PMID: 31841163). In summary, the clinical significance of this variant is classified as of uncertain significance based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_moderate, PS4_supporting, PM2_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396464772/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:49662 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0041582 infores:hetionet CHEBI:68554 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0030305 infores:hetionet CHEBI:3698 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0242350 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0020615 infores:hetionet GO:2000696 biolink:causes GO:0001822 infores:ubergraph knowledge_assertion manual_agent GO:2000696 GO:0001822 CHEBI:453011 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C0542571 infores:hetionet CHEBI:8774 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0030312 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0178298 infores:hetionet CHEBI:135005 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0020649 infores:hetionet CHEBI:5893 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0242350 infores:hetionet CHEBI:8499 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0011606 infores:hetionet CHEBI:8346 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0687713 infores:hetionet CHEBI:8707 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0021843 infores:hetionet CHEBI:2569 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0041657 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0011570 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235524 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235524 infores:hetionet NCBIGene:1305 biolink:causes MONDO:0014745 infores:monarchinitiative not_provided not_provided HGNC:2190 MONDO:0014745 uuid:33f76409-1895-4261-a940-00e848e8b06d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15854 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0028961 infores:hetionet CHEBI:3207 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0231218 infores:hetionet CHEBI:68579 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0033774 infores:hetionet CHEBI:6375 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C2363730 infores:hetionet CHEBI:17303 biolink:causes MONDO:0002265 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0038273 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0234215 infores:hetionet CHEBI:30659 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0009676 infores:hetionet CHEBI:8107 biolink:causes MONDO:0019956 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0014038 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235969 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0521491 infores:hetionet NCBIGene:10749 biolink:causes MONDO:0012651 infores:monarchinitiative not_provided not_provided HGNC:6317 MONDO:0012651 uuid:b2ab1950-3526-426f-9a01-1f164f6551f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0014591 infores:hetionet CAID:CA10588583 biolink:causes MONDO:0015152 infores:clingen CAID:CA10588583 MONDO:0015152 PMID: Pathogenic PVS1, PP4, PM2_Supporting PM3, PS1 The NM_000070.3: c.1115+5G>C variant in CAPN3 occurs in the splice donor region of intron 8 and is predicted to disrupt the splice donor site, with a SpliceAI score of 0.83. It is also predicted to disrupt the splice acceptor site of exon 8, with a SpliceAI score of 0.70. RNAseq analysis demonstrated this variant results in skipping of exon 8, which is expected to disrupt the reading frame and introduce a premature stop codon, leading to nonsense mediated decay in a gene in which loss of function is an established mechanism of disease (PMID: 32646536; PVS1_RNA). This variant has been reported in one individual with progressive muscle weakness, elevated CK and a myopathic muscle biopsy (PP4), where it was observed in trans with a variant of uncertain significance (PMID: 32646536; PM3_Supporting not met). This variant is absent from gnomAD v.4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/03/2025): PVS1_RNA, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588583/MONDO:0015152/187 2025-06-03 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:94385 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0013404 infores:hetionet CHEBI:10124 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085632 infores:hetionet NCBIGene:1643 biolink:causes MONDO:0010213 infores:monarchinitiative not_provided not_provided HGNC:2718 MONDO:0010213 uuid:ec922838-fe4c-4c81-87fe-dc2574cc5c11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0012833 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005301 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0026769 infores:hetionet CHEBI:4027 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0206062 infores:hetionet CHEBI:63618 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0013604 infores:hetionet CHEBI:5118 biolink:causes MONDO:0016011 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0015923 infores:hetionet CHEBI:253342 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0037274 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0541913 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0541913 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017160 infores:hetionet CHEBI:16335 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0151636 infores:hetionet CHEBI:5098 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0022354 infores:hetionet CHEBI:3504 biolink:causes MONDO:0021245 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0149744 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0267792 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0000737 infores:hetionet CHEBI:135920 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0009676 infores:hetionet CHEBI:92511 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C1321898 infores:hetionet CHEBI:46557 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0011991 infores:hetionet CHEBI:9654 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0151836 infores:hetionet CHEBI:7494 biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0151754 infores:hetionet NCBIGene:2312 biolink:causes MONDO:0007810 infores:monarchinitiative not_provided not_provided HGNC:3748 MONDO:0007810 uuid:743ea3c5-3505-4dae-af47-4ffcd91c19b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1384353 infores:hetionet CHEBI:43968 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0017178 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0233494 infores:hetionet CAID:CA229743 biolink:causes MONDO:0009861 infores:clingen CAID:CA229743 MONDO:0009861 PMID:7833954PMID:9634518PMID:7833954PMID:24401910 Pathogenic PM3, PP4_Moderate, PM2, PP3, PS3 PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs (PMID:7833954); PP4_Moderate: Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded (PMID:7833954; PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229743/MONDO:0009861/006 2018-08-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:73274 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0041834 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0232208 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0232208 infores:hetionet CHEBI:68584 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0080274 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0474378 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0474378 infores:hetionet CHEBI:82960 biolink:causes HP:0012228 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0033893 infores:hetionet CHEBI:5123 biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0010038 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0042769 infores:hetionet NCBITaxon:6333 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:6333 GO:0006954 DB00959_MESH_D014235_1DB01380_MESH_D014235_1DB00620_MESH_D014235_1DB00635_MESH_D014235_1DB00741_MESH_D014235_1DB00443_MESH_D014235_1 NCBIGene:9984 biolink:causes MONDO:0859524 infores:monarchinitiative not_provided not_provided HGNC:19070 MONDO:0859524 uuid:ddf7624e-7172-40b0-85a0-7aac5e44a4d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C2938875 infores:hetionet CHEBI:16755 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0086565 infores:hetionet PUBCHEM.COMPOUND:4786 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0080274 infores:hetionet CHEBI:87715 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0018944 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0009319 infores:hetionet GO:1904393 biolink:causes GO:0099173 infores:ubergraph knowledge_assertion manual_agent GO:1904393 GO:0099173 CHEBI:8597 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C2242996 infores:hetionet CHEBI:8346 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0237314 infores:hetionet CHEBI:75984 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0037274 infores:hetionet GO:0007317 biolink:causes GO:0044085 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0044085 CHEBI:8869 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0022081 infores:hetionet CHEBI:9086 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151632 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0085649 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0003123 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0009806 infores:hetionet CHEBI:408174 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0149725 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0008420 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0008420 uuid:14f9ee79-4689-4def-80af-0e413e6729c2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2567 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C2047937 infores:hetionet CHEBI:47381 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0014724 infores:hetionet UMLS:C0903898 biolink:causes UMLS:C0948873 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0948873 infores:hetionet CHEBI:4657 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0006384 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0009319 infores:hetionet CAID:CA401325116 biolink:causes MONDO:0009290 infores:clingen CAID:CA401325116 MONDO:0009290 PMID: Pathogenic PVS1, PM2, PP4, PM3_Supporting "The NM_000152.5:c.2407C>T (p.Gln803Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 (out of 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with late onset Pompe disease with this variant and treated by enzyme replacement therapy has been reported (PP4). This individual is compound heterozygous for the variant and ""IVS 0-45T>G"" (assumed to be c.-32-13T>G), a pathogenic variant in GAA, phase unknown (PMID: 26572913) (PM3_Supporting). Two additional patients have been reported to be compound heterozygous for p.Gln803Ter but the cDNA change provided is incorrect and thus this data was not included (PMID: 21940687). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 (1/111412 alleles) in the European-Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 552368). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023)" Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401325116/MONDO:0009290/010 2023-07-03 2023-09-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8665 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0042024 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0032285 infores:hetionet UMLS:C0065374 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0268000 infores:hetionet CHEBI:9605 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0002792 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0006684 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C1527311 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0027697 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0851341 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0521491 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0015376 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151666 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151666 infores:hetionet CHEBI:6413 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0014173 infores:hetionet UNII:VL0L558GCB biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00407 UMLS:C0085932 infores:hetionet CHEBI:52717 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0011124 infores:hetionet CHEBI:145499 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C2937358 infores:hetionet CHEBI:127780 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0151827 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0027339 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0002871 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0235906 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0235906 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1963789 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1963789 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0543698 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0543698 infores:hetionet CHEBI:9586 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0030252 infores:hetionet CHEBI:50729 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0018681 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0037274 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014742 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0041912 infores:hetionet CHEBI:27436 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0004509 infores:hetionet CHEBI:6909 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0035455 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151849 infores:hetionet CHEBI:9943 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033687 infores:hetionet CHEBI:52010 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C1306341 infores:hetionet CHEBI:32888 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0011603 infores:hetionet CHEBI:7447 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0036974 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0042109 infores:hetionet CHEBI:6887 biolink:causes UMLS:C1268766 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C1268766 infores:hetionet CHEBI:63621 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0017168 infores:hetionet CHEBI:50173 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0162830 infores:hetionet CHEBI:7465 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0041582 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0341164 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0341164 infores:hetionet CAID:CA913170089 biolink:causes MONDO:0044970 infores:clingen CAID:CA913170089 MONDO:0044970 PMID: Uncertain Significance PP3, PS4_Supporting, PM2_Supporting, PS3_Supporting PP1, BP4, PS2, PM6 The m.12316G>A variant in MT-TL2 has been reported in three unrelated individuals with primary mitochondrial disease. The three individuals had chronic progressive external ophthalmoplegia (CPEO). Other features seen included peripheral neuropathy, myopathy, and exercise intolerance. Muscle biopsy in affected individuals revealed ragged red fibers, COX-negative fibers, and decreased activities of respiratory chain complexes I and IV. The levels of the variant in affected individuals ranged from 40-55.6% in muscle when reported. Levels in other tissues varied from undetectable to 10% (PS4_supporting; PMIDs: 23847141, 20163808, 18603265). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (83.7 percentile) as does HmtVar with a score of 0.6 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed a higher degree of heteroplasmy in ragged red fibers (87.4% ± 8.5, n = 4) and COX-deficient fibers (59.7% ± 27.8, n = 4) compared to COX-positive muscle fibers (wild type mtDNA only, n = 6, Fig. 2). The difference between COX-positive and ragged red fibers was statistically significant (p<0.00001; PMID: 20163808; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 27, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913170089/MONDO:0044970/015 2023-02-27 2023-03-15 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CAID:CA1139665152 biolink:causes MONDO:0008723 infores:clingen CAID:CA1139665152 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.1409del (p.Leu470Argfs*22) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9328975, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. PM2_Supporting is met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting, (ClinGen ACADVL VCEP specifications version#1.0; approved 08-08-22). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA1139665152/MONDO:0008723/021 2022-09-13 2022-09-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:194135 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0001122 infores:hetionet CHEBI:9566 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0344232 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0002871 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020538 infores:hetionet CHEBI:77260 biolink:causes HP:0002789 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0231835 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004768 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0022573 infores:hetionet CHEBI:6539 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0009450 infores:hetionet CHEBI:7601 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0004093 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0011991 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0233472 infores:hetionet CHEBI:28177 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0018965 infores:hetionet CHEBI:75984 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0035078 infores:hetionet CHEBI:4469 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0040435 infores:hetionet CHEBI:6073 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C2830004 infores:hetionet CHEBI:6149 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0162297 infores:hetionet CHEBI:2663 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0002792 infores:hetionet CHEBI:68642 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0018965 infores:hetionet CHEBI:28830 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0030552 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0002871 infores:hetionet CAID:CA320603699 biolink:causes MONDO:0100083 infores:clingen CAID:CA320603699 MONDO:0100083 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.673C>T (p.Leu225Phe) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603699/MONDO:0100083/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63635 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0039231 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0227791 infores:hetionet CHEBI:251408 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0027497 infores:hetionet NCBIGene:2628 biolink:causes MONDO:0012996 infores:monarchinitiative not_provided not_provided HGNC:4175 MONDO:0012996 uuid:d1f42fd5-f4ac-4f07-8d65-2a888e663a17 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:251408 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01010 UMLS:C0018790 infores:hetionet CHEBI:134991 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0151786 infores:hetionet CHEBI:32293 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0015967 infores:hetionet CHEBI:8382 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0234894 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0151605 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0151605 infores:hetionet NCBIGene:10501 biolink:causes MONDO:0030034 infores:monarchinitiative not_provided not_provided HGNC:10739 MONDO:0030034 uuid:53d4b00d-e897-480d-8c77-a32744f39ea3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63610 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0852911 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0032461 infores:hetionet CHEBI:64355 biolink:causes MONDO:0003330 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0178879 infores:hetionet CHEBI:8707 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0038454 infores:hetionet CL:0000084 biolink:causes MONDO:0004963 infores:ubergraph knowledge_assertion manual_agent CL:0000084 MONDO:0004963 CAID:CA1611067988 biolink:causes MONDO:0011071 infores:clingen CAID:CA1611067988 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM5_Supporting, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, BS2, PP4, PP2, PP3, PP1 The NM_001754.5(RUNX1):c.782dup (p.Gln262SerfsTer338) is a frameshift variant not expected to undergo nonsense-mediated mRNA decay. Nevertheless, the altered region is crucial for protein function, as it involves a duplication that impacts the established positions for frameshift (+1) variants (i.e., c.780-c.1440) (PVS1_Strong) and is positioned downstream of c.98 (in transcript NM_001754.4) (PM5_Supporting). This variant is entirely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). To the best of our knowledge, this variant has not been reported in any study. In summary, this variant meets the criteria for a likely pathogenic classification, applying ACMG/AMP criteria specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2_Supporting, PM5_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1611067988/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:100241 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020580 infores:hetionet NCBITaxon:781 biolink:causes MONDO:0024472 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:781 MESH:D001907 DB00254_MESH_D001907_1DB00446_MESH_D001907_1DB02703_MESH_D001907_1 CHEBI:39585 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0027441 infores:hetionet CHEBI:68478 biolink:causes NCIT:C78504 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0476281 infores:hetionet CHEBI:16755 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0022346 infores:hetionet CHEBI:30830 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0042075 infores:hetionet CHEBI:5062 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0012833 infores:hetionet CHEBI:45081 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0001339 infores:hetionet CHEBI:94411 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0026961 infores:hetionet CHEBI:10110 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0700292 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0948525 infores:hetionet NCBIGene:80311 biolink:causes MONDO:0010508 infores:monarchinitiative not_provided not_provided HGNC:29347 MONDO:0010508 uuid:4a478aeb-73df-4b8d-80ec-3c730255d6c1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:61058 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0234233 infores:hetionet NCBIGene:6091 biolink:causes MONDO:0009762 infores:monarchinitiative not_provided not_provided HGNC:10249 MONDO:0009762 uuid:6a06e12d-df77-4435-9956-1f96f22a341e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0002886 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0151505 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1096282 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1096282 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0235511 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0235511 infores:hetionet CHEBI:59773 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0030252 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0042769 infores:hetionet CHEBI:52717 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003578 infores:hetionet NCBITaxon:5690 biolink:causes MONDO:0000940 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5690 MONDO:0000940 CHEBI:42797 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C1761613 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0011570 infores:hetionet CHEBI:92998 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020615 infores:hetionet CHEBI:2567 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0023418 infores:hetionet CHEBI:499361 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0016204 infores:hetionet CAID:CA2802051 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802051 MONDO:0001586 PMID: Uncertain Significance PP3 BS1, PM2, BP4 The NM_000203.5:c.670T>C variant in IDUA is a missense variant predicted to cause substitution of Serine by Proline at amino acid 224 (p.Ser224Pro). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0005077 (38/74842 alleles) in African/African American population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), and lower than the threshold for BS1 (>0.0025). Therefore, none of the population data codes are met. The computational predictor REVEL gives a score of 0.746 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (PMID: 36413997) (PP3). To our knowledge, this variant has not been reported in the literature in individuals with a confirmed diagnosis of MPS I. However, it has been identified in infants undergoing newborn screening who also carry pseudodeficiency variants (PMID: 37516270). There is a ClinVar entry for this variant (Variation ID: 2152483). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802051/MONDO:0001586/091 2024-12-06 2025-06-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA037389 biolink:causes MONDO:0007750 infores:clingen CAID:CA037389 MONDO:0007750 PMID: Uncertain Significance BS3_Supporting BP4, BA1, PS1, PS3, PS4, BS1, PM5, PM2, BS2, PP3 The NM_000527.5(LDLR):c.1911C>T (p.Ser637=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: BS3_Supporting: Level 3 assays - PMID 26020417 (Medeiros et al., 2016): Heterozygous patients' lymphocytes, RNA assays. Results: Normal LDLR transcript processing. Aberrant transcript not detected. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA037389/MONDO:0007750/013 2023-06-23 2025-09-16 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:585948 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0018418 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0234913 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0234916 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0234916 infores:hetionet CAID:CA270246 biolink:causes MONDO:0010726 infores:clingen CAID:CA270246 MONDO:0010726 PMID: Benign BS1, BS2 The allele frequency of the p.Pro388Leu (NM_004992.3) variant in MECP2 is 0.014% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Thep.Pro388Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). In summary, the p.Pro388Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270246/MONDO:0010726/016 2021-12-13 2021-12-27 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:2955 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027497 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235567 infores:hetionet UNII:F64QU97QCR biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0702166 infores:hetionet CHEBI:42797 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0005758 infores:hetionet CHEBI:31401 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0013491 infores:hetionet CHEBI:553473 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0042267 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0038454 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0549385 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0549385 infores:hetionet NCBIGene:4306 biolink:causes MONDO:0011517 infores:monarchinitiative not_provided not_provided HGNC:7979 MONDO:0011517 uuid:f01d7e1f-4a0a-431b-8bcd-fcedc46f8bee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:87681 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0004936 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005105 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0025202 infores:hetionet CHEBI:5130 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0002962 infores:hetionet CHEBI:391960 biolink:causes MONDO:0006554 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0085074 infores:hetionet CHEBI:9168 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0031039 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0037274 infores:hetionet CHEBI:31981 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0027424 infores:hetionet CHEBI:94807 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00507 UMLS:C0016204 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235848 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0426576 infores:hetionet CHEBI:8871 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0005741 infores:hetionet CHEBI:5784 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0037763 infores:hetionet CHEBI:4753 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C0041834 infores:hetionet CHEBI:6846 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C0003123 infores:hetionet CHEBI:17026 biolink:causes HP:0025429 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0235939 infores:hetionet NCBIGene:10939 biolink:causes MONDO:0012450 infores:monarchinitiative not_provided not_provided HGNC:315 MONDO:0012450 uuid:d08c02a0-17b7-4ca2-bb57-778e4a124286 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6367 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1167965 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0178298 infores:hetionet CHEBI:63631 biolink:causes HP:0011423 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0085679 infores:hetionet CHEBI:45951 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0004093 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0004623 infores:hetionet CHEBI:2950 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0030193 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004868 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0005424 infores:hetionet CHEBI:8356 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0030554 infores:hetionet NCBIGene:3849 biolink:causes MONDO:0007813 infores:monarchinitiative not_provided not_provided HGNC:6439 MONDO:0007813 uuid:525062d5-8e66-4a74-83da-ed3db87f413a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:84500 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0037763 infores:hetionet CHEBI:3696 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0018524 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0014742 infores:hetionet CHEBI:3761 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00628 UMLS:C0917801 infores:hetionet CHEBI:4511 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0234215 infores:hetionet CHEBI:204734 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0332534 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0856152 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0856152 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0521500 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0521500 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0012833 infores:hetionet NCBIGene:284403 biolink:causes MONDO:0011435 infores:monarchinitiative not_provided not_provided HGNC:24502 MONDO:0011435 uuid:9508504c-6c6e-4e3a-8cbc-3e68e9544d40 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17347 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0038362 infores:hetionet CHEBI:9215 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00919 UMLS:C0234233 infores:hetionet CHEBI:6129 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0002871 infores:hetionet CHEBI:47780 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0855333 infores:hetionet CHEBI:31932 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0033774 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0019360 infores:hetionet CHEBI:5138 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0017675 infores:hetionet CHEBI:9445 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0003811 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0521591 infores:hetionet CHEBI:47781 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C2047937 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0004936 infores:hetionet CHEBI:6367 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0031350 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0027765 infores:hetionet CHEBI:8207 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0025222 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0020456 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0948594 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0233472 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0006147 infores:hetionet CHEBI:7444 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0151517 infores:hetionet CHEBI:171719 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0019158 infores:hetionet CHEBI:94848 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0027497 infores:hetionet CHEBI:31859 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0232492 infores:hetionet CHEBI:453011 biolink:causes HP:0033425 infores:sider not_provided not_provided DRUGBANK:DB01188 UMLS:C1963964 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0025061 infores:hetionet CHEBI:64310 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C1384353 infores:hetionet CHEBI:28787 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0017178 infores:hetionet CHEBI:6847 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0235416 infores:hetionet CHEBI:7496 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0022081 infores:hetionet CHEBI:28901 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0027497 infores:hetionet CHEBI:46081 biolink:causes HP:0020221 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0234535 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0038045 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0038045 infores:hetionet CHEBI:15407 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0439857 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0020039 infores:hetionet CHEBI:4027 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0162834 infores:hetionet CAID:CA2802166 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802166 MONDO:0001586 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Strong PM5, PS3, PS1 The NM_000203.5(IDUA):c.1029C>G (p.Tyr343Ter) variant is a nonsense variant observed to cause a premature stop codon in biologically relevant exon 8 (out of 14), leading to nonsense-mediated decay in the IDUA gene in which loss-of-function is an established disease mechanism. Expression of the variant in COS-7 cells showed 1.1% of normal IDUA activity (PMID: 9391892) (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15956 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, 2 were heterozygous for the variant and a pathogenic or likely pathogenic variant (variants are: c.208C>T (p.Gln70Ter), c.3G>A (p.Met1?)), and one of those was confirmed in trans (PMIDs: 15081804, 9391892, 8019572) (PM3_Strong). At least 1 patient with this variant had undetectable IDUA activity in skin fibroblasts (PP4) (PMID: 15081804). There is a ClinVar entry for this variant (Variation ID: 550474). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Strong, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802166/MONDO:0001586/010 2024-12-05 2025-03-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:7581 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0032285 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0234913 infores:hetionet CHEBI:15544 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0020621 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0002453 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0234913 infores:hetionet CHEBI:7915 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0017178 infores:hetionet CHEBI:2676 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0009676 infores:hetionet CAID:CA120560 biolink:causes MONDO:0044970 infores:clingen CAID:CA120560 MONDO:0044970 PMID: Pathogenic PP3, PM6_Strong, PS4, PP1_Moderate The m.3243A>G variant in MT-TL1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 1670860, 2102678, 2268345, 17823937, 23806424, 16682545, 18391161, 9323566, 18294221, 16717204, 12874464, 9285090, 11260383, 30133155, 9323566, 23360351, 10799437, 12221518, 29560378). Clinical syndromes seen in affected individuals include mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), chronic progressive external ophthalmoplegia (CPEO), and Leigh syndrome. Clinical features seen in affected individuals are variable and include myopathy, neuropathy, seizures, hemiparesis, stroke-like episodes, ataxia, dementia, developmental delay and/or regression, headache, migraine, short stature, diabetes, gastrointestinal involvement (dysmotility, reduced appetite, vomiting, dysphagia, constipation, diarrhea), ophthalmoplegia, optic atrophy, retinal dystrophy, ptosis, sensorineural hearing loss, cardiomyopathy, Wolff-Parkinson-White, renal involvement (tubulopathy, focal segmental glomerulosclerosis), mood disorder, lactic acidosis, and ragged red fibers on muscle biopsy. Age of onset ranges from early in life to adulthood. There are several reported de novo occurrences of this variant (PM6_strong; PMIDs: 27331024, 27450679, 11168879). Additionally, this variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 1539604, 8492919, 7931425, 1487758). There are several occurrences of this variant in population databases. The computational predictor MitoTIP suggests this variant is pathogenic (58.8 percentile) and HmtVAR predicts it to be pathogenic with a score of 1 (PP3). Cybrid and single fiber studies support the functional impact of this variant (PMIDs: 18455161, 1378759, 1732728, 8154867, 9741403). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PP1_moderate, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120560/MONDO:0044970/015 2020-08-20 2025-08-07 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6633 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0033774 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0020517 infores:hetionet CHEBI:101278 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0014518 infores:hetionet CHEBI:3696 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0012569 infores:hetionet GO:0098904 biolink:causes GO:0086027 infores:ubergraph knowledge_assertion manual_agent GO:0098904 GO:0086027 CHEBI:63791 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0017152 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0235567 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005159 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0600139 infores:hetionet CHEBI:50859 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0034886 infores:hetionet CHEBI:45081 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0151827 infores:hetionet CHEBI:7983 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00312 UMLS:C0018681 infores:hetionet CHEBI:79699 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0013428 infores:hetionet NCBIGene:2542 biolink:causes MONDO:0030437 infores:monarchinitiative not_provided not_provided HGNC:4061 MONDO:0030437 uuid:87853875-de13-4d67-b438-355c0adbdfe1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17698 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0027765 infores:hetionet CHEBI:9352 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0162830 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0677500 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0151717 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0020651 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0026650 infores:hetionet CHEBI:3723 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040460 infores:hetionet CHEBI:3534 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C2242737 infores:hetionet CHEBI:6067 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1443060 infores:hetionet CHEBI:135920 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0015672 infores:hetionet CHEBI:82716 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0041582 infores:hetionet CHEBI:5132 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00499 UMLS:C0019158 infores:hetionet CHEBI:8768 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042514 infores:hetionet CHEBI:4708 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0040264 infores:hetionet CHEBI:49575 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0267792 infores:hetionet NCBIGene:2157 biolink:causes MONDO:0010602 infores:monarchinitiative not_provided not_provided HGNC:3546 MONDO:0010602 uuid:a0d5994a-ec52-4640-b353-f9e4a0be299a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0000751 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0240735 infores:hetionet CHEBI:9763 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0030312 infores:hetionet CHEBI:6413 biolink:causes NCIT:C78656 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0854069 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0857245 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0857245 infores:hetionet CHEBI:71219 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0018965 infores:hetionet CHEBI:4027 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0036974 infores:hetionet CAID:CA024910 biolink:causes MONDO:0007783 infores:clingen CAID:CA024910 MONDO:0007783 PMID: Likely Benign BS1 PP3, PM5, PM1, PS1, PS4, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with phenylalanine at codon 2776 of the RYR1 protein p.(Ser2776Phe). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00145, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), ( PMID:21965348, PMID:30236257 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.693 does not support a pathogenic or a benign status. This variant has been classified as Likely Benign. Criteria implemented: BS1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024910/MONDO:0007783/012 2021-03-18 2021-08-26 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA023687 biolink:causes MONDO:0007750 infores:clingen CAID:CA023687 MONDO:0007750 PMID: Pathogenic PS3_Moderate, PS4, PP1_Strong, PM3, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, BS2, PP2 The NM_000527.5(LDLR):c.301G>A (p.Glu101Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS4, PM2, PM3, PS3_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_strong - variant segregates with the FH phenotype in at least 19 relatives with the variant and LDL-C above the 75th percentile from several labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, Ambry, Robarts Research Institute), so PP1_Strong is met.PS4 - variant meets PM2 and is identified in at least 16 index cases who fulfill validated clinical criteria for FH from several labs (SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge and DLCN >=6 from Color, Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Robarts Research Institute), so PS4 is met.PM2 - PopMax MAF = 0.00003266 (0.003%) in south asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PM3 - variant meets PM2 and was identified in 1 index case with LDL 16.2 mmol/L and also LDLR exon 15 deletion from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) - Likely pathogenic by these guidelines, so PM3 is metPS3_moderate - Level 2 FS: Hobbs et al., 1992 (PMID 1301956): Hmz patient fibroblast, 125I-LDL assays - results: 15-30% LDLR activity. Activity is below 70% of wild-type, so PS3_Moderate is met.PP3 - REVEL = 0.896. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and is identified in at least 1 index case who fulfills SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. so, PP4 is met Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023687/MONDO:0007750/013 2021-12-13 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6923 biolink:causes UMLS:C0236083 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0236083 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235876 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235876 infores:hetionet CHEBI:28593 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0031256 infores:hetionet CHEBI:8212 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0008031 infores:hetionet CHEBI:404903 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0019079 infores:hetionet CHEBI:2469 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0948594 infores:hetionet CHEBI:8356 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0039231 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0012833 infores:hetionet CHEBI:8665 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0023380 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0036572 infores:hetionet CHEBI:37333 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0013395 infores:hetionet CHEBI:16796 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0233414 infores:hetionet CHEBI:91541 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0233571 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0149514 infores:hetionet CHEBI:37924 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0151825 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0020651 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0040046 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0037199 infores:hetionet CHEBI:28864 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0010200 infores:hetionet GO:0072094 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:0072094 GO:0072210 CHEBI:7640 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2242996 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0017178 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004235 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0012813 infores:hetionet CHEBI:7447 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00607 UMLS:C0020649 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001309 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0028866 infores:hetionet CHEBI:66964 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C1456784 infores:hetionet CHEBI:63581 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0152025 infores:hetionet CHEBI:63617 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0038358 infores:hetionet CHEBI:4469 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0009806 infores:hetionet CAID:CA512318998 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318998 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP2, BP3, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.108G>A (p.Thr36=) is a synonymous variant therefore REVEL score is not applicable and SpliceAI is ≤0.20 (acceptor loss 0.01) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.43361 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, and PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318998/MONDO:0011071/008 2022-04-08 2022-07-05 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:2266 biolink:causes MONDO:0008737 infores:monarchinitiative not_provided not_provided HGNC:3694 MONDO:0008737 uuid:8bbe98ff-423a-40a6-89c0-aef1edc8f07b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:15365 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0019087 infores:hetionet CHEBI:29688 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0014518 infores:hetionet CHEBI:31622 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0020651 infores:hetionet CHEBI:6067 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0004930 infores:hetionet CHEBI:63605 biolink:causes UMLS:C0234199 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0234199 infores:hetionet CHEBI:49662 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0030554 infores:hetionet CHEBI:5893 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0006840 infores:hetionet CHEBI:8871 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0023380 infores:hetionet CHEBI:9727 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0015230 infores:hetionet CHEBI:16714 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C1443060 infores:hetionet CHEBI:17263 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0042109 infores:hetionet CHEBI:9086 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018965 infores:hetionet CHEBI:171719 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042510 infores:hetionet UMLS:C0017797 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0232726 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005881 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0079924 infores:hetionet CHEBI:63638 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0085632 infores:hetionet CHEBI:63620 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011603 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0032155 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0000729 infores:hetionet CHEBI:119486 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0021368 infores:hetionet CAID:CA16020990 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020990 MONDO:0009861 PMID:24350308PMID:24350308 Likely Pathogenic PM2, PM5, PP4, PM3_Supporting PP3 The c.1301C>T (p.Ala434Val) variant in PAH has been reported in 1 individual with classic PKU detected with pathogenic variant p.R243X (PMID: 24350308). This variant is absent in population databases. Another missense change at the same amino acid (p.Ala434Asp) is likely pathogenic by 1 submitter and pathogenic by PAH VCEP. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020990/MONDO:0009861/006 2020-08-13 2021-11-21 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63598 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0836924 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0575090 infores:hetionet NCBIGene:5898 biolink:causes MONDO:0859142 infores:monarchinitiative not_provided not_provided HGNC:9839 MONDO:0859142 uuid:dbbc2aa1-17d3-4b51-943d-67d7a46670f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31980 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0015230 infores:hetionet CHEBI:3515 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0026821 infores:hetionet CHEBI:2955 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0006849 infores:hetionet CHEBI:7824 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0086439 infores:hetionet CHEBI:31623 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0011603 infores:hetionet CAID:CA390864803 biolink:causes MONDO:0100216 infores:clingen CAID:CA390864803 MONDO:0100216 PMID: Uncertain Significance BP4, PM2_Supporting, PM1_Supporting BP2, BA1, BS2, PP3, PP4, PP1, PM5, PS1, PS3, PS4, PS2, BS1, BS3, BS4 NM_177438.3(DICER1):c.5375C>G variant in DICER1 is a missense variant predicted to cause substitution of serine by cysteine at amino acid 1792 (p.Ser1792Cys). Although this variant has been observed in individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.485; MaxEntScan and SpliceAI: no effect on splicing) (BP4). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting. (Bayesian Points: 1; VCEP specifications version 1.4.0; 08/26/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA390864803/MONDO:0100216/024 2025-08-26 2025-09-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8890 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0042571 infores:hetionet CHEBI:3207 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0039231 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0033860 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0013295 infores:hetionet CAID:CA913191011 biolink:causes MONDO:0009290 infores:clingen CAID:CA913191011 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting The NM_000152.5:c.2655_2656del (p.Val886GlufsTer2) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two siblings with this variant and late-onset Pompe disease have been reported with GAA activity in dried blood spots below the normal range, and both are on enzyme replacement therapy (PMID 31392188, personal communication)(PP4_Moderate). These individuals are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 597005; 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913191011/MONDO:0009290/010 2021-09-01 2021-09-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:4315 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0023530 infores:hetionet CAID:CA10585400 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585400 MONDO:0007750 PMID: Pathogenic PS3, PS4_Moderate, PP1_Strong, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, BS2 NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PP1_Strong, PM2, PS4_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1 assay - PMID:25741862 - CHO cells, WB+FACS+CLSM, 7% low-density lipoprotein particle receptor biosynthetic process; 5% low-density lipoprotein particle binding; 10% low-density lipoprotein particle clearance.PP1_strong - 6 informative meioses in 3 families identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1).PS4_moderate - Variant meets PM2. Variant identified in 9 index cases.PP3 - REVEL: 0,907. PP4 - Variant meets PM2. Variant identified in 9 index cases fulfilling specific clinical criteria for FH (6 cases with Simon-Broome from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 3 cases with Simon-Broome criteria published in PMID: 20538126). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585400/MONDO:0007750/013 2021-06-09 2021-06-24 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:5001 biolink:causes EFO:0009624 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0856597 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0035854 infores:hetionet GO:0046602 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0046602 GO:0140014 CHEBI:51860 biolink:causes HP:0008765 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233762 infores:hetionet CHEBI:31348 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0014335 infores:hetionet NCBIGene:23093 biolink:causes MONDO:0014372 infores:monarchinitiative not_provided not_provided HGNC:19963 MONDO:0014372 uuid:098ec5b8-8adb-4f05-9830-ec5cfc5d49b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6067 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085631 infores:hetionet GO:0010082 biolink:causes GO:0022622 infores:ubergraph knowledge_assertion manual_agent GO:0010082 GO:0022622 CHEBI:8228 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0037274 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0948782 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0948782 infores:hetionet CHEBI:5130 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0039070 infores:hetionet CHEBI:6339 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0151539 infores:hetionet CHEBI:8404 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C0013144 infores:hetionet CHEBI:8764 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0268000 infores:hetionet CHEBI:50648 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0036508 infores:hetionet NCBIGene:2992 biolink:causes MONDO:0014526 infores:monarchinitiative not_provided not_provided HGNC:4699 MONDO:0014526 uuid:2ace448a-df47-442f-bc0d-0019c5b7ec97 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36704 biolink:causes MONDO:0004695 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C1112746 infores:hetionet CHEBI:135451 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01482 UMLS:C0017181 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0021053 infores:hetionet CHEBI:136040 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0018524 infores:hetionet CHEBI:16335 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0041657 infores:hetionet CHEBI:31176 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0010520 infores:hetionet CHEBI:75998 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0314719 infores:hetionet CHEBI:291342 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0013604 infores:hetionet CHEBI:168396 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0032227 infores:hetionet CHEBI:3215 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013182 infores:hetionet CHEBI:499361 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0040264 infores:hetionet CHEBI:5130 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0518988 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0027765 infores:hetionet CAID:CA10014505 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014505 MONDO:0011071 PMID: Uncertain Significance PM1 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, PM2, PM6, PVS1, BP7, BP5, PM5, PM4, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.490G>A (p.Val164Ile) is a missense variant which affects an amino acid residue within the RHD domain that is defined as a mutational hotspot by the ClinGen MM-VCEP (PM1_supporting). This variant is present on one allele in gnomAD v2.1.1 (251,430 alleles tested) and is absent from gnomAD v3.1.2 (mean depth coverage 30x). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014505/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:53760 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0278106 infores:hetionet CAID:CA320642805 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642805 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.205G>A (p.Gly69Ser) is a missense variant. The highest population minor allele frequency in gnomAD v3.1.2 is 0.0.00001470 (1/68046 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 not met). This missense variant has a REVEL score < 0.50 (0.439) and SpliceAI score is ≤ 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642805/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:15367 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0020580 infores:hetionet CHEBI:63608 biolink:causes MONDO:0019086 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0152018 infores:hetionet CHEBI:31711 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0235266 infores:hetionet CHEBI:48844 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0011991 infores:hetionet CHEBI:63611 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0030794 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0020514 infores:hetionet CHEBI:3485 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0018681 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0011570 infores:hetionet CHEBI:7824 biolink:causes UMLS:C0522172 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0522172 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0003123 infores:hetionet CHEBI:47657 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0232462 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002320 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0497552 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0002957 infores:hetionet CHEBI:48947 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00766 UMLS:C0042963 infores:hetionet CHEBI:9943 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002622 infores:hetionet CHEBI:3738 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0039231 infores:hetionet NCBIGene:84693 biolink:causes MONDO:0009615 infores:monarchinitiative not_provided not_provided HGNC:16732 MONDO:0009615 uuid:f26d84a5-3b7b-4569-a226-a7972edd8c5c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:82941 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0151904 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042373 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0234458 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0413252 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0413252 infores:hetionet NCBIGene:200576 biolink:causes MONDO:0007376 infores:monarchinitiative not_provided not_provided HGNC:23785 MONDO:0007376 uuid:02b0e90a-f22d-48be-9f20-53eb9bfe6f26 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:134991 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0558489 infores:hetionet CAID:CA8815479 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815479 MONDO:0009290 PMID: Likely Pathogenic PP4_Moderate, PP3, PM3, PM2_Supporting, PS3_Moderate The NM_000152.5:c.1796C>A variant in GAA is a missense variant predicted to cause substitution of serine by tyramine at amino acid 599 (p.Ser599Tyr). At least 4 probands have been reported with clinical symptoms consistent with Pompe, typically late onset of symptoms, and documentation of reduced enzyme activity in the affected range (PMID: 37087815 and/or on enzyme replacement therapy (PMID: 29122469, 29803406, 31710733). Additional patients have symptoms consistent with Pompe disease but no details were available on GAA activity (PMID: 32419263). At least 4 individuals are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.-32-13T>G (at least 2 patients) (PMID: 29122469, 31710733, 32419263, 37087815) (max 2 x 0.5 points = 1 point), and c.655G>A (p.Gly219Arg) (PMID: 18429042) (0.5 points). Another individuals is compound heterozygous for the variant and c.364A>G (p.Met122Val); phase unknown (PMID: 29803406). The allelic data for the proband will be used in the assessment of p.Met122Val and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v2.1.0 is 0.00002683 (3/111834; no homozygotes) and in gnomAD v4.1.0 it is 0.000005932 (7/1179950; no homozygotes) in the European (non-Finnish) population, which is lower than the ClinGen LD VCEP threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class A (“very severe”). An additional study demonstrated 0% GAA activity in Ad5-SV40 fibroblast cells and abnormal Western blot results, indicating that this variant may impact protein function (PMIDs 18425781, 18429042)(PS3_Moderate). The computational predictor REVEL gives a score of 0.974 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551558). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2): PS3_Moderate, PM3, PP3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815479/MONDO:0009290/010 2024-11-22 2024-12-17 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:30659 biolink:causes MONDO:0018382 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0149887 infores:hetionet CHEBI:75998 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0030196 infores:hetionet CHEBI:8764 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0028738 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0038358 infores:hetionet NCBITaxon:1392 biolink:causes MONDO:0004215 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1392 MESH:C531621 DB01053_MESH_C531621_1DB02703_MESH_C531621_1DB00254_MESH_C531621_1 CHEBI:9586 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0235198 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0006651 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D014606 DB00684_MESH_D014606_1DB02703_MESH_D014606_1 GO:0072124 biolink:causes GO:0072006 infores:ubergraph knowledge_assertion manual_agent GO:0072124 GO:0072006 CHEBI:77260 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C3263723 infores:hetionet CHEBI:27666 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0038325 infores:hetionet CHEBI:75984 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0018681 infores:hetionet CHEBI:135342 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0232462 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005754 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014549 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013395 infores:hetionet CAID:CA226463 biolink:causes MONDO:0100437 infores:clingen CAID:CA226463 MONDO:0100437 PMID: Pathogenic PVS1, PP1, PM2_Supporting, PS4_Supporting NM_001034853.2(RPGR):c.934+1G>A is a canonical splice site variant in intron 8 and is predicted to induce skipping of exon 8, which is expected to disrupt a critical functional domain in RPGR (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 10482958, 36445968, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through at least 2 affected meioses from 1 family. (PP1; PMID: 10482958). In summary, this variant is classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1, PM2_supporting, PS4_supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226463/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Supports CHEBI:6367 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0392025 infores:hetionet CHEBI:63605 biolink:causes UMLS:C1167779 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C1167779 infores:hetionet CHEBI:85078 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0011849 infores:hetionet CHEBI:135276 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0030554 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0002170 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0235431 infores:hetionet CHEBI:53760 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0235146 infores:hetionet CHEBI:17650 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0009782 infores:hetionet CHEBI:4315 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0042963 infores:hetionet CHEBI:31638 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0003864 infores:hetionet CHEBI:35778 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0040046 infores:hetionet CAID:CA415090852 biolink:causes MONDO:0010305 infores:clingen CAID:CA415090852 MONDO:0010305 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong The NM_005629.4:c.1685G>A variant in SLC6A8 is a nonsense variant (p.Trp562Ter) predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). This variant has been reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 17101918) (PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_Strong, PM2_Supporting, PP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415090852/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Supports CAID:CA359428682 biolink:causes MONDO:0012163 infores:clingen CAID:CA359428682 MONDO:0012163 PMID: Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1 NM_002185.5(IL7R):c.379G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 127 (p.Val127Ile). The highest population minor allele frequency in gnomAD v4 is 0.00002991 (1/33436) in African/African American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). c.379G>A mutation in IL7R abolishes splicing of exons 3-4 and replaces it with splicing of exons 2-4, which introduces a STOP site resulting in premature termination of IL-7Ra translation (Nonsense mediated decay) (PVS1) PMID: 35418989.Female patient with SCID (0.5 pt.), reduced CD127 expression demonstrated by flow cytometry (1 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) Total :1.75 pts. (PP4_met ; PMID: 35418989).The patient (PMID: 35418989) was found homozygous for the mutation (0.5 pt.) (PM3_supporting).In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PVS1, PP4_met,PM3_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359428682/MONDO:0012163/119 2024-02-01 2024-02-01 Autosomal recessive inheritance HP:0000007 Supports CAID:CA214300 biolink:causes MONDO:0015967 infores:clingen CAID:CA214300 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3 PS4, PS1, PP1 The c.326+4A>G variant in the HNF1 homeobox A gene, HNF1A, alters a nucleotide two base pairs downstream of the canonical splice donor site in intron 1 of transcript NM_000545.8. The computational splicing predictor SpliceAI gives a score of 0.56 for donor loss, predicting that this variant may disrupt splicing at the intron 1 donor site of HNF1A (PP3). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; PMID: 28862987). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 28862987, internal lab contributors). This variant segregated with diabetes with 1 informative meioses in a single family internal lab; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). The nucleotide change c.326+4A>C, which is predicted to disrupt splicing at intron 1 to a lesser extent than c.326+4A>G, has been observed in a proband with diabetes; however, the c.326+4A>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP at this time (internal lab contributors). In summary, c.326+4A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1, PP3, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214300/MONDO:0015967/017 2024-11-27 2024-11-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:23765 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0152198 infores:hetionet CHEBI:32315 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151904 infores:hetionet CHEBI:60761 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0152227 infores:hetionet CHEBI:36791 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0032617 infores:hetionet CHEBI:68478 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0852911 infores:hetionet CHEBI:85161 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0162298 infores:hetionet CHEBI:119915 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0235996 infores:hetionet CHEBI:6444 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0023380 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004785 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0005741 infores:hetionet UMLS:C0004609 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0008031 infores:hetionet CAID:CA410150105 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150105 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM2, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.865G>C (p.Gly289Arg) is a missense variant which has a REVEL score < 0.50 (0.268) and a SpliceAI score ≤ 0.20 (0.01) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150105/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:51380 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0085631 infores:hetionet CHEBI:50922 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0085616 infores:hetionet CAID:CA410203767 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203767 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP1, BS2 NM_001754.5(RUNX1):c.262G>C (p.Glu88Gln) is a missense variant which has a REVEL score ≥ 0.88 (0.921) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203767/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7936 biolink:causes UMLS:C0021294 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0021294 infores:hetionet CHEBI:3176 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0003862 infores:hetionet CHEBI:9943 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0023066 infores:hetionet CHEBI:27732 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0151578 infores:hetionet CHEBI:40303 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C2239176 infores:hetionet CHEBI:404903 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0016204 infores:hetionet CHEBI:84500 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C3665624 infores:hetionet CHEBI:4046 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00434 UMLS:C0042023 infores:hetionet CHEBI:36791 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015371 infores:hetionet NCBIGene:22868 biolink:causes MONDO:0030020 infores:monarchinitiative not_provided not_provided HGNC:29160 MONDO:0030020 uuid:d5728e3b-5da9-4a11-a3b1-c53bd3822717 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2955 biolink:causes UMLS:C0521491 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0521491 infores:hetionet CHEBI:41879 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0151970 infores:hetionet CHEBI:6402 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0009763 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018099 infores:hetionet CHEBI:6438 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0677500 infores:hetionet CHEBI:2668 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0019158 infores:hetionet CHEBI:8884 biolink:causes UMLS:C0235055 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0235055 infores:hetionet GO:0070562 biolink:causes GO:0071305 infores:ubergraph knowledge_assertion manual_agent GO:0070562 GO:0071305 CHEBI:119573 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0006852 infores:hetionet CHEBI:31711 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0033774 infores:hetionet CAID:CA134604 biolink:causes MONDO:0021060 infores:clingen CAID:CA134604 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.315C>T (p.Pro105=) variant in the MAP2K1 gene is 0.01% (64/66728) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134604/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:404903 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0750394 infores:hetionet NCBIGene:3818 biolink:causes MONDO:0012901 infores:monarchinitiative not_provided not_provided HGNC:6371 MONDO:0012901 uuid:9693b9de-f740-4bbf-a658-ed1ba43217af biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7931 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0002170 infores:hetionet CHEBI:119915 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0032227 infores:hetionet GO:0060657 biolink:causes GO:0060652 infores:ubergraph knowledge_assertion manual_agent GO:0060657 GO:0060652 CHEBI:17026 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0851341 infores:hetionet CHEBI:3749 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0038661 infores:hetionet CHEBI:6128 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0019054 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011616 infores:hetionet CHEBI:4657 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C2939147 infores:hetionet CAID:CA1251409 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251409 MONDO:0013144 PMID: Likely Pathogenic PS4, PP4, PP3, PM2_Supporting The NM_000488.4:c.449A>C variant in SERPINC1 is a missense variant predicted to cause substitution of Glutamine by Proline at amino acid 150 (p.Gln150Pro). This variant is also known as antithrombin Vienna (Legacy nomenclature: Gln118Pro) in the literature. At least one patient with this variant displayed AT deficiency (type II- HBD) which is highly specific for SERPINC1 (PP4, PMID: 7734360). The computational predictor REVEL gives a score of 0.865, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 gene function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 (1/113750 alleles) in the non-Finnish European population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002 ) for PM2_Supporting, meeting this criterion. In summary, this variant meets the criteria to be classified as a pathogenic forantithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP. (Specifications version 1.0.0; date of approval: 7/17/2023). Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251409/MONDO:0013144/084 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CAID:CA2575615880 biolink:causes MONDO:0100216 infores:clingen CAID:CA2575615880 MONDO:0100216 PMID:37248399 Likely Pathogenic PP3, PP4, PM2_Supporting, PS4_Supporting, PS3 PM6, BP4, BP2, BA1, BS2, PP1, PM5, PM3, PS2, BS1, BS4, BS3 The NM_177438.2:c.5365-4A>G variant in DICER1 is an intronic variant resulting in an A to G substitution 4 nucleotides upstream from coding exon 25. This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 37248399). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 related tumor predisposition (PP4, PMID: 37248399). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; PMID: 37248399). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PP3, PS3. (Bayesian Points: 8; VCEP specifications version 1.3.0; 06/24/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA2575615880/MONDO:0100216/024 2025-06-24 2025-07-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52172 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003811 infores:hetionet CHEBI:3082 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0015230 infores:hetionet CHEBI:3380 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0020649 infores:hetionet CHEBI:7459 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0022107 infores:hetionet CAID:CA267625 biolink:causes MONDO:0009861 infores:clingen CAID:CA267625 MONDO:0009861 PMID:21307867 Pathogenic PVS1, PP4_Moderate, PM2 The c.1066-2A>T variant in PAH is absent from all population databases, and has been identified in a patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine. PMID: 21307867. It is a null variant where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 11 is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PVS1, PM2. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267625/MONDO:0009861/006 2019-04-24 2019-04-24 Autosomal recessive inheritance HP:0000007 Supports GO:2000014 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000014 GO:0007275 CHEBI:5893 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0027339 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0037274 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0746883 infores:hetionet CHEBI:135935 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0085631 infores:hetionet CHEBI:6375 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0007859 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0423773 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0423773 infores:hetionet CHEBI:64354 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0039070 infores:hetionet CHEBI:4784 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0035078 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005555 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0235238 infores:hetionet CHEBI:17026 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0043094 infores:hetionet CHEBI:64064 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0015672 infores:hetionet CHEBI:4856 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0020546 infores:hetionet CHEBI:8869 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0020443 infores:hetionet CHEBI:18248 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0013604 infores:hetionet CHEBI:2639 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C3665347 infores:hetionet NCBIGene:6697 biolink:causes MONDO:0012994 infores:monarchinitiative not_provided not_provided HGNC:11257 MONDO:0012994 uuid:91aaafb1-5a29-47c1-902a-02ca5daf5f9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64310 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0041657 infores:hetionet CHEBI:3568 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235490 infores:hetionet CHEBI:473990 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0013395 infores:hetionet CHEBI:5778 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0002878 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014868 infores:hetionet CHEBI:45863 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151904 infores:hetionet CHEBI:135005 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0015371 infores:hetionet CAID:CA120598 biolink:causes MONDO:0044970 infores:clingen CAID:CA120598 MONDO:0044970 PMID:31181185 Uncertain Significance PS3_Moderate, PS4_Supporting, PP3, PP1 PM5, PM4, BP4, PS1, PM2 The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one with onset in early 20s, one with onset in 50s). Several affected individuals had a period of normal development followed by delay and regression. Progressive neuromuscular involvement in later onset forms has also been seen. Features include developmental delay, microcephaly, choreoathetotic movements, ataxia, axonal neuropathy, progressive cognitive impairment, retinal dystrophy, hearing loss, and increase of subsarcolemmal mitochondria in muscle. Brain MRI showed bilateral basal ganglia lesions, Leigh syndrome, and cerebellar atrophy; and lab abnormalities included elevated blood and CSF lactate, and elevated ammonia with febrile viral infection. Heteroplasmy levels were generally variable, >68% in multiple tissues; one healthy mother had 85% heteroplasmy; and one healthy sib had 50-60% heteroplasmy (PS4_supporting; PMIDs: 8554662, 23206802, 33704825). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1; PMIDs: 8554662, 23206802). There are several occurrences of this variant in healthy population databases. Several studies in yeast (PMID: 31181185) support the functional impact of this variant and showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.69 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120598/MONDO:0044970/014 2022-03-24 2022-03-24 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true GO:1902908 biolink:causes GO:0033059 infores:ubergraph knowledge_assertion manual_agent GO:1902908 GO:0033059 NCBIGene:64135 biolink:causes MONDO:0030692 infores:monarchinitiative not_provided not_provided HGNC:18873 MONDO:0030692 uuid:254cd307-0706-4a39-8688-e3fe384ad599 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:253342 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0043352 infores:hetionet CHEBI:2038 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0021053 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0235567 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0235567 infores:hetionet CHEBI:8245 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C2830004 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0085932 infores:hetionet CAID:CA10385250 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385250 MONDO:0100437 PMID: Benign BP4, BA1 BS2, BP5 NM_001034853.2(RPGR):c.2729G>A (p.Gly910Glu) is a missense variant causing substitution of glycine by glutamic acid at amino acid 910. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0002927 among hemizygous individuals, with 21 variant alleles / 71,743 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been observed in 1 male individual with features consistent with retinopathy as well as another RPGR variant, p.Gly95Arg, previously classified pathogenic by the ClinGen X-linked IRD VCEP specifications (PMID: 28488341, PMID: 36882936). However, the BP5 code is considered not applicable for RPGR. The computational predictor REVEL gives a score of 0.041, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01 for donor gain, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385250/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:182080 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0033774 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0034065 infores:hetionet CHEBI:44185 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0026946 infores:hetionet CHEBI:9352 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0349506 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0574067 infores:hetionet GO:1903224 biolink:causes GO:0001706 infores:ubergraph knowledge_assertion manual_agent GO:1903224 GO:0001706 CHEBI:63115 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0024312 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0162287 infores:hetionet CHEBI:135888 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0031350 infores:hetionet CHEBI:75998 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0085641 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0007787 infores:hetionet CHEBI:31644 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0232461 infores:hetionet CHEBI:10127 biolink:causes EFO:1001340 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0018843 infores:hetionet CHEBI:100246 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0004134 infores:hetionet CHEBI:15365 biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0392176 infores:hetionet CHEBI:3723 biolink:causes HP:0032198 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0580413 infores:hetionet CHEBI:134990 biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0234913 infores:hetionet CHEBI:51141 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0035455 infores:hetionet GO:0045191 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0045191 GO:0007275 CHEBI:31348 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0231528 infores:hetionet GO:0044003 biolink:causes GO:0008150 infores:ubergraph knowledge_assertion manual_agent GO:0044003 GO:0008150 CHEBI:6775 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0018378 infores:hetionet CAID:CA9870415 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870415 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PP1, PM2_Supporting, PM1_Supporting PS4 The c.938G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of Glycine to Valine at codon 313 (p.(Gly313Val)) of NM_175914.4. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and no copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.919. This variant is located within the ligand binding domain of HNF4A, which is critical for the protein’s function (PM1_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and macrosomia) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with 3 informative meioses in 1 family (PP1; internal lab contributor). This variant was identified in 2 unrelated individuals with diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate. In summary, c.938G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PP1, PM2_Supporting, PM1_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870415/MONDO:0015967/085 2024-01-22 2024-01-22 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9943 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0423791 infores:hetionet CHEBI:4562 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C1443060 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0595877 infores:hetionet CHEBI:63616 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0008031 infores:hetionet UMLS:C1738934 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0476280 infores:hetionet CHEBI:9448 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0020517 infores:hetionet CHEBI:9763 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0009319 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0021843 infores:hetionet CAID:CA10584821 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584821 MONDO:0007750 PMID: Pathogenic PS4_Supporting, PP1_Strong, PM5, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PVS1, PM6, BS2, PP2 The NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence PP1_Strong, PM2, PM5, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 11 informative meiosis from 2 families from PMID 20809525 (Marduel et al., 2010): F1: 4 affected relatives have the variant and 3 unaffected relatives do not have the variant; F2: 3 affected relatives have the variant and 1 unaffected relative does not have the variant, so PP1_Strong is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelinesThere is 1 variant classified as Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.833. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 4 index cases with SB criteria of FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), so PP4 is met.PS4_supporting - variant meets PM2 and was identified in 4 index cases with SB criteria of FH from PMID 20809525 (Marduel et al., 2010), (see PP4 for details), so PS4_Supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584821/MONDO:0007750/013 2021-12-30 2022-07-11 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:83804 biolink:causes MONDO:0043885 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0015403 infores:hetionet CHEBI:28593 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0262988 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009946 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0011551 infores:hetionet CHEBI:41423 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0002874 infores:hetionet CAID:CA229837 biolink:causes MONDO:0009861 infores:clingen CAID:CA229837 MONDO:0009861 PMID:10541324 Uncertain Significance PM4, PM2, PP4 The c.895_897del (p.Phe299del) variant in PAH has been reported in 1 individual with PKU without genotype information (BH4 deficiency not ruled out) (PMID: 10541324) . This variant is absent in gnomAD and the ESP population databases. The c.895_897del variant results in an in-frame deletion of phenylalanine 299 in a hydrophobic pocket of the hydroxylase domain of PAH. In summary, this variant meets the criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229837/MONDO:0009861/006 2019-07-14 2019-07-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:8356 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0234215 infores:hetionet CHEBI:168396 biolink:causes NCIT:C35651 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877303 infores:hetionet CHEBI:28148 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C2939147 infores:hetionet CHEBI:8772 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0041657 infores:hetionet CHEBI:9139 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0015967 infores:hetionet CHEBI:472657 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0005758 infores:hetionet CAID:CA031690 biolink:causes MONDO:0005835 infores:clingen CAID:CA031690 MONDO:0005835 PMID: Uncertain Significance BP4, PM2_Supporting BP5, PVS1 The MLH1 c.1963A>T variant is predicted as a missense variant, p.(Ile655Phe). It is extremely rare (<1 in 50,000 alleles) in gnomAD v.2.1.1 using the noncancer dataset and in gnomAD v4.1. Its MAPP+PolyPhen-2 prior probability for pathogenicity is <0.11 as per http://priors.hci.utah.edu/PRIORS. Therefore, this variant is classified as a variant of unknown significance. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA031690/MONDO:0005835/115 2024-09-19 2024-10-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:404903 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0600142 infores:hetionet CHEBI:8871 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0750394 infores:hetionet CHEBI:31638 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0004093 infores:hetionet CHEBI:55346 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0011991 infores:hetionet CHEBI:9622 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0521839 infores:hetionet CHEBI:41423 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0687713 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005326 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0038814 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0162429 infores:hetionet CHEBI:5855 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0035078 infores:hetionet CHEBI:9637 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0010200 infores:hetionet CHEBI:5280 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0011168 infores:hetionet CHEBI:3347 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0020557 infores:hetionet CHEBI:8212 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0009806 infores:hetionet CHEBI:32599 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0020649 infores:hetionet CHEBI:63638 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0031212 infores:hetionet NCBITaxon:1872 biolink:causes MONDO:0005119 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1872 MESH:D000881 DB13092_MESH_D000881_1 CHEBI:63681 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0042109 infores:hetionet CHEBI:3508 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0038325 infores:hetionet CHEBI:44915 biolink:causes HP:0033532 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0007166 infores:hetionet CHEBI:71028 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0027441 infores:hetionet CHEBI:92511 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0009450 infores:hetionet CAID:CA345916 biolink:causes MONDO:0044970 infores:clingen CAID:CA345916 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6 PP4, BA1, PS1, PS3, BS1, PM5 The m.10254G>A (p.D66N) variant in MT-ND3 has been reported in at least five unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with Leigh syndrome, with onset in or around the first year of life, and two individuals had features of optic neuropathy (PS4_moderate; PMIDs: 20202874, 27290639, 26238931, 36913248). There are at least two de novo occurrences reported in the literature (PM6; PMIDs: 20202874, 27290639). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.56 and 0.925, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA345916/MONDO:0044970/015 2023-10-23 2024-11-25 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:472657 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00671 UMLS:C0011603 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0227791 infores:hetionet CHEBI:3032 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00868 UMLS:C0036974 infores:hetionet CHEBI:63598 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1145670 infores:hetionet CHEBI:3510 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0002878 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0151763 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0036572 infores:hetionet CHEBI:70735 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0852733 infores:hetionet CHEBI:8707 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0233407 infores:hetionet CHEBI:9139 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0016867 infores:hetionet NCBIGene:64327 biolink:causes MONDO:0007615 infores:monarchinitiative not_provided not_provided HGNC:13243 MONDO:0007615 uuid:55e56dc9-3359-4e80-af36-c67558e8f02a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4909 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0042384 infores:hetionet CHEBI:127342 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0236075 infores:hetionet NCBIGene:79848 biolink:causes MONDO:0014288 infores:monarchinitiative not_provided not_provided HGNC:26193 MONDO:0014288 uuid:3f590540-acf0-48e2-86f5-2628fad36b2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63598 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0004936 infores:hetionet CHEBI:42797 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0151662 infores:hetionet NCBIGene:4638 biolink:causes MONDO:0100354 infores:monarchinitiative not_provided not_provided HGNC:7590 MONDO:0100354 uuid:0f1654f8-4076-438a-a764-d3bf61f060c8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0392025 infores:hetionet CHEBI:63681 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0085584 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0002170 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0001824 infores:hetionet CHEBI:8428 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB01035 UMLS:C2697368 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0152159 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0152159 infores:hetionet NCBIGene:79583 biolink:causes MONDO:0013994 infores:monarchinitiative not_provided not_provided HGNC:37234 MONDO:0013994 uuid:170c4cb7-12fc-43ec-8472-b3ba7e806c3b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46295 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0162830 infores:hetionet CHEBI:17474 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0018799 infores:hetionet CHEBI:3568 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0031117 infores:hetionet CHEBI:64312 biolink:causes MONDO:0044986 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0024228 infores:hetionet CHEBI:3219 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0013604 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0151744 infores:hetionet CHEBI:16796 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0020557 infores:hetionet CHEBI:144551 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0009763 infores:hetionet CAID:CA16608969 biolink:causes MONDO:0012999 infores:clingen CAID:CA16608969 MONDO:0012999 PMID: Likely Pathogenic PVS1, PM2_Supporting The NM_000156.6:c.481A>T (p.Lys161Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5 out of a total of 6 exons. While the variant is in the penultimate exon of GAMT, it is upstream of the region predicted to be missed by nonsense-mediated decay; this is expected to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74906 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 392462). To our knowledge, this variant has not been reported in an individual with GAMT deficiency in the published literature. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on October 7, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608969/MONDO:0012999/026 2025-10-07 2025-10-07 Autosomal recessive inheritance HP:0000007 Supports CAID:CA367398790 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398790 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP1_Moderate, PP4_Moderate, PP2, PP3, PM2_Supporting PS3 The c.1136C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 379 (p.(Ala379Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.968, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; PMID 18322640, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMIDs: 18322640, 17573900). This variant segregated with diabetes, with three informative meioses in two families with MODY (PP1_Moderate; PMID 18322640). Another missense variant, c.1136C>A p.Ala379Glu, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala379Val (PM5_supporting). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 18322640). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP1_Moderate, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398790/MONDO:0015967/086 2023-08-01 2023-08-01 Semidominant inheritance HP:0032113 Supports NCBIGene:337 biolink:causes MONDO:0976234 infores:monarchinitiative not_provided not_provided HGNC:602 MONDO:0976234 uuid:715eae0e-f644-4ebb-9574-2c1d4f9075e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1904103 biolink:causes GO:0007369 infores:ubergraph knowledge_assertion manual_agent GO:1904103 GO:0007369 CHEBI:9649 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0003123 infores:hetionet NCBIGene:63976 biolink:causes MONDO:0014152 infores:monarchinitiative not_provided not_provided HGNC:14000 MONDO:0014152 uuid:f93fbab3-6472-4be3-bc86-401cf6124d78 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3181 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0015967 infores:hetionet CHEBI:3654 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0042109 infores:hetionet CHEBI:68478 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0019079 infores:hetionet CHEBI:70707 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0016204 infores:hetionet CHEBI:404903 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0221201 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036572 infores:hetionet CHEBI:9137 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037763 infores:hetionet GO:0042509 biolink:causes GO:0007259 infores:ubergraph knowledge_assertion manual_agent GO:0042509 GO:0007259 CAID:CA2580080423 biolink:causes MONDO:0009595 infores:clingen CAID:CA2580080423 MONDO:0009595 PMID: Uncertain Significance PM2_Supporting The variant NC_000009.12:g.35657675T>C is absent in population databases such as gnomAD. The variant has not been described in patients with cartilage-hair hypoplasia.In summary, this variant is classified as Uncertain significance - insufficient evidence for Autosomal recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (SCID VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580080423/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5864 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0031542 infores:hetionet CHEBI:10119 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0026848 infores:hetionet CHEBI:44032 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0043094 infores:hetionet CHEBI:47499 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0042023 infores:hetionet NCBITaxon:122354 biolink:causes MONDO:0020959 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:122354 MONDO:0020959 CHEBI:4315 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0030781 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0235296 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0235296 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151827 infores:hetionet CHEBI:7936 biolink:causes MONDO:0004382 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023051 infores:hetionet NCBIGene:2784 biolink:causes MONDO:0014872 infores:monarchinitiative not_provided not_provided HGNC:4400 MONDO:0014872 uuid:b7b3ac5d-e20b-48dc-bae6-601882a6ba0b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0232462 infores:hetionet CHEBI:16755 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0012569 infores:hetionet CHEBI:63608 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0006277 infores:hetionet CHEBI:367163 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0032326 infores:hetionet CHEBI:27974 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0018681 infores:hetionet CHEBI:53760 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0038362 infores:hetionet CHEBI:135736 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0235266 infores:hetionet CHEBI:6078 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0009421 infores:hetionet CHEBI:18385 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0332534 infores:hetionet CHEBI:119573 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0020456 infores:hetionet GO:2000028 biolink:causes GO:0010228 infores:ubergraph knowledge_assertion manual_agent GO:2000028 GO:0010228 CHEBI:5441 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0042384 infores:hetionet CHEBI:7514 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0029408 infores:hetionet CHEBI:91834 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C2047937 infores:hetionet CHEBI:5123 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0027497 infores:hetionet CHEBI:52172 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0233407 infores:hetionet CHEBI:520985 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0030252 infores:hetionet CAID:CA327915723 biolink:causes MONDO:0100437 infores:clingen CAID:CA327915723 MONDO:0100437 PMID: Likely Benign BP4, BS1 PM2, PP3, BS2, PM5, PM1, PS1, PS3, PS4, BS3, BS4 NM_001034853.2(RPGR):c.2606A>G (p.Glu869Gly) is a missense variant encoding the substitution of glutamic acid with glycine at amino acid 869. This variant is present in gnomAD v4.1.0 at a frequency of 0.00002702 among hemizygous individuals, with 6 variant alleles / 222,040 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.062, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). This variant has been identified in at least one affected individual who also harbors a heterozygous variant (c.5882G>A; p.Gly1961Glu) in ABCA4, however this individual is female and lacks male family members known to be affected, so is not eligible for inclusion in PS4_Supporting (PMID: 30190494). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BS1 and BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA327915723/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true CHEBI:17474 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0015397 infores:hetionet CHEBI:7824 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0428977 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0542184 infores:hetionet CHEBI:6375 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0021177 infores:hetionet CHEBI:51450 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0020625 infores:hetionet CHEBI:3347 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0039231 infores:hetionet CHEBI:8805 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0948594 infores:hetionet CHEBI:63618 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0003467 infores:hetionet CHEBI:35854 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0042029 infores:hetionet CHEBI:3478 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0595916 infores:hetionet CHEBI:5138 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0013390 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0041969 infores:hetionet CHEBI:15552 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0085649 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0038525 infores:hetionet CHEBI:49668 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0015230 infores:hetionet CHEBI:50729 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151699 infores:hetionet CAID:CA060685 biolink:causes MONDO:0018493 infores:clingen CAID:CA060685 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1_Supporting, PP3_Moderate PS3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of cysteine with arginine at codon 4664 of the RYR1 protein, p.(Cys4664Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 19191333). One functional study was published for this variant. In this study, immortalized B-lymphocytes from patients carrying p.(Arg530His), p.(Asn2342Ser), p.(Glu2371Gly), and p.(Arg2454His) showed increased acidification rate when stimulated by 4CmC. B-lymphocytes from patients carrying p.(Cys4664Arg) were less activated by 4CmC, indicating a leaky channel. This assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID: 19191333). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.936) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA060685/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:6761 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0497156 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0021308 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0677500 infores:hetionet CHEBI:63717 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0018965 infores:hetionet CHEBI:63617 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0231530 infores:hetionet CHEBI:63580 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0035305 infores:hetionet CHEBI:55346 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0162429 infores:hetionet CHEBI:17347 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0476280 infores:hetionet CHEBI:6129 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0036974 infores:hetionet CAID:CA013398 biolink:causes MONDO:0004994 infores:clingen CAID:CA013398 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.3153G>A (p.Ala1051=) variant in the MYH7 gene is 0.68% (490/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013398/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51173 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0001339 infores:hetionet CHEBI:47426 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0002792 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0018799 infores:hetionet CHEBI:2549 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0019080 infores:hetionet CAID:CA397723028 biolink:causes MONDO:0008723 infores:clingen CAID:CA397723028 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 PM1, PM5, BA1, BS1 The c.494A>T variant in ACADVL is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 165 (p.Glu165Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.934, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). A palmitoyl-CoA oxidation assay in patient-derived lymphocytes from an individual carrying this variant and no other identified ACADVL variant showed 40% reduced residual assay (PMID: 30194637). However, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397723028/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA016546 biolink:causes MONDO:0005045 infores:clingen CAID:CA016546 MONDO:0005045 PMID: Likely Pathogenic PM2, PM1, PP1, PS4 BA1, PM5, PM4, PM6, PP3, PS3, BS1, BS3, BS4, BP4, BP7, BP2, BP5, PS1, PS2, PVS1 The NM_000257.4(MYH7):c.611G>A (p.Arg204His) variant has been identified in at least >45 individuals with HCM, at least 7 of whom had disease-causing variants in other cardiomyopathy associated genes (PS4; Richard 2003 PMID:12707239; Funada 2010 PMID:20975235; Berge 2014 PMID:24111713; Homburger 2016 PMID: 27247418; Ntusi 2016 PMID:27841901; Walsh 2017 PMID: 27532257; Burns 2017 PMID:28790153; Mattivi 2020 PMID:32894683; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in 4 affected relatives from 4 families (PP1; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.0006% (FAF 95% CI; 3/129190) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis did not provide evidence for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1, PM2, PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016546/MONDO:0005045/002 2022-04-27 2022-04-27 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0065374 biolink:causes EFO:0010670 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0159056 infores:hetionet CHEBI:66899 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0259799 infores:hetionet NCBIGene:84823 biolink:causes MONDO:0014685 infores:monarchinitiative not_provided not_provided HGNC:6638 MONDO:0014685 uuid:927a2c03-76cf-4396-ae65-b067eb0f8ab9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA229561 biolink:causes MONDO:0009861 infores:clingen CAID:CA229561 MONDO:0009861 PMID:10679941PMID:10679941 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 PAH-specific ACMG/AMP criteria applied: PM2: absent from ExAC, gnomAD, 1000G, ESP. PAGE MAF=0.00066; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.967; PP4_Moderate: Detected in a patient with classic PKU. Cofactor deficiency excluded. (PMID:10679941); PM3: Detected in trans with R408W (P) (PMID:10679941). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229561/MONDO:0009861/006 2018-08-10 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports UNII:U6XF9NP8HM biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01375 UMLS:C0011175 infores:hetionet CHEBI:91541 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0022107 infores:hetionet CHEBI:3723 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0018932 infores:hetionet CAID:CA020197 biolink:causes MONDO:0008667 infores:clingen CAID:CA020197 MONDO:0008667 PMID: Pathogenic PS4, PM2_Supporting, PVS1 The variant NM_000551.4(VHL):c.263G>A (p.Trp88Ter) in VHL is a truncating variant. This variant causes a premature stop codon in a biologically-relevant-exon predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been identified in at least 9 unrelated probands (and other related family members not counted within each) all meeting Danish VHL criteria, from literature evaluated in both CIViC and Hypothes.is VHL datasets. CIViC EIDs (https://civicdb.org): 8292;7606;5776;9374;6806;6538. This corresponds to Strong evidence (5-15 probands) (PS4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA020197/MONDO:0008667/078 2024-06-25 2024-07-17 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50742 biolink:causes UMLS:C0404572 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0429468 infores:hetionet CHEBI:8081 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0017178 infores:hetionet CAID:CA229484 biolink:causes MONDO:0009861 infores:clingen CAID:CA229484 MONDO:0009861 PMID:10495930PMID:21147011PMID:10495930PMID:10495930PMID:11051201PMID:11051201 Pathogenic PM2, PP4_Moderate, PM5, PP3, PP1, PM3_Strong PS3, BS3 The c.202A>G (p.Arg68Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 21147011). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID: 10495930); p.R408W (3 patients including 2 siblings); c.842+1G>A (2 patients) PMID: 24350308. Computational prediction tools and conservation analysis support a deleterious effect on the protein. Another missense variant at the same amino acid (p.Arg68Ser) is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3, PP1. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229484/MONDO:0009861/006 2020-07-02 2021-07-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2948 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C2047937 infores:hetionet CHEBI:85161 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0013404 infores:hetionet UMLS:C0145867 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0013378 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0022660 infores:hetionet CHEBI:131512 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0027066 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235146 infores:hetionet CHEBI:175901 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0037274 infores:hetionet CHEBI:3756 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0006840 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005990 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040584 infores:hetionet CHEBI:36795 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0013384 infores:hetionet CAID:CA343725757 biolink:causes MONDO:0005338 infores:clingen CAID:CA343725757 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.868A>G variant in MYOC is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 290 (p.Thr290Ala). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008491 (1 allele out of 1,177,772), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.271, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 14971589), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343725757/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8107 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151559 infores:hetionet CHEBI:63791 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042029 infores:hetionet CHEBI:3814 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0178298 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0033860 infores:hetionet GO:0045708 biolink:causes GO:0002168 infores:ubergraph knowledge_assertion manual_agent GO:0045708 GO:0002168 CHEBI:44915 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0035078 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0039971 infores:hetionet CHEBI:3504 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0423791 infores:hetionet CHEBI:47780 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0013604 infores:hetionet CAID:CA1619846 biolink:causes MONDO:0800472 infores:clingen CAID:CA1619846 MONDO:0800472 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PP1_Strong, PP3_Strong BA1, BP4, PM5, PM1, PM4, PS1, PS2, PS3, BS1, BS4, BP7, PVS1 The c.1169G>A variant in CYP1B1 is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 390 (p.Arg390His). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.0002635 (24 alleles out of 91,084), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.982, which met the ≥ 0.932 threshold for PP3_Strong, predicting a damaging effect on CYP1B1 function. There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. ≥3 affected segregations with a CYP1B1-related phenotype have been reported (PMID: 30820150), which fulfilled PP1_Strong. There were more family studies published than presented here. This variant has been identified in eight individuals with a CYP1B1-related phenotype. Six of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (phase unknown) (PMIDs: 21850185, 19247456, 19536304, 18852424, 17591938). Two individuals are homozygous (non-consanguineous) for the variant (PMID: 30270463). Total proband points = 4, meeting PM3_Very strong. There were more cases published than presented here. In summary, this variant met the criteria to receive a score of 17 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Very strong, PP1_Strong, PP3_Strong, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1619846/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4495 biolink:causes UMLS:C0009760 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0009760 infores:hetionet CHEBI:5098 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0948594 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0574067 infores:hetionet CHEBI:84050 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0019209 infores:hetionet GO:0060782 biolink:causes GO:0061458 infores:ubergraph knowledge_assertion manual_agent GO:0060782 GO:0061458 CHEBI:5118 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0031542 infores:hetionet CAID:CA012693 biolink:causes MONDO:0021056 infores:clingen CAID:CA012693 MONDO:0021056 PMID: Pathogenic PVS1, PS4, PM2_Supporting The NM_000038.6:c.694C>T p.(Arg232Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 7 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in at least 10 probands meeting phenotypic criteria, resulting in a total phenotype score of > 4 (PS4, [PMID: 1316610, 20223039, 7524601, 21110124, 19279422 and several more]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA012693/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45863 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0234909 infores:hetionet CHEBI:31236 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021177 infores:hetionet CHEBI:74947 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C1306341 infores:hetionet CHEBI:3723 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0028084 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0004238 infores:hetionet CAID:CA267671 biolink:causes MONDO:0009861 infores:clingen CAID:CA267671 MONDO:0009861 PMID:26666653PMID:26666653 Likely Pathogenic PM3, PM2, PP4, PP3 PM5 The c.785T>G (p.Val262Gly) variant in PAH is observed in 1 patient with classic PKU. BH4 deficiencies were not assessed. It was detected with a known pathogenic variant p.F39L. PMID: 26666653. This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen-2, MutationTaster, and REVEL=0.954. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA267671/MONDO:0009861/006 2018-12-10 2019-04-05 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6950 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0031350 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0877098 infores:hetionet CHEBI:6741 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0017168 infores:hetionet CHEBI:36791 biolink:causes MONDO:0002277 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0003850 infores:hetionet CHEBI:74947 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0220870 infores:hetionet CHEBI:3423 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0232462 infores:hetionet CHEBI:3699 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0018794 infores:hetionet CHEBI:47499 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0002390 infores:hetionet CHEBI:15367 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C1384353 infores:hetionet CHEBI:231594 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0018799 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0392176 infores:hetionet CAID:CA9302225 biolink:causes MONDO:0010938 infores:clingen CAID:CA9302225 MONDO:0010938 PMID: Likely Benign BS2_Supporting, BS1 The c.187A>G (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Isoleucine by Valine at amino acid 63 (p.Ile63Val).The popmax filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.00007135 (105/1179936 alleles) for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting; However, the highest MAF in the Ashkenazi Jewish population is 0.007061 (209/29600 alleles), which is above the SCID VCEP established threshold of >0.00100 for BS1. As this population is not known to have a higher prevalence, this is considered to meet BS1. One homozygote is described in gnomAD v.4 in the Ashkenazi Jewish population (BS2_Supporting).To our knowledge, this variant has not been reported in the literature in individuals affected with JAk3-SCID/related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting (VCEP specifications version 1.0). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA9302225/MONDO:0010938/121 2024-01-23 2024-01-23 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:584020 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0003862 infores:hetionet CHEBI:49960 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0011175 infores:hetionet CHEBI:134743 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0037274 infores:hetionet CHEBI:4708 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0018681 infores:hetionet CHEBI:63610 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0427008 infores:hetionet CHEBI:7478 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0042024 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0019158 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0010709 infores:hetionet CHEBI:4735 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0030554 infores:hetionet CHEBI:78543 biolink:causes MONDO:0041114 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0235490 infores:hetionet CHEBI:4466 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0018524 infores:hetionet CHEBI:3077 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0018800 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0005940 infores:hetionet CHEBI:50922 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0151908 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0233632 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0041912 infores:hetionet CHEBI:2676 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0042109 infores:hetionet NCBITaxon:173087 biolink:causes MONDO:0001209 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:173087 MONDO:0001209 CHEBI:6904 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C1443060 infores:hetionet CHEBI:2668 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0020580 infores:hetionet GO:0070805 biolink:causes GO:0070787 infores:ubergraph knowledge_assertion manual_agent GO:0070805 GO:0070787 CHEBI:9637 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0740394 infores:hetionet CHEBI:63635 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0014868 infores:hetionet CHEBI:49960 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0019080 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0013395 infores:hetionet CAID:CA16603285 biolink:causes MONDO:0100040 infores:clingen CAID:CA16603285 MONDO:0100040 PMID: Likely Benign BS2_Supporting, BP5, PM2_Supporting, BP4 The p.Ala92Val variant in FOXG1 is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). The p.Ala92Val variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Invitae) (BP5). Computational analysis prediction tools suggest that the p.Ala92Val variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala92Val variant in FOXG1 is absent from gnomAD (PM2_supporting).In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 1 unaffected individual and 2 individuals with an alternate molecular diagnosis, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion and classified this variant as Likely Benign (BS2_supporting, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603285/MONDO:0100040/035 2023-10-13 2023-12-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:94385 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0018944 infores:hetionet UMLS:C0657912 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233407 infores:hetionet CHEBI:10119 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0085641 infores:hetionet CAID:CA178021 biolink:causes MONDO:0021060 infores:clingen CAID:CA178021 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2238T>C (p.Asn746=) variant in the SOS1 gene is 0.232% (33/10404) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA178021/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:617099 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0231303 infores:hetionet CHEBI:49575 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0030318 infores:hetionet CAID:CA022554 biolink:causes MONDO:0007356 infores:clingen CAID:CA022554 MONDO:0007356 PMID: Pathogenic PP3_Moderate, PP1_Strong, PM5, PP4_Moderate, PM2_Supporting The NM_000251.3(MSH2):c.929T>G (p.Leu310Arg) variant is a missense variant replacing Leucin 310 to Arginin. The variant has been reported to co-segregate with disease in pedigree(s) with a combined* Bayes Likelihood Ratio >18.72 in ≥2 families (PMID: 30376427, 33848333) (PP1_STR).The variant is a missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity >0.81 as per http://priors.hci.utah.edu/PRIORS (PP3_MOD).The variant is a missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level; p.Leu310Pro classified as Class 5 by InSiGHT (PM5).The variant has been detected in at least 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markersg and/or loss of MMR protein expression consistent with the variant location (PP4_MOD).The variant is not reported in gnomAD v4.1 (PM2_SUP). In summary, this variant meets the criteria to be classified as pathogenic for autosomal-dominant inherited Lynch-syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PM5, PP1_strong, PP4_moderate, PP3_moderate and PM2_supporting applied. (VCEP specifications version 1) InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA022554/MONDO:0007356/137 2024-10-11 2024-10-11 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135791 biolink:causes MONDO:0006580 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0026113 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0851536 infores:hetionet NCBIGene:6102 biolink:causes MONDO:0010723 infores:monarchinitiative not_provided not_provided HGNC:10274 MONDO:0010723 uuid:ea6dfa2d-21a4-44e4-8970-d4033172b564 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75984 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0027769 infores:hetionet CHEBI:75722 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085624 infores:hetionet CHEBI:6715 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0232943 infores:hetionet CHEBI:5790 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0340865 infores:hetionet CHEBI:9086 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0028734 infores:hetionet CHEBI:9943 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0852911 infores:hetionet UMLS:C0065374 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0700225 infores:hetionet CHEBI:4024 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0015230 infores:hetionet CHEBI:408174 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0017152 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0442874 infores:hetionet CHEBI:5384 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0855242 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0024117 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0232431 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042075 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0010068 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0259768 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0259768 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0014118 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0004623 infores:hetionet CHEBI:3437 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0038454 infores:hetionet NCBIGene:55644 biolink:causes MONDO:0033007 infores:monarchinitiative not_provided not_provided HGNC:18028 MONDO:0033007 uuid:7117338e-1a7f-4506-900e-968f1271027b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0162429 infores:hetionet CAID:CA229845 biolink:causes MONDO:0009861 infores:clingen CAID:CA229845 MONDO:0009861 PMID:23514811PMID:7766951PMID:26413448PMID:23500595PMID:24941924PMID:27413125PMID:23514811PMID:8659548 Likely Pathogenic PP4_Moderate, PM2, PP3, PM3_Strong The c.912G>A (p.Gln304Gln) variant in PAH has been reported in multiple PKU patients (BH4 deficiency excluded in some) (PMID: 23514811). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF=0.000004). This is a synonymous variant that occurs at the junction of exon8/intron8, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~20%) the canonical donor site. p.Gln304= has been detected with multiple pathogenic variants without confirmation of parental testing to determine phase: R241H (VarID102804, PMID: 27413125); K363fsdelG (c.1089delG, VarID102518, PMID: 8659548); I65T (VarID636) and A300S (VarID92751, PMID: 2351481); p.R176L (VarID631, PMID: 23500595). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_strong, PP4_moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229845/MONDO:0009861/006 2019-08-06 2019-08-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3614 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0085624 infores:hetionet CHEBI:17474 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C3665347 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0013295 infores:hetionet CHEBI:109549 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0011570 infores:hetionet CHEBI:5558 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0042963 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151479 infores:hetionet NCBIGene:11285 biolink:causes MONDO:0020682 infores:monarchinitiative not_provided not_provided HGNC:930 MONDO:0020682 uuid:ba7cb922-8124-48b4-9cd6-3840216d231b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45652 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0034063 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0948594 infores:hetionet CHEBI:17303 biolink:causes HP:0010547 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026825 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0014130 infores:hetionet CHEBI:51450 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0027424 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0460048 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0460048 infores:hetionet CHEBI:135929 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0018799 infores:hetionet CHEBI:7824 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0235086 infores:hetionet UMLS:C1738934 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0151825 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020461 infores:hetionet CHEBI:7986 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0027769 infores:hetionet UNII:3U02EL437C biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0009806 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0013220 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0013220 infores:hetionet NCBIGene:501 biolink:causes MONDO:0020741 infores:monarchinitiative not_provided not_provided HGNC:877 MONDO:0020741 uuid:c5280bc1-16be-4595-bb6f-9fdc52e295d2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31302 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0002957 infores:hetionet CHEBI:65173 biolink:causes NCIT:C79684 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0267028 infores:hetionet CHEBI:9586 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0011168 infores:hetionet CHEBI:135530 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C0015230 infores:hetionet CHEBI:4453 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0227791 infores:hetionet CHEBI:50648 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0497156 infores:hetionet CHEBI:9674 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0549622 infores:hetionet CAID:CA10385520 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385520 MONDO:0100437 PMID: Likely Benign BP4 PM2, BS1 NM_001034853.2(RPGR):c.1201G>A (p.Val401Ile) is a missense variant encoding the substitution of valine with isoleucine at amino acid 401. This variant is present in gnomAD v4.1.0 at a frequency of 0.000002504 among hemizygous individuals, with 1 variant allele / 399,433 total alleles, which is lower than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 but higher than the PM2_Supporting threshold of <0.0000005, so neither criterion is met. The computational predictor REVEL gives a score of 0.028, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Moderate). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BP4_Moderate. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385520/MONDO:0100437/106 2025-09-07 2025-09-07 X-linked inheritance HP:0001417 Contradicts true CHEBI:474180 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0042075 infores:hetionet CHEBI:4530 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0917801 infores:hetionet CHEBI:75984 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0700200 infores:hetionet CHEBI:63631 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0037763 infores:hetionet UMLS:C0005740 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0332534 infores:hetionet CHEBI:4659 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0004093 infores:hetionet CHEBI:5959 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0035455 infores:hetionet CHEBI:8890 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0086565 infores:hetionet CHEBI:7581 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0424323 infores:hetionet CHEBI:3561 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0038362 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004588 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0028077 infores:hetionet CHEBI:6916 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0855242 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0542313 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0542313 infores:hetionet CHEBI:50663 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0011206 infores:hetionet NCBIGene:26610 biolink:causes MONDO:0014937 infores:monarchinitiative not_provided not_provided HGNC:1171 MONDO:0014937 uuid:d6b0c3aa-148c-441b-9917-707c224baa46 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:83804 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0024902 infores:hetionet CHEBI:51364 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0151878 infores:hetionet UMLS:C0879264 biolink:causes UMLS:C0521465 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0521465 infores:hetionet CHEBI:6909 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0235660 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0236071 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0009319 infores:hetionet CHEBI:6067 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0022568 infores:hetionet CHEBI:6402 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0030305 infores:hetionet CAID:CA226492 biolink:causes MONDO:0100368 infores:clingen CAID:CA226492 MONDO:0100368 PMID: Pathogenic PM3, PVS1, PP1, PP4, PM2_Supporting The NM_000329.3(RPE65):c.1207_1210dup (p.Glu404AlafsTer4) frameshift variant introduces a premature stop codon into exon 11 of 14 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant has also been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.2 c.1338+1 G>A variant confirmed in trans (1 point, PMID 32367544), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state. (PP1; PMID: 32367544). At least one proband harboring this variant was tested by exome sequencing (2.0 pts) and exhibits a phenotype including optic disc pallor (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), poor pupillary light response (0.5 pts), RPE mottling (0.5 pts), macular atrophy (0.5 pts), and decreased peripheral (1.0 pt) and central vision (1.0 pt) which together are specific for RPE65-related recessive retinopathy (6.5) points, (PMID: 32367544, PP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 2.800e-7 with 3/1613960 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_supporting, PM3, PP1 and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226492/MONDO:0100368/120 2025-03-31 2025-03-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:10650 biolink:causes UMLS:C0234222 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0234222 infores:hetionet CHEBI:4466 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0035222 infores:hetionet CHEBI:66903 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0000737 infores:hetionet CHEBI:184555 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0002962 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0037299 infores:hetionet CHEBI:28901 biolink:causes NCIT:C35992 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0333582 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0392025 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0392025 infores:hetionet CHEBI:6715 biolink:causes UMLS:C0238425 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0238425 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0019158 infores:hetionet CHEBI:617099 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0178298 infores:hetionet CHEBI:6128 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0002871 infores:hetionet CAID:CA9870282 biolink:causes MONDO:0015967 infores:clingen CAID:CA9870282 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting PP3, PP4, PM1 The c.454G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to serine at codon 152 (p.(Gly152Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.00000292 (below the MDEP threshold of 0.000003) and <=2 copies observed in the European non-Finnish population and <=1 copies in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributor). Additionally, this variant has a REVEL score of 0.232, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.454G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9870282/MONDO:0015967/085 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4798 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0033117 infores:hetionet CHEBI:46295 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0031350 infores:hetionet GO:2001222 biolink:causes GO:0007399 infores:ubergraph knowledge_assertion manual_agent GO:2001222 GO:0007399 CHEBI:9622 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01036 UMLS:C0016382 infores:hetionet CHEBI:194135 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0836924 infores:hetionet CHEBI:135342 biolink:causes UMLS:C0264733 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0264733 infores:hetionet CHEBI:28748 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151746 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0518015 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151828 infores:hetionet CHEBI:51230 biolink:causes MONDO:0007769 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0854438 infores:hetionet CHEBI:4909 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0085605 infores:hetionet CHEBI:2668 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085593 infores:hetionet CHEBI:52172 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0085649 infores:hetionet CAID:CA229596 biolink:causes MONDO:0009861 infores:clingen CAID:CA229596 MONDO:0009861 PMID: Uncertain Significance PM2, PP4, PM3_Supporting BP7 The c.510-6T>G variant in PAH is absent from population databases (PM2). It has been observed in at least one classic PKU patient (PMID: 23764561; PP4). The patient is compound heterozygous with pathogenic variant R408W (ClinVar 577; PM3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229596/MONDO:0009861/006 2020-09-12 2020-09-12 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:10124 biolink:causes MONDO:0006181 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151544 infores:hetionet CHEBI:8863 biolink:causes UMLS:C1142015 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C1142015 infores:hetionet CHEBI:10102 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0015230 infores:hetionet CHEBI:31624 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0004096 infores:hetionet CHEBI:50924 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0009782 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020557 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0011991 infores:hetionet CHEBI:50924 biolink:causes MONDO:0002527 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0022572 infores:hetionet CHEBI:4798 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C2364111 infores:hetionet NCBIGene:64787 biolink:causes MONDO:0033198 infores:monarchinitiative not_provided not_provided HGNC:21296 MONDO:0033198 uuid:47b34091-c395-4892-b0ae-baeba58bd6ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:78543 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0518015 infores:hetionet CAID:CA512341040 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341040 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, PM2, PM6, PVS1, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1323G>C (p.Leu441=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (1.49) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341040/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA176498 biolink:causes MONDO:0021060 infores:clingen CAID:CA176498 MONDO:0021060 PMID: Benign BP7, BP4, BA1 The c.-160A>G variant in KRAS is classified as benign because it has been identified in 0.22088% (95% CI of 27/8628) of African alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA176498/MONDO:0021060/004 2019-11-04 2019-11-04 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:27899 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0854467 infores:hetionet CHEBI:52172 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0038358 infores:hetionet NCBIGene:2562 biolink:causes MONDO:0014921 infores:monarchinitiative not_provided not_provided HGNC:4083 MONDO:0014921 uuid:fde0e65a-98b3-41d3-9f8e-6a6b862a0ed5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020598 infores:hetionet CHEBI:367163 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0028754 infores:hetionet CHEBI:8802 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0518015 infores:hetionet CHEBI:119486 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0917801 infores:hetionet CHEBI:63717 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0151786 infores:hetionet CHEBI:45863 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0028734 infores:hetionet CHEBI:63584 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0027497 infores:hetionet CHEBI:49960 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0151578 infores:hetionet CHEBI:136040 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0022660 infores:hetionet CHEBI:8707 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0033774 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235750 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0023067 infores:hetionet CHEBI:50378 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0027769 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0013595 infores:hetionet CHEBI:31711 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0041657 infores:hetionet CHEBI:83804 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0393760 infores:hetionet CHEBI:3176 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0231218 infores:hetionet CHEBI:3127 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0020580 infores:hetionet CHEBI:127780 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0004093 infores:hetionet CHEBI:72690 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0746883 infores:hetionet CHEBI:18248 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0013378 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0027051 infores:hetionet CHEBI:17303 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0011616 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0155947 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0155947 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0855242 infores:hetionet CHEBI:9667 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0002994 infores:hetionet CHEBI:41879 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0233472 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0036572 infores:hetionet CAID:CA145876 biolink:causes MONDO:0001586 infores:clingen CAID:CA145876 MONDO:0001586 PMID:11735025 Likely Benign BP4, BP2, BS3_Supporting, PM2_Supporting The NM_000203.5:c.1771G>A variant in IDUA is predicted to result in the substitution of alanine by threonine at amino acid 591 (p.Ala591Thr). The variant was reported in an Italian individual with MPS1 who is compound heterozygous for two variants that have been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP; those variants are c.878_889dup (p.Thr293_Tyr296dup) (ClinVar Variation ID: 550382; listed as 974ins12 in the publication) and c.1487C>G (p.Pro496Arg) (ClinVar Variation ID: 496861) (PMID: 11735025). While phasing studies were not reported, it is likely that p.Ala591Thr is in cis with one of these variants. Furthermore, when transiently expressed in COS cells, the variant resulted in 108% of wild type activity (PMID: 11735025) (BS3_Supporting). The computational predictor REVEL gives a score of 0.137 which is below the threshold of 0.29, evidence that does not predict a damaging effect on IDUA function (PMID: 36413997)(BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008361 (5/59802 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). While the rarity of this variant supports pathogenicity, this evidence is outweighed by the data supporting benignity. There is a ClinVar entry for this variant (Variantion ID: 92635). In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0): BP4, BS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145876/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:78543 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0014591 infores:hetionet CHEBI:5441 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0005779 infores:hetionet CHEBI:6456 biolink:causes NCIT:C3837 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235031 infores:hetionet CHEBI:3181 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0015397 infores:hetionet CHEBI:114785 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0035854 infores:hetionet CAID:CA415077944 biolink:causes MONDO:0010305 infores:clingen CAID:CA415077944 MONDO:0010305 PMID:22281021PMID:23644449 Uncertain Significance PS3_Supporting, PP3, PP4, PM2_Supporting The NM_005629.4:c.370T>C variant in SLC6A8 is a missense variant that is predicted to result in the substitution of tryptophan by arginine at amino acid 124 (p.Trp124Arg). This variant has been previously reported in one hemizygous male individual with elevated urinary creatine/creatinine (PMID: 23644449) (PP4). This variant was reported to result in undetectable creatine transport activity when expressed in SLC6A8 deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.866 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 2290132). In summary, while there is some suspicion for a pathogenic role, this variant currently meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. ACMG/AMP-specific SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415077944/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:63681 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0344232 infores:hetionet CAID:CA401369905 biolink:causes MONDO:0009290 infores:clingen CAID:CA401369905 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM5, PM2_Supporting, PS3_Moderate, PM3_Strong PS1 The NM_000152.5:c.1933G>T variant in GAA is a missense variant predicted to cause substitution of aspartic acid, by tyrosine at amino acid 645 (p.Asp645Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000335 (2/59698 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP threshold for PM2_Supporting (<0.001) meeting this criterion (PM2_Supporting). This variant has been detected in at least 6 individuals with Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and pathogenic variants (c.-32-13T>G and c.525delT) none of those were confirmed in trans. (PMID: 27711114, 17616415, 24715333). Two individuals were homozygous for the variant (PMID: 38250073) (PM3_Strong).At least three patients with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 24715333). Another four patients were reported to be on enzyme replacement therapy for Pompe disease (PMID: 38250073, 29573408, 27711114, 24715333) (PP4_Moderate). Expression of the variant in COS cells resulted in 0% wild type GAA activity in cells and medium and evidence of abnormal GAA synthesis and processing), variant to be described as Class B (“potentially less severe), indicating that this variant may impact protein function (PMID: 18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants (c.1933G > A, p.Asp645Asn, ClinVar Variation ID 188728, PMID: 9535769, 15145338, 16860134, 17723315, 23601496, 25139343, 26497565) and (c.1933G>C, p.Asp645His, ClinVar Variation ID 189013, PMID: (PMID: 12897283, 7695647) in the same codon have been classified as pathogenic and likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5).There is a ClinVar entry for this variant (Variation ID: 556386)In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PS3_Moderate, PM5, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401369905/MONDO:0009290/010 2024-12-19 2025-02-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8888 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0559031 infores:hetionet CHEBI:3568 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014591 infores:hetionet CAID:CA10014516 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014516 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BP2, BA1, PM2, PVS1, PM6, BS1, BS3, BS4, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.438T>C is a synonymous variant which has a SpliceAI score ≤ 0.20 (BP4) and is predicted by evolutionary conservation algorithms to occur at a site that is not conserved (PhyloP score ≤ 2.0 (1.446)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014516/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA003228 biolink:causes MONDO:0011450 infores:clingen CAID:CA003228 MONDO:0011450 PMID:30765603PMID:30209399PMID:30257991 Pathogenic PP3, PM2_Supporting, PP4_Strong, PS3, PP1_Moderate The c.5089T>C variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 1697 (p.Cys1697Arg). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.40, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.05 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 5.24, within the thresholds for moderate pathogenic evidence (LR >4.3 & ≤18.7) (PP1_Moderate met; internal lab contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2735.2 (based on Cosegregation LR=730.6; Pathology LR=2.41; Family History LR=1.56), above the thresholds for Very strong evidence towards pathogenicity (LR>350) (PP4_Very strong met; PMID: 31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP1_Moderate, PP4_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA003228/MONDO:0011450/092 2024-06-12 2024-06-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:5138 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0435002 infores:hetionet CHEBI:28748 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018926 infores:hetionet CHEBI:5123 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00623 UMLS:C0014457 infores:hetionet NCBITaxon:810 biolink:causes MONDO:0005808 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:810 MESH:D003235 DB00263_MESH_D003235_1 CHEBI:6715 biolink:causes UMLS:C0428409 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0428409 infores:hetionet CHEBI:76607 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB08932 UMLS:C0042029 infores:hetionet CHEBI:6887 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0002874 infores:hetionet CHEBI:5001 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0033575 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0442874 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0037274 infores:hetionet CHEBI:5790 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0023380 infores:hetionet CHEBI:17823 biolink:causes UMLS:C1262165 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C1262165 infores:hetionet CHEBI:9241 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0006142 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0086543 infores:hetionet CHEBI:35854 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0002871 infores:hetionet CHEBI:567361 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0009763 infores:hetionet CHEBI:5778 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0231218 infores:hetionet CHEBI:7959 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0040046 infores:hetionet CHEBI:2618 biolink:causes MONDO:0001208 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0264490 infores:hetionet CHEBI:2611 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0020514 infores:hetionet CHEBI:15544 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0033774 infores:hetionet CHEBI:5118 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0030312 infores:hetionet CHEBI:8764 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0025222 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0151559 infores:hetionet CHEBI:9555 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0235416 infores:hetionet CHEBI:63581 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0011991 infores:hetionet CHEBI:50692 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0042109 infores:hetionet CHEBI:68647 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0027947 infores:hetionet CHEBI:2636 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0041657 infores:hetionet CHEBI:8435 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0162830 infores:hetionet CHEBI:47780 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0042267 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0559546 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0341012 infores:hetionet CHEBI:50749 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB02300 UMLS:C0853700 infores:hetionet CAID:CA229456 biolink:causes MONDO:0009861 infores:clingen CAID:CA229456 MONDO:0009861 PMID:8889590PMID:8889590 Uncertain Significance PM2, PP4, PM3_Supporting PP3 The c.168+6T>G variant has been identified in at least 1 proband with classical PKU (PMIDs: 8889590) in trans with pathogenic variant c.47_48delCT (ClinVar 102696). This variant is absent from 1000G, ESP, and gnomAD databases. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229456/MONDO:0009861/006 2019-09-29 2019-10-02 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:194135 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011849 infores:hetionet CHEBI:8028 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0018681 infores:hetionet NCBIGene:5080 biolink:causes MONDO:0007350 infores:monarchinitiative not_provided not_provided HGNC:8620 MONDO:0007350 uuid:eaca7ee1-fa11-401c-afe7-b5317b322526 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63624 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0948594 infores:hetionet CHEBI:37924 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0042963 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0037036 infores:hetionet CHEBI:8207 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0232461 infores:hetionet UNII:3QJA87N40S biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0340865 infores:hetionet CHEBI:74947 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0020443 infores:hetionet NCBIGene:51112 biolink:causes MONDO:0044696 infores:monarchinitiative not_provided not_provided HGNC:24284 MONDO:0044696 uuid:6c9517c6-6542-469f-b751-909f62267e13 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:37924 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0085932 infores:hetionet CHEBI:5098 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0014518 infores:hetionet CHEBI:7573 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0013404 infores:hetionet CAID:CA200650 biolink:causes MONDO:0008723 infores:clingen CAID:CA200650 MONDO:0008723 PMID: Uncertain Significance PP4, BA1 PP3, PM5, PM1, PM3_Supporting, BP4 The c.1066A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 356 (p.Ile356Val). Several individuals with this variant were identified by newborn screen, but this information is insufficient to use toward classification (PMID: 30194637, 26385305, 23867825, 31031081, 27209629). One individual did display C14:1 level of 0.83, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 31031081). At least one of these individuals carried an additional likely pathogenic variant not confirmed to be in trans, but this does not meet the criteria to be counted toward PM3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009786 in the African population with 3 total homozygotes, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). However, due to the possibility of this variant being enriched in an under-sequenced population, the ACADVL VCEP has overridden the BA1 evidence code to be in conflict with the specificity of the C14:1 level identified in an affected individual (PP4 data, PMID: 31031081). Additionally, the ACADVL VCEP cannot exclude the possibility that the 3 homozygous individuals in gnomAD may be as-yet unaffected adults that could present with mild disease in the future. The computational predictor REVEL gives a score of 0.621, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on December 10, 2025. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA200650/MONDO:0008723/021 2024-12-10 2024-12-10 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:480999 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0021053 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0518015 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0435002 infores:hetionet CHEBI:3127 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0151907 infores:hetionet CHEBI:135961 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0332534 infores:hetionet CHEBI:31236 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0018799 infores:hetionet CHEBI:8774 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0012833 infores:hetionet CHEBI:6690 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0013362 infores:hetionet CHEBI:100241 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0220870 infores:hetionet CHEBI:68478 biolink:causes HP:0031690 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0029118 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0020456 infores:hetionet CHEBI:64310 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0017178 infores:hetionet CHEBI:8888 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0206062 infores:hetionet CHEBI:39585 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0002878 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0234215 infores:hetionet CHEBI:63620 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011124 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0221490 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0221490 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0152029 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0152029 infores:hetionet CAID:CA10613567 biolink:causes MONDO:0015924 infores:clingen CAID:CA10613567 MONDO:0015924 PMID: Benign BA1 PM2, PP1, PS3, PS4, BS1, BS4 The BMPR2 c.-669G>A variant is a 5’UTR variant with contradictory evidence for a functional promoter effect (PMID: 19223935 and PMID: 30336198). Both reports included luciferase assays comparing transcriptional activity of cells expressing wild-type or variant promoter constructs. PMID: 19223935 reported a negative effect on BMPR2 expression but the assay used a short 300 bp promoter fragment and no known pathogenic or benign variant controls. PMID: 30336198 reported no effect on BMPR2 expression using longer 1520 bp promoter fragments and included nine different PAH associated variants. Based on the latter report, PS3 was not applied. PMID: 26387786 reported three PAH probands with the c.-669G>A variant. However, the variant has also been identified in numerous individuals from control populations. In gnomAD v2.1.1 controls (11/2022), the Estonian population had an AF of 2.65% (105/3956 alleles, including 2 homozygotes) which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA10613567/MONDO:0015924/125 2024-05-01 2024-05-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:71255 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0151905 infores:hetionet CHEBI:36704 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0017168 infores:hetionet CHEBI:6950 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151836 infores:hetionet GO:2000387 biolink:causes GO:0046545 infores:ubergraph knowledge_assertion manual_agent GO:2000387 GO:0046545 CHEBI:7476 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0574067 infores:hetionet CHEBI:47612 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0040034 infores:hetionet CHEBI:63791 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0040264 infores:hetionet CHEBI:6129 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0241057 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0877042 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0877042 infores:hetionet CHEBI:3756 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0030252 infores:hetionet CHEBI:94501 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0232602 infores:hetionet CHEBI:567361 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0036983 infores:hetionet CHEBI:2637 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0456909 infores:hetionet CHEBI:3441 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0004604 infores:hetionet CHEBI:6931 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0232602 infores:hetionet NCBIGene:4629 biolink:causes MONDO:0025708 infores:monarchinitiative not_provided not_provided HGNC:7569 MONDO:0025708 uuid:0aad958f-e240-4b83-b668-a8dbe291d381 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4653 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0017181 infores:hetionet CHEBI:135736 biolink:causes HP:0012764 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085619 infores:hetionet CAID:CA16610662 biolink:causes MONDO:0015924 infores:clingen CAID:CA16610662 MONDO:0015924 PMID: Pathogenic PVS1, PP3, PM2_Supporting, PS4_Supporting BA1, BS1 The NM_001204.7(BMPR2) c.968-5A>G is an intronic variant at Intron 7. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to create a strong acceptor site gain (PP3_supporting) and PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD. The c.968-5G>A variant leads to the inclusion of 4 bases of intron 7 into the mature mRNA creating a frameshift and a STOP codon at position 327(PVS1_strong). The variant has been reported in 2 unrelated PAH patients: first proband is associated with the publication (PMID: 19555857) and the second proband, with no further information for co-segregation, is from an internal lab contributor (PS4_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting, PS4_supporting and PP3_supporting (VCEP specifications version 1.1, 1/18/2024) Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA16610662/MONDO:0015924/125 2024-05-03 2024-05-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8871 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0393761 infores:hetionet CHEBI:8212 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0232487 infores:hetionet CHEBI:68558 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0022660 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1861172 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0020538 infores:hetionet CHEBI:584020 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0013395 infores:hetionet CAID:CA135125 biolink:causes MONDO:0021060 infores:clingen CAID:CA135125 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.375T>G (p.Ser125=) variant in the BRAF gene is 0.054% (9/8644) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135125/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:4315 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0232492 infores:hetionet CHEBI:9139 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151905 infores:hetionet CHEBI:3228 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0018524 infores:hetionet CHEBI:50659 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0002994 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0019338 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0036202 infores:hetionet CHEBI:71415 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0162119 infores:hetionet CHEBI:63618 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0042963 infores:hetionet CHEBI:8245 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0017675 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0267792 infores:hetionet NCBIGene:4436 biolink:causes MONDO:0007356 infores:monarchinitiative not_provided not_provided HGNC:7325 MONDO:0007356 uuid:259f6a34-f65d-4c1b-a29d-83197a2fe229 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:499361 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0040046 infores:hetionet CAID:CA2573157363 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157363 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP7, BP5, PVS1, PM6, PM5, PM4, PM1, PM3, BS2, PP2, PP3, PP1, PP4 NM_001754.5(RUNX1):c.999_1010dup (p.Pro337_Ala338insArgGlnPhePro) is an in-frame duplication. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain due to insufficient evidence. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157363/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:64355 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0033774 infores:hetionet NCBIGene:51398 biolink:causes MONDO:0975877 infores:monarchinitiative not_provided not_provided HGNC:30203 MONDO:0975877 uuid:458da8b9-994c-4e5f-8fc4-acc130201278 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47426 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0232462 infores:hetionet CHEBI:9613 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0231218 infores:hetionet UMLS:C0879264 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0042963 infores:hetionet CHEBI:42797 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0042345 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0687133 infores:hetionet CHEBI:7931 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0009676 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0042109 infores:hetionet CHEBI:84050 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0004936 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0235351 infores:hetionet CAID:CA10654543 biolink:causes MONDO:0100488 infores:clingen CAID:CA10654543 MONDO:0100488 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM5, PM4, BS2, PP1, PP2, PP3, PP4, BP1, BP4, BP3, PS2, PS4, PS3, PS1 The NM_004360.4(CDH1):c.*2050T>A variant has an allele frequency of 0.02572 (2.572%, 224/8710 alleles, 1 homozygote) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10654543/MONDO:0100488/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:3215 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0016204 infores:hetionet UMLS:C0004609 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0018524 infores:hetionet CHEBI:45367 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0023530 infores:hetionet CHEBI:617099 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00389 UMLS:C0018681 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0494165 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0494165 infores:hetionet CHEBI:8499 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C2363731 infores:hetionet CAID:CA414823366 biolink:causes MONDO:0044970 infores:clingen CAID:CA414823366 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PP3, BA1, PS4, PS2, PS3, BS1, BS3, PM6, PM2 The m.14633A>G (p.M14T) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on March 28, 2023. There are no individuals or families with this variant reported in the medical literature to our knowledge. There are several occurrences in population databases. This variant is absent in GenBank MITOMAP sequences. It is present in 0.005% of individuals in gnomAD v3.1.2 (two homoplasmic occurrences in individuals of European background and haplogroup HV; one homoplasmic occurrence in an individual of African/African American background and haplogroup L3) and in 0.005% of individuals in the Helix dataset (10 homoplasmic occurrences and two heteroplasmic occurrences). In silico tools (APOGEE) predict this variant to be neutral (score of 0.4, BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414823366/MONDO:0044970/015 2023-03-28 2023-03-29 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:567361 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0002170 infores:hetionet CHEBI:8888 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020625 infores:hetionet CHEBI:5847 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0018681 infores:hetionet CHEBI:10119 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0232462 infores:hetionet CHEBI:4511 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0002792 infores:hetionet CHEBI:61049 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0595916 infores:hetionet CHEBI:63617 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0002170 infores:hetionet CHEBI:204928 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0038826 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020649 infores:hetionet CHEBI:404903 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0311468 infores:hetionet CHEBI:71417 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0011991 infores:hetionet CHEBI:75722 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0239935 infores:hetionet CHEBI:9123 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0036974 infores:hetionet CHEBI:85161 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0027765 infores:hetionet CHEBI:68610 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0003862 infores:hetionet CAID:CA219800 biolink:causes MONDO:0000572 infores:clingen CAID:CA219800 MONDO:0000572 PMID: Pathogenic PP4, PM2_Supporting, PS3_Moderate, PM1, PM3_Strong The NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) missense variant occurs in the NBD domain (amino acids 394-460), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199; PM1). The popmax allele frequency is 0.00003266 (1/30614 alleles) in the South Asisan population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). At least 11 patients have been reported with this variant (PMIDs: 26596586, 24290284, 23085344, 17572155, 11133745, 36596882, 29410113), including patient 11 of PMID: 26596586 whom meets diagnostic criteria for SCID with a T-B-NK+ lymphocyte subset profile which is specific to recombinase activating gene 1 deficiency (PP4). Six patients are homozygous for this variant (PMIDs: 24290284, 17572155,11133745; 1pt maximum) and five are compound heterozygous (PMIDs: 26596586, 23085344, 11133745, 36596882, 29410113), harboring this variant as well as c.256_257 (provisionally classified Pathogenic by the SCID VCEP; 1+0.5pt), Val433Met, Lys992Glu, or c.2018_2025del. Total 2.5pt (PM3_Strong). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Ala444Val was 1.4% of wild type +/- 0.2 (PMID: 24290284; PS3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM2_supporting, PP4, PM3_Strong, PS3_Moderate. (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA219800/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:40279 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0333355 infores:hetionet CHEBI:101853 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0162830 infores:hetionet CHEBI:31644 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0151889 infores:hetionet CAID:CA285289 biolink:causes MONDO:0008723 infores:clingen CAID:CA285289 MONDO:0008723 PMID: Benign BP4, BA1 The NM_000018.4(ACADVL): c.1600G>A (p.Glu534Lys) variant is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 534. The highest population minor allele frequency in gnomAD v4.1.0 is 0.02844 (2133/74992 alleles) in African/African American population, which is higher than the ClinGen VLCADD VCEP threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.279, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (ACADVL VCEP specifications version 2; approved May 1, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA285289/MONDO:0008723/021 2025-10-28 2025-10-28 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6801 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0012359 infores:hetionet CHEBI:3698 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0041969 infores:hetionet CHEBI:6761 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00371 UMLS:C0027497 infores:hetionet CHEBI:4325 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0021400 infores:hetionet CHEBI:5128 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0013362 infores:hetionet CAID:CA10578321 biolink:causes MONDO:0021056 infores:clingen CAID:CA10578321 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting BS2, PP1, PM6, PM1, PM3, BP2, PS4, PS3, PS2, BS3, BS4, BP5 The c.1626+2T>G variant in APC occurs within the canonical splice donor site (±1/2) of intron 13. It is predicted to cause skipping of exon 13, resulting in an in-frame deletion (removing amino acids 517-542) of an exon with sufficient supportive clinical data (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PM2_supporting (Specification Version 1.0; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578321/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:135920 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C2830004 infores:hetionet CHEBI:7959 biolink:causes MONDO:0018896 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0034155 infores:hetionet CHEBI:77260 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151786 infores:hetionet CAID:CA137916 biolink:causes MONDO:0021060 infores:clingen CAID:CA137916 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.192C>T (p.Val64=) variant in the MAP2K2 gene is 7.417% (1283/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137916/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63619 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0042510 infores:hetionet NCBIGene:57647 biolink:causes MONDO:8000015 infores:monarchinitiative not_provided not_provided HGNC:17210 MONDO:8000015 uuid:7e163873-8eb0-4038-bad8-6ad95e646546 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135736 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0039240 infores:hetionet CHEBI:7903 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0018965 infores:hetionet CHEBI:60761 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0011603 infores:hetionet CHEBI:4858 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0520966 infores:hetionet CHEBI:2666 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0023530 infores:hetionet CHEBI:2922 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0015397 infores:hetionet CHEBI:47780 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0020443 infores:hetionet CHEBI:3380 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0030312 infores:hetionet CHEBI:46295 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0037199 infores:hetionet CHEBI:8888 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C2242737 infores:hetionet CHEBI:44032 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C2004489 infores:hetionet CL:0000542 biolink:causes GO:0002449 infores:ubergraph knowledge_assertion manual_agent CL:0000542 GO:0002449 CHEBI:7494 biolink:causes HP:5200218 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0233754 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0234930 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0234930 infores:hetionet NCBIGene:3691 biolink:causes MONDO:0030768 infores:monarchinitiative not_provided not_provided HGNC:6158 MONDO:0030768 uuid:0b24abb8-a1dc-413e-9a3d-cddd7bc6c85e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47499 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0040264 infores:hetionet CAID:CA000546 biolink:causes MONDO:0017623 infores:clingen CAID:CA000546 MONDO:0017623 PMID: Uncertain Significance PM2, PP2, BS3_Supporting PVS1, PM6, BS1, BS4, BP5, BP7, BS2, PP1, PP3, PM1, PM4, PM5, BP2, BP4, BA1, PS2, PS4, PS3, PS1 PTEN c.685T>A (p.Ser229Thr) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populationsPP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of diseaseBS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000546/MONDO:0017623/003 2020-03-23 2020-03-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6149 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0340865 infores:hetionet NCBIGene:25802 biolink:causes MONDO:0030294 infores:monarchinitiative not_provided not_provided HGNC:6647 MONDO:0030294 uuid:83a91457-8111-4a70-b315-973a02176fc2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:100241 biolink:causes MONDO:0005316 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085166 infores:hetionet CHEBI:83527 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0151744 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0009450 infores:hetionet NCBIGene:171023 biolink:causes MONDO:0018881 infores:monarchinitiative not_provided not_provided HGNC:18318 MONDO:0018881 uuid:f5f3ef08-60b0-4609-9692-3957a1b62510 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0015397 infores:hetionet CHEBI:2663 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0011603 infores:hetionet CHEBI:63630 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0006826 infores:hetionet CAID:CA512341142 biolink:causes MONDO:0100083 infores:clingen CAID:CA512341142 MONDO:0100083 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.1275G>T (p.Pro425=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.562) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341142/MONDO:0100083/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:31711 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027497 infores:hetionet CHEBI:2038 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0003467 infores:hetionet CHEBI:8774 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0015230 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0518015 infores:hetionet CHEBI:175901 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0917801 infores:hetionet CAID:CA353603 biolink:causes MONDO:0019501 infores:clingen CAID:CA353603 MONDO:0019501 PMID: Likely Pathogenic PM5_Supporting, PP3, PP4, PM3, PM2_Supporting BA1 The c.4115T>G variant in MYO7A is a missense variant predicted to cause substitution of valine by glycine at amino acid 1372. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001332 (1/75054 alleles) in the African/African-American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.869, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID: 31836858). This individual was compound heterozygous for the variant and a pathogenic variant published by multiple submitters in ClinVar (c.6025del (p.Ala2009Profs*32)) and confirmed in trans by parental testing (1 PM3 point, PMID: 31836858). A different missense variant in the same codon (c.4114G>A (p.Val1372Met), PMID: 33576163), has been reported in the homozygous state in a patient with hearing loss and retinitis pigmentosa. However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing loss VCEP (PM5_Supporting). In summary, this variant has been classified as a likely pathogenic variant for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP3, PP4, PM2_Supporting, PM5_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/26/2024). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA353603/MONDO:0019501/005 2024-11-26 2025-01-06 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:61058 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0014518 infores:hetionet GO:2000074 biolink:causes GO:0003309 infores:ubergraph knowledge_assertion manual_agent GO:2000074 GO:0003309 HP:0031377 biolink:causes MONDO:0005105 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D008545 DB01005_MESH_D008545_1 CAID:CA340745588 biolink:causes MONDO:0100368 infores:clingen CAID:CA340745588 MONDO:0100368 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_000329.3(RPE65):c.825C>A (p.Tyr275Ter) variant is a nonsense variant that introduces a premature stop codon into exon 8 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including congenital night blindness (0.5 pts), extinguished rod ERG responses (0.5 pts), previous exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), symptomatic onset between birth and age five years (1 pt), retinal degeneration with attenuated vessels (0.5 pts), and extinguished cone ERG responses (1 pt), which together are specific for RPE65-related recessive retinopathy (5.5 points, PMID: 31273949, PP4). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA340745588/MONDO:0100368/120 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:77260 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0027726 infores:hetionet CHEBI:31547 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C1145628 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0150450 infores:hetionet CHEBI:45409 biolink:causes MONDO:0000004 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0405580 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0149931 infores:hetionet CHEBI:28748 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0022346 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0026650 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0948089 infores:hetionet CHEBI:36791 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0017152 infores:hetionet CHEBI:6437 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0011570 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0023895 infores:hetionet CHEBI:51041 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0012569 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0030252 infores:hetionet CHEBI:5775 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0020649 infores:hetionet CHEBI:15765 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0232462 infores:hetionet CHEBI:3215 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0151905 infores:hetionet GO:0060073 biolink:causes MONDO:0015649 infores:ubergraph knowledge_assertion manual_agent GO:0060073 MONDO:0015649 UMLS:C0879264 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0012833 infores:hetionet CHEBI:70746 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C1384353 infores:hetionet CHEBI:110423 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0011175 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C1384666 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0019087 infores:hetionet CHEBI:9586 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0042024 infores:hetionet CAID:CA013313 biolink:causes MONDO:0004994 infores:clingen CAID:CA013313 MONDO:0004994 PMID: Benign BA1, BP7 The filtering allele frequency of the c.3036C>T (p.Ala1012=) silent variant in the MYH7 gene is 0.7% (137/16512) of South Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1, BP7; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013313/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:52717 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0040479 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0232493 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232492 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0178298 infores:hetionet UMLS:C0065374 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0032227 infores:hetionet CHEBI:45783 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0151576 infores:hetionet NCBIGene:1146 biolink:causes MONDO:0009668 infores:monarchinitiative not_provided not_provided HGNC:1967 MONDO:0009668 uuid:1295ee27-d173-401b-b3b9-2c50a2bfa65f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4315 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0038325 infores:hetionet CHEBI:63598 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0085641 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0549373 infores:hetionet CHEBI:94686 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0687713 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0018681 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0239978 infores:hetionet CHEBI:136040 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0030252 infores:hetionet CHEBI:9168 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0232849 infores:hetionet CHEBI:51364 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0003811 infores:hetionet CHEBI:28971 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00415 UMLS:C0038362 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0235431 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020538 infores:hetionet CHEBI:63584 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0020580 infores:hetionet CHEBI:7443 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0032285 infores:hetionet CHEBI:3756 biolink:causes MONDO:0000986 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0032231 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0027769 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235431 infores:hetionet CHEBI:480999 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0277925 infores:hetionet CHEBI:8214 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0023380 infores:hetionet CHEBI:585948 biolink:causes HP:0012513 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0239377 infores:hetionet CHEBI:3723 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1368065 infores:hetionet CHEBI:10125 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0004093 infores:hetionet NCBIGene:9150 biolink:causes MONDO:0011402 infores:monarchinitiative not_provided not_provided HGNC:2498 MONDO:0011402 uuid:6da06d2b-acfd-42ab-b0c9-ebad1841a996 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1306341 infores:hetionet CHEBI:5147 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027765 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C2225524 infores:hetionet CHEBI:8356 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013456 infores:hetionet CHEBI:9352 biolink:causes UMLS:C1287298 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C1287298 infores:hetionet CHEBI:39585 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0033975 infores:hetionet CHEBI:16335 biolink:causes MONDO:0006810 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0151740 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0235889 infores:hetionet GO:1904031 biolink:causes GO:0051726 infores:ubergraph knowledge_assertion manual_agent GO:1904031 GO:0051726 CHEBI:50648 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011168 infores:hetionet CHEBI:23765 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085633 infores:hetionet CHEBI:4887 biolink:causes HP:0030765 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0037320 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0020649 infores:hetionet CHEBI:65349 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0041969 infores:hetionet CHEBI:16335 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0520887 infores:hetionet CHEBI:71417 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0085636 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1167965 infores:hetionet CHEBI:8871 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0009421 infores:hetionet CAID:CA10014235 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014235 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, PS2, BA1, BP2, PVS1, PM2, PM6, BS1, BS3, BS4, PM4, PM5, PM1, PP3, PP1 NM_001754.5(RUNX1):c.968-16C>G is an intronic variant located in intron 8. Evolutionary conservation prediction algorithms suggest the site is not conserved (phyloP100 score of 0.2, which is below the threshold of 2.0) (BP7). Additionally, SpliceAI predicts no impact on the splice consensus sequence and no creation of a new splice site (BP4). To date, this variant has not been reported in any patients with RUNX1-related diseases. In summary, this variant meets the criteria to be classified as likely benign. The ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014235/MONDO:0011071/008 2024-11-04 2024-11-04 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2682 biolink:causes HP:0000155 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0149745 infores:hetionet CHEBI:109549 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00980 UMLS:C0018681 infores:hetionet CHEBI:52010 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C2830004 infores:hetionet CHEBI:5855 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0025222 infores:hetionet CHEBI:6715 biolink:causes MONDO:0002654 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0042131 infores:hetionet CHEBI:135342 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0520966 infores:hetionet CHEBI:68647 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0002871 infores:hetionet CHEBI:16899 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0032617 infores:hetionet CHEBI:3215 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0235063 infores:hetionet CHEBI:100241 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0011206 infores:hetionet CHEBI:63621 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0267596 infores:hetionet CHEBI:27834 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0020437 infores:hetionet CHEBI:100241 biolink:causes MONDO:0009688 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0026896 infores:hetionet CAID:CA410202514 biolink:causes MONDO:0011071 infores:clingen CAID:CA410202514 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP7, BP5, BS1, BS3, BS4, PM4, PM5, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.482T>C (p.Leu161Pro) is a missense variant which has a REVEL score ≥ 0.88 (0.98) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 37415731). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_supporting, PM1_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410202514/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:2379 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0040264 infores:hetionet CHEBI:6375 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0002994 infores:hetionet CHEBI:42944 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0085610 infores:hetionet NCBIGene:6329 biolink:causes MONDO:0008224 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0008224 uuid:6b638fbb-1ee2-4a92-8f25-833c34b7d217 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0858797 infores:hetionet CHEBI:135935 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0043352 infores:hetionet CHEBI:71219 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0151539 infores:hetionet CHEBI:45951 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0037274 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0522348 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0522348 infores:hetionet NCBIGene:1836 biolink:causes MONDO:0009727 infores:monarchinitiative not_provided not_provided HGNC:10994 MONDO:0009727 uuid:dcf8d131-bbd1-4559-b293-6268e2193c4f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45327 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0030252 infores:hetionet NCBIGene:2068 biolink:causes MONDO:0012553 infores:monarchinitiative not_provided not_provided HGNC:3434 MONDO:0012553 uuid:b9daf104-623d-4ffb-86a6-23eed4566592 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63617 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0037023 infores:hetionet CHEBI:6909 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0004096 infores:hetionet NCBIGene:3679 biolink:causes MONDO:0013177 infores:monarchinitiative not_provided not_provided HGNC:6143 MONDO:0013177 uuid:5f118aba-0ddc-47f2-bdbf-edffb460555e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C1144403 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0006266 infores:hetionet CHEBI:63632 biolink:causes NCIT:C78341 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0522067 infores:hetionet CAID:CA8337657 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337657 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 The c.342+1G>A variant in ACADVL is a splice site variant affecting the canonical donor splice site in intron 5. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present at low frequency (<0.1%) in population databases (ExAC). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site (Splice AI). This variant has not been reported in the literature either in functional studies or in patients with VLCAD and there is no entry in ClinVar. This variant is classified as Likely Pathogenic based on ACADVL-specific ACMG/AMP criteria PVS1 and PM2. ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337657/MONDO:0008723/021 2022-09-23 2022-09-23 Autosomal recessive inheritance HP:0000007 Supports CHEBI:2955 biolink:causes UMLS:C0006147 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0006147 infores:hetionet CHEBI:50648 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0001824 infores:hetionet CHEBI:5062 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C2830004 infores:hetionet CHEBI:3504 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0235198 infores:hetionet CHEBI:51137 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0027849 infores:hetionet CHEBI:50859 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0042029 infores:hetionet CHEBI:9763 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0085633 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002104 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0009946 infores:hetionet CHEBI:63630 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0019270 infores:hetionet CHEBI:49375 biolink:causes MONDO:0004596 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0034072 infores:hetionet CHEBI:3650 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0027497 infores:hetionet CHEBI:7478 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0033774 infores:hetionet CHEBI:42797 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020565 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0000437 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0007758 infores:hetionet CHEBI:49668 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151723 infores:hetionet CHEBI:5138 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151827 infores:hetionet CHEBI:43968 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0151539 infores:hetionet CHEBI:71255 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0021368 infores:hetionet CHEBI:31401 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01166 UMLS:C0020580 infores:hetionet CHEBI:8802 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0011603 infores:hetionet CHEBI:3723 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0162298 infores:hetionet CHEBI:75722 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018944 infores:hetionet UNII:K2J09EMJ52 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB01438 UMLS:C0025637 infores:hetionet NCBIGene:126792 biolink:causes MONDO:0012282 infores:monarchinitiative not_provided not_provided HGNC:17978 MONDO:0012282 uuid:5ee9e101-2fd9-4077-97fe-2a704fc92446 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0005740 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0853813 infores:hetionet CAID:CA145870 biolink:causes MONDO:0001586 infores:clingen CAID:CA145870 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.1230C>G variant in IDUA is a synonymous (silent) variant (p.Thr410=). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.2954 in the South Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92628). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145870/MONDO:0001586/091 2025-01-02 2025-03-25 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:49575 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0080274 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0302295 infores:hetionet GO:2000061 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000061 GO:0007275 CHEBI:8107 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0023218 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0042401 infores:hetionet CHEBI:135935 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0002994 infores:hetionet UMLS:C0657912 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027066 infores:hetionet CHEBI:127780 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0010200 infores:hetionet CHEBI:50131 biolink:causes UMLS:C0742545 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0742545 infores:hetionet CHEBI:3504 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0009676 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0948525 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0333516 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0333516 infores:hetionet CHEBI:4702 biolink:causes MONDO:0008231 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0030848 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0032787 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0032787 infores:hetionet GO:0005884 biolink:causes GO:0030029 infores:ubergraph knowledge_assertion manual_agent GO:0005884 GO:0030029 CHEBI:8232 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0917801 infores:hetionet CHEBI:2682 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0013604 infores:hetionet CHEBI:45409 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0029408 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0014130 infores:hetionet CAID:CA512318583 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318583 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.756C>T (p.Ser252=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318583/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45783 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0020580 infores:hetionet CHEBI:119915 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0038999 infores:hetionet CHEBI:465284 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0085649 infores:hetionet CHEBI:39112 biolink:causes MONDO:0004967 infores:sider not_provided not_provided DRUGBANK:DB06616 UMLS:C0023449 infores:hetionet CHEBI:8214 biolink:causes EFO:0020917 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0236036 infores:hetionet CHEBI:7915 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0030193 infores:hetionet CHEBI:8869 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0033774 infores:hetionet CHEBI:63613 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0000768 infores:hetionet CHEBI:2682 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0009782 infores:hetionet CHEBI:5864 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0015371 infores:hetionet CHEBI:6078 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0014457 infores:hetionet NCBIGene:23396 biolink:causes MONDO:0012656 infores:monarchinitiative not_provided not_provided HGNC:8996 MONDO:0012656 uuid:c99f26d8-91ce-466c-b702-29778f38d0f6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0019360 infores:hetionet CAID:CA6198071 biolink:causes MONDO:0019501 infores:clingen CAID:CA6198071 MONDO:0019501 PMID: Uncertain Significance PP3, PM2_Supporting PP4, PM3 The c.3491G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1164 (p.Arg1164Gln). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4 is 0.00001446 (4/89272 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.935, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3. (ClinGen Hearing Loss VCEP specifications version 2, 01.17.2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA6198071/MONDO:0019501/005 2024-03-28 2024-03-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:3732 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0025061 infores:hetionet CHEBI:75045 biolink:causes UMLS:C0521540 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0521540 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0160390 infores:hetionet CHEBI:42068 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0027497 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0877211 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0877211 infores:hetionet CHEBI:31859 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0149931 infores:hetionet CHEBI:142290 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0020649 infores:hetionet CHEBI:9448 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0011603 infores:hetionet CHEBI:585948 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C1443060 infores:hetionet CHEBI:367163 biolink:causes UMLS:C0238097 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0238097 infores:hetionet CAID:CA410207002 biolink:causes MONDO:0011071 infores:clingen CAID:CA410207002 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP4, BP2, BP7, BS1, BS3, BS4, PM6, PVS1, PM5, PM4, PM1, PM3, PP4, PP3, PP1 NM_001754.5(RUNX1):c.658T>C (p.Ser220Pro) is a missense variant located in exon 7. This variant is completely absent from all population databases, including gnomAD v2.1.1 and v3.1.2, which provide coverage of at least 20x for RUNX1 at this genomic position (PM2_supporting). This missense variant has a REVEL score of 0.651, which precludes the application of computational evidence support. Additionally, this variant affects amino acid 220, which falls outside the RHD or residues 89-204. To our knowledge, there is no previous record of this variant, and no other pathogenic or likely pathogenic missense variants affecting the same amino acid residue or resulting in the same residue have been reported. In summary, the clinical significance of this variant is uncertain, and it meets ACMG/AMP criteria as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410207002/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:28748 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0006145 infores:hetionet CHEBI:28787 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0015967 infores:hetionet CHEBI:31524 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06262 UMLS:C0027497 infores:hetionet CHEBI:4856 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0017178 infores:hetionet CAID:CA10585466 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585466 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM2, PP4, PP1, PP3 BA1, BP2, BP4, PS3, PS2, PS1, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2 The NM_000527.5(LDLR):c.1463T>A (p.Ile488Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023.The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.84. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 unrelated FH index cases (2 cases meeting Simon-Broome criteria from PMID 11668640 (García-García et al., 2001), Spain; 1 case meeting Simon-Broome criteria from PMID 10978268 (Bertolini et al., 2000), Italy; at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583834.1)).PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID 10978268 (Bertolini et al., 2000), Italy: 2 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585466/MONDO:0007750/013 2023-06-23 2025-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:6367 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0040034 infores:hetionet NCBIGene:81833 biolink:causes MONDO:0957584 infores:monarchinitiative not_provided not_provided HGNC:14967 MONDO:0957584 uuid:dbe37977-8b0e-4646-aa9f-889b6f189f5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3441 biolink:causes HP:0001920 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0035067 infores:hetionet CHEBI:9654 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0241934 infores:hetionet CAID:CA005620 biolink:causes MONDO:0100316 infores:clingen CAID:CA005620 MONDO:0100316 PMID: Benign BA1, BP5, PP1 BP4, PS1, PS4, BS1, BS3, BS4, PM2, PM5, PM1, PM3, PP3, PP4 NM_000218.3(KCNQ1):c.1343C>G (p.Pro448Arg) is a missense variant predicted to cause substitution of proline by arginine at amino acid 448 (p.Pro448Arg). This variant has been reported as a polymorphism that is present in approximately 20% of Asian individuals (PMID: 11997281). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.09851, with 4408 alleles / 44746 total alleles and 203 homozygotes in the East Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). The variant has been reported to segregate with long QT syndrome 1 through the proband and 3 affected family members from one family (PP1; PMID: 17597962). This variant has been observed in 1 patient with an alternate molecular basis for disease with a phenotype that is not sufficiently specific (BP5; PMID 15242738). Functional studies have been performed on this variant (PMIDs: 15051636, 15242738), but it does not yet meet the criteria for PS3/BS3. In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1, BP5, and PP1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). Potassium Channel Arrhythmia VCEP https://erepo.genome.network/evrepo/ui/classification/CA005620/MONDO:0100316/112 2025-07-01 2025-07-02 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63635 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C2830004 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1321632 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1321632 infores:hetionet CHEBI:15365 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0016382 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0435002 infores:hetionet CHEBI:8774 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0020625 infores:hetionet CHEBI:135939 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0028738 infores:hetionet UMLS:C0017797 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0024902 infores:hetionet CHEBI:5864 biolink:causes MONDO:0001370 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0031039 infores:hetionet CHEBI:75998 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0232495 infores:hetionet CHEBI:36795 biolink:causes HP:0100735 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020546 infores:hetionet CHEBI:30830 biolink:causes MONDO:0008062 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0007384 infores:hetionet CHEBI:6741 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0231528 infores:hetionet CHEBI:7465 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0019196 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0037199 infores:hetionet CHEBI:50777 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0917801 infores:hetionet UMLS:C0065374 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0011175 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0038661 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0038661 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0270458 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0522224 infores:hetionet CAID:CA7511268 biolink:causes MONDO:0015152 infores:clingen CAID:CA7511268 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4, PM2_Supporting, PVS1_Strong PM5, PP3 The NM_000070.3: c.1187A>G variant is CAPN3 is a missense variant predicted to cause substitution of glutamic acid by glycine at amino acid 396, p.(Glu396Gly). This variant affects the seventh nucleotide from the boundary of exon and intron 9 and has a SpliceAI score of 0.09 for gain of an alternative donor site in intron 9. Minigene assays have demonstrated a splice effect of this variant, resulting in partial retention of intron 9 that is expected to lead to a frameshift, premature truncation, and subsequent nonsense mediated decay (PMID: 32668095). However, some degree of normal splicing appears to be retained (PVS1_Strong_RNA). This variant has been detected in trans with a pathogenic variant in at least one individual with limb girdle muscular dystrophy (c.1194-9A>G, 1.0 pt, PMID: 30564623; LOVD Individual #00222031; ClinVar SCV004285915.1 internal data communication) (PM3, PP4). The highest minor allele frequency of this variant is 0.000001697 in the European (non-Finnish) population in gnomAD v4.1.0 (2/1178556 genome chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025): PVS1_Strong_RNA, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7511268/MONDO:0015152/187 2025-04-22 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:77260 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0006145 infores:hetionet CHEBI:7577 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0019348 infores:hetionet CHEBI:7445 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0036508 infores:hetionet CHEBI:45783 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2363731 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005700 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0008049 infores:hetionet CAID:CA2387257476 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387257476 MONDO:0011071 PMID: Uncertain Significance PVS1_Strong, PM2_Supporting PS1, PS4, PS2, PS3, BP1, BP4, BP2, BP3, BA1, BP7, BP5, BS1, BS4, BS3, PM6, PM3, PM4, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.967+5G>A is an intronic variant that affects intron 8 at the canonical Donor site c.967 (SpliceAI value = Donor Loss 0.78 ≥0.38) (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387257476/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:421707 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0030305 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0039971 infores:hetionet CHEBI:2666 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0013362 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0030312 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0235293 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0235293 infores:hetionet CHEBI:77733 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0027497 infores:hetionet GO:0048399 biolink:causes GO:0048392 infores:ubergraph knowledge_assertion manual_agent GO:0048399 GO:0048392 CHEBI:8707 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0034065 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0235431 infores:hetionet CHEBI:49668 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151827 infores:hetionet CHEBI:6456 biolink:causes MONDO:0001117 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0025637 infores:hetionet CHEBI:43968 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0041657 infores:hetionet UNII:8NZ41MIK1O biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0042109 infores:hetionet CHEBI:49960 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0267792 infores:hetionet CHEBI:60761 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0151942 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0232462 infores:hetionet CHEBI:9654 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0040264 infores:hetionet CHEBI:48538 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0030567 infores:hetionet CHEBI:28787 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0546884 infores:hetionet CHEBI:50730 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0043144 infores:hetionet CHEBI:45951 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0234133 infores:hetionet CHEBI:18385 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0042109 infores:hetionet CHEBI:28748 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0018932 infores:hetionet CHEBI:116278 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0043352 infores:hetionet CHEBI:5130 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0020578 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0086543 infores:hetionet CHEBI:40303 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0040034 infores:hetionet CHEBI:50663 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0013456 infores:hetionet CAID:CA16616266 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616266 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS2, PS4, BA1, BP3, BS1, BP5, PM6, PM5, PM1, PM4, BS2, PP4 NM_001754.5(RUNX1):c.1166_1186dup (p.Pro395_Phe396insSerGlnAlaGlnGlyGlyPro) is an in-frame duplication variant which is predicted to cause a change in the length of the protein by duplicating 7 amino acids (p.S389_P395dup) in a nonrepeat region but not the runt homology domain (PM4 is not met). The splice site predictor SpliceAI indicated that the variant has no impact on splicing. This variant is absent from gnomAD v2 and v3 (PM2_supporting) and has not been reported in the literature. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616266/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:367163 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0018418 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0948595 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0948595 infores:hetionet GO:1905770 biolink:causes GO:0009790 infores:ubergraph knowledge_assertion manual_agent GO:1905770 GO:0009790 CHEBI:3077 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0041657 infores:hetionet CHEBI:42797 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0016867 infores:hetionet CHEBI:5106 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0013404 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005066 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0025517 infores:hetionet CHEBI:4798 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0235198 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0031212 infores:hetionet UMLS:C0004609 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0041657 infores:hetionet CHEBI:16755 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018834 infores:hetionet CHEBI:35778 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0030196 infores:hetionet NCBIGene:6473 biolink:causes MONDO:0007481 infores:monarchinitiative not_provided not_provided HGNC:10853 MONDO:0007481 uuid:afe5ebb9-2887-454b-82b6-cb4fdfb67817 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32221 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C1368065 infores:hetionet CHEBI:7640 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C2225524 infores:hetionet CHEBI:8499 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0015967 infores:hetionet CHEBI:63580 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0424295 infores:hetionet CHEBI:4027 biolink:causes MONDO:0024636 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0869523 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0031350 infores:hetionet CHEBI:63612 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0020433 infores:hetionet CHEBI:42068 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0042075 infores:hetionet CHEBI:6754 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0855242 infores:hetionet CHEBI:4814 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0010692 infores:hetionet CHEBI:261649 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0018524 infores:hetionet CAID:CA404086017 biolink:causes MONDO:0007750 infores:clingen CAID:CA404086017 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BP2, BA1, PS1, PS3, PS4, PS2, BP7, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, BS2, PP3, PP1, PP4 The NM_000527.5(LDLR):c.1435C>G (p.Leu479Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows:PM2: PopMax MAF = 0.00008 (0.008%) in African exomes (gnomAD v4.0.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404086017/MONDO:0007750/013 2024-02-23 2025-02-24 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:52717 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0262385 infores:hetionet CHEBI:71223 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0002871 infores:hetionet CHEBI:40279 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0002962 infores:hetionet CHEBI:63577 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0003862 infores:hetionet CHEBI:7514 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0235710 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0031542 infores:hetionet CHEBI:4911 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0003962 infores:hetionet CHEBI:4027 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0022660 infores:hetionet CHEBI:3508 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0023380 infores:hetionet CHEBI:32139 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0001122 infores:hetionet CHEBI:61049 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0014591 infores:hetionet CHEBI:10110 biolink:causes UMLS:C0236068 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0236068 infores:hetionet CHEBI:68579 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151699 infores:hetionet CHEBI:94686 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0037274 infores:hetionet CHEBI:3723 biolink:causes UMLS:C1611174 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C1611174 infores:hetionet CHEBI:31536 biolink:causes MONDO:0006573 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0023787 infores:hetionet CHEBI:63627 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0006266 infores:hetionet CHEBI:37333 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0085584 infores:hetionet CHEBI:3698 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0018681 infores:hetionet CHEBI:5847 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0948594 infores:hetionet CHEBI:2668 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0235848 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0013428 infores:hetionet CHEBI:480999 biolink:causes UMLS:C1963921 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C1963921 infores:hetionet CHEBI:4710 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0030252 infores:hetionet CHEBI:6067 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0040822 infores:hetionet CHEBI:46295 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151576 infores:hetionet CHEBI:7478 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0027051 infores:hetionet CHEBI:84500 biolink:causes HP:0000708 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0233514 infores:hetionet UMLS:C0657912 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020453 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0001824 infores:hetionet CHEBI:61049 biolink:causes MONDO:0018182 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021100 infores:hetionet CHEBI:28001 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0037274 infores:hetionet NCBITaxon:837 biolink:causes MONDO:0005076 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:837 MESH:D010518 DB00878_MESH_D010518_1 CHEBI:7931 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C1142412 infores:hetionet CHEBI:6797 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0018681 infores:hetionet CHEBI:36795 biolink:causes HP:5200265 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0233718 infores:hetionet CHEBI:64310 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0015397 infores:hetionet CHEBI:45924 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0004134 infores:hetionet CHEBI:8207 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0029928 infores:hetionet CHEBI:6062 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C3665347 infores:hetionet NCBIGene:81494 biolink:causes MONDO:0013892 infores:monarchinitiative not_provided not_provided HGNC:24668 MONDO:0013892 uuid:eec66a9c-4c62-4bf9-90ee-71ce8eb3b1a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA401367008 biolink:causes MONDO:0009290 infores:clingen CAID:CA401367008 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The NM_000152.5:c.1497G>A (p.Trp499Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 10 (GAA has 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient homozygous for this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity and is described as having cross-reactive immunologic material (CRIM)-negative infantile-onset Pompe disease (IOPD) (PMID: 29422078) (PP4_moderate). Two additional patients have been reported as having CRIM-negative IOPD based on cultured fibroblast western blot analysis (PMID: 22252923) but specific clinical information is not provided. At least one individual is described as having Pompe disease with symptom onset in early childhood and GAA enzyme activity that is 15% of normal in leukocytes (PMID: 11071489). This individual was compound heterozygous for the variant and a second known pathogenic variant, c.971C>T (PM3). Two additional individuals that were homozygous for the variant were described as having symptoms consistent with IOPD, but analysis of GAA enzyme activity was completed (PMID: 32125626). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1711447). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PVS1, PP4_moderate, PM3, PM2_supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 1, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401367008/MONDO:0009290/010 2025-07-01 2025-07-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:34911 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB04930 UMLS:C0030193 infores:hetionet CHEBI:3423 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0151786 infores:hetionet CHEBI:6149 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0025290 infores:hetionet CHEBI:9637 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0231528 infores:hetionet CHEBI:474180 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0006826 infores:hetionet CHEBI:5558 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0020458 infores:hetionet CHEBI:3640 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0009806 infores:hetionet CHEBI:32588 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0018794 infores:hetionet CHEBI:68556 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06196 UMLS:C0027497 infores:hetionet CHEBI:4551 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0004093 infores:hetionet CHEBI:47612 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0020517 infores:hetionet CHEBI:2704 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0022346 infores:hetionet CHEBI:9352 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C2979982 infores:hetionet CHEBI:6073 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0547030 infores:hetionet CHEBI:49662 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0518015 infores:hetionet CHEBI:10023 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151825 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0043494 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0003860 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0040034 infores:hetionet CHEBI:474180 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0020621 infores:hetionet CHEBI:43968 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0031350 infores:hetionet CHEBI:68579 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0013404 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0233632 infores:hetionet CHEBI:34967 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0033975 infores:hetionet NCBIGene:23418 biolink:causes MONDO:0008246 infores:monarchinitiative not_provided not_provided HGNC:2343 MONDO:0008246 uuid:c3cdcf28-0419-4c2c-b082-86316a3b44d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4453 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0011603 infores:hetionet CAID:CA013661 biolink:causes MONDO:0004994 infores:clingen CAID:CA013661 MONDO:0004994 PMID: Likely Benign BS1 PM2, PP3, PS4 The c.3382G>A (p.Ala1128Thr) variant in MYH7 has been identified in 0.02% (FAF 95% CI; 10/34232) of Latino chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013661/MONDO:0004994/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:10124 biolink:causes UMLS:C0559546 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0559546 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005283 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0035309 infores:hetionet CHEBI:8890 biolink:causes UMLS:C0002928 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0002928 infores:hetionet CHEBI:4903 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0687713 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0948594 infores:hetionet CHEBI:5790 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0006145 infores:hetionet CHEBI:50922 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0233472 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0024291 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0158570 infores:hetionet CHEBI:8597 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0000737 infores:hetionet CHEBI:6375 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1320474 infores:hetionet CHEBI:8060 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0011206 infores:hetionet CHEBI:50381 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0521839 infores:hetionet CHEBI:7465 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0009763 infores:hetionet CHEBI:2663 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0029134 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0031212 infores:hetionet CHEBI:194135 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0011606 infores:hetionet CAID:CA261440 biolink:causes MONDO:0010134 infores:clingen CAID:CA261440 MONDO:0010134 PMID: Likely Pathogenic PS3_Supporting, PP3, PP4, PM2_Supporting, PM3_Strong The c.845G>A (NM_000441.2) variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 282 (p.Cys282Tyr). The highest population minor allele frequency in gnomAD v.2.1.1 is 0.000053 (6/113490 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.0007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.719 which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in at least 4 individuals with hearing loss. Of those individuals, three were compound heterozygous for the variant and a pathogenic variant observed in trans and one had a rare VUS variant on other allele (c.1001+1G>A, c.233A > G, 3.25 PM3 points, PMID:26969326,33152970, SCV000060163.6, SCV000343642.4) (PM3_Strong). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype highly specific for Pendred syndrome (PP4, PMID:26969326,33152970, SCV000060163.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:26752218). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM2_Supporting, PP3, PM3_Strong, PP4, PS3_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261440/MONDO:0010134/005 2023-01-24 2023-02-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf UMLS:C1738934 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020456 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0029408 infores:hetionet CHEBI:16347 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0522055 infores:hetionet CHEBI:82716 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0009450 infores:hetionet CHEBI:8245 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0340464 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0235496 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0235496 infores:hetionet CHEBI:5855 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0015672 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005297 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0041976 infores:hetionet CHEBI:7936 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0344232 infores:hetionet UMLS:C0023610 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0033774 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0042075 infores:hetionet UMLS:C0120107 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0085593 infores:hetionet CHEBI:4511 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0033774 infores:hetionet NCBIGene:23345 biolink:causes MONDO:0012549 infores:monarchinitiative not_provided not_provided HGNC:17089 MONDO:0012549 uuid:b0634455-9375-41f2-a36c-109578c78844 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0853760 infores:hetionet CHEBI:107736 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0018524 infores:hetionet CHEBI:10650 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0026821 infores:hetionet UMLS:C0065374 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0151578 infores:hetionet CHEBI:7986 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0004093 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0022116 infores:hetionet CHEBI:50924 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0013404 infores:hetionet CHEBI:9123 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0004936 infores:hetionet CAID:CA2573051032 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051032 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP1 The c.71_72delAG variant in the HNF1 homeobox A gene, HNF1A, is a two base pair deletion resulting in a frameshift in the protein at codon 24 in NM_000545.8, adding 8 novel amino acids before encountering a stop codon (p.(Glu24GlyfsTer8)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with three informative meioses in one family (PP1; PMID: 12453976). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051032/MONDO:0015967/017 2022-04-01 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50173 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0034150 infores:hetionet CHEBI:63630 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0233471 infores:hetionet CHEBI:28901 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0015967 infores:hetionet CHEBI:231594 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0013404 infores:hetionet GO:0051963 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0051963 GO:0007275 CHEBI:3647 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C2830004 infores:hetionet CAID:CA358852 biolink:causes MONDO:0021060 infores:clingen CAID:CA358852 MONDO:0021060 PMID: Likely Pathogenic PP3, PM2_Supporting, PS2, PS4_Moderate, PS3_Supporting The NM_006767.4:c.742G>A (p.Gly248Arg) variant in LZTR1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 248. Evidence supports that this variant is associated with AD NS and is not associated with AR NS. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.839, which is above the threshold of 0.7, evidence that correlates with impact to LZTR1 function (PP3). ERK1/2 phosphorylation assays in HEK293 cells showed enhanced EGF-dependent ERK1/2 phosphorylation indicating that this variant impacts protein function (PMID: 30481304)(PS3_Supporting). This variant has been reported in 3 probands with features of RASopathy (PS4_Moderate; PMID:25795793, 30859559, 31533111). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:30859559). Schwannomatosis has not been observed in individuals harboring this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA358852/MONDO:0021060/094 2024-09-17 2024-09-30 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8214 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0020651 infores:hetionet CHEBI:32020 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0026848 infores:hetionet GO:0045065 biolink:causes CL:0000910 infores:ubergraph knowledge_assertion manual_agent GO:0045065 CL:0000910 CHEBI:32315 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151883 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0235146 infores:hetionet CHEBI:38562 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0085593 infores:hetionet CHEBI:40279 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2363731 infores:hetionet CAID:CA256014 biolink:causes MONDO:0010305 infores:clingen CAID:CA256014 MONDO:0010305 PMID:23644449PMID:22281021 Likely Pathogenic PS3_Supporting, PP3, PM2_Supporting, PP4_Strong PS4 The NM_005629.4:c.395G>T variant in SLC6A8 is a missense variant that is predicted to result in the substitution of a glycine for a valine at amino acid 132 (p.Gly132Val). This variant has been previously reported one hemizygous male (PMID: 17101918, PMID: 23644449) who had elevated urinary creatine/creatinine and absent creatine peak on brain MRS (PMID: 17101918) (PP4_Strong). This variant was reported to result in <10% creatine transport activity when expressed in SLC6A8-deficient fibroblasts. A creatine concentration of 25uM was used, meeting the requirement for the assay to be carried out with less than or equal to 125uM creatine (PMID: 22281021, 23644449) (PS3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.916 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID: 2290132). In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. ACMG/AMP SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA256014/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Supports CHEBI:100241 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0085692 infores:hetionet CHEBI:28748 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0022568 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0009782 infores:hetionet CHEBI:51230 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0011603 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0039971 infores:hetionet CHEBI:567361 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0003864 infores:hetionet CHEBI:8874 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0005779 infores:hetionet CHEBI:7865 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0033774 infores:hetionet CHEBI:42068 biolink:causes UMLS:C0262385 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0262385 infores:hetionet CHEBI:7444 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0085633 infores:hetionet CHEBI:52172 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0854467 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0033860 infores:hetionet CHEBI:63638 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0030554 infores:hetionet CAID:CA10584825 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584825 MONDO:0007750 PMID: Likely Pathogenic PS4_Supporting, PM1, PM2, PP3, PP4 BA1, BP1, BP4, BP3, PS3, BS1, BS3, BS4, BP7, BP5, PM4, PM3, PM5, PVS1, BS2, PP2, PP1 The NM_000527.5(LDLR):c.283T>G (p.Cys95Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.949. PM1: Variant meets PM2 and alters one highly conserved Cys residue (Cys95).PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill clinical diagnostic criteria for FH (1 case from Spain with MedPed criteria in PMID 16627557 (Blesa et al., 2006), and 2 cases from Japan meeting Japan Atherosclerosis Society criteria in PMID 18718593 (Miyake et al., 2009)). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584825/MONDO:0007750/013 2024-02-23 2025-08-29 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:3814 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0030193 infores:hetionet CHEBI:7476 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0497156 infores:hetionet CAID:CA10653554 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653554 MONDO:0011071 PMID: Benign BP2, BA1 PS4, PS3, PS1, BP4, PVS1, PM6, PM2, BS4, BS3, BS1, BP7, PM4, PM1, PM5, PP1, PP3 The NM_001754.4(RUNX1):c.*2768A>C variant in the 3' UTR has an MAF of 0.0935 (9%, 3917/41896 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 167 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653554/MONDO:0011071/008 2020-01-13 2020-01-14 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:6067 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0011570 infores:hetionet CHEBI:50663 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0038325 infores:hetionet CHEBI:15367 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0032227 infores:hetionet CHEBI:8874 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0877359 infores:hetionet CHEBI:7936 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0038435 infores:hetionet CHEBI:6339 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0014742 infores:hetionet CHEBI:45327 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0541782 infores:hetionet CHEBI:10127 biolink:causes MONDO:0005395 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0026650 infores:hetionet CHEBI:41977 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0002622 infores:hetionet CHEBI:3127 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0013144 infores:hetionet CHEBI:15854 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0033774 infores:hetionet CHEBI:8228 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C0017160 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0043345 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0043345 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0014518 infores:hetionet CHEBI:17698 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0037274 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0031117 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0023533 infores:hetionet CHEBI:31348 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151905 infores:hetionet CHEBI:64355 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0022346 infores:hetionet CHEBI:6909 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0015967 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0521490 infores:hetionet CAID:CA6748922 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748922 MONDO:0009861 PMID:28982351 Uncertain Significance PM3, PP4 PM2, BP7 The c.442-14C>T PAH variant has been reported in 1 Han Chinese patient with PAH deficiency (PMID: 28982351) detected with the pathogenic PAH variant p.Arg111Ter. A defect in BH4 metabolism was excluded by urinary pterin analysis only. This variant has a MAF of 0.0003510 in the gnomAD East Asian population. It is intronic in a highly conserved nucleotide and is predicted to be benign by splicing prediction algorithms. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748922/MONDO:0009861/006 2020-10-15 2020-10-15 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:68595 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0020676 infores:hetionet NCBITaxon:5052 biolink:causes HP:0020103 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5052 MESH:D055744 DB00582_MESH_D055744_1DB00681_MESH_D055744_1 CHEBI:8871 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151603 infores:hetionet CHEBI:6797 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0027769 infores:hetionet CHEBI:2453 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0858797 infores:hetionet CHEBI:5130 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0019087 infores:hetionet CHEBI:45081 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0016199 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020676 infores:hetionet CHEBI:4784 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0004096 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0424823 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0424823 infores:hetionet CHEBI:31176 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB04711 UMLS:C0002792 infores:hetionet CHEBI:16469 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042023 infores:hetionet CAID:CA270458 biolink:causes MONDO:0010726 infores:clingen CAID:CA270458 MONDO:0010726 PMID: Likely Benign BP5, BS2 BS1, PM1, PP4, PM2, BP4 The p.Pro173Ala variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome; this individual was reported to have a second variant in MECP2 that was classified as Pathogenic (PMID 11241840). The p.Pro173Ala variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro173Ala variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5). The p.Pro173Ala variant in MECP2 is present in 3 female and 2 male individual(s) in gnomAD (0.0024%) (not sufficient to meet BS1 criteria). In summary, the p.Pro173Ala variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA270458/MONDO:0010726/016 2022-10-11 2022-12-02 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:63612 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0151723 infores:hetionet CAID:CA2739267620 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267620 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.54dup (p.Arg19GlufsTer11) is a frameshift variant which occurs in an exon which is absent from isoforms a and b (PVS1 not applicable). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267620/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0044562 biolink:causes GO:0005249 infores:ubergraph knowledge_assertion manual_agent GO:0044562 GO:0005249 CAID:CA343720151 biolink:causes MONDO:0005338 infores:clingen CAID:CA343720151 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BS1, BS3, BP7, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.26G>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Serine at amino acid 9 (p.Cys9Ser). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.067, which was within the 0.017-0.183 range for BP4_Moderate, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 10196380), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343720151/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8024 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0000737 infores:hetionet CHEBI:63608 biolink:causes HP:0012377 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0018979 infores:hetionet CHEBI:5130 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0037199 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0542008 infores:hetionet GO:0060504 biolink:causes GO:0060503 infores:ubergraph knowledge_assertion manual_agent GO:0060504 GO:0060503 CAID:CA386952499 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952499 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4 The c.46C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 16 (p.(Leu16Val)) of NM_000545.8. This variant is absent from gnomAD v.2.1.1 and v4.1 (PM2_Supporting). This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Lastly, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.814, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PM1_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952499/MONDO:0015967/017 2025-06-09 2025-06-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4903 biolink:causes UMLS:C1963790 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1963790 infores:hetionet CHEBI:135888 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0013390 infores:hetionet CHEBI:135342 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0006277 infores:hetionet CHEBI:9434 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0151908 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011551 infores:hetionet CHEBI:63580 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0003862 infores:hetionet CHEBI:35854 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0041969 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0595877 infores:hetionet CHEBI:75984 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0042035 infores:hetionet CHEBI:53691 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0002622 infores:hetionet GO:0043309 biolink:causes GO:0002447 infores:ubergraph knowledge_assertion manual_agent GO:0043309 GO:0002447 NCBIGene:11146 biolink:causes MONDO:0007672 infores:monarchinitiative not_provided not_provided HGNC:14373 MONDO:0007672 uuid:ab4d0fcd-c7d8-441b-8b08-368e1f3ab0aa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6375 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0018965 infores:hetionet CHEBI:17334 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0085616 infores:hetionet CHEBI:31859 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0036974 infores:hetionet CHEBI:3994 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0015397 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0585186 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0585186 infores:hetionet CHEBI:63791 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0080274 infores:hetionet CHEBI:2788 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0008031 infores:hetionet CAID:CA658824422 biolink:causes MONDO:0011071 infores:clingen CAID:CA658824422 MONDO:0011071 PMID: Pathogenic PS4_Moderate, PM5_Supporting, PVS1, PM2_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BS1, BS3, BS4, BP7, BP5, PM4, PM1, PM3, BS2, PP2, PP3, PP4, PP1 The NM_001754.4:c.240_241del (p.Glu80fs) variant is a frameshift variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). Two unpublished probands meeting the RUNX1 phenotype criteria are noted (PS4_Moderate; SCV000807768.1). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting, PS4_Moderate. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824422/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8346 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0018939 infores:hetionet CAID:CA645369436 biolink:causes MONDO:0015967 infores:clingen CAID:CA645369436 MONDO:0015967 PMID: Uncertain Significance PM4, PM2_Supporting PS4, PP1, PP4 The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID: 31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA645369436/MONDO:0015967/086 2024-02-02 2024-02-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:3181 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0039070 infores:hetionet CHEBI:9086 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011053 infores:hetionet CHEBI:64355 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C2830004 infores:hetionet CHEBI:4974 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0236024 infores:hetionet CHEBI:3216 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0231218 infores:hetionet CHEBI:45716 biolink:causes MONDO:0015760 infores:sider not_provided not_provided DRUGBANK:DB02546 UMLS:C0079772 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0015230 infores:hetionet UMLS:C1144403 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0033774 infores:hetionet CHEBI:100241 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014591 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0010709 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0015397 infores:hetionet CHEBI:3568 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0017675 infores:hetionet GO:2000067 biolink:causes GO:0022622 infores:ubergraph knowledge_assertion manual_agent GO:2000067 GO:0022622 CHEBI:63580 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0019054 infores:hetionet CHEBI:4708 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0043352 infores:hetionet CHEBI:2922 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00995 UMLS:C0022346 infores:hetionet CHEBI:4995 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0004096 infores:hetionet CHEBI:92998 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0004093 infores:hetionet CHEBI:63611 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151904 infores:hetionet CHEBI:9599 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0423006 infores:hetionet GO:0097410 biolink:causes CL:1001569 infores:ubergraph knowledge_assertion manual_agent GO:0097410 CL:1001569 CHEBI:34967 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0012833 infores:hetionet CHEBI:9738 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0040034 infores:hetionet CHEBI:16755 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0162830 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0684249 infores:hetionet CHEBI:17263 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0025874 infores:hetionet NCBIGene:2892 biolink:causes MONDO:0010402 infores:monarchinitiative not_provided not_provided HGNC:4573 MONDO:0010402 uuid:13384043-9ef9-4e0d-bfe7-9c574ab50109 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7443 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0002390 infores:hetionet CHEBI:2682 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C1527344 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0877098 infores:hetionet CHEBI:63608 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0235378 infores:hetionet CHEBI:6690 biolink:causes UMLS:C2584688 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C2584688 infores:hetionet CHEBI:5778 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0011603 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0178298 infores:hetionet GO:0008284 biolink:causes MONDO:0007256 infores:drugmechdb knowledge_assertion manual_agent GO:0008284 MESH:D006528 DB08896_MESH_D006528_1DB00398_MESH_D006528_1 CHEBI:4514 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0011206 infores:hetionet CHEBI:127780 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0232462 infores:hetionet CAID:CA256011 biolink:causes MONDO:0010305 infores:clingen CAID:CA256011 MONDO:0010305 PMID: Pathogenic PS3_Supporting, PP3, PM2_Supporting, PP4_Strong, PP1_Strong The NM_005629.4:c.1141G>C variant in SLC6A8 is a missense variant that is predicted to lead to the substitution of a glycine for an arginine at amino acid 381 (p.Gly381Arg). This variant has been previously reported in one family with 5 affected males with elevated urinary creatine/creatinine and deficient creatine uptake in cultured fibroblasts (PP4_Strong) and segregated with disease in this family (PP1_Strong) (PMID: 11898126). This variant was reported to result in reduced (<10% of wild-type) creatine transport activity in SLC6A8 deficient fibroblasts (PMID: 22281021) (PS3_Supporting). In addition, the variant was shown to result in altered splicing via RT-PCR analysis (PMID: 11898126). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.923 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is a ClinVar entry for this variant (Variation ID 11697, zero-star review status), with one submitter classifying the variant as pathogenic. In summary, this variant meets criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting, PP3, PP1_Strong, PP4_Strong.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA256011/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Supports CHEBI:27690 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0039971 infores:hetionet CHEBI:194135 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1510410 infores:hetionet CHEBI:6030 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0231218 infores:hetionet CHEBI:35854 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0013604 infores:hetionet CHEBI:2682 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0009421 infores:hetionet CHEBI:100241 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0033975 infores:hetionet CHEBI:47381 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0015967 infores:hetionet CHEBI:33130 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB06723 UMLS:C0015376 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005219 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0016034 infores:hetionet CHEBI:66876 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0010200 infores:hetionet CHEBI:49668 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0020649 infores:hetionet NCBIGene:345193 biolink:causes MONDO:0014026 infores:monarchinitiative not_provided not_provided HGNC:24783 MONDO:0014026 uuid:cf973fca-bb54-48e9-897f-69d43c5f3ba9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:85078 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0013604 infores:hetionet CHEBI:45599 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0020621 infores:hetionet CHEBI:135961 biolink:causes NCIT:C71089 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0232333 infores:hetionet CHEBI:47898 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085633 infores:hetionet CHEBI:72296 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0151699 infores:hetionet CAID:CA274250 biolink:causes MONDO:0009290 infores:clingen CAID:CA274250 MONDO:0009290 PMID:17056254PMID:19588081PMID:17723315PMID:17056254 Pathogenic PM2, PVS1, PP4, PM3 This variant, c.2608C>T (p.Arg870Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting the ClinGen LSD VCEP’s threshold for PM2. This variant has been reported in patients meeting the ClinGen LSD VCEP’s PP4 criterion who also carry a known pathogenic variant in GAA, either c.-32-13T>G or c.525delT, phase unknown (PMIDs 17723315, 26497565), and a patient who is homozygous for the variant (PMID 26497565). Therefore, PP4 and PM3 can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMID 28763149), or a case with the same variant (not confirmed in trans) had already been included (PMID 17056254, 22676651). There is a ClinVar entry for this variant (Variation ID: 189009, 2 star review status) with five submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA274250/MONDO:0009290/010 2020-02-14 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ PUBCHEM.COMPOUND:657309 biolink:causes UMLS:C0235750 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0235750 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0235895 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0235895 infores:hetionet CHEBI:75722 biolink:causes NCIT:C78609 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0522251 infores:hetionet CHEBI:3515 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0311468 infores:hetionet CHEBI:490877 biolink:causes MONDO:0002081 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0026857 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1384353 infores:hetionet CHEBI:9086 biolink:causes HP:0100309 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0018946 infores:hetionet CHEBI:421707 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0027497 infores:hetionet CHEBI:7476 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0518015 infores:hetionet CHEBI:63608 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0151905 infores:hetionet CHEBI:9332 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0020615 infores:hetionet CHEBI:64028 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0233494 infores:hetionet CAID:CA229722 biolink:causes MONDO:0009861 infores:clingen CAID:CA229722 MONDO:0009861 PMID:26542770PMID:26542770 Pathogenic PM2, PM5, PP3, PP4, PM3_Strong PS3 The c.733G>A (p.Val245Met) variant in PAH has been reported in 2 individuals with PAH deficiency, detected in trans with pathogenic variants p.E178G (PMID: 26542770) and c.913-7A>G (PMID: 29316886). This variant is absent in population databases. Other missense variants at this same amino acid are interpreted as pathogenic (p.V245A, p.V245L, p.V245E). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229722/MONDO:0009861/006 2020-11-10 2022-02-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:40279 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0085096 infores:hetionet CHEBI:6375 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C1291078 infores:hetionet CHEBI:52172 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0016204 infores:hetionet CHEBI:61033 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0004093 infores:hetionet NCBIGene:1476 biolink:causes MONDO:0009698 infores:monarchinitiative not_provided not_provided HGNC:2482 MONDO:0009698 uuid:2fabe4e7-e7ce-4582-89c2-0046fcb17350 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:84300 biolink:causes MONDO:0014356 infores:monarchinitiative not_provided not_provided HGNC:21237 MONDO:0014356 uuid:812c22c5-3f41-429b-b6aa-23af0f2f7cdb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63619 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0344232 infores:hetionet CHEBI:41977 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0033774 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004985 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0005586 infores:hetionet CHEBI:144093 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0235378 infores:hetionet CHEBI:8212 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0039070 infores:hetionet CHEBI:8378 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0235146 infores:hetionet CHEBI:8093 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0151827 infores:hetionet CHEBI:10023 biolink:causes MONDO:0016218 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0018378 infores:hetionet CAID:CA16020725 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020725 MONDO:0009861 PMID:28982351PMID:26503515 Uncertain Significance PM3, PP4_Moderate, PM2, BP4 This c.61-3T>C variant in PAH was reported twice in the Chinese PKU population, although this may be the same patient (PMID: 26503515; 28982351). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. However, in silico splicing predictions suggest no splicing impact (HSP, MaxENT, TraP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM3, BP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020725/MONDO:0009861/006 2019-11-22 2020-01-25 Autosomal recessive inheritance HP:0000007 Inconclusive true PUBCHEM.COMPOUND:4786 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0233494 infores:hetionet CHEBI:7514 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0013144 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0233571 infores:hetionet CHEBI:178699 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0014868 infores:hetionet CHEBI:9448 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0231528 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0030554 infores:hetionet CHEBI:3485 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0018801 infores:hetionet CHEBI:6909 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0037763 infores:hetionet CHEBI:520985 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0020456 infores:hetionet CHEBI:10110 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1260880 infores:hetionet CHEBI:31236 biolink:causes NCIT:C113104 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0852795 infores:hetionet CHEBI:520985 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0151827 infores:hetionet CHEBI:367163 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0085593 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0853813 infores:hetionet CHEBI:4911 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0151907 infores:hetionet CHEBI:4708 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0428977 infores:hetionet CHEBI:134991 biolink:causes UMLS:C0235074 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0235074 infores:hetionet CHEBI:3504 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0025874 infores:hetionet CHEBI:6339 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0019080 infores:hetionet UMLS:C0017797 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0027497 infores:hetionet CHEBI:27504 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00305 UMLS:C0231218 infores:hetionet CHEBI:18248 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0497156 infores:hetionet CHEBI:7931 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011175 infores:hetionet CHEBI:7459 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0037383 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0151795 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0151795 infores:hetionet CHEBI:6015 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0006266 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0085096 infores:hetionet CHEBI:8461 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0349506 infores:hetionet CHEBI:5790 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0013456 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0580417 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0580417 infores:hetionet CHEBI:63617 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0025222 infores:hetionet CHEBI:9566 biolink:causes MONDO:0004745 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0033117 infores:hetionet CHEBI:9434 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0917801 infores:hetionet CHEBI:7773 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151744 infores:hetionet CAID:CA10385666 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385666 MONDO:0100437 PMID: Benign BA1 BP4 NM_001034853.2(RPGR):c.394G>A (p.Val132Ile) is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 132. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0002488 among hemizygous individuals, with 99 variant alleles / 397,905 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.000005 (BA1). The computational predictor REVEL gives a score of 0.054, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives a delta score of 0.12 for donor loss, which falls in the intermediate range above the ClinGen X-linked IRD VCEP recommended BP4 threshold of <0.1 but below the PP3 threshold of >0.2, so neither in silico code is met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385666/MONDO:0100437/106 2025-09-05 2025-09-05 X-linked inheritance HP:0001417 Contradicts true UMLS:C0657912 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085624 infores:hetionet CHEBI:2453 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0022346 infores:hetionet CHEBI:171719 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0023380 infores:hetionet CHEBI:101853 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0438142 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0948594 infores:hetionet CHEBI:3647 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0151564 infores:hetionet CHEBI:61049 biolink:causes UMLS:C1504532 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C1504532 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0007137 infores:hetionet CHEBI:50173 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0022904 infores:hetionet CHEBI:3515 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0039231 infores:hetionet CHEBI:3732 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0027769 infores:hetionet CHEBI:7936 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0231528 infores:hetionet CHEBI:4877 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0015967 infores:hetionet CHEBI:3996 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0003811 infores:hetionet CHEBI:4653 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C1956346 infores:hetionet CAID:CA2017997776 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997776 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PVS1, PP4, PP1, PM2_Supporting The c.1346_1362del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 4 novel amino acids before encountering a stop codon (p.(Ala449GlyfsTer4)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD (PM2_Supporting). This variant was identified in 5 unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate, internal lab contributors). This variant segregated with disease with 2 informative meioses in 2 families with MODY (PP1; internal lab contributors). In summary, the c.1346_1362del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP4, PS4_Moderate, PP1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997776/MONDO:0015967/086 2023-06-24 2023-06-24 Semidominant inheritance HP:0032113 Supports NCBIGene:5745 biolink:causes MONDO:0007982 infores:monarchinitiative not_provided not_provided HGNC:9608 MONDO:0007982 uuid:993c6490-8138-476d-9637-f22eeac67e6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0011570 infores:hetionet CAID:CA2739267606 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267606 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS2, PS4, BP1, BP4, BP2, BP3, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM3, PM5, PM4, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.805+4A>G is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267606/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0052167 biolink:causes GO:0045087 infores:ubergraph knowledge_assertion manual_agent GO:0052167 GO:0045087 UMLS:C0005740 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0151717 infores:hetionet CHEBI:3756 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0520966 infores:hetionet CHEBI:47499 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0013604 infores:hetionet CHEBI:50663 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0015672 infores:hetionet CHEBI:8863 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0036974 infores:hetionet CHEBI:144551 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0013428 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0013395 infores:hetionet CHEBI:175901 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0038325 infores:hetionet CHEBI:63589 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0004238 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002884 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0027339 infores:hetionet CAID:CA212529 biolink:causes MONDO:0010726 infores:clingen CAID:CA212529 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PM1, PP1, PS2_Very Strong, PS4, PM2_Supporting The p.Arg306Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 individuals with Rett Syndrome (PMID 10577905, 11309679, 19189931; internal database, GeneDx) (PS2_very strong). This variant has been observed in at least 4 other individuals with Rett syndrome (PMID 24511209, 23238081, RettBase) (PS4). The p.Arg306Cys variant occurs in the well-characterized transcriptional repression domain (TRD) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). This variant is absent in gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, p.Arg306Cys variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM1, PM2_supporting, PP3). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA212529/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:5100 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0004134 infores:hetionet NCBIGene:23676 biolink:causes MONDO:0024771 infores:monarchinitiative not_provided not_provided HGNC:11122 MONDO:0024771 uuid:e3f32997-fdeb-4538-a599-562c17909d1e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0152517 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0152517 infores:hetionet CHEBI:8245 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0020580 infores:hetionet CHEBI:17474 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0403632 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0025061 infores:hetionet CHEBI:521033 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0344315 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0267596 infores:hetionet GO:0060069 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:0060069 GO:0051641 UNII:D27V6190PM biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0574067 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0034063 infores:hetionet CAID:CA291241 biolink:causes MONDO:0012163 infores:clingen CAID:CA291241 MONDO:0012163 PMID: Benign BP7, BS2_Supporting, BA1 The c.495C>T (p.His165=) variant (NM_002185.5) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 5398/35384) of the c.495C>T variant in IL7R is 0.1491 for Latino/Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 2363 homozygous individuals were reported (BS2_Supporting is met).In summary, this variant is classified as Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BP7, BA1, and BS2_Supporting. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA291241/MONDO:0012163/119 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6472 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01627 UMLS:C0000833 infores:hetionet CHEBI:45863 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0022568 infores:hetionet CHEBI:4907 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0018681 infores:hetionet CHEBI:7494 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0016204 infores:hetionet CHEBI:64321 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0428977 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0033975 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0006826 infores:hetionet CHEBI:64064 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0008301 infores:hetionet CAID:CA405653178 biolink:causes MONDO:0018493 infores:clingen CAID:CA405653178 MONDO:0018493 PMID: Uncertain Significance PS4_Moderate PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with proline at codon 1675 of the RYR1 protein, p.(Leu1675Pro). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.798 supports neither a pathogenic nor a benign status for this variant.This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405653178/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:28864 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0006266 infores:hetionet CHEBI:3499 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01330 UMLS:C0033774 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005364 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0018213 infores:hetionet CHEBI:75998 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0033771 infores:hetionet CHEBI:6367 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013144 infores:hetionet GO:0010521 biolink:causes GO:0006278 infores:ubergraph knowledge_assertion manual_agent GO:0010521 GO:0006278 UMLS:C0010592 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0028734 infores:hetionet CHEBI:4672 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151970 infores:hetionet CHEBI:32588 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0013362 infores:hetionet CHEBI:9288 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0239981 infores:hetionet CHEBI:28901 biolink:causes NCIT:C185320 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0349410 infores:hetionet CHEBI:45863 biolink:causes MONDO:0010643 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0085669 infores:hetionet CHEBI:5280 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0010520 infores:hetionet NCBIGene:25839 biolink:causes MONDO:0013281 infores:monarchinitiative not_provided not_provided HGNC:18620 MONDO:0013281 uuid:7e857a63-5f79-4ea0-908d-9af0f83a2324 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C1323189 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1323189 infores:hetionet CHEBI:9667 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0031117 infores:hetionet CHEBI:51380 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0019158 infores:hetionet CHEBI:5778 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0015230 infores:hetionet CHEBI:3614 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0000833 infores:hetionet CHEBI:8774 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0149725 infores:hetionet CHEBI:3228 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0027769 infores:hetionet NCBIGene:8792 biolink:causes MONDO:0008275 infores:monarchinitiative not_provided not_provided HGNC:11908 MONDO:0008275 uuid:60ba3b2d-5f2a-4428-98d2-f623b5536ddb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6909 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0034359 infores:hetionet CHEBI:36791 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007859 infores:hetionet CHEBI:31348 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0041582 infores:hetionet CHEBI:51364 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0009676 infores:hetionet GO:2000093 biolink:causes GO:0061242 infores:ubergraph knowledge_assertion manual_agent GO:2000093 GO:0061242 CHEBI:8382 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0017181 infores:hetionet CHEBI:15553 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0010520 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020517 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0085622 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0085622 infores:hetionet CHEBI:10110 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0497156 infores:hetionet CHEBI:8310 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0013144 infores:hetionet CHEBI:49375 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0231528 infores:hetionet CHEBI:64312 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0025222 infores:hetionet CHEBI:9635 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0027497 infores:hetionet CHEBI:5384 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0013404 infores:hetionet CHEBI:5864 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C2830004 infores:hetionet CHEBI:63681 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0002170 infores:hetionet CHEBI:6015 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00753 UMLS:C0027497 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0027769 infores:hetionet CAID:CA410150334 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150334 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.818T>C (p.Ile273Thr) is a missense variant which has a REVEL score < 0.50 (0.025), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150334/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6539 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0033975 infores:hetionet CHEBI:5790 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0043144 infores:hetionet CHEBI:15551 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0020517 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235901 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235901 infores:hetionet CAID:CA410206641 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206641 MONDO:0011071 PMID: Likely Pathogenic PVS1_Strong, PM2_Supporting, PS4_Supporting PS3, PS1, PS2, BA1, BP1, BP4, BP3, BP2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+1G>T is canonical splice site variant which affects a donor splice site in intron 7. According to the Myeloid Malignancy VCEP rules for RUNX1, the donor splice site mutation will skip intron 7 with an in-frame deletion of delta206-269 and an R205N (AGG>AAT) mutation, removing 13% of the protein (PVS1_strong). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (gnomAD v2.1.1 and v3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; Internal Lab Data). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PVS1_strong, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206641/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7627 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0027769 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0023895 infores:hetionet CHEBI:4856 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0031350 infores:hetionet CHEBI:2704 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0521839 infores:hetionet CHEBI:291342 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0851341 infores:hetionet CHEBI:63608 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0016436 infores:hetionet CHEBI:85161 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0036974 infores:hetionet CHEBI:9599 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0022408 infores:hetionet CHEBI:63611 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0026821 infores:hetionet CHEBI:6073 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0039231 infores:hetionet CHEBI:204928 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0036974 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0549310 infores:hetionet CAID:CA347219920 biolink:causes MONDO:0015152 infores:clingen CAID:CA347219920 MONDO:0015152 PMID: Likely Pathogenic PM3, PVS1_Moderate, PP4, PM2_Supporting PS1 The NM_003494.4: c.4794+1G>A variant in DYSF, which is also known as NM_001130987.2: c.4911+1G>A, occurs within the dinucleotide splice donor site (+/- 1,2) of intron 43 and is predicted to disrupt the splice donor site and strengthen an alternative donor site further into the intron (SpliceAI score 0.99 for donor loss, 0.82 for donor gain). Skipping of exon 43 would be expected to result in an in-frame deletion of less than 10% of the protein, p.Gly1547_Lys1598del. Use of the alternative donor site would also be predicted to result in an in-frame event due to the inclusion of 45 bp of intron 43 (PVS1_Moderate). This variant has been reported in at least one patient with a clinical diagnosis of limb girdle muscular dystrophy, where it was confirmed in trans with a pathogenic variant (NM_003494.4: c.3373del p.(Glu1125LysfsTer9), 1.0 pt, PMID: 23243261) (PM3, PP4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Limb Girdle Muscular Dystrophy VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PVS1_Moderate, PM3, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347219920/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:200424 biolink:causes MONDO:0032922 infores:monarchinitiative not_provided not_provided HGNC:28313 MONDO:0032922 uuid:b61868b0-0076-4b4a-987f-609700b13e66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes HP:0041161 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0149531 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033975 infores:hetionet CAID:CA024353 biolink:causes MONDO:0007783 infores:clingen CAID:CA024353 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with leucine at codon 846 of the RYR1 protein, p.(Ser846Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.558 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024353/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:10102 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1368065 infores:hetionet CHEBI:63619 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0021141 infores:hetionet CAID:CA405688435 biolink:causes MONDO:0018493 infores:clingen CAID:CA405688435 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, PM1, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of leucine with proline at codon 487 of the RYR1 protein, p.(Leu487Pro). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:23558838). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.962) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405688435/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA658760464 biolink:causes MONDO:0021056 infores:clingen CAID:CA658760464 MONDO:0021056 PMID: Likely Pathogenic PP3, PS4_Moderate, PS3_Moderate, PM2_Supporting The NM_000038.6(APC):c.531+5_531+8del variant is located in intron 5 of the APC gene. RT-PCR demonstrated that this variant impacts splicing by skipping of exon 5 resulting in a premature stop codon (PS3_Moderate, PMID: 15459959). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). This variant has been reported in 5 probands meeting phenotypic criteria, resulting in a total phenotype score of 3.5 (PS4_Moderate; internal data Labcorp Genetics [formerly Invitae] and Institute of Human Genetics, Bonn, Germany, PMID: 15459959 and 20223039). The results from two in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: PS3_Moderate, PM2_Supporting, PP3, and PS4_Moderate (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760464/MONDO:0021056/089 2025-05-15 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10023 biolink:causes MONDO:0000736 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0025209 infores:hetionet CHEBI:6121 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0036974 infores:hetionet CHEBI:63605 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0021053 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0858797 infores:hetionet CHEBI:8024 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0042963 infores:hetionet CHEBI:8060 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00780 UMLS:C0151889 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0015104 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0162566 infores:hetionet CHEBI:75722 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0030252 infores:hetionet CAID:CA10385485 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385485 MONDO:0100437 PMID: Benign BP4_Strong, BA1 NM_001034853.2(RPGR):c.1399C>A (p.Gln467Lys) is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 467. This variant is present in gnomAD v4.1.0 at a frequency of 0.0001794 among hemizygous individuals, with 71 variant alleles / 395,690 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.013, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.06, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP4_Strong. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385485/MONDO:0100437/106 2025-08-01 2025-08-02 X-linked inheritance HP:0001417 Contradicts true NCBIGene:23767 biolink:causes MONDO:0014107 infores:monarchinitiative not_provided not_provided HGNC:3762 MONDO:0014107 uuid:f5f43377-2910-423d-8e5e-ea51fb08e8e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41977 biolink:causes MONDO:0001297 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0007177 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0010692 infores:hetionet CAID:CA145795 biolink:causes MONDO:0009290 infores:clingen CAID:CA145795 MONDO:0009290 PMID: Benign BA1 The NM_000152.5: c.921A>T (p.Ala307=) variant is a synonymous (silent) variant. The highest population minor allele frequency in gnomAD v2.1.1 is 0.23520 (569/24196 alleles, with 666 homozygotes) in the African population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92490; 2 star review status) with eight submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel (Specification Version 2.0): BA1.(Classification approved: August 17, 2021). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145795/MONDO:0009290/010 2021-08-25 2021-09-07 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:6715 biolink:causes UMLS:C0151512 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0151512 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C161592 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151754 infores:hetionet CAID:CA314802 biolink:causes MONDO:0012999 infores:clingen CAID:CA314802 MONDO:0012999 PMID: Benign BS2, BS1 PP3, PM5, BP4 The NM_000156.6:c.298C>T variant in GAMT is a missense variant that is predicted to cause the substitution of an arginine by a tryptophan at amino acid position 100 (p.Arg100Trp). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The GrpMax filtering allele frequency (95th % confidence) in gnomAD v4.1.0. is 0.002776 in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). There are 2 homozygotes in gnomAD v4.1.0. Because GAMT deficiency is a severe, pediatric-onset disorder, this data supports the benignity of the variant (BS2). The computational predictor REVEL gives a score of 0.331 which is neither above nor below the thresholds predicting a damaging (≥0.644) or benign (<0.29) impact on GAMT function. There is a ClinVar entry for this variant (Variation ID: 205579). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BS1, BS2.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA314802/MONDO:0012999/026 2025-03-18 2025-03-20 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31980 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0235639 infores:hetionet CHEBI:8888 biolink:causes HP:0031520 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0239783 infores:hetionet UNII:5V9KLZ54CY biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C2047937 infores:hetionet CAID:CA038361 biolink:causes MONDO:0021056 infores:clingen CAID:CA038361 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting PP3 The c.423-3_423-2del p.(?) variant in APC is an intronic variant which deletes two nucleotides at position -2 and -3 in intron 4. This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 (PS4_Supporting; Ambry Genetics, GeneDX and Invitae internal data). In addition, this variant has also been reported in over 20 individuals with a polyposis phenotype not meeting phenotypic criteria. The results from 2 in silico splicing predictors (VarSEAK and MaxEntScan) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 4 of APC, but SpliceAI predicts no impact (PP3 not met). This variant is absent from gnomAD v2.1.1 non-cancer dataset (PM2_Supporting). In summary, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA038361/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA10014177 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014177 MONDO:0011071 PMID: Uncertain Significance BP4 PS4, PS1, PS2, PS3, BP1, BP2, BP3, PVS1, PM2, PM6, BP7, BP5, BS1, BS3, BS4, PM5, PM3, PM1, PM4, BS2, PP2, PP1, PP4 NM_001754.5(RUNX1):c.1396A>G (p.Met466Val) is a missense variant which has a REVEL score ≤0.50 (0.203) and SpliceAI is ≤0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014177/MONDO:0011071/008 2025-05-02 2025-05-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9943 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0029882 infores:hetionet CHEBI:4672 biolink:causes MONDO:0044986 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0024228 infores:hetionet CAID:CA8815365 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815365 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM3, PS1_Supporting, PM2_Supporting The NM_000152.5:c.1551+1G>T variant alters the donor splice site of intron 10 in GAA. RT-PCR in fibroblasts revealed that this variant results in skipping of exon 10, with low levels of normal splicing (PMID 25243733). Skipping of exon 10 causes and in frame loss of 38 amino acids, encompassing part of the GAA catalytic barrel, and including two residues, Trp481 and Trp516, which are part of the active site (PMIDs 1856189, 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least four probands and one sibling with this variant have been reported; for 3 individuals, documented GAA activity is available in fibroblasts or dried blood spot and is in the affected range (PMID 25243733, 25703594) (PP4_Moderate). Three of these probands, each with late-onset Pompe disease, are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP. The phase is unconfirmed in all cases. The second variant is either c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902) (PMID: 31606152, 0.5 points) or c.-32-13T>G (ClinVar Variation ID: 4027) (2 patients and one sibling, PMID: 25703594, 30155607; 2 x 0.5 points). Another patient is compound heterozygous for the variant and c.1256A>T (p.Asp419Val) (PMID: 25243733, 27623443). The allelic data from this patient will be used in the assessment of p.Asp419Val and is not included here in order to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002228 in the East Asian population, which is lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Additional variants in the same splice region have been classified as pathogenic by the ClinGen LD VCEP including c.1551+1G>A (ClinVar Variation ID: 1065143), c.1551+1G>C (ClinVar Variation ID: 554983), and c.1551+3_1551+6del (aka c.1551+1_1551+4del) (PS1_Supporting; PMID: 37352859). There is a ClinVar entry for this variant (Variation ID: 555986). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0.0.): PVS1, PM3, PP4_Moderate, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 20, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815365/MONDO:0009290/010 2025-05-20 2025-05-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:15940 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0035410 infores:hetionet CHEBI:135888 biolink:causes UMLS:C0038826 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0038826 infores:hetionet CHEBI:8212 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0014724 infores:hetionet CHEBI:8871 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0007820 infores:hetionet CHEBI:231425 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0037274 infores:hetionet CHEBI:4735 biolink:causes UMLS:C0235723 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0235723 infores:hetionet NCBIGene:129880 biolink:causes MONDO:0014434 infores:monarchinitiative not_provided not_provided HGNC:970 MONDO:0014434 uuid:7d540b0e-3521-4d25-a983-fc01a884a5dd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:64312 biolink:causes MONDO:0005062 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0024299 infores:hetionet CHEBI:18067 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB01022 UMLS:C0333641 infores:hetionet CHEBI:63580 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0006277 infores:hetionet CHEBI:75922 biolink:causes HP:0000559 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0349702 infores:hetionet CHEBI:4551 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0151636 infores:hetionet CHEBI:51364 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0036974 infores:hetionet CHEBI:63638 biolink:causes MONDO:0018715 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0235753 infores:hetionet CHEBI:10101 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0016199 infores:hetionet CHEBI:50861 biolink:causes NCIT:C122437 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0740299 infores:hetionet CHEBI:8207 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0034359 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151717 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0341164 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0341164 infores:hetionet GO:0021859 biolink:causes CL:0000598 infores:ubergraph knowledge_assertion manual_agent GO:0021859 CL:0000598 CHEBI:45951 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0015672 infores:hetionet CHEBI:15428 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0344232 infores:hetionet CHEBI:32139 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0546817 infores:hetionet CHEBI:45327 biolink:causes UMLS:C0858924 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0858924 infores:hetionet CHEBI:70746 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0014868 infores:hetionet CHEBI:51041 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0018926 infores:hetionet NCBIGene:50617 biolink:causes MONDO:0011268 infores:monarchinitiative not_provided not_provided HGNC:866 MONDO:0011268 uuid:2ec66995-4459-4fa6-9639-ad43c0fab176 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31413 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0231528 infores:hetionet CAID:CA16020831 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020831 MONDO:0009861 PMID:21307867 Uncertain Significance PM2, PP4_Moderate, PP3 The c.656T>C (p.Phe219Ser) variant in PAH has been reported in a Chinese patient with PAH deficiency (referred to as P219S, BH4 deficiency excluded, PMID 21307867). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020831/MONDO:0009861/006 2020-03-07 2020-03-07 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:3176 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0023646 infores:hetionet CHEBI:4995 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0030554 infores:hetionet CHEBI:92511 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0037317 infores:hetionet CHEBI:6775 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C1609512 infores:hetionet CHEBI:16469 biolink:causes MONDO:0002715 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0153567 infores:hetionet CHEBI:2038 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0019079 infores:hetionet CHEBI:9763 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0836924 infores:hetionet CHEBI:3181 biolink:causes HP:5200321 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0312420 infores:hetionet CHEBI:5778 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0232462 infores:hetionet CHEBI:16347 biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0151735 infores:hetionet CHEBI:52717 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0043246 infores:hetionet CAID:CA057276 biolink:causes MONDO:0007947 infores:clingen CAID:CA057276 MONDO:0007947 PMID: Uncertain Significance PP4, PP2, PM1 The NM_00138 c.6724C>T is a missense variant in FBN1 predicted to cause a substitution of arginine by cysteine at amino acid 2242 (p.Arg2242Cys). This variant was found five times in the literature (PMID 34428338, PMID 32989268, PMID 25944730) in the context of Marfan syndrome (MFS). In four of the five cases, no phenotype was described. In the other case, the proband met the revised Ghent criteria (PMID 25944730, PP4). This variant has been reported once in ClinVar as Likely pathogenic, 4 times as uncertain significance and once as Likely benign (Variation ID: 384344). This variant is present in 40/1,111,616 (0.003%) alleles from the European non–Finnish population in gnomAD (https://gnomad.broadinstitute.org/ v4.0.0). Furthermore, this variant was found in 13/35,712 (0.036%) sequenced alleles in a general Icelandic population (PMID 37684520) but no phenotypic data of these cases was reported. This variant creates a Cys in a cb-EGF domain, which might affect the Cys disulfide bond formation (PM1). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2, gnomAD v4.0.0). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PP4, PP2. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA057276/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:51860 biolink:causes MONDO:0100042 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0085298 infores:hetionet CHEBI:72297 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0852911 infores:hetionet GO:0044477 biolink:causes GO:0007596 infores:ubergraph knowledge_assertion manual_agent GO:0044477 GO:0007596 CHEBI:9763 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0017152 infores:hetionet NCBIGene:3752 biolink:causes MONDO:0014621 infores:monarchinitiative not_provided not_provided HGNC:6239 MONDO:0014621 uuid:f4a23b67-aa10-4871-8016-87256a2b2d79 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4728 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0020456 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0277925 infores:hetionet NCBIGene:4983 biolink:causes MONDO:0010337 infores:monarchinitiative not_provided not_provided HGNC:8148 MONDO:0010337 uuid:3fa1b97e-63b8-4d90-b844-c8c90faef35d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:94449 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C1384353 infores:hetionet CAID:CA415087450 biolink:causes MONDO:0010305 infores:clingen CAID:CA415087450 MONDO:0010305 PMID: Likely Pathogenic PP3, PM2_Supporting, PP4_Strong PS4 The NM_005629.4:c.1421A>G variant in SLC6A8 is a missense variant that is predicted to result in the substitution of aspartate by glycine at amino acid 474 (p.Asp474Gly). This variant has been reported in one (hemizygous) male proband with mild intellectual disability, elevated urine creatine/creatinine, and absent creatine peak on brain MRS (PMID: 29435807) (PP4_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.971 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP4_Strong, PP3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, August 7, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415087450/MONDO:0010305/027 2023-08-07 2023-08-24 X-linked inheritance HP:0001417 Supports CHEBI:367163 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0178298 infores:hetionet CAID:CA405660749 biolink:causes MONDO:0007783 infores:clingen CAID:CA405660749 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, BP4 PP3, PM1, BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of lysine with glutamine at codon 2013 of the RYR1 protein, p.Lys2013Gln. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:20681998). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.397) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405660749/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:30830 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0232849 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151786 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0853813 infores:hetionet CHEBI:5778 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020651 infores:hetionet CHEBI:3732 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0700225 infores:hetionet CAID:CA400180670 biolink:causes MONDO:0015152 infores:clingen CAID:CA400180670 MONDO:0015152 PMID: Likely Pathogenic PP4_Strong, PM3, PM2_Supporting, PP3 PM5, PM4, PM1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4, PVS1, PM6, BP7, BP5, BS1, BS4, BS3, PP2, PP1, BS2 The NM_000023.4: c.662G>C variant in SGCA is a missense variant predicted to cause substitution of arginine by proline at amino acid 221 (p.Arg221Pro). This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM2_Supporting, PP3, PM3, PP4_Strong. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA400180670/MONDO:0015152/189 2025-01-07 2025-01-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5118 biolink:causes UMLS:C0948011 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0948011 infores:hetionet CAID:CA119179 biolink:causes MONDO:0005338 infores:clingen CAID:CA119179 MONDO:0005338 PMID:16466712PMID:16466712 Likely Benign BS1 BP7, BS3, PVS1, PM2, PP1, PP3, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.136C>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Arginine at amino acid 46 (p.Arg46Ter). Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. PVS1 did not apply, as the disease mechanism for MYOC variants associated with juvenile or primary open angle glaucoma (JOAG or POAG) is not loss-of-function. The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.006416, which met the ≥ 0.001 threshold set for BS1 (288 alleles out of 44,888), meeting the threshold of ≥ 5 of at least 2,000 observed alleles). There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -4 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS1 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA119179/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7476 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0005758 infores:hetionet CHEBI:10112 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0042267 infores:hetionet CAID:CA6831598 biolink:causes MONDO:0015967 infores:clingen CAID:CA6831598 MONDO:0015967 PMID: Benign BA1, BP5 The c.-160_-154dup variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.013, which is greater thanthe MDEP threshold for BA1 (≥0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.-160_-154dup meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BA1, BP5. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6831598/MONDO:0015967/017 2022-04-12 2022-07-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:50173 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0575081 infores:hetionet CHEBI:17026 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0037763 infores:hetionet CHEBI:16755 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0006277 infores:hetionet CHEBI:15765 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0020458 infores:hetionet CHEBI:10102 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0085628 infores:hetionet NCBITaxon:12058 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:12058 GO:0006954 DB00748_MESH_D003139_1 NCBIGene:4595 biolink:causes MONDO:0001056 infores:monarchinitiative not_provided not_provided HGNC:7527 MONDO:0001056 uuid:363d89c8-7f2a-47b5-9af6-75176d3d85a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50223 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0009806 infores:hetionet CHEBI:65173 biolink:causes NCIT:C50458 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0311394 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0003123 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0149904 infores:hetionet CHEBI:53760 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0231528 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0281981 infores:hetionet NCBIGene:55656 biolink:causes MONDO:0032818 infores:monarchinitiative not_provided not_provided HGNC:26048 MONDO:0032818 uuid:f5a354b4-2612-4a60-8602-33bf39af8a43 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:167638 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0023646 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0243026 infores:hetionet CHEBI:3756 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0042024 infores:hetionet CHEBI:45409 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0035455 infores:hetionet CHEBI:5383 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0020615 infores:hetionet CHEBI:5001 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0232849 infores:hetionet CHEBI:10125 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0018524 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0427008 infores:hetionet CAID:CA405673885 biolink:causes MONDO:0018493 infores:clingen CAID:CA405673885 MONDO:0018493 PMID: Uncertain Significance PS4_Moderate PP1, PP3, PM1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with methionine at codon 2627 of the RYR1 protein, p.(Val2627Met). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been identified in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), one of these individuals had a second variant of uncertain significance in RYR1 (p.Thr1431=, potential splice variant) and was not considered for PS4, PS4_Moderate (PMID:30236257; NZ MH investigation unit). This variant segregates with MHS in two individuals from one family, PP1 not met (PMID: 30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.808 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405673885/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:45409 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0042963 infores:hetionet CHEBI:4466 biolink:causes HP:0003073 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0239981 infores:hetionet CHEBI:93305 biolink:causes UMLS:C0677500 infores:sider not_provided not_provided DRUGBANK:DB00735 UMLS:C0677500 infores:hetionet CHEBI:16480 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0032326 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0233973 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0233973 infores:hetionet CHEBI:8412 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0302295 infores:hetionet CHEBI:9123 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235437 infores:hetionet CHEBI:5801 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0542184 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151596 infores:hetionet CHEBI:32139 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0016204 infores:hetionet CHEBI:36791 biolink:causes EFO:0009472 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0206504 infores:hetionet CHEBI:50378 biolink:causes HP:0002240 infores:sider not_provided not_provided DRUGBANK:DB00348 UMLS:C0019209 infores:hetionet CHEBI:6076 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0438142 infores:hetionet CHEBI:64064 biolink:causes HP:0012388 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0149514 infores:hetionet CHEBI:31711 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0020649 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0242350 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0241742 infores:hetionet CHEBI:2453 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0002792 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0340464 infores:hetionet NCBITaxon:10232 biolink:causes MONDO:0000295 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:10232 MONDO:0000295 CHEBI:2904 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0033774 infores:hetionet CHEBI:9137 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0016204 infores:hetionet CHEBI:5130 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0232849 infores:hetionet CHEBI:168396 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0007114 infores:hetionet UNII:54Z8M50D6Q biolink:causes HP:0007957 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0010038 infores:hetionet CHEBI:2904 biolink:causes MONDO:0002078 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0018816 infores:hetionet CHEBI:4653 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0003862 infores:hetionet CHEBI:49040 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0014457 infores:hetionet CHEBI:7936 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0040435 infores:hetionet CHEBI:49375 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0003123 infores:hetionet CAID:CA210022 biolink:causes MONDO:0100038 infores:clingen CAID:CA210022 MONDO:0100038 PMID:31558572 Pathogenic PS2, PS3, PP3_Moderate, PM1, PM2_Supporting The c.2558G>A variant in SCN2A is a missense variant predicted to cause subsitution of arginine by glutamine at amino acid 853 (p.Arg853Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) identified in the published literature (PMIDs: 23935176 , 23934111, 31139143, 28708303], with additional evidence published reports available (PS2). It is absent from gnomAD v2.1.1 (PM2_Supporting). Heterologous expression assay with voltage clamping showed a decrease in peak current of 51%, which is below the threshold of 72.1%, evidence that correlates with PS3. It is a missense variant that resides within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as PATHOGENIC for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2, PS3, PP3_Moderate, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications version 1.0) Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA210022/MONDO:0100038/068 2024-05-09 2024-05-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:16714 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0002994 infores:hetionet CHEBI:9763 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0004096 infores:hetionet GO:0106088 biolink:causes GO:0001568 infores:ubergraph knowledge_assertion manual_agent GO:0106088 GO:0001568 CAID:CA8815078 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815078 MONDO:0009290 PMID: Uncertain Significance PM2_Supporting, BS3_Supporting PP3, PP4, PM3, PM5, BP4 "The NM_000152.5:c.868A>G variant in GAA is predicted to result in the substitution of asparagine by aspartate at amino acid 290 (p.Asn290Asp). It has been identified in six individuals by newborn screening, none with clinical features consistent with Pompe disease (PMID: 32064362, 37414610; Essawi et al. 2021, Egypt J Med Hum Genet 22:87). Four of these individuals are homozygous for the variant and have African ancestry (PMID: 37414610), and two patients are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.2105G>A (p.Arg702His), phase unconfirmed, (ClinVar Variation ID: 426278, SCV004809068.1) (PMID: 32064362) or c.2238G>C (p.Trp746Cys) (ClinVar Variation ID: 265160, SCV002032122.1). In the latter, patient, the variants were confirmed to be in trans, and the father, who was described as ""completely normal"" but with reduced GAA activity, is homozygous for c.868A>G (p.Asn290Asp). Additional cases have been reported (PMID: 22644586, 33073007) but the second variant and clinical details were not provided. Due to the lack of evidence for clinical symptoms in the patients with this variant, PP4 and PM3 were not applied. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00004 (1/24356, no homozygotes) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant was classified as Class E (""presumably nonpathogenic"") by Kroos et al, 2012 (PMID:22644586). This includes 71% GAA activity in cells and 38% in medium, with synthesis and processing on Western blot (BS3_Supporting). The computational predictor REVEL gives a score of 0.561 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 498117). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 21, 2022. Since then, the data for this variant have been re-evaluated and new data have been included but the classification remains the same. The classification of variant of uncertain significance was reapproved on April 16, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, BS3_Supporting." Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815078/MONDO:0009290/010 2024-04-16 2024-04-17 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:83804 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0041969 infores:hetionet CHEBI:5280 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0015230 infores:hetionet CHEBI:50156 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0032961 infores:hetionet CHEBI:45081 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0000833 infores:hetionet CHEBI:64019 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0040034 infores:hetionet CHEBI:4672 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0017178 infores:hetionet CHEBI:6067 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0013428 infores:hetionet CHEBI:63627 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C2830004 infores:hetionet CHEBI:17303 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0026826 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0037274 infores:hetionet CAID:CA645294021 biolink:causes MONDO:0015924 infores:clingen CAID:CA645294021 MONDO:0015924 PMID: Pathogenic PM2, PVS1, PS4_Supporting, PS1 BA1, BS1 The BMPR2 c.418+3A>T variant is a non-canonical splice site (+3) variant located in intron 3. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in two (or more from Sztrymf?) individuals with PAH (PMID: 16429395; the same individuals also included in PMID: 29631995, 18356561) (PS4_supporting). In silico prediction indicated likely splice site donor loss (SpliceAI = 0.59) and cDNA analysis demonstrated an inframe deletion, p.Cys84_Ser140del, with loss of 47/99 amino acid residues of the conserved extracellular domain (PMID: 26387786) (PVS1 (RNA)). The variant occurs in the same splice region, and has the same molecular consequence, as an alternate variant classified as pathogenic by the PH VCEP (c.418+5G>A) (PS1). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1(RNA), PS1, PS4_supporting, PM2_supporting (VCEP specification version v1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA645294021/MONDO:0015924/125 2025-10-03 2025-10-03 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6456 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0547030 infores:hetionet CHEBI:404903 biolink:causes UMLS:C1142178 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1142178 infores:hetionet CHEBI:4903 biolink:causes MONDO:0000751 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0007855 infores:hetionet CHEBI:15367 biolink:causes HP:0100806 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0036690 infores:hetionet CHEBI:7931 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0151539 infores:hetionet CAID:CA013921 biolink:causes MONDO:0009144 infores:clingen CAID:CA013921 MONDO:0009144 PMID:21127202 Uncertain Significance PM2, PM4_Supporting, PS4_Supporting PP1 The c.3658_3660del (p.Glu1220del) variant in MYH7 has been reported in 2 individuals with Ebstein anomaly (PS4_Supporting; Postma 2010 PMID:21127202; Bettinelli 2013 PMID 23956225; Partners LMM ClinVar SCV000059512.5). This variant segregated with Ebstein anomaly in 3 affected individuals from one family (Partners LMM ClinVar SCV000059512.5). While the expert panel waived the ACMG/AMP recommendation for demonstrating segregation in more than one family given that MYH7 is a well-established cardiomyopathy gene, its role in Ebstein anomaly is less established. Therefore, the expert panel felt that the PP1 pathogenic code should not be applied in this case given that all segregations came from one family. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 1220 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant is classified as uncertain significance for Ebstein anomaly in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM4_Supporting; PS4_ Supporting. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013921/MONDO:0009144/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3242 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C1142412 infores:hetionet CHEBI:567361 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1258215 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0037274 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0521490 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0521490 infores:hetionet CHEBI:3723 biolink:causes MONDO:0004938 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0439857 infores:hetionet CHEBI:5138 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0001807 infores:hetionet CHEBI:6775 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0206061 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0232492 infores:hetionet CHEBI:32315 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0221423 infores:hetionet CHEBI:4315 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0022346 infores:hetionet CHEBI:127780 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0035078 infores:hetionet CHEBI:6067 biolink:causes HP:0001007 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0019572 infores:hetionet CHEBI:50859 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0020473 infores:hetionet CAID:CA383510973 biolink:causes MONDO:0015628 infores:clingen CAID:CA383510973 MONDO:0015628 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM5 The NM_000552.5:c.3569G>T variant in VWF is a missense variant predicted to cause substitution of cysteine by phenylalanine at amino acid 1190. At least 1 patient with this variant displayed excessive mucocutaneous bleeding (evidenced by inclusion in a VWD diagnosed cohort) as well as laboratory phenotypes of very low VWF activity VWF:GP1b and VWF:Collagen binding assay, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 36299619). Another missense variant NM_000552.5:c.3568T>C (p.Cys1190Arg) in the same codon has been classified as likely pathogenic for VWD type 2A by the ClinGen VWD VCEP (PM5). The computational predictor REVEL gives a score of 0.955, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The computational predictor REVEL gives a score of 0.955, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PM5_Supporting, PP3, PM2_Supporting. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0; date of approval) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383510973/MONDO:0015628/081 2025-04-02 2025-04-02 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4708 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0017574 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0234458 infores:hetionet CHEBI:6792 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0040822 infores:hetionet CHEBI:63589 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0027765 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0020517 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0749106 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0749106 infores:hetionet CHEBI:52172 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0011175 infores:hetionet CHEBI:7573 biolink:causes UMLS:C0236061 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0236061 infores:hetionet NCBIGene:56992 biolink:causes MONDO:0859570 infores:monarchinitiative not_provided not_provided HGNC:17273 MONDO:0859570 uuid:1f37267b-11fc-405b-a4df-49c0299cefef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8212 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0232462 infores:hetionet CHEBI:9123 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085583 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0038325 infores:hetionet CAID:CA410203587 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203587 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP1, BS2 NM_001754.5(RUNX1):c.301G>A (p.Val101Met) is a missense variant which has a REVEL score ≥ 0.88 (0.899) (PP3). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203587/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63629 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0231218 infores:hetionet CHEBI:9943 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0151578 infores:hetionet CHEBI:8772 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0227791 infores:hetionet UMLS:C1144403 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB04911 UMLS:C0332534 infores:hetionet CHEBI:31536 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0162834 infores:hetionet UNII:9YCX42I8IU biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00658 UMLS:C0013395 infores:hetionet CHEBI:50131 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0917801 infores:hetionet MONDO:0033642 biolink:causes NCBIGene:4953 infores:ubergraph knowledge_assertion manual_agent MONDO:0033642 HGNC:8109 CHEBI:63635 biolink:causes UMLS:C1141861 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1141861 infores:hetionet CHEBI:100241 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0009763 infores:hetionet CHEBI:8024 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0006266 infores:hetionet CHEBI:52172 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0853692 infores:hetionet CHEBI:28901 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0039231 infores:hetionet CHEBI:6541 biolink:causes MONDO:0006626 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011882 infores:hetionet CHEBI:60761 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0042963 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0428977 infores:hetionet CAID:CA210787 biolink:causes MONDO:0013144 infores:clingen CAID:CA210787 MONDO:0013144 PMID: Pathogenic PS4, PP1_Strong, PP3 PM2 The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature p.Leu99Phe, Antithrombin Budapest 3 (ATBp3)). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003516 (4/113752 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting (MAF =< 2.0 X 10-5 in gnomAD). The computational predictor REVEL gives a score of 0.853, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function (PP3). The variant has been reported to segregate with AT deficiency in at least 11 affected family members from 2 families (PP1_Strong; PMIDs: 32686144, 24072242). This variant has been reported in at least 100 probands with AT deficiency and is a founder variant in the Hugarian population. Further studies of the Hungarian cohort demonstrated that homozygosity was associated with thrombosis at a younger age and led to a high thrombotic risk while the heterozygous carriers also had venous and/or arterial thrombosis, as well as pregnancy complications. This variant was also reported in internal laboratory data (PS4_Very Strong; PMIDs: 26748602, 1555650, 32686144). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_strong, PP3, PS4_Very Strong Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210787/MONDO:0013144/084 2023-09-21 2023-09-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:40279 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0160390 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0020651 infores:hetionet CHEBI:6775 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0037274 infores:hetionet CHEBI:127342 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0001807 infores:hetionet CHEBI:63622 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0031117 infores:hetionet CHEBI:50693 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0151998 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151998 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C1510497 infores:hetionet CHEBI:681569 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0006840 infores:hetionet CHEBI:3176 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0917801 infores:hetionet NCBIGene:6773 biolink:causes MONDO:0030044 infores:monarchinitiative not_provided not_provided HGNC:11363 MONDO:0030044 uuid:d15196de-f090-4159-b37a-f9a2c7ff868b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0006954 biolink:causes MONDO:0850230 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D000080223 DB00637_MESH_D000080223_1DB06282_MESH_D000080223_1DB00967_MESH_D000080223_1DB00341_MESH_D000080223_1 CHEBI:6128 biolink:causes UMLS:C0857493 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0857493 infores:hetionet CHEBI:5441 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0015230 infores:hetionet CHEBI:2682 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0424790 infores:hetionet CAID:CA410147917 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147917 MONDO:0011071 PMID:27210295 Uncertain Significance BP4, PS4_Supporting PS2, PS1, PS3, BP2, BP1, BP3, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS4, BS3, PM3, PM5, PM4, PM1, BS2, PP1, PP4, PP2, PP3 The NM_001754.4:c.1160G>C (p.Gly387Ala) variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27210295). This missense variant has a REVEL score <0.15 (0.141) and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). This variant is present at a MAF of 0.000001727 (0.0001727%) in gnomADv4.1.0. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_ supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147917/MONDO:0011071/008 2025-02-24 2025-02-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63617 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0010200 infores:hetionet GO:1902490 biolink:causes GO:0007286 infores:ubergraph knowledge_assertion manual_agent GO:1902490 GO:0007286 CHEBI:31236 biolink:causes UMLS:C0341164 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0341164 infores:hetionet CHEBI:4798 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0021775 infores:hetionet CAID:CA587570153 biolink:causes MONDO:0009595 infores:clingen CAID:CA587570153 MONDO:0009595 PMID: Likely Pathogenic PM3_Strong, PP4_Moderate PM1, BA1, PS3, BS1, PM2, PP3, BS2 The NC_000009.12:g.35657755_35657764del variant is a 10 base pair deletion in RMRP (a non-coding gene). On transcript NR_003051.4 this variant is known as n.256_265delCTCAGCGCGG or n.258_267delCAGCGCGGCT (depending on left vs right shuffling). On transcript NR_003051.3 the variant is known as n.255_264delCTCAGCGCGG or n.257_266delCAGCGCGGCT (depending on left vs right shuffling). The variant may also be referred to as g.254_263delCTCAGCGCGG in the literature. The overall minor allele frequency (MAF) of this variant in gnomAD v4.1.0 is 0.00007166 (49/683800 alleles) and the highest subpopulation MAF (in Admixed American subpopulation) is 0.0008724 (43/49292 alleles). This exceeds the SCID VCEP's criteria for PM2 (<0.0000447) but does not exceed the criteria for BS1 (> 0.00089), therefore no population criteria code is met. Of note, although PM2 is not met, the highest population frequency in gnomAD is the Admixed American subpopulation and all affected individuals identified in the literature are likely from this same subpopulation. This variant has been identified in the literature in 3 unrelated female probands, all of Hispanic or Spanish/Mexican descent, affected with cartilage hair hypoplasia or anauxetic dysplasia (PMID: 17701897, 16838329). All 3 probands have metaphyseal dysplasia (1.0 point) meeting PP4 criteria. In addition to metaphyseal dysplasia, proband P9 in PMID: 16838329 also has hypotrichosis (0.5 point) (1.5 points total, meeting PP4 criteria) and proband P20 also has hypotrichosis (0.5 point), Hirschsprung disease (0.25 point), and T cell lymphopenia (0.5 point) (2.25 points total, meeting PP4_Moderate criteria). All 3 probands have a co-occurring second variant in RMRP. For proband P9 (PMID: 16838329), the co-occurring variant is 116A>G (NR_003051.3:n.117A>G) which has not yet been classified by the SCID VCEP and phase is unknown (0 point for PM3). For proband P20 (PMID: 16838329), the co-occurring variant is 195C>T (NR_003051.3:n.196C>T) which is classified as Pathogenic by the SCID VCEP, however, phase is unknown (0.5 point for PM3). For the proband in PMID: 17701897, the co-occurring variant is 195C>T (NR_003051.3:n.196C>T) which is classified as Pathogenic by the SCID VCEP, and the variants were confirmed in trans via parental testing (1 point for PM3). In addition to these 3 probands identified in the literature, this variant has also been observed in a male proband (of Hispanic descent) with a co-occurring RMRP variant in trans (SCV000640115.6) and indication of disproportionate short stature. The co-occurring variant is n.196C>T which is classified Pathogenic by the SCID VCEP and the variants are confirmed in trans (1 point for PM3). PMID: 17701897 additionally reports that sequencing of the RMRP RT-PCR product of patient with this variant showed absence of detectable levels of the mutation allele. The authors assert this variant is likely a null allele and therefore did not do further analysis for this variant in functional assays. This data does not qualify for PS3 under the SCID VCEP specifications for RMRP. In summary, this variant is classified as Likely Pathogenic based on the following ACMG codes PP4_Moderate (2.25 points), PM3_strong (2.5 points) (SCID VCEP RMRP specifications pilot v1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA587570153/MONDO:0009595/088 2025-06-10 2025-06-10 Autosomal recessive inheritance HP:0000007 Supports NCBIGene:51399 biolink:causes MONDO:0032894 infores:monarchinitiative not_provided not_provided HGNC:19943 MONDO:0032894 uuid:d3f25880-9cd9-473e-9716-f226aecb11fe biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31705 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0042373 infores:hetionet CHEBI:6438 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C1443060 infores:hetionet CHEBI:7959 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0014457 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0236065 infores:hetionet CHEBI:6375 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0020437 infores:hetionet CHEBI:9168 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0018099 infores:hetionet CHEBI:6717 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0025290 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0019112 infores:hetionet CHEBI:8888 biolink:causes MONDO:0020696 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0042847 infores:hetionet CHEBI:7936 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0043094 infores:hetionet CHEBI:7445 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0004093 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0562483 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0562483 infores:hetionet CHEBI:32221 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0917801 infores:hetionet CHEBI:16796 biolink:causes MONDO:0021739 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0033771 infores:hetionet CHEBI:681848 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0026838 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0037199 infores:hetionet CHEBI:66901 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0037195 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0006277 infores:hetionet CHEBI:45599 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0011175 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0035078 infores:hetionet CHEBI:92998 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0043094 infores:hetionet CHEBI:10125 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0086769 infores:hetionet CHEBI:82960 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0012833 infores:hetionet CHEBI:45409 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C2830004 infores:hetionet CHEBI:8499 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0007398 infores:hetionet CHEBI:9649 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042384 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0020621 infores:hetionet CHEBI:64355 biolink:causes HP:0006699 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0033036 infores:hetionet CHEBI:63580 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0027497 infores:hetionet CHEBI:84883 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0233472 infores:hetionet GO:0072043 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:0072043 GO:0007275 CHEBI:18358 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0917801 infores:hetionet CHEBI:6061 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0042963 infores:hetionet CHEBI:6367 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0151836 infores:hetionet CAID:CA145794 biolink:causes MONDO:0009290 infores:clingen CAID:CA145794 MONDO:0009290 PMID: Benign BA1 The highest continental population minor allele frequency for c.858+7_858+8insAGCGGGC in gnomAD v.2.1.1 is 0.7353 in the European non-Finnish population. This allele frequency is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.7783) and European Finnish (0.7613) populations. There is a ClinVar entry for this variant (Variation ID: 92489, 2 star review status), with 10 submitters all classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA145794/MONDO:0009290/010 2020-05-19 2020-06-02 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:478164 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0426576 infores:hetionet UMLS:C0145185 biolink:causes HP:0034033 infores:sider not_provided not_provided DRUGBANK:DB02638 UMLS:C0235532 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0025061 infores:hetionet CHEBI:39585 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0042024 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0151736 infores:hetionet CHEBI:4885 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C0011603 infores:hetionet CAID:CA160004 biolink:causes MONDO:0015967 infores:clingen CAID:CA160004 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting PS4, PM4 The c.73G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 25 (p.(Ala25Thr)) of transcript NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with MODY; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and not enough clinical information is provided to apply PP4 (PMID: 35673428). In summary, c.73G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM1_supporting, PM2_supporting.  Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA160004/MONDO:0015967/017 2025-06-18 2025-06-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3568 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0021843 infores:hetionet CHEBI:28001 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0018681 infores:hetionet CHEBI:31644 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085624 infores:hetionet CHEBI:7565 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0041582 infores:hetionet CHEBI:253342 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0027441 infores:hetionet CHEBI:45783 biolink:causes UMLS:C0424813 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0424813 infores:hetionet CHEBI:5384 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0149931 infores:hetionet CHEBI:134936 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00885 UMLS:C0004604 infores:hetionet NCBIGene:10682 biolink:causes MONDO:0020603 infores:monarchinitiative not_provided not_provided HGNC:3133 MONDO:0020603 uuid:dd755fc2-b2f7-4075-9288-eebf151ac866 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6904 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0011570 infores:hetionet CHEBI:27690 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0038325 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0014457 infores:hetionet CHEBI:63621 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0009782 infores:hetionet CAID:CA397842699 biolink:causes MONDO:0018875 infores:clingen CAID:CA397842699 MONDO:0018875 PMID: Uncertain Significance BS3_Supporting, PP3_Moderate, PM5_Supporting, PM2_Supporting BP1, BP4, BP3, BA1, PS1, PS3, PS4, PS2, PM4, PM1, BP7, BS1, BS4, PVS1, BS2, PP2, PP1, PP4 The NM_000546.6: c.413C>A variant in TP53 is a missense variant predicted to cause substitution of alanine by asparginine at amino acid 138 (p.Ala138Asp). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant received a total of 0.5 points across one proband. (PS4 not met; Internal lab contributor). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.5405; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). Another missense variant (c.412G>C (p.Ala138Pro)) (ClinVar Variation ID: 12376), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_supporting, BS3_supporting, PP3_moderate, PM5_Supporting. (Bayesian Points: 3; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA397842699/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0234987 infores:hetionet CHEBI:4814 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0011570 infores:hetionet NCBIGene:26224 biolink:causes MONDO:0011651 infores:monarchinitiative not_provided not_provided HGNC:13599 MONDO:0011651 uuid:2988736a-e7ae-4f98-b276-259ef5268163 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17334 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB01053 UMLS:C0392197 infores:hetionet UNII:54Z8M50D6Q biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0013395 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0687133 infores:hetionet CHEBI:9168 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0004604 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0152965 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0152965 infores:hetionet CHEBI:94440 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0011603 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0232492 infores:hetionet UNII:2N4O9L084N biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0009676 infores:hetionet CHEBI:45863 biolink:causes MONDO:0018100 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0151723 infores:hetionet CHEBI:10650 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0043352 infores:hetionet CHEBI:74947 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0151539 infores:hetionet CAID:CA148319 biolink:causes MONDO:0010726 infores:clingen CAID:CA148319 MONDO:0010726 PMID: Benign BP5, BS2, BA1, BP4 The allele frequency of the p.Thr203Met variant in MECP2 is 0.07% in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Thr203Met variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Thr203Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Thr203Met variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Thr203Met variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA148319/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:50659 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0020621 infores:hetionet CHEBI:15940 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0027540 infores:hetionet CHEBI:37941 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0002871 infores:hetionet CHEBI:3215 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0013362 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0032961 infores:hetionet CHEBI:51137 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0027424 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0033860 infores:hetionet CHEBI:9586 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C3665347 infores:hetionet GO:2000794 biolink:causes GO:0030324 infores:ubergraph knowledge_assertion manual_agent GO:2000794 GO:0030324 CHEBI:3561 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0231528 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0023530 infores:hetionet CHEBI:78320 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0020757 infores:hetionet CHEBI:50693 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0085612 infores:hetionet CHEBI:68554 biolink:causes UMLS:C0426576 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0426576 infores:hetionet CHEBI:6402 biolink:causes HP:0003537 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0221333 infores:hetionet CHEBI:4356 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0040034 infores:hetionet MONDO:0005644 biolink:causes GO:0006954 infores:drugmechdb knowledge_assertion manual_agent MESH:D000562 GO:0006954 DB00634_MESH_D000562_1 CAID:CA8423023 biolink:causes MONDO:0019497 infores:clingen CAID:CA8423023 MONDO:0019497 PMID: Likely Benign BP4, BS1_Supporting BS2, PM3 The c.1111C>A (p.Pro371Thr) variant in MYO15A was present in 0.208% (lower bound of the 95% CI of 295/128,454) of non-Finnish European alleles in gnomAD v2.1, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Conservation analyses suggest that this variant may not impact the protein (BP4). In summary, the p.Pro371Thr variant in MYO15A variant meets criteria to be considered likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA8423023/MONDO:0019497/005 2021-05-13 2022-05-13 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:64355 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0003123 infores:hetionet CHEBI:50777 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0702166 infores:hetionet CHEBI:6931 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0242184 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0024115 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0151838 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151838 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0424230 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0424230 infores:hetionet CHEBI:5120 biolink:causes UMLS:C0151310 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0151310 infores:hetionet CHEBI:48273 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0520966 infores:hetionet CAID:CA367398282 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398282 MONDO:0015967 PMID: Pathogenic PM1, PM5, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4 The c.1235T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to glutamic acid at codon 412 (p.(Val412Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 30245511, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, PMID: 30245511). This variant segregated with hyperglycemia with 2 informative meiosis 2 families (PP1; PMID: 30245511, internal lab contributors). Another missense variant, c.1235 p.Val412Ala, has been interpreted as pathogenic by the ClinGen MDEP, and p.Val412Glu has a greater Grantham distance (PM5). In summary, c.1235T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PM5, PP2, PP3, PP4_Moderate, PM2_Supporting, PP1. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398282/MONDO:0015967/086 2024-04-27 2024-04-27 Semidominant inheritance HP:0032113 Supports CHEBI:4909 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0038454 infores:hetionet CHEBI:8890 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0001925 infores:hetionet CHEBI:499361 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0948089 infores:hetionet CAID:CA229726 biolink:causes MONDO:0009861 infores:clingen CAID:CA229726 MONDO:0009861 PMID:12173030PMID:9012412 Uncertain Significance PM2, PP3, PP4, PM3_Supporting PM5 The c.737C>A (p.Ala246Asp) variant in PAH has been reported in 2 patients with PKU (PMID: 9012412,12173030), detected with pathogenic variant p.R408W in one patient (PMID: 31623983). This variant is absent in population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229726/MONDO:0009861/006 2020-11-13 2022-02-11 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31644 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0009676 infores:hetionet CHEBI:68595 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0013378 infores:hetionet CHEBI:49960 biolink:causes HP:0001900 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0549448 infores:hetionet CHEBI:61049 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0085636 infores:hetionet CHEBI:79699 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0002792 infores:hetionet CHEBI:38940 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0014868 infores:hetionet GO:2000606 biolink:causes GO:0001823 infores:ubergraph knowledge_assertion manual_agent GO:2000606 GO:0001823 CHEBI:291342 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0231528 infores:hetionet CHEBI:10101 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0040034 infores:hetionet CHEBI:44185 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0024117 infores:hetionet CHEBI:6076 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0085610 infores:hetionet CHEBI:3699 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0011603 infores:hetionet CHEBI:9649 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0233471 infores:hetionet CHEBI:6067 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0235266 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0040479 infores:hetionet CHEBI:83804 biolink:causes HP:0002305 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0004158 infores:hetionet CAID:CA2801158 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801158 MONDO:0001586 PMID: Benign BA1 The NM_000203.5:c.296C>T variant in IDUA is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 33 (p.Thr99Ile). The Grpmax Filtering AF (95% confidence) in gnomAD v4.1.0 is 0.01845 in the African/African American population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 280992). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801158/MONDO:0001586/091 2025-01-02 2025-01-02 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:28445 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0027947 infores:hetionet CHEBI:2682 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0232493 infores:hetionet CHEBI:8024 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037278 infores:hetionet CHEBI:63638 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0013447 infores:hetionet CHEBI:49662 biolink:causes NCIT:C117196 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0233471 infores:hetionet CHEBI:49575 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0231530 infores:hetionet CHEBI:5118 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0852911 infores:hetionet CHEBI:50173 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0013456 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0042401 infores:hetionet CHEBI:40237 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0231528 infores:hetionet CHEBI:8107 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0085636 infores:hetionet NCBIGene:9203 biolink:causes MONDO:0957496 infores:monarchinitiative not_provided not_provided HGNC:13054 MONDO:0957496 uuid:3d00e5cf-23ba-4b2a-aba3-f34e356bd1cd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA6402534 biolink:causes MONDO:0019565 infores:clingen CAID:CA6402534 MONDO:0019565 PMID: Benign BP4, BA1 BS2, BP2 The missense variant NM_000552.5(VWF):c.4414G>C (p.Asp1472His) is common in the general population with Grpmax filtering allele frequency of 0.5033 in gnomAD v4.1 (based on 38011/74882 alleles in the African/African American population). This is above the threshold of >0.1 (BA1). The computational predictor REVEL gives a score of 0.188, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI does not predict an impact to splicing with this variant. This variant does appear to impact laboratory values; the mean VWF:RCo/VWF:Ag ratio of 0.75-0.82 was significantly reduced compared to 0.91-0.97 for WT in 275 healthy adult individuals harboring the Asp1472His variant (PMID:20231421). In summary this variant meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6402534/MONDO:0019565/090 2024-08-13 2024-08-13 Undetermined mode of inheritance Contradicts true CHEBI:77733 biolink:causes MONDO:0005295 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0021775 infores:hetionet CAID:CA2499225882 biolink:causes MONDO:0011071 infores:clingen CAID:CA2499225882 MONDO:0011071 PMID: Likely Pathogenic PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.253_254insGGGG (p.His85fs) is a frameshift variant predicted to undergo NMD (PVS1, SNV tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1 and PM2_supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2499225882/MONDO:0011071/008 2022-03-21 2022-07-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7465 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0013604 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0270458 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0270458 infores:hetionet CHEBI:63618 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0035455 infores:hetionet CHEBI:63791 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0014518 infores:hetionet CHEBI:9139 biolink:causes HP:0100550 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0151937 infores:hetionet CHEBI:46345 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0013395 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151810 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151810 infores:hetionet CHEBI:45409 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0027947 infores:hetionet GO:1903023 biolink:causes GO:0030437 infores:ubergraph knowledge_assertion manual_agent GO:1903023 GO:0030437 CHEBI:35778 biolink:causes UMLS:C0858934 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0858934 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0006826 infores:hetionet CHEBI:75998 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0151908 infores:hetionet CAID:CA114135 biolink:causes MONDO:0015631 infores:clingen CAID:CA114135 MONDO:0015631 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM3, PS3 PP1, BA1 The NM_000552.4(VWF):c.2372C>T variant in VWF is a missense variant predicted to cause substitution of threonine by methionine at amino acid 791. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000006150 (based on 2/64030alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold <0.005 for PM2_Supporting, meeting this criterion (PM2_Supporting). At least four patients with this variant displayed excessive mucocutaneous bleeding as well as a low VWF:FVIII/VWF:Ag ratio which is highly specific for VWD type 2N (PP4_moderate, PMIDs: 2018834; 31741138; 22871923; 10706867). This variant has been detected in at least six individuals with VWD type 2N, with absent VWF:FVIII binding, compound heterozygous with a second variant (including Arg854Gln classified Pathogenic by the VWD VCEP without reported confirmation of trans phase 0.5pt PMID: 22102197) and two individuals were homozygous for the variant (PMIDs: 2018834; 22871923) (PM3). Factor VIII binding assay in HEK293 expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function (PMID: 19088379; PS3_supporting). The computational predictor REVEL gives a score of 0.869, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PS3, PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114135/MONDO:0015631/090 2024-08-13 2024-08-13 Autosomal recessive inheritance HP:0000007 Supports CAID:CA10649408 biolink:causes MONDO:0100326 infores:clingen CAID:CA10649408 MONDO:0100326 PMID: Likely Benign BP7, PM2_Supporting, BP4 PP3 The variant NM_000419.5(ITGA2B):c.945+10A>G has not been reported in the literature. It has previously been submitted to ClinVar (SCV000403381.3) however the affected status of the individual is unkown. The variant is absent from gnomAD (PM2_supporting). Meanwhile, the in silico predictor splice AI predics no impact on splicing and the variant occurs at a nucleotide position that is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, BP4, and BP7 (PD VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10649408/MONDO:0100326/011 2025-02-18 2025-02-18 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:31536 biolink:causes UMLS:C0221203 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0221203 infores:hetionet CHEBI:9570 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C1384666 infores:hetionet NCBIGene:2720 biolink:causes MONDO:0009660 infores:monarchinitiative not_provided not_provided HGNC:4298 MONDO:0009660 uuid:e2771b7b-abf5-40fb-9bbd-bcbdc378ef2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7936 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0235146 infores:hetionet CHEBI:31711 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0262662 infores:hetionet CHEBI:8871 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0086439 infores:hetionet CHEBI:2611 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0236075 infores:hetionet CHEBI:8212 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C1320474 infores:hetionet CHEBI:9448 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0027441 infores:hetionet CHEBI:135876 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00385 UMLS:C0085606 infores:hetionet CHEBI:2469 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0232462 infores:hetionet CHEBI:231425 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0151905 infores:hetionet CHEBI:5118 biolink:causes NCIT:C180702 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0312422 infores:hetionet CHEBI:17823 biolink:causes NCIT:C35297 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0241057 infores:hetionet NCBIGene:867 biolink:causes MONDO:0013308 infores:monarchinitiative not_provided not_provided HGNC:1541 MONDO:0013308 uuid:7d03fac6-3ac5-49bb-ab79-de485d717a8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31624 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0020580 infores:hetionet CHEBI:94392 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0009676 infores:hetionet CHEBI:119486 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0085632 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0018801 infores:hetionet CHEBI:63635 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C1141930 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0241164 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0241164 infores:hetionet CHEBI:231425 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB06212 UMLS:C0162529 infores:hetionet CHEBI:107736 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0002994 infores:hetionet CHEBI:474180 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0003962 infores:hetionet CHEBI:35778 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0022904 infores:hetionet CHEBI:68647 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0027765 infores:hetionet CHEBI:5613 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0013395 infores:hetionet CHEBI:567361 biolink:causes UMLS:C1096343 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C1096343 infores:hetionet CHEBI:79699 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0013595 infores:hetionet CAID:CA410148053 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148053 MONDO:0011071 PMID: Uncertain Significance BP4 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BS1, BS3, BS4, BP5, BP7, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1120G>A (p.Ala374Thr) is a missense variant which has a REVEL score < 0.50 (0.324), and a SpliceAI score ≤ 0.20 (0.0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148053/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:7986 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0002994 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0239978 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0239978 infores:hetionet CHEBI:8404 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00750 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0234215 infores:hetionet CHEBI:184555 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0002170 infores:hetionet CHEBI:45863 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0423791 infores:hetionet CHEBI:46557 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0002994 infores:hetionet NCBIGene:284098 biolink:causes MONDO:0014457 infores:monarchinitiative not_provided not_provided HGNC:23213 MONDO:0014457 uuid:299c5444-c678-4806-980d-58fdda798322 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51173 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0036572 infores:hetionet CHEBI:10110 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0018418 infores:hetionet CAID:CA10385176 biolink:causes MONDO:0100437 infores:clingen CAID:CA10385176 MONDO:0100437 PMID: Benign BP3, BA1 NM_001034853.2(RPGR):c.3183GGA[2] (p.Glu1066del) is a short in-frame deletion of 3 base pairs that encode amino acid 1066, which occurs within a purine-rich repetitive region in RPGR (PMID: 28549772, BP3). This variant is present in gnomAD v.4.1.0. at a frequency of 0.0006798 among hemizygous individuals, with 268 variant alleles / 394,250 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1 and BP3. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10385176/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance HP:0001417 Contradicts true CHEBI:27666 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0231218 infores:hetionet CHEBI:29688 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0026946 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0520806 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0520806 infores:hetionet CHEBI:44185 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0013491 infores:hetionet CHEBI:63616 biolink:causes MONDO:0005065 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0025500 infores:hetionet CHEBI:47519 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0003862 infores:hetionet CHEBI:63619 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0013604 infores:hetionet CHEBI:35553 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0427108 infores:hetionet CHEBI:63791 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2830004 infores:hetionet CHEBI:7573 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0042075 infores:hetionet CHEBI:7986 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0231528 infores:hetionet CAID:CA251545 biolink:causes MONDO:0009861 infores:clingen CAID:CA251545 MONDO:0009861 PMID: Likely Pathogenic PM2, PM3, PP4, PVS1_Strong The g.~6.7kbdel (p.Ex9_11del; c.914_1199+1del; CA251545) in PAH is a large deletion involving exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon 12 in long-range PCR (see PMID: 10472529). This region is critical to protein function, as exons 9 and 10 form part of the PAH catalytic domain, and include key amino acid residues. Therefore, this is a multi-exon deletion that disrupts the reading frame and is NOT predicted to undergo NMD, which truncates/alters a critical region for protein function. Thus, PVS1_Strong is applied.It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA251545/MONDO:0009861/006 2021-07-25 2021-09-19 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3215 biolink:causes NCIT:C50640 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0746961 infores:hetionet CHEBI:4708 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0744727 infores:hetionet NCBIGene:4609 biolink:causes MONDO:0007243 infores:monarchinitiative not_provided not_provided HGNC:7553 MONDO:0007243 uuid:fc41182e-bac2-4379-93ff-74aa544306e5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50381 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0855242 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0020538 infores:hetionet CHEBI:5959 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0021400 infores:hetionet CHEBI:78543 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0010200 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0040586 infores:hetionet NCBIGene:163183 biolink:causes MONDO:0014237 infores:monarchinitiative not_provided not_provided HGNC:26703 MONDO:0014237 uuid:8b3a32d3-44e4-4ea6-b1eb-091646d440a7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51141 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0042514 infores:hetionet CHEBI:68606 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0000737 infores:hetionet CHEBI:4470 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0855775 infores:hetionet CHEBI:15367 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0009676 infores:hetionet CHEBI:7565 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0151905 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0020538 infores:hetionet CHEBI:68595 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0003868 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0521591 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0521591 infores:hetionet CHEBI:35553 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0015230 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0003123 infores:hetionet CHEBI:9130 biolink:causes HP:0002045 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020672 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0013609 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0013609 infores:hetionet CHEBI:4885 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00609 UMLS:C2830004 infores:hetionet CHEBI:5801 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0878544 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0021167 infores:hetionet CHEBI:167638 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0028643 infores:hetionet CHEBI:4445 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0015967 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0021400 infores:hetionet CHEBI:3716 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0014457 infores:hetionet CHEBI:31236 biolink:causes HP:0020060 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0427457 infores:hetionet CHEBI:16664 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0042075 infores:hetionet UMLS:C0657912 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0037763 infores:hetionet CHEBI:3048 biolink:causes HP:0002367 infores:sider not_provided not_provided DRUGBANK:DB00245 UMLS:C0233763 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0917798 infores:hetionet GO:2000825 biolink:causes GO:0030522 infores:ubergraph knowledge_assertion manual_agent GO:2000825 GO:0030522 CHEBI:68554 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0041105 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0151736 infores:hetionet NCBIGene:84899 biolink:causes MONDO:0958228 infores:monarchinitiative not_provided not_provided HGNC:25904 MONDO:0958228 uuid:e7af485a-407d-4eba-9532-bab76340071b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5062 biolink:causes MONDO:0005628 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0238033 infores:hetionet CHEBI:3216 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1306341 infores:hetionet CHEBI:4659 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0011615 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0085082 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085082 infores:hetionet CHEBI:40279 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0018965 infores:hetionet CHEBI:7573 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0039070 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027651 infores:hetionet CHEBI:5959 biolink:causes MONDO:0024327 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0022661 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0011616 infores:hetionet CHEBI:50730 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0267792 infores:hetionet CHEBI:6958 biolink:causes UMLS:C0520758 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0520758 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0019158 infores:hetionet CHEBI:3506 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0000768 infores:hetionet NCBIGene:23387 biolink:causes MONDO:0032571 infores:monarchinitiative not_provided not_provided HGNC:29165 MONDO:0032571 uuid:efdace40-f087-4cbf-b75c-7a4350e5e416 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41879 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0162834 infores:hetionet CHEBI:5001 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0030196 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0033774 infores:hetionet CHEBI:3723 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085583 infores:hetionet CHEBI:8776 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0042963 infores:hetionet CAID:CA415086789 biolink:causes MONDO:0010305 infores:clingen CAID:CA415086789 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, BS2, PP3, BP4 The NM_005629.4:c.1313A>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a tyrosine for a phenylalanine at amino acid position 438 (p.Tyr438Phe). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00008812 (5/56743 aleles; 1 hemizygote) in the African/African American population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is one hemizygote in gnomAD v4.1.0. in the African/African American population. This is insufficient for the application of BS2 (2 or more hemizygotes required; BS2 not met).The computational predictor REVEL gives a score of 0.272, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 946475). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415086789/MONDO:0010305/027 2025-05-20 2025-05-20 X-linked inheritance HP:0001417 Inconclusive true CHEBI:4702 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0423006 infores:hetionet CHEBI:4672 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0542184 infores:hetionet CAID:CA341524 biolink:causes MONDO:0008723 infores:clingen CAID:CA341524 MONDO:0008723 PMID: Benign BA1, BP4 The c.68G>A variant in ACADVL is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid 23 (p.Arg23Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01223 in the Latino population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.123, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA341524/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:38545 biolink:causes HP:0002907 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0239937 infores:hetionet CHEBI:5120 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0022354 infores:hetionet CHEBI:30830 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0020538 infores:hetionet CHEBI:5296 biolink:causes MONDO:0002400 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0039103 infores:hetionet CHEBI:3011 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00542 UMLS:C0004096 infores:hetionet CHEBI:31644 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0233407 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0877097 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0877097 infores:hetionet CHEBI:82941 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0002994 infores:hetionet NCBIGene:7045 biolink:causes MONDO:0007375 infores:monarchinitiative not_provided not_provided HGNC:11771 MONDO:0007375 uuid:5460e670-b0f4-40ec-8b1d-9c2033788dea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28593 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0002962 infores:hetionet CHEBI:27899 biolink:causes MONDO:0001300 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0259749 infores:hetionet CHEBI:6062 biolink:causes HP:0030148 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0018808 infores:hetionet CHEBI:10650 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C1384666 infores:hetionet CAID:CA4239531 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239531 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS3 The c.749G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 250 (p.(Arg250His)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (pediatric patient with incidental diagnosis with FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persistently and negative antibodies (PP4_Moderate; PMID: 28170077, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African/African American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). Another missense variant, c.748C>T p.Arg250Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg250His (PM5_Supporting). The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and thermostability was not evaluated, and neither PS3 nor BS3 could be applied (PMID: 30592380). In summary, c.749G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239531/MONDO:0015967/086 2023-10-25 2023-10-25 Semidominant inheritance HP:0032113 Supports CHEBI:367163 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0011603 infores:hetionet CHEBI:2549 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0039240 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005898 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030578 infores:hetionet CHEBI:27786 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0031542 infores:hetionet CHEBI:8232 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0002871 infores:hetionet CHEBI:3207 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0004936 infores:hetionet CHEBI:51860 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0007859 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0040034 infores:hetionet NCBIGene:2664 biolink:causes MONDO:0010451 infores:monarchinitiative not_provided not_provided HGNC:4226 MONDO:0010451 uuid:9b65bf61-eead-47e0-9272-7f2b7b91dec5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17303 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0027441 infores:hetionet CHEBI:46081 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0010520 infores:hetionet CAID:CA8459324 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459324 MONDO:0011132 PMID:37419334 Likely Benign BS1 PP3, BP4, BS3 The NM_001369369.1(FOXN1):c.713G>A (p.Gly238Asp) missense variant has a gnomADv2.1.1 PopMax filtering AF of 0.003236, based on 75/19954 alleles in the East Asian population, which is above the >0.00141 threshold for BS1. Expression vectors containing Foxn1 variants were transfected into HeLa cells along with the β5t-luciferase reporter construct, a well-defined transcriptional target of Foxn1. This variant resulted in 105% activity in the reporter assay compared to WT (PMID: 37419334). After a comprehensive literature search, the variant has not been identified in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy. In summary, this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459324/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Contradicts true CHEBI:42797 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0037822 infores:hetionet CHEBI:2659 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0020456 infores:hetionet CHEBI:3716 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0033774 infores:hetionet CHEBI:9939 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0025061 infores:hetionet CHEBI:6129 biolink:causes UMLS:C0853336 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0853336 infores:hetionet CHEBI:7478 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C2242996 infores:hetionet CHEBI:168396 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018681 infores:hetionet CHEBI:8764 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0004604 infores:hetionet CHEBI:3127 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0857305 infores:hetionet CHEBI:63631 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0003467 infores:hetionet CHEBI:63611 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0558489 infores:hetionet CHEBI:5778 biolink:causes MONDO:0000467 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0264906 infores:hetionet CAID:CA913179809 biolink:causes MONDO:0044970 infores:clingen CAID:CA913179809 MONDO:0044970 PMID:15670724 Uncertain Significance PM2_Supporting, PS4_Supporting, PS3_Supporting PP3, PP1, PS2, PM6 The m.5543T>C variant in MT-TW has been reported in three unrelated individuals with primary mitochondrial disease. Clinical features in affected individuals include myopathy, exercise intolerance, headache, and COX-negative and ragged red fibers. Heteroplasmy levels in affected individuals ranged from undetectable in blood and skin fibroblasts to 80-95% in muscle (PS4_supporting; PMIDs: 15670724, 21712854, 26469001). There are no reported de novo occurrences of this variant to our knowledge. The variant was undetectable in blood from one mother however this variant was also undetectable in the proband’s blood precluding consideration for de novo occurrence (PMID: 15670724). In another family, the mother had the variant at lower heteroplasmy levels than the affected child (8% in blood, 29% in urine, and 14% in buccal sample) however this does not meet criteria to apply evidence for segregation as at least two segregations are needed. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictor tools are conflicting as MitoTIP suggests this variant is benign (47.3 percentile) and HmtVAR predicts it to be pathogenic (0.7). Single fiber testing showed higher levels of the variant in COX-negative fibers (99%) than in COX-positive fibers (76%), p<0.05 (PS3_supporting, PMID: 15670724). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913179809/MONDO:0044970/015 2024-05-13 2025-03-19 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true NCBIGene:1140 biolink:causes MONDO:0014582 infores:monarchinitiative not_provided not_provided HGNC:1961 MONDO:0014582 uuid:ce58f9eb-f05a-4a52-a7fb-ca7b90d101ae biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9168 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0025874 infores:hetionet CHEBI:8212 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0038990 infores:hetionet CHEBI:50122 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0002792 infores:hetionet CHEBI:45652 biolink:causes HP:0002913 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0027080 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0221706 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0221706 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0877338 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0877338 infores:hetionet CHEBI:8499 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0017178 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0037278 infores:hetionet CHEBI:100241 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0003537 infores:hetionet CHEBI:82960 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0028084 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0012569 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0002957 infores:hetionet CHEBI:92923 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0013604 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0005615 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0032131 infores:hetionet CHEBI:9449 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C2830004 infores:hetionet CHEBI:9398 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C2937350 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0012739 infores:hetionet CHEBI:8378 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0085633 infores:hetionet CAID:CA377482212 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482212 MONDO:0017623 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PS3 BS3, PP2 NM_000314.8(PTEN):c.334C>G (p.Leu112Val) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type OR RNA, mini-gene, or other assay shows impact on splicing. (internal laboratory contributor).PS4_M: Proband(s) with phenotype specificity score of 2-3.5. (PMID: 28677221).PM2_P: Absent in gnomAD.PP3: SpliceAI predicts a splicing impact. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482212/MONDO:0017623/003 2024-04-05 2024-04-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:79699 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0232462 infores:hetionet CHEBI:6062 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0042023 infores:hetionet GO:0140883 biolink:causes GO:0061709 infores:ubergraph knowledge_assertion manual_agent GO:0140883 GO:0061709 CHEBI:41423 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0030252 infores:hetionet CHEBI:50673 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00763 UMLS:C0013395 infores:hetionet CHEBI:8214 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0042963 infores:hetionet CHEBI:45783 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0027540 infores:hetionet CHEBI:135351 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0231218 infores:hetionet CHEBI:9398 biolink:causes MONDO:0005275 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0024115 infores:hetionet CHEBI:4903 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0042134 infores:hetionet CHEBI:7773 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0036572 infores:hetionet CHEBI:63611 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0151766 infores:hetionet CHEBI:7459 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01183 UMLS:C0178298 infores:hetionet CHEBI:68841 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0036572 infores:hetionet CHEBI:63620 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1368065 infores:hetionet CHEBI:32315 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0011168 infores:hetionet CHEBI:45409 biolink:causes HP:0011712 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085615 infores:hetionet CHEBI:3732 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C1609512 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0541831 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0541831 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0029456 infores:hetionet CHEBI:520985 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0039231 infores:hetionet CAID:CA10577185 biolink:causes MONDO:0044970 infores:clingen CAID:CA10577185 MONDO:0044970 PMID: Uncertain Significance BP4 PP1, PS4, PS2, PS3, PM6, PM2 The m.7502C>T variant in MT-TS1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 24, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual of Han Chinese descent with a tic disorder (PMID: 33289513). Other features were not reported and other genetic etiologies were not assessed. There are several occurrences in population databases. This variant is present in 0.007% of individuals in GenBank MITOMAP sequences, in 0.009% of individuals in gnomAD v3.1.2 (homoplasmic in all five individuals), and in 0.004% of individuals in the Helix dataset (six homoplasmic occurrences, one heteroplasmic). MitoTIP suggests this variant is benign (8.2 percentile) and HmtVAR predicts it to be polymorphic (0.1; BP4). There are no cybrid, single fiber, or other studies reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577185/MONDO:0044970/015 2023-07-24 2023-08-03 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:31236 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2047937 infores:hetionet CHEBI:8764 biolink:causes MONDO:0002447 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0476089 infores:hetionet CHEBI:3082 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0037822 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0424605 infores:hetionet NCBIGene:9702 biolink:causes MONDO:0013582 infores:monarchinitiative not_provided not_provided HGNC:30794 MONDO:0013582 uuid:94833542-1167-4a79-8b3a-46e5fd2c7e50 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes UMLS:C0858346 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0858346 infores:hetionet CHEBI:135351 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0040822 infores:hetionet CHEBI:474180 biolink:causes UMLS:C0740434 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0740434 infores:hetionet GO:1903538 biolink:causes GO:0009994 infores:ubergraph knowledge_assertion manual_agent GO:1903538 GO:0009994 CHEBI:6690 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0040034 infores:hetionet CHEBI:3228 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00237 UMLS:C0041657 infores:hetionet GO:0000079 biolink:causes GO:0051726 infores:ubergraph knowledge_assertion manual_agent GO:0000079 GO:0051726 CHEBI:7986 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0036572 infores:hetionet CHEBI:6717 biolink:causes UMLS:C0919737 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0919737 infores:hetionet CHEBI:8430 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0042963 infores:hetionet CHEBI:132233 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0030252 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0221742 infores:hetionet CHEBI:2675 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0520966 infores:hetionet CHEBI:9667 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0013604 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019158 infores:hetionet NCBIGene:116442 biolink:causes MONDO:0010289 infores:monarchinitiative not_provided not_provided HGNC:16499 MONDO:0010289 uuid:cace9f98-e1c7-4b6b-bf4c-a05683cf4e44 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0037199 infores:hetionet CHEBI:134966 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0520966 infores:hetionet CHEBI:94686 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0042267 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0004604 infores:hetionet CHEBI:9130 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0019158 infores:hetionet CHEBI:50922 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0040409 infores:hetionet CHEBI:64310 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0013395 infores:hetionet GO:0140845 biolink:causes GO:0006366 infores:ubergraph knowledge_assertion manual_agent GO:0140845 GO:0006366 CHEBI:79699 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0027765 infores:hetionet CHEBI:94501 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0037199 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0231218 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0003123 infores:hetionet CHEBI:52172 biolink:causes MONDO:0004126 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040147 infores:hetionet CHEBI:68478 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0020443 infores:hetionet CHEBI:4530 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00937 UMLS:C0948594 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0030920 infores:hetionet CHEBI:9332 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0037274 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001290 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0151436 infores:hetionet CHEBI:35553 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0040822 infores:hetionet CHEBI:6538 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0023380 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0027765 infores:hetionet CHEBI:31644 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020615 infores:hetionet CHEBI:100241 biolink:causes MONDO:0021163 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0022665 infores:hetionet CHEBI:6931 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0016927 infores:hetionet CHEBI:7852 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0011603 infores:hetionet CHEBI:31536 biolink:causes MONDO:0020089 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0877192 infores:hetionet CHEBI:8207 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0152009 infores:hetionet CHEBI:6887 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0019521 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151849 infores:hetionet CHEBI:71940 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0009806 infores:hetionet CHEBI:4325 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0010200 infores:hetionet CHEBI:46557 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0041834 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0037199 infores:hetionet CAID:CA167975 biolink:causes MONDO:0007648 infores:clingen CAID:CA167975 MONDO:0007648 PMID: Likely Benign BS2, BP4 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BP1, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.49-3C>T variant has been observed in at least 10 individuals without DGC, SRC tumours, or LBC & whose families do not suggest HDGC (BS2; SCV000186304.5, SCV000288486.4). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP4. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA167975/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true NCBIGene:126129 biolink:causes MONDO:0014568 infores:monarchinitiative not_provided not_provided HGNC:18540 MONDO:0014568 uuid:84847786-0a99-4894-a1d5-b6ce89b6957a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151828 infores:hetionet CHEBI:6076 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0011991 infores:hetionet CHEBI:5847 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0027540 infores:hetionet CHEBI:63925 biolink:causes UMLS:C0221743 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0221743 infores:hetionet CHEBI:6067 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0036529 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0948349 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0043251 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0043251 infores:hetionet CHEBI:116278 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0151836 infores:hetionet UMLS:C0011701 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0020625 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0233494 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002545 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0037928 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001466 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0259799 infores:hetionet CHEBI:7936 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042510 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0239385 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0302295 infores:hetionet CAID:CA291608 biolink:causes MONDO:0007113 infores:clingen CAID:CA291608 MONDO:0007113 PMID: Likely Benign BP7, BP4 BS1, PM2 The c.1119T>C p.(Asp373=) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.006% in the European (non-Finnish) sub population (no criteria met). The silent p.(Asp373=) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1119T>C p.(Asp373=) variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA291608/MONDO:0007113/016 2022-06-30 2022-06-30 Autosomal dominant inheritance (with paternal imprinting (HP:0012274)) HP:0012274 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:31236 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0017181 infores:hetionet GO:1900211 biolink:causes GO:0001656 infores:ubergraph knowledge_assertion manual_agent GO:1900211 GO:0001656 CHEBI:63621 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0033860 infores:hetionet CHEBI:3077 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151692 infores:hetionet CHEBI:63612 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0015967 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0549209 infores:hetionet CHEBI:9086 biolink:causes UMLS:C1609512 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C1609512 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0000833 infores:hetionet CHEBI:82960 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0027051 infores:hetionet CHEBI:5001 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0549373 infores:hetionet CL:0000586 biolink:causes MONDO:0005040 infores:ubergraph knowledge_assertion manual_agent CL:0000586 MONDO:0005040 UMLS:C0009315 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0475858 infores:hetionet CHEBI:231594 biolink:causes HP:0400008 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0232943 infores:hetionet CAID:CA16609762 biolink:causes MONDO:0015967 infores:clingen CAID:CA16609762 MONDO:0015967 PMID: Likely Benign PM2_Supporting, BS3_Supporting, BS2 PS4, PM1, PP1 The c.539C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 180 (p.(Ala180Val)) of NM_000545.8. Functional studies demonstrated the p.Ala180Val protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 28934671) (BS3_Supporting). Additionally, this variant was identified in the homozygous state in a normoglycemic individual (PMID: 28934671) (BS2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.539C>T meets the criteria to be classified as likely benign for monogenic diabetes, though it likely influences diabetes risk. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS3_Supporting, BS2, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16609762/MONDO:0015967/017 2024-07-29 2024-07-29 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2618 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0043352 infores:hetionet CHEBI:32588 biolink:causes HP:0001284 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0234146 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0857353 infores:hetionet CHEBI:6067 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085932 infores:hetionet CHEBI:63613 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0014742 infores:hetionet CHEBI:7986 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0085631 infores:hetionet NCBIGene:5081 biolink:causes MONDO:0009994 infores:monarchinitiative not_provided not_provided HGNC:8621 MONDO:0009994 uuid:94a7c0f1-7b23-478a-b2fb-0501514734c4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2682 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0042024 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005377 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0027726 infores:hetionet NCBIGene:3030 biolink:causes MONDO:0012173 infores:monarchinitiative not_provided not_provided HGNC:4801 MONDO:0012173 uuid:c60ed95c-3228-4e04-95ef-1133df7b0ca2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31711 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0027540 infores:hetionet CHEBI:8081 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0011991 infores:hetionet CHEBI:9137 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040128 infores:hetionet CHEBI:6538 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0017152 infores:hetionet CHEBI:101278 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0001925 infores:hetionet CHEBI:15765 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C2047937 infores:hetionet CHEBI:66899 biolink:causes MONDO:0016047 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0014236 infores:hetionet CHEBI:31622 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0012569 infores:hetionet CHEBI:4514 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0018799 infores:hetionet CHEBI:140621 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0242184 infores:hetionet CAID:CA023971 biolink:causes MONDO:0007783 infores:clingen CAID:CA023971 MONDO:0007783 PMID: Likely Pathogenic PS4_Moderate, PP1_Strong, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of serine with tyrosine at codon 4050 of the RYR1 protein, p.(Ser4050Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:30236257). Two families have been found to segregate this variant in a total of 10 affected individuals (MHS-VCEP laboratory), PP1_Strong. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.942) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023971/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:7907 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01337 UMLS:C1145670 infores:hetionet CHEBI:3996 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0040822 infores:hetionet CHEBI:8412 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0024141 infores:hetionet CHEBI:144551 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0232461 infores:hetionet CHEBI:7936 biolink:causes HP:0002396 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0151564 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0233794 infores:hetionet CHEBI:135351 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0026858 infores:hetionet CHEBI:7931 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0917798 infores:hetionet CHEBI:48273 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0085636 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0014130 infores:hetionet CHEBI:50859 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C2225524 infores:hetionet CHEBI:46295 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0151827 infores:hetionet CHEBI:2687 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00276 UMLS:C0019158 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0006794 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C2973529 infores:hetionet CHEBI:47381 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0006266 infores:hetionet CHEBI:31348 biolink:causes HP:0033361 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0264267 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0027765 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0020649 infores:hetionet NCBIGene:55628 biolink:causes MONDO:0859198 infores:monarchinitiative not_provided not_provided HGNC:19904 MONDO:0859198 uuid:a3a77f2e-e6d1-4743-8482-f5d85f04569e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C1443060 infores:hetionet CHEBI:9150 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0024141 infores:hetionet CHEBI:135005 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0000731 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007787 infores:hetionet NCBIGene:4633 biolink:causes MONDO:0859168 infores:monarchinitiative not_provided not_provided HGNC:7583 MONDO:0859168 uuid:11f56986-9f03-4569-8633-e2c08283d33c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA8622838 biolink:causes MONDO:0100326 infores:clingen CAID:CA8622838 MONDO:0100326 PMID: Uncertain Significance BP4 PM2, PP3, PP4 The c.62>T variant in ITGB3 is a missense variant predicted to cause substitution of alanine by valine at amino acid 21. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002964 (310122 alleles) in the Latino/Admixed American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.034, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGB3 function (BP4). The computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8622838/MONDO:0100326/011 2023-12-19 2023-12-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:6931 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0043352 infores:hetionet CHEBI:28593 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0004245 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0178298 infores:hetionet CHEBI:53760 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0002994 infores:hetionet CHEBI:7476 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027707 infores:hetionet CHEBI:50223 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0232462 infores:hetionet CHEBI:8764 biolink:causes NCIT:C54355 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151599 infores:hetionet CHEBI:7903 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0022081 infores:hetionet GO:2000090 biolink:causes GO:0061231 infores:ubergraph knowledge_assertion manual_agent GO:2000090 GO:0061231 CHEBI:5165 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0020453 infores:hetionet CHEBI:40279 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0220981 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011630 infores:hetionet CHEBI:16469 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0015672 infores:hetionet CHEBI:8768 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020473 infores:hetionet CHEBI:39867 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002994 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0006840 infores:hetionet CHEBI:3207 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0002792 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0020538 infores:hetionet CHEBI:3312 biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C1112525 infores:hetionet CHEBI:63681 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0231528 infores:hetionet CHEBI:34967 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB06155 UMLS:C0233494 infores:hetionet CHEBI:3216 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0000833 infores:hetionet CAID:CA023822 biolink:causes MONDO:0100150 infores:clingen CAID:CA023822 MONDO:0100150 PMID: Pathogenic PP3, PP1, PM3_Very Strong BP7, BP5, BS1, BS4, BS3, PVS1, PM2, PM6, PP2, PP4, BS2, BP3, BP1, BP4, BP2, BA1, PS1, PS4, PS2, PS3, PM4, PM1, PM5 The NM_000540.3:c.10204T>G (p.Cys3402Gly) variant in RYR1 is a missense variant predicted to cause a substitution of cysteine by glycine at amino acid 3402. The computational predictor REVEL gives a score of 0.851, which is above the threshold for predicting a damaging effect on RYR1 variants (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006 (7/117872 alleles) in European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≤0.00000697) for PM2_Supporting and lower than ClinGen Congenital Myopathies VCEP threshold (≥0.000697) for BS1, therefore no population criteria can be applied. The variant has been reported in trans with a second pathogenic RYR1 variant or a rare variant of uncertain significance in RYR1 in 10 probands with clinical features of congenital myopathy (PMID: 20583297; Synnovis internal data SCV001468505.1; Invitae internal data SCV000659742.9) (PM3_Very Strong). The variant along with another pathogenic variant in trans was identified in two siblings with congenital myopathy suggesting cosegregation (Invitae internal data) (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: PM3_Very Strong, PP1, PP3 (ClinGen Congenital Myopathies VCEP Specifications 2.0.0; 2/10/2025). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA023822/MONDO:0100150/179 2025-02-10 2025-04-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3723 biolink:causes MONDO:0002040 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0011630 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0267596 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0267596 infores:hetionet CHEBI:4453 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0015230 infores:hetionet CHEBI:63115 biolink:causes NCIT:C54056 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0521987 infores:hetionet CHEBI:6912 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00765 UMLS:C0018965 infores:hetionet UMLS:C0657912 biolink:causes HP:0001744 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0038002 infores:hetionet CHEBI:2569 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0011615 infores:hetionet CHEBI:28148 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0039070 infores:hetionet CHEBI:75045 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0021053 infores:hetionet CHEBI:31485 biolink:causes HP:0000523 infores:sider not_provided not_provided DRUGBANK:DB06781 UMLS:C0235259 infores:hetionet CHEBI:240107 biolink:causes HP:0001147 infores:sider not_provided not_provided DRUGBANK:DB00963 UMLS:C0240897 infores:hetionet CHEBI:3403 biolink:causes MONDO:0000918 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0014179 infores:hetionet CHEBI:47898 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0852911 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0235234 infores:hetionet CHEBI:38562 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0521839 infores:hetionet CHEBI:5138 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0025874 infores:hetionet CHEBI:83804 biolink:causes MONDO:0022007 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0043049 infores:hetionet CHEBI:6846 biolink:causes UMLS:C1760428 infores:sider not_provided not_provided DRUGBANK:DB05246 UMLS:C1760428 infores:hetionet CHEBI:135961 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0003862 infores:hetionet CHEBI:5790 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0021053 infores:hetionet CAID:CA8602773 biolink:causes MONDO:0100326 infores:clingen CAID:CA8602773 MONDO:0100326 PMID: Uncertain Significance PM5, PP4_Moderate, PM2_Supporting PM3, PP3 The NM_000419.5:c.2254C>G variant in ITGA2B is a missense variant predicted to cause substitution of leucine by valine at amino acid 752 (p.Leu752Val). At least one patient (Patient GM in PMID: 12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% as measured by flow cytometry (PP4_Moderate). Although this variant was reported in homozygosity in two individuals (Patients GM and PV in PMID: 12083483), PM3 was not applied at any level of strength because additional ITGA2B variants were also observed in both individuals (c.1139G>A (p.Gly380Asp) in heterozygosity in GM; c.2264G>C (p.Arg755Pro) in homozygosity in both GM and PV). The variant is absent from gnomADv4.0 (PM2_Supporting). Another missense variant (ITGA2B c.2255T>G (p.Leu752Arg)) in the same codon has been classified as pathogenic for Glanzmann thrombasthenia by the ClinGen Platelet Disorders VCEP (PM5). In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM5, PP4_Moderate. (VCEP specifications version 2; date of approval 04/16/2024) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8602773/MONDO:0100326/011 2024-04-16 2024-04-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CAID:CA288884 biolink:causes MONDO:0012999 infores:clingen CAID:CA288884 MONDO:0012999 PMID: Benign BS2, BA1, BP4 The NM_000156.6:c.626C>T variant in GAMT is a missense variant predicted to result in the substitution of threonine for methionine at amino acid 209 (p.Thr209Met). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.09656 (12354/ 127944 alleles) in the European non-Finnish population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 987 homozygotes in gnomAD v2.1.1. Given that GAMT deficiency has an early onset, this data supports that the variant does not cause the condition (BS2). The computational predictor REVEL gives a score of 0.313 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). It has been previously reported in a large Italian family (PMID: 12468279), where it did not segregate with AGAT deficiency, including being found in the homozygous state in the father, who was asymptomatic and had normal GAMT enzyme activity. It has also been found in presumed cis with the c.160G>C (p.Ala54Pro) variant in a patient with severe GAMT deficiency, as both parents were heterozygous for both the c.160G>C variant and c.626C>T variant and the patient was homozygous for both variants (PMID: 15108290). In this publication (PMID: 15108290), the c.626C>T was classified as a benign polymorphism due to its high frequency in a group of control individuals screened. It is noted in ClinVar (Variation ID: 21068). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA288884/MONDO:0012999/026 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8802 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0948525 infores:hetionet CHEBI:9649 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0002170 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0162429 infores:hetionet CHEBI:47898 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0522224 infores:hetionet CHEBI:7915 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0013378 infores:hetionet CHEBI:134743 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06290 UMLS:C0015672 infores:hetionet CHEBI:63617 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0236000 infores:hetionet CHEBI:28901 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0030305 infores:hetionet UMLS:C0065374 biolink:causes HP:0003419 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0024031 infores:hetionet CHEBI:68558 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0017152 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0233472 infores:hetionet CHEBI:51230 biolink:causes MONDO:0001308 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0162281 infores:hetionet CHEBI:188986 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0025874 infores:hetionet CHEBI:3696 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0027769 infores:hetionet CHEBI:45409 biolink:causes HP:0000512 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0476397 infores:hetionet CHEBI:75922 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0232910 infores:hetionet CHEBI:41423 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0013491 infores:hetionet CHEBI:9139 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0004604 infores:hetionet NCBIGene:2779 biolink:causes MONDO:0012497 infores:monarchinitiative not_provided not_provided HGNC:4393 MONDO:0012497 uuid:05e83b8c-205b-4b9d-9f4f-298df2135599 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4514 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0026961 infores:hetionet CHEBI:5141 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0016382 infores:hetionet UNII:D27V6190PM biolink:causes MONDO:0011786 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C2607914 infores:hetionet CHEBI:5280 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0008031 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0031117 infores:hetionet CHEBI:6541 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011606 infores:hetionet CHEBI:63584 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0243026 infores:hetionet CHEBI:7824 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0038220 infores:hetionet CHEBI:4653 biolink:causes NCIT:C35135 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0079027 infores:hetionet CHEBI:28787 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0013404 infores:hetionet CHEBI:63630 biolink:causes MONDO:0005059 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0023418 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0018799 infores:hetionet CHEBI:8207 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151830 infores:hetionet CAID:CA386960416 biolink:causes MONDO:0015967 infores:clingen CAID:CA386960416 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP4_Moderate, PP3 The c.478G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 160 (p.(Ala160Thr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.478G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386960416/MONDO:0015967/017 2025-01-03 2025-01-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:83804 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0020538 infores:hetionet CHEBI:135791 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0302295 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0018802 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0853084 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0853084 infores:hetionet CHEBI:68647 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0023530 infores:hetionet CHEBI:4975 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0428977 infores:hetionet CHEBI:9613 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0023530 infores:hetionet CHEBI:28445 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0030196 infores:hetionet CAID:CA658824437 biolink:causes MONDO:0007947 infores:clingen CAID:CA658824437 MONDO:0007947 PMID: Likely Pathogenic PM2_Supporting, PS4, PM4 PP2, PP3, BP1, BP4, BA1, BS1 The NM_00138 c.3632_3634del is an in-frame deletion in FBN1predicted to cause a deletion of a phenylalanine at position 1211 (p.Phe1211del). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (internal data, University of Ghent) (PP4). This variant was also found in a proband with ectopia lentis and an adverse aortic event and was found to segregate with the disease in two affected family members (internal data, University of Tokyo) (PP1). It has been reported in the literature in two unrelated individuals with ectopia lentis (PMID 19159394, 16222657), in one individual with a clinical diagnosis of Marfan syndrome (Ambry Genetics ClinVarentry) and in two unrelated individuals with thoracic aortic aneurysm and/or dissection (PMID 37042257, 33059708) (PS4). This variant is not present in gnomAD(PM2_sup; https://gnomad.broadinstitute.org/). This variant is located in a non-repeat region in a cbEGF-like domain of the protein (PM4). The variant in FBN1 has been reported three times in ClinVar as likely pathogenic (Variation ID: 549178). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM4, PM2_Sup, PP1, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA658824437/MONDO:0007947/022 2023-09-28 2023-09-28 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:41977 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C3665347 infores:hetionet CAID:CA040509 biolink:causes MONDO:0008667 infores:clingen CAID:CA040509 MONDO:0008667 PMID: Uncertain Significance PVS1_Strong PS4, BS1 NM_000551.4(VHL):c.341-25_370dup is a 55bp tandem duplication that contains part of the intron between Exon 1 and contains AA115-124 of Exon 2 (chr3:10,146,489-10,146,543, hg38). This is is presumed to disrupt the reading frame as well as add intronic sequence to the coding region, and results in an early truncation 26 amino acids downstream. This region is predicted to undergo Nonsense Mediated Decay. (PVS1_Strong). One of three commercial laboratories reports 1 case with this variant, and the case does not harbor VHL spectrum tumors. One academic laboratory reports 1 case with this variant. Case 1 (0.5 points) : a proband with pheochromocytoma, father and sibling both had RCC (but their VHL variant status is not confirmed). (PS4_NotMet). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.000001830 (6/1179074 from European, Non-Finnish Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of <=0.0000156 (0.00156%) for BS1, and therefore does not meet any population criterion (BS1, BA1, PM2_Supporting are not met). In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). VHL VCEP https://erepo.genome.network/evrepo/ui/classification/CA040509/MONDO:0008667/078 2024-06-25 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:71223 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0013604 infores:hetionet CAID:CA229759 biolink:causes MONDO:0009861 infores:clingen CAID:CA229759 MONDO:0009861 PMID:26666653PMID:26666653 Pathogenic PM5, PM2, PP3, PP4, PM3_Strong The PAH c.782G>C (p.Arg261Pro) variant has been reported in multiple affected individuals (PMID: 26666653, Bh4 deficiency not ruled out, PP4). It has been detected with 5 known pathogenic variants (PM3_S). It is absent from ExAC/gnomAD. Computational evidence supports a deleterious effect. Also, p.R261Q is interpreted as pathogenic. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_S, PM2, PM5, PP4, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229759/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports NCBITaxon:2104 biolink:causes MONDO:0005867 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2104 MESH:D011019 DB01155_MESH_D011019_1DB01059_MESH_D011019_1DB01208_MESH_D011019_1DB00207_MESH_D011019_1DB00199_MESH_D011019_1DB02703_MESH_D011019_1DB00254_MESH_D011019_1DB01165_MESH_D011019_1DB01044_MESH_D011019_1DB00218_MESH_D011019_1DB00685_MESH_D011019_1DB09335_MESH_D011019_1DB00954_MESH_D011019_1DB00976_MESH_D011019_1 CHEBI:36795 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0011603 infores:hetionet CHEBI:3077 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0002453 infores:hetionet NCBIGene:57531 biolink:causes MONDO:0014764 infores:monarchinitiative not_provided not_provided HGNC:21033 MONDO:0014764 uuid:694bae60-db8c-4600-adbc-c457da26e579 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9907 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0036974 infores:hetionet CHEBI:47381 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151736 infores:hetionet CHEBI:6538 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C2047937 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0015967 infores:hetionet UMLS:C0065374 biolink:causes UMLS:C0750197 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0750197 infores:hetionet CHEBI:5280 biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0013491 infores:hetionet CHEBI:7903 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0009782 infores:hetionet CHEBI:50742 biolink:causes UMLS:C3536683 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C3536683 infores:hetionet CHEBI:85078 biolink:causes HP:0001899 infores:sider not_provided not_provided DRUGBANK:DB06292 UMLS:C0239935 infores:hetionet CAID:CA001969 biolink:causes MONDO:0011450 infores:clingen CAID:CA001969 MONDO:0011450 PMID: Benign BP7_Strong, BS1_Supporting, BP5_Strong, BS3 PP3 The c.301+7G>A variant is an intronic variant occurring in intron 5 of the BRCA1 gene. The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00009711 in the European (non-Finnish) population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.21, predicting an impact on splicing (score threshold >0.20) (however, this prediction is to strengthen the native acceptor site and therefore PP3 is not applied). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30209399) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 4.848E-11 (based on Cosegregation LR=1.36; Pathology LR=0.001; Co-occurrence LR=0.068; Family History LR=0.037; Case-Control LR=1.28E-05), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP7_Strong (RNA), BS3, BP5_Very strong). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA001969/MONDO:0011450/092 2024-06-12 2024-06-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8863 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0042109 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0025061 infores:hetionet CAID:CA167218 biolink:causes MONDO:0007648 infores:clingen CAID:CA167218 MONDO:0007648 PMID: Likely Benign BS2, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PVS1, PM6, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2 The c.223T>C (p.Phe75Leu) missense variant has a frequency of 0.000003977 (1 of 251,418) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.000008795 (1 of 113,700) in the Non-Finnish European population (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_supporting, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA167218/MONDO:0007648/007 2023-08-18 2023-08-18 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:52717 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0236000 infores:hetionet CAID:CA10581615 biolink:causes MONDO:0010726 infores:clingen CAID:CA10581615 MONDO:0010726 PMID: Likely Pathogenic PM2_Supporting, PS4_Moderate, PS2 The p.Pro217Leu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in 2 individuals with neurodevelopmental disorders (PMID: 27824329, LabCorp) (PS2). The p.Pro217Leu variant has been observed in individuals with neurodevelopmental disorders (PMID: 27824329, LabCorp, Invitae internal database) (PS4_moderate). The p.Pro217Leu in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro217Leu variant in MECP2 is classified as likely pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PS4_moderate, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10581615/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Supports CHEBI:6367 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0020433 infores:hetionet CHEBI:49575 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C2242737 infores:hetionet CHEBI:63631 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C3665386 infores:hetionet CHEBI:3127 biolink:causes HP:0002093 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0035229 infores:hetionet CHEBI:5280 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0020578 infores:hetionet CHEBI:47898 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0035333 infores:hetionet CHEBI:6715 biolink:causes MONDO:0006696 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0007869 infores:hetionet GO:2000800 biolink:causes GO:0003179 infores:ubergraph knowledge_assertion manual_agent GO:2000800 GO:0003179 CHEBI:404903 biolink:causes UMLS:C1096049 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C1096049 infores:hetionet CHEBI:3508 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0030554 infores:hetionet CHEBI:5775 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0080274 infores:hetionet CHEBI:5383 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0233494 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0233632 infores:hetionet CHEBI:8890 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0034150 infores:hetionet CAID:CA8337840 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337840 MONDO:0008723 PMID: Likely Benign BP4, BS1 PP4 The c.753-27C>T variant in ACADVL is an intronic variant which occurs in intron 8. The highest population minor allele frequency in gnomAD v4.1 is 0.0036 in non-Finnish European population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.14 for acceptor loss suggesting that the variant has no impact on splicing (BP4). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 27246109). This variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4. (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337840/MONDO:0008723/021 2024-09-24 2024-09-24 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9288 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00428 UMLS:C0151539 infores:hetionet CHEBI:23765 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0220870 infores:hetionet CHEBI:8764 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0031154 infores:hetionet CHEBI:68579 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0234215 infores:hetionet CHEBI:50861 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0020649 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0002638 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C1510431 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0518015 infores:hetionet CHEBI:17347 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002871 infores:hetionet CHEBI:5778 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0549622 infores:hetionet CHEBI:5134 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0042769 infores:hetionet CHEBI:78543 biolink:causes NCIT:C83492 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0743400 infores:hetionet CHEBI:4470 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00514 UMLS:C0687713 infores:hetionet CHEBI:27732 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0009450 infores:hetionet CHEBI:5141 biolink:causes MONDO:0005832 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0024225 infores:hetionet GO:2000311 biolink:causes GO:0035235 infores:ubergraph knowledge_assertion manual_agent GO:2000311 GO:0035235 CAID:CA190198 biolink:causes MONDO:0100488 infores:clingen CAID:CA190198 MONDO:0100488 PMID: Benign BS1, BS2 PM2, BA1 The c.2638G>A (p.Glu880Lys) variant results in a missense change in the last exon of CDH1. This variant has been reported in at least five individuals meeting criteria for HDGC (PMID: 28522256, 32426482, 34537906, 32241597). However, this variant is present at a maximum frequency of 0.001153 (6 of 5,204 alleles) in the East Asian subpopulation in gnomAD, which is greater than expected for CDH1-related diffuse gastric and lobular breast cancer (BS1). This variant has also been observed in 112 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant is classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA190198/MONDO:0100488/007 2023-09-25 2023-09-27 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:68478 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0026858 infores:hetionet CHEBI:474180 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0011168 infores:hetionet CAID:CA382515111 biolink:causes MONDO:0700270 infores:clingen CAID:CA382515111 MONDO:0700270 PMID: Pathogenic PM2_Supporting, PM3_Strong, PM5_Supporting, PVS1 The c.3102T>G (p.Tyr1034Ter) variant in ATM is a nonsense variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent from gnomAD v.2.1.1. This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID: 26896183, 18321536, 33547824). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_strong, PM2_supporting , PM5_supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA382515111/MONDO:0700270/020 2024-01-24 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75722 biolink:causes UMLS:C0278008 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0278008 infores:hetionet CHEBI:31981 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0344232 infores:hetionet CHEBI:7915 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C2830004 infores:hetionet CHEBI:75722 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0227791 infores:hetionet CHEBI:17549 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0151505 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0009938 infores:hetionet CHEBI:5779 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0015230 infores:hetionet NCBIGene:1756 biolink:causes MONDO:0010542 infores:monarchinitiative not_provided not_provided HGNC:2928 MONDO:0010542 uuid:1f586edb-2c03-447b-b87d-f508fc3288e8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8774 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0022660 infores:hetionet CHEBI:41774 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0002453 infores:hetionet CHEBI:8080 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0012833 infores:hetionet CHEBI:68558 biolink:causes UMLS:C0241742 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0241742 infores:hetionet CHEBI:63115 biolink:causes MONDO:0003005 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0271051 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0232492 infores:hetionet CHEBI:31348 biolink:causes NCIT:C121616 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0406834 infores:hetionet GO:0099150 biolink:causes GO:0007416 infores:ubergraph knowledge_assertion manual_agent GO:0099150 GO:0007416 CAID:CA10568231 biolink:causes MONDO:0010602 infores:clingen CAID:CA10568231 MONDO:0010602 PMID: Benign BA1 PP3, BP4 The c.3280G>A variant in F8 is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 1094 (p.Glu1094Lys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001817 (27/14858 alleles) with 9 hemizygotes in the East Asian population, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.000333) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP (version 1.0.0, released 10/5/2023): BA1. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA10568231/MONDO:0010602/071 2025-03-10 2025-03-28 X-linked inheritance HP:0001417 Contradicts true CHEBI:82960 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0947999 infores:hetionet CHEBI:116278 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0002878 infores:hetionet CHEBI:9649 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C3665347 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009319 infores:hetionet CHEBI:8024 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0234215 infores:hetionet CHEBI:116278 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1306341 infores:hetionet CHEBI:5778 biolink:causes HP:0030834 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0037011 infores:hetionet CHEBI:29013 biolink:causes UMLS:C0038166 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0038166 infores:hetionet CHEBI:68647 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0235416 infores:hetionet CAID:CA377482258 biolink:causes MONDO:0017623 infores:clingen CAID:CA377482258 MONDO:0017623 PMID:29706350 Likely Pathogenic PP2, PP3, PS3_Moderate, PM2_Supporting, PM5 PP4, PP1, PS4 PTEN c.355G>T (p.Val119Phe) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.07 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350).PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 3256748).PP3: REVEL score > 0.7 (score of this variant = 0.966).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PM2_P: Absent in large sequenced populations (PMID 27535533). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA377482258/MONDO:0017623/003 2025-04-04 2025-05-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71255 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0038362 infores:hetionet CHEBI:3640 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0002878 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151883 infores:hetionet CHEBI:3655 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00356 UMLS:C0011603 infores:hetionet CHEBI:119573 biolink:causes NCIT:C107499 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0221423 infores:hetionet CHEBI:63620 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0004093 infores:hetionet UMLS:C0657912 biolink:causes HP:0003565 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151632 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0011053 infores:hetionet CHEBI:184555 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0020458 infores:hetionet CHEBI:7936 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0027849 infores:hetionet UMLS:C1709429 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0232462 infores:hetionet GO:0048328 biolink:causes GO:0048318 infores:ubergraph knowledge_assertion manual_agent GO:0048328 GO:0048318 CHEBI:15552 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0007859 infores:hetionet CHEBI:61390 biolink:causes HP:0005162 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0242698 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027813 infores:hetionet CHEBI:135929 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0027424 infores:hetionet CHEBI:92712 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0011168 infores:hetionet CHEBI:9586 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020458 infores:hetionet CHEBI:28001 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0038325 infores:hetionet CHEBI:6706 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C1258215 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027441 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006014 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0700345 infores:hetionet CHEBI:48669 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0037763 infores:hetionet CHEBI:8707 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0004134 infores:hetionet CHEBI:4858 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0236000 infores:hetionet CHEBI:4514 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0338831 infores:hetionet CHEBI:63605 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0017181 infores:hetionet UMLS:C0025241 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0008031 infores:hetionet CHEBI:3699 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0029221 infores:hetionet CHEBI:68554 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0028738 infores:hetionet CHEBI:8707 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0026826 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003725 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C1305875 infores:hetionet CAID:CA512318645 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318645 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.501T>C (p.Ser167=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.03) and evolutionary conservation algorithms predict the site as being not conserved (PhyloP score ≤ 2.0 (0.40) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318645/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8890 biolink:causes HP:0001998 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0158986 infores:hetionet CHEBI:94449 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0028738 infores:hetionet CHEBI:3515 biolink:causes UMLS:C0581879 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0581879 infores:hetionet NCBIGene:10516 biolink:causes MONDO:0013751 infores:monarchinitiative not_provided not_provided HGNC:3602 MONDO:0013751 uuid:ac4414d1-4c76-4c12-a0cb-a22c126df573 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63632 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0002871 infores:hetionet CAID:CA250432 biolink:causes MONDO:0700272 infores:clingen CAID:CA250432 MONDO:0700272 PMID: Pathogenic PS4, PP1_Strong, PM5_Supporting, PVS1 PS3, BS1, PM2 The c.1592del (p.L531Cfs*30) variant in PALB2 is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [HR 6.1 (95% CI 2.2-17.2, p = 0.01)] (PMID: 18628482). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. The variant has been reported to segregate with breast cancer in 6 affected family members from three families (Ambry Genetics and Invitae). The minor allele frequency in gnomAD v2.1.1 is 0.001871 in the Finnish population; however, this variant known to be a Finnish founder mutation thus explaining the higher than expected population frequency (PM2_Supporting, BS1, and BA1 are not met; PMID: 17287723). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PS4, PP1_Strong, PM5_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA250432/MONDO:0700272/077 2022-09-15 2025-09-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8863 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0034065 infores:hetionet CHEBI:18243 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00988 UMLS:C0030252 infores:hetionet CHEBI:681569 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0085631 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0151565 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0151565 infores:hetionet CHEBI:63791 biolink:causes UMLS:C0235889 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235889 infores:hetionet NCBIGene:30009 biolink:causes MONDO:0030483 infores:monarchinitiative not_provided not_provided HGNC:11599 MONDO:0030483 uuid:945bbe4c-62b7-4bf2-85ff-6cd8665639f4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4702 biolink:causes MONDO:0007935 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0024440 infores:hetionet CHEBI:5118 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151603 infores:hetionet CHEBI:3614 biolink:causes MONDO:0002507 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0017566 infores:hetionet CAID:CA10588623 biolink:causes MONDO:0007648 infores:clingen CAID:CA10588623 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.1354_1357delCTAC p.(Leu452fs) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10588623/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:8869 biolink:causes MONDO:0010811 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C1704272 infores:hetionet CHEBI:16335 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0002994 infores:hetionet CHEBI:9137 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0039240 infores:hetionet CHEBI:8481 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00782 UMLS:C0027497 infores:hetionet CHEBI:9588 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0836924 infores:hetionet CAID:CA152961 biolink:causes MONDO:0015967 infores:clingen CAID:CA152961 MONDO:0015967 PMID: Pathogenic PS4, PP1_Strong, PP4_Moderate, PP2, PM2_Supporting PS3, PP3, BP4 The c.787T>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to proline at codon 263 (p.(Ser263Pro)) of NM_000162.5. This variant was identified in at least 14 unrelated individuals with hyperglycemia (PS4; PMID: 32074423, internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.80e-7, which is below the threshold for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant segregated with diabetes/hyperglycemia, with at least 21 informative meioses in 9 families (PP1_Strong; PMID: 32074423, internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant has a REVEL score of 0.689, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and while the variant appears to result in thermal instability, the relative stability index was not calculated, therefore PS3_Supporting will not be applied (PMID: 16731834).In summary, c.787T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PM2_Supporting, PP1_Strong, PP2, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA152961/MONDO:0015967/086 2025-06-27 2025-06-27 Semidominant inheritance HP:0032113 Supports CHEBI:9123 biolink:causes HP:0030014 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C1112442 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0857093 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0857093 infores:hetionet CHEBI:6438 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0038454 infores:hetionet CHEBI:37941 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0031117 infores:hetionet CHEBI:3738 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0013395 infores:hetionet CHEBI:119573 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0520573 infores:hetionet CHEBI:84500 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0039231 infores:hetionet CHEBI:4784 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0009763 infores:hetionet NCBIGene:3141 biolink:causes MONDO:0009666 infores:monarchinitiative not_provided not_provided HGNC:4976 MONDO:0009666 uuid:1b87dc72-ca70-4c06-9ce6-c0c7548b516d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:194135 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0013604 infores:hetionet CHEBI:5118 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014724 infores:hetionet CHEBI:31236 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042029 infores:hetionet CHEBI:5165 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0034880 infores:hetionet CHEBI:2663 biolink:causes HP:0002925 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0586553 infores:hetionet CHEBI:553473 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0002874 infores:hetionet CHEBI:72564 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0013456 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0948594 infores:hetionet CHEBI:7824 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0497156 infores:hetionet CHEBI:6339 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0026858 infores:hetionet CHEBI:6541 biolink:causes MONDO:0001134 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0085580 infores:hetionet CAID:CA6748747 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748747 MONDO:0009861 PMID: Likely Pathogenic PM2, PM3, PP3, PP4 PS3 The c.1074A>T (p.Leu358Phe) variant in PAH meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Variant is present at low frequency in gnomAD (0.0000) and ExAC (0.00002). Absent from 1000 Genomes. PM3: Found to co-occur with F331S in one patient with mild HPA, but no additional studies to demonstrate phase of variants (PMID: 23764561). Found to co-occur with other non-PKU HPA mutation I306V, phase was not confirmed (PMID: 23357515). Found to co-occur in two patients with L348V and R408W with mild and classic PKU, respectively. (PMID: 24350308) PP3: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). PP4: In both studies, patients were recruited for their abnormal Phelevels defined as HPA <600umol or 120-600umol. There was no additional testing done to rule out other similar analyte disorders. PS3_Not Met: Functional studies in E. Coli model used and relative specific activity of L358F is 52+-0.7%, which is above our 50% threshold to apply this line of evidence. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748747/MONDO:0009861/006 2021-07-25 2021-07-25 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63608 biolink:causes MONDO:0007015 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0025297 infores:hetionet NCBIGene:2778 biolink:causes MONDO:0020735 infores:monarchinitiative not_provided not_provided HGNC:4392 MONDO:0020735 uuid:9db55eae-70b0-41ff-906c-06d4eb2f373b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45924 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0162429 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0022660 infores:hetionet NCBIGene:79645 biolink:causes MONDO:0957991 infores:monarchinitiative not_provided not_provided HGNC:25678 MONDO:0957991 uuid:89fd68af-f2b3-47b0-9943-c842d46a742b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10102 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0015967 infores:hetionet NCBITaxon:5579 biolink:causes MONDO:0001867 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5579 MONDO:0001867 CHEBI:35677 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C1291077 infores:hetionet CHEBI:45409 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0013456 infores:hetionet CHEBI:36795 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0001807 infores:hetionet CHEBI:291342 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0042109 infores:hetionet CHEBI:51364 biolink:causes MONDO:0000190 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0042510 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005794 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019372 infores:hetionet CHEBI:8768 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0042963 infores:hetionet CAID:CA229553 biolink:causes MONDO:0009861 infores:clingen CAID:CA229553 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PM2_Supporting, PM5_Supporting PP4 The c.451G>C (p.Asp151His) variant in PAH is reported in a phenylketonuria cohort of the British Isles (PMID: 9012412). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect (REVEL=0.977). Another missense variant [c.452A>G (p.Asp151Gly)] in the same codon has been classified as likely pathogenic for phenylketonuria by the ClinGen Phenylketonuria Variant Curation Expert Panel (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PM5_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229553/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:41423 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0011849 infores:hetionet CHEBI:39669 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00861 UMLS:C0033774 infores:hetionet CHEBI:46081 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0007222 infores:hetionet CHEBI:52172 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013456 infores:hetionet CHEBI:3696 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0151747 infores:hetionet CHEBI:3223 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0027424 infores:hetionet UNII:15G12L5X8K biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0018991 infores:hetionet GO:0061187 biolink:causes GO:0007000 infores:ubergraph knowledge_assertion manual_agent GO:0061187 GO:0007000 CHEBI:135925 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01255 UMLS:C0015397 infores:hetionet CHEBI:80630 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0006826 infores:hetionet CHEBI:3568 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0338831 infores:hetionet CHEBI:6715 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0009676 infores:hetionet CHEBI:28148 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0011603 infores:hetionet CHEBI:6339 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0232487 infores:hetionet CHEBI:7565 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0037199 infores:hetionet CAID:CA410206729 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206729 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.769A>G (p.Thr257Ala) is a missense variant which has a REVEL score < 0.50 (0.317), and a SpliceAI score ≤ 0.20 (0.02) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206729/MONDO:0011071/008 2024-09-16 2024-09-16 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0051988 biolink:causes GO:0098813 infores:ubergraph knowledge_assertion manual_agent GO:0051988 GO:0098813 CHEBI:37924 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0242339 infores:hetionet NCBIGene:50489 biolink:causes MONDO:0013251 infores:monarchinitiative not_provided not_provided HGNC:17935 MONDO:0013251 uuid:14726b87-326c-45d0-a0a1-527dd108e450 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes UMLS:C0156181 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0156181 infores:hetionet UMLS:C0004609 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0027497 infores:hetionet CAID:CA16608536 biolink:causes MONDO:0100083 infores:clingen CAID:CA16608536 MONDO:0100083 PMID:23817177 Likely Pathogenic PM1_Supporting, PS3, PM2_Supporting, PS4_Supporting, PP3 PS2, PS1, BA1, BP1, BP4, BP3, BP2, BP7, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM5, PM3, PP2, PP1, PP4, BS2 NM_001754.5(RUNX1):c.280A>C (p.Ser94Arg) is located within the RUNT homology domain but not within a mutational hotspot (PM1_supporting). Transactivation assays demonstrate reduced transactivation (<20% of wild-type) and data from a beta-heterodimerization assay demonstrate loss of beta-heterodimerization (PS3; unpublished data and PMID: 23817177). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000389962.2). This missense variant has a REVEL score ≥ 0.88 (0.947) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PS4_supporting, PM2_supporting, PP3, PM1_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16608536/MONDO:0100083/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:10112 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0020517 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0877365 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0877365 infores:hetionet NCBIGene:26580 biolink:causes MONDO:0014402 infores:monarchinitiative not_provided not_provided HGNC:15832 MONDO:0014402 uuid:9546ab49-dda7-4e5d-9aa4-8748fd28bc8f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA16020877 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020877 MONDO:0009861 PMID:22526846 Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.868C>T (p.His290Tyr) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded) detected in trans with p.R408E (Pathogenic in ClinVar; PP4_Moderate, PM3; PMID: 22526846). This variant is absent in population databases (PM2). Computational evidence suggests a damaging effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020877/MONDO:0009861/006 2019-08-11 2019-08-11 Autosomal recessive inheritance HP:0000007 Supports CHEBI:724125 biolink:causes MONDO:0005096 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0007137 infores:hetionet CAID:CA1244297 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244297 MONDO:0005338 PMID: Likely Benign BP7, BP4 BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BA1 The c.309C>T variant in MYOC is a synonymous variant (p.Thr103=). The highest minor allele frequency of this variant was in the South Asian genetic ancestry group of gnomAD (v4.1.0) = 0.0009349 (85 alleles out of 90,922), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The SpliceAI score = 0, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, BP7. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244297/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:144551 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0013144 infores:hetionet CHEBI:28593 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0019080 infores:hetionet CHEBI:7478 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0085606 infores:hetionet CAID:CA4239418 biolink:causes MONDO:0015967 infores:clingen CAID:CA4239418 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5, PP2, PP3, PP4, PM2_Supporting The c.1189C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 397 (p.(Arg397Cys)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, another missense variant, c.1190G>T p.(Arg397Leu) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg397Cys has a greater Grantham distance. (PM5). Taken together, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PS4_Moderate, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA4239418/MONDO:0015967/086 2023-09-08 2023-09-08 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4735 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0740394 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0033246 infores:hetionet CHEBI:50742 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0013390 infores:hetionet CHEBI:9168 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0016204 infores:hetionet CAID:CA2017997774 biolink:causes MONDO:0015967 infores:clingen CAID:CA2017997774 MONDO:0015967 PMID: Pathogenic PVS1, PP4_Moderate, PM2_Supporting PS4, PP1 The c.1339dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 12 novel amino acids before encountering a stop codon (p.(Arg447ProfsTer12)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a three generation family history of diabetes) (PP4_Moderate, internal lab contributor). While this variant was identified in one individual with diabetes, this does not meet the MDEP cutoff for PS4_Moderate. Additionally, this variant segregated with disease with one informative meiosis in this individual's family, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, the c.1339dup variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023x): PVS1, PP4_Moderate, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2017997774/MONDO:0015967/086 2023-06-25 2023-06-25 Semidominant inheritance HP:0032113 Supports CHEBI:4911 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0018799 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0020676 infores:hetionet CHEBI:38940 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0917801 infores:hetionet CHEBI:63608 biolink:causes MONDO:0005025 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0014118 infores:hetionet CHEBI:72690 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0004936 infores:hetionet CHEBI:9943 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0231218 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0267792 infores:hetionet CHEBI:5004 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0542184 infores:hetionet CHEBI:9907 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0007642 infores:hetionet CHEBI:4681 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00204 UMLS:C0030252 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0424000 infores:hetionet CHEBI:6541 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0009676 infores:hetionet CHEBI:9939 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0002792 infores:hetionet CHEBI:5893 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0006384 infores:hetionet CHEBI:68478 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0221776 infores:hetionet CAID:CA346367589 biolink:causes MONDO:0021060 infores:clingen CAID:CA346367589 MONDO:0021060 PMID: Uncertain Significance PS3_Supporting, PP2, PP3, PS4_Supporting, PM2_Supporting BA1, BS1, PM1, PP1 The NM_005633.4:c.844T>C variant in SOS1 is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 282 (p.Cys282Arg). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational prediction tool REVEL gives a score of 0.741 suggesting that this variant may impact protein function (PP3). It has been reported in two probands with a RASopathy (PS4_Supporting; GeneDx, ClinVar SCV001986888.2; Harvey Institute for Human Genetics internal data). In vitro functional studies showed that this variant increased EGF-dependent MAPK activation in amplitude and duration compared to wild-type (PS3_Supporting; PMID: 17339331). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathy based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 1/10/2025). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA346367589/MONDO:0021060/041 2025-01-10 2025-09-26 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3219 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0026837 infores:hetionet CHEBI:3387 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0028961 infores:hetionet CHEBI:5138 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020443 infores:hetionet CHEBI:9241 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0020461 infores:hetionet CHEBI:7931 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0006142 infores:hetionet CHEBI:71255 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0020649 infores:hetionet CHEBI:6904 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0003467 infores:hetionet UNII:G4PX8C4HKV biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0009421 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C2830004 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0040034 infores:hetionet CHEBI:42797 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020456 infores:hetionet CHEBI:23765 biolink:causes MONDO:0005886 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0006849 infores:hetionet CHEBI:4975 biolink:causes MONDO:0003037 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0020678 infores:hetionet CAID:CA10539080 biolink:causes MONDO:0018947 infores:clingen CAID:CA10539080 MONDO:0018947 PMID: Benign BA1, BP4, BP7 PP3, BS1, PM2 The variant NM_000252.3:c.339T>C in MTM1 is a synonymous (silent) variant (p.Cys113=). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.003242 (198/54107 alleles, 58 hemizygotes) in African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). In addition, SpliceAI does not predict impact to splicing, and the variant occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10539080/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:91541 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0027765 infores:hetionet CHEBI:17303 biolink:causes UMLS:C1610069 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C1610069 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0403632 infores:hetionet CHEBI:68579 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C1861172 infores:hetionet UMLS:C0120107 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0314719 infores:hetionet CHEBI:47612 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0687713 infores:hetionet CAID:CA16020917 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020917 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PM5, PP3, PM3_Supporting The c.998T>C (p.Leu333Pro) variant in PAH has been reported in individuals with PAH deficiency, detected with p.Pro281Leu (Likely pathogenic by PAH VCEP variation ID: 589) with exclusion of BH4 deficiency (PMID: 19394257). In-vitro functional studies are unavailable. This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. A different pathogenic missense change at the same codon, p.Leu333Phe is pathogenic (by PAH VCEP). In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PM5, PM3_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020917/MONDO:0009861/006 2022-03-13 2022-04-16 Autosomal recessive inheritance HP:0000007 Supports UNII:F64QU97QCR biolink:causes UMLS:C0392176 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0392176 infores:hetionet CHEBI:31859 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0031212 infores:hetionet CAID:CA254838 biolink:causes MONDO:0044970 infores:clingen CAID:CA254838 MONDO:0044970 PMID:9012410 Uncertain Significance PM2_Supporting, PS3_Supporting PP3, PP1, PS4, PS2, PM6 The m.12320A>G variant in MT-TL2 has been reported in one individual with primary mitochondrial disease to date (PMID: 9012410), in a woman with progressive myopathy, acidosis, ptosis, and ragged red and COX-negative fibers on muscle biopsy. The variant was present at 70% heteroplasmy in muscle on first biopsy and was found to be present at 90% on subsequent biopsy, coinciding with a 12-year progression in symptoms. There is no report of her family members being testing and there are no additional reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 37.3%; HmtVAR: 0.7). Single fiber testing showed higher levels of the variant in COX-negative fibers (88-96%) compared to COX positive fibers (60-88%; PMID: 9450773; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254838/MONDO:0044970/015 2024-04-22 2024-11-20 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:194135 biolink:causes HP:0002783 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0149725 infores:hetionet CHEBI:50131 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0007971 infores:hetionet CHEBI:5280 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0004134 infores:hetionet CHEBI:74947 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0278134 infores:hetionet CHEBI:567361 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0030312 infores:hetionet UMLS:C0657912 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0391870 infores:hetionet CHEBI:3478 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C1257843 infores:hetionet CHEBI:7823 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00842 UMLS:C0013604 infores:hetionet CHEBI:10650 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0031542 infores:hetionet CAID:CA10585134 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585134 MONDO:0007750 PMID: Pathogenic PM5_Strong, PP1_Moderate, PM2, PP3, PP4 BA1, BP1, BP4, BP2, BP3, PS1, PS3, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP1_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_Strong - 4 other missense variants in the same codon:- NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines,- NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely pathogenic by these guidelines,- NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines,- NM_000527.5(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines.There are 2 variants in the same codon classified as Pathogenic by these guidelines;PM2 - This variant is absent from gnomAD (gnomAD v2.1.1);PP1_Moderate - 5 informative meioses published in PMID 11196104.PP3 – REVEL = 0.97;PP4 - Variant meets PM2. Identified in 1 FH case fulfilling MEDPED criteria published in PMID 11196104. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585134/MONDO:0007750/013 2022-05-05 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:63791 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004096 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0012833 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0027765 infores:hetionet CHEBI:9649 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0004245 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0032285 infores:hetionet NCBIGene:9096 biolink:causes MONDO:0027676 infores:monarchinitiative not_provided not_provided HGNC:11595 MONDO:0027676 uuid:4c452556-12a4-4200-95df-acc7b8a6c540 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6775 biolink:causes UMLS:C0852922 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0852922 infores:hetionet CHEBI:119573 biolink:causes MONDO:0100010 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151936 infores:hetionet CHEBI:2639 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0012833 infores:hetionet CHEBI:52717 biolink:causes HP:0004386 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C1535950 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0151735 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0151735 infores:hetionet CHEBI:9445 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0242350 infores:hetionet GO:1902872 biolink:causes GO:0060042 infores:ubergraph knowledge_assertion manual_agent GO:1902872 GO:0060042 CHEBI:9667 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0018800 infores:hetionet CHEBI:45599 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0151529 infores:hetionet CHEBI:3699 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00501 UMLS:C0003862 infores:hetionet CHEBI:3506 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0424605 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0595877 infores:hetionet CHEBI:10101 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0237849 infores:hetionet CHEBI:8802 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0428977 infores:hetionet CHEBI:82960 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0003467 infores:hetionet CHEBI:8382 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0162835 infores:hetionet CHEBI:9168 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0039070 infores:hetionet CHEBI:63618 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0028084 infores:hetionet CHEBI:31236 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0027441 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0003569 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0010266 infores:hetionet CHEBI:2611 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0011603 infores:hetionet CHEBI:8412 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0018681 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0947999 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0947999 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0948594 infores:hetionet CHEBI:6950 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0028738 infores:hetionet CAID:CA409104024 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104024 MONDO:0015967 PMID: Likely Pathogenic PP4_Moderate, PP3, PM2_Supporting, PM1 The c.221G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to tyrosine at codon 74 (p.(Cys74Tyr)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with a clinical history highly specific for HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and large for gestational age in the absence of sufficient maternal hyperglycemia) (PP4_Moderate; internal lab contributor). This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein's function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.221G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4_Moderate, PM1, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104024/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CAID:CA404080622 biolink:causes MONDO:0007750 infores:clingen CAID:CA404080622 MONDO:0007750 PMID: Uncertain Significance PM2, PP3 BA1, BP4, BP3, BP2, PS3, PS4, PS2, PS1, BS1, BS3, BS4, PM4, PM1, PM3, PM5, PM6, PVS1, PP1, PP4, BS2 The NM_000527.5(LDLR):c.845T>C (p.Phe282Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.985. It is above 0.75, so PP3 is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA404080622/MONDO:0007750/013 2023-04-28 2023-04-30 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:7936 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019214 infores:hetionet CHEBI:2682 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151908 infores:hetionet CHEBI:29688 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0005779 infores:hetionet CAID:CA000387 biolink:causes MONDO:0018875 infores:clingen CAID:CA000387 MONDO:0018875 PMID: Pathogenic PS3, PS2, PS4, PM1, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting BP4, BA1, PS1, PM5, BS3, BS1, BS4, BS2 The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000387/MONDO:0018875/009 2024-08-05 2024-08-05 Autosomal dominant inheritance HP:0000006 Supports CHEBI:75722 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151539 infores:hetionet GO:1902627 biolink:causes GO:0042254 infores:ubergraph knowledge_assertion manual_agent GO:1902627 GO:0042254 CHEBI:3723 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0003467 infores:hetionet CHEBI:50648 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0314719 infores:hetionet CHEBI:41774 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0022408 infores:hetionet CHEBI:15367 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0424323 infores:hetionet CHEBI:2038 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0231528 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0017152 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0151824 infores:hetionet CAID:CA343724527 biolink:causes MONDO:0020367 infores:clingen CAID:CA343724527 MONDO:0020367 PMID: Uncertain Significance PM5_Supporting, PP3, PM2_Supporting BS1, BS3, BP7, PM6, PP1, PM4, PS1, PS4, PS3, PS2, BA1, BP4 The c.1150G>C variant in MYOC is a missense variant predicted to cause substitution of Aspartate by Histidine at amino acid 384 (p.Asp384His). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.977, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma (JOAG) had been reported (PMID: 29540704), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1150G>A, p.Asp384Asn, Grantham score = 23, ClinVar ID: 1342205) in the same codon has been classified as likely pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1150G>C, p.Asp384His, PMID: 29540704 variant has a higher Grantham score (= 81) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting, PM5_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343724527/MONDO:0020367/019 2023-07-05 2023-07-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4995 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0023530 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0035258 infores:hetionet CHEBI:10124 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0033774 infores:hetionet NCBITaxon:10310 biolink:causes MONDO:0043653 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10310 MESH:D006560 DB00787_MESH_D006560_1DB00577_MESH_D006560_1 NCBITaxon:5658 biolink:causes MONDO:0011989 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:5658 MESH:D007896 DB00681_MESH_D007896_1 CHEBI:10127 biolink:causes UMLS:C0281774 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0281774 infores:hetionet CHEBI:171719 biolink:causes UMLS:C0151555 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151555 infores:hetionet CHEBI:17347 biolink:causes UMLS:C1610049 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C1610049 infores:hetionet CHEBI:2639 biolink:causes MONDO:0001711 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0019151 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0012833 infores:hetionet CHEBI:7465 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0022107 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0234215 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0016479 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0016479 infores:hetionet CHEBI:7565 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0026821 infores:hetionet CHEBI:9137 biolink:causes MONDO:0002155 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0008325 infores:hetionet CHEBI:7640 biolink:causes MONDO:0004568 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0030446 infores:hetionet UMLS:C0023610 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0017178 infores:hetionet CHEBI:6339 biolink:causes UMLS:C1263855 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C1263855 infores:hetionet CHEBI:27777 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0027769 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0855242 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0852733 infores:hetionet CHEBI:51380 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0009806 infores:hetionet CHEBI:3423 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0006840 infores:hetionet CHEBI:63584 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0000731 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0020701 infores:hetionet CHEBI:9927 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0021053 infores:hetionet NCBIGene:6092 biolink:causes MONDO:0012573 infores:monarchinitiative not_provided not_provided HGNC:10250 MONDO:0012573 uuid:2ccda6c8-1c19-4722-bca8-33b2105a0990 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5855 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0026821 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002531 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0037286 infores:hetionet CAID:CA137972 biolink:causes MONDO:0021060 infores:clingen CAID:CA137972 MONDO:0021060 PMID: Benign BA1, BP4, BP5 PP3, BS1, PM2 The c.844C>T variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by serine at amino acid 282 (p.Pro282Ser). The filtering allele frequency in gnomAD v2.1.1 is 0.001415 (42/22756 alleles) in the African/African American population, meeting the criterion for BA1. The computational predictor REVEL gives a score of 0.072, which predicts no impact on protein function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID's 26957; SCV000207963.8). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5 (Specification Version 2.3, 12/3/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137972/MONDO:0021060/048 2024-12-03 2025-03-31 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63638 biolink:causes MONDO:0004922 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0011757 infores:hetionet CHEBI:3732 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0015397 infores:hetionet CAID:CA312289 biolink:causes MONDO:0008723 infores:clingen CAID:CA312289 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP1, PVS1_Moderate, PM3_Supporting, PP4_Moderate PM1 The c.1806_1807del (p.Leu602_Cys603insTer) variant in ACADVL is a frameshift variant that may cause loss of function of the protein due to impacting FAD interaction; however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_moderate). Two siblings with this variant displayed C14:1 levels >0.8 µM, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP1, PP4_moderate; PMID: 27209629). These same individuals were heterozygous for this variant and the pathogenic frameshift variant c.1173dup which was not confirmed to be in trans (PM3_supporting; PMID: 27209629). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_moderate, PP4_moderate, PM3_supporting, PP1, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312289/MONDO:0008723/021 2025-03-31 2025-03-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4858 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0948594 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0042109 infores:hetionet CHEBI:6715 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0751295 infores:hetionet CHEBI:7936 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023518 infores:hetionet CHEBI:65173 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0027424 infores:hetionet CHEBI:61033 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0017178 infores:hetionet CHEBI:8107 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0020578 infores:hetionet CHEBI:17263 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0002994 infores:hetionet CHEBI:5790 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0026821 infores:hetionet CHEBI:61033 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0035078 infores:hetionet CHEBI:42797 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0019080 infores:hetionet CHEBI:37333 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00225 UMLS:C0014724 infores:hetionet CHEBI:6717 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0016204 infores:hetionet CHEBI:10124 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0003578 infores:hetionet CHEBI:5280 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0038160 infores:hetionet CHEBI:83804 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0744727 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0042109 infores:hetionet CHEBI:71272 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB06335 UMLS:C0021051 infores:hetionet CHEBI:63589 biolink:causes NCIT:C86024 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0234238 infores:hetionet CHEBI:51141 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0029408 infores:hetionet CHEBI:6775 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0011206 infores:hetionet CHEBI:15428 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0030193 infores:hetionet CHEBI:63629 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0042023 infores:hetionet CHEBI:5106 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0162429 infores:hetionet CHEBI:83804 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C1443060 infores:hetionet CHEBI:68478 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0009763 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0038999 infores:hetionet CHEBI:119915 biolink:causes UMLS:C1112257 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C1112257 infores:hetionet CHEBI:8869 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0006444 infores:hetionet CHEBI:3696 biolink:causes HP:0001433 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0019214 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005649 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0003615 infores:hetionet NCBIGene:3242 biolink:causes MONDO:0007700 infores:monarchinitiative not_provided not_provided HGNC:5147 MONDO:0007700 uuid:d6a673b9-4608-43c6-9a5e-afb7c1302ec4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17698 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0687133 infores:hetionet CHEBI:8884 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00728 UMLS:C0006266 infores:hetionet CHEBI:135935 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0041969 infores:hetionet CAID:CA016051 biolink:causes MONDO:0021056 infores:clingen CAID:CA016051 MONDO:0021056 PMID: Benign BS2, BP1, BS1 PM2 The c.995G>A variant in APC is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 332 (p.Arg332Gln). This variant has been observed in heterozygous state in >100 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). The allele frequency of the c.995G>A variant in APC is 0.02% for the African sub-population (5/23604 alleles) in the non-cancer dataset from gnomAD (v2.1.1), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.001%) for BS1, and therefore meets BS1. APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA016051/MONDO:0021056/089 2023-02-18 2023-03-14 Autosomal dominant inheritance HP:0000006 Contradicts true GO:0048378 biolink:causes GO:0048369 infores:ubergraph knowledge_assertion manual_agent GO:0048378 GO:0048369 CHEBI:17026 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C1443060 infores:hetionet CHEBI:68584 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0012569 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0032584 infores:hetionet UNII:3U02EL437C biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0241136 infores:hetionet CHEBI:6367 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0010692 infores:hetionet CHEBI:40279 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C3665347 infores:hetionet CHEBI:2663 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0151766 infores:hetionet CAID:CA891862634 biolink:causes MONDO:0009861 infores:clingen CAID:CA891862634 MONDO:0009861 PMID:21147011PMID:18299955PMID:21147011PMID:18299955 Pathogenic PVS1, PP4_Moderate, PM2, PM3_Strong The PAH: c.47_48dupCT variant is a frameshift variant occurring in exon 1 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). The variant has been previously reported in trans with the known pathogenic L48S allele in 1 Israeli case with classic PKU (PMID: 18299955; PMID: 18294361) as assessed by plasma Phe levels; BH4 deficiency was excluded. It was also noted in 3 Turkish probands: in two, it was found in trans with the p.R243X allele, and in one, it was found in trans with the p.R261Q allele (PMID: 21147011); all three cases had classic as assessed by plasma Phe levels and BH4 deficiency was excluded by genetic testing. Thus PM3_Strong and PP4_Moderate apply. It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA891862634/MONDO:0009861/006 2019-02-26 2019-08-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:77733 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0232487 infores:hetionet CHEBI:87715 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0543467 infores:hetionet CHEBI:135530 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C1384353 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0007254 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0006142 infores:hetionet CHEBI:27999 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01124 UMLS:C0020615 infores:hetionet CHEBI:63619 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0151904 infores:hetionet CHEBI:7581 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0013362 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0857353 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0857353 infores:hetionet CHEBI:10127 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0085631 infores:hetionet CHEBI:16796 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0041657 infores:hetionet CHEBI:63681 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0037763 infores:hetionet CHEBI:47519 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0085636 infores:hetionet CHEBI:61058 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0267792 infores:hetionet CHEBI:5062 biolink:causes MONDO:0005339 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0162311 infores:hetionet UMLS:C0120107 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0032285 infores:hetionet CHEBI:63631 biolink:causes MONDO:0001330 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0033075 infores:hetionet CHEBI:5775 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01275 UMLS:C0009763 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0080276 infores:hetionet CHEBI:51364 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0235660 infores:hetionet CHEBI:28445 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0013604 infores:hetionet CHEBI:5118 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0027066 infores:hetionet CHEBI:116278 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0392525 infores:hetionet CHEBI:74947 biolink:causes MONDO:0002708 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0035333 infores:hetionet CHEBI:10650 biolink:causes HP:0025637 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0085616 infores:hetionet CHEBI:6741 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0547030 infores:hetionet CHEBI:8665 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0041657 infores:hetionet CAID:CA412361958 biolink:causes MONDO:0100039 infores:clingen CAID:CA412361958 MONDO:0100039 PMID: Likely Benign BS2_Supporting, BP4 BS1, PP4, PM2, PS4 The highest population minor allele frequency of the p.Thr538Ala variant in CDKL5 in gnomAD v4.1 is 0.000004468 in the Non-Finnish European population (not sufficient to meet BS1 criteria). The p.Thr538Ala variant is observed in at least 1 unaffected individual (Internal database - Ambry Genetics) (BS2_Supporting). The computational predictor REVEL gives a score of 0.214, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). In summary, the p.Thr538Ala variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2_Supporting, BP4). (CDKL5 Specifications v.4.1; curation approved on 06/25/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412361958/MONDO:0100039/034 2025-06-25 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:134991 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0020458 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0852928 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0852928 infores:hetionet CHEBI:4653 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0013378 infores:hetionet CHEBI:5134 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0014591 infores:hetionet CHEBI:3568 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0039520 infores:hetionet CHEBI:50841 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0344232 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001187 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0005684 infores:hetionet CHEBI:63620 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C2979982 infores:hetionet CHEBI:38940 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0042963 infores:hetionet CHEBI:9073 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00418 UMLS:C2830004 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0948594 infores:hetionet CHEBI:48844 biolink:causes HP:0012050 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0151603 infores:hetionet CHEBI:75922 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0920171 infores:hetionet CHEBI:5147 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0027441 infores:hetionet NCBIGene:84100 biolink:causes MONDO:0013312 infores:monarchinitiative not_provided not_provided HGNC:13210 MONDO:0013312 uuid:9c617697-41b4-4eac-8c6b-b36ea628d44c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3752 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0011991 infores:hetionet CAID:CA913177641 biolink:causes MONDO:0044970 infores:clingen CAID:CA913177641 MONDO:0044970 PMID: Uncertain Significance PP1, BP4, PS4_Moderate PS3, PM2 The m.4296G>A variant in MT-TI has been reported in four individuals with primary mitochondrial disease (PMIDs: 21982779, 23288206, 23395828, 31564700; PS4_moderate). Affected individuals had Leigh syndrome, encephalopathy, parkinsonism, dysarthria, clumsiness, seizures, cognitive decline, peripheral neuropathy, feeding difficulty, lethargy, respiratory insufficiency, hypogonadism, and diabetes. The variant was present at heteroplasmy levels between 78% and homoplasmy in blood and skin fibroblasts. The variant was present at <5% in blood, cheek cells, and urine sediment from one individual’s asymptomatic mother and sister (PMID: 21982779), and was present at lower heteroplasmy levels (4-58%) in two additional mothers (PMIDs: 23288206, 23395828) and between 1.4-31.6% in an asymptomatic sister (PMID: 23288206; PP1). This variant was also seen in an individual at 2% heteroplasmy who also had a single large scale mitochondrial DNA deletion at 64% heteroplasmy (PMID: 31965079). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there are 10 heteroplasmic occurrences in the Helix dataset. MitoTIP predicts the variant is possibly benign (46.6 percentile) and HmtVAR predicts the variant is neutral (score of 0.3; BP4). There are no single fiber studies or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, BP4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913177641/MONDO:0044970/015 2024-09-24 2025-11-06 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:8871 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0235146 infores:hetionet CHEBI:6078 biolink:causes NCIT:C157435 infores:sider not_provided not_provided DRUGBANK:DB00602 UMLS:C0856054 infores:hetionet CHEBI:6916 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0011168 infores:hetionet CHEBI:17347 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0002962 infores:hetionet CAID:CA10539132 biolink:causes MONDO:0018947 infores:clingen CAID:CA10539132 MONDO:0018947 PMID: Benign BP4, BA1, BP7 PP3, BS1, PM2 The variant NM_000252.3(MTM1):c.582C>T is a synonymous (silent) variant (p.Leu194=). The filtering allele frequency in gnomAD v4.1.0 is 0.002821 (112/33731 alleles, 2 homozygote, 36 hemizygotes) for the East Asian population, which is higher than the ClinGen congenital myopathy MTM1 threshold (≥0.000016) for BA1, and therefore meets this criterion (BA1). In addition, SpliceAI predicted no impact on splicing, meeting BP4/BP7 criteria. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA10539132/MONDO:0018947/149 2024-08-07 2024-10-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:4708 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0684249 infores:hetionet CHEBI:64312 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0008031 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151849 infores:hetionet CHEBI:7507 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0041834 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0027765 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0004096 infores:hetionet CAID:CA343718087 biolink:causes MONDO:0005338 infores:clingen CAID:CA343718087 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.518G>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Threonine at amino acid 173 (p.Ser173Thr). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.213, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: 39998747), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343718087/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:353116 biolink:causes MONDO:0030712 infores:monarchinitiative not_provided not_provided HGNC:26814 MONDO:0030712 uuid:7c5cb1cc-6f9a-4c65-9821-2dc63523d44b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32315 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0017178 infores:hetionet CHEBI:28830 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0015672 infores:hetionet CHEBI:6367 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0025222 infores:hetionet CHEBI:100241 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0030196 infores:hetionet CHEBI:9086 biolink:causes MONDO:0002443 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0006325 infores:hetionet NCBIGene:1302 biolink:causes MONDO:0008490 infores:monarchinitiative not_provided not_provided HGNC:2187 MONDO:0008490 uuid:62d3ce70-20b7-4473-ae24-039b1cd2978b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0220870 infores:hetionet CHEBI:7476 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0018932 infores:hetionet CHEBI:3077 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0018790 infores:hetionet CHEBI:5002 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0000737 infores:hetionet CHEBI:3568 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0030252 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C3263723 infores:hetionet CHEBI:3752 biolink:causes MONDO:0019773 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0025312 infores:hetionet CAID:CA8815176 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815176 MONDO:0009290 PMID: Uncertain Significance PP3, PM2_Supporting, PM5_Supporting PP4, PM3, PS3 The NM_000152.5:c.1123 C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 375 (p.Arg375Cys). This variant has been detected in seven individuals with abnormal newborn screening. Six patients with this variant had documented GAA deficiency with activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant (3 patients with c.-32-13T>G and with c.670C>T) and 3 of those were confirmed in trans by family testing (PMID: 36246652, internal laboratory). One individual was homozygous for the variant and another was compound heterozygous for the variant and c.2005_2010del (p.Pro669_Phe670del) (confirmed in trans) (PMID: 40981304), not yet classified by the VCEP. However, all patients were detected through abnormal newborn screening and there is no evidence of symptoms or diagnosis of Pompe disease. Therefore PM3 and PP4 will not be applied. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001208 (11/91062 alleles)in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1124G>T (p.Arg375Leu) (PMIDs: 24158270, 22081099) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). Expression of the variant in HEK293 cells showed 11.7% GAA enzyme activity. However, this assay does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP because this percentage is above the cut off established by the assay (11%) to be considered deficient enzyme activity. There is a ClinVar entry for this variant (Variation ID: 290225). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_Supporting, PM5_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases VCEP on October 28, 2025 Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815176/MONDO:0009290/010 2025-10-28 2025-10-28 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:63617 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0001122 infores:hetionet CHEBI:8310 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00781 UMLS:C0030193 infores:hetionet UMLS:C0657912 biolink:causes HP:0000966 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0553721 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0040479 infores:hetionet CHEBI:4356 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0036454 infores:hetionet CHEBI:3419 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0030312 infores:hetionet CHEBI:6339 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0038362 infores:hetionet CHEBI:4877 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00330 UMLS:C0012833 infores:hetionet CHEBI:4856 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C1306341 infores:hetionet GO:0070173 biolink:causes GO:0097186 infores:ubergraph knowledge_assertion manual_agent GO:0070173 GO:0097186 CHEBI:44185 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0014742 infores:hetionet NCBIGene:4330 biolink:causes MONDO:0011789 infores:monarchinitiative not_provided not_provided HGNC:7180 MONDO:0011789 uuid:5dbe22dc-6d26-4279-9b89-b9a0dfb004d0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:32293 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0042571 infores:hetionet CHEBI:3647 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0575081 infores:hetionet CHEBI:144093 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0009676 infores:hetionet GO:1905304 biolink:causes GO:0072359 infores:ubergraph knowledge_assertion manual_agent GO:1905304 GO:0072359 CHEBI:28445 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0018799 infores:hetionet CHEBI:194135 biolink:causes UMLS:C1565662 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1565662 infores:hetionet NCBIGene:8471 biolink:causes MONDO:0026732 infores:monarchinitiative not_provided not_provided HGNC:6128 MONDO:0026732 uuid:78be0faa-baa6-4ff0-8c36-3224d9d2cce1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10101 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0856151 infores:hetionet CHEBI:5855 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0018939 infores:hetionet CHEBI:17141 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0029453 infores:hetionet CHEBI:9137 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0080274 infores:hetionet CHEBI:50131 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C0007642 infores:hetionet CHEBI:45081 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0700225 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0162429 infores:hetionet CHEBI:6916 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0002170 infores:hetionet CHEBI:5778 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0030193 infores:hetionet CHEBI:63613 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0151763 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0262397 infores:hetionet CHEBI:391960 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0039070 infores:hetionet CHEBI:101853 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0004936 infores:hetionet CHEBI:142290 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0025222 infores:hetionet CHEBI:135351 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0040264 infores:hetionet CHEBI:6402 biolink:causes MONDO:0005079 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0032584 infores:hetionet CHEBI:3568 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020621 infores:hetionet CHEBI:29688 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0036974 infores:hetionet CHEBI:92998 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0006145 infores:hetionet CHEBI:82960 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0851341 infores:hetionet CHEBI:63598 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0019348 infores:hetionet CHEBI:68606 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0012833 infores:hetionet CHEBI:29013 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0023530 infores:hetionet NCBIGene:79001 biolink:causes MONDO:0011837 infores:monarchinitiative not_provided not_provided HGNC:23663 MONDO:0011837 uuid:323950e3-8c87-4243-a5e6-e02301bbed25 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA2918507 biolink:causes MONDO:0015152 infores:clingen CAID:CA2918507 MONDO:0015152 PMID: Pathogenic PM2_Supporting, PVS1_Moderate, PM3_Strong, PP4_Strong The NM_000232.5: c.85A>T p.(Arg29Ter) variant in SGCB is a nonsense variant that may cause loss of function of the protein. However, the premature stop encoded by this variant occurs within the first 100 base pairs, and the resulting transcript may escape nonsense mediated decay. The next in-frame methionine is at amino acid 100, and non-truncating variants upstream of this alternative start site are classified as likely pathogenic or pathogenic (c.265G>A p.(Val89Met), c.271C>T p.(Arg91Cys)) (PVS1_Moderate). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy (PMID: 11369190, 17994539, 25862795), including confirmed in trans with a likely pathogenic or pathogenic variant (c.377_384dup p.(Gly128GlnfsTer2), 1.0 pt; c.271C>T p.(Arg91Cys), 1.0 pt; PMID: 17994539, 25862795, 11369190) (PM3_Strong). At least one patient with this variant showed progressive limb girdle muscle weakness and absent or severely reduced expression of β-sarcoglycan protein in skeletal muscle, which is highly specific for SGCB-related LGMD (PP4_Strong; PMID: 25862795). The highest minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113756 exome chromosomes), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2918507/MONDO:0015152/184 2025-01-09 2025-01-09 Autosomal recessive inheritance HP:0000007 Supports GO:0055024 biolink:causes GO:0007507 infores:ubergraph knowledge_assertion manual_agent GO:0055024 GO:0007507 CHEBI:85161 biolink:causes UMLS:C0012359 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0012359 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0033775 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0033775 infores:hetionet CHEBI:10650 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0392699 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0025061 infores:hetionet CHEBI:7915 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0020580 infores:hetionet CHEBI:41423 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0003811 infores:hetionet CHEBI:3423 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0344232 infores:hetionet CHEBI:64355 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0042594 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0023895 infores:hetionet CHEBI:8382 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0015397 infores:hetionet CHEBI:27882 biolink:causes MONDO:0100130 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0035222 infores:hetionet UMLS:C1872203 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB06663 UMLS:C0020621 infores:hetionet CHEBI:367163 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C1384353 infores:hetionet CHEBI:3219 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C3665347 infores:hetionet CHEBI:47898 biolink:causes HP:0001877 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0391870 infores:hetionet CHEBI:6888 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0026946 infores:hetionet CHEBI:2636 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB01143 UMLS:C0162297 infores:hetionet CHEBI:8764 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0018939 infores:hetionet CHEBI:2675 biolink:causes UMLS:C0426584 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0426584 infores:hetionet CHEBI:9598 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0000737 infores:hetionet CHEBI:681848 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0003811 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151625 infores:hetionet CHEBI:44241 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0027765 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0860866 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0860866 infores:hetionet CHEBI:63617 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0017160 infores:hetionet CHEBI:3640 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00880 UMLS:C0349506 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0030807 infores:hetionet CHEBI:91541 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0002622 infores:hetionet CHEBI:8461 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0023530 infores:hetionet CHEBI:82981 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0003862 infores:hetionet CHEBI:46081 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0085631 infores:hetionet CHEBI:71941 biolink:causes NCIT:C50743 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0152030 infores:hetionet CHEBI:63791 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0699744 infores:hetionet CHEBI:27432 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00132 UMLS:C0151904 infores:hetionet CHEBI:6539 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0020625 infores:hetionet CHEBI:9649 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0085614 infores:hetionet CHEBI:6970 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0043352 infores:hetionet CHEBI:3061 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0018801 infores:hetionet CAID:CA2801882 biolink:causes MONDO:0001586 infores:clingen CAID:CA2801882 MONDO:0001586 PMID: Uncertain Significance PP3_Moderate, PM2_Supporting PM3, PM5, PP4 The NM_000203.5:c.355G>T variant in IDUA is a missense variant predicted to cause substitution of aspartate by tyrosine at amino acid 119 (p.Asp119Tyr). Four infants with this variant were identified by newborn screening, GAG testing was either negative, or 2-D EP results showed a distinct dermatan sulfate but a faint heparan sulfate pattern in the 2 affected infants and another (carrier suspected) was normal. (PMID: 33578874, PMID: 37516270, PMID: 29801497). Insufficient evidence to apply PP4. These infants were compound heterozygous for the variant and another variant in IDUA. For one of these infants, the second variant confirmed in trans is benign based on classification by the LD VCEP, c.99T>G (p.H33Q) (ClinVarID:92651). For the remaining infants, the second variants were c.767T>C (p.L256P) (ClinVarID:92648) and c.617C>T (p.S206L) (ClinVarID:1436435). These variants have not yet been classified by the LD VCEP. PM3 not met. The highest population minor allele frequency in gnomAD v4.1.0 is 0.000067 (3/44896 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.89 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). SpliceAI predicts that the variant has no impact on splicing (all scores <0.1). There is a ClinVar entry for this variant (ClinVarID: 2432701). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for MPS I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_supporting, PP3_moderate(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 6, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2801882/MONDO:0001586/091 2025-10-06 2025-10-17 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:367163 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0000737 infores:hetionet NCBIGene:1497 biolink:causes MONDO:0009064 infores:monarchinitiative not_provided not_provided HGNC:2518 MONDO:0009064 uuid:723ac415-1055-4cf4-a79c-9cc3eaab1d9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:R43D2573WO biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0438717 infores:hetionet CHEBI:8382 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0009806 infores:hetionet CHEBI:39585 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0236075 infores:hetionet CHEBI:63621 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0021368 infores:hetionet CHEBI:473990 biolink:causes MONDO:0007256 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C2239176 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0021925 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0040586 infores:hetionet CHEBI:63599 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0002792 infores:hetionet CHEBI:4702 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0011603 infores:hetionet CHEBI:209807 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01331 UMLS:C0423791 infores:hetionet CHEBI:681848 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0001925 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0021053 infores:hetionet CHEBI:27882 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01394 UMLS:C0151904 infores:hetionet CHEBI:8707 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027424 infores:hetionet UMLS:C0011701 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C1142412 infores:hetionet NCBIGene:6687 biolink:causes MONDO:0011803 infores:monarchinitiative not_provided not_provided HGNC:11237 MONDO:0011803 uuid:4ef79b2a-165a-4191-a536-c21b593b9ac9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:826 biolink:causes MONDO:0958334 infores:monarchinitiative not_provided not_provided HGNC:1481 MONDO:0958334 uuid:34af049e-bc4a-49dc-88e3-99ddb9427796 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49713 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0428977 infores:hetionet GO:0090178 biolink:causes GO:0021915 infores:ubergraph knowledge_assertion manual_agent GO:0090178 GO:0021915 CHEBI:135736 biolink:causes UMLS:C1096708 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1096708 infores:hetionet CHEBI:7601 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0855242 infores:hetionet CAID:CA226853 biolink:causes MONDO:0010725 infores:clingen CAID:CA226853 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4 The NM_000330.4(RS1):c.76G>T variant is a nonsense variant in amino acid 26, which results in a premature stop codon and causes a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male with diagnosis of X-linked retinoschisis (PMIDs: 9618178). However, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1 and PM2_supporting (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226853/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:7936 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0036508 infores:hetionet CHEBI:45327 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00194 UMLS:C0278134 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0031117 infores:hetionet CHEBI:16469 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0030252 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0521839 infores:hetionet CAID:CA409108855 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108855 MONDO:0015967 PMID: Likely Pathogenic PP3, PM2_Supporting, PS3 PP4, PP1, PM1, PS1 The c.1063G>C variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is predicted to cause an amino acid change of glycine to arginine at codon 355 (p.(Gly355Arg) in transcript NM_175914.5, however splicing prediction and minigene assay show that the c.1063G>C is a splicing variant resulting in transcripts with frame-shift and premature termination codon. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant has a REVEL score of 0.637, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. However, the computational splicing predictor SpliceAI gives a score of 0.94 for donor loss, predicting that this variant, located in the last nucleotide of exon 8, disrupts the donor site for intron 8 of HNF4A (PP3 met for splicing predictor). There is evidence from RNA and in silico studies that this non-canonical splicing variant results in aberrant splicing, indicating that this variant impacts protein function (ClinVar submission from Dept of Medical Genetics, AP-HP Sorbonne University, Pitié-Salpêtrière hospital - Accession: SCV004037073.1) (PS3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information. Moreover, this variant segregated with diabetes with one informative meiosis in this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP [internal lab contributor, the same case as in ClinVar Accession SCV004037073.1 and PMID: 31291970]. The nucleotide change c.1063G>A, which causes the same amino acid change and is also located in the last nucleotide of exon 8, is predicted to disrupt the donor site for intron 8 of HNF4A with a lower prediction value for donor loss by SpliceAI (0.66) in comparison to c.1063G>C (0.94), and the c.1063G>A variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.1063G>C meets the criteria to be classified as likely pathogenic (LP) for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PS3, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108855/MONDO:0015967/085 2024-11-21 2024-11-21 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7824 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0006266 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0233472 infores:hetionet CHEBI:6801 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0040822 infores:hetionet CAID:CA410206855 biolink:causes MONDO:0011071 infores:clingen CAID:CA410206855 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.708G>A (p.Met236Ile) is a missense variant which has a REVEL score < 0.50 (0.444) and a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410206855/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:Y2V2R4W9TQ biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0009806 infores:hetionet CHEBI:9398 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0011606 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0152227 infores:hetionet CHEBI:6367 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0028734 infores:hetionet CHEBI:10650 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0001807 infores:hetionet GO:1900032 biolink:causes GO:0090558 infores:ubergraph knowledge_assertion manual_agent GO:1900032 GO:0090558 CAID:CA414445922 biolink:causes MONDO:0010604 infores:clingen CAID:CA414445922 MONDO:0010604 PMID: Likely Pathogenic PM2_Supporting, PS4, PP3 PM5 The F9 c.1106T>C, p.Leu369Pro is completely absent from gnomAD v2.1.1 and v3.1.2, meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.948 and has a SpliceAI score of 0, meeting PP3 criteria (>=0.6). This variant has been reported in 5 probands meeting phenotypic criteria for hemophilia B (PS4_moderate; EAHAD Database, PMID: 31064749, PMID: 19699296). In summary, this variant meets the criteria to be classified as likely pathogenic for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP ClinGen Coagulation Factor Deficiency VCEP F9 (version 1.0.0, released 10/5/2023): PS4, PM2_Supporting, PP3. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414445922/MONDO:0010604/080 2025-08-15 2025-08-21 X-linked inheritance HP:0001417 Supports NCBIGene:9427 biolink:causes MONDO:0014028 infores:monarchinitiative not_provided not_provided HGNC:3147 MONDO:0014028 uuid:ac4b99b4-e2c4-46b0-aca2-764dc1b03851 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52010 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0040034 infores:hetionet CHEBI:75984 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C1510410 infores:hetionet CHEBI:17823 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0020538 infores:hetionet NCBIGene:4038 biolink:causes MONDO:0014578 infores:monarchinitiative not_provided not_provided HGNC:6696 MONDO:0014578 uuid:2824d17d-faf6-4474-a6da-f8364742fa82 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4710 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0006145 infores:hetionet CHEBI:64310 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0011991 infores:hetionet CAID:CA410205635 biolink:causes MONDO:0011071 infores:clingen CAID:CA410205635 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, PVS1, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.97G>T (p.Asp33Tyr) is a missense variant which has a SpliceAI score ≥ 0.38 (Donor Loss = 0.90) and is predicted to impact splicing (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410205635/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68579 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0015230 infores:hetionet CHEBI:50885 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0015300 infores:hetionet CHEBI:3696 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0542571 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0013985 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0013985 infores:hetionet CAID:CA296061 biolink:causes MONDO:0009026 infores:clingen CAID:CA296061 MONDO:0009026 PMID: Uncertain Significance BP4 PS4, BS1, PM2, PP2, PP3, BS2, BA1 The c.277A>G variant in the HRAS gene is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 93 (p.Ile93Val). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0002053% (2/63238 alleles) in the European (Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.141 and does not predict a damaging effect on HRAS function (BP4). The c.277A>G (p.Ile93Val) variant has been identified in 1 patient with a features of a RASopathy, however an additional proband inherited this variant from an asymptomatic parent (PS4_Supporting not met, BS2 not met; GeneDx internal data, Blueprint Genetics internal data; GTR ID's: 26957, 500188; ClinVar SCV000207855.10, SCV000188770.2). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 09/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296061/MONDO:0009026/046 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:168396 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0020461 infores:hetionet CHEBI:71940 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0003862 infores:hetionet CHEBI:3207 biolink:causes MONDO:0001531 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0005779 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0002622 infores:hetionet CHEBI:5128 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0948594 infores:hetionet CHEBI:32315 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0151315 infores:hetionet CAID:CA401370359 biolink:causes MONDO:0009290 infores:clingen CAID:CA401370359 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM3, PM2_Supporting The NM_000152.5:c.2055C>A (p.Tyr685Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 15 out of 20 total exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 2 individuals with late-onset Pompe disease who were both compound heterozygous for the variant and another variant that has been classified as pathogenic by the ClinGen LD VCEP, c.-32-13T>G (ClinVar Variation ID: 4027) (PMIDs 39879733, 17643989) (PM3, PP4). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1322965). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, August 31, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA401370359/MONDO:0009290/010 2025-08-31 2025-09-16 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:2639 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0855242 infores:hetionet CHEBI:9907 biolink:causes MONDO:0001795 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0042548 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0086543 infores:hetionet CHEBI:71219 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0016204 infores:hetionet NCBIGene:27034 biolink:causes MONDO:0012648 infores:monarchinitiative not_provided not_provided HGNC:87 MONDO:0012648 uuid:c0579ee1-9339-46b3-8fb7-f428d79e15ef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3082 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C3665386 infores:hetionet CHEBI:17823 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0438142 infores:hetionet CHEBI:47499 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0011603 infores:hetionet CAID:CA367398315 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398315 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PM1, PP2, PP3, PP4, PM2_Supporting The c.1228G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 410 (p.(Gly410Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 34406393, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with hyperglycemia, with 5 informative meioses in 1 family (PP1_Strong; internal lab contributors). In summary, c.1228G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PM1, PS4_Moderate, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398315/MONDO:0015967/086 2024-06-21 2024-06-21 Semidominant inheritance HP:0032113 Supports CHEBI:194135 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0028961 infores:hetionet CHEBI:9943 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002792 infores:hetionet CHEBI:49662 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0013395 infores:hetionet CHEBI:2637 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0018681 infores:hetionet CAID:CA002845 biolink:causes MONDO:0018875 infores:clingen CAID:CA002845 MONDO:0018875 PMID: Pathogenic PS3, PS2, PM1, PP3, PP1, PS4_Supporting, PM2_Supporting BA1, BP4, BP2, PS1, PM5, BS1, BS3, PM6, PP4, BS2 The NM_000546.6: c.329G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 110 (p.Arg110Leu). This variant has been reported in 3 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 30875412; Internal lab contributors). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 4 phenotype points (PS2; Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal contributors). This variant has an allele frequency of 0.000001240 (2/1612260 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has [XX] somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.213246; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS3, PM1, PP1, PP3, PM2_Supporting, PS4_Supporting. (Bayesian Points: 14; VCEP specifications version 2.3) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA002845/MONDO:0018875/009 2025-06-05 2025-07-18 Autosomal dominant inheritance HP:0000006 Supports NCBITaxon:5722 biolink:causes MONDO:0030707 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:5722 MONDO:0030707 NCBIGene:311 biolink:causes MONDO:0850514 infores:monarchinitiative not_provided not_provided HGNC:535 MONDO:0850514 uuid:89f29c28-e7dd-494b-876c-ff13b4434a9f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:6658 biolink:causes MONDO:0010252 infores:monarchinitiative not_provided not_provided HGNC:11199 MONDO:0010252 uuid:07464aa4-e0b9-4b7d-9794-a302a6b1c08c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3756 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0015397 infores:hetionet CHEBI:94686 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0016204 infores:hetionet CHEBI:83804 biolink:causes MONDO:0019771 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C2242577 infores:hetionet CHEBI:8430 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0015230 infores:hetionet CHEBI:50275 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0030554 infores:hetionet CAID:CA396470014 biolink:causes MONDO:0007648 infores:clingen CAID:CA396470014 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP7, BP5, BS1, BS3, BS4, PM4, PM1, PM3, PM6, BS2, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS4, PS1, PS3, PS2 The c.2272G>T (p.Lys758Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA396470014/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:135961 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C1306341 infores:hetionet CHEBI:45783 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C2830004 infores:hetionet CHEBI:53691 biolink:causes MONDO:0007008 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0041948 infores:hetionet GO:0045466 biolink:causes CL:0000707 infores:ubergraph knowledge_assertion manual_agent GO:0045466 CL:0000707 CHEBI:41774 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0016658 infores:hetionet CHEBI:4975 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0043352 infores:hetionet NCBIGene:7471 biolink:causes MONDO:0014086 infores:monarchinitiative not_provided not_provided HGNC:12774 MONDO:0014086 uuid:066693fb-c356-48fb-bb99-6dd6617284cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0000737 infores:hetionet CHEBI:135888 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0162835 infores:hetionet CHEBI:7601 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00585 UMLS:C0016204 infores:hetionet UNII:15G12L5X8K biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0005758 infores:hetionet CHEBI:6931 biolink:causes HP:0002305 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0004158 infores:hetionet CHEBI:4027 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0034065 infores:hetionet CHEBI:47657 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0018932 infores:hetionet CHEBI:55346 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0424790 infores:hetionet CHEBI:681848 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C2939147 infores:hetionet CHEBI:42355 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0014742 infores:hetionet CHEBI:3568 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0014866 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001697 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0476254 infores:hetionet CHEBI:47426 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C1306341 infores:hetionet CHEBI:41774 biolink:causes MONDO:0004717 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0030781 infores:hetionet CHEBI:72564 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0041912 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0235416 infores:hetionet NCBITaxon:2 biolink:causes MONDO:0006669 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:2 MESH:D004697 DB01053_MESH_D004697_1DB01598_MESH_D004697_1DB01597_MESH_D004697_1DB00916_MESH_D004697_1DB01327_MESH_D004697_1 CHEBI:3696 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0160390 infores:hetionet CHEBI:499361 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0041657 infores:hetionet CHEBI:31980 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB00556 UMLS:C0155626 infores:hetionet CHEBI:6916 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0220870 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0015230 infores:hetionet CHEBI:48390 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0016655 infores:hetionet CHEBI:6073 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C1443060 infores:hetionet CHEBI:9570 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0085692 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0002622 infores:hetionet CHEBI:3387 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0549567 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0015397 infores:hetionet CHEBI:9332 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01015 UMLS:C0151773 infores:hetionet CHEBI:71255 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0042963 infores:hetionet CHEBI:3077 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0022107 infores:hetionet CHEBI:50156 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB09015 UMLS:C0020461 infores:hetionet CHEBI:63618 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C3263723 infores:hetionet CHEBI:3723 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0476280 infores:hetionet CHEBI:5784 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00774 UMLS:C0740394 infores:hetionet CHEBI:40279 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0278134 infores:hetionet CHEBI:100241 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0014457 infores:hetionet CHEBI:8871 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0393760 infores:hetionet CHEBI:49375 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C2937358 infores:hetionet CHEBI:42944 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0037274 infores:hetionet CHEBI:45367 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0015230 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0235969 infores:hetionet CAID:CA384899215 biolink:causes MONDO:0010880 infores:clingen CAID:CA384899215 MONDO:0010880 PMID: Uncertain Significance PP3, PM2_Supporting, PS4_Supporting The NM_000020.3: c.500C>G variant in ACVRL1 is a missense variant predicted to cause substitution of serine by cysteine at amino acid 167 (p.Ser167Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in a proband with a phenotype consistent of HHT (PS4_Supporting; PMID: 32300199, Internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.84 for donor loss, predicting that the variant disrupts the donor splice site of intron 4 of ACVRL1 (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting, PP3 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA384899215/MONDO:0010880/135 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true NCBIGene:1807 biolink:causes MONDO:0009111 infores:monarchinitiative not_provided not_provided HGNC:3013 MONDO:0009111 uuid:deb35e67-d8ac-4a5f-9fa1-6b514e2fc795 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8382 biolink:causes HP:0025383 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0520573 infores:hetionet NCBIGene:84695 biolink:causes MONDO:0030697 infores:monarchinitiative not_provided not_provided HGNC:13869 MONDO:0030697 uuid:3c3f2a60-d498-4140-9b6a-ea46b8891249 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3077 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0018802 infores:hetionet CHEBI:35677 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0018681 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0013595 infores:hetionet CHEBI:9566 biolink:causes UMLS:C0021167 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0021167 infores:hetionet CHEBI:119573 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0240671 infores:hetionet CHEBI:50223 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0042963 infores:hetionet CHEBI:41977 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C1443060 infores:hetionet CHEBI:9137 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0151636 infores:hetionet CHEBI:4511 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0009676 infores:hetionet CHEBI:5138 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0000731 infores:hetionet CHEBI:114785 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0010043 infores:hetionet CHEBI:46557 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0015967 infores:hetionet CHEBI:6444 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C0039231 infores:hetionet CHEBI:8707 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0007398 infores:hetionet CHEBI:63584 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0023380 infores:hetionet CHEBI:3515 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0151578 infores:hetionet CHEBI:51860 biolink:causes UMLS:C2363731 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C2363731 infores:hetionet CHEBI:2469 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB00718 UMLS:C0020461 infores:hetionet CHEBI:5103 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0030193 infores:hetionet CHEBI:55346 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0012833 infores:hetionet CHEBI:188986 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0162834 infores:hetionet CHEBI:4953 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0948594 infores:hetionet CHEBI:47780 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0004245 infores:hetionet CHEBI:100241 biolink:causes HP:0002901 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0020598 infores:hetionet CHEBI:63589 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0005758 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0856880 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0856880 infores:hetionet CHEBI:7640 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0855242 infores:hetionet CAID:CA2586965986 biolink:causes MONDO:0001586 infores:clingen CAID:CA2586965986 MONDO:0001586 PMID: Pathogenic PM3_Supporting, PP4_Moderate, PVS1, PM2_Supporting The NM_000203.5:c.1593delG (p.Leu532CysfsTer28) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 12 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One proband with the variant with clinical symptoms of MPS 1, elevated urinary heparan and dermatan sulfate and low IDUA enzyme activity (PP4_Moderate). The proband was compound heterozygous, phase unconfirmed, for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.2T>C (PMID: 21480867, 0.5 point). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PM3_Supporting, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 6, 2025) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2586965986/MONDO:0001586/091 2025-10-06 2025-10-17 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0011701 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0027765 infores:hetionet CHEBI:31547 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0018418 infores:hetionet CHEBI:8461 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB01069 UMLS:C0543467 infores:hetionet CHEBI:6402 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0037763 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0087169 infores:hetionet NCBIGene:53904 biolink:causes MONDO:0011774 infores:monarchinitiative not_provided not_provided HGNC:7601 MONDO:0011774 uuid:04d35001-43e6-4354-9a36-0aa200364512 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:114785 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0019158 infores:hetionet CHEBI:51173 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00647 UMLS:C0151763 infores:hetionet CHEBI:5855 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0014724 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0018799 infores:hetionet CHEBI:474053 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01327 UMLS:C0038362 infores:hetionet NCBIGene:84690 biolink:causes MONDO:0975842 infores:monarchinitiative not_provided not_provided HGNC:30705 MONDO:0975842 uuid:84347b6c-fde9-4e16-8378-48cb75c13280 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44915 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C2242996 infores:hetionet CHEBI:50924 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0038325 infores:hetionet CHEBI:8207 biolink:causes MONDO:0002245 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151854 infores:hetionet CHEBI:91834 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C1443060 infores:hetionet CHEBI:42820 biolink:causes UMLS:C0234192 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0234192 infores:hetionet CAID:CA024756 biolink:causes MONDO:0007783 infores:clingen CAID:CA024756 MONDO:0007783 PMID: Likely Pathogenic PM1, PS4_Moderate, PP3_Moderate BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of alanine with valine at codon 2437 of the RYR1 protein, p.(Ala2437Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:15448513, personal communication, Leeds MH Unit, MH Investigation Unit (MHIU), UHN, Toronto). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.917) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024756/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CAID:CA338255 biolink:causes MONDO:0007648 infores:clingen CAID:CA338255 MONDO:0007648 PMID: Uncertain Significance PM2_Supporting, PS4_Moderate BP7, BP5, BS1, BS4, BS3, PM1, PM3, PM5, PM4, PM6, PVS1, PP1, PP2, PP3, PP4, BS2, BP2, BP3, BP1, BP4, BA1, PS1, PS2, PS3 The c.1613A>T (p.Asp538Val) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; SCV000254814.3). In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Moderate. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA338255/MONDO:0007648/007 2023-08-21 2023-08-21 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:63580 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0030252 infores:hetionet CHEBI:63791 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042345 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0043352 infores:hetionet CHEBI:27786 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0015230 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0019360 infores:hetionet CHEBI:32020 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB08860 UMLS:C0020580 infores:hetionet CHEBI:15428 biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB00145 UMLS:C0220994 infores:hetionet CHEBI:15940 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0016204 infores:hetionet CHEBI:45409 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015672 infores:hetionet CHEBI:8107 biolink:causes UMLS:C1141936 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C1141936 infores:hetionet CHEBI:63791 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0003811 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0011053 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0221100 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0221100 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0242528 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0031350 infores:hetionet CHEBI:6539 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0034063 infores:hetionet NCBIGene:54756 biolink:causes MONDO:0014103 infores:monarchinitiative not_provided not_provided HGNC:17616 MONDO:0014103 uuid:ce2ed21e-8c73-43a3-b5b6-83783ae00d19 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63791 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0036983 infores:hetionet CHEBI:31711 biolink:causes HP:0031179 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0025287 infores:hetionet CHEBI:8502 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0015967 infores:hetionet CHEBI:8890 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C1142135 infores:hetionet CHEBI:2682 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0017574 infores:hetionet CHEBI:10650 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0020456 infores:hetionet CHEBI:31174 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0002994 infores:hetionet CHEBI:3176 biolink:causes UMLS:C0549209 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0549209 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0595930 infores:hetionet CHEBI:3082 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0011570 infores:hetionet CHEBI:9398 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0004093 infores:hetionet CHEBI:8378 biolink:causes MONDO:0003085 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0022568 infores:hetionet GO:2000785 biolink:causes GO:0016236 infores:ubergraph knowledge_assertion manual_agent GO:2000785 GO:0016236 CHEBI:9667 biolink:causes UMLS:C1302752 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C1302752 infores:hetionet CHEBI:35854 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0013390 infores:hetionet CHEBI:8232 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0041969 infores:hetionet CHEBI:32315 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0018834 infores:hetionet CHEBI:63616 biolink:causes MONDO:0043919 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0206063 infores:hetionet CHEBI:70735 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0851578 infores:hetionet CHEBI:4995 biolink:causes HP:0012211 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151746 infores:hetionet CHEBI:5134 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0003862 infores:hetionet CHEBI:3561 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0423791 infores:hetionet CHEBI:37941 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0085932 infores:hetionet CHEBI:3515 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0023530 infores:hetionet NCBIGene:367 biolink:causes MONDO:0010735 infores:monarchinitiative not_provided not_provided HGNC:644 MONDO:0010735 uuid:04bf99a9-6a46-4ee6-8790-8165cd1b4145 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes MONDO:0100226 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037672 infores:hetionet CHEBI:63611 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0003864 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0018772 infores:hetionet CHEBI:3286 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0033774 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0549294 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0549294 infores:hetionet CHEBI:9168 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0000731 infores:hetionet CHEBI:8430 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0040822 infores:hetionet CAID:CA414438886 biolink:causes MONDO:0010604 infores:clingen CAID:CA414438886 MONDO:0010604 PMID:10381508 Likely Pathogenic PM2_Supporting, PM1, PS4_Moderate, PS3 PP3 NM_000133.4(F9):c.420A>T (p.Arg140Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.2 meeting PM2_Supporting. The variant occurs in exon 5 of the F9 gene, which is deemed critical for the encoded FIX protein function meeting criteria for PM1. A mutant construct containing the Arg140Ser variant was expressed in DHFR-deficient CHO cells (PMID: 10381508). The coagulant activity of FIX-R140S was 6% +/- 1% of plasma FIX, while that of WT recombinant FIX was 96% +/- 8% of plasma FIX meeting PS3 criteria. Finally, the variant is reported in at least two individuals with moderate hemophilia B in the literature (PMID: 22103590, 1680287) meeting PS4_Moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Moderate, PM1, PS3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414438886/MONDO:0010604/080 2025-04-04 2025-04-04 X-linked inheritance HP:0001417 Supports CHEBI:2618 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0020649 infores:hetionet CHEBI:7820 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB00621 UMLS:C0028960 infores:hetionet CHEBI:27974 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0038454 infores:hetionet NCBIGene:1387 biolink:causes MONDO:0008393 infores:monarchinitiative not_provided not_provided HGNC:2348 MONDO:0008393 uuid:a3a76657-24d4-4f27-9c28-31e42535b221 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA399795789 biolink:causes MONDO:0100326 infores:clingen CAID:CA399795789 MONDO:0100326 PMID:34275420 Likely Pathogenic PP4_Strong, PS3_Supporting, PM2_Supporting, PM3_Supporting PP3 The missense variant NM_000419.5(ITGA2B):c.2444A>G (p.Tyr815Cys) has been reported, in the homozygous state (PM3_supporting), in at least one GT proband (P15 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). The highest population minor allele frequency in gnomAD v4.1 is 0.00001333 (1/75002 alleles) in the African/African-American genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporting, PP4_strong. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399795789/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3638 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0033975 infores:hetionet CHEBI:2611 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0015672 infores:hetionet CHEBI:45783 biolink:causes HP:0002875 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0231807 infores:hetionet CHEBI:119573 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0002170 infores:hetionet CHEBI:9150 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0002878 infores:hetionet CHEBI:15552 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0014591 infores:hetionet GO:0001177 biolink:causes GO:0006366 infores:ubergraph knowledge_assertion manual_agent GO:0001177 GO:0006366 CHEBI:31348 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0600142 infores:hetionet CHEBI:7915 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0149931 infores:hetionet CHEBI:3534 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0014742 infores:hetionet CHEBI:142290 biolink:causes MONDO:0000468 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0151517 infores:hetionet NCBIGene:5979 biolink:causes MONDO:0008233 infores:monarchinitiative not_provided not_provided HGNC:9967 MONDO:0008233 uuid:01b9285d-fd4a-423d-bdb8-50667678407f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16469 biolink:causes MONDO:0007019 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042998 infores:hetionet CHEBI:8869 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0008031 infores:hetionet CHEBI:32315 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0233494 infores:hetionet CHEBI:68642 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0009806 infores:hetionet NCBIGene:92154 biolink:causes MONDO:0859303 infores:monarchinitiative not_provided not_provided HGNC:25094 MONDO:0859303 uuid:101ff527-7d95-4dbb-b0c5-7df869f7f52f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63627 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0085624 infores:hetionet CHEBI:50275 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C1167965 infores:hetionet CHEBI:72297 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0004604 infores:hetionet CHEBI:9086 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0016199 infores:hetionet CAID:CA400021913 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021913 MONDO:0100326 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.428T>C (p.Leu143Ser) missense variant is absent from gnomADv4.0.0 (PM2_supporting) and has a REVEL score of 0.973, above the >.0.7 threshold in support of a deleterious effect (PP3). Another missense variant NM_000212.3(ITGB3):c.428T>G (p.Leu143Trp) in the same codon has been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5_supporting). It has been reported once, homozygous in Patient 15 of PMID: 36672149 has history of bleeding and impaired aggregation to at least two agonists, but normal agglutination with ristocetin (PM3_supporting; PP4_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_supporting, PP3, PM5_supporting, PM3_supporting, PP4_Moderate. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021913/MONDO:0100326/011 2024-03-07 2024-03-08 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:2611 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0030318 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0003864 infores:hetionet CAID:CA410147650 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147650 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP3, BP1, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1250C>T (p.Ser417Phe) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score < 0.50 (0.466) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2089191). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147650/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8356 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0018681 infores:hetionet CHEBI:8024 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0085649 infores:hetionet CHEBI:92923 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0000833 infores:hetionet UNII:3U02EL437C biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0018681 infores:hetionet CHEBI:6931 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0022107 infores:hetionet NCBIGene:64072 biolink:causes MONDO:0010984 infores:monarchinitiative not_provided not_provided HGNC:13733 MONDO:0010984 uuid:440992b1-d201-4767-9f95-ed0da7bd110e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:521033 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0235969 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0009450 infores:hetionet UNII:54Z8M50D6Q biolink:causes UMLS:C1112525 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C1112525 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0151824 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151824 infores:hetionet CHEBI:5141 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0013378 infores:hetionet CHEBI:31348 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0030193 infores:hetionet CHEBI:27732 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C0518015 infores:hetionet CHEBI:47381 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0023380 infores:hetionet CHEBI:94501 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0028961 infores:hetionet CHEBI:28748 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0022354 infores:hetionet CHEBI:465284 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C1141930 infores:hetionet CHEBI:194135 biolink:causes HP:0001541 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0003962 infores:hetionet CHEBI:8080 biolink:causes MONDO:0006526 infores:sider not_provided not_provided DRUGBANK:DB00191 UMLS:C0149526 infores:hetionet CHEBI:480999 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0031542 infores:hetionet CHEBI:31644 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0030554 infores:hetionet CHEBI:31859 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0038325 infores:hetionet CHEBI:63619 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0020621 infores:hetionet CHEBI:6741 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0022890 infores:hetionet CHEBI:7931 biolink:causes MONDO:1010128 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0031154 infores:hetionet CAID:CA386952811 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952811 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 PS4 The c.94G>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 32 (p.(Glu32Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 22802087, internal lab contributors). In summary, c.94G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952811/MONDO:0015967/017 2022-04-02 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:63627 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0013144 infores:hetionet NCBIGene:26160 biolink:causes MONDO:0014618 infores:monarchinitiative not_provided not_provided HGNC:30391 MONDO:0014618 uuid:43311371-cf1e-4766-92b6-8ad2c6e15169 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9738 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0038362 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0235431 infores:hetionet CHEBI:3286 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0028084 infores:hetionet CHEBI:681850 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0025061 infores:hetionet CHEBI:31439 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00265 UMLS:C0033774 infores:hetionet CAID:CA359430569 biolink:causes MONDO:0012163 infores:clingen CAID:CA359430569 MONDO:0012163 PMID: Uncertain Significance PM2_Supporting NM_002185.5(IL7R):c.554G>T is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 185 (p.Ser185Ile). The filtering allele frequency (the upper threshold of the 95% CI of 3/44892) of the c.554G>T variant in IL7R is 0.00001772 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA359430569/MONDO:0012163/119 2024-06-21 2024-06-21 Autosomal recessive inheritance HP:0000007 Inconclusive true CAID:CA000255 biolink:causes MONDO:0017623 infores:clingen CAID:CA000255 MONDO:0017623 PMID: Benign BA1 PTEN c.1026+32T>G (IVS8+32T>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.374 (37.4%, 102,771/274,696 alleles) in the gnomAD cohort. (PMID 27535533) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000255/MONDO:0017623/003 2016-09-14 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27300 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0028734 infores:hetionet CHEBI:4909 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0038367 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005310 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004239 infores:hetionet GO:1905310 biolink:causes GO:0061309 infores:ubergraph knowledge_assertion manual_agent GO:1905310 GO:0061309 CHEBI:9943 biolink:causes HP:0003075 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0020639 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0034150 infores:hetionet CHEBI:27899 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0595916 infores:hetionet UNII:G4PX8C4HKV biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0547030 infores:hetionet CHEBI:45081 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0011603 infores:hetionet CHEBI:421707 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0003862 infores:hetionet CHEBI:6437 biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0434437 infores:hetionet CHEBI:41423 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0302809 infores:hetionet NCBIGene:146059 biolink:causes MONDO:0009135 infores:monarchinitiative not_provided not_provided HGNC:1713 MONDO:0009135 uuid:8fb1c228-072f-4426-8d58-afc8b4bc6934 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:3767 biolink:causes MONDO:0030087 infores:monarchinitiative not_provided not_provided HGNC:6257 MONDO:0030087 uuid:3534a6a8-814e-4ada-afe0-a1fdae6ce641 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3347 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0019158 infores:hetionet CHEBI:421707 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0026848 infores:hetionet CHEBI:82981 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00251 UMLS:C0542571 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0234215 infores:hetionet CHEBI:68579 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0151701 infores:hetionet CHEBI:27899 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0040264 infores:hetionet CHEBI:63584 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0006145 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0036508 infores:hetionet CHEBI:45783 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0001824 infores:hetionet NCBITaxon:1173061 biolink:causes MONDO:0005772 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1173061 MONDO:0005772 CHEBI:31643 biolink:causes HP:0012248 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0600125 infores:hetionet CHEBI:7903 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0006840 infores:hetionet CHEBI:6375 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0042571 infores:hetionet CAID:CA135134 biolink:causes MONDO:0021060 infores:clingen CAID:CA135134 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.708C>T (p.Asn236=) variant in the BRAF gene is 0.116% (27/16412) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA135134/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:50663 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0028084 infores:hetionet GO:0031664 biolink:causes GO:0009617 infores:ubergraph knowledge_assertion manual_agent GO:0031664 GO:0009617 CHEBI:48390 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01012 UMLS:C0027765 infores:hetionet CHEBI:53766 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0002170 infores:hetionet CHEBI:3756 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0043094 infores:hetionet CHEBI:9727 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0549405 infores:hetionet CHEBI:94609 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0017181 infores:hetionet CHEBI:7956 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0002994 infores:hetionet CHEBI:724125 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0030193 infores:hetionet CHEBI:465284 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0041105 infores:hetionet UMLS:C0879264 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0010520 infores:hetionet CHEBI:64318 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0278134 infores:hetionet CHEBI:63638 biolink:causes HP:0001257 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0026838 infores:hetionet CHEBI:63617 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0011253 infores:hetionet CHEBI:7959 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0042384 infores:hetionet CHEBI:3698 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0149904 infores:hetionet CHEBI:68584 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0015672 infores:hetionet PUBCHEM.COMPOUND:12162152 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C0013362 infores:hetionet CHEBI:9727 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00347 UMLS:C0014457 infores:hetionet CHEBI:63717 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00300 UMLS:C0042963 infores:hetionet CHEBI:4822 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0040046 infores:hetionet CHEBI:35553 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01074 UMLS:C0012569 infores:hetionet CHEBI:63605 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0039070 infores:hetionet CHEBI:16469 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0002792 infores:hetionet CHEBI:9352 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0008031 infores:hetionet CHEBI:44032 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0002170 infores:hetionet NCBIGene:1371 biolink:causes MONDO:0007369 infores:monarchinitiative not_provided not_provided HGNC:2321 MONDO:0007369 uuid:7a09daf2-b7f3-4632-aeab-9f29090348f0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135005 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0009450 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0086543 infores:hetionet NCBIGene:137682 biolink:causes MONDO:0032622 infores:monarchinitiative not_provided not_provided HGNC:28625 MONDO:0032622 uuid:4e42ae19-1cef-40f9-9835-103bb15d0c7b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6541 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0344232 infores:hetionet CHEBI:8207 biolink:causes MONDO:0021205 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0013447 infores:hetionet CHEBI:4911 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0007222 infores:hetionet CHEBI:6741 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0542571 infores:hetionet CHEBI:3216 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C1443060 infores:hetionet CHEBI:119915 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0021843 infores:hetionet CHEBI:4995 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0085583 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0013781 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013781 infores:hetionet CAID:CA410208159 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208159 MONDO:0011071 PMID: Uncertain Significance PM1, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM3, PP2, PP1, BS2 NM_001754.5(RUNX1):c.509G>A (p.Gly170Glu) is a missense variant, which has a REVEL score ≥ 0.88 (0.95) (PP3) and affects at least one of the following residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, and PM2_Supporting Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208159/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:UMD7G2653W biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0042963 infores:hetionet NCBIGene:2645 biolink:causes MONDO:0100165 infores:monarchinitiative not_provided not_provided HGNC:4195 MONDO:0100165 uuid:892f9236-4a75-4f28-b94d-770a6d69879c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49662 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0011603 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0020517 infores:hetionet CHEBI:28445 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0004936 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0037274 infores:hetionet GO:0072199 biolink:causes GO:0072189 infores:ubergraph knowledge_assertion manual_agent GO:0072199 GO:0072189 CHEBI:8707 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0010692 infores:hetionet CHEBI:15552 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0948594 infores:hetionet CHEBI:2038 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151786 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0277925 infores:hetionet CHEBI:31644 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0020625 infores:hetionet CHEBI:63627 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0235639 infores:hetionet CAID:CA2837995533 biolink:causes MONDO:0015967 infores:clingen CAID:CA2837995533 MONDO:0015967 PMID: Uncertain Significance PS4_Moderate, PP3, PM2_Supporting PS1, PP4 The c.864-7T>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 7 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.6 for acceptor gain , predicting that the variant disrupts the acceptor site of intron 7 of GCK (PP3). PS1_Supporting cannot be applied, as the nucleotide change c.864-7T>G, which is predicted to disrupt the intron 7 splice acceptor site to a similar extent as c.864-7T>A, has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. This variant was identified in four unrelated individuals with hyperglycemia or suspected MODY (PS4_Moderate; PMID: 10447526, 15928245, internal lab contributors). While this variant was identified in individuals with a phenotype suggestive of GCK-hyperglycemia, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 10447526, 15928245, internal lab contributors). In summary, c.864-7T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4_Moderate, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2837995533/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:167638 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0011609 infores:hetionet CHEBI:119573 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0948525 infores:hetionet CHEBI:6062 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0029408 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0010709 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0010709 infores:hetionet CHEBI:7478 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0428977 infores:hetionet CAID:CA16020739 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020739 MONDO:0009861 PMID:22513348PMID:22513348 Likely Pathogenic PM3, PM2, PP4, PP3 The c.185T>C (p.Leu62Pro) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency not assessed/reported). (PP4; PMID: 22513348). This variant is absent in population databases (PM2). This variant was detected with p.R408W (Pathogenic in ClinVar) (PM3; PMID: 22513348). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020739/MONDO:0009861/006 2020-01-29 2020-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:74947 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0012569 infores:hetionet CHEBI:261649 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0003123 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0006444 infores:hetionet GO:1903681 biolink:causes GO:0090132 infores:ubergraph knowledge_assertion manual_agent GO:1903681 GO:0090132 CHEBI:6715 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0235955 infores:hetionet NCBIGene:6329 biolink:causes MONDO:0013620 infores:monarchinitiative not_provided not_provided HGNC:10591 MONDO:0013620 uuid:95853148-b493-465a-8440-28df50a650b3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5441 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0007820 infores:hetionet CHEBI:94411 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB04843 UMLS:C0242350 infores:hetionet CHEBI:6532 biolink:causes MONDO:0001273 infores:sider not_provided not_provided DRUGBANK:DB00836 UMLS:C0025160 infores:hetionet CHEBI:82960 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0007859 infores:hetionet CHEBI:9586 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0030232 infores:hetionet CHEBI:6715 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0392676 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042075 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0085096 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0013922 infores:hetionet CHEBI:71941 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0232487 infores:hetionet CAID:CA16022246 biolink:causes MONDO:0021056 infores:clingen CAID:CA16022246 MONDO:0021056 PMID: Uncertain Significance PM2_Supporting, PVS1_Strong BS2, PS4 The NM_000038.6(APC):c.422G>C (p.Arg141Thr) variant in APC is a G to non-G change at the last nucleotide of exon 4. It is predicted to cause skipping of exon 4, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a phenotype score of 0.5 points (Invitae, internal data) (PS4 not applicable). Moreover, the variant has been observed in heterozygous state in two individuals without a colorectal cancer/polyposis associated phenotype, worth 1 healthy individual point in total (BS2_Supporting not met; [Ambry Genetics, internal data]). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1_Strong and PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16022246/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:50924 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0014130 infores:hetionet NCBIGene:3158 biolink:causes MONDO:0011614 infores:monarchinitiative not_provided not_provided HGNC:5008 MONDO:0011614 uuid:2b940827-5604-4e2c-a612-fb0b17b7891f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63631 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0232462 infores:hetionet CHEBI:47381 biolink:causes NCIT:C3327 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0151907 infores:hetionet CHEBI:63621 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040046 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0151828 infores:hetionet CAID:CA288074 biolink:causes MONDO:0007648 infores:clingen CAID:CA288074 MONDO:0007648 PMID:27582386PMID:27582386 Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PVS1, PM2, PM6, PP3, PP2, PP4, PP1, BP4, BP1, BP3, BP2, BA1, PS3, PS1, PS4, PS2 The c.670C>T (p.Arg224Cys) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA288074/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:50742 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0042134 infores:hetionet CHEBI:70718 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0042373 infores:hetionet CAID:CA1244128 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244128 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate BP7, BS1, BS3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.886C>T variant in MYOC is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 296 (p.Arg296Cys). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00004505 (53 alleles out of 1,176,462), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.827, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 19407846), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP3_Moderate, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244128/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA226107 biolink:causes MONDO:0100453 infores:clingen CAID:CA226107 MONDO:0100453 PMID: Likely Pathogenic PM1, PP3_Moderate, PM3_Supporting, PS3_Supporting, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.2927G>T (p.Arg976Leu) is a missense variant that replaces arginine with leucine at position p.976, which is located within the active site, a well-characterized functional domain that binds the GTP substrate and the Mg ion and is required for enzymatic activity (PM1, PMID: 9391039). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 total points, PMID: 10951519, PM3_Supporting). A second proband was not only homozygous for this variant but also for the NM_000180.4(GUCY2D):c.2766C>G (p.Tyr922Ter) variant, and so was not counted for the PM3 code (PMID: 24265693). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), severely reduced vision (1 pt) with onset from birth (1 pt), nystagmus (1 pt), unremarkable fundus, irregular pigmentation (0.5 pts), hypermetropia, electroretinogram responses below the detection limit from both rods (0.5 pts) and cones (1 pt), and macular atrophy, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 17525851, PP4). The computational predictor REVEL gives a score of 0.895, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of ≤10% activity, indicating that it triggers a severe defect in protein function (PMID: 11328726, PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM3_Supporting, PP4, PP3_Moderate, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226107/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8245 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0015672 infores:hetionet CHEBI:9460 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00894 UMLS:C0030554 infores:hetionet CHEBI:36795 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0037317 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0006852 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0006852 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0042401 infores:hetionet UNII:2N4O9L084N biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0011570 infores:hetionet CHEBI:6931 biolink:causes UMLS:C0428886 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C0428886 infores:hetionet CHEBI:7852 biolink:causes UMLS:C0427108 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0427108 infores:hetionet NCBITaxon:782 biolink:causes MONDO:0019362 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:782 MONDO:0019362 CHEBI:3506 biolink:causes UMLS:C0011974 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C0011974 infores:hetionet CHEBI:2950 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0521839 infores:hetionet CHEBI:46345 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0038999 infores:hetionet CHEBI:70746 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0235710 infores:hetionet CHEBI:28939 biolink:causes UMLS:C0392162 infores:sider not_provided not_provided DRUGBANK:DB06151 UMLS:C0392162 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C2748540 infores:hetionet CHEBI:46195 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0085605 infores:hetionet CHEBI:4672 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C1443060 infores:hetionet CHEBI:6950 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0151825 infores:hetionet CHEBI:5138 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0004936 infores:hetionet CHEBI:135929 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0236024 infores:hetionet CHEBI:63624 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0035078 infores:hetionet CHEBI:63598 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0003578 infores:hetionet CHEBI:8764 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0152020 infores:hetionet CHEBI:6339 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0011991 infores:hetionet CHEBI:100241 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0017181 infores:hetionet CHEBI:64045 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C0036572 infores:hetionet CHEBI:6717 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0231218 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0022081 infores:hetionet CHEBI:10110 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C1527344 infores:hetionet CHEBI:134991 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0011551 infores:hetionet CHEBI:2654 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB00357 UMLS:C0002390 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0231441 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0231441 infores:hetionet CHEBI:8364 biolink:causes UMLS:C1735601 infores:sider not_provided not_provided DRUGBANK:DB00457 UMLS:C1735601 infores:hetionet CHEBI:10127 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0011168 infores:hetionet CHEBI:23765 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0085641 infores:hetionet CAID:CA10360798 biolink:causes MONDO:0010725 infores:clingen CAID:CA10360798 MONDO:0010725 PMID: Likely Benign BP7, BP4 BS1, PM2 The NM_000330.4(RS1):c.184+9C>T variant is an intronic variant at intron 3, located 9 nucleotides after exon 2. The variant does not have an impact at splicing sites according to SpliceAI, which predicts a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP7). This variant is present in gnomAD v.4.1.0 at a frequency of 0.00001094 among hemizygous individuals, with 4 variant alleles / 365661 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 threshold of <0.000002 and >0.00002 and fails to meet these criteria. The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BP4 and BP7 (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360798/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance HP:0001417 Contradicts true CHEBI:119915 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0947912 infores:hetionet CHEBI:63607 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0043352 infores:hetionet CHEBI:49575 biolink:causes UMLS:C1504494 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C1504494 infores:hetionet CHEBI:2948 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0017178 infores:hetionet CHEBI:8597 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0013395 infores:hetionet CHEBI:17650 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0263449 infores:hetionet CHEBI:41879 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0263449 infores:hetionet CHEBI:68855 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0012833 infores:hetionet NCBITaxon:10359 biolink:causes MONDO:0000878 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:10359 MESH:D017726 DB01004_MESH_D017726_1 CAID:CA400021704 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021704 MONDO:0100326 PMID: Uncertain Significance PM2_Supporting, BP2 PP3, PP4 The c.383T>G variant in ITGB3 is a missense variant predicted tocause substitution of Isoleucine by Serine at amino acid 128 (p.Ile128Ser). At least one patient (Patient 10_F2 in PMID: 36672149) heterozygous for this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIb and β3 surface expression were reduced to 1% and 0%, respectively, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries and the patient was found to be also homozygous for NM_000212.3(ITGB3):c.422A>G (p.Tyr141Cys) which is classified Pathogenic by the PD VCEP (BP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain Significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP2 and PM2_Supporting (VCEP specifications version 2). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021704/MONDO:0100326/011 2025-06-19 2025-06-27 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9139 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0041834 infores:hetionet CHEBI:3242 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0023380 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0010399 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0010399 infores:hetionet CHEBI:66876 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0008031 infores:hetionet CAID:CA10584712 biolink:causes MONDO:0007750 infores:clingen CAID:CA10584712 MONDO:0007750 PMID: Uncertain Significance BS3_Supporting, PP1 BS4, PM2 The NM_000527.5 (LDLR):c.-88G>A, variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024.The supporting evidence is as follows:BS3_Supporting: Heterologous cells (HepG2) were used for luciferase assays which showed normal promoter activity, reported in PMID 21538688 (De Castro-Oros et al., 2011), from Universidad de Zaragoza, Spain; and in PMID 31395865 (Kircher et al., 2019), from University of Washington, USA.PP1: Variant segregates with FH phenotype in 3 informative meiosis from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, Italy; Genomic Medicine Unit, Navarrabiomed – idiSNA, Spain): 3 affected family members have the variant. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10584712/MONDO:0007750/013 2024-02-23 2025-08-29 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:63630 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0026826 infores:hetionet CHEBI:50729 biolink:causes NCIT:C35457 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0438142 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0342579 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0342579 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0575090 infores:hetionet CHEBI:6067 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0020473 infores:hetionet UNII:G4PX8C4HKV biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0242350 infores:hetionet NCBIGene:284382 biolink:causes MONDO:0030989 infores:monarchinitiative not_provided not_provided HGNC:28494 MONDO:0030989 uuid:3eaedaf8-c237-43e6-a583-b1da9913afd4 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31348 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0232461 infores:hetionet NCBIGene:6926 biolink:causes MONDO:0008411 infores:monarchinitiative not_provided not_provided HGNC:11602 MONDO:0008411 uuid:bbf3a311-014c-41e8-bd50-6466a9f50f02 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2549 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0011849 infores:hetionet CHEBI:44032 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0004610 infores:hetionet CHEBI:31859 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0003467 infores:hetionet CAID:CA410208129 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208129 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.521C>T (p.Thr174Ile) is a missense variant which has a REVEL score ≥ 0.88 (0.95) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208129/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:724125 biolink:causes UMLS:C0948299 infores:sider not_provided not_provided DRUGBANK:DB00992 UMLS:C0948299 infores:hetionet PR:000004716 biolink:causes GO:0099191 infores:ubergraph knowledge_assertion manual_agent PR:000004716 GO:0099191 CHEBI:168396 biolink:causes HP:0011105 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0546817 infores:hetionet CHEBI:23765 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0009676 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0851341 infores:hetionet CHEBI:46557 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0030554 infores:hetionet CHEBI:5441 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0033774 infores:hetionet CHEBI:34829 biolink:causes MONDO:0006651 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0042165 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0948991 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0948991 infores:hetionet CHEBI:5441 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0232462 infores:hetionet CHEBI:6822 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0014742 infores:hetionet CHEBI:4445 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0004238 infores:hetionet CAID:CA132656 biolink:causes MONDO:0019497 infores:clingen CAID:CA132656 MONDO:0019497 PMID:22116359PMID:31599023 Likely Benign BS3, BS1_Supporting BP7, BS4, PP2, PP3, PP1, PP4, PM3, PM4, PM5, PM1, PVS1, PM2, BP1, BP4, BP2, BP3, BA1, PS3, PS1 The c.1061T>C variant in SLC26A4 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 354 (p.Phe354Ser). The filtering allele frequency (95% CI) in gnomAD v.2.1.1 was 0.1102% (153/251206 alleles, 6 homozygotes) in Latino/Admixed American population which meets the AR threshold (≥0.07%) for BS1_P. Although the REVEL computational prediction analysis tool produced a score of 0.955, PP3 was not applied. It was observed in 3 probands with sensorineural hearing loss, however they were not scored due to the high FAF in gnomAD (PMID: 26226137, 32747562, 27861301). Functional studies have shown that this variant does not affect the ability of the protein to mediate iodide and chloride transport (PMID:22116359, 31599023) meeting BS3. In summary, this variant is likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: BS3, BS1_P (ClinGen Hearing Loss VCEP specifications version 2; 11/28/2023) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA132656/MONDO:0019497/005 2023-11-28 2024-04-01 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf true CHEBI:94385 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0151699 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0000833 infores:hetionet CAID:CA410208006 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208006 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS2, PS3, PS1, BA1, BP1, BP4, BP3, BP2, BS1, BS4, BS3, BP5, BP7, PM6, PVS1, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.578T>A (p.Ile193Asn) is a missense variant which resides within a region, amino acids 89-204, of RUNX1 that is defined as a critical functional domain by the ClinGen MM-VCEP (PM1_supporting). This variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_supporting). It has also been reported in a proband, his brother, and his mother all with thrombocytopenia, normal platelet size, and reduced alpha-granule content (PMID: 28240786, PMID: 36519321, and case cited on PMID: 32208489) (PS4_supporting, PP1 not met). In addition, the variant has been reported in 1/2396 patients undergoing testing with the ThromboGenomics HTS panel (PMID: 31064749) and 1/3323 treatment-naïve MDS patients from the International Working Group for the prognosis of Myelodysplastic Syndromes (cBioPortal.org - Papaemmanuil Lab, 2022), but germline origin could not be confirmed in these individuals. The computational predictor REVEL gives a score of 0.962, which is above the threshold of 0.88 (evidence that correlates with impact to RUNX1 function), and the splice site predictor SpliceAI indicated that the variant has no impact on splicing (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS4_supporting, PM1_supporting, PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208006/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5165 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0574067 infores:hetionet CHEBI:5118 biolink:causes NCIT:C78672 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151830 infores:hetionet CHEBI:2659 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0018926 infores:hetionet CHEBI:10125 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0034886 infores:hetionet NCBITaxon:235 biolink:causes MONDO:0001973 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:235 MONDO:0001973 CHEBI:5864 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0700225 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C0031350 infores:hetionet CHEBI:9570 biolink:causes MONDO:0004643 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0023470 infores:hetionet CHEBI:134991 biolink:causes HP:0012534 infores:sider not_provided not_provided DRUGBANK:DB00998 UMLS:C0392699 infores:hetionet CHEBI:6741 biolink:causes MONDO:0021108 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0025289 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037315 infores:hetionet CHEBI:5790 biolink:causes UMLS:C0948226 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0948226 infores:hetionet CHEBI:50861 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0853619 infores:hetionet CHEBI:9738 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0152198 infores:hetionet NCBIGene:1789 biolink:causes MONDO:0030355 infores:monarchinitiative not_provided not_provided HGNC:2979 MONDO:0030355 uuid:3864001e-848d-4f67-9665-78e70987017b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:101278 biolink:causes UMLS:C0270729 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0270729 infores:hetionet CHEBI:3312 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0020649 infores:hetionet UMLS:C0209366 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00050 UMLS:C0340865 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0236071 infores:hetionet CHEBI:63617 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0020578 infores:hetionet CHEBI:5165 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0522224 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001318 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0559031 infores:hetionet CHEBI:10127 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0030252 infores:hetionet CHEBI:9086 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0024902 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0853015 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0853015 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0243026 infores:hetionet CAID:CA367401680 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401680 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PS2_Moderate, PM5_Supporting, PP2, PP3, PP4, PM2_Supporting The c.524G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to glutamate at codon 175 (p.(Gly175Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.914, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 11508276, internal lab contributors). This variant was identified as a de novo occurrence with unconfirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6) (PS2_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Another missense variant, c.523G>A p.Gly175Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly175Glu (PM5_Supporting). In summary, c.524G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PS2_Moderate, PP4, PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401680/MONDO:0015967/086 2024-02-23 2024-02-23 Semidominant inheritance HP:0032113 Supports CAID:CA658760617 biolink:causes MONDO:0021056 infores:clingen CAID:CA658760617 MONDO:0021056 PMID: Pathogenic PVS1, PM2_Supporting, PM6_Supporting The c.1900dup p.(Ser634Lysfs*17) variant in APC is a frameshift variant located between codon 49 and 2645 and is predicted to cause a premature stop codon in biological-relevant exon 15 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with FAP, the total points scored based on available phenotypic information is 0.5 (PM6_Supporting; PMID 15024739). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PM2_Supporting, PM6_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA658760617/MONDO:0021056/089 2023-02-19 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:553473 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01332 UMLS:C0151828 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0403632 infores:hetionet CHEBI:5134 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB08906 UMLS:C0151692 infores:hetionet CHEBI:8772 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0011991 infores:hetionet CHEBI:7931 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0009763 infores:hetionet CHEBI:3732 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0852911 infores:hetionet CHEBI:77260 biolink:causes NCIT:C50726 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C2004489 infores:hetionet CAID:CA8815429 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815429 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PP3, PM2_Supporting, PS3_Moderate, PM3_Very Strong The NM_000152.5: c.1655T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 552 (p.Leu552Pro). More than 10 individuals diagnosed with Pompe disease have been reported with this variant including at least 7 probands for whom laboratory data is published showing GAA activity in the deficient range (PMID 12923862, 18285536, 25681614, 27666774)(PP4_Moderate). Eight of these individuals were compound heterozygous for the variant and a pathogenic variant, phase unknown in all cases (PMID 12923862, 18285536, 18607768, 20033296, 25681614, 29122469 29422078, and two individuals were homozygotes (PMID 27666774)(PM3_Very strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In two functional studies, this variant has been shown to result in significantly decreased GAA activity (<5%) and abnormal processing when expressed in COS cells (PMIDs 14695532, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 279811, 2 star review status) with nine submitters all classifying the variant as pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3.(Classification approved August 17, 2021) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815429/MONDO:0009290/010 2021-09-07 2021-09-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ GO:0010695 biolink:causes GO:0140014 infores:ubergraph knowledge_assertion manual_agent GO:0010695 GO:0140014 CHEBI:6640 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01397 UMLS:C0011991 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0036572 infores:hetionet CHEBI:9943 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017979 infores:hetionet CHEBI:4910 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C0003578 infores:hetionet CHEBI:53760 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0026827 infores:hetionet CHEBI:3504 biolink:causes UMLS:C0231170 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0231170 infores:hetionet CHEBI:6541 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0027497 infores:hetionet CHEBI:94449 biolink:causes MONDO:0005276 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0011334 infores:hetionet CHEBI:46081 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0033774 infores:hetionet CHEBI:4822 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB01253 UMLS:C0687133 infores:hetionet CHEBI:3441 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0011603 infores:hetionet NCBIGene:7086 biolink:causes MONDO:0014881 infores:monarchinitiative not_provided not_provided HGNC:11834 MONDO:0014881 uuid:17d24b80-e1ea-4179-975b-5b6c0352297a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3561 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C1306341 infores:hetionet CHEBI:3219 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027441 infores:hetionet CHEBI:135736 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0040822 infores:hetionet CHEBI:8764 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0035078 infores:hetionet CHEBI:2676 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0017178 infores:hetionet CHEBI:91541 biolink:causes EFO:0009574 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0728899 infores:hetionet CHEBI:63623 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0476280 infores:hetionet CHEBI:51364 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0026205 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0860811 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0860811 infores:hetionet CAID:CA386965838 biolink:causes MONDO:0015967 infores:clingen CAID:CA386965838 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PP3 PS4, PM5, PP4 The c.732A>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 244 (p.Arg244Ser) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 and v.4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.723, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors), so PP4 cannot be applied. Another missense variant, c.731G>T (p.Arg244Ile), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 cannot be applied. In summary, c.732A>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386965838/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16796 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0018965 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0425945 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0425945 infores:hetionet CHEBI:9434 biolink:causes UMLS:C0343863 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0343863 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030312 infores:hetionet CHEBI:27899 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0038454 infores:hetionet CHEBI:78543 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0032285 infores:hetionet CHEBI:7986 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00806 UMLS:C0023218 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0020517 infores:hetionet CHEBI:8069 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01174 UMLS:C0019158 infores:hetionet CHEBI:10101 biolink:causes HP:0025337 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235267 infores:hetionet CHEBI:194135 biolink:causes MONDO:0005567 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0038587 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C2047937 infores:hetionet CHEBI:45081 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0010520 infores:hetionet CHEBI:9649 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0853760 infores:hetionet HP:0031377 biolink:causes MONDO:0000607 infores:drugmechdb knowledge_assertion manual_agent HP:0031377 MESH:D016410 DB00553_MESH_D016410_1 CHEBI:178699 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0152227 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042109 infores:hetionet CHEBI:8707 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002994 infores:hetionet CAID:CA16020913 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020913 MONDO:0009861 PMID: Likely Pathogenic PP4, PM2_Supporting, PM3_Supporting, PP3_Moderate, PM5_Supporting PM1 The NM_000277.3(PAH):c.977G>C (p.Trp326Ser) variant is a missense variant in exon 10/13 of PAH. This variant has been previously reported in at least one proband with hyperphenylalanemia (HPA; Palmieri, A. (2013). MOLECULAR ANALYSIS OF PHENYLALANINE HYDROXYLASE GENE IN SOUTH ITALY PATIENTS AFFECTED BY PHENYLKETONURIA) in whom BH4 deficiency was not formally excluded by normal urine pterins and normal DHPR activity, or sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism (PP4_Supporting). This variant has been reported in at least one proband with the genotype p.Leu48Ser/p.Trp326Ser (phase not confirmed) phenotype (PMID: 32668217); the p.Leu48Ser variant is path in ClinVar by PAH VCEP (Var ID: 608) (PM3_Supporting). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.874) (PP3_Moderate). A different missense variant at the same site, p.Trp326Cys, has been previously reported in one patient with HPA (PMID: 36537053), BH4 deficiency not excluded, in presumed trans w/p.R408W (path by PAH VCEP, ClinVar ID 577); the p.W326C variant qualifies as likely path (PM3_Supp, PP3_Mod, PP4_Mod (hyperphenylalanemia, BH4 deficiency excluded by sequencing of genes in sequencing of genes in the BH4 cofactor metabolism pathway, PM2_Supp), such that PM5_Supporting is met. In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Supporting, PM5_Supporting, PP4_Supporting, PP3_Moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020913/MONDO:0009861/006 2024-09-06 2024-09-06 Autosomal recessive inheritance HP:0000007 Supports CAID:CA013276 biolink:causes MONDO:0004994 infores:clingen CAID:CA013276 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.297C>T (p.Pro99=) variant in the MYH7 gene is 0.54% (69/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA013276/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:567361 biolink:causes UMLS:C0150450 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0150450 infores:hetionet CHEBI:119486 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0015967 infores:hetionet CHEBI:50131 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C1443060 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0021141 infores:hetionet CHEBI:41977 biolink:causes MONDO:0004994 infores:sider not_provided not_provided DRUGBANK:DB00694 UMLS:C0878544 infores:hetionet CAID:CA16602324 biolink:causes MONDO:0007750 infores:clingen CAID:CA16602324 MONDO:0007750 PMID: Uncertain Significance PM2, PP3, PP4 The NM_000527.5 (LDLR):c.1186+5G>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMaxMAF = 0.0000809 in African/African American population in gnomAD (gnomAD v2.1.1).The PopMax is African/African American for this variant. However the allele number at this position for 19-11222320-G-C is 2 / 8710, which is < 10,000 in total and only genome data is available. Exome data from a neighboring variant 19-11222323-C-T, allele number 15994, was used for PopMaxMAF calculation:PopMaxMAF = 2 / (15994 + 8710) = 0.0000809 in African/African American populationPP3: Variant is located within canonical intron 8 donor motif, splicing prediction is performed using MES: Wild type canonical donor motif tggGTGAGC score = 7.23, Variant canonical donor motif tggGTGACC score = 0.50, Var Score/Wt Score Ratio = 0.0692 which is <0.8, therefore PP3 is met. Predicted impact for alternative splicing caused by this variant is also confirmed by SpliceAI.PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for possible FH and DLCN score = 6 (PMID 32220565, Table 2), after alternative causes of high cholesterol were excluded, reported by Brown et al, 2020, from Johns Hopkins University, US.PS3 not met: Functional data is not available. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA16602324/MONDO:0007750/013 2023-03-24 2023-04-01 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:17823 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0042029 infores:hetionet NCBIGene:3293 biolink:causes MONDO:0009916 infores:monarchinitiative not_provided not_provided HGNC:5212 MONDO:0009916 uuid:232b6ba5-e82c-490d-8f63-d1b8e609ede7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA220600683 biolink:causes MONDO:0000572 infores:clingen CAID:CA220600683 MONDO:0000572 PMID: Pathogenic PM3, PM2_Supporting, PVS1 The c.999T>A (p.Tyr333Ter) (NM_000448.3) variant in RAG1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/2 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68026 alleles) in European (Non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient OM8 in PMID 11313270 has the c.999T>A (p.Tyr333Ter) variant in trans with a frameshift variant (1pt, PM3).In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1,PM2_supporting,PM3 (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA220600683/MONDO:0000572/123 2024-06-14 2024-06-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16755 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0011570 infores:hetionet CHEBI:71219 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C2937358 infores:hetionet CHEBI:72323 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0027441 infores:hetionet CHEBI:5004 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0015967 infores:hetionet CHEBI:9613 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00839 UMLS:C0021141 infores:hetionet UNII:F64QU97QCR biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0027769 infores:hetionet CHEBI:72297 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0270996 infores:hetionet CHEBI:8768 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0020458 infores:hetionet CHEBI:180905 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0037199 infores:hetionet CAID:CA16603197 biolink:causes MONDO:0044970 infores:clingen CAID:CA16603197 MONDO:0044970 PMID: Benign BP4, BA1 PP1, PS2, PS3, PS4, PM2, PM6 The m.9091A>G (p.T189A) variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. There has been a report of this variant being present in an individual from a control cohort (PMID: 15120634). This variant has also been reported in the homoplasmic state in a family with Leber Hereditary Optic Neuropathy (from haplogroup H10) caused by the m.3733G>A variant (PMID: 22879922). There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 21/59,389 (0.035%). The frequency in the Helix dataset is 108/195,983 (0.055%), including 107 homoplasmic occurrences and 1 heteroplasmic occurrence, and occurring in individuals from haplogroups H, U, HV, K, and R. The frequency in gnomAD v3.1.2 is 20/56432 (0.035%), and these occurrences are homoplasmic in individuals of European and African ancestry. Furthermore, this variant has been reported in 14 out of 14 individuals in the H10 haplogroup in addition to the case described above in haplogroup H10, meeting criteria to be considered a top-level haplogroup defining variant (BA1). The computational predictor APOGEE gives a consensus rating of benign with a score of 0.28 (Min=0, Max=1), which predicts a benign effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied BP4, BA1. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603197/MONDO:0044970/015 2023-06-26 2023-08-03 Mitochondrial inheritance HP:0001427 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true UNII:2N4O9L084N biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0016382 infores:hetionet CHEBI:3723 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0015967 infores:hetionet CHEBI:36791 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0235266 infores:hetionet CAID:CA151529 biolink:causes MONDO:0700272 infores:clingen CAID:CA151529 MONDO:0700272 PMID: Benign BP2_Strong, BS2, BP1, BA1 BS1, PM2 The c.721A>G variant in PALB2 is a missense variant predicted to predicted to cause substitution of asparagine by aspartic acid at amino acid 241 (p.Asn241Asp). This variant has been observed in three homozygous individuals with no features of FANCN, a condition with full penetrance at an early age (Ambry Genetics). The highest population minor filtering allele frequency in gnomAD v2.1.1 is 0.005509 in the African population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (BA1, BS2, BP1) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA151529/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:144093 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0020437 infores:hetionet CHEBI:135679 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0423153 infores:hetionet CHEBI:127342 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0039231 infores:hetionet CHEBI:47519 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0003811 infores:hetionet CHEBI:84500 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C1384353 infores:hetionet CHEBI:135613 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0018790 infores:hetionet CHEBI:3561 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0021053 infores:hetionet CHEBI:5138 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0392684 infores:hetionet CAID:CA296098 biolink:causes MONDO:0021060 infores:clingen CAID:CA296098 MONDO:0021060 PMID: Likely Benign BP7, BP4 PS4, PM1, BS1, PM2, BS2, BA1 The c.1068+9A>G intronic variant in the MAP2K1 gene is classified as likely benign because it does not alter an amino acid residue, is not located within the canonical splice site, and computational splice prediction tools do not predict an impact on splicing (BP4, BP7). It has been identified in 0.01123% (lower bound of the 95% CI of 8/35440) of Latino chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP4, BP7. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA296098/MONDO:0021060/004 2019-09-24 2019-10-02 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:6690 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0013378 infores:hetionet CHEBI:6633 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06795 UMLS:C0011603 infores:hetionet CAID:CA412379060 biolink:causes MONDO:0010725 infores:clingen CAID:CA412379060 MONDO:0010725 PMID: Uncertain Significance PM2_Supporting, PP3 NM_000330.4(RS1):c.35T>G (p.Leu12Arg) is a missense variant encoding the substitution of leucine with arginine at amino acid 12. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.645, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as a variant of uncertain significance for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting and PP3. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412379060/MONDO:0010725/126 2025-09-23 2025-09-23 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Inconclusive true CHEBI:4735 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0020649 infores:hetionet UMLS:C0025241 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0235416 infores:hetionet CHEBI:3757 biolink:causes MONDO:0024290 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0014394 infores:hetionet CHEBI:3216 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0003467 infores:hetionet CHEBI:4710 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0003862 infores:hetionet CHEBI:8245 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0232462 infores:hetionet CHEBI:4907 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0020517 infores:hetionet CHEBI:2618 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0033975 infores:hetionet CHEBI:6950 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0029882 infores:hetionet CHEBI:8764 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0040264 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0085682 infores:hetionet CHEBI:63584 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB06772 UMLS:C0021053 infores:hetionet CHEBI:49668 biolink:causes HP:0200020 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0392163 infores:hetionet CHEBI:8888 biolink:causes MONDO:0011057 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0007820 infores:hetionet CHEBI:6904 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0234458 infores:hetionet CHEBI:10102 biolink:causes HP:0001252 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0026827 infores:hetionet CHEBI:83804 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0013395 infores:hetionet NCBIGene:51293 biolink:causes MONDO:0013341 infores:monarchinitiative not_provided not_provided HGNC:16692 MONDO:0013341 uuid:8fd69d3f-d94b-43c0-92ca-f8918742ec59 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28177 biolink:causes HP:0005943 infores:sider not_provided not_provided DRUGBANK:DB00277 UMLS:C0162297 infores:hetionet CHEBI:49375 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0002871 infores:hetionet NCBIGene:51702 biolink:causes MONDO:0020736 infores:monarchinitiative not_provided not_provided HGNC:18337 MONDO:0020736 uuid:dcc79f9d-c9d6-4ff0-8ddf-4c4933e5c1ad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0011071 infores:hetionet UMLS:C1738934 biolink:causes HP:0033771 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0008033 infores:hetionet CAID:CA7331249 biolink:causes MONDO:0100216 infores:clingen CAID:CA7331249 MONDO:0100216 PMID: Uncertain Significance BS2_Supporting PM2, BP4, BA1, PP3, PM5, PM1, PS4, BS1 The NM_177438.3:c.2417C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMID: 33630087; Internal lab contributors). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.00001116(18/1613564 alleles) with a highest population minor allele frequency of 0.00003294 (3/91066 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.746, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7331249/MONDO:0100216/024 2025-01-07 2025-01-27 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:17650 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0030305 infores:hetionet CHEBI:3181 biolink:causes EFO:0011047 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C3160947 infores:hetionet CHEBI:6690 biolink:causes MONDO:0001100 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C2225524 infores:hetionet CAID:CA16607074 biolink:causes MONDO:0012996 infores:clingen CAID:CA16607074 MONDO:0012996 PMID: Likely Benign BP4, BP7, PM2 The NM_001482.3:c.1245A>C (p.Arg415=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by PhyloP (BP7). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 386277). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GATM-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA16607074/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6367 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0011053 infores:hetionet CHEBI:7445 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0231528 infores:hetionet CHEBI:48273 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0013456 infores:hetionet CHEBI:16755 biolink:causes UMLS:C0333291 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0333291 infores:hetionet CHEBI:5050 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0232461 infores:hetionet CAID:CA000358 biolink:causes MONDO:0017623 infores:clingen CAID:CA000358 MONDO:0017623 PMID: Likely Benign BS2_Supporting, BS1, PP2 PTEN c.235G>A (p.A79T) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.0045 (0.45%, 9/1984 alleles) in the GME variome. (PMID 27428751)BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000222198.12)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000358/MONDO:0017623/003 2018-04-06 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:367163 biolink:causes MONDO:0005439 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0549399 infores:hetionet CHEBI:66903 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08828 UMLS:C0020621 infores:hetionet CHEBI:15765 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0037036 infores:hetionet CHEBI:182080 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0235146 infores:hetionet CHEBI:39867 biolink:causes MONDO:0002281 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0002886 infores:hetionet CHEBI:31859 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0428977 infores:hetionet CHEBI:135351 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0010200 infores:hetionet CHEBI:9586 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0037299 infores:hetionet CHEBI:10124 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0009782 infores:hetionet CHEBI:7581 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0018834 infores:hetionet CHEBI:136040 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0152198 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005180 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030567 infores:hetionet CHEBI:3732 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0231218 infores:hetionet CHEBI:585948 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0917801 infores:hetionet CHEBI:15367 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0001122 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0029882 infores:hetionet CHEBI:31623 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0338831 infores:hetionet CHEBI:3756 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0029408 infores:hetionet CHEBI:17474 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0014742 infores:hetionet CHEBI:8802 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0019080 infores:hetionet CHEBI:31348 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0018790 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0040034 infores:hetionet CHEBI:31932 biolink:causes UMLS:C0241863 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0241863 infores:hetionet CHEBI:391960 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00496 UMLS:C0014742 infores:hetionet CHEBI:10023 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0151539 infores:hetionet CHEBI:10023 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0010200 infores:hetionet CHEBI:47781 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0004093 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0020651 infores:hetionet CHEBI:27690 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C0542184 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0236106 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0236106 infores:hetionet CHEBI:2549 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0028084 infores:hetionet CHEBI:5613 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0008370 infores:hetionet CHEBI:28748 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0151734 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0027947 infores:hetionet NCBIGene:144535 biolink:causes MONDO:0700290 infores:monarchinitiative not_provided not_provided HGNC:26456 MONDO:0700290 uuid:ecae9c30-83ae-44b6-bdf2-9f244e70ed9d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0267792 infores:hetionet CHEBI:31711 biolink:causes HP:0012514 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0023222 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0235848 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0235848 infores:hetionet CHEBI:49040 biolink:causes MONDO:0016098 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C3267047 infores:hetionet CHEBI:6067 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0852911 infores:hetionet CHEBI:6402 biolink:causes UMLS:C0001364 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0001364 infores:hetionet CHEBI:3347 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0041912 infores:hetionet CHEBI:31515 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0012833 infores:hetionet CHEBI:5280 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0231528 infores:hetionet CHEBI:8382 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0019080 infores:hetionet CHEBI:8888 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0521839 infores:hetionet CHEBI:17650 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0033975 infores:hetionet CHEBI:8430 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0041834 infores:hetionet CHEBI:31348 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0021843 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0019054 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0019054 infores:hetionet CHEBI:50777 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0041969 infores:hetionet CHEBI:50742 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0085631 infores:hetionet CHEBI:4953 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C0231528 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0233494 infores:hetionet CHEBI:47381 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0013456 infores:hetionet CHEBI:94392 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0392386 infores:hetionet CAID:CA229431 biolink:causes MONDO:0009861 infores:clingen CAID:CA229431 MONDO:0009861 PMID:26503515PMID:28982351PMID:23932990PMID:16256386 Pathogenic PM2, PP4_Moderate, PM3_Very Strong PP3 This c.1315+6T>A (IVS12+6T>A) variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515). This variant was documented in at least 7 patients with PAH deficiency, with a pathogenic PAH variant in trans (PMID: 16256386, 23932990, 28982351). This variant is absent from the population databases ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PM3_very strong. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229431/MONDO:0009861/006 2019-11-05 2019-11-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:16755 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0018799 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0919874 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005099 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0038525 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0235146 infores:hetionet CHEBI:39867 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0917801 infores:hetionet CAID:CA380144975 biolink:causes MONDO:0000573 infores:clingen CAID:CA380144975 MONDO:0000573 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting NM_000536.4(RAG2):c.53G>T is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 18 (p.Gly18Val).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.00002415(1/41408 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA380144975/MONDO:0000573/124 2024-05-01 2024-05-01 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:31236 biolink:causes MONDO:0002177 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0020459 infores:hetionet CHEBI:92923 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0017574 infores:hetionet CHEBI:4315 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0016382 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes NCIT:C168284 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0237314 infores:hetionet CHEBI:6887 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0022107 infores:hetionet CAID:CA8815734 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815734 MONDO:0009290 PMID: Uncertain Significance BP4 PM2, PP4, BS1 The NM_000152.5: c.2417C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). The variant was reported to be identified on 5 alleles in a cohort of 2372 individuals with limb girdle muscular dystrophy undergoing NGS panel sequencing (PMID: 39678382). One of those individuals, from Russia, is reported to have Pompe disease (Supplemental Table 4) and to be heterozygous for the variant; however, the full genotype and clinical information were not provided (insufficient evidence to apply PP4 or PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00155 (93/59992 alleles) in the Admixed American population, which is higher than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting and lower than the threshold for BS1 (>0.005), and therefore none of the populations codes are met. The computational predictor REVEL gives a score of 0.435 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). There is a ClinVar entry for this variant (Variation ID: 252467). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on July 30, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815734/MONDO:0009290/010 2025-07-30 2025-07-30 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:84500 biolink:causes NCIT:C94438 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0030318 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0149904 infores:hetionet NCBIGene:51473 biolink:causes MONDO:0014537 infores:monarchinitiative not_provided not_provided HGNC:18141 MONDO:0014537 uuid:0c170e59-1558-4ab2-be40-1a21b48fdd33 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71415 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0002170 infores:hetionet CHEBI:23765 biolink:causes GO:0046541 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0036104 infores:hetionet CHEBI:36791 biolink:causes UMLS:C2938875 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C2938875 infores:hetionet GO:0035778 biolink:causes CL:1000090 infores:ubergraph knowledge_assertion manual_agent GO:0035778 CL:1000090 CHEBI:32192 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0033774 infores:hetionet CHEBI:7936 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C1971624 infores:hetionet CHEBI:44915 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0235639 infores:hetionet CHEBI:28864 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C0042109 infores:hetionet CHEBI:9738 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0043352 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0178298 infores:hetionet CHEBI:50275 biolink:causes MONDO:0005885 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0029134 infores:hetionet CHEBI:68478 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0392386 infores:hetionet CHEBI:10124 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0085624 infores:hetionet CHEBI:6958 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0012833 infores:hetionet NCBIGene:400916 biolink:causes MONDO:0014532 infores:monarchinitiative not_provided not_provided HGNC:15559 MONDO:0014532 uuid:2977c107-950e-474e-b692-3e20610f08b6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes HP:0031843 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0554976 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0151538 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151538 infores:hetionet CHEBI:52717 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0029408 infores:hetionet CHEBI:40237 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0948594 infores:hetionet CHEBI:51860 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0018939 infores:hetionet CHEBI:6690 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0030554 infores:hetionet UNII:8NZ41MIK1O biolink:causes UMLS:C0853813 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0853813 infores:hetionet CHEBI:49662 biolink:causes MONDO:0004848 infores:sider not_provided not_provided DRUGBANK:DB00328 UMLS:C0038367 infores:hetionet CHEBI:35778 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C1142412 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005070 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0027651 infores:hetionet UMLS:C0657912 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020578 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0020517 infores:hetionet CHEBI:9654 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0015967 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0022116 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0035078 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0027707 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0162848 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0521503 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0521503 infores:hetionet CHEBI:5130 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0013404 infores:hetionet CHEBI:4315 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0042571 infores:hetionet CHEBI:8776 biolink:causes UMLS:C0243065 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0243065 infores:hetionet CHEBI:2549 biolink:causes NCIT:C87097 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0032989 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0149931 infores:hetionet CHEBI:5098 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C1443060 infores:hetionet CHEBI:74947 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0028961 infores:hetionet CHEBI:3286 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0233414 infores:hetionet CHEBI:75045 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0020625 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0011603 infores:hetionet CHEBI:27666 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0001824 infores:hetionet CHEBI:4995 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0002871 infores:hetionet CHEBI:63630 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0855242 infores:hetionet CHEBI:465284 biolink:causes HP:0034265 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0024902 infores:hetionet CHEBI:17303 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0040822 infores:hetionet CHEBI:3441 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0151662 infores:hetionet CHEBI:6759 biolink:causes UMLS:C0233571 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0233571 infores:hetionet CHEBI:64354 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0031256 infores:hetionet CHEBI:5893 biolink:causes MONDO:0001384 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0027092 infores:hetionet CHEBI:8871 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0595930 infores:hetionet NCBIGene:54361 biolink:causes MONDO:0012734 infores:monarchinitiative not_provided not_provided HGNC:12783 MONDO:0012734 uuid:1a05ce36-e1c8-4d4d-9720-c05c2c841282 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:44423 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0011603 infores:hetionet CHEBI:681850 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0002871 infores:hetionet CHEBI:63638 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0085628 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0034065 infores:hetionet CHEBI:15367 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C2830004 infores:hetionet CHEBI:3312 biolink:causes UMLS:C3267206 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C3267206 infores:hetionet CHEBI:70735 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0035410 infores:hetionet CHEBI:10127 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0035078 infores:hetionet CHEBI:6375 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0043094 infores:hetionet CHEBI:6062 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0235896 infores:hetionet CHEBI:28748 biolink:causes HP:0001946 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0022638 infores:hetionet CHEBI:3561 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0020458 infores:hetionet CHEBI:10125 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042963 infores:hetionet CHEBI:83804 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0026826 infores:hetionet CHEBI:9241 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0015230 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0042514 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0456909 infores:hetionet CHEBI:7915 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042790 infores:hetionet CHEBI:474180 biolink:causes UMLS:C1868912 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C1868912 infores:hetionet CHEBI:68579 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0017181 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0041912 infores:hetionet CHEBI:5106 biolink:causes UMLS:C0276680 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0276680 infores:hetionet CHEBI:8107 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0231528 infores:hetionet CHEBI:75722 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0009676 infores:hetionet CHEBI:10125 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0037199 infores:hetionet CHEBI:50648 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0017181 infores:hetionet CHEBI:63631 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0162830 infores:hetionet CHEBI:9130 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0020433 infores:hetionet CHEBI:9086 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0043352 infores:hetionet CAID:CA415088272 biolink:causes MONDO:0010305 infores:clingen CAID:CA415088272 MONDO:0010305 PMID: Uncertain Significance PP3, PP4, PM2_Supporting PS4 The NM_005629.4:c.1529T>A variant in SLC6A8 is a missense variant that is predicted to result in the substitution of methionine by lysine at amino acid 510 (p.Met510Lys). This variant has been reported in one male proband with elevated urine creatine/creatinine (PMID: 29435807)(PP4). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the threshold of 0.75, evidence that correlates with impact to SLC6A8 function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, PP3, PP4.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on March 28, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA415088272/MONDO:0010305/027 2024-03-28 2024-03-28 X-linked inheritance HP:0001417 Inconclusive true CHEBI:17141 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0086565 infores:hetionet CHEBI:31932 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0039070 infores:hetionet CHEBI:100241 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0032227 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0855242 infores:hetionet CAID:CA214258 biolink:causes MONDO:0015967 infores:clingen CAID:CA214258 MONDO:0015967 PMID: Uncertain Significance BS1, PM2, PP3, PP4 The c.1265T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 422 (p.(Leu422Pro)) of NM_000545.8. The Grpmax filtering allele frequency of the c.1265T>C variant in gnomAD v4.1.0 is 0.0000036, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.604, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 30293189). In summary, c.1265T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): none. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA214258/MONDO:0015967/017 2025-07-24 2025-07-24 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0048686 biolink:causes GO:0031103 infores:ubergraph knowledge_assertion manual_agent GO:0048686 GO:0031103 CHEBI:6438 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB01210 UMLS:C0004245 infores:hetionet CHEBI:9449 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0233494 infores:hetionet CHEBI:27958 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00907 UMLS:C0040822 infores:hetionet CHEBI:4325 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00250 UMLS:C0917801 infores:hetionet CHEBI:3508 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0030193 infores:hetionet CHEBI:9586 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0017181 infores:hetionet NCBIGene:51684 biolink:causes MONDO:0958189 infores:monarchinitiative not_provided not_provided HGNC:16466 MONDO:0958189 uuid:da29af96-20ea-4d99-bbd9-2f3d906dae00 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50648 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0037199 infores:hetionet CHEBI:135961 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0002792 infores:hetionet CHEBI:37924 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0233472 infores:hetionet NCBIGene:115948 biolink:causes MONDO:0014465 infores:monarchinitiative not_provided not_provided HGNC:28303 MONDO:0014465 uuid:5ac3f393-22cb-4962-900f-153a401dd72a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0140646 biolink:causes GO:0002329 infores:ubergraph knowledge_assertion manual_agent GO:0140646 GO:0002329 CHEBI:75722 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0595930 infores:hetionet CHEBI:10119 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151889 infores:hetionet CHEBI:29007 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0014591 infores:hetionet CHEBI:585948 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01023 UMLS:C0013428 infores:hetionet UNII:R43D2573WO biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0700225 infores:hetionet CHEBI:65349 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0948594 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0011551 infores:hetionet CHEBI:28918 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0018991 infores:hetionet CHEBI:182080 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0013378 infores:hetionet CHEBI:135791 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0030193 infores:hetionet CHEBI:47781 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0015672 infores:hetionet CHEBI:75722 biolink:causes UMLS:C1868912 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1868912 infores:hetionet CHEBI:50173 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0011053 infores:hetionet CHEBI:68610 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C1384353 infores:hetionet CHEBI:40279 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0022660 infores:hetionet CHEBI:4356 biolink:causes HP:0000961 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0010520 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0235818 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0235818 infores:hetionet NCBIGene:7015 biolink:causes MONDO:0013521 infores:monarchinitiative not_provided not_provided HGNC:11730 MONDO:0013521 uuid:cad0b41c-19e4-4c0a-936d-34017a591cdc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8888 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0080274 infores:hetionet CHEBI:50173 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235266 infores:hetionet CAID:CA294307 biolink:causes MONDO:0700270 infores:clingen CAID:CA294307 MONDO:0700270 PMID:19431188 Likely Pathogenic PM3_Very Strong, PS3_Supporting BP4, PM2, PP3 The c.9022C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3008 (p.Arg3008Cys). This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMID: 12552566, 18573109, 25122203, 26896183, 30549301). Additionally, experimental studies showed that this variant impacts ATM kinase activity and radiosensitivity compared to wild type (PMID: 19431188). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PM3_Very Strong, PS3_Supporting) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA294307/MONDO:0700270/020 2024-11-26 2025-01-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49575 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0011551 infores:hetionet GO:0010061 biolink:causes GO:0090558 infores:ubergraph knowledge_assertion manual_agent GO:0010061 GO:0090558 CHEBI:4814 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0035455 infores:hetionet CHEBI:64355 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151786 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004845 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038363 infores:hetionet CHEBI:9586 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0017675 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0859032 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0859032 infores:hetionet CHEBI:5128 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00690 UMLS:C0003123 infores:hetionet CHEBI:66964 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0178298 infores:hetionet GO:0006954 biolink:causes HP:0025095 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D012912 DB01246_MESH_D012912_1DB08936_MESH_D012912_1DB01620_MESH_D012912_1DB00967_MESH_D012912_1DB00420_MESH_D012912_1 CHEBI:6541 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0011991 infores:hetionet CHEBI:45783 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0011603 infores:hetionet CHEBI:5001 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0014457 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006736 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0007868 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0853760 infores:hetionet CHEBI:6801 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0015397 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C1318520 infores:hetionet CHEBI:681850 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00872 UMLS:C0020625 infores:hetionet CHEBI:94392 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0027497 infores:hetionet CHEBI:3213 biolink:causes MONDO:0006789 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0476327 infores:hetionet CHEBI:64354 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0015230 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0155169 infores:hetionet CHEBI:171719 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0022346 infores:hetionet CHEBI:5138 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0231528 infores:hetionet NCBIGene:392255 biolink:causes MONDO:0007306 infores:monarchinitiative not_provided not_provided HGNC:4221 MONDO:0007306 uuid:180df911-86b4-40fd-972d-b43f47596b76 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4798 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0013604 infores:hetionet CHEBI:5280 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0011849 infores:hetionet CAID:CA023812 biolink:causes MONDO:0007783 infores:clingen CAID:CA023812 MONDO:0007783 PMID: Likely Benign BS1 PP3, PM1, PS4, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 3366 of the RYR1 protein, p.(Arg3366His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00135, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 25958340, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.68 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Benign. Criteria implemented: BS1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023812/MONDO:0007783/012 2022-03-14 2022-03-14 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:40279 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0014457 infores:hetionet NCBIGene:88 biolink:causes MONDO:0032852 infores:monarchinitiative not_provided not_provided HGNC:164 MONDO:0032852 uuid:43121790-f224-4b12-af87-6e9ba488b6b0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA412726773 biolink:causes MONDO:0100437 infores:clingen CAID:CA412726773 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 NM_001034853.2(RPGR):c.3373C>T (p.Gln1125Ter) is a nonsense variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to C- terminally truncate the protein product (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands who did not meet the PS4 requirement of some functional vision impairment in affected males by age 30 years, or decreased or absent cone and/or rod electroretinogram responses, so PS4_Supporting is not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412726773/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CAID:CA8337533 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337533 MONDO:0008723 PMID: Benign BA1, BP4 The c.63-35G>A variant in ACADVL is an intronic variant which occurs in intron 1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.02152 in the Latino/Admixed American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from 2 in silico splicing predictors (SpliceAI, NNSplice) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337533/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0023610 biolink:causes MONDO:0018555 infores:sider not_provided not_provided DRUGBANK:DB00644 UMLS:C0271623 infores:hetionet CHEBI:8346 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0948594 infores:hetionet CHEBI:10110 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0040822 infores:hetionet CHEBI:2675 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0030305 infores:hetionet NCBIGene:11019 biolink:causes MONDO:0013762 infores:monarchinitiative not_provided not_provided HGNC:16429 MONDO:0013762 uuid:f6de1856-f172-4f8f-8465-e8d240b5967b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4887 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0014742 infores:hetionet CHEBI:8890 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0231528 infores:hetionet CAID:CA023721 biolink:causes MONDO:0007750 infores:clingen CAID:CA023721 MONDO:0007750 PMID: Pathogenic PS3, PS4, PP1_Strong, PM1, PM2, PP4, PP3 BA1, PS2, BS1, BS3, BS4, PM6 The NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 January 2022. The supporting evidence is as follows:PM2 - PopMax MAF = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1).PP3 - REVEL = 0.85, which is above the threshold of 0.75.PM1 - variant meets PM2 and is located in exon 4.PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID: 34167030).PS4 - Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory).PP1_Strong - Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant)PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023721/MONDO:0007750/013 2022-01-28 2024-12-02 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:135530 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C1258215 infores:hetionet CHEBI:50859 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0036508 infores:hetionet CHEBI:70746 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0036974 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0042514 infores:hetionet CHEBI:50841 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0037763 infores:hetionet CHEBI:17347 biolink:causes HP:0033605 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0085641 infores:hetionet CHEBI:8430 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0023052 infores:hetionet CHEBI:63619 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0005940 infores:hetionet CHEBI:15854 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0162429 infores:hetionet CHEBI:80630 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0700225 infores:hetionet CHEBI:7627 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0006826 infores:hetionet CHEBI:30830 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0015732 infores:hetionet CHEBI:5138 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002453 infores:hetionet NCBIGene:7482 biolink:causes MONDO:0032575 infores:monarchinitiative not_provided not_provided HGNC:12781 MONDO:0032575 uuid:82b7078c-54b6-474b-a3af-fd1d9edddb3c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7959 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0085605 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0018799 infores:hetionet CHEBI:7931 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0010200 infores:hetionet CHEBI:3568 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018944 infores:hetionet CHEBI:42944 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0424295 infores:hetionet CHEBI:28901 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0026766 infores:hetionet CHEBI:27899 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0235378 infores:hetionet CHEBI:3749 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00845 UMLS:C0013144 infores:hetionet CHEBI:94848 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0080274 infores:hetionet CAID:CA000498 biolink:causes MONDO:0017623 infores:clingen CAID:CA000498 MONDO:0017623 PMID: Pathogenic PM2, PS2_Very Strong, PP2, PP1, PS4_Moderate, PS3 PTEN c.517C>T (p.R173C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 17526800, PMID 22628360, internal laboratory contributor(s) SCV000222220.10)PS3: Phosphatase activity <50% of wild type. (PMID 10866302)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 22628360, PMID 17526800, PMID 17526801)PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 22628360)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000498/MONDO:0017623/003 2017-10-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27363 biolink:causes UMLS:C1291078 infores:sider not_provided not_provided DRUGBANK:DB01593 UMLS:C1291078 infores:hetionet CHEBI:3508 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0001824 infores:hetionet CHEBI:61049 biolink:causes HP:0001714 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0340279 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0035243 infores:hetionet CAID:CA410203867 biolink:causes MONDO:0011071 infores:clingen CAID:CA410203867 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.221G>T (p.Gly74Val) is a missense variant which has a REVEL score < 0.50 (0.391), and a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410203867/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:45783 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0009806 infores:hetionet CHEBI:135736 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0004093 infores:hetionet CHEBI:15551 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00917 UMLS:C0404521 infores:hetionet CHEBI:5130 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0574067 infores:hetionet CHEBI:61390 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0234894 infores:hetionet CHEBI:7454 biolink:causes UMLS:C0235290 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0235290 infores:hetionet CHEBI:31536 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0231528 infores:hetionet CHEBI:6888 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0011253 infores:hetionet CHEBI:3504 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C2047937 infores:hetionet CHEBI:46195 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0267792 infores:hetionet CHEBI:9434 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0003864 infores:hetionet CHEBI:27786 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0236075 infores:hetionet CHEBI:63629 biolink:causes HP:0004787 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0302809 infores:hetionet CHEBI:3286 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0021177 infores:hetionet CHEBI:66964 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00470 UMLS:C0232462 infores:hetionet CHEBI:3478 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0040034 infores:hetionet CHEBI:6030 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0020433 infores:hetionet CHEBI:8890 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0004604 infores:hetionet CHEBI:51364 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0017979 infores:hetionet CHEBI:63620 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0233472 infores:hetionet CHEBI:27834 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0019360 infores:hetionet CHEBI:8764 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0011603 infores:hetionet CHEBI:8499 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0009450 infores:hetionet CHEBI:8346 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0015672 infores:hetionet UNII:DJJ95FJP1H biolink:causes HP:0000978 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0013491 infores:hetionet CHEBI:63629 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0031542 infores:hetionet CHEBI:9434 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0037299 infores:hetionet CHEBI:6073 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0030554 infores:hetionet CHEBI:27300 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00153 UMLS:C0020538 infores:hetionet NCBIGene:25923 biolink:causes MONDO:0014286 infores:monarchinitiative not_provided not_provided HGNC:24526 MONDO:0014286 uuid:2ea84508-1b52-48a8-a6f4-99478ea08cb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:17474 biolink:causes UMLS:C0235955 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0235955 infores:hetionet CHEBI:5118 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0853034 infores:hetionet CHEBI:5118 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0009450 infores:hetionet CHEBI:8207 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0036974 infores:hetionet CHEBI:36704 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0042790 infores:hetionet NCBIGene:8910 biolink:causes MONDO:0008044 infores:monarchinitiative not_provided not_provided HGNC:10808 MONDO:0008044 uuid:21e4e191-f64d-4549-8869-ac76c89feca0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9654 biolink:causes UMLS:C0151479 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0151479 infores:hetionet CHEBI:7514 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0020458 infores:hetionet CHEBI:3213 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0030305 infores:hetionet CHEBI:9434 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0020621 infores:hetionet CHEBI:7936 biolink:causes UMLS:C0863093 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0863093 infores:hetionet CHEBI:31236 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0002170 infores:hetionet GO:1905079 biolink:causes GO:0022037 infores:ubergraph knowledge_assertion manual_agent GO:1905079 GO:0022037 CHEBI:4717 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00450 UMLS:C0020517 infores:hetionet CHEBI:4653 biolink:causes UMLS:C0376297 infores:sider not_provided not_provided DRUGBANK:DB00975 UMLS:C0376297 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0036572 infores:hetionet CAID:CA016196 biolink:causes MONDO:0005021 infores:clingen CAID:CA016196 MONDO:0005021 PMID: Uncertain Significance PM2, PP3, PS4_Supporting PM5, PM4, PM1, PM6, PP1, PS3, BA1, BS1, BS3, BS4, PS1, PS2, BP4, BP7, BP2, BP5, PVS1 The c.5530G>A (p.Glu1844Lys) variant in MYH7 has been reported in 2 individuals with DCM, 1 individual with HCM and in 1 individual with LVNC (PS4_supporting; Walsh 2017 PMID:27532257, GeneDx pers. comm.). This variant has been identified in 0.0099% (1/10078) of Ashkenazi Jewish chromosomes, but is absent from all other populations in gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3; PM2; PS4_Supporting Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA016196/MONDO:0005021/002 2021-10-05 2021-10-05 Autosomal dominant inheritance HP:0000006 Inconclusive true UNII:2N4O9L084N biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00486 UMLS:C0085593 infores:hetionet CHEBI:63617 biolink:causes UMLS:C0162848 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0162848 infores:hetionet CHEBI:9649 biolink:causes MONDO:0006594 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0030807 infores:hetionet CHEBI:50859 biolink:causes MONDO:0003240 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0040128 infores:hetionet CHEBI:2673 biolink:causes MONDO:0001700 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0002888 infores:hetionet NCBIGene:201163 biolink:causes MONDO:0005575 infores:monarchinitiative not_provided not_provided HGNC:27310 MONDO:0005575 uuid:7add78c6-4a01-4b40-b1ff-f601e01cde83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63621 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0085932 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042345 infores:hetionet CHEBI:49575 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0023066 infores:hetionet CHEBI:6950 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C2363730 infores:hetionet CHEBI:53691 biolink:causes UMLS:C0021308 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0021308 infores:hetionet CAID:CA512341156 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341156 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP3, BP1, BP2, BS1, BS3, BS4, BP5, PM2, PM6, PVS1, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 Synonymous variant (no REVEL score applicable) with SpliceAI score ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.620 (< 2.0)) (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341156/MONDO:0011071/008 2024-06-24 2024-06-24 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:75998 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020456 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0235146 infores:hetionet CHEBI:8774 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0042029 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0005420 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0020676 infores:hetionet CHEBI:3654 biolink:causes UMLS:C0151476 infores:sider not_provided not_provided DRUGBANK:DB00310 UMLS:C0151476 infores:hetionet CHEBI:63580 biolink:causes NCIT:C78556 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0858635 infores:hetionet CHEBI:465284 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0002878 infores:hetionet CHEBI:75722 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C2939147 infores:hetionet CHEBI:50885 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0948594 infores:hetionet CHEBI:110423 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0700225 infores:hetionet CHEBI:37924 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0038325 infores:hetionet CHEBI:3994 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0013144 infores:hetionet CHEBI:7956 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C2830004 infores:hetionet CHEBI:9150 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0016204 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0232841 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0232841 infores:hetionet CHEBI:84500 biolink:causes MONDO:0004565 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0021843 infores:hetionet CHEBI:63607 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0035078 infores:hetionet CHEBI:5280 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0042571 infores:hetionet CHEBI:37941 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0013182 infores:hetionet CAID:CA626684863 biolink:causes MONDO:0100326 infores:clingen CAID:CA626684863 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting, PM3_Supporting The NM_000212.3(ITGB3):c.1406dup (p.Asn470Ter) variant in exon 10/15 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 (1/113752 alleles) in the European population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant has been reported in at least two GT patients, including the proband from PMID: 29615672, this patient displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced to 6-7%, as measured by flow cytometry (PP4_strong). Patient 2 of PMID: 14985172 is homozygous for this variant (PM3_supporting). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporitng, PP4_strong. (VCEP specifications version 2; date of approval 05/17/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626684863/MONDO:0100326/011 2022-05-17 2022-06-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:188986 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0011616 infores:hetionet CHEBI:31413 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0004936 infores:hetionet CHEBI:6149 biolink:causes MONDO:0006650 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0221069 infores:hetionet CHEBI:15854 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0011603 infores:hetionet CAID:CA10014734 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014734 MONDO:0011071 PMID: Uncertain Significance PS1, PS3, PS4, PS2, BA1, BP3, BP2, BP1, BP4, BP5, BP7, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM3, PM5, PM1, PP4, PP2, PP3, PP1, BS2 NM_001754.5(RUNX1):c.11A>G (p.Asp4Gly) is a missense variant which does not meet any ACMG/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014734/MONDO:0011071/008 2024-08-16 2024-08-16 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63791 biolink:causes UMLS:C2697368 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C2697368 infores:hetionet CHEBI:87681 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00243 UMLS:C0235431 infores:hetionet CHEBI:3380 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0032961 infores:hetionet CHEBI:75998 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0037763 infores:hetionet CHEBI:8232 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0015230 infores:hetionet CHEBI:253342 biolink:causes UMLS:C0151713 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C0151713 infores:hetionet CHEBI:15367 biolink:causes MONDO:0001910 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0028817 infores:hetionet CHEBI:46345 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0240557 infores:hetionet CHEBI:10101 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C2830004 infores:hetionet CAID:CA410148817 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148817 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.4(RUNX1):c.976G>T (p.Asp326Tyr) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148817/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true GO:0043374 biolink:causes CL:0000625 infores:ubergraph knowledge_assertion manual_agent GO:0043374 CL:0000625 CHEBI:8764 biolink:causes MONDO:0004789 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0008311 infores:hetionet CHEBI:135276 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01551 UMLS:C0036572 infores:hetionet CHEBI:135005 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0004093 infores:hetionet CHEBI:3738 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0027497 infores:hetionet CHEBI:77733 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0002792 infores:hetionet CHEBI:4876 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0004093 infores:hetionet CHEBI:9014 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01399 UMLS:C1384666 infores:hetionet CAID:CA253921 biolink:causes MONDO:0015152 infores:clingen CAID:CA253921 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PVS1, PP1 PM2 The NM_003494.4: c.855+1del variant in DYSF, which is also known as NM_001130987.2: c.951+1del, occurs within the canonical splice donor site of intron 8. It is predicted to cause skipping of biologically relevant exon 8/55, resulting in an in-frame deletion of 21 amino acids (PVS1_Moderate). RNAseq data has confirmed that this variant results in in aberrant splicing, suggesting use of an alternative acceptor site that deletes the first basepair of DYSF exon 9 and leads to a frameshift and premature truncation p.(Val286TrpfsTer2) (PMID: 36983702). This variant has been detected in at least 12 individuals with limb girdle muscular dystrophy (PMID: 20544924, 17828519, 18853459, 36983702). Of those individuals, at least two were compound heterozygous for the variant and a pathogenic variant (c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID: 20544924; c.3126G>A p.(Trp1024Ter): 1.0 pt, PMID: 18853459), and at least one was homozygous (0.25 pts, PMID: 18853459) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18853459, 36983702). The variant was also reported to co-segregate with the disease in two affected family members from two families (PMID: 18853459) (PP1, capped with PP4_Strong). The filtering allele frequency of the variant is 0.0009441 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 8/15286), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PP1. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA253921/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:45409 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0014724 infores:hetionet CHEBI:50275 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0151826 infores:hetionet CHEBI:6754 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0232462 infores:hetionet CHEBI:28593 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0020517 infores:hetionet CHEBI:77733 biolink:causes MONDO:0001571 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0018418 infores:hetionet NCBIGene:51142 biolink:causes MONDO:0014742 infores:monarchinitiative not_provided not_provided HGNC:21645 MONDO:0014742 uuid:edf61f96-3c0c-43f7-813a-ffc2586e5496 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6437 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0042769 infores:hetionet CHEBI:145499 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C3263723 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005571 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0032461 infores:hetionet CHEBI:6847 biolink:causes MONDO:0800113 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C1318520 infores:hetionet CHEBI:65173 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0344232 infores:hetionet CHEBI:2682 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0018926 infores:hetionet CHEBI:4975 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0011603 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0018683 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0263386 infores:hetionet CHEBI:3207 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C1527344 infores:hetionet CHEBI:4027 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0020625 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0027441 infores:hetionet CHEBI:51230 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0151908 infores:hetionet CHEBI:91583 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01058 UMLS:C0042109 infores:hetionet CHEBI:16755 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0011603 infores:hetionet CHEBI:6931 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00683 UMLS:C3263723 infores:hetionet CHEBI:5613 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0235146 infores:hetionet CHEBI:50841 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0080274 infores:hetionet NCBIGene:7474 biolink:causes MONDO:0024455 infores:monarchinitiative not_provided not_provided HGNC:12784 MONDO:0024455 uuid:42bc5a75-3eb5-437b-9399-274d50ff5885 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes UMLS:C0151767 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151767 infores:hetionet NCBIGene:10229 biolink:causes MONDO:0957874 infores:monarchinitiative not_provided not_provided HGNC:2244 MONDO:0957874 uuid:1d464a28-5935-4801-b94b-59d1c8740f6d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63620 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0011991 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0549250 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0549250 infores:hetionet CHEBI:71417 biolink:causes MONDO:0002459 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0020522 infores:hetionet CHEBI:8107 biolink:causes HP:0100543 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0338656 infores:hetionet CHEBI:4903 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0085606 infores:hetionet NCBIGene:2033 biolink:causes MONDO:0013364 infores:monarchinitiative not_provided not_provided HGNC:3373 MONDO:0013364 uuid:ef59e545-3f66-44e4-bf2f-6f9284e295ee biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8435 biolink:causes MONDO:0005570 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0018939 infores:hetionet CAID:CA116606 biolink:causes MONDO:0009290 infores:clingen CAID:CA116606 MONDO:0009290 PMID: Pathogenic PP4_Moderate, PM3_Very Strong, PVS1_Strong PS1, BS1 The NM_000152.5:c.-32-13T>G variant occurs in the acceptor splice site region of intron 1 of GAA and results in a reduced level of normally spliced GAA transcripts (“leaky splicing”) allowing for the production of residual GAA activity. This variant, historically termed IVS1-13T>G and -45T>G, is the most common GAA variant identified in patients with late-onset Pompe disease; about 36-90% of individuals with late-onset Pompe disease are heterozygous for this variant (PMID: 20301438, 31342611). Haplotype analysis suggests that c.-32-13T>G has arisen at least twice (PMID: 17210890).RT-PCR analysis of fibroblast RNA from patients with the variant, in addition to minigene studies assessing the splicing impact of c.-32-13T>G, have identified various aberrantly spliced transcripts as well as a low level of the normal transcript. The aberrant splice variants include SV1, which retains the first 36 nt of intron 1 and lacks exon 2; SV2, in which exon 2 is completely spliced out; and SV3, in which exon 2 is partially spliced out. The same aberrant splicing variants, missing all or part of exon 2, have also been found at low levels in the RNA of unaffected individuals and when the normal GAA sequence is analyzed in minigene studies (PMID: 7717400, 8817337, 17210890, 24150945). Overall, the variant appears to reduce the level of normal GAA transcripts to about 10-20% of wild type. This “leaky splicing” allows for some active GAA enzyme to be produced, thereby delaying onset of symptoms in individuals who carry this variant. It should be noted that these in vitro observations pertain to data collected in non muscle cell lines, the precise effect that this variant may have in vivo within muscle is not known. In cells from patients and cells transfected with the variant, antisense oligonucleotides and other treatments have been shown to increase the level of exon 2 inclusion, producing correctly spliced transcripts; to increase the residual activity of GAA; and to reduce the level of glycogen (PMID: 24150945, 28624228, 28629821, 31301153, 32317649, 33426149, 36401034). Based on the accumulation of evidence, PVS1 is applied at strong (PMID: 37352859).Hundreds of patients with this variant have been reported in the literature (see list of publications in https://www.pompevariantdatabase.nl/ ). There are numerous of examples of affected patients who are heterozygous for c.-32-13T>G and another variant in GAA that has been classified as pathogenic by the ClinGen LD GCEP (pathogenic classification does not require use of c.-32-13T>G for PM3). To provide some examples, the variant has been found in compound heterozygosity with c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (4 probands; max 2 x 0.5 points) (PMID: 27189384), c.1051delG (ClinVar Variation ID: 188841, SCV001371764.1) (0.5 points) (PMID: 27189384), c.2481+102_2646+31del (ClinVar Variation ID: 657307) (0.5 points) (PMID: 27189384), c.2331+2T>A (ClinGen Variation ID: 371281) (2 probands) (2 x 0.5 points) (PMID: 27189384), c.1548G>A (p.Trp516Ter) (ClinVar Variation ID: 189025, SCV001371740.1) (0.5 points) (PMID: 27189384), c.1441T>C (p.Trp481Arg) (ClinVar Variation ID: 189007, SCV004227917.1) (0.5 points) (PMID: 27189384), c.1551+1G>C (ClinVar Variation ID: 554983) (0.5 points) (PMID: 7881425), c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (0.5 points) (PMID: 25673129), and c.670C>T (p.Arg224Trp) (Variation ID: 189188, SCV001371775.1) (0.5 points) (PMID: 25673129), as well as homozygous individuals (max 2 x 0.5 points) (PMID: 25673129, 26231297 34405923). >7 points (PM3_VeryStrong).While the variant has never been associated with classical infantile-onset Pompe disease, the age of onset and severity of disease in patients with the variant can vary widely, even in individuals who are compound heterozygous for c.-32-13T>G and a complete loss of function variant (PMID: 17210890, 34405923). Clinically affected patients who are homozygous for the variant have also been reported. However, some homozygous individuals appear to remain asymptomatic, leading to discussions on how best to follow these individuals if identified on newborn screen (PMID: 30922962). Studies indicate that one of the factors that can modify the phenotype is the presence of another variant, c.510C>T, in cis with c.-32-13T>G. This variant has been shown to further reduce the level of normal GAA mRNA causing early onset and greater severity of symptoms (PMID: 30922962).The highest minor allele frequency (MAF) in gnomAD v2.1.1. is 0.005293 (614/116004 alleles) in the European non-Finnish population, with one homozygote in the “remaining individuals” group. In gnomAD v4.1.0, the highest population MAF is 0.006355 (7335/1154180 alleles; 19 homozygotes) in the European non-Finnish population. Although this allele frequency meets the BS1 threshold suggested by the LD VCEP, the fact that this variant is the most common variant in individuals with late onset Pompe disease accounts for the population based allele frequency that is observed. Therefore, BS1 was not applied. In addition there is abundant evidence to support its pathogenicity.Other variants in the same splice region have been identified in patients with Pompe disease including c.-32-3C>G, c.-32-3C>A, c.-32-2A>G, and c.-32-1G>C (PMID: 31301153, 33560568). The classification of c.-32-13T>G will be used to support the classification of these other variants. Therefore, to avoid circular logic, their classification was not used in the classification of c.-32-13T>G. There is a ClinVar entry for this variant (Variation ID: 4027).In summary, the c.-32-13T>G variant (also known as IVS1-13T>G) meets the criteria to be classified as pathogenic for Pompe disease. It results in residual GAA activity and is the most common GAA variant causing late-onset Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): PVS1_Strong, PM3_Very Strong, PP4_Moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1st, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA116606/MONDO:0009290/010 2024-10-01 2024-10-01 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:31302 biolink:causes UMLS:C0595883 infores:sider not_provided not_provided DRUGBANK:DB01558 UMLS:C0595883 infores:hetionet CHEBI:8707 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C2937350 infores:hetionet CHEBI:465284 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0233472 infores:hetionet CHEBI:3752 biolink:causes MONDO:0002387 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0345907 infores:hetionet CHEBI:5778 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0043144 infores:hetionet CHEBI:5100 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0518015 infores:hetionet CHEBI:7465 biolink:causes UMLS:C0852995 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0852995 infores:hetionet CHEBI:7443 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0917801 infores:hetionet NCBIGene:773 biolink:causes MONDO:0007163 infores:monarchinitiative not_provided not_provided HGNC:1388 MONDO:0007163 uuid:4e8c2c2c-5c4e-499f-8432-a72a3519f26a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9086 biolink:causes HP:0002375 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0086439 infores:hetionet GO:0007317 biolink:causes GO:0007308 infores:ubergraph knowledge_assertion manual_agent GO:0007317 GO:0007308 CHEBI:5384 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0039070 infores:hetionet CHEBI:16347 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0085595 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0151996 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0151996 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0376297 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0376297 infores:hetionet CHEBI:2788 biolink:causes UMLS:C0859253 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0859253 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0277925 infores:hetionet CHEBI:6888 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0156404 infores:hetionet CHEBI:107736 biolink:causes MONDO:0005804 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0020514 infores:hetionet CHEBI:6076 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0020517 infores:hetionet CHEBI:3419 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00395 UMLS:C0004134 infores:hetionet CHEBI:5383 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0042384 infores:hetionet CAID:CA332835 biolink:causes MONDO:0007648 infores:clingen CAID:CA332835 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS1, BS4, BS3, BP5, BP7, PM6, PM1, PM3, PM4, BS2, PP4, PP1, PP2, PP3, BA1, BP1, BP4, BP2, BP3, PS2, PS3, PS1 The c.2287G>T (p.Glu763Ter) variant results in a premature translational stop signal within the NMD competent region (PVS1, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in a family meeting HDGC criteria (PMID: 20373070), an individual with signet ring cell carcinoma diagnosed at 33 years of age (PMID: 15138207), and four individuals with DGC (2 <40 years, 2 > 40 years; PMID: 29589180). These reports are mostly out of New Zealand and it is unclear if the reported individuals are all part of a larger kindred (PS4_Supporting). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA332835/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:36791 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0040264 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0022660 infores:hetionet CHEBI:3756 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0233407 infores:hetionet CAID:CA015164 biolink:causes MONDO:0007947 infores:clingen CAID:CA015164 MONDO:0007947 PMID: Likely Pathogenic PP2, PP3, PM2_Supporting, PM1, PS4_Moderate PM6, PVS1, PP1, PP4, BS2, BA1, BP3, BP2, BP1, BP4, PM4, PM3, PM5, PS2, PS3, PS1, BP7, BP5, BS1, BS3, BS4 NM_000138.5 c.4526A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 1509 (p.Tyr1509Cys). This variant has been identified in at least four individuals including two probands with clinical diagnoses of Marfan syndrome, an individual with mild thoracic aortic aneurysm and dissection (TAAD) and systemic features without fulfilling Marfan syndrome diagnostic criteria, and an individual of tall stature with TAAD (PS4_moderate; PMID: 26787436; Johns Hopkins & University of Tokyo internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.916). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_moderate, PP2, PP3, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA015164/MONDO:0007947/022 2023-12-29 2023-12-29 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:42820 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0030252 infores:hetionet CHEBI:6367 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C1384353 infores:hetionet CHEBI:17026 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042029 infores:hetionet CHEBI:178699 biolink:causes MONDO:0000265 infores:sider not_provided not_provided DRUGBANK:DB06689 UMLS:C0032290 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0013132 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151737 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151737 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0033975 infores:hetionet CHEBI:10119 biolink:causes MONDO:0018546 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0699828 infores:hetionet CHEBI:3698 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0011124 infores:hetionet UMLS:C1709429 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0235431 infores:hetionet CHEBI:50173 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0007971 infores:hetionet CHEBI:31547 biolink:causes MONDO:0003634 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0033687 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0232910 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0232910 infores:hetionet NCBIGene:7010 biolink:causes MONDO:0010842 infores:monarchinitiative not_provided not_provided HGNC:11724 MONDO:0010842 uuid:28c04d6f-d1a3-439f-9736-3da045180ab7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:116735 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01086 UMLS:C0332575 infores:hetionet CHEBI:6847 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0032285 infores:hetionet CHEBI:9449 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00871 UMLS:C0037763 infores:hetionet CHEBI:4995 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0035455 infores:hetionet CHEBI:4876 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0042571 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0013922 infores:hetionet CHEBI:36791 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0020701 infores:hetionet CHEBI:15765 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0037763 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0948594 infores:hetionet CHEBI:8346 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C1443060 infores:hetionet CHEBI:8356 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0026946 infores:hetionet CAID:CA5689792 biolink:causes MONDO:0021060 infores:clingen CAID:CA5689792 MONDO:0021060 PMID: Likely Benign BS1 The filtering allele frequency of the c.1540+8C>T variant in the SHOC2 gene is 0.0374% (34/66702) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA5689792/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:51141 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00346 UMLS:C0002994 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0013595 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0281981 infores:hetionet CHEBI:47780 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0522055 infores:hetionet CHEBI:135736 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0267792 infores:hetionet CAID:CA1251403 biolink:causes MONDO:0013144 infores:clingen CAID:CA1251403 MONDO:0013144 PMID: Uncertain Significance BS1, PP3 PS4, BS3 The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID: 28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA1251403/MONDO:0013144/084 2023-09-21 2024-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:41774 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0151798 infores:hetionet CHEBI:7443 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0036974 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0009450 infores:hetionet CHEBI:28748 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0004509 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0162429 infores:hetionet UMLS:C0120107 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0027497 infores:hetionet CHEBI:204734 biolink:causes MONDO:0005108 infores:sider not_provided not_provided DRUGBANK:DB01260 UMLS:C0042769 infores:hetionet CHEBI:2618 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0039231 infores:hetionet CHEBI:3441 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C2830004 infores:hetionet CHEBI:3515 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0162119 infores:hetionet CHEBI:6888 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0029445 infores:hetionet CHEBI:36795 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042024 infores:hetionet NCBIGene:80155 biolink:causes MONDO:0030916 infores:monarchinitiative not_provided not_provided HGNC:30782 MONDO:0030916 uuid:62874c4e-52c7-49a1-9359-170bcb819db2 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9150 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0013378 infores:hetionet NCBIGene:3848 biolink:causes MONDO:0957303 infores:monarchinitiative not_provided not_provided HGNC:6412 MONDO:0957303 uuid:5c131d52-5adf-4bf4-b605-49e03696bb68 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42944 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0042029 infores:hetionet CHEBI:28445 biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00541 UMLS:C0236000 infores:hetionet CHEBI:3723 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0040435 infores:hetionet CHEBI:10102 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0006444 infores:hetionet CHEBI:3698 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0040822 infores:hetionet CHEBI:6367 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0030193 infores:hetionet CAID:CA8815382 biolink:causes MONDO:0009290 infores:clingen CAID:CA8815382 MONDO:0009290 PMID: Likely Benign BP4, BS1 PP4, PM3 The NM_000152.5:c.1552-13G>A variant is located near the acceptor splice region of intron 10 of GAA. The computational splicing predictor SpliceAI predicts that the variant has no impact on splicing (BP4). To our knowledge, functional studies investigating the impact of this variant on splicing are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004705 (607/129008 alleles) in the European non-Finnish population, which meets the ClinGen LSD VCEP’s threshold for BS1 (>0.005) when rounded up (BS1). There are 2 homozygotes in gnomAD v2.1.1. The variant was reported in a patient with Pompe disease along with a variant that has been classified as pathogenic by the ClinGen LD VCEP (c.841C>T (p.Arg281Trp); the phase was not reported in that patient (PMID: 31086307). However, analysis of clinical laboratory data in multiple patients with these two variants indicates that they likely occur in cis. There is a ClinVar entry for this variant (Variation ID: 255353). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BS1, BP4.Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 18th, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8815382/MONDO:0009290/010 2023-04-18 2023-07-11 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CL:0000136 biolink:causes MONDO:0006075 infores:ubergraph knowledge_assertion manual_agent CL:0000136 MONDO:0006075 CHEBI:71417 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0013144 infores:hetionet CHEBI:2611 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0151786 infores:hetionet CHEBI:367163 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0030196 infores:hetionet CHEBI:5893 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0011175 infores:hetionet CHEBI:7445 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0003123 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0235416 infores:hetionet CHEBI:9086 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0041582 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0007642 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0003864 infores:hetionet CHEBI:10101 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0027441 infores:hetionet CHEBI:61049 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0013604 infores:hetionet CHEBI:50648 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0040822 infores:hetionet CAID:CA410208050 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208050 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PP3 PS1, PS3, PS4, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, BS2, PP2, PP4, PP1 NM_001754.5(RUNX1):c.559G>T (p.Ala187Ser) is a missense variant which has a REVEL score ≥ 0.88 (0.946) (PP3). This variant affects a codon within the Runt Homology domain (AA 89-204) but does not occur within an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_supporting, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208050/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:16469 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0549373 infores:hetionet CHEBI:8107 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0032617 infores:hetionet CAID:CA6403892 biolink:causes MONDO:0019565 infores:clingen CAID:CA6403892 MONDO:0019565 PMID: Likely Benign BP4, BP7 BP5, BS1 The NM_000552.5:c.114C>T (p.Phe38=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4 & BP7). A case carrying the c.114C>T (p.Phe38=) variant was also found to carry the ClinGen VWD VCEP curated pathogenic variant c.2435del. The case is asserted to be VWD 3 which is typically a biallelic variant but there is not a second variant in this case curated pathogenic (PMID 16321553). Additionally, there are 8 submissions to ClinVar for this variant but for the submissions indicating affected status as yes, all classify the variant as likely benign. In summary, this variant meets the criteria to be classified as likely benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP4, BP7 (VWD VCEP specifications v1l) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6403892/MONDO:0019565/081 2025-11-04 2025-11-04 Undetermined mode of inheritance Contradicts true CHEBI:92511 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00920 UMLS:C0015230 infores:hetionet NCBIGene:440435 biolink:causes MONDO:0013807 infores:monarchinitiative not_provided not_provided HGNC:31371 MONDO:0013807 uuid:95422730-7b51-48ee-b8d2-58de5456e04a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6950 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0034065 infores:hetionet CAID:CA16028071 biolink:causes MONDO:0021056 infores:clingen CAID:CA16028071 MONDO:0021056 PMID: Likely Pathogenic PS3_Supporting, PS4_Moderate, PM2_Supporting, PP1_Strong The c.3077A>G variant in APC is a missense variant predicted to cause the substitution of asparagine by serine at amino acid position 1026 (p.Asn1026Ser). This variant has been reported to segregate with FAP in ≥ 7 meioses in 2 families (PP1_strong; PMID 18166348, Barcelona internal data). Increased β-catenin regulated transcription activity and decreased binding to β-catenin by surface plasmon resonance are also demonstrated (PS3_Supporting; PMID18166348). This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 3.5 points (PS4_Moderate, PMID 18166348, Invitae and Barcelona Internal data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PP1_Strong, PS4_Moderate, PS3_Supporting, and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA16028071/MONDO:0021056/089 2023-02-25 2023-03-14 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4710 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0235063 infores:hetionet CHEBI:63635 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0151827 infores:hetionet CHEBI:64312 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0852733 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233485 infores:hetionet CAID:CA2739267617 biolink:causes MONDO:0011071 infores:clingen CAID:CA2739267617 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.458del (p.Asn153fs) is a frameshift variant resulting in exon deletion that is predicted to undergo nonsense mediated decay (PVS1, PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant was reported in ClinVar in 2023 by Invitae but the affected status of the proband is unknown (Variation ID 2852907). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PM5_supporting, PVS1. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2739267617/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Supports CHEBI:7577 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0042023 infores:hetionet CHEBI:3175 biolink:causes UMLS:C1142135 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C1142135 infores:hetionet GO:0042173 biolink:causes GO:0009653 infores:ubergraph knowledge_assertion manual_agent GO:0042173 GO:0009653 CHEBI:480999 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0002792 infores:hetionet CHEBI:8597 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0151596 infores:hetionet CHEBI:27834 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0009806 infores:hetionet CHEBI:3478 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0003123 infores:hetionet CHEBI:35677 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB06698 UMLS:C0151636 infores:hetionet CHEBI:31705 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0013395 infores:hetionet CHEBI:3312 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01164 UMLS:C0013378 infores:hetionet CHEBI:75246 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0014591 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0020538 infores:hetionet CHEBI:8764 biolink:causes HP:0033431 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0341335 infores:hetionet CHEBI:4514 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0002994 infores:hetionet CHEBI:2904 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0040034 infores:hetionet CHEBI:74947 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085628 infores:hetionet CHEBI:6129 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0162429 infores:hetionet CHEBI:8024 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0019080 infores:hetionet CHEBI:63635 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0006277 infores:hetionet CHEBI:465284 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0149931 infores:hetionet CHEBI:50648 biolink:causes HP:0012587 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0473237 infores:hetionet CHEBI:61049 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0003460 infores:hetionet CHEBI:71223 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0013404 infores:hetionet CHEBI:92998 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0026821 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0429028 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0429028 infores:hetionet CHEBI:9927 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0700225 infores:hetionet CHEBI:47780 biolink:causes MONDO:0006939 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0034186 infores:hetionet CHEBI:83804 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0085636 infores:hetionet CHEBI:51164 biolink:causes MONDO:0018848 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0035357 infores:hetionet CAID:CA10653553 biolink:causes MONDO:0011071 infores:clingen CAID:CA10653553 MONDO:0011071 PMID: Benign BP4, BP7, BS1 PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM2, PM6, PVS1, BP5, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.*2840A>T is an intronic variant. Highest MAF at 0.0002 (0.02%, 3/15346,) in the European (Non-Finnish) subpopulation of gnomAD v2 cohort is between 0.00015 (0.015%) and 0.0015 (0.15%). Including alleles from gonmAD v3, variant present in ≥ 5 alleles (BS1). REVEL Score is not applicable and SpliceAI ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.311 < 2.0). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10653553/MONDO:0011071/008 2023-11-13 2023-11-13 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:51041 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0034065 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0151734 infores:hetionet CHEBI:94440 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C1510410 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0948089 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0004610 infores:hetionet CHEBI:4024 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0085636 infores:hetionet CAID:CA374978784 biolink:causes MONDO:0008535 infores:clingen CAID:CA374978784 MONDO:0008535 PMID: Uncertain Significance PP3, PM2_Supporting The NM_001114753.3: c.1160T>C variant in ENG is a missense variant predicted to cause substitution of leucine by proline at amino acid 387 (p.Leu387Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.78, which is above the threshold of ≥0.644, evidence that correlates with impact to ENG function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PP3 (specification version 1.0.0; 1/4/2024). Hereditary Hemorrhagic Telangiectasia VCEP https://erepo.genome.network/evrepo/ui/classification/CA374978784/MONDO:0008535/136 2024-03-15 2024-03-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8871 biolink:causes UMLS:C0151490 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0151490 infores:hetionet CHEBI:5790 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0015967 infores:hetionet CHEBI:4888 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB00754 UMLS:C0028643 infores:hetionet CHEBI:119573 biolink:causes MONDO:0006969 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0037023 infores:hetionet CHEBI:38940 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0423791 infores:hetionet CHEBI:50223 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0392386 infores:hetionet CHEBI:7577 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0011606 infores:hetionet GO:1903581 biolink:causes GO:0002275 infores:ubergraph knowledge_assertion manual_agent GO:1903581 GO:0002275 GO:2000790 biolink:causes GO:0007275 infores:ubergraph knowledge_assertion manual_agent GO:2000790 GO:0007275 CAID:CA913191010 biolink:causes MONDO:0009290 infores:clingen CAID:CA913191010 MONDO:0009290 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3 The NM_000152.5(GAA):c.1951_1952delinsT (p.Gly651SerfsTer45) variant in GAA is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). Two siblings with late onset Pompe disease are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G; phase unknown, and are treated with enzyme replacement therapy (PMID 31392188) (PP4). In addition, an adult patient with clinical symptoms consistent with Pompe disease, undergoing genetic testing in a clinical laboratory, is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.2014C>T (p.Arg672Trp) (PM3). There is a ClinVar entry for this variant (Variation ID: 633225). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 27, 2023) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913191010/MONDO:0009290/010 2023-06-27 2024-04-12 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:8888 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0016867 infores:hetionet CHEBI:94501 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0013378 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0595885 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0595885 infores:hetionet CHEBI:681569 biolink:causes MONDO:0001881 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0036983 infores:hetionet CAID:CA023815 biolink:causes MONDO:0100150 infores:clingen CAID:CA023815 MONDO:0100150 PMID: Uncertain Significance PM2_Supporting, PS4_Supporting The variant NM_000540.3:c.10100A>G in RYR1 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 3367 (p.Lys3367Arg). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. This variant has been reported in one proband with central core disease (PS4_Supporting; PMID: 16621918). In summary, this variant meets the criteria to be classified as uncertain significance for AD RYR1-related myopathy. ACMG/AMP criteria met, as specified by the Congenital Myopathies VCEP (Specification Version 1.0.0): PM2_Supporting, PS4_Supporting (ClinGen Congenital Myopathies VCEP specifications version 2.0.0; 11/18/2024). Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA023815/MONDO:0100150/150 2024-11-18 2025-04-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135342 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1456784 infores:hetionet CHEBI:49040 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0267792 infores:hetionet CHEBI:36791 biolink:causes MONDO:0008638 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0042345 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0004245 infores:hetionet CHEBI:3215 biolink:causes UMLS:C0269596 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0269596 infores:hetionet CHEBI:63620 biolink:causes HP:0002063 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0026837 infores:hetionet CHEBI:9570 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0268000 infores:hetionet CHEBI:66901 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB08820 UMLS:C0235996 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0948594 infores:hetionet UMLS:C0004609 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0232602 infores:hetionet UNII:8NZ41MIK1O biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0020461 infores:hetionet CHEBI:5959 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0040264 infores:hetionet CAID:CA2424844458 biolink:causes MONDO:0100437 infores:clingen CAID:CA2424844458 MONDO:0100437 PMID: Likely Pathogenic PVS1, PM2_Supporting PP4, PS4 NM_001034853.2(RPGR):c.2819_2838dup (p.Glu947fs) is a frameshift variant that introduces a premature stop codon into exon 15 of 15 before amino acid 1132, which is predicted not to trigger nonsense-mediated decay but rather to C-terminally truncate the protein product (PVS1).This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of retinopathy with childhood-onset (1 pts) and genotyping based on a 276-gene next-generation sequencing panel that did not identify an alternative cause of disease (2 pts), which together are specific for RPGR-related recessive retinopathy (4 points, PMID: 33546218). However, the proband's specific electroretinogram responses were not reported, so the PP4 code was not met. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PVS1 and PM2_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA2424844458/MONDO:0100437/106 2025-05-20 2025-05-21 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Supports CHEBI:2663 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0042571 infores:hetionet CHEBI:7852 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0575081 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005399 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C1861172 infores:hetionet CHEBI:3286 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0151766 infores:hetionet CHEBI:6413 biolink:causes UMLS:C0520587 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0520587 infores:hetionet CHEBI:2788 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0022107 infores:hetionet CHEBI:8764 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0546884 infores:hetionet CHEBI:2668 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0011551 infores:hetionet CHEBI:10102 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0040822 infores:hetionet CHEBI:84050 biolink:causes NCIT:C78341 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0522067 infores:hetionet CHEBI:77260 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0542571 infores:hetionet CHEBI:63624 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0011991 infores:hetionet CHEBI:9137 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C3665347 infores:hetionet CHEBI:72564 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0025323 infores:hetionet CHEBI:5959 biolink:causes UMLS:C0853619 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0853619 infores:hetionet UMLS:C0004609 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C3665386 infores:hetionet CHEBI:136040 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0039971 infores:hetionet CHEBI:4868 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0016382 infores:hetionet CHEBI:63605 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0027813 infores:hetionet CHEBI:28901 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0243026 infores:hetionet CHEBI:63617 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0037287 infores:hetionet CHEBI:72297 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0232461 infores:hetionet CHEBI:4710 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0151827 infores:hetionet CAID:CA16020959 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020959 MONDO:0009861 PMID: Uncertain Significance PM2, PP3, PP4 PM3, PS3 Thec.1194A>C (p.Lys398Asn) PAH variant has been reported in at least on mild HPA probrand (PMID: 17096675), having a compound heterozygous genotype with c.442-5C>G. This variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP. It is a missense variant predicted deleterious by SIFT (damaging), Polyphen (probably damaging) and MutationTaster (disease causing), with a REVEL score of 0.899. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020959/MONDO:0009861/006 2020-05-08 2022-02-20 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:45599 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0006277 infores:hetionet CHEBI:6822 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0042109 infores:hetionet CHEBI:15765 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0027051 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0234913 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0234913 infores:hetionet CHEBI:47898 biolink:causes HP:0003573 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0741494 infores:hetionet CHEBI:32315 biolink:causes MONDO:0002643 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0042594 infores:hetionet CHEBI:119915 biolink:causes HP:0200034 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0332563 infores:hetionet CHEBI:52172 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0003864 infores:hetionet CAID:CA320642855 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642855 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.186C>A (p.Asp62Glu) is a missense variant which has a REVEL score < 0.50 (0.31), and a SpliceAI score ≤ 0.20 (0.03) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642855/MONDO:0011071/008 2024-09-30 2024-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8713 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0231528 infores:hetionet CHEBI:36704 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0003811 infores:hetionet UMLS:C0065374 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0033860 infores:hetionet CHEBI:9943 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0017168 infores:hetionet CHEBI:8707 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151786 infores:hetionet CHEBI:50693 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0002792 infores:hetionet CHEBI:41423 biolink:causes UMLS:C0012817 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0012817 infores:hetionet CHEBI:4784 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0022354 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0520893 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0520893 infores:hetionet CHEBI:94501 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0428977 infores:hetionet CAID:CA398637054 biolink:causes MONDO:0019497 infores:clingen CAID:CA398637054 MONDO:0019497 PMID: Likely Pathogenic PM3_Supporting, PVS1 PM2 The c.9517+2T>C variant in MYO15A is within the canonical splice site (+/- 1,2) of exon 57/66 and is predicted to cause altered splicing in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). This variant has been detected in 1 proband with hearing loss with a second variant of uncertain significance in MYO15A where phase was not determined (PMID: 26969326). This variant was also seen in a proband with profound SNHL who carried another heterozygous LoF pathogenic variant in MYO15A, however parental testing was not performed. The c.9517+2T>C variant was present in 0.01167% (7/59990) of Latino/Admixed American alleles in gnomAD v4. In summary, the c.9517+2T>C variant in MYO15A meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Supporting, PVS1. (ClinGen Hearing Loss VCEP specifications version 1; 7/23/2024) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA398637054/MONDO:0019497/023 2024-07-23 2024-09-30 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf CHEBI:63598 biolink:causes MONDO:0005077 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0043167 infores:hetionet CHEBI:8024 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0009676 infores:hetionet CHEBI:45863 biolink:causes HP:0031245 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0239134 infores:hetionet CHEBI:66899 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0022081 infores:hetionet CHEBI:3510 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0038450 infores:hetionet CAID:CA5416895 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416895 MONDO:0011225 PMID: Uncertain Significance PM2 NM_001033855.3(DCLRE1C):c.350C>T is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 117 (p.Pro117Leu). The filtering allele frequency (the upper threshold of the 95% CI of 50/1178836) of the c.350C>T variant in DCLRE1C is 0.00003376 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore do not meet this criterion.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416895/MONDO:0011225/116 2024-02-15 2024-02-15 Autosomal recessive inheritance HP:0000007 Inconclusive true UMLS:C0025241 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0004093 infores:hetionet CHEBI:7824 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0013395 infores:hetionet CHEBI:64019 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB04861 UMLS:C0948089 infores:hetionet CHEBI:4514 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0043352 infores:hetionet CHEBI:28148 biolink:causes UMLS:C0151602 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0151602 infores:hetionet CHEBI:6067 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018524 infores:hetionet UMLS:C1709429 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB08889 UMLS:C0018790 infores:hetionet CHEBI:7444 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01203 UMLS:C0036974 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0037763 infores:hetionet CHEBI:46557 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0085649 infores:hetionet CHEBI:3127 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0948089 infores:hetionet GO:2000794 biolink:causes GO:0060541 infores:ubergraph knowledge_assertion manual_agent GO:2000794 GO:0060541 CHEBI:145499 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0233494 infores:hetionet CHEBI:145499 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0022346 infores:hetionet CHEBI:68584 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0018965 infores:hetionet CHEBI:63635 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0033975 infores:hetionet CHEBI:63627 biolink:causes NCIT:C3015 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C2240374 infores:hetionet CHEBI:2038 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0030312 infores:hetionet CHEBI:50922 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0026821 infores:hetionet CHEBI:9943 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0948586 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0025061 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005154 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0023895 infores:hetionet UBERON:0006799 biolink:causes MONDO:0006180 infores:ubergraph knowledge_assertion manual_agent UBERON:0006799 MONDO:0006180 CHEBI:63610 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0021368 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0030552 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0030552 infores:hetionet CHEBI:6715 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0006826 infores:hetionet CAID:CA626689269 biolink:causes MONDO:0015152 infores:clingen CAID:CA626689269 MONDO:0015152 PMID: Likely Pathogenic PM3, PP4_Strong, PM2_Supporting, PP3 PM5, PM4, PM1, BP1, BP4, BP3, BP2, BA1, PS1, PS3, PS2, PS4, PM6, PVS1, BP7, BP5, BS1, BS3, BS4, BS2, PP2, PP1 The NM_000023.4: c.957-11C>G variant in SGCA is an intronic variant located in intron 7 of 9. This variant has been detected in at least two individuals with autosomal recessive limb girdle muscular dystrophy, where it was identified in unknown phase or confirmed in trans with a pathogenic or likely pathogenic variant (c.229C>T p.(Arg77Cys), 0.5 pts, PMID: 32153140; c.850C>T p.(Arg284Cys), 1.0 pt, UCSD internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as significantly reduced or absent expression of encoded alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, UCSD internal clinic data communication). The highest minor allele frequency of this variant is 0.00002940 (2/68034 genome chromosomes) in the European (non-Finnish) population of gnomAD v3.1.2, which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (0.00009), meeting this criterion (PM2_Supporting). SpliceAI predicts the loss of the native acceptor site with a score of 0.49 and gain of a cryptic site with a score of 0.63, meeting criteria for PP3. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PP4_Strong, PM3, PP3, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA626689269/MONDO:0015152/189 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:27779 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0017181 infores:hetionet CAID:CA367398723 biolink:causes MONDO:0015967 infores:clingen CAID:CA367398723 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PP4 The c.1151C>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glycine at codon 384 (p.(Ala384Gly)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.86, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with reported hyperglycemia; however, there was insufficient clinical data to meet PP4 (internal lab contributors). Another missense variant at the same codon, c.1151C>A (p.Ala384Glu), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala384Pro (PM5_Supporting). In summary, c.1151C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PM2_Supporting, PP2, PP3, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367398723/MONDO:0015967/086 2025-06-06 2025-06-06 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:63630 biolink:causes MONDO:0006608 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0036508 infores:hetionet CHEBI:7822 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0232492 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0948525 infores:hetionet CHEBI:5141 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01213 UMLS:C0013144 infores:hetionet CAID:CA7330711 biolink:causes MONDO:0100216 infores:clingen CAID:CA7330711 MONDO:0100216 PMID: Uncertain Significance PP3, PM1_Supporting PM2, PM6, BP4, BP2, BA1, BS2, PP1, PP4, PM5, PS1, PS3, PS4, PS2, BS3, BS1, BS4 The NM_177438.2: c.5173C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 1725 (p.Arg1725Trp). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0003744 (2/53420 alleles) in the European (Finnish) population, followed by 0.000001799 (2/1111986) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.861) (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1- related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, PP3. (Bayesian Points: 2; VCEP specifications version 1.3.0; 02/27/2024). DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA7330711/MONDO:0100216/024 2024-02-27 2024-05-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:194135 biolink:causes HP:0100758 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0017086 infores:hetionet NCBIGene:326625 biolink:causes MONDO:0009614 infores:monarchinitiative not_provided not_provided HGNC:19331 MONDO:0009614 uuid:976b2990-c5e8-47d4-862b-c8314431c1bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:147872 biolink:causes MONDO:0957821 infores:monarchinitiative not_provided not_provided HGNC:26520 MONDO:0957821 uuid:9c7196dd-a63a-4c1c-bc2d-ed7cbfbfeb48 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47898 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0000731 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0017574 infores:hetionet CHEBI:3347 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0311468 infores:hetionet CHEBI:6822 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00703 UMLS:C0013395 infores:hetionet GO:1905413 biolink:causes GO:0051641 infores:ubergraph knowledge_assertion manual_agent GO:1905413 GO:0051641 CHEBI:101278 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0151636 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0234215 infores:hetionet CAID:CA318535 biolink:causes MONDO:0010278 infores:clingen CAID:CA318535 MONDO:0010278 PMID: Likely Benign BS1, BP4 The allele frequency of the p.Ala50Ser variant in SLC9A6 is 0.02% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Ala50Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala50Ser variant in SLC9A6 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA318535/MONDO:0010278/016 2021-03-26 2021-05-17 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:36791 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0027059 infores:hetionet CHEBI:3077 biolink:causes MONDO:0006610 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0151514 infores:hetionet CHEBI:31236 biolink:causes UMLS:C1168034 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C1168034 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0000598 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0003537 infores:hetionet CHEBI:50275 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0023518 infores:hetionet CHEBI:5280 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0086769 infores:hetionet CHEBI:27666 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0014518 infores:hetionet CHEBI:9943 biolink:causes HP:0000211 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0041105 infores:hetionet GO:0002573 biolink:causes CL:0000766 infores:ubergraph knowledge_assertion manual_agent GO:0002573 CL:0000766 CHEBI:47381 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0547030 infores:hetionet CHEBI:9328 biolink:causes UMLS:C1619718 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C1619718 infores:hetionet CHEBI:39585 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0575081 infores:hetionet CHEBI:7496 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0016436 infores:hetionet NCBIGene:285362 biolink:causes MONDO:0010088 infores:monarchinitiative not_provided not_provided HGNC:20376 MONDO:0010088 uuid:0c36f1e1-c2c3-4705-9a95-0f3e7c75e777 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0013378 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0011053 infores:hetionet CHEBI:45409 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0085932 infores:hetionet CHEBI:71229 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0042963 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0948089 infores:hetionet CHEBI:8888 biolink:causes HP:0010450 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0014866 infores:hetionet CHEBI:27666 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0027497 infores:hetionet GO:0042682 biolink:causes GO:0048749 infores:ubergraph knowledge_assertion manual_agent GO:0042682 GO:0048749 CHEBI:45081 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0018681 infores:hetionet CHEBI:7478 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0040034 infores:hetionet CHEBI:63791 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0235378 infores:hetionet CHEBI:71941 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00500 UMLS:C0019158 infores:hetionet CHEBI:7865 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0023380 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0000833 infores:hetionet CHEBI:64355 biolink:causes MONDO:0005359 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019193 infores:hetionet CHEBI:5613 biolink:causes HP:0010808 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0241442 infores:hetionet CHEBI:3756 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0011168 infores:hetionet UNII:5V9KLZ54CY biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0020517 infores:hetionet CHEBI:47381 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0041969 infores:hetionet CHEBI:4814 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0022408 infores:hetionet CHEBI:60761 biolink:causes NCIT:C95556 infores:sider not_provided not_provided DRUGBANK:DB00322 UMLS:C0234909 infores:hetionet CHEBI:9943 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0034880 infores:hetionet CHEBI:6897 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01214 UMLS:C0010200 infores:hetionet CHEBI:478164 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0553702 infores:hetionet NCBIGene:84842 biolink:causes MONDO:0033613 infores:monarchinitiative not_provided not_provided HGNC:28242 MONDO:0033613 uuid:257f981b-ee40-4612-98a6-b6ae9124686a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes UMLS:C0920102 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0920102 infores:hetionet CAID:CA367403876 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403876 MONDO:0015967 PMID: Uncertain Significance PP2, PP3, PP4, PP1, PM2_Supporting PS4 The c.47T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to glutamic acid at codon 16 (p.(Val16Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.857, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 17573900, 25174781, internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 25174781). Additionally, this variant segregated with hyperglycemia with 2 informative meioses in 2 families (PP1; PMIDs: 17573900, 25174781). In summary, c.47T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PP1, PP2, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403876/MONDO:0015967/086 2025-01-03 2025-01-03 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:63617 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0085649 infores:hetionet CHEBI:465284 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0015967 infores:hetionet CHEBI:8874 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0518015 infores:hetionet CHEBI:10119 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0030252 infores:hetionet CHEBI:4909 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C1443060 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002028 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0031212 infores:hetionet CHEBI:7931 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0243026 infores:hetionet NCBIGene:57410 biolink:causes MONDO:0014744 infores:monarchinitiative not_provided not_provided HGNC:14372 MONDO:0014744 uuid:f4075de5-ca5b-4bbb-96da-e80d15222f61 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:135920 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0267792 infores:hetionet NCBIGene:208 biolink:causes MONDO:0009416 infores:monarchinitiative not_provided not_provided HGNC:392 MONDO:0009416 uuid:8ad19455-139b-4ae0-a3db-3abc025eac1a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50663 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0021400 infores:hetionet CHEBI:131512 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0040822 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0038454 infores:hetionet CHEBI:7852 biolink:causes NCIT:C34630 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0016927 infores:hetionet CHEBI:37941 biolink:causes UMLS:C3241936 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C3241936 infores:hetionet NCBIGene:10682 biolink:causes MONDO:0010498 infores:monarchinitiative not_provided not_provided HGNC:3133 MONDO:0010498 uuid:bf332460-96e0-485e-84e0-b02aba4509f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002957 infores:hetionet CHEBI:10119 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0948807 infores:hetionet CHEBI:2663 biolink:causes HP:0034804 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0920171 infores:hetionet CAID:CA320637635 biolink:causes MONDO:0011071 infores:clingen CAID:CA320637635 MONDO:0011071 PMID: Benign BP4, BA1, BP7 PS1, PS3, PS4, PS2, BP1, BP2, BP3, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM5, PM1, PM3, PM4, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.508+169G>A is an intronic variant. This variant is present in the African/African American subpopulation of the gnomAD cohort v3 at MAF of 0.047, 4.7%, 408/8708 alleles (BA1). The intronic variant was not predicted to cause splicing effect and not evolutionary conserved (BP4, BP7). In summary, this variant meets criteria to be classified as Benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320637635/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:64355 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0151596 infores:hetionet CHEBI:9123 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0241705 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0002716 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0497156 infores:hetionet CHEBI:31547 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0009450 infores:hetionet CHEBI:167638 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0014591 infores:hetionet CAID:CA10549570 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549570 MONDO:0010305 PMID: Benign BS1, BS2, BP4 The NM_005629.4(SLC6A8):c.1596+24_1597-41dup variant in SLC6A8 is an intronic variant affecting the consensus splice site of intron 11/12. This variant has been previously reported as a variant of uncertain significance in an individual with suspected SLC6A8 deficiency (no further clinical data provided) (PMID: 20717164); thus PP4 does not apply. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003 (28/86410 alleles) in the European (non-Finnish) population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), and therefore meets this criterion (BS1). This variant has been observed in 9 hemizygotes in gnomAD v2.1.1 (BS2). The computational splicing predictor SpliceAI gives a score of 0.06 for acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 1585170, 1-star review status), with one submitter classifying this variant as benign. In summary, this variant meets criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on March 25, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549570/MONDO:0010305/027 2024-03-25 2024-03-25 X-linked inheritance HP:0001417 Contradicts true CAID:CA397724846 biolink:causes MONDO:0008723 infores:clingen CAID:CA397724846 MONDO:0008723 PMID: Pathogenic PP2_Moderate, PM3_Supporting, PM1_Supporting, PP3_Strong, PM2_Strong, PP1_Moderate ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA397724846/MONDO:0008723/021 2025-04-16 2025-04-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6754 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0009676 infores:hetionet CHEBI:68534 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0851341 infores:hetionet CHEBI:180905 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0013404 infores:hetionet CHEBI:47780 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C3665386 infores:hetionet CHEBI:38940 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0004623 infores:hetionet CHEBI:4995 biolink:causes MONDO:0016537 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0024314 infores:hetionet CHEBI:84500 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0038663 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0032285 infores:hetionet CHEBI:231594 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0008031 infores:hetionet CHEBI:7577 biolink:causes UMLS:C3257803 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C3257803 infores:hetionet CHEBI:5001 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0033774 infores:hetionet CHEBI:3387 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0041969 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0027796 infores:hetionet CHEBI:46345 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0278134 infores:hetionet CHEBI:8356 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0006384 infores:hetionet NCBIGene:411 biolink:causes MONDO:0009661 infores:monarchinitiative not_provided not_provided HGNC:714 MONDO:0009661 uuid:ed6a86ab-cc49-49d5-b80c-6291ea99ba55 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8802 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0037274 infores:hetionet CHEBI:75275 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00464 UMLS:C0027497 infores:hetionet CAID:CA658821284 biolink:causes MONDO:0009861 infores:clingen CAID:CA658821284 MONDO:0009861 PMID:30050108PMID:27243974 Likely Pathogenic PM4, PM2, PP4, PM3_Strong The c.124_126del (p.Lys42del) PAH variant has been reported in 2 patients with PAH deficiency, detected with the pathogenic PAH variant p.Arg111Ter (PMID: 30050108) and the likely pathogenic PAH variant c.824C>T (PMID: 27243974). A defect in BH4 metabolism was not excluded. This variant is absent from population databases. The protein length changes as a result of an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_strong, PM4, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA658821284/MONDO:0009861/006 2020-10-16 2020-10-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes NCIT:C35041 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0038435 infores:hetionet CHEBI:18385 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00152 UMLS:C0234233 infores:hetionet CHEBI:2618 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0151836 infores:hetionet CHEBI:92998 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0020517 infores:hetionet CHEBI:3752 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0042134 infores:hetionet CHEBI:2704 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151662 infores:hetionet NCBIGene:23600 biolink:causes MONDO:0013681 infores:monarchinitiative not_provided not_provided HGNC:451 MONDO:0013681 uuid:7f6f34f8-4274-4f60-88fc-d919080c21bc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:G4PX8C4HKV biolink:causes MONDO:0005412 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C0013295 infores:hetionet CHEBI:7445 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0003862 infores:hetionet CHEBI:46557 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0392171 infores:hetionet NCBIGene:55065 biolink:causes MONDO:0004573 infores:monarchinitiative not_provided not_provided HGNC:30225 MONDO:0004573 uuid:6cdaf842-7e57-4961-ae53-410f16182811 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2668 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0013378 infores:hetionet CHEBI:4511 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0037383 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0232492 infores:hetionet CHEBI:5118 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0151889 infores:hetionet CHEBI:7822 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0001824 infores:hetionet CHEBI:45409 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0034886 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0235431 infores:hetionet NCBITaxon:119095 biolink:causes MONDO:0001532 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:119095 MONDO:0001532 CHEBI:44423 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0015397 infores:hetionet CHEBI:7454 biolink:causes HP:0000746 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0011253 infores:hetionet CHEBI:10101 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0020538 infores:hetionet CHEBI:107736 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0042023 infores:hetionet CHEBI:7445 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00666 UMLS:C0019348 infores:hetionet CHEBI:31413 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0233407 infores:hetionet CHEBI:7936 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0023530 infores:hetionet CHEBI:66876 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0178298 infores:hetionet CHEBI:7478 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0027497 infores:hetionet CHEBI:3223 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C1443060 infores:hetionet CHEBI:49375 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0035078 infores:hetionet CAID:CA114131 biolink:causes MONDO:0015628 infores:clingen CAID:CA114131 MONDO:0015628 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PS4_Supporting PP1 The c.4837T>C variant in VWF is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1613 (p.Ser1613Pro). At least 1 patient (Patient 14 from PMID: 38053262) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity as indicated by a VWF activity-to-antigen ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additional consistent phenotypes were also reported in the patient including a FVIII activity consistent with VWF antigen (ratio >0.7) (PP4_Moderate). This variant has been reported in one additional proband (Zimmerman program) with activity/antigen ratio <0.37, abnormal multimers, and normal platelet binding (PS4_Supporting). The computational predictor REVEL gives a score of 0.7, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 1.0.0; date of approval). von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA114131/MONDO:0015628/081 2025-02-04 2025-02-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA226579 biolink:causes MONDO:0100368 infores:clingen CAID:CA226579 MONDO:0100368 PMID: Pathogenic PM3_Strong, PP3_Moderate, PS3_Supporting, PP4_Moderate, PM2_Supporting NM_000329.3(RPE65):c.715T>G is a predicted missense variant substituting tyrosine by aspartic acid at position 239. The computational predictor REVEL gives a score of 0.987, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI also gives a score of 0.34 for splice acceptor gain, which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002, with 3/129118 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 32032261). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant confirmed in trans (1 point, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pt) and significant, documented improvement of blue full-field stimulus testing after treatment with RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (8.5 points, PMID: 21911650, PP4_Moderate). The variant exhibited between 1% (PMID: 24849605) and 5% (PMID: 19431183) enzymatic activity in retinoid isomerase assays relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA226579/MONDO:0100368/120 2024-02-18 2024-02-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:23765 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0020651 infores:hetionet CHEBI:2549 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0018799 infores:hetionet CHEBI:5001 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0852911 infores:hetionet CAID:CA023561 biolink:causes MONDO:0007750 infores:clingen CAID:CA023561 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, BS3_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BP7, BP5, BS1, BS4, PM5, PM4, PM1, PM3, PVS1, PM6, PP2, PP1, BS2 NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.967.PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515.PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515.BS3_supporting - PMID: 25647241: Level 3 assay- study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity.- functional study is consistent with no damaging effect. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA023561/MONDO:0007750/013 2022-03-07 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:40279 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C2047937 infores:hetionet CHEBI:40279 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0030554 infores:hetionet CHEBI:4911 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00773 UMLS:C0023530 infores:hetionet NCBIGene:23534 biolink:causes MONDO:0012034 infores:monarchinitiative not_provided not_provided HGNC:17103 MONDO:0012034 uuid:981462d0-263d-41d8-97b3-ef59735a2006 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5296 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0178298 infores:hetionet CHEBI:66899 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB08819 UMLS:C0035455 infores:hetionet CHEBI:7573 biolink:causes MONDO:0001415 infores:sider not_provided not_provided DRUGBANK:DB00665 UMLS:C0156312 infores:hetionet CHEBI:6076 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0151505 infores:hetionet CHEBI:3172 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0020538 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0151736 infores:hetionet CHEBI:7494 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0038454 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0575090 infores:hetionet CHEBI:2379 biolink:causes MONDO:0043768 infores:sider not_provided not_provided DRUGBANK:DB01193 UMLS:C0857305 infores:hetionet CHEBI:9738 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0018794 infores:hetionet CHEBI:10119 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0030554 infores:hetionet CHEBI:4551 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00390 UMLS:C0085610 infores:hetionet CHEBI:28918 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0027540 infores:hetionet NCBIGene:8200 biolink:causes MONDO:0007216 infores:monarchinitiative not_provided not_provided HGNC:4220 MONDO:0007216 uuid:c6dd5148-1747-4794-8c0d-af4ea23912cc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9605 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00775 UMLS:C0038990 infores:hetionet CHEBI:28748 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0518988 infores:hetionet CHEBI:28901 biolink:causes MONDO:0013730 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0018133 infores:hetionet CHEBI:38562 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0030554 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0020517 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0233472 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0036572 infores:hetionet CHEBI:7852 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0025222 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0005138 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0684249 infores:hetionet CHEBI:5138 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0040034 infores:hetionet CHEBI:119915 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0011606 infores:hetionet CHEBI:70735 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0011071 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0023530 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0042023 infores:hetionet CHEBI:36791 biolink:causes UMLS:C1322281 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C1322281 infores:hetionet CHEBI:2948 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00993 UMLS:C0021053 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0040034 infores:hetionet CAID:CA023938 biolink:causes MONDO:0007783 infores:clingen CAID:CA023938 MONDO:0007783 PMID: Likely Benign PP3_Moderate, BS1 PM1, PS4, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of tyrosine with cysteine at codon 3933 of the RYR1 protein, p.(Tyr3933Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.001332, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 25958340, 20681998, 23558838, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.983) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is classified as Likely Benign, (PMID: 29300386). Criteria implemented: PP3_Moderate, BS1. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA023938/MONDO:0007783/012 2022-01-04 2022-01-04 Autosomal dominant inheritance HP:0000006 Contradicts https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:8382 biolink:causes UMLS:C0553548 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0553548 infores:hetionet CHEBI:31174 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0162285 infores:hetionet CHEBI:64355 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0038362 infores:hetionet CHEBI:75922 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0018681 infores:hetionet CHEBI:75722 biolink:causes HP:0005986 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1320474 infores:hetionet CHEBI:7627 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0012833 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0037284 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0037284 infores:hetionet CHEBI:8356 biolink:causes HP:0020083 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0242301 infores:hetionet CHEBI:3614 biolink:causes HP:0002757 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0016655 infores:hetionet CHEBI:3756 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0151610 infores:hetionet CHEBI:29007 biolink:causes UMLS:C0241426 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0241426 infores:hetionet NCBIGene:8292 biolink:causes MONDO:0011281 infores:monarchinitiative not_provided not_provided HGNC:2226 MONDO:0011281 uuid:11978892-24e6-4af3-9c35-9d4fcd3c54d9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0065374 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0002871 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0036974 infores:hetionet NCBIGene:84888 biolink:causes MONDO:0030448 infores:monarchinitiative not_provided not_provided HGNC:30227 MONDO:0030448 uuid:ef3287c4-b27f-442a-94ba-d3f07f8d0222 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:11431811 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C3665347 infores:hetionet CHEBI:10102 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0919980 infores:hetionet CAID:CA410148112 biolink:causes MONDO:0011071 infores:clingen CAID:CA410148112 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PM6, PVS1, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP1 NM_001754.5(RUNX1):c.1104G>A (p.Met368Ile) is a missense variant which has a REVEL score < 0.50 (0.444) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410148112/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:31174 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00210 UMLS:C0858797 infores:hetionet CHEBI:15940 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0023066 infores:hetionet CHEBI:36791 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0013404 infores:hetionet CHEBI:31625 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0344232 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0030790 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0030790 infores:hetionet CHEBI:8776 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0344232 infores:hetionet CHEBI:46345 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0011603 infores:hetionet CHEBI:8768 biolink:causes MONDO:0001356 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0162316 infores:hetionet CAID:CA658799363 biolink:causes MONDO:0015967 infores:clingen CAID:CA658799363 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, BP4 PP4 The c.1064-19C>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, is predicted to create a new AG dinucleotide and thus potentially create a novel splice acceptor site in intron 8 of NM_175914.5. However, the computational splicing predictor SpliceAI gives a score of 0.01 for acceptor loss, suggesting that the variant has no impact on splicing (BP4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (internal lab contributors). In summary, c.1064-19C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA658799363/MONDO:0015967/085 2023-12-25 2023-12-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA437918487 biolink:causes MONDO:0001586 infores:clingen CAID:CA437918487 MONDO:0001586 PMID: Uncertain Significance PM2_Supporting PP3, PP4, BS2, BP4, BP7 The NM_000203.5:c.394C>T variant in IDUA is a synonymous (silent) variant (p.Leu132=) that is not predicted to impact splicing. It has not been reported previously in the literature, and whilst it is found in extremely low frequency in control populations, there are no other applicable criteria that support pathogenicity. The highest population minor allele frequency in gnomAD v4.0. is 8.477e-7 (1/1179650 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The nearest splice site is nine base pairs upstream: the splice AI score for the creation of a new splice acceptor site is 0.17 (higher than the threshold for BP4, <0.1, but lower than the threshold for PP3). There is a ClinVar entry for this variant (Variation ID: 1162140). Overall, this variant meets the criteria to be classified as a variant of uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0..0): PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA437918487/MONDO:0001586/010 2024-12-05 2025-03-19 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:31348 biolink:causes MONDO:0002181 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1442903 infores:hetionet CHEBI:9943 biolink:causes HP:0034274 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0237938 infores:hetionet CHEBI:41879 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0085932 infores:hetionet CHEBI:8024 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0026826 infores:hetionet CHEBI:44032 biolink:causes MONDO:0700226 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0016470 infores:hetionet CHEBI:3723 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0085636 infores:hetionet CHEBI:94609 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0042109 infores:hetionet CHEBI:6375 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0017979 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0009450 infores:hetionet CHEBI:75922 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB06802 UMLS:C0151529 infores:hetionet CHEBI:64321 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0235063 infores:hetionet CHEBI:71415 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0013404 infores:hetionet NCBIGene:7957 biolink:causes MONDO:0958199 infores:monarchinitiative not_provided not_provided HGNC:3413 MONDO:0958199 uuid:b24b0682-573f-4690-a5d6-6c4520e94cad biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3723 biolink:causes UMLS:C0919980 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0919980 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0020649 infores:hetionet CHEBI:45863 biolink:causes HP:0011457 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0271321 infores:hetionet CHEBI:3561 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0456909 infores:hetionet CHEBI:6887 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0015967 infores:hetionet CHEBI:3223 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0033774 infores:hetionet CHEBI:6717 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0038362 infores:hetionet CHEBI:36791 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0152032 infores:hetionet CHEBI:28748 biolink:causes MONDO:0001119 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0025322 infores:hetionet CHEBI:6970 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C2242996 infores:hetionet CHEBI:47612 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB01393 UMLS:C0151849 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0020538 infores:hetionet UNII:Z5N076G8YQ biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB08874 UMLS:C0267792 infores:hetionet CHEBI:27786 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0085932 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0041912 infores:hetionet CHEBI:15765 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0027497 infores:hetionet CHEBI:44032 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0030193 infores:hetionet CHEBI:5441 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C3665347 infores:hetionet CHEBI:4672 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0151904 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0242350 infores:hetionet CHEBI:15552 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0011570 infores:hetionet NCBIGene:27151 biolink:causes MONDO:0015017 infores:monarchinitiative not_provided not_provided HGNC:23228 MONDO:0015017 uuid:8ddb70e5-f1b5-4bb5-b0a8-29b42ac22ffa biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5864 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C3665347 infores:hetionet CAID:CA229448 biolink:causes MONDO:0009861 infores:clingen CAID:CA229448 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4_Moderate, PM2, PP3 The c.161T>C (p.Leu54Ser) variant in PAH is a missense variant that is predicted to be deleterious in multiple lines of computational evidence. This variant was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring the dihydropteridine reductase activity (PMID: 27121329). This variant was detected in trans with pathogenic variant c.912+1G>A. It was found in extremely low frequency in gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4 moderate, PM3, and PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229448/MONDO:0009861/006 2020-07-23 2021-02-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3568 biolink:causes HP:0001640 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0018800 infores:hetionet CHEBI:37941 biolink:causes MONDO:0021667 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0027796 infores:hetionet CHEBI:6754 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00454 UMLS:C0037763 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0262977 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0262977 infores:hetionet CAID:CA1706631 biolink:causes MONDO:0015152 infores:clingen CAID:CA1706631 MONDO:0015152 PMID: Benign BA1, BP4, BP7 The NM_003494.4: c.3520+34G>T variant in DYSF, which is also known as NM_001130987.2: c.3574+34G>T, is an intronic variant that is not located in a splice region. The filtering allele frequency for this variant is 0.005307 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 520/91026 South Asian chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). In addition, this variant is not predicted to impact splicing (SpliceAI score 0.01) (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/14/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA1706631/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:9123 biolink:causes HP:0002104 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0003578 infores:hetionet CHEBI:2704 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0030554 infores:hetionet CHEBI:8707 biolink:causes HP:5200415 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0151836 infores:hetionet CHEBI:40237 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01261 UMLS:C0017160 infores:hetionet CHEBI:9674 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0009806 infores:hetionet CHEBI:8774 biolink:causes UMLS:C0863113 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0863113 infores:hetionet CHEBI:83531 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0011991 infores:hetionet CHEBI:6128 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0015230 infores:hetionet CAID:CA308740635 biolink:causes MONDO:0011229 infores:clingen CAID:CA308740635 MONDO:0011229 PMID: Benign BS2, BA1, BP7 PM2 The allele frequency of the c.712+181A>G variant in the ETHE1 gene is reported as >12% in gnomAD, including 167 homozygotes, which is high enough to be classified as benign based on thresholds defined by the ClinGen ETHE1 Variant Curation Expert Panel (>0.1% in gnomAD- BA1 and BS2). In silico splicing predictors (Splice AI) for this intronic variant do not predict a deleterious effect (BP7). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA308740635/MONDO:0011229/014 2021-05-07 2021-05-07 Autosomal recessive inheritance HP:0000007 Contradicts https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:7915 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0853692 infores:hetionet GO:2000025 biolink:causes GO:0048367 infores:ubergraph knowledge_assertion manual_agent GO:2000025 GO:0048367 CHEBI:63619 biolink:causes HP:0011885 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0015402 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0151625 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0151625 infores:hetionet CHEBI:3568 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0028961 infores:hetionet CAID:CA2580098847 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098847 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, PVS1, PM6, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PP2, PP3, PP1, PP4, BS2 NM_001754.5(RUNX1):c.806-5T>C is an intronic variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has a SpliceAI score ≤ 0.20 (0.00) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (1.81) (BP7). Multiple lines of computational evidence suggest no impact on gene /gene product (SpliceAI score ≤ 0.20 (Δ score 0.00) (BP4). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098847/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9137 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0037822 infores:hetionet CHEBI:3696 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0002878 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0019360 infores:hetionet NCBITaxon:1763 biolink:causes MONDO:0005649 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1763 MESH:D001064 DB01606_MESH_D001064_1 CHEBI:51164 biolink:causes HP:0034782 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0221152 infores:hetionet CHEBI:94449 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0027769 infores:hetionet CHEBI:5001 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0149871 infores:hetionet CHEBI:15367 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0036454 infores:hetionet CHEBI:31547 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0010200 infores:hetionet CAID:CA014774 biolink:causes MONDO:0005045 infores:clingen CAID:CA014774 MONDO:0005045 PMID:22765922PMID:24093860PMID:20075948PMID:21239446PMID:15358028PMID:21252143PMID:15563892 Likely Pathogenic PM2, PP1, PS4 The c.428G>A (p.Arg143Gln) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:15563892; PMID:15358028; PMID:21252143; PMID:20075948; PMID:21239446; PMID:22765922; PMID:24093860; Partners LMM ClinVar SCV000059551.5). This variant segregated with disease in 4 affected individuals (PP1; Partners LMM ClinVar SCV000059551.5). This variant has been identified in 1/66732 European chromosomes (PM2; http://exac.broadinstitute.org). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PP1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA014774/MONDO:0005045/002 2015-12-16 2018-11-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:30830 biolink:causes UMLS:C0948525 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0948525 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0152227 infores:hetionet CHEBI:6456 biolink:causes UMLS:C0235339 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0235339 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0595928 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0595928 infores:hetionet CHEBI:32139 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0039621 infores:hetionet CHEBI:136040 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0014130 infores:hetionet CHEBI:44423 biolink:causes MONDO:0043771 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0034561 infores:hetionet CHEBI:94501 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0858797 infores:hetionet CHEBI:3242 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0043352 infores:hetionet CHEBI:184555 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00686 UMLS:C0028738 infores:hetionet CHEBI:135342 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0030846 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0019112 infores:hetionet CAID:CA275941 biolink:causes MONDO:0009861 infores:clingen CAID:CA275941 MONDO:0009861 PMID: Uncertain Significance PM5, PM2, PP3 The c.895T>C (p.Phe299Leu) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 208182); no further information is provided. At the time of review (5/25/19), the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant results in the substitution of a highly conserved Phenylalanine residue with Leucine; the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., predicted deleterious in SIFT, Polyphen2, Mutation Taster; REVEL= 0.96) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Another missense variant at this site, p.Phe299Cys, has been previously reported Pathogenic/Likely Pathogenic by seven submitters in ClinVar (variant ID 613), where it was noted to be a recurrent allele among Norwegian PKU patients and have in-vitro data supporting that it impaired protein function. Another missense variant at this site, Phe299Ser, has also been reported in the BioPKU database (PAH0800). These reports of those variants support use of PM5. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA275941/MONDO:0009861/006 2019-06-09 2019-06-09 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:30830 biolink:causes HP:0009763 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0030196 infores:hetionet CHEBI:61049 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0740394 infores:hetionet CHEBI:41423 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0009763 infores:hetionet CAID:CA916081956 biolink:causes MONDO:0011071 infores:clingen CAID:CA916081956 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PM6, PVS1, BP5, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+6T>C is an intronic variant not predicted to affect splicing (BP4). This variant has a SpliceAI score ≤ 0.20 (0.14) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.836)) (BP7). This variant is not present in any population databases (PM2_Supporting). In summary, the clinical significance of this variant is Likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA916081956/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:114785 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0013404 infores:hetionet CHEBI:3207 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0042790 infores:hetionet CHEBI:119573 biolink:causes EFO:0020911 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0029944 infores:hetionet CHEBI:4995 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0043352 infores:hetionet CHEBI:32293 biolink:causes UMLS:C0549405 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0549405 infores:hetionet CHEBI:50885 biolink:causes MONDO:0006604 infores:sider not_provided not_provided DRUGBANK:DB00687 UMLS:C0239488 infores:hetionet CAID:CA341515 biolink:causes MONDO:0008723 infores:clingen CAID:CA341515 MONDO:0008723 PMID: Likely Benign BP4, BP7 The c.1284G>A (p.Lys428=) variant (NM_000018.3) is a synonymous (silent) variant that is not predicted by NNSplice, MaxEntScan, and SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). The highest population minor allele frequency in gnomAD v4.1 is 0.001 in Non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA341515/MONDO:0008723/021 2025-04-22 2025-04-22 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:100241 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013404 infores:hetionet CHEBI:63791 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0000731 infores:hetionet CHEBI:691037 biolink:causes UMLS:C0877098 infores:sider not_provided not_provided DRUGBANK:DB00547 UMLS:C0877098 infores:hetionet CAID:CA1244064 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244064 MONDO:0020367 PMID:16466712PMID:11152659PMID:10545602PMID:11004290 Likely Benign BS1, BS3_Supporting BP7, PM2, PM6, PP3, PP1, PM4, PM5, PS4, PS3, PS1, PS2, BP4, BA1 The c.1193A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 398 (p.Lys398Arg). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.005978, which met the ≥ 0.001 threshold set for BS1 (772 alleles out of 129,138, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.207, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMID: 16466712, 10545602, 11004290) demonstrated that the Lys398Arg protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -6 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244064/MONDO:0020367/019 2022-05-10 2022-05-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:119573 biolink:causes MONDO:0007774 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0151889 infores:hetionet CHEBI:161680 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0518015 infores:hetionet CHEBI:94501 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0151766 infores:hetionet CHEBI:31625 biolink:causes NCIT:C50601 infores:sider not_provided not_provided DRUGBANK:DB00324 UMLS:C0151692 infores:hetionet CHEBI:9123 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0456909 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0020621 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0687675 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0687675 infores:hetionet CHEBI:231594 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0042571 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002289 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0022078 infores:hetionet CHEBI:7936 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C2830004 infores:hetionet CHEBI:36791 biolink:causes HP:0100790 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0019270 infores:hetionet CHEBI:8890 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0085631 infores:hetionet CHEBI:2453 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0013404 infores:hetionet CHEBI:4868 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0008031 infores:hetionet CHEBI:50173 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0017178 infores:hetionet CHEBI:2659 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0002792 infores:hetionet CHEBI:64321 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0030193 infores:hetionet CHEBI:8430 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0013144 infores:hetionet CAID:CA229647 biolink:causes MONDO:0009861 infores:clingen CAID:CA229647 MONDO:0009861 PMID: Likely Pathogenic PM2, PP4_Moderate, PP3, PM3_Supporting PM5 The c.609C>G (p.Cys203Trp) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded) detected with pathogenic variant c.1315+1G>A (P 13 submitters) parental analysis not performed. (PMID: 23430918). This variant has extremely low frequency in 1000G (MAF=0.0004) and is absent from gnomAD. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229647/MONDO:0009861/006 2020-02-22 2021-06-11 Autosomal recessive inheritance HP:0000007 Supports UMLS:C0065374 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0036974 infores:hetionet CHEBI:38940 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0549249 infores:hetionet CHEBI:8890 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0242184 infores:hetionet CHEBI:45367 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0011991 infores:hetionet CHEBI:28901 biolink:causes HP:0031246 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0850149 infores:hetionet CAID:CA10014278 biolink:causes MONDO:0011071 infores:clingen CAID:CA10014278 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BP7, BS1, BS3, BS4, PVS1, PM2, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.872T>C (p.Ile291Thr) is a missense variant which is reported at a MAF of 0.00007236 (0.007%, 3/41460 alleles) in the African/African American sub-population of the gnomAD v3.1.2 cohort and does not meet the threshold for BA1 (≥0.0015) or BS1 (0.00015 - 0.0015). The variant has a REVEL score of 0.228, which meets the threshold for BP4 (<0.50). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA10014278/MONDO:0011071/008 2024-08-12 2024-08-12 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3650 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0042963 infores:hetionet CHEBI:8093 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00388 UMLS:C0152227 infores:hetionet CAID:CA10638244 biolink:causes MONDO:0007648 infores:clingen CAID:CA10638244 MONDO:0007648 PMID: Benign BP2, BA1 BP5, BP7, BS1, BS4, BS3, PVS1, PM2, PM6, PM3, PM1, PM5, PM4, BS2, PP4, PP1, PP2, PP3, BP1, BP4, BP3, PS4, PS2, PS3, PS1 The NM_004360.5(CDH1):c.*589C>T variant has an allele frequency of 0.20460 (20%, 1769/8646 alleles, 174 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10638244/MONDO:0007648/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:6759 biolink:causes UMLS:C0002928 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0002928 infores:hetionet CHEBI:7454 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0018790 infores:hetionet CHEBI:6541 biolink:causes HP:0003365 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0019559 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0235969 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0235969 infores:hetionet CHEBI:75722 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1368065 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0035305 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0877104 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0877104 infores:hetionet CHEBI:49668 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0746883 infores:hetionet CHEBI:8212 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0027849 infores:hetionet CAID:CA201316 biolink:causes MONDO:0019565 infores:clingen CAID:CA201316 MONDO:0019565 PMID: Benign BA1, BP4 BP2 NM_000552.5(VWF):c.2220G>A is a missense variant that replaces methionine with isoleucine at position 740. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1791 (based on 13626/75022 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). This variant has been observed in multiple VWD Type 2M probands in cis with the NM_000552.5(VWF):c.3614G>A (p.Arg1205His) variant, with the phase of the variants confirmed by family segregation analysis (PMID: 10959712). This second variant has been classified Pathogenic for VWD Type 2M by the ClinGen VWD VCEP (BP2). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA201316/MONDO:0019565/090 2024-07-09 2024-08-12 Undetermined mode of inheritance Contradicts true CHEBI:6073 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0267792 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0160390 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0231785 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0231785 infores:hetionet CHEBI:27732 biolink:causes UMLS:C1096460 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1096460 infores:hetionet CAID:CA412744485 biolink:causes MONDO:0100437 infores:clingen CAID:CA412744485 MONDO:0100437 PMID: Likely Pathogenic PP3_Strong, PM2_Supporting, PS4_Supporting PVS1, PM6, PP4, BS2, PM4, PM5, PS1, PS3, PS2, BA1, BP4, BP3, BP7, BS1, BS4 NM_001034853.2(RPGR):c.593G>A (p.Gly198Glu) is a missense variant encoding the substitution of glycine by glutamate at amino acid 198. Another missense variant in the same codon, NM_001034853.2(RPGR):c.592G>A (p.Gly198Arg) (PMIDs: 34985506, 31456290), has been classified as pathogenic for RPGR-related retinopathy based on the ClinGen X-linked IRD VCEP specifications, while no benign missense variants have been identified in this codon. However, the present variant has a lower Grantham’s distance (98) than the comparison variant (125), so the PM5 code has not been applied. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 years and/or decreased or absent electroretinogram responses (PMID: 18552978, PMID: 32821524, PS4_Supporting). At least one proband harboring the variant exhibits a phenotype including diagnosis at age 25 years, extinguished electroretinogram responses from both rods and cones, night blindness (0.5 pts), visual field defects (0.5 pts), and reduced visual acuity (0.5 pts), which together are not sufficiently specific for RPGR-related retinopathy, so PP4 is not met (1.5 points, PMID: 32821524). The computational predictor REVEL gives a score of 0.980, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RPGR function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.15 for donor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not strongly predict that the variant disrupts RPGR splicing. In summary, this variant is classified as likely pathogenic for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PS4_Supporting, PP3_Strong, and PM2_Supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA412744485/MONDO:0100437/106 2025-09-07 2025-09-08 X-linked inheritance HP:0001417 Supports CHEBI:4995 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0149931 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0155919 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0155919 infores:hetionet CAID:CA2802372 biolink:causes MONDO:0001586 infores:clingen CAID:CA2802372 MONDO:0001586 PMID: Likely Benign BS1, BP4 The NM_000203.5:c.1727+32T>A variant is located in intron 12 of IDUA. The highest population minor allele frequency in gnomAD v4.1.0 is 0.003211 (144/44840 alleles; 1 homozygote; GrpMax Filtering Allele Frequency (95% confidence) = 0.002784) in the East Asian population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.0025), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (all scores are <0.1) (BP4). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets the criteria to be classified as likely benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA2802372/MONDO:0001586/091 2024-12-06 2024-12-16 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:48669 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0026858 infores:hetionet CHEBI:9635 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00539 UMLS:C0025061 infores:hetionet CHEBI:6520 biolink:causes UMLS:C2363730 infores:sider not_provided not_provided DRUGBANK:DB01206 UMLS:C2363730 infores:hetionet GO:1903110 biolink:causes GO:0006260 infores:ubergraph knowledge_assertion manual_agent GO:1903110 GO:0006260 CHEBI:499361 biolink:causes NCIT:C35135 infores:sider not_provided not_provided DRUGBANK:DB00673 UMLS:C0079027 infores:hetionet CHEBI:3561 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0028084 infores:hetionet CAID:CA1244271 biolink:causes MONDO:0020367 infores:clingen CAID:CA1244271 MONDO:0020367 PMID: Benign BP4, BA1 BP7, BS1, BS3, PM2, PM6, PP1, PP3, PM4, PM5, PS4, PS3, PS1, PS2 The c.477A>G variant in MYOC is a synonymous variant (p.Leu159=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07458, which met the ≥ 0.01 threshold set for BA1 (1,860 alleles out of 24,938, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The CADD score (v1.6) = 6.353, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 4.49 (threshold <0), indicating conservation at this site. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BP4. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244271/MONDO:0020367/019 2022-02-07 2022-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:27786 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0600142 infores:hetionet CHEBI:40279 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0231530 infores:hetionet CHEBI:8768 biolink:causes UMLS:C0151785 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0151785 infores:hetionet CHEBI:8888 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C1145670 infores:hetionet CHEBI:134966 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0011991 infores:hetionet CHEBI:44032 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0041912 infores:hetionet CHEBI:7936 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0042024 infores:hetionet CHEBI:17688 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C1527344 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0853700 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0853700 infores:hetionet CHEBI:50730 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0013144 infores:hetionet CHEBI:473990 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00442 UMLS:C0015967 infores:hetionet CHEBI:404903 biolink:causes UMLS:C0919691 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0919691 infores:hetionet CHEBI:63598 biolink:causes HP:0003158 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0232831 infores:hetionet CAID:CA512318685 biolink:causes MONDO:0011071 infores:clingen CAID:CA512318685 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.651G>A (p.Gly217=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 1.06724 < 2.0) (BP7). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512318685/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0657912 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0344232 infores:hetionet CAID:CA10549339 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549339 MONDO:0010305 PMID: Uncertain Significance PM2_Supporting BS3 The NM_005629.4:c.880A>C variant in SLC6A8 is a missense variant predicted to cause substitution of a lysine for a glutamine at amino acid position 294 (p.Lys294Gln). This variant has been reported in a heterozygous (carrier) female individual in the Exome Variant Server database without further phenotypic information provided (PMID: 25861866); thus, neither BS2 nor PP4 apply. This variant was reported to result in ≥50% of wild-type creatine transporter activity (PMID: 25861866) but experiment did not use physiological creatine concentrations (≤125μM creatine) so BS3 is not met (PMID: 25861866) (BS3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.39, which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.2) impact on SLC6A8 function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 11, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549339/MONDO:0010305/027 2024-04-11 2024-06-12 X-linked inheritance HP:0001417 Inconclusive true CAID:CA250380 biolink:causes MONDO:0044970 infores:clingen CAID:CA250380 MONDO:0044970 PMID: Pathogenic PP1_Moderate, PS3_Supporting, PM5, PM2_Supporting, PM6_Strong, PP3, PS4 PP4, BA1, BP4, BS1 The m.8993T>G (p.L156R) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 2137962, 8250532, 8240109, 7605802, 8505474, 9221962, 10208283, 16525806, 10660580). There are several reports of de novo occurrences of this variant (PM6_strong, PMIDs: 29602698, 27450679, 12134275). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>C (p.L156P) (PM5). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 2137962, 1436530, 1550128, 8095070, 9221962). This variant is absent in population databases after removing known patients with mitochondrial disease (PM2_supporting). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 14998933, 8078883, 19875463). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM5, PM6_strong, PP1_moderate, PP3). Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA250380/MONDO:0044970/014 2021-05-07 2021-06-10 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:5001 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0085932 infores:hetionet CAID:CA8623396 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623396 MONDO:0100326 PMID: Benign BP7, BA1 The NM_000212.3(ITGB3):c.1914-7C>T variant is an intronic variant that is not predicted by SpliceAI to impact splicing (delta score 0.00). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 0.35 (BP7). The highest population minor allele frequency in gnomAD v4.1 is 0.003668 (275/74966 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1). This variant has been reported in ClinVar (SCV003276340.2; SCV004813504.1) but to our knowledge, no occurrence of c.1914-7C>T in individuals affected with Glanzmann Thrombasthenia and no experimental evidence demonstrating its impact on protein function have been reported. In summary this variant is classified as Benign for autosomal recessive Glanzmann thrombasthenia, with ACMG criteria applied as specified by the PD VCEP: BA1, BP7. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623396/MONDO:0100326/011 2024-08-20 2024-08-20 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:404903 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0243026 infores:hetionet CHEBI:35778 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0232492 infores:hetionet CHEBI:4708 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0039231 infores:hetionet CHEBI:94609 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0242429 infores:hetionet CHEBI:9570 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C2979982 infores:hetionet CHEBI:6062 biolink:causes UMLS:C2242737 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C2242737 infores:hetionet CAID:CA386969822 biolink:causes MONDO:0015967 infores:clingen CAID:CA386969822 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PP4_Moderate, PP3 PM5, PP1 The c.1295C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to tyrosine at codon 432 (p.(p.Ser432Tyr)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody-negative, and sensitive to sulfonylureas) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.1295C>T p.Ser432Phe and c.1295C>G p.Ser432Cys, have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1295C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 1/11/2023): PP4_Moderate, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386969822/MONDO:0015967/017 2023-07-30 2023-07-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:10125 biolink:causes MONDO:0100338 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0042029 infores:hetionet CHEBI:3286 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0600142 infores:hetionet CAID:CA2579830479 biolink:causes MONDO:0015967 infores:clingen CAID:CA2579830479 MONDO:0015967 PMID: Likely Pathogenic PS3_Supporting, PP4_Moderate, PM2_Supporting, PM1_Supporting, PP1_Strong PS4 The c.-146T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant within the promoter of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is located within a conserved region of the PDX1 binding site in the promoter (c.-151, -149 to -143) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:11590126, internal lab contributors). One of these individuals did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and h/o neonatal hypoglycemia) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes with 10 informative meioses in two families (PP1_Strong; PMID: 11590126, internal lab contributors). Functional studies demonstrated the c.-146T>C variant results in transactivation activity below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 11590126). In summary, c.-146T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0; approved 6/30/2025): PP1_Strong, PP4_Moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2579830479/MONDO:0015967/085 2025-08-29 2025-08-29 Autosomal dominant inheritance HP:0000006 Supports CHEBI:49668 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0013404 infores:hetionet UNII:9430ZR8ZAN biolink:causes UMLS:C2748540 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C2748540 infores:hetionet CHEBI:64312 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0013456 infores:hetionet CAID:CA397954516 biolink:causes MONDO:0100453 infores:clingen CAID:CA397954516 MONDO:0100453 PMID: Likely Pathogenic PM3, PM1_Supporting, PP3_Moderate, PP4, PM2_Supporting NM_000180.4(GUCY2D):c.2833C>T (p.His945Tyr) is a missense variant that replaces histidine with tyrosine at position p.945, which is located within the guanylate cyclase catalytic domain that exhibits intolerance to missense variation (PM1_Supporting). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 6.199e-7, with 1 allele /1613264 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.2927G>T (p.Arg976Leu) variant confirmed in trans, which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PMID: 17525851, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), severely reduced vision (1 pt) with onset from birth (1 pt), nystagmus (1 pt), unremarkable fundus, irregular pigmentation (0.5 pts), hypermetropia, electroretinogram responses below the detection limit from both rods (0.5 pts) and cones (1 pt), and macular atrophy, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 17525851, PP4). The computational predictor REVEL gives a score of 0.975, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RETGC-1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM1_Supporting, PM2_Supporting, PM3, PP4, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA397954516/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0236075 infores:hetionet CHEBI:6847 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00232 UMLS:C0030305 infores:hetionet CHEBI:18357 biolink:causes UMLS:C1168188 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C1168188 infores:hetionet CHEBI:6538 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00455 UMLS:C0687713 infores:hetionet CHEBI:6775 biolink:causes MONDO:0019203 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0085786 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0015397 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001941 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0456909 infores:hetionet CHEBI:74947 biolink:causes UMLS:C0853149 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0853149 infores:hetionet CHEBI:17688 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0085633 infores:hetionet CHEBI:135342 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C1306341 infores:hetionet CAID:CA405682354 biolink:causes MONDO:0018493 infores:clingen CAID:CA405682354 MONDO:0018493 PMID: Uncertain Significance PS4_Supporting, BP4 PP3, PM1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of histidine with tyrosine at codon 2976 of the RYR1 protein, p.(His2976Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:20681998). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.201) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Supporting, BP4. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405682354/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CAID:CA293486 biolink:causes MONDO:0021060 infores:clingen CAID:CA293486 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1594A>G (p.Ser532Gly) variant in the SHOC2 gene is 1.147% (138/10402) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA293486/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true GO:1903719 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:1903719 GO:0051716 CAID:CA213777 biolink:causes MONDO:0015967 infores:clingen CAID:CA213777 MONDO:0015967 PMID: Uncertain Significance PM5, PP2, PP3, PM2_Supporting PP4 The c.322T>G variant in the glucokinase gene,GCK, causes an amino acid change of tyrosine to aspartic acid at codon 108 (p.(Tyr108Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported as likely pathogenic in ClinVar; however, no clinical information was provided (ClinVar ID: 36212). Another missense variant, c.322T>C p.Tyr108His,has been interpreted as pathogenic by the ClinGen MDEP, and p.Tyr108Asp has a greater Grantham distance (PM5). In summary, c.322T>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213777/MONDO:0015967/086 2024-01-18 2024-01-18 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:6067 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0032285 infores:hetionet CAID:CA5416784 biolink:causes MONDO:0011225 infores:clingen CAID:CA5416784 MONDO:0011225 PMID: Uncertain Significance BS2_Supporting BA1, BS1, PM2 The c.550A>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 184 (p.Ser184Cys).The filtering allele frequency (the upper threshold of the 95% CI of 23/44878 alleles) of the c.550A>T variant in DCLRE1C is 0.0003498 for East Asian chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). There is one homozygous occurrence in gnomAD v4, BS2_Supporting.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2_Supporting (VCEP specifications version 1). Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA5416784/MONDO:0011225/116 2024-06-13 2024-06-13 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5959 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0234987 infores:hetionet GO:0044617 biolink:causes GO:0044557 infores:ubergraph knowledge_assertion manual_agent GO:0044617 GO:0044557 CHEBI:3216 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0029408 infores:hetionet CHEBI:7581 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0011603 infores:hetionet CAID:CA9043761 biolink:causes MONDO:0012999 infores:clingen CAID:CA9043761 MONDO:0012999 PMID: Uncertain Significance PM2_Supporting, BP4, BP7 The NM_000156.6:c.228A>T (p.Ser76=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.250) (BP4, BP7). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001008 (6/59514 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1552732). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA9043761/MONDO:0012999/026 2024-10-08 2024-10-25 Autosomal recessive inheritance HP:0000007 Inconclusive true NCBIGene:5828 biolink:causes MONDO:0013932 infores:monarchinitiative not_provided not_provided HGNC:9717 MONDO:0013932 uuid:64af626f-dd4b-497f-b017-9db3035f56b5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:75722 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0178298 infores:hetionet CHEBI:101853 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0036974 infores:hetionet CHEBI:3716 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0030193 infores:hetionet CHEBI:47426 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0007682 infores:hetionet CHEBI:61049 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0151849 infores:hetionet UNII:DJJ95FJP1H biolink:causes MONDO:0029000 infores:sider not_provided not_provided DRUGBANK:DB01401 UMLS:C0032343 infores:hetionet CHEBI:16469 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0042373 infores:hetionet CHEBI:465284 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0003467 infores:hetionet CHEBI:77260 biolink:causes UMLS:C1096311 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C1096311 infores:hetionet CHEBI:36791 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151744 infores:hetionet CHEBI:63624 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0012833 infores:hetionet CHEBI:80630 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0022116 infores:hetionet CHEBI:42797 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0234458 infores:hetionet CAID:CA10360459 biolink:causes MONDO:0100039 infores:clingen CAID:CA10360459 MONDO:0100039 PMID: Benign BP5_Strong, BS2, BP4 BS1, PS4 The highest population minor allele frequency of the c.2086G>A (p.Ala696Thr) variant in CDKL5 in gnomAD v4.1 is 0.00005 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ala696Thr variant is observed in at least 2 unaffected individuals (GeneDx: internal database) (BS2). The p.Ala696Thr variant is found in at least 3 patients with an alternate molecular basis of disease (GeneDx: internal database) (BP5_Strong). The computational predictor REVEL gives a score of 0.198, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). In summary, the p.Ala696Thr variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BS2, BP4, BP5_Strong). (CDKL5 Specifications v4.0; curation approved on 02/28/2025). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10360459/MONDO:0100039/034 2025-02-28 2025-03-28 X-linked inheritance HP:0001417 Contradicts true CHEBI:6909 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0302295 infores:hetionet CHEBI:32588 biolink:causes UMLS:C0015376 infores:sider not_provided not_provided DRUGBANK:DB00761 UMLS:C0015376 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0853760 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0853760 infores:hetionet CHEBI:3568 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0006840 infores:hetionet NCBIGene:81570 biolink:causes MONDO:0859237 infores:monarchinitiative not_provided not_provided HGNC:30664 MONDO:0859237 uuid:d89fa648-e68f-4acd-88cb-70b1e22b004e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47780 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0023218 infores:hetionet CHEBI:8382 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0085631 infores:hetionet CHEBI:7507 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00994 UMLS:C0027497 infores:hetionet GO:0051445 biolink:causes GO:0019953 infores:ubergraph knowledge_assertion manual_agent GO:0051445 GO:0019953 CHEBI:68855 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0027497 infores:hetionet CHEBI:63616 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0001824 infores:hetionet CHEBI:3219 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0542571 infores:hetionet CHEBI:52717 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0014868 infores:hetionet CHEBI:47898 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0028738 infores:hetionet CHEBI:63637 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0037274 infores:hetionet CHEBI:28001 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0027540 infores:hetionet CHEBI:68478 biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C3665624 infores:hetionet CHEBI:42944 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0018965 infores:hetionet CHEBI:8888 biolink:causes MONDO:0001953 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0034359 infores:hetionet NCBIGene:403 biolink:causes MONDO:0032577 infores:monarchinitiative not_provided not_provided HGNC:694 MONDO:0032577 uuid:f560bc66-3062-45b9-8f85-57a650621f11 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:10125 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0424296 infores:hetionet CAID:CA350341736 biolink:causes MONDO:0015924 infores:clingen CAID:CA350341736 MONDO:0015924 PMID: Likely Pathogenic PM5_Supporting, PP3, PM2_Supporting, PM1_Strong BP4 The BMPR2 c.1156G>A variant is a missense variant predicted to cause a glutamic acid to lysine substitution at amino acid position 386. The variant is absent from the gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). The variant was reported in two manuscripts (PMID: 18503968 and PMID: 26387786), but they described the same patient, and therefore, PS4 is not met. Glu386Lys is located in the catalytic kinase domain and Glu386 is known to be an indispensable residue (PM1_strong). Other likely pathogenic missense variants causing a different amino acid change at the same residue have been reported, including Glu386Gln, Glu386Ala, Glu386Val, and Glu386Gly (PM5_supporting). Computational evidence for pathogenicity included a REVEL score of 0.961, which meets the threshold of >0.75 defined by the ClinGen Pulmonary Hypertension VCEP, and AlphaMissense 0.9961 (PP3 met but not BP4). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence. Similarly, functional data is unavailable for this variant, so BS3 and PS3 were not evaluated. In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA350341736/MONDO:0015924/125 2024-11-06 2024-11-06 Autosomal dominant inheritance HP:0000006 Supports CAID:CA624860664 biolink:causes MONDO:0008723 infores:clingen CAID:CA624860664 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PVS1 PP4 The c.565_587del (p.Ile189fs) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_supporting). This variant was found in an individual identified via newborn screening, however no second variant was detected. Residual VLCAD enzyme activity was 34% of normal. Therefore this proband is not considered in this clarification (PMID 21932095). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. VCEP specifications version 1; 11/8/21). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA624860664/MONDO:0008723/021 2022-09-20 2022-09-20 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5778 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0020580 infores:hetionet CHEBI:47898 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0041657 infores:hetionet CHEBI:94440 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0042963 infores:hetionet CAID:CA120595 biolink:causes MONDO:0044970 infores:clingen CAID:CA120595 MONDO:0044970 PMID: Likely Pathogenic PP3, PP1, PM2_Supporting, PS4_Moderate PS2, PS3, PM6 The m.8528T>C variant in MT-ATP6 (p.M1T), MT-ATP8 (p.W55R) has been reported in seven unrelated individuals with primary mitochondrial disease with lactic acidosis, hyperammonemia, and hypertrophic cardiomyopathy. The levels of the variant in affected individuals ranged from 15% to homoplasmic (PS4_moderate; PMIDs: 30642647, 33180048, 19188198). There are no reported de novo occurrences of this variant to our knowledge. The variant segregated with disease manifestations in three families. In the first report (PMID: 19188198), two healthy family members had lower levels of the variant than the proband (proband had variant at 92-98% in 5 tissues; unaffected mother had the variant at 15-25%; unaffected aunt at 0%). In the second report (PMID: 26803244), the proband had the variant present at 90% heteroplasmy in heart and 86% in fibroblasts at autopsy; the healthy mother had the variant present at 1.4% in fibroblasts. In the third report (PMID: 33180048), the proband was homoplasmic for the variant and the variant was heteroplasmic in his mother who had mild features (short stature, frequent migraines; 82% in blood, 89% in urine, and 59% in saliva; PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.63 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given two gene products are affected by this variant and the consistent biochemical phenotype reported. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120595/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6775 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0026821 infores:hetionet CHEBI:168396 biolink:causes MONDO:0021094 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0021051 infores:hetionet CHEBI:47898 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0085649 infores:hetionet CHEBI:53691 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0018681 infores:hetionet CHEBI:31236 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C2129214 infores:hetionet CHEBI:6367 biolink:causes MONDO:0004779 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014534 infores:hetionet CHEBI:2950 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0004096 infores:hetionet CHEBI:5106 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0039070 infores:hetionet CHEBI:3696 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0020437 infores:hetionet CHEBI:39585 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00190 UMLS:C0023530 infores:hetionet CHEBI:3479 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0008370 infores:hetionet CHEBI:7514 biolink:causes GO:0030432 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C0031133 infores:hetionet CHEBI:6149 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0026946 infores:hetionet CHEBI:39867 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0028738 infores:hetionet CHEBI:36791 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0156404 infores:hetionet CHEBI:3441 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0010200 infores:hetionet CHEBI:8768 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0030305 infores:hetionet CHEBI:49375 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0036974 infores:hetionet CHEBI:47781 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB01151 UMLS:C0152128 infores:hetionet NCBIGene:339855 biolink:causes MONDO:0014922 infores:monarchinitiative not_provided not_provided HGNC:26576 MONDO:0014922 uuid:aa91776c-3410-4a32-8566-a53af94eae83 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3996 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0015672 infores:hetionet CHEBI:7822 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0018681 infores:hetionet CAID:CA7176713 biolink:causes MONDO:0021060 infores:clingen CAID:CA7176713 MONDO:0021060 PMID: Benign BA1 The c.3755_3757del (p.Ile1252del) variant in SOS2 is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid in a non-repeat region. The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00217 in the African/African American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1. (RASopathy VCEP specifications version 2.1; 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA7176713/MONDO:0021060/042 2024-09-17 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:42797 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0152227 infores:hetionet CHEBI:3510 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0019080 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0595930 infores:hetionet CHEBI:4672 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0040046 infores:hetionet NCBIGene:3861 biolink:causes MONDO:0007551 infores:monarchinitiative not_provided not_provided HGNC:6416 MONDO:0007551 uuid:a0e629c7-9eca-4ae8-a4b7-5aeb0d131303 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:4849 biolink:causes MONDO:0032864 infores:monarchinitiative not_provided not_provided HGNC:7879 MONDO:0032864 uuid:c26ebbc3-4f0a-4a36-86b2-0ee2694fb606 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CL:0000767 biolink:causes GO:0002560 infores:ubergraph knowledge_assertion manual_agent CL:0000767 GO:0002560 CHEBI:27899 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0015230 infores:hetionet CHEBI:84500 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0009782 infores:hetionet CHEBI:5383 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0015230 infores:hetionet CHEBI:75246 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01220 UMLS:C0027947 infores:hetionet CHEBI:39867 biolink:causes HP:0032860 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0270823 infores:hetionet CHEBI:5118 biolink:causes HP:0040184 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0029163 infores:hetionet CHEBI:72292 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08903 UMLS:C0151905 infores:hetionet CHEBI:5801 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0033774 infores:hetionet CAID:CA147633 biolink:causes MONDO:0100039 infores:clingen CAID:CA147633 MONDO:0100039 PMID: Benign BS2, BA1 The allele frequency of the p.Thr1028= variant in CDKL5 is 2.6% in Ashkenazi Jewish sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Thr1028= variant is observed in at least 2 unaffected individuals (internal database, BS2). In summary, the p.Thr1028= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA147633/MONDO:0100039/016 2022-08-25 2022-09-06 X-linked inheritance HP:0001417 Contradicts https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true GO:0052028 biolink:causes GO:0007165 infores:ubergraph knowledge_assertion manual_agent GO:0052028 GO:0007165 CHEBI:9637 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0042514 infores:hetionet CHEBI:3387 biolink:causes MONDO:0002476 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0003460 infores:hetionet CHEBI:3175 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C3665386 infores:hetionet UMLS:C0879264 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0009782 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005391 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0035258 infores:hetionet CHEBI:63619 biolink:causes MONDO:0002471 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0006444 infores:hetionet CHEBI:15854 biolink:causes MONDO:0004670 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0409974 infores:hetionet CHEBI:4975 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0022354 infores:hetionet CHEBI:7824 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0019521 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0233632 infores:hetionet CHEBI:63611 biolink:causes HP:0008151 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0853225 infores:hetionet CHEBI:63638 biolink:causes UMLS:C0858603 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0858603 infores:hetionet CHEBI:35778 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00789 UMLS:C0018799 infores:hetionet CHEBI:6062 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0007222 infores:hetionet CHEBI:7640 biolink:causes HP:0002312 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0233844 infores:hetionet CHEBI:47898 biolink:causes MONDO:0001566 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0020437 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0018801 infores:hetionet CHEBI:7577 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0018965 infores:hetionet CHEBI:4784 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0151773 infores:hetionet CHEBI:51860 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0151905 infores:hetionet GO:0006954 biolink:causes MONDO:0005101 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D003093 DB06674_MESH_D003093_1DB00065_MESH_D003093_1DB00051_MESH_D003093_1 CHEBI:45863 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0040034 infores:hetionet CHEBI:8869 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0042963 infores:hetionet CHEBI:50838 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01395 UMLS:C0178298 infores:hetionet CHEBI:65173 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0013384 infores:hetionet CHEBI:72297 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0231218 infores:hetionet GO:0085032 biolink:causes GO:0007249 infores:ubergraph knowledge_assertion manual_agent GO:0085032 GO:0007249 UMLS:C0657912 biolink:causes UMLS:C0042018 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042018 infores:hetionet CHEBI:194135 biolink:causes HP:0012375 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0271298 infores:hetionet CHEBI:4974 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0151766 infores:hetionet UNII:R43D2573WO biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0428977 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0948594 infores:hetionet CHEBI:168396 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0085932 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0235196 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0235196 infores:hetionet CHEBI:45081 biolink:causes UMLS:C0341012 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0341012 infores:hetionet CHEBI:75045 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C0852911 infores:hetionet CHEBI:47780 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0948594 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0014130 infores:hetionet CHEBI:119915 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0035078 infores:hetionet CAID:CA10632147 biolink:causes MONDO:0015967 infores:clingen CAID:CA10632147 MONDO:0015967 PMID: Uncertain Significance BS1, PM2 The c.*391G>C variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the 3' untranslated region of NM_000545.8. This variant has a minor allele frequency greater than the ClinGen MDEP PM2_Supporting threshold of 0.00002 in the gnomAD European non-Finnish population (actual value=0.0001298) and a gnomAD Popmax filtering allele frequency less than the ClinGen MDEP BS1 threshold of 0.00003 (actual value = 0.00002243). In summary, c.*1071G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): None. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10632147/MONDO:0015967/017 2022-05-13 2022-05-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63845 biolink:causes UMLS:C0442886 infores:sider not_provided not_provided DRUGBANK:DB00634 UMLS:C0442886 infores:hetionet CHEBI:2904 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0043144 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0332575 infores:hetionet NCBIGene:2550 biolink:causes MONDO:0957779 infores:monarchinitiative not_provided not_provided HGNC:4070 MONDO:0957779 uuid:68a8f275-44b1-4024-b245-a0dda2a521e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2611 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00404 UMLS:C0241934 infores:hetionet CHEBI:8382 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C3263723 infores:hetionet CHEBI:9738 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0042109 infores:hetionet CHEBI:50924 biolink:causes UMLS:C1262013 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C1262013 infores:hetionet CHEBI:408174 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0021400 infores:hetionet CHEBI:63631 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0392171 infores:hetionet CHEBI:3723 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0006840 infores:hetionet CHEBI:135888 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0009763 infores:hetionet CHEBI:83804 biolink:causes MONDO:0004981 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0004238 infores:hetionet CHEBI:116278 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0232462 infores:hetionet CAID:CA120644 biolink:causes MONDO:0044970 infores:clingen CAID:CA120644 MONDO:0044970 PMID:16996290 Uncertain Significance PP3, PM2_Supporting, PS3_Supporting The m.4681T>C (p.L71P) variant in MT-ND2 has been reported in one individual with primary mitochondrial disease to date, in a boy with Leigh syndrome and generalized muscle atrophy (PMIDs: 16996290, 16738010). He had elevated blood and cerebrospinal fluid lactate. Complex I deficiency was noted in skin fibroblasts. The variant was present at >95% heteroplasmy in blood, muscle, and fibroblasts. The variant was absent in his mother although technology performed at the time was limited in detecting low heteroplasmy levels. This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting, note the single occurrence in MITOMAP is likely from the reported patient). The computational predictor APOGEE suggests this variant is pathogenic (0.52, range 0-1; PP3). Cybrid studies supported the functional impact of this variant as mutant cybrids had reduced complex I activity and impaired complex I assembly (PS3_supporting; PMID: 16996290). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120644/MONDO:0044970/015 2023-10-23 2025-06-05 Mitochondrial inheritance HP:0001427 Inconclusive https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria true CHEBI:5864 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0018801 infores:hetionet CHEBI:3207 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0085649 infores:hetionet CHEBI:63631 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0042373 infores:hetionet CHEBI:3207 biolink:causes HP:0001609 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0019825 infores:hetionet CHEBI:94686 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0851578 infores:hetionet UMLS:C0010592 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0021177 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0041912 infores:hetionet NCBIGene:10735 biolink:causes MONDO:0026763 infores:monarchinitiative not_provided not_provided HGNC:11355 MONDO:0026763 uuid:6c8ea6e0-ef43-4139-a0fd-9355857cfe64 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8356 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0022107 infores:hetionet CHEBI:8888 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0033860 infores:hetionet CHEBI:8245 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0003123 infores:hetionet CHEBI:5138 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0277925 infores:hetionet CHEBI:3996 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00924 UMLS:C0344315 infores:hetionet CHEBI:140621 biolink:causes UMLS:C0428886 infores:sider not_provided not_provided DRUGBANK:DB00565 UMLS:C0428886 infores:hetionet CHEBI:8207 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0700200 infores:hetionet CHEBI:9086 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0011168 infores:hetionet CHEBI:92712 biolink:causes NCIT:C50622 infores:sider not_provided not_provided DRUGBANK:DB00572 UMLS:C0392684 infores:hetionet CHEBI:6367 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0042384 infores:hetionet CHEBI:36791 biolink:causes MONDO:0006814 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0022081 infores:hetionet CHEBI:7454 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0043144 infores:hetionet CHEBI:44185 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0235896 infores:hetionet CHEBI:6923 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01110 UMLS:C0232462 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0239385 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0239385 infores:hetionet CHEBI:10124 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0236071 infores:hetionet CHEBI:4024 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0043352 infores:hetionet CHEBI:5855 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0002792 infores:hetionet CHEBI:94449 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00986 UMLS:C0152198 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031117 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0039503 infores:hetionet CHEBI:175901 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0042963 infores:hetionet NCBIGene:121391 biolink:causes MONDO:0013514 infores:monarchinitiative not_provided not_provided HGNC:28929 MONDO:0013514 uuid:c18bacbe-ef73-469c-8492-1191387f74e9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63627 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0030794 infores:hetionet CHEBI:32315 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C0149931 infores:hetionet CHEBI:27732 biolink:causes UMLS:C1295666 infores:sider not_provided not_provided DRUGBANK:DB00201 UMLS:C1295666 infores:hetionet NCBIGene:84876 biolink:causes MONDO:0013007 infores:monarchinitiative not_provided not_provided HGNC:25896 MONDO:0013007 uuid:1862cf75-15e5-4284-aea3-24fc1dd67998 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:231594 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0041969 infores:hetionet UNII:3QJA87N40S biolink:causes MONDO:0008559 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0042487 infores:hetionet CHEBI:9123 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0026821 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0151539 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0020538 infores:hetionet CHEBI:8863 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020578 infores:hetionet CHEBI:4975 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0036572 infores:hetionet CHEBI:17987 biolink:causes UMLS:C1323189 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C1323189 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0033860 infores:hetionet NCBIGene:1351 biolink:causes MONDO:0033650 infores:monarchinitiative not_provided not_provided HGNC:2294 MONDO:0033650 uuid:70d514c6-74e8-48d0-80be-a87cabba4ed0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8874 biolink:causes HP:0003468 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0158775 infores:hetionet CHEBI:37941 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00758 UMLS:C0178298 infores:hetionet CHEBI:15765 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0234215 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002691 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0345904 infores:hetionet CHEBI:171719 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0349506 infores:hetionet CHEBI:3082 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0917801 infores:hetionet CHEBI:9943 biolink:causes MONDO:0005538 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0033246 infores:hetionet GO:0045445 biolink:causes CL:0000056 infores:ubergraph knowledge_assertion manual_agent GO:0045445 CL:0000056 CHEBI:64064 biolink:causes MONDO:0043370 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0271738 infores:hetionet CHEBI:9725 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01246 UMLS:C0027765 infores:hetionet CHEBI:2682 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0023218 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0018799 infores:hetionet CHEBI:32293 biolink:causes MONDO:0008375 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0035305 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021445 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0347197 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0314719 infores:hetionet CHEBI:45081 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0020580 infores:hetionet NCBIGene:3655 biolink:causes MONDO:0859233 infores:monarchinitiative not_provided not_provided HGNC:6142 MONDO:0859233 uuid:81ed7112-cc81-479b-a05c-287808332f2a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UMLS:C0657912 biolink:causes UMLS:C0085625 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0085625 infores:hetionet CHEBI:52010 biolink:causes MONDO:0002008 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0022893 infores:hetionet CHEBI:3077 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0003811 infores:hetionet CHEBI:4868 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0013604 infores:hetionet CHEBI:50859 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0030794 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0011603 infores:hetionet CHEBI:10119 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0151878 infores:hetionet NCBITaxon:1769 biolink:causes MONDO:0005124 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1769 MESH:D007918 DB00845_MESH_D007918_1DB00250_MESH_D007918_1 CHEBI:175901 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0038362 infores:hetionet CHEBI:63607 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0030554 infores:hetionet CHEBI:7824 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0015672 infores:hetionet CHEBI:3561 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0039231 infores:hetionet CHEBI:3380 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01197 UMLS:C0012833 infores:hetionet CHEBI:3696 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0013604 infores:hetionet CHEBI:100246 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0004604 infores:hetionet CHEBI:46081 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C1167965 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0151609 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0151609 infores:hetionet CHEBI:45863 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0013384 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0233494 infores:hetionet CHEBI:7454 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0000737 infores:hetionet CHEBI:50122 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0234632 infores:hetionet CHEBI:31547 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0039070 infores:hetionet CHEBI:63618 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0030554 infores:hetionet CHEBI:50729 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0854467 infores:hetionet CAID:CA333546 biolink:causes MONDO:0007113 infores:clingen CAID:CA333546 MONDO:0007113 PMID: Likely Benign BS2, BP7 PM2, BS1 The p.Asp607= variant in UBE3A (NM_130838.2) is present in 6 XX and 6 XY individual(s) in gnomAD v4 (0.005%) (not sufficient to meet BS1 criteria). The p.Asp607= variant is observed in at least 4 unaffected individuals (internal database - GeneDx) (BS2). The silent p.Asp627= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Asp607= variant in UBE3A (NM_130838.2) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA333546/MONDO:0007113/037 2023-12-06 2023-12-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9137 biolink:causes MONDO:0002406 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0013595 infores:hetionet CHEBI:4356 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0042109 infores:hetionet CHEBI:64354 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0009806 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0855652 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0855652 infores:hetionet CHEBI:52717 biolink:causes MONDO:0024313 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0038160 infores:hetionet CHEBI:119915 biolink:causes HP:0025095 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0037383 infores:hetionet CHEBI:4027 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0041582 infores:hetionet CHEBI:4453 biolink:causes HP:0025272 infores:sider not_provided not_provided DRUGBANK:DB00304 UMLS:C0025218 infores:hetionet NCBIGene:5795 biolink:causes MONDO:0957578 infores:monarchinitiative not_provided not_provided HGNC:9673 MONDO:0957578 uuid:5e34bed0-d2a7-4061-9abc-072c95bcdfd6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes UMLS:C0700184 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0700184 infores:hetionet CHEBI:3127 biolink:causes UMLS:C0239375 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0239375 infores:hetionet NCBIGene:38 biolink:causes MONDO:0008760 infores:monarchinitiative not_provided not_provided HGNC:93 MONDO:0008760 uuid:91d6b4b7-18d5-4781-98ce-1b8a1cd2ed41 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0025245 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0241060 infores:hetionet CHEBI:40303 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0033774 infores:hetionet CHEBI:4995 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151905 infores:hetionet CHEBI:135342 biolink:causes MONDO:0005137 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0162429 infores:hetionet UMLS:C0879264 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151699 infores:hetionet CHEBI:63611 biolink:causes MONDO:0006874 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0022354 infores:hetionet CHEBI:51041 biolink:causes MONDO:0008383 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0003873 infores:hetionet CHEBI:6541 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0017979 infores:hetionet CHEBI:15365 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00945 UMLS:C0036974 infores:hetionet CHEBI:36795 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0019080 infores:hetionet CHEBI:6950 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0015230 infores:hetionet CHEBI:64310 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0085605 infores:hetionet CHEBI:41423 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0042963 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001866 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0853193 infores:hetionet CHEBI:47381 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C1443060 infores:hetionet CHEBI:59773 biolink:causes MONDO:0019127 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0085655 infores:hetionet CHEBI:9328 biolink:causes UMLS:C0151788 infores:sider not_provided not_provided DRUGBANK:DB00359 UMLS:C0151788 infores:hetionet UMLS:C1738934 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0038663 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0851341 infores:hetionet CHEBI:40050 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00701 UMLS:C0017178 infores:hetionet CHEBI:3441 biolink:causes UMLS:C0267821 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0267821 infores:hetionet CHEBI:17474 biolink:causes MONDO:0002256 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0007867 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0042109 infores:hetionet NCBIGene:51594 biolink:causes MONDO:0014659 infores:monarchinitiative not_provided not_provided HGNC:15625 MONDO:0014659 uuid:4b9f0987-a051-4cfb-9efa-60bed57ce8d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8107 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151888 infores:hetionet CHEBI:45783 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0042373 infores:hetionet CHEBI:75045 biolink:causes NCIT:C26945 infores:sider not_provided not_provided DRUGBANK:DB08912 UMLS:C2979982 infores:hetionet GO:1901190 biolink:causes GO:0010467 infores:ubergraph knowledge_assertion manual_agent GO:1901190 GO:0010467 UMLS:C0011701 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0003467 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008114 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0600104 infores:hetionet CHEBI:171719 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C1565489 infores:hetionet CHEBI:10102 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0009319 infores:hetionet CHEBI:6690 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0014518 infores:hetionet UNII:9430ZR8ZAN biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0042571 infores:hetionet CHEBI:63617 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0030193 infores:hetionet CHEBI:50648 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0547030 infores:hetionet CHEBI:51380 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0026961 infores:hetionet CHEBI:584020 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C1443060 infores:hetionet CHEBI:5864 biolink:causes UMLS:C1095923 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C1095923 infores:hetionet CHEBI:16714 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00318 UMLS:C0041969 infores:hetionet CHEBI:50659 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB04855 UMLS:C0013378 infores:hetionet CAID:CA255146 biolink:causes MONDO:0010602 infores:clingen CAID:CA255146 MONDO:0010602 PMID: Pathogenic PS2_Very Strong, PVS1, PM2_Supporting, PS4 The F8 c.3637del (p.Ile1213Phefs*5) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay. This variant is completely absent from males in gnomAD v2.1.1 and gnomAD v3. This variant has been reported in >16 probands with moderate to severe hemophilia, meeting phenotypic criteria for F8 (PMID: 15921397; PMID: 20533009; PMID: 8307558; PMID: 16601827). This variant has been reported both with and without the development of inhibitors. This variant is reported as de novo in at least seven probands with maternity confirmed in the affected male (PMID: 29381227). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1, PS2_Very Strong, PS4_Very Strong, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023) Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA255146/MONDO:0010602/071 2024-06-25 2024-07-10 X-linked inheritance HP:0001417 Supports CHEBI:135342 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0025345 infores:hetionet CHEBI:36795 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0039070 infores:hetionet CHEBI:48669 biolink:causes MONDO:0001703 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0242225 infores:hetionet CHEBI:8764 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0151849 infores:hetionet CHEBI:87715 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0020517 infores:hetionet CHEBI:47780 biolink:causes HP:0002353 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0151611 infores:hetionet UMLS:C0010592 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0043352 infores:hetionet CHEBI:3175 biolink:causes UMLS:C0855704 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0855704 infores:hetionet CHEBI:70707 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB06684 UMLS:C0424000 infores:hetionet CHEBI:28748 biolink:causes NCIT:C78509 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0221776 infores:hetionet CAID:CA7963834 biolink:causes MONDO:0700272 infores:clingen CAID:CA7963834 MONDO:0700272 PMID: Likely Benign BP7, BP4 BS1, PM2 The c.135G>A (p.Lys45=) variant is a synonymous (silent) variantthat is not predicted by MaxEntScan or SpliceAI to impact splicing. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000008791 in the European non-Finnish population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP4, BP7) Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA7963834/MONDO:0700272/077 2023-04-05 2025-09-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:135285 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB04876 UMLS:C0948594 infores:hetionet CHEBI:135935 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06204 UMLS:C0020649 infores:hetionet CHEBI:41774 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0021368 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005111 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0149678 infores:hetionet CHEBI:3485 biolink:causes MONDO:0015925 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0206062 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0518015 infores:hetionet CHEBI:520985 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0042514 infores:hetionet CHEBI:2637 biolink:causes HP:0002157 infores:sider not_provided not_provided DRUGBANK:DB00479 UMLS:C0242528 infores:hetionet CHEBI:50924 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00398 UMLS:C0013922 infores:hetionet CHEBI:75998 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0011991 infores:hetionet CHEBI:29013 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB02703 UMLS:C0015397 infores:hetionet CHEBI:8863 biolink:causes UMLS:C0151898 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0151898 infores:hetionet CHEBI:83804 biolink:causes NCIT:C80098 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0333243 infores:hetionet CHEBI:134966 biolink:causes HP:0002133 infores:sider not_provided not_provided DRUGBANK:DB06201 UMLS:C0038220 infores:hetionet CHEBI:82960 biolink:causes UMLS:C1168174 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C1168174 infores:hetionet CHEBI:9435 biolink:causes MONDO:0005296 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0037315 infores:hetionet CHEBI:6775 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0001925 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0021053 infores:hetionet CHEBI:45409 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0011570 infores:hetionet CHEBI:4636 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0011603 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0521481 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0521481 infores:hetionet CHEBI:37924 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0014457 infores:hetionet CAID:CA8459436 biolink:causes MONDO:0011132 infores:clingen CAID:CA8459436 MONDO:0011132 PMID: Uncertain Significance PP3, PP4 BS1, PM2 NM_001369369.1(FOXN1):c.1135+5G>C is a splice site variant found after exon 7. The variant has a pop-max allele frequency of 0.0001044 based upon the admixed American subpopulation, which is greater than 0.0000447 and less than 0.00141 and thus does not meet PM2_supporting or BS1. At least one heterozygous patient has been reported with an absent thymic shadow, low T cell count for age 0.8x10^9/L, and low TRECs (P7 from PMID: 31447097, PP4). The patient was also sequenced and reportedly negative for other SCID causing genes. AI predictive splicing algorithm splice AI predicts a score of 0.26 for acceptor site loss (PP3). In summary this variant meets criteria to be classified as a variant of uncertain significance for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PP3 and PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA8459436/MONDO:0011132/113 2024-07-29 2024-07-29 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:4708 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0016204 infores:hetionet NCBIGene:1406 biolink:causes MONDO:0007362 infores:monarchinitiative not_provided not_provided HGNC:2383 MONDO:0007362 uuid:0fb87b7e-4a67-4439-8d3c-0c54f5e79882 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:29688 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C2242588 infores:hetionet CHEBI:6149 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0003862 infores:hetionet CHEBI:4975 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0917801 infores:hetionet CHEBI:6933 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C0037763 infores:hetionet CHEBI:50122 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0017178 infores:hetionet CHEBI:65349 biolink:causes MONDO:0006032 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0010692 infores:hetionet CHEBI:31547 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0700225 infores:hetionet CHEBI:68558 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0012833 infores:hetionet CHEBI:8863 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020517 infores:hetionet CHEBI:4907 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB01077 UMLS:C0023530 infores:hetionet CHEBI:83527 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0042075 infores:hetionet GO:0043484 biolink:causes GO:0032774 infores:ubergraph knowledge_assertion manual_agent GO:0043484 GO:0032774 GO:0071671 biolink:causes GO:0070887 infores:ubergraph knowledge_assertion manual_agent GO:0071671 GO:0070887 CHEBI:135929 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB06207 UMLS:C0855242 infores:hetionet CHEBI:5383 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0038325 infores:hetionet CAID:CA512341074 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341074 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1308C>T (p.Ser436=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341074/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA229495 biolink:causes MONDO:0009861 infores:clingen CAID:CA229495 MONDO:0009861 PMID: Likely Pathogenic PM3, PP4, PM2_Supporting, PP3_Moderate PM5 The c.232G>A (p.Glu78Lys) variant in PAH has been reported in at least two individuals with plasma Phe levels > 120 umol/L; in one patient, it was observed with c.194T>C (p.Ile65Thr) (classified as pathogenic by PAH VCEP Variation ID: 636) and in the other it was observed with c.1222C>T (p.Arg408Trp) (classified as pathogenic by PAH VCEP Variation ID: 577). Confirmation of phase and exclusion of BH4 deficiency were not specified (PMID: 23430918). c.232G>A has also been described without further information in two additional publications (PMID: 32668217, 32305867). Finally, c.232G>A has been observed in a patient with moderate PKU who also had c.1045T>C (p.Ser349Pro), which is not classified by the PAH VCEP (PMID: 31623983). In-vitro functional studies are unavailable. The Pop Max allele frequency is [8.476e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) for PM2_Supporting. In-silico predictions suggest this variant is pathogenic (REVEL=0.831). In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4, PM2-supporting, PP3-moderate. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229495/MONDO:0009861/006 2024-11-17 2024-11-17 Autosomal recessive inheritance HP:0000007 Supports CHEBI:47499 biolink:causes MONDO:0007240 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0006384 infores:hetionet CHEBI:6437 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0015397 infores:hetionet CAID:CA10654542 biolink:causes MONDO:0100488 infores:clingen CAID:CA10654542 MONDO:0100488 PMID: Benign BA1, BP2 BP5, BP7, BS1, BS4, BS3, PM3, PM1, PM4, PM5, PM2, PM6, PVS1, PP4, PP1, PP2, PP3, BS2, BP1, BP4, BP3, PS2, PS4, PS3, PS1 The NM_004360.4(CDH1):c.*2047A>G variant has an allele frequency of 0.99679 (99.68%, 8690/8718 alleles, 4331 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10654542/MONDO:0100488/007 2023-08-10 2023-08-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:80630 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0025061 infores:hetionet CHEBI:44423 biolink:causes UMLS:C0235416 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0235416 infores:hetionet CHEBI:6801 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0016204 infores:hetionet NCBIGene:2990 biolink:causes MONDO:0009662 infores:monarchinitiative not_provided not_provided HGNC:4696 MONDO:0009662 uuid:18ace84f-adf6-44af-ae0d-8d38abfe59df biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:59582 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00838 UMLS:C0011616 infores:hetionet CHEBI:135005 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0001807 infores:hetionet CHEBI:100147 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0014742 infores:hetionet CHEBI:9738 biolink:causes MONDO:0006777 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0235347 infores:hetionet CHEBI:5103 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0018681 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0021053 infores:hetionet CHEBI:29688 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0000731 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0263445 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0263445 infores:hetionet UMLS:C0010592 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0015230 infores:hetionet CHEBI:50859 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0011616 infores:hetionet CAID:CA234050 biolink:causes MONDO:0009290 infores:clingen CAID:CA234050 MONDO:0009290 PMID:24590251PMID:30564623PMID:21484825PMID:25544546PMID:27708273PMID:22644586 Pathogenic PP4_Moderate, PM2, PM3, PS3, PP3_Moderate PM5 This variant, c.1841C>A (p.Thr614Lys), has been found in two patients published in the literature and five patients in a clinical diagnostic laboratory who have Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. These patients are compound heterozygous for the variant and either c.1076–22T>G (PMID 21484825), c.-32-13T>G (PMID 24590251, 2 laboratory patients), c.2481+102_2646+31del (one patient), c.1402A>T (p.Ile468Phe) (one patient), and unconfirmed second variant (one patient). The phase of the variants is unknown for all patients. This in trans data meets PM3. Pseudodeficiency variants are absent in the patients identified in the clinical laboratory. Therefore, PP4_Moderate can be applied. When expressed in COS cells, this variant resulted in <5% wild type activity in cells and <2% wild type activity in medium, in addition to exhibiting abnormal synthesis and processing (PMID 22644586), meeting PS3. The score for the REVEL in silico predictor, 0.835, also suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 167113, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PP3, PP4_Moderate. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA234050/MONDO:0009290/010 2020-04-21 2020-05-28 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:17823 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0027441 infores:hetionet CHEBI:47381 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0036572 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0392197 infores:hetionet UNII:UMD7G2653W biolink:causes UMLS:C3665624 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C3665624 infores:hetionet CHEBI:194135 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1145670 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004496 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027059 infores:hetionet CHEBI:50859 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0043094 infores:hetionet CHEBI:50729 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0740394 infores:hetionet CHEBI:17026 biolink:causes HP:0040298 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0014173 infores:hetionet CHEBI:100246 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0085593 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0948594 infores:hetionet CHEBI:45285 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0740394 infores:hetionet CHEBI:61049 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C3160858 infores:hetionet CAID:CA16603947 biolink:causes MONDO:0100038 infores:clingen CAID:CA16603947 MONDO:0100038 PMID: Uncertain Significance PM2_Supporting, PP3_Moderate, PS1_Moderate PS4 The c.1170+5G>C (NM_001165963.4) variant in SCN1A is an intronic variant predicted to cause substitution of Guanine by Cytosine at nucleotide 1170+5. The variant has been reported in at least 1 proband with a phenotype of Epilepsy NOS (LabCorp Genetics Inc). It is absent from the population database gnomAD v3.1.2 and v4.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.88 for donor loss, predicting that the variant disrupts the donor splice site of intron 11 of SCN1A (PP3_Moderate). A different variant at the same position (c.1170+5G>A)(PMID:31069529, 31440721, ClinVar ID:646111) has been classified as Likely Pathogenic for Complex Neurodevelopmental Disorder by the ClinGen Sodium Channel Variant Curation Expert Panel (PS1_Moderate). An additional variant (c.1170+5G>T) has been reported in a patient with Epilepsy NOS (ClinVar ID:851265, LabCorp Genetics Inc). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Sodium Channel Variant Curation Expert Panel. In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP:PS1_Moderate, PM2_Supporting, PP3_Moderate. (version 1.0; September 24, 2024). Epilepsy Sodium Channel VCEP https://erepo.genome.network/evrepo/ui/classification/CA16603947/MONDO:0100038/067 2024-10-01 2024-11-05 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:9086 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0026826 infores:hetionet CAID:CA913178210 biolink:causes MONDO:0044970 infores:clingen CAID:CA913178210 MONDO:0044970 PMID: Likely Pathogenic PP3, PS4_Supporting, PM2_Supporting, PS2_Moderate, PS3_Supporting PP1, PM6 The m.4450G>A variant in MT-TM has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). The first individual reported was a girl with childhood onset myopathy (fatigue, proximal muscle weakness, exercise intolerance) and developmental delay. Muscle biopsy revealed COX-negative fibers and a combined respiratory chain enzyme deficiency. The variant was present at 67% in muscle, 10% in fibroblasts, and was undetectable in blood and buccal samples (PMID: 25468263). The variant was undetectable in her healthy mother’s blood, muscle, and urinary sediment (PS2_moderate). The second individual reported was a girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and the variant was present at varying levels (20-59%) in several tissues tested. Fibroblasts in this individual showed reduced oxygen consumption and reduced activities of respiratory chain complexes I and IV (PMID: 30739820). There are no other large families reported in the medical literature to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic (83.7 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed high heteroplasmy levels in ragged blue fibers (94% ± 5.4%) and variant was not detected in normal appearing fibers (PMID: 25468263, PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 27, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS2_moderate, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA913178210/MONDO:0044970/015 2023-02-27 2023-03-16 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:4710 biolink:causes UMLS:C0581912 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0581912 infores:hetionet CHEBI:63681 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0039231 infores:hetionet CHEBI:144093 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0042963 infores:hetionet CHEBI:51041 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0020517 infores:hetionet CHEBI:15854 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0041349 infores:hetionet CHEBI:135736 biolink:causes HP:0012542 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0263536 infores:hetionet CHEBI:100241 biolink:causes HP:0410019 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0232493 infores:hetionet CHEBI:8665 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0030554 infores:hetionet CHEBI:63577 biolink:causes UMLS:C0549297 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0549297 infores:hetionet CAID:CA658795256 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795256 MONDO:0009290 PMID: Pathogenic PVS1, PP4_Moderate, PM3, PM2_Supporting The NM_000152.5(GAA):c.1396del (p.Val466PhefsTer11) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 3 probands with residual GAA activity below the normal range or <10% normal (PMIDs 18285536, 23601496, 25786784) one of whom is also reported to be CRIM-negative and to have clinical improvements when on enzyme replacement therapy (PMID 23601496), as well as in an adult proband and her affected sibling with muscle weakness (PP4_Moderate). Three of these probands are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.-32-13T>G (PMID 25786784), c.2238G>C (p.Trp746Cys) (PMID 25526786), or c.1705dupT (PMID 23601496) Another proband is compound heterozygous for the variant and c.784G>A (p.Gln262Lys) (PMID 18285536); the allelic data from this patient was used in the assessment of p.Gln262Lys and is not included here to avoid circular logic (PM3). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2): PVS1, PM3, PP4_Moderate, PM2_Supporting. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795256/MONDO:0009290/010 2022-01-04 2022-01-04 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:87715 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0017178 infores:hetionet CHEBI:15367 biolink:causes NCIT:C78516 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0241136 infores:hetionet CHEBI:8502 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0013378 infores:hetionet CHEBI:9139 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0042109 infores:hetionet NCBIGene:5290 biolink:causes MONDO:0011723 infores:monarchinitiative not_provided not_provided HGNC:8975 MONDO:0011723 uuid:7cb9b1eb-0e54-4417-af0f-95463487d1e1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:0044483 biolink:causes GO:0007599 infores:ubergraph knowledge_assertion manual_agent GO:0044483 GO:0007599 CHEBI:116278 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0236075 infores:hetionet CHEBI:15407 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0917801 infores:hetionet CHEBI:41423 biolink:causes MONDO:0001752 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0013240 infores:hetionet CHEBI:51860 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0001807 infores:hetionet CHEBI:6965 biolink:causes MONDO:0009256 infores:sider not_provided not_provided DRUGBANK:DB01618 UMLS:C0235660 infores:hetionet CHEBI:17650 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0013922 infores:hetionet CHEBI:28593 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0027540 infores:hetionet CHEBI:47657 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB01656 UMLS:C0178298 infores:hetionet CHEBI:75998 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0020621 infores:hetionet CHEBI:261649 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0013378 infores:hetionet CHEBI:63623 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00566 UMLS:C0013428 infores:hetionet CHEBI:9130 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0036974 infores:hetionet CAID:CA293962 biolink:causes MONDO:0100488 infores:clingen CAID:CA293962 MONDO:0100488 PMID: Likely Benign BS2 BP7, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM1, PM3, PM5, PP2, PP3, PP1, PP4, BP1, BP4, BP3, BP2, BA1, PS3, PS4, PS2, PS1 The c.344C>T (p.Thr115Met) missense variant has a maximum subpopulation frequency of 0.0097% in the gnomAD v2.1.1 cohort (http://gnomad.broadinstitute.org). This variant has been observed in over 75 probands not meeting HDGC phenotype criteria (BS2; SCV000254830.11, SCV000210896.16, SCV000183817.7). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 06/26/2023) CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA293962/MONDO:0100488/007 2023-08-03 2023-08-03 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:68647 biolink:causes MONDO:0044033 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C3160858 infores:hetionet CHEBI:4814 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0013404 infores:hetionet CHEBI:63580 biolink:causes UMLS:C1306577 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C1306577 infores:hetionet CHEBI:31932 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0740394 infores:hetionet CHEBI:38940 biolink:causes UMLS:C0263111 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0263111 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0235196 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0235196 infores:hetionet CHEBI:6801 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0011175 infores:hetionet CHEBI:8232 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0687713 infores:hetionet CHEBI:15854 biolink:causes MONDO:0006572 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0023646 infores:hetionet NCBIGene:3897 biolink:causes MONDO:0010569 infores:monarchinitiative not_provided not_provided HGNC:6470 MONDO:0010569 uuid:b57d0ee2-8d49-41bd-804f-6f047b3ceca6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45599 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0030252 infores:hetionet UNII:7662KG2R6K biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01046 UMLS:C0037763 infores:hetionet CHEBI:44241 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01011 UMLS:C0042963 infores:hetionet CHEBI:83804 biolink:causes HP:0031355 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0393761 infores:hetionet CHEBI:6715 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C1456784 infores:hetionet NCBITaxon:139 biolink:causes MONDO:0019632 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:139 MONDO:0019632 CHEBI:3568 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0020625 infores:hetionet CHEBI:63611 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0023052 infores:hetionet CHEBI:8772 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00481 UMLS:C0041969 infores:hetionet CHEBI:63632 biolink:causes UMLS:C0851341 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0851341 infores:hetionet CHEBI:8871 biolink:causes MONDO:0021211 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0006118 infores:hetionet CHEBI:38562 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0004093 infores:hetionet CHEBI:9599 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0086543 infores:hetionet CHEBI:474180 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0034063 infores:hetionet CHEBI:5778 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C0232492 infores:hetionet CHEBI:6539 biolink:causes HP:0040223 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0151701 infores:hetionet CHEBI:135193 biolink:causes MONDO:0005477 infores:sider not_provided not_provided DRUGBANK:DB06716 UMLS:C0042514 infores:hetionet NCBIGene:523 biolink:causes MONDO:0027451 infores:monarchinitiative not_provided not_provided HGNC:851 MONDO:0027451 uuid:e5fdd60b-3b83-494d-8d61-ae55dd26928f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49375 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0032227 infores:hetionet CHEBI:7822 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00991 UMLS:C0009676 infores:hetionet CHEBI:4466 biolink:causes HP:0005972 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0001127 infores:hetionet CHEBI:10125 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0085631 infores:hetionet CHEBI:4910 biolink:causes UMLS:C1868752 infores:sider not_provided not_provided DRUGBANK:DB00292 UMLS:C1868752 infores:hetionet NCBIGene:3040 biolink:causes MONDO:0007705 infores:monarchinitiative not_provided not_provided HGNC:4824 MONDO:0007705 uuid:98fa83c1-752f-44e0-a605-9780b2db9c5a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2675 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0036974 infores:hetionet GO:0003168 biolink:causes CL:0002068 infores:ubergraph knowledge_assertion manual_agent GO:0003168 CL:0002068 CHEBI:48273 biolink:causes HP:0031417 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C1260880 infores:hetionet CHEBI:3437 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00521 UMLS:C0004245 infores:hetionet CHEBI:135930 biolink:causes NCIT:C26943 infores:sider not_provided not_provided DRUGBANK:DB00528 UMLS:C0151662 infores:hetionet CHEBI:3561 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0235639 infores:hetionet CAID:CA207041 biolink:causes MONDO:0015152 infores:clingen CAID:CA207041 MONDO:0015152 PMID: Likely Benign BP2, BS1, PP3 PM5, PM4, PM1, PM3, PS1, PS3, PS4, PS2, BP1, BP4, BP3, BA1, BP7, BP5, BS3, BS4, PVS1, PM2, PM6, BS2, PP2, PP1, PP4 The NM_003494.4: c.4577A>C variant in DYSF, which is also known as NM_001130987.2: c.4694A>C p.(Lys1565Thr), is a missense variant predicted to cause substitution of lysine by threonine at amino acid 1526, p.(Lys1526Thr). This variant has been observed in cis with the variant NM_003494.4: c.2643+1G>A, which is classified as pathogenic by the ClinGen LGMD VCEP, in multiple individuals (PMID: 18853459, 30564623, 33927379, 36983702) (BP2). The filtering allele frequency for this variant is 0.001995 for African/African American genome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 25/8710), which is greater than the ClinGen LGMD VCEP threshold >0.001 for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.71, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the predictive pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BS1, BP2, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA207041/MONDO:0015152/180 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:15765 biolink:causes MONDO:0019167 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C0034152 infores:hetionet CHEBI:188986 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0948594 infores:hetionet CHEBI:36704 biolink:causes MONDO:0021201 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0037278 infores:hetionet CHEBI:9137 biolink:causes UMLS:C0234458 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0234458 infores:hetionet CHEBI:135005 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB04896 UMLS:C0016204 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151888 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151888 infores:hetionet CHEBI:5801 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0042963 infores:hetionet CHEBI:63629 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0018991 infores:hetionet CAID:CA220676 biolink:causes MONDO:0100437 infores:clingen CAID:CA220676 MONDO:0100437 PMID: Uncertain Significance PS2_Supporting, PS4_Supporting, PM2_Supporting, PP3_Moderate PP4 NM_001034853.2(RPGR):c.806G>A (p.Gly269Glu) is a missense variant encoding the substitution of glycine with glutamate at amino acid 269. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.851, which is between the ClinGen X-linked IRD VCEP thresholds of 0.773 to 0.931 and predicts a damaging effect on RPGR function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.02 for donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RPGR splicing. This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMID: 32702353, 28559085, PS4_supporting). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 proband meeting the PS2 requirement of some functional vision impairment in affected males by age 30, with decreased or absent cone and/or rod ERG responses (PS2_Supporting, PMID: 28559085). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; PM2_supporting, PS2_supporting, PP3_moderate, and PS4_supporting. (date of approval 05/16/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA220676/MONDO:0100437/106 2025-05-20 2025-05-20 X-linked inheritance (dominant (HP:0001423)) HP:0001423 Inconclusive true CHEBI:63608 biolink:causes MONDO:0003199 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0279637 infores:hetionet CHEBI:6909 biolink:causes MONDO:0001196 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C1384606 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0031542 infores:hetionet CHEBI:70735 biolink:causes MONDO:0005566 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0027609 infores:hetionet CHEBI:135613 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0030193 infores:hetionet CHEBI:47519 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0040034 infores:hetionet CHEBI:3001 biolink:causes HP:0033434 infores:sider not_provided not_provided DRUGBANK:DB00394 UMLS:C0235761 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0860239 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0860239 infores:hetionet CHEBI:8874 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0232849 infores:hetionet CHEBI:204928 biolink:causes UMLS:C2242588 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C2242588 infores:hetionet CAID:CA8365647 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365647 MONDO:0100453 PMID: Likely Benign BP4 BS1, PM2 The NM_000180.4(GUCY2D):c.1081G>A (p.Val361Met) variant is predicted to replace the valine at position p.361 with methionine. The computational predictor REVEL gives a score of 0.189, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.0005837, with 733 alleles / 1179964 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0005085, with 815 alleles / 1602704 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365647/MONDO:0100453/167 2025-01-30 2025-01-30 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:31236 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0518988 infores:hetionet CHEBI:71940 biolink:causes UMLS:C0042134 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0042134 infores:hetionet CHEBI:8356 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0009421 infores:hetionet NCBIGene:367 biolink:causes MONDO:0010720 infores:monarchinitiative not_provided not_provided HGNC:644 MONDO:0010720 uuid:85d4e520-4b46-460b-851f-8cd77202b731 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes UMLS:C0012797 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0012797 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0243026 infores:hetionet CHEBI:34829 biolink:causes MONDO:0020378 infores:sider not_provided not_provided DRUGBANK:DB00253 UMLS:C0858617 infores:hetionet CHEBI:92923 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0035455 infores:hetionet CHEBI:17347 biolink:causes HP:0046503 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0021177 infores:hetionet CHEBI:9150 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB00641 UMLS:C0011570 infores:hetionet CHEBI:52010 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01114 UMLS:C0022107 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0151849 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0151849 infores:hetionet CHEBI:3478 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0002792 infores:hetionet CHEBI:15544 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0085606 infores:hetionet CHEBI:31547 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0004604 infores:hetionet CHEBI:65173 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB04946 UMLS:C0235234 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0019348 infores:hetionet CHEBI:10124 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0011168 infores:hetionet CHEBI:41423 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0043094 infores:hetionet CHEBI:6775 biolink:causes UMLS:C3160771 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C3160771 infores:hetionet CHEBI:38940 biolink:causes MONDO:0006633 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0267841 infores:hetionet CHEBI:10023 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0017181 infores:hetionet NCBIGene:160418 biolink:causes MONDO:0014992 infores:monarchinitiative not_provided not_provided HGNC:26899 MONDO:0014992 uuid:11b43aae-c13c-4cd5-9c73-822374f73776 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47519 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0019158 infores:hetionet CHEBI:167638 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00598 UMLS:C0042109 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0497365 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0497365 infores:hetionet CHEBI:92923 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0917801 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0858797 infores:hetionet CHEBI:64321 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB06717 UMLS:C0232292 infores:hetionet CHEBI:93635 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB01247 UMLS:C0027813 infores:hetionet CAID:CA186706 biolink:causes MONDO:0007648 infores:clingen CAID:CA186706 MONDO:0007648 PMID: Likely Benign BP7, BS2 BP5, BS1, BS3, BS4, PM5, PM4, PM3, PM1, PVS1, PM2, PM6, PP2, PP3, PP4, PP1, BP1, BP4, BP3, BP2, BA1, PS1, PS4, PS3, PS2 The c.2451G>A variant is predicted silent and has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). The nucleotide is not conserved (BP7). Therefore, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP7. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA186706/MONDO:0007648/007 2023-08-17 2023-08-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CAID:CA638054525 biolink:causes MONDO:0011071 infores:clingen CAID:CA638054525 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP3, PVS1, PM2, PM6, BP5, BS1, BS3, BS4, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.805+13T>C is an intronic variant not predicted to affect splicing (BP4). This variant has a SpliceAI score ≤ 0.20 (0.001) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.947)) (BP7). In summary, the clinical significance of this variant is Likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA638054525/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:8863 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0080274 infores:hetionet CHEBI:7476 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0026821 infores:hetionet CHEBI:4495 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C2047937 infores:hetionet CHEBI:5558 biolink:causes HP:0031354 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0393760 infores:hetionet CHEBI:32221 biolink:causes HP:0032171 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0232849 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0314719 infores:hetionet CHEBI:6838 biolink:causes UMLS:C0948692 infores:sider not_provided not_provided DRUGBANK:DB01403 UMLS:C0948692 infores:hetionet CAID:CA405643726 biolink:causes MONDO:0007783 infores:clingen CAID:CA405643726 MONDO:0007783 PMID: Uncertain Significance PP3, PM1, BS1, BA1, BP4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of proline with leucine at codon 3519 of the RYR1 protein, p.(Pro3519Leu). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.809 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405643726/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:63607 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00601 UMLS:C0003123 infores:hetionet CHEBI:7476 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0027497 infores:hetionet CHEBI:45783 biolink:causes MONDO:0006115 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0005699 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0013928 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0013928 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0005940 infores:hetionet CHEBI:31981 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0015967 infores:hetionet CHEBI:47499 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0341047 infores:hetionet CHEBI:59560 biolink:causes UMLS:C0232492 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0232492 infores:hetionet CHEBI:63622 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0085636 infores:hetionet CHEBI:94392 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0002878 infores:hetionet CHEBI:32192 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0547030 infores:hetionet CHEBI:194135 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0162834 infores:hetionet CHEBI:15367 biolink:causes UMLS:C0426732 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0426732 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0027765 infores:hetionet CHEBI:114785 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0237849 infores:hetionet CHEBI:31705 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0235431 infores:hetionet CHEBI:119486 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0003123 infores:hetionet CHEBI:31622 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01544 UMLS:C0040822 infores:hetionet UNII:Y2V2R4W9TQ biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB05260 UMLS:C0041834 infores:hetionet NCBIGene:5426 biolink:causes MONDO:0032684 infores:monarchinitiative not_provided not_provided HGNC:9177 MONDO:0032684 uuid:0d820498-285e-4312-a3d2-e2db273cee2e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8212 biolink:causes HP:0003115 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0522055 infores:hetionet CHEBI:3723 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0392525 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0085693 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0085693 infores:hetionet CHEBI:8871 biolink:causes MONDO:0001854 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0022904 infores:hetionet PUBCHEM.COMPOUND:3467 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00798 UMLS:C0042109 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0042267 infores:hetionet CHEBI:3515 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB01112 UMLS:C0037199 infores:hetionet CHEBI:84883 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0002170 infores:hetionet CHEBI:48538 biolink:causes MONDO:0011662 infores:sider not_provided not_provided DRUGBANK:DB00714 UMLS:C0030662 infores:hetionet CHEBI:61033 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0042963 infores:hetionet CHEBI:7956 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0040034 infores:hetionet CAID:CA035437 biolink:causes MONDO:0007750 infores:clingen CAID:CA035437 MONDO:0007750 PMID: Pathogenic PS4, PP1_Strong, PS3_Supporting, PM3, PM2, PP3, PP4 BP1, BP4, BP3, BP2, BA1, PS1, PS2, BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PVS1, PM6, PP2, BS2 The NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Strong, PM2, PM3, PP3, PP4, PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4 - variant meets PM2 and was identified in:- at least 1 index case with DLCN at least 8 (TC =700mg/dl) from Ambry Genetics, USA;- 14 unrelated index cases, all with DLCN >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- at least 5 unrelated index cases (3 with Simon Broome definite FH, 2 with Simon Broome possible FH) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 4 unrelated index cases, all with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia;- 2 unrelated index cases, all with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada;- at least 1 index case with DLCN>=6 from PMID 19318025 (Alonso et al., 2009), Spain;- at least 1 index case with SB criteria for FH from PMID 21376320 Chiou et al., 2011), Taiwan,--- 30 cases, so PS4 is metPP1_strong - variant segregates with the FH phenotype in 39 informative meiosis from at least 14 families:- 20 informative meiosis from 7 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: 16 relatives with the variant have LDL-C >75th percentile, and 4 relatives without the variant have LDL-C <50th percentile;- 1 informative meiosis from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 1 relative positive for variant had LDL-C >75th percentile;- 8 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): F1 with 2 relatives positive for variant and having LDL-C >75th percentile, and 2 relatives negative for variant and having LDL-C <50th percentile, F2: 1 relative who was positive for the variant and had LDL-C >75th percentile, F3: 2 relatives who were positive for variant with LDL-C >75th percentile, and 1 relative who was negative for the variant with LDL-C <50th percentile;- 2 informative meiosis from 2 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative positive for variant with LDL-C >75th percentile in each family;- 8 informative meiosis (unknown how many families) from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 5 relatives positive for variant with LDL-C >75th percentile, and 3 relatives were negative for variant with LDL-C <50th percentile.--- 39 segregations, so PP1_Strong is metPM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian exomes (gnomAD v2.1.1). It is below than 0.02%, so PM2 is met.PM3 - variant meets PM2 and was identified in:- 1 index case homozygous for the variant with TC = 700mg/dl at 7 years old from Ambry Genetics. ---> individual is homozygous for variant and has an homozygous phenotype, so PM3 is met.- 2 unrelated index cases, both homozygous for the variant, with LDL-C 352mg/dL under statin treatment (352/0.7 = 503mg/dl) and LDL-C=409mg/dl under statin treatment (409/0.7 = 584mg/dl), respectively, both from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) ---> individuals are homozygous for variant and have an homozygous phenotype, so PM3 is met.PP3 - REVEL = 0.888. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 30 unrelated index cases who fulfill clinical FH criteria (see PS4 for details), so PP4 is met.PS3_supporting - Level 3 FS: Sun et al., 1997 (PMID 9409298) - Htz patients' fibroblasts, immunoblot and 125I-LDL assays - results: 40-50% LDLR activity, cell surface LDLR 40-50% LDLR.--- Activity is below 85%, so PS3_Supporting is met. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA035437/MONDO:0007750/013 2022-08-28 2022-08-28 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CHEBI:8378 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0018681 infores:hetionet CHEBI:38562 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0349506 infores:hetionet CAID:CA261421 biolink:causes MONDO:0010134 infores:clingen CAID:CA261421 MONDO:0010134 PMID: Likely Pathogenic PP1, PP4, PM3, PM2_Supporting BP4 The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID: 26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID: 26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 8/22/2023 (PM2_Supporting, PP4, PM3, PP1) Hearing Loss VCEP https://erepo.genome.network/evrepo/ui/classification/CA261421/MONDO:0010134/005 2023-08-27 2023-10-05 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf CHEBI:27436 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB06710 UMLS:C0030554 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0549373 infores:hetionet CHEBI:75998 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0041834 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0021053 infores:hetionet CHEBI:3698 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0010200 infores:hetionet CHEBI:46345 biolink:causes UMLS:C0011304 infores:sider not_provided not_provided DRUGBANK:DB00544 UMLS:C0011304 infores:hetionet CHEBI:4511 biolink:causes UMLS:C0151596 infores:sider not_provided not_provided DRUGBANK:DB00485 UMLS:C0151596 infores:hetionet CHEBI:63617 biolink:causes MONDO:0005379 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0027932 infores:hetionet CAID:CA367401107 biolink:causes MONDO:0015967 infores:clingen CAID:CA367401107 MONDO:0015967 PMID: Pathogenic PS4_Moderate, PP1_Strong, PVS1, PP4_Moderate, PM2_Supporting, PS1_Supporting The c.679+2T>C variant in glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 6 of transcript NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 6 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with four informative meioses in three families (PP1_Strong; internal lab contributors). Another variant within same splice donor ±1,2 dinucleotide, c.679+1G>T, has been classified as pathogenic by the ClinGen MDEP, and both variants have the same predicted impact on splicing by SpliceAI (0.99) (PS1_Supporting). In summary, c.679+2T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PVS1, PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting, PS1_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367401107/MONDO:0015967/086 2025-09-17 2025-09-26 Semidominant inheritance HP:0032113 Supports CHEBI:3752 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0003467 infores:hetionet CHEBI:2038 biolink:causes HP:4000214 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0238844 infores:hetionet CHEBI:51364 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0004936 infores:hetionet CHEBI:92769 biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB06704 UMLS:C0151698 infores:hetionet CAID:CA645607374 biolink:causes MONDO:0011071 infores:clingen CAID:CA645607374 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, BS1, BS3, BS4, BP5, BP7, PM6, PM4, PM3, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.424del (p.Ala142LeufsTer3) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene where loss-of-function is an established mechanism (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA645607374/MONDO:0011071/008 2024-09-10 2024-09-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8869 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0917801 infores:hetionet CHEBI:3181 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C1456784 infores:hetionet CHEBI:8863 biolink:causes HP:0031189 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0231666 infores:hetionet CHEBI:63613 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00238 UMLS:C0020443 infores:hetionet NCBIGene:2683 biolink:causes MONDO:0957260 infores:monarchinitiative not_provided not_provided HGNC:924 MONDO:0957260 uuid:9cd3db22-ebdf-4b94-a39b-560802dca7b7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3172 biolink:causes UMLS:C0235462 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0235462 infores:hetionet CHEBI:5130 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0018524 infores:hetionet CHEBI:31413 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C1443060 infores:hetionet CHEBI:8707 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0011206 infores:hetionet CHEBI:142290 biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C3263723 infores:hetionet CHEBI:4672 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0085649 infores:hetionet CHEBI:3219 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0392171 infores:hetionet CHEBI:94686 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01083 UMLS:C0017152 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0021400 infores:hetionet NCBIGene:26146 biolink:causes MONDO:0014712 infores:monarchinitiative not_provided not_provided HGNC:17861 MONDO:0014712 uuid:d5381400-f19a-4ca9-86a3-fd3107488b6f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:76010 biolink:causes UMLS:C0856151 infores:sider not_provided not_provided DRUGBANK:DB08930 UMLS:C0856151 infores:hetionet CHEBI:119486 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0041349 infores:hetionet CHEBI:8107 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0152267 infores:hetionet CHEBI:194135 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0024312 infores:hetionet CHEBI:9448 biolink:causes UMLS:C0221742 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0221742 infores:hetionet CHEBI:8356 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037822 infores:hetionet CHEBI:4708 biolink:causes MONDO:0003105 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0033575 infores:hetionet CHEBI:28001 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0011603 infores:hetionet CHEBI:8869 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0026826 infores:hetionet CAID:CA10558497 biolink:causes MONDO:0010726 infores:clingen CAID:CA10558497 MONDO:0010726 PMID: Likely Benign BP5, BS2 BP4, PM1, BS1, PP3 The p.Pro381Ser variant in MECP2 (NM_004992.4) is observed in at least 19 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro381Ser variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Pro381Ser variant in MECP2 in gnomAD v4.1 is 0.00003574 in the African/African American population (not sufficient to meet BS1 criteria). In summary, the p.Pro381Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA10558497/MONDO:0010726/036 2024-10-30 2024-11-29 X-linked inheritance HP:0001417 Contradicts true CHEBI:31547 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011124 infores:hetionet CHEBI:8805 biolink:causes MONDO:0004995 infores:sider not_provided not_provided DRUGBANK:DB00912 UMLS:C0007222 infores:hetionet CHEBI:8405 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01087 UMLS:C0027497 infores:hetionet CHEBI:7936 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0019080 infores:hetionet CHEBI:567361 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0042963 infores:hetionet CHEBI:2682 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0026826 infores:hetionet CHEBI:45863 biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0016199 infores:hetionet NCBIGene:2735 biolink:causes MONDO:0029130 infores:monarchinitiative not_provided not_provided HGNC:4317 MONDO:0029130 uuid:88110de8-f015-4d09-8b48-34a00e9b2bdd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9586 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0549249 infores:hetionet UNII:R43D2573WO biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0020649 infores:hetionet CHEBI:8382 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0003811 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0232431 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0232431 infores:hetionet CHEBI:4903 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0027051 infores:hetionet CHEBI:53766 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01418 UMLS:C0518015 infores:hetionet CHEBI:50122 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0015230 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0475858 infores:hetionet CHEBI:135736 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0085649 infores:hetionet CAID:CA229681 biolink:causes MONDO:0009861 infores:clingen CAID:CA229681 MONDO:0009861 PMID:9012412PMID:21147011PMID:21147011 Likely Pathogenic PM2, PP4_Moderate, PM3, PP3 PM5 The c.665A>T (p.Asp222Val) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 9012412). This variant is absent in population databases. This variant was detected with pathogenic variants p.R243X and p.R241H (PMID: 21147011). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229681/MONDO:0009861/006 2020-08-17 2021-12-12 Autosomal recessive inheritance HP:0000007 Supports CHEBI:9763 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0542571 infores:hetionet CAID:CA2695224141 biolink:causes MONDO:0009276 infores:clingen CAID:CA2695224141 MONDO:0009276 PMID: Likely Pathogenic PP4, PM2_Supporting, PVS1_Strong, PM3_Supporting The c.278dup (p.Val94Serfs*58) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however the truncation includes the functionally important transmembrane domain (removes amino acids 532-553) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient BSS11.01 in PMID:23995613) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM3_Supporting and PM2_Supporting (VCEP specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA2695224141/MONDO:0009276/079 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports CHEBI:135342 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0085631 infores:hetionet CHEBI:30830 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0086769 infores:hetionet CHEBI:4909 biolink:causes UMLS:C1868919 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C1868919 infores:hetionet CHEBI:9674 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0018524 infores:hetionet CHEBI:6706 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00657 UMLS:C0344232 infores:hetionet CHEBI:45924 biolink:causes MONDO:0006771 infores:sider not_provided not_provided DRUGBANK:DB00440 UMLS:C0017675 infores:hetionet CHEBI:7478 biolink:causes HP:0001657 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0151878 infores:hetionet NCBIGene:25836 biolink:causes MONDO:0007387 infores:monarchinitiative not_provided not_provided HGNC:28862 MONDO:0007387 uuid:6f10121b-7037-4090-bd41-bf6fc57f337e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27690 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00819 UMLS:C1971624 infores:hetionet CHEBI:6375 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0086543 infores:hetionet CHEBI:49040 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0162830 infores:hetionet CHEBI:36704 biolink:causes UMLS:C0549356 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0549356 infores:hetionet CHEBI:71229 biolink:causes HP:0002153 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0020461 infores:hetionet CHEBI:63621 biolink:causes MONDO:0000878 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0206178 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0002622 infores:hetionet UNII:9430ZR8ZAN biolink:causes HP:0030157 infores:sider not_provided not_provided DRUGBANK:DB06705 UMLS:C0558489 infores:hetionet CHEBI:61049 biolink:causes HP:0004755 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0039240 infores:hetionet CHEBI:55346 biolink:causes HP:0003228 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0020488 infores:hetionet CHEBI:161680 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0030193 infores:hetionet CAID:CA287215802 biolink:causes MONDO:0009276 infores:clingen CAID:CA287215802 MONDO:0009276 PMID: Pathogenic PP4, PM2_Supporting, PM3_Strong, PP1_Strong PP3, PS3, PM1 The NM_000173.7:c.241T>C (p.Cys81Arg) variant in GP1BA is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 81. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in at least 9 individuals with Bernard-Soulier syndrome. At least one individual had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba measured by flow cytometry (PP4; PMID:25370924). One proband was homozygous and two additional probands that were compound heterozygotes for this variant and a second pathogenic variant, NM_000173.7(GP1BA):c.1620G>A, p.Trp540Ter with phase confirmed (PM3_strong; PMID:25370924). The variant was reported to segregate in the proband plus 6 additional homozygous BSS affected individuals from a small town in Iceland (PP1_strong; PMID:25370924). In summary, this variant meets the criteria to be classified as pathogenic for Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM2_supporting, PM3_strong, PP1_strong (Platelet VCEP GP1BA specifications version 1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA287215802/MONDO:0009276/079 2025-09-04 2025-09-04 Autosomal recessive inheritance HP:0000007 Supports CHEBI:125354 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0033774 infores:hetionet UMLS:C0010592 biolink:causes GO:0003009 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0541840 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0232459 infores:hetionet CAID:CA254849 biolink:causes MONDO:0044970 infores:clingen CAID:CA254849 MONDO:0044970 PMID: Likely Pathogenic PP1, PM2_Supporting, PS4_Supporting, PM6_Supporting, PVS1_Strong PP3 The m.8618dupT (p.Thr33Hisfs*32) variant in MT-ATP6 has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 32042910, 19124644). Clinical features in these individuals include developmental delay, learning difficulties, ataxia, spastic paraparesis, headache, cerebellar atrophy, white matter abnormalities, hearing loss, kidney failure, diabetes, cataracts, optic atrophy, retinal dystrophy, and short stature. The heteroplasmy levels in affected individuals ranged from 20% to 85%. This variant occurred de novo in one individual (absent in blood from mother, sister, and maternal aunt; PM6_supporting, PMID: 19124644). This variant segregated with disease in the other family (proband with heteroplasmy levels ranging from 20-65%; unaffected individuals including mother, sister, and maternal aunt with lower heteroplasmy levels ranging from 0-24%; PP1; PMID: 32042910). This frameshift variant results in a significant (>10%) truncation of the MT-ATP6 protein (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PP1, PM2_supporting, PVS1_strong. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA254849/MONDO:0044970/015 2024-08-12 2025-04-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6958 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01226 UMLS:C0011603 infores:hetionet CHEBI:49960 biolink:causes UMLS:C0422974 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0422974 infores:hetionet CHEBI:63791 biolink:causes UMLS:C1096257 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C1096257 infores:hetionet CHEBI:64318 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0277925 infores:hetionet CHEBI:36704 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C2939147 infores:hetionet CHEBI:6909 biolink:causes NCIT:C117162 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0700361 infores:hetionet CHEBI:63598 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0002792 infores:hetionet CHEBI:75988 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0009676 infores:hetionet CHEBI:6402 biolink:causes MONDO:0022205 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0152081 infores:hetionet NCBIGene:23395 biolink:causes MONDO:0014126 infores:monarchinitiative not_provided not_provided HGNC:17095 MONDO:0014126 uuid:6cfd9213-3191-45df-b627-97962f8fa744 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges GO:1905557 biolink:causes GO:0006997 infores:ubergraph knowledge_assertion manual_agent GO:1905557 GO:0006997 CHEBI:3223 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0015371 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002378 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0011649 infores:hetionet CHEBI:47499 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0233407 infores:hetionet CHEBI:8869 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00884 UMLS:C0036974 infores:hetionet CHEBI:6129 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0235198 infores:hetionet CHEBI:4753 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB01057 UMLS:C1510497 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0040270 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0151671 infores:hetionet CHEBI:6801 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00331 UMLS:C0039070 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0009319 infores:hetionet CHEBI:15553 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01160 UMLS:C0012833 infores:hetionet CHEBI:6149 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0700590 infores:hetionet CHEBI:3757 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0037299 infores:hetionet NCBITaxon:76773 biolink:causes MONDO:0005915 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:76773 MESH:D014010 DB00971_MESH_D014010_1DB00525_MESH_D014010_1DB01188_MESH_D014010_1DB01091_MESH_D014010_1DB00825_MESH_D014010_1DB01110_MESH_D014010_1 CHEBI:9139 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0086543 infores:hetionet CHEBI:6129 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0220870 infores:hetionet CAID:CA386952569 biolink:causes MONDO:0015967 infores:clingen CAID:CA386952569 MONDO:0015967 PMID: Uncertain Significance PM2_Supporting, PM1_Supporting, PS2_Supporting, PP3 PM5, PP4 The c.56C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to leucine at codon 19 (p.(Ser19Leu)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.875, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result <50%/HNF4A not tested) (PS2_Supporting; internal lab contributors). Another missense variant, c.55T>G (p.Ser19Ala), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.56C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP3, PS2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386952569/MONDO:0015967/017 2022-04-21 2022-04-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68584 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04953 UMLS:C0020458 infores:hetionet CHEBI:6717 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0015967 infores:hetionet CAID:CA16020911 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020911 MONDO:0009861 PMID:15159646PMID:15159646 Uncertain Significance PM3, PM2, PP4 PP3 The NM_000277.3:c.970A>G (p.Ile324Val) variant is a missense variant in exon 10/13 of PAH. It has been previously reported in a patient with mild hyperphenylalanemia (plasma Phe 230 uM) in confirmed trans with the c.441+5G>T variant (ClinVar Pathogenic (ID 92742); Pathogenic per ClinGen PAH VCEP); BH4 deficiency was not stated to have been excluded (PP4; PM3) (PMID: 15159646). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In-silico pathogenicity predictors are conflicting and REVEL=0.534, such that PP3 is not met.Classification: VUS – insufficient evidence Supporting Criteria: PM2; PM3; PP4 Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020911/MONDO:0009861/006 2020-07-25 2020-07-25 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:9139 biolink:causes MONDO:0002907 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0079102 infores:hetionet NCBIGene:678 biolink:causes MONDO:0859330 infores:monarchinitiative not_provided not_provided HGNC:1108 MONDO:0859330 uuid:787cc7ff-e748-4386-8e41-bbfb1286dfff biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36795 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0020443 infores:hetionet NCBIGene:6334 biolink:causes MONDO:0100092 infores:monarchinitiative not_provided not_provided HGNC:10596 MONDO:0100092 uuid:04b178d5-a54f-4767-8708-fd00e130775b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6076 biolink:causes MONDO:0002467 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0022890 infores:hetionet NCBIGene:51075 biolink:causes MONDO:0032887 infores:monarchinitiative not_provided not_provided HGNC:30739 MONDO:0032887 uuid:7d3d8ee0-f681-41b5-b61b-ba55dc726708 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8214 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0004936 infores:hetionet CHEBI:404903 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0042075 infores:hetionet CHEBI:50381 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0156404 infores:hetionet CHEBI:64310 biolink:causes MONDO:0021084 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0042790 infores:hetionet CHEBI:50648 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0017574 infores:hetionet CHEBI:521033 biolink:causes HP:0012879 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0278106 infores:hetionet CHEBI:63925 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00654 UMLS:C0011603 infores:hetionet CHEBI:7798 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0423006 infores:hetionet CHEBI:10127 biolink:causes HP:0100963 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0020453 infores:hetionet CHEBI:9637 biolink:causes MONDO:0005578 infores:sider not_provided not_provided DRUGBANK:DB00214 UMLS:C0003864 infores:hetionet GO:1903388 biolink:causes GO:0048488 infores:ubergraph knowledge_assertion manual_agent GO:1903388 GO:0048488 UMLS:C0879264 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151828 infores:hetionet CHEBI:50122 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00412 UMLS:C0595930 infores:hetionet CHEBI:50663 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0178298 infores:hetionet CHEBI:9571 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01623 UMLS:C0020456 infores:hetionet CHEBI:31515 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01184 UMLS:C0011991 infores:hetionet CHEBI:16755 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C1565489 infores:hetionet CHEBI:6797 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00660 UMLS:C0015230 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0349506 infores:hetionet CHEBI:42944 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0013378 infores:hetionet CHEBI:9674 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0018681 infores:hetionet CHEBI:6970 biolink:causes HP:0002105 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0019079 infores:hetionet CHEBI:63630 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C1142412 infores:hetionet CHEBI:31644 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0002418 infores:hetionet NCBIGene:84466 biolink:causes MONDO:0859515 infores:monarchinitiative not_provided not_provided HGNC:29634 MONDO:0859515 uuid:e249e436-abaa-4128-bdf8-a437f22dedca biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:36791 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0151798 infores:hetionet CHEBI:63791 biolink:causes MONDO:0001314 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0553730 infores:hetionet CHEBI:17823 biolink:causes UMLS:C0233485 infores:sider not_provided not_provided DRUGBANK:DB00136 UMLS:C0233485 infores:hetionet CHEBI:205919 biolink:causes HP:0200039 infores:sider not_provided not_provided DRUGBANK:DB01013 UMLS:C0241157 infores:hetionet CHEBI:4974 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00426 UMLS:C0011991 infores:hetionet CAID:CA367397313 biolink:causes MONDO:0015967 infores:clingen CAID:CA367397313 MONDO:0015967 PMID: Uncertain Significance PM5_Supporting, PP2, PP3, PM2_Supporting PP1, PP4 The c.1255T>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 419 (p.(Phe419Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1256T>C (p.Phe419Ser), has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). This variant segregated with the disease with two informative meioses in a single family with diabetes, however, this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918, internal lab contributors). This variant was identified in an individual with diabetes, however, PP4 is unable to be evaluated due to incomplete clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367397313/MONDO:0015967/086 2023-06-26 2023-06-26 Semidominant inheritance HP:0032113 Inconclusive true CHEBI:8874 biolink:causes UMLS:C0747979 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0747979 infores:hetionet CHEBI:8059 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0344232 infores:hetionet CHEBI:4735 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0030193 infores:hetionet CHEBI:135888 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00337 UMLS:C0005940 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151698 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151698 infores:hetionet CHEBI:5790 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0232461 infores:hetionet CHEBI:50729 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0151905 infores:hetionet NCBIGene:7849 biolink:causes MONDO:0024264 infores:monarchinitiative not_provided not_provided HGNC:8622 MONDO:0024264 uuid:b454d8ba-f89f-4505-a742-e2384885f77a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3568 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0032617 infores:hetionet CHEBI:5296 biolink:causes MONDO:0005113 infores:sider not_provided not_provided DRUGBANK:DB01241 UMLS:C0004623 infores:hetionet CHEBI:8874 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0000833 infores:hetionet CAID:CA10585137 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585137 MONDO:0007750 PMID: Likely Pathogenic PM5_Strong, PM2, PP3 BP1, BP4, BP2, BP3, BA1, PS1, PS3, PS4, PS2, BP5, BP7, BS1, BS3, BS4, PM1, PM3, PM4, PM6, PVS1, BS2, PP2, PP1, PP4 The NM_000527.5(LDLR): c.797A>T (p.Asp266Val) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).PM5_Strong - 4 other missense variants in the same codon:- NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines,- NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) (ClinVar ID 251458) – Likely pathogenic by these guidelines,- NM_000527.5(LDLR): c.796A>T (p.Asp266Tyr) (ClinVar ID 251456) – Pathogenic by these guidelines,- NM_000527.5(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines.There are 3 variants in the same codon classified as Pathogenic by these guidelines;PM2 - This variant is absent from gnomAD (gnomAD v2.1.1);PP3 - REVEL = 0.97; Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585137/MONDO:0007750/013 2021-11-14 2022-06-30 Semidominant inheritance HP:0032113 Supports https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ CAID:CA399791611 biolink:causes MONDO:0100326 infores:clingen CAID:CA399791611 MONDO:0100326 PMID: Likely Pathogenic PP4_Moderate, PS3_Moderate, PM2_Supporting, PVS1_Moderate PM3, PP3, BP4 The c.2828C>T variant in ITGA2B occurs as a cryptic splice site. It is observed to cause skipping of biologically-relevant-exon 28/30, resulting in an in-frame deletion (removes 34 amino acids). However, it is predicted to escape nonsense mediated decay and remove <10% of the protein. This prediction is confirmed by exontrap analysis (PVS1_Moderate; PMID: 17018384). At least one patient (Proband in PMID: 17018384) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, reduction in αIIbβ3 function was shown by loss of binding to fibrinogen as measured by functional flow cytometry. ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Surface expression of αIIbβ3 measured by flow cytometry in CHO cells transiently co-transfected with the αIIb variant and wild type β3 showed decreased expression at 24% (<25%) WT levels, indicating that this variant impacts protein function (PMID: 17018384)(PS3_moderate).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PP4_moderate, PM2_supporting, PS3_moderate. (VCEP specifications version 2; date of approval xx/xx/xxxx) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399791611/MONDO:0100326/011 2024-02-20 2024-02-20 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:3387 biolink:causes UMLS:C0853084 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0853084 infores:hetionet CHEBI:6715 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0014591 infores:hetionet CHEBI:17303 biolink:causes HP:0011848 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232488 infores:hetionet CHEBI:8245 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0917801 infores:hetionet CHEBI:3757 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C3203358 infores:hetionet CHEBI:167309 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0152128 infores:hetionet CHEBI:63621 biolink:causes EFO:0010072 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0040460 infores:hetionet NCBIGene:6662 biolink:causes MONDO:0010218 infores:monarchinitiative not_provided not_provided HGNC:11204 MONDO:0010218 uuid:56a348de-3f28-46aa-8fcf-4a79ad393f75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7773 biolink:causes UMLS:C0392197 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0392197 infores:hetionet CHEBI:38545 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C1443060 infores:hetionet UMLS:C1738934 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0015672 infores:hetionet CHEBI:135736 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0240671 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0033860 infores:hetionet CHEBI:27786 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00200 UMLS:C0004936 infores:hetionet CHEBI:72690 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0014591 infores:hetionet CHEBI:3561 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0151908 infores:hetionet CHEBI:50777 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0042963 infores:hetionet CHEBI:10110 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0004610 infores:hetionet CHEBI:83531 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0020649 infores:hetionet CHEBI:31705 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C1565489 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0877232 infores:hetionet CHEBI:49668 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151904 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0424000 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0424000 infores:hetionet CHEBI:79699 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0948594 infores:hetionet CHEBI:3223 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0080274 infores:hetionet CAID:CA085167 biolink:causes MONDO:0007750 infores:clingen CAID:CA085167 MONDO:0007750 PMID: Uncertain Significance BS3_Supporting, PM2, PP4 BP4, BP3, BP2, BA1, PS1, PS3, PS4, PS2, BS1, BS4, PM5, PM4, PM1, PM3, PM6, BS2, PP3, PP1 The NM_000527.5(LDLR):c.-13A>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002374 (0.0023%) in European (Non-Finnish) exomes+genomes (gnomAD v4.1.0). BS3_Supporting: Level 3 assays - PMID 25248394 (Khamis et al., 2015): Heterologous cells (Huh7), Luciferase assays: results - normal (96%) gene expression. PMID 31395865 (Kircher et al., 2019): Heterologous cells (HepG2), luciferase assays: results - 97-106% gene expression. So, BS3_Supporting is met.PP4: Variant meets PM2 and is identified in 1 case meeting Simon Broome criteria from the Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA085167/MONDO:0007750/013 2024-10-28 2025-02-07 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:27470 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00158 UMLS:C0016204 infores:hetionet CHEBI:17026 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0042267 infores:hetionet CAID:CA399806084 biolink:causes MONDO:0100326 infores:clingen CAID:CA399806084 MONDO:0100326 PMID:15717695 Pathogenic PM4, PP4_Moderate, PP3, PM2_Supporting, PS3, PM3_Supporting The NM_000419.5(ITGA2B):c.399C>G (p.Asp133Glu) missense variant was reported in a patient with type 1 GT (PMID 15717695). This variant is absent from the gnomAD database v2.1.1 (PM2_Supporting). It has a REVEL score of 0.288 which does not meet the threshold established by the PD EP, however, SpliceAI predicts the gain of a donor splice site (0.83) at this location (PP3_Met). Patient RNA confirmed that the c.399C>G variant creates a new donor splice site at this location, resulting in a 9–base pair deletion (c.400-408) that would result in an amino acid substitution Asp133Glu and an in-frame deletion of 3 amino acid residues (PM4).This variant was identified in a patient with GT type 1 (PMID 15717695) with severe intestinal bleeding. The patient's platelet aggregation study showed no response to ADP or collagen but did show a normal response to ristocetin. GPIIb was completely absent with a faint amount of GPIIIa when analyzed using immunoblot (PP4_Moderate). This variant was found to be homozygous in the patient in which it was identified (PM3_Supporting). 293-Tcells were transfected with mutant GPIIb cDNA of this missense variant constructed using PCR mutagenesis. The construct was cotransfected into 293-T cells with wild-type GPIIIa cDNA Flow cytometry demonstrated no detectable amounts of GPIIbIIIa complexes or GPIIb on the surface of transfected 293-T cells, but normal expression was observed with the wildtype GPIIb (PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3, PM3_Supporting, PP4_Moderate, PS3, PM4 (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA399806084/MONDO:0100326/011 2023-06-01 2023-06-02 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ UMLS:C0657912 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0020538 infores:hetionet CHEBI:127342 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0338831 infores:hetionet CHEBI:465284 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0151827 infores:hetionet CHEBI:9586 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C1510410 infores:hetionet CHEBI:6067 biolink:causes MONDO:0005560 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085584 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0018099 infores:hetionet CHEBI:16469 biolink:causes UMLS:C0521495 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0521495 infores:hetionet CHEBI:55346 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C0013404 infores:hetionet CHEBI:63618 biolink:causes MONDO:0004907 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0002170 infores:hetionet CHEBI:50173 biolink:causes UMLS:C0235746 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0235746 infores:hetionet CHEBI:2663 biolink:causes HP:0001806 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0085661 infores:hetionet CHEBI:6762 biolink:causes EFO:0020984 infores:sider not_provided not_provided DRUGBANK:DB06691 UMLS:C2939094 infores:hetionet UMLS:C0145867 biolink:causes HP:0002015 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0011168 infores:hetionet CHEBI:6887 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0011175 infores:hetionet CAID:CA16616514 biolink:causes MONDO:0011071 infores:clingen CAID:CA16616514 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP2, BP1, BP4, BP3, PVS1, PM6, BS1, BS3, BS4, BP7, BP5, PM3, PM4, PM1, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1159_1161del (p.Gly387del) is an in-frame deletion which does not affect any residues within the Runt Homology Domain (AA 89-204) (PM4 not applied). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA16616514/MONDO:0011071/008 2024-08-01 2024-08-01 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:144551 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0234215 infores:hetionet CHEBI:6367 biolink:causes HP:0030766 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0013456 infores:hetionet CHEBI:63599 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0038454 infores:hetionet PUBCHEM.COMPOUND:11431811 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB01409 UMLS:C0917801 infores:hetionet CHEBI:5441 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01016 UMLS:C0020615 infores:hetionet CHEBI:3077 biolink:causes HP:0040181 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0263449 infores:hetionet CHEBI:2639 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00594 UMLS:C0027424 infores:hetionet CHEBI:78543 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0333355 infores:hetionet CHEBI:9939 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01339 UMLS:C0039231 infores:hetionet CHEBI:9654 biolink:causes UMLS:C0543467 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0543467 infores:hetionet CHEBI:51041 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0423791 infores:hetionet CHEBI:51364 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0028084 infores:hetionet CHEBI:5002 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00800 UMLS:C0013404 infores:hetionet CHEBI:5106 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0344232 infores:hetionet GO:0006954 biolink:causes MONDO:0008383 infores:drugmechdb knowledge_assertion manual_agent GO:0006954 MESH:D001172 DB06674_MESH_D001172_1DB00859_MESH_D001172_2DB01397_MESH_D001172_1DB07402_MESH_D001172_1DB00065_MESH_D001172_1DB00995_MESH_D001172_1DB01600_MESH_D001172_1DB08904_MESH_D001172_1DB00051_MESH_D001172_1DB00005_MESH_D001172_1 CHEBI:3732 biolink:causes UMLS:C0302295 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0302295 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0027051 infores:hetionet CHEBI:4909 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C0027769 infores:hetionet UMLS:C0011701 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0030193 infores:hetionet CHEBI:2618 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0018790 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005558 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0029928 infores:hetionet NCBIGene:256471 biolink:causes MONDO:0014515 infores:monarchinitiative not_provided not_provided HGNC:28486 MONDO:0014515 uuid:a456c7b0-b725-4be0-9a8f-a3eaddd12848 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9139 biolink:causes MONDO:0002647 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0023067 infores:hetionet CHEBI:2618 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0575081 infores:hetionet CHEBI:114785 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C1565489 infores:hetionet CHEBI:9130 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0018681 infores:hetionet CHEBI:3479 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB01140 UMLS:C0595916 infores:hetionet NCBIGene:3572 biolink:causes MONDO:0032796 infores:monarchinitiative not_provided not_provided HGNC:6021 MONDO:0032796 uuid:ce5d9ff1-03d8-45f2-94a5-8c63cbe79791 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:790 biolink:causes MONDO:0014647 infores:monarchinitiative not_provided not_provided HGNC:1424 MONDO:0014647 uuid:a505487e-2a79-4197-a936-3a7d485ec90e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0151905 infores:hetionet CHEBI:45599 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00815 UMLS:C0042963 infores:hetionet GO:0110107 biolink:causes GO:0035220 infores:ubergraph knowledge_assertion manual_agent GO:0110107 GO:0035220 CHEBI:68841 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB06703 UMLS:C0011991 infores:hetionet CHEBI:63637 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0151908 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0003123 infores:hetionet CHEBI:44032 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151905 infores:hetionet CHEBI:194135 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0151578 infores:hetionet CHEBI:32184 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0005758 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0234215 infores:hetionet CHEBI:31932 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0037763 infores:hetionet CHEBI:3752 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0011053 infores:hetionet CHEBI:3561 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00341 UMLS:C0232462 infores:hetionet CHEBI:47780 biolink:causes MONDO:0005151 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0014130 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0475858 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0475858 infores:hetionet CAID:CA412363511 biolink:causes MONDO:0100039 infores:clingen CAID:CA412363511 MONDO:0100039 PMID: Likely Benign BS1, BS2_Supporting PM1, PP3, PM2, BP4 The allele frequency of the c.2318A>G p.Glu773Gly variant in CDKL5 (NM_001323289.2) is 0.008% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Glu773Gly variant is observed in at least 1 unaffected individual (GeneDx internal data) (BS2_Supporting). Computational prediction analysis tools are inconclusive for this variant (criteria not met). In summary, the c.2318A>G p.Glu773Gly variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BS2_Supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA412363511/MONDO:0100039/034 2023-06-22 2023-12-08 X-linked inheritance HP:0001417 Contradicts true CHEBI:3696 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0039231 infores:hetionet CHEBI:9139 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0403632 infores:hetionet CHEBI:4466 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C0546884 infores:hetionet CHEBI:144093 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0852911 infores:hetionet CHEBI:4702 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0018794 infores:hetionet CHEBI:45863 biolink:causes HP:0031851 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0744727 infores:hetionet CHEBI:72323 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06203 UMLS:C0020517 infores:hetionet CHEBI:3732 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0151766 infores:hetionet CHEBI:63616 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0746883 infores:hetionet CHEBI:8888 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0518988 infores:hetionet CHEBI:567361 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0013404 infores:hetionet CHEBI:9137 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0042963 infores:hetionet CHEBI:194135 biolink:causes MONDO:0018076 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0041296 infores:hetionet CHEBI:10650 biolink:causes HP:0031943 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0392156 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0009450 infores:hetionet NCBIGene:1788 biolink:causes MONDO:0032882 infores:monarchinitiative not_provided not_provided HGNC:2978 MONDO:0032882 uuid:64f10ec6-abc9-491c-9722-381cabfc9680 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA400021843 biolink:causes MONDO:0100326 infores:clingen CAID:CA400021843 MONDO:0100326 PMID: Likely Pathogenic PM3, PP4_Moderate, PP3, PM2_Supporting The NM_000212.3:c.415G>C variant in ITGB3 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 139 (p.Asp139His). This variant has been observed in compound heterozygosity in one individual (GT53 in PMID: 19691478) in trans (phase confirmed) with ITGB3 variant c.422A>G (p.Tyr141Cys, classified by the Platelet Disorders VCEP as a Pathogenic; PM3). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.986, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant is classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PM2_Supporting, PM3 PP3, PP4_Moderate. (VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA400021843/MONDO:0100326/011 2025-04-15 2025-05-13 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:51032 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00751 UMLS:C0037199 infores:hetionet NCBIGene:100147744 biolink:causes MONDO:0030362 infores:monarchinitiative not_provided not_provided HGNC:34033 MONDO:0030362 uuid:c1990258-3b7f-4ae6-b5f7-6024e54aefc6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0020458 infores:hetionet CHEBI:17347 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0423153 infores:hetionet CHEBI:2682 biolink:causes UMLS:C0281981 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0281981 infores:hetionet CHEBI:110423 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0006266 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0595885 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0595885 infores:hetionet CHEBI:47499 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0023530 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0877232 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0877232 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0033821 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0149726 infores:hetionet CHEBI:77260 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0020621 infores:hetionet CHEBI:4514 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0006145 infores:hetionet CHEBI:7565 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0423791 infores:hetionet CHEBI:6954 biolink:causes HP:0003124 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0020443 infores:hetionet CHEBI:10125 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0013428 infores:hetionet UNII:3U02EL437C biolink:causes UMLS:C0858797 infores:sider not_provided not_provided DRUGBANK:DB01190 UMLS:C0858797 infores:hetionet CHEBI:9943 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0031256 infores:hetionet CHEBI:9168 biolink:causes UMLS:C1735634 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C1735634 infores:hetionet CHEBI:9130 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01236 UMLS:C0009676 infores:hetionet CHEBI:77733 biolink:causes MONDO:0004567 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C1258215 infores:hetionet CHEBI:5384 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0030193 infores:hetionet CHEBI:94609 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00483 UMLS:C0037036 infores:hetionet CHEBI:9566 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00679 UMLS:C0003123 infores:hetionet CHEBI:3568 biolink:causes NCIT:C107587 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0015544 infores:hetionet CHEBI:8024 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C2830004 infores:hetionet CHEBI:68845 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB08822 UMLS:C0027497 infores:hetionet CHEBI:135530 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01591 UMLS:C1443060 infores:hetionet CHEBI:32888 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00431 UMLS:C0042109 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0040034 infores:hetionet CHEBI:50305 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C0018681 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0236024 infores:hetionet CAID:CA10577546 biolink:causes MONDO:0100488 infores:clingen CAID:CA10577546 MONDO:0100488 PMID: Likely Benign BS2, PM2_Supporting, PVS1_Moderate BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM6, PP2, PP3, PP1, PP4, BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS4, PS2 The c.1712-2A>C variant is a canonical splice variant that has been shown experimentally to lead to an in-frame 9 bp deletion in the extracellular domain (PVS1_Moderate; internal laboratory data). The variant is present in <1 out of 100,000 alleles in the European non-Finnish subpopulation of the gnomAD cohort (1/113,756 alleles, 0 homozygotes, gnomAD v2.1.1; PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been seen in at least 15 individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; internal laboratory data). In summary, this variant is classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, PVS1_Moderate, PM2_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577546/MONDO:0100488/007 2024-11-25 2024-12-17 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true GO:1904086 biolink:causes GO:0001702 infores:ubergraph knowledge_assertion manual_agent GO:1904086 GO:0001702 CHEBI:8356 biolink:causes HP:0001688 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0085610 infores:hetionet CHEBI:8890 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0020651 infores:hetionet CHEBI:9667 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0518015 infores:hetionet CHEBI:71219 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0015672 infores:hetionet CHEBI:4672 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0026766 infores:hetionet CHEBI:50275 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0042267 infores:hetionet CHEBI:5001 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0015230 infores:hetionet CHEBI:3756 biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB01068 UMLS:C0151559 infores:hetionet CAID:CA343720077 biolink:causes MONDO:0005338 infores:clingen CAID:CA343720077 MONDO:0005338 PMID: Uncertain Significance PM2_Supporting, BP4 BP7, BS1, BS3, PP3, PP1, PM4, PM5, PS2, PS4, PS3, PS1, BA1 The c.38C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 13 (p.Pro13Leu). This variant was not found in any genetic ancestry group of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.278, which is within the 0.184-0.290 range for BP4, suggesting that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 18776955), but they also carried another MYOC variant, (c.1010A>G p.Gln337ArgfsTer9 - a variant of uncertain significance) and therefore was not counted. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PM2_Supporting, BP4 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA343720077/MONDO:0005338/019 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true UMLS:C0657912 biolink:causes UMLS:C0042376 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0042376 infores:hetionet CHEBI:9123 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0015967 infores:hetionet CHEBI:63598 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0423153 infores:hetionet CAID:CA294584 biolink:causes MONDO:0100039 infores:clingen CAID:CA294584 MONDO:0100039 PMID: Pathogenic PM2_Supporting, PVS1, PS4_Moderate The p.Glu74Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu74Ter variant has been observed in 3 individuals with CDKL5-related disorders (PMID 3131328, PMID 25657822, GeneDx internal database) (PS4_moderate). The p.Glu74Ter variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Glu74Ter variant in CDKL5 is classified as pathogenic for CDKL5-related disorders based on the ACMG/AMP criteria (PVS1, PS4_moderate, PM2_supporting). (CDKL5 Specifications v4.1; curation approved on [5/7/2025]) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294584/MONDO:0100039/034 2025-05-07 2025-06-30 X-linked inheritance HP:0001417 Supports NCBITaxon:1485 biolink:causes MONDO:0024388 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1485 MONDO:0024388 CHEBI:61049 biolink:causes MONDO:0021187 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020473 infores:hetionet CHEBI:63617 biolink:causes MONDO:0000750 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0518988 infores:hetionet CHEBI:3752 biolink:causes MONDO:0004620 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0152267 infores:hetionet CHEBI:8774 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0016382 infores:hetionet CHEBI:18248 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0234233 infores:hetionet CAID:CA410150112 biolink:causes MONDO:0011071 infores:clingen CAID:CA410150112 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PP1 PS1, PS3, PS2, PS4, BP3, BP2, BP1, BP4, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, BS2, PP4, PP2, PP3 NM_001754.5(RUNX1):c.861C>G (p.Tyr287Ter) is a nonsense variant which affects all biologically relevant isoforms. This variant is a nonsense variant between c.98 - c.916, ranking at PVS1 according to the RUNX1 decision tree (PVS1). This variant was found to co-segregate with disease in 3 affected family members (PMID: 11830488, Pedigree 3) (PP1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1, PM2_supporting, PM5_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410150112/MONDO:0011071/008 2023-12-09 2023-12-09 Autosomal dominant inheritance HP:0000006 Supports CHEBI:50777 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0026858 infores:hetionet CHEBI:6904 biolink:causes MONDO:0005434 infores:sider not_provided not_provided DRUGBANK:DB00264 UMLS:C0349506 infores:hetionet CHEBI:367163 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0041657 infores:hetionet CHEBI:52717 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0013182 infores:hetionet CHEBI:9086 biolink:causes HP:0046502 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0234022 infores:hetionet CHEBI:2704 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0040053 infores:hetionet CHEBI:161680 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0036572 infores:hetionet CHEBI:78543 biolink:causes UMLS:C1608945 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C1608945 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0269002 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0269002 infores:hetionet CHEBI:4710 biolink:causes MONDO:0005480 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0011616 infores:hetionet CHEBI:5383 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0027497 infores:hetionet CHEBI:61049 biolink:causes MONDO:0004592 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0021099 infores:hetionet CHEBI:7640 biolink:causes MONDO:0000926 infores:sider not_provided not_provided DRUGBANK:DB00540 UMLS:C0152198 infores:hetionet CHEBI:51860 biolink:causes MONDO:0013792 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C2937358 infores:hetionet CHEBI:6690 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0004093 infores:hetionet CHEBI:5558 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01018 UMLS:C0009763 infores:hetionet CHEBI:194135 biolink:causes MONDO:0007186 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0018834 infores:hetionet CHEBI:6775 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0017178 infores:hetionet CHEBI:64355 biolink:causes HP:0100247 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0019521 infores:hetionet CHEBI:17987 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB06770 UMLS:C0011603 infores:hetionet CHEBI:47898 biolink:causes HP:0031657 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0577822 infores:hetionet CHEBI:291342 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0013384 infores:hetionet CHEBI:17303 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0017178 infores:hetionet CHEBI:168396 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004093 infores:hetionet CHEBI:3403 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0002792 infores:hetionet CHEBI:64355 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0028084 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001243 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0012739 infores:hetionet CHEBI:45652 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0003811 infores:hetionet CHEBI:37924 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0035078 infores:hetionet CHEBI:465284 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01004 UMLS:C0000737 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0239735 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0239735 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0020538 infores:hetionet CHEBI:74947 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0085624 infores:hetionet CHEBI:17698 biolink:causes MONDO:0001534 infores:sider not_provided not_provided DRUGBANK:DB00446 UMLS:C0155169 infores:hetionet NCBIGene:55967 biolink:causes MONDO:0032627 infores:monarchinitiative not_provided not_provided HGNC:23987 MONDO:0032627 uuid:4c038c82-dec4-4f67-ab67-2a92bac5d3b8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:168396 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0041912 infores:hetionet CHEBI:72297 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0002871 infores:hetionet CHEBI:204928 biolink:causes EFO:0011056 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0595916 infores:hetionet CAID:CA405696652 biolink:causes MONDO:0007783 infores:clingen CAID:CA405696652 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting, PP3_Moderate This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of isoleucine with phenylalanine at codon 3413 of the RYR1 protein, p.(Ile3413Phe). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:25735680). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.914) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405696652/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true UMLS:C0120107 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0042024 infores:hetionet CHEBI:8356 biolink:causes UMLS:C1262144 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C1262144 infores:hetionet CHEBI:36791 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0024312 infores:hetionet CHEBI:6950 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0038990 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0018799 infores:hetionet CAID:CA16020733 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020733 MONDO:0009861 PMID:28982351PMID:28982351 Pathogenic PM3, PM2, PP4_Moderate, PVS1_Strong The c.168+2T>C variant in PAH was reported in one patient with PKU (BH4 deficiency excluded) in trans with p.R243Q (PP4_Moderate, PM3; PMID: 28982351). This variant is absent from population databases, including gnomAD (PM2). This variant occurs at a canonical splice site, which will result in abnormal splicing at the donor site of intron 2 where LOF is a known mechanism of disease, exon skipping preserves reading frame, but the altered region is critical to protein function (14 non-truncating pathogenic variants in the region). (PVS1_strong). In summary, this variant meets the criteria to be classified pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PVS1_strong, PM2, PM3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020733/MONDO:0009861/006 2019-04-09 2019-04-09 Autosomal recessive inheritance HP:0000007 Supports CHEBI:136040 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB08918 UMLS:C0020649 infores:hetionet CHEBI:40279 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0013604 infores:hetionet CHEBI:8597 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0341047 infores:hetionet GO:1901509 biolink:causes GO:0003158 infores:ubergraph knowledge_assertion manual_agent GO:1901509 GO:0003158 CHEBI:32139 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01390 UMLS:C0234233 infores:hetionet CHEBI:114785 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00530 UMLS:C0151763 infores:hetionet CHEBI:41423 biolink:causes MONDO:0021392 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0949059 infores:hetionet NCBIGene:5078 biolink:causes MONDO:0012818 infores:monarchinitiative not_provided not_provided HGNC:8618 MONDO:0012818 uuid:d15ef351-704a-42ae-93e0-a230a5307b9a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA341289668 biolink:causes MONDO:0800406 infores:clingen CAID:CA341289668 MONDO:0800406 PMID: Likely Pathogenic PP3_Moderate, PM2_Supporting, PM3_Strong PM5, PP4, PS4 The NM_000350.3(ABCA4):c.629T>A variant in ABCA4 is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 210 (p.Leu210Gln). The total minor allele frequency in gnomAD v4.1.0 is 0.0000006198 (1/1613424 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.879 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). This variant has been detected in at least four individuals with ABCA4-related retinopathy, who were compound heterozygous for the variant and a likely pathogenic or pathogenic variant, with one confirmed via parental testing and three with phase unconfirmed (PMIDs: 32751377, 32915376, Zolnikova I.V. et al Ophthalmology in Russia. 2021, ClinVar IDs: SCV001239990.1 and SCV002993733.3; PM3_Strong). In summary, this variant meets the criteria to be classified as a likely pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): PM2_Supporting, PP3_Moderate, PM3_Strong. ABCA4 VCEP https://erepo.genome.network/evrepo/ui/classification/CA341289668/MONDO:0800406/164 2025-10-28 2025-11-14 Autosomal recessive inheritance HP:0000007 Supports CHEBI:175901 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C1384666 infores:hetionet CHEBI:7915 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0855242 infores:hetionet NCBITaxon:468 biolink:causes MONDO:0006878 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:468 MONDO:0006878 PUBCHEM.COMPOUND:12162152 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB08944 UMLS:C2129214 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0151828 infores:hetionet CHEBI:3504 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0015672 infores:hetionet CHEBI:49375 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0221201 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0740399 infores:hetionet CHEBI:8774 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0042384 infores:hetionet CAID:CA10583223 biolink:causes MONDO:0100216 infores:clingen CAID:CA10583223 MONDO:0100216 PMID: Likely Benign BP4, BP7 PM2, PM6, BA1, BP2, PP1, PM5, PM1, PS1, PS2, BS1, BS4 The NM_177438.3:c.1089C>T (p.Phe363=) variant is a synonymous (silent) variant that is not predicted to impact splicing by MaxEntScan or SpliceAI (BP4, BP7). The total allele frequency in gnomAD v4.1.0 is 0.000001368 (2/1461842 alleles) with a highest population minor allele frequency of 0.00003312 (2/60394 alleles) in a population of undisclosed ancestry (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, BP7. (Bayesian Points: -2; VCEP specifications version 1.3.0; 04/23/2024) DICER1 and miRNA-Processing Gene VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583223/MONDO:0100216/024 2024-04-23 2024-05-08 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:34385 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C0020517 infores:hetionet CHEBI:9927 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00177 UMLS:C0042075 infores:hetionet CHEBI:31711 biolink:causes UMLS:C0277925 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0277925 infores:hetionet CHEBI:64355 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0234215 infores:hetionet CHEBI:46295 biolink:causes UMLS:C0037195 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0037195 infores:hetionet CAID:CA512341284 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341284 MONDO:0011071 PMID: Uncertain Significance BP4, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1131C>T (p.Tyr377=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341284/MONDO:0011071/008 2024-10-29 2024-10-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68855 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB08824 UMLS:C0017178 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0036572 infores:hetionet CAID:CA8814955 biolink:causes MONDO:0009290 infores:clingen CAID:CA8814955 MONDO:0009290 PMID:22644586 Likely Benign PM2_Supporting, BP4, BS3_Supporting The NM_000152.5:c.658G>T variant is GAA is a missense variant that is predicted to result in the substitution of valine by leucine at amino acid 220 (p.Val220Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00075 (15/19928 alleles) in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS-7 cells, this variant results in normal GAA activity, and the protein is normally synthesized and/or processed (PMID 22644586) (BS3_Supporting). The computational predictor REVEL gives a score of 0.305 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). The variant has been reported in an individual with either suspected Pompe disease or a known carrier, but further details are not available (PMID 22644586). There is a ClinVar entry for this variant (Variation ID: 255365). While there is conflicting evidence, overall, the benign evidence, including functional studies (BS3_Supporting) and in silico data (BP4), outweighs the pathogenic evidence (PM2_Supporting). Therefore, the variant has been classified as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, BP4, BS3_Supporting (modified classification: likely benign, approved by ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 4, 2023). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA8814955/MONDO:0009290/010 2023-04-04 2023-04-05 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:7565 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0234193 infores:hetionet CHEBI:5103 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0030554 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0425669 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0425669 infores:hetionet CHEBI:63619 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0851578 infores:hetionet CHEBI:50841 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0015672 infores:hetionet CHEBI:7627 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0015672 infores:hetionet CHEBI:15367 biolink:causes MONDO:0002602 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0007682 infores:hetionet NCBIGene:3176 biolink:causes MONDO:0014759 infores:monarchinitiative not_provided not_provided HGNC:5028 MONDO:0014759 uuid:f438098b-c443-4012-a842-567b2decdd6c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8871 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0015732 infores:hetionet CAID:CA8328319 biolink:causes MONDO:0100438 infores:clingen CAID:CA8328319 MONDO:0100438 PMID: Uncertain Significance PM2_Supporting BS3, PP3, PM4, PM3 NM_014336.5(AIPL1):c.1054_1065dup (p.Ala352_Pro355dup) is predicted to cause a change in the length of the AIPL1 protein due to an in-frame duplication encoding 4 amino acids, with at least one of the neighboring base pairs highly conserved with a PhyloP conservation score of 2.1. However, this region of the protein is repetitive and specifically excluded from PM4. The splicing impact predictor SpliceAI gives a score of 0.10 for acceptor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00004961, with 80 / 1,612,666 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 3 probands with retinal dystrophy who harbored the variant in the heterozygous state (PMID: 10873396, PMID: 33067476). However, the probands were not counted for PM3 because no second AIPL1 variant was identified in trans and because sufficient phenotype details were unavailable to confirm severity and age of onset. The exogenously expressed variant protein was similar to the wild-type control in its expression, cytoplasmic distribution, interaction with HSP90alpha and HSP90beta, and ability to modulate PDE6 activity in cGMP homeostasis (PMID: 33067476). However, these assays have not been approved for BS3_Supporting. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/24/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8328319/MONDO:0100438/208 2025-09-29 2025-09-29 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:63581 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0021400 infores:hetionet CHEBI:28364 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00159 UMLS:C0017178 infores:hetionet CAID:CA16020969 biolink:causes MONDO:0009861 infores:clingen CAID:CA16020969 MONDO:0009861 PMID: Likely Pathogenic PP3_Strong, PM2_Supporting, PM5_Supporting PM3, PP4 The c.1204T>G (p.Phe402Val) variant in PAH is currently unreported in the literature. This variant is absent from population databases (PM2_Supporting), and is predicted deleterious by SIFT, PolyPhen2, MutationTester, and REVEL = 0.973 (PP3_Strong). Other missense variants [c.1204T>C (p.Phe402Leu); c.1205T>G (p.Phe402Cys)] in the same codon have been classified as likely pathogenic by the ClinGen Phenylketonuria Variant Curation Expert Panel (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_Supporting, PP3_Strong, PM5_supporting. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA16020969/MONDO:0009861/006 2024-11-17 2024-11-18 Autosomal recessive inheritance HP:0000007 Supports CHEBI:15407 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0340464 infores:hetionet CHEBI:31236 biolink:causes HP:0100520 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0028961 infores:hetionet CAID:CA320642685 biolink:causes MONDO:0011071 infores:clingen CAID:CA320642685 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS4, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PVS1, PM2, PM5, PM4, PM1, PM3, PP2, PP3, PP4, PP1 NM_001754.5:c.258G>A (p.Pro86=) is a synonymous variant which is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by its phyloP score (BP4, BP7). The germline variant has not been reported in patients meeting the RUNX1 phenotypic criteria and has been identified at an overall minor allele frequency of 0.0077% (1/13002 alleles) in ESP. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320642685/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true NCBIGene:79903 biolink:causes MONDO:0968977 infores:monarchinitiative not_provided not_provided HGNC:25875 MONDO:0968977 uuid:30c2c9ed-97d3-4161-8177-6010bfc58c66 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:23020 biolink:causes MONDO:0012477 infores:monarchinitiative not_provided not_provided HGNC:30859 MONDO:0012477 uuid:6c395157-6a72-4a1f-8a01-96f97318d048 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:283450 biolink:causes MONDO:0859516 infores:monarchinitiative not_provided not_provided HGNC:26611 MONDO:0859516 uuid:74158fac-8643-4186-893c-7d02956adfd7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41774 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0160390 infores:hetionet CHEBI:119486 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0009806 infores:hetionet CHEBI:7496 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0947912 infores:hetionet CHEBI:36795 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0042373 infores:hetionet GO:2000006 biolink:causes GO:0072210 infores:ubergraph knowledge_assertion manual_agent GO:2000006 GO:0072210 CHEBI:50777 biolink:causes MONDO:0002056 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0178421 infores:hetionet CHEBI:3738 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0235710 infores:hetionet CHEBI:75722 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0428977 infores:hetionet CHEBI:6717 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0151529 infores:hetionet CHEBI:101278 biolink:causes HP:0000017 infores:sider not_provided not_provided DRUGBANK:DB00343 UMLS:C0028734 infores:hetionet CHEBI:23765 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0013404 infores:hetionet CHEBI:75722 biolink:causes HP:0002311 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0520966 infores:hetionet CHEBI:38545 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0011991 infores:hetionet CHEBI:5001 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0039520 infores:hetionet CAID:CA415176953 biolink:causes MONDO:0010726 infores:clingen CAID:CA415176953 MONDO:0010726 PMID: Uncertain Significance PM1, PP4, PM2_Supporting The p.Thr99Pro variant in MECP2 occurs in the well-characterized methyl-DNA binding (MDB) functional domain of the MECP2 gene (PMID 21326358) (PM1). This variant has been reported in an individual with a clinical phenotype suggestive of Rett Syndrome (internal database) (PP4). The p.Thr99Pro variant is absent from gnomAD (PM2_supporting). In summary, the p.Thr99Pro variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM1, PM2_supporting, PP4). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415176953/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Inconclusive https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf true CHEBI:63617 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0917798 infores:hetionet CHEBI:50742 biolink:causes HP:0002883 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0020578 infores:hetionet CHEBI:132233 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00182 UMLS:C0003123 infores:hetionet CHEBI:4562 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0403632 infores:hetionet CAID:CA916079828 biolink:causes MONDO:0015967 infores:clingen CAID:CA916079828 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PVS1 PS4, PP4 The c.864dupG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 289 of NM_000545.8, adding 28 novel amino acids before encountering a stop codon (p.(Pro289AlafsTer28). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 25414397 and 30293189, internal lab contributors). None of the individuals had calculated MODY probability >50%; therefore, PP4 cannot be applied. In summary, c.864dupG meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA916079828/MONDO:0015967/017 2022-04-15 2022-07-12 Autosomal dominant inheritance HP:0000006 Supports CHEBI:6690 biolink:causes UMLS:C0152128 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0152128 infores:hetionet CAID:CA16620725 biolink:causes MONDO:0018947 infores:clingen CAID:CA16620725 MONDO:0018947 PMID: Benign BA1 BP4, BS1, PM2, PP2, PP3 The c.8A>G variant in DNM2 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 3. The highest population filtering allele frequency in gnomAD v4.1 is 0.00001190 (2/43076 alleles) in the Admixed American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000015) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.57, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function. DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2, not applied for this variant due to high allele frequency). In summary, this variant meets the criteria to be classified as benign for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/24) Congenital Myopathies VCEP https://erepo.genome.network/evrepo/ui/classification/CA16620725/MONDO:0018947/148 2024-08-07 2024-10-01 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:9763 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0855242 infores:hetionet CHEBI:4672 biolink:causes HP:0010741 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0239340 infores:hetionet CHEBI:63598 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0027497 infores:hetionet CAID:CA16042723 biolink:causes MONDO:0017623 infores:clingen CAID:CA16042723 MONDO:0017623 PMID:20962022PMID:20962022PMID:27477328PMID:20962022 Pathogenic PM2, PM6, PVS1 BP5, BP7, BS4, BS3, BS1, BS2, PP1, PP2, PM1, PM4, PM5, BP2, BP4, BA1, PS3, PS4, PS1, PS2 PTEN c.1027-1G>A (IVS8-1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor SCV000490754.2) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16042723/MONDO:0017623/003 2019-06-25 2019-07-23 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8774 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0002792 infores:hetionet CHEBI:7494 biolink:causes HP:0000741 infores:sider not_provided not_provided DRUGBANK:DB01149 UMLS:C0085632 infores:hetionet CHEBI:17141 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0002871 infores:hetionet CHEBI:408174 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0015967 infores:hetionet CHEBI:3696 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0033774 infores:hetionet CHEBI:5855 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0038362 infores:hetionet CHEBI:49375 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0746883 infores:hetionet CHEBI:91834 biolink:causes MONDO:0001835 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0015469 infores:hetionet CHEBI:30830 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027769 infores:hetionet CAID:CA282114 biolink:causes MONDO:0021060 infores:clingen CAID:CA282114 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1052G>A (p.Arg351Gln) variant in the PTPN11 gene is 0.263% (55/16488) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA282114/MONDO:0021060/004 2017-04-18 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true PUBCHEM.COMPOUND:45357473 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0036974 infores:hetionet CHEBI:68595 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB05521 UMLS:C0038325 infores:hetionet NCBIGene:5034 biolink:causes MONDO:0007204 infores:monarchinitiative not_provided not_provided HGNC:8548 MONDO:0007204 uuid:4a094917-961e-4018-a955-ce3de49ce504 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges NCBIGene:1604 biolink:causes MONDO:0009174 infores:monarchinitiative not_provided not_provided HGNC:2665 MONDO:0009174 uuid:f4420a9a-55ef-4883-be7f-09cc9bb44ea7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2666 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0030554 infores:hetionet CHEBI:72297 biolink:causes HP:0500005 infores:sider not_provided not_provided DRUGBANK:DB08827 UMLS:C0034886 infores:hetionet CHEBI:75722 biolink:causes HP:0000938 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0029453 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0002679 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0007785 infores:hetionet CHEBI:5959 biolink:causes MONDO:0002909 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C0020456 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0011053 infores:hetionet CHEBI:63577 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0031542 infores:hetionet CHEBI:48273 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00953 UMLS:C0151827 infores:hetionet NCBIGene:8364 biolink:causes MONDO:0030729 infores:monarchinitiative not_provided not_provided HGNC:4787 MONDO:0030729 uuid:0b5e299c-dd80-47c0-9934-7d10af72907d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:4786 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00397 UMLS:C0013384 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0151883 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0151883 infores:hetionet CHEBI:15367 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00755 UMLS:C0022107 infores:hetionet CHEBI:52172 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020458 infores:hetionet CHEBI:2208 biolink:causes HP:0002149 infores:sider not_provided not_provided DRUGBANK:DB01033 UMLS:C0740394 infores:hetionet CHEBI:2618 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00915 UMLS:C0004134 infores:hetionet CHEBI:8107 biolink:causes MONDO:0001085 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0027707 infores:hetionet CHEBI:9352 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0016204 infores:hetionet CHEBI:8871 biolink:causes EFO:0020912 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0232807 infores:hetionet CHEBI:47898 biolink:causes UMLS:C0438173 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0438173 infores:hetionet CHEBI:5864 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0030252 infores:hetionet CHEBI:4356 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00746 UMLS:C0023530 infores:hetionet CHEBI:131512 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00752 UMLS:C0003467 infores:hetionet CHEBI:261649 biolink:causes HP:0002329 infores:sider not_provided not_provided DRUGBANK:DB01294 UMLS:C0013144 infores:hetionet CHEBI:9943 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0002874 infores:hetionet CHEBI:61049 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0035410 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0039971 infores:hetionet CHEBI:61049 biolink:causes MONDO:0010627 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0549463 infores:hetionet NCBIGene:55209 biolink:causes MONDO:0014336 infores:monarchinitiative not_provided not_provided HGNC:25566 MONDO:0014336 uuid:9960e23f-3a45-49c7-aedc-b1b3943d3897 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4672 biolink:causes UMLS:C3495917 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C3495917 infores:hetionet CHEBI:77260 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0151736 infores:hetionet NCBIGene:1788 biolink:causes MONDO:0018874 infores:monarchinitiative not_provided not_provided HGNC:2978 MONDO:0018874 uuid:2be3b90c-184b-45c3-87aa-d466e8ce5e45 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:41423 biolink:causes HP:0200036 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0037287 infores:hetionet CHEBI:63616 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0031350 infores:hetionet CHEBI:68642 biolink:causes HP:0020110 infores:sider not_provided not_provided DRUGBANK:DB05812 UMLS:C0016658 infores:hetionet NCBIGene:11155 biolink:causes MONDO:0011094 infores:monarchinitiative not_provided not_provided HGNC:15710 MONDO:0011094 uuid:8e9f93b5-c79d-4e61-a02a-1fb785f17010 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51041 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00659 UMLS:C0014591 infores:hetionet CHEBI:63618 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00175 UMLS:C0042571 infores:hetionet NCBIGene:79068 biolink:causes MONDO:0013050 infores:monarchinitiative not_provided not_provided HGNC:24678 MONDO:0013050 uuid:5a50c59a-406e-48aa-a9d5-07cde4b29888 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0236051 infores:hetionet UMLS:C0879264 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0041834 infores:hetionet CHEBI:6704 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0002994 infores:hetionet CHEBI:9943 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0004096 infores:hetionet CHEBI:16347 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0037199 infores:hetionet CHEBI:5847 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0027497 infores:hetionet CHEBI:367163 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0022107 infores:hetionet CHEBI:2904 biolink:causes MONDO:0004766 infores:sider not_provided not_provided DRUGBANK:DB00335 UMLS:C0038218 infores:hetionet CHEBI:6413 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0027051 infores:hetionet CHEBI:66876 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06237 UMLS:C0018799 infores:hetionet CHEBI:5847 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0013604 infores:hetionet CHEBI:9907 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0162830 infores:hetionet CHEBI:144093 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0262397 infores:hetionet CHEBI:7565 biolink:causes HP:0011106 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0546884 infores:hetionet CHEBI:51230 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB00905 UMLS:C0024117 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0027769 infores:hetionet CHEBI:75722 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0002962 infores:hetionet CHEBI:75984 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0034063 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0948594 infores:hetionet CHEBI:51860 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C1306341 infores:hetionet CHEBI:100241 biolink:causes NCIT:C35105 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0041981 infores:hetionet CHEBI:64045 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB06288 UMLS:C2830004 infores:hetionet NCBIGene:1832 biolink:causes MONDO:0014355 infores:monarchinitiative not_provided not_provided HGNC:3052 MONDO:0014355 uuid:3563ad9a-aaae-4081-8b4b-0037352754b9 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28748 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0518015 infores:hetionet CHEBI:3508 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0019080 infores:hetionet CHEBI:5864 biolink:causes UMLS:C0686377 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0686377 infores:hetionet CHEBI:4814 biolink:causes MONDO:0004857 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0039503 infores:hetionet CHEBI:3127 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0036974 infores:hetionet CHEBI:75722 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0151827 infores:hetionet CAID:CA186314 biolink:causes MONDO:0007648 infores:clingen CAID:CA186314 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting BP5, BP7, BS1, BS4, BS3, PM3, PM4, PM1, PM6, PP1, PP4, PP2, PP3, BS2, BP2, BP1, BP4, BP3, BA1, PS4, PS2, PS3, PS1 The c.76G>T p.(Glu26Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA186314/MONDO:0007648/007 2023-08-04 2023-08-04 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:27899 biolink:causes MONDO:0021568 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0151747 infores:hetionet NCBIGene:64170 biolink:causes MONDO:0008905 infores:monarchinitiative not_provided not_provided HGNC:16391 MONDO:0008905 uuid:e71647cf-64ed-410d-b9fe-43e41314d401 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:142290 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0017181 infores:hetionet CHEBI:3403 biolink:causes NCIT:C3852 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0236075 infores:hetionet CHEBI:7903 biolink:causes HP:0001281 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0039621 infores:hetionet CHEBI:91834 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0007859 infores:hetionet CHEBI:8764 biolink:causes MONDO:0024355 infores:sider not_provided not_provided DRUGBANK:DB00688 UMLS:C0035243 infores:hetionet CHEBI:3647 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0025323 infores:hetionet CHEBI:5138 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0575081 infores:hetionet CHEBI:171719 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0042963 infores:hetionet CHEBI:10101 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0042023 infores:hetionet CHEBI:15765 biolink:causes MONDO:0043862 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C1527344 infores:hetionet CHEBI:5855 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0020625 infores:hetionet CHEBI:59445 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00534 UMLS:C0031542 infores:hetionet CHEBI:10101 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0039231 infores:hetionet CHEBI:3614 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00878 UMLS:C0018681 infores:hetionet CHEBI:9586 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0034880 infores:hetionet CHEBI:27779 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0013395 infores:hetionet CHEBI:3242 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0917801 infores:hetionet CHEBI:71940 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0027051 infores:hetionet CAID:CA136098 biolink:causes MONDO:0021060 infores:clingen CAID:CA136098 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.2371C>A (p.Leu791Ile) variant in the SOS1 gene is 0.081% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (67/66688 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA136098/MONDO:0021060/004 2017-04-03 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63577 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0015672 infores:hetionet CAID:CA294595 biolink:causes MONDO:0100039 infores:clingen CAID:CA294595 MONDO:0100039 PMID: Uncertain Significance PP3, PM2_Supporting BS1, BS3, BA1, PS3, PS4, PS1 The c.404-3C>A variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The c.404-3C>A variant has been observed in an individual with epilepsy (PMID: 29655203) (does not meet PS4). The computational splicing predictor SpliceAI gives a score of 0.64 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 5 of CDKL5 (PP3). In summary, the c.404-3C>A variant in CDKL5 is classified as uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, PP3). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA294595/MONDO:0100039/034 2025-08-27 2025-09-30 X-linked inheritance HP:0001417 Inconclusive true CHEBI:6413 biolink:causes GO:0042697 infores:sider not_provided not_provided DRUGBANK:DB01006 UMLS:C0025320 infores:hetionet CHEBI:15940 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0231528 infores:hetionet CHEBI:5613 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0494475 infores:hetionet CHEBI:8435 biolink:causes UMLS:C0032961 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0032961 infores:hetionet CHEBI:39867 biolink:causes EFO:0011052 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0235378 infores:hetionet CAID:CA415166340 biolink:causes MONDO:0010726 infores:clingen CAID:CA415166340 MONDO:0010726 PMID: Benign BS1, BP5, BS2 BP4, PM2, PP3 The highest population minor allele frequency of the p.Met418Thr variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.0002310 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Met418Thr variant is observed in at least 2 unaffected individuals (internal database - GeneDx; internal database - Ambry Genetics) (BS2). The p.Met418Thr variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Met418Thr variant in MECP2 (NM_004992.4) is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5). (MECP2 Specifications v.4.1; curation approved on 06/25/2025) Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA415166340/MONDO:0010726/036 2025-06-25 2025-08-01 X-linked inheritance HP:0001417 Contradicts true CHEBI:9599 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0027765 infores:hetionet CHEBI:63635 biolink:causes HP:0000790 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0018965 infores:hetionet NCBIGene:131669 biolink:causes MONDO:0010167 infores:monarchinitiative not_provided not_provided HGNC:26444 MONDO:0010167 uuid:be5413f1-7f7d-4751-a7df-9314feb99b32 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8776 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0009676 infores:hetionet NCBIGene:57094 biolink:causes MONDO:0024566 infores:monarchinitiative not_provided not_provided HGNC:17245 MONDO:0024566 uuid:8cd73e24-7291-4641-90c0-7f71c60c57f7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:74947 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0008031 infores:hetionet CAID:CA414909018 biolink:causes MONDO:0010602 infores:clingen CAID:CA414909018 MONDO:0010602 PMID: Pathogenic PP4_Moderate, PM2_Supporting, PP3, PS4 The c.2087C>T (p.Thr696Ile) variant is absent from males in gnomAD v2.1.1 & gnomAD v3. 1 allele is reported in gnomAD v3.1.1 meeting PM2_Supporting criteria. The missense variant has a REVEL score of 0.927 (>0.6) meeting PP3 criteria. The variant has been reported in at least 18 probands with mild hemophilia A meeting phenotypic criteria for F8 at the very strong evidence weight (PMID: 24845853 and My Life Our Future data - 29296726). This variant has also been associated with discrepant factor VIII activity levels (PMID: 32232366). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA414909018/MONDO:0010602/071 2024-02-02 2024-07-11 X-linked inheritance HP:0001417 Supports CHEBI:63598 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C1384353 infores:hetionet CHEBI:8382 biolink:causes MONDO:0001836 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0002453 infores:hetionet CHEBI:77260 biolink:causes MONDO:0020592 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0031345 infores:hetionet CAID:CA16612999 biolink:causes MONDO:0017623 infores:clingen CAID:CA16612999 MONDO:0017623 PMID: Uncertain Significance PM2 PTEN c.80-5C>T (IVS1-5C>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16612999/MONDO:0017623/003 2020-10-20 2022-09-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:4710 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0549373 infores:hetionet CHEBI:8382 biolink:causes UMLS:C0406479 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0406479 infores:hetionet CHEBI:40279 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0037274 infores:hetionet CHEBI:7931 biolink:causes HP:0002829 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0003862 infores:hetionet CAID:CA10577548 biolink:causes MONDO:0007648 infores:clingen CAID:CA10577548 MONDO:0007648 PMID: Pathogenic PM5_Supporting, PVS1, PS4_Supporting, PM2_Supporting BS4, BS1, BS3, BP5, BP7, PM3, PM1, PM4, PM6, BS2, PP1, PP4, PP2, PP3, BA1, BP2, BP1, BP4, BP3, PS2, PS3, PS1 The c.1779dup p.(Ile594fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Additionally, this variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 15235021). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA10577548/MONDO:0007648/007 2023-08-25 2023-08-25 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf CHEBI:7476 biolink:causes HP:0003076 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0017979 infores:hetionet CHEBI:10125 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00425 UMLS:C0025061 infores:hetionet CHEBI:2682 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0007642 infores:hetionet CHEBI:16755 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0031046 infores:hetionet CHEBI:5134 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0041912 infores:hetionet CHEBI:77260 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0001807 infores:hetionet CHEBI:2668 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0021053 infores:hetionet CHEBI:17347 biolink:causes MONDO:0000088 infores:sider not_provided not_provided DRUGBANK:DB01420 UMLS:C0034013 infores:hetionet CHEBI:84050 biolink:causes UMLS:C0877153 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0877153 infores:hetionet UBERON:0001335 biolink:causes MONDO:0003790 infores:ubergraph knowledge_assertion manual_agent UBERON:0001335 MONDO:0003790 CHEBI:9570 biolink:causes UMLS:C0393444 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0393444 infores:hetionet CHEBI:8888 biolink:causes MONDO:0002036 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0030846 infores:hetionet CHEBI:82941 biolink:causes MONDO:0004966 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0017152 infores:hetionet CHEBI:3723 biolink:causes HP:6001125 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0558401 infores:hetionet CAID:CA512341055 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341055 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1317C>G (p.Ser439=) is a synonymous variant which has a REVEL score < 0.50 (0) and a SpliceAI score ≤ 0.20 (0) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.3)) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341055/MONDO:0011071/008 2024-09-25 2024-09-25 Autosomal dominant inheritance HP:0000006 Contradicts true UNII:D27V6190PM biolink:causes MONDO:0010528 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0003126 infores:hetionet CHEBI:4495 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01119 UMLS:C0018099 infores:hetionet CHEBI:51164 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00589 UMLS:C0027765 infores:hetionet CHEBI:6950 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0231530 infores:hetionet CHEBI:9168 biolink:causes MONDO:0020590 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0026918 infores:hetionet CHEBI:3219 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0232495 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C0743680 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0743680 infores:hetionet CHEBI:8356 biolink:causes MONDO:0021259 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0033578 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0042109 infores:hetionet CHEBI:3696 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0042023 infores:hetionet NCBIGene:204219 biolink:causes MONDO:0014010 infores:monarchinitiative not_provided not_provided HGNC:23752 MONDO:0014010 uuid:7da201fe-76a1-4f43-83d2-283cbbdeb19d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6129 biolink:causes UMLS:C0151664 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0151664 infores:hetionet CHEBI:50275 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00736 UMLS:C0162830 infores:hetionet CHEBI:16469 biolink:causes HP:0200119 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0267797 infores:hetionet CHEBI:6367 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0149931 infores:hetionet CHEBI:31397 biolink:causes UMLS:C0877048 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0877048 infores:hetionet CAID:CA229355 biolink:causes MONDO:0009861 infores:clingen CAID:CA229355 MONDO:0009861 PMID: Pathogenic PVS1, PP4, PM2_Supporting, PM3_Supporting The c.1127del (p.Asn376fs) variant in PAH is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a Mexican patient with classic PKU with the pathogenic variant c.1066-11G>A (PMID: 24941924; PP4, PM3_supporting). This variant has an extremely low frequency in gnomAD (MAF=0.00002895). In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PM3_supporting, PP4. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA229355/MONDO:0009861/006 2023-10-15 2023-10-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:3698 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0001824 infores:hetionet CHEBI:50777 biolink:causes UMLS:C0853959 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0853959 infores:hetionet CHEBI:28748 biolink:causes MONDO:0005294 infores:sider not_provided not_provided DRUGBANK:DB00997 UMLS:C0085096 infores:hetionet CHEBI:63610 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB00929 UMLS:C0034065 infores:hetionet CHEBI:63627 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0030252 infores:hetionet CHEBI:45951 biolink:causes HP:0000711 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0700075 infores:hetionet CHEBI:6149 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01002 UMLS:C0036974 infores:hetionet CHEBI:421707 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0948594 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0233414 infores:hetionet CHEBI:31348 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0027497 infores:hetionet CHEBI:6690 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C0027051 infores:hetionet CAID:CA409104369 biolink:causes MONDO:0015967 infores:clingen CAID:CA409104369 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting PS3 The c.302C>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of alanine to aspartic acid at codon 101 (p.(Ala101Asp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.934, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.302C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0 approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409104369/MONDO:0015967/085 2023-09-29 2023-09-29 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:3216 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0009450 infores:hetionet NCBIGene:4621 biolink:causes MONDO:0008675 infores:monarchinitiative not_provided not_provided HGNC:7573 MONDO:0008675 uuid:6b604ed8-16d8-4386-ad8b-903a2af04f84 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0013395 infores:hetionet NCBIGene:5573 biolink:causes MONDO:0008057 infores:monarchinitiative not_provided not_provided HGNC:9388 MONDO:0008057 uuid:ccd428fc-8c68-4815-8387-f27cabf414bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:2673 biolink:causes UMLS:C0233632 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0233632 infores:hetionet CHEBI:84500 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0085649 infores:hetionet CAID:CA367400488 biolink:causes MONDO:0015967 infores:clingen CAID:CA367400488 MONDO:0015967 PMID: Likely Pathogenic PS4_Moderate, PM5_Supporting, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting The c.820G>A variant in the glucokinase gene, GCK, is a missense variant resulting in an amino acid change of aspartic acid to asparagine at codon 274 (p.(Asp274Asn)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). Additionally, it is predicted to be deleterious by computational evidence, with a REVEL score of 0.935, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributor). Furthermore, the variant segregated with diabetes in this family with three informative meioses (PP1, internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 32086287, 36257325, internal lab contributors). Another missense variant at the same amino acid, c.820G>A p.(Asp274Ala), has been classified as pathogenic by the ClinGen MDEP, but p.Asp274Asn has a smaller Grantham distance (PM5_Supporting). In summary, c.820G>A variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate; PM2_Supporting, PP2, PP3, PP4_Moderate, PP1, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367400488/MONDO:0015967/086 2025-10-28 2025-10-28 Semidominant inheritance HP:0032113 Supports CHEBI:3732 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0017160 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1141930 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1141930 infores:hetionet CAID:CA10549337 biolink:causes MONDO:0010305 infores:clingen CAID:CA10549337 MONDO:0010305 PMID: Uncertain Significance BS1, PM2, PP3, PM5, BP4 The NM_005629.4:c.833G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of an arginine by a histidine at amino acid position 278 (p.Arg278His). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00007 (2/27341 alleles) in the Latino population and 1 hemizygote across all populations, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.353, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 917570, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; one submitter: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA10549337/MONDO:0010305/027 2024-11-08 2024-11-13 X-linked inheritance HP:0001417 Inconclusive true CHEBI:42068 biolink:causes HP:0001410 infores:sider not_provided not_provided DRUGBANK:DB01177 UMLS:C0086565 infores:hetionet CHEBI:31536 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0015663 infores:hetionet CHEBI:16586 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00513 UMLS:C0018524 infores:hetionet CHEBI:7936 biolink:causes NCIT:C87131 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0043387 infores:hetionet CHEBI:9137 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0019112 infores:hetionet CHEBI:15552 biolink:causes MONDO:0005279 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0034065 infores:hetionet CHEBI:36791 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0007642 infores:hetionet CHEBI:63622 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0016204 infores:hetionet CHEBI:63599 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0085605 infores:hetionet CHEBI:6759 biolink:causes HP:0004308 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0085612 infores:hetionet CHEBI:32221 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0017181 infores:hetionet CHEBI:27666 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0687713 infores:hetionet CHEBI:41774 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0038999 infores:hetionet NCBIGene:55777 biolink:causes MONDO:0007974 infores:monarchinitiative not_provided not_provided HGNC:20444 MONDO:0007974 uuid:2699c5b0-3490-4532-96ea-9dd7771eb4f1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:45409 biolink:causes UMLS:C0015663 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0015663 infores:hetionet CHEBI:6128 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB01009 UMLS:C0547030 infores:hetionet CHEBI:9943 biolink:causes HP:0034004 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1510410 infores:hetionet CHEBI:59773 biolink:causes MONDO:0005904 infores:sider not_provided not_provided DRUGBANK:DB01003 UMLS:C0031046 infores:hetionet CHEBI:83804 biolink:causes HP:0040212 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0343494 infores:hetionet GO:0060008 biolink:causes CL:0000216 infores:ubergraph knowledge_assertion manual_agent GO:0060008 CL:0000216 CHEBI:5134 biolink:causes MONDO:0006521 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0234894 infores:hetionet CHEBI:46295 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0035455 infores:hetionet CHEBI:46195 biolink:causes UMLS:C0919874 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0919874 infores:hetionet CHEBI:63611 biolink:causes NCIT:C35524 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0750426 infores:hetionet CHEBI:9943 biolink:causes HP:0003473 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0947912 infores:hetionet CHEBI:3698 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0006266 infores:hetionet NCBIGene:3208 biolink:causes MONDO:0009141 infores:monarchinitiative not_provided not_provided HGNC:5144 MONDO:0009141 uuid:38d04e6d-c54a-4976-81a4-5cfaf58f58d1 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9137 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0014335 infores:hetionet CHEBI:77733 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB00661 UMLS:C0021400 infores:hetionet CAID:CA383506026 biolink:causes MONDO:0015630 infores:clingen CAID:CA383506026 MONDO:0015630 PMID: Uncertain Significance PP4_Moderate, PP3, PM2_Supporting PM6, BS2, PP1, BP4, BP2, PS3, PS4, PS2, PS1, PM3, PM5, BP5, BS3, BS4 The NM_000552.5(VWF):c.3961T>A variant in VWF is a missense variant predicted to cause substitution of tyrosine by asparagine at amino acid 1321. This variant is absent from gnomAD v4.1 (PM2_supporting). One patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio and abnormal collagen binding assay (PP4_Moderate). The computational predictor REVEL gives a score of 0.802, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Other missense variants in the same codon have been reported in patients with low RCo/Ag ratio and abnormal collagen binding; c.3962A>G, p.Tyr1321Cys and c.3961T>G, p.Tyr1321Asp (19506361; 22329792; 16409463). Due to insufficient evidence, this variant is classified as a variant of unknown significance for von Willebrand disease type 2M based on the ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PP3. von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA383506026/MONDO:0015630/081 2024-06-28 2024-12-03 Autosomal dominant inheritance HP:0000006 Inconclusive true CAID:CA202222 biolink:causes MONDO:0009276 infores:clingen CAID:CA202222 MONDO:0009276 PMID:15351858 Benign BA1, BP4, PS3_Supporting BP2, PP4, BS2, PM3 The c.466G>A (p.Ala156Thr) variant in GP9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 156. At least one patient (Case in PMID:15351858 or internal) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which is consistent with Bernard-Soulier syndrome, however this variant has a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.2194 (based on 9530/42710 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.187, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP9 function and splicing predictor SpliceAI predicts no impact on splicing with delta scores of 0.00 (BP4). Surface expression of GPIBa and GP9 measured by flow cytometry in CHO cells in cells transiently co-transfected with the c.466G>A variant and wild type GP1a and GP1b showed decreased expression at very low (<25%) WT levels, indicating that this variant impacts protein function (PMID:15351858)(PS3_supporting). In summary with BP4 (-1), BA1, PS3_supporting (+1), the other criteria cancel out and BA1 alone provides a Benign classification, ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP. Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA202222/MONDO:0009276/083 2025-02-11 2025-02-17 Autosomal recessive inheritance HP:0000007 Contradicts true UMLS:C0145867 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0151539 infores:hetionet CHEBI:8890 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0041657 infores:hetionet CHEBI:64310 biolink:causes NCIT:C83817 infores:sider not_provided not_provided DRUGBANK:DB08865 UMLS:C0855333 infores:hetionet CHEBI:3219 biolink:causes MONDO:0000948 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0022575 infores:hetionet CHEBI:51364 biolink:causes MONDO:0001152 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0002622 infores:hetionet CHEBI:17474 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB04574 UMLS:C0015672 infores:hetionet UMLS:C0004609 biolink:causes HP:0001974 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0023518 infores:hetionet CHEBI:100241 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1456784 infores:hetionet CHEBI:79699 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0086543 infores:hetionet CHEBI:63577 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C1384666 infores:hetionet CHEBI:3181 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB01200 UMLS:C0085631 infores:hetionet CHEBI:47381 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0017160 infores:hetionet CHEBI:4708 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0020517 infores:hetionet CHEBI:38940 biolink:causes MONDO:0007758 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0870082 infores:hetionet CHEBI:32293 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00460 UMLS:C0020538 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0002871 infores:hetionet CHEBI:17650 biolink:causes HP:0040189 infores:sider not_provided not_provided DRUGBANK:DB00741 UMLS:C0237849 infores:hetionet CHEBI:15552 biolink:causes NCIT:C93083 infores:sider not_provided not_provided DRUGBANK:DB01240 UMLS:C0086525 infores:hetionet CHEBI:71415 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00698 UMLS:C0009806 infores:hetionet CHEBI:50841 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0234133 infores:hetionet UMLS:C0017797 biolink:causes HP:0003418 infores:sider not_provided not_provided DRUGBANK:DB00130 UMLS:C0004604 infores:hetionet NCBIGene:92749 biolink:causes MONDO:0859364 infores:monarchinitiative not_provided not_provided HGNC:24245 MONDO:0859364 uuid:48dc327c-e6d3-464f-9bb8-2c01b851f1e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA392341191 biolink:causes MONDO:0007947 infores:clingen CAID:CA392341191 MONDO:0007947 PMID: Pathogenic PP1, PP2, PP4, PM2_Supporting, PS4, PM1 PM6, PVS1, PP3, BP2, BP1, BP4, BA1, PS2, PS1, PS3, PM5, BP5, BS1, BS4, BS3 The NM_00138 c.5743C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 1915 (p.Arg1915Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband with classical Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 6 times in ClinVar: once as pathogenic, 4 times as likely pathogenic, and once as uncertain significance (Variation ID: 495629). This variant has also been identified in at least 7 individuals with clinical diagnosis of MFS as well as in individuals with clinical features of MFS (PMID 27234404, 35916808, 33174221, 27906200, internal data; PS4). In two families with MFS, the variant was found to segregate with disease in three affected relatives (Internal lab data, PP1). Different missense variants at this position, c.5744G>A p.(Arg1915His) and c.5743C>A p.(Arg1915Ser), have previously been reported in individuals with MFS and/or MFS-related features (PMID 11700157, 31830381), however these variants have not yet been reviewed by the FBN1 Variant Curation Expert Panel. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant's protein function and structure (REVEL: 0.62). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PP1, PM2_Sup, PP2, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA392341191/MONDO:0007947/022 2024-02-22 2024-02-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:5280 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0022660 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C0235511 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0235511 infores:hetionet CHEBI:3423 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C1262036 infores:hetionet CHEBI:15854 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0232462 infores:hetionet CHEBI:7581 biolink:causes UMLS:C0424605 infores:sider not_provided not_provided DRUGBANK:DB01595 UMLS:C0424605 infores:hetionet CHEBI:9586 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0008031 infores:hetionet CHEBI:7476 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0020538 infores:hetionet CHEBI:63617 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C0549249 infores:hetionet CHEBI:681569 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0518015 infores:hetionet CHEBI:36704 biolink:causes MONDO:0005083 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0033860 infores:hetionet CHEBI:681569 biolink:causes MONDO:0043726 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0026766 infores:hetionet CHEBI:7627 biolink:causes UMLS:C0241028 infores:sider not_provided not_provided DRUGBANK:DB00717 UMLS:C0241028 infores:hetionet CHEBI:29007 biolink:causes MONDO:0017853 infores:sider not_provided not_provided DRUGBANK:DB01212 UMLS:C0002390 infores:hetionet CHEBI:63608 biolink:causes MONDO:0001339 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0155773 infores:hetionet CHEBI:2675 biolink:causes HP:0000967 infores:sider not_provided not_provided DRUGBANK:DB00543 UMLS:C0031256 infores:hetionet CHEBI:28901 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C0085692 infores:hetionet CHEBI:3478 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0852911 infores:hetionet CHEBI:567361 biolink:causes UMLS:C0332575 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0332575 infores:hetionet CHEBI:9599 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0233494 infores:hetionet CHEBI:61049 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0015672 infores:hetionet UMLS:C0004609 biolink:causes UMLS:C0020701 infores:sider not_provided not_provided DRUGBANK:DB00181 UMLS:C0020701 infores:hetionet NCBIGene:3239 biolink:causes MONDO:0007223 infores:monarchinitiative not_provided not_provided HGNC:5136 MONDO:0007223 uuid:9ac589bd-5c7c-42f6-bf47-7a817673fd75 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:188986 biolink:causes HP:0025314 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0346392 infores:hetionet CHEBI:49575 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0002957 infores:hetionet CHEBI:78543 biolink:causes UMLS:C0340726 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0340726 infores:hetionet CHEBI:23765 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0039971 infores:hetionet CHEBI:17347 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0032617 infores:hetionet CHEBI:2914 biolink:causes HP:0006511 infores:sider not_provided not_provided DRUGBANK:DB00732 UMLS:C0023066 infores:hetionet CHEBI:63620 biolink:causes MONDO:0004580 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0035304 infores:hetionet CHEBI:8774 biolink:causes MONDO:0019542 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0162557 infores:hetionet CAID:CA3530549 biolink:causes MONDO:0015152 infores:clingen CAID:CA3530549 MONDO:0015152 PMID: Pathogenic PM3_Supporting, PVS1, PP4, PM2_Supporting The NM_000337.6: c.289C>T p.(Arg97Ter) variant in SGCD is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/9, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).This variant has been identified in a homozygous state in at least two patients with LGMD who were from consanguineous families (0.5 pts, PMID: 34515763, 30733730; PM3_Supporting). At least one of these patients displayed progressive limb girdle weakness observed over more than six months (PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001146 (1/87260 alleles) in the South Asian population, which is lower than the ClinGen LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA3530549/MONDO:0015152/186 2025-01-08 2025-01-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:49668 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0151905 infores:hetionet CHEBI:4735 biolink:causes NCIT:C38031 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0423153 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0018099 infores:hetionet CHEBI:36791 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028084 infores:hetionet CHEBI:46295 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0004093 infores:hetionet CHEBI:4702 biolink:causes UMLS:C0854097 infores:sider not_provided not_provided DRUGBANK:DB00869 UMLS:C0854097 infores:hetionet CAID:CA10583955 biolink:causes MONDO:0020367 infores:clingen CAID:CA10583955 MONDO:0020367 PMID: Uncertain Significance PP3, PM2_Supporting BP7, BS1, BS3, PM6, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BP4, BA1 The c.1111T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 371 (p.Tyr371His). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.875, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 2 segregations had been reported for juvenile open angle glaucoma, including 1 proband (Teruya et al, 2008), not meeting the ≥ 3 segregations required for PP1 or the ≥ 2 probands threshold required to meet PS4_Supporting. These individuals are reported in ClinVar (SCV000268698.1). In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA10583955/MONDO:0020367/019 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6759 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0004245 infores:hetionet CHEBI:9435 biolink:causes HP:0001350 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0234518 infores:hetionet CHEBI:7577 biolink:causes MONDO:0005292 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0009319 infores:hetionet CHEBI:63619 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0027769 infores:hetionet CHEBI:4953 biolink:causes MONDO:0005010 infores:sider not_provided not_provided DRUGBANK:DB00990 UMLS:C1956346 infores:hetionet NCBIGene:57591 biolink:causes MONDO:0030013 infores:monarchinitiative not_provided not_provided HGNC:14334 MONDO:0030013 uuid:caff2cf8-fadf-425a-85c9-cbc299695773 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3013 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00436 UMLS:C0011991 infores:hetionet CHEBI:9435 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0003467 infores:hetionet CHEBI:63608 biolink:causes UMLS:C0851883 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0851883 infores:hetionet CHEBI:100241 biolink:causes MONDO:0002261 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0235270 infores:hetionet CHEBI:10110 biolink:causes HP:0001279 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0039070 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0233481 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0233481 infores:hetionet GO:0039580 biolink:causes GO:0039585 infores:ubergraph knowledge_assertion manual_agent GO:0039580 GO:0039585 CHEBI:6456 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00281 UMLS:C0009938 infores:hetionet CHEBI:6539 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0235146 infores:hetionet CHEBI:144093 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0027051 infores:hetionet CAID:CA658795235 biolink:causes MONDO:0009290 infores:clingen CAID:CA658795235 MONDO:0009290 PMID:19775921PMID:28838325 Pathogenic PM2, PVS1, PP4, PM3_Strong This variant, c.722_723del (p.Phe241CysfsTer), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This variant is absent in gnomAD v2.1.1, meeting PM2. It has been found in at least two patients with Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 19775921). One of these patients is compound heterozygous for the variant and c.1687C>T (p.Gln563Ter), and the other is compound heterozygous for the variant and c.1754+1G>A. In both cases, the variants were confirmed to be in trans. This data meets PM3_Strong. Additional cases have been reported, but did not meet PP4 (PMID 28838325). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Strong, PP4. Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA658795235/MONDO:0009290/010 2020-01-21 2020-05-26 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ CHEBI:75998 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0016436 infores:hetionet CAID:CA312291 biolink:causes MONDO:0008723 infores:clingen CAID:CA312291 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PP3, PM3, PP4_Moderate PM1, PS3 The c.553G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by serine at amino acid 185 (p.Gly185Ser). This variant has been detected in at least 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and distinct pathogenic variants (PM3, PMIDs: 31620161, 17999356).Two patients with this variant displayed beta Oxidation Flux <20% of normal and at least one individual showed increased acylcarnitines, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMIDs: 17999356, 31620161, 22841441). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA312291/MONDO:0008723/021 2022-12-14 2022-12-14 Autosomal recessive inheritance HP:0000007 Supports CAID:CA134750 biolink:causes MONDO:0021060 infores:clingen CAID:CA134750 MONDO:0021060 PMID:26918529PMID:31030682 Pathogenic PS2, PS4_Moderate, PM1, PM2, PP2 PM5 The c.776C>A (p.Ser259Tyr) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of Noonan syndrome (PS4_Moderate; PMIDs: 31030682, 26918529, GeneDx internal data). In one proband, the variant occurred de novo with parentage confirmation (PS2; PMID: 31030682). The c.776C>A (p.Ser259Tyr) variant occurs in the CR2 activation domain of RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). A different pathogenic missense variant has been previously identified at this codon of RAF1 supporting this residue is critical to the function of the protein (PM5 not applied; ClinVar 40601). The variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PS2, PM1, PP2. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134750/MONDO:0021060/004 2020-05-18 2020-05-21 Autosomal dominant inheritance HP:0000006 Supports https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:49575 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0027497 infores:hetionet UMLS:C0657912 biolink:causes HP:0011004 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151489 infores:hetionet CHEBI:4469 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01576 UMLS:C0015672 infores:hetionet CHEBI:100246 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0019158 infores:hetionet CHEBI:9137 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0021053 infores:hetionet CHEBI:681569 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0020517 infores:hetionet CHEBI:32599 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00653 UMLS:C0235063 infores:hetionet CHEBI:27666 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00970 UMLS:C0031350 infores:hetionet CHEBI:3647 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00477 UMLS:C0027849 infores:hetionet UNII:15G12L5X8K biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0043144 infores:hetionet CHEBI:27899 biolink:causes UMLS:C0746883 infores:sider not_provided not_provided DRUGBANK:DB00515 UMLS:C0746883 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0009938 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0009938 infores:hetionet CAID:CA8365937 biolink:causes MONDO:0100453 infores:clingen CAID:CA8365937 MONDO:0100453 PMID: Pathogenic PM3, PVS1, PP1, PM2_Supporting The NM_000180.4(GUCY2D):c.1956+1G>A variant disrupts a canonical splice site in intron 9 and is predicted to lead to in-frame skipping of a critical exon (PVS1). This variant is present in gnomAD v.4.1.0 at an allele frequency of 6.202e-7, with 1 allele / 1612348 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.1672G>A (p.Asp558Asn) and NM_000180.4(GUCY2D):c.1245del (p.Phe415fs) variants confirmed in trans (1 point, PMID: 32865313), one of which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 1 point, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 32865313, PP1). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_Supporting, PM3, and PP1. (VCEP specifications version 1.0.0; date of approval 01/22/2025). Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA8365937/MONDO:0100453/167 2025-01-31 2025-01-31 Autosomal recessive inheritance HP:0000007 Supports CHEBI:8232 biolink:causes UMLS:C0687133 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0687133 infores:hetionet CHEBI:3423 biolink:causes UMLS:C0240035 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0240035 infores:hetionet CHEBI:3814 biolink:causes MONDO:0004872 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0019112 infores:hetionet CHEBI:10650 biolink:causes UMLS:C0340464 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0340464 infores:hetionet CHEBI:4814 biolink:causes HP:0025145 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0424790 infores:hetionet CHEBI:9137 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0003467 infores:hetionet CHEBI:63631 biolink:causes UMLS:C1456865 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C1456865 infores:hetionet CHEBI:63580 biolink:causes UMLS:C0042035 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0042035 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0234987 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0234987 infores:hetionet CHEBI:38562 biolink:causes MONDO:0004298 infores:sider not_provided not_provided DRUGBANK:DB01095 UMLS:C0038354 infores:hetionet GO:0060334 biolink:causes GO:0071346 infores:ubergraph knowledge_assertion manual_agent GO:0060334 GO:0071346 CHEBI:101853 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0700225 infores:hetionet CHEBI:480999 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0009450 infores:hetionet CHEBI:2668 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00381 UMLS:C0037763 infores:hetionet NCBIGene:59341 biolink:causes MONDO:0007232 infores:monarchinitiative not_provided not_provided HGNC:18083 MONDO:0007232 uuid:98f53530-9c6c-4290-90e8-242041b62a1c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5138 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0011615 infores:hetionet CHEBI:6741 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0085649 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0019360 infores:hetionet CHEBI:135566 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00896 UMLS:C0085636 infores:hetionet CHEBI:5138 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0014591 infores:hetionet CHEBI:9168 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0852911 infores:hetionet CHEBI:72564 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0042571 infores:hetionet CAID:CA012605 biolink:causes MONDO:0004994 infores:clingen CAID:CA012605 MONDO:0004994 PMID: Benign BA1 The filtering allele frequency of the c.2553C>A (p.Ser851=) variant in the MYH7 gene is 0.18% (27/10406) of African chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA012605/MONDO:0004994/002 2016-12-15 2018-11-16 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:5001 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0018799 infores:hetionet CAID:CA916084365 biolink:causes MONDO:0007947 infores:clingen CAID:CA916084365 MONDO:0007947 PMID: Likely Pathogenic PM2, PP4, PM4, PM1 PM6, PP3, PP1, BA1, BP4, BP2, PS3, PS2, PS4, BS1, BS3, BS4 The NM_000138 c.5734_5736del is predicted to cause an in-frame deletion (PM4) of a highly conserved phenylalanine residue between the third and fourth cysteine in a calcium binding EGF-like (cbEGF-like) domain at amino acid 1912 (p.Phe1912del). This phenylalanine is part of a beta-hydroxylase consensus sequence (CXD/NXXXXF/YXCXC) that is present in all cbEGF-like domains in fibrillin-1, and a phenylalanine or tyrosine must be intact at this position in order for beta-hydroxylation to occur (PM1) (PMID 12511552, 2826439). This variant was found in a proband with a reported Marfan syndrome diagnosis, with features including wrist or thumb, hindfoot deformity, pes planus, myopia, mitral valve prolapse, and ectopia lentis, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). This variant has not been reported in ClinVar. This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic variant for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM4, PM2_Supportive, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA916084365/MONDO:0007947/022 2023-06-15 2023-06-15 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:53760 biolink:causes HP:0002591 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0232461 infores:hetionet CHEBI:7443 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C1443060 infores:hetionet GO:1904073 biolink:causes GO:0001824 infores:ubergraph knowledge_assertion manual_agent GO:1904073 GO:0001824 CHEBI:2704 biolink:causes UMLS:C0151736 infores:sider not_provided not_provided DRUGBANK:DB01217 UMLS:C0151736 infores:hetionet CHEBI:94501 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0085631 infores:hetionet CHEBI:4814 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0234215 infores:hetionet CHEBI:6887 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0344232 infores:hetionet CHEBI:4657 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0030232 infores:hetionet CHEBI:2955 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0011615 infores:hetionet CHEBI:87715 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0042075 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0235351 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0235351 infores:hetionet CHEBI:2569 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00802 UMLS:C0015397 infores:hetionet CHEBI:52172 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0344232 infores:hetionet CHEBI:8707 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0233472 infores:hetionet CHEBI:3082 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0020621 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0233414 infores:hetionet CHEBI:3752 biolink:causes MONDO:0007342 infores:sider not_provided not_provided DRUGBANK:DB00882 UMLS:C0009081 infores:hetionet CHEBI:4027 biolink:causes MONDO:0003329 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0041956 infores:hetionet CHEBI:5864 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0234233 infores:hetionet CHEBI:6715 biolink:causes NCIT:C35272 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0232495 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005015 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0011849 infores:hetionet CHEBI:17263 biolink:causes MONDO:0008170 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C1140680 infores:hetionet CHEBI:53760 biolink:causes MONDO:0001126 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0038358 infores:hetionet CHEBI:521033 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01126 UMLS:C0262397 infores:hetionet CHEBI:61058 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0242350 infores:hetionet CHEBI:84050 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB05109 UMLS:C0027947 infores:hetionet NCBIGene:57545 biolink:causes MONDO:0030797 infores:monarchinitiative not_provided not_provided HGNC:29253 MONDO:0030797 uuid:611ff8dd-6746-4ca4-bc4f-7050cad76a2d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50742 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0037274 infores:hetionet NCBIGene:10369 biolink:causes MONDO:0013657 infores:monarchinitiative not_provided not_provided HGNC:1406 MONDO:0013657 uuid:1ee958a2-934d-400d-bb17-564943225f51 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16335 biolink:causes MONDO:0006624 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0085606 infores:hetionet CHEBI:8888 biolink:causes MONDO:0006515 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0001339 infores:hetionet CHEBI:7956 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00299 UMLS:C0012833 infores:hetionet NCBIGene:137682 biolink:causes MONDO:0030056 infores:monarchinitiative not_provided not_provided HGNC:28625 MONDO:0030056 uuid:e77437c2-8ba0-482f-8e24-0c3b36b85b33 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:18332 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0009676 infores:hetionet CHEBI:75722 biolink:causes UMLS:C0553698 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0553698 infores:hetionet CHEBI:3441 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0034150 infores:hetionet CHEBI:3082 biolink:causes UMLS:C0423602 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0423602 infores:hetionet CHEBI:6832 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00423 UMLS:C0027497 infores:hetionet CHEBI:3732 biolink:causes MONDO:0001609 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0001824 infores:hetionet CHEBI:119573 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0040264 infores:hetionet CHEBI:8707 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0013404 infores:hetionet CAID:CA355945206 biolink:causes MONDO:0001586 infores:clingen CAID:CA355945206 MONDO:0001586 PMID: Pathogenic PM3, PVS1, PP4, PM2_Supporting The NM_000203.5:c.1A>G (p.Met1?) variant in IDUA is predicted to cause an N-terminal truncated or absent protein by altering the start codon of the coding sequence. The next in-frame ATG is at position 133. If that ATG is used as a start signal, the lysosomal signal sequence (amino acids 1-27) would be lost (https://www.uniprot.org/uniprotkb/P35475/entry) (PVS1). Two patients with severe MPS1 (Hurler syndrome) are reported to be homozygous for the variant (PMID: 27146977, 28752568) (PM3). One patient, from India, had clinical features consistent with a severe presentation of MPS 1 including dysostosis multiplex, coarse facial features, cardiomegaly, and intellectual disability, as well as documented deficient activity of IDUA in leukocytes (PMID: 27146977), while a second patient, from Spain, was reported to have a confirmed diagnosis based on IDUA deficiency (PMID: 21394825) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 8.893e-7 (1/1124490) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Of note, other variants that abolish the start ATG have been identified in individuals with mucopolysaccharidosis type 1 (c.1A>C, ClinVar Variation ID: 550458; c.2T>C, ClinVar Variation ID: 639529). There is a ClinVar entry for c.1A>G (Variation ID:1323098). In summary, this variant, c.1A>G (p.Met1?) meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA355945206/MONDO:0001586/091 2024-12-06 2024-12-15 Autosomal recessive inheritance HP:0000007 Supports CHEBI:6888 biolink:causes MONDO:0000440 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0220981 infores:hetionet NCBIGene:490 biolink:causes MONDO:0030891 infores:monarchinitiative not_provided not_provided HGNC:814 MONDO:0030891 uuid:20eb8511-b2ae-4a2c-8185-1dd4376ae222 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9649 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0852911 infores:hetionet CHEBI:116278 biolink:causes MONDO:0000705 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C1257843 infores:hetionet UNII:UMD7G2653W biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00710 UMLS:C1971624 infores:hetionet UNII:5V9KLZ54CY biolink:causes HP:0040264 infores:sider not_provided not_provided DRUGBANK:DB00570 UMLS:C0236000 infores:hetionet NCBIGene:4069 biolink:causes MONDO:0971009 infores:monarchinitiative not_provided not_provided HGNC:6740 MONDO:0971009 uuid:0e2ea1d2-ad44-4ecd-a52c-f961bc0c28a8 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:119486 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0030305 infores:hetionet CHEBI:84500 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0003811 infores:hetionet CHEBI:10650 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0853986 infores:hetionet CHEBI:8874 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0151744 infores:hetionet CHEBI:125354 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06809 UMLS:C0392386 infores:hetionet CHEBI:49040 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0009676 infores:hetionet CHEBI:37924 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C2830004 infores:hetionet CHEBI:5384 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB01067 UMLS:C0016204 infores:hetionet CHEBI:5847 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00293 UMLS:C0004093 infores:hetionet CHEBI:478164 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0006277 infores:hetionet CHEBI:63608 biolink:causes MONDO:0004652 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0004626 infores:hetionet CHEBI:15940 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00627 UMLS:C0030193 infores:hetionet GO:0075010 biolink:causes GO:0009847 infores:ubergraph knowledge_assertion manual_agent GO:0075010 GO:0009847 CHEBI:7465 biolink:causes MONDO:0006948 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0035302 infores:hetionet CAID:CA6748883 biolink:causes MONDO:0009861 infores:clingen CAID:CA6748883 MONDO:0009861 PMID:31332730PMID:21307867 Likely Pathogenic PM5, PM2, PP4_Moderate, PP3 The c.674C>T (p.Pro225Leu) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded (PMID: 21307867). This variant has extremely low frequency in gnomAD MAF=0.000008800. Computational evidence support a deleterious effect. The p.Pro225Thr variant is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3. Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA6748883/MONDO:0009861/006 2020-03-08 2020-03-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:5855 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB01050 UMLS:C0243026 infores:hetionet CHEBI:71940 biolink:causes MONDO:0001409 infores:sider not_provided not_provided DRUGBANK:DB00820 UMLS:C0014868 infores:hetionet GO:0036522 biolink:causes GO:1905161 infores:ubergraph knowledge_assertion manual_agent GO:0036522 GO:1905161 CHEBI:47381 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0040822 infores:hetionet CHEBI:63581 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0042963 infores:hetionet CHEBI:51380 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0026821 infores:hetionet CAID:CA011976 biolink:causes MONDO:0005045 infores:clingen CAID:CA011976 MONDO:0005045 PMID: Uncertain Significance PM2, PM1 PM5, PM6, PM4, PP3, PP1, PS3, BA1, BS1, BS3, BS4, PS1, PS4, PS2, BP4, BP2, BP5, BP7, PVS1 The c.2213G>C (p.Ser738Thr) variant in MYH7 has been reported in 1 individual with HCM (Hamburger 2016 PMID:27247418); however this data is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). However, computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM1 Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA011976/MONDO:0005045/002 2021-03-22 2021-08-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63620 biolink:causes MONDO:0002009 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C1269683 infores:hetionet CAID:CA16044135 biolink:causes MONDO:0017623 infores:clingen CAID:CA16044135 MONDO:0017623 PMID:28086757PMID:28086757 Likely Pathogenic PP2, PP3, PS3_Moderate, PM6_Strong, PM2_Supporting PVS1, BP5, BP7, BS4, BS1, BS3, PP1, PP4, BS2, PM3, PM5, PM4, PM1, BA1, BP2, BP1, BP4, BP3, PS4, PS1, PS2 PTEN c.740T>C (p.Leu247Ser) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2_Supporting: Absent in large sequenced populations (PMID: 27535533).PM6_Strong: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMIDs: 28086757 and 29752200)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PS3_Moderate: Functional studies showing a damaging effect on protein function. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350). This variant: score of -1.669765892.PP3: REVEL score > 0.7 (this variant: score=0.918). PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA16044135/MONDO:0017623/003 2023-08-04 2023-10-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:45951 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00831 UMLS:C0043094 infores:hetionet CHEBI:3082 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0023218 infores:hetionet CHEBI:110423 biolink:causes UMLS:C0079043 infores:sider not_provided not_provided DRUGBANK:DB00720 UMLS:C0079043 infores:hetionet CHEBI:31397 biolink:causes HP:0033521 infores:sider not_provided not_provided DRUGBANK:DB01410 UMLS:C0231919 infores:hetionet CHEBI:2453 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C0015967 infores:hetionet CAID:CA226726 biolink:causes MONDO:0010725 infores:clingen CAID:CA226726 MONDO:0010725 PMID: Likely Pathogenic PS4_Supporting, PM2_Supporting, PP3_Moderate, PS3_Supporting, PM5, PP1 PP4 NM_000330.4(RS1):c.421C>G (p.Arg141Gly) is a missense variant encoding the substitution of arginine with glycine at amino acid 141. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). Another missense variant in the same codon, NM_000330.4(RS1):c.422G>A (p.Arg141His), (PMIDs: 34645606, 30450322, 29739629, 35984651, 30652005, 19093009) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (125) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 9618178, 15937075, 28272453, PS4_Supporting). The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family that includes two affected brothers (PP1; PMID: 15937075). The computational predictor REVEL gives a score of 0.864, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_Moderate). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predicted splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 30040949, PS3_Supporting). This variant was found to affect a surface residue within the loop region causing RS1 to lose its ability to bind other molecules (PMID: 28848397). In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PP3_moderate, PS3_supporting, PP1, PM5, and PS4_supporting. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226726/MONDO:0010725/126 2025-09-21 2025-09-21 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CAID:CA512341357 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341357 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM6, PVS1, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.1032C>T (p.Asp344=) is a synonymous variant with a SpliceAI Δ score ≤ 0.20 (0.00) (BP4). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score 0.86978 < 2.0), and the variant is the reference nucleotide in three mammal species (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341357/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7496 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0019158 infores:hetionet CHEBI:17026 biolink:causes UMLS:C0549310 infores:sider not_provided not_provided DRUGBANK:DB00396 UMLS:C0549310 infores:hetionet CHEBI:3698 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0013395 infores:hetionet CHEBI:27777 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00551 UMLS:C0027497 infores:hetionet CHEBI:5801 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01611 UMLS:C0004936 infores:hetionet CHEBI:3223 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00490 UMLS:C0043094 infores:hetionet CHEBI:3082 biolink:causes HP:0004420 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0151942 infores:hetionet CHEBI:4798 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0700590 infores:hetionet CHEBI:2955 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0027769 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0575090 infores:hetionet CHEBI:45409 biolink:causes HP:0000282 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0542571 infores:hetionet CHEBI:3723 biolink:causes MONDO:0005392 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0036439 infores:hetionet CHEBI:75722 biolink:causes MONDO:0000595 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0549622 infores:hetionet CHEBI:31932 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0030305 infores:hetionet CHEBI:8028 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0011991 infores:hetionet CAID:CA025281 biolink:causes MONDO:0700269 infores:clingen CAID:CA025281 MONDO:0700269 PMID: Likely Pathogenic PM2_Supporting, PVS1_Strong, PS3 The c.7805+3A>C variant is an intronic variant occurring in intron 16 of the BRCA2 gene. This variant is reported to result in aberrant mRNA splicing. Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 16 (75.3%), utilization of cryptic donor sites 100 bp upstream in exon 16 (13.3%), and retention of 20 bp from intron 16 (3.8%) resulting in >90% of transcripts leading to a frameshift and generating a premature stop codon (PMID: 29881398). Appropriate code strength was determined by comparison of results to PVS1 decision tree with PVS1 (RNA) downgraded to PVS1_Strong (RNA). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by two calibrated studies incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMIDs:39779857, 39779848) (PS3 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Strong (RNA), PM2_Supporting, PS3). ENIGMA BRCA1 and BRCA2 VCEP https://erepo.genome.network/evrepo/ui/classification/CA025281/MONDO:0700269/097 2025-08-18 2025-08-18 Autosomal dominant inheritance HP:0000006 Supports CHEBI:52172 biolink:causes MONDO:0007402 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0853034 infores:hetionet CHEBI:49375 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01254 UMLS:C0040822 infores:hetionet CHEBI:17303 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0522063 infores:hetionet CHEBI:8871 biolink:causes HP:0000858 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0156404 infores:hetionet CHEBI:6402 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0015967 infores:hetionet NCBIGene:1674 biolink:causes MONDO:0011482 infores:monarchinitiative not_provided not_provided HGNC:2770 MONDO:0011482 uuid:d88f8671-6981-442d-963b-c4fe7f46d380 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:16467 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0016382 infores:hetionet CHEBI:8874 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0002871 infores:hetionet CHEBI:367163 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0151786 infores:hetionet CHEBI:63629 biolink:causes UMLS:C0022650 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0022650 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0232459 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0232459 infores:hetionet CHEBI:168396 biolink:causes UMLS:C0877635 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0877635 infores:hetionet CHEBI:3286 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00248 UMLS:C0085649 infores:hetionet CHEBI:9123 biolink:causes HP:0001692 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085611 infores:hetionet CHEBI:119915 biolink:causes MONDO:0005381 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0005940 infores:hetionet CHEBI:49040 biolink:causes MONDO:0001040 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0027441 infores:hetionet CHEBI:75722 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0085633 infores:hetionet CHEBI:3176 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0040822 infores:hetionet CHEBI:4670 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB00841 UMLS:C0151636 infores:hetionet CHEBI:2682 biolink:causes HP:0000952 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0022346 infores:hetionet CHEBI:32315 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB01198 UMLS:C2047937 infores:hetionet CHEBI:9435 biolink:causes NCIT:C35607 infores:sider not_provided not_provided DRUGBANK:DB00231 UMLS:C0852911 infores:hetionet CHEBI:10127 biolink:causes UMLS:C0235431 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0235431 infores:hetionet CHEBI:5120 biolink:causes MONDO:0001913 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0028960 infores:hetionet CHEBI:6129 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0231528 infores:hetionet CHEBI:10023 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0009763 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0004936 infores:hetionet CHEBI:47426 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0235198 infores:hetionet CAID:CA347212168 biolink:causes MONDO:0015152 infores:clingen CAID:CA347212168 MONDO:0015152 PMID: Pathogenic PP4_Strong, PM3_Strong, PM2_Supporting, PS3_Moderate PM5, PP3 The NM_003494.4: c.1020C>A variant in DYSF, which is also known as NM_001130987.2: c.1116C>A p.(Ser372Arg), is a missense variant predicted to cause substitution of serine by arginine at amino acid 340, p.(Ser340Arg). This variant has been reported in at least five individuals with features consistent with LGMD or dysferlinopathy (PMID: 26404900, 19528035, 21522182; LOVD DYSF_000360; Jain Foundation Dysferlin Registry), including in a homozygous state in two individuals with known or likely familial consanguinity (0.25 pts x2, Jain Foundation Dysferlin Registry internal data communication) and confirmed in trans with a likely pathogenic or pathogenic variant in two individuals (NM_003494.4: c.1254del, 1.0 pt, PMID: 26404900; NM_003494.4: c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID: 21522182) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant had both a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin expression in skeletal muscle (PMID: 21522182; PP4_Strong). The highest population allele frequency for this variant in gnomAD v4.1.0 is 0.00002196 (2/91084 South Asian chromosomes), which is less than the threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.695, which is below the LGMD VCEP threshold of ≥0.70 for PP3 (criterion not met), but immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Ser340Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538; PS3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 09/17/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PS3_Moderate. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA347212168/MONDO:0015152/180 2025-09-17 2025-10-09 Autosomal recessive inheritance HP:0000007 Supports UMLS:C1738934 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0003811 infores:hetionet CHEBI:9398 biolink:causes HP:0012877 infores:sider not_provided not_provided DRUGBANK:DB00706 UMLS:C0403673 infores:hetionet CHEBI:71255 biolink:causes UMLS:C0919578 infores:sider not_provided not_provided DRUGBANK:DB06216 UMLS:C0919578 infores:hetionet CHEBI:63598 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0001122 infores:hetionet CAID:CA222168 biolink:causes MONDO:0015152 infores:clingen CAID:CA222168 MONDO:0015152 PMID: Benign BA1, BP4, BP7 The NM_003494.4: c.4374C>T p.(Ile1458=) variant in DYSF, which is also known as NM_001130987.2: c.4428C>T (p.Ile1476=), is a synonymous (silent) variant that is not located in a splice region (outside of the first and the last 3 bases of the exon). The filtering allele frequency for this variant is 0.008924 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 434/44852 East Asian chromosomes), which is higher than the VCEP threshold of 0.003 (BA1). In addition, this variant is not predicted to impact splicing (SpliceAI score 0.02) (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 08/14/2025): BA1, BP4, BP7. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222168/MONDO:0015152/180 2025-08-14 2025-09-05 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:6954 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0004134 infores:hetionet CHEBI:8435 biolink:causes MONDO:0019288 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0549567 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0438717 infores:hetionet CAID:CA405650411 biolink:causes MONDO:0007783 infores:clingen CAID:CA405650411 MONDO:0007783 PMID: Uncertain Significance PS4_Supporting PP3 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of alanine with valine at codon 3709 of the RYR1 protein, p.(Ala3709Val). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:21965348). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.793 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA405650411/MONDO:0007783/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:94385 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00278 UMLS:C0027051 infores:hetionet UNII:54Z8M50D6Q biolink:causes UMLS:C0235229 infores:sider not_provided not_provided DRUGBANK:DB00411 UMLS:C0235229 infores:hetionet CHEBI:6887 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0518015 infores:hetionet CHEBI:9667 biolink:causes MONDO:0004247 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0030920 infores:hetionet CAID:CA343772421 biolink:causes MONDO:0013144 infores:clingen CAID:CA343772421 MONDO:0013144 PMID: Uncertain Significance PM5_Supporting, PP4, PP3, PM2_Supporting The c.1306G> variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by proline at amino acid 436 (p.Ala436Pro). At least one patient with this variant displayed an antithrombin activity level of <0.8 IU/mL with repeated independent samples over time, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:24684277). This variant is absent from gnomAD v2.1.1, 3.1.2 and 4.1.0 (PM2_Supporting).Another missense variant c.1306G>A (p.Ala436Thr) (ClinVarID:18003) in the same codon has been classified as likely pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PP4, PM2_Supporting, PM5_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA343772421/MONDO:0013144/084 2025-02-21 2025-02-21 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:63608 biolink:causes MONDO:0004992 infores:sider not_provided not_provided DRUGBANK:DB04835 UMLS:C0006826 infores:hetionet CHEBI:7852 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0235996 infores:hetionet NCBIGene:23503 biolink:causes MONDO:0010044 infores:monarchinitiative not_provided not_provided HGNC:20761 MONDO:0010044 uuid:c0db926a-e9c2-4766-bd11-3aa0115af895 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31859 biolink:causes UMLS:C0233472 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0233472 infores:hetionet CHEBI:91541 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00747 UMLS:C0004093 infores:hetionet CHEBI:3510 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0232462 infores:hetionet CHEBI:6067 biolink:causes GO:0046960 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C1325847 infores:hetionet CHEBI:6375 biolink:causes UMLS:C0151629 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0151629 infores:hetionet CHEBI:64318 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00696 UMLS:C0042571 infores:hetionet GO:0048345 biolink:causes GO:0048342 infores:ubergraph knowledge_assertion manual_agent GO:0048345 GO:0048342 CHEBI:3723 biolink:causes UMLS:C0233973 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0233973 infores:hetionet CHEBI:7936 biolink:causes MONDO:0002263 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0017411 infores:hetionet CHEBI:8028 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020580 infores:hetionet UMLS:C0025241 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01042 UMLS:C0042075 infores:hetionet CHEBI:31711 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB08947 UMLS:C0013384 infores:hetionet CHEBI:8776 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0011991 infores:hetionet CHEBI:16755 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0009676 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0948586 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0948586 infores:hetionet CHEBI:4735 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00974 UMLS:C0030312 infores:hetionet CAID:CA8623068 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623068 MONDO:0100326 PMID: Pathogenic PP4_Strong, PVS1, PM2_Supporting PM3 The NM_000212.3(ITGB3):c.847_848del (p.Ala283IlefsTer12) frameshift variant causes a premature stop codon at exon 6 and is predicted to undergo nonsense mediated decay (PVS1). This variant has been reported in one compound heterozygous individual (Patient LD in PMID:10891446 which reported the variant as c.867_868del using an alternate nucleotide numbering system, confirmed in Figure 4). One affected individual displayed abnormal bleeding and an impaired response to agonists, with a normal response to ristocetin, which is characteristic of GT). Additionally, αIIbβ3 was found to have a surface expression of 10% (<25%), as measured by flow cytometry (Patient LD in PMID:10891446; PP4_strong). The variant was found at a very low rate (0.000008796) in the European (Non-Finnish) population in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_strong, PM2_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623068/MONDO:0100326/011 2022-11-15 2022-12-07 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:7466 biolink:causes NCIT:C120262 infores:sider not_provided not_provided DRUGBANK:DB08804 UMLS:C0042755 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0042267 infores:hetionet CHEBI:3723 biolink:causes HP:0001336 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0027066 infores:hetionet CHEBI:6375 biolink:causes MONDO:0003749 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014852 infores:hetionet CHEBI:4876 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00903 UMLS:C0232487 infores:hetionet NCBIGene:57654 biolink:causes MONDO:0013834 infores:monarchinitiative not_provided not_provided HGNC:29304 MONDO:0013834 uuid:e4850795-dd8c-4ece-83fb-45aac0739eef biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:42797 biolink:causes MONDO:0001858 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0040213 infores:hetionet CHEBI:18357 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00368 UMLS:C0020458 infores:hetionet GO:1901207 biolink:causes GO:0061371 infores:ubergraph knowledge_assertion manual_agent GO:1901207 GO:0061371 CHEBI:4315 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB01406 UMLS:C0042109 infores:hetionet CAID:CA000631 biolink:causes MONDO:0017623 infores:clingen CAID:CA000631 MONDO:0017623 PMID: Likely Benign BP5, BP2 PVS1, PM6, PM2, BP7, BS4, BS3, BS1, PP4, PP1, PP2, PP3, BS2, PM1, PM4, PM5, BA1, BP4, PS2, PS4, PS3, PS1 PTEN c.-909T>C (NC_000010.10:g.87863560T>C) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BP2: Observed in trans with a pathogenic or likely pathogenic PTEN variant. (internal laboratory contributor ClinVar Organization ID 19864)BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributors SCV000185347.1, SCV000149485.5) PTEN VCEP https://erepo.genome.network/evrepo/ui/classification/CA000631/MONDO:0017623/003 2018-07-25 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts true GO:1901028 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:1901028 GO:0051716 CHEBI:100147 biolink:causes UMLS:C0155001 infores:sider not_provided not_provided DRUGBANK:DB00779 UMLS:C0155001 infores:hetionet CHEBI:47499 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0232462 infores:hetionet NCBITaxon:11709 biolink:causes MONDO:0005109 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:11709 MONDO:0005109 CHEBI:8871 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0019158 infores:hetionet CHEBI:9763 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0002994 infores:hetionet CHEBI:6367 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00555 UMLS:C0014724 infores:hetionet CHEBI:50692 biolink:causes GO:0070471 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C0042130 infores:hetionet CHEBI:9448 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0036454 infores:hetionet GO:0048349 biolink:causes GO:0048339 infores:ubergraph knowledge_assertion manual_agent GO:0048349 GO:0048339 CAID:CA16606683 biolink:causes MONDO:0007947 infores:clingen CAID:CA16606683 MONDO:0007947 PMID: Likely Pathogenic PP4, PP2, PP3, PM2_Supporting, PM1 PM5 The NM_00138 c.8002G>T is a missense variant in FBN1 predicted to cause a substitution of a glycine by cysteine at amino acid 2668 (p.Gly2668Cys). This cysteine-creating variant impacts a critical glycine between Cys3 and Cys4 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant has been reported twice in ClinVar: once as likely pathogenic, and once as uncertain significance (Variation ID: 381609). This variant has been reported in three individuals from the same study who met revised Ghent criteria; however, the relatedness of these individuals was not provided (PMID 26787436, PP4). This variant was also found in an individual with thoracic aortic dissection and striae (Internal lab data, PMID 11700157). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.8003G>A p.Gly2668Asp, has previously been reported in individuals with a clinical diagnosis of Marfan syndrome (MFS) or MFS-related features (PMID 26787436, internal lab data), however the p.Gly2668Asp variant has not yet been reviewed the FBN1 Variant Curation Expert Panel. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.987, PP3). The constraint z-score for missense variants affecting FBN1 is 8.18 (PP2; https://gnomad.broadinstitute.org/ v4.0.0). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM2_Sup, PP2, PP3, PP4. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA16606683/MONDO:0007947/022 2024-08-22 2024-08-22 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4708 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0027051 infores:hetionet CHEBI:50648 biolink:causes MONDO:0004625 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0031542 infores:hetionet CHEBI:7931 biolink:causes HP:0046504 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0011124 infores:hetionet CHEBI:38940 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018932 infores:hetionet CHEBI:63620 biolink:causes MONDO:0002770 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0227791 infores:hetionet CHEBI:51137 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0242350 infores:hetionet CHEBI:92923 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01180 UMLS:C0030193 infores:hetionet CHEBI:6541 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00678 UMLS:C0086543 infores:hetionet CHEBI:50841 biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00408 UMLS:C0220870 infores:hetionet CHEBI:71223 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB06813 UMLS:C0028081 infores:hetionet CHEBI:5613 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0023052 infores:hetionet CAID:CA8623301 biolink:causes MONDO:0100326 infores:clingen CAID:CA8623301 MONDO:0100326 PMID: Benign BP4, BA1 BP7 The ITGB3 synonymous variant NM_000212.3:c.1641C>T is common in control population databases, occurring at a frequency of 0.3015% in the East Asian population of gnomAD v2.1.1. The c.1641C>T (p.Cys547=) variant is a synonymous variant that is not predicted by SpliceAI to impact splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4. (VCEP specifications version 2; date of approval 04/07/2022) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA8623301/MONDO:0100326/011 2022-04-13 2022-06-12 Autosomal recessive inheritance HP:0000007 Contradicts https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:9555 biolink:causes EFO:0006890 infores:sider not_provided not_provided DRUGBANK:DB00352 UMLS:C0016059 infores:hetionet CHEBI:8774 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0013604 infores:hetionet CHEBI:6954 biolink:causes UMLS:C0575090 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0575090 infores:hetionet CHEBI:8232 biolink:causes UMLS:C0149904 infores:sider not_provided not_provided DRUGBANK:DB00319 UMLS:C0149904 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0434437 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0434437 infores:hetionet NCBIGene:4233 biolink:causes MONDO:0014739 infores:monarchinitiative not_provided not_provided HGNC:7029 MONDO:0014739 uuid:085bef1e-914b-44ad-8f1d-606303f8cb81 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:27446 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00417 UMLS:C0042963 infores:hetionet CHEBI:3441 biolink:causes MONDO:0006932 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0034063 infores:hetionet CAID:CA410208005 biolink:causes MONDO:0011071 infores:clingen CAID:CA410208005 MONDO:0011071 PMID: Uncertain Significance PM1_Supporting, PM2_Supporting, PS4_Supporting, PP3 PS1, PS3, PS2, BA1, BP1, BP4, BP3, BP2, PVS1, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM5, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.579C>G (p.Ile193Met) is a missense variant which has a REVEL score ≥ 0.88 (0.88) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 28927163). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3, PM1_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410208005/MONDO:0011071/008 2025-07-14 2025-07-14 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:18248 biolink:causes MONDO:0001793 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0152227 infores:hetionet CHEBI:29688 biolink:causes MONDO:0000775 infores:sider not_provided not_provided DRUGBANK:DB00976 UMLS:C0013182 infores:hetionet CHEBI:3216 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0344232 infores:hetionet CHEBI:4708 biolink:causes UMLS:C0151717 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0151717 infores:hetionet CHEBI:50730 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0015230 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002122 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0027813 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0242350 infores:hetionet CHEBI:17347 biolink:causes UMLS:C0595930 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0595930 infores:hetionet CHEBI:4672 biolink:causes EFO:0009426 infores:sider not_provided not_provided DRUGBANK:DB01248 UMLS:C0027540 infores:hetionet CHEBI:101853 biolink:causes HP:0000969 infores:sider not_provided not_provided DRUGBANK:DB01155 UMLS:C0013604 infores:hetionet CHEBI:36795 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0015967 infores:hetionet CHEBI:52717 biolink:causes MONDO:0002243 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0019087 infores:hetionet UNII:D27V6190PM biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C2047937 infores:hetionet CHEBI:4710 biolink:causes HP:0011801 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0341047 infores:hetionet CHEBI:38940 biolink:causes MONDO:0024644 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0151744 infores:hetionet CHEBI:3176 biolink:causes MONDO:0003900 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0009782 infores:hetionet CHEBI:3568 biolink:causes HP:0031217 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0600142 infores:hetionet CHEBI:5103 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB01205 UMLS:C0037036 infores:hetionet CHEBI:8028 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00850 UMLS:C0020651 infores:hetionet CHEBI:40279 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0030193 infores:hetionet CHEBI:46295 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C0008031 infores:hetionet GO:0072124 biolink:causes GO:0032835 infores:ubergraph knowledge_assertion manual_agent GO:0072124 GO:0032835 CHEBI:38940 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0030193 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0151734 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0151734 infores:hetionet CHEBI:9445 biolink:causes MONDO:0001020 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0002418 infores:hetionet CAID:CA512341152 biolink:causes MONDO:0011071 infores:clingen CAID:CA512341152 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS1, PS3, PS4, PS2, BA1, BP1, BP3, BP2, PM6, PVS1, BS1, BS3, BS4, BP5, PM4, PM3, PM5, PM1, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1272G>T (p.Ser424=) is a synonymous variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-1.97) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_Supporting, BP4, BP7 Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512341152/MONDO:0011071/008 2025-02-25 2025-02-25 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:188986 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00287 UMLS:C0037274 infores:hetionet CHEBI:75722 biolink:causes MONDO:0005791 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0019338 infores:hetionet GO:1904331 biolink:causes GO:0006260 infores:ubergraph knowledge_assertion manual_agent GO:1904331 GO:0006260 CHEBI:116278 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00978 UMLS:C0036572 infores:hetionet CHEBI:4657 biolink:causes HP:0001259 infores:sider not_provided not_provided DRUGBANK:DB00280 UMLS:C0009421 infores:hetionet CHEBI:31932 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00275 UMLS:C0017178 infores:hetionet CHEBI:31236 biolink:causes UMLS:C0542313 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0542313 infores:hetionet CHEBI:3732 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0015230 infores:hetionet CHEBI:46081 biolink:causes MONDO:0005936 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0876973 infores:hetionet NCBIGene:51308 biolink:causes MONDO:0957958 infores:monarchinitiative not_provided not_provided HGNC:17975 MONDO:0957958 uuid:bd38c323-fd01-4770-8f66-ef2db5eee07c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:7476 biolink:causes UMLS:C0011609 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0011609 infores:hetionet CHEBI:2788 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB00964 UMLS:C0700200 infores:hetionet CHEBI:4798 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0042963 infores:hetionet CHEBI:3478 biolink:causes HP:0002902 infores:sider not_provided not_provided DRUGBANK:DB00833 UMLS:C0020625 infores:hetionet CHEBI:6970 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0027497 infores:hetionet CHEBI:6030 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB00951 UMLS:C0235032 infores:hetionet CHEBI:47898 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00445 UMLS:C0011206 infores:hetionet CHEBI:46557 biolink:causes HP:0001387 infores:sider not_provided not_provided DRUGBANK:DB00399 UMLS:C0162298 infores:hetionet UMLS:C0657912 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0016867 infores:hetionet NCBIGene:9130 biolink:causes MONDO:0010284 infores:monarchinitiative not_provided not_provided HGNC:18786 MONDO:0010284 uuid:a9894710-5746-41ba-a746-40d8304d5096 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4784 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0009676 infores:hetionet CHEBI:44423 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB01005 UMLS:C0085605 infores:hetionet CAID:CA409105926 biolink:causes MONDO:0015967 infores:clingen CAID:CA409105926 MONDO:0015967 PMID: Uncertain Significance PP4_Moderate, PM2_Supporting PP3, PM1, BP4 The c.457G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of aspartic acid to asparagine at codon 153 (p.(Asp153Asn)) of NM_175914.5. This variant has a REVEL score of 0.528, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). In summary, c.457G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409105926/MONDO:0015967/085 2025-02-28 2025-02-28 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5280 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0687713 infores:hetionet CHEBI:8356 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0037274 infores:hetionet CHEBI:94501 biolink:causes HP:0100660 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0013384 infores:hetionet UMLS:C0010592 biolink:causes EFO:0010270 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0025345 infores:hetionet NCBIGene:7809 biolink:causes MONDO:0011242 infores:monarchinitiative not_provided not_provided HGNC:16512 MONDO:0011242 uuid:4ae1fdfc-5c55-4064-b68c-c7e2168561e6 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA220585 biolink:causes MONDO:0009861 infores:clingen CAID:CA220585 MONDO:0009861 PMID:2014036 Pathogenic PVS1, PS3 PAH-specific ACMG/AMP criteria applied: PVS1: nonsense variant; PS3: <1% of normal PAH activity (PMID:2014036). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PS3). Phenylketonuria VCEP https://erepo.genome.network/evrepo/ui/classification/CA220585/MONDO:0009861/006 2018-08-07 2019-04-06 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63605 biolink:causes UMLS:C0522063 infores:sider not_provided not_provided DRUGBANK:DB04845 UMLS:C0522063 infores:hetionet CHEBI:3994 biolink:causes UMLS:C0740399 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0740399 infores:hetionet CHEBI:182080 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00652 UMLS:C0020458 infores:hetionet CHEBI:5864 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0038999 infores:hetionet CHEBI:31644 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00538 UMLS:C0085593 infores:hetionet CHEBI:51137 biolink:causes HP:0100754 infores:sider not_provided not_provided DRUGBANK:DB06148 UMLS:C0241934 infores:hetionet CHEBI:135351 biolink:causes MONDO:0100081 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0851578 infores:hetionet CHEBI:9943 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C1443060 infores:hetionet NCBIGene:56975 biolink:causes MONDO:0009821 infores:monarchinitiative not_provided not_provided HGNC:22140 MONDO:0009821 uuid:cd8db21d-8324-4960-b5ef-bdbf5aab0412 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3216 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0033975 infores:hetionet CHEBI:135736 biolink:causes HP:0034306 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0262662 infores:hetionet CHEBI:17688 biolink:causes HP:0000572 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C3665386 infores:hetionet CHEBI:52172 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0022281 infores:hetionet CHEBI:144093 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01128 UMLS:C0010200 infores:hetionet CHEBI:39867 biolink:causes UMLS:C0851536 infores:sider not_provided not_provided DRUGBANK:DB00313 UMLS:C0851536 infores:hetionet CHEBI:134990 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB06594 UMLS:C0267792 infores:hetionet CAID:CA226683 biolink:causes MONDO:0010725 infores:clingen CAID:CA226683 MONDO:0010725 PMID: Pathogenic PM2_Supporting, PS4_Supporting, PVS1, PP1 The NM_000330.4(RS1):c.326+1G>A variant is a canonical splice site variant in intron 4, located 1 nucleotide after exon 4. This variant occurs at a canonical splice site in intron 4 and is predicted to disrupt splicing and induce skipping of exon 5, which is expected to disrupt a critical functional domain in RS1 (PVS1). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The variant has been reported to segregate with retinal dystrophy through 1 meiosis in a family with two affected brothers (PP1; PMID: 15937075). This variant has been reported in at least 2 apparently unrelated probands diagnosed with X-linked retinoschisis (PMID: 9618178, 15937075, 29099798, 30025115, 34822951, PS4_supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PVS1, PM2_supporting, PS4_supporting, and PP1. (date of approval 01/24/2025). X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226683/MONDO:0010725/126 2025-05-19 2025-05-20 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports UNII:R43D2573WO biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0948594 infores:hetionet CHEBI:3175 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0030193 infores:hetionet CHEBI:46195 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0036572 infores:hetionet CHEBI:31348 biolink:causes UMLS:C0151773 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0151773 infores:hetionet CHEBI:10102 biolink:causes MONDO:0001165 infores:sider not_provided not_provided DRUGBANK:DB00962 UMLS:C0040409 infores:hetionet CHEBI:50693 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00235 UMLS:C0015230 infores:hetionet CHEBI:47499 biolink:causes UMLS:C0087169 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0087169 infores:hetionet CAID:CA367402585 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402585 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PP1, PM2_Supporting PS4, PM1 The c.349G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 117 (p.(Gly117Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 25555642, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (persistent FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributor). This variant segregated with hyperglycemia with 3 informative meioses in 1 family (PP1; internal lab contributors). Another missense variant, c.350G>T p.Gly117Val, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.349G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP4_Moderate, PP1, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402585/MONDO:0015967/086 2023-12-02 2023-12-02 Semidominant inheritance HP:0032113 Supports CHEBI:74947 biolink:causes MONDO:0002026 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0006840 infores:hetionet CHEBI:6076 biolink:causes HP:6000319 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C1291077 infores:hetionet CHEBI:85083 biolink:causes UMLS:C0233414 infores:sider not_provided not_provided DRUGBANK:DB08934 UMLS:C0233414 infores:hetionet CHEBI:82941 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01319 UMLS:C0518015 infores:hetionet NCBIGene:2811 biolink:causes MONDO:0008332 infores:monarchinitiative not_provided not_provided HGNC:4439 MONDO:0008332 uuid:6755bbd6-6195-4d12-8cc3-b197c393fe8c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:404903 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0006145 infores:hetionet CAID:CA386776360 biolink:causes MONDO:0021060 infores:clingen CAID:CA386776360 MONDO:0021060 PMID:15940693 Uncertain Significance PM2, PP3, PP2, PS4_Supporting PM1 The c.127C>T (p.Leu43Phe) variant in PTPN11 is absent from large population studies (PM2; gnomad.broadinstitute.org). This variant has been identified in patients with clinical features of a RASopathy (PS4_Supporting; SCV000808252.1, SCV000945863.1). This variant is located in PTPN11, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Finally, Computational prediction tools and conservation analysis suggest that the p.Leu43Phe variant may impact the protein (PP3). In summary, the clinical significance of the p.Leu43Phe variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Supporting, PP2, PP3. RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA386776360/MONDO:0021060/004 2020-06-25 2020-06-25 Autosomal dominant inheritance HP:0000006 Inconclusive https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:15765 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01235 UMLS:C2830004 infores:hetionet CHEBI:4784 biolink:causes NCIT:C3399 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0038999 infores:hetionet CHEBI:9599 biolink:causes HP:0033841 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0022281 infores:hetionet CHEBI:8502 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0027697 infores:hetionet CAID:CA409107446 biolink:causes MONDO:0015967 infores:clingen CAID:CA409107446 MONDO:0015967 PMID: Likely Pathogenic PP3, PP4, PM2_Supporting, PM5_Strong The c.733C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glycine at codon 245 (p.(Arg245Gly)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.904, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, two other missense variants, c.733C>T (p.Arg245Cys) and c.734G>A (p.Arg245His), have been interpreted as pathogenic by the ClinGen MDEP and p.Arg245Gly has a greater Grantham distance than p.Arg245His (PM5_Strong). In summary, c.733C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM5_Strong, PP3, PP4, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409107446/MONDO:0015967/085 2024-05-10 2024-05-10 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8890 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C2830004 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes MONDO:0006022 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0001122 infores:hetionet CHEBI:194135 biolink:causes MONDO:0001292 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1145628 infores:hetionet CHEBI:119915 biolink:causes HP:0002625 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0149871 infores:hetionet CHEBI:567361 biolink:causes HP:0004326 infores:sider not_provided not_provided DRUGBANK:DB00242 UMLS:C0006625 infores:hetionet CHEBI:135351 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0027497 infores:hetionet CHEBI:3738 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB00283 UMLS:C0020649 infores:hetionet CHEBI:9671 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00384 UMLS:C0011603 infores:hetionet CHEBI:5383 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0030252 infores:hetionet CHEBI:10101 biolink:causes UMLS:C0038663 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0038663 infores:hetionet CHEBI:16755 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0030305 infores:hetionet CHEBI:9086 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0026821 infores:hetionet CHEBI:3219 biolink:causes HP:0000718 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0001807 infores:hetionet CHEBI:34385 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB06637 UMLS:C1443060 infores:hetionet CHEBI:50742 biolink:causes UMLS:C0028259 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0028259 infores:hetionet CHEBI:71229 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB06402 UMLS:C0000833 infores:hetionet GO:0022400 biolink:causes GO:0007603 infores:ubergraph knowledge_assertion manual_agent GO:0022400 GO:0007603 CHEBI:68647 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB08896 UMLS:C0151905 infores:hetionet CHEBI:119915 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0521839 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C0151559 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C0151559 infores:hetionet CHEBI:84500 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0018799 infores:hetionet CHEBI:3219 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0027424 infores:hetionet CHEBI:8707 biolink:causes MONDO:0001357 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0002884 infores:hetionet CHEBI:8382 biolink:causes UMLS:C2987469 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C2987469 infores:hetionet CHEBI:63637 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB08881 UMLS:C0014457 infores:hetionet CHEBI:31638 biolink:causes UMLS:C0542008 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0542008 infores:hetionet CHEBI:231594 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0003811 infores:hetionet CHEBI:52717 biolink:causes EFO:0010680 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0018944 infores:hetionet CHEBI:3172 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0002962 infores:hetionet CAID:CA213702 biolink:causes MONDO:0015967 infores:clingen CAID:CA213702 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting PS4, PP1 The c.1019+16G>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. The computational splicing predictor SpliceAI gives a score of 0.53 for donor loss, predicting that the variant disrupts the donor site of intron 8 of GCK (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with diabetes with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1019+16G>A meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP3, PM2_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA213702/MONDO:0015967/086 2025-06-02 2025-06-02 Semidominant inheritance HP:0032113 Inconclusive true CAID:CA2580610860 biolink:causes MONDO:0800472 infores:clingen CAID:CA2580610860 MONDO:0800472 PMID: Uncertain Significance PM2_Supporting, PM3, PVS1_Moderate PP1, PP3, BP4, BA1, PS3, PS1, PS2, PM1, PM4, PM5, BP7, BS1, BS4 The c.1597del variant in CYP1B1 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 18 of the frameshift (p.Val533SerfsTer18). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. This frameshift variant was not predicted to undergo NMD and does not remove the haem-binding domain (PVS1_Moderate met). There was no functional evidence predicting a damaging or benign impact of this variant on CYP1B1 function. This variant has been identified in an individual with a CYP1B1-related phenotype. This individual is compound heterozygous for the variant and a pathogenic or likely pathogenic variant (confirmed in trans) (PMID: 15255109). Total proband points = 1, meeting PM3. In summary, this variant met the criteria to receive a score of 5 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5, adapted from PMID: 32720330) for CYP1B1- related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3, PVS1_Moderate, PM2_Supporting. Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580610860/MONDO:0800472/104 2025-11-19 2025-11-18 Autosomal recessive inheritance HP:0000007 Inconclusive true CHEBI:5062 biolink:causes UMLS:C0262397 infores:sider not_provided not_provided DRUGBANK:DB01216 UMLS:C0262397 infores:hetionet CHEBI:8212 biolink:causes MONDO:0005090 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0036341 infores:hetionet CHEBI:9139 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0011606 infores:hetionet UMLS:C0879264 biolink:causes HP:0003138 infores:sider not_provided not_provided DRUGBANK:DB01141 UMLS:C0151539 infores:hetionet CHEBI:6759 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0040822 infores:hetionet CHEBI:45652 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00202 UMLS:C0015230 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes MONDO:0001075 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0038238 infores:hetionet CHEBI:52717 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0232462 infores:hetionet NCBIGene:83552 biolink:causes MONDO:0012299 infores:monarchinitiative not_provided not_provided HGNC:18121 MONDO:0012299 uuid:cd711ecd-99f9-41c0-8f3a-4c2e35e102db biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0023510 infores:hetionet CHEBI:31705 biolink:causes MONDO:0002492 infores:sider not_provided not_provided DRUGBANK:DB01249 UMLS:C0022660 infores:hetionet CHEBI:45409 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0233494 infores:hetionet CHEBI:127780 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0423791 infores:hetionet CHEBI:5106 biolink:causes MONDO:0023557 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0404521 infores:hetionet CHEBI:4636 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB01075 UMLS:C0043352 infores:hetionet CHEBI:119486 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0162834 infores:hetionet CHEBI:49575 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0162830 infores:hetionet CHEBI:17263 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00655 UMLS:C0022107 infores:hetionet CAID:CA6403094 biolink:causes MONDO:0019565 infores:clingen CAID:CA6403094 MONDO:0019565 PMID: Uncertain Significance BP4 BS2, BS1 The NM_000552.5:c.2340C>G variant in VWF is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 780. There are 4 ClinVar submissions for carriers of this variant with one asserting unaffected status. Additionally, there is a single publication that reports this variant but in neither the ClinVar nor publication is there any phenotype data. The computational predictor REVEL gives a score of 0.289, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BP4. (ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0) von Willebrand Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA6403094/MONDO:0019565/081 2025-10-07 2025-10-10 Undetermined mode of inheritance Inconclusive true CHEBI:63635 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0038362 infores:hetionet NCBIGene:2697 biolink:causes MONDO:0008111 infores:monarchinitiative not_provided not_provided HGNC:4274 MONDO:0008111 uuid:30f2391a-23f8-4d8c-a5c4-4a8b3134d473 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5118 biolink:causes MONDO:0000466 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0085614 infores:hetionet CHEBI:6970 biolink:causes MONDO:0005129 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0086543 infores:hetionet CHEBI:17347 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0700590 infores:hetionet CHEBI:6741 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0392171 infores:hetionet CHEBI:75722 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0575081 infores:hetionet GO:1901620 biolink:causes GO:0021532 infores:ubergraph knowledge_assertion manual_agent GO:1901620 GO:0021532 CHEBI:53760 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0231530 infores:hetionet CHEBI:4710 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C1443060 infores:hetionet CHEBI:4659 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00822 UMLS:C0030193 infores:hetionet CHEBI:47780 biolink:causes MONDO:0004770 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0015300 infores:hetionet CHEBI:18332 biolink:causes MONDO:0043789 infores:sider not_provided not_provided DRUGBANK:DB00451 UMLS:C0036830 infores:hetionet CHEBI:31348 biolink:causes HP:0001881 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0152009 infores:hetionet CHEBI:50173 biolink:causes HP:0001324 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151786 infores:hetionet CHEBI:3077 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0011603 infores:hetionet CHEBI:51364 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0424295 infores:hetionet CHEBI:3127 biolink:causes MONDO:0020576 infores:sider not_provided not_provided DRUGBANK:DB00612 UMLS:C0262988 infores:hetionet CHEBI:2038 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB00928 UMLS:C0151908 infores:hetionet CHEBI:3814 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00375 UMLS:C0232462 infores:hetionet CAID:CA207869 biolink:causes MONDO:0009290 infores:clingen CAID:CA207869 MONDO:0009290 PMID: Uncertain Significance BP4 PM2, BS1 The NM_000152.5:c.688G>A variant in GAA is a missense variant predicted to result in the substitution of valine by methionine at amino acid 230 (p.Val230Met). The highest population minor allele frequency in gnomAD v4.1.0. is 0.001748 (131/74928 alleles) in the African/African American population, which is higher than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, and lower than the threshold (>0.005) for BS1. Therefore none of the population data criteria are met. The computational predictor REVEL gives a score of 0.482 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 196222). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP, Sept. 9, 2025). Lysosomal Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA207869/MONDO:0009290/010 2025-09-09 2025-09-09 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/ true CHEBI:175901 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0036973 infores:hetionet CHEBI:6062 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0013428 infores:hetionet CHEBI:63598 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0039971 infores:hetionet CHEBI:72296 biolink:causes UMLS:C0855619 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0855619 infores:hetionet CHEBI:2682 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0151578 infores:hetionet CHEBI:3504 biolink:causes HP:0012702 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0232726 infores:hetionet CHEBI:2666 biolink:causes MONDO:0004842 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0038362 infores:hetionet CHEBI:7954 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB01359 UMLS:C0013395 infores:hetionet CHEBI:77260 biolink:causes MONDO:0005546 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0016053 infores:hetionet CHEBI:9434 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00966 UMLS:C0042963 infores:hetionet CAID:CA010493 biolink:causes MONDO:0005045 infores:clingen CAID:CA010493 MONDO:0005045 PMID: Pathogenic PP1_Strong, PM1, PS4 BS1, PP3, PM2, BA1 NM_000256.3(MYBPC3):c.1504C>T (p.Arg502Trp) - This variant is one of the most common pathogenic variants in MYBPC3 and has been reported in numerous individuals with HCM (statistically increased in individuals with cardiomyopathy compared to controls [OR lower 95% CI >20]), and shown to segregate with disease in numerous individuals across multiple families (PMIDs: 9562578, 12707239, 15519027, 16199542, 18809796, 19574547, 20031618, 20378854, 22386539, 22555271, 23054336, 23396983, 23711808, 27532257, 29121657, LMM data, OMGL data). Therefore, the PS4 and PP1_Strong criteria have been applied. This variant lies in a region of the protein where variants are statistically more likely to be disease-associated with HCM (PM1; Walsh 2019 PMID: 30696458). Functional studies have shown that this variant alters protein function (PMIDs: 25058872, 30554920), but were insufficient to apply PS3. This variant is present in gnomAD (v2.1.1) and did not meet the threshold for PM2_Supporting. Computational prediction tools are inconclusive about the potential impact of this variant (REVEL score <0.7). In summary, this variant is classified as Pathogenic for HCM in an autosomal dominant manner based on PS4, PP1_Strong, and PM1. Cardiomyopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA010493/MONDO:0005045/095 2025-11-13 2025-11-13 Autosomal dominant inheritance HP:0000006 Supports CHEBI:71028 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB06775 UMLS:C0015230 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0521839 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0521839 infores:hetionet CHEBI:7959 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0948594 infores:hetionet CHEBI:59560 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0085649 infores:hetionet CHEBI:8776 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00863 UMLS:C0039231 infores:hetionet CHEBI:6916 biolink:causes HP:0010867 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0004134 infores:hetionet CAID:CA226841 biolink:causes MONDO:0010725 infores:clingen CAID:CA226841 MONDO:0010725 PMID: Likely Pathogenic PM2_Supporting, PS4_Supporting, PS3_Supporting, PM5_Supporting, PP3_Strong, PP1 PS2, PM6, PM1 NM_000330.4(RS1):c.655T>C (p.Cys219Arg) is a missense variant encoding the substitution of cysteine with arginine at amino acid 219. Another missense variant in the same codon, NM_000330.4(RS1):c.655T>G (p.Cys219Gly) has been classified as likely pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (180) than the comparison variant (159), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5_Supporting). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 39462066, PMID: 35982512, PMID: 9618178, PS4_Supporting). The variant has been reported to segregate with X-linked retinoschisis through 2 affected family members (PP1; PMID: 39462066). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual meeting the PS2 phenotype requirement of a male diagnosed with retinoschisis (PMID: 9618178). No description was provided of parental genotyping, so PS2 was not met. COS-1 cells exogenously expressing the variant protein exhibit loss of RS1 secretion into the medium relative to the wild-type control, caused by misfolding, aggregation, and ER retention of the variant protein (PMID: 12746437, PS3_Supporting). The computational predictor REVEL gives a score of 0.978, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). PM1_Strong is not met as this code is ineligible to be used in combination with PP3_Strong. In summary, this variant is classified as likely pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PM5_Supporting, PS3_Supporting, PS4_Supporting, and PP1. X-linked Inherited Retinal Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA226841/MONDO:0010725/126 2025-10-04 2025-10-05 X-linked inheritance (recessive (HP:0001419)) HP:0001419 Supports CHEBI:4903 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00977 UMLS:C0003467 infores:hetionet CHEBI:5118 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0041912 infores:hetionet NCBIGene:805 biolink:causes MONDO:0014550 infores:monarchinitiative not_provided not_provided HGNC:1445 MONDO:0014550 uuid:93c39227-4724-4bd4-909c-4bb09b657191 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70735 biolink:causes HP:0025269 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0086769 infores:hetionet CHEBI:72690 biolink:causes NCIT:C78238 infores:sider not_provided not_provided DRUGBANK:DB08910 UMLS:C0476280 infores:hetionet CHEBI:63629 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00697 UMLS:C0029882 infores:hetionet CHEBI:8802 biolink:causes MONDO:0000745 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0018790 infores:hetionet CHEBI:8890 biolink:causes MONDO:0006496 infores:sider not_provided not_provided DRUGBANK:DB00296 UMLS:C0522224 infores:hetionet CHEBI:10127 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C0037763 infores:hetionet CHEBI:3723 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0030232 infores:hetionet CHEBI:8502 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0013395 infores:hetionet CHEBI:94501 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00889 UMLS:C0002792 infores:hetionet CHEBI:168396 biolink:causes MONDO:0007179 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0004364 infores:hetionet NCBIGene:10621 biolink:causes MONDO:0030813 infores:monarchinitiative not_provided not_provided HGNC:15763 MONDO:0030813 uuid:b48bccfd-c3c1-4162-8ce5-ea2286acdc3e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:5165 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0009450 infores:hetionet CHEBI:28787 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0009450 infores:hetionet CHEBI:161680 biolink:causes HP:0100812 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0018520 infores:hetionet CHEBI:5864 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB01181 UMLS:C0004936 infores:hetionet CHEBI:478164 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01413 UMLS:C0033774 infores:hetionet CHEBI:50742 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB04839 UMLS:C0151904 infores:hetionet CHEBI:3506 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB01150 UMLS:C1443060 infores:hetionet NCBITaxon:1491 biolink:causes MONDO:0005498 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:1491 MESH:D001906 DB01053_MESH_D001906_1 CHEBI:10650 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0973461 infores:hetionet CHEBI:63621 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0042373 infores:hetionet CHEBI:63612 biolink:causes MONDO:0005229 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C0004610 infores:hetionet CHEBI:8214 biolink:causes HP:0012722 infores:sider not_provided not_provided DRUGBANK:DB00960 UMLS:C0018794 infores:hetionet CHEBI:6741 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0011603 infores:hetionet CHEBI:42944 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00674 UMLS:C0035455 infores:hetionet CHEBI:50648 biolink:causes MONDO:0012105 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C3495801 infores:hetionet CHEBI:144551 biolink:causes UMLS:C0086132 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0086132 infores:hetionet CHEBI:4445 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0033774 infores:hetionet CHEBI:8228 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01132 UMLS:C1384353 infores:hetionet CHEBI:5779 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB00956 UMLS:C0037274 infores:hetionet CHEBI:52172 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0018681 infores:hetionet NCBIGene:6165 biolink:causes MONDO:0012925 infores:monarchinitiative not_provided not_provided HGNC:10345 MONDO:0012925 uuid:4432cce1-1eb0-4d65-b79d-d27da774b6ac biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:63589 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0036974 infores:hetionet CAID:CA367403544 biolink:causes MONDO:0015967 infores:clingen CAID:CA367403544 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PP2, PP3, PM2_Supporting PS4, PP1 The c.110T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 37 (p.(Met37Thr)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, and persistent impaired fasting glucose) (PP4_Moderate; PMID 28170077). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9559, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.110T>C (p.Met37Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met37Thr (PM5_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDS: 33477506, 28170077, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 28170077). In summary, c.110T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367403544/MONDO:0015967/086 2023-12-08 2023-12-08 Semidominant inheritance HP:0032113 Supports CHEBI:8863 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0020569 infores:hetionet CHEBI:28787 biolink:causes UMLS:C0236051 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C0236051 infores:hetionet CHEBI:75722 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0017178 infores:hetionet CHEBI:474180 biolink:causes HP:0003259 infores:sider not_provided not_provided DRUGBANK:DB00520 UMLS:C0700225 infores:hetionet CHEBI:50922 biolink:causes MONDO:0002769 infores:sider not_provided not_provided DRUGBANK:DB00216 UMLS:C0023533 infores:hetionet CHEBI:4856 biolink:causes HP:0002069 infores:sider not_provided not_provided DRUGBANK:DB00187 UMLS:C0494475 infores:hetionet CHEBI:4814 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0043352 infores:hetionet CHEBI:92998 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C0037299 infores:hetionet CAID:CA263242 biolink:causes MONDO:0012996 infores:clingen CAID:CA263242 MONDO:0012996 PMID: Pathogenic PP4, PM2_Supporting, PM3_Supporting, PVS1 The NM_001482.3(GATM):c.505C>T (p.Arg169Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is reported to be homozygous in a proband and sibling, both of whom have undetectable GAA in plasma and urine, and reduced creatine peak (about 2/3 normal) on brain MRS with elevated NAA/creatine ratio (PMID 20625172, 23660394, 26490222)(PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055) meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 55919). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA263242/MONDO:0012996/025 2022-06-06 2022-10-07 Autosomal recessive inheritance HP:0000007 Supports CHEBI:63619 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0036572 infores:hetionet CHEBI:8871 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0002792 infores:hetionet CHEBI:6062 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0002871 infores:hetionet NCBIGene:387733 biolink:causes MONDO:0012591 infores:monarchinitiative not_provided not_provided HGNC:16644 MONDO:0012591 uuid:b71a804a-a064-4bf6-8510-30e94e3c703b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50663 biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB00558 UMLS:C0085593 infores:hetionet CHEBI:45081 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C1456784 infores:hetionet CHEBI:50692 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00834 UMLS:C1443060 infores:hetionet CHEBI:6887 biolink:causes MONDO:0005550 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0009450 infores:hetionet CHEBI:7798 biolink:causes UMLS:C0085393 infores:sider not_provided not_provided DRUGBANK:DB00198 UMLS:C0085393 infores:hetionet CHEBI:68558 biolink:causes HP:0031972 infores:sider not_provided not_provided DRUGBANK:DB08816 UMLS:C0700200 infores:hetionet CHEBI:46295 biolink:causes HP:0012875 infores:sider not_provided not_provided DRUGBANK:DB00862 UMLS:C2937350 infores:hetionet CHEBI:63621 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0011175 infores:hetionet CHEBI:408174 biolink:causes MONDO:0008903 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0242379 infores:hetionet CHEBI:4909 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00749 UMLS:C2047937 infores:hetionet CHEBI:64312 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0442874 infores:hetionet CHEBI:42797 biolink:causes MONDO:0005362 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0242350 infores:hetionet CHEBI:8346 biolink:causes MONDO:0005093 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C0037274 infores:hetionet CHEBI:28787 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00727 UMLS:C1142412 infores:hetionet CHEBI:44915 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C1761613 infores:hetionet CHEBI:5050 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0004093 infores:hetionet CHEBI:85161 biolink:causes HP:0000217 infores:sider not_provided not_provided DRUGBANK:DB00377 UMLS:C0043352 infores:hetionet CHEBI:44915 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0008031 infores:hetionet CHEBI:175901 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0234215 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0015397 infores:hetionet CHEBI:4728 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0011991 infores:hetionet CHEBI:5001 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0003467 infores:hetionet CHEBI:8774 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB00178 UMLS:C0021053 infores:hetionet CHEBI:16755 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0027497 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0151828 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005298 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0029456 infores:hetionet CHEBI:63632 biolink:causes HP:0034267 infores:sider not_provided not_provided DRUGBANK:DB01030 UMLS:C0030794 infores:hetionet CHEBI:4024 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00979 UMLS:C0085631 infores:hetionet CHEBI:84500 biolink:causes HP:0000103 infores:sider not_provided not_provided DRUGBANK:DB01273 UMLS:C0032617 infores:hetionet CHEBI:421707 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0019158 infores:hetionet GO:0048395 biolink:causes GO:0048393 infores:ubergraph knowledge_assertion manual_agent GO:0048395 GO:0048393 CHEBI:9667 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0162820 infores:hetionet CHEBI:53760 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00402 UMLS:C0013404 infores:hetionet CHEBI:68478 biolink:causes UMLS:C0013922 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0013922 infores:hetionet UMLS:C0657912 biolink:causes UMLS:C0041747 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0041747 infores:hetionet CHEBI:8024 biolink:causes HP:0002360 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0037317 infores:hetionet UMLS:C0120107 biolink:causes HP:0033667 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0278061 infores:hetionet CHEBI:4466 biolink:causes MONDO:0021113 infores:sider not_provided not_provided DRUGBANK:DB00633 UMLS:C1145670 infores:hetionet CHEBI:8207 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0085633 infores:hetionet CHEBI:161680 biolink:causes MONDO:0002249 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0836924 infores:hetionet CHEBI:2673 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0012833 infores:hetionet CHEBI:49575 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0004093 infores:hetionet CAID:CA367402232 biolink:causes MONDO:0015967 infores:clingen CAID:CA367402232 MONDO:0015967 PMID: Likely Pathogenic PM5_Supporting, PP4_Moderate, PM2, PP2, PP3 The c.364C>A variant in the glucokinase gene, GCK, causes an amino acid change of leucine to isoleucine at codon 122 (p.(Leu122Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA367402232/MONDO:0015967/086 2024-03-07 2024-03-07 Semidominant inheritance HP:0032113 Supports CAID:CA518861298 biolink:causes MONDO:0010604 infores:clingen CAID:CA518861298 MONDO:0010604 PMID: Uncertain Significance PM2_Supporting BP7, BP4 The F9 c.471T>C (p.Cys157=) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The Cys157= synonymous variant is with a acceptor and donor gain score of 0.08 based on SpliceAI, and therefore not being eligible for the BP4 and BP7 codes. We are not aware of any cases of hemophilia B in the literature or in databases at this time. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PM2_Supporting. Coagulation Factor Deficiency VCEP https://erepo.genome.network/evrepo/ui/classification/CA518861298/MONDO:0010604/080 2024-12-06 2024-12-06 X-linked inheritance HP:0001417 Inconclusive true CHEBI:8207 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0151827 infores:hetionet CHEBI:204928 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB00493 UMLS:C0027947 infores:hetionet CHEBI:10112 biolink:causes UMLS:C0341439 infores:sider not_provided not_provided DRUGBANK:DB00744 UMLS:C0341439 infores:hetionet CHEBI:135679 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01106 UMLS:C0015230 infores:hetionet CHEBI:8874 biolink:causes HP:0004305 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0235086 infores:hetionet CAID:CA120576 biolink:causes MONDO:0044970 infores:clingen CAID:CA120576 MONDO:0044970 PMID:14967777PMID:15111688 Likely Pathogenic PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting, PM6 PS2 The m.12147G>A variant in MT-TH has been reported in two unrelated probands with features of primary mitochondrial disease. Both individuals were males with symptom onset in late teens to early 20s, developed seizures, and had COX-negative fibers identified on muscle biopsy. One individual also had ragged red fibers, and complex I and IV deficiencies. Additional features seen include sensorineural hearing loss, optic atrophy, ptosis, migraines, ataxia, myoclonus, muscle weakness, hepatic failure consistent with Reye syndrome, lactic acidosis, and hyperCKemia. Heteroplasmy in the affected individuals ranged from 86% in muscle to undetectable in hair (PS4_supporting; PMIDs: 14967777, 15111688). This variant occurred de novo in one individual (absent in blood, urine, hair, and muscle from mother as well as two sisters, two maternal aunts, and two maternal uncles; PM6, PMID: 15111688). The computational predictor MitoTIP suggests this variant is pathogenic (93.5 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in muscle fibers from both affected individuals, supporting the functional impact of this variant (PS3_supporting). In one individual, the mean heteroplasmy level in abnormal fibers was 90% ± 2% (n=22) and in normal fibers was 58% ± 6% (n=15; P = 0.007). Furthermore, in ragged red fibers, the mean heteroplasmy level was 94% (PMID: 14967777). In the other individual, the mean heteroplasmy level in COX-deficient fibers was 94.6 ± 1.53% (n = 12) and in COX-positive fibers was 32.5 ± 6.18% (n = 10; p < 0.0001; PMID: 15111688). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6, PM2_supporting, PP3, PS3_supporting. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120576/MONDO:0044970/015 2023-01-09 2023-03-14 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:77260 biolink:causes HP:0012592 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0001925 infores:hetionet CHEBI:51860 biolink:causes HP:0100607 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0013390 infores:hetionet CAID:CA293046 biolink:causes MONDO:0000572 infores:clingen CAID:CA293046 MONDO:0000572 PMID: Benign BA1, BP7, BS2_Supporting The c.303G>A (p.Ala101=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 799/30614) of the c.303G>A variant in RAG1 is 0.02460 for South Asian chromosomes by gnomAD v2.1.1 which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and therefore meets this criterion (BA1). Additionally, 76 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as a Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BA1, BS2_Supporting, and BP7. Severe Combined Immunodeficiency Disease VCEP https://erepo.genome.network/evrepo/ui/classification/CA293046/MONDO:0000572/123 2024-01-17 2024-01-17 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:7476 biolink:causes NCIT:C121577 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0855775 infores:hetionet CAID:CA410147953 biolink:causes MONDO:0011071 infores:clingen CAID:CA410147953 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting, PP3 PS1, PS3, PS4, PS2, BA1, BP1, BP4, BP3, BP2, BP5, BP7, BS1, BS3, BS4, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP4, PP1, BS2 NM_001754.5(RUNX1):c.1148C>T (p.Pro383Leu) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score >0.88 (0.906) (PP3). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2078130). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410147953/MONDO:0011071/008 2024-07-25 2024-07-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:8768 biolink:causes MONDO:0002898 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0007114 infores:hetionet CHEBI:16755 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB06777 UMLS:C0026858 infores:hetionet CHEBI:7476 biolink:causes MONDO:0006821 infores:sider not_provided not_provided DRUGBANK:DB00788 UMLS:C0022667 infores:hetionet CHEBI:8499 biolink:causes MONDO:0007915 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0024141 infores:hetionet CHEBI:7915 biolink:causes MONDO:0002234 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042267 infores:hetionet CAID:CA207744 biolink:causes MONDO:0015967 infores:clingen CAID:CA207744 MONDO:0015967 PMID: Pathogenic PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting, PS4, PM1_Supporting The c.925C>T variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, causes an amino acid change of Arginine to Cysteine at codon 309 (p.(Arg309Cys)) of NM_175914.5. This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Internal lab contributors). This variant is located within the ligand-binding domain of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002970 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant segregated with diabetes, with 1 informative meiosis in each of 3 families with MODY (PP1_moderate; Internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.787, which is greater than to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in several individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, responsiveness to sulfonylureas, and 1 family member with persistent neonatal hypoglycemia) (PP4_Moderate; Internal lab contributors). In summary, c.925C>T meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PM1_Supporting, PM2_Supporting, PP1_Moderate, PP3, PP4_Moderate. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA207744/MONDO:0015967/085 2024-04-06 2024-04-06 Autosomal dominant inheritance HP:0000006 Supports CHEBI:8713 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00881 UMLS:C0040034 infores:hetionet CAID:CA298025 biolink:causes MONDO:0700270 infores:clingen CAID:CA298025 MONDO:0700270 PMID: Pathogenic PM3_Very Strong, PM2_Supporting, PM5_Supporting, PVS1 The ATM c.3245_3247delinsTGAT (p.His1082LeufsTer14) variant is absent in the GnomAD cohort (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. Hereditary Breast, Ovarian and Pancreatic Cancer VCEP https://erepo.genome.network/evrepo/ui/classification/CA298025/MONDO:0700270/020 2022-03-09 2025-09-15 Autosomal dominant inheritance HP:0000006 Supports UMLS:C0657912 biolink:causes HP:0040315 infores:sider not_provided not_provided DRUGBANK:DB00230 UMLS:C0151610 infores:hetionet CHEBI:8888 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0036454 infores:hetionet CHEBI:64028 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB04844 UMLS:C0917801 infores:hetionet UMLS:C0010592 biolink:causes UMLS:C0234193 infores:sider not_provided not_provided DRUGBANK:DB00091 UMLS:C0234193 infores:hetionet CHEBI:480999 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0002871 infores:hetionet CHEBI:9588 biolink:causes MONDO:0003664 infores:sider not_provided not_provided DRUGBANK:DB00208 UMLS:C0002878 infores:hetionet CHEBI:2955 biolink:causes MONDO:0002251 infores:sider not_provided not_provided DRUGBANK:DB00207 UMLS:C0019158 infores:hetionet CHEBI:75984 biolink:causes HP:0200026 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0151827 infores:hetionet CHEBI:135736 biolink:causes UMLS:C0854425 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0854425 infores:hetionet CHEBI:63621 biolink:causes MONDO:0004946 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C0020615 infores:hetionet CHEBI:63589 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB06414 UMLS:C0042963 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0427008 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0427008 infores:hetionet NCBITaxon:782 biolink:causes MONDO:0019362 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:782 MESH:D014438 DB00254_MESH_D014438_1DB02703_MESH_D014438_1 CHEBI:63791 biolink:causes HP:0000020 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0042024 infores:hetionet CHEBI:63611 biolink:causes UMLS:C0243026 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0243026 infores:hetionet CHEBI:31624 biolink:causes UMLS:C0521501 infores:sider not_provided not_provided DRUGBANK:DB00693 UMLS:C0521501 infores:hetionet CAID:CA409108255 biolink:causes MONDO:0015967 infores:clingen CAID:CA409108255 MONDO:0015967 PMID: Likely Pathogenic PP1_Moderate, PM5_Supporting, PP4_Moderate, PP3, PM2_Supporting, PM1_Supporting, PS4_Moderate BP4, BA1, BS1 The c.926G>T variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of arginine to leucine at codon 309 (p.(Arg309Leu)) of NM_175914.5. This variant is located within the ligand binding domain of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting; PMID: 18829458). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.925C>T p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance (PM5_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.834, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and personal history of being large for gestational age) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). In summary, c.926G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PM2_supporting, PM1_supporting, PP3, PP4_moderate, PP1_moderate, PS4_Moderate, PM5_supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA409108255/MONDO:0015967/085 2023-05-27 2023-05-27 Autosomal dominant inheritance HP:0000006 Supports CHEBI:27834 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB00552 UMLS:C0009763 infores:hetionet CHEBI:16480 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00435 UMLS:C0018681 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0973461 infores:hetionet CHEBI:3568 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0040264 infores:hetionet CHEBI:72296 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB06605 UMLS:C0040034 infores:hetionet CHEBI:84883 biolink:causes MONDO:0003781 infores:sider not_provided not_provided DRUGBANK:DB08887 UMLS:C0006277 infores:hetionet CHEBI:31348 biolink:causes UMLS:C1442826 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C1442826 infores:hetionet CHEBI:47381 biolink:causes MONDO:0043839 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0041582 infores:hetionet CHEBI:4798 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0041912 infores:hetionet CAID:CA2387300768 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387300768 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS4, PS3, PS2, PS1, BA1, BP2, BP3, BP1, BP5, BS1, BS3, BS4, PVS1, PM6, PM1, PM3, PM4, PM5, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.59-4T>C is an intronic variant which is not predicted by SpliceAI to impact splicing (BP4). Additionally, an evolutionary conservation algorithm predicts the site as not being highly conserved (PhyloP score = 0.867551 in GRCh38) (BP7). Although the variant is absent from gnomAD v2, v3, and v4 (PM2_Supporting), it has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387300768/MONDO:0011071/008 2024-08-28 2024-08-28 Autosomal dominant inheritance HP:0000006 Contradicts true UMLS:C0011701 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C2047937 infores:hetionet CHEBI:5098 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00301 UMLS:C0036572 infores:hetionet CHEBI:5383 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00222 UMLS:C0003467 infores:hetionet NCBIGene:6905 biolink:causes MONDO:0014968 infores:monarchinitiative not_provided not_provided HGNC:11582 MONDO:0014968 uuid:07795bbc-1eb8-4d4c-91e0-4f8160f9c6cb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:30830 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0027497 infores:hetionet NCBIGene:139818 biolink:causes MONDO:0957494 infores:monarchinitiative not_provided not_provided HGNC:23483 MONDO:0957494 uuid:41345a2a-381e-41f9-a140-55dece2560bb biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges UNII:8NZ41MIK1O biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB01225 UMLS:C0085932 infores:hetionet CHEBI:63616 biolink:causes HP:0002027 infores:sider not_provided not_provided DRUGBANK:DB00642 UMLS:C0687713 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151505 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151505 infores:hetionet CAID:CA6832031 biolink:causes MONDO:0015967 infores:clingen CAID:CA6832031 MONDO:0015967 PMID: Likely Benign BP5, BP7 BS1, PM2 The c.1383C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 461 (p.(Pro461=)) of NM_000545.8. This variant was identified in a patient with an alternate molecular basis for disease (BP5; ClinVar: SCV000595127.1, personal communication from Genetic Services Laboratory, University of Chicago). Additionally, this synonymous variant is not predicted by SpliceAI to impact splicing (BP7). The variant frequency fell between the ClinGen MDEP BS1 and PM2_Supporting cutoffs; therefore, neither was applied. In summary, c.1383C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BP5, BP7. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA6832031/MONDO:0015967/017 2022-04-16 2022-04-16 Autosomal dominant inheritance HP:0000006 Contradicts true CAID:CA2573334475 biolink:causes MONDO:0010305 infores:clingen CAID:CA2573334475 MONDO:0010305 PMID: Pathogenic PVS1, PP4, PM2_Supporting The NM_005629.4:c.856del (p.Leu286TrpfsTer22) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One male patient has been rreported with elevated urine creatine/creatinine ratio (PMID: 23660394) (PP4). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1, PP4, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on March 9, 2023) Cerebral Creatine Deficiency Syndromes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573334475/MONDO:0010305/027 2024-02-10 2024-02-10 X-linked inheritance HP:0001417 Supports CHEBI:8382 biolink:causes MONDO:0005485 infores:sider not_provided not_provided DRUGBANK:DB00635 UMLS:C0033975 infores:hetionet CAID:CA210791 biolink:causes MONDO:0013144 infores:clingen CAID:CA210791 MONDO:0013144 PMID: Likely Pathogenic PS4, PP3, PM2_Supporting BS1, BA1 The c.442T>C (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of serine by proline at amino acid 148 (p.Ser148Pro). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.654, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL and a family history of reduced antithrombin activity levels with reported values, and there are at least 7 additional probands with an antithrombin activity level of < 0.8 IU/mL without a reported family history or repeat testing (PS4; PMIDs: 35720094, 24162787, 31030036, 8443391, 24613695); however, one proband was not applied due to having a second SERPINC1 variant of unknown clinical significance and antithrombin activity levels in the heterozygous range. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP3, PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA210791/MONDO:0013144/084 2025-09-19 2025-09-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:9649 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0917801 infores:hetionet CHEBI:7931 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB00910 UMLS:C0015230 infores:hetionet CHEBI:63612 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01280 UMLS:C1306341 infores:hetionet CHEBI:6715 biolink:causes MONDO:0005152 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020635 infores:hetionet NCBIGene:3075 biolink:causes MONDO:0007472 infores:monarchinitiative not_provided not_provided HGNC:4883 MONDO:0007472 uuid:bb402f53-aa92-46de-bbe7-593a47f84601 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9674 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0015672 infores:hetionet CHEBI:50648 biolink:causes HP:0001944 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0011175 infores:hetionet CHEBI:83531 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB01171 UMLS:C0020538 infores:hetionet CHEBI:5130 biolink:causes MONDO:0006662 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0025290 infores:hetionet CHEBI:408174 biolink:causes UMLS:C0080203 infores:sider not_provided not_provided DRUGBANK:DB01274 UMLS:C0080203 infores:hetionet CHEBI:3387 biolink:causes HP:0001266 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0085583 infores:hetionet PUBCHEM.COMPOUND:657309 biolink:causes HP:0007906 infores:sider not_provided not_provided DRUGBANK:DB00332 UMLS:C0234708 infores:hetionet CHEBI:8245 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0015230 infores:hetionet CHEBI:61058 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00968 UMLS:C0030312 infores:hetionet CHEBI:45081 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0012833 infores:hetionet CHEBI:5138 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0020458 infores:hetionet CHEBI:7773 biolink:causes UMLS:C0151763 infores:sider not_provided not_provided DRUGBANK:DB00904 UMLS:C0151763 infores:hetionet CHEBI:44915 biolink:causes MONDO:0004843 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0028738 infores:hetionet NCBIGene:658 biolink:causes MONDO:0012274 infores:monarchinitiative not_provided not_provided HGNC:1077 MONDO:0012274 uuid:9c0d8811-1d36-4738-82f3-4d814931650c biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9241 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00421 UMLS:C0018681 infores:hetionet CHEBI:77032 biolink:causes MONDO:0005492 infores:sider not_provided not_provided DRUGBANK:DB09019 UMLS:C0042109 infores:hetionet CHEBI:10023 biolink:causes MONDO:0004782 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0011848 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0085624 infores:hetionet UMLS:C0005740 biolink:causes MONDO:0000496 infores:sider not_provided not_provided DRUGBANK:DB00290 UMLS:C0085692 infores:hetionet CHEBI:71417 biolink:causes MONDO:0019289 infores:sider not_provided not_provided DRUGBANK:DB01168 UMLS:C0162834 infores:hetionet CHEBI:9649 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB00519 UMLS:C0042075 infores:hetionet NCBIGene:84295 biolink:causes MONDO:0010537 infores:monarchinitiative not_provided not_provided HGNC:18145 MONDO:0010537 uuid:5d456513-aa1c-4c8d-887d-f9b1c1ac8be7 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52172 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0021400 infores:hetionet CHEBI:3219 biolink:causes MONDO:0005365 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0011053 infores:hetionet CHEBI:77260 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0040034 infores:hetionet CHEBI:48669 biolink:causes MONDO:0004980 infores:sider not_provided not_provided DRUGBANK:DB00302 UMLS:C0011615 infores:hetionet CAID:CA024738 biolink:causes MONDO:0007783 infores:clingen CAID:CA024738 MONDO:0007783 PMID: Likely Pathogenic PS3_Moderate, PM1, PS4_Moderate, PP3_Moderate BS1, BA1 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Alanine with Threonine at codon 2428 of the RYR1 protein, p.(Ala2428Thr). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:12059893, PMID:16163667, PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:16163667). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in two individuals (PMID:12059893). A REVEL score of 0.85 supports a pathogenic status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024738/MONDO:0007783/012 2023-04-07 2023-04-07 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ CHEBI:63620 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0042963 infores:hetionet CHEBI:50648 biolink:causes MONDO:0005053 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0022116 infores:hetionet CHEBI:7852 biolink:causes MONDO:0006802 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0021141 infores:hetionet CHEBI:5106 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00180 UMLS:C0006266 infores:hetionet CHEBI:36791 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0015672 infores:hetionet NCBIGene:1131 biolink:causes GO:0006939 infores:drugmechdb knowledge_assertion manual_agent UniProtKB:P20309 GO:0006939 DB12086_MESH_D029424_4 CHEBI:31413 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0344232 infores:hetionet NCBIGene:153241 biolink:causes MONDO:0033310 infores:monarchinitiative not_provided not_provided HGNC:26690 MONDO:0033310 uuid:fbe4d395-13e0-45bf-a6dd-0c85d492cfb0 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8207 biolink:causes MONDO:0005812 infores:sider not_provided not_provided DRUGBANK:DB01085 UMLS:C0021400 infores:hetionet CHEBI:5004 biolink:causes MONDO:0043237 infores:sider not_provided not_provided DRUGBANK:DB00573 UMLS:C0017672 infores:hetionet CHEBI:28593 biolink:causes UMLS:C0919715 infores:sider not_provided not_provided DRUGBANK:DB00908 UMLS:C0919715 infores:hetionet CHEBI:61049 biolink:causes MONDO:0005469 infores:sider not_provided not_provided DRUGBANK:DB00864 UMLS:C0020651 infores:hetionet CHEBI:32184 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0085624 infores:hetionet CHEBI:3441 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0017178 infores:hetionet CHEBI:50859 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0040034 infores:hetionet NCBIGene:3064 biolink:causes MONDO:0007739 infores:monarchinitiative not_provided not_provided HGNC:4851 MONDO:0007739 uuid:73bf2945-3585-4f61-9259-988174cce9e3 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:48844 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C2047937 infores:hetionet UNII:3QJA87N40S biolink:causes HP:0001948 infores:sider not_provided not_provided DRUGBANK:DB08884 UMLS:C0002063 infores:hetionet CHEBI:168396 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0036974 infores:hetionet CAID:CA410146847 biolink:causes MONDO:0011071 infores:clingen CAID:CA410146847 MONDO:0011071 PMID: Uncertain Significance BP4 PS3, PS1, PS2, PS4, BP1, BP3, BP2, BA1, PVS1, PM2, PM6, BP5, BP7, BS1, BS3, BS4, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.1397T>C (p.Met466Thr) is a missense variant. The highest population minor allele frequency is 0.001910% (1/52368) in the European(non-Finnish) subpopulation of gnomAD v2.1. However the coverage is poor in this region (15x) so BS1 can not be applied. One proband is reported in ClinGen but no phenotypic information was provided. This missense variant has a REVEL score <0.50 (0.246)(BP4). In summary, this variant meets criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA410146847/MONDO:0011071/008 2025-01-15 2025-01-15 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5118 biolink:causes MONDO:0043579 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0014335 infores:hetionet CHEBI:68579 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB06228 UMLS:C0042075 infores:hetionet CHEBI:3757 biolink:causes UMLS:C0241705 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0241705 infores:hetionet CHEBI:144551 biolink:causes MONDO:0001186 infores:sider not_provided not_provided DRUGBANK:DB01062 UMLS:C0011551 infores:hetionet NCBIGene:8600 biolink:causes MONDO:0009816 infores:monarchinitiative not_provided not_provided HGNC:11926 MONDO:0009816 uuid:07bba6a2-4c08-40be-88ff-8e355e695e6e biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:52717 biolink:causes MONDO:0005618 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0003469 infores:hetionet CHEBI:50223 biolink:causes UMLS:C0553702 infores:sider not_provided not_provided DRUGBANK:DB00380 UMLS:C0553702 infores:hetionet CAID:CA10585462 biolink:causes MONDO:0007750 infores:clingen CAID:CA10585462 MONDO:0007750 PMID: Uncertain Significance PM2 BP4, BA1, PS1, BS1, PM5, PP3, PP4 The NM_000527.5(LDLR):c.1456A>G (p.Ser486Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA10585462/MONDO:0007750/013 2024-10-28 2025-01-19 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9123 biolink:causes MONDO:0004982 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0030305 infores:hetionet CHEBI:3082 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00195 UMLS:C0036974 infores:hetionet CHEBI:2950 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00972 UMLS:C0008031 infores:hetionet CHEBI:135791 biolink:causes MONDO:0019290 infores:sider not_provided not_provided DRUGBANK:DB01130 UMLS:C0162835 infores:hetionet GO:0060314 biolink:causes GO:0051716 infores:ubergraph knowledge_assertion manual_agent GO:0060314 GO:0051716 CHEBI:161680 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00355 UMLS:C0040034 infores:hetionet CHEBI:82716 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB08990 UMLS:C0015230 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0085932 infores:hetionet CHEBI:16664 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB00518 UMLS:C0042571 infores:hetionet CHEBI:8707 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0020580 infores:hetionet NCBIGene:3762 biolink:causes MONDO:0013279 infores:monarchinitiative not_provided not_provided HGNC:6266 MONDO:0013279 uuid:0f07d594-c963-4241-bcdf-028071251f10 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:31236 biolink:causes MONDO:0002046 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0085762 infores:hetionet CHEBI:27779 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0235996 infores:hetionet CHEBI:3732 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB01211 UMLS:C0392386 infores:hetionet CHEBI:6444 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00854 UMLS:C3665347 infores:hetionet CHEBI:28148 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB05630 UMLS:C0030252 infores:hetionet CHEBI:45863 biolink:causes UMLS:C0332534 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0332534 infores:hetionet NCBITaxon:784 biolink:causes MONDO:0019365 infores:drugmechdb knowledge_assertion manual_agent NCBITaxon:784 MESH:D012612 DB00254_MESH_D012612_1DB02703_MESH_D012612_1 CHEBI:8499 biolink:causes UMLS:C0344320 infores:sider not_provided not_provided DRUGBANK:DB00571 UMLS:C0344320 infores:hetionet CAID:CA024165 biolink:causes MONDO:0018493 infores:clingen CAID:CA024165 MONDO:0018493 PMID: Uncertain Significance PM1_Supporting, PP3_Moderate PS4 This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with methionine at codon 4842 of the RYR1 protein, p.(Val4842Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0002, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:21455645). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. Malignant Hyperthermia Susceptibility VCEP https://erepo.genome.network/evrepo/ui/classification/CA024165/MONDO:0018493/012 2023-04-06 2023-04-06 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/ true CHEBI:167309 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00333 UMLS:C0040822 infores:hetionet CHEBI:40303 biolink:causes NCIT:C187286 infores:sider not_provided not_provided DRUGBANK:DB00227 UMLS:C0235266 infores:hetionet CHEBI:6402 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0015230 infores:hetionet CAID:CA082749 biolink:causes MONDO:0044970 infores:clingen CAID:CA082749 MONDO:0044970 PMID: Likely Pathogenic PM6_Strong, PM2_Supporting, PS3_Moderate, PS4_Moderate PP1, PP4, PP3, PS2 The m.3902_3908inv (p.DLA199GKV) variant in MT-ND1 has been reported in four unrelated individuals in the literature with primary mitochondrial disease with a range of clinical features including myopathy, exercise intolerance, Leigh syndrome, cardiomyopathy, failure to thrive, lactic acidosis, nephropathy, sensorineural hearing loss, and diabetes mellitus (PS4_moderate; PMIDs: 10775530, 16492986, 27290639, 34135385). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are at least three de novo occurrences reported in the literature and this variant in the case reported by the expert panel member also occurred de novo (PM6_strong; PMIDs: 16492986, 10775530, 27290639). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). E. coli models demonstrated two different functional defects, reduced complex activity and reduced proton translocation (PS3_moderate; PMIDs; 34135385, 35234296). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 9, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PS3_moderate. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA082749/MONDO:0044970/015 2022-06-30 2022-06-30 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:3568 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0085649 infores:hetionet UMLS:C0011701 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00035 UMLS:C0004936 infores:hetionet CHEBI:50648 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0917801 infores:hetionet CHEBI:94848 biolink:causes HP:0001742 infores:sider not_provided not_provided DRUGBANK:DB00985 UMLS:C0027424 infores:hetionet NCBIGene:9217 biolink:causes MONDO:0008453 infores:monarchinitiative not_provided not_provided HGNC:12649 MONDO:0008453 uuid:a39c65fd-82f8-4c69-88ad-e867478c2b5b biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:46081 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C2047937 infores:hetionet CHEBI:8707 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0037763 infores:hetionet CHEBI:44032 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0008370 infores:hetionet CHEBI:4027 biolink:causes MONDO:0020579 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0333355 infores:hetionet CHEBI:6375 biolink:causes HP:0011855 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0236024 infores:hetionet CHEBI:6375 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00448 UMLS:C0014591 infores:hetionet CHEBI:17549 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00855 UMLS:C0015967 infores:hetionet CHEBI:47426 biolink:causes MONDO:0005155 infores:sider not_provided not_provided DRUGBANK:DB00695 UMLS:C0023890 infores:hetionet CHEBI:100241 biolink:causes UMLS:C0035127 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0035127 infores:hetionet CHEBI:3061 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB01244 UMLS:C0036974 infores:hetionet CHEBI:36795 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00476 UMLS:C0018681 infores:hetionet CHEBI:135351 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB05271 UMLS:C0006145 infores:hetionet CHEBI:6916 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0013395 infores:hetionet CHEBI:231594 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00367 UMLS:C0027769 infores:hetionet CHEBI:64064 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0013395 infores:hetionet CHEBI:119573 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB00705 UMLS:C0035455 infores:hetionet CHEBI:5147 biolink:causes UMLS:C0235639 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0235639 infores:hetionet CHEBI:4995 biolink:causes UMLS:C0151826 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0151826 infores:hetionet CHEBI:4027 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0033774 infores:hetionet CAID:CA386959765 biolink:causes MONDO:0015967 infores:clingen CAID:CA386959765 MONDO:0015967 PMID: Likely Pathogenic PM2_Supporting, PM1_Supporting, PM5_Supporting, PP4_Moderate, PP3 The c.415C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 139 (p.(Leu139Val)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.848, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies, and sulfonylurea-responsive) (PP4_Moderate; PMID: 27810688). Another missense variant, c.416T>C p.Leu139Pro, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.415C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA386959765/MONDO:0015967/017 2024-09-24 2024-09-24 Autosomal dominant inheritance HP:0000006 Supports CHEBI:79699 biolink:causes MONDO:0003014 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0035455 infores:hetionet CHEBI:5280 biolink:causes UMLS:C0236065 infores:sider not_provided not_provided DRUGBANK:DB01044 UMLS:C0236065 infores:hetionet CHEBI:5100 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0030312 infores:hetionet CHEBI:17688 biolink:causes UMLS:C0234215 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0234215 infores:hetionet CHEBI:63631 biolink:causes UMLS:C0521592 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0521592 infores:hetionet CAID:CA2387297219 biolink:causes MONDO:0011071 infores:clingen CAID:CA2387297219 MONDO:0011071 PMID: Pathogenic PM5_Supporting, PVS1, PM2_Supporting, PS4_Supporting PS1, PS3, PS2, BP2, BP1, BP4, BP3, BA1, PM6, BP5, BP7, BS1, BS3, BS4, PM3, PM4, PM1, BS2, PP4, PP2, PP3, PP1 NM_001754.5(RUNX1):c.165dup (p.Leu56ValfsTer?) is a duplication frameshift variant which results in a termination sequence 82 residues later. This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (+) c.98-c.779 as per VCEP specifications) (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 18723428). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM5_supporting, PM2_supporting, PS4_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2387297219/MONDO:0011071/008 2024-03-26 2024-03-26 Autosomal dominant inheritance HP:0000006 Supports CHEBI:28901 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB01008 UMLS:C2830004 infores:hetionet CHEBI:70746 biolink:causes MONDO:0005267 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0018799 infores:hetionet NCBIGene:6400 biolink:causes MONDO:0976131 infores:monarchinitiative not_provided not_provided HGNC:10717 MONDO:0976131 uuid:9378bca2-fadf-4901-87f0-e40668f1357f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:71219 biolink:causes UMLS:C0476414 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0476414 infores:hetionet NCBIGene:51778 biolink:causes MONDO:0013455 infores:monarchinitiative not_provided not_provided HGNC:1330 MONDO:0013455 uuid:02037238-aa55-4cfd-940f-c7caf70c70a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges PUBCHEM.COMPOUND:45357473 biolink:causes UMLS:C3495440 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C3495440 infores:hetionet NCBIGene:1889 biolink:causes MONDO:0013473 infores:monarchinitiative not_provided not_provided HGNC:3146 MONDO:0013473 uuid:ac978945-9244-4725-ad25-a899e07fbc67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:49960 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0011570 infores:hetionet CHEBI:16899 biolink:causes MONDO:0001358 infores:sider not_provided not_provided DRUGBANK:DB00742 UMLS:C0006266 infores:hetionet CHEBI:6067 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0853714 infores:hetionet NCBIGene:22954 biolink:causes MONDO:0014439 infores:monarchinitiative not_provided not_provided HGNC:16380 MONDO:0014439 uuid:ca83867e-0c58-4c76-b589-e8f3765ba222 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47499 biolink:causes MONDO:0100053 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0002792 infores:hetionet CHEBI:9448 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0030312 infores:hetionet CHEBI:2666 biolink:causes HP:0033031 infores:sider not_provided not_provided DRUGBANK:DB00321 UMLS:C0392676 infores:hetionet CHEBI:6076 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01167 UMLS:C0009676 infores:hetionet CHEBI:4784 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB00584 UMLS:C0038454 infores:hetionet CHEBI:4710 biolink:causes NCIT:C34857 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0028643 infores:hetionet CHEBI:8888 biolink:causes MONDO:0008420 infores:sider not_provided not_provided DRUGBANK:DB00268 UMLS:C0022603 infores:hetionet CHEBI:31623 biolink:causes MONDO:0005709 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0009443 infores:hetionet CHEBI:3636 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB01161 UMLS:C0344232 infores:hetionet CHEBI:15544 biolink:causes UMLS:C0853714 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0853714 infores:hetionet CHEBI:9123 biolink:causes HP:0100716 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0085271 infores:hetionet CHEBI:74947 biolink:causes HP:0033834 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0231218 infores:hetionet CHEBI:135736 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C1306341 infores:hetionet CHEBI:32221 biolink:causes UMLS:C0728993 infores:sider not_provided not_provided DRUGBANK:DB01600 UMLS:C0728993 infores:hetionet CHEBI:50648 biolink:causes HP:0007663 infores:sider not_provided not_provided DRUGBANK:DB00523 UMLS:C0234632 infores:hetionet CHEBI:3216 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0006145 infores:hetionet CHEBI:31547 biolink:causes HP:0003326 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0231528 infores:hetionet CHEBI:5001 biolink:causes MONDO:0006999 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0040435 infores:hetionet CHEBI:63681 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0036974 infores:hetionet GO:0048886 biolink:causes CL:0000856 infores:ubergraph knowledge_assertion manual_agent GO:0048886 CL:0000856 CHEBI:45783 biolink:causes NCIT:C26791 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0019080 infores:hetionet CHEBI:50381 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB00419 UMLS:C0004936 infores:hetionet CHEBI:3534 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB00567 UMLS:C0151905 infores:hetionet CHEBI:10650 biolink:causes HP:0100608 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0025874 infores:hetionet CAID:CA8337549 biolink:causes MONDO:0008723 infores:clingen CAID:CA8337549 MONDO:0008723 PMID: Likely Benign BP4, BP7 The c.117C>T variant is a synonymous (silent) variant (p.Pro39=) which occurs in exon 10. The results from 2 in silico splicing predictors (SpliceAI, MutationTaster) support that this variant does not affect splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 8, 2021) ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA8337549/MONDO:0008723/021 2022-07-28 2022-07-28 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:16796 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01065 UMLS:C0233494 infores:hetionet CHEBI:119915 biolink:causes HP:0000019 infores:sider not_provided not_provided DRUGBANK:DB00813 UMLS:C0152032 infores:hetionet CHEBI:45783 biolink:causes MONDO:0100192 infores:sider not_provided not_provided DRUGBANK:DB00619 UMLS:C0085605 infores:hetionet UNII:D27V6190PM biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0013404 infores:hetionet CHEBI:6916 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00379 UMLS:C0547030 infores:hetionet CHEBI:7903 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00282 UMLS:C0232462 infores:hetionet CHEBI:45367 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C1443060 infores:hetionet CHEBI:50730 biolink:causes UMLS:C0848377 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0848377 infores:hetionet CHEBI:5165 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01320 UMLS:C0010200 infores:hetionet CHEBI:3441 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB01136 UMLS:C0003123 infores:hetionet NCBIGene:7143 biolink:causes MONDO:0859212 infores:monarchinitiative not_provided not_provided HGNC:11953 MONDO:0859212 uuid:d8b3f81b-867f-484a-b705-46959b415242 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:171719 biolink:causes HP:0006682 infores:sider not_provided not_provided DRUGBANK:DB01346 UMLS:C0151636 infores:hetionet CHEBI:63627 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00911 UMLS:C0009806 infores:hetionet CHEBI:10124 biolink:causes UMLS:C1142412 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C1142412 infores:hetionet CHEBI:367163 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0020517 infores:hetionet CHEBI:31623 biolink:causes MONDO:0004577 infores:sider not_provided not_provided DRUGBANK:DB00591 UMLS:C0010043 infores:hetionet CHEBI:27974 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB04573 UMLS:C0085649 infores:hetionet CHEBI:31638 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00947 UMLS:C0311468 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005542 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0948089 infores:hetionet CHEBI:91834 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C2830004 infores:hetionet CHEBI:46195 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0015967 infores:hetionet CHEBI:70718 biolink:causes HP:0002018 infores:sider not_provided not_provided DRUGBANK:DB06590 UMLS:C0027497 infores:hetionet CHEBI:82960 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB06817 UMLS:C0000731 infores:hetionet NCBIGene:3048 biolink:causes MONDO:0013511 infores:monarchinitiative not_provided not_provided HGNC:4832 MONDO:0013511 uuid:560dac48-7385-40b4-9b45-29f268b897a5 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:50861 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00374 UMLS:C0018802 infores:hetionet CHEBI:3757 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00575 UMLS:C0018802 infores:hetionet CHEBI:9137 biolink:causes MONDO:0000481 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0040485 infores:hetionet CAID:CA512232098 biolink:causes MONDO:0011071 infores:clingen CAID:CA512232098 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS4, PS3, PS1, BA1, BP2, PVS1, PM6, PM2, BS4, BS3, BS1, PM5, PM1, PM4, PP1, PP3 This synonymous variant is predicted by SSF, MES, and SpliceAI to lead to either no change/an increase/a decrease by no more than 10% in the canonical splice site score and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score = 0.223181 in GRCh37/0.744953 in GRCh38 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA512232098/MONDO:0011071/008 2021-01-12 2021-01-12 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:63599 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01073 UMLS:C0030312 infores:hetionet CHEBI:480999 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00361 UMLS:C0854467 infores:hetionet CHEBI:17303 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00295 UMLS:C0232462 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0002239 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0017181 infores:hetionet CHEBI:2682 biolink:causes HP:0012531 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0030193 infores:hetionet UMLS:C0120107 biolink:causes HP:0002248 infores:sider not_provided not_provided DRUGBANK:DB00014 UMLS:C0018926 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0014742 infores:hetionet CHEBI:52172 biolink:causes HP:0003474 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0020580 infores:hetionet CHEBI:31236 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB01238 UMLS:C0004093 infores:hetionet CHEBI:100246 biolink:causes UMLS:C0973461 infores:sider not_provided not_provided DRUGBANK:DB01059 UMLS:C0973461 infores:hetionet CHEBI:16335 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0003467 infores:hetionet CHEBI:75984 biolink:causes HP:0003155 infores:sider not_provided not_provided DRUGBANK:DB01195 UMLS:C0750857 infores:hetionet CHEBI:10110 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0004093 infores:hetionet NCBIGene:8506 biolink:causes MONDO:0014569 infores:monarchinitiative not_provided not_provided HGNC:8011 MONDO:0014569 uuid:f6d5e431-82b0-4195-b653-61ee2a4cf51d biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CAID:CA222222 biolink:causes MONDO:0015152 infores:clingen CAID:CA222222 MONDO:0015152 PMID: Likely Pathogenic PM3_Supporting, PP3, PP4, PM2_Supporting, PS3_Moderate PM5 The NM_003494.4: c.865T>C variant in DYSF, which is also known as NM_001130987.2: c.961T>C p.(Ser321Pro), is a missense variant predicted to cause substitution of serine by proline at amino acid 289, p.(Ser289Pro). This variant has been reported in two patients with features consistent with LGMD (PMID: 36983702; PMID: 30564623; LOVD DYSF_000780), including in unconfirmed phase with a pathogenic variant (NM_003494.4: c.757C>T p.(Arg253Trp), 0.5 pts; PMID: 0564623, LOVD Individual #00222734) (PM3_Supporting). One of the patients with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and reduced range dysferlin by blood monocyte assay (PP4; PMID: 36983702). The filtering allele frequency of this variant is 0.000007 in the European (non-Finnish) population of gnomAD v4.1.0 (the upper threshold of the 95% CI of 3/1112008 exome chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Ser289Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.71, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 06/24/2025): PM3_Supporting, PP4, PM2_Supporting, PS3_Moderate, PP3. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222222/MONDO:0015152/180 2025-06-24 2025-07-08 Autosomal recessive inheritance HP:0000007 Supports CHEBI:4728 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00651 UMLS:C0039231 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0236071 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0236071 infores:hetionet CHEBI:3723 biolink:causes EFO:0010678 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0270996 infores:hetionet CHEBI:3084 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C0016382 infores:hetionet CHEBI:63621 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB01232 UMLS:C1384353 infores:hetionet CHEBI:63620 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB01367 UMLS:C0917798 infores:hetionet CHEBI:3723 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0595877 infores:hetionet CHEBI:78543 biolink:causes MONDO:0000313 infores:sider not_provided not_provided DRUGBANK:DB08901 UMLS:C0085682 infores:hetionet CHEBI:63791 biolink:causes NCIT:C3244 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0026858 infores:hetionet CHEBI:4514 biolink:causes MONDO:0011441 infores:sider not_provided not_provided DRUGBANK:DB00804 UMLS:C0034931 infores:hetionet CHEBI:8802 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00899 UMLS:C0013404 infores:hetionet GO:0045704 biolink:causes GO:0009887 infores:ubergraph knowledge_assertion manual_agent GO:0045704 GO:0009887 CHEBI:6539 biolink:causes HP:0000622 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0344232 infores:hetionet CHEBI:6887 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0162830 infores:hetionet CHEBI:3650 biolink:causes UMLS:C0541900 infores:sider not_provided not_provided DRUGBANK:DB00672 UMLS:C0541900 infores:hetionet CAID:CA1244154 biolink:causes MONDO:0005338 infores:clingen CAID:CA1244154 MONDO:0005338 PMID: Likely Benign BP7, BP4 BS1, BS3, PM2, PP3, PP1, PM4, PM5, PS3, PS1, PS2, PS4, BA1 The c.801T>C variant in MYOC is a synonymous variant (p.Tyr267=). The highest minor allele frequency of this variant, in a genetic ancestry group ≥ 2,000 alleles was in the Middle Eastern genetic ancestry group of gnomAD (v4.1.0) = 0.0003299 (2 alleles out of 6,062), which which did not meet the ≥ 0.001 threshold nor the ≥5 alleles necessary to meet BS1. The highest minor allele frequency of this variant, in a population ≥ 10,000 alleles, was in the South Asian population of gnomAD (v4.1.0) = 0.0002745 (25 alleles out of 91,074), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The SpliceAI score = 0.01, which met the ≤ 0.1 threshold for BP4, suggesting that the variant does not impact MYOC function. This synonymous variant meets BP4, so BP7 is met. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant was identified in laboratory based testing, but has not yet been found in a proband with juvenile or primary open angle glaucoma. Additionally, as PM2_Supporting was not met, PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BP4, BP7 Glaucoma VCEP https://erepo.genome.network/evrepo/ui/classification/CA1244154/MONDO:0005338/019 2025-10-09 2025-10-09 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:7936 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00715 UMLS:C0039971 infores:hetionet UMLS:C1738934 biolink:causes MONDO:0004781 infores:sider not_provided not_provided DRUGBANK:DB08873 UMLS:C0155626 infores:hetionet CHEBI:75722 biolink:causes HP:0002573 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C0018932 infores:hetionet CHEBI:17688 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00184 UMLS:C0231530 infores:hetionet CHEBI:6717 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00784 UMLS:C0042963 infores:hetionet CHEBI:9667 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0011603 infores:hetionet CHEBI:127342 biolink:causes UMLS:C0549373 infores:sider not_provided not_provided DRUGBANK:DB00289 UMLS:C0549373 infores:hetionet CHEBI:17141 biolink:causes MONDO:0005299 infores:sider not_provided not_provided DRUGBANK:DB00847 UMLS:C0917798 infores:hetionet CHEBI:4710 biolink:causes UMLS:C0435002 infores:sider not_provided not_provided DRUGBANK:DB01142 UMLS:C0435002 infores:hetionet CHEBI:3207 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB01222 UMLS:C0518015 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0160390 infores:hetionet GO:0060950 biolink:causes CL:0010020 infores:ubergraph knowledge_assertion manual_agent GO:0060950 CL:0010020 CHEBI:3176 biolink:causes MONDO:0002515 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0267792 infores:hetionet CHEBI:46081 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0002871 infores:hetionet CHEBI:46081 biolink:causes UMLS:C0039971 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0039971 infores:hetionet CHEBI:2673 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB01351 UMLS:C0424295 infores:hetionet CHEBI:6954 biolink:causes MONDO:0004730 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0037822 infores:hetionet CHEBI:3084 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB01019 UMLS:C2939147 infores:hetionet CHEBI:681569 biolink:causes HP:0001337 infores:sider not_provided not_provided DRUGBANK:DB00631 UMLS:C0040822 infores:hetionet CHEBI:6690 biolink:causes UMLS:C1320835 infores:sider not_provided not_provided DRUGBANK:DB00934 UMLS:C1320835 infores:hetionet CHEBI:44185 biolink:causes MONDO:0003757 infores:sider not_provided not_provided DRUGBANK:DB00563 UMLS:C0030486 infores:hetionet CHEBI:42355 biolink:causes NCIT:C50476 infores:sider not_provided not_provided DRUGBANK:DB00199 UMLS:C0085624 infores:hetionet CHEBI:6067 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0085649 infores:hetionet NCBIGene:55788 biolink:causes MONDO:0010183 infores:monarchinitiative not_provided not_provided HGNC:23038 MONDO:0010183 uuid:9584711f-c6a1-4ab2-bda7-097eb1896cea biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:8426 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB01032 UMLS:C0014742 infores:hetionet CHEBI:3698 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB01340 UMLS:C0040264 infores:hetionet CHEBI:490877 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB00900 UMLS:C0160390 infores:hetionet CHEBI:6062 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0043094 infores:hetionet CHEBI:145499 biolink:causes MONDO:0002076 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0032326 infores:hetionet CHEBI:45081 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00738 UMLS:C0235710 infores:hetionet CHEBI:5130 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0011606 infores:hetionet CHEBI:7565 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB01115 UMLS:C0877055 infores:hetionet CHEBI:8212 biolink:causes MONDO:0015909 infores:sider not_provided not_provided DRUGBANK:DB01100 UMLS:C0002874 infores:hetionet CHEBI:7959 biolink:causes MONDO:0004184 infores:sider not_provided not_provided DRUGBANK:DB00859 UMLS:C0041969 infores:hetionet CHEBI:8024 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00790 UMLS:C0016204 infores:hetionet CHEBI:31981 biolink:causes HP:0012250 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0520887 infores:hetionet CHEBI:6888 biolink:causes UMLS:C0333641 infores:sider not_provided not_provided DRUGBANK:DB00959 UMLS:C0333641 infores:hetionet CHEBI:44915 biolink:causes HP:0002791 infores:sider not_provided not_provided DRUGBANK:DB00818 UMLS:C0235063 infores:hetionet CHEBI:9168 biolink:causes UMLS:C0043250 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0043250 infores:hetionet CHEBI:71219 biolink:causes UMLS:C0860803 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0860803 infores:hetionet CHEBI:5134 biolink:causes HP:0100540 infores:sider not_provided not_provided DRUGBANK:DB00588 UMLS:C0162285 infores:hetionet CAID:CA036228 biolink:causes MONDO:0007750 infores:clingen CAID:CA036228 MONDO:0007750 PMID: Uncertain Significance PS4_Supporting, PM2, PP3, PP4 BA1, BP1, BP4, BP3, BP2, PS1, PS3, PS2, BS1, BS3, BS4, BP7, BP5, PM5, PM4, PM1, PM3, PM6, PVS1, BS2, PP2, PP1 NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS4_supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001848 (0.01848%) in European (Finnish) exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.937.PP4 - Variant meets PM2. Identified in 2 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome score possible/definite, after alternative causes of high cholesterol were excluded.PS4_supporting - Variant meets PM2. Variant identified in 2 index cases Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome criteria (possible/definite). Familial Hypercholesterolemia VCEP https://erepo.genome.network/evrepo/ui/classification/CA036228/MONDO:0007750/013 2022-03-30 2022-07-12 Semidominant inheritance HP:0032113 Inconclusive https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/ true CHEBI:9667 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB00620 UMLS:C0003811 infores:hetionet CHEBI:8245 biolink:causes HP:0030828 infores:sider not_provided not_provided DRUGBANK:DB01291 UMLS:C0043144 infores:hetionet CHEBI:10127 biolink:causes UMLS:C1167965 infores:sider not_provided not_provided DRUGBANK:DB00909 UMLS:C1167965 infores:hetionet UMLS:C0903898 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB00731 UMLS:C0022408 infores:hetionet CHEBI:5100 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01099 UMLS:C0035078 infores:hetionet CHEBI:68478 biolink:causes MONDO:0005372 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0021364 infores:hetionet CHEBI:8455 biolink:causes MONDO:0001529 infores:sider not_provided not_provided DRUGBANK:DB01131 UMLS:C0030312 infores:hetionet CHEBI:3508 biolink:causes MONDO:0005027 infores:sider not_provided not_provided DRUGBANK:DB00438 UMLS:C0036572 infores:hetionet CHEBI:50730 biolink:causes MONDO:0018882 infores:sider not_provided not_provided DRUGBANK:DB00471 UMLS:C0042384 infores:hetionet CHEBI:3077 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0026946 infores:hetionet CHEBI:77260 biolink:causes MONDO:0013662 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0004763 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0020517 infores:hetionet CHEBI:9139 biolink:causes MONDO:0004855 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0039520 infores:hetionet CHEBI:2453 biolink:causes UMLS:C2047937 infores:sider not_provided not_provided DRUGBANK:DB00787 UMLS:C2047937 infores:hetionet CHEBI:83804 biolink:causes UMLS:C0948349 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0948349 infores:hetionet CHEBI:3423 biolink:causes EFO:0007053 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0854467 infores:hetionet CHEBI:8378 biolink:causes MONDO:0005380 infores:sider not_provided not_provided DRUGBANK:DB00860 UMLS:C0085660 infores:hetionet CHEBI:7852 biolink:causes HP:0033842 infores:sider not_provided not_provided DRUGBANK:DB00497 UMLS:C0239233 infores:hetionet CHEBI:6933 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00211 UMLS:C1443060 infores:hetionet CHEBI:8874 biolink:causes MONDO:0000465 infores:sider not_provided not_provided DRUGBANK:DB00989 UMLS:C0004245 infores:hetionet CHEBI:3723 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB00215 UMLS:C0014724 infores:hetionet CHEBI:23765 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0007859 infores:hetionet CHEBI:43968 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00760 UMLS:C0518015 infores:hetionet CHEBI:16469 biolink:causes MONDO:0006598 infores:sider not_provided not_provided DRUGBANK:DB00783 UMLS:C0162830 infores:hetionet GO:0160177 biolink:causes GO:0016236 infores:ubergraph knowledge_assertion manual_agent GO:0160177 GO:0016236 CHEBI:9570 biolink:causes MONDO:0005152 infores:sider not_provided not_provided DRUGBANK:DB04572 UMLS:C0020635 infores:hetionet CHEBI:135736 biolink:causes NCIT:C50550 infores:sider not_provided not_provided DRUGBANK:DB06268 UMLS:C0014724 infores:hetionet CHEBI:63622 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00489 UMLS:C0011603 infores:hetionet CHEBI:50777 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00294 UMLS:C0041834 infores:hetionet CHEBI:253342 biolink:causes UMLS:C1142335 infores:sider not_provided not_provided DRUGBANK:DB00969 UMLS:C1142335 infores:hetionet CHEBI:6704 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00643 UMLS:C0020517 infores:hetionet CHEBI:3504 biolink:causes EFO:0009844 infores:sider not_provided not_provided DRUGBANK:DB01416 UMLS:C0028084 infores:hetionet CHEBI:5959 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB01029 UMLS:C1565489 infores:hetionet UMLS:C0009315 biolink:causes EFO:0010670 infores:sider not_provided not_provided DRUGBANK:DB01111 UMLS:C0159056 infores:hetionet CHEBI:8871 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00734 UMLS:C0037199 infores:hetionet CHEBI:40279 biolink:causes HP:0002605 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0151798 infores:hetionet CHEBI:64064 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00938 UMLS:C0042963 infores:hetionet CHEBI:50729 biolink:causes MONDO:0005047 infores:sider not_provided not_provided DRUGBANK:DB01204 UMLS:C0021359 infores:hetionet CHEBI:16347 biolink:causes HP:0031249 infores:sider not_provided not_provided DRUGBANK:DB00583 UMLS:C0013378 infores:hetionet CHEBI:59560 biolink:causes HP:0000752 infores:sider not_provided not_provided DRUGBANK:DB00360 UMLS:C0424295 infores:hetionet CHEBI:175901 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00441 UMLS:C0020621 infores:hetionet CHEBI:135961 biolink:causes MONDO:0005468 infores:sider not_provided not_provided DRUGBANK:DB06699 UMLS:C0020649 infores:hetionet CAID:CA2573157364 biolink:causes MONDO:0011071 infores:clingen CAID:CA2573157364 MONDO:0011071 PMID: Uncertain Significance PM2_Supporting PS1, PS3, PS4, PS2, BP1, BP4, BP3, BP2, BA1, BS1, BS3, BS4, BP5, BP7, PVS1, PM6, PM4, PM3, PM5, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1):c.191_196del (p.Gly64_Ala65del) is an in-frame deletion which does not affect any known functional domains. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573157364/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:68534 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB08899 UMLS:C0151908 infores:hetionet CHEBI:6950 biolink:causes MONDO:0043303 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0034880 infores:hetionet CHEBI:42797 biolink:causes NCIT:C34762 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0023218 infores:hetionet CHEBI:32192 biolink:causes MONDO:0002657 infores:sider not_provided not_provided DRUGBANK:DB00469 UMLS:C0006145 infores:hetionet CHEBI:5118 biolink:causes MONDO:0004758 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0036454 infores:hetionet CHEBI:421707 biolink:causes HP:0012735 infores:sider not_provided not_provided DRUGBANK:DB01048 UMLS:C0010200 infores:hetionet CHEBI:520985 biolink:causes HP:0000360 infores:sider not_provided not_provided DRUGBANK:DB00918 UMLS:C0040264 infores:hetionet NCBIGene:4760 biolink:causes MONDO:0011668 infores:monarchinitiative not_provided not_provided HGNC:7762 MONDO:0011668 uuid:9e3a5e3f-68c4-47db-84d0-19dec7b2eb88 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9316 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00708 UMLS:C0042963 infores:hetionet NCBIGene:27232 biolink:causes MONDO:0011698 infores:monarchinitiative not_provided not_provided HGNC:4415 MONDO:0011698 uuid:4882e067-9619-4634-bf5d-5d1b7c68a6bd biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:47381 biolink:causes UMLS:C0852908 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0852908 infores:hetionet CHEBI:50305 biolink:causes MONDO:0001209 infores:sider not_provided not_provided DRUGBANK:DB01179 UMLS:C3665596 infores:hetionet CHEBI:3172 biolink:causes NCIT:C117107 infores:sider not_provided not_provided DRUGBANK:DB01158 UMLS:C0221201 infores:hetionet CHEBI:9599 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0013428 infores:hetionet CHEBI:28864 biolink:causes EFO:0020928 infores:sider not_provided not_provided DRUGBANK:DB00684 UMLS:C1262036 infores:hetionet CHEBI:80630 biolink:causes HP:0001260 infores:sider not_provided not_provided DRUGBANK:DB00762 UMLS:C0013362 infores:hetionet CHEBI:2659 biolink:causes MONDO:0005002 infores:sider not_provided not_provided DRUGBANK:DB01223 UMLS:C0024117 infores:hetionet CHEBI:9943 biolink:causes HP:0001288 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0575081 infores:hetionet UNII:15G12L5X8K biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00743 UMLS:C2939147 infores:hetionet CAID:CA320248552 biolink:causes MONDO:0011071 infores:clingen CAID:CA320248552 MONDO:0011071 PMID: Uncertain Significance PS3, PS4, PS2, BP4, BP2, BA1, PVS1, PM2, PM6, BP7, BS1, BS3, BS4, PM4, PM1, PP3, PP1 NM_001754.5(RUNX1):c.*3557C>T is a 3' UTR change which does not meey any ACMg/AMP criteria. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: None. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320248552/MONDO:0011071/008 2024-11-13 2024-11-13 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:135920 biolink:causes HP:0012398 infores:sider not_provided not_provided DRUGBANK:DB06702 UMLS:C0085649 infores:hetionet CHEBI:36791 biolink:causes MONDO:0011122 infores:sider not_provided not_provided DRUGBANK:DB01175 UMLS:C0028754 infores:hetionet CHEBI:70746 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB06695 UMLS:C0002962 infores:hetionet CHEBI:7496 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0023530 infores:hetionet CHEBI:7454 biolink:causes HP:0000738 infores:sider not_provided not_provided DRUGBANK:DB00844 UMLS:C0018524 infores:hetionet CHEBI:10110 biolink:causes MONDO:0011918 infores:sider not_provided not_provided DRUGBANK:DB00495 UMLS:C0003467 infores:hetionet CHEBI:49668 biolink:causes MONDO:0004335 infores:sider not_provided not_provided DRUGBANK:DB00317 UMLS:C0017178 infores:hetionet CHEBI:8107 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0151828 infores:hetionet CHEBI:8435 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00433 UMLS:C0008370 infores:hetionet CHEBI:91834 biolink:causes UMLS:C0151828 infores:sider not_provided not_provided DRUGBANK:DB09009 UMLS:C0151828 infores:hetionet CHEBI:75988 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00444 UMLS:C0004093 infores:hetionet CHEBI:9352 biolink:causes UMLS:C0854456 infores:sider not_provided not_provided DRUGBANK:DB00605 UMLS:C0854456 infores:hetionet CHEBI:83804 biolink:causes MONDO:0005178 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0029408 infores:hetionet CHEBI:7915 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0040053 infores:hetionet CHEBI:48844 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00778 UMLS:C0011603 infores:hetionet CHEBI:6129 biolink:causes MONDO:0006545 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0014742 infores:hetionet CHEBI:63635 biolink:causes MONDO:0002118 infores:sider not_provided not_provided DRUGBANK:DB01610 UMLS:C0042075 infores:hetionet CHEBI:5138 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0037763 infores:hetionet CHEBI:63638 biolink:causes HP:0002487 infores:sider not_provided not_provided DRUGBANK:DB01080 UMLS:C0037763 infores:hetionet CHEBI:94440 biolink:causes HP:0000980 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0030232 infores:hetionet CAID:CA320603725 biolink:causes MONDO:0011071 infores:clingen CAID:CA320603725 MONDO:0011071 PMID: Likely Benign BP4, BP7 PS1, PS3, PS2, PS4, BP1, BP3, BP2, BA1, BP5, BS1, BS3, BS4, PM2, PM6, PVS1, PM4, PM5, PM3, PM1, PP2, PP3, PP4, PP1, BS2 NM_001754.5(RUNX1): c.642C>A (p.Thr214=) is a synonymous variant which is not located at a highly conserved nucleotide (PhyloP = 1.87127 in GRCh38), and SpliceAI does not predict (Δ scores ≤ 0.20) a significant impact on splicing (BP4, BP7). The variant has not been reported in the literature. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA320603725/MONDO:0011071/008 2024-07-11 2024-07-11 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:367163 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB01264 UMLS:C0039231 infores:hetionet CHEBI:79699 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB06287 UMLS:C0151578 infores:hetionet CHEBI:16467 biolink:causes UMLS:C0008301 infores:sider not_provided not_provided DRUGBANK:DB00125 UMLS:C0008301 infores:hetionet CHEBI:9139 biolink:causes MONDO:0002508 infores:sider not_provided not_provided DRUGBANK:DB00203 UMLS:C0017574 infores:hetionet CHEBI:37924 biolink:causes MONDO:0005230 infores:sider not_provided not_provided DRUGBANK:DB01072 UMLS:C0007642 infores:hetionet CHEBI:10124 biolink:causes NCIT:C50748 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0234233 infores:hetionet CHEBI:78320 biolink:causes HP:0000958 infores:sider not_provided not_provided DRUGBANK:DB06768 UMLS:C0151908 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0025061 infores:hetionet CHEBI:63681 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00358 UMLS:C0040034 infores:hetionet CHEBI:31348 biolink:causes MONDO:0005527 infores:sider not_provided not_provided DRUGBANK:DB01101 UMLS:C0235032 infores:hetionet CAID:CA315413826 biolink:causes MONDO:0015967 infores:clingen CAID:CA315413826 MONDO:0015967 PMID: Uncertain Significance PP3, PM2_Supporting, PM1_Supporting PP4 The c.917A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of tyrosine to cysteine at codon 306 (p.(Tyr306Cys)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.713, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% (internal lab contributors). In summary, c.917A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM1_Supporting, PM2_Supporting, PP3. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA315413826/MONDO:0015967/085 2025-06-02 2025-06-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:5147 biolink:causes UMLS:C0236072 infores:sider not_provided not_provided DRUGBANK:DB00983 UMLS:C0236072 infores:hetionet CHEBI:75722 biolink:causes HP:0025085 infores:sider not_provided not_provided DRUGBANK:DB00193 UMLS:C1321898 infores:hetionet CHEBI:51860 biolink:causes UMLS:C0854382 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0854382 infores:hetionet CHEBI:47519 biolink:causes HP:0012378 infores:sider not_provided not_provided DRUGBANK:DB01026 UMLS:C0015672 infores:hetionet CHEBI:7865 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB01192 UMLS:C0009676 infores:hetionet CHEBI:52172 biolink:causes MONDO:0000831 infores:sider not_provided not_provided DRUGBANK:DB04868 UMLS:C0040053 infores:hetionet CHEBI:15407 biolink:causes MONDO:0007263 infores:sider not_provided not_provided DRUGBANK:DB01364 UMLS:C0003811 infores:hetionet CHEBI:42797 biolink:causes HP:0500001 infores:sider not_provided not_provided DRUGBANK:DB00996 UMLS:C0085595 infores:hetionet CHEBI:55346 biolink:causes HP:0000505 infores:sider not_provided not_provided DRUGBANK:DB00362 UMLS:C3665347 infores:hetionet CHEBI:74947 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01041 UMLS:C0031117 infores:hetionet CHEBI:41423 biolink:causes HP:0003645 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0240671 infores:hetionet CHEBI:6954 biolink:causes HP:0000651 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0012569 infores:hetionet CHEBI:9586 biolink:causes UMLS:C0020039 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0020039 infores:hetionet CHEBI:8863 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00740 UMLS:C0013395 infores:hetionet CHEBI:4868 biolink:causes MONDO:0002800 infores:sider not_provided not_provided DRUGBANK:DB01196 UMLS:C0040046 infores:hetionet CHEBI:45409 biolink:causes MONDO:0004979 infores:sider not_provided not_provided DRUGBANK:DB00503 UMLS:C0004096 infores:hetionet CHEBI:7025 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00410 UMLS:C0020517 infores:hetionet CHEMBL.COMPOUND:CHEMBL2368925 biolink:causes MONDO:0002280 infores:sider not_provided not_provided DRUGBANK:DB00757 UMLS:C0002871 infores:hetionet CHEBI:49575 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00829 UMLS:C0428977 infores:hetionet UMLS:C0065374 biolink:causes HP:0000737 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0022107 infores:hetionet CHEBI:4887 biolink:causes MONDO:0018229 infores:sider not_provided not_provided DRUGBANK:DB00593 UMLS:C0038325 infores:hetionet CHEBI:63631 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0041657 infores:hetionet GO:0048399 biolink:causes GO:0048391 infores:ubergraph knowledge_assertion manual_agent GO:0048399 GO:0048391 CHEBI:6402 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0021053 infores:hetionet CHEBI:50859 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00307 UMLS:C0162287 infores:hetionet CHEBI:45367 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00615 UMLS:C0013404 infores:hetionet CHEBI:10101 biolink:causes HP:0031987 infores:sider not_provided not_provided DRUGBANK:DB00943 UMLS:C0235198 infores:hetionet CHEBI:7824 biolink:causes HP:0000613 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0085636 infores:hetionet CHEBI:3423 biolink:causes NCIT:C78253 infores:sider not_provided not_provided DRUGBANK:DB00262 UMLS:C0549249 infores:hetionet NCBIGene:2632 biolink:causes MONDO:0009897 infores:monarchinitiative not_provided not_provided HGNC:4180 MONDO:0009897 uuid:71334a8c-4796-49e6-a15f-4ab9d947c938 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:4814 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00876 UMLS:C0020557 infores:hetionet CHEBI:135613 biolink:causes HP:0002098 infores:sider not_provided not_provided DRUGBANK:DB06213 UMLS:C0476273 infores:hetionet NCBIGene:825 biolink:causes MONDO:0029133 infores:monarchinitiative not_provided not_provided HGNC:1480 MONDO:0029133 uuid:8fab33a0-e397-4b90-867d-96d25af3fb23 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:6121 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB01221 UMLS:C0011603 infores:hetionet CHEBI:10023 biolink:causes UMLS:C0178298 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0178298 infores:hetionet CHEBI:3077 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB00443 UMLS:C0042373 infores:hetionet CHEBI:3219 biolink:causes UMLS:C0002957 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0002957 infores:hetionet CHEBI:3994 biolink:causes MONDO:0010481 infores:sider not_provided not_provided DRUGBANK:DB01176 UMLS:C0002994 infores:hetionet CHEBI:8081 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00692 UMLS:C0428977 infores:hetionet CHEBI:53691 biolink:causes MONDO:0043797 infores:sider not_provided not_provided DRUGBANK:DB00271 UMLS:C0037929 infores:hetionet CHEBI:73274 biolink:causes HP:0003119 infores:sider not_provided not_provided DRUGBANK:DB08907 UMLS:C0242339 infores:hetionet CHEBI:142290 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00261 UMLS:C0030252 infores:hetionet CHEBI:47381 biolink:causes HP:0001276 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0026826 infores:hetionet CHEBI:49713 biolink:causes UMLS:C0020569 infores:sider not_provided not_provided DRUGBANK:DB01356 UMLS:C0020569 infores:hetionet CHEBI:44032 biolink:causes HP:0011897 infores:sider not_provided not_provided DRUGBANK:DB00224 UMLS:C0151683 infores:hetionet CHEBI:9674 biolink:causes MONDO:0005044 infores:sider not_provided not_provided DRUGBANK:DB00897 UMLS:C0020538 infores:hetionet CHEBI:10119 biolink:causes MONDO:0045057 infores:sider not_provided not_provided DRUGBANK:DB00246 UMLS:C0011206 infores:hetionet CHEBI:9137 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB01105 UMLS:C0016867 infores:hetionet CHEBI:41423 biolink:causes MONDO:0021666 infores:sider not_provided not_provided DRUGBANK:DB00482 UMLS:C0699744 infores:hetionet CHEBI:6950 biolink:causes NCIT:C111970 infores:sider not_provided not_provided DRUGBANK:DB00370 UMLS:C0005758 infores:hetionet CHEBI:49960 biolink:causes MONDO:0006547 infores:sider not_provided not_provided DRUGBANK:DB05294 UMLS:C0015230 infores:hetionet CHEBI:9599 biolink:causes MONDO:0800105 infores:sider not_provided not_provided DRUGBANK:DB00373 UMLS:C0007398 infores:hetionet CHEBI:8430 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00721 UMLS:C0233494 infores:hetionet CHEBI:28001 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00512 UMLS:C0013404 infores:hetionet UNII:G4PX8C4HKV biolink:causes UMLS:C3263723 infores:sider not_provided not_provided DRUGBANK:DB01120 UMLS:C3263723 infores:hetionet CHEBI:6792 biolink:causes UMLS:C0548823 infores:sider not_provided not_provided DRUGBANK:DB00816 UMLS:C0548823 infores:hetionet CHEBI:4858 biolink:causes UMLS:C0235146 infores:sider not_provided not_provided DRUGBANK:DB01215 UMLS:C0235146 infores:hetionet CHEBI:7577 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0027769 infores:hetionet CHEBI:15854 biolink:causes MONDO:0019337 infores:sider not_provided not_provided DRUGBANK:DB00468 UMLS:C0085932 infores:hetionet CHEBI:3716 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00827 UMLS:C0018681 infores:hetionet CHEBI:6775 biolink:causes HP:0031273 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0036974 infores:hetionet CHEBI:31981 biolink:causes UMLS:C0160390 infores:sider not_provided not_provided DRUGBANK:DB01608 UMLS:C0160390 infores:hetionet NCBITaxon:785 biolink:causes MONDO:0000330 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:785 MONDO:0000330 CHEBI:5001 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB01039 UMLS:C0027769 infores:hetionet NCBIGene:3908 biolink:causes MONDO:0011925 infores:monarchinitiative not_provided not_provided HGNC:6482 MONDO:0011925 uuid:e4e5af82-b7c4-440d-a73a-ee7ea488bcaf biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:9763 biolink:causes UMLS:C0518015 infores:sider not_provided not_provided DRUGBANK:DB00685 UMLS:C0518015 infores:hetionet NCBIGene:7248 biolink:causes MONDO:0011705 infores:monarchinitiative not_provided not_provided HGNC:12362 MONDO:0011705 uuid:29c749f0-c059-4d48-bbf7-1656613d6578 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:70735 biolink:causes MONDO:0001106 infores:sider not_provided not_provided DRUGBANK:DB08815 UMLS:C0035078 infores:hetionet CHEBI:127780 biolink:causes MONDO:0005961 infores:sider not_provided not_provided DRUGBANK:DB00529 UMLS:C0037199 infores:hetionet CHEBI:71219 biolink:causes MONDO:0005098 infores:sider not_provided not_provided DRUGBANK:DB06589 UMLS:C0038454 infores:hetionet CHEBI:61390 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0020621 infores:hetionet CHEBI:7514 biolink:causes UMLS:C1736186 infores:sider not_provided not_provided DRUGBANK:DB01400 UMLS:C1736186 infores:hetionet CHEBI:100241 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C0013428 infores:hetionet CHEBI:6759 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00961 UMLS:C0340865 infores:hetionet CHEBI:31413 biolink:causes MONDO:0013600 infores:sider not_provided not_provided DRUGBANK:DB00349 UMLS:C0917801 infores:hetionet CHEBI:5790 biolink:causes MONDO:0006769 infores:sider not_provided not_provided DRUGBANK:DB00327 UMLS:C0152020 infores:hetionet CHEBI:7478 biolink:causes NCIT:C3137 infores:sider not_provided not_provided DRUGBANK:DB00952 UMLS:C0021368 infores:hetionet CHEBI:3216 biolink:causes UMLS:C0041912 infores:sider not_provided not_provided DRUGBANK:DB00921 UMLS:C0041912 infores:hetionet CHEBI:63577 biolink:causes MONDO:0006552 infores:sider not_provided not_provided DRUGBANK:DB00709 UMLS:C0016436 infores:hetionet CHEBI:5613 biolink:causes HP:0001987 infores:sider not_provided not_provided DRUGBANK:DB00502 UMLS:C0220994 infores:hetionet CHEBI:28830 biolink:causes HP:0010546 infores:sider not_provided not_provided DRUGBANK:DB00291 UMLS:C0231530 infores:hetionet CHEBI:7496 biolink:causes UMLS:C0853692 infores:sider not_provided not_provided DRUGBANK:DB00220 UMLS:C0853692 infores:hetionet CHEBI:7443 biolink:causes MONDO:0002268 infores:sider not_provided not_provided DRUGBANK:DB00461 UMLS:C0013395 infores:hetionet CHEBI:4445 biolink:causes UMLS:C0424332 infores:sider not_provided not_provided DRUGBANK:DB01189 UMLS:C0424332 infores:hetionet CHEBI:68478 biolink:causes MONDO:0043233 infores:sider not_provided not_provided DRUGBANK:DB01590 UMLS:C0011606 infores:hetionet CHEBI:7915 biolink:causes NCIT:C94475 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0232602 infores:hetionet CHEBI:3347 biolink:causes HP:0002910 infores:sider not_provided not_provided DRUGBANK:DB00796 UMLS:C0438717 infores:hetionet CHEBI:64354 biolink:causes HP:0000713 infores:sider not_provided not_provided DRUGBANK:DB00524 UMLS:C0085631 infores:hetionet CHEBI:68610 biolink:causes UMLS:C0025061 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0025061 infores:hetionet CHEBI:46081 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00196 UMLS:C0037036 infores:hetionet CHEBI:49040 biolink:causes HP:0001962 infores:sider not_provided not_provided DRUGBANK:DB00973 UMLS:C0030252 infores:hetionet CHEBI:31536 biolink:causes HP:0002653 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0151825 infores:hetionet CHEBI:2676 biolink:causes MONDO:0001166 infores:sider not_provided not_provided DRUGBANK:DB01060 UMLS:C0027697 infores:hetionet CHEBI:6954 biolink:causes MONDO:0002312 infores:sider not_provided not_provided DRUGBANK:DB00648 UMLS:C0029119 infores:hetionet CHEBI:31859 biolink:causes EFO:0020918 infores:sider not_provided not_provided DRUGBANK:DB00745 UMLS:C0340865 infores:hetionet GO:0045667 biolink:causes GO:0001503 infores:ubergraph knowledge_assertion manual_agent GO:0045667 GO:0001503 CHEBI:8768 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB01129 UMLS:C0019348 infores:hetionet CHEBI:8412 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00794 UMLS:C0004093 infores:hetionet CHEBI:92998 biolink:causes UMLS:C1384353 infores:sider not_provided not_provided DRUGBANK:DB00629 UMLS:C1384353 infores:hetionet CHEBI:5778 biolink:causes MONDO:0003159 infores:sider not_provided not_provided DRUGBANK:DB00999 UMLS:C1368065 infores:hetionet CHEBI:9598 biolink:causes HP:0034057 infores:sider not_provided not_provided DRUGBANK:DB01133 UMLS:C0000768 infores:hetionet CAID:CA120640 biolink:causes MONDO:0044970 infores:clingen CAID:CA120640 MONDO:0044970 PMID: Pathogenic PP3, PM2_Supporting, PS4, PS3_Supporting, PP1_Moderate, PM6 The m.10197G>A (p.A47T) variant in MT-ND3 has been reported in at least 22 probands with primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to childhood to adulthood). Features included Leigh syndrome, Leigh syndrome/MELAS overlap, and LHON with good visual recovery. Heteroplasmy levels were variable among tissues and affected individuals, and ranged from 10% (in an individual with LHON) to homoplasmy (in an individual with Leigh syndrome; PS4; PMIDs: 15372108, 17152068, 17413873, 18977334, 19458970, 20818383, 20972245, 24708134, 30128709, 30199507, 30776730, 32045392; two articles with no PMIDs: Pereira et al., 2019; JIEMS, 2019, Vol7: e20180003; Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 17152068, 17413873, 30128709, 30776730). This variant occurred de novo in at least three individuals (PM6_moderate, PMIDs: 24708134, 17413873; article with no PMID: Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). There are four occurrences of this variant in the GenBank dataset, and three of these four are not listed as patient sequences. However, upon discussion on the Expert Panel (EP) call, concern was raised that phylogenetic studies use patient samples and submit these to GenBank. This variant is absent in gnomAD v3.1.2 and in Helix dataset so the EP agreed to consider this supporting line of evidence (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 17152068). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.88 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PP1_moderate, PS3_supporting, PM6_moderate, PS4. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA120640/MONDO:0044970/015 2022-07-25 2022-09-02 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:6402 biolink:causes MONDO:0005249 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0032285 infores:hetionet CHEBI:9586 biolink:causes MONDO:0005227 infores:sider not_provided not_provided DRUGBANK:DB00906 UMLS:C0000833 infores:hetionet CAID:CA157951 biolink:causes MONDO:0007648 infores:clingen CAID:CA157951 MONDO:0007648 PMID: Benign BA1 BP7, BP5, BS1, BS3, BS4, PM5, PM4, PM1, PM3, PM2, PM6, PVS1, PP3, PP2, PP1, PP4, BS2, BP4, BP1, BP3, BP2, PS1, PS3, PS4, PS2 The c.1888C>G (p.Leu630Val) variant has an allele frequency of 0.00519 (0.52%, 98/18,866 alleles) in the East Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. CDH1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA157951/MONDO:0007648/007 2023-08-08 2023-08-08 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf true CHEBI:9445 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01162 UMLS:C0007859 infores:hetionet CHEBI:7492 biolink:causes UMLS:C2939147 infores:sider not_provided not_provided DRUGBANK:DB00716 UMLS:C2939147 infores:hetionet CHEBI:5130 biolink:causes MONDO:0004805 infores:sider not_provided not_provided DRUGBANK:DB00712 UMLS:C0023510 infores:hetionet NCBIGene:5309 biolink:causes MONDO:0012527 infores:monarchinitiative not_provided not_provided HGNC:9006 MONDO:0012527 uuid:5490d5f8-472c-4d1a-8a17-7976a3b2c36f biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifierbiolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:23765 biolink:causes MONDO:0006816 infores:sider not_provided not_provided DRUGBANK:DB01208 UMLS:C0022408 infores:hetionet CHEBI:3403 biolink:causes HP:0025144 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0036973 infores:hetionet CHEBI:63580 biolink:causes MONDO:0005277 infores:sider not_provided not_provided DRUGBANK:DB00811 UMLS:C0149931 infores:hetionet NCBIGene:1741 biolink:causes MONDO:0010452 infores:monarchinitiative not_provided not_provided HGNC:2902 MONDO:0010452 uuid:f0ba5775-6fbf-405d-adc3-e7719871ea16 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:51860 biolink:causes MONDO:0002265 infores:sider not_provided not_provided DRUGBANK:DB06701 UMLS:C0038273 infores:hetionet CHEBI:32184 biolink:causes MONDO:0005347 infores:sider not_provided not_provided DRUGBANK:DB00799 UMLS:C0020557 infores:hetionet CHEBI:6437 biolink:causes MONDO:0001475 infores:sider not_provided not_provided DRUGBANK:DB01202 UMLS:C0027947 infores:hetionet CHEBI:8356 biolink:causes UMLS:C0574067 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0574067 infores:hetionet CHEBI:9720 biolink:causes UMLS:C1443060 infores:sider not_provided not_provided DRUGBANK:DB00376 UMLS:C1443060 infores:hetionet CHEBI:4995 biolink:causes HP:0002202 infores:sider not_provided not_provided DRUGBANK:DB00949 UMLS:C0032227 infores:hetionet CHEBI:8346 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB06715 UMLS:C2129214 infores:hetionet CHEBI:51450 biolink:causes MONDO:0005071 infores:sider not_provided not_provided DRUGBANK:DB00559 UMLS:C0027765 infores:hetionet CHEBI:63598 biolink:causes HP:0010307 infores:sider not_provided not_provided DRUGBANK:DB01137 UMLS:C0038450 infores:hetionet NCBIGene:9423 biolink:causes MONDO:0032641 infores:monarchinitiative not_provided not_provided HGNC:8029 MONDO:0032641 uuid:2e045714-9ea1-426f-83f3-2e5e72b1ee8a biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:28918 biolink:causes UMLS:C0235169 infores:sider not_provided not_provided DRUGBANK:DB00668 UMLS:C0235169 infores:hetionet CHEBI:6402 biolink:causes MONDO:0002269 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0017160 infores:hetionet CHEBI:681848 biolink:causes HP:0031352 infores:sider not_provided not_provided DRUGBANK:DB00561 UMLS:C0232292 infores:hetionet CHEBI:47499 biolink:causes HP:0001649 infores:sider not_provided not_provided DRUGBANK:DB00458 UMLS:C0039231 infores:hetionet CHEBI:9086 biolink:causes UMLS:C0151547 infores:sider not_provided not_provided DRUGBANK:DB01037 UMLS:C0151547 infores:hetionet CAID:CA134591 biolink:causes MONDO:0021060 infores:clingen CAID:CA134591 MONDO:0021060 PMID: Benign BA1 The filtering allele frequency of the c.1068+12_1068+15delTATT variant in the MAP2K1 gene is 0.285% (214/66740) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA134591/MONDO:0021060/004 2017-05-09 2018-12-10 Autosomal dominant inheritance HP:0000006 Contradicts https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:8707 biolink:causes MONDO:0005478 infores:sider not_provided not_provided DRUGBANK:DB01224 UMLS:C0040479 infores:hetionet CHEBI:63581 biolink:causes HP:0032142 infores:sider not_provided not_provided DRUGBANK:DB00649 UMLS:C0239571 infores:hetionet CHEBI:4562 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00320 UMLS:C0002962 infores:hetionet CHEBI:291342 biolink:causes HP:0002071 infores:sider not_provided not_provided DRUGBANK:DB00967 UMLS:C0015371 infores:hetionet CHEBI:3175 biolink:causes MONDO:0005271 infores:sider not_provided not_provided DRUGBANK:DB00484 UMLS:C0020517 infores:hetionet CHEBI:145499 biolink:causes HP:0000712 infores:sider not_provided not_provided DRUGBANK:DB00843 UMLS:C0085633 infores:hetionet CHEBI:135342 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0023530 infores:hetionet CHEBI:38545 biolink:causes MONDO:0005336 infores:sider not_provided not_provided DRUGBANK:DB01098 UMLS:C0026848 infores:hetionet CAID:CA2580098633 biolink:causes MONDO:0011071 infores:clingen CAID:CA2580098633 MONDO:0011071 PMID: Likely Benign BP4, BP7, PM2_Supporting PS3, PS1, PS2, PS4, BA1, BP1, BP3, BP2, BS1, BS3, BS4, BP5, PVS1, PM6, PM4, PM3, PM1, PM5, BS2, PP2, PP3, PP4, PP1 NM_001754.5(RUNX1):c.508+14C>A is a variant in intron 5. Splice prediction algorithms do not predict an effect on splicing (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). The nucleotide is not highly conserved phyloP100 way=1.6 (BP7). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP7, BP4, PM2_supporting. Myeloid Malignancy VCEP https://erepo.genome.network/evrepo/ui/classification/CA2580098633/MONDO:0011071/008 2024-09-18 2024-09-18 Autosomal dominant inheritance HP:0000006 Contradicts true CHEBI:2682 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00681 UMLS:C0020621 infores:hetionet CHEBI:16335 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00640 UMLS:C0233494 infores:hetionet CHEBI:6402 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB01097 UMLS:C0037299 infores:hetionet CHEBI:10124 biolink:causes MONDO:0000701 infores:sider not_provided not_provided DRUGBANK:DB00315 UMLS:C0162529 infores:hetionet CHEBI:6909 biolink:causes MONDO:0005328 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0015397 infores:hetionet GO:0060222 biolink:causes GO:0060042 infores:ubergraph knowledge_assertion manual_agent GO:0060222 GO:0060042 CHEBI:83804 biolink:causes MONDO:0005046 infores:sider not_provided not_provided DRUGBANK:DB01267 UMLS:C0021053 infores:hetionet CAID:CA000042 biolink:causes MONDO:0018875 infores:clingen CAID:CA000042 MONDO:0018875 PMID: Likely Benign BP4, BS2, PM2_Supporting, PS4_Supporting BA1, PS3, PS2, PS1, PM1, PM5, BS1, BS3, BS4, PP3, PP1, PP4 The NM_000546.6: c.1135C>A variant in TP53 is a missense variant predicted to cause substitution of argine by serine at amino acid 379 (p.Arg379Ser). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor: Invitae). This variant has been reported in 1 proband meeting Revised Chompret criteria and is reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: Invitae, GeneDx). This variant has an allele frequency of 0.000005932 (7/1179994 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Computational predictor scores (BayesDel = -0.1497; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PS4_Supporting, PM2_Supporting, BS4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025) TP53 VCEP https://erepo.genome.network/evrepo/ui/classification/CA000042/MONDO:0018875/009 2025-01-16 2025-01-16 Autosomal dominant inheritance HP:0000006 Contradicts true NCBITaxon:1824 biolink:causes MONDO:0017776 infores:ubergraph knowledge_assertion manual_agent NCBITaxon:1824 MONDO:0017776 CHEBI:38940 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB01268 UMLS:C0018801 infores:hetionet CHEBI:135939 biolink:causes UMLS:C0043246 infores:sider not_provided not_provided DRUGBANK:DB06218 UMLS:C0043246 infores:hetionet CHEBI:51364 biolink:causes UMLS:C0855242 infores:sider not_provided not_provided DRUGBANK:DB01624 UMLS:C0855242 infores:hetionet CHEBI:6970 biolink:causes UMLS:C0235234 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0235234 infores:hetionet CHEBI:2663 biolink:causes HP:0006515 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0206061 infores:hetionet CHEBI:63791 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00480 UMLS:C0007787 infores:hetionet CAID:CA014858 biolink:causes MONDO:0007947 infores:clingen CAID:CA014858 MONDO:0007947 PMID: Uncertain Significance BS1 PM2, PM6, PVS1, PP2, PP3, PP1, PP4, BS2, BA1, BP1, BP4, BP2, BP3, PM5, PM1, PM3, PM4, PS1, PS3, PS4, PS2, BP5, BP7, BS3, BS4 NM00138 c.4214T>G is a missense variant in FBN1 predicted to cause a substitution of leucine by an arginine at amino acid position 1405. This variant has been reported 14 times in ClinVar: 7 times as likely benign and 7 times as of uncertain significance (Variation ID: 200041). This variant has been reported in the literature and identified by multiple institutions in probands with various features of connective tissue but none with a diagnosis of Marfan syndrome (PMID: 19012347; Mayo Clinic, Bichat Hospital, Universitair Ziekenhuis Gent, Universitair Ziekenhuis Antwerpen). In one family, this variant was found to segregate with mitral valve dystrophy in one family member (Bichat Hospital). This variant has been identified in 0.021% (27/129150) of alleles in the European population in gnomAD v2.1.1 (BS1; https://gnomad.broadinstitute.org/variant/15-48764870-A-C). Computational prediction and evolutionary conservation anaylsis tools are unclear about this variant‘s predicted impact (REVEL = 0.726 which is below 0.750 threshold). Due to there being insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA014858/MONDO:0007947/022 2022-12-01 2022-12-01 Autosomal dominant inheritance HP:0000006 Inconclusive https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ true CHEBI:63611 biolink:causes HP:0100716 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0085271 infores:hetionet CHEBI:94440 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00478 UMLS:C0009676 infores:hetionet CHEBI:3485 biolink:causes MONDO:0019810 infores:sider not_provided not_provided DRUGBANK:DB00535 UMLS:C0014518 infores:hetionet CHEBI:168396 biolink:causes MONDO:0005393 infores:sider not_provided not_provided DRUGBANK:DB01024 UMLS:C0018099 infores:hetionet CHEBI:107736 biolink:causes MONDO:0015281 infores:sider not_provided not_provided DRUGBANK:DB01233 UMLS:C0541782 infores:hetionet UMLS:C0145867 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0233494 infores:hetionet CAID:CA222120 biolink:causes MONDO:0015152 infores:clingen CAID:CA222120 MONDO:0015152 PMID: Pathogenic PP4_Strong, PVS1_Strong, PM3_Supporting, PM2_Supporting PS1 The NM_003494.4: c.1053+1G>A variant in DYSF, which is also known as NM_001130987.2: c.1149+1G>A, occurs within the canonical splice donor site of intron 11. RNAseq analysis has shown that this variant disrupts splicing, resulting in two different frameshifts and premature truncations, p.Arg313ProfsTer8 and p.His314GlufsTer9, as well as an inframe deletion of 66 amino acids, p.Val286_Pro351del (PMID: 36983702; PVS1_Strong_RNA). This variant has been identified in at least four individuals with LGMD (PMID: 27602406; 24488599; 36983702), including in unknown phase with a pathogenic variant (NM_003494.4: c.610C>T p.(Arg204Ter), 0.5 pts, PMID: 27602406; PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PMID: 36983702; PP4_Strong). Another nucleotide change affecting the same splice motif, NM_003494.4: c.1053+5G>A, has also been shown to result in skipping of exon 11 and is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. The filtering allele frequency of this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1111878 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/17/2025): PVS1_Strong_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting. Limb Girdle Muscular Dystrophy VCEP https://erepo.genome.network/evrepo/ui/classification/CA222120/MONDO:0015152/180 2025-04-17 2025-05-16 Autosomal recessive inheritance HP:0000007 Supports CHEBI:17347 biolink:causes UMLS:C0455880 infores:sider not_provided not_provided DRUGBANK:DB00624 UMLS:C0455880 infores:hetionet GO:0070062 biolink:causes GO:0099156 infores:ubergraph knowledge_assertion manual_agent GO:0070062 GO:0099156 CHEBI:6970 biolink:causes MONDO:0024278 infores:sider not_provided not_provided DRUGBANK:DB00764 UMLS:C0033247 infores:hetionet CHEBI:50173 biolink:causes HP:0002307 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0037036 infores:hetionet CAID:CA115846 biolink:causes MONDO:0100326 infores:clingen CAID:CA115846 MONDO:0100326 PMID: Pathogenic PP4_Strong, PP1, PM2_Supporting, PM3_Strong PP3 The NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr) missense variant has been reported in the homozygous state in at least 2 apparently unrelated individuals (PMID: 22513797, 20020534) and in the compound heterozygous state in 4 individuals (PMID: 9215749, 9734640, 34552732, 25373348). The second variants in these patients are c.3060+2T>C (classified Pathogenic by the PD-VCEP; without confirmation of trans phase), Glu355Lys (classified Pathogenic by the PD-VCEP; with confirmation of trans phase), c.2841+1G>T, and c.408G>C (latter two not considered here to avoid circularity) respectively (PM3_Strong). The proband from PMID: 22513797 meets criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3. It was found to co-segregate with disease in 1 additional family member (PP1). Ile596Thr is reported in gnomAD v4.0.0 at a frequency of 0.00008305 (98/1179968 alleles) in the non-Finnish European population, below the PM2_supporting threshold of <0.0001. In summary, this variant is classified Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific codes applied: PP4_Strong, PM2_Supporting, PM3_Strong, PP1. (PD-VCEP specifications version 2) Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA115846/MONDO:0100326/011 2023-11-17 2023-11-03 Autosomal recessive inheritance HP:0000007 Supports https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ CHEBI:6741 biolink:causes HP:0000016 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0080274 infores:hetionet CHEBI:5138 biolink:causes HP:0040186 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0423791 infores:hetionet CHEBI:41774 biolink:causes HP:0030166 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0028081 infores:hetionet CHEBI:30659 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00509 UMLS:C0018801 infores:hetionet CHEBI:63619 biolink:causes NCIT:C27045 infores:sider not_provided not_provided DRUGBANK:DB01182 UMLS:C0003813 infores:hetionet CHEBI:6062 biolink:causes UMLS:C1306341 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C1306341 infores:hetionet CHEBI:64355 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB01263 UMLS:C0008370 infores:hetionet CHEBI:40279 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0014591 infores:hetionet CHEBI:9943 biolink:causes MONDO:0002203 infores:sider not_provided not_provided DRUGBANK:DB00285 UMLS:C0009806 infores:hetionet CHEBI:135342 biolink:causes HP:0012418 infores:sider not_provided not_provided DRUGBANK:DB00234 UMLS:C0242184 infores:hetionet CHEBI:50173 biolink:causes HP:0003010 infores:sider not_provided not_provided DRUGBANK:DB00459 UMLS:C0151529 infores:hetionet CHEBI:7915 biolink:causes HP:0100515 infores:sider not_provided not_provided DRUGBANK:DB00213 UMLS:C0042023 infores:hetionet CHEBI:8059 biolink:causes MONDO:0002317 infores:sider not_provided not_provided DRUGBANK:DB01579 UMLS:C0012833 infores:hetionet CHEBI:41879 biolink:causes MONDO:0006525 infores:sider not_provided not_provided DRUGBANK:DB01234 UMLS:C0162820 infores:hetionet CHEBI:51380 biolink:causes UMLS:C0948807 infores:sider not_provided not_provided DRUGBANK:DB00366 UMLS:C0948807 infores:hetionet PUBCHEM.COMPOUND:45357473 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00286 UMLS:C0030554 infores:hetionet CAID:CA10578390 biolink:causes MONDO:0021056 infores:clingen CAID:CA10578390 MONDO:0021056 PMID: Likely Pathogenic PVS1, PM2_Supporting PS4 The NM_000038.6(APC):c.5038C>T (p.Gln1680Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in 1 proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PS4 not met; Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP https://erepo.genome.network/evrepo/ui/classification/CA10578390/MONDO:0021056/089 2025-05-19 2025-05-19 Autosomal dominant inheritance HP:0000006 Supports CHEBI:4975 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00927 UMLS:C0035410 infores:hetionet CAID:CA121700 biolink:causes MONDO:0010726 infores:clingen CAID:CA121700 MONDO:0010726 PMID: Pathogenic PS3_Supporting, PVS1, PS2_Very Strong, PS4, PM2_Supporting The p.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Arg294* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with Rett syndrome (PMID: 15737703, 11960578, 19722030, 21982064, RettBASE) (PS4). A transcription assay performed in Xenopus oocytes has shown that this variant impacts protein function (PMID 11058114) (PS3_supporting). The p.Arg294* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg294* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting). Rett and Angelman-like Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA121700/MONDO:0010726/016 2021-03-26 2021-05-17 X-linked inheritance HP:0001417 Supports https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf CHEBI:17076 biolink:causes MONDO:0015691 infores:sider not_provided not_provided DRUGBANK:DB01082 UMLS:C0014457 infores:hetionet CHEBI:3638 biolink:causes MONDO:0001824 infores:sider not_provided not_provided DRUGBANK:DB00608 UMLS:C0152025 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005264 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0007787 infores:hetionet CHEBI:5120 biolink:causes MONDO:0100459 infores:sider not_provided not_provided DRUGBANK:DB01185 UMLS:C0004509 infores:hetionet CHEBI:7465 biolink:causes HP:0001289 infores:sider not_provided not_provided DRUGBANK:DB00704 UMLS:C0009676 infores:hetionet CHEBI:6909 biolink:causes UMLS:C0231303 infores:sider not_provided not_provided DRUGBANK:DB00916 UMLS:C0231303 infores:hetionet UNII:F64QU97QCR biolink:causes HP:0025143 infores:sider not_provided not_provided DRUGBANK:DB01219 UMLS:C0085593 infores:hetionet CHEBI:52717 biolink:causes MONDO:0019269 infores:sider not_provided not_provided DRUGBANK:DB00188 UMLS:C0020757 infores:hetionet CHEBI:35854 biolink:causes NCIT:C78249 infores:sider not_provided not_provided DRUGBANK:DB00577 UMLS:C0151578 infores:hetionet CHEBI:3510 biolink:causes HP:0002249 infores:sider not_provided not_provided DRUGBANK:DB01415 UMLS:C0025222 infores:hetionet PUBCHEM.COMPOUND:5284632 biolink:causes HP:0033589 infores:sider not_provided not_provided DRUGBANK:DB00209 UMLS:C0016204 infores:hetionet CHEBI:5893 biolink:causes UMLS:C0403632 infores:sider not_provided not_provided DRUGBANK:DB00808 UMLS:C0403632 infores:hetionet CHEBI:64312 biolink:causes MONDO:0003799 infores:sider not_provided not_provided DRUGBANK:DB01043 UMLS:C0009763 infores:hetionet CHEBI:31643 biolink:causes HP:0000989 infores:sider not_provided not_provided DRUGBANK:DB00597 UMLS:C0033774 infores:hetionet CHEBI:2549 biolink:causes HP:0100518 infores:sider not_provided not_provided DRUGBANK:DB01001 UMLS:C0013428 infores:hetionet CHEBI:27779 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB00400 UMLS:C0011603 infores:hetionet CHEBI:15544 biolink:causes NCIT:C182234 infores:sider not_provided not_provided DRUGBANK:DB00770 UMLS:C0278134 infores:hetionet CHEBI:3387 biolink:causes UMLS:C0852733 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0852733 infores:hetionet CHEBI:7824 biolink:causes MONDO:0017384 infores:sider not_provided not_provided DRUGBANK:DB00776 UMLS:C0877055 infores:hetionet CHEBI:5050 biolink:causes MONDO:0005441 infores:sider not_provided not_provided DRUGBANK:DB00950 UMLS:C0029882 infores:hetionet CHEBI:18248 biolink:causes HP:0031964 infores:sider not_provided not_provided DRUGBANK:DB01592 UMLS:C0151905 infores:hetionet CHEBI:6775 biolink:causes HP:0100749 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0008031 infores:hetionet CHEBI:63617 biolink:causes MONDO:0021054 infores:sider not_provided not_provided DRUGBANK:DB01186 UMLS:C1704327 infores:hetionet CHEBI:36704 biolink:causes MONDO:0002102 infores:sider not_provided not_provided DRUGBANK:DB00724 UMLS:C0007971 infores:hetionet CHEBI:65349 biolink:causes HP:0003270 infores:sider not_provided not_provided DRUGBANK:DB08893 UMLS:C0000731 infores:hetionet CAID:CA220223 biolink:causes MONDO:0008723 infores:clingen CAID:CA220223 MONDO:0008723 PMID: Likely Pathogenic PM2_Supporting, PM4, PM3, PP4_Moderate, PS3_Supporting NM_000018.4(ACADVL):c.896_898del (p.Lys299del) variant in ACADVL is an in-frame deletion (removes amino acids Lys299) in exon 10/20 that is not predicted to impact splicing (SpliceAI: 0.02). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The c.896_898del variant is predicted to cause a change in the length of the protein (p.Lys299del) due to an in-frame deletion of an amino acid in a non-repeat region (PM4). This variant is reported in the literature in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency in compound heterozygous fashion, with at least one of whom exhibiting reduced VLCAD enzyme levels (< 20% WT control), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:10738914). This patient also carried a likely pathogenic variant c.753-2A>C in trans (PM3 score = 1.0, PM3, PMID:10738914). Well controlled functional studies by CHO cell transfection found that both the resultant mRNA and protein were significantly unstable, resulting in pronounced reduction in VLCAD activity (PS3_Supporting, PMID:8554073). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM4, PP4_Moderate, PM3, and PS3_Supporting (ACADVL VCEP specifications version 2; approved May 01, 2025). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA220223/MONDO:0008723/021 2025-09-09 2025-10-03 Autosomal recessive inheritance HP:0000007 Supports CHEBI:50131 biolink:causes NCIT:C87128 infores:sider not_provided not_provided DRUGBANK:DB01262 UMLS:C2129214 infores:hetionet CHEBI:6539 biolink:causes EFO:0020914 infores:sider not_provided not_provided DRUGBANK:DB00186 UMLS:C0233407 infores:hetionet CHEBI:63611 biolink:causes MONDO:0004609 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0019348 infores:hetionet CHEBI:9738 biolink:causes MONDO:0002052 infores:sider not_provided not_provided DRUGBANK:DB00726 UMLS:C0024205 infores:hetionet NCBIGene:2316 biolink:causes MONDO:0010704 infores:monarchinitiative not_provided not_provided HGNC:3754 MONDO:0010704 uuid:753c9fc8-3993-4f18-b68c-d7c2096dff67 biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:3219 biolink:causes UMLS:C0015256 infores:sider not_provided not_provided DRUGBANK:DB01156 UMLS:C0015256 infores:hetionet CAID:CA287437666 biolink:causes MONDO:0008723 infores:clingen CAID:CA287437666 MONDO:0008723 PMID: Uncertain Significance PM2_Supporting, PP3 The c.1013A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of asparagine by serine at amino acid 338 (p.Asn338Ser). To our knowledge, this variant has not been reported in the medical literature. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.917, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA287437666/MONDO:0008723/021 2024-08-27 2024-08-27 Autosomal recessive inheritance HP:0000007 Inconclusive true UNII:D27V6190PM biolink:causes UMLS:C0948294 infores:sider not_provided not_provided DRUGBANK:DB00768 UMLS:C0948294 infores:hetionet UMLS:C0065374 biolink:causes NCIT:C78302 infores:sider not_provided not_provided DRUGBANK:DB00722 UMLS:C0392171 infores:hetionet CHEBI:180905 biolink:causes HP:0000975 infores:sider not_provided not_provided DRUGBANK:DB00622 UMLS:C0700590 infores:hetionet CHEBI:3176 biolink:causes MONDO:0005385 infores:sider not_provided not_provided DRUGBANK:DB01194 UMLS:C0042373 infores:hetionet CAID:CA145601 biolink:causes MONDO:0008723 infores:clingen CAID:CA145601 MONDO:0008723 PMID: Benign BA1, BP4, BP7 The c.1038G>A variant in ACADVL is a synonymous variant which occurs in exon 10. The highest population minor allele frequency in gnomAD v2.1.1 is 0.08089 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from 2 in silico splicing predictors (SpliceAI, MutationTaster) support that this variant does not affect splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4, BP7 (VCEP specifications v2.0, approved on 09/16/2021). ACADVL VCEP https://erepo.genome.network/evrepo/ui/classification/CA145601/MONDO:0008723/021 2022-03-08 2022-03-08 Autosomal recessive inheritance HP:0000007 Contradicts true CHEBI:8107 biolink:causes MONDO:0002049 infores:sider not_provided not_provided DRUGBANK:DB00252 UMLS:C0040034 infores:hetionet CHEBI:6067 biolink:causes NCIT:C50771 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C2242996 infores:hetionet CAID:CA626684826 biolink:causes MONDO:0100326 infores:clingen CAID:CA626684826 MONDO:0100326 PMID: Uncertain Significance PM4, PM2_Supporting, PM3_Supporting PP4 The NM_000212.3(ITGB3):c.1658_1660del (p.Ser553del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid in a non-repeat region (PM4). The highest population minor allele frequency in gnomAD v2.1.1+ gnomAD v3.2.1 is 0.0000829 (4/48280 alleles) in the Latino/Admixed American population which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Patient 2, of PMID: 31029159, is reported to have a clinical diagnosis of GT and is homozygous for this variant (PM3_supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM4, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). Platelet Disorders VCEP https://erepo.genome.network/evrepo/ui/classification/CA626684826/MONDO:0100326/011 2023-04-06 2023-04-07 Autosomal recessive inheritance HP:0000007 Inconclusive https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/ true CHEBI:5118 biolink:causes HP:0000132 infores:sider not_provided not_provided DRUGBANK:DB00472 UMLS:C0025323 infores:hetionet CHEBI:6061 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00883 UMLS:C0016382 infores:hetionet CHEBI:30830 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB01440 UMLS:C0041657 infores:hetionet CHEBI:194135 biolink:causes UMLS:C0314719 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C0314719 infores:hetionet CAID:CA2573051297 biolink:causes MONDO:0015967 infores:clingen CAID:CA2573051297 MONDO:0015967 PMID: Pathogenic PM2_Supporting, PVS1, PP4 PS4 The c.549_552del variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 184 (p.(Gly184Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in a single individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative HNF4A testing) (PP4; internal lab contributors). In summary, c.549_552del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PM2_Supporting, PP4. Monogenic Diabetes VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051297/MONDO:0015967/017 2025-04-16 2025-04-16 Autosomal dominant inheritance HP:0000006 Supports CHEBI:31547 biolink:causes HP:0001699 infores:sider not_provided not_provided DRUGBANK:DB00700 UMLS:C0011071 infores:hetionet CHEBI:6129 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00465 UMLS:C0232462 infores:hetionet CHEBI:42820 biolink:causes MONDO:0003785 infores:sider not_provided not_provided DRUGBANK:DB00536 UMLS:C0023530 infores:hetionet CHEBI:63631 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB00273 UMLS:C0031350 infores:hetionet CHEBI:61033 biolink:causes MONDO:0005351 infores:sider not_provided not_provided DRUGBANK:DB00569 UMLS:C0003123 infores:hetionet CHEBI:6741 biolink:causes MONDO:0005068 infores:sider not_provided not_provided DRUGBANK:DB00814 UMLS:C0027051 infores:hetionet CHEBI:8502 biolink:causes HP:0002113 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0235896 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes UMLS:C0233494 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0233494 infores:hetionet CHEBI:63630 biolink:causes HP:0003201 infores:sider not_provided not_provided DRUGBANK:DB00323 UMLS:C0035410 infores:hetionet CHEBI:2567 biolink:causes MONDO:0003783 infores:sider not_provided not_provided DRUGBANK:DB00630 UMLS:C0024312 infores:hetionet CHEBI:45285 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00339 UMLS:C0015967 infores:hetionet CHEBI:68554 biolink:causes MONDO:0002258 infores:sider not_provided not_provided DRUGBANK:DB08826 UMLS:C0031350 infores:hetionet CHEBI:3213 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB00887 UMLS:C0018681 infores:hetionet CHEBI:8356 biolink:causes MONDO:0001162 infores:sider not_provided not_provided DRUGBANK:DB00413 UMLS:C0021122 infores:hetionet CHEBI:9123 biolink:causes MONDO:0002050 infores:sider not_provided not_provided DRUGBANK:DB01104 UMLS:C0011570 infores:hetionet CHEBI:68610 biolink:causes HP:0011123 infores:sider not_provided not_provided DRUGBANK:DB08882 UMLS:C0011603 infores:hetionet CHEBI:63115 biolink:causes MONDO:0005609 infores:sider not_provided not_provided DRUGBANK:DB08868 UMLS:C0019360 infores:hetionet CHEBI:94392 biolink:causes HP:0002315 infores:sider not_provided not_provided DRUGBANK:DB01218 UMLS:C0018681 infores:hetionet CHEBI:10023 biolink:causes MONDO:0005076 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0031099 infores:hetionet CHEBI:9907 biolink:causes HP:0012027 infores:sider not_provided not_provided DRUGBANK:DB01586 UMLS:C0023052 infores:hetionet NCBIGene:1906 biolink:causes MONDO:0014312 infores:monarchinitiative not_provided not_provided HGNC:3176 MONDO:0014312 uuid:3bc4aa9c-ef0d-4aad-9c32-a453fca31adc biolink:CausalGeneToDiseaseAssociationbiolink:EntityToDiseaseAssociationMixinbiolink:GeneToEntityAssociationMixinbiolink:GeneToDiseaseAssociationbiolink:GeneToDiseaseOrPhenotypicFeatureAssociationbiolink:EntityToPhenotypicFeatureAssociationMixinbiolink:Associationbiolink:Entitybiolink:FrequencyQuantifierbiolink:EntityToFeatureOrDiseaseQualifiersMixinbiolink:FrequencyQualifierMixinbiolink:RelationshipQuantifier omim_gene_to_disease_edges CHEBI:77260 biolink:causes MONDO:0003523 infores:sider not_provided not_provided DRUGBANK:DB00338 UMLS:C0017150 infores:hetionet CHEBI:49603 biolink:causes MONDO:0005244 infores:sider not_provided not_provided DRUGBANK:DB01259 UMLS:C0031117 infores:hetionet CHEBI:63624 biolink:causes UMLS:C0549475 infores:sider not_provided not_provided DRUGBANK:DB01265 UMLS:C0549475 infores:hetionet CHEBI:584020 biolink:causes HP:0001945 infores:sider not_provided not_provided DRUGBANK:DB00247 UMLS:C0015967 infores:hetionet CHEBI:4708 biolink:causes HP:0002013 infores:sider not_provided not_provided DRUGBANK:DB00590 UMLS:C0042963 infores:hetionet CHEBI:68606 biolink:causes MONDO:0005231 infores:sider not_provided not_provided DRUGBANK:DB08864 UMLS:C0019196 infores:hetionet CHEBI:6887 biolink:causes NCIT:C50805 infores:sider not_provided not_provided DRUGBANK:DB00422 UMLS:C0547030 infores:hetionet CHEBI:10023 biolink:causes MONDO:0001751 infores:sider not_provided not_provided DRUGBANK:DB00582 UMLS:C0008370 infores:hetionet CHEBI:92712 biolink:causes HP:0001254 infores:sider not_provided not_provided DRUGBANK:DB00424 UMLS:C0023380 infores:hetionet UNII:R43D2573WO biolink:causes NCIT:C118255 infores:sider not_provided not_provided DRUGBANK:DB00492 UMLS:C0220870 infores:hetionet CHEBI:9448 biolink:causes HP:0000224 infores:sider not_provided not_provided DRUGBANK:DB00857 UMLS:C0151934 infores:hetionet CHEBI:28915 biolink:causes UMLS:C0162287 infores:sider not_provided not_provided DRUGBANK:DB00828 UMLS:C0162287 infores:hetionet CHEBI:5138 biolink:causes HP:0001681 infores:sider not_provided not_provided DRUGBANK:DB00176 UMLS:C0002962 infores:hetionet CAID:CA269524632 biolink:causes MONDO:0007947 infores:clingen CAID:CA269524632 MONDO:0007947 PMID: Likely Pathogenic PM2, PVS1 PP1, BA1, PS4, PM1, BS1 The NM_00138 c.6506G>T, is a nonsense variant in FBN1 expected to cause a premature stop codon and likely results in an absent or disrupted protein product (PVS1). This variant has been previously reported in one individual with incomplete Marfan syndrome (PMID 17657824). This variant has not been reported in ClinVar. This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PM2_supporting. FBN1 VCEP https://erepo.genome.network/evrepo/ui/classification/CA269524632/MONDO:0007947/022 2023-02-01 2023-02-01 Autosomal dominant inheritance HP:0000006 Supports https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/ CHEBI:4798 biolink:causes HP:0000725 infores:sider not_provided not_provided DRUGBANK:DB00494 UMLS:C0338614 infores:hetionet CHEBI:4027 biolink:causes UMLS:C0595877 infores:sider not_provided not_provided DRUGBANK:DB00531 UMLS:C0595877 infores:hetionet PUBCHEM.COMPOUND:122173801 biolink:causes HP:0033050 infores:sider not_provided not_provided DRUGBANK:DB00104 UMLS:C0242429 infores:hetionet CHEBI:6339 biolink:causes UMLS:C0241379 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0241379 infores:hetionet CHEBI:9654 biolink:causes HP:0000616 infores:sider not_provided not_provided DRUGBANK:DB00656 UMLS:C0026205 infores:hetionet CHEBI:47381 biolink:causes HP:0200042 infores:sider not_provided not_provided DRUGBANK:DB00586 UMLS:C0037299 infores:hetionet CHEBI:40279 biolink:causes MONDO:0100595 infores:sider not_provided not_provided DRUGBANK:DB00437 UMLS:C0016867 infores:hetionet CHEBI:46195 biolink:causes HP:0011499 infores:sider not_provided not_provided DRUGBANK:DB00316 UMLS:C0026961 infores:hetionet CHEBI:6339 biolink:causes HP:0030833 infores:sider not_provided not_provided DRUGBANK:DB01628 UMLS:C0007859 infores:hetionet CAID:CA414773311 biolink:causes MONDO:0044970 infores:clingen CAID:CA414773311 MONDO:0044970 PMID: Likely Pathogenic PP3, PM2_Supporting, PS4_Moderate, PM6_Supporting, PS3_Supporting The m.3688G>A (p.Ala128Thr) variant in MT-ND1 has been reported in at least six unrelated individuals with primary mitochondrial disease. These individuals had Leigh syndrome with onset ranging from infancy to childhood. Heteroplasmy ranged from 5% in blood to homoplasmic, but was generally > 80% (PS4_moderate; PMIDs: 18977334; 34025555; 34716721; 27111573; 27290639; 37038312; ISBN:9780128008775). This variant occurred de novo in one individual (absent in lymphocytes and fibroblasts from mother; PM6_supporting, PMID: 18977334). Cybrid studies showed a strong inverse correlation between heteroplasmy level and complex I activity (PS3_supporting, PMID: 18977334). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.885 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PS3_supporting, PM2_supporting, PP3. Mitochondrial Diseases VCEP https://erepo.genome.network/evrepo/ui/classification/CA414773311/MONDO:0044970/015 2023-12-21 2024-11-26 Mitochondrial inheritance HP:0001427 Supports https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria CHEBI:61390 biolink:causes HP:0000421 infores:sider not_provided not_provided DRUGBANK:DB08916 UMLS:C0014591 infores:hetionet CHEBI:6775 biolink:causes UMLS:C0027769 infores:sider not_provided not_provided DRUGBANK:DB00244 UMLS:C0027769 infores:hetionet CHEBI:45979 biolink:causes HP:0001262 infores:sider not_provided not_provided DRUGBANK:DB00730 UMLS:C2830004 infores:hetionet CHEBI:3696 biolink:causes HP:0002607 infores:sider not_provided not_provided DRUGBANK:DB00369 UMLS:C0015732 infores:hetionet CHEBI:3403 biolink:causes HP:0007185 infores:sider not_provided not_provided DRUGBANK:DB00429 UMLS:C0041657 infores:hetionet CHEBI:2663 biolink:causes UMLS:C0542184 infores:sider not_provided not_provided DRUGBANK:DB01118 UMLS:C0542184 infores:hetionet CHEBI:100241 biolink:causes HP:0030953 infores:sider not_provided not_provided DRUGBANK:DB00537 UMLS:C1761613 infores:hetionet CHEBI:9168 biolink:causes HP:0004324 infores:sider not_provided not_provided DRUGBANK:DB00877 UMLS:C0043094 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0042401 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0042401 infores:hetionet CHEBI:3215 biolink:causes MONDO:0002610 infores:sider not_provided not_provided DRUGBANK:DB00297 UMLS:C0034150 infores:hetionet CHEBI:7577 biolink:causes MONDO:0000945 infores:sider not_provided not_provided DRUGBANK:DB00401 UMLS:C0042485 infores:hetionet CHEBI:10650 biolink:causes HP:0001662 infores:sider not_provided not_provided DRUGBANK:DB00669 UMLS:C0428977 infores:hetionet CHEBI:8665 biolink:causes HP:0003394 infores:sider not_provided not_provided DRUGBANK:DB00545 UMLS:C0026821 infores:hetionet CHEBI:3387 biolink:causes MONDO:0019790 infores:sider not_provided not_provided DRUGBANK:DB00564 UMLS:C0027849 infores:hetionet CHEBI:72564 biolink:causes HP:0031956 infores:sider not_provided not_provided DRUGBANK:DB00853 UMLS:C0151904 infores:hetionet CAID:CA2061285 biolink:causes MONDO:0015924 infores:clingen CAID:CA2061285 MONDO:0015924 PMID: Uncertain Significance PM2, BP4, PM1 PP3, BS2, BA1, PS4, BS1 The BMPR2 c.1087C>G is a missense variant predicted to cause substitution of leucine to valine at amino acid position 363 ((p.(Leu363Val)). This variant is absent from gnomAD version2.1.1 controls and v3.1.2 (PM2_supporting met). The variant resides in the highly conserved protein kinase domain without functional evidence for a critical or non-critical role on protein function (PM1 met). The variant is predicted to have no effect on protein function with REVEL score of 0.24, which meets the threshold for BP4 (<0.25). There is another individual with the same variant in ClinVar but with insufficient evidence for a pulmonary arterial hypertension diagnosis. In summary, the variant meets the criteria to be classified as a variant of unknown significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1, BP4 (VCEP specification version 1.1, 1/18/2024). Pulmonary Hypertension VCEP https://erepo.genome.network/evrepo/ui/classification/CA2061285/MONDO:0015924/125 2024-04-30 2024-04-30 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:6067 biolink:causes MONDO:0001170 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0018991 infores:hetionet CHEBI:3568 biolink:causes UMLS:C0236023 infores:sider not_provided not_provided DRUGBANK:DB00185 UMLS:C0236023 infores:hetionet CHEBI:83527 biolink:causes MONDO:0005084 infores:sider not_provided not_provided DRUGBANK:DB06700 UMLS:C0004936 infores:hetionet CHEBI:6067 biolink:causes HP:0004396 infores:sider not_provided not_provided DRUGBANK:DB00982 UMLS:C0232462 infores:hetionet CHEBI:18358 biolink:causes UMLS:C0175167 infores:sider not_provided not_provided DRUGBANK:DB00553 UMLS:C0175167 infores:hetionet CHEBI:45863 biolink:causes MONDO:0002041 infores:sider not_provided not_provided DRUGBANK:DB01229 UMLS:C0026946 infores:hetionet CHEBI:8597 biolink:causes HP:0025406 infores:sider not_provided not_provided DRUGBANK:DB00344 UMLS:C0004093 infores:hetionet CHEBI:8502 biolink:causes HP:0003401 infores:sider not_provided not_provided DRUGBANK:DB00550 UMLS:C0030554 infores:hetionet CHEBI:41774 biolink:causes MONDO:0002715 infores:sider not_provided not_provided DRUGBANK:DB00675 UMLS:C0153567 infores:hetionet CHEBI:63611 biolink:causes HP:0011896 infores:sider not_provided not_provided DRUGBANK:DB00218 UMLS:C0038534 infores:hetionet CHEBI:6715 biolink:causes MONDO:0003019 infores:sider not_provided not_provided DRUGBANK:DB00603 UMLS:C0020621 infores:hetionet CHEBI:6073 biolink:causes MONDO:0005252 infores:sider not_provided not_provided DRUGBANK:DB00270 UMLS:C0018801 infores:hetionet UMLS:C0145867 biolink:causes MONDO:0001673 infores:sider not_provided not_provided DRUGBANK:DB01583 UMLS:C0011991 infores:hetionet CHEBI:6062 biolink:causes MONDO:0008171 infores:sider not_provided not_provided DRUGBANK:DB01020 UMLS:C0392525 infores:hetionet CHEBI:31536 biolink:causes MONDO:0024288 infores:sider not_provided not_provided DRUGBANK:DB00879 UMLS:C0020433 infores:hetionet CAID:CA137966 biolink:causes MONDO:0021060 infores:clingen CAID:CA137966 MONDO:0021060 PMID: Uncertain Significance BP4 PP3, BA1, PS4, BS1, PM2 The c.784G>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 262 (p.Val262Ile). The filtering allele frequency in gnomAD v4.1.0 is 0.01543% (201/1178752 alleles) in the European (non-Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.219, which predicts no impact on protein function (BP4). This variant has been identified in 4 independent occurrences in patients with disparate phenotypes of RASopathy (PS4 not met; GeneDx, LMM internal data; GTR ID's 26957, 21766; SCV000207950.9, SCV000063182.5). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 9/17/2024) RASopathy VCEP https://erepo.genome.network/evrepo/ui/classification/CA137966/MONDO:0021060/048 2024-09-17 2024-10-02 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:194135 biolink:causes HP:0011999 infores:sider not_provided not_provided DRUGBANK:DB01165 UMLS:C1456784 infores:hetionet CHEBI:47780 biolink:causes MONDO:0011438 infores:sider not_provided not_provided DRUGBANK:DB01242 UMLS:C0702166 infores:hetionet CHEBI:119486 biolink:causes HP:0002094 infores:sider not_provided not_provided DRUGBANK:DB00625 UMLS:C0013404 infores:hetionet CHEBI:404903 biolink:causes HP:0010783 infores:sider not_provided not_provided DRUGBANK:DB00303 UMLS:C0016382 infores:hetionet CHEBI:3242 biolink:causes UMLS:C0392702 infores:sider not_provided not_provided DRUGBANK:DB00611 UMLS:C0392702 infores:hetionet CAID:CA2573051124 biolink:causes MONDO:0013144 infores:clingen CAID:CA2573051124 MONDO:0013144 PMID: Uncertain Significance PM2_Supporting PS4 The NM_000488.4(SERPINC1):c.265_266delinsGC variant predicts a missense variant at position 89 from Arginine to Alanine. No patients with AT deficiency and the Arg89Ala variant have been described in the literature, to the best of our knowledge. This variant is completely absent from gnomAD v2.1.1 and v3.1.2. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PM2_Supporting. Thrombosis VCEP https://erepo.genome.network/evrepo/ui/classification/CA2573051124/MONDO:0013144/084 2024-01-25 2024-01-25 Autosomal dominant inheritance HP:0000006 Inconclusive true CHEBI:75998 biolink:causes UMLS:C0948594 infores:sider not_provided not_provided DRUGBANK:DB08911 UMLS:C0948594 infores:hetionet CHEBI:87715 biolink:causes HP:0002170 infores:sider not_provided not_provided DRUGBANK:DB06209 UMLS:C0151699 infores:hetionet